PMID- 27483086 TI - The Use of CAD/CAM Technology for Fabricating Cast Gold Survey Crowns under Existing Partial Removable Dental Prosthesis. A Clinical Report. AB - The fabrication of a survey crown under an existing partial removable dental prosthesis (PRDP) has always been a challenge to many dental practitioners. This clinical report presents a technique for fabricating accurate cast gold survey crowns to fit existing PRDPs using CAD/CAM technology. The report describes a technique that would digitally scan the coronal anatomy of a cast gold survey crown and an abutment tooth under existing PRDPs planned for restoration, prior to any preparation. The information is stored in the digital software where all the coronal anatomical details are preserved without any modifications. The scanned designs are then applied to the scanned teeth preparations, sent to the milling machine and milled into full-contour clear acrylic resin burn-out patterns. The acrylic resin patterns are tried in the patient's mouth the same day to verify the full seating of the PRDP components. The patterns are then invested and cast into gold crowns and cemented in the conventional manner. PMID- 27483087 TI - Reply. PMID- 27483088 TI - Impact of Rheumatoid Arthritis on the Mortality of Elderly Patients Who Develop Cancer: A Population-Based Study. AB - OBJECTIVE: Comorbidity among cancer patients poses additional risks for mortality. The possible impact of rheumatoid arthritis (RA) on cancer patient survival is unclear. Our objective was to examine survival among elderly patients with RA who develop cancer. METHODS: Patients diagnosed with breast, prostate, colorectal, or lung cancer between 2001 and 2010 were identified from the Texas Cancer Registry and Medicare-linked databases. The cohort was categorized into 3 groups according to the number of claims patients had with a diagnosis of RA in the year prior to the cancer diagnosis: 2-RA (patients with >=2 claims), 1-RA (1 claim), and no claims. Overall survival was estimated for these groups and for each cancer, using Cox proportional hazards models adjusting for covariates. RESULTS: The cohort included 139,097 patients with cancer (35,026 breast, 43,181 prostate, 31,103 colorectal, and 29,787 lung); 1.7% had 1 RA claim, and 1.1% had 2 or more. Adjusted hazard ratios for patients in the 2-RA group were 1.41 (95% confidence interval [95% CI] 1.21-1.65) for breast and 1.53 (95% CI 1.26-1.85) for prostate. No significant differences were observed for those with colorectal or lung cancer. CONCLUSION: Mortality was increased by 40% and 50%, respectively, in elderly patients with RA who developed breast or prostate cancer, after controlling for other comorbidities. This association was not seen in cancers with shorter survival time (colorectal or lung). Research is needed to determine whether the increased risk is related to comorbid burden or to differential utilization of cancer or rheumatoid therapies in patients with both diseases. PMID- 27483089 TI - First-Trimester Diagnosis of Congenital Diaphragmatic Hernia. PMID- 27483090 TI - Synthesis of Spherical Carbon Nitride-Based Polymer Composites by Continuous Aerosol-Photopolymerization with Efficient Light Harvesting. AB - Here we report a novel, facile, and sustainable approach for the preparation of spherical submicrometer carbon nitride-based polymer composites by a continuous aerosol-photopolymerization process. In this regard, spherical mesoporous carbon nitride (SMCN) nanoparticles were initially prepared via a nanocasting approach using spray-drying synthesized spherical mesoporous silica (SMS) nanoparticles as hard templates. In addition to experimental characterization, the effect of porosity on the light absorption enhancement and consequently the generation rate of electron-hole pairs inside the SMCN was simulated using a three-dimensional finite difference time-domain (FDTD) method. To produce the carbon nitride-based polymer composite, SMCN nanoparticles exhibit excellent performance in photopolymerization of butyl acrylate (PBuA) monomer in the presence of n methyldiethanolamine (MDEA) as a co-initiator in a continuous aerosol-based process. In this one-pot synthesis, SMCN nanoparticles act not only as photoinitiators but at the same time as fillers and templates. The average aerosol residence time in the photoreactor is about 90 s. The presented aerosol photopolymerization process avoids the need for solvent and surfactant, operates at room temperature, and, more importantly, is suitable to produce the spherical composite with hydrophobic polymers. Furthermore, we simulated the condition of SMCN nanoparticles during illumination in the gas phase process, which can freely rotate. The results demonstrated that the hole (h(+)) density is almost equally distributed in the whole part of the SMCN nanoparticles due to their rotation, leading to efficient light harvesting and more homogeneous photoreaction. The combination of the outstanding features of environmentally friendly SMCN, photopolymerization, and aerosol processing might open new avenues, especially in green chemistry, to produce novel polymer composites with multifunctional properties. PMID- 27483091 TI - Halo-Type Distraction Device Used to Treat a Severe Midface Depression Fracture. AB - The deep layers of the nasoethmoid region comprise a thin-walled lacrimal bone, a paper-thin ethmoid plate, and ethmoidal cells, forming an extremely fragile and easily crushed structure. In a nasoethmoid complex fracture where the support structure itself is destroyed, epithesis and immobilization are difficult and can lead to residual saddle nose deformities. Therefore, bone grafts are often necessary at a later date. Recently, the authors occasionally see reports of nasoethmoid complex fractures that are treated with Halo distraction devices. Advantages of this device are that it applies constant traction to maintain the shape of the structures until the ruptured nasoethmoid bone and mucosa are repaired, thus minimizing relapse. There is no need for rigid fixation with a plate, no limitations on how much distraction is possible, and no major skin incisions are required for the approach. The authors treated a 30-year-old man who suffered a severe and widespread depressed facial deformation due to a nasoethmoid fracture that included a midface comminuted fracture using a Halo type distraction device. A gentle traction was maintained on the nasoethmoid bone and part of the maxilla pulling it forward, and resulted in an extremely good outcome both esthetically and functionally. This method is believed to be extremely useful and effective, requiring only minimally invasive surgery for comminuted midface fractures involving a nasoethmoid fracture with a depressed frontal process of the maxilla. Below, the authors provide a detailed description of their experience with this device. PMID- 27483092 TI - Penetrating Neck Injury Remnant Mimicking Chronic Cutaneous Neck Fistula. PMID- 27483093 TI - Assessment of Smell Function in Syndromic Craniosynostosis Patients. AB - Craniosynostosis is defined as premature fusion of the cranial suture lines and is part of a syndrome in 15% to 40% of the patients. There is limited literature available regarding these children's ability to smell. Most of them will undergo numerous surgical procedures, some of which may alter their sense of smell, potentially leading to significant social as well as safety implications. Ethical approval was obtained for this pilot study. Children with syndromic craniosynostosis were recruited and underwent anterior rhinoscopy, prior to performing a smell test utilizing the Sensonic pediatric Smell wheel. The results were compared to an age-matched control group. Eight children with syndromic craniosynostosis participated in the study. Of a possible total score of 11, their mean average score was 6.6 and the median was 6. In comparison, the mean average score for the control group was 7.5 and the median was 7. Although the study group was small, this pilot study demonstrates that children with syndromic craniosynostosis have a similar ability to identify smells to an age-matched cohort. Further research can now be undertaken to see whether or not midface advancement procedures affect these children's sense of smell. PMID- 27483094 TI - Symptomatic Giant Lipoma Under the Latissimus Muscle. AB - Lipoma is a common benign tumor derived from stroma that can arise in any location where fat is normally present. Giant lipoma is defined as a lesion that is >10 cm in length and weighs >1000 g. Axillary region might have been exposed to microtraumas with each movement of upper extremity, leading to the development of giant lipoma. In this report, a 56-year-old man visited us because of a soft tissue mass on the left axilla that had been noticed 5 years before. We removed the tumor from the patient under general anesthesia. A lipoma measuring 21 cm * 12 cm in size was removed, and the weight of the mass was 455 g. The case of our patient is very interesting because there have been few reported patients with a diagnosis of a giant lipoma in a sublatissimusdorsi muscle. PMID- 27483095 TI - Overcorrection of a Medial Orbital Wall Fracture Using the Endonasal Approach. AB - Although the endonasal approach is frequently used, and the inadvertent displacement of a bone fragment into the orbital cavity is possible, no reports have yet described the overcorrection of medial orbital wall fractures using the endonasal approach. The authors report 2 patients of the overcorrection of a medial orbital wall fracture using an endonasal approach.In the first patient, a 26-year-old Chinese-Korean woman experienced a fracture of the right medial orbital wall without entrapment of the medial rectus muscle. Eleven days after the trauma, endonasal reduction was performed. Postoperative computed tomography revealed overcorrection of the medial orbital wall and lateral displacement of the medial rectus muscle. On postoperative day 19, exophthalmos of the operated side was still observed (o.d. 20 mm/o.s. 17 mm). In the second patient, a 25-year old Korean man experienced a fracture of the left medial orbital wall without entrapment of the medial rectus muscle. Postoperative computed tomography showed overcorrection of the medial orbital wall and a laterally displaced medial rectus muscle. On postoperative day 4, exophthalmos of the operated side was observed (o.d. 23 mm/o.s. 26 mm).For fractures of the medial wall, surgery should be performed according to the recommended indications. When the endonasal approach is used to treat medial orbital wall fractures, great care is required in reducing the herniated orbital tissue and inserting the sheet to avoid overcorrection. PMID- 27483096 TI - Orbital Rehabilitation Implant-Retained: An Alternative to Adhesives Cutaneous Hypersensitivity. PMID- 27483097 TI - Muscle Tension Line Groups Reconstruction in Bilateral Cleft Lip Repair. AB - BACKGROUND: Bilateral cleft lip is considered to be the most difficult cleft lip to repair. More and more surgeries are concerned about the reconstruction of orbicularis muscle and the pursuit of philtrum shaping in bilateral cleft lip repair, but most have little success. Years of study on the orbicularis muscle of children with cleft lip resulted in authors' creation of muscle tension line groups theory. Through implementation of this theory, the authors have achieved favorable results in microform cleft lip repair. The authors also applied this concept to bilateral cleft lip repair. METHODS: Between January 2010 and December 2014, 31 children with bilateral cleft lip received operations in authors' department, and underwent muscle tension line group reconstruction in accordance with the theory of muscle tension line groups. Two third-party doctors judged postoperative results using a 3-point visual analogue scale. RESULTS: Twenty-two of the 31 children completed a follow-up 6 months to 1 year after surgery. Most postoperative and follow-up results were satisfactory. CONCLUSION: Fully reconstructed muscle tension line groups can not only assist with close fractures, but, for example, also help adduct the nasal alar, and elevate the nasal floor. Furthermore, the surgery can be used to reconstruct the 3 dimensional structure of the philtrum. Ultimately, surgical application of the muscle tension line groups theory proved its feasibility and potential for further development. PMID- 27483098 TI - Caudal Septal Stabilization Suturing Technique to Treat Crooked Noses. AB - AIM: To rotate the nasal axis and septum to the midline using an L-strut graft and a novel caudal septal stabilization suturing technique to treat crooked noses. PATIENTS AND METHODS: Thirty-six patients were included in the study. First, an L-strut graft was prepared by excising the deviated cartilage site in all patients. Second, multiple stabilization suturing, which we describe as a caudal septal stabilization suturing technique with a "fishing net"-like appearance, was applied between the anterior nasal spine and caudal septum in all patients. This new surgical technique, used to rotate the caudal septum, was applied to 22 I-type and 14 C-type crooked noses. Correction rates for the crooked noses were compared between the 2 inclination types with angular estimations. RESULTS: Deviation angles were measured using the AutoCAD 2012 software package and frontal (anterior) views, with the Frankfurt horizontal line parallel to the ground. Nasal axis angles showing angle improvement graded 4 categories as excellent, good, acceptable, and unsuccessful for evaluations at 6 months after surgery in the study. The success rate in the C-type nasal inclination was 86.7% (+/-21.9) and 88% (+/-16.7) in the I-type. The overall success rate of L-strut grafting and caudal septal stabilization suturing in crooked nose surgeries was 87.5% (+/-18.6). "Unsuccessful" results were not reported in any of the patients. CONCLUSIONS: L-strut grafting and caudal septal stabilization suturing techniques are efficacious in crooked noses according to objective measurement analysis results. However, a longer follow-up duration in a larger patient population is needed. PMID- 27483099 TI - Traumatic Fracture of the Premaxilla in the Bilateral Cleft Patient. AB - Traumatic fracture of the premaxilla is a rare event, and there is minimal data regarding the presentation, management, and outcome of these patients. This article reports 2 patients with bilateral cleft lip and palate who each presented with traumatic fracture and displacement of the premaxilla. To authors' knowledge, the occurrence and management of a traumatic fracture and displacement of the premaxilla in a patient with cleft lip and palate has not been reported. PMID- 27483100 TI - Descriptive Analysis of Sphenovomerine Suture and Its Importance in Neurosurgery. AB - PURPOSE: Articulation of rostrum of sphenoid bone with alae of vomer forms a schindylesis type of joint. The circumference of this joint, called sphenovomerine suture (SVS), is very important in establishing a reliable surgical field in the endoscopic transsphenoidal pituitary surgery. Because of its vital role in endoscopic transsphenoidal pituitary surgery, this radio anatomical study was designed to establish the morphological properties of SVS. METHODS: In this study, the authors examined SVS in 235 patients (121 females and 114 males) on the computed tomography images of the paranasal sinus and made 4 measurements to describe SVS. RESULTS: The mean distance between superior margin of the upper labial philtrum and top of SVS was 6.66 +/- 0.43 cm for females and 7.44 +/- 0.54 cm for males. The distance between the top of SVS and dorsum sellae was 3.08 +/- 0.33 cm for females and 3.19 +/- 0.32 cm for males, the alae of vomer angle in the upper surface was 74.22 +/- 20.06 degrees for females and 74.23 +/- 19.68 degrees for males. The distance between the most lateral points of 2 alae of vomer was 0.99 +/- 0.17 and 1.01 +/- 0.19 cm for females and males, respectively. CONCLUSIONS: For an easy and successful operation, removal of the SVS is very important as it will provide a better view of the sellar base and make the management of the surgical instruments easier in the wider safe surgical field thus created. PMID- 27483101 TI - Sunken Eye Induced by Superior Orbital Wall Defect After Craniofacial Surgery. AB - Enophthalmos after a ventriculo-peritoneal (V-P) shunt placement is very rare. Previous defects of the orbital wall with intracranial hypotension can cause enophthalmos after V-P shunting. The authors present 2 patients of enophthalmos with orbital wall defects resulting from anterior clinoidectomy that was performed during previous aneurysmal surgery. Both patients received a V-P shunt for hydrocephalus after subarachnoid hemorrhage. Although the hydrocephalus was improved by V-P shunts in both patients, sunken eyes were observed. The patients received reconstructive surgery of the superior orbital wall using titanium mesh and recovered after surgery without any neurological deficits. Here, the authors present 2 patients of enophthalmos with orbital wall defects treated by orbital wall reconstruction. PMID- 27483102 TI - A Rare Case of Unilateral Isolated Naso-Ocular Cleft Treated by a Rotation Advancement Technique. AB - The isolated naso-ocular cleft is rare. In this article, the authors report an extremely rare case of unilateral isolated naso-ocular cleft. And a new rotation advancement technique was used in repair. Result was satisfied, especially the esthetical scar location. But if an upper lid flap was performed simultaneously, the result should be better. PMID- 27483103 TI - Lobular Capillary Hemangioma Originating From the Posterior Portion of the Inferior Turbinate. PMID- 27483104 TI - The Surgical Strategy for the Intraorbital Foreign Bodies. AB - PURPOSE: Four patients with intraorbital foreign bodies admitting to our clinic between 2001 and 2011 are presented. Their clinical and radiologic findings and surgical strategies are discussed. OBJECTIVE: The success of surgery for the intraorbital foreign bodies largely depends on the determination of the exact localization of them. Radiologic examination should follow clinical diagnosis. Computed tomographic views are especially required to demonstrate the foreign body. MATERIALS AND METHODS: Four patients with different etiologies of trauma are presented. Each had computed tomography views for foreign body localization. All but 1 had surgery for removal of the object under general anesthesia. RESULTS: No complications were observed postoperatively. Only 1 patient is followed up without an operation due to the risk of damaging delicate structures that the foreign body is close to. He has no loss of function. CONCLUSION: Early removal of foreign bodies in orbital region is usually preferred due to the risk of neurologic damage and other complications. Surgical removal is quite challenging for foreign bodies like wood. Magnets can be used for metallic bodies. PMID- 27483105 TI - Nasal Tip Schwannoma Coexisting With Vestibular Schwannoma. AB - Although a schwannoma can originate from any central or peripheral nerves, schwannomas originating from the nasal tip are extremely rare and only 4 cases have been reported so far in English literature. These 4 cases appeared solely without any other accompanying schwannomas. However, the authors recently treated a patient with a nasal tip schwannoma coexisting with vestibular schwannoma. The nasal tip schwannoma was successfully removed without cosmetic deformity by using an open rhinoplasty approach. PMID- 27483106 TI - Orbital Fat Prolapse Into the Nasal Cavity in Orbital Blowout Fracture. AB - In this study, the authors describe the first report of 2 patients of fat prolapse into the nasal cavity by orbital blowout fracture. The patients were a 58-year-old male and an 86-year-old female. The patients could not attain binocular single vision in any eye position because of severe impairment of the extraocular muscle motility. Computed tomographic images of both patients revealed orbital blowout fractures with orbital fat prolapse into the nasal cavity. The fractures were reduced under transconjunctival/transcaruncular and endonasal endoscopic approaches. Six months postoperatively, the patients attained a binocular single vision field, including in the primary eye position. PMID- 27483107 TI - Oral Lesions in Pycnodysostosis Syndrome: Eleven Years of Follow-Up. AB - Pycnodysostosis is a rare genetic disease that is characterized by osteosclerosis, short stature, and bone fragility. There are not cases of gnathic bones lesions reported on the international literature. This study aims to describe a clinical case of a 10-year-old girl with pycnodysostosis syndrome and an uncommon association with 4 distinct lesions (dentigerous cyst, central giant cell lesions, and 2 fibro-osseous lesions). PMID- 27483108 TI - Dumbbell-Shaped Epidural Cavernous Hemangioma in the Thoracic Spine Mimicking Schwannoma. AB - Dumbbell-shaped epidural cavernous hemangiomas (CHs) are extremely rare, and they are easily misdiagnosed as spinal schwannomas. Herein, the authors report 1 rare case of dumbbell-shaped epidural CH in the thoracic spine. To the best of our knowledge, only a few cases of dumbbell-shaped epidural CHs in thoracic spine have been reported. Furthermore, the clinical characteristics and treatments for spinal epidural CHs were investigated and reviewed. PMID- 27483109 TI - Membrane Compartmentalization Reducing the Mobility of Lipids and Proteins within a Model Plasma Membrane. AB - The cytoskeleton underlying cell membranes may influence the dynamic organization of proteins and lipids within the bilayer by immobilizing certain transmembrane (TM) proteins and forming corrals within the membrane. Here, we present coarse grained resolution simulations of a biologically realistic membrane model of asymmetrically organized lipids and TM proteins. We determine the effects of a model of cytoskeletal immobilization of selected membrane proteins using long time scale coarse-grained molecular dynamics simulations. By introducing compartments with varying degrees of restraints within the membrane models, we are able to reveal how compartmentalization caused by cytoskeletal immobilization leads to reduced and anomalous diffusional mobility of both proteins and lipids. This in turn results in a reduced rate of protein dimerization within the membrane and of hopping of membrane proteins between compartments. These simulations provide a molecular realization of hierarchical models often invoked to explain single-molecule imaging studies of membrane proteins. PMID- 27483110 TI - The effects of different types of ankle-foot orthoses on postural responses in individuals with walking impairments. AB - The aim of this study was to examine the immediate and long-term effects of different ankle-foot orthosis (AFO) types on postural responses in patients with various pathological conditions who, because of their walking disorders, wore an AFO. A total of 37 patients with different pathological conditions who visited the outpatient clinic for orthotics because of walking problems, already used or were referred for an AFO and had no other impairments that may influence balance were included in the study. The participants were divided into four groups according to the type of AFO that they wore. The postural responses were assessed with and without AFO using two force-plates following perturbations in different directions at the level of the pelvis. The centre of pressure was examined in the sagittal and frontal plane and compared with the normative data from healthy individuals. The results showed an improvement in postural responses to the lateral and backward perturbation directions when wearing the AFO, particularly responses in the anterior-posterior direction. The best results were achieved with the custom-made posterior leaf spring AFO for correction of equinovarus deformity. The time of wearing the AFO had an impact on postural responses in perturbation directions where the patients could not rely only on AFO. The custom made AFO improved overall postural responses, especially dynamic stability, in lateral directions, whereas all stiff AFOs contributed towards an improvement in responses to all perturbations to the affected side. Results showed that long term use of an AFO can be important for the overall improvement of postural responses. PMID- 27483111 TI - Adolf Meyer: His Achievements and Legacy. AB - This lecture, given to celebrate the centennial of the founding of the Henry Phipps Psychiatric Service at Johns Hopkins, addresses the career and contributions to psychiatry and neurology of Adolf Meyer, the first Phipps Professor. It reviews his achievements historically describing the bleak clinical situation of psychiatry when he began as a neuropathologist at Kankakee Hospital in Illinois in 1892, what he did to address them, the sources of help he found and exploited from leading figures in the emerging Progressive Era (1890-1917) in American life, and how he confronted and overcame resistances to his empirical, psychobiological conceptions of mental illness as he advanced. His legacy is reflected in the signal contributions of four leaders of American psychiatry (Drs. Leo Kanner, Alexander Leighton, Jerome Frank, and Paul Lemkau) who had been his residents and in those aspects of contemporary teaching and research at Hopkins that reflect his thought. PMID- 27483112 TI - Profiles of Depression Help Seeking Among Black Americans: A Latent Class Approach. AB - Although Black Americans have lower prevalence of depression compared to non Hispanic Whites (10% vs. 17%), they are nearly twice as likely to have worse outcomes. One contributor to poor depression outcomes involves the ways in which Black Americans seek help for depression. However, little is known about depression help-seeking behavior, and the use of multiple sources of help, among Black Americans. This study used latent class analysis to identify unique constellations of depression help seeking, from multiple sources, among African American and Black Caribbeans. Results indicated four profiles of depression help seeking including Informal/Primary Care Utilizers (41.4%), Formal Mental Health Utilizers (40.6%), All Support Utilizers (9.8%), and Mixed Source Utilizers (8.2%). The constellation of each profile and demographic differences in class assignment are discussed. Results have implications for tailored depression interventions for Black Americans including community-based psychoeducation and cultural competence training for mental health providers. PMID- 27483113 TI - Psychiatric Disorders and Predictors Hereof Among Refugee Children in Early Adulthood: A Register-Based Cohort Study. AB - Studies show a high level of mental health problems among refugee children and adults. This study aimed to examine psychiatric disorders among refugee children in early adulthood. A total of 15,264 young adult refugees, who obtained residence permission January 1, 1993 to December 31, 2010, were matched 1:6 on age and sex with 99,313 Danish-born children. Rate ratios (RR) of having a first time in- or outpatient hospital diagnosis with an affective (F30-39), psychotic (F29-30), neurotic (F40-48), or any psychiatric disorder (F00-99) according to ICD-10 were computed. Refugees had higher RRs of psychotic (RR: 1.81, 95%CI: 1.41 2.32) and nervous (RR: 1.28, 95% CI: 1.14-1.43) disorders compared with Danish born children. The RRs of having an affective disorder among refugees was 0.74 (95% CI: 0.60-0.90) compared with Danish-born children. Sex, geographical origin, migrant status, household income, age at residence permission, and accompanied/unaccompanied arrival predicted psychiatric contacts among refugees. A focus on both prevention and treatment in vulnerable groups is needed. PMID- 27483114 TI - Sensory Gating Deficits in First-Episode Psychosis: Evidence From Neurophysiology, Psychophysiology, and Neuropsychology. AB - Sensory gating deficits are commonly found in patients with schizophrenia. However, there is still scarce research on this issue. Thirty-eight patients with first-episode psychosis (FEP) were compared to thirty-eight controls. A condition test paradigm of event-related potentials (ERP), prepulse inhibition (PPI), and some specific tasks of the MATRICS Consensus Cognitive Battery (MCCB) were used (i.e., TMT, BACS-SC, and Fluency for processing speed and CPT-IP for attention and vigilance). The ERP components measured were P50, N1, and P2. The PPI intervals examined were 30, 60, and 120 msec. Regarding the MCCB, processing speed and attention/vigilance cognitive domains were selected. FEP patients showed significant deficits in N1 and P2 components, at 30 and 60 PPI levels and in all the MCCB subtests selected. We obtained significant relationships in N1 with PPI-60, and with one MCCB subtest for processing speed. In addition, this same subtest showed significant association with P2. Therefore, sensory gating functioning is widely impaired since the very early stages of schizophrenia. PMID- 27483115 TI - Electrical conductivity of oxidized-graphenic nanoplatelets obtained from bamboo: effect of the oxygen content. AB - The large-scale production of graphene and reduced-graphene oxide (rGO) requires low-cost and eco-friendly synthesis methods. We employed a new, simple, cost effective pyrolytic method to synthetize oxidized-graphenic nanoplatelets (OGNP) using bamboo pyroligneous acid (BPA) as a source. Thorough analyses via high resolution transmission electron microscopy and electron energy-loss spectroscopy provides a complete structural and chemical description at the local scale of these samples. In particular, we found that at the highest carbonization temperature the OGNP-BPA are mainly in a sp(2) bonding configuration (sp(2) fraction of 87%). To determine the electrical properties of single nanoplatelets, these were contacted by Pt nanowires deposited through focused-ion-beam-induced deposition techniques. Increased conductivity by two orders of magnitude is observed as oxygen content decreases from 17% to 5%, reaching a value of 2.3 * 10(3) S m(-1) at the lowest oxygen content. Temperature-dependent conductivity reveals a semiconductor transport behavior, described by the Mott three dimensional variable range hopping mechanism. From the localization length, we estimate a band-gap value of 0.22(2) eV for an oxygen content of 5%. This investigation demonstrates the great potential of the OGNP-BPA for technological applications, given that their structural and electrical behavior is similar to the highly reduced rGO sheets obtained by more sophisticated conventional synthesis methods. PMID- 27483116 TI - [Not Available]. PMID- 27483117 TI - [Not Available]. PMID- 27483118 TI - [Not Available]. PMID- 27483119 TI - [Not Available]. PMID- 27483120 TI - [Not Available]. PMID- 27483121 TI - Mixotrophy in the Marine Plankton. AB - Mixotrophs are important components of the bacterioplankton, phytoplankton, microzooplankton, and (sometimes) zooplankton in coastal and oceanic waters. Bacterivory among the phytoplankton may be important for alleviating inorganic nutrient stress and may increase primary production in oligotrophic waters. Mixotrophic phytoflagellates and dinoflagellates are often dominant components of the plankton during seasonal stratification. Many of the microzooplankton grazers, including ciliates and Rhizaria, are mixotrophic owing to their retention of functional algal organelles or maintenance of algal endosymbionts. Phototrophy among the microzooplankton may increase gross growth efficiency and carbon transfer through the microzooplankton to higher trophic levels. Characteristic assemblages of mixotrophs are associated with warm, temperate, and cold seas and with stratification, fronts, and upwelling zones. Modeling has indicated that mixotrophy has a profound impact on marine planktonic ecosystems and may enhance primary production, biomass transfer to higher trophic levels, and the functioning of the biological carbon pump. PMID- 27483122 TI - N-(2-hydroxyphenyl)-2-propylpentanamide, a valproic acid aryl derivative designed in silico with improved anti-proliferative activity in HeLa, rhabdomyosarcoma and breast cancer cells. AB - Epigenetic alterations are associated with cancer and their targeting is a promising approach for treatment of this disease. Among current epigenetic drugs, histone deacetylase (HDAC) inhibitors induce changes in gene expression that can lead to cell death in tumors. Valproic acid (VPA) is a HDAC inhibitor that has antitumor activity at mM range. However, it is known that VPA is a hepatotoxic drug. Therefore, the aim of this study was to design a set of VPA derivatives adding the arylamine core of the suberoylanilide hydroxamic acid (SAHA) with different substituents at its carboxyl group. These derivatives were submitted to docking simulations to select the most promising compound. The compound 2 (N-(2 hydroxyphenyl)-2-propylpentanamide) was the best candidate to be synthesized and evaluated in vitro as an anti-cancer agent against HeLa, rhabdomyosarcoma and breast cancer cell lines. Compound 2 showed a better IC50 (MUM range) than VPA (mM range) on these cancer cells. And also, 2 was particularly effective on triple negative breast cancer cells. In conclusion, 2 is an example of drugs designed in silico that show biological properties against human cancer difficult to treat as triple negative breast cancer. PMID- 27483123 TI - Network-level Mechanisms of Ketamine Anesthesia. PMID- 27483124 TI - Success of Intubation Rescue Techniques after Failed Direct Laryngoscopy in Adults: A Retrospective Comparative Analysis from the Multicenter Perioperative Outcomes Group. AB - BACKGROUND: Multiple attempts at tracheal intubation are associated with mortality, and successful rescue requires a structured plan. However, there remains a paucity of data to guide the choice of intubation rescue technique after failed initial direct laryngoscopy. The authors studied a large perioperative database to determine success rates for commonly used intubation rescue techniques. METHODS: Using a retrospective, observational, comparative design, the authors analyzed records from seven academic centers within the Multicenter Perioperative Outcomes Group between 2004 and 2013. The primary outcome was the comparative success rate for five commonly used techniques to achieve successful tracheal intubation after failed direct laryngoscopy: (1) video laryngoscopy, (2) flexible fiberoptic intubation, (3) supraglottic airway as part of an exchange technique, (4) optical stylet, and (5) lighted stylet. RESULTS: A total of 346,861 cases were identified that involved attempted tracheal intubation. A total of 1,009 anesthesia providers managed 1,427 cases of failed direct laryngoscopy followed by subsequent intubation attempts (n = 1,619) that employed one of the five studied intubation rescue techniques. The use of video laryngoscopy resulted in a significantly higher success rate (92%; 95% CI, 90 to 93) than other techniques: supraglottic airway conduit (78%; 95% CI, 68 to 86), flexible bronchoscopic intubation (78%; 95% CI, 71 to 83), lighted stylet (77%; 95% CI, 69 to 83), and optical stylet (67%; 95% CI, 35 to 88). Providers most frequently choose video laryngoscopy (predominantly GlideScope [Verathon, USA]) to rescue failed direct laryngoscopy (1,122/1,619; 69%), and its use has increased during the study period. CONCLUSIONS: Video laryngoscopy is associated with a high rescue intubation success rate and is more commonly used than other rescue techniques. PMID- 27483125 TI - Avoiding Repeated Attempts at Tracheal Intubation: Can Videolaryngoscopes Be the Answer? PMID- 27483126 TI - Contribution of the Suppressor of Variegation 3-9 Homolog 1 in Dorsal Root Ganglia and Spinal Cord Dorsal Horn to Nerve Injury-induced Nociceptive Hypersensitivity. AB - BACKGROUND: Peripheral nerve injury-induced gene alterations in the dorsal root ganglion (DRG) and spinal cord likely participate in neuropathic pain genesis. Histone methylation gates gene expression. Whether the suppressor of variegation 3-9 homolog 1 (SUV39H1), a histone methyltransferase, contributes to nerve injury induced nociceptive hypersensitivity is unknown. METHODS: Quantitative real-time reverse transcription polymerase chain reaction analysis, Western blot analysis, or immunohistochemistry were carried out to examine the expression of SUV39H1 mRNA and protein in rat DRG and dorsal horn and its colocalization with DRG MU opioid receptor (MOR). The effects of a SUV39H1 inhibitor (chaetocin) or SUV39H1 siRNA on fifth lumbar spinal nerve ligation (SNL)-induced DRG MOR down-regulation and nociceptive hypersensitivity were examined. RESULTS: SUV39H1 was detected in neuronal nuclei of the DRG and dorsal horn. It was distributed predominantly in small DRG neurons, in which it coexpressed with MOR. The level of SUV39H1 protein in both injured DRG and ipsilateral fifth lumbar dorsal horn was time dependently increased after SNL. SNL also produced an increase in the amount of SUV39H1 mRNA in the injured DRG (n = 6/time point). Intrathecal chaetocin or SUV39H1 siRNA as well as DRG or intraspinal microinjection of SUV39H1 siRNA impaired SNL-induced allodynia and hyperalgesia (n = 5/group/treatment). DRG microinjection of SUV39H1 siRNA also restored SNL-induced DRG MOR down-regulation (n = 6/group). CONCLUSIONS: The findings of this study suggest that SUV39H1 contributes to nerve injury-induced allodynia and hyperalgesia through gating MOR expression in the injured DRG. SUV39H1 may be a potential target for the therapeutic treatment of nerve injury-induced nociceptive hypersensitivity. PMID- 27483127 TI - Sedation with Dexmedetomidine or Propofol Impairs Hypoxic Control of Breathing in Healthy Male Volunteers: A Nonblinded, Randomized Crossover Study. AB - BACKGROUND: In contrast to general anesthetics such as propofol, dexmedetomidine when used for sedation has been put forward as a drug with minimal effects on respiration. To obtain a more comprehensive understanding of the regulation of breathing during sedation with dexmedetomidine, the authors compared ventilatory responses to hypoxia and hypercapnia during sedation with dexmedetomidine and propofol. METHODS: Eleven healthy male volunteers entered this randomized crossover study. Sedation was administered as an intravenous bolus followed by an infusion and monitored by Observer's Assessment of Alertness/Sedation (OAA/S) scale, Richmond Agitation Sedation Scale, and Bispectral Index Score. Hypoxic and hypercapnic ventilatory responses were measured at rest, during sedation (OAA/S 2 to 4), and after recovery. Drug exposure was verified with concentration analysis in plasma. RESULTS: Ten subjects completed the study. The OAA/S at the sedation goal was 3 (3 to 4) (median [minimum to maximum]) for both drugs. Bispectral Index Score was 82 +/- 8 and 75 +/- 3, and the drug concentrations in plasma at the sedation target were 0.66 +/- 0.14 and 1.26 +/- 0.36 MUg/ml for dexmedetomidine and propofol, respectively. Compared with baseline, sedation reduced hypoxic ventilation to 59 and 53% and the hypercapnic ventilation to 82 and 86% for dexmedetomidine and propofol, respectively. In addition, some volunteers displayed upper airway obstruction and episodes of apnea during sedation. CONCLUSIONS: Dexmedetomidine-induced sedation reduces ventilatory responses to hypoxia and hypercapnia to a similar extent as sedation with propofol. This finding implies that sedation with dexmedetomidine interacts with both peripheral and central control of breathing. PMID- 27483128 TI - Anesthesiologists and Healthcare Redesign: Time to Team Up with Experts. PMID- 27483129 TI - Pharmacokinetic Studies of Sustained-Release Depot of Dexamethasone in Beagle Dogs. AB - PURPOSE: To examine the pharmacokinetic characteristics of sustained-release dexamethasone depots in two separate canine studies. METHODS: Dexamethasone depots loaded with a clinically representative (0.4 mg) dose (DEXTENZATM; Ocular Therapeutix) or an elevated (0.7 mg) dose were inserted into the canaliculi of beagle eyes (n = 37 and n = 34, respectively). Tear fluid was collected for pharmacokinetic analysis of dexamethasone in both studies at predetermined time points. Explanted 0.4 mg depots were collected weekly to measure remaining drug level. Clinical observations and ophthalmic examinations were performed in both studies at each visit. RESULTS: The 0.4 mg depots released a median 308 MUg by day 15 and tapered to complete drug release by day 28. Median dexamethasone tear fluid concentrations in the 0.4 mg study group decreased from 2,805 ng/mL at day 7 to 0 ng/mL on day 28. Median dexamethasone tear fluid concentrations in the 0.7 mg study group decreased from 4,370 ng/mL at 6 h post insertion to 830 ng/mL on day 35. Mean +/- standard deviation intraocular pressures in the 0.4 and 0.7 mg study groups were 20.7 +/- 2.8 and 19.0 +/- 4.1 mmHg at baseline, respectively, and demonstrated no meaningful change (20.5 +/- 3.0 and 20.6 +/- 2.9 mmHg, respectively) over the studies' durations. No ocular toxicities were attributed to the dexamethasone depot. CONCLUSION: Sustained-release dexamethasone produced no identifiable ocular toxicity in this animal model, and pharmacokinetics demonstrated a sustained and tapered drug release over 28 days at a 0.4 mg dose and exceeded 35 days at a 0.7 mg dose. PMID- 27483130 TI - Acute and Long-Term Cardiovascular Effects of Stimulant, Guanfacine, and Combination Therapy for Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVES: This study examines cardiovascular (CV) effects of guanfacine immediate-release (GUAN-IR), dexmethylphenidate extended-release (DMPH), and their combination (COMB) during acute and long-term treatment of youth with attention-deficit/hyperactivity disorder. METHODS: Two hundred seven participants aged 7-14 years enrolled in an 8-week double-blind randomized trial of GUAN-IR (1 3 milligrams (mg)/day), DMPH (5-20 mg/day), or COMB with fixed-flexible dosing and titrated to optimal behavioral response. Heart rate, systolic blood pressure (BP), diastolic BP, and electrocardiograms were assessed at baseline, end of blinded optimization, and over a 1-year open-label maintenance phase. RESULTS: During acute titration, GUAN-IR decreased heart rate, systolic BP, and diastolic BP; DMPH increased heart rate, systolic BP, diastolic BP, and corrected QT (QTc) interval; COMB increased diastolic BP, but had no effects on heart rate, systolic BP, or QTc. During maintenance, GUAN-IR-associated decreases in heart rate and DMPH-associated increases in systolic BP returned to baseline values. Other variables across the three groups remained unchanged from the end of blinded titration. There were no discontinuations due to CV adverse events. CONCLUSION: GUAN-IR, DMPH, and COMB were well tolerated and safe. Expected changes in CV parameters during acute titration were seen in GUAN-IR and DMPH groups, with COMB values falling intermediately between the two other treatment groups. No serious CV events occurred in any participant. GUAN-IR- and DMPH-associated CV changes generally returned to baseline with sustained therapy. These data suggest that COMB treatment might attenuate long-term CV effects of GUAN-IR and stimulant monotherapy, possibly reducing risk of the small but statistically significant changes associated with either single treatment. Clinicaltrials.gov Identifier: NCT00429273. PMID- 27483131 TI - Multiple metrics quantify and differentiate responses of vegetation to composition B. AB - Quantifying vegetation response to explosive compounds has focused predominantly on morphological impacts and uptake efficiency. A more comprehensive understanding of the total impacts of explosives on vegetation can be gained using a multivariate approach. We hypothesized that multiple variables representing morphological and physiological responses will more clearly differentiate species and treatments than any single variable. Individuals of three plant species were placed in soils contaminated with Composition B, which comprises 60% hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and 40% 2,4,6 trinitrotoluene (TNT), and grown for 2 months. Response metrics used included photosynthetic operation, water relations, growth characteristics, as well as nitrogen and carbon concentrations and isotopic compositions. Individual metrics showed high variability in response across the three species tested. Water relations and nitrogen isotopic composition exhibited the most consistent response across species. By comparing multiple variables simultaneously, better separation of both species and exposure was observed. The inclusion of novel metrics can reinforce previously established concepts and provide a new perspective. Additionally, the inclusion of various other metrics can greatly increase the ability to identify and differentiate particular groups. By using multivariate analyses and standard vegetation metrics, new aspects of the vegetation response to explosive compounds can be identified. PMID- 27483132 TI - Infectious Complications after Major Abdominal Cancer Surgery: In Search of Improvable Risk Factors. AB - BACKGROUND: Major resections for esophageal, gastric, hepatic, pancreatic, and colorectal cancer continue to be associated with a high peri-operative morbidity of up to 30%-40%. To a large extent, this morbidity is caused by infectious complications that add up to a considerable burden to patients and hospital costs. The objective of this large retrospective cross-sectional study was to determine independent patient and operation-related risk factors for infectious complications after major abdominal cancer operations to elucidate how infection rates can be reduced and improve health-care quality. PATIENTS AND METHODS: In 1,389 cancer patients who underwent a major resection procedure between 2009 and 2013, infectious complications and their independent determinants were analyzed by multivariable logistic regression (p < 0.05). RESULTS: Male gender was a risk factor for infections in general, whereas patients >=65 y (odds ratio [OR] 1.75; p = 0.008), urinary tract infection (OR 0.51; p = 0.004), American Society of Anesthesiologists score (OR 1.55; p = 0.004), overall (OR 1.70; p = 0.037), vascular (OR 1.59; p = 0.020), and neurologic comorbidity (OR 2.22; p = 0.001) were associated significantly with pneumonia. Intra-abdominal drainage (OR 1.41; p = 0.024) and a duration of surgery of >=180 min (OR 1.85; p = 0.001) were risk factors for surgical site infections. Total parenteral nutrition was significantly associated with intravascular catheter-induced infections (OR 18.09; p < 0.001) and sepsis (OR 6.69; p < 0.001). CONCLUSIONS: In this study, several independent risk factors for infectious complications in major abdominal cancer operations were identified, providing opportunities for further reducing peri-operative infections. General awareness and focus on preventing infectious complications may have a significant impact on health-care outcomes and costs. PMID- 27483133 TI - Investigation of Metabolism of Exogenous Glucose at the Early Stage and Onset of Diabetes Mellitus in Otsuka Long-Evans Tokushima Fatty Rats Using [1, 2, 3 13C]Glucose Breath Tests. AB - This study aimed to evaluate changes in glucose metabolism at the early stage and onset of diabetes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Specifically, after the oral administration of [1, 2, 3-13C]glucose, the levels of exhaled 13CO2, which most likely originated from pyruvate decarboxylation and tricarboxylic acid, were measured. Eight OLETF rats and eight control rats (Long Evans Tokushima Otsuka [LETO]) were administered 13C-glucose. Three types of 13C glucose breath tests were performed thrice in each period at 2-week intervals. [3 13C]glucose results in a 13C isotope at position 1 in the pyruvate molecule, which provides 13CO2. The 13C at carbons 1 and 2 of glucose is converted to 13C at carbons 2 and 1 of acetate, respectively, which produce 13CO2. Based on metabolic differences of the labeled sites, glucose metabolism was evaluated using the results of three breath tests. The increase in 13CO2 excretion in OLETF rats was delayed in all three breath tests compared to that in control rats, suggesting that OLETF rats had a lower glucose metabolism than control rats. In addition, overall glucose metabolism increased with age in both groups. The utilization of [2-13C]glucose was suppressed in OLETF rats at 6-12 weeks of age, but they showed higher [3-13C]glucose oxidation than control rats at 22-25 weeks of age. In the [1-13C]glucose breath test, no significant differences in the area under the curve until 180 minutes (AUC180) were observed between OLETF and LETO rats of any age. Glucose metabolism kinetics were different between the age groups and two groups of rats; however, these differences were not significant based on the overall AUC180 of [1-13C]glucose. We conclude that breath 13CO2 excretion is reduced in OLETF rats at the primary stage of prediabetes, indicating differences in glucose oxidation kinetics between OLETF and LETO rats. PMID- 27483134 TI - Graphene Jet Nanomotors in Remote Controllable Self-Propulsion Swimmers in Pure Water. AB - A remote controllable working graphite nanostructured swimmer based on a graphene jet nanomotor has been demonstrated for the first time. Graphite particles with pyramidal-like morphologies were fabricated by the creation of suitable defects in wide high-purity graphite flakes followed by a severe sonication. The particles were able to be self-exfoliated in water after Na intercalation between the graphene constituents. The self-exfoliation resulted in jet ejection of graphene flakes from the end of the swimmers (with speeds as high as ~7000 m/s), producing a driving force (at least ~0.7 L (pN) where L (MUm) is swimmer size) and consequently the motion of the swimmer (with average speed of ~17-40 MUm/s). The jet ejection of the graphene flakes was assigned to the explosion of H2 nanobubbles produced between the Na intercalated flakes. The direction of motion of the swimmers equipped with TiO2 nanoparticles (NPs) can be controlled by applying a magnetic field in the presence of UV irradiation (higher UV intensity, lower radius of rotation). In fact, the negative surface charge of the graphene flakes of the swimmers increased by UV irradiation due to transferring the photoexcited electrons of TiO2 NPs into the flakes. Because of higher production of H2 nanobubbles under UV irradiation, the speed of swimmers exposed to UV light significantly increased. In contrast, UV irradiation with various intensities could not affect total distance traversed by the self-exfoliated swimmers having the same initial sizes. These confirmed the mass ejection mechanism for motion of the swimmers. The self-exfoliation of swimmers (and so their motion) occurred only in water (and not, e.g., in organic solutions). Such swimmers promise the design of remote controllable nanovehicles with the capability of initiating and/or improving their operations in response to environmental changes in order to realize broad ranges of versatile and fantastic nanotechnology-based applications. PMID- 27483135 TI - Surface Molecules Released by Trypanosoma cruzi Metacyclic Forms Downregulate Host Cell Invasion. AB - BACKGROUND: The question whether metacylic trypomastigote (MT) forms of different T. cruzi strains differentially release surface molecules, and how they affect host cell invasion, remains to be fully clarified. We addressed that question using T. cruzi strains that differ widely in the ability to invade cells. METHODOLOGY/PRINCIPAL FINDINGS: Metacyclic forms were incubated at 37 degrees C for 1 h in complete D10 medium or in nutrient-deprived PBS containing Ca2+ and Mg2+ (PBS++). The conditioned medium (CM), collected after parasite centrifugation, was used for cell invasion assays and Western blot analysis, using monoclonal antibodies directed to gp82 and gp90, the MT surface molecules that promote and negatively regulate invasion, respectively. CM of poorly invasive G strain (G-CM) contained high amounts of gp90 and gp82, either in vesicles or as soluble molecules. CM of highly invasive CL strain (CL-CM) contained gp90 and gp82 at very low levels. HeLa cells were incubated for 1 h with CL strain MT in D10, in absence or in the presence of G-CM or CL-CM. Parasite invasion was significantly inhibited by G-CM, but not by CL-CM. As G strain MT invasion rate in D10 is very low, assays with this strain were performed in PBS++, which induces invasion-promoting lysosome-spreading. G-CM, but not CL-CM, significantly inhibited G strain internalization, effect that was counteracted by preincubating G-CM with an anti-gp90 monoclonal antibody or anti gp82 polyclonal antibody that do not recognize live MT. G strain CM generated in PBS++ contained much lower amounts of gp90 and gp82 as compared to CM produced in D10, and exhibited lower inhibitory effect on host cell invasion. CONCLUSION/SIGNIFICANCE: Our data suggest that the surface molecules spontaneously released by MT impair parasite-host cell interaction, gp82 presumably competing with the molecule expressed on MT surface for the host cell receptor, and gp90 further contributing to down modulate invasion. PMID- 27483136 TI - South Asia as a Reservoir for the Global Spread of Ciprofloxacin-Resistant Shigella sonnei: A Cross-Sectional Study. AB - BACKGROUND: Antimicrobial resistance is a major issue in the Shigellae, particularly as a specific multidrug-resistant (MDR) lineage of Shigella sonnei (lineage III) is becoming globally dominant. Ciprofloxacin is a recommended treatment for Shigella infections. However, ciprofloxacin-resistant S. sonnei are being increasingly isolated in Asia and sporadically reported on other continents. We hypothesized that Asia is a primary hub for the recent international spread of ciprofloxacin-resistant S. sonnei. METHODS AND FINDINGS: We performed whole-genome sequencing on a collection of 60 contemporaneous ciprofloxacin-resistant S. sonnei isolated in four countries within Asia (Vietnam, n = 11; Bhutan, n = 12; Thailand, n = 1; Cambodia, n = 1) and two outside of Asia (Australia, n = 19; Ireland, n = 16). We reconstructed the recent evolutionary history of these organisms and combined these data with their geographical location of isolation. Placing these sequences into a global phylogeny, we found that all ciprofloxacin-resistant S. sonnei formed a single clade within a Central Asian expansion of lineage III. Furthermore, our data show that resistance to ciprofloxacin within S. sonnei may be globally attributed to a single clonal emergence event, encompassing sequential gyrA-S83L, parC-S80I, and gyrA-D87G mutations. Geographical data predict that South Asia is the likely primary source of these organisms, which are being regularly exported across Asia and intercontinentally into Australia, the United States and Europe. Our analysis was limited by the number of S. sonnei sequences available from diverse geographical areas and time periods, and we cannot discount the potential existence of other unsampled reservoir populations of antimicrobial-resistant S. sonnei. CONCLUSIONS: This study suggests that a single clone, which is widespread in South Asia, is likely driving the current intercontinental surge of ciprofloxacin-resistant S. sonnei and is capable of establishing endemic transmission in new locations. Despite being limited in geographical scope, our work has major implications for understanding the international transfer of antimicrobial-resistant pathogens, with S. sonnei acting as a tractable model for studying how antimicrobial-resistant Gram-negative bacteria spread globally. PMID- 27483137 TI - Sustaining and Expanding Telehealth: A Survey of Business Models from Selected Prominent U.S. Telehealth Centers. AB - INTRODUCTION: Telehealth centers across the country, including our own center, are addressing sustainability and best practice business models. We undertook this survey to explore the business models being used at other established telehealth centers. In the literature on telehealth and sustainability, there is a paucity of comparative studies as to how successful telehealth centers function. METHODS: In this study, we compared the business models of 10 successful telehealth centers. We conducted the study by interviewing key individuals at the centers, either through teleconference or telephone. RESULTS: We found that there are five general approaches to sustaining a telehealth center: grants, telehealth network membership fees, income from providing clinical services, per encounter charges, and operating as a cost center. We also found that most centers use more than one approach. CONCLUSION: We concluded that, although the first four approaches can contribute to the success of a center, telehealth centers are and should remain cost centers for their respective institutions. PMID- 27483139 TI - Formation of Highly Thermostable Copper-Containing Energetic Coordination Polymers Based on Oxidized Triaminoguanidine. AB - A series of novel highly thermostable energetic coordination polymers (ECPs), with promising mechanical sensitivity properties, were prepared by an in situ oxidation-coordination reaction of triaminoguanidine hydrochloride with copper nitrate in aqueous solution. The molecular structures and properties of these ECPs could be tuned, by varying the ratios and concentrations of the starting materials. Our ECPs exhibit remarkable thermostability (>390 degrees C) and very low sensitivity to impact (Im > 98 J). The best-performing material (ECP-5) has a calculated detonation velocity of 8969 m.s(-1) and a decomposition peak temperature of 396.9 degrees C, demonstrating an outstanding balance between two inherently contradicting properties: high detonation performance and very low sensitivity. PMID- 27483138 TI - Shared Genetic Factors Involved in Celiac Disease, Type 2 Diabetes and Anorexia Nervosa Suggest Common Molecular Pathways for Chronic Diseases. AB - BACKGROUND AND OBJECTIVES: Genome-wide association studies (GWAS) have identified several genetic regions involved in immune-regulatory mechanisms to be associated with celiac disease. Previous GWAS also revealed an over-representation of genes involved in type 2 diabetes and anorexia nervosa associated with celiac disease, suggesting involvement of common metabolic pathways for development of these chronic diseases. The aim of this study was to extend these previous analyses to study the gene expression in the gut from children with active celiac disease. MATERIAL AND METHODS: Thirty six target genes involved in type 2 diabetes and four genes associated with anorexia nervosa were investigated for gene expression in small intestinal biopsies from 144 children with celiac disease at median (range) age of 7.4 years (1.6-17.8) and from 154 disease controls at a median (range) age 11.4.years (1.4-18.3). RESULTS: A total of eleven of genes were differently expressed in celiac patients compared with disease controls of which CD36, CD38, FOXP1, SELL, PPARA, PPARG, AGT previously associated with type 2 diabetes and AKAP6, NTNG1 with anorexia nervosa remained significant after correction for multiple testing. CONCLUSION: Shared genetic factors involved in celiac disease, type 2 diabetes and anorexia nervosa suggest common underlying molecular pathways for these diseases. PMID- 27483140 TI - Meniscus Shape and Wetting Competition of a Drop between a Cone and a Plane. AB - The formation of a liquid bridge between a cone and a plane is related to dip-pen nanolithography. The meniscus shape and rupture process of a liquid meniscus between a cone and a plane are investigated by Surface Evolver, many-body dissipative particle dynamics, and macroscopic experiments. Dependent on the cone geometry, cone-plane separation, and wetting properties of cone and plane, three types of menisci can be observed before rupture and two types of wetting competition outcomes are seen after breakup. It is interesting to find that after rupture, the bulk of the liquid bridge volume is not necessarily retained by the cone which is more wettable. In fact, a sharp hydrophilic cone often loses wetting competition to a hydrophobic plane. To explain our findings, the "apparent" contact angle of the cone is introduced and the behavior of drop-on cone/plane system is analogous to that of a liquid bridge between two parallel planes based on this concept. PMID- 27483141 TI - Systematic Proteomic Identification of the Heat Shock Proteins (Hsp) that Interact with Estrogen Receptor Alpha (ERalpha) and Biochemical Characterization of the ERalpha-Hsp70 Interaction. AB - Heat shock proteins (Hsps) are known to associate with estrogen receptors (ER) and regulate ER-mediated cell proliferation. Historically, the studies in this area have focused on Hsp90. However, some critical aspects of the Hsp-ERalpha interactions remain unclear. For example, we do not know which Hsps are the major or minor ERalpha interactants and whether or not different Hsp isoforms associate equally with ERalpha. In the present study, through a quantitative proteomic method we found that 21 Hsps and 3 Hsp cochaperones were associated with ERalpha in human 293T cells that were cultured in a medium containing necessary elements for cell proliferation. Four Hsp70s (Hsp70-1, Hsc70, Grp75, and Grp78) were the most abundant Hsps identified to associate with ERalpha, followed by two Hsp90s (Hsp90alpha and Hsp90beta) and three Hsp110s (Hsp105, HspA4, and HspA4L). Hsp90alpha was found to be 2-3 times more abundant than Hsp90beta in the ERalpha containing complexes. Among the reported Hsp cochaperones, we detected prostaglandin E synthase 3 (p23), peptidyl-prolyl cis-trans isomerase FKBP5 (FKBP51), and E3 ubiquitin-protein ligase CHIP (CHIP). Studies with the two most abundant ERalpha-associated Hsps, Hsp70-1 and Hsc70, using human breast cancer MCF7 cells demonstrate that the two Hsps interacted with ERalpha in both the cytoplasm and nucleus when the cells were cultured in a medium supplemented with fetal bovine serum and phenol red. Interestingly, the ERalpha-Hsp70-1/Hsc70 interactions were detected only in the cytoplasm but not in the nucleus under hormone starvation conditions, and stimulation of the starved cells with 17beta estradiol (E2) did not change this. In addition, E2-treatment weakened the ERalpha-Hsc70 interaction but had no effect on the ERalpha-Hsp70-1 interaction. Further studies showed that significant portions of Hsp70-1 and Hsc70 were associated with transcriptionally active chromatin and inactive chromatin, and the two Hsps interacted with ERalpha in both forms of the chromatins in MCF7 cells. PMID- 27483142 TI - Asymmetric Regulation of Peripheral Genes by Two Transcriptional Regulatory Networks. AB - Transcriptional regulatory network (TRN) reconstitution and deconstruction occur simultaneously during reprogramming; however, it remains unclear how the starting and targeting TRNs regulate the induction and suppression of peripheral genes. Here we analyzed the regulation using direct cell reprogramming from human dermal fibroblasts to monocytes as the platform. We simultaneously deconstructed fibroblastic TRN and reconstituted monocytic TRN; monocytic and fibroblastic gene expression were analyzed in comparison with that of fibroblastic TRN deconstruction only or monocytic TRN reconstitution only. Global gene expression analysis showed cross-regulation of TRNs. Detailed analysis revealed that knocking down fibroblastic TRN positively affected half of the upregulated monocytic genes, indicating that intrinsic fibroblastic TRN interfered with the expression of induced genes. In contrast, reconstitution of monocytic TRN showed neutral effects on the majority of fibroblastic gene downregulation. This study provides an explicit example that demonstrates how two networks together regulate gene expression during cell reprogramming processes and contributes to the elaborate exploration of TRNs. PMID- 27483156 TI - Art in the Digital Age AB - The genre of "computer art" began in the 1950s, when long exposure photography was used to capture images created by an oscilloscope manipulating electronic waves on a small fluorescent screen. Through the 1960s, most works of computer art were created using plotters and impact printers by the scientists and engineers who had access to emerging computing technology. By the 1970s, artists were learning to program, and some universities began to integrate computers into the fine arts curriculum. The widespread adoption of computers and the availability of off-the-shelf paint programs in the 1980s brought computer art to the masses. At the same time, computer graphics and special effects were beginning their takeover of the entertainment industry through Hollywood films, TV shows, and video games. By the 1990s, the term computer art was fading, and computers were becoming a mainstream part of arts and entertainment. PMID- 27483159 TI - The Application of Magnetic Bead Selection to Investigate Interactions between the Oral Microbiota and Salivary Immunoglobulins. AB - The effect of humoral immunity on the composition of the oral microbiota is less intensively investigated than hygiene and diet, in part due to a lack of simple and robust systems for investigating interactions between salivary immunoglobulins and oral bacteria. Here we report the application of an ex situ method to investigate the specificity of salivary immunoglobulins for salivary bacteria. Saliva collected from six volunteers was separated into immunoglobulin and microbial fractions, and the microbial fractions were then directly exposed to salivary immunoglobulins of "self" and "non-self" origin. Antibody-selected bacteria were separated from their congeners using a magnetic bead system, selective for IgA or IgG isotypes. The positively selected fractions were then characterized using gel-based eubacterial-specific DNA profiling. The eubacterial profiles of positively selected fractions diverged significantly from profiles of whole salivary consortia based on volunteer (P<= 0.001%) and immunoglobulin origin (P<= 0.001%), but not immunoglobulin isotype (P = 0.2). DNA profiles of separated microbial fractions were significantly (p<= 0.05) less diverse than whole salivary consortia and included oral and environmental bacteria. Consortia selected using self immunoglobulins were generally less diverse than those selected with immunoglobulins of non-self origin. Magnetic bead separation facilitated the testing of interactions between salivary antibodies and oral bacteria, showing that these interactions are specific and may reflect differences in recognition by self and non-self immunoglobulins. Further development of this system could improve understanding of the relationship between the oral microbiota and the host immune system and of mechanisms underlying the compositional stability of the oral microbiota. PMID- 27483161 TI - Cationic Ionic Liquids Organic Ligands Based Metal-Organic Frameworks for Fabrication of Core-Shell Microspheres for Hydrophilic Interaction Liquid Chromatography. AB - In this study, new metal-organic frameworks (MOFs) nanocrystals modified SiO2 core-shell microspheres were designed with cationic ionic liquids (ILs) 1,3-bis(4 carboxybutyl)imidazolium bromide (ILI) as organic ligands. By further adjustment the growth cycles, the new ILI-01@SiO2 core-shell stationary phase was facilely fabricated. The developed stationary phase was respectively characterized via element analysis, thermogravimetric analysis, scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectrometry. Because the introduction of cationic imidazolium-based ILs ILI for fabrication of the MOFs nanocrystals shell, the new stationary phase exhibits the retention mechanism of hydrophilic interaction liquid chromatography (HILIC). Many polar samples, such as amides, vitamins, nucleic acid bases, and nucleosides, were utilized to investigate the performance of the prepared ILI-01@SiO2 column. Compared to the conventional aminosilica column, the new ILI-01@SiO2 column displays high separation selectivity in a shorter separation time. Furthermore, the new ILI 01@SiO2 column was also used for detection of illegal melamine addition in the baby formula. All the above results demonstrate the new ILI-01@SiO2 core-shell stationary phase is of good potentials for high-selectivity separation the polar samples. PMID- 27483160 TI - The Yield of Community-Based "Retrospective" Tuberculosis Contact Investigation in a High Burden Setting in Ethiopia. AB - OBJECTIVE: To determine the yield and determinants of retrospective TB contact investigation in selected zones in Ethiopia. MATERIALS AND METHODS: This was a community-based cross-sectional study conducted during June-October 2014.Trained lay providers performed symptom screening for close contacts of index cases with all types of TB registered for anti-TB treatment within the last three years. We used logistic regression to determine factors associated with TB diagnosis among the contacts. RESULTS: Of 272,441 close contacts of 47, 021 index cases screened, 13,886 and 2, 091 had presumptive and active TB respectively. The yield of active TB was thus 768/100, 000, contributing 25.4% of the 7,954 TB cases reported from the study zones over the study period. The yield was highest among workplace contacts (12,650/100, 000). Active TB was twice more likely among contacts whose index cases had been registered for TB treatment within the last 12 months compared with those who had been registered 24 or more months earlier (adjusted odds ratio, AOR: 1.77 95% CI 1.42-2.21). Sex or clinical type of TB in index cases was not associated with the yield. Smear negative (SS-) index cases (AOR: 1.74 955 CI 1.13-2.68), having index cases who registered for treatment within <12 months (AOR: 2.41 95% CI 1.51-3.84) and being household contact (AOR: 0.072 95% CI 0.01-0.52) were associated with the occurrence of active TB in children. CONCLUSIONS: The yield of retrospective contact investigation was about six times the case notification in the study zones, contributing a fourth of all TB cases notified over the same period. The yield was highest among workplace contacts and in those with recent past history of contact. Retrospective contact screening can serve as additional strategy to identify high risk groups not addressed through currently recommended screening approaches. PMID- 27483162 TI - The PE_PGRS Proteins of Mycobacterium tuberculosis Are Ca(2+) Binding Mediators of Host-Pathogen Interaction. AB - The phenomenal success of Mycobacterium tuberculosis (M.tb) as a pathogen is primarily based on its ability to modulate host immune responses. The genome of M.tb encodes multiple immunomodulatory proteins, including several members of the multigenic PE_PPE family of which the PE_PGRS proteins are a subset. Curiously, 56 of the 61 PE_PGRS proteins contain multiple copies of the glycine-rich sequence motif GGXGXD/NXUX, a nonapeptide sequence predicted to bind Ca(2+), but the functional significance of these motifs remains a mystery. Here we provide evidence via isothermal titration calorimetry, (45)Ca blotting, fluorescence, and circular dichroism spectroscopy that Ca(2+) binds to the PE_PGRS proteins, PE_PGRS33 (Rv1818c) (10 motifs) and PE_PGRS61 (Rv3653) (one motif). Ca(2+) was observed not to bind to PE_PGRS8 (Rv0742), which lacks nonapeptide motifs. Using recombinant Mycobacterium smegmatis strains expressing Rv1818c and Rv3653 and the THP-1 macrophage model of infection, we show that the two proteins mediate Ca(2+) dependent upregulation of the anti-inflammatory cytokine IL-10, events critical to the pathogenesis of M.tb. Both Rv1818c and Rv3653 interact with TLR2 in a Ca(2+)-dependent manner, providing a novel mechanistic basis for their immunomodulatory effects. Mutations in the nonapeptide motif of Rv3653 led to compromised Ca(2+) binding, validating the functional criticality of this motif. This study demonstrates for the first time not only their Ca(2+) binding properties but also an essential role for Ca(2+) in the functioning of the M.tb PE_PGRS proteins, opening up the possibility of developing novel anti tuberculosis therapeutics that inhibit Ca(2+)-PE_PGRS binding. PMID- 27483164 TI - "The Golden Method": Electrochemical Synthesis Is an Efficient Route to Gold Complexes. AB - Gold compounds to be obtained by the direct electrochemical oxidation of a noble metal are reported. This achievement provides an alternative procedure to obtaining neutral gold compounds with potential medical or catalytic applications. PMID- 27483163 TI - Aminophylline Dosage In Asthma Exacerbations in Children: A Systematic Review. AB - BACKGROUND: Adequate asthma treatment of childhood exacerbations with IV aminophylline depends on appropriate dosage. Recommendations to aim for a target therapeutic range may be inappropriate as serum concentrations correlate poorly with clinical improvement. This review aims to evaluate the evidence for the optimum dosage strategy of intravenous aminophylline in children suffering an exacerbation of asthma. METHODS: A systematic review comparing dosage regimens of intravenous aminophylline in children suffering an exacerbation of asthma. Primary outcomes were time until resolution of symptoms, mortality and need for mechanical ventilation. Secondary outcomes were date until discharge criteria are met, actual discharge and adverse effects. DATA SOURCES: CENTRAL, CINAHL, MEDLINE and Web of Science. Search performed in March 2016. ELIGIBILITY CRITERIA: Studies using intravenous aminophylline in children with an acute exacerbation of asthma which reported the dosage and clinical outcomes. FINDINGS: 14 RCTs were included. There is a poor relationship between the dosage administered to children and symptom resolution, length of stay or need for mechanical ventilation. This study is limited due to its use of indirect evidence. CONCLUSION: The currently recommended dosage regimens may not represent the optimum safety and efficacy of intravenous aminophylline. There is a need to develop the evidence base correlating dosage with patient centered clinical outcomes, to improve prescribing practices. PMID- 27483165 TI - Facile Synthesis of Sub-20 nm Silver Nanowires through a Bromide-Mediated Polyol Method. AB - Essentially all of the Ag nanowires reported in the literature have sizes larger than 30 nm in diameter. In this article, we report a simple and robust approach to the synthesis of Ag nanowires with diameters below 20 nm and aspect ratios over 1000 using a one-pot polyol method. The Ag nanowires took a penta-twinned structure, and they could be obtained rapidly (<35 min) and in high morphology purity (>85% of the as-obtained solid product) under atmospheric pressure. The key to the success of this synthesis is to restrain the nanowires from lateral growth by employing both Br(-) ions and poly(vinylpyrrolidone) with a high molecular weight of 1 300 000 g/mol to cap the {100} side faces, together with the use of a syringe pump to slowly introduce AgNO3 into the reaction solution. By optimizing the ratios between the capping agents and AgNO3, we were able to slow down the reduction kinetics and effectively direct the Ag nanowires to grow along the longitudinal direction only. The nanowires showed great mechanical flexibility and could be bent with acute angles without breaking. Because of their small diameters, the transverse localized surface plasmon resonance peak of the Ag nanowires could be pushed down to the ultraviolet region, below 400 nm, making them ideal conductive elements for the fabrication of touch screens, solar cells, and smart windows. PMID- 27483166 TI - Total Focusing Method With Virtual Sources in the Presence of Unknown Geometry Interfaces. AB - Auto-focused virtual source imaging (AVSI) has been recently presented as an alternative method for synthetic aperture focusing through arbitrarily shaped interfaces with arrays. This paper extends the AVSI concept to the case of the total focusing method (TFM-AVSI) using several virtual receivers for each virtual source. This approach overcomes the known contrast limitation of AVSI, while preserving the advantage of performing synthetic focusing in the second medium only [no time-of-flight (TOF) calculations through the interface]. In contrast, equipment with more active channels must be used to digitalize the signals received by all the array elements after each focused emission. When compared with the conventional TFM, the proposed method reduces the processing complexity of the most time consuming task: TOF calculation in the presence of interfaces. This improvement could lead to more efficient real-time implementations of the TFM in non-destructive testing applications where water immersion or flexible wedges are used. In this paper, the mathematical formulation for the new method is given, accounting for the surface slope and the array angular sensitivity. Its performance is evaluated by numerical simulation, experimentally and compared with AVSI and the conventional TFM. It was found that the TFM-AVSI achieves the same resolution and contrast as that of the TFM, although it shows a wider blind zone below the interface due to focusing with normal incidence. PMID- 27483171 TI - Thermodynamic Hydricity of Transition Metal Hydrides. AB - Transition metal hydrides play a critical role in stoichiometric and catalytic transformations. Knowledge of free energies for cleaving metal hydride bonds enables the prediction of chemical reactivity, such as for the bond-forming and bond-breaking events that occur in a catalytic reaction. Thermodynamic hydricity is the free energy required to cleave an M-H bond to generate a hydride ion (H( )). Three primary methods have been developed for hydricity determination: the hydride transfer method establishes hydride transfer equilibrium with a hydride donor/acceptor pair of known hydricity, the H2 heterolysis method involves measuring the equilibrium of heterolytic cleavage of H2 in the presence of a base, and the potential-pKa method considers stepwise transfer of a proton and two electrons to give a net hydride transfer. Using these methods, over 100 thermodynamic hydricity values for transition metal hydrides have been determined in acetonitrile or water. In acetonitrile, the hydricity of metal hydrides spans a range of more than 50 kcal/mol. Methods for using hydricity values to predict chemical reactivity are also discussed, including organic transformations, the reduction of CO2, and the production and oxidation of hydrogen. PMID- 27483170 TI - De Novo Assembly and Comparative Transcriptome Analyses of Red and Green Morphs of Sweet Basil Grown in Full Sunlight. AB - Sweet basil (Ocimum basilicum), one of the most popular cultivated herbs worldwide, displays a number of varieties differing in several characteristics, such as the color of the leaves. The development of a reference transcriptome for sweet basil, and the analysis of differentially expressed genes in acyanic and cyanic cultivars exposed to natural sunlight irradiance, has interest from horticultural and biological point of views. There is still great uncertainty about the significance of anthocyanins in photoprotection, and how green and red morphs may perform when exposed to photo-inhibitory light, a condition plants face on daily and seasonal basis. We sequenced the leaf transcriptome of the green-leaved Tigullio (TIG) and the purple-leaved Red Rubin (RR) exposed to full sunlight over a four-week experimental period. We assembled and annotated 111,007 transcripts. A total of 5,468 and 5,969 potential SSRs were identified in TIG and RR, respectively, out of which 66 were polymorphic in silico. Comparative analysis of the two transcriptomes showed 2,372 differentially expressed genes (DEGs) clustered in 222 enriched Gene ontology terms. Green and red basil mostly differed for transcripts abundance of genes involved in secondary metabolism. While the biosynthesis of waxes was up-regulated in red basil, the biosynthesis of flavonols and carotenoids was up-regulated in green basil. Data from our study provides a comprehensive transcriptome survey, gene sequence resources and microsatellites that can be used for further investigations in sweet basil. The analysis of DEGs and their functional classification also offers new insights on the functional role of anthocyanins in photoprotection. PMID- 27483172 TI - Correction: Prooxidative Potential of Photo-Irradiated Aqueous Extracts of Grape Pomace, a Recyclable Resource from Winemaking Process. AB - [This corrects the article DOI: 10.1371/journal.pone.0158197.]. PMID- 27483175 TI - Atypical presentation of posterior reversible encephalopathy syndrome: Clinical and radiological characteristics in eclamptic patients. AB - Posterior reversible encephalopathy syndrome (PRES) is an obstetric emergency frequently occurring in a pregnant or puerperal woman, manifested with an acute headache, consciousness impairment, seizures, and visual deficits and is associated with white matter changes predominantly affecting the posterior parietal and occipital lobes of the brain. Apart from the above-described typical location of the changes, the most common atypical location involves the brain stem and basal ganglia. Since magnetic resonance imaging (MRI) is more sensitive and specific imaging technique compared to computerized tomography, establishing the diagnosis and follow-up in patients with PRES is based mainly on MRI findings. It is particularly important not to exclude PRES as a possible diagnosis when we have the appropriate clinical presentation accompanied by the atypical radiological findings, since this clinical-radiological syndrome can often be manifested with an atypical MRI image. PMID- 27483173 TI - MTHFR and ACE Polymorphisms Do Not Increase Susceptibility to Migraine Neither Alone Nor in Combination. AB - OBJECTIVE: The aim of this study was to confirm previous reports in order to substantiate the hypothesis that functional variants of two genes, namely methylenetetrahydrofolate reductase and angiotensin I converting enzyme, both involved in an important pathway of migraine, increase migraine susceptibility when present in combination. BACKGROUND: Migraine is a complex genetic disease. The migraine attack is thought to be the result of an interaction of neuronal and vascular events, possibly originating in the brainstem leading to activation of the pain processing trigeminovascular system. Functional variants in the methylenetetrahydrofolate gene and the angiotensin I converting enzyme have influence on vascular mechanism and have been investigated intensively in migraine. The published results were inconsistent; however, both polymorphisms in combination have been shown to increase migraine susceptibility. METHODS: In this genetic association study, the prevalence of the functionally relevant polymorphisms C677T in the MTHFR gene and I/D polymorphism in the ACE gene was compared in 420 patients with migraine vs 258 migraine-free controls using a chi square statistic and binary logistic regression. RESULTS: Susceptibility to any type of migraine (migraine with aura, migraine without aura, and both types combined) was neither increased by each polymorphism on its own, nor in combination (MTHFR: X(2) = 0.18 [P = .91]; ACE: X(2) = 1.62 [P = .45]; combined: OR = 1.02 [95% CI 0.98-1.05] P = .97). CONCLUSIONS: We could not replicate a previous study that showed significant increase in migraine susceptibility for two functional polymorphisms in genes affecting relevant pathways. PMID- 27483180 TI - Missense splice variant (g.20746A>G, p.Ile183Val) of interferon gamma receptor 1 (IFNGR1) coincidental with mycobacterial osteomyelitis - a screen of osteoarticular lesions. AB - Previously, dominant partial interferon-gamma receptor 1 (IFN-g-R1) susceptibility to environmental mycobacteria was found with IFNGR1 deletions or premature stop. Our aim was to search for IFNGR1 variants in patients with mycobacterial osteoarticular lesions. Biopsies from the patients were examined for acid-fast bacilli, inflammatory cell infiltration, and mycobacterial niacin. Mycobacterial rRNA was analyzed using a target-amplified rRNA probe test. Peripheral-blood-leukocyte genomic DNA was isolated from 19 patients using the QIAamp DNA Mini Kit, and all IFNGR1 exons were sequenced using an ABIPRISM 3130 device. After the discovery of an exon 5 variant, a Polish newborn population sample (n = 100) was assayed for the discovered variant. Splice sites and putative amino acid interactions were analyzed. All patients tested were positive for mycobacteria; one was heterozygous for the IFNGR1 exon 5 single-nucleotide missense substitution (g.20746A>G, p.Ile183Val). No other variant was found. The splice analysis indicated the creation of an exonic splicing silencer, and alternatively, molecular graphics indicated that the p.Ile183Val might alter beta strand packing (loss of van der Waals contacts; Val183/Pro205), possibly altering the IFN-g-R1/IFN-g-R2 interaction. The probability of non-deleterious variant was estimated as <10%. Heterozygous IFNGR1:p.Ile183Val (frequency 0.003%) was found to be coincidental with mycobacterial osteomyelitis. The small amount of variation detected in the patients with osteoarticular lesions indicates that screens should not yet be restricted: Intronic variants should be analyzed as well as the other genes affecting Type 1 T-helper-cell-mediated immunity. PMID- 27483185 TI - Can text messages increase safer sex behaviours in young people? Intervention development and pilot randomised controlled trial. AB - BACKGROUND: Younger people bear the heaviest burden of sexually transmitted infections (STIs). Partner notification, condom use and STI testing can reduce infection but many young people lack the knowledge, skills and confidence needed to carry out these behaviours. Text messages can provide effective behavioural support. The acceptability and feasibility of a randomised controlled trial of safer sex support delivered by text message are not known. OBJECTIVES: To assess the acceptability and feasibility of a randomised controlled trial of a safer sex intervention delivered by text message for young people aged 16-24 years. DESIGN: (1) Intervention development; (2) follow-up procedure development; (3) a pilot, parallel-arm randomised controlled trial with allocation via remote automated randomisation (ratio of 1 : 1) (participants were unmasked, whereas researchers analysing samples and data were masked); and (4) qualitative interviews. SETTING: Participants were recruited from sexual health services in the UK. PARTICIPANTS: Young people aged 16-24 years diagnosed with chlamydia or reporting unprotected sex with more than one partner in the last year. INTERVENTIONS: A theory- and evidence-based safer sex intervention designed, with young people's input, to reduce the incidence of STIs by increasing the correct treatment of STIs, partner notification, condom use and STI testing before unprotected sex with a new partner. The intervention was delivered via automated mobile phone messaging over 12 months. The comparator was a monthly text message checking contact details. MAIN OUTCOME MEASURES: (1) Development of the intervention based on theory, evidence and expert and user views; (2) follow-up procedures; (3) pilot trial primary outcomes: full recruitment within 3 months and follow-up rate for the proposed primary outcomes for the main trial; and (4) participants' views and experiences regarding the acceptability of the intervention. RESULTS: In total, 200 participants were randomised in the pilot trial, of whom 99 were allocated to the intervention and 101 were allocated to the control. We fully recruited early and achieved an 81% follow-up rate for our proposed primary outcome of the cumulative incidence of chlamydia at 12 months. There was no differential follow up between groups. In total, 97% of messages sent were successfully delivered to participants' mobile phones. Recipients reported that the tone, language, content and frequency of messages were appropriate. Messages reportedly increased knowledge of and confidence in how to use condoms and negotiate condom use and reduced stigma about STIs, enabling participants to tell a partner about a STI. CONCLUSIONS: Our research shows that the intervention is acceptable and feasible to deliver. Our pilot trial demonstrated that a main trial is feasible. It remains unclear which behaviour change techniques and elements of the intervention or follow-up procedures are associated with effectiveness. A further limitation is that in the trial one person entering data and the participants were unmasked. A randomised controlled trial to establish the effects of the intervention on STIs at 12 months is needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02304709. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 57. See the NIHR Journals Library website for further project information. PMID- 27483186 TI - Identification of Covalent Binding Sites Targeting Cysteines Based on Computational Approaches. AB - Covalent drugs have attracted increasing attention in recent years due to good inhibitory activity and selectivity. Targeting noncatalytic cysteines with irreversible inhibitors is a powerful approach for enhancing pharmacological potency and selectivity because cysteines can form covalent bonds with inhibitors through their nucleophilic thiol groups. However, most human kinases have multiple noncatalytic cysteines within the active site; to accurately predict which cysteine is most likely to form covalent bonds is of great importance but remains a challenge when designing irreversible inhibitors. In this work, FTMap was first applied to check its ability in predicting covalent binding site defined as the region where covalent bonds are formed between cysteines and irreversible inhibitors. Results show that it has excellent performance in detecting the hot spots within the binding pocket, and its hydrogen bond interaction frequency analysis could give us some interesting instructions for identification of covalent binding cysteines. Furthermore, we proposed a simple but useful covalent fragment probing approach and showed that it successfully predicted the covalent binding site of seven targets. By adopting a distance based method, we observed that the closer the nucleophiles of covalent warheads are to the thiol group of a cysteine, the higher the possibility that a cysteine is prone to form a covalent bond. We believe that the combination of FTMap and our distance-based covalent fragment probing method can become a useful tool in detecting the covalent binding site of these targets. PMID- 27483188 TI - Metabolomics to Detect Response of Lettuce (Lactuca sativa) to Cu(OH)2 Nanopesticides: Oxidative Stress Response and Detoxification Mechanisms. AB - There has been an increasing influx of nanopesticides into agriculture in recent years. Understanding the interaction between nanopesticides and edible plants is crucial in evaluating the potential impact of nanotechnology on the environment and agriculture. Here we exposed lettuce plants to Cu(OH)2 nanopesticides (1050 2100 mg/L) through foliar spray for one month. Inductively coupled plasma-mass spectrometry (ICP-MS) results indicate that 97-99% (1353-2501 mg/kg) of copper was sequestered in the leaves and only a small percentage (1-3%) (17.5-56.9 mg/kg) was translocated to root tissues through phloem loading. Gas chromatography-time-of-flight mass spectrometry (GC-TOF-MS) based metabolomics combined with partial least squares-discriminant analysis (PLS-DA) multivariate analysis revealed that Cu(OH)2 nanopesticides altered metabolite levels of lettuce leaves. Tricarboxylic (TCA) cycle and a number of amino acid-related biological pathways were disturbed. Some antioxidant levels (cis-caffeic acid, chlorogenic acid, 3,4-dihydroxycinnamic acid, dehydroascorbic acid) were significantly decreased compared to the control, indicating that oxidative stress and a defense response occurred. Nicotianamine, a copper chelator, increased by 12-27 fold compared to the control, which may represent a detoxification mechanism. The up-regulation of polyamines (spermidine and putrescine) and potassium may mitigate oxidative stress and enhance tolerance. The data presented here provide a molecular-scale perspective on the response of plants to copper nanopesticides. PMID- 27483187 TI - Increased activity in frontal motor cortex compensates impaired speech perception in older adults. AB - Understanding speech in noisy environments is challenging, especially for seniors. Although evidence suggests that older adults increasingly recruit prefrontal cortices to offset reduced periphery and central auditory processing, the brain mechanisms underlying such compensation remain elusive. Here we show that relative to young adults, older adults show higher activation of frontal speech motor areas as measured by functional MRI during a syllable identification task at varying signal-to-noise ratios. This increased activity correlates with improved speech discrimination performance in older adults. Multivoxel pattern classification reveals that despite an overall phoneme dedifferentiation, older adults show greater specificity of phoneme representations in frontal articulatory regions than auditory regions. Moreover, older adults with stronger frontal activity have higher phoneme specificity in frontal and auditory regions. Thus, preserved phoneme specificity and upregulation of activity in speech motor regions provide a means of compensation in older adults for decoding impoverished speech representations in adverse listening conditions. PMID- 27483189 TI - An aminopyrimidine-functionalized cage-based metal-organic framework exhibiting highly selective adsorption of C2H2 and CO2 over CH4. AB - There has been considerable interest in adsorptive separation of C2H2/CH4 and CO2/CH4 gas mixtures due to its industrial significance and scientific challenge. In this work, we have designed and synthesized a bent diisophthalate ligand functionalized with aminopyrimidine groups, and constructed via a solvothermal reaction, a porous copper-based framework. Single-crystal X-ray diffraction studies show that the framework is a three-dimensional network containing three different types of polyhedral nanocages, which are stacked together to form two distinct types of one-dimensional channels along the crystallographic c axis. The compound after activation shows exceptionally high C2H2 and CO2 uptakes of 211 and 120 cm(3) (STP) g(-1) at 295 K and 1 atm, as well as impressive adsorption selectivities towards C2H2 and CO2 over CH4. High C2H2 and CO2 uptake capacities as well as significant adsorption selectivities of C2H2 and CO2 over CH4 imply potential applications in the adsorptive separation and purification of C2H2/CH4 and CO2/CH4 gas mixtures, which have been verified by column breakthrough experiments. Several important binding sites for C2H2 and CO2 in ZJNU-54 were revealed by quantum chemical calculations, demonstrating that the organic linkers in ZJNU-54 form unique structures that facilitate the adsorption of C2H2, while the amine groups and the Lewis basic pyrimidine-ring nitrogen sites in the organic linker improve the adsorption energies for CO2, finally leading to the increase of adsorption capacities for these two gas molecules. This work provides an efficient strategy for incorporating specific functional groups into cage based MOFs for generating new adsorbents for highly selective gas storage and separation. PMID- 27483192 TI - Photoisomerization of beta-Ionone Protonated Schiff Base in the Gas Phase. AB - The photoisomerization of beta-ionone protonated Schiff base (BIPSB) is investigated in the gas phase by irradiating mobility-selected ions in a tandem ion mobility spectrometer with tunable radiation. Four distinguishable isomers are produced by electrospray ionization whose structures are deduced from their collision cross sections and photoisomerization behavior along with density functional theory calculations. They include two geometric isomers of BIPSB with trans or cis configurations about the polyene chain's terminal C?N double bond, a bicyclic structure formed through electrocyclization of the polyene chain, and a Z-retro-gamma-ionone isomer. Although trans-BIPSB and 9-cis-BIPSB have similar photoisomerization action spectra, with a maximum response at 375 nm, they photoconvert to different isomers. The trans-BIPSB isomer transforms to the bicyclic form upon exposure to light over the 320-400 nm range, whereas the cis BIPSB isomer is prevented by steric hindrance from forming the bicyclic BIPSB isomer following irradiation and is proposed instead to form the 7,9-di-cis isomer. Neither the bicyclic isomer nor the Z-retro-gamma-ionone isomer respond strongly to near-UV light. PMID- 27483190 TI - Side-Chain Conformational Preferences Govern Protein-Protein Interactions. AB - Protein secondary structures serve as geometrically constrained scaffolds for the display of key interacting residues at protein interfaces. Given the critical role of secondary structures in protein folding and the dependence of folding propensities on backbone dihedrals, secondary structure is expected to influence the identity of residues that are important for complex formation. Counter to this expectation, we find that a narrow set of residues dominates the binding energy in protein-protein complexes independent of backbone conformation. This finding suggests that the binding epitope may instead be substantially influenced by the side-chain conformations adopted. We analyzed side-chain conformational preferences in residues that contribute significantly to binding. This analysis suggests that preferred rotamers contribute directly to specificity in protein complex formation and provides guidelines for peptidomimetic inhibitor design. PMID- 27483193 TI - Atomically Thin MoS2 Narrowband and Broadband Light Superabsorbers. AB - We present a combined theoretical and experimental effort to enable strong light absorption (>70%) in atomically thin MoS2 films (<=4 layers) for either narrowband incidence with arbitrarily prespecified wavelengths or broadband incidence like solar radiation. This is achieved by integrating the films with resonant photonic structures that are deterministically designed using a unique reverse design approach based on leaky mode coupling. The design starts with identifying the properties of leaky modes necessary for the targeted strong absorption, followed by searching for the geometrical features of nanostructures to support the desired modes. This process is very intuitive and only involves a minimal amount of computation, thanks to the straightforward correlations between optical functionality and leaky modes as well as between leaky modes and the geometrical feature of nanostructures. The result may provide useful guidance for the development of high-performance atomic-scale photonic devices, such as solar cells, modulators, photodetectors, and photocatalysts. PMID- 27483194 TI - The Role of the Hydrogen Source on the Selective Production of gamma Valerolactone and 2-Methyltetrahydrofuran from Levulinic Acid. AB - A mechanistic study of the hydrogenation reaction of levulinic acid (LA) to 2 methyltetrahydrofuyran (MTHF) was performed using three different solvents under reactive H2 and inert N2 atmospheres. Under the applied reaction conditions, catalytic transfer hydrogenation and hydrogenation with molecular H2 were effective at producing high yields of gamma-valerolactone. However, the conversion of this stable intermediate to MTHF required the combination of both hydrogen sources (the solvent and the H2 atmosphere) to achieve good yields. The reaction system with 2-propanol as solvent and Ni-Cu/Al2 O3 as catalyst allowed full conversion of LA and a MTHF yield of 80 % after 20 h reaction time at 250 degrees C and 40 bar of H2 (at room temperature). The system showed the same catalytic activity at LA feed concentrations of 5 and up to 30 wt%, and also when high acetone concentration at the beginning of the reaction were added, which confirmed the potential industrial applications of this solvent/catalyst system. PMID- 27483195 TI - pKa at Quartz/Electrolyte Interfaces. AB - Acidity of silanol sites at the crystalline quartz/aqueous electrolyte (NaCl, NaI, KCl) interfaces are calculated from ab initio molecular dynamics simulations. pKa's are found to follow a combination of the cationic and anionic Hofmeister series in the order pKa(neat solution) < pKa(NaCl) < pKa(NaI) < pKa(KCl), in agreement with experimental measurements. Rationalization of this ranking is achieved in terms of the microscopic local solvation of the protonated silanols and their conjugated bases, the silanolates SiO(-). The change in the pKa is the result of both water destructuring by alkali halides, as well as of the specific cation/SiO(-) interaction, depending on the electrolyte. Molecular modeling at the atomistic level is required to achieve such comprehension, with ab initio molecular dynamics being able to model complex inhomogeneous charged interfaces and the associated interfacial chemical reactivity. PMID- 27483196 TI - Differential influences of local subpopulations on regional diversity and differentiation for greater sage-grouse (Centrocercus urophasianus). AB - The distribution of spatial genetic variation across a region can shape evolutionary dynamics and impact population persistence. Local population dynamics and among-population dispersal rates are strong drivers of this spatial genetic variation, yet for many species we lack a clear understanding of how these population processes interact in space to shape within-species genetic variation. Here, we used extensive genetic and demographic data from 10 subpopulations of greater sage-grouse to parameterize a simulated approximate Bayesian computation (ABC) model and (i) test for regional differences in population density and dispersal rates for greater sage-grouse subpopulations in Wyoming, and (ii) quantify how these differences impact subpopulation regional influence on genetic variation. We found a close match between observed and simulated data under our parameterized model and strong variation in density and dispersal rates across Wyoming. Sensitivity analyses suggested that changes in dispersal (via landscape resistance) had a greater influence on regional differentiation, whereas changes in density had a greater influence on mean diversity across all subpopulations. Local subpopulations, however, varied in their regional influence on genetic variation. Decreases in the size and dispersal rates of central populations with low overall and net immigration (i.e. population sources) had the greatest negative impact on genetic variation. Overall, our results provide insight into the interactions among demography, dispersal and genetic variation and highlight the potential of ABC to disentangle the complexity of regional population dynamics and project the genetic impact of changing conditions. PMID- 27483197 TI - A Sequential Method to Prepare Polymorphs and Solvatomorphs of [Fe(1,3-bpp)2 ](ClO4 )2 ?nH2 O (n=0, 1, 2) with Varying Spin-Crossover Behaviour. AB - Two polymorphs of the spin crossover (SCO) compound [Fe(1,3-bpp)2 ](ClO4 )2 (1 and 2; 1,3-bpp=2-(pyrazol-1-yl)-6-(pyrazol-3-yl)pyridine) were prepared using a novel, stepwise procedure. Crystals of 1 deposit from dry solvents, while 2 is obtained from a solid-state procedure, by sequentially removing lattice H2 O molecules from the solvatomorph [Fe(1,3-bpp)2 ](ClO4 )2 ?2 H2 O (2?2 H2 O), using single-crystal-to-single-crystal (SCSC) transformations. Hydrate 2?2 H2 O is obtained through the same reaction as 1, now with 2.5 % of water added. Compounds 2 and 2?2 H2 O are unstable in the atmosphere and absorb or lose one equivalent of water, respectively, to both yield the stable solvatomorph [Fe(1,3-bpp)2 ](ClO4 )2 ?H2 O (2?H2 O), also following SCSC processes. The four derivatives have been characterised by single-crystal X-ray diffraction (SCXRD). Furthermore, the homogeneity of the various compounds as well as their SCSC interconversions have been confirmed by powder X-ray diffraction (PXRD). Polymorphs 1 and 2 exhibit abrupt SCO behaviour near room temperature with T1/2? =279/316 K and T1/2? =276/314 K (near 40 K of shift) and different cooperativity. PMID- 27483198 TI - Acute mountain sickness and duration of pre-exposure to high altitude. PMID- 27483199 TI - Tuning Slow Magnetic Relaxation in a Two-Dimensional Dysprosium Layer Compound through Guest Molecules. AB - A novel two-dimensional dysprosium(III) complex, [Dy(L)(CH3COO)].0.5DMF.H2O.2CH3OH (1), has been successfully synthesized from a new pyridine-N-oxide (PNO)-containing ligand, namely, N'-(2-hydroxy-3 methoxybenzylidene)pyridine-N-oxidecarbohydrazide (H2L). Single-crystal X-ray diffraction studies reveal that complex 1 is composed of a dinuclear dysprosium subunit, which is further extended by the PNO part of the ligand to form a two dimensional layer. Magnetic studies indicate that complex 1 shows well-defined temperature- and frequency-dependent signals under a zero direct-current (dc) field, typical of slow magnetic relaxation with an effective energy barrier Ueff of 33.6 K under a zero dc field. Interestingly, powder X-ray diffraction and thermogravimetric analysis reveal that compound 1 undergoes a reversible phase transition that is induced by the desorption and absorption of methanol and water molecules. Moreover, the desolvated sample [Dy(L)(CH3COO)].0.5DMF (1a) also exhibits slow magnetic relaxation but with a higher anisotropic barrier of 42.0 K, indicating the tuning effect of solvent molecules on slow magnetic relaxation. PMID- 27483200 TI - The Acid and/or Thermal Mediated Ring Contraction of 4H-1,2,6-Thiadiazines To Afford 1,2,5-Thiadiazoles. AB - A near-quantitative acid and/or thermal mediated ring contraction of 3',5' diarylspiro(benzo[d][1,3]dioxole-2,4'-[1,2,6]thiadiazines) affords 3-aryl-4-(2 arylbenzo[d][1,3]dioxol-2-yl)-1,2,5-thiadiazoles. The reaction scope was studied providing 11 examples of this ring contraction. A double Wagner-Meerwein reaction mechanism is proposed. PMID- 27483201 TI - Reply to "Allocation Based on Virtual Crossmatch Alone: Not Yet Ready for Primetime". PMID- 27483202 TI - Reply. PMID- 27483203 TI - Spatiotemporal relationship between adult census size and genetic population size across a wide population size gradient. AB - Adult census population size (N) and effective number of breeders (Nb ) are highly relevant for designing effective conservation strategies. Both parameters are often challenging to quantify, however, making it of interest to determine whether one parameter can be generalized from the other. Yet, the spatiotemporal relationship between N and Nb has not been well characterized empirically in many taxa. We analysed this relationship for 5-7 consecutive years in twelve brook trout populations varying greatly in N (49-10032) and Nb (3-567) and identified major environmental variables affecting the two parameters. N or habitat size alone explained 47-57% of the variance in Nb , and Nb was strongly correlated with effective population size. The ratio Nb /N ranged from 0.01 to 0.45 and increased at small N or following an annual decrease in N, suggesting density dependent constraints on Nb . We found no evidence for a consistent, directional difference between variability in Nb and/or Nb /N among small and large populations; however, small populations had more varying temporal variability in Nb /N ratios than large populations. Finally, Nb and Nb /N were 2.5- and 2.3-fold more variable among populations than temporally within populations. Our results demonstrate a clear linkage between demographic and evolutionary parameters, suggesting that Nb could be used to approximate N (or vice versa) in natural populations. Nevertheless, using one variable to infer the other to monitor trends within populations is less recommended, perhaps even less so in small populations given their less predictable Nb vs. N dynamics. PMID- 27483204 TI - Synthetic biology for basic and applied plant research. PMID- 27483205 TI - Synthetic redesign of plant lipid metabolism. AB - Plant seed lipid metabolism is an area of intensive research, including many examples of transgenic events in which oil composition has been modified. In the selected examples described in this review, progress towards the predictive manipulation of metabolism and the reconstitution of desired traits in a non native host is considered. The advantages of a particular oilseed crop, Camelina sativa, as a flexible and utilitarian chassis for advanced metabolic engineering and applied synthetic biology are considered, as are the issues that still represent gaps in our ability to predictably alter plant lipid biosynthesis. Opportunities to deliver useful bio-based products via transgenic plants are described, some of which represent the most complex genetic engineering in plants to date. Future prospects are considered, with a focus on the desire to transition to more (computationally) directed manipulations of metabolism. PMID- 27483206 TI - Direct Monitoring of gamma-Glutamyl Transpeptidase Activity In Vivo Using a Hyperpolarized (13) C-Labeled Molecular Probe. AB - The gamma-glutamyl transpeptidase (GGT) enzyme plays a central role in glutathione homeostasis. Direct detection of GGT activity could provide critical information for the diagnosis of several pathologies. We propose a new molecular probe, gamma-Glu-[1-(13) C]Gly, for monitoring GGT activity in vivo by hyperpolarized (HP) (13) C magnetic resonance (MR). The properties of gamma-Glu [1-(13) C]Gly are suitable for in vivo HP (13) C metabolic analysis since the chemical shift between gamma-Glu-[1-(13) C]Gly and its metabolic product, [1-(13) C]Gly, is large (4.3 ppm) and the T1 of both compounds is relatively long (30 s and 45 s, respectively, in H2 O at 9.4 T). We also demonstrate that gamma-Glu-[1 (13) C]Gly is highly sensitive to in vivo modulation of GGT activity induced by the inhibitor acivicin. PMID- 27483207 TI - Mesoporous Carbon Materials with Functional Compositions. AB - Since the 1990s, there has been rapidly expanding development of solid materials with mesoporous structure, of which mesoporous carbons are an important family. Toward the design of functional materials, mesoporous carbons with various compositions have been prepared for specific uses, such as catalysts, adsorbents, and electrode materials. Some of those novel materials indeed show promising performance in several fields, such as nitrogen-doped mesoporous carbon for oxygen reduction reactions in fuel cells and mesoporous carbon nitride for photocatalysis. This Minireview summarizes recent advances in the design, synthesis, characterization, and application of mesoporous carbons with functional compositions and briefly discusses next-generation mesoporous carbons. PMID- 27483208 TI - Regional distribution of ventilation in horses in dorsal recumbency during spontaneous and mechanical ventilation assessed by electrical impedance tomography: a case series. AB - OBJECTIVE: To evaluate the regional distribution of ventilation in horses during spontaneous breathing and controlled mechanical ventilation (CMV) using electrical impedance tomography (EIT). STUDY DESIGN: Prospective, experimental case series. ANIMALS: Four anaesthetized experimental horses. METHODS: Horses were anaesthetized with isoflurane in an oxygen-air mixture and medetomidine continuous rate infusion, placed in dorsal recumbency with an EIT belt around the thorax, and allowed to breathe spontaneously until PaCO2 reached 13.3 kPa (100 mmHg), when volume CMV was started. For each horse, the EIT signal was recorded for at least 2 minutes immediately before (T1), and at 30 (n = 3) or 60 (n = 1) minutes after the start of CMV (T2). The centre of ventilation (CoV), dependent silent spaces (DSS) (likely to represent atelectatic lung areas), non-dependent silent spaces (NSS) (likely to represent lung areas with low ventilation) and total ventilated area (TVA) were evaluated. Cardiac output (CO) was measured and venous admixture and oxygen delivery (DO2) were calculated at T1 and T2. Data are presented as median and range. RESULTS: After the initiation of CMV, the CoV moved ventrally towards the non-dependent lung by 10% [from 57.4% (49.6-60.2%) to 48.3% (41.9-54.4%)]. DSS increased [from 4.1% (0.2-13.9%) to 18.7% (7.5-27.5%)], while NSS [21.7% (9.4-29.2%) to 9.9% (1.0-20.7%)] and TVA [920 (699-1051) to 837 (662-961) pixels] decreased. CO, venous admixture and DO2 also decreased. CONCLUSIONS AND CLINICAL RELEVANCE: In spontaneously breathing anaesthetized horses in dorsal recumbency, ventilation was essentially centred within the dependent dorsal lung regions and moved towards non-dependent ventral regions as soon as CMV was started. This shows a major lack of ventilation in the dependent lung, which may be indicative of atelectasis. PMID- 27483209 TI - An Efficient Particle-Based DNA Circuit System: Catalytic Disassembly of DNA/PEG Modified Gold Nanoparticle-Magnetic Bead Composites for Colorimetric Detection of miRNA. AB - An efficient particle-based DNA circuit system for a new colorimetric miRNA assay is designed and devised based on a catalytic disassembly strategy through a target miRNA-triggered DNA circuit mechanism. The new particle-based DNA circuit system shows a rapid color change as well as significant improvement of sensitivity without need for other enzymes or instruments. PMID- 27483210 TI - Digital Versus Conventional Impressions in Fixed Prosthodontics: A Review. AB - PURPOSE: To conduct a systematic review to evaluate the evidence of possible benefits and accuracy of digital impression techniques vs. conventional impression techniques. MATERIALS AND METHODS: Reports of digital impression techniques versus conventional impression techniques were systematically searched for in the following databases: Cochrane Central Register of Controlled Trials, PubMed, and Web of Science. A combination of controlled vocabulary, free-text words, and well-defined inclusion and exclusion criteria guided the search. RESULTS: Digital impression accuracy is at the same level as conventional impression methods in fabrication of crowns and short fixed dental prostheses (FDPs). For fabrication of implant-supported crowns and FDPs, digital impression accuracy is clinically acceptable. In full-arch impressions, conventional impression methods resulted in better accuracy compared to digital impressions. CONCLUSIONS: Digital impression techniques are a clinically acceptable alternative to conventional impression methods in fabrication of crowns and short FDPs. For fabrication of implant-supported crowns and FDPs, digital impression systems also result in clinically acceptable fit. Digital impression techniques are faster and can shorten the operation time. Based on this study, the conventional impression technique is still recommended for full-arch impressions. PMID- 27483211 TI - Are Rheumatoid Factor, Anti-Citrullinated Protein Antibodies, and Anti Carbamylated Protein Antibodies Linked by Posttranslational Modification of IgG? Comment on the Article by Koppejan et al. PMID- 27483212 TI - Generalized Hyperalgesia in Children and Adults Diagnosed With Hypermobility Syndrome and Ehlers-Danlos Syndrome Hypermobility Type: A Discriminative Analysis. AB - OBJECTIVE: Lowered pressure-pain thresholds have been demonstrated in adults with Ehlers-Danlos syndrome hypermobility type (EDS-HT), but whether these findings are also present in children is unclear. Therefore, the objectives of the study were to determine whether generalized hyperalgesia is present in children with hypermobility syndrome (HMS)/EDS-HT, explore potential differences in pressure pain thresholds between children and adults with HMS/EDS-HT, and determine the discriminative value of generalized hyperalgesia. METHODS: Patients were classified in 1 of 3 groups: HMS/EDS-HT, hypermobile (Beighton score >=4 of 9), and healthy controls. Descriptive data of age, sex, body mass index, Beighton score, skin laxity, and medication usage were collected. Generalized hyperalgesia was quantified by the average pressure-pain thresholds collected from 12 locations. Confounders collected were pain locations/intensity, fatigue, and psychological distress. Comparisons between children with HMS/EDS-HT and normative values, between children and adults with HMS/EDS-HT, and corrected confounders were analyzed with multivariate analysis of covariance. The discriminative value of generalized hyperalgesia employed to differentiate between HMS/EDS-HT, hypermobility, and controls was quantified with logistic regression. RESULTS: Significantly lower pressure-pain thresholds were found in children with HMS/EDS-HT compared to normative values (range -22.0% to -59.0%; P <= 0.05). When applying a threshold of 30.8 N/cm2 for males and 29.0 N/cm2 for females, the presence of generalized hyperalgesia discriminated between individuals with HMS/EDS-HT, hypermobility, and healthy controls (odds ratio 6.0). CONCLUSION: Children and adults with HMS/EDS-HT are characterized by hypermobility, chronic pain, and generalized hyperalgesia. The presence of generalized hyperalgesia may indicate involvement of the central nervous system in the development of chronic pain. PMID- 27483213 TI - Ultrasound Mediated One-Pot, Three Component Synthesis, Docking and ADME Prediction of Novel 5-Amino-2-(4-chlorophenyl)-7-Substituted Phenyl-8,8a-dihydro 7H-(1,3,4)thiadiazolo(3,2-alpha)pyrimidine-6-carbonitrile Derivatives as Anticancer Agents. AB - Herein, we report an environmentally friendly, rapid, and convenient one-pot ultrasound-promoted synthesis of 5-amino-2-(4-chlorophenyl)-7-substituted phenyl 8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-alpha)pyrimidine-6-carbonitrile derivatives. The in-vitro anticancer activities of these compounds were evaluated against four human tumor cell lines. Among all the synthesized derivatives, compound 4i, which has substituent 3-hydroxy-4-methoxyphenyl is found to have the highest GI50 value of 32.7 MUM, 55.3 MUM, 34.3 MUM, 28.9 MUM for MCF-7, K562, HeLa and PC-3 cancer cell lines respectively. A docking study of the newly synthesized compounds were performed, and the results showed good binding mode in the active site of thymidylate synthase enzyme. ADME properties of synthesized compounds were also studied and showed good drug like properties. PMID- 27483214 TI - Influences of Adhesion Variability on the "Living" Dynamics of Filamentous Bacteria in Microfluidic Channels. AB - Microfabricated devices have increasingly incorporated bacterial cells for microscale studies and exploiting cell-based functions in situ. However, the role of surface interactions in controlling the bacterial cell behavior is not well understood. In this study, microfluidic substrates of varied bacterial-binding affinity were used to probe the interaction-driven behavior of filamentous Escherichia coli. In particular, cell alignment under controlled shear flow as well as subsequent orientation and filamentation were compared between cells presenting distinct outer membrane phenotypes. We demonstrated that filaments retained position under flow, which allowed for dynamic single-cell monitoring with in situ elongation of over 100 MUm for adherent cells. This maximum was not reached by planktonic cells and was, therefore, adhesion-dependent. The bound filaments initially aligned with flow under a range of flow rates and their continual elongation was traced in terms of length and growth path; analysis demonstrated that fimbriae-mediated adhesion increased growth rate, increased terminal length, as well as dramatically changed the adherent geometry, particularly buckling behavior. The effects to filament length and buckling were further exaggerated by the strongest, specificity-driven adhesion tested. Such surface-guided control of the elongation process may be valuable to yield interesting "living" filamentous structures in microdevices. In addition, this work may offer a biomedically relevant platform for further elucidation of filamentation as an immune-resistant morphology. Overall, this work should inspire broader exploration of microfabricated devices for the study and application of single bacterial cells. PMID- 27483215 TI - Native Mass Spectrometry in Fragment-Based Drug Discovery. AB - The advent of native mass spectrometry (MS) in 1990 led to the development of new mass spectrometry instrumentation and methodologies for the analysis of noncovalent protein-ligand complexes. Native MS has matured to become a fast, simple, highly sensitive and automatable technique with well-established utility for fragment-based drug discovery (FBDD). Native MS has the capability to directly detect weak ligand binding to proteins, to determine stoichiometry, relative or absolute binding affinities and specificities. Native MS can be used to delineate ligand-binding sites, to elucidate mechanisms of cooperativity and to study the thermodynamics of binding. This review highlights key attributes of native MS for FBDD campaigns. PMID- 27483216 TI - Bioactive Molecule Prediction Using Extreme Gradient Boosting. AB - Following the explosive growth in chemical and biological data, the shift from traditional methods of drug discovery to computer-aided means has made data mining and machine learning methods integral parts of today's drug discovery process. In this paper, extreme gradient boosting (Xgboost), which is an ensemble of Classification and Regression Tree (CART) and a variant of the Gradient Boosting Machine, was investigated for the prediction of biological activity based on quantitative description of the compound's molecular structure. Seven datasets, well known in the literature were used in this paper and experimental results show that Xgboost can outperform machine learning algorithms like Random Forest (RF), Support Vector Machines (LSVM), Radial Basis Function Neural Network (RBFN) and Naive Bayes (NB) for the prediction of biological activities. In addition to its ability to detect minority activity classes in highly imbalanced datasets, it showed remarkable performance on both high and low diversity datasets. PMID- 27483217 TI - N,N'-Bis(2-cyclohexylethyl)naphtho[2,3-b:6,7-b']dithiophene Diimides: Effects of Substituents. AB - Naphtho[2,3-b:6,7-b']dithiophene-4,5,9,10-tetracarboxylic diimide (NDTI) is a promising electron-deficient building block for n-type organic conductors, and the performance of NDTI-based field-effect transistors (FETs) is largely dependent on the substituents that alter the supramolecular organization in the solid state and, in turn, the intermolecular orbital overlap. For this reason, the rational selection of substituent on imide nitrogen atoms and/or thiophene alpha-positions is the key to developing superior n-type organic semiconductors. We here report new NDTI derivatives having N-(2-cyclohexylethyl) groups. Despite their one-dimensional packing structures in the solid state regardless of the presence or absence of chlorine groups at the thiophene alpha-positions, their FETs show promising performance with electron mobilities higher than 0.1 cm2.V( 1).s(-1) under ambient conditions. We also discuss how the cyclohexylethyl groups affect the packing structure in comparison with analogous n-octyl derivatives having the same number of carbon atoms. PMID- 27483218 TI - Lutein, a Natural Carotenoid, Induces alpha-1,3-Glucan Accumulation on the Cell Wall Surface of Fungal Plant Pathogens. AB - alpha-1,3-Glucan, a component of the fungal cell wall, is a refractory polysaccharide for most plants. Previously, we showed that various fungal plant pathogens masked their cell wall surfaces with alpha-1,3-glucan to evade plant immunity. This surface accumulation of alpha-1,3-glucan was infection specific, suggesting that plant factors might induce its production in fungi. Through immunofluorescence observations of fungal cell walls, we found that carrot (Daucus carota) extract induced the accumulation of alpha-1,3-glucan on germlings in Colletotrichum fioriniae, a polyphagous fungal pathogen that causes anthracnose disease in various dicot plants. Bioassay-guided fractionation of carrot leaf extract successfully identified two active substances that caused alpha-1,3-glucan accumulation in this fungus: lutein, a carotenoid widely distributed in plants, and stigmasterol, a plant-specific membrane component. Lutein, which had a greater effect on C. fioriniae, also induced alpha-1,3-glucan accumulation in other Colletotrichum species and in the phylogenetically distant rice pathogen Cochliobolus miyabeanus, but not in the rice pathogen Magnaporthe oryzae belonging to the same phylogenetic subclass as Colletotrichum. Our results suggested that fungal plant pathogens reorganize their cell wall components in response to specific plant-derived compounds, which these pathogens may encounter during infection. PMID- 27483219 TI - Coffee Consumption and Oxidative Stress: A Review of Human Intervention Studies. AB - Research on the potential protective effects of coffee and its bioactives (caffeine, chlorogenic acids and diterpenes) against oxidative stress and related chronic disease risk has been increasing in the last years. The present review summarizes the main findings on the effect of coffee consumption on protection against lipid, protein and DNA damage, as well as on the modulation of antioxidant capacity and antioxidant enzymes in human studies. Twenty-six dietary intervention studies (involving acute and chronic coffee intake) have been considered. Overall, the results suggest that coffee consumption can increase glutathione levels and improve protection against DNA damage, especially following regular/repeated intake. On the contrary, the effects of coffee on plasma antioxidant capacity and antioxidant enzymes, as well as on protein and lipid damage, are unclear following both acute and chronic exposure. The high heterogeneity in terms of type of coffee, doses and duration of the studies, the lack of information on coffee and/or brew bioactive composition, as well as the choice of biomarkers and the methods used for their evaluation, may partially explain the variability observed among findings. More robust and well-controlled intervention studies are necessary for a thorough understanding of the effect of coffee on oxidative stress markers in humans. PMID- 27483220 TI - Efficacy of Acetylshikonin in Preventing Obesity and Hepatic Steatosis in db/db Mice. AB - Zicao (Lithospermum erythrorhizon) has been used in clinics as a traditional Chinese medicine for thousands of years. Acetylshikonin (AS) is the main ingredient of Zicao, Xinjiang, China. The objective of this study was to investigate the anti-obesity and anti-nonalcoholic fatty liver disease (NAFLD) efficacy of AS in a model of spontaneous obese db/db mice. Mice were divided into Wild Type (WT) groups and db/db groups, which received no treatment or treatment with 100 mg/kg/day clenbuterol (CL) hydrochloride or 540 mg/kg/day AS by oral gavage for eight weeks. The results provided the evidence that AS prevented obesity and NAFLD including reduction in body weight, food efficiency ratio, serum triglyceride (TG) and free fatty acid (FFA) levels in db/db mice. Administration of AS markedly suppressed the levels of hepatic alanine aminotransferase (ALT), aspartate aminotransferase (AST) and pro-inflammatory cytokines in treated groups when compared with that of db/db groups. Further investigation of the lipid synthesis-related protein using Western blotting revealed that hepatic protein expression of sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthetase (FAS) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) were significantly downregulated by AS treatment. These findings suggest that AS exerts anti-obesity and anti-NAFLD effects through the regulation of lipid metabolism and anti-inflammatory effects. PMID- 27483221 TI - In Vitro Neuroprotective and Anti-Inflammatory Activities of Natural and Semi Synthetic Spirosteroid Analogues. AB - Two spirosteroid analogues were synthesized and evaluated for their in vitro neuroprotective activities in PC12 cells, against glutamate-induced excitotoxicity and mitochondrial damage in glucose deprivation conditions, as well as their anti-inflammatory potential in LPS/IFNgamma-stimulated microglia primary cultures. We also evaluated the in vitro anti-excitotoxic and anti inflammatory activities of natural and endogenous steroids. Our results show that the plant-derived steroid solasodine decreased PC12 glutamate-induced excitotoxicity, but not the cell death induced by mitochondrial damage and glucose deprivation. Among the two synthetic spirosteroid analogues, only the (25R)-5alpha-spirostan-3,6-one (S15) protected PC12 against ischemia-related in vitro models and inhibited NO production, as well as the release of IL-1beta by stimulated primary microglia. These findings provide further insights into the role of specific modifications of the A and B rings of sapogenins for their neuroprotective potential. PMID- 27483222 TI - Recent Advances in Metal-Free Quinoline Synthesis. AB - The quinoline ring system is one of the most ubiquitous heterocycles in the fields of medicinal and industrial chemistry, forming the scaffold for compounds of great significance. These include anti-inflammatory and antitumor agents, the antimalarial drugs quinine and chloroquine, and organic light-emitting diodes. Quinolines were first synthesized in 1879, and since then a multitude of synthetic routes have been developed. Many of these methods, such as the Skraup, Doebner-Von Miller, and Friedlander quinoline syntheses, are well-known but suffer from inefficiency, harsh reaction conditions, and toxic reagents. This review focuses on recent transition metal-free processes toward these important heterocycles, including both novel routes and modifications to established methods. For example, variations on the Skraup method include microwave irradiation, ionic liquid media, and novel annulation partners, all of which have shown increased reaction efficiency and improved yield of the heteroring unsubstituted quinoline products. Similarly, modifications to other synthetic routes have been implemented, with the quinoline products displaying a wide variety of substitution patterns. PMID- 27483223 TI - Isolation of a Cyclic (Alkyl)(amino)germylene. AB - A 1,4-addition of a dichlorogermylene dioxane complex with alpha,beta-unsaturated imine 1 gave a dichlorogermane derivative 2 bearing a GeC3N five-membered ring skeleton. By reducing 2 with KC8, cyclic (alkyl)(amino)germylene 3 was synthesized and fully characterized. Germylene 3 readily reacted with TEMPO, N2O and S8, producing the 1:2 adduct 4, the oxo-bridged dimer 5 and the sulfido bridged dimer 6, respectively. PMID- 27483224 TI - Prenylated Chalcone 2 Acts as an Antimitotic Agent and Enhances the Chemosensitivity of Tumor Cells to Paclitaxel. AB - We previously reported that prenylated chalcone 2 (PC2), the O-prenyl derivative (2) of 2'-hydroxy-3,4,4',5,6'-pentamethoxychalcone (1), induced cytotoxicity of tumor cells via disruption of p53-MDM2 interaction. However, the cellular changes through which PC2 exerts its cytotoxic activity and its antitumor potential, remain to be addressed. In the present work, we aimed to (i) characterize the effect of PC2 on mitotic progression and the underlying mechanism; and to (ii) explore this information to evaluate its ability to sensitize tumor cells to paclitaxel in a combination regimen. PC2 was able to arrest breast adenocarcinoma MCF-7 and non-small cell lung cancer NCI-H460 cells in mitosis. All mitosis arrested cells showed collapsed mitotic spindles with randomly distributed chromosomes, and activated spindle assembly checkpoint. Live-cell imaging revealed that the compound induced a prolonged delay (up to 14 h) in mitosis, culminating in massive cell death by blebbing. Importantly, PC2 in combination with paclitaxel enhanced the effect on cell growth inhibition as determined by cell viability and proliferation assays. Our findings demonstrate that the cytotoxicity induced by PC2 is mediated through antimitotic activity as a result of mitotic spindle damage. The enhancement effects of PC2 on chemosensitivity of cancer cells to paclitaxel encourage further validation of the clinical potential of this combination. PMID- 27483225 TI - Chemo-Enzymatic Synthesis of Chiral Epoxides Ethyl and Methyl (S)-3-(Oxiran-2 yl)propanoates from Renewable Levoglucosenone: An Access to Enantiopure (S)-Dairy Lactone. AB - Chiral epoxides-such as ethyl and methyl (S)-3-(oxiran-2-yl)propanoates ((S) 1a/1b)-are valuable precursors in many chemical syntheses. Until recently, these compounds were synthesized from glutamic acid in four steps (deamination, reduction, tosylation and epoxide formation) in low to moderate overall yield (20%-50%). Moreover, this procedure requires some harmful reagents such as sodium nitrite ((eco)toxic) and borane (carcinogen). Herein, starting from levoglucosenone (LGO), a biobased chiral compound obtained through the flash pyrolysis of acidified cellulose, we propose a safer and more sustainable chemo enzymatic synthetic pathway involving lipase-mediated Baeyer-Villiger oxidation, palladium-catalyzed hydrogenation, tosylation and treatment with sodium ethoxide/methoxide as key steps. This route afforded ethyl and methyl (S)-3 (oxiran-2-yl)propanoates in 57% overall yield, respectively. To demonstrate the potentiality of this new synthetic pathway from LGO, the synthesis of high value added (S)-dairy lactone was undertaken from these epoxides and provided the target in 37% overall yield from LGO. PMID- 27483226 TI - A Well-Defined {[(PhCH2O)2P(CH3)2CHNCH(CH3)2]2PdCl2} Complex Catalyzed Hiyama Coupling of Aryl Bromides with Arylsilanes. AB - A palladium (II) complex {[(PhCH2O)2P(CH3)2CHNCH(CH3)2]2PdCl2} catalyzed Hiyama cross-coupling reaction between aryl bromides and arylsilanes has been developed. The substituted biaryls were produced in moderate to high yields, regardless of electron-withdrawing or electron-donating. PMID- 27483227 TI - Selective Extraction of Flavonoids from Sophora flavescens Ait. by Mechanochemistry. AB - Flavonoids from Sophora flavescens were selectively extracted by mechanochemical promoted extraction technology (MPET) after using response surface methodology to determine the optimal extraction parameters. The highest yield of 35.17 mg/g was achieved by grinding the roots with Na2CO3 (15%) at 440 rpm/min for 17.0 min and water was used as the sole solvent with a ratio of solvent to solid material of 25 mL/g. Flavonoids prepared by MPET demonstrated relatively higher antioxidant activities in subsequent DPPH and hydroxyl radical scavenging assays. Main constituents in the extracts, including kurarinol, kushenol I/N and kurarinone, were characterized by HPLC-MS/MS, indicating good selective extraction by MPET. Physicochemical property changes of powder during mechanochemical milling were identified by scanning electron microscopy, X-ray powder diffraction, and UV-Vis diffuse-reflectance spectroscopy. Compared with traditional extraction methods, MPET possesses notable advantages of higher selectivity, lower extraction temperature, shorter extraction time, and organic solvent free properties. PMID- 27483228 TI - Chemical Composition and Inhibitory Effect of Lentinula edodes Ethanolic Extract on Experimentally Induced Atopic Dermatitis in Vitro and in Vivo. AB - The ethanolic extract of Lentinula edodes was partially analyzed and then characterized for its efficacy in treating atopic dermatitis. Polyphenols were determined to be the major antioxidant component in the extract (6.12 mg/g), followed by flavonoids (1.76 mg/g), beta-carotene (28.75 MUg/g), and lycopene (5.25 MUg/g). An atopic dermatitis (AD) model was established and epidermal and dermal ear thickness, mast cell infiltration, and serum immunoglobulin levels were measured after oral administration of the L. edodes extract for 4 weeks. L. edodes extract decreased Dermatophagoides farinae extract (DFE) and 4 dinitrochlorobenzene (DNCB)-induced expression of several inflammatory cytokines in the ears, cervical lymph nodes, and splenocytes. Consequently, L. edodes extract may have therapeutic potential in the treatment of AD attributable to its immunomodulatory effects. PMID- 27483229 TI - Phenylethanoid Glycosides: Research Advances in Their Phytochemistry, Pharmacological Activity and Pharmacokinetics. AB - Phenylethanoid glycosides (PhGs) are widely distributed in traditional Chinese medicines as well as in other medicinal plants, and they were characterized by a phenethyl alcohol (C6-C2) moiety attached to a beta-glucopyranose/beta allopyranose via a glycosidic bond. The outstanding activity of PhGs in diverse diseases proves their importance in medicinal chemistry research. This review summarizes new findings on PhGs over the past 10 years, concerning the new structures, their bioactivities, including neuroprotective, anti-inflammatory, antioxidant, antibacterial and antivirus, cytotoxic, immunomodulatory, and enzyme inhibitory effects, and pharmacokinetic properties. PMID- 27483230 TI - Antioxidant Capacities of Fractions of Bamboo Shaving Extract and Their Antioxidant Components. AB - This research was conducted for evaluation of antioxidant activities of four fractions from bamboo shavings extract (BSE) and their antioxidant components. The antioxidant capacities of BSE and four fractions on ABTS, DPPH, FRAP and total antioxidant capacity assays exhibited the following descending order: DF > n-butanol fraction (BF) > BSE ~ ethyl acetate fraction (AF) > water fraction (WF). Among the identified phenolic compounds, caffeic acid exhibited the highest antioxidant capacities on DPPH, FRAP and total antioxidant capacity assays. An extremely significant positive correlation between the antioxidant activities with the contents of total flavonoids, total phenolic acids, or total phenolics was observed in this study. The result indicated that the bamboo shaving extract and its solvent fractions could act as natural antioxidants in light of their potent antioxidant activities. PMID- 27483231 TI - Computational Approaches to Toll-Like Receptor 4 Modulation. AB - Toll-like receptor 4 (TLR4), along with its accessory protein myeloid differentiation factor 2 (MD-2), builds a heterodimeric complex that specifically recognizes lipopolysaccharides (LPS), which are present on the cell wall of Gram negative bacteria, activating the innate immune response. Some TLR4 modulators are undergoing preclinical and clinical evaluation for the treatment of sepsis, inflammatory diseases, cancer and rheumatoid arthritis. Since the relatively recent elucidation of the X-ray crystallographic structure of the extracellular domain of TLR4, research around this fascinating receptor has risen to a new level, and thus, new perspectives have been opened. In particular, diverse computational techniques have been applied to decipher some of the basis at the atomic level regarding the mechanism of functioning and the ligand recognition processes involving the TLR4/MD-2 system at the atomic level. This review summarizes the reported molecular modeling and computational studies that have recently provided insights into the mechanism regulating the activation/inactivation of the TLR4/MD-2 system receptor and the key interactions modulating the molecular recognition process by agonist and antagonist ligands. These studies have contributed to the design and the discovery of novel small molecules with promising activity as TLR4 modulators. PMID- 27483232 TI - Pro-Apoptotic Activity of New Honokiol/Triphenylmethane Analogues in B-Cell Lymphoid Malignancies. AB - Honokiol and triphenylmethanes are small molecules with anti-tumor properties. Recently, we synthesized new honokiol analogues (HAs) that possess common features of both groups. We assessed the anti-tumor effectiveness of HAs in B cell leukemia/lymphoma cells, namely in chronic lymphocytic leukemia (CLL) cells ex vivo and in pre-B-cell acute lymphoblastic leukemia (Nalm-6), Burkitt lymphoma (BL; Raji), diffuse large B-cell lymphoma (DLBCL; Toledo) and multiple myeloma (MM; RPMI 8226) cell lines. Four of these compounds appeared to be significantly active against the majority of cells examined, with no significant impact on healthy lymphocytes. These active HAs induced caspase-dependent apoptosis, causing significant deregulation of several apoptosis-regulating proteins. Overall, these compounds downregulated Bcl-2 and XIAP and upregulated Bax, Bak and survivin proteins. In conclusion, some of the HAs are potent tumor-selective inducers of apoptosis in ex vivo CLL and in BL, DLBCL and MM cells in vitro. Further preclinical studies of these agents are recommended. PMID- 27483233 TI - A General Catalytic Enantioselective Transfer Hydrogenation Reaction of beta,beta Disubstituted Nitroalkenes Promoted by a Simple Organocatalyst. AB - Given its synthetic relevance, the catalytic enantioselective reduction of beta,beta-disubstituted nitroalkenes has received a great deal of attention. Several bio-, metal-, and organo-catalytic methods have been developed, which however are usually applicable to single classes of nitroalkene substrates. In this paper, we present an account of our previous work on this transformation, which implemented with new disclosures and mechanistic insights results in a very general protocol for nitroalkene reductions. The proposed methodology is characterized by (i) a remarkably broad scope encompassing various nitroalkene classes; (ii) Hantzsch esters as convenient (on a preparative scale) hydrogen surrogates; (iii) a simple and commercially available thiourea as catalyst; (iv) user-friendly procedures. Overall, the proposed protocol gives a practical dimension to the catalytic enantioselective reduction of beta,beta-disubstituted nitroalkenes, offering a useful and general platform for the preparation of nitroalkanes bearing a stereogenic center at the beta-position in a highly enantioenriched form. A transition state model derived from control kinetic experiments combined with literature data is proposed and discussed. This model accounts and justifies the observed experimental results. PMID- 27483234 TI - Stimuli-Responsive Polymeric Systems for Controlled Protein and Peptide Delivery: Future Implications for Ocular Delivery. AB - Therapeutic proteins and peptides have become notable in the drug delivery arena for their compatibility with the human body as well as their high potency. However, their biocompatibility and high potency does not negate the existence of challenges resulting from physicochemical properties of proteins and peptides, including large size, short half-life, capability to provoke immune responses and susceptibility to degradation. Various delivery routes and delivery systems have been utilized to improve bioavailability, patient acceptability and reduce biodegradation. The ocular route remains of great interest, particularly for responsive delivery of macromolecules due to the anatomy and physiology of the eye that makes it a sensitive and complex environment. Research in this field is slowly gaining attention as this could be the breakthrough in ocular drug delivery of macromolecules. This work reviews stimuli-responsive polymeric delivery systems, their use in the delivery of therapeutic proteins and peptides as well as examples of proteins and peptides used in the treatment of ocular disorders. Stimuli reviewed include pH, temperature, enzymes, light, ultrasound and magnetic field. In addition, it discusses the current progress in responsive ocular drug delivery. Furthermore, it explores future prospects in the use of stimuli-responsive polymers for ocular delivery of proteins and peptides. Stimuli responsive polymers offer great potential in improving the delivery of ocular therapeutics, therefore there is a need to consider them in order to guarantee a local, sustained and ideal delivery of ocular proteins and peptides, evading tissue invasion and systemic side-effects. PMID- 27483235 TI - The in Vitro and in Vivo Antitumor Activities of Tetracyclic Triterpenoids Compounds Actein and 26-Deoxyactein Isolated from Rhizome of Cimicifuga foetida L. AB - AIMS: This work aims to study the in vitro and in vivo antitumor activities of tetracyclic triterpenoids compounds actein and 26-deoxyactein. Further, the mechanism is investigated. METHODS: In vitro, a modified MTT method was used to assay the cytotoxicities of actein and 26-deoxyactein in 12 human tumor cell lines. In vivo, mouse sarcoma S180 and human lung cancer A549 cells were respectively implanted subcutaneously in ICR mice and nude mice to establish implanted tumor models. Flow cytometry (FCM) was used to assay the cycle distribution of the tumor cells. Immunohistochemistry was used to measure CD31 positive expression in the xenogrft tumor by analyzing microvessel density (MVD). In addition, acute toxicities of actein and 26-deoxyactein were also evaluated. RESULTS: Actein and 26-deoxyactein inhibited the proliferation of the 12 human cancer cell lines tested with the values of 50% inhibitory concentrations (IC50) between 12.29 and 88.39 MUg/mL. In vivo, both actein (3-27 mg/kg) and 26 deoxyactein (3-27 mg/kg) significantly inhibited the growth of the implanted sarcoma S180 in a dose-dependent manner. Actein (10, 30 mg/kg) and 26-deoxyactein (10, 30 mg/kg) markedly inhibited the xenograft growth with T/C (%) values of 38%, 55% for actein, and 35%, 49% for 26-deoxyactein. Compared with the vehicle control, actein (10, 30 mg/kg) and 26-deoxyactein (10, 30 mg/kg) significantly reduced the MVD in the xenograft tumor. The FCM result showed that human leukemia HL-60 cells were arrested at G1 phase after treated with either actein (6.25-25 MUg/mL) or 26-deoxyactein (6.25-25 MUg/mL) for 48 h. A limited trial in mice showed that both of the minimal lethal doses (MLDs) of actein and 26-deoxyactein were over 5 g/kg. CONCLUSIONS: Both actein and 26-deoxyactein have low toxicities. Importantly, both these two tetracyclic triterpenoids compounds isolated from rhizome of Cimicifuga foetida L. have significant antitumor activities in vitro and in vivo, which is associated with cell cycle arrest and angiogenesis inhibition. PMID- 27483236 TI - Antiproliferative and Pro-Apoptotic Effect of Novel Nitro-Substituted Hydroxynaphthanilides on Human Cancer Cell Lines. AB - Ring-substituted hydroxynaphthanilides are considered as cyclic analogues of salicylanilides, compounds possessing a wide range of pharmacological activities, including promising anticancer properties. The aim of this study was to evaluate the potential anticancer effect of novel nitro-substituted hydroxynaphthanilides with a special focus on structure-activity relationships. The antiproliferative effect was assessed by Water Soluble Tetrazolium Salts-1 (WST-1) assay, and cytotoxicity was evaluated via dye exclusion test. Flow cytometry was used for cell cycle analysis and detection of apoptosis using Annexin V-FITC/PI assay. Protein expression was estimated by Western blotting. Our data indicate that the potential to cause the antiproliferative effect increases with the shift of the nitro substituent from the ortho- to the para-position. The most potent compounds, 3-hydroxy-N-(3-nitrophenyl)naphthalene-2-carboxamide (2), and 2 hydroxy-N-(4-nitrophenyl)-naphthalene-1-carboxamide (6) showed antiproliferative activity against THP-1 and MCF-7 cancer cells without affecting the proliferation of 3T3-L1 non-tumour cells. Compounds 2 and 6 induced the accumulation of THP-1 and MCF-7 cells in G1 phase associated with the downregulation of cyclin E1 protein levels, while the levels of cyclin B1 were not affected. Moreover, compound 2 was found to exert the pro-apoptotic effect on the THP-1 cells. These results suggest that hydroxynaphthanilides might represent a potential model structure for the development of novel anticancer agents. PMID- 27483237 TI - Genome-Wide Identification and Characterization of Carboxypeptidase Genes in Silkworm (Bombyx mori). AB - The silkworm (Bombyx mori) is an economically-important insect that can secrete silk. Carboxypeptidases have been found in various metazoan species and play important roles in physiological and biochemical reactions. Here, we analyzed the silkworm genome database and characterized 48 carboxypeptidases, including 34 metal carboxypeptidases (BmMCP1-BmMCP34) and 14 serine carboxypeptidases (BmSCP1 BmSCP14), to better understand their diverse functions. Compared to other insects, our results indicated that carboxypeptidases from silkworm have more family members. These silkworm carboxypeptidases could be divided into four families: Peptidase_M2 carboxypeptidases, Peptidase_M14 carboxypeptidases, Peptidase_S10 carboxypeptidases and Peptidase_S28 carboxypeptidases. Microarray analysis showed that the carboxypeptidases had distinct expression patterns, whereas quantitative real-time PCR demonstrated that the expression level of 13 carboxypeptidases significantly decreased after starvation and restored after re feeding. Overall, our study provides new insights into the functional and evolutionary features of silkworm carboxypeptidases. PMID- 27483238 TI - Screening and Validation of Housekeeping Genes of the Root and Cotyledon of Cunninghamia lanceolata under Abiotic Stresses by Using Quantitative Real-Time PCR. AB - Cunninghamia lanceolata (Chinese fir) is a fast-growing and commercially important conifer of the Cupressaceae family. Due to the unavailability of complete genome sequences and relatively poor genetic background information of the Chinese fir, it is necessary to identify and analyze the expression levels of suitable housekeeping genes (HKGs) as internal reference for precise analysis. Based on the results of database analysis and transcriptome sequencing, we have chosen five candidate HKGs (Actin, GAPDH, EF1a, 18S rRNA, and UBQ) with conservative sequences in the Chinese fir and related species for quantitative analysis. The expression levels of these HKGs in roots and cotyledons under five different abiotic stresses in different time intervals were measured by qRT-PCR. The data were statistically analyzed using the following algorithms: NormFinder, BestKeeper, and geNorm. Finally, RankAggreg was applied to merge the sequences generated from three programs and rank these according to consensus sequences. The expression levels of these HKGs showed variable stabilities under different abiotic stresses. Among these, Actin was the most stable internal control in root, and GAPDH was the most stable housekeeping gene in cotyledon. We have also described an experimental procedure for selecting HKGs based on the de novo sequencing database of other non-model plants. PMID- 27483239 TI - Full-Length cDNA Cloning, Molecular Characterization and Differential Expression Analysis of Lysophospholipase I from Ovis aries. AB - Lysophospholipase I (LYPLA1) is an important protein with multiple functions. In this study, the full-length cDNA of the LYPLA1 gene from Ovis aries (OaLypla1) was cloned using primers and rapid amplification of cDNA ends (RACE) technology. The full-length OaLypla1 was 2457 bp with a 5'-untranslated region (UTR) of 24 bp, a 3'-UTR of 1740 bp with a poly (A) tail, and an open reading frame (ORF) of 693 bp encoding a protein of 230 amino acid residues with a predicted molecular weight of 24,625.78 Da. Phylogenetic analysis showed that the OaLypla1 protein shared a high amino acid identity with LYPLA1 of Bos taurus. The recombinant OaLypla1 protein was expressed and purified, and its phospholipase activity was identified. Monoclonal antibodies (mAb) against OaLypla1 that bound native OaLypla1 were generated. Real-time PCR analysis revealed that OaLypla1 was constitutively expressed in the liver, spleen, lung, kidney, and white blood cells of sheep, with the highest level in the kidney. Additionally, the mRNA levels of OaLypla1 in the buffy coats of sheep challenged with virulent or avirulent Brucella strains were down-regulated compared to untreated sheep. The results suggest that OaLypla1 may have an important physiological role in the host response to bacteria. The function of OaLypla1 in the host response to bacterial infection requires further study in the future. PMID- 27483240 TI - Minocycline Loaded Hybrid Composites Nanoparticles for Mesenchymal Stem Cells Differentiation into Osteogenesis. AB - Bone transplants are used to treat fractures and increase new tissue development in bone tissue engineering. Grafting of massive implantations showing slow curing rate and results in cell death for poor vascularization. The potentials of biocomposite scaffolds to mimic extracellular matrix (ECM) and including new biomaterials could produce a better substitute for new bone tissue formation. A purpose of this study is to analyze polycaprolactone/silk fibroin/hyaluronic acid/minocycline hydrochloride (PCL/SF/HA/MH) nanoparticles initiate human mesenchymal stem cells (MSCs) proliferation and differentiation into osteogenesis. Electrospraying technique was used to develop PCL, PCL/SF, PCL/SF/HA and PCL/SF/HA/MH hybrid biocomposite nanoparticles and characterization was analyzed by field emission scanning electron microscope (FESEM), contact angle and Fourier transform infrared spectroscopy (FT-IR). The obtained results proved that the particle diameter and water contact angle obtained around 0.54 +/ 0.12 to 3.2 +/- 0.18 um and 43.93 +/- 10.8 degrees to 133.1 +/- 12.4 degrees respectively. The cell proliferation and cell-nanoparticle interactions analyzed using (3-(4,5-dimethyl thiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) 2H-tetrazolium inner salt) MTS assay (Promega, Madison, WI, USA), FESEM for cell morphology and 5-Chloromethylfluorescein diacetate (CMFDA) dye for imaging live cells. Osteogenic differentiation was proved by expression of osteocalcin, alkaline phosphatase activity (ALP) and mineralization was confirmed by using alizarin red (ARS). The quantity of cells was considerably increased in PCL/SF/HA/MH nanoparticles when compare to all other biocomposite nanoparticles and the cell interaction was observed more on PCL/SF/HA/MH nanoparticles. The electrosprayed PCL/SF/HA/MH biocomposite nanoparticle significantly initiated increased cell proliferation, osteogenic differentiation and mineralization, which provide huge potential for bone tissue engineering. PMID- 27483241 TI - A Female-Biased Odorant Receptor from Apolygus lucorum (Meyer-Dur) Tuned to Some Plant Odors. AB - Apolygus lucorum (Meyer-Dur) (Hemiptera: Miridae) is a serious pest of cotton, jujube, grape and many other crops around the world. Understanding how olfactory information directs this insect to its host plants may provide environment friendly approaches to the control of its population in agriculture. In our study, we cloned an odorant receptor gene, AlucOR46, that was specifically expressed in antennae and female-biased. Functional expression of AlucOR46 in Xenopus oocytes showed that it is tuned to six plant volatiles (S)-(-)-Limonene, (R)-(+)-Limonene, (E)-2-Hexenal, (E)-3-Hexenol, 1-Heptanol and (1R)-(-)-Myrtenol. Electroantennogram (EAG) recordings revealed that all six compounds could elicit electrophysiological responses from the antennae of A. lucorum, higher in females. Our results are in agreement with previous reports showing that (E)-2 Hexenal could attract female A. lucorum in behavior experiments. These results suggest that AlucOR46 might play an important role in locating the host plants of A. lucorum and therefore represents a suitable target for green pest control. PMID- 27483242 TI - Theoretical and Kinetic Tools for Selecting Effective Antioxidants: Application to the Protection of Omega-3 Oils with Natural and Synthetic Phenols. AB - Radical-scavenging antioxidants play crucial roles in the protection of unsaturated oils against autoxidation and, especially, edible oils rich in omega 3 because of their high sensitivity to oxygen. Two complementary tools are employed to select, among a large set of natural and synthetic phenols, the most promising antioxidants. On the one hand, density functional theory (DFT) calculations provide bond dissociation enthalpies (BDEs) of 70 natural (i.e., tocopherols, hydroxybenzoic and cinnamic acids, flavonoids, stilbenes, lignans, and coumarins) and synthetic (i.e., 2,6-di-tert-butyl-4-methylphenol (BHT), 3 tert-butyl-4-hydroxyanisol (BHA), and tert-butylhydroquinone (TBHQ)) phenols. These BDEs are discussed on the basis of structure-activity relationships with regard to their potential antioxidant activities. On the other hand, the kinetic rate constants and number of hydrogen atoms released per phenol molecule are measured by monitoring the reaction of phenols with 2,2-diphenyl-1-picrylhydrazyl (DPPH(*)) radical. The comparison of the results obtained with these two complementary methods allows highlighting the most promising antioxidants. Finally, the antioxidant effectiveness of the best candidates is assessed by following the absorption of oxygen by methyl esters of linseed oil containing 0.5 mmol L(-1) of antioxidant and warmed at 90 degrees C under oxygen atmosphere. Under these conditions, some natural phenols namely epigallocatechin gallate, myricetin, rosmarinic and carnosic acids were found to be more effective antioxidants than alpha-tocopherol. PMID- 27483243 TI - Synthesis, Crystal Study, and Anti-Proliferative Activity of Some 2 Benzimidazolylthioacetophenones towards Triple-Negative Breast Cancer MDA-MB-468 Cells as Apoptosis-Inducing Agents. AB - On account of its poor prognosis and deficiency of therapeutic stratifications, triple negative breast cancer continues to form the causative platform of an incommensurate number of breast cancer deaths. Aiming at the development of potent anticancer agents as a continuum of our previous efforts, a novel series of 2-((benzimidazol-2-yl)thio)-1-arylethan-1-ones 5a-w was synthesized and evaluated for its anti-proliferative activity towards triple negative breast cancer (TNBC) MDA-MB-468 cells. Compound 5k was the most active analog against MDA-MB-468 (IC50 = 19.90 +/- 1.37 uM), with 2.1-fold increased activity compared to 5-fluorouracil (IC50 = 41.26 +/- 3.77 uM). Compound 5k was able to induce apoptosis in MDA-MB-468, as evidenced by the marked boosting in the percentage of florecsein isothiocyanate annexin V (Annexin V-FITC)-positive apoptotic cells (upper right (UR) + lower right (LR)) by 2.8-fold in comparison to control accompanied by significant increase in the proportion of cells at pre-G1 (the first gap phase) by 8.13-fold in the cell-cycle analysis. Moreover, a quantitative structure activity relationship (QSAR) model was established to investigate the structural requirements orchestrating the anti-proliferative activity. Finally, we established a theoretical kinetic study. PMID- 27483245 TI - Incretin-Based Therapies for Diabetic Complications: Basic Mechanisms and Clinical Evidence. AB - An increase in the rates of morbidity and mortality associated with diabetic complications is a global concern. Glycemic control is important to prevent the development and progression of diabetic complications. Various classes of anti diabetic agents are currently available, and their pleiotropic effects on diabetic complications have been investigated. Incretin-based therapies such as dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are now widely used in the treatment of patients with type 2 diabetes. A series of experimental studies showed that incretin-based therapies have beneficial effects on diabetic complications, independent of their glucose lowering abilities, which are mediated by anti-inflammatory and anti-oxidative stress properties. Based on these findings, clinical studies to assess the effects of DPP-4 inhibitors and GLP-1RA on diabetic microvascular and macrovascular complications have been performed. Several but not all studies have provided evidence to support the beneficial effects of incretin-based therapies on diabetic complications in patients with type 2 diabetes. We herein discuss the experimental and clinical evidence of incretin-based therapy for diabetic complications. PMID- 27483244 TI - Effects of Secondary Plant Metabolites on Microbial Populations: Changes in Community Structure and Metabolic Activity in Contaminated Environments. AB - Secondary plant metabolites (SPMEs) play an important role in plant survival in the environment and serve to establish ecological relationships between plants and other organisms. Communication between plants and microorganisms via SPMEs contained in root exudates or derived from litter decomposition is an example of this phenomenon. In this review, the general aspects of rhizodeposition together with the significance of terpenes and phenolic compounds are discussed in detail. We focus specifically on the effect of SPMEs on microbial community structure and metabolic activity in environments contaminated by polychlorinated biphenyls (PCBs) and polyaromatic hydrocarbons (PAHs). Furthermore, a section is devoted to a complex effect of plants and/or their metabolites contained in litter on bioremediation of contaminated sites. New insights are introduced from a study evaluating the effects of SPMEs derived during decomposition of grapefruit peel, lemon peel, and pears on bacterial communities and their ability to degrade PCBs in a long-term contaminated soil. The presented review supports the "secondary compound hypothesis" and demonstrates the potential of SPMEs for increasing the effectiveness of bioremediation processes. PMID- 27483246 TI - The Metabolic Role of Gut Microbiota in the Development of Nonalcoholic Fatty Liver Disease and Cardiovascular Disease. AB - The prevalence of metabolic disorders, such as type 2 diabetes (T2D), obesity, and non-alcoholic fatty liver disease (NAFLD), which are common risk factors for cardiovascular disease (CVD), has dramatically increased worldwide over the last decades. Although dietary habit is the main etiologic factor, there is an imperfect correlation between dietary habits and the development of metabolic disease. Recently, research has focused on the role of the microbiome in the development of these disorders. Indeed, gut microbiota is implicated in many metabolic functions and an altered gut microbiota is reported in metabolic disorders. Here we provide evidence linking gut microbiota and metabolic diseases, focusing on the pathogenetic mechanisms underlying this association. PMID- 27483247 TI - Genetic Mapping of a Major Resistance Gene to Pea Aphid (Acyrthosipon pisum) in the Model Legume Medicago truncatula. AB - Resistance to the Australian pea aphid (PA; Acyrthosiphon pisum) biotype in cultivar Jester of the model legume Medicago truncatula is mediated by a single dominant gene and is phloem-mediated. The genetic map position for this resistance gene, APR (Acyrthosiphon pisum resistance), is provided and shows that APR maps 39 centiMorgans (cM) distal of the A. kondoi resistance (AKR) locus, which mediates resistance to a closely related species of the same genus bluegreen aphid (A. kondoi). The APR region on chromosome 3 is dense in classical nucleotide binding site leucine-rich repeats (NLRs) and overlaps with the region harbouring the RAP1 gene which confers resistance to a European PA biotype in the accession Jemalong A17. Further screening of a core collection of M. truncatula accessions identified seven lines with strong resistance to PA. Allelism experiments showed that the single dominant resistance to PA in M. truncatula accessions SA10481 and SA1516 are allelic to SA10733, the donor of the APR locus in cultivar Jester. While it remains unclear whether there are multiple PA resistance genes in an R-gene cluster or the resistance loci identified in the other M. truncatula accessions are allelic to APR, the introgression of APR into current M. truncatula cultivars will provide more durable resistance to PA. PMID- 27483248 TI - Association between IRS1 Gene Polymorphism and Autism Spectrum Disorder: A Pilot Case-Control Study in Korean Males. AB - The insulin-like growth factor (IGF) pathway is thought to play an important role in brain development. Altered levels of IGFs and their signaling regulators have been shown in autism spectrum disorder (ASD) patients. In this study, we investigated whether coding region single-nucleotide polymorphisms (cSNPs) of the insulin receptor substrates (IRS1 and IRS2), key mediators of the IGF pathway, were associated with ASD in Korean males. Two cSNPs (rs1801123 of IRS1, and rs4773092 of IRS2) were genotyped using direct sequencing in 180 male ASD patients and 147 male control subjects. A significant association between rs1801123 of IRS1 and ASD was shown in additive (p = 0.022, odds ratio (OR) = 0.66, 95% confidence interval (CI) = 0.46-0.95) and dominant models (p = 0.013, OR = 0.57, 95% CI = 0.37-0.89). Allele frequency analysis also showed an association between rs1801123 and ASD (p = 0.022, OR = 0.66, 95% CI = 0.46-0.94). These results suggest that IRS1 may contribute to the susceptibility of ASD in Korean males. PMID- 27483249 TI - Peroxisome Proliferator-Activated Receptor gamma Expression Is Inversely Associated with Macroscopic Vascular Invasion in Human Hepatocellular Carcinoma. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated nuclear receptor that regulates cellular lipid and glucose metabolism and also plays an inhibitory role in various cancers. However, the role of PPARgamma in hepatocellular carcinoma (HCC) remains controversial. This study aimed to investigate the prognostic value of PPARgamma in HCC and its role in inhibiting tumor progression, namely, HCC cell growth, migration, and angiogenesis. Immunohistochemical PPARgamma staining was examined in 83 HCC specimens to investigate the clinicopathological correlations between PPARgamma expression and various parameters. The functional role of PPARgamma was determined via PPARgamma overexpression and knockdown in HCC cells. Patients with low HCC tissue PPARgamma expression were significantly younger (p = 0.006), and exhibited more tumor numbers (p = 0.038), more macroscopic vascular invasion (MVI) (p = 0.008), and more advanced TNM (size of primary tumor, number of regional lymph nodes, and distant metastasis) stages at diagnosis (p = 0.013) than patients with high HCC tissue PPARgamma expression. PPARgamma knockdown increased HCC cell growth, migration, and angiogenesis, while PPARgamma overexpression reduced HCC cell growth, migration, and angiogenesis. These results suggest that low PPARgamma expression is an independent predictor of more MVI in HCC patients. PPARgamma contributes to the suppression of HCC cell growth, migration, and angiogenesis. Therefore, PPARgamma may be a therapeutic target in HCC patients. PMID- 27483250 TI - Is Upregulation of Aquaporin 4-M1 Isoform Responsible for the Loss of Typical Orthogonal Arrays of Particles in Astrocytomas? AB - The astrocytic endfoot membranes of the healthy blood-brain barrier-contacting the capillary-are covered with a large number of the water channel aquaporin 4 (AQP4). They form orthogonal arrays of particles (OAPs), which consist of AQP4 isoform M1 and M23. Under pathologic conditions, AQP4 is distributed over the whole cell and no or only small OAPs are found. From cell culture experiments, it is known that cells transfected only with AQP4-M1 do not form OAPs or only small ones. We hypothesized that in astrocytomas the situation may be comparable to the in vitro experiments expecting an upregulation of AQP4-M1. Quantitative Real-time PCR (qRT-PCR) of different graded astrocytomas revealed an upregulation of both isoforms AQP4 M1 and M23 in all astrocytomas investigated. In freeze fracture replicas of low-grade malignancy astrocytomas, more OAPs than in high-grade malignancy astrocytomas were found. In vitro, cultured glioma cells did not express AQP4, whereas healthy astrocytes revealed a slight upregulation of both isoforms and only a few OAPs in freeze fracture analysis. Taken together, we found a correlation between the decrease of OAPs and increasing grade of malignancy of astrocytomas but this was not consistent with an upregulation of AQP4-M1 in relation to AQP4 M23. PMID- 27483252 TI - Correction: Yan Chen, et al. Dual Agent Loaded PLGA Nanoparticles Enhanced Antitumor Activity in a Multidrug-Resistant Breast Tumor Eenograft Model. Int. J. Mol. Sci. 2014, 15, 2761-2772. AB - Theauthorswishtomakeachangetotheirpublishedpaper[1].[...]. PMID- 27483251 TI - The Interactions of Aquaporins and Mineral Nutrients in Higher Plants. AB - Aquaporins, major intrinsic proteins (MIPs) present in the plasma and intracellular membranes, facilitate the transport of small neutral molecules across cell membranes in higher plants. Recently, progress has been made in understanding the mechanisms of aquaporin subcellular localization, transport selectivity, and gating properties. Although the role of aquaporins in maintaining the plant water status has been addressed, the interactions between plant aquaporins and mineral nutrients remain largely unknown. This review highlights the roles of various aquaporin orthologues in mineral nutrient uptake and transport, as well as the regulatory effects of mineral nutrients on aquaporin expression and activity, and an integrated link between aquaporins and mineral nutrient metabolism was identified. PMID- 27483253 TI - Biological Effect of a Hybrid Anticancer Agent Based on Kinase and Histone Deacetylase Inhibitors on Triple-Negative (MDA-MB231) Breast Cancer Cells. AB - We examined the effects of the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) combined with the vascular endothelial growth factor receptor-1/2 inhibitor (3Z)-5-hydroxy-3-(1H-pyrrol-2-ylmethylidene) 2,3-dihydro-1H-indol-2-one on MDA-MB-231 breast cancer cells (triple-negative) in the form of both a cocktail of the separate compounds and a chemically synthesized hybrid (N-hydroxy-N'-[(3Z)-2-oxo-3-(1H-pyrrol-2-ylmethylidene)-2,3 dihydro-1H-indol-5-yl]octanediamide). Comparative flow cytometric and Western blot analyses were performed on cocktail- and hybrid-treated cells to evaluate cell cycle distribution, autophagy/apoptosis modulation, and mitochondrial metabolic state in order to understand the cellular basis of the cytotoxic effect. Cell cycle analysis showed a perturbation of the rate of progression through the cycle, with aspects of redistribution of cells over different cycle phases for the two treatments. In addition, the results suggest that the two distinct classes of compounds under investigation could induce cell death by different preferential pathways, i.e., autophagy inhibition (the cocktail) or apoptosis promotion (the hybrid), thus confirming the enhanced potential of the hybrid approach vs. the combination approach in finely tuning the biological activities of target cells and also showing the hybrid compound as an additional promising drug-like molecule for the prevention or therapy of "aggressive" breast carcinoma. PMID- 27483254 TI - Urinary Dopamine as a Potential Index of the Transport Activity of Multidrug and Toxin Extrusion in the Kidney. AB - Dopamine is a cationic natriuretic catecholamine synthesized in proximal tubular cells (PTCs) of the kidney before secretion into the lumen, a key site of its action. However, the molecular mechanisms underlying dopamine secretion into the lumen remain unclear. Multidrug and toxin extrusion (MATE) is a H+/organic cation antiporter that is highly expressed in the brush border membrane of PTCs and mediates the efflux of organic cations, including metformin and cisplatin, from the epithelial cells into the urine. Therefore, we hypothesized that MATE mediates dopamine secretion, a cationic catecholamine, into the tubule lumen, thereby regulating natriuresis. Here, we show that [3H]dopamine uptake in human (h) MATE1-, hMATE-2K- and mouse (m) MATE-expressing cells exhibited saturable kinetics. Fluid retention and decreased urinary excretion of dopamine and Na+ were observed in Mate1-knockout mice compared to that in wild-type mice. Imatinib, a MATE inhibitor, inhibited [3H]dopamine uptake by hMATE1-, hMATE2-K- and mMATE1-expressing cells in a concentration-dependent manner. At clinically relevant concentrations, imatinib inhibited [3H]dopamine uptake by hMATE1- and hMATE2-K-expressing cells. The urinary excretion of dopamine and Na+ decreased and fluid retention occurred in imatinib-treated mice. In conclusion, MATE transporters secrete renally-synthesized dopamine, and therefore, urinary dopamine has the potential to be an index of the MATE transporter activity. PMID- 27483255 TI - Navicula sp. Sulfated Polysaccharide Gels Induced by Fe(III): Rheology and Microstructure. AB - A sulfated polysaccharide extracted from Navicula sp. presented a yield of 4.4 (% w/w dry biomass basis). Analysis of the polysaccharide using gas chromatography showed that this polysaccharide contained glucose (29%), galactose (21%), rhamnose (10%), xylose (5%) and mannose (4%). This polysaccharide presented an average molecular weight of 107 kDa. Scanning electron microscopy (SEM) micrographs showed that the lyophilized Navicula sp. polysaccharide is an amorphous solid with particles of irregular shapes and sharp angles. The polysaccharide at 1% (w/v) solution in water formed gels in the presence of 0.4% (w/v) FeCl3, showing elastic and viscous moduli of 1 and 0.7 Pa, respectively. SEM analysis performed on the lyophilized gel showed a compact pore structure, with a pore size of approximately 150 nm. Very few studies on the gelation of sulfated polysaccharides using trivalent ions exist in the literature, and, to the best of our knowledge, this study is the first to describe the gelation of sulfated polysaccharides extracted from Navicula sp. PMID- 27483256 TI - VEGF and FGF2 Improve Revascularization, Survival, and Oocyte Quality of Cryopreserved, Subcutaneously-Transplanted Mouse Ovarian Tissues. AB - This study was conducted to investigate the effect of the vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2) on revascularization, survival, and oocyte quality of cryopreserved, subcutaneously-transplanted mouse ovarian tissue. Autologous subcutaneous transplantation of vitrified-thawed mouse ovarian tissues treated with (experimental group) or without (control group) VEGF and FGF2 was performed. After transplantation to the inguinal region for two or three weeks, graft survival, angiogenesis, follicle development, and oocyte quality were examined after gonadotropin administration. VEGF coupled with FGF2 (VEGF/FGF2) promoted revascularization and significantly increased the survival rate of subcutaneously-transplanted cryopreserved ovarian tissues compared with untreated controls. The two growth factors did not show long-term effects on the ovarian grafts. In contrast to the untreated ovarian grafts, active folliculogenesis was revealed as the number of follicles at various stages and of mature oocytes in antral follicles after gonadotropin administration were remarkably higher in the VEGF/FGF2-treated groups. Although the fertilization rate was similar between the VEGF/FGF2 and control groups, the oocyte quality was much better in the VEGF/FGF2-treated grafts as demonstrated by the higher ratio of blastocyst development. Introducing angiogenic factors, such as VEGF and FGF2, may be a promising strategy to improve revascularization, survival, and oocyte quality of cryopreserved, subcutaneously-transplanted mouse ovarian tissue. PMID- 27483257 TI - SMA Human iPSC-Derived Motor Neurons Show Perturbed Differentiation and Reduced miR-335-5p Expression. AB - Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival Motor Neuron 1 gene, resulting in very low levels of functional Survival of Motor Neuron (SMN) protein. SMA human induced Pluripotent Stem Cells (hiPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. MicroRNAs (miRNAs) are often reported as playing a key role in regulating neuronal differentiation and fate specification. In this study SMA hiPSCs have been differentiated towards early motor neurons and their molecular and immunocytochemical profile were compared to those of wild type cells. Cell cycle proliferation was also evaluated by fluorescence-activated cell sorting (FACS). SMA hiPSCs showed an increased proliferation rate and also higher levels of stem cell markers. Moreover; when differentiated towards early motor neurons they expressed lower levels of NCAM and MN specific markers. The expression of miR-335-5p; already identified to control self-renewal or differentiation of mouse embryonic stem cells (mESCs); resulted to be reduced during the early steps of differentiation of SMA hiPSCs compared to wild type cells. These results suggest that we should speculate a role of this miRNA both in stemness characteristic and in differentiation efficiency of these cells. PMID- 27483260 TI - A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort. AB - Sequencing of sarcomere protein genes in patients fulfilling the clinical diagnostic criteria for hypertrophic cardiomyopathy (HCM) identifies a disease causing mutation in 35% to 60% of cases. Age at diagnosis and family history may increase the yield of mutations screening. In order to assess whether Next Generation Sequencing (NGS) may fulfil the molecular diagnostic needs in HCM, we included 17 HCM-related genes in a sequencing panel run on PGM IonTorrent. We selected 70 HCM patients, 35 with early (<=25 years) and 35 with late (>=65 years) diagnosis of disease onset. All samples had a 98.6% average of target regions, with coverage higher than 20* (mean coverage 620*). We identified 41 different mutations (seven of them novel) in nine genes: MYBPC3 (17/41 = 41%); MYH7 (10/41 = 24%); TNNT2, CAV3 and MYH6 (3/41 = 7.5% each); TNNI3 (2/41 = 5%); GLA, MYL2, and MYL3 (1/41=2.5% each). Mutation detection rate was 30/35 (85.7%) in early-onset and 8/35 (22.9%) in late-onset HCM patients, respectively (p < 0.0001). The overall detection rate for patients with positive family history was 84%, and 90.5% in patients with early disease onset. In our study NGS revealed higher mutations yield in patients with early onset and with a family history of HCM. Appropriate patient selection can increase the yield of genetic testing and make diagnostic testing cost-effective. PMID- 27483259 TI - Is the Mouse a Good Model of Human PPARgamma-Related Metabolic Diseases? AB - With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models-mainly mouse models-have been generated to investigate the role of PPARgamma in different tissues. This review focuses on the metabolic features of human and mouse PPARgamma-related diseases and the utility of the mouse as a model. PMID- 27483261 TI - Time-Varying Vocal Folds Vibration Detection Using a 24 GHz Portable Auditory Radar. AB - Time-varying vocal folds vibration information is of crucial importance in speech processing, and the traditional devices to acquire speech signals are easily smeared by the high background noise and voice interference. In this paper, we present a non-acoustic way to capture the human vocal folds vibration using a 24 GHz portable auditory radar. Since the vocal folds vibration only reaches several millimeters, the high operating frequency and the 4 * 4 array antennas are applied to achieve the high sensitivity. The Variational Mode Decomposition (VMD) based algorithm is proposed to decompose the radar-detected auditory signal into a sequence of intrinsic modes firstly, and then, extract the time-varying vocal folds vibration frequency from the corresponding mode. Feasibility demonstration, evaluation, and comparison are conducted with tonal and non-tonal languages, and the low relative errors show a high consistency between the radar-detected auditory time-varying vocal folds vibration and acoustic fundamental frequency, except that the auditory radar significantly improves the frequency-resolving power. PMID- 27483258 TI - Molecular Mechanisms of Cutaneous Inflammatory Disorder: Atopic Dermatitis. AB - Atopic dermatitis (AD) is a multifactorial inflammatory skin disease resulting from interactions between genetic susceptibility and environmental factors. The pathogenesis of AD is poorly understood, and the treatment of recalcitrant AD is still challenging. There is accumulating evidence for new gene polymorphisms related to the epidermal barrier function and innate and adaptive immunity in patients with AD. Newly-found T cells and dendritic cell subsets, cytokines, chemokines and signaling pathways have extended our understanding of the molecular pathomechanism underlying AD. Genetic changes caused by environmental factors have been shown to contribute to the pathogenesis of AD. We herein present a review of the genetics, epigenetics, barrier dysfunction and immunological abnormalities in AD with a focus on updated molecular biology. PMID- 27483262 TI - Three-Dimensional Photon Counting Imaging with Axially Distributed Sensing. AB - In this paper, we review three-dimensional (3D) photon counting imaging with axially distributed sensing. Under severely photon-starved conditions, we have proposed various imaging and algorithmic approaches to reconstruct a scene in 3D, which are not possible by using conventional imaging system due to lack of sufficient number of photons. In this paper, we present an overview of optical sensing and imaging system along with dedicated algorithms for reconstructing 3D scenes by photon counting axially distributed sensing, which may be implemented by moving a single image sensor along its optical axis. To visualize the 3D image, statistical estimation methods and computational reconstruction of axially distributed sensing is applied. PMID- 27483263 TI - Monolithic Cylindrical Fused Silica Resonators with High Q Factors. AB - The cylindrical resonator gyroscope (CRG) is a typical Coriolis vibratory gyroscope whose performance is determined by the Q factor and frequency mismatch of the cylindrical resonator. Enhancing the Q factor is crucial for improving the rate sensitivity and noise performance of the CRG. In this paper, for the first time, a monolithic cylindrical fused silica resonator with a Q factor approaching 8 * 105 (ring-down time over 1 min) is reported. The resonator is made of fused silica with low internal friction and high isotropy, with a diameter of 25 mm and a center frequency of 3974.35 Hz. The structure of the resonator is first briefly introduced, and then the experimental non-contact characterization method is presented. In addition, the post-fabrication experimental procedure of Q factor improvement, including chemical and thermal treatment, is demonstrated. The Q factor improvement by both treatments is compared and the primary loss mechanism is analyzed. To the best of our knowledge, the work presented in this paper represents the highest reported Q factor for a cylindrical resonator. The proposed monolithic cylindrical fused silica resonator may enable high performance inertial sensing with standard manufacturing process and simple post fabrication treatment. PMID- 27483264 TI - Object Detection Applied to Indoor Environments for Mobile Robot Navigation. AB - To move around the environment, human beings depend on sight more than their other senses, because it provides information about the size, shape, color and position of an object. The increasing interest in building autonomous mobile systems makes the detection and recognition of objects in indoor environments a very important and challenging task. In this work, a vision system to detect objects considering usual human environments, able to work on a real mobile robot, is developed. In the proposed system, the classification method used is Support Vector Machine (SVM) and as input to this system, RGB and depth images are used. Different segmentation techniques have been applied to each kind of object. Similarly, two alternatives to extract features of the objects are explored, based on geometric shape descriptors and bag of words. The experimental results have demonstrated the usefulness of the system for the detection and location of the objects in indoor environments. Furthermore, through the comparison of two proposed methods for extracting features, it has been determined which alternative offers better performance. The final results have been obtained taking into account the proposed problem and that the environment has not been changed, that is to say, the environment has not been altered to perform the tests. PMID- 27483265 TI - Fast Object Motion Estimation Based on Dynamic Stixels. AB - The stixel world is a simplification of the world in which obstacles are represented as vertical instances, called stixels, standing on a surface assumed to be planar. In this paper, previous approaches for stixel tracking are extended using a two-level scheme. In the first level, stixels are tracked by matching them between frames using a bipartite graph in which edges represent a matching cost function. Then, stixels are clustered into sets representing objects in the environment. These objects are matched based on the number of stixels paired inside them. Furthermore, a faster, but less accurate approach is proposed in which only the second level is used. Several configurations of our method are compared to an existing state-of-the-art approach to show how our methodology outperforms it in several areas, including an improvement in the quality of the depth reconstruction. PMID- 27483266 TI - Practical Application of Electrochemical Nitrate Sensor under Laboratory and Forest Nursery Conditions. AB - The reduction of nitrate leaching to ensure greater protection of groundwater quality has become a global issue. The development of new technologies for more accurate dosing of nitrates helps optimize fertilization programs. This paper presents the practical application of a newly developed electrochemical sensor designed for in situ quantification of nitrate. To our knowledge, this paper is the first to report the use of electrochemical impedance to determine nitrate concentrations in growing media under forest nursery conditions. Using impedance measurements, the sensor has been tested in laboratory and compared to colorimetric measurements of the nitrate. The developed sensor has been used in water-saturated growing medium and showed good correlation to certified methods, even in samples obtained over a multi-ion fertilisation season. A linear and significant relationship was observed between the resistance and the concentration of nitrates (R2 = 0.972), for a range of concentrations of nitrates. We also observed stability of the sensor after exposure of one month to the real environmental conditions of the forest nursery. PMID- 27483267 TI - A Robust Distributed Multipoint Fiber Optic Gas Sensor System Based on AGC Amplifier Structure. AB - A harsh environment-oriented distributed multipoint fiber optic gas sensor system realized by automatic gain control (AGC) technology is proposed. To improve the photoelectric signal reliability, the electronic variable gain can be modified in real time by an AGC closed-loop feedback structure to compensate for optical transmission loss which is caused by the fiber bend loss or other reasons. The deviation of the system based on AGC structure is below 4.02% when photoelectric signal decays due to fiber bending loss for bending radius of 5 mm, which is 20 times lower than the ordinary differential system. In addition, the AGC circuit with the same electric parameters can keep the baseline intensity of signals in different channels of the distributed multipoint sensor system at the same level. This avoids repetitive calibrations and streamlines the installation process. PMID- 27483268 TI - Micromechanical Characterization of Polysilicon Films through On-Chip Tests. AB - When the dimensions of polycrystalline structures become comparable to the average grain size, some reliability issues can be reported for the moving parts of inertial microelectromechanical systems (MEMS). Not only the overall behavior of the device turns out to be affected by a large scattering, but also the sensitivity to imperfections gets enhanced. In this work, through on-chip tests, we experimentally investigate the behavior of thin polysilicon samples using standard electrostatic actuation/sensing. The discrepancy between the target and actual responses of each sample has then been exploited to identify: (i) the overall stiffness of the film and, according to standard continuum elasticity, a morphology-based value of its Young's modulus; (ii) the relevant over-etch induced by the fabrication process. To properly account for the aforementioned stochastic features at the micro-scale, the identification procedure has been based on particle filtering. A simple analytical reduced-order model of the moving structure has been also developed to account for the nonlinearities in the electrical field, up to pull-in. Results are reported for a set of ten film samples of constant slenderness, and the effects of different actuation mechanisms on the identified micromechanical features are thoroughly discussed. PMID- 27483269 TI - Safety and Traceability in Patient Healthcare through the Integration of RFID Technology for Intravenous Mixtures in the Prescription-Validation-Elaboration Dispensation-Administration Circuit to Day Hospital Patients. AB - This work presents the integration of the RFID technology with the aim of ensuring the traceability of patients and minimization of adverse events during the process of prescription-validation-elaboration-dispensation-administration of medication by means of the implementation of various passive and active WIFI RFID systems in the Pharmacy and Day Hospital services of the Complejo Hospitalario Universitario A Coruna. Obtaining patient traceability and using the patient/drug binomial during this process allows us to minimize the occurrence of adverse events. The key points in this work are the unmistakably unique identification and accurate real time location of the controlled items (patients and medication). RFID technology has proved to be invaluable in assisting with the everyday clinical practice of a hospital, and has been successfully implemented in this environment and others. In services such as the day hospital, the implementation of said technology is further justified by the high costs of the service and the high risk to the patient. PMID- 27483270 TI - A Long-Term Performance Enhancement Method for FOG-Based Measurement While Drilling. AB - In the oil industry, the measurement-while-drilling (MWD) systems are usually used to provide the real-time position and orientation of the bottom hole assembly (BHA) during drilling. However, the present MWD systems based on magnetic surveying technology can barely ensure good performance because of magnetic interference phenomena. In this paper, a MWD surveying system based on a fiber optic gyroscope (FOG) was developed to replace the magnetic surveying system. To accommodate the size of the downhole drilling conditions, a new design method is adopted. In order to realize long-term and high position precision and orientation surveying, an integrated surveying algorithm is proposed based on inertial navigation system (INS) and drilling features. In addition, the FOG based MWD error model is built and the drilling features are analyzed. The state space system model and the observation updates model of the Kalman filter are built. To validate the availability and utility of the algorithm, the semi physical simulation is conducted under laboratory conditions. The results comparison with the traditional algorithms show that the errors were suppressed and the measurement precision of the proposed algorithm is better than the traditional ones. In addition, the proposed method uses a lot less time than the zero velocity update (ZUPT) method. PMID- 27483271 TI - Fiber-Optic Surface Temperature Sensor Based on Modal Interference. AB - Spatially-integrated surface temperature sensing is highly useful when it comes to controlling processes, detecting hazardous conditions or monitoring the health and safety of equipment and people. Fiber-optic sensing based on modal interference has shown great sensitivity to temperature variation, by means of cost-effective image-processing of few-mode interference patterns. New developments in the field of sensor configuration, as described in this paper, include an innovative cooling and heating phase discrimination functionality and more precise measurements, based entirely on the image processing of interference patterns. The proposed technique was applied to the measurement of the integrated surface temperature of a hollow cylinder and compared with a conventional measurement system, consisting of an infrared camera and precision temperature probe. As a result, the optical technique is in line with the reference system. Compared with conventional surface temperature probes, the optical technique has the following advantages: low heat capacity temperature measurement errors, easier spatial deployment, and replacement of multiple angle infrared camera shooting and the continuous monitoring of surfaces that are not visually accessible. PMID- 27483272 TI - Eigenspace-Based Generalized Sidelobe Canceler Beamforming Applied to Medical Ultrasound Imaging. AB - The use of a generalized sidelobe canceler (GSC) can significantly improve the lateral resolution of medical ultrasound systems, but the contrast improvement isn't satisfactory. Thus a new Eigenspace-based generalized sidelobe canceler (EBGSC) approach is proposed for medical ultrasound imaging, which can improve both the lateral resolution and contrast of the system. The weight vector of the EBGSC is obtained by projecting the GSC weight vector onto a vector subspace constructed from the eigenstructure of the covariance matrix, and using the new weight vector instead of the GSC ones leads to reduced sidelobe level and improved contrast. Simulated and experimental data are used to evaluate the performance of the proposed method. The Field II software is applied to obtain the simulated echo data of scattering points and circular cysts. Imaging of scattering points show that EBGSC has the same full width at half maximum (FWHM) as GSC, while the lateral resolution improves by 35.3% and 52.7% compared with synthetic aperture (SA) and delay-and-sum (DS), respectively. Compared with GSC, SA and DS, EBGSC improves the peak sidelobe level (PSL) by 23.55, 33.11 and 50.38 dB, respectively. Also the cyst contrast increase by EBGSC was calculated as 16.77, 12.43 and 26.73 dB, when compared with GSC, SA and DS, respectively. Finally, an experiment is conducted on the basis of the complete echo data collected by a medical ultrasonic imaging system. Results show that the proposed method can produce better lateral resolution and contrast than non-adaptive beamformers. PMID- 27483273 TI - Exact Distributions of Finite Random Matrices and Their Applications to Spectrum Sensing. AB - The exact and simple distributions of finite random matrix theory (FRMT) are critically important for cognitive radio networks (CRNs). In this paper, we unify some existing distributions of the FRMT with the proposed coefficient matrices (vectors) and represent the distributions with the coefficient-based formulations. A coefficient reuse mechanism is studied, i.e., the same coefficient matrices (vectors) can be exploited to formulate different distributions. For instance, the same coefficient matrices can be used by the largest eigenvalue (LE) and the scaled largest eigenvalue (SLE); the same coefficient vectors can be used by the smallest eigenvalue (SE) and the Demmel condition number (DCN). A new and simple cumulative distribution function (CDF) of the DCN is also deduced. In particular, the dimension boundary between the infinite random matrix theory (IRMT) and the FRMT is initially defined. The dimension boundary provides a theoretical way to divide random matrices into infinite random matrices and finite random matrices. The FRMT-based spectrum sensing (SS) schemes are studied for CRNs. The SLE-based scheme can be considered as an asymptotically-optimal SS scheme when the dimension K is larger than two. Moreover, the standard condition number (SCN)-based scheme achieves the same sensing performance as the SLE-based scheme for dual covariance matrix K = 2 . The simulation results verify that the coefficient-based distributions can fit the empirical results very well, and the FRMT-based schemes outperform the IRMT based schemes and the conventional SS schemes. PMID- 27483274 TI - Applying High-Speed Vision Sensing to an Industrial Robot for High-Performance Position Regulation under Uncertainties. AB - It is traditionally difficult to implement fast and accurate position regulation on an industrial robot in the presence of uncertainties. The uncertain factors can be attributed either to the industrial robot itself (e.g., a mismatch of dynamics, mechanical defects such as backlash, etc.) or to the external environment (e.g., calibration errors, misalignment or perturbations of a workpiece, etc.). This paper proposes a systematic approach to implement high performance position regulation under uncertainties on a general industrial robot (referred to as the main robot) with minimal or no manual teaching. The method is based on a coarse-to-fine strategy that involves configuring an add-on module for the main robot's end effector. The add-on module consists of a 1000 Hz vision sensor and a high-speed actuator to compensate for accumulated uncertainties. The main robot only focuses on fast and coarse motion, with its trajectories automatically planned by image information from a static low-cost camera. Fast and accurate peg-and-hole alignment in one dimension was implemented as an application scenario by using a commercial parallel-link robot and an add-on compensation module with one degree of freedom (DoF). Experimental results yielded an almost 100% success rate for fast peg-in-hole manipulation (with regulation accuracy at about 0.1 mm) when the workpiece was randomly placed. PMID- 27483275 TI - A Design Method of Code Correlation Reference Waveform in GNSS Based on Least Squares Fitting. AB - The multipath effect is one of the main error sources in the Global Satellite Navigation Systems (GNSSs). The code correlation reference waveform (CCRW) technique is an effective multipath mitigation algorithm for the binary phase shift keying (BPSK) signal. However, it encounters the false lock problem in code tracking, when applied to the binary offset carrier (BOC) signals. A least squares approximation method of the CCRW design scheme is proposed, utilizing the truncated singular value decomposition method. This algorithm was performed for the BPSK signal, BOC(1,1) signal, BOC(2,1) signal, BOC(6,1) and BOC(7,1) signal. The approximation results of CCRWs were presented. Furthermore, the performances of the approximation results are analyzed in terms of the multipath error envelope and the tracking jitter. The results show that the proposed method can realize coherent and non-coherent CCRW discriminators without false lock points. Generally, there is performance degradation in the tracking jitter, if compared to the CCRW discriminator. However, the performance promotions in the multipath error envelope for the BOC(1,1) and BPSK signals makes the discriminator attractive, and it can be applied to high-order BOC signals. PMID- 27483276 TI - Gaussian Process Regression Plus Method for Localization Reliability Improvement. AB - Location data are among the most widely used context data in context-aware and ubiquitous computing applications. Many systems with distinct deployment costs and positioning accuracies have been developed over the past decade for indoor positioning. The most useful method is focused on the received signal strength and provides a set of signal transmission access points. However, compiling a manual measuring Received Signal Strength (RSS) fingerprint database involves high costs and thus is impractical in an online prediction environment. The system used in this study relied on the Gaussian process method, which is a nonparametric model that can be characterized completely by using the mean function and the covariance matrix. In addition, the Naive Bayes method was used to verify and simplify the computation of precise predictions. The authors conducted several experiments on simulated and real environments at Tianjin University. The experiments examined distinct data size, different kernels, and accuracy. The results showed that the proposed method not only can retain positioning accuracy but also can save computation time in location predictions. PMID- 27483277 TI - Integrating a DNA Strand Displacement Reaction with a Whispering Gallery Mode Sensor for Label-Free Mercury (II) Ion Detection. AB - Mercury is an extremely toxic chemical pollutant of our environment. It has attracted the world's attention due to its high mobility and the ease with which it accumulates in organisms. Sensitive devices and methods specific for detecting mercury ions are, hence, in great need. Here, we have integrated a DNA strand displacement reaction with a whispering gallery mode (WGM) sensor for demonstrating the detection of Hg(2+) ions. Our approach relies on the displacement of a DNA hairpin structure, which forms after the binding of mercury ions to an aptamer DNA sequence. The strand displacement reaction of the DNA aptamer provides highly specific and quantitative means for determining the mercury ion concentration on a label-free WGM sensor platform. Our approach also shows the possibility for manipulating the kinetics of a strand displacement reaction with specific ionic species. PMID- 27483278 TI - A Novel Single-Excitation Capacitive Angular Position Sensor Design. AB - This paper presents a high-precision capacitive angular position sensor (CAPS). The CAPS is designed to be excited by a single voltage to eliminate the matching errors of multi-excitations, and it is mainly composed of excitation electrodes, coupling electrodes, petal-form sensitive electrodes and a set of collection electrodes. A sinusoidal voltage is applied on the excitation electrodes, then the voltage couples to the coupling electrodes and sensitive electrodes without contact. The sensitive electrodes together with the set of collection electrodes encode the angular position to amplitude-modulated signals, and in order to increase the scale factor, the sensitive electrodes are patterned in the shape of petal-form sinusoidal circles. By utilizing a resolver demodulation method, the amplitude-modulated signals are digitally decoded to get the angular position. A prototype of the CAPS is fabricated and tested. The measurement results show that the accuracy of the sensor is 0.0036 degrees , the resolution is 0.0009 degrees and the nonlinearity over the full range is 0.008 degrees (after compensation), indicating that the CAPS has great potential to be applied in high-precision applications with a low cost. PMID- 27483279 TI - Design of an HF-Band RFID System with Multiple Readers and Passive Tags for Indoor Mobile Robot Self-Localization. AB - Radio frequency identification (RFID) technology has already been explored for efficient self-localization of indoor mobile robots. A mobile robot equipped with RFID readers detects passive RFID tags installed on the floor in order to locate itself. The Monte-Carlo localization (MCL) method enables the localization of a mobile robot equipped with an RFID system with reasonable accuracy, sufficient robustness and low computational cost. The arrangements of RFID readers and tags and the size of antennas are important design parameters for realizing accurate and robust self-localization using a low-cost RFID system. The design of a likelihood model of RFID tag detection is also crucial for the accurate self localization. This paper presents a novel design and arrangement of RFID readers and tags for indoor mobile robot self-localization. First, by considering small sized and large-sized antennas of an RFID reader, we show how the design of the likelihood model affects the accuracy of self-localization. We also design a novel likelihood model by taking into consideration the characteristics of the communication range of an RFID system with a large antenna. Second, we propose a novel arrangement of RFID tags with eight RFID readers, which results in the RFID system configuration requiring much fewer readers and tags while retaining reasonable accuracy of self-localization. We verify the performances of MCL-based self-localization realized using the high-frequency (HF)-band RFID system with eight RFID readers and a lower density of RFID tags installed on the floor based on MCL in simulated and real environments. The results of simulations and real environment experiments demonstrate that our proposed low-cost HF-band RFID system realizes accurate and robust self-localization of an indoor mobile robot. PMID- 27483280 TI - Development of a Distributed Crack Sensor Using Coaxial Cable. AB - Cracks, the important factor of structure failure, reflect structural damage directly. Thus, it is significant to realize distributed, real-time crack monitoring. To overcome the shortages of traditional crack detectors, such as the inconvenience of installation, vulnerability, and low measurement range, etc., an improved topology-based cable sensor with a shallow helical groove on the outside surface of a coaxial cable is proposed in this paper. The sensing mechanism, fabrication method, and performances are investigated both numerically and experimentally. Crack monitoring experiments of the reinforced beams are also presented in this paper, illustrating the utility of this sensor in practical applications. These studies show that the sensor can identify a minimum crack width of 0.02 mm and can measure multiple cracks with a spatial resolution of 3 mm. In addition, it is also proved that the sensor performs well to detect the initiation and development of cracks until structure failure. PMID- 27483282 TI - Maximum Data Collection Rate Routing Protocol Based on Topology Control for Rechargeable Wireless Sensor Networks. AB - In Rechargeable Wireless Sensor Networks (R-WSNs), in order to achieve the maximum data collection rate it is critical that sensors operate in very low duty cycles because of the sporadic availability of energy. A sensor has to stay in a dormant state in most of the time in order to recharge the battery and use the energy prudently. In addition, a sensor cannot always conserve energy if a network is able to harvest excessive energy from the environment due to its limited storage capacity. Therefore, energy exploitation and energy saving have to be traded off depending on distinct application scenarios. Since higher data collection rate or maximum data collection rate is the ultimate objective for sensor deployment, surplus energy of a node can be utilized for strengthening packet delivery efficiency and improving the data generating rate in R-WSNs. In this work, we propose an algorithm based on data aggregation to compute an upper data generation rate by maximizing it as an optimization problem for a network, which is formulated as a linear programming problem. Subsequently, a dual problem by introducing Lagrange multipliers is constructed, and subgradient algorithms are used to solve it in a distributed manner. At the same time, a topology controlling scheme is adopted for improving the network's performance. Through extensive simulation and experiments, we demonstrate that our algorithm is efficient at maximizing the data collection rate in rechargeable wireless sensor networks. PMID- 27483281 TI - A Portable Real-Time Ringdown Breath Acetone Analyzer: Toward Potential Diabetic Screening and Management. AB - Breath analysis has been considered a suitable tool to evaluate diseases of the respiratory system and those that involve metabolic changes, such as diabetes. Breath acetone has long been known as a biomarker for diabetes. However, the results from published data by far have been inconclusive regarding whether breath acetone is a reliable index of diabetic screening. Large variations exist among the results of different studies because there has been no "best-practice method" for breath-acetone measurements as a result of technical problems of sampling and analysis. In this mini-review, we update the current status of our development of a laser-based breath acetone analyzer toward real-time, one-line diabetic screening and a point-of-care instrument for diabetic management. An integrated standalone breath acetone analyzer based on the cavity ringdown spectroscopy technique has been developed. The instrument was validated by using the certificated gas chromatography-mass spectrometry. The linear fittings suggest that the obtained acetone concentrations via both methods are consistent. Breath samples from each individual subject under various conditions in total, 1257 breath samples were taken from 22 Type 1 diabetic (T1D) patients, 312 Type 2 diabetic (T2D) patients, which is one of the largest numbers of T2D subjects ever used in a single study, and 52 non-diabetic healthy subjects. Simultaneous blood glucose (BG) levels were also tested using a standard diabetic management BG meter. The mean breath acetone concentrations were determined to be 4.9 +/- 16 ppm (22 T1D), and 1.5 +/- 1.3 ppm (312 T2D), which are about 4.5 and 1.4 times of the one in the 42 non-diabetic healthy subjects, 1.1 +/- 0.5 ppm, respectively. A preliminary quantitative correlation (R = 0.56, p < 0.05) between the mean individual breath acetone concentration and the mean individual BG levels does exist in 20 T1D subjects with no ketoacidosis. No direct correlation is observed in T1D subjects, T2D subjects, and healthy subjects. The results from a relatively large number of subjects tested indicate that an elevated mean breath acetone concentration exists in diabetic patients in general. Although many physiological parameters affect breath acetone, under a specifically controlled condition fast (<1 min) and portable breath acetone measurement can be used for screening abnormal metabolic status including diabetes, for point-of-care monitoring status of ketone bodies which have the signature smell of breath acetone, and for breath acetone related clinical studies requiring a large number of tests. PMID- 27483283 TI - Dynamic Calibration and Verification Device of Measurement System for Dynamic Characteristic Coefficients of Sliding Bearing. AB - The identification accuracy of dynamic characteristics coefficients is difficult to guarantee because of the errors of the measurement system itself. A novel dynamic calibration method of measurement system for dynamic characteristics coefficients is proposed in this paper to eliminate the errors of the measurement system itself. Compared with the calibration method of suspension quality, this novel calibration method is different because the verification device is a spring mass system, which can simulate the dynamic characteristics of sliding bearing. The verification device is built, and the calibration experiment is implemented in a wide frequency range, in which the bearing stiffness is simulated by the disc springs. The experimental results show that the amplitude errors of this measurement system are small in the frequency range of 10 Hz-100 Hz, and the phase errors increase along with the increasing of frequency. It is preliminarily verified by the simulated experiment of dynamic characteristics coefficients identification in the frequency range of 10 Hz-30 Hz that the calibration data in this frequency range can support the dynamic characteristics test of sliding bearing in this frequency range well. The bearing experiments in greater frequency ranges need higher manufacturing and installation precision of calibration device. Besides, the processes of calibration experiments should be improved. PMID- 27483284 TI - Analysis on Node Position of Imperfect Resonators for Cylindrical Shell Gyroscopes. AB - For cylindrical shell gyroscopes, node position of their operating eigenmodes has an important influence on the gyroscopes' performance. It is considered that the nodes are equally separated from each other by 90 degrees when the resonator vibrates in the standing wave eigenmode. However, we found that, due to manufacturing errors and trimming, the nodes may not be equally distributed. This paper mainly analyzes the influences of unbalanced masses on the cylindrical resonators' node position, by using FEM simulation and experimental measurement. PMID- 27483285 TI - Genetic Particle Swarm Optimization-Based Feature Selection for Very-High Resolution Remotely Sensed Imagery Object Change Detection. AB - In the field of multiple features Object-Based Change Detection (OBCD) for very high-resolution remotely sensed images, image objects have abundant features and feature selection affects the precision and efficiency of OBCD. Through object based image analysis, this paper proposes a Genetic Particle Swarm Optimization (GPSO)-based feature selection algorithm to solve the optimization problem of feature selection in multiple features OBCD. We select the Ratio of Mean to Variance (RMV) as the fitness function of GPSO, and apply the proposed algorithm to the object-based hybrid multivariate alternative detection model. Two experiment cases on Worldview-2/3 images confirm that GPSO can significantly improve the speed of convergence, and effectively avoid the problem of premature convergence, relative to other feature selection algorithms. According to the accuracy evaluation of OBCD, GPSO is superior at overall accuracy (84.17% and 83.59%) and Kappa coefficient (0.6771 and 0.6314) than other algorithms. Moreover, the sensitivity analysis results show that the proposed algorithm is not easily influenced by the initial parameters, but the number of features to be selected and the size of the particle swarm would affect the algorithm. The comparison experiment results reveal that RMV is more suitable than other functions as the fitness function of GPSO-based feature selection algorithm. PMID- 27483286 TI - Modeling and Experimental Analysis on the Temperature Response of AlN-Film Based SAWRs. AB - The temperature responses of aluminum nitride (AlN) based surface acoustic wave resonator (SAWR) are modeled and tested. The modeling of the electrical performance is based on a modified equivalent circuit model introduced in this work. For SAWR consisting of piezoelectric film and semiconducting substrate, parasitic parameters from the substrate is taken into consideration for the modeling. By utilizing the modified model, the high temperature electrical performance of the AlN/Si and AlN/6H-SiC based SAWRs can be predicted, indicating that a substrate with a wider band gap will lead to a more stable high temperature behavior, which is further confirmed experimentally by high temperature testing from 300 K to 725 K with SAWRs having a wavelength of 12 MUm. Temperature responses of SAWR's center frequency are also calculated and tested, with experimental temperature coefficient factors (TCF) of center frequency being -29 ppm/K and -26 ppm/K for the AlN/Si and AlN/6H-SiC based SAWRs, which are close to the predicted values. PMID- 27483287 TI - On-Ground Processing of Yaogan-24 Remote Sensing Satellite Attitude Data and Verification Using Geometric Field Calibration. AB - Satellite attitude accuracy is an important factor affecting the geometric processing accuracy of high-resolution optical satellite imagery. To address the problem whereby the accuracy of the Yaogan-24 remote sensing satellite's on-board attitude data processing is not high enough and thus cannot meet its image geometry processing requirements, we developed an approach involving on-ground attitude data processing and digital orthophoto (DOM) and the digital elevation model (DEM) verification of a geometric calibration field. The approach focuses on three modules: on-ground processing based on bidirectional filter, overall weighted smoothing and fitting, and evaluation in the geometric calibration field. Our experimental results demonstrate that the proposed on-ground processing method is both robust and feasible, which ensures the reliability of the observation data quality, convergence and stability of the parameter estimation model. In addition, both the Euler angle and quaternion could be used to build a mathematical fitting model, while the orthogonal polynomial fitting model is more suitable for modeling the attitude parameter. Furthermore, compared to the image geometric processing results based on on-board attitude data, the image uncontrolled and relative geometric positioning result accuracy can be increased by about 50%. PMID- 27483288 TI - TRPV1 and TRPM8 in Treatment of Chronic Cough. AB - Chronic cough is common in the population, and among some there is no evident medical explanation for the symptoms. Such a refractory or idiopathic cough is now often regarded as a neuropathic disease due to dysfunctional airway ion channels, though the knowledge in this field is still limited. Persistent coughing and a cough reflex easily triggered by irritating stimuli, often in combination with perceived dyspnea, are characteristics of this disease. The patients have impaired quality of life and often reduced work capacity, followed by social and economic consequences. Despite the large number of individuals suffering from such a persisting cough, there is an unmet clinical need for effective cough medicines. The cough treatment available today often has little or no effect. Adverse effects mostly follow centrally acting cough drugs comprised of morphine and codeine, which demands the physician's awareness. The possibilities of modulating airway transient receptor potential (TRP) ion channels may indicate new ways to treat the persistent cough "without a reason". The TRP ion channel vanilloid 1 (TRPV1) and the TRP melastin 8 (TRPM8) appear as two candidates in the search for cough therapy, both as single targets and in reciprocal interaction. PMID- 27483289 TI - Differential Activation of TRP Channels in the Adult Rat Spinal Substantia Gelatinosa by Stereoisomers of Plant-Derived Chemicals. AB - Activation of TRPV1, TRPA1 or TRPM8 channel expressed in the central terminal of dorsal root ganglion (DRG) neuron increases the spontaneous release of l glutamate onto spinal dorsal horn lamina II (substantia gelatinosa; SG) neurons which play a pivotal role in regulating nociceptive transmission. The TRP channels are activated by various plant-derived chemicals. Although stereoisomers activate or modulate ion channels in a distinct manner, this phenomenon is not fully addressed for TRP channels. By applying the whole-cell patch-clamp technique to SG neurons of adult rat spinal cord slices, we found out that all of plant-derived chemicals, carvacrol, thymol, carvone and cineole, increase the frequency of spontaneous excitatory postsynaptic current, a measure of the spontaneous release of l-glutamate from nerve terminals, by activating TRP channels. The presynaptic activities were different between stereoisomers (carvacrol and thymol; (-)-carvone and (+)-carvone; 1,8-cineole and 1,4-cineole) in the extent or the types of TRP channels activated, indicating that TRP channels in the SG are activated by stereoisomers in a distinct manner. This result could serve to know the properties of the central terminal TRP channels that are targets of drugs for alleviating pain. PMID- 27483290 TI - 5-Episinuleptolide Decreases the Expression of the Extracellular Matrix in Early Biofilm Formation of Multi-Drug Resistant Acinetobacter baumannii. AB - Nosocomial infections and increasing multi-drug resistance caused by Acinetobacter baumannii have been recognized as emerging problems worldwide. Moreover, A. baumannii is able to colonize various abiotic materials and medical devices, making it difficult to eradicate and leading to ventilator-associated pneumonia, and bacteremia. Development of novel molecules that inhibit bacterial biofilm formation may be an alternative prophylactic option for the treatment of biofilm-associated A. baumannii infections. Marine environments, which are unlike their terrestrial counterparts, harbor an abundant biodiversity of marine organisms that produce novel bioactive natural products with pharmaceutical potential. In this study, we identified 5-episinuleptolide, which was isolated from Sinularia leptoclados, as an inhibitor of biofilm formation in ATCC 19606 and three multi-drug resistant A. baumannii strains. In addition, the anti biofilm activities of 5-episinuleptolide were observed for Gram-negative bacteria but not for Gram-positive bacteria, indicating that the inhibition mechanism of 5 episinuleptolide is effective against only Gram-negative bacteria. The mechanism of biofilm inhibition was demonstrated to correlate to decreased gene expression from the pgaABCD locus, which encodes the extracellular polysaccharide poly-beta (1,6)-N-acetylglucosamine (PNAG). Scanning electron microscopy (SEM) indicated that extracellular matrix of the biofilm was dramatically decreased by treatment with 5-episinuleptolide. Our study showed potentially synergistic activity of combination therapy with 5-episinuleptolide and levofloxacin against biofilm formation and biofilm cells. These data indicate that inhibition of biofilm formation via 5-episinuleptolide may represent another prophylactic option for solving the persistent problem of biofilm-associated A. baumannii infections. PMID- 27483291 TI - High-EPA Biomass from Nannochloropsis salina Cultivated in a Flat-Panel Photo Bioreactor on a Process Water-Enriched Growth Medium. AB - Nannochloropsis salina was grown on a mixture of standard growth media and pre gasified industrial process water representing effluent from a local biogas plant. The study aimed to investigate the effects of enriched growth media and cultivation time on nutritional composition of Nannochloropsis salina biomass, with a focus on eicosapentaenoic acid (EPA). Variations in fatty acid composition, lipids, protein, amino acids, tocopherols and pigments were studied and results compared to algae cultivated on F/2 media as reference. Mixed growth media and process water enhanced the nutritional quality of Nannochloropsis salina in laboratory scale when compared to algae cultivated in standard F/2 medium. Data from laboratory scale translated to the large scale using a 4000 L flat panel photo-bioreactor system. The algae growth rate in winter conditions in Denmark was slow, but results revealed that large-scale cultivation of Nannochloropsis salina at these conditions could improve the nutritional properties such as EPA, tocopherol, protein and carotenoids compared to laboratory-scale cultivated microalgae. EPA reached 44.2% +/- 2.30% of total fatty acids, and alpha-tocopherol reached 431 +/- 28 ug/g of biomass dry weight after 21 days of cultivation. Variations in chemical compositions of Nannochloropsis salina were studied during the course of cultivation. Nannochloropsis salina can be presented as a good candidate for winter time cultivation in Denmark. The resulting biomass is a rich source of EPA and also a good source of protein (amino acids), tocopherols and carotenoids for potential use in aquaculture feed industry. PMID- 27483293 TI - Assessing the Contribution of the Environmental Parameters to Eutrophication with the Use of the "PaD" and "PaD2" Methods in a Hypereutrophic Lake. AB - Lake Pamvotis (Greece) is a shallow hypereutrophic lake with a natural tendency to eutrophication. Several restoration measures were applied, but with no long term success. To examine the causes for this an Artificial Neural Network (ANN) was created in order to simulate the chlorophyll-a (Chl-a) levels and to investigate the role of the associated environmental parameters. The ANN managed to simulate with good correlation the simulated Chl-a and can be considered as a reliable predictor. The relative importance of the environmental parameters to the simulated Chl-a was calculated with the use of the "Partial Derivatives" ("PaD") sensitivity method. The water temperature (WT) and soluble reactive phosphorus (SRP) had the highest relative importance, with values of 50% and 17%, respectively. The synergistic effect of the paired parameters was calculated with the use of the "PaD2" algorithm. The SRP-WT paired parameter was the most influential, with a relative contribution of 22%. The ANN showed that Lake Pamvotis is prone to suffer the effects of climatic change, because of the major contribution of WT. The ANN also revealed that combined nutrients reduction would improve water quality status. The ANN findings can act as an advisory tool regarding any restoration efforts. PMID- 27483294 TI - Bi-Objective Modelling for Hazardous Materials Road-Rail Multimodal Routing Problem with Railway Schedule-Based Space-Time Constraints. AB - The transportation of hazardous materials is always accompanied by considerable risk that will impact public and environment security. As an efficient and reliable transportation organization, a multimodal service should participate in the transportation of hazardous materials. In this study, we focus on transporting hazardous materials through the multimodal service network and explore the hazardous materials multimodal routing problem from the operational level of network planning. To formulate this problem more practicably, minimizing the total generalized costs of transporting the hazardous materials and the social risk along the planned routes are set as the optimization objectives. Meanwhile, the following formulation characteristics will be comprehensively modelled: (1) specific customer demands; (2) multiple hazardous material flows; (3) capacitated schedule-based rail service and uncapacitated time-flexible road service; and (4) environmental risk constraint. A bi-objective mixed integer nonlinear programming model is first built to formulate the routing problem that combines the formulation characteristics above. Then linear reformations are developed to linearize and improve the initial model so that it can be effectively solved by exact solution algorithms on standard mathematical programming software. By utilizing the normalized weighted sum method, we can generate the Pareto solutions to the bi-objective optimization problem for a specific case. Finally, a large-scale empirical case study from the Beijing Tianjin-Hebei Region in China is presented to demonstrate the feasibility of the proposed methods in dealing with the practical problem. Various scenarios are also discussed in the case study. PMID- 27483292 TI - Fucoidans in Nanomedicine. AB - Fucoidans are widespread cost-effective sulfated marine polysaccharides which have raised interest in the scientific community over last decades for their wide spectrum of bioactivities. Unsurprisingly, nanomedicine has grasped these compounds to develop innovative therapeutic and diagnostic nanosystems. The applications of fucoidans in nanomedicine as imaging agents, drug carriers or for their intrinsic properties are reviewed here after a short presentation of the main structural data and biological properties of fucoidans. The origin and the physicochemical specifications of fucoidans are summarized in order to discuss the strategy of fucoidan-containing nanosystems in Human health. Currently, there is a need for reproducible, well characterized fucoidan fractions to ensure significant progress. PMID- 27483295 TI - Endocrine Aspects of Environmental "Obesogen" Pollutants. AB - Growing evidence suggests the causal link between the endocrine-disrupting chemicals (EDCs) and the global obesity epidemics, in the context in the so called "obesogenic environment". Dietary intake of contaminated foods and water, especially in association with unhealthy eating pattern, and inhalation of airborne pollutants represent the major sources of human exposure to EDCs. This is of particular concern in view of the potential impact of obesity on chronic non-transmissible diseases, such as type 2 diabetes, cardiovascular disease, and hormone-sensitive cancers. The key concept is the identification of adipose tissue not only as a preferential site of storage of EDCs, but also as an endocrine organ and, as such, susceptible to endocrine disruption. The timing of exposure to EDCs is critical to the outcome of that exposure, with early lifetime exposures (e.g., fetal or early postnatal) particularly detrimental because of their permanent effects on obesity later in life. Despite that the mechanisms operating in EDCs effects might vary enormously, this minireview is aimed to provide a general overview on the possible association between the pandemics of obesity and EDCs, briefly describing the endocrine mechanisms linking EDCs exposure and latent onset of obesity. PMID- 27483296 TI - Expression of Hepcidin and Ferroportin in the Placenta, and Ferritin and Transferrin Receptor 1 Levels in Maternal and Umbilical Cord Blood in Pregnant Women with and without Gestational Diabetes. AB - BACKGROUND: Regulation of iron transfer from mother to fetus via the placenta is not fully understood and the relationship between stored iron status in the mothers' serum and gestational diabetes (GDM) in case-control studies is controversial. The present study aimed to detect circulating soluble transferrin receptor (sTfR) and ferritin levels in maternal and umbilical cord blood. We also examined the expression of hepcidin (Hep), transferrin receptor (TfR1), and ferroportin (FPN) in the placenta in pregnant women with and without GDM at full term. METHODS: Eighty-two women participated (42 with GDM and 40 without GDM [controls]). Maternal samples were collected at 37-39 weeks' gestation. Umbilical cord blood was collected at birth. Ferritin and sTfR levels in maternal serum and umbilical cord blood, and Hep, TfR1, and FPN protein expression in plac enta were compared between the GDM and non-GDM groups. Serum ferritin (SF) was measured by electrochemiluminescence assay and sTfR was measured by ELISA. Hep, TfR1, and FPN expression was measured by immunohistochemistry. RESULTS: Maternal serum sTfR levels were significantly elevated in the GDM group compared with the non-GDM group (p = 0.003). SF levels in cord blood in the GDM group were significantly higher than those in the non-GDM group (p = 0.003). However, maternal hemoglobin and SF, and umbilical cord sTfR levels were not different between the groups. In placental tissue, FPN expression was higher and hepcidin expression was lower in the GDM group compared with the non-GDM group (p = 0.000 and p = 0.044, respectively). There was no significant difference in TfR1 between the groups (p = 0.898). CONCLUSIONS: Women with GDM transport iron more actively than those without GDM at term pregnancy. Maternal iron metabolism in GDM may play a role in fetal/placental iron demand and in the overall outcome of pregnancy. PMID- 27483298 TI - The Optimum Production Method for Quality Improvement of Recycled Aggregates Using Sulfuric Acid and the Abrasion Method. AB - There has been increased deconstruction and demolition of reinforced concrete structures due to the aging of the structures and redevelopment of urban areas resulting in the generation of massive amounts of construction. The production volume of waste concrete is projected to increase rapidly over 100 million tons by 2020. However, due to the high cement paste content, recycled aggregates have low density and high absorption ratio. They are mostly used for land reclamation purposes with low added value instead of multiple approaches. This study was performed to determine an effective method to remove cement paste from recycled aggregates by using the abrasion and substituting the process water with acidic water. The aim of this study is to analyze the quality of the recycled fine aggregates produced by a complex method and investigate the optimum manufacturing conditions for recycled fine aggregates based on the design of experiment. The experimental parameters considered were water ratio, coarse aggregate ratio, and abrasion time and, as a result of the experiment, data concerning the properties of recycled sand were obtained. It was found that high-quality recycled fine aggregates can be obtained with 8.57 min of abrasion-crusher time and a recycled coarse aggregate ratio of over 1.5. PMID- 27483297 TI - Polybrominated Diphenyl Ethers in Maternal Serum, Breast Milk, Umbilical Cord Serum, and House Dust in a South Korean Birth Panel of Mother-Neonate Pairs. AB - Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants. Although many reports have indicated an association between exposure to PBDEs and developmental neurotoxicity, the relative contributions of different sources of dust PBDE congeners to the levels in various tissues of mother-baby pairs is not well understood. The aims of this study were thus to measure the quantitative relationship between the level of PBDEs in house dust and tissues of mother neonate pairs, and to investigate the chemical sources of the PBDEs. Forty-one mother-neonate pairs were recruited and provided samples of maternal serum (n = 29), umbilical cord serum (n = 25), breast milk (n = 50), and house dust (n = 41), where PBDEs were determined with high-resolution gas chromatography coupled with high-resolution mass spectrometry. While deca- (e.g., BDE 209, detected 100%), nona- (BDE 206/207, 95.1%), octa- (BDE 183, 100%), penta- (BDE 99/153, 100%, 98%) and tetra-BDEs (BDE 47, 100%) were detected abundantly in dust, penta- (BDE 99, 76%, 92%) and tetra-BDEs (BDE 47, 84%, 98%) were detected abundantly in umbilical cord serum and breast milk, respectively; tetra-BDEs (BDE 47, 86%) were detected more often relative to other congeners in maternal serum. Spearman's pairwise comparison showed that the levels of BDE 47 (rho = 0.52, p < 0.001) and 99 (rho = 0.64, p < 0.01) in umbilical cord serum were associated with BDE 209 levels in dust; BDE 47 in maternal serum also showed correlation with BDE 99 in cord serum (rho = 0.48, p < 0.01) but there was no significant correlation between maternal BDE 47 and dust BDE 209. On the other hand, a comparison of the distribution among congeners suggested probable associations of BDE 47 in maternal serum, breast milk, and umbilical cord serum with BDE 209 in dust; and of BDE 99 in maternal and umbilical cord serum, breast milk, and dust with BDE 209 in dust. Although further studies are needed, a radar chart-based distributional comparison among congeners supported associations between BDE 47 or -99 in human tissues and BDE 209 in dust. PMID- 27483299 TI - Analysis of Consumption of Energy Drinks by a Group of Adolescent Athletes. AB - BACKGROUND: Energy drinks (EDs) have become widely popular among young adults and, even more so, among adolescents. Increasingly, they are consumed by athletes, particularly those who have just begun their sporting career. Uncontrolled and high consumption of EDs, in addition to other sources of caffeine, may pose a threat to the health of young people. Hence, our objective was to analyze the consumption of EDs among teenagers engaged in sports, including quantity consumed, identification of factors influencing consumption, and risks associated with EDs and EDs mixed with alcohol (AmEDs). METHODS: The study involved a specially designed questionnaire, which was completed by 707 students, 14.3 years of age on average, attending secondary sports schools. RESULTS: EDs were consumed by 69% of the young athletes, 17% of whom drank EDs quite often: every day or 1-3 times a week. Most respondents felt no effects after drinking EDs, but some reported symptoms, including insomnia, anxiety, tachycardia, nervousness and irritability. The major determinant of the choice of EDs was taste (47%), followed by price (21%). One in ten respondents admitted to consumption of AmEDs. Among the consequences reported were: abdominal pains, nausea, vomiting, amnesia, headache, and hangover. CONCLUSIONS: EDs consumption among adolescent athletes was relatively high. Considering the habit of AmEDs and literature data, it is worth emphasizing that it may lead to health problems in the near future, alcohol- or drug-dependence, as well as other types of risk behaviour. PMID- 27483300 TI - Prevalence and Risk Factors of Heart Failure with Preserved Ejection Fraction: A Population-Based Study in Northeast China. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has attracted increasing attention worldwide. We aimed to estimate the prevalence of HFpEF and analyze its correlates in a sample of residents of northeast China; METHODS: A population-based study of 2230 participants >=35 years old was conducted in rural areas of Liaoning Province from January 2012 through August 2013. Information about lifestyle and other potential risk factors was obtained. HFpEF was diagnosed according to the recommendations of European Society of Cardiology; RESULTS: The overall prevalence of HFpEF was 3.5% (1.8% in men and 4.9% in women). The prevalence of HFpEF increased with age in both genders and was greater in women than in men for every age group. Multivariable logistic regression analysis found that female gender (OR, 3.575; 95% CI, 1.761-7.256), hypertension (OR, 3.711; 95% CI, 2.064-6.674), and history of heart disease (2.086; 95% CI, 1.243-3.498) were associated factors for prevalent HFpEF; CONCLUSIONS: In a general population from rural northeast China, we found that female gender, hypertension, and history of heart disease were risk factors for prevalent HFpEF. PMID- 27483301 TI - Measles Virus Host Invasion and Pathogenesis. AB - Measles virus is a highly contagious negative strand RNA virus that is transmitted via the respiratory route and causes systemic disease in previously unexposed humans and non-human primates. Measles is characterised by fever and skin rash and usually associated with cough, coryza and conjunctivitis. A hallmark of measles is the transient immune suppression, leading to increased susceptibility to opportunistic infections. At the same time, the disease is paradoxically associated with induction of a robust virus-specific immune response, resulting in lifelong immunity to measles. Identification of CD150 and nectin-4 as cellular receptors for measles virus has led to new perspectives on tropism and pathogenesis. In vivo studies in non-human primates have shown that the virus initially infects CD150+ lymphocytes and dendritic cells, both in circulation and in lymphoid tissues, followed by virus transmission to nectin-4 expressing epithelial cells. The abilities of the virus to cause systemic infection, to transmit to numerous new hosts via droplets or aerosols and to suppress the host immune response for several months or even years after infection make measles a remarkable disease. This review briefly highlights current topics in studies of measles virus host invasion and pathogenesis. PMID- 27483302 TI - NXT1, a Novel Influenza A NP Binding Protein, Promotes the Nuclear Export of NP via a CRM1-Dependent Pathway. AB - Influenza remains a serious worldwide public health problem. After infection, viral genomic RNA is replicated in the nucleus and packed into viral ribonucleoprotein, which will then be exported to the cytoplasm via a cellular chromosome region maintenance 1 (CRM1)-dependent pathway for further assembly and budding. However, the nuclear export mechanism of influenza virus remains controversial. Here, we identify cellular nuclear transport factor 2 (NTF2)-like export protein 1 (NXT1) as a novel binding partner of nucleoprotein (NP) that stimulates NP-mediated nuclear export via the CRM1-dependent pathway. NXT1 knockdown cells exhibit decreased viral replication kinetics and nuclear accumulated viral RNA and NP. By contrast, NXT1 overexpression promotes nuclear export of NP in a CRM1-dependent manner. Pull-down assays suggest the formation of an NXT1, NP, and CRM1 complex, and demonstrate that NXT1 binds to the C terminal region of NP. These findings reveal a distinct mechanism for nuclear export of the influenza virus and identify the NXT1/NP interaction as a potential target for antiviral drug development. PMID- 27483303 TI - Low Iron Diet Increases Susceptibility to Noise-Induced Hearing Loss in Young Rats. AB - We evaluated the role of iron deficiency (ID) without anemia on hearing function and cochlear pathophysiology of young rats before and after noise exposure. We used rats at developmental stages as an animal model to induce ID without anemia by dietary iron restriction. We have established this dietary restriction model in the rat that should enable us to study the effects of iron deficiency in the absence of severe anemia on hearing and ribbon synapses. Hearing function was measured on Postnatal Day (PND) 21 after induction of ID using auditory brainstem response (ABR). Then, the young rats were exposed to loud noise on PND 21. After noise exposure, hearing function was again measured. We observed the morphology of ribbon synapses, hair cells and spiral ganglion cells (SGCs), and assessed the expression of myosin VIIa, vesicular glutamate transporter 3 and prestin in the cochlea. ID without anemia did not elevate ABR threshold shifts, but reduced ABR wave I peak amplitude of young rats. At 70, 80, and 90 dB SPL, amplitudes of wave I (3.11 +/- 0.96 uV, 3.52 +/- 1.31 uV, and 4.37 +/- 1.08 uV, respectively) in pups from the ID group were decreased compared to the control (5.92 +/- 1.67 uV, 6.53 +/- 1.70 uV, and 6.90 +/- 1.76 uV, respectively) (p < 0.05). Moreover, ID without anemia did not impair the morphology hair cells and SGCs, but decreased the number of ribbon synapses. Before noise exposure, the mean number of ribbon synapses per inner hair cell (IHC) was significantly lower in the ID group (8.44 +/- 1.21) compared to that seen in the control (13.08 +/- 1.36) (p < 0.05). In addition, the numbers of ribbon synapses per IHC of young rats in the control (ID group) were 6.61 +/- 1.59, 3.07 +/- 0.83, 5.85 +/- 1.63 and 12.25 +/- 1.97 (3.75 +/- 1.45, 2.03 +/- 1.08, 3.81 +/- 1.70 and 4.01 +/- 1.65) at 1, 4, 7 and 14 days after noise exposure, respectively. Moreover, ABR thresholds at 4 and 8 kHz in young rats from the ID group were significantly elevated at 7 and 14 days after noise exposure compared to control (p < 0.05). The average number of young rat SGCs from the ID group were significantly decreased in the basal turn of the cochlea compared to the control (p < 0.05). Therefore, ID without anemia delayed the recovery from noise-induced hearing loss and ribbon synapses damage, increased SGCs loss, and upregulated prestin after noise exposure. Thus, the cochleae in rat pups with ID without anemia were potentially susceptible to loud noise exposure, and this deficit may be attributed to the reduction of ribbon synapses and SGCs. PMID- 27483304 TI - Validity and Reproducibility of a Dietary Questionnaire for Consumption Frequencies of Foods during Pregnancy in the Born in Guangzhou Cohort Study (BIGCS). AB - This study aimed to examine the reproducibility and validity of a new food frequency questionnaire (FFQ) used in a birth cohort study to estimate the usual consumption frequencies of foods during pregnancy. The reference measure was the average of three inconsecutive 24 h diet recalls (24 HR) administrated between two FFQs, and the reproducibility was measured by repeating the first FFQ (FFQ1) approximately eight weeks later (FFQ2). A total of 210 pregnant women from the Born in Guangzhou Cohort Study (BIGCS) with full data were included in the analysis. The Spearman's correlation coefficients of FFQ1 and FFQ2 ranged from 0.33 to 0.71. The intraclass correlation coefficients of the two FFQs ranged from 0.22 to 0.71. The Spearman's correlation coefficients of the 24 HR and FFQ2 ranged from 0.23 to 0.62. Cross-classification analysis showed 65.1% of participants were classified into same and contiguous quintiles, while only 3.2% were misclassified into the distant quintiles. Bland-Altman methods showed good agreement for most food groups across the range of frequencies between FFQ1 and FFQ2. Our findings indicated that the reproducibility and validity of the FFQ used in BIGCS for assessing the usual consumption frequencies of foods during pregnancy were acceptable. PMID- 27483305 TI - Suppressive Effects of Tea Catechins on Breast Cancer. AB - Tea leaf (Camellia sinensis) is rich in catechins, which endow tea with various health benefits. There are more than ten catechin compounds in tea, among which epigallocatechingallate (EGCG) is the most abundant. Epidemiological studies on the association between tea consumption and the risk of breast cancer were summarized, and the inhibitory effects of tea catechins on breast cancer, with EGCG as a representative compound, were reviewed in the present paper. The controversial results regarding the role of tea in breast cancer and areas for further study were discussed. PMID- 27483306 TI - The Association of Vitamin D Status with Dyslipidaemia and Biomarkers of Endothelial Cell Activation in Older Australians. AB - BACKGROUND/AIMS: Vitamin D has been investigated for many non-skeletal effects. The objective of this study was to determine whether circulating lipids, systemic inflammation, and biomarkers of endothelial cell activation varied with the vitamin D status of older Australians. METHODS: One hundred and one participants were proportionately and randomly sampled across tertiles of 25 hydroxy vitamin D (25(OH)D) from a larger cohort of free living older adults (T1 median = 97; T2 median = 74.5; T3 median = 56.8 nmol/L). Overnight fasting blood samples were assayed for 25(OH)D, parathyroid hormone (PTH), insulin, triacylglycerol (TAG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C). Markers of systemic inflammation (high sensitivity C-reactive protein (hsCRP), tumour necrosis factor-alpha (TNF-alpha)) and endothelial activation (hepatocyte growth factor (HGF), P-selectin and soluble vascular cell adhesion molecule (sVCAM), soluble intracellular adhesion molecule (sICAM)) were determined. A general linear model multivariate analysis with a backward elimination procedure was performed. RESULTS: Eighty-three participants (48 women, 35 men), aged 65 +/- 7.7 years, BMI 28 +/- 4.5 kg/m2, with complete data were analyzed. The final parsimonious model controlled for age, gender, BMI, and McAuley's index, but excluded season, medications, and PTH. There were significant differences across 25(OH)D tertiles in TC (T1 < T3, p = 0.003; T2 < T3, p = 0.001), LDL-C (T1 < T3, p = 0.005; T2 < T3, p = 0.001), TAG (T2 < T3, p = 0.026), HGF (T1 > T3, p = 0.009) and sVCAM (T1 > T3, P = 0.04). CONCLUSIONS: Higher vitamin D status may protect the endothelium through reduced dyslipidaemia and increased HGF. PMID- 27483307 TI - Dietary Interventions and Changes in Cardio-Metabolic Parameters in Metabolically Healthy Obese Subjects: A Systematic Review with Meta-Analysis. AB - The aim of this systematic review was to assess the effect of diet on changes in parameters describing the body size phenotype of metabolically healthy obese subjects. The databases Medline, Scopus, Web of Knowledge and Embase were searched for clinical studies carried out between 1958 and June 2016 that reported the effect of dietary intervention on BMI, blood pressure, concentration of fasting triglyceride (TG), high density lipoprotein cholesterol (HDL-C), fasting glucose level, the homoeostatic model assessment of insulin resistance (HOMA-IR) and high sensitivity C-Reactive Protein (hsCRP) in metabolically healthy, obese subjects. Twelve clinical studies met inclusion criteria. The combined analyzed population consists of 1827 subjects aged 34.4 to 61.1 with a BMI > 30 kg/m2. Time of intervention ranged from eight to 104 weeks. The baseline characteristics related to lipid profile were more favorable for metabolically healthy obese than for metabolically unhealthy obese. The meta-analyses revealed a significant associations between restricted energy diet and BMI (95% confidence interval (CI): -0.88, -0.19), blood pressure (systolic blood pressure (SBP): 4.73 mmHg; 95% CI: -7.12, -2.33; and diastolic blood pressure (DBP): -2.75 mmHg; 95% CI: -4.30, -1.21) and TG (-0.11 mmol/l; 95% CI: -0.16, -0.06). Changes in fasting glucose, HOMA-IR and hsCRP did not show significant changes. Sufficient evidence was not found to support the use of specific diets in metabolically healthy obese subjects. This analysis suggests that the effect of caloric restriction exerts its effects through a reduction in BMI, blood pressure and triglycerides in metabolically healthy obese (MHO) patients. PMID- 27483309 TI - Trends and Predictors of Prelacteal Feeding Practices in Nigeria (2003-2013). AB - Prelacteal feeding practices are associated with an increased risk of diarrhoea and many early-life diseases. This paper examined trends and predictors of prelacteal feeding practices in Nigeria. A sample of 6416 infants aged 0-6 months from the Nigeria Demographic and Health Survey data for the period (2003-2013) was used. Trends and multilevel logistic regression analyses were used to determine the predictors. The trends of prelacteal feeding rates fluctuated between 55% and 66% over the study period and were significantly lower among mothers with secondary or higher levels of education (13.1%, 95% confidence interval (CI): 0.54-25.9, p-value = 0.041), delivered at the health facility (13.7%, CI: 1.39-25.9, p-value = 0.029), from more affluent households (18.7%, CI: 1.53-35.9, p-value = 0.033), and lived in urban areas (26.9%, CI: 18.3-35.5, p-value < 0.001). Multivariable analyses revealed that mothers with no schooling, younger mothers (aged 15-24 years), mothers who delivered at home, and delivered by caesarean section were more likely to introduce prelacteal feeds. Many mothers still engage in prelacteal feeding practices in Nigeria, with prelacteal feeding more prevalent in young mothers, mothers with no schooling, and mothers who delivered at home. Interventions involving community health volunteers are needed to improve feeding practices in Nigeria. PMID- 27483308 TI - Regular-Fat Dairy and Human Health: A Synopsis of Symposia Presented in Europe and North America (2014-2015). AB - In recent history, some dietary recommendations have treated dairy fat as an unnecessary source of calories and saturated fat in the human diet. These assumptions, however, have recently been brought into question by current research on regular fat dairy products and human health. In an effort to disseminate, explore and discuss the state of the science on the relationship between regular fat dairy products and health, symposia were programmed by dairy industry organizations in Europe and North America at The Eurofed Lipids Congress (2014) in France, The Dairy Nutrition Annual Symposium (2014) in Canada, The American Society for Nutrition Annual Meeting held in conjunction with Experimental Biology (2015) in the United States, and The Federation of European Nutrition Societies (2015) in Germany. This synopsis of these symposia describes the complexity of dairy fat and the effects regular-fat dairy foods have on human health. The emerging scientific evidence indicates that the consumption of regular fat dairy foods is not associated with an increased risk of cardiovascular disease and inversely associated with weight gain and the risk of obesity. Dairy foods, including regular-fat milk, cheese and yogurt, can be important components of an overall healthy dietary pattern. Systematic examination of the effects of dietary patterns that include regular-fat milk, cheese and yogurt on human health is warranted. PMID- 27483310 TI - Protective Effect of Garlic on Cellular Senescence in UVB-Exposed HaCaT Human Keratinocytes. AB - Ultraviolet (UV) irradiation generates reactive oxygen species (ROS) in the cells, which induces the cellular senescence and photoaging. The present study investigated the protective effects of garlic on photo-damage and cellular senescence in UVB-exposed human keratinocytes, HaCaT cells. An in vitro cell free system was used to examine the scavenging activity of 2,2-diphenyl-1 picrylhydrazyl (DPPH) free radicals and nitric oxide (NO). The effect of garlic extract on ROS formation, MMP-1 protein and mRNA expressions, cytokines such as interleukin (IL)-1beta and IL-6, senescence associated-beta-galactosidase (SA beta-gal) activity, and silent information regulator T1 (SIRT1) activity were determined in UVB-irradiated HaCaT cells. Garlic exhibited strong DPPH radical and NO scavenging activity in cell free system exhibiting IC50 values of 2.50 mg/mL and 4.38 mg/mL, respectively. Garlic pretreatment attenuated the production of UVB-induced intracellular ROS. MMP-1 level, which has been known to be induced by ROS, was dramatically elevated by UVB irradiation, and UVB-induced MMP-1 mRNA and protein expressions were significantly reduced by garlic treatment (50 ug/mL) comparable to those of UV-unexposed control cells. UV-induced pro-inflammatory cytokine productions (IL-6 and IL-1beta) were significantly inhibited by pretreatment with garlic in a dose-dependent manner. SA-beta-gal activity, a classical biomarker of cellular senescence, and SIRT1 activity, which has attracted attention as an anti-aging factor in recent years, were ameliorated by garlic treatment in UV-irradiated HaCaT cells. The present study provides the first evidence of garlic inhibiting UVB-induced photoaging as a result of augmentation of cellular senescence in HaCaT human keratinocytes. PMID- 27483311 TI - Lipid-Induced Insulin Resistance in Skeletal Muscle: The Chase for the Culprit Goes from Total Intramuscular Fat to Lipid Intermediates, and Finally to Species of Lipid Intermediates. AB - The skeletal muscle is the largest organ in the body. It plays a particularly pivotal role in glucose homeostasis, as it can account for up to 40% of the body and for up to 80%-90% of insulin-stimulated glucose disposal. Hence, insulin resistance (IR) in skeletal muscle has been a focus of much research and review. The fact that skeletal muscle IR precedes beta-cell dysfunction makes it an ideal target for countering the diabetes epidemic. It is generally accepted that the accumulation of lipids in the skeletal muscle, due to dietary lipid oversupply, is closely linked with IR. Our understanding of this link between intramyocellular lipids (IMCL) and glycemic control has changed over the years. Initially, skeletal muscle IR was related to total IMCL. The inconsistencies in this explanation led to the discovery that particular lipid intermediates are more important than total IMCL. The two most commonly cited lipid intermediates for causing skeletal muscle IR are ceramides and diacylglycerol (DAG) in IMCL. Still, not all cases of IR and dysfunction in glycemic control have shown an increase in either or both of these lipids. In this review, we will summarise the latest research results that, using the lipidomics approach, have elucidated DAG and ceramide species that are involved in skeletal muscle IR in animal models and human subjects. PMID- 27483312 TI - A Diet Score Assessing Norwegian Adolescents' Adherence to Dietary Recommendations-Development and Test-Retest Reproducibility of the Score. AB - Assessment of adolescents' dietary habits is challenging. Reliable instruments to monitor dietary trends are required to promote healthier behaviours in this group. The purpose of this cross-sectional study was to assess adolescents' adherence to Norwegian dietary recommendations with a diet score and to report results from, and test-retest reliability of, the score. The diet score involved seven food groups and one physical activity indicator, and was applied to answers from a semi-quantitative food frequency questionnaire (FFQ) administered twice. Reproducibility of the score was assessed with Cohen's Kappa (kappa statistics) at an interval of three months. The setting was eight lower-secondary schools in Hordaland County, Norway, and subjects were adolescents (n = 472) aged 14-15 years and their caregivers. Results showed that the proportion of adolescents consistently classified by the diet score was 87.6% (kappa = 0.465). For food groups, proportions ranged from 74.0% to 91.6% (kappa = 0.249 to kappa = 0.573). Less than 40% of the participants were found to adhere to recommendations for frequencies of eating fruits, vegetables, added sugar, and fish. Highest compliance to recommendations was seen for choosing water as beverage and limit the intake of red meat. The score was associated with parental socioeconomic status. The diet score was found to be reproducible at an acceptable level. Health promoting work targeting adolescents should emphasize to increase the intake of recommended foods to approach nutritional guidelines. PMID- 27483313 TI - Usual Intake of Key Minerals among Children in the Second Year of Life, NHANES 2003-2012. AB - Iron, calcium, and zinc are important nutrients for the young, developing child. This study describes the usual intake of iron, calcium, and zinc among US children in the second year of life using two days of dietary intake data from the National Health and Nutrition Examination Survey 2003-2012. Estimates were calculated using PC-SIDE to account for within and between person variation. Mean usual iron, calcium, and zinc intakes were 9.5 mg/day, 1046 mg/day, and 7.1 mg/day, respectively. Over a quarter of children had usual iron intakes less than the Recommended Dietary Allowance (RDA) (26.1%). Eleven percent of children had usual calcium intakes below the RDA and over half of children had usual intakes of zinc that exceeded the tolerable upper intake level (UL). Two percent or less had usual intakes below the Estimated Average Requirement (EAR) for iron, calcium, and zinc. Our findings suggest that during 2003-2012, one in four children and one in ten children had usual intakes below the RDA for iron and calcium, respectively. Children who are not meeting their nutrient requirements could be at increased risk for developing deficiencies such as iron deficiency or could lead to a shortage in adequate nutrients required for growth and development. One in every two children is exceeding the UL for zinc, but the interpretation of these estimates should be done with caution given the limited data on adverse health outcomes. Continued monitoring of zinc intake and further assessment for the potential of adverse health outcomes associated with high zinc intakes may be needed. PMID- 27483314 TI - Lean Mass and Body Fat Percentage Are Contradictory Predictors of Bone Mineral Density in Pre-Menopausal Pacific Island Women. AB - Anecdotally, it is suggested that Pacific Island women have good bone mineral density (BMD) compared to other ethnicities; however, little evidence for this or for associated factors exists. This study aimed to explore associations between predictors of bone mineral density (BMD, g/cm2), in pre-menopausal Pacific Island women. Healthy pre-menopausal Pacific Island women (age 16-45 years) were recruited as part of the larger EXPLORE Study. Total body BMD and body composition were assessed using Dual X-ray Absorptiometry and air-displacement plethysmography (n = 83). A food frequency questionnaire (n = 56) and current bone-specific physical activity questionnaire (n = 59) were completed. Variables expected to be associated with BMD were applied to a hierarchical multiple regression analysis. Due to missing data, physical activity and dietary intake factors were considered only in simple correlations. Mean BMD was 1.1 +/- 0.08 g/cm2. Bone-free, fat-free lean mass (LMO, 52.4 +/- 6.9 kg) and age were positively associated with BMD, and percent body fat (38.4 +/- 7.6) was inversely associated with BMD, explaining 37.7% of total variance. Lean mass was the strongest predictor of BMD, while many established contributors to bone health (calcium, physical activity, protein, and vitamin C) were not associated with BMD in this population, partly due to difficulty retrieving dietary data. This highlights the importance of physical activity and protein intake during any weight loss interventions to in order to minimise the loss of muscle mass, whilst maximizing loss of adipose tissue. PMID- 27483316 TI - Dietary Inflammatory Index and Risk of Colorectal Cancer: A Case-Control Study in Korea. AB - The role of diet-associated inflammation in colorectal cancer is of interest. Accordingly, we aimed to examine whether the dietary inflammatory index (DII) was associated with the risk of colorectal cancer in a case-control study conducted in Korea. The DII was based on dietary intake, which was determined by a 106-item semi-quantitative food frequency questionnaire completed by 923 colorectal cancer cases and 1846 controls. Logistic regression was used to estimate odd ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by the anatomical site of the cancer, sex, and other risk factors. Higher DII scores were associated with an increased incidence of colorectal cancer (OR (95% CI) = 2.16 (1.71, 2.73) for highest vs. lowest tertile). The magnitude differed by anatomical site and sex. This association was slightly weaker in subjects with proximal colon cancer (1.68 (1.08, 2.61)) and was stronger in women (2.50 (1.64, 3.82)). Additionally, stronger associations were observed in subjects who were older than 50 years (p for interaction = 0.004) and engaged in physical activity (p for interaction < 0.001). Results from this study suggest that diet-associated inflammation may increase the risk of colorectal cancer, and this effect may differ by certain factors, such as anatomical site, age, sex, and lifestyle. PMID- 27483315 TI - Bioactive Compounds and Their Neuroprotective Effects in Diabetic Complications. AB - Hyperglycemia, hyperlipidemia and impaired insulin signaling during the development of diabetes can cause diabetic complications, such as diabetic neuropathy, resulting in significant morbidity and mortality. Although various therapeutics are available for the treatment of diabetic neuropathy, no absolute cure exists, and additional research is necessary to comprehensively understand the underlying pathophysiological pathways. A number of studies have demonstrated the potential health benefits of bioactive compounds, i.e., flavonoids and vitamins, which may be effective as supplementary treatments for diabetes and its complications. In this review, we highlight the most recent reports about the mechanisms of action of bioactive compounds (flavonoids and vitamins) possessing potential neuroprotective properties in diabetic conditions. Additional clinical studies are required to determine the appropriate dose and duration of bioactive compound supplementation for neuroprotection in diabetic patients. PMID- 27483317 TI - Protein-Pacing Caloric-Restriction Enhances Body Composition Similarly in Obese Men and Women during Weight Loss and Sustains Efficacy during Long-Term Weight Maintenance. AB - Short-Term protein-pacing (P; ~6 meals/day, >30% protein/day) and caloric restriction (CR, ~25% energy deficit) improves total (TBF), abdominal (ABF) and visceral (VAT) fat loss, energy expenditure, and biomarkers compared to heart healthy (HH) recommendations (3 meals/day, 15% protein/day) in obese adults. Less is known whether obese men and women respond similarly to P-CR during weight loss (WL) and whether a modified P-CR (mP-CR) is more efficacious than a HH diet during long-term (52 week) weight maintenance (WM). The purposes of this study were to evaluate the efficacy of: (1) P-CR on TBF, ABF, resting metabolic rate (RMR), and biomarkers between obese men and women during WL (weeks 0-12); and (2) mP-CR compared to a HH diet during WM (weeks 13-64). During WL, men (n = 21) and women (n = 19) were assessed for TBF, ABF, VAT, RMR, and biomarkers at weeks 0 (pre) and 12 (post). Men and women had similar reductions (p < 0.01) in weight (10%), TBF (19%), ABF (25%), VAT (33%), glucose (7%-12%), insulin (40%), leptin (>50%) and increase in % lean body mass (9%). RMR (kcals/kg bodyweight) was unchanged and respiratory quotient decreased 9%. Twenty-four subjects (mP-CR, n = 10; HH, n = 14) completed WM. mP-CR regained significantly less body weight (6%), TBF (12%), and ABF (17%) compared to HH (p < 0.05). Our results demonstrate P-CR enhances weight loss, body composition and biomarkers, and maintains these changes for 52-weeks compared to a traditional HH diet. PMID- 27483318 TI - Beverage Intake Assessment Questionnaire: Relative Validity and Repeatability in a Spanish Population with Metabolic Syndrome from the PREDIMED-PLUS Study. AB - We assess the repeatability and relative validity of a Spanish beverage intake questionnaire for assessing water intake from beverages. The present analysis was performed within the framework of the PREDIMED-PLUS trial. The study participants were adults (aged 55-75) with a BMI >=27 and <40 kg/m2, and at least three components of Metabolic Syndrome (MetS). A trained dietitian completed the questionnaire. Participants provided 24-h urine samples, and the volume and urine osmolality were recorded. The repeatability of the baseline measurement at 6 and 1 year was examined by paired Student's t-test comparisons. A total of 160 participants were included in the analysis. The Bland-Altman analysis showed relatively good agreement between total daily fluid intake assessed using the fluid-specific questionnaire, and urine osmolality and 24-h volume with parameter estimates of -0.65 and 0.22, respectively (R2 = 0.20; p < 0.001). In the repeatability test, no significant differences were found between neither type of beverage nor total daily fluid intake at 6 months and 1-year assessment, compared to baseline. The proposed fluid-specific assessment questionnaire designed to assess the consumption of water and other beverages in Spanish adult individuals was found to be relatively valid with good repeatability. PMID- 27483320 TI - Associations of Fat Mass and Fat-Free Mass with Physical Fitness in 4-Year-Old Children: Results from the MINISTOP Trial. AB - Physical fitness is a powerful marker of health in youth. Studies in adolescents and adults suggest that higher fat mass is related to worse physical fitness. However, there is limited knowledge whether fat mass and fat-free mass are associated with physical fitness already in preschoolers. Baseline data from the MINISTOP (Mobile-based INtervention Intended to STop Obesity in Preschoolers) trial was utilized for this cross-sectional analysis. Body composition was assessed using air-displacement plethysmography. Fat mass index [fat mass (kg)/height2 (m)] and fat-free mass index [fat-free mass (kg)/height2 (m)] were used to provide height-adjusted measures of body composition. Physical fitness was measured using the PREFIT (FITness testing in PREschool children) battery, which assesses cardiorespiratory fitness, upper-body and lower-body muscular strength as well as motor fitness. In total, this study included 303 children (168 boys and 135 girls), who were on average 4.48 +/- 0.15 years old. Higher fat mass index was associated with worse cardiorespiratory fitness (standardized beta = -0.17, p = 0.002), lower-body muscular strength (beta = -0.17, p = 0.003) and motor fitness (beta = -0.21, p < 0.001) in regression analyses adjusted for age, sex and mutually adjusted for fat-mass index and fat-free mass index. Conversely, higher fat-free mass index was associated with better cardiorespiratory fitness (beta = 0.18, p = 0.002), upper-body muscular strength (beta = 0.39, p < 0.001), lower-body muscular strength (beta = 0.22, p < 0.001) and motor fitness (beta = 0.17, p = 0.004). Thus, fat mass and fat-free mass in preschoolers appear to have joint but opposite associations with physical fitness, an important marker for current and future health. PMID- 27483319 TI - Probiotics and Time to Achieve Full Enteral Feeding in Human Milk-Fed and Formula Fed Preterm Infants: Systematic Review and Meta-Analysis. AB - Probiotics have been linked to a reduction in the incidence of necrotizing enterocolitis and late-onset sepsis in preterm infants. Recently, probiotics have also proved to reduce time to achieve full enteral feeding (FEF). However, the relationship between FEF achievement and type of feeding in infants treated with probiotics has not been explored yet. The aim of this systematic review and meta analysis was to evaluate the effect of probiotics in reducing time to achieve FEF in preterm infants, according to type of feeding (exclusive human milk (HM) vs. formula). Randomized-controlled trials involving preterm infants receiving probiotics, and reporting on time to reach FEF were included in the systematic review. Trials reporting on outcome according to type of feeding (exclusive HM vs. formula) were included in the meta-analysis. Fixed-effect or random-effects models were used as appropriate. Results were expressed as mean difference (MD) with 95% confidence interval (CI). Twenty-five studies were included in the systematic review. In the five studies recruiting exclusively HM-fed preterm infants, those treated with probiotics reached FEF approximately 3 days before controls (MD -3.15 days (95% CI -5.25/-1.05), p = 0.003). None of the two studies reporting on exclusively formula-fed infants showed any difference between infants receiving probiotics and controls in terms of FEF achievement. The limited number of included studies did not allow testing for other subgroup differences between HM and formula-fed infants. However, if confirmed in further studies, the 3-days reduction in time to achieve FEF in exclusively HM-fed preterm infants might have significant implications for their clinical management. PMID- 27483321 TI - Hydrolytic Fate of 3/15-Acetyldeoxynivalenol in Humans: Specific Deacetylation by the Small Intestine and Liver Revealed Using in Vitro and ex Vivo Approaches. AB - In addition to deoxynivalenol (DON), acetylated derivatives, i.e., 3-acetyl and 15-acetyldexynivalenol (or 3/15ADON), are present in cereals leading to exposure to these mycotoxins. Animal and human studies suggest that 3/15ADON are converted into DON after their ingestion through hydrolysis of the acetyl moiety, the site(s) of such deacetylation being still uncharacterized. We used in vitro and ex vivo approaches to study the deacetylation of 3/15ADON by enzymes and cells/tissues present on their way from the food matrix to the blood in humans. We found that luminal deacetylation by digestive enzymes and bacteria is limited. Using human cells, tissues and S9 fractions, we were able to demonstrate that small intestine and liver possess strong deacetylation capacity compared to colon and kidneys. Interestingly, in most cases, deacetylation was more efficient for 3ADON than 15ADON. Although we initially thought that carboxylesterases (CES) could be responsible for the deacetylation of 3/15ADON, the use of pure human CES1/2 and of CES inhibitor demonstrated that CES are not involved. Taken together, our original model system allowed us to identify the small intestine and the liver as the main site of deacetylation of ingested 3/15ADON in humans. PMID- 27483322 TI - Human Papillomavirus Genotype Distribution in Invasive Cervical Cancer in Pakistan. AB - Few studies have assessed the burden of human papillomavirus (HPV) infection in Pakistan. We aim to provide specific information on HPV-type distribution in invasive cervical cancer (ICC) in the country. A total of 280 formalin-fixed paraffin-embedded tissue blocks were consecutively selected from Shaukat Khanum Memorial Cancer Hospital and Research Centre (Lahore, Pakistan). HPV-DNA was detected by SPF10 broad-spectrum PCR followed by DNA enzyme immunoassay and genotyping by LiPA25. HPV-DNA prevalence was 87.5% (95%CI: 83.0-91.1), with 96.1% of cases histologically classified as squamous cell carcinoma. Most of the HPV DNA positive cases presented single infections (95.9%). HPV16 was the most common type followed by HPV18 and 45. Among HPV-DNA positive, a significantly higher contribution of HPV16/18 was detected in Pakistan (78.4%; 72.7-83.3), compared to Asia (71.6%; 69.9-73.4) and worldwide (70.8%; 69.9-71.8) and a lower contribution of HPVs31/33/45/52/58 (11.1%; 7.9-15.7 vs. 19.8%; 18.3-21.3 and 18.5%; 17.7 19.3). HPV18 or HPV45 positive ICC cases were significantly younger than cases infected by HPV16 (mean age: 43.3, 44.4, 50.5 years, respectively). A routine cervical cancer screening and HPV vaccination program does not yet exist in Pakistan; however, the country could benefit from national integrated efforts for cervical cancer prevention and control. Calculated estimations based on our results show that current HPV vaccine could potentially prevent new ICC cases. PMID- 27483323 TI - The Balance between Recombination Enzymes and Accessory Replicative Helicases in Facilitating Genome Duplication. AB - Accessory replicative helicases aid the primary replicative helicase in duplicating protein-bound DNA, especially transcribed DNA. Recombination enzymes also aid genome duplication by facilitating the repair of DNA lesions via strand exchange and also processing of blocked fork DNA to generate structures onto which the replisome can be reloaded. There is significant interplay between accessory helicases and recombination enzymes in both bacteria and lower eukaryotes but how these replication repair systems interact to ensure efficient genome duplication remains unclear. Here, we demonstrate that the DNA content defects of Escherichia coli cells lacking the strand exchange protein RecA are driven primarily by conflicts between replication and transcription, as is the case in cells lacking the accessory helicase Rep. However, in contrast to Rep, neither RecA nor RecBCD, the helicase/exonuclease that loads RecA onto dsDNA ends, is important for maintaining rapid chromosome duplication. Furthermore, RecA and RecBCD together can sustain viability in the absence of accessory replicative helicases but only when transcriptional barriers to replication are suppressed by an RNA polymerase mutation. Our data indicate that the minimisation of replisome pausing by accessory helicases has a more significant impact on successful completion of chromosome duplication than recombination-directed fork repair. PMID- 27483325 TI - Deliberate Establishment of Asymptomatic Bacteriuria-A Novel Strategy to Prevent Recurrent UTI. AB - We have established a novel strategy to reduce the risk for recurrent urinary tract infection (UTI), where rapidly increasing antibiotic resistance poses a major threat. Epidemiologic studies have demonstrated that asymptomatic bacteriuria (ABU) protects the host against symptomatic infections with more virulent strains. To mimic this protective effect, we deliberately establish ABU in UTI-prone patients, who are refractory to conventional therapy. The patients are inoculated with Escherichia coli (E. coli) 83972, now widely used as a prototype ABU strain. Therapeutic efficacy has been demonstrated in a placebo controlled trial, supporting the feasibility of using E. coli 83972 as a tool to prevent recurrent UTI and, potentially, to outcompete antibiotic-resistant strains from the human urinary tract. In addition, the human inoculation protocol offers unique opportunities to study host-parasite interaction in vivo in the human urinary tract. Here, we review the clinical evidence for protection using this approach as well as some molecular insights into the pathogenesis of UTI that have been gained during these studies. PMID- 27483324 TI - Telomerase: The Devil Inside. AB - High telomerase activity is detected in nearly all human cancers but most human cells are devoid of telomerase activity. There is well-documented evidence that reactivation of telomerase occurs during cellular transformation. In humans, tumors can rely in reactivation of telomerase or originate in a telomerase positive stem/progenitor cell, or rely in alternative lengthening of telomeres, a telomerase-independent telomere-length maintenance mechanism. In this review, we will focus on the telomerase positive tumors. In this context, the recent findings that telomerase reverse transcriptase (TERT) promoter mutations represent the most common non-coding mutations in human cancer have flared up the long-standing discussion whether cancer originates from telomerase positive stem cells or telomerase reactivation is a final step in cellular transformation. Here, we will discuss the pros and cons of both concepts in the context of telomere length-dependent and telomere length-independent functions of telomerase. Together, these observations may provoke a re-evaluation of telomere and telomerase based therapies, both in telomerase inhibition for cancer therapy and telomerase activation for tissue regeneration and anti-ageing strategies. PMID- 27483326 TI - The Impact of Rendered Protein Meal Oxidation Level on Shelf-Life, Sensory Characteristics, and Acceptability in Extruded Pet Food. AB - Pet foods are expected to have a shelf-life for 12 months or more. Sensory analysis can be used to determine changes in products and to estimate products' shelf-life. The objectives of this study were to (1) investigate how increasing levels of oxidation in rendered protein meals used to produce extruded pet food affected the sensory properties and (2) determine the effect of shelf-life on pet owners' acceptability of extruded pet food diet formulated without the use of preservative. Pet food diets contained beef meat bone meal (BMBM) and chicken byproduct meal (CBPM) in which the oxidation was retarded with ethoxyquin, mixed tocopherols, or none at all, and then extruded into dry pet foods. These samples represented low, medium, and high oxidation levels, respectively. Samples were stored for 0, 3, 6, 9, and 12 months at ambient temperature. Each time point, samples were evaluated by six highly trained descriptive panelists for sensory attributes related to oxidation. Samples without preservatives were chosen for the acceptability test, since the differences in sensory characteristics over storage time were more distinguishable in those samples. Pet owners evaluated samples for aroma, appearance and overall liking. Descriptive sensory analysis detected significant changes in oxidized-related sensory characteristics over storage time. However, the differences for CBPM samples were more pronounced and directional. The consumer study showed no differences in pet owners' acceptability for BMBM samples. However, the noticeable increase in aroma characteristics (rancid aroma 0.33-4.21) in CBPM samples over storage time did have a negative effect on consumer's liking (overall liking 5.52-4.95). PMID- 27483327 TI - Combining Coagulation/MIEX with Biological Activated Carbon Treatment to Control Organic Fouling in the Microfiltration of Secondary Effluent. AB - Coagulation, magnetic ion exchange resin (MIEX) and biological activated carbon (BAC) were examined at lab scale as standalone, and sequential pre-treatments for controlling the organic fouling of a microfiltration membrane by biologically treated secondary effluent (BTSE) using a multi-cycle approach. MIEX gave slightly greater enhancement in flux than coagulation due to greater removal of high molecular weight (MW) humic substances, although it was unable to remove high MW biopolymers. BAC treatment was considerably more effective for improving the flux than coagulation or MIEX. This was due to the biodegradation of biopolymers and/or their adsorption by the biofilm, and adsorption of humic substances by the activated carbon, as indicated by size exclusion chromatography. Coagulation or MIEX followed by BAC treatment further reduced the problematic foulants and significantly improved the flux performance. The unified membrane fouling index showed that the reduction of membrane fouling by standalone BAC treatment was 42%. This improved to 65%, 70%, and 93% for alum, ferric chloride and MIEX pre-treatment, respectively, when followed by BAC treatment. This study showed the potential of sequential MIEX and BAC pre treatment for controlling organic fouling and thus enhancing the performance of microfiltration in the reclamation of BTSE. PMID- 27483329 TI - Effects of Cardiorespiratory Fitness and Obesity on Salivary Secretory IgA and Alpha-Amylase in South African Children. AB - This study examined whether cardiorespiratory fitness (CRF) and body composition are associated with salivary secretory immunoglobulin A (SIgA), a mucosal immunity marker, and salivary alpha-amylase (sAA), a marker of stress-related sympathetic nervous system (SNS) activity, in South African children. Morning (7:30-8:00 a.m.) saliva samples were collected from 132 children (10.05 +/- 1.68 years old, 74 females, 58 males). Body composition, resting blood pressure, and predicted maximal aerobic capacity (VO2max) were determined, and SIgA and sAA were quantified. Obese children had significantly higher sAA compared with overweight and normal weight children (p < 0.01). SIgA secretion rate was significantly lower in obese and overweight vs. normal weight children (p < 0.01). Multiple-linear regression analysis revealed that body mass index (BMI) (p < 0.05) and diastolic blood pressure (DBP) (p < 0.05) were independent predictors of sAA with CRF acting as a mitigator. Age and BMI predicted SIgA secretion rate (p < 0.05) with BMI (p < 0.001) found to be an independent predictor of SIgA secretion rate. Obesity, based on BMI, was associated with elevated SNS activity and lowered mucosal immunity. CRF-mitigated sympathetic activation was not associated with mucosal immunity. PMID- 27483330 TI - Fluorene-Perylene Diimide Arrays onto Graphene Sheets for Photocatalysis. AB - A facile approach for introducing photoactive poly(fluorene-perylene diimide) arrays (PFPDI) onto graphene sheets was accomplished. Noncovalent PFPDI/graphene ensembles formed via pi-pi stacking interactions between the two components and covalent PFPDI-graphene hybrids realized upon a Stille polycondensation reaction between an iodobenzyl-functionalized graphene, a 9,9-dialkyl substituted fluorene diboronic acid, and a 1,7-dibromo-PDI derivative were prepared. The morphology of PFPDI/graphene and PFPDI-graphene was evaluated by high-resolution transmission electron microscopy (HR-TEM), revealing the presence of even monolayered graphene sheets. Moreover, their photophysical and redox properties as assessed by electronic absorption spectroscopy and steady-state as well as time-resolved photoluminescence assays and electrochemistry, respectively, disclosed charge transfer characteristics owing to the high photoluminescence quenching of PFPDI in the presence of graphene and the fast component attributed to the decay of the emission intensity of the singlet excited state of PFPDI in both PFPDI/graphene and PFPDI-graphene. Next, testing their ability to operate in energy conversion schemes, the PFPDI-graphene was successfully employed as catalyst for the reduction of 4-nitrophenol to 4-aminophenol. Notably, the kinetics for the reduction were enhanced by visible light photoirradiation as compared to dark conditions as well as the presence of PFPDI-graphene, contrasting the case where only PFPDI, in the absence of graphene, was employed. Finally, recycling of the catalyst PFPDI-graphene was achieved and reutilization in successive reduction reactions of 4-nitrophenol was found to proceed with the same efficiency. PMID- 27483328 TI - Functional Consequences of Differential O-glycosylation of MUC1, MUC4, and MUC16 (Downstream Effects on Signaling). AB - Glycosylation is one of the most abundant post-translational modifications that occur within the cell. Under normal physiological conditions, O-linked glycosylation of extracellular proteins is critical for both structure and function. During the progression of cancer, however, the expression of aberrant and truncated glycans is commonly observed. Mucins are high molecular weight glycoproteins that contain numerous sites of O-glycosylation within their extracellular domains. Transmembrane mucins also play a functional role in monitoring the surrounding microenvironment and transducing these signals into the cell. In cancer, these mucins often take on an oncogenic role and promote a number of pro-tumorigenic effects, including pro-survival, migratory, and invasive behaviors. Within this review, we highlight both the processes involved in the expression of aberrant glycan structures on mucins, as well as the potential downstream impacts on cellular signaling. PMID- 27483331 TI - Vision-related Quality of Life in Glaucoma Suspect or Early Glaucoma Patients. AB - PURPOSE: To determine the association of vision-related quality of life (QoL) to demographic factors and visual function in glaucoma suspect or early glaucoma patients. MATERIALS AND METHODS: We administered the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) on the same day as a comprehensive ocular examination to participants either with glaucoma or at high risk for developing glaucoma. Regression models were used to determine the association between VFQ-25 composite and subscale scores, visual field status, logMAR equivalent visual acuity (VA), age, and sex. In all analyses we used data from the eye with the best mean deviation (MD), best pattern SD, and best VA. RESULTS: Data from 198 participants were analyzed. The mean best MD (+/-SD) was 0.02+/-1.52 dB (range, -5.11 to 2.63 dB) and the mean best pattern SD was 1.75+/ 1.03 dB (range, 0.91 to 8.36 dB). The mean VFQ-25 composite score was 91.6+/-6.7 (range, 54.5 to 100.0). Composite score and the Distance Activities, Color Vision subscale scores were associated with best MD (P<=0.05). The General Vision and Driving subscale scores were associated with best VA (P<=0.03). The composite score and the Distance Activities, Driving, and Color Vision subscale scores were associated with age (P<=0.05). Finally, the Distance Activities, Driving, and Peripheral Vision subscale scores were associated with sex (P<=0.04). CONCLUSIONS: Vision-related QoL is associated with visual field status even in early and suspected glaucoma. It is also associated with VA, age, and sex. Particular decreases in QoL are related to distance activities, driving, and color vision. PMID- 27483332 TI - Spontaneous Resolution of Presumed Idiopathic Elevated Episcleral Venous Pressure. AB - PURPOSE: To report a case of presumed idiopathic elevated episcleral venous pressure (EVP) initially requiring medical management. METHODS: We present a case report of a 28-year-old white man presenting with eye redness and soreness as a referral to the glaucoma service. He was diagnosed with idiopathic elevated EVP after systematic workup. RESULTS: Unilateral elevated intraocular pressure was detected along with dilated episcleral vessels, mild cupping of optic nerve head, and blood in Schlemm's canal, yet negative angiographic imaging and hypercoagulable labs. Topical antiglaucoma medication normalized intraocular pressure, which then maintained with resolution of episcleral vessel caliper and blood in Schlemm's canal after discontinuation of medication. CONCLUSIONS: This is the first reported case of spontaneous resolution of presumed idiopathic elevated EVP, persisting after discontinuation of medical therapy and without surgical intervention. PMID- 27483333 TI - New Ultrasound Biomicroscopy Iris Findings in Juvenile Xanthogranuloma. AB - We report a case of juvenile xanthogranuloma in a 12-month-old girl presenting with heterochromia, hyphema, and elevated intraocular pressure. This case demonstrates new ultrasound biomicroscopy iris findings of a generalized bumpy iris contour, suggesting diffuse heterogeneous involvement. This imaging finding has not been previously described. Untreated, iris juvenile xanthogranuloma may lead to corneal blood staining, glaucoma, and amblyopia. An understanding of the full range of ultrasound features of juvenile xanthogranuloma expands our appreciation for the clinical findings in this condition. PMID- 27483334 TI - Gas-Phase Interaction of Anions with Polyisobutylenes: Collision-Induced Dissociation Study and Quantum Chemical Modeling. AB - The gas-phase interaction of anions including fluoride, chloride, bromide, iodide, ethyl sulfate, chlorate, and nitrate with polyisobutylene (PIB) derivatives was studied using collision-induced dissociation (CID). The gas-phase adducts of anions with PIBs ([PIB + anion](-)) were generated from the electrosprayed solution of PIBs in the presence of the corresponding anions. The so-formed adducts subjected to CID showed a loss of anion at different characteristic collision energies, thus allowing the study of the strength of interaction between the anions and nonpolar PIBs having different end-groups. The values of characteristic collision energies (the energy needed to obtain 50% fragmentation) obtained by CID experiments correlated linearly with the binding enthalpies between the anion and PIB, as determined by density functional theory calculations. In the case of halide ions, the critical energies for dissociation, that is, the binding enthalpies for [PIB + anion](-) adducts, increased in the order of I(-) < Br(-) < Cl(-) < F(-). Furthermore, it was found that the binding enthalpies for the adducts formed with halide ions decreased approximately with the square radius of the halide ion, suggesting that the strength of interaction is mainly determined by the "surface" charge density of the halide ion. In addition, the characteristic collision energy versus the number of isobutylene units revealed a linear dependence. PMID- 27483335 TI - Work Characteristics as Predictors of Correctional Supervisors' Health Outcomes. AB - OBJECTIVE: This study examined associations among health behaviors, psychosocial work factors, and health status. METHODS: Correctional supervisors (n = 157) completed a survey that assessed interpersonal and organizational views on health. Chi-square and logistic regressions were used to examine relationships among variables. RESULTS: Respondents had a higher prevalence of obesity and comorbidities compared with the general US adult population. Burnout was significantly associated with nutrition, physical activity, sleep duration, sleep quality, diabetes, and anxiety/depression. Job meaning, job satisfaction, and workplace social support may predict health behaviors and outcomes. CONCLUSIONS: Correctional supervisors are understudied and have poor overall health status. Improving health behaviors of middle-management employees may have a beneficial effect on the health of the entire workforce. This paper demonstrates the importance of psychosocial work factors that may contribute to health behaviors and outcomes. PMID- 27483336 TI - Air Pollution During Pregnancy and Cord Blood Immune System Biomarkers. AB - OBJECTIVES: We aimed to determine whether average and trimester-specific exposures to ambient measures of nitrogen dioxide (NO2) and particular matter (PM2.5) were associated with elevated cord blood concentrations of immunoglobulin E (IgE) and two epithelial cell produced cytokines: interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP). METHODS: This study utilized data and biospecimens from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study. There were 2001 pregnant women recruited between 2008 and 2011 from 10 Canadian cities. Maternal exposure to NO2 and PM2.5 was estimated using land use regression and satellite-derived models. RESULTS: We observed statistically significant associations between maternal NO2 exposure and elevated cord blood concentrations of both IL-33 and TSLP among girls but not boys. CONCLUSIONS: Maternal NO2 exposure may impact the development of the newborn immune system as measured by cord blood concentrations of two cytokines. PMID- 27483338 TI - Transmission electron microscopy of carbon-coated and iron-doped titania nanoparticles. AB - We present a study on the properties of iron (Fe)-doped and carbon (C)-coated titania (TiO2) nanoparticles (NPs) which has been compiled by using x-ray diffraction (XRD), transmission electron microscopy (TEM), and x-ray photoelectron spectroscopy (XPS). These TiO2 NPs were prepared by using the flame synthesis method. This method allows the simultaneous C coating and Fe doping of TiO2 NPs. XRD investigations revealed that the phase of the prepared NPs was anatase TiO2. Conventional TEM analysis showed that the average size of the TiO2 NPs was about 65 nm and that the NPs were uniformly coated with the element C. Furthermore, from the x-ray energy dispersive spectrometry analysis, it was found that about 8 at.% Fe was present in the synthesized samples. High-resolution TEM (HRTEM) revealed the graphitized carbon structure of the layer surrounding the prepared TiO2 NPs. HRTEM analysis further revealed that the NPs possessed the crystalline structure of anatase titania. Energy-filtered TEM (EFTEM) analysis showed the C coating and Fe doping of the NPs. The ratio of L3 and L2 peaks for the Ti-L23 and Fe-L23 edges present in the core loss electron energy loss spectroscopy (EELS) revealed a +4 oxidation state for the Ti and a +3 oxidation state for the Fe. These EELS results were further confirmed with XPS analysis. The electronic properties of the samples were investigated by applying Kramers Kronig analysis to the low-loss EELS spectra acquired from the prepared NPs. The presented results showed that the band gap energy of the TiO2 NPs decreased from an original value of 3.2 eV to about 2.2 eV, which is quite close to the ideal band gap energy of 1.65 eV for photocatalysis semiconductors. The observed decrease in band gap energy of the TiO2 NPs was attributed to the presence of Fe atoms at the lattice sites of the anatase TiO2 lattice. In short, C-coated and Fe doped TiO2 NPs were synthesized with a rather cost-effective and comparatively easily scalable method. The presented analysis enables us to predict the excellent efficiency of these NPs for solar-cell and photo-catalysis applications. PMID- 27483337 TI - Chronic Condition Combinations and Productivity Loss Among Employed Nonelderly Adults (18 to 64 Years). AB - OBJECTIVE: We examined the relationship between specific chronic condition combinations and productivity loss measured by missed work days among nonelderly employed adults with at least two physical chronic conditions of arthritis, diabetes mellitus, heart disease, and hypertension. METHODS: We analyzed data from the Medical Expenditure Panel Survey for the years 2004 to 2012. RESULTS: Adults with arthritis/diabetes/heart disease had the highest average missed work days (14.42). In the adjusted model, compared with adults with arthritis/hypertension, adults with diabetes/heart disease and arthritis/heart disease/hypertension had significantly higher missed work days, while adults with diabetes/hypertension had significantly lower missed work days. CONCLUSION: Specific chronic condition combinations have a high burden of disease in terms of productivity loss. Workplace health programs that address multiple health conditions at the same time should be implemented to reduce missed work days. PMID- 27483339 TI - Accelerating Drug Development: Antiviral Therapies for Emerging Viruses as a Model. AB - Drug discovery and development is a lengthy and expensive process. Although no one, simple, single solution can significantly accelerate this process, steps can be taken to avoid unnecessary delays. Using the development of antiviral therapies as a model, we describe options for acceleration that cover target selection, assay development and high-throughput screening, hit confirmation, lead identification and development, animal model evaluations, toxicity studies, regulatory issues, and the general drug discovery and development infrastructure. Together, these steps could result in accelerated timelines for bringing antiviral therapies to market so they can treat emerging infections and reduce human suffering. PMID- 27483340 TI - A Life of Neurotransmitters. AB - Development of scientific creativity is often tied closely to mentorship. In my case, two years with Julius Axelrod, the sum total of my research training, was transformative. My mentoring generations of graduate students and postdoctoral fellows has been as nurturing for me as it has been for them. Work in our lab over fifty years has covered the breadth of neurotransmitters and related substances, focusing on the discovery and characterization of novel messenger molecules. I can't conceptualize a more rewarding professional life. PMID- 27483341 TI - Single-Photon Emission Computed Tomography/Computed Tomography Imaging in a Rabbit Model of Emphysema Reveals Ongoing Apoptosis In Vivo. AB - Evaluation of lung disease is limited by the inability to visualize ongoing pathological processes. Molecular imaging that targets cellular processes related to disease pathogenesis has the potential to assess disease activity over time to allow intervention before lung destruction. Because apoptosis is a critical component of lung damage in emphysema, a functional imaging approach was taken to determine if targeting apoptosis in a smoke exposure model would allow the quantification of early lung damage in vivo. Rabbits were exposed to cigarette smoke for 4 or 16 weeks and underwent single-photon emission computed tomography/computed tomography scanning using technetium-99m-rhAnnexin V-128. Imaging results were correlated with ex vivo tissue analysis to validate the presence of lung destruction and apoptosis. Lung computed tomography scans of long-term smoke-exposed rabbits exhibit anatomical similarities to human emphysema, with increased lung volumes compared with controls. Morphometry on lung tissue confirmed increased mean linear intercept and destructive index at 16 weeks of smoke exposure and compliance measurements documented physiological changes of emphysema. Tissue and lavage analysis displayed the hallmarks of smoke exposure, including increased tissue cellularity and protease activity. Technetium-99m-rhAnnexin V-128 single-photon emission computed tomography signal was increased after smoke exposure at 4 and 16 weeks, with confirmation of increased apoptosis through terminal deoxynucleotidyl transferase dUTP nick end labeling staining and increased tissue neutral sphingomyelinase activity in the tissue. These studies not only describe a novel emphysema model for use with future therapeutic applications, but, most importantly, also characterize a promising imaging modality that identifies ongoing destructive cellular processes within the lung. PMID- 27483342 TI - Multidrug-Resistant Aeromonas veronii Recovered from Channel Catfish (Ictalurus punctatus) in China: Prevalence and Mechanisms of Fluoroquinolone Resistance. AB - To emphasize the importance of the appropriate use of antibiotics in aquaculture systems, the prevalence of resistance to 25 antimicrobials was investigated in 42 Aeromonas veronii strains isolated from farm-raised channel catfish in China in 2006-2012. All experiments were based on minimal inhibitory concentrations (MICs), and susceptibility was assessed according to the Clinical and Laboratory Standards Institute. Some isolates displayed antibiotic resistance to the latest generation fluoroquinolones (i.e., ciprofloxacin, levofloxacin, and norfloxacin) in vitro. Therefore, we screened for genes conferring resistance to fluoroquinolones and performed conjugation experiments to establish the resistance mechanisms. The antibiotic resistance rates were 14.29-21.42% to three kinds of fluoroquinolones: ciprofloxacin, levofloxacin, and norfloxacin. Among the 42 strains isolated, 15 carried the qnrS2 gene. The MICs of the fluoroquinolones in transconjugants with qnrS2 were more than fourfold higher compared with the recipient. Among the fluoroquinolone-resistant A. veronii strains, eight had point mutations in both gyrA codon 83 (Ser83->Ile83) and parC codon 87 (Ser87->Ile87). However, five isolates with point mutations in parC codon 52 remained susceptible to the three fluoroquinolones. In conclusion, the mechanisms of fluoroquinolone resistance in A. veronii isolates may be related to mutations in gyrA codon 83 and parC codon 87 and the presence of the qnrS2 gene. PMID- 27483343 TI - The SMAD Pathway Is Required for Hepcidin Response During Endoplasmic Reticulum Stress. AB - Hepcidin, the iron hormone, is regulated by a number of stimulatory and inhibitory signals. The cAMP responsive element binding protein 3-like 3 (CREB3L3) mediates hepcidin response to endoplasmic reticulum (ER) stress. In this study we asked whether hepcidin response to ER stress also requires the small mother against decapentaplegic (SMAD)-1/5/8 pathway, which has a major role in hepcidin regulation in response to iron and other stimuli. We analyzed hepcidin mRNA expression and promoter activity in response to ER stressors in HepG2 cells in the presence of the bone morphogenetic protein (BMP) type I receptor inhibitor LDN-193189, mutated hepcidin promoter or small interfering RNA against different SMAD proteins. We then used a similar approach in vivo in wild type, Smad1/5, or Creb3l3-/- animals undergoing ER stress. In vitro, LDN-193189 prevented hepcidin mRNA induction by different ER stressors. Seemingly, mutation of a BMP-responsive element in the hepcidin promoter prevented ER stress-mediated up-regulation. Moreover, in vitro silencing of SMAD proteins by small interfering RNA, in particular SMAD5, blunted hepcidin response to ER stress. On the contrary, hepcidin induction by ER stress was maintained when using antibodies against canonical BMP receptor ligands. In vivo, hepcidin was induced by ER stress and prevented by LDN-193189. In addition, in Smad1/5 knockout mice, ER stress was unable to induce hepcidin expression. Finally, in Creb3l3 knockout mice, in response to ER stress, SMAD1/5 were correctly phosphorylated and hepcidin induction was still appreciable, although to a lesser extent as compared with the control mice. In conclusion, our study indicates that hepcidin induction by ER stress involves the central regulatory SMAD1/5 pathway. PMID- 27483344 TI - Correlation between afferent rearrangements and behavioral deficits after local excitotoxic insult in the mammalian vestibule: a rat model of vertigo symptoms. AB - Damage to inner ear afferent terminals is believed to result in many auditory and vestibular dysfunctions. The sequence of afferent injuries and repair, as well as their correlation with vertigo symptoms, remains poorly documented. In particular, information on the changes that take place at the primary vestibular endings during the first hours following a selective insult is lacking. In the present study, we combined histological analysis with behavioral assessments of vestibular function in a rat model of unilateral vestibular excitotoxic insult. Excitotoxicity resulted in an immediate but transient alteration of the balance function that was resolved within a week. Concomitantly, vestibular primary afferents underwent a sequence of structural changes followed by spontaneous repair. Within the first two hours after the insult, a first phase of pronounced vestibular dysfunction coincided with extensive swelling of afferent terminals. In the next 24 h, a second phase of significant but incomplete reduction of the vestibular dysfunction was accompanied by a resorption of swollen terminals and fiber retraction. Eventually, within 1 week, a third phase of complete balance restoration occurred. The slow and progressive withdrawal of the balance dysfunction correlated with full reconstitution of nerve terminals. Competitive re-innervation by afferent and efferent terminals that mimicked developmental synaptogenesis resulted in full re-afferentation of the sensory epithelia. By deciphering the sequence of structural alterations that occur in the vestibule during selective excitotoxic impairment, this study offers new understanding of how a vestibular insult develops in the vestibule and how it governs the heterogeneity of vertigo symptoms. PMID- 27483345 TI - The role of the dopamine D1 receptor in social cognition: studies using a novel genetic rat model. AB - Social cognition is an endophenotype that is impaired in schizophrenia and several other (comorbid) psychiatric disorders. One of the modulators of social cognition is dopamine, but its role is not clear. The effects of dopamine are mediated through dopamine receptors, including the dopamine D1 receptor (Drd1). Because current Drd1 receptor agonists are not Drd1 selective, pharmacological tools are not sufficient to delineate the role of the Drd1. Here, we describe a novel rat model with a genetic mutation in Drd1 in which we measured basic behavioural phenotypes and social cognition. The I116S mutation was predicted to render the receptor less stable. In line with this computational prediction, this Drd1 mutation led to a decreased transmembrane insertion of Drd1, whereas Drd1 expression, as measured by Drd1 mRNA levels, remained unaffected. Owing to decreased transmembrane Drd1 insertion, the mutant rats displayed normal basic motoric and neurological parameters, as well as locomotor activity and anxiety like behaviour. However, measures of social cognition like social interaction, scent marking, pup ultrasonic vocalizations and sociability, were strongly reduced in the mutant rats. This profile of the Drd1 mutant rat offers the field of neuroscience a novel genetic rat model to study a series of psychiatric disorders including schizophrenia, autism, depression, bipolar disorder and drug addiction. PMID- 27483346 TI - Nicotine ameliorates schizophrenia-like cognitive deficits induced by maternal LPS exposure: a study in rats. AB - Maternal exposure to infectious agents is a predisposing factor for schizophrenia with associated cognitive deficits in offspring. A high incidence of smoking in these individuals in adulthood might be, at least in part, due to the cognitive enhancing effects of nicotine. Here, we have used prenatal exposure to maternal lipopolysaccharide (LPS, bacterial endotoxin) at different time points as a model for cognitive deficits in schizophrenia to determine whether nicotine reverses any associated impairments. Pregnant rats were treated subcutaneously with LPS (0.5 mg/kg) at one of three neurodevelopmental time periods [gestation days (GD) 10-11, 15-16, 18-19]. Cognitive assessment in male offspring commenced in early adulthood [postnatal day (PND) 60] and included: prepulse inhibition (PPI), latent inhibition (LI) and delayed non-matching to sample (DNMTS). Following PND 100, daily nicotine injections (0.6 mg/kg, subcutaneously) were administered, and animals were re-tested in the same tasks (PND 110). Only maternal LPS exposure early during fetal neurodevelopment (GD 10-11) resulted in deficits in all tests compared to animals that had been prenatally exposed to saline at the same gestational time point. Repeated nicotine treatment led to global (PPI) and selective (LI) improvements in performance. Early but not later prenatal LPS exposure induced consistent deficits in cognitive tests with relevance for schizophrenia. Nicotine reversed the LPS-induced deficits in selective attention (LI) and induced a global enhancement of sensorimotor gating (PPI). PMID- 27483347 TI - Increased trabecular bone and improved biomechanics in an osteocalcin-null rat model created by CRISPR/Cas9 technology. AB - Osteocalcin, also known as bone gamma-carboxyglutamate protein (Bglap), is expressed by osteoblasts and is commonly used as a clinical marker of bone turnover. A mouse model of osteocalcin deficiency has implicated osteocalcin as a mediator of changes to the skeleton, endocrine system, reproductive organs and central nervous system. However, differences between mouse and human osteocalcin at both the genome and protein levels have challenged the validity of extrapolating findings from the osteocalcin-deficient mouse model to human disease. The rat osteocalcin (Bglap) gene locus shares greater synteny with that of humans. To further examine the role of osteocalcin in disease, we created a rat model with complete loss of osteocalcin using the CRISPR/Cas9 system. Rat osteocalcin was modified by injection of CRISPR/Cas9 mRNA into the pronuclei of fertilized single cell Sprague-Dawley embryos, and animals were bred to homozygosity and compound heterozygosity for the mutant alleles. Dual-energy X ray absorptiometry (DXA), glucose tolerance testing (GTT), insulin tolerance testing (ITT), microcomputed tomography (uCT), and a three-point break biomechanical assay were performed on the excised femurs at 5 months of age. Complete loss of osteocalcin resulted in bones with significantly increased trabecular thickness, density and volume. Cortical bone volume and density were not increased in null animals. The bones had improved functional quality as evidenced by an increase in failure load during the biomechanical stress assay. Differences in glucose homeostasis were observed between groups, but there were no differences in body weight or composition. This rat model of complete loss of osteocalcin provides a platform for further understanding the role of osteocalcin in disease, and it is a novel model of increased bone formation with potential utility in osteoporosis and osteoarthritis research. PMID- 27483348 TI - Identification of a nutrient-sensing transcriptional network in monocytes by using inbred rat models on a cafeteria diet. AB - Obesity has reached pandemic levels worldwide. The current models of diet-induced obesity in rodents use predominantly high-fat based diets that do not take into account the consumption of variety of highly palatable, energy-dense foods that are prevalent in Western society. We and others have shown that the cafeteria (CAF) diet is a robust and reproducible model of human metabolic syndrome with tissue inflammation in the rat. We have previously shown that inbred rat strains such as Wistar Kyoto (WKY) and Lewis (LEW) show different susceptibilities to CAF diets with distinct metabolic and morphometric profiles. Here, we show a difference in plasma MCP-1 levels and investigate the effect of the CAF diet on peripheral blood monocyte transcriptome, as powerful stress-sensing immune cells, in WKY and LEW rats. We found that 75.5% of the differentially expressed transcripts under the CAF diet were upregulated in WKY rats and were functionally related to the activation of the immune response. Using a gene co-expression network constructed from the genes differentially expressed between CAF diet-fed LEW and WKY rats, we identified acyl-CoA synthetase short-chain family member 2 (Acss2) as a hub gene for a nutrient-sensing cluster of transcripts in monocytes. The Acss2 genomic region is significantly enriched for previously established metabolism quantitative trait loci in the rat. Notably, monocyte expression levels of Acss2 significantly correlated with plasma glucose, triglyceride, leptin and non-esterified fatty acid (NEFA) levels as well as morphometric measurements such as body weight and the total fat following feeding with the CAF diet in the rat. These results show the importance of the genetic background in nutritional genomics and identify inbred rat strains as potential models for CAF diet-induced obesity. PMID- 27483349 TI - Conditional deletion of AP-2beta in mouse cranial neural crest results in anterior segment dysgenesis and early-onset glaucoma. AB - Anterior segment dysgenesis (ASD) encompasses a group of developmental disorders in which a closed angle phenotype in the anterior chamber of the eye can occur and 50% of patients develop glaucoma. Many ASDs are thought to involve an inappropriate patterning and migration of the periocular mesenchyme (POM), which is derived from cranial neural crest cells (NCCs) and mesoderm. Although, the mechanism of this disruption is not well understood, a number of transcriptional regulatory molecules have previously been implicated in ASDs. Here, we investigate the function of the transcription factor AP-2beta, encoded by Tfap2b, which is expressed in NCCs and their derivatives. Wnt1-Cre-mediated conditional deletion of Tfap2b in NCCs resulted in post-natal ocular defects typified by opacity. Histological data revealed that the conditional AP-2beta NCC knockout (KO) mutants exhibited dysgenesis of multiple structures in the anterior segment of the eye including defects in the corneal endothelium, corneal stroma, ciliary body and disruption in the iridocorneal angle with adherence of the iris to the cornea. We further show that this phenotype leads to a significant increase in intraocular pressure and a subsequent loss of retinal ganglion cells and optic nerve degeneration, features indicative of glaucoma. Overall, our findings demonstrate that AP-2beta is required in the POM for normal development of the anterior segment of the eye and that the AP-2beta NCC KO mice might serve as a new and exciting model of ASD and glaucoma that is fully penetrant and with early post-natal onset. PMID- 27483350 TI - A rat model for hepatitis E virus. AB - Hepatitis E virus (HEV) is one of the prime causes of acute viral hepatitis, and chronic hepatitis E is increasingly recognized as an important problem in the transplant setting. Nevertheless, the fundamental understanding of the biology of HEV replication is limited and there are few therapeutic options. The development of such therapies is partially hindered by the lack of a robust and convenient animal model. We propose the infection of athymic nude rats with the rat HEV strain LA-B350 as such a model. A cDNA clone, pLA-B350, was constructed and the infectivity of its capped RNA transcripts was confirmed in vitro and in vivo Furthermore, a subgenomic replicon, pLA-B350/luc, was constructed and validated for in vitro antiviral studies. Interestingly, rat HEV proved to be less sensitive to the antiviral activity of alpha-interferon, ribavirin and mycophenolic acid than genotype 3 HEV (a strain that infects humans). As a proof of-concept, part of the C-terminal polymerase sequence of pLA-B350/luc was swapped with its genotype 3 HEV counterpart: the resulting chimeric replicon replicated with comparable efficiency as the wild-type construct, confirming that LA-B350 strain is amenable to humanization (replacement of certain sequences or motifs by their counterparts from human HEV strains). Finally, ribavirin effectively inhibited LA-B350 replication in athymic nude rats, confirming the suitability of the rat model for antiviral studies. PMID- 27483351 TI - MicroRNA screening identifies a link between NOVA1 expression and a low level of IKAP in familial dysautonomia. AB - Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a mutation in intron 20 of the IKBKAP gene (c.2204+6T>C), leading to tissue specific skipping of exon 20 and a decrease in the synthesis of the encoded protein IKAP (also known as ELP1). Small non-coding RNAs known as microRNAs (miRNAs) are important post-transcriptional regulators of gene expression and play an essential role in the nervous system development and function. To better understand the neuronal specificity of IKAP loss, we examined expression of miRNAs in human olfactory ecto-mesenchymal stem cells (hOE-MSCs) from five control individuals and five FD patients. We profiled the expression of 373 miRNAs using microfluidics and reverse transcription coupled to quantitative PCR (RT-qPCR) on two biological replicate series of hOE-MSC cultures from healthy controls and FD patients. This led to the total identification of 26 dysregulated miRNAs in FD, validating the existence of a miRNA signature in FD. We then selected the nine most discriminant miRNAs for further analysis. The signaling pathways affected by these dysregulated miRNAs were largely within the nervous system. In addition, many targets of these dysregulated miRNAs had been previously demonstrated to be affected in FD models. Moreover, we found that four of our nine candidate miRNAs target the neuron-specific splicing factor NOVA1. We demonstrated that overexpression of miR-203a-3p leads to a decrease of NOVA1, counter-balanced by an increase of IKAP, supporting a potential interaction between NOVA1 and IKAP. Taken together, these results reinforce the choice of miRNAs as potential therapeutic targets and suggest that NOVA1 could be a regulator of FD pathophysiology. PMID- 27483352 TI - Autophagy resolves early retinal inflammation in Igf1-deficient mice. AB - Insulin-like growth factor-1 (IGF-1) is a growth factor with differentiating, anti-apoptotic and metabolic functions in the periphery, and anti-inflammatory properties in the nervous system. Mice that have mutations in the Igf1 gene, rendering the gene product inactive (Igf1(-/-)), present with age-related visual loss accompanied by structural alterations in the first synapses of the retinal pathway. Recent advances have revealed a crucial role of autophagy in immunity and inflammation. Keeping in mind this close relationship, we aimed to decipher these processes in the context of the defects that occur during ageing in the retina of Igf1(-/-) mice. Tnfa and Il1b mRNAs, and phosphorylation of JNK and p38 MAPK were elevated in the retinas of 6- and 12-month old Igf1(-/-) mice compared to those in age-matched Igf1(+/+) controls. In 6-month-old Igf1(-/-) retinas, increased mRNA levels of the autophagy mediators Becn1, Atg9, Atg5 and Atg4, decreased p62 (also known as SQSTM1) protein expression together with an increased LC3-II:LC3-I ratio reflected active autophagic flux. However, in retinas from 12-month-old Igf1(-/-) mice, Nlrp3 mRNA, processing of the IL1beta pro-form and immunostaining of active caspase-1 were elevated compared to those in age-matched Igf1(+/+) controls, suggesting activation of the inflammasome. This effect concurred with accumulation of autophagosomes and decreased autophagic flux in the retina. Microglia localization and status of activation in the retinas of 12-month-old Igf1(+/+) and Igf1(-/-) mice, analyzed by immunostaining of Cd11b and Iba-1, showed a specific distribution pattern in the outer plexiform layer (OPL), inner plexiform layer (IPL) and inner nuclear layer (INL), and revealed an increased number of activated microglia cells in the retina of 12-month-old blind Igf1(-/-) mice. Moreover, reactive gliosis was exclusively detected in the retinas from 12-month-old blind Igf1(-/-) mice. In conclusion, this study provides new evidence in a mouse model of IGF-1 deficiency that autophagy is an adaptive response that might confer protection against persistent inflammation in the retina during ageing. PMID- 27483353 TI - YBR/EiJ mice: a new model of glaucoma caused by genes on chromosomes 4 and 17. AB - A variety of inherited animal models with different genetic causes and distinct genetic backgrounds are needed to help dissect the complex genetic etiology of glaucoma. The scarcity of such animal models has hampered progress in glaucoma research. Here, we introduce a new inherited glaucoma model: the inbred mouse strain YBR/EiJ (YBR). YBR mice develop a form of pigmentary glaucoma. They exhibit a progressive age-related pigment-dispersing iris disease characterized by iris stromal atrophy. Subsequently, these mice develop elevated intraocular pressure (IOP) and glaucoma. Genetic mapping studies utilizing YBR as a glaucoma susceptible strain and C57BL/6J as a glaucoma-resistant strain were performed to identify genetic loci responsible for the iris disease and high IOP. A recessive locus linked to Tyrp1(b) on chromosome 4 contributes to iris stromal atrophy and high IOP. However, this is not the only important locus. A recessive locus on YBR chromosome 17 causes high IOP independent of the iris stromal atrophy. In specific eyes with high IOP caused by YBR chromosome 17, the drainage angle (through which ocular fluid leaves the eye) is largely open. The YBR alleles of genes on chromosomes 4 and 17 underlie the development of high IOP and glaucoma but do so through independent mechanisms. Together, these two loci act in an additive manner to increase the susceptibility of YBR mice to the development of high IOP. The chromosome 17 locus is important not only because it causes IOP elevation in mice with largely open drainage angles but also because it exacerbates IOP elevation and glaucoma induced by pigment dispersion. Therefore, YBR mice are a valuable resource for studying the genetic etiology of IOP elevation and glaucoma, as well as for testing new treatments. PMID- 27483355 TI - A chemical with proven clinical safety rescues Down-syndrome-related phenotypes in through DYRK1A inhibition. AB - DYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases. PMID- 27483354 TI - Alterations in nuclear structure promote lupus autoimmunity in a mouse model. AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the development of autoantibodies that recognize components of the cell nucleus. The vast majority of lupus research has focused on either the contributions of immune cell dysfunction or the genetics of the disease. Because granulocytes isolated from human SLE patients had alterations in neutrophil nuclear morphology that resembled the Pelger-Huet anomaly, and had prominent mis-splicing of mRNA encoding the nuclear membrane protein lamin B receptor (LBR), consistent with their Pelger-Huet-like nuclear morphology, we used a novel mouse model system to test the hypothesis that a disruption in the structure of the nucleus itself also contributes to the development of lupus autoimmunity. The lupus-prone mouse strain New Zealand White (NZW) was crossed with c57Bl/6 mice harboring a heterozygous autosomal dominant mutation in Lbr (B6.Lbr(ic/+)), and the (NZW*B6.Lbr(ic))F1 offspring were evaluated for induction of lupus autoimmunity. Only female (NZW*B6.Lbr(ic))F1 mice developed lupus autoimmunity, which included splenomegaly, kidney damage and autoantibodies. Kidney damage was accompanied by immune complex deposition, and perivascular and tubule infiltration of mononuclear cells. The titers of anti-chromatin antibodies exceeded those of aged female MRL-Fas(lpr) mice, and were predominantly of the IgG2 subclasses. The anti nuclear antibody staining profile of female (NZW*B6.Lbr(ic))F1 sera was complex, and consisted of an anti-nuclear membrane reactivity that colocalized with the A type lamina, in combination with a homogeneous pattern that was related to the recognition of histones with covalent modifications that are associated with gene activation. An anti-neutrophil IgM recognizing calreticulin, but not myeloperoxidase (MPO) or proteinase 3 (PR3), was also identified. Thus, alterations in nuclear structure contribute to lupus autoimmunity when expressed in the context of a lupus-prone genetic background, suggesting a mechanism for the development of lupus autoimmunity in genetically predisposed individuals that is induced by the disruption of nuclear architecture. PMID- 27483356 TI - Small heat shock proteins mediate cell-autonomous and -nonautonomous protection in a Drosophila model for environmental-stress-induced degeneration. AB - Cell and tissue degeneration, and the development of degenerative diseases, are influenced by genetic and environmental factors that affect protein misfolding and proteotoxicity. To better understand the role of the environment in degeneration, we developed a genetic model for heat shock (HS)-stress-induced degeneration in Drosophila This model exhibits a unique combination of features that enhance genetic analysis of degeneration and protection mechanisms involving environmental stress. These include cell-type-specific failure of proteostasis and degeneration in response to global stress, cell-nonautonomous interactions within a simple and accessible network of susceptible cell types, and precise temporal control over the induction of degeneration. In wild-type flies, HS stress causes selective loss of the flight ability and degeneration of three susceptible cell types comprising the flight motor: muscle, motor neurons and associated glia. Other motor behaviors persist and, accordingly, the corresponding cell types controlling leg motor function are resistant to degeneration. Flight motor degeneration was preceded by a failure of muscle proteostasis characterized by diffuse ubiquitinated protein aggregates. Moreover, muscle-specific overexpression of a small heat shock protein (HSP), HSP23, promoted proteostasis and protected muscle from HS stress. Notably, neurons and glia were protected as well, indicating that a small HSP can mediate cell nonautonomous protection. Cell-autonomous protection of muscle was characterized by a distinct distribution of ubiquitinated proteins, including perinuclear localization and clearance of protein aggregates associated with the perinuclear microtubule network. This network was severely disrupted in wild-type preparations prior to degeneration, suggesting that it serves an important role in muscle proteostasis and protection. Finally, studies of resistant leg muscles revealed that they sustain proteostasis and the microtubule cytoskeleton after HS stress. These findings establish a model for genetic analysis of degeneration and protection mechanisms involving contributions of environmental factors, and advance our understanding of the protective functions and therapeutic potential of small HSPs. PMID- 27483359 TI - At Least They Know I Give a Damn! PMID- 27483358 TI - Comparison of the long-term effects of single-dose methotrexate and salpingectomy on ovarian reserve in terms of anti-mullerian hormone levels. AB - The aim of this study was to compare the effects of single-dose methotrexate (MTX) and salpingectomy on ovarian reserve in women with ectopic pregnancy in the late post-treatment period. A total of 181 patients were included in the study; 56 of them received a single-dose of MTX, 45 of them had undergone salpingectomy treatment for ectopic pregnancy in the previous 12-18 months, and 80 healthy women constituted an age-matched control group. The anti-mullerian hormone (AMH), follicle stimulating hormone (FSH) and oestrogen (E2) levels, as well as antral follicle counts (AFC) of the patients were evaluated. The average age was similar in both groups (p = 0.094) and there was no statistically significant difference in the smoking status of the patients (p = 0.949). None of the three groups displayed a significant difference in terms of AFC (p = 0.528), AMH (p = 0.147), FSH (p = 0.393) and E2 levels (p = 0.117). In the treatment of ectopic pregnancy neither the single-dose MTX application nor the salpingectomy had any permanent detrimental effect on the ovarian reserve; serum AMH levels and AFC are unaltered in the long term following single-dose MTX or salpingectomy. PMID- 27483357 TI - The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN. AB - The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients. PMID- 27483360 TI - Adjunctive Amantadine Treatment for Aggressive Behavior in Children: A Series of Eight Cases. AB - PURPOSE: Amantadine has a growing body of evidence for the treatment of aggressive behavior in patients with traumatic brain injury, autism spectrum disorder, and developmental disability. We describe our experience with adjunctive amantadine treatment for aggressive behavior in eight hospitalized children. METHODS: We conducted a retrospective chart review of psychiatric inpatients initiated on amantadine for the management of aggressive behavior. RESULTS: The majority of patients were male (n = 7) ranging in age from 6 to 10 years (mean 8.5). The most common diagnoses were attention-deficit/hyperactivity disorder (n = 6), intermittent explosive disorder (n = 4), oppositional defiant disorder (n = 4), and bipolar disorder (n = 3). Five patients had either borderline intellectual functioning or an unspecified cognitive disorder, and four patients had either confirmed or suspected in utero substance exposure. Included patients received amantadine for a minimum of 20 days. Mean adjunctive amantadine starting dose was 2.6 mg/(kg.day) and mean discharge dose was 6.7 mg/(kg.day). The treating child and adolescent psychiatrist described five patients as very much improved and three patients as much improved following amantadine therapy. Average seclusions and PRN medications per week were reduced from baseline to week 1 of amantadine (1.81, 95% CI [1.02, 2.61] versus 0.25, 95% CI [0.00, 0.55] (p = 0.01) and 4, 95% CI [2.22, 5.78] versus 1.63, 95% CI [0.71, 2.54] (p = 0.02)), respectively. Both physical restraints and seclusions were reduced from baseline in the second week of amantadine (1.56, 95% CI [0.45, 2.68] versus 0.00, 95% CI [0.00, 0.00] [p = 0.04] and 1.81, 95% CI [1.02, 2.61] versus 0.13, 95% CI [0.00, 0.35] [p = 0.01]), respectively. No adverse events related to amantadine were identified. CONCLUSIONS: We describe clinical improvement supported by objective measures in eight children with aggressive behavior treated with adjunctive amantadine. These findings warrant further investigation as patients were taking other mood stabilizing medications and there are limitations associated with retrospective chart reviews. PMID- 27483361 TI - Clinical and genetic characteristics in patients with Huntington's disease from China. AB - Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of unstable CAG repeats in the HTT gene. There are scarce data about HD in China. Fifty-eight HD patients were consecutively recruited and assessed using the Unified HD Rating Scale (UHDRS) motor section and UHDRS behaviour assessment (UHDRS-b). Genetic analyses were also conducted. Thirty-three women and Twenty five men were diagnosed with a mean age of 46.1 +/- 11.2 years and a mean number of CAG triplet repeats 44.6 +/- 4.4. CAG triplet repeat number was negatively correlated with age at onset, and positively correlated with UHDRS-b total score, and its subdomains including depressed mood, low self-esteem, anxiety and irritability. On the other hand, negative correlations were identified between age at onset and UHDRS-b total score, and its subdomains include low self-esteem, anxiety, suicidal thought, irritability and apathy. Disease durations were correlated with UHDRS motor scores and anxiety domain of UHDRS-b. This is the largest series of Chinese HD patients with demographic, clinical and genetic data confirms the demographic features of Chinese HD patients are comparable to those in other ethnic backgrounds. CAG triplet repeat number may also predict the severity of behaviour problems in HD patients besides its predication for age of onset. PMID- 27483362 TI - Inclusion of Vancomycin as Part of Broad-Spectrum Coverage Does Not Improve Outcomes in Patients with Intra-Abdominal Infections: A Post Hoc Analysis. AB - BACKGROUND: Management of complicated intra-abdominal infections (cIAIs) includes broad-spectrum antimicrobial coverage and commonly includes vancomycin for the empiric coverage of methicillin-resistant Staphylococcus aureus (MRSA). Ideally, culture-guided de-escalation follows to promote robust antimicrobial stewardship. This study assessed the impact and necessity of vancomycin in cIAI treatment regimens. PATIENTS AND METHODS: A post hoc analysis of the Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial was performed. Patients receiving piperacillin-tazobactam (P/T) and/or a carbapenem were included with categorization based on use of vancomycin. Univariate and multivariable analyses evaluated effects of including vancomycin on individual and the composite of undesirable outcomes (recurrent IAI, surgical site infection [SSI], or death). RESULTS: The study cohort included 344 patients with 110 (32%) patients receiving vancomycin. Isolation of MRSA occurred in only eight (2.3%) patients. Vancomycin use was associated with a similar composite outcome, 29.1%, vs. no vancomycin, 22.2% (p = 0.17). Patients receiving vancomycin had (mean [standard deviation]) higher Acute Physiology and Chronic Health Evaluation II scores (13.1 [6.6] vs. 9.4 [5.7], p < 0.0001), extended length of stay (12.6 [10.2] vs. 8.6 [8.0] d, p < 0.001), and prolonged antibiotic courses (9.1 [8.0] vs. 7.1 [4.9] d, p = 0.02). After risk adjustment in a multivariate model, no significant difference existed for the measured outcomes. CONCLUSIONS: This post hoc analysis reveals that addition of vancomycin occurred in nearly one third of patients and more often in sicker patients. Despite this selection bias, no appreciable differences in undesired outcomes were demonstrated, suggesting limited utility for adding vancomycin to cIAI treatment regimens. PMID- 27483363 TI - Comparison of the ability of mammalian eEF1A1 and its oncogenic variant eEF1A2 to interact with actin and calmodulin. AB - The question as to why a protein exerts oncogenic properties is answered mainly by well-established ideas that these proteins interfere with cellular signaling pathways. However, the knowledge about structural and functional peculiarities of the oncoproteins causing these effects is far from comprehensive. The 97.5% homologous tissue-specific A1 and A2 isoforms of mammalian translation elongation factor eEF1A represent an interesting model to study a difference between protein variants of a family that differ in oncogenic potential. We propose that the different oncogenic impact of A1 and A2 might be explained by differences in their ability to communicate with their respective cellular partners. Here we probed this hypothesis by studying the interaction of eEF1A with two known partners - calmodulin and actin. Indeed, an inability of the A2 isoform to interact with calmodulin is shown, while calmodulin is capable of binding A1 and interferes with its tRNA-binding and actin-bundling activities in vitro. Both A1 and A2 variants revealed actin-bundling activity; however, the form of bundles formed in the presence of A1 or A2 was distinctly different. Thus, a potential inability of A2 to be controlled by Ca2+-mediated regulatory systems is revealed. PMID- 27483364 TI - Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer. AB - Most members of the kallikrein-related peptidase family have been demonstrated to be dysregulated in ovarian cancer and modulate tumor growth, migration, invasion, and resistance to chemotherapy. In the present study, we assessed the mRNA expression levels of KLK6 and KLK8 by quantitative PCR in 100 patients with advanced serous ovarian cancer FIGO stage III/IV. A pronounced correlation between KLK6 and KLK8 mRNA expression (rs = 0.636, p < 0.001) was observed, indicating coordinate expression of both peptidases. No significant associations of clinical parameters with KLK6, KLK8, and a combined score KLK6+KLK8 were found. In univariate Cox regression analysis, elevated mRNA levels of KLK6 were significantly linked with shortened overall survival (OS) (hazard ratio [HR] = 2.07, p = 0.007). While KLK8 values were not associated with patients' outcome, high KLK6+KLK8 values were significantly associated with shorter progression-free survival (HR = 1.82, p = 0.047) and showed a trend towards significance in the case of OS (HR = 1.82, p = 0.053). Strikingly, in multivariable analysis, elevated KLK6 mRNA values, apart from residual tumor mass, remained an independent predictive marker for poor OS (HR = 2.33, p = 0.005). As KLK6 mRNA and protein levels correlate, KLK6 may represent an attractive therapeutic target for potent and specific inhibitors of its enzymatic activity. PMID- 27483365 TI - An Evaluation of Mobile Applications for Reproductive Endocrinology and Infertility Providers. AB - OBJECTIVE: To identify and rate reproductive endocrinology and infertility (REI) mobile applications (apps) targeted toward REI providers. DESIGN: A list of REI apps was found in both the Apple iTunes and Google Play stores using the following seven MeSH terms: reproductive endocrinology, REI, infertility, fertility, In Vitro Fertilization, IVF, and embryology. Patient-centered apps were excluded. The remaining apps were then evaluated for accuracy using reliable references. SETTING: Mobile technology. PATIENTS/INTERVENTIONS: None. MAIN OUTCOME MEASURES: Accurate apps were evaluated for comprehensiveness (the extent of the ability to aid in clinical decision-making) and rated with objective and subjective components using the APPLICATIONS scoring system. RESULTS: Using the seven REI-related MeSH terms, 985 apps and 1,194 apps were identified in the Apple iTunes and Google Play stores, respectively. Of these unique apps, only 20 remained after excluding patient-centered apps. Upon further review for applicability to REI specifically and content accuracy, only seven apps remained. These seven apps were then rated using the APPLICATIONS scoring system. CONCLUSION: Only 0.32% of 2,179 apps reviewed for this study were useful to REI providers. There is potential for further mobile resource development in the area of REI, given the limited number and varying comprehensiveness and quality of available apps. PMID- 27483366 TI - Anti-HIV Antibody Responses and the HIV Reservoir Size during Antiretroviral Therapy. AB - BACKGROUND: A major challenge to HIV eradication strategies is the lack of an accurate measurement of the total burden of replication-competent HIV (the "reservoir"). We assessed the association of anti-HIV antibody responses and the estimated size of the reservoir during antiretroviral therapy (ART). METHODS: We evaluated anti-HIV antibody profiles using luciferase immunoprecipitation systems (LIPS) assay in relation to several blood-based HIV reservoir measures: total and 2-LTR DNA (rtPCR or droplet digital PCR); integrated DNA (Alu PCR); unspliced RNA (rtPCR), multiply-spliced RNA (TILDA), residual plasma HIV RNA (single copy PCR), and replication-competent virus (outgrowth assay). We also assessed total HIV DNA and RNA in gut-associated lymphoid tissue (rtPCR). Spearman correlations and linear regressions were performed using log-transformed blood- or tissue-based reservoir measurements as predictors and log-transformed antibody levels as outcome variables. RESULTS: Among 51 chronically HIV-infected ART-suppressed participants (median age = 57, nadir CD4+ count = 196 cells/mm3, ART duration = 9 years), the most statistically significant associations were between antibody responses to integrase and HIV RNA in gut-associated lymphoid tissue (1.17 fold increase per two-fold RNA increase, P = 0.004) and between antibody responses to matrix and integrated HIV DNA in resting CD4+ T cells (0.35 fold-decrease per two fold DNA increase, P = 0.003). However, these associations were not statistically significant after a stringent Bonferroni-adjustment of P<0.00045. Multivariate models including age and duration of ART did not markedly alter results. CONCLUSIONS: Our findings suggest that anti-HIV antibody responses may reflect the size of the HIV reservoir during chronic treated HIV disease, possibly via antigen recognition in reservoir sites. Larger, prospective studies are needed to validate the utility of antibody levels as a measure of the total body burden of HIV during treatment. PMID- 27483367 TI - Hand Mycetoma: The Mycetoma Research Centre Experience and Literature Review. AB - Mycetoma is a devastating, neglected tropical disease characterised by extensive tissue involvement resulting in destruction, deformities and disabilities in the affected patients. The hand is commonly affected by mycetoma thus compromises its functionality and hinder the patient's daily activities of living. In this communication, we report on 533 patients with hand mycetoma managed over a period of 24 years at the Mycetoma Research Centre, University of Khartoum, Khartoum, Sudan. Eumycetoma was the commonest type of mycetoma (83.3%) encountered. Males were predominately affected (69.2%) with a sex ratio of 2.2:1. The majority of the patients (84%) were young adult below the age of 40 years old at presentation. The generality of patients (86.4%) were from the Sudan mycetoma belt. Children and adolescents (28.1%), farmers (18.2%) and workers (17.4%) were more frequently affected. The majority of patients (67.4%) had disease duration of less than 5 years at presentation. The study, did not document significant history of local trauma, familial tendency, concomitant medical diseases or other predisposing cause for mycetoma in this population. Pain (23.1%) was not a disease feature in this series and 52% of patients had past surgery for mycetoma and recurrence. The right hand was affected most (60.4%), and 64% of them had small lesion at presentation. Conventional x-ray was only helpful in patients with advanced disease and the MRI accurately determined the disease extension. Cytological smears, surgical biopsies histopathological examination and grains culture were the principal diagnostic tools for causative organisms' identification. In the present series it was difficult to determine the treatment outcome due to high patients follow up dropout. PMID- 27483368 TI - Adverse Renal, Endocrine, Hepatic, and Metabolic Events during Maintenance Mood Stabilizer Treatment for Bipolar Disorder: A Population-Based Cohort Study. AB - BACKGROUND: There is limited, poorly characterized information about adverse events occurring during maintenance treatment of bipolar disorder. We aimed to determine adverse event rates during treatment with lithium, valproate, olanzapine, and quetiapine. METHODS AND FINDINGS: We conducted a propensity score adjusted cohort study using nationally representative United Kingdom electronic health records from January 1, 1995, until December 31, 2013. We included patients who had a diagnosis of bipolar disorder and were prescribed lithium (n = 2148), valproate (n = 1670), olanzapine (n = 1477), or quetiapine (n = 1376) as maintenance mood stabilizer treatment. Adverse outcomes were chronic kidney disease, thyroid disease, hypercalcemia, weight gain, hypertension, type 2 diabetes mellitus, cardiovascular disease, and hepatotoxicity. The propensity score included important demographic, physical health, and mental health predictors of drug treatment allocation. The median duration of drug treatment was 1.48 y (interquartile range 0.64-3.43). Compared to patients prescribed lithium, those taking valproate, olanzapine, and quetiapine had reduced rates of chronic kidney disease stage 3 or more severe, following adjustment for propensity score, age, and calendar year, and accounting for clustering by primary care practice (valproate hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.45-0.69; p < 0.001, olanzapine HR 0.57; 95% CI 0.45-0.71; p < 0.001, quetiapine HR 0.62; 95% CI 0.47-0.80; p < 0.001). Hypothyroidism was reduced in those taking valproate (HR 0.60; 95% CI 0.40-0.89; p = 0.012) and olanzapine (HR 0.48; 95% CI 0.29-0.77; p = 0.003), compared to those taking lithium. Rates of new onset hyperthyroidism (valproate HR 0.24; 95% CI 0.09-0.61; p = 0.003, olanzapine HR 0.31; 95% CI 0.13-0.73; p = 0.007) and hypercalcemia (valproate HR 0.25; 95% CI 0.10-0.60; p = 0.002, olanzapine HR 0.32; 95% CI 0.14-0.76; p = 0.008, quetiapine HR 0.23; 95% CI 0.07-0.73; p = 0.013) were also reduced relative to lithium. However, rates of greater than 15% weight gain on valproate, olanzapine, and quetiapine were higher (valproate HR 1.62; 95% CI 1.31-2.01; p < 0.001, olanzapine HR 1.84; 95% CI 1.47-2.30; p < 0.001, quetiapine HR 1.67; 95% CI 1.24-2.20; p < 0.001) than in individuals prescribed lithium, as were rates of hypertension in the olanzapine treated group (HR 1.41, 95% CI 1.06-1.87; p = 0.017). We found no significant difference in rates of chronic kidney disease stage 4 or more severe, type 2 diabetes mellitus, cardiovascular disease, or hepatotoxicity. Despite estimates being robust following sensitivity analyses, limitations include the potential for residual confounding and ascertainment bias and an inability to examine dosage effects. CONCLUSIONS: Lithium use is associated with more renal and endocrine adverse events but less weight gain than commonly used alternative mood stabilizers. Risks need to be offset with the effectiveness and anti-suicidal benefits of lithium and the potential metabolic side effects of alternative treatment options. PMID- 27483369 TI - Modelling Transcapillary Transport of Fluid and Proteins in Hemodialysis Patients. AB - BACKGROUND: The kinetics of protein transport to and from the vascular compartment play a major role in the determination of fluid balance and plasma refilling during hemodialysis (HD) sessions. In this study we propose a whole body mathematical model describing water and protein shifts across the capillary membrane during HD and compare its output to clinical data while evaluating the impact of choosing specific values for selected parameters. METHODS: The model follows a two-compartment structure (vascular and interstitial space) and is based on balance equations of protein mass and water volume in each compartment. The capillary membrane was described according to the three-pore theory. Two transport parameters, the fractional contribution of large pores (alphaLP) and the total hydraulic conductivity (LpS) of the capillary membrane, were estimated from patient data. Changes in the intensity and direction of individual fluid and solute flows through each part of the transport system were analyzed in relation to the choice of different values of small pores radius and fractional conductivity, lymphatic sensitivity to hydraulic pressure, and steady-state interstitial-to-plasma protein concentration ratio. RESULTS: The estimated values of LpS and alphaLP were respectively 10.0 +/- 8.4 mL/min/mmHg (mean +/- standard deviation) and 0.062 +/- 0.041. The model was able to predict with good accuracy the profiles of plasma volume and serum total protein concentration in most of the patients (average root-mean-square deviation < 2% of the measured value). CONCLUSIONS: The applied model provides a mechanistic interpretation of fluid transport processes induced by ultrafiltration during HD, using a minimum of tuned parameters and assumptions. The simulated values of individual flows through each kind of pore and lymphatic absorption rate yielded by the model may suggest answers to unsolved questions on the relative impact of these not measurable quantities on total vascular refilling and fluid balance. PMID- 27483370 TI - Immunologic Function and Molecular Insight of Recombinant Interleukin-18. AB - In recent years, cytokine-mediated therapy has emerged as further advance alternative in cancer therapy. Interleukin-18 (IL-18) has exhibited interesting anti-cancer properties especially when combined with IL-12. We engineered IL-18 in order to improve its activity using single point mutagenesis. IL-18 mutants were constructed according to binding residues and polarity which we tried to increase polarity in M33Q and M60Q, enhanced cationicity in E6K, and flexibility in T63A. All IL-18 proteins were expressed in Pichia pastoris, purified, and then measured the activity by treating with the NK-92MI cell line to evaluate interferon-gamma (IFN-gamma) stimulation. The E6K and T63A mutant forms showed higher activity with respect to native proteins at the concentration of 200 ng mL 1 by inducing the expression of IFN-gamma, about factors of 9 and 4, respectively. Meanwhile, M33Q and M60Q had no significant activity to induce IFN gamma. Interestingly, the combination of E6K and T63A mutations could synergize the induction activity of IL-18 to be 16 times at 200 ng mL-1. Furthermore, molecular dynamics studies have elucidated the effect due to mutation on conformation of the binding site of IL-18. The results turn out that E6K provides structural perseverance against mutation, while M33Q and M60Q promote vivid overall change in protein conformation, especially at the binding site. For T63A, mutation yields small difference in structure but clearly increases structural flexibility. However, a small structural change was observed when T63A was combined with E6K. Our research resulted in a novel version of IL-18 which could be a new key candidate for cytokine-mediated therapy. PMID- 27483371 TI - How Does Awareness Modulate Goal-Directed and Stimulus-Driven Shifts of Attention Triggered by Value Learning? AB - In order to behave adaptively, attention can be directed in space either voluntarily (i.e., endogenously) according to strategic goals, or involuntarily (i.e., exogenously) through reflexive capture by salient or novel events. The emotional or motivational value of stimuli can also strongly influence attentional orienting. However, little is known about how reward-related effects compete or interact with endogenous and exogenous attention mechanisms, particularly outside of awareness. Here we developed a visual search paradigm to study subliminal value-based attentional orienting. We systematically manipulated goal-directed or stimulus-driven attentional orienting and examined whether an irrelevant, but previously rewarded stimulus could compete with both types of spatial attention during search. Critically, reward was learned without conscious awareness in a preceding phase where one among several visual symbols was consistently paired with a subliminal monetary reinforcement cue. Our results demonstrated that symbols previously associated with a monetary reward received higher attentional priority in the subsequent visual search task, even though these stimuli and reward were no longer task-relevant, and despite reward being unconsciously acquired. Thus, motivational processes operating independent of conscious awareness may provide powerful influences on mechanisms of attentional selection, which could mitigate both stimulus-driven and goal-directed shifts of attention. PMID- 27483372 TI - Kin Recognition in a Clonal Fish, Poecilia formosa. AB - Relatedness strongly influences social behaviors in a wide variety of species. For most species, the highest typical degree of relatedness is between full siblings with 50% shared genes. However, this is poorly understood in species with unusually high relatedness between individuals: clonal organisms. Although there has been some investigation into clonal invertebrates and yeast, nothing is known about kin selection in clonal vertebrates. We show that a clonal fish, the Amazon molly (Poecilia formosa), can distinguish between different clonal lineages, associating with genetically identical, sister clones, and use multiple sensory modalities. Also, they scale their aggressive behaviors according to the relatedness to other females: they are more aggressive to non-related clones. Our results demonstrate that even in species with very small genetic differences between individuals, kin recognition can be adaptive. Their discriminatory abilities and regulation of costly behaviors provides a powerful example of natural selection in species with limited genetic diversity. PMID- 27483373 TI - Variation in Indole-3-Acetic Acid Production by Wild Saccharomyces cerevisiae and S. paradoxus Strains from Diverse Ecological Sources and Its Effect on Growth. AB - Phytohormone indole-3-acetic acid (IAA) is the most common naturally occurring and most thoroughly studied plant growth regulator. Microbial synthesis of IAA has long been known. Microbial IAA biosynthesis has been proposed as possibly occurring through multiple pathways, as has been proven in plants. However, the biosynthetic pathways of IAA and the ecological roles of IAA in yeast have not been widely studied. In this study, we investigated the variation in IAA production and its effect on the growth of Saccharomyces cerevisiae and its closest relative Saccharomyces paradoxus yeasts from diverse ecological sources. We found that almost all Saccharomyces yeasts produced IAA when cultured in medium supplemented with the primary precursor of IAA, L-tryptophan (L-Trp). However, when cultured in medium without L-Trp, IAA production was only detected in three strains. Furthermore, exogenous added IAA exerted stimulatory and inhibitory effects on yeast growth. Interestingly, a negative correlation was observed between the amount of IAA production in the yeast cultures and the IAA inhibition ratio of their growth. PMID- 27483374 TI - Myosin Light Chain Kinase (MLCK) Gene Influences Exercise Induced Muscle Damage during a Competitive Marathon. AB - Myosin light chain kinase (MLCK) phosphorylates the regulatory light chain (RLC) of myosin producing increases in force development during skeletal muscle contraction. It has been suggested that MLCK gene polymorphisms might alter RLC phosphorylation thereby decreasing the ability to produce force and to resist strain during voluntary muscle contractions. Thus, the genetic variations in the MLCK gene might predispose some individuals to higher values of muscle damage during exercise, especially during endurance competitions. The aim of this investigation was to determine the influence of MLCK genetic variants on exercise induced muscle damage produced during a marathon. Sixty-seven experienced runners competed in a marathon race. The MLCK genotype (C37885A) of these marathoners was determined. Before and after the race, a sample of venous blood was obtained to assess changes in serum myoglobin concentrations and leg muscle power changes were measured during a countermovement jump. Self-reported leg muscle pain and fatigue were determined by questionnaires. A total of 59 marathoners (88.1%) were CC homozygotes and 8 marathoners (11.9%) were CA heterozygotes. The two groups of participants completed the race with a similar time (228 +/- 33 vs 234 +/- 39 min; P = 0.30) and similar self-reported values for fatigue (15 +/- 2 vs 16 +/- 2 A.U.; P = 0.21) and lower-limb muscle pain (6.2 +/- 1.7 vs 6.6 +/- 1.8 cm; P = 0.29). However, CC marathoners presented higher serum myoglobin concentrations (739 +/- 792 vs 348 +/- 144 MUg.mL-1; P = 0.03) and greater pre-to-post- race leg muscle power reduction (-32.7 +/- 15.7 vs -21.2 +/- 21.6%; P = 0.05) than CA marathoners. CA heterozygotes for MLCK C37885A might present higher exercise induced muscle damage after a marathon competition than CC counterparts. PMID- 27483375 TI - Gender disparities in mortality from infectious diseases in Serbia, 1991-2014: a time of civil wars and global crisis. AB - Infectious diseases remain one of the leading causes of death worldwide. The aim of this descriptive epidemiological study was to analyse the trends in mortality from infectious diseases in Serbia (excluding the Autonomous Province of Kosovo & Metohia) from 1991 to 2014 using joinpoint regression analysis. The mortality rates from infectious diseases were found to have increased markedly from 1991 to 1994 (+12.4% per year), followed by a significant decline from 1994 to 2009 ( 4.6% per year) and then another increase from 2009 to 2014 (+4.3% per year). Throughout the study period, mortality rates were consistently higher in men than in women. Although a substantial decline was observed for young people of both sexes, no consistent pattern was evident for the middle-aged nor the elderly. Since 1991, septicaemia has emerged as a leading cause of infectious disease mortality, particularly in older men. The Yugoslav civil wars in the 1990s and the global financial crisis in 2008 corresponded with changes in the trends in mortality from infectious diseases in Serbia, with the elderly showing particular vulnerability during those time periods. Data presented in this study might be useful to improve control of infectious diseases in Serbia. PMID- 27483376 TI - Characteristics of child daycare centres associated with clustering of major enteropathogens. AB - Insights into transmission dynamics of enteropathogens in children attending daycare are limited. Here we aimed at identifying daycare centre (DCC) characteristics associated with time-clustered occurrence of enteropathogens in DCC-attending children. For this purpose, we used the KIzSS network, which comprises 43 DCCs that participated in infectious disease surveillance in The Netherlands during February 2010-February 2013. Space-time scan statistics were used to identify clusters of rotavirus, norovirus, astrovirus, Giardia lamblia and Cryptosporidium spp. in a two-dimensional DCC characteristic space constructed using canonical correlation analysis. Logistic regression models were then used to further identify DCC characteristics associated with increased or decreased odds for clustering of enteropathogens. Factors associated with increased odds for enteropathogen clustering in DCCs were having indoor/outdoor paddling pools or sandpits, owning animals, high numbers of attending children, and reporting outbreaks to local health authorities. Factors associated with decreased odds for enteropathogen clustering in DCCs were cleaning child potties in designated waste disposal stations, cleaning vomit with chlorine-based products, daily cleaning of toys, extra cleaning of toys during a suspected outbreak, and excluding children with gastroenteritis. These factors provide targets for reducing the burden of gastrointestinal morbidity associated with time-clustered occurrence of major enteropathogens in DCC attendees. PMID- 27483377 TI - The authors reply. PMID- 27483378 TI - Mapping Uncertainty Due to Missing Data in the Global Ocean Health Index. AB - Indicators are increasingly used to measure environmental systems; however, they are often criticized for failing to measure and describe uncertainty. Uncertainty is particularly difficult to evaluate and communicate in the case of composite indicators which aggregate many indicators of ecosystem condition. One of the ongoing goals of the Ocean Health Index (OHI) has been to improve our approach to dealing with missing data, which is a major source of uncertainty. Here we: (1) quantify the potential influence of gapfilled data on index scores from the 2015 global OHI assessment; (2) develop effective methods of tracking, quantifying, and communicating this information; and (3) provide general guidance for implementing gapfilling procedures for existing and emerging indicators, including regional OHI assessments. For the overall OHI global index score, the percent contribution of gapfilled data was relatively small (18.5%); however, it varied substantially among regions and goals. In general, smaller territorial jurisdictions and the food provision and tourism and recreation goals required the most gapfilling. We found the best approach for managing gapfilled data was to mirror the general framework used to organize, calculate, and communicate the Index data and scores. Quantifying gapfilling provides a measure of the reliability of the scores for different regions and components of an indicator. Importantly, this information highlights the importance of the underlying datasets used to calculate composite indicators and can inform and incentivize future data collection. PMID- 27483379 TI - Circumventing the natural, frequent oestrogen waves of the female cheetah (Acinonyx jubatus) using oral progestin (Altrenogest). AB - Cheetah are induced ovulators, experiencing short, variable oestrogen waves year round. Exogenous gonadotrophin administration induces ovulation, but success is variable and often improves if ovaries are quiescent. After affirming the presence of short-term oestrogenic waves, we examined the effect of the timing of administration of exogenous equine and human chorionic gonadotrophins (eCG-hCG) within the oestrogen concentration pattern on subsequent follicle development and oocyte and corpus luteum quality. We also investigated ovarian suppression using an oral progestin (Altrenogest, 7 days) and assessed whether Altrenogest moderated adrenal activity by reducing glucocorticoid metabolites. All cheetahs exhibited short (every ~7-10 days), sporadic, year-round increases in faecal oestradiol punctuated by unpredictable periods (4-10 weeks) of baseline oestradiol (anoestrous). Gonadotrophin (eCG-hCG) efficacy was not affected by oestradiol 'wave' pattern if administered >=3 days after an oestrogen peak. Such cheetahs produced normative faecal progestagen patterns and higher numbers (P<0.06) of mature oocytes than females given gonadotrophins <=2 days after an oestradiol peak. Altrenogest supplementation expanded the interval between oestradiol peaks to 12.9 days compared with 7.3 days without progestin pretreatment. Altrenogest-fed females excreted less (P<0.05) glucocorticoid metabolites than non-supplemented counterparts. Results show that Altrenogest is effective for suppressing follicular activity, may contribute to reduced glucocorticoid production and may result in more effective ovulation induction via gonadotrophin therapy. PMID- 27483380 TI - MicroRNAs as biomarkers for major depression: a role for let-7b and let-7c. AB - There is a growing emphasis in the field of psychiatry on the need to identify candidate biomarkers to aid in diagnosis and clinical management of depression, particularly with respect to predicting response to specific therapeutic strategies. MicroRNAs are small nucleotide sequences with the ability to regulate gene expression at the transcriptomic level and emerging evidence from a range of studies has highlighted their biomarker potential. Here we compared healthy controls (n=20) with patients diagnosed with major depression (n=40) and who were treatment-resistant to identify peripheral microRNA biomarkers, which could be used for diagnosis and to predict response to electroconvulsive therapy (ECT) and ketamine (KET) infusions, treatments that have previously shown to be effective in treatment-resistant depression (TRD). At baseline and after treatment, blood samples were taken and symptom severity scores rated using the Hamilton Depression Rating Scale (HDRS). Samples were analyzed for microRNA expression using microarray and validated using quantitative PCR. As expected, both treatments reduced HDRS scores. Compared with controls, the baseline expression of the microRNA let-7b was less by ~40% in TRD patients compared with controls. The baseline expression of let-7c was also lower by ~50% in TRD patients who received ECT. Bioinformatic analysis revealed that let-7b and let-7c regulates the expression of 27 genes in the PI3k-Akt-mTOR signaling pathway, which has previously been reported to be dysfunctional in depression. The expression of miR 16, miR-182, miR-451 and miR-223 were similar to that in controls. Baseline microRNA expression could not predict treatment response and microRNAs were unaffected by treatment. Taken together, we have identified let-7b and let-7c as candidate biomarkers of major depression. PMID- 27483381 TI - Persistent post-stroke depression in mice following unilateral medial prefrontal cortical stroke. AB - Post-stroke depression (PSD) is a common outcome following stroke that is associated with poor recovery. To develop a preclinical model of PSD, we targeted a key node of the depression-anxiety circuitry by inducing a unilateral ischemic lesion to the medial prefrontal cortex (mPFC) stroke. Microinjection of male C57/BL6 mice with endothelin-1 (ET-1, 1600 pmol) induced a small (1 mm(3)) stroke consistently localized within the left mPFC. Compared with sham control mice, the stroke mice displayed a robust behavioral phenotype in four validated tests of anxiety including the elevated plus maze, light-dark, open-field and novelty suppressed feeding tests. In addition, the stroke mice displayed depression-like behaviors in both the forced swim and tail suspension test. In contrast, there was no effect on locomotor activity or sensorimotor function in the horizontal ladder, or cylinder and home cage activity tests, indicating a silent stroke due to the absence of motor abnormalities. When re-tested at 6 weeks post stroke, the stroke mice retained both anxiety and depression phenotypes. Surprisingly, at 6 weeks post stroke the lesion site was infiltrated by neurons, suggesting that the ET-1-induced neuronal loss in the mPFC was reversible over time, but was insufficient to promote behavioral recovery. In summary, unilateral ischemic lesion of the mPFC results in a pronounced and persistent anxiety and depression phenotype with no evident sensorimotor deficits. This precise lesion of the depression circuitry provides a reproducible model to study adaptive cellular changes and preclinical efficacy of novel interventions to alleviate PSD symptoms. PMID- 27483382 TI - Transcriptomic signatures of neuronal differentiation and their association with risk genes for autism spectrum and related neuropsychiatric disorders. AB - Genes for autism spectrum disorders (ASDs) are also implicated in fragile X syndrome (FXS), intellectual disabilities (ID) or schizophrenia (SCZ), and converge on neuronal function and differentiation. The SH-SY5Y neuroblastoma cell line, the most widely used system to study neurodevelopment, is currently discussed for its applicability to model cortical development. We implemented an optimal neuronal differentiation protocol of this system and evaluated neurodevelopment at the transcriptomic level using the CoNTeXT framework, a machine-learning algorithm based on human post-mortem brain data estimating developmental stage and regional identity of transcriptomic signatures. Our improved model in contrast to currently used SH-SY5Y models does capture early neurodevelopmental processes with high fidelity. We applied regression modelling, dynamic time warping analysis, parallel independent component analysis and weighted gene co-expression network analysis to identify activated gene sets and networks. Finally, we tested and compared these sets for enrichment of risk genes for neuropsychiatric disorders. We confirm a significant overlap of genes implicated in ASD with FXS, ID and SCZ. However, counterintuitive to this observation, we report that risk genes affect pathways specific for each disorder during early neurodevelopment. Genes implicated in ASD, ID, FXS and SCZ were enriched among the positive regulators, but only ID-implicated genes were also negative regulators of neuronal differentiation. ASD and ID genes were involved in dendritic branching modules, but only ASD risk genes were implicated in histone modification or axonal guidance. Only ID genes were over-represented among cell cycle modules. We conclude that the underlying signatures are disorder specific and that the shared genetic architecture results in overlaps across disorders such as ID in ASD. Thus, adding developmental network context to genetic analyses will aid differentiating the pathophysiology of neuropsychiatric disorders. PMID- 27483384 TI - Correction: Direct Measurements of Oxygen Gradients in Spheroid Culture System Using Electron Parametric Resonance Oximetry. AB - [This corrects the article DOI: 10.1371/journal.pone.0149492.]. PMID- 27483383 TI - An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation. AB - Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-d-aspartate receptor agonist, are increased. The enzyme amino-beta-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Asberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior. PMID- 27483385 TI - A perspective on liquid salts for energy and materials. AB - Liquid salts comprising molten salts and ionic liquids offer important media to address both energy and materials challenges. Here we review topics presented in this Faraday Discussion volume related to improved electrowinning of metals, optimisation of processes, new electrochemical device concepts, chemistry in ionic liquids, conversion of biomass, carbon chemistry and nuclear applications. The underlying phenomenology is then reviewed and commentary given. Some future applications are then discussed, further exemplifying the high potential rewards achievable from these chemistries. PMID- 27483387 TI - Body mass-corrected molecular rate for bird mitochondrial DNA. AB - Mitochondrial DNA remains one of the most widely used molecular markers to reconstruct the phylogeny and phylogeography of closely related birds. It has been proposed that bird mitochondrial genomes evolve at a constant rate of ~0.01 substitution per site per million years, that is that they evolve according to a strict molecular clock. This molecular clock is often used in studies of bird mitochondrial phylogeny and molecular dating. However, rates of mitochondrial genome evolution vary among bird species and correlate with life history traits such as body mass and generation time. These correlations could cause systematic biases in molecular dating studies that assume a strict molecular clock. In this study, we overcome this issue by estimating corrected molecular rates for birds. Using complete or nearly complete mitochondrial genomes of 475 species, we show that there are strong relationships between body mass and substitution rates across birds. We use this information to build models that use bird species' body mass to estimate their substitution rates across a wide range of common mitochondrial markers. We demonstrate the use of these corrected molecular rates on two recently published data sets. In one case, we obtained molecular dates that are twice as old as the estimates obtained using the strict molecular clock. We hope that this method to estimate molecular rates will increase the accuracy of future molecular dating studies in birds. PMID- 27483388 TI - Arene Selectivity by a Flexible Coordination Polymer Host. AB - The coordination polymers [Ag4 (O2 CCF3 )4 (phen)3 ]? phen?arene (1?phen?arene) (phen=phenazine; arene=toluene, p-xylene or benzene) have been synthesised from the solution phase in a series of arene solvents and crystallographically characterised. By contrast, analogous syntheses from o-xylene and m-xylene as the solvent yield the solvent-free coordination polymer [Ag4 (O2 CCF3 )4 (phen)2 ] (2). Toluene, p-xylene and benzene have been successfully used in mixed-arene syntheses to template the formation of coordination polymers 1?phen?arene, which incorporate o- or m-xylene. The selectivity of 1?phen?arene for the arene guests was determined, through pairwise competition experiments, to be p xylene>toluene~benzene>o-xylene>m-xylene. The largest selectivity coefficient was determined as 14.2 for p-xylene:m-xylene and the smallest was 1.0 for toluene:benzene. PMID- 27483389 TI - CaMKII inhibition promotes neuronal apoptosis by transcriptionally upregulating Bim expression. AB - The effects of Ca/calmodulin-dependent protein kinase II (CaMKII) on neuronal apoptosis are complex and contradictory, and the underlying mechanisms remain unclear. Bcl-2-interacting mediator of cell death (Bim) is an important proapoptotic protein under many physiological and pathophysiological conditions. However, there is no evidence that CaMKII and Bim are mechanistically linked in neuronal apoptosis. In this study, we showed that CaMKII inhibition by the inhibitors KN-62 and myristoylated autocamtide-2-related inhibitory peptide promoted apoptosis in cerebellar granule neurons in a dose-dependent manner. CaMKII inhibition increased Bim protein and messenger RNA levels. The expression of early growth response factor-1, a transcription factor of Bim, was also induced by CaMKII inhibitors. These data suggested that CaMKII repressed the transcriptional expression of Bim. Moreover, knockdown of Bim using small interfering RNAs attenuated the proapoptotic effects of CaMKII inhibition. Taken together, this is the first report to show that CaMKII inhibition transcriptionally upregulates Bim expression to promote neuronal apoptosis, providing new insights into the proapoptotic mechanism of CaMKII inhibition. PMID- 27483390 TI - Diagnostic dry bone histology in human paleopathology. AB - Paleopathology is the study of trauma and disease as may be observed in ancient (human) remains. In contrast to its central role in current medical practice, microscopy plays a rather modest role in paleopathology. This is at least partially due to the differences between fresh and decomposed (i.e., skeletonized or "dry bone") tissue samples. This review discusses these differences and describes how they affect the histological analysis of paleopathological specimens. First, we provide a summary of some general challenges related to the histological analysis of palaeopathological specimens. Second, the reader is introduced in bone tissue histology and bone tissue dynamics. The remainder of the paper is dedicated to the diagnostic value of dry bone histology. Its value and limitations are illustrated by comparing several well-studied paleopathological cases with similar contemporary, clinical cases. This review illustrates that due to post-mortem loss of soft tissue, a limited number of disorders display pathognomonic features during histological analysis of skeletonized human remains. In the remainder of cases, histology may help to narrow down the differential diagnosis or is diagnostically unspecific. A comprehensive, multidisciplinary diagnostic approach therefore remains essential. Clin. Anat. 29:831-843, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27483391 TI - Pimasertib, a selective oral MEK1/2 inhibitor: absolute bioavailability, mass balance, elimination route, and metabolite profile in cancer patients. AB - AIM: This trial (NCT: 01713036) investigated the absolute bioavailability, mass balance and metabolite profile of pimasertib in a new design combining these investigations in a single group of patients. METHODS: Six male patients with pathologically confirmed, locally advanced or metastatic solid tumours were enrolled. Exclusion criteria included Eastern Cooperative Oncology Group performance status >1. In Part A of the trial, patients received a 60 mg oral dose of unlabelled pimasertib followed by an intravenous (i.v.) tracer dose of [14 C]pimasertib 2 MUg (equalling 9 kBq) as a bolus injection, one hour after the oral dose, on Day 1. On Day 8, all patients received 60 mg pimasertib capsules spiked with 2.6 MBq of [14 C]pimasertib. Patients received 60 mg oral unlabelled pimasertib twice daily from Day 3 to Day 21 of Part A and in subsequent 21-day cycles in Part B. RESULTS: Following i.v. administration, [14 C]pimasertib exhibited a geometric mean total body clearance of 45.7 l h-1 (geometric coefficient of variation [geometric CV]: 47.2%) and a volume of distribution of 229 l (geometric CV: 42.0%). Absolute bioavailability was 73%. The majority of the oral [14 C] dose (85.1%) was recovered in excreta. Total radioactivity was mainly excreted into urine (52.8%) and faeces (30.7%) with 78.9% of the [14 C] dose recovered as metabolites. Two major circulating metabolites were identified in plasma: a carboxylic acid (M445) and a phosphoethanolamine conjugate (M554). The safety profile was in line with the published pimasertib trials. CONCLUSION: Pimasertib showed a favourable pharmacokinetic profile with high absolute bioavailability and a unique metabolic pathway (conjugation with phosphoethanolamine). PMID- 27483392 TI - Power and Confounding in Diffuse Alveolar Hemorrhage Secondary to Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Comment on the Article by Cartin-Ceba et al. PMID- 27483393 TI - Single Nucleotide Polymorphisms and Long-Term Clinical Outcome in Renal Transplant Patients: A Validation Study. AB - Genome-wide association studies (GWAS) are designed to investigate single nucleotide polymorphisms (SNPs) and the association with a clinical phenotype. A previous GWAS performed in 300 renal transplant recipients identified two SNPs (rs3811321 and rs6565887) associated with serum creatinine and clinical outcome. We sought to validate these findings. Genotyping of the two SNPs was performed using Taqman assays in 1638 Caucasians participating in the Assessment of LEscol in Renal Transplant (ALERT) study. Primary endpoint was death-censored graft loss, and secondary endpoint was all-cause mortality. Applying Cox regression, no crude association to graft loss was found for rs3811321 on chromosome 14 (hazard ratio [HR] 0.87, 95% CI 0.59-1.29, p = 0.50) or rs6565887 on chromosome 18 (HR 0.88, CI 0.62-1.25, p = 0.48). Multivariable adjustments did not change results, nor did evaluation of the number of risk alleles formed by the two SNPs. No association with mortality was detected. In conclusion, an impact of two SNPs on chromosomes 14 and 18 on death-censored graft survival or all-cause mortality was not confirmed. Our results emphasize the importance of validating findings from high-throughput genetics studies and call for large collaborative research initiatives in the field of transplantation outcomes. PMID- 27483395 TI - Directed Assembly of Soft Anisotropic Nanoparticles by Colloid Electrospinning. AB - Directed assembly of triblock copolymer worms to produce nanostructured fibers is achieved via colloid electrospinning. These copolymer worms are conveniently prepared by polymerization-induced self-assembly in concentrated aqueous dispersion. Addition of a second water-soluble component, poly(vinyl alcohol), is found to be critical for the production of well-defined fibers: trial experiments performed using the worms alone produce only spherical microparticles. Transmission electron microscopy studies confirm that the worm morphology survives electrospinning and the worms become orientated parallel to the main axis of the fibers during their generation. The average deviant angle (thetadev ) between the worm orientation and fiber axis decreases from 17 degrees to 9 degrees as the worm/PVA mass ratio increases from 1.15:1 to 5:1, indicating a greater degree of worm alignment within fibers with higher worm contents and smaller fiber diameters. Thus triblock copolymer fibers of ~300 +/- 120 nm diameter can be readily produced that comprise aligned worms on the nanoscale. PMID- 27483394 TI - Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure. AB - Acute-on-chronic liver failure (ACLF) in cirrhosis is characterized by acute decompensation (AD), organ failure(s), and high short-term mortality. Recently, we have proposed (systemic inflammation [SI] hypothesis) that ACLF is the expression of an acute exacerbation of the SI already present in decompensated cirrhosis. This study was aimed at testing this hypothesis and included 522 patients with decompensated cirrhosis (237 with ACLF) and 40 healthy subjects. SI was assessed by measuring 29 cytokines and the redox state of circulating albumin (HNA2), a marker of systemic oxidative stress. Systemic circulatory dysfunction (SCD) was estimated by plasma renin (PRC) and copeptin (PCC) concentrations. Measurements were performed at enrollment (baseline) in all patients and sequentially during hospitalization in 255. The main findings of this study were: (1) Patients with AD without ACLF showed very high baseline levels of inflammatory cytokines, HNA2, PRC, and PCC. Patients with ACLF showed significantly higher levels of these markers than those without ACLF; (2) different cytokine profiles were identified according to the type of ACLF precipitating event (active alcoholism/acute alcoholic hepatitis, bacterial infection, and others); (3) severity of SI and frequency and severity of ACLF at enrollment were strongly associated. The course of SI and the course of ACLF (improvement, no change, or worsening) during hospitalization and short-term mortality were also strongly associated; and (4) the strength of association of ACLF with SI was higher than with SCD. CONCLUSION: These data support SI as the primary driver of ACLF in cirrhosis. (Hepatology 2016;64:1249-1264). PMID- 27483396 TI - Photon Energy Becomes the Third Dimension in Crystallographic Texture Analysis. AB - Conventional analysis of the preferred orientation of crystallites (crystallographic texture) involves X-ray diffraction with area detectors and 2D data output. True 3D, spatially resolved information requires sample rotation in the beam, thus changing the probed volume, which introduces signal smearing and precludes the scanning of complex structures. This obstacle has been overcome by energy-dispersive Laue diffraction. A method has been devised to reach a large portion of reciprocal space and translate the X-ray photon energy into the missing third dimension of space. Carbon fibers and lobster exoskeleton as examples of biomineralized tissue have been analyzed. The major potential of this method lies in its "one-shot" nature and the direct 3D information requiring no previous knowledge of the sample. It allows the texture of large samples with complex substructures to be scanned and opens up the conceptual possibility of following texture changes in situ, for example, during crystallization. PMID- 27483397 TI - Gated Channels and Selectivity Tuning of CO2 over N2 Sorption by Post-Synthetic Modification of a UiO-66-Type Metal-Organic Framework. AB - The highly porous and stable metal-organic framework (MOF) UiO-66 was altered using post-synthetic modifications (PSMs). Prefunctionalization allowed the introduction of carbon double bonds into the framework through a four-step synthesis from 2-bromo-1,4-benzenedicarboxylic acid; the organic linker 2-allyl 1,4-benzenedicarboxylic acid was obtained. The corresponding functionalized MOF (UiO-66-allyl) served as a platform for further PSMs. From UiO-66-allyl, epoxy, dibromide, thioether, diamine, and amino alcohol functionalities were synthesized. The abilities of these compounds to adsorb CO2 and N2 were compared, which revealed the structure-selectivity correlations. All synthesized MOFs showed profound thermal stability together with an increased ability for selective CO2 uptake and molecular gate functionalities at low temperatures. PMID- 27483399 TI - In-vitro antileishmanial potential of peptide drug hirudin. AB - Hirudin is clinically an important drug used for the treatment of cardiac diseases, but has never been elucidated for antileishmanial potential. This study was designed to determine the therapeutic utility of hirudin against leishmaniasis. Binding affinities of 28 potent proteinase inhibitors were screened computationally against leishmanolysin (GP63), out of which hirudin exhibited higher binding affinity with GP63 and good expected IC50 values. Experimentally, hirudin showed most promising activity against promastigote and axenic amastigote forms of leishmanial parasites with IC50 values of 0.60 +/- 0.36 MUg/mL and 0.43 +/- 0.23 MUg/mL, respectively, in a dose- and time-dependent assay. The cytotoxicity assay revealed no adverse effects on human macrophages with LD50 value of 860.11 +/- 53.44 MUg/mL. Hirudin caused leishmanial cell death mainly by apoptosis and membrane permeability. In spite of the basic knowledge obtained, hirudin mechanism is considerably less prone to the induction of resistance than classical drugs. Collectively, this study fosters further studies for the hirudin as new antileishmania lead with a new mode of action. PMID- 27483398 TI - Cell wall biochemical alterations during Agrobacterium-mediated expression of haemagglutinin-based influenza virus-like vaccine particles in tobacco. AB - Influenza virus-like particles (VLPs) have been shown to induce a safe and potent immune response through both humoral and cellular responses. They represent promising novel influenza vaccines. Plant-based biotechnology allows for the large-scale production of VLPs of biopharmaceutical interest using different model organisms, including Nicotiana benthamiana plants. Through this platform, influenza VLPs bud from the plasma membrane and accumulate between the membrane and the plant cell wall. To design and optimize efficient production processes, a better understanding of the plant cell wall composition of infiltrated tobacco leaves is a major interest for the plant biotechnology industry. In this study, we have investigated the alteration of the biochemical composition of the cell walls of N. benthamiana leaves subjected to abiotic and biotic stresses induced by the Agrobacterium-mediated transient transformation and the resulting high expression levels of influenza VLPs. Results show that abiotic stress due to vacuum infiltration without Agrobacterium did not induce any detectable modification of the leaf cell wall when compared to non infiltrated leaves. In contrast, various chemical changes of the leaf cell wall were observed post Agrobacterium infiltration. Indeed, Agrobacterium infection induced deposition of callose and lignin, modified the pectin methylesterification and increased both arabinosylation of RG-I side chains and the expression of arabinogalactan proteins. Moreover, these modifications were slightly greater in plants expressing haemagglutinin-based VLP than in plants infiltrated with the Agrobacterium strain containing only the p19 suppressor of silencing. PMID- 27483400 TI - [Not Available]. AB - In this case report we illustrate how incorrectly prepared and cooked seeds from white lupin - a common snack among people from parts of the Mediterranean and Middle East - caused an anticholinergic syndrome in a previously healthy man. The symptoms subsided without treatment and the patient was discharged from the hospital in good health. Anticholinergic syndrome results from inhibition of the parasympatic nervous system. The symptoms commonly include dry mouth, confusion, hallucinations, fever, tachycardia, and urine retention. The syndrome may most frequently be provoked by overdose of drugs such as prometazin, hyoscyamin, and biperidin or by ingestion of plants such as belladonna, datura and henbane. The aim of this report is to increase clinicians' awareness of white lupin's anticholinergic effects. PMID- 27483402 TI - [Not Available]. PMID- 27483401 TI - [Not Available]. AB - Biochemical changes after strenuous exercise - data from the Kalmar Ironman Strenuous and prolonged exercise like marathon, ultra running and triathlon can lead to changes in biomarkers of cardiac, muscle and kidney functional damage. We present the data of 30 (15 men, 15 women) participants of the Kalmar Ironman 2015. Pre-race electrocardiograms and echocardiograms showed a high frequency of abnormalities. Post race elevations of troponin T, creatine kinase, myoglobin, N terminal prohormone of brain natriuretic peptide, and creatinine returned to normal in almost all cases within 5-8 days. In all but one participant the troponin T pattern was compatible with the diagnosis of myocardial infarction. It is an up-to-date unanswered question whether the increase of troponin represents myocardial damage or just is a benign consequence of an intermittent change of the permeability of myocardial cell membranes. PMID- 27483403 TI - [Not Available]. PMID- 27483405 TI - [Not Available]. PMID- 27483404 TI - [Not Available]. PMID- 27483406 TI - [Not Available]. PMID- 27483408 TI - [Not Available]. PMID- 27483407 TI - [Not Available]. PMID- 27483409 TI - Irrigating grazed pasture decreases soil carbon and nitrogen stocks. AB - The sustainability of using irrigation to produce food depends not only on the availability of sufficient water, but also on the soil's 'response' to irrigation. Stocks of carbon (C) and nitrogen (N) are key components of soil organic matter (SOM), which is important for sustainable agricultural production. While there is some information about the effects of irrigation on soil C stocks in cropping systems, there is a paucity of such studies in pastoral food production systems. For this study, we sampled soils from 34 paired, irrigated and unirrigated pasture sites across New Zealand (NZ) and analysed these for total C and N. On average, irrigated pastures had significantly (P < 0.05) less soil carbon (C) and nitrogen (N) than adjacent unirrigated pastures, with differences of 6.99 t C ha-1 and 0.58 t N ha-1 in the uppermost 0.3 m. Differences in C and N tended to occur throughout the soil profile, so the cumulative differences increased with depth, and the proportion of the soil C lost from deeper horizons was large. There were no relationships between differences in soil C and N stocks and the length of time under irrigation. This study suggests SOM will decrease when pastures under a temperate climate are irrigated. On this basis, increasing the area of temperate pasture land under irrigation would result in more CO2 in the atmosphere and may directly and indirectly increase N leaching to groundwater. Given the large and increasing area of land being irrigated both in NZ and on a global scale, there is an urgent need to determine whether the results found in this study are also applicable in other regions and under different land management systems (e.g. arable). PMID- 27483410 TI - Improvement of High-Density Lipoprotein Function in Patients With Early Rheumatoid Arthritis Treated With Methotrexate Monotherapy or Combination Therapies in a Randomized Controlled Trial. AB - OBJECTIVE: Abnormal function of high-density lipoprotein (HDL) has been implicated as a potential mechanism for the increased incidence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA). This study was undertaken to evaluate changes in HDL function and HDL-associated proteins over 2 years of follow-up in patients with early RA receiving either methotrexate (MTX) monotherapy, MTX + etanercept (ETN) combination therapy, or MTX + sulfasalazine (SSZ) + hydroxychloroquine (HCQ) triple therapy in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial. METHODS: The antioxidant capacity of HDL, paraoxonase 1 (PON-1) activity, and levels of HDL-associated haptoglobin (Hp), HDL-associated apolipoprotein A-I (Apo A-I), and myeloperoxidase (MPO) were measured in 550 TEAR participants at 4 time points (time 0 [pretreatment] and at 24, 48, and 102 weeks of treatment). Repeated-measures analysis using mixed effects linear models with an autoregressive covariate structure was performed to model the within-subject covariance over time. RESULTS: Mixed-effects models, which were controlled for traditional CV risk factors, treatment regimen, prednisone use, and statin use, demonstrated significant associations between RA disease activity, measured using the Disease Activity Score in 28 joints, erythrocyte sedimentation rate, or C-reactive protein level, and the profile of HDL function over time. Specifically, decreases in RA disease activity over time were associated with increases in PON-1 activity and levels of HDL-associated Apo A-I, and decreases in the HDL inflammatory index and levels of MPO and HDL associated Hp. CONCLUSION: Reduced disease activity in patients with early RA treated with MTX monotherapy, MTX + ETN combination therapy, or MTX + SSZ + HCQ triple therapy in the TEAR trial was associated with improvements in the HDL function profile. Additional studies are warranted to evaluate abnormal HDL function as a potential mechanism and therapeutic target for CV risk in patients with RA. PMID- 27483411 TI - Is the Site of Back Pain Related to the Location of Magnetic Resonance Imaging Lesions in Patients With Chronic Back Pain? Results From the Spondyloarthritis Caught Early Cohort. AB - OBJECTIVE: To determine associations between magnetic resonance imaging (MRI) lesions originating from either axial spondyloarthritis (SpA) or from degeneration and pain in patients with chronic back pain of <2 years duration. METHODS: Patients from the Spondyloarthritis Caught Early (SPACE) cohort identified the sites of pain (thoracic, lumbar, buttock). The average MRI scores from 2 readers for axial SpA lesions and from 2 different readers for degenerative lesions were used. Associations between sacroiliac (SI) joint lesions and buttock pain were investigated by logistic regression analysis, and associations between axial SpA or degenerative lesions and pain in the spine (thoracic and lumbar) were investigated using generalized estimating equations. Interactions with sex, age, HLA-B27, and fulfillment of Assessment of SpondyloArthritis international Society (ASAS) criteria were tested. RESULTS: In 348 patients (126 males, 127 fulfilling ASAS criteria, mean age 29.4 years), spinal MRI (and SI joint images in 342) were available. Pain was localized in the thoracic spine (35.9%), the lumbar spine (82.5%), or in the buttock(s) (57.8%). Inflammatory lesions of the SI joint (odds ratio [OR] 1.06; P = 0.04) and erosions of the SI joint in patients <25 years (OR 1.16; P = 0.04) were associated with buttock pain. Axial SpA spinal lesions were not associated with pain. Modic type 1 lesions in patients >35 years (OR 5.19; P = 0.001), high intensity zone lesions in females not fulfilling ASAS criteria (OR 5.09; P = 0.001), and herniation in various subgroups (OR range 2.07-4.66) were associated with pain. CONCLUSION: Specific degenerative lesions, but not typical axial SpA lesions, of the spine are associated with pain at the same location in some subgroups. Inflammatory lesions in the SI joint are associated with buttock pain. PMID- 27483412 TI - Association between Mediterranean diet and head and neck cancer: results of a large case-control study in Italy. AB - The Mediterranean diet (MD) is a known protective factor for head and neck cancer (HNC); however, there is still a lack of studies investigating this association by HNC subsite. The aim of the present study was therefore to evaluate the association between adherence to MD and HNC overall and by cancer subsite, as well as the effect of the individual food components on HNC risk. A case-control study was carried out at the Gemelli Hospital of Rome (Italy). A total of 500 HNC cases and 433 controls were interviewed. Dietary intake was assessed through a validated food frequency questionnaire that collected information on over 25 food items. Odds ratios (ORs) and 95% confidence intervals (CI) of HNC were calculated using a multiple logistic regression model. We found a reduced risk of both oral cavity and pharynx cancer (OR=0.61; CI: 0.54-0.70) and larynx cancer (OR=0.64; CI: 0.56-0.73) with increasing adherence to MD. We also found a high consumption of fruit, vegetables, and legumes to be significantly associated with a lower risk of larynx as well as oral cavity and pharynx cancers. Our study showed that adherence to MD acts protectively against HNC overall and by cancer subsite. PMID- 27483413 TI - Prostate cancer incidence and mortality in Portugal: trends, projections and regional differences. AB - There is a large geographical variability in prostate cancer incidence and mortality trends, mostly because of heterogeneity in control efforts across regions. We aimed to describe the time trends in prostate cancer incidence and mortality in Portugal, overall and by region, and to estimate the number of incident cases and deaths in 2020. The number of cases and incidence rates in 1998-2009 were collected from the Regional Cancer Registries. The number of deaths and mortality rates were obtained from the WHO mortality database (1988 2003 and 2007-2013) and Statistics Portugal (2004-2006; 1991-2013 by region). JoinPoint analyses were used to identify significant changes in trends in age standardized incidence and mortality rates. Incidence and mortality predictions for 2020 were performed using Poisson regression models and population projections provided by Statistics Portugal. In Portugal, prostate cancer incidence has been increasing since 1998 (1.8%/year), with the exception of the North Region, with a decrease since 2006 (-3.2%/year). An overall mortality decline has been observed since 1997 (-2.2%/year), although there were two patterns of mortality variation at the regional level: one with an inflection point or significant variation in the rates and the other without significant variation. If these trends are maintained, ~8600 incident cases and 1700 deaths may be expected to occur in Portugal in 2020. Despite the overall increasing incidence and decreasing mortality, there is a large heterogeneity across regions. Future studies should address regional differences in the trends of prostate specific antigen screening and in the effective management of prostate cancer. PMID- 27483414 TI - The Addition of Epinephrine to Proxymetacaine or Oxybuprocaine Solution Increases the Depth and Duration of Cutaneous Analgesia in Rats. AB - BACKGROUND: The aim of this experiment was to investigate the interaction between epinephrine and 2 local anesthetics (proxymetacaine or oxybuprocaine) using subcutaneous injections under the hairy skin, thereby simulating infiltration blocks. METHODS: Using a rat model of cutaneous trunci muscle reflex in response to local skin pinpricks, the anesthetic properties of proxymetacaine and oxybuprocaine alone and in combination with epinephrine as an infiltrative anesthetic were tested. Isobolographic analysis was used for the analgesic interactions between adjuvant epinephrine and the local anesthetics. Lidocaine was used as a control group. RESULTS: Oxybuprocaine, proxymetacaine, and lidocaine elicited a dose-dependent block to pinpricks. On the 50% effective dose (ED50) basis, their relative potencies were proxymetacaine [0.126 (0.113-0.141) MUmol] greater than oxybuprocaine [0.208 (0.192-0.226) MUmol] greater than lidocaine [6.331 (5.662-7.079) MUmol] (P < 0.01 for each comparison). On an equipotent basis (ED25, ED50, and ED75), sensory block duration elicited by oxybuprocaine or proxymetacaine was greater than that elicited by lidocaine (P < 0.01). Coadministration of proxymetacaine, oxybuprocaine, or lidocaine with epinephrine produced a synergistic analgesic effect and prolonged the cutaneous analgesic effect. After adding epinephrine, oxybuprocaine was much faster, reaching its maximal blockade, than proxymetacaine or lidocaine (P < 0.01). CONCLUSIONS: We concluded that proxymetacaine and oxybuprocaine were more potent and produced greater duration of nociceptive block than lidocaine. The use of epinephrine augmented the potency and prolonged the duration of proxymetacaine, oxybuprocaine, and lidocaine as an infiltrative anesthetic. PMID- 27483415 TI - Relative Contribution of Adjuvants to Local Anesthetic for Prolonging the Duration of Peripheral Nerve Blocks in Rats. AB - BACKGROUND AND OBJECTIVES: A chemically compatible, safe 4-drug multimodal formulation of bupivacaine combined with 3 adjuvants (clonidine, buprenorphine, and dexamethasone) has been proposed for long-lasting single-injection peripheral nerve blocks in patients. However, the relative importance of each of the adjuvants of the 4-drug formulation in producing long-lasting nerve blocks has not been determined. The aim of this study in rats was to determine which adjuvants (clonidine, buprenorphine, or dexamethasone) are essential for producing a long-lasting nerve block. METHODS: After baseline sensory and motor responses were recorded, 0.1 mL of drug solution was injected into the sciatic notch of rats. Animals were reevaluated at 10-minute intervals after injection for the absence or presence of sensory and motor response in the sciatic nerve. The 4-drug formulation of 0.25% bupivacaine plus all 3 adjuvants (clonidine, buprenorphine, and dexamethasone), 0.25% bupivacaine with 1 or 2 of the adjuvants added separately, and 0.25% bupivacaine alone were compared for duration of nerve block. RESULTS: The 4-drug multimodal solution produced a longer duration of sensory and motor nerve block than 0.25% bupivacaine alone (P < 0.0001). Bupivacaine plus clonidine also produced a longer duration of nerve block than 0.25% bupivacaine alone (P = 0.0157), but bupivacaine plus buprenorphine or bupivacaine plus dexamethasone did not prolong nerve block compared to bupivacaine alone. There was no difference (P = 0.1414) in the duration of nerve block between the 4-drug multimodal solution versus bupivacaine plus clonidine. CONCLUSIONS: This animal study confirmed that the 4-drug multimodal formulation proposed for clinical nerve block produces superior duration of action compared to local anesthetic alone. This rat sciatic nerve model also indicated that one of the 3 adjuvants, clonidine, could by itself account for the extended duration of nerve block of bupivacaine. PMID- 27483416 TI - Drug Resistance Characteristics and Macrolide-Resistant Mechanisms of Streptococcus pneumoniae in Wenzhou City, China. AB - BACKGROUND Streptococcus pneumoniae (SP) is a Gram-positive, alpha-hemolytic, facultative anaerobic member of the genus Streptococcus. The erythromycin resistant methylase (erm) gene and macrolide efflux (mef) gene are the 2 main genes that can mediate SP. Transposon (Tn) also plays an important role in the collection and metastasis of the gene. In the present study we investigated the drug resistance characteristics and the macrolide-resistant mechanisms of SP in Wenzhou City, China. MATERIAL AND METHODS Sixty-eight strains of SP were isolated from sputum samples of hospitalized children in the Second Affiliated Hospital of Wenzhou Medical University. These strains were analyzed using antimicrobial susceptibility tests to determine their drug resistance to 10 kinds of antibacterials. Macrolide-resistant phenotypes were identified using K-B method. PCR method was used to analyze the erm B gene, mef A gene, and int Tn gene. RESULTS Drug resistance rates of 68 strains of SP were 98.5%, 100.0%, 63.2%, 52.9%, 94.1%, 89.7%, 0.0%, 0.0%, 16.2%, and 14.7% for clindamycin, erythromycin, penicillin G, cefotaxime, tetracycline, sulfamethoxazole/trimethoprim, levofloxacin, vancomycin, chloramphenicol, and amoxicillin, respectively. Total detection rates of the erm B gene, mef A gene, and int Tn gene were 98.5%, 91.2%, and 100.0%, respectively. CONCLUSIONS SP shows significant multi-drug resistance in Wenzhou City, whereas there is no clinical value of macrolides antibiotics for SP. cMLSB mediated by erm B gene is the most predominant phenotype among macrolide-resistant SP. The int Tn gene may play an important role in horizontal transfer and clonal dissemination of SP drug resistance genes in Wenzhou City. PMID- 27483417 TI - Combined Approach to Phacoemulsification and Trabeculectomy Results in Less Ideal Refractive Outcomes Compared With the Sequential Approach. AB - PURPOSE: To compare the refractive outcomes of combined versus sequential trabeculectomy and then phacoemulsification. METHODS: We compared eyes that underwent uncomplicated combined phacotrabeculectomy (combined group, 87 eyes), phacoemulsification at least 3 months after trabeculectomy (sequential group, 56 eyes), and phacoemulsification only (control group, 78 eyes) between January 1, 2006 and January 1, 2014. The main outcome measure was refractive prediction error (RPE)-defined as postoperative subjective spherical equivalent refraction minus predicted spherical equivalent refraction. RESULTS: The study population was predominantly Chinese and the mean age at their cataract surgery was 67.2+/ 9.59 years. Compared with controls, RPE (-0.40+/-0.70 vs. -0.01+/-0.50, P<0.001) and mean absolute error (0.62+/-0.50 vs. 0.39+/-0.31, P=0.003) were greater for the combined group but not for the sequential group. Proportionately fewer patients in the combined group achieved final subjective refraction within +/ 0.5D (27.6% vs. 46.2%, P=0.01) compared with controls. Within the sequential group, there were no differences in RPE when the fellow eye axial length was used to predict refractive outcome (P=0.17) or between the group with precataract surgery IOPs of <=11 mm Hg (-0.28+/-0.82) and the group with >11 mm Hg (-0.28+/ 0.53, P=0.99). For the sequential group, the use of contact A scan yielded less RPE compared with IOLMaster (P=0.01). CONCLUSIONS: Combined approach to trabeculectomy and phacoemulsification resulted in greater myopic RPEs that were expectedly greater than those found in the phacoemulsification group. PMID- 27483418 TI - Structure-Functional Parameters in Differentiating Between Patients With Different Degrees of Glaucoma. AB - PURPOSE: We evaluated spectral-domain optical coherence tomography (SD-OCT) parameters and visual field parameters in patients with different degrees of open angle glaucoma (preperimetric, mild, moderate, and severe glaucoma) to determine which parameter best identifies each glaucomatous group. MATERIALS AND METHODS: A total of 131 patients (66 preperimetric, 41 mild, 35 moderate, 40 severe glaucomatous eyes) and 40 normal eyes (control group) were included in this prospective study. The SD-OCT parameters [mean ganglion cell complex (GCC), superior GCC, inferior GCC, global loss volume, focal loss volume, mean circumpapillary retinal nerve fiber layer (RNFL), superior circumpapillary retinal nerve fiber layer [cpRNFL], and inferior cpRNFL] and visual field parameters (mean deviation and pattern SD) were evaluated. The area under the receiver operating characteristic curve (AUROC) was calculated for each parameter to determine which best identified glaucomatous changes. RESULTS: Of the SD-OCT parameters, inferior (AUROC, 0.792) and mean GCC thickness (AUROC, 0.741) best discriminated between normal eyes and preperimetric glaucoma eyes. CONCLUSIONS: GCC measurements were more efficient than cpRNFL measurements in detecting preperimetric glaucomatous damage. This finding could be an aid to an early diagnosis. PMID- 27483419 TI - Bleb Revision With Temporalis Fascia Autograft. AB - PURPOSE: We report the first description of temporalis fascia autograft to repair a late leakage bleb with scleral defect that occurred long time after trabeculectomy with mitomycin C. PATIENT: A 65-year-old woman was referred to our hospital with chronic late bleb leakage on her right eye. She had previously undergone a trabeculectomy with mitomycin C 3 years ago for a pigmentary glaucoma. Bleb leakage occurred 11/2 year after the initial surgery. She underwent 2 surgical revisions consisting of a conjunctival advancement then an autologous conjunctival with partial scleral grafts without success. The initial best-corrected visual acuity of the right eye was 20/50 (Snellen scale). Slit lamp examination revealed an avascular filtering bleb with leakage (massive positive Seidel test) and a scleral defect. The anterior chamber was deep and intraocular pressure (IOP) was 9 mm Hg.Faced with the risk of blebitis, endophthalmitis, and with the failure of the previous surgeries announced earlier, a surgical revision with autologous superficial temporalis fascia graft was decided to repair the leaking bleb. After local anesthesia, a sample of superficial temporalis fascia was harvested. The necrotic avascular conjunctiva around the bleb was dissected to separate and excise it from the sclera. The autologous fascia graft was sutured on the scleral defect with 10-0 nylon. Subsequently healthy conjunctiva was sutured above the graft. RESULTS: No bleb leakage occurred postoperatively, best-corrected visual acuity improved to 20/25, and IOP remained within normal levels 6 months after surgery without IOP-lowering medication. CONCLUSIONS: Superficial temporalis fascia autograft seems to be an effective, safe, and easy technique for ophthalmologists. It is a new procedure in the management of late-onset bleb leakage. PMID- 27483420 TI - Long-term Outcomes of a Modified Technique Using the Baerveldt Glaucoma Implant for the Treatment of Refractory Glaucoma. AB - PURPOSE OF THE STUDY: The purpose of the study was to evaluate the long-term effectiveness and safety profile of Baerveldt glaucoma implant (BGI) in patients with refractory glaucoma operated using a modified technique to avoid postoperative complications. PATIENTS AND METHODS: A total of 160 eyes from 147 glaucomatous patients were enrolled in a consecutive interventional noncomparative case series. All the patients were treated with a 350-mm BGI using a modified technique. Intraocular pressure (IOP), the number of medications, the complications, and the postoperative interventions were reported preoperatively and during the follow-up. Postoperative IOP and the rate of complications were the primary outcome measures. The complete and qualified surgical success was the second endpoint. RESULTS: BGI obtained a mean IOP reduction from 31.8+/-6.4 mm Hg (baseline) to 14.4+/-3.5 mm Hg after a mean follow-up period of 38.4+/-9.6 months. The mean number of medications reduced between preoperative (n=3.17+/ 1.03) and postoperative period (n=0.58+/-0.83) (P<0.0001). Cumulative probability of maintaining an IOP between 5 and 21 mm Hg and/or a 25% or greater reduction in IOP was 78.7% at 1 year and 72.1% at 4 years, including 39 eyes (24.4%) in which postoperative interventions were required (qualified success). If we exclude those eyes from the analysis, the probability of complete success was 93.4% at 1 year and 91.4% at 4 years in 75.4% of the eyes. CONCLUSIONS: This modified technique achieved a high percentage of surgical success during the whole follow up time and was effective in preventing the most serious immediate complications of nonvalved tube shunts. PMID- 27483421 TI - Association of the BDNF Val66Met polymorphism with BMI in chronic schizophrenic patients and healthy controls. AB - Several lines of evidence suggest that a functional variant of the brain-derived neurotrophic factor gene (BDNF Val66Met) correlates with a number of eating disorders. Studies have also shown that the BDNF Val66Met polymorphism was associated with weight gain in patients with schizophrenia on long-term antipsychotic treatment. This study aimed to determine whether there was a relationship between the BDNF Val66Met polymorphism and BMI values in patients with chronic schizophrenia. We compared 308 Han Chinese patients with schizophrenia on long-term antipsychotic medication with 304 healthy normal controls on BDNF polymorphism. Body weight and BMI were measured before breakfast on the day blood samples were taken. The symptomatology of schizophrenia was assessed using the Positive and Negative Syndrome Scale. The results showed that the BDNF Val66Met polymorphism was associated with the BMI value, with genotype having a strong effect on the mean BMI value in male but not in female patients. Our results suggest that variation in the BDNF gene may be a risk factor for weight gain in male patients with schizophrenia on long-term antipsychotic treatment. PMID- 27483426 TI - Natural Mineral-Based Solid Oxide Fuel Cell with Heterogeneous Nanocomposite Derived from Hematite and Rare-Earth Minerals. AB - Solid oxide fuel cells (SOFCs) have attracted much attention worldwide because of their potential for providing clean and reliable electric power. However, their commercialization is subject to the high operating temperatures and costs. To make SOFCs more competitive, here we report a novel and attractive nanocomposite hematite-LaCePrOx (hematite-LCP) synthesized from low-cost natural hematite and LaCePr-carbonate mineral as an electrolyte candidate. This heterogeneous composite exhibits a conductivity as high as 0.116 S cm(-1) at 600 degrees C with an activation energy of 0.50 eV at 400-600 degrees C. For the first time, a fuel cell using such a natural mineral-based composite demonstrates a maximum power density of 625 mW cm(-2) at 600 degrees C and notable power output of 386 mW cm(-2) at 450 degrees C. The extraordinary ionic conductivity and device performances are primarily attributed to the heterophasic interfacial conduction effect of the hematite-LCP composite. These superior properties, along with the merits of ultralow cost, abundant storage, and eco-friendliness, make the new composite a highly promising material for commercial SOFCs. PMID- 27483428 TI - Measurements of nanoresonator-qubit interactions in a hybrid quantum electromechanical system. AB - Experiments to probe the basic quantum properties of motional degrees of freedom of mechanical systems have developed rapidly over the last decade. One promising approach is to use hybrid electromechanical systems incorporating superconducting qubits and microwave circuitry. However, a critical challenge facing the development of these systems is to achieve strong coupling between mechanics and qubits while simultaneously reducing coupling of both the qubit and mechanical mode to the environment. Here we report measurements of a qubit-coupled mechanical resonator system consisting of an ultra-high-frequency nanoresonator and a long coherence-time superconducting transmon qubit, embedded in a superconducting coplanar waveguide cavity. It is demonstrated that the nanoresonator and transmon have commensurate energies and transmon coherence times are one order of magnitude larger than for all previously reported qubit coupled nanoresonators. Moreover, we show that numerical simulations of this new hybrid quantum system are in good agreement with spectroscopic measurements and suggest that the nanoresonator in our device resides at low thermal occupation number, near its ground state, acting as a dissipative bath seen by the qubit. We also outline how this system could soon be developed as a platform for implementing more advanced experiments with direct relevance to quantum information processing and quantum thermodynamics, including the study of nanoresonator quantum noise properties, reservoir engineering, and nanomechanical quantum state generation and detection. PMID- 27483429 TI - Odor Identification Test in Idiopathic REM-Behavior Disorder and Parkinson's Disease in China. AB - BACKGROUND: Olfactory dysfunction is common in Parkinson's disease (PD) and idiopathic rapid eye movement sleep behavior disorder (iRBD), which is a risk factor in the development of PD. However, a few studies have conflicting results when comparing dysosmia in the patients with iRBD and PD. There is no study investigating the olfactory function in Chinese patients with iRBD. Additionally, the Sniffin' Sticks screening 12 test (SS-12) contains several odors that are not familiar to people in different cultures. METHODS: Odor identification was evaluated in iRBD patients (n = 54), PD patients (n = 54) and healthy controls (n = 54). With the identification data, a brief odor identification test was established and then validated in other subjects. RESULTS: Odor identification scores in iRBD patients were significantly higher than those in PD patients (P<0.001) but lower than those in controls (P<0.001). At the cut-off value of 7.5, the Sniffin' Sticks clearly differentiated iRBD and PD patients from the controls, and the brief test could increase the specificity in diagnosing PD. Neither the Sniffin' Sticks nor the brief test could clearly differentiate PD and iRBD patients from each other. CONCLUSIONS: Olfaction is more impaired in PD patients than in iRBD patients, possibly due to the heterogeneity of iRBD patients. The Sniffin' Sticks could be a useful tool for differentiating iRBD patients from the healthy population, and it could be useful for screening people at high-risk of PD in China, especially when combined with polysomnography. To reduce the expense and time required for the Sniffin' Sticks test, this study shows that a brief test is feasible. PMID- 27483430 TI - Multidrug-Resistant Tuberculosis Treatment in North Korea: Is Scale-Up Possible? AB - Kwonjune Seung and colleagues describe the Eugene Bell Foundation's experience of treating MDR-TB in North Korea. PMID- 27483431 TI - Post-exposure Treatment with Anti-rabies VHH and Vaccine Significantly Improves Protection of Mice from Lethal Rabies Infection. AB - Post-exposure prophylaxis (PEP) against rabies infection consists of a combination of passive immunisation with plasma-derived human or equine immune globulins and active immunisation with vaccine delivered shortly after exposure. Since anti-rabies immune globulins are expensive and scarce, there is a need for cheaper alternatives that can be produced more consistently. Previously, we generated potent virus-neutralising VHH, also called Nanobodies, against the rabies glycoprotein that are effectively preventing lethal disease in an in vivo mouse model. The VHH domain is the smallest antigen-binding functional fragment of camelid heavy chain-only antibodies that can be manufactured in microbial expression systems. In the current study we evaluated the efficacy of half-life extended anti-rabies VHH in combination with vaccine for PEP in an intranasal rabies infection model in mice. The PEP combination therapy of systemic anti rabies VHH and intramuscular vaccine significantly delayed the onset of disease compared to treatment with anti-rabies VHH alone, prolonged median survival time (35 versus 14 days) and decreased mortality (60% versus 19% survival rate), when treated 24 hours after rabies virus challenge. Vaccine alone was unable to rescue mice from lethal disease. As reported also for immune globulins, some interference of anti-rabies VHH with the antigenicity of the vaccine was observed, but this did not impede the synergistic effect. Post exposure treatment with vaccine and human anti-rabies immune globulins was unable to protect mice from lethal challenge. Anti-rabies VHH and vaccine act synergistically to protect mice after rabies virus exposure, which further validates the possible use of anti-rabies VHH for rabies PEP. PMID- 27483432 TI - The Prognostic and Clinicopathological Roles of Sirtuin-3 in Various Cancers. AB - Sirtuin-3 (SIRT3) is a major mitochondrial NAD(+)-dependent deacetylase and plays a key role in the progression and development of human cancers. Although the prognostic and clinicopathological features of SIRT3 expression in various cancers have been investigated by different research groups, however, inconsistent and opposing results can be observed. In this study, we therefore performed a meta-analysis to evaluate the significance of SIRT3 expression in various cancers. Systematic literature searching was performed in PubMed, Embase, China National Knowledge Infrastructure, and Wanfang Data up to November 2015. Total effect analyses and subgroup analyses were performed to evaluate the relationship between SIRT3 expression and overall survival, cancer/non-cancer tissues, lymph node metastasis, pathological differentiation, tumor node metastasis (TNM) stage, tumor size, and gender, in various cancer patients. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to clarify the risk or hazard association. A total of 14 studies comprising 2165 cancer patients were included to assess the association between SIRT3 immunohistochemical expression and overall survival or clinicopathological characteristics. SIRT3 expression was significantly associated with overall survival in gastric cancer (HR = 0.62, 95% CI = 0.43-0.89, P = 0.009) and hepatocellular carcinoma patients (HR = 0.56, 95% CI = 0.42-0.74, P<0.0001), cancer/non-cancer tissues in hepatocellular carcinoma patients (OR = 0.04, 95% CI = 0.01-0.16, P<0.0001), lymph node metastasis in breast cancer patients (OR = 2.20, 95% CI = 1.49-3.26, P<0.0001), and also pathological differentiation in hepatocellular carcinoma patients (OR = 0.69, 95% CI = 0.48-0.98, P = 0.04) and gastric cancer patients (OR = 0.33, 95% CI = 0.21-0.50, P<0.00001), by subgroup analyses. Furthermore, SIRT3 expression was significantly associated with pathological differentiation in total effect analysis (OR = 0.46, 95% CI = 0.29 0.74, P = 0.001). No detectable relation between SIRT3 expression and other clinicopathological parameters were found. This meta-analysis indicates that SIRT3 expression level is associated with prognostic and clinical features in specific cancers. PMID- 27483433 TI - Modification of the Tumor Microenvironment in KRAS or c-MYC-Induced Ovarian Cancer-Associated Peritonitis. AB - The most common properties of oncogenes are cell proliferation and the prevention of apoptosis in malignant cells, which, as a consequence, induce tumor formation and dissemination. However, the effects of oncogenes on the tumor microenvironment (TME) have not yet been examined in detail. The accumulation of ascites accompanied by chronic inflammation and elevated concentrations of VEGF is a hallmark of the progression of ovarian cancer. We herein demonstrated the mechanisms by which oncogenes contribute to modulating the ovarian cancer microenvironment. c-MYC and KRAS were transduced into the mouse ovarian cancer cell line ID8. ID8, ID8-c-MYC, or ID8-KRAS cells were then injected into the peritoneal cavities of C57/BL6 mice and the production of ascites was assessed. ID8-c-MYC and ID8-KRAS both markedly accelerated ovarian cancer progression in vivo, whereas no significant differences were observed in proliferative activity in vitro. ID8-KRAS in particular induced the production of ascites, which accumulated between approximately two to three weeks after the injection, more rapidly than ID8 and ID8-c-MYC (between nine and ten weeks and between six and seven weeks, respectively). VEGF concentrations in ascites significantly increased in c-MYC-induced ovarian cancer, whereas the concentrations of inflammatory cytokines in ascites were significantly high in KRAS-induced ovarian cancer and were accompanied by an increased number of neutrophils in ascites. A cytokine array revealed that KRAS markedly induced the expression of granulocyte macrophage colony-stimulating factor (GM-CSF) in ID8 cells. These results suggest that oncogenes promote cancer progression by modulating the TME in favor of cancer progression. PMID- 27483434 TI - Luminescent platforms for monitoring changes in the solubility of amylin and huntingtin in living cells. AB - Luminescent, cell-based assays capable of monitoring the aggregation potential of the disease-relevant proteins known as amylin (type 2 diabetes) and huntingtin (Huntington's disease) are presented. These sensitive platforms report on the influence of mutations as well as small molecules on protein solubility. PMID- 27483435 TI - Protein Kinase RNA-Like Endoplasmic Reticulum Kinase-Mediated Bcl-2 Protein Phosphorylation Contributes to Evodiamine-Induced Apoptosis of Human Renal Cell Carcinoma Cells. AB - We investigated the anticancer mechanism of evodiamine (EVO) against the viability of human A498 renal cell carcinoma (RCC) cells in vitro and in vivo. The in vitro study showed that EVO decreased the viability of A498 cells with the occurrence of apoptotic characteristics such as hypodiploid cells, DNA ladders, chromatin-condensed cells, and cleaved caspase (Casp)-3/poly(ADP ribose) polymerase (PARP) proteins. Pharmacological studies using chemical inhibitors of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) indicated that phosphorylation of the c-Jun N-terminal kinase (JNK) protein participated in EVO-induced cell death of A498 cells, and application of the JNK inhibitor, SP600125 (SP), inhibited EVO-induced cleavage of the Casp-3/PARP proteins and chromatin condensation according to Giemsa staining. EVO disruption of the mitochondrial membrane potential (MMP) with increased protein levels of the phosphorylated Bcl-2 protein (p-Bcl-2) was prevented by JNK inhibitors in A498 cells. A structure-activity relationship study showed that a methyl group at position 14 in EVO was important for its apoptotic effects and increased p-Bcl-2 protein in A498 cells. Furthermore, significant increases in the phosphorylated endoplasmic reticular stress protein, protein kinase RNA-like endoplasmic reticulum kinase (p-PERK at Thr980), by EVO were detected in A498 cells, and the PERK inhibitor, GSK2606414, significantly suppressed EVO-induced apoptosis, p JNK, p-PERK, and cleaved PARP proteins. The in vivo study showed that EVO significantly reduced RCC growth elicited by a subcutaneous injection of A498 cells, and an increased protein level of p-PERK was observed according to an immunohistochemical analysis. Apoptosis by EVO was also demonstrated in other RCC cells such as 786-O, ACHN, and Caki-1 cells. This is the first study to demonstrate the anti-RCC effect of EVO via apoptosis in vitro and in vivo, and activation of JNK and PERK to induce Bcl-2 protein phosphorylation, which led to disruption of the MMP. PMID- 27483437 TI - Flow Cytometric Immunophenotyping Is Sensitive for the Early Diagnosis of De Novo Aggressive Natural Killer Cell Leukemia (ANKL): A Multicenter Retrospective Analysis. AB - Aggressive natural killer cell leukemia (ANKL) is a fatal hematological neoplasm characterized by a fulminating clinical course and extremely high mortality. Current diagnosis of this disease is not effective during the early stages and it is easily misdiagnosed as other NK cell disorders. We retrospectively analyzed the clinical characteristics and flow cytometric immunophenotype of 47 patients with ANKL. Patients with extranodal NK/T cell lymphoma, nasal type (ENKTL) and chronic lymphoproliferative disorder of NK cell (CLPD-NK), who were diagnosed during the same time period were used for comparisons. Abnormal NK cells in ANKL were found to have a distinctiveCD56bright/CD16dim immunophenotype and markedly increased Ki-67 expression, whereas CD57 negativity and reduced expression of killer immunoglobulin-like receptor (KIR), CD161, CD7, CD8 and perforin were exhibited compared with other NK cell proliferative disorders (p<0.05). The positive rates of flow cytometry detection (97.4%) was higher than those of cytomorphological (89.5%), immunohistochemical (90%), cytogenetic (56.5%) and F 18 fluorodeoxyglucose positron emission tomography/computer tomography (18-FDG PET/CT) examinations (50%) (p<0.05). ANKL is a highly aggressive leukemia with high mortality. Flow cytometry detection is sensitive for the early and differential diagnosis of ANKL with high specificity. PMID- 27483438 TI - Oxidized Lipoprotein as a Major Vessel Cell Proliferator in Oxidized Human Serum. AB - Oxidative stress is correlated with the incidence of several diseases such as atherosclerosis and cancer, and oxidized biomolecules have been determined as biomarkers of oxidative stress; however, the detailed molecular relationship between generated oxidation products and the promotion of diseases has not been fully elucidated. In the present study, to clarify the role of serum oxidation products in vessel cell proliferation, which is related to the incidence of atherosclerosis and cancer, the major vessel cell proliferator in oxidized human serum was investigated. Oxidized human serum was prepared by free radical exposure, separated using gel chromatography, and then each fraction was added to several kinds of vessel cells including endothelial cells and smooth muscle cells. It was found that a high molecular weight fraction in oxidized human serum specifically induced vessel cell proliferation. Oxidized lipids were contained in this high molecular weight fraction, while cell proliferation activity was not observed in oxidized lipoprotein-deficient serum. Oxidized low-density lipoproteins induced vessel cell proliferation in a concentration-dependent manner. Taken together, these results indicate that oxidized lipoproteins containing lipid oxidation products function as a major vessel cell proliferator in oxidized human serum. These findings strongly indicate the relevance of determination of oxidized lipoproteins and lipid oxidation products in the diagnosis of vessel cell proliferation-related diseases such as atherosclerosis and cancer. PMID- 27483439 TI - Benefits of Intraaortic Balloon Support for Myocardial Infarction Patients in Severe Cardiogenic Shock Undergoing Coronary Revascularization. AB - BACKGROUND: Prior studies have suggested intraaortic balloon pump (IABP) have a neutral effect on acute myocardial infarction (AMI) patients with cardiogenic shock (CS). However, the effects of IABP on patients with severe CS remain unclear. We therefore investigated the benefits of IABP in AMI patients with severe CS undergoing coronary revascularization. METHODS AND RESULTS: This study identified 14,088 adult patients with AMI and severe CS undergoing coronary revascularization from Taiwan's National Health Insurance Research Database between January 1, 1997 and December 31, 2011, dividing them into the IABP group (n = 7044) and the Nonusers group (n = 7044) after propensity score matching to equalize confounding variables. The primary outcomes included myocardial infarction(MI), cerebrovascular accidents or cardiovascular death. In-hospital events including dialysis, stroke, pneumonia and sepsis were secondary outcomes. Primary outcomes were worse in the IABP group than in the Nonusers group in 1 month (Hazard ratio (HR) = 1.97, 95% confidence interval (CI) = 1.84-2.12). The MI rate was higher in the IABP group (HR = 1.44, 95% CI = 1.16-1.79), and the cardiovascular death was much higher in the IABP group (HR = 2.07, 95% CI = 1.92 2.23). The IABP users had lower incidence of dialysis (8.5% and 9.5%, P = 0.04), stroke (2.6% and 3.8%, P<0.001), pneumonia (13.9% and 16.5%, P<0.001) and sepsis (13.2% and 16%, P<0.001) during hospitalization than Nonusers. CONCLUSION: The use of IABP in patients with myocardial infarction and severe cardiogenic shock undergoing coronary revascularization did not improve the outcomes of recurrent myocardial infarction and cardiovascular death. However, it did reduce the incidence of dialysis, stroke, pneumonia and sepsis during hospitalization. PMID- 27483440 TI - Epigenetic contribution to successful polyploidizations: variation in global cytosine methylation along an extensive ploidy series in Dianthus broteri (Caryophyllaceae). AB - Polyploidization is a significant evolutionary force in plants which involves major genomic and genetic changes, frequently regulated by epigenetic factors. We explored whether natural polyploidization in Dianthus broteri complex resulted in substantial changes in global DNA cytosine methylation associated to ploidy. Global cytosine methylation was estimated by high-performance liquid chromatography (HPLC) in 12 monocytotypic populations with different ploidies (2*, 4*, 6*, 12*) broadly distributed within D. broteri distribution range. The effects of ploidy level and local variation on methylation were assessed by generalized linear mixed models (GLMMs). Dianthus broteri exhibited a higher methylation percent (~33%) than expected by its monoploid genome size and a large variation among study populations (range: 29.3-35.3%). Global methylation tended to increase with ploidy but did not significantly differ across levels due to increased variation within the highest-order polyploidy categories. Methylation varied more among hexaploid and dodecaploid populations, despite such cytotypes showing more restricted geographic location and increased genetic relatedness than diploids and tetraploids. In this study, we demonstrate the usefulness of an HPLC method in providing precise and genome reference-free global measure of DNA cytosine methylation, suitable to advance current knowledge of the roles of this epigenetic mechanism in polyploidization processes. PMID- 27483441 TI - High Fat Diet Inhibits Dendritic Cell and T Cell Response to Allergens but Does Not Impair Inhalational Respiratory Tolerance. AB - The incidence of obesity has risen to epidemic proportions in recent decades, most commonly attributed to an increasingly sedentary lifestyle, and a 'western' diet high in fat and low in fibre. Although non-allergic asthma is a well established co-morbidity of obesity, the influence of obesity on allergic asthma is still under debate. Allergic asthma is thought to result from impaired tolerance to airborne antigens, so-called respiratory tolerance. We sought to investigate whether a diet high in fats affects the development of respiratory tolerance. Mice fed a high fat diet (HFD) for 8 weeks showed weight gain, metabolic disease, and alteration in gut microbiota, metabolites and glucose metabolism compared to age-matched mice fed normal chow diet (ND). Respiratory tolerance was induced by repeated intranasal (i.n.) administration of ovalbumin (OVA), prior to induction of allergic airway inflammation (AAI) by sensitization with OVA in alum i.p. and subsequent i.n. OVA challenge. Surprisingly, respiratory tolerance was induced equally well in HFD and ND mice, as evidenced by decreased lung eosinophilia and serum OVA-specific IgE production. However, in a pilot study, HFD mice showed a tendency for impaired activation of airway dendritic cells and regulatory T cells compared with ND mice after induction of respiratory tolerance. Moreover, the capacity of lymph node cells to produce IL-5 and IL-13 after AAI was drastically diminished in HFD mice compared to ND mice. These results indicate that HFD does not affect the inflammatory or B cell response to an allergen, but inhibits priming of Th2 cells and possibly dendritic cell and regulatory T cell activation. PMID- 27483442 TI - Transcriptome modulation during host shift is driven by secondary metabolites in desert Drosophila. AB - High-throughput transcriptome studies are breaking new ground to investigate the responses that organisms deploy in alternative environments. Nevertheless, much remains to be understood about the genetic basis of host plant adaptation. Here, we investigate genome-wide expression in the fly Drosophila buzzatii raised in different conditions. This species uses decaying tissues of cactus of the genus Opuntia as primary rearing substrate and secondarily, the necrotic tissues of the columnar cactus Trichocereus terscheckii. The latter constitutes a harmful host, rich in mescaline and other related phenylethylamine alkaloids. We assessed the transcriptomic responses of larvae reared in Opuntia sulphurea and T. terscheckii, with and without the addition of alkaloids extracted from the latter. Whole-genome expression profiles were massively modulated by the rearing environment, mainly by the presence of T. terscheckii alkaloids. Differentially expressed genes were mainly related to detoxification, oxidation-reduction and stress response; however, we also found genes involved in development and neurobiological processes. In conclusion, our study contributes new data onto the role of transcriptional plasticity in response to alternative rearing environments. PMID- 27483443 TI - Outcomes and satisfaction of two optional cadaveric dissection courses: A 3-year prospective study. AB - Teaching time dedicated to anatomy education has been reduced at many medical schools around the world, including Nova Medical School in Lisbon, Portugal. In order to minimize the effects of this reduction, the authors introduced two optional, semester-long cadaveric dissection courses for the first two years of the medical school curriculum. These courses were named Regional Anatomy I (RAI) and Regional Anatomy II (RAII). In RAI, students focus on dissecting the thorax, abdomen, pelvis, and perineum. In RAII, the focus shifts to the head, neck, back, and upper and lower limbs. This study prospectively analyzes students' academic achievement and perceptions within the context of these two, newly-introduced, cadaveric dissection courses. Students' satisfaction was assessed anonymously through a questionnaire that included items regarding students' perception of the usefulness of the courses for undergraduate teaching, as well as with regards to future professional activity. For each of the three academic years studied, the final score (1 to 20) in General Anatomy (GA), RAI, and RAII was on average 14.26 +/- 1.89; 16.94 +/- 1.02; 17.49 +/- 1.01, respectively. The mean results were lower in GA than RAI or RAII (P < 0.001). Furthermore, students who undertook these courses ranked them highly with regards to consolidating their knowledge of anatomy, preparing for other undergraduate courses, and training for future clinical practice. These survey data, combined with data on participating students' academic achievement, lend strong support to the adoption of similar courses as complementary and compulsory disciplines in a modern medical curriculum. Anat Sci Educ 10: 127-136. (c) 2016 American Association of Anatomists. PMID- 27483444 TI - Vapor-Phase Deposition and Modification of Metal-Organic Frameworks: State-of-the Art and Future Directions. AB - Materials processing, and thin-film deposition in particular, is decisive in the implementation of functional materials in industry and real-world applications. Vapor processing of materials plays a central role in manufacturing, especially in electronics. Metal-organic frameworks (MOFs) are a class of nanoporous crystalline materials on the brink of breakthrough in many application areas. Vapor deposition of MOF thin films will facilitate their implementation in micro- and nanofabrication research and industries. In addition, vapor-solid modification can be used for postsynthetic tailoring of MOF properties. In this context, we review the recent progress in vapor processing of MOFs, summarize the underpinning chemistry and principles, and highlight promising directions for future research. PMID- 27483445 TI - Ethics Reporting in Biospecimen and Genetic Research: Current Practice and Suggestions for Changes. AB - Modern approaches for research with human biospecimens employ a variety of substantially different types of ethics approval and informed consent. In most cases, standard ethics reporting such as "consent and approval was obtained" is no longer meaningful. A structured analysis of 120 biospecimen studies recently published in top journals revealed that more than 85% reported on consent and approval, but in more than 90% of cases, this reporting was insufficient and thus potentially misleading. Editorial policies, reporting guidelines, and material transfer agreements should include recommendations for meaningful ethics reporting in biospecimen research. Meaningful ethics reporting is possible without higher word counts and could support public trust as well as networked research. PMID- 27483446 TI - Analysis of Multiple HPV E6 PDZ Interactions Defines Type-Specific PDZ Fingerprints That Predict Oncogenic Potential. AB - The high-risk Human Papillomavirus (HPV) E6 oncoproteins are characterised by the presence of a class I PDZ-binding motif (PBM) on their extreme carboxy termini. The PBM is present on the E6 proteins derived from all cancer-causing HPV types, but can also be found on some related non-cancer-causing E6 proteins. We have therefore been interested in investigating the potential functional differences between these different E6 PBMs. Using an unbiased proteomic approach in keratinocytes, we have directly compared the interaction profiles of these different PBMs. This has allowed us to identify the potential PDZ target fingerprints of the E6 PBMs from 7 different cancer-causing HPV types, from 3 HPV types with weak cancer association, and from one benign HPV type that possesses an ancestral PBM. We demonstrate a striking increase in the number of potential PDZ targets bound by each E6 PBM as cancer-causing potential increases, and show that the HPV-16 and HPV-18 PBMs have the most flexibility in their PDZ target selection. Furthermore, the specific interaction with hScrib correlates directly with increased oncogenic potential. In contrast, hDlg is bound equally well by all the HPV E6 PBMs analysed, indicating that this is an evolutionarily conserved interaction, and was most likely one of the original E6 PBM target proteins that was important for the occupation of a potential new niche. Finally, we present evidence that the cell junction components ZO-2 and beta-2 syntrophin are novel PDZ domain-containing targets of a subset of high-risk HPV types. PMID- 27483448 TI - Solitary fibrous tumour presenting as a submucosal colonic polyp: a new addition to the family of mesenchymal polyps of the gastrointestinal tract. PMID- 27483447 TI - Validation of a Chiral Liquid Chromatographic Method for the Degradation Behavior of Flumequine Enantiomers in Mariculture Pond Water. AB - In this work, flumequine (FLU) enantiomers were separated using a Chiralpak OD-H column, with n-hexane-ethanol (20:80, v/v) as the mobile phase at a flow rate of 0.6 mL/min. Solid phase extraction (SPE) was used for cleanup and enrichment. The limit of detection, limit of quantitation, linearity, precision, and intra/interday variation of the chiral high-performance liquid chromatography (HPLC) method were determined. The developed method was then applied to investigate the degradation behavior of FLU enantiomers in mariculture pond water samples. The results showed that the degradation of FLU enantiomers under natural, sterile, or dark conditions was not enantioselective. Chirality 28:649 655, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27483449 TI - Differences in the Spectrum of Anti-Citrullinated Protein Antibody Fine Specificities Between Malaysian and Swedish Patients With Rheumatoid Arthritis: Implications for Disease Pathogenesis. AB - OBJECTIVE: Antibodies to the citrullinated protein antigens (ACPAs) are important in the diagnosis and pathogenesis of rheumatoid arthritis (RA). However, the prevalence of ACPAs with different fine specificities in different populations is unclear. This study sought to examine the fine specificity of the antibody responses toward citrullinated proteins in RA patients from Malaysia, an area where genetic and environmental determinants of RA are different from those in more frequently studied cohorts of Caucasian subjects. METHODS: A multiplex analytic microarray system was used to analyze the occurrence of antibodies to 10 different citrullinated peptides (filaggrin [fil307-324], vimentin [Vim2-17, Vim60-75], fibrinogen [Fibalpha563-583, Fibalpha580-600, Fibbeta36-52, Fibbeta62 81a, Fibbeta62-81b], enolase [Eno5-21], and type II collagen [CitCII355-378]) in serum samples from 4,089 RA patients (1,231 Malaysian and 2,858 Swedish) and 827 healthy control subjects (249 Malaysian and 578 Swedish). The positive reaction threshold for each peptide was set separately for each population based on a specificity of 98%. RESULTS: Distinct differences in the frequencies of 5 ACPA fine specificities (Vim60-75, Vim2-17, Fibbeta62-81b, Eno5-21, and CitCII355-378) were found between the Malaysian and Swedish RA populations, despite a nearly identical percentage of patients in each population who were positive for anti cyclic citrullinated peptide 2 antibodies. In Malaysian RA patients compared with Swedish RA patients, the frequencies of antibodies to Vim60-75 (54% versus 44%, corrected P [Pcorr ] = 1.06 * 10-8 ) and CitCII355-378 (17% versus 13%, Pcorr = 0.02) were significantly higher, while the frequencies of antibodies to Vim2-17 (25% versus 32%, Pcorr = 1.91 * 10-4 ), Fibbeta62-81b (15% versus 30%, Pcorr = 2.47 * 10-22 ), and Eno5-21 (23% versus 50%, Pcorr = 3.64 * 10-57 ) were significantly lower. CONCLUSION: Serum ACPA fine specificities differ between RA patients in different populations, although the total proportions of individuals positive for ACPAs are similar. Differing patterns of ACPA fine specificity could be attributed to variations in genetic and/or environmental factors. PMID- 27483450 TI - Effect of Conidiobolus coronatus on the Cuticular and Internal Lipid Composition of Tettigonia viridissima Males. AB - Conidiobolus coronatus is an entomopathogenic fungus which has a potential as a biological control agent of insects. The cuticular and internal lipid composition of infected and noninfected Tettigonia viridissima males were analyzed by GC/MS. A total of 49 compounds were identified in the infected and noninfected males, including fatty acids, fatty acid methyl esters (FAMEs), n-alkanes, alcohols, sterols, and other organic compounds. The most abundant components of the cuticular and internal lipids of the insects were fatty acids. After exposure to C. coronatus, the cuticular lipids of the T. viridissima males contained 17 free fatty acids from C(8) to C(22), while the cuticular lipids of the noninfected insects contained only 15 fatty acids from C(12) to C(24). The cuticular and internal lipids of both the infected and the noninfected males also contained five FAMEs from C(15) to C(19), seven n-alkanes from C(25) to C(34), five alcohols from C(16) to C(25), five sterols, and the following six other organic compounds: azelaic acid, phenylacetic acid, glutaric acid, benzoic acid, sebacic acid, and glycerol. The compounds which were present only in the cuticular lipids of the infected males could be due to fungal infection. PMID- 27483451 TI - Prospective study of guideline-tailored therapy with direct-acting antivirals for hepatitis C virus-associated mixed cryoglobulinemia. AB - : Hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) vasculitis commonly regresses upon virus eradication, but conventional therapy with pegylated interferon and ribavirin yields approximately 40% sustained virologic responses (SVR). We prospectively evaluated the efficacy and safety of sofosbuvir based direct-acting antiviral therapy, individually tailored according to the latest guidelines, in a cohort of 44 consecutive patients with HCV-associated MC. In two patients MC had evolved into an indolent lymphoma with monoclonal B-cell lymphocytosis. All patients had negative HCV viremia at week 12 (SVR12) and at week 24 (SVR24) posttreatment, at which time all had a clinical response of vasculitis. The mean (+/-standard deviation) Birmingham Vasculitis Activity Score decreased from 5.41 (+/-3.53) at baseline to 2.35 (+/-2.25) (P < 0.001) at week 4 on treatment to 1.39 (+/-1.48) (P < 0.001) at SVR12 and to 1.27 (+/-1.68) (P < 0.001) at SVR24. The mean cryocrit value fell from 7.2 (+/-15.4)% at baseline to 2.9 (+/-7.4)% (P < 0.01) at SVR12 and to 1.8 (+/-5.1)% (P < 0.001) at SVR24. Intriguingly, in the 2 patients with MC and lymphoma there was a partial clinical response of vasculitis and ~50% decrease of cryocrit, although none experienced a significant decrease of monoclonal B-cell lymphocytosis. Adverse events occurred in 59% of patients and were generally mild, with the exception of 1 patient with ribavirin-related anemia requiring blood transfusion. CONCLUSION: Interferon free, guideline-tailored therapy with direct-acting antivirals is highly effective and safe for HCV-associated MC patients; the overall 100% rate of clinical response of vasculitis, on an intention-to-treat basis, opens the perspective for curing the large majority of these so far difficult-to-treat patients. (Hepatology 2016;64:1473-1482). PMID- 27483452 TI - A Novel and Non-Cytotoxic Self-Healing Supramolecular Elastomer Synthesized with Small Molecular Biological Acids. AB - A novel and non-cytotoxic self-healing supramolecular elastomer (SE) is synthesized with small-molecular biological acids by hydrogen-bonding interactions. The synthesized SEs behave as rubber at room temperature without additional plasticizers or crosslinkers, which is attributed to the phase separated structure. The SE material exhibits outstanding self-healing capability at room temperature and essential non-cytotoxicity, which makes it a potential candidate for biomedical applications. PMID- 27483453 TI - A Precise Chemical Strategy To Alter the Receptor Specificity of the Adeno Associated Virus. AB - The ability to target the adeno-associated virus (AAV) to specific types of cells, by altering the cell-surface receptor it binds, is desirable to generate safe and efficient therapeutic vectors. Chemical attachment of receptor-targeting agents onto the AAV capsid holds potential to alter its tropism, but is limited by the lack of site specificity of available conjugation strategies. The development of an AAV production platform is reported that enables incorporation of unnatural amino acids (UAAs) into specific sites on the virus capsid. Incorporation of an azido-UAA enabled site-specific attachment of a cyclic-RGD peptide onto the capsid, retargeting the virus to the alphav beta3 integrin receptors, which are overexpressed in tumor vasculature. Retargeting ability was site-dependent, underscoring the importance of achieving site-selective capsid modification. This work provides a general chemical approach to introduce various receptor binding agents onto the AAV capsid with site selectivity to generate optimized vectors with engineered infectivity. PMID- 27483454 TI - Synthesis of an Open-Cage Structure POSS Containing Various Functional Groups and Their Effect on the Formation and Properties of Langmuir Monolayers. AB - Recently, silsesquioxanes have been recognized as a new group of film-forming materials. This study has been aimed at determining the effect of the kind of functional groups present in two different open-cage structure POSS molecules on the possibility of the formation of Langmuir monolayers and their properties. To achieve this goal, two new POSS derivatives (of open-cage structures) containing polyether and fluoroalkyl functional groups have been synthesized on the basis of a hydrosilylation process. An optimization of the process was performed, which makes it possible to obtain the above-mentioned derivatives with high yields. In the next step, the Langmuir technique was applied to measurements of the surface pressure (pi) - the mean molecular area (A) isotherms during the compression of monolayers formed by molecules of the two POSS derivatives considered. Subsequently, the monolayers were transferred onto quartz plates according to the Langmuir-Blodgett technique. Both derivatives are able to form insoluble Langmuir films at the air-water interface, which can be transferred onto a solid substrate and effectively change its wetting properties. PMID- 27483455 TI - On Children, Blood, and Cancer: A new section of PBC. PMID- 27483456 TI - Real-time PCR detection of Didemnum perlucidum (Monniot, 1983) and Didemnum vexillum (Kott, 2002) in an applied routine marine biosecurity context. AB - Prevention and early detection are well recognized as the best strategies for minimizing the risks posed by nonindigenous species (NIS) that have the potential to become marine pests. Central to this is the ability to rapidly and accurately identify the presence of NIS, often from complex environmental samples like biofouling and ballast water. Molecular tools have been increasingly applied to assist with the identification of NIS and can prove particularly useful for taxonomically difficult groups like ascidians. In this study, we have developed real-time PCR assays suited to the specific identification of the ascidians Didemnum perlucidum and Didemnum vexillum. Despite being recognized as important global pests, this is the first time specific molecular detection methods have been developed that can support the early identification and detection of these species from a broad range of environmental sample types. These fast, robust and high-throughput assays represent powerful tools for routine marine biosecurity surveillance, as detection and confirmation of the early presence of species could assist in the timely establishment of emergency responses and control strategies. This study applied the developed assays to confirm the ability to detect Didemnid eDNA in water samples. While previous work has focused on detection of marine larvae from water samples, the development of real-time PCR assays specifically aimed at detecting eDNA of sessile invertebrate species in the marine environment represents a world first and a significant step forwards in applied marine biosecurity surveillance. Demonstrated success in the detection of D. perlucidum eDNA from water samples at sites where it could not be visually identified suggests value in incorporating such assays into biosecurity survey designs targeting Didemnid species. PMID- 27483457 TI - The carbon fertilization effect over a century of anthropogenic CO2 emissions: higher intracellular CO2 and more drought resistance among invasive and native grass species contrasts with increased water use efficiency for woody plants in the US Southwest. AB - From 1890 to 2015, anthropogenic carbon dioxide emissions have increased atmospheric CO2 concentrations from 270 to 400 mol mol-1 . The effect of increased carbon emissions on plant growth and reproduction has been the subject of study of free-air CO2 enrichment (FACE) experiments. These experiments have found (i) an increase in internal CO2 partial pressure (ci ) alongside acclimation of photosynthetic capacity, (ii) variable decreases in stomatal conductance, and (iii) that increases in yield do not increase commensurate with CO2 concentrations. Our data set, which includes a 115-year-long selection of grasses collected in New Mexico since 1892, is consistent with an increased ci as a response to historical CO2 increase in the atmosphere, with invasive species showing the largest increase. Comparison with Palmer Drought Sensitivity Index (PDSI) for New Mexico indicates a moderate correlation with Delta13 C (r2 = 0.32, P < 0.01) before 1950, with no correlation (r2 = 0.00, P = 0.91) after 1950. These results indicate that increased ci may have conferred some drought resistance to these grasses through increased availability of CO2 in the event of reduced stomatal conductance in response to short-term water shortage. Comparison with C3 trees from arid environments (Pinus longaeva and Pinus edulis in the US Southwest) as well as from wetter environments (Bromus and Poa grasses in New Mexico) suggests differing responses based on environment; arid environments in New Mexico see increased intrinsic water use efficiency (WUE) in response to historic elevated CO2 while wetter environments see increased ci . This study suggests that (i) the observed increases in ci in FACE experiments are consistent with historical CO2 increases and (ii) the CO2 increase influences plant sensitivity to water shortage, through either increased WUE or ci in arid and wet environments, respectively. PMID- 27483458 TI - Ustekinumab Treatment and Improvement of Physical Function and Health-Related Quality of Life in Patients With Psoriatic Arthritis. AB - OBJECTIVE: To examine the effects of ustekinumab on patient-reported outcomes (PROs) in PSUMMIT 1 and PSUMMIT 2 patients with active psoriatic arthritis (PsA) who were methotrexate (MTX) naive, MTX experienced, or anti-tumor necrosis factor (TNF) experienced. METHODS: Patients in the phase 3, PSUMMIT 1 (n = 615) and PSUMMIT 2 (n = 312) studies randomly (1:1:1) received placebo, ustekinumab 45-mg, or ustekinumab 90-mg subcutaneous injections at weeks 0, 4, 16, 28, 40, and 52. The PROs (Health Assessment Questionnaire [HAQ] disability index [DI], Dermatology Life Quality Index [DLQI], 36-Item Short Form [SF-36] health survey physical (PCS) and mental component summary scores, patient assessments of pain and disease activity, and impact of disease on productivity) were assessed at weeks 0, 24, and 52. In these post hoc analyses, outcomes were compared between the ustekinumab and placebo groups for 3 mutually exclusive antecedent-exposure populations from the combined studies: MTX/anti-TNF naive (placebo, n = 56; 45 mg, n = 58; and 90 mg, n = 66), MTX experienced, biologic agent naive (placebo, n = 192; 45 mg, n = 190; and 90 mg, n = 185), and anti-TNF experienced with or without MTX (placebo, n = 62; 45 mg, n = 60; and 90 mg, n = 58). RESULTS: At week 24, mean improvements from baseline in HAQ DI, DLQI, and SF-36 PCS scores were significantly greater in both ustekinumab groups versus placebo across antecedent exposure groups. Greater proportions of ustekinumab-treated than placebo-treated patients (all P < 0.05) had clinically meaningful improvements in HAQ DI (>=0.3), DLQI (>=5), and SF-36 (>=5) scores at week 24, irrespective of drug exposure. Improvements in pain, disease activity, and impact of disease on productivity were similar, and benefits were maintained through week 52. CONCLUSION: Significant improvements in PROs with ustekinumab versus placebo were observed in 3 antecedent-exposure populations of PsA patients, including those with prior MTX and anti-TNF use. PMID- 27483459 TI - Soft Ngram Representation and Modeling for Protein Remote Homology Detection. AB - Remote homology detection represents a central problem in bioinformatics, where the challenge is to detect functionally related proteins when their sequence similarity is low. Recent solutions employ representations derived from the sequence profile, obtained by replacing each amino acid of the sequence by the corresponding most probable amino acid in the profile. However, the information contained in the profile could be exploited more deeply, provided that there is a representation able to capture and properly model such crucial evolutionary information. In this paper, we propose a novel profile-based representation for sequences, called soft Ngram. This representation, which extends the traditional Ngram scheme (obtained by grouping N consecutive amino acids), permits considering all of the evolutionary information in the profile: this is achieved by extracting Ngrams from the whole profile, equipping them with a weight directly computed from the corresponding evolutionary frequencies. We illustrate two different approaches to model the proposed representation and to derive a feature vector, which can be effectively used for classification using a support vector machine (SVM). A thorough evaluation on three benchmarks demonstrates that the new approach outperforms other Ngram-based methods, and shows very promising results also in comparison with a broader spectrum of techniques. PMID- 27483460 TI - Batch Mode TD($?lambda$ ) for Controlling Partially Observable Gene Regulatory Networks. AB - External control of gene regulatory networks (GRNs) has received much attention in recent years. The aim is to find a series of actions to apply to a gene regulation system making it avoid its diseased states. In this work, we propose a novel method for controlling partially observable GRNs combining batch mode reinforcement learning (Batch RL) and TD() algorithms. Unlike the existing studies inferring a computational model from gene expression data, and obtaining a control policy over the constructed model, our idea is to interpret the time series gene expression data as a sequence of observations that the system produced, and obtain an approximate stochastic policy directly from the gene expression data without estimation of the internal states of the partially observable environment. Thereby, we get rid of the most time consuming phases of the existing studies, inferring a model and running the model for the control. Results show that our method is able to provide control solutions for regulation systems of several thousands of genes only in seconds, whereas existing studies cannot solve control problems of even a few dozens of genes. Results also show that our approximate stochastic policies are almost as good as the policies generated by the existing studies. PMID- 27483461 TI - Triangular Alignment (TAME): A Tensor-Based Approach for Higher-Order Network Alignment. AB - Network alignment has extensive applications in comparative interactomics. Traditional approaches aim to simultaneously maximize the number of conserved edges and the underlying similarity of aligned entities. We propose a novel formulation of the network alignment problem that extends topological similarity to higher-order structures and provides a new objective function that maximizes the number of aligned substructures. This objective function corresponds to an integer programming problem, which is NP-hard. Consequently, we identify a closely related surrogate function whose maximization results in a tensor eigenvector problem. Based on this formulation, we present an algorithm called Triangular AlignMEnt (TAME), which attempts to maximize the number of aligned triangles across networks. Using a case study on the NAPAbench dataset, we show that triangular alignment is capable of producing mappings with high node correctness. We further evaluate our method by aligning yeast and human interactomes. Our results indicate that TAME outperforms the state-of-art alignment methods in terms of conserved triangles. In addition, we show that the number of conserved triangles is more significantly correlated, compared to the conserved edge, with node correctness and co-expression of edges. Our formulation and resulting algorithms can be easily extended to arbitrary motifs. PMID- 27483462 TI - Investigation of hexagonal boron nitride as an atomically thin corrosion passivation coating in aqueous solution. AB - Hexagonal boron nitride (h-BN) atomic layers were utilized as a passivation coating in this study. A large-area continuous h-BN thin film was grown on nickel foil using a chemical vapor deposition method and then transferred onto sputtered copper as a corrosion passivation coating. The corrosion passivation performance in a Na2SO4 solution of bare and coated copper was investigated by electrochemical methods including cyclic voltammetry (CV), Tafel polarization and electrochemical impedance spectroscopy (EIS). CV and Tafel analysis indicate that the h-BN coating could effectively suppress the anodic dissolution of copper. The EIS fitting result suggests that defects are the dominant leakage source on h-BN films, and improved anti-corrosion performances could be achieved by further passivating these defects. PMID- 27483463 TI - The Toll Signaling Pathway in the Chinese Oak Silkworm, Antheraea pernyi: Innate Immune Responses to Different Microorganisms. AB - The Toll pathway is one of the most important signaling pathways regulating insect innate immunity. Spatzle is a key protein that functions as a Toll receptor ligand to trigger Toll-dependent expression of immunity-related genes. In this study, a novel spatzle gene (ApSPZ) from the Chinese oak silkworm Antheraea pernyi was identified. The ApSPZ cDNA is 1065 nucleotides with an open reading frame (ORF) of 777 bp encoding a protein of 258 amino acids. The protein has an estimated molecular weight of 29.71 kDa and an isoelectric point (PI) of 8.53. ApSPZ is a nuclear and secretory protein with no conserved domains or membrane helices and shares 40% amino acid identity with SPZ from Manduca sexta. Phylogenetic analysis indicated that ApSPZ might be a new member of the Spatzle type 1 family, which belongs to the Spatzle superfamily. The expression patterns of several genes involved in the Toll pathway were examined at different developmental stages and various tissues in 5th instar larvae. The examined targets included A. pernyi spatzle, GNBP, MyD88, Tolloid, cactus and dorsalA. The RT-PCR results showed that these genes were predominantly expressed in immune responsive fat body tissue, indicating that the genes play a crucial role in A. pernyi innate immunity. Moreover, A. pernyi infection with the fungus Nosema pernyi and the gram-positive bacterium Enterococcus pernyi, but not the gram negative bacterium Escherichia coli, activated the Toll signaling pathway. These results represent the first study of the Toll pathway in A. pernyi, which provides insight into the A. pernyi innate immune system. PMID- 27483464 TI - Improving Clinical Risk Stratification at Diagnosis in Primary Prostate Cancer: A Prognostic Modelling Study. AB - INTRODUCTION: Over 80% of the nearly 1 million men diagnosed with prostate cancer annually worldwide present with localised or locally advanced non-metastatic disease. Risk stratification is the cornerstone for clinical decision making and treatment selection for these men. The most widely applied stratification systems use presenting prostate-specific antigen (PSA) concentration, biopsy Gleason grade, and clinical stage to classify patients as low, intermediate, or high risk. There is, however, significant heterogeneity in outcomes within these standard groupings. The International Society of Urological Pathology (ISUP) has recently adopted a prognosis-based pathological classification that has yet to be included within a risk stratification system. Here we developed and tested a new stratification system based on the number of individual risk factors and incorporating the new ISUP prognostic score. METHODS AND FINDINGS: Diagnostic clinicopathological data from 10,139 men with non-metastatic prostate cancer were available for this study from the Public Health England National Cancer Registration Service Eastern Office. This cohort was divided into a training set (n = 6,026; 1,557 total deaths, with 462 from prostate cancer) and a testing set (n = 4,113; 1,053 total deaths, with 327 from prostate cancer). The median follow up was 6.9 y, and the primary outcome measure was prostate-cancer-specific mortality (PCSM). An external validation cohort (n = 1,706) was also used. Patients were first categorised as low, intermediate, or high risk using the current three-stratum stratification system endorsed by the National Institute for Health and Care Excellence (NICE) guidelines. The variables used to define the groups (PSA concentration, Gleason grading, and clinical stage) were then used to sub-stratify within each risk category by testing the individual and then combined number of risk factors. In addition, we incorporated the new ISUP prognostic score as a discriminator. Using this approach, a new five-stratum risk stratification system was produced, and its prognostic power was compared against the current system, with PCSM as the outcome. The results were analysed using a Cox hazards model, the log-rank test, Kaplan-Meier curves, competing-risks regression, and concordance indices. In the training set, the new risk stratification system identified distinct subgroups with different risks of PCSM in pair-wise comparison (p < 0.0001). Specifically, the new classification identified a very low-risk group (Group 1), a subgroup of intermediate-risk cancers with a low PCSM risk (Group 2, hazard ratio [HR] 1.62 [95% CI 0.96 2.75]), and a subgroup of intermediate-risk cancers with an increased PCSM risk (Group 3, HR 3.35 [95% CI 2.04-5.49]) (p < 0.0001). High-risk cancers were also sub-classified by the new system into subgroups with lower and higher PCSM risk: Group 4 (HR 5.03 [95% CI 3.25-7.80]) and Group 5 (HR 17.28 [95% CI 11.2-26.67]) (p < 0.0001), respectively. These results were recapitulated in the testing set and remained robust after inclusion of competing risks. In comparison to the current risk stratification system, the new system demonstrated improved prognostic performance, with a concordance index of 0.75 (95% CI 0.72-0.77) versus 0.69 (95% CI 0.66-0.71) (p < 0.0001). In an external cohort, the new system achieved a concordance index of 0.79 (95% CI 0.75-0.84) for predicting PCSM versus 0.66 (95% CI 0.63-0.69) (p < 0.0001) for the current NICE risk stratification system. The main limitations of the study were that it was registry based and that follow-up was relatively short. CONCLUSIONS: A novel and simple five-stratum risk stratification system outperforms the standard three stratum risk stratification system in predicting the risk of PCSM at diagnosis in men with primary non-metastatic prostate cancer, even when accounting for competing risks. This model also allows delineation of new clinically relevant subgroups of men who might potentially receive more appropriate therapy for their disease. Future research will seek to validate our results in external datasets and will explore the value of including additional variables in the system in order in improve prognostic performance. PMID- 27483465 TI - Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism. AB - BACKGROUND & AIMS: The etiology of acute liver failure (ALF) remains elusive in almost half of affected children. We hypothesized that inherited mitochondrial and fatty acid oxidation disorders were occult etiological factors in patients with idiopathic ALF and impaired energy metabolism. METHODS: Twelve patients with elevated blood molar lactate/pyruvate ratio and indeterminate etiology were selected from a retrospective cohort of 74 subjects with ALF because their fixed and frozen liver samples were available for histological, ultrastructural, molecular and biochemical analysis. RESULTS: A customized next-generation sequencing panel for 26 genes associated with mitochondrial and fatty acid oxidation defects revealed mutations and sequence variants in five subjects. Variants involved the genes ACAD9, POLG, POLG2, DGUOK, and RRM2B; the latter not previously reported in subjects with ALF. The explanted livers of the patients with heterozygous, truncating insertion mutations in RRM2B showed patchy micro- and macrovesicular steatosis, decreased mitochondrial DNA (mtDNA) content <30% of controls, and reduced respiratory chain complex activity; both patients had good post-transplant outcome. One infant with severe lactic acidosis was found to carry two heterozygous variants in ACAD9, which was associated with isolated complex I deficiency and diffuse hypergranular hepatocytes. The two subjects with heterozygous variants of unknown clinical significance in POLG and DGUOK developed ALF following drug exposure. Their hepatocytes displayed abnormal mitochondria by electron microscopy. CONCLUSION: Targeted next generation sequencing and correlation with histological, ultrastructural and functional studies on liver tissue in children with elevated lactate/pyruvate ratio expand the spectrum of genes associated with pediatric ALF. PMID- 27483466 TI - Gongjin-Dan Enhances Hippocampal Memory in a Mouse Model of Scopolamine-Induced Amnesia. AB - We evaluated the neuropharmacological effects of Gongjin-Dan (GJD) on the memory impairment caused by scopolamine injection. BALB/c mice were orally treated with GJD (100, 200, or 400 mg/kg, daily) or tacrine (THA, 10 mg/kg) for 10 days, and scopolamine (2 mg/kg) was injected intraperitoneally. The radial arm maze and passive avoidance tests were performed to evaluate the animal's learning and memory. Scopolamine increased the task completing time, the number of total errors (reference and working memory error) in the radial arm maze task, and the latency time in the passive avoidance test, which were significantly ameliorated by treatment with GJD. The GJD treatment also attenuated the scopolamine-induced hyperactivation of acetylcholinesterase activity, and suppression of the expression of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and their receptors in the hippocampus. These effects of GJD were supported by both the doublecortin (DCX)-positive staining and Nissl staining, which were used to measure hippocampal neurogenesis and atrophy, respectively. These findings strongly suggest that GJD exerts a potent anti-amnesic effect, and its underlying mechanism might involve the modulation of cholinergic activity. PMID- 27483467 TI - Perfectionism and Effort-Related Cardiac Activity: Do Perfectionists Try Harder? AB - Do perfectionists try harder? Previous research on perfectionism and effort has used self-report items and task performance as indicators of effort. The current study investigated whether individual differences in perfectionism predicted effort-related cardiac activity during a mental effort task. Based on past research that suggests adaptive perfectionism is associated with higher effort, it was hypothesized that self-oriented perfectionism (SOP) would predict increased effort on the task. One hundred and eleven college students completed the Multidimensional Perfectionism Scale (MPS) and a self-paced parity task in which they received a small cash reward (3 cents) for each correct response. Impedance cardiography was used to assess autonomic reactivity, and regression models tested whether SOP and socially prescribed perfectionism (SPP) explained autonomic reactivity. Overall, participants showed both sympathetic (faster pre ejection period; PEP) and parasympathetic activation (elevated high-frequency heart rate variability; HRV) during the task, reflecting higher effort and engagement. Contrary to predictions, individual differences in perfectionism did not moderate cardiac reactivity. These findings draw attention to the importance of assessing physiological components of effort and motivation directly rather than inferring them from task performance or self-reported effort. PMID- 27483468 TI - PD-1 Antibody Monotherapy for Malignant Melanoma: A Systematic Review and Meta Analysis. AB - Antibodies targeting programmed death 1 (PD-1) help prevent tumor cells from escaping immune-mediated destruction. We conducted this systematic review and meta-analysis to gain insight into the efficacy of PD-1 antibodies for the treatment of melanoma. Five trials involving 2,828 adult patients were included in this meta-analysis. In patients with previously untreated or refractory melanoma, treatment with PD-1 antibodies significantly improved the six-month progression-free survival (PFS) (HR 0.55, 95% CI 0.50-0.60, P<0.00001) and the overall response rate (OR 3.89, 95% CI 3.12-4.83, P<0.00001). This meta-analysis indicated that anti-PD-1 treatment might provide a significant survival benefit in patients with melanoma. In addition, we found that patients treated with nivolumab reported significantly fewer treatment-related adverse events (OR 0.74, 95% CI 0.57-0.97, P = 0.03) than those treated with other agents, but there was a dose-dependent increase in the frequency of adverse events in patients treated with pembrolizumab. PMID- 27483469 TI - CFTR Deletion in Mouse Testis Induces VDAC1 Mediated Inflammatory Pathway Critical for Spermatogenesis. AB - Cystic fibrosis is the most common genetic disease among Caucasians and affects tissues including lung, pancreas and reproductive tracts. It has been shown that Endoplasmic Reticulum (ER) stress and heat shock response are two major deregulated functional modules related to CFTR dysfunction. To identify the impact of CFTR deletion during spermatogenesis, we examined the expression of spermiogenesis-related genes in the testis of CFTR mutant mice (CF mice). We confirmed expression changes of MSY2, a germ cell specific RNA binding protein, resulting from deletion of CFTR in testis. Furthermore, real time PCR and Western blot results showed that an inflammatory response was activated in CF mice testis, as reflected by the altered expression of cytokines. We demonstrate for the first time that expression of MSY2 is decreased in CF mice. Our results suggest that CFTR deletion in testis influences inflammatory responses and these features are likely to be due to the unique environment of the seminiferous tubule during the spermatogenesis process. The current study also suggests avenues to understand the pathophysiology of CFTR during spermatogenesis and provides targets for the possible treatment of CFTR-related infertility. PMID- 27483470 TI - A Single-Batch Fermentation System to Simulate Human Colonic Microbiota for High Throughput Evaluation of Prebiotics. AB - We devised a single-batch fermentation system to simulate human colonic microbiota from fecal samples, enabling the complex mixture of microorganisms to achieve densities of up to 1011 cells/mL in 24 h. 16S rRNA gene sequence analysis of bacteria grown in the system revealed that representatives of the major phyla, including Bacteroidetes, Firmicutes, and Actinobacteria, as well as overall species diversity, were consistent with those of the original feces. On the earlier stages of fermentation (up to 9 h), trace mixtures of acetate, lactate, and succinate were detectable; on the later stages (after 24 h), larger amounts of acetate accumulated along with some of propionate and butyrate. These patterns were similar to those observed in the original feces. Thus, this system could serve as a simple model to simulate the diversity as well as the metabolism of human colonic microbiota. Supplementation of the system with several prebiotic oligosaccharides (including fructo-, galacto-, isomalto-, and xylo oligosaccharides; lactulose; and lactosucrose) resulted in an increased population in genus Bifidobacterium, concomitant with significant increases in acetate production. The results suggested that this fermentation system may be useful for in vitro, pre-clinical evaluation of the effects of prebiotics prior to testing in humans. PMID- 27483471 TI - Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance. AB - Antimalarial chloroquine (CQ) prevents haematin detoxication when CQ-base concentrates in the acidic digestive vacuole through protonation of its p aminopyridine (pAP) basic aromatic nitrogen and sidechain diethyl-N. CQ export through the variant vacuolar membrane export channel, PFCRT, causes CQ-resistance in Plasmodium falciparum but 3-methyl CQ (sontochin SC), des-ethyl amodiaquine (DAQ) and bis 4-aminoquinoline piperaquine (PQ) are still active. This is determined by changes in drug accumulation ratios in parasite lipid (LAR) and in vacuolar water (VAR). Higher LAR may facilitate drug binding to and blocking PFCRT and also aid haematin in lipid to bind drug. LAR for CQ is only 8.3; VAR is 143,482. More hydrophobic SC has LAR 143; VAR remains 68,523. Similarly DAQ with a phenol substituent has LAR of 40.8, with VAR 89,366. In PQ, basicity of each pAP is reduced by distal piperazine N, allowing very high LAR of 973,492, retaining VAR of 104,378. In another bis quinoline, dichlorquinazine (DCQ), also active but clinically unsatisfactory, each pAP retains basicity, being insulated by a 2-carbon chain from a proximal nitrogen of the single linking piperazine. While LAR of 15,488 is still high, the lowest estimate of VAR approaches 4.9 million. DCQ may be expected to be very highly lysosomotropic and therefore potentially hepatotoxic. In 11 pAP antimalarials a quadratic relationship between logLAR and logResistance Index (RI) was confirmed, while log (LAR/VAR) vs logRI for 12 was linear. Both might be used to predict the utility of structural modifications. PMID- 27483472 TI - Genetic Variation of 25 Y-Chromosomal and 15 Autosomal STR Loci in the Han Chinese Population of Liaoning Province, Northeast China. AB - In the present study, we investigated the genetic characteristics of 25 Y chromosomal and 15 autosomal short tandem repeat (STR) loci in 305 unrelated Han Chinese male individuals from Liaoning Province using AmpFISTR(r) Yfiler(r) Plus and IdentifilerTM PCR amplification kits. Population comparison was performed between Liaoning Han population and different ethnic groups to better understand the genetic background of the Liaoning Han population. For Y-STR loci, the overall haplotype diversity was 0.9997 and the discrimination capacity was 0.9607. Gene diversity values ranged from 0.4525 (DYS391) to 0.9617 (DYS385). Rst and two multi-dimensional scaling plots showed that minor differences were observed when the Liaoning Han population was compared to the Jilin Han Chinese, Beijing Han Chinese, Liaoning Manchu, Liaoning Mongolian, Liaoning Xibe, Shandong Han Chinese, Jiangsu Han Chinese, Anhui Han Chinese, Guizhou Han Chinese and Liaoning Hui populations; by contrast, major differences were observed when the Shanxi Han Chinese, Yunnan Bai, Jiangxi Han Chinese, Guangdong Han Chinese, Liaoning Korean, Hunan Tujia, Guangxi Zhuang, Gansu Tibetan, Xishuangbanna Dai, South Korean, Japanese and Hunan Miao populations. For autosomal STR loci, DP ranged from 0.9621 (D2S1338) to 0.8177 (TPOX), with PE distributing from 0.7521 (D18S51) to 0.2988 (TH01). A population comparison was performed and no statistically significant differences were detected at any STR loci between Liaoning Han, China Dong, and Shaanxi Han populations. The results showed that the 25 Y-STR and 15 autosomal STR loci in the Liaoning Han population were valuable for forensic applications and human genetics, and Liaoning Han was an independent endogenous ethnicity with a unique subpopulation structure. PMID- 27483474 TI - SleepSense: A Noncontact and Cost-Effective Sleep Monitoring System. AB - Quality of sleep is an important indicator of health and well being. Recent developments in the field of in-home sleep monitoring have the potential to enhance a person's sleeping experience and contribute to an overall sense of well being. Existing in-home sleep monitoring devices either fail to provide adequate sleep information or are obtrusive to use. To overcome these obstacles, a noncontact and cost-effective sleep monitoring system, named SleepSense, is proposed for continuous recognition of the sleep status, including on-bed movement, bed exit, and breathing section. SleepSense consists of three parts: a Doppler radar-based sensor, a robust automated radar demodulation module, and a sleep status recognition framework. Herein, several time-domain and frequency domain features are extracted for the sleep recognition framework. A prototype of SleepSense is presented and evaluated using two sets of experiments. In the short term controlled experiment, the SleepSense achieves an overall 95.1% accuracy rate in identifying various sleep status. In the 75-minute sleep study, SleepSense demonstrates wide usability in real life. The error rate for breathing rate extraction in this study is only 6.65%. These experimental results indicate that SleepSense is an effective and promising solution for in-home sleep monitoring. PMID- 27483473 TI - How Quorum Sensing Connects Sporulation to Necrotrophism in Bacillus thuringiensis. AB - Bacteria use quorum sensing to coordinate adaptation properties, cell fate or commitment to sporulation. The infectious cycle of Bacillus thuringiensis in the insect host is a powerful model to investigate the role of quorum sensing in natural conditions. It is tuned by communication systems regulators belonging to the RNPP family and directly regulated by re-internalized signaling peptides. One such RNPP regulator, NprR, acts in the presence of its cognate signaling peptide NprX as a transcription factor, regulating a set of genes involved in the survival of these bacteria in the insect cadaver. Here, we demonstrate that, in the absence of NprX and independently of its transcriptional activator function, NprR negatively controls sporulation. NprR inhibits expression of Spo0A-regulated genes by preventing the KinA-dependent phosphorylation of the phosphotransferase Spo0F, thus delaying initiation of the sporulation process. This NprR function displays striking similarities with the Rap proteins, which also belong to the RNPP family, but are devoid of DNA-binding domain and indirectly control gene expression via protein-protein interactions in Bacilli. Conservation of the Rap residues directly interacting with Spo0F further suggests a common inhibition of the sporulation phosphorelay. The crystal structure of apo NprR confirms that NprR displays a highly flexible Rap-like structure. We propose a molecular regulatory mechanism in which key residues of the bifunctional regulator NprR are directly and alternatively involved in its two functions. NprX binding switches NprR from a dimeric inhibitor of sporulation to a tetrameric transcriptional activator involved in the necrotrophic lifestyle of B. thuringiensis. NprR thus tightly coordinates sporulation and necrotrophism, ensuring survival and dissemination of the bacteria during host infection. PMID- 27483475 TI - Body-Earth Mover's Distance: A Matching-Based Approach for Sleep Posture Recognition. AB - Sleep posture is a key component in sleep quality assessment and pressure ulcer prevention. Currently, body pressure analysis has been a popular method for sleep posture recognition. In this paper, a matching-based approach, Body-Earth Mover's Distance (BEMD), for sleep posture recognition is proposed. BEMD treats pressure images as weighted 2D shapes, and combines EMD and Euclidean distance for similarity measure. Compared with existing work, sleep posture recognition is achieved with posture similarity rather than multiple features for specific postures. A pilot study is performed with 14 persons for six different postures. The experimental results show that the proposed BEMD can achieve 91.21% accuracy, which outperforms the previous method with an improvement of 8.01%. PMID- 27483476 TI - Computer simulations of the interaction of human immunodeficiency virus (HIV) aspartic protease with spherical gold nanoparticles: implications in acquired immunodeficiency syndrome (AIDS). AB - The interaction of gold nanoparticles (AuNP) with human immune-deficiency virus aspartic protease (HIVPR) is modelled using a regime of molecular dynamics simulations. The simulations of the 'docking', first as a rigid-body complex, and eventually through flexible-fit analysis, creates 36 different complexes from four initial orientations of the nanoparticle strategically positioned around the surface of the enzyme. The structural deviations of the enzymes from the initial x-ray crystal structure during each docking simulation are assessed by comparative analysis of secondary structural elements, root mean square deviations, B-factors, interactive bonding energies, dihedral angles, radius of gyration (R g), circular dichroism (CD), volume occupied by C alpha , electrostatic potentials, solvation energies and hydrophobicities. Normalisation of the data narrows the selection from the initial 36 to one 'final' probable structure. It is concluded that, after computer simulations on each of the 36 initial complexes incorporating the 12 different biophysical techniques, the top five complexes are the same no matter which technique is explored. The significance of the present work is an expansion of an earlier study on the molecular dynamic simulation for the interaction of HIVPR with silver nanoparticles. This work is supported by experimental evidence since the initial 'orientation' of the AgNP with the enzyme is the same as the 'final' AuNP-HIVPR complex generated in the present study. The findings will provide insight into the forces of the binding of the HIVPR to AuNP. It is anticipated that the protocol developed in this study will act as a standard process for the interaction of any nanoparticle with any biomedical target. PMID- 27483477 TI - Clinical relevance of isolated prolongation of the activated partial thromboplastin time in a cohort of adults undergoing surgical procedures. AB - BACKGROUND: Coagulation screening prior to surgery is performed routinely worldwide to identify patients at risk of bleeding during the procedure. Evidence from medical and surgical literature suggests that the activated partial thromboplastin time (aPTT) alone is suitable for predicting individual bleeding risk during surgery and it is current practice in our hospital to measure this parameter. MATERIALS AND METHODS: We retrospectively reviewed aPTT ratio results in 8,069 consecutive adult subjects undergoing elective surgery from January 1 to December 31, 2014 to confirm the validity of this approach. RESULTS: In 7,606 patients (94.2%) the aPTT ratio was within the normal range while it was abnormal in 463 (5.8%). Out of these 463, 223 aPTT ratios were between 1.2 and 1.3 and we considered these results not worthy enough of further investigations. In 240 patients the aPTT ratio was higher than 1.3; in the vast majority of these cases (201/240; 83%) this abnormality was associated with oral anticoagulant treatment. Seventeen of the other 39 cases underwent detailed investigations which revealed lupus anticoagulant (n=7), decompensated chronic liver disease (n=4), factor XII deficiency (n=3), mild combined reduction of FXI and FXII (n=1) and mild haemophilia A (n=2). The other 22 patients underwent successful surgery without further investigation. DISCUSSION: Our results from a pre-surgical setting seem to confirm the low prevalence of coagulation defects in the general population. Increased aPTT ratios were mainly attributable to oral anticoagulant therapy, with a few cases caused by mild, clinically irrelevant clotting factor deficiencies. A carefully taken personal history, including medications (i.e. oral anticoagulants) and/or previous bleeding symptoms seem more useful than coagulation screening tests to predict the risk of bleeding. PMID- 27483478 TI - Borrowing (once again) from the animal kingdom. PMID- 27483479 TI - Anticoagulants for the prevention and treatment of catheter-related thrombosis in adults and children on parenteral nutrition: a systematic review and critical appraisal. AB - BACKGROUND: Patients on parenteral nutrition require a central venous access and are at risk of catheter-related thrombosis, pulmonary embolism, and vena cava syndrome. Parenteral nutrition guidelines suggest anticoagulation for the primary prevention of catheter-related thrombosis during long-term parenteral nutrition. We conducted a systematic review of the efficacy, safety and feasibility of anticoagulant use for preventing and treating catheter-related thrombosis during parenteral nutrition. MATERIALS AND METHODS: We searched for interventional and observational studies on adults and children receiving systemic anticoagulants during either short- or long-term parenteral nutrition delivered via central venous access. Primary outcomes were: objectively-confirmed catheter-related thrombosis, pulmonary embolism and bleeding. Secondary outcomes were: heparin induced thrombocytopenia, prevalence of anticoagulation, and quality of International Normalised Ratio management in vitamin K antagonist-treated patients. RESULTS: We identified 1,199 studies, of which 23 were included. Seven interventional studies of short-term parenteral nutrition (adult population, n=5) were classified as low-quality: in those, intravenous unfractionated heparin did not prevent catheter-related thrombosis if compared to saline. No interventional studies were conducted in patients on long-term parenteral nutrition. Observational data were sparse, rarely focusing on anticoagulation, and overall of low quality. The reported use of anticoagulants was between 22 and 66% in recent multicentre cohorts. DISCUSSION: The amount and quality of data in this area are very suboptimal: most studies are outdated and involved heterogeneous populations. Currently, there is insufficient evidence to allow conclusions to be reached regarding the efficacy and safety of anticoagulants in this setting. PMID- 27483481 TI - The relative efficacy of three interventions to favour return to give blood. AB - BACKGROUND: The aim of the study was to test the relative efficacy of action planning and reward distribution to promote retention of whole blood donors. MATERIALS AND METHODS: A sample of 7,399 donors was randomised to one of three interventions: "action planning" (n=2,585); "reward" (n=2,397); and "thank you" (n=2,417). Participants in the action planning condition were invited to write the date of their next donation on a post-it note before taking it home at the end of the donation process. Participants in the "reward" condition were given an anti-theft credit card sleeve at the end of the donation process. The "thank you" intervention is the usual condition at the end of the process; it was considered the control condition. The dependent variable was the proportion of donors who registered to give blood at six months. RESULTS: Overall, 4,444 (60.06%) donors registered to give blood at six months. There were no differences between the three interventions in the proportions of donors who registered to give blood (d.f. 2, chi-square=3.72, p<0.15). However, gender modified the effect of the intervention (d.f. 2, chi-square=6.57, p<0.0375); more women registered in the "thank you" condition than in the other two. DISCUSSION: The results suggest that action planning and the distribution of a reward have no motivational effect on the return to give blood. Nonetheless, women appear to respond more negatively to these interventions at the end of the donation process. PMID- 27483480 TI - Molecular immunohaematology round table discussions at the AABB Annual Meeting, Anaheim 2015. PMID- 27483482 TI - Platelet gel: a new therapeutic tool with great potential. AB - Chronic wounds, such as diabetic foot ulcers, represent a serious clinical problem for patients and clinicians. Management of these wounds has a strong economic impact worldwide. Complications resulting from injuries are a frequent cause of morbidity and mortality. Chronic wounds lead to infections, painful dressings and prolonged hospitalisation. This results in poor patient Quality of Life and in high healthcare costs. Platelet concentrates (PC) are defined as autologous or allogeneic platelet derivatives with a platelet concentration higher than baseline. PC are widely used in different areas of Regenerative Medicine in order to enhance wound healing processes; they include platelet-rich plasma (PRP), platelet gel (PG), platelet-rich fibrin (PRF), serum eye drops (E S), and PRP eye drops (E-PRP). This review highlights the use of platelet-rich plasma (PRP) and platelet gel (PG) preparation for clinical use. PMID- 27483483 TI - Intravenous iron supplementation with intra-articular administration of tranexamic acid reduces the rate of allogeneic transfusions after simultaneous bilateral total knee arthroplasty. AB - BACKGROUND: Peri-operative intravenous administration of iron supplementation seems a good option to reduce allogeneic blood transfusion in major orthopaedic surgery. However, its efficacy in simultaneous bilateral total knee arthroplasty has not been studied. MATERIALS AND METHODS: From December 2014 to May 2015, a total of 72 consecutive patients underwent simultaneous bilateral total knee arthroplasty and received peri-operative intravenous iron supplementation (iron isomaltoside 1000: 600 mg pre-operatively and 400 mg 1 week post-operatively) and intra-articular tranexamic acid (2 g in 20 mL saline at the end of surgery), and were managed with a restrictive transfusion trigger (haemoglobin <7 g/dL). Post operatively, we observed patients closely for symptoms of anaemia and checked their haemoglobin levels on days 1, 6 and 13 after surgery. RESULTS: The mean baseline haemoglobin level was 13.1 g/dL. The levels remained above 7.0 g/dL on post-operative days 1, 6 and 13 (mean, 11.4 g/dL, 9.9 g/dL and 10.4 g/dL, respectively) in all but one patient who experienced melaena and required allogeneic blood transfusion. DISCUSSION: Intravenous iron supplementation combined with intra-articular administration of tranexamic acid seems to be an effective strategy for reducing the rate of allogeneic blood transfusion in patients undergoing simultaneous bilateral total knee arthroplasty managed with a restrictive transfusion trigger. PMID- 27483484 TI - Porcine recombinant factor VIII: an additional weapon to handle anti-factor VIII antibodies. AB - This review focuses on the use of recombinant porcine factor VIII (FVIII) for the treatment of bleeding episodes in patients with severe haemophilia A complicated by inhibitors and in those with acquired haemophilia A due to the onset of anti FVIII autoantibodies. We present the main characteristics of recombinant porcine factor VIII (FVIII) and provide a summary of the published results of the clinical studies of this novel recombinant FVIII. There is a special emphasis on how the use of recombinant porcine factor VIII (FVIII) is expected to improve the clinical management of these patients. PMID- 27483485 TI - The increased demand for plasma-derived factor VIII in Italy. PMID- 27483486 TI - Quality indicators for Transfusion Medicine in Spain: a survey among hospital transfusion services. AB - BACKGROUND: Transfusion services in the European Union must implement quality management systems to improve quality. Quality indicators (QI) play a key role in quality management because they can supply important information about the performance of the transfusion service, which can then be used for benchmarking. However, little is known about the actual use of QI in hospitals. We tried to ascertain the use and characteristics of QI in Spanish hospital transfusion services. MATERIALS AND METHODS: We performed a survey among transfusion services in order to learn which QI they use. We classified indicators into categories and concepts, according to the steps of the transfusion process or the activities the indicators referred to. RESULTS: Seventy-six hospitals (17.9% of the hospitals actively transfusing in the country) reported 731 QI. Twenty-two of them (29%) were tertiary level hospitals. The number of indicators per hospital and by activity varied greatly. QI were assigned to some basic categories: transfusion process (23% of indicators), transfusion activity and stock management (22%), haemovigilance (20%), stem cell transplantation (9%), transfusion laboratory (9%), quality management system (8%), blood donation (3.4%), apheresis and therapeutic activities (2.5%) and immunohaematology of pregnancy (2%). DISCUSSION: Although most hospitals use QI in their quality management system and share a core group of indicators, we found a great dispersion in the number and characteristics of the indicators used. The use of a commonly agreed set of QI could be an aid to benchmarking among hospitals and to improving the transfusion process. PMID- 27483487 TI - Functional characterisation of the type 1 von Willebrand disease candidate VWF gene variants: p.M771I, p.L881R and p.P1413L. AB - BACKGROUND: Abnormalities in the biosynthetic pathway or increased clearance of plasma von Willebrand factor (VWF) are likely to contribute to decreased plasma VWF levels in inherited type 1 von Willebrand disease (VWD). Recent studies demonstrated that 65% of type 1 VWD patients have candidate VWF mutations, the majority of which are missense variants. The purpose of this study was to explore the effects of three VWF missense mutations (p.M771I, p.L881R and p.P1413L) located in different functional domains of VWF, reported as candidate mutations in type 1 VWD patients in the course of the MCMDM-1VWD study. MATERIALS AND METHODS: The focus of these studies was on the intracellular biosynthetic processing and localisation of VWF in a heterologous cell system. Molecular dynamic simulation for p.M771I and p.P1413L was also performed to analyse the conformational effects of the changes. RESULTS: As determined by immunofluorescence antibody staining and confocal microscopy of HEK293 cells, the intracellular localisation of recombinant VWF with the p.M771I variation was impaired. Transient transfection studies and phorbol myristate acetate stimulation in COS-7 cells revealed significant intracellular retention. In addition, major loss of VWF multimers was observed for only the p.M771I mutation. Molecular dynamic simulations on p.M771I mutant VWF revealed distinct structural rearrangements including a large deviation in the E' domain, and significant loss of beta-sheet secondary structure. DISCUSSION: The pathogenic effects of candidate VWF gene mutations were explored in this study. In vitro expression studies in heterologous cell systems revealed impaired secretion of VWF and a dominant negative effect on the processing of the wild-type protein for only the p.M771I mutation and none of the mutations affected the regulated secretion. PMID- 27483489 TI - 27 Congreso Anual de la SETS: Bilbao (Espana), 23-25 Junio 2016. PMID- 27483488 TI - Hepatitis E virus infections in travellers: assessing the threat to the Australian blood supply. AB - BACKGROUND: In many developed countries hepatitis E virus (HEV) infections have occurred predominantly in travellers to countries endemic for HEV. HEV is a potential threat to blood safety as the virus is transfusion-transmissible. To minimise this risk in Australia, individuals diagnosed with HEV are deferred. Malarialdeferrals, when donors are restricted from donating fresh blood components following travel toanareain which malaria is endemic, probably also decrease the HEV risk, by deferring donors who travel to many countries also endemic for HEV. The aim of this study is to describe overseas-acquired HEV cases in Australia, in order to determine whether infection in travellers poses a risk to Australian blood safety. MATERIALS AND METHODS: Details of all notified HEV cases in Australia from 2002 to 2014 were accessed, and importation rates estimated. Countries in which HEV was acquired were compared to those for which donations are restricted following travel because of a malaria risk. RESULTS: Three hundred and thirty-two cases of HEV were acquired overseas. Travel to India accounted for most of these infections, although the importation rate was highest for Nepal and Bangladesh. Countries for which donations are restricted following travel due to malaria risk accounted for 94% of overseas-acquired HEV cases. DISCUSSION: The vast majority of overseas-acquired HEV infections were in travellers returning from South Asian countries, which are subject to donation related travel restrictions for malaria. This minimises the risk HEV poses to the Australian blood supply. PMID- 27483490 TI - Physical-Perceptual Correspondence for Dynamic Thermal Stimulation. AB - Thermal displays have been applied in various haptic applications, from material simulation to interpersonal communication; however, there is insufficient knowledge about the temporal processing in human thermal sense to provide a knowledge basis for thermal display design. In this study, we investigated the physical-perceptual correspondence for dynamic thermal stimulation to shed a light on the temporal processing of human thermal sense. In the experiments, participants reported subjective timings of the temperature onset and temperature peak of continuous temperature changes applied to the thenar eminence. We found that the physical-perceptual correspondence was not consistent for warm and cold stimulations. For warm stimulation, the subjective experience always came after the corresponding physical event. On the other hand, for cold stimulation, while the subjective onset always lagged the physical onset, the subjective temperature peak preceded the physical temperature peak. We analyzed these results in the framework of linear systems theory. The results suggest that the senses of warmth and cold have distinct temporal filtering properties, with the sense of cold being more transient than the sense of warmth. These findings advance our knowledge regarding temporal processing in human thermal sense and serve as a basis for thermal display design. PMID- 27483491 TI - Hierarchical Address Event Routing for Reconfigurable Large-Scale Neuromorphic Systems. AB - We present a hierarchical address-event routing (HiAER) architecture for scalable communication of neural and synaptic spike events between neuromorphic processors, implemented with five Xilinx Spartan-6 field-programmable gate arrays and four custom analog neuromophic integrated circuits serving 262k neurons and 262M synapses. The architecture extends the single-bus address-event representation protocol to a hierarchy of multiple nested buses, routing events across increasing scales of spatial distance. The HiAER protocol provides individually programmable axonal delay in addition to strength for each synapse, lending itself toward biologically plausible neural network architectures, and scales across a range of hierarchies suitable for multichip and multiboard systems in reconfigurable large-scale neuromorphic systems. We show approximately linear scaling of net global synaptic event throughput with number of routing nodes in the network, at 3.6*107 synaptic events per second per 16k-neuron node in the hierarchy. PMID- 27483492 TI - 3D Ta/TaO x /TiO2/Ti synaptic array and linearity tuning of weight update for hardware neural network applications. AB - The implementation of highly anticipated hardware neural networks (HNNs) hinges largely on the successful development of a low-power, high-density, and reliable analog electronic synaptic array. In this study, we demonstrate a two-layer Ta/TaO x /TiO2/Ti cross-point synaptic array that emulates the high-density three dimensional network architecture of human brains. Excellent uniformity and reproducibility among intralayer and interlayer cells were realized. Moreover, at least 50 analog synaptic weight states could be precisely controlled with minimal drifting during a cycling endurance test of 5000 training pulses at an operating voltage of 3 V. We also propose a new state-independent bipolar-pulse-training scheme to improve the linearity of weight updates. The improved linearity considerably enhances the fault tolerance of HNNs, thus improving the training accuracy. PMID- 27483493 TI - Interval-Valued Model Level Fuzzy Aggregation-Based Background Subtraction. AB - In a recent work, the effectiveness of neighborhood supported model level fuzzy aggregation was shown under dynamic background conditions. The multi-feature fuzzy aggregation used in that approach uses real fuzzy similarity values, and is robust for low and medium-scale dynamic background conditions such as swaying vegetation, sprinkling water, etc. The technique, however, exhibited some limitations under heavily dynamic background conditions, as features have high uncertainty under such noisy conditions and these uncertainties were not captured by real fuzzy similarity values. Our proposed algorithm is particularly focused toward improving the detection under heavy dynamic background conditions by modeling uncertainties in the data by interval-valued fuzzy set. In this paper, real-valued fuzzy aggregation has been extended to interval-valued fuzzy aggregation by considering uncertainties over real similarity values. We build up a procedure to calculate the uncertainty that varies for each feature, at each pixel, and at each time instant. We adaptively determine membership values at each pixel by the Gaussian of uncertainty value instead of fixed membership values used in recent fuzzy approaches, thereby, giving importance to a feature based on its uncertainty. Interval-valued Choquet integral is evaluated using interval similarity values and the membership values in order to calculate interval-valued fuzzy similarity between model and current. Adequate qualitative and quantitative studies are carried out to illustrate the effectiveness of the proposed method in mitigating heavily dynamic background situations as compared to state-of-the-art. PMID- 27483494 TI - Pinning Control of Lag-Consensus for Second-Order Nonlinear Multiagent Systems. AB - Lag consensus means that the corresponding state vectors of the followers are behind the leader with a lag time. In this paper, Lyapunov functional and matrix theory are applied to analyze pinning-controlled lag consensus of second-order nonlinear multiagent systems. The focus is twofold: 1) to find out which agents should be pinned and 2) to determine what the coupling strength should be, so that the multiagent systems can reach lag consensus. Moreover, the practical problem in a noisy environment is considered. Finally, an illustrative example is provided to demonstrate the effectiveness of the proposed pinning control protocol. PMID- 27483495 TI - Dynamics of Metabolism and Decision Making During Alcohol Consumption: Modeling and Analysis. AB - Heavy alcohol consumption is considered an important public health issue in the United States as over 88 000 people die every year from alcohol-related causes. Research is being conducted to understand the etiology of alcohol consumption and to develop strategies to decrease high-risk consumption and its consequences, but there are still important gaps in determining the main factors that influence the consumption behaviors throughout the drinking event. There is a need for methodologies that allow us not only to identify such factors but also to have a comprehensive understanding of how they are connected and how they affect the dynamical evolution of a drinking event. In this paper, we use previous empirical findings from laboratory and field studies to build a mathematical model of the blood alcohol concentration dynamics in individuals that are in drinking events. We characterize these dynamics as the result of the interaction between a decision-making system and the metabolic process for alcohol. We provide a model of the metabolic process for arbitrary alcohol intake patterns and a characterization of the mechanisms that drive the decision-making process of a drinker during the drinking event. We use computational simulations and Lyapunov stability theory to analyze the effects of the parameters of the model on the blood alcohol concentration dynamics that are characterized. Also, we propose a methodology to inform the model using data collected in situ and to make estimations that provide additional information to the analysis. We show how this model allows us to analyze and predict previously observed behaviors, to design new approaches for the collection of data that improves the construction of the model, and help with the design of interventions. PMID- 27483496 TI - School Siting Near Industrial Chemical Facilities: Findings from the U.S. Chemical Safety Board's Investigation of the West Fertilizer Explosion. AB - BACKGROUND: The U.S. Chemical Safety and Hazard Investigation Board (CSB) investigated the 17 April 2013 explosion at the West Fertilizer Company (WFC) that resulted in 15 fatalities, more than 260 injuries, and damage to more than 150 buildings. Among these structures were four nearby school buildings cumulatively housing children in grades kindergarten-12, a nursing care facility, and an apartment complex. The incident occurred during the evening when school was not in session, which reduced the number of injuries. OBJECTIVES: The goal of this commentary is to illustrate the consequences of siting schools near facilities that store or use hazardous chemicals, and highlight the need for additional regulations to prevent future siting of schools near these facilities. DISCUSSION: We summarize the findings of the CSB's investigation related to the damaged school buildings and the lack of regulation surrounding the siting of schools near facilities that store hazardous chemicals. CONCLUSIONS: In light of the current lack of federal authority for oversight of land use near educational institutions, state and local governments should take a proactive role in promulgating state regulations that prohibit the siting of public receptors, such as buildings occupied by children, near facilities that store hazardous chemicals. CITATION: Tinney VA, Denton JM, Sciallo-Tyler L, Paulson JA. 2016. School siting near industrial chemical facilities: findings from the U.S. Chemical Safety Board's investigation of the West Fertilizer Explosion. Environ Health Perspect 124:1493-1496; http://dx.doi.org/10.1289/EHP132. PMID- 27483497 TI - Modeling human diseases: an education in interactions and interdisciplinary approaches. AB - Traditionally, most investigators in the biomedical arena exploit one model system in the course of their careers. Occasionally, an investigator will switch models. The selection of a suitable model system is a crucial step in research design. Factors to consider include the accuracy of the model as a reflection of the human disease under investigation, the numbers of animals needed and ease of husbandry, its physiology and developmental biology, and the ability to apply genetics and harness the model for drug discovery. In my lab, we have primarily used the zebrafish but combined it with other animal models and provided a framework for others to consider the application of developmental biology for therapeutic discovery. Our interdisciplinary approach has led to many insights into human diseases and to the advancement of candidate drugs to clinical trials. Here, I draw on my experiences to highlight the importance of combining multiple models, establishing infrastructure and genetic tools, forming collaborations, and interfacing with the medical community for successful translation of basic findings to the clinic. PMID- 27483498 TI - Show and tell: disclosure and data sharing in experimental pathology. AB - Reproducibility of data from experimental investigations using animal models is increasingly under scrutiny because of the potentially negative impact of poor reproducibility on the translation of basic research. Histopathology is a key tool in biomedical research, in particular for the phenotyping of animal models to provide insights into the pathobiology of diseases. Failure to disclose and share crucial histopathological experimental details compromises the validity of the review process and reliability of the conclusions. We discuss factors that affect the interpretation and validation of histopathology data in publications and the importance of making these data accessible to promote replicability in research. PMID- 27483499 TI - Evaluating the Impact of the U.S. National Toxicology Program: A Case Study on Hexavalent Chromium. AB - BACKGROUND: Evaluating the impact of federally funded research with a broad, methodical, and objective approach is important to ensure that public funds advance the mission of federal agencies. OBJECTIVES: We aimed to develop a methodical approach that would yield a broad assessment of National Toxicology Program's (NTP's) effectiveness across multiple sectors and demonstrate the utility of the approach through a case study. METHODS: A conceptual model was developed with defined activities, outputs (products), and outcomes (proximal, intermediate, distal) and applied retrospectively to NTP's research on hexavalent chromium (CrVI). Proximal outcomes were measured by counting views of and requests for NTP's products by external stakeholders. Intermediate outcomes were measured by bibliometric analysis. Distal outcomes were assessed through Web and LexisNexis searches for documents related to legislation or regulation changes. RESULTS: The approach identified awareness of NTP's work on CrVI by external stakeholders (proximal outcome) and citations of NTP's research in scientific publications, reports, congressional testimonies, and legal and policy documents (intermediate outcome). NTP's research was key to the nation's first-ever drinking water standard for CrVI adopted by California in 2014 (distal outcome). By applying this approach to a case study, the utility and limitations of the approach were identified, including challenges to evaluating the outcomes of a research program. CONCLUSIONS: This study identified a broad and objective approach for assessing NTP's effectiveness, including methodological needs for more thorough and efficient impact assessments in the future. Citation: Xie Y, Holmgren S, Andrews DMK, Wolfe MS. 2017. Evaluating the impact of the U.S. National Toxicology Program: a case study on hexavalent chromium. Environ Health Perspect 125:181-188; http://dx.doi.org/10.1289/EHP21. PMID- 27483501 TI - Crisis Standards of Care: A Systems Framework for Catastrophic Disaster Response. PMID- 27483500 TI - Residential Exposure to Natural Background Radiation and Risk of Childhood Acute Leukemia in France, 1990-2009. AB - BACKGROUND: Exposures to high-dose ionizing radiation and high-dose rate ionizing radiation are established risk factors for childhood acute leukemia (AL). The risk of AL following exposure to lower doses due to natural background radiation (NBR) has yet to be conclusively determined. METHODS: AL cases diagnosed over 1990-2009 (9,056 cases) were identified and their municipality of residence at diagnosis collected by the National Registry of Childhood Cancers. The Geocap study, which included the 2,763 cases in 2002-2007 and 30,000 population controls, was used for complementary analyses. NBR exposures were modeled on a fine scale (36,326 municipalities) based on measurement campaigns and geological data. The power to detect an association between AL and dose to the red bone marrow (RBM) fitting UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) predictions was 92%, 45% and 99% for exposure to natural gamma radiation, radon and total radiation, respectively. RESULTS: AL risk, irrespective of subtype and age group, was not associated with the exposure of municipalities to radon or gamma radiation in terms of yearly exposure at age reached, cumulative exposure or RBM dose. There was no confounding effect of census-based socio-demographic indicators, or environmental factors (road traffic, high voltage power lines, vicinity of nuclear plants) related to AL in the Geocap study. CONCLUSIONS: Our findings do not support the hypothesis that residential exposure to NBR increases the risk of AL, despite the large size of the study, fine scale exposure estimates and wide range of exposures over France. However, our results at the time of diagnosis do not rule out a slight association with gamma radiation at the time of birth, which would be more in line with the recent findings in the UK and Switzerland. PMID- 27483502 TI - Healing the Wounds After the Fight: Army Medical Care to Repatriated Captives, Part II. PMID- 27483503 TI - 10-Pound Weight Loss and Lower Abdominal Pain. PMID- 27483504 TI - A New Era of Partnership Between The Uniformed Services University and The Armed Forced Medical College, Pune, India. PMID- 27483505 TI - Waiting for the Cry. PMID- 27483506 TI - The Impact of Combat Deployment on Health Care Provider Burnout in a Military Emergency Department: A Cross-Sectional Professional Quality of Life Scale V Survey Study. AB - BACKGROUND: Compassion fatigue is a problem for many health care providers manifesting as physical, mental, and spiritual exhaustion. Our objective was to evaluate the association between prior combat deployment and compassion fatigue among military emergency medicine providers. METHODS: We conducted a nonexperimental cross-sectional survey of health care providers assigned to the San Antonio Military Medical Center, Department of Emergency Medicine. We used the Professional Quality of Life Scale V survey instrument that evaluates provider burnout, secondary traumatic stress, and compassion satisfaction. Outcomes included burnout, secondary traumatic stress, and compassion satisfaction raw scores. Scores were compared between providers based on previous combat deployments using two-tailed independent sample t tests and multiple regression models. RESULTS: Surveys were completed by 105 respondents: 42 nurses (20 previously deployed), 30 technicians (11 previously deployed), and 33 physicians (16 previously deployed). No statistically significant differences in burnout, secondary traumatic stress, or compassion satisfaction scores were detected between previously deployed providers versus providers not previously deployed. DISCUSSION: There was no association between previous combat deployment and emergency department provider burnout, secondary traumatic stress, or compassion satisfaction scores. PMID- 27483507 TI - A Qualitative Study of Male Veterans' Violence Perpetration and Treatment Preferences. AB - Prevention and treatment of intimate partner violence (IPV) has increasingly focused on engaging men; however, very little work has examined how men manage the negative emotions associated with relationship conflict, as well as their preferences for and perceived barriers to treatment. Given the overrepresentation of IPV among men with post-traumatic stress disorder, the perspectives of male veterans with and without post-traumatic stress disorder are critical to informing IPV prevention and treatment within the Veterans Administration (VA) healthcare system. This qualitative study involved interviews with 25 male veterans who reported recent IPV perpetration. Interview themes included coping with emotions associated with violence and preferences and barriers to seeking treatment related to IPV. Results found the participants were interested in receiving IPV treatment at the Veterans Administration, and interviews offered several suggestions for developing or adapting prevention and treatment options for male veterans and their families to take into account violence in their relationships. PMID- 27483508 TI - Seeking Safety Pilot Outcome Study at Walter Reed National Military Medical Center. AB - Post-traumatic stress disorder (PTSD) and substance use disorder are two of the most prominent psychiatric disorders among military service members. Seeking Safety (SS) is an evidence-based behavioral therapy model for this comorbidity. This article reports results of a study of SS conducted in a military setting. Our pilot trial addressed outcomes, feasibility, and satisfaction. SS was conducted as is to evaluate its impact without adaptation for military culture. The sample was 24 outpatient service members (from the Army, Navy, Air Force, and Marines) with 33% minority representation. Inclusion criteria were current PTSD and/or SUD. Ten clinicians participated in this study after receiving SS training. Results showed significant improvements on most outcomes, including substance use on the Brief Addiction Monitor; PTSD symptoms on the PTSD Checklist Military Version (total and criterion D); and the Trauma Symptom Checklist-40 (sexual abuse trauma index and anxiety subscale); functioning on the Sheehan Disability Scale (total and family subscale); psychopathology on the Zung Depression Scale total; the Behavior and Symptom Identification Scale (BASIS)-24 (total and subscales depression functioning, emotional liability, and psychosis); and the Brief Symptom Inventory-18 (total and anxiety subscale); and coping on the Coping Self-Efficacy Scale (total). Satisfaction was strong. Discussion includes methodology limitations and next steps. PMID- 27483509 TI - Dialectical Behavior Therapy Training and Desired Resources for Implementation: Results From a National Program Evaluation in the Veterans Health Administration. AB - CONTEXT: Little is known about nonresearch training experiences of providers who implement evidence-based psychotherapies for suicidal behaviors among veterans. EVIDENCE ACQUISITION: This national program evaluation identified the history of training, training needs, and desired resources of clinicians who work with at risk veterans in a national health care system. This sequential mixed methods national program evaluation used a post-only survey design to obtain needs assessment data from clinical sites (N = 59) within Veterans Health Administration (VHA) facilities that implemented dialectical behavior therapy (DBT). Data were also collected on resources preferred to support ongoing use of DBT. RESULTS: While only 33% of clinical sites within VHA facilities reported that staff attended a formal DBT intensive training workshop, nearly 97% of participating sites reported having staff who completed self-study using DBT manuals. Mobile apps for therapists and clients and templates for documentation in the electronic health records to support measurement-based care were desired clinical resources. CONCLUSION: Results indicate that less-intensive training models can aid staff in implementing DBT in real-world health care settings. While more training is requested, a number of VHA facilities have successfully implemented DBT into the continuum of care for veterans at risk for suicide. PMID- 27483510 TI - Effect of Uniform Design on the Speed of Combat Tourniquet Application: A Simulation Study. AB - BACKGROUND: Tourniquets are issued to deployed members of both the United States (U.S. military and the Australian Defence Force (ADF). The ease of removing the tourniquet from the pocket of the combat uniform may influence its time to application. The ADF uniform uses buttons to secure the pocket, whereas the U.S. uniform uses a hook and loop fastener system. National differences in training may influence the time to and effectiveness of tourniquet application. OBJECTIVES: To compare the time taken to retrieve and apply a tourniquet from the pocket of the Australian and the U.S. combat uniform and compare the effectiveness of tourniquet application. METHODS: Twenty participants from both nations were randomly selected. Participants were timed on their ability to remove a tourniquet from their pockets and then apply it effectively. RESULTS: The U.S. personnel removed their tourniquets in shorter time (median 2.5 seconds) than Australians (median 5.72 seconds, p < 0.0001). ADF members (mean 41.36 seconds vs. 58.87 seconds, p < 0.037) applied the tourniquet more rapidly once removed from the pocket and trended to apply it more effectively (p = 0.1). CONCLUSIONS: The closure system of pockets on the combat uniform might influence the time taken to apply a tourniquet. Regular training might also reduce the time taken to apply a tourniquet effectively. PMID- 27483511 TI - Assessing the Dengue Diagnosis Capability Gap in the Military Health System. AB - Dengue, one of the most widespread infectious diseases, has affected U.S. military readiness throughout history. We explored the dengue diagnosis capability gap by circulating a questionnaire among military end users to determine in what capacity diagnostic test results are needed and how these results would be used at various roles of care in the Military Health System. Results were used to generate target product profiles for potential diagnostic tests. We determined that at far-forward locations, diagnostic tests need to be rugged and easy to use and are primarily needed to inform medical evacuation decisions. In mobile or fixed hospitals, diagnostics can be less portable but must be accurate enough to inform patient care decisions reliably. We then evaluated the suitability of using rapid diagnostic tests and enzyme-linked immunosorbent assays based on published performance characteristics, and we used a model to determine positive and negative predictive values in certain simulated deployments. In far-forward settings, a rapid diagnostic test comprising both antigen- and antibody-based detection can fulfill the capability gap with reasonable accuracy, whereas at higher roles of care immunoglobulin M-enzyme linked immunosorbent assay was determined to be the most suitable option. PMID- 27483512 TI - Supplemental Oxygen Requirements of Critically Injured Adults: An Observational Trial. AB - OBJECTIVES: The optimal amount of oxygen to deploy with pararescue personnel for combat casualty care is currently unknown. The purpose of this prospective observational trial was to determine the proportion of trauma patients requiring supplemental oxygen, whether high or low flow rates were needed, and to evaluate associations between injury characteristics and oxygen requirements. SUBJECTS AND METHODS: Over 6 months, dedicated study assistants observed oxygen requirements and delivery during the first 3 hours of emergency care for trauma patients meeting our institution's highest level trauma team activation criteria. RESULTS: The mean age of 204 enrolled subjects was 37 years, 79% were male, median injury severity score was 9 (interquartile range 1-21), 58% suffered penetrating injuries. Most (69%) were admitted; 17% went directly to the operating room, and 38% went directly to the intensive care unit from the emergency department. 136/160 nonintubated patients were managed with no or low-flow supplemental oxygen. Penetrating injuries were less likely to require supplemental oxygen (relative risk 0.65, 95% confidence interval 0.50-0.84). Subjects with Glasgow Coma Scale scores <15, abdominal or chest injury, or hypotension were more likely to require supplemental oxygen. CONCLUSION: There is significant opportunity to reduce the need for high-flow oxygen delivery to the battlespace. PMID- 27483513 TI - Elbow Arthrodesis as a Salvage Procedure for Combat-Related Upper Extremity Trauma. AB - INTRODUCTION: Upper extremity amputation is associated with significant disability. Elbow arthrodesis (EA) is a rarely indicated salvage procedure with a narrow set of indications. The purpose of this case series is to describe the clinical course of those patients undergoing an EA following severe combat related, upper extremity trauma. METHODS: 5 patients treated for combat-related upper extremity injuries treated with an EA between 2003 and 2012 were identified. Demographic information, injury characteristics, and treatment course were evaluated. RESULTS: 5 male patients with a mean age of 23.8 years were treated with an EA in relative extension following severe upper extremity trauma. 3 patients undergoing EA had concomitant bilateral above-knee amputations and 2 patients underwent fusion of their dominant arm. Successful arthrodesis was achieved in all patients. All patients reported good pain control without evidence of deep infection, the mean time from injury to arthrodesis was 305 days, and the mean time to arthrodesis was 714 days. The mean fusion angle among these patients was 138 degrees . CONCLUSION: EA following severe combat-related, upper extremity trauma is a viable treatment option. In the multiply injured patient, arthrodesis in a position of extension may be advantageous to accommodate transfers and mobility. PMID- 27483514 TI - An Analysis and Summary of the Recommendations Made by the U.S. DoD 2010-2014 Recovering Warrior Task Force. AB - In 2010, the U.S. Congress directed the Department of Defense to establish the Recovering Warrior Task Force (RWTF) to examine the effectiveness of, and recommend improvements to, military programs and policies for the care, management, and transition of wounded, ill, and injured personnel. To meet its comprehensive mandate, RWTF gathered extensive primary and secondary data that, in combination with RWTF members' relevant experience and expertise, informed and substantiated the recommendations that RWTF published each year. With the 2014 sunset of the Task Force, the authors, who provided research support to RWTF throughout its tenure, sought to systematically summarize RWTF's overall impressions regarding the shortfalls in the RW program and policy arena by analyzing the 87 recommendations that these shortfalls motivated. Our 3-part qualitative analysis included sorting by congressionally determined topics, thematic analysis, and examining topic/theme convergence. We use the results of these analyses as a framework for discussing program and policy areas that RWTF found most in need of attention over its 4 years of operation. Among these were continuing gaps in Department of Defense-wide policy governing the delivery of needed resources to RWs and family caregivers, which result in disparities across Services, Components, and locations. PMID- 27483515 TI - Pilot Study: The Role of Predeployment Ethics Training, Professional Ethics, and Religious Values on Naval Physicians' Ethical Decision Making. AB - Military physicians serving overseas in cross-cultural settings face the challenge of meeting patients' needs and adhering to their personal and professional ethics while abiding by military obligations and duties. Predeployment ethics training for Naval physicians continues to be received in many forms, if received at all, and has largely not addressed their specific roles as medical providers in the military. This study explores the perceived effectiveness of predeployment ethics training received by Naval physicians. Additionally, it considers the contribution of different types of ethics training, religious values, and the professional ethics on Naval physicians' perceived ability to effectively manage ethically challenging scenarios while on deployment. A total of 49 Naval physicians participated in an online survey. 16.3% reported not receiving any form of ethics training before deployment. Of those that reported receiving ethics training before deployment, 92.7% found the ethics training received was helpful in some way while on deployment. While a medical school course was most contributory overall to their ability to handle ethically difficult situations while on deployment (70.7%), what most Naval physicians felt would help them better handle these types of situations would be a mandatory military training/military course (63.2%) or personal mentorship (57.9%). PMID- 27483516 TI - Psychophysiological Investigation of Combat Veterans with Subthreshold Post traumatic Stress Disorder Symptoms. AB - OBJECTIVE: Military service members (SMs) with subthreshold combat-related post traumatic stress disorder (PTSD) symptoms often have clinically significant functional impairment, even though they do not meet full PTSD criteria. We therefore assessed the psychophysical responses of SMs, upon their return from Afghanistan or Iraq, to a fear conditioning paradigm to better understand the biological underpinnings of symptom severity. METHODS: Heart rate (HR), skin conductance, electromyography startle, and respiratory rate (RR) were monitored throughout three distinct phases of the paradigm-fear acquisition, fear inhibition, and fear extinction-while plasma catecholamines (epinephrine, norepinephrine, and dopamine) were measured at the end of fear inhibition. RESULTS: Those with higher PTSD symptom severity demonstrated elevations in HR and startle response to danger cues; elevated self-reported depression and anxiety; impaired functional status; poor skin conductance discrimination between danger and safety; and increases in HR and RR during fear extinction. Moreover, an inverse relationship was seen between plasma dopamine and HR during fear inhibition for those with high symptoms. CONCLUSION: Overall, the physiological responses we observed in our subthreshold PTSD population parallel what has been previously observed in full PTSD, making a case for addressing subthreshold PTSD symptoms in combat veterans. PMID- 27483517 TI - Poorer Physical Health is Associated With Greater Mental Health Service Utilization in a Sample of Depressed U.S. Army National Guard Soldiers. AB - OBJECTIVE: Operation Iraqi Freedom/Operation Enduring Freedom service members returning from deployment suffer from high rates of depression and report low levels of physical functioning compared to age-adjusted norms. Treatment for depression may be limited in this group and there are few data on whether Veterans receive medication treatment versus psychotherapy. We assessed rates of depression, physical functioning, and treatment with either medication or psychotherapy among recently returning service members. METHODS: Study participants were recruited from National Guard soldiers in a Midwestern state (n = 1,448). Logistic regression modeling was used to examine associations between physical health and odds of receiving different types of mental health treatment for depressed individuals (n = 299). RESULTS: 21% of soldiers reported significant depression and 44% of depressed service members reported poor physical health. Poorer physical health was associated with increased odds of any treatment (odds ratio: 1.27, confidence interval: 1.1-1.45) and medication treatment (odds ratio: 1.23, confidence interval: 1.08-1.40) but physical health was not associated with individual psychotherapy. CONCLUSIONS: Poor physical health is associated with increased likelihood of pharmacological but not individual psychotherapeutic treatment. Physical health problems may increase the need for depression care or increase contact with the medical system leading to higher levels of pharmacological treatment. Access to psychotherapy may need to be increased for Veterans with poor physical health. PMID- 27483518 TI - Alcohol Use and Reasons for Drinking as Risk Factors for Suicidal Behavior in the U.S. Army. AB - OBJECTIVE: High levels of alcohol use and alcohol-related problems are associated with suicidal behaviors (i.e., seriously considering and/or attempting suicide) in military and civilian populations. Examination of reasons for drinking alcohol may identify subgroups of soldiers who may either be at risk for suicidal behaviors or resilient to suicidality. METHOD: We examined the associations among reasons for drinking, level of alcohol use, and past year suicidality in 3,813 U.S. Army soldiers using the Department of Defense Survey of Health-Related Behaviors among Active Duty Military Personnel. RESULTS: Six percent of soldiers reported suicidal thoughts and behaviors within the past year. Those who reported the highest level of alcohol use were more likely to have seriously considered and/or attempted suicide. Drinking to avoid rejection/"fit in" was associated with suicidality, even after adjusting for level of alcohol consumption, post traumatic stress disorder, and depression. Although unadjusted analyses revealed a relation of pleasure-seeking drinking motives to suicidality, this association did not remain significant after controlling for covariates. CONCLUSIONS: Drinking to avoid rejection/"fit in" is associated with suicidality above overall alcohol consumption. Screening for this reason for drinking may be useful for suicide prediction and prevention. PMID- 27483519 TI - The Impact of Environment and Occupation on the Health and Safety of Active Duty Air Force Members: Database Development and De-Identification. AB - Preparing data for medical research can be challenging, detail oriented, and time consuming. Transcription errors, missing or nonsensical data, and records not applicable to the study population may hamper progress and, if unaddressed, can lead to erroneous conclusions. In addition, study data may be housed in multiple disparate databases and complex formats. Merging methods may be incomplete to obtain temporally synchronized data elements. We created a comprehensive database to explore the general hypothesis that environmental and occupational factors influence health outcomes and risk-taking behavior among active duty Air Force personnel. Several databases containing demographics, medical records, health survey responses, and safety incident reports were cleaned, validated, and linked to form a comprehensive, relational database. The final step involved removing and transforming personally identifiable information to form a Health Insurance Portability and Accountability Act compliant limited database. Initial data consisted of over 62.8 million records containing 221 variables. When completed, approximately 23.9 million clean and valid records with 214 variables remained. With a clean, robust database, future analysis aims to identify high-risk career fields for targeted interventions or uncover potential protective factors in low risk career fields. PMID- 27483520 TI - Evaluating the Impact of Hospital Efficiency on Wellness in the Military Health System. AB - Like all health care delivery systems, the U.S. Department of Defense Military Health System (MHS) strives to achieve top preventative care and population health outcomes for its members while operating at an efficient level and containing costs. The objective of this study is to understand the overall efficiency performance of military hospitals and investigate the relationship between efficiency and wellness. This study uses data envelopment analysis and stochastic frontier analysis to compare the efficiency of 128 military treatment facilities from the Army, Navy, and Air Force during the period of 2011 to 2013. Fixed effects panel regression is used to determine the association between the hospital efficiency and wellness scores. The results indicate that data envelopment analysis and stochastic frontier analysis efficiency scores are congruent in direction. Both results indicate that the majority of the MHS hospitals and clinics can potentially improve their productive efficiency by managing their input resources better. When comparing the performance of the three military branches of service, Army hospitals as a group outperformed their Navy and Air Force counterparts; thus, best practices from the Army should be shared across service components. The findings also suggest no statistically significant, positive association between efficiency and wellness over time in the MHS. PMID- 27483521 TI - Burnout in U.S. Military Orthopaedic Residents and Staff Physicians. AB - OBJECTIVE: The purpose of this study was to measure the prevalence of burnout among military orthopaedic residents and staff surgeons at the U.S. Army Medical Center. METHODS: 37 residents and 21 staff surgeons of a military orthopaedic residency program were asked to voluntarily complete an anonymous electronic survey. The survey consisted of two parts: first, a demographic section including questions about relationship status, work hours, deployment history, medical education debt, mentorship, and job satisfaction and second, the Maslach Burnout Inventory. RESULTS: 27 residents and 11 staff completed the survey for a 67% response rate. The rate of burnout among military orthopaedic surgeons in our study was 7.7% (3.7% of residents and 16.7% of staff surgeons). In addition, 25.6% of surgeons (33% of residents and 8.3% of staff) were found to be at risk of burnout. CONCLUSIONS: Future studies should focus on causal relationships among specific aspects of the work environment and possible preventive or protective measures. Expanding future studies to include multiple study sites would improve the quality and generalizability of the results. PMID- 27483522 TI - Reporting Military Sexual Trauma: A Mixed-Methods Study of Women Veterans' Experiences Who Served From World War II to the War in Afghanistan. AB - Since 2004, there has been increased effort to reduce military sexual trauma (MST) in the U.S. military. Although MST covers a range of inappropriate behaviors, the majority of research, treatment, and outreach are focused on sexual assault and the experiences of individuals serving in Afghanistan and Iraq. During a study on veterans' involvement in a national peace organization, participants were asked about their military experiences. Veterans served from World War II to current conflicts in Iraq and Afghanistan. Emerging out of the responses were descriptions of women's experiences with MST, barriers to reporting incidents of sexual misconduct and sexual assault, and the challenges they faced when seeking care. Data were gathered using anonymous questionnaires and semi-structured interviews. Out of 52 female veterans, the majority (90%) was subjected to at least one form of MST, and 15% (8) attempted to report the incident(s). Over half of the assailants were of a higher rank than the survivors. The majority of veterans remained silent due to lack of options to report, the status of perpetrators, and fear of retaliation. These data provide a glimpse into the challenges many women veterans faced when seeking assistance reporting incidents or obtaining health care for their MST. PMID- 27483523 TI - Role 1 Pediatric Trauma Care on the Israeli-Syrian Border-First Year of the Humanitarian Effort. AB - BACKGROUND: This article summarizes the experience with Role 1 care for 135 Syrian children who received medical care during the year 2013 as part of an ongoing humanitarian effort. METHODS: The database included demographic information, point-of-injury assessment and outcome, and was analyzed using SPSS. RESULTS: Trauma casualties were the majority of the group (84 cases), and mostly male. Almost one-third of casualties arrived more than 6 hours after injury, and time of injury was unknown in another third. The most common mechanism of injury was shrapnel (51.2%), followed by gunshot wounds (22.6%). Gunshot wound victims were significantly older than shrapnel and artillery victims (p < 0.01, < 0.05, respectively). Only 14 cases (14.28%) underwent previous interventions in Syria. Most of the casualties (44 cases, 52.4%) underwent at least one procedure during Role 1 treatment with a high overall success rate (93.18%) that was not correlated to Advanced Life Support provider type (physician [MD], emergency medical technician-paramedic, or both). Mortality was low (3 cases). CONCLUSION: The study cohort exhibits several unique features, including a delay in arrival to medical care, paucity of prior care and information, and the specific mechanisms of injury. Our study suggests that Advanced Life Support providers do not differ significantly in Role 1 treatment choices and procedure success. PMID- 27483524 TI - Parenting Stress After Deployment in Navy Active Duty Fathers. AB - Military fathers are being deployed, and leaving their families, for greater lengths of time and more frequently than ever before. The purpose of this study was to examine the impact of recent deployment on parenting stress in U.S. Navy fathers with young children. Of the 111 participants who completed the one-time study questionnaire at a large military outpatient clinic on the Eastern seaboard, 67.6% had returned from a ship-based deployment. Regression analyses were performed, using the Parenting Stress Index as the outcome variable, deployment elements (such as time away from home in the past 5 years) as predictors, and adjusting for other factors such as post-traumatic stress disorder (PTSD) and depression. Higher perceived threat and greater warfare exposure were both associated with increased parenting stress (p < 0.05) in the unadjusted model. These associations were greatly attenuated and no longer significant after adjustment for depression. In addition, rates of positive screens for PTSD and depression (17.1%) in this sample were higher than in other recent studies. In summary, these data indicate that various deployment factors are associated with increased parenting stress in Navy fathers back from deployment within the past year; these relationships are largely explained by depressive symptoms. Clinical implications are discussed. PMID- 27483525 TI - Evaluation of a Technology-Based Adaptive Learning and Prevention Program for Stress Response-A Randomized Controlled Trial. AB - To prevent deployment-related disorders, Chaos Driven Situations Management Retrieval System (CHARLY), a computer-aided training platform with a biofeedback interface has been developed. It simulates critical situations photorealistic for certain target and occupational groups. CHARLY was evaluated as a 1.5 days predeployment training method comparing it with the routine training. The evaluation was carried out for a matched random sample of N = 67 soldiers deployed in Afghanistan (International Security Assistance Force). Data collection took place before and after the prevention program and 4 to 6 weeks after deployment, which included mental state, post-traumatic stress disorder (PTSD) symptoms, knowledge of and attitude toward PTSD, and deployment-specific stressors. CHARLY has been significantly superior to the control group in terms of psychoeducation and attitude change. As to the mental state, both groups showed a significant increase in stress after deployment with significant lower increase in CHARLY. For PTSD-specific symptoms, CHARLY achieved a significant superiority. The fact that PTSD-specific scales showed significant differences at the end of deployment substantiates the validity of a specifically preventive effect of CHARLY. The study results tentatively indicate that highly standardized, computer-based primary prevention of mental disorders in soldiers on deployment might be superior to other more personal and less standardized forms of prevention. PMID- 27483526 TI - Staying Strong With Schools: A Civilian School-Based Intervention to Promote Resilience for Military-Connected Children. AB - Since September 11, 2001, over 2 million U.S. service members have been deployed to Iraq or Afghanistan, resulting in hundreds of thousands of military-connected children (MCC) having experienced a parental deployment. Although parental deployments have significantly burdened these children, few evidence-based interventions designed to support their resilience to these stressors are available. To address this gap, we developed a civilian school-based intervention to promote resilience in MCC living in the community. Our intervention, Staying Strong With Schools (SSWS), aims to deliver: a training to all school professionals early in the school year to educate them about challenges for children and families experiencing parental deployment and signs of deployment related distress; and a year-long training for the school guidance counselor who coordinates communication and provides psychosocial support to MCC within the school community. We piloted SSWS in two civilian elementary schools and found promising feasibility and acceptability. PMID- 27483527 TI - Variable Mortality From the 1918-1919 Influenza Pandemic During Military Training. AB - During the 1918-1919 pandemic, influenza mortality widely varied across populations and locations. Records of U.S. military members in mobilization camps (n = 40), military academies, and officer training schools were examined to document differences in influenza experiences during the fall 1918. During the fall-winter 1918-1919, mortality percentages were higher among soldiers in U.S. Army mobilization camps (0.34-4.3%) than among officer trainees (0-1.0%). Susceptibility to infection and clinical expressions of 1918 pandemic influenza varied largely based on host epidemiological characteristics rather than the inherent virulence of the virus. PMID- 27483528 TI - Feasibility and Patient Acceptance of Emergency Department-Based Influenza Vaccination in a Military Medical Center. AB - Influenza vaccination rates in the United States remain low. Many emergency department (ED) patients may not routinely seek care elsewhere. In a survey of ED visitors, 36.8% of unvaccinated respondents were willing to consider influenza vaccination during their visit. Participants at high risk for influenza complications were more likely to have been previously vaccinated, but unvaccinated participants at high risk were not significantly more likely to consider ED-based vaccination compared with other participants. ED-based influenza vaccination may be an effective method to expand vaccine coverage. PMID- 27483529 TI - Military Occupations Most Affected by Head/Sensory Injuries and the Potential Job Impact of Those Injuries. AB - OBJECTIVE: Identifying Department of Defense (DoD) occupations affected by injuries to the head and sensory systems. METHODS: We explored the Defense Medical Epidemiology Database to identify occupations with the highest incidence of injured personnel, then ranked how frequently they occurred in a top 10 list for each of four injury categories (head/brain, visual, auditory, vestibular) encompassing 25 injury codes. Across all four categories, the most affected occupations were identified, among which we chose three Army combat-related military occupational specialties (MOSs) for detailed study. We identified skills needed to perform these MOSs and explored whether MOS-critical deficits could be expected following the injuries. RESULTS: Some DoD occupations are more likely to suffer from these injuries, including Infantry, Combat Operations Control, Artillery/Gunnery, Motor Vehicle Operator, Combat Engineering, and Armor/Amphibious. Within these DoD occupations, we explored three Army combatant MOSs: Infantry (11B), Cavalry Scout (19D), and Artillery (13B), confirming that these jobs are likely to be disrupted by injuries within the four categories. CONCLUSIONS: Head and sensory injuries disproportionately affect certain military occupations. Relatively few injuries disrupt combat-related abilities that are job critical (e.g., firearms operation) and job specific (e.g., Artillery gunnery problems); these should be the focus of efforts to improve rehabilitation and RTD outcomes. PMID- 27483530 TI - Perceptions of ICU Diary Utility and Feasibility in a Combat ICU. AB - Severely injured patients have difficulty recalling their intensive care unit (ICU) experience which may contribute to emotional trauma. An ICU patient journal contains a short summary of key events during the ICU stay, and has been shown to improve emotional well-being. This project evaluated the feasibility and perceptions of ICU journals in a combat ICU. A one-page survey was distributed to ICU nursing staff at Craig Joint Theater Hospital before and after the use of ICU journals as a process improvement initiative. 16 preimplementation and 10 postimplementation surveys were collected to determine the perception of the utility and feasibility of ICU journals, as well as changes to nursing job satisfaction. Overall, nurses had positive perceptions of ICU journaling; after implementation they felt it could also benefit nurses (31% vs. 80%, p = 0.002). ICU nurses that used journals were also more likely to feel their work makes a difference (90%, p = 0.012) and they could connect with their patient on a personal level (50%, p = 0.037). Primary barriers were time to journal and legal concerns. This study demonstrates with the right guidance, ICU journals can be incorporated into an ICU in a deployed environment and nursing staff feel they benefit the patient, family, unit, and staff. PMID- 27483531 TI - Descriptive Epidemiology of Musculoskeletal Injuries in the Army 101st Airborne (Air Assault) Division. AB - The purpose of this study was to describe the epidemiology of musculoskeletal injuries among Soldiers of the 101st Airborne (Air Assault) Division. A total of 451 subjects (age: 27.6 +/- 6.2 years, gender: males 395/451 = 87.6%) volunteered. Musculoskeletal injury data were extracted from subjects' medical charts and injuries that occurred during 1 year were described. Injury frequency, injury anatomic location and sublocation, injury cause, activity when injury occurred, and injury type were described. Injury frequency was 29.5 injuries per 100 subjects per year. Most injures affected the lower extremity (60.2% of injuries) and common anatomic sublocations for injuries were the ankle (17.3%) and knee (15.0%). Frequent causes of injuries were running (13.5%) and direct trauma (9.0%). Physical training was associated with 29.3% of the injuries. A majority of injuries were classified as pain/spasm/ache (29.3%), without further elucidation of pathology. Other frequent injury types were sprain (21.8%) and strain (14.3%). The descriptive epidemiology of musculoskeletal injuries in this population underscores the need to explore the modifiable risk factors of potentially preventable lower extremity injuries associated with physical training and running. There is scope for the development of an optimized and targeted physical training program for injury prevention in this population. PMID- 27483532 TI - Efficacy of Hemostatic Agents in Humans With Rotational Thromboelastometry: An in vitro Study. AB - OBJECTIVES: Hemorrhage is the leading cause of preventable death in military conflicts. Different types of hemostatic dressings have been compared in animal studies for their ability to control bleeding. However, the effects of hemostatic agents in animals may be different from those in humans. The aim of this study was to assess the efficacy of hemostatic dressings in human blood. METHODS: Clotting time, clot formation time, alpha-angle, maximum clot firmness, and lysis index of human blood incubated with QuikClot Gauze, Celox Gauze, QuikClot ACS+, and standard gauze, were compared using rotational thromboelastometry (ROTEM). Nonactivated, intrinsically activated, extrinsically activated, and fibrin-based ROTEM were used to elucidate different mechanisms of action of those dressings. RESULTS: QuikClot Gauze was the most efficacious hemostatic dressing, followed by Celox Gauze and standard gauze. QuikClot ACS+ was clearly outperformed. CONCLUSIONS: Modern hemostatic dressings such as QuikClot Gauze and Celox Gauze should be preferred to previous generations of hemostatic dressings, such as QuikClot ACS+. In vitro studies like ROTEM can provide valuable information about the mechanisms of action of hemostatic dressings. A combination of different mechanisms of action may increase the efficacy of hemostatic dressings. PMID- 27483533 TI - The Relationship Between Enlistment Body Mass Index and the Development of Obstructive Sleep Apnea in the U.S. Military. AB - BACKGROUND: The incidence of obstructive sleep apnea (OSA) in the military has risen dramatically. OSA is considered "service connected" and compensable by the Veterans Administration. The association between body mass index (BMI) (kg/m(2)) measured at initial enlistment and development of OSA has yet to be assessed. METHODS: Data were obtained from the Defense Medical Surveillance System, the Armed Forces Health Surveillance Center, U.S. Department of Defense, Silver Spring, Maryland (inclusive dates:1993-2012; release date: December 2013). A study population of 550,000 randomly-selected active duty enlisted personnel was followed retrospectively from January 1, 2008, through December 31, 2012, or until diagnosis with OSA, separation from the military, or death occurred. The main exposure of interest was BMI recorded at time of enlistment. RESULTS: Adjusted hazard ratios for enlistment BMI were calculated using BMI of 23 to 23.9 as reference. Exponentially increasing risk for OSA was observed as BMI increased. The heaviest individuals (BMI > 35) were at the highest risk (hazard ratio: 3.93; 95% confidence interval [CI]: 3.35-4.62) for developing OSA. CONCLUSION: Enlistment BMI's role in developing OSA may be valuable in designing screening tools and preventive interventions in higher-risk groups, as well as prompt further consideration in the realm of military enlistment policy. PMID- 27483534 TI - Effect of a Polyp Tracking and Notification Program on Colon Adenoma Surveillance and Compliance to Guideline Recommendations. AB - BACKGROUND: Colorectal cancer is the third leading cause of cancer in the United States. Surveillance colonoscopy has been shown to reduce colorectal cancer risk. Medical institutions have implemented polyp tracking and notification programs (registries) to ensure adequate surveillance. AIM: To assess the effectiveness of a registry notification program initiated in January 2006 on the surveillance colonoscopy completion rate and adherence to surveillance guidelines. METHODS: Retrospective record review of beneficiaries with an adenomatous polyp between 2004 and 2007, with expected repeat surveillance colonoscopy between 2007 and 2012. Records were divided in 2 groups: Pre-Registry (4/04-12/05) and Registry (1/06-6/07). Successful surveillance was defined as beneficiaries who completed or were offered a colonoscopy within 12 months after the recommended interval. RESULTS: A total of 853 beneficiary records were reviewed, with 88 records excluded. Pre-Registry mean age was 60.1 years and %male gender was 63.5%, compared to Registry mean age of 60.9 years and %male gender of 58.4%. Significantly more beneficiaries completed or were offered colonoscopy surveillance in the Registry group, compared to the Pre-Registry group, (85.1% vs. 43.7%, p < 0.001). CONCLUSION: The use of a polyp tracking registry and notification program improves adherence to current polyp surveillance guidelines. PMID- 27483535 TI - Intimate Partner Maltreatment Recidivism in U.S. Air Force Families. AB - Research has demonstrated that perpetrator characteristics (gender, age, and military status) and incident characteristics (perpetrator substance use and initial incident severity) are associated with intimate partner maltreatment recidivism. This study assessed whether these variables were associated with intimate partner maltreatment recidivism in U.S. Air Force families during a 16 yr period (1997-2013). During the study period, 21% of the intimate partner maltreatment perpetrators in the U.S. Air Force committed more than one incident of maltreatment. In terms of perpetrator characteristics, male perpetrators reoffended more than female perpetrators, younger perpetrators reoffended more than older perpetrators, and active duty perpetrators reoffended more than civilians. Whether a perpetrator was enlisted or an officer was not associated with the likelihood of recidivism. In terms of incident characteristics, substance use (which was mainly alcohol use) during an initial maltreatment incident was associated with recidivism, but the severity of perpetrators' initial maltreatment incident was not. However, for perpetrators who reoffended, the severity of their initial incident was associated with the severity of subsequent incidents. On the basis of these findings, the need for targeted interventions to reduce intimate partner maltreatment recidivism is discussed. PMID- 27483536 TI - Characterization of Metacarpal Fractures in a Military Population. AB - The purpose of this study was to investigate the incidence and type of metacarpal (MC) fractures in a military population, and whether these fractures are related to age, military occupational specialty, aggression, or accidental injury. A retrospective record-based review was conducted at a single military center over a 5-year period. Service members with index finger through small finger MC fracture were identified. Data were collected utilizing Armed Forces Health Longitudinal Technology Application and electronic profile (e-profile) databases. Data collected included demographic information, mechanism of injury, nature of injury, total number of visits, and estimated time on physical restriction. 400 patients met inclusion criteria. Males accounted for 94% of the study population, 75% of fractures were of the small finger MC, 54% of patients were between 20 and 24 years, 90% were sustained by junior enlisted personnel, and most occurred by punching. Men aged <25 years were more likely to have intentional injuries. Total time on limited duty profile averaged 38 days and the average medically nondeployable profile was 26 days. MC fractures most commonly affect young, male, junior enlisted service members and are often self-inflicted. As a result, these injuries account for time lost at work, reduced job performance, and decreased medical readiness. PMID- 27483537 TI - Comparison of Penetrating Neck Injury Management in Combat Versus Civilian Trauma: A Review of 55 Cases. AB - The objective was to describe a case series of penetrating neck injuries (PNIs) and compare their management in combat versus civilian trauma. METHODS: From 2012 to 2014, all soldiers and civilians referred to Percy Military Training Hospital for PNI were analyzed. The mechanism of injury, type and site of the lesion, and initial emergency management were noted. RESULTS: Among the 55 patients, 26 were wounded in action, and 29 were civilians. PNIs were commonly stab wounds resulting from an assault. Anatomical zone II, as well as the central neck compartment, was the most affected area. The most affected organ was the larynx. 74% of patients underwent computed tomography angiography (CTA), surgical exploration was performed for 42% of patients, and 33% of patients required intensive care unit monitoring. The differences between the two groups in terms of management were not statistically significant. CONCLUSIONS: The current management is based on clinical examination and CTA and is similar between soldiers and civilians. Surgical exploration is less commonly used than CTA, which is a fast and accurate method to evaluate PNI for stable patients. The classification by compartment seems more relevant than the classification by anatomical zone, particularly in absence of medical imaging. PMID- 27483538 TI - Pandemic, 1918. PMID- 27483539 TI - Consider Autotransfusion in the Field. AB - Massive hemothorax is a life-threatening condition that can present as hemorrhagic shock, cardiogenic shock, or elements of both. It is described by the American College of Surgeons, in the 9th Edition of Advanced Trauma Life Support, as a rapid accumulation of more than 1,500 mL of blood or one-third or more of the patient's blood volume. The use of autotransfusion systems has been implemented for the treatment of hemothorax in hospital settings. The implementation of autotransfusion has been documented in situations where an extended period can elapse before definitive treatment can occur. This article is the first described case where an autotransfusion system has been implemented in a prehospital setting, at a Role 1 medical facility, for massive hemothorax in Afghanistan. PMID- 27483540 TI - A Patient-Controlled Analgesia Adaptor to Mitigate Postsurgical Pain for Combat Casualties With Multiple Limb Amputation: A Case Series. AB - The use of explosive armaments during Operation Iraqi Freedom, Operation Enduring Freedom, and Operation New Dawn has resulted in a significant number of injured U.S. service members. These weapons often generate substantial extremity trauma requiring multiple surgical procedures to preserve life, limb, and restore function. For those individuals who require multiple surgeries, the use of patient-controlled analgesia (PCA) devices can be an effective way to achieve adequate pain management and promote successful rehabilitation and recovery during inpatient treatment. A subpopulation of patients are unable to independently control a PCA device because of severe multiple limb dysfunction and/or loss. In response to the needs of these patients, our team designed and developed a custom adaptor to assist service members who would otherwise not be able to use a PCA. Patient feedback of the device indicated a positive response, improved independence, and overall satisfaction during inpatient hospitalization. PMID- 27483541 TI - Functional Improvement Following Diastasis Rectus Abdominus Repair in an Active Duty Navy Female. AB - Return to physical activity following childbirth can be a difficult process complicated by structural changes during pregnancy. A common problem is the development of a diastasis of the rectus abdominus (DRA), defined as a horizontal separation of the abdominus muscles at the linea alba. Recent data indicate that the greater the distance of separation of the muscle, the worse the functional ability. We describe a 24-year-old active duty U.S. Navy female G1P2 with a diagnosis of DRA. At 2 months postpartum, she was referred to physical therapy because of back pain and inability to meet baseline activities of daily living. After 4 months of physical therapy, she was unable to complete curl ups as required by U.S. Navy physical fitness standards. Abdominoplasty with imbrication of the abdominal wall diastasis was performed followed by additional physical therapy, after which she returned to baseline functioning. The restoration of functional ability postoperatively suggests there is a therapeutic indication for surgical correction of DRA. In high-functioning military patients with DRA who fail to return to baseline level of activity following a trial of physical therapy, surgical intervention should be considered to obtain the optimal functional ability. PMID- 27483542 TI - Chronic Left Lower Lobe Pulmonary Infiltrates During Military Deployment. AB - Deployment to Southwest Asia is associated with increased airborne hazards such as geologic dusts, burn pit smoke, vehicle exhaust, or air pollution. There are numerous ongoing studies to evaluate the potential effects of inhaled particulate matter on reported increases in acute and chronic respiratory symptoms. Providers need to be aware of potential causes of pulmonary disease such as acute eosinophilic pneumonia, asthma, and vocal cord dysfunction that have been associated with deployment. Other pulmonary disorders such as interstitial lung disease are infrequently reported. Not all deployment-related respiratory complaints may result from deployment airborne hazards and a broad differential should be considered. We present the case of a military member with a prolonged deployment found to have lobar infiltrates secondary to pulmonary vein stenosis from treatment for atrial fibrillation. PMID- 27483543 TI - Occult Pneumomediastinum in the Deployed Setting: Evaluation and Management. AB - Pneumomediastinum can occur after both blunt and penetrating trauma. The greatest concern involving this finding in a trauma patient is an aerodigestive tract injury. Prompt evaluation, identification, and management of these injuries are extremely important. This case describes a soldier who was involved in an improvised explosive device blast with no evidence of cavity penetration. During the routine evaluation of his head and neck an occult pneumomediastinum was identified. The patient was asymptomatic and was further evaluated with computed tomography because of the absence of endoscopy and bronchoscopy in theatre. The imaging showed no evidence of esophageal or tracheobronchial injury. The patient was observed and when noted to be stable was transferred to the local Role 3 hospital for management of his other injuries. PMID- 27483544 TI - Penetrating Orbital Injury From a Needlefish. AB - Orbital penetrating injuries are an unfortunately common occurrence; however, those from marine animals are rare. Injuries from marine animals can be quite profound and there are no known reports of complete visual recovery after an orbital penetrating injury. Complications range from secondary infection to a carotid-cavernous fistula, which can complicate the management of these patients. We report a case of penetrating orbital injury from a needlefish with complete return of visual function after surgical removal of foreign debris and an extended course of antibiotics. PMID- 27483545 TI - Cirrhosis in an Active Duty Soldier With Concomitant Isolated Polycystic Disease and H63D Homozygosity. AB - We report the case of a 45-year-old male soldier who was evaluated for a rapidly expanding hepatic mass following cholecystectomy and was eventually found to have isolated polycystic liver disease and express HFE H63D homozygosity. Both H63D homozygosity and isolated polycystic liver disease are only rarely associated with clinical cirrhosis. This is the first reported case of their concomitant presentation. PMID- 27483546 TI - Specialists seek to enhance trust in their credentials. PMID- 27483547 TI - Need, fairness debated in nonprofit roles. PMID- 27483548 TI - Technicians pushing for new name: veterinary nurse. PMID- 27483549 TI - Practicing caution with prescription of antimicrobials. PMID- 27483550 TI - The authors respond. PMID- 27483551 TI - Fond memories of veterinary mentors. PMID- 27483552 TI - Treatment of immune-mediated polyarthritis in dogs. PMID- 27483554 TI - Findings of Research Misconduct. PMID- 27483553 TI - [Forms of intra-erythrocytes asexual multiplication of P. falciparium. Production of monoclonal antibodies]. PMID- 27483555 TI - Women's Health Coverage Since the ACA: Improvements for Most, But Insurer Exclusions Put Many at Risk. AB - Issue: Since enactment of the Affordable Care Act (ACA), many more women have health insurance than before the law, in part because it prohibits insurer practices that discriminate against women. However, gaps in women's health coverage persist. Insurers often exclude health services that women are likely to need, leaving women vulnerable to higher costs and denied claims that threaten their economic security and physical health. Goal: To uncover the types and incidence of insurer exclusions that may disproportionately affect women's coverage. Method: The authors examined qualified health plans from 109 insurers across 16 states for 2014, 2015, or both years. Key findings and conclusions: Six types of services are frequently excluded from insurance coverage: treatment of conditions resulting from noncovered services, maintenance therapy, genetic testing, fetal reduction surgery, treatment of self-inflicted conditions, and preventive services not covered by law. Policy change recommendations include prohibiting variations within states' "essential health benefits" benchmark plans and requiring transparency and simplified language in plan documents. PMID- 27483556 TI - Rapid separation of the major phospholipid classes on a single aminopropyl cartridge. AB - A rapid method for the separation of the individual phospholipid classes phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI) by a single solid-phase extraction was developed. PC, PE, PS and PI were sequentially eluted from aminopropyl bonded silica with acetonitrile/n-propanol (2?1, vol/vol), methanol, isopropanol/methanolic HCl (4?1, vol/vol) and methanol/methanolic HCl (9?1, vol/vol). Standard recoveries were over 95% for PC and PE and over 85% for PS and PI with undistorted fatty acid composition. The separation of complex lipid mixtures on aminopropyl minicolumns can be refined to the level of individual phospholipid classes. PMID- 27483557 TI - General ward and pneumonia size as predictors of noninvasive ventilation failure. AB - INTRODUCTION: Shortage of intensive care beds has led to more frequent use of noninvasive ventilation (NIV) outside respiratory units, and data on NIV efficacy and safety on general wards is lacking. OBJECTIVE: The aim was to identify potential predictors for NIV failure. METHODS: This was a retrospective analysis of patients treated with NIV at the Institute for Pulmonary Diseases of Vojvodina from 2009 to 2013. Demographics, blood gases, chest radiographs, setting, and outcomes were analyzed to identify predictors of NIV failure. RESULTS: A total of 138 patients (65% men, mean age 66 +/- 11 years) were treated with NIV. Indications for NIV were acute exacerbation of chronic obstructive pulmonary disease (85%) and cardiogenic pulmonary edema (7%), as well as respiratory insufficiency related to obesity and central hypoventilation (5%) and neuromuscular disease (3%). Rate of NIV failure was 34.8%. In 86 patients NIV was applied in the High Dependency Unit (HDU), while 52 received NIV on the general ward. Baseline characteristics in terms of gender, arterial blood gases, and the extent of consolidation on chest radiographs were similar. Patients treated in HDU were younger (64.4 +/- 1.2 vs. 69.4 +/- 1.5 years, p < 0.001). NIV on the general ward compared to HDU had higher rates of NIV failure (28/52 vs. 20/86, p < 0.001). Presence of consolidation involving two or more quadrants on chest radiograph (55% vs. 29%, p < 0.001) was associated with NIV failure. When adjusted for age and the extent of consolidation on chest radiograph, NIV failure was still less likely in patients treated in HDU (OR 0.23, 95% Cl 0.10-0.50). CONCLUSION: Patients with consolidation on chest X-ray and patients treated with NIV outside of dedicated respiratory units are at a higher risk for NIV failure. PMID- 27483558 TI - Comparison of the efficiency of clomiphene citrate and letrozole in combination with metformin in moderately obese clomiphene citrate-resistant polycystic ovarian syndrome patients. AB - INTRODUCTION: Polycystic ovary syndrome is the most common endocrinopathy in women of reproductive-age. Therapy for those who want to get pregnant involves ovulation induction using clomiphene citrate, metformin, letrozole and gonadotropins. OBJECTIVE: The aim of the study was to compare the efficacy of combinations of clomiphene citrate-metformin and letrozole-metformin in obese patients who are resistant to clomiphene citrate alone. METHODS: The investigation was conducted as a retrospective study involving 60 moderately obese patients with polycystic ovary syndrome. Thirty-one of them received the clomiphene citrate-metformin, and 29 letrozole-metformin therapy. Stimulation was carried out for the procedures of intrauterine insemination (IUI). RESULTS: The age of patients, duration of infertility, and body mass index in both groups were similar. There was statistically significant difference in the thickness of the endometrium in favor of the group having the letrozole-metformin therapy (8.9 +/- 1.7 mm) compared with the group receiving the clomiphene citrate-metformin treatment (6.3 +/- 1.3 mm). The number of follicles was not statistically significantly different. Pregnancy rate in the first cycle of IUI in the clomiphene citrate group was 6.4%, and 17.2% in the letrozole group, which also was not statistically different. After the third IUI cycle, the pregnancy rate was significantly higher in the letrozole group (20.6%), while in the clomiphene citrate group it was (9.6%). CONCLUSION: This retrospective study demonstrated the advantages of the use of letrozole over clomiphene citrate in combination with metformin in moderately obese patients with polycystic ovary syndrome who are resistant to stimulation with clomiphene citrate alone. PMID- 27483559 TI - The effect of anterior cruciate ligament reconstruction on hamstring and quadriceps muscle function outcome ratios in male athletes. AB - INTRODUCTION: Maximal strength ratios such as the limb symmetry index (LSI) and hamstring-to-quadriceps ratio (HQ) may be considered the main outcome measures in the monitoring of recovery after anterior cruciate ligament (ACL) reconstruction. Although explosive strength is much more important than maximal strength, it is generally disregarded in the follow-up of muscle function recovery. OBJECTIVE: The purpose of this study was to compare ratios between maximal (Fmax) and explosive strength (rate of force development--RFD) in individuals with ACL reconstruction. METHODS: Fifteen male athletes were enrolled and had maximum voluntary isometric quadriceps and hamstring contractions tested (4.0 +/- 0.1 months post reconstruction). In addition to Fmax RFD was estimated (RFDmax, as well as RFD at 50, 100, and 200 ms from onset of contraction) and LSI and HQ ratios were calculated. RESULTS: The involved leg demonstrated significant hamstring and quadriceps deficits compared to uninvolved leg (p < 0.01). Deficits were particularly significant in the involved quadriceps, causing higher HQ ratios (average 0.63), compared to the uninvolved leg (0.44). LSI was significantly lower for RFD variables (average 55%) than for Fmax (66%). CONCLUSION: The assessment of RFD may be considered an objective recovery parameter for one's readiness to return to sports and should be an integral part of standard follow-up protocol for athletes after ACL reconstruction. Moreover, the combination of indices derived from maximal and explosive strength may provide better insight in muscle strength balance, as well as a clear picture of functional implications. PMID- 27483560 TI - Ability to solve riddles in patients with speech and language impairments after stroke. AB - INTRODUCTION: Successful riddle solving requires recognition of the meaning of words, attention, concentration, memory, connectivity and analysis of riddle content, and sufficiently developed associative thinking. OBJECTIVE: The aim of the study was to determine the ability to solve riddles in stroke patients who do or do not have speech and language disorders (SLDs), to determine the presence of SLDs in relation to the lesion localization, as well as to define the relationship between riddle-solving and functional impairment of a body side. METHODS: The sample consisted of 88 patients. The data used included age, sex, educational level, time of stroke onset, presence of an SLD, lesion localization, and functional damage of the body side. The patients were presented with a task of solving 10 riddles. RESULTS: A significant SLD was present in 38.60% of the patients. Brain lesions were found distributed at 46 different brain sites. Patients with different lesion localization had different success in solving riddles. Patients with perisylvian cortex brain lesions, or patients with Wernicke and global aphasia, had the poorest results. The group with SLDs had an average success of solved riddles of 26.76% (p = 0.000). The group with right sided functional impairments had average success of 37.14%, and the group with functional impairments of the left side of the body 56.88% (p = 0.002). CONCLUSION: Most patients with SLDs had a low ability of solving riddles. Most of the patients with left brain lesions and perisylvian cortex damage demonstrated lower ability in solving riddles in relation to patients with right hemisphere lesions. PMID- 27483561 TI - Determinants of job satisfaction of healthcare professionals in public hospitals in Belgrade, Serbia--Cross-sectional analysis. AB - INTRODUCTION: The quality of health care significantly depends on the satisfaction of the employees. OBJECTIVE: The objective of this study was to establish the level of professional satisfaction of healthcare professionals in state hospitals in Belgrade, Serbia, and to determine and to rank the factors which impact on their satisfaction or dissatisfaction. METHOD: Professional satisfaction survey was designed and conducted as a cross-sectional study in 2008. Completed questionnaires were returned by 6,595 healthcare professionals from Belgrade's hospitals. Statistical analysis was performed using the Student's t-test, chi2 test and ANOVA. Factor analysis was applied in order to define determinants of professional satisfaction, i.e. dissatisfaction. RESULTS: This study showed that the degree of professional satisfaction of Serbian healthcare professionals was low. The main causes of professionals'dissatisfaction were wages, equipment, the possibility of continuous medical education/training and the opportunities for professional development. Healthcare professionals with university education were more satisfied with all the individual aspects of job satisfaction than those with secondary school and college education. CONCLUSION: There were significantly more healthcare professionals satisfied with their job among males, older than 60 years, in the age group 50-59 years, with managerial function, and with 30 or more years of service. Development strategy of human resources in the Serbian health care system would significantly improve the professional satisfaction and quality of the provided health care. PMID- 27483562 TI - Outcome of orthograde endodontic retreatment--A two-year follow-up. AB - INTRODUCTION: Endodontic retreatment is a complex intervention that requires detailed analysis of possible reasons for failure, and flawless practical execution of the procedure. OBJECTIVE: The aim of the study was to assess the outcome of endodontic retreatment based on clinical and radiographic criteria after a two-year observation period. METHODS: Clinical study included 49 teeth indicated for endodontic retreatment based on periapical index (PAI). All teeth were divided into two groups. Group I comprised teeth without any periapical lesion (PAI score of 1 and 2) while Group II consisted of teeth with visible periapical radiolucency (PAI score of 3, 4, and 5). Endodontic retreatment was completed in two visits with inter-appointment medication of 2% chlorhexidine and calcium hydroxide for two weeks. Outcome of endodontic retreatment was evaluated 12-24 months after final obturation. RESULTS: Endodontic retreatment was successful in 93.3% in Group I after 24 months. In Group II, successful treatment and complete healing was found in 52.9% of teeth, whereas 14.7% of teeth showed only partial healing. However, clinical symptomatology was not present in any of the cases. Considering the absence of clinical signs and subjective symptoms, retreatment was successful in 67.6% of cases where chronic periapical inflammation was present. CONCLUSION: Endodontic retreatment was successful in high percentage in teeth with and without periapical lesions. PMID- 27483563 TI - Posture in dentists: Sitting vs. standing positions during dentistry work--An EMG study. AB - INTRODUCTION: Adequate working posture is important for overall health. Inappropriate posture may increase fatigue, decrease efficiency, and eventually lead to injuries. OBJECTIVE: The purpose was to examine posture positions used during dentistry work. METHODS: In order to quantify different posture positions, we recorded muscle activity and positions of body segments. The position (inclination) data of the back was used to assess two postures: sitting and standing during standard dental interventions. RESULTS: During standard interventions, whether sitting or standing, a tilt of less than 20 degrees was most prevalent in the forward and lateral flexion directions. Amplitude of electromyography signals corresponding to the level of muscle activity were higher in sitting compared with the electromyography in standing position for all muscle groups on the left and right side of the body. Significant difference between muscle activity in two working postures was evident in splenius capitis muscle on the left (p = 0.032), on the right side of the body (p = 0.049) and in muscle activity of mastoid muscle on the left side (p = 0.029). CONCLUSION: These findings show that risk for increased fatigue and possible injures can be reduced by combining the sitting and standing occupational postures. PMID- 27483564 TI - Analysis of load distribution in tooth-implant supported fixed partial dentures by the use of resilient abutment. AB - INTRODUCTION: Differences between the tooth and implant response to load can lead to many biological and technical implications in the conditions of occlusal forces. OBJECTIVE: The objective of this study was to analyze load distribution in tooth/implant-supported fixed partial dentures with the use of resilient TSA (Titan Shock Absorber, BoneCare GmbH, Augsburg, Germany) abutment and conventional non-resilient abutment using finite element method. METHODS: This study presents two basic 3D models. For one model a standard non-resilient abutment is used, and on the implant of the second model a resilient TSA abutment is applied. The virtual model contains drawn contours of tooth, mucous membranes, implant, cortical bones and spongiosa, abutment and suprastructure. The experiment used 500 N of vertical force, applied in three different cases of axial load. Calculations of von Mises equivalent stresses of the tooth root and periodontium, implants and peri-implant tissue were made. RESULTS: For the model to which a non-resilient abutment is applied, maximum stress values in all three cases are observed in the cortical part of the bone (maximum stress value of 49.7 MPa). Measurements of stress and deformation in the bone tissue in the model with application of the resilientTSA abutment demonstrated similar distribution; however, these values are many times lower than in the model with non-resilient TSA abutment (maximum stress value of 28.9 MPa). CONCLUSION: Application of the resilient TSA abutment results in more equal distribution of stress and deformations in the bone tissue under vertical forces. These values are many times lower than in the model with the non-resilient abutment. PMID- 27483565 TI - Surgical treatment of intramural hematoma of the ascending aorta. AB - INTRODUCTION: Intramural hematoma of the aorta presents potentially fatal condition developing as a result of a vasa vasorum rupture. It is a major risk factor for developing a frank aortic dissection. CASE OUTLINE: A 65-year-old woman was admitted to our clinic for the second time, after her symptoms of chest pain and vertigo (with no electrocardiographic signs of myocardial infarction) hadn't disappeared after several months of medicament treatment (indicated in the first hospitalization). Computed tomography arteriography of the aorta showed no sign of acute aortic dissection, but revealed a contrast depo in the aortic wall of 8 x 14 mm dimensions, with no extravasation of contrast. Also, massive pericardial effusion was observed (10-30 mm in thickness). Transesophageal echocardiography confirmed these findings completely. The patient underwent surgery, in which plaque exulceration was detected on the convex side of the ascending aorta, 3 cm above the aortic valve, 1 cm in diameter, with no signs of intimal tear. A resection of the ascending aorta was performed, and the aorta was reconstructed with a 30 mm Dacron tube graft. The patient was discharged on the 14th postoperative day with satisfactory results. CONCLUSION: Intramural hematoma is not a common event, but it is potentially a fatal one. Open surgery in patients with an intramural hematoma is an effective treatment strategy, although percutaneous endovascular treatment options are being described. PMID- 27483566 TI - Challenges in interpretation of thyroid hormone test results. AB - INTRODUCTION: In interpreting thyroid hormones results it is preferable to think of interference and changes in concentration of their carrier proteins. OUTLINE OF CASES: We present two patients with discrepancy between the results of thyroid function tests and clinical status. The first case presents a 62-year-old patient with a nodular goiter and Hashimoto thyroiditis. Thyroid function test showed low thyroid-stimulating hormone (TSH) and normal to low fT4. By determining thyroid status (TSH, T4, fT4,T3, fT3) in two laboratories, basal and after dilution, as well as thyroxine-binding globulin (TBG), it was concluded that the thyroid hormone levels were normal. The results were influenced by heterophile antibodies leading to a false lower TSH level and suspected secondary hypothyroidism.The second case, a 40-year-old patient, was examined and followed because of the variable size thyroid nodule and initially borderline elevated TSH, after which thyroid status showed low level of total thyroid hormones and normal TSH. Based on additional analysis it was concluded that low T4 and T3 were a result of low TBG. It is a hereditary genetic disorder with no clinical significance. CONCLUSION: Erroneous diagnosis of thyroid disorders and potentially harmful treatment could be avoided by proving the interference or TBG deficiency whenever there is a discrepancy between the thyroid function results and the clinical picture. PMID- 27483567 TI - Severe neonatal subgaleal hemorrhage as the first presentation of hemophilia A. AB - INTRODUCTION: Subgaleal hemorrhage is a rare but potentially fatal birth trauma. It is caused by rupture of the emissary veins (connections between the dural sinuses and scalp veins), followed by the accumulation of blood between the epicranial aponeurosis and the periosteum. Usually, it is associated with instrumental delivery (vacuum extraction, forceps delivery), but it may also occur spontaneously, suggesting the possibility of congenital bleeding disorder. CASE OUTLINE: A full term male neonate was born at 40 weeks gestation by spontaneous vaginal delivery, with birth weight of 3,700 g. The Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. At the age of 23 hours, the baby became pale and lethargic. Large fluctuant swelling on his head was noted. He developed severe anemia and hypovolemia as a result of massive subgaleal hemorrhage. After successful treatment, the baby fully recovered. Follow-up and further evaluation revealed hemophilia A as a result of a de novo mutation. CONCLUSION: This case illustrates that subgaleal hemorrhage may be the first presentation of hemophilia A. Infants without obvious risk factors for developing subgaleal hemorrhage should be evaluated for congenital bleeding disorder. Successful outcome in affected infants requires early diagnosis, careful monitoring and prompt treatment. PMID- 27483568 TI - Hypercalcemia with multiple osteolytic lesions and increased circulating tumor necrosis factor in an adult patient with B-cell acute lymphoblastic leukemia. AB - INTRODUCTION: Acute lymphoblastic leukemia (ALL) is very rarely presented with diffuse osteolytic lesions and hypercalcemia. CASE OUTLINE: We report a 28-year old male with the B-cell ALL who presented with extensive osteolytic lesions, bone pain, hepatosplenomegaly, and pancytopenia without circulating blasts in peripheral blood. An increased serum level of tumor necrosis factor (TNF-alpha) was registered while the levels of IL-1alpha and IL-1beta were normal. The patient failed to achieve remission on two induction regimens but achieved one after the successful allogeneic stem cell transplantation, which lasted for six months, after which he developed a relapse and died. CONCLUSION: The presented case may serve as a clinical demonstration of possible involvement of TNF-alpha as a pathogenic factor in the evolution of osteolytic lesions that are occasionally observed in patients with ALL. This might have relevance in the management of such patients as chemotherapy alone may not represent the beneficial option in this clinical context. PMID- 27483569 TI - Laparoscopic gastric wedge resection as the method of choice in the treatment of gastrointestinal stromal tumors--A case report. AB - INTRODUCTION: The gastrointestinal stromal tumors (GIST) are the most frequent mesenchymal tumors of the gastrointestinal tract. The surgery of resectable gastric GIST is the primary therapy for these tumors, but the decision regarding the surgical radicality of the procedures is still a point of discussion among surgeons and oncologists. CASE OUTLINE: A 74-year-old patient was admitted to hospital with signs of bleeding from the upper parts of the gastrointestinal tract. Urgent gastroscopy was performed and a subepithelial gastric lesion with bleeding ulceration was noted in the region of the fornix. A computed tomography scan of the abdomen showed a tumor in the fornix region with the dimensions of 48 x 32 mm, which was growing mostly intraluminally. After an adequate preoperative preparation the patient underwent a laparoscopic wedge resection of gastric fornix with intramural tumor lesion. The histopathological analysis of the specimen showed a well differentiated GIST (histological grade Gi), of the spindle cell type. Based on the immunohistochemical analysis of thespecimen it was concluded that the patient was in the IA stage of the disease with a low risk of malignant progression. In the population of patients with GIST, this is the most common group (43%), with low malignant potential, and relapses present in only 3.6% of cases.The patient started with oral food intake on the first postoperative day, the first bowel movement occurred 36 hours after surgery, and the patient was released from hospital on the fourth postoperative day. CONCLUSION: Based on the aforementioned, we consider that the laparoscopic gastric wedge resection is a safe and efficient surgical procedure. This is primary therapy for most common group of patients with resectable gastric GIST. PMID- 27483570 TI - Granulomatous interstitial nephritis associated with influenza A: H1N1 infection- A case report. AB - INTRODUCTION: The causes of acute tubulointerstitial nephritis can be grouped into four broad categories: medications, infections, immunologic diseases, or idiopathic processes. Here we report a 17-year-old female who developed acute kidney injury (AKI) due to granulomatous interstitial nephritis (GIN) associated with influenza A: H1N1 infection. CASE OUTLINE: The illness presented after two weeks of respiratory tract infection, skin rash and hypermenorrhea. On admission the patient was febrile, with bilateral pedal edema, macular skin rash, and auscultatory finding that suggested pneumonia. Laboratory investigations showed normocytic anemia, azotemia, hematuria and proteinuria. Renal ultrasound was normal. Antinuclear antibodies, antineutrophil cytoplasmic antibodies, lupus anticoagulant, antiphospholipid antibodies were negative with normal complement. Urine cultures including analysis for Mycobacterium tuberculosis were negative. The diagnosis of influenza A: H1N1 infection was made by positive serology. A kidney biopsy showed interstitial nephritis with peritubular granulomas. Glomeruli were normal. Staining for immunoglobulins A, M, G, and F was negative. The girl was treated with oseltamivir phosphate (Tamiflu; Genentech, Inc., South San Francisco, CA, USA) for five days, as well as with tapered prednisone after a starting dose of 2 mg/kg. The treatment resulted in a complete remission during two years of follow-up. CONCLUSION: We present a severe but reversible case of GIN and AKI associated with influenza A: H1N1 infection. Although a causal effect cannot be confirmed, this case suggests that influenza A: H1N1 should be considered in the differential diagnosis of GIN manifested with AKI in children. PMID- 27483571 TI - A massive bleeding from a gastrointestinal stromal tumor of a Meckel's diverticulum. AB - INTRODUCTION: Meckel's diverticulum is the most common congenital anomaly of the gastro intestinal tract, present in about 2% of population. CASE OUTLINE: The article presents the case of a 44-year-old otherwise healthy man with anemia, who was diagnosed lower gastrointestinal bleeding. An abdominal CT scan revealed a clearly demarcated solid tumor in hypogastric region, measuring 65 x 45 mm. A laparotomy through lower midline incision was performed. A surgical resection of a lesion of a Meckel's diverticulum was carried out and a final diagnosis of gastrointestinal stromal tumor was made.The patient made an uneventful recovery. CONCLUSION: The preoperative diagnosis of a complicated Meckel's diverticulum may be challenging. CT is usually an adequate method to diagnose tumors arising from Meckel's diverticulum. PMID- 27483572 TI - Carbon nanomaterials: Biologically active fullerene derivatives. AB - Since their discovery, fullerenes, carbon nanotubes, and graphene attract significant attention of researches in various scientific fields including biomedicine. Nano-scale size and a possibility for diverse surface modifications allow carbon nanoallotropes to become an indispensable nanostructured material in nanotechnologies, including nanomedicine. Manipulation of surface chemistry has created diverse populations of water-soluble derivatives of fullerenes, which exhibit different behaviors. Both non-derivatized and derivatized fullerenes show various biological activities. Cellular processes that underline their toxicity are oxidative, genotoxic, and cytotoxic responses.The antioxidant/cytoprotective properties of fullerenes and derivatives have been considered in the prevention of organ oxidative damage and treatment. The same unique physiochemical properties of nanomaterials may also be associated with potential health hazards. Non-biodegradability and toxicity of carbon nanoparticles still remain a great concern in the area of biomedical application. In this review, we report on basic physical and chemical properties of carbon nano-clusters--fullerenes, nanotubes, and grapheme--their specificities, activities, and potential application in biological systems. Special emphasis is given to our most important results obtained in vitro and in vivo using polyhydroxylated fullerene derivative C60(OH)24. PMID- 27483573 TI - [Acute renal failure in patients with tumour lysis sindrome]. AB - 'Hematologic malignancies (leukemia, lymphoma, multiple myeloma, et al.), as well as solid tumours (renal, liver, lung, ovarian, etc.), can lead to acute or chronic renal failure.The most common clinical manifestation is acute renal failure within the tumour lysis syndrome (TLS). It is characterized by specific laboratory and clinical criteria in order to prove that kidney disorders result from cytolysis of tumour cells after chemotherapy regimen given, although on significantly fewer occasions it is likely to occur spontaneously or after radiotherapy. Essentially, failure is the disorder of functionally conserved kidney or of kidney with varying degrees of renal insufficiency, which render the kidney impaired and unable to effectively eliminate the end products of massive cytolysis and to correct the resulting disorders: hyperuricemia, hyperkalemia, hypocalcaemia, hyperphosphatemia, and others. The risk of TLS depends on tumour size, proliferative potential of malignant cells, renal function and the presence of accompanying diseases and disorders. Hydration providing adequate diuresis and administration of urinary suppressants (allopurinol, febuxostat) significantly reduce the risk of developing TLS. If prevention of renal impairment isn't possible, the treatment should be supplemented with hemodynamic monitoring and pharmacological support, with the possible application of recombinant urate oxidase enzyme (rasburicase). Depending on the severity of azotemia and hydroelectrolytic disorders, application of some of the methods of renal replacement therapy may be considered. PMID- 27483575 TI - Editorial. PMID- 27483574 TI - [Treatment by bloodletting in the past and present]. AB - INTRODUCTION: Therapeutic bloodletting has been practiced at least 3000 years as one of the most frequent methods of treatment in general, whose value was not questioned until the 19th century, when it was gradually abandoned in Western medicine, while it is still practiced in Arabic and traditional Chinese medicine. CONTENT: In modern medicine bloodletting is practiced for very few indications. Its concept was modeled on the process of menstrual bleeding, for which it was believed to"purge women of bad humours. "Thus, bloodletting was based more on the belief that it helps in the reestablishment of proper balance of body "humours" than on the opinion that it serves to remove excessive amount of blood as well as to remove toxic "pneumas" that accumulate in human body. It was indicated for almost all known diseases, even in the presence of severe anemia. Bloodletting was carried out by scarification with cupping, by phlebotomies (venesections), rarely by arteriotomies, using specific instruments called lancets, as well as leeches. In different periods of history bloodletting was practiced by priests, doctors, barbers, and even by amateurs. In most cases, between one half of liter and two liters of blood used to be removed. Bloodletting was harmful to vast majority of patients and in some of them it is believed that it was either fatal or that it strongly contributed to such outcome. In the 20th century in the "Western"medicine bloodletting was still practiced in the treatment of hypertension and in severe cardiac insufficiency and pulmonary edema, but these indications were later abandoned. CONCLUSION: Bloodletting is still indicated for a few indications such as polycythemia, haemochromatosis, and porphyria cutanea tarda, while leeches are still used in plastic surgery, replantation and other reconstructive surgery, and very rarely for other specific indications. PMID- 27483576 TI - [Today's importance of ultrasound in ENT]. AB - Since ultrasound has been established for diagnosis in ENT several new techniques have been introduced. But also ultrasonography has technically developed and thus has earned even more importance and indications. This was to be shown by this paper as well as the advantages and pitfalls. Ultrasound is quite useful in inflammatory, infectious and tumor pathology in order to make a better diagnosis or staging and to help the surgeon for punture or incision of a pathologic lesion (cytology, bacteriology, drainage). Especially in ENT oncology and post-treatment follow up ultrasound is a very precious technique. Ultrasound can be realized by the ENT specialist himself anywhere and at any time. It is a non aggressive, non invasive technique and its cost is relatively low. Unfortunately by itself it is not very performant to distinguish benign and malignant lesions. But its specificity can be considerably enhanced by combinating it with cytology (UGFNAB, ultrasound guided fine needle aspiration biopsy). Another important field of ultrasound is the examination of salivary glands. PMID- 27483577 TI - Value of the preservation of an osseous mandibular rim with a fibula free flap reconstruction. AB - BACKGROUND: Reconstruction of the mandible with microvascularized fibula transplants is actually a well-established procedure, yet the major component is the limited diameter of the diaphysis that can induce oral rehabilitation's failure, especially in dentate patients. In this paper, we report our surgical procedure allowing preservation of the mandibular height. The primary objective was to assess aesthetic and functional improvements of preservation of an osseous mandibular rim with a fibula free flap reconstruction. PATIENTS AND METHODS: Five patients (all males, mean age of 60 years) were treated with this method. Aetiologies were tumour in 3 cases, and osteoradionecrosis in the two others cases. We described all step of our surgical procedure and the functional, aesthetic and carcinologic results were evaluated. The follow up varies from 6 to 30 months. RESULTS: One patient died at 12 days from unrelated affection. For the other patients, both the aesthetics and functional outcomes were better than in case of mandibular interruption surgery. In fact, the mandibular contour of the mandibule was preserved and the height of mandible was restored. One patient is in progress of dental rehabilitation with osseous implants. Carcinologically, no local recurrence was observed. CONCLUSION: This technique is reliable and enables to optimize oral rehabilitation with endosteal implants. Nevertheless, we consider that the 3D scanner is essential before the intervention to evaluate the osseous reach. Moreover, if necessarily the procedure can be modified intraoperatively. PMID- 27483578 TI - Cholesteatoma presenting as a late complication of cochlear implant surgery: Case report and literature review. AB - A male patient with post lingual hearing loss was implanted at 16 years of age with a Nucleus cochlear implant (Cochlear) in his left ear. Twenty two years later, he developed a cholesteatoma in relation to the mastoid portion of the facial nerve and in contact with the electrodes array. The cholesteatoma was removed and the ear canal reconstructed. There was no post-operative facial palsy and the cochlear implant was preserved. Although cholesteatoma is a rare complication of the cochlear implant surgery, it still can occur and can be a source of potential damage to the implant. The origin of this late-presenting complication could be excessive bone drilling associated with the pressure caused by the loop of the electrodes array on the posterior canal wall. Implanted patients must have a close and particular long-term follow-up, especially when a surgical breach of the canal wall or a tear of the tympanic membrane have occurred during surgery, as well as in those patients in whom excessive thinning out of the posterior meatal wall was done. PMID- 27483579 TI - [Sarcoidosis of the thyroid: A case report]. AB - OBJECTIVE: To present a case of thyroid sarcoidosis revealed by a multinodular goiter and cervical and mediastinal adenopathies. METHODS: We summarize the clinical presentation of a thyroid sarcoidosis. A review of literature regarding this topic is also presented. RESULTS: A 48-year-old woman presented dysphagia without dyspnea. Clinical and radiological explorations find a multinodular goiter with cervical and mediastinal adenopathies. The symptomatic side of the goiter and the association with adenopathies justify the surgery. Total thyroidectomy and mediastinal lymphadenectomy are processed. Histopathological examination of the thyroid reveal a goiter without malignity, a vesicular nodule, and non necrotizing granulomas consistent with sarcoidosis, as in the adenopathy. CONCLUSION: The interest here, is the difficulty to make the diagnostic without histopathology, between a thyroid cancer with lymphadenopathies and extrapulmonary sarcoidosis (involving thyroid and adenopathies). PMID- 27483580 TI - Chondrosarcoma of the hyoid bone: Case report and review of the literature. AB - INTRODUCTION: Chondrosarcomas are cartilaginous tumors that range from low-grade tumors with low metastatic potential to high-grade aggressive tumors with premature and high metastatic rate. Low-grade types have few karyotype abnormalities and are near-diploid, while high-grade chondrosarcomas originate from complex karyotypes and are aneuploid. The most common karyotype aberrations found include 12q13-15 and 9p21 rearrangements. Here, it is presented a case of chondrosarcoma of the hyoid bone with its image, surgical procedure and pathological correlation as well as a review of the literature. CASE PRESENTATION: A sixty-three year old man presented with a large cervical mass located at submental level. The CT scan revealed a voluminous and well-limited mass of 5 x 4 x 3 cm located in the suprahyoid region. The operative finding revealed a grade 2 chondrosarcoma originating from the hyoid bone. DISCUSSION: Chondrosarcoma of the. hyoid bone is a rare pathology, thus making it difficult to diagnose. Fine needle biopsies have high diagnostic accuracy, although correct grading is only obtained 46% of the time. CT scan is the golden standard to characterize tumor extension and origin. Surgical excision is the treatment of choice for chondrosarcoma. PMID- 27483581 TI - Epitympanic osteoma of the middle ear: A case report and literature review. AB - INTRODUCTION: Contrary to osteomas and exostosis of the external ear canal, middle ear osteomas are rare benign tumors that are usually revealed by progressive hearing loss. CASE REPORT: We here report the case of 56-year-old woman who had a left ear conductive hearing loss. A CT-scan showed a bone-density tumor in the left posterior epitympanum, hanging up to the tegmen tympani. A surgical middle ear exploration showed an epitympanic osteoma, confirmed by a histological exploration. The tumor was left in place and an ossicular prosthesis was inserted, which permitted a significant gain in the audiogram air-bone gap. DISCUSSION: Middle ear osteomas are rare benign tumors (31 cases described from 1964), with male preponderance (sex ratio: 1.75). They always present with a hearing loss, and the diagnosis is made by CT-scan. The treatment is surgical in cases of significant discomfort and generally produces a good improvement in symptoms. PMID- 27483582 TI - [A post-styloid mass revealing a parapharyngeal schwannoma]. AB - INTRODUCTION: The schwannoma of the glossopharyngeal nerve is a rare etiology among the tumor masses developed in the parapharyngeal space. CASE REPORT: We report the case of a 33 years old woman in whom a large schwannoma of the left glossopharyngeal nerve was discovered incidentally on a brain MRI. Respiratory evolutionary prognosis imposed trans-oral surgical treatment. DISCUSSION: We discuss the diagnostic and therapeutic strategy for the benign tumors of the parapharyngeal space. CONCLUSION: The schwannoma of the glossopharyngeal nerve is a benign rare lesion. The difficulty lies on the surgical strategy and the choice of the approach. The functional suites are marked by difficulty swallowing and require intensive speech therapy. PMID- 27483583 TI - What's the matter with Florida? Healthcare fraud flourishes despite enforcement efforts. PMID- 27483584 TI - Providers invest in the next frontier by delving into patients' genetic data. PMID- 27483585 TI - Big surpluses, big debate: Not-for-profits dominate top 10 list of most profitable hospitals. PMID- 27483586 TI - Commercial insurance margins offset rising Medicare losses. PMID- 27483587 TI - Logistics: The next target in the war on device costs. PMID- 27483588 TI - Breast cancer screening guidelines spark a racial divide. PMID- 27483589 TI - The great cost shift. PMID- 27483590 TI - Guidance on 340B drug program delivers mismatch of policy and priorities from HHS. PMID- 27483591 TI - 'Healthcare has a bull's-eye on its back'. PMID- 27483592 TI - Find the right tech tools for population management. PMID- 27483594 TI - How anger is fraying the doctor-patient relationship. PMID- 27483593 TI - GETTING PAID FOR HOME VISITS. PMID- 27483595 TI - Prepare now before CMS removes the ICD-10 safety net. PMID- 27483596 TI - Urgent care and how it relates to your practice. PMID- 27483597 TI - MACRAnomics: A guide for physicians. PMID- 27483598 TI - Don't skip your security risk assessment. PMID- 27483599 TI - What single-payer healthcare would mean to doctors. PMID- 27483600 TI - Still time for Congress to act on healthcare. PMID- 27483602 TI - Lifelong Learning Opportunities for Personal Growth. PMID- 27483601 TI - Discovering the Art of Nursing: Meet Judith Kimchi-Woods. PMID- 27483603 TI - Choosing an Educational Program That is the Right Fit. PMID- 27483604 TI - Considerations in Choosing Career Goals. PMID- 27483605 TI - Questions for New President of ONA Sally Morgan. PMID- 27483606 TI - Reference Proposals: Defining Initiatives for the Biennium. PMID- 27483607 TI - SPENCER COX: THE LEGACY OF AN ACTIVIST. PMID- 27483608 TI - CEOs reject veering sharply from ACA's path. PMID- 27483609 TI - Hospitals push Medicare to soften readmission penalties in light of socio economic risks. PMID- 27483611 TI - Hedge fund boss drops CHS, UHS stocks, pares back health insurance investments. PMID- 27483610 TI - Out-of-network ER pay and charges fuel ire from docs and patients alike. PMID- 27483612 TI - Tapping new dimensions. Manufacturers, drugmakers see promise in 3-D printing. PMID- 27483613 TI - Moving patient payment upfront. PMID- 27483614 TI - What's a new cancer drug worth? PMID- 27483615 TI - Proposed consolidation among health insurers could be hazardous to the nation's health. PMID- 27483616 TI - Helping ex-inmates get Medicaid. PMID- 27483617 TI - 'Legislation that requires health systems to post their charges ... just doesn't help'. PMID- 27483619 TI - Problems with Drugs or Alcohol? PMID- 27483618 TI - The Top Five Risk Management Principles for Florida Dentists. PMID- 27483620 TI - Case Study: Process Failures Lead to Patient Harm. PMID- 27483621 TI - Taking Ownership for Your Leadership. Three Steps to Creating a Culture of Learning in Your Practice. PMID- 27483623 TI - The Myth of Philanthropy. PMID- 27483622 TI - Five Tips to Building a Successful Sleep Practice. PMID- 27483624 TI - Diagnostic Discussion: Malignant melanoma. PMID- 27483625 TI - DDS: Double Down Solution to Florida's Access to Care. Florida's DDS Coordinator Helps Program Grow. PMID- 27483626 TI - The Myth of More. PMID- 27483627 TI - [Pyrophosphate in medicine]. AB - In all organisms from bacteria to humans, specific hydrolases--pyrophosphatases- hydrolyse inorganic pyrophosphate to phosphate. Without this, DNA, RNA and protein synthesis stops. Pyrophosphatases are thus essential for all life. In humans, disorders in pyrophosphate metabolism cause chondrocalcinosis and hypophosphatasia. Currently, pyrophosphate analogues, e.g. alendronate, are in clinical use in osteoporosis and Paget's disease but also for e.g. complications of prostate cancer. In bacteria and protozoan parasites, membrane-bound pyrophosphatases (mPPases), which do not occur in humans, convert pyrophosphate to a proton or sodium gradient. mPPases, which are crucial for protozoan parasites, are thus promising drug targets e.g. for malaria and leishmaniasis. PMID- 27483628 TI - [The latest antipsychotics--novelties or reiteration of the old?]. AB - Both conventional and more recent antipsychotics are effective in the treatment of hallucinatory and delusional symptoms in psychotic patients. With the exception of clozapine, no major differences in the efficacy of different antipsychotics have been found in clinical drug trials. There are, however, significant differences between drugs in their adverse effects, and the new antipsychotics or dosage forms introduced over the past ten years actually provide novel alternatives for the treatment of patients having body weight issues or cardiometabolic risk factors. Long-acting injections in turn reduce the need for psychiatric hospital care. PMID- 27483629 TI - [Update on current care guidelines: Self-medication, Current Care Guideline]. AB - Self-medication should always be temporary. Self-medication can be used to relief or treat many symptoms and conditions. In general self-medication is safe when used properly. However all medicines may cause adverse events or have interactions with other drugs. It is important to consider all used drugs and other self-medication products when new drugs are added to the medication list. Persons using the drugs as well as health care personnel should be aware of benefits and harms of drugs.The guideline has recommendations for 10 symptoms that are typically treated with self-medication. PMID- 27483630 TI - [Risk factors and possibilities of prevention of bowel cancer]. AB - The incidence of bowel cancer has doubled over the past 50 years. Although the treatment outcome has improved, 40% of those affected with the disease still die from it. Treatment in the terminal phase of the disease is expensive and requires plenty of resources without resulting in patient recovery. Bowel cancer could theoretically be reduced by changing the living habits. Focusing of endoscopy resources to screening of symptomless patients would be a more realistic means. Because bowel cancer develops through an endoscopically detectable and slow growing precancerous adenoma, it is possible to reduce massive disease burden through screening. PMID- 27483631 TI - [Principles of oncologic drug therapy following surgery for bowel cancer]. AB - Adjuvant chemotherapy for 6 months following curative resection of colorectal cancer (CRC) reduces recurrence risk and improves survival in lymph node positive, stage III disease. In stage II CRC the benefit of adjuvant chemotherapy is smaller and only recommended if high risk prognostic factors are present. Microsatellite instability in stage II CRC is associated with a favourable prognosis and when present adjuvant chemotherapy is not needed. Adjuvant chemotherapy improves disease outcome also in elderly patients (>= 70 years) with stage III CRC, but is not recommended in stage II disease. Adjuvant chemotherapy should be started within 8 weeks following surgery. PMID- 27483632 TI - [Novel techniques in the treatment of rectal cancer]. AB - Rectal cancer is the eighth and tenth most common kind of cancer in men and women, respectively, with an increasing frequency of occurrence. Together with cancer of the large intestine it forms the third most common cancer entity. Surgical therapy is the most important form of treatment of rectal cancer; in combination with adjuvant therapy it will cure a significant proportion of the patients and provide relief for tumor-induced hemorrhagic and obstructive symptoms. The operation has usually been conducted as an open surgery with the use of simple instruments. In recent times, the operative techniques have become more versatile, and mini-invasive techniques have resulted in quicker recovery of the patients from the operation. PMID- 27483633 TI - [Streamlined treatment pathway for a colorectal cancer patient]. AB - The organization of colorectal cancer patient treatment, the pathway, is an important component of the quality of care of a large patient group as nearly 3000 colorectal cancer patients are diagnosed and treated annually in Finland. By designing and describing the whole pathway, the more streamlined approach can be made and thus improve patient care. Multidisciplinary team work between colorectal surgeons, oncologists, pathologists and radiologists is flexible team work, having been proven to improve overall treatment results. This method of working together is also a good tool for the development of the pathway to a better organized treatment. PMID- 27483634 TI - [Imaging of rectal cancer--key to treatment decisions]. AB - The current guidelines (EURECCA consensus statement 2013) for preoperative imaging of rectal cancer recommend MRI for local staging and CT of the chest, abdomen and pelvis for detection of distant metastases. High resolution MR enables preoperative identification of poor prognostic features. These poor prognostic features are correlated with an increased risk of local recurrence and/or metastatic disease. MRI enables the preoperative multidisciplinary team to decide whether a patient benefits from adjuvant therapy and which surgical technique should be used. A radiological structured report helps clinicians get the most out of the report and increases the number of optimal reports. PMID- 27483635 TI - [Multidisciplinary tailoring of therapy of metastatic colon cancer]. AB - Treatment of colon cancer requires multidisciplinary team work. The multitude of therapies in metastatic colon cancer have led to longer overall survival with fewer symptoms. Median survival has increased from 5 months with the best supportive care to 30-40 months in randomized studies, even with curative treatment in some patients. Tailoring of the treatment is best done by a multidisciplinary team considering radiotherapy and operation of the primary tumor, resection of liver, lung and peritoneal metastases, medical treatment alternatives, palliative care, ablative methods etc. Without skillful surgeons, oncologists, pathologists, geneticists, radiologists etc. the best treatment opportunities may be missed. PMID- 27483636 TI - [What will determine the first-line treatment of a patient with rectal cancer?]. AB - Treatment of a rectal cancer patient is devised by a multidisciplinary expert team. The first thing to be solved is whether a curative treatment, one slowing the progression of the disease, or a symptomatic treatment is aimed at. The extent of the disease is assessed by using whole body CT scan and MR imaging of the rectum. When aiming at curative treatment, the need for preoperative radiation therapy and the surgical technique is assessed on the basis of MRI and clinical examination. The patient's physical condition, associated diseases or pelvic radiotherapy previously applied due to other diseases may restrict the choice of treatment. In an advanced disease, cytostatic chemotherapy is usually the first-line therapy, unless the tumor is obstructing the bowel. PMID- 27483637 TI - [Is there a threat to ban the herbicide glyphosate?]. PMID- 27483638 TI - [Iodized salt as a supplement - necessary or not?]. PMID- 27483639 TI - [Health promotion program "care for chronic condition" is extended]. PMID- 27483640 TI - [With kinesthetic infant handling for better quality of life]. PMID- 27483641 TI - [Wanderer between the worlds]. PMID- 27483642 TI - [With introduction of the nursing complex measures score the first successes appeared in nursing]. PMID- 27483643 TI - [Researchers of tomorrow. A visit to the student laboratory of air and space travel]. PMID- 27483644 TI - [Hospital CIRS net Germany delivers valuable instructions for nursing organization, delegation and coordination in the nursing and physician realm]. PMID- 27483645 TI - [A happy solution for Gabriel - seriously ill boy may go from the intensive care unit to his home. Nursing counseling suggested ways and possible help sources]. PMID- 27483646 TI - [What Kind of Physicians are Anesthesiologists?]. PMID- 27483647 TI - [Ultrasound-guided Rectus Sheath Block vs Transversus Abdominis Plane Block in Children Undergoing Umbilical Hernia Repair]. AB - BACKGROUND: Although many reports describe the usefulness of the rectus sheath block (RSB) in the umbilical hernia repair, the efficacy of the transversus abdominis plane block (TAPB) is rarely reported. The purpose of this study was to compare the efficacy and technique of ultrasound-guided RSB and TAPB in children undergoing umbilical hernia repair. METHODS: Thirty-four children younger than 12 years of age scheduled for umbilical hernia repair were enrolled in this prospective observer-blinded randomized clinical trial. They were randomly assigned either to RSB group (median age, 3.7 years) or TAPB group (median age, 3.8 years). After the induction of general anesthesia with sevoflurane, nitrous oxide, and oxygen children in both groups received regional anesthesia with 0.3 ml x kg(-1) of 0.25% ropivacaine on each side under ultrasound guidance. Hemodynamic changes at the skin incision, postoperative pain scores and parental satisfaction were recorded. Anesthesiologists rated the quality of ultrasound images and easiness of the block performance. RESULTS: The patients' demographics of the two groups were similar. There were no significant differences in the time needed for the block procedure, quality of ultrasound images and the change of the heart rate and blood pressure at the skin incision between the two groups. Postoperative pain score (immediately, 2 and 4 hours after the operation), need for rescue analgesia and satisfaction of the parents also did not differ. There were no major complications in the patients. CONCLUSION: TAPB provided comparable perioperative analgesia and easiness of block performance to RSB in the pediatric umbilical hernia repair. PMID- 27483648 TI - [Assessment of Fibrinogen Replacement Therapy by the Combined Simulation of the Fibrinogen Concentration and Fibrin Polymerization]. AB - BACKGROUND: Fibrinogen replacement therapy is effective for attaining perioperative hemostasis in critical bleeding due to acquired hypofibrinogenemia. By simulating the fibrinogen level and fibrin polymerization, we compared the effect of fibrinogen replacement therapy using cryoprecipitate or fibrinogen concentrate versus the effect of fresh frozen plasma. METHODS: We simulated the plasma concentration of fibrinogen during fibrinogen replacement therapy in a model of cardiopulmonary bypass (CPB) and intensive care unit (ICU). We estimated fibrin polymerization (FIBTEM A10, thromboelastometry) by the simulated fibrinogen level, and compared this value with the fibrinogen level and FIBTEM in clinical patients. RESULTS: In the simulation model of CPB and ICU, cryoprecipitate and fibrinogen concentrate both effectively restored the fibrinogen level and FIBTEM, compared to fresh frozen plasma. In clinical patients, the simulated values of the fibrinogen level and FIBTEM after administering the fibrinogen concentrate were similar to the measured values. CONCLUSIONS: In the simulation model, which combines the fibrinogen level and fibrin polymerization, cryoprecipitate and fibrinogen concentrate effectively normalize the fibrinogen level and fibrin polymerization, compared to fresh frozen plasma. The fibrinogen concentrate also demonstrated efficacy in treating hypofibrinogenemia in clinical patients. The combined simulation model is useful in assessing the efficacy of fibrinogen replacement therapy by cryoprecipitate or by fibrinogen concentrate. PMID- 27483649 TI - [Evaluation of the Effects of Remifentanil Doses on Hemodynamics and Perfusion Index at the Onset of Pneumoperitoneum during Laparoscopic Surgery]. AB - BACKGROUND: The aim of this study was to investigate whether changes in perfusion index (PI) correlate with non-invasive haemodynamic parameters (HR, BP) following the onset of pneumoperitoneum under two doses (moderate-dose (MD) and high-dose (HD)) of remifentanil and to compare its reliability. METHODS: We divided 33 patients who were scheduled for laparoscopic surgery under general anesthesia into two groups according to the dose of continuously infused remifentanil: moderate dose 0.5 MUg x kg(-1) x min(1) (MD group, n = 16) and high dose 1.0 MUg x kg(-1) x min(-1) (HD group, n = 17). Non-invasive blood pressure (NIBP), HR, and PI were measured before the start of surgery (time 1), after the start of surgery (time 2), before the start of pneumoperitoneum (time 3), and 1 min after the stable state of pneumoperitoneum (time 4). RESULTS: PI decreased from the baseline after pneumoperitoneum in MD group, on the other hand PI did not change in HD group. Between the two groups, the magnitude of the PI changes was statistically different although MBP and HR were not statistically different CONCLUSIONS: PI may be a reliable and easier alternative to conventional haemodynamic parameters for detection of stress response to pneumoperitoneum during remifentanil anaesthesia in adult patients. PMID- 27483650 TI - [Fibrin-related Markers in Acute Phase of Pulmonary Embolism and Deep Venous Thrombosis]. AB - BACKGROUND: The fibrin-related markers are considered to be useful in diagnosing pulmonary embolism (PE) and deep vein thrombus (DVT). We measured D-dimer (DD) and soluble fibrin monomer complex (SFMC) in these cases, in order to examine the usefulness of these markers. METHODS: PE patients (P group: 14 cases) and DVT patients (D group : 16 cases) treated in our hospital, were examined. We measured the value of DD and SFMC on the first visit day and the second day. In PE cases, comparative examination of the markers were carried out between dead and survived cases. RESULTS: The value of both markers in P group ware significantly higher compared with D group, on the second day. There was a significant correlation between SFMC and DD in P group, but in D group, significant correlation was not observed. CONCLUSIONS: It seems that measuring DD and SFMC is useful to evaluate the pathology of PE and DVT. PMID- 27483651 TI - [The Influence of Preoperative Oral Carbohydrate Administration on Perioperative Blood Sugar Levels and Patients' Satisfaction]. AB - BACKGROUND: After introducing preoperative oral carbohydrate as a part of enhanced recovery after surgery (ERAS) protocols, we assessed the influence of carbohydrate administration on the perioperative blood sugar levels (BS), the variation of vital signs and patients' satisfaction. METHODS: After IRB's approval and obtaining patients' consent, patients were divided into two groups; taking carbohydrate (Group AW) or not (Group NAW). Anesthesia was induced and maintained with total intravenous anesthesia using propofol, remifentanil and rocuronium. We measured BS six times during perioperative period. We also compared blood pressures and heart rates during induction of anesthesia. Moreover, we carried out questionnaire surveys about degree of satisfaction for ERAS among patients and nurses. RESULTS: Heart rates were significantly higher in Group AW (P < 0.05), but there were no significant difference in blood pressures or BS between the groups. Patients in Group AW had more anxiety for surgeries (P = 0.003), but more than 85% of patients and nurses were satisfied with carbohydrates. CONCLUSIONS: The carbohydrate administration had little influence on the perioperative vital signs. However, we gained high reputations from patients and paramedics. PMID- 27483652 TI - [Perioperative Management of a Child with Vocal Adhesion Leading to Unexpected Difficult Airway]. AB - We report a child with vocal cord adhesion encountered during induction of anesthesia. A 4-month-old girl was scheduled for bilateral lip plasty. She was intubated for one week due to pneumonia at the age of 3 days. Hoarseness and stridor appeared just after extubation. Although laryngo-fiberoptic examination had been tried several times, otorhinologists could not find any abnormality. We once decided to postpone the operation because of severe stridor. However, laryngofiberoptic examination could not reveal any abnormality, and we rescheduled the operation. Tracheal intubation using laryngoscope was not possible due to vocal cord adhesion. Finally, 2.5 mm ID tracheal tube was intubated by using a fiberscope, and lip plasty was performed. The patient stayed in the ICU for 7 days after surgery. Tracheotomy was performed 3 weeks after the operation. We should pay attention to stridor in an infant before general anesthesia, since it suggests severe airway narrowing although laryngo-fiberoptic examination could not find any abnormalities. PMID- 27483653 TI - [Successful One-lung Ventilation with a Right-sided Double-lumen Tube in a Patient with a Right Upper Tracheal Bronchus, who Underwent Left Pneumonectomy for Left Hilar Lung Cancer]. AB - A 60-year-old male patient with left hilar lung cancer was scheduled to undergo left pneumonectomy or left sleeve lower lobectomy. Preoperative computer tomographic and bronchoscopic examinations revealed that the bronchus (B1) to the right apical segment (S1) was a tracheal bronchus (TB) originating from the trachea approximately 10 mm above the carina. Because the left main bronchus was to be dissected, a right-sided double-lumen tube (DLT) was selected to completely protect the right lung from spillage of secretions or cancer cells from the left lung. The right-sided DLT was placed so as to fit its lateral opening of the bronchial lumen to normal upper branches (B2, B3), while sacrificing ventilation of S1 with an abnormal branch (B1). However, one-lung ventilation (OLV) of the right lung could not be achieved, since a gas leakage from the opened tracheal lumen occurred, most probably due to intra-lobar micro-airway communications between S1 and S2/S3. The DLT was withdrawn until the blue bronchial cuff occluded the orifice of the TB (B1). Although the upper half of the blue bronchial cuff appeared above the tracheal carina, OLV through the two bronchial lumen openings could be achieved due to a specific, slanted doughnut shape of the blue bronchial cuff and the location of the abnormal branch (B1) approximate to the carina. Left pneumonectomy using successful OLV was completed safely without hypoxemia or hypercapnea. Our experience indicates that management of OLV for patients with a thoracheal bronchus needs special considerations of the exact location of the TB and intra-lobar micro-airway communications, in addition to types of scheduled surgical procedures. PMID- 27483654 TI - [Utility of McGRATH MAC for a Patient with a Large Epiglottic Cyst]. AB - A 76-year-old man with an epiglottic cyst was scheduled for transoral rigid endoscopic epiglottic cystectomy under general anesthesia. The epiglottic cyst was found accidentally when he had an operation of radical cystectomy 2 weeks before. When he had the radical cystectomy, the ventilation through a mask was easy. He had no subjective respiratory symptoms. We chose rapid induction with propofol, remifentanl, and rocuronium. When we inserted the McGRATH MAC laryngoscope, we could only see a big epiglottic cyst not vocal cord but the pressure on the neck enabled the laryngologist to see the vocal cord. We could identify the space through which we could insert tracheal tube without touching the cyst. After the operation, his trachea was extubed. PMID- 27483655 TI - [Emergent Caesarean Section in a Patient with a Mediastinal Tumor and Von Recklinghausen Disease: A Case Report]. AB - It is rare to encounter a pregnant patient with a mediastinal tumor, and if the tumor size increases as the pregnancy progresses, this increase can cause complications such as airway constriction and vascular occlusion. We report a case of a pregnant patient diagnosed with von Recklinghausen disease at the age of seven and diagnosed with a mediastinal tumors just after her present admission. The impending suffocation progressed and fetal heart rate decreased during her hospitalization. Her trachea was intubated and she was moved to an operating room for an emergent cesarean section under general anesthesia. With this rapid response, we could rescue both patient and infant. If the size of mediastinal tumor increases as pregnancy progresses, the tumor will cause suffocation by airway compression from the outside, in addition to specific airway edema on the inward side. The present case demonstrates that appropriate desisoins must be made for airway manegement and initiation of surgery. PMID- 27483656 TI - [Anesthetic Management of Peritonectomy and Extended Operation for Peritoneal Pseudomyxoma Combined with Massive Ascites]. AB - We report successful anesthetic management of extended operation for peritoneal pseudomyxoma combined with massive ascites (16.5 l). A 66-year-old man (weight 76 kg) who could not keep a supine position due to massive ascites associated with peritoneal pseudomyxoma was scheduled for elective peritonectomy and extended surgery. With the patient in the semisitting position, we administered 3% sevoflurane to induce loss of consciousness while preserving spontaneous ventilation. We then performed crush induction with propofol and rocuronium after topical anesthesia to the tongue base. Tracheal intubation with the Macintosh laryngoscope was successful. During the operation, we aspirated about 16.5 l of ascites over 20 l normal saline irrigation. To maintain the body temperature, we performed both active and passive extracorporeal warming. The operation included not only total peritonectomy but also distal gastrectomy, right colon resection, splenectomy, and cholecystectomy. To perform effective postoperative analgesia, we placed two epidural catheters from the upper and lower thoracic epidural spaces. The patient was extubated 3 days after operation, and discharged uneventfully on the 18th postoperative day. PMID- 27483657 TI - [A Case of EXIT (Ex-utero Intrapartum Treatment) in a Fetus with Prenatal Diagnosis of a Giant Cervical Tumor: Successful Airway Management but without Indication of Treatment for a Tumor]. AB - The ex-utero intrapartum treatment (EXIT) is a rare procedure, and often comes as an emergency surgery. A careful preparation is crucial and a multidisciplinary team discussion during the prenatal period is necessary because it may be practically and ethically difficult to plan a surgical treatment for a fetus for EXIT. An elective caesarean section and EXIT for a fetus with a giant cervical tumor, which may cause airway obstruction and difficult intubation, were scheduled. The anesthesiologist tried oral intubation by direct laryngoscope; however, neither blade nor rigid bronchoscope insertion was impossible as a firm mass protruded in oral cavity from the left side. Tracheotomy was successfully performed and the airway was secured. As for maternal anesthesia, adequate uterine relaxation was obtained by inhalational agents and nitroglycerine. After ligation of the umbilical cord, anesthesia was maintained with propofol and fentanyl, and good uterine contraction was provided by infusion of oxytocin. The duration of EXIT was 44 minutes. The fetal tumor, containing both solid and cystic components, was 14 centimeters in diameter, and infiltrated into intracranial space. There was no indication of resection nor chemotherapy for the tumor. Palliative care was selected, and the neonate died forty days after birth. PMID- 27483658 TI - [Anesthetic Management of a 69-year-old Patient with Eisenmenger Syndrome for Abdominoperineal Resection]. AB - Although life expectancy of the patients with Eisenmenger syndrome (ES) is currently reported to be lower than 40 years, life span of the patients with ES may be extended because of development of medical care. According to recently reported middle-aged patients with ES undergoing non-cardiac surgeries, per operative mortality and morbidity of the patients with ES undergoing non-cardiac surgeries may be lower than previously thought, and even elderly patients may be able to undergo major surgeries such as laparotomies for cancers. We described the anesthetic management of a 69-year-old patient with ES who had undergone abdominoperineal resection. In the anesthetic management it is important to maintain adequate blood volumne and systemic vascular resistance and this avoids increases of right-to-left shunt. Perioperative monitoring of pulmonary arterial pressure was useful for hemodynamic management. Good pain control and management of body temperature were also needed for a perioperative course with no adverse events. The appropriate anesthetic management of the 69-year-old patient with ES for abdominoperineal resection resulted in the successful perioperative course. PMID- 27483659 TI - [Acute Postoperative Negative Pressure Pulmonary Edema Caused by the Compression of Brachiocephalic Artery]. AB - We report a case of negative-pressure pulmonary edema occurring by tracheal obstruction caused by the brachiocephalic artery. The patient had deformed thorax with cerebral palsy, which deformed thorax placing the brachiocephalic artery high over the trachea, resulting in close and tight contact between the artery and trachea. Additional deformity of the thorax associated with myotonic attacks after general anesthesia might shorten the distance between the sternal notch and the vertebral body, resulting in the tracheal obstruction by the artery. PMID- 27483660 TI - [Safe and Effective Analgesia with Bilateral Continuous TAP Block for a Patient with Marfan Syndrome after Open Abdominal Aortic Aneurysm Repair]. AB - A patient with Marfan syndrome underwent emergency open abdominal aortic aneurysm repair. She was referred to our department for postoperative analgesia. Taking the risk of possible dural ectasia into consideration, we avoided epidural block. Alternatively, we performed bilateral continuous transversus abdominis plane (TAP) block with sufficient analgesia. Lumbosacral dural ectasia is frequently observed in patients with Marfan syndrome. A few reports described that their fragile dura may contribute to an increased risk of dural puncture and postdural puncture headache (PDPH). Thus, in planning neuraxial block for a patient with Marfan syndrome, the possible consequences of lumbosacral dural ectasia should be considered. A case we herein present shows bilateral continuous TAP block could be a safe and effective alternative to epidural block. PMID- 27483661 TI - [The Use of Arginine Vasopressin and PhosphodiesteraseIII Inhibitor for Circulatory Shock after the Resection of a Massive Adrenal Pheochromocytoma]. AB - A 72-year-old man developed hypertensive crisis five month previously, and was diagnosed with massive adrenal pheochromocytoma, with a diameter of 14.5 cm. Preoperative echocardiography revealed normal cardiac function. The open abdominal surgery was performed under general anesthesia. During manipulation of the tumor he developed hypertension and tachycardia. Severe hypotension (50/25 mmHg) and mild bradycardia (70 beats x min(-1)) followed the resection of the tumor. In addition to volume replacement noradrenaline and adrenaline were administered, but the systolic blood pressure rose only to 60-70 mmHg. In order to treat vasodilatory shock, we started to administer arginine vasopressin infusion at 0.03 units x min(-1). His systolic blood pressure rose to 90 mmHg. The patient was transferred to the intensive care unit (ICU) postoperatively. The echocardiography revealed diffuse hypokinetic cardiac function. In order to treat cardiogenic shock, we started to administer olprinone (phosphodiesteraseIII inhibitor, infusion of 0.1 MUg x kg(-1) x min(-1)). On postoperative day 2, circulatory shock improved and the patient was discharged from the ICU. In conclusion, circulatory shock after the resection of a massive pheochromocytoma was due to the down regulation of alpha and beta adrenergic receptors. The non adrenergic vasoconstrictor and inotrope were useful for this situation. PMID- 27483662 TI - [Involuntary Movement of Bilateral Lower Limbs Caused by Epidural Anesthesia: A Case Report]. AB - Regional anesthesia, especially epidural anesthesia, rarely causes involuntary movement Here we present a case of a patient who demonstrated myoclonus-like involuntary movement of the lower limbs during continuous infusion of ropivacaine, fentanyl, and droperidol through the thoracic epidural catheter. This movement disappeared when the epidural infusion was stopped, but reappeared when the epidural infusion was restarted. Naloxone did not eliminate the movement The patient was thereafter discharged uneventfully. This case and other reports in the literature suggest that involuntary movement associated with regional anesthesia is rare and self-limiting. However, careful consideration should be given to exclude other, potentially dangerous complications. PMID- 27483663 TI - [Anesthetic Management of Cesarean Section in a Pregnant Woman with Advanced Tongue Cancer]. AB - It is very difficult to decide the best time to deliver the baby for a pregnant woman with advanced cancer. We experienced the perioperative and perinatal management of a 39-year-old pregnant woman with advanced tongue cancer. The cancer had already metastasized to the lung and lymph nodes. Furthermore a recurrent thumb-sized tumor was found in her mouth. She had firmly desired to discontinue all anticancer treatment for protecting the fetus. On the other hand, her family could not accept her determination yet. Therefore the medical team was organized with doctors and co-medicals from multiple departments such as gynecology, pediatrics, radiology, oncology, midwife, psychotherapy and anesthesiology. After several conferences including herself and family, finally cesarean section was scheduled for the 30th gestational week. Prepared for unexpected emergency delivery, airway stenosis was ruled out by fiberoptic laryngoscopy and the consent for emergency tracheostomy was obtained. The operation was performed successfully under spinal anesthesia without any severe troubles. Medical care as a team from early phase enabled elaborate observation and preparation through the perioperative and perinatal period. Furthermore, it was efficient to provide satisfaction to the patient and her family as well. PMID- 27483664 TI - [Anesthetic Management of a Patient who Developed Intraoperative Paroxysmal Supraventricular Tachycardia with Pulseless Electric Activity]. AB - A 75-year-old woman was scheduled to undergo an ileus operation under general combined with epidural anesthesia. Preoperative electrocardiogram (ECG) showed first-degree atrioventricular block. The patient received no preoperative antiarrhythmic medication. During surgery, paroxysmal supraventricular tachycardia (PSVT) occurred unexpectedly with radial artery pulsation disappearing, indicating pulseless electric activity (PEA). After a five-second episode of PSVT, her sinus rhythm recovered spontaneously. However, the patient had repeated short duration of PSVT with PEA. Continuous infusion of ultra-short acting beta-blocker landiolol successfully terminated the PSVT, and sinus rhythm was restored. Postoperative ECG showed sinus rhythm. This case report indicates that beta-blocker can be a drug of choice in patients with PSVT associated with PEA. PMID- 27483665 TI - [Two Cases of Caudal Alcohol Block for Perineal Pain that Occurred in Cancer End of-Life]. AB - We experienced two cases of end-of-life cancer patients with perineal pain, whose pain was relieved by 5 ml absolute ethanol caudal block. Although the first injection was ineffective, the second injection resulted in significant relief of pain in both cases. Although the indication should be carefully considered, alcohol caudal block is an analgesic method worth considering for the end-of-life cancer patients complaining of perineal pain. PMID- 27483666 TI - [Pressure Ulcer Caused by Long-term Keeping of the Same Body Position during Epidural Labour Analgesia]. AB - We report the case of a 34-year-old woman (height: 153 cm, weight : 62.4 kg, non pregnant weight : 52 kg, uniparous) without underlying diseases who developed pressure ulcer due to keeping a similar body position during long-term epidural delivery. Induction of childbirth was started in gestational week 40, causing reduction of fetal heart rate, which improved after adoption of a right lateral recumbent position. Severe contractions occurred and epidural labour analgesia was started. The fetal heart rate decreased again and induction of childbirth was suspended, but the right lateral recumbent position was maintained. Epidural administration was continued due to persistent contractions. Next morning, induction of childbirth was restarted and birth occurred in approximately 6 hours. The right lateral recumbent position was maintained for approximately 20 hours. At childbirth, a pressure ulcer was present in the intertrochanteric part of the right femur. The causes included insufficient knowledge of medical staff about the risk of pressure ulcer during epidural delivery, and no position change. A decreased sensation and blocked motor nerve caused by epidural anesthesia might have accelerated pressure ulcer development. This case suggests that preventive measures against pressure ulcer are required in epidural anesthesia in pregnant women. PMID- 27483667 TI - [A Case of Rocuronium Anaphylaxis in which Anesthesia was Safely Performed after Selection of an Alternative Drug after a Skin Test]. AB - We report our experience of a patient with a history of anaphylactic shock suspected to be caused by rocuronium who was scheduled to undergo hepatic tumor resection. The patient was a 17-year-old female (height : 166 cm, weight : 46 kg). During general anesthesia at another hospital several years ago, she had an anaphylactic shock, and rocuronium was suspected to be the offending drug. To collect information and search for the cause, skin tests were performed for rocuronium, vecuronium and suxamethonium. She was positive for rocuronium, and negative for other drugs. At anesthesia induction, we administered vecuronium and confirmed no development of anaphylaxis before commencement of surgery. In the perioperative period, she had no symptoms that indicated anaphylaxis. Since there is potential high cross-reactivity among muscle relaxants, it is important to perform a test for alternative drugs when a muscle relaxant may be a cause of anaphylaxis. Selection and administration of an alternative drug should be carefully performed, even when a skin test is negative for the alternative drug. PMID- 27483668 TI - [Anesthetic Management of a Patient with Central Core Disease for Scoliosis Surgery]. AB - Central core disease (CCD) is a dominantly inherited congenital myopathy. CCD is also associated with muscular and skeletal abnormalities such as abnormal curvature of the spine (scoliosis), hip dislocation, and joint deformities. CCD and malignant hyperthermia (MH) are both associated with mutations in the ryanodine receptor on chromosome 19q13.1. An 11-year-old boy with CCD complicated with severe scoliosis was scheduled for spinal fusion surgery under general anesthesia. Furthermore, he had trismus caused by temporomandibular contracture. He was considered as MH susceptible. Anesthesia was managed with remifentanil and propofol without using muscle relaxtants and volatile anesthetics. We could intubate the trachea with Airtraq laryngoscope without any complications. The perioperative course was uneventful. PMID- 27483669 TI - [A Case of Acetaminophen Poisoning Associated with Tramcet Overdose]. AB - Tramcet is a mixture of tramadol and acetaminophen. Acetaminophen poisoning may be caused by excessive intake of Tramcet. A 17-year-old female took excessive quantity of Tramcet before noon. She reported it herself in the emergency room. Her main complaint was nausea and dizziness. Acetaminophen may cause liver damage with dose-dependent manner. Because there was a possibility of acetaminophen poisoning, we started oral acetylcysteine. She was discharged from hospital 5 days later without side effects of acetylecysteine and liver damage. PMID- 27483670 TI - [The Formative Years of Modern Anesthesiology in Japan--A Dialogue between Hideo Yamamura and Akitomo Matsuki]. AB - In a dialogue with Akitomo Matsuki as the moderator, Hideo Yamamura, the first Professor of Anesthesiology in Japan at the University of Tokyo who had enormously contributed toward improving the standard of the specialty in Japan, gave detailed accounts of following topics: his training as a surgeon, Saklad's lectures in 1950, the establishment of a departmental anesthesia group, the conversion to anesthesiologist, studying in the United States, the foundation of the Japan Society of Anesthesiology, movements for the governmental approval of registered anesthesiologists and the qualification system of board certified anesthesiologists, international activities in holding the Second Asian Australasian Congress of Anaesthesiologists in 1966 and the Fifth World Congress of Anaesthesiologists in 1972, and the opening of pain clinics and the foundation of its society. Yamamura's accounts illustrate unknown episodes in the history of the formative period of modern anesthesiology in Japan. PMID- 27483671 TI - LEVERAGE YOUR VALUE. How to negotiate narrow neworks. PMID- 27483672 TI - MACRA likely will mean penalties for small practices. PMID- 27483673 TI - Transitional care management. Billing and coding it the right way. PMID- 27483674 TI - How physicians can deal with high-deductible plans. PMID- 27483675 TI - POPULATION HEALTH. Making it work. PMID- 27483676 TI - New Health IT program continues legacy of Meaningful Use. PMID- 27483677 TI - Take a step-by-step approach to HIPAA compliance. PMID- 27483678 TI - THE FUTURE OF THE AFFORDABLE CARE ACT. PMID- 27483679 TI - The role of private counsel in medical malpractice cases. PMID- 27483680 TI - Medicare overpayment rule leaves practices scrambling. PMID- 27483681 TI - Getting the most out of CME on a budget. PMID- 27483682 TI - GOP Doctors Caucus looking at ambitious 2016. PMID- 27483683 TI - [Not Available]. PMID- 27483684 TI - [Differential diagnostic considerations using ICD-10 in chronic back pain with special regard to persistent somatoform pain disorder with somatic and psychological factors (ICD-10 F45.41)]. AB - It is often difficult to pass an expert opinion in cases of chronic back pain. This article analyses the differential diagnostic considerations related to coding various causes in line with ICD-10. It emphasises the I importance of making a careful distinction between orthopoedic and psychiatric conditions and disorders. Simultaneous coding of orthopoedic and psychiatric illnesses and disorders based on a distinct cluster of symptoms necessitates an interdisciplinary approach that consistently applies the ICD-10 definitions of mental an behavioural disorders in order to clearly identify the main reason for a functional impairment in the insurance and sociomedical context. Persistant somatoform pain disorder with somatic and psychological factors (ICD-10 F45.41) should be regarded as related to the underlying disease and be used primarily as an additional and descriptive diagnosis. PMID- 27483685 TI - [Medical negligence]. AB - Medical negligence is a matter of growing public interest. This review outlines various aspects of medical negligence: epidemiology, taxonomy, and the risks, causes, psychology, management and prevention of errors. PMID- 27483686 TI - [Postvaccinal complication and medical malpractice law]. AB - The case report involves a 38-year-old female patient with muscular atrophy, paresis and sensory deficits in the right upper limb following several vaccinations. A legal dispute ensued over whether medical malpractice could have caused the neurological deficits. Medical malpractice could not be confirmed. Even vaccinations administered correctly can lead to neurological impairment. PMID- 27483687 TI - [Quantified self movement--the new mantra of life insurance companies]. AB - Wearables are small personal minicomputers that register biometric data. In such a way, the insurance industry hopes to create new sales opportunities and products, and simplify underwriting. Lower premiums will promote the use of wearables. The related possibilities and unanswered questions are discussed in this article. Utilisation of big data offers the insurance industry a range of new opportunities. The benefit must be proven in the future, however. PMID- 27483688 TI - [Potential for intervention of private health insurers in discharge management using the example of stroke patients]. AB - The study reveals that stroke patients today can still experience gaps in the provision of healthcare and fragmented therapy. This is often the case on transferral from the inpatient to outpatient sector, causing complications that could be avoided by means of good discharge management across all sectors. Private health insurance can actively support and positively influence the treatment process in the form of case management. Individual contact with stroke patients and their relatives allows for early planning and organisation of the next steps, and offers patients the support they need during a difficult phase of life. PMID- 27483689 TI - [Not Available]. PMID- 27483690 TI - [Not Available]. PMID- 27483691 TI - [Not Available]. PMID- 27483692 TI - [Not Available]. PMID- 27483693 TI - [Not Available]. PMID- 27483694 TI - [Not Available]. PMID- 27483695 TI - ADVANCEMENT REGARDING THE ROLE OF ENDOTHELIUM IN ARTERIAL WALL DYSFUNCTION. PMID- 27483696 TI - EATING BEHAVIOR IN RESPONSE TO ACUTE STRESS. AB - Obesity is a medical and social problem with a dramatically increasing prevalence. It is important to take action since childhood to prevent and treat obesity and metabolic syndrome. Infantile obesity affects all body systems starting in childhood and continuing to adulthood. Understanding the impact of stressors on weight status may be especially important for preventing obesity. The relationship between stress, eating behavior and obesity is not fully understood. However, there is evidence that stress causes disorders in hypothalamic-pituitary-adrenal (HPA) axis, system that regulates both stress and feeding responses. Also, the response is different depending on the type of stressors. Chronic stress, especially when people live in a palatable food environment, induces HPA stimulation, excess glucocorticoids, insulin resistance, which lead to inhibition of lipid mobilization, accumulation of triglyceride and retention of abdominal fat. PMID- 27483697 TI - NEW CLASS OF DRUGS: THERAPEUTIC RNAi INHIBITION OF PCSK9 AS A SPECIFIC LDL-C LOWERING THERAPY. AB - Hyperlipidemia is a well-known risk factor for coronary heart disease, the leading cause of death for both men and women. Current lipid-lowering treatment is not always efficient, therefore new pharmacological interventions that reduce LDL cholesterol (LDL-C) have been developed. This paper presents new class of specific LDL lipid-lowering drugs under investigation in phase II or III clinical trials. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), a key enzyme in cholesterol homeostasis, improve the liver's ability to clear LDL from the plasma, reducing LDL-C levels. Currently, three monoclonal antibodies PCSK9 inhibitors (alirocumab, evolocumab and bococizumab) are evaluated in clinical outcome trials. ALN-PCSsc, the new first-in- class therapeutic RNA interference (RNAi) inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) is also the first-in-class investigational medicine that acts by turning off PCSK9 synthesis in the liver. The development leadership of ALN-PCSsc has now transferred from Alnylam Pharmaceuticals to The Medicines Company, who has initiated the ORION-1 Phase II study at the beginning of 2016. ALN-PCSsc has significant potential given its highly competitive profile as compared with monoclonal antibodies anti-PCSK9 MAbs, a recently approved class of LDL-C lowering drugs. PMID- 27483698 TI - SCORING IN ACUTE PANCREATITIS: WHEN IMAGING IS APPROPRIATE?. AB - Acute pancreatitis (AP) is a frequent presentation to the emergency departments with a rising incidence and a great variability in clinical severity and outcome. The aim of this review is to offer a succinct presentation on acute pancreatitis scoring systems and the use of different imaging methods in severity prediction: Ranson criteria, Glasgow criteria, Hong Kong Score, Acute Physiology and Chronic Health Evaluation II (APACHE II), computed tomography scoring systems, Bedside Index of Severity in Acute Pancreatitis (BISAP) score, Panc 3, Japanese Severity Score (JSS), Harmless Acute Pancreatitis Score (HAPS), Pancreatitis Outcome Prediction (POP), Sequential Organ Failure Assessment (SOFA). This article also describes the Revised Atlanta Classification of AP (2012) and the correlation with computed tomography. PMID- 27483699 TI - INFLUENCE OF SLEEP ON OBESITY IN CHILDREN. AB - Childhood obesity is a global epidemic with long term implications. The main cause of obesity is an increase in calorie intake and a decrease in physical activity, but also there is clear evidence suggesting a link between the duration and quality of sleep and obesity risk. Good sleep habits are involved in increased ability to concentrate at school, improvement of general state, immune system development, increased quality of life. On the other hand, there are several mechanisms by which chronic sleep deprivation induces weight gain: disturbance of hormones that control hunger center, increased time for meals, reduced physical activity, metabolic changes. Recently, nighttime sleep duration has declined, in contrast with the increasing prevalence of obesity. Childhood sleep habits have a long term effect on weight, with repercussions even into adulthood. This is the reason why there is increasing interest to include sleep quality on the list for childhood obesity prevention. Sleep represents an important and independent risk factor of obesity in children and adolescents and it should be taken into consideration in the management of obesity. PMID- 27483700 TI - MUSCULOSKELETAL IMPAIRMENT IN PRYMARY HYPOTHYROIDISM. AB - This article contains bibliographical data concerning the rheumatic clinical manifestations in hypothyroidism: polyarthralgias, lack of recent skill of fine movements of the hands, carpal tunnel syndrome or tarsal, degenerative arthropathy or acute type (gout, chondrocalcinosis), adhesive capsulitis (frozen shoulder syndrome), generalized muscular stiffness, hypothyroid myopathy, secondary osteoarthritis, Dupuytren's contracture, "trigger finger" (also called as stenosing tenosynovitis or trigger thumb) etc. and data on the short history, epidemiology, of these disorders. Review include 60 bibliographical sources. PMID- 27483701 TI - POTENTIAL NEW ROLES OF LEPTIN IN HEALTH AND DISEASE. AB - Leptin is an adipose-tissue specific cytokine described 20 years ago and classically thought to be involved in regulation of food intake and energy homeostasis. More recently, leptin was proven to exert other multiple roles in carbohydrate and lipid metabolism, reproductive system, and inflammatory and immune reactions. Emerging data propose leptin to be a modulator of bone mass. In some particular circumstances leptin synthesis follow specific patterns in inflammation and sepsis, not being proportional with fat mass. Therefore, it may be used as diagnostic or prognostic marker for critical illness. PMID- 27483702 TI - TREATMENT OF METABOLIC ALTERATIONS IN POLYCYSTIC OVARY SYNDROME. AB - Polycystic ovary syndrome is a common endocrinopathy characterized by oligo ovulation or anovulation, signs of androgen excess and multiple small ovarian cysts. It includes various metabolic abnormalities: insulin resistance, hyperinsulinemia, impaired glucose tolerance, visceral obesity, inflammation and endothelial dysfunction, hypertension and dyslipidemia. All these metabolic abnormalities have long-term implications. Treatment should be individualized and must not address a single sign or symptom. Studies are still needed to determine the benefits and the associated risks of the medication now available to practitioners. PMID- 27483703 TI - MEDICAL PRACTICE IN CHILDREN PRESENTING FEVER WITH PETECHIAL RASH TO AN EMERGENCY DEPARTMENT. AB - INTRODUCTION: The association of fever and petechiae in children is one of the most alarming findings for a paediatrician. To quickly distinguish between benign and life-threatening conditions is challenging in many cases. We aimed to evaluate the clinical practice of children presenting with fever and petechiae as initial symptoms. METHODS: 41 patients (age 3 months-11 years) presenting with fever and petechiae were identified in an Emergency Paediatric Assessment Unit over a period of 9 months. General data, symptoms and signs were assessed for each patient. The work-up consisted in: complete blood count, inflammatory tests, coagulation tests, Monospot test, nasopharyngeal rapid tests, blood culture, and cerebrospinal fluid culture where appropriate. RESULTS: Most children were <5 years of age (70.7%). Female to male ratio was 1:2.4. The most common clinical diagnoses were: viral respiratory illness (48.8%, 20/41) and upper respiratory tract infection (17.1%, 7/41). Meningococcal disease was found in one case. CRP>6 mg/l was poorly correlated with serious illness. The following variables were strongly associated with serious illness: ill appearance, shivering, lethargy, back rigidity, ESR>50 mm/h and prolonged capillary refill time. 59% (24/41) of children were treated with antibiotics, however, at discharge 42%(10/24) of them, did not have a work-up suggestive for a bacterial illness. CONCLUSIONS: Screening for low prevalence but high morbidity conditions, as the meningococcal disease, with an extensive work-up is time and resource consuming and may lead to unmotivated antibiotic use. Larger studies are needed to change the emergency practice for management of fever and rash. PMID- 27483704 TI - ANATOMICAL AND CLINICAL ORBSERVATIONS ON STRUCTURAL CHANGES OF THE HIP JOINT. AB - The hip, the second largest joint of the human body, with its primary contribution to locomotion, is exposed to numerous traumatic or non-traumatic risks. Regardless of the initial pathology, there is always almost the same result: diminution of range of motion, onset of pain and functional impotence, as well as change of biomechanics of walking. Through its high frequency, morpho functional imbalance (clinically expressed both imagistic and biologically, in one or several joints), osteoarthritis is a disease with a multifactorial etiology and a complex pathogeny. MATERIAL AND METHOD: The study included 244 patients aged between 18-85 years, clinically and paraclinically investigated, especially for the osteoarthritis of the hip, admitted to Rheumatology Clinic I, Rehabilitation Hospital in Iasi, from January 2012 to December 2014. RESULTS AND DISCUSSION: The high prevalence of degenerative diseases of the joints in old age is analyzed in accordance with the results of the estimations, which showed that, in fact, most of the patients remain undetected, undiagnosed and untreated. Main symptoms are pain in the coxofemoral joint, radiating or not on the lateral or anterior face of the thigh down to the knee, morning stiffness after a long rest, limping or walking with small steps, and muscle atrophy of the group of muscles that are responsible for the stability of the joint. CONCLUSIONS: A strict discipline is needed from the patient's side, in order to keep and apply the doctor's indications in a chronic disease that requires a long therapy, on one hand; on the other hand, a close cooperation between various experts is needed, in order to customize and apply the most effective program, at the right time. PMID- 27483706 TI - CORTICOSTEROID TREATMENT IN THE SETTING OF DECOMPENSATED LIVER CIRRHOSIS WITH RELATIVE ADRENAL INSUFFICIENCY: A CASE REPORT AND A BRIEF REVIEW OF THE LITERATURE. AB - Relative adrenal insufficiency (RAI) is the term used to describe inadequate production or action of glucocorticoids with respect to the severity of the illness. RAI is frequently found in critically ill patients particularly with septic complications and it is also present in both critically ill and stable patients with liver cirrhosis. In the following study a case report of a patient with decompensated cirrhosis and RAI is presented followed by a brief review of the literature. A 65-year-old male with liver cirrhosis of alcoholic etiology was admitted to hospital with bilateral leg edema, ascites, and marked weakness. At admission, his blood pressure was 82/52 mmHg and he had sinus tachycardia of 130/min. Laboratory analysis revealed hyponatremia (122 mmol/L), while ascites fluid analysis showed no infection. During the first 48 hours of hospitalization the patient remained persistently hypotensive despite adequate vascular filling and the addition of noradrenaline. A standard-dose short synacthen test was performed which revealed a poor cortisol response, which is a compatible criterion for the diagnosis of RAI. Intravenous hydrocortisone therapy was initiated, which resulted in a rapid improvement in patient's general condition, and increase in blood pressure. As the patient became hemodynamically stable without the need of noradrenaline, the hydrocortisone dose was weaned progressively, and he was discharged after 18 days of hospitalization in a stable condition. PMID- 27483705 TI - EXTRADIGESTIVE MANIFESTATIONS OF GASTROESOPHAGEAL REFLUX DISEASE: DEMOGRAPHIC, CLINICAL, BIOLOGICAL AND ENDOSCOPIC FEATURES. AB - Gastroesophageal reflux disease (GERD) with extradigestive manifestations is a disorder increasingly recognized both by gastroenterologists, pneumologists, otolaryngologists and cardiologists. AIM: To evaluate the demographical, clinical, biological and endoscopic features of the patients with gastroesophageal reflux disease and extradigestive manifestations (chronic laryngitis, asthma, pseudoangina). MATERIAL AND METHODS: Prospective case-control study, including 137 patients selected from patients referred to the Iasi Institute of Gastroenterology and Hepatology between July 2014-September 2015. In the presence of typical GERD symptoms (heartburn or regurgitation), the patients were assessed by upper digestive endoscopy for the detection or exclusion of esophagitis. Despite the absence of esophageal lesions, the patients were further assessed by impedance-pHmetry. RESULTS: Depending on the dominant extradigestive manifestation, the patients were assigned into 3 groups: 94 chronic laryngitis patients, 24 asthma patients and 19 pseudoangina patients. Females were more frequent among pseudoangina patients (68.4%). Mean age of the male patients with dysphonia or asthma was lower (p=0.002), the majority (78.1%) living in urban areas. Obesity was predominant in pseudoangina group (52.6%), as compared to dysphonia group (16%) the differences being statistically significant (p=0.002). A share of 57.9% of pseudoangina patients were dyslipidemic, in contrast to dysphonia (24.5%) or asthma group (37.5%) (p=0.013). Esophagitis was also more frequent at pseudoangina group (84.2%), but with no significant statistical difference between the study groups (79.8% and 75%, respectively) (p=0.115). It seems that Helicobacterpylori infection tends to be protective in patients with GERD and pseudoangina (RR=0.61), but it can not be extrapolated to the general population (p=0.459). CONCLUSION: GERD with extradigestive manifestations is a prevalent and heterogeneous disease. There are demographic, clinical, biological and endoscopic differences between patiens with extradigestive GERD. PMID- 27483707 TI - THE "DARK SIDE" OF DEEP VEIN THROMBOSIS--CASE REPORT. AB - Venous thromboembolism (VTE) is an increasingly common cause of morbidity and mortality in cancer patients. In various malignancies the incidence of thrombosis ranges from 5% to 60%, that is four times higher in cancer patients compared to the general population. Large retrospective studies have shown that in men the tumors which are most commonly associated with VTE are lung cancer and pancreatic cancer and, in women cancer of the genital area, pancreas, colon and rectum. Thromboembolic events may often occur before the cancer diagnosis. We present the case of a 41-year-old female patient with a history of genital cancer which was surgically treated and who is now admitted for clinical signs of ileofemoral deep vein thrombosis (DVT) of the left leg. The diagnosis was confirmed by laboratory data and Doppler ultrasound and the patient received anticoagulant treatment. Given the history of the patient, abdominal and pelvic ultrasound and computer tomography (CT) were performed to detect the cause who predisposed to the thrombotic event. These confirmed the ovarian cancer, this time on the right side, and the presence of hepatic and pulmonary metastasis. This case highlights the importance of screening for a cause of the thromboembolic event in patients, especially in those who have a history of a neoplasia. PMID- 27483708 TI - NEUROPSYCHOLOGICAL GROUNDS IN THE AWAKE BRAIN SURGERY. AB - Traditionally, the awake cerebral neurosurgical interventions are carried out when the primary motor areas and the areas involved in language are concerned. This procedure is also known as mapping (Intraoperative Brain Mapping). The intraoperative neuropsychological protocol supposes the setting of a list of steps and tasks that the patient must perform during the surgery, taking into account the lesion localization (both the cortical and the subcortical structures), the cognitive functions involved and the individual particularities of each patient. As a result of the high validity of certain tests, we propose a common minimal set of tests, which can allow a minimal standardization and replicability. PMID- 27483709 TI - VENOUS ULCER--A NEW THERAPEUTIC APPROACH. AB - Trophic leg ulcer is a major health problem affecting approximately 1-2% of the population, the incidence being higher in the elderly (70-80 years). It is a multifactorial condition, but the most common cause is chronic venous insufficiency. This can be attributed to reflux in the saphenous system and calf perforator vein incompetence. These were first described by Linton, the first intervention designed to correct perforator vein incompetence bearing his name. Today Linton's operation has been abandoned due to the large unaesthetic incision and great postoperative pain. Also, ulcer healing time is long (2 months) and recurrence rate is high. Currently a series of minimally invasive procedures are used to close these perforator veins, such as ultrasound-guided sclerotherapy. The advantages of these techniques are less discomfort to the patients, low rate of complications, short hospital stay. PMID- 27483710 TI - CLASIC VERSUS NOVEL IN REDUCTION OF ACUTE ANTERIOR DISLOCATION OF THE SHOULDER: A COMPARISON OF FOUR REDUCTION TECHNIQUES. AB - AIM: The purpose of our study is to compare four different techniques for reduction shoulder dislocation in term of efficacy, duration until reduction and pain felt by patient during the procedure. MATERIAL AND METHODS: During 2015 year, we conducted a study on 50 chronological patients with anterior shoulder dislocation. After exclusion of four patients, the remaining 46 (74% males, mean age 44.6 +/- 20.03 years, range 18 to 89) were randomly assigned in four groups and reduced by Cunningham (C), Kocher (K), Mothes (M) and Hipocrat (H) techniques. All the patients were sedated using Midazolam (2 mg) and Fentanyl (1 microg/kgbw) except patients who underwent Cunningham technique. RESULTS: The success rate was 76.9% in C group, 98.4% in K group, 90.2% in M group and 87.96% in H group (p>0.05). The level of pain in C group was similar to the other groups in the absence of pain medication (p<0.05). CONCLUSIONS: Cunningham technique is a simple, single person technique, drug free, less painful and safer, comparable with other "classical" methods. PMID- 27483711 TI - BILATERAL BREAST CANCER: DIAGNOSIS AND PROGNOSIS. AB - AIM: To assess bilateral breast cancer patients, initially diagnosed with stage II unilateral breast cancer. MATERIAL AND METHODS: 113 patients with stage 0-II breast cancer diagnosed between 1983 and 2011 were assessed. Of these, 8 patients had bilateral breast cancer: 7 patients with metachronous bilateral breast cancer and 1 patient with synchronous breast cancer. Breast ultrasound, mammography, computed tomography and magnetic resonance imaging were used to diagnose recurrence, loco regional and distant metastasis. RESULTS: Age at diagnosis ranged from 37 to 59 years, with a maximum age incidence in the 4th decade (age between: 31-40 years). The average time interval between the two breast cancers was 8.125 years. The most common histological type was invasive ductal carcinoma. All eight patients with bilateral breast cancer had at least one type of recurrence/metastasis, mostly in the liver, and statistically the pleuropulmonary and liver metastases were the most frequent causes of death. CONCLUSIONS: Patients in the 4th decade diagnosed with unilateral breast cancer are at risk of developing bilateral breast cancer. In metachronous breast cancer, the time interval between the detection of the second breast cancer and death is directly proportional to the time interval between the two breast cancers. TASTASES, DEATH. PMID- 27483712 TI - COMPARISONS BETWEEN THE NON-PROLIFERATIVE AND PROLIFERATIVE THERAPY IN FIBROCYSTIC MASTOSIS. AB - AIM: Fibrocystic mastosis (FCM) is the most frequent benign breast lesion. Most treatments for fibrocystic mastosis are: hormonl, with beneficial results and non hormonal, with fluctuating results. MATERIAL AND METHODS: A number of 210 cases were studied, which were divided into 7 groups. The study lasted for 9 months and it was carried out on the basis of a personal examination sheet. The following were monitored: age groups, mastodynia, reducing breast nodules, a significant reduction in the volume of the mastosic cysts, reducion of the fibrous tissue, medication tolerance. RESULTS: Mastodynia has declined by 90% in the cases treated with Tamoxifen and Danazol, by 70% in the case of Lynestrenol and Bromocriptine, by 50% in the 15 patients who were given Utrogestan. Knowing the advantages and disadvantages of drugs (contraindications, side effects), age category, breast pain reduction, antiproliferative activity, tolerability, relapse allow us to assess the benefit-risk. Even in those circumstances that remained incompletely clarified for objective reasons, related to the inaccurate/incorrect reporting by the patients, there is a significant difference (p < 0.05) between the frequency of relapses following the treatment with Tamoxifen and the other categories of drugs who were administered. CONCLUSIONS: Our study shows that in the groups that were administered Logest, Utrogestan and Bromocriptine, only antalgic effects were achieved (disappearance or only decrease of mastodynia) and no anti-proliferative effects were obtained. Basically, hormone treatment should be made based on a histopathological examination. PMID- 27483713 TI - OUTCOMES OF SURGERY IN PROLIFERATIVE VITREORETINOPATHY. AB - AIM: To present the anatomical and functional outcomes of surgery in cases of rhegmatogenous retinal detachment complicated (at presentation) by proliferative vitreoretinopathy (PVR). MATERIAL AND METHODS: Retrospective study of the cases operated upon by a single surgeon between October 2012 and September 2014. RESULTS: A total of 49 eyes of 49 patients had PVR at presentation (12 cases with PVR stage B, 21 with stage C and 16 with stage D). 82% had a VA < or = 0.05 at presentation. Peripheral retinectomy was the primary surgery in 57% of cases. Reinterventions was required in 16.3% of the cases (silicon oil extraction was not considered reintervention). Although at the first postoperative examination 32% of eyes had an IOP > 21 mmHg without medication, only 8% retained a high lOP at the last visit. At the last visit 73.4% of eyes presented attached retina (an additional 6% had an attached macula under silicone oil, but sub retinal fluid in the inferior quadrants). A final VA > or = 0.05 was recorded in 67.3% of eyes (of which half had VA > or = 0.1) CONCLUSIONS: In cases presenting with retinal detachment complicated by PVR the possibility of reinterventions and the risk of intraocular hypertension should be considered. Unfortunately, even some cases with favorable anatomical outcome will not present ambulatory vision. Keywords: PMID- 27483714 TI - EARLY COMPLICATIONS FOLLOWING ANATOMIC LUNG RESECTIONS--EXPERIENCE OF A THORACIC SURGICAL ONCOLOGY UNIT. AB - AIM: To analyze the medical and socioeconomic impact of the complications of anatomic lung resections performed at the Thoracic Surgery Unit of the Iasi Regional Cancer Institute. METHODS: This retrospective study included patients who underwent anatomic lung resections between January 2013 and August 2015. RESULTS: Over this interval a total of 172 major lung resections were performed: 31 (18.02%) pneumonectomies, 5 (2.91%) bilobectomies, and 136 (79.06%) lobectomies. Complications occurred in 36 patients, including bronchial stump fistula in 7 patients (4.06%), bronchopneumonia (9/5.23%), pleural empyema without bronchoscopically documented bronchial stump fistula (1/0.58%), chylothorax (1/0.58%), postoperative arrhythmia (3/1.74%), early postoperative stroke (1/0.58%), prolonged air leak (requiring hospital stay longer than 14 days) (11/6.38%), and postoperative hemothorax requiring reintervention (3/1.74%). Secondary to complications, a number of 3 (1.74%) patients died early postoperatively. CONCLUSIONS: The incidence of immediate and early postoperative complications is comparable to those reported by other authors. PMID- 27483715 TI - INFLUENCE OF GLAUCOMA ON DIABETES-INDUCED CHANGES IN THE ANTERIOR OCULAR SEGMENT. AB - AIM: To monitor the influence of glaucoma on the changes caused by diabetes in the anterior ocular segment. MATERIAL AND METHODS: Prospective, comparative clinical study, which included the patients with glaucoma and diabetes assessed at the Iasi "Sf. Spiridon" Hospital, "Euro Medi Center" Clinic and "Oftaprof" Clinic. The study included a number of 142 patients, divided into two groups: 67 patients with glaucoma and diabetes (study group) and 75 patients with diabetes mellitus (control group). Upon enrollment the patients were subjected to a complete assessment of their ophthalmologic and metabolic status. Monitored aspects: prevalence of lens changes, extent of ocular surface disease and identification of the changes in corneal biomechanical parameters in the patients with glaucoma and diabetes. RESULTS: In both monitored groups, the cortical lens changes prevailed, both at the beginning and at the end of the study, with no statistically significant differences between groups (p>0.05). The risk of developing lens changes reaches 50% in the patients who have had diabetes for 20 years. In the patients in the study group, tear secretion was significantly lower at the end of the study (Schirmer's test values 11.61 vs. 10.67 mm, p=0.045). Tear film instability was present in 37.3% of the patients. Corneal hysteresis (CH) and comeal resistance factor were significantly reduced in the group with glaucoma and diabetes, as compared to the group with diabetes (p=0.001). CONCLUSIONS: There is significant ocular surface disease in the patients with glaucoma and diabetes, as compared to those with diabetes alone. Glaucoma and the number of antiglaucoma drugs are associated with a significant reduction in tear secretion. The association of glaucoma resulted in the reduction in CH and corneal resistance factor in the patients with glaucoma and diabetes as compared to the healthy ones. PMID- 27483716 TI - LEFT ATRIAL, LEFT ATRIAL APPENDAGE AND PULMONARY VEINS ANATOMICAL VARIANTS IN PATIENTS WITH ATRIAL FIBRILLATION VERSUS PATIENTS IN SINUS RHYTHM. AB - The aim of the study is to evaluate by multidetector computed tomography (MDCT) the prevalence, location and size of LA (left atrial) diverticula and accessory appendages, the prevalence of PVs anatomical variants and LAA (left atrial appendage) shapes in patients with atrial fibrillation (AF) compared to patients in sinus rhythm (SR). Images obtained by MDCT in a group of 100 patients with <1 year paroxysmal or persistent AF prior to radiofrequency catheter ablation and in a group of 100 patients in SR with unconfirmed or insignificant (<50%) coronary arteries stenoses were compared. The prevalence of LA diverticula (22% in AF group, 19% in SR group) and accessory appendages (6% in AF group, 5% in SR group) was not significantly different between the two groups. Similar sizes of LA diverticula and accessory appendages were registered in patients with AF and in SR. The prevalence of a common left venous trunk was significantly higher in patients with AF (30%) compared to patients in SR (18%) (p=0.047) and proved to be an independent predictor for AF (odds ratio (OR) 1.32; 95% confidence interval (CI) 0.93-1.51; p=0.002) at multivariate logistic regression. LAA had a complex shape but no significant differences concerning the prevalence of the 4 major types were registered between the groups. In conclusion, the only parameter associated with AF was the presence of a left common trunk suggesting that it is either a consequence or a predisposing factor for the development of AF. PMID- 27483717 TI - IMMUNOHISTOCHEMISTRY IN ENDOMETRIAL HYPERPLASIA AND ENDOMETRIAL ADENOCARCINOMA. AB - AIM: Endometrial hyperplasia is a proliferation of endometrial glands due to the prolonged stimulation with estrogens of the endometrium that occurs in women receiving exogenous estrogens, with anovulatory cycles, or in patients with ovarian tumours with estrogen secretion. MATERIAL AND METHODS: The study performed by the authors included 575 patients with endometrial hyperplasia and 163 patients with endometrial adenocarcinoma admitted to the "Cuza-Voda" Obstetrics and Gynaecology Clinical Hospital of Iasi, between 2005-2007. RESULTS: There were selected, for these immunohistochemistry reactions, 22 cases of simple hyperplasia without atypia, 26 cases of complex hyperplasia without atypia, 23 cases of endometrial adenocarcinoma of endometrioid type, well differentiated, 22 cases of endometrial adenocarcinoma of endometrioid type, moderately differentiated, and 19 cases of non-endometrioid adenocarcinomas represented by nine clear cells and 10 serous endometrial adenocarcinomas. Estrogen receptors have been positive in about 85-90% of the tumour cells of the well-differentiated endometrial adenocarcinomas of endometrioid type (GI). In endometrioid-type endometrial adenocarcinomas moderately differentiated (GII), the estrogen receptors were positive in approximately 70-85% of the tumour cells. CONCLUSIONS: Endometrial hyperplasia, especially complex endometrial hyperplasia with atypia, increase the risk for endometrial adenocarcinoma, and their early detection becomes mandatory under cancer prevention. Well-differentiated endometrioid endome- trial adenocarcinomas were ER and PR-positive, so that the ER expression correlated with the PR expression. Well-differentiated endometrioid endometrial adenocarcinomas (GI) in the studied group also showed a higher content of ER and PR compared to the endometrial moderately-differentiated endometrioid endometrial adenocarcinomas (GII). In nonendometrioid adenocarcinomas, represented by clear cell endometrial adenocarcinomas, the ER content was reduced and the PR expression was negative. Serous adenocarcinomas failed to show an immunohistochemically expression for ER and PR. PMID- 27483718 TI - THE RELEVANCE OF CYTOLOGICAL DIAGNOSTIC IN THE MAMMARY GLAND CANCER. AB - Breast cancer is the second leading cause of cancer death in women, while in Eastern Europe the most common form of diagnosed cancer. Out of the multiple possibilities of early detection of mammary neoplasia that have been elaborated, only mammography has proved to be a simple, efficient method and of a high sensitivity, almost 90% However, the cytological confirmation of diagnosis allows us to perform the preoperative radiotherapy treatment or poly chemotherapy. MATERIAL AND METHODS: we analyzed the informative value of these diagnosis methods in stage I mammary gland cancer (MGC). In this way, in the present paper we demonstrated that collecting samples through fine-needle aspiration biopsy allows the cytological confirmation of the diagnosis of stage I MGC in 30.7% cases. RESULTS AND DISCUSSION: In stage I MGC young patients, under 35 years, the cytological confirmation rate is 22.2% and is lower as compared to the cytological confirmation rate in patients older than 35 years which is 37.9% Also, for a tumor diameter < 0.5 cm, the prevalence of cytological confirmation was only 10.3%, while for the diameter of 0.6-1.0 cm the cytological confirmation was around 40.0%. Therefore, in order to improve the cytological diagnosis confirmation rate the tumor biopsy through the USG of the mammary glands is required. Moreover, the cytological investigation of the smear obtained by the first and second puncture was instrumental in confirming the diagnosis in 41.3% and 17.4% cases; the subsequent repetition of the punctures was not useful as it helped to confirmation of the diagnosis only in 9.3% cases. The frequency of diagnosis cytological confirmation depends on the tumor histopathological form and type of growth. CONCLUSIONS: Thus, the lowest prevalence was in the mixed forms--12.5% cases, lobular cancer--24.4% cases, while regarding the type of growth, for the rare forms the cytological confirmation rate was 7.7% and 31.5% cases for the schiros growth type. PMID- 27483719 TI - PANCREATIC CANCER CT IMAGING: COMPARISON WITH SURGERY. AB - AIM: To establish the best protocol for pancreatic computer tomography and criteria for staging (mainly for vascular invasion). MATERIAL AND METHODS: Our research included 49 consecutive patients with pancreatic cancer examined at the Iasi "Sf. Spiridon" Hospital between January and December 2014 with a Siemens 16 Emotion CT unit. CT protocol included no enhanced CT and pancreatic phase of the superior abdomen, portal venous phase of the abdomen and pelvis. RESULTS AND DISCUSSION: The study patients were stratified into 5 age groups and the most frequently affected by pancreatic cancer were the patients aged 60 to 79 years. For T staging the extension in the per pancreatic fat tissue, into surrounding organs (5 patients had extension in other organs) and vessels was evaluated. We determined the degree of contact between the tumor and the artery, thrombosis and deformity of the veins and we have found 8 resettable lesions, 28 tumors in stage T3 and 13 pancreatic cancers in stage T4. Thirty-three patients had lymphadenopathies and 31 of them had distant metastases. CONCLUSIONS: Our study proved that computed tomography is a good method of examination for pancreatic cancer when the right imaging protocol is used; during the pancreatic phase the arteries and the tumor are well depicted, liver metastases are best evaluated during the portal venous phase. The best criterion for arterial invasion is tumor contiguity with more than half of vessel circumference, and for vein invasion deformity or thrombosis. Comparison with surgical staging was o good backup for the radiologist and depicted several differences with imaging staging, more often understating than over staging. PMID- 27483720 TI - MANAGEMENT OF BILATERAL FEMORAL NECK FRACTURE IN A NONAGENARIAN PATIENT--CASE REPORT. AB - Simultaneous bilateral femoral neck fracture is rare injury. Cases with this type of fracture have been reported in the literature since the 1950s, following the introduction of electroconvulsive therapy which generates violent hip muscle contractions. In young patients' simultaneous bilateral femoral neck fracture results from high energy trauma (car accident or fall from height) in a normal bone. Pathological changes in bone structure occurring in chronic kidney disease, vitamin D deficiency, osteomalacia, osteoporosis, metabolic imbalances and administration of corticosteroids explain the occurrence of this particular type of fracture following low-energy trauma. We present the case of a 90-year-old female patient who suffered a simple fall from her own height resulting in a Garden IV bilateral femoral neck fracture. Our therapeutic option in this patient was bilateral uncemented bipolar hemiarthroplasty in a single session using a single tray of sterile surgical instruments and two sterile drapes. Postoperative outcome was very good, allowing the initiation of functional recovery on the first postoperative day. Uncemented hemiarthroplasty proved to be a good choice in such a patient in the associated diseases may trigger the risk of cardiovascular disturbances specific to bone cement implantation syndrome. PMID- 27483721 TI - COMBINED APPROACH FOR LARGE TUMORS OF THE NOSE AND PARANASAL SINUSES--CASE REPORT. AB - Due to the insidious onset and common symptoms, the diagnostic of sinonasal tumors is late in the evolution. Usually, at that time, the preferred endoscopic approach alone is not recommended, therefore a mixed openendoscopic approach appears to be the best choice in terms of exposure of the tumor and a clear margin resection. The purpose of this case report study is to demonstrate the necessity of careful preoperative assessment and the advantages of combined approach for a complete resection and favorable long-term results. PMID- 27483722 TI - SURGICAL TREATMENT OF POSTPARTUM ILIOFEMORAL DEEP VEIN THROMBOSIS--CASE REPORTS. AB - The writing committee for Antithrombotic Therapy for Venous Thromboembolic Disease of the 2008 ACCP guidelines made the following recommendations for thrombus removal strategies in patients with deep vein thrombosis (DVT): open surgical thrombectomy is recommended in patients with acute iliofemoral DVT to reduce symptoms and post-thrombotic morbidity; whenever available, catheter directed thrombolysis is preferred to surgical venous thrombectomy, the risk of hemorrhage being diminished; surgical venous thrombectomy is recognized to be efficient in cases where catheter-directed thrombolysis is unavailable or the patients are not suitable candidates for such a procedure. Randomized studies comparing surgical thrombectomy and anticoagulant therapy in patients with iliofemoral DVT (IFDVT) showed that at 6 months, 5 years, and 10 years the patients in the thrombectomy group presented increased permeability, lower venous pressure, less edema, and fewer postthrombotic symptoms compared to the patients receiving anticoagulant therapy. In this article we present 3 cases of IFDVT in postpartum patients diagnosed by Doppler ultrasound of the deep venous system. The 3 patients received anticoagulant therapy prior to surgery. Surgery consisted in thrombectomy of the common, superficial and deep femoral veins, external and internal iliac veins, and femoral-saphenous arteriovenous fistula. The patients received postoperative antithrombotic therapy and were followed-up at 3, 6 and 9 months by Doppler ultrasound of the deep venous system. PMID- 27483723 TI - ADENOCARCINOMA AND TUBERCULOSIS OF THE SIGMOID COLON AND FALLOPIAN TUBE--A RARE ASSOCIATION. A CASE REPORT AND REVIEW OF THE LITERATURE. AB - Association of adenocarcinoma and tuberculosis (TB) of the sigmoid colon is a rare clinical condition even in an endemic country as Romania, with challenging diagnosis and treatment. Case report. We present the case of a 57-year-old female patient who was admitted on emergency basis for a diagnosis of obstructive sigmoid adenocarcinoma. The patient was operated on and it an obstructive sigmoid tumor with serosal invasion, adherent (invading) to the body of uterus and left adnexa and urinary bladder serosa, no liver or peritoneal metastases. A sigmoidectomy was performed "en bloc" with subtotal hysterectomy, left adnexectomy and extramucosal cistectomy. The histopathological exam showed a moderately differentiated, ulcerated adenocarcinoma, widely infiltrating the colon wall invading the myometrium. Ziehl Neelsen (ZN) stain identified the presence of metachromatic bacillary structures in the colonic wall, lymph nodes and adnexal areas. Postoperative course was uneventful and the patient was discharged 10 days postoperatively in good clinical condition. After one year when the patient completed the full course of anti-tubercular drugs, a thorough work-up was performed. Colonoscopy, CT of the thorax, abdomen, pelvis showed no signs of recurrence while tumoral marker CEA (1.62 ng/ml - n<3.4) and QFT (Quantiferon-TB Gold) test were within normal range. Discussion and conclusion. Although digestive tuberculosis is included in differential diagnosis for those patients presenting abdominal pain or obstructive digestive symptoms in endemic regions, in this case the absence of TB infection criteria and positive endoscopic biopsy for colonic adenocarcinoma did not allow a complete pre- or perioperative diagnosis. PMID- 27483724 TI - PELVIC ACTINOMYCOSIS MIMICKING A LOCALLY ADVANCED PELVIC MALIGNANCY--CASE REPORT. AB - We present the case of a former user of an intrauterine contraceptive device (IUD) for 10 years, diagnosed with a bulky, fixed pelvic tumor involving the internal genital organs and the recto sigmoid, causing luminal narrowing of the rectum, interpreted as locally advanced pelvic malignancy, probably of genital origin. Intraoperatively, a high index of suspicion made us collect a sample from the fibrous wall of the tumor mass, large Actinomyces colonies were thus identified. Surgery consisted in debridement, removal of a small amount of pus and appendectomy, thus avoiding a mutilating and useless surgery. Specific antibiotic therapy was administered for 3 months, with favorable postoperative and long-term outcomes. Pelvic actinomycosis should always be considered in the differential diagnosis of pelvic tumors in women using an IUD. The association of long-term antibiotic treatment is essential to eradicate the infection and prevent relapses. PMID- 27483725 TI - MITOCHONDRIAL MYOPATHY: A NEW THERAPEUTIC APPROACH. AB - Restoration of deoxyribonucleic acid in mitochondrial myopathies may occur after a mechanical or chemical injury of striated muscle or by endurance training. Therapies with enzymes, gene therapies, or treatments with substances that stimulate mitochondrial biogenesis are used at the moment. Genesis of mitochondria may also come from myonuclei by releasing the nuclear respiratory factor-1/2 during muscle contractions. Multiplying of myonuclei depends on muscle satellite cell activation. Since the electromyostimulation increase the number of circulating stem cells that may participate in the genesis of new muscle fibers (adding to the deposit of specific stem cells of the muscle), and intermittent hypoxia stimulates the proliferation of muscle satellite cells, we propose to combine the two processes for the treatment of mitochondrial myopathies. Respective combined therapy may be useful for restoring damaged mitochondria by drug side effects. PMID- 27483726 TI - VITAMIN D AND TISSULAR EXPRESSION OF VITAMIN D RECEPTOR IN OBESITY. AB - Vitamin D (VitD), a lipid-soluble hormone, is able to regulate the transcription of many genes through vitamin D receptor (vitD receptor-VDR). It has been shown that VitD deficiency is associated with obesity, characterized by a low degree inflammatory state, which contribute to the pathogeny of metabolic syndrome and type 2 diabetes mellitus. VitD deficiency is a public health problem, at the same time the global prevalence of obesity and cardiovascular diseases is continuously growing. Evidence from recent studies on animal models suggest that VitD or VDR deficiency promotes cardiomyocyte hypertrophy, which can be one of the mechanisms for increasing cardiovascular risk. The heart is one of the target organs of action for VitD, because VDR is expressed in cardiomyocytes. Also, previous in vitro studies have shown that VitD is able to inhibit the production of monocyte chemotactic factors (MCP-1) and other pro-inflammatory mediators in human preadipocytes and mature adipocytes. Inflammation is an important factor in the pathogenesis of atherosclerosis. In obesity there are not known data about correlations between plasma levels of VitD and VDR expression in the subcutaneous fat tissue, epicardial visceral adipose tissue, and in particular in myocardium. Also, there are still no studies to test VDR expression in myocardial cells and to investigate the results of dietary VitD supplementation on the expression of VDR in the epicardial adipose tissue and myocardium. PMID- 27483727 TI - CONSIDERATIONS ON ANATOMY AND PHYSIOLOGY OF LYMPH VESSELS OF UPPER AERO DIGESTIVE ORGANS AND CERVICAL SATELLITE LYMPH NODE GROUP. AB - The almost constant local regional development of the cancers of upper aero digestive organs requires the same special attention to cervical lymph node metastases, as well as to the primary neoplastic burning point. The surgical therapy alone or associated has a mutilating, damaging character, resulting in loss of an organ and function, most of the times with social implications, involving physical distortions with aesthetic consequences, which make the reintegration of the individual into society questionable. The problem of cervical lymph node metastases is vast and complex, reason why we approached several anatomical and physiological aspects of lymph vessels of the aero digestive organs. Among the available elements during treatment, the headquarters of the tumour, its histologic degree, and its infiltrative nature, each of them significantly influences the possibility of developing metastases. PMID- 27483728 TI - STRESS IN PEDIATRIC PATIENTS--THE EFFECT OF PROLONGED HOSPITALIZATION. AB - Long-term hospitalization emotionally impacts any patient, especially children, and is defined as a long period of time during which the patient is hospitalized and experiences isolation from his or her family, friends and home. Stressful situations trigger a nonspecific response that involves multiple physiological mechanisms. Currently, because of the complexity of these mechanisms, there are no laboratory markers that allow the quantification of the stress intensity felt by the patient. Laboratory determinations currently used in evaluating the response to stress are neuroendocrine, immunological and metabolic. The neuroendocrine system is the first to respond to stressful events. Stress stimulates the hypothalamus, leading to the release of CRH, which stimulates the pituitary gland to produce ACTH. Chronic stress directs the synthesis towards cortisol, which may lead to hypo secretion of the other adrenal steroid hormones. The hospital and the disease are stressors for children and caregivers, since stress can interfere with the normal development of young patients, affecting them in the long term. Admitting a child to hospital means interrupting his or her normal daily life and changing the environment that is familiar to him or her. Therefore, the involvement of the family doctor is very important, as many conditions can be solved by visiting his or her office and thus eliminating the need for hospitalization in a pediatric hospital. If, however, the nature of the condition requires that the child should be seen by a pediatrician, the period of hospitalization should not be much extended so as to prevent the appearance of other possible problems that might influence the child's state. PMID- 27483729 TI - EPIDEMIOLOGIC RESEARCH REGARDING THE IMPACT OF RISK FACTORS ON HEALTH-RELEATED QUALITY OF LIFE IN CANCER PATIENTS. AB - AIM: To assess the health-related quality of life in cancer patients and the relative and attributable risks for the degree of dissatisfaction related to intrinsic and extrinsic factors. MATERIAL AND METHODS: Our research included 128 cancer patients treated at the Surgical Clinic II of the Iasi Regional Cancer Institute between December 2014 and June 2015. Thus, data were collected by using an inquiry sheet derived from the SF-36 questionnaire, which included closed and open questions about the quality of life, socioemographic data and such risk factors as smoking, alcohol use, related diseases and risk behaviours. Results: The patient sample had a mean age of 60.85 years, 51.6% of them lived in urban areas, were high school graduates, and of low economic status. DISCUSSION: As to the behavioural risk factors we found that over 80% of the patients were non smokers, did not use alcohol, and were normal weighted. Pain was experienced by 70.7% of the cancer patients and depression affected 74% of the study cases. Patients were asked to self-assess their own health status on a scale of 0 (worst) to 100 (the best health status). CONCLUSIONS: Our study showed a poor health status (mean score 65) in the study cancer patients. The relative and attributable risks for the degree of dissatisfaction related to intrinsic and extrinsic factors were calculated and ranked factors in decreasing order: smoking, depression, pain, alcohol use, male gender, obesity, low income. We found that prolonged'suffering affects the psyche and causes depression and that the patients of low financial status, most of them living in villages, have difficulty in accessing medical care. The obtained data about the quality of life in relation with risk factors are in agreement with the data in the literature. PMID- 27483730 TI - ALCOHOL CONSUMPTION WITH FAMILY PATTERN RELATED TO STRONG PERSONALITIES: A CASE CONTROL STUDY IN MARRIED ROMANIAN STUDENTS. AB - In the study conducted the aim was to investigate strong personalities (SP) related to alcohol consumption in married students from Romania. MATERIAL OF STUDY: Consisted in 2 samples: a case-sample (23 alcohol consumer students with a family pattern of weekly consumption, 47.8% male and 52.2% female, aged 21-29 years) and a control-sample (42 no-alcohol consumer students without a family pattern of consumption, 26.2% male and 73.8% female, aged 21-29 years), selected from a sample of 176 married students. METHOD: An observational inquiry (case control) consisted in applying 2 questionnaires: Health Questionnaire (60 items, 7: Q43-Q49 -alcohol consumption) and Strong Personalities Questionnaire (88 items, alpha-Crohnbach index-0.823). Statistical analysis was performed by the aid of SPSS 20 Program. RESULTS: For alcohol consumer students with weekly pattern of consumption the main reason of alcohol consumption was curiosity (60.9%) and the most frequent consumed alcohol was beer (38.6%, 500-3000 ml/week). Personalities' profiles revealed V-hyperthymic, III-hyperperseverant and X-emotive strong personalities (SP) as being symptomatic (over 50% symptomatic level-SL) for both samples, with a difference (control-case) for X emotive SP (71.7% students--57.1% students, respectively). I-demonstrative, VII cyclothymic and IV-unruly SP presented a difference between case (symptomatic: 61.8%; 61.8% and 61.8% students, respectively) and control (symptomatic: 36.8%; 37.5% and 45% students, respectively) samples. A statistically significant difference case-control samples was demonstrated for I-Demonstrative (item S29: chi square chi2 = 10.65; Sig.0.002; gamma correlation gamma=0.73; Sig.0.002) and for X-emotive (item S25: chi2 = 8.76; gamma = -0.66; Sig.0.003) SP. In conclusion, a relation SP-alcohol consumption in married students is suggested. PMID- 27483731 TI - EVALUATION OF THE SYNTHESIS AND STRUCTURE OF NEW AZETIDIN-2-ONES OF FERULIC ACID. AB - AIM: To synthesize some new azetidin-2-ones of ferulic acid and to evaluate them from physicochemical and spectral point of view. MATERIAL AND METHODS: The synthesis was carried out in several steps: (i) obtaining the ferulic acid chloride; (ii) obtaining the ferulic acid hydrazide with hydrazine hydrate (98%); (iii) condensation of ferulic acid hydrazide with different benzaldehydes (2 hydroxy-/2-nitro-/4-chloro-/4- fluoro-/4-bromo-benzaldehyde) in order to obtain the corresponding hydrazones; (iv) cy- clization of ferulic acid hydrazones with chloroacethyl chloride in freshly distilled toluene medium and in the presence of triethylamine, resulting in the corresponding azetidin-2-ones. RESULTS: Six new azetidin-2-ones of ferulic acid were synthesized. They were characterized in terms of their physicochemical properties and their structure was confirmed by IR and 1H-NMR spectroscopy. CONCLUSIONS: Six new azetidin-2-ones of ferulic acid were synthesized, physicochemically characterized and validated spectrally. A PMID- 27483732 TI - EVALUATION OF ANTIOXIDANT ACTIVITY OF SOME IMINES DERIVATIVES OF L-ARGININE. AB - L-Arginine is an a-amino acid which plays important roles in different diseases or processes, such as Alzheimer disease, inflammatory process, healing and tissue regeneration and it also could be useful as an anti-atherosclerotic agent. AIM: Considering the large amount of studies on the beneficial effects of different antioxidants, this paper is focused on the evaluation of the antioxidant potential of some imine derivatives, synthesized by the authors and described in a previous article. MATERIAL AND METHODS: The evaluation of the antioxidant power was performed using phosphomolydenum-reducing antioxidant power (PRAP) and ferric reducing antioxidant power (FRAP) assays, tests described in the literature and which are used with some minor modifications. RESULTS: It was found that most of the imine derivatives are more active than the L-Arginine in the PPAP and FRAP assays. The most active derivative was the compound obtained by condensation of L arginine with 2,3-dihydroxybenzaldehyde (2k) and 2-nitrobenzaldehyde (2g). CONCLUSIONS: Following the described protocol, some imine derivatives of L arginine were evaluated in terms of antioxidant potential using in vitro methods. The most favorable influence was obtained by the aromatic substitution with nitro and hydroxyl, the corresponding derivatives being the most active derivatives compared to L-arginine. PMID- 27483733 TI - INFLUENCE OF CARBOXYMETHYLCELLULOSE SODIUM AND LUTROL ON THE SWELLING INDEX AND DISINTEGRATION TIME OF BIOMUCOADHESIVE TABLETS WITH MICONAZOLE NITRATE. AB - PURPOSE. To develop original pharmaceutical formulation with miconazole nitrate, biomucoadhesive tablets, used in antifungal medication. MATERIAL AND METHODS: The oral biomucoadhesive tablets with miconazole nitrate were developed by direct compression of the excipient mixture: carboxymethylcellulose sodium and lutrol 6000, excipients used for bioadhesivity, mannitol as a sugar substitute and aerosil as a lubricant. The main goal of the study is to determine the disintegration time and the swelling index of biomucoadhesive tablets with miconazole nitrate in order to estimate the time of contact with mucosa, respectively the prolongation of drug substance release. RESULTS: The swelling index was calculated depending on time in all the 5 formulations that included the carboxymethylcellulose sodium and Lutrol 6000 as matrix-forming, and the studied were time and association ratio between polymers. CONCLUSIONS: Analysing the results, we noticed that out of the four excipients we used, carboxymethylcellulose sodium had the higher influence on the swelling index and disintegration time. PMID- 27483734 TI - IN VITRO MEASUREMENT OF TOTAL ANTIOXIDANT CAPACITY OF CRATAEGUS MACRACANTHA LODD LEAVES. AB - Crataegus macracantha Lodd, family Rosaceae, is a very rare species in Europe, and unlike Crataegus monogyna is less investigated for pharmacologic activity. AIM: To analyze the ability of the lyophilisate of extract obtained from leaves of Crataegus macracantha Lodd (single plant at the Iasi Botanical Garden) to capture free radicals in vitro. MATERIAL AND METHODS: The lyophilisate obtained in Department of Pharmacognosy, Faculty of Pharmacy, "Grigore T. Popa" University of Medicine and Pharmacy Iasi. The decreased absorbance of chromophore chlorpromazine radical cation in the presence of the lyophilized solutions was studied spectrophotometrically. The indicator radical cation, obtained by oxidation of chlorpromazine by potassium persulfate, has the maximum absorbance at 525 nm. Ascorbic acid was used as a standard antioxidant. RESULTS: The absorbance of radical solution was determined after the addition of a certain amount of lyophilisate at different time intervals. The antioxidant activity was calculated using the calibration curve obtained by plotting the variation in radical solution absorbance depending on ascorbic acid concentration. For each ascorbic acid concentration the area under the curve was calculated from plotting the percentage inhibition of the absorbance at two pre-established time intervals. CONCLUSIONS: The results confirm the antioxidant activity of the leaves of Crataegus Macracantha Lodd and by optimizing the proposed analytical methods the antiradical activity can be quickly evaluated with minimal reagent consumption. PMID- 27483735 TI - CATECHINS PROFILE, CAFFEINE CONTENT AND ANTIOXIDANT ACTIVITY OF CAMELLIA SINENSIS TEAS COMMERCIALIZED IN ROMANIA. AB - AIM: Catechins profile, caffeine content and antioxidant activity of different green tea and white tea samples commercialized on the Romanian market were investigated. MATERIAL AND METHODS: Five green tea samples and five white tea samples commonly available on the Romanian market were processed by infusion and the lyophilisates of infusions were analyzed. Total phenolic content was determined using the Folin-Ciocalteu method. Catechins and caffeine profile was analyzed by RP-HPLC-DAD (Agilent Eclipse XDB-C18 column, binary mobile phase (A) 3% acetic acid and (B) methanol). In vitro antioxidant activity was assessed by free radical scavenging and ferrous ion chelating assays. RESULTS AND DISCUSSIONS: Total phenolic content ranged between 44.73 +/- 0.63 and 63.57 +/- 0.45 GAE% in green tea samples and between 9.69 +/- 0.90 and 52.99 +/- 0.45 GAE% in white tea samples. RP-HPLC-DAD analysis allowed the identification of epigallocatechin gallate (45.18-118.58 mg/g lyophilisate) and caffeine (47.79 108.07 mg/g lyophilisate) in all tea samples; epicatechin was detected in all samples (5.04-31.04 mg/g lyophilisate) except for two white teas infusions. Green tea samples scavenged DPPH radical and chelated ferrous ion with EC50=9.68 +/- 0.02-16.11 +/- 0.02 microg/mL and 10.91 +/- 0.04-18.65 +/- 0.03 microg/mL, respectively. For white teas, EC50 values varied between 9.50 +/- 0.02-20.95 +/- 0.02 microg/mL in DPPH assay and 12.49 +/- 0.03-20.32 +/- 0.07 microg/mL in ferrous ion chelating assay. CONCLUSIONS: This study showed a large variability in the content of catechins and caffeine and in the antioxidant capacity of both green and white tea samples. PMID- 27483736 TI - LOW LEVELS OF SERUM CYANOCOBALAMIN IN A METFORMIN-TREATED PATIENT. CASE REPORT AND COMPARISON WITH LITERATURE DATA. AB - Metformin is a widely used oral antidiabetic biguanide compound. According to the literature, metformin may lower the serum cyanocobalamin levels. We present the case of a 71-old-male treated with metformin for 15 years. When presenting to a periodic checkup, low serum cyanocobalamin levels where found. Laboratory tests showed levels below normal range for hemoglobin (12.7 g/dL) and hematocrit (37.8%). After patient reevaluation, a change in antidiabetic treatment will be considered if metformin will be found the cause of low serum cyanocobalamin levels. Other cases reported in the literature support this hypothesis, justifying the study of the influence of metformin therapy on serum vitamin B12 levels in patients diagnosed with diabetes. The influence of patient age, metformin dosage, duration of treatment and time since diabetes diagnosis on serum levels of vitamin B12 also need to be determined. PMID- 27483737 TI - Andrew Herxheimer: his life's work, to be continued. PMID- 27483738 TI - Phonological Encoding in Mandarin Chinese: Evidence from Tongue Twisters. AB - Models of connected speech production in Mandarin Chinese must specify how lexical tone, speech segments, and phrase-level prosody are integrated in speech production. This study used tongue twisters to test predictions of the two different models of word form encoding. Tongue twisters were constructed from 5 sets of characters that rotated pairs of initial segments or pairs of tones, or both, across format (ABAB, ABBA), and across position of the characters in four character tongue twister strings. Fifty two native Mandarin Chinese speakers read aloud 120 tongue twisters, repeating each one six times in a row. They made a total of 3503 (2.34%) segment errors and 1372 (.92%) tone errors. Segment errors occurred on the onsets of the first and third characters in the ABBA but not ABAB segment-alternating tongue twisters, and on the onsets of the second and fourth characters of the tone-alternating tongue twisters. Tone errors were highest on the third and fourth characters in the tone-alternating tongue twisters. The pattern of tone errors is consistent with the claim that tone is associated to a metrical frame prior to segment encoding, while the format by position interaction found for the segment-alternating tongue twisters suggest articulatory gestures oscillate in segment production as proposed by gestural phonology. PMID- 27483739 TI - Tune in to the Tone: Lexical Tone Identification is Associated with Vocabulary and Word Recognition Abilities in Young Chinese Children. AB - Lexical tone is one of the most prominent features in the phonological representation of words in Chinese. However, little, if any, research to date has directly evaluated how young Chinese children's lexical tone identification skills contribute to vocabulary acquisition and character recognition. The present study distinguished lexical tones from segmental phonological awareness and morphological awareness in order to estimate the unique contribution of lexical tone in early vocabulary acquisition and character recognition. A sample of 199 Cantonese children aged 5-6 years was assessed on measures of lexical tone identification, segmental phonological awareness, morphological awareness, nonverbal ability, vocabulary knowledge, and Chinese character recognition. It was found that lexical tone awareness and morphological awareness were both associated with vocabulary knowledge and character recognition. However, there was a significant relationship between lexical tone awareness and both vocabulary knowledge and character recognition, even after controlling for the effects of age, nonverbal ability, segmental phonological awareness and morphological awareness. These findings suggest that lexical tone is a key factor accounting for individual variance in young children's lexical acquisition in Chinese, and that lexical tone should be considered in understanding how children learn new Chinese vocabulary words, in either oral or written forms. PMID- 27483740 TI - Priming Implicit Prosody: Prosodic Boundaries and Individual Differences. AB - Using the structural priming paradigm, the present study explores predictions made by the implicit prosody hypothesis (IPH) by testing whether an implicit prosodic boundary generated from a silently read sentence influences attachment preference for a novel, subsequently read sentence. Results indicate that such priming does occur, as evidenced by an effect on relative clause attachment. In particular, priming an implicit boundary directly before a relative clause--cued by commas in orthography--encouraged high attachment of that relative clause, although the size of the effect depended somewhat on individual differences in pragmatic/communication skills (as measured by the Autism Spectrum Quotient). Thus, in addition to supporting the basic claims of the IPH, the present study demonstrates the relevance of such individual differences to sentence processing, and that implicit prosodic structure, like syntactic structure, can be primed. PMID- 27483741 TI - Asking or Telling--Real-time Processing of Prosodically Distinguished Questions and Statements. AB - We introduce a targeted language game approach using the visual world, eye movement paradigm to assess when and how certain intonational contours affect the interpretation of utterances. We created a computer-based card game in which elliptical utterances such as "Got a candy" occurred with a nuclear contour most consistent with a yes-no question (H* H-H%) or a statement (L* L-L%). In Experiment I we explored how such contours are integrated online. In Experiment 2 we studied the expectations listeners have for how intonational contours signal intentions: do these reflect linguistic categories or rapid adaptation to the paradigm? Prosody had an immediate effect on interpretation, as indexed by the pattern and timing of fixations. Moreover, the association between different contours and intentions was quite robust in the absence of clear syntactic cues to sentence type, and was not due to rapid adaptation. Prosody had immediate effects on interpretation even though there was a construction-based bias to interpret "got a" as a question. Taken together, we believe this paradigm will provide further insights into how intonational contours and their phonetic realization interact with other cues to sentence type in online comprehension. PMID- 27483742 TI - Social Expectation Improves Speech Perception in Noise. AB - Listeners' use of social information during speech perception was investigated by measuring transcription accuracy of Chinese-accented speech in noise while listeners were presented with a congruent Chinese face, an incongruent Caucasian face, or an uninformative silhouette. When listeners were presented with a Chinese face they transcribed more accurately than when presented with the Caucasian face. This difference existed both for listeners with a relatively high level of experience and for listeners with a relatively low level of experience with Chinese-accented English. Overall, these results are inconsistent with a model of social speech perception in which listener bias reduces attendance to the acoustic signal. These results are generally consistent with exemplar models of socially indexed speech perception predicting that activation of a social category will raise base activation levels of socially appropriate episodic traces, but the similar performance of more and less experienced listeners suggests the need for a more nuanced view with a role for both detailed experience and listener stereotypes. PMID- 27483743 TI - Abstract and Lexically Specific Information in Sound Patterns: Evidence from /r/ sandhi in Rhotic and Non-rhotic Varieties of English. AB - Phonological theories differ as to whether phonological knowledge is abstract (e.g., phonemic), concrete (e.g., exemplar-based), or some combination of the two. The abstractness/concreteness of phonological knowledge was examined by analyzing the process of /r/-sandhi in two corpora of spoken English. Two predictions of exemplar-based theories were examined: the extent to which a word manifests a particular sound pattern like /r/-deletion should be influenced by (1) its lexical frequency and (2) its distribution in the language with respect to the sound pattern's conditioning environment. Lexical frequency was found to influence /r/-sandhi in a corpus of rhotic American English but not in a corpus of predominantly non-rhotic British English. No effect of a word's long-term distribution was found in either corpus. These results support theories proposing that phonological knowledge is both word-specific and abstract and indicate that speakers do not store all phonetic detail that is in principle available to them. The factors that may favor the use of word-specific versus abstract representations are discussed. PMID- 27483744 TI - Generalization of Phonetic Detail: Cross-Segmental, Within-Category Priming of VOT. AB - The current study examined whether fine-grained phonetic detail (voice onset time (VOT)) of one segment (/p/ or /k/) generalizes to a different segment (/t/) within the same natural class. Two primes were constructed to exploit the natural variation of VOT: a velar stop followed by a high vowel (keen) resulting in a naturally long VOT and a labial stop followed by a low vowel (pan) resulting in a naturally shorter VOT. Two experiments were conducted, one in which the speakers produced both the prime and the target, and a second in which the speakers heard the primes and then produced the targets. In Experiment 1, VOTs for initial /t/ were shorter following pan than following keen. In Experiment 2 where participants heard the primes, priming was found only when the primes had unexpected relative VOT values (short for keen and long for pan). These results provide evidence for cross-segmental generalization of phonetic detail and also suggest that natural, within-category variability is encoded during language processing. PMID- 27483745 TI - A Special Section on The Role of Nanotechnology for Sustainable Energy and Environment. PMID- 27483746 TI - A Review on Quantitative Measurement of Cell Adhesion Strength. AB - There is an explosion of interest in characterizing cell adhesion process and the mechanochemical players that is critical to a wide range of physiological and pathological consequences. Much, however, still remains uncertain and controversial about the quantitative measurement of cell adhesion strength (i.e., cell-substratum adhesion force, cell-cell adhesion force, etc.). The main reason for this deficit is a lack of well-established and comprehensive experimental methods that quantitatively measure cell adhesion strength at cellular and even molecular levels. This leads to the need for conducting a literature review on the methods for characterizing the adhesion force of anchorage-dependent cells. In this review article, we discern and critique available techniques for measuring cell adhesion strength that is required for an adherent cell (or cells) of interest to detach from the neighboring cell or the substratum. This review focuses on recent advances in the technique for measuring cell adhesion strength to weigh up the strengths and weaknesses of each technique, together with a brief description for the biological aspects of cell adhesion process. The summary of this article might help us both to develop a standard method for measuring cell adhesion strength and to broaden and deepen our understanding of cell adhesion process. PMID- 27483747 TI - Recent Advances in Nanoplasmonic Sensors for Environmental Detection and Monitoring. AB - The great attention in environmental pollution urges the development of innovative monitoring system enabling rapid, sensitive, specific detection and easy operation. Recent progress in nanoplasmonic sensors allowing real-time, highly-sensitive, label-free and multiplex detection provides a promising alternative to conventional environmental analyzing techniques. This review summarizes novel nanoplasmonic approaches categorized by optical detection technologies, which include surface plasmon resonance spectroscopy, dark-field nanospectroscopy, Raman spectroscopy, and even naked eyes. The focus of this review will be on how plasmonic nanostructures can be utilized to detect environmental pollutants, and remarkable accomplishments to enhance the detection performances. In addition, we discuss current challenge and future direction for ubiquitous environmental sensing and monitoring. PMID- 27483748 TI - Review of Molecular Simulations of Methane Storage in Metal-Organic Frameworks. AB - Methane storage in porous materials is one of the hot issues because it can replace dangerous high-pressure compressed natural gas (CNG) tanks in natural gas vehicles. Among the diverse adsorbents, metal-organic frameworks (MOFs) are considered to be promising due to their extremely high surface areas and low crystal densities. Molecular simulation has been considered as an important tool for finding an appropriate MOF for methane storage. We review several important roles of molecular modeling for the studies of methane adsorption in MOFs. PMID- 27483749 TI - CO2 Adsorption Over Metal-Organic Frameworks: A Mini Review. AB - Metal-organic frameworks (MOFs) are a class of porous materials that are comprised of metal ion-containing nodes linked by multi-dentate organic ligand bridges principally through coordination bonding. Over the last few decades, MOFs have been studied widely as CO2 adsorbents. CO2 adsorption in MOFs can be enhanced by tuning their physicochemical properties. This short review discusses CO2 adsorption over MOFs with particular focus on the contributory effects of (1) inherent textural properties, (2) coordinatively unsaturated open metal sites, (3) surface functionalization, (4) structural interpenetration (catenation), and (5) ion-exchange. PMID- 27483750 TI - Synthesis of TiO2 Materials Using Ionic Liquids and Its Applications for Sustainable Energy and Environment. AB - Titanium dioxide (TiO2) has received significant attention because of the global climate change and the consumption of fossil fuel resources. Specifically, using TiO2 in photocatalytic applications, such as the removal of organic pollutants and a hydrogen production has become an important issue. Thus, many researchers have attempted to prepare highly active TiO2 materials using various synthetic approaches. Modifications of the conventional sol-gel method, such as the addition of surfactants, have been employed in synthetic procedures. Moreover, hydrothermal, solvothermal, sonochemical and microwave methods have also been used as alternative approaches. Recently, the use of ionic liquids represents a burgeoning direction in inorganic material synthesis. Ionic liquids are exceptional solvents consisting of ions possessing low vapor pressure and tunable solvent properties. This article reviews the preparation of TiO2 materials using ionic liquids with various synthetic approaches. Also, sustainable energy and environmental cleanup applications of TiO2 materials, including the treatment of hazardous organic substances and hydrogen energy derived from electrochemical methods, are discussed. PMID- 27483751 TI - A Comprehensive Review of Gas Sensors Using Carbon Materials. AB - In recent years, interest in carbon materials for use in gas sensors has increased. Carbon materials have unique electrical, optical and mechanical properties, making these materials very interesting. In this review, the properties of carbon materials are first introduced. Surface modification for carbon materials, fabrication for gas sensors, and the gas-sensing conditions and mechanisms according to the different types of carbon materials are chiefly described. In particular, this review focuses on the enhancement of the gas sensing properties of carbon materials depending on the modification methods used and its mechanism. PMID- 27483752 TI - Electrochemical Properties of Graphene Oxide/Resol Composites as Electrode Materials for Supercapacitor Applications. AB - RGO/Resol carbon composites were prepared from a mixture of reduced GO and a low molecular-weight phenolic resin (Resol) solution. The effects of the calcination temperature, amount of Resol added and KOH treatment on the electrochemical performance of the RGO/Resol composites were investigated. The physical and electrochemical properties of the composite materials were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Brunauer, Emmett and Teller (BET) surface areas measurements, and cyclic voltammetry (CV). The relationships between their physical properties and their electrochemical performance were examined for use as super-capacitors (SCs). The RGO/Resol composite calcined at 400 degrees C after the KOH loading showed dramatically improved electrochemical properties, showing a high BET surface and capacitance of 2190 m2/g and 220 F/g, respectively. The RGO/Resol composites calcined after the KOH treatment showed much better capacitor performance than those treated only thermally at the same temperature without KOH impregnation. The fabrication of high surface electrodes was essential for improving the SCs properties. PMID- 27483753 TI - Dynamic Behavior of Nano-Size Dust Particles in a Magnetic Field Channel. AB - Removal of very small dust from indoor public spaces, such as metro subway stations, is a challenge. A large proportion of subway dust, particularly that of submicron sizes, contains iron compounds. This study sought to understand the dynamic behavior of such fine iron dust in a magnetic field. The computer aided fluid dynamics (CFD) calculation revealed that the design and configuration of a rectangular flow channel with magnets determine the dynamic motion of particles. An attractive magnetic emitter arrangement produced higher magnetic flux density than a repulsive arrangement. Additional ferromagnetic wire mesh inserted into the duct channel could provide a more systematic magnetic field and collect more dust. The field gradient for 0.3 mm thick wire was more than twice that of 0.5 mm wire. The provision of a magnetic field could contribute a 20% increase in 100 nm particle collection and an increase of 5% in 10 nm. PMID- 27483754 TI - The Effect of K and Acidity of NiW-Loaded HY Zeolite Catalyst for Selective Ring Opening of 1-Methylnaphthalene. AB - Bi-functional catalysts were prepared using HY zeolites with various SiO2/Al2O3 ratios for acidic function, NiW for metallic function, and K for acidity control. 1-Methylnaphthalene was selected as a model compound for multi-ring aromatics in heavy oil, and its selective ring opening reaction was investigated using the prepared bi-functional catalysts with different levels of acidity in a fixed bed reactor system. In NiW/HY catalysts without K addition, the acidity decreased with the SiO2/Al2O3 mole ratio of the HY zeolite. Ni1.1W1.1/HY(12) catalyst showed the highest acidity but slightly lower yields for the selective ring opening than Ni1.1W1.1/HY(30) catalyst. The acidity of the catalyst seemed to play an important role as the active site for the selective ring opening of 1 methylnaphthalene but there should be some optimum catalyst acidity for the reaction. Catalyst acidity could be controlled between Ni1.1W1.1/HY(12) and Ni1.1W1.1/HY(30) by adding a moderate amount of K to Ni1.1W1.1/HY(12) catalyst. K0.3Ni1.1W1.1/HY(12) catalyst should have the optimum acidity for the selective ring opening. The addition of a moderate amount of K to the NiW/HY catalyst must improve the catalytic performance due to the optimization of catalyst acidity. PMID- 27483755 TI - Adsorption and Photocatalytic Degradation of Methylene Blue Using Potassium Polytitanate and Solar Simulator. AB - Solar photocatalytic degradation of organic water pollutants can be used to degrade toxic organic pollutants in water. In this study, potassium titanate nanofibres were synthesized by an aqueous peroxide route at high pH and examined as photocatalysts for photodegradation of methylene blue (MB) using a solar simulator. Initially, MB was adsorbed on the surface of potassium polytitanates to achieve adsorption equilibrium before the photocatalysts were illuminated using solar simulator. The results showed that potassium polytitanate nanofibres were effective adsorbents of MB and also facilitated its photocatalytic degradation. Sulphate ion evolution during photocatalysis confirmed that some mineralisation occurred and hence photo-oxidative degradation of MB took place. The optimum operational conditions for the photocatalytic degradation of MB were found at 0.05 g/L of photocatalyst load, 10 mg/L MB and pH 7. The stability and regeneration of the photocatalyst specimen was also studied for 3 degradation cycles using adsorption/photocatalysis model. Morphological structure analysis of potassium titanate showed nanocrystallines structure of longitudinally-oriented isolated fibre with a length up to several micrometres with diameters ranging from 10 to 20 nanometres. PMID- 27483756 TI - Roles of Promoters in V2O5/TiO2 Catalysts for Selective Catalytic Reduction of NOx with NH3: Effect of Order of Impregnation. AB - Recently, various promoters for commercial selective catalytic reduction (SCR) catalysts are used to improve DeNOx activity at low temperature. We aimed at finding the optimum condition to prepare V2O5/TiO2 catalyst by changing promoters (W, Ce, Zr and Mn), not only for improving SCR reactivity, but also for reducing N2O formation at high temperature. In addition, we changed the order of impregnation between promoter and vanadium precursors on TiO2 support and observed its effect on activity and N2O selectivity. We utilized various analytical techniques, such as N2 adsorption-desorption, X-ray Diffraction (XRD), Raman spectroscopy, UV-visible Diffuse Reflectance Spectroscopy (UV-vis DRS) and Temperature Programmed Reduction with hydrogen (H2-TPR) to investigate the physicochemical properties of V2O5/TiO2 catalysts. It was found that W and Ce added V2O5/TiO2 catalysts showed the most active DeNOx properties at low temperature. Additionally, the difference in impregnation order affected the SCR activity. The superiority of low temperature activity of the vanadium firstly added catalysts (W or Ce/V/TiO2) is attributed to the formation of more polymerized V2O5 on the sample. PMID- 27483757 TI - Heterogeneous Electrocatalyst of Palladium-Cobalt-Phosphorus on Carbon Support for Oxygen Reduction Reaction in High Temperature Proton Exchange Membrane Fuel Cells. AB - Palladium-cobalt-phosphorus (PdCoP) catalysts supported on carbon (Ketjen Black) were investigated as a cathode catalyst for oxygen reduction reaction (ORR) in high temperature proton exchange membrane fuel cells (HT-PEMFCs). The PdCoP catalyst was synthesized via a modified polyol process in teflon-sealed reactor by microwave-heating. From X-ray diffraction and transmission electron microscopic analysis, the PdCoP catalyst exhibits a face-centered cubic structure, similar to palladium (Pd), which is attributed to form a good solid solution of Co atoms and P atoms in the Pd lattice. The PdCoP nanoparticles with average diameter of 2.3 nm were uniformly distributed on the carbon support. The electrochemical surface area (ECSA) and ORR activity of PdP, PdCo and PdCoP catalysts were measured using a rotating disk electrode technique with cyclic voltammetry and the linear sweep method. The PdCoP catalysts showed the highest performances for ECSA and ORR, which might be attributed both to formation of small nanoparticle by phosphorus atom and to change in lattice constant of Pd by cobalt atom. Furthermore, The HT-PEMFCs single cell performance employing PdCoP catalyst exhibited an enhanced cell performance compared to a single cell using the PdP and PdCo catalysts. This result indicates the importance of electric and geometric control of Pd alloy nanoparticles that can improve the catalytic activity. This synergistic combination of Co and P with Pd could provide the direction of development of non-Pt catalyst for fuel cell system. PMID- 27483758 TI - Effectiveness of Modal Decomposition for Tapping Atomic Force Microscopy Microcantilevers in Liquid Environment. AB - The modal decomposition of tapping mode atomic force microscopy microcantilevers in liquid environments was studied experimentally. Microcantilevers with different lengths and stiffnesses and two sample surfaces with different elastic moduli were used in the experiment. The response modes of the microcantilevers were extracted as proper orthogonal modes through proper orthogonal decomposition. Smooth orthogonal decomposition was used to estimate the resonance frequency directly. The effects of the tapping setpoint and the elastic modulus of the sample under test were examined in terms of their multi-mode responses with proper orthogonal modes, proper orthogonal values, smooth orthogonal modes and smooth orthogonal values. Regardless of the stiffness of the microcantilever under test, the first mode was dominant in tapping mode atomic force microscopy under normal operating conditions. However, at lower tapping setpoints, the flexible microcantilever showed modal distortion and noise near the tip when tapping on a hard sample. The stiff microcantilever had a higher mode effect on a soft sample at lower tapping setpoints. Modal decomposition for tapping mode atomic force microscopy can thus be used to estimate the characteristics of samples in liquid environments. PMID- 27483759 TI - Physico-Chemical Property and Catalytic Activity of a CeO2-Doped MnO(x)-TiO2 Catalyst with SO2 Resistance for Low-Temperature NH3-SCR of NO(x). AB - The effects of CeO2 addition on the catalytic activity and the SO2 resistance of CeO2-doped MnO(x)-TiO2 catalysts were investigated for the low-temperature selective catalytic reduction (SCR) with NH3 of NO(x) emissions in marine applications. The most active catalyst was obtained from 30 wt% CeO2-MnO(x)-TiO2 catalyst in the whole temperature range of 100-300 degrees C at a low gas hourly space velocity (GHSV) of 10,000 h(-)1, and its de-NO(x) efficiency was higher than 90% over 250 degrees C. The enhanced catalytic activity may contribute to the dispersion state and catalytic acidity on the catalyst surface, and the highly dispersed Mn and Ce on the nano-scaled TiO2 catalyst affects the increase of Lewis and Bronsted acid sites. A CeO2-rich additive on MnO(x)-TiO2 could provide stronger catalytic acid sites, associated with NH3 adsorption and the SCR performance. As the results of sulfur resistance in flue gas that contains SO2, the de-NO(x) efficiency of MnO(x)-TiO2 decreased by 15% over 200 degrees C, whereas that of 30 wt% ceria-doped catalyst increased by 14-21% over 150 degrees C. The high SO2 resistance of CeO2-MnO(x)-TiO2 catalysts that resulted from the addition of ceria suppressed the formation of Mn sulfate species, which led to deactivation on the surface of nano-catalyst. PMID- 27483760 TI - Aromatization of Ethanol Over Desilicated ZSM-5 Zeolites: Effect of Pore Size in the Mesoporous Region. AB - Mesoporous ZSM-5 zeolites were obtained from microporous ZSM-5 by desilication using aqueous NaOH solutions, and their catalytic activity in the aromatization of ethanol was investigated in order to understand the effects of pore size, in the mesoporous region, on the product distribution and stability of the catalysts. Mesopores generally enhanced the selectivities towards aromatics and stability for aromatization. Mesopores with a maximum pore diameter of around 13 nm were the most effective in the aromatization process (especially for benzene and toluene), suggesting that pore-diameter optimization is necessary for efficient catalysis such as aromatization. PMID- 27483761 TI - Effect of Gold Particle Size on Steam Reforming of Methanol Over Au/CeO2-ZrO2 Catalysts. AB - We examined the effect of the particle size of gold on steam reforming of methanol over Au/CeO2-ZrO2 catalysts. Gold was loaded onto CeO2-ZrO2 through deposition-precipitation. The average particle size (2-12 nm) of the gold was controlled by thermal reduction under H2 at various temperatures and by chemical reduction with various reducing agents. The catalytic activity decreased significantly with increasing particle size of the gold. The turnover frequency at the interface between gold and a support appeared to be independent of particle size in the range 2-5 nm, which implies that the perimeter of the particle may be the active site for this reaction. Methanol adsorption and conversion over these catalysts were also investigated with in-situ diffuse reflectance infrared Fourier transform spectroscopy. Analytical results for various adsorbed intermediate species during methanol conversion suggests that transformation of methoxy species is facilitated by use of smaller gold particles. PMID- 27483762 TI - Stabilization of Hydrogen Production via Methanol Steam Reforming in Microreactor by Al2O3 Nano-Film Enhanced Catalyst Adhesion. AB - In hydrogen production by methanol steam reforming reaction with microchannel reactor, Al2O3 thin film formed by atomic layer deposition (ALD) was introduced on the surface of microchannel reactor prior to the coating of catalyst particles. Methanol conversion rate and hydrogen production rate, increased in the presence of Al2O3 thin film. Over-view and cross-sectional scanning electron microscopy study showed that the adhesion between catalyst particles and the surface of microchannel reactor enhanced due to the presence of Al2O3 thin film. The improvement of hydrogen production rate inside the channels of microreactor mainly came from the stable fixation of catalyst particles on the surface of microchannels. PMID- 27483763 TI - Low Frequency Ultrasonication of Degussa P25 TiO2 and Its Superior Photocatalytic Properties. AB - We report the simple and effective method for enhancing the photocatalytic properties of Degussa P25 TiO2 by low frequency ultrasonication. The improvement in the crystallinity of ultrasonicated TiO2 was confirmed by the X-ray diffraction and Raman spectroscopy studies. Further, the X-ray photoelectron spectroscopy was utilized to study the changes in chemical nature and band edge due to the effect of ultrasonication and H2O2 solvent. The transmission electron microscope (TEM) was used to analysis the surface distortion. The Moire fringes in TEM were examined to understand the partial transformation of amorphous to crystalline anatase structure and overlapping of rutile over anatase crystal. The photocatalytic results indicated improvement in the degradation of methylene blue dye. The degradation efficiency was estimated to be 86% for ultrasonicated TiO2, which is higher as compared to 40% of P25. The rate constant values revealed four times superior degradation property of ultrasonicated TiO2. The improvement in the photocatalytic efficiency was correlated to the formation of rutile/anatase TiO2 aggregation and its consequences on electron-hole recombination. PMID- 27483764 TI - Electro-Catalytic Activity of RuO2-IrO2-Ta2O5 Mixed Metal Oxide Prepared by Spray Thermal Decomposition for Alkaline Water Electrolysis. AB - Oxygen evolution reaction for alkaline water electrolysis was studied using various mixed metal oxide catalysts. Mixed metal oxide electrodes consisting of RuO2, IrO2, and Ta2O5 with various ratios on a titanium substrate were prepared by spray thermal decomposition. The crystallinity of the synthesized catalyst was investigated via X-ray diffraction, and the oxidation state of each component was determined using X-ray photoelectron spectroscopy (XPS). Surface morphology was investigated by scanning electron microscopy, and the roughness factor was determined by cyclic voltammetry (CV) in 1 M H2SO4. Electo-catalytic activity for oxygen evolution reaction was measured by cyclic voltammetry (CV) in 1 M KOH at room temperature, and it was found to be strongly dependent.on composition of catalyst. Among all electrodes tested, catalyst with a composition of Ru:Ir:Ta = 1:2:2.5 exhibited the highest current density of 100 mA cm(-2) at 1.67 V, corresponding to an overpotential of 0.44 V. PMID- 27483765 TI - Sulfation and Desulfation Behavior of Pt-BaO/MgO-Al2O3 NOx Storage Reduction Catalyst. AB - The comparative study between Pt-BaO/Al2O3 and Pt-BaO/MgO-Al2O3 gives the information about the effect of MgO addition to Al2O3 support on the sulfation and desulfation behavior of Pt-BaO/MgO-Al2O3 NOx storage reduction catalyst. The sulfated two samples were analyzed by using element analysis (EA), X-ray diffraction (XRD), H2 temperature programmed reaction (H2 TPRX) and NOx uptake measurement. The amount of sulfur uptake on 2 wt% Pt-20 wt% BaO/Al2O3 and 2 wt% Pt-20 wt% BaO/MgO-Al2O3 are almost identical as 0.45 and 0.40 of S/Ba, respectively, which yields the drastic decrease in NOx uptake for both sulfated samples. However, after desulfa- tion with H2 at 600 degrees C, the residual sulfur amount on MgO-Al2O3 supported catalyst is three times larger than that on Al2O3 supported one, indicating that sulfur species formed on the former are more stable than those on the latter. It is also well corresponding to the H2 TPRX results where the main H2S peak from MgO-Al2O3 supported sample is observed at higher temperature than Al2O3 supported one, resulting in the lower NOx uptake activity of former sample than the latter one. Meanwhile, after desulfation of MgO-Al2O3 supported sample at 700 degrees C and 800 degrees C, the activity is recovered more significantly due to the removal of the large amount of sulfur while Al2O3 supported one decreases monotonically due to the sintering of Pt crystallite and the formation of BaAl2O4 phase. It is summarized that MgO-Al2O3 supported catalyst enhances the thermal stability of the catalyst, however, forms the stable sulfate species, which needs to be improved to develop the more sulfur resistant NSR catalyst system. PMID- 27483766 TI - Morphology Control of Zinc Oxide Nanostructure on Single Layer Graphene. AB - Various morphologies of zinc oxide (ZnO) nanostructures on single layer graphene were synthesized by electrodeposition method. The current density was utilized to control the morphology of the ZnO. The Scanning Electron Microscope (SEM) was used to examine the surface morphology of the samples. SEM analysis shows morphology changes to nanorod, flower, and flakes with increase in the current density from 0.1, 0.2, and 0.3 mA/cm(-1) respectively. The XRD, XPS, and Raman spectroscopy were adopted to characterize the ZnO nanostructure and to understand the formation of various morphologies. The Raman result clearly shows extra modes due to for flakes structure caused by c-axis orientation along the substrate direction. Further, XPS data also supports formation of ZnO without any other intermediate compound such as Zn(OH)2. The formation of various morphologies was correlated to the formation different ratio of Zn2+ and OH- ions and the change in growth direction due to various current densities. PMID- 27483767 TI - Contact Force Compensated Thermal Stimulators for Holistic Haptic Interfaces. AB - We present a contact force compensated thermal stimulator that can provide a consistent tempera- ture sensation on the human skin independent of the contact force between the thermal stimulator and the skin. Previous passive thermal stimulators were not capable of providing a consistent tem- perature on the human skin even when using identical heat source voltage due to an inconsistency of the heat conduction, which changes due to the force-dependent thermal contact resistance. We propose a force-based feedback method that monitors the contact force and controls the heat source voltage according to this contact force, thus providing consistent temperature on the skin. We composed a heat circuit model equivalent to the skin heat-transfer rate as it is changed by the contact forces; we obtained the optimal voltage condition for the constant skin heat-transfer rate independent of the contact force using a numerical estimation simulation tool. Then, in the experiment, we heated real human skin at the obtained heat source voltage condition, and investigated the skin heat transfer-rate by measuring the skin temperature at various times at different levels of contact force. In the numerical estimation results, the skin heat-transfer rate for the contact forces showed a linear profile in the contact force range of 1-3 N; from this profile we obtained the voltage equation for heat source control. In the experimental study, we adjusted the heat source voltage according to the contact force based on the obtained equation. As a result, without the heat source voltage control for the contact forces, the coefficients of variation (CV) of the skin heat-transfer rate in the contact force range of 1-3 N was found to be 11.9%. On the other hand, with the heat source voltage control for the contact forces, the CV of the skin heat-transfer rate in the contact force range of 1-3 N was found to be barely 2.0%, which indicate an 83.2% improvement in consistency compared to the skin heat-transfer rate without the heat source voltage control. The present technique provides a consistent temperature sensation on the human skin independent of the body movement environment; therefore, it has high potential for use in holistic haptic interfaces that have thermal displays. PMID- 27483768 TI - Quantitative Assessment of Friction Characteristics of Single-Layer MoS2 and Graphene Using Atomic Force Microscopy. AB - Atomically thin layered materials such as MoS2 and graphene have attracted a lot of interest as protective coating layers for micro- and nano-electromechanical devices based on their superior mechanical properties and chemical inertness. In this work, the frictional characteristics of single layer MoS2 and graphene prepared by the mechanical exfoliation method were quantitatively investigated using atomic force microscopy. The results showed that both MoS2 and graphene exhibited relatively low friction forces of 1-3 nN under normal forces ranging from 1 to 30 nN. However, a higher increase in the friction force as the normal force increased was observed in the case of MoS2. The differences in the adhesion characteristics and mechanical properties of atomically thin layered materials may influence the puckering of the layer, which in turn influences the frictional behavior. PMID- 27483769 TI - Catalytic Reforming of Lignin-Derived Bio-Oil Over a Nanoporous Molecular Sieve Silicoaluminophosphate-11. AB - Catalytic pyrolysis of lignin, a major constituent of biomass, was performed. A nanoporous molecular sieve silicoaluminophosphate-11 (SAPO-11) was selected as catalyst. Thermogravimetric analysis showed that 500 degrees C was the optimal pyrolysis temperature. Pyrolyzer-gas chromatography/mass spectroscopy was used to investigate the pyrolysis product distribution. Production of phenolics, the dominant product from the pyrolysis of lignin, was promoted by the increase in the catalyst dose. In particular, low-molecular-mass phenolics were produced more over SAPO-11, while high-molecular-mass phenolics and double-bond-containing phenolics were produced less. The fraction of aromatic compounds, including benzene, toluene, xylene, and ethylbenzene, was also increased by catalytic reforming. The catalytic effects were more pronounced when the catalyst/biomass ratio was increased. The enhanced production of aromatic compounds by an acidic catalyst obtained in this study is in good agreement with the results of previous studies. PMID- 27483770 TI - Effects of Porous Carbon Cathode Additives on the Electrochemical Performance of Li-S Cells. AB - In this paper, the effects of porous carbon additives, which included microporous, mesoporous and macroporous carbon, on the electrochemical properties of a sulfur cathode were examined. The type of carbon additive significantly affected the initial capacity reduction, though it did not affect the cycling stability of the sulfur cathodes. The cathodes that incorporated mesoporous and macroporous carbon additives delivered much higher initial capacities of -970 and -900 mAh/g, respectively, compared with those (-715 mAh/g) with graphite and microporous carbon additives. The EDS results showed that these features are strongly related to the absorption characteristics of the carbon additives. Importantly, it was found that the macroporous carbons with a pore size of -65 nm effectively confined dissolved polysulfides. Interestingly, the sulfur cathodes with microporous carbon additives exhibited extremely similar electrochemical behavior to those with nonporous graphite, which suggests that activated carbon particles do not serve as polysulfide reservoirs during discharge. PMID- 27483771 TI - Green Synthesis of Metal Nanoparticles Using Sprout Plants: Pros and Cons. AB - A critical need in the field of nanotechnology is the development of a sustainable and eco-friendly process for the synthesis of metallic nanoparticles (NPs). To accomplish this, the use of live plants becomes essential for the production of low-cost, energy-efficient, and nontoxic metallic NPs. In this study, we tried in-vivo synthesis (green synthesis) of silver and gold NPs using seeds of bean, radish, and alfalfa, which were grown hydroponically in aqueous solutions containing metal salts, 20-25 nm sized NPs were found on the inner surfaces of the plants' vascular cylinders and cortex. The amounts of NPs taken up by the intracellular systems were clearly dependent on the exposure time and concentration of the metal salts. Although these results regarding the green synthesis of NPs on the growth of plant species are somewhat interesting and effective, metal salts adversely affected the root growth of the plants. Silver ions in the growth media showed a more negative impact on root growth compared to gold ions. Therefore, even though biosynthesis of metal NPs using live plants is considered as green synthesis, we have to consider their phytotoxicity on plant growth. PMID- 27483772 TI - Characterization on the Expanding Nature of Graphite in Microwave-Irradiated Exfoliation. AB - Much still remains uncertain and controversial about the mechanophysical parameters involved in graphite exfoliation. Here, we quantify the expansion characteristics of natural graphite in the microwave-irradiated exfoliation where KMnO4 and HNO3 are used as an oxidant and an intercalant, respectively. As a mark of the degree to which graphite becomes exfoliated, the expansion ratio of graphite is investigated as a function of mix ratio by weight of 3 ingredients (i.e., graphite, KMnO4, and HNO3), mixing time, and graphite physical properties. The findings of this study will lead to a better understanding of graphite exfoliation and make it possible to achieve the industrial-scale production of defect-free graphene. PMID- 27483773 TI - Inhibitory Effects of Silver Nanoparticles on Removal of Organic Pollutants and Sulfate in an Anaerobic Biological Wastewater Treatment Process. AB - The increasing use of silver nanoparticles (AgNPs) in commercial products and industrial processes raises issues regarding the toxicity of sludge biomass in biological wastewater treatment plants, due to potential antimicrobial properties. This study investigated the effects of AgNPs on removal of organic pollutants and sulfate in an anaerobic biological sulfate reduction process. At AgNPs concentrations of up to 10 mg/L, no significant inhibition of sulfate and COD removal was observed. However, at higher concentrations (50-200 mg/L) sulfate and COD removal efficiencies were significantly decreased to 51.8% and 33.6%, respectively. Sulfate and COD reduction followed first-order kinetics at AgNPs concentrations of up to 10 mg/L and second-order kinetics at AgNPs concentrations of 50-200 mg/L. Lactate dehydrogenase release profiles showed increases in cytotoxicity at AgNPs concentrations greater than 50 mg/L suggesting cell membrane disruption. Analysis of extracellular polymeric substances (EPS) from sulfidogenic sludge biomass and of Fourier transform infrared (FT-IR) spectra showed a decrease in concentrations of carbohydrates, proteins, humic substances, and lipids in the presence of AgNPs. Moreover, the interaction of AgNPs with sludge biomass and the damage caused to cell walls were confirmed through scanning electron microscopy with energy dispersive X-ray spectroscopy. PMID- 27483774 TI - Formation of RNA Beads from Various DNA Nanoring Structures. AB - By taking advantages of rolling circle transcription, one of the powerful methods to overcome the instability of RNA, we successfully synthesized RNA particles having high copy numbers of RNA strands. To examine dependence of RNA particle formation to template circular DNA strands, we synthesized RNA beads with 65-nt, 92-nt and 200-nt DNA nanoring structures as template circular DNA. Our conclusion is that characteristics of RNA beads could be controlled with various template circular DNA for RCT. It is feasible that our RNA beads could be used for RNAzyme based metal sensors such as aqueous lead ion sensing. In this case, we expect that multi-metal ion detection would be possible by using 200-nt circular DNA bearing multiple desired functions as a template for RNA bead formation. Furthermore, certain features of RNA beads such as sensitivity to nuclease digestion and maximum loading amount of drugs when used as a carrier are expected to be further adjusted by choosing appropriate porosity and size. PMID- 27483775 TI - Effective Removal of Heavy Metals from Wastewater Using Modified Clay. AB - We report an economical and eco-friendly way to remove the heavy metal pollutant using modified clay. The modification of clay was done by calcining the natural clay from Kyushu region in Japan. Further, the removal efficiency for various pH and contact time was evaluated. The morphology of the clays was studied using the scanning electron microscopy (SEM). The structural and chemical analyses of modified clay were done by using X-ray diffraction (XRD), Raman spectroscopy, and Energy dispersion analysis (EDAX) to understand the properties related to the removal of heavy metal pollutant. Further, we studied the absorption efficiency of clay for various pH and contacting time using Ni polluted water. The modified clays show better removal efficiency for all pH with different saturation time. The adsorption follows pseudo-second order kinetics and the adsorption capacity of modified clay is 1.5 times larger than that of natural clay. The increase in the adsorption efficiency of modified clay was correlated to the increase in hematite phase along with increase in surface area due to surface morphological changes. PMID- 27483776 TI - Surface-Energetic Heterogeneity of Nanoporous Solids for CO2 and CO Adsorption: The Key to an Adsorption Capacity and Selectivity at Low Pressures. AB - This study has been focused on surface energetic heterogeneity of zeolite (H mordenite, "HM"), activated carbon ("RB2") and metal-organic framework family ("Z1200") materials and their isotherm features in adsorption of CO2 and CO at 25 degrees C and low pressures <= 850 Torr. The nanoporous solids showed not only distinctive shape of adsorption isotherms for CO2 with relatively high polarizability and quadrupole moment but also different capacities in the CO2 adsorption. These differences between the adsorbents could be well correlated with their surface nonuniformity. The most heterogeneous surfaces were found with the HM that gave the highest CO2 uptake at all pressures allowed, while the Z1200 consisted of completely homogeneous surfaces and even CO2 adsorption linearly increased with pressure. An intermediate character was indicated on the surface of RB2 and thus this sorbent possessed isotherm features between the HM and Z1200 in CO2 adsorption. Such different surface energetics was fairly consistent with changes in CO2/CO selectivity on the nanoporous adsorbents up to equilibrated pressures near 850 Torr. PMID- 27483777 TI - Conversion of Acetic Acid from the Catalytic Pyrolysis of Xylan Over CeO2. AB - CeO2 was synthesized hydrothermally in supercritical water and applied to the catalytic pyrolysis of xylan. Acetic acid, which is the main component in bio-oil produced from the non-catalytic pyrolysis of xylan, deteriorates the fuel quality of the oil. Catalysis over CeO2 effectively converted the acetic acid to ketone species, such as acetone, thereby reducing the acidity of the oil considerably. The content of aromatics in bio-oil was also increased substantially by catalysis. PMID- 27483778 TI - Facile Synthesis of Iron Oxide/Graphene Nanocomposites Using Liquid Phase Plasma Method. AB - Liquid phase plasma (LPP) method was applied, for the first time, to the impregnation of iron oxide nanoparticles onto graphene sheet. Iron oxide nanoparticles with the size of 50 nm were precipitated with uniform dispersion on the surface of graphene sheet. The amount of iron oxide nanoparticles precipitated on graphene sheets increased with increasing LPP process times. The XPS, Raman and EDX analyses showed that the iron oxide/graphene composites synthesized by the LPP process. PMID- 27483779 TI - Aerosol-Processed Nanomaterials for Antimicrobial Air Filtration. AB - Health-care products are a dominant application of various nanotechnologies. Silver nanoparticles are widely used in commercial products requiring antimicrobial activity. Due to the limitations of wet processing in nanotechnology applications, dry aerosol processes have been developed for indoor antimicrobial air filtration. In this work, various aerosol processes for the synthesis or generation of nanomaterials, natural-product nanoparticles, and hybrid nanoparticles are reviewed. Key aerosol processes and the morphologies of various antimicrobial nanoparticles generated using a variety of systems or deposited on filter fibers are introduced. PMID- 27483780 TI - Application of Silver and Silver Oxide Nanoparticles Impregnated on Activated Carbon to the Degradation of Bromate. AB - Silver and silver oxide nanoparticles were impregnated on the surface of powdered activated carbon (PAC) using a single-step liquid phase plasma (LPP) method. Spherical silver and silver oxide nanoparticles of 20 to 100 nm size were dipersed evenly on the surface of PAC. The impregnated PAC exhibited a higher activity for the decomposition of bromate than bare PAC. The XPS, Raman and EDX analyses showed that the Ag/PAC composites synthesized by the LPP process. PMID- 27483781 TI - Facile Synthesis of F-TiO2/TiOF2 Mixture by High-Thermal Direct Fluorination and Its Photocatalytic Evaluation. AB - In this study, the mixture of F-TiO2/TiOF2 has been easily synthesized using titanium (IV) isopropoxide (TTIP) as titanium source by direct fluorination at high temperature according to different partial pressure of fluorine gas. The morphological properties and crystalline of thermally fluorinated photocatalysts were investigated using scanning electron microscope (SEM) and X-ray diffraction (XRD). Chemical composition and optical properties of thermally fluorinated photocatalysts were analyzed by X-ray Photoelectron Spectroscopy (XPS) and Photoluminescence (PL) spectrometer. The phase of F-TiO2/TiOF2 mixture was generated with different proportion by high-thermal direct fluorination. With the increase of the fluorine partial pressure, the proportion of cubic-shaped TiOF2 increased in comparison with globular-shaped TiO2. Also, the degradation rate constant of thermally fluorinated photocatalysts exhibited approximately 70 times more than that of TiO2, which were not treated fluorine gas. It is attributable to the increase of the surface hydroxyl group content and oxygen vacancies. PMID- 27483782 TI - Synthesis and Characterisation of Porous Titania-Silica Composite Aerogel for NO(x) and Acetaldehyde Removal. AB - In this study, the synthesis of porous titania-silica (TiO2-SiO2) composite aerogel at ambient pressure by using non-hazardous chemicals as a source of silica was investigated. TiO2-SiO2 composite aerogels were characterised and their photocatalytic performances were investigated for the removal efficiency of acetaldehyde and NO(x) under UV light. Results showed that porous composite aerogel with aggregated morphology, high surface area and an increased mesoporosity were formed. TiO2-SiO2(1.8) composite, with high Ti/Si ratio, showed the best results in terms of photocatalytic removal of acetaldehyde and nitrogen oxide. PMID- 27483783 TI - Synthesis of Dicyclopentadiene Oligomer Over Nanoporous Al-MCM-41 Catalysts. AB - One step reaction composed of DCPD oligomerization and DCPD oligomer isomerization was investigated over nanoporous Al-MCM-41 catalysts. The effects of aluminum grafting over MCM-41 on the catalyst characteristics were studied with respect to the synthesis of TCPD isomer. Physical and chemical properties of the catalysts were analyzed by N2 adsorption, temperature-programmed desorption of ammonia, and infrared spectroscopy of adsorbed pyridine. The overall number of acid sites as well as the number of Lewis acid sites increased with increasing of aluminum content over MCM-41. When utilizing MCM-41 and Al-MCM-41 as the catalyst, DCPD oligomerization reaction activity greatly increased compared to the thermal reaction. The highest TCPD isomer selectivity over the Al-MCM-41 catalyst with the highest aluminum content could be ascribed to the largest amount of acid sites. This study showed an increased level of TCPD isomer selectivity by an increasing level of Lewis acid sites through aluminum addition over MCM-41. PMID- 27483784 TI - The Study on the Performance of Carbon Supported PtSnM (M = W, Pd, and Ni) Ternary Electro-Catalysts for Ethanol Electro-Oxidation Reaction. AB - PtSn/C and Pt5Sn4M/C (M = W, Pd, Ni) electrocatalysts were prepared by impregnation method using NaBH4 as a reducing agent. Chemical composition, crystalline size, and alloy formation were determined by EDX, XRD and TEM. The average particle sizes of the synthesized catalysts were approximately 3.64-4.95 nm. The electro-chemical properties were measured by CO stripping, cyclic voltammetry, linear sweep voltammetry, and chronoamperometry. The maximum specific activity of the electro-catalysts for ethanol electro-oxidation was 406.08 mA m(-2) in Pt5Sn4Pd/C. The poisoning rate of the Pt5Sn4Pd/C (0.0017% s( 1)) was 4.5 times lower than that of the PtSn/C (0.0076% s(-1)). PMID- 27483785 TI - Mn(2+)-Ion Site Distribution of Zeolite Y (FAU, Si/Al = 1.56) Depending on the Ion-Exchange Ratio. AB - To investigate the tendency of Mn(2+)-ion exchange into zeolite Y, four single crystals of fully dehydrated Mn2+, Na(+)-exchanged zeolite Y (Si/Al = 1.56) were prepared by the exchange of Na75-Y (INa75I[Si117Al75,O384]-FAU) with aqueous of various concentrations by Mn2+ and Na+ in a total 0.05 M for molar ratios of 1:1 (crystal 1), 1:25 (crystal 2), 1:50 (crystal 3), and 1:100 (crystal 4), respectively, followed by vacuum dehydration at 400 degrees C. Their single crystal structures were determined by synchrotron X-ray diffraction techniques in the cubic space group Fd3(-)m and were refined to the final error indices R1/wR2 = 0.0440/0.1545, 0.0369/0.1153, 0.0373/0.1091, and 0.0506/0.1667, respectively. Their unit-cell formulas are approximately LMn33.5Na8I[Si117Al75O384]-FAU, IMn20.5Na34I[Si117Al75O384]-FAU, IMn20.5Na34I[Si117Al75O384]-FAU, and IMn16.5Na42I[Si117Al75O384]-FAU, respectively. The degree of Mn2+-ion exchange increases from 44.3% to 89.1% with increasing the initial Mn2+ concentrations as Na+ content and the unit cell constant of the zeolite framework decrease. PMID- 27483786 TI - Synthesis of Hybrid Reduced Graphene Oxide Decorated with Ru(bpy)3(2+)-Doped Silica Nanoparticles. AB - Hybrid materials consisting of electrically conductive reduced graphene oxide (RGO) and Ru(bpy)3(2+)-doped silica (Ru@SiO2) nanoparticles were synthesized by hydrolysis of TEOS in the presence of Ru(bpy)3Cl2 and RGO. Many spherical Ru@SiO2 nanoparticles, of an average size of 96 nm, were observed to be strongly anchored on a planar RGO surface in SEM and TEM images. FTIR and EDS analyses confirmed the chemical compositions and functional groups of Ru@SiO2 and partially reduced RGO. The RGO prepared by 200 degrees C thermal treatment of GO in N2 was probed to have a multilayered sheet structure by XRD. An absorption spectrum of the hybrid exhibited a considerable red-shift in the characteristic visible peak of free Ru(bpy)3(2+) centered at 452 nm due to electrostatic interactions between Ru(bpy)3(2+) and negatively charged silica, indicating strong immobilization of Ru(bpy)3(2+) in the silica matrix. PMID- 27483787 TI - L-Lactide Ring-Opening Polymerization with Tris(acetylacetonate)Titanium(IV) for Renewable Material. AB - A new Ti-type of catalyst for L-lactide polymerization was synthesized by reaction of titanium(IV) isopropoxide (TTIP) with acetylacetone (AA). Moreover, PLA was prepared by the bulk ring-opening polymerization using synthesized Ti catalyst. Polymerization behaviors were examined depending on monomer/catalyst molar ratio, polymerization temperature and time. The structure of synthesized catalysts was verified with FT-IR and 1H NMR and the properties of poly(L lactide) (PLLA) were examined by GPC, DSC and FT-IR. There existed about 30 minutes of induction time at the monomer/catalyst molar ratio of 300. The molecular weight (MW) increased as monomer/catalyst molar ratio increased. The MW increased almost linearly as polymerization progressed. Increasing polymerization temperature increased the molecular weight of PLLA as well as monomer/catalyst molar ratio. The melting point (T(m)) of polymers was in the range of 142 to 167 degrees C. Lower T(m) was expected to be resulted from relatively lower molecular weight. PMID- 27483788 TI - Heterogeneous Decomposition of Volatile Organic Compounds by Visible-Light Activated N, C, S-Embedded Titania. AB - In this study, a N-, C-, and S-doped titania (NCS-TiO2) composite was prepared by combining the titanium precursor with a single dopant source, and the photocatalytic activity of this system for the decomposition of volatile organic compounds (VOCs) at indoor-concentration levels, under exposure to visible light, was examined. The NCS-TiO2 composite and the pure TiO2 photocatalyst, used as a reference, were characterized via X-ray diffraction, scanning electron microscopy, ultraviolet-visible diffuse reflectance spectroscopy, X-ray photoelectron spectroscopy, and Fourier transform infrared spectroscopy. The average efficiencies of benzene, toluene, ethyl benzene, and o-xylene decomposition using NCS-TiO2 for were 70, 87, -100, and -100%, respectively, whereas the values obtained using the pure TiO2 powder were -0, 18, 49, and 51%, respectively. These results suggested that, for the photocatalytic decomposition of toxic VOCs under visible-light exposure conditions, NCS-TiO2 was superior to the reference photocatalyst. The decomposition efficiencies of the target VOCs were inversely related to the initial concentration and relative humidity as well as to the air-flow rate. The decomposition efficiencies of the target chemicals achieved with a conventional lamp/NCS-TiO2 system were higher than those achieved with a light emitting diode/NCS-TiO2 system. Overall, NCS-TiO2 can be used for the efficient decomposition of VOCs under visible-light exposure, if the operational conditions are optimized. PMID- 27483789 TI - Evaluation of Cytotoxicity and Hypoxic Effect of Nitroimidazole Embedded Nanoparticles. AB - Adenylate cyclase is a key intracellular enzyme involved in energy imbalance leading to tumor hypoxia and cytotoxicity. In this study, adenylate cyclase activities in isolated hepatocytes and Kupffer cells were compared in the presence of several metabolic stimulators. In cultured hepatocyte cells, adenylate cyclase was stimulated by guanylyl imidotriphosphate (GITP), guanosine triphosphate (GTP), progesterone and nitroimidazole embedded nanoparticle (NNP) effectors, while prostaglandin E2 and F2alpha were used as effectors in cultured Kupffer cells. The results showed that NNPs decreased adenylate cyclase specific activity in a dose-dependent manner after preincubation of hepatocytes with NNPs. The NNPs stimulated adenylate cyclase activities in hepatocytes were evaluated based on measurement of cyclic adenosine monophosphate (cAMP). The stimulatory effects of NNPs on adenylate cyclase were independent of the presence of GTP and may have been due to a direct effect on the catalytic subunit of adenylate cyclase. In addition, basal cAMP generation in hepatocyte cells was efficiently suppressed by the NNPs. In conclusion, NNPs exerted direct effects on the catalytic subunit of the adenylate cyclase system, and adenylate cyclase was hormone sensitive in liver cells. PMID- 27483790 TI - Catalytic Fast Pyrolysis of Wild Reed Over Nanoporous SBA-15 Catalysts. AB - Wild reed was pyrolyzed over two nanoporous SBA-15 catalysts with different acid characteristics: Si-SBA-15 and Al-SBA-15. Al was grafted on Si-SBA-15 to increase the acidity and enhance the catalytic activity. Fast pyrolysis was carried out using a pyrolysis-gas chromatography/mass spectrometry system at 550 degrees C for real-time analysis of the products. Significant improvement of the product bio-oil quality was attained by catalytic reforming over nanoporous Al-SBA-15. The fraction of total oxygenates was reduced because of the decrease in. the fraction of ketones, aldehydes, and carboxylates, which deteriorate the fuel quality of bio-oil. On the other hand, the fractions of furans and aromatics, which are the chemicals with high value-added, were increased by the catalytic reforming. The catalytic activity of Al-SBA-15 was considerably higher than that of Si-SBA-15 because the incorporation of Al increased the catalyst acidity. PMID- 27483791 TI - Highly Dispersed Pt Nanoparticles for the Production of Aromatic Hydrocarbons by the Catalytic Degrading of Alkali Lignin. AB - Aromatic hydrocarbons were produced from lignin, a complex natural amorphous polymer commonly regarded as by-product of the pulping process and from biofuel production. The catalytic decomposition of lignin using supported Pt catalysts was performed to produce small molecule hydrocarbons. Aromatic small-molecule hydrocarbon products were identified and quantified using GC/MS and GC-FID, which demonstrated that 27.6% of aromatic hydrocarbons were obtained from the activated carbon-supported Pt (Pt/AC) catalyst which had the highest Pt surface area. PMID- 27483792 TI - Catalytic Depolymerization of Alkali Lignin Using Supported Pt Nanoparticle Catalysts. AB - Alkali lignin, a byproduct of the pulping process, was depolymerized using Pt nanoparticle catalysts. A depolymerized lignin with a lower molecular weight was obtained and characterized with GPC and NMR. 31P-NMR using OH-sensitive probing molecules showed the formation of guaiacyl OHs during the reaction, indicating the cleavage of guaiacyl ether bonds. PMID- 27483793 TI - Complete Oxidation of Benzene Over CuO-CeO2 Catalysts Prepared Using Different Process. AB - Catalytic combustion of benzene over CuO-CeO2 mixed oxides has been investigated. The CuO-CeO2 mixed oxides were prepared using various methods and characterized by XRD, BET and TPR. For the CuO-CeO2 catalysts with a Cu/(Cu + Ce) molar ratio of more than 0.5, highly dispersed copper oxide species were shown at 2theta = 35.5 degrees and 38.8 degrees. The CuO-CeO2 catalyst prepared using co precipitation method showed the highest activity. In addition, the highest activity is shown on Cu0.35 (the index denotes the molar ratio Cu/(Cu + Ce)) sample and then it decreases on Cu0.5 and Cu0.6 samples. PMID- 27483794 TI - Direct Dehydrogenation of n-Butane Over Pt/Sn/Zn-K/Al2O3 Catalyst: Effect of Hydrogen in the Feed. AB - Al2O3 was prepared by a sol-gel method for use as a support. Pt/Sn/Zn-K/Al2O3 catalyst was then prepared by a sequential impregnation method, and it was applied to the direct dehydrogenation of n-butane to n-butenes and 1,3-butadiene. Physicochemical properties of Pt/Sn/Zn-K/Al2O3 catalyst were examined by X-ray diffraction (XRD), nitrogen adsorption-desorption isotherm, inductively coupled plasma atomic emission spectroscopy (ICP-AES), temperature-programmed reduction (TPR), CO chemisorption, and temperature-programmed oxidation (TPO) measurements. In order to improve the catalyst stability, the effect of hydrogen in the feed on the catalytic performance in the direct dehydrogenation of n-butane was studied. The catalyst stability and reusability in the direct dehydrogenation of n-butane was also investigated. Experimental results revealed that the addition of hydrogen in the feed decreased conversion of n-butane and yield for total dehydrogenation products but improved the stability of the catalyst. The catalytic activity and stability of regenerated Pt/Sn/Zn-K/Al2O3 catalyst in the presence of hydrogen slightly decreased compared to those of fresh Pt/Sn/Zn K/Al2O3 catalyst due to the slight sintering of platinum particles. PMID- 27483795 TI - Bio-Diesel Production from Deoxygenation Reaction Over Ce0.6Zr0.4O2 Supported Transition Metal (Ni, Cu, Co, and Mo) Catalysts. AB - Ce0.6Zr0.4O2 supported transition metal (Me = Ni, Cu, Co, and Mo) catalysts have been investigated to screen for the catalytic activity and selectivity for deoxygenation reaction of oleic acid. Me-Ce0.6Zr0.4O2 catalysts were prepared by a co-precipitation method. Ni-Ce0.6Zr0.4O2 catalyst exhibited much higher oleic acid conversion, selectivity for C9 to C17 compounds, and oxygen removal efficiency than the others. This is mainly ascribed to the presence of free Ni species, synergy effects between Ni and Ce0.6Zr0.4O2, and the highest BET surface area. PMID- 27483796 TI - Technical Advances in Intracellular Detection Using Immuno-Gold Particles: Simple Cryofixation with Metal Contact Quick Freezing. AB - The preparation of biological specimens using cryofixation techniques ensures excellent visibility of intracellular structures and preserves the antigenic sites of subcellular molecules. Hence, cryofixation is an effective method of preparing samples for analyses using antibodies conjugated to gold nanoparticles that are designed to detect the localization of specific target molecules within cells. However, cryofixation cannot be utilized easily because it requires expensive equipment and skilled technologists, resulting in a high level of expense for researchers. Here, we describe a simple technical approach to cryofixation that uses metal contact quick freezing followed by a modified freeze substitution technique and immuno-gold labeling electron microscopy. Micrograph images of cells prepared using this modified cryofixation method demonstrated its superiority over chemical fixation for high contrast visualization of the morphologies of cellular components and preservation of antigenicity for immuno gold labeling. This report provides valuable technical information related to the advancement of metal contact quick freezing techniques, which can be used to visualize biomedical events of interest in an easy, simple, and rapid manner. PMID- 27483797 TI - Preparation of Nano-Porous Activated Carbon Aerogel Using a Single-Step Activation Method for Use as High-Power EDLC Electrode in Organic Electrolyte. AB - Carbon aerogel was chemically activated with KOH using two different activation methods (conventional activation method and single-step activation method) to yield the nano-porous activated carbon aerogel. Both nano-porous activated carbon aerogels exhibited a better capacitive behavior than carbon aerogel in organic electrolyte. However, a drastic decrease in the specific capacitance with increasing current density was observed in the ACA_C (activated carbon aerogel prepared by a conventional activation method), which is a general tendency of carbon electrode for EDLC in organic electrolyte. Interestingly, the specific capacitance of ACA_S electrode (activated carbon aerogel prepared by a single step activation method) decreased slowly with increasing current density and its CV curve maintained a rectangular shape well even at a high scan rate of 500 mV/s. The enhanced electrochemical performance of ACA_S at a high current density was attributed to its low ionic resistance caused by the well-developed pore structure with appropriate pore size for easy moving of organic electrolyte ion. Therefore, it can be concluded that single-step activation method could be one of the efficient methods for preparation of nano-porous activated carbon aerogel electrode for high-power EDLC in organic electrolyte. PMID- 27483798 TI - Hydrogen Production by Steam Reforming of Liquefied Natural Gas (LNG) Over Nickel Phosphorus-Alumina Xerogel Catalyst Prepared by a Carbon-Templating Epoxide Driven Sol-Gel Method. AB - A nickel-phosphorus-alumina xerogel catalyst was prepared by a carbon-templating epoxide-driven sol-gel method (denoted as CNPA catalyst), and it was applied to the hydrogen production by steam reforming of liquefied natural gas (LNG). For comparison, a nickel-phosphorus-alumina xerogel catalyst was also prepared by a similar method in the absence of carbon template (denoted as NPA catalyst). The effect of carbon template addition on the physicochemical properties and catalytic activities of the catalysts in the steam reforming of LNG was investigated. Both CNPA and NPA catalysts showed excellent textural properties with well-developed mesoporous structure. However, CNPA catalyst retained a more reducible nickel aluminate phase than NPA catalyst. XRD analysis of the reduced CNPA and NPA catalysts revealed that nickel sintering on the CNPA catalyst was suppressed compared to that on the NPA catalyst. From H2-TPD and CH4-TPD measurements of the reduced CNPA and NPA catalysts, it was also revealed that CNPA catalyst with large amount of hydrogen uptake and strong hydrogen-binding sites showed larger amount of methane adsorption than NPA catalyst. In the hydrogen production by steam reforming of LNG, CNPA catalyst with large methane adsorption capacity showed a better catalytic activity than NPA catalyst. PMID- 27483799 TI - Catalytic Performance of Microwave Functionalized NH2-MIL-53 for Cyclic Carbonate Synthesis from CO2 and Epoxides. AB - The efficacy of microwave irradiation in the quaternization of amino functionalized MIL-53 metal-organic framework (MOF) as well as the catalytic activity of the resultant MOF in the cycloaddition of carbon dioxide with epoxides under solvent-free conditions has been studied. A series of NH2-MIL-53 were synthesized and quaternized by reacting alkyl halide of various alkyl chains and anions under microwave irradiation. The post-functionalized F-MIL-53-AXs were characterized through solid-state XRD, FT-IR, XPS, and TGA. F-MIL-53-Mel prepared by microwave method showed higher AGC yield than that by the conventional heating method. F-MIL-53-AXs with iodide anion exhibited the best catalytic activity irrespective of the alkyl chain length, in agreement with the generally accepting order of nucleophilicity, Cl 1 wt% Pd/SiO2 > 1 wt% Pd/gamma-Al2O3. A strong interaction between the palladium and support was found, which affected the palladium surface concentration and particle size. The higher catalytic activity of the Pd/TiO2 catalyst was attributed to the higher palladium surface concentration and larger particle size. PMID- 27483804 TI - Effect of Molar Concentration of NH4OH on Photocatalytic Activity in Preparation of Nanosized TiO2 Powder from Spent Titanium Chip by Sol-Gel Method. AB - The TiO2 powder was prepared from the spent titanium chips by applying the sol gel method. The spent titanium chip was dissolved in HCl solution, and then NH4OH solution was added. The molar concentration of NH4OH solution was 2 M, 4 M, 8 M, and 10 M. Obtained TiO2 powders were calcined at 200 degrees C, 400 degrees C, and 600 degrees C. The prepared TiO2 powder was characterized using a particle size analysis, BET surface area, and XRD analysis. The crystal structure of the TiO2 powder was rutile type and anatase. The highest BET surface area of TiO2 powder was 432.8 m2/g. The photocatalytic property of the TiO2 powder was evaluated as decomposition rate of methylene blue(MB) by using a liquid phase stirred reactor. UV source was a UV-A, and concentration of MB in most experiments was 8 ppm. The concentration of MB was measured by absorbance at 664 nm using UV spectroscopy. Photocatalytic efficiency of prepared TiO2 powder depended highly on concentration of NH4OH solution. The TiO2 powder prepared with 8 M-NH4OH solution showed the highest efficiency, the decomposition efficiency at decomposition time of 2 hr and MB concentration of pH 8 was 98%. PMID- 27483805 TI - Catalytic Decomposition of N2O at Low Temperature by Reduced Cobalt Oxides. AB - Various forms of cobalt oxide (Co3O4 and C0203) were subsequently prepared and tested for decomposition of N2O at low temperature in a fix bed differential reactor at steady state conditions. These different types of oxides were prepared by precipitation method (PM) and by calcination of commercially available CoCO3. Commercially available cobalt oxides C03O4 and C02O3 were also tested for N2O decomposition at different temperatures. All types of prepared and commercially available cobalt oxide were found inactive for N2O decomposition in the presence of oxygen at temperature less than 300 degrees C. Similar unsatisfactory results were found at low temperature N2O decomposition after impregnation of alkali metal (10% Na) and alkaline earth metal (10% Ba) over Co3O4. These catalysts were then reduced under reduction media (H2 gas). It was found that after reduction cobalt oxide catalysts became active for N2O decomposition for short time in the presence of oxygen at low temperature. The reduced form of Co3O4 catalyst showed enormous efficiency i.e., 98% at temperature (300 degrees C) under the same conditions. From results it seems that Co3O4 itself is not active for N2O decomposition but its reduced form is highly active for this reaction due to oxidation state change of C03O4 during reduction process. PMID- 27483806 TI - Progress on Synthesis and Applications of Cr2O3 Nanoparticles. AB - As is known to us that nanosized chromic oxide (Cr2O3) is an important transition metal oxide. Because it has many excellent properties, it can be used in many fields such as pigment, catalyst, Lithium material etc. This article briefly reviewed the preparation and applications of Cr2O3 nanoparticles. In this paper, some specific applications will be listed according to different fields. Nanosized chromic oxide (Cr2O3) can be obtained via many methods. A summary of the methods have been made. The preparation methods are divided into three main types, including vapor phase method, solid phase method and liquid phase method. Simultaneously, different types of methods have been simply evaluated in this paper. And the advantage and disadvantage are simply noted. PMID- 27483807 TI - Effect of Nitrogen and Hydrogen Gases on the Synthesis of Carbon Nanomaterials from Coal Waste Fly Ash as a Catalyst. AB - Various reducing and inert gases have been used in the catalytic chemical vapour deposition (CCVD) synthesis of carbon nanomaterials (CNMs). In this paper we report on the effects that hydrogen and nitrogen gases have on the production of CNMs from acetylene on fly ash catalysts. Parameters such as temperature and gas environments were investigated. Transmission electron microscopy (TEM) revealed that CNMs of various morphologies such as carbon nanofibers (CNFs) and carbon nanospheres (CNSs) were formed. When hydrogen was used the carbonaceous products were formed in higher yields as compared to when nitrogen was used. This could be due to the multifunctional roles that hydrogen plays as compared to nitrogen. Laser Raman and Mossbauer spectroscopy measurements revealed that three types of products were formed, namely: amorphous carbon, graphitic carbon and iron carbide. Significantly cementite (Fe3C) was identified as the main intermediate carbide species in the catalytic growth of well-ordered CNMs. PMID- 27483808 TI - Analysis of the Impact of Variations on Signal Electro-Migration and Optimization of Interconnects in FinFET Designs. AB - The An AC current induced electro-migration (EM) on clock and logic signals becomes a significant problem even in the presence of reverse-recovery effect. Compared to power network, clock and logic signal interconnects are much narrower and suffer from fast switching and large driving current from FinFETs. Thus, the high current density on those signal interconnects can cause a serious failure. In this paper, we analyze EM on signal interconnects in 16 nm FinFET design, and characterize the impact of process variations, e.g., lithography and etch process, CMP (chemical-mechanical polishing) process, redundant via, etc. We also analyze signal-line EM with transistor-level PVT (process-voltage-temperature) variation corners. Then we optimize the signal lines with various design approaches to mitigate EM problem in 16 nm design. PMID- 27483809 TI - Facet-Controlled CeO2 Nanocrystals for Oxidative Coupling of Methane. AB - Whether the catalysts of the high temperature reaction such methane oxidation coupling has a structure-sensitive catalytic behavior or not, it is discussed and confirmed the shape-specific impact on methane activity by designing the catalysts with different crystal facets exposed. CeO2 nanowires enclosed by {110} and {100} planes show the higher CH4 conversion and higher C2 hydrocarbons (C2H4 and C2H6) selectivity, compared with particle CeO2 rounded by {111} and {100} planes, suggesting that CeO2 (110) surface favors the activation of CH4. Encouraged by the result, to control facet-controlled synthesis of catalysts for tailoring the catalytic properties at high temperature, the CeO2 (110) surface is chosen as doped sites to form the doped catalyst such as Ca doped CeO2 nanowires for OCM reaction, enhancing C2 hydrocarbons selectivity dramatically and suppressing the deep oxidation product (CO and CO2) selectivity. PMID- 27483810 TI - Dual Effort to Correlate the Electron Field Emission Performance of Carbon Nanotubes with Synthesis As Well As Annealing Temperature: Theoretical Support of the Experimental Finding. AB - Here a dual approach has been adopted to study the effect of both synthesis as well as annealing temperature on the electron field emission property of differently synthesized carbon nanotubes (CNTs) that include solid state chemical reaction as well as chemical vapour deposition (CVD). Experimental findings were supported by theoretical simulation. All the samples were characterized by X-ray diffraction (XRD), Fourier transformed infrared spectroscopy, Raman spectroscopy, field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM). XRD as well as TEM study confirms the amorphous nature (aCNTs) of the samples for both the synthesis techniques which is attributed to lower synthesis temperature. Prominent morphological differences of these two types of aCNTs are clearly observed from both FESEM and TEM images. It is found that electron field emission characteristics of aCNTs synthesized by CVD shows better field emission properties as compared to aCNTs synthesized by solid state reaction. Finite element based simulation shows that temperature has prominent effect on morphology, screening effect or degree of graphitization that leads to improved field emission characteristics for the CVD synthesized aCNTs. PMID- 27483811 TI - Neuromorphic System Based on CMOS Inverters and Si-Based Synaptic Device. AB - We developed an analog neuron circuit that can work with Si-based synaptic devices. N-channel and p-channel synaptic devices connected to current mirrors constitute the synaptic connection and integration parts to implement the excitation and inhibition mechanisms of biological neurons. The normal inverter controlling delay time and the modified inverter making negative pulse constitute the action-potential generation part to generate output action-potential. Connecting output potential to the synaptic device, we implement the spike-timing dependent-plasticity (STDP) mechanism, adjusting the conductance of synapse. As we have constituted the analog neuron circuit using 4-terminal synaptic device without additional switch and logic operation, we can emulate the operation of the neuron with minimum number of devices and power dissipation. PMID- 27483812 TI - The Influence of Variability Sources on SRAM Stability in 90 A Non-Rectangular Bulk FinFET SRAM Cell. AB - The temperature dependency of influence of variability sources on SRAM stability were simulated and analyzed in 90 A non-rectangular Bulk FinFET SRAM cell. RDF is the most dominant variability source. In addition, it is also shown that standard deviation of read static noise margin (sigma(RSNM)) by WFV and RDF decreases with increasing temperature, whereas sigma-(RSNM) by LER increases with increasing temperature. Finally, the analyses on the simulation results mentioned above were performed. PMID- 27483813 TI - Applying Electrospun Gelatin/Poly(lactic acid-co-glycolic acid) Bilayered Nanofibers to Fabrication of Meniscal Tissue Engineering Scaffold. AB - The menisci are fibrocartilaginous tissues composed primarily of an interlacing network of collagen fibers with nanoscale diameter. Electrospinning is a suitable process of producing nanoscale fibers that mimic collagen fibers. In this study, a bilayered scaffold (group B), which consists of a gelatin nanofiber mesh and a PLGA nanofiber mesh, has been fabricated through an electrospinning method. At the same time, we electrospun pure PLGA fibrous mesh (group A) and gelatin/PLGA composite fibrous mesh (group C) as control groups. In order to compare all scaffold morphologies, the scaffolds were imaged by SEM and some parameters were measured and analyzed as following: Diameters of fibrils are from the smallest of less than average 0.14 MUm for group C to the biggest of nearly average 0.38 MUm for group B. The scaffolds pore diameters are from average 4.9 MUm for group A to average 11.2 MUm for group B. Porosity rates show that the group B has the highest porosity rate at about 91%. The scaffolds' properties were compared and analyzed, including hydrophilicity property (water contact angle) and mechanical properties (tensile strength). The results of water contact angle showed the group B is the most hydrophil among the groups. The results of tensile strength showed the tensile strength of group C is the weakest among the groups. All the results showed significant differences between the groups. Finally, in vitro, the meniscal cells derived from New Zealand white rabbits menisci were seeded in the scaffolds. We observed the cells proliferation behavior in the scaffolds. All above demonstrates that a bi-layered gelatin/PLGA scaffold reveals not only concurrent effects of mechanics and cytocompatibility in a fibrous context, but also a promising scaffold for future meniscal repair strategies. PMID- 27483814 TI - Efficient Fenton Oxidation of Congo Red Dye by Magnetic MgFe2O4 Nanorods. AB - We reported a highly active magnetic MgFe2O4 nanorods catalyst by annealing Mg(OH)2 deposited alpha-FeOOH nanorods. The catalyst was fully characterized by X ray diffraction (XRD), High Resolution Transmission Electron Microscopy (HRTEM), and Vibrating Sample Magnetometer (VSM), and the results showed that the magnetic MgFe2O4 nanorods were a diameter of 50 nm. The as-prepared MgFe2O4 nanorods were used to catalyze Fenton oxidation of Congo red (CR) solution, and the degradation rate of CR reached 95% after 2 h. The catalytic activity remained high after five cycles. The magnetic MgFe2O4 nanorods could be easily separated from organic solvent. The effects of parameters such as temperature, dosage of catalyst, and H2O2 were also analyzed. This opens new perspectives for the synthesis of one dimensional magnetic catalyst based on a template method and effective treatment of aqueous hazardous dye. PMID- 27483815 TI - Magnetic Nanoparticles: Synthesis, Characterization and Magnetic Properties of Cobalt Aluminum Ferrite. AB - Nanoparticles of the ferrite system CoFe(2-x)Al(x)O4 (x = 0.0, 0.3, 0.7 and 1.0) were synthesized through the co-precipitation technique. Thermal decomposition process and formation of a single crystalline phase were followed using thermal differential analysis technique (DTA). X-ray powder diffraction patterns of the samples confirmed the formation of a nano-size single spinel phase. The average crystallite size was found to be in the range 20-63 nm for all samples. This was further confirmed by TEM of one of the samples, with concentration x = 1.0 which was found statistically to be 27 nm. This agrees well with the value of 24 nm deduced by means of X-ray diffraction method for the same sample. A considerable decrease in the intensity of the octahedral bands is observed as the aluminum concentration increases, and even vanishes completely at x = 1.0 indicating the migration of cations between the octahedral and tetrahedral sites. The magnetic hysteresis loops at room temperature showed decrease in both, coercivity and saturation magnetization as the non-magnetic Al3+ ions content increases. The relative values of M(r0/M(s) were found to be between 0.44 and 0.31 for the samples with a remarkable change in the squareness of the loops. This is highly beneficial for the microwave and memory devices applications of these nano sized ferrite system. PMID- 27483816 TI - Analysis of the Electrical Properties of an Electron Injection Layer in Alq3 Based Organic Light Emitting Diodes. AB - We investigated the carrier transfer and luminescence characteristics of organic light emitting diodes (OLEDs) with structure ITO/HAT-CN/NPB/Alq3/Al, ITO/HAT CN/NPB/Alq3/Liq/Al, and ITO/HAT-CN/NPB/Alq3/LiF/A. The performance of the OLED device is improved by inserting an electron injection layer (EIL), which induces lowering of the electron injection barrier. We also investigated the electrical transport behaviors of p-Si/Alq3/Al, p-Si/Alq3/Liq/Al, and p-Si/Alq3/LiF/Al Schottky diodes, by using current-voltage (L-V) and capacitance-voltage (C-V) characterization methods. The parameters of diode quality factor n and barrier height phi(b) were dependent on the interlayer materials between Alq3 and Al. The barrier heights phi(b) were 0.59, 0.49, and 0.45 eV, respectively, and the diode quality factors n were 1.34, 1.31, and 1.30, respectively, obtained from the I-V characteristics. The built in potentials V(bi) were 0.41, 0.42, and 0.42 eV, respectively, obtained from the C-V characteristics. In this experiment, Liq and LiF thin film layers improved the carrier transport behaviors by increasing electron injection from Al to Alq3, and the LiF schottky diode showed better I-V performance than the Liq schottky diode. We confirmed that a Liq or LiF thin film inter-layer governs electron and hole transport at the Al/Alq3 interface, and has an important role in determining the electrical properties of OLED devices. PMID- 27483817 TI - Accurate Analysis and Characterization of Silicon Field Effect Transistor-Based Terahertz Wave Detector with Quasi-Plasma Two-Dimensional Electron Gas. AB - We report the nonresonant plasmonic terahertz (THz) wave detector based on the silicon (Si) field effect transistor (FET) with a technology computer-aided design (TCAD) platform. The plasma wave behavior has been modeled by a quasi plasma electron box as a two-dimensional electron gas (2DEG) in the channel of the FET. The incoming alternating current (AC) signal as the THz wave radiation can induce the direct-current (DC) voltage difference between the source and drain, which is called the photoresponse. For accurate analysis of the modulation and propagation of the channel electron density as the plasma wave, we have characterized the quasi-plasma 2DEG model with two key parameters, such as quasi plasma 2DEG length (I(QP)) and density (N(QP)). By using our normalization method, I(QP) and N(QP) is defined exactly as extracting the average point of the electron density. We also investigate the performance enhancement of the plasmonic terahertz wave detector based on Si FET by scaling down the gate oxide thickness (t(ox)), which is a significant parameter of FET-based plasmonic terahertz detector for the channel electron density modulation. According to scaling down t(ox), the responsivity (R(v)) and noise equivalent power (NEP), which are the important performance metrics of the THz wave detector, have been enhanced. The proposed methodologies will provide the advanced physical analysis and structural design platform for developing the plasmonic terahertz detectors operating in nonresonant regime. PMID- 27483818 TI - Multiple Negative Differential Resistance Device by Using the Ambipolar Behavior of Tunneling Field Effect Transistor with Fast Switching Characteristics. AB - We propose a novel double-peak negative differential resistance (NDR) characteristic at the conventional single-peak MOS-NDR circuit by employing ambipolar behavior of TFET. The fluctuated voltage transfer curve (VTC) from ambipolar inverter is analyzed with simple model and successfully demonstrated with TFET, as a practical example, on the device simulation. We also verified that the fluctuated VTC generates additional peak and valleys on NDR characteristics by using circuit simulations. Moreover, by adjusting the threshold voltage of conventional MOSFET, ultra-high 1st and 2nd peak-to-valley current ratio (PVCR) over 10(7) is obtained with fully suppressed valley currents. The proposed double-peak NDR circuit expected to apply on faster switching and low power multi-functional applications. PMID- 27483819 TI - Effects of High-Pressure Hydrogen Annealing (HPHA) on Reliability Characteristics of RRAM. AB - Reliability characteristics (retention and endurance) of RRAM are critical for its practical realization and need to be improved. In this work, we confirmed the trade-off between retention and endurance by using various top electrode thickness conditions. The trade-off between retention and endurance characteristics was mainly due to the different amount of oxygen in scavenging layer (Ta) and the amount of oxygen vacancy in switching layer (HfO2). The amount of the oxygen in scavenging layer (Ta) and the amount of the oxygen vacancy in switching layer (HfO2) will be increased with the increase of Ta thickness. Therefore, the thicker Ta cells have worse retention because the large amount of oxygen in scavenging layer (Ta) can diffuse back into switching layer (HfO2) and recombine with oxygen vacancies in the filament. However, it has longer endurance because the large amount of oxygen vacancy in switching layer (HfO2) can be a source of the filament. Hence, there exists a trade-off relation between retention and endurance under the various Ta thickness conditions. To improve both retention and endurance characteristics, we proposed a new method by using high-pressure hydrogen annealing (HPHA). The thin Ta cells have longer retention and worse endurance because it has small amount of both oxygen in scavenging layer (Ta) and oxygen vacancy in switching layer (HfO2). Therefore, to generate more oxygen vacancies in switching layer (HfO2) maintaining small amount of oxygen in scavenging layer (Ta), we treated the samples by HPHA before Ta deposition. Finally, we obtained both improved retention and endurance characteristics in HfO2 based RRAM devices after high-pressure hydrogen annealing treatment. PMID- 27483820 TI - Synthesis of Leucas Aspera Extract Loaded Gold-PLA-PEG-PLA Amphiphilic Copolymer Nanoconjugates: In Vitro Cytotoxicity and Anti-Inflammatory Activity Studies. AB - Gold nanoparticles (GNPs) are synthesized using the medicinal plant Leucas Aspera extract (LAE) and poly lactic acid-co-poly ethylene glycol-co-poly lactic acid (PLA-PEG-PLA) copolymer by water-in-oil (W/O) emulsion method. The proposed method of W/O emulsion technique involves synthesis of GNPs and loading of Leucas Aspera extract on to the PLA-PEG-PLA copolymer matrix simultaneously. The synthesized GNPs are characterized by Fourier transform infra-red (FTIR) spectroscopy, dynamic light scattering (DLS), X-ray diffractometry (XRD) and transmission electron microscopy (TEM). The GNPs-LAE loaded polymer NPs are examined for the in vitro cytotoxicity on South African green monkey's kidney cells. The GNPs-LAE loaded polymer nanoconjugates exhibit maximum up to 95% of cell viability with 100 MUg concentration of GNPs in the sample. The GNPs-LAE loaded polymer NPs exhibit better anti-inflammatory activity when compared to the pure LAE. PMID- 27483821 TI - Electrostatic Layer-By-Layer Self-Assembled Graphene/Multi-Walled Carbon Nanotubes Hybrid Multilayers as Efficient 'All Carbon' Supercapacitors. AB - In this work, covalently bonded graphene/carbon nanotube (Gr/CNT) conjoined materials are fabricated as engineered three-dimensional hybrid multilayer supercapacitors for high-performance integrated electrochemical energy storage. Stable aqueous dispersion of polymer-modified graphene sheets are prepared in the presence of cationic poly(ethyleneimine), PEI (PEI-Gr) for sequential or electrostatic layer-by-layer (E-LBL) self-assembly with negatively charged acid oxidized or functionalized multi-walled CNT (fMWCNT), forming (PEI-Gr/fMWCNT)n architecture as "all carbon" super-capacitor, where n = 1, 2, 4, 6, 9, 12 and 15. These films possess an interconnected network of mesoporous nanocarbon structure with well-defined interfaces allowing sufficient surface adsorption and faster ion transport due to short diffusion distances. They exhibit nearly rectangular cyclic voltammograms at an exceedingly high scan rate of 1 V/s with an average specific capacitance of -450 F g(-1) and specific energy density of 75.5 Wh kg( 1) based on electrode weight, measured at a current density of 0.3 A g(-1), comparable to that of Ni metal hydride battery and charged/discharged within a few seconds or a minute. This is attributed to the maximized synergistic effect of the highest specific surface areas by preventing re-aggregation of PEI-Gr or PEI-rGO via fMWCNT as spacers. We also determined relative contributions of the interfacial capacitance (C(dl)) and charge transfer (R(ct)) properties of the hybrids and investigated interfacial properties by SECM technique. PMID- 27483822 TI - Effects of Low Temperature Anneal on the Interface Properties of Thermal Silicon Oxide for Silicon Surface Passivation. AB - High quality surface passivation has gained a significant importance in photovoltaic industry for reducing the surface recombination and hence fabricating low cost and high efficiency solar cells using thinner wafers. The formation of good-quality SiO2 films and SiO2/Si interfaces at low processing temperatures is a prerequisite for improving the conversion efficiency of industrial solar cells with better passivation. High-temperature annealing in inert ambient is promising to improve the SiO2/Si interface. However, annealing treatments could cause negative effects on SiO2/Si interfaces due to its chemical at high temperatures. Low temperature post oxidation annealing has been carried out to investigate the structural and interface properties of Si-SiO2 system. Quasi Steady State Photo Conductance measurements shows a promising effective carrier lifetime of 420 MUs, surface recombination velocity of 22 cm/s and a low interface trap density (D(it)) of 4 x 10(11) states/cm2/eV after annealing. The fixed oxide charge density was reduced to 1 x 10(11)/cm2 due to the annealing at 500 degrees C. The FWHM and the Si-O peak wavenumber corresponding to the samples annealed at 500 degrees C reveals that the Si dangling bonds in the SiO2 films due to the oxygen defects was reduced by the low temperature post oxidation annealing. PMID- 27483823 TI - Fabrication and Characteristics of High Mobility InSnZnO Thin Film Transistors. AB - In this paper, we describe the fabrication of thin film transistors (TFTs) with amorphous indium-tin-zinc-oxide (ITZO) as the active material. A transparent ITZO channel layer was formed under an optimized oxygen partial pressure (OPP (%) = O2/(Ar + O2)) and subsequent annealing process. The electrical properties exhibited by this device include field-effect mobility (MU(eff)), sub-threshold swing (SS), and on/off current ratio (I(ON/OFF)) values of 28.97 cm2/V x s, 0.2 V/decade, and 2.64 x 10(7), respectively. The average transmittance values for each OPP condition in the visible range were greater than 80%. The positive gate bias stress resulted in a positive threshold voltage (V(th)) shift in the transfer curves and degraded the parameters MU(eff) and SS. These phenomena originated from electron trapping from the ITZO channel layer into the oxide/ITZO interface trap sites. PMID- 27483824 TI - Synthesis and Application of Si/Carbon Nanofiber Composites Based on Ni and Mo Catalysts for Anode Material of Lithium Secondary Batteries. AB - In this paper, carbon nanofibers (CNFs) and Si/carbon nanofiber composites were synthesized for use as the anode material of lithium secondary batteries. Catalysts were prepared based on Ni and Mo metals and CNFs were grown through chemical vapor deposition (CVD). In addition, the grown CNFs were mixed with silicon particles to synthesize Si/carbon nanofibers composites. The physiochemical characteristics of the synthesized CNFs and Si/carbon nanofiber composites were analyzed by SEM, EDS, XRD, Raman, BET and XPS. The electrochemical characteristics were investigated by using cyclic voltammetry and galvanostatic charge-discharge. Using CNFs and Si/carbon nanofiber composites as the anode material, three electrode cells were assembled and the electrochemical characteristics were measured using LiPF6 and LiClO4 as electrolytes. As a result of the galvanostatic charge-discharge of CNFs that were grown through catalysts with Ni and Mo concentration ratio of 6:4, the initial discharge capacity when using LiPF6 as the electrolyte was 570 mAh/g and the retention rate was 15.05%. In the case of using LiClO4 as the electrolyte, the initial discharge capacity was 263 mAh/g and the retention rate was 67.23%. PMID- 27483825 TI - Analysis of Current Fluctuation Due to Trap and Percolation Path in Nano-Scale Bulk FinFET. AB - An electron in the channel can be trapped into the trap inside gate oxide and detrapped into the channel, resulting in the fluctuation in drain current. To investigate the drain current fluctuation (DeltaI(D)) caused by trapping/detrapping of an electron in 22 nm bulk FinFET, 3-D device simulation was performed extensively. The DeltaI(D) is changed by changing the position of the trap in the gate oxide along the surface of fin body. In the bulk FinFET, the trap located near the center of side surface of the fin body gives the larger DeltaI(D) compared to those of the traps located at the top center, top corner, and side bottom. At a fixed trap position, the shallower trap depth (x(T)) from the interface between the gate oxide and the fin body gives the lager DeltaI(D). With decreasing fin width (W(fin)) and fin height (H(fin)), the DeltaI(D) increases. Especially, decreasing H(fin) increases DeltaI(D) significantly. As the trap is close to a percolation path, the DeltaI(D) also increases. PMID- 27483826 TI - Post-Cleaning Effect on a HfO2 Gate Stack Using a NF3/NH3 Plasma. AB - The effects of dry cleaning of a HfO2 gate stack using NF3 only and a NF3/NH3 gas mixture plasma were investigated. The plasma dry cleaning process was carried out after HfO2 deposition using an indirect down-flow capacitively coupled plasma (CCP) system. An analysis of the chemical composition of the HfO2 gate stacks by XPS indicated that fluorine was incorporated into the HfO2 films during the plasma dry cleaning. Significant changes in the HfO2 chemical composition were observed as a result of the NF3 dry cleaning, while they were not observed in this case of NF3/NH3 dry cleaning. TEM results showed that the interfacial layer (IL) between the HfO2 and Si thickness was increased by the plasma dry cleaning. However, in the case of NF3/NH3 dry cleaning using 150 W, the IL thickness was suppressed significantly compared to the sample that had not been dry cleaned. Its electrical properties were also improved, including the low gate leakage currents, and reduced EOT. Finally, the finding show that the IL thickness of the HfO2 gate stack can be controlled by using the novel NF3/NH3 dry cleaning process technique without any the significant changes in chemical composition and metal oxide-semiconductor (MOS) capacitor characteristics. PMID- 27483827 TI - Synthesis of Fe Doped ZnO Nanowire Arrays that Detect Formaldehyde Gas. AB - Owing to their chemical and thermal stability and doping effects on providing electrons to the conduction band, doped ZnO nanowires have generated interest for use in electronic devices. Here we report hydrothermally grown Fe-doped ZnO nanowires and their gas-sensing properties. The synthesized nanowires have a high crystallinity and are 60 nm in diameter and 1.7 MUm in length. Field-emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), X ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) are employed to understand the doping effects on the microstructures and gas sensing properties. When the Fe-doped ZnO nanowire arrays were evaluated for gas sensing, responses were recorded through changes in temperature and gas concentration. Gas sensors consisting of ZnO nanowires doped with 3-5 at.% Fe showed optimum formaldehyde (HCHO) sensing performance at each working temperature. PMID- 27483828 TI - Resistive Switching in Al/Al2O3/TiO2/Al/PES Flexible Device for Nonvolatile Memory Application. AB - Resistive switching memory devices with superior properties are possibly used in next-generation nonvolatile memory to replace the flash memory. In addition, flexible electronics has also attracted much attention because of its light weight and flexibility. Therefore, an Al/Al2O3/TiO2/Al/PES flexible resistive switching memory is employed in this study. The resistive switching characteristics and stability of the flexible device are improved by inserting the Al2O3 film. The resistive switching of the flexible device can be repeated over hundreds of times after the bending test. A possible resistive switching model of the flexible device is also proposed. In addition, the non-volatility of the flexible device is demonstrated. Based on our research results, the proposed Al2O3/TiO2-based resistive switching memory is possibly used in next-generation flexible electronics and nonvolatile memory applications. PMID- 27483829 TI - Conformational, Optoelectronic and Vibrational Properties of the Entacapone Molecule: A Quantum Chemistry Study. AB - A quantum chemistry study were carried out looking for the conformational, optoelectronic and vibrational properties of the entacapone molecule, an efficient drug used in the Parkinson's disease treatment. Classical annealing was performed to explore the entacapone's molecular configurations, searching for optimal geometries. The quantum optimization calculations were made using three different functional combination levels of the density functional theory (DFT). The structural data (bond length, bond and torsion angles), charge population analysis (absorption spectra) and molecular orbital study (HOMO and LUMO) were obtained considering the lower energy optimized conformation of the entacapone molecule. Furthermore, a complete assignment of the harmonic vibrational frequencies were achieved through their infrared (IR) and Raman spectra. PMID- 27483830 TI - Graphene Oxide Modified TiO2 Micro Whiskers and Their Photo Electrochemical Performance. AB - Harnessing the solar energy and producing clean fuel hydrogen through efficient photo-electrochemical water splitting has remained one of the most challenging endeavors in materials science. The core problem is to develop a suitable photo catalyst material that absorbs a significant part of the solar spectrum and produces electron-hole pairs that can be easily separated without recombination. In the recent times, the composite of Titanium dioxide with graphene have been investigated to explore the advantages of both class of materials. Here we report on the photo-electrochemical properties of reduced graphene oxide functionalised TiO2 whiskers. The TiO2 whiskers are obtained from potassium titanium oxide (KTi8O16) synthesized through hydrothermal technique followed by ion exchange method and heat treatment. Graphene oxide was deposited on the as prepared TiO2 whiskers using hydrothermal method. As formed samples were characterized by Raman spectroscopy to confirm the presence of reduced graphene oxide (RGO) attached to TiO2 whiskers. Comparative photo electrochemical studies were carried out for TiO2 and reduced graphene oxide modified TiO2 whiskers. Among these, RGO modified TiO2 whiskers show significantly higher photo current density possibly due to enhancement in charge separation ability and longer electron life times. PMID- 27483831 TI - The Role of Nanocrystal Size in Solution Processable CdSe:P3HT Hybrid Photovoltaic Devices. AB - Hybrid photovoltaic devices were fabricated using different sizes of CdSe quantum dots with different loading concentrations in P3HT matrix. CdSe quantum dots were synthesized chemically using olive oil as the capping agent, instead of toxic phosphine. The efficiency of hybrid poly-(3-hexylthiophene-2,5-diyl) P3HT:CdSe photovoltaic device was found to depend on the size as well as the loading of the nanocrystals. A maximum power conversion efficiency of -0.8% was achieved under AM1.5G solar illumination for the device with -5.3 nm CdSe nanocrystals. A hybrid photovoltaic device was demonstrated on polyethylene terephthalate (PET) substrates paving the way to achieve flexible,transparent and printable devices. PMID- 27483832 TI - Boron Oxygen Pair Effect in p+ Emitter and Nanosized Boron Rich Layer by Fold Coordination Analysis for Crystalline Silicon Solar Cell Applications. AB - N-type substrates possess better material characteristics than p-type substrates for high efficiency mass producible Si solar cells with HIT, IBC structures. The major drawbacks of these structures are a complicated fabrication process and an expensive unit cost. In this paper, the boron emitter doping profile of a nanosized boron rich layer (BRL), for which the boron and oxygen concentrations are correlated, is optimized to fabricate high efficiency solar cells on an n type substrate. Boron doping was carried out using a BBr3 furnace with varying oxygen gas ratios and the surface was treated with acid etching. The effect of the oxygen on the nanosized BRL was analyzed using both FTIR spectroscopy and XPS, where by conductivity and the Si-B bond were observed for the three-fold and four-fold coordinated borons, respectively. The results showed that the oxygen quantities in the boron doped emitter and the nanosized BRL affected the characteristics of the solar cell. Regarding the solar cells that were fabricated using the boron emitter and shallow emitter (90 ohm/sq) processes, the open circuit voltage increased by 54 mV and the short circuit current (J(sc)) increased by 3.7 mA/cm2. The J(sc) increase was due to an increased quantum efficiency in the short wavelength range. The shallow emitter etch back process minimized the boron-oxygen defects in the doping profile. PMID- 27483833 TI - Trap Profiling Based on Frequency Varied Charge Pumping Method for Hot Carrier Stressed Thin Gate Oxide Metal Oxide Semiconductors Field Effect Transistors. AB - In this study, pulse frequency and reverse bias voltage is modified in charge pumping and advanced technique is presented to extract oxide trap profile in hot carrier stressed thin gate oxide metal oxide semiconductor field effect transistors (MOSFETs). Carrier trapping-detrapping in a gate oxide was analyzed after hot carrier stress and the relationship between trapping depth and frequency was investigated. Hot carrier induced interface traps appears in whole channel area but induced border traps mainly appears in above pinch-off region near drain and gradually decreases toward center of the channel. Thus, hot carrier stress causes interface trap generation in whole channel area while most border trap generation occurs in the drain region under the gate. Ultimately, modified charge pumping method was performed to get trap density distribution of hot carrier stressed MOSFET devices, and the trapping-detrapping mechanism is also analyzed. PMID- 27483834 TI - Effects of Sulfurization Temperature on Cu(In, Ga)S2 Thin Film Solar Cell Performance by Rapid Thermal Process. AB - Cu(In, Ga)S2 (CIGS) absorbers were prepared using two-step process. Cu-In-Ga precursors were deposited by sputtering method and then were sulfurized by rapid thermal process based on H2S gas. Sulfurization temperature was changed from 470 degrees C to 510 degrees C. As the processing temperature increased, larger grains and denser absorbers were observed. The polycrystalline chalcopyrite structure of CuInGaS2 was shown in all samples, and their XRD peak was dominantly observed at (112) direction. CIGS thin film solar cells were fabricated with wide bandgap absorbers obtained by varying sulfurization temperature. The best efficiency was shown with the processing temperature of 490 degrees C and 8.93% with 1.507 eV of wide optical bandgap. PMID- 27483835 TI - Fabrication of InGaZnO Nonvolatile Memory Devices at Low Temperature of 150 degrees C for Applications in Flexible Memory Displays and Transparency Coating on Plastic Substrates. AB - We directly deposited amorphous InGaZnO (a-IGZO) nonvolatile memory (NVM) devices with oxynitride-oxide-dioxide (OOO) stack structures on plastic substrate by a DC pulsed magnetron sputtering and inductively coupled plasma chemical vapor deposition (ICPCVD) system, using a low-temperature of 150 degrees C. The fabricated bottom gate a-IGZO NVM devices have a wide memory window with a low operating voltage during programming and erasing, due to an effective control of the gate dielectrics. In addition, after ten years, the memory device retains a memory window of over 73%, with a programming duration of only 1 ms. Moreover, the a-IGZO films show high optical transmittance of over 85%, and good uniformity with a root mean square (RMS) roughness of 0.26 nm. This film is a promising candidate to achieve flexible displays and transparency on plastic substrates because of the possibility of low-temperature deposition, and the high transparent properties of a-IGZO films. These results demonstrate that the a-IGZO NVM devices obtained at low-temperature have a suitable programming and erasing efficiency for data storage under low-voltage conditions, in combination with excellent charge retention characteristics, and thus show great potential application in flexible memory displays. PMID- 27483836 TI - Highly Durable Ti-Mesh Based Triboelectric Nanogenerator for Self-Powered Device Applications. AB - We describe a highly durable Ti-mesh based triboelectric nanogenerator (Ti-TENG) with a sandwich structure that harvests electrical energy from contact electrification. The electrical output from the fabricated Ti-TENG by compressing and releasing strain was measured under different applied loads and frequencies. The Ti-TENG generated a peak voltage and current up to -1.1 V and -14 nA at an applied force of 30 N and frequency of 1.1 Hz. Obtained potentials were used to charge a capacitor and power a commercially available light emitting diode (LED). In particular, the Ti-TENG, which exhibited high electrical stability, can be used in applications requiring high levels of robustness and durability. For example, the Ti-TENG was applied as step counter while walking and running, demonstrating its capability to self-power devices. We believe that the device provides a highly promising, robust and durable platform for self-powered applications that effectively harnesses energy from mechanical movements. PMID- 27483837 TI - Hydrogenated Amorphous Silicon Germanium Active Layer for Top Cell of a Multi Junction Cell Structure. AB - Intrinsic hydrogenated amorphous silicon-germanium (a-SiGe:H) alloy is generally used in the bottom cell because of its low band gap. The a-SiGe:H has a higher photo conductivity in comparison to the a-Si:H; thus, it is expected that the a SiGe:H can show better short circuit current density than that of the a-Si:H based solar cell. Therefore, we optimized a-SiGe:H active layer that can be a suitable choice for the front cell of a multi junction.solar cell. Furthermore, we carried out a comparative study of the solar cells that have a-SiGe:H and a Si:H as respective active layers. The a-SiGe:H based solar cells show higher short circuit current density, while the a-Si:H based cells show higheropen circuit voltage. The current-voltage characteristics of these cells are as follows: (a) V(oc) = 770 mV, J(sc) = 15.0 mA/cm2, FF = 64.5%, and eta = 7.47% for a-SiGe:H based cell; and (b) V(oc) = 826 mV, J(sc) = 13.63 mA/cm2, FF = 72.0%, and eta = 8.1% for a-Si:H based cell. PMID- 27483838 TI - Improvement of Charge Transportation in Si Quantum Dot-Sensitized Solar Cells Using Vanadium Doped TiO2. AB - The multiple exciton generation characteristics of quantum dots have been expected to enhance the performance of photochemical solar cells. In previous work, we first introduced Si quantum dot for sensitized solar cells. The Si quantum dots were fabricated by multi-hollow discharge plasma chemical vapor deposition, and were characterized optically and morphologically. The Si quantum dot-sensitized solar cells had poor performance due to significant electron loss by charge recombination. Although the large Si particle size resulted in the exposure of a large TiO2 surface area, there was a limit to ho much the particle size could be decreased due to the reduced absorbance of small particles. Therefore, this work focused on decreasing the internal impedance to improve charge transfer. TiO2 was electronically modified by doping with vanadium, which can improve electron transfer in the TiO2 network, and which is stable in the redox electrolyte. Photogenerated electrons can more easily arrive at the conductive electrode due to the decreased internal impedance. The dark photovoltaic properties confirmed the reduction of charge recombination, and the photon-to-current conversion efficiency reflected the improved electron transfer. Impedance analysis confirmed a decrease in internal impedance and an increased electron lifetime. Consequently, these improvements by vanadium doping enhanced the overall performance of Si quantum dot-sensitized solar cells. PMID- 27483839 TI - Salicylic Acid-Based Organic Dyes Acting as the Photosensitizer for Solar Cells. AB - A D-pi-A metal-free organic dye, featuring salicylic acid as a novel acceptor/anchoring unit, has been designed, synthesized and applied to dye sensitized solar cell. The detailed photophysical, electrochemical, photovoltaic and sensitizing properties of the organic dye were investigated, in addition to the computational studies of the dye and dye-(TiO2)6 system. A solar cell device using this new organic dye as a sensitizer produced a solar to electric power conversion efficiency (PCE) of 3.49% (J(sc) = 6.69 mAcm-2, V(oc) = 0.74 V and ff = 0.70) under 100 mWcm(-2) simulated AM 1.5 G solar irradiation, demonstrating that the salicylic acid-based organic dye is a suitable alternative to currently used organometallic dyes. PMID- 27483840 TI - Method for Fabricating Textured High-Haze ZnO:Al Transparent Conduction Oxide Films on Chemically Etched Glass Substrates. AB - We developed a technique for forming textured aluminum-doped zinc oxide (ZnO:Al) transparent conductive oxide (TCO) films on glass substrates, which were etched using a mixture of hydrofluoric (HF) and hydrochloric (HCl) acids. The etching depth and surface roughness increased with an increase in the HF content and the etching time. The HF-based residues produced insoluble hexafluorosilicate anion- and oxide impurity-based semipermeable films, which reduced the etching rate. Using a small amount of HCl dissolved the Ca compounds, helping to fragment the semipermeable film. This formed random, complex structures on the glass substrates. The angled deposition of three layers of ZnO:Al led to the synthesis of multiscaled ZnO:Al textures on the glass substrates. The proposed approach resulted in textured ZnO:Al TCO films that exhibited high transmittance (-80%) and high haze (> 40%) values over wavelengths of 400-1000 nm, as well as low sheet resistances (< 18 Omega/sq)..Si tandem solar cells based on the ZnO:Al textured TCO films exhibited photocurrents and cell efficiencies that were 40% higher than those of cells with conventional TCO films. PMID- 27483841 TI - Characteristics of Nitrogen Doped Diamond-Like Carbon Films Prepared by Unbalanced Magnetron Sputtering for Electronic Devices. AB - Synthetic diamond-like carbon (DLC) is a carbon-based material used mainly in cutting tool coatings and as an abrasive material. The market for DLC has expanded into electronics, optics, and acoustics because of its distinct electrical and optical properties. In this work, n-doped DLC (N:DLC) films were deposited on p-type silicon substrates using an unbalanced magnetron sputtering (UBMS) method. We investigated the effect of the working pressure on the microstructure and electrical properties of n-doped DLC films. The structural properties of N:DLC films were investigated by Raman spectroscopy and SEM-EDX, and the electrical properties of films were investigated by observing the changes in the resistivity and current-voltage (I-V) properties. The N:DLC films prepared by UBMS in this study demonstrated good conducting and physical properties with n doping. PMID- 27483842 TI - Electrical Characteristics of Metal-Oxide-Semiconductor Capacitor with High kappa/Metal Gate Using Oxygen Scavenging Process. AB - It has been widely accepted that the mismatch of lattice constants between HfO2 and Si generates interface traps at the HfO2-Si interface, which causes the degradation of device performances. For better interface quality, very thin SiO2 film (< 2 nm) has been inserted as an interlayer (IL) between HfO2 and Si despite of the increase of EOT. In order to obtain both the better interface quality and the reduction of EOT, we used Ti metal on HfO2/IL SiO2 stack as a scavenging layer to absorb oxygens in the SiO2 and various annealing conditions were applied to optimize the thickness of the SiO2. As a result, we can effectively shrink the EOT from 3.55 nm to 1.15 nm while maintaining the same physical thickness of gate stacks. Furthermore, the diffusion of oxygen was confirmed by high resolution transmission electron microscopy (HRTEM) and time-of-flight secondary ion mass Spectrometry (SIMS). PMID- 27483843 TI - The Analysis of Characteristics in Dry and Wet Environments of Silicon Nanowire Biosensor. AB - Our study investigates differences in sensitivity of dry and wet environment in the field of biosensing experiment in detail and depth. The sensitivity of biosensing varies by means of surrounding conditions of silicon nanowire field effect transistor (SiNW FET). By examining charged polymer reaction in the silicon nanowire transistor (SiNW), we have discovered that the threshold voltage (V(T)) shift and change of subthreshold slope (SS) in wet environment are smaller than that of the air. Furthermore, we analyzed the sensitivity through modifying electrolyte concentration in the wet condition, and confirmed that V(T) shift increases in low concentration condition of phosphate buffered saline (PBS) due to the Debye length. We believe that the results we have found in this study would be the cornerstone in contributing to advanced biosensing experiment in the future. PMID- 27483844 TI - Interfacial Layer Control by Dry Cleaning Technology for Polycrystalline and Single Crystalline Silicon Growth. AB - Native oxide removal prior to poly-Si contact and epitaxial growth of Si is the most critical technology to ensure process and device performances of poly-Si plugs and selective epitaxial growth (SEG) layers for DRAM, flash memory, and logic device. Recently, dry cleaning process for interfacial oxide removal has attracted a world-wide attention due to its superior passivation properties to conventional wet cleaning processes. In this study, we investigated the surface states of Si substrate during and after dry cleaning process, and the role of atomic elements including fluorine and hydrogen on the properties of subsequent deposited silicon layer using SIMS, XPS, and TEM analysis. The controlling of residual fluorine on the Si surface after dry cleaning is a key factor for clean interface. The mechanism of native oxide re-growth caused by residual fluorine after dry cleaning is proposed based on analytical results. PMID- 27483845 TI - GaN Epitaxial Layer Grown with Conductive Al(x)Ga(1-x)N Buffer Layer on SiC Substrate Using Metal Organic Chemical Vapor Deposition. AB - This study investigated GaN epitaxial layer growth with a conductive Al(x)Ga(1 x)N buffer layer on n-type 4H-SiC by high-temperature metalorganic chemical vapor deposition (HT-MOCVD). The Al composition of the Al(x)Ga(1-x)N buffer was varied from 0% to 100%. In terms of the crystal quality of the GaN layer, 79% Al was the optimal composition of the Al(x)Ga(1-x)N buffer layer in our experiment. A vertical conductive structure was fabricated to measure the current voltage (I-V) characteristics as a function of Al composition, and the I-V curves showed that the resistance increased with increasing Al concentration of the Al(x)Ga(1-x)N buffer layer. PMID- 27483846 TI - Dual-Gate p-GaN Gate High Electron Mobility Transistors for Steep Subthreshold Slope. AB - A steep subthreshold slope characteristic is achieved through p-GaN gate HEMT with dual-gate structure. Obtained subthreshold slope is less than 120 MUV/dec. Based on the measured and simulated data obtained from single-gate device, breakdown of parasitic floating-base bipolar transistor and floating gate charged with holes are responsible to increase abruptly in drain current. In the dual gate device, on-current degrades with high temperature but subthreshold slope is not changed. To observe the switching speed of dual-gate device and transient response of drain current are measured. According to the transient responses of drain current, switching speed of the dual-gate device is about 10(-5) sec. PMID- 27483847 TI - Reaction Mechanism Underlying Atomic Layer Deposition of Antimony Telluride Thin Films. AB - The mechanism underlying the deposition of SbTe films by alternating exposures to Sb(NMe2)3 and Te(GeMe3)2 was investigated. Sb(NMe2)3 and Te(GeMe3)2 were selected because they have very high vapor pressure and are free of Si, Cl, and O atoms in the molecules. The mechanism of deposition was proposed by density functional theory (DFT) calculation and was verified by in-situ quartz crystal microbalance (QCM) analysis. DFT calculation expected the ligand-exchange reactions between the Sb and Te precursors to form Me2NGeMe3 as the byproduct. QCM analysis indicated that a single -NMe2 group in Sb(NMe2)3 reacts with -TeGeMe3 on the surface to form an Sb2Te3 film, and that a small fraction of Sb is incorporated into the film by the thermal decomposition of Sb(NMe2)3. The Te(GeMe3)2 molecules were thermally stable up to 120 degrees C, while the Sb(NMe2)3 molecules decomposed at temperatures of 60 degrees C and higher. Sb-rich SbTe films with different Sb contents were prepared by controlling the partial decomposition of Sb(NMe2)3 molecules, which was enhanced by increasing the pulse time of the precursor. PMID- 27483848 TI - Bacteria-Directed Construction of ZnO/CdS Hollow Rods and Their Enhanced Photocatalytic Activity. AB - Zinc oxide (ZnO) hollow rods were fabricated by precipitation method with Bacillus subtilis as template. CdS nanoparticles were then decorated on the surface of the ZnO rods through hydrothermal method. The as-prepared samples were characterized using X-ray diffraction, scanning electron microscopy, high resolution transmission electron microscope and ultraviolet-visible spectroscopy techniques. The ZnO/CdS composite hollow rods copied the morphology of Bacillus subtiis. A possible formation mechanism of the rods was proposed. The photocatalytic activity of the samples was further evaluated through the photodegradation of Rhodamine B under a simulated solar-light irradiation. Results indicated that the photocatalytic activity of the rods improved greatly. PMID- 27483849 TI - Preparation, Characterization and Intracellular Imaging of 2,4 Dichlorophenoxyacetic Acid Conjugated Gold Nanorods. AB - Visualizing the biodistribution of pesticides inside living cells is great importance for enhancing targeting of pesticides. Here we reported for the first time that gold nanorods (Au NRs) with size of 39.4 nm x 11.3 nm could be used as a fluorescent tracer to examine the distribution of a typical herbicide, 2,4 dichlorophenoxyacetic acid (2,4-D), in tobacco bright yellow 2 (BY-2) cells. The nanostructures of hybrid materials were analyzed by using Raman spectra and X-ray photoelectron spectroscopy (XPS), including spectra assignments and electronic property. These data revealed 2,4-D has successfully conjugated MP-Au NRs according to Raman and XPS. The biodistribution of the conjugates inside BY-2 cells was directly examined at 12 and 24 h by the two-photon microscopy. The intensity of two-photon luminescence (TPL) inside cells demonstrated that the conjugates could be localized and excluded by BY-2 cells. Thus, this labeling approach opens up new avenues to the facile and efficient labeling of pesticides. PMID- 27483850 TI - The Influence of Chelating Agent on the Structural and Magnetic Properties of CoFe2O4, Nanoparticles. AB - We have studied the influence of chelating agents (glycerin and sucrose) on the structural and magnetic properties of cobalt ferrite (CoFe2O4) nanoparticles synthesized via co-precipitation method. The Rietveld refinements from X-ray diffraction patterns confirm that all samples are single phase identified in a cubic crystalline system belonging to the space group Fd-3m. Besides, we have verified that the addition of chelating agents produces a decreasing in the particles average size from 14(2) to 5(1) nm. Magnetization measurements as a function of temperature show a decrease in the blocking temperature (T(B)) to sample obtained with addition of sucrose. A superparamagnetic behavior at room temperature was observed by magnetic measurements as function of field in the sample with 0.020 mol/L of sucrose. The results show that character chelating of sucrose reduces the coalescence effect and magnetic interaction in the CoFe2O4 nanoparticles. These results suggest that sucrose could be an alternative to control the structural and magnetic properties of other oxides nanoparticles. PMID- 27483851 TI - Enhanced Cytotoxicity of Biomolecules Loaded Metallic Silver Nanoparticles Against Human Liver (HepG2) and Prostate (PC3) Cancer Cell Lines. AB - Green nanoparticle synthesis was achieved using environmentally acceptable plant extracts reducing and capping agents. The present study was based on assessments to the anticancer activities to determine the effect of synthesized silver nanoparticles (AgNPs) from three medicinal plants on human liver (HepG2) and prostate (PC3) cancer cell lines. The synthesis of AgNPs using Plumbago zeylanica (Pz), Semecarpus anacardium (Sa) and Terminalia arjuna (Ta) plant extracts in the reaction mixture was monitored by UV-visible spectroscopy. FTIR results clearly illustrated that the plant extracts containing prominent peaks of functional groups and biomolecules viz., tannins, phenols, flavonoids and triterpenoids those act as capping agents and involved in the stabilization of the synthesised silver nanoparticles. Synthesized AgNPs were spherical and cuboid in shape which is determined by SEM. Average size of the AgNPs were between 80-98, 60-95 and 34 70 nm for PzAgNPs, SaAgNPs and TaAgNPs, respectively. Further, the synthesized AgNPs were characterized by XRD, EDX, DLS and Zeta potential analysis. Moreover, the synthesized AgNPs exhibited a dose-dependent cytotoxicity against human liver and prostate cancer cell lines. The inhibitory concentration (IC50) values of HepG2, PC3 and Vero cells were found to be 70.97, 58.61, 96.41; 10.04, 42.77, 83.86; and 28.42, 41.78, 69.48 MUg/ml for PzAgNPs, SaAgNPs and TaAgNPs at 48 h incubation. An induction of apoptosis was confirmed by DNA fragmentation, Hoechst, Rhodamine and AO/EtBr staining. The present results strongly suggested that the AgNPs synthesized using P. zeylanica, S. anacardium and T. arjuna extracts showed potential anticancer activity of HepG2 and PC3 cell lines. PMID- 27483852 TI - Naturally Produced Co/CoO Nanocrystalline Magnetic Multilayers: Structure and Inverted Hysteresis. AB - Cobalt-based multilayers with excellent sequencing are grown via radiofrequency magnetron sputtering with the use of one Co target and natural oxidation. The Co layers are continuous, fully textured {111} and have the face centered cubic structure. At the end of deposition of each Co layer air is let to flow into the vacuum chamber via a fine (leak) valve. The top of Co is oxidized. The oxidized layers consist of cubic CoO crystallites. Near the film surface hexagonal Co(OH)2 is also detected. Magneto-optical Kerr effect hysteresis loops show in-plane magnetized films. The magnetic saturation field in the out-of-plane measurements is large exceeding 12 kOe. This observation supports indirectly the fact that Co is face centered cubic; if it was c-axis textured hexagonal the magnetocrystalline anisotropy would be large resulting in smaller values of the saturation field. As the Co-layer thickness decreases the in-plane loops show reduced remanence, slow approach to magnetic saturation and the out-of-plane loops show inverted hysteresis and/or crossing loop features with sizeable remanence. The effects are discussed with respect to the enhanced orbital magnetic moment of Co and the antiferromagnetic coupling between Co spins at the Co/CoO interface. PMID- 27483853 TI - Influence of Heat Treatment Conditions on the Properties of Vanadium Oxide Thin Films for Thermochromic Applications. AB - In present work, the effects of the heat treatment on the structural, optical, and thermochromic properties of vanadium oxide films were investigated. Vanadium dioxide (VO2) thin films were deposited on glass substrate by reactive pulsed DC magnetron sputtering from a vanadium metal target in mixture atmosphere of argon and oxygen gas. Various heat treatment conditions were applied in order to evaluate their influence on the crystal phases formed, surface morphology, and optical properties. The films were characterized by an X-ray diffraction (XRD) in order to investigate the crystal structure and identify the phase change as post annealing temperature of 500-600 degrees C for 5 minutes. Surface conditions of the obtained VO2(M) films were analyzed by field emission scanning electron microscopy (FE-SEM) and the semiconductor-metal transition (SMT) characteristics of the VO2 films were evaluate by optical spectrophotometry in the UV-VIS-NIR, controlling temperature of the films. PMID- 27483854 TI - Characteristics of SnO2:Sb Films as Transparent Conductive Electrodes of Flexible Inverted Organic Solar Cells. AB - Antimony-doped tin oxide (ATO) films were deposited on polyethersulfone (PES) substrates by means of a radio frequency (RF) magnetron sputtering method, using a SnO2 target mixed with 6 wt% Sb at room temperature and using various RF powers; these films were used as transparent electrodes in inverted organic solar cells (IOSC). We investigated the structural, optical, and electrical properties of the resulting films by means of various analyses, including X-ray diffraction (XRD), UV-visible spectroscopy, and Hall effect measurements. The crystallinity and conductivity of the ATO films were increased by increasing the RF power used. Based on the experimental data acquired, we fabricated IOSCs based on ATO electrodes deposited by using various conditions. Each IOSC device was composed of an ATO electrode, a ZnO buffer layer, a photoactive layer (P3HT:PCBM), and an Al cathode. The IOSC based on an ATO electrode fabricated at the RF power of 160 W exhibited good device performance due to the electrode's high conductivity and crystallinity. PMID- 27483855 TI - Effective Light Trapping in Thin Film Silicon Solar Cells with Nano- and Microscale Structures on Glass Substrate. AB - For thin film silicon-based solar cells, effective light trapping at a broad range of wavelengths (400-1100 nm) is necessary. Normally, etching is only carried out with TCOs, such as SnO2:F and impurity doped ZnO, to form nano-sized craters in the surface morphology to confer a light trapping effect. However, in this study, prior to ZnO:Al etching, periodic structures on the glass substrates were made by photolithography and wet etching to increase the light scattering and internal reflection. The use of periodic structures on the glass substrate resulted in higher haze ratios in the range from 550 nm to 1100 nm, which is the optical absorption wavelength region for thin film silicon solar cells, than obtained by simple ZnO:Al etching. The periodically textured glass with micro sized structures compensates for the low haze ratio at the middle and long wavelengths of wet etched ZnO:Al. ZnO:Al was deposited on the periodically textured glass, after which the ZnO:Al surface was also etched randomly using a mixed acid solution to form nano-sized craters. The thin film silicon solar cells with 350-nm-thick amorphous silicon absorber layer deposited on the periodic structured glass and etched ZnO:Al generated up to 10.68% more photocurrent, with 11.2% increase of the conversion efficiency compared to the cell deposited on flat glass and etched ZnO:Al. PMID- 27483856 TI - Improving Memory Characteristics of Hydrogenated Nanocrystalline Silicon Germanium Nonvolatile Memory Devices by Controlling Germanium Contents. AB - Nonvolatile memory (NVM) with silicon dioxide/silicon nitride/silicon oxynitride (ONO(n)) charge trap structure is a promising flash memory technology duo that will fulfill process compatibility for system-on-panel displays, down-scaling cell size and low operation voltage. In this research, charge trap flash devices were fabricated with ONO(n) stack gate insulators and an active layer using hydrogenated nanocrystalline silicon germanium (nc-SiGe:H) films at a low temperature. In this study, the effect of the interface trap density on the performance of devices, including memory window and retention, was investigated. The electrical characteristics of NVM devices were studied controlling Ge content from 0% to 28% in the nc-SiGe:H channel layer. The optimal Ge content in the channel layer was found to be around 16%. For nc-SiGe:H NVM with 16% Ge content, the memory window was 3.13 V and the retention data exceeded 77% after 10 years under the programming condition of 15 V for 1 msec. This showed that the memory window increased by 42% and the retention increased by 12% compared to the nc Si:H NVM that does not contain Ge. However, when the Ge content was more than 16%, the memory window and retention property decreased. Finally, this research showed that the Ge content has an effect on the interface trap density and this enabled us to determine the optimal Ge content. PMID- 27483857 TI - Characteristics of W Doped Nanocrystalline Carbon Films Prepared by Unbalanced Magnetron Sputtering. AB - Nanocrystalline tungsten doped carbon (WC) films were prepared by unbalanced magnetron sputtering. Tungsten was used as the doping material in carbon thin films with the aim of application as a contact strip in an electric railway. The structural, physical, and electrical properties of the fabricated WC films with various DC bias voltages were investigated. The films had a uniform and smooth surface. Hardness and frication characteristics of the films were improved, and the resistivity and sheet resistance decreased with increasing negative DC bias voltage. These results are associated with the nanocrystalline WC phase and sp(2) clusters in carbon networks increased by ion bombardment enhanced with increasing DC bias voltage. Consequently, the increase of sp(2) clusters containing WC nanocrystalline in the carbon films is attributed to the improvement in the physical and electrical properties. PMID- 27483858 TI - Transparent Electrode for Si Heterojunction Photoelectric Devices. AB - The transparent conductive oxide layers are of great interest in recent researches because of their tunable properties which avail them to be used in varieties of applications. The important and most widely used TCO materials such as ITO and AZO films were prepared with three different layer thicknesses using DC sputtering system. The structural, optical and electrical characteristics of both ITO and AZO samples were analyzed and compared to reveal thickness dependent tunable properties of TCO materials. The maximum transmittance of 99.5% was obtained for AZO films at 600-700 nm wavelength range. The resistivity of ITO films was 200 times lesser than that of AZO films. The internal and external quantum efficiencies of ITO devices increased with increasing layer thickness whereas this situation was just opposite in case of AZO devices. The optical and electrical properties of ITO samples were found easily adjustable by changing layer thickness as compared to AZO samples. This study explores the strong association between the layer thickness and the properties of TCO films. This would be useful to extend the applications boundary of TCO materials. PMID- 27483859 TI - Gravure-Offset Printed Metallization of Multi-Crystalline Silicon Solar Cells with Low Metal-Line Width for Mass Production. AB - The gravure offset method has been developed toward an industrially viable printing technique for electronic circuitry. In this paper, a roller type gravure offset manufacturing process was developed to fabricate fine line for using front electrode for solar cells. In order to obtain the optimum metallization printing lines, thickness of 20 MUm which is narrow line is required. The main targets are the reduction of metallized area to reduce the shading loss, and a high conductivity to transport the current as loss free as possible out of the cell. However, it is well known that there is a poor contact resistance between the front Ag electrode and the n(+) emitter. Nickel plating was conducted to prevent the increase of contact resistance and the increase of fill factor (FF). The performance of n-Si/Ag (seed layer)/Ni solar cells were observed in 609 mV of open circuit voltage, 35.54 mA/cm2 of short circuit current density, 75.75% of fill factor, and 16.04% of conversion efficiency. PMID- 27483860 TI - Improvement of Pre-Annealed Cu(In, Ga)Se2 Absorbers for High Efficiency. AB - We used a DC-sputtering method to deposit the precursor (Cu3Ga/In) onto Mo with 1 um thick/soda-lime glass (SLG). We moved it onto a graphite crucible for the pre annealing process, and the pressure of the process tube was about 10 torr without Ar gas flow. The crucible in quartz tube was heated by halogen lamp to 250 degrees C for 30 min, and then raised to 550 degrees C for 10 min under a selenium atmosphere. To complete the solar cells, a buffer layer of 50 nm CdS was then deposited by chemical bath deposition (CBD), followed by a double layer (high resistivity/low resistivity) of RF sputtered i-ZnO/Al-ZnO thin films. The Al front contacts were deposited by thermal evaporator. PMID- 27483861 TI - Improvement in the Photocurrent of Inverted Organic Solar Cells Using MoO(x) Doped TAPC as a P-Type Optical Spacer. AB - In this work, we demonstrate enhancement in the short-circuit current of inverted organic photovoltaic cells (OPVs) using a p-type optical spacer. The p-type optical spacer, which consists of molybdenum oxide (MoO(x))-doped 1,1-bis[(di-4 tolylamino)phenyl]cyclohexane (TAPC), shows improved transmittance at visible light with high electrical conductivity. The electrical field distribution of incident light at the active layer of OPVs can be controlled by tuning the thickness of the optical spacer in the OPVs. Specifically, the incorporation of the 20-nm optical spacer layer in the OPV leads to enhanced spectral response of the device in the wavelength range of 400-600 nm, which is consistent with the combined results of improved optical absorption and better charge transport characteristics. As a result, the OPV with a 20-nm p-type optical spacer shows improvement in the short-circuit current compared with a device with 10 nm of embedded MoO(x). PMID- 27483862 TI - Enhanced Haze Ratio on Glass by Novel Vapor Texturing Method. AB - State-of-the-art optical trapping designs are required to enhance the light trapping capabilities of tandem thin film silicon solar cells. The wet etch process is used to texture the glass surface by dipping in diluted acidic solutions such as HNO3 (nitric acid) and HF (hydrofluoric acid). For vapor texturing, the vapor was generated by adding silicon to HF:HNO3 acidic solution. The anisotropic etching of vapor textured wafers resulted in an etching depth of about 2.78 MUm with reduced reflectance of 5%. We achieved a high haze value of 74.6% at a 540 nm wavelength by increasing the etching time and HF concentration. PMID- 27483863 TI - Dibenzothiophene-Substituted Fullerene Derivative as Electron Acceptor for Polymer Solar Cells. AB - A new fullerene derivative, [6,6]-dibenzo[b,d]thiophene-C61-butyric acid methyl ester (DBTC61BM) was synthesized from C60 using tosylhydrazone, and used as an electron-acceptor material for poly(3-hexylthiophene) (P3HT)-based organic photovoltaic cells. The synthesized DBTC61BM was used to modify the basic structure of [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM) by replacing the aromatic part with dibenzo[b,d]thiophene. The solubilities of DBTC61BM and PC61BM are similar; they have good solubilities in common organic solvents such as dichloromethane, chloroform, toluene, and 1,2-dichlorobenzene. The Stern-Volmer quenching constant (K(sv)) of DBTC61BM was 7.14 x 10(3) M(-1), and was correlated with the binding affinity between the fluorophore and a quencher. The lowest unoccupied molecular orbital energy level of DBTC61BM was -3.71 eV. The charge carrier mobility of a P3HT:DBTC61BM blend film was determined using the space charge-limited current method; the electron mobility value obtained for the P3HT:DBTC61BM blend film was 2.13 x 10(-4) cm2 V(-1) s(-1). Photovoltaic devices were fabricated using P3HT as the electron donor and DBTC61BM as the electron acceptor. Among the fabricated devices, photovoltaic cells with the structure ITO/PEDOT:PSS/P3HT:DBTC61BM/LiF/Al showed the highest power conversion efficiency, namely 3.23%, with an open-circuit voltage of 0.64 V, short-circuit current density of 8.14 mA cm(-2), and fill factor of 0.59, under AM 1.5 G (100 mW cm(-2)) illumination. PMID- 27483864 TI - Patterning ITO by Template-Assisted Colloidal-Lithography for Enhancing Power Conversion Efficiency in Organic Photovoltaic. AB - Highly structured interfaces are very desirable in organic photovoltaic solar cells (OPVs), in order to enhance power conversion efficiency (PCE) by decreasing of the transport path for excited charge carriers in the absorber and increasing the optical path length for photon absorption. Many complicated, high-cost lithographic methods have been attempted to modify the surface of the absorber or substrate. However, solution-based colloidal-lithography processes are scalable and cost-effective, but generally result in non-uniform structured surfaces. In this report, we demonstrated an optimized silica-templated colloidal lithographical approach to create a well-defined and controlled transparent ITO layer for enhancing power conversion efficiency (PCE). Additionally, morphological effects of the patterned ITO on optical properties and PCE were analyzed in detail. PMID- 27483865 TI - Hydrogenated g-C4N3 for Metal-Free Photocatalysis: A First-Principles Study. AB - Using the first principles method, we explored physical properties of hydrogenated g-C4N3. We found that the vacany site became the most stable H adsorption site. The electronic band structure and magnetic properties were strongly affected by the H adsorption concentration. At low H concentration, the g-C4N3 still preserved half metallic state. However, we observed a semiconducting band gap at 14.3% H concentration and the magnetic state disappeared. Despite this suppression of magnetic state, we found that the semiconducting H-g-C4N3 could be used for metal-free photocatalyst. The calculated band gap was 2.93 eV, and this corresponds to an optical wavelength of 423 nm. The conduction band (CB) edge was positioned at 1.54 eV higher in energy than H+/H2 level. This indicates that it has a strong ability to reduce H+ to H2. At the same time, the valence band (VB) edge position was 0.15 eV lower in energy than O2/H2O level. Overall, we propose that the hydrogenated g-C4N3 can be used as a potential metal-free photocatalytic material. PMID- 27483866 TI - Chemical Amination via Cycloaddition of Graphene for Use in a Glucose Sensor. AB - Graphene was chemically aminated via cycloaddition. Aziridine-ring linkages were formed by covalently modifying the C-C double bonds in graphene. The aminated graphene presents an enhanced hydrophilicity, the contact angle with water decreases from 80.5 degrees to 58.5 degrees. And the conductivity of aminated graphene exhibits exponential decay as the reaction time increase. If the reaction time is 90 min, the resistance of aminated graphene was increased from 32 Omega to -2744 Omega. Because the amino group has good biocompatibility, the aminated graphene is designed for use as an enzyme sensor platform, such as glucose sensor based on glucose oxidase. The aminated graphene exhibited a good detection response for glucose. The increase in device current is about 12% in 1.2 mg/mL glucose solution. PMID- 27483867 TI - Design and Fabrication of Integrated Fabry-Perot Type Color Reflector for Reflective Displays. AB - A Fabry-Perot type integrated color reflector, with red/blue/green colors as subpixels, was designed and fabricated with Si substrate. Ag films were used as reflective mirror layers, SiO2 films were used as Fabry-Perot cavity layers and W films were used as partially reflective layers for the cavity. To minimize the effects of the thickness variation of the oxide cavity layers, the structure of the color reflector was optimized, and the differential deposition scheme was devised and applied in the fabrication process. The integrated color reflector was successfully fabricated with the proposed fabrication scheme. The measured white reflectance was > 45% in the visible spectrum range and -49% at 550 nm wavelength. The fabricated reflector had moderate color gamut of 17% of the National Television System Committee (NTSC) standard and it showed very high white reflectivity. The fabricated color reflector is expected to be applicable to reflective displays. PMID- 27483868 TI - Dependence of Grain Size on the Performance of a Polysilicon Channel TFT for 3D NAND Flash Memory. AB - We investigated the dependence of grain size on the performance of a polycrystalline silicon (poly-Si) channel TFT for application to 3D NAND Flash memory devices. It has been found that the device performance and memory characteristics are strongly affected by the grain size of the poly-Si channel. Higher on-state current, faster program speed, and poor endurance/reliability properties are observed when the poly-Si grain size is large. These are mainly attributed to the different local electric field induced by an oxide valley at the interface between the poly-Si channel and the gate oxide. In addition, the trap density at the gate oxide interface was successfully measured using a charge pumping method by the separation between the gate oxide interface traps and traps at the grain boundaries in the poly-Si channel. The poly-Si channel with larger grain size has lower interface trap density. PMID- 27483869 TI - Performance of AlGaN/GaN Nanowire Omega-Shaped-Gate Fin-Shaped Field-Effect Transistor. AB - The AlGaN/GaN nanowire omega-shaped-gate FinFET have been successfully fabricated demonstrating much improved performance compared to conventional AlGaN/GaN MISHFET. The AlGaN/GaN omega-shaped-gate FinFET exhibited the remarkable on-state performances, such as maximum drain current of 1.1 A/mm, low on-resistance, and low current collapse compared to that of the conventional device structure. In addition, the excellent off-state performances were measured: low off-state leakage current as low as -10(-10) mA, the theoretical SS value of -62 mV/dec, and high I(ON)/I(OFF) ratio (-10(9)). Improved dc performances were obtained for omega-shaped-gate structure due to the fully depletion of the active fin body and perfectly separation of the depleted fin from the underlying thick GaN buffer layer. Furthermore, the additional reason for the enhanced device performance of the proposed device is the improved gate controllability compared to the conventional MISHFET. The proposed nano-structure device is very promising candidate for the steep switching device applications. PMID- 27483870 TI - Characteristics of Ga-Rich Cu(In, Ga)Se2 Solar Cells Grown on Ga-Doped ZnO Back Contact. AB - Wide bandgap Cu(In,Ga)Se2 (CIGS) thin films were deposited on Ga-rich Ga:ZnO (GZO) or MoN/GZO by single-stage co-evaporation. CIGS/TCO interface phases, such as resistive n-type Ga2O3, which are likely to have formed during the high temperature growth of Ga-rich CIGS, can deteriorate the solar cell performance. Although some Ga accumulation was observed in both of the CIGS/GZO and CIGS/MoN/GZO interfaces formed at 520 degrees C, the Ga oxide layer was absent. On the other hand, their current-voltage characteristics showed strong roll-over behavior regardless of the MoN diffusion barrier. The strong Schottky barrier formation at the CLGS/GZO junction due to the low work function of GZO, was attributed to current blocking at a high forward bias. PMID- 27483871 TI - Transparent Layer Derived from Layered Europium Hydroxide Sensitized with 2 Thenoyltrifluoroacetone. AB - In this study, we present a novel layered material (LEuH-TTA) consisting of layered europium hydroxide (LEuH) and organic sensitizer 2 thenoyltrifluoroacetone (TTA) in a simple and environmental benign way and it was characterized by FT-IR and XRD. The luminescence intensity of LEuH-TTA increased significantly after modified with TTA, almost 8 times that of LEuH at 612 nm. The luminescence behavior of LEuH-TTA was investigated by luminescence analysis, the results showed that red emission is caused by energy transfer from the TTA ligand to the coordinated Eu3+ ions. Furthermore, the thickness of luminescence film was measured and the SEM showed that it is about 1 MUm. PMID- 27483872 TI - CO2 Capturing and Mineralization by (Mg)-Phyllosilicate Coated with Fabrics. AB - To promote the practicality of magnesium (Mg)-phyllosilicate as a potent carbonation agent, two inexpensive cotton and nylon fabrics are selected and examined to assess their feasibility for use as supporting media of Mg phyllosilicate. Mg-phyllosilicate is coated onto the fabrics via a sol-gel method, whose mechanism is explained. The characteristics of the Mg phyllosilicate coated cotton, along with those of the carbonation products, are explored. Mg-phyllosilicate is found to mediate the carbon dioxide (CO2) mineralization process actively, even on cotton of a supporting material. Conclusively, the obtained results clearly support the potential of mineralization as a feasible option for capturing CO2, in particular with the abiotic catalyst of Mg-phyllosilicate coated onto flexible cotton. PMID- 27483873 TI - Non-Stoichiometric Amorphous Indium Selenide Thin Films as a Buffer Layer for CIGS Solar Cells with Various Temperatures in Rapid Thermal Annealing. AB - The conventional structure of most of copper indium gallium diselenide (Culn(1 x)Ga(x)Se2, CIGS) solar cells includes a CdS thin film as a buffer layer. Cd-free buffer layers have attracted great interest for use in photovoltaic applications to avoid the use of hazardous and toxic materials. The RF magnetron sputtering method was used with an InSe2 compound target to prepare the indium selenide precursor. Rapid thermal annealing (RTA) was conducted in ambient N2 gas to control the concentration of volatile Se from the precursor with a change in temperature. The nature of the RTA-treated indium selenide thin films remained amorphous under annealing temperatures of <= 700 degrees C. The Se concentration of the RTA-treated specimens demonstrated an opposite trend to the annealing temperature. The optical transmittance and band gap energies were 75.33% and 2.451-3.085 eV, respectively, and thus were suitable for the buffer layer. As the annealing temperature increased, the resistivity decreased by an order-of magnitude from 10(4) to 10(1) Omega-cm. At lower Se concentrations, the conductivity abruptly changed from p-type to n-type without crystallite formation in the amorphous phase, with the carrier concentration in the order of 10(17) cm( 3). PMID- 27483874 TI - Optimization of CdS Buffer Layer for High Efficiency CIGS Solar Cells. AB - In present work, effects of the thickness on the structural and optical properties of chemically deposited CdS thin films were investigated. In addition, we fabricated Cu(In, Ga)Se2 solar cells with various thicknesses of CdS buffer layer and optimized the thickness for a high efficiency. When the CdS thin films were thicker, the crystallinity improved but the transmittance decreased. The short-circuit current density (J(sc)) and the fill factor are the major efficiency limiting factors for the CIGS solar cells. As the thickness of the CdS buffer layer, the open-circuit voltage (V(oc)) and the fill factor increased, whereas the J(sc) slightly decreased. The improvement of the fill factor and thus efficiency resulted from larger shunt resistance. For the solar cells without a high resistive intrinsic ZnO layer, the highest efficiency was acquired at the thickness of 89 nm. With further increasing the thickness, the J(sc) decreased significantly, resulting in poor efficiency. PMID- 27483875 TI - Characteristics of Sputtered ZnO Thin Films for an Inverted Organic Solar Cell. AB - Several research groups have claimed high energy conversion efficiency in organic solar cells. However, it still has low efficiency and is unstable, because organic materials are easily oxidized by atmospheric humidity and UV light. In this work, ZnO thin film as the blocking layer attributed to the interference of the injection of the hole from the P3HT and no charge carrier recombination. We obtained the maximum power conversion efficiency of 1.9% under AM 1.5 G spectral illumination of 100 MWcm(-2), when we used a ZnO film of 60 nm and the optimized P3HT:PCBM, and Au as the back electrode to solve the reaction problem of Al electrode and to control the work function between the HOMO level of P3HT and the energy level of the metal electrode. Power conversion efficiency of inverted organic solar cell (IOSC) is significantly dependent on the thickness of the ZnO thin film deposited by unbalanced magnetron sputtering method. Also, the stability of IOSC is measured under ambient conditions. PMID- 27483876 TI - Synthesis of CZTS Nanoparticles for Low-Cost Solar Cells. AB - In this work, uniformly sized Cu2ZnSnS4 (CZTS) nanoparticles with easy control of chemical composition were synthesized and printable ink containing CZTS nanoparticles was prepared for low-cost-solar cell applications. In addition, we studied the effects of synthesis conditions, such as reaction temperature and time, on properties of the CZTS nanoparticles. For CZTS nanoparticles synthesis process, the reactants were mixed as the 2:1:1:4 molar ratios. The reaction temperature and time was varied from 220 degrees C to 320 degrees C and from 3 hours to 5 hours, respectively. The crystal structure and morphology of CZTS nanoparticles prepared under the various conditions were investigated by X-ray diffraction (XRD) and field-emission scanning electron microscopy (FE-SEM), and energy dispersive X-ray spectroscopy (EDS) was used for compositional analysis of the CZTS nanoparticles. PMID- 27483877 TI - Structural, Electrical, and Optical Properties of ZnO Film Used as Buffer Layer for CIGS Thin-Film Solar Cell. AB - The CuIn(x)Ga(1-x)Se2 (CIGS) using the solution-based fabrication method is attractive for thin film solar cells because of its possibilities for large-area and low-cost production. ZnO films between transparent conductive oxide (TCO) and the CdS films can improve the performances of CIGS thin-film solar cells. In this study, we investigated the characteristics of ZnO film between TCO and CIGS layers in a solar cell (AZO/ZnO/CdS/CIGS/Mo), which were deposited at various thicknesses to investigate the role of the films in CIGS solar cells. It was confirmed that the conversion efficiency of a CIGS solar cell depends on the ZnO film. For a ZnO film thickness of 80 nm, the highest power conversion efficiency that a solar cell achieved was J(sc) of 18.73 mA/cm2. PMID- 27483878 TI - DRAM Weak Cell Characterization for Retention Time. AB - This work proposes a sequence of tests for detecting refresh weak cells based on data retention time distribution in the main cell array of DRAMs and verify the feasibility of the proposed method through analysis of 30 nm design-rule DRAM cells with Recess Channel Array Transistor (RCAT) and Buried Channel Array Transistor (BCAT). Basic idea of the proposed mechanism is to test with different bias conditions and break down retention failures based on their root causes such as Gate Induced Drain Leakage, sub-threshold leakage and junction leakage. This categorization helps to determine the physical locations of each failure group, enabling precise Physical Failure Analysis (PFA). The characterization of data retention weak cells for 30 nm design rule DRAMs with BCAT and RCAT has been investigated. Most weak cells were classified as GIDL leaky cells in both cases. In the case of BCAT, the distance between the word line and the storage node, caused by the process distribution, is the main origin of weak cells. In the case of RCAT, the sharp corner of the active layer in the storage node is the main cause of weak cells. PMID- 27483879 TI - Electrical and Optical Properties of Hydrogen Doped Aluminum-Doped Zinc Oxide Thin Films for Low Cost Applications. AB - Aluminum-doped zinc oxide (AZO) thin films were prepared on glass substrate using a magnetron sputtering system. In this work, a powder target was used as a source material for low cost applications, instead of a conventional sintered ceramic target. The effects of the hydrogen gas ratio on the electrical and optical properties of the AZO films. The hydrogen doped AZO (AZO:H) films had a hexagonal polycrystalline structure. A small amount of hydrogen gas deteriorated the electrical and optical properties of the AZO:H films. However, these properties improved, as the H2/(H2 + Ar) gas ratio increased. The AZO:H films grown at an H2/(H2+Ar) ratio of 10% showed good properties for low cost applications, such as a low resistivity of 1.35 x 10(-3) Omega-cm, high average transmittance of 83.1% in the visible range of light. PMID- 27483880 TI - Influence of Deposition Pressure on the Properties of Round Pyramid Textured a Si:H Solar Cells for Maglev. AB - HIT (Heterojunction with Intrinsic Thin-layer) photovoltaic cells is one of the highest efficiencies in the commercial solar cells. The pyramid texturization for reducing surface reflectance of HIT solar cells silicon wafers is widely used. For the low leakage current and high shunt of solar cells, the intrinsic amorphous silicon (a-Si:H) on substrate must be uniformly thick of pyramid structure. However, it is difficult to control the thickness in the traditional pyramid texturing process. Thus, we textured the intrinsic a-Si:H thin films with the round pyramidal structure by using HNO3, HF, and CH3COOH solution. The characteristics of round pyramid a-Si:H solar cells deposited at pressure of 500, 1000, 1500, and 2000 mTorr by PECVD (Plasma Enhanced Chemical Vapor Deposition) was investigated. The lifetime, open circuit voltage, fill factor and efficiency of a-Si:H solar cells were investigated with respect to various deposition pressure. PMID- 27483881 TI - Simultaneous Engineering of the Substrate Temperature and Mixing Ratio to Improve the Performance of Organic Photovoltaic Cells. AB - In this study, we investigated the effect of the donor/acceptor mixing ratio and the substrate temperature (T(SUB)) during the co-deposition process on the performance of bulk heterojunction organic photovoltaic cells. We found that the ratio of dispersed donor islands (less than 10 nm), which hinders charge carrier transport, increased as the donor concentration (C(D)) increased in the film processed at room temperature. By contrast, the donor cluster (larger than 10 nm), providing percolation paths for the carriers, was enlarged in the film containing a high C(D) fabricated at high T(SUB) (70 degrees C). This enhanced phase separation in the mixed layer led to an improved fill factor and a decreased activation energy of the short-circuit current (J(SC)). Therefore, we demonstrated a 23% improvement in the device performance by employing an elevated T(SUB) and optimized mixing ratio in comparison with the device fabricated at room temperature. PMID- 27483882 TI - Work Function Modification of Tungsten-Doped Indium Oxides Deposited by the Co Sputtering Method. AB - We have studied the work function modification of tungsten-doped indium oxides (IWOs) through the co-sputtering of indium oxide (In2O3) and indium tungsten oxide (In2O3 80 wt% + WO3 20 wt%) via a radio frequency (RF) magnetron sputtering system. By controlling the elemental deposition of IWOs, the resultant work functions varied from 4.37 eV to 4.1 eV. The IWO thin films showed excellent properties for application as transparent conducting oxide materials in the region of 0 to 2.43 at.% of tungsten versus the total metal content. The carrier concentration of n-type IWO thin films varied from 8.39 x 10(19) cm(-3) to 8.58 x 10(21) cm(-3), while the resistivity varied from 3.15 x 10(-4) Omegacm to 2.26 x 10(-3) Omegacm. The largest measured optical band gap was 3.82 eV determined at 2.43 at.% of tungsten atoms relative to the total amount of metal atoms, while the smallest optical band gap was 3.6 eV at 4.78 at.% of tungsten. IWO films containing more than 2.43 at.% of tungsten atoms relative to the total number of metal atoms revealed an average transmittance of over 80% within the visible light region. PMID- 27483883 TI - Effect of Reaction Temperature of CdS Buffer Layers by Chemical Bath Deposition Method. AB - This study investigated CdS deposition on a Cu(In,Ga)Se2 (CIGS) film via chemical bath deposition (CBD) in order to obtain a high-quality optimized buffer layer. The thickness and reaction temperature (from 50 degrees C to 65 degrees C) were investigated, and we found that an increase in the reaction temperature during CBD, resulted in a thicker CdS layer. We obtained a thin film with a thickness of 50 nm at a reaction temperature of 60 degrees C, which also exhibited the highest photoelectric conversion efficiency for use in solar cells. Room temperature time resolved photoluminescence (TR-PL) measurements were performed on the Cu(In,Ga)Se2 (CIGS) thin film and CdS/CIGS samples to determine the recombination process of the photo-generated minority carrier. The device performance was found to be dependent on the thickness of the CdS layer. As the thickness of the CdS increases, the fill factor and the series resistance increased to 61.66% and decreased to 8.35 Omega, respectively. The best condition was observed at a reaction temperature of 60 degrees C, and its conversion efficiency was 12.20%. PMID- 27483884 TI - Rapid Annealing of Cu-In-Ga-Se Precursors by Electron Beam Irradiation Method. AB - Cu-In-Ga-Se precursors were prepared by RF- and DC-sputtering methods and then irradiated with an in-situ electron beam irradiation unit. Ternary (In,Ga)Se2 and binary CuSe targets were simultaneously used for preparation of precursors. The electron dose and irradiation time were kept constant at 300 seconds and 200 W of RF power, respectively, while intensities of accelerated electrons were varied from 2.5 to 4.5 keV. The thickness of all e-beam irradiated CuInGaSe2 (CIGS) films decreased from 1,250 nm to 470 nm. The crystalline properties of e-beam irradiated CIGS films were clearly shown on all samples and the highest intensity of (112) peak at 3.5 keV. The compositional ratio of Cu/(In + Ga) in the e-beam sample irradiated at 3.5 keV was coincident with that of the precursors. The degree of Ga content on the depth of the e-beam sample irradiated at 3.5 keV was uniformly distributed between the TCO/CdS layer and Mo back contact. Electron beam irradiation onto Cu-In-Ga-Se precursors as a rapid annealing method could be an excellent candidate for crystallization to the Cu(In,Ga)Se2 films. PMID- 27483885 TI - Characterization of Flexible CIGS Thin Film Solar Cells or Stainless Steel with Intrinsic ZnO Diffusion Barriers. AB - ZnO diffusion barrier layer was deposited by RF magnetron sputtering by using the same method as intrinsic ZnO layer. The CIGS solar cells were fabricated on stainless steel substrate. The 50-200 nm thin ZnO diffusion barriers effectively reduced the diffusion of Fe and Cr, from stainless steel substrates into the CIGS absorbers. The CIGS solar cells with ZnO diffusion barriers increased the J(sc) and FF, which resulted in an increase of cell efficiency from 5.9% up to 9.06%. PMID- 27483886 TI - Amorphous Indium Selenide Thin Films Prepared by RF Sputtering: Thickness-Induced Characteristics. AB - The influence of indium composition, controlled by changing the film thickness, on the optical and electrical properties of amorphous indium selenide thin films was studied for the application of these materials as Cd-free buffer layers in CI(G)S solar cells. Indium selenide thin films were prepared using RF magnetron sputtering method. The indium composition of the amorphous indium selenide thin films was varied from 94.56 to 49.72 at% by increasing the film thickness from 30 to 70 nm. With a decrease in film thickness, the optical transmittance increased from 87.63% to 96.03% and Eg decreased from 3.048 to 2.875 eV. Carrier concentration and resistivity showed excellent values of >=1015 cm(-3) and <= 10(4) Omega x cm, respectively. The conductivity type of the amorphous indium selenide thin films could be controlled by changing the film-thickness-induced amount of In. These results indicate the possibility of tuning the properties of amorphous indium selenide thin films by changing their composition for use as an alternate buffer layer material in CI(G)S solar cells. PMID- 27483887 TI - Preparation of BaTiO3/Cu2O and BaTiO3/Cu2O/Au Complexes: Their Photocatalytic and Antipathogenic Effect. AB - BaTiO3/Cu2O and BaTiO3/Cu2O/Au complexes were prepared from CuCl2, HAuCl4 solution, and BaTiO3 by the solution method. BaTiO3 particles were dispersed in a CuCl2 solution, and the BaTiO3/CuO complex was produced through crystallization of CuO onto the BaTiO3 surface by hydrolysis of CuCl2 in the first stage. After the reaction, CuO was reduced to Cu2O by treatment with glucose, thereby yielding the BaTiO3/Cu2O complex. The BaTiO3/Cu2O/Au complex was prepared by treating the BaTiO3/Cu2O particles with HAuCl4. Under visible light, the obtained BaTiO3/Cu2O0/Au complex showed higher photocatalytic activity than the Degussa P 25sample. In addition, the BaTiO3/Cu2O complex showed excellent antipathogenic effect. PMID- 27483888 TI - Influence of Oxygen Gas Ratio on the Properties of Aluminum-Doped Zinc Oxide Films Prepared by Radio Frequency Magnetron Sputtering. AB - Aluminum-doped zinc oxide (AZO) thin films were deposited on glass and polyimide substrates using radio frequency magnetron sputtering. We investigated the effects of the oxygen gas ratio on the properties of the AZO films for Cu(In,Ga)Se2 thin-film solar cell applications. The structural and optical properties of the AZO thin films were measured using X-ray diffraction (XRD), field emission scanning electron microscope (FE-SEM), and UV-Visible-NIR spectrophotometry. The oxygen gas ratio played a crucial role in controlling the optical as well as electrical properties of the films. When oxygen gas was added into the film, the surface AZO thin films became smoother and the grains were enlarged while the preferred orientation changed from (0 0 2) to (1 0 0) plane direction of the hexagonal phase. An improvement in the transmittance of the AZO thin films was achieved with the addition of 2.5-% oxygen gas. The electrical resistivity was highly increased even for a small amount of the oxygen gas addition. PMID- 27483889 TI - Effects of Bias Pulsing on Etching of SiO2 Pattern in Capacitively-Coupled Plasmas for Nano-Scale Patterning of Multi-Level Hard Masks. AB - In order to study the effects of bias pulsing on the etching characteristics of a silicon dioxide (SiO2) layer using multi-level hard mask (MLHM) structures of ArF photoresist/bottom anti-reflected coating/SiO2/amorphous carbon layer (ACL)/SiO2, the effects of bias pulsing conditions on the etch characteristics of a SiO2 layer with an ACL mask pattern in C4F8/CH2F2/O2/Ar etch chemistries were investigated in a dual-frequency capacitively-coupled plasma (CCP) etcher. The effects of the pulse frequency, duty ratio, and pulse-bias power in the 2 MHz low frequency (LF) power source were investigated in plasmas generated by a 27.12 MHz high-frequency (HF) power source. The etch rates of ACL and SiO2 decreased, but the etch selectivity of SiO2/ACL increased with decreasing duty ratio. When the ACL and SiO2 layers were etched with increasing pulse frequency, no significant change was observed in the etch rates and etch selectivity. With increasing LF pulse-bias power, the etch rate of ACL and SiO2 slightly increased, but the etch selectivity of SiO2/ACL decreased. Also, the precise control of the critical dimension (CD) values with decreasing duty ratio can be explained by the protection of sidewall etching of SiO2 by increased passivation. Pulse-biased etching was successfully applied to the patterning of the nano-scale line and space of SiO2 using an ACL pattern. PMID- 27483890 TI - Analysis of Stress Effect on (110)-Oriented Single-Gate SOI nMOSFETs Using a Silicon-Thickness-Dependent Deformation Potential. AB - The stress effect in uniaxially strained (100)- and (110)-oriented single-gate (SG) silicon-on-insulator (SOI) n-type metal-oxide-semiconductor field-effect transistors (MOSFETs) was analyzed. A model of a silicon-thickness-dependent deformation potential (D(as_T(si))) was used for accurate calculation of mobility using a Schrodinger-Poisson solver. The simulation results obtained using the D(ac_T(si)) model exhibited excellent agreement with the measured mobility for both strained and unstrained conditions. The enhancements in electron mobility under conditions of longitudinal tensile strain were analyzed as a function of the silicon thickness and strain. As the silicon thickness decreased, the mobility enhancement in (100) SG MOSFETs reached a peak, whereas it diminished in (110) SG MOSFETs. As the strain increased, mobility enhancement increased in the (110) case, whereas it saturated in the (100) case. Therefore, larger mobility enhancement in the (110) orientation is expected. These differences in enhancement between the (100) and (110) cases resulted from differences in the quantization mass, which affect the energy difference between the 1st subbands of two-fold and four-fold degenerate valleys, as well as occupancy change. PMID- 27483891 TI - InGaAs/InP Avalanche Photodiode for Single Photon Detection with Zinc Diffusion Process Using Metal Organic Chemical Vapor Deposition. AB - In this paper, we describe a design, simulation, and fabrication of an InGaAs/InP single photon avalanche photodiode (SPAD), which requires a much higher gain, compared to APD's for conventional optical communications. To achieve a higher gain, an efficient multiplication width control is essential because it significantly affects the overall performance including not only gain but also noise characteristics. Normally, the multiplication layer width is controlled by the Zinc diffusion process. For the reliable and controllable diffusion process, we used metal organic chemical vapor deposition (MOCVD). The controllability of the proposed diffusion process is proved by the diffusion depth measurement of the fabricated devices which show the proportional dependence on the square root of the diffusion time. As a result, we successfully implemented the SPAD that exhibits a high gain enough to detect single photons and a very low dark current level of about 0.1 nA with 0.95 breakdown voltage. The single photon detection efficiency of 15% was measured at the 100 kHz gate pulse rate and the temperature of 230 K. PMID- 27483892 TI - Electrical Characteristics of Top-Gated Graphene Field Effect Transistors Fabricated on Stainless Steel (STS) Substrate. AB - Top-gated Graphene transistors with Al2O3 gate-dielectric on the flexible stainless steel substrate have been demonstrated. Graphene was synthesized on copper foil using a chemical vapor deposition method and transferred onto the stainless steel substrate by wet transfer technique. The stainless steel substrate was polished by chemical mechanical polishing method and the spin-on glass layer was coated on the surface to improve the surface roughness. The average surface roughness R(a) was as low as 5.9 nm from the AFM measurement. The measured hole and electron mobilities from the current-voltage characteristics at room temperature were calculated as high as 310 and 45 cm2/Vs, respectively. In addition, the effect of surrounding temperature up to 355 K on the electrical variations was investigated. The mobility was inversely proportional to the temperature with negligible hysteresis where the temperature coefficient was calculated as low as -0.65 %/K. PMID- 27483893 TI - Multi-Bit Nano-Electromechanical Nonvolatile Memory Cells (Zigzag T Cells) for the Suppression of Bit-to-Bit Interference. AB - Multi-bit nano-electromechanical (NEM) nonvolatile memory cells such as T cells were proposed for higher memory density. However, they suffered from bit-to-bit interference (BI). In order to suppress BI without sacrificing cell size, this paper proposes zigzag T cell structures. The BI suppression of the proposed zigzag T cell is verified by finite-element modeling (FEM). Based on the FEM results, the design of zigzag T cells is optimized. PMID- 27483894 TI - Two-Step Growth of Epitaxial InP Layers by Metal Organic Chemical Vapor Deposition. AB - In this study, we report experimental results on the epitaxial growth of InP layer on GaAs (001) substrate by using MOCVD. We have systematically controlled nucleation steps in order to obtain InP epitaxial layers with high crystallinity quality. The controlling parameters were flow ratio of V/IIIsources and thicknesses of nucleation layer for nucleation steps. We successfully improved the surface roughness and crystallinity of IIP epitaxial layers on GaAs substrates. PMID- 27483895 TI - Nano-Nucleation Characteristic of Cu-Ag Alloy Directly Electrodeposited on W Diffusion Barrier for Microelectronic Device Interconnect. AB - Cu-Ag alloy interconnect is promising for ultra-large-scale integration (ULSI) microelectronic system of which device dimension keeps shrinking. In this study, seedless electrodeposition of Cu-Ag alloy directly on W diffusion barrier as interconnect technology is presented in respect of nano-nucleation control. Chemical equilibrium state of electrolyte was fundamentally investigated according to the pH of electrolyte because direct nano-nucleation of Cu-Ag alloy on W surface is challenging. Chelation behavior of Cu2+ and Ag+ ions with citrate (Cit) and ammonia ligands was dependent on the pH of electrolyte. The amount and kind of Cu- and Ag-based complexes determine the deposition rate, size, elemental composition, and surface morphology of Cu-Ag alloy nano-nuclei formed on W surface. PMID- 27483896 TI - Charge Carrier Transport Through the Interface Between Hybrid Electrodes and Organic Materials in Flexible Organic Light Emitting Diodes. AB - We investigated the electronic properties of composite-type hybrid transparent conductive electrodes (h-TCEs) based on Ag nanowire networks (AgNWs) and indium tin oxide (ITO). These h-TCEs were developed to replace ITO, and their mechanical flexibility is superior to that of ITO. However, the characteristics of charge carriers and the mechanism of charge-carrier transport through the interface between the h-TCE and an organic material are not well understood when the h-TCE is used as the anode in a flexible organic light-emitting diode (f-OLED). AgNWs were spin coated onto polymer substrates, and ITO was sputtered atop the AgNWs. The electronic energy structures of h-TCEs were investigated by ultraviolet photoelectron spectroscopy. f-OLEDs were fabricated on both h-TCEs and ITO for comparison. The chemical bond formation at the interface between the h-TCE and the organic layer in f-OLEDs was investigated by X-ray photoelectron spectroscopy. The performances of f-OLEDs were compared based on the analysis results. PMID- 27483897 TI - Effects of Precursor Concentration on Structural and Optical Properties of ZnO Thin Films Grown on Muscovite Mica Substrates by Sol-Gel Spin-Coating. AB - The structural and optical properties of the ZnO thin films grown on mica substrates for different precursor concentrations were investigated. The surface morphologies of all the samples indicated that they consisted of granular structures with spherical nano-sized crystallites. The thickness of the ZnO thin films increased significantly and the optical band gap exhibited a blue shift with an increase in the precursor concentration. It is remarkable that the highest I(NBE)/I(DLE) ratio was observed for the ZnO thin film with 0.8 M precursor concentration, even though cracks formed on the surface of this film. PMID- 27483898 TI - Synthesis, Morphology Control and Electromagnetic Wave Absorption Properties of Electrospun FeCo Alloy Nanofibers. AB - Recently, increasing interest has been focused on one-dimensional (1 D) magnetic nanomaterials that have significant anisotropic electromagnetic parameters and size effects that can be used to achieve improved shielding efficiency. In this study, the simple, low-cost and scalable synthesis of FeCo nanofibers is demonstrated by combining an electrospinning process with sequential thermal treatment involving calcination in air followed by reduction in H2 atmosphere. A citric acid has an influence on the morphology of the electrospun product. The as spun precursor nanofibers are transformed into CoFe2O4 and FeCo phases through the sequential thermal treatment while maintaining the fibrous shapes. To evaluate the electromagnetic (EM) wave-absorbing abilities of the FeCo nanofibers, epoxy matrix composites with the nanofibers are fabricated. The composites show excellent EM wave absorption properties where the power loss of the FeCo nanofibers increased to 20 GHz without any degradation. PMID- 27483899 TI - Preparation and Characterization of Nanostructured Manganese Oxide for Supercapacitors. AB - Nanostructured manganese oxides were synthesized by a sol-gel method using manganese acetate (MnAc2) and citric acid (C6H8O7,) as precursors, and characterized by Brunauer-Emmett-Teller (BET) analysis, Barrett-Joyner-Halenda (BJH), X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) techniques. The nano-rod structure of MnO2 developed gradually when the calcination temperature varied from 380 to 580 degrees C. As the pH increased, the pore size increased, while the specific surface area decreased. The effects of the pH and calcination temperature on the electrochemical properties of the nano-MnO2 electrode, including the supercapacitive behavior, were investigated by cyclic voltammetry (CV) tests. The tests were performed between 0 and 0.8 V versus Ag/AgCl in 1 M Na2SO4 electrolyte at various scan rates (10-200 mVs(-1)). The specific capacitance of the SP-380 sample, prepared at pH 6, was equal to 269.3 Fg(-1). After 300 cycles, approximately a 3.4% increase of the specific capacitance was measured, confirming the excellent cyclability. PMID- 27483900 TI - Morphology and Optical Properties of Bare and Silica Coated Hybrid Silver Nanoparticles. AB - Owing to their wide applications in the field of optoelectronics, photonics, catalysis, and medicine; plasmonic metal nanoparticles are attaining considerable interest nowadays. The optical properties of these metal nanoparticles depend upon their size, shape, and surrounding medium. The present work studies the morphology and optical properties of bare silver nanoparticles and silica coated hybrid silver nanoparticles. Aqueous phase mediated synthesis and water-in-oil microemulsion mediated synthesis are two different wet chemical routes employed for nanosynthesis. Direct coating of silica is performed in water-in-oil microemulsion on pre-synthesized silver nanoparticles using tetraethyl orthosilicate as silica precursor. This study shows that using different wet chemical routes the size of the synthesized nanoparticles could be tuned. In addition, using reverse micelles as nanoreactors, the thickness of the silica shell around the core silver nanoparticles could be significantly controlled. Further, the optical properties of silver nanoparticles could be adjusted through the size and the surface coating. PMID- 27483901 TI - Carbon Nanomaterials Alter Global Gene Expression Profiles. AB - Carbon nanomaterials (CNMs), which include carbon nanotubes (CNTs) and their derivatives, have diverse technological and biomedical applications. The potential toxicity of CNMs to cells and tissues has become an important emerging question in nanotechnology. To assess the toxicity of CNTs and fullerenol C60(OH)24, we in the present work used the budding yeast Saccharomyces cerevisiae, one of the simplest eukaryotic organisms that share fundamental aspects of eukaryotic cell biology. We found that treatment with CNMs, regardless of their physical shape, negatively affected the growth rates, end-point cell densities and doubling times of CNM-exposed yeast cells when compared to unexposed cells. To investigate potential mechanisms behind the CNMs-induced growth defects, we performed RNA-Seq dependent transcriptional analysis and constructed global gene expression profiles of fullerenol C60(OH)24- and CNT treated cells. When compared to non-treated control cells, CNM-treated cells displayed differential expression of genes whose functions are implicated in membrane transporters and stress response, although differentially expressed genes were not consistent between CNT- and fullerenol C60(OH)24-treated groups, leading to our conclusion that CNMs could serve as environmental toxic factors to eukaryotic cells. PMID- 27483902 TI - A Hydrostatic Bearing Test System for Measuring Bearing Load Using Magnetic-Fluid Lubricants. AB - This paper conducts a study on the design of a hydrostatic bearing test system. It involves the determination of viscous properties of magnetic-fluid lubricants. The load of a hydrostatic thrust bearing using a water-based magnetite nanofluid of varying volume flow rate is measured under an applied external induction field via the test system. Results reveal that the presence of nanoparticles in a carrier liquid would cause an enhanced bearing load. Such an effect could be further magnified by increasing the lubricant volume flow rate or the external induction field strength. PMID- 27483903 TI - Analysis of the Effect of Silicon with Nano-Size Surface Structure on an Electrode Formed Using Screen Printing. AB - In this paper, we report an investigation into the effects of the texturing size of silicon on the efficiency of a screen-printed Si solar cell. To accomplish this, we produced solar cells with various textured surfaces. The method we used to produce these cells included methods such as anisotropic chemical etching (texturing size of about 4 MUm) using a mixed solution of KOH and IPA, reactive ion etching (texturing size of about 0.2 MUm), and Ag catalyzed etching (texturing size of about 90 nm). The solar cells with an Ag-catalyzed etching textured structure showed the lowest efficiency of 11.87%, with the highest series resistance of 1.32 Omega. In the case of anisotropic chemical etching, the solar cell had the best efficiency of 17.84%, with the lowest series resistance. This means that the electrodes and silicon surfaces were not well-connected with the nano-sized textured silicon surface. The results revealed that conventional silver paste at an average of 1.6 MUm is unsuitable for nano-sized textured Si solar cells. PMID- 27483904 TI - Structural and Optical Properties of Sputtered Cadmium Telluride Thin Films Deposited on Flexible Substrates for Photovoltaic Applications. AB - Cadmium telluride (CdTe) is a photovoltaic technology based on the use of thin films of CdTe to absorb and convert sunlight into electricity. In this paper, polycrystalline CdTe thin films were deposited using radio frequency magnetron sputtering onto flexible substrates including polyimide and molybdenum foil. The structural and optical properties of the films grown at various sputtering pressures were investigated using X-ray diffraction (XRD), field-emission scanning electron microscope (FE-SEM), and UV/Nis/NIR spectrophotometry. The sputtering pressure was found to have significant effects on the structural properties, including crystallinity, preferential orientation, and microstructure. Deterioration of the optical properties of CdTe thin films were observed at high sputtering pressure. PMID- 27483905 TI - Sintering and Microstructure of BaTiO3 Nano Particles Synthesized by Molten Salt Method. AB - In order to establish thinner dielectric layers in thick film electronic components such as MLCC (Multilayer ceramic capacitor), BaTiO3 nanoparticles have been utilized. However, studies on the synthesis of nanoparticles smaller than 20 nm, the characteristics of the BaTiO3 powder, and the powder's sintering are lacking. Therefore, this paper aims to synthesize BaTiO3 particles smaller than 20 nm by using the molten salt method and evaluate the microstructure and dielectric properties by varying the sintering temperature from 750 degrees C to 1200 degrees C. Through the molten salt method and by using KOH-KCl mixed salt, 20 nm BaTiO3 powder was synthesized at a low temperature of 150 degrees C. Sintering the pellets formed from the synthesized 20 nm BaTiO3 nano powder led to the observation of an unusual phenomenon where the particles grew to approximate sizes below 850 degrees C where densification progressed. At sintering temperatures above 950 degrees C, particles that expanded into rod shapes were observed and these particles were identified to be unreacted TiO2 based on the results of the EDX (Energy Dispersive X-ray Spectroscopy) analysis and phase analysis results. PMID- 27483906 TI - Thermally Induced Tensile Strain of Epitaxial Ge Layers Grown by a Two-Step e Beam Evaporation Process on Si Substrates. AB - We have investigated the thermally induced tensile strain in Ge-on-Si for use in optical sources of interconnection systems. Epitaxial Ge layers were grown using a two-step hetero-epitaxy at low and high temperatures. The as-grown Ge-on-Si was then annealed for direct bandgap conversion. A tensile strain of 0.06% in the as grown Ge increased to 0.31% after annealing at 850 degrees C. As the thermal budget of this post-growth anneal was increased, the tensile strain of relaxed Ge on-Si also increases and a Si-Ge alloy forms. Physical characterization indicates a tunable tensile stain in Ge-on-Si can be realized using post-growth annealing, which will allow for a wide range of frequencies in optical interconnections. PMID- 27483907 TI - Self-Boosted Tunnel Field-Effect Transistor Using Nitride Charge Trapping Layer for Low Supply Voltage Operation. AB - Tunneling field-effect transistors (TFETs) have been studied as a candidate for low-power device due to the remarkable subthreshold characteristics. However, digital circuits composed of TFET have significantly large propagation delay compared with the conventional MOSFET circuits because of small current drivability and large gate-to-drain capacitance. In this work, the electrical characteristics of the self-boosted TFETs with nitride charge trapping layer have been studied using TCAD simulations. Trapped charges in the nitride layer improve subthreshold characteristics and on-current (I(ON)) of both nTFET and pTFET during gate bias sweep. In addition, the benefits of the self-boosted TFET devices to low supply voltage system application are investigated. Energy consumption and propagation delay of both conventional and self-boosted TFET inverters are compared by the mixed-mode circuit simulation study. Energy consumption is almost same but the propagation delay of the self-boosted TFET inverter is reduced especially for ultra-low voltage operation where system delay is increased dramatically. PMID- 27483908 TI - Extraction of Distance Between Interface Trap and Oxide Trap from Random Telegraph Noise in Gate-Induced Drain Leakage. AB - This paper presents an analysis of the Random Telegraph Noise (RTN) of the Gate Induced Drain Leakage (GIDL) of a Metal Oxide Semiconductor Field Effect Transistor (MOSFET). The RTN data that was measured and analytical equations are used to extract the values of the parameters for the vertical distance of the oxide trap from the interface and of the energy level of the interface trap. These values and equations allow for the distance r between the interface trap and the oxide trap to be extracted. For the first time, the accurate field enhancement factor gamma(F), which depends on the magnitude of the electric field at the Si/SiO2 interface, was used to calculate the current ratio before and after the electron trapping, and the value extracted for r is completely different depending on the enhancement factor that is used. PMID- 27483909 TI - Development of Multi-Degree-Of-Freedom Piezoelectric Energy Harvester Using Interdigital Shaped Cantilevers. AB - A piezoelectric vibration energy harvester with interdigital shaped cantilever was developed by using silicon bulk micromachining technology. The proposed energy harvester was designed to obtain multi degree-of-freedom (m-DOF). Most of the piezoelectric vibration energy harvesters are comprised of mass-loaded cantilever beams having several resonant frequencies. The second resonant frequency of such a device has lower amplitude compared to its first resonant frequency (fundamental frequency). Therefore, the interdigital shaped cantilever has been proposed for multiple fundamental resonant frequencies. The fabricated piezoelectric vibration energy harvester is composed of main cantilever (MC), sub main cantilever (SMC), and secondary cantilevers (SC). MC surrounds SMC and SC which have same dimension of 5600 x 800 x 10 MUm3. The fabricated piezoelectric energy harvester can generate 51.4 mV(p-p) and 11 mV(p-p) of output voltages at 24.2 Hz and 33 Hz of its resonant frequencies by MC. Moreover, it can generate 8 mV(p-p) and 6.6 mV(p-p) of output voltages at 24.2 Hz and 33.2 Hz of its resonant frequencies by SMC; and 364 mV(p-p) of output voltage at 33.6 Hz of its resonant frequency by SC. PMID- 27483910 TI - Influence of Number Fluctuation and Position Variation of Channel Dopants and Gate Metal Grains on Tunneling Field-Effect Transistors (TFETs). AB - The influence of number fluctuation and position variation on channel dopants and gate metal grains on tunneling field-effect transistors (TFETs) have been discussed in comparison with metal-oxide-semiconductor FETs (MOSFETs). Based on the simulation results of randomly generated device samples, the shape of the statistical threshold voltage (V(th)) distribution of TFETs associated with individual variation sources such as random dopant fluctuation (RDF) and work function variation (WFV) have been found to be significantly different than that of MOSFETs. This analysis provides a detailed insight into the variation sources related to underlying physics of TFETs. PMID- 27483911 TI - Development and Operation of Dual-Mode Analyzers for Wireless Power Consortium/Power Matters Alliance Wireless Power Systems. AB - We have designed a protocol analyzer to be used in wireless power systems and analyzed the operation of wireless chargers defined by standards of Qi of Wireless Power Consortium (WPC) and Power Matters Alliance (PMA) protocols. The integrated circuit (IC, or microchip) developed so far for wireless power transmission is not easily adopted by chargers for specific purposes. A device for measuring the performance of test equipment currently available is required to transform and expand the types of protocol. Since a protocol analyzer with these functions is required, we have developed a device that can analyze the two protocols of WPC and PMA at the same time. As a result of our research, we present a dual-mode system that can analyze the protocols of both WPC and PMA. PMID- 27483912 TI - Surfactant Effect in Polypyrrole and Polypyrrole with Multi Wall Carbon Nanotube Counter Electrodes: Improved Power Conversion Efficiency of Dye-Sensitized Solar Cell. AB - In our present study, polypyrrole-1 (PPy1), polypyrrole-2 (PPy2), and polypyrrole 2/multi wall carbon nanotube composite film (PPy2/MWCNT) were proposed as counter electrodes (CEs) in dye-sensitized solar cells (DSSCs) to replace the precious Pt CE. These films were fabricated on fluorine-doped tin oxide substrates by using a facile electrochemical polymerization route, and served as CEs in DSSCs. It is shown that the introduction of anionic surfactant, sodium dodecyl sulfate (SDS), enhanced the catalytic activity, thus leading to an improvement in the performance of PPy2. Further, introduction of MWCNT resulted in increase in conversion efficiency of DSSCs with PPy2/MWCNT composite film. The Tafel and electrochemical impedance analysis revealed that the PPy2 and PPy2/MWCNT CEs prepared with anionic surfactant possessed more catalytic activity and lower charge transfer resistance in comparison with PPy1 -based CE. This resulted in a better conversion efficiency of 5.88% for PPy2/MWCNT-based DSSC under 1 sun condition, reaching 86% of the DSSC based on reference Pt counter electrode (6.86%). These results indicate that the composite film with high catalytic properties for I3- reduction can potentially be used as the CE in a high performance DSSC. PMID- 27483913 TI - Use of Artificial Neural Network for the Simulation of Radon Emission Concentration of Granulated Blast Furnace Slag Mortar. AB - In this study, an artificial neural networks study was carried out to predict the quantity of radon of Granulated Blast Furnace Slag (GBFS) cement mortar. A data set of a laboratory work, in which a total of 3 mortars were produced, was utilized in the Artificial Neural Networks (ANNs) study. The mortar mixture parameters were three different GBFS ratios (0%, 20%, 40%). Measurement radon of moist cured specimens was measured at 3, 10, 30, 100, 365 days by sensing technology for continuous monitoring of indoor air quality (IAQ). ANN model is constructed, trained and tested using these data. The data used in the ANN model are arranged in a format of two input parameters that cover the cement, GBFS and age of samples and, an output parameter which is concentrations of radon emission of mortar. The results showed that ANN can be an alternative approach for the predicting the radon concentration of GBFS mortar using mortar ingredients as input parameters. PMID- 27483914 TI - Characterization of a Fe-Based Soft Magnetic Alloy System with High Saturation Magnetization. AB - The ratios of Fe/Co and Fe/B in a ferromagnetic alloy system, Fe(87-x-y) Co(x) Ti7 Zr6 By (x = 20, 30, and 40 at% and y = 2 and 4 at%), which was produced by the melt-spinning technique in the form of thin ribbons, were investigated to improve the saturation magnetization. The thermal properties T(x) were in the range of 792.0 K to 838.0 K, and it decreased by decreasing Fe/Co ratio. In the as-spun amorphous ribbons, the saturation magnetization and coercivity ranged from 137.5 emu/g to 164.2 emu/g and from 0.027 Oe to 1.245 Oe, respectively. The optimum Fe/Co ratio for the Fe(83-x) Co(x) Ti7 Zr6 B4 system was determined to be 64:36. In other words, the optimum system was Fe60 Co25 Ti7 Zr6 B2, which exhibited robust soft magnetic properties, such as a low coercivity of 0.252 Oe, and high saturation magnetization of 164.2 emu/g (1.55 T). Also, in this system, magnetic properties such as the saturation magnetization and coercivity increased with decreasing Fe/Co ratio. PMID- 27483915 TI - Growth and Structural Characteristics of CuGaSe2 Films Fabricated from Metallic Precursors Followed by an Elemental Se Reaction Process. AB - We investigated the growth, structural and optical characteristics of CuGaSe2 thin films prepared with the selenium reaction. Metallic precursor layers from Cu0:5Ga0.5 and Cu0.8Ga0.2 alloy targets were prepared on a sodalime glass substrate by using DC magnetron sputtering, and then annealed to form CuGaSe2 in a rapid thermal process (RTP) with selenium radicals generated by a thermal cracker. The base and sputtering pressures were < 5 x 10(-7) Torr and 30 mTorr, respectively. At ambient temperature, the precursors from the Cu0.5Ga0.5 and Cu0.8Ga0.2 targets were deposited at the rates of 42 nm/min. and 45 nm/min., respectively. The film thicknesses were about 300 nm. Selenization was carried out at different annealing temperatures of T(a) = 450 degrees C, 500 degrees C, 550 degrees C, and 600 degrees C for time periods of 15 min., 30 min., and 60 min. We found that high quality CuGaSe2 films of crystal grains (-1 MUm in dia.) fabricated with a reaction using elemental Se at temperatures as low as 450 degrees C for 30 min. When T(a) <= 350 degrees C, the Se reaction was insufficient to form CuGaSe2. However, the annealing time had little effect on the formation of CuGaSe2 at T(a) >= 450 degrees C. For all the samples, the photoluminescence (PL) emission was only from the donor-acceptor interband transition D1A1 for all the composition ratios of the films [Ga]/[Cu] -1. PMID- 27483916 TI - Low-Temperature Process for Atomic Layer Chemical Vapor Deposition of an Al2O3 Passivation Layer for Organic Photovoltaic Cells. AB - Flexible organic photovoltaic (OPV) cells have drawn extensive attention due to their light weight, cost efficiency, portability, and so on. However, OPV cells degrade quickly due to organic damage by water vapor or oxygen penetration when the devices are driven in the atmosphere without a passivation layer. In order to prevent damage due to water vapor or oxygen permeation into the devices, passivation layers have been introduced through methods such as sputtering, plasma enhanced chemical vapor deposition, and atomic layer chemical vapor deposition (ALCVD). In this work, the structural and chemical properties of Al2O3 films, deposited via ALCVD at relatively low temperatures of 109 degrees C, 200 degrees C, and 300 degrees C, are analyzed. In our experiment, trimethylaluminum (TMA) and H2O were used as precursors for Al2O3 film deposition via ALCVD. All of the Al2O3 films showed very smooth, featureless surfaces without notable defects. However, we found that the plastic flexible substrate of an OPV device passivated with 300 degrees C deposition temperature was partially bended and melted, indicating that passivation layers for OPV cells on plastic flexible substrates need to be formed at temperatures lower than 300 degrees C. The OPV cells on plastic flexible substrates were passivated by the Al2O3 film deposited at the temperature of 109 degrees C. Thereafter, the photovoltaic properties of passivated OPV cells were investigated as a function of exposure time under the atmosphere. PMID- 27483917 TI - Effects of Plasma Treatment on Carbon Nanowalls Grown by Microwave Plasma Enhanced Chemical Vapor Deposition. AB - In this study, the effects of post-plasma treatment on synthesized carbon nanowalls (CNWs) grown with a microwave were investigated. CNWs were synthesized by microwave plasma enhanced chemical vapor deposition (PECVD), employing a mixture of CH4 and H2 gases. The plasma treatment was done in different plasma environments (O2 and H2) but under the same condition of synthesized CNWs. Raman spectroscopy, field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDS), and fourier transform infrared spectroscopy (FT-IR) were used to analyze the effects of the post-plasma treatment on the synthesized CNWs. After the H2 post-plasma treatment, no significant changes in the appearance and characteristics of the CNWs were observed. After the O2 post plasma treatment, on the other hand, the CNWs were etched at a rate of 18.05 nm/sec. The Raman analysis confirmed, however, that the structural changes in the CNWs caused by the O2 post-plasma treatment were insignificant. PMID- 27483918 TI - Reaction Gas Ratio Effect on the Growth of a Diamond Film Using Microwave Plasma Enhanced Chemical Vapor Deposition. AB - In this study, diamond films were prepared using the microwave plasma-enhanced chemical vapor deposition (PECVD) system, which included a DC bias system to enhance the nucleation of the films. The films were synthesized on Si wafers with different ratios of methane (CH4) and hydrogen (H2) gases. We have studied the effects of the CH4-to-H2 ratio on the structural and optical properties of diamond films. The thickness and surface profile of the films were characterized via field emission scanning electron microscopy (FE-SEM). Raman was used to investigate the structural properties of the diamond films. The refractive indexes as functions of the CH4-to-H2 ratio were measured using an ellipsometer. The FE-SEM analysis showed that the 3 and 5 sccm CH4 created diamond films. The Raman analysis indicated that a nanocrystalline diamond film was formed at 3 sccm; a general diamond film, at 5 sccm; and films similar to the a-C:H film, at 7 sccm. The ellipsometer measurement showed that the refractive index of the synthesized diamond film was around 2.42 at 3 sccm. This value decreased as the CH4 volume increased. PMID- 27483919 TI - Optical Properties of Oxygen Plasma-Treated Carbon Nanowalls Grown on Glass Substrates. AB - In this paper, we investigated the effect of oxygen (02) plasma treatment on a synthesized carbon nanowall (CNW). A microwave plasma-enhanced chemical vapor deposition (PECVD) system was facilitated to grow CNWs on a glass, using a mixture of CH4 and H2 gases. First, the CNWs were post-plasma-treated for different treatment durations, and then their optical properties were analyzed. In addition, the cross-sectional and planar images of the CNWs were examined via field-emission scanning electron microscopy (FE-SEM) depending on the different post-plasma-treatment durations. Then the structural characteristics were analyzed via Raman spectroscopy, and the changes in the light transmittance depending on the O2 plasma treatment durations were analyzed using UV-Vis spectroscopy. The effects of the post-plasma treatments on the synthesized CNWs were evaluated. The results confirmed that O2 gas is effective for plasma etching of CNWs. PMID- 27483920 TI - Properties of Dye-Sensitized Solar Cells Using Carbon Nanowall Counter Electrodes. AB - This research investigates plasma-treated and metal-coated carbon nanowalls (CNWs) for use as counter electrodes of dye-sensitized solar cells (DSSCs). The CNWs were synthesized on a fluorine-tin-oxide (FTO) glass substrate using the microwave plasma-enhanced chemical vapor deposition (PECVD) system with methane (CH4) gas. The post-plasma treatment was performed on the CNWs with hydrogen (H2) plasma using PECVD, and the CNWs were sputter-coated with metal films using the RF magnetron sputtering system with a four-inch tungsten (W) target. Then the post-plasma-treated and metal-coated CNWs were used as counter electrodes for the fabrication of the DSSCs. Field-emission scanning electron microscopy (FE-SEM) was performed to obtain cross-sectional and planar images of the grown CNWs. The energy conversion efficiencies of the DSSCs manufactured using the post-plasma treated and metal-layer-coated CNWs as the counter electrodes were measured. PMID- 27483921 TI - Effect of Perovskite Overlayers on TiO2 Electrodes in Perovskite-Sensitized Solar Cells. AB - In this paper, we have studied the effect of the thickness of a CH3NH3PbI3 perovskite overlayer on mesoporous TiO2 electrodes in perovskite solar cells. The overlayers were prepared by spin coating PbI2 films on the electrodes, which were subsequently exposed to a CH3NH3I/2-propanol solution. We controlled the thickness of the perovskite overlayer by changing the PbI2 solution concentration. The thicknesses of the overlayers spin-coated from 0.5, 0.75, 0.9, and 1 M PbI2 solutions were approximately 179, 262, 316, and 341 nm, respectively. Perovskite solar cells with an approximately 316-nm-thick overlayer showed the highest efficiency of 9.11%. We conclude that optimization of the perovskite overlayer thickness in the solar cell structure is necessary to improve the cell efficiency. PMID- 27483922 TI - Influence of Deposition Conditions on Properties of All Sputtered CdS/CdTe Thin Film Solar Cells. AB - The effects of deposition conditions, such as substrate temperature and CdCl2 post treatments, on the structural and optical properties of CdTe films were investigated. In addition, CdS/CdTe thin-film solar cells were fabricated by an all-sputtering process, and their photovoltaic characteristics were studied. The CdTe films had a polycrystalline, cubic structure with a preferred orientation of the [1 1 1] direction parallel to the substrate surface, regardless of the substrate temperature. As the substrate temperature increased, the crystallinity of CdTe films improved. The grain size of the CdTe films increased after CdCl2 post treatment. In addition, the optical band gap increased with the substrate temperature. The conversion efficiency of the CdS/CdTe solar cell improved at higher substrate temperatures. The maximum efficiency, 9.23%, was obtained at a substrate temperature of 400 degrees C, with an open-circuit voltage (V(oc)) of 0.78 V, a short-circuit current density (J(sc)) of 20.4 mA/cm2, and a fill factor of 0.58. PMID- 27483923 TI - Surface Stabilized InP/GaP/ZnS Quantum Dots with Mg Ions for WLED Application. AB - One of the most highlighted cadmium-free quantum dots (QDs), InP-based QDs, have improved their optical properties. However, InP-based QDs have some practical drawbacks, for example, stability, compared with CdSe-based QDs. Poor stability of InP-based QDs yields critical problems, such as agglomeration and photoluminescence quenching in light emitting diode (LED). It has to be solved for applications and most research has focused on thick outer shells as an effective solution. We introduced magnesium cations for improving stability of InP-based QDs. We applied very small amounts of Mg cations as surface stabilizers, as a result, stability of QDs is clearly improved. Then, QD based LED chips also yield improved values including RA of 84.4, CCT of 3799 K, and luminous efficiency of 129.57 Im/W, which are highly improved data compared with our previous results. PMID- 27483924 TI - Universal Verification Methodology Based Register Test Automation Flow. AB - In today's SoC design, the number of registers has been increased along with complexity of hardware blocks. Register validation is a time-consuming and error pron task. Therefore, we need an efficient way to perform verification with less effort in shorter time. In this work, we suggest register test automation flow based UVM (Universal Verification Methodology). UVM provides a standard methodology, called a register model, to facilitate stimulus generation and functional checking of registers. However, it is not easy for designers to create register models for their functional blocks or integrate models in test-bench environment because it requires knowledge of SystemVerilog and UVM libraries. For the creation of register models, many commercial tools support a register model generation from register specification described in IP-XACT, but it is time consuming to describe register specification in IP-XACT format. For easy creation of register model, we propose spreadsheet-based register template which is translated to IP-XACT description, from which register models can be easily generated using commercial tools. On the other hand, we also automate all the steps involved integrating test-bench and generating test-cases, so that designers may use register model without detailed knowledge of UVM or SystemVerilog. This automation flow involves generating and connecting test-bench components (e.g., driver, checker, bus adaptor, etc.) and writing test sequence for each type of register test-case. With the proposed flow, designers can save considerable amount of time to verify functionality of registers. PMID- 27483925 TI - Effects of Lithium Oxide Addition on Sintering Behavior and Electrical Conductivity of Ce0.8Gd0.2O1.9 Ceramics Prepared by Commercial Powders. AB - The densification behavior and electrical conductivity of Ce0.8Gd0.2O1.9 ceramics with lithium oxide concentrations ranging from 0 to 7 mol% were investigated. The sintered density was found to increase with increasing Li2O content up to 2 mol% and then to decrease somewhat upon further Li20 addition. Dense Ce0.8Gd0.2O1.9 ceramics with 97% of the theoretical density could be obtained by sintering the milled mixture with 2 mol% Li2O addition at 1250 degrees C for 5 h. The conductivity of the 2 mol% Li2O-added specimen showed a maximum value of 4.99 x 10(-3) Omega(-1) x cm(-1) at 700 degrees C. Pure Ce0.8Gd0.2O1.9 ceramics needed to be sintered at 1550 degrees C in order to obtain an equivalent theoretical density and conductivity. The addition of Li2O was found to promote the sintering properties and electrical conductivities of Gd2O3-doped CeO2. PMID- 27483927 TI - Nanoporous Electrospun Fibrous Meshes: Size-Controlled Reverse Micelles Strategy. AB - A simple and efficient method to fabricate size-controlled nanoporous-nanofibrous meshes has been demonstrated by introducing and removing novel size-controllable porogens, reverse micelles, on electrospun polymeric nanofibers. Poly(D,L lactide) and reverse micelles composed of amphiphilic diblock copolymer, poly(ethylene glycol) methyl ether-block-poly(epsilon-caprolactone), were first dissolved in an acetone/chloroform (3:1, v/v) mixture and then electrospun into nanofibers, followed by 70% EtOH post-treatment. During the post-treatment, the reverse micelles were dissolved in 70% EtOH at room temperature thus separated from the poly(D,L-lactide) nanofibers backbone, resulting in a nanoporous nanofibrous structure. The pores on the nanofibers are size-controllable because the sizes of the reverse micelles can be adjusted by varying the water content inside them. The sizes of reverse micelles, which ranged from 100 nm to 700 nm, are investigated by dynamic light scattering. The pores of various sizes on the poly(D,L-lactide) nanofibers have areas ranging from 20 MUm2 to 80 MUm2 were observed by field-emission scanning electron microscopy. PMID- 27483926 TI - Thyrotropin-Releasing Hormone Loaded and Chitosan Engineered Polymeric Nanoparticles: Towards Effective Delivery of Neuropeptides. AB - Thyrotropin-Releasing Hormone (TRH), a tripeptide amide with molecular formula L pGlu-L-His-L- Pro-NH2, is used in the treatment of brain/spinal injury and certain central nervous system (CNS) disorders, including schizophrenia, Alzheimer's disease, epilepsy, depression, shock and ischemia due to its profound effects on the CNS. However, TRH's therapeutic activity is severely hampered because of instability and hydrophilicity owing to its peptidic nature which results into ineffective penetration into the blood brain barrier. In the present study, we report the synthesis and stability studies of novel chitosan engineered TRH encapsulated poly(lactide-co-glycolide) (PLGA) based nanoformulation. The aim of such an encapsulation is to allow effective delivery of TRH in biological systems as the peptidase degrade naked TRH. The synthesis of TRH was carried out manually in solution phase followed by its encapsulation using PLGA to form polymeric nanoparticles (NPs) via nanoprecipitation technique. Different parameters such as type of organic phase, concentration of stabilizer, ratio of organic phase and aqueous phase, rate of addition of organic phase were optimized, tested and evaluated for particle size, encapsulation efficiency, and stability of NPs. The TRH-PLGA NPs were then surface modified with chitosan to achieve positive surface charge rendering them potential membrane penetrating agents. PLGA, PLGA-TRH, Chitosan-PLGA and Chitosan-PLGA-TRH NPs were characterized and analyzed using Dynamic Light Scattering (DLS), Transmissiom Electron Microscopy (TEM) and Infra-red spectroscopic techniques. PMID- 27483928 TI - Crystal Structure and Photocatalytic Activity of Al-Doped TiO2 Nanofibers for Methylene Blue Dye Degradation. AB - Al-TiO2 nanofibers were prepared using a sol-gel derived electrospinning by varying the Al/Ti molar ratio from 0 to 0.73 to investigate the effect of Al doping on the crystal structure and the photocatalytic activity of Al-TiO2 for methylene blue (MB) degradation. XRD results indicated that as the Al/Ti molar ratio rose, crystal structure of Al-TiO2 was changed from anatase/rutile (undoped), anatase (0.07-0.18), to amorphous phase (0.38-0.73), which was confirmed by XPS and Raman analysis. The degradation kinetic constant increased from 7.3 x 10(-4) min(-1) to 4.5 x 10(-3) min(-1) with the increase of Al/Ti molar ratios from 0 to 0.38, but decreased to 3.4 x 10(-3) min(-1) when the Al/Ti molar ratio reached 0.73. The Al-TiO2 catalyst doped with 0.38 Al/Ti molar ratio demonstrated the best MB degradation. Experimental results indicated that the Al doping in Al-TiO2 was mainly attributed to the crystal structure of TiO2 and the photocatalytic degradation of MB. PMID- 27483931 TI - Applications of TiO2, ZnO and Ag Nanomaterials to Denim Fabric. AB - In previous studies much research has reported the determination of applications of TiO2 (rutile and anatase), ZnO and Ag nanomaterials onto various textile surfaces, but in this study for the first time application to denim fabric and testing of the finished fabric for antimicrobial activities of these nanomaterials was investigated. The presence of nanoparticles on dyed denim fabric surfaces was confirmed by Scanning Electron Microscope (SEM). The nanomaterial-impregnated denim fabric (100% cotton) showed significant antibacterial activity against Staphylococcus aureus, Escherichia coli and Escherichia coli isolated from pasta. Additionally, the UV tests indicated excellent improvement in the UV absorbing activity of the TiO2 (rutile and anatase), ZnO and Ag nanomaterial-treated fabrics. PMID- 27483930 TI - Polydopamine-Coated TiO2 Nanotubes for Selective Photocatalytic Oxidation of Benzyl Alcohol to Benzaldehyde Under Visible Light. AB - TiO2 nanotube arrays grown by anodization were coated with thin layers of polydopamine as visible light sensitizer. The PDA-coated TiO2 scaffolds were used as photocatalyst for selective oxidation of benzyl alcohol under monochromatic irradiation at 473 nm. Benzaldehyde was selectively formed and no by-products could be detected. A maximized reaction yield was obtained in O2-saturated acetonitrile. A mechanism is proposed that implies firstly the charge carrier generation in polydopamine as a consequence of visible light absorption. Secondly, photo-promoted electrons are injected in TiO2 conduction band, and subsequently transferred to dissolved O2 to form O*2- radicals. These radicals react with benzyl alcohol and lead to its selective dehydrogenation oxidation towards benzaldehyde. PMID- 27483929 TI - Effects of Platinum Nanocolloid in Combination with Gamma Irradiation on Normal Human Esophageal Epithelial Cells. AB - Our previous study demonstrated that platinum nanocolloid (Pt-nc), combined with lower-dose gamma irradiation at 3, 5, and 7 Gy significantly decreased proliferation and accelerated apoptosis of the human esophageal squamous cell carcinoma-derived cell line KYSE-70. The aim of the present study was to determine, under the same conditions as our previous study where gamma rays combined with Pt-nc were carcinostatic to KYSE-70 cells, if we could induce a radioprotective or the radiation-sensitizing effect on the human normal esophageal epithelial cells (HEEpiC). HEEpiC were treated with various Pt-nc concentrations and then irradiated with various gamma-ray doses. The proliferative status of HEEpiC was evaluated using trypan blue dye-exclusion and WST-8 assays. The cellular and nucleic morphological features were determined using crystal violet and Hoechst 33342 stainings, respectively. The intracellular level of reactive oxygen species (ROS) in HEEpiC was evaluated with a nitro blue tetrazolium (NBT) assay. The apoptotic status was detected with caspase-3, Bax, and Bcl-2 by Western blotting. Either Pt-nc or gamma irradiation could inhibit the growth of HEEpiC; however, their combined use exerted a significant proliferation-inhibitory effect in a Pt-nc dose-dependent manner than gamma irradiation alone. Pt-nc resulted in radiation sensitization rather than radiation protection on HEEpiC in vitro similar to KYSE-70 cells, when Pt-nc was administrated alone or combined with gamma irradiation. Thus, Pt-nc has an inhibitory effect on cell proliferation, a facilitative effect on apoptosis, and a certain degree of toxicity against HEEpiC. PMID- 27483932 TI - Nano-Web Cobalt Modified Silica Nanoparticles Catalysts for Water Oxidation and MB Oxidative Degradation. AB - Dioxygen generating materials, using water as oxygen source, can be used as catalysts in hypoxic environments. Cobalt(II) modified silica (SiO2@NPCo) nanoparticles were synthesized through coordination of cobalt(II) ions with nitrogen atoms from 2-acetylpyridine modified silica (SiO2@NP). The SiO2@NPCo nanoparticles further reacted with 1,3,5-benzenetricarboxylic acids, forming porous nano-web nanoparticles (SiO2@NPCoCOOH). The synthesized SiO2@NPCoCOOH nanoparticles were demonstrated as better white LED light driven photochemical catalysts for oxidation of water than individual nanoparticles (SiO2@NPCo). Moreover, the SiO2@NPCoCOOH/water system could decrease the content of methylene blue (MB) in solution and therefore, the nanoweb cobalt(II) modified silica nanoparticles can be environmentally friendly catalysts for oxidative degradation of MB, using water as the oxygen source. PMID- 27483933 TI - Advances in Poly(4-aminodiphenylaniline) Nanofibers Preparation by Electrospinning Technique. AB - Polyaniline (PANI) nanofibers are drawing a great deal of interest from academia and industry due to their multiple applications, especially in biomedical field. PANI nanofibers were successfully electrospun for the first time by MacDiarmid and co-workers at the beginning of the millennium and since then many efforts have been addressed to improve their quality. However, traditional PANI prepared from aniline monomer shows some drawbacks, such as presence of toxic (i.e., benzidine) and inorganic (salts and metals) co-products, that complicate polymer post-treatment, and low solubility in common organic solvents, making hard its processing by electrospinning technique. Some industrial sectors, such as medical and biomedical, need to employ materials free from toxic and polluting species. In this regard, the oxidative polymerization of N-(4-aminophenyl)aniline, aniline dimer, to produce poly(4-aminodiphenylaniline), P4ADA, a kind of PANI, represents an innovative alternative to the traditional synthesis because the obtained polymer results free from carcinogenic and/or polluting co-products, and, moreover, more soluble than traditional PANI. This latter feature can be exploited to obtain P4ADA nanofibers by electrospinning technique. In this paper we report the advances obtained in the P4ADA nanofibers electrospinnig. A comparison among polyethylene oxide (PEO), polymethyl methacrylate (PMMA) and polystyrene (PS), as the second polymer to facilitate the electrospinning process, is shown. In order to increase the conductivity of P4ADA nanofibers, two strategies were adopted and compared: selective insulating binder removal from electrospun nanofibers by a rinsing tratment, afterwards optimizing the minimum amount of binder necessary for the electrospinning process. Moreover, the effect of PEO/P4ADA weight ratio on the fibers morphology and conductivity was highlighted. PMID- 27483934 TI - Characterization of Zn(O,S) Buffer Layers for Cu(In,Ga)Se2 Solar Cells. AB - Zn(O,S) thin films were deposited using a ZnS target under Ar/O2 gases by radio frequency magnetron sputtering. As the O2 concentration increased, the deposition rates of the Zn(O,S) films decreased due to increase of O-. The crystalline structure of Zn(O,S) was maintained at up to 0.6% O2, while the films became unstable at the condition exceeding 0.8% O2. This was attributed to incomplete nucleation and film growth on the substrate at the room temperature. Additionally, optical emission spectroscopy analysis indicated that an increased O- intensity at high O2 concentration was responsible for the slow deposition rate and increased oxygen concentration of the films. X-ray diffraction and scanning electron microscopy revealed the formation of a Zn(O,S) crystal structure with partial substitution of O for S and uniform and dense grains of the films. X-ray photoelectron spectroscopy showed that the Zn(O,S) films have a uniform composition of each element and consisted of a mixed crystal structure of Zn(O,S) with Zn-O bonding. Overall, the results of this study confirmed that Zn(O,S) films deposited by radio-frequency sputtering using Ar/O2 gas at room temperature can be applied to Cu(In,Ga)Se2 solar cells as a buffer layer. PMID- 27483935 TI - Effects of Bending Radii on the Characteristics of Flexible Organic Solar Cells Investigated by Impedance Analysis. AB - Flexible organic solar cells (OSCs) were fabricated on an indium-tin-oxide (ITO)/poly(ethylene terephthalate) (PET) substrate and were subjected to bending tests with various bending radii. We observed that the photovoltaic properties of the OSCs precipitously deteriorated at a bending radius <= 0.75 cm. In order to investigate the effects of the bending test, the changes in the surface morphology and the sheet resistance of the ITO-coated PET samples were investigated, and the photovoltaic properties of bent and unbent OSCs were evaluated. Thereafter, equivalent circuits for the OSCs were assumed and the change in their parameters, such as resistance and capacitance, was observed. PMID- 27483936 TI - Effects of Plasma Polymer Films and Their Deposition Powers on the Barrier Characteristics of the Multilayer Encapsulation for Organic Devices. AB - Organic electronic devices (OEDs) are quite suitable for use in flexible devices due to their ruggedness and flexibility. A number of researchers have studied the use of OEDs on flexible substrates in transparent, flexible devices in the near future. However, water and oxygen can permeate through the flexible substrates and can reduce the longevity of OEDs made from organic materials, which are weak to moisture and oxygen. In order to prevent the degradation of the OEDs, researchers have applied an encapsulation layer to the flexible substrates. In this study, Al2O3/plasma polymer film/Al2O3 multi-layers were deposited on polyethylene-naphthalate substrates through a combination of atomic layer deposition and plasma-enhanced chemical vapor deposition (PECVD). The plasma polymer film, which is located between the Al2O3 films, is deposited via PECVD with the use of a tetrakis(trimethylsilyloxy)silane precursor. The power of the plasma deposition varied from 10 to 50 W. The hydrophobicity of the plasma polymer film surfaces was investigated by measuring the water contact angle. The chemical structures of the plasma polymer films were measured via ex-situ Fourier transform infrared analysis. The permeation curves of the various films were analyzed by performing a calcium (Ca)-test. PMID- 27483937 TI - Electrical and Optical Properties of Si-Incorporated a-C:H Films via the Radio Frequency Plasma-Enhanced Chemical Vapor Deposition Method. AB - The optical and electrical properties of silicon-incorporated hydrogenated amorphous carbon (a-C:H:Si) films deposited via the radio frequency (RF) plasma enhanced chemical vapor deposition (PECVD) method using a mixture of CH4, H2, and SiH4 were observed. The silane gas whose ranged from 0 to 25 vol.% [SiH4/(SiH4 + CH4) was fed into the reactor while the other deposition parameters were kept constant. The basic properties of these films were investigated via Raman spectroscopy, UV-visible spectrometry, I-V measurement, and surface profiling. The experiment results showed that the film thickness increased from 300 nm to 800 nm for the same deposition time as the silane gas increased. The Raman spectrum obtained from the silicon-incorporated a-C:H films suggested that the film property changed from graphitic-like to more diamond-like. As the silane gas increased, the optical gap, E04, slightly increased from 1.98 eV to 2.62 eV. It was shown that the Si atoms incorporated into the a-C:H films reduced the size of the sp2 clusters. As for the I-V characteristics, the Si-incorporated a-C:H films had a lower leakage current than the a-C:H films without Si. PMID- 27483938 TI - Optimization of the ZnS Buffer Layer by Chemical Bath Deposition for Cu(In,Ga)Se2 Solar Cells. AB - We evaluated a ZnS buffer layer prepared using a chemical bath deposition (CBD) process for application in cadmium-free Cu(In,Ga)Se2 (CIGS) solar cells. The ZnS buffer layer showed good transmittance (above 90%) in the spectral range from 300 to 800 nm and was non-toxic compared with the CdS buffer layers normally used in CIGS solar cells. The CBD process was affected by several deposition conditions. The deposition rate was dependent on the ammonia concentration (complexing agent). When the ammonia concentration was either too high or low, a decrease in the deposition rate was observed. In addition, post heat treatments at high temperatures had detrimental influences on the ZnS buffer layers because portions of the ZnS thin films were transformed into ZnO. With optimized deposition conditions, a CIGS solar cell with a ZnS buffer layer showed an efficiency of 14.18% with a 0.23 cm2 active area under 100 mW/cm2 illumination. PMID- 27483939 TI - Crystallization Behavior of Amorphous Si3N4 and Particle Size Control of the Crystallized alpha-Si3N4. AB - Amorphous silicon nitride powder prepared by low-temperature vapor-phase reaction was heat treated at various temperatures for different periods of time to examine the crystallization behavior. The effects of the heat-treatment temperature and duration on the degree of crystallization were investigated along with the effect of the heat-up rate on the particle size, and its distribution, of the crystallized alpha-phase silicon nitride powder. A phase transition from amorphous to alpha-phase occurred at a temperature above 1400 degrees C. The crystallization. process was completed after heat treatment at 1500 degrees C for 3 h or at 1550 degrees C for 1 h. The crystallization process starts at the surface of the amorphous particle: while the outer regions of the particle become crystalline, the inner part remains amorphous. The re-arrangement of the Si and N atoms on the surface of the amorphous particle leads to the formation of hexagonal crystals that are separated from the host amorphous particle. The particle size and size distribution can be controlled by varying the heat treatment profile (namely, the heat-treatment temperature, heating rate, and heating duration at the specified temperature), which can be used to control the relative extent of the nucleation and growth. The completion of most of the nucleation process by lowering the heat-up rate can be used to achieve a singlet particle size distribution. Bimodal particle size distribution can be achieved by fast heat-up during the crystallization process. PMID- 27483940 TI - Electrodeposition of Nanotwin Cu by Pulse Current for Through-Si-Via (TSV) Process. AB - Recently, the through-Si-via (TSV) had been focused as an optimal solution for interconnecting the 3-dimensionaly stacked semiconductor devices. One of core processes in the TSV technology is the Cu filling process which electrochemically forms the Cu in the via with high aspect ratio. The nanotwin Cu is effective candidate for replacing the conventional electrodeposited Cu due to its ultrahigh mechanical strength and good electrical conductivity. In this work, the formation of the nanotwin Cu in the TSV by applying pulse current was systematically studied. Also, TSV filling behavior by electrodeposition with pulse current was compared with direct current. The variation of mechanical properties as well as the electrical resistivity of electrodeposited Cu by the pulse current also investigated. PMID- 27483941 TI - Extreme Ultraviolet Multilayer Defect Compensation in Computational Lithography. AB - For the extreme ultraviolet (EUV) lithography, multilayer (ML) defects such as bump and pit defects can disrupt the phase of reflected field and degrade aerial images on wafer. In this paper, a defect printability and repair simulator (DPRS) is introduced to predict and repair the effect of ML defects in EUV aerial images. DPRS is composed of multilayer growth by using Gaussian function and Stearns's method, mask simulation by using a scattering matrix (S-matrix) analysis method, and projection simulation by using Kohler's illumination. For bump and pit ML defects, the combining the modified absorber and the layer-by layer ML peeling is better than other methods. This study can be helpful in understanding EUV defect and also give insight into the EUV defect compensation for the device volume production. PMID- 27483942 TI - Assembly of Submicron Sized Ag, Co, and Ni Particles Into Thin Films at Liquid/Liquid Interfaces. AB - Submicron sized particles of Ag, Co and Ni were synthesised by reducing metal salts in ethylene glycol (EG) in the presence of polyvinylpyrrolidone (PVP). These particles on dispersion in water when held in contact with a toluene layer were found to assemble into dense films extending over large areas at the interface between the two liquids. The effect of reaction conditions (solvent, precursor concentration, temperature) on the synthesis and assembly of the particles was studied. The characteristics of the interfacial deposits and the particulate dispersions were studied by scanning electron microscopy (SEM), X-ray diffraction (XRD), ultraviolet-visible (UV-Vis) spectroscopy and dynamic light scattering (DLS). PMID- 27483943 TI - Silica Modified Chitosan/Polyethylenimine Nanogel for Improved Stability and Gene Carrier Ability. AB - Although chitosan-based hydrogel has been widely used as a gene carrier material, further improvement in this aspect is still needed. Herein a new method was proposed for preparing the effective chitosan-based gene carrier nanogel. The new method based on the fact that supra-molecular interactions between silica, polyethylenimine (PEI) and chitosan could be used to self-assemble them together to form a rigid and stable gene carrier material in the reverse microemulsion system. When compared with chemical cross-linking route, the proposed method is simple and easy to adjust components of the resulting nanogel and, therefore, can improve its gene carrying ability. Our results showed that, doping of the PEI and silica into the chitosan hydrogel obviously increased its strength, stability and gene carrying ability. PMID- 27483944 TI - [Foreword]. PMID- 27483945 TI - [Epigenetic alterations and biological phenomena caused by mutation in an IDH gene]. PMID- 27483946 TI - [Senescence-inducing stress and glycolytic enzyme, PGAM]. PMID- 27483947 TI - [Regulation of cellular energy metabolism by prolyl hydroxylase PHD]. PMID- 27483948 TI - [Post-transcriptional regulation and metabolism]. PMID- 27483949 TI - [Metabolic activation by a histone H3 lysine 36 demethylase, Fbxl10 in leukemogenesis]. PMID- 27483950 TI - [Regulation of RNA methylation and epigeneticis effects by the ALKBH family]. PMID- 27483951 TI - [Molecular basis of tRNA methylthiolation and the pathological implications]. PMID- 27483952 TI - [Control of undifferentiated state by RB tumor suppressor]. PMID- 27483953 TI - [Hippocampus-synthesized androgens and estrogens enhance memory formation]. PMID- 27483954 TI - [Structure and function of glycolipids]. PMID- 27483955 TI - [Molecular dynamics and regulatory mechanisms for signals of glycosphingolipids in membrane lipid rafts]. PMID- 27483956 TI - [Study on functional structures of artificial antibodies]. PMID- 27483957 TI - [Why Won't the Intractable MRSA Infections Go Away?]. PMID- 27483958 TI - [Structural basis of synaptic organizer complexes for inducing synapse formation in the central nervous system]. PMID- 27483959 TI - [Methionine metabolism regulates biotransformation of glucose via protein arginine methylation in cancer cells]. PMID- 27483960 TI - [N-glycans in the maintenance of stemness]. PMID- 27483961 TI - [Dynamic Recognition of Unfolded Proteins by the Trigger Factor Chaperone as investigated by NMR]. PMID- 27483962 TI - [Host cholesterol biosynthesis as a potential target for anti-hepatitis C virus strategies]. PMID- 27483963 TI - [Heterotrimeric G protein Gbetagamma subunits-regulated Rho family small G protein-specific guanine nucleotide exchange factors]. PMID- 27483964 TI - [Pattern recognition receptor-mediated sensing mechanism during hepatitis virus infection]. PMID- 27483965 TI - LONG-TERM THRIVERS. PMID- 27483966 TI - HEALING THROUGH BARRIERS. PMID- 27483967 TI - BEYOND OUR COMFORT ZONE. PMID- 27483968 TI - TAINTED PASSION. PMID- 27483969 TI - AMBASSADOR KATE. PMID- 27483970 TI - GRINDR AND PrEP. PMID- 27483971 TI - 'SOMETHING MORE IMPORTANT THAN FEAR'. PMID- 27483972 TI - HEALTHCARE FORECASTING IN THE UNITED ARAB EMIRATES (UAE). AB - This study has been designed to address the issue of the forecasting of the healthcare needs of the United Arab Emirate (UAE) from 1974 to 2011. This includes predicting the health system's need for hospitals and hospital beds, as well as the public health manpower (example, physicians, nurses) requirements. The analysis was based on historical data: the number of hospitals, number of nurses, number of hospital beds, which have been posited as the measures of life expectancy in the Emirate. The study found that, although significant changes designed to enhance public health outcomes in the UAE have been made, beds to population ratio was the most significant factor in enhancing healthcare and the public health. PMID- 27483973 TI - A POST ANALYSIS OF A PREVENTIVE AND CHRONIC HEALTHCARE TOOL. AB - This study uses the data set from Kaiser Permanente to examine the post implementation of a preventive and chronic care that utilizes clinical information system, delivery system design, and clinical decision support to maximize the office visit. The analysis suggests a significant positive relationship between frequency of utilization rates to address preventive and chronic care gaps. There is no implication of a significant positive relationship with the successfully captured rate, which satisfies closing the care gap within 45 days. The use of the preventive care tool will assist members in satisfying the preventive care gap, cervical cancer screening, within 45 days of the encounter. PMID- 27483974 TI - EARNINGS MANAGEMENT IN U.S. HOSPITALS. AB - OBJECTIVE: This paper examines the hospital management practices of manipulating financial earnings within the bounds of generally accepted accounting principles (GAAP). STUDY DESIGN: We conduct regression analyses that relate earnings management to hospital characteristics to assess the economic determinants of hospital earnings management behavior. METHOD AND DATA: From the CMS Cost Reports we collected hospital financial data of all U.S. hospitals that request reimbursement from the federal government for treating Medicare patients, and regress discretionary accruals on hospital size, profitability, asset liquidity, operating efficiency, labor cost, and ownership. RESULTS: Hospitals with higher profit margin, current ratio, working capital, days of patient receivables outstanding and total wage are associated with more earnings management, whereas those with larger size and higher debt level, asset turnover, days cash on hand, fixed asset age are associated with lower level of earnings manipulation. Additionally, managers of non-profit hospitals are more likely to undertake some form of window-dressing by manipulating accounting accruals without changing business models or pricing strategies than their public hospital counterparts. CONCLUSIONS: We provide direct evidence of the use of discretionary accruals to manage financial earnings among U.S. hospitals and the finding has profound policy implications in terms of assessing the pervasiveness of accounting manipulation and the overall integrity of financial reporting in this very special public and quasi-public service sector. PMID- 27483975 TI - COSTS OF DEPRESSION FROM CLAIMS DATA FOR MEDICARE RECIPIENTS IN A POPULATION BASED SAMPLE. AB - BACKGROUND: Many persons with depressive disorder are not treated and associated costs are not recorded. AIMS OF THE STUDY: To determine whether major depressive disorder (MDD) is associated with higher medical cost among Medicare recipients. METHODS: Four waves of the Baltimore-Epidemiologic Catchment Area (Baltimore ECA) Study conducted between 1981 and 2004 were linked to Medicare claims data for the years 1999 to 2004 from the Centers for Medicare and Medicaid Services (CMS). Generalized linear models specified with a gamma distribution and log link function were used to examine direct medical care costs associated with MDD. RESULTS: Medicare recipients with no history of MDD in either the ECA or CMS data had mean six-year medical costs of US $40,670, compared to $87,445 for Medicare recipients with MDD as recorded in CMS data and $43,583 for those with MDD as recorded in Baltimore-ECA data. Multivariable regressions found that compared to Medicare recipients with no history of depression, those with depression identified in the CMS data had significantly higher medical costs; about 1.87 times (95% confidence interval (CI) 1.32 to 2.67) higher. Medicare recipients with a history of depression identified in the ECA data were no more likely to have higher costs than were Medicare recipients with no history of depression (relative ratio 1.33, 95% CI 0.87 to 2.02). DISCUSSION: Medicare recipients with a history of depression identified in claims data had significantly higher medical costs than recipients with no history of depression. However, no significant differences were found between Medicare recipients with depression in the community-based Baltimore ECA data and those with no history of depression. The results show that the source of diagnosis, in treatment versus survey data, produces differences in results as regards costs. LIMITATIONS: This study involved only Medicare recipients with claims data over the six years 1999 to 2004. Many of the ECA respondents were too young to qualify for Medicare. IMPLICATIONS FOR HEALTH POLICY: Depressive disorder involves substantial medical care costs. The findings provide information on the economic burden of depression, an important but often omitted dimension and perspective of the burden of mental illnesses. PMID- 27483976 TI - QUANTITATIVE ASSESSMENT OF SOME PREVENTIVE HEALTH SERVICES PROVIDED FOR ADOLESCENT INDIVIDUALS IN DUBAI. AB - The United Arab Emirate (UAE) of Dubai, faces significant adolescent health problems. In 2009, evidence based clinical guidelines were developed for primary health care professionals in Dubai to help reduce adolescent health problems. This research study explores adolescents' self-reports about health education services received between 2008 and 2010. The sample consisted of 730 public high school students in grades 10 through 12 between the ages of 15 and 19. 357 (48.9%) of the sample were males and 373 (51.1%) were female. The major language spoken in the home was Arabic (77.4%). All students completed a 27-item survey in Arabic that was adapted from the Young Adult Health Care Survey (YAHCS). The YAHCS is a 56-item research instrument traditionally administered in English and Spanish. The sample reported they had received little or no health education from their health care providers. 94.2% reported receiving no information about using a helmet for bicycle and motorbike safety; 88.2% reported receiving no information about drug use; and 81.9% reported that they received no information about smoking. The instrument also explored the health education material students received within the last 12 months. 65.5% of the sample reported seeing and/or hearing safety tips; 84.9% reported hearing and/or seeing health information about healthy diet, physical activity and exercise; and 79.2% reported seeing and/or hearing information about the risks of smoking and substance abuse. PMID- 27483977 TI - FACTORS ASSOCIATED WITH THE UPTAKE OF SODIUM DICHLOROISOCYANURATE (NADCC) TABLETS AS HOUSEHOLD WATER-TREATMENT PRODUCT AMONG CAREGIVERS OF CHILDREN UNDER FIVE IN BENIN, WEST AFRICA. AB - Improving access to safe drinking water is a critical step in mitigating diarrheal diseases that affect millions of children under 5 years throughout the developing world each year. While the delivery of safe water is out of the reach of many countries, the utilization of Sodium dichloroisocyanurate (NaDCC) is a proven cost-effective alternative to prevent diarrhea caused by waterborne pathogens. However, its uptake remains low in many developing countries, such as the Republic of Benin. This study examines the trends and the determinants of NaDCC uptake in Benin. Population Services International and its affiliate conducted two multistage household surveys among caregivers of children under five in Benin to examine the practices towards diarrheal disease in children under five and identify the factors associated with the use of NaDCC in this population. 2912 respondents/caregivers of children under five were interviewed in 2009 versus 3196 in 2011. The proportion of caregivers who reported ever treating water with NaDCC increased from 5.8% in 2009 to 11.5% in 2011, p < 0.001. The logistic regression model showed that caregivers who knew places that sell NaDCC in the community; those who felt capable of utilizing NADCC correctly to treat drinking water as well as caregivers who reported to be Muslim were more likely than their counterparts to use NaDCC as water treatment product. In order to increase the use of NADCC among caregivers, the Government of Benin and its development partners should focus not only on making NADCC available in the community and informing the community members about the different points of sale, but also in building up the capacity and confidence of caregivers in utilizing it. PMID- 27483978 TI - AN OVERVIEW OF THE EFFICACY OF THE 12-STEP GROUP THERAPY FOR SUBSTANCE ABUSE TREATMENT. AB - This study was designed to determine if 12-Steps groups efficacy for substance abuse treatment significantly improve abstinence rates of heroin addicts in the short run and long run (1-year and 5-year period); and if abstinence rates are found to be lower for heroin addicts that have attended 12-Step groups at the 1 year mark, and if similar results would be expected at the 5-year mark. Secondary data from the Inter-University Consortium of Political and Social Research (ICPSR) was extracted and analyzed for the aforementioned hypothesis. Using SSPS to test the research hypothesis for the 1-Year Follow Up, the chi-square test shows a p-value below of .10, and the analysis determined that there was significant evidence to support the hypothesis that cases in a 12-Steps or self help program have a higher success than cases not in a program for the 1-year follow up. For 5-Year Follow Up, the cases that attended a 12-Step program or a self-help program and about 27% went on to use heroin during the last 12 months compared to 34% cases that did not go to a program. PMID- 27483979 TI - The streamlined Allostatic Load Index: a replication of study results. AB - According to the World Health Organization stress in the workplace is becoming a major challenge of employers worldwide. While perceived stress levels can be assessed by questionnaires there is growing evidence that stress-related wear and tear of our body can be measured by the Allostatic Load Index (ALI). In a sample of 12,477 German industrial employees (19.6% female, 18-65 years) self-rated stress was explored by the effort-reward imbalance (ERI) questionnaire. A voluntary health check included biomarkers such as diastolic blood pressure, waist circumference, glycosylated hemoglobin, low-density lipoprotein, and heart rate variability. Based on predefined subclinical cutoff values, a 5-variable ALI was calculated. Differences in ALI according to low (ERI <=1.0) and high (ERI >1.0) stress levels were tested. The association of ERI and ALI was explored using logistic regression analysis controlling for multiple confounders. Employees perceiving high stress levels showed significant higher ALI scores (p < .001) compared to lower stressed employees. This association was stronger in men and independent of age. ALI was associated with work stress in adjusted models (OR 1.18 +/- .08 [95% CI 1.03, 1.36]; p < .05). This study replicates former results in a large sample of industrial employees indicating that work stress is associated with a short form ALI. PMID- 27483980 TI - Business and Breakthrough: Framing (Expanded) Genetic Carrier Screening for the Public. AB - A growing body of research has given attention to issues surrounding genetic testing, including expanded carrier screening (ECS), an elective medical test that allows planning or expecting parents to consider the potential occurrence of genetic diseases and disorders in their children. These studies have noted the role of the mass media in driving public perceptions about such testing, giving particular attention to ways in which coverage of genetics and genetic testing broadly may drive public attitudes and choices concerning the morality, legality, ethics, and parental well-being involved in genetic technologies. However, few studies have explored how mass media are covering the newer test, ECS. Drawing on health-related framing studies that have shown in varying degrees the impact particular frames such as gain/loss and thematic/episodic can have on the public, this study examines the frame selection employed by online media in its coverage of ECS. This analysis-combined with an analysis of the sources and topics used in such coverage and how they relate to selected frames-helps to clarify how mass media are covering an increasingly important medical test and offers considerations of how such coverage may inform mass media scholarship as well as health-related practices. PMID- 27483981 TI - Investigating a toxic risk (self-inflicted) the example of conventional and advanced studies of a novel Tobacco Heating System. AB - This special issue of Regulatory Toxicology and Pharmacology contains 9 scientific papers from Philip Morris International about the laboratory and 1 about early clinical investigation of a novel 'Tobacco Heating System'. The studies have employed conventional and a wide range of newer 'omics and bioinformatics techniques to seek and explore potential toxic actions of the inhalable vapour it generates. The methods of study and display of results employed are considered to be a valuable guide and model for wider application in other toxicological investigations because they are directed more to proximal causes of effects than to the cruder distal end points revealed by conventional, empirical procedures. As such they should be regarded as a paradigm for the applicability and accuracy of the testing and prediction of toxic risks. PMID- 27483982 TI - Placental gene expression of the placental growth factor (PlGF) in intrauterine growth restriction. AB - OBJECTIVE: We analyzed changes in gene expression of placental growth factor (PIGF) in human placental samples obtained postpartum from pregnancies with IUGR. METHODS: During a twelve-month study period representing the calendar year of 2012 placental samples from 101 pregnancies with IUGR and from 140 normal pregnancies were obtained for analysis of a potential difference in PIGF gene expression. RESULTS: There was no significant difference in gene activity of the PIGF gene between the IUGR versus normal pregnancy groups (Ln2alpha: 0.92; p < 0.06). Within the IUGR group, no fetal gender-dependent differences were seen in placental PIGF gene expression (Ln2alpha: 0.72; p = 0.05). Placental PIGF gene activity was significantly lower in fetuses with more severe IUGR versus less severe cases (Ln2alpha: -1.49; p < 0.03). CONCLUSION: We found no difference in gene expression of PIGF in placental samples obtained from IUGR pregnancies versus normal pregnancy suggesting the absence of a direct role of PIGF gene activity in the development of defective angiogenesis in IUGR during the later stages of gestation. However, in more severe cases of intrauterine growth restriction PIGF expression does show a significant decrease indicating its potential role in the profound defect in angiogenesis in these cases. PMID- 27483984 TI - Manipulating the Biosynthesis of Bioactive Compound Alkaloids for Next-Generation Metabolic Engineering in Opium Poppy Using CRISPR-Cas 9 Genome Editing Technology. AB - Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated9 (Cas9) endonuclease system is a powerful RNA-guided genome editing tool. CRISPR/Cas9 has been well studied in model plant species for targeted genome editing. However, few studies have been reported on plant species without whole genome sequence information. Currently, no study has been performed to manipulate metabolic pathways using CRISPR/Cas9. In this study, the type II CRISPR/SpCas9 system was used to knock out, via nonhomologous end-joining genome repair, the 4'OMT2 in opium poppy (Papaver somniferum L.), a gene which regulates the biosythesis of benzylisoquinoline alkaloids (BIAs). For sgRNA transcription, viral-based TRV and synthetic binary plasmids were designed and delivered into plant cells with a Cas9 encoding-synthetic vector by Agrobacterium-mediated transformation. InDels formed by CRISPR/Cas9 were detected by sequence analysis. Our results showed that the biosynthesis of BIAs (e.g. morphine, thebaine) was significantly reduced in the transgenic plants suggesting that 4'OMT2 was efficiently knocked-out by our CRISPR-Cas9 genome editing approach. In addition, a novel uncharacterized alkaloid was observed only in CRISPR/Cas9 edited plants. Thus, the applicabilitiy of the CRISPR/Cas9 system was demonstrated for the first time for medicinal aromatic plants by sgRNAs transcribed from both synthetic and viral vectors to regulate BIA metabolism and biosynthesis. PMID- 27483985 TI - Bacterial repopulation of drinking water pipe walls after chlorination. AB - The short-term kinetics of bacterial repopulation were evaluated after chlorination of high-density polyethylene (HDPE) colonized with drinking water biofilms and compared with bare HDPE surfaces. The effect of chlorination was partial as a residual biofilm persisted and was time-limited as repopulation occurred immediately after water resupply. The total number of bacteria reached the same levels on both the bare and chlorinated biofilm-fouled HDPE after a seven-day exposure to drinking water. Due to the presence of a residual biofilm, the hydrophobicity of chlorinated biofilm-fouled surface exhibited much lower adhesion forces (2.1 nN) compared to bare surfaces (8.9 nN). This could explain the rapid repopulation after chlorination, with a twofold faster bacterial accumulation rate on the bare HDPE surface. gamma-Proteobacteria dominated the early stages of repopulation of both surfaces and a shift in the dominance occurred over the colonization time. Such observations define a timescale for cleaning frequency in industrial environments and guidelines for a rinsing procedure using drinking water. PMID- 27483986 TI - Autophagy promotes cell motility by driving focal adhesion turnover. AB - In eukaryotic cells, cell migration is a dynamic and complex process that involves finely tuned orchestration of a multitude of proteins including, for example, those involved in focal adhesions (FAs). Cell migration plays an indispensable role in particular stages of development and its proper regulation is crucial in various biological processes, from wound healing to the immune response. FAs are transmembrane protein complexes that traverse cytoskeletal infrastructures all the way to the extracellular matrix, producing traction at the leading edge of the cell, thus allowing for motility. The assembly of FAs has been extensively studied, whereas disassembly remains poorly understood. Here, we highlight 2 recent studies (see the corresponding puncta in the previous and current issues of the journal) that demonstrate a requirement for macroautophagy/autophagy in FA disassembly. These studies also provide a deeper understanding of how autophagy can contribute to cell migration among multiple cell types. PMID- 27483987 TI - Modelling chronotaxicity of cellular energy metabolism to facilitate the identification of altered metabolic states. AB - Altered cellular energy metabolism is a hallmark of many diseases, one notable example being cancer. Here, we focus on the identification of the transition from healthy to abnormal metabolic states. To do this, we study the dynamics of energy production in a cell. Due to the thermodynamic openness of a living cell, the inability to instantaneously match fluctuating supply and demand in energy metabolism results in nonautonomous time-varying oscillatory dynamics. However, such oscillatory dynamics is often neglected and treated as stochastic. Based on experimental evidence of metabolic oscillations, we show that changes in metabolic state can be described robustly by alterations in the chronotaxicity of the corresponding metabolic oscillations, i.e. the ability of an oscillator to resist external perturbations. We also present a method for the identification of chronotaxicity, applicable to general oscillatory signals and, importantly, apply this to real experimental data. Evidence of chronotaxicity was found in glycolytic oscillations in real yeast cells, verifying that chronotaxicity could be used to study transitions between metabolic states. PMID- 27483988 TI - Gene Editing of Human Hematopoietic Stem and Progenitor Cells: Promise and Potential Hurdles. AB - Hematopoietic stem and progenitor cells (HSPCs) have great therapeutic potential because of their ability to both self-renew and differentiate. It has been proposed that, given their unique properties, a small number of genetically modified HSPCs could accomplish lifelong, corrective reconstitution of the entire hematopoietic system in patients with various hematologic disorders. Scientists have demonstrated that gene addition therapies-targeted to HSPCs and using integrating retroviral vectors-possess clear clinical benefits in multiple diseases, among them immunodeficiencies, storage disorders, and hemoglobinopathies. Scientists attempting to develop clinically relevant gene therapy protocols have, however, encountered a number of unexpected hurdles because of their incomplete knowledge of target cells, genomic control, and gene transfer technologies. Targeted gene-editing technologies using engineered nucleases such as ZFN, TALEN, and/or CRISPR/Cas9 RGEN show great clinical promise, allowing for the site-specific correction of disease-causing mutations-a process with important applications in autosomal dominant or dominant-negative genetic disorders. The relative simplicity of the CRISPR/Cas9 system, in particular, has sparked an exponential increase in the scientific community's interest in and use of these gene-editing technologies. In this minireview, we discuss the specific applications of gene-editing technologies in human HSPCs, as informed by prior experience with gene addition strategies. HSPCs are desirable but challenging targets; the specific mechanisms these cells evolved to protect themselves from DNA damage render them potentially more susceptible to oncogenesis, especially given their ability to self-renew and their long-term proliferative potential. We further review scientists' experience with gene editing technologies to date, focusing on strategies to move these techniques toward implementation in safe and effective clinical trials. PMID- 27483990 TI - Potentiation of sprint cycling performance: the effects of a high-inertia ergometer warm-up. AB - Participant and protocol factors affect post-activation potentiation response. Performance enhancement is more consistent in highly-trained participants following multiple sets of a biomechanically similar conditioning activity. Providing optimal conditions, 6 international-level sprint cyclists executed multiple sets of short maximal conditioning contractions on a high-inertia ergometer before metered sprint performance. Three trial conditions were completed on separate days after a standardised warm-up: dynamic (DYN: 4 * 4 crank-cycles), isometric (ISO: 4 * 5-sec maximal voluntary contraction (MVC)), and control (CON: rest). Performance was measured from standing start to maximum velocity on an inertial-load ergometer at baseline (Pre), 4 (Post4), 8 (Post8) and 16 (Post16) min post-conditioning. Performance and biomechanical measures were assessed across 4 sprint segments, with magnitude-based inferences used to assess the likelihood that any affect was beneficial. Performance time only improved in DYN Post4, a 3.9% reduction during the first crank cycle (92% likely). On the ascending limb of the power-cadence relationship, peak torque and average power increased by 6.2% (94% likely) and 4.0% (87% likely), respectively. In ISOPost16, optimal cadence increased (82% likely) and average power improved over the descending limb (76% likely). DYN and ISO potentiated extremities of the torque-cadence relationship at distinct recovery times post-conditioning. This study suggests merit in including a high-inertia warm-up for sprint cycling. PMID- 27483989 TI - Angiopoietin-like protein 2 expression is suppressed by angiotensin II via the angiotensin II type 1 receptor in rat cardiomyocytes. AB - The present study aimed to determine the inhibitory effects of angiotensin II (AngII) on angiopoietin-like protein 2 (Angptl2) in rat primary cardiomyocytes, and to investigate the potential association between angiotensin II type 1 receptor (AT1R) and these effects. Cardiomyocytes were isolated from 3-day-old Wistar rats, and were cultured and identified. Subsequently, the expression levels of Angptl2 were detected following incubation with various concentrations of AngII for various durations using western blotting, reverse transcription quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence. Finally, under the most appropriate conditions (100 nmol/l AngII, 24 h), the cardiomyocytes were divided into six groups: Normal, AngII, AngII + losartan, normal + losartan, AngII + PD123319 and normal + PD123319 groups, in order to investigate the possible function of AT1R in Angptl2 suppression. Losartan and PD123319 are antagonists of AT1R and angiotensin II type 2 receptor, respectively. The statistical significance of the results was analyzed using Student's t-test or one-way analysis of variance. The results demonstrated that Angptl2 expression was evidently suppressed (P<0.05) following incubation with 100 nmol/l AngII for 24 h. Conversely, the expression levels of Angptl2 were significantly increased in the AngII + losartan group compared with the AngII group (P<0.01). However, no significant difference was detected between the AngII + PD123319, normal + losartan or normal + PD123319 groups and the normal group. The present in vitro study indicated that AngII was able to suppress Angptl2 expression, whereas losartan was able to significantly reverse this decrease by inhibiting AT1R. PMID- 27483991 TI - VivaScope(r) 1500 and 3000 systems for detecting and monitoring skin lesions: a systematic review and economic evaluation. AB - BACKGROUND: Skin cancer is one of the most common cancers in the UK. The main risk factor is exposure to ultraviolet radiation from sunlight or the use of sunbeds. Patients with suspicious skin lesions are first examined with a dermoscope. After examination, those with non-cancerous lesions are discharged, but lesions that are still considered clinically suspicious are surgically removed. VivaScope((r)) is a non-invasive technology designed to be used in conjunction with dermoscopy to provide a more accurate diagnosis, leading to fewer biopsies of benign lesions or to provide more accurate presurgical margins reducing the risk of cancer recurrence. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of VivaScope((r)) 1500 (Caliber Imaging and Diagnostics, Rochester, NY, USA; Lucid Inc., Rochester, NY, USA; or Lucid Inc., MAVIG GmbH, Munich, Germany) and VivaScope((r)) 3000 (Caliber Imaging and Diagnostics, Rochester, NY, USA) in the diagnosis of equivocal skin lesions, and VivaScope 3000 in lesion margin delineation prior to surgical excision of lesions. DATA SOURCES: Databases (MEDLINE, EMBASE and The Cochrane Library) were searched on 14 October 2014, reference lists of included papers were assessed and clinical experts were contacted for additional information on published and unpublished studies. METHODS: A systematic review was carried out to identify randomised controlled trials (RCTs) or observational studies evaluating dermoscopy plus VivaScope, or VivaScope alone, with histopathology as the reference test. A probabilistic de novo economic model was developed to synthesise the available data on costs and clinical outcomes from the UK NHS perspective. All costs were expressed as 2014 prices. RESULTS: Sixteen studies were included in the review, but they were too heterogeneous to be combined in a meta-analysis. One of two diagnostic studies that were deemed most representative of UK clinical practice reported that dermoscopy plus VivaScope 1500 was significantly more sensitive than dermoscopy alone in the diagnosis of melanoma (97.8% vs. 94.6%; p = 0.043) and significantly more specific than dermoscopy alone in the diagnosis of non-melanoma (92.4% vs. 26.74%; p < 0.000001). The results of another study suggest 100% [95% confidence interval (CI) 86.16% to 100%] sensitivity for dermoscopy plus VivaScope 1500 versus 100% (95% CI 91.51% to 100%) for dermoscopy alone. Specificity varied from 51.77% to 80.2% depending on the analysis set used. In terms of margin delineation with VivaScope, one study found that 17 out of 29 patients with visible lentigo maligna (LM) had subclinical disease of > 5 mm beyond the dermoscopically identified margin. Using 'optimistic' diagnostic data, the economic model resulted in an incremental cost effectiveness ratio (ICER) of L8877 per quality-adjusted life-year (QALY) (L9362 per QALY), while the 'less favourable' diagnostic data resulted in an ICER of L19,095 per QALY (L25,453 per QALY) in the diagnosis of suspected melanomas. VivaScope was also shown to be a dominant strategy when used for the diagnostic assessment of suspected basal cell carcinoma (BCC). Regarding margin delineation of LM, mapping with VivaScope was cost-effective, with an ICER of L10,241 per QALY (L11,651 per QALY). However, when VivaScope was used for diagnosis as well as mapping of LM, then the intervention cost was reduced and VivaScope became a dominant strategy. LIMITATIONS: There is an absence of UK data in the included studies and, therefore, generalisability of the results to the UK population is unclear. CONCLUSIONS: The use of VivaScope appears to be a cost-effective strategy in the diagnostic assessment of equivocal melanomas and BCCs, and in margin delineation of LM prior to surgical treatment. FUTURE WORK: High-quality RCTs are required in a UK population to assess the diagnostic accuracy of VivaScope in people with equivocal lesions. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014014433. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 27483992 TI - Development and characterization of repellent formulations based on nanostructured hydrogels. AB - Diseases caused by insects could lead to epidemic scenarios in urban areas and insect repellents are a shield against a wide range of insects, but they need to be safe without compromising efficacy. Ethyl butylacetylaminopropionate (EB) is a synthetic mosquito repellent, which could be used in products for adults and children due to its low-allergenic potential. The aim of this study was to develop and characterize EB and Poloxamer 407 nanoemulsions regarding their droplets mean size, pH, rheological properties, cytotoxicity and in vitro permeation profile. The developed formulations (F1 with 12.5% of EB and F2 with 25% of EB) were compared with a commercial formulation containing 12.5% of EB. Droplets mean size was determined by DLS, and for both nanoemulsions they were around 200 nm; however, the commercial formulation presented a droplets mean size of 10 nm, which could contribute to its high permeation. F1 and F2 presented a gel-like behavior, however F2 presented lower viscosity due to the presence of more EB between the polymer chains preventing them to interact with each other. Also, F2 was less retained by the epidermis when compared to F1 probably due to its lower viscosity. For the cytotoxicity assay only F2, which presented the highest concentration of EB was tested, and it was not toxic to the cells. This result could be also extended to F1 which presented half the EB concentration. The present study demonstrated that EB and Poloxamer 407 nanoemulsions are promising as new insect-repellent formulations. PMID- 27483993 TI - Cost and impact of policies to remove and reduce fees for obstetric care in Benin, Burkina Faso, Mali and Morocco. AB - BACKGROUND: Across the Africa region and beyond, the last decade has seen many countries introducing policies aimed at reducing financial barriers to obstetric care. This article provides evidence of the cost and effects of national policies focussed on improving financial access to caesarean and facility deliveries in Benin, Burkina Faso, Mali and Morocco. METHODS: The study uses a comparative case study design with mixed methods, including realist evaluation components. This article presents results across 14 different data collection tools, used in 4-6 research sites in each of the four study countries over 2011-13. The methods included: document review; interviews with key informants; analysis of secondary data; structured extraction from medical files; cross-sectional surveys of patients and staff; interviews with patients and observation of care processes. RESULTS: The article finds that the policies have contributed to continued increases in skilled birth attendance and caesarean sections and a narrowing of inequalities in all four countries, but these trends were already occurring so a shift cannot be attributed solely to the policies. It finds a significant reduction in financial burdens on households after the policy, suggesting that the financial protection objectives may have been met, at least in the short term, although none achieved total exemption of targeted costs. Policies are domestically financed and are potentially sustainable and efficient, and were relatively thoroughly implemented. Further, we find no evidence of negative effects on technical quality of care, or of unintended negative effects on untargeted services. CONCLUSIONS: We conclude that the policies were effective in meeting financial protection goals and probably health and equity goals, at sustainable cost, but that a range of measures could increase their effectiveness and equity. These include broadening the exempted package (especially for those countries which focused on caesarean sections alone), better calibrated payments, clearer information on policies, better stewardship of the local health system to deal with underlying systemic weaknesses, more robust implementation of exemptions for indigents, and paying more attention to quality of care, especially for newborns. PMID- 27483994 TI - The impact of differences between subjective and objective social class on life satisfaction among the Korean population in early old age: Analysis of Korean longitudinal study on aging. AB - BACKGROUND: Several previous studies have established the relationship between the effects of socioeconomic status or subjective social strata on life satisfaction. However, no previous study has examined the relationship between social class and life satisfaction in terms of a disparity between subjective and objective social status. OBJECTIVE: To investigate the relationship between differences in subjective and objective social class and life satisfaction. METHODS: Data from the Korean Longitudinal Study of Aging with 8252 participants aged 45 or older was used. Life satisfaction was measured by the question, "How satisfied are you with your quality of life?" The main independent variable was differences in objective (income and education) and subjective social class, which was classified according to nine categories (ranging from high-high to low low). This association was investigated by linear mixed model due to two waves data nested within individuals. RESULTS: Lower social class (income, education, subjective social class) was associated with dissatisfaction. The impact of objective and subjective social class on life satisfaction varied according to the level of differences in objective and subjective social class. Namely, an individual's life satisfaction declined as objective social classes decreased at the same level of subjective social class (i.e., HH, MH, LH). In both dimensions of objective social class (education and income), an individual's life satisfaction declined as subjective social class decreased by one level (i.e., HH, HM, HL). CONCLUSION: Our findings indicated that social supports is needed to improve the life satisfaction among the population aged 45 or more with low social class. The government should place increased focus on policies that encourage not only the life satisfaction of the Korean elderly with low objective social class, but also subjective social class. PMID- 27483995 TI - The chaotic journey: Recovering from hip fracture in a nursing home. AB - PURPOSE OF THE STUDY: To understand the journey experienced by nursing home residents following hip fracture and impressions of an outreach rehabilitation program offered after their return home. DESIGN AND METHODS: A qualitative investigation was undertaken in parallel with a randomised controlled trial investigating the efficacy and cost utility of providing a hospital outreach rehabilitation program for older nursing home residents who have recently returned from hospital following hip fracture. Family members and nursing home staff of 28 (out of the first 30) participants (14 from intervention and 14 from control) agreed to participate in interviews and focus groups to provide information and perceptions of each person's journey. NVivo 10 qualitative data analysis software package was used to identify major themes (via open, then axial and finally selective coding). RESULTS: Both family members and staff described nursing home residents with dementia as receiving poor post-operative care from hospital staff who seemed unfamiliar with dementia and delirium. Discharge from hospital soon after surgery (median 4.5days) occurred with poor transfer of information. Difficulties with residents' emotions, pain management and commencing mobilisation seemed more prevalent within usual care group, whereas fewer overall problems were encountered by those with access to a geriatrician and additional therapy. IMPLICATIONS: This research suggests that an integrated care pathway including the hospital stay and first weeks back at nursing homes should be developed. Performance indicators should include carer measures on the quality of the transfer, pain management measures in the first month and return to walking. PMID- 27483996 TI - Diagnosed diabetes mellitus and in-hospital stroke mortality in a major sub Saharan African urban medical unit. AB - BACKGROUND: Estimates from developed countries show that early mortality after stroke is unaffected by diabetes status. Despite the high burden of both conditions in sub-Saharan Africa, data on the association between diabetes status and early mortality are lacking. OBJECTIVE: In a major referral hospital in the Capital city of Cameroon, among acute stroke patients diagnosed using the World Health Organization criteria, we compared mortality rates in patents with and without known diabetes. METHODS: Stroke patients with and without known diabetes were compared for demographic characteristics, risk factors, clinical, radiological, laboratory characteristic, and in-hospital mortality. Heterogeneities in mortality rates across major subgroups were investigated via interaction tests, and logistic regression accelerated failure-time models used to adjust for confounders. RESULTS: Of the 1667 acute stroke patients included, 213 (12.8%) had diabetes mellitus. In general diabetic patients were older (median age 64.0 vs. 62.0 years, p=0.0006), and were more likely to have other stroke risk factors including a higher triglyceride levels on admission (106 vs. 97mg/dL, p=0.044), a history of stroke (19.7% vs. 13.6%, p=0.022), and a history of hypertension (89.7% vs. 64.8%, p<0.0001). The death rates of diabetic patients and that of non-diabetic patients were similar (22.1% vs. 20.1%. p=0.524). This finding was similar across all pre-specified groups, with no evidence of interaction. Diabetes was unrelated with mortality in adjusted regression models. CONCLUSION: Diabetes is frequent among stroke patients in this setting, and often co-exists with other stroke risk factors. In-hospital mortality rate is equally high in diabetic and non-diabetic patients. PMID- 27483997 TI - Membership in a diabetes-care network and adherence to clinical practice guidelines for treating type 2 diabetes among general practitioners: A four-year follow-up. AB - OBJECTIVES: To assess whether private general practitioners (GPs) belonging to a diabetes-care network adhered more closely to clinical practice guidelines for diabetes care than GPs not in such a network, for all their patients with type 2 diabetes treated with medication (patients with diabetes), regardless of whether they received care through a network (that is, whether a halo effect occurred). RESEARCH DESIGN AND MEASURES: The study, based on health insurance reimbursement databases in southeastern France, included 468 GPs in two networks and 468 non network GPs in the same geographical area, matched one-to-one by propensity scores. We followed up their patients with diabetes (n=22,808) from 2008 through 2011, conducting multivariate time-to-event analyses (Cox models) that took the matching design into account to evaluate time from inclusion until performance of the given number of each of six recommended examinations/tests. RESULTS: GPs belonging to a diabetes-care network adhered more closely to clinical practice guidelines but our result were slightly pronounced. Hazard ratios (HR) were significantly higher for patients of network GPs for the implementation of 3 HbA1C assays (HRa=1.13; [95%CI=1.10-1.16]), or 1 microalbuminuria assay (1.4 [1.35-1.45]); they were lower for LDL-cholesterol assays (1.04 [1.01-1.07]) and ophthalmological checkups (1.07 [1.04-1.10]), and not significant for creatinemia or cardiac monitoring. CONCLUSIONS: Network GPs had better diabetes monitoring practices for all their patients with diabetes than the other GPs, especially for the most diabetes-specific tests. Further research is needed in other settings to confirm the existence of this halo effect. PMID- 27483998 TI - A combined NMR and molecular dynamics simulation study to determine the conformational properties of rat/mouse 35-55 myelin oligodendrocyte glycoprotein epitope implicated in the induction of experimental autoimmune encephalomyelitis. PMID- 27483999 TI - Capparis Spinosa L. promotes anti-inflammatory response in vitro through the control of cytokine gene expression in human peripheral blood mononuclear cells. AB - BACKGROUND: Capparis Spinosa L. is an aromatic plant growing wild in dry regions around the Mediterranean basin. Capparis Spinosa was shown to possess several properties such as antioxidant, antifungal, and anti-hepatotoxic actions. In this work, we aimed to evaluate immunomodulatory properties of Capparis Spinosa leaf extracts in vitro on human peripheral blood mononuclear cells (PBMCs) from healthy individuals. RESULTS: Using MTT assay, we identified a range of Capparis Spinosa doses, which were not toxic. Unexpectedly, we found out that Capparis Spinosa aqueous fraction exhibited an increase in cell metabolic activity, even though similar doses did not affect cell proliferation as shown by CFSE. Interestingly, Capparis Spinosa aqueous fraction appeared to induce an overall anti-inflammatory response through significant inhibition of IL-17 and induction of IL-4 gene expression when PBMCs were treated with the non toxic doses of 100 and/or 500 MUg/ml. Phytoscreening analysis of the used Capparis Spinosa preparations showed that these contain tannins; sterols, alkaloids; polyphenols and flavonoids. Surprisingly, quantification assays showed that our Capparis Spinosa preparation contains low amounts of polyphenols relative to Capparis Spinosa used in other studies. This Capparis Spinosa also appeared to act as a weaker scavenging free radical agent as evidenced by DPPH radical scavenging test. Finally, polyphenolic compounds including catechin, caffeic acid, syringic acid, rutin and ferulic acid were identified by HPLC, in the Capparis spinosa preparation. CONCLUSION: Altogether, these findings suggest that our Capparis Spinosa preparation contains interesting compounds, which could be used to suppress IL-17 and to enhance IL-4 gene expression in certain inflammatory situations. Other studies are underway in order to identify the compound(s) underlying this effect. PMID- 27484000 TI - The mid-term outcome of primary open valvotomy for critical aortic stenosis in early infancy - a retrospective single center study over 18 years. AB - BACKGROUND: The objective of this study was to examine early and long-term results of surgical aortic valvotomy in neonates and infants aged less than four months and to identify predictors of outcome. METHODS: Between August 1994 and April 2012, 83 consecutive patients younger than 4 months of age underwent open heart valvotomy for critical aortic stenosis in our institution. Median age was 17 days (range 0-111 days). We examined clinical records to establish determinants of outcome and illustrate long-term results. RESULTS: Fifty-six patients (67 %) were neonates. Associated cardiac malformations were found in 24 patients (29 %), including multilevel left heart obstruction in 5. The median follow-up was 4.2 years. The time-related survival rate was 87 and 85 % at 5 and 15 years, respectively. The time-related survival without reintervention was respectively 51, 35 and 18 % at 5, 10 and 15 years. The time-related survival without aortic valve replacement was respectively 67, 54 and 39 % at 5, 10 and 15 years. Ventricular dysfunction (p = 0.04), delayed sternal closure (p = 0.007), endocardial fibroelastosis (p = 0.02) and low z-score of the aortic annulus (p = 0.04) were found predictors of global mortality. Ventricular dysfunction (p = 0.01) and endocardial fibroelastosis (p = 0.04) were found predictors of reintervention. CONCLUSIONS: The experience, in our center, on the management of critical aortic stenosis, shows a low early and late mortality, but the aortic valvotomy is a palliative procedure and we see unfortunately a high rate of reintervention among which the aortic valve replacement. These results suggest to reconsider the use of aortic balloon valvotomy, and particularly for the neonates with a low cardiac output in order to avoid the myocardial stress and the neurological injury due to the cardiopulmonary bypass. PMID- 27484001 TI - Exercise strategies to protect against the impact of short-term reduced physical activity on muscle function and markers of health in older men: study protocol for a randomised controlled trial. AB - BACKGROUND: Muscles get smaller and weaker as we age and become more vulnerable to atrophy when physical activity is reduced or removed. This research is designed to investigate the potentially protective effects of two separate exercise strategies against loss in skeletal muscle function and size, and other key indices of health, following 14 days of reduced physical activity in older men. METHODS: Three groups of 10 older men (aged 65-80 years) will undertake 2 weeks of reduced activity by decreasing daily steps from more than 3500 to less than 1500 (using pedometers to record step count). Two of the three groups will then undertake additional exercise interventions, either: 4 weeks of progressive resistance training prior to the step-reduction intervention (PT-group), or home based 'exercise snacking' three times per day during the step-reduction intervention (ES-group). The third group undertaking only the step-reduction intervention (control) will provide a comparison against which to assess the effectiveness of the protective exercise strategies. Pre and post step-reduction assessments of muscle function, standing balance, anthropometry and muscle architecture will be taken. Pre and post step-reduction in postprandial metabolic control, resting systemic inflammation, adipose inflammation, oxidative stress, immune function, sleep quality, dietary habits, and quality of life will be measured. The stress response to exercise, and signalling protein and gene expression for muscle protein synthesis and breakdown following an acute bout of exercise will also be assessed pre and post step-reduction. Rates of muscle protein synthesis and adipose triglyceride turnover during the step-reduction intervention will be measured using stable isotope methodology. All participants will then undertake 2 weeks of supervised resistance training with the aim of regaining any deficit from baseline in muscle function and size. DISCUSSION: This study aims to identify exercise strategies that could be implemented to protect against loss of muscle power during 2 weeks of reduced activity in older men, and to improve understanding of the way in which a short-term reduction in physical activity impacts upon muscle function and health. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02495727 (Initial registration: 25 June 2015). PMID- 27484002 TI - An exploration of men's experiences of undergoing active surveillance for favourable-risk prostate cancer: A mixed methods study protocol. AB - BACKGROUND: Prostate cancer is one of the most common male cancers worldwide. Active Surveillance (AS) has been developed to allow men with lower risk disease to postpone or avoid the adverse side effects associated with curative treatments until the disease progresses. Despite the medical benefits of AS, it is reported that living with untreated cancer can create a significant emotional burden for patients. METHODS/DESIGN: The aim of this study is to gain insight into the experiences of men eligible to undergo AS for favourable-risk PCa. This study has a mixed-methods sequential explanatory design consisting of two phases: quantitative followed by qualitative. Phase 1 has a multiple point, prospective, longitudinal exploratory design. Ninety men diagnosed with favourable-risk prostate cancer will be assessed immediately post-diagnosis (baseline) and followed over a period of 12 months, in intervals of 3 month. Ninety age-matched men with no cancer diagnosis will also be recruited using peer nomination and followed up in the same 3 month intervals. Following completion of Phase 1, 10-15 AS participants who have reported both the best and worst psychological functioning will be invited to participate in semi-structured qualitative interviews. Phase 2 will facilitate further exploration of the quantitative results and obtain a richer understanding of participants' personal interpretations of their illness and psychological wellbeing. DISCUSSION: To our knowledge, this is the first study to utilise early baseline measures; include a healthy comparison group; calculate sample size through power calculations; and use a mixed methods approach to gain a deeper more holistic insight into the experiences of men diagnosed with favourable-risk prostate cancer. PMID- 27484003 TI - Expression Profiling of Activin type IIB Receptor During Ontogeny in Broiler and Indigenous Chicken. AB - Augmenting the meat production is among the primary breeding objective of genetic selection programs in poultry production. However, the knowledge about the expression of genes regulating muscle growth at the molecular level is inadequate. Activin type IIB receptor (ACTRIIB) has been reported to play vital role in the negative regulation of muscle growth by binding to multiple members of transforming growth factor-beta superfamily. The present investigation was carried out to comprehend the trend of ACTRIIB messenger RNA in pectoralis major muscle during embryonic (E5-20) and post embryonic age (days 1, 14, 28, and 42) in both Control Broiler (CB) and Aseel by using Real-time PCR. The expression profile of ACTRIIB gene displayed a similar trend in CB and Aseel, however Aseel showed significantly (P < 0.001) higher transcription throughout the period. The fold change in expression of ACTRIIB in Aseel relative to CB varied from 3.94 to 14.72 folds and 3.28 to 7.14 folds during embryonic and post embryonic age, respectively. ACTRIIB exhibited its peak on E7, E11, and E16 during embryonic age, which coincides with the formation of primary and secondary muscle fibers in both lines. While at the time of post-embryonic age, ACTRIIB showed highest transcription on day 1 and lowest transcription on day 28 in both CB and Aseel. Within each line, the expression of ACTRIIB differed significantly (P < 0.001) between days in the course of embryonic and post-embryonic period. ACTRIIB gene expression had significant (P < 0.05) effect on all carcass traits except neck weight. Our results suggest that Aseel expressed higher levels of ACTRIIB transcript than CB. The study inferred that expression pattern of ACTRIIB was analogous in both CB and Aseel, which might imply that molecular mechanisms underlying muscle development and regulation are comparable in nature. PMID- 27484005 TI - A cross-sectional, facility based study of comorbid non-communicable diseases among adults living with HIV infection in Zimbabwe. AB - BACKGROUND: Increased antiretroviral therapy uptake in sub-Saharan Africa has resulted in improved survival of the infected. Opportunistic infections are declining as leading causes of morbidity and mortality. Though comprehensive data are lacking, concern has been raised about the rapid emergence of non communicable diseases (NCDs) in the African HIV care setting. We therefore set out to characterise the NCD/HIV burden among adults living and ageing with HIV infection in Zimbabwe. METHODS: We conducted a cross-sectional study among patients receiving care in a public sector facility. We reviewed patient records and determined the prevalence of comorbid and multi-morbid NCDs. Associations with patient characteristics were evaluated using univariate and multi-variate logistic regression modelling. Significance testing was done using 2-sided p values and 95 % confidence intervals calculated. RESULTS: We recruited 1033 participants. 31 % were men. Significant gender differences included: older median age, more advanced disease at baseline, and greater use of stavudine and protease inhibitor containing regimens in men compared to women. The prevalence of comorbidity and multi-morbidity were, respectively, 15.3 % (95 % CI 13.3-17.7 %) and 4.5 % (95 % CI 3.4-6.0 %). Women had higher rates than men of both co morbidity and multi-morbid ity: 21.8 vs. 14.9 %; p = 0.010 and 5.3 vs. 2.9 %; p = 0.025 respectively. The commonly observed individual NCDs were hypertension [10.2 %; (95 % CI 8.4-12.2 %)], asthma [4.3 % (95 % CI 3.1-5.8 %)], type 2 diabetes mellitus [2.1 % (95 % CI 1.3-3.2 %)], cancer [1.8 % (95 % CI 1.1-2.8 %)], and congestive cardiac failure [1.5 % (95 % CI 0.9-2.5 %)]. After adjusting for confounding, only age categories 45-<=55 years (AOR 2.25; 95 % CI 1.37-3.69) and >55 years (AOR 5.42; 95 % CI 3.17-9.26), and female gender (AOR 2.12; 95 % CI 1.45-3.11) remained significantly and strongly associated with comorbidity risk. CONCLUSIONS: We found a substantial burden of comorbid non-communicable diseases among HIV infected patients in a high HIV and low-income setting. Integrating non communicable diseases care, including active screening, with HIV care is recommended. PMID- 27484007 TI - Corrigendum. PMID- 27484006 TI - A meta-analysis of long follow-up outcomes of laparoscopic Nissen (total) versus Toupet (270 degrees ) fundoplication for gastro-esophageal reflux disease based on randomized controlled trials in adults. AB - BACKGROUND: Laparoscopic Nissen fundoplication (LNF) is the most common surgical procedure for the surgical management of gastro-esophageal reflux disease (GERD). Laparoscopic Toupet fundoplication (LTF) has been reported to have a lower prevalence of postoperative complications yet still obtain a similar level of reflux control. We conducted a meta-analysis to confirm the value of LNF and LTF. METHODS: PubMed, Medline, Embase, Cochrane Library and Springerlink were searched for randomized controlled trials (RCTs) comparing LNF and LTF. Data regarding the benefits and adverse results of two techniques were extracted and compared using a meta-analysis. RESULTS: Eight eligible RCTs comparing LNF (n = 625) and LTF (n = 567) were identified. There were no significant differences between LNF and LTF with regard to hospitalization duration, perioperative complications, patient satisfaction, postoperative heartburn, regurgitation, postoperative DeMeester scores, or esophagites. A shorter operative time and higher postoperative lower esophageal sphincter pressure were associated with LNF. Prevalence of postoperative dysphagia, gas-bloating, inability to belch, dilatation for dysphagia and reoperation were higher after LNF, but subgroup analyses showed that differences with respect to dysphagia between LNF and LTF disappeared over time. Subgroup analyses did not support "tailored therapy" according to preoperative esophageal motility. CONCLUSIONS: LNF and LTF have equivalently good control of GERD and result in a similar prevalence of patient satisfaction. Based on current evidence, it is not rational or advisable to abandon LNF when choosing a surgical procedure for GERD. PMID- 27484008 TI - Unique Transcriptomic Profile of Collecting Duct Carcinomas Relative to Upper Tract Urothelial Carcinomas and other Kidney Carcinomas. AB - Collecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggested an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Herein, we performed for the first time transcriptome sequencing of CDC and compared them to UTUC and renal cell carcinoma subtypes. We discovered that CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response consistent with increased tumor infiltrating lymphocytes, particularly within metastatic cases. In addition, pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. We conclude that CDC harbors a pathognomonic transcriptomic signature characterized by immunogenic and a metabolic aberrations, indicating that targeting these processes might provide therapeutic options for patients. PMID- 27484009 TI - Explaining large mortality differences between adjacent counties: a cross sectional study. AB - BACKGROUND: Extensive geographic variation in adverse health outcomes exists, but global measures ignore differences between adjacent geographic areas, which often have very different mortality rates. We describe a novel application of advanced spatial analysis to 1) examine the extent of differences in mortality rates between adjacent counties, 2) describe differences in risk factors between adjacent counties, and 3) determine if differences in risk factors account for the differences in mortality rates between adjacent counties. METHODS: We conducted a cross-sectional study in Missouri, USA with 2005-2009 age-adjusted all-cause mortality rate as the outcome and county-level explanatory variables from a 2007 population-based survey. We used a multi-level Gaussian model and a full Bayesian approach to analyze the difference in risk factors relative to the difference in mortality rates between adjacent counties. RESULTS: The average mean difference in the age-adjusted mortality rate between any two adjacent counties was -3.27 (standard deviation = 95.5) per 100,000 population (maximum = 258.80). Six variables were associated with mortality differences: inability to obtain medical care because of cost (beta = 2.6), hospital discharge rate (beta = 1.03), prevalence of fair/poor health (beta = 2.93), and hypertension (beta = 4.75) and poverty prevalence (beta = 6.08). CONCLUSIONS: Examining differences in mortality rates and associated risk factors between adjacent counties provides additional insight for future interventions to reduce geographic disparities. PMID- 27484010 TI - OPRM1 genotype interacts with serotonin system dysfunction to predict alcohol heightened aggression in primates. AB - Although the notion that alcohol promotes violence is widespread, not all individuals are aggressive while intoxicated. Genetic variation could be a contributing factor to individual differences in alcohol-heightened aggression. The present study examines the effects of OPRM1C77G genotype on responses to threat in rhesus macaques under normal conditions and following alcohol administration. Prior studies have shown that a low CSF level of 5-HIAA is a trait marker for individuals prone to escalated aggression. We wanted to examine whether the predictive value for this marker on aggression was moderated by OPRM1 genotype. Animals were administered alcohol (BAC 100-200 mg%), were provoked by a human intruder, and aggressive responses were recorded. Factor analysis was performed to generate aggressive response factors, which were then used as dependent variables for ANOVA, with OPRM1 genotype and CSF 5-HIAA as independent variables. Factor analysis generated three factors ('Threatening', 'Distance Decreasing' and 'High Intensity'). We found that High Intensity aggression was increased among carriers of the OPRM1 G allele, especially among individuals with low CSF levels of 5-HIAA. Aggression in the non-intoxicated state was predicted by 5-HIAA, but not by genotype. This study demonstrates that OPRM1 genotype predicts alcohol-heightened aggression in rhesus macaques with low CSF levels of 5-HIAA. Because OPRM1 variation predicts similar effects on alcohol response and behavior in humans and macaques, this study could suggest a role for OPRM1 genotype in alcohol-heightened aggression in humans. If so, it may be that compounds that block this receptor could reduce alcohol-associated violence in selected patient populations. PMID- 27484011 TI - Chemistry, manufacturing and control (CMC) and clinical trial technical support for influenza vaccine manufacturers. AB - With the support of the Biomedical Advanced Research and Development Authority (BARDA) of the US Department of Health and Human Services, PATH has contributed to the World Health Organization's (WHO's) Global Action Plan for Influenza Vaccines (GAP) by providing technical and clinical assistance to several developing country vaccine manufacturers (DCVMs). GAP builds regionally based independent and sustainable influenza vaccine production capacity to mitigate the overall global shortage of influenza vaccines. The program also ensures adequate influenza vaccine manufacturing capacity in the event of an influenza pandemic. Since 2009, PATH has worked closely with two DCVMs in Vietnam: the Institute of Vaccines and Medical Biologicals (IVAC) and VABIOTECH. Beginning in 2013, PATH also began working with Torlak Institute in Serbia; Instituto Butantan in Brazil; Serum Institute of India Private Ltd. in India; and Changchun BCHT Biotechnology Co. (BCHT) in China. The DCVMs supported under the GAP program all had existing influenza vaccine manufacturing capability and required technical support from PATH to improve vaccine yield, process efficiency, and product formulation. PATH has provided customized technical support for the manufacturing process to each DCVM based on their respective requirements. Additionally, PATH, working with BARDA and WHO, supported several DCVMs in the clinical development of influenza vaccine candidates progressing toward national licensure or WHO prequalification. As a result of the activities outlined in this review, several companies were able to make excellent progress in developing state-of-the-art manufacturing processes and completing early phase clinical trials. Licensure trials are currently ongoing or planned for several DCVMs. PMID- 27484012 TI - Influence of adenovirus and MVA vaccines on the breadth and hierarchy of T cell responses. AB - Viral-vectored vaccines are in clinical development for several infectious diseases where T-cell responses can mediate protection, and responses to sub dominant epitopes is needed. Little is known about the influence of MVA or adenoviral vectors on the hierarchy of the dominant and sub-dominant T-cell epitopes. We investigated this aspect in mice using a malaria immunogen. Our results demonstrate that the T-cell hierarchy is influenced by the timing of analysis, rather than by the vector after a single immunization, with hierarchy changing over time. Repeated homologous immunization reduced the breadth of responses, while heterologous prime-boost induced the strongest response to the dominant epitope, albeit with only modest response to the sub-dominant epitopes. PMID- 27484014 TI - Radiotherapy for breast cancer: The predictable consequences of an unmet need. AB - Radiotherapy has had a transformative impact on the treatment of breast cancer, but is unavailable to the majority of breast cancer patients in low- and middle income countries. In these settings, where many women present with advanced disease at an age when they are often the primary caregiver for their families, the lack of access to radiotherapy is particularly devastating. Until recently, this disparity has been largely neglected in the medical literature and it had been difficult to convince governments, industry, and policymakers of the importance of investing in radiotherapy, as well as broader cancer control strategies, in low-resource settings. The Lancet Radiotherapy Commission report published in 2015 challenged many assumptions about the affordability of radiotherapy treatment. Data from the Commission is presented here to support radiotherapy investment for breast cancer and discuss how the morbidity and premature mortality among adult women caused by breast cancer has a huge detrimental effect on both the health sector and the economy. PMID- 27484013 TI - Effect of 4 % chlorhexidine on cord colonization among hospital and community births in India: a randomized controlled study. AB - BACKGROUND: Infections are the single most important cause of neonatal mortality in developing countries. Results from trials in Asia evaluating the effect of chlorhexidine on neonatal mortality have been encouraging but limited data are available on the impact of cord cleansing on bacterial colonization. Further, no data from facility deliveries and impact with time is available. This pilot study was aimed to evaluate the impact of 4 % commercially prepared chlorhexidine on cord colonization and density of colonization among newborns in India. METHODS: Three hundred twenty-six newborns (hospital-247; community-79) were enrolled within 24 h of birth and randomly assigned to one of three groups: chlorhexidine, placebo or dry cord care. Umbilical swabs were collected at baseline, 2- and 48- hours after intervention application. RESULTS: At baseline, growth positivity (any bacterial growth) was 20 % (50 of 247 swabs) and 81 % (64 of 79 swabs) among hospital and community born neonates, respectively. In both settings, chlorhexidine compared to placebo and dry cord care, reduced colonization following 2- and 48-hour post application. Chlorhexidine significantly reduced 48 hour post application colony counts in comparison to placebo [Hospital: mean difference = -1.01; 95 % CI: -1.72, -0.30 Community: mean difference = -1.76; 95 % CI: -2.60, -0.93] and dry cord care [Hospital: mean difference = -1.16; 95 % CI: -1.93, -0.39 Community: mean difference = -2.23; 95 % CI: -3.18, -1.29]. Differences were similar for gram-positive and gram-negative bacteria. CONCLUSIONS: Cord cleansing with 4 % chlorhexidine soon after birth reduced colonization as well as density of colonization significantly; however this pilot study does not address the impact of chlorhexidine on mortality. The control preparation neither increased or decreased colonization. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION: clinicaltrials.gov: NCT01528852, Registered February 7, 2012. PMID- 27484015 TI - Perspectives from a weary surgical oncologist in Sub-Saharan Africa. AB - This is an personal reflection on the challenges of managing advanced breast cancer in a resource-poor setting, focussing on financial constraints, unavailability of treatment options, and the personal cost to patient and surgeon. PMID- 27484016 TI - Effects of a regional guideline for completion axillary lymph node dissection in women with breast cancer to reduce variation in surgical practice: A qualitative study of physicians' views. AB - BACKGROUND: Recently the impact of completion axillary lymph node dissection (cALND) after positive sentinel lymph node biopsy on significant outcomes has been questioned, leading to variation in surgical practice. To address this variation, a multidisciplinary working group created a regional guideline for cALND. We explored the views and experiences of surgeons, medical oncologists (MOs), radiation oncologists (ROs) in a qualitative study that examined guideline implementation in practice. METHODS: The Pathman framework (awareness, agreement, adoption and adherence) informed the interview guide design and analysis. Semi structured interviews were conducted with MOs, ROs and surgeons and transcribed. Transcripts were coded independently by 2 members of the study team and analyzed. Disagreements were resolved through consensus. RESULTS: Twenty-eight physicians (5 MO; 6RO; 17S) of 41 (68% of those approached) were interviewed. Ten of 11 (91%) hospital sites (54% community; 46% academic) and all 4 cancer clinics within the region were represented. Twenty-seven physicians (96%) were aware of the guideline, with all physicians reporting agreement and general adherence to the guideline. Most physicians indicated nodal factors, age and patient preference were key components of cALND decision-making. Physicians from all disciplines perceived that the guideline helped reduce variation in practice across the region. There were concerns that the guideline could be applied rigidly and not permit individual decision-making. CONCLUSIONS: Physicians identified breast cancer as an increasingly complex and multidisciplinary issue. Facilitators to guideline implementation included perceived flexibility and buy in from all disciplines, while individual patient factors and controversial supporting evidence may hinder its implementation. PMID- 27484017 TI - Similar biological activity in skin prick test for Oralair(r) (8200 BAU) and Grazax(r) (6200 BAU) reinforces effective SLIT dosing level. AB - In Europe, allergen extracts are standardized based on skin prick wheal size in 20-30 allergic subjects. To understand the biological activity of clinically effective Sublingual immunotherapy, we used this method to determine the biological activity of solution and tablet Timothy grass pollen (TIM) extracts, compared to an FDA-approved extract (Reference) of 10 000 BAU/ml. Blinded, quadruplicate skin prick tests with concentrate and three serial half-log dilutions allowed the construction of a semilogarithmic regression line per extract. Bioequivalent allergy units (BAU) values were obtained from the comparison with reference. Extracts and dilutions showed a neat linear dose response (all: R2 > 0.98) in 33 rhinitis patients. Relative potencies: Staloral(r) 12 000 BAU/ml, Soluprick(r) 10 300 BAU/ml, Oralair(r) 8200 BAU, and Grazax(r) 6200 BAU. Even though all extract concentrates differed in wheal size (P = 0.01-0.001), Grazax(r) producing a 25% smaller wheal size than Oralair(r) , and the biological activity of these clinically effective TIM tablets led in the same range (6200-8200 BAU; 0.92-1.23 cm2 ). SLIT dose-finding studies for other pollens might start with allergen extracts producing 1.1 cm2 wheal surface. PMID- 27484018 TI - Impact of an evidence-based guideline on the management of community-acquired bacterial meningitis: a prospective cohort study. AB - OBJECTIVES: To study the impact of an evidence-based guideline on the management of community-acquired bacterial meningitis. METHODS: We performed an interrupted time series analysis in a prospective nationwide cohort study from 2006 to 2015. The guideline stresses the importance of cranial imaging before lumbar puncture (LP) in selected patients based on clinical criteria, and early treatment with amoxicillin and a third-generation cephalosporin for adults with suspected community-acquired bacterial meningitis. The guideline was published in April 2013. RESULTS: We included 1326 episodes before and 210 episodes after guideline introduction. Cranial imaging was performed before LP in 497 (84%) of 591 episodes with clinical criteria warranting computed tomography (CT). The guideline did not improve this (increase of 2%; 95% confidence interval (CI), -15 to 19). Without these criteria, imaging before LP occurred in 606 (67%) of 900 episodes, also without effect of the guideline (increase of 1%; 95% CI, -25 to 28). The estimate of effect of the guideline for treatment with the recommended antibiotic regimen was an increase of 19.5% (95% CI, 13.5 to 25.5), and there was a trend towards more frequent initiation of treatment before CT. There was no association between delay in antibiotic treatment due to imaging before LP and unfavourable outcome (odds ratio, 1.14; 95% CI 0.86 to 1.52). CONCLUSIONS: Cranial imaging is performed before LP in the majority of patients with bacterial meningitis, irrespective of guideline indications. The guideline introduction was associated with a trend towards early initiation of treatment before imaging and with increased adherence to antibiotic policy. PMID- 27484019 TI - Corrigendum to 'Response to Letter to the Editor "Alcohol hand rub consumption objectives in European hospitals need to be revisited"' [Clin Microbiol Infect (2016) 578]. PMID- 27484020 TI - Discontinuation of echinocandin and azole treatments led to the disappearance of an FKS alteration but not azole resistance during clonal Candida glabrata persistent candidaemia. AB - To give an indication of a fitness cost conferred by FKS mutation-associated echinocandin resistance in Candida glabrata during human infection. Six C. glabrata clinical strains sequentially isolated from blood and a hepatic abscess in a solid organ transplant recipient were analysed. The patient had received long-term azole and echinocandin therapy for invasive aspergillosis and persistent candidaemia. Minimal inhibitory concentrations were determined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution method. Molecular mechanisms of antifungal resistance were determined by sequencing hot spots of the FKS. Strain relatedness was determined using a microsatellite-based typing method. Typing analysis revealed an identical microsatellite pattern for all isolates, supporting a close relation. The first C. glabrata isolate showed wild-type phenotype (i.e. susceptibility to echinocandins and low level of azole resistance). After voriconazole therapy, the C. glabrata quickly acquired pan-azole resistance. Later, echinocandin treatment led to the emergence of a FKS2 S663P alteration and echinocandin resistance. After disruption of both azole and echinocandin therapy in favour of liposomal amphotericin B, C. glabrata isolates regained full susceptibility to echinocandin and lost the FKS2 S663P alteration while nonetheless maintaining their pan-azole resistance. Our clinical report supports the potential existence of a fitness cost conferred by FKS mutation in C. glabrata, as disruption of treatment led to a rapid disappearance of the resistant clone. This suggests that a more restricted use and/or a discontinuous administration of echinocandins may limit the spread of clinical resistance to this class. PMID- 27484022 TI - Abstracts of the 50th Workshop for Pediatric Research. PMID- 27484021 TI - Reduced nocturnal hypoglycaemia with basal insulin peglispro compared with insulin glargine: pooled analyses of five randomized controlled trials. AB - Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action, resulting from reduced peripheral effects. This report summarizes hypoglycaemia data from five BIL phase III studies with insulin glargine as the comparator, including three double-blind trials. Prespecified pooled analyses (n = 4927) included: patients with type 2 diabetes (T2D) receiving basal insulin only, those with T2D on basal-bolus therapy, and those with type 1 diabetes (T1D). BIL treatment resulted in a 36-45% lower nocturnal hypoglycaemia rate compared with glargine, despite greater reduction in glycated haemoglobin (HbA1c) and higher basal insulin dosing. The total hypoglycaemia rate was similar in patients with T2D on basal treatment only, trended towards being higher (10%) in patients with T2D on basal-bolus treatment (p = .053), and was 15% higher (p < .001) with BIL versus glargine in patients with T1D, with more daytime hypoglycaemia in the T1D and T2D groups who were receiving basal-bolus therapy. In T1D, during the maintenance treatment period (26-52 weeks), the total hypoglycaemia rate was not significantly different. There were no differences in severe hypoglycaemia in the T1D or T2D pooled analyses. BIL versus glargine treatment resulted in greater HbA1c reduction with less nocturnal hypoglycaemia in all patient populations, higher daytime hypoglycaemia with basal-bolus therapy in the T1D and T2D groups, and an associated increase in total hypoglycaemia in the patients with T1D. PMID- 27484023 TI - Acceptability and feasibility of point-of-care CD4 testing on HIV continuum of care in low and middle income countries: a systematic review. AB - BACKGROUND: CD4 testing is, and will remain an important part of HIV treatment and care in low and middle income countries (LMICs). We report the findings of a systematic review assessing acceptability and feasibility of POC CD4 testing in field settings. METHODS: Electronic databases were searched for studies published in English between 2005 and 2015 that describe POC CD4 platforms. Studies conducted in LMICs and under field conditions outside a laboratory environment were eligible. Qualitative and descriptive data analysis was used to present the findings. RESULTS: Twelve studies were included, 11 of which were conducted in sub-Saharan countries and used one POC CD4 test (The Alere Pima CD4). Patients reported positively regarding the implementation of POC CD4 testing at primary health care and community level with >=90 % of patients accepting the test across various study settings. Health service providers expressed preference toward POC CD4 testing as it is easy-to-use, efficient and satisfied patients' needs to a greater extent as compared to conventional methods. However, operational challenges including preference toward venous blood rather than finger-prick sampling, frequent device failures and operator errors, quality of training for test operators and supervisors, and increased staff workload were also identified. CONCLUSIONS: POC CD4 testing seems acceptable and feasible in LIMCs under field conditions. Further studies using different POC CD4 tests available on the market are required to provide critical data to support countries in selection and implementation of appropriate POC CD4 technologies. PMID- 27484025 TI - [Co-existence of cardiovascular risk factors in patients with diabetes and peripheral vascular disease]. PMID- 27484024 TI - The dehydroalanine effect in the fragmentation of ions derived from polypeptides. AB - The fragmentation of peptides and proteins upon collision-induced dissociation (CID) is highly dependent on sequence and ion type (e.g. protonated, deprotonated, sodiated, odd electron, etc.). Some amino acids, for example aspartic acid and proline, have been found to enhance certain cleavages along the backbone. Here, we show that peptides and proteins containing dehydroalanine, a non-proteinogenic amino acid with an unsaturated side-chain, undergo enhanced cleavage of the N-Calpha bond of the dehydroalanine residue to generate c- and z ions. Because these fragment ion types are not commonly observed upon activation of positively charged even-electron species, they can be used to identify dehydroalanine residues and localize them within the peptide or protein chain. While dehydroalanine can be generated in solution, it can also be generated in the gas phase upon CID of various species. Oxidized S-alkyl cysteine residues generate dehydroalanine upon activation via highly efficient loss of the alkyl sulfenic acid. Asymmetric cleavage of disulfide bonds upon collisional activation of systems with limited proton mobility also generates dehydroalanine. Furthermore, we show that gas-phase ion/ion reactions can be used to facilitate the generation of dehydroalanine residues via, for example, oxidation of S-alkyl cysteine residues and conversion of multiply-protonated peptides to radical cations. In the latter case, loss of radical side-chains to generate dehydroalanine from some amino acids gives rise to the possibility for residue specific backbone cleavage of polypeptide ions. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27484026 TI - Reference Values of Total Lean Mass, Appendicular Lean Mass, and Fat Mass Measured with Dual-Energy X-ray Absorptiometry in a Healthy Mexican Population. AB - The aim of this study was to develop age- and gender-specific reference values of total lean body mass (LBM), appendicular lean body mass (ALBM), and fat mass (FM) by dual-energy X-ray absorptiometry (DXA) data in a healthy Mexican population. A cross-sectional analysis was conducted on 9518 healthy subjects 7-89 years of age participating in the baseline measurement of the Health Workers Cohort Study. Using DXA, LBM, ALBM, and FM were measured. Using these data, LBM index (LBMI), ALBM index (ALBMI), and fat mass index (FMI) were calculated. LMI, ALMI, and FMI were calculated as the LBM, ALBM, and FM kg divided by the height in meters squared. Males and females were analyzed separately; sex-specific means and standard deviations for LBM, ALBM, FM, LBMI, ALBMI, and FMI were calculated. A total of 2829 males and 6694 females were included in the final analysis. Strong sex gaps were observed after 12 years in LBM, ALBM, LBMI, and ALBMI (P < 0.01). LBM and ALBM values continue to increase for males up to age 20; females plateaued approximately after age 15. Significant sex differences were also observed for FM and FMI. Significant sex- and age-related differences exist in LBM, ALBM, and FM in the Mexican population. In addition, given the null data available in this area, these reference values may be useful in the evaluation of a variety of childhood and adult abnormalities involving lean body mass deficits, mainly in the assessment of muscle wasting, with important medical and epidemiological uses. PMID- 27484027 TI - Associations Between Body Composition and Bone Health in Children and Adolescents: A Systematic Review. AB - More clarification on the associations between children's and adolescents' lean and fat mass (LM and FM) on the one hand and their bone health on the other hand is needed, given the rising prevalence of overweight and obesity in this population. This systematic literature review aimed to describe the current evidence on these associations. Data sources were Medline/PubMed, EMBASE, CINAHL and The Cochrane Library (up to November 2014). Search items included LM, FM, children and adolescents (0-18 years), bone health measured with dual-energy X ray absorptiometry and peripheral quantitative computed tomography (pQCT) and search items concerning study design: observational and longitudinal studies. The study populations were healthy children and adolescents including obese children. Children with other diseases and clinical series of study subjects were excluded. Based on the studies included in this review (n = 19), there is a consensus that the contribution of LM to the variance of the different bone parameters is larger than the contribution of FM and that an increase in LM is associated with an increase in bone parameters. Most of the studies indicated that the increase in bone parameters seen in overweight and obese children and adolescents is due to an increase in LM and not to greater FM. The results on the association between body fat and bone parameters were contradictory and depended on children's age and sex. Still more data from studies with a longitudinal study design using (high resolution) pQCT and a representative sample are needed to get further insight in the associations between body fat and bone parameters in children, specifically concerning differences in sex, skeletal site and fat depots. PMID- 27484029 TI - Down to the Molecular Mechanisms of Host-Pathogen Interactions. PMID- 27484028 TI - Decompensated liver cirrhosis and neural regulation of mesenteric vascular tone in rats: role of sympathetic, nitrergic and sensory innervations. AB - We evaluated the possible alterations produced by liver cholestasis (LC), a model of decompensated liver cirrhosis in sympathetic, sensory and nitrergic nerve function in rat superior mesenteric arteries (SMA). The vasoconstrictor response to electrical field stimulation (EFS) was greater in LC animals. Alpha adrenoceptor antagonist phentolamine and P2 purinoceptor antagonist suramin decreased this response in LC animals more than in control animals. Both non specific nitric oxide synthase (NOS) L-NAME and calcitonin gene related peptide (CGRP) (8-37) increased the vasoconstrictor response to EFS more strongly in LC than in control segments. Vasomotor responses to noradrenaline (NA) or CGRP were greater in LC segments, while NO analogue DEA-NO induced a similar vasodilation in both experimental groups. The release of NA was not modified, while those of ATP, nitrite and CGRP were increased in segments from LC. Alpha 1 adrenoceptor, Rho kinase (ROCK) 1 and 2 and total myosin phosphatase (MYPT) expressions were not modified, while alpha 2B adrenoceptor, nNOS expression and nNOS and MYPT phosphorylation were increased by LC. Together, these alterations might counteract the increased splanchnic vasodilation observed in the last phases of decompensated liver cirrhosis. PMID- 27484030 TI - Mixed dentition space analysis among Nepalese Brahmins/Chhetris. AB - BACKGROUND: Mixed dentition space analysis forms an important part of orthodontic diagnosis and treatment planning. Regression equations are widely used for mixed dentition analysis which can vary among races. This study aimed to find out the new regression equation in estimating the size of unerupted canines and premolars for Nepalese Brahmins/Chhetris. METHODS: Hundred Nepalese Brahmins/Chhetris (50 males and 50 females) who met our criteria were selected among the patients attending to the Orthodontic Out-Patient Department, Institute of Medicine, Kathmandu. The mesiodistal widths of all mandibular permanent incisors; maxillary and mandibular canines and premolars were measured and analyzed. The results were also compared with predicted values from the Moyers and the Tanaka and Johnston methods. Correlation and linear regression analyses were performed between the predicted and actual tooth sizes for Nepalese Brahmins/Chhetris and standard regression equations were developed. RESULTS: No significant differences were observed when the sum of canine and premolars of one quadrant is compared between sides and sex. Significant and high positive correlations were found between the mandibular incisors and the combined mesiodistal widths of the canines and premolars for the maxillary (r = 0.72) and mandibular (r = 0.73) segments. Significant differences were observed between the measured values from this study and from Moyers (50 % and 75 % probability) and Tanaka-Johnston methods. CONCLUSIONS: The equations and charts commonly used for North American children (50(th) or 75(th) percentile) did not accurately predict for our sample, so new regression equations and tables were developed for Nepalese Brahmins/Chhetris children. PMID- 27484031 TI - Complete human CD1a deficiency on Langerhans cells due to a rare point mutation in the coding sequence. PMID- 27484032 TI - Rapid molecular diagnostics of severe primary immunodeficiency determined by using targeted next-generation sequencing. AB - BACKGROUND: Primary immunodeficiency diseases (PIDDs) are inherited disorders of the immune system. The most severe form, severe combined immunodeficiency (SCID), presents with profound deficiencies of T cells, B cells, or both at birth. If not treated promptly, affected patients usually do not live beyond infancy because of infections. Genetic heterogeneity of SCID frequently delays the diagnosis; a specific diagnosis is crucial for life-saving treatment and optimal management. OBJECTIVE: We developed a next-generation sequencing (NGS)-based multigene targeted panel for SCID and other severe PIDDs requiring rapid therapeutic actions in a clinical laboratory setting. METHODS: The target gene capture/NGS assay provides an average read depth of approximately 1000*. The deep coverage facilitates simultaneous detection of single nucleotide variants and exonic copy number variants in one comprehensive assessment. Exons with insufficient coverage (<20* read depth) or high sequence homology (pseudogenes) are complemented by amplicon-based sequencing with specific primers to ensure 100% coverage of all targeted regions. RESULTS: Analysis of 20 patient samples with low T-cell receptor excision circle numbers on newborn screening or a positive family history or clinical suspicion of SCID or other severe PIDD identified deleterious mutations in 14 of them. Identified pathogenic variants included both single nucleotide variants and exonic copy number variants, such as hemizygous nonsense, frameshift, and missense changes in IL2RG; compound heterozygous changes in ATM, RAG1, and CIITA; homozygous changes in DCLRE1C and IL7R; and a heterozygous nonsense mutation in CHD7. CONCLUSION: High-throughput deep sequencing analysis with complete clinical validation greatly increases the diagnostic yield of severe primary immunodeficiency. Establishing a molecular diagnosis enables early immune reconstitution through prompt therapeutic intervention and guides management for improved long-term quality of life. PMID- 27484033 TI - Successful hematopoietic stem cell transplantation for myelofibrosis in an adult with warts-hypogammaglobulinemia-immunodeficiency-myelokathexis syndrome. PMID- 27484034 TI - Reply. PMID- 27484035 TI - Transcriptional profiling identifies the long noncoding RNA plasmacytoma variant translocation (PVT1) as a novel regulator of the asthmatic phenotype in human airway smooth muscle. AB - BACKGROUND: The mechanism underlying nonsevere and severe asthma remains unclear, although it is commonly associated with increased airway smooth muscle (ASM) mass. Long noncoding RNAs (lncRNAs) are known to be important in regulating healthy primary airway smooth muscle cells (ASMCs), whereas changed expression has been observed in CD8 T cells from patients with severe asthma. METHODS: Primary ASMCs were isolated from healthy subjects (n = 9) and patients classified as having nonsevere (n = 9) or severe (n = 9) asthma. ASMCs were exposed to dexamethasone and FCS. mRNA and lncRNA expression was measured by using a microarray and quantitative real-time PCR. Bioinformatic analysis was used to examine relevant biological pathways. Finally, the lncRNA plasmacytoma variant translocation 1 (PVT1) was inhibited by transfection of primary ASMCs with small interfering RNAs, and the effect on ASMC phenotype was examined. RESULTS: The mRNA expression profile was significantly different between patient groups after exposure to dexamethasone and FCS, and these were associated with biological pathways that might be relevant to the pathogenesis of asthma, including cellular proliferation and pathways associated with glucocorticoid activity. We also observed a significant change in lncRNA expression, yet the expression of only one lncRNA (PVT1) is decreased in patients with corticosteroid-sensitive nonsevere asthma and increased in patients with corticosteroid-insensitive severe asthma. Subsequent targeting studies demonstrated the importance of this lncRNA in controlling both proliferation and IL-6 release in ASMCs from patients with severe asthma. CONCLUSIONS: lncRNAs are associated with the aberrant phenotype observed in ASMCs from asthmatic patients. Targeting PVT1 might be effective in reducing airway remodeling in asthmatic patients. PMID- 27484036 TI - T-cell receptor-mediated cross-reactivity to different allergens is driven by recognition of homologous, phylogenetically conserved epitopes. PMID- 27484037 TI - Relationships among aeroallergen sensitization, peripheral blood eosinophils, and periostin in pediatric asthma development. AB - BACKGROUND: Biomarkers, preferably noninvasive, that predict asthma inception in children are lacking. OBJECTIVE: Little is known about biomarkers of type 2 inflammation in early life in relation to asthma inception. We evaluated aeroallergen sensitization, peripheral blood eosinophils, and serum periostin as potential biomarkers of asthma in children. METHODS: Children enrolled in the Childhood Origins of ASThma study were followed prospectively from birth. Blood samples were collected at ages 2, 4, 6, and 11 years, and serum-specific IgE levels, blood eosionophil counts, and periostin levels were measured in 244 children. Relationships among these biomarkers, age, and asthma were assessed. RESULTS: Serum periostin levels were approximately 2- to 3-fold higher in children than previously observed adult levels. Levels were highest at 2 years (145 ng/mL), and did not change significantly between 4 and 11 years (128 and 130 ng/mL). Age 2 year periostin level of 150 ng/mL or more predicted asthma at age 6 years (odds ratio [OR], 2.3; 95% CI, 1.3-4.4). Eosinophil count of 300 cells/MUL or more and aeroallergen sensitization at age 2 years were each associated with increased risk of asthma at age 6 years (OR, 3.1; 95% CI, 1.7-6.0 and OR, 3.3; 95% CI, 1.7-6.3). Children with any 2 of the biomarkers had a significantly increased risk of developing asthma by school age (>=2 biomarkers vs none: OR, 6.6; 95% CI, 2.7-16.0). CONCLUSIONS: Serum periostin levels are significantly higher in children than in adults, likely due to bone turnover, which impairs clinical utility in children. Early life aeroallergen sensitization and elevated blood eosinophils are robust predictors of asthma development. Children with evidence of activation of multiple pathways of type 2 inflammation in early life are at greatest risk for asthma development. PMID- 27484038 TI - Tumor progression locus 2 reduces severe allergic airway inflammation by inhibiting Ccl24 production in dendritic cells. AB - BACKGROUND: The molecular and cellular pathways driving the pathogenesis of severe asthma are poorly defined. Tumor progression locus 2 (TPL-2) (COT, MAP3K8) kinase activates the MEK1/2-extracellular-signal regulated kinase 1/2 MAP kinase signaling pathway following Toll-like receptor, TNFR1, and IL-1R stimulation. OBJECTIVE: TPL-2 has been widely described as a critical regulator of inflammation, and we sought to investigate the role of TPL-2 in house dust mite (HDM)-mediated allergic airway inflammation. METHODS: A comparative analysis of wild-type and Map3k8-/- mice was conducted. Mixed bone marrow chimeras, conditional knockout mice, and adoptive transfer models were also used. Differential cell counts were performed on the bronchoalveolar lavage fluid, followed by histological analysis of lung sections. Flow cytometry and quantitative PCR was used to measure type 2 cytokines. ELISA was used to assess the production of IgE, type 2 cytokines, and Ccl24. RNA sequencing was used to characterize dendritic cell (DC) transcripts. RESULTS: TPL-2 deficiency led to exacerbated HDM-induced airway allergy, with increased airway and tissue eosinophilia, lung inflammation, and IL-4, IL-5, IL-13, and IgE production. Increased airway allergic responses in Map3k8-/- mice were not due to a cell intrinsic role for TPL-2 in T cells, B cells, or LysM+ cells but due to a regulatory role for TPL-2 in DCs. TPL-2 inhibited Ccl24 expression in lung DCs, and blockade of Ccl24 prevented the exaggerated airway eosinophilia and lung inflammation in mice given HDM-pulsed Map3k8-/- DCs. CONCLUSIONS: TPL-2 regulates DC-derived Ccl24 production to prevent severe type 2 airway allergy in mice. PMID- 27484039 TI - Wnt3a is critical for endothelial progenitor cell-mediated neural stem cell proliferation and differentiation. AB - The present study aimed to determine whether co-culture with bone marrow-derived endothelial progenitor cells (EPCs) affects the proliferation and differentiation of spinal cord-derived neural stem cells (NSCs), and to investigate the underlying mechanism. The proliferation and differentiation of the NSCs were evaluated by an MTT cell proliferation and cytotoxicity assay, and immunofluorescence, respectively. The number of neurospheres and the number of beta-tubulin III-positive cells were detected by microscopy. The wingless-type MMTV integration site family, member 3a (Wnt3a)/beta-catenin signaling pathway was analyzed by western blot analysis and reverse transcription-quantitative polymerase chain reaction to elucidate the possible mechanisms of EPC-mediated NSC proliferation and differentiation. The results revealed that co-culture with EPCs significantly induced NSC proliferation and differentiation. In addition, co culture with EPCs markedly induced the expression levels of Wnt3a and beta catenin and inhibited the phosphorylation of glycogen synthase kinase 3beta (GSK 3beta). By contrast, Wnt3a knockdown using a short hairpin RNA plasmid in the EPCs reduced EPC-mediated NSC proliferation and differentiation, accompanied by inhibition of the EPC-mediated expression of beta-catenin, and its phosphorylation and activation of GSK-3beta. Taken together, the findings of the present study demonstrated that Wnt3a was critical for EPC-mediated NSC proliferation and differentiation. PMID- 27484040 TI - A sandwich-like strategy for the label-free detection of oligonucleotides by surface plasmon fluorescence spectroscopy (SPFS). AB - For the detection of oligonucleotides a sandwich-like detection strategy has been developed by which the background fluorescence is significantly lowered in comparison with surface-bound molecular beacons. Surface bound optical molecular beacons are DNA hairpin structures comprising a stem and a loop. The end of the stem is modified with a fluorophore and a thiol anchor for chemisorption on gold surfaces. In the closed state the fluorophore is in close proximity to the gold surface, and most of the fluorescence is quenched. After hybridization with a target the hairpin opens, the fluorophore and surface become separated, and the fluorescence drastically increases. Using this detection method the sensitivity is limited by the difference in the fluorescence intensity in the closed and open state. As the background fluorescence is mainly caused by non-quenched fluorophores, a strategy to reduce the background fluorescence is to cut the beacon in two halves. First a thiolated ssDNA capture probe strand (first half) is chemisorbed to a gold surface together with relatively short thiol spacers. Next the target is hybridized by one end to the surface-anchored capture probe and by the other to a fluorophore-labeled reporter probe DNA (second half). The signal readout is done by surface plasmon fluorescence spectroscopy (SPFS). Using this detection strategy the background fluorescence can be significantly lowered, and the detection limit is lowered by more than one order of magnitude. The detection of a target takes only a few minutes and the sensor chips can be used for multiple detection steps without a significant decrease in performance. PMID- 27484041 TI - Transperineal sonographic findings of vulvar neurofibromatosis Type 1. PMID- 27484042 TI - The protective role of vitamin D3 in a murine model of asthma via the suppression of TGF-beta/Smad signaling and activation of the Nrf2/HO-1 pathway. AB - Asthma is a common worldwide health burden, the prevalence of which is increasing. Recently, the biologically active form of vitamin D3, 1,25 dihydroxyvitamin D3, has been reported to have a protective role in murine asthma; however, the molecular mechanisms by which vitamin D3 attenuates asthma associated airway injury remain elusive. In the present study, BALB/c mice were sensitized to ovalbumin (OVA) and were administered 100 ng 1,25-dihydroxyvitamin D3 (intraperitoneal injection) 30 min prior to each airway challenge. The inflammatory responses were measured by ELISA, airway damage was analyzed by hematoxylin and eosin staining, airway remodeling was analyzed by Masson staining and periodic acid-Schiff staining, markers of oxidative stress were measured by commercial kits, and the expression levels of alpha-smooth muscle actin (alpha SMA) and the activity of the NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO 1) and the transforming growth factor-beta (TGF-beta)/Smad signaling pathways were measured by immunohistochemistry and western blotting. The results demonstrated that OVA-induced airway inflammation and immunoglobulin E overexpression were significantly reduced by vitamin D3 treatment. In addition, treatment with vitamin D3 decreased alpha-SMA expression, collagen deposition and goblet cell hyperplasia, and inhibited TGF-beta/Smad signaling in the asthmatic airway. The upregulated levels of malondialdehyde, and the reduced activities of superoxide dismutase and glutathione in OVA-challenged mice were also markedly restored following vitamin D3 treatment. Furthermore, treatment with vitamin D3 enhanced activation of the Nrf2/HO-1 pathway in the airways of asthmatic mice. In conclusion, these findings suggest that vitamin D3 may protect airways from asthmatic damage via the suppression of TGF-beta/Smad signaling and activation of the Nrf2/HO-1 pathway; however, these protective effects were shown to be accompanied by hypercalcemia. PMID- 27484043 TI - Analysis of 3D strain in the human medial meniscus. AB - This study presents a method to evaluate three-dimensional strain in meniscal tissue using medical imaging. Strain is calculated by tracking small teflon markers implanted within the meniscal tissue using computed tomography imaging. The results are presented for strains in the middle and posterior third of the medial menisci of 10 human cadaveric knees, under simulated physiologically relevant loading. In the middle position, an average compressive strain of 3.4% was found in the medial-lateral direction, and average tensile strains of 1.4% and 3.5% were found in the anterior-posterior and superior-inferior directions respectively at 5 degrees of knee flexion with an applied load of 1* body weight. In the posterior position, under the same conditions, average compressive strains of 2.2% and 6.3% were found in the medial-lateral and superior-inferior directions respectively, and an average tensile strain of 3.8% was found in the anterior-posterior direction. No statistically significant difference between strain in the middle or posterior of the meniscus or between the global strains is uncovered. PMID- 27484044 TI - Reply to Comment on 'A new method to measure electron density and effective atomic number using dual-energy CT images'. AB - In this note, we would like to respond to the comments made by Professor Bouchard on our recent published work and clarify some aspects of it. PMID- 27484045 TI - Alkylamine-functionalized hexagonal boron nitride nanoplatelets as a novel material for the reduction of friction and wear. AB - Hexagonal boron nitride nanoplatelets (h-BNNPs), which are structurally analogous to graphene, were prepared via the ultrasound-assisted exfoliation of h-BN powder using N-methyl pyrrolidone as the solvent. The alkylamines with variable alkyl chains and electron-rich nitrogen atoms were grafted onto the boron sites of the h-BNNPs based on Lewis acid-base chemistry. The grafting of the alkylamines onto the h-BNNPs was confirmed using FTIR, XPS, TGA and (13)C SSNMR analyses. The crystalline and structural features of the alkylamine-functionalized h-BNNPs were studied using XRD and HRTEM analyses. The TGA and FTIR results revealed a higher grafting of octadecylamine (ODA) on the h-BNNPs compared to trioctylamine (TOA). The cohesive interaction between the alkyl chains grafted onto the h-BNNPs and the hydrocarbon chains of mineral lube base oil facilitates the dispersion of the alkylamine-functionalized h-BNNPs. The TOA-grafted h-BNNPs (h-BNNPs-TOA) exhibited long-term dispersion stability compared to the ODA-grafted h-BNNPs and this was attributed to a higher degree of van der Waals interactions between the octyl chains of the TOA molecules grafted onto the h-BNNPs and the hydrocarbon chains of the mineral lube base oil. The tribo-performance of the h-BNNPs-TOA as an additive to mineral lube base oil was evaluated in terms of the coefficient of friction and wear using ball-on-disc contact geometry. A minute dosing (0.02 mg mL(-1)) of h-BNNPs-TOA significantly improved the lubrication characteristics of the mineral lube base oil and showed a 35 and 25% reduction of friction and wear, respectively. The presence of boron and nitrogen on the worn scar of an aluminium disc, as deduced from elemental mapping, confirmed the formation of a tribo chemical thin film of h-BN lamellae on the contact interfaces, which not only reduced the friction but also protected the contact interfaces against undesirable wear events. PMID- 27484046 TI - Longitudinal bone growth is impaired by direct involvement of caffeine with chondrocyte differentiation in the growth plate. AB - We showed previously that caffeine adversely affects longitudinal bone growth and disrupts the histomorphometry of the growth plate during the pubertal growth spurt. However, little attention has been paid to the direct effects of caffeine on chondrocytes. Here, we investigated the direct effects of caffeine on chondrocytes of the growth plate in vivo and in vitro using a rapidly growing young rat model, and determined whether they were related to the adenosine receptor signaling pathway. A total of 15 male rats (21 days old) were divided randomly into three groups: a control group and two groups fed caffeine via gavage with 120 and 180 mg kg-1 day-1 for 4 weeks. After sacrifice, the tibia processed for the analysis of the long bone growth and proliferation of chondrocytes using tetracycline and BrdU incorporation, respectively. Caffeine fed animals showed decreases in matrix mineralization and proliferation rate of growth plate chondrocytes compared with the control. To evaluate whether caffeine directly affects chondrocyte proliferation and chondrogenic differentiation, primary rat chondrocytes were isolated from the growth plates and cultured in either the presence or absence of caffeine at concentrations of 0.1-1 mm, followed by determination of the cellular proliferation or expression profiles of cellular differentiation markers. Caffeine caused significant decreases in extracellular matrix production, mineralization, and alkaline phosphatase activity, accompanied with decreases in gene expression of the cartilage-specific matrix proteins such as aggrecan, type II collagen and type X. Our results clearly demonstrate that caffeine is capable of interfering with cartilage induction by directly inhibiting the synthetic activity and orderly expression of marker genes relevant to chondrocyte maturation. In addition, we found that the adenosine type 1 receptor signaling pathway may be partly involved in the detrimental effects of caffeine on chondrogenic differentiation, specifically matrix production and mineralization, as evidenced by attenuation of the inhibitory effects of caffeine by blockade of this receptor. Thus, our study provides novel information on the integration of caffeine and adenosine receptor signaling during chondrocyte maturation, extending our understanding of the effect of caffeine at a cellular level on chondrocytes of the growth plate. PMID- 27484047 TI - Victimization of Lesbian, Gay, and Bisexual People in Childhood: Associations with Attempted Suicide. AB - Higher rates of attempted suicide have been documented among people who identify themselves as gay, lesbian, and bisexual (LGB) compared with heterosexuals. This study sought to ascertain the association between childhood abuse and neglect and attempted suicide, comparing LGBs and heterosexuals. Childhood sexual abuse among men and childhood sexual and physical abuse among women were found to mediate the association between LGB identity and attempted suicide. The experience of childhood abuse likely plays a significant role in the relationship between LGB identity and attempted suicide, but other factors such as experience of discrimination are also important. PMID- 27484049 TI - 1st Joint ANIRCEF-SISC Congress. PMID- 27484048 TI - Efficacy and safety of mycophenolate mofetil in patients with active moderate-to severe Graves' orbitopathy. AB - CONTEXT: Graves' orbitopathy (GO) is a potentially sight-threatening disease for which currently available medical therapy is not reliably successful. Mycophenolate mofetil (MMF) is a selective immunosuppressant used widely in many autoimmune diseases. Preliminary studies have shown that MMF is effective in the treatment of active GO. OBJECTIVE: To evaluate the efficacy and safety of MMF in patients with active moderate-to-severe GO. PATIENTS: One hundred and 74 patients with active moderate-to-severe GO were randomized to receive either MMF or glucocorticoids (GC). MAIN OUTCOME MEASURES: The primary outcome was overall response at the 12th and 24th weeks; the outcome assessments included clinical activity score (CAS), soft tissue involvement, pain, visual acuity, proptosis, diplopia and reduction in eye movements. The secondary outcome was changes in those individual parameters. Adverse effects were recorded at each visit. RESULTS: A greater overall response rate was found in the MMF group compared with the GC group at the 24th week (91.3% vs 67.9%, P = 0.000). MMF therapy showed a better CAS response than GC (92.5% vs 70.5% improved, P < 0.05). Patients treated with MMF showed a significantly improved rate of diplopia and proptosis than patients treated with GC at the 24th week (90.4% and 68.8% improved, respectively). Disease reactivation was not observed in the patients treated with MMF but was observed in five patients after GC therapy. Adverse events occurred in 4 of 80 patients treated with MMF (5%), all of which were mild to moderate. A severe adverse event was only observed in one patient treated with GC but not at all in patients treated with MMF. CONCLUSION: Compared with GC treatment, MMF therapy is more effective and safer for patients with active moderate-to-severe GO. PMID- 27484050 TI - Antimicrobial Susceptibility Patterns of Clostridium difficile Isolates from Family Dairy Farms. AB - A significant risk factor for developing Clostridium difficile infection (CDI) in humans and animals is associated with the antimicrobial use. It has often been hypothesized that farm animals could be the source for human infection with Clostridium difficile (CD). In the European Union, family-run dairy farms are the predominant farming model, which are more interlinked within the community compared to large-scale intensive dairy or beef farms. Therefore, it is important to investigate antimicrobial susceptibility patterns of CD in such environment. A total of 159 CD isolates from 20 family dairy farms were tested with a customized broth microdilution plate for their antimicrobial resistance. Seventeen antimicrobials were selected (amoxicillin, ceftriaxone, clindamycin, daptomycin, erythromycin, fusidic acid, imipenem, levofloxacin, linezolid, metronidazole, moxifloxacin, oxacillin, rifampicin, tetracycline, tigecycline, trimethoprim/sulfamethoxazole and vancomycin), which are commonly used for treatment of CDI in veterinary and human medicine, or were previously applied in CD epidemiological studies. Antimicrobials, which are used for treatment of CDI in humans (metronidazole, vancomycin, fusidic acid, tigecycline, linezolid) inhibited CD growth in vitro. Most CD isolates were resistant to erythromycin (93.1%), daptomycin (69.2%) and clindamycin (46.5%). High multiple-resistance was found in CD ribotype 012 (n = 5, 100%), some CD SLO 060 (n = 4, 25%) and one CD 033 (n = 1, 1.1%). High multiple-resistance in this study was linked with CD ribotypes and not with the origin of CD. The low prevalence of these ribotypes (6.3%; 10/159) indicates that family-run dairy farms are an unlikely source of CD with multiple-resistance to antimicrobials. PMID- 27484051 TI - Angelman syndrome-derived neurons display late onset of paternal UBE3A silencing. AB - Genomic imprinting is an epigenetic phenomenon resulting in parent-of-origin specific gene expression that is regulated by a differentially methylated region. Gene mutations or failures in the imprinting process lead to the development of imprinting disorders, such as Angelman syndrome. The symptoms of Angelman syndrome are caused by the absence of functional UBE3A protein in neurons of the brain. To create a human neuronal model for Angelman syndrome, we reprogrammed dermal fibroblasts of a patient carrying a defined three-base pair deletion in UBE3A into induced pluripotent stem cells (iPSCs). In these iPSCs, both parental alleles are present, distinguishable by the mutation, and express UBE3A. Detailed characterization of these iPSCs demonstrated their pluripotency and exceptional stability of the differentially methylated region regulating imprinted UBE3A expression. We observed strong induction of SNHG14 and silencing of paternal UBE3A expression only late during neuronal differentiation, in vitro. This new Angelman syndrome iPSC line allows to study imprinted gene regulation on both parental alleles and to dissect molecular pathways affected by the absence of UBE3A protein. PMID- 27484052 TI - Contrasting Frustrated Lewis Pair Reactivity with Selenium- and Boron-Based Lewis Acids. AB - The activation of pi-bonds in diynyl esters has been investigated by using soft and hard Lewis acids. In the case of the soft selenium Lewis acid PhSeCl, sequential activation of the alkyne bonds leads initially to an isocoumarin (1 equiv PhSeCl) and then to a tetracyclic conjugated structure with the isocoumarin subunit fused to a benzoselenopyran (3 equiv PhSeCl). Conversely, the reaction with the hard Lewis acidic borane B(C6 F5 )3 initiates a cascade reaction to yield a complex pi-conjugated system containing phthalide and indene subunits. PMID- 27484053 TI - Congenital heart defects in newborns with apparently isolated single gastrointestinal malformation: A retrospective study. AB - BACKGROUND: Congenital gastrointestinal system malformations/abdominal wall defects (GISM) may appear as isolated defects (single or complex), or in association with multiple malformations. The high incidence of association of GISM and congenital heart defects (CHD) in patients with syndromes and malformative sequences is known, but less expected is the association of apparently isolated single GISM and CHD. The aim of this study was to investigate the frequency of CHD in newborns with isolated GISM, and the possibility to modify the diagnostic-therapeutic approach just before the onset of cardiac symptoms or complications. METHODS: Anamnestic, clinical, and imaging data of newborns requiring abdominal surgery for GISM, between 2009 and 2014, were compared with a control group of healthy newborns. Distribution of GISM and cardiovascular abnormalities were analyzed, and risk factors for adverse outcomes were identified. RESULTS: Seventy-one newborns with isolated GISM were included in this study. More frequent GISM were intestinal rotation and fixation disorders. CHD were observed in 15.5% of patients, augmenting their risk for morbidity. Risk factors for morbidity related to sepsis were identified in central venous catheter, intestinal stoma, and H2-inhibitor-drugs. Moreover, 28.2% of newborns presented only functional cardiac disorders but an unexpectedly higher mortality. CONCLUSIONS: The high incidence of congenital heart disease in infants with apparently isolated GISM confirms the need to perform an echocardiographic study before surgery to improve perioperative management and prevent complications such as sepsis and endocarditis. PMID- 27484054 TI - Development and validation of a streamlined autism case confirmation approach for use in epidemiologic risk factor research in prospective cohorts. AB - The cost associated with incorporating standardized observational assessments and diagnostic interviews in large-scale epidemiologic studies of autism spectrum disorders (ASD) risk factors can be substantial. Streamlined approaches for confirming ASD case status would benefit these studies. We conducted a multi site, cross-sectional criterion validity study in a convenience sample of 382 three-year olds scheduled for neurodevelopmental evaluation. ASD case classification as determined by three novel assessment instruments (the Early Video-guided Autism Screener E-VAS; the Autism Symptom Interview, ASI; the Screening Tool for Autism in Toddlers Expanded, STAT-E) each designed to be administered in less than 30 minutes by lay staff, was compared to ADOS scores and DSM-based diagnostic assessment from a qualified clinician. Sensitivity and specificity of each instrument alone and in combination were estimated. Alternative cutpoints were identified under different criteria and two-stage cross validation was used to avoid overfitting. Findings were interpreted in the context of a large, prospective pregnancy cohort study utilizing a two-stage approach to case identification. Under initial cutpoints, sensitivity ranged from 0.63 to 0.92 and specificity from 0.35 to 0.70. Cutpoints giving equal weight to sensitivity and specificity resulted in sensitivity estimates ranging from 0.45 to 0.83 and specificity ranging from 0.49 to 0.86. Several strategies were well suited for application as a second-stage case-confirmation. These included the STAT-E alone and the parallel administration of both the E-VAS and the ASI. Use of more streamlined methods of case-confirmation in large-scale prospective cohort epidemiologic investigations of ASD risk factors appears feasible. Autism Res 2017, 10: 485-501. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27484055 TI - Expression pattern of matrix metalloproteinases changes during folliculogenesis in the cat ovary. AB - Matrix metalloproteinase (MMP) has been implicated as having roles in ovarian folliculogenesis. Here, we determined the expression pattern of six MMPs (MMP1, MMP2, MMP3, MMP7, MMP9 and MMP13) and their endogenous tissue inhibitor, TIMP1, during cat follicle growth. Different developmental stage follicles were mechanically isolated and gene expression analysed by real-time qPCR while MMP1, 2, 9 and 13 localization was determined by immunohistochemistry. With the exception of MMP13, the amount of MMP mRNA was lowest in primordial follicles and increased thereafter. Peak levels were detected in early antral follicles for MMP1 (72.2-fold increase above primordial follicle amount), MMP2 (10-fold), MMP3 (57-fold) and MMP9 (2.8-fold). MMP7 transcripts increased 2-fold by the primary follicle stage and then plateaued. MMP13 mRNA peaked in primary follicles (2.5 fold) and was lower in more advanced counterparts. TIMP1 sharply increased (6 fold) in secondary follicles and gradually declined in the later stages. MMP1 and MMP9 expression were expressed in the granulosa cells of all follicle stages. MMP2 was immunoreactive in early and antral follicles, especially at granulosa cells adjacent to the antral cavity. By contrast, the MMP13 was weakly detected in primary follicles onward. In summary, there are distinctive and consistent changes in MMPs and TIMP1 expression during follicle development, suggesting that these enzymes play one or more roles in cat folliculogenesis. In particular, high mRNA and protein expression levels of MMP1 and MMP2, especially at the antral stage, indicate that these enzymes likely are involved in antrum formation and expansion. PMID- 27484056 TI - 1,3,4-Thiadiazole Based Anticancer Agents. AB - In recent years, researchers like medicinal chemists in the field of medicinal chemistry have widely utilized the 1,3,4-thiadiazole nucleus to investigate its biological and pharmacological effects. This heterocyclic structure has demonstrated various bioactivities such as antifungal, antimicrobial, antiviral, antileishmanial, anti-inflammatory, antihypertensive, antiepileptic, and anticancer effects among others. Anticancer activity is one of its promising effect as five membered heterocyclic rings have widely been investigated by researchers in the recent years. Herein, we reviewed the chemical structures bearing 1,3,4-thiadiazole template exerting anticancer activity. PMID- 27484058 TI - Building a More Diverse Workforce in HIV/AIDS Research: The Time has Come. AB - Investigators from diverse racial and ethnic backgrounds are grossly underrepresented in the nation's biomedical research enterprise. Projections of current demographic trends suggest that population growth rates of minority populations will outpace that of the Caucasian population by 2060. Thus, this workforce will remain a poor reflection of the U.S. POPULATION: As a result of this underrepresentation of all sectors of the U.S. populace, the majority of the HIV research involving minority populations-those disproportionately impacted by HIV infection-will be conducted by investigators who do not resemble them. Although this does not necessarily preclude scientifically valid and important research, it produces research without the important cultural and contextual issues that can enhance the utility and generalizability of specific findings or interventions. The goal of this review is to not only raise awareness of the small numbers of minority investigators engaged in biomedical research, but also to identify the challenges to recruiting and retaining these investigators. In this article, while we discuss issues of diversity in general, the focus will be upon the mental health aspects of the HIV epidemic for illustrative purposes: to demonstrate the issues associated with enhancing investigator diversity as a strategy for remediating the chronic shortage of historically underrepresented investigators in scientific research. After presenting the magnitude of the problem and a rationale for enhancing diversity of the biomedical research workforce, we identify a number of potential reasons and challenges for the shortage of minority investigators. Aspects of the mentoring process, together with ten key suggestions, are discussed as the backdrop for the supplement papers that follow (dealing with mentoring principles, challenges, and mentoring-related issues on mentee, mentor, mentee-mentor relationship, and programs). By identifying these realities we hope to: (1) promote greater discussions of these challenges in academic institutions and settings; (2) suggest meaningful strategies to address these challenges; and (3) foster a national discussion about the long-term investment necessary for permanent change, as there are no easy 'fixes' for these challenges. PMID- 27484059 TI - Future HIV Mentoring Programs to Enhance Diversity. AB - This paper proposes a general template to guide future mentoring program development addressing: (i) considerations to ensure an adequate research workforce; (ii) key guidelines and principles of mentoring; and (iii) use of a logic model to develop program milestones, outcomes and evaluation. We focus on these areas to guide and inform the most effective mentoring program components, which we find to be more helpful than identifying specific features and ingredients. Although the focus is on the development of a new generation of investigators from diverse backgrounds, this template may also apply to mentoring programs for other investigators and for disciplines beyond HIV. PMID- 27484057 TI - Disrupted autophagy undermines skeletal muscle adaptation and integrity. AB - This review assesses the importance of proteostasis in skeletal muscle maintenance with a specific emphasis on autophagy. Skeletal muscle appears to be particularly vulnerable to genetic defects in basal and induced autophagy, indicating that autophagy is co-substantial to skeletal muscle maintenance and adaptation. We discuss emerging evidence that tension-induced protein unfolding may act as a direct link between mechanical stress and autophagic pathways. Mechanistic links between protein damage, autophagy and muscle hypertrophy, which is also induced by mechanical stress, are still poorly understood. However, some mouse models of muscle disease show ameliorated symptoms upon effective targeting of basal autophagy. These findings highlight the importance of autophagy as therapeutic target and suggest that elucidating connections between protein unfolding and mTOR-dependent or mTOR-independent hypertrophic responses is likely to reveal specific therapeutic windows for the treatment of muscle wasting disorders. PMID- 27484060 TI - Mentoring the Mentors of Underrepresented Racial/Ethnic Minorities Who are Conducting HIV Research: Beyond Cultural Competency. AB - The majority of literature on mentoring focuses on mentee training needs, with significantly less guidance for the mentors. Moreover, many mentoring the mentor models assume generic (i.e. White) mentees with little attention to the concerns of underrepresented racial/ethnic minorities (UREM). This has led to calls for increased attention to diversity in research training programs, especially in the field of HIV where racial/ethnic disparities are striking. Diversity training tends to address the mentees' cultural competency in conducting research with diverse populations, and often neglects the training needs of mentors in working with diverse mentees. In this article, we critique the framing of diversity as the problem (rather than the lack of mentor consciousness and skills), highlight the need to extend mentor training beyond aspirations of cultural competency toward cultural humility and cultural safety, and consider challenges to effective mentoring of UREM, both for White and UREM mentors. PMID- 27484061 TI - Exercise Promotion in Geriatric Oncology. AB - Evidence of the benefits of exercise for people with cancer from diagnosis through survivorship is growing. However, most cancers occur in older adults and little exercise advice is available for making specific recommendations for older adults with cancer. Individualized exercise prescriptions are safe, feasible, and beneficial for the geriatric oncology population. Oncology providers must be equipped to discuss the short- and long-term benefits of exercise and assist older patients in obtaining appropriate exercise prescriptions. This review provides detailed information about professionals and their roles as it relates to functional assessment, intervention, and evaluation of the geriatric oncology population. This review addresses the importance of functional status assessment and appropriate referrals to other oncology professionals. PMID- 27484062 TI - Immune Checkpoint Blockade: A New Era for Non-Small Cell Lung Cancer. AB - Despite better understanding of it's molecular biology, non-small cell lung cancer (NSCLC) remains a challenging disease to treat. Unfortunately, treatment options are still very limited and prognosis for advanced disease is poor. Immune surveillance plays a crucial role in a host's defence against tumour cells, and this is particular relevant for lung cancer due to it's high somatic mutational load, which increases the chances for the immune system to recognize cancer cells as 'non-self'. Novel immunotherapies are emerging as an effective treatment for this disease. In this review, we present the data on immune checkpoint inhibitors for NSCLC, describing their mechanism of action, data efficacy from recent clinical trials, and strategies to select patients more likely to benefit from these agents. PMID- 27484063 TI - Perifollicular blood flow and its relationship with endometrial vascularity, follicular fluid EG-VEGF, IGF-1, and inhibin-a levels and IVF outcomes. AB - PURPOSE: The aim of this study is to investigate the association of perifollicular blood flow (PFBF) with follicular fluid EG-VEGF, inhibin-a, and insulin-like growth factor-1 (IGF-1) concentrations, endometrial vascularity, and IVF outcomes. METHODS: Forty women with tubal factor infertility were included in a prospective cohort study. Each woman underwent IVF/ICSI procedure. Individual follicles of >=16 mm (n = 156) were evaluated by power Doppler analysis and categorized as well-vascularized follicles (WVFs) or poorly vascularized follicles (PVFs). WVFs referred to those with perifollicular vascularity of 51 100 %. Each follicular fluid (FF) was individually aspirated and FF/serum EG VEGF, inhibin-a, and FF IGF-1 levels were evaluated. Zones III-IV endometrial vascularity was classified as a well-vascularized endometrium (WVE). The presence of a WVE and mature oocytes, in addition to the embryo quality and clinical pregnancy rate (CPR), were recorded for each follicle. The main outcome measures were FF serum EG-VEGF, inhibin-a, IGF-1 levels, and WVE and IVF outcome per PFBF. RESULTS: For WVFs, the level of FF EG-VEGF (p = 0.008), oocyte quality (p = 0.001), embryo quality (p = 0.002), a WVE (p = 0.001), and CPR (p = 0.04) increased significantly. The pregnant group was characterized by increased numbers of WVFs (p = 0.044), a WVE (p = 0.022), and increased levels of FF IGF-1 (p = 0.001) and serum EG-VEGF (p = 0.03). FF IGF-1 >50 ng/mL (AUC 0.72) had 75 % sensitivity and 64 % specificity for predicting CPR. CONCLUSIONS: WVFs yield high quality oocytes and embryos, a WVE, increased FF EG-VEGF levels, and increased CPRs. PMID- 27484064 TI - Hepatocellular carcinoma with gastric metastasis treated by simultaneous hepatic and gastric resection: report of a case. AB - Hepatocellular carcinoma (HCC) with gastric metastasis is extremely rare. There have been few reports on curative surgical resection for gastric metastasis of HCC. We herein report such a case successfully treated by simultaneous surgical resection. A 73-year-old male was admitted for evaluation and treatment of a liver tumor. Computed tomography showed an exophytic tumor of 170 mm in diameter located in the left lobe of the liver with poor delineation to the gastric wall. Upper gastrointestinal endoscopy revealed a submucosal tumor with ulceration in the antrum of the stomach. With a diagnosis of HCC with invasion to the gastric wall, an en bloc resection was planned, and the patient underwent laparotomy. The patients underwent left hemihepatectomy with partial resection of the stomach for adhesion and distal gastrectomy for the tumor. Pathological examination of the liver tumor revealed poorly differentiated HCC, and pathological diagnosis of the tumor in the submucosal and muscular layer of the stomach was compatible with metastasis from HCC, which was separate from the liver tumor. Therefore, we diagnosed the tumor as HCC with hematogenous gastric metastasis. The patient remains well with no evidence of tumor recurrence as of 13 months after resection. PMID- 27484065 TI - Cultural variation in antismoking video ads between the United States, Taiwan, and China. AB - Antitobacco advertisement components, including types of messages and advertising appeals, have not been evaluated among multinational groups. This study identified and compared the content of antismoking video ads across three countries. We reviewed 86 antismoking video advertisements for the following information: severity of the consequences of smoking, types of risks, appeals to audiences' self-efficacy, benefits of not smoking, targeted social-ecological level and types of message appeal used. Two researchers independently coded each advertisement with an average inter-coder reliability of 0.79.Analyses showed a variety of focuses: smoking-related health risks (86%), severe consequences of smoking (54.7%), self-efficacy beliefs (40.7%) and benefits of not smoking (84.9%). Compared to the United States and Taiwanese ads, Chinese ads were more likely to target at the community level (10% versus 23.3% versus 47.2%). Additionally, 55% of the United States ads used the fear approach, whereas 61.1% of Chinese ads used the social approach. Taiwanese ads were evenly distributed among both approaches. In conclusion, the countries used different targeting strategies and approaches during message delivery. Although China's neighboring country, Taiwan, has many similar cultural aspects, including the same language, they are greatly influenced by US antitobacco campaigns. As a result, Taiwan's tobacco campaigns appear to have similar components to both China and the United States. Further research is warranted to understand the reasons for each method and to examine the effectiveness of the ads in reducing smoking rates. PMID- 27484066 TI - Mesenchymal stem cells attenuate ischemia-reperfusion injury after prolonged cold ischemia in a mouse model of lung transplantation: a preliminary study. AB - PURPOSE: Mesenchymal stem cells (MSCs) suppress inflammation and immune responses. We conducted this study to find out if MSCs attenuate ischemia reperfusion injury in a mouse model of lung transplantation. METHODS: C57BL/6J mouse lungs perfused with low-potassium dextran glucose solution were preserved at 4 degrees C for 18 h. Human MSCs were slowly injected into the left pulmonary artery of the lung grafts, and orthotopic left lung transplantation was then performed. The lung isografts were reperfused for 6 h, and bronchoalveolar lavage fluid (BALF) from the left lung graft was collected. We measured the protein concentration, cell count, and proinflammatory cytokine concentrations in the BALF. RESULTS: The protein concentration and cell count in the BALF were significantly lower in the MSC-administered grafts than in the PBS-administered controls. Concentrations of proinflammatory cytokines, including IL-1beta, IL 17A, and TNF-alpha, in BALF tended to be lower in the MSC-administered grafts than in the controls, but the difference was not significant. CONCLUSION: The pre transplant administration of MSCs via the pulmonary artery of the lung graft attenuated ischemia-reperfusion injury after prolonged cold ischemia in this mouse model of lung transplantation. PMID- 27484067 TI - Does segmentectomy really preserve the pulmonary function better than lobectomy for patients with early-stage lung cancer? AB - PURPOSE: Recently, segmentectomy has been considered as an alternative to lobectomy in early peripheral non-small lung cancer (NSCLC); however, controversy has remained regarding the long-term functional advantage after segmentectomy. The aim of this study was to analyze the postoperative lung function after segmentectomy and lobectomy for non-small cell lung cancer. METHODS: Patients with p-T1aN0M0 NSCLC who had undergone segmentectomy (n = 37) or lobectomy (n = 33) were retrospectively analyzed. The ratios of postoperative to preoperative forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were defined as the recovery rates. The radiological lung volume and weight were evaluated before and more than 6 months after surgery, and the postoperative values were compared with the predicted values that were calculated from the preoperative values, subtracting the resected lobes or segments. RESULTS: The clinical characteristics, including the preoperative lung function showed no significant differences between the groups. No statistical differences were recognized in the trend lines for recovery ratios of FVC and FEV1.0 (P = 0.96 and P = 0.33). The recovery ratios for radiologic lung volume and weight showed no significant differences (P = 0.46 and P = 0.22). The postoperative lung volume and weight were almost the same as the predicted values after segmentectomy, whereas those after lobectomy were significantly higher than the predicted values. CONCLUSIONS: No functional advantage for segmentectomy was observed during long-term follow-up, possibly due to compensatory lung growth after lobectomy. PMID- 27484069 TI - Functional study of the upregulation of miRNA-27a and miRNA-27b in 3T3-L1 cells in response to berberine. AB - Berberine is the major active component of Rhizoma Coptidis derived from a traditional Chinese herbal medicine and is known to regulate micro (mi)RNA levels, although the mechanism for this action remains unknown. The present study confirmed that treatment of 3T3-L1 cells with berberine inhibited cell viability and differentiation in a dose- and time-dependent manner, and significantly increased the mRNA expression levels of miRNA-27a and miRNA-27b. In addition, in 3T3-L1 cells treated with berberine, overexpression of miRNA-27a and miRNA-27b improved the berberine-mediated inhibition of cell differentiation and reduction of triglyceride contents. By contrast, miRNA-27a and miRNA-27b inhibitors attenuated the berberine-mediated inhibition of cell differentiation and reduction of triglyceride contents. Additionally, peroxisome proliferator activated receptors (PPAR)-gamma was confirmed to be a target of miRNA-27a in the 3T3-L1 cells. A dual-luciferase reporter assay indicated that the expression of PPAR-gamma was negatively regulated by miRNA-27a. These findings may provide novel mechanistic insight into the antiobesity effects of certain compounds in traditional Chinese herbal medicine. PMID- 27484070 TI - Standard Approaches to the Acetabulum Part 1: Kocher-Langenbeck Approach. AB - Historically, standard approaches for surgical treatment of displaced acetabular fractures were the KocherLangenbeck approach, the ilioinguinal approach and the extended iliofemoral approach (12). Presently, several modifications of these approaches are accepted alternatives, especially anterior modifications based on the intrapelvic approach described by Hirvensalo (8). Single access approaches allowing visualization of one acetabular column are the posterior Kocher Langenbeck approach and the anterior ilioinguinal approach (12) and the use of a single approach is favoured (9, 24). For more complex situations, in the 80s and 90s extended approaches (extended iliofemoral approach according to Letournel (12), its modification to Reinert (19) (Baltimore approach), and the Triradiate approach according to Mears (14)) were introduced. These approaches are presently rarely choosen due to the extensive soft tissue dissection and higher complication rates (28). Alternatively, the combination of an anterior and posterior standard approach was recommended (7, 21, 22) having the disadvantage of longer operating time and blood loss and showed no superior results compared to a single approach. The meta-analysis by Giannoudis et al. stated that 48,7% of patients were treated using the Kocher-Langenbeck approach, followed by 21,9% ilioinguinal approaches and 12,4% extended approaches (6). More recent data from the years 2005-2007, showed that anterior approaches are now predominantly used according to a higher number of acetabular fractures with anterior column involvement. Overall, more than 40% of all patients with acetabular fractures are still approached via the Kocher-Langenbeck approach (18). Therefore, the Kocher Langenbeck approach is still a "working horse" in approaching displaced acetabular fractures. The Kocher-Langenbeck approach consists of two parts. In 1874 von Langenbeck described a longitudinal incision starting from above the greater sciatic notch to the greater trochanter, dissecting the gluteal muscles for treating hip joint infections (11). Theodor Kocher in 1911 described a curved incision starting from the posterior-inferior corner of the greater trochanter, running across the postero-superior tip of the greater trochanter passing oblique in line with the fibres of the gluteus maximus muscle in direction to the posterior superior iliac spine (10). The aim of the present analysis is the detailed anatomi - cal analysis of this standard approach, focusing on fracture indication, positioning of the patient, exposure, dissection, reduction techniques of special fracture types, approach modifications/extensions, complications and approach-specific results. PMID- 27484068 TI - S-Nitrosoglutathione Attenuates Airway Hyperresponsiveness in Murine Bronchopulmonary Dysplasia. AB - Bronchopulmonary dysplasia (BPD) is characterized by lifelong obstructive lung disease and profound, refractory bronchospasm. It is observed among survivors of premature birth who have been treated with prolonged supplemental oxygen. Therapeutic options are limited. Using a neonatal mouse model of BPD, we show that hyperoxia increases activity and expression of a mediator of endogenous bronchoconstriction, S-nitrosoglutathione (GSNO) reductase. MicroRNA-342-3p, predicted in silico and shown in this study in vitro to suppress expression of GSNO reductase, was decreased in hyperoxia-exposed pups. Both pretreatment with aerosolized GSNO and inhibition of GSNO reductase attenuated airway hyperresponsiveness in vivo among juvenile and adult mice exposed to neonatal hyperoxia. Our data suggest that neonatal hyperoxia exposure causes detrimental effects on airway hyperreactivity through microRNA-342-3p-mediated upregulation of GSNO reductase expression. Furthermore, our data demonstrate that this adverse effect can be overcome by supplementing its substrate, GSNO, or by inhibiting the enzyme itself. Rates of BPD have not improved over the past two decades; nor have new therapies been developed. GSNO-based therapies are a novel treatment of the respiratory problems that patients with BPD experience. PMID- 27484071 TI - [Minimal Invasive Fixation of Pelvic Injury: CT-Study of the Pelvic Bone Dimensions]. AB - PURPOSE OF THE STUDY This radiographic study was focused on measuring the dimensions of pelvic bones at sites of minimally invasive screw insertion with the aim to assess the risk of damage to vascular and nervous structures. MATERIAL AND METHODS The group consisted of 77 patients (39 women and 38 men) aged between 19 and 85 years (average, 65; women, 65; men, 64) who underwent CT examination of the pelvis because of reasons other than injury. On the left side, a total of 14 dimensions of the superior pubic ramus, supraacetabular region, retroacetabular region, quadrilateral surface of the acetabulum and lateral foraminal sides of the S1 and S2 vertebral bodies were measured. The results were evaluated using descriptive statistics. RESULTS The inner antero-posterior dimension of the isthmic area of the superior pubic ramus was 8 mm or less in four women (10.3%) and 9 or 10 mm in further 14 women (35.9%). The inner cranio-caudal dimension of the superior pubic ramus was 8 mm or less in 14 women (35.9%) and 9 or 10 mm in further 16 women (41.0%). These dimensions obtained in men were as follows: 8 mm and less in three men (7.9%) (7 mm in one, 8 mm in two), and 9 or 10 mm in nine men. Sizes of the other pelvic bones were large enough to allow for safe insertion of single screws. DISCUSSION Single screws most frequently used in minimally invasive treatment of pelvic fractures are cannulated screws 7.3 mm or 6.5 mm in diameter; less frequently used are 4.5-mm cancellous screws (e.g. in treatment of avulsion injuries) or long 3.5-mm cortical "creeping" screws to be inserted in the superior pubic ramus. The use of "creeping" screws reported by several authors indicates problems associated with placement of standard screws (diameter, 7.3 mm and 6.5 mm) through the isthmus into the superior ramus. In slim high pelvises of some patients with gracile skeletons or in low pelvises of small women, the screws can protrude over the cortical margin. However, the risk of injury to nervous or vascular structures is low when the intraosseous screw is exactly inserted and it is so even in case its thread cuts into cortical bone. Neither the femoral artery nor the femoral nerve is situated too close to the superior pubic ramus. The "corona mortis" may potentially be jeopardised because of its contact with both the superior and posterior cortical bones of the superior ramus, but it usually follows a course more lateral to the isthmus of the ramus. CONCLUSIONS The results of the study showed that the size of the superior pubic ramus in its isthmic area may cause difficulties during insertion of cannulated screws with standard diameters (7.3 mm and 6.5 mm) in the majority of women and in some men. The risk of damage to vascular and nervous structures during screw insertion is associated only with the superior and posterior walls of the superior pubic ramus and with the area of the S2 foramen in case the correct procedure of intraosseous screw insertion is not strictly followed. KEY WORDS: retrograde pubic screw, iliosacral screw, supraacetabular screw, retrograde posterior column screw. PMID- 27484072 TI - [Analysis of Oxidative Damage to Components Removed from Beznoska/Poldi Total Hip Replacements]. AB - PURPOSE OF THE STUDY Ultrahigh molecular weight polyethylene (UHMWPE) is today the most frequently used bearing surface in total joint replacements (TJR) because of its properties, i.e., excellent biocompatibility, good mechanical and tribological performance and high wear resistance. UHMWPE liners are the most loaded TJR components and, therefore, their properties are decisive for TJR longevity. This study had three objectives: 1) to evaluate the oxidative degradation of explanted UHMWPE components; 2) to look for a statistically significant relationship between the extent of oxidative degradation and the durability of joint replacements; and 3) to investigate whether the durability of a TJR was related to the type of sterilisation used in manufacture. MATERIAL AND METHODS The study included 26 acetabular components obtained at revision arthroplasty between 2004 and 2013 from patients in whom a Beznoska/Poldi total hip replacement was used in the period from 1977 to 2002. The average age of the patients at the time of primary implantation was 57.9 years, the average longevity of the components removed was 18.63 years (range, 6.9 to 27.9 years). Samples of worn out and unworn areas from explanted components were processed in a three-step procedure in order to finally obtain 2-mm microtome sections. These were studied by infrared microspectroscopy. Oxidative damage to UHMWPE was determined as the oxidation index (OI); radiation damage to UHMWPE during sterilization was evaluated as the transvinylene index (VI); oxidation-induced changes in the polymer structure and its properties were characterised as the crystallinity index (CI); and local changes in mechanical properties due to oxidative degradation were assessed as microhardness (MH). Spearman's correlation coefficient and the Wilcoxon two-sample test were used for statistical analysis. RESULTS The OI values (average and maximum) in both worn out and unworn surface areas were related to component longevity. The difference between the oxidation index of ruptured components and that of the other components was statistically significant. Significant differences were also found between the average and maximum OI values of worn out areas and those of unworn surfaces. The relationship between the average oxidation index in both the unworn and worn out areas of UHMWPE components and the longevity of cracked components was statistically significant. DISCUSSION Our results show that the OI values obtained by microspectroscopy correlated with both the microscopic damage and the longevity of UHMWPE liners and the correlation was statistically significant also in relation to the longevity of total replacements. Relationships amongst OI, VI, CI and MH values as well as their relation to failure and longevity of total replacements are discussed. CONCLUSIONS It can be concluded that infrared microspectroscopic measurement of OI values is a simple and fast method to characterise UHMWPE liners. In addition, the IR spectra also show other supplementary characteristics, such as VI and CI indices. These values provide information on the quality of various UHMWPE types currently used in TJR surgery. The types of UHMWPE which exhibit high oxidative degradation should be avoided in clinical practice due to increased risk of early TJR failure. Responsible orthopedic surgeons should be aware of this fact and, if possible, collaborate with an independent, noncommercial laboratory in order to evaluate the quality of various UHMWPE liners used in their hospitals. KEY WORDS: UHMWPE, oxidation, total joint replacement, infrared spectroscopy, microhardness. PMID- 27484073 TI - [Alloplastic Materials and their Propensity to Bacterial Colonisation]. AB - PURPOSE OF THE STUDY The alloplastic materials currently used for protective surface layers on implants were tested in vitro under microbiological laboratory conditions by contamination with microbial agents most frequently found in deep infection of total joint replacements. The objective was to find out how the resistance to bacterial colonisation was related to different surface finishes. MATERIAL AND METHODS Each of 14 samples of alloplastic material currently used in the manufacture of orthopaedic implants was inoculated with each of the group of microorganisms most frequently infecting joint replacements; these were Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Enterococcus faecalis and Escherichia coli. At 24 hours of incubation, biofilms produced on sample surfaces were collected, stained with crystalline violet and assessed by spectrophotometry. The average value of biofilm absorbances (AV595) for the group of microorganism tested was taken as a basic characteristic of each material sample indicating its sensitivity to bacterial. RESULTS Of the metal materials with smooth surface finish, Vitalium (AV595, 0.368) showed the lowest affinity to microbial colonisation; next was titanium (AV595, 0.459) and steel (AV595, 0.505). A significant increase in sensitivity to bacterial colonisation was recorded in all types of surface finish of steel (AV595, 0.571) and in titanium alloy with a rough surface texture (AV595, 0.737 to 1.676); p < 0.05. Porous titanium surfaces significantly increased material affinity to colonisation. DISCUSSION Our study had certain limitations concerning in vitro evaluation of porous surfaces that have high affinity to bacterial colonisation. Porous titanium, and its hydroxyapatite layer in particular, considerably promotes osteoblast colonisation of the surface as well as implant osseointegration in the bone bed. Microorganisms therefore have no room for surface colonisation. Problematic may remain the surface parts outside contact with bone that keep their affinity to bacterial colonisation. CONCLUSIONS The material of choice for cemented implants is Vitalium which, of all metal surfaces, has the lowest sensitivity to bacterial colonisation. The materials of choice for cementless implants are titanium alloys. However, an osteoactive surface not in contact with bone remains a problem. On the one hand, its roughness and porosity are crucial to good osseointegration, on the other hand, its affinity to bacterial colonisation is high. KEY WORDS: alloplastic material, biofilm, joint replacement infection. PMID- 27484074 TI - [Management of Osteochondral Lesions of the Ankle Joint by Implantation of Autologous Chondrocytes]. AB - PUPOSE OF THE STUDY The treatment of osteochondral lesions of weight-bearing joints remains a serious therapeutic challenge, largely due to the minimal ability of articular hyaline cartilage to regenerate. The authors present the long-term clinical and MRI results of treating deep chondral and osteochondral defects of the ankle joint by the method of implantation of autologous chondrocytes in the form of a solid chondrograft. MATERIAL AND METHODS The method of solid chondrograft implantation in the ankle joint was used in our Department from the year 2003. Between 2003 and 2013, this method was used in 31 patients, 16 men and 15 women. Their average age at the time of implantation was 29 years (16 to 50 years). The follow-up period ranged from 16 to 145 months (average, 57 months). The clinical outcome was evaluated using the Mazur questionnaire. At follow-up all patients underwent regular MRI examinations and the results were assessed on the basis of Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores. Twelve patients required a second-look arthroscopy. RESULTS A comparison of the Mazur pre-operative scores with those obtained at 1, 2 and 5 years post-operatively showed marked improvement of ankle joint function. The average pre-operative value of 30.0 (based on responses of 31 patients) increased to the average of 89.7 (based on results of 11 patients). At 1 year post-operatively, the average MOCART score for a group of 18 patients was 78.3; at 5 post-operative years, the average value for nine patients examined was 77.0. Complete filling of defects at 1 year of follow-up was found in 88.1% and , at 5 years, it was recorded in 83.3% of the patients examined. DISCUSSION The articular hyaline cartilage is a highly differentiated tissue and its ability of repair is very limited. Therefore every damage to the articular surface should be regarded as a pre-arthritic condition// disease. Currently, there are several options of treating a damaged articular cartilage, but none of them makes its complete healing certain. A lot of studies concerned with longterm results of implanting autologous chondrocytes in the knee are available in the literature, but only few authors present long-term clinical and radiographic outcomes of ankle joint treatment similar to ours. CONCLUSIONS Based on our clinical and MRI results, the method of autologous chondrocyte implantation can be recommended since it has good long-term results, provides repair of articular cartilage and allows for patients' return to activities of daily living. KEY WORDS: chondral defect, hyaline cartilage, autologous chondrocyte, ankle joint. PMID- 27484075 TI - [Use of Patient Specific Instruments at Total Knee Arthroplasty. One-Year Results of a Prospective Randomised Study]. AB - PURPOSE OF THE STUDY The aim of this prospective study was to evaluate, at one year of follow-up, radiographic and clinical results of total knee arthroplasty (TKA) performed with use of Zimmer(r) Patient Specific Instruments (PSIs) which allow for planning and customising each patient's TKA. MATERIAL AND METHODS Of the patients with knee arthritis who were eligible for joint replacement, 23 were randomly selected and included in this study. There were 11 men and 12 women, with 11 right and 12 left knee joints. On the basis of pre-operative CT scans, PSI custom-made pin guides, which conformed to the individual patient's anatomy, were produced and then used in the THA surgery involving a NexGen (CR) system. All patients were examined before surgery and at 1 year after THA. The evaluation at a follow-up visit included standing full-length radiographs (antero-posterior and lateral), Knee Score results, range of motion (ROM), patient's satisfaction report, and post-operative complications. The X-ray views were examined for mechanical leg axis alignment, TKA alignment in antero-posterior and lateral projection and signs of potential loosening. RESULTS At 1 post-operative year, the average Knee Society Score (KSS) was 85.5 points and the average functional score was 82.6 point. The satisfaction rate was 94% and, on a school rating system, the average mark was 1.3. The average postoperative ROM value was 116 degrees . All patients were willing to undergo the surgery again. The only complication was thrombosis in one patient. Radiographic findings of knee alignment were optimal in 18, correct (up to 3 degrees deviation) in three and incorrect (above 3 degrees deviation) in two patients. Radiographic signs of loosening were not recorded. DISCUSSION Correct knee alignment is one of the requirements for achieving a good TKA outcome. Various techniques are used to improve the total knee process (computer-aided surgery, customised guides). Zimmer Patient Specific Instruments provide advanced pre-operative planning and more accurate implant sizing and alignment. An experienced surgeon can achieve the same good results with conventional planning under standard conditions but the use of PSIs is clearly more beneficial in patients with extra-articular deformities and in patients in whom femoral intramedullary guides cannot be employed. To produce a custom-made pin guide requires a CT scan of the whole leg and is also associated with additional paperwork. The PSIs simplify the total knee process from start to finish and surgeons have complete flexibility to make fine-tuning adjustments during the procedure. CONCLUSIONS Zimmer Patient Specific Instruments allow for exact alignment of both the femoral and the tibial component in a TKA process. Under standard circumstances, clinical and radiographic outcomes are comparable with those of conventional planning. However, the use of PSIs is clearly more beneficial in patients with extra articular deformities and in patients in whom femoral intramedullary guides cannot be employed. KEY WORDS: total knee arthroplasty, TKA, Patient Specific Instruments, PSIs. PMID- 27484076 TI - [Positions of Sustentacular Screw in Osteosynthesis of Calcaneal Fractures: Clinical and Radiographic Study]. AB - PURPOSE OF THE STUDY The aim of the study was to analyse the options for sustentacular screw placement in osteosynthesis of intra-articular fractures of the heel bone and to assess the effect of various screw positions on failure to maintain the reduction in the postoperative period. In addition, problems related to screw-end protrusion over the medial cortical bone or to screw penetration into the talocalcaneal joint were assessed. MATERIAL AND METHODS The group comprised 23 patients with a total of 25 intra-articular fractures of the heel bone treated by surgery. The procedure involved insertion of a sustentacular screw under fluoroscopic guidance. Post-operatively, screw position in the sustentacular fragment was evaluated on CT scans. During follow-up, attention was focused on the effect of screw placement on maintenance of fracture reduction, and clinical symptoms potentially associated with screw malposition were recorded. RESULTS All sustentacular screws were fixed sustentacular fragments. Seven screws (28%) were inserted in the talar shelf, seven (28%) were placed under and nine (36%) over the sustentaculum tali. Two screws penetrated into the talocalcaneal joint (8%). The end of a screw projecting by 2 mm over the medial wall of the calcaneus was found in 11 cases (44%). Two patients with screws penetrating into the talocalcaneal joint had problems. On the other hand, no clinical effect of a screw extending over the medial wall of the calcaneus was recorded. No significant association of screw position with late //delayed failure of fracture reduction was detected. DISCUSSION Although the ideal trajectory for a sustentacular screw have been defined using a model of the calcaneus, it is not easy to achieve optimal screw placement due to the complex anatomy of the calcaneus and limited possibilities of intra-operative control of screw insertion. Any sustentacular screw malposition is a potential risk factor, particularly if the screw has penetrated into the talocalcaneal joint. Therefore, it will be useful to seek methods allowing for safer screw insertion and elimination of risks associated with screw misplacement. The technique of sustentacular screw insertion by means of a compression-based device, described by the authors, designated to allow for screw placement in distal humerus fractures is one of the options. CONCLUSIONS Optimisation of techniques for sustentacular screw insertion in the osteosynthesis of calcaneal fractures should contribute to reduction of risks related to screw malposition. The assessment of effects which the position of a screw may have on delayed failure of fracture reduction should be based on a thorough biomechanical study. KEY WORDS: sustentacular screw, calcaneal fracture, insertion, malposition. PMID- 27484077 TI - Eastbourne Miami-J Protocol: a Pilot Study for the Care of Cervical Injuries in the Community. AB - PURPOSE OF THE STUDY The aim of this pilot study was to develop The Eastbourne Miami-J Protocol for care of cervical injuries within the community. Led by orthopaedic senior practitioners, a multidisciplinary approach was developed to provide education and collar care for patients on a weekly basis. MATERIALS AND METHODS A total of 51 patients (17 male and 33 female), mean age 74 years (21 to 95) with CT confirmed cervical injuries during November 2010 and May 2014 followed the Eastbourne Miami-J Protocol. RESULTS Patients required collar care on average for 7.25 weeks. Thirty-two patients had single level cervical injuries with C2 the commonest. Complications included: 6 patients with psychosocial issues; 10 patients with skin erythema due to ill-fitting collars and 2 patients with skin breakdown requiring dressings. CONCLUSION The Eastbourne Miami-J protocol demonstrates that a multidisciplinary approach, championed by the casting department, can provide care for patients with cervical injuries within the community. KEY WORDS: cervical spine, C-spine, cervical collar, community, rehabilitation. PMID- 27484078 TI - [Giant Ganglioneuroma of the Spine and Mediastinum]. AB - The case of a 15-year-old girl with a large ganglioneuroma in the mediastinum and spinal canal is presented. The tumour initially manifested as scoliosis. Its diagnosis was made on the basis of CT scanning and magnetic resonance imaging, and confirmed by thoracoscopic mediastinal biopsy. Radical tumour excision was indicated. The first stage involved removal of the tumour from the spinal canal through a posterior approach, and transpedicular fixation of the spinal column with correction of the curve. At the second-stage procedure, the tumour was removed from the pleural cavity and mediastinum through thoracotomy. At two years after surgery, the spondylodesis was completed with autologous bone grafts that healed within 6 months. At 3-year follow-up the patient was with neither clinical findings, nor subjective complains and imaging methods showed no signs of tumour recurrence. KEY WORDS: ganglioneuroma, scoliosis, correction, thoracotomy, spinal canal, mediastinum. PMID- 27484079 TI - [Isolated Displaced Fracture of the Acromion - Case Report]. AB - Displaced fractures of the acromion are rare injuries. A 45-year-old lady presented with an isolated acromion fracture (type III, Kuhn classification) resulting from a direct blow to the top of her right shoulder in a fall while skiing. After standard clinical and radiological examination of the shoulder, an open reduction and internal plate fixation using a postero-superior approach to the scapula was performed. Early rehabilitation of the arm and shoulder was initiated. At 50 days after surgery the patient achieved a full range of motion in her right shoulder and muscle strength equal to that of the contralateral extremity. By 12 weeks radiographic union of the fracture was recorded. The final functional outcome after open reduction and internal plate fixation of the fracture was comparable with results reported in the literature and, in comparison with conservative treatment, the risk of non-union was significantly reduced. KEY WORDS: acromion fracture, scapula, osteosynthesis. PMID- 27484080 TI - [Generalised Form of Synovial Chondromatosis of the Knee Joint]. AB - This study describes a diagnostic and therapeutic algorithm in a 53-year-old male patient who was diagnosed with a synovial chondromatosis of the knee joint extending to the popliteal fossa and soft tissues around the knee. Because of the presence of massive nodules, the patient was indicated for total synovectomy, with removal of pathologically changed cartilaginous tissue, performed by combined anterior and posterior approaches to the knee joint. Despite complete removal of the synovium and loose cartilage bodies and the patient's pain relief in the post-operative time, three years after the operation new problems appeared. Magnetic resonance imaging (MRI) confirmed a relapse of synovial chondromatosis and the patient was indicated for revision surgery of the knee joint. The results of physical examination and MRI scans, and intra-operative findings in the patient are reported. KEY WORDS: synovial chondromatosis, total synovectomy, direct anterior and posterior approaches to the knee joint. PMID- 27484081 TI - Insurance-related disparities in primary care quality among U.S. Type 2 diabetes patients. AB - BACKGROUND: This study explored insurance-related disparities in primary care quality among Americans with type 2 diabetes. METHODS: Data came from the household component of the 2012 Medical Expenditure Panel Survey (MEPS). Analysis focused on adult subjects with type 2 diabetes. Logistic regressions were performed to investigate the associations between insurance status and primary care attributes related to first contact, longitudinality, comprehensiveness, and coordination, while controlling for confounding factors. RESULTS: Preliminary findings revealed differences among three insurance groups in the first contact domain of primary care quality. After controlling for confounding factors, these differences were no longer apparent, with all insurance groups reporting similar primary care quality according to the four domains of interest in the study. There were significant differences in socioeconomic status among different insurance groups. CONCLUSION: This study reveals equitable primary care quality for diabetes patients despite their health insurance status. In addition to insurance-related differences, the other socioeconomic stratification factors are assumed to be the root cause of disparities in care. This research emphasizes the crucial role that primary care plays in the accessibility and quality of care for chronically ill patients. Policy makers should continue their commitment to reduce gaps in insurance coverage and improve access as well as quality of diabetic care. PMID- 27484082 TI - A phase III, multi-centre, double-masked randomised controlled trial of adjunctive intraocular and peri-ocular steroid (triamcinolone acetonide) versus standard treatment in eyes undergoing vitreoretinal surgery for open globe trauma (ASCOT): statistical analysis plan. AB - BACKGROUND: Open globe ocular trauma complicated by intraocular scarring (proliferative vitreoretinopathy) is a relatively rare, blinding, but potentially treatable condition for which, at present, surgery is often unsatisfactory and visual results frequently poor. To date, no pharmacological adjuncts to surgery have been proven to be effective. The aim of the Adjunctive Steroid Combination in Ocular Trauma (ASCOT) randomised controlled trial is to determine whether adjunctive steroid (triamcinolone acetonide), given at the time of surgery, can improve the outcome of vitreoretinal surgery in patients with open globe ocular trauma. This article presents the statistical analysis plan for the main publication as approved and signed off by the Trial Steering Committee prior to the first data extraction for the Data Monitoring Committee meeting report. METHODS/DESIGN: ASCOT is a pragmatic, multi-centre, parallel-group, double-masked randomised controlled trial. The aim of the study is to recruit from 20-25 centres in the United Kingdom and randomise 300 eyes (from 300 patients) into two treatment arms. Both groups will receive standard surgical treatment and care; the intervention arm will additionally receive a pre-operative steroid combination (triamcinolone acetonide) into the vitreous cavity consisting of 4 mg/0.1 ml and 40 mg/1 ml sub-Tenon's. Participants will be followed for 6 months post-surgery. The primary outcome is the proportion of patients achieving a clinically meaning improvement in visual acuity in the study eye at 6 months after initial surgery, defined as a 10 letter score improvement in the ETDRS (the standard scale to test visual acuity). TRIAL REGISTRATION: ISRCTN30012492 . Registered on 5 September 2014. EudraCT2014-002193-37 . Registered on 5 September 2014. PMID- 27484083 TI - The best time for surgery on a patient with recurrent pneumothorax and undetectable culprit lesions is at the exact time air leakage is discovered: a case report. AB - BACKGROUND: One cause of recurrent spontaneous pneumothorax includes overlooking bullae during a previous surgery for pneumothorax; and the identification of the culprit lesions is necessary for prevention of recurrence. CASE PRESENTATION: A 28-year-old man was referred to our hospital because of spontaneous right-sided pneumothorax. He underwent video-assisted thoracoscopic surgery, which did not reveal air leakage. The patient was subsequently seen at our hospital for 2 additional episodes of recurrent right-sided pneumothorax. At the third admission we observed intermittent air leakage while the patient was in the sitting position after chest drainage, and we performed surgery. An intraoperative submersion test showed air leakage dorsally from the pleural surface of S(6) and a minute culprit lesion, which were not seen at the first operation and confirmed the leakage site. The area was ligated and coated with regenerated oxidized cellulose mesh and autologous blood. CONCLUSION: In cases of pneumothorax with repeated recurrence, the best time to perform surgery on the patient with undetectable culprit lesion is the exact time that air leakage is observed. PMID- 27484085 TI - Risk factors associated with intestinal parasitic infections among inmates of Kisii prison, Kisii county, Kenya. AB - BACKGROUND: Intestinal parasitic infections are a major health problem worldwide. In Kenya intestinal parasitic infections are highly prevalent especially in prisons due to poor and/or inadequate infrastructure. The aim of this study was to establish the risk factors associated with intestinal parasites infection among inmates of Kisii prison, Kisii county, Kenya. METHODS: Fresh stool samples of 384 inmates in Kisii prison aged 20 years and above, were screened for intestinal parasitic infections between February and August 2015. Stool samples were processed using direct fecal smear and formol-ether sedimentation techniques for confirmation then they were examined microscopically. Multiple logistic regression analysis was used to establish the relationship of various factors and practices with the occurrence of intestinal parasites. The differences were considered statistically significant at P < 0.05. RESULTS AND DISCUSSION: Of the 384 inmates screened, 95 (24.7 %) were infected with one or more intestinal parasites. Of the positive inmates, 58 (15.1 %) were infected with one species of protozoa while 24 (5.2 %) were infected with at least one species of helminthes and 13 (3.5 %) had mixed infections of species of intestinal parasites. Washing of hands before meals and after visiting toilets significantly reduced risk of infections (P < 0.05). The level of education was inversely related to the risk of intestinal parasites infection where by inmates at post primary education were least infected with intestinal parasites infection as compared to unschooled inmates (P < 0.05). Wearing of shoes was seen to significantly reduce parasitic infections (P <= 0.05). Duties assigned to inmates did not significantly determine the risk of intestinal parasitic infection (P > 0.05). Male inmates had significantly more intestinal parasites infections 57 (21.8 %) compared to females 28 (8.1 %) (P < 0.05). Inmates within ages 20-29 years were more infected (11.3 %) compared to the age group of >60 years (0.6 %) (P < 0.05). There was no statistical significant difference between the number of infections among the length of the jail terms (P < 0.05). CONCLUSIONS: Prevalence of intestinal parasites was high among inmates in the study area than the general population. Practices like wearing of shoes, washing of hands before meals after visiting a toilet and level of education affect the spread of the infections. PMID- 27484084 TI - ClpP-deletion impairs the virulence of Legionella pneumophila and the optimal translocation of effector proteins. AB - BACKGROUND: The opportunistic bacterial pathogen Legionella pneumophila uses substrate effectors of Dot/Icm type IVB secretion system (T4BSS) to accomplish survival and replication in amoebae cells and mammalian alveolar macrophages. During the conversion between its highly resistant, infectious dormant form and vigorously growing, uninfectious replicative form, L. pneumophila utilizes a complicated regulatory network in which proteolysis may play a significant role. As a highly conserved core protease, ClpP is involved in various cellular processes as well as virulence in bacteria, and has been proved to be required for the expression of transmission traits and cell division of L. pneumophila. RESULTS: The clpP-deficient L. pneumophila strain failed to replicate and was digested in the first 3 h post-infection in mammalian cells J774A.1. Further investigation demonstrates that the clpP deficient mutant strain was unable to escape the endosome-lysosomal pathway in host cells. We also found that the clpP deficient mutant strain still expresses T4BSS components, induces contact dependent cytotoxicity and translocate effector proteins RalF and LegK2, indicating that its T4BSS was overall functional. Interestingly, we further found that the translocation of several effector proteins is significantly reduced without ClpP. CONCLUSIONS: The data indicate that ClpP plays an important role in regulating the virulence and effector translocation of Legionella pneumophila. PMID- 27484086 TI - Risk factors and spatial distribution of extended spectrum beta-lactamase producing- Escherichia coli at retail poultry meat markets in Malaysia: a cross sectional study. AB - BACKGROUND: The significant role of retail poultry meat as an important exposure pathway for the acquisition and transmission of extended spectrum beta-lactamase producing Escherichia coli (ESBL-EC) into the human population warrants understanding concerning those operational practices associated with dissemination of ESBL-EC in poultry meat retailing. Hence, the objective of this study was to determine the prevalence, spatial distribution and potential risk factors associated with the dissemination of ESBL-EC in poultry meat retail at wet-markets in Selangor, Malaysia. METHODS: Poultry meat (breast, wing, thigh, and keel) as well as the contact surfaces of weighing scales and cutting boards were sampled to detect ESBL-EC by using culture and disk combination methods and polymerase chain reaction assays. Besides, questionnaire was used to obtain data and information pertaining to those operational practices that may possibly explain the occurrence of ESBL-EC. The data were analysed using logistic regression analysis at 95 % CI. RESULTS: The overall prevalence of ESBL-EC was 48.8 % (95 % CI, 42 - 55 %). Among the risk factors that were explored, type of countertop, sanitation of the stall environment, source of cleaning water, and type of cutting board were found to be significantly associated with the presence of ESBL-EC. CONCLUSIONS: Thus, in order to prevent or reduce the presence of ESBL EC and other contaminants at the retail-outlet, there is a need to design a process control system based on the current prevailing practices in order to reduce cross contamination, as well as to improve food safety and consumer health. PMID- 27484087 TI - Appraisal of clinical practice guidelines on community-acquired pneumonia in children with AGREE II instrument. AB - BACKGROUND: Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality worldwide among children. The growing number of guidelines have been accompanied with a growing concern about variance and conflicts among guideline recommendations. There is a need to critically appraise clinical practice guidelines (CPGs) in order to ensure safe and effective practices. METHODS: A literature search was systematically conducted in English and Chinese major academic databases (from January 2000 to March 2015). CPGs related to CAP in children were evaluated by four independent assessors, according to AGREE II instruments. Standardized domain scores were calculated for each guideline. Inter rater reliability was assessed by intraclass correlation coefficient. The software used for analysis was SPSS 17.0. RESULTS: A total of 10 guidelines met the inclusion criteria and were appraised. Scope and purpose (69.03 %) and clarity of presentation (83.33 %) achieved relative high scores, while the scores of the other four domains were low: stakeholder involvement (42.78 %), rigour of development (44.95 %), applicability (37.60 %), and editorial independence (23.74 %). 3 guidelines were strongly recommended as a result of the overall scores were greater than 60 %. CONCLUSION: The qualities of CPGs for CAP in children were generally acceptable with several flaws. Stakeholder involvement, rigour of development, applicability and editorial independence should be considered and well described in the future development of CPGs. PMID- 27484088 TI - The efficacy of sound regulations on the listening levels of pop concerts. AB - This analysis of new and previously collected data was done to validate the efficacy of recommendations for limits regarding sound exposure levels at live pop concerts. After the World Health Organization (WHO) recommended limiting the sound levels at such concerts to avoid noise induced hearing damage among the audience, the actual levels at concerts where these recommendations are observed, have stabilized around 100 dBA. This is a level that is considered acceptable by WHO. At concerts where there are no limitations, however, the sound levels in the audience area are still increasing far beyond safe limits and thus the exposure may represent a serious threat to people's hearing. PMID- 27484089 TI - The success of the Uttarakhand Cluster: a case study of organisational change towards disability inclusive development. AB - BACKGROUND: Persons with disability are often marginalised and excluded from international development efforts. This case study reviews the success of Uttarakhand Cluster of development NGOs in changing organisational behaviour towards being disability inclusive in their development (DID) activities. METHODS: A triangulation of qualitative research methods was used, including key informant interviews, focus group discussions and review of textual data. RESULTS: The results synthesise data into Kotter's framework for organisational change, explaining the different stages of change experienced by the Cluster as it moved towards DID. Development of a disability mission, sharing of capacity and resources, and presence of disability champions were key in the organisations' transition towards DID. CONCLUSION: This case study demonstrates that the Cluster, a low - cost network, was able to drive organisational change and promote DID. PMID- 27484090 TI - Factor structure and psychometric properties of Chinese version of Beck Anxiety Inventory in Chinese doctors. AB - This study analyses the factor structure and psychometric properties of the Chinese version of Beck Anxiety Inventory on Chinese doctors. Participants include 762 doctors sampled in 18 public hospitals in three cities in Eastern China. Exploratory factor analysis is employed to identify the potential factor structure of the inventory. Confirmatory factor analysis is referred to for model fit. The results indicate that the Chinese version of Beck Anxiety Inventory has satisfactory reliability and validity, but its factor structure is unstable and has great differences compared with international versions. Naming the four extracted factors is difficult. In general, the Chinese version of Beck Anxiety Inventory is appropriate for Chinese doctors and can be used as a good screener to detect the anxiety of Chinese doctors. PMID- 27484091 TI - A closer look at school bonding among African American adolescents in low-income communities: A latent class analysis. AB - Positive school bonding is a significant precursor to students' school success. However, African American youth report lower school success compared with their White counterparts. This study examined correlates of school bonding among 633 African American youth who were recruited from community settings in Chicago. Major findings indicated that negative peer norms, exposure to community violence, and poor mental health were negatively correlated with school bonding, while parental monitoring, positive self-regard, and future orientation were correlated with higher school motivation. Students classified as having high or moderate school bonding were more likely to live with both parents, experience higher levels of parental monitoring, and exhibit positive self-regard. Implications are discussed in view of these findings. PMID- 27484092 TI - Resilience and hope during advanced disease: a pilot study with metastatic colorectal cancer patients. AB - BACKGROUND: The balance between hope-hopelessness plays an important role in the way terminally ill patients report quality of life, and personal resilience may be related to hope at the end of life. The objective of this study was to explore associations between personal resilience, hope, and other possible predictors of hope in advanced cancer patients. METHODS: A cross-sectional pilot study was carried out with metastatic colorectal cancer patients in a tertiary hospital. The patients answered the Connor-Davidson Resilience Scale, Herth Hope Index, Barthel Index, an instrument addressing family and social support, visual-numeric scales for pain and suffering, a two-item screening for depression, socio demographic and socio-economic information about the family. RESULTS: Forty-four patients were interviewed (mean age 56 years; range 29-86). A strong correlation was noted between resilience and hope (0.63; p < 0.05). No correlation was found between hope and independence for activities of daily living, support from family and community, and pain and suffering levels. Of the 44 patients, 20 presented with depressive symptoms. These depressive patients had lower resilience (p = 0.005) and hope (p = 0.003), and higher scores of suffering (p < 0.001). The association between resilience and hope kept stable after adjusting for age, gender, and presence of depression (p < 0.001). CONCLUSION: Given that resilience is a dynamic, changeable path that can improve hope, resilience-fostering interventions should be most valued in palliative care settings and should be commenced as soon as possible with cancer patients. Patients with advanced stages of non-malignant conditions would also probably benefit from such interventions. PMID- 27484093 TI - The clinical significance of forkhead box protein A1 and its role in colorectal cancer. AB - Forkhead box protein A1 (FOXA1) is a transcription factor; recent studies have reported that FOXA1 has an oncogenic or tumor suppressive role in human malignancies, and its expression is associated with the prognosis of patients with cancer. However, further studies are required to determine the clinical significance of FOXA1 and its role in colorectal cancer (CRC). In the present study, FOXA1 expression was detected in 90 samples of CRC tissues and matched noncancerous tissues using immunohistochemistry. In these cases, FOXA1 expression was detected in 57.8% (52/90) of the CRC samples, whereas only 37.8% (34/90) of the noncancerous specimens exhibited a positive FOXA1 signal. In addition, the present study demonstrated that the mRNA expression levels of FOXA1 were significantly increased in CRC tissues compared with in matched tumor-adjacent tissues. Furthermore, the positive expression of FOXA1 was associated with poor clinicopathological characteristics of CRC, including poor tumor differentiation, large tumor size, lymph node metastases and advanced tumor-node-metastasis tumor stage. Notably, patients with CRC with positive FOXA1 expression exhibited a significantly reduced 5-year survival rate compared with those with negative FOXA1 expression. Multivariate Cox regression analysis revealed that FOXA1 expression was an independent prognostic indicator for patients with CRC. In addition, FOXA1 knockdown evidently inhibited cell proliferation and induced apoptosis in SW480 and HCT116 CRC cells. Notably, FOXA1 knockdown also prominently reduced the expression of yes-associated protein (YAP) in SW480 and HCT116 cells. In conclusion, the results of the present study indicated that FOXA1 may be considered a potential prognostic marker, and may promote tumor growth of CRC by upregulating YAP expression. PMID- 27484094 TI - Atorvastatin ameliorates endothelium-specific insulin resistance induced by high glucose combined with high insulin. AB - The aim of the present study was to establish an endothelial cell model of endothelium-specific insulin resistance to evaluate the effect of atorvastatin on insulin resistance-associated endothelial dysfunction and to identify the potential pathway responsible for its action. Cultured human umbilical vein endothelial cells (HUVECs) were pretreated with different concentrations of glucose with, or without, 10-5 M insulin for 24 h, following which the cells were treated with atorvastatin. The tyrosine phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1), the production of nitric oxide (NO), the activity and phosphorylation level of endothelial NO synthase (eNOS) on serine1177, and the mRNA levels of endothelin-1 (ET-1) were assessed during the experimental procedure. Treatment of the HUVECs with 30 mM glucose and 10-5 M insulin for 24 h impaired insulin signaling, with reductions in the tyrosine phosphorylation of IR and protein expression of IRS-1 by almost 75 and 65%, respectively. This, in turn, decreased the activity and phosphorylation of eNOS on serine1177, and reduced the production of NO by almost 80%. By contrast, the mRNA levels of ET-1 were upregulated. All these changes were ameliorated by atorvastatin. Taken together, these results demonstrated that high concentrations of glucose and insulin impaired insulin signaling leading to endothelial dysfunction, and that atorvastatin ameliorated these changes, acting primarily through the phosphatidylinositol 3-kinase/Akt/eNOS signaling pathway. PMID- 27484096 TI - Reduced Mucosa-associated Butyricicoccus Activity in Patients with Ulcerative Colitis Correlates with Aberrant Claudin-1 Expression. AB - BACKGROUND AND AIMS: Butyricicoccus is a butyrate-producing clostridial cluster IV genus whose numbers are reduced in the stool of ulcerative colitis [UC] patients. Conditioned medium of Butyricicoccus [B.] pullicaecorum prevents tumour necrosis factor alpha [TNFalpha]-induced increase in epithelial permeability in vitro. Since butyrate influences intestinal barrier integrity, we further investigated the relationship between the abundance of mucosa-associated Butyricicoccus and the expression of butyrate-regulated tight junction [TJ] genes. METHODS: Tight junction protein 1 [TJP1], occludin [OCLN], claudin-1 [CLDN1], and Butyricicoccus 16S rRNA expression was analysed in a collection of colonic biopsies of healthy controls and UC patients with active disease. The effect of butyrate and B. pullicaecorum conditioned medium on TJ gene expression was investigated in TNFalpha-stimulated Caco-2 monolayers and inflamed mucosal biopsies of UC patients. RESULTS: TJP1 expression was significantly decreased in inflamed UC mucosa, whereas CLDN1 mRNA levels were increased. OCLN did not differ significantly between the groups. Mucosa-associated Butyricicoccus 16S rRNA transcripts were reduced in active UC patients compared with healthy controls. Interestingly, Butyricicoccus activity negatively correlated with CLDN1 expression. Butyrate reversed the inflammation-induced increase of CLDN1 protein levels, and stimulation of inflamed UC biopsies with B. pullicaecorum conditioned medium normalized CLDN1 mRNA levels. CONCLUSIONS: Butyricicoccus is a mucosa associated bacterial genus under-represented in colonic mucosa of patients with active UC, whose activity inversely correlates with CLDN1 expression. Butyrate and B. pullicaecorum conditioned medium reduce CLDN1 expression, supporting its use as a pharmabiotic preserving epithelial TJ integrity. PMID- 27484095 TI - Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer. AB - BACKGROUND: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. METHODS: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. RESULTS: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. CONCLUSIONS: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC. PMID- 27484097 TI - Phase 1 Clinical Study of siRNA Targeting Carbohydrate Sulphotransferase 15 in Crohn's Disease Patients with Active Mucosal Lesions. AB - BACKGROUND AND AIMS: Carbohydrate sulphotransferase 15 [CHST15] is a specific enzyme biosynthesizing chondroitin sulphate E that binds various pathogenic mediators and is known to create local fibrotic lesions. We evaluated the safety of STNM01, a synthetic double-stranded RNA oligonucleotide directed against CHST15, in Crohn's disease [CD] patients whose mucosal lesions were refractory to conventional therapy. METHODS: This was a randomized, double-blind, placebo controlled, concentration-escalation study of STNM01 by a single-dose endoscopic submucosal injection in 18 CD patients. Cohorts of increasing concentration of STNM01 were enrolled sequentially as 2.5nM [n = 3], 25nM [n = 3], and 250nM [n = 3] were applied. A cohort of placebo [n = 3] was included in each concentration. Safety was monitored for 30 days. Pharmacokinetics was monitored for 24h. The changes from baseline in the segmental Simple Endoscopic Score for CD [SES-CD] as well as the histological fibrosis score were evaluated. RESULTS: STNM01 was well tolerated and showed no drug-related adverse effects in any cohort of treated patients. There were no detectable plasma concentrations of STNM01 at all measured time points in all treatment groups. Seven of nine subjects who received STNM01 showed reduction in segmental SES-CD at Day 30, when compared with those who received placebo. Histological analyses of biopsy specimens revealed that STNM01 reduced the extent of fibrosis. CONCLUSION: Local application of STNM01 is safe and well tolerated in CD patients with active mucosal lesions. PMID- 27484098 TI - A case of IgG4-related hepatic inflammatory pseudotumor replaced by an abscess after steroid treatment. AB - BACKGROUND: Hepatic inflammatory pseudotumor (IPT) is a rare disease which often mimics a malignant tumor and is therefore often misdiagnosed and surgically resected. Recently, a concept of IgG4-related diseases (IgG4-RD) has been proposed that is becoming widely recognized and includes IgG4-related hepatic IPT. Corticosteroids are widely accepted as the standard treatment. CASE PRESENTATION: A 72-year-old Japanese man, who had been followed for ten years after surgery and chemotherapy for treatment of hilar and lower bile duct cancers, developed intermittent fever and abdominal pain and visited this hospital. Blood examinations revealed an inflammatory reaction, worsened glucose intolerance, and an increased level of serum IgG4 (137 mg/dL). Computed tomography (CT) revealed a 5 cm-sized mass in hepatic segment 7. Because of his cancer history, not only was a benign mass suspected, but there was also the possibility of a recurrent biliary malignancy. Liver biopsy was performed and the histology met the criteria for IgG4-related IPT. Corticosteroid therapy was initiated and his symptoms quickly resolved. However, two months later, a repeat CT demonstrated that the hepatic mass had been replaced by an abscess. The abscess was initially refractory, despite tapering corticosteroid treatment, controlling diabetes by intensive insulin therapy, administration of antibiotics, and percutaneous abscess drainage. Finally, after six months, the condition resolved. CONCLUSION: The diagnosis of hepatic IPT is sometimes difficult. To differentiate it from a malignant tumor, histological examination is necessary. Although corticosteroids are recognized as the standard therapy, unexpected and critical complications can develop in cases of IgG4-related hepatic IPT. PMID- 27484099 TI - Contents of Ag and other metals in food-contact plastics with nanosilver or Ag ion and their migration into food simulants. AB - Six nanosilver-labelled products and five silver ion (Ag(+))-labelled products were investigated to measure the migration of Ag from food-contact plastics, including nanosilver into various food simulants. The products were obtained in Japanese markets in 2012. Zinc (Zn), another major antimicrobial agent, and three harmful metals, cadmium (Cd), lead (Pb) and arsenic (As), were also examined. Ag and Zn were detected in all six nanosilver products at concentrations of 21-200 and 8.4-140 mg kg(-1), respectively. These metals were also detected in all five Ag(+) products at the same level as nanosilver products. Cd, Pb and As were not detected in any sample. Migrations of Ag and Zn were highest in 4% acetic acid, but also observed in water and 20% ethanol. Big differences were not observed in the migration ratio between nanosilver products and Ag(+) products. The ultrafiltration experiments suggested that the Ag that migrated from nanosilver products into 4% acetic acid was in its ionic form, while that into water and 20% ethanol was in its nanoparticle form. PMID- 27484100 TI - CT in ovarian cancer staging: how to review and report with emphasis on abdominal and pelvic disease for surgical planning. AB - CT of the abdomen and pelvis is the first line imaging modality for staging, selecting treatment options and assessing disease response in ovarian cancer. The staging CT provides disease distribution, disease burden and is the imaging surrogate for surgico-pathological FIGO staging. Optimal cyto-reductive surgery offers patients' the best chance for disease control or cure, but sub-optimal resection confers no advantage over chemotherapy and adversely increases the risk of post surgical complications. Although there is extensive literature comparing performance of CT against laparoscopy and surgery, for the staging abdominal and pelvic CT, there are currently no accepted guidelines for interpretation or routinely used minimum data set templates for reporting these complex CT scans often with extensive radiological findings. This review provides a systematic approach for identifying the important radiological findings and highlighting important sites of disease within the abdomen and pelvis, which may alter or preclude surgery at presentation or after adjuvant chemotherapy. The distribution of sites and volume of disease can be used to categorize patients as suitable, probably suitable or not suitable for optimal cyto-reductive surgery. This categorization can potentially assist oncological surgeons and oncologists as a semi objective assessment tool useful for selecting patient treatment, streamlining multi disciplinary discussion and improving the reproducibility and correlation of CT with surgical findings. The review also highlights sites of disease and complications of ovarian cancer which should be included as part of the radiological report as these may require additional surgical input from non gynaecological surgeons or influence treatment selection. PMID- 27484101 TI - Creating Possible ... Aesthetically Engaging Life Amid Reminders of Our Mortality. PMID- 27484102 TI - The impact of uphill cycling and bicycle suspension on downhill performance during cross-country mountain biking. AB - Non-propulsive work demand has been linked to reduced energetic economy of cross country mountain biking. The purpose of this study was to determine mechanical, physiological and performance differences and observe economy while riding a downhill section of a cross-country course prior to and following the metabolic "load" of a climb at race pace under two conditions (hardtail and full suspension) expected to alter vibration damping mechanics. Participants completed 1 lap of the track incorporating the same downhill section twice, under two conditions (hardtail and full suspension). Performance was determined by time to complete overall lap and specific terrain sections. Power, cadence, heart rate and oxygen consumption were sampled and logged every second while triaxial accelerometers recorded accelerations (128 Hz) to quantify vibration. No differences between performance times (P = 0.65) or power outputs (P = 0.61) were observed while physiological demand of loaded downhill riding was significantly greater (P < 0.0001) than unloaded. Full suspension decreased total vibrations experienced (P < 0.01) but had no effect on performance (P = 0.97) or physiological (P > 0.05) measures. This study showed minimal advantage of a full suspension bike in our trial, with further investigations over a full race distance warranted. PMID- 27484103 TI - An integrated approach of network-based systems biology, molecular docking, and molecular dynamics approach to unravel the role of existing antiviral molecules against AIDS-associated cancer. AB - A serious challenge in cancer treatment is to reposition the activity of various already known drug candidates against cancer. There is a need to rewrite and systematically analyze the detailed mechanistic aspect of cellular networks to gain insight into the novel role played by various molecules. Most Human Immunodeficiency Virus infection-associated cancers are caused by oncogenic viruses like Human Papilloma Viruses and Epstein-Bar Virus. As the onset of AIDS associated cancers marks the severity of AIDS, there might be possible interconnections between the targets and mechanism of both the diseases. We have explored the possibility of certain antiviral compounds to act against major AIDS associated cancers: Kaposi's Sarcoma, Non-Hodgkin Lymphoma, and Cervical Cancer with the help of systems pharmacology approach that includes screening for targets and molecules through the construction of a series of drug-target and drug-target-diseases network. Two molecules (Calanolide A and Chaetochromin B) and the target "HRAS" were finally screened with the help of molecular docking and molecular dynamics simulation. The results provide novel antiviral molecules against HRAS target to treat AIDS defining cancers and an insight for understanding the pharmacological, therapeutic aspects of similar unexplored molecules against various cancers. PMID- 27484104 TI - NBR1-dependent selective autophagy is required for efficient cell-matrix adhesion site disassembly. AB - Macroautophagy/autophagy has classically been recognized for its vital role in supporting cellular survival during various stresses. However, emerging work has demonstrated that selective autophagy has an impact on diverse cell biological processes by mediating the degradation of various cellular contents during normal cellular homeostasis. We recently established that selective autophagy supports cell migration by promoting the turnover of integrin-based cell-matrix adhesion sites, or focal adhesions (FAs). The autophagy cargo receptor NBR1 acts as a critical mediator of this pathway by promoting targeting of autophagosomes to FAs, leading to their disassembly via the sequestration of FA proteins. Our results demonstrate FAs as a new cellular target for selective autophagy. PMID- 27484105 TI - Exaggerated phosphorylation of brain tau protein in CRH KO mice exposed to repeated immobilization stress. AB - Neuroendocrine and behavioral stress responses are orchestrated by corticotropin releasing hormone (CRH) and norepinephrine (NE) synthesizing neurons. Recent findings indicate that stress may promote development of neurofibrillary pathology in Alzheimer's disease. Therefore, we investigated relationships among stress, tau protein phosphorylation, and brain NE using wild-type (WT) and CRH knockout (CRH KO) mice. We assessed expression of phosphorylated tau (p-tau) at the PHF-1 epitope and NE concentrations in the locus coeruleus (LC), A1/C1 and A2/C2 catecholaminergic cell groups, hippocampus, amygdala, nucleus basalis magnocellularis, and frontal cortex of unstressed, singly stressed or repeatedly stressed mice. Moreover, gene expression and protein levels of tyrosine hydroxylase (TH) and CRH receptor mRNA were determined in the LC. Plasma corticosterone levels were also measured. Exposure to a single stress increases tau phosphorylation throughout the brain in WT mice when compared to singly stressed CRH KO animals. In contrast, repeatedly stressed CRH KO mice showed exaggerated tau phosphorylation relative to WT controls. We also observed differences in extent of tau phosphorylation between investigated structures, e.g. the LC and hippocampus. Moreover, CRH deficiency leads to different responses to stress in gene expression of TH, NE concentrations, CRH receptor mRNA, and plasma corticosterone levels. Our data indicate that CRH effects on tau phosphorylation are dependent on whether stress is single or repeated, and differs between brain regions. Our findings indicate that CRH attenuates mechanisms responsible for development of stress-induced tau neuropathology, particularly in conditions of chronic stress. However, the involvement of central catecholaminergic neurons in these mechanisms remains unclear and is in need of further investigation. PMID- 27484106 TI - Static and Functional Balance in Individuals With COPD: Comparison With Healthy Controls and Differences According to Sex and Disease Severity. AB - BACKGROUND: Studies have shown that individuals with COPD have impaired body balance, probably caused by the disease's multisystemic manifestations plus age related decline in balance, potentially increasing the risk of falling and its consequences. However, little is known about the profile of individuals with COPD who present balance impairments, especially related to sex and disease severity stages. The aim of this work was to compare static and functional balance between subjects with COPD and healthy controls and to check possible differences according to sex and degrees of disease severity. METHODS: Forty-seven subjects with COPD and 25 healthy controls were included in this study. Their static balance was assessed in one-legged stance using a force platform and functional balance with the Timed Up and Go test. Additionally, participants performed spirometry, the 6-min walk test and isometric quadriceps maximal voluntary contraction assessment. Disease severity was classified according to the Global Initiative for Obstructive Lung Disease stages and BODE (body mass index, air flow obstruction, dyspnea, and exercise capacity) scores. RESULTS: In comparison with healthy controls, subjects with COPD had worse static (center of pressure displacement area: 9.3 +/- 1.9 cm2 vs 11.6 +/- 4.0 cm2, respectively, P = .01) and functional balance (Timed Up and Go test: 8.5 +/- 1.3 s vs 10.3 +/- 1.8 s, respectively, P < .001). In the COPD group, men performed better in the Timed Up and Go test than women (9.8 +/- 1.2 s vs 10.9 +/- 2.2 s, respectively, P = .03), whereas women presented a better static balance in comparison with men for all parameters related to center of pressure (P < .005 for all). Disease severity did not affect any balance results. CONCLUSIONS: Individuals with COPD had worse static and functional balance in comparison with healthy controls. Sex can mediate these results, depending on the type of balance evaluation (force platform or functional test). Balance performance was similar among the groups classified according to disease severity. PMID- 27484107 TI - Impulse Oscillometry and Spirometry Small-Airway Parameters in Mild to Moderate Bronchiectasis. AB - BACKGROUND: Both impulse oscillometry and spirometry can reflect small-airway disorders. The objective of this work was to investigate the diagnostic value of impulse oscillometry and spirometry small-airway parameters and their correlation with radiology, disease severity, and sputum bacteriology in mild to moderate bronchiectasis (bronchiectasis severity index <9) and to validate these findings in sensitivity analyses (mild bronchiectasis). METHODS: We recruited 94 subjects with mild to moderate bronchiectasis and 26 healthy subjects. The diagnostic value of small-airway parameters was compared using the receiver operating characteristic curve. Chest high-resolution computed tomography (HRCT), impulse oscillometry measurement, spirometry, and sputum culture were performed. Correlation between small-airway parameters and clinical indices was determined, adjusting for age, sex, body mass index, and smoking history. Sensitivity analyses were repeated when excluding subjects with bronchiectasis severity index >=9 or HRCT score >=13. RESULTS: Impulse oscillometry and spirometry small-airway parameters could discriminate mild to moderate bronchiectasis from healthy subjects and correlated significantly with HRCT score and the number of bronchiectatic lobes and the bronchiectasis severity index (all P < .01). Small airway parameters were more aberrant in subjects with dyshomogeneity and cystic bronchiectasis but were independent of Pseudomonas aeruginosa isolation or the location of predominant bronchiectatic lobes. Spirometry, but not impulse oscillometry, small-airway parameters differed statistically between subjects with isolated peripheral-airway bronchiectasis and those with peripheral plus central-airway bronchiectasis (all P < .01). Subgroup analyses yielded similar findings, except for the lack of correlation between small-airway parameters and clinical parameters in subjects with HRCT score <=6. CONCLUSIONS: Impulse oscillometry and spirometry small-airway parameters have similar diagnostic value in reflecting peripheral-airway disorders and correlate with the HRCT scores, the bronchiectasis severity index, and the number of bronchiectatic lobes in mild to moderate bronchiectasis. Assessment of small-airway parameters should be incorporated in future lung function investigations in bronchiectasis. PMID- 27484108 TI - Rationale and Description of Right Ventricle-Protective Ventilation in ARDS. AB - Pulmonary vascular dysfunction is associated with ARDS and leads to increased right-ventricular afterload and eventually right-ventricular failure, also called acute cor pulmonale. Interest in acute cor pulmonale and its negative impact on outcome in patients with ARDS has grown in recent years. Right-ventricular function in these patients should be closely monitored, and this is helped by the widespread use of echocardiography in intensive care units. Because mechanical ventilation may worsen right-ventricular failure, the interaction between the lungs and the right ventricle appears to be a key factor in the ventilation strategy. In this review, a rationale for a right ventricle-protective ventilation approach is provided, and such a strategy is described, including the reduction of lung stress (ie, the limitation of plateau pressure and driving pressure), the reduction of PaCO2 , and the improvement of oxygenation. Prone positioning seems to be a crucial part of this strategy by protecting both the lungs and the right ventricle, resulting in increased survival of patients with ARDS. Further studies are required to validate the positive impact on prognosis of right ventricle-protective mechanical ventilation. PMID- 27484109 TI - Modalities and Complications Associated With the Use of High-Flow Nasal Cannula: Experience in a Pediatric ICU. AB - BACKGROUND: High-flow nasal cannula (HFNC) therapy is increasingly used in pediatric ICUs as an intermediate level of support between conventional oxygen delivery and noninvasive ventilation (NIV). The safety of HFNC has seldom been studied, and some cases of barotrauma have been reported. This retrospective study aims to describe HFNC use in a tertiary care pediatric ICU, with a focus on the complications associated with this therapy. METHODS: Between January 2013 and January 2014, all children <18 y old treated with HFNC in the pediatric ICU were included. Demographic data, HFNC settings, chest radiograph reports, and blood gas values were gathered from the electronic medical records. Episodes of pneumothorax, pneumomediastinum, and significant epistaxis were noted. Pneumothorax was distinguished from chest tube-related air leak (frequent after cardiac surgery), which was defined as a small pneumothorax with no clinical impact that resolved spontaneously after chest tube removal. RESULTS: During the 1-y study period, there were 177 HFNC episodes, involving 145 subjects with a median (interquartile range) age of 8 (2-28) months. HFNC was used as primary support in 31% of episodes, after extubation in 36% and after NIV in 18%. HFNC was administered exclusively for nitric oxide delivery in 16% of episodes. Two children (1%) developed new pneumothoraces that required chest tube insertion, whereas 5 (3%) chest tube-related air leaks were noted. One (0.6%) episode of significant epistaxis was noted. Among 6 preexisting pneumothoraces, none worsened under HFNC. Failure of HFNC occurred in 32 episodes, requiring transition to NIV in 28 cases and endotracheal intubation in 5 cases. CONCLUSIONS: Support with HFNC following a clinical protocol in pediatric ICUs was associated with a relatively low rate of complications. Since HFNC use is increasing, further evidence is needed to confirm its efficacy and safety. PMID- 27484110 TI - Silica Exposure and Effect on Peak Expiratory Flow: Slate Pencil Workers' Study. AB - BACKGROUND: Peak expiratory flow (PEF) is a spirometric test that detects obstructive changes in the respiratory tract; has good correlation with the FEV1; and is much less expensive, simpler, and easier to perform under field conditions than FEV1. Chronic silicosis is also known to have obstructive features in advanced stages. Thus, this study was performed to assess the effect of silica exposure on PEF and the factors related to it. METHODS: The present study was carried out among 193 slate pencil cutting workers of Multanpura village of Madhya Pradesh, India. An interview technique was used to record demographic characteristics and occupational history on a predesigned form, which included a questionnaire regarding occupational history and silica-related respiratory morbidities. This was followed by a complete medical examination and measurement of PEF using a spirometer. RESULTS: The mean age was 43.35 +/- 11.31 y, and the mean duration of exposure was 18.72 +/- 9.33 y. In the present study, PEF was found to be significantly reduced in those age >=40 y, those who were female, those having duration of exposure >10 y, and those having respiratory morbidity, whereas the reduction in PEF was statistically nonsignificant for smokers. CONCLUSIONS: Higher age, female sex, higher duration of exposure, and respiratory morbidity were found to be important correlates of PEF. PMID- 27484111 TI - A neural substrate for object permanence in monkey inferotemporal cortex. AB - We take it for granted that objects continue to exist after being occluded. This knowledge - known as object permanence - is present even in childhood, but its neural basis is not fully understood. Here, we show that monkey inferior temporal (IT) neurons carry potential signals of object permanence even in animals that received no explicit behavioral training. We compared two conditions with identical visual stimulation: the same object emerged from behind an occluder as expected following its occlusion, or unexpectedly after occlusion of a different object. Some neurons produced a larger (surprise) signal when the object emerged unexpectedly, whereas other neurons produced a larger (match) signal when the object reappeared as expected. Neurons carrying match signals also reinstated selective delay period activity just before the object emerged. Thus, signals related to object permanence are present in IT neurons and may arise through an interplay of memory and match computations. PMID- 27484112 TI - The Thyroid Hormone Receptors Inhibit Hepatic Interleukin-6 Signaling During Endotoxemia. AB - Decreased thyroidal hormone production is found during lipopolysaccharide (LPS) induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-kappaB and ERK, which play a key role in the response to inflammatory cytokines during sepsis. TR knockout mice showed down-regulation of hepatic inflammatory mediators, including interleukin 6 (IL-6) in response to LPS. Paradoxically, STAT3 and ERK activity were higher, suggesting that TRs could act as endogenous repressors of these pathways. Furthermore, hyperthyroidism increased cytokine production and mortality in response to LPS, despite decreasing hepatic STAT3 and ERK activity. This suggested that TRs could directly repress the response of the cells to inflammatory mediators. Indeed, we found that the thyroid hormone T3 suppresses IL-6 signalling in macrophages and hepatocarcinoma cells, inhibiting STAT3 activation. Consequently, the hormone strongly antagonizes IL-6-stimulated gene transcription, reducing STAT3 recruitment and histone acetylation at IL-6 target promoters. In conclusion, TRs are potent regulators of inflammatory responses and immune homeostasis during sepsis. Reduced responses to IL-6 should serve as a negative feedback mechanism for preventing deleterious effects of excessive hormone signaling during infections. PMID- 27484113 TI - High intensity focused ultrasound in the treatment of breast fibroadenomata: results of the HIFU-F trial. AB - OBJECTIVES: Breast fibroadenomata (FAD) are the most common breast lumps in women. High intensity focused ultrasound (HIFU) is a non-invasive ablative technique that can be used to treat FAD but is associated with prolonged treatment times. In the HIFU-F trial, we evaluated the change in volume over time with circumferential HIFU treatment of FAD and compared this to no treatment. METHODS: Patients >=18 years, diagnosed with symptomatic, palpable FAD, visible on ultrasound (US) were recruited. Twenty patients were treated using US-guided HIFU under local anaesthesia. Another 20 participants underwent an US 6 months after diagnosis. Outcome measures included: reduction in treatment time compared to whole lesion ablation; feasibility to achieve a 50% reduction in volume after 6 months; decrease in volume compared to a control group and reduction in symptoms. RESULTS: Circumferential ablation reduced the mean treatment time by 37.5% (SD 20.1%) compared to whole lesion ablation. US demonstrated a significant mean reduction in FAD volume of 43.5% (SD 38.8%; p = 0.016, paired t-test) in the HIFU group compared to 4.6% (SD 46.0%; p = 0.530) in the control group after 6 months. This mean reduction in FAD volume between the two groups was significant in favour of the HIFU group (p = 0.002, grouped t-test). Pre-treatment pain completely resolved in 6 out of 8 patients 6 months post-treatment. CONCLUSION: Circumferential HIFU ablation of FAD is feasible, with a significant reduction in pain and volume compared to control participants. It provides a simple, non invasive, outpatient-based alternative to surgical excision for FAD. PMID- 27484114 TI - Polydopamine Thin Films as Protein Linker Layer for Sensitive Detection of Interleukin-6 by Surface Plasmon Enhanced Fluorescence Spectroscopy. AB - Polydopamine (PDA) thin films are introduced to the surface modification of biosensor surfaces utilizing surface plasmon enhanced fluorescence spectroscopy (SPFS) as the linker layer of capture antibody on to the sensor surfaces. The capture antibody can be directly attached to the sensor surface without using any coupling agent by functionalizing the gold sensor surface with PDA thin films. The PDA coating is performed by a single-step preparation process by applying the dopamine solution on the sensor surface, which requires an extremely short incubation time (10 min). The real-time in situ measurement of the adsorption kinetics of the capture antibody onto the PDA-coated sensor surface is studied by surface plasmon resonance (SPR) spectroscopy. It reveals that the immobilization of capture antibody immediately occurs after introduction of a solution containing capture antibody, and the sensor surface is fully covered with the capture antibody. The sensitive detection of the cytokine marker interleukin-6 (IL-6) is performed by SPFS using a sandwich assay format with fluorescently labeled detection antibody. The sensor chips functionalized by PDA chemistry exhibited sensitive sensor responses with low nonspecific adsorption of the detection antibody onto the sensor surface. The detection limit of IL-6 with the developed SPFS biosensor is determined to be 2 pg/mL (100 fM), which is within the range of the diagnostic criteria. Our observation elucidates the remarkable utility of PDA coatings for chemical modification of the metallic sensor surfaces by a simple, brief, and inexpensive manner. PMID- 27484116 TI - Peripheral KATP activation inhibits pain sensitization induced by skin/muscle incision and retraction via the nuclear factor-kappaB/c-Jun N-terminal kinase signaling pathway. AB - The aim of the current study was to assess the effect of pinacidil activation of ATP-sensitive potassium (KATP) channels prior to skin/muscle incision and retraction (SMIR) surgery on peripheral and central sensitization, and investigate molecular interferential targets for preventive analgesia. Male Sprague-Dawley rats were randomly assigned to one of the following five groups: Control, incision (sham surgery), incision plus retraction (SMIR) group, SMIR plus pinacidil (pinacidil) group and the SMIR plus pyrrolidine dithiocarbamate (PDTC) group. The rats in the pinacidil and PDTC groups were intraperitoneally injected with pinacidil or PDTC, respectively, prior to the SMIR procedure. The mechanical withdrawal threshold (MWT) was determined. Western blotting was performed to detect the alterations in the subunits of the KATP channels, Kir6.1 and SUR2, levels of nuclear factor-kappaB (NF-kappaB) in the tissue around the incision and c-Jun N-terminal kinase (JNK) in the spinal cord. There was a significant increase observed in the levels of NF-kappaB and JNK following SMIR surgery compared with the control group, and a significant reduction in MWT and the levels of Kir6.1 and SUR2. Additionally, intraperitoneal administration of pinacidil inhibited the reduction in MWT, and Kir6.1 and SUR2 levels. SMIR was observed to result in increases in the levels of NF-kappaB and JNK. In addition, in the PDTC group, the alterations in MWT, NF-kappaB, JNK, Kir6.1 and SUR2 resulting from SMIR were blocked. The results of the current study suggest that the deteriorations in the microenvironment resulting from the SMIR procedure can induce peripheral and central sensitization, and that the activation of peripheral KATP by pinacidil prior to SMIR is able to inhibit peripheral and central sensitization via the NF-kappaB/JNK signaling pathway, thus resulting in preventive analgesia. PMID- 27484115 TI - Osteopontin Deficiency Alters Biliary Homeostasis and Protects against Gallstone Formation. AB - The precipitation of excess biliary cholesterol as solid crystals is a prerequisite for cholesterol gallstone formation, which occurs due to disturbed biliary homeostasis. Biliary homeostasis is regulated by an elaborate network of genes in hepatocytes. If unmanaged, the cholesterol crystals will aggregate, fuse and form gallstones. We have previously observed that the levels of osteopontin (OPN) in bile and gallbladder were reduced in gallstone patients. However, the role and mechanism for hepatic OPN in cholesterol gallstone formation is undetermined. In this study, we found that the expression of hepatic OPN was increased in gallstone patients compared with gallstone-free counterparts. Then, we observed that OPN-deficient mice were less vulnerable to cholesterol gallstone formation than wild type mice. Further mechanistic studies revealed that this protective effect was associated with alterations of bile composition and was caused by the increased hepatic CYP7A1 expression and the reduced expression of hepatic SHP, ATP8B1, SR-B1 and SREBP-2. Finally, the correlations between the expression of hepatic OPN and the expression of these hepatic genes were validated in gallstone patients. Taken together, our findings reveal that hepatic OPN contributes to cholesterol gallstone formation by regulating biliary metabolism and might be developed as a therapeutic target for gallstone treatments. PMID- 27484117 TI - EDITORIAL: Chemodescriptor Based QSARs of Structurally Homogeneous Versus Heterogeneous Chemical Data Sets: Some Comments on the Congenericity Principle vis-a-vis Diversity Begets Diversity Principle. PMID- 27484118 TI - Molecular Dynamics Simulation Reveal the Mechanism of Resistance of Mutant Actins to Latrunculin A - Insight into Specific Modifications to Design Novel Drugs to Overcome Resistance. AB - BACKGROUND: Mutant actins D157E and R183A-D184A are reported to resist the anticancer drug Latrunculin A (LAT); though identified, the mechanism of resistance is not clearly understood. OBJECTIVE: To design better molecules that can overcome the resistance caused by mutations it is important to define precise pharmacophoric regions in LAT based on the mechanism of resistance on the mutant actin -LAT interactions. METHODS: To address this we have conducted 20 nano seconds (ns) simulation of mutant actins - LAT complex and compared it with the 20ns simulation of wild actin - LAT complex. Functions as the binding free energy, distance between LAT and binding site residues, LAT and actin domains, dihedral angle analysis, motional correlation were studied of these simulations. RESULTS: Grounded on these studies, four sites in LAT are identified to be crucial for modification. Bulkier ring moieties containing nitrogen in place of the double bonded oxygen in the macrocyclic lactone ring may be considered to establish interactions with Glu214. The nitrogen in 2-thiazolidinone moiety can be substituted with a hydrophobic ring to stabilise the interaction with the Asp157Glu and the oxygen in the cyclohexane of LAT with hydrophilic groups to strengthen their interaction with Tyr69. The nitrogen of the 2-thiazolidinone moiety can be replaced with nitrogen containing rings to improve inhibition of the actin polymerisation. Apart from this chemical groups on the sulphur of 2 thiazolidinone moiety to improve the hydrophobic interaction with actin is also identified for modification. CONCLUSION: Based on this a combinatorial library of 46 LAT analogs was generated and docked with the wild and mutant actins to identify potent leads to become anti-actin anticancer drugs. PMID- 27484119 TI - Biological sex identification in the endangered dusky gopher frog (Lithobates sevosa): a comparison of body size measurements, secondary sex characteristics, ultrasound imaging, and urinary hormone analysis methods. AB - BACKGROUND: Accurate sex identification techniques are important for wildlife demographic studies and for genetic management of captive breeding colonies. Various non-invasive methods for identification of biological sex in the weakly dimorphic endangered dusky gopher frog (DGF; Lithobates sevosa) were explored to support planned recovery efforts for this species including breeding and augmentation of wild populations. METHODS: Body size (snout-vent length and body weight) measurements, observation of nuptial pads, ultrasound imaging, and urinary hormone analysis for testosterone and estrone were performed on 27 male and 19 female DGFs. For each method, the mean and range of measurement values were determined for male and female DGFs housed in a captive breeding population. The ability of these methods to accurately predict the true biological sex of the individuals was assessed retrospectively. RESULTS: Body size measurements were of limited use for sex identification purposes, as males and females demonstrated overlapping body lengths and weights. Observation of the presence/absence of nuptial pads in males and females, respectively, proved to be accurate and easy to perform in most cases. Ultrasound imaging was useful for predicting the sex of female frogs, particularly when females were gravid. Commercial enzyme immunoassay kits were validated to measure urinary hormones in the DGF. Mean urinary testosterone (males: 2.22 +/- 0.38 ng/ml; females: 0.92 +/- 0.11 ng/ml) and estrone (males: 0.08 +/- 0.01 ng/ml; females: 1.50 +/- 0.39 ng/ml) concentrations were significantly (p < 0.05) different between the sexes. However, there was some overlap in hormone concentrations between the sexes. When a ratio of testosterone (T) to estrone (E) concentrations was calculated for each individual, males demonstrated significantly greater T/E ratios compared to females (p < 0.05). Use of this ratio showed greater accuracy in predicting the sex of the animal compared to using testosterone or estrone concentrations alone. CONCLUSIONS: Monitoring for presence/absence of nuptial pads and using urinary testosterone to estrone hormone ratios were the most accurate methods for identifying the biological sex of adult DGFs. Urinary hormone measurements for sex identification may be useful in other weakly dimorphic and monomorphic amphibian species in both ex situ and in situ settings. PMID- 27484120 TI - Genetic and pathogenic difference between Streptococcus agalactiae serotype Ia fish and human isolates. AB - BACKGROUND: Streptococcus agalactiae (GBS) is a common pathogen to infect newborn, woman, the elderly, and immuno-compromised human and fish. 37 fish isolates and 554 human isolates of the GBS in 2007-2012 were investigated in serotypes, antibiotic susceptibility, genetic difference and pathogenicity to tilapia. RESULTS: PCR serotyping determined serotype Ia for all fish GBS isolates and only in 3.2 % (3-4.2 %) human isolates. For fish isolates, all consisted a plasmid less than 6 kb and belonged to ST7 type, which includes mainly pulsotypes I and Ia, with a difference in a deletion at the largest DNA fragment. These fish isolates were susceptible to all antimicrobials tested in 2007 and increased in non-susceptibility to penicillin, and resistance to clindamycin and ceftriaxone in 2011. Differing in pulsotype and lacking plasmid from fish isolates, human serotype Ia isolates were separated into eight pulsotypes II-IX. Main clone ST23 included pulsotypes II and IIa (50 %) and ST483 consisted of pulsotype III. Human serotype Ia isolates were all susceptible to ceftriaxone and penicillin and few were resistant to erythromycin, azithromycin, clindamycin, levofloxacin and moxifloxacine with the resistant rate of 20 % or less. Using tilapia to analyze the pathogenesis, fish isolates could cause more severe symptoms, including hemorrhage of the pectoral fin, hemorrhage of the gill, and viscous black and common scites, and mortality (>95 % for pulsotype I) than the human isolates (<30 %); however, the fish pulostype Ia isolate 912 with deletion caused less symptoms and the lowest mortality (<50 %) than pulsotype I isolates. CONCLUSION: Genetic, pathogenic, and antimicrobial differences demonstrate diverse origin of human and fish serotype Ia isolates. The pulsotype Ia of fish serotype Ia isolates may be used as vaccine strains to prevent the GBS infection in fish. PMID- 27484121 TI - Hemolytic anemia caused by aortic flap and inversion of felt strip after ascending aorta replacement. AB - BACKGROUNDS: Hemolysis related to a kinked prosthetic graft or inner felt strip is a very rare complication after aortic surgery. We describe herein a case of hemolytic anemia that developed due to aortic flap of the dissection and inversion of an inner felt strip that was applied at the proximal anastomosis of a replaced ascending aorta 10 years previously. CASE PRESENTATION: A 74-year-old woman presented with consistent hemolytic anemia 10 years after replacement of the ascending aorta to treat Stanford type A acute aortic dissection. The cause of hemolysis was attributed to mechanical injury of red blood cells at a site of stenosis caused by aortic flap of the dissection and inversion of the felt strip used for the proximal anastomosis. Repeated resection of the strip and graft replacement of the ascending aorta resolved this problem. CONCLUSIONS: We considered that blood flow disrupted by a jet of blood at the site of the proximal inner felt strip was the cause of severe hemolysis, we describe rare hemolytic anemia at the site of aortic flap and inverted felt strip after replacement of the ascending aorta. PMID- 27484122 TI - Catestatin, vasostatin, cortisol, temperature, heart rate, respiratory rate, scores of the short form of the Glasgow composite measure pain scale and visual analog scale for stress and pain behavior in dogs before and after ovariohysterectomy. AB - BACKGROUND: The stress reaction induced by surgery and associated pain may be detrimental for patient recovery and should be minimized. The neuropeptide chromogranin A (CGA) has shown promise as a sensitive biomarker for stress in humans. Little is known about CGA and its derived peptides, catestatin (CST) and vasostatin (VS), in dogs undergoing surgery. The objectives of this study were to investigate and compare concentrations of CGA epitopes CST and VS, cortisol, body temperature, heart rate, respiratory rate, scores of the short form of the Glasgow composite measure pain scale (CMPS-SF) and visual analog scales (VAS) for stress and pain behavior in dogs before and after ovariohysterectomy. METHODS: Thirty healthy privately owned female dogs admitted for elective ovariohysterectomy were included. Physical examination, CMPS-SF, pain behavior VAS, and stress behavior VAS were recorded and saliva and blood samples were collected before surgery, 3 h after extubation, and once at recall 7-15 days after surgery. Dogs were premedicated with morphine and received carprofen as analgesia for 7 days during the postoperative period. RESULTS: At 3 h after extubation, CMPS-SF and pain behavior VAS scores had increased (p < 0.0001) and stress behavior VAS scores, temperature, respiratory rate (p < 0.0001), plasma CST concentrations (p = 0.002) had decreased significantly compared to before surgery. No significant differences were observed in the subjective and physiological parameters between before surgery and at recall, but plasma CST (p = 0.04) and serum cortisol (p = 0.009) were significantly lower at recall. Plasma VS, saliva CST, and heart rate did not differ significantly at any observed time. CONCLUSION: Study parameters for evaluating surgery-induced stress and pain changed in dogs subjected to ovariohysterectomy. To further evaluate CST and VS usefulness as pain biomarkers, studies on dogs in acute painful situations are warranted. PMID- 27484123 TI - What criteria do decision makers in Thailand use to set priorities for vaccine introduction? AB - BACKGROUND: There is a need to identify rational criteria and set priorities for vaccines. In Thailand, many licensed vaccines are being considering for introduction into the Expanded Program on Immunization; thus, the government has to make decisions about which vaccines should be adopted. This study aimed to set priorities for new vaccines and to facilitate decision analysis. METHODS: We used a best-worst scaling study for rank-ordering of vaccines. The candidate vaccines were determined by a set of criteria, including burden of disease, target age group, budget impact, side effect, effectiveness, severity of disease, and cost of vaccine. The criteria were identified from a literature review and by in depth, open-ended interviews with experts. The priority-setting model was conducted among three groups of stakeholders, including policy makers, healthcare professionals and healthcare administrators. The vaccine data were mapped and then calculated for the probability of selection. RESULTS: From the candidate vaccines, the probability of hepatitis B vaccine being selected by all respondents (96.67 %) was ranked first. This was followed, respectively, by pneumococcal conjugate vaccine-13 (95.09 %) and Haemophilus influenzae type b vaccine (90.87 %). The three groups of stakeholders (policy makers, healthcare professionals and healthcare administrators) showed the same ranking trends. Most severe disease, high fever rate and high disease burden showed the highest coefficients for criterion levels being selected by all respondents. This result can be implied that a vaccine which can prevent most severe disease with high disease burden and has low safety has a greater chance of being selected by respondents in this study. CONCLUSIONS: The priority setting of vaccines through a multiple-criteria approach could contribute to transparency and accountability in the decision-making process. This is a step forward in the development of an evidence-based approach that meets the need of developing country. The methodology is generalizable but its application to another country would require the criteria as relevant to that country. PMID- 27484124 TI - Measuring the burden of preventable diabetic hospitalisations in the Mexican Institute of Social Security (IMSS). AB - BACKGROUND: The prevalence of diabetes among adults in Mexico has increased markedly from 6.7 % in 1994 to 14.7 % in 2015. Although the main diabetic complications can be prevented or delayed with timely and effective primary care, a high percentage of diabetic patients have developed them imposing an important preventable burden on Mexican society and on the health system. This paper estimates the financial and health burden caused by potentially preventable hospitalisations due to diabetic complications in hospitals operated by the largest social security institution in Latin America, the Mexican Institute of Social Security (IMSS), in the period 2007-2014. METHODS: Hospitalisations in IMSS hospitals whose main cause was a diabetic complication were identified. The financial burden was estimated using IMSS diagnostic-related groups. To estimate the health burden, DALYs were computed under the assumption that patients would not have experienced complications if they had received timely and effective primary care. RESULTS: A total of 322,977 hospitalisations due to five diabetic complications were identified during the period studied, of which hospitalisations due to kidney failure and diabetic foot represent 78 %. The financial burden increased by 8.4 % in real terms between 2007 and 2014. However, when measured as cost per IMSS affiliate, it decreased by 11.3 %. The health burden had an overall decrease of 13.6 % and the associated DALYs in 2014 reached 103,688. CONCLUSIONS: Resources used for the hospital treatment of diabetic complications are then not available for other health care interventions. In order to prevent these hospitalisations more resources might need to be invested in primary care; the first step could be to consider the financial burden of these hospitalisations as a potential target for switching resources from hospital care to primary care services. However, more evidence of the effectiveness of different primary care interventions is needed to know how much of the burden could be prevented by better primary care. PMID- 27484125 TI - Placenta abruption surface and perinatal outcome. AB - OBJECTIVE: To identify the relationship between the placenta abruption (PA) surface and the perinatal outcome. METHODS: This prospective descriptive study was carried out from 1 February to 30 September 2014. We recruited all women whose delivery was complicated by PA with onset preceded by the presence of active fetal movement. PA surface was assessed by placental examination after delivery. Main outcome measures were gestational age, Apgar score, and location and percentage of PA. Data were analyzed using SPSS 17.0 Fisher's exact test was used for comparison. RESULTS: PA occurred in 47 women (1.3%). Mean gestational age was 36.0 weeks. PA percentages varied between 5% and 60%. Detachment >=45% was always associated with stillbirth and was significantly observed in central PA (p < 0.0002), while separation of 25-44% was associated with various degrees of neonatal asphyxia. Compared to marginal separation of the placenta, central separation was significantly associated with stillbirth (77.8% versus 10.5%, p < 0.0002) and perinatal death (88.9% versus 13.1%, p < 0.0001). CONCLUSION: PA surface >=45% was associated with stillbirth. This knowledge can be helpful in identifying the cause of stillbirth when PA is found. Central PA was significantly associated with poor perinatal outcome and PA surface >=45%. Therefore, its diagnosis calls for rapid intervention. PMID- 27484126 TI - Effectiveness and cost-utility of a guided self-help exercise program for patients treated with total laryngectomy: protocol of a multi-center randomized controlled trial. AB - BACKGROUND: Total laryngectomy with or without adjuvant (chemo)radiation often induces speech, swallowing and neck and shoulder problems. Speech, swallowing and shoulder exercises may prevent or diminish these problems. The aim of the present paper is to describe the study, which is designed to investigate the effectiveness and cost-utility of a guided self-help exercise program built into the application "In Tune without Cords" among patients treated with total laryngectomy. METHODS/DESIGN: Patients, up to 5 years earlier treated with total laryngectomy with or without (chemo)radiation will be recruited for participation in this study. Patients willing to participate will be randomized to the intervention or control group (1:1). Patients in the intervention group will be provided access to a guided self-help exercise program and a self-care education program built into the application "In Tune without Cords". Patients in the control group will only be provided access to the self-care education program. The primary outcome is the difference in swallowing quality (SWAL-QOL) between the intervention and control group. Secondary outcome measures address speech problems (SHI), shoulder disability (SDQ), quality of life (EORTC QLQ-C30, QLQ H&N35 and EQ-5D), direct and indirect costs (adjusted iMCQ and iPCQ measures) and self-management (PAM). Patients will be asked to complete these outcome measures at baseline, immediately after the intervention or control period (i.e. at 3 months follow-up) and at 6 months follow-up. DISCUSSION: This randomized controlled trial will provide knowledge on the effectiveness of a guided self help exercise program for patients treated with total laryngectomy. In addition, information on the value for money of such an exercise program will be provided. If this guided self-help program is (cost)effective for patients treated with total laryngectomy, the next step will be to implement this exercise program in current clinical practice. TRIAL REGISTRATION: NTR5255 Protocol version 4 date September 2015. PMID- 27484127 TI - Establishment of reference intervals of thyroid function tests from cord blood of neonates in two selected hospitals, Addis Ababa, Ethiopia. AB - BACKGROUND: Reference intervals are affected by different factors such as lifestyle, ethnicity, age/developmental stage, gender, nutrition and other environmental factors (Clin Biochem Rev: 29,2008). Therefore, it is obvious that it should be established for every population in different regions even within a country. Then the aim of this study is to establish population specific reference intervals of thyroid stimulating hormone, free thyroxine and free triidothyronine levels of cord blood. RESULTS: One hundred twenty three cord blood samples collected from the umbilical cord of newborns were analyzed for thyroid stimulating hormone, free thyroxine and free triidothyronine values. The birth weights ranged between 2500 and 4700 g with mean (SD) value of 3241.46 (459.495) gram. Their gestational age ranged between 37 and 44 weeks with an average of 39.74 weeks. The 2.5(th) and 97.5(th) percentiles of values were found to be 3.48 mIU/L and 27.57 mIU/L for thyroid stimulating hormone, 0.89 ng/dl and 1.53 ng/dl for free thyroxine and 1.19 pg/ml and 2.51 pg/ml for free triidothyronine respectively. CONCLUSION: In the present study the reference intervals of thyroid stimulating hormone, free thyroxine and free triidothyronine were established and based on the results obtained, were 3.48-27.56 mIU/L for thyroid stimulating hormone, 0.89-1.53 ng/dl for free thyroxine and 1.19-2.51 pg/ml for free triidothyronine. It has been concluded that the result can provide us with an important baseline to establish population specific reference intervals for our country using large scale studies. PMID- 27484128 TI - Pathogenic Differences between Nipah Virus Bangladesh and Malaysia Strains in Primates: Implications for Antibody Therapy. AB - Nipah virus (NiV) is a paramyxovirus that causes severe disease in humans and animals. There are two distinct strains of NiV, Malaysia (NiVM) and Bangladesh (NiVB). Differences in transmission patterns and mortality rates suggest that NiVB may be more pathogenic than NiVM. To investigate pathogenic differences between strains, 4 African green monkeys (AGM) were exposed to NiVM and 4 AGMs were exposed to NiVB. While NiVB was uniformly lethal, only 50% of NiVM-infected animals succumbed to infection. Histopathology of lungs and spleens from NiVB infected AGMs was significantly more severe than NiVM-infected animals. Importantly, a second study utilizing 11 AGMs showed that the therapeutic window for human monoclonal antibody m102.4, previously shown to rescue AGMs from NiVM infection, was much shorter in NiVB-infected AGMs. Together, these data show that NiVB is more pathogenic in AGMs under identical experimental conditions and suggests that postexposure treatments may need to be NiV strain specific for optimal efficacy. PMID- 27484130 TI - Current and future treatments of alopecia areata and trichotillomania in children. AB - INTRODUCTION: Treatment options for hair disorders are generally very limited. These options are even more limited in children due to the lack of trials and clinical research. Moreover, physicians are sometimes scared to treat children with drugs without safety data, especially because most hair disorders are benign. AREAS COVERED: The objective of this paper is to review current and future treatments for alopecia areata and trichotillomania, two disorders that are sometimes encountered in differential diagnosis or even occur together and probably affect the mental condition of the patient involved more than others. EXPERT OPINION: Hair disorders are very stressful in paediatric population. Both physicians and families are often unsatisfied leading to non-compliance. New drugs with less side- effects are needed to increase the percentage of cure. It is also crucial to refine genetic studies on alopecia areata in order to identify new potential drugs worth studying. Moreover, studies on trichotillomania should not be evaluated only by psychiatrics, but also by dermatologists. PMID- 27484129 TI - Increased CSF levels of aromatic amino acids in hip fracture patients with delirium suggests higher monoaminergic activity. AB - BACKGROUND: To examine whether delirium in hip fracture patients was associated with changes in the levels of amino acids and/or monoamine metabolites in cerebrospinal fluid (CSF) and serum. METHODS: In this prospective cohort study, 77 patients admitted with an acute hip fracture to Oslo University Hospital, Norway, were studied. The concentrations of amino acids in CSF and serum were determined by high performance liquid chromatography. The patients were assessed daily for delirium by the Confusion Assessment Method (pre-operatively and post operative day 1-5 (all) or until discharge (delirious patients)). Pre-fracture dementia status was decided by an expert panel. Serum was collected pre operatively and CSF immediately before spinal anesthesia. RESULTS: Fifty-three (71 %) hip fracture patients developed delirium. In hip fracture patients without dementia (n = 39), those with delirium had significantly higher CSF levels of tryptophan (40 % higher), tyrosine (60 % higher), phenylalanine (59 % higher) and the monoamine metabolite 5-hydroxyindoleacetate (23 % higher) compared to those without delirium. The same amino acids were also higher in CSF in delirious patients with dementia (n = 38). The correlations between serum and CSF amino acid levels were poor. CONCLUSION: Higher CSF levels of monoamine precursors in hip fracture patients with delirium suggest a higher monoaminergic activity in the central nervous system during delirium in this patient group. PMID- 27484131 TI - Analog filtering methods improve leading edge timing performance of multiplexed SiPMs. AB - Multiplexing many SiPMs to a single readout channel is an attractive option to reduce the readout complexity of high performance time of flight (TOF) PET systems. However, the additional dark counts and shaping from each SiPM cause significant baseline fluctuations in the output waveform, degrading timing measurements using a leading edge threshold. This work proposes the use of a simple analog filtering network to reduce the baseline fluctuations in highly multiplexed SiPM readouts. With 16 SiPMs multiplexed, the FWHM coincident timing resolution for single [Formula: see text] mm LYSO crystals was improved from 401 +/- 4 ps without filtering to 248 +/- 5 ps with filtering. With 4 SiPMs multiplexed, using an array of [Formula: see text] mm LFS crystals the mean time resolution was improved from 436 +/- 6 ps to 249 +/- 2 ps. Position information was acquired with a novel binary positioning network. All experiments were performed at room temperature with no active temperature regulation. These results show a promising technique for the construction of high performance multiplexed TOF PET readout systems using analog leading edge timing pickoff. PMID- 27484133 TI - 5th Norwegian Environmental Toxicology Symposium: Recognizing, understanding, and minimizing the impacts of human activity. PMID- 27484132 TI - Association between SKIV2L polymorphism rs429608 and age-related macular degeneration: A meta-analysis. AB - PURPOSE: This study was conducted to comprehensively evaluate the potential association of SKIV2L polymorphism rs429608 with age-related macular degeneration (AMD) through a meta-analysis. METHODS: We performed a literature search in EMBASE, PubMed, Web of Science, and the Chinese Biomedical Database for AMD genetic studies published before August 30, 2015. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for single-nucleotide polymorphisms (SNPs) using fixed-effect models or random effect models according to between-study heterogeneity. Publication bias analyses were conducted using Egger's test. RESULTS: A total of five studies from published articles were included, and a total number of 2789 AMD cases and 3451 healthy controls were tested in this meta-analysis. The results demonstrated that SKIV2L rs429608 is associated with AMD under allelic model (A vs. G; OR = 0.52, 95% CI 0.44-0.62, p < 0.001), heterozygous model (AG vs. GG; OR = 0.51; 95%CI, 0.38-0.68; p < 0.001; PQ = 0.48; I2 = 0) and dominant model (AA+AG vs. GG; OR = 0.49; 95%CI 0.37-0.65; p < 0.001; PQ = 0.44; I2 = 0), but not under other genetic models. CONCLUSIONS: This meta-analysis showed that SKIV2L rs429608 was statistically associated with AMD and it might exert a protective effect on AMD. Further investigations are needed to validate the association and confirm the role of SKIV2L in AMD. PMID- 27484134 TI - Lipid peroxidation and oxidative stress responses in juvenile salmon exposed to waterborne levels of the organophosphate compounds tris(2-butoxyethyl)- and tris(2-chloroethyl) phosphates. AB - There is limited knowledge on the toxicological, physiological, and molecular effects attributed to organophosphate (OP) compounds currently used as flame retardants or additives in consumer products. This study investigated the effects on oxidative stress and lipid peroxidation in juvenile Atlantic salmon liver and brain samples after exposure to two OP compounds, tris(2-butoxyethyl) phosphate (TBOEP) and tris(2-chloroethyl) phosphate (TCEP). In this study, groups of juvenile Atlantic salmon were exposed using a semistatic experimental protocol over a 7-d period to 3 different concentrations (0.04, 0.2, or 1 mg/L) of TBOEP and TCEP. When toxicological factors such as bioaccumulation and bioconcentration, and chemical structural characteristics and behavior, including absorption to solid materials, are considered, these concentrations represent environmentally relevant concentrations. The concentrations of the contaminants were derived from levels of their environmental occurrence. The expression of genes related to oxidative stress-glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST)-and to lipid peroxidation peroxisome proliferator-activated receptors (PPAR)-were determined using quantitative (real-time) polymerase chain reaction (PCR). The presence of PPAR proteins was also investigated using immunochemical methods. Levels of thiobarbituric acid-reactive substances (TBARS) in liver were used as a measure of lipid peroxidation. Overall, our data show an increase in lipid peroxidation, and this was associated with an augmented expression of genes from the glutathione family of responses. Interestingly, PPAR expression in liver after exposure to TBOEP and TCEP was consistently decreased compared to controls, while expression in brain did not show a similar trend. The results suggest that OP contaminants may induce oxidative stress and thus production of reactive oxygen substances (ROS), and modulate lipid peroxidation processes in organisms. PMID- 27484135 TI - Behavioral responses of brown shrimp (Crangon crangon) to reduced seawater pH following simulated leakages from sub-sea geological storage of CO2. AB - Large-scale storage of CO2 within sub-sea geological formations is a viable option for reducing the volume of this greenhouse gas released directly to the atmosphere from anthropogenic activities. Risks to benthic marine life following possible leakage of gas through the seabed from this carbon capture and storage (CCS) initiative are not yet well established. This study examined behavior (activity patterns) in brown shrimp (Crangon crangon), exposed to a range of reduced seawater pH conditions (7.6, 7, or 6.5) simulating leakage scenarios of varying scales. Brown shrimp have an endogenous rhythmicity associated with their activity, which dictates they are most active during hours of darkness, presumably as protection against vision-dependent predators. This endogenous rhythm in activity continues to be expressed when shrimp are held under constant low-light conditions in the lab and provides an ecologically relevant endpoint to measure when examining the influence of reduced pH on the behavior of these animals. No marked differences in activity pattern were observed between control shrimp maintained at pH 8.1 and those at pH 7.6. However, changes in activity were evident at pH 7 and pH 6.5, where significant shifts in timing and intensity of activity occurred. There was an unexpected increase in activity within periods of expected light, probably signaling efforts by shrimp to migrate away from reduced seawater pH conditions. The loss of this important member of the benthic community due to migration may have important consequences for many of the resilient species that remain. PMID- 27484136 TI - Endocrine effects of real-life mixtures of persistent organic pollutants (POP) in experimental models and wild fish. AB - A series of studies have assessed the occurrence, levels, and potential adverse effects of persistent organic pollutants (POP) in fish from Lake Mjosa. In this lake, high levels of various POP were detected in biota. Fish from the nearby Lake Losna contain background levels of POP and served as reference (controls) in these studies. Significantly higher prevalence of mycobacteriosis and pathological changes were documented in burbot (Lota lota) from Mjosa compared to burbot from Losna. Further, transcriptional profiling identified changes in gene expression in burbot from Mjosa compared to burbot from Losna associated with drug metabolism enzymes and oxidative stress. POP extracted from burbot liver oil from the two lakes was used to expose zebrafish (Danio rerio) during two consecutive generations. During both generations, POP mixtures from both lakes increased the rate of mortality, induced earlier onset of puberty, and skewed sex ratio toward males. However, opposite effects on weight gain were found in exposure groups compared to controls during the two generations. Exposure to POP from both lakes was associated with suppression of ovarian follicle development. Analyses of genome-wide transcription profiling identified functional networks of genes associated with weight homeostasis, steroid hormone functions, and insulin signaling. In human cell studies using adrenocortical H295R and primary porcine theca and granulosa cells, exposure to lake extracts from both populations modulated steroid hormone production with significant difference from controls. The results suggest that POP from both lakes may possess the potential to induce endocrine disruption and may adversely affect health in wild fish. PMID- 27484137 TI - Acute toxicity of dispersed crude oil on the cold-water copepod Calanus finmarchicus: Elusive implications of lipid content. AB - In this investigation, acute toxicity data were used from two previously reported studies where cold-water copepods were exposed to mechanically dispersed (MD) and chemically (CD) dispersed oil. In one of these studies, concentration-dependent mortality was observed, whereas no apparent relationship between exposure concentration and mortality was found in the other. The only marked difference between the studies is that copepods in the first experiment displayed a lower lipid sac volume (on average) than in the second one. In this study additional biometric data on lipid content were utilized and observed effects and toxicokinetics modeling applied in order to investigate whether differences in sensitivity between copepod cohorts might be explained by differences in lipid content. Results suggest that although a considerable lipid sac might retard toxicokinetics, the observed differences in lipid volume are not sufficient to explain differences in toxicity. Further, there are no apparent indications that acute toxic stress leads to lipid depletion, or that acute increased mortality rate selectively affects lipid-poor individuals. It is conceivable that other potential explanations exist, but the causal relationship between lipid content and increased mortality frequency remains elusive. PMID- 27484138 TI - Exposure of first-feeding cod larvae to dispersed crude oil results in similar transcriptional and metabolic responses as food deprivation. AB - Exposure of first-feeding cod larvae (Gadus morhua) to dispersed oil results in reduced feeding during an important transition period. First-feeding cod larvae were subjected to a 4-d treatment of food deprivation and sampled for microarray analyses. These microarray data were combined with data from cod larvae treated with mechanically and chemically dispersed oil in an attempt to understand to what extent starvation might explain some of the effects observed in first feeding cod larvae during oil exposure. Transcriptional profiling of cod larvae suggested that the influence of oil exposure was almost as dramatic as being completely deprived of food. Protein and cellular degradation and loss of amino acids and glucose appear to be concomitant responses to both oil exposure and starvation. Fluorescence imaging of gut content indicated low uptake of food, and reduced growth (decrease in dry weight and in carbon and nitrogen content) was also noted in oil-exposed larvae, providing phenotypic anchoring of microarray data. The study displays the importance in combining use of high-throughput molecular tools with assessment of fitness-related endpoints in order to provide a greater understanding of toxicant-induced responses. This combined-approach investigation suggests that reduction of food uptake is an important process to be included when predicting effects of accidental oil spills. Finally, when comparing data from two oil treatments, exposure to chemically dispersed oil did not appear to result in greater toxicity than exposure to mechanically dispersed oil. PMID- 27484139 TI - Predicting environmental risk: A road map for the future. AB - Frameworks for environmental risk assessment (ERA) focus on comparing results from separate exposure and effect assessments. Exposure assessment generally relies on mechanistic fate models, whereas the effects assessment is anchored in standard test protocols and descriptive statistics. This discrepancy prevents a useful link between these two pillars of ERA, and jeopardizes the realism and efficacy of the entire process. Similar to exposure assessment, effects assessment requires a mechanistic approach to translate the output of fate models into predictions for impacts on populations and food webs. The aim of this study was to discuss (1) the central importance of the individual level, (2) different strategies of dealing with biological complexity, and (3) the role that toxicokinetic-toxicodynamic (TKTD) models, energy budgets, and molecular biology play in a mechanistic revision of the ERA framework. Consequently, an outline for a risk assessment paradigm was developed that incorporates a mechanistic effects assessment in a consistent manner, and a "roadmap for the future." Such a roadmap may play a critical role to eventually arrive at a more scientific and efficient ERA process, and needs to be used to shape our long-term research agendas. PMID- 27484140 TI - Individual and molecular level effects of produced water contaminants on nauplii and adult females of Calanus finmarchicus. AB - In the Barents Sea region new petroleum fields are discovered yearly and extraction of petroleum products is expected to increase in the upcoming years. Despite enhanced technology and stricter governmental legislation, establishment of the petroleum industry in the Barents Sea may potentially introduce a new source of contamination to the area, as some discharges of produced water will be allowed. Whether the presence of produced water poses a risk to the Arctic marine life remains to be investigated. The aim of this study was to examine effects of exposure to several compounds found in produced water-a mixture of selected organic compounds (APW), radium-226 ((226)Ra), barium (Ba), and a scale inhibitor on the copepod species Calanus finmarchicus. Experiments were performed using exposure concentrations at realistic levels based on those detected in the vicinity of known discharge points. The influence of lethal and sublethal effects on early life stages was determined and significantly lower survival in the APW exposure groups was found. In the Ba treatment the life stage development did not proceed to the same advanced stages as observed in the control (filtered sea water). The scale inhibitor and (226)Ra treatments showed no significant difference from control. In addition, adult females were exposed to APW, (226)Ra, and a mixture of the two. Both individual-level effects (egg production and feeding) and molecular-level effects (gene expression) were assessed. On the individual level endpoints, only treatments including APW produced an effect compared to control. However, on the molecular level the possibility that also (226)Ra induced toxicologically relevant effects cannot be ruled out. PMID- 27484141 TI - Parental exposure to natural mixtures of persistent organic pollutants (POP) induced changes in transcription of apoptosis-related genes in offspring zebrafish embryos. AB - Apoptosis is an integral element of development that may also be initiated by environmental contaminants. The aim of the present study was to assess potential changes in the regulation of apoptotic genes in zebrafish embryos following parental exposure to two natural mixtures of persistent organic pollutants (POP). The mixture from Lake Mjosa contained exceptionally high concentrations of polybrominated diphenyl ethers (PBDE), as well as relatively high levels of polychlorinated biphenyls (PCB) and dichlorodiphenyltrichloroethane (DDT). The mixture from Lake Losna contained background concentrations of POP. Genes involved in the apoptotic machinery were screened for their expression profile at four time points during embryonic development. Thirteen and 15 genes involved in apoptosis were found to be significantly upregulated in the high-exposure and background exposure groups, respectively, compared with controls. Modulation of apoptotic genes was restricted only to the first time point, which corresponds with the blastula stage. Although there were substantial differences in POP concentrations between mixtures, genes underlying the apoptosis process showed almost similar responses to the two mixtures. In both exposure groups the main executors of apoptosis p53, casp 2, casp 6, cassp 8, and BAX displayed upregulation compared to controls, suggesting that these POP induce apoptosis via a p53-dependent mechanism. Upregulation of genes that play a critical role in apoptosis suggests that disturbance of normal apoptotic signaling during gametogenesis and embryogenesis may be one of the central mechanisms involved in adverse reproductive effects produced by POP in zebrafish. PMID- 27484142 TI - Transcriptional effects of metal-rich acid drainage water from the abandoned Lokken Mine on Atlantic salmon (Salmo salar) smolt. AB - Runoff of metals represents one of the major environmental challenges related to historic and ongoing mining activity. In this study, transcriptomics (direct RNA sequencing [RNA-seq] and reverse-transcription quantitative polymerase chain reaction [RT-qPCR]) was used to predict toxicity of metal-rich acid mine drainage (AMD) water collected in the abandoned copper (Cu) mine called Lokken Mine on Atlantic salmon liver and kidney, the main target organs of Cu-induced toxicity in fish. Smolts were exposed to control and diluted AMD water, which contains a mixture of metals but is especially enriched with Cu, at 4 concentrations in freshwater (FW) for 96 h, and then were transferred to and kept in seawater (SW) for another 24 h. Significant accumulation of Cu was observed in the gills, but not liver and kidney tissues, after 96 h of exposure. Short-term exposure to metal-rich ADM (high exposure group) significantly upregulated 3201 transcripts and downregulated 3782 transcripts in liver. The strongest effect attributed to exposure was observed on the KEGG pathway "protein processing in endoplasmic reticulum," followed by "steroid biosynthesis." Gene ontology (GO) analysis suggested that exposure predominantly affected "protein folding," possibly by disrupting disulfide bonds as a result of endoplasmic-reticulum-generated stress, and "sterol biosynthetic processes." Transfer to uncontaminated SW for 24 h amended the transcription of several genes, suggesting a transient effect of treatment on some mechanisms. In conclusion, the data show that trace metals in AMD from abandoned pyrite mines might disturb molecular mechanisms linked to protein folding in Atlantic salmon smolt endoplasmic reticulum. PMID- 27484143 TI - Biological effects of polycyclic aromatic hydrocarbons (PAH) and their first metabolic products in in vivo exposed Atlantic cod (Gadus morhua). AB - The monitoring of the presence of polycyclic aromatic hydrocarbons (PAH) in the aquatic environment is a worldwide activity since some of these compounds are well-established carcinogens and mutagens. Contaminants in this class are in fact regarded as priority hazardous substances for environmental pollution (Water Framework Directive 2000/60/EC). In this study, Atlantic cod (Gadus morhua) was selected to assess in vivo effects of two PAH and their first metabolic products, namely, the corresponding trans-dihydrodiols, using biological markers. Fish were exposed for 1 wk to a single PAH (naphthalene or chrysene) and its synthetic metabolites ((1R,2R)-1,2-dihydronaphthalene-1,2-diol and (1R,2R)-1,2 dihydrochrysene-1,2-diol) by intraperitoneal injection in a continuous seawater flow system. After exposure, PAH metabolism including PAH metabolites in bile and ethoxyresorufin O-deethylase (EROD) activity, oxidative stress glutathione S transferases (GST) and catalase (CAT) activities, and genotoxicity such as DNA adducts were evaluated, as well as general health conditions including condition index (CI), hepatosomatic index (HSI), and gonadosomatic index (GSI). PAH metabolite values were low and not significantly different when measured with the fixed-wavelength fluorescence screening method, while the gas chromatography-mass spectroscopy (GC-MS) method showed an apparent dose response in fish exposed to naphthalene. DNA adduct levels >=0.16 * 10(-8) relative adduct level (RAL) were detected. It should be noted that 0.16 * 10(-8) RAL is considered the maximal acceptable background level for this species. The other biomarkers activities of catalase, GST, and EROD did not display a particular compound- or dose-related response. The GSI values were significantly lower in some chrysene- and in both naphthalene- and naphthalene diol-exposed groups compared to control. PMID- 27484144 TI - An evaluation of coral lophelia pertusa mucus as an analytical matrix for environmental monitoring: A preliminary proteomic study. AB - For the environmental monitoring of coral, mucus appears to be an appropriate biological matrix due to its array of functions in coral biology and the non intrusive manner in which it can be collected. The aim of the present study was to evaluate the feasibility of using mucus of the stony coral Lophelia pertusa (L. pertusa) as an analytical matrix for discovery of biomarkers used for environmental monitoring. More specifically, to assess whether a mass spectrometry-based proteomic approach can be applied to characterize the protein composition of coral mucus and changes related to petroleum discharges at the seafloor. Surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS) screening analyses of orange and white L. pertusa showed that the mucosal protein composition varies significantly with color phenotype, a pattern not reported prior to this study. Hence, to reduce variability from phenotype difference, L. pertusa white individuals only were selected to characterize in more detail the basal protein composition in mucus using liquid chromatography, mass spectrometry, mass spectrometry (LC-MS/MS). In total, 297 proteins were identified in L. pertusa mucus of unexposed coral individuals. Individuals exposed to drill cuttings in the range 2 to 12 mg/L showed modifications in coral mucus protein composition compared to unexposed corals. Although the results were somewhat inconsistent between individuals and require further validation in both the lab and the field, this study demonstrated preliminary encouraging results for discovery of protein markers in coral mucus that might provide more comprehensive insight into potential consequences attributed to anthropogenic stressors and may be used in future monitoring of coral health. PMID- 27484145 TI - Effect of dispersed crude oil on the feeding activity, retention efficiency, and filtration rate of differently sized blue mussels (Mytilus edulis). AB - The use of physiological response endpoints in environmental monitoring represents an opportunity to provide an integrated picture of health status and ecological fitness of individuals, and may provide an indication of potential longer term effects on aquatic organisms in the environment. The feeding behavior response sensitivity of blue mussels (Mytilus edulis) of differing size to dispersed crude oil (DCO) was investigated in a lab exposure experiment. The ability of mussels to recover following a single exposure was also investigated, as well as the response to consecutive exposures, in order to assess the utility of employing the same individuals in chronic environmental monitoring. Feeding physiology was assessed by measuring retention efficiency and filtration rate of individual mussels in a live-algae feeding assay. In addition, the percentage of mussels actively filtering during testing was calculated. The feeding physiology parameters were sensitive and able to discriminate exposed mussels from controls. Further, data indicated that larger mussels appear more suitable in environmental monitoring, as these animals showed both sensitivity and an ability to adapt and recover from exposure while remaining sensitive to subsequent treatments. Smaller mussels were also sensitive to the measured endpoints, even if these animals suffered higher rates of mortality during the exposure. Finally, when exposed to the high concentration of DCO, mussels displayed a tendency to close the valves and terminate filtration. PMID- 27484146 TI - p18 inhibits reprogramming through inactivation of Cdk4/6. AB - Pluripotent stem cells (PSCs), including embryonic and induced pluripotent stem cells (iPSCs), show atypical cell cycle regulation characterized by a high proliferation rate and a shorter G1 phase compared with somatic cells. The mechanisms by which somatic cells remodel their cell cycle to achieve the high proliferation rate of PSCs during reprogramming are unclear. Here we identify that the Ink4 protein p18, which is expressed at high levels in somatic cells but at low levels in PSCs, is a roadblock to successful reprogramming. Mild inhibition of p18 expression enhances reprogramming efficiency, while ectopic expression of p18 completely blocks reprogramming. Mechanistic studies show that expression of wild-type p18, but not a p18(D68N) mutant which cannot inhibit Cdk4/6, down-regulates expression of Cdk4/6 target genes involved in DNA synthesis (TK, TS, DHFR, PCNA) and cell cycle regulation (CDK1 and CCNA2) and thus inhibits reprogramming. These results indicate that p18 blocks reprogramming by targeting Cdk4/6-mediated cell cycle regulation. Taken together, our results define a novel pathway that inhibits somatic cell reprogramming, and provide a new target to enhance reprogramming efficiency. PMID- 27484147 TI - Chronic myeloid leukemia patients call for quality and consistency when generics are introduced to treat their cancer. PMID- 27484148 TI - Analysis of different components in the peritumoral tissue microenvironment of colorectal cancer: A potential prospect in tumorigenesis. AB - The present study aimed to observe the varying expression of biomarkers in the microenvironment adjacent to colorectal cancer lesions to provide additional insight into the functions of microenvironment components in carcinogenesis and present a novel or improved indicator for early diagnosis of cancer. A total of 144 human samples from three different locations in 48 patients were collected, these locations were 10, 5 and 2 cm from the colorectal cancer lesion, respectively. The biomarkers analyzed included E-cadherin, cytokeratin 18 (CK18), hyaluronidase-1 (Hyal-1), collagen type I (Col-I), Crumbs3 (CRB3), vimentin, proteinase activated receptor 3 (PAR-3), alpha-smooth muscle actin (alpha-SMA), cyclin D1 (CD1) and cluster of differentiation (CD)133. In addition, crypt architecture was observed. Related functional analysis of proteins was performed using hierarchical index cluster analysis. More severe destroyed crypt architecture closer to the cancer lesions was observed compared with the 10 cm sites, with certain crypts degraded entirely. Expression levels of E-cadherin, CK18, CRB3 and PAR-3 were lower in 2 cm sites compared with the 10 cm sites (all P<0.001), while the expression levels of the other biomarkers in the 2 cm sites were increased compared with 10 cm sites (all P<0.0001). Notably, the expression of CK18 in 2 cm sites was higher than in the 5 cm site (P<0.0001), which was different from the expression of E-cadherin, CRB3 and PAR-3. The expression levels of Hyal-1 and Col-I at the 2 cm sites were lower than that of the 5 cm sites (P>0.05 and P=0.0001, respectively), while the expression of vimentin, alpha-SMA, CD1 and CD133 were not. Hyal-1 and Col-I may be independently important in cancer initiation in the tumor microenvironment. The results of the present study suggest that the biomarkers in the tissue microenvironment are associated with early tumorigenesis and may contribute to the development of carcinomas. These observations may be useful for early diagnosis of colorectal cancer. PMID- 27484150 TI - Spatiotemporal dynamics of autophagy receptors in selective mitophagy. AB - Damaged mitochondria are turned over through a process of selective autophagy termed mitophagy. In mitophagy, unhealthy mitochondria are recognized and ubiquitinated by Parkinson disease-linked proteins PINK1 and PARK2. The subsequent recruitment of ubiquitin-binding autophagy receptors leads in turn to the sequestration of the damaged organelles into LC3-positive phagophores, precursors to autophagosomes. The precise identity of these receptors and how they are regulated has been the focus of considerable attention. Our recent work uses live-cell imaging to explore the dynamics and regulation of autophagy receptor recruitment. Utilizing multiple paradigms to induce mitochondrial damage, we identified the rapid, 2-step recruitment of autophagy receptors OPTN, CALCOCO2/NDP52, and TAX1BP1. All 3 receptors are recruited to damaged mitochondria with similar kinetics; however, only OPTN is necessary for efficient formation of a phagophore sequestering damaged mitochondria from the cytosol. OPTN is co-recruited to damaged mitochondria along with its upstream kinase TBK1. Depletion of OPTN or TBK1, or expression of amyotrophic lateral sclerosis (ALS) linked mutations in either protein, interfere with efficient autophagic engulfment of depolarized mitochondria. These observations suggest that insufficient autophagy of damaged mitochondria may contribute to neurodegenerative disease. PMID- 27484149 TI - Perceived Risk of HIV Infection Among Drug-Using African American Male Prisoners: One Year After Community Re-entry. AB - BACKGROUND: African Americans represent 13% of the U.S. population but 46% of people living with HIV and nearly 40% of state and federal prisoners. Disproportionate rates of HIV among African American males involved in the criminal justice system have been associated with risk factors, including: contracting sexually transmitted infections (STIs), substance misuse, and inconsistent condom use. However, many African American males may not perceive an elevated risk of HIV upon re-entering the community. OBJECTIVE: The current study examines correlates of perceived HIV risk among incarcerated African American drug-using males about one year after release from prison. METHODS: Derived from a larger Health Services Utilization study, interviewing (N = 661) incarcerated men at baseline with a 92% follow-up rate approximately one year after community re-entry, the current study is a secondary data analyses from self-identified African American men (N = 250). After list-wise deletion, the total N = 221 for the final study results. RESULTS: An ordered logistic regression model examining perceived risk of HIV as the dependent variable found age, cocaine use before sex, and condom use were significant correlates in the model. Alcohol use before sex mediated the relationship between cocaine use before sex and perceived HIV risk. CONCLUSIONS: Results suggest men in this study are engaged in HIV risk behaviors and risk perception varies. Implications for individual-level, community-level and policy interventions are discussed. PMID- 27484151 TI - Thyroid Function Characteristics and Determinants: The Rotterdam Study. AB - BACKGROUND: Information on determinants and change of thyroid function over time is sparse and conflicting but crucial for clinical interpretation and research. Therefore, our aim was to systematically investigate determinants of thyroid stimulating hormone (TSH), free thyroxine (FT4) (as markers of thyroid function), their mutual relation (as marker of thyroid function set point) and changes in thyroid function over time. METHODS: We included 9402 participants from the Rotterdam Study not taking thyroid medication and with available thyroid function measurements. Repeated measurements (6.5-year interval) were available for 1225 participants. The association of selected determinants with TSH, FT4, and their mutual relation (reflecting thyroid function set point) was estimated using linear regression models using restricted cubic splines with three knots. The factors investigated were age, sex, body mass index (BMI), tobacco smoking, alcohol use, thyroperoxidase antibodies (TPOAb), and common genetic factors. RESULTS: Most influential determinants of TSH were age, smoking, genetic determinants, and TPOAb levels (p < 0.001). For FT4, most influential determinants were age, BMI, sex, genetic determinants and TPOAb levels (p < 0.001). Older age, female sex, and increased TPOAb levels were associated with a stronger relation between TSH and FT4. TSH levels did not change over time, irrespective of age. FT4 levels increased over time, most prominently in those older than 65 years of age (mean increase of 4.5 pmol/L). CONCLUSIONS: The main factors that influence the relationship between thyroid hormone and molar concentrations of TSH in our population-based cohort study are age, smoking, BMI, TPOAb levels, and common genetic variants. The set point that determines TSH secretion as it relates to negative thyroid hormone feedback is modified by age, sex and TPOAb positivity. FT4 levels increase over time, with a more pronounced increase in the elderly, while TSH values seem stable over time. Our results question the current notion of an increase of TSH with increasing age. PMID- 27484152 TI - Predictors of Cell Phone Use in Distracted Driving: Extending the Theory of Planned Behavior. AB - This study examines the predictors of six distracted driving behaviors, and the survey data partially support Ajzen's (1991) Theory of Planned Behavior (TPB). The data suggest that the attitude variable predicted intention to engage in all six distracted driving behaviors (reading and sending text messages, making and answering cell phone calls, reading/viewing social media, and posting on social media while driving). Extending the model to include past experience and the variable perceived safety of technology yielded an improvement in the prediction of the distraction variables. Specifically, past experience predicted all six distracted driving behaviors, and the variable perceived safety of technology predicted intentions to read/view social media and intention to post on social media while driving. The study provides evidence for the importance of incorporating expanded variables into the original TPB model to predict cell phone use behaviors while driving, and it suggests that it is essential to tailor campaign materials for each specific cell phone use behavior to reduce distracted driving. PMID- 27484153 TI - Acute effects of small changes in crank length on gross efficiency and pedalling technique during submaximal cycling. AB - The main purpose of this study was to assess the acute effects of small changes in crank length (assumable by competitive cyclists) on metabolic cost and pedalling technique during submaximal cycling. Twelve amateur road cyclists performed three sets of submaximal pedalling (150, 200 and 250 W) at a constant cadence (91.3 +/- 0.8 rpm) in a randomised order with three commonly used crank lengths, preferred (172.5-175 mm), +5 mm and -5 mm. Energy cost of pedalling, kinetic and kinematic variables were simultaneously registered. Changes in crank length had no significant effect on heart rate (144 +/- 13, 145 +/- 12 and 145 +/ 13 bpm, respectively) and gross efficiency (GE) (20.4 +/- 2.1, 20.1 +/- 2.2 and 20.3 +/- 2.4%, respectively). A longer crank induced a significant (P < 0.05) reduction of positive impulse proportion (PIP) (0.9-1.9%) due to a greater maximum (1.0-2.3 N . m) and minimum torque (1.0-2.2 N . m). At the same time, the maximum flexion and range of motion of the hip and knee joints were significantly increased (1.8-3.4 degrees and P < 0.05), whereas the ankle joint was not affected. In conclusion, the biomechanical changes due to a longer crank did not alter the metabolic cost of pedalling, although they could have long-term adverse effects. Therefore, in case of doubt between two lengths, the shorter one might be recommended. PMID- 27484154 TI - Mutations induce conformational changes in folliculin C-terminal domain: possible cause of loss of guanine exchange factor activity and Birt-Hogg-Dube syndrome. PMID- 27484155 TI - Keep in touch (KIT): perspectives on introducing internet-based communication and information technologies in palliative care. AB - BACKGROUND: Hospitalized palliative patients need to keep in touch with their loved ones. Regular social contact may be especially difficult for individuals on palliative care in-patient units due to the isolating nature of hospital settings. Technology can help mitigate isolation by facilitating social connection. This study aimed to explore the acceptability of introducing internet based communication and information technologies for patients on a palliative care in-patient unit. METHODS: In the first phase of the Keep in Touch (KIT) project, a diverse group of key informants were consulted regarding their perspectives on web-based communication on in-patient palliative care units. Participants included palliative patients, family members, direct care providers, communication and information technology experts, and institutional administrators. Data was collected through focus groups, interviews and drop-in consultations, and was analyzed for themes, consensus, and major differences across participant groups. RESULTS: Hospitalized palliative patients and their family members described the challenges of keeping in touch with family and friends. Participants identified numerous examples of ways that communication and information technologies could benefit patients' quality of life and care. Patients and family members saw few drawbacks associated with the use of such technology. While generally supportive, direct care providers were concerned that patient requests for assistance in using the technology would place increased demands on their time. Administrators and IT experts recognized issues such as privacy and costs related to offering these technologies throughout an organization and in the larger health care system. CONCLUSIONS: This study affirmed the acceptability of offering internet-based communication and information technologies on palliative care in-patient units. It provides the foundation for trialing these technologies on a palliative in-patient unit. Further study is needed to confirm the feasibility of offering these technologies at the bedside. PMID- 27484156 TI - The use of DNA barcodes in food web construction-terrestrial and aquatic ecologists unite! AB - By depicting who eats whom, food webs offer descriptions of how groupings in nature (typically species or populations) are linked to each other. For asking questions on how food webs are built and work, we need descriptions of food webs at different levels of resolution. DNA techniques provide opportunities for highly resolved webs. In this paper, we offer an expose of how DNA-based techniques, and DNA barcodes in particular, have recently been used to construct food web structure in both terrestrial and aquatic systems. We highlight how such techniques can be applied to simultaneously improve the taxonomic resolution of the nodes of the web (i.e., the species), and the links between them (i.e., who eats whom). We end by proposing how DNA barcodes and DNA information may allow new approaches to the construction of larger interaction webs, and overcome some hurdles to achieving adequate sample size. Most importantly, we propose that the joint adoption and development of these techniques may serve to unite approaches to food web studies in aquatic and terrestrial systems-revealing the extent to which food webs in these environments are structured similarly to or differently from each other, and how they are linked by dispersal. PMID- 27484157 TI - Expression of interferon regulatory factor 5 is regulated by the Sp1 transcription factor. AB - The transcription factor, interferon regulatory factor 5 (IRF5), is important in the induction of type I interferon, proinflammatory cytokines and chemokines, and is involved in autoimmune diseases and tumourigenesis. However, the mechanisms underlying the transcriptional regulation of wild-type IRF5 remain to be fully elucidated. The present study was primarily designed to clarify whether specificity protein 1 (Sp1) was involved in the regulation of IRF5. Initially, the IRF5 promoter region was cloned and its promoter activity was examined using Hela and HEK 293 cells. Deletion analyses revealed that the region spanning -179 to +62 was the minimal promoter of IRF5. Bioinformatics analyses showed that this region contained three putative Sp1 binding sites, and mutational analyses revealed that all the Sp1 sites contributed to transcriptional activity. Secondly, the overexpression of Sp1 was found to increase the activity of the IRF5 promoter and the mRNA level of IRF5, determined using reporter gene assays and polymerase chain reaction analysis, respectively. By contrast, treatment with mithramycin and Sp1 small interfering RNA significantly reduced the activity of the IRF5 promoter and the mRNA level of IRF5. Finally, the results of an electrophoretic mobility shift assay and a chromatin immunoprecipitation assay demonstrated that Sp1 bound to the promoter region of IRF5 in vitro and in vivo. These results suggested that the Sp1 transcription factor is the primary determinant for activating the basal transcription of the IRF5. PMID- 27484158 TI - Cost-effectiveness of a herpes zoster vaccination program among the French elderly people. AB - A vaccine against herpes zoster (HZ) and its complications has already proven safe and effective against infection and pain and against the related deterioration of quality of life in the elderly. In order to inform the vaccination decision-making process regarding inclusion of this vaccine in the French immunization schedule, we assessed the cost-effectiveness of several vaccination scenarios, compared to no vaccination. We chose to use a previously published Markov model. Starting vaccination in elderly individuals aged 65, 70 and 75 y old appears more cost-effective than vaccination for those aged 60 y old, with a cost-effectiveness ratio between 30,000 and 35,000 euros per quality adjusted-life year (QALY) gained for the first 3 age groups versus 54,500 ?; for the latter group. These results largely contributed to the recommendation to include the HZ vaccination in the French immunization schedule for people aged between 65 and 74 y old in France. PMID- 27484159 TI - Co-morbid conditions in use of recombinant tissue plasminogen activator (rt-PA) for the treatment of acute ischaemic stroke. AB - BACKGROUND: The objective of this study was to characterize the comorbidities in a population of patients with an acute ischaemic stroke, comparing patients that received recombinant tissue plasminogen activator (rt-PA) to those that did not receive rt-PA. METHOD: In a retrospective sample of 663 patients admitted for acute ischaemic stroke, this study analysed the effects of co-morbid conditions in the use of rt-PA. It determined non-cerebrovascular risk factors (comorbidities) that differentiate patients who received rt-PA from those who did not receive rt-PA. RESULT: Patients with a history of carotid stenosis, CHF and previous strokes are significantly (p < 0.05) associated with high risk of not receiving rt-PA. A significant number of patients with a history of hypertension and smoking received rt-PA (p < 0.05). CONCLUSION: The findings indicate that certain risk factors including carotid stenosis, CHF and previous stroke history impact the treatment of patients with acute ischaemic stroke, specifically the decision to administer rt-PA. Treatment with rt-PA is dependent on stroke severity and onset to treatment time, but the findings suggest that rt-PA use may also depend on patient comorbidities. PMID- 27484160 TI - Structural modulation of lithium metal-electrolyte interface with three dimensional metallic interlayer for high-performance lithium metal batteries. AB - The use of lithium (Li) metal anodes has been reconsidered because of the necessity for a higher energy density in secondary batteries. However, Li metal anodes suffer from 'dead' Li formation and surface deactivation which consequently form a porous layer of redundant Li aggregates. In this work, a fibrous metal felt (FMF) as a three-dimensional conductive interlayer was introduced between the separator and the Li metal anode to improve the reversibility of the Li metal anode. The FMF can facilitate charge transfer in the porous layer, rendering it electrochemically more active. In addition, the FMF acted as a robust scaffold to accommodate Li deposits compactly in its interstitial sites. The FMF-integrated Li metal (FMF/Li) electrode operated with a small polarisation even at a current density of 10 mA cm(-2), and it exhibited a seven times longer cycle-life than that of an FMF-free Li electrode in a symmetric cell configuration. A Li metal battery (LMB) using the FMF/Li electrode and a LiFePO4 electrode exhibited a two-fold increase in cycling stability compared with that of a bare Li metal electrode, demonstrating the practical effectiveness of this approach for high performance LMBs. PMID- 27484161 TI - ZnCr2S4: Highly effective photocatalyst converting nitrate into N2 without over reduction under both UV and pure visible light. AB - We propose several superiorities of applying some particular metal sulfides to the photocatalytic nitrate reduction in aqueous solution, including the high density of photogenerated excitons, high N2 selectivity (without over-reduction to ammonia). Indeed, ZnCr2S4 behaved as a highly efficient photocatalyst, and with the assistance of 1 wt% cocatalysts (RuOx, Ag, Au, Pd, or Pt), the efficiency was greatly improved. The simultaneous loading of Pt and Pd led to a synergistic effect. It offered the highest nitrate conversion rate of ~45 mg N/h together with the N2 selectivity of ~89%. Such a high activity remained steady after 5 cycles. The optimal apparent quantum yield at 380 nm was 15.46%. More importantly, with the assistance of the surface plasma resonance effect of Au, the visible light activity achieved 1.352 mg N/h under full arc Xe-lamp, and 0.452 mg N/h under pure visible light (lambda > 400 nm). Comparing to the previous achievements in photocatalytic nitrate removal, our work on ZnCr2S4 eliminates the over-reduction problem, and possesses an extremely high and steady activity under UV-light, as well as a decent conversion rate under pure visible light. PMID- 27484162 TI - Leveraging the power of pooled data for cancer outcomes research. AB - BACKGROUND: Clinical trials continue to be the gold standard for determining the efficacy of novel cancer treatments, but they may also expose participants to the potential risks of unpredictable or severe toxicities. The development of validated tools that better inform patients of the benefits and risks associated with clinical trial participation can facilitate the informed consent process. The design and validation of such instruments are strengthened when we leverage the power of pooled data analysis for cancer outcomes research. MAIN BODY: In a recent study published in the Journal of Clinical Oncology entitled "Determinants of early mortality among 37,568 patients with colon cancer who participated in 25 clinical trials from the adjuvant colon cancer endpoints database," using a large pooled analysis of over 30,000 study participants who were enrolled in clinical trials of adjuvant therapy for early-stage colon cancer, we developed and validated a nomogram depicting the predictors of early cancer mortality. This database of pooled individual-level data allowed for a comprehensive analysis of poor prognostic factors associated with early death; furthermore, it enabled the creation of a nomogram that was able to reliably capture and quantify the benefit to-risk profile for patients who are considering clinical trial participation. This tool can facilitate treatment decision-making discussions. CONCLUSION: As China and other Asian countries continue to conduct oncology clinical trials, efforts to collate patient-level information from these studies into a large data repository should be strongly considered since pooled data can increase future capacity for cancer outcomes research, which, in turn, can enhance patient physician discussions and optimize clinical care. PMID- 27484163 TI - Reviewing the Nutrition and Health Claims Regulation (EC) No. 1924/2006: What do we know about its challenges and potential impact on innovation? AB - Health claims potentially represent an opportunity for firms to engage in product differentiation and thereby induce investment into R&D and innovation in the food sector. The Nutrition and Health Claims Regulation (EC) No. 1924/2006 (NHCR) aims at protecting and promoting innovation as one of its objectives. However, existing studies indicate that this regulation may create several challenges for innovation in the food sector. To this end, we review the challenges related to the NHCR (Article 13.1) and its impact on innovation. Extant literature suggests that companies face challenges related to changing list of ingredients, missing transparency, wording of claims, limited financial resources, limited R&D resources, switching product categories and abandoning the functional foods sector. Moreover, current studies imply that so far the NHCR (in specific Article 13.1) does not seem to encourage innovation in the EU food sector. PMID- 27484165 TI - Huge enhancement of upconversion luminescence by broadband dye sensitization of core/shell nanocrystals. AB - Upconversion nanocrystals (UCNCs) hold promise for bioimaging, solar cells, photocatalysis and volumetric displays. However, their upconversion luminescence intensities are usually low due to the weak and narrowband near-infrared absorption of lanthanide ions. Herein, we introduce and validate a strategy to hugely enhance upconversion luminescence intensity by using an organic near infrared dye as an antenna to sensitize core/shell UCNCs. The dye can increase absorptivity and broaden the absorption spectrum of the UCNCs. Such dye sensitization, in combination with a core/shell structure, can tremendously enhance the upconversion luminescence (UCL) intensity of the UCNCs. The UCL intensity of dye-sensitized UCNCs excited at 820 nm is 800-folds higher than that of pure UCNCs excited at 980 nm. Further enhancement can be obtained by optimization of the dye emission and UCNC absorption spectral overlap. Moreover, the proposed approach can be extended to cover any part of the solar spectrum by using a set of dyes. This work provides new insights into the efficient enhancement of upconversion luminescence of the UCNCs and facilitates their applications. PMID- 27484164 TI - High fat diet-induced TGF-beta/Gbb signaling provokes insulin resistance through the tribbles expression. AB - Hyperglycemia, hyperlipidemia, and insulin resistance are hallmarks of obesity induced type 2 diabetes, which is often caused by a high-fat diet (HFD). However, the molecular mechanisms underlying HFD-induced insulin resistance have not been elucidated in detail. In this study, we established a Drosophila model to investigate the molecular mechanisms of HFD-induced diabetes. HFD model flies recapitulate mammalian diabetic phenotypes including elevated triglyceride and circulating glucose levels, as well as insulin resistance. Expression of glass bottom boat (gbb), a Drosophila homolog of mammalian transforming growth factor beta (TGF-beta), is elevated under HFD conditions. Furthermore, overexpression of gbb in the fat body produced obese and insulin-resistant phenotypes similar to those of HFD-fed flies, whereas inhibition of Gbb signaling significantly ameliorated HFD-induced metabolic phenotypes. We also discovered that tribbles, a negative regulator of AKT, is a target gene of Gbb signaling in the fat body. Overexpression of tribbles in flies in the fat body phenocopied the metabolic defects associated with HFD conditions or Gbb overexpression, whereas tribbles knockdown rescued these metabolic phenotypes. These results indicate that HFD induced TGF-beta/Gbb signaling provokes insulin resistance by increasing tribbles expression. PMID- 27484166 TI - Infrared matrix-assisted laser desorption electrospray ionization mass spectrometry imaging analysis of biospecimens. AB - Infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging (MSI) is a technique well suited for analysis of biological specimens. This tutorial review focuses on recent advancements and applications of IR-MALDESI MSI to better understand key biological questions. Through optimization of user-defined source parameters, comprehensive and quantitative MSI data can be obtained for a variety of analytes. The effect of an ice matrix layer is well defined in the context of desorption dynamics and resulting ion abundance. Optimized parameters and careful control of conditions affords quantitative MSI data which provides valuable information for targeted, label-free drug distribution studies and untargeted metabolomic datasets. Challenges and limitations of MSI using IR-MALDESI are addressed in the context of the bioimaging field. PMID- 27484167 TI - Dislocation Reduction and Stress Relaxation of GaN and InGaN Multiple Quantum Wells with Improved Performance via Serpentine Channel Patterned Mask. AB - The existence of high threading dislocation density (TDD) in GaN-based epilayers is a long unsolved problem, which hinders further applications of defect sensitive GaN-based devices. Multiple-modulation of epitaxial lateral overgrowth (ELOG) is used to achieve high-quality GaN template on a novel serpentine channel patterned sapphire substrate (SCPSS). The dislocation blocking brought by the serpentine channel patterned mask, coupled with repeated dislocation bending, can reduce the dislocation density to a yet-to-be-optimized level of ~2 * 10(5) to 2 * 10(6) cm(-2). About 80% area utilization rate of GaN with low TDD and stress relaxation is obtained. The periodical variations of dislocation density, optical properties and residual stress in GaN-based epilayers on SCPSS are analyzed. The quantum efficiency of InGaN/GaN multiple quantum wells (MQWs) on it can be increased by 52% compared with the conventional sapphire substrate. The reduced nonradiative recombination centers, the enhanced carrier localization, and the suppressed quantum confined Stark effect, are the main determinants of improved luminous performance in MQWs on SCPSS. This developed ELOG on serpentine shaped mask needs no interruption and regrowth, which can be a promising candidate for the heteroepitaxy of semipolar/nonpolar GaN and GaAs with high quality. PMID- 27484169 TI - The gestational diabetes tsunami: Can we survive it? PMID- 27484171 TI - Clostridium difficile PCR ribotypes 001 and 176 - the common denominator of C. difficile infection epidemiology in the Czech Republic, 2014. AB - In 2014, 18 hospitals in the Czech Republic participated in a survey of the incidence of Clostridium difficile infections (CDI) in the country. The mean CDI incidence was 6.1 (standard deviation (SD):7.2) cases per 10,000 patient bed-days and 37.8 cases (SD: 41.4) per 10,000 admissions. The mean CDI testing frequency was 39.5 tests (SD: 25.4) per 10,000 patient bed-days and 255.8 tests (SD: 164.0) per 10,000 admissions. A total of 774 C. difficile isolates were investigated, of which 225 (29%) belonged to PCR ribotype 176, and 184 isolates (24%) belonged to PCR ribotype 001. Multilocus variable-number tandem repeat analysis (MLVA) revealed 27 clonal complexes formed by 84% (190/225) of PCR ribotype 176 isolates, and 14 clonal complexes formed by 77% (141/184) of PCR ribotype 001 isolates. Clonal clusters of PCR ribotypes 176 and 001 were observed in 11 and 7 hospitals, respectively. Our data demonstrate the spread of two C. difficile PCR ribotypes within 18 hospitals in the Czech Republic, stressing the importance of standardising CDI testing protocols and implementing mandatory CDI surveillance in the country. PMID- 27484170 TI - Identification of a PTPN11 hot spot mutation in a child with atypical LEOPARD syndrome. AB - LEOPARD syndrome (LS) is an autosomal dominant inherited disorder primarily caused by mutations in the PTPN11, RAF1 and BRAF genes. Characteristic features include lentigines, craniofacial dysmorphism, myocardium or valve abnormalities, eletrocardiographic conduction defects and deafness. LS, neurofibromatosis type 1, Noonan syndrome and Legius syndrome are a group of highly overlapped disorders termed 'RASopathies'. Therefore, clinical discrimination between these syndromes represents a huge challenge. The present study reports a young child diagnosed with LS via identification of a common p.Thr468Met mutation in PTPN11. Taking into account two Taiwanese LS cases with an identical mutation, Thr468Met is likely to be the most prevalent mutation in the Chinese population. Furthermore, this study suggests that a clinical diagnosis of LS should be considered for individuals with congenital cardiac defects and atypical lentigines (i.e., light brown freckles) scattered particularly on the face. PMID- 27484172 TI - The Human Capital of Knowledge Brokers: An analysis of attributes, capacities and skills of academic teaching and research faculty at Kenyan schools of public health. AB - BACKGROUND: Academic faculty involved in public health teaching and research serve as the link and catalyst for knowledge synthesis and exchange, enabling the flow of information resources, and nurturing relations between 'two distinct communities' - researchers and policymakers - who would not otherwise have the opportunity to interact. Their role and their characteristics are of particular interest, therefore, in the health research, policy and practice arena, particularly in low- and middle-income countries. We investigated the individual attributes, capacities and skills of academic faculty identified as knowledge brokers (KBs) in schools of public health (SPH) in Kenya with a view to informing organisational policies around the recruitment, retention and development of faculty KBs. METHODS: During April 2013, we interviewed 12 academics and faculty leadership (including those who had previously been identified as KBs) from six SPHs in Kenya, and 11 national health policymakers with whom they interact. Data were qualitatively analyzed using inductive thematic analysis to unveil key characteristics. RESULTS: Key characteristics of KBs fell into five categories: sociodemographics, professional competence, experiential knowledge, interactive skills and personal disposition. KBs' reputations benefitted from their professional qualifications and content expertise. Practical knowledge in policy relevant situations, and the related professional networks, allowed KB's to navigate both the academic and policy arenas and also to leverage the necessary connections required for policy influence. Attributes, such as respect and a social conscience, were also important KB characteristics. CONCLUSION: Several changes in Kenya are likely to compel academics to engage increasingly with policymakers at an enhanced level of debate, deliberation and discussion in the future. By recognising existing KBs, supporting the emergence of potential KBs, and systematically hiring faculty with KB-specific characteristics, SPHs can enhance their collective human capital and influence on public health policy and practice. Capacity strengthening of tangible skills and recognition of less tangible personality characteristics could contribute to enhanced academic policymaker networks. These, in turn, could contribute to the relevance of SPH research and teaching programs as well as evidence-informed public health policies. PMID- 27484173 TI - The beneficial effects of cognitive training with simple calculation and reading aloud in an elderly postsurgical population: study protocol for a randomized controlled trial. AB - BACKGROUND: This project proposes a pilot study to investigate the positive healing effects of cognitive training with simple arithmetic and reading aloud on elderly postsurgical patients. Elderly patients undergoing surgery have an increased risk of Postoperative Cognitive Decline (POCD), a condition in which learning, memory, and processing speed is greatly reduced after surgery. Since elderly patients are more likely to exhibit symptoms of POCD, the incidence is increasing as the population receiving surgery has aged. Little effort has been expended, however, to find treatments for POCD. Learning therapy, which consists of a combination of reading aloud and solving simple arithmetic problems, was developed in Japan as a treatment for Alzheimer's Disease to improve cognitive functions. Because patients with Alzheimer's Disease experience similar issues as those with POCD in learning, memory, and processing speed, a cognitive intervention based on the learning-therapy treatments used for Alzheimer's Disease could show advantageous outcomes for those at risk of POCD. METHODS/DESIGN: Cognitive function will be measured before and after surgery using three different tests (Mini-Mental Status Exam, Frontal Assessment Battery, and Cogstate computerized tests). Subjects will be randomly divided into two groups-one that receives a Simple Calculation and Reading Aloud intervention (SCRA) and a waitlisted control group that does not receive SCRA. To measure cognition before and after the intervention, the previously mentioned three tests will be used. The obtained data will be analyzed using statistical tests such as ANCOVA to indicate whether the cognitive intervention group has made improvements in their cognitive functions. In addition, questionnaires will also be administered to collect data on mental and emotional statuses. DISCUSSION: This report will be the first pilot study to investigate the beneficial effects of SCRA on elderly surgical patients. Previous studies have shown sufficient evidence on the effectiveness of learning therapy in healthy elderly people and in those with Dementia. Therefore, this study will clarify whether SCRA can improve cognitive function in the more specialized group of elderly surgical patients. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry, UMIN000019832 . Registered on 18 November 2015. PMID- 27484174 TI - A novel role for STOMATAL CARPENTER 1 in stomata patterning. AB - BACKGROUND: Guard cells (GCs) are specialised cells within the plant epidermis which form stomatal pores, through which gas exchange can occur. The GCs derive through a specialised lineage of cell divisions which is specified by the transcription factor SPEECHLESS (SPCH), the expression of which can be detected in undifferentiated epidermal cells prior to asymmetric division. Other transcription factors may act before GC specification and be required for correct GC patterning. Previously, the DOF transcription factor STOMATAL CARPENTER 1 (SCAP1) was shown to be involved in GC function, by activating a set of GC specific genes required for GC maturation and activity. It is thus far unknown whether SCAP1 can also affect stomatal development. RESULTS: Here we show that SCAP1 expression can also be observed in young leaf primordia, before any GC differentiation occurs. The study of transgenic plants carrying a proSCAP1:GUS GFP transcriptional fusion, coupled with qPCR analyses, indicate that SCAP1 expression peaks in a temporal window which is coincident with expression of stomatal patterning genes. Independent scap1 loss-of-function mutants have a reduced number of GCs whilst SCAP1 over expression lines have an increased number of GCs, in addition to altered GC distribution and spacing patterns. The study of early markers for stomatal cell lineage in a background carrying gain-of-function alleles of SCAP1 revealed that, compared to the wild type, an increased number of protodermal cells are recruited in the GC lineage, which is reflected in an increased number of meristemoids. CONCLUSIONS: Our results suggest an early role for SCAP1 in GC differentiation. We propose that a function of SCAP1 is to integrate different aspects of GC biology including specification, spacing, maturation and function. PMID- 27484175 TI - Editorial (Mini Thematic Isssue: Learning and Well-Being in Later Life). PMID- 27484176 TI - Screening differential circular RNA expression profiles reveals the regulatory role of circTCF25-miR-103a-3p/miR-107-CDK6 pathway in bladder carcinoma. AB - Circular RNAs (circRNAs), a kind of non-coding RNAs, have shown large capabilities in gene regulation. However, the mechanisms underlying circRNAs remain largely unknown so far. Recent studies demonstrated that circRNAs play miRNA sponge effects and regulate gene expression by microRNA response elements. Here, we screened circRNA expression profiles of bladder carcinoma using microarray assay. A total of 469 dysregulated circular transcripts are found in bladder cancer compared with normal tissues, among which 285 were up-regulated and 184 were down-regulated. Six circRNAs were identified to have significant differences by qRT-PCR. We speculated that circRNAs might involve in cancer related pathways via interactions with miRNA by multiple bioinformatical approaches. Therefore, we further predicted that circTCF25 could sequester miR 103a-3p/miR-107, which potentially lead to the up-regulation of thirteen targets related to cell proliferation, migration and invasion. Subsequently, we demonstrated that over-expression of circTCF25 could down-regulate miR-103a-3p and miR-107, increase CDK6 expression, and promote proliferation and migration in vitro and vivo. This is the first study to exploit circRNA profiling and circRNA/miRNA interactions in bladder cancer. Our work laid the foundation to investigate the functions of circRNAs in cancers. The data also suggest that circTCF25 might be a new promising marker for bladder cancer. PMID- 27484178 TI - State-civil society partnerships for HIV/AIDS treatment and prevention in Ghana: exploring factors associated with successes and challenges. AB - BACKGROUND: The past decade has seen an increased number of state-civil society partnerships in the global Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) response of many countries. However, there has been limited research carried out concerning the successes and challenges of these partnerships. METHODS: In-depth qualitative interviews were conducted with 23 participants from 21 different state-civil society partnerships throughout Ghana including all three major geographical zones (Northern, Middle, and Southern zones) to examine the nature of these partnerships and their positive and negative effects in responding to the national HIV/AIDS epidemic. RESULTS: Major themes included: 1) commitment by the government and civil society organizations to work cooperatively in order to support the development and implementation of HIV/AIDS interventions in Ghana; 2) the role of civil society organizations in facilitating community mobilization; capacity building; and information, resources and skills exchange to increase the efficiency and effectiveness of these partnerships for HIV prevention and treatment; and 3) significant challenges including funding issues and other structural barriers for these partnerships that need to be addressed moving forward. CONCLUSIONS: Future research should focus on examining the impact of recommended changes on state civil partnerships and studying the extent and nature of these partnerships in other countries in order to establish the generalizability of the findings from this study. PMID- 27484177 TI - Factors associated with married women's support of male circumcision for HIV prevention in Uganda: a population based cross-sectional study. AB - BACKGROUND: Despite the protective effect of male circumcision (MC) against HIV in men, the acceptance of voluntary MC in priority countries for MC scale-up such as Uganda remains limited. This study examined the role of women's sociodemographic characteristics, knowledge of HIV and sexual bargaining power as determinants of women's support of male circumcision (MC). METHODS: Data from the Uganda AIDS Indicator Survey, 2011 were analyzed (n = 4,874). Bivariate and multivariate logistic regression analyses with random intercept were conducted to identify factors that influence women's support of MC. RESULTS: Overall, 67.0 % (n = 3,276) of the women in our sample were in support of MC but only 28.0 % had circumcised partners. Women who had the knowledge that circumcision reduces HIV risk were about 6 times as likely to support MC than women who lacked that knowledge [AOR (adjusted odds ratio) = 5.85, 95 % CI (confidence interval) = 4.83 7.10]. The two indicators of women's sexual bargaining power (i.e., ability to negotiate condom use and ability to refuse sex) were also positively associated with support of MC. Several sociodemographic factors particularly wealth index were also positively associated with women's support of MC. CONCLUSIONS: The findings in this study will potentially inform intervention strategies to enhance uptake of male circumcision as a strategy to reduce HIV transmission in Uganda. PMID- 27484179 TI - Grey matter atrophy in prodromal stage of dementia with Lewy bodies and Alzheimer's disease. AB - BACKGROUND: Little is known about the patterns of brain atrophy in prodromal dementia with Lewy bodies (pro-DLB). METHODS: In this study, we used SPM8 with diffeomorphic anatomical registration through exponentiated lie algebra to measure grey matter (GM) volume and investigate patterns of GM atrophy in pro-DLB (n = 28) and prodromal Alzheimer's disease (pro-AD) (n = 27) and compared and contrasted them with those in elderly control subjects (n = 33) (P <= 0.05 corrected for family-wise error). RESULTS: Patients with pro-DLB showed diminished GM volumes of bilateral insulae and right anterior cingulate cortex compared with control subjects. Comparison of GM volume between patients with pro AD and control subjects showed a more extensive pattern, with volume reductions in temporal (hippocampi and superior and middle gyri), parietal and frontal structures in the former. Direct comparison of prodromal groups suggested that more atrophy was evident in the parietal lobes of patients with pro-AD than patients with pro-DLB. In patients with pro-DLB, we found that visual hallucinations were associated with relative atrophy of the left cuneus. CONCLUSIONS: Atrophy in pro-DLB involves the insulae and anterior cingulate cortex, regions rich in von Economo neurons, which we speculate may contribute to the early clinical phenotype of pro-DLB. PMID- 27484181 TI - The potential role of incorporating real-time PCR and DNA sequencing for amplification and detection of 16S rRNA gene signatures in neonatal sepsis. AB - OBJECTIVES: This study aimed to explore whether 16S rRNA gene amplification by real time PCR and sequencing could serve as genetic-based methods in rapid and accurate diagnosis of neonatal sepsis. PATIENTS AND METHODS: This case control study was conducted on 40 neonates suffering from sepsis like manifestations recruited from the neonatal intensive care unit of Menoufia university hospital over a period of 6 months. Their blood samples were used for paired analysis of bacterial growth using BACTEC 9050 instrument and real time PCR assay with subsequent DNA sequencing for bacterial species identification. RESULTS: The detection rate of culture proven sepsis was 70%. By using real time 16S r RNA PCR amplification method, the detection of bacteria was improved to 80%. Real time PCR revealed sensitivity, specificity, positive predictive value and negative predictive value of [100%, 66.7%, 87.5% and 100%] respectively. Compared to culture, the 16S rRNA real time PCR demonstrated a high negative value for ruling out neonatal sepsis. There was significant statistical difference between the PCR positive and negative cases as regards the hematological sepsis score. The results demonstrated the ability of DNA sequencing to recognize 4 pathogens which were negative by blood culture. The time consumed to detect sepsis using blood culture was up to 5 days while it took up to 16 h only by PCR and sequencing methods. CONCLUSION: 16S rRNA gene amplification by real time PCR and sequence analysis could be served as ideal and reliable genetic-based methods to diagnose and rule out sepsis with provision of additional data that cannot be obtained by routine laboratory tests with a shorter turnaround time than those with culture based protocols. PMID- 27484180 TI - Vinflunine for the treatment of breast cancer. AB - INTRODUCTION: Breast cancer is the most frequently diagnosed cancer and the highest cause of cancer mortality in females worldwide. The development of drugs improving overall survival in late-stage metastatic breast cancer remains a challenge. Vinflunine is the most recently developed drug in the vinca alkaloid class. Its arrival has been eagerly awaited for treatment of solid tumors, and in particular, for metastatic breast cancer. AREAS COVERED: The pharmacological features of vinflunine are described. Its clinical development as monotherapy or in combination in metastatic breast cancer is detailed. A literature search on the topic was conducted through PubMed, clinical trials and the proceedings of the main cancer congresses. EXPERT OPINION: The overall results from phase III studies, and in particular those that combined vinflunine with capecitabine, have been less favorable. The combination's effectiveness was at best moderate compared with other drugs which also target metastatic breast cancer, and complicated by significant hematological and gastrointestinal adverse effects. Its use in advanced metastatic breast cancer cannot currently be recommended. PMID- 27484182 TI - Mediastinal chyloma after lung cancer surgery: case report. AB - BACKGROUND: Chylothorax is a relatively rare but well-known complication of thoracic surgery. CASE PRESENTATION: A 70-year-old man underwent right upper and middle bilobectomy and systematic lymph node dissection through a posterolateral thoracotomy for lung cancer. On the second postoperative day, he developed chylothorax that was treated with dietary management and pleurodesis. The discharge diminished and his chest tube was removed on the ninth postoperative day. On the 14(th) postoperative day, the patient complained of dyspnea and dysphagia, and imaging studies revealed mediastinal chyloma. Thoracoscopic surgical drainage was performed and the site of chyle leakage was sutured. CONCLUSIONS: This report presents an unexpected complication of chemical pleurodesis and reviews the indications for surgical intervention in cases of postoperative chylothorax. PMID- 27484183 TI - Emergent behavior in strongly correlated electron systems. AB - I describe early work on strongly correlated electron systems (SCES) from the perspective of a theoretical physicist who, while a participant in their reductionist top-down beginnings, is now part of the paradigm change to a bottom up 'emergent' approach with its focus on using phenomenology to find the organizing principles responsible for their emergent behavior disclosed by experiment-and only then constructing microscopic models that incorporate these. After considering the organizing principles responsible for the emergence of plasmons, quasiparticles, and conventional superconductivity in SCES, I consider their application to three of SCES's sister systems, the helium liquids, nuclei, and the nuclear matter found in neutron stars. I note some recent applications of the random phase approximation and examine briefly the role that paradigm change is playing in two central problems in our field: understanding the emergence and subsequent behavior of heavy electrons in Kondo lattice materials; and finding the mechanism for the unconventional superconductivity found in heavy electron, organic, cuprate, and iron-based materials. PMID- 27484184 TI - Factors influencing transitional care from adolescents to young adults with cancer in Taiwan: A population-based study. AB - BACKGROUND: To investigate the progress of transition from paediatric to adult health care for patients with cancer in Taiwan's medical system. METHODS: The data were retrieved from the Longitudinal Health Insurance Database (LHID), which contains the original inpatient and outpatient medical claims data for 1,000,000 enrollees randomly sampled from the NHIRD between 1997 and 2010. RESULTS: Among the 1,411 cancer patients selected for this study, 98.09 % received adult oriented therapy before the age of 18. In addition, only 1.91 % of the patients received paediatric-oriented therapy during adolescence. The primary factors that determine whether these patients would receive paediatric-oriented therapy or adult-oriented therapy at an early age were as follows: the age of the patient at the first visit and the performance-level of the hospital (p < 0.001). CONCLUSIONS: Previous studies conducted in developed countries have demonstrated that the unwillingness of patients to switch from paediatric-oriented therapy to adult-oriented therapy being the major obstacle that hinders the transition process. However, this study revealed a different result: the implementation of the National Health Insurance system in Taiwan makes healthcare affordable for the adolescent patients who may not possess adequate knowledge about paediatric health care and may not appreciate paediatric-oriented therapy, thereby hindering the transition process. PMID- 27484185 TI - CHEK2 represses breast stromal fibroblasts and their paracrine tumor-promoting effects through suppressing SDF-1 and IL-6. AB - BACKGROUND: Active fibroblasts, the predominant and the most active cells of breast cancer stroma, are responsible for tumor growth and spread. However, the molecular mediators and pathways responsible for stromal fibroblast activation, and their paracrine pro-carcinogenic effects are still not well defined. The CHEK2 tumor suppressor gene codes for a protein kinase, which plays important roles in the cellular response to various genotoxic stresses. METHODS: Immunoblotting, quantitative RT-PCR and Immunofluorescence were used to assess the expression of CHEK2 in different primary breast fibroblasts and in tissues. The effect of CHEK2 on the expression and secretion of SDF-1 and IL-6 was evaluated by immunoblotting and ELISA. The WST-1 colorimetric assay was used to assess cell proliferation, while the BD BioCoat Matrigel invasion chambers were utilized to determine the effects of CHEK2 on the migratory and the invasiveness capacities of breast stromal fibroblasts as well as breast cancer cells. RESULTS: We have shown that CHEK2 is down-regulated in most cancer-associated fibroblasts (CAFs) as compared to their corresponding tumor counterpart fibroblasts (TCFs) at both the mRNA and protein levels. Interestingly, CHEK2 down-regulation using specific siRNA increased the expression/secretion of both cancer-promoting cytokines SDF-1 and IL-6, and transdifferentiated stromal fibroblasts to myofibroblasts. These cells were able to enhance the proliferation of non cancerous epithelial cells, and also boosted the migration/invasion abilities of breast cancer cells in a paracrine manner. The later effect was SDF-1/IL-6 dependent. Importantly, ectopic expression of CHEK2 in active CAFs converted these cells to a normal state, with lower migration/invasion capacities and reduced paracrine pro-carcinogenic effects. CONCLUSION: These results indicate that CHEK2 possesses non-cell-autonomous tumor suppressor functions, and present the Chk2 protein as an important mediator in the functional interplay between breast carcinomas and their stromal fibroblasts. PMID- 27484186 TI - Remediation of mercury-polluted soils using artificial wetlands. AB - Mexico's mercury mining industry is important for economic development, but has unfortunately contaminated soils due to open-air disposal. This case was seen at two sites in the municipality of Pinal de Amoles, State of Queretaro, Mexico. This paper presents an evaluation of mercury dynamics and biogeochemistry in two soils (mining waste soil) using ex-situ wetlands over 36 weeks. In soils sampled in two former mines of Pinal de Amoles, initial mercury concentrations were 424 +/- 29 and 433 +/- 12 mg kg-1 in La Lorena and San Jose, former mines, respectively. Typha latifolia and Phragmites australis were used and 20 reactors were constructed (with and without plants). The reactors were weekly amended with a nutrient solution (NPK), for each plant, at a pH of 5.0. For remediation using soils from San Jose 70-78% of mercury was removed in T. latifolia reactors and 76 82% in P. australis reactors, and for remediation of soils from La Lorena, mercury content was reduced by 55-71% using T. latifolia and 58-66% in P. australis reactors. Mercury emissions into the atmosphere were estimated to be 2 4 mg m-2 h-1 for both soils. PMID- 27484188 TI - Advanced Mitigation Process (AMP) for Improving Laser Damage Threshold of Fused Silica Optics. AB - The laser damage precursors in subsurface of fused silica (e.g. photosensitive impurities, scratches and redeposited silica compounds) were mitigated by mineral acid leaching and HF etching with multi-frequency ultrasonic agitation, respectively. The comparison of scratches morphology after static etching and high-frequency ultrasonic agitation etching was devoted in our case. And comparison of laser induce damage resistance of scratched and non-scratched fused silica surfaces after HF etching with high-frequency ultrasonic agitation were also investigated in this study. The global laser induce damage resistance was increased significantly after the laser damage precursors were mitigated in this case. The redeposition of reaction produce was avoided by involving multi frequency ultrasonic and chemical leaching process. These methods made the increase of laser damage threshold more stable. In addition, there is no scratch related damage initiations found on the samples which were treated by Advanced Mitigation Process. PMID- 27484187 TI - Ruling out nosocomial transmission of Cryptosporidium in a renal transplantation unit: case report. AB - BACKGROUND: Cryptosporidium spp. is a ubiquitous parasite affecting humans as well as domestic and wild vertebrates, causing diarrhea in both immunocompetent and immunocompromised hosts worldwide. Its transmission occurs primarily by the fecal-oral route. In humans, C. parvum and C. hominis are the most prevalent species, whereas immunocompetent and immunocompromised individuals can also be infected by other zoonotic species. Renal transplant patients are prone to develop cryptosporidiosis, which can induce severe and life-threatening diarrhea. CASE PRESENTATION: We report here a series of nearly concomitant cases of acute symptomatic cryptosporidiosis in three renal transplant patients attending the Strasbourg University Hospital Nephrology Unit. The clinical presentation was persistent diarrhea and acute renal failure. The diagnosis was confirmed by microscopic stool examination using a modified Ziehl-Neelsen staining method and species identification by molecular tools. All patients were treated with nitazoxanide and recovered from diarrhea after 14 days of therapy. CONCLUSION: Genotypic species identification was not consistent with an epidemic context, thus underlining the need for genotyping to monitor at risk patients. PMID- 27484189 TI - The Value of Mitotic Count and Ki67 Proliferation Index in Congenital Mesoblastic Nephroma. AB - OBJECTIVE: We aimed to define the histopathologic features and proliferative rate of congenital mesoblastic nephroma (CMN) as a risk factor for recurrence. METHODS: Fourteen cases of CMN among 138 registered pediatric renal tumors were retrospectively reviewed. The prognostic impact for mitotic rate and Ki67 index was investigated. RESULTS: There were four (28.6%) classic, six (42.9%) cellular, and four (28.6%) mixed type CMNs, with average Ki-67 counts of 16.75% in the classic CMN, and 53.2% in the tumors with cellular components (both mixed and cellular CMNs). Twelve patients (85.7%) were aged less than six months. Tumors with cellular component showed significantly larger tumor diameter and higher Ki 67 index (p = 0.015 and p = 0.016, respectively). The patient with cellular CMN, whose tumor showed the highest mitotic rate (4.9/HPF), but not the highest Ki67 index (57.4%), died of recurrent disease with distant metastasis. CONCLUSION: Proliferative markers-mitotic count and Ki67 index-have limited value to predict recurrence or metastasis in CMNs with a cellular component. PMID- 27484192 TI - Abstracts of the 51st Workshop for Pediatric Research. PMID- 27484190 TI - Innate lymphoid cells: models of plasticity for immune homeostasis and rapid responsiveness in protection. AB - Innate lymphoid cells (ILCs) have stormed onto the immune landscape as "newly discovered" cell types. These tissue-resident sentinels are enriched at mucosal surfaces and engage in complex cross talk with elements of the adaptive immune system and microenvironment to orchestrate immune homeostasis. Many parallels exist between innate cells and T cells leading to the initial partitioning of ILCs into rather rigid subsets that reflect their "adaptive-like" effector cytokines profiles. ILCs themselves, however, have unique attributes that are only just beginning to be elucidated. These features result in complementarity with, rather than complete duplication of, functions of the adaptive immune system. Key transcription factors determine the pathway of differentiation of progenitors towards an ILC1, ILC2, or ILC3 subset. Once formed, flexibility in the responses of these subsets to stimuli unexpectedly allows transdifferentation between the different subsets and the acquisition of altered phenotypes and function. This provides a mechanism for rapid innate immune responsiveness. Here, we discuss the models of differentiation for maintenance and activation of tissue resident ILCs in maintaining immune homeostasis and protection. PMID- 27484191 TI - #Vapelife: An Exploratory Study of Electronic Cigarette Use and Promotion on Instagram. AB - BACKGROUND: The growth of social networking services has enabled the sharing of electronic cigarette opinions and experiences via user-generated content. OBJECTIVES: This exploratory study analyzed electronic cigarette content found on the visual social networking service, Instagram, in order to highlight public health challenges created by this content and support understanding of electronic cigarette promotion and usage. METHODS: A qualitative content analysis was performed on Instagram posts made with the hashtags #ecig or #vape in October 2014. Images, text, and hashtags from 85 posts (43 #ecig, 42 #vape) were analyzed. In addition, the total number of posts made with eight key electronic cigarette hashtags was recorded at four points between March 2014 and October 2015. RESULTS: The total number of #vape posts on Instagram grew by 4,163,274 during the study period, while #ecig posts increased by 741,916. Of the posts examined in-depth, corporate users made up over half of posts. No posts were critical of electronic cigarettes. Few mentioned electronic cigarettes in the context of health benefits. No posts included major brands, and mod style electronic cigarettes were mentioned or depicted in over half of posts. A majority of posts included hashtags expressing vaping identity and community. In addition, users mentioned novel practices such as sub-ohming. Conclusions/Importance: Instagram users in our sample characterized electronic cigarettes primarily as novel devices rather than equivalents to cigarettes. Further, hashtag communities and identities appear to be forming around vaping. Future research should consider the public health implications of these hashtags, as well as novel electronic cigarette practices. PMID- 27484194 TI - Prevalence and assessment of traumatic brain injury in prison inmates: A systematic PRISMA review. AB - OBJECTIVES: The primary objectives of the present systematic PRISMA review were: (1) to explore the range of prevalence of TBI in offenders and whether this is higher than in a control sample; (2) to determine which screening measures are available and evaluate the evidence on these; and, lastly, (3) to evaluate whether prevalence of TBI is associated with increased prevalence of other health conditions and/or offending behaviour. METHODS: The present systematic PRISMA review explores the peer-reviewed literature published since 2005 which has investigated TBI in incarcerated populations using five databases (CINAHL, MEDLINE, PsycARTICLES, Psychology and Behavioral Sciences Collection, PsycINFO) in addition to separate searches conducted on 'Google Scholar' using specific search criteria. RESULTS: Seventeen studies were identified which explored the prevalence of TBI in inmates. Only five of the seventeen studies which investigated prevalence of TBI in offender populations looked at juvenile offending. Interestingly, only seven of the 17 studies included both male and female samples (two of which did not report findings separately for males and females). In terms of the assessments used to investigate prevalence, three studies investigated the prevalence of TBI using The Ohio State University (OSU) TBI Identification method (OSU-TBI-ID). Nine studies used one or two questions in order to elicit information on whether the offender had previously experienced a TBI. Only two studies used the Traumatic Brain Injury Questionnaire (TBIQ). One study used the Brain Injury Screening Index (BISI). One study investigated patients discharged from non-federal South Carolina Emergency Departments or hospitals with a TBI-related ICD-9-CM code. Lastly evidence of TBI checklist from medical record (14 items) was used in one study. CONCLUSIONS: In terms of the implication for further research and practice, the studies identified in this review clearly emphasize the need to account for TBI in managing care in offender populations, which may contribute to reduction in offending behaviours. Additionally, there is a need for further research investigating the clinical utility of screening tools for detecting TBI in offender populations such as The Traumatic Brain Injury Questionnaire (TBIQ), The Brain Injury Screening Index (BISI) and The Ohio State University (OSU-TBI-ID) TBI Identification method. PMID- 27484193 TI - Endocannabinoid system: Role in depression, reward and pain control (Review). AB - Depression and pain co-exist in almost 80% of patients and are associated with impaired health-related quality of life, often contributing to high mortality. However, the majority of patients who suffer from the comorbid depression and pain are not responsive to pharmacological treatments that address either pain or depression, making this comorbidity disorder a heavy burden on patients and society. In ancient times, this depression-pain comorbidity was treated using extracts of the Cannabis sativa plant, known now as marijuana and the mode of action of Delta9-tetrahydrocannabinol, the active cannabinoid ingredient of marijuana, has only recently become known, with the identification of cannabinoid receptor type 1 (CB1) and CB2. Subsequent investigations led to the identification of endocannabinoids, anandamide and 2-arachidonoylglycerol, which exert cannabinomimetic effects through the CB1 and CB2 receptors, which are located on presynaptic membranes in the central nervous system and in peripheral tissues, respectively. These endocannabinoids are produced from membrane lipids and are lipohilic molecules that are synthesized on demand and are eliminated rapidly after their usage by hydrolyzing enzymes. Clinical studies revealed altered endocannabinoid signaling in patients with chronic pain. Considerable evidence suggested the involvement of the endocannabinoid system in eliciting potent effects on neurotransmission, neuroendocrine, and inflammatory processes, which are known to be deranged in depression and chronic pain. Several synthetic cannabinomimetic drugs are being developed to treat pain and depression. However, the precise mode of action of endocannabinoids on different targets in the body and whether their effects on pain and depression follow the same or different pathways, remains to be determined. PMID- 27484195 TI - Muscleblind-like 3 deficit results in a spectrum of age-associated pathologies observed in myotonic dystrophy. AB - Myotonic dystrophy type I (DM1) exhibits distinctive disease specific phenotypes and the accelerated onset of a spectrum of age-associated pathologies. In DM1, dominant effects of expanded CUG repeats result in part from the inactivation of the muscleblind-like (MBNL) proteins. To test the role of MBNL3, we deleted Mbnl3 exon 2 (Mbnl3(DeltaE2)) in mice and examined the onset of age-associated diseases over 4 to 13 months of age. Accelerated onset of glucose intolerance with elevated insulin levels, cardiac systole deficits, left ventricle hypertrophy, a predictor of a later onset of heart failure and the development of subcapsular and cortical cataracts is observed in Mbnl3(DeltaE2) mice. Retention of embryonic splice isoforms in adult organs, a prominent defect in DM1, is not observed in multiple RNAs including the Insulin Receptor (Insr), Cardiac Troponin T (Tnnt2), Lim Domain Binding 3 (Ldb3) RNAs in Mbnl3(DeltaE2) mice. Although rare DM1-like splice errors underlying the observed phenotypes cannot be excluded, our data in conjunction with the reported absence of alternative splice errors in embryonic muscles of a similar Mbnl3(DeltaE2) mouse by RNA-seq studies, suggest that mechanisms distinct from the adult retention of embryonic splice patterns may make important contributions to the onset of age-associated pathologies in DM1. PMID- 27484196 TI - iLIR database: A web resource for LIR motif-containing proteins in eukaryotes. AB - Atg8-family proteins are the best-studied proteins of the core autophagic machinery. They are essential for the elongation and closure of the phagophore into a proper autophagosome. Moreover, Atg8-family proteins are associated with the phagophore from the initiation of the autophagic process to, or just prior to, the fusion between autophagosomes with lysosomes. In addition to their implication in autophagosome biogenesis, they are crucial for selective autophagy through their ability to interact with selective autophagy receptor proteins necessary for the specific targeting of substrates for autophagic degradation. In the past few years it has been revealed that Atg8-interacting proteins include not only receptors but also components of the core autophagic machinery, proteins associated with vesicles and their transport, and specific proteins that are selectively degraded by autophagy. Atg8-interacting proteins contain a short linear LC3-interacting region/LC3 recognition sequence/Atg8-interacting motif (LIR/LRS/AIM) motif which is responsible for their interaction with Atg8-family proteins. These proteins are referred to as LIR-containing proteins (LIRCPs). So far, many experimental efforts have been carried out to identify new LIRCPs, leading to the characterization of some of them in the past 10 years. Given the need for the identification of LIRCPs in various organisms, we developed the iLIR database ( https://ilir.warwick.ac.uk ) as a freely available web resource, listing all the putative canonical LIRCPs identified in silico in the proteomes of 8 model organisms using the iLIR server, combined with a Gene Ontology (GO) term analysis. Additionally, a curated text-mining analysis of the literature permitted us to identify novel putative LICRPs in mammals that have not previously been associated with autophagy. PMID- 27484198 TI - Innate heart regeneration: endogenous cellular sources and exogenous therapeutic amplification. AB - INTRODUCTION: The -once viewed as heretical- concept of the adult mammalian heart as a dynamic organ capable of endogenous regeneration has recently gained traction. However, estimated rates of myocyte turnover vary wildly and the underlying mechanisms of cardiac plasticity remain controversial. It is still unclear whether the adult mammalian heart gives birth to new myocytes through proliferation of resident myocytes, through cardiomyogenic differentiation of endogenous progenitors or through both mechanisms. AREAS COVERED: In this review, the authors discuss the cellular origins of postnatal mammalian cardiomyogenesis and touch upon therapeutic strategies that could potentially amplify innate cardiac regeneration. EXPERT OPINION: The adult mammalian heart harbors a limited but detectable capacity for spontaneous endogenous regeneration. During normal aging, proliferation of pre-existing cardiomyocytes is the dominant mechanism for generation of new cardiomyocytes. Following myocardial injury, myocyte proliferation increases modestly, but differentiation of endogenous progenitor cells appears to also contribute to cardiomyogenesis (although agreement on the latter point is not universal). Since cardiomyocyte deficiency underlies almost all types of heart disease, development of therapeutic strategies that amplify endogenous regeneration to a clinically-meaningful degree is of utmost importance. PMID- 27484197 TI - Reversible lysine acetylation is involved in DNA replication initiation by regulating activities of initiator DnaA in Escherichia coli. AB - The regulation of chromosomal replication is critical and the activation of DnaA by ATP binding is a key step in replication initiation. However, it remains unclear whether and how the process of ATP-binding to DnaA is regulated. Here, we show that DnaA can be acetylated, and its acetylation level varies with cell growth and correlates with DNA replication initiation frequencies in E. coli. Specifically, the conserved K178 in Walker A motif of DnaA can be acetylated and its acetylation level reaches the summit at the stationary phase, which prevents DnaA from binding to ATP or oriC and leads to inhibition of DNA replication initiation. The deacetylation process of DnaA is catalyzed by deacetylase CobB. The acetylation process of DnaA is mediated by acetyltransferase YfiQ, and nonenzymatically by acetyl-phosphate. These findings suggest that the reversible acetylation of DnaA ensures cells to respond promptly to environmental changes. Since Walker A motif is universally distributed across organisms, acetylation of Walker A motif may present a novel regulatory mechanism conserved from bacteria to eukaryotes. PMID- 27484199 TI - Impact of literacy and years of education on the diagnosis of dementia: A population-based study. AB - BACKGROUND: The effect of different educational indices on clinical diagnosis of dementia requires more investigation. OBJECTIVE: We compared the differential influence of two educational indices (EIs): years of schooling and level of education (i.e., null/low literacy, can read and write, primary school, and secondary school) on global cognition, functional performance, and the probability of having a dementia diagnosis. METHOD: A total of 3,816 participants were selected from the population-based study of older adults "Neurological Disorders in Central Spain" (NEDICES). The 37-item version of the Mini-Mental State Examination (MMSE-37) and the Pfeffer's questionnaire were applied to assess cognitive and functional performance, respectively. The diagnosis of dementia was performed by expert neurologists according to Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) criteria. Logistic regression models adjusted for potential confounders were carried out to test the association between the two EIs and dementia diagnosis. RESULTS: Both EIs were significantly associated with cognitive and functional scores, but individuals with null/low literacy performed significantly worse on MMSE-37 than literates when these groups were compared in terms of years of schooling. The two EIs were also related to an increased probability of dementia diagnosis in logistic models, but the association's strength was stronger for level of education than for years of schooling. CONCLUSION: Literacy predicted cognitive performance over and above the years of schooling. Lower education increases the probability of having a dementia diagnosis but the impact of different EIs is not uniform. PMID- 27484200 TI - Leaching of PAHs from agricultural soils treated with oil shale combustion ash: an experimental study. AB - The present study focuses on the fate of polycyclic aromatic hydrocarbons (PAHs) in soils amended with oil shale ash (OSA). Leachability studies to assess the release of PAHs to the environment are essential before the application of OSA in agriculture. A quantitative estimation of the leaching of PAHs from two types of soil and two types of OSA was undertaken in this study. Two leaching approaches were chosen: (1) a traditional one step leaching scheme and (2) a leaching scheme with pretreatment, i.e.., incubation of the material in wet conditions imitating the field conditions, followed by a traditional leaching procedure keeping the total amount of water constant. The total amount of PAHs leached from soil/OSA mixtures was in the range of 15 to 48 MUg/kg. The amount of total PAHs leached was higher for the incubation method, compared to the traditional leaching method, particularly for Podzolic Gleysols soil. This suggests that for the incubation method, the content of organic matter and clay minerals of the soil influence the fate of PAHs more strongly compared to the traditional leaching scheme. The amount of PAHs leached from OSA samples is higher than from soil/OSA mixtures, which suggests soils to inhibit the release of PAHs. Calculated amount of PAHs from experimental soil and OSA leaching experiments differed considerably from real values. Thus, it is not possible to estimate the amount of PAHs leached from soil/OSA mixtures based on the knowledge of the amount of PAHs leached from soil and OSA samples separately. PMID- 27484201 TI - Residue decline and risk assessment of fluopyram + tebuconazole (400SC) in/on onion (Allium cepa). AB - A method was validated for estimating fluopyram and tebuconazole in onion on LC MS/MS using dispersive QuEChERS. Three sprays of a combination fungicide fluopyram + tebuconazole (Luna experience, 400 SC) were applied @ 75 + 75 and 150 + 150 g a.i. ha-1 at an interval of 10 days on onion using Knapsack sprayer. First spray was made at bulb setting stage. Spring onion samples were drawn at 0 (1 h), 1, 3, 5, 7, 10, 15, and 20 days and matured onion bulb at harvest (52 days) after the last spray. Soil samples were also drawn at harvest. Foliar application of the combination product resulted in 1.14 and 2.86 mg kg-1 fluopyram residues on spring onion at standard and double dose, respectively, one hour after the last application. The levels of fluopyram residues gradually declined and recorded 0.25 and 0.58 mg kg-1 on 20th day of application with half lives of 8.8 and 9.1 days at standard and double dose, respectively. For tebuconazole, the corresponding residues observed after 1 h (0 day) of application were 0.92 and 2.29 mg kg-1. The levels declined gradually to 0.12 and 0.33 mg kg-1 on 20th days with half-life of 6.7 to 7.7 days at standard and double dose, respectively. Here, we are proposing a pre-harvest interval of 7 day for fluopyram and tebuconazole in spring onion when applied at 75 + 75 g a.i. ha 1 (400 SC). Risk assessment was done by calculating hazard quotient and by comparing theoretical maximum residue intake (TMRI) with maximum permissible intake (MPI). In all the cases, results of the study showed that HQ (Hazard Quotient) <=1 and TMDI < MPI. Hence, the use of this combination product can be recommended with pre harvest interval of 7 days. The data can be used in establishing MRLs (maximum residue limits) for spring onion after considering multilocation trials. PMID- 27484203 TI - Strategies for bioengineered scaffolds that support adipose stem cells in regenerative therapies. AB - Regenerative medicine possesses the potential to ameliorate damage to tissue that results from a vast range of conditions, including traumatic injury, tumor resection and inherited tissue defects. Adult stem cells, while more limited in their potential than pluripotent stem cells, are still capable of differentiating into numerous lineages and provide feasible allogeneic and autologous treatment options for many conditions. Adipose stem cells are one of the most abundant types of stem cell in the adult human. Here, we review recent advances in the development of synthetic scaffolding systems used in concert with adipose stem cells and assess their potential use for clinical applications. PMID- 27484202 TI - Heavy metals in tissues of scorpionfish (Scorpaena porcus) caught from Black Sea (Turkey) and potential risks to human health. AB - Scorpionfish (Scorpaena porcus) is a demersal fish species commercially important for its of which meat is tough and delicious. The aim of this study was to determine heavy metal (Al, Cu, Ni, As, Cd, Hg, Pb, U) concentrations in this fish species which is traditionally consumed in the Black Sea Area and, to compare the concentrations of various toxic elements in different organs of the fish specimens (muscle, liver, gill, and skin). Within this scope, the mineralization was performed using microwave digestion system. Thirty-two scorpionfish caught from Sinop Inland Port during 2010 were analyzed. The heavy metal concentrations were determined with the method of inductively coupled plasma mass spectroscopy (ICP-MS). Verification of the method was demonstrated by analysis of standard reference material (NRCC-TORT-2 lobster hepatopancreas). After evaluation of the results, it was determined that the highest heavy metal accumulation was generally found in the liver. The maximum aluminum level and the minimum uranium level were found in the analyzed tissues. In terms of heavy metals, Al, Cu, Cd, and Hg showed a statistically significant difference between tissues (p < 0.05). It was determined that heavy metal concentrations obtained from the muscle tissues did not exceed the national and international recommended limits; and also it was found that daily intake amounts did not exceed tolerable daily intake amounts. Furthermore, in THQ based risk evaluation, the value 1 which is crucial for children and adults was not surpassed. In terms of public health, it was found out that there was not any risk in consumption of scorpionfish in the study area. PMID- 27484204 TI - Impact of tumor histology and grade on treatment success of percutaneous renal cryoablation. AB - BACKGROUND: We analyzed oncological outcomes in patients who underwent percutaneous renal cryoablation (PRC) with documented renal cell carcinoma (RCC) by perioperative biopsy. METHODS: Multicenter retrospective analysis of 153 patients [median follow-up 48 months] who underwent PRC from 09/2005 to 08/2014 was performed. We divided the cohort into patients who developed recurrence versus no recurrence. Kaplan-Meier analyses examined recurrence-free survival (RFS) according to grade and histology. Multivariable analysis (MVA) was performed to identify factors associated with tumor recurrence. RESULTS: One hundred and fifty-three patients were analyzed [18 patients (11.8 %) with recurrence and 135 (88.2 %) patients without recurrence]. There were no differences between the groups with respect to demographics, RENAL score, and number of probes utilized. Recurrence group had larger tumor size (3.1 vs. 2.4 cm; p = 0.011), upper pole tumor location (p = 0.016), and greater proportions of high-grade tumor (33 vs. 0.7 %; p < 0.001) and clear cell histology (77.8 vs. 45.9 %; p = 0.011). Four-year RFS was 100 versus 80 % for grade 1 versus grade 2/3 tumors (p = 0.0002), and 97 versus 88 % for other RCC versus clear cell RCC (p = 0.07). MVA demonstrated tumor size >3 cm (OR 2.46; p = 0.019), clear cell histology (OR 2.12; p = 0.027), and high tumor grade (OR 2.33, p < 0.001) as independent risk factors associated with tumor recurrence. CONCLUSIONS: Association of higher grade and clear cell histology with recurrence and progression suggests need for increased emphasis on preoperative risk stratification by biopsy, with grade 1 and non-clear cell RCC being associated with improved treatment success than higher grade and clear cell RCC. PMID- 27484205 TI - Neural supply of the male urethral sphincter: comprehensive anatomical review and implications for continence recovery after radical prostatectomy. AB - PURPOSE: To review the anatomical facts of urethral sphincter (US) innervation discovered over the last three decades and to determine the implications for continence recovery after radical prostatectomy (RP). METHODS: Using the PubMed(r) database, we searched for peer-reviewed articles in English between January 1985 and September 2015, with the following terms: 'urethral sphincter,' 'urethral rhabdosphincter,' 'urinary continence and nerve supply' and 'neuroanatomy and nerve sparing.' The anatomical methodology, number of bodies examined, data, figures, relevant facts and text were analyzed. RESULTS: Seventeen articles on 254 anatomical subjects were reviewed. Coexisting pathways were described in every article. Dissection, histology, simulation or electron microscopy evidence supported arguments for somatic and autonomic pathways. From the most to the least substantiated, somatic sphincteric fibers were described extra- or intrapelvic as: direct from the distal pudendal nerve (PuN), recurrent from the dorsal nerve of the penis, from the proximal PuN with an intrapelvic course, extrapudendal somatic fibers dispersed among autonomic pelvic fibers. From the pelvic plexus, or from the neurovascular bundles, autonomic fibers to the US have been described in 13 of the reviewed articles, with at least each of the available anatomical methods. CONCLUSION: Because continence depends on a number of factors, it is challenging to delineate the specific impact of periprostatic nerve sparing on continence, but the anatomical data suggest that RP surgeons should steer toward the preservation and protection of these nerves whenever possible. PMID- 27484206 TI - Future directions in prostate cancer testing: a comment upon results from the prospective population-based diagnostic STHLM3 study-Gronberg H et al. Lancet Oncology. 2015 Nov 9; doi:10.1016/S1470-2045(15)00361-7. PMID- 27484207 TI - Early Childhood Environment and Genetic Interactions: the Diathesis for Suicidal Behavior. AB - Adverse childhood experiences are associated with higher risk for suicide and suicidal behavior later in life. There are known associations between childhood trauma, particularly sexual abuse, and higher rates of suicide, non-lethal suicide attempts, and non-suicidal self-injurious behaviors in adolescence and adulthood. Emotional abuse/neglect, disrupted parental attachment, and cumulative effect of multiple forms of maltreatment, also increase risk. Yet, the causal relationship remains unclear. The diathesis-stress model provides a framework for understanding how early life adverse experiences contribute to suicide vulnerability. Current findings from the fields of biology, neurology, and genetics shed new light on mediating variables and possible causal links between early childhood trauma and suicide. In this paper, we review recent advances, particularly regarding the interaction of early life environmental adverse events with genetics factors, that increase the diathesis for psychological traits are associated with subsequent deliberate self-harm behaviors. PMID- 27484208 TI - miR-22-5p revealed as a potential biomarker involved in the acute phase of myocardial infarction via profiling of circulating microRNAs. AB - Acute myocardial infarction (AMI) is a life-threatening episode of coronary artery disease. Recently, circulating myocardial-derived microRNAs (miRNAs) have been reported as potential biomarkers of infarction. The present study aimed to identify differentially expressed miRNAs in patients with ST-segment elevation myocardial infarction that could be potentially dysregulated in response to early myocardial damage. miRNA expression profile analysis was performed using the Serum/Plasma Focus miRNA Polymerase Chain Reaction (PCR) panel of Exiqon A/S (Vedbaek, Denmark) on plasma samples of patients on the first day of AMI (admission) and on samples from the identical patients collected six months following AMI. Selected miRNAs were validated by reverse transcription quantitative PCR (RT-qPCR) using independent patients with AMI and a control group of patients with a stable coronary artery disease. Thirty-two species of plasma miRNA were differentially expressed (P<0.05) on admission compared with six months following AMI. Subsequent validation in an independent patient group confirmed that miR-133b and miR-22-5p were significantly up-regulated in the serum of patients with AMI. The receiver operating characteristic (ROC) curve analysis demonstrated a diagnostic utility for miR-22-5p, which has not previously been reported to be associated with AMI. Among the selected miRNAs, miR-22-5p represents a novel promising biomarker for the diagnosis of AMI. PMID- 27484209 TI - Factors influencing the health-related quality of life of Chinese advanced cancer patients and their spousal caregivers: a cross-sectional study. AB - BACKGROUND: Cancer and its treatment have a major impact on the lives of patients and their intimate partners, such as on their health-related quality of life (HRQOL). The aims of this study are to: (i) assess the HRQOL of advanced cancer patients and spousal caregivers, and explore the relationship between the HRQOL of cancer patients and that of their spousal caregivers; (ii) detect factors influencing the HRQOL of cancer patients and spousal caregivers; and (iii) explore the impact of anxiety and depression on the HRQOL of couples. METHODS: A total of 131 couples where one of the partners was hospitalized for advanced cancer were invited to complete a survey to assess their demographic and background information, HRQOL, and anxiety and depression. HRQOL was measured using the SF-12, while anxiety and depression were measured using the Hospital Anxiety and Depression Scale. Data were analyzed using a T-test, Pearson correlations, multiple linear regressions, and structural equation modeling. RESULTS: In general, the spousal caregivers had higher levels of HRQOL (seven out of eight SF-12 domains and two SF-12 dimensions) p = 0.038-0.000, anxiety (p = 0.002), and depression (p = 0.011) than patients. Correlations of HRQOL between patients and spouses were small to moderate (r = 0.193-0.398). Multiple independent factors influencing the physical component summary (PCS), mental component summary (MCS), vitality (VT), and role emotional (RE) sections of the SF-12 were identified, including: gender, time since diagnosis, levels of education, working status, the extent to which spousal caregivers were informed about the disease, improved marital relationship after the diagnosis of cancer, and anxiety and depression. For both patients and spousal caregivers, the strongest independent factor influencing HRQOL (SF-12 PCS, MCS, VT, and RE) was anxiety and depression. Anxiety and depression may have both actor and partner effects on the HRQOL of couples to various degrees. CONCLUSIONS: The findings of this study call attention to the HRQOL of couples and its influencing factors. Individual characteristics of cancer patients and spouses, marital relationship, and anxiety and depression are highlighted as areas in which couples coping with cancer could benefit from interventions to improve their HRQOL. PMID- 27484210 TI - mTOR is a fine tuning molecule in CDK inhibitors-induced distinct cell death mechanisms via PI3K/AKT/mTOR signaling axis in prostate cancer cells. AB - Purvalanol and roscovitine are cyclin dependent kinase (CDK) inhibitors that induce cell cycle arrest and apoptosis in various cancer cells. We further hypothesized that co-treatment of CDK inhibitors with rapamycin, an mTOR inhibitor, would be an effective combinatory strategy for the inhibition of prostate cancer regard to androgen receptor (AR) status due to inhibition of proliferative pathway, PI3K/AKT/mTOR, and induction of cell death mechanisms. Androgen responsive (AR+), PTEN(-/-) LNCaP and androgen independent (AR-), PTEN(+/-) DU145 prostate cancer cells were exposed to purvalanol (20 uM) and roscovitine (30 uM) with or without rapamycin for 24 h. Cell viability assay, immunoblotting, flow cytometry and fluorescence microscopy was used to define the effect of CDK inhibitors with or without rapamycin on proliferative pathway and cell death mechanisms in LNCaP and DU145 prostate cancer cells. Co-treatment of rapamycin modulated CDK inhibitors-induced cytotoxicity and apoptosis that CDK inhibitors were more potent to induce cell death in AR (+) LNCaP cells than AR ( ) DU145 cells. CDK inhibitors in the presence or absence of rapamycin induced cell death via modulating upstream PI3K/AKT/mTOR signaling pathway in LNCaP cells, exclusively only treatment of purvalanol have strong potential to inhibit both upstream and downstream targets of mTOR in LNCaP and DU145 cells. However, co-treatment of rapamycin with CDK inhibitors protects DU145 cells from apoptosis via induction of autophagy mechanism. We confirmed that purvalanol and roscovitine were strong apoptotic and autophagy inducers that based on regulation of PI3K/AKT/mTOR signaling pathway. Co-treatment of rapamycin with purvalanol and roscovitine exerted different effects on cell survival and death mechanisms in LNCaP and DU145 cell due to their AR receptor status. Our studies show that co treatment of rapamycin with CDK inhibitors inhibit prostate cancer cell viability more effectively than either agent alone, in part, by targeting the mTOR signaling cascade in AR (+) LNCaP cells. In this point, mTOR is a fine-tuning player in purvalanol and roscovitine-induced apoptosis and autophagy via regulation of PI3K/AKT and the downstream targets, which related with cell proliferation. PMID- 27484211 TI - Inhibition of autophagy by chloroquine induces apoptosis in primary effusion lymphoma in vitro and in vivo through induction of endoplasmic reticulum stress. AB - Autophagy plays a crucial role in cancer cell survival and the inhibition of autophagy is attracting attention as an emerging strategy for the treatment of cancer. Chloroquine (CQ) is an anti-malarial drug, and is also known as an inhibitor of autophagy. Recently, it has been found that CQ induces cancer cell death through the inhibition of autophagy; however, the underlying mechanism is not entirely understood. In this study, we identified the role of CQ-induced cancer cell death using Primary Effusion Lymphoma (PEL) cells. We found that a CQ treatment induced caspase-dependent apoptosis in vitro. CQ also suppressed PEL cell growth in a PEL xenograft mouse model. We showed that CQ activated endoplasmic reticulum (ER) stress signal pathways and induced CHOP, which is an inducer of apoptosis. CQ-induced cell death was significantly decreased by salbrinal, an ER stress inhibitor, indicating that CQ-induced apoptosis in PEL cells depended on ER stress. We show here for the first time that the inhibition of autophagy induces ER stress-mediated apoptosis in PEL cells. Thus, the inhibition of autophagy is a novel strategy for cancer chemotherapy. PMID- 27484212 TI - "Heart failure, whole-body insulin resistance and myocardial insulin resistance: An intriguing puzzle". PMID- 27484213 TI - Conducting and interpreting high-quality systematic reviews and meta-analyses. AB - Systematic reviews and meta-analyses are powerful tools for summarizing existing literature and combining evidence from multiple studies. These methods employ complex searches, statistical techniques, and presentation techniques with which the clinical audience may not be very familiar. This review article aims to familiarize the clinical audience with the various techniques employed to conduct a high-quality systematic review and meta-analysis. PMID- 27484214 TI - Prospective evaluation of shape similarity based pose prediction method in D3R Grand Challenge 2015. AB - Evaluation of ligand three-dimensional (3D) shape similarity is one of the commonly used approaches to identify ligands similar to one or more known active compounds from a library of small molecules. Apart from using ligand shape similarity as a virtual screening tool, its role in pose prediction and pose scoring has also been reported. We have recently developed a method that utilizes ligand 3D shape similarity with known crystallographic ligands to predict binding poses of query ligands. Here, we report the prospective evaluation of our pose prediction method through the participation in drug design data resource (D3R) Grand Challenge 2015. Our pose prediction method was used to predict binding poses of heat shock protein 90 (HSP90) and mitogen activated protein kinase kinase kinase kinase (MAP4K4) ligands and it was able to predict the pose within 2 A root mean square deviation (RMSD) either as the top pose or among the best of five poses in a majority of cases. Specifically for HSP90 protein, a median RMSD of 0.73 and 0.68 A was obtained for the top and the best of five predictions respectively. For MAP4K4 target, although the median RMSD for our top prediction was only 2.87 A but the median RMSD of 1.67 A for the best of five predictions was well within the limit for successful prediction. Furthermore, the performance of our pose prediction method for HSP90 and MAP4K4 ligands was always among the top five groups. Particularly, for MAP4K4 protein our pose prediction method was ranked number one both in terms of mean and median RMSD when the best of five predictions were considered. Overall, our D3R Grand Challenge 2015 results demonstrated that ligand 3D shape similarity with the crystal ligand is sufficient to predict binding poses of new ligands with acceptable accuracy. PMID- 27484216 TI - Moms and Media: Exploring the Effects of Online Communication on Infant Feeding Practices. AB - Using a survey of mothers with young children (N = 455), this study applies Fishbein and Ajzen's reasoned action approach (RAA) to examine the relationship between online communication and infant feeding practices. Contrary to expectations, attitudes, perceived normative pressure, and perceived behavioral control (PBC) did not fully mediate the relationship between time spent online and behavioral intentions. Our findings indicate a significant, direct, negative association between time spent online and breastfeeding intentions In this article, theoretical and practical implications for health communication are discussed. PMID- 27484215 TI - Hydrogen polysulfide (H2S n ) signaling along with hydrogen sulfide (H2S) and nitric oxide (NO). AB - Hydrogen sulfide (H2S) is a physiological mediator with various roles, including neuro-modulation, vascular tone regulation, and cytoprotection against ischemia reperfusion injury, angiogenesis, and oxygen sensing. Hydrogen polysulfide (H2S n ), which possesses a higher number of sulfur atoms than H2S, recently emerged as a potential signaling molecule that regulates the activity of ion channels, a tumor suppressor, transcription factors, and protein kinases. Some of the previously reported effects of H2S are now attributed to the more potent H2S n . H2S n is produced by 3-mercaptopyruvate sulfurtransferase (3MST) from 3 mercaptopyruvate (3MP) and is generated by the chemical interaction of H2S with nitric oxide (NO). H2S n sulfhydrates (sulfurates) cysteine residues of target proteins and modifies their activity, whereas H2S sulfurates oxidized cysteine residues as well as reduces cysteine disulfide bonds. This review focuses on the recent progress made in studies concerning the production and physiological roles of H2S n and H2S. PMID- 27484217 TI - The incidence and mortality of major cancers in China, 2012. AB - BACKGROUND: The National Central Cancer Registry (NCCR) collected population based cancer registration data in 2012 from local registries and estimated the cancer incidence and mortality in China. METHODS: In the middle of 2015, 261 cancer registries submitted reports on new cancer cases and deaths occurred in 2012. Qualified data from 193 registries were used for analysis after evaluation. Crude rates, number of cases, and age-standardized rates stratified by area (urban/rural), sex, age group, and cancer type were calculated according to the national population in 2012. RESULTS: The covered population were 198,060,406 from 193 qualified cancer registries (74 urban and 119 rural registries). The major indicators of quality control, percentage of cases morphologically verified (MV%), death certificate-only cases (DCO%), and the mortality to incidence (M/I) ratio, were 69.13%, 2.38%, and 0.62, respectively. It was estimated that there were 3,586,200 new cancer cases and 2,186,600 cancer deaths in 2012 in China with an incidence of 264.85/100,000 [age-standardized rate of incidence by the Chinese standard population (ASRIC) of 191.89/100,000] and a mortality of 161.49/100,000 [age-standardized rate of mortality by the Chinese standard population (ASRMC) of 112.34/100,000]. The ten most common cancer sites were the lung, stomach, liver, colorectum, esophagus, female breast, thyroid, cervix, brain, and pancreas, accounting for approximately 77.4% of all new cancer cases. The ten leading causes of cancer death were lung cancer, liver cancer, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, female breast cancer, brain tumor, leukemia, and lymphoma, accounting for 84.5% of all cancer deaths. CONCLUSIONS: Continuous cancer registry data provides basic information in cancer control programs. The cancer burden in China is gradually increasing, both in urban and rural areas, in males and females. Efficient cancer prevention and control, such as health education, tobacco control, and cancer screening, should be paid attention by the health sector and the whole society of China. PMID- 27484218 TI - Synthesis and characterization of a Bi10O8(OAr)16 oxo-cluster supported by p-tert butylcalix[5]arene ligands. AB - Reaction of a non-dried monobenzylated [(t)BuC5(OBn)(OH)4] ligand with excess of Bi[N(SiMe3)2]3 yields a mixture of the dimeric complex 1 [Bi{(t)BuC5(OBn)(OH)}]2 in 12% yield and complex 2 [Bi10O8{(t)BuC5(OBn)(OH)}4] in 48% yield. The highly symmetric complex 2 features a Bi10O8(OAr)16 central core with tetra-, hexa- and heptacoordinated bismuth(iii) centers, and (MU2)-(MU4) bridging oxygen atoms all arranged in a I4 symmetrical pattern. Cluster 2 represents the largest bismuth oxo-cluster supported by calix[n]arene ligands reported to date. PMID- 27484219 TI - Thyroid Function Variations Within the Reference Range Do Not Affect Quality of Life, Mood, or Cognitive Function in Community-Dwelling Older Men. AB - BACKGROUND: Variations in thyroid function within the laboratory reference range have been associated with a number of clinical outcomes. However, quality of life, mood, and cognitive function have not been extensively studied, and it is not clear whether mild variations in thyroid function have major effects on these neurocognitive outcomes. METHODS: Data were analyzed from the Osteoporotic Fractures in Men (MrOS) Study, a cohort of community-dwelling men aged 65 years and older in the United States. A total of 539 participants who were not taking thyroid medications and had age-adjusted TSH levels within the reference range underwent detailed testing of quality of life, mood, and cognitive function at baseline. The same quality of life, mood, and cognitive outcomes were measured again in 193 of the men after a mean follow-up of 6 years. Outcomes were analyzed using thyrotropin (TSH) and free thyroxine (FT4) levels as continuous independent variables, adjusting for relevant covariates. RESULTS: At baseline, there were no associations between TSH or FT4 levels and measures of quality of life, mood, or cognition in the 539 euthyroid men. Baseline thyroid function did not predict changes in these outcomes over a mean of 6 years in the 193 men in the longitudinal analysis. CONCLUSIONS: Variations in thyroid function within the age adjusted laboratory reference range are not associated with variations in quality of life, mood, or cognitive function in community-dwelling older men. PMID- 27484220 TI - Identification and analysis of copine/BONZAI proteins among evolutionarily diverse plant species. AB - Copines are evolutionarily conserved calcium-dependent membrane-binding proteins with potentially critical biological functions. In plants, the function of these proteins has not been analyzed except for in Arabidopsis thaliana where they play critical roles in development and disease resistance. To facilitate functional studies of copine proteins in crop plants, genome-wide identification, curation, and phylogeny analysis of copines in 16 selected plant species were conducted. All the identified 32 plant copines have conserved features of the two C2 domains (C2A and C2B) and the von Willebrand factor A (vWA) domain. Different from animal and protozoa copines, plant copines have glycine at the second residue potentially acquiring a unique protein myristoylation modification. Phylogenetic analysis suggests that copine was present as one copy when evolving from green algae to basal flowering plants, and duplicated before the divergence of monocots and dicots. In addition, gene expression and protein localization study of rice copines suggests both conserved and different properties of copines in dicots and monocots. This study will contribute to uncovering the role of copine genes in different plant species. PMID- 27484221 TI - Mycobacterium tuberculosis H37 Rv1222: structural insight in transcription inhibition. PMID- 27484222 TI - Ru-Containing Magnetically Recoverable Catalysts: A Sustainable Pathway from Cellulose to Ethylene and Propylene Glycols. AB - Biomass processing to value-added chemicals and biofuels received considerable attention due to the renewable nature of the precursors. Here, we report the development of Ru-containing magnetically recoverable catalysts for cellulose hydrogenolysis to low alcohols, ethylene glycol (EG) and propylene glycol (PG). The catalysts are synthesized by incorporation of magnetite nanoparticles (NPs) in mesoporous silica pores followed by formation of 2 nm Ru NPs. The latter are obtained by thermal decomposition of ruthenium acetylacetonate in the pores. The catalysts showed excellent activities and selectivities at 100% cellulose conversion, exceeding those for the commercial Ru/C. High selectivities as well as activities are attributed to the influence of Fe3O4 on the Ru(0)/Ru(4+) NPs. A facile synthetic protocol, easy magnetic separation, and stability of the catalyst performance after magnetic recovery make these catalysts promising for industrial applications. PMID- 27484223 TI - Boronic acid based imprinted electrochemical sensor for rutin recognition and detection. AB - Multi-walled carbon nanotubes (MWNTs) and boronic acid based molecular imprinting polymer (MIP) were successively modified on a glassy carbon electrode surface to fabricate a novel electrochemical sensor for rutin recognition and detection. 3 Aminophenylboronic acid (APBA) was chosen as a monomer for the electropolymerization of MIP film in the presence of rutin. In addition to the imprinted cavities in MIP film to complement the template molecule in shape and functional groups, the high affinity between the boronic acid group of APBA and vicinal diols of rutin also enhanced the selectivity of the sensor, which made the sensor display a good selectivity to rutin. Moreover, the modified MWNTs improved the sensitivity of the sensor for rutin detection. The mole ratios of rutin and APBA, electropolymerized scan cycles and rates, and pH value of the detection solution were optimized. Under optimal conditions, the sensor was used to detect rutin in a linear range from 4.0 * 10-7 to 1.0 * 10-5 mol L-1 with a detection limit of 1.1 * 10-7 mol L-1. The sensor has also been applied to assay rutin in tablets with satisfactory results. PMID- 27484224 TI - Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDO-RCA): safety and efficacy of low-dose prostacyclin administration and blood pressure target in addition to standard therapy, as compared to standard therapy alone, in post cardiac arrest syndrome patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Morbidity and mortality following initial survival of cardiac arrest remain high despite great efforts to improve resuscitation techniques and post resuscitation care, in part due to the ischemia-reperfusion injury secondary to the restoration of the blood circulation. Patients resuscitated from cardiac arrest display evidence of endothelial injury and coagulopathy (hypocoagulability, hyperfibrinolysis), which in associated with poor outcome. Recent randomized controlled trials have revealed that treatment with infusion of prostacyclin reduces endothelial damage after major surgery and AMI. Thus, a study is pertinent to investigate if prostacyclin infusion as a therapeutic intervention reduces endothelial damage without compromising, or even improving, the hemostatic competence in resuscitated cardiac arrest patients. Post-cardiac arrest patients frequently have a need for vasopressor therapy (catecholamines) to achieve the guideline-supported blood pressure goals. To evaluate a possible catecholamine interaction with the primary endpoints of this study, included patients will be randomized into two different blood pressure goals within guideline-recommended targets. METHODS/DESIGN: A randomized, placebo-controlled, double-blind investigator-initiated pilot trial in 40 out-of-hospital-cardiac arrest (OHCA) patients will be conducted. Patients will be randomly assigned to either the active treatment group (48 hours of active study drug (iloprost, 1 ng/kg/min) or to the control group [placebo (saline) infusion]. Target mean blood pressure levels will be allocated 1:1 to 65 mmHg or approximately 75 mmHg, which gives four different permutations, namely: (i) iloprost/65 mHg, (ii) iloprost/75 mmHg, (iii) placebo/65 mmHg, and (iv) placebo/75 mmHg. All randomized patients will be treated in accordance with state-of-the art therapy including targeted temperature management. The primary endpoint of this study is change in biomarkers indicative of endothelial activation and damage, [soluble thrombomodulin (sTM), sE-selectin, syndecan-1, soluble vascular endothelial growth factor (sVEGF), nucleosomes] and sympathoadrenal over activation (epinephrine/norepinephrine) from baseline to 48 hours post-randomization. The secondary endpoints of this trial will include: (1) the hemostatic profile [change in functional hemostatic blood test (thrombelastography (TEG) and whole blood platelet aggregometry (multiplate)) blood cell and endothelial cell-derived microparticles]; (2) feasibility of blood pressure target intervention (target 90 %); (3) interaction of primary endpoints and blood pressure target; (4) levels of neuron-specific enolase at 48 hours post-inclusion according to blood pressure targets. DISCUSSION: The ENDO-RCA study is a pilot study trial that investigates safety and efficacy of low-dose infusion of prostacyclin administration as compared to standard therapy in post-cardiac arrest syndrome patients. TRIAL REGISTRATION: Trial registration at ClinicalTrials.gov (identifier NCT02685618 ) on 18 February 2016. PMID- 27484225 TI - Does molecular analysis increase the efficacy of bronchoalveolar lavage in the diagnosis and management of respiratory infections in hemato-oncological patients? AB - OBJECTIVES: The identification of the specific pathogen responsible for a respiratory infection in patients with hematological malignancies (HM) would ensure relevant treatment and prevent toxicity associated with anti-infective therapy. This large-scale study aimed to explore the clinical impact of fiberoptic bronchoscopy with bronchoalveolar lavage (FOB-BAL) in conjunction with molecular analysis on the diagnosis and management of respiratory infections in hemato-oncological patients. METHODS: All consecutive patients with HM and pulmonary infiltrates, who underwent FOB-BAL between January 2008 and January 2013, were included in the analysis. Clinical characteristics, FOB-BAL results, and treatment adjustments were recorded, and factors predicting a positive BAL were assessed. RESULTS: Four hundred and twenty-five FOB-BAL procedures were analyzed. BAL revealed a specific diagnosis in 219 (51.5%) patients, 208 of them with a pulmonary infection. Infectious etiological agents found were mainly Aspergillus spp (n=142), bacterial species (n=44), and Pneumocystis jirovecii (n=34). Multivariate analysis showed that a lymphoproliferative disease, >=2 symptoms (dyspnea/cough/hemoptysis/pleuritic pain), and less than 4 days between symptom appearance and FOB-BAL, predicted a positive FOB-BAL result. BAL results prompted a treatment modification in 48% of subjects. CONCLUSIONS: FOB-BAL in conjunction with molecular assays is efficient in the rapid detection of life threatening infections, allowing for adjustment of anti-infective therapy, which may result in better outcomes and reduce treatment-related toxicity. PMID- 27484226 TI - Gtpbp2 is a positive regulator of Wnt signaling and maintains low levels of the Wnt negative regulator Axin. AB - BACKGROUND: Canonical Wnt signals, transduced by stabilized beta-catenin, play similar roles across animals in maintaining stem cell pluripotency, regulating cell differentiation, and instructing normal embryonic development. Dysregulated Wnt/beta-catenin signaling causes diseases and birth defects, and a variety of regulatory processes control this pathway to ensure its proper function and integration with other signaling systems. We previously identified GTP-binding protein 2 (Gtpbp2) as a novel regulator of BMP signaling, however further exploration revealed that Gtpbp2 can also affect Wnt signaling, which is a novel finding reported here. RESULTS: Knockdown of Gtpbp2 in Xenopus embryos causes severe axial defects and reduces expression of Spemann-Mangold organizer genes. Gtpbp2 knockdown blocks responses to ectopic Wnt8 ligand, such as organizer gene induction in ectodermal tissue explants and induction of secondary axes in whole embryos. However, organizer gene induction by ectopic Nodal2 is unaffected by Gtpbp2 knockdown. Epistasis tests, conducted by activating Wnt signal transduction at sequential points in the canonical pathway, demonstrate that Gtpbp2 is required downstream of Dishevelled and Gsk3beta but upstream of beta catenin, which is similar to the previously reported effects of Axin1 overexpression in Xenopus embryos. Focusing on Axin in Xenopus embryos, we find that knockdown of Gtpbp2 elevates endogenous or exogenous Axin protein levels. Furthermore, Gtpbp2 fusion proteins co-localize with Dishevelled and co immunoprecipitate with Axin and Gsk3b. CONCLUSIONS: We conclude that Gtpbp2 is required for canonical Wnt/beta-catenin signaling in Xenopus embryos. Our data suggest a model in which Gtpbp2 suppresses the accumulation of Axin protein, a rate-limiting component of the beta-catenin destruction complex, such that Axin protein levels negatively correlate with Gtpbp2 levels. This model is supported by the similarity of our Gtpbp2-Wnt epistasis results and previously reported effects of Axin overexpression, the physical interactions of Gtpbp2 with Axin, and the correlation between elevated Axin protein levels and lost Wnt responsiveness upon Gtpbp2 knockdown. A wide variety of cancer-causing Wnt pathway mutations require low Axin levels, so development of Gtpbp2 inhibitors may provide a new therapeutic strategy to elevate Axin and suppress aberrant beta catenin signaling in cancer and other Wnt-related diseases. PMID- 27484227 TI - Dexmedetomidine-ketamine versus Dexmedetomidine-midazolam-fentanyl for monitored anesthesia care during chemoport insertion: a Prospective Randomized Study. AB - BACKGROUND: Dexmedetomidine as a sole agent showed limited use for painful procedures due to its insufficient sedative/analgesic effect, pronounced hemodynamic instability and prolonged recovery. The aim of this study was to compare the effects of dexmedetomidine-ketamine (DK) versus dexmedetomidine midazolam-fentanyl (DMF) combination on the quality of sedation/analgesia and recovery profiles for monitored anesthesia care (MAC). METHODS: Fifty six patients undergoing chemoport insertion were randomly assigned to group DK or DMF. All patients received 1 MUg.kg(-1) dexmedetomidine over 10 min followed by 0.2-1.0 MUg.kg(-1)h(-1) in order to maintain 3 or 4 of modified Observer's Assessment of Analgesia and Sedation score checked every 3 min. At the start of dexmedetomidine infusion, patients in group DK or DMF received 0.5 mg.kg(-1) ketamine or 0.05 mg.kg(-1) midazolam + 0.5 MUg.kg(-1) fentanyl intravenously, respectively. When required, rescue sedatives (0.5 mg.kg-1 of ketamine or 0.05 mg.kg-1 of midazolam) and analgesics (0.5 mg.kg-1 of ketamine or 0.5 MUg.kg-1 of fentanyl) were given to the patients in DK or DMF group, respectively. The primary outcome of this study was the recovery parameters (time to spontaneous eye opening and the length of the recovery room stay). The secondary outcomes were parameters indicating quality of sedation/analgesia, cardiorespiratory variables, and satisfaction scores. RESULTS: There were no significant differences in the onset time, time to spontaneous eye opening, recovery room stay, the incidences of inadequate analgesia, hypotension and bradycardia between the two groups. Despite lower infusion rate of dexmedetomidine, more patients in the DMF group had bispectral index (BIS) < 60 than in the DK group and vice versa for need of rescue sedatives. The satisfaction scores of patients, surgeon, and anesthesiologist in the DMF group were significantly better than the DK group. CONCLUSIONS: The DK and DMF groups showed comparable recovery time, onset time, cardiorespiratory variables, and analgesia. However, the DMF group showed a better sedation quality and satisfaction scores despite the lower infusion rate of dexmedetomidine, and a higher incidence of BIS < 60 than the DK group. TRIAL REGISTRATION: Clinical Trial Registry of Korea KCT0000951 , registered 12/12/2013. PMID- 27484228 TI - Ovarian Stimulation, Intrauterine Insemination, Multiple Pregnancy and Major Congenital Malformations: A Systematic Review and Meta- Analysis- The ART_Rev Study. AB - INTRODUCTION: Multiple pregnancies are a recognized adverse effect of assisted reproductive technologies; nevertheless, there is no consensus on the incremental risk associated with the ovarian stimulation (OS) used alone and intrauterine insemination (IUI). The relationship between OS and IUI and the risk of major congenital malformations (MCM) is unclear. OBJECTIVE: To summarise the literature and evaluate the risk of multiple pregnancy and MCM associated with OS used alone and IUI used with or without OS compared to natural conception (spontaneously conceived infants without any type of fertility treatments). METHODS: We carried out a systematic review to identify published papers between 1966 and 2014 in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. We included observational studies and randomized clinical trials related to the risk of multiple pregnancies and MCM conceived following OS alone or IUI compared to natural conception (spontaneously conceived infants without any fertility treatments). The quality of the included studies was evaluated using The Cochrane Collaboration's tool for assessing risk of bias for RCTs and the Newcastle-Ottawa Scale for observational studies. RESULTS: There were 63 studies included in this review. Our systematic review suggests that the use of any OS alone was associated with an increased risk of multiple pregnancy compared to natural conception (pooled RR 8.80, 95% CI 5.09- 15.20; p= 0.000; 9 studies). Similar increases in the risk of multiple pregnancies were observed following clomiphene citrate used without assisted reproductive technologies. Compared to natural conception, the use of IUI with or without OS was associated with an increased risk of multiple pregnancy (pooled RR 9.73, 95% CI 7.52 -12.60; p= 0.000; 6 studies). Compared to natural conception, the use of any OS alone was associated with an increased risk of any MCM (RR pooled 1.18, 95%CI 1.03-1.36; 11 studies), major musculoskeletal malformations (pooled RR 1.48, 95%CI 1.21-1.81; 7 studies), and malformations of the nervous system (pooled RR 1.73, 95%CI 1.15-2.61; 6 studies). Compared to natural conception, the use of IUI was associated with an increased risk of any MCM (pooled RR 1.23, 95%CI 1.10-1.37; 10 studies), major urogenital (pooled RR 1.52, 95%CI 1.04-2.22; 7 studies), and musculoskeletal malformations (pooled RR 1.54, 95%CI 1.20-1.98; 7 studies). The overall quality of the included studies was acceptable. CONCLUSIONS: The increased risk of multiple pregnancy and certain types of MCM associated with the use of less invasive fertility treatments, such as OS and IUI, found in this review, highlights the importance of the practice framing. Heterogeneity in OS protocols, the combination with other fertility agents, the limited number of studies and the methodological quality differences reduce our ability to draw conclusions on specific treatment. More observational studies, assessing the risk of multiple pregnancy or MCM, as a primary outcome, using standardized methodologies, in larger and better clinically defined populations are needed. PMID- 27484229 TI - Geniculate Ganglion Tumors: Clinical Presentation and Surgical Results. AB - OBJECTIVE: Facial nerve tumors are rare lesions mostly located in the geniculate ganglion. This study aims to compare those tumors limited to the geniculate ganglion in terms of clinical features and postoperative outcomes. STUDY DESIGN: Case series with chart review. SETTINGS: University tertiary reference center. SUBJECTS AND METHODS: Medical charts were reviewed for 17 patients who had surgery for geniculate ganglion tumor removal (10 hemangiomas, 6 schwannomas, 1 meningioma). Hemangiomas and schwannomas were compared for preoperative facial nerve function, hearing, tumor size, and postoperative outcomes. RESULTS: Facial palsy was observed in all cases. Regarding the preoperative facial nerve function, severe facial palsy (House-Brackmann grades V and VI) was present in 70% of cases for hemangiomas and for no case of schwannoma (P = .01), although hemangiomas were significantly smaller tumors (P = .01). Hearing loss was observed in 4 cases (23.5%) and was related to tumor volume (P < .0001). A complete excision was achieved in all cases, and a facial nerve graft was performed immediately after interruption in 16 patients (94%). Postoperative facial nerve function was improved or stabilized in 94% of cases. A preoperative House-Brackman grade VI was shown as a negative factor for postoperative facial nerve function. CONCLUSIONS: Differences in clinical presentations could help in establishing the good therapeutic option depending on the tumor type. Surgery, when indicated, is safe and effective, and postoperative outcomes are not related to tumor type. PMID- 27484230 TI - Predicting Outcomes after Uvulopalatopharyngoplasty for Adult Obstructive Sleep Apnea: A Meta-analysis. AB - OBJECTIVE: Uvulopalatopharyngoplasty (UPPP) remains one of the most common surgical treatments for patients with obstructive sleep apnea. However, the results after UPPP are unpredictable. The purpose of this meta-analysis is to identify predictors of success after UPPP. DATA SOURCES: A literature search was performed utilizing PubMed, EMBASE, SCOPUS, and the Cochrane Library. REVIEW METHODS: The keywords and medical subject heading terms used were uvulopalatopharyngoplasty and UPPP. Studies were included if UPPP was used as a single surgical procedure for the treatment of obstructive sleep apnea and results were presented separately as responder (surgical success) and nonresponder (surgical failure). Exclusion criteria included pediatric patients and other surgical procedures (eg, nasal and hypopharyngeal) performed at the same time as the UPPP. Age, body mass index, preoperative apnea-hypopnea index, Friedman stage, and several cephalometric variables were compared between responders and nonresponders. RESULTS: A total of 1257 studies were screened, with 15 studies included in this meta-analysis. Our results demonstrate that Friedman stage I is a strong predictor for success after UPPP, while Friedman stage III and low hyoid position are negative predictors. Age, body mass index, preoperative apnea-hypopnea index, and other cephalometric measurements were not significant. CONCLUSION: Friedman stage and hyoid position are important predictors for UPPP. PMID- 27484231 TI - Laryngeal Verrucous Carcinoma. AB - Objective Laryngeal verrucous carcinoma (LVC) is a rare, locally invasive neoplasm comprising 1% to 3.4% of laryngeal carcinomas. Management strategies are a topic of ongoing conversation, and no definitive treatment protocol based on T stage and presentation exists. This review examines characteristics, treatment modalities, and patient outcomes of LVC. Data Sources PubMed, MEDLINE, EMBASE, and Web of Science. Methods Databases were searched through October 29, 2015, for literature detailing individual patient cases of LVC. Variables analyzed included patient demographics, tumor characteristics, tumor size, treatment, and outcomes. Results Thirty-seven articles with 369 cases were included. LVC was found more commonly in males (13.8:1), at an average age of 58.7 years, and located in the glottis (74.0%). Most patients had local disease at presentation (94.9%). The most common presenting symptom was hoarseness (92.3%). The most common primary treatment was surgery alone (72.3%), with local excision as the most common technique (56.8%). In patients with data available on both surgical modality and T stage, most patients who presented as T1 and were managed surgically underwent local excision (79.2%). Surgical treatment alone led to high rates of disease free survival at follow-up (86.8%). A large number of patients presenting with T1 disease were disease free at follow-up (88.6%). Overall survival was 80.3%. Conclusion LVC is most often managed surgically. The extent of surgical resection may be guided by T stage, with smaller tumors resected via local excision and larger tumors via partial or total laryngectomy. Regardless of T stage or therapy, LVC has a good posttreatment prognosis. PMID- 27484232 TI - Laryngeal, Retropharyngeal, and Cervical Glomangiopericytomas: A Case Report. PMID- 27484233 TI - Therapeutic Mastoidectomy in the Management of Noncholesteatomatous Chronic Otitis Media: Literature Review and Cost Analysis. AB - OBJECTIVE: Despite evidence that therapeutic mastoidectomy does not improve outcomes in noncholesteatomatous chronic otitis media, it remains widely performed. An up-to-date systematic review is undertaken and conclusions drawn regarding the best evidence-based practice of its management. DATA SOURCES: PubMed, Google Scholar, Medline Embase, Cochrane, and Web of Science. REVIEW METHOD: A combination of the following words was used: chronic otitis media, chronic suppurative otitis media, COM, CSOM, mastoidectomy, tympanoplasty, atelectasis, retraction, tympanic perforation, and therapeutic. RESULTS: From 1742 studies, 7 were selected for full analysis with respect to the benefit of mastoidectomy in the management of active and inactive mucosal chronic otitis media. Most were retrospective studies, with 1 prospective randomized controlled trial available. Overall, there was no evidence to support routine mastoidectomy in conjunction with tympanoplasty in chronic otitis media. For ears with sclerotic mastoids, the evidence suggested that there may be some benefit as a staged procedure. Two studies were analyzed for the benefit of mastoidectomy in addition to tympanoplasty for the management of the atelectatic ear (inactive squamous chronic otitis media). The conclusion was also that mastoidectomy added no benefit. CONCLUSIONS: Examination of the available literature supports the notion that therapeutic mastoidectomy does not lend any additional benefit to the management of noncholesteatomatous chronic otitis media. This has implications for patient care, both clinically and financially. Further research, ideally in the form of a prospective, multi-institutional, geographically wide, ethnically diverse, randomized controlled trial, is needed to further support this notion. PMID- 27484234 TI - Perceptual Assessment of Velopharyngeal Dysfunction by Otolaryngology Residents. AB - OBJECTIVE: To assess the ability of otolaryngology residents to rate the hypernasal resonance of patients with velopharyngeal dysfunction. We hypothesize that experience (postgraduate year [PGY] level) and training will result in improved ratings of speech samples. STUDY DESIGN: Prospective cohort study. SETTING: Otolaryngology training programs at 2 academic medical centers. SUBJECTS AND METHODS: Thirty otolaryngology residents (PGY 1-5) were enrolled in the study. All residents rated 30 speech samples at 2 separate times. Half the residents completed a training module between the rating exercises, with the other half serving as a control group. Percentage agreement with the expert rating of each speech sample and intrarater reliability were calculated for each resident. Analysis of covariance was used to model accuracy at session 2. RESULTS: The median percentage agreement at session 1 was 53.3% for all residents. At the second session, the median scores were 53.3% for the control group and 60% for the training group, but this difference was not statistically significant. Intrarater reliability was moderate for both groups. Residents were more accurate in their ratings of normal and severely hypernasal speech. There was no correlation between rating accuracy and PGY level. Score at session 1 positively correlated with score at session 2. CONCLUSION: Perceptual training of otolaryngology residents has the potential to improve their ratings of hypernasal speech. Length of time in residency may not be best predictor of perceptual skill. Training modalities incorporating practice with hypernasal speech samples could improve rater skills and should be studied more extensively. PMID- 27484235 TI - Discharge Destination after Head and Neck Surgery: Predictors of Discharge to Postacute Care. AB - OBJECTIVE: In recent decades, there has been a reduction in the length of postoperative hospital stay, with a corresponding increase in discharge to postacute care. Discharge to postacute care facilities represents a meaningful patient-centered outcome; however, little has been published about this outcome after head and neck surgery. STUDY DESIGN: Retrospective review of national database. SETTING: American College of Surgeons National Surgical Quality Improvement Program from 2011 to 2013. SUBJECTS AND METHODS: We compared the rate of discharge to home versus postacute care facilities in patients admitted after head and neck surgery and used multivariable logistic regression to identify predictors of discharge to postacute care. RESULTS: The overall rate of discharge to postacute care facilities after head and neck surgery (n = 15,890) was 15.7% after major surgery (including laryngectomy, composite resection, and free tissue transfer), 4.4% after moderate surgery (including regional tissue transfer, oropharyngeal or oral cavity resection, and neck dissection), and 1.1% after minor head and neck surgery (including endocrine or salivary gland surgery). On multivariable analysis, significant preoperative predictors of discharge to postacute care were advanced age, functional status, major or moderate surgical procedures, tracheostomy, advanced American Society of Anesthesiologists class, low body mass index, and dyspnea. CONCLUSION: Our study indicates that patients undergoing major or moderate head and neck surgery, patients with reduced functional status, and patients with advanced comorbidities are at substantial risk of discharge to postacute care. The possibility of discharge to postacute care should be discussed with high-risk patients. PMID- 27484236 TI - Bimodal Stimulation in Prelingually Deaf Children: Lessons from a Cross-sectional Survey. AB - OBJECTIVE: (1) To survey the use of bimodal stimulation by prelingually deaf children receiving unilateral cochlear implantation and (2) to investigate demographic and audiologic factors explaining the use of bimodal stimulation. STUDY DESIGN: Cross-sectional survey. SETTING: Tertiary care institution. SUBJECTS AND METHODS: The study included 44 unilaterally implanted prelingually deaf children from a single institution, with a minimum follow-up of 1 year. During routine follow-up visits, an examiner interviewed parents on their children's use of bimodal stimulation. At the same time, residual hearing and hearing aid gain in the contralateral ear were assessed. RESULTS: Approximately half of patients (52%) used bimodal stimulation. On average, bimodal users showed better mean unaided and aided thresholds than nonbimodal users (P < .001). A mean 250- to 500-Hz unaided threshold <=90 dB HL in the contralateral, nonimplanted ear was associated with a higher probability of bimodal use (P = .008). Parental satisfaction with the contralateral hearing aid was inversely correlated with mean 125- to 500-Hz and 1000- to 4000-Hz unaided thresholds (P < .001) and mean 250- to 500-Hz and 1000- to 4000-Hz aided thresholds (P < .001). CONCLUSIONS: A mean 250- to 500-Hz unaided threshold <=90 dB HL is associated with a higher probability of bimodal use by prelingually deaf children. Better residual hearing is associated with a higher degree of parental satisfaction with the contralateral hearing aid. This information could be useful to counsel parents of prelingually deaf children, when deciding between bimodal stimulation and simultaneous bilateral cochlear implantation. PMID- 27484238 TI - Mild Camurati-Engelamann disease presenting with exophthalmos as the first and only manifestation: A case report. AB - Camurati-Engelmann disease (CED; MIM 131300), or progressive diaphyseal dysplasia, is a rare autosomal dominant bone disease, which is caused by mutations in the transforming growth factor-beta1 (TGFbeta1) gene on chromosome 19q13.1-13.3. Extremely variable penetrance has been reported to be associated with CED, the most common features of which are limb pain, waddling gait and muscle weakness. The present study reported on a consanguineous Chinese family with one affected individual that initially presented with exophthalmos, which has not previously been reported as an initial manifestation of CED. The proband was a 22-year-old woman that presented with progressive proptosis. Except for increased serum levels of alkaline phosphatase and C-terminal telopeptide of type I collagen, no other biochemical abnormalities were detected. Whole-body radiological and bone scintigraphic investigations revealed that hyperostosis and sclerosis predominantly affected the cranial bones, including the skull base, and only mildly affected the long bones. A heterozygous mutation involving a G to A transition at the cDNA position +653 of TGFbeta1 was detected in the patient only, but not in her family members, by automated DNA sequencing using an ABI DNA sequencer (Model 377). Based on the clinical, biochemical, radiological and genetic findings, a diagnosis of CED was confirmed. Considering the phenotypic variability associated with CED and the unique manifestations of the patient described in the present study, CED should be taken into account regarding the differential diagnosis of exophthalmos. PMID- 27484237 TI - Genetic and Environmental Determinants of Otitis Media in an Indigenous Filipino Population. AB - OBJECTIVE: To identify genetic and environmental risk factors for otitis media in an indigenous Filipino population. STUDY DESIGN: Cross-sectional study. SETTING: Indigenous Filipino community. SUBJECTS AND METHODS: Clinical history and information on breastfeeding, tobacco smoke exposure, and swimming were obtained from community members. Heads of households were interviewed for family history and personal beliefs on ear health. Height and weight were measured. Otoscopic findings were described for the presence and character of perforation or discharge. An A2ML1 duplication variant that confers otitis media susceptibility was Sanger sequenced in all DNA samples. Co-occurrence of middle ear bacteria detected by 16S rRNA gene sequencing was determined according to A2ML1 genotype and social cluster. RESULTS: The indigenous Filipino population has a ~50% prevalence of otitis media. Young age was associated with otitis media (4 age strata; P = .004); however, age was nonsignificant as a bistratal or continuous variable. There was no association between otitis media and sex, body mass index, breastfeeding, tobacco exposure, or deep swimming. In multivariate analyses, A2ML1 genotype is the strongest predictor of otitis media, with an odds ratio of 3.7 (95% confidence interval: 1.3-10.8; P = .005). When otitis media diagnoses were plotted across ages, otitis media was observed within the first year of life, and chronic otitis media persisted up to adulthood, particularly in A2ML1 variant carriers. CONCLUSION: Among indigenous Filipinos, A2ML1 genotype is the primary risk factor for otitis media and main determinant of disease progression, although age, the middle ear microbiome, and social clusters might modulate the effect of the A2ML1 genotype. PMID- 27484240 TI - Copper-Catalyzed N-Arylation of 2-Pyridones Employing Diaryliodonium Salts at Room Temperature. AB - A new and mild synthetic approach for the N-arylation of 2-pyridones with diaryliodonium salts has been developed. Most reactions proceed readily at room temperature in the presence of 10 mol % of copper chloride. As a result, a wide range of N-arylpyridine-2-ones were synthesized in yields of 23% to 99%. With this method, an antifibrotic drug, Pirfenidone, was successfully synthesized in 99% yield within 30 min at room temperature. PMID- 27484239 TI - Real-time imaging of Huntingtin aggregates diverting target search and gene transcription. AB - The presumptive altered dynamics of transient molecular interactions in vivo contributing to neurodegenerative diseases have remained elusive. Here, using single-molecule localization microscopy, we show that disease-inducing Huntingtin (mHtt) protein fragments display three distinct dynamic states in living cells - 1) fast diffusion, 2) dynamic clustering and 3) stable aggregation. Large, stable aggregates of mHtt exclude chromatin and form 'sticky' decoy traps that impede target search processes of key regulators involved in neurological disorders. Functional domain mapping based on super-resolution imaging reveals an unexpected role of aromatic amino acids in promoting protein-mHtt aggregate interactions. Genome-wide expression analysis and numerical simulation experiments suggest mHtt aggregates reduce transcription factor target site sampling frequency and impair critical gene expression programs in striatal neurons. Together, our results provide insights into how mHtt dynamically forms aggregates and disrupts the finely-balanced gene control mechanisms in neuronal cells. PMID- 27484241 TI - Statin-induced myopathy in a usual care setting-a prospective observational study of gender differences. AB - PURPOSE: The study aims to identify the occurrence and remission of statin induced myopathy including patient perception and symptom characteristics with a gender perspective. METHODS: The study was designed as a prospective, non interventional investigation in 192 outpatients receiving statin treatment in usual care with 12 months follow-up. Main outcome measure was myopathy related to statin treatment and classified as probable using WHO criteria for adverse drug reaction (ADR) assessment. RESULTS: Fourteen percent developed myopathy, risk ratio for women 1.52 [95 % CI 1.37; 1.66] as compared to men. The majority graded their pain as "severe." CK values were within normal range. Eighty percent of the women compared to 43 % of the men reported that the muscular symptoms affected their daily life activities to a moderate or severe extent. For those who stopped treatment, mypopathy was the reason for 70 % of the women and 25 % of the men. There was a difference in mean dose between men with and without myopathy, but not in women. Among the patients with myopathy, 76 % reported other ADRs as compared to 21 % of the patients without myopathy (p = 0.002). Twenty-nine percent of the women and 18 % of the men reported other ADRs. CONCLUSION: Women reported a higher frequency of myopathy and other ADRs as well as a larger impact on daily life activities. In men, but not in women, the risk of myopathy was dose dependent. Patients with myopathy were more susceptible to other statin-induced ADRs which raises the question about common underlying mechanisms. PMID- 27484242 TI - Prevention of selective outcome reporting: let us start from the beginning. AB - BACKGROUND: Healthcare professionals and patients could be negatively influenced in their judgments by articles and meta-analyses presenting selective outcome reporting. Clinical trials should be transparent from inception to the publication of results. To this end, trial prospective registration is an ethical and scientific requirement that have shown to be effective in preventing selective reporting of outcomes. However, even journals with a clear pre registration policy publish trial results that were retrospectively registered. SITUATION: Analyses of registration of randomized clinical trials recently published in top specialty journals and of meta-analyses with suspicion of including trials with outcome reporting bias have shown that retrospective registration is in the range from 56 to 76 %. This translates into publication of primary endpoints that differ from those included in the registry: some 30 % of trials showed discrepancies between the primary endpoint in the trial registry and the article. Furthermore, it has been shown that 8 % of all clinical trials published by 6 high-impact ICMJE-member journals was retrospectively registered after primary endpoint ascertainment could have had taken place, raising concerns that endpoints may not have been pre-specified, or were changed. With regards to meta-analyses, 34 % of Cochrane systematic reviews included one or more trials with a high suspicion of selective reporting bias for the primary outcome. PROPOSAL: Retrospective registration of trials may foster selective outcome reporting unless journal editors implement specific quality control processes aiming to prevent or minimize this type of bias. Prospective registration of trials-and protocol public disclosure if proven effective in future studies prevents outcome reporting bias, a must to ensure clinicians and patients have access to reliable clinical trial results. Journal editors should enforce, rather than encourage, appropriate measures to ensure publication of trials free of outcome reporting bias. PMID- 27484243 TI - Hepatoprotection and hepatotoxicity of Heshouwu, a Chinese medicinal herb: Context of the paradoxical effect. AB - Heshouwu (Polygonum multiflorum Thunb.) has been a common Chinese medicine and a folk Taoist medicine for over a thousand years. There are two drug forms, Shengshouwu (Polygoni Multiflori Radix) and Zhiheshouwu (Polygoni Multiflori Radix Prapaerata) in the Chinese Pharmacopoeia. In this review, we retrieved articles with such keywords as Heshouwu, liver protection and liver toxicity in the databases of PubMed and the China National Knowledge Infrastructure (CNKI). Hepatoprotection and hepatotoxicity of Shengshouwu and Zhiheshouwu in vitro and in vivo, and their clinical settings and adverse drug reactions (ADR) were summarized, analyzed and critically reviewed. In bench research, both drug forms had effects against nonalcoholic fatty liver disease, oxidation, fibrosis, cirrhosis, and liver cancer. Clinically, Heshouwu was used for treating fatty liver disease (FLD), hyperlipidemia, cirrhosis and hepatitis B. In contrast, both drug forms could lead to drug-induced liver injury and even death in vitro, in vivo and in clinical settings. In addition, the active components of both drug forms had hepatic benefits and toxicity in interaction with emodin, physcion, and probably 2,3,5,4'-tetrahydroxy-stilbene-2-O-beta-d-glucoside (TSG). In conclusion, Heshouwu exhibited both hepatoprotection and hepatotoxicity. It is essential to evaluate the advantages and disadvantages when Heshouwu is in clinical use. PMID- 27484244 TI - In vivo evaluation of mutagenic and recombinagenic activities of Brazilian propolis. AB - Propolis is a resinous, complex mixture of compounds collected by the bee species Apis mellifera. This study investigated the genotoxicity of green and brown propolis collected in southeast Brazil using the somatic mutation and recombination test (SMART) in Drosophila melanogaster. The effect of five concentrations (0.5, 1.0, 2.0, 4.0, and 7.5 mg/mL) of both propolis types was analyzed in standard (ST) and high-bioactivation (HB) crosses, which have normal and high levels of cytochrome P450 enzymes, respectively. The results show that the types of propolis evaluated have no mutagenic action, in either cross. Moreover, chromatography findings revealed that the propolis types analyzed have different chemical compositions. Brown propolis had lower levels of polyphenols (~7.2 mg/mL), compared to the green type (34.9 mg/g). Taken together, the findings of the present study and literature reports point to the safety in consuming low amounts of propolis, considering the risk of genetic damage, and confirm the absence of mutagenic and recombinagenic actions of the propolis types investigated. PMID- 27484245 TI - Space-related confabulations after right hemisphere damage. AB - Confabulations usually refer to memory distortions, characterized by the production of verbal statements or actions that are inconsistent with the patient's history and present situation. However, behavioral patterns reminiscent of memory confabulations can also occur in patients with right hemisphere damage, in relation to their personal, peripersonal or extrapersonal space. Thus, such patients may be unaware of their left hemiplegia and confabulate about it (anosognosia), deny the ownership of their left limbs (somatoparaphrenia), insult and hit them (misoplegia), or experience a "third", supernumerary left limb. Right brain-damaged patients can also sometimes confabulate about the left, neglected part of images presented in their peripersonal space, or believe to be in another place (reduplicative paramnesia). We review here these instances of confabulation occurring after right hemisphere damage, and propose that they might reflect, at least partially, the attempts of the left hemisphere to make sense of inappropriate input received from the damaged right hemisphere. PMID- 27484246 TI - Direct evidence for role of anti-saliva antibodies against salivary gland homogenate of P. argentipes in modulation of protective Th1-immune response against Leishmania donovani. AB - Currently the main concerns regarding control of visceral leishmaniasis (VL) caused by L. donovani are immunosuppression, relating toxicity of anti leishmanial drug and little development in appropriate vaccine and vector (P. argentipes) control. Reports available from ex-vivo studies reflect significance of vector salivary gland homogenate (SGH) in reverting immunosuppression of infected VL subjects and as such the immunogenic nature of SGH can be a strategy to modulate immune system and anti-leishmanial function to enable immune response to control the disease. Several related studies also identified a better utility of vector anti-saliva antibodies in achieving such effects by an adoptive transfer approach instead of direct stimulation with SGH protein. However, conclusive evidences on VL cases are far beyond satisfactory to suggest role of SGH into modulation of host immune response in VL subjects in India. This study was under taken to make comparison on change in cytokines (TH1 and TH2) response pattern and anti-leishmanial macrophage (Mphi) function following stimulation of their PBMCS with SGH protein derived from P. argentipes sand fly vector for VL or anti SGH antibodies raised in rabbit. This study reports for the first time that L. donovani sensitized healthy subject demonstrates an up-regulated Interferon gamma (TH1) and down regulate Interleukin-10 (TH2) production following stimulation of their PBMCs by P. argentipes anti-saliva antibodies accompanied with an improvement in anti-leishmanial Mphi function for nitric oxide (NO) production. Subsequent experiments suggest that P. argentipes based anti-SGH antibodies when used to stimulate LD infected PBMCs in healthy subjects resulted in better clearance of Leishmania amastigotes load compare to SGH protein. Possibly the immunogenic components of anti-saliva an antibody maintains the level of protective cytokine (INF-gamma) and seems to restrict the infection by host protection by vector saliva. PMID- 27484247 TI - In-silico optimisation of two-dimensional high performance liquid chromatography for the determination of Australian methamphetamine seizure samples. AB - In-silico optimisation of a two-dimensional high performance liquid chromatography (2D-HPLC) separation protocol has been developed for the interrogation of methamphetamine samples including model, real world seizure, and laboratory synthesised samples. The protocol used Drylab((r)) software to rapidly identify the optimum separation conditions from a library of chromatography columns. The optimum separation space was provided by the Phenomonex Kinetex PFP column (first dimension) and an Agilent Poroshell 120 EC-C18 column (second dimension). To facilitate a rapid 2D-HPLC analysis the particle packed C18 column was replaced with a Phenomenex Onyx Monolithic C18 withought sacrificing separation performance. The Drylab((r)) optimised and experimental separations matched very closely, highlighting the robust nature of HPLC simulations. The chemical information gained from an intermediate methamphetamine sample was significant and complimented that generated from a pure seizure sample. The influence of the two-dimensional separation on the analytical figures of merit was also investigated. The limits of detection for key analytes in the second dimension determined for methamphetamine (4.59*10(-4)M), pseudoephedrine (4.03*10(-4)M), caffeine (5.16*10(-4)M), aspirin (9.32*10(-4)M), paracetamol (5.93*10(-4)M) and procaine (2.02*10(-3)M). PMID- 27484248 TI - Can "contamination" occur in body bags?-The example of background fibres in body bags used in Australia. AB - Impurities that are transferred to a crime scene or a body can have a significant negative impact on the investigation if the existence of the contamination is not known, and the source of the contamination is not identified. Forensic consumables, such as DNA swabs, have been known to have caused contaminations, wrongfully linking crimes throughout Europe. In that context, this study focused on body bags, widely used to transfer a corpse from the crime scene to the morgue. Our preliminary survey showed that several countries and Australian Jurisdictions are conducting the sampling of trace evidence at the morgue after the transportation of the body. Potential impurities present in body bags could thus interfere with pertinent traces. The aim of this work was to qualify and quantify the background contamination of trace evidence in body bags used within Australia. Fifteen body bags from four Australian Jurisdictions or laboratories were searched for micro traces. Impurities such as fibres and unidentified particles were detected in each examined body bag, with an estimated average of 3603 coloured fibres and 1429 unidentified particles. This number of fibres is similar to the amount found on a vinyl cinema seat in other studies. Various other contaminants such as pieces of fabric, hairs, parts of insects or feathers were also observed. It is hypothesised that these impurities are introduced during the manufacturing process. This high number of impurities can lead to incorrect conclusions and misleading investigative leads. This paper presents an overview of the problems these impurities can cause and proposes several strategies to prevent future issues. PMID- 27484249 TI - Evaluation of the Reliability of Cone-beam Computed Tomography Scanning and Electronic Apex Locator Measurements in Working Length Determination of Teeth with Large Periapical Lesions. AB - INTRODUCTION: This study evaluates the endodontic working-length measurements in teeth with large periapical lesions and persistent intracanal exudate by using preexisting cone-beam computed tomography (CBCT). It compares the measurements with clinical root canal lengths determined by using 2 electronic apex locators. METHODS: All patients had undergone a CBCT scan independent of the present study and needed root canal treatment of at least 1 tooth visible in the field of view. Seventy-three teeth with single roots and canals were studied. An endodontist measured each root canal length with 2 different electronic apex locators. The measurements were repeated 3 times by using a digital caliper, and the mean was recorded. This mean was compared with the root canal length as measured on CBCT sections by an oral radiologist not involved in the endodontic treatment. The CBCT measurements were taken twice for analysis of intrarater reliability. The data were statistically analyzed. RESULTS: There were no significant measurement differences between the methods used (P > .05). CONCLUSIONS: In teeth with large periapical lesions and persistent intracanal exudate, measurement of the root canal length by using CBCT was as reliable as measurements that used apex locators. PMID- 27484250 TI - Effects of a Bioactive Scaffold Containing a Sustained Transforming Growth Factor beta1-releasing Nanoparticle System on the Migration and Differentiation of Stem Cells from the Apical Papilla. AB - INTRODUCTION: This 2-part study hypothesized that a bioactive scaffold containing a sustained transforming growth factor (TGF)-beta1-releasing nanoparticle system will promote migration and enhance differentiation of stem cells from the apical papilla (SCAP). The study aimed to develop and characterize a novel modified chitosan-based scaffold containing TGF-beta1-releasing chitosan nanoparticles (TGF-beta1-CSnp) to enhance migration and differentiation of SCAP. METHODS: Part I concerns the synthesis and characterization of a carboxymethyl chitosan-based scaffold and TGF-beta1-CSnp. Part II examines the effect of sustained TGF-beta1 release from scaffold containing TGF-beta1-CSnp on odontogenic differentiation of SCAP. RESULTS: The scaffold demonstrated properties conducive to cellular activities. The incorporation of TGF-beta1 in CSnp allowed sustained release of TGF-beta1, facilitating delivery of a critical concentration of TGF-beta1 at the opportune time. TGF-beta1 bioactivity was maintained for up to 4 weeks. SCAP showed greater viability, migration, and biomineralization in the presence of TGF beta1-CSnp than in the presence of free TGF-beta1. SCAP cultured in TGF-beta1 CSnp + scaffold showed significantly higher dentin matrix protein-1 and dentin sialophosphoprotein signals compared with free TGF-beta1 + scaffold or CSnp + scaffold. CONCLUSIONS: These experiments highlighted the potential of a carboxymethyl chitosan-based scaffold with growth factor releasing nanoparticles to promote migration and differentiation of SCAP. The results of this study may have direct application to improve current endodontic regenerative protocols. PMID- 27484251 TI - Quality attributes and microbial survival on whole cantaloupes with antimicrobial coatings containing chitosan, lauric arginate, cinnamon oil and ethylenediaminetetraacetic acid. AB - Cantaloupes are susceptible to microbiological contamination in pre- or postharvest environments. Novel intervention strategies, such as antimicrobial coatings, are needed to improve the microbiological safety of cantaloupes. The objective of this study was to prepare whole cantaloupes coated with mixtures containing chitosan, lauric arginate (LAE), cinnamon oil (CO), and ethylenediaminetetraacetic acid (EDTA) and determine survival characteristics of inoculated foodborne pathogens during storage as well as cantaloupe quality attributes. Chitosan coating with 0.1% LAE, 0.1% EDTA, and 1% CO was the most effective for inactivating foodborne pathogens inoculated on cantaloupes. This coating caused a >3logCFU/cm(2) reduction of Escherichia coli O157:H7 and Listeria monocytogenes immediately after coating and reduced Salmonella enterica to below the detection limit during a 14-day storage. Total molds and yeasts also were reduced to the detection limit by the coating. The redness and yellowness of uncoated cantaloupes were significantly higher than coated ones from day 6. The firmness of uncoated cantaloupes and those coated with chitosan only was significantly lower than other treatments from day 10. No significant differences were found in total soluble solids content or weight loss between coated and uncoated cantaloupes. Results showed the potential benefits of applying the coating mixtures to improve the quality and microbiological safety of cantaloupes. PMID- 27484252 TI - Social capital and refraining from medical care among elderly people in Japan. AB - BACKGROUND: Refraining from required medical care can worsen health, particularly for the elderly, and increase public medical expenditure, which destabilizes the financial aspect of social security. Social capital, such as trust between residents and the norms of reciprocity in the community, is a possible measure to prevent refraining from medical care. METHODS: We studied survey data collected in a small area in Japan that included a high response rate (91.6 %) to evaluate refraining from medical care. Self-reported refraining from required medical care from among 1016 elderly people, aged >=60 (male = 490; female = 526), was used as a dependent variable. Social capital indicators were mean values of people's attitude toward the generalized trust and norms of reciprocity in each community. We estimated the association between community level social capital and individuals' probability of refraining from medical care while controlling individual factors such as age, education, and marital status. RESULTS: Logit estimation results showed that only generalized trust is associated with low probability of refraining from medical care among the elderly in small communities. The marginal effect for 0.1 increase in community level trust is 4 % decrease in the probability of refraining from medical care. In larger communities, generalized trust is not associated with the probability of refraining from medical care. CONCLUSIONS: This finding suggests that the generalized trust is effective in smaller communities as far as related to access to medical care. In small communities, policy to increase generalized trust to support medical care for elderly is recommended. PMID- 27484253 TI - Comprehending Sentences With the Body: Action Compatibility in British Sign Language? AB - Previous studies show that reading sentences about actions leads to specific motor activity associated with actually performing those actions. We investigate how sign language input may modulate motor activation, using British Sign Language (BSL) sentences, some of which explicitly encode direction of motion, versus written English, where motion is only implied. We find no evidence of action simulation in BSL comprehension (Experiments 1-3), but we find effects of action simulation in comprehension of written English sentences by deaf native BSL signers (Experiment 4). These results provide constraints on the nature of mental simulations involved in comprehending action sentences referring to transfer events, suggesting that the richer contextual information provided by BSL sentences versus written or spoken English may reduce the need for action simulation in comprehension, at least when the event described does not map completely onto the signer's own body. PMID- 27484255 TI - Hemophagocytic lymphohistiocytosis with leukoencephalopathy in a patient with dermatomyositis accompanied with peripheral T-cell lymphoma: a case report. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis associated with autoimmune diseases is seen in patients with systemic juvenile idiopathic arthritis, adult onset Still's disease, and systemic lupus erythematosus, whereas it is rarely seen in patients with dermatomyositis. In addition, central nervous system involvement with dermatomyositis is rare. To the best of our knowledge, this is the first case of hemophagocytic lymphohistiocytosis complicated by leukoencephalopathy in a patient with dermatomyositis accompanied with peripheral T-cell lymphoma. CASE PRESENTATION: A 17-year-old Asian male adolescent with dermatomyositis and hemophagocytic lymphohistiocytosis that were controlled with corticosteroid therapy presented to our hospital with high fever and altered consciousness. Brain magnetic resonance imaging revealed multiple cerebral lesions. We diagnosed the central nervous system lesions as leukoencephalopathy secondary to dermatomyositis and hemophagocytic lymphohistiocytosis. Because corticosteroid and cyclophosphamide pulse therapy was ineffective, he was treated with a modified hemophagocytic lymphohistiocytosis-2004 protocol, which resulted in the disappearance of the lesions of his central nervous system. CONCLUSIONS: Our findings suggest that the hemophagocytic lymphohistiocytosis-2004 protocol including etoposide should be initiated immediately in patients with hemophagocytic lymphohistiocytosis who respond poorly to treatment for the underlying disease. Moreover, irrespective of the underlying disease, patients with hemophagocytic lymphohistiocytosis with central nervous system lesions might require bone marrow transplantation. PMID- 27484256 TI - Anxiety associated with diagnostic uncertainty in early pregnancy. AB - OBJECTIVES: To determine anxiety levels of women presenting to an early pregnancy assessment unit (EPAU) with abdominal pain and/or vaginal bleeding and to assess how these levels change over time and according to ultrasonographic diagnosis. METHODS: We undertook a prospective cohort study in an EPAU in a large UK teaching hospital. Women with abdominal pain and/or vaginal bleeding in early pregnancy (< 12 weeks' gestation) presenting for the first time were eligible for inclusion in the study. State anxiety levels were assessed using the standardized short form of Spielberger's state-trait anxiety inventory (STAI) on three occasions (before, immediately after and 48-72 hours after an ultrasound scan). Scores were correlated with ultrasonographic diagnosis. The diagnosis was either certain or uncertain. Certain diagnoses were either positive, i.e. a viable intrauterine pregnancy (IUP), or negative, i.e. a non-viable IUP or ectopic pregnancy. Uncertain diagnoses included pregnancy of unknown location and pregnancy of uncertain viability. Statistical analysis involved mixed ANOVAs and the post-hoc Tukey-Kramer test. RESULTS: A total of 160 women were included in the study. Anxiety levels decreased over time for women with a certain diagnosis (n = 128), even when negative (n = 64), and increased over time for women with an uncertain diagnosis (n = 32). Before the ultrasound examination, anxiety levels were high (STAI value, 21.96 +/- 1.11) and there was no significant difference between the five groups. Immediately after the ultrasound examination, anxiety levels were lower in the viable IUP group (n = 64; 7.75 +/- 1.13) than in any other group. The difference between the five groups was significant (P < 0.005). After 48-72 hours, women with a certain diagnosis had significantly lower anxiety levels than had those with an uncertain diagnosis (10.77 +/- 4.30 vs 22.94 +/- 1.65; P < 0.005). CONCLUSIONS: The experience of abdominal pain and/or vaginal bleeding in early pregnancy is highly anxiogenic. Following an ultrasound examination, the certainty of the diagnosis affects anxiety levels more than does the positive or negative connotations associated with the diagnosis per se. Healthcare providers should be aware of this when communicating uncertain diagnoses. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27484254 TI - A retrospective study of predictive factors for unexpectedly prolonged or shortened progression-free survival and overall survival among patients with metastatic renal cell carcinoma who received first-line targeted therapy. AB - BACKGROUND: To identify predictors of prolonged or shortened progression-free survival (PFS) and overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) who received first-line targeted therapies. METHODS: This retrospective study included 146 patients with mRCC who were treated during 2007 2015. These patients were divided into a group with the worst response (WG), an expected group (EG), and a group with the best response (BG), based on their PFS (<=3 monthsnths, 3-18 monthsnths, and >18 monthsnths, respectively) and OS (<1 year, 1-3 years, and >3 years, respectively). To identify significant predictive factors, the BG and WG were compared to the EG using the Memorial Sloan Kettering Cancer Center and Heng risk models. RESULTS: The overall PFS and OS were 9.3 months and 16.4 months, respectively. The median PFS for the WG (41.8 %), EG (45.9 %), and BG (12.3 %) were 2.7 months, 9.3 months, and 56.6 months, respectively, and the median OS for the WG (45.9 %), EG (35.6 %), and BG (18.5 %) were 5.5 months, 21.6 months, and 63.1 months, respectively; these outcomes were significantly different (p < 0.001). Nephrectomy (odds ratio [OR]: 7.15) was a significant predictor of PFS in the BG, and the significant predictors of OS in the BG were MSKCC intermediate risk (OR: 0.12), poor risk (OR: 0.04), and a disease-free interval of <1 year (OR: 0.23) (all, p < 0.05). Anemia (OR: 3.25) was a significant predictor of PFS in the WG, and the significant predictors of OS were age (OR: 1.05), anemia (OR: 4.13), lymphocytopenia (OR: 4.76), disease free interval of <1 year (OR: 4.8), and synchronous metastasis (OR: 3.52) (all, p < 0.05). CONCLUSION: We identified several significant predictors of unexpectedly good and poor response to first-line targeted therapy among patients with mRCC. PMID- 27484257 TI - Characterising the extent of misreporting of high blood pressure, high cholesterol, and diabetes using the Australian Health Survey. AB - BACKGROUND: Measuring and monitoring the true prevalence of risk factors for chronic conditions is essential for evidence-based policy and health service planning. Understanding the prevalence of risk factors for cardiovascular disease (CVD) in Australia relies heavily on self-report measures from surveys, such as the triennial National Health Survey. However, international evidence suggests that self-reported data may substantially underestimate actual risk factor prevalence. This study sought to characterise the extent of misreporting in a large, nationally-representative health survey that included objective measures of clinical risk factors for CVD. METHODS: This study employed a cross-sectional analysis of 7269 adults aged 18 years and over who provided fasting blood samples as part of the 2011-12 Australian Health Survey. Self-reported prevalence of high blood pressure, high cholesterol and diabetes was compared to measured prevalence, and univariate and multivariate logistic regression analyses identified socio-demographic characteristics associated with underreporting for each risk factor. RESULTS: Approximately 16 % of the total sample underreported high blood pressure (measured to be at high risk but didn't report a diagnosis), 33 % underreported high cholesterol, and 1.3 % underreported diabetes. Among those measured to be at high risk, 68 % did not report a diagnosis for high blood pressure, nor did 89 % of people with high cholesterol and 29 % of people with high fasting plasma glucose. Younger age was associated with underreporting high blood pressure and high cholesterol, while lower area-level disadvantage and higher income were associated with underreporting diabetes. CONCLUSIONS: Underreporting has important implications for CVD risk factor surveillance, policy planning and decisions, and clinical best-practice guidelines. This analysis highlights concerns about the reach of primary prevention efforts in certain groups and implications for patients who may be unaware of their disease risk status. PMID- 27484258 TI - Context processing in adolescents with autism spectrum disorder: How complex could it be? AB - The ability of individuals with Autism Spectrum Disorder (ASD) to process context has long been debated: According to the Weak Central Coherence theory, ASD is characterized by poor global processing, and consequently-poor context processing. In contrast, the Social Cognition theory argues individuals with ASD will present difficulties only in social context processing. The complexity theory of autism suggests context processing in ASD will depend on task complexity. The current study examined this controversy through two priming tasks, one presenting human stimuli (facial expressions) and the other presenting non-human stimuli (animal faces). Both tasks presented visual targets, preceded by congruent, incongruent, or neutral auditory primes. Local and global processing were examined by presenting the visual targets in three spatial frequency conditions: High frequency, low frequency, and broadband. Tasks were administered to 16 adolescents with high functioning ASD and 16 matched typically developing adolescents. Reaction time and accuracy were measured for each task in each condition. Results indicated that individuals with ASD processed context for both human and non-human stimuli, except in one condition, in which human stimuli had to be processed globally (i.e., target presented in low frequency). The task demands presented in this condition, and the performance deficit shown in the ASD group as a result, could be understood in terms of cognitive overload. These findings provide support for the complexity theory of autism and extend it. Our results also demonstrate how associative priming could support intact context processing of human and non-human stimuli in individuals with ASD. Autism Res 2017, 10: 520-530. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27484259 TI - Enhancement of Tb(III) -Cu(II) Single-Molecule Magnet Performance through Structural Modification. AB - We report a series of 3d-4f complexes {Ln2 Cu3 (H3 L)2 Xn } (X=OAc(-) , Ln=Gd, Tb or X=NO3 (-) , Ln=Gd, Tb, Dy, Ho, Er) using the 2,2'-(propane-1,3 diyldiimino)bis[2-(hydroxylmethyl)propane-1,3-diol] (H6 L) pro-ligand. All complexes, except that in which Ln=Gd, show slow magnetic relaxation in zero applied dc field. A remarkable improvement of the energy barrier to reorientation of the magnetisation in the {Tb2 Cu3 (H3 L)2 Xn } complexes is seen by changing the auxiliary ligands (X=OAc(-) for NO3 (-) ). This leads to the largest reported relaxation barrier in zero applied dc field for a Tb/Cu-based single-molecule magnet. Ab initio CASSCF calculations performed on mononuclear Tb(III) models are employed to understand the increase in energy barrier and the calculations suggest that the difference stems from a change in the Tb(III) coordination environment (C4v versus Cs ). PMID- 27484260 TI - Thoracoscopic lobectomy for lung cancer in a patient with a partial anomalous pulmonary venous connection: a case report. AB - BACKGROUND: A partial anomalous pulmonary venous connection is a rare congenital defect in which blood from the pulmonary vein is returned to the right atrium. Asymptomatic patients with a partial anomalous pulmonary venous connection with a small left-to-right shunt do not require surgical treatment. If such patients require a major lung resection, the surgical procedure could precipitate fetal right heart failure if the anomalous venous connection remains uncorrected. CASE PRESENTATION: A 59-year-old man was found to have an abnormal shadow on chest roentgenogram. Chest computed tomography imaging showed a mass in the right upper lobe. At the same time, we incidentally found an anomalous vessel. We diagnosed the abnormality as a partial anomalous pulmonary venous connection. Because the mass may have been lung cancer, a right upper lobectomy was performed using video assisted thoracoscopic surgery. The right upper lobe vein drained into the superior vena cava. The anomaly was not corrected and the surgery was successful. His postoperative course was uneventful without cardiac failure. CONCLUSIONS: Before performing a major lung resection, surgeons should be aware of this rare anomaly and carefully interpret clinical images of all pulmonary veins. PMID- 27484263 TI - The expanding role of methotrexate for treating skin disease. PMID- 27484261 TI - Wheat bran components modulate intestinal bacteria and gene expression of barrier function relevant proteins in a piglet model. AB - The objective of this study was to determine the impact of wheat bran and its main polysaccharides on intestinal bacteria and gene expression of intestinal barrier function relevant proteins. Thirty freshly weaned male piglets were assigned randomly to five dietary treatment groups with six piglets per group. Accordingly, five synthetic diets including a basal control diet without fiber components (CON), wheat bran diet (10% wheat bran, WB), arabinoxylan diet (AX), cellulose diet (CEL) and combined diet of arabinoxylan and cellulose (CB) were studied. The piglets were fed ad libitum for 30 d. Lower Escherichia coli (E. coli) populations in WB group and higher probiotic (Lactobacillus and Bifidobacterium) populations in groups fed diets containing arabinoxylan (WB, AX and CB) were observed and compared with CON group. Compared with CON group, the gene expressions of cystic fibrosis transmembrane conductance regulator (CFTR), calcium-activated chloride channel regulator 1 (CLCA1) and voltage-gated chloride channel 2 (CIC2) were suppressed in the WB group. And wheat bran down-regulated gene expression of pro-inflammation (TNF-alpha, IL-1beta, IL-6) and TLRs/MyD88/NF kappaB pathway compared with CON group. In conclusion, wheat bran and its main polysaccharides could change intestinal microflora and down-regulate the gene expression of intestinal barrier function relevant proteins in the distal small intestinal mucosa. PMID- 27484264 TI - Bookish inclinations. PMID- 27484265 TI - Hirsutism management needs to be more patient oriented. PMID- 27484266 TI - Helicobacter cinaedi - an emerging form of cellulitis. PMID- 27484267 TI - Cutaneous T-cell lymphomas: an urgent need for more improved therapies. PMID- 27484268 TI - Collaboration between dermatologists and dentists in autoimmune bullous diseases and immunoglobulin A antibodies in pemphigus. PMID- 27484269 TI - Is there a pathogenic role for IgE in psoriasis? PMID- 27484270 TI - CARD14 mutations may predict response to antitumour necrosis factor-alpha therapy in psoriasis: a potential further step towards personalized medicine. PMID- 27484271 TI - Quantifying disease extent in pemphigus. PMID- 27484272 TI - Discordance between physician assessment of psoriasis and patient self assessment: the importance of itch. PMID- 27484273 TI - Deciphering the lipidomic profile of irritant contact dermatitis. PMID- 27484274 TI - Not the usual suspect: a case of basal cell naevus syndrome caused by a SMO mutation alone. PMID- 27484275 TI - British Association of Dermatologists' guidelines for the safe and effective prescribing of methotrexate for skin disease 2016. PMID- 27484276 TI - An ethical dilemma: malignant melanoma in a 51-year-old patient awaiting simultaneous kidney and pancreas transplantation for type 1 diabetes. AB - Malignant melanoma is a high-risk skin cancer that, in potential transplant recipients, is considered a substantial contraindication to solid organ transplantation due to significant risk of recurrence with immunosuppression. Current guidelines stipulate waiting between 3 and 10 years after melanoma diagnosis. However, in young patients with end-stage organ failure and malignant melanoma, complex ethical and moral issues arise. Assessment of the true risk associated with transplantation in these patients is difficult due to lack of prospective data, but an autonomous patient can make a decision that clinicians may perceive to be high risk. The national and worldwide shortage of available organs also has to be incorporated into the decision to maximize the net benefit and minimize the risk of graft failure and mortality. The incidence of malignant melanoma worldwide is increasing faster than that of any other cancer and continues to pose ethically challenging decisions for transplant specialists evaluating recipients for solid organ transplantation. PMID- 27484278 TI - Corrigenda. PMID- 27484277 TI - Cover Image: Acquired generalized lipodystrophy in a patient with systemic lupus erythematosus. PMID- 27484279 TI - Corrigenda. PMID- 27484281 TI - Corrigenda. PMID- 27484280 TI - Corrigenda. PMID- 27484283 TI - Image Gallery: Dermoscopy of phthiriasis pubis: a handy and useful tool. PMID- 27484286 TI - Duration of action of two insulin glargine products, LY2963016 insulin glargine and Lantus insulin glargine, in subjects with type 1 diabetes mellitus. AB - AIMS: LY2963016 (LY IGlar) and Lantus (IGlar) are insulin glargine products manufactured by distinct processes, but with identical amino acid sequences. This study compared the duration of action of LY IGlar and IGlar in subjects with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This was a randomized, double blind, single-dose, two-period, crossover study. Twenty subjects underwent 42 hour euglycaemic clamps after a single subcutaneous 0.3-U/kg dose of LY IGlar or IGlar. In this study, the duration of action was defined as the time required for blood glucose levels to rise consistently above a predefined cut-off of 8.3 mmol/L (150 mg/dL) from a state of euglycaemia. Blood samples were collected to measure blood glucose for pharmacodynamic (PD) evaluations. RESULTS: End of action was reached within 42 hours in 26 of 40 clamps (13 LY IGlar and 13 IGlar). The median duration of action for all subjects was 37.1 and 40.0 hours, and the mean duration of action (calculated using only patients who reached end of action) was 23.8 and 25.5 hours for LY IGlar and IGlar, respectively. The duration of action was demonstrated to be similar between the treatments using time-to-event analysis (log-rank test of equality p = .859). Following administration of LY IGlar and IGlar, the PD parameters of maximum glucose infusion rate (R max ) and total glucose infusion during the clamp (G tot ) were comparable. CONCLUSION: LY IGlar and IGlar had similar duration of action and comparable PD parameters in subjects with T1DM. PMID- 27484287 TI - Extraction and isolation of lithospermic acid B from Salvia miltiorrhiza Bunge using aqueous two-phase extraction followed by high-performance liquid chromatography. AB - A rapid and effective method integrating separation and purification of lithospermic acid B from Salvia miltiorrhiza Bunge was developed by combining an aqueous two-phase system extraction with preparative chromatography. An aqueous two-phase system of n-butyl alcohol/KH2 PO4 was chosen from seven systems. The influence of parameters including concentration of KH2 PO4 , n-butyl alcohol concentration, pH, and the ratio of an aqueous two-phase system to crude extract were investigated using a single factor design. Response surface methodology was subsequently used to find the optimal compositions of an aqueous two-phase system. Keeping a solvent-to-solid ratio of 10, the final optimized composition of an aqueous two-phase system was 39.1% w/w n-butyl alcohol and 22.6% w/w KH2 PO4 . Under these conditions a recovery yield of 99.8% and a high partition coefficient of 310.4 were obtained. In a pilot-scale experiment using optimized conditions, 18.79 g of lithospermic acid B with a purity of 70.5% and in a yield of 99.8% was separated from 0.5 kg of crude extract. Subsequently, 9.94 g lithospermic acid B with a purity of 99.3% and recovery yield of 70.3% was obtained with a preparative chromatographic process, and the two-step total recovery was 70.1%. PMID- 27484288 TI - The future of academic innovation in the field of medical devices: is innovation still possible in orthopedics? AB - Academic research is essential to bring disruptive innovation on medical devices market because the risk-taking is too high for companies and their investors. Performing clinical trials is essential to technical files but no one wants to accept responsibility for implanted off-label devices. The paper explains the academic process for innovation. We see that academic research depends, at the end, on the motivation of companies to develop a product. The key to innovation stands in the early collaboration between the surgeons, the research teams and the companies in a project. Innovation is a good idea supported by the expertise of the right people at the right moment. In orthopaedics, we need, more than ever, to stay focused on the patient benefits. PMID- 27484289 TI - MicroRNA-491 regulates the proliferation and apoptosis of CD8(+) T cells. AB - T lymphocyte-mediated immune responses are critical for antitumour immunity; however, T cell function is impaired in the tumour environment. MicroRNAs are involved in regulation of the immune system. While little is known about the function of intrinsic microRNAs in CD8(+) T cells in the tumour microenvironment. Here, we found that miR-491 was upregulated in CD8(+) T cells from mice with colorectal cancer. Retroviral overexpression of miR-491 in CD8(+) and CD4(+) T cells inhibited cell proliferation and promoted cell apoptosis and decreased the production of interferon-gamma in CD8(+) T cells. We found that miR-491 directly targeted cyclin-dependent kinase 4, the transcription factor T cell factor 1 and the anti-apoptotic protein B-cell lymphoma 2-like 1 in CD8(+) T cells. Furthermore, tumour-derived TGF-beta induced miR-491 expression in CD8(+) T cells. Taken together, our results suggest that miR-491 can act as a negative regulator of T lymphocytes, especially CD8(+) T cells, in the tumour environment; thus, this study provides a novel insight on dysfunctional CD8(+) T cells during tumourigenesis and cancer progression. In conclusion, miR-491 may be a new target for antitumour immunotherapy. PMID- 27484290 TI - The HOVON68 CLL trial revisited: performance status and comorbidity affect survival in elderly patients with chronic lymphocytic leukemia. AB - In the HOVON68 CLL trial, patients 65 to 75 years of age had no survival benefit from the addition of low-dose alemtuzumab to fludarabine and cyclophosphamide (FC) in contrast to younger patients. The reasons are explored in this 5-year trial update using both survival analysis and competing risk analysis on non-CLL related mortality. Elderly FCA patients died more frequently from causes not related to CLL, and more often related to comorbidity (mostly cardiovascular) than to infection. In a Cox multivariate analysis, del(17p), performance status >0, and comorbidity were associated with a higher non-CLL-related mortality in the elderly independent of the treatment modality. Thus, while the 'fit' elderly with no comorbidity or performance status of 0 might potentially benefit from chemo-immunotherapy with FC, caution is warranted, when considering alemtuzumab treatment in elderly patients with cardiovascular comorbidity. PMID- 27484291 TI - Whole-animal genome-wide RNAi screen identifies networks regulating male germline stem cells in Drosophila. AB - Stem cells are regulated both intrinsically and externally, including by signals from the local environment and distant organs. To identify genes and pathways that regulate stem-cell fates in the whole organism, we perform a genome-wide transgenic RNAi screen through ubiquitous gene knockdowns, focusing on regulators of adult Drosophila testis germline stem cells (GSCs). Here we identify 530 genes that regulate GSC maintenance and differentiation. Of these, we further knock down 113 selected genes using cell-type-specific Gal4s and find that more than half were external regulators, that is, from the local microenvironment or more distal sources. Some genes, for example, versatile (vers), encoding a heterochromatin protein, regulates GSC fates differentially in different cell types and through multiple pathways. We also find that mitosis/cytokinesis proteins are especially important for male GSC maintenance. Our findings provide valuable insights and resources for studying stem cell regulation at the organismal level. PMID- 27484293 TI - ESICM LIVES 2014. PMID- 27484292 TI - Effect of high pressure treatment on the aging characteristics of Chinese liquor as evaluated by electronic nose and chemical analysis. AB - Several high pressure (HP) treatments (100-400 MPa; 15 and 30 min) were applied to Chinese "Junchang" liquor, and aging characteristics of the liquor were evaluated. Results from the principal component analysis and the discriminant factor analysis of E-Nose demonstrated that HP treatment at 300 and 400 MPa resulted in significant (p < 0.05) changes in aroma components of the liquor. An increase in total ester content and a decrease in total acid content were observed for all treated samples (p < 0.05), which was verified by gas chromatography analysis. In addition, a slight decrease in alcohol content was found for HP treatment at 400 MPa for 30 min. These changes and trends were in accordance with the natural aging process of Chinese liquor. However, HP treatment caused a slight increase in solid content, which might be somewhat undesirable. Sensory evaluation results confirmed that favorable changes in color and flavor of Chinese liquor were induced by HP treatment; however, overall gaps still existed between the quality of treated and six-year aged samples. HP treatment demonstrated a potential to accelerate the natural aging process for Chinese liquor, but long term studies may be needed further to realize the full potential. PMID- 27484294 TI - Assessment of antisperm antibodies in a sample of Egyptian patients with hepatitis C virus infection. AB - Association of hepatitis C virus (HCV) with autoimmune phenomena and impaired semen parameters has been previously reported. The aim of this study was to investigate the influence of HCV infection on the development of antisperm antibodies (ASAs) in HCV-positive males. The study was conducted on 30 HCV infected individuals and 30 healthy control subjects. In both patients and control groups, liver enzymes and reproductive hormones were measured; computer assisted semen analysis (CASA) was performed; HCV-RNA in serum was measured and IgG and IgA ASAs in semen were determined. Free testosterone, sperm concentration, progressive and total motility were significantly lower in HCV patients than in the control group, whereas ASAs of the IgG and IgA classes were significantly higher in HCV patients. However, correlations between viral load and the examined semen parameters and ASAs were nonsignificant. In conclusion, HCV may be responsible for the increased ASAs detected in HCV patients in the present study, possibly providing another plausible explanation for the decreased sperm motility reported in HCV patients. These findings could be of value in fertility management of HCV patients. PMID- 27484295 TI - Laser cooling in solids: advances and prospects. AB - This review discusses the progress and ongoing efforts in optical refrigeration. Optical refrigeration is a process in which phonons are removed from a solid by anti-Stokes fluorescence. The review first summarizes the history of optical refrigeration, noting the success in cooling rare-earth-doped solids to cryogenic temperatures. It then examines in detail a four-level model of rare-earth-based optical refrigeration. This model elucidates the essential roles that the various material parameters, such as the spacing of the energy levels and the radiative quantum efficiency, play in the process of optical refrigeration. The review then describes the experimental techniques for cryogenic optical refrigeration of rare earth-doped solids employing non-resonant and resonant optical cavities. It then examines the work on laser cooling of semiconductors, emphasizing the differences between optical refrigeration of semiconductors and rare-earth-doped solids and the new challenges and advantages of semiconductors. It then describes the significant experimental results including the observed optical refrigeration of CdS nanostructures. The review concludes by discussing the engineering challenges to the development of practical optical refrigerators, and the potential advantages and uses of these refrigerators. PMID- 27484296 TI - Prevalence of prediabetes and its association with obesity among college students in Kuwait: A cross-sectional study. AB - This cross-sectional study sought to estimate the prevalence of prediabetes and assess its association with obesity among young adults in Kuwait; a country with a high prevalence of obesity and diabetes. The estimated prevalence of prediabetes was 6.3% (95% CI: 4.8-8.1) and obesity was associated with elevated prediabetes prevalence. PMID- 27484298 TI - Characteristics and Outcomes of Blood Product Transfusion During Critical Care Transport. AB - BACKGROUND: Civilian out-of-hospital transfusions have not been adequately studied. This study seeks to characterize patients receiving out-of-hospital blood product transfusion during critical care transport. STUDY DESIGN AND METHODS: We studied patients transported by a regional critical care air-medical service who received blood products during transport. This service carries two units of uncrossmatched packed Red Blood Cells (pRBCs) on every transport in addition to blood obtained from referring facilities. The pRBC are administered according to a protocol for the treatment of hemorrhagic shock or based on medical command physician order. Transfusion amount was categorized into three groups based on the volume transfused (<350 mL, 350-700 mL, >700 mL). The association between prehospital transfusion and in-hospital outcomes (mortality, subsequent blood transfusion and emergent surgery) was estimated using logistic regression models, controlling for age, first systolic blood pressure, first heart rate, Glasgow Coma Score, time of transfer, and length of hospital admission. RESULTS: Among the 1,440 critical care transports with transfusions examined, 81% were for medical patients, being gastrointestinal hemorrhage the most common indication (26%, CI 24-28%). pRBC transfusions were associated with emergent surgery (OR = 1.81, 95% CI = 1.31-2.52) and in-hospital transfusions (OR = 2.00, 95% CI = 1.46-2.76). Those with transfusions >700 mL were associated with emergent surgery (OR = 1.79, 95% CI = 1.10-2.92) and mortality (OR = 2.11; 95% CI = 1.21-3.69). CONCLUSIONS: In this sample, the majority of patients receiving blood products during air-medical transport were transfused for medic conditions; gastrointestinal hemorrhage was the most common chief complaint. The pRBC transfusions were associated with emergent surgery and in-hospital transfusion. Transfusions of >700 mL were associated with mortality. PMID- 27484299 TI - One-year effects of two intensive inpatient treatments for severely obese children and adolescents. AB - BACKGROUND: Intensive inpatient lifestyle treatment may be a suitable alternative for severely obese children and adolescents who do not benefit from ambulatory obesity treatment. The aim was to evaluate the effectiveness of two intensive one year lifestyle treatments with varying inpatient periods for severely obese children and adolescents with regard to SDS-BMI and cardiometabolic risk factors. METHODS: The study was designed as a randomized controlled trial with two active treatment groups. Eighty participants (8-19 years) with severe obesity received treatment at a specialized childhood obesity center in the Netherlands. Severe obesity was defined as a SDS-BMI >= 3.0 or a SDS-BMI >= 2.3 in combination with obesity-related comorbidity. Participants received an intensive one-year lifestyle treatment with an inpatient period of either two months and biweekly return visits during the next four months (short-stay group) or six months (long stay group), both followed by six monthly return visits. Outcomes were assessed at baseline, six and 12 months and included SDS-BMI as primary outcome and cardiometabolic risk factors such as SDS-waist circumference, systolic- and diastolic blood pressure, and blood measurements as secondary outcomes. To evaluate differences in the course of the primary- and secondary outcomes over time between the two treatment groups, Generalized Estimating Equations (GEE) were performed. RESULTS: No differences in the course of SDS-BMI or secondary outcomes over time were found between the two treatment groups after one year of treatment. SDS-BMI decreased statistically significantly after one year of treatment compared with baseline in both groups (0.33 (0.48) in the short-stay and 0.52 (0.49) in the long-stay group). Similar results were found for SDS-waist circumference, diastolic blood pressure and HDL-cholesterol. CONCLUSIONS: Since there were no significant differences in effects between the short- and long-stay treatment and considering the burden of the long-stay treatment for children and families, we recommend implementation of the short-stay treatment. TRIAL REGISTRATION: Netherlands Trial Register NTR1678 , registered 20-Feb-2009. PMID- 27484300 TI - Engineering Saccharomyces cerevisiae for improvement in ethanol tolerance by accumulation of trehalose. AB - A genetic recombinant Saccharomyces cerevisiae starter with high ethanol tolerance capacities was constructed. In this study, the gene of trehalose-6 phosphate synthase (encoded by tps1), which catalyzes the first step in trehalose synthesis, was cloned and overexpressed in S. cerevisiae. Moreover, the gene of neutral trehalase (encoded by nth1, trehalose degrading enzyme) was deleted by using a disruption cassette, which contained long flanking homology regions of nth1 gene (the upstream 0.26 kb and downstream 0.4 kb). The engineered strain increased its tolerance against ethanol and glucose stress. The growth of the wild strain was inhibited when the medium contained 6 % or more ethanol, whereas growth of the engineered strain was affected when the medium contained 10 % or more ethanol. There was no significant difference in the ethanol yield between the wild strain and the engineered strain when the fermentation broth contained 10 % glucose (p > 0.05). The engineered strain showed greater ethanol yield than the wild type strain when the medium contained more than 15 % glucose (p < 0.05). Higher intracellular trehalose accumulation by overexpression of tps1 and deletion of nth1 might provide the ability for yeast to protect against environmental stress. PMID- 27484301 TI - Estimating the probability of coexistence in cross-feeding communities. AB - The dynamics of many microbial ecosystems are driven by cross-feeding interactions, in which metabolites excreted by some species are metabolised further by others. The population dynamics of such ecosystems are governed by frequency-dependent selection, which allows for stable coexistence of two or more species. We have analysed a model of cross-feeding based on the replicator equation, with the aim of establishing criteria for coexistence in ecosystems containing three species, given the information of the three species' ability to coexist in their three separate pairs, i.e. the long term dynamics in the three two-species component systems. The triple-system is studied statistically and the probability of coexistence in the species triplet is computed for two models of species interactions. The interaction parameters are modelled either as stochastically independent or organised in a hierarchy where any derived metabolite carries less energy than previous nutrients in the metabolic chain. We differentiate between different modes of coexistence with respect to the pair wise dynamics of the species, and find that the probability of coexistence is close to 12 for triplet systems with three pair-wise coexistent pairs and for the so-called intransitive systems. Systems with two and one pair-wise coexistent pairs are more likely to exist for random interaction parameters, but are on the other hand much less likely to exhibit triplet coexistence. Hence we conclude that certain species triplets are, from a statistical point of view, rare, but if allowed to interact are likely to coexist. This knowledge might be helpful when constructing synthetic microbial communities for industrial purposes. PMID- 27484302 TI - Examining the Relationship Between Traumatic Brain Injury and Substance Use Outcomes in the Canadian Population. AB - BACKGROUND: The literature has opposing views regarding the magnitude of the association between substance use and TBI. Most studies have examined clinical samples which are not representative of the entire head injured population. Clinical samples provide very limited insight into TBI patients whom do not seek care. OBJECTIVES: This paper examines the associations between TBI and substance use/misuse. Its primary aim is to test whether or not individuals with a past year TBI have higher rates of substance use/misuse than Canadians without a TBI or back and/or spine injury controls drawing on self-report population level data. METHODS: Using the 2009-2010 Canadian Community Health Survey, a nationally representative cross-sectional survey of Canadians 12 years and older, this paper assessed substance use (i.e., illicit drug use; drinking and binge drinking; current smoking) among those with a TBI, as compared to two control groups: (1) individuals with a back or spinal injury (BSI); and (2) healthy noninjured controls. Multivariate regressions (logistic and multinomial), both unadjusted and adjusting for a range of injury and sociodemographic covariates, were used in hypothesis testing. RESULTS: Those with a past-year TBI demonstrated significantly elevated rates of illicit drug use relative to non-injured Canadians. Relative to the BSI group those with a TBI were less likely to drink alcohol, did not differ in binge drinking, cigarette smoking and illicit drug use. CONCLUSION: Health care professionals working with the TBI population should integrate screening, brief intervention, and referral programming as a means to reduce future harm related to substance misuse. PMID- 27484303 TI - Coding in 2D: Using Intentional Dispersity to Enhance the Information Capacity of Sequence-Coded Polymer Barcodes. AB - A 2D approach was studied for the design of polymer-based molecular barcodes. Uniform oligo(alkoxyamine amide)s, containing a monomer-coded binary message, were synthesized by orthogonal solid-phase chemistry. Sets of oligomers with different chain-lengths were prepared. The physical mixture of these uniform oligomers leads to an intentional dispersity (1st dimension fingerprint), which is measured by electrospray mass spectrometry. Furthermore, the monomer sequence of each component of the mass distribution can be analyzed by tandem mass spectrometry (2nd dimension sequencing). By summing the sequence information of all components, a binary message can be read. A 4-bytes extended ASCII-coded message was written on a set of six uniform oligomers. Alternatively, a 3-bytes sequence was written on a set of five oligomers. In both cases, the coded binary information was recovered. PMID- 27484304 TI - Herpes simplex virus type 1 and type 2 in the Netherlands: seroprevalence, risk factors and changes during a 12-year period. AB - BACKGROUND: Genital herpes results in considerable morbidity, including risk of neonatal herpes, and is increasingly being caused by Herpes Simplex Virus (HSV) type 1. Possibly children are less often HSV-1 infected, leaving them susceptible until sexual debut. We assessed changes in the Dutch HSV-1 and HSV-2 seroprevalence over time and determinants associated with HSV seropositivity. METHODS: We used data from two population-based seroepidemiological studies conducted in 1995-6 and 2006-7 with a similar study design. Serum samples of 6 months to 44-year-old participants were tested for type-specific HSV antibodies using HerpesSelect(r) with a cut-off level of >1.10 for seropositivity. Age and sex-specific HSV-1 and HSV-2 seroprevalence was weighted for the Dutch population. Logistic regression was performed to investigate determinants associated with HSV seropositivity. RESULTS: Overall, weighted HSV-1 seroprevalence was significantly lower in 2006-7 [42.7 % 95 % confidence interval (CI) 39.9-45.4] than in 1995-6 (47.7 % 95 % CI 44.8-50.7), especially among 10- to 14-year-olds. Overall, weighted HSV-2 seroprevalence remained stable: 6.8 % in 1995-6 and 6.0 % in 2006-7. Adults who ever had sexual intercourse were more often seropositive for HSV-1 [adjusted Odds Ratio (aOR) 1.69 95 % CI 1.33-2.16] and HSV-2 (aOR 2.35 95 % CI 1.23-4.52). Age at sexual debut was the only sexual risk determinant associated with HSV-1 seropositivity. CONCLUSIONS: Because of the lower HSV-1 seroprevalence in 2006-7 compared to 1995-6, more adults are susceptible to genital HSV-1, including women of reproductive age. Given the higher risk of neonatal herpes when HSV is acquired during pregnancy, prevention and control measures during pregnancy also targeting HSV-1, are important. PMID- 27484305 TI - Effects of arbuscular mycorrhizal fungi on CH4 emissions from rice paddies. AB - Arbuscular mycorrhizal fungi (AMF) play a key role in soil carbon storage and release; however, they have never been considered as a factor affecting methane (CH4) emissions from rice paddies. To reveal the role of AMF, the diurnal variations of CH4 emissions from the noninoculated and inoculated rice field plots were compared at midseason drainage, reflooding stage, and end-of-season drainage. The results showed that the diurnal variation patterns in the two treatments both closely tracked soil water content at midseason drainage and end of-season drainage, while correlated very well with the stomatal conductance of rice at reflooding stage. There were no significant differences between treatments in soil water content and stomatal conductance. However, the diurnal CH4 emission fluxes at the three stages ranged from 4.8 to 39.3, 0.9 to 12.4, and 0.2 to 2.3 mg m-2 h-1 in the noninoculated plots, and those in the inoculated plots ranged from 2.1 to 18.7, 0.9 to 5.0, and 0.3 to 1.2 mg m-2 h-1. The significant differences resulted from carbon-to-nitrogen ratios (C:N) of the noninoculated and inoculated soil, which had a negative linear correlation with maximum diurnal CH4 fluxes. Compared with the noninoculated treatment, inoculating with AMF significantly increased soil C:N by improving the dry matter of rice, which intensified N limit for CH4 production. PMID- 27484306 TI - Expanding the phenotypic spectrum of Succinyl-CoA ligase deficiency through functional validation of a new SUCLG1 variant. AB - Deficiency of the TCA cycle enzyme Succinyl-CoA Synthetase/Ligase (SCS), due to pathogenic variants in subunits encoded by SUCLG1 and SUCLA2, causes mitochondrial encephalomyopathy, methylmalonic acidemia, and mitochondrial DNA (mtDNA) depletion. In this study, we report an 11year old patient who presented with truncal ataxia, chorea, hypotonia, bilateral sensorineural hearing loss and preserved cognition. Whole exome sequencing identified a heterozygous known pathogenic variant and a heterozygous novel missense variant of uncertain clinical significance (VUS) in SUCLG1. To validate the suspected pathogenicity of the novel VUS, molecular and biochemical analyses were performed using primary skin fibroblasts from the patient. The patient's cells lack the SUCLG1 protein, with significantly reduced levels of SUCLA2 and SUCLG2 protein. This leads to essentially undetectable SCS enzyme activity, mtDNA depletion, and cellular respiration defects. These abnormal phenotypes are rescued upon ectopic expression of wild-type SUCLG1 in the patient's fibroblasts, thus functionally confirming the pathogenic nature of the SUCLG1 VUS identified in this patient and expanding the phenotypic spectrum for SUCLG1 deficiency. PMID- 27484307 TI - Stable isotope composition of cocoa beans of different geographical origin. AB - The isotopic profile (delta(13) C, delta(15) N, delta(18) O, delta(2) H, delta(34) S) was used to characterise a wide selection of cocoa beans from different renowned production areas (Africa, Asia, Central and South America). The factors most influencing the isotopic signatures of cocoa beans were climate and altitude for delta(13) C and the isotopic composition of precipitation water for delta(18) O and delta(2) H, whereas delta(15) N and delta(34) S were primarily affected by geology and fertilisation practises. Multi-isotopic analysis was shown to be sufficiently effective in determining the geographical origin of cocoa beans, and combining it with Canonical Discriminant Analysis led to more than 80% of samples being correctly reclassified. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27484308 TI - Anatomical imbalance between cortical networks in autism. AB - Influential psychological models of autism spectrum disorder (ASD) have proposed that this prevalent developmental disorder results from impairment of global (integrative) information processing and overload of local (sensory) information. However, little neuroanatomical evidence consistent with this account has been reported. Here, we examined relative grey matter volumes (rGMVs) between three cortical networks, how they changed with age, and their relationship with core symptomatology. Using public neuroimaging data of high-functioning ASD males and age-/sex-/IQ-matched controls, we first identified age-associated atypical increases in rGMVs of the regions of two sensory systems (auditory and visual networks), and an age-related aberrant decrease in rGMV of a task-control system (fronto-parietal network, FPN) in ASD children. While the enlarged rGMV of the auditory network in ASD adults was associated with the severity of autistic socio communicational core symptom, that of the visual network was instead correlated with the severity of restricted and repetitive behaviours in ASD. Notably, the atypically decreased rGMV of FPN predicted both of the two core symptoms. These findings suggest that disproportionate undergrowth of a task-control system (FPN) may be a common anatomical basis for the two ASD core symptoms, and relative overgrowth of the two different sensory systems selectively compounds the distinct symptoms. PMID- 27484309 TI - Indications to Epigenetic Dysfunction in the Pathogenesis of Common Variable Immunodeficiency. AB - Primary immunodeficiencies (PIDs) are a group of rare genetic diseases resulting in the impairment of one or more functions of the human immune system. Common variable immunodeficiency (CVID) is one of the most prevalent PIDs, yet despite extensive genetic analysis, most patients do not have a monogenetic diagnosis. This has led to the theory that CVID must be a polygenetic condition. An alternative theory to a monogenetic or polygenetic underlying cause of CVID is that it is epigenetic phenomena that are causal in the majority of CVID patients. I will briefly discuss epigenetic regulation in B-cell biology and development, current examples of epigenetic diseases causing CVID-like primary antibody deficiencies, and how these observations may guide future investigation into the role of epigenetics in CVID. PMID- 27484310 TI - Insulin degludec + liraglutide: a complementary combination. AB - INTRODUCTION: The treatment of patients with type 2 diabetes mellitus remains challenging, as it goes beyond adequate glycemic control, in particular addressing weight, blood pressure and other contributors to cardiovascular disease. In addition, the progressive nature of type 2 diabetes mellitus demands the intensification and combination of glucose lowering therapies. In many patients, there is a clinical inertia for the initiation of insulin therapy, leading to failure in reaching glycemic targets in many patients. AREAS COVERED: Recently a fixed-ratio combination therapy of the basal insulin degludec and the glucagon-like peptide-1 analogue liraglutide has been developed and approved by the EMA. The rationale for this combination, as well as an overview of the published phase III clinical trials (DUAL I,II,V), are covered, highlighting the most important conclusions. EXPERT OPINION: The combination therapy of insulin degludec and liraglutide is an attractive therapeutic strategy in patients with type 2 diabetes mellitus as it gives a robust glycemic control with a low risk for hypoglycemia and less weight gain or even weight loss. The fixed-ratio combination of insulin degludec and liraglutide offers a smart therapeutic strategy in patients with type 2 diabetes mellitus where basal insulin needs to be initiated or intensified. PMID- 27484311 TI - Dynamics Correlation Network for Allosteric Switching of PreQ1 Riboswitch. AB - Riboswitches are a class of metabolism control elements mostly found in bacteria. Due to their fundamental importance in bacteria gene regulation, riboswitches have been proposed as antibacterial drug targets. Prequeuosine (preQ1) is the last free precursor in the biosynthetic pathway of queuosine that is crucial for translation efficiency and fidelity. However, the regulation mechanism for the preQ1 riboswitch remains unclear. Here we constructed fluctuation correlation network based on all-atom molecular dynamics simulations to reveal the regulation mechanism. The results suggest that the correlation network in the bound riboswitch is distinctly different from that in the apo riboswitch. The community network indicates that the information freely transfers from the binding site of preQ1 to the expression platform of the P3 helix in the bound riboswitch and the P3 helix is a bottleneck in the apo riboswitch. Thus, a hypothesis of "preQ1 binding induced allosteric switching" is proposed to link riboswitch and translation regulation. The community networks of mutants support this hypothesis. Finally, a possible allosteric pathway of A50-A51-A52-U10-A11-G12-G56 was also identified based on the shortest path algorithm and confirmed by mutations and network perturbation. The novel fluctuation network analysis method can be used as a general strategy in studies of riboswitch structure-function relationship. PMID- 27484312 TI - Frontotemporal dementia and language networks: cortical thickness reduction is driven by dyslexia susceptibility genes. AB - Variations within genes associated with dyslexia result in a language network vulnerability, and in patients with Frontotemporal Dementia (FTD), language disturbances represent a disease core feature. Here we explored whether variations within three related-dyslexia genes, namely KIAA0319, DCDC2, and CNTNAP, might affect cortical thickness measures in FTD patients. 112 FTD patients underwent clinical and neuropsychological examination, genetic analyses and brain Magnetic Resonance Imaging (MRI). KIAA0319 rs17243157 G/A, DCDC2 rs793842 A/G and CNTNAP2 rs17236239 A/G genetic variations were assessed. Cortical thickness was analysed by Freesurfer. Patients carrying KIAA0319 A*(AG or AA) carriers showed greater cortical thickness atrophy in the left fusiform and inferior temporal gyri, compared to KIAA0319 GG (p <= 0.001). Patients carrying CNTNAP2 G*(GA or GG) showed reduced cortical thickness in the left insula thenCNTNAP2 AA carriers (p<=0.001). When patients with both at-risk polymorphisms were considered (KIAA0319 A* and CNTNAP2 G*), greater and addictive cortical thickness atrophy of the left insula and the inferior temporal gyrus was demonstrated (p <= 0.001). No significant effect of DCDC2 was found. In FTD, variations of KIAA0319 and CNTNAP2 genes were related to cortical thickness abnormalities in those brain areas involved in language abilities. These findings shed light on genetic predisposition in defining phenotypic variability in FTD. PMID- 27484313 TI - CCR4 and CAF1 deadenylases have an intrinsic activity to remove the post-poly(A) sequence. AB - MicroRNAs (miRNAs) recruit the CCR4-NOT complex, which contains two deadenylases, CCR4 and CAF1, to promote shortening of the poly(A) tail. Although both CCR4 and CAF1 generally have a strong preference for poly(A) RNA substrates, it has been reported from yeast to humans that they can also remove non-A residues in vitro to various degrees. However, it remains unknown how CCR4 and CAF1 remove non-A sequences. Herein we show that Drosophila miRNAs can promote the removal of 3' terminal non-A residues in an exonucleolytic manner, but only if an upstream poly(A) sequence exists. This non-A removing reaction is directly catalyzed by both CCR4 and CAF1 and depends on the balance between the length of the internal poly(A) sequence and that of the downstream non-A sequence. These results suggest that the CCR4-NOT complex has an intrinsic activity to remove the 3'-terminal non A modifications downstream from the poly(A) tail. PMID- 27484316 TI - Proteomic analysis of the effects of CSF-1 and IL-1alpha on dental follicle cells. AB - Tooth eruption is a complex physiological process involving both osteogenesis and bone resorption. Signals from the dental follicle (DF) regulate bone remodeling during tooth eruption. Interleukin-1alpha (IL-1alpha) may be the initial promoter of tooth eruption, whereas colony-stimulating factor-1 (CSF-1) may attract monocytes into the DF and stimulate osteoclast differentiation. In the present study, differential proteomics was employed to explore protein changes in rat DF cells (DFCs) under the effects of CSF-1 and IL-1alpha. A total of 47 protein spots were differentially expressed in rat DFCs, and 40 protein spots were identified by MALDI-TOF-MS. The identified proteins were grouped into functional categories including cytoskeletal proteins, metal-binding proteins, proteins involved in secretion and degradation, cell cycle proteins and stress proteins. In IL-1alpha-induced rat DFCs, 31 proteins were upregulated compared with the control and included heat shock protein beta-1 (HSP25, also known as HSP27/HSPbeta1), vimentin, TMEM43, the GTP-binding protein Rab-3D, 6-pyruvoyl tetrahydrobiopterin synthase and actin. In total, 7 proteins were downregulated, including serum albumin, GIPC1, DNA primase large subunit, cullin-5 and cyclin G1. In CSF-1-induced rat DFCs, 3 proteins were upregulated and 7 proteins were downregulated when compared with the controls. The upregulated proteins included the GTP-binding protein Rab-3D and alpha-actin. The downregulated proteins included cullin-5, serum albumin, PDZ domain-containing protein and cyclin-G1. The differential expression of vimentin, actin, HSP25 and Rab-3D was verified by western blotting and reverse transcription-quantitative polymerase chain reaction analyses. The present findings provide an insight into the mechanisms involved in tooth eruption. PMID- 27484317 TI - Left Ventricular Mechanics in Untrained and Trained Males with Tetraplegia. AB - Reduced left ventricular (LV) function is common in tetraplegia, yet it is unknown whether intrinsic myocardial function is attenuated. This study examined the effect of SCI and exercise-training status on LV mechanics (intrinsic function) and LV systolic/diastolic function by comparing untrained (UT) and trained (TT) individuals with tetraplegia and able-bodied (AB) individuals. Individuals with tetraplegia had a traumatic, chronic, motor-complete cervical spinal cord injury. Nine UT males (40 +/- 10 years), 8 TT males (30 +/- 5 years), and nine AB males (37 +/- 9 years) participated in the study. LV indices were assessed using two-dimensional transthoracic echocardiography, with speckle tracking analysis for the determination of LV mechanics. For systolic function, stroke volumes were lower in both UT (59 +/- 9 mL; p < 0.001) and TT (63 +/- 9 mL; p < 0.001) relative to AB (82 +/- 11 mL), whereas systolic mechanics were similar across groups. Diastolic function was only reduced in UT, including a lower ratio of early-to-late transmitral filling velocity (1.55 +/- 0.28) relative to TT (2.07 +/- 0.42; p < 0.05) and AB (2.44 +/- 0.61; p < 0.01) and longer isovolumetric relaxation times in UT (101 +/- 7 ms) relative to TT (88 +/- 11 ms; p < 0.05) and AB (85 +/- 6 ms; p < 0.01). Diastolic mechanics (apical circumferential strain rate) were significantly enhanced in TT (3.03 +/- 0.83 s 1) compared to AB (1.85 +/- 0.65 s-1; p < 0.05). There was a trend (p = 0.062) for a between-group difference in apical radial diastolic strain rate (UT: -2.51 +/- 0.83 s-1; TT: -3.92 +/- 1.96 s-1; AB: -1.84 +/- 0.46 s-1). In tetraplegia, attenuated LV systolic function is not attributed to intrinsic dysfunction, whereas exercise-training status appears to improve both global LV diastolic function and LV mechanics. PMID- 27484319 TI - Promoting Global Health - Prevention and Treatment of Substance Abuse and HIV in Asia. AB - This special issue contains 20 papers including 3 Perspectives, 1 Brief Report, 6 Invited Reviews, and 10 Original Articles, which highlight the work by presenters at the second meeting of the biennial Conference Series to Promote Global Health held on April 22-24, 2015 in Hangzhou, Zhejiang, China. These papers focused on the prevalent substance misuse of amphetamine-type-stimulants and opioids, and the increasing prevalence of HIV-infection in Asian countries. The Conference Series is sponsored by the National Institute on Drug Abuse of the U.S. National Institutes of Health, with the goal of exchanging knowledge and ideas related to, and promoting international collaborative work on, the prevention and treatment of substance use disorders and HIV-infection, in order to promote health in Asian and Pacific Islanders and other populations. PMID- 27484318 TI - Effects of HIV and Methamphetamine on Brain and Behavior: Evidence from Human Studies and Animal Models. AB - Methamphetamine (Meth) use is frequent among HIV-infected persons. Combined HIV and Meth insults may exacerbate neural injury in vulnerable neuroanatomic structures or circuitries in the brain, leading to increased behavioral disturbance and cognitive impairment. While acute and chronic effects of Meth in humans and animal models have been studied for decades, the neurobehavioral effects of Meth in the context of HIV infection are much less explored. In-depth understanding of the scope of neurobehavioral phenotypes and mechanisms in HIV/Meth intersection is needed. The present report summarizes published research findings, as well as unpublished data, in humans and animal models with regard to neurobehavioral disturbance, neuroimaging, and neuropathology, and in vitro experimental systems, with an emphasis on findings emerging from the National Institute on Drug Abuse (NIDA) funded Translational Methamphetamine AIDS Research Center (TMARC). Results from human studies and animal (primarily HIV-1 gp120 transgenic mouse) models thus far suggest that combined HIV and Meth insults increase the likelihood of neural injury in the brain. The neurobehavioral effects include cognitive impairment and increased tendencies toward impaired behavioral inhibition and social cognition. These impairments are relevant to behaviors that affect personal and social risks, e.g. worse medication adherence, riskier behaviors, and greater likelihood of HIV transmission. The underlying mechanisms may include electrochemical changes in neuronal circuitries, injury to white matter microstructures, synaptodendritic damage, and selective neuronal loss. Utilization of research methodologies that are valid across species is instrumental in generating new knowledge with clinical translational value. PMID- 27484320 TI - Longer coronary anastomosis provides lower energy loss in coronary artery bypass grafting. AB - Distal anastomosis technique affects graft patency and long-term outcomes in coronary artery bypass grafting, however, there is no standard for the appropriate length of distal anastomosis. The purpose of this study is to evaluate whether longer distal anastomosis provides higher quality of distal anastomosis and better hemodynamic patterns. Off pump CABG training simulator, YOUCAN (EBM Corporation, Japan), was used for distal anastomosis model. Two lengths of distal anastomosis model (10 versus 4 mm) were prepared by end-to-side anastomosis technique. After CT scan constructed three-dimensional inner shape of distal anastomosis, computational flow dynamics (CFD) was used to analyze hemodynamic patterns. The working flow was defined as Newtonian fluid with density of 1050 kg/m3 and viscosity of 4 mPa s. The boundary condition was set to 100 mmHg at inlet, 50 ml/min at outlet, and 100 % stenosis of proximal coronary artery. Three-dimensional CT imaging showed quality of distal anastomosis in 10 mm model was more uniform without vessel wall inversion or kinking compared to 4 mm model. Anastomotic flow area was significantly larger in 10 mm model than that in 4 mm model (28.67 +/- 4.91 versus 8.89 +/- 3.18 mm2, p < 0.0001). Anastomotic angle was significantly smaller in 10 mm model compared to 4 mm model (10.2 +/- 5.65 degrees versus 20.6 +/- 3.31 degrees , p < 0.0001). CFD analysis demonstrated 10 mm model had streamlined flow with smooth graft curvature, whereas 4 mm model had abrupt blood flow direction changes with flow separation at the toe. 10 mm model had significantly lower energy loss than 4 mm model (34.78 +/- 6.90 versus 77.10 +/- 21.47 MUW, p < 0.0001). Longer distal anastomosis provided higher quality of distal anastomosis, larger anastomotic flow area, smaller anastomotic angle, and smoother graft curvatures. These factors yielded lower energy loss at distal anastomosis. PMID- 27484321 TI - The impact of a simulated intervention on attitudes of undergraduate nursing and medical students towards end of life care provision. AB - BACKGROUND: The concerns of undergraduate nursing and medical students' regarding end of life care are well documented. Many report feelings of emotional distress, anxiety and a lack of preparation to provide care to patients at end of life and their families. Evidence suggests that increased exposure to patients who are dying and their families can improve attitudes toward end of life care. In the absence of such clinical exposure, simulation provides experiential learning with outcomes comparable to that of clinical practice. The aim of this study was therefore to assess the impact of a simulated intervention on the attitudes of undergraduate nursing and medical students towards end of life care. METHODS: A pilot quasi-experimental, pretest-posttest design. Attitudes towards end of life care were measured using the Frommelt Attitudes Towards Care of the Dying Part B Scale which was administered pre and post a simulated clinical scenario. 19 undergraduate nursing and medical students were recruited from one large Higher Education Institution in the United Kingdom. RESULTS: The results of this pilot study confirm that a simulated end of life care intervention has a positive impact on the attitudes of undergraduate nursing and medical students towards end of life care (p < 0.001). CONCLUSIONS: Active, experiential learning in the form of simulation teaching helps improve attitudes of undergraduate nursing and medical students towards end of life. In the absence of clinical exposure, simulation is a viable alternative to help prepare students for their professional role regarding end of life care. PMID- 27484322 TI - The Application of Standards and Recommendations to Clinical Ethics Consultation in Practice: An Evaluation at German Hospitals. AB - The executive board of the Academy for Ethics in Medicine (AEM) and two AEM working groups formulated standards and recommendations for clinical ethics consultation in 2010, 2011, and 2013. These guidelines comply with the international standards like those set by the American Society for Bioethics and Humanities. There is no empirical data available yet that could indicate whether these standards and recommendations have been implemented in German hospitals. This desideratum is addressed in the present study. We contacted 1.858 German hospitals between September 2013 and January 2014. A follow-up survey was conducted between October 2014 and January 2015. The data of the initial survey and the follow-up survey were merged and evaluated. The statements of the participants were compared with the standards and recommendations. The standards of the AEM concerning the tasks of clinical ethics consultation (including ethics consultation, ethics training and the establishment of policy guidelines) are employed by a majority of participants of the study. Almost all of these participants document their consultation activities by means of protocols or entries in the patient file. There are deviations from the recommendations of the AEM working groups regarding the drafting of statutes, activity reports, and financial support. The activities of clinical ethics consultation predominantly comply with the standards of the AEM and recommendations for the documentation. The recommendations for evaluation should be improved in practice. This applies particularly for activity reports in order to evaluate the activities. Internal evaluation could take place accordingly. PMID- 27484323 TI - Impact factors 2015; NHJ on the rise! PMID- 27484324 TI - Assessment of mineral intake in the diets of Polish postmenopausal women in relation to their BMI-the RAC-OST-POL study : Mineral intake in relation to BMI. AB - BACKGROUND: The diets of postmenopausal women in Western countries tend to be deficient in minerals, even if the energy value is at the recommended level. The objective of the presented population-based cohort study was to assess the intake of minerals (sodium, potassium, calcium, phosphorus, magnesium, iron, zinc and copper) in the diets of women aged above 55 years and to analyse the relations between BMI and mineral intake in this group. METHODS: The study was conducted in a group of 406 women who were randomly recruited from the general population of those aged above 55 years. The main outcome measures included BMI, reported sodium, potassium, calcium, phosphorus, magnesium, iron, zinc and copper intake assessed by dietary record (conducted during two typical, non-consecutive days). The distribution was verified with the use of the Shapiro-Wilk test. The comparison between groups was conducted using ANOVA with the LSD post hoc test or Kruskal-Wallis ANOVA with multiple comparisons. A comparison of satisfying nutritional needs was conducted using the chi-square test. RESULTS: Normal body weight individuals were characterised by lower sodium intake per 1000 kcal of diet than obese class II and III individuals (BMI >= 35.0 kg/m(2)). Overweight individuals were characterised by lower potassium and magnesium intake per 1000 kcal of diet than obese class I individuals (BMIepsilon < 30.0; 35.0 kg/m(2)). The majority of individuals was characterised by insufficient potassium, calcium and magnesium intake. No differences in satisfying nutritional needs between BMI groups were observed for all minerals. CONCLUSIONS: Following an improperly balanced diet was observed in the group of postmenopausal female individuals analysed. It was stated that the daily intake of all the assessed minerals was not BMI-dependent for the postmenopausal female individuals, but the nutrient density of diet (for sodium, potassium and magnesium) was associated with BMI. PMID- 27484325 TI - Intention to Use Long-Term Care Facilities: Differences beween Korean Pre-elderly and Korean Baby-boomers. AB - With the rapidly increasing number of older adults, dealing with long-term care (LTC) needs becomes an emerging issue in South Korea. This study aims to examine factors affecting the intention to use longtermcare facilities with two groups of young-old adults: (1) Korean pre-elderly (KPE) and (2) Korean babyboomers (KBB). Guided by Andersen's behavioral model of health service use and prior research, predisposing characters, enabling resources, need factors, availabilities of informal care and self-care activities were used as predictors. In the final analyses, 803 KPE and 966 KBB were included. The results of logistic regression analyses showed different findings in two groups. Age, education, spouse's physicalhealth, and self-care activities for relationship with family and friends are significantly associated with intention to use LTC facilities among KPE. However, income, physical health of respondents, and relationship satisfaction with children are significantly related to intention of use LTC facilities in the group of KBB. This study suggests different LTC needs between KPE and KBB. Health care professionals and policy makers need to consider such differences to provide quality LTC care for them. PMID- 27484327 TI - Base-controlled [3+3] cycloaddition of isoquinoline N-oxides with azaoxyallyl cations. AB - A base-controlled [3+3] cycloaddition reaction of isoquinoline N-oxides with azaoxyallyl cations is developed. 1,11b-dihydro-[1,2,4]oxadiazino[3,2 a]isoquinolin-2(3H)-ones are obtained when isoquinoline N-oxides are treated with alpha-halohydroxamates in the presence of sodium carbonate, while 2-(isoquinolin 1-yloxy)acetamides are unexpectedly produced when the base is changed to cesium carbonate. This transformation proceeds through an azaoxyallyl cation generated in situ from alpha-bromohydroxamate, and the [3+3] cycloaddition reaction is the key step for the final outcome. PMID- 27484326 TI - Socioeconomic Status, Health Behaviors, Obesity and Self-Rated Health among Older Arabs in Israel. AB - Socioeconomic inequalities in health are well documented. Recently, researchers have shown interest in exploring the mechanisms by which measures of SES operate through it to impact SRH, such as material, psychosocial and behavioral factors. To examine the relationships between SES indicators and self-rated health (SRH); and to determine whether health behaviors and obesity mediate the association between SES indicators and SRH. A secondary analysis of data previously collected through the third survey of socioeconomic and health status of the Arab population in Israel, in which the SRH of 878 Arab-Israelis age 50 or older were analyzed using logistic regression. The results showed that higher education level and current employment in old age are associated with better SRH. However, neither subjective economic status nor family income was associated with SRH. Greater physical activity was found to be related to good?very good SRH, while obesity was associated with less than good SRH. Finally, health behaviors (physical activity) and obesity were revealed as mediators between SES indicators (education and employment status) and SRH. The results highlight the importance of high education level and employment status in old age to reduce health inequalities. The findings also show that the relationship between SES and SRH can operate through behavioral mechanisms (i.e., physical activity) and their consequences (i.e., obesity), that can, however, be changed in old age. PMID- 27484329 TI - Narratives of Stress in Health Meanings of African Americans in Lake County, Indiana. AB - Across the life course, African Americans bear an unequal burden of disease compared to other racial groups. In spite of the widespread acknowledgment of racial health disparities, the voices of African Americans, their articulations of health and their local etiologies of health disparities are limited. In this article, we highlight the important role of communication scholarship to understand the everyday enactment of health disparities. Drawing upon the culture centered approach (CCA) to co-construct narratives of health with African Americans residents of Lake County, Indiana, we explore the presence of stress in the everyday narratives of health. These narratives voice the social and structural sources of stress, and articulate resistive coping strategies embedded in relationship to structures. PMID- 27484328 TI - Canine babesiosis and tick activity monitored using companion animal electronic health records in the UK. AB - Recent publications highlighting autochthonous Babesia canis infection in dogs from Essex that have not travelled outside the UK are a powerful reminder of the potential for pathogen emergence in new populations. Here the authors use electronic health data collected from two diagnostic laboratories and a network of 392 veterinary premises to describe canine Babesia cases and levels of Babesia concern from January 2015 to March 2016, and the activity of ticks during December 2015-March 2016. In most areas of the UK, Babesia diagnosis in this population was rare and sporadic. In addition, there was a clear focus of Babesia cases in the affected area in Essex. Until February 2016, analysis of health records indicated only sporadic interest in Babesia largely in animals coming from overseas. Following media coverage in March 2016, there was a spike in owner concern that was geographically dispersed beyond the at-risk area. Tick activity (identified as ticks being removed from animals in veterinary consultations) was consistent but low during the period preceding the infections (<5 ticks/10,000 consultations), but increased in March. This highlights the use of electronic health data to describe rapidly evolving risk and concern that follows the emergence of a pathogen. PMID- 27484330 TI - The Safety and Efficacy of Weekly Paclitaxel Administration for Anaplastic Thyroid Cancer Patients: A Nationwide Prospective Study. AB - BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare and extremely aggressive malignancy, with a median survival of less than 6 months due to rapid progression and resistance to multimodal therapies. Effective treatment strategies have not been identified. A prospective clinical study was performed to objectively evaluate outcomes of treatment with paclitaxel. METHODS: An investigator initiated, multicenter, nonrandomized, open-label, single-arm study to evaluate the feasibility and efficacy of weekly paclitaxel (80 mg/m(2)) administration for patients with pathologically confirmed ATC was conducted in a nationwide organization. RESULTS: Feasibility was analyzed in 56 patients. More than one course of treatment was performed in 52 (93%) patients retaining sufficient dose intensity (>84%). No patient had to terminate the treatment because of an adverse event. The median overall survival was 6.7 months [confidence interval 4.4-9.0]. The 6-month survival was 54%. Among the 42 patients with an evaluable lesion, none demonstrated complete remission, 9 (21%) showed partial remission, 22 (52%) achieved stable disease, and 8 (19%) exhibited progressive disease; 3 did not complete the initial treatment course. The objective response rate was 21%, and the clinical benefit rate was 73%. The median time to progression was 1.6 months. Statistically, no additional effect of concomitant radiation was demonstrated in 6 patients receiving combined therapy. Eight patients, in whom a complete post treatment surgical removal of the tumor was feasible, survived significantly longer (median 7.6 months [CI 8.1-23.0]) than the other 34 patients in whom the tumor could not be completely removed after chemotherapy (5.4 months [CI 3.0 7.8], p = 0.018). SUMMARY: The study demonstrates objective and accurate information concerning the feasibility and efficacy of a standardized treatment with weekly paclitaxel administration for ATC patients. CONCLUSIONS: Weekly paclitaxel administration for ATC patients can be of clinical benefit in a neo adjuvant setting. PMID- 27484331 TI - The effect of melatonin and vitamin C treatment on the experimentally induced tympanosclerosis: study in rats. AB - INTRODUCTION: The ethiopathogenesis of tympanosclerosis has not been completely under- stood yet. Recent studies have shown that free oxygen radicals are important in the formation of tympanosclerosis. Melatonin and Vitamin C are known to be a powerful antioxidant, interacts directly with Reactive Oxygen Species and controls free radical-mediated tissue damage. OBJECTIVE: To demonstrate the possible preventative effects of melatonin and Vitamin C on tympanosclerosis in rats by using histopathology and determination of total antioxidant status total antioxidant status. METHODS: Standard myringotomy and standard injury were performed in the middle ear of 24 rats. The animals were divided into three groups: Group 1 received melatonin, Group 2 received vitamin C, and Group 3 received saline solution. RESULTS: The mean values of total antioxidant status were similar in the all study groups before the treatment period. The mean values of total antioxidant status were significantly higher in the melatonin and vitamin C groups compared to control group but vitamin C with melatonin groups were similar after the treatment period (p<0.001). Minimum and maximum wall thicknesses were lower in the melatonin and vitamin C groups compared to the control group but the differences were insignificant. CONCLUSION: Melatonin increases total antioxidant status level and might have some effect on tympanosclerosis that develops after myringotomy. PMID- 27484332 TI - Characterization of interactions of simvastatin, pravastatin, fluvastatin, and pitavastatin with bovine serum albumin: multiple spectroscopic and molecular docking. AB - The binding interactions of simvastatin (SIM), pravastatin (PRA), fluvastatin (FLU), and pitavastatin (PIT) with bovine serum albumin (BSA) were investigated for determining the affinity of four statins with BSA through multiple spectroscopic and molecular docking methods. The experimental results showed that SIM, PRA, FLU, and PIT statins quenched the intrinsic fluorescence of BSA through a static quenching process and the stable stains-BSA complexes with the binding constants in the order of 104 M-1 at 298 K were formed through intermolecular nonbond interaction. The values of DeltaH0, DeltaS0 and DeltaG0 in the binding process of SIM, PRA, FLU, and PIT with BSA were negative at the studied temperature range, suggesting that the binding process of four statins and BSA was spontaneous and the main interaction forces were van der Waals force and hydrogen-bonding interactions. Moreover, the binding of four statins with BSA was enthalpy-driven process due to |DeltaH degrees |>|TDeltaS degrees | under the studied temperature range. From the results of site marker competitive experiments and molecular docking, subdomain IIIA (site II) was the primary binding site for SIM, PRA, FLU, and PIT on BSA. The results of UV-vis absorption, synchronous fluorescence, 3D fluorescence and FT-IR spectra proved that the slight change in the conformation of BSA, while the significant changes in the conformation of SIM, PRA, FLU, and PIT drug in statin-BSA complexes, indicating that the flexibility of statin molecules plays an important role in increasing the stability of statin-BSA complexes. PMID- 27484333 TI - Magnetic field effects of photocarrier generation in bulk heterojunctions at low temperature. AB - We report an experimental investigation of the magnetic field effect (MFE) in polymer bulk heterojunction devices at temperatures below 10 K using photocarrier extraction by linearly increasing voltages. The examined devices were composed of an active layer of poly(3-hexylthiophene) and [6,6]-phenyl-C61-butyric acid methyl ester. In the experiments, the delay time (td) dependence of the MFE was investigated in detail. For td < 80 MUs, a positive MFE was observed in the field region B < 0.1 T and a negative MFE was observed for B > 0.2 T. For td > 8 ms, only a positive MFE proportional to B2 was observed. For the photocurrent pulse detected immediately after light irradiation, the MFE was negligibly small. In a high magnetic field of 15 T, a significant MFE exceeding 80% was observed at 1.8 K for td = 800 ms. We discuss the results based on a model of triplet-singlet (or singlet-triplet) conversion in the magnetic field and estimate the exchange integral for the charge-transfer exciton in this photovoltaic cell. PMID- 27484334 TI - Statistical analysis plan for the PlAtelet Transfusion in Cerebral Haemorrhage (PATCH) trial: a multicentre randomised controlled trial. AB - BACKGROUND: Use of antiplatelet therapy shortly before stroke due to spontaneous primary intracerebral haemorrhage (ICH) is associated with higher case fatality in comparison to ICH without prior antithrombotic drug use. The PlAtelet Transfusion in Cerebral Haemorrhage (PATCH) trial aimed to assess the effect of platelet transfusion in patients presenting with ICH while using antiplatelet therapy. The main hypothesis of PATCH was that platelet transfusion would reduce death or dependence by reducing ICH growth. METHODS/DESIGN: PATCH was a multicentre prospective, randomised, open, blinded endpoint (PROBE) parallel group trial, conducted at 60 hospitals in The Netherlands, Scotland and France. Forty-one sites enrolled 190 patients with spontaneous supratentorial ICH aged >=18 years, who had used antiplatelet therapy for >=7 days preceding ICH, if Glasgow Coma Scale was >=8. Participants were randomised (1:1, with a secure web based system using permuted blocks, stratified by study centre and type of antiplatelet therapy pre-ICH) to receive either platelet transfusion within 6 hours of symptom onset and 90 minutes of diagnostic brain imaging, or standard care without platelet transfusion. The primary outcome was modified Rankin Scale (mRS) score assessed blind to treatment allocation at 3 months after ICH. Planned secondary outcomes included ICH growth on brain imaging performed approximately 24 hours after randomisation, survival at 3 months, disability at 3 months scored using the Amsterdam Medical Centre linear disability score, heterogeneity of treatment effect on mRS and ICH growth according to presence of the computed tomography angiography spot sign, causes of poor outcome, and cost-effectiveness. Safety outcomes were transfusion reactions, thromboembolic complications, and serious adverse events occurring during hospitalisation. This statistical analysis plan was written without knowledge of the unblinded data. TRIAL REGISTRATION: The trial was registered with the Netherlands Trial Register on 29 April 2008 ( NTR1303 ). PMID- 27484335 TI - 1,3,4-Thiadiazole derivatives of R-(+)-limonene benzaldehyde-thiosemicarbazones cause death in Trypanosoma cruzi through oxidative stress. AB - This work evaluated the in vitro and in vivo activity of TDZ 2 on Trypanosoma cruzi amastigotes and determined the possible mechanism of action of this compound on T. cruzi death. TDZ 2 inhibited T. cruzi proliferation in vitro and had low haemolytic potential. It also induced morphological and ultrastructural alterations. We observed a reduction of cell volume, the depolarization of the mitochondrial membrane, an increase in ROS production, lipoperoxidation of the cell membrane, lipid bodies formation and production of nitric oxide, a decrease in reduced thiols levels and, presence of autophagic vacuoles. The in vivo study found a reduction of parasitemia in animals treated with TDZ 2 alone or combined with benznidazole. Altogether, the alterations induced by TDZ 2 point to an oxidative stress condition that lead to T. cruzi cell death. PMID- 27484336 TI - Development of sedentary behavior across childhood and adolescence: longitudinal analysis of the Gateshead Millennium Study. AB - BACKGROUND: In many parts of the world policy and research interventions to modify sedentary behavior of children and adolescents are now being developed. However, the evidence to inform these interventions (e.g. how sedentary behavior changes across childhood and adolescence) is limited. This study aimed to assess longitudinal changes in sedentary behavior, and examine the degree of tracking of sedentary behavior from age 7y to 15y. METHODS: Participants were part of the Gateshead Millennium Study cohort. Measures were made at age 7y (n = 507), 9y (n = 510), 12y (n = 425) and 15y (n = 310). Participants were asked to wear an ActiGraph GT1M and accelerometer epochs were defined as sedentary when recorded counts were <=25 counts/15 s. Differences in sedentary time and sedentary fragmentation were examined using the Friedman test. Tracking was examined using Spearman's correlation coefficients and trajectories over time were assessed using multilevel linear spline modelling. RESULTS: Median daily sedentary time increased from 51.3% of waking hours at 7y to 74.2% at 15y. Sedentary fragmentation decreased from 7y to 15y. The median number of breaks/hour decreased from 8.6 to 4.1 breaks/hour and the median bout duration at 50% of the cumulative sedentary time increased from 2.4 min to 6.4 min from 7y to 15y. Tracking of sedentary time and sedentary fragmentation was moderate from 7y to 15y however, the rate of change differed with the steepest increases/decreases seen between 9y and 12y. CONCLUSION: In this study, sedentary time was high and increased to almost 75% of waking hours at 15y. Sedentary behavior became substantially less fragmented as children grew older. The largest changes in sedentary time and sedentary fragmentation occurred between 9y to 12y, a period which spans the transition to secondary school. These results can be used to inform future interventions aiming to change sedentary behavior. PMID- 27484338 TI - Boolean network identification from perturbation time series data combining dynamics abstraction and logic programming. AB - Boolean networks (and more general logic models) are useful frameworks to study signal transduction across multiple pathways. Logic models can be learned from a prior knowledge network structure and multiplex phosphoproteomics data. However, most efficient and scalable training methods focus on the comparison of two time points and assume that the system has reached an early steady state. In this paper, we generalize such a learning procedure to take into account the time series traces of phosphoproteomics data in order to discriminate Boolean networks according to their transient dynamics. To that end, we identify a necessary condition that must be satisfied by the dynamics of a Boolean network to be consistent with a discretized time series trace. Based on this condition, we use Answer Set Programming to compute an over-approximation of the set of Boolean networks which fit best with experimental data and provide the corresponding encodings. Combined with model-checking approaches, we end up with a global learning algorithm. Our approach is able to learn logic models with a true positive rate higher than 78% in two case studies of mammalian signaling networks; for a larger case study, our method provides optimal answers after 7min of computation. We quantified the gain in our method predictions precision compared to learning approaches based on static data. Finally, as an application, our method proposes erroneous time-points in the time series data with respect to the optimal learned logic models. PMID- 27484337 TI - Periodic mechanical stress induces the extracellular matrix expression and migration of rat nucleus pulposus cells by upregulating the expression of intergrin alpha1 and phosphorylation of downstream phospholipase Cgamma1. AB - Intervertebral disk degeneration (IDD) is a major cause of low back pain and an important socioeconomic burden. Degradation of the extracellular matrix (ECM) of nucleus pulposus (NP) cells in the interverterbal disk is important for IDD. Stress of a suitable frequency and amplitude promotes the synthesis of the ECM of NP cells, however, the associated mechanisms remain to be fully elucidated The present study aimed to investigate the effect of integrin alpha1 on the migration and ECM synthesis of NP cells under soft periodic mechanical stress. Rat NP cells were isolated and plated onto slides, and were then treated with or without the use of a periodic mechanical stress system. The expression levels of integrin alpha1, alpha5 and alphav, ECM collagen 2A1 (Col2A1) and aggrecan, and the phosphorylation of phospholipase C-gamma1 (PLCgamma1) were measured using reverse transcription-quantitative polymerase chain reaction and western blot analyses. Cell migration was assayed using a scratch experiment. The results showed that exposure to periodic mechanical stress significantly induced the mRNA expression levels of Col2A1 and aggrecan, cell migration, mRNA expression of integrin alpha1 and phosphorylation of PLC-gamma1 of the NP, compared with the control (P<0.05). Inhibition of the PLCgamma1 protein by U73122 significantly decreased the ECM expression under periodic mechanical stress (P<0.05). Small interfering RNA mediated integrin alpha1 gene knockdown suppressed the mRNA expression levels of Col2A1 and aggrecan, and suppressed the migration and phosphorylation of PLCgamma1 of the NP cells under periodic mechanical stress, compared with the control (P<0.05). In conclusion, periodic mechanical stress induced ECM expression and the migration of NP cells via upregulating the expression of integrin alpha1 and the phosphorylation of downstream PLCgamma1. These findings provide novel information to aid the understanding of the pathogenesis and development of IDD. PMID- 27484340 TI - Total Synthesis of (-)-Carinatine A and (+)-Lycopladine A. AB - An efficient synthesis of two Lycopodium alkaloids, (-)-carinatine A and (+) lycopladine A, is achieved in eight steps. The synthesis features an intramolecular aldol reaction for assembling the 6,5-fused ring system, a subsequent Tsuji-Trost allylation for generating a quarternary carbon center, and a 6pi-electrocyclization to form the pyridine ring. PMID- 27484339 TI - Effects of remifentanil and remifentanil-alfentanil administration on emergence agitation after brief ophthalmic surgery in children. AB - BACKGROUND: Sevoflurane is commonly usedin pediatric anesthesia due to its non irritating airway properties, and rapid induction and emergence. However, it is associated with emergence agitation (EA) in children. EA may cause injury to the child or damage to the surgical site and is a cause of stress to both caregivers and families. The efficacy of remifentanil and additional alfentanil on EA in the pediatric patients underwent ophthalmic surgery with sevofluraneanesthesiawas not well evaluated to date. This study was designed to compare the effects of remifentanil and remifentanil plus alfentanil on EA in children undergoing ophthalmic surgery with sevofluraneanesthesia. METHODS: Children (aged 3-9 years) undergoing ophthalmic surgery undersevoflurane anesthesia were randomly assigned to group S (sevoflurane alone), group R (sevofluraneandremifentanil infusion, 0.1 MUg/kg/min), or group RA (sevoflurane withremifentanil infusion and intravenous injection of alfentanil 5 MUg/kg 10 min before the end of surgery). Mean arterial pressure (MAP), heart rate (HR), and sevoflurane concentration were checked every 15 min after induction of anesthesia. The incidence of EA, time to extubation from discontinuation of sevoflurane inhalation, and time to discharge from the postanesthesia care unit was assessed. RESULTS: The incidence of EA was significantly lower in groups R (32 %, 11/34; P = 0.01) and RA (31 %, 11/35; P = 0.008) than group S (64 %, 21/33). The time to extubation was prolonged in group RA (11.2 +/- 2.3 min; P = 0.004 and P = 0.016) compared with groups S (9.2 +/- 2.3 min) andR (9.5 +/- 2.4 min). MAP and HR were similar in all three groups, apart from a reduction in HR at 45 min in groups R and RA. However, the sevoflurane concentration was lower in groups R and RA than group S (P < 0.001). CONCLUSIONS: The administration of remifentanil to children undergoing ophthalmic surgery undersevoflurane anesthesia reduced the incidence of EA without clinically significant hemodynamic changes. However, the addition of alfentanil(5 MUg/kg)10 min before the end of surgery provided no additional benefit compared withremifentanil alone. TRIAL REGISTRATION: CLINICAL TRIAL NUMBER: NCT02486926 , June.29.2015. PMID- 27484341 TI - Visually Induced Inhibition of Return Affects the Integration of Auditory and Visual Information. AB - Multisensory integration (MSI) and exogenous spatial attention can both speedup responses to perceptual events. Recently, it has been shown that audiovisual integration at exogenously attended locations is reduced relative to unattended locations. This effect was observed at short cue-target intervals (200-250 ms). At longer intervals, however, the initial benefits of exogenous shifts of spatial attention at the cued location are often replaced by response time (RT) costs (also known as Inhibition of Return, IOR). Given these opposing cueing effects at shorter versus longer intervals, we decided to investigate whether MSI would also be affected by IOR. Uninformative exogenous visual spatial cues were presented between 350 and 450 ms prior to the onset of auditory, visual, and audiovisual targets. As expected, IOR was observed for visual targets (invalid cue RT < valid cue RT). For auditory and audiovisual targets, neither IOR nor any spatial cueing effects were observed. The amount of relative multisensory response enhancement and race model inequality violation was larger for uncued as compared with cued locations indicating that IOR reduces MSI. The results are discussed in the context of changes in unisensory signal strength at cued as compared with uncued locations. PMID- 27484342 TI - Comparative Transcriptomic Analysis of the Response of Dunaliella acidophila (Chlorophyta) to Short-Term Cadmium and Chronic Natural Metal-Rich Water Exposures. AB - Heavy metals are toxic compounds known to cause multiple and severe cellular damage. However, acidophilic extremophiles are able to cope with very high concentrations of heavy metals. This study investigated the stress response under natural environmental heavy metal concentrations in an acidophilic Dunaliella acidophila. We employed Illumina sequencing for a de novo transcriptome assembly and to identify changes in response to high cadmium concentrations and natural metal-rich water. The photosynthetic performance was also estimated by pulse amplitude-modulated (PAM) fluorescence. Transcriptomic analysis highlights a number of processes mainly related to a high constitutive expression of genes involved in oxidative stress and response to reactive oxygen species (ROS), even in the absence of heavy metals. Photosynthetic activity seems to be unaltered under short-term exposition to Cd and chronic exposure to natural metal-rich water, probably due to an increase in the synthesis of structural photosynthetic components preserving their functional integrity. An overrepresentation of Gene Ontology (GO) terms related to metabolic activities, transcription, and proteosomal catabolic process was observed when D. acidophila grew under chronic exposure to natural metal-rich water. GO terms involved in carbohydrate metabolic process, reticulum endoplasmic and Golgi bodies, were also specifically overrepresented in natural metal-rich water library suggesting an endoplasmic reticulum stress response. PMID- 27484343 TI - The Interplay Between Predation, Competition, and Nutrient Levels Influences the Survival of Escherichia coli in Aquatic Environments. AB - Nutrient levels, competition from autochthonous microorganisms, and protozoan predation may all influence survival of fecal microorganisms as they transition from the gastrointestinal tract to aquatic habitats. Although Escherichia coli is an important indicator of waterborne pathogens, the effects of environmental stressors on its survival in aquatic environments remain poorly understood. We manipulated organic nutrient, predation, and competition levels in outdoor microcosms containing natural river water, sediments, and microbial populations to determine their relative contribution to E. coli survival. The activities of predator (protozoa) and competitor (indigenous bacteria) populations were inhibited by adding cycloheximide or kanamycin. We developed a statistical model of E. coli density over time that fits with the data under all experimental conditions. Predation and competition had significant negative effects on E. coli survival, while higher nutrient levels increased survival. Among the main effects, predation accounted for the greatest variation (40 %) compared with nutrients (25 %) or competition (15 %). The highest nutrient level mitigated the effect of predation on E. coli survival. Thus, elevated organic nutrients may disproportionately enhance the survival of E. coli, and potentially that of other enteric bacteria, in aquatic habitats. PMID- 27484344 TI - Attitudes and barriers uncontrolled asthma in Spain. Abanico study. PMID- 27484345 TI - Resveratrol, a natural antioxidant, protects monosodium iodoacetate-induced osteoarthritic pain in rats. AB - BACKGROUND: Osteoarthritis (OA) is a chronic progressive joint disease characterized by advanced joint pain, subchondral bone sclerosis and articular cartilage degeneration. Resveratrol has been shown to have anti-inflammatory, cardioprotective and antioxidant properties and to inhibit platelet aggregation and coagulation. However, the effects of resveratrol on OA have not been examined. In this study, we investigate the protective effects of resveratrol on monosodium iodoacetate (MIA)-induced OA through inhibition of cyclooxygenase (COX 2) and inducible nitric oxide synthase (iNOS) signaling pathway in a rat model. METHODS: A single intra-articular injection of MIA was injected into rats for the induction of OA. The mechanical, heat and cold hyperalgesia were measured at days 0, 7 and 14. The serum and synovial fluid levels of IL-1beta, IL-10 and TNF-alpha and osteocalcin were measured by enzyme-linked immunosorbent assay. The mRNA and protein expressions of IL-1beta, IL-10, TNF-alpha, Il-6, MMP-13 and COX-2 and iNOS were determined by RT-PCR and western blot, respectively. Osteoarthritic lesion in the knee joint was evaluated by histological analysis. RESULTS: MIA injected rats treated with resveratrol at a dose of either 5 or 10mg/kg body weight were significantly reduced hyperalgesia of mechanical, heat and cold and increased the vertical and horizontal movements. Subsequently, MIA-injected rats increased serum and synovial fluid levels of IL-1beta, IL-10, IL-6, TNF-alpha, MMP-13 and osteoclastic activity marker, osteocalcin and its articular cartilage mRNA and protein expressions. Further, MIA-injected rats increased COX-2 and iNOS mRNA and protein expressions were decreased by resveratrol. The protective effect of resveratrol was comparable to a reference drug, etoricoxib. The cartilage damage induced by MIA were attenuated by resveratrol. CONCLUSIONS: Taken together, resveratrol has the potential to improve MIA-induced cartilage damage by inhibiting the levels and expressions of inflammatory mediators suggesting that resveratrol may be a potential therapeutic agent for OA. PMID- 27484346 TI - New effective azelaic acid liposomal gel formulation of enhanced pharmaceutical bioavailability. AB - Azelaic acid is a naturally occurring saturated C9-dicarboxylic acid which has been shown to be effective in the treatment of comedonal acne and inflammatory acne, as well as hiperpigmentary skin disorders. The aim of the present study is to compare new developed liposomal hydrogel (lipogel) and commercially available product in terms of the active substance-azelaic acid bioavailability. Topical formulations were evaluated for physical parameters, such as pH measurement, organoleptic evaluation and liposome size analysis in lipogel formulation. In addition, studies were performed on in vitro antimicrobial preservation, stability and accumulation in the stratum corneum according to guidelines established by European Pharmacopoeia and International Conferences on Harmonisation. The new formula for liposomal gel with azelaic acid has the stability required for pharmaceutical preparations. Moreover, presented formulation F2 reveals a very high accumulation (187.5MUg/cm2) of an active substance in the stratum corneum, which results in opportunity to decrease of the API content to 10% in comparison to a reference formula: commercially available cream with 20% of azelaic acid. The study reveals that the final formula of lipogel F2 with azelaic acid had acceptable physical parameters that showed that they were compatible with the skin and in addition this formulation passed stability studies. In vitro antimicrobial preservation studies showed that the formulated lipogel F2 showed strong antibacterial activity; thus, no preservatives were added to the final composition of the preparation. The present study concludes that the formulated lipogel F2 with azelaic acid is stable, efficient in antimicrobial preservation and reveals improved active substance bioavailability. PMID- 27484347 TI - The combined application of human adipose derived stem cells and Chondroitinase ABC in treatment of a spinal cord injury model. AB - BACKGROUND: Although stem cell therapy has become a major focus as a new option for management of spinal cord injury (SCI), its effectiveness should be promoted. In this study, we investigated the effects of co-administrating human adipose derived stem cells (hADSCs) and Chondroitinase ABC (ChABC) in a rat model of spinal cord injury. MATERIAL AND METHODS: hADSCs derived from superficial layer of abdominal adipose tissue were used to treat a contusion-induced SCI. Animals were randomly allocated to five equal groups including sham (only laminectomy), SCI (SCI+vehicle injection), hADSCs (1*106 hADSCs/10MUl intra-spinal injection), ChABC (10MUl of 100U/ml ChABC intra-spinal injection injection), and hADSCs+ChABC. Basso, Beattie and Bresnahan tests were used to evaluate locomotor function. 8weeks after treatment, cavity size, myelination, cell differentiation (neuron and astrocyte), and chondroitin sulfate amount were analyzed. RESULTS: hADSC transplanted animals, ChABC injected animals (P<0.001), and hADSC+ChABC treated rats (P<0.001) displayed significant motor improvement compared to SCI group. Combination therapy of hADSCs and ChABC led to greater locomotor recovery compared to using hADSCs (P<0.001) or ChABC (P<0.01) alone. Spinal cords in the combined and single therapy groups had cavities filled with myelinated areas and less chondroitin sulfate content in comparison with the control group (P<0.001). hADSCs expressed GFAP, B III tubulin and Map2. CONCLUSION: Combination therapy with ChABC and hADSCs exhibits more significant functional recovery than single therapy using either. This result may be applicable in selection of the best therapeutic strategy for SCI. PMID- 27484348 TI - Implementing shared decision making in federally qualified health centers, a quasi-experimental design study: the Office-Guidelines Applied to Practice (Office-GAP) program. AB - BACKGROUND: Use of Shared Decision-Making (SDM) and Decision Aids (DAs) has been encouraged but is not regularly implemented in primary care. The Office Guidelines Applied to Practice (Office-GAP) intervention is an application of a previous model revised to address guidelines based care for low-income populations with diabetes and coronary heart disease (CHD). OBJECTIVE: To evaluate Office-GAP Program feasibility and preliminary efficacy on medication use, patient satisfaction with physician communication and confidence in decision in low-income population with diabetes and coronary heart disease (CHD) in a Federally Qualified Healthcare Center (FQHC). METHOD: Ninety-five patients participated in an Office-GAP program. A quasi-experimental design study, over 6 months with 12-month follow-up. Office-GAP program integrates health literacy, communication skills education for patients and physicians, patient/physician decision support tools and SDM into routine care. MAIN MEASURES: 1) Implementation rates of planned program elements 2) Patient satisfaction with communication and confidence in decision, and 3) Medication prescription rates. We used the GEE method for hierarchical logistic models, controlling for confounding. RESULTS: Feasibility of the Office-GAP program in the FQHC setting was established. We found significant increase in use of Aspirin/Plavix, statin and beta-blocker during follow-up compared to baseline: Aspirin OR 1.5 (95 % CI: 1.1, 2.2) at 3-months, 1.9 (1.3, 2.9) at 6-months, and 1.8 (1.2, 2.8) at 12 months. Statin OR 1.1 (1.0, 1.3) at 3-months and 1.5 (1.1, 2.2) at 12-months; beta-blocker 1.8 (1.1, 2.9) at 6-months and 12-months. Program elements were consistently used (>= 98 % clinic attendance at training and tool used). Patient satisfaction with communication and confidence in decision increased. CONCLUSIONS: The use of Office-GAP program to teach SDM and use of DAs in real time was demonstrated to be feasible in FQHCs. It has the potential to improve satisfaction with physician communication and confidence in decisions and to improve medication use. The Office-GAP program is a brief, efficient platform for delivering patient and provider education in SDM and could serve as a model for implementing guideline based care for all chronic diseases in outpatient clinical settings. Further evaluation is needed to establish feasibility outside clinical study, reach, effectiveness and cost-effectiveness of this approach. PMID- 27484349 TI - Radiation recall gastritis secondary to combination of gemcitabine and erlotinib in pancreatic cancer and response to PPI - a case report. AB - BACKGROUND: Radiation recall gastritis is rare but can be induced after concurrent chemoradiation for pancreatic cancer. We report a patient with pancreatic cancer who developed radiation-recall gastritis related to a combination of gemcitabine and erlotinib. CASE PRESENTATION: A 54-year-old female with unresectable pancreatic cancer received gemcitabine in combination with radiation therapy followed by chemotherapy with gemcitabine and erlotinib. After completing 2 cycles of chemotherapy, the patient had epigastric pain, nausea, and vomiting. Abdominal computed tomography (CT) scan revealed diffuse wall thickening of the stomach, and esophagogastroduodenoscopy (EGD) showed multiple gastric ulcers. The patient was treated with proton pump inhibitors (PPI) and was continued on maintenance chemotherapy. Two months later, the patient presented with the similar symptoms and persistent gastric ulcers were observed during subsequent EGD. Nevertheless, the patient's symptom had resolved with PPI therapy. Thus, the patient underwent maintenance chemotherapy with gemcitabine and erlotinib for additional 4 cycles. Eventually, follow-up abdominal CT Scan and EGD at 6 months demonstrated resolution of the gastric ulcers. CONCLUSIONS: Physicians should be aware of the possibility of radiation recall gastritis associated with a combination of gemcitabine and erlotinib. Administration of PPIs may mitigate the adverse effects of gemcitabine and erlotinib in the presence of radiation recall gastritis; however further studies are warranted. PMID- 27484350 TI - Three siblings with familial non-medullary thyroid carcinoma: a case series. AB - BACKGROUND: In 2015, thyroid carcinoma affected approximately 63,000 people in the USA, yet it remains one of the most treatable cancers. It is mainly classified into medullary and non-medullary types. Conventionally, medullary carcinoma was associated with heritability but increasing reports have now begun to associate non-medullary thyroid carcinoma with a genetic predisposition as well. It is important to identify a possible familial association in patients diagnosed with non-medullary thyroid carcinoma because these cancers behave more destructively than would otherwise be expected. Therefore, it is important to aggressively manage such patients and screening of close relatives might be justified. Our case series presents a diagnosis of familial, non-syndromic, non medullary carcinoma of the thyroid gland in three brothers diagnosed over a span of 6 years. CASE PRESENTATIONS: We report the history, signs and symptoms, laboratory results, imaging, and histopathology of the thyroid gland of three Pakistani brothers of 58 years, 55 years, and 52 years from Sindh with non medullary thyroid carcinoma. Only Patients 1 and 3 had active complaints of swelling and pruritus, respectively, whereas Patient 2 was asymptomatic. Patients 2 and 3 had advanced disease at presentation with lymph node metastasis. All patients underwent a total thyroidectomy with Patients 2 and 3 requiring a neck dissection as well. No previous exposure to radiation was present in any of the patients. Their mother had died from adrenal carcinoma but also had a swelling in the front of her neck which was never investigated. All patients remained stable at follow-up. CONCLUSIONS: Non-medullary thyroid carcinoma is classically considered a sporadic condition. Our case report emphasizes a high index of suspicion, a detailed family history, and screening of first degree relatives when evaluating patients with non-medullary thyroid carcinoma to rule out familial cases which might behave more aggressively. PMID- 27484351 TI - Cohort of one million patients initiating antidepressant treatment in France: 12 month follow-up. AB - AIMS: Previous studies have shown that the recommended minimum 6-month period for antidepressant treatment is actually observed for only a minority of patients. The objectives of this study were to characterise patients with newly prescribed antidepressant treatment in France and identify factors possibly associated with insufficient duration of treatment or the occurrence of certain events such as sick leave, hospitalisations and suicide attempts. METHODS: Data were extracted from the French health insurance database (SNIIRAM) and the national hospitalisation database (PMSI) for patients covered by the main French health insurance scheme representing 75% of the French population. Patients were included if they had a newly prescribed antidepressant in 2011, but no prior psychiatric diagnosis identified in the databases and no significant psychiatric medication (such as antipsychotic or mood stabiliser) in 2009-2010. RESULTS: A total of 998 710 patients (2% of the overall population), with a mean age of 50 years and 66% of females, initiated an antidepressant in 2011, which was prescribed by a general practitioner in 89% of cases. Five generic names, including three selective serotonin reuptake inhibitors, accounted for 75% of first prescriptions. Only one reimbursement was observed for 40% of patients. Treatment duration was less than 6 months for more than 80% of patients, more frequently for low income earners, and varied according to age, gender and region. The median time lag between first visit and antidepressant initiation was 27 days. Hospitalisation related to a psychiatric disease over the following 12 months was observed for 3% of patients. CONCLUSION: Duration of treatment and follow-up were both insufficient for the majority of French patients initiating antidepressant treatment in 2011, which may reflect poor quality of care for people with mood or anxiety disorders, possibly because of overdiagnosis and inappropriate drug treatment, or poor adherence and side effects, or poor follow up. PMID- 27484352 TI - Alkyltelluro Substitution Improves the Radical-Trapping Capacity of Aromatic Amines. AB - The synthesis of a variety of aromatic amines carrying an ortho-alkyltelluro group is described. The new antioxidants quenched lipidperoxyl radicals much more efficiently than alpha-tocopherol and were regenerable by aqueous-phase N acetylcysteine in a two-phase peroxidation system. The inhibition time for diaryl amine 9 b was four-fold longer than recorded with alpha-tocopherol. Thiol consumption in the aqueous phase was found to correlate inversely to the inhibition time and the availability of thiol is the limiting factor for the duration of antioxidant protection. The proposed mechanism for quenching of peroxyl radicals involves O-atom transfer from peroxyl to Te followed by H-atom transfer from amine to alkoxyl radical in a solvent cage. PMID- 27484353 TI - Neighborhood safety factors associated with older adults' health-related outcomes: A systematic literature review. AB - RATIONALE: Neighborhood safety is important for older adults' health and wellbeing, but there has not been a synthesis in the literature of what is currently known about this construct. OBJECTIVES: This systematic literature review, following the PRISMA guidelines, focuses on identifying neighborhood safety factors associated with health-related outcomes and behaviors of older adults in the U.S. METHODS: A search was conducted in 2014 via Academic Search Complete, CINAHL, Embase, MEDLINE, SportDis, and Transportation Databases. Based on our inclusion and exclusion criteria, we identified thirty-two articles for review. RESULTS: Sixteen studies examined health outcomes such as health status, mental health, physical function, morbidity/mortality, and obesity; the other sixteen studies focused on health behaviors, such as physical activity and walking. Four domains of neighborhood safety were identified: overall/general neighborhood safety; crime-related safety; traffic-related safety; and proxies for safety (e.g., vandalism, graffiti). Overall/general neighborhood safety appeared most relevant to mental health and physical function. Traffic-related safety was most pertinent to physical activity, while crime-related safety was more consistently associated with mental health and walking. While all safety variables were significantly associated with mental health, no significant associations were found for obesity. We also found that specific measures or constructs of safety were not applied consistently across the examined studies, making it difficult to compare the results. CONCLUSION: This review identified several important gaps in the existing studies dealing with neighborhood safety health relationships among older adults. Further studies are needed that examine the different roles of multidimensional neighborhood safety in promoting the community health, not only in the U.S., but globally. PMID- 27484354 TI - Strengthening health disaster risk management in Africa: multi-sectoral and people-centred approaches are required in the post-Hyogo Framework of Action era. AB - BACKGROUND: In November 2012, the 62nd session of the Regional Committee for Africa adopted a comprehensive 10-year regional strategy for health disaster risk management (DRM). This was intended to operationalize the World Health Organization's core commitments to health DRM and the Hyogo Framework for Action 2005-2015 in the health sectors of the 47 African member states. This study reported the formative evaluation of the strategy, including evaluation of the progress in achieving nine targets (expected to be achieved incrementally by 2014, 2017, and 2022). We proposed recommendations for accelerating the strategy's implementation within the Sendai Framework for Disaster Risk Reduction. METHODS: This study used a mixed methods design. A cross-sectional quantitative survey was conducted along with a review of available reports and information on the implementation of the strategy. A review meeting to discuss and finalize the study findings was also conducted. RESULTS: In total, 58 % of the countries assessed had established DRM coordination units within their Ministry of Health (MOH). Most had dedicated MOH DRM staff (88 %) and national level DRM committees (71 %). Only 14 (58 %) of the countries had health DRM subcommittees using a multi-sectoral disaster risk reduction platform. Less than 40 % had conducted surveys such as disaster risk analysis, hospital safety index, and mapping of health resources availability. Key challenges in implementing the strategy were inadequate political will and commitment resulting in poor funding for health DRM, weak health systems, and a dearth of scientific evidence on mainstreaming DRM and disaster risk reduction in longer-term health system development programs. CONCLUSIONS: Implementation of the strategy was behind anticipated targets despite some positive outcomes, such as an increase in the number of countries with health DRM incorporated in their national health legislation, MOH DRM units, and functional health sub-committees within national DRM committees. Health system-based, multi-sectoral, and people-centred approaches are proposed to accelerate implementation of the strategy in the post Hyogo Framework of Action era. PMID- 27484355 TI - Coronary artery rupture in blunt thoracic trauma: a case report and review of literature. AB - BACKGROUND: Blunt thoracic trauma can rarely result in coronary artery injury. Blunt trauma can result in occlusion of any of the coronary arteries or can lead to its rupture and bleeding. Traumatic coronary artery occlusion can lead to myocardial infarction, while its rupture and bleeding can result in hemopericardium and cardiac tamponade, and can be rapidly fatal. Survival after coronary artery rupture in blunt thoracic trauma is exceedingly rare. CASE PRESENTATION: We present a case of a young male who sustained a blunt thoracic trauma in a motor vehicle collision, that resulted in rupture of the left anterior descending (LAD) coronary artery and subsequent cardiac tamponade. Prompt surgical intervention with pericardiotomy and ligation of the artery has resulted in survival of the patient. CONCLUSIONS: In cases of traumatic coronary artery rupture, early surgical intervention is crucial to avoid mortality. Ligation of the injured coronary is a viable option in selected cases, and can be the most expeditious option in patients in extremis. PMID- 27484357 TI - Mediterranean diet and nonalcoholic fatty liver disease: molecular mechanisms of protection. AB - Nutritional habits modifications have shown an important impact in preventing and ameliorating metabolic alterations, such as nonalcoholic fatty liver disease (NAFLD). Among several dietary approaches that exert positive effects in NAFLD patients, the Mediterranean dietary pattern has shown notable benefits. This review explores the molecular mechanisms through which the Mediterranean diet would improve risk factors associated with metabolic syndrome and NAFLD. The main features of the Mediterranean diet acting on metabolism are represented by its whole-grain and low glycemic index cereal-based items, its fatty acid profile, and its content in phytochemical compounds. Carbohydrate-rich foods high in dietary fiber inducing low glycemic response are able to interact with glucose and insulin metabolism. Unsaturated fatty acids are associated with better hepatic lipid metabolism. Finally, phytochemical compounds, such as dietary polyphenols, are thought to ameliorate inflammation, which is considered one of the mechanisms through which NALFD may evolve into nonalcoholic steatohepatitis (NASH). PMID- 27484356 TI - Longitudinal study of computerized cardiotocography in early fetal growth restriction. AB - OBJECTIVES: To explore whether, in early fetal growth restriction (FGR), the longitudinal pattern of fetal heart rate (FHR) short-term variation (STV) can be used to identify imminent fetal distress and whether abnormalities of FHR recordings are associated with 2-year infant outcome. METHODS: The original TRUFFLE study assessed whether, in early FGR, delivery based on ductus venosus (DV) Doppler pulsatility index (PI), in combination with safety-net criteria of very low STV on cardiotocography (CTG) and/or recurrent FHR decelerations, could improve 2-year infant survival without neurological impairment in comparison with delivery based on CTG monitoring only. This was a secondary analysis of women who delivered before 32 weeks and had consecutive STV data recorded > 3 days before delivery and known infant outcome at 2 years of age. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values, except the last one before delivery, were calculated. Life tables and Cox regression analysis were used to calculate the daily risk for low STV or very low STV and/or FHR decelerations (below DV group safety-net criteria) and to assess which parameters were associated with this risk. Furthermore, it was assessed whether STV pattern, last STV value or recurrent FHR decelerations were associated with 2-year infant outcome. RESULTS: One hundred and forty-nine women from the original TRUFFLE study met the inclusion criteria. Using the individual STV regression lines, prediction of a last STV below the cut-off used by the CTG monitoring group had sensitivity of 42% and specificity of 91%. For each day after study inclusion, the median risk for low STV (CTG group cut-off) was 4% (interquartile range (IQR), 2-7%) and for very low STV and/or recurrent FHR decelerations (below DV group safety-net criteria) was 5% (IQR, 4-7%). Measures of STV pattern, fetal Doppler (arterial or venous), birth-weight multiples of the median and gestational age did not usefully improve daily risk prediction. There was no association of STV regression coefficients, a low last STV and/or recurrent FHR decelerations with short- or long-term infant outcomes. CONCLUSION: The TRUFFLE study showed that a strategy of DV monitoring with safety-net criteria of very low STV and/or recurrent FHR decelerations for delivery indication could increase 2-year infant survival without neurological impairment. This post-hoc analysis demonstrates that, in early FGR, the daily risk of abnormal CTG, as defined by the DV group safety-net criteria, is 5%, and that prediction is not possible. This supports the rationale for CTG monitoring more often than daily in these high-risk fetuses. Low STV and/or recurrent FHR decelerations were not associated with adverse infant outcome and it appears safe to delay intervention until such abnormalities occur, as long as DV-PI is within normal range. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27484358 TI - Non-monotonic temperature dependence of radiation defect dynamics in silicon carbide. AB - Understanding response of solids to particle irradiation remains a major materials physics challenge. This applies even to SiC, which is a prototypical nuclear ceramic and wide-band-gap semiconductor material. The lack of predictability is largely related to the complex, dynamic nature of radiation defect formation. Here, we use a novel pulsed-ion-beam method to study dynamic annealing in 4H-SiC ion-bombarded in the temperature range of 25-250 degrees C. We find that, while the defect recombination efficiency shows an expected monotonic increase with increasing temperature, the defect lifetime exhibits a non-monotonic temperature dependence with a maximum at ~100 degrees C. This finding indicates a change in the dominant defect interaction mechanism at ~100 degrees C. The understanding of radiation defect dynamics may suggest new paths to designing radiation-resistant materials. PMID- 27484359 TI - Determination of haloacetic acids in water using layered double hydroxides as a sorbent in dispersive solid-phase extraction followed by liquid chromatography with tandem mass spectrometry. AB - In the present study, highly efficient and simple dispersive solid-phase extraction procedure for the determination of haloacetic acids in water samples has been established. Three different types of layered double hydroxides were synthesized and used as a sorbent in dispersive solid-phase extraction. Due to the interesting behavior of layered double hydroxides in an acidic medium (pH?4), the analyte elution step was not needed; the layered double hydroxides are simply dissolved in acid immediately after extraction to release the analytes which are then directly introduced into a liquid chromatography with tandem mass spectrometry system for analysis. Several dispersive solid-phase extraction parameters were optimized to increase the extraction efficiency of haloacetic acids such as temperature, extraction time and pH. Under optimum conditions, good linearity was achieved over the concentration range of 0.05-100 MUg/L with detection limits in the range of 0.006-0.05 MUg/L. The relative standard deviations were 0.33-3.64% (n = 6). The proposed method was applied to different water samples collected from a drinking water plant to determine the concentrations of haloacetic acids. PMID- 27484360 TI - Novel complex mutation in NPM1 gene in patient with acute myeloid leukemia. PMID- 27484361 TI - Multivariate analysis of ultrasound-recorded dorsal strain sequences: Investigation of dynamic neck extensions in women with chronic whiplash associated disorders. AB - Whiplash Associated Disorders (WAD) refers to the multifaceted and chronic burden that is common after a whiplash injury. Tools to assist in the diagnosis of WAD and an increased understanding of neck muscle behaviour are needed. We examined the multilayer dorsal neck muscle behaviour in nine women with chronic WAD versus healthy controls during the entire sequence of a dynamic low-loaded neck extension exercise, which was recorded using real-time ultrasound movies with high frame rates. Principal component analysis and orthogonal partial least squares were used to analyse mechanical muscle strain (deformation in elongation and shortening). The WAD group showed more shortening during the neck extension phase in the trapezius muscle and during both the neck extension and the return to neutral phase in the multifidus muscle. For the first time, a novel non invasive method is presented that is capable of detecting altered dorsal muscle strain in women with WAD during an entire exercise sequence. This method may be a breakthrough for the future diagnosis and treatment of WAD. PMID- 27484362 TI - Drosophila melanogaster females restore their attractiveness after mating by removing male anti-aphrodisiac pheromones. AB - Males from many species ensure paternity by preventing their mates from copulating with other males. One mate-guarding strategy involves marking females with anti-aphrodisiac pheromones (AAPs), which reduces the females' attractiveness and dissuades other males from courting. Since females benefit from polyandry, sexual conflict theory predicts that females should develop mechanisms to counteract AAPs to achieve additional copulations, but no such mechanisms have been documented. Here we show that during copulation Drosophila melanogaster males transfer two AAPs: cis-Vaccenyl Acetate (cVA) to the females' reproductive tract, and 7-Tricosene (7-T) to the females' cuticle. A few hours after copulation, females actively eject cVA from their reproductive tract, which results in increased attractiveness and re-mating. Although 7-T remains on those females, we show that it is the combination of the two chemicals that reduces attractiveness. To our knowledge, female AAP ejection provides the first example of a female mechanism that counter-acts chemical mate-guarding. PMID- 27484363 TI - Testicular toxicity following separate and combined administration of PDE5 inhibitors and opioid: assessment of recovery following their withdrawal. AB - We previously observed that PDE5 inhibitors and opioids were widely abused in Nigeria. Here, we examined the effect of high doses of sildenafil, tadalafil, tramadol and sildenafil + tramadol on reproductive toxicity in male rats. Rats were either administered normal saline (0.2 ml), sildenafil (10 mg/kg), tadalafil (10 mg/kg), tramadol (20 mg/kg) or sildenafil + tramadol (10 and 20 mg/kg respectively) p. o. for 8 weeks. The recovery groups were allowed 8-week recovery period before sacrifice. Results showed that body weight change, testicular and epididymal weights, epididymal sperm count and sperm viability were significantly reduced in all treated groups compared with the control. Spermatozoa with abnormal morphology were significantly increased in all treated groups compared with the control. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH) were significantly reduced, while malondialdehyde (MDA) was significantly increased in all treated groups compared with the control. The severity of toxicity was highest in sildenafil + tramadol group. There was no complete recovery from reproductive toxicity following withdrawal of the various treatments. High doses of sildenafil, tadalafil, tramadol or sildenafil + tramadol result in testicular oxidative stress-induced reproductive toxicity with poor reversal following withdrawal. PMID- 27484364 TI - Symbiotic gut commensal bacteria act as host cathepsin S activity regulators. AB - Cathepsin S (CTSS) is a lysosomal protease whose activity regulation is important for MHC-II signaling and subsequent activation of CD4+ T cell mediated immune responses. Dysregulation of its enzymatic activity or enhanced secretion into extracellular environments is associated with the induction or progression of several autoimmune diseases. Here we demonstrate that commensal intestinal bacteria influence secretion rates and intracellular activity of host CTSS and that symbiotic bacteria, i.e. Bacteroides vulgatus mpk, may actively regulate this process and help to maintain physiological levels of CTSS activities in order to prevent from induction of pathological inflammation. The symbiont controlled regulation of CTSS activity is mediated by anticipating reactive oxygen species induction in dendritic cells which, in turn, maintains cystatin C (CysC) monomer binding to CTSS. CysC monomers are potent endogenous CTSS inhibitors. This Bacteroides vulgatus caused and CysC dependent CTSS activity regulation is involved in the generation of tolerant intestinal dendritic cells contributing to prevention of T-cell mediated induction of colonic inflammation. Taken together, we demonstrate that symbionts of the intestinal microbiota regulate host CTSS activity and secretion and might therefore be an attractive approach to deal with CTSS associated autoimmune diseases. PMID- 27484365 TI - Strategies for Improving Patient Comfort During Intravitreal Injections: Results from a Survey-Based Study. AB - INTRODUCTION: Many ocular diseases require intravitreal injections of pharmacological agents. Optimizing patients' experiences during injections is important to ensure compliance and maintenance of quality of life. The objective of this study was to identify strategies to help alleviate discomfort during intravitreal injections. METHODS: A cross-sectional study surveying 128 patients during clinic visits between 2014 and 2015 in two outpatient Retina Clinics (one academic and one private). Patients receiving an intravitreal injection(s) for any retinal disorder were given a questionnaire with 10-yes/no responses for various potential strategies. Responses were stratified by sex, age (<30 years, 30-60 years, and >60 years) and total number of prior injections (0-9 injections, 10-20 injections and >20 injections). RESULTS: A total of 128 patients were surveyed: 59 males, 41 females and 28 with no sex specified. Our results identified four favorable strategies as those receiving more than 50% "yes" votes. These included the presence of technician/staff during the procedure, the use of a neck pillow, a verbal warning before the injection and performing injections in both eyes on the same day. Other specific strategies were identified for females, younger patients and those with greatest experience. These included: females preferred having their hand held during injections (P = 0.001) and using a stress ball (P = 0.000) when compared to males. Stratifying by age, patients 30-60 years old preferred having their hand held (P = 0.008) and background music (P = 0.007). Stratifying by prior injections, patients with >20 prior injections preferred having their hand held (P = 0.001), using a stress ball (P = 0.021) and, if necessary, having bilateral injections performed the same day to improve comfort (P = 0.037). CONCLUSIONS: Having an extra staff member present during the injection, having a neck pillow, having a verbal warning prior to injection and having both eyes injected on the same day were indicated as favorable strategies by over half of those surveyed. Further, specific strategies were identified for females, younger patients (30-60 years old) and those with greatest experience (>20 injections). PMID- 27484366 TI - Introduction to the special issue on crystal structure prediction. PMID- 27484367 TI - Crystal structure prediction: are we there yet? AB - This contribution comments on the advances of the latest Crystal Structure Prediction blind test and the challenges still lying ahead. PMID- 27484369 TI - Transferable force field for crystal structure predictions, investigation of performance and exploration of different rescoring strategies using DFT-D methods. AB - A new force field, here called AZ-FF, aimed at being used for crystal structure predictions, has been developed. The force field is transferable to a new type of chemistry without additional training or modifications. This makes the force field very useful in the prediction of crystal structures of new drug molecules since the time-consuming step of developing a new force field for each new molecule is circumvented. The accuracy of the force field was tested on a set of 40 drug-like molecules and found to be very good where observed crystal structures are found at the top of the ranked list of tentative crystal structures. Re-ranking with dispersion-corrected density functional theory (DFT D) methods further improves the scoring. After DFT-D geometry optimization the observed crystal structure is found at the leading top of the ranking list. DFT-D methods and force field methods have been evaluated for use in predicting properties such as phase transitions upon heating, mechanical properties or intrinsic crystalline solubility. The utility of using crystal structure predictions and the associated material properties in risk assessment in connection with form selection in the drug development process is discussed. PMID- 27484370 TI - An optimized intermolecular force field for hydrogen-bonded organic molecular crystals using atomic multipole electrostatics. AB - We present a re-parameterization of a popular intermolecular force field for describing intermolecular interactions in the organic solid state. Specifically we optimize the performance of the exp-6 force field when used in conjunction with atomic multipole electrostatics. We also parameterize force fields that are optimized for use with multipoles derived from polarized molecular electron densities, to account for induction effects in molecular crystals. Parameterization is performed against a set of 186 experimentally determined, low temperature crystal structures and 53 measured sublimation enthalpies of hydrogen bonding organic molecules. The resulting force fields are tested on a validation set of 129 crystal structures and show improved reproduction of the structures and lattice energies of a range of organic molecular crystals compared with the original force field with atomic partial charge electrostatics. Unit-cell dimensions of the validation set are typically reproduced to within 3% with the re-parameterized force fields. Lattice energies, which were all included during parameterization, are systematically underestimated when compared with measured sublimation enthalpies, with mean absolute errors of between 7.4 and 9.0%. PMID- 27484371 TI - Crystal structure prediction of rigid molecules. AB - A non-polarizable force field based on atomic multipoles fit to reproduce experimental crystal properties and ab initio gas-phase dimers is described. The Ewald method is used to calculate both long-range electrostatic and 1/r(6) dispersion energies of crystals. The dispersion energy of a crystal calculated by a cutoff method is shown to converge slowly to the exact Ewald result. A method for constraining space-group symmetry during unit-cell optimization is derived. Results for locally optimizing 4427 unit cells including volume, cell parameters, unit-cell r.m.s.d. and CPU timings are given for both flexible and rigid molecule optimization. An algorithm for randomly generating rigid molecule crystals is described. Using the correct experimentally determined space group, the average and maximum number of random crystals needed to find the correct experimental structure is given for 2440 rigid single component crystals. The force field energy rank of the correct experimental structure is presented for the same set of 2440 rigid single component crystals assuming the correct space group. A complete crystal prediction is performed for two rigid molecules by searching over the 32 most probable space groups. PMID- 27484372 TI - Organic crystal polymorphism: a benchmark for dispersion-corrected mean-field electronic structure methods. AB - We analyze the energy landscape of the sixth crystal structure prediction blind test targets with various first principles and semi-empirical quantum chemical methodologies. A new benchmark set of 59 crystal structures (termed POLY59) for testing quantum chemical methods based on the blind test target crystals is presented. We focus on different means to include London dispersion interactions within the density functional theory (DFT) framework. We show the impact of pairwise dispersion corrections like the semi-empirical D2 scheme, the Tkatchenko Scheffler (TS) method, and the density-dependent dispersion correction dDsC. Recent methodological progress includes higher-order contributions in both the many-body and multipole expansions. We use the D3 correction with Axilrod-Teller Muto type three-body contribution, the TS based many-body dispersion (MBD), and the nonlocal van der Waals density functional (vdW-DF2). The density functionals with D3 and MBD correction provide an energy ranking of the blind test polymorphs in excellent agreement with the experimentally found structures. As a computationally less demanding method, we test our recently presented minimal basis Hartree-Fock method (HF-3c) and a density functional tight-binding Hamiltonian (DFTB). Considering the speed-up of three to four orders of magnitudes, the energy ranking provided by the low-cost methods is very reasonable. We compare the computed geometries with the corresponding X-ray data where TPSS-D3 performs best. The importance of zero-point vibrational energy and thermal effects on crystal densities is highlighted. PMID- 27484368 TI - Report on the sixth blind test of organic crystal structure prediction methods. AB - The sixth blind test of organic crystal structure prediction (CSP) methods has been held, with five target systems: a small nearly rigid molecule, a polymorphic former drug candidate, a chloride salt hydrate, a co-crystal and a bulky flexible molecule. This blind test has seen substantial growth in the number of participants, with the broad range of prediction methods giving a unique insight into the state of the art in the field. Significant progress has been seen in treating flexible molecules, usage of hierarchical approaches to ranking structures, the application of density-functional approximations, and the establishment of new workflows and 'best practices' for performing CSP calculations. All of the targets, apart from a single potentially disordered Z' = 2 polymorph of the drug candidate, were predicted by at least one submission. Despite many remaining challenges, it is clear that CSP methods are becoming more applicable to a wider range of real systems, including salts, hydrates and larger flexible molecules. The results also highlight the potential for CSP calculations to complement and augment experimental studies of organic solid forms. PMID- 27484373 TI - How important is thermal expansion for predicting molecular crystal structures and thermochemistry at finite temperatures? AB - Molecular crystals expand appreciably upon heating due to both zero-point and thermal vibrational motion, yet this expansion is often neglected in molecular crystal modeling studies. Here, a quasi-harmonic approximation is coupled with fragment-based hybrid many-body interaction calculations to predict thermal expansion and finite-temperature thermochemical properties in crystalline carbon dioxide, ice Ih, acetic acid and imidazole. Fragment-based second-order Moller Plesset perturbation theory (MP2) and coupled cluster theory with singles, doubles and perturbative triples [CCSD(T)] predict the thermal expansion and the temperature dependence of the enthalpies, entropies and Gibbs free energies of sublimation in good agreement with experiment. The errors introduced by neglecting thermal expansion in the enthalpy and entropy cancel somewhat in the Gibbs free energy. The resulting ~ 1-2 kJ mol(-1) errors in the free energy near room temperature are comparable to or smaller than the errors expected from the electronic structure treatment, but they may be sufficiently large to affect free energy rankings among energetically close polymorphs. PMID- 27484374 TI - Generation of crystal structures using known crystal structures as analogues. AB - This analysis attempts to answer the question of whether similar molecules crystallize in a similar manner. An analysis of structures in the Cambridge Structural Database shows that the answer is yes - sometimes they do, particularly for single-component structures. However, one does need to define what we mean by similar in both cases. Building on this observation we then demonstrate how this correlation between shape similarity and packing similarity can be used to generate potential lattices for molecules with no known crystal structure. Simple intermolecular interaction potentials can be used to minimize these potential lattices. Finally we discuss the many limitations of this approach. PMID- 27484375 TI - Exploring polymorphism of benzene and naphthalene with free energy based enhanced molecular dynamics. AB - Prediction and exploration of possible polymorphism in organic crystal compounds are of great importance for industries ranging from organic electronics to pharmaceuticals to high-energy materials. Here we apply our crystal structure prediction procedure and the enhanced molecular dynamics based sampling approach called the Crystal-Adiabatic Free Energy Dynamics (Crystal-AFED) method to benzene and naphthalene. Crystal-AFED allows the free energy landscape of structures to be explored efficiently at any desired temperature and pressure. For each system, we successfully predict the most stable crystal structures at atmospheric pressure and explore the relative Gibbs free energies of predicted polymorphs at high pressures. Using Crystal-AFED sampling, we find that mixed structures, which typically cannot be discovered by standard crystal structure prediction methods, are prevalent in the solid forms of these compounds at high pressure. PMID- 27484377 TI - Effect of packing motifs on the energy ranking and electronic properties of putative crystal structures of tricyano-1,4-dithiino[c]-isothiazole. AB - We present an analysis of putative structures of tricyano-1,4-dithiino[c] isothiazole (TCS3), generated within the sixth crystal structure prediction blind test. Typical packing motifs are identified and characterized in terms of distinct patterns of close contacts and regions of electrostatic and dispersion interactions. We find that different dispersion-inclusive density functional theory (DFT) methods systematically favor specific packing motifs, which may affect the outcome of crystal structure prediction efforts. The effect of crystal packing on the electronic and optical properties of TCS3 is investigated using many-body perturbation theory within the GW approximation and the Bethe-Salpeter equation (BSE). We find that a structure with Pna21 symmetry and a bilayer packing motif exhibits intermolecular bonding patterns reminiscent of pi-pi stacking and has markedly different electronic and optical properties than the experimentally observed P21/n structure with a cyclic dimer motif, including a narrower band gap, enhanced band dispersion and broader optical absorption. The Pna21 bilayer structure is close in energy to the observed structure and may be feasible to grow. PMID- 27484376 TI - Using crystal structure prediction to rationalize the hydration propensities of substituted adamantane hydrochloride salts. AB - The crystal energy landscapes of the salts of two rigid pharmaceutically active molecules reveal that the experimental structure of amantadine hydrochloride is the most stable structure with the majority of low-energy structures adopting a chain hydrogen-bond motif and packings that do not have solvent accessible voids. By contrast, memantine hydrochloride which differs in the substitution of two methyl groups on the adamantane ring has a crystal energy landscape where all structures within 10 kJ mol(-1) of the global minimum have solvent-accessible voids ranging from 3 to 14% of the unit-cell volume including the lattice energy minimum that was calculated after removing water from the hydrated memantine hydrochloride salt structure. The success in using crystal structure prediction (CSP) to rationalize the different hydration propensities of these substituted adamantane hydrochloride salts allowed us to extend the model to predict under blind test conditions the experimental crystal structures of the previously uncharacterized 1-(methylamino)adamantane base and its corresponding hydrochloride salt. Although the crystal structure of 1-(methylamino)adamantane was correctly predicted as the second ranked structure on the static lattice energy landscape, the crystallization of a Z' = 3 structure of 1 (methylamino)adamantane hydrochloride reveals the limits of applying CSP when the contents of the crystallographic asymmetric unit are unknown. PMID- 27484378 TI - An insight into real and average structure from diffuse X-ray scattering - a case study. AB - Two-dimensional diffuse X-ray scattering from an organic salt [N-(3-(2,6 dimethylanilino)-1-methylbut-2-enylidene)-2,6-dimethylanilinium chloride, C21H27N2(+)Cl(-)] was interpreted with the help of an analytical model of diffuse scattering. An analysis of the relationship between symmetry and diffuse scattering for the studied system has been undertaken. The symmetry of the system explains the extinction pattern, taking the form of curves, on the diffuse scattering planes. We have also tested the relationship between the average structure model and scattering intensities. Two models, differing in their representation of overlapping atoms, were used. In the case of diffuse scattering the difference between resulting intensities is immense, while for the Bragg intensities it is much smaller. This sensitivity of diffuse scattering could potentially be used to improve the description of the average structure. PMID- 27484379 TI - Self-assembly modes of glycyrrhetinic acid esters in view of the crystal packing of related triterpene molecules. AB - The crystal structures of three ester derivatives of glycyrrhetinic acid (GE) are reported. X-ray crystallography revealed that despite differences in the size of the ester substituents (ethyl, isopropyl and 2-morpholinoethyl) the scheme of molecular self-assembly is similar in all three cases but differs significantly from that observed in other known GE esters. According to our analysis, the two basic patterns of self-assembly of GE esters observed in their unsolvated crystals correspond to two distinct orientations of the ester groups relative to the triterpene backbone. Moreover, comparison of the self-assembly modes of GE esters in their unsolvated forms with the supramolecular organization of GE and carbenoxolone in their solvated crystals revealed that ester substituents replace solvent molecules hydrogen bonded to the COOH group at the triterpene skeleton, resulting in similar packing arrangements of these compounds. PMID- 27484380 TI - Growth, morphology, structure and characterization of L-histidinium dihydrogen arsenate orthoarsenic acid single crystal. AB - L-Histidinium dihydrogen arsenate orthoarsenic acid (LHAS) crystals were grown by the slow evaporation method. Single-crystal X-ray diffraction confirms monoclinic structure. The growth rates of various planes of LHAS crystals were estimated by morphological study. Hirshfeld surface and fingerprint plots were analyzed to investigate the intermolecular interactions at 0.002 a.u. present in the crystal structure. The functional groups and phase behavior of the compound are studied by FTIR spectroscopy and differential scanning calorimetry (DSC). A ferroelectric to paraelectric phase transition at 307 K was observed in dielectric studies. The piezoelectric charge coefficients of the grown crystal were found to be 2 pC/N. The values of coercive field (Ec), remnant polarization (Pr) and spontaneous polarization (Ps) in the hysteresis loop are found to be 5.236 kV cm(-1), 0.654 uC cm(-2) and 2.841 uC cm(-2), respectively. Piezoelectricity and ferroelectricity are reported for the first time in LHAS crystals. The mechanical strength was confirmed from microhardness study and void volume. Due to the low value of the dielectric constant, and good piezoelectric and ferroelectric properties, LHAS crystals can be used in microelectronics, sensors and advanced electronic devices. PMID- 27484381 TI - Bond-length distributions for ions bonded to oxygen: alkali and alkaline-earth metals. AB - Bond-length distributions have been examined for 55 configurations of alkali metal ions and 29 configurations of alkaline-earth-metal ions bonded to oxygen, for 4859 coordination polyhedra and 38 594 bond distances (alkali metals), and for 3038 coordination polyhedra and 24 487 bond distances (alkaline-earth metals). Bond lengths generally show a positively skewed Gaussian distribution that originates from the variation in Born repulsion and Coulomb attraction as a function of interatomic distance. The skewness and kurtosis of these distributions generally decrease with increasing coordination number of the central cation, a result of decreasing Born repulsion with increasing coordination number. We confirm the following minimum coordination numbers: ([3])Li(+), ([3])Na(+), ([4])K(+), ([4])Rb(+), ([6])Cs(+), ([3])Be(2+), ([4])Mg(2+), ([6])Ca(2+), ([6])Sr(2+) and ([6])Ba(2+), but note that some reported examples are the result of extensive dynamic and/or positional short range disorder and are not ordered arrangements. Some distributions of bond lengths are distinctly multi-modal. This is commonly due to the occurrence of large numbers of structure refinements of a particular structure type in which a particular cation is always present, leading to an over-representation of a specific range of bond lengths. Outliers in the distributions of mean bond lengths are often associated with anomalous values of atomic displacement of the constituent cations and/or anions. For a sample of ([6])Na(+), the ratio Ueq(Na)/Ueq(bonded anions) is partially correlated with <([6])Na(+)-O(2-)> (R(2) = 0.57), suggesting that the mean bond length is correlated with vibrational/displacement characteristics of the constituent ions for a fixed coordination number. Mean bond lengths also show a weak correlation with bond length distortion from the mean value in general, although some coordination numbers show the widest variation in mean bond length for zero distortion, e.g. Li(+) in [4]- and [6]-coordination, Na(+) in [4]- and [6]-coordination. For alkali-metal and alkaline-earth-metal ions, there is a positive correlation between cation coordination number and the grand mean incident bond-valence sum at the central cation, the values varying from 0.84 v.u. for ([5])K(+) to 1.06 v.u. for ([8])Li(+), and from 1.76 v.u. for ([7])Ba(2+) to 2.10 v.u. for ([12])Sr(2+). Bond-valence arguments suggest coordination numbers higher than [12] for K(+), Rb(+), Cs(+) and Ba(2+). PMID- 27484382 TI - On the effective ionic radii for ammonium. AB - A set of effective ionic radii corresponding to different coordination numbers (CNs) and compatible with the radii system by Shannon [Acta Cryst. (1976), A32, 751-767] has been derived for ammonium: 1.40 A (CN = IV), 1.48 A (CN = VI), 1.54 A (CN = VIII) and 1.67 A (CN = XII). The bond-valence parameters r0 = 2.3433 A and B = 0.262 A have been determined for ammonium-fluorine bonds. PMID- 27484383 TI - Structure and topology of three-dimensional hydrocarbon polymers. AB - A new family of three-dimensional hydrocarbon polymers which are more energetically favorable than benzene is proposed. Although structurally these polymers are closely related to well known diamond and lonsdaleite carbon structures, using topological arguments we demonstrate that they have no known structural analogs. Topological considerations also give some indication of possible methods of synthesis. Taking into account their exceptional optical, structural and mechanical properties these polymers might have interesting applications. PMID- 27484384 TI - Modulated crystal structure of InMo4O6. AB - The (3 + 1)-dimensional modulated crystal structure of the metal-rich cluster compound InMo4O6 was solved and refined from single-crystal data in the superspace group P4/mbm(00gamma)00ss [q = 0, 0, 0.1536 (4); a = 9.6664 (9), c = 2.8645 (3) A; R1(all) = 0.046, wR(all) = 0.076]. The crystal structure is closely related to the NaMo4O6 structure type. It is built from rods of Mo6 clusters condensed via trans edges. These form channels parallel to [001], in which In6 and In7 oligomers alternate. Weak diffuse planes parallel to (001)* interconnect the satellite reflections; they occur due to two-dimensional rod disorder of the In oligomer chains. PMID- 27484385 TI - Structures of N-acetyl-DL-isoleucine, N-acetyl-DL-alloisoleucine and their ammonium salts; role of ammonium ions in crystal structure formation. AB - The crystal structures of N-acetyl-DL-isoleucine, N-acetyl-DL-alloisoleucine and their ammonium salts show that these four compounds exist as racemic compounds around room temperature. The two ammonium salts are arranged around a 21 screw axis, forming a helical column which consists of ammonium ions and single enantiomeric anions similar to the crystals of the ammonium salts of optically active N-acetyl-L-isoleucine and N-acetyl-D-alloisoleucine. The ammonium ion and the carboxylate ion in the helix are connected by three hydrogen bonds, the fourth hydrogen bond being formed between the ammonium ion and an external acetyl amino group of the neighboring helical column. The fourth hydrogen bond is formed between the ammonium ion and an external acetyl amino group of the neighboring 21 column. Ammonium N-acetyl-DL-alloisoleucinate was revealed to exist as an unstable racemic compound due to conformational similarity between the racemic and optically active compounds in the solid state and was optically resolved by fractional crystallization at 293 K. PMID- 27484386 TI - Magnetic Resonance Imaging Underestimation of Prostate Cancer Geometry: Use of Patient Specific Molds to Correlate Images with Whole Mount Pathology. AB - PURPOSE: We evaluated the accuracy of magnetic resonance imaging in determining the size and shape of localized prostate cancer. MATERIALS AND METHODS: The subjects were 114 men who underwent multiparametric magnetic resonance imaging before radical prostatectomy with patient specific mold processing of the specimen from 2013 to 2015. T2-weighted images were used to contour the prostate capsule and cancer suspicious regions of interest. The contours were used to design and print 3-dimensional custom molds, which permitted alignment of excised prostates with magnetic resonance imaging scans. Tumors were reconstructed in 3 dimensions from digitized whole mount sections. Tumors were then matched with regions of interest and the relative geometries were compared. RESULTS: Of the 222 tumors evident on whole mount sections 118 had been identified on magnetic resonance imaging. For the 118 regions of interest mean volume was 0.8 cc and the longest 3-dimensional diameter was 17 mm. However, for matched pathological tumors, of which most were Gleason score 3 + 4 or greater, mean volume was 2.5 cc and the longest 3-dimensional diameter was 28 mm. The median tumor had a 13.5 mm maximal extent beyond the magnetic resonance imaging contour and 80% of cancer volume from matched tumors was outside region of interest boundaries. Size estimation was most accurate in the axial plane and least accurate along the base apex axis. CONCLUSIONS: Magnetic resonance imaging consistently underestimates the size and extent of prostate tumors. Prostate cancer foci had an average diameter 11 mm longer and a volume 3 times greater than T2-weighted magnetic resonance imaging segmentations. These results may have important implications for the assessment and treatment of prostate cancer. PMID- 27484389 TI - Experimental design-based optimization of lipid nanocarrier as delivery system against Mycobacterium species: in vitro and in vivo evaluation. AB - The study aimed to optimize self-nanoemulsifying drug delivery system using experimental design using excipients holding innate anti-mycobacterium activities followed with characterizations for responses such as optical clarity (Y1), zone of inhibition (ZOI) against Mycobacterium smegmatis strains (Y2, Y3), and globular size (Y4). The optimized formulations (OF1-OF3) were further characterized for responses and evaluated for zeta potential, minimum inhibition concentration (MIC) against non-pathogenic and tubercular strains, morphological (electron microscopy and atomic force microscopy), and confocal laser scanning microscopy (CLSM) studies. The desirability analysis suggested that the predicted values of the OF1 for the responses Y1, Y2, Y3, and Y4 were 0.137, 22.77 mm, 21.9 mm, and 191.11 nm, respectively. The morphological assessment confirmed the in vitro studies and established the inhibition mechanism as evidenced with oozing, ablation, and cell-wall fragmentation followed with cell disruption. The OF1, OF2, and OF3 showed an MIC value at 8.8 +/- 0.56 mg/ml, 12.5 +/- 0.22 mg/ml, and 15.0 +/- 0.4 mg/ml, respectively, corroborating effectiveness against tubercular strain. CLSM studies revealed 75.1, 80.3, and 88.7% as an intense fluorescence intensity of OF1, OF2, and OF3, respectively, as compared with dye solution (~53%). Conclusively, it can be inferred that the delivery of anti-tubercular drugs might be reassessed using excipients with inherent anti-mycobacterium activities. PMID- 27484391 TI - Sub-Saharan African migrant youths' help-seeking barriers and facilitators for mental health and substance use problems: a qualitative study. AB - BACKGROUND: Many young migrants and their parents are reluctant to seek help for mental health and substance use problems. Help-seeking delays can result in longer duration of untreated problems and poorer outcomes. In this study, we aimed to identify the help-seeking barriers and facilitators for anxiety, depression and alcohol and drug use problems in young people from recently established sub-Saharan African migrant communities. METHODS: A qualitative study, incorporating individual, in-depth interviews and focus group discussions, was undertaken in Melbourne, Australia. Twenty-eight young sub-Saharan African migrants participated in the individual interviews, and 41 sub-Saharan African born parents and key community leaders participated in 4 focus groups. All participants were aged 16 years or over. A thematic analysis of the data was undertaken. RESULTS: Themes and related sub-themes were abstracted from the data, reflecting the young people's, parents' and key community leaders' beliefs about barriers and facilitators to help-seeking for mental health and substance use problems. Four help-seeking barriers were identified: stigma of mental illness, lack of mental health literacy in parents and young people, lack of cultural competency of formal help sources, and financial costs deterring access. Five help-seeking facilitators were abstracted: being open with friends and family, strong community support systems, trustworthiness and confidentiality of help sources, perceived expertise of formal help-sources, increasing young people's and parents' mental health literacy. CONCLUSION: Programs that identify and build on help-seeking facilitators while addressing help-seeking barriers are needed to address mental health issues among young sub-Saharan African migrants. Strategies to address help-seeking barriers should consider counteracting stigma and increasing mental health literacy in sub-Saharan African communities, increasing health providers' cultural competency and perceived trustworthiness, and addressing financial barriers to accessing services. PMID- 27484392 TI - Mostly Smokers: Identifying Subtypes of Emerging Adult Substance Users. AB - BACKGROUND: The concurrent use of marijuana and other substances among emerging adults (ages 18-25) is a major public health problem. This study examined if there are distinct subtypes of emerging adult marijuana users and if these are associated with demographic and substance use variables. METHODS: The design was a cross-sectional interview with a community sample of 1,503 emerging adults in the northeastern U.S. who reported last month marijuana use. We used latent class analysis (LCA) to identify distinct subtypes of emerging adults who used additional substances and examined predictors of the latent classes. RESULTS: We identified three distinct classes of emerging adults who use substances: "mostly smokers" (those who primarily use marijuana and nicotine), "moderate users" (those who primarily use marijuana and/or heavy episodic alcohol), and "polysubstance users." Polysubstance users had higher probabilities of use of all assessed substances (e.g. cocaine, opiates, sleep medications, stimulants, synthetic marijuana, and inhalants) than the other two groups. Not being currently enrolled in school and male gender were associated with mostly smokers and polysubstance users group status. CONCLUSIONS: We identified a distinct group of emerging adult marijuana users who primarily smoke marijuana and cigarettes, suggesting that there could be a shared vulnerability for risk of co-occurrence. PMID- 27484393 TI - Homochiral [2.2]Paracyclophane Self-Assembly Promoted by Transannular Hydrogen Bonding. AB - [2.2]paracyclophane (pCp), unlike many pi-building blocks, has been virtually unexplored in supramolecular constructs. Reported here is the synthesis and characterization of the first pCp derivatives capable of programmed self-assembly into extended cofacial pi-stacks in solution and the solid state. The design employs transannular (intramolecular) hydrogen bonds (H-bonds), hitherto unstudied in pCps, between pseudo-ortho-positioned amides of a pCp-4,7,12,15 tetracarboxamide (pCpTA) to preorganize the molecules for intermolecular H bonding with pi-stacked neighbors. X-ray crystallography confirms the formation of homochiral, one-dimensional pCpTA stacks helically laced with two H-bond strands. The chiral sense is dictated by the planar chirality (Rp or Sp ) of the pCpTA monomers. A combination of NMR, IR, and UV/Vis studies confirms the formation of the first supramolecular pCp polymers in solution. PMID- 27484394 TI - Sexual objectification in women's daily lives: A smartphone ecological momentary assessment study. AB - Sexual objectification, particularly of young women, is highly prevalent in modern industrialized societies. Although there is plenty of experimental and cross-sectional research on objectification, prospective studies investigating the prevalence and psychological impact of objectifying events in daily life are scarce. We used ecological momentary assessment to track the occurrence of objectifying events over 1 week in the daily lives of young women (N = 81). Participants reported being targeted by a sexually objectifying event - most often the objectifying gaze - approximately once every 2 days and reported witnessing sexual objectification of others approximately 1.35 times per day. Further, multilevel linear regression analyses showed that being targeted by sexual objectification was associated with a substantial increase in state self objectification. Overall, individual differences had little impact in moderating these effects. PMID- 27484395 TI - Effects of Funnelliformis mosseae inoculation on alleviating atrazine damage in Canna indica L. var. flava Roxb. AB - Atrazine residue in the environment continually damages plants and therefore requires immediate attention and effective development of methods for its decontamination. The effects of Funnelliformis mosseae inoculation on growth and physiology in atrazine-treated Canna indica L. var. flava Roxb. were investigated. At atrazine concentrations up to 15 mg L-1, the growth of C. indica plants were negatively affected. Inoculation with F. mosseae alleviated the atrazine inhibition of plant growth and biomass. Furthermore, the chlorophyll content and root function increased under F. mosseae inoculation, and the oxidative stress of malondialdehyde, peroxidase, and superoxide dismutase activities induced by atrazine were also alleviated by F. mosseae inoculation. The removal rate of atrazine by untreated C. indica was significant, with removal rates of 20.5-55.3% by the end of a 14-day experiment; however, F. mosseae inoculation increased the removal rate to 35.6-75.1%. In conclusion, F. mosseae inoculation can alleviate the damage induced by atrazine in C. indica. Accordingly, C. indica inoculated with F. mosseae has excellent potential to be used in phytoremediation in habitats polluted by high atrazine concentrations. PMID- 27484396 TI - Polarized dosimetry method for Gafchromic EBT3. AB - PURPOSE: To analyze the changes in the polarization state of the flatbed scanner light caused by the EBT3 films and to propose a new method for correcting the lateral effects. METHODS AND MATERIALS: The polarization changes induced by radiochromic films are analyzed using linear polarizing film. Based on the results, the linear polarizing films are used in the scanning process of the EBT3 films. This method is tested against the conventional EBT3 dosimetry using a series of simple regular beams and 21 cases of IMRT. RESULTS: The mean results are statically different from the conventional dosimetry with EBT3. Depending on the transmission axis of the polarizing sheet, the results are better or worse compared to conventional dosimetry EBT3 film. When the transmission axis of the polarizing sheet is parallel to the coating direction, the dosimetry results are better and its variability is smaller. However, when the polarizer transmission axis is perpendicular to the coating direction, results are worse as well as its variability. CONCLUSION: Using a polarized film with the polarization axis parallel to the coating direction of the radiochromic film, and preferably above it, significantly improves the dosimetry results and is an easy and inexpensive way to correct the lateral artifacts of the conventional EBT3 dosimetry. PMID- 27484397 TI - Spectral optimization of iodine-enhanced CT: Quantifying the effect of tube voltage on image quality and radiation exposure determined at an anthropomorphic phantom. AB - PURPOSE: To provide an experimental basis for spectral optimization of iodine enhanced CT by a quantitative analysis of image quality and radiation dose characteristics consistently measured for a large variety of scan settings at an anthropomorphic phantom. METHODS: CT imaging and thermoluminescent dosimetry were performed at an anthropomorphic whole-body phantom with iodine inserts for different tube voltages (U, 70-140kV) and current-time products (Q, 60-300mAs). For all U-Q combinations, the iodine contrast (C), the noise level (N) and, from these, the contrast-to-noise ratio (CNR) of reconstructed CT images were determined and parameterized as a function of U, Q or the measured absorbed dose (D). Finally, two characteristic curves were derived that give the relative increase of CNR at constant D and the relative decrease of D at constant CNR when lowering U. RESULTS: Lowering U affects the measured CNR only slightly but markedly reduces D. For example, reducing U from 120kV to 70kV increases the CNR at constant D by a factor of nearly 1.8 or, alternatively, reduces D at constant CNR by a factor of nearly 5. CONCLUSION: Spectral optimization by lowering U is an effective approach to attain the necessary CNR for a specific diagnostic task at hand while at the same time reducing radiation exposure as far as practically achievable. The characteristic curves derived in this study from extensive measurements at a reference 'person' can support CT users in an easy-to-use manner to select an appropriate voltage for various clinical scenarios. PMID- 27484398 TI - Early-Stage Capital Cost Estimation of Biorefinery Processes: A Comparative Study of Heuristic Techniques. AB - Biorefineries offer a promising alternative to fossil-based processing industries and have undergone rapid development in recent years. Limited financial resources and stringent company budgets necessitate quick capital estimation of pioneering biorefinery projects at the early stages of their conception to screen process alternatives, decide on project viability, and allocate resources to the most promising cases. Biorefineries are capital-intensive projects that involve state of-the-art technologies for which there is no prior experience or sufficient historical data. This work reviews existing rapid cost estimation practices, which can be used by researchers with no previous cost estimating experience. It also comprises a comparative study of six cost methods on three well-documented biorefinery processes to evaluate their accuracy and precision. The results illustrate discrepancies among the methods because their extrapolation on biorefinery data often violates inherent assumptions. This study recommends the most appropriate rapid cost methods and urges the development of an improved early-stage capital cost estimation tool suitable for biorefinery processes. PMID- 27484399 TI - Risk factors for tuberculosis smear non-conversion in Eden district, Western Cape, South Africa, 2007-2013: a retrospective cohort study. AB - BACKGROUND: Tuberculosis (TB) continues to be a major global health problem. While progress has been made to improve TB cure rates, South Africa's 76 % smear positive pulmonary TB (PTB) case cure rate remains below the WHO target of 85 %. We report on the trends of TB smear non-conversion and their predictors at the end of an intensive phase of treatment, and how this impacted on treatment outcomes of smear-positive PTB cases in Eden District, Western Cape Province, South Africa. METHODS: Routinely collected, retrospective data of smear-positive PTB cases from the electronic TB register in Eden District between 2007 and 2013 was extracted. Non-conversion was defined as persistent sputum smear-positive PTB cases at the end of the two or three month intensive phase of treatment. Chi square test for linear trend and simple linear regression analysis were used to analyse the change in percentages and slope of TB smear non-conversion rates over time. Risk factors for TB non-conversion, and their impact on treatment outcomes, were evaluated using logistic regression models. RESULTS: Of 12,742 total smear positive PTB cases included in our study, 12.8 % (n = 1627) did not sputum smear convert; 13.3 % (1411 of 10,574) of new cases and 9.9 % (216 of 2168) of re treatment cases. Although not statistically significant in either new or re treatment cases, between 2007 and 2013, smear non-conversion decreased from 16.4 to 12.7 % (slope = -0.60; 95 % CI: -1.49 to 0.29; p = 0.142) in new cases, and from 11.3 to 10.8 % in re-treatment cases (slope = -0.29; 95 % CI: -1.06 to 0.48; p = 0.376). Male gender, HIV co-infection and a >2+ acid fast bacilli (AFB) smear grading at the start of TB treatment were independent risk factors for non conversion (p < 0.001). Age was a risk factor for non-conversion in new cases, but not for re-treatment cases. Non-conversion was also associated with unsuccessful treatment outcomes (p < 0.01), including treatment default and treatment failure. CONCLUSIONS: Smear-positive PTB cases, especially men and those with identified risk factors for non-conversion, should be closely monitored throughout their treatment period. The South African TB control program should invest in patient adherence counselling and education to mitigate TB non conversion risk factors, and to improve conversion and TB cure rates. PMID- 27484400 TI - Helicobacter pylori infection contributes to placental impairment in preeclampsia: basic and clinical evidences. AB - BACKGROUND: Preeclampsia (PE) is a major cause of maternal and neonatal morbidity and mortality. Epidemiological association between Helicobacter pylori (Hp) infection and PE onset has been widely shown. The aim of this study was to analyze a possible correlation between Hp infection and the severity of clinical presentation of PE and to identify an immunologic mechanism triggered by Hp infection potentially contributing to the pathogenesis of PE. MATERIALS AND METHODS: Sera from 93 preeclamptic women and 87 healthy pregnant women were tested for Hp infection by immunoassay and for anti-CagA antibodies by Western blot assay. The serologic results were correlated with the clinical features of PE. The functional effect of serum IgG fractions, positive or negative for Hp, from preeclamptic women or controls were tested on trophoblast and endothelial cell cultures and in a murine model of angiogenesis. RESULTS: Preeclamptic women showed higher seroprevalence of Hp infection (57.0%) compared to controls (33.3%) (P<.001). The seropositivity for CagA-positive strains of Hp was 45.2% in preeclamptic women vs 13.7% in controls (P<.001). In PE women, Hp infection was associated with abnormality of uterine arteries Doppler (P<.001). Hp+ IgG fractions from preeclamptic women bound to trophoblast and endometrial endothelial cell cultures, reducing in vitro invasiveness and angiogenesis, respectively, and inhibited angiogenesis in mice. CONCLUSIONS: Our data show, for the first time, an association between Hp infection and PE with abnormal uterine arteries Doppler velocimetry, suggesting a role for Hp infection in impairing placental development and increasing the risk to develop PE. This study opens the new perspective of a potential screening and treatment for Hp infection in pregnancy. PMID- 27484401 TI - High-brightness organic light-emitting diodes for optogenetic control of Drosophila locomotor behaviour. AB - Organic light emitting diodes (OLEDs) are in widespread use in today's mobile phones and are likely to drive the next generation of large area displays and solid-state lighting. Here we show steps towards their utility as a platform technology for biophotonics, by demonstrating devices capable of optically controlling behaviour in live animals. Using devices with a pin OLED architecture, sufficient illumination intensity (0.3 mW.mm(-2)) to activate channelrhodopsins (ChRs) in vivo was reliably achieved at low operating voltages (5 V). In Drosophila melanogaster third instar larvae expressing ChR2(H134R) in motor neurons, we found that pulsed illumination from blue and green OLEDs triggered robust and reversible contractions in animals. This response was temporally coupled to the timing of OLED illumination. With blue OLED illumination, the initial rate and overall size of the behavioural response was strongest. Green OLEDs achieved roughly 70% of the response observed with blue OLEDs. Orange OLEDs did not produce contractions in larvae, in agreement with the spectral response of ChR2(H134R). The device configuration presented here could be modified to accommodate other small model organisms, cell cultures or tissue slices and the ability of OLEDs to provide patterned illumination and spectral tuning can further broaden their utility in optogenetics experiments. PMID- 27484404 TI - Tissue engineering using pluripotent stem cells: multidisciplinary approaches to accelerate bench-to-bedside transition. PMID- 27484403 TI - Composite alginate gels for tunable cellular microenvironment mechanics. AB - The mechanics of the cellular microenvironment can be as critical as biochemistry in directing cell behavior. Many commonly utilized materials derived from extra cellular-matrix create excellent scaffolds for cell growth, however, evaluating the relative mechanical and biochemical effects independently in 3D environments has been difficult in frequently used biopolymer matrices. Here we present 3D sodium alginate hydrogel microenvironments over a physiological range of stiffness (E = 1.85 to 5.29 kPa), with and without RGD binding sites or collagen fibers. We use confocal microscopy to measure the growth of multi-cellular aggregates (MCAs), of increasing metastatic potential in different elastic moduli of hydrogels, with and without binding factors. We find that the hydrogel stiffness regulates the growth and morphology of these cell clusters; MCAs grow larger and faster in the more rigid environments similar to cancerous breast tissue (E = 4-12 kPa) as compared to healthy tissue (E = 0.4-2 kpa). Adding binding factors from collagen and RGD peptides increases growth rates, and change maximum MCA sizes. These findings demonstrate the utility of these independently tunable mechanical/biochemistry gels, and that mechanical confinement in stiffer microenvironments may increase cell proliferation. PMID- 27484402 TI - Association between bilirubin and risk of Non-Alcoholic Fatty Liver Disease based on a prospective cohort study. AB - The study aimed to assess the association between total, direct, and indirect bilirubin and nonalcoholic fatty live disease (NAFLD) risk given its high prevalence and serious clinical prognosis. Among 27,009 subjects who participated in a healthy screening program from the Dongfeng-Tongji cohort study in 2008, 8189 eligible subjects (aged 35-86 years; males, 43.95%) were ultimately enrolled. The incidence rates of NAFLD in 2013 were compared with respect to baseline bilirubin levels among subjects free of NAFLD, and the effect sizes were estimated by logistic regression analysis. During 5 years follow-up, we observed 1956 cases of newly developed NAFLD with the overall incidence of 23.88%. Direct bilirubin was presented to inversely associate with NAFLD risk. Compared with quartile 1 of direct bilirubin, the multivariable-adjusted ORs (95% CIs) for NAFLD of quartile 2 to 4 were 1.104 (0.867-1.187), 0.843 (0.719-0.989), and 0.768 (0.652-0.905), respectively, P for trend 0.002). Similarly, inverse effects of direct bilirubin on NAFLD incidence were also observed when stratified by sex and BMI. However, no significant associations were found between total, and indirect bilirubin and NAFLD risk. Direct bilirubin reduced NAFLD risk independent of possible confounders among middle-aged and elderly Chinese population, probably based on the endogenous antioxidation of bilirubin. PMID- 27484405 TI - Semaphorin 3A-modified adipose-derived stem cell sheet may improve osseointegration in a type 2 diabetes mellitus rat model. AB - Although titanium (Ti) implants are considered to be an optimal choice for the replacement of missing teeth, it remains difficult to obtain sufficient osseointegration in patients with type 2 diabetes mellitus (T2DM). The present study aimed to investigate whether adipose-derived stem cells (ASCs) may be used to improve Ti implant osseointegration in T2DM conditions with the addition of semaphorin 3A (Sema3A), a recently identified osteoprotective protein. Cell morphology was observed using a scanning electron microscope. Cell proliferation was determined using Cell Counting Kit-8. Osteogenic differentiation was confirmed by the staining of alkaline phosphatase, collagen secretion and calcium deposition. An in vivo evaluation was performed in the T2DM rat model, which was induced by a high-fat diet and a low-dose streptozotocin intraperitoneal injection. A Sema3A-modified ASC sheet was wrapped around the Ti implant, which was subsequently inserted into the tibia. The rats were then exposed to Sema3A stimulation. The morphology and proliferation ability of ASCs remained unchanged; however, their osteogenic differentiation ability was increased. Micro-computed tomography scanning and histological observations confirmed that formation of new bone was improved with the use of the Sema3A-modified ASCs sheet. The present study indicated that the Sema3A-modified ASCs sheet may be used to improve osseointegration under T2DM conditions. PMID- 27484407 TI - Bupropion improved apathy in behavioral variant frontotemporal dementia: a case report. AB - Apathy is a common neurobehavioral sign in cases of behavioral variant frontotemporal dementia. However, there is still no established sustained effective treatment. We present the case of a 65-year-old man with behavioral variant frontotemporal dementia who suffered from severe apathy, but his apathy improved after a 10-month period of bupropion treatment. His single photon emission computed tomography report also showed slight improvement. To the best of our knowledge, such a case with imaging evidence has never been reported. Further studies to correlate the effects of bupropion on apathy in behavioral variant frontotemporal dementia patients are clearly needed. PMID- 27484408 TI - Effect of variety on content of bioactive phenolic compounds in common elder (Sambucus nigra L.). AB - The inflorescence of common elder (Sambucus nigra L., Adoxaceae) is known to be rich in phenolic compounds. The content of five selected phenolic compounds (rutin, chlorogenic acid, isoquercitrin, isorhamnetin-3-O- rutinoside and dicaffeoylquinic acid) was determined in methanolic extracts from flowers and floral stems by HPLC in samples obtained from 20 varieties of S. nigra cultivated in Czech Republic. In all samples, there were determined rutin (11-54 mg/g), chlorogenic acid (23-46 mg/g), isoquercitrin (0.6-18 mg/g), isorhamnetin-3-O rutinoside (3-10 mg/g), calculated on air-dried material. The content of dicaffeoylquinic acid was 0-13 mg/g of air-dried material. The amount of the analysed compounds in floral stems was lower than the flowers. The results are a unique set of information on the content of main phenolics in the inflorescence of cultured elderberry varieties. PMID- 27484409 TI - A novel approach to neonatal abdominal surgery via a circular incision around the umbilical cord. AB - We present a new, scarless, circular incisional approach around the umbilical cord for neonates with intestinal atresia. This novel approach achieves truly woundless surgery. It is simple, safe, and can be used for an intestinal surgical treatment in neonates. PMID- 27484406 TI - Regulation of centriolar satellite integrity and its physiology. AB - Centriolar satellites comprise cytoplasmic granules that are located around the centrosome. Their molecular identification was first reported more than a quarter of a century ago. These particles are not static in the cell but instead constantly move around the centrosome. Over the last decade, significant advances in their molecular compositions and biological functions have been achieved due to comprehensive proteomics and genomics, super-resolution microscopy analyses and elegant genetic manipulations. Centriolar satellites play pivotal roles in centrosome assembly and primary cilium formation through the delivery of centriolar/centrosomal components from the cytoplasm to the centrosome. Their importance is further underscored by the fact that mutations in genes encoding satellite components and regulators lead to various human disorders such as ciliopathies. Moreover, the most recent findings highlight dynamic structural remodelling in response to internal and external cues and unexpected positive feedback control that is exerted from the centrosome for centriolar satellite integrity. PMID- 27484410 TI - The outcomes of a frenulotomy on breastfeeding infants followed up for 3 months at Thammasat University Hospital. AB - PURPOSE: To study the effects of frenulotomy on nipple pain, latch and the success in exclusive breastfeeding (EBF) at 3-month follow-up. METHODS: A prospective cross-sectional study of 328 mother-infant pairs with both tongue-tie and breastfeeding problems was performed. Nipple pain and latch were evaluated using numeric rating scale and LATCH score, respectively, and compared between pre and post-operatively at 24 h and 1 week. The success rate of EBF was assessed at 3 months after frenulotomy. RESULTS: Nipple pain score were significantly decreased (median difference = 3 and 4, P < 0.001) and LATCH score were significantly increased (mean difference = 1.92 and 2.13, P < 0.001) at 24 h and 1 week post-operatively. At 3 months, a success rate of EBF was 66.67 %. Multivariable analysis clustering by maternal age of 18 years was performed. Factors that were significantly (P < 0.05) associated with the success were: girls, age at surgery <=24 h, higher number of children in family, low birth weight, tongue-tie severity, nipple grading, LATCH score >=8 and nipple sensation at 1 week after surgery. CONCLUSION: Frenulotomy could significantly reduce nipple pain and increase LATCH score in tongue-tied infants with breastfeeding difficulty. Several factors are positively associated with the success of EBF. Tongue-tie severity, LATCH score and nipple sensation were the factors that can be modified by frenulotomy. PMID- 27484411 TI - Classification of ankle joint movements based on surface electromyography signals for rehabilitation robot applications. AB - Electromyography (EMG)-based control is the core of prostheses, orthoses, and other rehabilitation devices in recent research. Nonetheless, EMG is difficult to use as a control signal given the complex nature of the signal. To overcome this problem, the researchers employed a pattern recognition technique. EMG pattern recognition mainly involves four stages: signal detection, preprocessing feature extraction, dimensionality reduction, and classification. In particular, the success of any pattern recognition technique depends on the feature extraction stage. In this study, a modified time-domain features set and logarithmic transferred time-domain features (LTD) were evaluated and compared with other traditional time-domain features set (TTD). Three classifiers were employed to assess the two feature sets, namely linear discriminant analysis (LDA), k nearest neighborhood, and Naive Bayes. Results indicated the superiority of the new time domain feature set LTD, on conventional time-domain features TTD with the average classification accuracy of 97.23 %. In addition, the LDA classifier outperformed the other two classifiers considered in this study. PMID- 27484412 TI - Classifications In Brief: The Paprosky Classification of Femoral Bone Loss. PMID- 27484413 TI - CORR Insights((r)): Shoulder Activity Level is Associated with Type of Employment and Income in the Normative Population Without Shoulder Disorders. PMID- 27484414 TI - Improving palliative care in selected settings in England using quality indicators: a realist evaluation. AB - BACKGROUND: There is a gap between readily available evidence of best practice and its use in everyday palliative care. The IMPACT study evaluated the potential of facilitated use of Quality Indicators as tools to improve palliative care in different settings in England. METHODS: 1) Modelling palliative care services and selecting a set of Quality Indicators to form the core of an intervention, 2) Case studies of intervention using the Quality Indicator set supported by an expert in service change in selected settings (general practice, community palliative care teams, care homes, hospital wards, in-patient hospices) with a before-and-after evaluation, and 3) realist evaluation of processes and outcomes across settings. Participants in each setting were supported to identify no more than three Quality Indicators to work on over an eight-month period in 2013/2014. RESULTS: General practices could not be recruited to the study. Care homes were recruited but not retained. Hospital wards were recruited and retained, and using the Quality Indicator (QI) set achieved some of their desired changes. Hospices and community palliative care teams were able to use the QI set to achieve almost all their desired changes, and develop plans for quality improvements. Improvements included: increasing the utility of electronic medical records, writing a manual for end of life care, establishing working relationships with a hospice; standardising information transfer between settings, holding regular multi-disciplinary team meetings, exploration of family carers' views and experiences; developing referral criteria, and improvement of information transfer at patient discharge to home or to hospital. Realist evaluation suggested that: 1) uptake and use of QIs are determined by organisational orientation towards continuous improvement; 2) the perceived value of a QI package was not powerful enough for GPs and care homes to commit to or sustain involvement; 3) the QI set may have been to narrow in focus, or more specialist than generalist; and 4) the greater the settings' 'top-down' engagement with this change project, the more problematic was its implementation. CONCLUSIONS: Whilst use of QIs may facilitate improvements in specialist palliative care services, different QI sets may be needed for generalist care settings. PMID- 27484415 TI - Measurement of Uranium Isotope Ratios in Keratinous Materials: A Noninvasive Bioassay for Special Nuclear Material. AB - Hair, toenail, and fingernail are noninvasive, integrative biological monitors routinely used to assess mineral intake.1-4 In this study, we demonstrate the feasibility of distinguishing between exposure to natural, depleted, and enriched U by measuring the (235)U/(238)U, (234)U/(238)U, and (236)U/(238)U ratios in the hair, fingernails, and toenails of occupationally exposed workers and control volunteers. The exposure history of cases and controls to non-natural U was assessed through voluntary self-reporting using a simple questionnaire. The measured U isotope ratios and U concentration in the hair, toenail, and fingernail of cases were compared to a nonexposed control group. No difference was observed in the uranium concentration between the two groups. Significant differences between the cases and the control group were observed in the (235)U/(238)U and (236)U/(238)U isotope ratios but not the (234)U/(238)U. This is the first time that hair, fingernail, and toenail have been demonstrated to be sensitive to occupational exposure to enriched and depleted U, a result with significant implications for proliferation compliance monitoring. PMID- 27484417 TI - [Aggression and restlessness following baclofen overdose: the narrow line between intoxication and withdrawal symptoms]. AB - BACKGROUND: Baclofen is increasingly prescribed for alcohol dependency. Subsequently, the risk of self-intoxication with this medicinal product is increasing. CASE DESCRIPTION: A 23-year-old man with a history of alcohol dependence was admitted to our hospital after self-intoxication with 2700 mg baclofen and 330 mg mirtazapine. Respiratory insufficiency as a result of the baclofen intoxication required intubation and admission to the ICU. During the first day, despite the use of sedatives, the patient became intermittently agitated and aggressive. In the following days, he developed severe delirium, probably due to baclofen withdrawal. The reintroduction of baclofen quickly resolved these symptoms. CONCLUSION: In the case of baclofen, in practice it is difficult to differentiate between intoxication and withdrawal. To prevent potentially severe withdrawal symptoms, we recommend reintroduction of baclofen when the first signs of restlessness and agitation arise following intoxication. PMID- 27484416 TI - Repurposing FDA-approved drugs for anti-aging therapies. AB - There is great interest in drugs that are capable of modulating multiple aging pathways, thereby delaying the onset and progression of aging. Effective strategies for drug development include the repurposing of existing drugs already approved by the FDA for human therapy. FDA approved drugs have known mechanisms of action and have been thoroughly screened for safety. Although there has been extensive scientific activity in repurposing drugs for disease therapy, there has been little testing of these drugs for their effects on aging. The pool of FDA approved drugs therefore represents a large reservoir of drug candidates with substantial potential for anti-aging therapy. In this paper we employ FINDSITEcomb, a powerful ligand homology modeling program, to identify binding partners for proteins produced by temperature sensing genes that have been implicated in aging. This list of drugs with potential to modulate aging rates was then tested experimentally for lifespan and healthspan extension using a small invertebrate model. Three protein targets of the rotifer Brachionus manjavacas corresponding to products of the transient receptor potential gene 7, ribosomal protein S6 polypeptide 2 gene, or forkhead box C gene, were screened against a compound library consisting of DrugBank drugs including 1347 FDA approved, non-nutraceutical molecules. Twenty nine drugs ranked in the top 1 % for binding to each target were subsequently included in our experimental analysis. Continuous exposure of rotifers to 1 uM naproxen significantly extended rotifer mean lifespan by 14 %. We used three endpoints to estimate rotifer health: swimming speed (mobility proxy), reproduction (overall vitality), and mitochondria activity (cellular senescence proxy). The natural decline in swimming speed with aging was more gradual when rotifers were exposed to three drugs, so that on day 6, mean swimming speed of females was 1.19 mm/s for naproxen (P = 0.038), 1.20 for fludarabine (P = 0.040), 1.35 for hydralazine (P = 0.038), as compared to 0.88 mm/s in the control. The average reproduction of control females in the second half of their reproductive lifespan was 1.08 per day. In contrast, females treated with 1 uM naproxen produced 1.4 offspring per day (P = 0.027) and females treated with 10 uM fludarabine or 1 uM hydralazine produced 1.72 (P = <0.001) and 1.66 (P = 0.001) offspring per day, respectively. Mitochondrial activity naturally declines with rotifer aging, but B. manjavacas treated with 1 uM hydralazine or 10 uM fludarabine retained 49 % (P = 0.038) and 89 % (P = 0.002) greater mitochondria activity, respectively, than untreated controls. Our results demonstrate that coupling computation to experimentation can quickly identify new drug candidates with anti-aging potential. Screening drugs for anti-aging effects using a rotifer bioassay is a powerful first step in identifying compounds worthy of follow-up in vertebrate models. Even if lifespan extension is not observed, certain drugs could improve healthspan, slowing age dependent losses in mobility and vitality. PMID- 27484418 TI - [The unresponsive wakefulness syndrome: Dutch perspectives]. AB - The unresponsive wakefulness syndrome (UWS), formerly known as the vegetative state, is one of the most dramatic outcomes of acquired brain injury. Patients with UWS open their eyes spontaneously but demonstrate only reflexive behavior; there are no signs of consciousness. Research shows that, for years now, the Netherlands has the world's lowest documented prevalence of UWS. Unfortunately, this small group of vulnerable patients does not receive the care it needs. Access to specialized rehabilitation is limited, misdiagnosis rates are high and a substantial number of UWS patients receive life-prolonging treatment beyond chances of recovery, despite a framework allowing for discontinuation of such treatment once recovery of consciousness has become unlikely. By comparing data from 2012 with that of 2003, this paper illustrates the current situation and outlook for UWS patients in the Netherlands and makes recommendations for the optimization of treatment and care, as well as for future research. PMID- 27484419 TI - [Skin to skin contact and breast-feeding after birth: not always without risk!]. AB - Skin-to-skin contact after birth is propagated to facilitate breast-feeding and mother-child bonding. We describe two term infants with sudden unexpected postnatal collapse (SUPC) during skin-to-skin contact. The infants were found with abnormal colour, hypotonia and apnoea, in a prone position on the chest of their mothers, both of whom were primipara with a high BMI. After stimulation, both infants recovered completely. No specific potential cause, other than the position, could be found. These cases illustrate that skin-to-skin contact after birth is not without risk. In available literature, risk factors for SUPC include primiparity and infant orientation such as prone and lateral positions. These positions are also risk factors for sudden infant death syndrome (SIDS). To improve safety, a primipara should be supervised during skin-to-skin contact and not be left alone in the first hours after delivery; the infant should be guaranteed a free airway, especially when the mother has a high BMI. PMID- 27484420 TI - [Kleine Levin Syndrome: more than just periodic hypersomnia]. AB - BACKGROUND: Kleine Levin Syndrome (KLS) is a rare disease with periodic hypersomnia as its main feature. Hyperphagia and hypersexuality are also described as classical symptoms, although quite recently it has become clear that the full triad is absent in the majority of patients. CASE DESCRIPTION: A 14-year old boy developed KLS after a period of flu-like symptoms. Over the course of three years he suffered from seven one-week episodes of extreme hypersomnia (sleeping 18 hours a day), depersonalisation, apathy, anxiety, paranoia, confusion, hallucinations and uninhibited sexual behaviour. He ate little. Ancillary investigations did not reveal any abnormalities. In between these episodes he had no symptoms. CONCLUSION: From this case description and a summary of the symptoms of twelve other patients with KLS, it appears that neuropsychiatric symptoms are much more prominent than hyperphagia and hypersexuality. It is important that the typical KLS phenotype be reappraised, so that the condition can be recognised early and patients managed appropriately. PMID- 27484421 TI - [The placebo effects of good communication]. AB - - Good communication is important for patients and can elicit placebo effects: true psychobiological effects not attributable to the medical-technical intervention.- It is, however, often unclear which communication behaviours influence specific patient outcomes.- In this article we present insights into the potential effect of specific communication, via specific mechanisms, on specific patient outcomes, including patients' perception of pain.- A recent systematic review and additional literature demonstrate that (a) manipulating patients' expectations, (b) demonstrating empathy, and (c) providing procedural information, might influence patient outcomes.- These placebo effects probably occur via (a) neurobiological responses comparable to the effects of pain medication, (b) reduction of anxiety and stress, and PMID- 27484422 TI - [A woman with a cavity in an intervertebral disc on the CT-scan]. AB - The CT scan of a 77-year-old woman showed hypodense structures in the spine called vacuum phenomenon as an incidental finding. The cause in the majority of cases is the degeneration of tissue but vacuum phenomenon is also associated with other disorders. It is important to distinguish between benign causes and malignant causes. Unfamiliarity with this vacuum phenomenon may lead to suboptimal treatment. PMID- 27484423 TI - [Photo stories instead of leaflets: support for people with low health literacy]. AB - In the Netherlands, almost 30 percent of adults have limited levels of health literacy. They have difficulties finding, understanding and using health information. Comprehensible health information is extra important for people with low health literacy. A systematic review revealed that narrative health communication is a promising strategy to increase comprehension. We have investigated which interventions may improve comprehensibility of health-related documents for older adults with different levels of health literacy. We are currently exploring if and how photo stories on care and health topics can support people with low health literacy. PMID- 27484424 TI - [A girl with a cold foot]. AB - A 14-year-old girl presented with a progressively cold, pale foot. Pedal pulses were absent and there was sensory and motor loss. CT angiography revealed a thromboembolic occlusion of the crural arteries and a popliteal artery entrapment. Following thromboembolectomy with popliteal artery patch angioplasty and release of the gastrocnemius muscle, the girl fully recovered. PMID- 27484425 TI - [Practice assistant sometimes misses urgent request for help: telephone triage in general practice]. AB - OBJECTIVE: To assess the organisation and appropriateness of telephone triage in general practices in the Netherlands. DESIGN: Cross-sectional observational study. METHODS: Via e-mail we invited all members of the Dutch Association of practice assistants to complete an online survey. The questionnaire included questions about practice assistants' background characteristics and the practices' triage organisation. Furthermore, they were asked to assess the indicated type of care for a number of fictive case scenarios involving a variety of health problems and levels of urgency. To determine the appropriateness of the respondents' assessments, each was compared to a reference standard agreed by experts. In addition, the association between practice assistants' background characteristics and organizational setup of the triage organisation with the appropriateness of triage was examined. RESULTS: The response rate was 41.1% (N=973). The required care was assessed appropriately in 63.6% of the cases, over estimated in 19.3% and under-estimated in 17.1% of cases. The sensitivity of identifying patients with a highly urgent problem was 76.7%, whereas the specificity was 94.0%. The appropriateness of the assessments of the required care was higher for more experienced assistants and assistants with regular daily work meetings with the GP. Triage training, use of a triage tool and authorization of advice provision were not associated with appropriateness of triage. CONCLUSION: Triage by practice assistants in general practices is efficient, but potentially unsafe in highly urgent cases. It is therefore important to train practice assistants in the identification of highly urgent cases. PMID- 27484426 TI - [Supervisors being assessed]. AB - OBJECTIVE: Since 2015, a permanent quality cycle is mandatory for medical residency specialist training. One aspect of this cycle is the System for Evaluation of Teaching Qualities (SETQ), which allows trainees to give feedback about their supervisor. We analysed how these quality evaluations are discussed within groups of supervisors. DESIGN: Questionnaire study amongst residency training program directors. METHOD: From September 2013 till February 2014, an online questionnaire was distributed amongst 255 program directors of medical residency specialist training in 54 teaching hospitals. The questionnaire assessed (a) if feedback was discussed, (b) the purpose of the feedback discussions, (c) their format, (d) the perceived outcomes and (e) any need for supervisor support in relation to any future feedback discussions. RESULTS: The response rate for the questionnaire was 61%. The majority of supervisor groups (86%) followed up on their individual SETQ feedback. Formats included individually between the program director and supervisor (34%), in a peer group of supervisors (69%), and in group format involving both trainees and supervisors (68%). Respondents listed the mutual learning process and devising improvement plans as aims of discussing feedback in a group format. There is considerable variation between groups of supervisors in terms of how the feedback is discussed. Over fifty percent of the group discussions resulted in concrete agreements for improvement plans. CONCLUSION: The feedback by trainees on the teaching performance of their supervisors is not wasted. The vast majority of supervisors follow up on their teaching performance feedback in peer group meetings. PMID- 27484427 TI - [A man with slowly progressive dyspnea on exertion]. AB - A 42-year-old man with a medical history of liver cirrhosis and portal hypertension was admitted to the hospital because of slowly progressive shortness of breath and hypoxemia. The diagnosis hepatopulmonary syndrome was confirmed by a pulmonary perfusion scan with 99m Tc-albumin. The scan showed a right-left shunt, because the 99m Tc-albumin transited the lungs and appeared in the brain, the thyroid gland, the kidneys and the spleen. The patient received a liver transplantation, which is considered the only definitive treatment. PMID- 27484428 TI - [A woman with abdominal pain and retroperitoneal free air]. AB - A 62-year-old female was admitted to the hospital with pain in the lower abdomen and fever since 1 week. A CT scan showed retroperitoneal air around the inferior mesenteric vein and diverticulitis of the sigmoid. We made the diagnosis of intramesocolic diverticular perforation of the sigmoid, a rare phenomenon, and performed an emergency sigmoidectomy. PMID- 27484429 TI - [Big data, Roemer's law and avoidable hospital admissions]. AB - From an analysis of data from 23 European countries to determine the impact of primary care on avoidable hospital admissions for uncontrolled diabetes it appeared that, contrary to expectation, countries with strong primary care did not have a lower rate of avoidable hospital admission. It is clear that Roemer's law, 'a bed built is a bed filled,' still applies. However, the validity of this sort of analysis can be questioned, as these data are highly aggregated, and registration quality differs between countries. It is also questionable if these datasets can be considered as 'big data' as there are relatively small numbers per country. Big data analyses are useful for discerning patterns and formulating hypotheses, but not for proving causality. An unwanted side effect of this kind of analysis might be that policymakers use these not so valid results to underpin their policy to their advantage. PMID- 27484430 TI - [Triage in primary care: overkill?]. AB - Based on triage during out-of-hours emergency services with physical contact with patients, the Dutch Triage Standard - a telephone triage algorithm - has been developed for use in primary care out-of-hours services. However, it is also used in the daytime setting. We argue that this tool should be evaluated by actually evaluating the telephone contacts that are backed up during triage and using the final diagnoses of these contacts as the reference standard. We have serious doubts whether the Dutch Triage Standard is an effective tool in the primary care daytime setting with its very low prevalence of high urgency. Adequate triage is time consuming, and may result in reduced accessibility thus creating critical situations. Well-evaluated pilots should precede large-scale implementation of decision support systems. PMID- 27484431 TI - ['Primum non nocebo' and the obligatory placebo; how can we better please the patient?]. AB - There is ample evidence to support the notion that the context of a treatment influences the efficacy of that treatment. Most doctors feel uncomfortable with the intentional introduction of contextual elements that have no plausible biological effect, because it is not in line with their biomechanical world view and training. Withholding certain information to prevent nocebo effects may even go against our duty to inform patients. We argue that our primary duty is to serve the interest of our patients and that to withhold positive contextual elements or to introduce negative contextual elements conflicts with this duty. PMID- 27484432 TI - [Practice guideline 'Urinary incontinence in women' from the Dutch College of General Practitioners]. AB - - The Dutch College of General Practitioners' (NHG) practice guideline 'Urinary incontinence in women' provides guidelines for diagnosis and management of stress, urgency and mixed urinary incontinence in adult women.- General practitioners (GPs) should be alert to signals for urinary incontinence in women and offer active diagnosis and treatment if necessary.- Shared decision making is central in the guideline; the GP and the patient should discuss therapeutic options and decide on treatment policy in mutual consultation.- Women with stress urinary incontinence can choose between pelvic floor exercises or a pessary as initial treatment. Placing a midurethral sling (MUS) will be discussed if initial treatment is insufficiently effective or in the case of serious symptoms.- When bladder training is ineffective in urgency incontinence, the GP will discuss the pros and cons of adding an anticholinergic agent.- Exercise therapy can take place in the GPs practice or under supervision of a pelvic physical therapist. PMID- 27484433 TI - Molecular mechanisms of experience-dependent structural and functional plasticity in the brain. AB - Experiences and environments have a variety of effects on brain plasticity at levels ranging from the molecular and cellular to the behavioral. Brain plasticity is one of the most important characteristics of animal survival. In particular, environmental enrichment and exercise induce many structural and functional changes in the brain, and it is noteworthy that these changes result in further beneficial effects at behavioral levels, such as improved learning behavior and antidepressant effects. The effects of enrichment and exercise, and the mechanisms involved in both, provide crucial evidence for the prevention and treatment of brain disorders. However, the enriched environment- and exercise induced mechanisms underlying the structural and behavioral effects in the brain remain poorly understood. In this review I discuss the molecular mechanisms of environment- and experience-dependent brain plasticity based on the results of studies carried out by our research group at the Department of Neuroscience and Cell Biology, Osaka University. This review consists of three parts: first, a description of a role for the motor protein KIF1A in enhanced synaptogenesis and memory function induced by environmental enrichment; second, a discussion of the function of the 5-HT3 receptor in hippocampal neurogenesis and behavioral changes induced by exercise; third, a discussion of the role of the 5-HT3 receptor in fear extinction. PMID- 27484434 TI - Exercise-induced hypoalgesia: potential mechanisms in animal models of neuropathic pain. AB - Physical exercise, such as forced treadmill running and swimming, can sufficiently improve mechanical allodynia and heat hyperalgesia in animal models of neuropathic pain (NPP), including partial sciatic nerve ligation, chronic constriction injury, and spinal nerve ligation models. Thus, physical exercise has been established as a low-cost, safe, and effective way to manage NPP conditions, but the exact mechanisms underlying such exercise-induced hypoalgesia (EIH) are not fully understood. A growing body of evidence has identified several factors that work at different levels of the nervous system as playing important roles in producing EIH in animal models of NPP. The objective of this review is to provide an overview of key players associated with EIH, and then to discuss our current understanding of the mechanisms underlying EIH. Relevant studies have demonstrated that physical exercise can dramatically alter the levels of inflammatory cytokines, neurotrophins, neurotransmitters, endogenous opioids, and histone acetylation at various sites in the nervous system, such as injured peripheral nerves, dorsal root ganglia, and spinal dorsal horn in animal models of NPP, thereby contributing to the production of EIH. These results suggest that EIH is produced through multiple cellular and molecular events in the pain pathway. PMID- 27484435 TI - Endohedral dynamics of push-pull rotor-functionalized cages. AB - A series of [Pd2L4] coordination cages featuring endohedral functionalities in central backbone positions was synthesized. Although attached via C[double bond, length as m-dash]C double bonds, the substituents behave as molecular rotors. This is explained by their pronounced donor-acceptor character which lowers rotational barriers and allows for electronic control over the spinning rates inside the cage. The dynamic behaviour of the free ligands, assembled cages and host-guest complexes is compared with the aid of NMR experiments, X-ray structure analysis and molecular modelling. PMID- 27484436 TI - Comparison of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis: Japanese Osteoporosis Intervention Trial-03. AB - The aim of this study was to investigate the efficacy of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis and to explore subsets of patients for which concurrent treatment is particularly efficacious. Women with osteoporosis aged 65 years or older were recruited from 123 institutes in Japan and allocated to take either vitamin K2 (45 mg/day) and risedronate (2.5 mg/day or 17.5 mg/week) or risedronate (2.5 mg/day or 17.5 mg/week) alone. The primary end point was the incidence of any fracture (vertebral and nonvertebral). The secondary end points were bone mineral density, height, undercarboxylated osteocalcin concentration, quality of life, and safety. Over a 2-year follow-up, vertebral or nonvertebral fractures occurred in 117 or 22 sites respectively among 931 patients in the risedronate and vitamin K2 group and in 104 or 26 sites respectively among 943 patients in the risedronate alone group. The rates of any incident fracture were similar between the two groups (incidence rate ratio 1.074, 95 % confidence interval 0.811-1.422, p = 0.62), implying that the primary end point was not met. There were no differences in the degree of increase in bone mineral density between the two groups. Undercarboxylated osteocalcin concentration decreased from 5.81 +/- 3.93 ng/mL to 2.59 +/- 1.52 ng/mL at 6 months in the risedronate and vitamin K2 group, whereas the change in the risedronate alone group was minimal (from 5.96 +/- 4.36 ng/mL to 4.05 +/- 3.40 ng/mL at 6 months) (p < 0.01). The treatment discontinuation rate was higher in the risedronate and vitamin K2 group than in the risedronate alone group (10.0 % vs 6.7 %). No unknown adverse drug reactions were reported. In conclusion, concurrent treatment with vitamin K2 and risedronate was not efficacious compared with monotherapy with risedronate in terms of fracture prevention. PMID- 27484439 TI - Prevalence of depression in patients of type 2 diabetes mellitus: A cross sectional study in a tertiary care centre. AB - AIMS: The present study aims to study the prevalence of depression in patients with uncomplicated type II diabetes mellitus and to find its association with various socio-demographic factors in the same. MATERIALS AND METHODS: A cross sectional, single interview study was performed in an outpatient department of an endocrinology institute. Total 80 type II DM patients without any associated complications of diabetes were included in this study. To diagnose Depressive Episode, structured clinical interview for DSM V was applied. Severity of depression was assessed by Hamilton Rating Scale for Depression (HAM-D). To assess socio-demographic characteristics of the patients, all of them were evaluated with a semi-structured socio-demographic performa. RESULTS: 38.75% patients (N=31) were found to be suffering from depression. Among them 48.38% were moderately depressed and none were suffering from very severe depression. Significant association was not found between depression and socio-demographic factors of age (p=0.920), gender (p=0.251), economic profile (p=0.583), local background of the patient (p=0.646), educational qualification (p=0.935) and marital status (p=0.644). Similarly no association was found with duration of diabetes, HbA1c and BMI. CONCLUSION: Exclusion of complicated cases didn't seem to influence overall prevalence of depression, although reduction in severity was apparent. Thus even in those diabetic patients who are leading a complication free life, a detailed psychiatric analysis to rule out depression is mandatory. PMID- 27484437 TI - The Effects of Supplementation with p-Synephrine Alone and in Combination with Caffeine on Metabolic, Lipolytic, and Cardiovascular Responses during Resistance Exercise. AB - OBJECTIVE: The purpose of this study was to examine the metabolic, lipolytic, and cardiovascular responses to supplementation with p-synephrine alone and in combination with caffeine during resistance exercise (RE). METHODS: Twelve healthy men performed a control RE protocol (6 * 10 repetitions of squats) and were randomly assigned (using a double-blind crossover design with random protocol sequencing) to a supplement sequence: p-synephrine (S; 100 mg), p synephrine + caffeine (SCF; 100 mg of p-synephrine plus 100 mg of caffeine), or a placebo (P). Subjects reported to the lab at a standard time, consumed a supplement, sat quietly for 45 minutes, performed the RE protocol, and sat quietly for 30 minutes. Blood samples were collected at rest (T1), after sitting quietly for 45 minutes (T2), immediately following RE (T3), and 15 minutes (T4) and 30 minutes (T5) postexercise. Oxygen consumption (VO2) and heart rate (HR) data were collected throughout. RESULTS: Serum glycerol was significantly elevated at T2 only in S and SCF and T3 to T5 in all treatments. Nonesterified fatty acid (NEFA) concentrations did not differ between treatments. Plasma glucose was significantly elevated compared to T1 with highest area under the curve values seen in SCF. Mean VO2 and energy expenditure (EE) were significantly higher in S and SCF through 30 minutes postexercise. Fat oxidation rates favored S and SCF between 25 and 30 minutes postexercise. Mean HR during RE was significantly highest in SCF. CONCLUSIONS: Supplementation with S and SCF increases lipolysis primarily at rest and increases VO2, EE, and fat oxidation rates 30 minutes following RE. No HR changes were observed unless caffeine was added. PMID- 27484441 TI - Effect of omega-3 fatty acids supplementation on insulin resistance in women with polycystic ovary syndrome: Meta-analysis of randomized controlled trials. AB - BACKGROUND: Several studies have shown that omega-3 polyunsaturated fatty acids (PUFA) may improve insulin resistance in various diseases. However, the possible effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on insulin resistance in PCOS still remains unclear. We evaluated the effect of omega-3 PUFA supplementation on insulin resistance in women with PCOS in a meta-analysis. METHODS: Literature searches of MEDLINE, PubMed Central and EMBASE for publications in English were conducted up to December 2015. We included all randomized controlled trials (RCTs) that investigated effects of omega-3 fatty acids supplements on insulin resistance in women with PCOS. Results are summarized as mean differences (MD) with 95% confidence intervals (CI). Effect sizes of eligible studies were pooled using random-effects models (the DerSimonian-Laird estimator). We assessed the potential sources of heterogeneity using the standard chi2 test. RESULTS: Of 1202 papers, three RCTs were eligible for inclusion which involved 72 cases and 73 controls. The dose range for omega3 supplement was 1.2g to 3.6g and the duration of follow-up was from 6 to 8 weeks. There was no significant effect of omega-3 fatty acids supplements compared to placebo on insulin resistance (MD: 6.18; CI; -3.347, 15.382; p=0.208) and HOMA IR (MD: 0.276; 95% CI=-1.428, 1.981; p=0.751) in women with PCOS. CONCLUSION: The results provide an evidence that supplementation with omega-3 fatty acids may not have a beneficial effect on improving insulin resistance in women with PCOS. PMID- 27484440 TI - A study on comparative efficacy and cost effectiveness of Pregabalin and Duloxetine used in diabetic neuropathic pain. AB - AIM: The study was designed for comparing the efficacy and cost effectiveness of Pregabalin and Duloxetine used in Diabetic Neuropathic Pain. METHODS: The prospective interventional 6 month study was conducted in a diabetic clinic of a 500 bedded tertiary care hospital in South India. The subjects having diagnosed with diabetic neuropathy and not treated with Pregabalin and Duloxetine or any other drugs of its class were selected. The data were collected using NPS and Neuro QoL questionnaires. The cost of both drugs used in the study was calculated as the mean of the price of 3 leading common brands of those drugs. The comparative efficacy was calculated by comparing the mean difference produced by both drugs in NPS and QoL scores. The cost effectiveness were calculated by ICER ratio. RESULTS: The results have shown a significant improvement in the mean difference of NPS and Neuro QoL scores of both Pregabalin (p=<0.001) and Duloxetine (p=<0.001) before and after the therapy, the Duloxetine dominates over Pregabalin in both. The mean cost of Pregabalin for 3 months therapy was found to be INR 668.7 and that for Duloxetine was INR 756. Duloxetine showed a better effect but more expensive. ICER ratio was calculated and found that a cost of INR 61.47 per extra QoL gained by Duloxetine. CONCLUSION: The study have revealed that, both drugs are found to be effective.On conducting cost effective analysis, a significant better improvement in QoL of patients was obtained by Duloxetine with comparatively mild increase in the price. PMID- 27484443 TI - The first organocopper tetrazole derivative: synthesis and characterization. AB - 1-(5-Amino-3-azapentyl)tetrazole dihydrochloride (HL.2HCl) was prepared by heterocyclization of diethylenetriamine with triethyl orthoformate and sodium azide followed by treatment with potassium carbonate and hydrochloric acid. The reaction of CuCl2, HL.2HCl and triethylamine (NEt3) in a molar ratio of 1 : 1 : 3 in water was found to generate a novel organometallic tetrazole derivative Cu2L2Cl2. This compound is present as a binuclear centrosymmetric molecular complex, in which C-deprotonated tetrazole L acts as a chelating ligand via the two amino N and tetrazole ring C coordination sites and the two copper atoms are linked together through two tetrazole ring N(4)-C(5) bridges. This complex is the first organocopper tetrazole derivative. When the molar ratio of the reagents in the abovementioned reaction was changed to 1 : 2 : 2, the complex Cu(HL)2Cl2 was formed along with Cu2L2Cl2. Pure Cu(HL)2Cl2 was isolated after reaction of the reagents in a molar ratio of 1 : 3 : 6. The complex Cu(HL)2Cl2 is present as a mononuclear molecular complex, with a chelating coordination mode of HL via the two amino N atoms only. Both complexes as well as HL.2HCl were characterized by single-crystal X-ray analysis. PMID- 27484442 TI - Automated assignment of NMR chemical shifts based on a known structure and 4D spectra. AB - Apart from their central role during 3D structure determination of proteins the backbone chemical shift assignment is the basis for a number of applications, like chemical shift perturbation mapping and studies on the dynamics of proteins. This assignment is not a trivial task even if a 3D protein structure is known and needs almost as much effort as the assignment for structure prediction if performed manually. We present here a new algorithm based solely on 4D [(1)H,(15)N]-HSQC-NOESY-[(1)H,(15)N]-HSQC spectra which is able to assign a large percentage of chemical shifts (73-82 %) unambiguously, demonstrated with proteins up to a size of 250 residues. For the remaining residues, a small number of possible assignments is filtered out. This is done by comparing distances in the 3D structure to restraints obtained from the peak volumes in the 4D spectrum. Using dead-end elimination, assignments are removed in which at least one of the restraints is violated. Including additional information from chemical shift predictions, a complete unambiguous assignment was obtained for Ubiquitin and 95 % of the residues were correctly assigned in the 251 residue-long N-terminal domain of enzyme I. The program including source code is available at https://github.com/thomasexner/4Dassign . PMID- 27484444 TI - Recurrent Ventricular Tachycardia and Peripheral Gangrene in a Young Child. AB - A 10-year-old girl presented with sudden onset recurrent ventricular tachycardia and symmetrical distal peripheral gangrene. She also had pulmonary thromboembolism and cerebral sinus venous thrombosis. Investigations revealed anemia, hemolysis, hypocomplementemia, and elevated IgM anti-beta2 glycoprotein antibody levels. Electrocardiogram and echocardiogram suggested features of a rare cardiac anomaly, which was confirmed at autopsy. PMID- 27484445 TI - Cultivating Lifelong Learning Skills During Graduate Medical Training. AB - Lifelong learning is referred to as learning practiced by the individual for the whole life, is flexible, and is accessible at all times. Medical Council of India has included lifelong learning as a competency in its new regulations for graduate medical training. Acquisition of metacognitive skills, self-directed learning, self-monitoring, and reflective attitude are the main attributes of lifelong learning; and all of these can be inculcated in the students by using appropriate instructional methodologies. It is time to deliberate upon the instructional designs to foster the lifelong learning skills and behaviors in medical graduates. In this communication, we aim to debrief the concept of lifelong learning, particularly in context with medical training and detailing the process that can be explicitly used to cultivate the attitude of lifelong learning in medical graduates. PMID- 27484446 TI - Risk Factors for Central line associated Bloodstream Infections. AB - OBJECTIVE: To carry out surveillance of central line associated bloodstream infections in a Pediatric intensive care unit (PICU) and determine associated risk factors. METHODS: This prospective study was conducted over 1.5 years in the PICU. CDC definitions for these infections were followed and associated risk factors were identified. RESULTS: Of 265 enrolled children with central line, 13 developed blood stream infections (incidence density 5.03/1000 central line days). Significant risk factors included changing the central-line, especially triple lumen, and frequently accessing the central line. CONCLUSION: Central line associated bloodstream infections are preventable primary bacteremias and intervention strategies for prevention should be based on evidence generated to devise future protocols. PMID- 27484447 TI - Xpert MTB/RIF for Diagnosis of Tuberculosis and Drug Resistance in Indian Children. PMID- 27484448 TI - Maternal Age at Childbirth and Perinatal and Under five Mortality in a Prospective Birth Cohort from Delhi. AB - OBJECTIVE: To evaluate the relationship between maternal age at child birth, and perinatal and under-five mortality. DESIGN: Prospective birth cohort. SETTING: Urban community. PARTICIPANTS: 9169 pregnancies in the New Delhi Birth Cohort resulted in 8181 live births. These children were followed for survival status and anthropometric measurements at birth (+3 days), 3,6,9 and 12 months (7 days), and every 6 months thereafter until 21 years age. Information on maternal age at child birth and socio-demographic profile was also obtained. OUTCOME MEASURES: Offspring mortality from 28 weeks gestation till 5 years age. RESULTS: Offspring mortality (stillbirths - 5 years; n=328) had a U-shaped association with maternal age (P<0.001). Compared to the reference group (20-24 years), younger (<=19 years) and older (>=35 years) maternal ages were associated with a higher risk of offspring mortality (HR: 1.68; 95% CI 1.16, 2.43 and HR 1.48; 95% CI 1.01, 2.16, respectively). In young mothers, the increased risk persisted after adjustment for socio-economic confounders (maternal education, household income and wealth; HR 1.51; 95% CI 1.03, 2.20) and further for additional behavioral (place of delivery) and biological mediators (gestation and birthweight) (HR 2.14; 95% CI 1.25,3.64). Similar associations were documented for post-perinatal deaths but for perinatal mortality the higher risk was not statistically significant (P >0.05). In older mothers, the increased mortality risk was not statistically significant (P >0.05) after adjustment for socio-economic confounders. CONCLUSION: Young motherhood is associated with an increased risk of post perinatal mortality and measures to prevent early childbearing should be strengthened. PMID- 27484449 TI - Point of Care Neonatal Ultrasound - Head, Lung, Gut and Line Localization. AB - CONTEXT: Knowledge and skills of heart, head, lung, gut and basic abdominal ultrasound is of immense utility to clinicians in their day-to-day patient management, and in acute events, in the absence of specialist service back-up. This review examines the potential role of clinician-performed ultrasound in the neonatal intensive care unit. EVIDENCE ACQUISITION: The bibliographic search of English-language literature was performed electronically using PubMed and EMBASE databases for the different topics we have covered under this review. RESULTS: Bedside head ultrasound can be used to identify and screen for intraventricular hemorrhage, periventricular leukomalacia and post-hemorrhagic ventricular dilatation. It is also a useful adjuvant tool in the evaluation of hypoxic ischemic encephalopathy. The relatively new lung ultrasound technique is useful in identifying transient tachypnea, pneumonia, pneumothorax, fluid overload and pleural effusion. Gut ultrasound is useful in identifying necrotizing enterocolitis and probably is better than X-ray in prognostication. Ultrasound is also useful in identifying vascular line positions without radiation exposure. MAIN CONCLUSIONS: Ultrasound performed by the clinician has an extensive role in the neonatal intensive care unit. Basic ultrasound knowledge of head, lung and gut is a useful supplement to clinical decision-making. PMID- 27484450 TI - Ineffective correction of PPARgamma signaling in cystic fibrosis airway epithelial cells undergoing repair. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) represents a potential target to treat airway mucus hypersecretion in cystic fibrosis (CF). We aimed to determine if PPARgamma is altered in CF human airway epithelial cells (HAECs), if PPARgamma contributes to mucin expression and HAEC differentiation, and if PPARgamma ligand therapy corrects the CF phenotype. To this end, well differentiated CF and NCF HAEC primary cultures were wounded to monitor the expression of key genes involved in PPARgamma activation and mucus homeostasis, and to evaluate the effect of a PPARgamma agonist, at different times of repair. Hydroxyprostaglandin dehydrogenase (HPGD) converts prostaglandin E2 to 15-keto PGE2 (15kPGE2), an endogenous PPARgamma ligand. Interestingly, PPARgamma and HPGD expression dramatically decreased in CF HAECs. These changes were accompanied by an increase in the expression of MUC5B. The correlation between PPARgamma and MUC5B was confirmed in an airway epithelial cell line after CFTR knock-down. Exposure of HAECs to 15kPGE2 did not correct the CF phenotype but revealed a defect in the process of basal cell (BC) differentiation. The HPGD/PPARgamma axis is deregulated in primary HAEC cultures from CF patients, which may impact the maturation of BCs to differentiated luminal cells. Importantly, PPARgamma therapy was inefficient in correcting the CF defect. PMID- 27484451 TI - Wtip is required for proepicardial organ specification and cardiac left/right asymmetry in zebrafish. AB - Wilm's tumor 1 interacting protein (Wtip) was identified as an interacting partner of Wilm's tumor protein (WT1) in a yeast two-hybrid screen. WT1 is expressed in the proepicardial organ (PE) of the heart, and mouse and zebrafish wt1 knockout models appear to lack the PE. Wtip's role in the heart remains unexplored. In the present study, we demonstrate that wtip expression is identical in wt1a-, tcf21-, and tbx18-positive PE cells, and that Wtip protein localizes to the basal body of PE cells. We present the first genetic evidence that Wtip signaling in conjunction with WT1 is essential for PE specification in the zebrafish heart. By overexpressing wtip mRNA, we observed ectopic expression of PE markers in the cardiac and pharyngeal arch regions. Furthermore, wtip knockdown embryos showed perturbed cardiac looping and lacked the atrioventricular (AV) boundary. However, the chamber-specific markers amhc and vmhc were unaffected. Interestingly, knockdown of wtip disrupts early left-right (LR) asymmetry. Our studies uncover new roles for Wtip regulating PE cell specification and early LR asymmetry, and suggest that the PE may exert non autonomous effects on heart looping and AV morphogenesis. The presence of cilia in the PE, and localization of Wtip in the basal body of ciliated cells, raises the possibility of cilia-mediated PE signaling in the embryonic heart. PMID- 27484453 TI - MANAGEMENT OF ENDOCRINE DISEASE: The effect of vitamin D supplementation on glycaemic control in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. AB - OBJECTIVE: Epidemiologic studies suggest that vitamin D status plays a role in glycaemic control in patients with type 2 diabetes. However, intervention studies yielded inconsistent results. The aim of this study is to systematically review the effect of vitamin D supplementation on glycaemic control in patients with type 2 diabetes. METHODS: Systematic review and meta-analysis. We searched Medline, Embase and the Cochrane Library for RCTs examining the effect of vitamin D supplementation on glycaemic control in patients with type 2 diabetes. A random effects model meta-analysis was performed to obtain a summarized outcome of vitamin D supplementation on HbA1c, fasting glucose and homeostasis model assessment - insulin resistance (HOMA-IR). RESULTS: Twenty-three RCTs were included in this systematic review representing a total of 1797 patients with type 2 diabetes. Mean (+/- s.d.) change in serum 25-hydroxyvitamin D varied from 1.8 +/- 10.2 nmol/L to 80.1 +/- 54.0 nmol/L. Nineteen studies included HbA1c as outcome variable. Combining these studies no significant effect in change of HbA1c was seen after vitamin D intervention compared with placebo. A significant effect of vitamin D supplementation was seen on fasting glucose in a subgroup of studies (n = 4) with a mean baseline HbA1c >= 8% (64 mmol/mol) (standardized difference in means: 0.36; 95% CI: 0.12-0.61, P = 0.003). CONCLUSIONS: Current evidence of RCTs does not support short-term vitamin D supplementation in a heterogeneous population with type 2 diabetes. However, in patients with poorly controlled diabetes, a favourable effect of vitamin D is seen on fasting glucose. PMID- 27484452 TI - A brief history of the search for the protein(s) involved in the acute regulation of steroidogenesis. AB - The synthesis of steroid hormones occurs in specific cells and tissues in the body in response to trophic hormones and other signals. In order to synthesize steroids de novo, cholesterol, the precursor of all steroid hormones, must be mobilized from cellular stores to the inner mitochondrial membrane (IMM) to be converted into the first steroid formed, pregnenolone. This delivery of cholesterol to the IMM is the rate-limiting step in this process, and has long been known to require the rapid synthesis of a new protein(s) in response to stimulation. Although several possibilities for this protein have arisen over the past few decades, most of the recent attention to fill this role has centered on the candidacies of the proteins the Translocator Protein (TSPO) and the Steroidogenic Acute Regulatory Protein (StAR). In this review, the process of regulating steroidogenesis is briefly described, the characteristics of the candidate proteins and the data supporting their candidacies summarized, and some recent findings that propose a serious challenge for the role of TSPO in this process are discussed. PMID- 27484454 TI - MANAGEMENT OF ENDOCRINE DISEASE: Hypothyroidism-associated hyponatremia: mechanisms, implications and treatment. AB - BACKGROUND: Patients with moderate to severe hypothyroidism and mainly patients with myxedema may exhibit reduced sodium levels (<135 mmol/L). SUMMARY: The aim of this short review is the presentation of the mechanisms of hyponatremia and of the available data regarding its implications and treatment in patients with hypothyroidism. Hypothyroidism is one of the causes of hyponatremia, thus thyroid stimulating hormone determination is mandatory during the evaluation of patients with reduced serum sodium levels. The main mechanism for the development of hyponatremia in patients with chronic hypothyroidism is the decreased capacity of free water excretion due to elevated antidiuretic hormone levels, which are mainly attributed to the hypothyroidism-induced decrease in cardiac output. However, recent data suggest that the hypothyroidism-induced hyponatremia is rather rare and probably occurs only in severe hypothyroidism and myxedema. Other possible causes and superimposed factors of hyponatremia (e.g. drugs, infections, adrenal insufficiency) should be considered in patients with mild/moderate hypothyroidism. Treatment of hypothyroidism and fluid restriction are usually adequate for the management of mild hyponatremia in patients with hypothyroidism. Patients with possible hyponatremic encephalopathy should be urgently treated according to current guidelines. CONCLUSIONS: Severe hypothyroidism may be the cause of hyponatremia. All hypothyroid patients with low serum sodium levels should be evaluated for other causes and superimposed factors of hyponatremia and treated accordingly. PMID- 27484455 TI - Application of Roof-Shape Amines as Chiral Solvating Agents for Discrimination of Optically Active Acids by NMR Spectroscopy: Study of Match-Mismatch Effect and Crystal Structure of the Diastereomeric Salts. AB - Optically active roof-shape amines were prepared and scanned as chiral solvating agents to study molecular recognition of acids by NMR analysis. Three types of amines were studied to establish a match-mismatch effect for structurally diverse acid analytes. Single-crystal X-ray diffraction analysis was performed on the diastereomeric salts of roof-shape amines and both isomers of mandelic acid to establish molecular conformation and correlate the absolute configuration with the observed NMR shift. The present system also recognizes the two isomers of weakly acidic BINOL and its derivatives. PMID- 27484456 TI - Transcranial direct current stimulation in post-stroke sub-acute aphasia: study protocol for a randomized controlled trial. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a promising new technique to optimize the effect of regular Speech and Language Therapy (SLT) in the context of aphasia rehabilitation. The present study focuses on the effect of tDCS provided during SLT in the sub-acute stage after stroke. The primary aim is to evaluate the potential effect of tDCS on language functioning, specifically on word-finding, as well as generalization effects to verbal communication. The secondary aim is to evaluate its effect on social participation and quality of life, and its cost-effectiveness. METHODS: We strive to include 58 stroke patients with aphasia, enrolled in an inpatient or outpatient stroke rehabilitation program, in a multicenter, double-blind, randomized controlled trial with two parallel groups and 6 months' follow-up. Patients will participate in two separate intervention weeks, with a pause of 2 weeks in between, in the context of their regular aphasia rehabilitation program. The two intervention weeks comprise daily 45-minute sessions of word-finding therapy, combined with either anodal tDCS over the left inferior frontal gyrus (1 mA, 20 minutes; experimental condition) or sham-tDCS over the same region (control condition). The primary outcome measure is word-finding. Secondary outcome measures are verbal communication, social participation, quality of life, and cost effectiveness of the intervention. DISCUSSION: Our results will contribute to the discussion on whether tDCS should be implemented in regular aphasia rehabilitation programs for the sub-acute post-stroke population in terms of (cost-)effectiveness. TRIAL REGISTRATION: Nederlands Trail Register: NTR4364 . Registered on 21 February 2014. PMID- 27484457 TI - Development and validation of the Self-Regulation of Eating Behaviour Questionnaire for adults. AB - BACKGROUND: Eating self-regulatory capacity can help individuals to cope with the obesogenic environment and achieve, as well as maintain, a healthy weight and diet. At present, there is no comprehensive, reliable and valid questionnaire for assessing this capacity and measuring change in response to self-regulation interventions in adults. This paper reports the development of the Self regulation of Eating Behaviour Questionnaire (SREBQ) for use in UK adults, and presents evidence for its reliability and construct validity. The development of the SREBQ involved generation of an item pool, followed by two pilot studies (Samples 1 and 2) and a test of the questionnaire's underlying factor structure (Sample 3). The final version of the SREBQ was then assessed for reliability and construct validity (Sample 4). RESULTS: Development of the SREBQ resulted in a 5 item questionnaire. The face validity was satisfactory, as assessed by the pilot studies. The factor structure analysis (Sample 3) suggested that it has a single underlying factor, which was confirmed in a second sample (Sample 4). The SREBQ had strong construct validity, showing a positive correlation with general measures of self-regulation. It was also positively correlated with motivation and behavioural automaticity, and negatively correlated with food responsiveness and emotional over-eating (p < 0.001). It showed good discriminant validity, as it was only weakly associated with satiety responsiveness, food fussiness and slowness in eating. CONCLUSIONS: The SREBQ is a reliable and valid measure for assessment of eating self-regulatory capacity in the general UK adult population. PMID- 27484459 TI - A biologically-assisted curved muscle model of the lumbar spine: Model validation. AB - BACKGROUND: Biomechanical models have been developed to predict spinal loads in vivo to assess potential risk of injury in workplaces. Most models represent trunk muscles with straight-lines. Even though straight-line muscles behave reasonably well in simple exertions, they could be less reliable during complex dynamic exertions. A curved muscle representation was developed to overcome this issue. However, most curved muscle models have not been validated during dynamic exertions. Thus, the objective of this study was to investigate the fidelity of a curved muscle model during complex dynamic lifting tasks, and to investigate the changes in spine tissue loads. METHODS: Twelve subjects (7 males and 5 females) participated in this study. Subjects performed lifting tasks as a function of load weight, load origin, and load height to simulate complex exertions. Moment matching measures were recorded to evaluate how well the model predicted spinal moments compared to measured spinal moments from T12/L1 to L5/S1 levels. FINDINGS: The biologically-assisted curved muscle model demonstrated better model performance than the straight-line muscle model between various experimental conditions. In general, the curved muscle model predicted at least 80% of the variability in spinal moments, and less than 15% of average absolute error across levels. The model predicted that the compression and anterior-posterior shear load significantly increased as trunk flexion increased, whereas the lateral shear load significantly increased as trunk twisted more asymmetric during lifting tasks. INTERPRETATION: A curved muscle representation in a biologically assisted model is an empirically reasonable approach to accurately predict spinal moments and spinal tissue loads of the lumbar spine. PMID- 27484458 TI - Dreaming under anesthesia: is it a real possiblity? Investigation of the effect of preoperative imagination on the quality of postoperative dream recalls. AB - BACKGROUND: Images evoked immediately before the induction of anesthesia by means of suggestions may influence dreaming during anesthesia. This study is a retrospective re-evaluation of the original prospective randomized trial. METHODS: Dream reports were studied in two groups. In group 1. dreams of patients who received suggestions, and in group 2, those of the control group of patients who did not. The incidence of dream reports and the characteristics and the theme of the reported dreams were compared among the groups. RESULTS: In general, the control and the psychological intervention groups were different in terms of dreaming frequency, and non-recall dreaming. The incidence of dream reports was significantly higher in the suggestion group (82/190 at 10 min and 71/190 at 60 min respectively) than in the control group (16/80 at 10 min and 13/80 at 60 min, respectively; p10 = 0.001 and p60 = 0.002). There were no differences in the nature (thought- like or cinematic), quality (color or B&W) and the mood (positive vs. negative) of the recalled dreams. In general, the contents of the imaginary favorite place and the reported dream were identical in 73.2 %. Among the topics most successfully applied in the operating theater were loved ones (83.8 %), holiday (77.8 %) and sport (63.6 %). CONCLUSION: The results of the present study suggest that dreams during anesthesia are influenced by suggestions administered immediately preceding anesthesia. TRIAL REGISTRATION: The study was registered in ClinicalTrials.gov. Identifier: Q1 NCT01839201 , Date: 12 Apr. 2013. PMID- 27484460 TI - Preferred SLA class I/class II haplotype combinations in German Landrace pigs. AB - Major histocompatibility complex (MHC) molecules are responsible for the antigen presentation to T lymphocytes. High recombination rates in the MHC genes, as observed in humans, are believed to serve the evolutionary goal to achieve a high genetic diversity, allowing for a broad and efficient immune response. In a cohort of 155 pedigreed German Landrace pigs (65 founders and 90 piglets), we found that MHC genes occur in particular class I and class II haplotype combinations. This phenomenon has not been described before, probably because most of the earlier MHC studies in pigs were not pedigree-based. After comparing our data with published genotypes of different European pig breeds and Asian pigs, we hypothesise that the combination of particular but different haplotypes in different geographical regions may have developed under the evolutionary pressure of regionally endemic pathogens. This proposed mechanism ensures an efficient immune response despite low recombination rates. PMID- 27484462 TI - Shell Biorefinery: Dream or Reality? AB - Shell biorefinery, referring to the fractionation of crustacean shells into their major components and the transformation of each component into value-added chemicals and materials, has attracted growing attention in recent years. Since the large quantities of waste shells remain underexploited, their valorization can potentially bring both ecological and economic benefits. This Review provides an overview of the current status of shell biorefinery. It first describes the structural features of crustacean shells, including their composition and their interactions. Then, various fractionation methods for the shells are introduced. The last section is dedicated to the valorization of chitin and its derivatives for chemicals, porous carbon materials and functional polymers. PMID- 27484461 TI - Construction and internal validation of a new mortality risk score for patients admitted to the intensive care unit. AB - BACKGROUND: The existing models to predict mortality in intensive care units (ICU) present difficulties in clinical practice. OBJECTIVES: The aim of this study was to develop and internally validate a points system to predict mortality in the ICU, which can be applied instantly and with high discriminating power. METHODS: This cohort study comprised all patients admitted to the ICU in a Spanish region between January 2013 and April 2014, followed from admission to death or discharge (N=1113). Primary variable: ICU mortality. Secondary variables at admission: gender, Fried criteria for frailty, function scale, medical admission, cardiac arrest, cardiology admission, sepsis, mechanical ventilation, inotropic support, age, frailty index and clinical frailty scale. The sample was divided randomly into two groups (80% and 20%): construction (n=844) and internal validation (n=269). Construction: A logistic regression model was implemented and adapted to the points system. VALIDATION: the area under the ROC curve (AUC) of the model was calculated and the risk quintiles were created to determine whether differences existed between observed and expected deaths. RESULTS: The points system included: function scale, medical admission, cardiology admission, sepsis, mechanical ventilation and inotropic support. The validation showed: (i) AUC=0.95 (95% CI: 0.91-0.99, p<.001); (ii) No differences between observed and expected deaths (p=.799). CONCLUSIONS: A predictive model of mortality in the ICU has been constructed and internally validated. This model improves on the previous models through its simplicity, its discriminating power and free use. External validation studies are needed in other geographical areas. PMID- 27484463 TI - Clinical significance of the oral corticosteroid reversibility test in asthma with fixed airflow obstruction. PMID- 27484464 TI - Missed Opportunity: Why Parents Refuse Influenza Vaccination for Their Hospitalized Children. AB - BACKGROUND AND OBJECTIVES: Hospitals are required to screen and administer the influenza vaccine to all admitted children unless contraindicated or refused by parents, yet vaccination rates remain low. Our goal was to examine reasons for refusal among pediatric patients admitted during influenza season. METHODS: All children age 6 months to 18 years admitted to 2 network community hospitals from October 1, 2013 to March 31, 2014, without contraindications, were offered influenza vaccination prior to discharge. Parents who refused vaccination were asked their reason for refusal. Chi-square tests and logistic regression were used to determine factors associated with refusing the vaccine in the inpatient setting. RESULTS: Three hundred twenty-five of 786 unique patients admitted during influenza season were eligible for vaccination. Of these, 49.8% refused. Parents of females, whites, and those with private insurance were more likely to refuse vaccination. Patients whose immunization status was otherwise up to date were more likely to accept (Odds Ratio 2.39, 95% Confidence Interval 1.05-5.41). Commonly cited reasons for refusal were: preference to have vaccination by the primary care provider (24.1%), concern for side effects (16.1%), not wanting vaccination (13%), doubt in efficacy (8%), concern that the child was already sick (6.8%), no prior influenza vaccination (6.7%) and feeling that it was not needed (5.6%). CONCLUSIONS: Hospitalization during influenza season provides an opportunity for health-care providers to educate families about influenza and vaccinate patients if appropriate. However, nearly half of parents of eligible children declined vaccination. More study is required to determine strategies that can increase influenza vaccination acceptance. PMID- 27484465 TI - Types of health care facilities and the quality of primary care: a study of characteristics and experiences of Chinese patients in Guangdong Province, China. AB - BACKGROUND: In China, most people tend to use hospitals rather than health centers for their primary care generally due to the perception that quality of care provided in the hospital setting is superior to that provided at the health centers. No studies have been conducted in China to compare the quality of primary care provided at different health care settings. The purpose of this study is to compare the quality of primary care provided in different types of health care facilities in China. METHODS: A cross-sectional survey with patients was conducted in Guangdong province of China, using the validated Chinese Primary Care Assessment Tool (PCAT). ANOVA was performed to compare the overall and 10 domains of primary care quality for patients in tertiary, secondary, and primary health care settings. Multivariate analyses were used to assess the association between types of facility and quality of primary care attributes while controlling for sociodemographic and health care characteristics. RESULTS: The final number of respondents was 864 including 161 from county hospitals, 190 from rural community health centers (CHCs), 164 from tertiary hospitals, 80 from secondary hospitals, and 269 from urban CHCs. Type of health care facilities was significantly associated with total PCAT score and domain scores. CHC was associated with higher total PCAT score and scores for first contact-access, ongoing care, comprehensiveness-services available, and community orientation than secondary and/or tertiary hospitals, after controlling for patients' demographic and health characteristics. Higher PCAT score was associated with greater satisfaction with primary care received. CHC patients were more likely to report satisfactory experiences compared to patients from secondary and tertiary facilities. CONCLUSIONS: The study demonstrated that CHCs provided better quality primary care when compared with secondary and tertiary health care facilities, justifying CHCs as a model of primary care delivery. PMID- 27484467 TI - Inflammatory bowel disease mimicking granulomatosis with polyangiitis: a case report. AB - BACKGROUND: We report a case in which the extraintestinal manifestations of inflammatory bowel disease preceded development of gastrointestinal symptoms by nearly 9 months in the context of an unusual autoantibody panel, mimicking granulomatosis with polyangiitis. This case highlights the intricacies and overlap of autoimmune diseases, and illustrates an interesting clinical phenotype: cytoplasmic anti-neutrophil cytoplasmic antibody positive inflammatory bowel disease with predominantly extraintestinal manifestations. Perinuclear anti neutrophil cytoplasmic antibody positivity has been frequently reported in association with inflammatory bowel disease, but cytoplasmic anti-neutrophil cytoplasmic antibody positivity is uncommon. CASE PRESENTATION: A 54-year-old African-American man presented to our internal medicine resident clinic at the Johns Hopkins Hospital with several months of systemic inflammatory features: anterior uveitis, auricular chondritis, monoarthritis, fever, and weight loss. He did not have a primary care physician due to lack of health insurance and had been seen in our emergency department several times over the past year. These features fit nicely with a diagnosis of granulomatosis with polyangiitis, especially given positive cytoplasmic anti-neutrophil cytoplasmic antibodies. However, 9 months into his clinical course he developed hematochezia with perirectal abscess and fistula. A colonoscopy with biopsy confirmed a diagnosis of inflammatory bowel disease. CONCLUSIONS: This case highlights the fact that extraintestinal manifestations may precede gastrointestinal symptoms of inflammatory bowel disease for months, which may delay diagnosis if not understood and recognized. It further highlights an interesting disease phenotype that has not been widely reported, but may deserve further study. Lastly, the case stresses the importance of the internist in identifying a unifying diagnosis in a slowly evolving clinical process with the assistance of subspecialists. In this respect, the case is of interest to general internists, as well as rheumatologists and gastroenterologists. PMID- 27484466 TI - Inhibition of nuclear factor-kappa B enhances the tumor growth of ovarian cancer cell line derived from a low-grade papillary serous carcinoma in p53-independent pathway. AB - BACKGROUND: NF-kB can function as an oncogene or tumor suppressor depending on cancer types. The role of NF-kB in low-grade serous ovarian cancer, however, has never been tested. We sought to elucidate the function of NF-kB in the low-grade serous ovarian cancer. METHODS: The ovarian cancer cell line, HOC-7, derived from a low-grade papillary serous carcinoma. Introduction of a dominant negative mutant, IkBalphaM, which resulted in decrease of NF-kB function in ovarian cancer cell lines. The transcription ability, tumorigenesis, cell proliferation and apoptosis were observed in derivative cell lines in comparison with parental cells. RESULTS: Western blot analysis indicated increased expression of the anti apoptotic proteins Bcl-xL and reduced expression of the pro-apoptotic proteins Bax, Bad, and Bid in HOC-7/IKBalphaM cell. Further investigations validate this conclusion in KRAS wildtype cell line SKOV3. Interesting, NF-kB can exert its pro apoptotic effect by activating mitogen-activated protein kinase (MAPK) phosphorylation in SKOV3 ovarian cancer cell, whereas opposite changes detected in p-MEK in HOC-7 ovarian cancer cell, the same as some chemoresistant ovarian cancer cell lines. In vivo animal assay performed on BALB/athymic mice showed that injection of HOC-7 induced subcutaneous tumor growth, which was completely regressed within 7 weeks. In comparison, HOC-7/IKBalphaM cells caused sustained tumor growth and abrogated tumor regression, suggesting that knock-down of NF-kB by IKBalphaM promoted sustained tumor growth and delayed tumor regression in HOC 7 cells. CONCLUSION: Our results demonstrated that NF-kB may function as a tumor suppressor by facilitating regression of low grade ovarian serous carcinoma through activating pro-apoptotic pathways. PMID- 27484468 TI - Can policy ameliorate socioeconomic inequities in obesity and obesity-related behaviours? A systematic review of the impact of universal policies on adults and children. AB - This systematic review examined the impact of universal policies on socioeconomic inequities in obesity, dietary and physical activity behaviours among adults and children. PRISMA-Equity guidelines were followed. Database searches spanned from 2004 to August 2015. Eligible studies assessed the impact of universal policies on anthropometric, dietary or physical activity-related outcomes in adults or children according to socioeconomic position. Thirty-six studies were included. Policies were classified as agentic, agento-structural or structural, and their impact on inequities was rated as positive, neutral, negative or mixed according to the dominant associations observed. Most policies had neutral impacts on obesity-related inequities regardless of whether they were agentic (60% neutral), agento-structural (68% neutral) or structural (67% neutral). The proportion of positive impacts was similar across policy types (10% agentic, 18% agento structural and 11% structural), with some differences for negative impacts (30% agentic, 14% agento-structural and 22% structural). The majority of associations remained neutral when stratified by participant population, implementation level and socioeconomic position measures and by anthropometric and behavioural outcomes. Fiscal measures had consistently neutral or positive impacts on inequities. Findings suggest an important role for policy in addressing obesity in an equitable manner and strengthen the case for implementing a broad complement of policies spanning the agency-structure continuum. PMID- 27484469 TI - Comparison of glycosaminoglycan chemical exchange saturation transfer using Gaussian-shaped and off-resonant spin-lock radiofrequency pulses in intervertebral disks. AB - PURPOSE: To investigate, if a train of spin-lock pulses (chemical exchange saturation transfer with spin-lock pulses = CESL) improves biochemical glycosaminoglycan imaging compared with conventional chemical exchange saturation transfer with Gaussian-shaped pulses (CEST) in lumbar intervertebral discs. METHODS: T2 , CEST, and CESL imaging was performed in lumbar intervertebral discs of 15 healthy volunteers at 3 Tesla. Mean and standard deviation of the asymmetric magnetization transfer ratio (MTRasym ), the asymmetric spin-lock ratio (SLRasym ) and T2 values were calculated for nucleus pulposus (NP) and annulus fibrosus (AF). Wilcoxon test was used to analyze differences between MTRasym and SLRasym . Pearson correlation was used to determine the relationship between MTRasym , SLRasym and T2 . RESULTS: Data showed no significant difference between MTRasym and SLRasym (NP: P = 0.35; AF: P = 0.34). MTRasym and SLRasym values differed significantly between NP and AF (MTRasym : P = 0.014, SLRasym : P = 0.005). T2 values correlated significantly with MTRasym (NP: rho = 0.76, P < 0.001; AF: rho = 0.60, P < 0.001) and SLRasym (NP: rho = 0.73, P < 0.001; AF: rho = 0.47, P < 0.001). CONCLUSION: CESL does not improve the chemical exchange asymmetry effect compared with conventional CEST, but leads to comparable results. Magn Reson Med 78:280-284, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27484471 TI - Exploring the Nutrition and Health Claims Regulation (EC) No. 1924/2006: What is the impact on innovation in the EU food sector? AB - Literature suggests that despite its positive aim of promoting innovation, the Nutrition and Health Claims Regulation (EC) No. 1924/2006 (NHCR) may bring along several compliance challenges, which might affect innovation in the EU food sector. This study investigates the challenges faced by companies to comply with the NHCR (specifically Article 13.1) and their impact on innovation. To this end, we conducted an online survey with 105 companies involved in the EU food sector. Results indicate that companies perceive wording of claims, missing transparency and limited financial resources as major challenges to comply with the NHCR (Article 13.1). Companies reported not to have increased their R&D expenditure or innovation activities after the NHCR (Article 13.1) was implemented. Thus, this study highlights specific compliance challenges related to the NHCR (Article 13.1) and indicates that currently, the regulation does not seem to have fostered innovation in the EU food sector. PMID- 27484470 TI - Physical activity, body mass index and heart rate variability-based stress and recovery in 16 275 Finnish employees: a cross-sectional study. AB - BACKGROUND: Physical inactivity, overweight, and work-related stress are major concerns today. Psychological stress causes physiological responses such as reduced heart rate variability (HRV), owing to attenuated parasympathetic and/or increased sympathetic activity in cardiac autonomic control. This study's purpose was to investigate the relationships between physical activity (PA), body mass index (BMI), and HRV-based stress and recovery on workdays, among Finnish employees. METHODS: The participants in this cross-sectional study were 16 275 individuals (6863 men and 9412 women; age 18-65 years; BMI 18.5-40.0 kg/m(2)). Assessments of stress, recovery and PA were based on HRV data from beat-to-beat R R interval recording (mainly over 3 days). The validated HRV-derived variables took into account the dynamics and individuality of HRV. Stress percentage (the proportion of stress reactions, workday and working hours), and stress balance (ratio between recovery and stress reactions, sleep) describe the amount of physiological stress and recovery, respectively. Variables describing the intensity (i.e. magnitude of recognized reactions) of physiological stress and recovery were stress index (workday) and recovery index (sleep), respectively. Moderate to vigorous PA was measured and participants divided into the following groups, based on calculated weekly PA: inactive (0 min), low (0 < 150 min), medium (150-300 min), and high (>300 min). BMI was calculated from self-reported weight and height. Linear models were employed in the main analyses. RESULTS: High PA was associated with lower stress percentages (during workdays and working hours) and stress balance. Higher BMI was associated with higher stress index, and lower stress balance and recovery index. These results were similar for men and women (P < 0.001 for all). CONCLUSION: Independent of age and sex, high PA was associated with a lower amount of stress on workdays. Additionally, lower BMI was associated with better recovery during sleep, expressed by a greater amount and magnitude of recovery reactions, which suggests that PA in the long term resulting in improved fitness has a positive effect on recovery, even though high PA may disturb recovery during the following night. Obviously, several factors outside of the study could also affect HRV-based stress. PMID- 27484472 TI - Outcomes following emergent open repair for thoracic aortic dissection are improved at higher volume centers in direct admissions and transfers. AB - BACKGROUND: The purpose of this study is (1) to define the proportion of patients undergoing emergent open repair of thoracic aortic dissection admitted directly through the emergency room versus those transferred from outside hospitals and (2) to determine if a volume-outcomes relationship exists for those patients across admission types. METHODS: De-identified patient-level data was obtained from the Nationwide Inpatient Sample (2004-2008). Patients undergoing emergent aortic surgery for thoracic aortic dissection (n = 1,507) were identified by ICD 9 codes and stratified by annual center volume into low volume (<=5 cases/year) (n = 963; 63.9 %), intermediate volume (6-10 cases/year) (n = 370; 24.5 %), and high volume (>=11 cases/year) (n = 174; 11.6 %) groups. The analysis was further stratified by admission type: direct admission (DA), transfer admission (TA), and other. The primary outcome was in-hospital mortality. Multivariate logistic regression analysis was performed comparing outcomes between high vs low and high vs intermediate volume centers. RESULTS: Overall in-hospital mortality was 21.8 % (n = 328/1,507). Absolute percent mortality at high volume centers was significantly lower (12.6 %) than at medium (20.6 %) and low volume (23.9 %) centers. For DA patients, mortality was 10.6, 21.4, and 24.0 % for high, medium, and low volume centers respectively. For TA patients, mortality was 10.2, 12.7, and 23.5 % for high, medium, and low volume centers, respectively. Multivariate analysis suggested that patients in low volume center were more likely to die compared to high volume center (Odds Ratio 2.06, 95 % CI 1.25 - 3.38, p = 0.004). Admission source was not associated with increased mortality. CONCLUSIONS: Direct admissions comprise the largest proportion of dissections regardless of volume strata, and they comprise the largest proportion in the low and intermediate volume cohorts. Admission to low volume center is an independent risk factor for increased mortality. Patients transferred to high volume centers from low volume centers have similar outcome as direct admits in terms of mortality. PMID- 27484473 TI - Effect of magnesium ions on the structure of DNA thin films: an infrared spectroscopy study. AB - Utilizing Fourier transform infrared spectroscopy we have investigated the vibrational spectrum of thin dsDNA films in order to track the structural changes upon addition of magnesium ions. In the range of low magnesium concentration ([magnesium]/[phosphate] = [Mg]/[P] < 0.5), both the red shift and the intensity of asymmetric PO2 stretching band decrease, indicating an increase of magnesium phosphate binding in the backbone region. Vibration characteristics of the A conformation of the dsDNA vanish, whereas those characterizing the B conformation become fully stabilized. In the crossover range with comparable Mg and intrinsic Na DNA ions ([Mg]/[P] ~ 1) B conformation remains stable; vibrational spectra show moderate intensity changes and a prominent blue shift, indicating a reinforcement of the bonds and binding in both the phosphate and the base regions. The obtained results reflect the modified screening and local charge neutralization of the dsDNA backbone charge, thus consistently demonstrating that the added Mg ions interact with DNA via long-range electrostatic forces. At high Mg contents ([Mg]/[P] > 10), the vibrational spectra broaden and show a striking intensity rise, while the base stacking remains unaffected. We argue that at these extreme conditions, where a charge compensation by vicinal counterions reaches 92-94%, DNA may undergo a structural transition into a more compact form. PMID- 27484474 TI - Differential peak calling of ChIP-seq signals with replicates with THOR. AB - The study of changes in protein-DNA interactions measured by ChIP-seq on dynamic systems, such as cell differentiation, response to treatments or the comparison of healthy and diseased individuals, is still an open challenge. There are few computational methods comparing changes in ChIP-seq signals with replicates. Moreover, none of these previous approaches addresses ChIP-seq specific experimental artefacts arising from studies with biological replicates. We propose THOR, a Hidden Markov Model based approach, to detect differential peaks between pairs of biological conditions with replicates. THOR provides all pre- and post-processing steps required in ChIP-seq analyses. Moreover, we propose a novel normalization approach based on housekeeping genes to deal with cases where replicates have distinct signal-to-noise ratios. To evaluate differential peak calling methods, we delineate a methodology using both biological and simulated data. This includes an evaluation procedure that associates differential peaks with changes in gene expression as well as histone modifications close to these peaks. We evaluate THOR and seven competing methods on data sets with distinct characteristics from in vitro studies with technical replicates to clinical studies of cancer patients. Our evaluation analysis comprises of 13 comparisons between pairs of biological conditions. We show that THOR performs best in all scenarios. PMID- 27484475 TI - YphC and YsxC GTPases assist the maturation of the central protuberance, GTPase associated region and functional core of the 50S ribosomal subunit. AB - YphC and YsxC are GTPases in Bacillus subtilis that facilitate the assembly of the 50S ribosomal subunit, however their roles in this process are still uncharacterized. To explore their function, we used strains in which the only copy of the yphC or ysxC genes were under the control of an inducible promoter. Under depletion conditions, they accumulated incomplete ribosomal subunits that we named 45SYphC and 44.5SYsxC particles. Quantitative mass spectrometry analysis and the 5-6 A resolution cryo-EM maps of the 45SYphC and 44.5SYsxC particles revealed that the two GTPases participate in the maturation of the central protuberance, GTPase associated region and key RNA helices in the A, P and E functional sites of the 50S subunit. We observed that YphC and YsxC bind specifically to the two immature particles, suggesting that they represent either on-pathway intermediates or that their structure has not significantly diverged from that of the actual substrate. These results describe the nature of these immature particles, a widely used tool to study the assembly process of the ribosome. They also provide the first insights into the function of YphC and YsxC in 50S subunit assembly and are consistent with this process occurring through multiple parallel pathways, as it has been described for the 30S subunit. PMID- 27484476 TI - Origins of tmRNA: the missing link in the birth of protein synthesis? AB - The RNA world hypothesis refers to the early period on earth in which RNA was central in assuring both genetic continuity and catalysis. The end of this era coincided with the development of the genetic code and protein synthesis, symbolized by the apparition of the first non-random messenger RNA (mRNA). Modern transfer-messenger RNA (tmRNA) is a unique hybrid molecule which has the properties of both mRNA and transfer RNA (tRNA). It acts as a key molecule during trans-translation, a major quality control pathway of modern bacterial protein synthesis. tmRNA shares many common characteristics with ancestral RNA. Here, we present a model in which proto-tmRNAs were the first molecules on earth to support non-random protein synthesis, explaining the emergence of early genetic code. In this way, proto-tmRNA could be the missing link between the first mRNA and tRNA molecules and modern ribosome-mediated protein synthesis. PMID- 27484477 TI - Identification of distinct biological functions for four 3'-5' RNA polymerases. AB - The superfamily of 3'-5' polymerases synthesize RNA in the opposite direction to all other DNA/RNA polymerases, and its members include eukaryotic tRNA(His) guanylyltransferase (Thg1), as well as Thg1-like proteins (TLPs) of unknown function that are broadly distributed, with family members in all three domains of life. Dictyostelium discoideum encodes one Thg1 and three TLPs (DdiTLP2, DdiTLP3 and DdiTLP4). Here, we demonstrate that depletion of each of the genes results in a significant growth defect, and that each protein catalyzes a unique biological reaction, taking advantage of specialized biochemical properties. DdiTLP2 catalyzes a mitochondria-specific tRNA(His) maturation reaction, which is distinct from the tRNA(His) maturation reaction typically catalyzed by Thg1 enzymes on cytosolic tRNA. DdiTLP3 catalyzes tRNA repair during mitochondrial tRNA 5'-editing in vivo and in vitro, establishing template-dependent 3'-5' polymerase activity of TLPs as a bona fide biological activity for the first time since its unexpected discovery more than a decade ago. DdiTLP4 is cytosolic and, surprisingly, catalyzes robust 3'-5' polymerase activity on non-tRNA substrates, strongly implying further roles for TLP 3'-5' polymerases in eukaryotes. PMID- 27484478 TI - Meiotic prophase roles of Rec8 in crossover recombination and chromosome structure. AB - Rec8 is a prominent component of the meiotic prophase chromosome axis that mediates sister chromatid cohesion, homologous recombination and chromosome synapsis. Here, we explore the prophase roles of Rec8. (i) During the meiotic divisions, Rec8 phosphorylation mediates its separase-mediated cleavage. We show here that such cleavage plays no detectable role for chromosomal events of prophase. (ii) We have analyzed in detail three rec8 phospho-mutants, with 6, 24 or 29 alanine substitutions. A distinct 'separation of function' phenotype is revealed. In the mutants, axis formation and recombination initiation are normal, as is non-crossover recombination; in contrast, crossover (CO)-related events are defective. Moreover, the severities of these defects increase coordinately with the number of substitution mutations, consistent with the possibility that global phosphorylation of Rec8 is important for these effects. (iii) We have analyzed the roles of three kinases that phosphorylate Rec8 during prophase. Timed inhibition of Dbf4-dependent Cdc7 kinase confers defects concordant with rec8 phospho-mutant phenotypes. Inhibition of Hrr25 or Cdc5/polo-like kinase does not. Our results suggest that Rec8's prophase function, independently of cohesin cleavage, contributes to CO-specific events in conjunction with the maintenance of homolog bias at the leptotene/zygotene transition of meiotic prophase. PMID- 27484479 TI - Self-assembly of fully addressable DNA nanostructures from double crossover tiles. AB - DNA origami and single-stranded tile (SST) are two proven approaches to self assemble finite-size complex DNA nanostructures. The construction elements appeared in structures from these two methods can also be found in multi-stranded DNA tiles such as double crossover tiles. Here we report the design and observation of four types of finite-size lattices with four different double crossover tiles, respectively, which, we believe, in terms of both complexity and robustness, will be rival to DNA origami and SST structures. PMID- 27484480 TI - Identify bilayer modules via pseudo-3D clustering: applications to miRNA-gene bilayer networks. AB - Module identification is a frequently used approach for mining local structures with more significance in global networks. Recently, a wide variety of bilayer networks are emerging to characterize the more complex biological processes. In the light of special topological properties of bilayer networks and the accompanying challenges, there is yet no effective method aiming at bilayer module identification to probe the modular organizations from the more inspiring bilayer networks. To this end, we proposed the pseudo-3D clustering algorithm, which starts from extracting initial non-hierarchically organized modules and then iteratively deciphers the hierarchical organization of modules according to a bottom-up strategy. Specifically, a modularity function for bilayer modules was proposed to facilitate the algorithm reporting the optimal partition that gives the most accurate characterization of the bilayer network. Simulation studies demonstrated its robustness and outperformance against alternative competing methods. Specific applications to both the soybean and human miRNA-gene bilayer networks demonstrated that the pseudo-3D clustering algorithm successfully identified the overlapping, hierarchically organized and highly cohesive bilayer modules. The analyses on topology, functional and human disease enrichment and the bilayer subnetwork involved in soybean fat biosynthesis provided both the theoretical and biological evidence supporting the effectiveness and robustness of pseudo-3D clustering algorithm. PMID- 27484481 TI - A multi-step model for facilitated unwinding of the yeast U4/U6 RNA duplex. AB - The small nuclear RNA (snRNA) components of the spliceosome undergo many conformational rearrangements during its assembly, catalytic activation and disassembly. The U4 and U6 snRNAs are incorporated into the spliceosome as a base paired complex within the U4/U6.U5 small nuclear ribonucleoprotein (tri-snRNP). U4 and U6 are then unwound in order for U6 to pair with U2 to form the spliceosome's active site. After splicing, U2/U6 is unwound and U6 annealed to U4 to reassemble the tri-snRNP. U6 rearrangements are crucial for spliceosome formation but are poorly understood. We have used single-molecule Forster resonance energy transfer and unwinding assays to identify interactions that promote U4/U6 unwinding and have studied their impact in yeast. We find that U4/U6 is efficiently unwound using DNA oligonucleotides by coupling unwinding of U4/U6 stem II with strand invasion of stem I. Unwinding is stimulated by the U6 telestem, which transiently forms in the intact U4/U6 RNA complex. Stabilization of the telestem in vivo results in accumulation of U4/U6 di-snRNP and impairs yeast growth. Our data reveal conserved mechanisms for U4/U6 unwinding and indicate telestem dynamics are critical for tri-snRNP assembly and stability. PMID- 27484482 TI - Co-incident insertion enables high efficiency genome engineering in mouse embryonic stem cells. AB - CRISPR/Cas9 nucleases have enabled powerful, new genome editing capabilities; however, the preponderance of non-homologous end joining (NHEJ) mediated repair events over homology directed repair (HDR) in most cell types limits the ability to engineer precise changes in mammalian genomes. Here, we increase the efficiency of isolating precise HDR-mediated events in mouse embryonic stem (ES) cells by more than 20-fold through the use of co-incidental insertion (COIN) of independent donor DNA sequences. Analysis of on:off-target frequencies at the Lef1 gene revealed that bi-allelic insertion of a PGK-Neo cassette occurred more frequently than expected. Using various selection cassettes targeting multiple loci, we show that the insertion of a selectable marker at one control site frequently coincided with an insertion at an unlinked, independently targeted site, suggesting enrichment of a sub-population of HDR-proficient cells. When individual cell events were tracked using flow cytometry and fluorescent protein markers, individual cells frequently performed either a homology-dependent insertion event or a homology-independent event, but rarely both types of insertions in a single cell. Thus, when HDR-dependent selection donors are used, COIN enriches for HDR-proficient cells among heterogeneous cell populations. When combined with a self-excising selection cassette, COIN provides highly efficient and scarless genome editing. PMID- 27484484 TI - Ovarian masses with papillary projections diagnosed and removed during pregnancy: ultrasound features and histological diagnosis. AB - OBJECTIVE: To elucidate the ultrasound features that can discriminate between benign and malignant ovarian cysts with papillary projections but no other solid component in pregnant women. METHODS: Thirty-four women with an ultrasound diagnosis of an ovarian cyst with papillary projections but no other solid component that had been removed surgically during pregnancy were identified from the databases of four ultrasound units. Some clinical and ultrasound information was collected prospectively. Missing information was obtained retrospectively from ultrasound images, ultrasound reports and patient records. Using prospectively and retrospectively collected data, the ultrasound appearance of the tumors was described using the terms and definitions of the International Ovarian Tumor Analysis group. The ultrasound characteristics were compared with the histological diagnosis. RESULTS: Of the 34 cases included, 19 (56%) lesions were benign (16 decidualized endometriomas, one cystadenofibroma, one simple cyst, one struma ovarii), 12 (35%) were borderline tumors and three (9%) were primary invasive tumors (two immature teratomas, one endometrioid cystadenocarcinoma). The contour of the cyst papillations was smooth in 79% (15/19) of benign tumors vs 27% (4/15) of malignant tumors (P = 0.002). The cystic content showed ground-glass echogenicity in 74% (14/19) of benign tumors vs 13% (2/15) of malignant tumors (P = 0.0006). All ovarian masses with smooth papillations and ground-glass content (n = 12) were decidualized endometriomas. The papillary projections were vascularized and the color score was 3 or 4 in 88% (14/16) of decidualized endometriomas vs 42% (5/12) of borderline tumors (P = 0.013). CONCLUSIONS: In pregnant women, ovarian cysts with ground-glass echogenicity and papillations with a smooth contour on ultrasound are most likely to be decidualized endometriomas. Cysts with anechoic or low-level echogenicity and papillations with an irregular contour suggest borderline malignancy. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27484483 TI - An aromatic-rich loop couples DNA binding and ATP hydrolysis in the PriA DNA helicase. AB - Helicases couple ATP hydrolysis to nucleic acid binding and unwinding via molecular mechanisms that remain poorly defined for most enzyme subfamilies within the superfamily 2 (SF2) helicase group. A crystal structure of the PriA SF2 DNA helicase, which governs restart of prematurely terminated replication processes in bacteria, revealed the presence of an aromatic-rich loop (ARL) on the presumptive DNA-binding surface of the enzyme. The position and sequence of the ARL was similar to loops known to couple ATP hydrolysis with DNA binding in a subset of other SF2 enzymes, however, the roles of the ARL in PriA had not been investigated. Here, we show that changes within the ARL sequence uncouple PriA ATPase activity from DNA binding. In vitro protein-DNA crosslinking experiments define a residue- and nucleotide-specific interaction map for PriA, showing that the ARL binds replication fork junctions whereas other sites bind the leading or lagging strands. We propose that DNA binding to the ARL allosterically triggers ATP hydrolysis in PriA. Additional SF2 helicases with similarly positioned loops may also couple DNA binding to ATP hydrolysis using related mechanisms. PMID- 27484485 TI - Enantiomeric separation of new phytoalexin analogs with cyclofructan chiral stationary phases in normal-phase mode. AB - For the first time, three different derivatized cyclofructan chiral stationary phases were used for the direct high-performance liquid chromatographic enantiomeric separation of 11 new racemic analogs of a natural indole phytoalexin. This class of compounds is known to have significant antiproliferative activity and other potentially useful pharmacological properties. The effect of various experimental factors was investigated to optimize the separations in the normal-phase mode. It was found that the nature of polar modifier and additive in the mobile phase have significant impact on the enantioseparations. Better chiral recognition of analyzed compounds was achieved on (R)-naphthylethyl carbamate cyclofructan 6 than on isopropyl carbamate cyclofructan 6 and dimethylphenyl carbamate cyclofructan 7. The thermodynamic parameters showed that the chiral separation was enthalpy controlled in all cases. PMID- 27484486 TI - Facilitators and Barriers to Implementing Transitional Care Managers Within a Public Health Care System. AB - Transitional care is crucial to ensure quality of care and safety for elderly patients. In the context of health care reforms promoting a shift from a hospital centered approach to a home care approach, transitional care becomes a vital component and social workers can play an important role in easing transitions. Most recent studies have focused on the development or improvement of transitional care intervention models or tools, but few have addressed implementation issues. In this study, the implementation process of an innovative intervention aiming to integrate transitional care managers (TCMs) from Health and Social Services Centres (HSSC) within two Canadian hospitals was evaluated. Data collection comprised focus groups (n = 8), direct observations, meeting minutes, activity grids and logbooks. To facilitate the implementation of TCMs, decisions were made to clearly indicate their involvement in patients' files and concentrated their efforts on a restricted number of units. Barriers included confusion about target clientele, inequitable information exchange between partners, limited powers regarding coordination of care, and organizational constraints limiting additional measures to improve transitional care. Evaluating implementation processes is crucial to efficiently identify obstacles and apply additional implementation strategies to promote the integration of new practices within the health care system. PMID- 27484488 TI - Higher Doses of Fish Oil-Based Lipid Emulsions Used to Treat Inadequate Weight Gain and Rising Triene:Tetraene Ratio in a Severely Malnourished Infant With Intestinal Failure-Associated Liver Disease. AB - Fish oil-based lipid emulsions (FOLEs) have been used to treat cholestasis in children with intestinal failure-associated liver disease (IFALD). When FOLEs are dosed at 1 g/kg/d, essential fatty acid (EFA) deficiency typically does not occur. We describe the clinical course of a severely malnourished parenteral nutrition-dependent infant with IFALD. Baseline EFA panels were normal upon starting FOLE at 1 g/kg/d. Despite biochemical improvement in IFALD, weight velocity was below target and biochemical EFA status worsened, even after correction for other factors affecting weight. The FOLE dose was increased to 1.5 g/kg/d, resulting in improvement of weight velocity and EFA status. This suggests that in severely malnourished infants being treated for IFALD, higher doses of FOLE may be required for adequate growth and to prevent EFA deficiency. PMID- 27484487 TI - Agglutinating mouse IgG3 compares favourably with IgMs in typing of the blood group B antigen: Functionality and stability studies. AB - Mouse immunoglobulins M (IgMs) that recognize human blood group antigens induce haemagglutination and are used worldwide for diagnostic blood typing. Contrary to the current belief that IgGs are too small to simultaneously bind antigens on two different erythrocytes, we obtained agglutinating mouse IgG3 that recognized antigen B of the human ABO blood group system. Mouse IgG3 is an intriguing isotype that has the ability to form Fc-dependent oligomers. However, F(ab')2 fragments of the IgG3 were sufficient to agglutinate type B red blood cells; therefore, IgG3-triggered agglutination did not require oligomerization. Molecular modelling indicated that mouse IgG3 has a larger range of Fab arms than other mouse IgG subclasses and that the unique properties of mouse IgG3 are likely due to the structure of its hinge region. With a focus on applications in diagnostics, we compared the stability of IgG3 and two IgMs in formulated blood typing reagents using an accelerated storage approach and differential scanning calorimetry. IgG3 was much more stable than IgMs. Interestingly, the rapid decrease in IgM activity was caused by aggregation of the molecules and a previously unknown posttranslational proteolytic processing of the MU heavy chain. Our data point to mouse IgG3 as a potent diagnostic tool. PMID- 27484489 TI - Nutrition Therapy in Critically Ill Patients Following Cardiac Surgery: Defining and Improving Practice. AB - BACKGROUND: Malnutrition is a predictor of poor outcome following cardiac surgery. We define nutrition therapy after cardiac surgery to identify opportunities for improvement. METHODS: International prospective studies in 2007 2009, 2011, and 2013 were combined. Sites provided institutional and patient characteristics from intensive care unit (ICU) admission to ICU discharge for a maximum of 12 days. Patients had valvular, coronary artery bypass graft (CABG) surgery, or combined procedures and were mechanically ventilated and staying in the ICU for >=3 days. RESULTS: There were 787 patients from 144 ICUs. In total, 120 patients (15.2%) had valvular surgery, 145 patients (18.4%) had CABG, and 522 patients (66.3%) underwent a combined procedure. Overall, 60.1% of patients received artificial nutrition support. For these patients, 78% received enteral nutrition (EN) alone, 17% received a combination of EN and parenteral nutrition (PN), and 5% received PN alone. The remaining 314 patients (40%) received no nutrition. The mean (SD) time from ICU admission to EN initiation was 2.3 (1.8) days. The adequacy of calories was 32.4% +/- 31.9% from EN and PN and 25.5% +/- 27.9% for patients receiving only EN. In EN patients, 57% received promotility agents and 20% received small bowel feeding. There was no significant relationship between increased energy or protein provision and 60-day mortality. CONCLUSION: Postoperative cardiac surgery patients who stay in the ICU for 3 or more days are at high risk for inadequate nutrition therapy. Further studies are required to determine if targeted nutrition therapy may alter clinical outcomes. PMID- 27484490 TI - The Cost and Outcome Effectiveness of Total Hip Replacement: Technique Choice and Volume-Output Effects Matter. AB - BACKGROUND: Total hip replacement (THR) must be managed in a more sustainable manner. More cost-effective surgical techniques and the centralization/regionalization of services are two solutions. The former requires an assessment of newer minimally invasive and muscle-sparing surgical techniques. The latter necessitates an effective volume-outcome (VO) relationship. Prior studies have failed to evaluate and control for the VO relation. OBJECTIVE: The objective of this study was to evaluate the relative cost and outcome effectiveness of two minimally invasive and one muscle-sparing techniques while evaluating and controlling for a potentially endogenous VO relation. METHODS: An all payer claims database for all THR performed in Maine in 2011 was used. The cost and outcome effectiveness of newer minimally invasive (modified Hardinge) and muscle-sparing (modified Watson-Jones) techniques were compared with the standard bearer posterior minimally invasive method. Using regression analysis, the outcomes analyzed were as follows: total costs, length of hospital stay, nursing care and home discharges, and use of physical therapy. Regression analysis was also used to evaluate and control for VO effects. RESULTS: (1) Newer muscle-sparing and minimally invasive approaches are substantially more effective; (2) irrespective of technique, higher volume surgeons are more effective; (3) technique-specific VO effects for more complex techniques exist and show substantial savings when yearly volume exceeds 30-50; and (4) the anterolateral muscle-sparing technique is accessible to the average surgeon. CONCLUSION: Reliance on newer surgical techniques and centralization/regionalization of THR services can reduce costs. PMID- 27484491 TI - Investigation of mechanisms of vagus nerve stimulation for seizure using finite element modeling. AB - OBJECTIVE: While the efficacy of vagus nerve stimulation (VNS) to reduce seizures in pharmaco-resistant patients is clinically proven, its efficacy and side effects mechanisms are not fully understood. Our goals were 1) to use a finite element model (FEM) and axon models to examine different fiber activation and blocking thresholds and 2) examine fiber activation and blocking in three fiber groups likely to be responsible for efficacy and side effects. METHODS: Using FEM, we examined the field potential along axons within a vagus nerve model with fascicles. These data were input to a computational fiber model to estimate numbers of axons activated across all diameters. We estimated numbers of activated and blocked fibers by diameter. RESULTS: 1) At the low end of VNS amplitudes, little efficacy for seizure control is appreciated while large Abeta fibers associated with the recurrent laryngeal nerve are recruited. As amplitudes are increased, Abeta fibers can produce hoarseness, and next recruited are fast B fibers associated with the aortic fascicle. We hypothesize these B fibers are the source of efficacy in treating seizure. As amplitudes are further increased, coughing may occur, possibly due to recruitment of smaller and deeper pulmonary fibers. 2) Clinical parameters are in a range that could cause inadvertent blocking at the cathode and activation at the anode. Conversely, innovative approaches to field shape and charge-balancing can allow controlled fiber activation at the cathode for maximum activation of the fibers responsible for efficacy, and possibly blocking at the anode to minimize side effects and expand therapeutic range. In design and operation, the cathode and anode can each be approached as a band pass filter. SIGNIFICANCE: The B fiber group is necessary and possibly sufficient to produce VNS efficacy in epilepsy. This group may emanate from aortic baroreceptors that, via synapses in the solitary tract nucleus, stimulate the locus coeruleus, hypothalamus and other influential targets such as the hippocampus. Responder rates may be increased with a lead that fully encircles the nerve. With better identification of the fiber groups involved in VNS, efficacy, side effects, therapeutic range and responder rates can be optimized. PMID- 27484492 TI - Pre-Clinical Study of a Novel Recombinant Botulinum Neurotoxin Derivative Engineered for Improved Safety. AB - Cyto-012 is a recombinant derivative of Botulinum neurotoxin Type A (BoNT/A). It primarily differs from wild type (wt) BoNT/A1 in that it incorporates two amino acid substitutions in the catalytic domain of the light chain (LC) metalloprotease (E224 > A and Y366 > A), designed to provide a safer clinical profile. Cyto-012 is specifically internalized into rat cortical and hippocampal neurons, and cleaves Synaptosomal-Associated Protein 25 (SNAP-25), the substrate of wt BoNT/A, but exhibits slower cleavage kinetics and therefore requires a higher absolute dose to exhibit pharmacologic activity. The pharmacodynamics of Cyto-012 and wt BoNT/A have similar onset and duration of action using the Digital Abduction Assay (DAS). Intramuscular LD50 values for Cyto-012 and wt BoNT/A respectively, were 0.63 ug (95% CI = 0.61, 0.66) and 6.22 pg (95% CI = 5.42, 7.02). ED50 values for Cyto-012 and wt BoNT/A were respectively, 0.030 ug (95% CI = 0.026, 0.034) and 0.592 pg (95% CI = 0.488, 0.696). The safety margin (intramuscular LD50/ED50 ratio) for Cyto-012 was found to be improved 2-fold relative to wt BoNT/A (p < 0.001). The DAS response to Cyto-012 was diminished when a second injection was administered 32 days after the first. These data suggest that the safety margin of BoNT/A can be improved by modulating their activity towards SNAP-25. PMID- 27484493 TI - Perceptions of childhood undernutrition among rural households on the Kenyan coast - a qualitative study. AB - BACKGROUND: Nutrition plays an important role in child survival and development. Treatment action in the management of child health and nutrition is influenced by perceptions of illness, and gender plays an important role. However, little is known about if and how moderate undernutrition is recognised among lay populations, or how local social norms and intra-household dynamics affect decisions to seek biomedical assistance for nutritional concerns. In this paper we describe how childhood nutritional problems are recognised and understood within rural households. We demonstrate how context influences local constructs of 'normal', and suggest the centrality of gender in the management of child health and nutrition in our research context. METHODS: This qualitative study was undertaken in Kilifi County on the Kenyan Coast. A set of 15 households whose children were engaged in a community-based nutrition intervention were followed up over a period of twelve months. Over a total of 54 household visits, group and individual in-depth interviews were conducted with a range of respondents, supplemented by non-participant observations. Eight in-depth interviews with community representatives were also conducted. RESULTS: Local taxonomies of childhood undernutrition were found to overlap with, but differ from, biomedical categories. In particular, moderate undernutrition was generally not recognised as a health problem requiring treatment action, but rather as routine and manageable, typically seasonal, weight-loss. Where symptoms were considered more serious and requiring remedial action, household management strategies were typically based on perceived aetiology of the illness. Additionally, gender emerged as a potentially central theme in childhood nutrition problems and related management. Women reported that they have primary responsibility for ensuring children's good health and nutritional status, and that they are often held accountable when their children are of sub-optimal health. CONCLUSION: Perceptions of child nutrition and illness and gendered roles within households influence treatment action, and engagement with nutrition interventions. Community-based nutrition interventions must recognise these complex realities. PMID- 27484494 TI - [Chronic coronary occlusions : When and how should revascularization be performed?] AB - Chronic occlusion of coronary arteries also known as chronic total occlusions (CTO) are found in approximately 20 % of patients undergoing percutaneous coronary interventions (PCI) and in approximately 50 % of patients after coronary artery bypass grafts (CABG). As a result of technical advancements in retrograde recanalization techniques specialized centers can now achieve success rates of over 85 %, regardless of the CTO anatomy. Given the complexity of retrograde CTO techniques, a consensus paper issued by the Euro CTO Club requires interventional cardiologists to have sufficient experience in antegrade approaches (>300 antegrade CTO cases and >50 per year) with an additional training program (25 retrograde cases each as first and second operating surgeon) before becoming a qualified independent retrograde surgeon. The increased investment in time and technical resources can only be justified if the patient has a clear clinical benefit. This technical advancement and the progressively clearer evidence that complete revascularization can be achieved in patients with multivessel coronary artery disease have attracted growing interest in recent years from interventional cardiologists in the recanalization of CTO. PMID- 27484495 TI - Kidney epithelium specific deletion of kelch-like ECH-associated protein 1 (Keap1) causes hydronephrosis in mice. AB - BACKGROUND: Transcription factor Nrf2 protects from experimental acute kidney injury (AKI) and is promising to limit progression in human chronic kidney disease (CKD) by upregulating multiple antioxidant genes. We recently demonstrated that deletion of Keap1, the endogenous inhibitor of Nrf2, in T lymphocytes significantly protects from AKI. In this study, we investigated the effect of Keap1 deletion on Nrf2 mediated antioxidant response in the renal tubular epithelial cells. METHODS: We deleted Keap1 exon 2 and 3 in the renal tubular epithelial cells by crossing Ksp-Cre mice with Keap1 floxed (Keap1 (f/f)) mice. Deletion of Keap1 gene in the kidney epithelial cells of Ksp-Keap1 (-/-) mice and its effect on Nrf2 target gene expression was performed using PCR and real-time PCR respectively. Histological evaluation was performed on H&E stained sections. Complete blood count, serum and urine analysis were performed to assess systemic effects of defective kidney development. Student's T test was used to determine statistical difference between the groups. RESULTS: Ksp-Cre resulted in the deletion of Keap1 exon 2 and 3 and subsequent upregulation of Nrf2 target genes, Nqo1, Gclm and Gclc in the kidney epithelial cells of Ksp-Keap1 (-/-) mice at baseline. Renal epithelial cell specific deletion of Keap1 in Ksp-Keap1 (-/-) mice caused marked renal pelvic expansion and significant compression of medullary parenchyma consistent with hydronephrosis in both (3 month-old) males and females. Kidneys from 6 month-old Ksp-Keap1 (-/-) mice showed progressive hydronephrosis. Hematological, biochemical and urinary analysis showed significantly higher red blood cell count (p = 0.04), hemoglobin (p = 0.01), hematocrit (p = 0.02), mean cell volume (p = 0.02) and mean cell hemoglobin concentration (p = 0.003) in Ksp-Keap1 (-/-) mice in comparison to Keap1 (f/f) mice. CONCLUSIONS: These unexpected findings demonstrate that Keap1 deletion in renal tubular epithelial cells results in an abnormal kidney development consistent with hydronephrosis and reveals a novel Keap1 mediated signaling pathway in renal development. PMID- 27484496 TI - Numerical Bifurcation Analysis of Physiologically Structured Populations: Consumer-Resource, Cannibalistic and Trophic Models. AB - With the aim of applying numerical methods, we develop a formalism for physiologically structured population models in a new generality that includes consumer-resource, cannibalism and trophic models. The dynamics at the population level are formulated as a system of Volterra functional equations coupled to ODE. For this general class, we develop numerical methods to continue equilibria with respect to a parameter, detect transcritical and saddle-node bifurcations and compute curves in parameter planes along which these bifurcations occur. The methods combine curve continuation, ODE solvers and test functions. Finally, we apply the methods to the above models using existing data for Daphnia magna consuming Algae and for Perca fluviatilis feeding on Daphnia magna. In particular, we validate the methods by deriving expressions for equilibria and bifurcations with respect to which we compute errors, and by comparing the obtained curves with curves that were computed earlier with other methods. We also present new curves to show how the methods can easily be applied to derive new biological insight. Schemes of algorithms are included. PMID- 27484497 TI - Comfort experience in palliative care: a phenomenological study. AB - BACKGROUND: Palliative care aims to provide maximum comfort to the patient. However it is unknown what factors facilitate or hinder the experience of comfort, from the perspective of inpatients of palliative care units. This lack of knowledge hinders the development of comfort interventions adjusted to these patients. The aim of this research is to describe the comfort and discomfort experienced by inpatients at palliative care units. METHODS: A phenomenological descriptive study was undertaken. Ten inpatients were recruited from a Spanish palliative care unit and seven from a Portuguese palliative care unit. Data were collected using individual interviews and analysed following the method of Giorgi. RESULTS: Four themes reflect the essence of the lived experience: The Palliative Care as a response to the patient's needs with advanced disease, attempt to naturalize advanced disease, confrontation with their own vulnerability, openness to the spiritual dimension. CONCLUSIONS: Informants revealed that they experience comfort through humanized care, differentiated environment, symptomatic control, hope and relationships. The discomfort emerges from the losses and powerlessness against their situation. Even if such findings may seem intuitive, documenting them is essential because it invites us to reflect on our convictions about what it means to be comfortable for these patients, and allows incorporating this information in the design of focused interventions to maximize the comfort experience. PMID- 27484498 TI - Systems Pharmacology Dissection of the Protective Effect of Myricetin Against Acute Ischemia/Reperfusion-Induced Myocardial Injury in Isolated Rat Heart. AB - In this paper, we investigated the multi-target effect of myricetin as a therapeutic for cardiovascular disease, using an acute ischemia/reperfusion induced myocardial injury model to gain insight into its mechanism of action. The compound-target interaction profiles of myricetin were determined using a combination of text mining, chemometric and chemogenomic methods. The effect of myricetin on cardiac function was investigated by carrying out experiments in rats subjected to ischemia/reperfusion (I/R) using Langendorff retrograde perfusion technology. Compared to the I/R group, pretreatment with 5 MUM myricetin was observed to improve the maximum up/down rate of left ventricular pressure (dp/dt max) and coronary flow, raise left ventricular developed pressure, and decrease creatine kinase and lactate dehydrogenase levels in coronary flow. In addition, myricetin treatment was shown to have beneficial effects through its ability to reduce both infarct size and levels of cardiomyocyte apoptosis. Myricetin was also observed to have antioxidant properties, as evidenced by its ability to reduce MDA levels, while increasing both SOD levels and the GSH/GSSG ratio. Finally, an upregulation of 6 phosphogluconate dehydrogenase and fatty acid synthase expression and a downregulation of cyclooxygenase-2, cytochrome P450 and p38 mitogen-activated protein kinase expression suggest that myricetin acts through mechanisms which alter relevant signaling pathways. In summary, our results demonstrate that myricetin has protective cardiovascular effects against I/R-induced myocardial injury. PMID- 27484499 TI - Safety and efficacy in ablation of premature ventricular contraction: data from the German ablation registry. AB - BACKGROUND: Patients with frequent premature ventricular contractions (PVCs) are often highly symptomatic with significantly reduced quality-of-life. We evaluated the outcome and success of PVC ablation in patients in the German Ablation Registry. METHODS: The German Ablation Registry is a nationwide prospective multicenter database of patients who underwent an ablation procedure, initiated by the "Stiftung Institut fur Herzinfarktforschung" (IHF), Ludwigshafen, Germany. Data were acquired from March 2007 to May 2011. Patients underwent PVC ablation in the enrolling ablation centers. RESULTS: A total of 408 patients (age 53.5 +/- 15 years, 55 % female) undergoing ablation for PVCs were included. 32 % of patients showed a co-existing structural heart disease. Acute ablation success of the procedure was 82 % in the overall patient group. In patients without structural heart disease, acute success was significantly higher compared with patients with structural heart disease (86 vs. 74 %, p = 0.002). All patients were discharged alive after a median of 3 days. No patient suffered an acute myocardial infarction, stroke, or major bleeding. After 12 months' follow-up, 99 % of patients were still alive showing a significant different mortality between patients with structural heart disease compared with those without (2.3 vs. 0 %, p = 0.012). In addition, 76 % of patients showed significantly improved symptoms after 12 months of follow-up. CONCLUSION: Based on the data from this registry, ablation of PVCs is a safe and efficient procedure with an excellent outcome and improved symptoms after 12 months. PMID- 27484500 TI - Biological study of the effect of water soluble [N-(2-hydroxybenzyl)-L-aspartato] gallium complexes on breast carcinoma and fibrosarcoma cells. AB - Two water soluble gallium complexes described as [Ga(III)LCl], where L is the deprotonated form of N-2-hydroxybenzyl aspartic acid derivatives, were synthesized and characterized by (1)H NMR, (13)C NMR, FT-IR, mass spectrometry, and elemental analysis. The 2-(5-chloro-2-hydroxybenzylamino)succinic acid derivative (GS2) has been found to be a promising anticancer drug candidate. This compound was found to be more cytotoxic against human breast carcinoma MDA-MB231 and fibrosarcoma HT-1080 cell lines than the unsubstituted derivative and GaCl3. GS2 was able to induce apoptosis through downregulation of AKT phosphorylation, G2M arrest in cell cycle, and caspase 3/7 pathway. This gallium complex was found to induce an increase in mitochondrial ROS level in HT-1080 cells but not in MDA MB231 cells. This suggests that the mechanism of action of GS2 would not be mediated by the drug-induced oxidative stress but probably by directly and indirectly inhibiting the AKT cell-signaling pathway. PMID- 27484501 TI - Immunomodulatory Properties of Mesenchymal Stem Cells Can Mitigate Oxidative Stress and Inflammation Process in Human Mustard Lung. AB - Oxidative stress and inflammation are one of the main pathological consequences of sulfur mustard on human lungs. Unfortunately, there is no effective treatment to mitigate pathological effects of sulfur mustard in mustard lungs. Here, we aimed to evaluate potential efficacy of systemic mesenchymal stem cells administration on expression of oxidative stress- and inflammation-related genes in sulfur mustard-exposed patients. Our patient received 100 million cells per injection, which was continued for four injections within 2 months. Sputum samples were provided after each injection. Oxidative stress was evaluated by determining sputum levels of malondialdehyde and glutathione. Furthermore, changes in expression of several oxidative stress- (metallothionein 3, glutathione reductase, oxidative stress responsive 1, glutathione peroxidase 2, lacto peroxidase, forkhead box M1) and inflammation-related genes (matrix metallopeptidase 2, matrix metallopeptidase 9, transforming growth factor-beta1, vascular endothelial growth factor, metallopeptidase inhibitor 1, metallopeptidase inhibitor 2) were also evaluated using real-time PCR after treatments. Two-lung epithelial-specific proteins including Clara cell protein 16 and Mucin-1 protein levels were measured using enzyme immunoassay method. No significant differences were found between serum levels of Clara cell protein 16 and serum Mucin-1 protein in patient before and after cell therapy. Most of the oxidative stress responsive genes, particularly oxidative stress responsive 1, were overexpressed after treatments. Expressions of antioxidants genes such as metallothionein 3, glutathione reductase and glutathione peroxidase 2 were increased after cell therapy. Upon comparison of inflammation-related genes, we observed upregulation of vascular endothelial growth factor and matrix metallopeptidase 9 after mesenchymal stem cells therapy. Additionally, a trend for increased value of glutathione and decreased levels of malondialdehyde was observed from baseline to final evaluation times. Mesenchymal stem cells administration mitigates oxidative stress and inflammation in sulfur mustard exposed patients. PMID- 27484502 TI - Functional screening implicates miR-371-3p and peroxiredoxin 6 in reversible tolerance to cancer drugs. AB - Acquired resistance to cancer drug therapies almost always occurs in advanced stage patients even following a significant response to treatment. In addition to mutational mechanisms, various non-mutational resistance mechanisms have now been recognized. We previously described a chromatin-mediated subpopulation of reversibly drug-tolerant persisters that is dynamically maintained within a wide variety of tumour cell populations. Here we explore a potential role for microRNAs in such transient drug tolerance. Functional screening of 879 human microRNAs reveals miR-371-3p as a potent suppressor of drug tolerance. We identify PRDX6 (peroxiredoxin 6) as a key target of miR-371-3p in establishing drug tolerance by regulating PLA2/PKCalpha activity and reactive oxygen species. PRDX6 expression is associated with poor prognosis in cancers of multiple tissue origins. These findings implicate miR-371-3p as a suppressor of PRDX6 and suggest that co-targeting of peroxiredoxin 6 or modulating miR-371-3p expression together with targeted cancer therapies may delay or prevent acquired drug resistance. PMID- 27484503 TI - Patterns of Primary Immunodeficiency Disorders Among a Highly Consanguineous Population: Cairo University Pediatric Hospital's 5-Year Experience. AB - INTRODUCTION: Primary immunodeficiency disorders (PIDs) are heterogeneous disorders that mainly present with severe, persistent, unusual, or recurrent infections in childhood. Reports from different parts of the world indicate a difference between Western and Eastern populations. AIM: The aim of this study was to report on the different patterns of PIDs and identify subgroup characteristics in a highly consanguineous population in Egypt. METHODS: We performed a retrospective chart review for children below 18 years diagnosed with PID at Cairo University Pediatric Hospital from 2010 to 2014. RESULTS: Four hundred seventy-six children were diagnosed with PID disorders. Major categories included combined immunodeficiency disorders, which constituted a large proportion (30 %) of cases, along with predominantly antibody disorders (18 %) followed by syndromic combined disorders (16.8 %), phagocytic disorders (13.2 %), immune dysregulation disorders (10.5 %), and autoinflammatory disorders (9 %). CONCLUSION: PIDs have different patterns within inbred populations with high consanguinity. PMID- 27484504 TI - Phenotypic and Functional Comparison of Class Switch Recombination Deficiencies with a Subgroup of Common Variable Immunodeficiencies. AB - Primary antibody deficiencies (PADs) are the most common immunodeficiency in humans, characterized by low levels of immunoglobulins and inadequate antibody responses upon immunization. These PADs may result from an early block in B cell development with a complete absence of peripheral B cells and lack of immunoglobulins. In the presence of circulating B cells, some PADs are genetically caused by a class switch recombination (CSR) defect, but in the most common PAD, common variable immunodeficiency (CVID), very few gene defects have as yet been characterized despite various phenotypic classifications. Using a functional read-out, we previously identified a functional subgroup of CVID patients with plasmablasts (PBs) producing IgM only. We have now further characterized such CVID patients by a direct functional comparison with patients having genetically well-characterized CSR defects in CD40L, activation-induced cytidine deaminase (AID) and uracil N-glycosylase activity (UNG). The CSR-like CVID patients showed a failure in B cell activation patterns similar to the classical AID/UNG defects in three out of five CVID patients and distinct more individual defects in the two other CVID cases when tested for cellular activation and PB differentiation. Thus, functional categorization of B cell activation and differentiation pathways extends the expected variation in CVID to CSR-like defects of as yet unknown genetic etiology. PMID- 27484505 TI - The shouted voice: A pilot study of laryngeal physiology under extreme aerodynamic pressure. AB - INTRODUCTION: The objective was to study the behavior of the larynx during shouted voice production, when the larynx is exposed to extremely high subglottic pressure. MATERIALS AND METHODS: The study involved electroglottographic, acoustic, and aerodynamic analyses of shouts produced at maximum effort by three male participants. RESULTS AND DISCUSSION: Under a normal speaking voice, the voice sound pressure level (SPL) is proportional to the subglottic pressure. However, when the subglottic pressure reached high levels, the voice SPL reached a maximum value and then decreased as subglottic pressure increased further. Furthermore, the electroglottographic signal sometimes lost its periodicity during the shout, suggesting irregular vocal fold vibration. PMID- 27484506 TI - Soleal vein dilatation assessed by ultrasonography is an independent predictor for deep vein thrombosis after major orthopedic surgery. AB - BACKGROUND: Deep vein thrombosis (DVT) develops after major orthopedic surgery despite the current use of prophylaxis. DVT frequently develops in the soleal vein (SV) and might develop easily at the site of SV dilatation because of blood flow stasis. However, whether preoperative SV dilatation detected by ultrasonography predicts DVT after major orthopedic surgery remains unknown. OBJECTIVE: We examined whether SV dilatation detected by preoperative ultrasonography predicts DVT after major orthopedic surgery. METHODS: Ultrasonography was performed preoperatively and postoperatively in 243 patients with orthopedic diseases (mean age of 67+/-13 years, 77% women) who underwent total hip arthroplasty (THA, n=180) or total knee arthroplasty (TKA, n=63). Presence of DVT was diagnosed by ultrasonography and SV diameter >=10mm was defined as SV dilatation. Patients with preoperative DVT were excluded. RESULTS: Sixty-nine patients (28%) developed postoperative DVT. SV dilatation was found in 24 patients (10%), and 16 (67%) of those patients had postoperative DVT. Multivariate logistic regression analysis showed that female gender [odds ratio (OR): 4.09, p=0.004], TKA (OR: 2.52, p=0.011), and SV dilatation (OR: 6.67, p<0.001), but not presence of comorbidities, medications, or plasma d-dimer value, independently predict postoperative DVT. Subgroup analyses according to the operation site showed that female gender (OR: 3.27, p=0.043) and SV dilatation (OR: 3.72, p=0.022) were independent predictors of postoperative DVT in the THA group. SV dilatation (OR: 12.0, p=0.027) was an independent predictor of postoperative DVT also in the TKA group. CONCLUSIONS: In addition to gender and TKA, SV dilatation detected by ultrasonography is an independent predictor of DVT after major orthopedic surgery. Determination of SV diameter by ultrasonography before major orthopedic surgery is useful for assessing the risk of postoperative DVT. PMID- 27484508 TI - Identification of new potent phthalazine derivatives with VEGFR-2 and EGFR kinase inhibitory activity. AB - Efforts to develop new antitumor agents are now directed towards multitarget therapies that are believed to have high potency and low tendency to resistance compared to conventional drugs. Herein, we highlighted the synthesis and antitumor activity of five series of phthalazine-based compounds featuring a variety of bioactive chemical fragments at position 1 of the phthalazine nucleus. The antitumor activity of the target compounds was performed against fourteen cancer cell lines where all compounds were active in the nanomolar level. In addition, the mechanism of action of the target compounds was investigated through an enzymatic inhibitory assay against VEGFR-2 and EGFR kinases, revealing potent and preferential activity toward VEGFR-2. Binding mode of the most active compounds was studied using docking experiment. PMID- 27484507 TI - Effect of inspiratory muscle training with load compared with sham training on blood pressure in individuals with hypertension: study protocol of a double-blind randomized clinical trial. AB - BACKGROUND: Hypertension is a complex chronic condition characterized by elevated arterial blood pressure. Management of hypertension includes non-pharmacologic strategies, which may include techniques that effectively reduce autonomic sympathetic activity. Respiratory exercises improve autonomic control over cardiovascular system and attenuate muscle metaboreflex. Because of these effects, respiratory exercises may be useful to lower blood pressure in subjects with hypertension. METHODS/DESIGN: This randomized, double-blind clinical trial will test the efficacy of inspiratory muscle training in reducing blood pressure in adults with essential hypertension. Subjects are randomly allocated to intervention or control groups. Intervention consists of inspiratory muscle training loaded with 40 % of maximum inspiratory pressure, readjusted weekly. Control sham intervention consists of unloaded exercises. Systolic and diastolic blood pressures are co-primary endpoint measures assessed with 24 h ambulatory blood pressure monitoring. Secondary outcome measures include cardiovascular autonomic control, inspiratory muscle metaboreflex, cardiopulmonary capacity, and inspiratory muscle strength and endurance. DISCUSSION: Previously published work suggests that inspiratory muscle training reduces blood pressure in persons with hypertension, but the effectiveness of this intervention is yet to be established. We propose an adequately sized randomized clinical trial to test this hypothesis rigorously. If an effect is found, this study will allow for the investigation of putative mechanisms to mediate this effect, including autonomic cardiovascular control and metaboreflex. TRIAL REGISTRATION: ClinicalTrials.gov NCT02275377 . Registered on 30 September 2014. PMID- 27484509 TI - Design, synthesis and evaluation of pyrazole derivatives as non-nucleoside hepatitis B virus inhibitors. AB - In continuation of our efforts toward the discovery of potent non-nucleoside hepatitis B virus (HBV) inhibitors with novel structures, we have employed bioisosterism and hybrid pharmacophore-based strategy to explore the chemically diverse space of bioactive compounds. In this article, the original thiazole platform was replaced with pyrazole scaffold to yield the optimal pharmacophore moieties in order to generate novel non-nucleoside HBV inhibitors with desirable potency. Some of the new compounds were able to inhibit HBV activity in the low micromolar range. In particular, compound 6a3 displayed the most potent activity against the secretion of HBsAg and HBeAg with IC50 of 24.33 MUM and 2.22 MUM, respectively. The preliminary structure-activity relationship (SAR) of this new series of compounds was investigated, which may help designing more potent molecules. PMID- 27484510 TI - Synthesis and biological evaluation of C1-O-substituted-3-(3-butylamino-2-hydroxy propoxy)-xanthen-9-one as topoisomerase IIalpha catalytic inhibitors. AB - Topoisomerase II poison blocks the transitorily generated DNA double-strand breaks (DSBs) from religation, thereby causes severe DNA damage and gene toxicity. While topoisomerase II catalytic inhibitor does not form cleavable DNA enzyme complex because its function attributes to inhibition of the catalytic steps of the enzyme such as before generating DNA DSBs or in the last step of the catalytic cycle after religation. It has been reported that the stabilizing effect of etoposide on transient cleavable DNA-topoisomerase IIbeta complex attributes to its secondary malignancy. Therefore, topoisomerase IIalpha has been considered as more attractive target than topoisomerase IIbeta for the development of chemotherapeutic agents. In the previous work, we reported compounds I and II as novel topoisomerase IIalpha catalytic inhibitors targeting for ATP binding site of human topoisomerase IIalpha ATP-binding domain. As a continuous work, we have designed and synthesized 43 compounds of C1-O-alkyl and arylalkyl substitiuted compounds with or without methoxy group on ring A. In the topoisomerase IIalpha inhibitory test, among the tested C1-O-4-chlorophenethyl substituted compounds 37 and 47 were more active than others, and compound 37 showed strongest topoisomerase IIalpha inhibitory activity with 94.4% and 23.0% inhibition, respectively, at 100 and 20 MUM. Compounds 37 and 47 have also showed much enhanced cytotoxic activity against T47D cells; IC50 (MUM): 0.63 +/- 0.01 and 0.19 +/- 0.02, respectively, which are stronger than reference drugs. Band depletion assay and cleavage complex assay results showed compounds 37 and 47 were potential topoisomerase IIalpha catalytic inhibitor with low DNA damage. PMID- 27484511 TI - Aromatic heterocyclic esters of podophyllotoxin exert anti-MDR activity in human leukemia K562/ADR cells via ROS/MAPK signaling pathways. AB - Currently, multi-drug resistance (MDR) to antineoplastic drugs is a major obstacle to successful treatment of carcinoma. Looking for novel agents with anti MDR activity is an effectively way to overcome cancer drug resistance. Our previous study showed that podophyllotoxin derivative exhibited potent anti proliferative effect and down-regulated the expression level of P-gp in K562/ADR cells, which probably was related with the MAPK pathways. However, the relation of P-gp expression and MAPK pathways still remains unclear. In this study, a series of aromatic heterocyclic esters of podophyllotoxin were synthesized and their anticancer effects were evaluated against two human chronic myeloid leukemia cell lines (K562 and K562/ADR), simultaneously, the initial structure activity relationship was summarized. The most potent compound, Z5, displayed an IC50 value of 0.032 +/- 0.006 MUM against K562/ADR cells, with a lower resistant factor value of 1.280. Treatment of K562/ADR cells with Z5 caused S cell cycle arrest through reductions in cyclinA, cyclinB1, CDK1 and CDK2 levels. Moreover, Z5 treatment resulted in the induction of apoptosis as characterized by DNA staining, flow cytometry analysis and cleavage of procaspases-3, -8, -9 and PARP. Notably, Z5 significantly inhibited P-gp expression in K562/ADR cells. Additionally, Z5 also caused reactive oxygen species (ROS) generation, which was further demonstrated by preincubation with the antioxidant N-acetylcysteine (NAC). Western blotting revealed that Z5 markedly stimulated the MAPK pathways, including ERK1/2, JNK and P38, however, the mechanisms were prevented by NAC. Finally, the employment of NAC and MAPK inhibitors (U0126, SP600125 and SB203580) remarkably blocked the S phase arrest, apoptosis and down-regulation of P-gp induced by Z5. Taken together, Z5 strongly possessed the potential anti-MDR activity in K562/ADR cells through ROS/MAPK pathways-dependent S phase arrest, apoptosis and down-regulation of P-gp expression. PMID- 27484512 TI - Therapeutic potential of coumarins as antiviral agents. AB - Coumarins have received a considerable attention in the last three decades as a lead structures for the discovery of orally bioavailable non-peptidic antiviral agents. A lot of structurally diverse coumarins analogues were found to display remarkable array of affinity with the different molecular targets for antiviral agents and slight modifications around the central motif result in pronounced changes in its antiviral spectrum. This manuscript thoroughly reviews the design, discovery and structure-activity relationship studies of the coumarin analogues as antiviral agents focusing mainly on lead optimization and its development into clinical candidates. PMID- 27484513 TI - The therapeutic journey of pyridazinone. AB - Pyridazinones have drawn a substantial attention within the field of research analysis and development. The moiety is a subject matter of intensive research because of its wide spectrum of biological activities and therapeutic applications. The synthesis of pyridazinone and investigation of their chemical and biological activities have gained additional importance in recent years. In this review, we have compiled and discussed various biological and therapeutic potential of pyridazinone derivatives. PMID- 27484514 TI - Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer's disease. AB - A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Abeta interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC50: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE induced and Cu(2+)-induced Abeta1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 MUM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Abeta1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy. PMID- 27484515 TI - Synthesis and structure-activity relationship study of tacrine-based pyrano[2,3 c]pyrazoles targeting AChE/BuChE and 15-LOX. AB - A series of tacrine-based pyrazolo[4',3':5,6]pyrano[2,3-b]quinolines and related compounds were designed and synthesized for targeting AChE, BuChE and 15-LOX enzymes in the field of Alzheimer's disease therapy. Most of compounds showed potent activity against cholinesterases and mild potency toward 15-LOX enzyme. In particular, compounds 29, 32 and 40 displayed inhibition at nano-molar level against AChE and BuChE (IC50s = 0.005-0.08 MUM), being more potent than reference drug tacrine. Moreover, compound 32 with IC50 value of 31 MUM was the most potent compound against 15-LOX. The cytotoxicity assay on HepG2 cells revealed that compounds 29 and 32 showed no significant cytotoxic activity even at concentration of 50 MUM. The cytotoxicity of compounds 29 and 32 was significantly less than that of tacrine at higher concentrations. PMID- 27484516 TI - 2,4,5-Trisubstituted thiazole derivatives as HIV-1 NNRTIs effective on both wild type and mutant HIV-1 reverse transcriptase: Optimization of the substitution of positions 4 and 5. AB - In our previous work, novel 2,4,5-trisubstituted thiazole derivatives (TSTs) were synthesized, and their activities were evaluated against HIV-1 reverse transcriptase. Some interesting results were obtained, which led us to a new discovery regarding these TSTs. In the present study, 21 new 2,4,5-trisubstituted thiazole derivatives were rationally designed and synthesized as HIV-1 non nucleoside reverse transcriptase inhibitors (NNRTIs) in accordance with our previous study. Among the synthesized target compounds, compounds 14, 16, 17, and 19 showed more potent inhibitory activities against HIV-1 with an IC50 value of 0.010 MUM. Compounds 4, 9, 10, 11, 13 and 16 were further tested on nine NNRTI resistant HIV-1 strains, and all of these compounds exhibited inhibitory effects. A molecular docking study was conducted, and the results showed a consistent and stable binding mode for the typical compounds. These results have provided deeper insights and SAR of these types of NNRTIs. PMID- 27484518 TI - Metal storage in reeds from an acid mine drainage contaminated field. AB - Phragmites australis has been used to treat acid mine drainage (AMD)-contaminated soil. However, the mechanism about metal translocation in reeds was not widely reported. This study investigated metal (Fe, Al, and Mn) storage location in reeds grown in five different sampling sites of an AMD field. As expected, the more metals in soil, the more metals entered the belowground organs of plants. Reeds grown in soils with the highest levels of metals accumulated 0.16 +/- 0.04 mg/g Mn, 16.29 +/- 4.15 mg/g Fe, and 1.31 +/- 0.22 mg/g Al in roots. Most of the iron was sequestered in the roots, while Al was transferred to the shoots. Histological staining found that most of the iron was sequestered in the exodermis, while Al extended the endodermis of roots. Al even entered the stele of roots grown in soil with higher Al levels. The epidermis, cortex, and central cylinder of rhizomes were the main tissues for Fe and Al storage. The more metals in rhizomes, the stronger intensity of the staining was observed around the vascular systems of rhizomes. No structural difference was observed among reeds collected from different sites. Further studies may be needed to enhance the transfer of metals in reeds and increase the phytoremediation efficiency. PMID- 27484519 TI - Urgent action needed to address key worker housing crisis. AB - We report this week that a group of nurses living in a block of flats in south east London faced with a 20% rent hike have been given just 8 weeks to pay up or move out. PMID- 27484517 TI - Synthesis and cytotoxic activity of novel A-ring cleaved ursolic acid derivatives in human non-small cell lung cancer cells. AB - Ursolic acid (UA) is a pentacyclic triterpenoid with recognized anticancer properties. We prepared a series of new A-ring cleaved UA derivatives and evaluated their antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines using 2D and 3D culture models. Compound 17, bearing a cleaved A-ring with a secondary amide at C3, was found to be the most active compound, with potency in 2D systems. Importantly, even in 3D systems, the effect was maintained albeit a slight increase in the IC50. The molecular mechanism underlying the anticancer activity was further investigated. Compound 17 induced apoptosis via activation of caspase-8 and caspase-7 and via decrease of Bcl-2. Moreover, induction of autophagy was also detected with increased levels of Beclin-1 and LC3A/B-II and decreased levels of mTOR and p62. DNA synthetic capacity and cell cycle profiles were not affected by the drug, but total RNA synthesis was modestly but significantly decreased. Given its activity and mechanism of action, compound 17 might represent a potential candidate for further cancer research. PMID- 27484520 TI - Large tax rebates possible for thousands of nurses. AB - Nurses who took part in an NHS training scheme could be eligible for tax rebates that may be worth thousands of pounds. PMID- 27484521 TI - Star turn. AB - A nursing assistant's moving version of an Adele hit has been viewed thousands of times around the world. PMID- 27484522 TI - Staff told to 'back off' over allegations of surgeon misconduct - hearing told. AB - A senior nurse at an NHS hospital instructed a colleague not to raise concerns about a surgeon who operated on the wrong finger of a patient, a Nursing and Midwifery Council (NMC) hearing was told. PMID- 27484524 TI - Nurse's murder sentence is upheld. AB - Former nurse Victorino Chua has failed in a bid to challenge his conviction and sentence. PMID- 27484525 TI - Rent crisis exposed as key workers hit with 20% hike. AB - The RCN has called for more affordable accommodation for nurses as key workers in London faced a 20% rent hike. PMID- 27484527 TI - Brexit could hit nursing regulator's finances. AB - The UK's decision to leave the EU could hit the Nursing and Midwifery Council's income, the regulator has warned. PMID- 27484528 TI - nursing.standard.com. AB - 1 The first-ever publication of statistics on female genital mutilation (FGM) has revealed 5,700 new cases in England over the past year. Nurses, midwives, doctors and teachers are legally required to report cases of FGM involving girls aged under 18 to the police. Read more rcni.com/FGM-reporting. PMID- 27484529 TI - University of Salford's L1.7m training facilities recreate real hospital environment. AB - The next generation of nurses and midwives will be honing their skills on manikins that can breathe, 'speak', sweat and blink at a L1.7 million training suite at the University of Salford. PMID- 27484530 TI - Raising awareness with Sir Elton John. AB - A sexual health nurse joined Sir Elton John and Prince Harry at a conference in South Africa to raise awareness of HIV/Aids. PMID- 27484531 TI - Length of service proposal to reduce student debt. AB - How much graduate nurses repay their student debt could be linked to length of service in the NHS, a nursing expert has said. PMID- 27484532 TI - 'Weak' research undermines profession. AB - The contribution of nursing is being underestimated because of 'weak and small scale' research, a leading workforce expert has warned. PMID- 27484533 TI - Call to boost peers with nursing background to House of Lords. AB - Increasing the number of nurse peers in the House of Lords would give the profession more political cache, according to a University of Sydney professor of nursing and midwifery. PMID- 27484534 TI - Healthcare workers urged to improve hand hygiene to prevent spread of AMR. AB - Nurses can help to prevent the spread of antimicrobial resistance by improving their hand hygiene, a health professional has said. PMID- 27484535 TI - The lasting legacy of #hellomynameis. AB - Three years ago, while in hospital with a post-operative infection, Kate Granger discussed with her husband the failure of some staff on a ward to introduce themselves to her. PMID- 27484538 TI - Sickle cell disease. AB - Essential facts Sickle cell disease is a group of disorders of red blood cells that is believed to affect up to 15,000 people in the UK. The lifelong condition can have a significant impact on morbidity and mortality. PMID- 27484539 TI - Rise in alcohol tax could cut violence-related A&E visits. AB - A small rise in alcohol duty could cut violence-related emergency department visits by 6,000 a year in England and Wales, say researchers. PMID- 27484540 TI - Exercise as effective as surgery for common knee injury. AB - Supervised exercise therapy should be considered as a treatment option for middle aged patients with a common knee injury, say researchers. PMID- 27484541 TI - Patients with sleep apnoea and resistant hypertension at increased risk of heart disease. AB - People with resistant hypertension are more likely to experience sleep apnoea than those with nonresistant hypertension, increasing the risk of ischaemic heart events and congestive heart failure, new study results suggests. PMID- 27484543 TI - Computer model sheds light on amyloid plaque formation. AB - Researchers from the University of Cambridge's department of chemistry have shown that it may be possible to control the mechanism that leads to the rapid build-up of amyloid plaques - a key hallmark of Alzheimer's disease. PMID- 27484544 TI - Inside the fragile world of eating disorders. AB - 'Take yourself back to the age of 15. What thoughts swirled around your head? Did you worry about how you looked or what your friends and teachers thought of you?' Wendy Clarke, specialist lead for eating disorders at Aneurin Bevan University Health Board in South Wales, believes nurses should be asking themselves these questions if they are to fully empathise, engage with and help young people with eating disorders. PMID- 27484545 TI - Gardening your way to health. AB - A King's Fund report published in May found overwhelming evidence of the beneficial effects of gardening on physical and mental wellbeing. PMID- 27484546 TI - Revalidation is not a test. AB - Much has been written about the steps necessary for nurses and midwives to comply with revalidation. But what does it actually achieve? PMID- 27484547 TI - Organise a learning event and see the benefits. AB - The first step is to make managers aware of your intentions and get them on board. They can advise you about the best time to have the event to ensure a good turnout. If you have decided on a theme, make sure you line up a guest speaker early. Your motto has to be 'fail to prepare, prepare to fail'. PMID- 27484548 TI - Building bridges in an uncertain world. AB - Three months into my new role at the International Council of Nurses (ICN), it is clear that nursing is high on the agenda of big global institutions. PMID- 27484549 TI - What needs to change. AB - Earlier this year we heard how Southern Health NHS Foundation Trust had failed to investigate the deaths of more than 1,000 patients with mental health problems. It was a reminder to me of the importance of my work as a clinical adviser to the Parliamentary and Health Service Ombudsman, the body that makes final decisions on unresolved complaints about the NHS in England. PMID- 27484550 TI - Getting over the bursary blues. AB - The decision to scrap bursaries will discourage people from applying for degree courses. PMID- 27484551 TI - Specialist complex care. AB - I agree with your editorial on how NHS England and the Department of Health (DH) have failed to realise that specialist care for complex diseases requires experienced and knowledgeable support. PMID- 27484554 TI - District nursing is vital. AB - Queen's Nursing Institute chief executive Crystal Oldman has welcomed the RCN congress resolution urging RCN council to lobby for all district nurses to have a specialist practice qualification. This provides the ideal route for future talent and must be supported. PMID- 27484555 TI - Correction. AB - The CPD article Palliative and end of life care for people living with dementia in care homes: part 2 (29 June 2016) wrongly referred to oxycodone as a 'mild' opioid. Oxycodone is a controlled opioid for the management of high levels of pain and care must be taken in its administration. PMID- 27484556 TI - Readers' panel - Should personal use of illegal drugs be decriminalised? AB - Our experts consider a hot topic of the day. PMID- 27484557 TI - Learning can be a joy when others are willing to teach. AB - 'He who is afraid of asking is ashamed of learning,' says a Danish proverb. I get the drift, but I think 'he who is afraid of asking is being taught by the wrong person' is nearer the mark. PMID- 27484559 TI - Headspace - Guided Meditation and Mindfulness Techniques. AB - Mindfulness has been recommended by the National Institute for Health and Care Excellence and the NHS to help mental wellbeing, but can the Headspace app be used by nurses and health professionals in clinical settings? PMID- 27484561 TI - Student life - Twitter - a great medium for learning and debate. AB - Twitter is ideal for nurses and nursing students to start a discussion and debate, share innovative practice and, as lifelong learners, keep up to date with evidence-based care. The social media platform is often the first place new ideas and concepts are aired. Even if you don't tweet, it is likely you know about campaigns that used Twitter to raise awareness, such as the late Kate Granger's #hellomnynameis campaign. Tommy Whitelaw, a keynote speaker at this year's RCN congress in Glasgow, tweets under @TommyNtour to raise awareness of dementia by sharing his mother's story. PMID- 27484562 TI - All patients deserve holistic care. AB - Towards the end of my first year of training, I was on placement on a hospital ward when I heard the alarm bell go off in a bathroom. PMID- 27484563 TI - Learning how to promote effective communication. AB - With the importance attached to freedom of speech, it is easy to take voicing your thoughts for granted. But communication can be a challenge for many people. PMID- 27484564 TI - 'You have to explain the risks and benefits'. AB - Oncology trials nurse Juliah Jonasi became a clinical nurse researcher five years ago, and has not looked back. 'I don't think I would want to do anything else now,' she says. PMID- 27484565 TI - 'I love the variety of the role'. AB - Jason Warriner held senior NHS nursing positions before becoming clinical director at the Terrence Higgins Trust. He was also a UK director of quality and clinical services at Marie Stopes International, and chair of the RCN public health nursing forum. PMID- 27484566 TI - How to submit your revalidation application. AB - Rationale and key points This is the final in a series of eight articles providing information about the Nursing and Midwifery Council revalidation process. This article focuses on submitting a revalidation application to the NMC. " Nurses and midwives must demonstrate that they have: completed 450 hours of practice, or 900 hours if revalidating as both a nurse and midwife; undertaken 35 hours of continuing professional development, 20 hours of which must be participatory; recorded five examples of feedback on their practice; written five reflective accounts; had a reflective discussion with an NMC registrant; and sought confirmation that they have met these requirements. " Nurses and midwives who fail to submit their revalidation application by the stated date will put the renewal of their registration at risk. Reflective activity 'How to' revalidate articles can help to update your practice and provide information about the revalidation process, including how you can submit your revalidation application. Reflect on and write a short account of: 1. The professional accountability associated with declaring that you have met the revalidation requirements. 2. How you could use this article to educate your colleagues. Subscribers can upload their reflective accounts at: rcni.com/portfolio . PMID- 27484567 TI - Assessment and accountability: part 3 - sign-off mentors. AB - Assessment in clinical practice is a complex role undertaken by mentors and practice teachers. This article is the third of three articles about assessment in practice. Part one focused on the importance of assessment and identified assessment methods used in clinical practice, while part two discussed the importance of feedback and managing failing students. This article examines the concepts of responsibility and accountability as well as ethical issues for mentors and practice teachers in relation to the assessment process. The role of the sign-off mentor, the issue of due regard, and ethical principles are discussed. The meaning of competence and partnership working when making assessment decisions are explored. This article relates to the third domain and outcomes of the Nursing and Midwifery Council's Standards to Support Learning and Assessment in Practice on assessment and accountability. PMID- 27484568 TI - Assessment of injury severity in patients with major trauma. AB - Major trauma centres provide specialised care for patients who have experienced serious traumatic injury. This article provides information about major trauma centres and outlines the assessment tools used in this setting. Since patients in major trauma centres will be transferred to other settings, including inpatient wards and primary care, this article is relevant for both nurses working in major trauma centres and in these areas. Traumatic injuries require rapid assessment to ensure the patient receives prompt, adequate and appropriate treatment. A range of assessment tools are available to assist nurses in major trauma centres and emergency care to assess the severity of a patient's injury. The most commonly used tools are triage, Catastrophic Haemorrhage Airway to Exposure assessment, pain assessment and the Glasgow Coma Scale. This article summarises the use of these assessment tools in these settings, and discusses the use of the Injury Severity Score (ISS) to determine the severity of patient injuries. PMID- 27484569 TI - Nursing and Midwifery Council revalidation. AB - What was the nature of the CPD activity and/or practice-related feedback and/or event or experience in your practice? The CPD article discussed the Nursing and Midwifery Council (NMC) revalidation process for nurses and midwives in the UK. It outlined the requirements for revalidation that every nurse and midwife in the UK must meet to remain on the NMC register. PMID- 27484570 TI - 'I could not have survived without Kelly and her team'. AB - With her team of unsung heroes at Sandwell General Hospital in the West Midlands, Kelly carries out sterling work in the aftercare of patients with bowel cancer, rectal cancer and other debilitating aspects of incontinence. PMID- 27484571 TI - Appropriate care for people with learning disabilities. AB - How can nurses meet the healthcare needs of people with learning disabilities in the community? Solutions include addressing communication difficulties and issues of consent, and developing professionals' education. PMID- 27484572 TI - Telehealth brings benefits. AB - A telehealth clinical lead writing in Primary Health Care says that for the NHS to thrive, front line staff and patients must be empowered. New ways of working are needed and the use of technology should be maximised. Telehealth allows nurses to work more efficiently, communicate better with patients and families, and improve health outcomes cost-effectively. The author encourages frontline nurses to implement changes in the work place and suggests NHS Change Day in October as a starting point. The article also notes the importance of social media in opening up opportunities to connect with other nurses. PMID- 27484573 TI - Big picture. AB - 'Higher doses of radiotherapy could result in prostate cancer patients undergoing treatment in half of the time'. PMID- 27484574 TI - Developing a career in nursing research. AB - What is the best way to build a career in nursing research? In Nurse Researcher Michelle Cleary and colleagues provide an overview of the career essentials for nurses at the beginning careers as researchers. They discusses collaborations, research support, grants, supervising students and climbing the research career ladder. PMID- 27484575 TI - Online. AB - 'I recently found myself on a placement with limited learning opportunities, which I found exasperating. Yet it is important to reflect on our experiences, even the bad ones. There is always a lesson to learn, however small'. PMID- 27484576 TI - Post hoc analysis of the glutamics-trial: intravenous glutamate infusion and use of inotropic drugs after cabg. AB - BACKGROUND: Intravenous glutamate reduced the risk of developing severe circulatory failure after isolated coronary artery bypass graft surgery (CABG) for acute coronary syndrome (ACS) in a double-blind randomised clinical trial (GLUTAMICS-ClinicalTrials.gov Identifier: NCT00489827 ). Here our aim was to study if glutamate was associated with reduced the use of inotropes. METHODS: Post-hoc analysis of 824 patients undergoing isolated CABG for ACS in the GLUTAMICS-trial. ICU-records were retrospectively scrutinised including hourly registration of inotropic drug infusion, dosage and total duration during the operation and postoperatively. RESULTS: ICU-records were found for 171 out of 177 patients who received inotropes perioperatively. Only one fourth of the patients treated with inotropes fulfilled study criteria for postoperative heart failure at weaning from cardiopulmonary bypass (CPB) or later in the ICU. Inotropes were mainly given preemptively to facilitate weaning from CPB or to treat postoperative circulatory instability (bleeding, hypovolaemia). Except for a significantly lower use of epinephrine there were only trends towards lower need of other inotropes overall in the glutamate group. In patients treated with inotropes (glutamate n = 17; placebo n = 13) who fulfilled study criteria for left ventricular failure at weaning from CPB the average duration of inotropic treatment (34 +/- 20 v 80 +/- 77 h; p = 0.014) and the number of inotropes used (1.35 +/- 0.6 v 1.85 +/- 0.7; p = 0.047) were lower in the glutamate group. CONCLUSIONS: Intravenous glutamate was associated with a minor influence on inotrope use overall in patients undergoing CABG for ACS whereas a considerable and significant reduction was observed in patients with heart failure at weaning from CPB. PMID- 27484577 TI - Cryopreservation of Peruvian Paso horse spermatozoa: dimethylacetamide preserved an optimal sperm function compared to dimethyl sulfoxide, ethylene glycol and glycerol. AB - The objective was to evaluate the effect of different cryoprotectant agents in the cryopreservation of Peruvian Paso horse semen. Twenty semen samples were collected from five Peruvian Paso horse stallions. Each sample was divided into 12 parts to form the groups: dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), ethylene glycol (EG) and glycerol (GLY), at 3%, 4% and 5%. Samples were frozen using a rate-controlled freezer. Sperm parameters evaluated were motility and viability/acrosomal status. After thawing, progressive motility in DMA group was higher (p < .05) than in DMSO, EG and GLY groups. Similarly, viable acrosome intact spermatozoa were higher (p < .05) using DMA in comparison with DMSO. No differences were found when comparing concentrations for any of the cryoprotectant agents. In conclusion, DMA seems to be a good cryoprotectant agent for the cryopreservation of Peruvian Paso horse stallion semen. PMID- 27484578 TI - Diverse modes of NMDA receptor positive allosteric modulation: Mechanisms and consequences. AB - NMDA Receptors (NMDARs) play key roles in synaptic physiology and NMDAR hypofunction has been implicated in various neurological conditions. In recent years an increasing number of positive allosteric modulators (PAMs) of NMDARs have been discovered and characterized. These diverse PAM classes vary not only in their binding sites and GluN2 subunit selectivity profiles, but also in the nature of their impacts on channel function. Major differences exist in the degree of slowing of channel deactivation and shifting of apparent agonist affinity between different classes of PAMs. Here we review the diverse modes of potentiation by the currently known classes of NMDAR PAMs and discuss the potential consequences of different types of potentiation in terms of desirable and undesirable effects on brain function. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'. PMID- 27484579 TI - Preferential Nucleation during Polymorphic Transformations. AB - Polymorphism is the ability of a solid material to exist in more than one phase or crystal structure. Polymorphism may occur in metals, alloys, ceramics, minerals, polymers, and pharmaceutical substances. Unresolved are the conditions for preferential nucleation during polymorphic transformations in which structural relationships or special crystallographic orientation relationships (OR's) form between the nucleus and surrounding matrix grains. We measured in situ and simultaneously the nucleation rates of grains that have zero, one, two, three and four special OR's with the surrounding parent grains. These experiments show a trend in which the activation energy for nucleation becomes smaller - and therefore nucleation more probable - with increasing number of special OR's. These insights contribute to steering the processing of polymorphic materials with tailored properties, since preferential nucleation affects which crystal structure forms, the average grain size and texture of the material, and thereby to a large extent - the final properties of the material. PMID- 27484580 TI - Race and General Strain Theory: Examining the Impact of Racial Discrimination and Fear on Adolescent Marijuana and Alcohol Use. AB - BACKGROUND: To extend our knowledge of general strain theory by exploring how under-researched strains such as racial discrimination, witnessing violence, physical victimization and verbal bullying affect adolescent substance use while considering differences according to racial identification. METHODS: This research utilized data from wave three of the Project on Human Development in Chicago Neighborhoods. Statistical analysis was primarily composed of path analysis using full information maximum likelihood parameter estimates. RESULTS: The findings reveal that reporting fear decreased alcohol and marijuana use among adolescents and that racial discrimination, witnessing violence, and being the victim of verbal bullying indirectly affected marijuana and alcohol use through fear. No support was found for depression as a mediating variable. Physical victimization was the only social strain that had a direct positive effect on marijuana and alcohol use but only for Hispanics and African Americans. CONCLUSIONS: The results suggest that strains may be operating differently and there may be differential levels of exposure to certain strains according to one's race. PMID- 27484582 TI - Elucidating the effects of pH shift on IgG1 monoclonal antibody acidic charge variant levels in Chinese hamster ovary cell cultures. AB - Charge variants, especially acidic charge variants, in recombinant monoclonal antibodies are critical quality attributes, which can affect antibodies' properties in vitro and in vivo. Meanwhile, charge variants are cumulative effects of various post-translational modifications and chemical degradations on antibody. In this work, to investigate the effect of lowering culture pH in the stationary phase on acidic charge variant contents in fed-batch cultures and its mechanism, cell culture experiments in 2-L bioreactors were firstly performed to explore the changes in the charge distribution under the pH downshift condition using weak cation exchange chromatography. It is found that acidic charge variant contents were significantly decreased by pH downshift. Then, to reveal the mechanism by which the content of acidic charge variants is reduced under pH downshift condition, the variation of post-translational modifications and chemical degradations under the pH downshift condition was explored. Meanwhile, the structure of the acidic charge variants was characterized. Several analysis experiments including size exclusion chromatography, capillary electrophoresis sodium dodecyl sulfate under non-reducing conditions, tryptic peptide map, and reduced antibody mass were applied in this study. The results show that the mechanism by which the content of acidic charge variants is reduced is that the contents of disulfide bond reduction, galactosylation, and asparagine deamination of the HC-N388 in the Fc domain were reduced by pH downshift. PMID- 27484581 TI - Solar-Driven H2 O2 Generation From H2 O and O2 Using Earth-Abundant Mixed-Metal Oxide@Carbon Nitride Photocatalysts. AB - Light-driven generation of H2 O2 only from water and molecular oxygen could be an ideal pathway for clean production of solar fuels. In this work, a mixed metal oxide/graphitic-C3 N4 (MMO@C3 N4 ) composite was synthesized as a dual-functional photocatalyst for both water oxidation and oxygen reduction to generate H2 O2 . The MMO was derived from a NiFe-layered double hydroxide (LDH) precursor for obtaining a high dispersion of metal oxides on the surface of the C3 N4 matrix. The C3 N4 is in the graphitic phase and the main crystalline phase in MMO is cubic NiO. The XPS analyses revealed the doping of Fe(3+) in the dominant NiO phase and the existence of surface defects in the C3 N4 matrix. The formation and decomposition kinetics of H2 O2 on the MMO@C3 N4 and the control samples, including bare MMO, C3 N4 matrix, Ni- or Fe-loaded C3 N4 and a simple mixture of MMO and C3 N4 , were investigated. The MMO@C3 N4 composite produced 63 MUmol L( 1) of H2 O2 in 90 min in acidic solution (pH 3) and exhibited a significantly higher rate of production for H2 O2 relative to the control samples. The positive shift of the valence band in the composite and the enhanced water oxidation catalysis by incorporating the MMO improved the light-induced hole collection relative to the bare C3 N4 and resulted in the enhanced H2 O2 formation. The positively shifted conduction band in the composite also improved the selectivity of the two-electron reduction of molecular oxygen to H2 O2 . PMID- 27484583 TI - Chaperone-assisted expression of KfiC glucuronyltransferase from Escherichia coli K5 leads to heparosan production in Escherichia coli BL21 in absence of the stabilisator KfiB. AB - The heparosan synthase of Escherichia coli K5 is composed of the glycosyltransferases KfiA and KfiC which synthesize the polysaccharide heparosan (N-acetylheparosan). A third protein, KfiB, is required to stabilize the KfiAC complex in the bacteria and to transport this complex to the inner membrane where the initiation of polymerization occurs. In this report, we fused KfiC with the E. coli trigger factor (TF) to stabilize KfiC, thus activating the enzyme in the absence of KfiB. Different recombinant plasmids were constructed to compare the impact of the presence or absence of KfiB and the presence of the trigger factor as a fusion protein. Several E. coli BL21-derived strains were transformed with recombinant plasmids and cultivated in fed-batch conditions on minimal medium. The bTCA strain overexpressing fused TF-KfiC together with KfiA and KfiD, but lacking KfiB produced 1.5 g/L of total heparosan after 24 h of fed-batch cultivation. This heparosan was essentially intracellular early in the culture, providing evidence that KfiB primarily plays a role in the exportation process. However, over time, heparosan became mostly extracellular, likely due to passive diffusion or partial cell disruption upon product accumulation. PMID- 27484584 TI - High Mobility Group A proteins in esophageal carcinomas. AB - We have recently shown that HMGA2 is overexpressed in esophageal squamous cell carcinoma (ESCC) and its detection allows to discriminate between cancer and normal surrounding tissue proposing HMGA2 as a novel diagnostic marker. Interestingly, esophageal adenocarcinoma shows an opposite behavior with the overexpression of HMGA1 but not HMGA2. Moreover, we show that the suppression of HMGA2 in 2 ESCC cell lines reduces the malignant phenotype. Then, this paper highlights a differential induction of the HMGA proteins, depending on the cancer histological type, and reinforces the perspective of an innovative esophageal cancer therapy based on the suppression of the HMGA protein function and/or expression. PMID- 27484585 TI - Factors that can alter the melatonin circadian rhythm. PMID- 27484586 TI - The effect of PAMAM dendrimer concentration, generation size and surface functional group on the aqueous solubility of candesartan cilexetil. AB - This article investigates the aqueous solubility of the poorly soluble drug candesartan cilexetil (CC) in the presence of poly(amidoamine) (PAMAM) dendrimers. The effect of variables such as concentration, generation size (G2 G4), and surface groups (NH2, COOH and TRIS) of PAMAMs on the aqueous solubility of CC was studied. A two-factor factorial (3 * 3) ANOVA design was used to study the effect of generation size and surface functional group of the PAMAMs. The results showed that the aqueous solubility of CC in the presence of carboxyl and TRIS-terminated PAMAMs was higher than those of amine-terminated PAMAMs, and the effect of surface functional group of the PAMAMs on the aqueous solubility of CC was dependent on the generation size (p < 0.05). The sequence of the observed solubility fold enhancement due to PAMAMs was G4.COOH (8378)>G3.COOH (3456)>G4.TRIS (2362)>G2.COOH (1013)>G3.TRIS (749)>G2.TRIS (293)>G4.NH2 (91)>G3.NH2 (50)>G2.NH2 (37). The CC-PAMAM dendrimer inclusion complexes were characterized by UV-Vis, attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and differential thermal analysis (DTA) techniques. Regarding the results of these techniques, improvement in the solubility of CC is expected primarily through the intermolecular hydrogen bonding between the drug and internal tertiary and surface functional groups of the studied PAMAMs. PMID- 27484587 TI - Optimization of Reference Genes for Normalization of Reverse Transcription Quantitative Real-Time Polymerase Chain Reaction Results in Senescence Study of Mesenchymal Stem Cells. AB - Recently, it has been suggested that cellular senescence is associated with stem cell exhaustion, which reduces the regenerative potential of tissues and contributes to aging and age-related diseases. Mesenchymal stem cells (MSCs) attract a large amount of attention in stem cell research and regeneration medicine because they possess multiple advantages and senescent MSCs could be one of the most useful stem cell models in aging studies. It is important to quantitatively evaluate senescence markers to both identify and study the mechanisms involved in MSC senescence. Reverse transcription quantitative real time polymerase chain reaction (RT-qPCR) is currently the most widely used tool to quantify the mRNA levels of markers. However, no report has demonstrated the optimal reference genes that should be used to normalize RT-qPCR in senescence studies of MSCs. In this study, we compared 16 commonly used reference genes (GAPDH, ACTB, RPL13A, TBP, B2M, GUSB, RPLPO, YWHAZ, RPS18, EEF1A1, ATP5F1, HPRT1, PGK1, TFRC, UBC, and PPIA) in proliferating or replicative-senescent human adipose-derived MSCs (hAD-MSCs) that were isolated from seven healthy donors aged 29-59 years old. Three algorithms (geNorm, NormFinder, and BestKeeper) were used to determine the most optimal reference gene. The results showed that PPIA exhibited the most stable expression during senescence, while the widely used ACTB exhibited the lowest stability. We also confirmed that different reference genes lead to different evaluations of senescence markers. Our work ensures that results obtained from senescence studies of hAD-MSCs will be appropriately evaluated in both basic research and clinical trials. PMID- 27484588 TI - X-chromosome gene dosage as a determinant of impaired pre and postnatal growth and adult height in Turner syndrome. PMID- 27484589 TI - Astaxanthin blocks preeclampsia progression by suppressing oxidative stress and inflammation. AB - To investigate the antioxidative effect of astaxanthin on Nomega-nitro-L-arginine methyl ester (L-NAME)-induced preeclamptic rats. Cell survival, the level of reactive oxygen species (ROS) and the changes in mitochondrial membrane potential (MMP) were examined in astaxanthin and H2O2-treated human umbilical vein endothelial cells (HUVECs). The preeclamptic Sprague-Dawley (SD) rat model was established by injection of L-NAME and treatment with astaxanthin. The activities of malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide synthase (NOS) in serum were analyzed. Pathological changes were examined by hematoxylin and eosin (H&E) staining. The expression of nuclear factor (NF)-kappaB, Rho associated protein kinase II (ROCK II), heme oxygenase-1 (HO-1) and caspase 3 in preeclamptic placentas were examined by immunohistochemistry. Astaxanthin significantly reduced H2O2-induced HUVEC cell death, decreased ROS and increased MMP. Astaxanthin significantly reduced blood pressure and the content of MDA, but significantly increased the activity of SOD in preeclamptic rats. The urinary protein and the level of NO and NOS were also decreased. H&E staining revealed that the thickness of the basilar membrane was increased, while the content of trophoblast cells and spiral arteries were reduced following astaxanthin treatment. Immunohistochemistry results showed that the expression of NF-kappaB, ROCK II and caspase 3 in preeclamptic placentas was significantly decreased after astaxanthin treatment, while HO-1 expression was increased. In conclusion, astaxanthin inhibited H2O2-induced oxidative stress in HUVECs. Astaxanthin treatment significantly improved L-NAME-induced preeclamptic symptoms and reduced the oxidative stress and inflammatory damages in preeclamptic placentas. Astaxanthin treatment may effectively prevent and treat preeclampsia. PMID- 27484591 TI - Regiodivergent Ring-Opening Reaction of Trichloromethylcyclopropane Carboxylates. AB - Reagent-controlled regiodivergent ring-opening reactions of trichloromethylcyclopropane carboxylates have been developed. The regioselectivity of bond cleavage is completely controlled by the proper choice of silver salts; the treatment of trichloromethylcyclopropane with AgBF4 led to C2-C3 bond cleavage and fluorination to afford fluorinated beta,gamma-unsaturated ester with high stereoselectivity, while the reaction with AgOAc in THF gave a gamma,delta-unsaturated ester through the reductive cleavage of the C1-C2 bond. PMID- 27484590 TI - Eating, feeding, and feeling: emotional responsiveness mediates longitudinal associations between maternal binge eating, feeding practices, and child weight. AB - BACKGROUND: Although it is known that maternal disordered eating is related to restrictive feeding practices, there is little research exploring mechanisms for this association or its effects on other feeding practices. The purpose of this study was to assess whether maternal emotion responses mediate the association between maternal binge eating (BE) and child feeding practices, in order to identify potential risk factors for feeding practices that influence child weight. METHODS: This longitudinal observational study included (n = 260) mothers and children from the STRONG Kids Panel Survey. At Wave 1, children were an average of 37 months old (SD = 6.9), and at Wave 2 children were an average of 57 months old (SD = 8.3). Mothers self-reported their frequency of binge eating behavior (Wave 1), responses to children's negative emotions (Wave 1), feeding practices (Wave 1 and Wave 2), and child height and weight were measured at both time points. Using bias-corrected bootstrapping procedures, we tested the hypothesis that longitudinal associations between maternal BE and nonresponsive parent feeding practices would be mediated by parents' unsupportive responses to children's negative emotion. We also tested a serial mediation model positing that maternal BE predicts child body mass index (BMI) percentile change 18-24 months later, indirectly through unsupportive responses to negative emotion and nonresponsive feeding practices. RESULTS: Maternal BE predicted use of more nonresponsive feeding practices (e.g. Emotion Regulation, Restriction for Health, Pressure to Eat, and Food as Reward), indirectly through more Distress responses to children's negative emotions. In the serial mediation model, maternal BE was associated with greater use of Distress responses, which indirectly predicted higher child BMI percentile through Food as Reward feeding practices. CONCLUSIONS: These results suggest that maternal eating and emotion responsiveness are important for understanding the interpersonal context of feeding behaviors, and child weight outcomes. Distress responses may serve as a risk factor for use of unhealthful feeding practices among mothers with BE and these responses may increase children's risk for weight gain. TRIAL REGISTRATION: This study used an observational prospective design. Therefore, it has not been registered as a clinical intervention trial. PMID- 27484592 TI - Onco-Golgi: The Missed Target. AB - The Golgi apparatus or complex, a highly dynamic organelle, is a factory in which proteins are processed and sorted for transport to various target organelles.(1) It was first discovered by Camillo Golgi in 1898 and was described as an intracellular reticular apparatus stained by the 'black reaction' in neuronal cells.(1,2) Despite of several research works, this complex remains one of the most inexplicable structures of the cytoplasmic organelles. PMID- 27484593 TI - Prophylactic and Therapeutic Antibiotic Patterns of Lebanese Dentists for the Management of Dentoalveolar Abscesses. AB - INTRODUCTION: General dentists issue approximately 10% of antibiotic prescriptions across the global medical community consummation. The use of antibiotics for the management of dentoalveolar infections should be considered only in the presence of an increased risk of a systemic involvement or to prevent metastatic infections. This study aimed to investigate the prophylactic and therapeutic antibiotic prescription patterns of Lebanese dentists for the management of dentoalveolar abscesses. The aim was to evaluate the influence of the patients' medical condition and clinical signs data on the patterns of antibiotics prescription. MATERIALS AND METHODS: Only patients with a dentoalveolar abscess were included in the study. Age, medical history, reason for consultation, clinical signs and symptoms, diagnosis, type of local treatment, and type of antibiotherapy were collected for each patient attending dental clinics in Beirut. The data were analyzed with chi-square test and multivariate regression. RESULTS: Out of the 563 initial patients, 127 were selected for the study and received a local treatment. The patient's medical condition and age did not affect the decision to prescribe antibiotics 36.2% patients with pain and 11.8% patients with swelling were prescribed antibiotics. Pain and swelling contributed to a higher level of antibiotic prescription compared to other signs and symptoms. Antibiotics were prescribed inappropriately to 51.76 and 38.10% among patients with an acute or chronic dentoalveolar abscess respectively. The main prescribed antibiotic was amoxicillin. CONCLUSION: This study showed that dentists often did not follow the current prophylactic and therapeutic antibiotic prescription guidelines. CLINICAL SIGNIFICANCE: Antibiotics prescriptions in dentistry will be more pertinent, leading to a decrease in inadequacy of prescriptions, microbial resistance, and the development of multiresistant germs against antibiotics. PMID- 27484594 TI - Assessment of Dental Arch Changes and Buccal Bone Thickness in Patients treated with Self-ligating Brackets. AB - AIMS: To evaluate changes in transverse dimensions of upper arch and thickness of the buccal bone plate in patients undergoing orthodontic treatment during the leveling phase. MATERIALS AND METHODS: Sixteen patients aged between 11 and 30 years, presenting with class I and II malocclusion, with minimum of 2 mm crowding treated without extraction, were divided into two groups: GI (n = 8), self ligating brackets (Easyclip Aditek), and GII (n = 8), conventional preadjusted brackets (3M Unitek). The intercanines, interpremolar, and intermolar widths were measured in dental casts using a digital caliper, before (T1) and after 6 months of treatment (T2). Measurements of the thickness of the bone plate were performed by using cone-beam computed tomography (CBCT) scans and Dolphin three-dimensional program. Paired and nonpaired t tests were applied to analyze the results in and between the groups for the changes in the transversal arch dimensions and buccal bone thickness. RESULTS: In all statistical tests, the significance level was set at 5%. A nonsignificant increase in transverse dimensions and a slight reduction on thickness of the buccal bone plate were observed in both groups. CONCLUSION: The dimensional changes of transverse and thickness of the bone plate during the initial phase of treatment were similar, regardless of the bracket design. CLINICAL SIGNIFICANCE: It should be noted that the bracket design does not influence the treatment course regarding transversal dimensions and buccal bone thickness. PMID- 27484595 TI - Evaluation of Gingival Health Status among 6- and 12-years-old Children in Dhamar City, Yemen: A Cross-sectional Study. AB - INTRODUCTION: Epidemiological data on gingivitis in children are important for understanding the natural course of the disease, identifying its risk factors, and predicting its time trends. The objective of this study was to evaluate the prevalence and severity of gingivitis among 6- and 12-year-old school children in Dhamar city, Yemen. MATERIALS AND METHODS: A total of 663 children (310 children of 6 years old and 353 children of 12 years old) were examined from 10 public primary schools. Gingival health status was assessed using the plaque index (PI), calculus index (CI), and gingival index (GI) on the six Ramfjord teeth. The latter index was used to categorize gingivitis severity at the subject level. Data were analyzed using independent f-test, chi-squared test, and Spearman's correlation. A p-value of < 0.05 was considered significant. RESULTS: Both age groups had high mean of PI and GI with nonsignificant difference. The 12-year-old children had calculus deposits much higher than the 6-year-old group with significant difference. There was a significant correlation between age and gender of the whole sample with CI [(odds ratio, OR = 1.65, p = 0.003) and (OR = 0.74, p = 0.05) respectively]. Most of the participants presented with gingival inflammation, which was less in 12-year-old females. CONCLUSION: Poor oral hygiene and mild gingivitis were highly prevalent among Yemeni school children. CLINICAL SIGNIFICANCE: The early assessment and intervention of gingivitis and periodontitis will minimize the chance of tooth loss. It has been reported that marginal gingivitis begins early in childhood, increases in prevalence and severity at puberty, and then subsides slightly to the remainder of the second decade of life. PMID- 27484596 TI - An Evaluation of GuttaFlow2 in Filling Artificial Internal Resorption Cavities: An in vitro Study. AB - INTRODUCTION: Obturation of root canal with internal resorption represents a major challenge in Endodontics. In spite of that, usual obturation techniques are often employed without considering the best technique to solve this problem. The goal of this study was to investigate the ability of GuttaFlow2 in filling artificial internal resorption cavities. MATERIALS AND METHODS: The study sample included 36 human upper central incisors that were prepared using Protaper system (F4). Internal resorption cavities were prepared by cutting each tooth at 7 mm from the apex and preparing hemispherical cavities on both the sides and then re attaching them. The sample was randomly separated into three groups (n = 12 in each group). In the first group, thermal injection technique (Obtura II) was employed and served as the control group. In the second group, injection of cold free-flow obturation technique with a master cone (GF2-C) was employed, whereas in the third group injection of cold free-flow obturation without a master cone (GF2) was followed. The teeth were re-cut at the same level as before and examined under a stereomicroscope. Subsequently, the captured images were transferred to AutoCAD program to measure the percentage of total filling "TF," gutta-percha "G," sealer "S," and voids "V" out of the total surface of the cross sections. RESULTS: All materials showed high filling properties in terms of "total filling," ranging from 99.17% (for Obtura II) to 99.72% (for GF2-C). Regarding gutta-percha percentages of filling, they ranged from 83.15 to 83.93%, whereas those for the sealer ranged from 5.71 to 15.24%. GuttaFlow2 group with a master cone appeared to give the best results despite the insignificant differences among the three groups. CONCLUSION: The GuttaFlow2 with a master cone technique seemed to be a promising filling material and gave results similar to those observed with Obtura II. It is recommended for use to obturate internal resorption cavities in clinical practice due to its good adaptability to root canal walls, ease of handling, and application. CLINICAL SIGNIFICANCE: Internal resorption defects can be successfully filled with GuttaFlow2 material when supplemented with a master cone, and the results are comparable with those obtained with the Obtura II technique. PMID- 27484597 TI - Assessment of the Influence of Meal Type on Fluoride Absorption due to Ingestion of professionally Applied Gels. AB - AIMS: The aim of this study is to assess the influence of eating, prior to application of professionally used gels, on the rate of fluoride absorption due to the ingestion of 1.23% acidulated phosphate fluoride (APF). MATERIALS AND METHODS: After fasting for 12 hours, 16 adult volunteers (> 65 kg) ingested two types of meal: Breakfast (n = 8) and Lunch (n = 8). Accidental ingestion of fluoride gel used in molding trays was simulated (12,300 ppm; 61.5 mg F; pH = 4.65) 15 minutes after eating. After ingestion of the fluoride solution, 3 mL of venous blood were collected at the following times: Zero (before ingestion) and 15, 30, 45 minutes, 1, 2, and 3 hours. Fluoride concentrations in blood plasma were determined using an ion selective electrode. RESULTS: With the exception of time 0 (p > 0.05), the average blood plasma concentration of the breakfast group (BG) (0.34 +/- 0.04 mg/L) was higher than that of the lunch group (LG) (0.24 +/- 0.03 mg/L), with the moment of peak concentration being 2 hours after ingestion for both groups (BG = 0.4 mg/L; LG = 0.28 mg/L). CONCLUSION: Results reinforce the idea that eating before undergoing professional application of fluoride is a factor of extreme importance regarding its safety, and that the time following a patient's heaviest meal should be the time of choice for planning clinical care. CLINICAL SIGNIFICANCE: Our results should be considered when planning collective action that involves the application of the gel on children in a school environment, thus ensuring the procedure's safety. PMID- 27484598 TI - In vitro Analysis of Cytotoxicity of Temporary Resilient Relining Materials. AB - AIMS: The aim of this study is to evaluate the in vitro response of human gingival fibroblasts in primary cultures to two materials for temporary relining of dentures: Temporary Soft (TDV, Brazil) and Trusoft (Bosworth, USA) for 24 hours, 7 and 30 days by using a multi-parametric analysis. MATERIALS AND METHODS: Each material sample (TDV, TS, Polystyrene, Latex) was prepared and incubated in a culture medium for 1, 7, and 30 days at 37 degrees C. Human gingival fibroblasts were exposed to the extracts and cell viability was evaluated by a multi-parametric assay, which allowed sequential analysis of mitochondrial activity (XTT), membrane integrity [neutral red (NR)], and cell density [crystal violet dye exclusion (CVDE)] in the same cells. Analysis of variance (ANOVA) was used to test the interactions of the three sources of variation (material, test method, and time) with the proportions of viable cells for each relining material. RESULTS: Both evaluated materials (TDV and TS) had low cytotoxic effects during 1, 7, and 30 days after manipulation of the material, as assessed by all three methods used. A statistical difference was found when comparing the negative control group (latex fragments) with the other groups, which showed high toxicity and low percentage of cell viability in all tests used. There was no significant difference among other materials (p > 0.05). CONCLUSION: Low cytotoxicity levels were detected by representatives of the major groups of temporary prosthetic relining materials, as evaluated by multiple cellular viability parameters in human fibroblasts. CLINICAL SIGNIFICANCE: There are various soft materials on the market for relining prostheses; however, the effects of these materials on tissues need to be clarified to avoid problems for patients. PMID- 27484599 TI - Functional Evaluation of the Behavior of Masticatory Muscles in Zygomaticomaxillary Complex Fracture: A Prospective Study. AB - AIMS: The purpose of this study is to functionally evaluate the behavior of the masticatory muscles (masseter and temporalis) following zygomaticomaxillary complex (ZMC) fractures by assessing bite force, electromyography (EMG), and mandibular movements. MATERIALS AND METHODS: Group I consisted of 20 patients with unilateral ZMC fractures who were treated surgically with one-, two-, or three-point fixations at the frontozygomatic, infraorbital, or zygomaticomaxillary buttress region as per clinical and radiological assessments. Group II control group included 20 normal patients. The muscle activity was functionally evaluated before and after the surgery for a period of 6 months. The evaluation consisted of bite force measurement, EMG analysis of masseter and temporalis muscles, and measurements of mandibular movements. RESULTS: There was an increase in bite force and EMG activity throughout the evaluated postoperative period, but at the end of 6 months, the values were still below the control levels for majority of the patients. Maximum mouth opening increased considerably after the surgery. CONCLUSION: According to bite force and EMG, the masticatory musculature returned to near normal levels by the 3rd month after the surgery. CLINICAL SIGNIFICANCE: Management of fractures of the zygoma by open reduction and fixation raises the question of the location of fixation points owing to the action of masseter and temporalis on the ZMC. This study supports the current clinical concept of minimized fixation in treating ZMC fractures. PMID- 27484600 TI - Assessment of Patients Referred to Specialty Dental Hospitals for Dental Implant Procedure: A Retrospective Cohort Analysis. AB - INTRODUCTION: One of the most common and effective ways of replacing missing teeth is by dental implants. Both quality and quantity of bone along with the area of implant placement govern the prognosis of the implant procedure. Certain risk factors predispose the implant treatment to high failure rate. Hence, we assessed the implant patients who were referred from private practitioners to the specialty hospitals from 2010 to 2014. MATERIALS AND METHODS: All the patients being referred from private clinics to the specialty dental hospital for the purpose of prosthetic rehabilitation by dental implants from June 2010 to July 2014 were included in the present study. Skilled oral and maxillofacial surgeons were appointed for performing the implant surgical procedures. Prosthetic rehabilitation was done after 6 to 8 weeks and after 10 to 14 weeks in implant cases without and with bone augmentation procedures respectively. Distribution of dental implants based on the indications, location, dimension of augmentation procedure, and complication of implants was analyzed and assessed for the level of significance. RESULTS: Of the patients, 712 were females, while the remaining were males. Most of the patients were in the age group of 50 to 59 years. As compared with completely edentulous patients, most of the patients required rehabilitation by a single implant. Maximum dental implants were placed in maxillary premolar region and mandibular first molar region. Over 1,000 cases in this study required rehabilitation by augmentation procedure. CONCLUSION: Partially edentulous patients are most commonly referred to specialized dental hospitals for prosthetic rehabilitation by dental implants, mostly with the purpose of implant placement. Failure rate can be minimized by following strict patient selection protocols along with following a standard surgical criterion. CLINICAL SIGNIFICANCE: Following standard surgical protocols and strict treatment planning, prognosis of the dental implant procedures can be improved to a greater extent, thereby increasing its clinical success rate. PMID- 27484601 TI - Assessment of Oral Status in Pediatric Patients with Special Health Care Needs receiving Dental Rehabilitation Procedures under General Anesthesia: A Retrospective Analysis. AB - INTRODUCTION: Dental problems serve as additional burden on the children with special health care needs (CSHCN) because of additional hospitalization pressure, they face for the treatment of various serious medical problems. These patients have higher incidence of dental caries due to increased quantity of sugar involved in the drug therapies and lower salivary flow in the oral cavity. Such patients are difficult to treat with local anesthesia or inhaled sedatives. Single-sitting dental treatment is possible in these patients with general anesthesia. Therefore, we conducted this retrospective analysis of oral health status of CSHCN receiving various dental treatments in a given population. MATERIALS AND METHODS: A total of 200 CSHCN of age 14 years or less reporting in the pediatric wing of the general hospital from 2005 to 2014 that underwent comprehensive dental treatment under general anesthesia were included in the study. Patients with history of any additional systemic illness, any malignancy, any known drug allergy, or previous history of any dental treatment were excluded from the study. Complete mouth rehabilitation was done in these patients under general anesthesia following standard protocols. Data regarding the patient's disability, type, duration, and severity of disability was collected and analyzed. All the results were analyzed by Statistical Package for the Social Sciences (SPSS) software. Chi-square test, Student's t-test, and one-way analysis of variance were used to assess the level of significance. RESULTS: Statistically significant results were obtained while analyzing the subject's decayed missing filled/decayed extracted filled teeth indices divided based on age. Significant difference was observed only in cases where patients underwent complete crown placement even when divided based on type of disability. While analyzing the prevalence, statistically significant results were observed in patients when divided based on their age. CONCLUSION: In CSHCN, dental pathologies and caries indices are increased regardless of the type or extent of disability. CLINICAL SIGNIFICANCE: Children with special health care needs should be given special oral health care, and regular dental checkup should be conducted as they are more prone to have dental problems. PMID- 27484602 TI - Comparative Evaluation of C-reactive Proteins in Pregnant Women with and without Periodontal Pathologies: A Prospective Cohort Analysis. AB - INTRODUCTION: Inflammation of tooth supporting structures is referred to as periodontitis. C-reactive proteins (CRP) levels are usually increased in case of chronic inflammatory process like periodontitis. Association of CRP with pregnancy has been observed in the past, which includes most commonly preterm delivery, preeclampsia, etc. Therefore, it can be hypothesized that CRP may act as a link between periodontitis and adverse pregnancy outcomes. Hence, we aim to evaluate the plasma CRP levels in pregnant women with and without periodontal pathologies. MATERIALS AND METHODS: The study included 210 pregnant women who reported to the hospital with periodontal problems and for routine checkups. All the patients were divided into three groups based on the presence and absence of periodontal pathologies. Russell's Periodontal Index Score was used for the evaluation of periodontal status of the subjects. RESULTS: While comparing the mean CRP levels in all the three study groups, statistically significant results were obtained. Statistically significant results were obtained while comparing the mean CRP levels in group C patients before treatment and after treatment therapy. The CRP levels were estimated by taking blood samples. Paired t-test and one-way analysis of variance was used to assess the correlation between the two parameters. CONCLUSION: Casual association might exist between the CRP levels and periodontal diseases in pregnant women and the CRP levels may also get elevated in pregnant women. PMID- 27484603 TI - Nonsurgical Periodontal Therapy decreases the Severity of Rheumatoid Arthritis: A Case-control Study. AB - INTRODUCTION: Rheumatoid arthritis (RA) and periodontitis are common chronic inflammatory conditions. Several studies suggested a relationship between RA and periodontitis. Recent studies have shown a beneficial effect of periodontal treatment on the severity of active RA. So the aim of this study was to examine the effect of nonsurgical periodontal therapy on the clinical parameters of RA. MATERIALS AND METHODS: A total of 60 subjects with moderate-to-severe chronic generalized periodontitis and active RA in the age range 18 to 65 were selected for the study. They were divided into two groups. Group A (control group) consisted of 30 subjects with chronic generalized periodontitis and RA, and group B of 30 subjects with chronic generalized peri-odontitis and RA and they received nonsurgical periodontal therapy (scaling, root planning, and oral hygiene instructions). Evaluation of clinical observations of Simplified Oral Hygiene Index (OHI-S), gingival index (GI), bleeding on probing (BOP), probing pocket depth (PPD), clinical attachment level (CAL), number of swollen joints (SJ), number of tender joints (TJ), values of erythrocyte sedimentation rate (ESR), visual analogue scale (VAS) for patient's global assessment, 3 months disease activity score (DAS) index, and C-reactive protein (CRP) was done at baseline and 3 months. Statistical evaluation of clinical observations was carried out. RESULTS: Group B subjects who received nonsurgical periodon-tal therapy showed statistically significant improvement in all periodontal and RA parameters at 3 months, compared with group A who did not receive periodontal therapy. CONCLUSION: It can be concluded from the result that nonsurgical periodontal therapy may contribute to reduction in severity and symptoms of RA. CLINICAL SIGNIFICANCE: Rheumatoid arthritis patients should be evaluated for periodontitis and treated for the same in order to reduce its severity level. PMID- 27484604 TI - Evaluation of Spontaneous Bone Regeneration after Enucleation of Large Cysts of the Jaws using Radiographic Computed Software. AB - INTRODUCTION: Spontaneous regeneration of bone is commonly seen in the small surgical defects caused by enucleation of cysts. However, in case of large surgical defects caused by the enucleation, spontaneous regeneration of bone is a rare phenomenon and it depends on factors, such as age of the patient, intact periosteum, and proper stabilization. MATERIALS AND METHODS: The study included 16 patients, who reported to the department of oral and maxillofacial surgery with the complaint of pain and swelling in the jaws diagnosed as cyst. The sample included equal numbers of male and female subjects aged between 15 and 40 years. Panoramic radiographs were taken pre- and postoperatively on day 2 of the enucleation. The dimensions of the cyst were evaluated on the radiograph according to the proforma. Subsequent radiographs were taken at regular intervals of 1.5, 3, and 6 months using standard parameters and were analyzed using MCIDTM analysis software of imaging research. RESULTS: Mean reduction was seen in up to 39 and 60% in the cystic cavity size and increase in the mean density up to 59 and 90.2% at 3 and 6 months intervals respectively. CONCLUSION: Spontaneous bone regeneration was seen even after primary closure of the large cystic defect without the need for placement of foreign substances or grafts and it also eliminated the complications resulting from placement of foreign substance. Further studies are required in a larger sample with longer follow-up durations to confirm the outcome of the present work for the benefit of patients. CLINICAL SIGNIFICANCE: The present study depicted that spontaneous bone regeneration can occur with accepted results after simple enucleation of jaw cyst without the aid of any graft material. Hence, simple enucleation may be considered as a first line of treatment modality for cystic lesion of the jaws. This simplifies the surgical procedure, decreases the economic and biologic costs, and reduces the risk of postoperative complications. Follow-up is necessary along with patient's compliance for the success of treatment. PMID- 27484605 TI - The Effect of Using Self-ligating Brackets on Maxillary Canine Retraction: A Split-mouth Design Randomized Controlled Trial. AB - INTRODUCTION: The results of previous studies about the efficacy of using self ligating brackets (SLBs) in controlling canine movement during retraction are not in harmony. Therefore, the current study aimed to compare the effects of using new passive SLBs on maxillary canine retraction with sliding mechanics vs conventional ligating brackets (CLBs) tied with metal ligatures. MATERIALS AND METHODS: The sample comprised 15 adult patients (4 males, 11 females; 18-24 years) requiring bilateral extraction of maxillary first premolars. Units of randomization are the left or right maxillary canines within the same patient. The two maxillary canines in each patient were randomly assigned to one of the two groups in a simple split-mouth design. The canines in the SLBs group (n = 15) were bracketed with SLBs (Damon QTM), while the canines in the CLBs group (n = 15) were bracketed with conventional brackets (Mini Master Series). Transpalatal bars were used for anchorage. After leveling and alignment, 0.019 * 0.025" stainless steel working archwires were placed. Canines were retracted using a nickel-titanium close-coil springs with a 150 gm force. The amount and rate of maxillary canine retraction, canine rotation, and loss of anchorage were measured on study models collected at the beginning of canine retraction (T0) and 12 weeks later (T1). Differences were analyzed using paired-samples t-tests. RESULTS: The effect differences were statistically significant (p < 0.001). Using Damon QTM SLBs, the amount and rate of canine retraction were greater, while canine rotation and anchorage loss were less. CONCLUSION: From a clinical perspective, extraction space closure can be accomplished more effectively using SLBs. CLINICAL SIGNIFICANCE: Self-ligating brackets gave better results compared to the CLBs in terms of rate of movement, amount of canine rotation following extraction, and anchorage loss. PMID- 27484606 TI - Oral Cancer-related Inherited Cancer Syndromes: A Comprehensive Review. AB - Oral squamous cell carcinoma is the most common malignancy of the oral cavity, which is usually preceded by a myriad of oral potentially malignant disorders (OPMDs). In the classification of OPMDs, inherited cancer syndromes (ICSs) were proposed as one of the categories. Inherited cancer syndromes are genetic disorders in which inherited genetic mutation in one or more genes predispose the affected individuals to the development of cancer and may also cause its early onset. Many of these syndromes are caused by mutations in tumor suppressor genes, oncogenes, and genes involved in angiogenesis. General dental practitioners frequently come across OPMDs in their day-to-day practice. It becomes of paramount importance to have knowledge about these rare but prognostically important OPMDs. With this view in mind, in this article, efforts have been made to comprehensively discuss about various ICSs that have higher potential of transformation into oral cancer. The ICSs discussed in this article are xeroderma pigmentosum (XP), ataxia telangiectasia (AT), Bloom syndrome (BS), Fanconi's anemia (FA), and Li-Fraumeni syndrome (LFS), with special emphasis on signs, symptoms, and genetic considerations. PMID- 27484607 TI - Decompensated HCV patients with co morbidities including HIV who are medically treated are shown to minimize decompensation related admissions and healthcare cost: A case series. AB - Hepatitis C virus infection is a hot topic for both effective treatment and elevated cost. This case series describes the cost saving for the healthcare system of any nation of treating HCV in many situations, including that of overt cirrhosis. Case#1 is of a HCV/HIV infected cirrhotic patient with MELD score of 17, Child Pugh score B, recurrent esophageal bleeds ceased after successful treatment with sofosbuvir and simepravir. Case#2 is a patient also co-infected with HCV/HIV MELD score of 18, Child Pugh score B, with grade 3 esophageal varices and frequent bleed with significant anemia. With a regimen of sofosbuvir and ribavirin the patient had no more hospitalization for GI bleed. HCV infection is still underdiagnosed, picking up on it early, sufficient treatment and follow up may reduce healthcare costs in the long run by significant measures. PMID- 27484608 TI - Mapping the MMPI-2-RF Specific Problems Scales Onto Extant Psychopathology Structures. AB - A main objective in developing the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008 ) was to link the hierarchical structure of the instrument's scales to contemporary psychopathology and personality models for greater enhancement of construct validity. Initial evidence published with the Restructured Clinical scales has indicated promising results in that the higher order structure of these measures maps onto those reported in the extant psychopathology literature. This study focused on evaluating the internal structure of the Specific Problems and Interest scales, which have not yet been examined in this manner. Two large, mixed-gender outpatient and correctional samples were used. Exploratory factor analyses revealed consistent evidence for a 4-factor structure representing somatization, negative affect, externalizing, and social detachment. Convergent and discriminant validity analyses in the outpatient sample yielded a pattern of results consistent with expectations. These findings add further evidence to indicate that the MMPI-2-RF hierarchy of scales map onto extant psychopathology literature, and also add support to the notion that somatization and detachment should be considered important higher order domains in the psychopathology literature. PMID- 27484609 TI - Improved Broth Microdilution Method for Antimicrobial Susceptibility Testing of Francisella Noatunensis Orientalis. AB - In this project we optimized a minimal inhibitory concentration testing protocol for Francisella noatunensis orientalis. Thirty-three F. noatunensis orientalis isolates recovered from different fish species and locations were tested, and Escherichia coli ATCC 25922 was used as a quality control reference strain. A modified cation-adjusted Mueller Hinton broth supplemented with 2% IsoVitalex and 0.1% glucose (MMH) was tested at a pH of 6.4 +/- 0.1, 7.1 +/- 0.1, and 7.3 +/- 0.1. Growth curves generated for F. noatunensis orientalis indicated that MMH at a pH of 6.4 +/- 0.1 provided optimal growth. There were no significant differences in the growth curves obtained from isolates recovered from different fish species or from fresh or marine water. The pH of 6.4 +/- 0.1 in the MMH media interfered with the inhibitory properties of the potentiated sulfonamides (ormetoprim-sulfadimethoxine and trimethoprim-sulfamethoxazole) when using the E. coli ATCC reference strain. Minimal inhibitory concentrations of eight antimicrobials (gentamicin, enrofloxacin, ampicillin, oxytetracycline, erythromycin, florfenicol, flumequine, and oxolinic acid) were similar for all F. noatunensis orientalis isolates. The in vitro susceptibility data provided here can provide a baseline for monitoring the development of antimicrobial resistance among F. noatunensis orientalis isolates, as well as provide valuable data in the development of potential therapeutics. Received October 27, 2015; accepted April 13, 2016. PMID- 27484610 TI - Materials and surface modification for tissue engineered vascular scaffolds. AB - Although vascular implantation has been used as an effective treatment for cardiovascular disease for many years, off-the-shelf and regenerable vascular scaffolds are still not available. Tissue engineers have tested various materials and methods of surface modification in the attempt to develop a scaffold that is more suitable for implantation. Extracellular matrix-based natural materials and biodegradable polymers, which are the focus of this review, are considered to be suitable materials for production of tissue-engineered vascular grafts. Various methods of surface modification that have been developed will also be introduced, their impacts will be summarized and assessed, and challenges for further research will briefly be discussed. PMID- 27484611 TI - LC-MS profiling of glucosinolates in the seeds of Brassica elongata Ehrh., and of the two stenoendemic B. botteri Vis and B. cazzae Ginzb. & Teyber. AB - The glucosinolates (GLs) present in seed extracts of Brassica elongata Ehrh., B. botteri Vis and B. cazzae Ginzb. & Teyber from Croatia were identified by LC-MS. 4-Hydroxyindol-3-ylmethyl GL (3) was the major GL in the seeds of B. elongata, along with the four minor GLs 2-(R)-hydroxy-3-butenyl- (1), 3-butenyl- (2), 4 pentenyl- (4) and indol-3-ylmethyl (5). The seeds of B. botteri (Vis island) and B. cazzae (Susac island) contained 2 as the major GL as well as 1, 3, 5 and 4 methoxyindol-3-ylmethyl GL (6). However, the GLs in B. botteri (Palagruza island) differed from other varieties having 2-propenyl GL (7) as the major GL in the seeds, and the four minor GLs 2, 3, 5 and 6. This first report of the GL content in the seeds of B. elongata, B. botteri and B. cazzae indicates that the unique GL profiles could be specific to the geographical origin of the plant. PMID- 27484612 TI - Red light activated "caged" reagents for microRNA research. AB - "Caged" reagents for miRNA research (siRNA targeting EGFR, involved in miRNA maturation, and mimics of miR-20a, playing a key role in tumor formation and metastasis) were prepared. It was demonstrated that these reagents can be activated by non-toxic to cells red light both in cells and in cell free settings. PMID- 27484613 TI - Spectroscopically Characterized Synthetic Mononuclear Nickel-Oxygen Species. AB - Iron, copper, and manganese are the predominant metals found in oxygenases that perform efficient and selective hydrocarbon oxidations and for this reason, a large number of the corresponding metal-oxygen species has been described. However, in recent years nickel has been found in the active site of enzymes involved in oxidation processes, in which nickel-dioxygen species are proposed to play a key role. Owing to this biological relevance and to the existence of different catalytic protocols that involve the use of nickel catalysts in oxidation reactions, there is a growing interest in the detection and characterization of nickel-oxygen species relevant to these processes. In this Minireview the spectroscopically/structurally characterized synthetic superoxo, peroxo, and oxonickel species that have been reported to date are described. From these studies it becomes clear that nickel is a very promising metal in the field of oxidation chemistry with still unexplored possibilities. PMID- 27484614 TI - Atypical Cat Scratch Disease With Hepatosplenic Involvement. PMID- 27484615 TI - Xanthogranulomatous Cholecystitis as the Cause of Abdominal Pain in a 15-Year-Old Boy. PMID- 27484617 TI - Direct NHC-catalysed redox amidation using CO2 for traceless masking of amine nucleophiles. AB - The N-heterocyclic carbene (NHC)-catalysed redox amidation reaction is poorly developed and usually requires catalytic co-additives for electron-rich amine nucleophiles. We report a masking strategy (using CO2) that couples release of the free amine nucleophile to catalytic turnover, and in doing so, enables direct catalytic redox amidation of electron-rich amines. PMID- 27484616 TI - A Multinuclear Metal Complex Based DNase-Mimetic Artificial Enzyme: Matrix Cleavage for Combating Bacterial Biofilms. AB - Extracellular DNA (eDNA) is an essential structural component during biofilm formation, including initial bacterial adhesion, subsequent development, and final maturation. Herein, the construction of a DNase-mimetic artificial enzyme (DMAE) for anti-biofilm applications is described. By confining passivated gold nanoparticles with multiple cerium(IV) complexes on the surface of colloidal magnetic Fe3 O4 /SiO2 core/shell particles, a robust and recoverable artificial enzyme with DNase-like activity was obtained, which exhibited high cleavage ability towards both model substrates and eDNA. Compared to the high environmental sensitivity of natural DNase in anti-biofilm applications, DMAE exhibited a much better operational stability and easier recoverability. When DMAE was coated on substratum surfaces, biofilm formation was inhibited for prolonged periods of time, and the DMAE excelled in the dispersion of established biofilms of various ages. Finally, the presence of DMAE remarkably potentiated the efficiency of traditional antibiotics to kill biofilm-encased bacteria and eradiate biofilms. PMID- 27484618 TI - Laserballoon and Cryoballoon Pulmonary Vein Isolation in Persistent and Longstanding Persistent Atrial Fibrillation. AB - BACKGROUND: Visually guided laserballoon (LB) ablation has recently been introduced for pulmonary vein (PV) isolation (PVI). We analyzed efficacy and safety results of the newly introduced LB ablation technique in patients with persistent and longstanding persistent atrial fibrillation (AF), and compared this with an established standard method using the cryoballoon (CB). METHODS: A total of 35 patients with symptomatic persistent AF underwent LB ablation and were followed-up for 1 year. Results were compared to 35 patients who underwent CB ablation at the same institution and case matched for age, sex, CHA2 DS2 -VASc score, and left atrial volume. RESULTS: Complete isolation of all PVs was achieved in 68.6% in the LB and 97.1% in the CB group (P < 0.01). No significant differences were found for AF-free survival after 12 months in the complete cohort of all patients (LB: 53.3% vs CB: 70.4%; P = n.s.) and after excluding patients without complete PVI (LB: 57.8% vs CB: 72.5%; P = n.s.). LB ablation resulted in longer procedure (158.5 +/- 37.9 minutes vs 110.9 +/- 26.5 minutes; P < 0.01) and fluoroscopy durations (28.4 +/- 11.1 minutes vs 23.5 +/- 9.4 minutes; P = 0.04.), and a trend toward more major complications (14.3% vs 2.9%; P = n.s.). Procedure durations and complications declined over time and were level with CB-treated patients when reaching the last quartile of the LB patients. CONCLUSION: PVI in patients with persistent AF using the LB or the CB resulted in comparable success rates. Initial prolongations in procedure and safety parameters as a result of a learning curve effect for the LB have to be considered before starting to use this technique. PMID- 27484619 TI - Macromolecular crowding explains overflow metabolism in cells. AB - Overflow metabolism is a metabolic phenotype of cells characterized by mixed oxidative phosphorylation (OxPhos) and fermentative glycolysis in the presence of oxygen. Recently, it was proposed that a combination of a protein allocation constraint and a higher proteome fraction cost of energy generation by OxPhos relative to fermentation form the basis of overflow metabolism in the bacterium, Escherichia coli. However, we argue that the existence of a maximum or optimal macromolecular density is another essential requirement. Here we re-evaluate our previous theory of overflow metabolism based on molecular crowding following the proteomic fractions formulation. We show that molecular crowding is a key factor in explaining the switch from OxPhos to overflow metabolism. PMID- 27484620 TI - Ovarian nongestational choriocarcinoma and associated adenocarcinoma with the same germ cell origin determined by a molecular genetic approach: A case report. AB - Ovarian non-gestational choriocarcinomas co-existing with adenocarcinoma are extremely rare and have been reported as epithelial ovarian carcinomas of a "non germ cell origin" with "choriocarcinomatous differentiation". Although the cellular origin of non-gestational choriocarcinoma may be post-meiotic ovarian germ cells or the dedifferentiation of epithelial ovarian carcinoma, detailed genetic evidence has not yet been obtained to support this. We herein present a case of ovarian non-gestational choriocarcinoma co-existing with adenocarcinoma in a 29-year-old woman. The tumor rapidly increased in size and lung metastases appeared soon after parturition. We genetically demonstrated that the cellular origin of ovarian non-gestational choriocarcinoma was a post-meiotic germ cell derivation using a short tandem repeat analysis. The co-existing adenocarcinoma component was also shown to be of the same germ cell origin. These tumors showed the same homozygous pattern. A molecular genetic approach may be important for understanding the clinicopathological features of such tumors. PMID- 27484621 TI - Automated detection and labeling of high-density EEG electrodes from structural MR images. AB - OBJECTIVE: Accurate knowledge about the positions of electrodes in electroencephalography (EEG) is very important for precise source localizations. Direct detection of electrodes from magnetic resonance (MR) images is particularly interesting, as it is possible to avoid errors of co-registration between electrode and head coordinate systems. In this study, we propose an automated MR-based method for electrode detection and labeling, particularly tailored to high-density montages. APPROACH: Anatomical MR images were processed to create an electrode-enhanced image in individual space. Image processing included intensity non-uniformity correction, background noise and goggles artifact removal. Next, we defined a search volume around the head where electrode positions were detected. Electrodes were identified as local maxima in the search volume and registered to the Montreal Neurological Institute standard space using an affine transformation. This allowed the matching of the detected points with the specific EEG montage template, as well as their labeling. Matching and labeling were performed by the coherent point drift method. Our method was assessed on 8 MR images collected in subjects wearing a 256-channel EEG net, using the displacement with respect to manually selected electrodes as performance metric. MAIN RESULTS: Average displacement achieved by our method was significantly lower compared to alternative techniques, such as the photogrammetry technique. The maximum displacement was for more than 99% of the electrodes lower than 1 cm, which is typically considered an acceptable upper limit for errors in electrode positioning. Our method showed robustness and reliability, even in suboptimal conditions, such as in the case of net rotation, imprecisely gathered wires, electrode detachment from the head, and MR image ghosting. SIGNIFICANCE: We showed that our method provides objective, repeatable and precise estimates of EEG electrode coordinates. We hope our work will contribute to a more widespread use of high-density EEG as a brain-imaging tool. PMID- 27484623 TI - A CRISPR-Cas9 sex-ratio distortion system for genetic control. AB - Genetic control aims to reduce the ability of insect pest populations to cause harm via the release of modified insects. One strategy is to bias the reproductive sex ratio towards males so that a population decreases in size or is eliminated altogether due to a lack of females. We have shown previously that sex ratio distortion can be generated synthetically in the main human malaria vector Anopheles gambiae, by selectively destroying the X-chromosome during spermatogenesis, through the activity of a naturally-occurring endonuclease that targets a repetitive rDNA sequence highly-conserved in a wide range of organisms. Here we describe a CRISPR-Cas9 sex distortion system that targets ribosomal sequences restricted to the member species of the Anopheles gambiae complex. Expression of Cas9 during spermatogenesis resulted in RNA-guided shredding of the X-chromosome during male meiosis and produced extreme male bias among progeny in the absence of any significant reduction in fertility. The flexibility of CRISPR Cas9 combined with the availability of genomic data for a range of insects renders this strategy broadly applicable for the species-specific control of any pest or vector species with an XY sex-determination system by targeting sequences exclusive to the female sex chromosome. PMID- 27484622 TI - Mental disorders among college students in the World Health Organization World Mental Health Surveys. AB - BACKGROUND: Although mental disorders are significant predictors of educational attainment throughout the entire educational career, most research on mental disorders among students has focused on the primary and secondary school years. METHOD: The World Health Organization World Mental Health Surveys were used to examine the associations of mental disorders with college entry and attrition by comparing college students (n = 1572) and non-students in the same age range (18 22 years; n = 4178), including non-students who recently left college without graduating (n = 702) based on surveys in 21 countries (four low/lower-middle income, five upper-middle-income, one lower-middle or upper-middle at the times of two different surveys, and 11 high income). Lifetime and 12-month prevalence and age-of-onset of DSM-IV anxiety, mood, behavioral and substance disorders were assessed with the Composite International Diagnostic Interview (CIDI). RESULTS: One-fifth (20.3%) of college students had 12-month DSM-IV/CIDI disorders; 83.1% of these cases had pre-matriculation onsets. Disorders with pre-matriculation onsets were more important than those with post-matriculation onsets in predicting subsequent college attrition, with substance disorders and, among women, major depression the most important such disorders. Only 16.4% of students with 12-month disorders received any 12-month healthcare treatment for their mental disorders. CONCLUSIONS: Mental disorders are common among college students, have onsets that mostly occur prior to college entry, in the case of pre-matriculation disorders are associated with college attrition, and are typically untreated. Detection and effective treatment of these disorders early in the college career might reduce attrition and improve educational and psychosocial functioning. PMID- 27484624 TI - Synthetic and Natural Lipase Inhibitors. AB - Lipases are enzymes that catalyse the hydrolysis of ester bonds of triglycerides ranging among biocatalysts of considerable physiological significance and industrial potential. Better understanding of the catalytic functions and achieving the possibility to control the biocatalysis process, in particular exploring some activators and inhibitors of lipases, seems to be crucial in the context of novel applications. The lipase activity is a function of interfacial composition: the enzyme can be there activated as well as denaturated or deactivated and the interface is an appropriate site for modulating lipolysis. Lipase inhibitor, interacts directly with the enzyme and inhibits lipase action. Alternatively, some compounds can postpone the lipolytic reaction via adsorption to the interphase or to the substrate molecules. The aim of this review is to summarise the current knowledge concerning human, animal and microbial lipase inhibitors, which were grouped into two categories: synthetic lipase inhibitors (including phosphonates, boronic acids and fats analogues) and natural compounds (including beta-lactones and some botanical foodstuffs - plant extracts and plant metabolites, mainly polyphenols and saponins as well as peptides and some dietary fibers). The topics discussed include also inhibition issues from the viewpoint of obesity treatment. Among natural compounds able to inhibit lipase activity are beta- lactones including orlistat. Orlistat is the only registered drug for obesity treatment in many countries and lipases are essential enzymes for lipid absorption - thus fat absorption or obesity can be controlled by lipase inhibition, especially pancreatic lipase which is responsible for the hydrolysis of over 80% of total dietary fats. Its effectiveness in obesity treatment was also described. PMID- 27484625 TI - New Progress in Azole Compounds as Antimicrobial Agents. AB - The increasing incidence of microbial resistance and newly emerging pathogens have become a serious challenge for public health. More and more efforts have been directed to the development of new antimicrobial agents with distinct mechanisms from the well-known classes of clinical drugs. The extensive clinical utilization of azole-based medicinal drugs has evoked numerous attentions, and their researches and developments have been a quite rapid developing and active highlight topic with an infinite space. Consideration of our researches on azole compounds and other literature in recent three years, this review scientifically reviewed the new progress of azole derivatives as antibacterial, antifungal, antitubercular and antiviral agents, including mono-nitrogen azoles (oxazoles, thiazoles and carbazoles), bis-nitrogen azoles (imidazoles, pyrazoles and benzimidazoles) and tri-nitrogen azoles (triazoles and benzotriazoles) as well as tetrazole derivatives. It was hoped that this review would be helpful for the design and development of highly efficient azole derivatives with high bioactivity and low toxicity. PMID- 27484626 TI - Evolving Novel Chemical Entities for Management of Benign Prostatic Hyperplasia. AB - BACKGROUND: Proliferation of the smooth muscle and epithelial cells within the prostatic transition zone in older men leads to benign prostatic hyperplasia (BPH), which is hallmarked by the troublesome lower urinary tract symptoms. The affair responsible for the initiation and promotion of disease is still unresolved, though alpha-blockers and 5alpha-reductase inhibitors are used as management options for relief from the dynamic and static components respectively. METHOD: Combination therapy including both the alpha blocker and 5alpha-reductase inhibitor is emerging as inclusive parcel for treatment. However, selective androgen receptor modulators (SARM) and selective estrogen receptor modulators (SERM) are the other management resources, which are in the limelight. RESULT: This review gives a glimpse of BPH and the various chemical entities which have been reported in literature till date for the condition since 2005. PMID- 27484628 TI - Synergistic photomagnetic effects in coordination polymer heterostructure particles of Hofmann-like Fe(4-phenylpyridine)2[Ni(CN)4].0.5H2O and K0.4Ni[Cr(CN)6]0.8.nH2O. AB - New nanometer scale heterostructure particles of the two-dimensional Hofmann-like Fe(ii) spin-crossover network, Fe(phpy)2[Ni(CN)4].0.5H2O {phpy = 4 phenylpyridine}, and the Prussian blue analogue K0.4Ni1.0[Cr(CN)6]0.8.nH2O (NiCr PBA) have been developed, exhibiting synergistic photomagnetic effects, whereby the LIESST (light-induced electron spin-state trapping) effect in the Hofmann like material induces a magnetization change in the NiCr-PBA. A variety of microscopic and spectroscopic techniques demonstrate the heterogeneous growth of the NiCr-PBA on the Hofmann seed particles and show the Hofmann compound retains its thermal and photoinduced spin transition properties in the heterostructure. The photoinduced magnetization change in the NiCr-PBA network arises from coupling of the two lattices despite dissimilar structure types. Isothermal magnetization minor hysteresis loop studies at 5 K show light absorption leads to changes in the local anisotropy of NiCr-PBA magnetic domains, providing direct evidence for a general magnetomechanical mechanism of light-switchable magnetism in coordination polymer heterostructures combining a photoactive material with a magnet. PMID- 27484627 TI - Recent Advances in the Discovery of HIF-1alpha-p300/CBP Inhibitors as Anti-Cancer Agents. AB - Hypoxia-inducible factor-1 (HIF-1), a heterodimeric (containing alpha and beta subunits) transcription factor, is involved in hypoxia response pathway that regulates the expression of many tumorrelated genes. The stabilized HIF-1 heterodimer couples to the general co-activators p300/CBP (CREB binding protein), forming an active transcription factor to initiate hypoxic responses. Inhibiting the transcription factor-coactivator HIF-1alpha-p300/CBP interaction represents an attractive approach for blocking hypoxia pathway in tumors. Recently, diverse HIF-1alpha-p300/CBP inhibitors have been designed and their anti-tumor activities have been evaluated. The developments of inhibitors of HIF-1alpha- p300/CBP are discussed in this review. An outline of structures and biological activities of these inhibitors can be traced, along with the approaches for inhibitors discovery. The challenges in identifying novel and selective potent inhibitors of HIF-1alpha-p300/CBP are also put forward. PMID- 27484629 TI - Modulatory effects of levamisole and garlic oil on the immune response of Wistar rats: Biochemical, immunohistochemical, molecular and immunological study. AB - Levamisole (LEVA) and garlic are prevalent immunomodulators in humans and animals. Therefore, the present study aimed to examine the immunomodulatory effects of LEVA and garlic oil (GO) alone or in combination on the immune response of Wistar rats. A total of 24 male Wistar rats were allocated into four equal groups: Control group, which was given ad libitum access to food and water; and groups 2-4, which were orally administered LEVA [2.5 mg/kg body weight (BW) every 2 days], GO, (5 ml/kg BW daily), or LEVA plus GO, respectively for 4 consecutive weeks. Serum immunoglobulin (Ig)G and IgM levels were measured using a radial immunodiffusion assay. Serum cytokine levels, including interferon (IFN) gamma, interleukin (IL)-5 and tumor necrosis factor (TNF)-alpha, were measured using enzyme-linked immunosorbent assay kits. Total blood counts were measured automatically using a cell counter. Serum lysozyme enzymatic activity was determined by measuring the diameters of the zones of clearance relative to lysozyme. Immunohistochemical detection of CD4 and CD8 was carried out using the streptavidin-biotin-peroxidase method. Furthermore, the mRNA expression levels of IL-4, IL-5 and IL-12 were measured in the leukocytes and thymus gland by semi quantitative polymerase chain reaction. The results revealed that LEVA increased serum levels of IFN-gamma, IL-5 and TNF-alpha cytokines, whereas co administration of LEVA and GO decreased the stimulatory action of LEVA alone. LEVA and GO alone increased the serum levels of IgG, IgM and total blood cell counts, and co-administration of GO and LEVA inhibited the effects of LEVA. At the cellular level, in the spleen, LEVA increased immunoreactivity of CD4 and CD8, whereas co-administration of GO with LEVA decreased this strong expression. At the molecular level, in leukocytes, LEVA upregulated the mRNA expression levels of IL-2, IL-4 and IL-5, whereas GO alone downregulated mRNA expression. Co administration of GO with LEVA inhibited the LEVA-induced upregulation of IL-2, IL-4 and IL-5 mRNA expression. In the thymus, both LEVA and GO upregulated the mRNA expression levels of IL-4 and IL-5, whereas LEVA alone did not affect IL-12 mRNA expression. Co-administration of GO with LEVA inhibited LEVA-induced upregulation of IL-4 and GO-induced upregulation of IL-12 expression, and had an additive upregulatory effect on IL-5 expression. In conclusion, LEVA stimulated T helper (Th)1 cytokines, whereas GO stimulated a Th2 response, and co administration of GO with LEVA inhibited the stimulatory effects of LEVA and balanced the Th1/Th2 response. PMID- 27484631 TI - Cognitive performance, fatigue and event-related potentials in patients with clinically isolated syndrome. AB - OBJECTIVES: Cognitive impairment and fatigue are regarded as important aspects of multiple sclerosis. The aim of this study was to evaluate cognitive performance, the level of fatigue and parameters of event-related potentials (ERP) in patients diagnosed with clinically isolated syndrome (CIS). PATIENTS AND METHODS: The study comprised 44 patients with CIS and 45 healthy controls. Cognitive performance was assessed using the Brief Repeatable Battery of Neuropsychological Tests (BRBNT), fatigue - using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS). Auditory ERP were performed and the parameters of N200 and P300 components were analyzed. Neuropsychological and electrophysiological measures were referred to clinical and radiological features of the disease activity. RESULTS: Forty five% of patients failed in at least one test from BRBNT, mainly within the domains of memory and attention. In 18% of patients FSS corresponded with moderate or severe fatigue. The mean latency of N200 and P300 was significantly longer and amplitude of P300 was lower in those patients with CIS than in the controls. Significant correlations were found between the results of MFIS and tests evaluating verbal memory and attention, as well as between N200 latency and results of tests for verbal memory. CONCLUSIONS: Cognitive performance and fatigue deserve attention from the earliest clinical stage of MS. Abnormalities of event-related potentials in CIS suggest early impact of the disease on functional neural networks. PMID- 27484630 TI - The dimerization equilibrium of a ClC Cl(-)/H(+) antiporter in lipid bilayers. AB - Interactions between membrane protein interfaces in lipid bilayers play an important role in membrane protein folding but quantification of the strength of these interactions has been challenging. Studying dimerization of ClC-type transporters offers a new approach to the problem, as individual subunits adopt a stable and functionally verifiable fold that constrains the system to two states monomer or dimer. Here, we use single-molecule photobleaching analysis to measure the probability of ClC-ec1 subunit capture into liposomes during extrusion of large, multilamellar membranes. The capture statistics describe a monomer to dimer transition that is dependent on the subunit/lipid mole fraction density and follows an equilibrium dimerization isotherm. This allows for the measurement of the free energy of ClC-ec1 dimerization in lipid bilayers, revealing that it is one of the strongest membrane protein complexes measured so far, and introduces it as new type of dimerization model to investigate the physical forces that drive membrane protein association in membranes. PMID- 27484632 TI - Improving the applicability of guidelines on nonmelanoma skin cancer in frail older adults: a multidisciplinary expert consensus and systematic review of current guidelines. AB - BACKGROUND: Balancing treatment decisions in frail older adults with nonmelanoma skin cancer (NMSC) can be challenging. Clinical practice guidelines (CPGs) could provide assistance. OBJECTIVES: To collect and prioritize items related to frail older adults with NMSC for integration into CPGs and to assess the current extent of this integration. METHODS: Items were collected and prioritized by a multidisciplinary working group (29 members) using a modified Delphi procedure and a five-point Likert scale. To assess current integration of these items in CPGs, a systematic review was subsequently performed by two independent reviewers using five medical databases (PubMed, Embase, Cochrane Library, SUMsearch and Trip Database), websites of guideline developers/databases, and (inter)national dermatological societies. RESULTS: Prioritization of a final 13-item list showed that 'limited life expectancy' (4.5 +/- 0.9) and 'treatment goals other than cure' (4.4 +/- 0.7) were most desired to be integrated into CPGs; both were included in six (46%) of the CPGs found (n = 13). Attention to 'tumour characteristics' and 'comorbidities' were included in CPGs most often (100% and 77%, respectively). CONCLUSIONS: More attention to items related to frail older adults in NMSC CPGs is broadly desired, but CPG integration of these items is currently limited. More integration might stimulate more holistic, personalized and patient-centred care in frail older adults. PMID- 27484633 TI - Dimers or trimers? A characterization of the halogen bonded complexes of CF3X (X=I or Br) with dimethyl ether and acetone in cryosolutions. AB - Acetone molecules dissolved in liquid krypton are inclined to self-associate into dimers. This behavior affects its use as a prototype Lewis base in studies of weak intermolecular interactions. In this study infrared spectra of mixed solutions of dimethyl ether and CF3X and of acetone and CF3X (with X=I or Br) dissolved in liquid argon and liquid krypton are recorded at constant temperature. The dataset for dimethyl ether is used to validate a numerical method based on least-squares fitting of a model including contributions of both monomers and a heterodimer with 1:1 stoichiometry. The resulting monomer and dimer spectra show excellent agreement with previous studies found in literature. The analysis of the dataset for acetone requires an extension of the model with contributions for the acetone homodimer and for (acetone)2.CF3X and acetone.(CF3X)2 trimers. The results show that many signals for acetone.CF3I and (acetone)2.CF3I are observed, while only a few bands due to acetone.(CF3I)2 occur. The use of numerical approaches adjusted to the specificities of a mixture of two compounds allows to reliably resolve overlapping spectra of monomers and heterocomplexes and characterizing heterocomplex features that could not be deduced using earlier methods. To support the assignments made, ab initio calculations predicting geometries, relative stabilities and harmonic vibrational frequencies for the species envisaged are performed. PMID- 27484634 TI - Resting state theta band source distribution and functional connectivity in remitted schizophrenia. AB - Increased resting theta activity is one consistent observation occurring during all the phases of schizophrenia. However, the resting theta oscillations during the remission phase are yet unclear. We studied resting theta current source density and functional connectivity in remitted schizophrenia and compared with healthy controls. Significantly increased current source density was found in the dominant anterior cingulate cortex. Increased connectivity between the inferior parietal lobe bilaterally and between the left inferior parietal lobe and right middle frontal gyrus was also found. It may be concluded that schizophrenia patients have aberrant regional theta band current source density and functional connectivity even during remission. PMID- 27484635 TI - Decreased VEGFR2 expression and increased phosphorylated Akt1 in the prefrontal cortex of individuals with schizophrenia. AB - The Akt signaling pathway involves various cellular processes and depends on extracellular stimuli. Since Akt signaling participates in cytoprotection, synapse plasticity, axon extension, and neurotransmission in the nervous system, alteration in Akt signaling might be a potential cause of schizophrenia. In this study, we performed multiplex fluorescent bead based immunoassays for members of the Akt signaling pathway in postmortem brains of controls and patients with schizophrenia. Vascular endothelial growth factor receptor 2 (VEGFR2/KDR) was significantly decreased in the prefrontal cortex (PFC) of patients with schizophrenia, and the expression level of VEGFR2 was inversely correlated with the positive symptom subscale of the Diagnostic Instrument for Brain Studies (DIBS) in patients with schizophrenia. There was also an increase in phosphorylated Akt1 in the PFC in the patients, though the ratio of phospho/total Akt1 is not significantly different. In the nucleus accumbens (NAcc) there was no significant difference in expression and phosphorylation levels of Akt signaling proteins. Genetic analysis revealed a significant correlation of a SNP of KDR (rs7692791) with ERK1/2 and Akt1 phospho/total rates. Since VEGFR2 participates in angiogenesis and neurotrophic activation, either or both functions might be responsible for onset of schizophrenia. PMID- 27484636 TI - Tannerella forsythia GroEL induces inflammatory bone resorption and synergizes with interleukin-17. AB - Tannerella forsythia is a major periodontal pathogen, and T. forsythia GroEL is a molecular chaperone homologous to human heat-shock protein 60. Interleukin-17 (IL 17) has been implicated in the pathogenesis of periodontitis and several systemic diseases. This study investigated the potential of T. forsythia GroEL to induce inflammatory bone resorption and examined the cooperative effect of IL-17 and T. forsythia GroEL on inflammatory responses. Human gingival fibroblasts (HGFs) and periodontal ligament (PDL) fibroblasts were stimulated with T. forsythia GroEL and/or IL-17. Gene expression of IL-6, IL-8, and cyclooxygenase-2 (COX-2) and concentrations of IL-6, IL-8, and prostaglandin E2 (PGE2 ) were measured by real time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays, respectively. After stimulation of MG63 cells with T. forsythia GroEL and/or IL-17, gene expression of osteoprotegerin (OPG) was examined. After subcutaneous injection of T. forsythia GroEL and/or IL-17 above the calvaria of BALB/c mice, calvarial bone resorption was assessed by micro computed tomography and histological examination. Tannerella forsythia GroEL induced IL-6 and IL-8 production in HGFs and PDL cells, and IL-17 further promoted IL-6 and IL-8 production. Both T. forsythia GroEL and IL-17 synergistically increased PGE2 production and inhibited OPG gene expression. Calvarial bone resorption was induced by T. forsythia GroEL injection, and simultaneous injection of T. forsythia GroEL and IL-17 further increased bone resorption. These results suggest that T. forsythia GroEL is a novel virulence factor that can contribute to inflammatory bone resorption caused by T. forsythia and synergizes with IL-17 to exacerbate inflammation and bone resorption. PMID- 27484637 TI - Melatonin-induced increase in sensitivity of human hepatocellular carcinoma cells to sorafenib is associated with reactive oxygen species production and mitophagy. AB - Effects of sorafenib in hepatocellular carcinoma (HCC) are frequently transient due to tumor-acquired resistance, a phenotype that could be targeted by other molecules to reduce this adaptive response. Because melatonin is known to exert antitumor effects in HCC cells, this study investigated whether and how melatonin reduces resistance to sorafenib. Susceptibility to sorafenib (10 nmol/L to 50 MUmol/L) in the presence of melatonin (1 and 2 mmol/L) was assessed in HCC cell lines HepG2, HuH7, and Hep3B. Cell viability was reduced by sorafenib from 1 MUmol/L in HepG2 or HuH7 cells, and 2.5 MUmol/L in Hep3B cells. Co-administration of melatonin and sorafenib exhibited a synergistic cytotoxic effect on HepG2 and HuH7 cells, while Hep3B cells displayed susceptibility to doses of sorafenib that had no effect when administrated alone. Co-administration of 2.5 MUmol/L sorafenib and 1 mmol/L melatonin induced apoptosis in Hep3B cells, increasing PARP hydrolysis and BAX expression. We also observed an early colocalization of mitochondria with lysosomes, correlating with the expression of mitophagy markers PINK1 and Parkin and a reduction of mitofusin-2 and mtDNA compared with sorafenib administration alone. Moreover, increased reactive oxygen species production and mitochondrial membrane depolarization were elicited by drug combination, suggesting their contribution to mitophagy induction. Interestingly, Parkin silencing by siRNA to impair mitophagy significantly reduced cell killing, PARP cleavage, and BAX expression. These results demonstrate that the pro-oxidant capacity of melatonin and its impact on mitochondria stability and turnover via mitophagy increase sensitivity to the cytotoxic effect of sorafenib. PMID- 27484638 TI - Canine distemper virus isolated from a monkey efficiently replicates on Vero cells expressing non-human primate SLAM receptors but not human SLAM receptor. AB - BACKGROUND: In 2008, an outbreak of canine distemper virus (CDV) infection in monkeys was reported in China. We isolated CDV strain (subsequently named Monkey BJ01-DV) from lung tissue obtained from a rhesus monkey that died in this outbreak. We evaluated the ability of this virus on Vero cells expressing SLAM receptors from dog, monkey and human origin, and analyzed the H gene of Monkey BJ01-DV with other strains. RESULTS: The Monkey-BJ01-DV isolate replicated to the highest titer on Vero cells expressing dog-origin SLAM (10(5.2+/-0.2) TCID50/ml) and monkey-origin SLAM (10(5.4+/-0.1) TCID50/ml), but achieved markedly lower titers on human-origin SLAM cells (10(3.3+/-0.3) TCID50/ml). Phylogenetic analysis of the full-length H gene showed that Monkey-BJ01-DV was highly related to other CDV strains obtained during recent CDV epidemics among species of the Canidae family in China, and these Monkey strains CDV (Monkey-BJ01-DV, CYN07-dV, Monkey-KM-01) possessed a number of amino acid specific substitutions (E276V, Q392R, D435Y and I542F) compared to the H protein of CDV epidemic in other animals at the same period. CONCLUSIONS: Our results suggested that the monkey origin-CDV-H protein could possess specific substitutions to adapt to the new host. Monkey-BJ01-DV can efficiently use monkey- and dog-origin SLAM to infect and replicate in host cells, but further adaptation may be required for efficient replication in host cells expressing the human SLAM receptor. PMID- 27484640 TI - New congenital coronary artery anomaly - double supply of single left anterior descending coronary artery from the left and right coronary sinuses: a case report. AB - BACKGROUND: A normal anatomy of coronary arteries is important to have adequate cardiac muscle blood supply especially during extraneous physical activities. This case report describes a rare coronary anomaly in which the accessory coronary artery arose from the right coronary artery, reentered the left anterior descending coronary artery, and then ran as a single vessel. CASE PRESENTATION: We present a case of a coronary anomaly in a 47-year-old white man who presented with atypical angina. Computed tomographic angiography and coronary angiography showed a variant of dual left anterior descending coronary artery not previously described. Our patient's accessory coronary artery arose from his right coronary artery. It took an intramuscular course beneath the right ventricular outflow tract in the interventricular septal area to the anterior interventricular sulcus, giving off septal perforators that reentered his medial left anterior descending coronary artery. Both vessels ran after the anastomosis in the anterior interventricular sulcus as a single vessel. CONCLUSIONS: We propose that this anomaly represents a new variant of coronary artery anomaly. This coronary artery anomaly does not cause ischemia. Recognition of this coronary anomaly is important in patients undergoing percutaneous coronary intervention or coronary artery bypass graft operations. PMID- 27484639 TI - Overexpression of the miR-141/200c cluster promotes the migratory and invasive ability of triple-negative breast cancer cells through the activation of the FAK and PI3K/AKT signaling pathways by secreting VEGF-A. AB - BACKGROUND: The role of microRNA-200 (miR-200) family members in the migration and invasion of breast cancer is controversial. This study investigated the mechanisms by which the miR-200 family members modulated the migratory and invasive abilities of an aggressive triple-negative breast cancer (TNBC) cell line, MDA-MB-231. METHODS: The miR-200 family (miR-200b/200a/429 and miR-141/200c clusters) and green fluorescence protein (GFP) were transduced into MDA-MB-231 cells using a lentiviral system. Stable cells highly expressing the miR-200 family and GFP were isolated by puromycin selection and fluorescence-activated cell sorting. Gene expression was evaluated using real-time polymerase chain reaction (PCR) and reverse transcriptase-PCR (RT-PCR). The migratory and invasive abilities were assessed using trans-well and wound-healing assays. The secreted cytokines and growth factors in cultured media were quantified using a Bio Plex200 multiplex array system. Western blot assays and immunofluorescence staining were conducted to investigate miR-200 family-regulated signaling pathways. The entire dataset obtained in this study was statistically evaluated using a one-way ANOVA followed by a t-test. RESULTS: The stable overexpression of the miR-200b/200a/429 or miR-141/200c cluster suppressed cell growth and significantly increased migration and invasion of MDA-MB-231 cells. miR-141/200c overexpression was more effective in decreasing cell growth and promoting migration and invasion of MDA-MB-231 cells than was miR-200b/200a/429 overexpression. In addition, the overexpression of the miR-200b/200a/429 or miR 141/200c cluster led to an increase in the phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT). Chemical inhibitors of FAK and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT suppressed the migration and invasion of MDA-MB-231 cells that was enhanced by the overexpression of the miR-200b/200a/429 or miR-141/200c cluster. Compared to the miR-200b/200a/429 cluster-transduced MDA-MB-231 cells, the miR-141/200c cluster transduced MDA-MB-231 cells exhibited a significant increase in vascular endothelial growth factor (VEGF)-A secretion and integrin-alphaV (integrin alphaV) expression. Treatment with an anti-VEGF-A-neutralizing antibody inhibited the increase in migration and invasion in both the miR-200b/200a/429- and miR 141/200c-transduced MDA-MB-231 cells but significantly reduced the phosphorylation of FAK and AKT in only the miR-141/200c cluster-transduced MDA-MB 231 cells. CONCLUSIONS: Taken together, our data demonstrate a mechanism in which the miR-141/200c cluster, through FAK- and PI3K/AKT-mediated signaling by means of increased VEGF-A secretion, promotes the migratory and invasive abilities of MDA-MB-231 cells. PMID- 27484641 TI - Protein kinase A inhibitor, H89, significantly enhances survival rate of dissociated human embryonic stem cells following cryopreservation. AB - OBJECTIVES: Human embryonic stem cells (hESCs) have huge potential for establishment of disease models and for treating degenerative diseases. However, the extremely low survival level of dissociated hESCs following cryopreservation is been a tremendous problem to allow for their rapid expansion, genetic manipulation and future medical applications. In this study, we have aimed to develop an efficient strategy to improve survival of dissociated hESCs after cryopreservation. MATERIALS AND METHODS: Human embryonic stem cells (H9 line), dissociated into single cells, were cryopreserved using the slow-freezing method. Viable cells and their colony numbers in culture after cryopreservation were evaluated when treated with protein kinase A inhibitor H89. Western blotting was carried out to investigate mechanisms of low survival levels of dissociated hESCs following cryopreservation. Immunofluorescence, reverse transcription-polymerase chain reaction (RT-PCR), in vitro and in vivo differentiation were performed to testify to pluripotency and differentiation ability of hte cryopreserved cells treated with H89. RESULTS: H89 significantly improved survival level of dissociated hESCs after cryopreservation through ROCK inhibition. H89-treated cells still maintained their pluripotency and differentiation capacity. CONCLUSIONS: This new approach for cryopreservation of single hESCs, using H89, can promote potential use of hESCs in regenerative medicine in the future. PMID- 27484642 TI - The impact of phylogenetic dating method on interpreting trait evolution: a case study of Cretaceous-Palaeogene eutherian body-size evolution. AB - The fossil record of the earliest Cenozoic contains the first large-bodied placental mammals. Several evolutionary models have been invoked to explain the transition from small to large body sizes, but methods for determining evolutionary mode of trait change depend on input from tree topology and divergence dates. Different dating methods may therefore affect inference of evolutionary model. Here, we fit models of body mass evolution onto dated phylogenies of Cretaceous and Palaeogene mammals, comparing the effect of dating method on interpretation of evolutionary model. Among traditional palaeontological dating approaches, an Ornstein-Uhlenbeck model with high alpha parameters is recovered as best-fitting when minimum-age dating is used, while branch-sharing methods are highly sensitive to topology. Release or release radiate models are preferred when Bayesian fossilized birth-death method is used, but when using stochastic cal3 dating of trees, a model of increased evolutionary rate without a release in constraint at the Cretaceous-Palaeogene boundary has highest support. These results demonstrate unambiguously that choice of dating method is critical for interpretation of continuous trait evolution, and that care must therefore be taken to consider these effects in macroevolutionary studies. PMID- 27484643 TI - Male-biased sex allocation in ageing parents; a longitudinal study in a long lived seabird. AB - Optimal sex allocation is frequency-dependent, but senescence may cause behaviour at old age to be suboptimal. We investigated whether sex allocation changes with parental age, using 16 years of data comprising more than 2500 molecularly sexed offspring of more than 600 known-age parents in common terns (Sterna hirundo), slightly sexually size-dimorphic seabirds. We decomposed parental age effects into within-individual change and sex allocation-associated selective (dis)appearance. Individual parents did not differ consistently in sex allocation, but offspring sex ratios at fledging changed from female- to male biased as parents aged. Sex ratios at hatching were not related to parental age, suggesting sons to outperform daughters after hatching in broods of old parents. Our results call for the integration of sex allocation theory with theory on ageing and demography, as a change in sex allocation with age per se will cause the age structure of a population to affect the frequency-dependent benefits and the age-specific strength of selection on sex allocation. PMID- 27484644 TI - Exoskeletons and economics: indoor arthropod diversity increases in affluent neighbourhoods. AB - In urban ecosystems, socioeconomics contribute to patterns of biodiversity. The 'luxury effect', in which wealthier neighbourhoods are more biologically diverse, has been observed for plants, birds, bats and lizards. Here, we used data from a survey of indoor arthropod diversity (defined throughout as family-level richness) from 50 urban houses and found that house size, surrounding vegetation, as well as mean neighbourhood income best predict the number of kinds of arthropods found indoors. Our finding, that homes in wealthier neighbourhoods host higher indoor arthropod diversity (consisting of primarily non-pest species), shows that the luxury effect can extend to the indoor environment. The effect of mean neighbourhood income on indoor arthropod diversity was particularly strong for individual houses that lacked high surrounding vegetation ground cover, suggesting that neighbourhood dynamics can compensate for local choices of homeowners. Our work suggests that the management of neighbourhoods and cities can have effects on biodiversity that can extend from trees and birds all the way to the arthropod life in bedrooms and basements. PMID- 27484645 TI - Aposematism: balancing salience and camouflage. AB - Aposematic signals are often characterized by high conspicuousness. Larger and brighter signals reinforce avoidance learning, distinguish defended from palatable prey and are more easily memorized by predators. Conspicuous signalling, however, has costs: encounter rates with naive, specialized or nutritionally stressed predators are likely to increase. It has been suggested that intermediate levels of aposematic conspicuousness can evolve to balance deterrence and detectability, especially for moderately defended species. The effectiveness of such signals, however, has not yet been experimentally tested under field conditions. We used dough caterpillar-like baits to test whether reduced levels of aposematic conspicuousness can have survival benefits when predated by wild birds in natural conditions. Our results suggest that, when controlling for the number and intensity of internal contrast boundaries (stripes), a reduced-conspicuousness aposematic pattern can have a survival advantage over more conspicuous signals, as well as cryptic colours. Furthermore, we find a survival benefit from the addition of internal contrast for both high and low levels of conspicuousness. This adds ecological validity to evolutionary models of aposematic saliency and the evolution of honest signalling. PMID- 27484646 TI - Survival is linked with reaction time and spatial memory in African striped mice. AB - Studying the association between fitness and cognition in free-living animals is a fundamental step in the elucidation of the evolution of cognition. We assessed whether survival until the onset of the breeding season was related to reaction time or spatial memory in the African striped mouse Rhabdomys pumilio, a rodent that has to survive summer drought before breeding. We tested a total of 90 individuals at the beginning of summer. Female survival was related to a faster response to predation stimuli. Male survival increased with greater spatial memory, possibly because it is important for males to remember the configuration of the environment during dispersal. This study revealed that individual variation in reaction time and spatial memory can be related to survival probability, which is important for understanding the selection pressures acting on basic cognitive traits. PMID- 27484647 TI - Partially incorrect fossil data augment analyses of discrete trait evolution in living species. AB - Ancestral state reconstruction of discrete character traits is often vital when attempting to understand the origins and homology of traits in living species. The addition of fossils has been shown to alter our understanding of trait evolution in extant taxa, but researchers may avoid using fossils alongside extant species if only few are known, or if the designation of the trait of interest is uncertain. Here, I investigate the impacts of fossils and incorrectly coded fossils in the ancestral state reconstruction of discrete morphological characters under a likelihood model. Under simulated phylogenies and data, likelihood-based models are generally accurate when estimating ancestral node values. Analyses with combined fossil and extant data always outperform analyses with extant species alone, even when around one quarter of the fossil information is incorrect. These results are especially pronounced when model assumptions are violated, such as when there is a trend away from the root value. Fossil data are of particular importance when attempting to estimate the root node character state. Attempts should be made to include fossils in analysis of discrete traits under likelihood, even if there is uncertainty in the fossil trait data. PMID- 27484648 TI - Trait-mediated indirect interactions of ant shape on the attack of caterpillars and fruits. AB - Mainly owing to their high diversity and abundance, ants are formidable as predators and defenders of foliage. Consequently, ants can exclude both invertebrate and vertebrate activity on plants via direct and indirect interactions as already shown in many previous studies. Here we present empirical evidence that objects resembling ant shape on dummy caterpillars were able to repel visually oriented predators. Moreover, we also show that rubber ants on dummy fruits can repel potential fruit dispersers. Our results have direct implications on the ecological and evolutionary dynamics of interactions in ant based systems, as ant presence could affect the fitness of its partners. In short, our study highlights the importance of visual cues in interspecific interactions and opens a new way to study the effects of ant presence to test ecological and evolutionary hypotheses. PMID- 27484649 TI - Bioturbation enhances the aerobic respiration of lake sediments in warming lakes. AB - While lakes occupy less than 2% of the total surface of the Earth, they play a substantial role in global biogeochemical cycles. For instance, shallow lakes are important sites of carbon metabolism. Aerobic respiration is one of the important drivers of the carbon metabolism in lakes. In this context, bioturbation impacts of benthic animals (biological reworking of sediment matrix and ventilation of the sediment) on sediment aerobic respiration have previously been underestimated. Biological activity is likely to change over the course of a year due to seasonal changes of water temperatures. This study uses microcosm experiments to investigate how the impact of bioturbation (by Diptera, Chironomidae larvae) on lake sediment respiration changes when temperatures increase. While at 5 degrees C, respiration in sediments with and without chironomids did not differ, at 30 degrees C sediment respiration in microcosms with 2000 chironomids per m(2) was 4.9 times higher than in uninhabited sediments. Our results indicate that lake water temperature increases could significantly enhance lake sediment respiration, which allows us to better understand seasonal changes in lake respiration and carbon metabolism as well as the potential impacts of global warming. PMID- 27484650 TI - Early diving behaviour in juvenile penguins: improvement or selection processes. AB - The early life stage of long-lived species is critical to the viability of population, but is poorly understood. Longitudinal studies are needed to test whether juveniles are less efficient foragers than adults as has been hypothesized. We measured changes in the diving behaviour of 17 one-year-old king penguins Aptenodytes patagonicus at Crozet Islands (subantartic archipelago) during their first months at sea, using miniaturized tags that transmitted diving activity in real time. We also equipped five non-breeder adults with the same tags for comparison. The data on foraging performance revealed two groups of juveniles. The first group made shallower and shorter dives that may be indicative of early mortality while the second group progressively increased their diving depths and durations, and survived the first months at sea. This surviving group of juveniles required the same recovery durations as adults, but typically performed shallower and shorter dives. There is thereby a relationship between improved diving behaviour and survival in young penguins. This long period of improving diving performance in the juvenile life stage is potentially a critical period for the survival of deep avian divers and may have implications for their ability to adapt to environmental change. PMID- 27484651 TI - Association of interleukin-16 polymorphisms with disease progression and susceptibility in endometriosis. AB - Interleukin-16 (IL-16) is a multifunctional pro-inflammatory cytokine that was previously found in association with complex disorders, and it is now cleared that this cytokine plays a critical role in regulation of cellular functions such as homoeostasis. Due to the complexity of endometriosis and its resemblance to cancer, we designed present case-control study to determine the effects of genetic polymorphisms of the human IL-16 gene on Iranian women's susceptibility to endometriosis. A total of 126 patients with endometriosis (stages I-IV) and 144 healthy women as control group were recruited to the study. We genotyped four single nucleotide polymorphisms of IL-16 gene (rs11556218 T>G, rs4778889 T>C, rs4072111 C>T and rs1131445 C>T). Genotyping was performed using PCR and restriction fragment length polymorphism. Our results showed that genotype distribution in two exonic polymorphisms including rs11556218 and rs4072111 was significantly different between Endometriosis patients and healthy individuals (P < 0.05). We have also found an association between rs4072111 and rs1131445 with progression to the severe stages (III-IV) of endometriosis (P < 0.05). Finally, we may conclude that IL-16 gene polymorphisms are highly associated with increased risk of endometriosis and could be considered as a susceptibility factor for endometriosis. PMID- 27484653 TI - The "Other" in Ourselves: Exploring the Educational Power of the Humanities and Arts. PMID- 27484652 TI - Have adults lost their sense of play? An observational study of the social dynamics of physical (in)activity in German and Hawaiian leisure settings. AB - BACKGROUND: Physical inactivity is one of the biggest health problems nowadays. Recent research shows that socio-cultural barriers to physical activity are mostly related to modern lifestyles. However, there is a lack of research on how social and group dynamics influence engagement in physical activity. Furthermore, there are few cross-cultural studies that have compared the social dynamics of (in)activity in different cultural settings. This paper therefore aims to analyse how social group dynamics influence physical activity and inactivity in informal social environments and whether physical activity is influenced by the socio cultural settings. METHODS: The paper presents the qualitative data collected within a covert participant observation study. Data was collected by keeping observational notes in order to record typical, regular patterns regarding physical (in)activity related behaviour of groups at an artificial open air swimming pool in Germany and a natural pond in Hawai'i. The data collection period was eight and a half months. Data was interpreted based on constant comparative analysis in order to identify most generative patterns in the field notes. RESULTS: Group structures appear to play a significant role regarding the activity of the group members. In this study, we identified four key factors that influence group based physical activity: 1) Physical activity seems to be a group disturbing behaviour particularly in larger groups of adults; 2) Physical activity appears to be more functional and less joyful in adults than in children; 3) Group activity is influenced by (in)activity anchors, including 'domestication' of a group's site, obesity, and controlling parents. 4) Physical activity is to a certain extent socially contagious, particularly with regard to playful activities. CONCLUSIONS: Successful promotion of physical activity should target the social structures of inactive individuals' groups. In this regard, one of the main problems is that fun and wellbeing, as very important targets of public health strategies for the adult population, appear not to be compatible with physical activity. Developing strategies to reframe physical activity rather as 'fun' and less as functional may be one way to engage inactive individuals in physical activity in leisure settings. PMID- 27484654 TI - State of rare disease management in Southeast Asia. AB - BACKGROUND: Rare diseases, also referred to as orphan diseases, are characterised by their low prevalence with majority of them are chronically debilitating and life threatening. Given the low prevalence and the widely dispersed but very small patient base for each disease, there may often be a disproportion in the availability of treatments and resources to manage patients, spur research and train experts. This is especially true in Southeast Asian countries that are currently in the process of implementing or revising their universal health coverage schemes. This paper aims to examine the status of rare disease management in Southeast Asian countries. It will serve as the basis for a more active discussion on how countries in the region can address an under-recognised rare disease burden and enhance national and regional capacities. METHODS: The study consists of literature reviews and key stakeholders interviews in six focus countries, including the Philippines, Singapore, Malaysia, Indonesia, Vietnam, and Thailand and five countries as best practice, comprising of France, Canada, Australia, Taiwan, and South Korea. Rare disease management initiatives across each country were examined based on the World Health Organization's framework for action in strengthening health systems. RESULTS: The results suggest rare disease management remains challenging across Southeast Asia, as many of the focus countries face fundamental issues from basic healthcare systems to funding. Nonetheless, there are substantial improvement opportunities, including leveraging best practices from around the world and organising a multi stakeholder and regional approach and strategy. CONCLUSIONS: Southeast Asian countries have made significant progress in the management of rare disease, but there remain key areas for substantial development opportunities. PMID- 27484655 TI - Efficient Suppression of Hepatitis C Virus Replication by Combination Treatment with miR-122 Antagonism and Direct-acting Antivirals in Cell Culture Systems. AB - Direct-acting antivirals (DAAs) against Hepatitis C virus (HCV) show effective antiviral activity with few side effects. However, the selection of DAA resistance mutants is a growing problem that needs to be resolved. In contrast, miR-122 antagonism shows extensive antiviral effects among all HCV genotypes and a high barrier to drug resistance. In the present study, we evaluated three DAAs (simeprevir, daclatasvir, and sofosbuvir) in combination with anti-miR-122 treatment against HCV genotype 1a in cell cultures. We found that combination treatments with anti-miR-122 and a DAA had additive or synergistic antiviral effects. The EC50 values of simeprevir in simeprevir-resistant mutants were significantly decreased by combining simeprevir with anti-miR-122. A similar reduction in EC50 in daclatasvir-resistant mutants was achieved by combining daclatasvir with anti-miR-122. Combination treatment in HCV-replicating cells with DAA and anti-miR-122 sharply reduced HCV RNA amounts. Conversely, DAA single treatment with simeprevir or daclatasvir reduced HCV RNA levels initially, but the levels later rebounded. DAA-resistant mutants were less frequently observed in combination treatments than in DAA single treatments. In summary, the addition of miR-122 antagonism to DAA single treatments had additive or synergistic antiviral effects and helped to efficiently suppress HCV replication and the emergence of DAA-resistant mutants. PMID- 27484656 TI - The Cardiac Conduction System: Generation and Conduction of the Cardiac Impulse. AB - In this article, the authors outline the key components behind the automated generation of the cardiac impulses and the effect these impulses have on cardiac myocytes. Also, a description of the key components of the normal cardiac conduction system is provided, including the sinoatrial node, the atrioventricular node, the His bundle, the bundle branches, and the Purkinje network. Finally, an outline of how each stage of the cardiac conduction system is represented on the electrocardiogram is described, allowing the reader of the electrocardiogram to translate background information about the normal cardiac conduction system to everyday clinical practice. PMID- 27484657 TI - The Normal Electrocardiogram: Resting 12-Lead and Electrocardiogram Monitoring in the Hospital. AB - The electrocardiogram (ECG) is a well-established diagnostic tool extensively used in clinical settings. Knowledge of cardiac rhythm and mastery of cardiac waveform interpretation are fundamental for intensive care nurses. Recognition of the normal findings for the 12-lead ECG and understanding the significance of changes from baseline in continuous cardiac monitoring are essential steps toward ensuring safe patient care. This article highlights historical developments in electrocardiography, describes the normal resting 12-lead ECG, and discusses the need for continuous cardiac monitoring. In addition, future directions for the ECG are explored briefly. PMID- 27484658 TI - Bradyarrhythmias: Clinical Presentation, Diagnosis, and Management. AB - Bradyarrhythmias are common clinical findings consisting of physiologic and pathologic conditions (sinus node dysfunction and atrioventricular [AV] conduction disturbances). Bradyarrhythmias can be benign, requiring no treatment; however, acute unstable bradycardia can lead to cardiac arrest. In patients with confirmed or suspected bradycardia, a thorough history and physical examination should include possible causes of sinoatrial node dysfunction or AV block. Management of bradycardia is based on the severity of symptoms, the underlying causes, presence of potentially reversible causes, presence of adverse signs, and risk of progression to asystole. Pharmacologic therapy and/or pacing are used to manage unstable or symptomatic bradyarrhythmias. PMID- 27484659 TI - Paroxysmal Supraventricular Tachycardia: Pathophysiology, Diagnosis, and Management. AB - Paroxysmal supraventricular tachycardia (PSVT) is a well-known and thoroughly studied clinical syndrome, characterized by regular tachycardia rhythm with sudden onset and abrupt termination. Most patients present with palpitations and dizziness, and their electrocardiogram demonstrates a narrow QRS complex and regular tachycardia with hidden or inverted P waves. PSVT is caused by re-entry due to the presence of inhomogeneous, accessory, or concealed conducting pathways. Hemodynamically stable patients are treated by vagal maneuvers, intravenous adenosine, diltiazem, or verapamil, hemodynamically unstable patients are treated by cardioversion. Patients with symptomatic and recurrent PSVT can be treated with long-term drug treatment or catheter ablation. PMID- 27484660 TI - Ventricular Tachycardias: Characteristics and Management. AB - Ventricular tachycardias include ventricular tachycardia, ventricular fibrillation, and torsades de pointes; although these rhythms may be benign and asymptomatic, others may be life threatening and lead to increased morbidity and mortality. To optimize patient outcomes, ventricular tachycardias need to be rapidly diagnosed and managed, and often the electrocardiogram (ECG) is the first and only manifestation of a cardiac defect. Understanding of the initial electrocardiographic pattern and subsequent changes can lead to early intervention and an improved outcome. This article describes mechanisms, ECG characteristics, and management of ventricular tachycardias. PMID- 27484662 TI - Acute Coronary Syndrome and ST Segment Monitoring. AB - Acute coronary syndrome (ACS) is caused by a critical obstruction of a coronary artery because of atherosclerotic coronary artery disease. Three specific conditions are included: ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina. The ST segment on the electrocardiogram is a sensitive and specific marker of myocardial ischemia and infarction; however, ST segment deviation is regional not global, thus the ECG lead must be placed over the affected region of the myocardium. This article describes ACS and infarction and the use of ST segment monitoring to detect these conditions. PMID- 27484661 TI - Cardiac Monitoring in the Emergency Department. AB - Patients present to the emergency department (ED) with a wide range of complaints and ED clinicians are responsible for identifying which conditions are life threatening. Cardiac monitoring strategies in the ED include, but are not limited to, 12-lead electrocardiography and bedside cardiac monitoring for arrhythmia and ischemia detection as well as QT-interval monitoring. ED nurses are in a unique position to incorporate cardiac monitoring into the early triage and risk stratification of patients with cardiovascular emergencies to optimize patient management and outcomes. PMID- 27484663 TI - Basic Cardiac Electrophysiology and Common Drug-induced Arrhythmias. AB - Drugs can be a double-edged sword, providing the benefit of symptom alleviation and disease modification but potentially causing harm from adverse cardiac arrhythmic events. Proarrhythmia is the ability of a drug to cause an arrhythmia, the number one reason for drugs to be withdrawn from the patient. Drug-induced arrhythmias are defined as the production of de novo arrhythmias or aggravation of existing arrhythmias, as a result of previous or concomitant pharmacologic treatment. This review summarizes normal cardiac cell and tissue functioning and provides an overview of drugs that effect cardiac repolarization and the adverse effects of commonly administered antiarrhythmics. PMID- 27484664 TI - Arrhythmias and Cardiac Bedside Monitoring in the Neonatal Intensive Care Unit. AB - Cardiac physiology is unique in neonates and infants; there are several physiologic changes that occur in the first weeks of life. Important changes can be captured on the bedside monitor and provide vital data in a noninvasive way to providers. The importance of diligent observation cannot be overstated. Bedside monitoring has improved in the last decade, which has enhanced the ability to detect changes in heart rates and rhythms. The purpose here is to review cardiac physiology, describe those arrhythmias able to be observed on bedside monitors, and highlight heart rate changes that can be early signs of sepsis. PMID- 27484665 TI - In-Hospital Cardiac Arrest: An Update on Pulseless Electrical Activity and Asystole. AB - Nonshockable rhythms, including pulseless electrical activity (PEA) and asystole, precede more than 70% of in-hospital cardiac arrests (I-HCA). Compared with shockable rhythms (ventricular fibrillation and ventricular tachycardia), nonshockable rhythms have higher mortality and morbidity. Therefore, investigating the underlying mechanisms of these arrhythmias to improve the quality of care and outcome for patients who suffer cardiac arrest is a priority. As the first responders to I-HCA, nurses must have the proper knowledge and training to provide timely and efficient cardiopulmonary resuscitation therapy. This article provides an overview of nonshockable cardiac arrhythmias preceding I HCA as a means of addressing the gap between science and clinical practice. PMID- 27484666 TI - Cardiac Arrhythmias. PMID- 27484667 TI - Prognostic enrichment design in clinical trials for autosomal dominant polycystic kidney disease: the HALT-PKD clinical trial. AB - Background: Patients with mild autosomal dominant polycystic kidney disease (ADPKD) are less likely to be informative in randomized clinical trials (RCTs). We previously developed an imaging classification of ADPKD (typical diffuse cyst distribution Class 1A-E and atypical cyst distribution Class 2) for prognostic enrichment design in RCTs. We investigated whether using this classification would have increased the power to detect a beneficial treatment effect of rigorous blood pressure (BP) control on HALT-PKD participants with early disease (Study A). Methods: Post hoc analysis of the early disease HALT-PKD study, an RCT that studied the effect of rigorous versus standard BP control on rates of total kidney volume (TKV) increase and estimated glomerular filtration rate (eGFR) decline in ADPKD patients with eGFR >60 mL/min/1.73 m2. Results: Five hundred and fifty-one patients were classified by two observers (98.2% agreement) into Class 1A (6.2%), 1B (20.3%), 1C (34.1%), 1D (22.1%), 1E (11.8%) and 2 (5.4%). The TKV increase and eGFR decline became steeper from Class 1A through 1E. Rigorous BP control had been shown to be associated with slower TKV increase, without a significant overall effect on the rate of eGFR decline (faster in the first 4 months and marginally slower thereafter). Merging Classes 1A and 2 (lowest severity), 1B and 1C (intermediate severity) and 1D and 1E (highest severity) detected stronger beneficial effects on TKV increase and eGFR decline in Class 1D and E with a smaller number of patients. Conclusions: Strategies for prognostic enrichment, such as image classification, should be used in the design of RCTs for ADPKD to increase their power and reduce their cost. PMID- 27484668 TI - Fermentative production of high titer gluconic and xylonic acids from corn stover feedstock by Gluconobacter oxydans and techno-economic analysis. AB - High titer gluconic acid and xylonic acid were simultaneously fermented by Gluconobacter oxydans DSM 2003 using corn stover feedstock after dry dilute sulfuric acid pretreatment, biodetoxification and high solids content hydrolysis. Maximum sodium gluconate and xylonate were produced at the titer of 132.46g/L and 38.86g/L with the overall yield of 97.12% from glucose and 90.02% from xylose, respectively. The drawbacks of filamentous fungus Aspergillus niger including weak inhibitor tolerance, large pellet formation and no xylose utilization were solved by using the bacterium strain G. oxydans. The obtained sodium gluconate/xylonate product was highly competitive as cement retarder additive to the commercial product from corn feedstock. The techno-economic analysis (TEA) based on the Aspen Plus modeling was performed and the minimum sodium gluconate/xylonate product selling price (MGSP) was calculated as $0.404/kg. This study provided a practical and economic competitive process of lignocellulose utilization for production of value-added biobased chemicals. PMID- 27484669 TI - Boosting dark fermentation with co-cultures of extreme thermophiles for biohythane production from garden waste. AB - Proof of principle of biohythane and potential energy production from garden waste (GW) is demonstrated in this study in a two-step process coupling dark fermentation and anaerobic digestion. The synergistic effect of using co-cultures of extreme thermophiles to intensify biohydrogen dark fermentation is demonstrated using xylose, cellobiose and GW. Co-culture of Caldicellulosiruptor saccharolyticus and Thermotoga maritima showed higher hydrogen production yields from xylose (2.7+/-0.1molmol(-1) total sugar) and cellobiose (4.8+/-0.3molmol(-1) total sugar) compared to individual cultures. Co-culture of extreme thermophiles C. saccharolyticus and Caldicellulosiruptor bescii increased synergistically the hydrogen production yield from GW (98.3+/-6.9Lkg(-1) (VS)) compared to individual cultures and co-culture of T. maritima and C. saccharolyticus. The biochemical methane potential of the fermentation end-products was 322+/-10Lkg(-1) (CODt). Biohythane, a biogas enriched with 15% hydrogen could be obtained from GW, yielding a potential energy generation of 22.2MJkg(-1) (VS). PMID- 27484670 TI - Mitigation of carbon dioxide by oleaginous microalgae for lipids and pigments production: Effect of light illumination and carbon dioxide feeding strategies. AB - Oleaginous microalgae Nannochloropsis sp. was selected as potential strain for CO2 mitigation into lipids and pigments. The synergistic effects of light intensity and photoperiod were evaluated to provide the adequate light energy for this strain. The saturation light intensity was 60MUmol.photon.m(-2)s(-1). With full illumination, the biomass obtained was 0.850+/-0.16g.L(-1) with a lipid content of 44.7+/-1.2%. The pigments content increased with increasing light energy supply. Three main operating factors including initial cell concentration, CO2 content and gas flow rate were optimized through Response Surface Methodology. The feedings with low CO2 content at high gas flow rate gave the maximum biomass but with low lipid content. After optimization, the biomass and lipid production were increased up to 1.30+/-0.103g.L(-1) and 0.515+/-0.010g.L( 1), respectively. The CO2 fixation rate was as high as 0.729+/-0.04g.L(-1)d(-1). The fatty acids of Nannochloropsis sp. lipids were mainly C16-C18 indicating its potential use as biodiesel feedstocks. PMID- 27484671 TI - Study on the bio-methane yield and microbial community structure in enzyme enhanced anaerobic co-digestion of cow manure and corn straw. AB - The use of enzymes to improve anaerobic co-digestion (AcoD) of cow manure and corn straw was explored in this study, including cellulase pretreatment and direct additions of amylase and protease. The effects of enzymes on microbial community structure were investigated though PCR-DGGE method. Results showed that AcoD with amylase achieved the highest methane yield of 377.63ml.CH4/g.VS, which was an increase of 110.79%. The methane increment consumed the amylase of 4.18*10(-5)g/ml.CH4. Enzymes mainly affected the bacteria in the hydrolysis stage rather than the bacteria in the hydrogenesis and acetogenesis stage and the archaea in the methanogenesis stage. However, the experimental results demonstrated that enzymes had no negative influence on microbial communities; the predominant microbial communities were similar. Therefore, AcoD with amylase was an effective way to improve the bio-methane yield of cow manure and corn straw. PMID- 27484672 TI - Butanol production in acetone-butanol-ethanol fermentation with in situ product recovery by adsorption. AB - Activated carbon Norit ROW 0.8, zeolite CBV901, and polymeric resins Dowex Optipore L-493 and SD-2 with high specific loadings and partition coefficients were studied for n-butanol adsorption. Adsorption isotherms were found to follow Langmuir model, which can be used to estimate the amount of butanol adsorbed in acetone-butanol-ethanol (ABE) fermentation. In serum-bottle fermentation with in situ adsorption, activated carbon showed the best performance with 21.9g/L of butanol production. When operated in a fermentor, free- and immobilized-cell fermentations with adsorption produced 31.6g/L and 54.6g/L butanol with productivities of 0.30g/L.h and 0.45g/L.h, respectively. Thermal desorption produced a condensate containing ~167g/L butanol, which resulted in a highly concentrated butanol solution of ~640g/L after spontaneous phase separation. This in situ product recovery process with activated carbon is energy efficient and can be easily integrated with ABE fermentation for n-butanol production. PMID- 27484673 TI - Interplay between up-regulation of cytochrome-c-oxidase and hemoglobin oxygenation induced by near-infrared laser. AB - Photobiomodulation, also known as low-level laser/light therapy (LLLT), refers to the use of red-to-near-infrared light to stimulate cellular functions for physiological or clinical benefits. The mechanism of LLLT is assumed to rely on photon absorption by cytochrome c oxidase (CCO), the terminal enzyme in the mitochondrial respiratory chain that catalyzes the reduction of oxygen for energy metabolism. In this study, we used broadband near-infrared spectroscopy (NIRS) to measure the LLLT-induced changes in CCO and hemoglobin concentrations in human forearms in vivo. Eleven healthy participants were administered with 1064-nm laser and placebo treatments on their right forearms. The spectroscopic data were analyzed and fitted with wavelength-dependent, modified Beer-Lambert Law. We found that LLLT induced significant increases of CCO concentration (Delta[CCO]) and oxygenated hemoglobin concentration (Delta[HbO]) on the treated site as the laser energy dose accumulated over time. A strong linear interplay between Delta[CCO] and Delta[HbO] was observed for the first time during LLLT, indicating a hemodynamic response of oxygen supply and blood volume closely coupled to the up-regulation of CCO induced by photobiomodulation. These results demonstrate the tremendous potential of broadband NIRS as a non-invasive, in vivo means to study mechanisms of photobiomodulation and perform treatment evaluations of LLLT. PMID- 27484674 TI - Parenting while living with advanced cancer: A qualitative study. AB - BACKGROUND: Patients with advanced cancer who have dependent children are an important population with a life-limiting illness and high levels of psychological distress. Few studies have addressed the experience of being a parent with advanced cancer and their potential palliative needs. AIM: To describe the experience of living with advanced cancer as a parent, including illness experience, parental concerns, and treatment decision making and to explore whether these experiences differ by their functional status. DESIGN: We conducted a cross-sectional, qualitative study using in-depth, semi-structured interviews. Data were analyzed using thematic content analysis. SETTING AND PARTICIPANTS: A total of 42 participants with metastatic cancer and with at least one child under the age of 18 years were recruited from a comprehensive cancer center. 25 participants were rated as having high functional status (the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale = 0-1) and 17 with low functional status (ECOG=2-4). RESULTS: We identified four themes regarding the experience of being a parent with advanced cancer: (1) parental concerns about the impact of their illness and death on their children, (2) "missing out" and losses of parental role and responsibilities, (3) maintaining parental responsibilities despite life-limiting illness, and (4) parental identity influencing decision making about treatment. Parental functional status influenced not only physical responsibilities but also intensified parenting psychological concerns. CONCLUSION: Parents with metastatic cancer may have unique palliative care needs as they experience parenting concerns while managing the psychological and physical demands of advanced cancer. PMID- 27484675 TI - Molecular and Pharmacologic Properties of the Anticancer Quinolone Derivative Vosaroxin: A New Therapeutic Agent for Acute Myeloid Leukemia. AB - Vosaroxin is a first-in-class anticancer quinolone derivative that targets topoisomerase II and induces site-selective double-strand breaks in DNA, leading to tumor cell apoptosis. Vosaroxin has chemical and pharmacologic characteristics distinct from other topoisomerase II inhibitors due to its quinolone scaffold. The efficacy and safety of vosaroxin in combination with cytarabine were evaluated in patients with relapsed/refractory acute myeloid leukemia (AML) in a phase III, randomized, multicenter, double-blind, placebo-controlled study (VALOR). In this study, the addition of vosaroxin produced a 1.4-month improvement in median overall survival (OS; 7.5 months with vosaroxin/cytarabine vs. 6.1 months with placebo/cytarabine; hazard ratio [HR] 0.87, 95 % confidence interval [CI] 0.73-1.02; unstratified log-rank p [Formula: see text] 0.061; stratified log-rank p [Formula: see text]0.024), with the greatest OS benefit observed in patients >=60 years of age (7.1 vs. 5.0 months; HR 0.75, 95 % CI 0.62 0.92; p [Formula: see text]0.003) and patients with early relapse (6.7 vs. 5.2 months; HR 0.77, 95 % CI 0.59-1.00; p [Formula: see text] 0.039), two AML patient groups that typically have poor prognosis. Here we review the chemical and pharmacologic properties of vosaroxin, how these properties are distinct from those of currently available topoisomerase II inhibitors, how they may contribute to the efficacy and safety profile observed in the VALOR trial, and the status of clinical development of vosaroxin for treatment of AML. PMID- 27484676 TI - Klokwerk + study protocol: An observational study to the effects of night-shift work on body weight and infection susceptibility and the mechanisms underlying these health effects. AB - BACKGROUND: Night-shift work may cause severe disturbances in the worker's circadian rhythm, which has been associated with the onset of health problems and diseases. As a substantial part of the workforce is exposed to night-shift work, harmful aspects of night-shift work should not be overlooked. The aim of the Klokwerk + study is to study the effects of night-shift work on body weight and infection susceptibility and the mechanisms underlying these health effects. First, we will study the relation between night-shift work exposure and body weight and between night-shift work exposure and infection susceptibility. Second, we will examine the mechanisms linking night-shift work exposure to body weight and infection susceptibility, with a specific focus on sleep, physical activity, diet, light exposure, vitamin D level, and immunological factors. Lastly, we will focus on the identification of biomarkers for chronic circadian disturbance associated with night-shift work. METHODS/DESIGN: The design of this study is a prospective observational cohort study consisting of 1,960 health care workers aged 18-65 years. The study population will consist of a group of night shift workers and an equally sized group of non-night-shift workers. During the study, there will be two measurement periods. As one of the main outcomes of this study is infection susceptibility, the measurement periods will take place at approximately the first (September/October) (T0) and the last month (April/May) (T1, after 6 months) of the flu season. The measurements will consist of questionnaires, anthropometric measurements, a smartphone application to determine infection susceptibility, food diaries, actigraphy, light sensors, and blood sample analyses. DISCUSSION: The Klokwerk + study will contribute to the current need for high-quality data on the health effects of night-shift work and its underlying behavioral and physiological mechanisms. The findings can be the starting point for the development of interventions that prevent negative health effects caused by night-shift work. In addition, the identification of biomarkers indicative of loss of homeostasis due to circadian disturbance may be an important asset in monitoring the effects of such interventions. PMID- 27484677 TI - Optimization of Routine Monitoring of Workers Exposed to Plutonium Aerosols. AB - In case of incidental confinement failure, mixed oxide (MOX) fuel preparation may expose workers to plutonium aerosols. Due to its potential toxicity, occupational exposure to plutonium compounds should be kept as low as reasonably achievable. To ensure the absence of significant intake of radionuclides, workers at risk of internal contamination are monitored by periodic bioassay planned in a routine monitoring programme. From bioassay results, internal dose may be estimated. However, accurate dose calculation relies on known exposure conditions, which are rarely available when the exposure is demonstrated by routine monitoring only. Therefore, internal dose calculation is subject to uncertainty from unknown exposure conditions and from activity measurement variability. The present study calculates the minimum detectable dose (MDD) for a routine monitoring programme by considering all plausible conditions of exposure and measurement uncertainty. The MDD evaluates the monitoring quality and can be used for optimization. Here, MDDs were calculated for the monitoring of workers preparing MOX fuel. Uncertain parameters were modelled by probability distributions defined according to information provided by experts of routine monitoring, of workplace radiological protection and of bioassay analysis. Results show that the current monitoring is well adapted to potential exposure. A sensitivity study of MDD highlights high dependence on exposure condition modelling. Integrating all expert knowledge is therefore crucial to obtain reliable MDD estimates, stressing the value of a holistic approach to worker monitoring. PMID- 27484679 TI - [Osteosynthesis of displaced fractures of the greater tuberosity with the Bamberg plate]. AB - OBJECTIVE: Internal fixation of displaced fractures of the greater tuberosity allowing functional aftercare. INDICATIONS: Displaced fractures of the greater tuberosity >5 mm. Displaced fractures of the greater tuberosity >3 mm in athletes or overhead workers. Multiply fragmented fractures of the greater tuberosity. CONTRAINDICATIONS: Displaced 3- or 4-part fractures of the proximal humerus. Nondisplaced fractures of the greater tuberosity. SURGICAL TECHNIQUE: Exposure of the fracture of the greater tuberosity by an anterolateral approach. Open reduction and temporary retention with a Kirschner wire or a "Kugelspiebeta" or reinforcement of the supraspinatus tendon and distal retention. Bending and positioning of the Bamberg plate and fixation by conventional or locking screws. Optional fixation of the rotator cuff to the plate. Exact monitoring of the implant position using the image intensifier to avoid inadequate distalization of the greater tuberosity. POSTOPERATIVE MANAGEMENT: Arm sling (e. g. Gilchrist) for 2 weeks. Start passive assisted exercise on postoperative day 1. Movement allowed up to the pain threshold. Physiotherapeutic treatment to prevent adhesions and capsular shrinking. RESULTS: In all, 10 patients with displaced fractures of the greater tuberosity underwent osteosynthesis using the Bamberg plate. After a follow-up of at least 6 months, a Constant-Murley score of 94.2 points (range 91 98 points) was achieved. The patients' average age was 45.6 years (range 29-68 years). PMID- 27484678 TI - [Surgical treatment of anterosuperior impingement of the shoulder]. AB - OBJECTIVE: Therapy of intraarticular lesions and elimination of structural risk factors for those suffering from clinical manifest anterosuperiorer impingement (ASI) of the shoulder. This includes as a maximum version the arthroscopic repair of supraspinatus (SST) and subscapularis tendon (SCT) tears with subsequent subpectoral tenodesis of the long head of the biceps tendon (LBT) and arthroscopic coracoplasty. INDICATIONS: Clinical manifest anterosuperiorer impingement of the shoulder with anterior shoulder pain, failed conservative treatment and clear intraarticular damage in radiological imaging. This involves in detail lesions of the SST, SCT and damage to the LBT. CONTRAINDICATIONS: Lack of structural intraarticular lesions or massive osteoarthritis. Persistent dysfunction of active and passive glenohumeral and scapulathoracal motion, due to neurologic deficits or stiff shoulder. A hypertrophic or deformed healed coracoid process is seen as a structural risk factor for suffering from ASI and should be addressed surgically when causing impingement. SURGICAL TECHNIQUE: Arthroscopic tenotomy of the LBT with subsequent repair of the SST and SCT. Arthroscopic coracoplasty if indicated and subpectoral tenodesis of the long head of the biceps. POSTOPERATIVE MANAGEMENT: No biceps activity and intermittent immobilization in sling for 6 weeks. Limitation of abduction, flexion and external rotation for 6 weeks depending on rotator cuff tendon repair. Start of sport-specific training after 3 months, over-head sports 6 months postoperatively. RESULTS: The arthroscopic repair of anterosuperior rotator cuff tears provides reliable results for improvement in function, decreases in pain and improvement in shoulder scores. The overall rate of adverse events is low. PMID- 27484680 TI - Total synthesis of teixobactin. AB - To cope with the global bacterial multidrug resistance, scientific communities have devoted significant efforts to develop novel antibiotics, particularly those with new modes of actions. Teixobactin, recently isolated from uncultured bacteria, is considered as a promising first-in-class drug candidate for clinical development. Herein, we report its total synthesis by a highly convergent Ser ligation approach and this strategy allows us to prepare several analogues of the natural product. PMID- 27484681 TI - Fluid overload in the ICU: evaluation and management. AB - BACKGROUND: Fluid overload is frequently found in acute kidney injury patients in critical care units. Recent studies have shown the relationship of fluid overload with adverse outcomes; hence, manage and optimization of fluid balance becomes a central component of the management of critically ill patients. DISCUSSION: In critically ill patients, in order to restore cardiac output, systemic blood pressure and renal perfusion an adequate fluid resuscitation is essential. Achieving an appropriate level of volume management requires knowledge of the underlying pathophysiology, evaluation of volume status, and selection of appropriate solution for volume repletion, and maintenance and modulation of the tissue perfusion. Numerous recent studies have established a correlation between fluid overload and mortality in critically ill patients. Fluid overload recognition and assessment requires an accurate documentation of intakes and outputs; yet, there is a wide difference in how it is evaluated, reviewed and utilized. Accurate volume status evaluation is essential for appropriate therapy since errors of volume evaluation can result in either in lack of essential treatment or unnecessary fluid administration, and both scenarios are associated with increased mortality. There are several methods to evaluate fluid status; however, most of the tests currently used are fairly inaccurate. Diuretics, especially loop diuretics, remain a valid therapeutic alternative. Fluid overload refractory to medical therapy requires the application of extracorporeal therapies. In critically ill patients, fluid overload is related to increased mortality and also lead to several complications like pulmonary edema, cardiac failure, delayed wound healing, tissue breakdown, and impaired bowel function. Therefore, the evaluation of volume status is crucial in the early management of critically ill patients. Diuretics are frequently used as an initial therapy; however, due to their limited effectiveness the use of continuous renal replacement techniques are often required for fluid overload treatment. Successful fluid overload treatment depends on precise assessment of individual volume status, understanding the principles of fluid management with ultrafiltration, and clear treatment goals. PMID- 27484682 TI - Association Between Initial Opioid Prescribing Patterns and Subsequent Long-Term Use Among Opioid-Naive Patients: A Statewide Retrospective Cohort Study. AB - BACKGROUND: Long-term efficacy of opioids for non-cancer pain is unproven, but risks argue for cautious prescribing. Few data suggest how long or how much opioid can be prescribed for opioid-naive patients without inadvertently promoting long-term use. OBJECTIVE: To examine the association between initial opioid prescribing patterns and likelihood of long-term use among opioid-naive patients. DESIGN: Retrospective cohort study; data from Oregon resident prescriptions linked to death certificates and hospital discharges. PARTICIPANTS: Patients filling opioid prescriptions between October 1, 2012, and September 30, 2013, with no opioid fills for the previous 365 days. Subgroup analyses examined patients under age 45 who did not die in the follow-up year, excluding most cancer or palliative care patients. MAIN MEASURES: Exposure: Numbers of prescription fills and cumulative morphine milligram equivalents (MMEs) dispensed during 30 days following opioid initiation ("initiation month"). OUTCOME: Proportion of patients with six or more opioid fills during the subsequent year ("long-term users"). KEY RESULTS: There were 536,767 opioid-naive patients who filled an opioid prescription. Of these, 26,785 (5.0 %) became long-term users. Numbers of fills and cumulative MMEs during the initiation month were associated with long-term use. Among patients under age 45 using short-acting opioids who did not die in the follow-up year, the adjusted odds ratio (OR) for long-term use among those receiving two fills versus one was 2.25 (95 % CI: 2.17, 2.33). Compared to those who received < 120 total MMEs, those who received between 400 and 799 had an OR of 2.96 (95 % CI: 2.81, 3.11). Patients initiating with long acting opioids had a higher risk of long-term use than those initiating with short-acting drugs. CONCLUSIONS: Early opioid prescribing patterns are associated with long-term use. While patient characteristics are important, clinicians have greater control over initial prescribing. Our findings may help minimize the risk of inadvertently initiating long-term opioid use. PMID- 27484683 TI - A co-design process developing heuristics for practitioners providing end of life care for people with dementia. AB - BACKGROUND: The end of life for someone with dementia can present many challenges for practitioners; such as, providing care if there are swallowing difficulties. This study aimed to develop a toolkit of heuristics (rules-of-thumb) to aid practitioners making end-of-life care decisions for people with dementia. METHODS: An iterative co-design approach was adopted using a literature review and qualitative methods, including; 1) qualitative interviews and focus groups with family carers and 2) focus groups with health and care professionals. Family carers were recruited from a national charity, purposively sampling those with experience of end-of-life care for a person with dementia. Health and care professionals were purposively sampled to include a broad range of expertise including; general practitioners, palliative care specialists, and geriatricians. A co-design group was established consisting of health and social care experts and family carers, to synthesise the findings from the qualitative work and produce a toolkit of heuristics to be tested in practice. RESULTS: Four broad areas were identified as requiring complex decisions at the end of life; 1) eating/swallowing difficulties, 2) agitation/restlessness, 3) ending life sustaining treatment, and 4) providing "routine care" at the end of life. Each topic became a heuristic consisting of rules arranged into flowcharts. Eating/swallowing difficulties have three rules; ensuring eating/swallowing difficulties do not come as a surprise, considering if the situation is an emergency, and considering 'comfort feeding' only versus time-trialled artificial feeding. Agitation/restlessness encourages a holistic approach, considering the environment, physical causes, and the carer's wellbeing. Ending life-sustaining treatment supports practitioners through a process of considering the benefits of treatment versus quality-of-life and comfort. Finally, a heuristic on providing routine care such as bathing, prompts practitioners to consider adapting the delivery of care, in order to promote comfort and dignity at the end of life. CONCLUSIONS: The heuristics are easy to use and remember, offering a novel approach to decision making for dementia end-of-life care. They have the potential to be used alongside existing end-of-life care recommendations, adding more readily available practical assistance. This is the first study to synthesise experience and existing evidence into easy-to-use heuristics for dementia end-of-life care. PMID- 27484685 TI - Circulating ferritin concentrations are differentially associated with serum adipokine concentrations in Japanese men and premenopausal women. AB - PURPOSE: Increased iron storage, as measured by circulating ferritin, has been linked to an increased risk of various diseases including diabetes. We examined the association of circulating ferritin with serum adiponectin, leptin, resistin, plasminogen activator inhibitor-1 (PAI-1), and visfatin levels. METHODS: We conducted a cross-sectional study among 429 Japanese employees (284 men and 145 premenopausal women, mean age: 42.5 +/- 10.5 years). Serum adipokines were measured using Luminex suspension bead-based multiplexed array, and serum ferritin was determined using a chemiluminescence immunoassay. Multivariable regression analysis was performed to calculate mean concentrations of adipokine according to the tertile of ferritin concentrations with adjustment for potential confounders. RESULTS: Leptin and visfatin concentrations increased with increasing ferritin concentrations in men after multivariable adjustment of physical activity, smoking, alcohol use, and body mass index (P for trend = 0.02 and 0.01 for leptin and visfatin, respectively). Serum ferritin concentrations were inversely and significantly associated with adiponectin in women (P for trend = 0.01). Resistin and PAI-1 were not appreciably associated with ferritin concentration. CONCLUSIONS: Increased iron storage may be associated with higher circulating concentrations of leptin and visfatin in men and with lower concentrations of adiponectin in women. PMID- 27484686 TI - Risks associated with antipsychotic treatment in pregnancy: Comparative cohort studies based on electronic health records. AB - BACKGROUND: Limited information is available on whether antipsychotics prescribed in pregnancy are associated with increased risks of adverse outcomes. METHODS: We used electronic health records from pregnant women and their children to examine risks of adverse maternal and child outcomes in three cohorts of women who: (A) received antipsychotic treatment in pregnancy (n=416) (B) discontinued antipsychotic treatment before pregnancy (n=670), and (C) had no records of antipsychotic treatment before or during pregnancy (n=318,434). Absolute and risk ratios were estimated and adjusted for health and lifestyle and concomitant medications. RESULTS: Caesarean section was more common in cohort A (25%) than C (18%), but non-significant after adjustment for health and lifestyle factors (Risk Ratio (adj.) 1.09 (95% CI: 0.92, 1.30). Proportion of gestational diabetes was similar in cohort A (2.6%) and B (2.7%), but lower in A than B after adjustments (RRadj: 0.43 (0.20, 0.93). Premature birth/low birthweight were more common in cohort A (10%) than B (4.3%) and C (3.9%), A versus B (RRadj: 2.04 (1.13, 3.67), A versus C (RRadj: 1.43 (0.99, 2.05). Major congenital malformations were more common in A (3.4%), than B (2.2%) and C (2%). However no significant difference was observed (A versus B: RRadj: 1.79 (0.72, 4.47) A versus C RRadj: 1.59 (0.84, 3.00)). Risks estimates were similar for women prescribed atypical and typical antipsychotics. CONCLUSIONS: Antipsychotic treatment in pregnancy carries limited risks of adverse pregnancy and birth outcomes once adjustments have been made for health and lifestyle factors. PMID- 27484687 TI - Synthesis and characterization of a novel near-infrared fluorescent probe for applications in imaging A549 cells. AB - OBJECTIVE: To design and synthesize a novel near-infrared (NIR) fluorescent probe based on indocyanine Green (ICG), that can be applied in imaging living cells. RESULTS: A highly fluorescent novel NIR fluorescent probe (IR-793) was synthesized in two steps. IR-793 had better fluorescence and optical stability than ICG. In addition, no obvious cytotoxicity effect of IR-793 was observed and cell viability was above 75% at the maximum concentration (120 nM). IR-793 also exhibited good performance in imaging living A549 cells. CONCLUSION: IR-793, a novel NIR fluorescent probe that is stable, low-cost, highly fluorescent and low cytotoxicity, has been designed and synthesized for imaging living cells. PMID- 27484684 TI - Vitamin D Deficiency and Rheumatoid Arthritis. AB - Vitamin D (VitD) is a hormone primarily synthesized in human skin under the stimulation of ultraviolet radiation. Beyond its endocrine role in bone metabolism, VitD is endowed with remarkable immunomodulatory properties. The effects of VitD on the immune system include the enhancement of microbicidal ability of monocytes/macrophages and the down-modulation of inflammatory cytokines produced by T lymphocytes. VitD deficiency is involved in many health problems, including immune-mediated diseases such as autoimmune disorders. Rheumatoid arthritis (RA) is a chronic inflammatory systemic autoimmune disease that compromises the joints, causing cartilage destruction and bone erosion. RA treatment usually consists of combined therapies that generally suppress the entire immune response leading to increased susceptibility to infections. This review describes the main effects of VitD on innate and adaptive immune system and also VitD status in inflammatory rheumatic diseases such as RA. Despite some controversies, the majority of reports reinforce the idea that lower VitD levels correlate with more severe clinical manifestations in RA and other rheumatic diseases. Therefore, supplementation with VitD to achieve normal serum levels is worthwhile as an aforethought. Original data concerning the potential applicability of 1,25-dihydroxyvitamin D3 (VitD3), the active form of vitamin D, as a tolerogenic adjuvant are also included. In this sense, the effect of VitD3 associated with proteoglycan (PG), which is a specific cartilage antigen, was tested in the course of experimental arthritis. This association significantly lowered clinical scores and local histopathological alterations. Even though local analysis of T cell subsets and cytokine production did not reveal any difference between the experimental groups, VitD3+PG association significantly reduced cytokine production by spleen cells. These results suggest that VitD3 played a role as a tolerogenic adjuvant by down-modulating the course of experimental RA. Considering this tolerogenic effect of VitD3+PG association, further investigations will reveal its plausible use in human RA. PMID- 27484688 TI - Silencing of Mythimna separata chitinase genes via oral delivery of in planta expressed RNAi effectors from a recombinant plant virus. AB - OBJECTIVES: To evaluate transient expression of RNA interference (RNAi) effectors in Nicotiana benthamiana plants by using recombinant virus vectors and also oral delivery of the effectors for silencing of Mythimna separata endogenous gene expression. RESULTS: Mythimna separata is a serious pest of corn production in China. To evaluate RNAi approaches to target specific RNAs in M. separate, we cloned fragments of the M. separata chitinase sequences into a virus vector in order to produce RNAi effectors during virus infection and replication in plants. When the infected plants were fed to M. separata, expression levels of target MseChi1 and MseChi2 genes were down-regulated by 76 and 45 %, respectively, and sequence-specific siRNAs were detected in recipient insects. RNAi-based silencing of chitinase genes also led to body weight decreases by 43 %. CONCLUSION: Our research demonstrates target mRNA knockdown and suggests a promising application for controlling of M. separata by in planta expression of RNAi effectors using a recombinant plant virus. PMID- 27484689 TI - Exosomes derived from tumor cells genetically modified to express Mycobacterium tuberculosis antigen: a novel vaccine for cancer therapy. AB - OBJECTIVES: To examine the potential of exosomes derived from the tumor cells, which had been genetically modified to express a Mycobacterium tuberculosis antigen, as a cancer vaccine aimed at overcoming the weak immunogenicity of tumor antigens. RESULTS: We transfected B16 melanoma cells with a plasmid encoding the M. tuberculosis antigen, early secretory antigenic target-6 (ESAT-6). The secreted exosomes bearing both tumor-associated antigens and the pathogenic antigen (or their epitopes) were collected. When the exosomes were injected into foot pads of mice, they significantly (p < 0.05) evoked cellular immunity against both ESAT-6, and B16 tumor cells. Intra-tumoral injection of the exosomes significantly suppressed (p < 0.001) tumor growth in syngeneic B16 tumor-bearing mice, while the exosomes derived from the non-transfected B16 cells showed no effect on tumor growth, although both exosomes should have similar tumor antigens. CONCLUSIONS: Exosomes bearing both tumor antigens and the M. tuberculosis antigen (or their epitopes) have a high potential as a candidate for cancer vaccine to overcome the immune escape by tumor cells. PMID- 27484690 TI - The influence of water resistance therapy on vocal fold vibration: a high-speed digital imaging study. AB - PURPOSE: This study investigated the influence of tube phonation into water on vocal fold vibration. METHOD: Eight participants were analyzed via high-speed digital imaging while phonating into a silicon tube with the free end submerged into water. Two test sequences were studied: (1) phonation pre, during, and post tube submerged 5 cm into water; and (2) phonation into tube submerged 5 cm, 10 cm, and 18 cm into water. Several glottal area parameters were calculated using phonovibrograms. RESULTS: The results showed individual differences. However, certain trends were possible to identify based on similar results found for the majority of participants. Amplitude-to-length ratio, harmonic-to-noise ratio, and spectral flatness (derived from glottal area) decreased for all tube immersion depths, while glottal closing quotient increased for 10 cm immersion and contact quotient for 18 cm immersion. Closed quotient decreased during phonation into the tube at 5 cm depth, and jitter decreased during and after it. CONCLUSION: Results suggest that the depth of tube submersion appears to have an effect on phonation. Shallow immersion seems to promote smoother and more stable phonation, while deeper immersion may involve increased respiratory and glottal effort to compensate for the increased supraglottal resistance. This disparity, which is dependent upon the degree of flow resistance, should be considered when choosing treatment exercises for patients with various diagnoses, namely hyperfunctional or hypofunctional dysphonia. PMID- 27484691 TI - In This Issue: Antiestrogen Withdrawal, Yoga, and a Reflection on Quality of Clinical Trials. PMID- 27484693 TI - Modulation of cardiac autonomic tone in non-hypotensive hypovolemia during blood donation. AB - Non-hypotensive hypovolemia, observed during mild haemorrhage or blood donation leads to reflex readjustment of the cardiac autonomic tone. In the present study, the cardiac autonomic tone was quantified using heart rate and blood pressure variability during and after non-hypotensive hypovolemia of blood donation. 86 voluntary healthy male blood donors were recruited for the study (age 35 +/- 9 years; weight 78 +/- 12 kg; height 174 +/- 6 cms). Continuous lead II ECG and beat-to-beat blood pressure was recorded before, during and after blood donation followed by offline time and frequency domain analysis of HRV and BPV. The overall heart rate variability (SDNN and total power) did not change during or after blood donation. However, there was a decrease in indices that represent the parasympathetic component (pNN50 %, SDSD and HF) while an increase was observed in sympathetic component (LF) along with an increase in sympathovagal balance (LF:HF ratio) during blood donation. These changes were sustained for the period immediately following blood donation. No fall of blood pressure was observed during the period of study. The blood pressure variability showed an increase in the SDNN, CoV and RMSSD time domain measures in the post donation period. These results suggest that mild hypovolemia produced by blood donation is non hypotensive but is associated with significant changes in the autonomic tone. The increased blood pressure variability and heart rate changes that are seen only in the later part of donation period could be because of the progressive hypovolemia associated parasympathetic withdrawal and sympathetic activation that manifest during the course of blood donation. PMID- 27484694 TI - Phytoremediation: State-of-the-art and a key role for the plant microbiome in future trends and research prospects. AB - Phytoremediation is increasingly adopted as a more sustainable approach for soil remediation. However, significant advances in efficiency are still necessary to attain higher levels of environmental and economic sustainability. Current interventions do not always give the expected outcomes in field settings due to an incomplete understanding of the multicomponent biological interactions. New advances in -omics are gradually implemented for studying microbial communities of polluted land in situ. This opens new perspectives for the discovery of biodegradative strains and provides us new ways of interfering with microbial communities to enhance bioremediation rates. This review presents retrospectives and future perspectives for plant microbiome studies relevant to phytoremediation, as well as some knowledge gaps in this promising research field. The implementation of phytoremediation in soil clean-up management systems is discussed, and an overview of the promoting factors that determine the growth of the phytoremediation market is given. Continuous growth is expected since elimination of contaminants from the environment is demanded. The evolution of scientific thought from a reductionist view to a more holistic approach will boost phytoremediation as an efficient and reliable phytotechnology. It is anticipated that phytoremediation will prove the most promising for organic contaminant degradation and bioenergy crop production on marginal land. PMID- 27484695 TI - Targeted tissue perfusion versus macrocirculation-guided standard care in patients with septic shock (TARTARE-2S): study protocol and statistical analysis plan for a randomized controlled trial. AB - BACKGROUND: Septic shock has a 90-day mortality risk of up to 50 %. The hemodynamic targets, including mean arterial pressure (MAP) are not based on robust clinical data. Both severe hypotension and high doses of vasopressors may be harmful. Hence, re-evaluation of hemodynamic targets in septic shock is relevant. METHODS/DESIGN: The targeted tissue perfusion versus macrocirculation guided standard care in patients with septic shock (TARTARE-2S) trial is a prospective, two-parallel-group, randomized, open-label, multicenter trial with assessor-blinded outcome evaluation. We will randomize at least 200 patients with septic shock in four European intensive care units (ICUs) to test whether a tissue perfusion-guided treatment strategy based on capillary refill time, peripheral temperature, arterial lactate concentrations, and accepting lower MAP levels, leads to a faster resolution of shock than macrocirculation target-guided standard care. The primary outcome measure is days alive in 30 days with normal arterial blood lactate (first value of <2 mmol/L) and without any inotropic or vasopressor agent. Secondary outcomes include individual components of the primary outcome, days alive without renal replacement, days alive without mechanical ventilation in 30 days, and new acute kidney injury. The sample size enables detection of a 13.5-h difference in the primary outcome with a type 1 error of 5 % and power of 80 %, assuming 25 % mortality and a mean of 650 h (SD 30) among the 30-day survivors. After 150 included patients the statistician masked for allocation group will recalculate the sample size potentially increasing the sample up to 300. The Data Safety and Monitoring Board (DSMB) will review the safety data after 100 patients. DISCUSSION: The TARTARE-2S trial will provide important clinical data on treatment targets in septic shock, evaluating the impact of clinical tissue perfusion-guided hemodynamic treatment on a surrogate outcome combining resolution of shock (hyperlactatemia and vasopressors/inotropes), and 30-day mortality. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02579525 . Registered on 19 October 2015. PMID- 27484696 TI - Preventive effects of Resveratrol against azoxymethane-induced testis injury in rats. AB - To evaluate the protective effects of Resveratrol (RES) on azoxymethane (AOM) induced testicular damage using histopathology and biochemical analyses, 28 male rats were randomly divided into four groups. Groups were control, RES, AOM and ARES. At the end of the 7 weeks, following routine tissue processing procedure, testis sections were stained with haematoxylin-eosin and Masson's trichrome. The blood samples were taken for biochemical analysis of testosterone, total oxidative stress, total antioxidant status and oxidative stress index. Degenerative changes in the seminiferous tubules such as atrophy, loss in the number of germ cells and arrested spermatogenic cell, and increase in the connective tissue of the tunica albuginea in the groups with AOM treatment were found. RES treatment (ARES) reduced the number of affected seminiferous tubules significantly (p < .05) compared to AOM alone. The testosterone levels in AOM group were significantly lower than in the control group (p < .05). The total oxidative stress levels were significantly higher in AOM group compared to control group (p < .05). The total antioxidant status levels in ARES group were significantly higher than in the AOM group (p < .05). This study results suggest that an antioxidant like Resveratrol may be useful for decreasing the harmful effects of azoxymethane. PMID- 27484697 TI - Cognitive fusion and emotion differentiation: does getting entangled with our thoughts dysregulate the generation, experience and regulation of emotion? AB - We tested whether cognitive fusion impairs emotion differentiation and thereby mediates relations between cognitive fusion and depression and panic symptoms among 55 adults (Mage = 26.8 (3.9), 50.9% women). Using visual stimuli, we elicited multiple emotion states and measured (a) emotional intensity - the subjective emotion intensity of elicited emotions (i.e. Specific Emotion Intensity - SEI), as well as (b) emotional differentiation - the degree of co activation of multiple negative emotions when a specific emotion was elicited (i.e. Multiple Emotion Co-Activation - MECA). First, as hypothesised, we found that cognitive fusion predicted lower levels of emotion differentiation (MECA). In contrast, as hypothesised, these effects were significantly greater than the (null) effects of cognitive fusion on emotion intensity (SEI). Second, as predicted, MECA, but not SEI, predicted depression and panic symptoms. Finally, we found that MECA mediated the effects of cognitive fusion on depression and panic symptoms. The present findings contribute novel, preliminary empirical insight into associations between cognitive fusion, impaired emotion differentiation and mental ill-health. PMID- 27484692 TI - Are Alcohol Anti-relapsing and Alcohol Withdrawal Drugs Useful in Cannabinoid Users? AB - Cannabinoids are still classified as illegal psychoactive drugs despite their broad and increasingly acknowledged therapeutic potential. These substances are most famous for their wide recreational use, particularly among young adults to either alter the state of consciousness, intensify pleasure induced by other psychoactive substances or as an alternative to the previously abused drugs. It is important to emphasize that cannabinoids are often taken together with a variety of medications intended for the treatment of alcohol use disorder (AUD) or alcohol withdrawal syndrome (AWS). These medications include disulfiram, acamprosate, and naltrexone. In this paper, we summarize recent advances in the knowledge of possible beneficial effects and interactions between cannabinoids and drugs commonly used for treatment of AUD and AWS either comorbid or existing as a separate disorder. PMID- 27484698 TI - Effect of stress and attention on startle response and prepulse inhibition. AB - The startle reflex magnitude can be modulated when a weak stimulus is presented before the onset of the startle stimulus, a phenomenon termed prepulse inhibition (PPI). Previous research has demonstrated that emotional processes can modulate PPI and startle intensity, but the available evidence is inconclusive. In order to obtain additional evidence in this domain, we conducted two experiments intended to analyze the effect of induced stress and attentional load on PPI and startle magnitude. Specifically, in Experiment 1 we used a between subject strategy to evaluate the effect on startle response and PPI magnitude of performing a difficult task intended to induce stress in the participants, as compared to a group exposed to a control task. In Experiment 2 we evaluated the effect of diverting attention from the acoustic stimulus on startle and PPI intensity. The results seem to indicate that induced stress can reduce PPI, and that startle reflex intensity is reduced when attention is directed away from the auditory stimulus that induces the reflex. PMID- 27484699 TI - Melatonin modulates tonic immobility and vigilance behavioural responses of broiler chickens to lighting regimens during the hot-dry season. AB - Experiments were conducted with the aim of determining the influence of melatonin administration on vigilance and tonic immobility (TI) responses of Marshall broiler chickens. The broiler chickens were reared on different lighting regimens and subjected to heat stress during the hot-dry season. Simple random sampling was used to assign 300 broiler chicks into three groups, comprising 100 broiler chicks each. Group I (12D:12L cycle) was raised under natural photoperiod of 12-h light and 12-h darkness, without melatonin supplementation. Group II (CL) was kept under 24-h continuous lighting, without melatonin administration. Group III (CL+MEL) was raised under 24-h continuous lighting; with melatonin supplementation at 0.5mg/kg per os, via drinking water using a syringe. Beginning from day-old, broiler chickens in group III were individually administered with melatonin once daily for 8weeks at 17:00h. TI was induced by manual restraint, and vigilance elicited at self-righting graded for three days, two weeks apart, in 15 labeled broiler chickens from each of the three groups; at 06:00h, 13:00h and 18:00h, starting from week 4-8. Each broiler chicken was laid on its back in a U-shaped cradle, covered with cloth. Thermal microenvironment parameters of dry bulb temperature (DBT) and relative humidity (RH) were recorded at the experimental site, concurrently during the vigilance and TI tests. Inside the broiler chickens' house, the weekly temperature-humidity index (THI) was lowest at week 4 of the study, with the value of 48.60+/-0.08 degrees C. At week 4, the relationship between the THI and TI induction attempts was stronger in 12D:12L cycle (r=0.589, P<0.001) than CL (r=0.264, P>0.05) or CL+MEL (r=0.096, P>0.05) broiler chickens. This indicated that the broiler chickens on 12D:12L cycle were more active compared to their melatonin-treated counterparts, apparently due to adverse effects of high DBT and high RH on the broiler chickens during the hot dry season. The highest numbers of TI induction trial attempts were recorded at 13:00h in 12D:12L cycle and CL groups (2.13+/-0.34 and 2.15+/-0.22, respectively), when the broiler chickens were at week 8. The overall mean values of induction trial attempts differed significantly (P<0.0001) between the groups; with the lowest mean values of 1.22+/-0.4 recorded in CL+MEL broiler chickens. At day 42, the lowest mean TI duration of 101.87+/-10.24s in the CL group, recorded at 06:00h rose (P<0.001) to 184.07+/-23.69s at 13:00h. The overall mean duration of TI differed significantly (P<0.0001) again between the groups; with the highest mean duration of 167.82+/-8.35s, recorded in CL+MEL broiler chickens administered with melatonin. The overall mean vigilance behavioural ranking values of 1.85+0.07 and 1.70+0.08, obtained in 12D:12L cycle and CL broiler chickens, respectively were higher (P<0.0001) than the value of 1.44+0.05 recorded in melatonin-treated broiler chickens. The results indicated that broiler chickens belonging to both 12D:12L cycle and CL groups were more emotional, fearful or anxious, compared to CL+MEL broiler chickens. It was concluded that melatonin administration elicits boldness and confidence by suppressing freezing behaviour in broiler chickens, and it may improve their welfare and productivity. PMID- 27484700 TI - Mapping epigenetic changes to the host cell genome induced by Burkholderia pseudomallei reveals pathogen-specific and pathogen-generic signatures of infection. AB - The potential for epigenetic changes in host cells following microbial infection has been widely suggested, but few examples have been reported. We assessed genome-wide patterns of DNA methylation in human macrophage-like U937 cells following infection with Burkholderia pseudomallei, an intracellular bacterial pathogen and the causative agent of human melioidosis. Our analyses revealed significant changes in host cell DNA methylation, at multiple CpG sites in the host cell genome, following infection. Infection induced differentially methylated probes (iDMPs) showing the greatest changes in DNA methylation were found to be in the vicinity of genes involved in inflammatory responses, intracellular signalling, apoptosis and pathogen-induced signalling. A comparison of our data with reported methylome changes in cells infected with M. tuberculosis revealed commonality of differentially methylated genes, including genes involved in T cell responses (BCL11B, FOXO1, KIF13B, PAWR, SOX4, SYK), actin cytoskeleton organisation (ACTR3, CDC42BPA, DTNBP1, FERMT2, PRKCZ, RAC1), and cytokine production (FOXP1, IRF8, MR1). Overall our findings show that pathogenic-specific and pathogen-common changes in the methylome occur following infection. PMID- 27484701 TI - Effects of Dexmedetomidine on motor- and somatosensory-evoked potentials in patients with thoracic spinal cord tumor: a randomized controlled trial. AB - BACKGROUND: We hypothesized that the addition of dexmedetomidine in a clinically relevant dose to propofol-remifentanil anesthesia regimen does not exert an adverse effect on motor-evoked potentials (MEP) and somatosensory-evoked potentials (SSEP) in adult patients undergoing thoracic spinal cord tumor resection. METHODS: Seventy-one adult patients were randomized into three groups. Propofol group (n = 25): propofol-remifentanil regimenand the dosage was adjusted to maintain the bispectral index (BIS) between 40 and 50. DP adjusted group (n = 23): Dexmedetomidine (0.5 MUg/kg loading dose infused over 10 min followed by a constant infusion of 0.5 MUg/kg/h) was added to the propofol-remifentanil regimen and propofol was adjusted to maintain BIS between 40 and 50. DP unadjusted group (n = 23): Dexmedetomidine (administer as DP adjusted group) was added to the propofol-remifentanil regimen and propofol was not adjusted. All patients received MEP, SSEP and BIS monitoring. RESULTS: There were no significant changes in the amplitude and latency of MEP and SSEP among different groups (P > 0.05). The estimated propofol plasma concentration in DP adjusted group (2.7 +/- 0.3 MUg/ml) was significantly lower than in propofol group (3.1 +/- 0.2 MUg/ml) and DP unadjusted group (3.1 +/- 0.2 MUg/ml) (P = 0.000). BIS in DP unadjusted group (35 +/- 5) was significantly lower than in propofol group (44 +/- 3) (P = 0.000). CONCLUSIONS: The addition of dexmedetomidine to propofol-remifentanil regimen does not exert an adverse effect on MEP and SSEP monitoring in adult patients undergoing thoracic spinal cord tumor resection. TRIAL REGISTRATION: The study was registered with the Chinese Clinical Trial Registry on January 31st, 2014. The reference number was ChiCTR-TRC-14004229. PMID- 27484702 TI - Chronic Smoking, Trait Anxiety, and the Physiological Response to Stress. AB - BACKGROUND AND OBJECTIVES: Both chronic smoking and trait anxiety have been associated with dysregulations in psychobiological stress response systems. However, these factors have not been studied in conjunction. We expected trait anxiety and smoking status to attenuate stress reactivity. Furthermore, we expected an allostatic load effect resulting in particularly attenuated stress reactivity in high-anxious smokers. In addition, high-anxious smokers were expected to exhibit increased urges to smoke in response to stress. METHODS: 115 smokers and 37 nonsmokers, aged 18-64 years, completed a laboratory session including mental stressors such as evaluated public speaking and mental arithmetic. Trait anxiety was assessed using Spielberger's State-Trait Anxiety Inventory. Cardiovascular autonomic indices, salivary cortisol, and the desire to smoke were measured at baseline, during stressors, and at recovery. RESULTS: Regression analyses showed that smokers exhibited attenuated cardiovascular stress responses in comparison to nonsmokers. Higher trait anxiety predicted attenuated systolic blood pressure responses to stress. No interaction effect of smoking status and trait anxiety was found in stress response measures. Higher trait anxiety predicted an increased desire to smoke in response to stress among smokers. CONCLUSION: Results indicate that both smoking status and trait anxiety are associated with blunted sympatho-adrenal cardiovascular stress reactivity. Elevated urges to smoke in response to stress found among smokers with high trait anxiety suggest an important role of anxiety in smoking propensity and relapse. PMID- 27484704 TI - Blunt traumatic rupture of the right ventricle: visualization of spurting blood using transthoracic echocardiography. PMID- 27484703 TI - Delayed gadolinium-enhanced MRI of cartilage and T2 mapping for evaluation of reparative cartilage-like tissue after autologous chondrocyte implantation associated with Atelocollagen-based scaffold in the knee. AB - OBJECTIVE: To elucidate the quality of tissue-engineered cartilage after an autologous chondrocyte implantation (ACI) technique with Atelocollagen gel as a scaffold in the knee in the short- to midterm postoperatively, we assessed delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) and T2 mapping and clarified the relationship between T1 and T2 values and clinical results. MATERIALS AND METHODS: In this cross-sectional study, T1 and T2 mapping were performed on 11 knees of 8 patients (mean age at ACI, 37.2 years) with a 3.0-T MRI scanner. T1implant and T2implant values were compared with those of the control cartilage region (T1control and T2control). Lysholm scores were also assessed for clinical evaluation. The relationships between the T1 and T2 values and the clinical Lysholm score were also assessed. RESULTS: There were no significant differences in the T1 values between the T1implant (386.64 +/- 101.78 ms) and T1control (375.82 +/- 62.89 ms) at the final follow up. The implants showed significantly longer T2 values compared to the control cartilage (53.83 +/- 13.89 vs. 38.21 +/- 4.43 ms). The postoperative Lysholm scores were significantly higher than the preoperative scores. A significant correlation was observed between T1implant and clinical outcomes, but not between T2implant and clinical outcomes. CONCLUSION: Third-generation ACI implants might have obtained an almost equivalent glycosaminoglycan concentration compared to the normal cartilage, but they had lower collagen density at least 3 years after transplantation. The T1implant value, but not the T2 value, might be a predictor of clinical outcome after ACI. PMID- 27484705 TI - Rapid reconstitution of CD4 T cells and NK cells protects against CMV reactivation after allogeneic stem cell transplantation. AB - BACKGROUND: Epstein-Barr virus and Cytomegalovirus reactivations frequently occur after allogeneic stem cell transplantation (SCT). METHODS: Here we investigated the role of immune cell reconstitution in the onset and subsequent severity of EBV- and CMV-reactivation. To this end, 116 patients were prospectively sampled for absolute T cell (CD4 and CD8), B-cell (CD19) and NK-cell (CD16 and CD56) numbers weekly post-SCT during the first 3 months and thereafter monthly until 6 months post-SCT. Viral load was monitored in parallel. RESULTS: In contrast to the general belief, we found that early T-cell reconstitution does not play a role in the onset of viral reactivation. CMV reactivation in the first 7 weeks after SCT however resulted in higher absolute CD8(+) T-cell numbers 6 months post SCT in patients with high-level reactivation, many of which were CMV-specific. Interestingly, rapid reconstitution of CD4(+) T-cells, as well as NK cells and the presence of donor KIR3DL1, are associated with the absence of CMV reactivation after SCT, suggestive of a protective role of these cells. In contrast, EBV-reactivations were not affected in any way by the level of immune reconstitution after SCT. CONCLUSION: In conclusion, these data suggest that CD4(+) T-cells and NK cells, rather than CD8(+) T-cells, are associated with protection against CMV-reactivation. PMID- 27484707 TI - Preparation of a compressible and hierarchically porous polyimide sponge via the sol-gel process of an aliphatic tetracarboxylic dianhydride and an aromatic triamine. AB - A compressible and monolithic microporous polyimide sponge was prepared from an aliphatic tetracarboxylic dianhydride and an aromatic triamine. The sponge had a hierarchical pore structure, in which spherical microporous polyimide particles were interconnected to form a macroscopic network. It showed an amphiphilic character, because of the balanced presence of hydrophobic and hydrophilic groups. PMID- 27484706 TI - Active CMV and EBV infections in renal transplant recipients with unexplained fever and elevated serum creatinine. AB - Proper identification of active cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections are helpful for monitoring antiviral treatment in transplant recipients. Qualitative and quantitative CMV, EBV DNA PCR techniques in the context of serological tests are performed for early detection and differentiation of active and latent CMV and EBV infections in renal transplantation. Basically, 129 renal transplanted recipients monitored carefully and hospitalized for unexplained elevated creatinine levels or high fever and 21 of their donors were studied. CMV DNA was detected in 63.5% of the febrile episodes following transplantation and in 46.42% of readmitted patients using qualitative PCR method. In the first group, 15% of the patients and in the second group 42.85% of the patients had copy numbers more than cutoff point (900 copies/mL). Cutoff point had 100% sensitivity and 82.5% specificity for active and symptomatic CMV infection. Only 15.5% of the subjects were positive for EBV infection by qualitative PCR method. Among them 5% had >2000 copies/mL and were symptomatic. One subject with a history of three times hospitalization had higher EBV viral load and developed post-transplant lymphoproliferative disorder. CMV load was significantly correlated with elevated creatinine levels (OR = 3.1, p = 0.006), abnormal heart sounds (OR = 4.7; p = 0.02) and hypertension (OR = 3.6; p = 0.03). Only qRT-PCR could differentiate between latent and active infections and might be clinically useful for monitoring symptomatic CMV and EBV infections and initiation of the antiviral therapy. Elevated creatinine levels, hypertension, and abnormal heart sounds could be considered as main manifestations of HCMV infection in kidney recipients. PMID- 27484709 TI - bFGF Promotes Migration and Induces Cancer-Associated Fibroblast Differentiation of Mouse Bone Mesenchymal Stem Cells to Promote Tumor Growth. AB - Tumors recruit bone mesenchymal stem cells (BMSCs) to localize to tumor sites, which induces their conversion into cancer-associated fibroblasts (CAFs) that facilitate tumor progression. However, this process is poorly understood on the molecular level. In this study, we found that 4T1 breast cancer cells promoted the migration of BMSCs, and bFGF neutralizing antibody inhibited the migration of BMSCs induced by a tumor-conditioned medium. In addition, exogenous bFGF enhanced the migration of BMSCs in a dose-dependent manner in vitro. Furthermore, BMSCs promoted the proliferation of 4T1 tumor cells under BMSC-conditioned medium and in tumor xenograft model. Dramatically, BMSCs expressed CAF markers and produced collagen in the tumor microenvironment, and this transition was blocked by bFGF antibody. In addition, exogenous bFGF induced CAF differentiation of BMSCs. And bFGF increased phosphorylation of Erk1/2 and Smad3 in BMSCs and Erk inhibitor PD98059 was shown to block bFGF-induced Erk and Smad3 phosphorylation, suggesting that Erk/Smad3 signaling pathway involved in BMSC transdifferentiation induced by bFGF. Collectively, our results indicate that bFGF signaling plays indispensable roles in BMSC recruitment and transdifferentiation into CAFs and the consequent protumor effects, and targeting tumor stroma through bFGF inhibition maybe a promising strategy to suppress tumor progression. PMID- 27484708 TI - The African-specific S47 polymorphism of p53 alters chemosensitivity. AB - The TP53 protein is known to affect the sensitivity of tumor cells to cell death by DNA damaging agents. We recently reported that human and mouse cells containing an African-specific coding region variant of p53, Pro47Ser (hereafter S47), are impaired in the transactivation of a small subset of p53 target genes including GLS2 and SCO2, and are markedly resistant to cisplatin. Further, mice containing this variant are markedly predisposed to cancer. Together these findings suggested that cancer-affected humans with the S47 variant might not be effectively treated with cisplatin. To more directly test this premise, we created transformed derivatives of mouse embryo fibroblasts (MEFs) containing wild type p53 (WT) and the S47 variant and analyzed them for chemosensitivity. We find that transformation with E1A and Ras actually reverses the chemosensitivity/transcriptional differences between WT p53 and S47. Specifically, E1A/Ras-transformed S47 cells show increased sensitivity to cisplatin and paclitaxel, and comparable transactivation of GLS2 and SCO2, compared to cells with WT p53. These data suggest that the functional differences between WT p53 and S47 in primary cells may not hold true for transformed cells. They also offer hope that cisplatin and paclitaxel may be effective chemotherapeutic drugs for S47 individuals with cancer. PMID- 27484710 TI - Effect of multipurpose solutions on in vivo surface wettability of a silicone hydrogel lens. AB - PURPOSE: To compare the in vivo surface wettability of silicone hydrogel (SiHy) contact lenses pre-soaked overnight in different multipurpose solutions (MPS) and normal saline. METHODS: In this double-blinded, randomized and self-controlled study, 36 subjects were fitted with three pairs of contact lenses (senofilcon A) pre-soaked overnight in five different MPS and saline in a randomized order. Each pair of lenses (pre-soaked in two different solutions the night before) were worn for 15min before assessment of pre-lens non-invasive tear break-up time (PL NITBUT) using the Medmont corneal topographer (video recording). Corneal integrity was assessed using a slit lamp and a resting interval of 20min was allowed between each pair of lenses to ensure post-lens wear corneal integrity. RESULTS: Thirty subjects completed the study. The median PL-NITBUT ranged from 2.84s to 3.08s with lenses pre-soaked in different MPS, compared to 2.78s with lenses pre-soaked in saline. No significant differences in PL-NITBUT were found among lenses pre-soaked in different solutions (p=0.647). CONCLUSION: In vivo surface wettability, in terms of PL-NITBUT after 15min of lens wear, of senofilcon A contact lenses pre-soaked overnight in different MPS were not significantly different from those pre-soaked in saline. PMID- 27484711 TI - Influenza A Virus in Backyard Pigs and Poultry in Rural Cambodia. AB - Surveillance of influenza virus in humans and livestock is critical, given the worldwide public health threats and livestock production losses. Livestock farming involving close proximity between humans, pigs and poultry is often practised by smallholders in low-income countries and is considered an important driver of influenza virus evolution. This study determined the prevalence and genetic characteristics of influenza A virus (IAV) in backyard pigs and poultry in Cambodia. A total of 751 animals were tested by matrix gene-based rRT-PCR, and influenza virus was detected in 1.5% of sampled pigs, 1.4% of chickens and 1.0% of ducks, but not in pigeons. Full-length genome sequencing confirmed triple reassortant H3N2 in all IAV-positive pigs and various low pathogenic avian influenza subtypes in poultry. Phylogenetic analysis of the swine influenza viruses revealed that these had haemagglutinin and neuraminidase genes originating from human H3N2 viruses previously isolated in South-East Asia. Phylogenetic analysis also revealed that several of the avian influenza subtypes detected were closely related to internal viral genes from highly pathogenic H5N1 and H9N2 formerly sequenced in the region. High sequence homology was likewise found with influenza A viruses circulating in pigs, poultry and wild birds in China and Vietnam, suggesting transboundary introduction and cocirculation of the various influenza subtypes. In conclusion, highly pathogenic subtypes of influenza virus seem rare in backyard poultry, but virus reassortment, involving potentially zoonotic and pandemic subtypes, appears to occur frequently in smallholder pigs and poultry. Increased targeted surveillance and monitoring of influenza circulation on smallholdings would further improve understanding of the transmission dynamics and evolution of influenza viruses in humans, pigs and poultry in the Mekong subregion and could contribute to limit the influenza burden. PMID- 27484712 TI - Forecast models for suicide: Time-series analysis with data from Italy. AB - The prediction of suicidal behavior is a complex task. To fine-tune targeted preventative interventions, predictive analytics (i.e. forecasting future risk of suicide) is more important than exploratory data analysis (pattern recognition, e.g. detection of seasonality in suicide time series). This study sets out to investigate the accuracy of forecasting models of suicide for men and women. A total of 101 499 male suicides and of 39 681 female suicides - occurred in Italy from 1969 to 2003 - were investigated. In order to apply the forecasting model and test its accuracy, the time series were split into a training set (1969 to 1996; 336 months) and a test set (1997 to 2003; 84 months). The main outcome was the accuracy of forecasting models on the monthly number of suicides. These measures of accuracy were used: mean absolute error; root mean squared error; mean absolute percentage error; mean absolute scaled error. In both male and female suicides a change in the trend pattern was observed, with an increase from 1969 onwards to reach a maximum around 1990 and decrease thereafter. The variances attributable to the seasonal and trend components were, respectively, 24% and 64% in male suicides, and 28% and 41% in female ones. Both annual and seasonal historical trends of monthly data contributed to forecast future trends of suicide with a margin of error around 10%. The finding is clearer in male than in female time series of suicide. The main conclusion of the study is that models taking seasonality into account seem to be able to derive information on deviation from the mean when this occurs as a zenith, but they fail to reproduce it when it occurs as a nadir. Preventative efforts should concentrate on the factors that influence the occurrence of increases above the main trend in both seasonal and cyclic patterns of suicides. PMID- 27484713 TI - Neural speech recognition: continuous phoneme decoding using spatiotemporal representations of human cortical activity. AB - OBJECTIVE: The superior temporal gyrus (STG) and neighboring brain regions play a key role in human language processing. Previous studies have attempted to reconstruct speech information from brain activity in the STG, but few of them incorporate the probabilistic framework and engineering methodology used in modern speech recognition systems. In this work, we describe the initial efforts toward the design of a neural speech recognition (NSR) system that performs continuous phoneme recognition on English stimuli with arbitrary vocabulary sizes using the high gamma band power of local field potentials in the STG and neighboring cortical areas obtained via electrocorticography. APPROACH: The system implements a Viterbi decoder that incorporates phoneme likelihood estimates from a linear discriminant analysis model and transition probabilities from an n-gram phonemic language model. Grid searches were used in an attempt to determine optimal parameterizations of the feature vectors and Viterbi decoder. MAIN RESULTS: The performance of the system was significantly improved by using spatiotemporal representations of the neural activity (as opposed to purely spatial representations) and by including language modeling and Viterbi decoding in the NSR system. SIGNIFICANCE: These results emphasize the importance of modeling the temporal dynamics of neural responses when analyzing their variations with respect to varying stimuli and demonstrate that speech recognition techniques can be successfully leveraged when decoding speech from neural signals. Guided by the results detailed in this work, further development of the NSR system could have applications in the fields of automatic speech recognition and neural prosthetics. PMID- 27484714 TI - Optimal configurations for bipolar radiofrequency ablation that allow deeper lesion formation: Good catheter-tip cooling, good catheter-tissue contact, and the next approach. PMID- 27484715 TI - Prevalence and mechanism of rotor activation identified during atrial fibrillation by noncontact mapping: Lack of evidence for a role in the maintenance of atrial fibrillation. AB - BACKGROUND: It remains unclear whether atrial fibrillation (AF) is maintained by the rotor. OBJECTIVE: We evaluated the role of the rotor and examined its mechanism. METHODS: Among 75 patients with AF (60 paroxysmal, 15 persistent AF) who underwent 3-dimensional noncontact left atrial mapping during AF, we examined the prevalence and location of rotor activation and elucidated its mechanism. Catheter ablation was performed in a stepwise fashion (linear roof lesion and complex fractionated atrial electrogram ablation after pulmonary vein [PV) isolation) until AF termination. RESULTS: Rotor activation was observed in 11 patients (14.7%; 10 paroxysmal and 1 persistent AF) (tachycardia cycle length 160.0 +/- 19.8 ms). Rotors were observed transiently (duration 6128 +/- 9094 ms) during AF at the roof (n = 5), septum (n = 3), and ostium of the left superior PV (n = 3). Five rotors circulated in clockwise and 6 in counterclockwise directions. The length of the block line at the center of the rotor was 15.2 +/- 6.9 mm. The electrograms at the block line showed low-amplitude multiple deflections (n = 7) or double potentials (n = 4), and the amplitudes during rotor activation were significantly lower than those during sinus rhythm (0.27 +/- 0.18 mV vs 1.22 +/- 0.92 mV; P < .01). No conduction disturbances were found during sinus rhythm, suggesting that the central line of block was formed functionally. AF was terminated by PV isolation alone without additional lesions in patients with rotors. CONCLUSION: Functionally formed rotor activation was observed during AF in a limited number of patients. These rotor activations may not be related to AF maintenance, but rather may reflect a transient organization of random propagation. PMID- 27484716 TI - Celastrol inhibits IL-1beta-induced inflammation in orbital fibroblasts through the suppression of NF-kappaB activity. AB - Graves' disease is an autoimmune disease of the thyroid gland, which is characterized by hyperthyroidism, diffuse goiter and Graves' ophthalmopathy (GO). Although several therapeutic strategies for the treatment of GO have been developed, the effectiveness and the safety profile of these therapies remain to be fully elucidated. Therefore, examination of novel GO therapies remains an urgent requirement. Celastrol, a triterpenoid isolated from traditional Chinese medicine, is a promising drug for the treatment of various inflammatory and autoimmune diseases. CCK-8 and apoptosis assays were performed to investigate cytotoxicity of celastrol and effect on apoptosis on orbital fibroblasts. Reverse transcription-polymerase chain reaction, western blotting and ELISAs were performed to examine the effect of celastrol on interleukin (IL)-1beta-induced inflammation in orbital fibroblasts from patients with GO. The results demonstrated that celastrol significantly attenuated the expression of IL-6, IL 8, cyclooxygenase (COX)-2 and intercellular adhesion molecule-1 (ICAM-1), and inhibited IL-1beta-induced increases in the expression of IL-6, IL-8, ICAM-1 and COX-2. The levels of prostaglandin E2 in orbital fibroblasts induced by IL-1beta were also suppressed by celastrol. Further investigation revealed that celastrol suppressed the IL-1beta-induced inflammatory responses in orbital fibroblasts through inhibiting the activation of nuclear factor (NF)-kappaB. Taken together, these results suggested that celastrol attenuated the IL-1beta-induced pro inflammatory pathway in orbital fibroblasts from patients with GO, which was associated with the suppression of NF-kappaB activation. PMID- 27484717 TI - Aluminum alkoxide, amide and halide complexes supported by a bulky dipyrromethene ligand: synthesis, characterization, and preliminary epsilon-caprolactone polymerization activity. AB - Aluminum halide, alkoxide and amide complexes 2-6 of the form (N,N)AlX2-nYn (n = 0, 1 and (N,N) = 1,9-dimesityl-5-phenyldipyrromethene (1)) were synthesized and characterized by NMR spectroscopy and X-ray crystallography. The in situ generated lithium salt of dipyrromethene 1 was reacted with AlX3 to afford aluminum halide complexes (N,N)AlX2 (X = Cl (2), I (3)) which were isolated as dichroic crystals. Salt metathesis reactions were employed to produce alkoxide complexes (N,N)Al(Cl)(O(t)Bu) (4) and (N,N)Al(O(t)Bu)2 (5) from compound 2. The dimethylamide complex (N,N)Al(NMe2)2 (6) was prepared by reaction of dipyrromethene 1 with [Al(NMe2)3]2. Crystallographic data revealed that the dipyrromethene is non-planar when bulky coligands are present as in compounds 3 6, while in the dichloride complex 2 the dipyrromethene is planar. Halide complexes 2 and 3 reacted with adventitious moisture in toluene to afford crystalline acid-base adducts (N,N)H.HX, (X = Cl (7), I (8)), which adopted structures reminiscent of anion receptors. Alkoxide and dimethylamide complexes 5 and 6 were also applied as precatalysts for the ring-opening polymerization of epsilon-caprolactone and preliminary results are reported. PMID- 27484718 TI - Effects and synergy of feed ingredients on canine neoplastic cell proliferation. AB - BACKGROUND: Adjunctive use of nutraceuticals in human cancer has shown promise, but little work has been done in canine neoplasia. Previous human research has shown that polyphenols and carotenoids can target multiple pathways in vitro and in vivo. These compounds could synergize or antagonize with currently used chemotherapies, either increasing or decreasing the effectiveness of these drugs. Considering the routine and well controlled feeding practices of most dogs, the use of nutraceuticals incorporated into pet food is attractive, pending proof that the extracts are able to improve remission rates. The aim of this study was to examine five feed ingredients for antiproliferative effects, as well as the interaction with toceranib phosphate and doxorubicin hydrochloride, when treating canine neoplastic cell lines in vitro. RESULTS: Screening using MTT proliferation assays showed that green tea, turmeric, and rosemary extracts were the most effective. Turmeric extract (TE) was the most potent and exhibited synergy with a rosemary extract (RE) at concentrations from 1 to 25 MUg mL(-1). This combination had an additive or synergistic effect with chemotherapeutic agents at selected concentrations within each cell line. No significant effects on cell viability were observed when the combination therapy was used with normal primary cells. CONCLUSIONS: The use of turmeric and rosemary extracts in combination may be worthwhile to investigate in the pre-clinical and clinical neoplastic considering there are no negative effects on traditional chemotherapy treatment. Further studies into the pharmacokinetics and mechanisms of action of these extracts should be investigated. PMID- 27484719 TI - Redox-responsive alginate microsphere containing cystamine. AB - Redox-responsive microspheres were prepared by solidifying the alginate- and cystamine-containing water droplets of O/W emulsion using calcium ion. Emulsions were prepared using alginate/cystamine mixture solution whose the carboxylic group/the amino group molar ratio was 1:1, 1:2, and 1:3, and whose the total concentration was kept to 2% (w/v). The microspheres on Scanning electron microscopy photographs were almost spherical and they were less than 1 MUm in diameter. According to the energy-dispersive X-ray spectroscopy, the sulfur content of the microspheres was found to be 6.1, 11.4, and 14.8% (w/w), respectively, not markedly different from the calculated content. The release degree of blue dextran loaded in the microspheres was higher as the cystamine content was higher. Microspheres released almost the same amount of dye regardless of dithiothreitol (DTT, a reducing agent) concentration when the cystamine content was relatively low (e.g. 14.5% (w/w)), whereas they released dye in DTT concentration-dependent manner when the cystamine content was relatively high (e.g. 27.0 and 35.1% (w/w)). The light scattering intensity of alginate/cystamine mixture solution was stronger at a larger amount of cystamine, indicating that cystamine could cross-link alginate chains. The light scattering intensity decreased with increasing DTT concentration, possibly because of the breakdown of the disulfide bond of cystamine. The breakdown of the disulfide bond could account for why the DTT concentration-dependent release of dye loaded in the microspheres was observed. PMID- 27484720 TI - KCNE4 and KCNE5: K(+) channel regulation and cardiac arrhythmogenesis. AB - KCNE proteins are single transmembrane-segment voltage-gated potassium (Kv) channel ancillary subunits that exhibit a diverse range of physiological functions. Human KCNE gene mutations are associated with various pathophysiological states, most notably cardiac arrhythmias. Of the five isoforms in the human KCNE gene family, KCNE4 and the X-linked KCNE5 are, to date, the least-studied. Recently, however, interest in these neglected genes has been stoked by their putative association with debilitating or lethal cardiac arrhythmias. The sometimes-overlapping functional effects of KCNE4 and KCNE5 vary depending on both their Kv alpha subunit partner and on other ancillary subunits within the channel complex, but mostly fall into two contrasting categories - either inhibition, or fine-tuning of gating kinetics. This review covers current knowledge regarding the molecular mechanisms of KCNE4 and KCNE5 function, human disease associations, and findings from very recent studies of cardiovascular pathophysiology in Kcne4(-/-) mice. PMID- 27484722 TI - Inherited platelet function disorders. Diagnostic approach and management. AB - Inherited platelet function disorders (IPFDs) make up a significant proportion of congenital bleeding diatheses, but they remain poorly understood and often difficult to diagnose. Therefore, a rational diagnostic approach, based on a standardized sequence of laboratory tests, with consecutive steps of increasing level of complexity, plays a crucial role in the diagnosis of most IPFDs. In this review we discuss a diagnostic approach through platelet phenotyping and genotyping and we give an overview of the options for the management of bleeding in these disorders and an account of the few systematic studies on the bleeding risk associated with invasive procedures and its treatment. PMID- 27484721 TI - The fibronectin III-1 domain activates a PI3-Kinase/Akt signaling pathway leading to alphavbeta5 integrin activation and TRAIL resistance in human lung cancer cells. AB - BACKGROUND: Fibronectin is a mechanically sensitive protein which is organized in the extracellular matrix as a network of interacting fibrils. The lung tumor stroma is enriched for fibronectin which is thought to contribute to metastasis and drug resistance. Fibronectin is an elastic, multi-modular protein made up of individually folded domains, some of which can stretch in response to increased mechanical tension. Very little is known about the relationship of fibronectin's unfolded domains to lung cancer resistance to chemotherapy. In the present study, we evaluated the impact of unfolding the first Type III domain of fibronectin (FnIII-1c) on TNF-related apoptosis inducing ligand (TRAIL) resistance. METHODS: NCI-H460 non-small cell lung cancer cells were treated with FnIII-1c then assessed for TRAIL-induced apoptosis. Subsequent analysis of FnIII-1c-mediated signaling pathways was also completed. Human non-small cell lung cancer tissue sections were assessed for the expression of vitronectin by immunohistochemistry. RESULTS: FnIII-1c inhibited TRAIL-induced activation of caspase 8 and subsequent apoptosis in NCI-H460 lung cancer cells. FnIII-1c treatment was associated with the activation of the phosphatidylinositol-3-kinase/alpha serine/threonine kinase (PI3K/Akt) pathway and the alphavbeta5 integrin receptor for vitronectin, both of which were required for TRAIL resistance. Immunohistochemical staining of sections from non-small cell lung cancers showed that vitronectin was localized around blood vessels and in the tumor-stroma interface. CONCLUSIONS: Unfolding of Type III domains within the fibronectin matrix may promote TRAIL resistance through the activation of a PI3K/Akt/alphavbeta5 signaling axis and point to a novel mechanism by which changes in secondary structure of fibronectin contribute to cancer cell resistance to apoptosis. PMID- 27484723 TI - Nickel-Promoted Recognition of Long DNA Sites by Designed Peptide Derivatives. AB - We describe the synthesis of designed peptidic modules that self-assemble in specific DNA sequences of 12 base pairs in the presence of Ni(II) salts. The modules consist of modified fragments of transcription factors that have been appropriately engineered to include metal-chelating His and bipyridine ligands. PMID- 27484724 TI - Unraveling the Thermodynamics of the Folding and Interconversion of Human Telomere G-Quadruplexes. AB - Why human telomere DNA fragments fold into different G-quadruplex structures with parallel, hybrid, and antiparallel strand orientations depending on the temperature and concentration of co-solutes remains poorly understood. Similarly, the formation of intermediate structures along the folding or interconversion pathways is not well understood. Herein, we address these questions by introducing a conceptual framework, based on the global thermodynamic analysis of DSC and CD spectroscopy data, which led to a detailed description of the topological phase space (phase diagram) of the stability of the human telomere fragment 5'-AGGG(TTAGGG)3 -3' (Tel22). This framework clarifies the driving forces of quadruplex folding and interconversion processes over a wide range of temperatures and ion (K(+) , Na(+) ) and polyethylene glycol (PEG) concentrations and demonstrates their linkage to the human telomere DNA structural features. PMID- 27484725 TI - Co-expression of ING4 and P53 enhances hypopharyngeal cancer chemosensitivity to cisplatin in vivo. AB - Hypopharyngeal cancer is a distinct type of malignant head and neck tumor, which exhibits low sensitivity to anti-cancer drugs. The importance of developing methods for reducing chemotherapy resistance, and improving and enhancing prognosis has previously been emphasized and is considered a challenge for effective clinical treatment of hypopharyngeal cancer. The current study investigated the effects of co-expression of inhibitor of growth protein 4 (ING4) and P53, a tumor suppressor gene, on chemosensitivity to cisplatin in human hypopharyngeal cancer xenografts in vivo, and the potential molecular mechanisms involved. A tumor model was established by injecting athymic nude mice with FADU human hypopharyngeal cancer cells. Five days after intratumoral and peritumoral injections of an empty adenoviral vector (Ad), Ad-ING4-P53, cisplatin, or a combination of Ad-ING4-P53 and cisplatin (Ad-ING4-P53 + cisplatin) every other day for 5 days, the mice were euthanized and their tumors, livers, and kidneys were removed. The tumor weights were used to calculate the inhibition rate, and the expression levels of ING4 and P53 were detected by reverse transcription polymerase chain reaction. Additionally, apoptotic cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling, and immunohistochemistry determined the levels ING4, P53, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) protein expression. The results demonstrated increased expression of ING4 and P53 in the Ad-ING4-P53 groups compared with PBS and Ad groups, indicating successful introduction of the genes into the tumor cells. Notably, the Ad-ING4-P53 + cisplatin group exhibited a higher inhibition rate compared with the four other groups. The results of immunohistochemistry analysis demonstrated that Bax expression was increased and Bcl-2 was decreased in the Ad-ING4-P53 + cisplatin group. This suggested that the enhanced cisplatin chemosensitivity with Ad-ING4-P53 gene therapy in hypopharyngeal cancer xenografts may be associated with apoptosis induction through upregulation of Bax expression and downregulation of Bcl-2. The results of the present study indicated that gene therapy combined with cisplatin treatment may be a promising treatment for human hypopharyngeal cancer. PMID- 27484726 TI - Functioning in the Real World: Using Storytelling to Improve Validity in the Assessment of Executive Functions. AB - Real-world contexts differ in the clarity of expectations for desired responses, as do assessment procedures, ranging along a continuum from maximal conditions that provide well-defined expectations to typical conditions that provide ill defined expectations. Executive functions guide effective social interactions, but relations between them have not been studied with measures that are matched in the clarity of response expectations. In predicting teacher-rated social competence (SC) from kindergarteners' performance on tasks of executive functions (EFs), we found better model-data fit indexes when both measures were similar in the clarity of response expectations for the child. The maximal EF measure, the Developmental Neuropsychological Assessment, presents well-defined response expectations, and the typical EF measure, 5 scales from the Thematic Apperception Test (TAT), presents ill-defined response expectations (i.e., Abstraction, Perceptual Integration, Cognitive-Experiential Integration, and Associative Thinking). To assess SC under maximal and typical conditions, we used 2 teacher rated questionnaires, with items, respectively, that emphasize well-defined and ill-defined expectations: the Behavior Rating Inventory: Behavioral Regulation Index and the Social Skills Improvement System: Social Competence Scale. Findings suggest that matching clarity of expectations improves generalization across measures and highlight the usefulness of the TAT to measure EF. PMID- 27484728 TI - Long -term results of transradial rotational atherectomy for heavily calcified coronary artery lesions. AB - OBJECTIVE: Percutaneous coronary intervention (PCI) for the heavily calcified coronary lesions remains a challenge, and the periprocedural complication rates of the transfemoral approach are high. This study was conducted to investigate the feasibility and long-term results of the transradial approach for rotational atherectomy (RA) prior to stent implantation via the transradial approach in patients with heavily calcified coronary artery lesions. METHODS: RA followed by stent implantation via the transradial approach was performed in 47 patients with severely calcified coronary artery lesions in this retrospectively case-control study. The success rate of the procedure and the 3-year follow-up (36+/-7.5 months) results were analyzed. RESULTS: RA with subsequent stent implantation or balloon angioplasty procedures were successfully performed in all cases. 6F guiding catheters were used in 45 cases, and 7F catheters were used in 2 patients. Rotablation was performed with a 1.25-mm burr in 29 cases, a 1.25-mm burr followed by a 1.5-mm burr in 17 patients, and a 1.75-mm burr in 1 patient. Percutaneous transluminal coronary angioplasty after RA was performed, followed by stent implantation in all 47 patients. Restenosis was found in 7 cases (7/38) at 13 months (13+/-3.6) and in 13 cases (13/28) at 36 months (36+/-7.5) after the procedure; 3 patients died during the 3-year follow-up. The post-procedure cumulative 3-year event-free survival rate was 78%. CONCLUSION: RA prior to stent implantation via the transradial approach is feasible and safe, the success rate is high, and long-term outcome is satisfactory in patients with heavily calcified lesions of the coronary artery. PMID- 27484729 TI - Hematological and Histological Changes in Prussian Carp Carassius gibelio Infected with Cyprinid Herpesvirus 2. AB - Outbreaks of cyprinid herpesvirus 2 (CyHV-2) disease, also known as herpesviral hematopoietic necrosis, among cultured Prussian Carp Carassius gibelio has occurred each year in Jiangsu province, China, since 2009. In autumn 2014, hematological, blood biochemical, and histological changes in naturally infected moribund Prussian Carp were investigated after CyHV-2 was confirmed as the sole etiologic agent by etiological analyses. Total erythrocyte count, total leukocyte count, hemoglobin concentration, and thrombocyte count were significantly reduced (P < 0.01), whereas erythrocyte osmotic brittleness was significantly increased (P < 0.01) in infected fish compared with control fish. In addition, monocyte count was higher (P < 0.01) and lymphocyte count was lower (P < 0.01) in diseased fish than in control fish. The blood biochemical analyses indicated significant increases (P < 0.01) in the activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase as well as in the levels of total protein, globulin, total bilirubin, creatinine, and urea along with significant decreases (P < 0.01) in glucose and albumin in the diseased group. Histopathological examinations indicated that the kidneys and spleens of moribund Prussian Carp were the most severely lesioned organs, followed by the gills and hearts. Hypertrophied nuclei with marginated chromatin also appeared in the hearts and renal tubular epithelia from diseased fish. Pathological analysis of blood cells showed that approximately 78% of erythrocytes and 94% of leukocytes were lesioned with different levels of degeneration and necrosis in the diseased group. These previously unreported observations may be useful in the diagnosis of CyHV-2 disease. Received May 11, 2015; accepted March 24, 2016. PMID- 27484727 TI - Adipose tissue-derived stem cells suppress hypertrophic scar fibrosis via the p38/MAPK signaling pathway. AB - BACKGROUND: Hypertrophic scars (HS) generally occur after injury to the deep layers of the dermis, resulting in functional deficiency for patients. Growing evidence has been identified that the supernatant of adipose tissue-derived stem cells (ADSCs) significantly ameliorates fibrosis of different tissues, but limited attention has been paid to its efficacy on attenuating skin fibrosis. In this study, we explored the effect and possible mechanism of ADSC-conditioned medium (ADSC-CM) on HS. METHOD: Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of collagen I (Col1), collagen III (Col3), and alpha-smooth muscle actin (alpha-SMA) after fibroblasts and cultured HS tissues were stimulated with ADSC-CM and p38 inhibitor/activator. Immunofluorescence staining was performed to test the expression of alpha-SMA. Masson's trichrome staining, hematoxylin and eosin (H&E) staining, and immunohistochemistry staining were carried out to assess the histological and pathological change of collagen in the BALB/c mouse excisional model. All data were analyzed by using SPSS17.0 software. Statistical analysis was performed by Student's t tests. RESULTS: The in vitro and ex vivo study revealed ADSC-CM decreased the expression of Col1, Col3, and alpha-SMA. Together, thinner and orderly arranged collagen was manifested in HS tissues cultured with ADSC-CM. Dramatically, the assessed morphology showed an accelerated healing rate, less collagen deposition, and col1- and col3-positive cells in the ADSC-CM treated group. Importantly, the protein level of p-p38 was downregulated in a concentration-dependent manner in HS-derived fibroblasts with ADSC-CM treatment, which further decreased the expression of p-p38 after the application of its inhibitor, SB203580. SB203580 led to an obvious decline in the expression of Col1, Col3, and alpha-SMA in fibroblasts and cultured HS tissues and presented more ordered arrangement and thinner collagen fibers in BALB/c mice. Lastly, anisomycin, an agonist of p38, upregulated the expression of fibrotic proteins and revealed more disordered structure and denser collagen fibers. CONCLUSION: This study demonstrated that ADSC-CM could decrease collagen deposition and scar formation in in vitro, ex vivo and in vivo experiments. The regulation of the p38/MAPK signaling pathway played an important role in the process. The application of ADSC-CM may provide a novel therapeutic strategy for HS treatment, and the anti-scarring effect can be achieved by inhibition of the p38/MAPK signaling pathway. PMID- 27484731 TI - Effects of melatonin and gonadal androgens on cell proliferation in the pituitary of viscachas (Lagostomus maximus maximus). AB - OBJECTIVES: Melatonin and androgens are involved in the regulation of cell proliferation. However, effects of these hormones on pituitary pars distalis (PD) of male viscachas is not fully understood. In the present study, we analysed melatonin and gonadal androgens' effects on proliferating cell nuclear antigen (PCNA) expression. MATERIALS AND METHODS: Pituitary glands from foetuses, immature individuals, prepubertal individuals and adult viscachas during their reproductive cycle, after melatonin administration and after castration, were used. PCNA-ir cells were detected by immunocytochemistry and morphometrically quantified using image analysis. RESULTS: Total percentage of PCNA-ir cells varied seasonally in the adult pituitary, with maximum values during the reproductive period and minima during gonadal regression periods. Percentages of PCNA-ir cells increased after melatonin administration, whereas it decreased after castration. Caudal end and ventral regions were the PD zones which were most affected by seasonal variations and castration. PCNA expression was highest in foetal pituitary from midpregnancy. Numbers of PCNA-ir cells decreased during sexual maturity. CONCLUSIONS: Our results demonstrate the effect of gonadal androgens on cell proliferation during the reproductive period and sexual maturity of these animals. Exogenous melatonin increased PD cell proliferation in adults. Thus, these hormones seem to be involved in different mechanisms that regulate cell renewal of PD in this seasonally breeding rodent. PMID- 27484730 TI - Arsenite-loaded nanoparticles inhibit PARP-1 to overcome multidrug resistance in hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is one of the highest incidences in cancers; however, traditional chemotherapy often suffers from low efficiency caused by drug resistance. Herein, we report an arsenite-loaded dual-drug (doxorubicin and arsenic trioxide, i.e., DOX and ATO) nanomedicine system (FeAsOx@SiO2-DOX, Combo NP) with significant drug synergy and pH-triggered drug release for effective treatment of DOX resistant HCC cells (HuH-7/ADM). This nano-formulation Combo NP exhibits the synergistic effect of DNA damage by DOX along with DNA repair interference by ATO, which results in unprecedented killing efficiency on DOX resistant cancer cells. More importantly, we explored the possible mechanism is that the activity of PARP-1 is inhibited by ATO during the treatment of Combo NP, which finally induces apoptosis of HuH-7/ADM cells by poly (ADP-ribosyl) ation suppression and DNA lesions accumulation. This study provides a smart drug delivery strategy to develop a novel synergistic combination therapy for effectively overcome drug- resistant cancer cells. PMID- 27484732 TI - A new sesquiterpene lactone from yacon leaves. AB - The chemical constituents of 60% EtOH extract of yacon leaves were separated to yield a new compound, together with four known compounds, which were isolated for the first time from yacon. The new compound was characterised and named as chlorodalin (1) on the basis of NMR (1D and 2D), HR-MS and other spectral methods. The cytotoxic activities of 1-5 were evaluated on two human tumour cell lines and the new compound showed significant cytotoxic activity. PMID- 27484733 TI - Melatonin enhances thermotolerance by promoting cellular protein protection in tomato plants. AB - Melatonin is a pleiotropic signaling molecule that provides physiological protection against diverse environmental stresses in plants. Nonetheless, the mechanisms for melatonin-mediated thermotolerance remain largely unknown. Here, we report that endogenous melatonin levels increased with a rise in ambient temperature and that peaked at 40 degrees C. Foliar pretreatment with an optimal dose of melatonin (10 MUmol/L) or the overexpression of N-acetylserotonin methyltransferase (ASMT) gene effectively ameliorated heat-induced photoinhibition and electrolyte leakage in tomato plants. Both exogenous melatonin treatment and endogenous melatonin manipulation by overexpression of ASMT decreased the levels of insoluble and ubiquitinated proteins, but enhanced the expression of heat-shock proteins (HSPs) to refold denatured and unfolded proteins under heat stress. Meanwhile, melatonin also induced expression of several ATG genes and formation of autophagosomes to degrade aggregated proteins under the same stress. Proteomic profile analyses revealed that protein aggregates for a large number of biological processes accumulated in wild-type plants. However, exogenous melatonin treatment or overexpression of ASMT reduced the accumulation of aggregated proteins. Aggregation responsive proteins such as HSP70 and Rubisco activase were preferentially accumulated and ubiquitinated in wild-type plants under heat stress, while melatonin mitigated heat stress-induced accumulation and ubiquitination of aggregated proteins. These results suggest that melatonin promotes cellular protein protection through induction of HSPs and autophagy to refold or degrade denatured proteins under heat stress in tomato plants. PMID- 27484734 TI - Seropositivity of Varicella zoster virus in vaccinated Korean children and MAV vaccine group. AB - In 2005, a single-dose varicella vaccination was incorporated into the national immunization program in Korea. Although the Oka strain is the most commonly circulating Varicella zoster virus (VZV) genotype in Korea, a domestically manufactured vaccine based on the MAV strain is widely distributed in Korea. High vaccination coverage was achieved, but breakthrough infections were frequently reported. Therefore, in this study, we aimed to analyze the maintenance of immunity after single-dose vaccination and to compare the immunity provided by the MAV and Oka vaccines. Enzyme-linked immunosorbent assays of samples from 715 vaccinated Korean children were used to assess seropositivity rates against VZV. Additionally, fluorescent-antibody-to-membrane-antigen (FAMA) tests were performed in 35 individuals in the MAV vaccine group, and seropositivity rates against the Oka strain were determined. The progressive decrease of the seropositivity rate was demonstrated from ages 1 to 4 as follows: 65% in age 1, 59% in age 2, 53% in age 3, 49% in age 4. It then increased to 62% in age 5 and 70% in age 6. Both the MAV and Oka vaccine groups showed a progressive decrease of the seropositivity rate from the age of 1 to 4 years, but the MAV vaccine group had higher seropositivity rates. In FAMA test, the MAV group demonstrated 71% seropositivity against the Oka strain. This study indicates that immunity wanes after single-dose varicella vaccination and that the MAV vaccine is not inferior to the Oka vaccine in providing immunity against VZV. The MAV vaccine also induced cross-immunity against circulating Oka strain. PMID- 27484735 TI - Self-Printing on Graphitic Nanosheets with Metal Borohydride Nanodots for Hydrogen Storage. AB - Although the synthesis of borohydride nanostructures is sufficiently established for advancement of hydrogen storage, obtaining ultrasmall (sub-10 nm) metal borohydride nanocrystals with excellent dispersibility is extremely challenging because of their high surface energy, exceedingly strong reducibility/hydrophilicity and complicated composition. Here, we demonstrate a mechanical-force-driven self-printing process that enables monodispersed (~6 nm) NaBH4 nanodots to uniformly anchor onto freshly-exfoliated graphitic nanosheets (GNs). Both mechanical-forces and borohydride interaction with GNs stimulate NaBH4 clusters intercalation/absorption into the graphite interlayers acting as a 'pen' for writing, which is accomplished by exfoliating GNs with the 'printed' borohydrides. These nano-NaBH4@GNs exhibit favorable thermodynamics (decrease in ?H of ~45%), rapid kinetics (a greater than six-fold increase) and stable de-/re hydrogenation that retains a high capacity (up to ~5 wt% for NaBH4) compared with those of micro-NaBH4. Our results are helpful in the scalable fabrication of zero dimensional complex hydrides on two-dimensional supports with enhanced hydrogen storage for potential applications. PMID- 27484736 TI - Happle-Tinschert syndrome can be caused by a mosaic SMO mutation and is suggested to be a variant of Curry-Jones syndrome. PMID- 27484737 TI - The withdrawal of antiepileptic drugs in patients with low-grade and anaplastic glioma. AB - INTRODUCTION: The withdrawal of antiepileptic drugs (AEDs) in World Health Organization (WHO) grade II-III glioma patients with epilepsy is controversial, as the presence of a symptomatic lesion is often related to an increased risk of seizure relapse. However, some glioma patients may achieve long-term seizure freedom after antitumor treatment, raising questions about the necessity to continue AEDs, particularly when patients experience serious drug side effects. Areas covered: In this review, we show the evidence in the literature from 1990 2016 for AED withdrawal in glioma patients. We put this issue into the context of risk factors for developing seizures in glioma, adverse effects of AEDs, seizure outcome after antitumor treatment, and outcome after AED withdrawal in patients with non-brain tumor related epilepsy. Expert commentary: There is currently scarce evidence of the feasibility of AED withdrawal in glioma patients. AED withdrawal could be considered in patients with grade II-III glioma with a favorable prognosis, who have achieved stable disease and long-term seizure freedom. The potential benefits of AED withdrawal need to be carefully weighed against the presumed risk of seizure recurrence in a shared decision-making process by both the clinical physician and the patient. PMID- 27484738 TI - ff14IDPs force field improving the conformation sampling of intrinsically disordered proteins. AB - Intrinsically disordered proteins are proteins which lack of specific tertiary structure and unable to fold spontaneously without the partner binding. These intrinsically disordered proteins are found to associate with various diseases, such as diabetes, cancer, and neurodegenerative diseases. However, current widely used force fields, such as ff99SB, ff14SB, OPLS/AA, and Charmm27, are insufficient in sampling the conformational characters of intrinsically disordered proteins. In this study, the CMAP method was used to correct the phi/psi distributions of disorder-promoting amino acids. The simulation results show that the force filed parameters (ff14IDPs) can improve the phi/psi distributions of the disorder-promoting amino acids, with RMSD less than 0.10% relative to the benchmark data of intrinsically disordered proteins. Further test suggests that the calculated secondary chemical shifts under ff14IDPs are in quantitative agreement with the data of NMR experiment for five tested systems. In addition, the simulation results show that ff14IDPs can still be used to model structural proteins, such as tested lysozyme and ubiquitin, with better performance in coil regions than the original general Amber force field ff14SB. These findings confirm that the newly developed Amber ff14IDPs is a robust model for improving the conformation sampling of intrinsically disordered proteins. PMID- 27484739 TI - Diffuse reduction of cerebral grey matter volumes in Erdheim-Chester disease. AB - BACKGROUND: Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytosis characterized by systemic inflammation and granulomatous infiltration of multiple organs including the central nervous system (CNS), bones, and retroperitoneum. CNS infiltration occurs in one third of patients, but cognitive changes are common in patients without CNS disease. Here we investigate whether there is a neuroanatomic basis to observed cognitive deficits, even in absence of CNS disease. METHODS: We present a volumetric analysis of eleven ECD patients without CNS tumors or prior neurotoxic treatments. RESULTS: Compared to age-matched controls, ECD patients have diffuse, bihemispheric reduction in cortical thickness and subcortical gray matter. CONCLUSIONS: These findings provide the first corroborating evidence for neurologic disease in ECD patients without direct CNS infiltration. PMID- 27484740 TI - Socioeconomic costs and health-related quality of life in juvenile idiopathic arthritis: a cost-of-illness study in the United Kingdom. AB - BACKGROUND: Juvenile idiopathic arthritis (JIA) refers to a number of rare chronic inflammatory diseases. Although JIA imposes a significant societal burden, limited data are available on the cost of JIA. The study's objective is to quantify the socioeconomic burden of JIA patients in the United Kingdom (UK), along with their health-related quality of life (HRQoL). METHODS: A bottom-up, cross-sectional, cost-of-illness analysis of 23 patients was carried out. To collect data on demographic characteristics, health resource utilization, informal care, productivity losses and HRQoL, questionnaires were administered to and completed by patients or their caregivers. The EuroQol five dimensions (EQ 5D) instrument was used to measure HRQoL. RESULTS: This study found that the average annual cost for a JIA patient was ?31,546, with direct health care costs equalling ?14,509 (46.0 % of total costs), direct non-health care costs amounting to ?8,323 (26.4 %) and productivity losses being ?8,715 (27.6 %). This was calculated using unit costs for 2012. The largest expenditures on average were accounted for by early retirement (27.0 %), followed by informal care (24.1 %), medications (21.1 %), outpatient and primary health care visits (13.2 %) and diagnostic tests (7.9 %). Important differences existed between JIA patients in need of caregiver assistance and those with no need (?39,469 vs. ?25,452 respectively). Among adult JIA patients, mean EQ-5D index scores and visual analogue scale (VAS) scores were found to be 0.26 and 49.00 respectively; the same scores among caregivers were 0.66 and 67.14 respectively. CONCLUSION: JIA poses a significant cost burden on the UK society. Over half of the total average costs (54 %) are related to non-health care and productivity losses. HRQoL of JIA patients is considerably worse than the UK general population. PMID- 27484741 TI - Bioaccumulation of thallium and other trace metals in Biscutella laevigata nearby a decommissioned zinc-lead mine (Northeastern Italian Alps). AB - The mineral body exploited in Salafossa (Eastern Dolomites) was one of the largest lead/zinc-containing mineral deposits in Europe. Both metals were mainly present as sulphides (sphalerite, ZnS and galena, PbS). Mining activity started around 1550, but it was only around 1960 that the richest veins of the minerals were discovered. The mine closed in 1985, and concentrations of several trace metals, such as thallium (Tl), iron (Fe), manganese (Mn), lead (Pb) and zinc (Zn), were detected in the soils and plant samples (Biscutella laevigata L.) that were collected from eighteen sites selected outside the mine. B. laevigata is a pseudometallophyta species, and it often grows near mining areas where the soil's metal concentrations are significantly higher than those of soil with a natural geochemical background. The total metal concentrations in the plant tissue (roots and leaves of Biscutella laevigata) and in the soil samples - both bulk-soil and the B. laevigata root system (rhizo-soil) - were determined through Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). The metal extractability and leachability of the soil samples were estimated using soil extractions with DTPA (Diethylenetriaminepentaacetic acid). In addition, metal mobility caused by rainwater runoff was estimated by using a leaching test with a dilute solution of H2SO4 and HNO3. The results showed that metals were present in a chemical form available for uptake by the plants' roots. In fact, high concentrations of the metals were also found in the plant tissue (roots and leaves) of B. laevigata, and these concentrations were higher than those whose soils present natural geochemical background levels in the corresponding rhizo-soil. Thus, B. laevigata has shown a marked ability to bioaccumulate trace metals, especially Tl and, to a lesser extent, Zn, Pb, Fe and Mn, and it can influence metal mobility in the rhizo-soil. To assess the uptake and translocation processes of the trace metals, resulting in their bioaccumulation, two different indices were calculated: the enrichment factor in roots (EFr), as the ratio between the metal concentration in belowground biomass and in the respective rhizo-soil, and the translocation factor (TF), as the ratio between the metal concentration in the leaves and the corresponding roots. For both indices, values > 1 denoted enrichment of the metal in the roots or its translocation to the upper tissues. The results showed that EFr and TF were considerably high only for Tl, reaching a maximum value of 60 for EFr and 11.6 for TF. Conversely, the other investigated metals did not show significant bioaccumulation (EFr < 1), and they showed TF > 1 only at a few sites. PMID- 27484742 TI - A health fundraising experiment using the "foot-in-the-door" technique. AB - Foot-in-the-door (FITD) involves obtaining compliance with a small request to boost compliance with a larger request. Only a few studies to date have tested the technique in health and fundraising contexts, and even fewer have examined the psychological processes involved. To address these gaps, we conducted an experiment as an actual fundraiser for a cancer-awareness organization. The technique activated a self-concept as a supporter of cancer awareness among those in the FITD condition. Donation amount was also higher among those in FITD, but only among those with higher levels of worry and low to moderate levels of preference for consistency. PMID- 27484744 TI - Fimbriatols A-J, Highly Oxidized ent-Kaurane Diterpenoids from Traditional Chinese Plant Flickingeria fimbriata (B1.) Hawkes. AB - Fimbriatols A-J (1-10), ten new ent-kaurane diterpenoids possessing differently highly oxidized sites, were isolated from Flickingeria fimbriata (B1.) Hawkes. The structures of these new compounds were determined by HRESI-MS, NMR, CD spectra and X-ray diffraction analysis. Compound 1 displayed moderately inhibitory ratio (48.5%) compared with the positive compound NSC-87877 (81.6%) at the concentration of 0.022 MUg/mL. Compounds 7-10 possess 3, 4-seco-ent-kaurane skeleton containing a disaccharide moiety with an unusual linkage at C-2' to C 1'' instead of the common linkage at C-6' to C-1'', and this is the first report in 600 more ent-kauranes found in nature, which might be originated from ent kaurane diterpenoids through post-modified reactions of Baeyer-Villiger oxygenation and glycosylation. PMID- 27484743 TI - S-Nitrosoglutathione ameliorates acute renal dysfunction in a rat model of lipopolysaccharide-induced sepsis. AB - OBJECTIVE: Sepsis induces an inflammatory response that results in acute renal failure (ARF). The current study is to evaluate the role of S-Nitrosoglutathione (GSNO) in renoprotection from lipopolysaccharide (LPS)-induced sepsis. METHODS: Rats were divided to three groups. First group received LPS (5 mg/kg body weight), second group was treated with LPS + GSNO (50 MUg/kg body weight), and third group was administered with vehicle (saline). They were sacrificed on day 1 and 3 post-LPS injection. Serum levels of nitric oxide (NO), creatinine and blood urea nitrogen (BUN) were analysed. Tissue morphology, T lymphocyte infiltrations, and the expression of inflammatory (TNF-alpha, iNOS) and anti-inflammatory (IL 10) mediators as well as glutathione (GSH) levels were determined. KEY FINDING: Lipopolysaccharide significantly decreased body weight and increased cellular T lymphocyte infiltration, caspase-3 and iNOS and decreased PPAR-gamma in renal tissue. NO, creatinine and BUN were significantly elevated after LPS challenge, and they significantly decreased after GSNO treatment. TNF-alpha level was found significantly increased in LPS-treated serum and kidney. GSNO treatment of LPS challenged rats decreased caspase-3, iNOS, TNF-alpha, T lymphocyte infiltration and remarkably increased levels of IL-10, PPAR-gamma and GSH. CONCLUSION: GSNO can be used as a renoprotective agent for the treatment of sepsis-induced acute kidney injury. PMID- 27484745 TI - Design and characterization of a polyamine derivative inhibiting the expression of type III secretion system in Pseudomonas aeruginosa. AB - The type III secretion system (TTSS) of Pseudomonas aeruginosa is a key virulence determinant for infection of eukaryotic hosts. Based on the findings that spermidine-mediated host-pathogen signalling is important for activation of type III secretion systems (TTSS), in this study, we designed, synthesized and evaluated a series of polyamine derivatives for their potentials in inhibiting the expression TTSS in P. aeruginosa. In vitro assay of 15 compounds synthesized in this study unveiled stringent structural requirements for TTSS-inhibitory activity. Among them, R101SPM, a conjugate between rhodamine 101 and spermine, showed a potent activity in inhibition of the TTSS gene expression and in attenuation of the TTSS-mediated cytotoxicity on human cells. In vivo analysis demonstrated that R101SPM could rescue mice from the lethal infection by P. aeruginosa. Moreover, genetic analysis showed that the full TTSS-inhibitory activity of R101SPM required a functional spermidine transporter. Taken together, our results present a new class of lead molecules for developing anti-virulence drugs and demonstrate that the spermidine transporter SpuDEGHF of P. aeruginosa is a promising drug target. PMID- 27484746 TI - The Medina Embolic Device: early clinical experience from a single center. AB - OBJECTIVE: To report our initial experience with the Medina Embolic Device (MED) in unruptured intracranial aneurysms either as sole treatment or in conjunction with additional devices. METHODS: 15 consecutive patients (6 women, 9 men) with unruptured aneurysms were treated between September 2015 and April 2016. The aneurysm fundus measured at least 5 mm. We evaluated the angiographic appearances of treated aneurysms at the end of the procedure and at follow-up, the clinical status, complications, and requirement for adjunctive devices. RESULTS: The MED was successfully deployed in all but one case and adjunctive devices were required in 10 cases. Aneurysm locations were middle cerebral artery bifurcation (n=3), internal carotid artery (ICA) bifurcation (n=1), supraclinoid ICA (n=5), posterior communicating artery (n=1), anterior communicating artery (n=2), cavernous ICA (n=2), distal basilar sidewall (n=1), basilar tip (n=1). Three patients had complications although none could be attributed to the MED. Immediate angiographic results were modified Raymond-Roy classification (mRRC) I=1, mRRC II=5, mRRC IIIa=3, mRRC IIIb=5, and one patient showed contrast stasis within the fundus of the aneurysm. Follow-up angiography was available in 11 patients, with four showing complete aneurysm exclusion, six with stable remnants and one patient with an enlarging neck remnant. CONCLUSIONS: The MED represents a major step forward in the treatment of intracranial aneurysms. It can result in rapid exclusion of an aneurysm from the circulation and has a good safety profile. We believe that the true value of the MED will be in combining its use with adjunctive devices such as endoluminal flow diverters that will result in rapid aneurysmal exclusion. PMID- 27484747 TI - List-learning and verbal memory profiles in childhood epilepsy syndromes. AB - Findings of material-specific influences on memory performance in pediatric epilepsy are inconsistent and merit further investigation. This study compared 90 children (aged 6years to 16years) with childhood absence epilepsy (CAE), frontal lobe epilepsy (FLE), and temporal lobe epilepsy (TLE) to determine whether they displayed distinct list-learning and verbal memory profiles on the California Verbal Learning Test - Children's Version (CVLT-C). Group comparison identified greater risk of memory impairment in children with TLE and FLE syndromes but not for those with CAE. While children with TLE performed worst overall on Short Delay Free Recall, groups with TLE and FLE performed similarly on Long Delay Free Recall. Contrast indices were then employed to explore these differences. Children with TLE demonstrated a significantly greater retroactive interference (RI) effect compared with groups with FLE and CAE. Conversely, children with FLE demonstrated a significantly worse learning efficiency index (LEI), which compares verbal memory following repetition with initial recall of the same list, than both children with TLE and CAE. These findings indicated shallow encoding related to attentional control for children with FLE and retrieval deficits in children with TLE. Finally, our combined sample showed significantly higher rates of extreme contrast indices (i.e., 1.5 SD difference) compared with the CVLT-C standardization sample. These results underscore the high prevalence of memory dysfunction in pediatric epilepsy and offer support for distinct patterns of verbal memory performance based on childhood epilepsy syndrome. PMID- 27484748 TI - The relationship between white matter abnormalities and cognitive functions in new-onset juvenile myoclonic epilepsy. AB - Diffusion tensor imaging (DTI) has revealed evidence of subcortical white matter abnormalities in the frontal area in juvenile myoclonic epilepsy (JME). Decreased fractional anisotropy (FA) and increased mean diffusivity (MD) in the corticothalamic pathway have been detected in adult patients with JME. It has been demonstrated that, in adult patients with JME, frontal dysfunction is related to subcortical white matter damage and decreased volume in frontal cortical gray matter and the thalamus. Many studies have focused on adult patients. Twenty-four patients and 28 controls were evaluated. The group with JME had significantly worse results for the word fluency, trail-B, and Stroop tests that assessed executive functions. A significant decrease in FA values in the dorsolateral prefrontal cortex (DLPFC), the supplementary motor area (SMA), the right thalamus, the posterior cingulate, the corpus callosum anterior, the corona radiata, and the middle frontal white matter (MFWM) and an increase in ADC values in patients with JME were detected. The correlation between FA values in DLPFC and the letter fluency test results was positive, and the correlation with the Stroop and trail-B test results was negative. We found a negative correlation between SMA, anterior thalamus, and MFWM FA values and the trail-B test results and a positive correlation between the SMA, anterior thalamus, and MFWM FA values and the letter fluency test results. We detected white matter and gray matter abnormalities in patients with new-onset JME using DTI. In addition, we determined the relationship between cognitive deficit and microstructural abnormalities by evaluating the correlation between the neuropsychological test battery results and DTI parameters. We evaluated newly diagnosed patients with JME in our study. That leads us to believe that microstructural abnormalities exist from the very beginning of the disease and that they result from the genetic basis of the disease. PMID- 27484749 TI - Management of Juvenile Idiopathic Arthritis: A Clinical Guide. AB - Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood. The outcome in patients with JIA has markedly improved with the advent of biologic drugs. Although early aggressive therapy with biologics seems to be very effective, this approach leads to overtreatment in patients who would respond to classic disease-modifying anti-rheumatic drugs. Therefore, methotrexate remains first-line long-term therapy for most children with polyarticular JIA. Tumor necrosis factor-alpha inhibitors have shown tremendous benefit in children with refractory non-systemic JIA. Similar effects have been observed with interleukin-1 and interleukin-6 blockade in patients with systemic JIA. Correct choice and timely use of available medications to achieve early and sustained remission with as few side effects as possible remain challenges for the treating physician. In this review, a practical, clinically oriented guide to the management of JIA is provided, focusing on pharmacological treatment with non steroidal anti-inflammatory drugs, intra-articular and systemic corticosteroids, disease-modifying anti-rheumatic drugs, and biologic agents. In addition, issues regarding treatment failure, early aggressive treatment, and drug tapering are discussed, with alternative treatment options being suggested. PMID- 27484750 TI - Alcohol consumption among partners of pregnant women in Sweden: a cross sectional study. AB - BACKGROUND: Antenatal care in Sweden involves a visit in pregnancy week 6-7 for counseling about lifestyle issues, including alcohol. The aim of this study was to investigate alcohol consumption among partners of pregnant women, their motives for changing drinking patterns when becoming a parent and their perceptions of the midwife's counseling about alcohol. METHOD: The study was conducted at 30 antenatal care centers across Sweden in 2009-2010. All partners who accompanied a pregnant women in pregnancy week >17 were asked to participate. The questionnaire included questions on alcohol consumption. RESULTS: Questionnaires from 444 partners were analyzed. Most, 95 %, of the partners reported alcohol consumption before pregnancy; 18 % were binge drinking (6 standard drinks or more per occasion, each drink containing 12 grams of pure alcohol) at least once every month during the last year. More than half, 58 %, of all partners had decreased their alcohol consumption following pregnancy recognition and a higher proportion of binge drinkers decreased their consumption compared to non-frequent binge drinkers (p = 0.025). Their motives varied; the pregnancy itself, fewer social gatherings (potentially involving alcohol consumption) and a sense of responsibility for the pregnant partner were reported. Of the partners, 37 % reported support for decreased drinking from others (pregnant partner, parents, friend or workmates). Further, most partners appreciated the midwife's counseling on alcohol. CONCLUSION: A majority of partners decreased their alcohol consumption in transition to parenthood, which also appears to be a crucial time for changing alcohol-drinking patterns. The partners with higher AUDIT-C scores reported more support for decreased drinking. Most partners appreciated the midwife's talk about alcohol and pregnancy and those who filled out AUDIT in early pregnancy reported that the counseling was more engaging. During pregnancy it is possible to detect partners with high alcohol consumption, and promote interventions for decreased drinking, also for the partners. Written information addressing alcohol use and directed to partners is needed. PMID- 27484751 TI - Quantum electromechanics on silicon nitride nanomembranes. AB - Radiation pressure has recently been used to effectively couple the quantum motion of mechanical elements to the fields of optical or microwave light. Integration of all three degrees of freedom-mechanical, optical and microwave would enable a quantum interconnect between microwave and optical quantum systems. We present a platform based on silicon nitride nanomembranes for integrating superconducting microwave circuits with planar acoustic and optical devices such as phononic and photonic crystals. Using planar capacitors with vacuum gaps of 60 nm and spiral inductor coils of micron pitch we realize microwave resonant circuits with large electromechanical coupling to planar acoustic structures of nanoscale dimensions and femtoFarad motional capacitance. Using this enhanced coupling, we demonstrate microwave backaction cooling of the 4.48 MHz mechanical resonance of a nanobeam to an occupancy as low as 0.32. These results indicate the viability of silicon nitride nanomembranes as an all-in-one substrate for quantum electro-opto-mechanical experiments. PMID- 27484752 TI - Comment on "Costs associated with emergency care and hospitalization for severe hypoglycemia". PMID- 27484753 TI - Reply from the authors to "Comments on 'Association of consumption of dairy products and meat with retinal vessel calibers in subjects at increased cardiovascular risk'". PMID- 27484754 TI - Comments on "Impact of lifestyle interventions on depressive symptoms in individuals at-risk of, or with, type 2 diabetes mellitus: Clinical importance of lifestyle interventions". PMID- 27484755 TI - The association of lean and fat mass with all-cause mortality in older adults: The Cardiovascular Health Study. AB - BACKGROUND AND AIMS: Understanding contributions of lean and fat tissue to cardiovascular and non-cardiovascular mortality may help clarify areas of prevention in older adults. We aimed to define distributions of lean and fat tissue in older adults and their contributions to cause-specific mortality. METHODS AND RESULTS: A total of 1335 participants of the Cardiovascular Health Study (CHS) who underwent dual-energy x-ray absorptiometry (DEXA) scans were included. We used principal components analysis (PCA) to define two independent sources of variation in DEXA-derived body composition, corresponding to principal components composed of lean ("lean PC") and fat ("fat PC") tissue. We used Cox proportional hazards regression using these PCs to investigate the relationship between body composition with cardiovascular and non-cardiovascular mortality. Mean age was 76.2 +/- 4.8 years (56% women) with mean body mass index 27.1 +/- 4.4 kg/m2. A greater lean PC was associated with lower all-cause (HR = 0.91, 95% CI 0.84-0.98, P = 0.01) and cardiovascular mortality (HR = 0.84, 95% CI 0.74 0.95, P = 0.005). The lowest quartile of the fat PC (least adiposity) was associated with a greater hazard of all-cause mortality (HR = 1.24, 95% CI 1.04 1.48, P = 0.02) relative to fat PCs between the 25th-75th percentile, but the highest quartile did not have a significantly greater hazard (P = 0.70). CONCLUSION: Greater lean tissue mass is associated with improved cardiovascular and overall mortality in the elderly. The lowest levels of fat tissue mass are linked with adverse prognosis, but the highest levels show no significant mortality protection. Prevention efforts in the elderly frail may be best targeted toward improvements in lean muscle mass. PMID- 27484756 TI - Efficacy and safety of linagliptin according to patient baseline characteristics: A pooled analysis of three phase 3 trials. AB - BACKGROUND AND AIMS: We aimed to determine if patient baseline characteristics affect responses to linagliptin and identify relevant predictors of glycated hemoglobin (HbA1c) reduction in patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: Data were pooled from three 24-week, placebo-controlled trials of similar design (linagliptin, n = 1651; placebo, n = 607). Patients were categorized according to baseline characteristics: age, T2DM duration, gender, body mass index (BMI), Homeostasis Model Assessment of Insulin Resistance (HOMA IR), and metabolic syndrome (MetS). Changes from baseline in HbA1c after 24 weeks were assessed with analysis of covariance (ANCOVA). The proportion of patients with baseline HbA1c >7% achieving HbA1c of <=7% at week 24 were evaluated. Independent predictors of HbA1c response with linagliptin were analyzed in a multivariate analysis with ANCOVA. Linagliptin treatment led to significant mean (SE) placebo-corrected reductions from baseline in HbA1c across all subgroups ( 0.42% [+/-0.11] to -0.79% [0.08]; all p < 0.001). Within subgroups, HbA1c reduction was more pronounced in patients without MetS (-0.74% [0.06]; treatment interaction p = 0.0489). The proportion of patients with baseline HbA1c >7% achieving a target HbA1c <=7% was greater with linagliptin versus placebo (30.2% vs 11.5%; odds ratio 3.82; 95% CI 2.82 to 5.17; p < 0.001). Characteristics significantly predicting HbA1c reductions after 24 weeks were fasting plasma glucose and race (both p < 0.05). CONCLUSION: This post-hoc analysis supports that linagliptin achieved clinically meaningful improvements in hyperglycemia in patients with diverse clinical characteristics. These improvements were more pronounced in patients without MetS. PMID- 27484757 TI - Daytime napping, sleep duration and increased 8-year risk of type 2 diabetes in a British population. AB - BACKGROUND AND AIMS: Few studies have prospectively examined the relationship between daytime napping and risk of type 2 diabetes. We aimed to study the effects of daytime napping and the joint effects of napping and sleep duration in predicting type 2 diabetes risk in a middle- to older-aged British population. METHODS AND RESULTS: In 1998-2000, 13 465 individuals with no known diabetes participating in the European Prospective Investigation into Cancer-Norfolk study reported daytime napping habit and 24-h sleep duration. Incident type 2 diabetes cases were identified through multiple data sources until 31 July 2006. After adjustment for age and sex, daytime napping was associated with a 58% higher diabetes risk. Further adjustment for education, marital status, smoking, alcohol intake, physical activity, comorbidities and hypnotic drug use had little influence on the association, but additional adjustment for BMI and Waist Circumference attenuated the Odds ratio (OR) (95% CI) to 1.30 (1.01, 1.69). The adjusted ORs (95% CI) associated with short and long sleep duration were 1.46 (1.10, 1.90) and 1.64 (1.16, 2.32), respectively. When sleep duration and daytime napping were examined together, the risk of developing diabetes more than doubled for those who took day naps and had less than 6 h of sleep, compared to those who did not nap and had 6-8 h of sleep. CONCLUSION: Daytime napping was associated with an increased risk of type 2 diabetes, particularly when combined with short sleep duration. Further physiological studies are needed to confirm the interaction between different domains of sleep in relation to diabetes risk. PMID- 27484759 TI - Characterisation of the responsive properties of two running-specific prosthetic models. AB - BACKGROUND: The need for information regarding running-specific prosthetic properties has previously been voiced. Such information is necessary to assist in athletes' prostheses selection. OBJECTIVES: This study aimed to describe the characteristics of two commercially available running-specific prostheses. STUDY DESIGN: The running-specific prostheses were tested (in an experimental setup) without the external interference of athlete performance variations. METHODS: Four stiffness categories of each running-specific prosthetic model (XtendTM and XtremeTM) were tested at seven alignment setups and three drop masses (28, 38 and 48 kg). Results for peak ground reaction force (GRFpeak), contact time ( tc), flight time ( tf), reactive strength index (RSI) and maximal compression (Delta L) were determined during controlled dropping of running-specific prostheses onto a force platform with different masses attached to the experimental setup. RESULTS: No statistically significant differences were found between the different setups of the running-specific prostheses. Statistically significant differences were found between the two models for all outcome variables (GRFpeak, Xtend > Xtreme; tc, Xtreme > Xtend; tf, Xtreme > Xtend; RSI, Xtend > Xtreme; Delta L, Xtreme > Xtend; p < 0.05). CONCLUSION: These findings suggest that the Xtreme stores more elastic energy than the Xtend, leading to a greater performance response. The specific responsive features of blades could guide sprint athletes in their choice of running-specific prostheses. Clinical relevance Insights into the running-specific prosthesis (RSP) properties and an understanding of its responsive characteristics have implications for athletes' prosthetic choice. Physiologically and metabolically, a short sprint event (i.e. 100 m) places different demands on the athlete than a long sprint event (i.e. 400 m), and the RSP should match these performance demands. PMID- 27484758 TI - [Chest pain at 32 weeks' gestation: pregnancy-related spontaneous coronary artery dissection]. AB - A 32-year-old woman at 32 weeks gestation presented with cardiac arrest due to ventricular tachycardia following acute chest pain at home. After immediate defibrillation with return of spontaneous circulation (ROSC), an ST segment elevation myocardial infarction due to coronary artery dissection was confirmed. Two drug-eluting stents were implanted and she was placed on dual antiplatelet therapy (DAPT). The echocardiogram showed akinesis of the apex and anterior wall. The patients risk for stent thrombosis was considered high and therefore DAPT was continued until cesarean section at 35 weeks gestation. Intraoperatively she received two units of packed red blood cells, one platelet concentrate, 4 g fibrinogen and 2 g tranexamic acid. Left ventricular ejection fraction deteriorated 8 days after delivery and the patient developed congestive heart failure. PMID- 27484761 TI - Self-Efficacy, Depression, and Self-Care Activities in Adult Jordanians with Type 2 Diabetes: The Role of Illness Perception. AB - Diabetes mellitus is reaching epidemic levels worldwide. In a developing country like Jordan, type 2 diabetes mellitus (T2DM) has reached a prevalence rate of 17.1%. This cross-sectional study examined the relationship between self-care activities and: illness perception, depression, social support, religiosity and spiritual coping, and self-efficacy among patients with T2DM. A random sample of 220 patients with T2DM, who attended Jordan University Hospital in Jordan were enrolled. The data were collected through a structured interview and the medical files. The instruments consisted of a sociodemographic and clinical standardised questionnaires: Brief Illness Perception Questionnaire, Patients' Health Questionnaire-9; ENRICH Social Support Instrument; Religious and Spiritual Coping Subscale; Diabetes Management Self-Efficacy Scale; and Summary of Diabetes Self Care Activities. Bivariate analysis investigated the relationship between variables. Structure Equation Modelling (SEM) was performed to test the proposed conceptual model. The study found that approximately 70% of the respondents suffered some form of depressive symptoms. The SEM showed a direct relationship between self-efficacy and self-care activities (beta = 0.40; p < 0.001). Depression was indirectly related to self-care activities through self-efficacy (beta = -0.20; p = 0.003); nevertheless, it was directly related to perception of: treatment control, consequences, and emotional representations. Overall, the sequence between illness perception and self-efficacy was mediated by depression. Strategies to promote self-efficacy and illness perception are vital in customising a diabetes health plan to meet Arabic cultural expectations. PMID- 27484760 TI - Integrating emotional and psychological support into the end-stage renal disease pathway: a protocol for mixed methods research to identify patients' lower-level support needs and how these can most effectively be addressed. AB - BACKGROUND: As a result of difficulties related to their illness, diagnosis and treatment, patients with end-stage renal disease experience significant emotional and psychological problems, which untreated can have considerable negative impact on their health and wellbeing. Despite evidence that patients desire improved support, management of their psychosocial problems, particularly at the lower level, remains sub-optimal. There is limited understanding of the specific support that patients need and want, from whom, and when, and also a lack of data on what helps and hinders renal staff in identifying and responding to their patients' support needs, and how barriers to doing so might be overcome. Through this research we therefore seek to determine what, when, and how, support for patients with lower-level emotional and psychological problems should be integrated into the end-stage renal disease pathway. METHODS/DESIGN: The research will involve two linked, multicentre studies, designed to identify and consider the perspectives of patients at five different stages of the end-stage renal disease pathway (Study 1), and renal staff working with them (Study 2). A convergent, parallel mixed methods design will be employed for both studies, with quantitative and qualitative data collected separately. For each study, the data sets will be analysed separately and the results then compared or combined using interpretive analysis. A further stage of synthesis will employ data-driven thematic analysis to identify: triangulation and frequency of themes across pathway stages; patterns and plausible explanations of effects. DISCUSSION: There is an important need for this research given the high frequency of lower-level distress experienced by end-stage renal disease patients and lack of progress to date in integrating support for their lower-level psychosocial needs into the care pathway. Use of a mixed methods design across the two studies will generate a holistic patient and healthcare professional perspective that is more likely to identify viable solutions to enable implementation of timely and integrated care. Based on the research outputs, appropriate support interventions will be developed, implemented and evaluated in a linked follow-on study. PMID- 27484762 TI - Schidandrin B kills tumor cells by initiating apoptosis in glioma SHG-44 cells. AB - OBJECTIVE: To observe the proliferation inhibition, cell cycle, and apoptosis of human glioma cell line SHG-44 treated with different concentration of Schidandrin B and explore the effect of Schidandrin B on glioma SHG-44 cells. METHODS: Glioma SHG-44 cells were treated with Schidandrin B (0, 50, 100 or 200 MUg/mL) for 24, 48, 72 and 96 h, and cells were treated with vehicle as control. Viability of cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis; cell cycle was examined with flow cytometry assay; apoptosis was detected with annexin V assay. Bax and caspase-3 proteins expression were checked by Western blot. RESULTS: MTT analysis showed that viability of glioma SHG-44 cells significantly decreased after exposure to Schidandrin B for the indicated time. Flow cytometry revealed that the number of cells in the sub G1 phase was increased, however, the number of cells in G0/G1, S and G2/M phases were decreased after treatment with 50, 100 or 200 MUg/mL Schidandrin B, compared with the respective control group. Annexin V analysis confirmed that apoptosis rates of the control group, 50, 100, and 200 MUg/mL Schidandrin B group were 1.76%+/-0.47%, 13.98%+/-5.05%, 19.64%+/-5.53% and 63.28%+/-6.88% respectively, apoptotic rate increased significantly with dose dependent manner, and apoptosis of cells were observed under the inverted microscope after 100 MUg/mL Schidandrin B treatment. Bax and caspase-3 protein were highly expressed in Schidandrin B group compared with the control group. CONCLUSION: The apoptosis could be induced by different concentration of Schidandrin B on glioma SHG-44 cells, and the mechanism may be directly excited by Schidandrin B in glioma SHG-44 cells through activating mitochondrial pathway. PMID- 27484763 TI - Clinical observation of Shuanghuang Shengbai Granule () on prevention and treatment of myelosuppression caused by chemotherapy in cancer patients. AB - OBJECTIVE: To study the efficacy and safety of Shuanghuang Shengbai Granule (, SSG), a traditional Chinese herbal medicine, on myelosuppression of cancer patients caused by chemotherapy. METHODS: A total of 330 patients were randomly assigned to the treatment group (220 cases, analysed 209 cases) and the control group (110 cases, analysed 102 cases) with a 2:1 ratio by envelope method. The patients in the treatment group at the first day of chemotherapy started to take SSG for 14 days, while the patients in the control group took Leucogon Tablets. The changes of the blood routine, clinical symptoms and immune function in both groups were observed for safety and efficacy evaluation. RESULTS: At the 7th day of chemotherapy, the white blood cells (WBCs) level in the treatment group was significantly higher than that in the control group (P<0.05). After treatment, the WBCs rate in the normal range accounted for 50.2% in the treatment group, the myelosuppression of WBCs and neutrophil were mainly grade I, while 8.1% and 5.7% of patients emerged grade III and grade IV myelosuppression, respectively. The incidence of myelosuppression of the treatment group was significantly lower than that of the control group (P<0.05). The total effective rate of Chinese medicine syndrome in the treatment group was significantly higher than that in the control group (84.2% vs. 72.5%, P<0.05). The immune cell levels in both groups were maintained in the normal range. Compared with that before treatment, the levels of CD3+ and CD4+ cells were significantly increased in the treatment group after treatment (P<0.05). The discrepancy of CD3+ and CD4+ cell activity before and after treatment in both groups were significantly different (P<0.05). No obvious adverse event occurred in both groups. CONCLUSION: SSG had a protection effect on bone marrow suppression, and alleviated the clinical symptoms together with clinical safety. PMID- 27484764 TI - Chinese medicine as complementary therapy for female infertility. AB - Chinese medicine (CM) has been used in clinical treatment for thousands of years in China, Japan, Korea, and other countries. CM is at present attracting many attentions around the world for reproductive health care and disease prevention, including treatment of female infertility. This review focuses on the CM treatment for female infertility patients, and supplies a summary on the efficacy, safety, and mechanism of some Chinese herbal medicines, herbal medicine derived active compounds, and acupuncture. A large number of researches have reported that CM could alleviate or even cure female infertility by regulating hormone, improving reproductive outcome of in vivo fertilization, affecting embryonic implantation, curing polycystic ovarian syndrome, endometriosis, pelvic inflammatory disease, relieving mental stress, and regulating immune system. Meanwhile, a few studies claimed that there was little adverse reaction of CM in randomized controlled trials. However, up to present there is a lack of adequate evidences with molecular mechanistic researches and randomized controlled trials to prove the CM as an effective and safe treatment for infertility. Thus, utility of CM as a complementary medicine will be a feasible method to improve the outcome of female infertility treatment. PMID- 27484765 TI - Is manipulative therapy clinically necessary for relief of neck pain? A systematic review and meta-analysis. AB - OBJECTIVE: To summarize and critically assess the effificacy of Eastern and Western manipulative therapies for the treatment of neck pain in adults. METHODS: A search of PubMed/MEDLINE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, EMBASE, etc. from their inception date to January 2014 with Chinese, Japanese, and Korean databases. Two reviewers independently selected randomized controlled trials (RCTs) with negative control or blank control, extracted data and assessed methodological quality. Meta-analysis and levels of evidence were performed by Revman5.1 and Grades of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Nineteen clinical trials with adequate randomization were included in this review, 11 of them had a low risk of bias. The primary outcome for short-term pain had no significant differences, however, the secondary outcome, only the Numerical Pain Rating Scale (NPRS) score of intermediate-term [n=916, pooled mean differences (MD) =-0.29, P=0.02], the Neck Disability Index (NDI) score of short-term (n=1,145, pooled MD= 2.10, P<0.01), and intermediate-term (n=987, pooled MD=-1.45, P=0.01) were signifificantly reduced with moderate quality evidence. However, it supported the minimally clinically important difference (MCID) of the Visual Analogue Scale and NPRS pain score to be 13 mm, while NDI was 3.5 points. The meta-analysis only suggested a trend in favor of manipulative therapy rather than clinical signifificance. CONCLUSIONS: The results do not support the existing evidences for the clinical value of Eastern or Western manipulative therapy for neck pain of short-term follow-up according to MCIDs. The limitations of our review related to blinding, allocation concealment and small sample size. PMID- 27484766 TI - Efficacy of Aidi Injection () on overexpression of P-glycoprotein induced by vinorelbine and cisplatin regimen in patients with non-small cell lung cancer. AB - OBJECTIVE: To investigate the efficacy of Aidi Injection () on overexpression of P-glycoprotein (P-gp) induced by vinorelbine and cisplatin (NP) regimen in patients with non-small cell lung cancer (NSCLC), and study the difference between intravenous administration and targeting intratumor administration of Aidi Injection with thoracoscope. METHODS: Totally 150 patients with NSCLC were randomly assigned to the control group, the intravenous group and the intratumor group by the random envelope method, 50 cases in each group. The patients were treated with NP regimen (2 cycles), NP regimen (2 cycles) plus Aidi intravenous injection, or NP regimen (2 cycles) plus Aidi intratumor injection with thoracoscope, respectively for 6 weeks. The clinical effificacy was observed based on Response Evaluation Criteria in Solid Tumors (RECIST) rules, the expression of P-gp in the tumor tissue was tested before, 3 and 6 weeks after treatment, the safety was evaluated by monitoring the toxicity in the process of treatment, and the progression-free survival (PFS) was measured. RESULTS: Fifteen cases dropped out because of the irreconcilable conditions which had no relationship with the treatment, 4 in the control group, 5 in the intravenous group, and 6 in the intratumor group, respectively. Compared with the control group, the response rates (complete remission + partial response) and the disease control rates (complete remission + partial response + stable disease) were significantly higher, the P-gp expressions were significantly decreased after 3 and 6 weeks of treatment, and the Kaplan-Meier survival curves of PFS were significantly longer in the intravenous and intratumor groups (P<0.05 or P<0.01), and the intratumor group showed better effects than the intravenous group (P<0.05 or P<0.01). Compared with the control group, the occurrences of rash, nausea and leukocytopenia were signifificantly decreased in the intravenous and intratumor groups (P<0.05), but without signifificant difference between the intravenous and intratumor groups (P>0.05). CONCLUSION: Aidi Injection not only improves the effificacy of NP regime, but also has the function of reducing adverse events and preventing against overexpression of P-gp induced by chemotherapy of NP regimen. PMID- 27484767 TI - Ethanol extract of Phellinus merrillii protects against diethylnitrosamine- and 2 acetylaminofluorene-induced hepatocarcinogenesis in rats. AB - OBJECTIVE: To study whether the ethanol extract of Phellinus merrillii (EPM) has chemopreventive potential against liver carcinogenesis. METHODS: Thirty male Spraque-Dawley rats were randomly divided into control group, EPM control group, hepatocarcinoma control group, low-dose EPM group and high-dose EPM group, 6 in each group. Using the Solt and Farber protocol in a rat model of hepatocarcinogenesis, the chemopreventive effect of EPM on diethylnitrosamine (DEN)-initiated, 2-acetylaminofluorene (2-AAF) and partial hepatectomy (PH) promoted liver carcinogenesis in rats was evaluated. Basic pathophysiological and histological examinations, together with the serum levels of glutamic oxaloacetic transaminase (sGOT), glutamic pyruvic transaminase (sGPT) and gamma-glutamyl transpeptidase (gamma-GT) were measured. RESULTS: Treatment of EPM at the concentration of 2 g/kg body weight in the diet for 8 weeks clearly prevented the development of carcinogenesis and reduced the levels of sGOT, sGPT, and serum gamma-GT of rats as compared with the hepatocarcinoma control group (P<0.05 or P<0.01). These phenotypes were accompanied by a significant increase in natural killer cell activity. CONCLUSION: EPM showed a strong liver preventive effect against DEN+2-AAF+PH-induced hepatocarcinogenesis in a rat model. PMID- 27484768 TI - Inhibitory effects of an aqueous extract from Cortex Phellodendri on the growth and replication of broad-spectrum of viruses in vitro and in vivo. AB - BACKGROUND: Cortex Phellodendri (C. Phellodendri), the dried trunk bark of Phellodendron amurense Ruprecht, has been known as a traditional herbal medicine, showing several bioactivities. However, antiviral activity of C. Phellodendri aqueous extract (CP) not reported in detail, particularly aiming the prophylactic effectiveness. METHODS: In vitro CP antiviral activity evaluated against Influenza A virus (PR8), Vesicular Stomatitis Virus (VSV), Newcastle Disease Virus (NDV), Herpes Simplex Virus (HSV), Coxsackie Virus (H3-GFP) and Enterovirus 71 (EV-71) infection on immune (RAW264.7) and epithelial (HEK293T/HeLa) cells. Such antiviral effects were explained by the induction of antiviral state which was determined by phosphorylation of signal molecules, secretion of IFNs and cytokines, and cellular antiviral mRNA expression. Furthermore, Compounds present in the aqueous fractions confirmed by HPLC analysis and evaluated their anti viral activities. Additionally, in vivo protective effect of CP against divergent influenza A subtypes was determined in a BALB/c mouse infection model. RESULTS: An effective dose of CP significantly reduced the virus replication both in immune and epithelial cells. Mechanically, CP induced mRNA expression of anti viral genes and cytokine secretion in both RAW264.7 and HEK293T cells. Furthermore, the main compound identified was berberine, and shows promising antiviral properties similar to CP. Finally, BALB/c mice treated with CP displayed higher protection levels against lethal doses of highly pathogenic influenza A subtypes (H1N1, H5N2, H7N3 and H9N2). CONCLUSION: CP including berberine play an immunomodulatory role with broad spectrum antiviral activity, due to induction of antiviral state via type I IFN stimulation mechanism. Consequently, C. Phellodendri could be a potential source for promising natural antivirals or to design other antiviral agents for animal and humans. PMID- 27484769 TI - A Regional Outbreak of Clostridium difficile PCR-Ribotype 027 Infections in Southeastern France from a Single Long-Term Care Facility. AB - OBJECTIVE To describe and analyze a large outbreak of Clostridium difficile 027 (CD-027) infections. METHODS Confirmed CD-027 cases were defined as CD infection plus real-time polymerase chain reaction assay (PCR) positive for CD-027. Clinical and microbiological data on patients with CD-027 infection were collected from January 2013 to December 2015 in the Provence-Alpes-Cote-d'Azur region (southeastern France). RESULTS In total, 19 healthcare facilities reported 144 CD-027 infections (112 confirmed and 32 probable CD-027 infections) during a 22-month period outbreak. Although the incidence rate per 10,000 bed days was lower in long-term care facilities (LTCFs) than in acute care facilities (0.05 vs 0.14; P<.001), cases occurred mainly in LTCFs, one of which was the probable source of this outbreak. After centralization of CD testing, the rate of confirmed CD-027 cases from LTCFs or residential-care homes increased significantly (69% vs 92%; P<.001). Regarding confirmed CD-027 patients, the sex ratio and the median age were 0.53 and 84.2 years, respectively. The 30-day crude mortality rate was 31%. Most patients (96%) had received antibiotics within 3 months prior to the CD colitis diagnosis. During the study period, the rate of patients with CD-027 (compared with all patients tested in the point-of-care laboratories) decreased significantly (P=.03). CONCLUSIONS A large CD-027 outbreak occurred in southeastern France as a consequence of an initial cluster of cases in a single LTCF. Successful interventions included rapid isolation and testing of residents with potentially infectious diarrhea and cohorting of case patients in a specialized infectious diseases ward to optimize management. Infect Control Hosp Epidemiol 2016;1-5. PMID- 27484770 TI - Kyphoscoliosis peptidase (KY) mutation causes a novel congenital myopathy with core targetoid defects. PMID- 27484771 TI - The expression of monocarboxylate transporters in thyroid carcinoma can be associated with the morphological features of BRAF V600E mutation. AB - BRAF V600E mutation, usually performed by DNA techniques, is one of the most common diagnostic markers in papillary thyroid carcinoma. Few papers have demonstrated that plump cells (eosinophilic cytoplasms and papillary thyroid carcinoma nuclei) and peculiar sickle-shaped nuclei represent morphological features of BRAF V600E on papillary thyroid carcinomas. These features seem to be linked to glycolytic phenotype whereby monocarboxylate transporters 1-4 are hypothesized to have a dominant role as lactate transporters. We investigated the association between these morphological features and monocarboxylate transporters 1 and 4 in 48 cyto-histological samples diagnosed as "positive for malignancy favoring papillary thyroid carcinoma". These cases were processed with liquid based cytology and underwent BRAF V600E mutational analysis (pyrosequencing) on liquid-based cytology and monocarboxylate transporters immunostaining on histology. The expression of monocarboxylate transporter 1, monocarboxylate transporter 4, glucose trasporter-1 and carbonic anhidrase were scored semi quantitatively with expression from 0 to 3+ (strong positivity). The 33 mutated and 15 wild type cases showed 100 % cyto-histological concordance. The cytological evaluation revealed plump cells and sickle nuclear shape in 100 % mutated cases. Monocarboxylate transporter 1 yielded 76 % positivity in the mutated cases especially in both the plump cells and sickle-shaped nuclei, whereas the wild types showed 13.3 % positive monocarboxylate transporter 1 (p = 0.00013). Monocarboxylate transporter 4 resulted in 100 % positivity in mutated and 40 % in wild types (p < 0.005). Furthermore, 20 % of the wild types showed weak monocarboxylate transporter 1 nuclear expression associated to a less aggressive behavior. The analysis of glucose trasporter-1 and carbonic anhidrase did not highlight any statistical significance (p > 0.05). This is the first report analyzing the association between monocarboxylate transporter expression and the morphological features of BRAF V600E mutated papillary thyroid carcinomas suggesting the possible involvement of lactate in the morphological features. PMID- 27484772 TI - Metabolic implications of menstrual cycle length in non-hyperandrogenic women with polycystic ovarian morphology. AB - This cross-sectional study aimed to investigate the association between menstrual cycle lenght and metabolic parameters in non-hyperandrogenic women with polycystic ovarian morphology, n = 250. Metabolic profiles of all participants were evaluated using anthropometric parameters (body mass index, waist circumference), parameters of dyslipidemia (total cholesterol, HDL-cholesterol, triglycerides) and markers of insulin resistance (fasting insulin, homeostasis model assessment for insulin resistance index). The associations between menstrual cycle lenght and cardiometabolic risk factors such as insulin resistance, dyslipidemia, and obesity were investigated. In non-hyperandrogenic women with polycystic ovarian morphology, menstrual cycle lenght was associated with hypertriglyceridemia and insulin resistance independently of body mass index. Moreover, menstrual cycle lenght added value to body mass index in predicting hypertriglyceridemia. The optimal menstrual cycle lenght cut-off value for identifying of non-hyperandrogenic women with polycystic ovarian morphology at metabolic risk was found to be 45 days. Metabolic profile of non hyperandrogenic women with polycystic ovarian morphology (n = 75) with menstrual cycle lenght >45 days was similar to that of hyperandrogenic women with polycystic ovarian morphology (n = 138) while metabolic profile of non hyperandrogenic women with polycystic ovarian morphology with menstrual cycle lenght <=45 days (n = 112) was similar to that of controls (n = 167). Non hyperandrogenic women with polycystic ovarian morphology with menstrual cycle lenght >45 days had higher prevalence of cardiometabolic risk factors compared to those with menstrual cycle lenght <=45 days. Non-hyperandrogenic women with polycystic ovarian morphology are not metabolically homogeneous. Menstrual cycle lenght is an easy-to-obtain clinical parameter positively associated with the probability of unfavorable metabolic status in non-hyperandrogenic women with polycystic ovarian morphology. Menstrual cycle lenght cut-off value of 45 days was found to have the best capacity in discriminating non-hyperandrogenic women with polycystic ovarian morphology with and without metabolic derangement(s) corroborating in favor of the cardiometabolic risk factors screening and management in non-hyperandrogenic women with polycystic ovarian morphology with menstrual cycle lenght >45 days through strategies for prevention of cardiovascular disease. PMID- 27484773 TI - Infectious diseases and immunological responses in adult subjects with lifetime untreated, congenital GH deficiency. AB - Growth hormone is important for the development and function of the immune system, but there is controversy on whether growth hormone deficiency is associated to immune disorders. A model of isolated growth hormone deficiency may clarify if the lack of growth hormone is associated with increased susceptibility to infections, or with an altered responsiveness of the immune system. We have studied the frequency of infectious diseases and the immune function in adults with congenital, untreated isolated growth hormone deficiency. In a cross sectional study, 35 adults with isolated growth hormone deficiency due to a homozygous mutation in the growth hormone releasing hormone receptor gene and 31 controls were submitted to a clinical questionnaire, physical examination serology for tripanosomiasis, leishmaniasis, HIV, tetanus, hepatitis B and C, and serum total immunoglobulin G, M, E and A measurement. The immune response was evaluated in a subset of these subjects by skin tests and response to vaccination for hepatitis B, tetanus, and bacillus Calmette-Guerin. There was no difference between the groups in history of infectious diseases and baseline serology. Isolated growth hormone deficiency subjects had lower total IgG, but within normal range. There was no difference in the response to any of the vaccinations or in the positivity to protein Purified Derived, streptokinase or candidin. Adult untreated isolated growth hormone deficiency does not cause an increased frequency of infectious diseases, and does not alter serologic tests, but is associated with lower total IgG levels, without detectable clinical impact. PMID- 27484774 TI - Role and regulation of ferritin-like proteins in iron homeostasis and oxidative stress survival of Caulobacter crescentus. AB - Iron is an essential nutrient that is poorly available to living organisms but can be harmful when in excess due to the production of reactive oxygen species. Bacteria and other organisms use iron storage proteins called ferritins to avoid iron toxicity and as a safe iron source in the cytosol. The alpha-proteobacterium Caulobacter crescentus has two putative ferritins, Bfr and Dps, and some other proteins belonging to the ferritin-like superfamily, among them the one encoded by CC_0557. In this work, we have analyzed the role and regulation of these three putative ferritin-like proteins. Using lacZ-transcriptional fusions, we found that bfr expression is positively regulated (2.5-fold induction) by the Fe responsive regulator Fur in iron sufficiency, as expected for an iron storage protein. Expression of dps was induced 1.5-fold in iron limitation in a Fur independent manner, while the expression of the product of CC_0557 was unaffected by either iron supply or Fur. With respect to growth phase, while bfr expression was constant during growth, expression of dps (1.4-fold) and CC_0557 (around seven times) increased in the transition from exponential to stationary phase. Deletion mutant strains for each gene and a double dps/bfr mutant were obtained and tested for oxidative stress resistance. The dps mutant was very sensitive to H2O2, and this phenotype was not relieved by the addition of the iron chelator 2',2-dipyridyl in the conditions tested. While bfr and CC_0557 showed no phenotype as to H2O2 resistance, the double dps/bfr mutant had a similar phenotype to the dps mutation alone. These findings indicate that in C. crescentus Bfr contributes to iron homeostasis and Dps has a role in protection against oxidative stress. The role of the protein CC_0557 containing a ferritin like fold remains unclear. PMID- 27484776 TI - Understanding body representations. PMID- 27484775 TI - Linking patients with community resources: use of a free YMCA membership among low-income black women. AB - Given the increasing interest in expanding obesity prevention efforts to cover community-based programs, we examined whether individuals would access a YMCA for physical activity promotion. We provided a no-cost 12-month YMCA membership to socioeconomically disadvantaged black women who were randomized to the intervention arm of a weight gain prevention trial (n = 91). Analyses examined associations of membership activation and use with baseline psychosocial, contextual, health-related, and sociodemographic factors. Many participants (70.3 %) activated their memberships; however, use was low (42.2 % had no subsequent visits, 46.9 % had one to ten visits). There were no predictors of membership activation, but individuals living below/borderline the federal poverty line were more likely to use the center (1+ visits), as were those who met physical activity guidelines at baseline. More comprehensive and intensive interventions may be necessary to promote use of community resources-even when provided free among high-risk populations of women with obesity that live in rural areas of the USA. PMID- 27484777 TI - Primary Care Behavioral Health Provider Training: Systematic Development and Implementation in a Large Medical System. AB - The expansion of integrated, collaborative, behavioral health services in primary care requires a trained behavioral health workforce with specific competencies to deliver effective, evidence-informed, team-based care. Most behavioral health providers do not have training or experience working as primary care behavioral health consultants (BHCs), and require structured training to function effectively in this role. This article discusses one such training program developed to meet the needs of a large healthcare system initiating widespread implementation of the primary care behavioral health model of service delivery. It details the Department of Defense's experience in developing its extensive BHC training program, including challenges of addressing personnel selection and hiring issues, selecting a model for training, developing and implementing a phased training curriculum, and improving the training over time to address identified gaps. Future directions for training improvements and lessons learned in a large healthcare system are discussed. PMID- 27484778 TI - Testing vision with angular and radial multifocal designs using Adaptive Optics. AB - Multifocal vision corrections are increasingly used solutions for presbyopia. In the current study we have evaluated, optically and psychophysically, the quality provided by multizone radial and angular segmented phase designs. Optical and relative visual quality were evaluated using 8 subjects, testing 6 phase designs. Optical quality was evaluated by means of Visual Strehl-based-metrics (VS). The relative visual quality across designs was obtained through a psychophysical paradigm in which images viewed through 210 pairs of phase patterns were perceptually judged. A custom-developed Adaptive Optics (AO) system, including a Hartmann-Shack sensor and an electromagnetic deformable mirror, to measure and correct the eye's aberrations, and a phase-only reflective Spatial Light Modulator, to simulate the phase designs, was developed for this study. The multizone segmented phase designs had 2-4 zones of progressive power (0 to +3D) in either radial or angular distributions. The response of an "ideal observer" purely responding on optical grounds to the same psychophysical test performed on subjects was calculated from the VS curves, and compared with the relative visual quality results. Optical and psychophysical pattern-comparison tests showed that while 2-zone segmented designs (angular & radial) provided better performance for far and near vision, 3- and 4-zone segmented angular designs performed better for intermediate vision. AO-correction of natural aberrations of the subjects modified the response for the different subjects but general trends remained. The differences in perceived quality across the different multifocal patterns are, in a large extent, explained by optical factors. AO is an excellent tool to simulate multifocal refractions before they are manufactured or delivered to the patient, and to assess the effects of the native optics to their performance. PMID- 27484780 TI - Acid Fast Property of Histoplasma: A Concept Revitalized. PMID- 27484779 TI - Control of fibrotic changes through the synergistic effects of anti-fibronectin antibody and an RGDS-tagged form of the same antibody. AB - TGF-beta and myofibroblasts play a key role in fibrosis, characterized by aberrant synthesis and deposition of extracellular matrix (ECM) proteins, such as fibronectin (Fn) and collagen type I. There are two major roles played by integrins in the fibrotic pathology: (i) Fn-integrin interaction, coupled with cytokines like TGF-beta, facilitates the self-polymerization of Fn and regulates cell-matrix fibrillar adhesions, thereby promoting fibrillogenesis; (ii) Integrin interaction with an RGD (arginine-glycine-aspartic) consensus sequence in the latent TGF-beta, resulting in its activation. This study describes an anti fibrotic strategy using a combination of two antibodies: Fn52 (targeted against the N-terminal 30 kDa region of fibronectin, a major site for Fn self association), and its engineered form, Fn52RGDS (which binds to integrins). Interestingly, a synergistic effect of the cocktail in causing a decline in fibrotic features was confirmed in the context of fibrotic posterior capsular opacification (PCO), mediated by the lens epithelial cells (left behind after cataract surgery). Inclusion of Fn52RGDS to Fn52 aids in better diffusion of the antibodies; such combination therapies could be useful in the context of pathologies involving extensive remodeling of the fibronectin matrix, where the thick ECM offers a major challenge for efficient drug delivery. PMID- 27484781 TI - Parenthood, Child Care, and Heroin Use: Outcomes After Three Years. AB - BACKGROUND: Internationally there is a lack of measurement on the impact of childcare on people who use drugs. OBJECTIVES: The aim of this article was to longitudinally measure drug use, familial and social status and criminal involvement between parents and nonparents who use heroin and have children in their care. METHODS: From 2003 to 2006, 404 participants were recruited to the Research Outcome Study in Ireland Evaluating Drug Treatment Effectiveness (ROSIE) as part of a longitudinal cohort study design. Participants completed the Maudsley Addiction Profile and 88% (n = 356) completed interviews at the 3-year period. One way between groups ANOVA with post hoc tests and backward, stepwise multiple regression were employed for analysis. RESULTS: At follow-up, parents who had children in their care used heroin (p = .004), illicit methadone (p <= .001) and cocaine (p = .024) on fewer days than those who had no children, or those who had children but did not have children in their care. These differences were not observed at intake. Living with someone at intake who used drugs was found to be significantly associated with increased heroin (p <= .001), benzodiazepine (p = .039), and tobacco (p = .030) use at 3 years. Furthermore, a change in childcare status to caring for a child was associated with increased cannabis use (p = .025). Conclusion/Importance: While caring for children was associated with reduced heroin use at 3 years, living with a person who used at intake removed this effect, thus indicating that while individual based addiction theories reflected observed outcomes, social network connectedness was more influential. PMID- 27484782 TI - A single-blind, dose escalation, phase I study of high-fluence light-emitting diode-red light (LED-RL) on human skin: study protocol for a randomized controlled trial. AB - BACKGROUND: Skin fibrosis is involved in a variety of pathologic conditions ranging from scar formation secondary to surgery or trauma to immune-mediated processes. Skin fibrosis is a significant international health problem with an estimated incidence of greater than 100 million people affected per year worldwide with few effective treatment options available. Preliminary in vitro data generated by our research group suggests that red light can function as a stand-alone treatment for skin fibrosis. To our knowledge, no prior clinical trials have been performed to determine the safety of high-fluence (dose) light emitting diode-red light (LED-RL) phototherapy. The goal of this study is to evaluate the safety of LED-RL fluences from 160 J/cm(2) up to 640 J/cm(2) in healthy subjects. METHODS/DESIGN: This is a single-blind, dose escalation, randomized controlled, phase I study to evaluate the safety of high-fluence LED RL on human skin. The protocol for dose escalation requires subjects be enrolled sequentially in groups of five. Within each group, three subjects will be randomized to LED-RL phototherapy and two subjects randomized to mock therapy. Subjects in group 1 randomized to LED-RL phototherapy will receive the maximum recommended starting dose (160 J/cm(2)). LED-RL dose will be escalated in subsequent groups (320 J/cm(2), 480 J/cm(2) and 640 J/cm(2)). The maximally tolerated dose (MTD) is defined as the dose level below the dose producing unacceptable but reversible toxicity and is considered to be the upper limit of subject tolerance. After either a MTD has been established, or the study endpoint of 640 J/cm(2) has been achieved, an additional 27 LED-RL phototherapy subjects (for a total of 30) and 18 mock therapy subjects (for a total of 20) (determined randomly) will be enrolled. Each subject will receive a total of nine procedures, three times per week for three consecutive weeks. DISCUSSION: This study may provide important safety information on the effects of high-fluence LED-RL phototherapy on human skin and help facilitate future phase II studies to evaluate the efficacy of high-fluence LED-RL as a potential noninvasive, safe, portable, at-home therapy for treatment of skin fibrosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02630303 . Registered on 9 December 2015. PMID- 27484783 TI - Dexmedetomidine versus remifentanil for sedation during awake intubation using a Shikani optical stylet: a randomized, double-blinded, controlled trial. AB - BACKGROUND: The purpose of this study was to compare the efficacy and safety of dexmedetomidine versus remifentanil for sedation during awake intubation using a Shikani optical stylet (SOS). METHODS: Sixty-eight patients with cervical trauma or severe cervical spondylosis undergoing cervical spinal surgery were enrolled in this prospective study. They were randomly assigned to receive dexmedetomidine (Group D) or remifentanil (Group R). In Group D, the patients received an intravenous loading dose of dexmedetomidine 1 MUg . kg(-1) over 10 min followed by a continuous infusion of 0.7 MUg . kg(-1) . h(-1). In Group R, a target controlled infusion of remifentanil was administered to achieve a plasma concentration of 2.5 ng . ml(-1), increased to 3 ng . ml(-1) 10 min later. An endotracheal tube was inserted using a SOS under dexmedetomidine or remifentanil sedation after topical anesthesia to the airway. Midazolam was given as rescue sedation. We recorded the first attempt intubation success rate, the dose of midazolam, duration of intubation, Ramsay Sedation Scale (RSS) score, tracheal tube tolerance score, duration of drug infusion, adverse events and patient satisfaction score. RESULTS: The RSS score was significantly higher in Group D than in Group R. First attempt success rate, rescue midazolam dose and the duration of intubation did not differ between the groups. Patients in Group R were significantly more tolerant of the tracheal tube. The incidence of hypoxia was significantly higher in Group R than Group D, but there was no significant difference in the incidence of other adverse events between the groups. The hemodynamic responses of the two groups were similar, but more patients in Group R were able to recall airway instrumentation. CONCLUSIONS: Both dexmedetomidine and remifentanil are effective sedatives for awake intubation using an SOS. Although the first attempt success rates were similar, patients sedated with remifentanil tolerated the tracheal tube better after intubation with moderately increased risk of desaturation. TRIAL REGISTRATION: www.chictr.org.cn ; ChiCTR TRC-13003052 (February 4th, 2013). PMID- 27484784 TI - Activating Transcription Factor 4 (ATF4)-ATF3-C/EBP Homologous Protein (CHOP) Cascade Shows an Essential Role in the ER Stress-Induced Sensitization of Tetrachlorobenzoquinone-Challenged PC12 Cells to ROS-Mediated Apoptosis via Death Receptor 5 (DR5) Signaling. AB - Tetrachlorobenzoquinone (TCBQ) is a downstream metabolite of pentachlorophenol (PCP). Previously, we demonstrated that TCBQ caused cytotoxicity due to mitochondrial-related apoptosis. Here, we confirmed the upregulation of death receptor 5 (DR5) followed by the construction of the death-inducing signaling complex (DISC). We also detected the activation of the caspase cascade, which was correlated with TCBQ-induced apoptotic cell death in PC12 cells. The upregulation of DR5 included transcriptional activation and de novo protein synthesis in response to TCBQ. We also identified the endoplasmic reticulum (ER) as a new target for the TCBQ challenge in PC12 cells. The protein kinase R-like ER kinase/eukaryotic translation initiation factor 2alpha (PERK/eIF2alpha)-mediated activating transcription factor 4 (ATF4)-ATF3-C/EBP homologous protein (CHOP) signaling pathway contributed to the process of TCBQ-induced ER stress. Blocking ATF4, ATF3, or CHOP signaling by gene silencing technology resulted in decreased cell apoptosis after exposure to TCBQ. Finally, NAC ameliorated TCBQ-induced apoptosis and ER stress, which illustrated that TCBQ-induced apoptosis is somehow ROS-dependent. In summary, this study provided important mechanistic insight into how TCBQ utilizes ER stress-related signaling to exhibit pro-apoptotic activity in PC12 cells. PMID- 27484785 TI - Renal ischemia/reperfusion against nephrectomy for induction of acute lung injury in rats. AB - PURPOSE: Acute kidney injury (AKI) induces acute lung injury (ALI) through releasing injurious mediators or impairing clearance of systemic factors. To determine the links between AKI and ALI, pulmonary and blood variables were evaluated following induction of AKI via different experimental models of bilateral renal ischemia/reperfusion (BIR: renal ischemia with uremia), unilateral renal ischemia/reperfusion (UIR: renal ischemia without uremia), bilateral nephrectomy (BNX: uremia without renal ischemia), and unilateral nephrectomy (UNX: without uremia and renal ischemia). METHODS: Ninety male Sprague-Dawley rats were divided into six groups. Animals had 1-h bilateral or 2 h unilateral renal ischemia followed by 24-h reperfusion in the BIR and UIR groups, respectively, and 24-h period following bilateral or unilateral nephrectomy in the BNX and UNX groups, respectively. There were also sham and control groups with and without sham-operation, respectively. RESULTS: Plasma malondialdehyde and nitric oxide were elevated by BIR more than UIR, but not changed by UNX and BNX. UIR slightly increased plasma creatinine, whereas BIR and BNX largely increased plasma creatinine, urea, K+ and osmolality and decreased arterial HCO3-, pH, and CO2. UNX and UIR did not affect lung, but BIR and BNX induced ALI with equal capillary leak and macrophages infiltration. However, there were more prominent lung edema and vascular congestion following BNX and more severe neutrophils infiltration and PaO2/FiO2 reduction following BIR. CONCLUSION: Acutely accumulated systemic mediators following renal failure in the absence of kidneys vary from those due to combined renal failure with ischemic reperfused kidneys and consequently they induce ALI with distinct characteristics. PMID- 27484787 TI - Enzyme-mediated polymerization inside engineered protein cages. AB - Engineered variants of the capsid-forming enzyme lumazine synthase, AaLS, were used as nanoreactors for an enzyme-mediated polymerization. Oxidation of 3,3 diaminobenzidine (DAB) by the engineered ascorbate peroxidase APEX2 encapsulated in AaLS capsids resulted in templated formation of polyDAB-capsid nanoparticles of homogeneous size and shape. PMID- 27484786 TI - Expression of cancer related BRCA1 missense variants decreases MMS-induced recombination in Saccharomyces cerevisiae without altering its nuclear localization. AB - BRCA1 tumor suppressor gene is found mutated in familial breast and ovarian cancer. Most cancer related mutations were found located at the RING (Really Interesting New Gene) and at the BRCT (BRca1 C-Terminal) domain. However, 20 y after its identification, the biological role of BRCA1 and which domains are more relevant for tumor suppression are still being elucidated. We previously reported that expression of BRCA1 cancer related variants in the RING and BRCT domain increases spontaneous homologous recombination in yeast indicating that BRCA1 may interact with yeast DNA repair/recombination. To finally demonstrate whether BRCA1 interacts with yeast DNA repair, we exposed yeast cells expressing BRCA1wt, the cancer-related variants C-61G and M1775R to different doses of the alkylating agent methyl methane-sulfonate (MMS) and then evaluated the effect on survival and homologous recombination. Cells expressing BRCA1 cancer variants were more sensitive to MMS and less inducible to recombination as compared to cell expressing BRCA1wt. Moreover, BRCA1-C61G and -M1775R did not change their nuclear localization form as compared to the BRCA1wt or the neutral variant R1751Q indicating a difference in the DNA damage processing. We propose a model where BRCA1 cancer variants interact with the DNA double strand break repair pathways producing DNA recombination intermediates, that maybe less repairable and decrease MMS-induced recombination and survival. Again, this study strengthens the use of yeast as model system to characterize the mechanisms leading to cancer in humans carrying the BRCA1 missense variant. PMID- 27484788 TI - From Early Embryonic to Adult Stage: Comparative Study of Action Potentials of Native and Pluripotent Stem Cell-Derived Cardiomyocytes. AB - Cardiomyocytes (CMs) derived from induced pluripotent stem cells (iPS-CMs) are promising candidates for cell therapy, drug screening, and developmental studies. It is known that iPS-CMs possess immature electrophysiological properties, but an exact characterization of their developmental stage and subtype differentiation is hampered by a lack of knowledge of electrophysiological properties of native CMs from different developmental stages and origins within the heart. Thus, we sought to systematically investigate action potential (AP) properties of native murine CMs and to establish a database that allows classification of stem cell derived CMs. Hearts from 129S2PasCrl mice were harvested at days 9-10, 12-14, and 16-18 postcoitum, as well as 1 day, 3-4 days, 1-2 weeks, 3-4 weeks, and 6 weeks postpartum. AP recordings in left and right atria and at apical, medial, and basal left and right ventricles were performed with sharp glass microelectrodes. Measurements revealed significant changes in AP morphology during pre- and postnatal murine development and significant differences between atria and ventricles, enabling a classification of developmental stage and subtype differentiation of stem cell-derived CMs based on their AP properties. For iPS CMs derived from cell line TiB7.4, a typical ventricular phenotype was demonstrated at later developmental stages, while there were electrophysiological differences from atrial as well as ventricular native CMs at earlier stages. This finding supports that iPS-CMs can develop AP properties similar to native CMs, but points to differences in the maturation process between iPS-CMs and native CMs, which may be explained by dissimilar conditions during in vitro differentiation and in vivo development. PMID- 27484789 TI - Imaging prediction of residual hepatocellular carcinoma after locoregional therapy in patients undergoing liver transplantation or partial hepatectomy. AB - PURPOSE: Locoregional therapies for hepatocellular carcinoma (HCC) offer alternatives for patients unable to undergo resection or awaiting transplant. We sought to evaluate the prevalence and interobserver agreement of imaging features suggestive of viable tumor at posttherapy CT/MRI and to determine a size threshold for tumor detection. METHODS: Patients having undergone liver transplant or hepatectomy between 2012 and 2014 with presurgical embolization or ablation of HCC were identified. Imaging was retrospectively reviewed, and enhancement characteristics of each lesion were noted by two radiologists. Original pathology slides were reviewed, and the size of nodular viable tumor was noted, if present. Cohen's kappa was used to evaluate interobserver agreement. RESULTS: 87 patients with 129 HCCs were reviewed retrospectively following IRB approval. 50% (65/129) of lesions showed viable tumor at pathology. 86 lesions (67%) were imaged with CT and 43 (33%) with MR. Of viable lesions, 25 (38%) showed nodular arterial enhancement and 18 (28%) demonstrated washout. One lesion had capsule appearance. Sensitivity/specificity for nodular enhancement, washout, and capsule were 0.38/0.83, 0.28/0.89, and 0.02/1.00, respectively. Overall detection rate was 41% of <1 cm, 54% of 1-2 cm, and 57% of >2 cm viable lesions. CONCLUSIONS: Nodular arterial enhancement was most frequently observed, followed by washout. Both showed moderate interobserver agreement. Sensitivity of any imaging feature was less than 50%, though findings were specific for viable disease. There is limited detection of nodules of viable tumor <1 cm and only marginal detection of larger lesions, though MRI outperformed CT for the detection of subcentimeter viable tumor. PMID- 27484790 TI - Trans 18-carbon monoenoic fatty acid has distinct effects from its isomeric cis fatty acid on lipotoxicity and gene expression in Saccharomyces cerevisiae. AB - Epidemiological studies have suggested that an excess intake of trans-unsaturated fatty acids increases the risk of coronary heart disease. However, the mechanisms of action of trans-unsaturated fatty acids in eukaryotic cells remain unclear. Since the budding yeast Saccharomyces cerevisiae can grow using fatty acids as the sole carbon source, it is a simple and suitable model organism for understanding the effects of trans-unsaturated fatty acids at the molecular and cellular levels. In this study, we compared the physiological effects of Delta9 cis and trans 18-carbon monoenoic fatty acids (oleic acid and elaidic acid) in yeast cells. The results obtained revealed that the two types have distinct effects on the expression of OLE1, which encodes Delta9 desaturase, and lipotoxicity in are1Deltaare2Deltadga1Deltalro1Delta and gat1Delta cells. Our results suggest that cis and trans 18-carbon monoenoic fatty acids exert different physiological effects in the regulation of gene expression and processing of excess fatty acids in yeast. PMID- 27484792 TI - Genetic Characterization of Serotypes A and Asia-1 Foot-and-mouth Disease Viruses in Balochistan, Pakistan, in 2011. AB - This study reports characterization of foot-and-mouth disease virus (FMDV) in samples collected from Balochistan, Pakistan. FMDV was detected by pan-FMDV real time RT-PCR in 31 samples (epithelial and oral swabs) collected in 2011 from clinical suspect cases. Of these, 29 samples were serotyped by serotype-specific real-time RT-PCR assays and were confirmed by sequencing the VP1 coding region. Sixteen samples were found positive for serotype A and eight for serotype Asia-1, whereas five samples were found positive for both serotypes A and Asia-1. Two serotype A positive samples were found positive for two different strains of serotype A FMDV each. Phylogenetic analyses of serotype A FMDVs showed circulation of at least three different sublineages within the A-Iran05 lineage. These included two earlier reported sublineages, A-Iran05HER-10 and A-Iran05FAR 11 , and a new sublineage, designated here as A-Iran05BAL-11 . This shows that viruses belonging to the A-Iran05 lineage are continuously evolving in the region. Viruses belonging to the A-Iran05FAR-11 sublineage showed close identity with the viruses circulating in 2009 in Pakistan and Afghanistan. However, viruses belonging to the A-Iran05HER-10 detected in Balochistan, Pakistan, showed close identity with the viruses circulating in Kyrgyzstan, Iran and Kazakhstan in 2011 and 2012, showing that viruses responsible for outbreak in these countries have a common origin. Serotype Asia-1 FMDVs reported in this study all belonged to the earlier reported Group-VII (Sindh-08), which is currently a dominant strain in the West Eurasian region. Detection of two different serotypes of FMDV or/and two different strains of the same serotype in one animal/sample shows complexity in occurrence of FMD in the region. PMID- 27484791 TI - Molecular and epigenetic features of melanomas and tumor immune microenvironment linked to durable remission to ipilimumab-based immunotherapy in metastatic patients. AB - BACKGROUND: Ipilimumab (Ipi) improves the survival of advanced melanoma patients with an incremental long-term benefit in 10-15 % of patients. A tumor signature that correlates with this survival benefit could help optimizing individualized treatment strategies. METHODS: Freshly frozen melanoma metastases were collected from patients treated with either Ipi alone (n: 7) or Ipi combined with a dendritic cell vaccine (TriMixDC-MEL) (n: 11). Samples were profiled by immunohistochemistry (IHC), whole transcriptome (RNA-seq) and methyl-DNA sequencing (MBD-seq). RESULTS: Patients were divided in two groups according to clinical evolution: durable benefit (DB; 5 patients) and no clinical benefit (NB; 13 patients). 20 metastases were profiled by IHC and 12 were profiled by RNA- and MBD-seq. 325 genes were identified as differentially expressed between DB and NB. Many of these genes reflected a humoral and cellular immune response. MBD-seq revealed differences between DB and NB patients in the methylation of genes linked to nervous system development and neuron differentiation. DB tumors were more infiltrated by CD8(+) and PD-L1(+) cells than NB tumors. B cells (CD20(+)) and macrophages (CD163(+)) co-localized with T cells. Focal loss of HLA class I and TAP-1 expression was observed in several NB samples. CONCLUSION: Combined analyses of melanoma metastases with IHC, gene expression and methylation profiling can potentially identify durable responders to Ipi-based immunotherapy. PMID- 27484794 TI - Stacking fault energy of face-centered cubic metals: thermodynamic and ab initio approaches. AB - The formation energy of the interface between face-centered cubic (fcc) and hexagonal close packed (hcp) structures is a key parameter in determining the stacking fault energy (SFE) of fcc metals and alloys using thermodynamic calculations. It is often assumed that the contribution of the planar fault energy to the SFE has the same order of magnitude as the bulk part, and thus the lack of precise information about it can become the limiting factor in thermodynamic predictions. Here, we differentiate between the interfacial energy for the coherent fcc(1 1 1)/hcp(0 0 0 1) interface and the 'pseudo-interfacial energy' that enters the thermodynamic expression for the SFE. Using first principles calculations, we determine the coherent and pseudo-interfacial energies for six elemental metals (Al, Ni, Cu, Ag, Pt, and Au) and three paramagnetic Fe-Cr-Ni alloys. Our results show that the two interfacial energies significantly differ from each other. We observe a strong chemistry dependence for both interfacial energies. The calculated pseudo-interfacial energies for the Fe-Cr-Ni steels agree well with the available literature data. We discuss the effects of strain on the description of planar faults via thermodynamic and ab initio approaches. PMID- 27484793 TI - Circadian variation of cytotoxicity and genotoxicity induced by an immunosuppressive agent "Mycophenolate Mofetil" in rats. AB - Immunosuppressive drugs such as Mycophenolate Mofetil (MMF) are used to suppress the immune system activity in transplant patients and reduce the risk of organ rejection. The present study investigates whether the potential cytotoxicity and genotoxicity varied according to MMF dosing-time in Wistar Rat. A potentially toxic MMF dose (300 mg/kg) was acutely administered by the i.p. route in rats at four different circadian stages (1, 7, 13 and 19 hours after light onset, HALO). Rats were sacrificed 3 days following injection, blood and bone marrow were removed for determination of cytotoxicity and genotoxicity analysis. The genotoxic effect of this pro-drug was investigated using the comet assay and the micronucleus test. Hematological changes were also evaluated according to circadian dosing time. MMF treatment induced a significant decrease at 7 HALO in red blood cells, in the hemoglobin rate and in white blood cells. These parameters followed a circadian rhythm in controls or in treated rats with an acrophase located at the end of the light-rest phase. A significant, thrombocytopenia was observed according to MMF circadian dosing time. Furthermore, abnormally shaped red cells, sometimes containing micronuclei, poikilocytotic in red cells and hypersegmented neutrophil nuclei were observed with MMF treatment. The micronucleus test revealed damage to chromosomes in rat bone marrow; the comet assay showed significant DNA damage. This damage varied according to circadian MMF dosing time. The injection of MMF in the middle of the dark-activity phase produced a very mild hematological toxicity and low genotoxicity. Conversely, it induced maximum hematological toxicity and genotoxicity when the administration occurred in the middle of the light-rest phase, which is physiologically analogous to the end of the activity of the diurnal phase in human patients. PMID- 27484795 TI - Codon usage in Alphabaculovirus and Betabaculovirus hosted by the same insect species is weak, selection dominated and exhibits no more similar patterns than expected. AB - Mutations shape synonymous codon usage bias in certain organism genomes, while selection shapes it in others. Lepidopteran-specific Alphabaculovirus and Betabaculovirus are two large genera in the family of Baculoviridae. In this study, we analyzed the codon usage patterns in 17 baculoviruses, including 10 alphabaculoviruses and 7 betabaculoviruses, which were isolated from seven insect species, and we characterized the codon usage patterns between Alphabaculovirus and Betabaculovirus. Our results show that all the baculoviruses possessed a general weak trend of codon bias. The differences of ENc (effective number of codons) values, nucleotide contents and the impacts of nucleotide content on ENc value within alpha-/betabaculovirus pairs were independent of whether the host species are the same or different. Furthermore, the majority of amino acid sequences adopted codons unequally in all viruses, but the numbers of common preferred codons between alpha- and betabaculoviruses hosted by the same insect species were not significantly different from the differences observed between alpha- and betabaculoviruses hosted by different insect species. In addition, the amino acids that adopt the same synonymous codon composition between alpha- and betabaculoviruses hosted by the same insect species were statistically as few as those between alpha- and betabaculoviruses hosted by different insect species. Correspondence analysis revealed that no major factors resulted in the codon bias in these baculoviruses, implying multiple minor influential factors exist. Neutrality plot analysis indicated that selection pressure dominated mutations in shaping the codon usage. However, the levels of selection pressure were not significantly different among viruses hosted by the same insect species. We expect that evolution would cause the alpha- and betabaculoviruses hosted by the same insect species to share more patterns, but this effect was not observed. PMID- 27484796 TI - Effects of cisplatin on the LSD1-mediated invasion and metastasis of prostate cancer cells. AB - Prostate cancer poses a major public health problem in men. Metastatic prostate cancer is incurable, and ultimately threatens the life of patients. Lysine specific demethylase 1 (LSD1) is an androgen receptor-interacting protein that exerts a key role in regulating gene expression and is involved in numerous biological processes associated with prostate cancer. Cisplatin, also known as cis-diamminedichloroplatinum or DDP, is a standard chemotherapeutic agent used to treat prostate cancer; however, it has the disadvantage of various serious side effects. The present study aimed to investigate the effects of LSD1 knockdown, and the interplay between LSD1 and DDP, on prostate cancer cell proliferation, apoptosis and invasion, and, therefore, the potential of LSD1 as a target for prostate cancer therapy. Flow cytometric analysis, Cell Counting kit 8 assay, Transwell assay and western blotting results revealed that LSD1 knockdown, in combination with DDP treatment, exerted antiproliferative, proapoptotic and anti invasive effects on PC3 prostate cancer cells. In addition, knockdown of LSD1 acted synergistically with DDP, thereby enhancing the induction of apoptosis, and the inhibition of proliferation and invasion in prostate cancer cells. These results indicated that LSD1 may serve as a potential therapeutic target, and may enhance the sensitivity of PC3 cells to DDP. PMID- 27484797 TI - Blue Light-excited Light-Oxygen-Voltage-sensing Domain 2 (LOV2) Triggers a Rearrangement of the Kinase Domain to Induce Phosphorylation Activity in Arabidopsis Phototropin1. AB - Phototropin1 is a blue light (BL) receptor in plants and shows BL-dependent kinase activation. The BL-excited light-oxygen-voltage-sensing domain 2 (LOV2) is primarily responsible for the activation of the kinase domain; however, the molecular mechanism by which conformational changes in LOV2 are transmitted to the kinase domain remains unclear. Here, we investigated BL-induced structural changes of a minimum functional fragment of Arabidopsis phototropin1 composed of LOV2, the kinase domain, and a linker connecting the two domains using small angle x-ray scattering (SAXS). The fragment existed as a dimer and displayed photoreversible SAXS changes reflected in the radii of gyration of 42.9 A in the dark and 48.8 A under BL irradiation. In the dark, the molecular shape reconstructed from the SAXS profiles appeared as two bean-shaped lobes in a twisted arrangement that was 170 A long, 80 A wide, and 50 A thick. The molecular shape under BL became slightly elongated from that in the dark. By fitting the crystal structure of the LOV2 dimer and a homology model of the kinase domain to their inferred shapes, the BL-dependent change could be interpreted as the positional shift in the kinase domain relative to that of the LOV2 dimer. In addition, we found that lysine 475, a functionally important residue, in the N terminal region of LOV2 plays a critical role in transmitting the structural changes in LOV2 to the kinase domain. The interface between the domains is critical for signaling, suitably changing the structure to activate the kinase in response to conformational changes in the adjoining LOV2. PMID- 27484798 TI - The A-Kinase Anchoring Protein (AKAP) Glycogen Synthase Kinase 3beta Interaction Protein (GSKIP) Regulates beta-Catenin through Its Interactions with Both Protein Kinase A (PKA) and GSK3beta. AB - The A-kinase anchoring protein (AKAP) GSK3beta interaction protein (GSKIP) is a cytosolic scaffolding protein binding protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Here we show that both the AKAP function of GSKIP, i.e. its direct interaction with PKA, and its direct interaction with GSK3beta are required for the regulation of beta-catenin and thus Wnt signaling. A cytoplasmic destruction complex targets beta-catenin for degradation and thus prevents Wnt signaling. Wnt signals cause beta-catenin accumulation and translocation into the nucleus, where it induces Wnt target gene expression. GSKIP facilitates control of the beta-catenin stabilizing phosphorylation at Ser 675 by PKA. Its interaction with GSK3beta facilitates control of the destabilizing phosphorylation of beta-catenin at Ser-33/Ser-37/Thr-41. The influence of GSKIP on beta-catenin is explained by its scavenger function; it recruits the kinases away from the destruction complex without forming a complex with beta-catenin. The regulation of beta-catenin by GSKIP is specific for this AKAP as AKAP220, which also binds PKA and GSK3beta, did not affect Wnt signaling. We find that the binding domain of AKAP220 for GSK3beta is a conserved GSK3beta interaction domain (GID), which is also present in GSKIP. Our findings highlight an essential compartmentalization of both PKA and GSK3beta by GSKIP, and ascribe a function to a cytosolic AKAP-PKA interaction as a regulatory factor in the control of canonical Wnt signaling. Wnt signaling controls different biological processes, including embryonic development, cell cycle progression, glycogen metabolism, and immune regulation; deregulation is associated with diseases such as cancer, type 2 diabetes, inflammatory, and Alzheimer's and Parkinson's diseases. PMID- 27484799 TI - Human Naa50 Protein Displays Broad Substrate Specificity for Amino-terminal Acetylation: DETAILED STRUCTURAL AND BIOCHEMICAL ANALYSIS USING TETRAPEPTIDE LIBRARY. AB - Amino-terminal acetylation is a critical co-translational modification of the newly synthesized proteins in a eukaryotic cell carried out by six amino-terminal acetyltransferases (NATs). All NATs contain at least one catalytic subunit, and some contain one or two additional auxiliary subunits. For example, NatE is a complex of Naa10, Naa50, and Naa15 (auxiliary). In the present study, the crystal structure of human Naa50 suggested the presence of CoA and acetylated tetrapeptide (AcMMXX) that have co-purified with the protein. Biochemical and thermal stability studies on the tetrapeptide library with variations in the first and second positions confirm our results from the crystal structure that a peptide with Met-Met in the first two positions is the best substrate for this enzyme. In addition, Naa50 acetylated all MXAA peptides except for MPAA. Transcriptome analysis of 10 genes that make up six NATs in humans from eight different cell lines suggests that components of NatE are transcribed in all cell lines, whereas others are variable. Because Naa10 is reported to acetylate all amino termini that are devoid of methionine and Naa50 acetylates all other peptides that are followed by methionine, we believe that NatE complex can be a major contributor for amino-terminal acetylation at the ribosome exit tunnel. PMID- 27484800 TI - Ligand-induced Epitope Masking: DISSOCIATION OF INTEGRIN alpha5beta1-FIBRONECTIN COMPLEXES ONLY BY MONOCLONAL ANTIBODIES WITH AN ALLOSTERIC MODE OF ACTION. AB - We previously demonstrated that Arg-Gly-Asp (RGD)-containing ligand-mimetic inhibitors of integrins are unable to dissociate pre-formed integrin-fibronectin complexes (IFCs). These observations suggested that amino acid residues involved in integrin-fibronectin binding become obscured in the ligand-occupied state. Because the epitopes of some function-blocking anti-integrin monoclonal antibodies (mAbs) lie near the ligand-binding pocket, it follows that the epitopes of these mAbs may become shielded in the ligand-occupied state. Here, we tested whether function-blocking mAbs directed against alpha5beta1 can interact with the integrin after it forms a complex with an RGD-containing fragment of fibronectin. We showed that the anti-alpha5 subunit mAbs JBS5, SNAKA52, 16, and P1D6 failed to disrupt IFCs and hence appeared unable to bind to the ligand occupied state. In contrast, the allosteric anti-beta1 subunit mAbs 13, 4B4, and AIIB2 could dissociate IFCs and therefore were able to interact with the ligand bound state. However, another class of function-blocking anti-beta1 mAbs, exemplified by Lia1/2, could not disrupt IFCs. This second class of mAbs was also distinguished from 13, 4B4, and AIIB2 by their ability to induce homotypic cell aggregation. Although the epitope of Lia1/2 was closely overlapping with those of 13, 4B4, and AIIB2, it appeared to lie closer to the ligand-binding pocket. A new model of the alpha5beta1-fibronectin complex supports our hypothesis that the epitopes of mAbs that fail to bind to the ligand-occupied state lie within, or very close to, the integrin-fibronectin interface. Importantly, our findings imply that the efficacy of some therapeutic anti-integrin mAbs could be limited by epitope masking. PMID- 27484802 TI - Can herbicide safeners allow selective control of weedy rice infesting rice crops? AB - BACKGROUND: Rice is a major field crop of paramount importance for global food security. However, the increased adoption of more profitable and resource efficient direct-seeded rice (DSR) systems has contributed to greater weed infestations, including weedy rice, which has become a severe problem in several Asian regions. In this study we have developed a conceptually novel method to protect rice plants at high doses of clomazone and triallate. RESULTS: The insecticide phorate applied to rice seeds provided a substantial level of protection against the herbicides clomazone or triallate. A quantity of 15 kg phorate ha-1 significantly increased the LD50 values, which were more than twofold greater than for rice plants treated only with clomazone. A quantity of 20 kg phorate ha-1 in combination with 2000 g triallate ha-1 safened rice plants (80% survival) with LD50 >3.4-fold greater than in phorate-untreated rice. Weed control efficacy was not lowered by the presence of phorate-treated rice seeds. CONCLUSION: Weedy rice is one of the most damaging global weeds and a major threat to DSR systems. In this study we have developed a proof-of-concept method to allow selective weedy rice control in rice crops. We call for herbicide discovery programmes and research to identify candidate safener and herbicide combinations to achieve selective herbicide control of weedy rice and alleviate weed infestations in global rice crops. (c) 2016 Society of Chemical Industry. PMID- 27484803 TI - Solvothermal synthesis of a silicon hierarchical structure composed of 20 nm Si nanoparticles coated with carbon for high performance Li-ion battery anodes. AB - A silicon hierarchical structure composed of 20 nm Si nanoparticles (Si-20) is synthesized using a solvothermal method. After coating with a carbon layer by pyrolysis of acetylene gas, the fabricated Si-20@C composites exhibit a superior cycling performance with 915.8 mA h g(-1) at 3.6 A g(-1) over 500 cycles and a high rate performance with 746.2 mA h g(-1) at 10.8 A g(-1). PMID- 27484801 TI - Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2 positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial. AB - BACKGROUND: The aim of this work was to evaluate the impact of (and relative contribution of) tumor-related and immune-related diversity of HER2-positive disease on the response to neoadjuvant chemotherapy plus anti-HER2 agents. PATIENTS AND METHODS: The CherLOB phase II study randomized 121 HER2-positive breast cancer patients to neoadjuvant chemotherapy plus trastuzumab, lapatinib or both. Tumor samples from diagnostic core biopsy were centralized. Tumor infiltrating lymphocytes (TILs) were evaluated on H&E slides. Intrinsic subtyping was carried out using the research-based 50-gene prediction analysis of a microarray (PAM50) subtype predictor. Immune-related gene signatures were also evaluated. RESULTS: Continuous Str-TILs and It-TILs were significantly associated with pCR [OR 1.03, 95% CI 1.02-1.05 (P < 0.001) and OR 1.09, 95% CI 1.04-1.15 (P < 0.001) for Str-TILs and It-TILs, respectively]. According to PAM50, the subtype distribution was as follows: HER2-enriched 26.7%, Luminal A 25.6%, Luminal B 16.3%, Basal-like 14% and Normal-like 17.4%. The highest rate of pCR was observed for the HER2-enriched subtype (50%), followed by Basal-like, Luminal B and Luminal A (chi(2) test, P = 0.026). Immune gene signatures significantly associated with pCR in univariate analyses were identified: most of them maintained a significant association with pCR in multivariate analyses corrected for PAM50 subtypes, whereas TILs did not. CONCLUSIONS: In this study, both tumor related and immune-related features contribute to the modulation of pCR after neoadjuvant chemotherapy plus anti-HER2 agents. Immune signatures rather than TILs added significant prediction of pCR beyond PAM50 intrinsic subtypes. PMID- 27484804 TI - Reduction, alignment and visualisation of large diverse sequence families. AB - BACKGROUND: Current volumes of sequence data can lead to large numbers of hits identified on a search, typically in the range of 10s to 100s of thousands. It is often quite difficult to tell from these raw results whether the search has been a success or has picked-up sequences with little or no relationship to the query. The best approach to this problem is to cluster and align the resulting families, however, existing methods concentrate on fast clustering and either do not align the sequences or only perform a limited alignment. RESULTS: A method (MULSEL) is presented that combines fast peptide-based pre-sorting with a following cascade of mini-alignments, each of which are generated with a robust profile/profile method. From these mini-alignments, a representative sequence is selected, based on a variety of intrinsic and user-specified criteria that are combined to produce the sequence collection for the next cycle of alignment. For moderate sized sequence collections (10s of thousands) the method executes on a laptop computer within seconds or minutes. CONCLUSIONS: MULSEL bridges a gap between fast clustering methods and slower multiple sequence alignment methods and provides a seamless transition from one to the other. Furthermore, it presents the resulting reduced family in a graphical manner that makes it clear if family members have been misaligned or if there are sequences present that appear inconsistent. PMID- 27484805 TI - Reproducibility and uptake time dependency of volume-based parameters on FDG-PET for lung cancer. AB - BACKGROUND: Volume-based parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), on F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) are useful for predicting treatment response in nonsmall cell lung cancer (NSCLC). We aimed to examine intra- and inter-operator reproducibility to measure the MTV and TLG, and to estimate their dependency on the uptake time. METHODS: Fifty NSCLC patients underwent preoperative FDG-PET. After an injection of FDG, the whole body was scanned twice: at the early phase (61.4 +/- 2.8 min) and delayed phase (117.7 +/- 1.6 min). Two operators independently defined the tumor boundary using three different delineation methods: (1) the absolute SUV threshold method (MTVp and TLGp; p = 2.0, 2.5, 3.0, 3.5), (2) the fixed% SUVmax threshold method (MTVq% and TLGq%; q = 35, 40, 45), and (3) the adaptive region-growing method (MTVARG and TLGARG). Parameters were compared between operators and between phases. RESULTS: Both the intra- and inter operator reproducibility were high for all parameters using any method (intra class correlation > 0.99 each). MTV3.0 and MTV3.5 resulted in a significant increase from the early to delayed phase (P < 0.05 for both), whereas MTV2.0 and MTV2.5 neither increased nor decreased (P = n.s.). All of the MTVq% values significantly decreased over time (P < 0.01), whereas MTVARG and TLG with any delineation method increased significantly (P < 0.05). CONCLUSIONS: High reproducibility of MTV and TLG was obtained by all of the methods used. MTV2.0 and MTV2.5 were the least sensitive to uptake time, and may be good alternatives when we compare images acquired with different uptake times, although applying constant uptake time is important for volume measurement. PMID- 27484806 TI - A prognostic predictor panel with DNA methylation biomarkers for early-stage lung adenocarcinoma in Asian and Caucasian populations. AB - BACKGROUND: The incidence of lung adenocarcinoma (LUAD) is increasing worldwide with different prognosis even in early-stage patients. We aimed to identify a prognostic panel with multiple DNA methylation biomarkers to predict survival in early-stage LUAD patients of different racial groups. METHODS: The methylation array, pyrosequencing methylation assay, Cox regression and Kaplan-Meier analyses were conducted to build the risk score equations of selected probes in a training cohort of 69 Asian LUAD patients. The risk score model was verified in another cohort of 299 Caucasian LUAD patients in The Cancer Genome Atlas (TCGA) database. RESULTS: We performed a Cox regression analysis, in which the regression coefficients were obtained for eight probes corresponding to eight genes (AGTRL1, ALDH1A3, BDKRB1, CTSE, EFNA2, NFAM1, SEMA4A and TMEM129). The risk score was derived from sum of each methylated probes multiplied by its corresponding coefficient. Patients with the risk score greater than the median value showed poorer overall survival compared with other patients (p = 0.007). Such a risk score significantly predicted patients showing poor survival in TCGA cohort (p = 0.036). A multivariate analysis was further performed to demonstrate that the eight-probe panel association with poor outcome in early-stage LUAD patients remained significant even after adjusting for different clinical variables including staging parameters (hazard ratio, 2.03; p = 0.039). CONCLUSIONS: We established a proof-of-concept prognostic panel consisting of eight-probe signature to predict survival of early-stage LUAD patients of Asian and Caucasian populations. PMID- 27484809 TI - Meeting Report and Special Issue Preface: The 54th Seminar of the Korean Society of Gastrointestinal Endoscopy. PMID- 27484808 TI - Molecularly Imprinted Intelligent Scaffolds for Tissue Engineering Applications. AB - The development of molecularly imprinted polymers (MIPs) using biocompatible production methods enables the possibility to further exploit this technology for biomedical applications. Tissue engineering (TE) approaches use the knowledge of the wound healing process to design scaffolds capable of modulating cell behavior and promote tissue regeneration. Biomacromolecules bear great interest for TE, together with the established recognition of the extracellular matrix, as an important source of signals to cells, both promoting cell-cell and cell-matrix interactions during the healing process. This review focuses on exploring the potential of protein molecular imprinting to create bioactive scaffolds with molecular recognition for TE applications based on the most recent approaches in the field of molecular imprinting of macromolecules. Considerations regarding essential components of molecular imprinting technology will be addressed for TE purposes. Molecular imprinting of biocompatible hydrogels, namely based on natural polymers, is also reviewed here. Hydrogel scaffolds with molecular memory show great promise for regenerative therapies. The first molecular imprinting studies analyzing cell adhesion report promising results with potential applications for cell culture systems, or biomaterials for implantation with the capability for cell recruitment by selectively adsorbing desired molecules. PMID- 27484807 TI - Therapeutic effects of human gingiva-derived mesenchymal stromal cells on murine contact hypersensitivity via prostaglandin E2-EP3 signaling. AB - BACKGROUND: The immunomodulatory and anti-inflammatory functions of human gingiva derived mesenchymal stromal cells (GMSCs) have been demonstrated in contact hypersensitivity (CHS) models; however, their therapeutic effect during the late phase of CHS has been poor. METHODS: The murine CHS model was induced by applying oxazolone to the ears of mice. Mesenchymal stromal cells were applied via two methods (intravenous or local injection) at three time points: 1 day before sensitization, 1 day before challenge, or 1 h after challenge. Prostaglandin E2 (PGE2) and sulprostone were administered subcutaneously 1 h after challenge. RESULTS: The application of GMSCs, bone marrow mesenchymal stem cells, and adipose-derived stem cells all effectively suppressed CHS; however, GMSC treatment exhibited the greatest efficacy. Local injection of GMSCs led to a more marked attenuation of CHS compared with intravenous injection, especially during the late phase of CHS, and this manifested as decreased infiltration of inflammatory cells, suppression of the levels of various proinflammatory cytokines, reconstruction of the disrupted Th1/Th2 balance, and upregulation of regulatory T cells in the allergen contact areas. Pretreatment with indomethacin significantly abrogated the GMSC-mediated immunosuppressive effects, while PGE2 application reversed the effects of indomethacin pretreatment of GMSCs. Moreover, GMSC administration promoted the expression of EP3, a prostaglandin E receptor, and the application of sulprostone, an agonist of EP3, significantly attenuated CHS to a similar degree as that of GMSC administration. CONCLUSIONS: GMSCs have reproducible and powerful immunomodulatory functions. Local injection of GMSCs is the superior mode for therapeutic application. PGE2-EP3 signaling plays an important role in the immunomodulatory functions of GMSCs in murine CHS. PMID- 27484810 TI - How to Improve the Quality of Screening Endoscopy in Korea: National Endoscopy Quality Improvement Program. AB - In Korea, gastric cancer screening, either esophagogastroduodenoscopy or upper gastrointestinal series (UGIS), is performed biennially for adults aged 40 years or older. Screening endoscopy has been shown to be associated with localized cancer detection and better than UGIS. However, the diagnostic sensitivity of detecting cancer is not satisfactory. The National Endoscopy Quality Improvement (QI) program was initiated in 2009 to enhance the quality of medical institutions and improve the effectiveness of the National Cancer Screening Program (NCSP). The Korean Society of Gastrointestinal Endoscopy developed quality standards through a broad systematic review of other endoscopic quality guidelines and discussions with experts. The standards comprise five domains: qualifications of endoscopists, endoscopic unit facilities and equipment, endoscopic procedure, endoscopy outcomes, and endoscopic reprocessing. After 5 years of the QI program, feedback surveys showed that the perception of QI and endoscopic practice improved substantially in all domains of quality, but the quality standards need to be revised. How to avoid missing cancer in endoscopic procedures in daily practice was reviewed, which can be applied to the mass screening endoscopy. To improve the quality and effectiveness of NCSP, key performance indicators, acceptable quality standards, regular audit, and appropriate reimbursement are necessary. PMID- 27484811 TI - Predictors of Inadequate Bowel Preparation and Salvage Options on Colonoscopy. AB - Inadequate bowel preparation is observed in more than 25% of all colonoscopies. Identification of predictive factors for inadequate colon cleaning is helpful and more detailed preparation methods should be used for patients at high risk. Age, male sex, inpatient status, and comorbidities were identified as independent risk factors in several previous studies. In patients with insufficient colon preparation, colon irrigation with endoscopic pumps or next-day colonoscopy following further bowel cleaning should be performed. In order to improve the efficacy and safety of both bowel preparation and colonoscopy, the endoscopic team should identify the patient's medical conditions and choose the optimal bowel preparation agent and regimen. PMID- 27484812 TI - Optimal Colonoscopy Surveillance Interval after Polypectomy. AB - The detection and removal of adenomatous polyps and postpolypectomy surveillance are considered important for the control of colorectal cancer (CRC). Surveillance using colonoscopy is an effective tool for preventing CRC after colorectal polypectomy, especially if compliance is good. In current practice, the intervals between colonoscopies after polypectomy are variable. Different recommendations for recognizing at risk groups and defining surveillance intervals after an initial finding of colorectal adenomas have been published. However, high-grade dysplasia and the number and size of adenomas are known major cancer predictors. Based on this, a subgroup of patients that may benefit from intensive surveillance colonoscopy can be identified. PMID- 27484813 TI - Endoscopic Diagnosis and Differentiation of Inflammatory Bowel Disease. AB - Patients with inflammatory bowel disease have significantly increased in recent decades in Korea. Intestinal tuberculosis (ITB) and intestinal Behcet's disease (BD), which should be differentiated from Crohn's disease (CD), are more frequent in Korea than in the West. Thus, the accurate diagnosis of these inflammatory diseases is problematic in Korea and clinicians should fully understand their clinical and endoscopic characteristics. Ulcerative colitis mostly presents with rectal inflammation and continuous lesions, while CD presents with discontinuous inflammatory lesions and frequently involves the ileocecal area. Involvement of fewer than four segments, a patulous ileocecal valve, transverse ulcers, and scars or pseudopolyps are more frequently seen in ITB than in CD. A few ulcers with discrete margins are a typical endoscopic finding of intestinal BD. However, the differential diagnosis is difficult in many clinical situations because typical endoscopic findings are not always observed. Therefore, clinicians should also consider symptoms and laboratory, pathological, and radiological findings, in addition to endoscopic findings. PMID- 27484814 TI - Recent Advanced Endoscopic Management of Endoscopic Retrograde Cholangiopancreatography Related Duodenal Perforations. AB - The management strategy for endoscopic retrograde cholangiopancreatography related duodenal perforation can be determined based on the site and extent of injury, the patient's condition, and time to diagnosis. Most cases of perivaterian or bile duct perforation can be managed with a biliary stent or nasobiliary drainage. Duodenal wall perforations had been treated with immediate surgical repair. However, with the development of endoscopic devices and techniques, endoscopic closure has been reported to be a safe and effective treatment that uses through-the-scope clips, ligation band, fibrin glue, endoclips and endoloops, an over-the-scope clipping device, suturing devices, covering luminal stents, and open-pore film drainage. Endoscopic therapy could be instituted in selected patients in whom perforation was identified early or during the procedure. Early diagnosis, proper conservative management, and effective endoscopic closure are required for favorable outcomes of non-surgical management. If endoscopic treatment fails, or in the cases of clinical deterioration, prompt surgical management should be considered. PMID- 27484816 TI - Three-dimensional analysis of marginal and internal fit of copings fabricated with polyetherketoneketone (PEKK) and zirconia. AB - PURPOSE: The purpose of this in vitro study was to compare and analyze the three dimensional marginal and internal fit of PEKK and zirconia copings. METHODS: Two acrylic models of the right maxillary canine, first molar were fabricated as master dies and duplicated by one-step dual viscosity impressions. Five stone replicas from each model were digitized with a blue-light scanner and copings were machined from Pekkton and Zirconia blanks. The inner surface of all the copings and two original acrylic models were digitized by a highly accurate optical scanner. By superimposing the digitized coping data with the CAD reference die three-dimensionally, visual fit-discrepancies were drawn by calculating the root mean square (RMS) and visualized on a color-difference map. Each calculated RMS-value was statistically analyzed by 3-way ANOVA. In addition, Student's t-test was conducted in order to verify the significance (alpha=.05) of fit-discrepancies based on the type of abutment tooth and the materials. RESULTS: Mean RMS-values for marginal fit (internal fit) ranged from 51.64+/-1.5 (36.12+/ 1.34) to 69.62+/-8.11 (41.6+/-1.63)MUm. Differences in marginal fit (canine: P=.001; molar: P=.047) and internal fit (canine: P=.017; molar: P=.046) were statistically significant. The results of the 3-way ANOVA showed statistically significant differences in the RMS values of the two groups for the material (P<.001), the types of the abutment tooth (P<.001), and the measured region (P<.001). CONCLUSIONS: The marginal and internal fit of both PEKK and zirconia copings of both canine and molar were within the clinically acceptable range. However, the PEKK presented better fitness compared with the zirconia. PMID- 27484815 TI - Primary immunodeficiency associated with chromosomal aberration - an ESID survey. AB - BACKGROUND: Patients with syndromic features frequently suffer from recurrent respiratory infections, but little is known about the spectrum of immunological abnormalities associated with their underlying chromosomal aberrations outside the well-known examples of Down and DiGeorge syndromes. Therefore, we performed this retrospective, observational survey study. METHODS: All members of the European Society for Immunodeficiencies (ESID) were invited to participate by reporting their patients with chromosomal aberration (excluding Down and DiGeorge syndromes) in combination with one or more identified immunological abnormalities potentially relating to primary immunodeficiency. An online questionnaire was used to collect the patient data. RESULTS: Forty-six patients were included from 16 centers (24 males, 22 females; median age 10.4 years [range 1.0-69.2 years]; 36 pediatric, 10 adult patients). A variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immune deficiency was reported. The most important clinical presentation prompting the immunological evaluation was 'recurrent ear-nose-throat (ENT) and airway infections'. Immunoglobulin isotype and/or IgG-subclass deficiencies were the most prevalent immunological abnormalities reported. CONCLUSIONS: Our survey yielded a wide variety of chromosomal aberrations associated with immunological abnormalities potentially relating to primary immunodeficiency. Although respiratory tract infections can often also be ascribed to other causes (e.g. aspiration or structural abnormalities), we show that a significant proportion of patients also have an antibody deficiency requiring specific treatment (e.g. immunoglobulin replacement, antibiotic prophylaxis). Therefore, it is important to perform immunological investigations in patients with chromosomal aberrations and recurrent ENT or airway infections, to identify potential immunodeficiency that can be specifically treated. PMID- 27484817 TI - CIP2A regulates proliferation and apoptosis of multiple myeloma cells. AB - Multiple myeloma (MM) is one of the most common causes of mortality from hematological malignancy in China. Recent studies have demonstrated that cancerous inhibitor of protein phosphatase 2A (CIP2A) may exhibit a role in promoting the growth of cancer; however, the function of CIP2A in MM remains unknown. In the present study, the expression and molecular mechanism underlying the effects of CIP2A in patients with MM and in MM cell lines were elucidated. Firstly, the expression of CIP2A was detected in patients with MM and in MM cell lines by reverse transcription-quantitative polymerase chain reaction. Furthermore, silencing of CIP2A with short hairpin RNA was performed in MM cells, and the impact on the proliferation and apoptosis of RPMI-8226 cells was analyzed (as endogenous CIP2A is highly expressed in RPMI-8226 cell lines compared with other cells). CIP2A was significantly elevated in patients with MM and in MM cell lines, and silencing of CIP2A could inhibit the proliferation ability of RPMI 8226 cells in vitro. In addition, CIP2A knockdown induced apoptosis and led to substantial reduction of c-Myc protein levels in MM cell lines. This study suggested that CIP2A inhibition may provide a promising therapeutic strategy for patients with MM. PMID- 27484818 TI - First molecular detection and characterization of Sarcocystis species in slaughtered cattle in North-West Tunisia. AB - Sarcocystis spp. is one of the most prevalent foodborne parasites infecting both animals and humans. Consumption of raw or undercooked infected meat is a risk factor of human intestinal sarcocystosis. The present study aimed to estimate the prevalence of Sarcocystis species infecting slaughtered Tunisian cattle in North West Tunisia (Beja governorate). DNA was extracted from 150 beef meat samples and a PCR-restriction fragment length polymorphism was used for identification. The overall infection prevalence of Sarcocystis spp. was 38% (57/150). Two species were identified, namely S. hominis (25%; 39/150) and S. cruzi (12%; 18/150). For both species, the highest prevalence was in Thibar locality (52.9 and 17.6% for S. hominis and S. cruzi, respectively). The molecular prevalence of S. cruzi was significantly higher in animals aged between two and eight years (19.2%; 10/52). This is the first molecular identification of Sarcocystis species in Tunisian cattle. Further studies in both human and animal Tunisian populations are needed to rank this parasitic disease among others. PMID- 27484819 TI - Eutrophication, Ammonia Intoxication, and Infectious Diseases: Interdisciplinary Factors of Mass Mortalities in Cultured Nile Tilapia. AB - The present study was designed to assess the possible causes of the mass mortalities of Nile Tilapia Oreochromis niloticus at El-Behera Governorate, Egypt, in relationship to environmental and microbiotic factors. Water samples were collected from fish farms at different locations and from Lake Edku to analyze water temperature, water pH, salinity, biological oxygen demand, dissolved oxygen, total ammonia nitrogen, and un-ionized ammonia. A number of moribund and freshly dead fish were sampled and submitted to our laboratory for microbiological, molecular, and histopathological examination. Water analysis of the fish farms revealed noticeable increases in the previously mentioned physicochemical parameters. Clinical examinations of moribund fish showed severe gill rot and massive external and internal hemorrhages. Ordinary and molecular laboratory findings confirmed the presence of Branchiomyces sp. in gill tissue and mixed bacterial fish pathogens (Streptococcus agalactiae, Vibrio alginolyticus, V. parahaemolyticus, Pseudomonas anguilliseptica, and P. aeruginosa) in visceral organs. The histopathological and transmission electron microscopic examinations revealed severe necrosis of gill filaments and blockage of branchial blood vessels and lamellar capillaries with Branchiomyces sp. hyphae and spores mixed with different shapes of bacteria. Severe inflammations were detected in liver, kidney, heart, and brain tissues. Ultimately, we can conclude that the syndrome of mass fish kills in this area is a consequence of ecological damage to the aquatic environment, which is mainly related to natural and anthropogenic factors, as well as to the presence of infectious agents. Received September 30, 2015; accepted April 12, 2016. PMID- 27484820 TI - Factors associated with diagnostic stage of hip osteoarthritis due to acetabular dysplasia among Japanese female patients: a cross-sectional study. AB - BACKGROUND: In Japan, the majority of hip osteoarthritis (OA) was caused by acetabular dysplasia, and about 90 % of patients were female. The present study focused on Japanese female patients with hip OA due to acetabular dysplasia, and examined the associated factors with OA staging at diagnosis, in special reference to body weight. METHODS: Study subjects were 336 Japanese women who were newly diagnosed with hip OA caused by acetabular dysplasia at 15 hospitals in 2008. The self-administered questionnaire elicited patients' body weight at age 20 and at OA diagnosis. Four ranked OA staging according to radiographic findings of the hip joint (pre-OA, initial stage, advanced stage or terminal stage) was regarded as the outcome index. Proportional odds models in logistic regression were used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for severer stage of OA. RESULTS: At diagnosis, 45 % of patients suffered from terminal stage of OA, whereas 13 % and 14 % were categorized into pre-OA and initial stage, respectively. After adjustment for potential confounders, weight gain since age 20 revealed the increased ORs for severer OA stage at diagnosis (OR 2.02; 95 % CI, 1.07-3.80). Other significant characteristics were age (67+ vs. 20-49 years, OR 12.4), lower education (junior high school vs. junior college or higher, OR 4.00), parity (OR 2.19), lower acetabular head index (<60.0 vs. 71.1+, OR 2.36), and longer duration since symptom onset (6.0+ vs. <1.0 year, OR 2.94). CONCLUSIONS: Weight gain since age 20 might be involved in mechanisms of OA development, which is independent of age or severity of acetabular dysplasia. PMID- 27484821 TI - Patient Education for Consumer-Mediated HIE. A Pilot Randomized Controlled Trial of the Department of Veterans Affairs Blue Button. AB - OBJECTIVES: Consumer-mediated health information exchange (HIE) is one of the three types of HIE designated by the Office of the National Coordinator. HIE is intended to improve the quality of care while reducing cost, yet empirical support for this claim is mixed. Future research should identify the contexts whereby HIE is most effective. METHODS: This study was conducted as a pilot two arm randomized controlled trial. In the intervention arm, 27 veterans were taught how to generate a Continuity of Care Document (CCD) within the Blue Button feature of their VA patient portal and were then asked to share it with their community non-VA provider. In the attention control condition, 25 Veterans were taught how to look up health information on the Internet. The impact of this training on the next non-VA medical visit was examined. RESULTS: Nineteen (90%) veterans in the intervention arm shared their CCD with their non-VA provider as compared with 2 (17%) in the attention control arm (p<0.001). Both veterans and non-VA providers indicated high satisfaction with the CCD. Comparison of medical records between the VA and non-VA providers did not indicate improved medication reconciliation (p=0.72). If veterans shared their CCD prior to their non-VA providers ordering laboratory tests, the number of duplicate laboratories was significantly reduced (p=0.02). CONCLUSIONS: In this pilot randomized controlled trial, training 52 veterans to share their CCD was feasible and accepted by both patients and providers. Sharing this document appeared to reduce duplicate laboratory draws, but did not have an impact on documented medication list concordance. PMID- 27484822 TI - Estimating Marginal Healthcare Costs Using Genetic Variants as Instrumental Variables: Mendelian Randomization in Economic Evaluation. AB - Accurate measurement of the marginal healthcare costs associated with different diseases and health conditions is important, especially for increasingly prevalent conditions such as obesity. However, existing observational study designs cannot identify the causal impact of disease on healthcare costs. This paper explores the possibilities for causal inference offered by Mendelian randomization, a form of instrumental variable analysis that uses genetic variation as a proxy for modifiable risk exposures, to estimate the effect of health conditions on cost. Well-conducted genome-wide association studies provide robust evidence of the associations of genetic variants with health conditions or disease risk factors. The subsequent causal effects of these health conditions on cost can be estimated using genetic variants as instruments for the health conditions. This is because the approximately random allocation of genotypes at conception means that many genetic variants are orthogonal to observable and unobservable confounders. Datasets with linked genotypic and resource use information obtained from electronic medical records or from routinely collected administrative data are now becoming available and will facilitate this form of analysis. We describe some of the methodological issues that arise in this type of analysis, which we illustrate by considering how Mendelian randomization could be used to estimate the causal impact of obesity, a complex trait, on healthcare costs. We describe some of the data sources that could be used for this type of analysis. We conclude by considering the challenges and opportunities offered by Mendelian randomization for economic evaluation. PMID- 27484823 TI - Service evaluation of an educational intervention to improve sexual health services in primary care implemented using a step-wedge design: analysis of chlamydia testing and diagnosis rate changes. AB - BACKGROUND: Providing sexual health services in primary care is an essential step towards universal provision. However they are not offered consistently. We conducted a national pilot of an educational intervention to improve staff's skills and confidence to increase chlamydia testing rates and provide condoms with contraceptive information plus HIV testing according to national guidelines, known as 3Cs&HIV. The effectiveness of the pilot on chlamydia testing and diagnosis rates in general practice was evaluated. METHODS: The pilot was implemented using a step-wedge design over three phases during 2013 and 2014 in England. The intervention combined educational workshops with posters, testing performance feedback and continuous support. Chlamydia testing and diagnosis rates in participating general practices during the control and intervention periods were compared adjusting for seasonal trends in chlamydia testing and differences in practice size. Intervention effect modification was assessed for the following general practice characteristics: chlamydia testing rate compared to national median, number of general practice staff employed, payment for chlamydia screening, practice urban/rurality classification, and proximity to sexual health clinics. RESULTS: The 460 participating practices conducted 26,021 tests in the control period and 18,797 tests during the intervention period. Intention-to-treat analysis showed no change in the unadjusted median tests and diagnoses per month per practice after receiving training: 2.7 vs 2.7; 0.1 vs 0.1. Multivariable negative binomial regression analysis found no significant change in overall testing or diagnoses post-intervention (incidence rate ratio (IRR) 1.01, 95 % confidence interval (CI) 0.96-1.07, P = 0.72; 0.98 CI 0.84-1.15, P = 0.84, respectively). Stratified analysis showed testing increased significantly in practices where payments were in place prior to the intervention (IRR 2.12 CI 1.41-3.18, P < 0.001) and in practices with 6-15 staff (6-10 GPs IRR 1.35 (1.07-1.71), P = 0.012; 11-15 GPs IRR 1.37 (1.09-1.73), P = 0.007). CONCLUSION: This national pilot of short educational training sessions found no overall effect on chlamydia testing in primary care. However, in certain sub groups chlamydia testing rates increased due to the intervention. This demonstrates the importance of piloting and evaluating any service improvement intervention to assess the impact before widespread implementation, and the need for detailed understanding of local services in order to select effective interventions. PMID- 27484824 TI - Patient and physician views of accompanied consultations in occupational health. AB - Background: Accompanied (triadic) consultations, or consultations where a third person is present, are poorly researched and little research has been carried out in an occupational health (OH) setting. Aims: To elicit the views of patients and OH physicians about accompanied consultations. Methods: OH receptionists gave a self-administered questionnaire to patients after they attended OH consultations with a companion. We interviewed participating OH physicians to ascertain their views on accompanied consultations. Results: Twenty-six patient questionnaires were completed (response rate 52%). Seventy-three per cent (19) of responders were accompanied by a spouse and 12% (3) by non-family members. Patients reported their companion was helpful with recall of information (100%), supportive (100%), provided extra information to the physician (81%) and enabled them to discuss the outcome afterwards (92%). In two consultations, the companion attended to provide support on procedural matters. Patients were not concerned that the consultation might involve sensitive discussion or physical examination. OH physicians reported concerns that the companion would make the consultation more difficult or influence its outcome. They felt that written information, guidelines and training in how to manage accompanied consultations would be useful. Conclusions: Patients who attended OH consultations with a companion felt the companion was beneficial to the consultation and did not have concerns about personal issues. OH physicians felt that further guidance and training on accompanied consultations would be useful. Written information could usefully be provided to patients attending an OH consultation with a companion. PMID- 27484825 TI - [Robot-assisted minimally invasive esophagectomy. German version]. AB - Esophagolymphadenectomy is the cornerstone of multimodality treatment for resectable esophageal cancer. The preferred surgical approach is transthoracic, with a two-field lymph node dissection and gastric conduit reconstruction. A minimally invasive approach has been shown to reduce postoperative complications and increase quality of life. Robot-assisted minimally invasive esophagectomy (RAMIE) was developed to facilitate this complex thoracoscopic procedure. RAMIE has been shown to be safe with good oncologic results and reduced morbidity. The use of RAMIE opens new indications for curative surgery in patients with T4b tumors, high mediastinal tumors, and lymph node metastases after neoadjuvant treatment. PMID- 27484826 TI - [Infections of the spine : Therapeutic strategies]. AB - Spinal infections are relatively rare entities but the incidence is significantly increasing due to the rapidly growing numbers of interventions on the spine. Primary infections of intervertebral discs (spondylodiscitis) and vertebral bodies (spondylitis) are distinguished from secondary postinterventional infections. Treatment relies primarily on either conservative or surgical management. In the absence of indications for surgery, a conservative approach is indicated when the patient is neurologically intact and the bony destruction is minimal. Conservative therapeutic options are based on the microbiological diagnosis and use of antibiotics, immobilization, analgesics and orthotics. Indications for a surgical intervention are the presence of neurological deficits, intraspinal abscesses, extensive osseous destruction and failure of conservative management. Surgical therapy focusses on the decompression of neural structures, debridement and eradication of the focus of infection, pathogen identification, correction of the deformity and restoration of a physiological spinal profile. Following a postoperative infection a timely diagnosis including assessment of the extent of infection is crucial. In the case of a purely superficial infection, antibiotic prophylaxis and close monitoring is indicated. If findings are pronounced surgical revision, debridement together with antibiotic therapy and if necessary vacuum-assisted closure as well as revision ranging from exchange of implants to complete removal of osteosynthetic material are required. Spinal infections are severe conditions frequently with residual long-term sequelae, whether the patients are managed conservatively or surgically. PMID- 27484829 TI - [Lower right abdominal pain in a young woman : An ordinary appendicitis]. PMID- 27484827 TI - [Treatment of periprosthetic infections]. AB - The increasing number of prosthesis implantations and higher life expectancy lead to a growing number of periprosthetic infections (PPI). Optimal therapy necessitates interdisciplinary coordination of surgical and antimicrobial treatment. Challenges in the treatment are the increased occurrence of resistant pathogens, selection of adequate antimicrobial and surgical treatment strategies, inappropriate pretreatment and comorbidities of patients. Current treatment concepts lead to a high success rate in terms of infection eradication, when correctly applied. The individual expectations and underlying conditions of each patient must be considered when determining the therapy concept. The first step is to distinguish between acute and chronic infections. In acute infections the prosthesis can be retained but chronic infections necessitate a complete exchange of the prosthesis. Complicating factors, such as compromising soft tissue and bone conditions, osteomyelitis and infections caused by difficult-to-treat bacteria should, however, always be treated by a complete exchange of the prosthesis, even for acute infections. The antimicrobial treatment must be tailored to the causative agent, the surgical strategy as well as comorbidities and drug intolerances of the patient. It is important to distinguish between biofilm-active eradication therapy with rifampicin for gram-positive pathogens and quinolones for gram-negative organisms and suppression therapy. This article gives a structured presentation of the therapy algorithm. PMID- 27484828 TI - [Promoting Young Talents in Trauma Surgery through Students-On-Call]. AB - BACKGROUND: Due to restrictions on admission to medical school, changing claims to an optimized work-life balance and occupational perspectives, surgical professions in particular are struggling with strategies to motivate young academics. Surgical disziplines aim towards a profound transfer of knowledge and pique student's interest by ensuring a sustainable education at university. OBJECTIVES: The goal of this study was to evaluate a Students-On-Call System (SOCS) and to identify a financial benefit. MATERIALS AND METHODS: In this study the SOCS was compared pre-/postevaluation using questionnaires and the supporting X-rays within a curricular teaching module of orthopedic trauma surgery, with students in the fourth semester of specialism and those in the practical semester at medical school. RESULTS: The students of SOCS showed significantly better results prior to the course and afterwards than the two other groups. By establishing SOCS medical students get involved into the treatment of emergency patients in the trauma resuscitation unit (TRU) and operating room (OR). Students get the chance to enhance their comprehension of diagnostics, therapy and decision making in surgical context. This highly valuable traineeship combines a minimized teaching effort with an effective motivation of young academcis for the surgical profession. A SOCS has reduced the workload of medical colleagues. Establishing SOCS spare the residents being on call and results in reduced costs of 23,659.86 Euro per year. CONCLUSION: The results presented show that the SOCS leads to an excellent cost-benefit balance, which has been established in multiple surgical departments at the medical school of the University of Gottingen. Apart from practice-oriented surgical teaching, the SOCS is a way of promoting successful young talent saving resources in the medical on-call services. PMID- 27484830 TI - A Multidimensional Diversity-Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles. AB - Synthetic macrocycles are an attractive area in drug discovery. However, their use has been hindered by a lack of versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries. Herein, we describe a new concept in library synthesis, termed multidimensional diversity-oriented synthesis, and its application towards macrocycles. This enabled the step efficient generation of a library of 45 novel, structurally diverse, and highly functionalized macrocycles based around a broad range of scaffolds and incorporating a wide variety of biologically relevant structural motifs. The synthesis strategy exploited the diverse reactivity of aza-ylides and imines, and featured eight different macrocyclization methods, two of which were novel. Computational analyses reveal a broad coverage of molecular shape space by the library and provides insight into how the various diversity-generating steps of the synthesis strategy impact on molecular shape. PMID- 27484831 TI - Hybrid external fixation in the treatment of tibial pilon fractures: A retrospective analysis of 162 fractures. AB - OBJECTIVES: To determine the efficacy of hybrid external fixation in the treatment of tibial pilon fractures. DESIGN: Retrospective, multicentre study. PATIENTS/PARTICIPANTS: Adult patients with tibial pilon fractures treated with hybrid external fixation. INTERVENTION: Fracture reduction with ligamentotaxis and fixation with XCaliber hybrid external fixator. MAIN OUTCOME MEASUREMENTS: Fracture union, complications, functional outcome (Mazur Ankle Score). RESULTS: Union was obtained in 159 fractures at an average of 125days; there were three delayed unions and three non-unions. The most frequent complication was superficial pin-track infections (48), all of which responded to local wound care and antibiotics. There were no deep infections and no DVT. Only one fracture had loss of reduction that required frame revision. The overall functional scores were 91 (excellent) for AO/OTA type A fractures, 89 (good) for type B fractures, and 75 (satisfactory) for type C fractures. CONCLUSIONS: Hybrid external fixation is an effective method of stabilising tibial pilon fractures, particularly those with marked comminution. The minimally-invasive technique and stable fixation enable early mobilisation, with good functional results and minimal complications. LEVEL OF EVIDENCE: Level IV Case series. PMID- 27484832 TI - Two new sesquiterpenoids produced by halophilic Nocardiopsis chromatogenes YIM 90109. AB - Two new germacradiene-type sesquiterpenoids, including 1(10)E,5E-germacradiene 9beta,11-diol (or 9beta-hydroxyl germacradienol) (1) and 11-hydroxy-1(10)E,5E germacradien-2-one (2-oxygermacradienol) (2), together with a known geosmin-type sesquiterpenoid (1beta,4beta,4abeta,7alpha,8aalpha)-4,8a dimethyloctahydronaphthalene-1,4a,7(2H)-triol (3), were elucidated by their NMR spectroscopic data, HR-ESI-MS and single-crystal X-ray diffraction from the halophilic strain Nocardiopsis chromatogenes YIM 90109. The antimicrobial activities were evaluated by paper diffusion method. PMID- 27484833 TI - Divergent Annexin A1 expression in periphery and gut is associated with systemic immune activation and impaired gut immune response during SIV infection. AB - HIV-1 disease progression is paradoxically characterized by systemic chronic immune activation and gut mucosal immune dysfunction, which is not fully defined. Annexin A1 (ANXA1), an inflammation modulator, is a potential link between systemic inflammation and gut immune dysfunction during the simian immunodeficiency virus (SIV) infection. Gene expression of ANXA1 and cytokines were assessed in therapy-naive rhesus macaques during early and chronic stages of SIV infection and compared with SIV-negative controls. ANXA1 expression was suppressed in the gut but systemically increased during early infection. Conversely, ANXA1 expression increased in both compartments during chronic infection. ANXA1 expression in peripheral blood was positively correlated with HLA-DR+CD4+ and CD8+ T-cell frequencies, and negatively associated with the expression of pro-inflammatory cytokines and CCR5. In contrast, the gut mucosa presented an anergic cytokine profile in relation to ANXA1 expression. In vitro stimulations with ANXA1 peptide resulted in decreased inflammatory response in PBMC but increased activation of gut lymphocytes. Our findings suggest that ANXA1 signaling is dysfunctional in SIV infection, and may contribute to chronic inflammation in periphery and with immune dysfunction in the gut mucosa. Thus, ANXA1 signaling may be a novel therapeutic target for the resolution of immune dysfunction in HIV infection. PMID- 27484834 TI - Spontaneous temperature-sensitive Pluronic((r)) based niosomes: Triggered drug release using mild hyperthermia. AB - Inclusion of lipids or polymers with a transition temperature closer to physiological body temperature (40-42 degrees C) is a strategy used in tumor therapy for more than 30 years, because it allows induction of drug release from delivery systems by mild hyperthermia. Unfortunately, most of these thermo sensitive carriers are removed from circulation before completion of their function. Thus, novel multi-functional niosomes possessing spontaneous stealth and thermo-sensitive properties were developed from L64 Pluronic((r)) and L64ox as its derivative, in presence or absence of cholesterol. The use of L64 both as amphiphilic constituent and thermo-sensitive molecule, gave the possibility to bypass the use of additional excipients and increased the system biocompatibility. Niosomes diameter ranged from 400 to 750nm and were long term stable. Calcein and 5-FU possess great affinity to niosomal matrices rich in PEO groups. Negative Z-potential values were attributed to the negative charges onto the niosomes surface and generally change according to the temperature. The in vitro drugs release studies were performed at 25 degrees C, 37 degrees C and 42 degrees C, that are representative of certain conditions (storage, physiological condition and mild hyperthermia, respectively). Results showed that L64-based niosomes possess spontaneous thermo-sensitive properties: drugs releases were found to be more pronounced at 42 degrees C. These early results are a promising first step for the development of multi-functional devices that combine several advantages such as stealth properties and temperature controllability at the desired location and time, for a more specific and efficient pharmacological therapy. PMID- 27484835 TI - Tumor microenvironment-responsive micelles for pinpointed intracellular release of doxorubicin and enhanced anti-cancer efficiency. AB - Internal stimuli, such as intracellular lysosomal pH, enzyme, redox and reduction, can be applied to improve biological specificity of chemotherapeutic drugs for cancer therapy. Thus, functionalized copolymers based on their response to specific microenvironment of tumor regions have been designed as smart drug vesicles for enhanced anti-cancer efficiency and reduced side effects. Herein, we reported dually pH/reduction-responsive novel micelles based on self-assembly of carboxymethyl chitosan-cysteamine-N-acetyl histidine (CMCH-SS-NA) and doxorubicin (DOX). The tailor-made dually responsive micelles demonstrated favorable stability in normal physiological environment and triggered rapid drug release in acidic and/or reduction environment. Additionally, the nanocarriers responded to the intracellular environment in an ultra-fast manner within several minutes, which led to the pinpointed release of DOX in tumor cells effectively and ensured higher DOX concentrations within tumor areas with the aid of targeted delivery, thereby leading to enhanced tumor ablation. Thus, this approach with sharp drug release behavior represented a versatile strategy to provide a promising paradigm for cancer therapy. PMID- 27484836 TI - Angiopep2-functionalized polymersomes for targeted doxorubicin delivery to glioblastoma cells. AB - A targeted drug delivery nanosystem for glioblastoma multiforme (GBM) based on polymersomes (Ps) made of poly(dimethylsiloxane)-poly(2-methyloxazoline) (PDMS PMOXA) diblock copolymers was developed to evaluate their potential to actively target brain cancer cells and deliver anticancer drugs. Angiopep2 was conjugated to the surface of preformed Ps to target the low density lipoprotein receptor related protein 1 that are overexpressed in blood brain barrier (BBB) and glioma cells. The conjugation efficiency yield for angiopep2 was estimated to be 24%. The angiopep2-functionalized Ps showed no cellular toxicity after 24h and enhanced the cellular uptake around 5 times more in U87MG glioblastoma cells compared to the non-targeted Ps. The encapsulation efficiency of doxorubicin (DOX) in Ps was 13% by co-solvent method, compared to a film rehydration method (4%). The release profiles of the DOX from Ps showed a release of 42% at pH 5.5 and 40% at pH 7.4 after 24h, indicating that Ps can efficiently retain the DOX with a slow release rate. Furthermore, the in vitro antiproliferative activity of DOX-loaded Ps-Angiopep2 showed enhanced toxicity to U87MG glioblastoma cells, compared to non-targeted Ps. Overall, our in vitro results suggested that angiopep2-conjugated Ps can be used as nanocarriers for efficient targeted DOX delivery to glioblastoma cells. PMID- 27484837 TI - Mutations in the TMCO3 Gene are Associated with Cornea Guttata and Anterior Polar Cataract. AB - The molecular basis for cornea guttata and anterior polar cataract remains idiopathic in most cases. In this study, our aim was to identify the disease associated gene in Chinese patients with these conditions. Patients with the conditions from two Chinese families, and ten sporadic patients, were investigated. Genome-wide linkage and exome sequencing analyses showed transmembrane and coiled-coil domain 3 (TMCO3) as the disease candidate gene for a coding heterozygous mutation c.41C > T, resulting in a P14L amino acid change that co-segregated with the disease phenotype as discovered in Family A. TMCO3 belongs to the monovalent cation: protein antiporter 2 transporter family, a moderately large group whose members all share a very similar function under normal physiological conditions. The gene is expressed in the human cornea, lens capsule, and choroid-retinal pigment epithelium. This study reveals, for the first time, that mutations in TMCO3 are associated with cornea guttata and anterior polar cataract, warranting further investigation into the pathogenesis of this disorder. PMID- 27484838 TI - IGFBP5 enhances osteogenic differentiation potential of periodontal ligament stem cells and Wharton's jelly umbilical cord stem cells, via the JNK and MEK/Erk signalling pathways. AB - OBJECTIVES: Mesenchymal stem cell (MSC)-mediated tissue regeneration represents a promising strategy for repair of tissue defects, but its molecular mechanisms remain unclear, restricting the use of MSCs. Our previous study indicated that insulin-like growth factor-binding protein 5 (IGFBP5) exerted a valuable effect on osteogenic differentiation of MSCs, but its molecular mechanisms underlying directed differentiation remained unclear. In this study, we have investigated the molecular role of IGFBP5 in regulating this osteogenic differentiation potential. MATERIALS AND METHODS: Periodontal ligament stem cells (PDLSCs) were isolated from periodontal ligament tissue. Wharton's jelly of umbilical cord stem cells (WJCMSCs) was obtained commercially. Lentiviral IGFBP5 shRNA was used to silence IGFBP5. Retroviruses expressing wild-type IGFBP5 were used to overexpress IGFBP5 in the WJCMSCs. Recombinant human IGFBP5 protein (rhIGFBP5) was used to treat PDLSCs for 24 h. Western blot analysis was used to detect the MAPK signalling pathway, and alkaline phosphatase (ALP) activity, Alizarin Red staining and quantitative calcium analysis were used to study osteogenic differentiation potentials. RESULTS: Overexpression of IGFBP5 or rhIGFBP5 increased expression levels of phosphorylated c-Jun N-terminal kinase (p-JNK), phosphorylated mitogen-activated protein kinase 1 and 2 (p-MEK1/2) and phosphorylated extracellular regulated protein kinases (p-Erk1/2) in both WJCMSCs and PDLSCs. Consistently, silenced IGFBP5 was found to effectively inhibit expression of p-JNK, p-Erk1/2 and p-MEK1/2 in PDLSCs and WJCMSCs. Furthermore, inhibition of JNK by its inhibitor, SP600125, or MEK/Erk signalling by its inhibitor, PD98059, dramatically blocked IGFBP5-enhanced ALP activity and in vitro mineralization in both PDLSCs and WJCMSCs. CONCLUSIONS: Our results demonstrated that IGFBP5 promoted osteogenic differentiation potentials of PDLSCs and WJCMSCs via the JNK and MEK/Erk signalling pathways. PMID- 27484839 TI - A Validation Study of the Need for Affect Questionnaire-Short Form in Legal Contexts. AB - We evaluated the psychometric properties of scores on the Need for Affect-Short Form (NAQ-S) in 3 samples: undergraduate students (Sample I), jury-eligible community members (Sample II), and forensic clinicians (Sample III). Concerning factor structure, the NAQ-S 2-factor structure displayed good fit to the data in Sample I, with mostly acceptable levels of internal consistency for both approach and avoidance scores. Construct validity patterns were observed such that approach scores were most strongly correlated with female gender and trait agreeableness scores, whereas avoidance scores were most strongly correlated to trait agreeableness scores. Criterion validity associations emerged in that approach scores displayed main effects on mock juror judgments in hate crimes, and forensic clinician judgments of violence risk estimation. Finally, avoidance scores displayed moderating effects on recommended sentencing length by hate crime victim type. Implications are discussed for emotion in legal decision making and future research. PMID- 27484841 TI - PCR methodology and applications for the detection of human fungal pathogens. AB - INTRODUCTION: Polymerase chain reaction (PCR) has emerged as a promising technology for the rapid and reliable detection and identification of medical mycoses. Recent technological advancements - including microarray, multiplex PCR with magnetic resonance, and beacon probes - have mitigated the technical difficulties of performing nucleic amplification in fungi, thereby improving the sensitivity and specificity of PCR-based assays. In this paper, we examine current applications of PCR in the diagnosis of human fungal infections and look ahead to emerging techniques that may play a larger role in molecular diagnostics in the future. AREAS COVERED: This review includes a brief overview of the advantages and disadvantages of PCR using various clinical specimens, manual versus automated DNA extraction procedures, panfungal versus specific targets, and spectrum of pathogens detected. This is followed by a brief synopsis of species-specific PCR approaches and a more in-depth look at the obstacles to widespread implementation. Expert commentary: The review concludes with a short perspective for the next five years, including the hurdles to standardization and validation, as well as the role of PCR coupled with electrospray-ionization mass spectrometry (PCR/ESI-MS) or nuclear magnetic resonance for the diagnosis of medical mycoses. PMID- 27484840 TI - MRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity. AB - The myogenic regulatory factor MRF4 is highly expressed in adult skeletal muscle but its function is unknown. Here we show that Mrf4 knockdown in adult muscle induces hypertrophy and prevents denervation-induced atrophy. This effect is accompanied by increased protein synthesis and widespread activation of muscle specific genes, many of which are targets of MEF2 transcription factors. MEF2 dependent genes represent the top-ranking gene set enriched after Mrf4 RNAi and a MEF2 reporter is inhibited by co-transfected MRF4 and activated by Mrf4 RNAi. The Mrf4 RNAi-dependent increase in fibre size is prevented by dominant negative MEF2, while constitutively active MEF2 is able to induce myofibre hypertrophy. The nuclear localization of the MEF2 corepressor HDAC4 is impaired by Mrf4 knockdown, suggesting that MRF4 acts by stabilizing a repressor complex that controls MEF2 activity. These findings open new perspectives in the search for therapeutic targets to prevent muscle wasting, in particular sarcopenia and cachexia. PMID- 27484842 TI - Cytotoxicity of methanol extracts of 10 Cameroonian medicinal plants towards multi-factorial drug-resistant cancer cell lines. AB - BACKGROUND: Cancer chemotherapy is still hampered by clinical failures due to multi-drug resistance (MDR) of tumor cells. In the present study, we have investigated the cytotoxicity of 20 methanol extracts from 10 medicinal plants against the sensitive leukemia CCRF-CEM cells. The most cytotoxic extracts were then further tested on a panel of 8 human cancer cell lines, including various MDR phenotypes. METHODS: The cytotoxicity of the 20 methanol extracts from 10 Cameroonian medicinal plants was determined using a resazurin reduction assay. Meanwhile, flow cytometry was used to measure cell cycle, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS). RESULTS: In the preliminary assay using CCRF-CEM cells, 12 extracts from five plants displayed IC50 values below 80 MUg/mL, namely Albizia adianthifolia, Alchornea cordifolia, Alchornea laxiflora, Pennisetum purpureum, and Spathodea campanulata. the four best extracts were from two plants: Albizia adianthifolia roots (AAR) and bark (AAB) as well as Alchornea cordifolia leaves (ACL) and bark (ACB) had respective IC50 values of 0.98 MUg/mL, 1.45 MUg/mL, 8.02 MUg/mL and 12.57 MUg/mL in CCRF-CEM cells. They were further tested in 8 other cell lines as well as in normal AML12 hepatocytes. IC50 values ranging from 2.71 MUg/mL (towards glioblastoma U87MG.DeltaEGFR cells) to 10.30 MUg/mL (towards breast adenocarcinoma MDA-MB-231-BCRP cells) for AAB, from 3.43 MUg/mL (towards U87MG cells) to 10.77 MUg/mL (towards colon carcinoma HCT116 (p53 (-/-) ) cells) for AAR and from 0.11 MUg/mL (towards CCRF-CEM cells) to 108 MUg/mL (towards leukemia CEM/ADR5000 cells) for doxorubicin (as control drug) were obtained. ACL and ACB extracts displayed selective activities. AAR and ACL extracts induced apoptosis in CCRF-CEM cells, through caspases activation and loss of MMP, while apoptotic cell death was mediated by MMP diruption and increase ROS production for ACL. CONCLUSION: Some of the tested plants namely Albizia adianthifolia, Alchornea cordifolia, Alchornea laxiflora, Pennisetum purpureum, Spathodea campanulata represent a potential source of novel anticancer drugs. Especially, Albizia adianthifolia and Alchornea cordifolia revealed considerable cytotoxic activities that could be exploited to develop phytomedicines to fight cancers including MDR phenotypes. PMID- 27484844 TI - Differential abundance of muscle proteome in cultured channel catfish (Ictalurus punctatus) subjected to ante-mortem stressors and its impact on fillet quality. AB - The effects of environmental and handling stress during catfish (Ictalurus punctatus) aquaculture were evaluated to identify the biochemical alterations they induce in the muscle proteome and their impacts on fillet quality. Temperature (25 degrees C and 33 degrees C) and oxygen (~2.5mg/L [L] and >5mg/L [H]) were manipulated followed by sequential socking (S) and transport (T) stress to evaluate changes in quality when fish were subjected to handling (25-H-ST; temperature-oxygen-handling), oxygen stress (25-L-ST), temperature stress (33-H ST) and severe stress (33-L-ST). Instrumental color and texture of fillets were evaluated, and muscle proteome profile was analyzed. Fillet redness, yellowness and chroma decreased, and hue angle increased in all treatments except temperature stress (33-H-ST). Alterations in texture compared to controls were observed when oxygen levels were held high. In general, changes in the abundance of structural proteins and those involved in protein regulation and energy metabolism were identified. Rearing under hypoxic conditions demonstrated a shift in metabolism to ketogenic pathways and a suppression of the stress-induced changes as the severity of the stress increased. Increased proteolytic activity observed through the down-regulation of various structural proteins could be responsible for the alterations in color and texture. PMID- 27484843 TI - Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0 Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi institutional Series. AB - BACKGROUND: Three prospective randomised trials reported discordant findings regarding the impact of adjuvant radiation therapy (aRT) versus observation for metastasis-free survival (MFS) and overall survival (OS) among patients with pT3N0 prostate cancer treated with radical prostatectomy (RP). None of these trials systematically included patients who underwent early salvage radiation therapy (esRT). OBJECTIVE: To test the hypothesis that aRT was associated with better cancer control and survival compared with observation followed by esRT. DESIGN, SETTING, AND PARTICIPANTS: Using a multi-institutional cohort from seven tertiary referral centres, we retrospectively identified 510 pT3pN0 patients with undetectable prostate-specific antigen (PSA) after RP between 1996 and 2009. Patients were stratified into two groups: aRT (group 1) versus observation followed by esRT in case of PSA relapse (group 2). Specifically, esRT was administered at a PSA level <=0.5ng/ml. INTERVENTION: We compared aRT versus observation followed by esRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The evaluated outcomes were MFS and OS. Multivariable Cox regression analyses tested the association between groups (aRT vs observation followed by esRT) and oncologic outcomes. Covariates consisted of pathologic stage (pT3a vs pT3b or higher), pathologic Gleason score (<=6, 7, or >=8), surgical margin status (negative vs positive), and year of surgery. An interaction with groups and baseline patient risk was tested for the hypothesis that the impact of aRT versus observation followed by esRT was different by pathologic characteristics. The nonparametric curve fitting method was used to explore graphically the relationship between MFS and OS at 8 yr and baseline patient risk (derived from the multivariable analysis). RESULTS AND LIMITATIONS: Overall, 243 patients (48%) underwent aRT, and 267 (52%) underwent initial observation. Within the latter group, 141 patients experienced PSA relapse and received esRT. Median follow-up after RP was 94 mo (interquartile range [IQR]: 53-126) and 92 mo (IQR: 70-136), respectively (p=0.2). MFS (92% vs 91%; p=0.9) and OS (89% vs 92%; p=0.9) at 8 yr after surgery were not significantly different between the two groups. These results were confirmed in multivariable analysis, in which observation followed by esRT was not associated with a significantly higher risk of distant metastasis (hazard ratio [HR]: 1.35; p=0.4) and overall mortality (HR: 1.39; p=0.4) compared with aRT. Using the nonparametric curve fitting method, a comparable proportion of MFS and OS at 8 yr among groups was observed regardless of pathologic cancer features (p=0.9 and p=0.7, respectively). Limitations consisted of the retrospective nature of the study and the relatively small size of the patient population. CONCLUSIONS: At long-term follow-up, no significant differences between aRT and esRT were observed for MFS and OS. Our study, although based on retrospective data, suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT. PATIENT SUMMARY: At long term follow-up, no significant differences in terms of distant metastasis and mortality were observed between immediate postoperative adjuvant radiation therapy (aRT) and initial observation followed by early salvage radiation therapy (esRT) in case of prostate-specific antigen relapse. Our study suggests that esRT does not compromise cancer control and potentially reduces overtreatment associated with aRT. PMID- 27484845 TI - Production and characterization of spray-dried theophylline powders prepared from fresh milk for potential use in paediatrics. AB - OBJECTIVE: This work evaluates the potential of using fresh milk to deliver theophylline to children. METHODS: Theophylline-fresh milk systems were prepared using different solids ratios (0 : 1-1 : 0) and three fat contents in commercial milks (low, medium and high), which were spray-dried at different inlet air temperatures (Tinlet - 105, 130 and 150 degrees C). The process was evaluated for yield and the resulting powders for moisture content (MC), particle size and shape, density and wettability. Theophylline-milk potential interactions (differential scanning calorimetry (DSC) and FT-IR) and chemical (theophylline content) and microbiological stability of powders (shelf and in-use) were also evaluated. KEY FINDINGS: The production yield (13.6-76.0%), MC (0.0-10.3%) and contact angles in water (77.29-93.51 degrees ) were significantly (P < 0.05) affected by Tinlet , but no differences were found concerning the mean particle size (3.0-4.3 MUm) of the different powders. The milk fat content significantly (P < 0.05) impacted on the density (1.244-1.552 g/cm3 ). Theophylline content remained stable after 6 months of storage, before extemporaneous reconstitution. After reconstitution in water, low-fat milk samples (stored at 4 degrees C) met the microbial pharmacopoeia criteria for up to 7 days. No theophylline-milk components interaction was observed. CONCLUSION: Spray-dried milk-composed powders may be used as vehicles for theophylline delivery in paediatrics following further characterization and in-vivo evaluation. PMID- 27484846 TI - Hairy matters: MtDNA quantity and sequence variation along and among human head hairs. AB - Hairs from the same donor have been found to differ in mtDNA sequence within and among themselves and from other tissues, which impacts interpretation of results obtained in a forensic setting. However, little is known on the magnitude of this phenomenon and published data on systematic studies are scarce. We addressed this issue by generating mtDNA control region (CR) profiles of >450 hair fragments from 21 donors by Sanger-type sequencing (STS). To mirror forensic scenarios, we compared hair haplotypes from the same donors to each other, to the corresponding buccal swab reference haplotypes and analyzed several fragments of individual hairs. We also investigated the effects of hair color, donor sex and age, mtDNA haplogroup and chemical treatment on mtDNA quantity, amplification success and variation. We observed a wide range of individual CR sequence variation. The reference haplotype was the only or most common (>=75%) hair haplotype for most donors. However, in two individuals, the reference haplotype was only found in about a third of the investigated hairs, mainly due to differences at highly variable positions. Similarly, most hairs revealed the reference haplotype along their entire length, however, about a fifth of the hairs contained up to 71% of segments with deviant haplotypes, independent of the longitudinal position. Variation affected numerous positions, typically restricted to the individual hair and in most cases heteroplasmic, but also fixed (i.e. homoplasmic) substitutions were observed. While existing forensic mtDNA interpretation guidelines were found still sufficient for all comparisons to reference haplotypes, some comparisons between hairs from the same donor could yield false exclusions when those guidelines are strictly followed. This study pinpoints the special care required when interpreting mtDNA results from hair in forensic casework. PMID- 27484847 TI - Propensity score-based analysis of outcomes of laparoscopic versus open liver resection for colorectal metastases. AB - BACKGROUND: There is a need for high-level evidence regarding the added value of laparoscopic (LLR) compared with open (OLR) liver resection. The aim of this study was to compare the surgical and oncological outcomes of patients with colorectal liver metastases (CRLM) undergoing LLR and OLR using propensity score matching to minimize bias. METHODS: This was a single-centre retrospective study using a prospective database of patients undergoing liver resection for CRLM between August 2004 and April 2015. Co-variates selected for matching included: number and size of lesions, tumour location, extent and number of resections, phase of surgical experience, location and lymph node status of primary tumour, perioperative chemotherapy, unilobar or bilobar disease, synchronous or metachronous disease. Prematching and postmatching analyses were compared. Surgical and oncological outcomes were analysed. RESULTS: Some 176 patients undergoing LLR and 191 having OLR were enrolled. After matching, 133 patients from each group were compared. At prematching analysis, patients in the LLR group showed a longer overall survival (OS) and higher R0 rate than those in the OLR group (P = 0.047 and P = 0.030 respectively). Postmatching analyses failed to confirm these results, showing similar OS and R0 rate between the LLR and OLR group (median OS: 55.2 versus 65.3 months respectively, hazard ratio 0.70 (95 per cent c.i. 0.42 to 1.05; P = 0.082); R0 rate: 92.5 versus 86.5 per cent, P = 0.186). The 5-year OS rate was 62.5 (95 per cent c.i. 45.5 to 71.5) per cent) for OLR and 64.3 (48.2 to 69.5) per cent for LLR. Longer duration of surgery, lower blood loss and morbidity, and shorter postoperative stay were found for LLR on postmatching analysis. CONCLUSION: Propensity score matching showed that LLR for CRLM may provide R0 resection rates and long-term OS comparable to those for OLR, with lower blood loss and morbidity, and shorter postoperative hospital stay. PMID- 27484849 TI - Tin nanoparticles as an effective conductive additive in silicon anodes. AB - We have found that the addition of tin nanoparticles to a silicon-based anode provides dramatic improvements in performance in terms of both charge capacity and cycling stability. Using a simple procedure and off-the-shelf additives and precursors, we developed a structure in which the tin nanoparticles are segregated at the interface between the silicon-containing active layer and the solid electrolyte interface. Even a minor addition of tin, as small as ~2% by weight, results in a significant decrease in the anode resistance, as confirmed by electrochemical impedance spectroscopy. This leads to a decrease in charge transfer resistance, which prevents the formation of electrically inactive "dead spots" in the anode structure and enables the effective participation of silicon in the lithiation reaction. PMID- 27484848 TI - Multiple sclerosis: clinical profiling and data collection as prerequisite for personalized medicine approach. AB - Multiple sclerosis (MS) is a highly heterogeneous disease as it can present inter individually as well as intra-individually, with different disease phenotypes emerging during different stages in the long-term disease course. In addition to advanced immunological, genetic and magnetic resonance imaging (MRI) profiling of the patient, the clinical profiling of MS patients needs to be widely implemented in clinical practice and improved by including a greater range of relevant parameters as patient-reported outcomes. It is crucial to implement a high standard of clinical characterization of individual patients as this is key to effective long-term observation and evaluation.To generate reliable real-world data, individual clinical data should be collected in specific MS registries and/or using intelligent software instruments as the Multiple Sclerosis Documentation System 3D. Computational analysis of biological processes will play a key role in the transition to personalized MS treatment. Major breakthroughs in the areas of bioinformatics and computational systems biology will be required to process this complex information to enable improved personalization of treatment for MS patients. PMID- 27484850 TI - Optogenetic and chemogenetic strategies for sustained inhibition of pain. AB - Spatially targeted, genetically-specific strategies for sustained inhibition of nociceptors may help transform pain science and clinical management. Previous optogenetic strategies to inhibit pain have required constant illumination, and chemogenetic approaches in the periphery have not been shown to inhibit pain. Here, we show that the step-function inhibitory channelrhodopsin, SwiChR, can be used to persistently inhibit pain for long periods of time through infrequent transdermally delivered light pulses, reducing required light exposure by >98% and resolving a long-standing limitation in optogenetic inhibition. We demonstrate that the viral expression of the hM4D receptor in small-diameter primary afferent nociceptor enables chemogenetic inhibition of mechanical and thermal nociception thresholds. Finally, we develop optoPAIN, an optogenetic platform to non-invasively assess changes in pain sensitivity, and use this technique to examine pharmacological and chemogenetic inhibition of pain. PMID- 27484851 TI - Clinicopathological feature and prognosis of primary hepatic gastrointestinal stromal tumor. AB - Compared to gastric gastrointestinal stromal tumor (GIST), hepatic GIST is very rare in clinic. Reports on clinicopathological feature and prognosis of this rare disease are limited in literature. The purpose of this study was, therefore, to summarize clinical and pathological features as well as prognosis of the primary hepatic GIST. One case of primary hepatic GIST from our center and 22 cases reported in MEDLINE or China National Knowledge Infrastructure (CNKI) were enrolled into this study. Clinicopathological features as well as survival data of hepatic GIST were analyzed and compared with 297 gastric GISTs and 59 small intestinal GISTs from our center. Majority of the 22 cases (95.7%) of hepatic GIST was larger than 5 cm in size, and 75.0% of the tumors were over 5/50 HPF in mitotic index. Most of the hepatic GISTs (85.7%) displayed spindle cell shape in morphology. All of the hepatic GIST (100%) enrolled in this study were classified as high-risk category by the National Institute of Health (NIH) risk classification. The 5-year median disease-free survival (DFS) time was 24.0 months and 5-year disease-specific survival (DSS) rate was 33.3%, respectively. Distribution of clinicopathological features was significantly different among hepatic, gastric, and small intestinal GIST. The DFS and DSS of hepatic GIST were significantly lower than those of the other two groups. Majority of the hepatic GIST is large in size and highly malignant. Prognosis of the primary hepatic GIST is worse than that of gastric GIST and small intestinal GIST. PMID- 27484853 TI - Evidence for a functional role of calsequestrin 2 in mouse atrium. AB - AIM: Several genetically modified mice models were studied so far to investigate the role of cardiac calsequestrin (CSQ2) for the contractile function of the ventricle and for the occurrence of ventricular tachycardia. Using a CSQ2 knockout mouse, we wanted to study also the atrial function of CSQ2. METHODS: The influence of CSQ2 on atrial function and, for comparison, ventricular function was studied in isolated cardiac preparations and by echocardiography as well as electrocardiography in mice with deletion of CSQ2. RESULTS: Using deletion of exon 1, we have successfully generated a constitutive knockout mouse of the calsequestrin 2 gene (CSQ2-/- ). CSQ2 protein was absent in the heart (atrium, ventricle), but also in oesophagus and skeletal muscle of homozygous knockout mice. In 6-month-old CSQ2-/- mice, relative left atrial weight was increased, whereas relative heart weight was unchanged. The staircase phenomena in paced left atrial preparations on force of contraction and the post-rest potentiation were different between wild type and CSQ2-/- indicative for a decreased sarcoplasmic Ca2+ load and supporting an important role of CSQ2 also in the atrium. The incidence of arrhythmias was increased in CSQ2-/- . In 2-year-old CSQ2-/- mice, cardiac hypertrophy and heart failure were noted possibly as a result of chronically increased cytosolic Ca2+ levels. CONCLUSION: These data suggest a functional role of CSQ2 not only in the ventricle but also in the atrium of mammalian hearts. Loss of CSQ2 function can cause not only arrhythmias, but also cardiac hypertrophy and heart failure. PMID- 27484852 TI - KIF1A mediates axonal transport of BACE1 and identification of independently moving cargoes in living SCG neurons. AB - Neurons rely heavily on axonal transport to deliver materials from the sites of synthesis to the axon terminals over distances that can be many centimetres long. KIF1A is the neuron-specific kinesin with the fastest reported anterograde motor activity. Previous studies have shown that KIF1A transports a subset of synaptic proteins, neurofilaments and dense-core vesicles. Using two-colour live imaging, we showed that beta-secretase 1 (BACE1)-mCherry moves together with KIF1A-GFP in both the anterograde and retrograde directions in superior cervical ganglions (SCG) neurons. We confirmed that KIF1A is functionally required for BACE1 transport by using KIF1A siRNA and a KIF1A mutant construct (KIF1A-T312M) to impair its motor activity. We further identified several cargoes that have little or no co-migration with KIF1A-GFP and also move independently from BACE1-mCherry. Together, these findings support a primary role for KIF1A in the anterograde transport of BACE1 and suggest that axonally transported cargoes are sorted into different classes of carrier vesicles in the cell body and are transported by cargo-specific motor proteins through the axon. PMID- 27484854 TI - Neural architecture of the "transient" ON directionally selective (class IIb1) ganglion cells in rabbit retina, partly co-stratified with starburst amacrine cells. AB - Recent physiological studies coupled with intracellular staining have subdivided ON directionally selective (DS) ganglion cells of rabbit retina into two types. One exhibits more "transient" and more "brisk" responses (ON DS-t), and the other has more "sustained' and more "sluggish" responses (ON DS-s), although both represent the same three preferred directions and show preference for low stimulus velocity, as reported in previous studies of ON DS ganglion cells in rabbit retina. ON DS-s cells have the morphology of ganglion cells previously shown to project to the medial terminal nucleus (MTN) of the accessory optic system, and the MTN-projecting, class IVus1 cells have been well-characterized previously in terms of their dendritic morphology, branching pattern, and stratification. ON DS-t ganglion cells have a distinctly different morphology and exhibit heterotypic coupling to amacrine cells, including axon-bearing amacrine cells, with accompanying synchronous firing, while ON DS-s cells are not coupled. The present study shows that ON DS-t cells are morphologically identical to the previously well-characterized, "orphan" class IIb1 ganglion cell, previously regarded as a member of the "brisk-concentric" category of ganglion cells. Its branching pattern, quantitatively analyzed, is similar to that of the morphological counterparts of X and Y cells, and very different from that of the ON DS-s ganglion cell. Close analysis of the dendritic stratification of class IIb1 ganglion cells together with fiducial cells indicates that they differ from that of the ON DS-s cells. In agreement with one of the three previous studies, class IIb1/ON DS-t cells, unlike class IVus1/ON DS-s ganglion cells, in the main do not co-stratify with starburst amacrine cells. As the present study shows, however, portions of their dendrites do deviate from the main substratum, coming within range of starburst boutons. Parsimony favors DS input from starburst amacrine cells both to ON DS-s and to ON DS-t ganglion cells, given the similarity of their DS responses, but further studies will be required to substantiate the origin of the DS responses of ON DS-t cells. Previously reported OFF DS responses in ON DS-t cells, unmasked by pharmacological agents, and mediated by gap junctions with amacrine cells, suggests an unusual trans sublaminar organization of directional selectivity in the inner plexiform layer, connecting sublamina a and sublamina b. PMID- 27484855 TI - High frequency of vertebral fracture and low bone quality in patients with rheumatoid arthritis-Results from TOMORROW study. AB - OBJECTIVES: Osteoporosis is one of the complications in patients with rheumatoid arthritis (RA). In this study, we researched the morbidity of existing vertebral fractures and the risk factors for vertebral fractures in patients with RA. METHODS: This study included 413 participants, 208 patients with RA, and 205 age- and sex-matched controls without RA. Clinical data, radiographic assessment of vertebral fracture from T4 to L4 in thoracic and lumber spine, bone mineral density (BMD), and bone metabolic markers (BMM) were analyzed. RESULTS: Vertebral fractures were observed more frequently, severe and multiple in patients with RA. In the logistic regression analysis, age (adjusted odds ratios (OR): 1.07, 95% confidence interval (CI): 1.04-1.09) and RA (adjusted OR: 1.72, 95% CI: 1.04 2.83) were risk factors for existing vertebral fracture. Moreover, two bone matrix-related markers, undercarboxylated osteocalcin (ucOC) (adjusted OR: 1.68, 95% CI: 1.02-2.78), and urinary pentocidine (adjusted OR: 2.51, 95% CI: 1.48 4.24) were associated with existing vertebral fracture. CONCLUSIONS: High frequent, multiple, and severe vertebral fractures were found in patients with RA compared to the controls. Low bone quality might be the cause of the frequent prevalence of vertebral fracture in patients with RA. PMID- 27484856 TI - The biplanar open wedge high tibial osteotomy preserving the tibial tubercle. AB - BACKGROUND: High tibial osteotomy (HTO) is a treatment option for relatively young patients with isolated medial compartment arthritis of the knee. Medial open wedge osteotomies allow easier control of correction, but can lead to patella infera as a result of distalization of the tibial tubercle. This retrospective study reports results of a biplanar tibial tubercle preserving HTO, designed to preserve patellar height. METHODS: The study is a retrospective analysis of 12 consecutive patients (11 men, 1 woman) average age 39.6 years who underwent the procedure between 2009 and 2012. A biplanar open wedge tibial osteotomy was performed and stabilised with a medial locking plate. Patients were allowed full weight bearing at 6 weeks. Preoperative and postoperative function was recorded on the Oxford knee score, Lysholm score and Tegner activity scale. Minimum follow up was 26 months. RESULTS: All patients had healing of the osteotomy with no delayed union. Eleven patients reported improvement in symptoms with an average preoperative Oxford score of 26 and postoperative score of 39 out of 48. The Lysholm score improved from 58 to 72 out of 100. There was one point improvement in Tegner activity scale. There was no statistical difference in patellar height before and one year after surgery. The correction in varus averaged 8.3 degrees . CONCLUSION: The biplanar High tibial Osteotomy allows preservation of patellar height, while achieving desired varus correction. PMID- 27484858 TI - Enduring sleep complaints predict health problems: a six-year follow-up of the survey of health and retirement in Europe. AB - OBJECTIVES: Sleep complaints are common and enduring among old people. The study aimed to extend current knowledge by exploring the effects of episodic versus chronic sleep complaints on a range of physical and mental health outcomes. METHODS: Older adults (N = 8934, mean age = 64) who participated in Waves 1, 2 and 4 of the Survey of Health, Ageing and Retirement in Europe (SHARE) reported sleep and health outcome measures. Episodic sleep complaints, in the first or in the second wave and chronic sleep complaints, in both waves were recorded. Outcomes in Wave 4 included physical symptoms, difficulties in activities of daily living and low quality of life. RESULTS: Logistic regressions examined whether episodic and chronic sleep complaints at W1 and W2 predict W4 health outcomes. Chronic sleep complaints predicted worse outcomes, compared to no sleep difficulties and to episodic sleep complaints, even after adjusting for demographic characteristics and previous levels of health. CONCLUSION: Sleep complaints and mainly chronic sleep complaints are related to elevated risk of future health and functional problems. Caregivers are encouraged to address sleep complaints and provide their older patients with help before sleep complaints become persistent. PMID- 27484859 TI - Online Determination of Graphene Lattice Orientation Through Lateral Forces. AB - Rapid progress in graphene engineering has called for a simple and effective method to determine the lattice orientation on graphene before tailoring graphene to the desired edge structures and shapes. In this work, a wavelet transform based frequency identification method is developed to distinguish the lattice orientation of graphene. The lattice orientation is determined through the different distribution of the frequency power spectrum just from a single scan line. This method is proven both theoretically and experimentally to be useful and controllable. The results at the atomic scale show that the frequencies vary with the lattice orientation of graphene. Thus, an adjusted angle to the desired lattice orientation (zigzag or armchair) can easily be calculated based on the frequency obtained from the single scan line. Ultimately, these results will play a critical role in wafer-size graphene engineering and in the manufacturing of graphene-based nanodevices. PMID- 27484860 TI - Influence of Thickness on the Electrical Transport Properties of Exfoliated Bi2Te3 Ultrathin Films. AB - In this work, the mechanical exfoliation method has been utilized to fabricate Bi2Te3 ultrathin films. The thickness of the ultrathin films is revealed to be several tens of nanometers. Weak antilocalization effects and Shubnikov de Haas oscillations have been observed in the magneto-transport measurements on individual films with different thickness, and the two-dimensional surface conduction plays a dominant role. The Fermi level is found to be 81 meV above the Dirac point, and the carrier mobility can reach ~6030 cm(2)/(Vs) for the 10-nm film. When the film thickness decreases from 30 to 10 nm, the Fermi level will move 8 meV far from the bulk valence band. The coefficient alpha in the Hikami Larkin-Nagaoka equation is shown to be ~0.5, manifesting that only the bottom surface of the Bi2Te3 ultrathin films takes part in transport conductions. These will pave the way for understanding thoroughly the surface transport properties of topological insulators. PMID- 27484857 TI - Finding their way: themes in germ cell migration. AB - Embryonic germ cell migration is a vital component of the germline lifecycle. The translocation of germ cells from the place of origin to the developing somatic gonad involves several processes including passive movements with underlying tissues, transepithelial migration, cell adhesion dynamics, the establishment of environmental guidance cues and the ability to sustain directed migration. How germ cells accomplish these feats in established model organisms will be discussed in this review, with a focus on recent discoveries and themes conserved across species. PMID- 27484861 TI - Induced Pluripotent Stem Cells for Disease Modeling and Evaluation of Therapeutics for Niemann-Pick Disease Type A. AB - : : Niemann-Pick disease type A (NPA) is a lysosomal storage disease caused by mutations in the SMPD1 gene that encodes acid sphingomyelinase (ASM). Deficiency in ASM function results in lysosomal accumulation of sphingomyelin and neurodegeneration. Currently, there is no effective treatment for NPA. To accelerate drug discovery for treatment of NPA, we generated induced pluripotent stem cells from two patient dermal fibroblast lines and differentiated them into neural stem cells. The NPA neural stem cells exhibit a disease phenotype of lysosomal sphingomyelin accumulation and enlarged lysosomes. By using this disease model, we also evaluated three compounds that reportedly reduced lysosomal lipid accumulation in Niemann-Pick disease type C as well as enzyme replacement therapy with ASM. We found that alpha-tocopherol, delta-tocopherol, hydroxypropyl-beta-cyclodextrin, and ASM reduced sphingomyelin accumulation and enlarged lysosomes in NPA neural stem cells. Therefore, the NPA neural stem cells possess the characteristic NPA disease phenotype that can be ameliorated by tocopherols, cyclodextrin, and ASM. Our results demonstrate the efficacies of cyclodextrin and tocopherols in the NPA cell-based model. Our data also indicate that the NPA neural stem cells can be used as a new cell-based disease model for further study of disease pathophysiology and for high-throughput screening to identify new lead compounds for drug development. SIGNIFICANCE: Currently, there is no effective treatment for Niemann-Pick disease type A (NPA). To accelerate drug discovery for treatment of NPA, NPA-induced pluripotent stem cells were generated from patient dermal fibroblasts and differentiated into neural stem cells. By using the differentiated NPA neuronal cells as a cell-based disease model system, alpha-tocopherol, delta-tocopherol, and hydroxypropyl-beta cyclodextrin significantly reduced sphingomyelin accumulation in these NPA neuronal cells. Therefore, this cell-based NPA model can be used for further study of disease pathophysiology and for high-throughput screening of compound libraries to identify lead compounds for drug development. PMID- 27484869 TI - Linking cognitive and visual perceptual decline in healthy aging: The information degradation hypothesis. AB - Several hypotheses attempt to explain the relation between cognitive and perceptual decline in aging (e.g., common-cause, sensory deprivation, cognitive load on perception, information degradation). Unfortunately, the majority of past studies examining this association have used correlational analyses, not allowing for these hypotheses to be tested sufficiently. This correlational issue is especially relevant for the information degradation hypothesis, which states that degraded perceptual signal inputs, resulting from either age-related neurobiological processes (e.g., retinal degeneration) or experimental manipulations (e.g., reduced visual contrast), lead to errors in perceptual processing, which in turn may affect non-perceptual, higher-order cognitive processes. Even though the majority of studies examining the relation between age related cognitive and perceptual decline have been correlational, we reviewed several studies demonstrating that visual manipulations affect both younger and older adults' cognitive performance, supporting the information degradation hypothesis and contradicting implications of other hypotheses (e.g., common cause, sensory deprivation, cognitive load on perception). The reviewed evidence indicates the necessity to further examine the information degradation hypothesis in order to identify mechanisms underlying age-related cognitive decline. PMID- 27484870 TI - Devices for visually impaired people: High technological devices with low user acceptance and no adaptability for children. AB - Considering that cortical plasticity is maximal in the child, why are the majority of technological devices available for visually impaired users meant for adults and not for children? Moreover, despite high technological advancements in recent years, why is there still no full user acceptance of existing sensory substitution devices? The goal of this review is to create a link between neuroscientists and engineers by opening a discussion about the direction that the development of technological devices for visually impaired people is taking. Firstly, we review works on spatial and social skills in children with visual impairments, showing that lack of vision is associated with other sensory and motor delays. Secondly, we present some of the technological solutions developed to date for visually impaired people. Doing this, we highlight the core features of these systems and discuss their limits. We also discuss the possible reasons behind the low adaptability in children. PMID- 27484871 TI - Commentary on the special issue "The Adolescent Brain": How can we run operant paradigms in a preclinical adolescent model? Technical tips and future perspectives. PMID- 27484868 TI - Consequences of adolescent use of alcohol and other drugs: Studies using rodent models. AB - Studies using animal models of adolescent exposure to alcohol, nicotine, cannabinoids, and the stimulants cocaine, 3,4-methylenedioxymethampethamine and methamphetamine have revealed a variety of persisting neural and behavioral consequences. Affected brain regions often include mesolimbic and prefrontal regions undergoing notable ontogenetic change during adolescence, although it is unclear whether this represents areas of specific vulnerability or particular scrutiny to date. Persisting alterations in forebrain systems critical for modulating reward, socioemotional processing and cognition have emerged, including apparent induction of a hyper-dopaminergic state with some drugs and/or attenuations in neurons expressing cholinergic markers. Disruptions in cognitive functions such as working memory, alterations in affect including increases in social anxiety, and mixed evidence for increases in later drug self administration has also been reported. When consequences of adolescent and adult exposure were compared, adolescents were generally found to be more vulnerable to alcohol, nicotine, and cannabinoids, but generally not to stimulants. More work is needed to determine how adolescent drug exposure influences sculpting of the adolescent brain, and provide approaches to prevent/reverse these effects. PMID- 27484872 TI - Affordance processing in segregated parieto-frontal dorsal stream sub-pathways. AB - The concept of affordances indicates "action possibilities" as characterized by object properties the environment provides to interacting organisms. Affordances relate to both perception and action and refer to sensory-motor processes emerging from goal-directed object interaction. In contrast to stable properties, affordances may vary with environmental context. A sub-classification into stable and variable affordances was proposed in the framework of the ROSSI project (Borghi et al., 2010; Borghi and Riggio, 2015, 2009). Here, we present a coordinate-based meta-analysis of functional imaging studies on object interaction targeting consistent anatomical correlates of these different types of affordances. Our review revealed the existence of two parallel (but to some extent overlapping) functional pathways. The network for stable affordances consists of predominantly left inferior parietal and frontal cortices in the ventro-dorsal stream, whereas the network for variable affordances is localized preferentially in the dorso-dorsal stream. This is in line with the proposal of differentiated affordances: stable affordances are characterized by the knowledge of invariant object features, whereas variable affordances underlie adaptation to changing object properties. PMID- 27484873 TI - Structural evolution and strength change of a metallic glass at different temperatures. AB - The structural evolution of a Zr64.13Cu15.75Ni10.12Al10 metallic glass is investigated in-situ by high-energy synchrotron X-ray radiation upon heating up to crystallization. The structural rearrangements on the atomic scale during the heating process are analysed as a function of temperature, focusing on shift of the peaks of the structure factor in reciprocal space and the pair distribution function and radial distribution function in real space which are correlated with atomic rearrangements and progressing nanocrystallization. Thermal expansion and contraction of the coordination shells is measured and correlated with the bulk coefficient of thermal expansion. The characteristics of the microstructure and the yield strength of the metallic glass at high temperature are discussed aiming to elucidate the correlation between the atomic arrangement and the mechanical properties. PMID- 27484874 TI - A robust preference for cheap-and-easy strategies over reliable strategies when verifying personal memories. AB - People depend on various sources of information when trying to verify their autobiographical memories. Yet recent research shows that people prefer to use cheap-and-easy verification strategies, even when these strategies are not reliable. We examined the robustness of this cheap strategy bias, with scenarios designed to encourage greater emphasis on source reliability. In three experiments, subjects described real (Experiments 1 and 2) or hypothetical (Experiment 3) autobiographical events, and proposed strategies they might use to verify their memories of those events. Subjects also rated the reliability, cost, and the likelihood that they would use each strategy. In line with previous work, we found that the preference for cheap information held when people described how they would verify childhood or recent memories (Experiment 1), personally important or trivial memories (Experiment 2), and even when the consequences of relying on incorrect information could be significant (Experiment 3). Taken together, our findings fit with an account of source monitoring in which the tendency to trust one's own autobiographical memories can discourage people from systematically testing or accepting strong disconfirmatory evidence. PMID- 27484875 TI - Total hip replacement: increasing femoral offset improves functional outcome. AB - INTRODUCTION: The aim of this study was to assess the independent effect of radiographic measures of implant position, relative to pre-operative anatomical assessment, on the functional outcome of total hip arthroplasty according to change in the Oxford hip score (OHS) 1 year post surgery. METHODS: A prospective cohort study was preformed to assess whether improvement in functional outcome (change in OHS at 1 year) and the relationship with femoral offset and length, and acetabular offset and height. After a power calculation 359 patients were recruited to the study and radiographic measures were performed by blinded observers. Regression analysis was used to assess the independent effect of the four radiographic measurements after adjusting for confounding variables. RESULTS: There was a significant (p < 0.001) decrease in acetabular offset [5.3 mm, 95 % confidence interval (CI) 4.4-6.2] and increase in femoral offset (6.1 mm, 95 % CI 5.4-6.8). Hence there was no significant change in overall offset. Femoral offset was the only radiographic measure to be achieved statistical significance (r = 0.198, 95 % CI 0.063-0.333, p = 0.004) in relation to clinical outcome, with increasing offset being associated with a greater improvement in the OHS. On combining femoral and acetabular offset increasing offset was associated with a greater improvement in the OHS (r = 0.10, 95 % CI 0.01-0.19, p = 0.04). CONCLUSION: This study supports the long-held biomechanical theory of medialisation of the acetabular component with compensatory increased femoral offset results in improved functional outcome. PMID- 27484876 TI - Graft position in arthroscopic anterior cruciate ligament reconstruction: anteromedial versus transtibial technique. AB - INTRODUCTION: When treating anterior cruciate ligament (ACL) injuries, the position of the ACL graft plays a key role in regaining postoperative knee function and physiologic kinematics. In this study, we aimed to compare graft angle, graft position in tibial tunnel, and tibial and femoral tunnel positions in patients operated with anteromedial (AM) and transtibial (TT) methods to those of contralateral healthy knees. MATERIALS AND METHODS: Forty-eight patients who underwent arthroscopic ACL reconstruction with ipsilateral hamstring tendon autograft were included. Of these, 23 and 25 were treated by AM and TT techniques, respectively. MRI was performed at 18.4 and 19.7 months postoperatively in AM and TT groups. Graft angles, graft positions in the tibial tunnel and alignment of tibial and femoral tunnels were noted and compared in these two groups. The sagittal graft insertion tibia midpoint distance (SGON) has been used for evaluation of graft position in tunnel. RESULTS: Sagittal ACL graft angles in operated and healthy knees of AM patients were 57.78 degrees and 46.80 degrees (p < 0.01). With respect to TT patients, ACL graft angle was 58.87 degrees and 70.04 degrees on sagittal and frontal planes in operated knees versus 47.38 degrees and 61.82 degrees in healthy knees (p < 0.001). ACL graft angle was significantly different between the groups on both sagittal and frontal planes (p < 0.001). Sagittal graft insertion tibia midpoint distance ratio was 0.51 and 0.48 % in the operated and healthy knees of AM group (p < 0.001) and 0.51 and 0.48 % in TT group (p < 0.001). Sagittal tibial tunnel midpoint distance ratio did not differ from sagittal graft insertion tibia midpoint distance of healthy knees in either group. Femoral tunnel clock position was better in AM [right knee 10:19 o'clock-face position (310 degrees +/- 4 degrees ); left knee 1:40 (50 degrees +/- 3 degrees )] compared with TT group [right knee 10:48 (324 degrees +/- 5 degrees ); left knee 1:04 (32 degrees +/- 4 degrees )]. With respect to the sagittal plane, the anterior-posterior position of femoral tunnel was better in AM patients. Lysholm scores and range of motion of operated knees in the AM and TT groups showed no significant difference (p > 0.05). CONCLUSIONS: Precise reconstruction on sagittal plane cannot be obtained with either AM or TT technique. However, AM technique is superior to TT technique in terms of anatomical graft positioning. Posterior-placed grafts in tibial tunnel prevent ACL reconstruction, although tibial tunnel is drilled on sagittal plane. PMID- 27484877 TI - Association Between Any Major Discrimination and Current Cigarette Smoking Among Adult African American Men. AB - BACKGROUND: Findings from previous research has demonstrated a positive relationship between interpersonal discrimination and cigarette smoking. Cigarette smoking is proposed to be an externalizing coping mechanism used to alleviate discrimination. At the national level, it is unclear if discrimination is associated with cigarette smoking among African American men. OBJECTIVE: The aim of the study was to examine the association between discrimination and cigarette smoking among a national sample of African American men. METHODS: Using data from the National Survey of American Life (n = 1,271), multivariable logistic regression was used to examine the relationship between discrimination and cigarette smoking. RESULTS: Thirty-two percent of the men were current smokers. Controlling for everyday discrimination, major discrimination, major stress, depressive symptoms, age, being married, household income, and education, African American men who experienced major discrimination had a higher odd of being a current smoking (odds ratio: 1.11, 95% confidence interval: 1.02-1.21) than African American men who did not experience major discrimination. Conclusion/Importance: Findings suggest that African American men may use cigarette smoking as a mechanism to alleviate the experiences of discrimination. Future studies should continue to examine factors associated with African American men's smoking behavior in efforts to inform culturally relevant interventions. PMID- 27484879 TI - Treatment of early-stage human epidermal growth factor 2-positive cancers among medicare enrollees: age and race strongly associated with non-use of trastuzumab. AB - Adjuvant trastuzumab for human epidermal growth factor receptor-2 (HER2)-positive breast cancer is highly efficacious regardless of age. Recent data suggested that many older patients with HER2-positive disease do not receive adjuvant trastuzumab. Nevertheless, some of this 'under-treatment' may be clinically appropriate. We used Surveillance, Epidemiology and End Results (SEER)-Medicare data to identify patients aged >= 66 with stage >= Ib-III, HER2-positive breast cancer diagnosed during 2010-2011 (HER2 status available) who did not have a history of congestive heart failure. We described all systemic treatments received and sociodemographic and clinical characteristics associated with treatment patterns. Among 770 women 44.4 % did not receive trastuzumab, including 21.8 % who received endocrine therapy only, 6.3 % who received chemotherapy (+/ endocrine therapy) and 16.2 % who did not receive any systemic therapy. In addition to age and grade, race was strongly associated with non-use of trastuzumab (64.4 % of Non-Hispanic blacks vs. 43.6 % of whites did not receive trastuzumab, adjusted ORNon-Hispanic black vs. white = 3.14, 95 %CI = 1.38-7.17), and many patients with stage III disease did not receive trastuzumab. Further, 16.2 % of patients did not receive any systemic treatment and this occurred more frequently for black patients. Over 40 % of older patients with indication to receive adjuvant trastuzumab did not receive it and nearly 20 % of these patients did not receive any other treatment. Although treatment omission may be appropriate in some cases, we observed concerning differences in trastuzumab receipt, particularly for black women. Strategies to optimize care for older patients and to eliminate treatment disparities are urgently needed. PMID- 27484878 TI - Brainstem Monitoring in the Neurocritical Care Unit: A Rationale for Real-Time, Automated Neurophysiological Monitoring. AB - Patients with severe traumatic brain injury or large intracranial space-occupying lesions (spontaneous cerebral hemorrhage, infarction, or tumor) commonly present to the neurocritical care unit with an altered mental status. Many experience progressive stupor and coma from mass effects and transtentorial brain herniation compromising the ascending arousal (reticular activating) system. Yet, little progress has been made in the practicality of bedside, noninvasive, real-time, automated, neurophysiological brainstem, or cerebral hemispheric monitoring. In this critical review, we discuss the ascending arousal system, brain herniation, and shortcomings of our current management including the neurological exam, intracranial pressure monitoring, and neuroimaging. We present a rationale for the development of nurse-friendly-continuous, automated, and alarmed-evoked potential monitoring, based upon the clinical and experimental literature, advances in the prognostication of cerebral anoxia, and intraoperative neurophysiological monitoring. PMID- 27484880 TI - A pooled analysis of CYP2D6 genotype in breast cancer prevention trials of low dose tamoxifen. AB - Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We examined the impact of CYP2D6 genotype on tamoxifen pharmacokinetics, biomarker activity, and efficacy in a pooled analysis of low dose tamoxifen. Four randomized breast cancer prevention trials of very-low-dose (1 mg/day, n = 52 or 10 mg/week, n = 152) or low-dose tamoxifen (5 mg/day, n = 171) were pooled. DNA from 367 subjects was genotyped for CYP2D6 alleles associated with absent (PM allele: *3, *4, *5, *6, *7, *8, *12, and *14), reduced (IM allele: *9, *10, *17, *29, *41), normal (EM allele), or increased (UM: *XN) enzyme activity. Associations of tamoxifen, metabolites, activity biomarkers, and event-free survival with rapid (UM/EM, UM/IM, EM/EM, EM/IM, or EM/PM alleles) versus slow metabolizers (PM/IM or PM/PM) were investigated through random effects models, with 'study' as the random factor, and Cox regression models, adjusting for confounders. Rapid metabolizers had higher endoxifen levels than slow metabolizers: 15.3 versus 12.2 ng/mL (P = 0.018) with 5 mg/day, and 3.8 versus 2.8 ng/mL (P = 0.004) with 1 mg/day or 10 mg/week tamoxifen. The IGF-I decrease correlated with endoxifen (P = 0.002) and 4-hydroxytamoxifen levels, demonstrating steeper decreases at higher metabolite levels (P = 0.001). After a median follow-up of 12 years, rapid metabolizers with prior history of breast neoplasms allocated to tamoxifen 5 mg/day had a 60 % reduction of risk of recurrences (HR = 0.40, 95 % CI: 0.16-0.99) compared to slow metabolizers. CYP2D6 genotype may have an impact on tamoxifen efficacy at low doses. Trials investigating tamoxifen dose adjustments based on the woman's hormonal context and CYP2D6 genotype are warranted. PMID- 27484882 TI - New Insights into the Reliability of Automatic Dynamic Methods for Oral Bioaccessibility Testing: A Case Study for BGS102 soil. AB - Dynamic flow-through extraction is attracting a great deal of attention for real time monitoring of the bioaccessible fraction of metal species in environmental solid substrates compared to its batchwise manual counterparts. There is however a lack of studies on the harmonization and validation of in vitro dynamic methods for physiologically based extraction tests against in vivo bioavailability methods. This work is aimed at evaluating the reliability of dynamic flow-through extraction methods for estimation of oral bioaccessible fractions of Cu, Zn, Pb, Ni, Cr, and As under worst-case extraction conditions in the gastric compartment based on the BGS102 guidance soil using the in vivo validated Unified BARGE (UBM) test, commonly performed under batchwise mode. Good overall agreement between batch and dynamic UBM results was obtained for the tested elements, except for Pb, as a consequence of the slow leaching kinetics identified with the dynamic method and the contribution of readsorption phenomena in the course of the gastric digestion. Metal-soil phase associations and their relationship with gastric bioaccessible fractions were elucidated using the so-called Chemometric Identification of Substrates and Element Distributions method based on sequential extraction with a variety of chemicals of increasing acidity as applied to both static and dynamic bioaccessibility data. PMID- 27484881 TI - Higher Activities of Defense-Associated Enzymes may Contribute to Greater Resistance of Manchurian Ash to Emerald Ash Borer Than A closely Related and Susceptible Congener. AB - Emerald ash borer (EAB) is an invasive beetle native to Asia that infests and kills ash (Fraxinus spp.) in North America. Previous experiments indicated that larvae feeding on co-evolved, resistant Manchurian ash (F. mandshurica) have increased antioxidant and quinone-protective enzyme activities compared to larvae feeding on susceptible North American species. Here, we examined mechanisms of host-generated oxidative and quinone-based stress and other putative defenses in Manchurian ash and the closely related and chemically similar, but susceptible, black ash (F. nigra), with and without exogenous application of methyl jasmonate (MeJA) to induce resistance mechanisms. Peroxidase activities were 4.6-13.3 times higher in Manchurian than black ash, although both species appeared to express the same three peroxidase isozymes. Additionally, peroxidase-mediated protein cross-linking activity was stronger in Manchurian ash. Polyphenol oxidase, beta glucosidase, chitinase, and lipoxygenase activities also were greater in Manchurian ash, but only lipoxygenase activity increased with MeJA application. Phloem H2O2 levels were similar and were increased by MeJA application in both species. Lastly, trypsin inhibitor activity was detected in methanol and water extracts that were not allowed to oxidize, indicating the presence of phenolic based trypsin inhibitors. However, no proteinaceous trypsin inhibitor activity was detected in either species. In response to MeJA application, Manchurian ash had higher trypsin inhibitor activity than black ash using the unoxidized water extracts, but no treatment effects were detected using methanol extracts. Based on these results we hypothesize that peroxidases, lignin polymerization, and quinone generation contribute to the greater resistance to EAB displayed by Manchurian ash. PMID- 27484883 TI - Curcumin alleviates ischemia reperfusion-induced acute kidney injury through NMDA receptor antagonism in rats. AB - OBJECTIVE: The present study investigated the role of N-methyl-d-aspartate (NMDA) receptors in curcumin-mediated renoprotection against ischemia reperfusion (I/R) induced acute kidney injury (AKI) in rats. METHODS: Rats were subjected to bilateral renal I/R (40 min I, 24 hours R) to induce AKI. Kidney injury was assessed by measuring creatinine clearance, blood urea nitrogen, plasma uric acid, potassium level, fractional excretion of sodium, and macroproteinuria. Oxidative stress in renal tissues was assessed by measuring myeloperoxidase activity, thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione content. Hematoxylin & eosin staining was done to assess histological changes in renal tissues. Curcumin (30 and 60 mg/kg) was administered one hour before subjecting rats to AKI. In separate groups, NMDA receptor agonists, glutamic acid (200 mg/kg), and spermidine (20 mg/kg) were administered prior to curcumin treatment in rats followed by AKI. RESULTS: I/R induced AKI was demonstrated by significant change in plasma and urine parameters along with marked increase in oxidative stress and histological changes in renal tissues that were aggravated with pretreatment of glutamic acid and spermidine in rats. Administration of curcumin resulted in significant protection against AKI. However, glutamic acid and spermidine pretreatments prevented curcumin-mediated renoprotection. CONCLUSION: It is concluded that NMDA receptor antagonism significantly contributes towards curcumin-mediated protection against I/R induced AKI. PMID- 27484884 TI - One-dimensional self-assembly of perylene-diimide dyes by unidirectional transit of zeolite channel openings. AB - Confined supramolecular architectures of chromophores are key components in artificial antenna composites for solar energy harvesting and storage. A typical fabrication process, based on the insertion of dye molecules into zeolite channels, is still unknown at the molecular level. We show that slipping of perylene diimide dyes into the one-dimensional channels of zeolite L and travelling inside is only possible because of steric-interaction-induced cooperative vibrational modes of the host and the guest. The funnel-like structure of the channel opening, larger at the entrance, along with a directionally asymmetric entrance-exit probability, ensures a favorable self assembly process of the perylene units. PMID- 27484885 TI - SUMO wrestles breaks to the nuclear ring's edge. PMID- 27484886 TI - A putative adenosine kinase family protein possesses adenosine diphosphatase activity. AB - Adenosine kinase is a potential target for development of new types of drugs. The COG1839 family has been defined as "adenosine-specific kinase" family based on structural analysis and the adenosine-binding ability of a family member, PAE2307. However, there has been no experimental evidence with regard to the enzymatic function of this protein family. Here we measured the enzymatic activity of TTHA1091, a COG1839 family protein from Thermus thermophilus HB8. The phosphorylation of adenosine by TTHA1091 was undetectable when ATP or ADP were used as phosphate donor. However, the degradation of ADP to AMP was detected, indicating that this protein possessed adenosine diphosphatase (ADPase) activity. The (ADPase) activity was inhibited by divalent cations and was specific to ADP and CDP. Thus, this study provides the first experimental evidence for the enzymatic function of the "adenosine-specific kinase" family and suggests a need to reexamine its functional annotation. PMID- 27484887 TI - Sugammadex facilitates early recovery after surgery even in the absence of neuromuscular monitoring in patients undergoing laryngeal microsurgery: a single center retrospective study. AB - BACKGROUND: In many countries, routine clinical anaesthesia does not always involve neuromuscular monitoring. In these clinical settings, the efficacy and safety of sugammadex use has not yet been confirmed. We investigated the efficacy and safety of sugammadex in the absence of neuromuscular monitoring. METHODS: One hundred and forty patients who underwent laryngeal microsurgery with the use of rocuronium as a neuromuscular blocking agent, without the use of a neuromuscular monitoring device, were retrospectively investigated. The patients were randomly chosen among all the patients who met the inclusion criteria at a tertiary university hospital between July 2013 and February 2015 and were allocated to group S (sugammadex group) or group P (pyridostigmine group) according to the neuromuscular reversal agent administered. Five patients were excluded from analysis and 135 patients completed the study. Primary outcome was extubation time. Secondary outcomes were anaesthesia time, the correlation between anaesthesia time and extubation time, the total amount of rocuronium, and postoperative adverse events in the post-anaesthesia care unit (PACU). RESULTS: Extubation time was significantly shorter in group S (6.3 +/- 3.9 min) than in group P (9.0 +/- 5.4 min). Anaesthesia time was also significantly shorter in group S (30.7 +/- 10.3 min) than in group P (35.8 +/- 12.6 min). In the patients with an anaesthesia time of 30 min or less, there was a positive correlation between anaesthesia time and extubation time in group P (r = 0.453), but there was no significant relationship in group S. The total amount of rocuronium used was higher in group S (0.62 +/- 0.11 mg kg(-1)) than in group P (0.38 +/- 0.14 mg kg(-1)). Postoperative adverse events in the PACU were comparable between the groups, except for tachycardia events: the incidence of tachycardia was significantly lower in group S (8.0 %) than in group P (17.3 %). CONCLUSIONS: Sugammadex could shorten anaesthesia and extubation times as well as recovery time in the PACU and reduce postoperative hemodynamic complications in a clinical setting in the absence of neuromuscular monitoring. This may enhance the patients' recovery in the operating room and PACU while improving the postoperative condition of patients. TRIAL REGISTRATION: The trial was registered in the UMIN clinical trials registry ( www.umin.ac.jp/ctr/index/htm ; unique trial number: UMIN000016602; registration number: R000019266 ; principal investigator's name: Byung Gun Lim; date of registration: February 22, 2015). PMID- 27484888 TI - [Is stress cardiovascular magnetic resonance really useful to detect ischemia and predict events in patients with different cardiovascular risk profile?] AB - OBJECTIVE: The aim of this study was to evaluate the diagnostic and prognostic usefulness of stress cardiovascular magnetic resonance (stress CMR) in patients with different cardiovascular risk profile and to assess if the degree of hypoperfusion is important to guide clinical decisions. METHOD: We included patients submitted to adenosine stress CMR to rule out myocardial ischemia. We evaluated its diagnostic accuracy with likelihood ratio (LR) and its prognostic value with survival curves and a Cox regression model. RESULTS: 295 patients were studied. The positive LR was 3.40 and the negative one 0.47. The maximal usefulness of the test was found in patients without previous ischemic cardiomyopathy (positive LR 4.85), patients with atypical chest pain (positive LR 8.56), patients with low or intermediate cardiovascular risk (positive LR 3.87) and those with moderate or severe hypoperfusion (positive LR 8.63). Sixty cardiovascular major events were registered. The best survival prognosis was found in patients with a negative result (p=0.001) or mild hypoperfusion (p=0.038). In the multivariate analysis, a moderate or severe hypoperfusion increased cardiovascular event probability (HR=2.2; IC 95% 1.26-3.92), with no differences between a mild positive and a negative result (HR=0.93; IC 95% 0.38 2.28). CONCLUSIONS: Stress CMR was specially useful in patients with low or intermediate cardiovascular risk, patients with atypical chest pain, patients without previous ischemic cardiomyopathy and those with moderate or severe hypoperfusion. Hypoperfusion degree was the main issue factor to guide clinical decisions. PMID- 27484889 TI - Development of a Novel Reverse Transcription Loop-Mediated Isothermal Amplification Assay for the Rapid Detection of African Horse Sickness Virus. AB - African horse sickness (AHS) is a disease of equids caused by African Horse Sickness Virus (AHSV) and is transmitted by Culicoides midges. AHS is endemic in sub-Saharan Africa, but during the past century, outbreaks of significant economic importance and elevated mortality have been recorded in Northern African countries, the Iberian and Arabian Peninsula, the Middle East and the Indian subcontinent. Effective control combines the application of early warning systems, accurate laboratory diagnosis and reporting, animal movement restrictions, suitable vaccination and surveillance programs, and the coordination of all these measures by efficient veterinary services. Conventional reverse-transcriptase (RT) PCR (RT-PCR) and real-time RT-PCR (rRT-PCR) assays have improved the sensitivity and rapidity of diagnosing AHS, resulting in the adoption of these methods as recommended tests by the World Organisation for Animal Health (OIE). However, currently these assays are only performed within laboratory settings; therefore, the development of field diagnostics for AHS would improve the fast implementation of control policies. Loop-mediated isothermal amplification (LAMP) is an isothermal, autocycling, strand displacement nucleic acid amplification technique which can be performed in the field. LAMP assays are attractive molecular assays because they are simple to use, rapid, portable and have sensitivity and specificity within the range of rRT PCR. This study describes the development of a novel RT-LAMP assay for the detection of AHSV. The AHSV RT-LAMP assay has an analytical sensitivity of 96.1% when considering an rRT-PCR cut-off value of CT > 36, or 91.3% when no rRT-PCR cut-off is applied. Diagnostic sensitivity and specificity were 100%. This assay provides for a rapid and low cost AHS diagnostic for use in the field. PMID- 27484890 TI - Dilatation of the initially non-aneurysmal ascending aorta after replacement of a bicuspid versus tricuspid aortic valve. AB - Objective To compare the aortic diameter after isolated aortic valve replacement (AVR) in patients with a bicuspid (BAV) or tricuspid aortic valve (TAV) and an initially normal ascending aorta. Methods Patients with an ascending aortic diameter of < 45 mm who had undergone isolated AVR were studied. Ultrasonic cardiographic measurements of the ascending aortic diameter made pre- and postoperatively and follow-up data concerning adverse aortic events and death were analyzed. Results A total of 613 patients were included in this retrospective study; of these, 211 had a BAV and 402 had a TAV. In both groups, the ascending aorta significantly expanded but was non-aneurysmal during follow up; however, the difference between the two groups was not significant. Cox regression analysis showed no significant effect associated with the presence of a BAV on adverse aortic events or death. Conclusion Dilatation of the ascending aorta was observed after AVR in both groups, but was not more pronounced in patients with a BAV. Long-term follow-up for ascending aortic aneurysm is necessary after AVR in both patients with a BAV and those with a TAV. PMID- 27484891 TI - Parents' assessment of circadian preference in elementary school-aged children: Validity and relations to educational outcomes. AB - Meta-analyses suggest that morning-oriented students obtain better school grades than evening-oriented students. This finding has generally been found for students in high school using self-report data for the assessment of circadian preference. Two studies (N = 2718/192) investigated whether these findings generalize across samples (i.e. elementary school-aged students) and methods (i.e. parent reports). These studies also explored whether the relation between circadian preference and school achievement could be explained within an expectancy-value framework. To this end, the Lark-Owl Chronotype Indicator (LOCI) was modified to obtain parents' evaluations of their children's circadian preference, while students completed a battery of assessments designed to explore the test-criterion evidence. Structural equation modeling and correlational analyses revealed: (1) morning and evening orientation were two separable factors of children's circadian preference; (2) correlations with behavioral (e.g. sleep and eating times) and psychological (e.g. cognitive ability) data supported the test-criterion validity of both factors; (3) morning orientation was positively related to school achievement and (4) consistent with an expectancy-value framework this relation was mediated by children's academic self-concept (ASC). These findings have important research and policy implications for considering circadian preference in the schooling of elementary students. PMID- 27484892 TI - Spin excitations in systems with hopping electron transport and strong position disorder in a large magnetic field. AB - We discuss the spin excitations in systems with hopping electron conduction and strong position disorder. We focus on the problem in a strong magnetic field when the spin Hamiltonian can be reduced to the effective single-particle Hamiltonian and treated with conventional numerical technics. It is shown that in a 3D system with Heisenberg exchange interaction the spin excitations have a delocalized part of the spectrum even in the limit of strong disorder, thus leading to the possibility of the coherent spin transport. The spin transport provided by the delocalized excitations can be described by a diffusion coefficient. Non homogenous magnetic fields lead to the Anderson localization of spin excitations while anisotropy of the exchange interaction results in the Lifshitz localization of excitations. We discuss the possible effect of the additional exchange-driven spin diffusion on the organic spin-valve devices. PMID- 27484893 TI - Chaperone mediated autophagy in aging: Starve to prosper. AB - The major lysosomal proteolytic pathways essential for maintaining proper cellular homeostasis are macroautophagy, chaperone-mediated autophagy (CMA) and microautophagy. What differentiates CMA from the other types of autophagy is the fact that it does not involve vesicle formation; the unique feature of this pathway is the selective targeting of substrate proteins containing a CMA targeting motif and the direct translocation into the lysosomal lumen, through the aid of chaperones/co-chaperones localized both at the cytosol and the lysosomes. CMA operates at basal conditions in most mammalian cell models analyzed so far, but it is mostly activated in response to stressors, such as trophic deprivation or oxidative stress. The activity of CMA has been shown to decline with age and such decline, correlating with accumulation of damaged/oxidized/aggregated proteins, may contribute to tissue dysfunction and, possibly, neurodegeneration. Herein, we review the recent knowledge regarding the molecular components, regulation and physiology of the CMA pathway, the contribution of impaired CMA activity to poor cellular homeostasis and inefficient response to stress during aging, and discuss the therapeutic opportunities offered by the restoration of CMA-dependent proteolysis in age associated degenerative diseases. PMID- 27484894 TI - Cerebral circulation in aging. AB - Cerebral circulation is known to be protected by the regulatory function against the hypoperfusion that will affect the cognitive function as a result of brain ischemia and energy failure. The regulatory function includes cerebrovascular autoregulation, chemical control, metabolic control, and neurogenic control, and those compensatory mechanisms can be influenced by hypertension, atherosclerosis, cardiac diseases, cerebrovascular diseases and aging. On the other hand, large and/or small infarction, intracranial hemorrhage, subarachnoid hemorrhage, atherosclerosis, amylod angiopathy are also more directly associated with cognitive decline not only in those with vascular cognitive impairment or vascular dementia but also those with Alzheimer's disease. PMID- 27484895 TI - Testing patient targeted therapies in patients with temporomandibular joint disorder with the arthrokinetic reflex: individual patient research. AB - Traditional research in the health sciences has involved control and experimental groups of patients, and descriptive and inferential statistical analyses performed on the measurements obtained from the samples in each group. As the novel model of translational healthcare, which integrates translational research and translational effectiveness, becomes increasingly established in modern contemporary medicine, healthcare continues to evolve into a model of care that is evidence-based, effectiveness-focused and patient-centered. Patient-centered care and patient-targeted therapies require the timely and critical development and validation of a new research paradigm, individual patient research (IPR), as opposed to the customary group research approach. Here, we propose a model of individual patient research to define and characterize the effectiveness of a novel therapeutic intervention for temporomandibular joint disorder. The intervention must be tailor-made for each individual patient, and the data from each patient must be analyzed individually. We propose that this endeavor is best achieved by means of an adaptive cluster randomized stepped wedge blinded controlled trial, because it permit individual patient outcomes research and analysis, ensures equipoise, and maintains adequate power. The patient targeted therapies section of the Journal of Translational Medicine must endeavor to facilitate the dissemination of studies that focus broadly on translational research for the ultimate benefit of individual patients. PMID- 27484897 TI - Giant spin-phonon bottleneck effects in evaporable vanadyl-based molecules with long spin coherence. AB - Vanadium(iv) complexes have recently shown record quantum spin coherence times that in several circumstances are limited by spin-lattice relaxation. The role of the environment and vibronic properties in the low temperature dynamics is here investigated by a comparative study of the magnetization dynamics as a function of crystallite size and the steric hindrance of the beta-diketonate ligands in VO(acac)2 (1), VO(dpm)2 (2) and VO(dbm)2 (3) evaporable complexes (acac- = acetylacetonate, dpm- = dipivaloylmethanate, and dbm- = dibenzoylmethanate). A pronounced crystallite size dependence of the relaxation time is observed at unusually high temperatures (up to 40 K), which is associated with a giant spin phonon bottleneck effect. We model this behaviour by an ad hoc force field approach derived from density functional theory calculations, which evidences a correlation of the intensity of the phenomenon with ligand dimensions and the unit cell size. PMID- 27484896 TI - LncRNA HOTAIR controls the expression of Rab22a by sponging miR-373 in ovarian cancer. AB - Increasing evidence suggests that the long non-coding RNA, HOX transcript antisense intergenic RNA (HOTAIR) is widely involved in the progression and metastasis of cancer. However, the specific role of HOTAIR in ovarian carcinogenesis remains to be fully elucidated. In the present study, the levels of HOTAIR were detected in 30 paired cancer and noncancer tissues using reverse transcription-quantitative polymerase chain reaction analysis. The effect of HOTAIR on the ovarian cancer cells was examined by overexpression or small interfering RNA interference experiments. To examine the competitive endogenous RNA (ceRNAs) mechanism, a luciferase reporter assay was used. In patients with ovarian cancer, HOTAIR was significantly upregulated. Furthermore, the upregulation of HOTAIR increased the proliferation, migration and invasion of ovarian cancer cells. By contrast, the knockdown of HOTAIR repressed cell invasion and viability. HOTAIR functioned as a ceRNA, and acted as a sink for microRNA (miR)-373, thereby regulating the expression of Rab22a. The upregulation of HOTAIR contributed to the malignant progression of ovarian cancer cells. Therefore, the positive regulation between HOTAIR and Rab22a can be partially attributed to the ceRNA regulatory network through miR-373. PMID- 27484898 TI - Amitraz and its metabolite differentially activate alpha- and beta-adrenergic like octopamine receptors. AB - BACKGROUND: Amitraz is a formamidine acaricide and insecticide used to control ticks, mites and fleas. N2 -(2,4-Dimethylphenyl)-N1 -methyformamidine (DPMF), a metabolite of amitraz, is thought to be an active agent that exerts acaricidal and insecticidal effects by acting as an agonist on octopamine receptors. The emergence of cattle ticks resistant to amitraz is a serious problem that requires urgent attention. The objective of this research was to determine which type of octopamine receptor is the primary target of amitraz and thereby understand the molecular mechanisms of action and resistance to amitraz. RESULTS: Amitraz and DPMF potently activated Bombyx mori alpha- and beta-adrenergic-like octopamine receptors (alpha- and beta-AL OARs) that were stably expressed in HEK-293 cells. Notably, DPMF elevated intracellular cAMP levels, with an EC50 of 79.6 pm in beta AL OARs, the transcripts of which were prevalently and widely localised in B. mori body parts. Furthermore, DPMF elevated the intracellular Ca2+ levels, with an EC50 of 1.17 nm in alpha-AL OARs. CONCLUSION: Although both amitraz and DPMF acted as OAR agonists, the metabolite DPMF was more potent than amitraz and differentially activated alpha- and beta-AL OARs. The present findings provide a basis for studies to examine the mechanism of amitraz resistance and to develop novel acaricides and insecticides. (c) 2016 Society of Chemical Industry. PMID- 27484900 TI - Chemotherapy and radiation therapy elicits tumor specific T cell responses in a breast cancer patient. AB - BACKGROUND: Experimental evidence and clinical studies in breast cancer suggest that some anti-tumor therapy regimens generate stimulation of the immune system that accounts for tumor clinical responses, however, demonstration of the immunostimulatory power of these therapies on cancer patients continues to be a formidable challenge. Here we present experimental evidence from a breast cancer patient with complete clinical response after 7 years, associated with responsiveness of tumor specific T cells. METHODS: T cells were obtained before and after anti-tumor therapy from peripheral blood of a 63-years old woman diagnosed with ductal breast cancer (HER2/neu+++, ER-, PR-, HLA-A*02:01) treated with surgery, followed by paclitaxel, trastuzumab (suspended due to cardiac toxicity), and radiotherapy. We obtained a leukapheresis before surgery and after 8 months of treatment. Using in vitro cell cultures stimulated with autologous monocyte-derived dendritic cells (DCs) that produce high levels of IL-12, we characterize by flow cytometry the phenotype of tumor associated antigens (TAAs) HER2/neu and NY-ESO 1 specific T cells. The ex vivo analysis of the TCR-Vbeta repertoire of TAA specific T cells in blood and Tumor Infiltrating Lymphocytes (TILs) were performed in order to correlate both repertoires prior and after therapy. RESULTS: We evidence a functional recovery of T cell responsiveness to polyclonal stimuli and expansion of TAAs specific CD8+ T cells using peptide pulsed DCs, with an increase of CTLA-4 and memory effector phenotype after anti tumor therapy. The ex vivo analysis of the TCR-Vbeta repertoire of TAA specific T cells in blood and TILs showed that whereas the TCR-Vbeta04-02 clonotype is highly expressed in TILs the HER2/neu specific T cells are expressed mainly in blood after therapy, suggesting that this particular TCR was selectively enriched in blood after anti-tumor therapy. CONCLUSIONS: Our results show the benefits of anti-tumor therapy in a breast cancer patient with clinical complete response in two ways, by restoring the responsiveness of T cells by increasing the frequency and activation in peripheral blood of tumor specific T cells present in the tumor before therapy. PMID- 27484899 TI - BRG1 interacts with GLI2 and binds Mef2c gene in a hedgehog signalling dependent manner during in vitro cardiomyogenesis. AB - BACKGROUND: The Hedgehog (HH) signalling pathway regulates cardiomyogenesis in vivo and in differentiating P19 embryonal carcinoma (EC) cells, a mouse embryonic stem (mES) cell model. To further assess the transcriptional role of HH signalling during cardiomyogenesis in stem cells, we studied the effects of overexpressing GLI2, a primary transducer of the HH signalling pathway, in mES cells. RESULTS: Stable GLI2 overexpression resulted in an enhancement of cardiac progenitor-enriched genes, Mef2c, Nkx2-5, and Tbx5 during mES cell differentiation. In contrast, pharmacological blockade of the HH pathway in mES cells resulted in lower expression of these genes. Mass spectrometric analysis identified the chromatin remodelling factor BRG1 as a protein which co immunoprecipitates with GLI2 in differentiating mES cells. We then determined that BRG1 is recruited to a GLI2-specific Mef2c gene element in a HH signalling dependent manner during cardiomyogenesis in P19 EC cells, a mES cell model. CONCLUSIONS: Thus, we propose a mechanism where HH/GLI2 regulates the expression of Mef2c by recruiting BRG1 to the Mef2c gene, most probably via chromatin remodelling, to ultimately regulate in vitro cardiomyogenesis. PMID- 27484902 TI - Identification of endoplasmic reticulum-shaping proteins in Plasmodium parasites. PMID- 27484901 TI - Motor neuron-derived Thsd7a is essential for zebrafish vascular development via the Notch-dll4 signaling pathway. AB - BACKGROUND: Development of neural and vascular systems displays astonishing similarities among vertebrates. This parallelism is under a precise control of complex guidance signals and neurovascular interactions. Previously, our group identified a highly conserved neural protein called thrombospondin type I domain containing 7A (THSD7A). Soluble THSD7A promoted and guided endothelial cell migration, tube formation and sprouting. In addition, we showed that thsd7a could be detected in the nervous system and was required for intersegmental vessels (ISV) patterning during zebrafish development. However, the exact origin of THSD7A and its effect on neurovascular interaction remains unclear. RESULTS: In this study, we discovered that zebrafish thsd7a was expressed in the primary motor neurons. Knockdown of Thsd7a disrupted normal primary motor neuron formation and ISV sprouting in the Tg(kdr:EGFP/mnx1:TagRFP) double transgenic zebrafish. Interestingly, we found that Thsd7a morphants displayed distinct phenotypes that are very similar to the loss of Notch-delta like 4 (dll4) signaling. Transcript profiling further revealed that expression levels of notch1b and its downstream targets, vegfr2/3 and nrarpb, were down-regulated in the Thsd7a morphants. These data supported that zebrafish Thsd7a could regulate angiogenic sprouting via Notch-dll4 signaling during development. CONCLUSIONS: Our results suggested that motor neuron-derived Thsd7a plays a significant role in neurovascular interactions. Thsd7a could regulate ISV angiogenesis via Notch dll4 signaling. Thus, Thsd7a is a potent angioneurin involved in the development of both neural and vascular systems. PMID- 27484903 TI - Beyond the classroom lecture: Liang Wang's personal war on tuberculosis in China. PMID- 27484904 TI - Elimination of the geomagnetic field stimulates the proliferation of mouse neural progenitor and stem cells. AB - Living organisms are exposed to the geomagnetic field (GMF) throughout their lifespan. Elimination of the GMF, resulting in a hypogeomagnetic field (HMF), leads to central nervous system dysfunction and abnormal development in animals. However, the cellular mechanisms underlying these effects have not been identified so far. Here, we show that exposure to an HMF (<200 nT), produced by a magnetic field shielding chamber, promotes the proliferation of neural progenitor/stem cells (NPCs/NSCs) from C57BL/6 mice. Following seven-day HMF exposure, the primary neurospheres (NSs) were significantly larger in size, and twice more NPCs/NSCs were harvested from neonatal NSs, when compared to the GMF controls. The self-renewal capacity and multipotency of the NSs were maintained, as HMF-exposed NSs were positive for NSC markers (Nestin and Sox2), and could differentiate into neurons and astrocyte/glial cells and be passaged continuously. In addition, adult mice exposed to the HMF for one month were observed to have a greater number of proliferative cells in the subventricular zone. These findings indicate that continuous HMF-exposure increases the proliferation of NPCs/NSCs, in vitro and in vivo. HMF-disturbed NPCs/NSCs production probably affects brain development and function, which provides a novel clue for elucidating the cellular mechanisms of the bio-HMF response. PMID- 27484905 TI - The effect of door-to-balloon delay in primary percutaneous coronary intervention on clinical outcomes of STEMI: a systematic review and meta-analysis protocol. AB - BACKGROUND: Acute myocardial infarction (AMI) is a medical emergency in which sudden occlusion of coronary artery(ies) results in ischemia and necrosis of the cardiac tissues. Reperfusion therapies that aim at reopening the occluded artery remain the mainstay of treatment for AMI. Primary percutaneous coronary intervention (PCI), which enables the restoration of blood flow by reopening the occluded artery(ies) via a catheter with an inflatable balloon, is currently the preferred treatment for AMI with ST segment elevation (STEMI). The door-to balloon (D2B) delay refers to the time interval counting from the arrival of a patient with STEMI at a hospital to the time of the balloon inflation (or stent deployment) that reopens the occluded artery(ies). Reducing this delay in primary PCI is thought to be an important strategy toward achieving better patient outcomes. Unfortunately, significant reduction of D2B delay in the USA over the last decade has not been shown to be associated with improved STEMI mortality. It has been suggested that the lack of impact could be due to the expanding use of primary PCI in STEMI as well as the survival cohort effect, leading to a shift toward a higher risk population receiving the procedure. Others have suggested that reduction in D2B delay may not be as impactful as expected, given that it only represents a small fraction of the total ischemic time. Although most existing evidence have pointed to the presence of a beneficial effect of shorter D2B delay, some inconsistencies however exist. This study aims to synthesize available evidence in order to answer the following questions: (1) what is the overall effect of D2B delay on clinical outcomes in patients with STEMI treated with primary PCI? (2) What factors explain the differences of the effect estimates among the studies? (3) What are the important strength and limitation of the existing body of evidence? METHOD: We will search PubMed/MEDLINE, EMBASE, ClinicalTrials.gov, WHO International Clinical Trials Registry, CINAHL Database, and the Cochrane Library using a predefined search strategy. Other sources of literature will include proceedings from the European Society of Cardiology, the American College of Cardiology, the American Heart Association, the EUROPCR, and the ProQuest Dissertations and Theses Database. We will include data from observational studies (case-control and cohort study design) and randomized control trials (that have investigated the relationship of D2B time and clinical outcome(s) in an adult (older than 18) STEMI population). Mortality (cardiac related and all-cause) and incidence heart failure (HF) have been prioritized as the primary outcomes. All eligible studies will be assessed for risk of bias using the Risk Of Bias in Non-randomized Studies - of Interventions tool. The Grading of Recommendations, Assessment, and Evaluation (GRADE) framework will be used to report the quality of evidence and strength of recommendations. We will proceed to analyze the data quantitatively if the pre-specified conditions are satisfied. DISCUSSION: Recent discussion on the negative findings of improved D2B delay over time being unrelated to better STEMI outcomes at the population level has reminded us of an important knowledge gap we have on this domain. This systematic review will serve to address some of these key questions not previously examined. Answers to these questions could clarify the controversies and offer empirical support for or against the suggested hypotheses. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015026069. PMID- 27484906 TI - MicroRNA-203 As a Stemness Inhibitor of Glioblastoma Stem Cells. AB - Glioblastoma stem cells (GBM-SCs) are believed to be a subpopulation within all glioblastoma (GBM) cells that are in large part responsible for tumor growth and the high grade of therapeutic resistance that is so characteristic of GBM. MicroRNAs (miR) have been implicated in regulating the expression of oncogenes and tumor suppressor genes in cancer stem cells, including GBM-SCs, and they are a potential target for cancer therapy. In the current study, miR-203 expression was reduced in CD133(+) GBM-SCs derived from six human GBM biopsies. MicroRNA-203 transfected GBM-SCs had reduced capacity for self-renewal in the cell sphere assay and increased expression of glial and neuronal differentiation markers. In addition, a reduced proliferation rate and an increased rate of apoptosis were observed. Therefore, miR-203 has the potential to reduce features of stemness, specifically in GBM-SCs, and is a logical target for GBM gene therapy. PMID- 27484907 TI - Epigenetic and Glucocorticoid Receptor-Mediated Regulation of Glutathione Peroxidase 3 in Lung Cancer Cells. AB - Glutathione peroxidase 3 (GPx3), an antioxidant enzyme, acts as a modulator of redox signaling, has immunomodulatory function, and catalyzes the detoxification of reactive oxygen species (ROS). GPx3 has been identified as a tumor suppressor in many cancers. Although hyper-methylation of the GPx3 promoter has been shown to down-regulate its expression, other mechanisms by which GPx3 expression is regulated have not been reported. The aim of this study was to further elucidate the mechanisms of GPx3 regulation. GPx3 gene analysis predicted the presence of ten glucocorticoid response elements (GREs) on the GPx3 gene. This result prompted us to investigate whether GPx3 expression is regulated by the glucocorticoid receptor (GR), which is implicated in tumor response to chemotherapy. The corticosteroid dexamethasone (Dex) was used to examine the possible relationship between GR and GPx3 expression. Dex significantly induced GPx3 expression in H1299, H1650, and H1975 cell lines, which exhibit low levels of GPx3 expression under normal conditions. The results of EMSA and ChIP-PCR suggest that GR binds directly to GRE 6 and 7, both of which are located near the GPx3 promoter. Assessment of GPx3 transcription efficiency using a luciferase reporter system showed that blocking formation of the GR-GRE complexes reduced luciferase activity by 7-8-fold. Suppression of GR expression by siRNA transfection also induced down-regulation of GPx3. These data indicate that GPx3 expression can be regulated independently via epigenetic or GR-mediated mechanisms in lung cancer cells, and suggest that GPx3 could potentiate glucocorticoid (GC)-mediated anti-inflammatory signaling in lung cancer cells. PMID- 27484908 TI - Expanding the clinical spectrum of COL1A1 mutations in different forms of glaucoma. AB - BACKGROUND: Primary congenital glaucoma (PCG) and early onset glaucomas are one of the major causes of children and young adult blindness worldwide. Both autosomal recessive and dominant inheritance have been described with involvement of several genes including CYP1B1, FOXC1, PITX2, MYOC and PAX6. However, mutations in these genes explain only a small fraction of cases suggesting the presence of further candidate genes. METHODS: To elucidate further genetic causes of these conditions whole exome sequencing (WES) was performed in an Italian patient, diagnosed with PCG and retinal detachment, and his unaffected parents. Sanger sequencing of the complete coding region of COL1A1 was performed in a total of 26 further patients diagnosed with PCG or early onset glaucoma. Exclusion of pathogenic variations in known glaucoma genes as CYP1B1, MYOC, FOXC1, PITX2 and PAX6 was additionally done per Sanger sequencing and Multiple Ligation-dependent Probe Amplification (MLPA) analysis. RESULTS: In the patient diagnosed with PCG and retinal detachment, analysis of WES data identified compound heterozygous variants in COL1A1 (p.Met264Leu; p.Ala1083Thr). Targeted COL1A1 screening of 26 additional patients detected three further heterozygous variants (p.Arg253*, p.Gly767Ser and p.Gly154Val) in three distinct subjects: two of them diagnosed with early onset glaucoma and mild form of osteogenesis imperfecta (OI), one patient with a diagnosis of PCG at age 4 years. All five variants affected evolutionary, highly conserved amino acids indicating important functional restrictions. Molecular modeling predicted that the heterozygous variants are dominant in effect and affect protein stability and thus the amount of available protein, while the compound heterozygous variants act as recessive alleles and impair binding affinity to two main COL1A1 binding proteins: Hsp47 and fibronectin. CONCLUSIONS: Dominant inherited mutations in COL1A1 are known causes of connective tissues disorders such as OI. These disorders are also associated with different ocular abnormalities, although recognition of the common pathology for both features is seldom being recognized. Our results expand the role of COL1A1 mutations in different forms of early-onset glaucoma with and without signs of OI. Thus, we suggest including COL1A1 mutation screening in the genetic work-up of glaucoma cases and detailed ophthalmic examinations with fundus analysis in patients with OI. PMID- 27484909 TI - Alginate Microfiber System for Expansion and Direct Differentiation of Human Embryonic Stem Cells. AB - Pluripotent human embryonic stem cells (hESCs) are a potential renewable cell source for regenerative medicine and drug testing. To obtain adequate cell numbers for these applications, there is a need to develop scalable cell culture platforms to propagate hESCs. In this study, we encapsulated hESCs in calcium alginate microfibers as single cells, for expansion and differentiation under chemically defined conditions. hESCs were suspended in 1% (w/v) alginate solution at high cell density (>10(7) cells/mL) and extruded at 5 m/min into a low calcium concentration bath (10 mM) for gelation. Mild citrate buffer (2.5 mM), which did not affect hESCs viability, was used to release the cells from the calcium alginate hydrogel. Encapsulation as single cells was critical, as this allowed the hESCs to grow in the form of relatively small and uniform aggregates. This alginate microfiber system allowed for expansion of an hESC line, HUES7, for up to five passages while maintaining pluripotency. Immunohistochemistry, polymerase chain reaction, and other analyses showed that passage 5 (P5) HUES7 cells expressed proteins and genes characteristic of pluripotent stem cells, possessed normal karyotype, and were able to form representative tissues of the three embryonic germ layers in vitro and in vivo. Encapsulated HUES7 cells at P5 could also be induced to directly differentiate into liver-like cells. Collectively, our experiments show that the alginate microfiber system can be used as a three dimensional cell culture platform for long-term expansion and differentiation of hESCs under defined conditions. PMID- 27484910 TI - Identification of a novel beta-adrenergic octopamine receptor-like gene (betaAOR like) and increased ATP-binding cassette B10 (ABCB10) expression in a Rhipicephalus microplus cell line derived from acaricide-resistant ticks. AB - BACKGROUND: The cattle tick Rhipicephalus (Boophilus) microplus is an economically important parasite of livestock. Effective control of ticks using acaricides is threatened by the emergence of resistance to many existing compounds. Several continuous R. microplus cell lines have been established and provide an under-utilised resource for studies into acaricide targets and potential genetic mutations associated with resistance. As a first step to genetic studies using these resources, this study aimed to determine the presence or absence of two genes and their transcripts that have been linked with acaricide function in cattle ticks: beta-adrenergic octopamine receptor (betaAOR, associated with amitraz resistance) and ATP-binding cassette B10 (ABCB10, associated with macrocyclic lactone resistance) in six R. microplus cell lines, five other Rhipicephalus spp. cell lines and three cell lines representing other tick genera (Amblyomma variegatum, Ixodes ricinus and Hyalomma anatolicum). METHODS: End-point polymerase chain reaction (PCR) was used for detection of the betaAOR gene and transcripts in DNA and RNA extracted from the tick cell lines, followed by capillary sequencing of amplicons. Quantitative real-time PCR (qPCR) was performed to determine the levels of expression of ABCB10. RESULTS: betaAOR gene expression was detected in all Rhipicephalus spp. cell lines. We observed a second amplicon of approximately 220 bp for the betaAOR gene in the R. microplus cell line BME/CTVM6, derived from acaricide-resistant ticks. Sequencing of this transcript variant identified a 36 bp insertion in the betaAOR gene, leading to a 12-amino acid insertion (LLKTLALVTIIS) in the first transmembrane domain of the protein. In addition, nine synonymous SNPs were also discovered in R. appendiculatus, R. evertsi and R. sanguineus cell lines. Some of these SNPs appear to be unique to each species, providing potential tools for differentiating the tick species. The BME/CTVM6 cell line had significantly higher ABCB10 (P = 0.002) expression than the other R. microplus cell lines. CONCLUSIONS: The present study has identified a new betaAOR gene and demonstrated a higher ABCB10 expression level in the BME/CTVM6 cell line, indicating that tick cell lines provide a useful experimental tool for acaricide resistance studies and further elucidation of tick genetics. PMID- 27484911 TI - Giant ventral hernia-relationship between abdominal wall muscle strength and hernia area. AB - BACKGROUND: Symptoms arising from giant ventral hernia have been considered to be related to weakening of the abdominal muscles. The aim of this study was to investigate the relationship between the area of the abdominal wall defect and abdominal wall muscle strength measured by the validated BioDex system together with a back/abdominal unit. METHODS: Fifty-two patients with giant ventral hernia (>10 cm wide) underwent CT scan, clinical measurement of hernia size and BioDex measurement of muscle strength prior to surgery. The areas of the hernia derived from CT scan and from clinical measurement were compared with BioDex forces in the modalities extension, flexion and isometric contraction. The Spearman rank test was used to calculate correlations between area, BMI, gender, age, and muscle strength. RESULT: The hernia area calculated from clinical measurements correlated to abdominal muscle strength measured with the Biodex for all modalities (p-values 0.015-0.036), whereas no correlation was seen with the area calculated by CT scan. No relationship was seen between BMI, gender, age and the area of the hernia. DISCUSSION: The inverse correlation between BioDex abdominal muscle strength and clinically assessed hernia area, seen in all modalities, was so robust that it seems safe to conclude that the area of the hernia is an important determinant of the degree of loss of abdominal muscle strength. Results using hernia area calculated from the CT scan showed no such correlation and this would seem to concur with the results from a previous study by our group on patients with abdominal rectus diastasis. In that study, defect size assessed clinically, but not that measured by CT scan, was in agreement with the size of the diastasis measured intra-operatively. The point at which the area of a hernia begins to correlate with loss of abdominal wall muscle strength remains unknown since this study only included giant ventral hernias. PMID- 27484912 TI - Peripheral nervous system assessment in acromegaly patients under somatostatin analogue therapy. AB - PURPOSE: Acromegaly is known to affect peripheral nervous system (PNS) causing carpal tunnel syndrome (CTS) and polyneuropathy. The frequency of these disorders and the evaluation methods vary among studies. In the present study, we aimed to examine PNS of acromegaly patients under somatostatin analogue (SSA) therapy. METHODS: Forty-eight acromegaly patients (26 F/22 M, 45.58 +/- 11.6 years) under SSA treatment and 44 healthy controls (25 F/19 M, 47.46 +/- 8.7 years) were assessed by symptom questionnaires, neurologic examination and electrophysiological studies. RESULTS: 87.5 % of the acromegaly patients had at least one abnormal finding regarding PNS. With the incorporation of palm-wrist median nerve conduction velocity method, we detected CTS in 50 % of patients. Polyneuropathy was less frequent (29.2 %). Both conditions were independent from the coexisting diabetes mellitus (p = 0.22 for CTS, p = 0.71 for polyneuropathy). Polyneuropathy but not CTS was more common among biochemically uncontrolled acromegaly patients rather than those under control (p = 0.03; p = 0.68, respectively). CONCLUSION: Our findings emphasize the high prevalence of peripheral nervous system involvement in acromegaly patients under SSA therapy and importance of neurological evaluation of these patients. Early diagnosis and treatment of the disease may reduce the PNS involvement. PMID- 27484913 TI - Malignant peritoneal mesothelioma and Crohn disease. AB - AIMS: Mesothelial reaction simulating peritoneal diffuse malignant mesothelioma (MM) has been reported in the setting of Crohn ileitis. To our knowledge, peritoneal MM arising in patients with inflammatory bowel disease (IBD) has not been reported. The purpose of this study is to report the clinicopathological characteristics of patients with peritoneal MM and IBD. METHODS: A database of approximately 3800 MM was reviewed for cases of MM in patients with IBD. RESULTS: Three patients (0.08%) with peritoneal MM and Crohn disease (CD) were identified, including two women and one man ranging in age from 56 to 65 years. All had a long-standing history of diarrhoea and an established diagnosis of CD of 3 years or greater duration. Two had epithelial MM and one had biphasic MM. Only one had documented asbestos exposure. CONCLUSIONS: Peritoneal MM occurs rarely in patients with IBD, but interestingly, has only been observed in the setting of CD and not in patients with ulcerative colitis. Chronic inflammation has been associated with the development of MM in rare instances and these three cases suggest that CD with transmural inflammation may also be a precursor. The precise role of CD-related transmural inflammation in the carcinogenesis of peritoneal MM remains to be determined. PMID- 27484914 TI - HBME-1 is expressed by erythroid precursors in early maturation stage and can be a valuable tool for evaluation of dyserythropoiesis in bone marrow core biopsy specimens. AB - The reaction of Hector Battifora mesothelial epitope-1 (HBME-1) antibody with scattered pronormoblasts in normal bone marrow core biopsy specimens has been reported. This study evaluated the immunohistochemical profile of HBME-1 in a panel of 52 normal, dyserythropoietic and neoplastic marrow samples. We compared the staining property of HBME-1 with that of the commonly used erythroid marker, glycophorin A (CD235a) and in each case, we semi-quantitatively evaluated the HBME-1/CD235a-positive cells ratio. In normal samples, HBME-1 labelled scattered immature erythroid precursors. In dyserythropoietic specimens, HBME-1 stained nucleated erythroid precursors in varying degrees, from pronormoblast through normoblast stages, with the highest intensity in immature forms. Overall, the cellular background of non-erythroid progenitors, erythrocytes and neoplastic cells did not react with HBME-1, except in leukaemia cases with myelodysplasia related changes. Our study shows that HBME-1 is a useful marker to identify immature erythroid precursors and that an HBME-1/CD235a-positive cells ratio >=10% is associated with dyserythropoiesis. PMID- 27484915 TI - The impact of alcohol care teams on emergency secondary care use following a diagnosis of alcoholic liver disease - a national cohort study. AB - BACKGROUND: The increasing mortality rates from alcohol-related liver disease (ARLD) are a public health concern. To address this, alcohol care teams (ACT) case-find and lead management of alcohol issues for these patients. Local assessments of ACTs have shown reductions in emergency admissions and emergency department attendances. We examine the impact of ACTs on emergency hospital activity following a diagnosis of ARLD. METHODS: Administrative Hospital Episode Statistics (HES) data were extracted. Information on ACT provision at English NHS hospital trusts and sites in 2009/10 was taken from a survey by Public Health England. We undertook a difference-in-difference analysis to compare emergency hospital activity for a cohort of individuals diagnosed with ARLD who presented to hospitals either with or without an ACT in the one year before and after a first ARLD diagnosis during 2009/10. RESULTS: Over the study period, 9,165 individuals eligible for inclusion in our study had a first diagnosis of ARLD. 4,768 presented to one of 41 hospital trusts with an ACT (59 sites) and 4,397 presented to one of 50 non-ACT hospital trusts (65 sites). Whilst age and sex demographics were similar between the two cohorts, the ACT hospital cohort had a higher proportion of individuals in the most deprived quintile (41.6 % v 28.5 % p < .0001). In the difference-in-difference analysis, the presence of an ACT at a hospital trust was not associated with a change in all-cause emergency admissions (0.020 (95 % CI -0.070, 0.111), p = 0.656), alcohol-related emergency admissions (-0.025 (95 % CI -0.104, 0.054), p = 0.536) or all-cause emergency department attendances (0.042 (95 % CI -0.087, 0.171), p = 0.521). Sensitivity analyses by sex and hospital site did not affect the study findings. CONCLUSIONS: In this study, the presence of an ACT at the NHS hospital trust where individuals have their first recorded diagnosis of ARLD does not appear to be associated with subsequent emergency hospital activity within these populations. Further analysis focussing on the components and specific effects of ACT interventions on individuals and systems both pre- and post-diagnosis of ARLD may reveal important avenues to improve care. PMID- 27484916 TI - Local Treatment of Penile Prosthesis Infection as Alternative to Immediate Salvage Surgery. AB - INTRODUCTION: Penile prosthesis (PP) is the established treatment for patients with erectile dysfunction (ED) who do not respond to phosphodiesterase inhibitors and intracavernosal injections. In general, these devices have been largely successful but there are not free of serious complication such as PP infection (PPI). PPI requires immediate surgical removal or salvage rescue of the PP. AIM: In this report, we present two clinical cases with inflatable PP (IPP) treated locally with antibiotic and high pressure irrigation and then avoid the PP removal or salvage rescue. METHODS: We present two patients with PPI in our institution and literature review. MAIN OUTCOME MEASURES: Resolution of the two cases. RESULTS: Patient A (A) was 44 years old and patient B (B) 51 years old presented PPI after three weeks (A) and eight weeks (B). Both patients were diabetic. Physical exploration revealed an open scrotal incision at its margin with a clear discharge. The rest of the incision and scrotum were clean and dry. They had not scrotum pain/tenderness or systemic/septic symptoms. The bacterial culture of the incisional drainage revealed a Staphylococcus aureus (A) and Staphylococcus epidermidis (B). In both cases, we performed an excision of the tissue around the pump with a high pressure pulsed irrigation (Interpulse; Stryker Corp, Kalamazoo, MI, USA). For the irrigation we used three different solutions that included povidone-iodine, antibiotics (gentamicin plus vancomicin), and hydrogen peroxyde. Finally, we performed a multilayered surgical closure with the use of aspirate drainage over 24 hours and intravenous antibiotics. The patients had a total resolution of its symptoms after 20 months (A) and 36 months (B), and the IPP worked properly. CONCLUSION: This treatment could be an option for to perform specific patients with local IPP infection without systemic symptoms instead of surgical removal. PMID- 27484917 TI - What Do Patients Want? A Needs Assessment of Vulvodynia Patients Attending a Vulvar Diseases Clinic. AB - INTRODUCTION: Vulvodynia is a chronic pain disorder that negatively impacts the quality of life of affected women. AIM: The goal of this study was to identify unmet needs among localized provoked vulvodynia patients. METHODS: A qualitative needs assessment was performed in a subspecialized vulvar clinic in a single academic institution in Canada. Semistructured interviews were conducted, recorded, and analyzed using the constant comparative method of grounded theory to identify common themes. MAIN OUTCOME MEASURES: Interviews were conducted until theme saturation was achieved. RESULTS: A diverse sample of 8 patients completed all components of the study. The most prominent unmet needs raised by patients in their interviews were categorized into 3 main themes: (1) challenges related to obtaining a diagnosis of vulvodynia and finding practitioners who are knowledgeable about vulvodynia; (2) challenges related to the current impact of the disease physically, emotionally, and in social relationships with patients' intimate partners; and (3) barriers to adherence with recommended therapy. Solutions recommended by patients include better education of physicians regarding vulvodynia and the development of multidisciplinary programs that provide access to physiotherapy, sex therapy, mindfulness and psychology services on-site, information classes for new patients, and the creation of peer support networks for patients and their partners. CONCLUSION: A patient-focused needs assessment suggests optimal vulvodynia care requires better education of physicians and a multimodal approach to therapy, ideally with multiple services offered in 1 location. PMID- 27484918 TI - A New Paradigm to Analyze Data Completeness of Patient Data. AB - BACKGROUND: There is a need to develop a tool that will measure data completeness of patient records using sophisticated statistical metrics. Patient data integrity is important in providing timely and appropriate care. Completeness is an important step, with an emphasis on understanding the complex relationships between data fields and their relative importance in delivering care. This tool will not only help understand where data problems are but also help uncover the underlying issues behind them. OBJECTIVES: Develop a tool that can be used alongside a variety of health care database software packages to determine the completeness of individual patient records as well as aggregate patient records across health care centers and subpopulations. METHODS: The methodology of this project is encapsulated within the Data Completeness Analysis Package (DCAP) tool, with the major components including concept mapping, CSV parsing, and statistical analysis. RESULTS: The results from testing DCAP with Healthcare Cost and Utilization Project (HCUP) State Inpatient Database (SID) data show that this tool is successful in identifying relative data completeness at the patient, subpopulation, and database levels. These results also solidify a need for further analysis and call for hypothesis driven research to find underlying causes for data incompleteness. CONCLUSION: DCAP examines patient records and generates statistics that can be used to determine the completeness of individual patient data as well as the general thoroughness of record keeping in a medical database. DCAP uses a component that is customized to the settings of the software package used for storing patient data as well as a Comma Separated Values (CSV) file parser to determine the appropriate measurements. DCAP itself is assessed through a proof of concept exercise using hypothetical data as well as available HCUP SID patient data. PMID- 27484919 TI - Resveratrol inhibits phosphorylation within the signal transduction and activator of transcription 3 signaling pathway by activating sirtuin 1 in SW1353 chondrosarcoma cells. AB - The present study assessed the mechanism by which resveratrol (Res) inhibits the growth of SW1353 chondrosarcoma cells and examined whether sirtuin 1 (Sirt1) activation affects phosphorylation within the signal transduction and activator of transcription 3 (STAT3) signaling pathway. The present study used SW1353 chondrosarcoma cells in the logarithmic phase of growth (control and treatment groups). The latter group was treated with Res at 25 and 50 umol/l for 24 h, and cell viability, proliferation and apoptosis were analyzed using the cell counting kit-8 assay, colony counting and Hoechst staining, respectively. The expression levels of caspase-3, cleaved caspase-3, B-cell lymphoma-2 (BCL-2), BCL-2 associated X protein (Bax), STAT3 and phosphorylated (p-)STAT3) were measured by Western blotting. SW1353 cells were transfected with small interfering (si)RNA targeting Sirt1 and the expression levels of Sirt1, STAT3 and p-STAT3 were assessed. Exposure of SW1353 cells to Res reduced cell viability in a dose dependent manner (P<0.01). Additionally, cell proliferation was significantly inhibited and the cell nuclei exhibited apoptotic characteristics. Cleaved caspase-3, Sirt1 and Bax levels were upregulated. The expression levels of BCL-2 and p-STAT3 were downregulated. Additionally, the BCL-2/Bax ratio was reduced compared with the control group. The total STAT3 level was unaffected. Res treatment activated Sirt1, however, in cells transfected with Sirt1-siRNA, the ability of resveratrol to suppress p-STAT3 expression was compromised. Overall, it was revealed that Res treatment induced apoptosis, inhibited proliferation and affected phosphorylation within the STAT3 signaling pathway by activating Sirt1 in SW1353 chondrosarcoma cells. PMID- 27484920 TI - Effect of Tributyltin, Cadmium, and Their Combination on Physiological Responses in Juvenile Grass Carp. AB - Tributyltin (TBT) and cadmium (Cd) are two common pollutants in aquatic environments. This study was designed to examine the physiological responses of juvenile Grass Carp Ctenopharyngodon idella to TBT, Cd, and their combination. Fish were apportioned into a control group, a TBT group (7.5 MUg/L), a Cd group (2.97 mg/L), and a TBT-Cd group (7.5 MUg/L TBT, 2.97 mg/L Cd(2+)) for 7 d. The following activities were measured: Na(+),K(+)-ATPase in gill tissues; nitric oxide synthase (NOS), acetylcholinesterase (AChE), and monoamine oxidase (MAO) in brain tissues; and lipid peroxidation (LPO), malondialdehyde (MDA), total antioxidative capacity (T-AOC), and glutathione (GSH) in liver tissues. Cadmium induced stress was suggested by alterations in antioxidant responses (MDA, LPO, and T-AOC) and neurological parameters (AChE, MAO, and NOS). Cadmium also induced Na(+),K(+)-ATPase and GSH activity. Compared with the responses among the Cd group, the combination of TBT and Cd not only decreased the level of GSH and Na(+),K(+)-ATPase but also increased the levels of MDA, LPO, AChE, MAO, and NOS. These results suggest that a combination of TBT and Cd could reduce the adverse effects of Cd on Grass Carp. However, the exact mechanisms for the combined effects TBT and Cd on these biomarkers require further investigation. Received September 28, 2015; accepted April 17, 2016. PMID- 27484921 TI - Structural characterization of suppressor lipids by high-resolution mass spectrometry. AB - RATIONALE: Suppressor lipids were originally identified in 1993 and reported to encompass six lipid classes that enable Saccharomyces cerevisiae to live without sphingolipids. Structural characterization, using non-mass spectrometric approaches, revealed that these suppressor lipids are very long chain fatty acid (VLCFA)-containing glycerophospholipids with polar head groups that are typically incorporated into sphingolipids. Here we report, for the first time, the structural characterization of the yeast suppressor lipids using high-resolution mass spectrometry. METHODS: Suppressor lipids were isolated by preparative chromatography and subjected to structural characterization using hybrid quadrupole time-of-flight and ion trap-orbitrap mass spectrometry. RESULTS: Our investigation recapitulates the overall structural features of the suppressor lipids and provides an in-depth characterization of their fragmentation pathways. Tandem mass analysis identified the positionally defined molecular lipid species phosphatidylinositol (PI) 26:0/16:1, PI mannoside (PIM) 16:0/26:0 and PIM inositol-phosphate (PIMIP) 16:0/26:0 as abundant suppressor lipids. This finding differs from the original study that only inferred the positional isomer PI 16:0/26:0 and prompts new insight into the biosynthesis of suppressor lipids. Moreover, we also report the identification of a novel suppressor lipid featuring an amino sugar residue linked to a VLCFA-containing PI molecule. CONCLUSIONS: Fragmentation pathways of yeast suppressor lipids have been delineated. In addition, the fragmentation information has been added to our open source ALEX lipid database to support automated identification and quantitative monitoring of suppressor lipids in yeast and bacteria that produce similar lipid molecules. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27484922 TI - After-hours primary care for people with intellectual disabilities in The Netherlands-Current arrangements and challenges. AB - BACKGROUND: Little is known about the organisation of after-hours primary care for people with intellectual disabilities (ID), and mainstream care is not self evidently accessible or fit for this group. A first step towards improvement is a greater understanding of current after-hours primary ID care. AIMS: This study explores the organisation of and experiences with after-hours primary care provided for people with ID in The Netherlands. METHODS AND PROCEDURES: A telephone survey amongst 68 care provider services including questions on organisational characteristics, problem areas, facilitators, and inhibitors. OUTCOMES AND RESULTS: A multitude of different after-hours primary care arrangements were found. Primary care physicians (PCPs) were involved in almost all care provider services, often in alliance with PCP cooperatives. Specialised ID physicians had differing roles as gatekeeper, primary caregiver, or consultant. Most problems during the after-hours arose regarding daily care professionals' competences. Facilitators and inhibitors of after-hours primary care were themed around complexity of, and need for, specialised care, multidisciplinary team of professionals, communication and information, and prerequisites at organisational level. CONCLUSIONS AND IMPLICATIONS: Evidence on specific after-hours health needs of people with ID is needed to strengthen collaboration between specialist ID care services and mainstream healthcare services to adequately provide care. PMID- 27484923 TI - Searching for rare diseases in PubMed: a blind comparison of Orphanet expert query and query based on terminological knowledge. AB - BACKGROUND: Despite international initiatives like Orphanet, it remains difficult to find up-to-date information about rare diseases. The aim of this study is to propose an exhaustive set of queries for PubMed based on terminological knowledge and to evaluate it versus the queries based on expertise provided by the most frequently used resource in Europe: Orphanet. METHODS: Four rare disease terminologies (MeSH, OMIM, HPO and HRDO) were manually mapped to each other permitting the automatic creation of expended terminological queries for rare diseases. For 30 rare diseases, 30 citations retrieved by Orphanet expert query and/or query based on terminological knowledge were assessed for relevance by two independent reviewers unaware of the query's origin. An adjudication procedure was used to resolve any discrepancy. Precision, relative recall and F-measure were all computed. RESULTS: For each Orphanet rare disease (n = 8982), there was a corresponding terminological query, in contrast with only 2284 queries provided by Orphanet. Only 553 citations were evaluated due to queries with 0 or only a few hits. There were no significant differences between the Orpha query and terminological query in terms of precision, respectively 0.61 vs 0.52 (p = 0.13). Nevertheless, terminological queries retrieved more citations more often than Orpha queries (0.57 vs. 0.33; p = 0.01). Interestingly, Orpha queries seemed to retrieve older citations than terminological queries (p < 0.0001). CONCLUSION: The terminological queries proposed in this study are now currently available for all rare diseases. They may be a useful tool for both precision or recall oriented literature search. PMID- 27484924 TI - Long-term functional outcomes following mesh-augmented posterior vaginal prolapse repair. AB - OBJECTIVE: To assess long-term patient-centered functional outcomes following posterior vaginal wall repair using mesh implants. METHOD: The present prospective telephone interview study enrolled a cohort of women who had undergone posterior vaginal wall repair with mesh between January 1, 2006 and February 28, 2009, at a single center in Israel. Patients were asked to report long-term outcomes, and demographic, clinical, intraoperative, and postoperative follow-up data were retrieved from patients' medical files. Multivariable logistic regression models were used to asses associations between baseline characteristics and long-term outcomes. RESULTS: In total, 102 patients were contacted, with 80 (78.4%) at 61-83months after surgery agreeing to participate. A recurrence of prolapse symptoms was reported by 14 patients (18%) (12 required a corrective procedure), mesh had been removed from two patients owing to erosion/extrusion, and two others had undergone removal of granulation tissue. Long-term, bothersome symptoms were reported by 13 (16%) patients. Parity and previous hysterectomy were associated with lower odds of long-term adverse outcomes, and the location of the apical (C/D) pelvic organ prolapse quantification point and a change in its position following surgery were associated with increased odds of adverse outcomes. CONCLUSION: The long-term adverse-outcome rate was low for patients who underwent posterior vaginal mesh augmentation. These results highlight the importance of apical support for good long-term functional outcomes. PMID- 27484925 TI - Area under curve of temporal estradiol measurements for prediction of the detrimental effect of estrogen exposure on implantation. AB - OBJECTIVE: To assess whether the area under the curve of temporal estradiol measurements (AUCEM) during cycles of assisted reproductive technology (ART) can be used to predict failure of implantation and clinical pregnancy. METHODS: In a prospective study, women aged 24-39years undergoing ART at a center in Turkey were enrolled between January and December 2014. Eligible patients had a regular menstrual cycle, normal levels of serum prolactin, and no hormone treatment within the past 3months. The area under the curve of the time course of estradiol measurements was calculated for each participant, and assessed for its ability to predict successful implantation. RESULTS: Among 282 participants, 109 (38.6%) women had successful implantation. There was a significant difference between the two groups of women in AUCEM, estradiol per day (AUCEM divided by duration of stimulation), and endometrial thickness on the day of human chorionic gonadotropin administration (P<0.05 for all). CONCLUSION: The area under the curve of estradiol measurements during ART cycles might be useful for predicting failure of implantation and clinical pregnancy. PMID- 27484927 TI - Defense Mechanism Card Pull in TAT Stories. AB - This study investigates the question of whether different Thematic Apperception Test (TAT; Murray, 1943 ) cards are likely to prompt stories that are characterized by different defense mechanisms. This condition is known as card pull and refers to the probability that different TAT cards elicit different personality scores for the same variable. If so, the assessment of defense use would be importantly influenced by the TAT cards used in an assessment. TAT stories from 3 different community samples were examined (Ns = 91, 98, 121), using a statistical method developed by Stein et al ( 2014 ). The results indicated that different TAT cards pull for different defenses, as assessed by the Defense Mechanism Manual (DMM: Cramer, 1991b ). However, the nature of card pull was not always consistent across samples. These dissimilarities could be due to group differences, or to the presence of different TAT cards used in the test battery, indicating that card pull is importantly determined by context. PMID- 27484926 TI - Cingulin and actin mediate midbody-dependent apical lumen formation during polarization of epithelial cells. AB - Coordinated polarization of epithelial cells is a key step during morphogenesis that leads to the formation of an apical lumen. Rab11 and its interacting protein FIP5 are necessary for the targeting of apical endosomes to the midbody and apical membrane initiation site (AMIS) during lumenogenesis. However, the machinery that mediates AMIS establishment and FIP5-endosome targeting remains unknown. Here we identify a FIP5-interacting protein, Cingulin, which localizes to the AMIS and functions as a tether mediating FIP5-endosome targeting. We analysed the machinery mediating AMIS recruitment to the midbody and determined that both branched actin and microtubules are required for establishing the site of the nascent lumen. We demonstrate that the Rac1-WAVE/Scar complex mediates Cingulin recruitment to the AMIS by inducing branched actin formation, and that Cingulin directly binds to microtubule C-terminal tails through electrostatic interactions. We propose a new mechanism for apical endosome targeting and AMIS formation around the midbody during epithelial lumenogenesis. PMID- 27484928 TI - Synaptic Basis for the Generation of Response Variation in Auditory Cortex. AB - Cortical neurons can exhibit significant variation in their responses to the same sensory stimuli, as reflected by the reliability and temporal precision of spikes. However the synaptic mechanism underlying response variation still remains unclear. Here, in vivo whole-cell patch-clamp recording of excitatory neurons revealed variation in the amplitudes as well as the temporal profiles of excitatory and inhibitory synaptic inputs evoked by the same sound stimuli in layer 4 of the rat primary auditory cortex. Synaptic inputs were reliably induced by repetitive stimulation, although with large variation in amplitude. The variation in the amplitude of excitation was much higher than that of inhibition. In addition, the temporal jitter of the synaptic onset latency was much smaller than the jitter of spike response. We further demonstrated that the amplitude variation of excitatory inputs can largely account for the spike variation, while the jitter in spike timing can be primarily attributed to the temporal variation of excitatory inputs. Furthermore, the spike reliability of excitatory but not inhibitory neurons is dependent on tone frequency. Our results thus revealed an inherent cortical synaptic contribution for the generation of variation in the spike responses of auditory cortical neurons. PMID- 27484929 TI - Gastroprotective potential of hydro-alcoholic extract of Pattanga (Caesalpinia sappan Linn.). AB - ETHNO-PHARMACOLOGICAL RELEVANCE: Pattanga is botanically equated as Caesalpinia sappan Linn. (Family: Caesalpiniaceae) and is used in Ayurveda system of medicine since ages. According to Ayurveda, useful part is Heartwood, which is bitter, astringent and acrid and is useful in vitiated conditions of vata and pitta, burning sensation, wounds, ulcers, leprosy, skin diseases, menorrhagia, leucorrhea, and diabetes. It is used as a major ingredient in Ayurvedic formulations and preparations like Patrangasava, Chandanadya Thalia, and Karpuradyarka. AIM OF THE STUDY: The present study is planned to evaluate the gastroprotective activity of the selected Ayurvedic drug using three different in vivo gastric ulcer models, so as to provide scientific evidence for the Ayurvedic claims. MATERIALS AND METHODS: For this study, Wistar albino rats fasted overnight were selected. The hydroalcoholic extract of Caesalpinia sappan heartwood at the dose level 250 and 500mg/kg body weight was selected and administered orally before necrotizing agents. Antioxidant and antiulcer parameters were evaluated and the stomach samples were subjected for histopathological studies. In addition, PGE2 estimation and protein expressions of COX-1, COX-2 and iNOS were analyzed by Western blot. The plant extract was subjected to LCMS/MS analysis. In addition, Cytoprotective effect in isolated gastric mucosal cells, TUNEL Assay, Acid neutralizing capacity assay, H+/K+ ATPase inhibitory assay were performed. RESULTS: The ulcer protection was found to be 92%, 86% and 64% against ethanol, NSAID and pylorus ligation induced ulcer respectively. The hydro-alcoholic extract of C. sappan heartwood exhibited cytoprotective effect with 76.82% reduction against indomethacin-induced cytotoxicity at the concentration of 25ug/ml. C. sappan showed 63.91% inhibition in H+/K+ ATPase inhibitory assay at the concentration 500ug/ml. CONCLUSIONS: Our results depict that Caesalpinia sappan heartwood possesses gastroprotective activity, possibly mediated through cytoprotection and antioxidant mechanisms. The data obtained in the present study provides scientific support for the traditional use of Caesalpinia sappan in the management of peptic ulcer. PMID- 27484931 TI - Ethnopharmacological study and topical anti-inflammatory activity of crude extract from Poikilacanthus glandulosus (Nees) Ariza leaves. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ethnopharmacological studies are important tools as records and documentation of the empirical uses of medicinal plants in traditional communities with the purpose of generating useful knowledge to lead to the development of new medicines, biodiversity conservation and enhancement of knowledge and local culture. Poikilacanthus glandulosus is widely used by the population of City of Santiago, in Brazil, nevertheless, it does not have any validation regarding its use and its medicinal effects. AIM: The objective of this study was to perform one ethnopharmacological survey about P. glandulosus in the City of Santiago and determine the anti-inflammatory activity in order to prove its uses in popular medicine. METHODS: Personal and ethnopharmacological data were collected through a prepared questionnaire. The phytochemical analysis was performed observing the individual methodology for each reaction and by HPLC UV. The antiedematogenic and anti-inflammatory (cell infiltration and histological procedure) activities of the P. glandulosus (0.01-1000MUg/ear) were evaluated in the ear edema model induced by topical application of croton oil. RESULTS: P. glandulosus is known in City of Santiago as "Gaiana" and its macerated leaves and branches are prepared with alcohol or sugarcane liquor especially for insect bites, cicatrization and inflammation. HPLC analysis revealed the presence of maslinic acid (2.024+/-0.10mg/g), uvaol (0.124+/ 0.02mg/g) and sitosterol (0.502+/-0.05mg/g). The topical application of crude extract of P. glandulosus reduced in a dose-dependent manner the croton oil induced ear edema and myeloperoxidase activity (neutrophils infiltration marker) with maximum inhibition of 87+/-2% and 64+/-12%, respectively at 1000ug/ear. Dexamethasone (100ug/ear), used as a positive control, inhibited croton oil induced ear edema in 89+/-3% and decreased myeloperoxidase activity in 50+/-3%. Both P. glandulosus as dexamethasone reduced cell infiltration when evaluated by histological procedure CONCLUSION: This work allowed us to understand the specie P. glandulosus through ethnopharmacological study and it showed that the crude extract presented antiedematogenic and anti-inflammatory actions, proving their traditional use as anti-inflammatory. PMID- 27484930 TI - Ethnopharmacology in the fight against Plasmodium parasites and brain disorders: In memoriam of Philippe Rasoanaivo. AB - Prof. Philippe Rasoanaivo was a highly dedicated and brilliant scientist in the field of ethnopharmacology. He worked for the Institut Malgache de Recherches Appliquees and the University of Antananarivo, Madagascar. His research was mainly focused on the endemic medicinal and aromatic plants used by traditional healers in Madagascar against a range of parasites, with special reference to Plasmodium spp. In this Editorial, we resumed the key findings of his research activity, with special reference to the discovery of alkaloids that markedly enhance the action of chloroquine against malaria parasites. PMID- 27484932 TI - Nitrate uptake varies with tide height and nutrient availability in the intertidal seaweed Fucus vesiculosus. AB - Intertidal seaweeds must cope with a suite of stressors imposed by aerial exposure at low tide, including nutrient limitation due to emersion. Seaweeds can access nutrients only when submerged, so individuals living higher compared to lower on the shore may have adaptations allowing them to acquire sufficient amounts of nutrients to survive and maintain growth. Using a combination of observations and experiments, we aimed to identify intraspecific variation in nitrate uptake rates across the intertidal distribution of F. vesiculosus, as well as test for acclimation in response to a change in tide height. We replicated our study at sites spanning nearly the entire Gulf of Maine coastline, to examine how local environmental variability may alter intraspecific variation in nitrate uptake. We found that average nitrate uptake rates were ~18% higher in upper compared to lower intertidal Fucus vesiculosus. Furthermore, we found evidence for both acclimation and adaptation to tide height during a transplant experiment. F. vesiculosus transplanted from the lower to the upper intertidal zone was characterized by increased nitrate uptake, but individuals transplanted from the upper to the lower intertidal zone retained high uptake rates. Our observations differed among Gulf of Maine regions and among time points of our study. Importantly, these differences may reflect associations between nitrate uptake rates and abiotic environmental conditions and seaweed nutrient status. Our study highlights the importance of long-term variation in ambient nutrient supply in driving intraspecific variation of seaweeds across the intertidal gradient and local and seasonal variation in ambient nutrient levels in mediating intraspecific differences. PMID- 27484933 TI - Editorial: the burden of chronic liver disease - an ecological method sees the wood for the trees. PMID- 27484934 TI - Editorial: the burden of chronic liver disease - an ecological method sees the wood for the trees. Authors' reply. PMID- 27484935 TI - Editorial: dark chocolate may improve NAFLD and metabolic syndrome by reducing oxidative stress. PMID- 27484936 TI - Letter: clinical outcomes of HBsAg loss in chronic HBV infection. PMID- 27484937 TI - Letter: clinical outcomes of HBsAg loss in chronic HBV infection - author's reply. PMID- 27484938 TI - Letter: long-term safety of nucleoside and nucleotide analogues in HBV monoinfected patients. PMID- 27484939 TI - Letter: long-term safety of nucleoside and nucleotide analogues in HBV monoinfected patients - authors' reply. PMID- 27484940 TI - Corrigendum. PMID- 27484941 TI - Recurrent selection explains parallel evolution of genomic regions of high relative but low absolute differentiation in a ring species. AB - Recent technological developments allow investigation of the repeatability of evolution at the genomic level. Such investigation is particularly powerful when applied to a ring species, in which spatial variation represents changes during the evolution of two species from one. We examined genomic variation among three subspecies of the greenish warbler ring species, using genotypes at 13 013 950 nucleotide sites along a new greenish warbler consensus genome assembly. Genomic regions of low within-group variation are remarkably consistent between the three populations. These regions show high relative differentiation but low absolute differentiation between populations. Comparisons with outgroup species show the locations of these peaks of relative differentiation are not well explained by phylogenetically conserved variation in recombination rates or selection. These patterns are consistent with a model in which selection in an ancestral form has reduced variation at some parts of the genome, and those same regions experience recurrent selection that subsequently reduces variation within each subspecies. The degree of heterogeneity in nucleotide diversity is greater than explained by models of background selection, but is consistent with selective sweeps. Given the evidence that greenish warblers have had both population differentiation for a long period of time and periods of gene flow between those populations, we propose that some genomic regions underwent selective sweeps over a broad geographic area followed by within-population selection-induced reductions in variation. An important implication of this 'sweep-before-differentiation' model is that genomic regions of high relative differentiation may have moved among populations more recently than other genomic regions. PMID- 27484942 TI - SCAT3 assessment of non-head injured and head injured athletes competing in a large international youth soccer tournament. AB - To our knowledge, no study has evaluated Sideline Concussion Assessment Tool -3rd Edition (SCAT3) scores during competition in athletes who have not had a head injury. The purpose of our pilot study was to compare SCAT3 scores in non-injured (NI), injured (but not head injured) (I), and head injured (HI) youth soccer players during competition and to establish preliminary baseline data for non head injured athletes in a competitive setting. The HI group demonstrated significantly more symptoms (M = 9.7, SE = 0.8) than the I and NI (3.3, SE = 1.2, and 3.2, SE = 0.7, respectively) groups. The HI group also demonstrated a significantly higher symptom severity score (25.3, SE = 2.8) than the I and NI groups (7.7, SE = 4.1, and 5.9, SE = 2.5, respectively). There were no statistically significant differences in mean total Standardized Assessment of Concussion (SAC) scores and mean subsection SAC scores between the groups. Clinicians should also be aware that non-injured in-competition athletes may report more symptoms on the SCAT3 than those evaluated in a non-competition setting. PMID- 27484943 TI - Stabilization of a Chiral Dirhodium Carbene by Encapsulation and a Discussion of the Stereochemical Implications. AB - For the first time, the stereochemical course of an asymmetric cyclopropanation can be discussed on the basis of experimental structural information on a pertinent chiral dirhodium carbene intermediate. Key to success was the formation of racemic single crystals of a heterochiral [Rh2 {(S*)-PTTL}4 {=C(Ar)COOMe}][Rh2 {(R*)-PTTL}4 ] (Ar=MeOC6 H4 ; PTTL=N-phthaloyl-tert-leucinate) capsule, which has been characterized by X-ray diffraction. NMR spectroscopic data confirm that the obtained structural portrait is also relevant in solution and provide additional information about the dynamics of this species. The chiral binding pocket is primarily defined by the conformational preferences of the N-phthaloyl-protected amino acid ligands and reinforced by a network of weak interligand interactions that get stronger when chlorinated phthalimide residues are used. PMID- 27484944 TI - Multiple regression analysis to assess the role of plankton on the distribution and speciation of mercury in water of a contaminated lagoon. AB - Spatial and seasonal variation of mercury species aqueous concentrations and distributions was carried out during six sampling campaigns at four locations within Laranjo Bay, the most mercury-contaminated area of the Aveiro Lagoon (Portugal). Inorganic mercury (IHg(II)) and methylmercury (MeHg) were determined in filter-retained (IHgPART, MeHgPART) and filtered (<0.45MUm) fractions (IHg(II)DISS, MeHgDISS). The concentrations of IHgPART depended on site and on dilution with downstream particles. Similar processes were evidenced for MeHgPART, however, its concentrations increased for particles rich in phaeophytin (Pha). The concentrations of MeHgDISS, and especially those of IHg(II)DISS, increased with Pha concentrations in the water. Multiple regression models are able to depict MeHgPART, IHg(II)DISS and MeHgDISS concentrations with salinity and Pha concentrations exhibiting additive statistical effects and allowing separation of possible addition and removal processes. A link between phytoplankton/algae and consumers' grazing pressure in the contaminated area can be involved to increase concentrations of IHg(II)DISS and MeHgPART. These processes could lead to suspended particles enriched with MeHg and to the enhancement of IHg(II) and MeHg availability in surface waters and higher transfer to the food web. PMID- 27484945 TI - Evaluating laser-driven Bremsstrahlung radiation sources for imaging and analysis of nuclear waste packages. AB - A small scale sample nuclear waste package, consisting of a 28mm diameter uranium penny encased in grout, was imaged by absorption contrast radiography using a single pulse exposure from an X-ray source driven by a high-power laser. The Vulcan laser was used to deliver a focused pulse of photons to a tantalum foil, in order to generate a bright burst of highly penetrating X-rays (with energy >500keV), with a source size of <0.5mm. BAS-TR and BAS-SR image plates were used for image capture, alongside a newly developed Thalium doped Caesium Iodide scintillator-based detector coupled to CCD chips. The uranium penny was clearly resolved to sub-mm accuracy over a 30cm(2) scan area from a single shot acquisition. In addition, neutron generation was demonstrated in situ with the X ray beam, with a single shot, thus demonstrating the potential for multi-modal criticality testing of waste materials. This feasibility study successfully demonstrated non-destructive radiography of encapsulated, high density, nuclear material. With recent developments of high-power laser systems, to 10Hz operation, a laser-driven multi-modal beamline for waste monitoring applications is envisioned. PMID- 27484946 TI - Comparative metagenomic analysis of PAH degradation in soil by a mixed microbial consortium. AB - In this study, we used a taxonomic and functional metagenomic approach to analyze some of the effects (e.g. displacement, permanence, disappearance) produced between native microbiota and a previously constructed Polycyclic Aromatic Hydrocarbon (PAH)-degrading microbial consortium during the bioremediation process of a soil polluted with PAHs. Bioaugmentation with a fungal-bacterial consortium and biostimulation of native microbiota using corn stover as texturizer produced appreciable changes in the microbial diversity of polluted soils, shifting native microbial communities in favor of degrading specific populations. Functional metagenomics showed changes in gene abundance suggesting a bias towards aromatic hydrocarbon and intermediary degradation pathways, which greatly favored PAH mineralization. In contrast, pathways favoring the formation of toxic intermediates such as cytochrome P450-mediated reactions were found to be significantly reduced in bioaugmented soils. PAH biodegradation in soil using the microbial consortium was faster and reached higher degradation values (84% after 30 d) as a result of an increased co-metabolic degradation when compared with other mixed microbial consortia. The main differences between inoculated and non-inoculated soils were observed in aromatic ring-hydroxylating dioxygenases, laccase, protocatechuate, salicylate and benzoate-degrading enzyme genes. Based on our results, we propose that several concurrent metabolic pathways are taking place in soils during PAH degradation. PMID- 27484947 TI - Oil removal of spent hydrotreating catalyst CoMo/Al2O3 via a facile method with enhanced metal recovery. AB - Deoiling process is a key issue for recovering metal values from spent hydrotreating catalysts. The oils can be removed with organic solvents, but the industrialized application of this method is greatly hampered by the high cost and complex processes. Despite the roasting method is simple and low-cost, it generates hardest-to-recycle impurities (CoMoO4 or NiMoO4) and enormous toxic gases. In this study, a novel and facile approach to remove oils from the spent hydrotreating catalysts is developed. Firstly, surface properties of spent catalysts are characterized to reveal the possibility of oil removal. And then, oils are removed with water solution under the conditions of 90 degrees C, 0.1wt% SDS, 2.0wt% NaOH and 10ml/gL/S ratio for 4h. Finally, thermal treatment and leaching tests are carried out to further explore the advantages of oil removal. The results show that no hardest-to-recycle impurity CoMoO4 is found in XPS spectra of thermally treated samples after deoiling and molybdenum is leached completely with sodium carbonate solution. It means that the proposed deoiling method can not only remove oils simply and without enormous harmful gases generating, but also avoid the generation of detrimental impurity and promote recycling of valuable metals from spent hydrotreating catalysts. PMID- 27484948 TI - Rice ingestion is a major pathway for human exposure to organophosphate flame retardants (OPFRs) in China. AB - Although organophosphate flame retardants (OPFRs) have been shown to accumulate in abiotic and biotic environmental compartments, data about OPFRs concentrations in various foods are limited and are none in humans through diets. In this work, the concentrations of 6 typical OPFRs were investigated in 50 rice samples, 75 commonly consumed foods and 45 human hair samples from China. The dietary intakes of OPFRs for adult people via food ingestion were estimated. The concentrations of SigmaOPFRs in foods ranged from 0.004ng/g to 287ng/g. OPFRs were detected in 53.3% of the human hair samples. The highest OPFRs concentrations were found in rice and vegetables. Tri(2-chloroethyl)phosphate(TCEP), tris(2 chloroisopropyl)phosphate(TCIPP), and tri(2-ethyltexyl)phosphate(TEHP) were predominant in all food samples. OPFRs concentrations in foods were not significantly affected by the packaging materials. The mean dietary intakes of SigmaOPFRs for adult males and females were 539 and 601ng/kg body weight/day, respectively. The greatest contribution to these values is from rice, accounting for approximately 60% of the total intake, particularly from rice protein. Rice ingestion was considered a potential major pathway for human exposure to OPFRs, and regional differences in the levels of OPFRs in foods and dietary differences should be given more attention in the future. PMID- 27484950 TI - Strong, healthy, energized: Striving for a healthy weight in an older lesbian population. AB - The Office on Women's Health funded five pilot healthy weight intervention studies for lesbian and bisexual (LB) women, which included a program called Strong. Healthy. Energized (SHE). SHE was a 12-session program, targeted toward LB women age 60 and older, which focused on exercise, including a pedometer to track steps; nutrition; stress management; and group discussions. The program enrolled 39 participants. Waist circumference decreased by 3.7% across the group (p < .01). Participants with the lowest one-third baseline step count saw a marked step increase. This intervention was effective in improving health behaviors and short-term health outcomes for older LB women. PMID- 27484951 TI - New family of biosensors for monitoring BTX in aquatic and edaphic environments. AB - Benzene, toluene, ethylbenzene and xylenes (BTEX) contamination is a serious threat to public health and the environment, and therefore, there is an urgent need to detect its presence in nature. The use of whole-cell reporters is an efficient, easy-to-use and low-cost approach to detect and follow contaminants outside specialized laboratories; this is especially important in oil spills that are frequent in marine environments. The aim of this study is the construction of a bioreporter system and its comparison and validation for the specific detection of monocyclic aromatic hydrocarbons in different host bacteria and environmental samples. Our bioreporter system is based on the two component regulatory system TodS-TodT of P. putida DOT-T1E, and the PtodX promoter fused to the GFP protein as the reporter protein. For the construction of different biosensors, this bioreporter was transferred into three different bacterial strains isolated from three different environments, and their performance was measured. Validation of the biosensors on water samples spiked with petrol, diesel and crude oil on contaminated waters from oil spills and on contaminated soils demonstrated that they can be used in mapping and monitoring some BTEX compounds (specifically benzene, toluene and two xylene isomers). Validation of biosensors is an important issue for the integration of these devices into pollution-control programmes. PMID- 27484949 TI - microRNA-132/212 deficiency enhances Abeta production and senile plaque deposition in Alzheimer's disease triple transgenic mice. AB - The abnormal regulation of amyloid-beta (Abeta) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimer's disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR 132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Abeta production and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Abeta metabolism, including Tau, Mapk, and Sirt1. Consistent with these findings, we show that the modulation of miR-132, or its target Sirt1, can directly regulate Abeta production in cells. Finally, both miR-132 and Sirt1 levels correlated with Abeta load in humans. Overall, our results support the hypothesis that the miR 132/212 network, including Sirt1 and likely other target genes, contributes to abnormal Abeta metabolism and senile plaque deposition in AD. This study strengthens the importance of miR-dependent networks in neurodegenerative disorders, and opens the door to multifactorial drug targets of AD by targeting Abeta and Tau. PMID- 27484952 TI - REM sleep behavior disorder was associated with Parkinson's disease: a community based study. AB - BACKGROUND: Our study was aimed to validate a modified RBD (REM sleep behavior disorder) single question (RBD1Q-C), study the prevalence of probable RBD (pRBD) in a rural community based on RBD1Q-C and investigate the association between pRBD and Parkinson's disease (PD). METHODS: The validation study of RBD1Q-C included 32 Chinese participants (14 idiopathic RBD patients and 18 controls). All participants underwent a polysomnogram (PSG). We then conducted a door-to door survey to estimate the prevalence of pRBD assessed by RBD1Q-C, and its association with PD among 19614 residents who lived in Malu community of Shanghai, China. RESULTS: RBD1Q-C demonstrated a high sensitivity of 100%, a moderate specificity of 55.6%. The agreement between RBD1Q-C and PSG-based RBD diagnosis was good (k = 0.552). PPV of the RBD1Q-C was 63.6% and NPV was 100%. The prevalence of pRBD in Malu community was 4.9%. In people over 50 years old, presence of pRBD was significantly associated with increased risk of having PD (odds ratio = 2.61, 95% CI: 1.56-4.39). CONCLUSION: RBD1Q-C was shown to be a useful screening tool. Based on the RBD1Q-C, we found that pRBD was not rare in Chinese rural population and associated with odds of PD, calling for more attention from patients, caregivers and physicians. PMID- 27484953 TI - Microhardness of human cancellous bone tissue in progressive hip osteoarthritis. AB - Bone tissue is a biological system in which the dynamic processes of, among others, bone formation or internal reconstruction will determine the spatial structure of the tissue and its mechanical properties. The appearance of a factor disturbing the balance between biological processes, e.g. a disease, will cause changes in the spatial structure of bones, thus affecting its mechanical properties. One of the bone diseases most common in an increasingly ageing population is osteoarthritis, also referred to as degenerative joint disease. It is estimated that in 2050 about 1300 million people will show symptoms of OA. The appearance of a pathological stimulus disturbs the balance of the processes of degradation and synthesis of articular cartilage, chondrocytes and the extracellular matrix, and the subchondral bone layer. As osteoarthritis progresses, study of the epiphysis reveals increasingly widespread changes of the articular surface and the internal structure of bone tissue. In this paper, the authors point out the differences in the mechanical properties of cancellous bone tissue forming the proximal epiphysis of the femoral bone during the progressive stages of OA. In order to determine microproperties of bone trabeculae, specimens from different stages of the disease (N=9) were subjected to microindentation testing, which made it possible to determine the material properties of bone tissue, such as microhardness HV and Young's modulus E. In addition, mechanical tests were supplemented with Raman spectroscopy, which determine the degree of bone mineralization, and measurements of structural properties based on analysis using microCT. The conducted tests were used to establish both quantitative and quantitative description of changes in the structural and mechanical properties connected with reorganization of trabeculae making up the bone in the various stages of osteoarthritis. The proposed description will supplement existing knowledge in the literature about identification of the processes occurring during the development of this disease. PMID- 27484954 TI - A simultaneous diagnosis and genotyping method for global surveillance of cetacean morbillivirus. AB - Cetacean morbillivirus (CeMV) is considered one of the most important viral pathogens in cetaceans. CeMV outbreaks of lethal disease have repeatedly been observed in Europe, the Americas, and Australia, while large herds of gregarious species were found to be the likely reservoirs and sources of CeMV infection to susceptible species in the Atlantic and Pacific Oceans. Furthermore, three new strains were detected recently in Hawaii, Brazil and Australia. To clarify the real global distribution of CeMV and possible carriers, we showed a novel technique successfully diagnosing and distinguishing different virus strains (DMV, PWMV and novel CeMVs) using FFPE samples from 1996 to 2011. This efficient method that combines qRT-PCR and high resolution melting (HRM) could be applied to the future retrospective global studies for better understanding of different prevalence and outbreak conditions among ocean basins and the mechanism of variable host response to pathogens. PMID- 27484956 TI - Detecting hepatitis B virus in surgical smoke emitted during laparoscopic surgery. AB - BACKGROUND: Hepatitis B virus (HBV) transmission is known to occur through direct contact with infected blood. There has been some suspicion that the virus can also be detected in aerosol form. However, this has never been directly shown. The purpose of this study was to sample and analyse surgical smoke from laparoscopic surgeries on patients with hepatitis B to determine whether HBV is present. METHODS: A total of 11 patients who underwent laparoscopic or robotic abdominal surgeries between October 2014 and February 2015 at Korea University Anam Hospital were included in this study. A high efficiency collector was used to obtain surgical smoke in the form of hydrosol. The smoke was analysed by using nested PCR. RESULTS: Robotic or laparoscopic colorectal resections were performed in 5 cases, laparoscopic gastrectomies in 3 cases and laparoscopic hepatic wedge resections in another 3 cases. Preoperatively, all of the patients had positive hepatitis B surface antigen (HBsAg). 2 patients had detectable HBsAb, and 2 were positive for hepatitis B e antigen. 3 patients were taking antihepatitis B viral medications at the time of the study. The viral load measured in the patients' blood was undetectable to 1.7*108 IU/mL. HBV was detected in surgical smoke in 10 of the 11 cases. CONCLUSIONS: HBV is detectable in surgical smoke. This study provides preliminary data in the investigation of airborne HBV infection. PMID- 27484955 TI - Risk of renal cell carcinoma following exposure to metalworking fluids among autoworkers. AB - OBJECTIVES: Metalworking fluids (MWF), used to cool and lubricate metal in occupational settings, are linked to several cancers but data on kidney cancer are limited. We examine how MWF influence the rate of renal cell carcinoma (RCC) in a large prospective study. METHODS: A cohort of Michigan autoworkers consisting of 33 421 individuals was followed from 1985 to 2009. The cohort was linked to the Michigan Cancer Registry to identify new cases of RCC. We analysed RCC in relation to cumulative exposure to each specific type of MWF (straight, soluble and synthetic) and all 3 types pooled into a single MWF variable, with a 15-year lag. Cox proportional hazards regression with splines were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), controlling for age, gender, race, calendar year, year hired, time since hire, plant and other MWF types. RESULTS: There were 135 incident cases. A linear increase in the log HR was observed for RCC with increasing cumulative exposure to each MWF type and total MWF exposure. At the mean of total MWF exposure (18.80 mg/m(3)-year), the estimated HR was 1.11 (95% CI 1.04 to 1.19). CONCLUSIONS: Our results provide evidence for a dose-dependent association between MWF exposure and RCC. The influence of components of oil-based and water-based MWF needs further examination. PMID- 27484958 TI - Anti-photoaging properties of the phosphodiesterase 3 inhibitor cilostazol in ultraviolet B-irradiated hairless mice. AB - We investigated whether cilostazol, an activator of cyclic adenosine monophosphate (cAMP)-dependent intracellular signaling, could inhibit ultraviolet B (UVB) irradiation-induced photoaging in HR-1 hairless mice. Cilostazol decreased wrinkle formation and skin thickness in UVB-irradiated mice, as well as increased staining of collagen fibers and inhibition of reactive oxygen species (ROS) formation in the skin. Moreover, the proteolytic activities of gelatinase matrix metalloproteinase (MMP)-9 and collagenase MMP-3 were significantly decreased in UVB-irradiated mice treated with cilostazol. Western blotting showed that UVB-induced activation of p38 mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-kappaB was significantly inhibited by cilostazol, whereas the activation of Akt was significantly enhanced by cilostazol. Confirmation of localized protein expression in the skin revealed marked p38 MAPK and NF-kappaB activation that was mainly detected in the dermis. Marked Akt activation was mainly detected in the epidermis. Our results suggest that cilostazol may have anti-photoaging effects on UVB-induced wrinkle formation by maintaining the extracellular matrix density in the dermis, which occurs via regulation of ROS and related p38 MAPK and NF-kappaB signaling, and subsequent down-regulation of MMPs. Therefore, cilostazol may protect against photoaging-induced wrinkle formation. PMID- 27484959 TI - Modulation of type 1 and type 2 diabetes risk by the intestinal microbiome. AB - The prevalence of type 1 and type 2 diabetes have both risen dramatically over the last 50 years. Recent findings point towards the gut microbiota as a potential contributor to these trends. The hundred trillion bacteria residing in the mammalian gut have established a symbiotic relation with their host and influence many aspects of host metabolism, physiology, and immunity. In this review, we examine recent data linking gut microbiome composition and function to anti-pancreatic immunity, insulin-resistance, and obesity. Studies in rodents and human longitudinal studies suggest that an altered gut microbiome characterized by lower diversity and resilience is associated with type 1 and type 2 diabetes. Through its metabolites and enzymatic arsenal, the microbiota shape host metabolism, energy extracted from the diet and contribute to the normal development of the immune system and to tissue inflammation. Increasing evidence underscores the importance of the maternal microbiome, the gestational environment and the conditions of newborn delivery in establishing the gut microbiota of the offspring. Perturbations of the maternal microbiome during gestation, or that of the offspring during early infant development may promote a pro-inflammatory environment conducive to the development of autoimmunity and metabolic disturbance. Collectively the findings reviewed herein underscore the need for mechanistic investigations in rodent models and in human studies to better define the relationships between microbial and host inflammatory activity in diabetes, and to evaluate the potential of microbe-derived therapeutics in the prevention and treatment of both forms of diabetes. PMID- 27484957 TI - Noninvasive early detection of anthracycline-induced cardiotoxicity in patients with hematologic malignancies using the phased tracking method. AB - Anthracyclines are among the most effective and widely used anticancer drugs; however, their use is limited by serious cardiotoxicity. Early detection is necessary to prevent the high mortality rate associated with heart failure (HF). We evaluated cardiac function in 142 patients using conventional echocardiography and the phased tracking method (PTM), which was measured using the minute vibration and the rapid motion components, neither of which is recognized in standard M-mode nor in tissue Doppler imaging. For systolic function comparison, we compared left ventricular ejection fraction (LVEF) in conventional echocardiography with the average velocity of ventricular septum myocytes (Vave ) in the PTM. The Vave of 12 healthy volunteers was 1.5 (m/s)/m or more. At baseline of 99 patients, there was a positive correlation between LVEF and Vave in all patients. There were no significant differences in baseline cardiac function between patients with and without HF. There was a negative correlation between the cumulative anthracycline dose and LVEF or Vave among all patients. We determined that Vave 1.5 (m/s)/m was equivalent to LVEF 60%, 1.25 (m/s)/m to 55%, and 1.0 (m/s)/m to 50%. During the follow-up period, there was a pathological decrease in LVEF (<55%) and Vave (<1.25 m/s/m) in patients with HF; decreases in Vave were detected significantly earlier than those in LVEF (P < 0.001). When Vave declined to 1.5 (m/s)/m or less, careful continuous observation and cardiac examination was required. When Vave further declined to 1.0 (m/s)/m or lower, chemotherapy was postponed or discontinued; thus, serious drug-induced cardiomyopathy was avoided in patients who did not relapse. The PTM was superior to echocardiography for early, noninvasive detection and intermediate-term monitoring of left ventricle systolic function associated with anthracycline chemotherapy, among patients with hematologic malignancies. The PTM was an effective laboratory procedure to avoid the progression to serious cardiomyopathy. PMID- 27484960 TI - The ALPPS procedure for hepatocellular carcinoma larger than 10 centimeters. AB - INTRODUCTION: The only means of achieving long-term survival in hepatocellular carcinoma is complete tumor resection or liver transplantation. Patients with large hepatocellular carcinomas are currently not considered for liver transplantation. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is indicated in selected patients. We present the case of a patient with a huge hepatocellular carcinoma who underwent an ALPPS procedure. PRESENTATION OF CASE: A 57-year-old man initially presented with a tumor measuring 19cm*10cm in the right lobe of the liver. The liver function was normal and there was no evidence of portal hypertension. The first part of the procedure was performed without mobilizing the liver. The middle hepatic vein was divided during parenchymal transection. The second procedure was performed after 15days. During that procedure the right hepatic artery, right bile duct, and the right hepatic vein were ligated and divided. Liver segments 4-8 with the tumor were removed. The patient developed moderate ascites but recovered after ten days. After 90days, the patient is doing well with no signs of recurrence. DISCUSSION: Hepatocellular carcinoma is a complicated disease and ALPPS is not considered an optimal treatment option. However, patients with large tumors are not considered for liver transplantation or chemotherapy. Patients with Child-Pugh A liver disease without portal hypertension can benefit from surgical treatment for hepatocellular carcinoma; in some situations, surgery may be considerably better than other forms of treatment. CONCLUSION: ALPPS should be considered in selected patients with large hepatocellular carcinomas. PMID- 27484961 TI - Methods for investigating the local spatial anisotropy and the preferred orientation of cones in adaptive optics retinal images. AB - The ability to noninvasively image the cone photoreceptor mosaic holds significant potential as a diagnostic for retinal disease. Central to the realization of this potential is the development of sensitive metrics for characterizing the organization of the mosaic. Here we evaluated previously described and newly-developed (Fourier- and Radon-based) methods of measuring cone orientation in simulated and real images of the parafoveal cone mosaic. The proposed algorithms correlated well across both simulated and real mosaics, suggesting that each algorithm provides an accurate description of photoreceptor orientation. Despite high agreement between algorithms, each performed differently in response to image intensity variation and cone coordinate jitter. The integration property of the Fourier transform allowed the Fourier-based method to be resistant to cone coordinate jitter and perform the most robustly of all three algorithms. Conversely, when there is good image quality but unreliable cone identification, the Radon algorithm performed best. Finally, in cases where the cone coordinate reliability was excellent, the method previously described by Pum and colleagues performed best. These descriptors are complementary to conventional descriptive metrics of the cone mosaic, such as cell density and spacing, and have the potential to aid in the detection of photoreceptor pathology. PMID- 27484962 TI - Fractalkine/CX3CL1 in rheumatoid arthritis. AB - Fractalkine is a CX3C chemokine that exists in both membrane-bound and soluble forms. Interaction between fractalkine and its unique receptor (CX3CR1) induces cell adhesion, chemotaxis, crawling, "accessory cell" activity, and survival. The serum level of fractalkine is elevated in patients with rheumatoid arthritis (RA) and is correlated with disease activity. Peripheral blood CD16+ monocytes and a subset of T cells express CX3CR1, while fractalkine is expressed on fibroblast like synoviocytes and endothelial cells in the synovial tissue of patients with RA. Fractalkine expression is enhanced by tumor necrosis factor-alpha and interferon-gamma, and it promotes the migration of monocytes, T cells, and osteoclast precursors into RA synovial tissue. Fractalkine also induces the production of inflammatory mediators by macrophages, T cells, and fibroblast-like synoviocytes. Moreover, fractalkine promotes angiogenesis and osteoclastogenesis. In an animal model of RA, arthritis was improved by the abrogation of fractalkine. Recently, a clinical trial of an anti-fractalkine monoclonal antibody for the treatment of RA commenced in Japan. We review the multiple roles of fractalkine in the pathogenesis of RA and its potential as a therapeutic target for this disease. PMID- 27484963 TI - Aging of the endocrine system and its potential impact on sarcopenia. AB - Sarcopenia, occurring as a primary consequence of aging, is a progressive generalized decline of skeletal muscle mass, strength and function. The pathophysiology of sarcopenia is complex and multifactorial. One major cause of muscle mass and strength loss with aging appears to be the alteration in hormonal networks involved in the inflammatory processes, muscle regeneration and protein synthesis. This review describes the recent findings concerning the role of the aging on the endocrine system in the development of sarcopenia. We also report the benefits and safety of hormone replacement therapy in elderly subjects and discuss future perspectives in the therapy and prevention of skeletal muscle aging. PMID- 27484964 TI - Fetal cerebral and umbilical Doppler in pregnancies complicated by late-onset placental abruption. AB - OBJECTIVE: To evaluate whether changes in the cerebroplacental Doppler and birth weight (BW) suggestive of chronic fetal hypoxemia, precede the development of late-onset placental abruption (PA) after 32 weeks. METHODS: In a multicenter retrospective study, the Doppler examinations of the fetal umbilical artery (UA) and middle cerebral artery (MCA) recorded after 32 weeks were collected in pregnancies subsequently developing PA. The BW centiles were calculated and the MCA pulsatility indices (PI), and UA PI were converted into multiples of the median (MoM). Afterwards, a comparison was made with a group of fetuses, which did not develop PA. Logistic regression was used to adjust for potential confounders and evaluate the feasibility of the prediction model. RESULTS: Pregnancies complicated by late-onset PA (n = 31) presented lower MCA PI (p = 0.015) and were smaller (p < 0.001) than those who did not (n = 1294). Logistic regression analysis indicated that cerebral vasodilation was more important than umbilical flow in the explanation of PA (MCA PI OR = 0.106, p = 0.014 and UA PI OR 1.901, p = 0.32). In addition, the influence of BW exerted was residual (BW centile OR = 0.989, p = 0.15). CONCLUSIONS: Fetuses developing late-onset PA demonstrate significant cerebral vasodilation with scarce placental dysfunction, suggesting the existence of some kind of chronic hypoxemia that follows the late onset pattern. PMID- 27484965 TI - Repetitive thinking, executive functioning, and depressive mood in the elderly. AB - OBJECTIVES: Previous findings and the depressive-executive dysfunction hypothesis suggest that the established association between executive functioning and depression is accounted for by repetitive thinking. Investigating the association between executive functioning, repetitive thinking, and depressive mood, the present study empirically tested this mediational model in a sample of older adults, while focusing on both concrete and abstract repetitive thinking. This latter distinction is important given the potential protective role of concrete repetitive thinking, in contrast to the depletive effect of abstract repetitive thinking. METHOD: A sample of 43 elderly volunteers, between 75 and 95 years of age, completed tests of executive functioning (the Stroop test, the Trail Making test, and the Fluency test), and questionnaires of repetitive thinking and depression. RESULTS: Positive correlations were observed between abstract repetitive thinking and depressive mood, and between concrete repetitive thinking and executive functioning; a negative correlation was observed between depressive mood and executive functioning. Further, mediational analysis evidenced that the relation between executive functioning and depressive mood was mediated by abstract repetitive thinking. CONCLUSION: The present data provide, for the first time, empirical support to the depressive-executive dysfunction hypothesis: the lack of executive resources would favor a mode of abstract repetitive thinking, which in turn would deplete mood. It suggests that clinical intervention targeting depression in the elderly should take into consideration repetitive thinking modes and the executive resources needed to disengage from rumination. PMID- 27484966 TI - Exploring the interaction between picoplatin and human serum albumin: The effects on protein structure and activity. AB - For the first time, the effects of picoplatin on the structure and esterase-like catalytic activity of human serum albumin (HSA) have been investigated by spectroscopic approaches and molecular modeling. The circular dichroism (CD) spectral examinations indicated that the binding of picoplatin with HSA induced a slight decrease of a-helix content of protein and unfolded the constituent polypeptides of the protein. The synchronous fluorescence and three-dimensional fluorescence spectral methods were used to estimate the effect of picoplatin on the micro-environmental changes of the Trp and Tyr residues of HSA, indicating that the micro-environment around the Tyr and Trp residue is partly disturbed by picoplatin. UV-vis absorption spectral result indicated the formation of the ground state complex between picoplatin with HSA. The ANS binding assay indicated the existence of competitive combination of picoplatin and ANS with HSA. The studies on the effects of picoplatin on the binding of HSA with bilirubin and heme showed that picoplatin binding caused a change of angle between two chromophores of bound bilirubin and the binding site of picoplatin does not locate in subdomain IB in HSA that bound with heme. The molecular modeling results showed that picoplatin binds to the connection between domain I and domain II by hydrophobic, hydrogen bonds, and van der Waals forces. In addition, HSA maintains most of its esterase activity in the presence of picoplatin. The investigations on how picoplatin interacts with HSA are important for the understanding of the anticancer mechanism and toxicity of platinum-based anticancer drug. PMID- 27484967 TI - Adjusting irradiance to enhance growth and lipid production of Chlorella vulgaris cultivated with monosodium glutamate wastewater. AB - Light is one of the most important factors affecting microalgae growth and biochemical composition. The influence of illumination on Chlorella vulgaris cultivated with diluted monosodium glutamate wastewater (MSGW) was investigated. Six progressive illumination intensities (0, 30, 90, 150, 200 and 300MUmol.m( 2)s(-1)), were used for C. vulgaris cultivation at 25 degrees C. Under 150MUmol.m(-2)s(-1), the corresponding specific light intensity of 750*10( 6)MUmol.m(-2)s(-1) per cell, algae obtained the maximum biomass concentration (1.46g.L(-1)) on the 7th day, which was 3.5 times of that under 0MUmol.m(-2)s( 1), and the greatest average specific growth rate (0.79 d(-1)) in the first 7days. The results showed the importance role of light in mixotrophic growth of C. vulgaris. High light intensities of 200 and 300MUmol.m(-2)s(-1) would inhibit microalgae growth to a certain degree. The algal lipid content was the greatest (30.5%) at 150MUmol.m(-2)s(-1) light intensity, which was 2.42 times as high as that cultured in dark. The protein content of C. vulgaris decreased at high light intensities of 200 and 300MUmol.m(-2)s(-1). The effect of irradiance on carbohydrate content was inversely correlated with that on protein. The available light at an appropriate intensity, not higher than 200MUmol.m(-2)s(-1), was feasible for economical cultivation of C. vulgaris in MSGW. PMID- 27484968 TI - An erythematous palmoplantar rash due to human parechovirus. PMID- 27484969 TI - Developing, implementing and evaluating integrated care models for infants, children, young people and their families. PMID- 27484970 TI - New patient-reported experience measure for children with allergic disease: development, validation and results from integrated care. AB - OBJECTIVES: To develop and validate a new allergy-specific patient-reported experience measure (PREM) for children and their parents, and to collect feedback in an integrated care setting. DESIGN: Two allergy-specific PREMs were produced using focus groups, cognitive testing, two prospective validation studies (collaboration: Royal College of Paediatrics and Child Health, Picker Institute Europe, Imperial College/London): 'Your Allergy Care', for children aged 8-16 years; 'Your Child's Allergy Care', for parents of children aged 0-7 years. SETTING: Community event, primary/secondary/tertiary allergy care settings. MAIN OUTCOME MEASURES: Performance of PREMs in validation study; reported experience of allergy care. PARTICIPANTS: 687 children with allergic conditions and their parents/carers. RESULTS: In total, 687 questionnaires were completed; 503/687 (253 child; 250 parent) for the final survey. In both surveys, demographic variations were not associated with differences in results. Although 71% of patients reported one or more allergic conditions (food allergy/eczema/hay fever/asthma), 62% required multiple visits before receiving final diagnosis. Overall, patient experience was good for communication with patient/parent, competence and confidence in ability, and 73% felt looked after 'very well' and 23% 'quite well'. Areas for improvement included communication with nurseries/schools, more information on side effects, allergic conditions and allergen/irritant avoidance. Allergy care in primary/emergency care settings was associated with higher problem-scores (worse experience) than in specialist clinics. CONCLUSIONS: These new PREMs will allow allergy-specific patient experience reporting for children and parents and help identification of priority areas for improvement and commissioning of care. Efforts towards better allergy care provision must be targeted at primary and emergency care settings and underpinned by improving communication between healthcare providers and the community. PMID- 27484971 TI - Outcome of adenotonsillectomy in children with Down syndrome and obstructive sleep apnoea. AB - OBJECTIVE: To evaluate the outcome of adenotonsillectomy (AT) in a cohort of children with Down syndrome (DS) and obstructive sleep apnoea (OSA). DESIGN: Retrospective, cross-sectional study. SETTING: Tertiary care centre. PATIENTS: Children with DS and OSA, without previous upper airway (UA) surgery. INTERVENTIONS: AT and full overnight polysomnography. MAIN OUTCOME RESULTS: A significant improvement of the obstructive apnoea-hypopnoea index (oAHI) after AT was obtained. No differences in sleep efficiency or sleep fragmentation were found postoperatively. Almost half of the children had persistent OSA (oAHI >=5/hour). RESULTS: Data are presented as median (lower-upper quartile). Thirty four children were included, median age 4.0 years (2.7-5.8), body mass index (BMI) z-score 0.81 (-0.46-1.76), and oAHI 11.4/hour (6.5-22.7). The majority presented with severe OSA (58.9%). AT was performed in 22 children, tonsillectomy in 10 and adenoidectomy in two. Postoperatively, a significant improvement of the oAHI was measured from 11.4/hour (6.5-22.7) to 3.6/hour (2.1-9.5) (p=0.001), with a parallel increase of the minimum oxygen saturation (p=0.008). Children with initially more severe OSA had significantly more improvement after UA surgery (p=0.001). Persistent OSA was found in 47.1% of the children. CONCLUSIONS: AT results in a significant improvement of OSA in children with DS without a change in sleep efficiency or sleep stage distribution. Severe OSA was associated with a larger reduction of OSA severity. Almost half of the children had persistent OSA, which was not correlated to age, gender or BMI z-score. PMID- 27484972 TI - Hemodynamics through the congenitally bicuspid aortic valve: a computational fluid dynamics comparison of opening orifice area and leaflet orientation. AB - A computational fluid dynamics model of a bicuspid aortic valve has been developed using idealised three-dimensional geometry. The aim was to compare how the orifice area and leaflet orientation affect the hemodynamics of a pure bicuspid valve. By applying physiologic material properties and boundary conditions, blood flow shear stresses were predicted during peak systole. A reduced orifice area altered blood velocity, the pressure drop across the valve and the wall shear stress through the valve. Bicuspid models predicted impaired blood flow similar to a stenotic valve, but the flow patterns were specific to leaflet orientation. Flow patterns developed in bicuspid aortic valves, such as helical flow, were sensitive to cusp orientation. In conclusion, the reduced opening area of a bicuspid aortic valve amplifies any impaired hemodynamics, but cusp orientation determines subsequent flow patterns which may determine the specific regions downstream from the valve most at risk of clinical complications. PMID- 27484973 TI - Preoperative hemoglobin level: the best predictor of transfusion of packed red cells. AB - Blood transfusions could have serious consequences for patients. A reduction in the transfusion rate could be accomplished by an optimized blood management. Clear guidelines and awareness among all employees at a single institution have resulted in a reduction in transfusion rates in recent years. Identification of the group of patients who still received a blood transfusion in recent years could result in a further reduction. This study enrolled 4022 patients undergoing cardiothoracic surgery between 2008 and 2013. Patients were divided into three groups: "no blood transfusion", "transfusion of packed red cells only" and "any other combinations of blood transfusion". In total, 16 variables were tested for their association with the administration of homologous blood. The variables associated with blood transfusion were included in a stepwise multinomial logistic regression analysis to find the variables with the strongest association.For the transfusion of packed red cells only and any other combinations of blood transfusion, the following predictors are found: gender, age, weight, type of surgery, reoperation, unstable angina pectoris, endocarditis, recent myocardial infarction, preoperative creatinine level, preoperative hemoglobin level and preoperative platelet count. The best predictor for the transfusion of packed red cells is preoperative hemoglobin level (4.1 to 7.8 mmol/l). For other blood products, the strongest association was found with type of surgery (aortic surgery, ventricular septal rupture and intracardiac tumour). PMID- 27484974 TI - Cross-talk between the dipeptidyl peptidase-4 and stromal cell-derived factor-1 in stem cell homing and myocardial repair: Potential impact of dipeptidyl peptidase-4 inhibitors. AB - Dipeptidyl peptidase-4 (DPP-4), glycyl-prolyl-naphthylamidase, is a serine protease that catalyzes the hydrolysis of various proline-containing polypeptides. It is involved in the inactivation of glucagon-like peptide-1 (GLP 1) and glucose-dependent insulinotropic polypeptide (GIP), having in this way a profound influence on glucose metabolism. During organ damage, stromal and endothelial cells produce a chemokine known as stromal cell-derived factor-1 (SDF 1), a powerful chemoattractant of stem/progenitor cells. SDF-1 binds to a specific alpha-chemokine receptor (CXCR4) and can be degraded by proteases, including matrix DPP-4/CD26, presented in the circulation, or activated in injured tissues. DPP-4 inhibition has received considerable attention because of its significant therapeutic benefits in the regulation of insulin secretion and tissue insulin sensitivity, the regulation of tumor growth and metastasis, angiogenesis, tissue repair, especially after myocardial infarction, and regulation of endocrine function. Inhibition of circulating proteases appears to maintain the optimal endogenous SDF-1 concentration and may enhance homing of endothelial progenitor cells. In the present article, we present an overview of some basic facts about the role of DPP-4 in glucose homeostasis, the mechanism of its inhibition, and a brief summary of available DPP-4 inhibitors. Furthermore, since protection against the overactivity of proteases is important for restorating cardiac function and repair after myocardial damage, necrosis and apoptosis, we propose that administration of a DPP-4 inhibitor may also be beneficial following myocardial infarction by the prevention of cleavage of stem cell chemoattractant cytokine SDF-1. PMID- 27484975 TI - Study of Binding Interaction between Pif80 Protein Fragment and Aragonite. AB - Pif is a crucial protein for the formation of the nacreous layer in Pinctada fucata. Three non-acidic peptide fragments of the aragonite-binding domain (Pif80) are selected, which contain multiple copies of the repeat sequence DDRK, to study the interaction between non-acidic peptides and aragonite. The polypeptides DDRKDDRKGGK (Pif80-11) and DDRKDDRKGGKDDRKDDRKGGK (Pif80-22) have similar binding affinity to aragonite. Solid-state NMR data indicate that the backbones of Pif80-11 and Pif80-22 peptides bound on aragonite adopt a random coil conformation. Pif80-11 is a lot more effective than Pif80-22 in promoting the nucleation of aragonite on the substrate of beta-chitin. Our results suggest that the structural arrangement at a protein-mineral interface depends on the surface structure of the mineral substrate and the protein sequence. The side chains of the basic residues, which function as anchors to the aragonite surface, have uniform structures. The role of basic residues as anchors in protein-mineral interaction may play an important role in biomineralization. PMID- 27484976 TI - Changes in Gastric Volume and Their Implications for Weight Loss after Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is a relatively new surgical technique for the treatment of morbid obesity. It is unclear whether the volume of the gastric remnant can expand after surgery as a result of intraluminal pressure maintained over time. If this were the case, the increased volume could affect weight loss and the improvement in comorbidities. This study aims to assess the evolution of residual gastric volume (RGV) during the first year after LSG and its relationship with weight loss. MATERIAL AND METHODS: We conducted a prospective study of 112 patients who underwent LSG from February 2009 to December 2013. In order to measure the RGV after surgery, all patients were evaluated radiologically by an esophagogastroduodenal (EGD) transit at 1 and 12 postoperative months. RESULTS: All patients showed a significant reduction in BMI compared with the preoperative measurement (33.48 +/- 5.78 vs. 50.54 +/- 6.69 kg/m2; p < 0.001). Increased RGV was observed when comparing the results obtained by EGD transit at 1 (68.39 +/- 25.89 cm3) and 12 postoperative months (122.58 +/- 38.76 cm3; p < 0.001). There was no association between increase in gastric volume and weight loss at 1-year follow-up (r = 0.01; p = 0.910). CONCLUSIONS: The volume of the gastric remnant increased significantly during the first year after LSG. However, this increase was not associated with weight loss. Further prospective research with longer follow-up periods is needed to confirm or contrast the present results. PMID- 27484977 TI - Arsenic, Lead, and Cadmium in U.S. Mushrooms and Substrate in Relation to Dietary Exposure. AB - Wild mushrooms can absorb high quantities of metal(loid)s, yet the concentration, speciation, and localization of As, Pb, and Cd in cultivated mushrooms, particularly in the United States, are unresolved. We collected 40 samples of 12 types of raw mushrooms from 2 geographic locations that produce the majority of marketable U.S. mushrooms and analyzed the total As, Pb, and Cd content, the speciation and localization of As in select samples, and assessed the metal sources and substrate-to-fruit transfer at one representative farm. Cremini mushrooms contained significantly higher total As concentrations than Shiitake and localized the As differently; while As in Cremini was distributed throughout the fruiting body, it was localized to the hymenophore region in Shiitake. Cd was significantly higher in Royal Trumpet than in White Button, Cremini, and Portobello, while no difference was observed in Pb levels among the mushrooms. Concentrations of As, Pb, and Cd were less than 1 MUg g(-1) d.w. in all mushroom samples, and the overall risk of As, Cd, and Pb intake from mushroom consumption is low in the U.S. However, higher percentages of tolerable intake levels are observed when calculating risk based on single serving-sizes or when substrate contains elevated levels of metal(loid)s. PMID- 27484979 TI - Solvent-dependent singlet oxygen lifetimes: temperature effects implicate tunneling and charge-transfer interactions. AB - The effect of solvent on the lifetime of singlet oxygen, O2(a(1)Deltag), particularly the pronounced H/D solvent isotope effect, has drawn the attention of chemists for almost 50 years. The currently accepted model for this phenomenon is built on a foundation in which the electronic excitation energy of O2(a(1)Deltag) is transferred to vibrational modes in a solvent molecule, with oxygen returning to its ground electronic state, O2(X(3)Sigmag(-)). This model of electronic-to-vibrational (e-to-v) energy transfer specifically focusses on the solvent as a "sink" for the excitation energy of O2(a(1)Deltag). On the basis of temperature-dependent changes in the solvent-mediated O2(a(1)Deltag) lifetime, we demonstrate that this energy-sink-based model has limitations and needs to be re formulated. We now show that the effect of solvent on the O2(a(1)Deltag) lifetime is more reasonably interpreted by considering an activation barrier that reflects the extent to which a solvent molecule perturbs the forbidden O2(a(1)Deltag) -> O2(X(3)Sigmag(-)) transition. For a given solvent molecule, this barrier reflects contributions from (a) the oxygen-solvent charge transfer state that mediates nonradiative coupling between the O2(a(1)Deltag) and O2(X(3)Sigmag(-)) states, and (b) vibrations of specific bonds in the solvent molecule. The latter establishes connectivity to the desirable features of the energy-sink-based model. Moreover, temperature-dependent H/D solvent isotope effects imply that tunneling through this barrier plays a role in the mechanism for O2(a(1)Deltag) deactivation, even at room temperature. Although we focus on a long-standing problem involving O2(a(1)Deltag), our results and interpretation touch fundamental issues of interest to chemists at large. PMID- 27484978 TI - Monoamines and cortisol as potential mediators of the relationship between exercise and depressive symptoms. AB - A randomized controlled trial was conducted to assess the effects of exercise plus pharmacotherapy on monoamine neurotransmitters (dopamine, noradrenaline, adrenaline, serotonin) and cortisol levels. A total of 26 women with clinical depression were randomly assigned to one of the two groups: aerobic exercise plus pharmacotherapy or only pharmacotherapy. The exercise program consisted of aerobic exercise, 45-50 min/session, three times/week, for 16 weeks. The biological parameters were measured before and after the exercise program. Adding exercise to pharmacotherapy had no additional effects on monoamines and cortisol plasma levels. These data are preliminary outcomes from a small sample and should be replicated. PMID- 27484980 TI - Long-Term Outcomes and Prognostic Factors in Periampullary Carcinoma. AB - PURPOSE: The aim of the study was to analyze the long-term survival and the various prognostic factors that influence overall survival in patients undergoing pancreaticoduodenectomy (PD) with non-pancreatic periampullary carcinomas. METHODS: A retrospective analysis of consecutive patients diagnosed with non pancreatic periampullary carcinomas who underwent PD at a tertiary cancer center was performed. Univariate analysis of various prognostic factors influencing the disease-free survival (DFS) was performed using log-rank test. Factors identified to be significant in univariate analysis were included in the multivariate analysis, which was performed using the Cox proportional hazard model. The survival estimates were calculated by life-table method. Statistical significance was considered when p value was <0.05. The SPSS v16.0.1 software was used for statistical analysis. RESULTS: Between 1995 and 2010, 78 patients underwent PD with or without (Whipple's operation) pylorus preservation for non-pancreatic periampullary adenocarcinomas. Of these, eight patients received adjuvant chemotherapy. The most common subsite was ampulla (60 patients), followed by the second part duodenum (11 patients), and distal common bile duct (7 patients). The median duration of follow-up of all patients in this study was 50 months. The recurrence rate was 39.7 %. The 5-year disease-free survival and overall survival was 57 %. Patients without nodal metastasis had a non-significant trend towards better 5-year disease-free survival when compared to those with nodal metastasis (64 vs 45 %, p = 0.11). On multivariate analysis, it was found that male gender (p = 0.05) and presence of lymphovascular invasion (p = 0.04) predicted a significantly poor 5-year disease-free survival. CONCLUSION: Periampullary carcinomas have a favorable prognosis after surgery. Male gender and presence of lymphovascular invasion are independent prognostic factors in patients diagnosed with non-pancreatic periampullary carcinomas who underwent PD in this study. PMID- 27484981 TI - Mechanisms behind Topoisomerase II SUMOylation in chromosome segregation. PMID- 27484983 TI - Probing the Influence of Amino Acids on Photoluminescence from Carbon Nanotubes Suspended with DNA. AB - The quantitative analysis of amino acid levels in the human organism is required for the early clinical diagnosis of a variety of diseases. In this work the influence of 13 amino acid doping on the photoluminescence (PL) from the semiconducting single-walled carbon nanotubes (SWNTs) suspended with single stranded DNA (ssDNA) in water has been studied. Amino acid doping leads to the PL enhancement and the strongest increase was found after cysteine doping of the nanotube suspension while addition of other amino acids yielded the significantly smaller effect. The emphasis of cysteine molecules is attributed to presence of the reactive thiol group that turns cysteine into reducing agent that passivates the p-defects on the nanotube sidewall and increases the PL intensity. The reasons of PL enhancement after doping with other amino acids are discussed. The response of nanotube PL to cysteine addition depends on the nanotube aqueous suspension preparation with tip or bath sonication treatment. The enhancement of the emission from different nanotube species after cysteine doping was analyzed too. It was shown that the increase of the carbon nanotube PL at addition of cysteine allows successful monitoring of the cysteine concentration in aqueous solution in the range of 50-1000 MUM. PMID- 27484982 TI - Meiotic pairing and gene expression disturbance in germ cells from an infertile boar with a balanced reciprocal autosome-autosome translocation. AB - Individuals carrying balanced constitutional reciprocal translocations generally have a normal phenotype, but often present reproductive disorders. The aim of our research was to analyze the meiotic process in an oligoasthenoteratospermic boar carrying an asymmetric reciprocal translocation involving chromosomes 1 and 14. Different multivalent structures (quadrivalent and trivalent plus univalent) were identified during chromosome pairing analysis. Some of these multivalents were characterized by the presence of unpaired autosomal segments with histone gammaH2AX accumulation sometimes associated with the XY body. Gene expression in spermatocytes was studied by RNA-DNA-FISH and microarray-based testis transcriptome analysis. Our results revealed a decrease in gene expression for chromosomes 1 and 14 and an up-regulated expression of X-chromosome genes for the translocated boar compared with normal individuals. We hypothesized that the observed meiotic arrest and reproductive failure in this boar might be due to silencing of crucial autosomal genes (MSUC) and disturbance of meiotic sex chromosome inactivation (MSCI). Further analysis revealed abnormal meiotic recombination (frequency and distribution) and the production of a high rate of unbalanced spermatozoa. PMID- 27484984 TI - Synthesis, Aggregation Induced Emission and Mechanochromic Luminescence of New beta-Diketone Derivatives Bearing Tetraphenylene Moieties. AB - A series of beta-diketone derivatives bearing tetraphenylene (TPE) moieties were synthesized and characterized. Their photophysical properties were investigated systematically via spectroscopic and theoretical methods. All compounds exhibit broad absorption bands between 300 and 450 nm, which are assigned to the 1pi-pi* transition of the conjugated system mixed intramolecular charge-transfer (ICT) transitions. Meanwhile, the emission of these compounds in solution at room temperature (lambda em = 458 ~ 509 nm) can be attributed to the 1pi,pi*/1ICT state. Introduction of freely rotatable TPE to conventional beta-diketone luminophors quenches their light emissions in the solutions, but endows these molecules with aggregation-induced emission (AIE) characteristics in the condensed phase due to the restriction of intramolecular rotation. The spectroscopic studies and theoretical calculations indicate that the photophysical properties of these beta-diketone derivatives can be tuned by the appended substituents, which would be useful for rational design of AIE compounds with high solid state luminescence performance. Furthermore, these AIE-active compounds exhibited distinct piezofluorochromic properties and switched reversibly upon grinding-fuming. Their photophysical properties have been investigated with the aim to provide a basis for elucidating the structure property correlations and developing new multi-stimuli responsive luminescent materials. PMID- 27484985 TI - Relationship between fasting glucose levels and in-hospital mortality in Chinese patients with acute myocardial infarction and diabetes mellitus: a retrospective cohort study. AB - BACKGROUND: Previous studies have demonstrated that elevated admission and fasting glucose (FG) is associated with worse outcomes in patients with acute myocardial infarction (AMI). However, the quantitative relationship between FG levels and in-hospital mortality in patients with AMI remains unknown. The aim of the study is to assess the prevalence of elevated FG levels in hospitalized Chinese patients with AMI and diabetes mellitus and to determine the quantitative relationship between FG levels and the in-hospital mortality as well as the optimal level of FG in patients with AMI and diabetes mellitus. METHODS: A retrospective study was carried out in 1856 consecutive patients admitted for AMI and diabetes mellitus from 2002 to 2013. Clinical variables of baseline characteristics, in-hospital management and in-hospital adverse outcomes were recorded and compared among patients with different FG levels. RESULTS: Among all patients recruited, 993 patients (53.5 %) were found to have FG >=100 mg/dL who exhibited a higher in-hospital mortality than those with FG < 100 mg/dL (P < 0.001). Although there was a high correlation between FG levels and in-hospital mortality in all patients (r = 0.830, P < 0.001), the relationship showed a J curve configuration with an elevated mortality when FG was less than 80 mg/dL. Using multivariate logistic regression models, we identified that age, FG levels and Killip class of cardiac function were independent predictors of in-hospital mortality in AMI patients with diabetes mellitus. CONCLUSIONS: More than half of patients with AMI and diabetes mellitus have FG >=100 mg/dL and the relationship between in-hospital mortality and FG level was a J-curve configuration. Both FG >= 100 mg/dL and FG <80 mg/dL were identified to be independent predictors of in hospital mortality and thus the optimal FG level in AMI patients with diabetes mellitus appears to be 80-100 mg/dL. PMID- 27484987 TI - Impact of e-cigarette refill liquid with or without nicotine on liver function in adult rats. AB - This study was conducted to evaluate the effects of e-cigarette refill liquid administration alone or with nicotine on the antioxidant defense status, functional and histopathological changes in adult rat liver tissue. For this purpose, 32 rats were treated for 28 days as follows: control group was injected intra-peritoneally with physiological saline; e-cigarette 0% treated group received an intra-peritoneal injection of e-liquid without nicotine diluted in physiological saline, e-cigarette-treated group received an intra-peritoneal injection of e-liquid containing 0.5 mg of nicotine/kg of body weight/day diluted in physiological saline and nicotine-treated group received an intra-peritoneal injection of 0.5 mg of nicotine/kg of body weight/day diluted in physiological saline. In e-liquid without nicotine-exposed group, activities of the liver biomarkers aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and lactate dehydrogenase increase. Interestingly, oxidative stress indicators showed decreased total protein content, associated with a reduction in the antioxidant enzymes activities superoxide dismutase, catalase and glutathione S-transferase, and an elevation in malondialdehyde content, highlighting the promotion of lipid peroxidation and oxidative stress. Histological studies identified inflammatory cells infiltration and cell death. Thus, e-liquid seems to promote oxidative tissue injuries, which in turn lead to the observed histopathological finding. In comparison, nicotine alone induced less oxidative stress and less histopathological disorders, whereas e-liquid with nicotine gave rise to more histopathological injuries. Thereby, e-liquid, per se, is able to induce hepatotoxicity and supplementation with nicotine worsens this state. PMID- 27484986 TI - Therapeutic effects of paeonol on methyl-4-phenyl-1,2,3,6 tetrahydropyridine/probenecid-induced Parkinson's disease in mice. AB - Paeonol is a major phenolic compound of the Chinese herb, Cortex Moutan, and is known for its antioxidant, anti-inflammatory and antitumor properties. The present study was designed to investigate the therapeutic potential and underlying mechanisms of paeonol on a 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine/probenecid (MPTP/p)-induced mouse model of Parkinson's disease (PD). MPTP (25 mg/kg), followed by probenecid (250 mg/kg), was administered via i.p. injection for five consecutive days to induce the mouse model of PD. Paeonol (20 mg/kg) was administrated orally for 21 days. Behavior was assessed using the rotarod performance and open-field tests. Additionally, the levels of tyrosine hydroxylase (TH), microglia, interleukin-1beta (IL-1beta), and brain-derived neurotrophic factor (BDNF) in the substantia nigra pars compacta (SNpc) were evaluated by immunohistochemical staining. MPTP/p-induced motor deficits were observed to be significantly improved following long-term treatment with paeonol. Paeonol treatment decreased MPTP/p-induced oxidative stress, as determined by evaluating the activity levels of superoxide dismutase, catalase and glutathione. Additionally, MPTP/p-induced neuroinflammation was assessed by examining the levels of microglia and IL-1beta, which were significantly decreased following paeonol treatment. Paeonol treatment improved the MPTP/p-induced dopaminergic neurodegeneration, as measured by observing the increased TH level in the SNpc. Furthermore, the BDNF level was significantly elevated in the paeonol treatment group compared with mice treated with MPTP/p only. In conclusion, paeonol exerted therapeutic effects in the MPTP/p-induced mouse model of PD, possibly by decreasing the damage from oxidative stress and neuroinflammation, and by enhancing the neurotrophic effect on dopaminergic neurons. The results demonstrate paeonol as a potential novel treatment for PD. PMID- 27484988 TI - Scar Assessment After Breast Augmentation Surgery with Axillary Incision versus Inframammary Fold Incision: Long-Term Follow-Up in Chinese Patients. AB - BACKGROUND: The inframammary fold (IMF) incision is widely used in Western countries for breast augmentation surgery, whereas the axillary incision is the dominant approach used in China, because many Chinese surgeons believe that the Asian population has a higher risk of developing hypertrophic scars. However, comparative data of scar assessment through different incisions in Chinese patients are scarce. The aims of the study were as follows: (1) to evaluate the outcomes of scar assessment using the Vancouver scar scale (VSS), combined with patient satisfaction scoring, in the scar assessment after breast augmentation surgery; (2) to compare the long-term cosmetic effects of surgical scars between axillary and IMF incisions. METHODS: Consecutive patients coming to our department for follow-up care at least 1 year after primary breast augmentation surgeries with axillary and IMF incisions between January 1, 2014 and December 31, 2014 were included in the research. Internal consistency, inter-rater reliability, and convergent validity were examined for the VSS and patient satisfaction scoring. The baseline characteristics and scar scores were tested using the Mann-Whitney U-test and Student's t test between the two groups. RESULTS: Sixty-one patients underwent implantation surgeries through the axillary incisions, and 17 patients through the IMF incisions. There were no significant differences in age, follow-up time, body mass index, implant volume, or implant projection between groups. Reliability and validity of the VSS and patient satisfaction scoring were satisfactory. The scores of pigmentation were higher in the IMF group than those in the axilla group with statistical significance (P < 0.05). The scores of other subscales, overall VSS scores, and patient satisfaction were not statistically significant. The scars were significantly longer in the axilla group compared with the IMF group (P < 0.05). CONCLUSIONS: The VSS combined with patient satisfaction scoring constitutes an effective tool to evaluate incision scars after augmentation mammaplasty. Scars in the axilla and IMF can achieve comparable cosmetic effects and patient satisfaction in Chinese women. Chinese patients with proper indications can receive breast augmentation surgery through the IMF incision, with fewer risks and less trauma, and get satisfactory scar appearance as through the axillary incision. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27484990 TI - Burkitt Lymphoma Presenting as an Intracardiac Mass: Case Report and Review of Literature. AB - BACKGROUND Non-neoplastic causes such as infections and thrombi account for most intracardiac masses. Primary tumors such as myxomas and metastasis from breast cancer, lung cancer, or melanomas account for many of the remaining cases. Burkitt lymphoma manifesting as an intracardiac mass is a rare entity, with 21 cases reported in the English literature. CASE REPORT We report the case of a man infected with human immunodeficiency virus (HIV) who presented with non-specific cardiac symptoms and was later found to have intracardiac mass caused by Burkitt lymphoma. His rapid decline with unexpected complications was reversed with prompt management. Subsequent to induction, the patient achieved a near complete response with considerable improvement in his condition. CONCLUSIONS Lymphoma should be considered in the differential diagnosis of intracardiac masses. Associated cardiac symptoms are frequently non-specific and can often be overlooked or underappreciated. Burkitt lymphoma has a short doubling time and an intracardiac lesion can become life-threatening in a matter of days. Early recognition and prompt treatment are crucial to achieving optimal outcomes. PMID- 27484989 TI - Lack of concordance between residual viremia and viral variants driving de novo infection of CD4(+) T cells on ART. AB - BACKGROUND: In most patients, current antiretroviral therapy (ART) regimens can rapidly reduce plasma viral load. However, even after years of effective treatment, a significant proportion of patients show residual plasma viremia below the clinical detection limit. Although residual viremia might be associated with increased chronic immune activation and morbidity, its origin and its potential role in the replenishment of the viral reservoir during suppressive ART is not completely understood. We performed an in-depth genetic analysis of the total and episomal cell-associated viral DNA (vDNA) repertoire in purified CD4(+) T cell subsets of three HIV-infected individuals, and used phylogenetic analysis to explore its relationship with plasma viruses. RESULTS: The predominant proviral reservoir was established in naive or memory (central and transitional) CD4(+) T cell subsets in patients harboring X4- or R5-tropic viruses, respectively. Regardless of the viral tropism, most plasma viruses detected under suppressive ART resembled the proviral reservoir identified in effector and transitional memory CD4(+) T-cell subsets in blood, suggesting that residual viremia originates from these cells in either blood or lymphoid tissue. Most importantly, sequences in episomal vDNA in CD4(+) T-cells were not well represented in residual viremia. CONCLUSIONS: Viral tropism determines the differential distribution of viral reservoir among CD4(+) T-cell subsets. In spite of viral tropism, the effector and transitional memory CD4(+) T-cells subsets are the main source of residual viremia during suppressive ART, even though their contribution to the total proviral pool is small. However, the lack of concordance between residual viremia and viral variants driving de novo infection of CD4(+) T cells on ART may reflect the predominance of defective plasma HIV RNA genomes. These findings highlight the need for monitoring the multiple viral RNA/DNA persistence markers, based on their differential contribution to viral persistence. PMID- 27484991 TI - Preparation of chicken IgY against recombinant E2 protein of bovine viral diarrhea virus (BVDV) and development of ELISA and ICA for BVDV detection. AB - Bovine viral diarrhea virus (BVDV) infects cattle and may lead to persistent infection (PI). The PI animals harbor BVDV throughout their life and become immune tolerant against BVDV. Thus, diagnosis of this virus in herd is highly important. Recombinant E2 protein expression (using pET-32a in Escherichia coli) was confirmed by SDS-PAGE and Western blotting; then purified by Ni+ affinity chromatography. Chickens were immunized with BVDV-E2 protein, and IgY antibodies were extracted from egg yolk by PEG-6000. The peak titer of anti-BVDV-E2-IgY was 1:128,000 after the fifth immunization. IgY-based enzyme-linked immuno sorbent assay (ELISA) and immunochromatographic assay (ICA) were further developed. Coincidence of ELISA and ICA test with RT-PCR was 95.45 and 90.91%, respectively. The anti-BVDV-E2 IgY could be used in routine screening of BVDV infection. Besides, it can also be applicable while licensing and/or using live vaccines; screening of imported products containing bovine serum and strong surveillance of BVDV outbreaks. PMID- 27484992 TI - Parallel or convergent evolution in human population genomic data revealed by genotype networks. AB - BACKGROUND: Genotype networks are representations of genetic variation data that are complementary to phylogenetic trees. A genotype network is a graph whose nodes are genotypes (DNA sequences) with the same broadly defined phenotype. Two nodes are connected if they differ in some minimal way, e.g., in a single nucleotide. RESULTS: We analyze human genome variation data from the 1,000 genomes project, and construct haploid genotype (haplotype) networks for 12,235 protein coding genes. The structure of these networks varies widely among genes, indicating different patterns of variation despite a shared evolutionary history. We focus on those genes whose genotype networks show many cycles, which can indicate homoplasy, i.e., parallel or convergent evolution, on the sequence level. CONCLUSION: For 42 genes, the observed number of cycles is so large that it cannot be explained by either chance homoplasy or recombination. When analyzing possible explanations, we discovered evidence for positive selection in 21 of these genes and, in addition, a potential role for constrained variation and purifying selection. Balancing selection plays at most a small role. The 42 genes with excess cycles are enriched in functions related to immunity and response to pathogens. Genotype networks are representations of genetic variation data that can help understand unusual patterns of genomic variation. PMID- 27484993 TI - Recapitulating epithelial tumor microenvironment in vitro using three dimensional tri-culture of human epithelial, endothelial, and mesenchymal cells. AB - BACKGROUND: Three-dimensional (3-D) cultures of cancer cells can potentially bridge the gap between 2-D drug screening and in vivo xenografts. The objective of this study was to characterize the cellular and extracellular matrix characteristics of spheroids composed of human lung epithelial cells (epi), pulmonary vascular endothelial (endo) cells, and human marrow-derived mesenchymal stems cells (MSCs). METHODS: Spheroids composed of epi/endo/MSCs, termed herein as synthetic tumor microenvironment mimics (STEMs), were prepared by the hanging drop method. Cellular composition and distribution in the STEMs was characterized using fluorescence microscopy. Induction of reactive oxygen species and upregulation of efflux transporters was quantified using fluorometry and PCR, respectively, and phenotypic markers were qualitatively assessed using immunohistochemistry. RESULTS: STEMs exhibited three unique characteristics not captured in other spheroid cultures namely, the presence of a spheroid core devoid of epithelial cells and primarily composed of MSCs, a small viable population of endothelial cells hypothesized to be closely associated with MSCs within the hypoxic core, and discrete regions with high expression for vimentin and cytokeratin-18, whose co-expression is co-related with enhanced metastasis. Although cells within STEMs show elevated levels of reactive oxygen species and mRNA for ABC-B1, an efflux transporter associated with drug resistance, they exhibited only modest resistance to paclitaxel and gemcitabine in comparison to 2 D tri-cultures. CONCLUSIONS: The epi/endo/MSC spheroid model described herein offers a promising platform for understanding tumor biology and drug testing in vitro. PMID- 27484994 TI - The influence of body composition on renal function in patients with coronary artery disease and its prognostic significance: a retrospective cohort study. AB - OBJECTIVE: We try to analyse the effect of renal functions on death in CAD patients with different body compositions. METHODS: A retrospective analysis was conducted in 2989 consecutive patients with CAD confirmed by coronary angiography were enrolled and were grouped into two categories: basically preserved renal function (PRF) (eGFR >=60 ml/min) and obviously reduced renal function (RRF) (eGFR <60 ml/min). The influence of renal insufficiency on mortality of CAD was detected in every tertile of body composition, including body mass index (BMI), body fat (BF) and lean mass index (LMI). The end points were all-cause mortality. RESULTS: The mean follow-up time was 29.1 +/- 12.5 months and death events occurred in 271 cases. The percentage of patients with RRF was positively correlated with BF and inversely correlated with the LMI, but no relationship to BMI. The survival curves showed that the risk of death was significantly higher in the RRF patients in all subgroups stratified using BMI, BF, or LMI (log rank test, all p < 0.001). The COX multivariate regression analysis showed that the risk of death was significantly higher in the RRF patients with high BF (HR 1.95, CI 1.25-3.05) and low LMI (HR 1.82, CI 1.19-2.79). Meanwhile, risk of death was significantly higher in RRF patients with a high BMI (HR 2.08, CI 1.22-3.55) or low BMI (HR 1.98, CI 1.28-3.08) but this risk was not significant in patients with a medium BMI (HR 1.12, 0.65-1.94). The subgroup analysis of patients with acute coronary syndrome (ACS) showed similar results. CONCLUSIONS: For patients with CAD, renal insufficiency was positively correlated with BF, inversely correlated with LMI, and unrelated to BMI. The effect of renal insufficiency on the risk of death of CAD was related to body composition. PMID- 27484995 TI - Characteristics and trends in publication of scientific papers presented at the European Congress of Radiology: a comparison between 2000 and 2010. AB - OBJECTIVE: To determine journal publication rates of scientific papers presented orally at the European Congress of Radiology (ECR) 2010, with comparison of country data to ECR 2000. METHODS: All oral presentations from ECR 2010 were evaluated for publication between 2010 and 2014 using the MEDLINE database. Countries, collaborations, subspecialties, modalities and study design were ranked by publication percentage. Chi-square tests were used to compare publication percentages for each category of variables. Hazard ratios (HR) were calculated for each country relative to the host nation, Austria. ECR 2010 country statistics were compared with analogous data from ECR 2000. RESULTS: In total, 360/840 abstracts were subsequently published (43 %). The author's country of origin (p = 0.02), subspecialty (p = 0.02) and study design (p = 0.001) were significantly associated with subsequent publication. Switzerland, the Netherlands, France and Germany were among the top six countries by publication percentage in 2000 and 2010. In 2010, Switzerland had the highest publication rate (62 %) and HR in comparison to Austria (HR 2.62 [1.31-5.25], p = 0.01). Three Asian nations increased relative publication rates over the 10-year period. CONCLUSION: Several European nations consistently convert relatively high percentages of oral abstracts at ECR into publications, and the influence of Asian countries is increasing. MAIN MESSAGES: * Certain European nations consistently publish high percentages of orally presented abstracts at ECR. * The influence of several Asian countries on ECR is increasing. * Country, subspecialty and study design are significantly associated with journal publication. * Authors collaborating internationally have the highest publication rates and mean impact factors. * Among all modalities, PET-CT, MRI and CT have the highest publication percentages. PMID- 27484997 TI - Effects of unequal electrode pairs on an x-strip thickness-shear mode multi channel quartz crystal microbalance. AB - We study the thickness-shear vibrations of an x-strip monolithic piezoelectric plate made from AT-cut quartz crystals with two unequal electrode pairs. The Tiersten-Smythe scalar differential equations for electroded and unelectroded quartz plates are separately employed, resulting in free vibration distributions and frequencies of operating modes. The vibrations of these operating modes are mainly trapped in the electroded regions. The loss of the structural symmetry can lead to a weak vibration interaction between two electroded regions. The influences of electrode difference on the vibration and frequency interference between two adjacent resonators are investigated in detail. The obtained results provide a fundamental reference to the design and optimization of multi-channel quartz crystal microbalance. PMID- 27484996 TI - Checklist to operationalize measurement characteristics of patient-reported outcome measures. AB - BACKGROUND: The purpose of this study was to advance a checklist of evaluative criteria designed to assess patient-reported outcome (PRO) measures' developmental measurement properties and applicability, which can be used by systematic reviewers, researchers, and clinicians with a varied range of expertise in psychometric measure development methodology. METHODS: A directed literature search was performed to identify original studies, textbooks, consensus guidelines, and published reports that propose criteria for assessing the quality of PRO measures. Recommendations from these sources were iteratively distilled into a checklist of key attributes. Preliminary items underwent evaluation through 24 cognitive interviews with clinicians and quantitative researchers. Six measurement theory methodological novices independently applied the final checklist to assess six PRO measures encompassing a variety of methods, applications, and clinical constructs. Agreement between novice and expert scores was assessed. RESULTS: The distillation process yielded an 18-item checklist with six domains: (1) conceptual model, (2) content validity, (3) reliability, (4) construct validity, (5) scoring and interpretation, and (6) respondent burden and presentation. With minimal instruction, good agreement in checklist item ratings was achieved between quantitative researchers with expertise in measurement theory and less experienced clinicians (mean kappa 0.70; range 0.66-0.87). CONCLUSIONS: We present a simplified checklist that can help guide systematic reviewers, researchers, and clinicians with varied measurement theory expertise to evaluate the strengths and weakness of candidate PRO measures' developmental properties and the appropriateness for specific applications. PMID- 27485001 TI - Checkpoint Immunotherapy: Picking a Winner. AB - Robust biomarkers of response that predict which patients will or will not respond to immune checkpoint blockade need to be identified. New data suggest that the presence of an adaptive immune signature in the tumor biopsies of patients with melanoma early on therapy compared to pretreatment can identify responders from nonresponders. Cancer Discov; 6(8); 818-20. (c)2016 AACR.See related article by Chen et al., p. 827. PMID- 27485002 TI - Adipocytes and Neutrophils Give a Helping Hand to Pancreatic Cancers. AB - Obesity-induced inflammation can build up a confined microenvironment in pancreatic adenocarcinoma that is associated with increased desmoplasia, neutrophil recruitment, reduced delivery of chemotherapeutic drugs, and immune evasion. Targeting molecular pathways empowering this circuit might represent a necessary measure to reach clinical efficacy for combination therapies in patients with excess body weight. Cancer Discov; 6(8); 821-3. (c)2016 AACR.See related article by Incio et al., p. 852. PMID- 27484998 TI - A Korean multi-center, real-world, retrospective study of first-line pazopanib in unselected patients with metastatic renal clear-cell carcinoma. AB - BACKGROUND: The efficacy and/or tolerability of pazopanib in patients with metastatic renal cell carcinoma (mRCC) have been found to differ in Western and Asian populations. This retrospective multicenter study analyzed the results of first-line pazopanib treatment in 93 consecutive patients with mRCC who were treated at the medical oncology departments of three tertiary cancer centers in Seoul, Korea. METHODS: The decision to administer pazopanib as first-line therapy was at the discretion of the treating physician in all patients with mRCC. Patients enrolled in clinical trials were excluded to ensure that the results would reflect real-world outcomes representative of daily clinical settings. All patients received 800 mg/day pazopanib. Outcomes included response rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: The 93 patients included72 (77 %) male and 21 (23 %) female individuals, of median age 65 years (range, 19-84 years). The median number of metastatic sites per patient was two (range, 1-5), with the lungs being the most frequently involved site. Most patients had favorable (n = 46) or intermediate (n = 36) risk as determined by Memorial Sloan Kettering Cancer Center criteria. Pazopanib was generally welltolerated: the major hematologic adverse effect was grade 1/2 anemia (14 %); and the most frequently observed non-hematologic toxicity was grade 1/2 mucositis (22 %), followed by hair discoloration and hypertension. Of the 93 patients, three (3 %) showed complete response, 52 (56 %) showed partial response, and 21 (23 %) showed stable disease, making the objective response rate 59 % and the disease control rate 82 %. At a median follow-up of 21 months, the estimated median PFS and OS were 12.2 months (95 % confidence interval, 7.1-17.4 months) and 21.9 months (95 % confidence interval, 12.9-30.9 months), respectively. CONCLUSIONS: In this retrospective study, first-line therapy with pazopanib demonstrated clinically relevant efficacy and tolerability in unselected real-world Korean patients with mRCC. OS and PFS of these Korean patients were similar to those reported in phase III trials. PMID- 27485003 TI - Genomic Amplifications Cause False Positives in CRISPR Screens. AB - In CRISPR-based screens for essential genes, Munoz and colleagues and Aguirre and colleagues show that gene-independent targeting of genomic amplifications in human cancer cell lines reduces proliferation or survival. The correlation between CRISPR target site copy number and lethality demonstrates the need for scrutiny and complementary approaches to rule out off-target effects and false positives in CRISPR screens. Cancer Discov; 6(8); 824-6. (c)2016 AACR.See related article by Munoz et al., p. 900See related article by Aguirre et al., p. 914. PMID- 27485004 TI - Cerebral vasoconstriction reactions and plasma levels of ETBR, ET-1, and eNOS in patients with chronic high altitude disease. AB - The aim of the present study was to examine cerebral vasoconstriction in patients with chronic high altitude disease [cerebrovascular reactivity (CVR)], and to evaluate differences in alterations of brain vascular contractile reactivity of chronic mountain sickness (CMS) patients and healthy controls. Alterations of endothelin (ET) and its receptor, as well as endothelial nitric oxide synthase (eNOS) levels in the plasma were examined to determine the cerebral reservation capacities in CMS patients. Transcranial Doppler ultrasound and carbon dioxide analysis methods were used to detect the CVR variances. At the same time, enzyme linked immunosorbent assay approaches were utilized to detect the ET and ET B receptor and the eNOS levels in serum of the CMS patients and healthy controls. CVR and CVRI levels in CMS patients were lower than those of the healthy control subjects and the difference was statistically significant (P<0.05). By contrast, eNOS and ET-1 levels were not statistically significant for CMS and healthy controls (P>0.05). However, the ET receptor concentration level was higher in CMS than the healthy controls. Thus, ET-1 may not be a direct etiological variation but may play compensatory roles in CMS patients. The results of the study may provide scientific clues for the prevention and treatment of CMS with higher blood coagulation states of cerebral infarction in patients with chronic high altitude disease. PMID- 27485006 TI - Treatment for non-thyroidal illness syndrome in advanced chronic kidney disease: a single-blind controlled study. AB - AIM: Non-thyroidal illness syndrome (NTIS) is common among patients with advanced chronic kidney disease (CKD) and is strongly associated with poor prognosis. However, it remains unclear in how to correct this disorder and this study aimed to evaluate the effectiveness of sodium bicarbonate (SB) and N-acetyl-cysteine (NAC) for correcting NTIS status. METHODS: Patients with CKD stage 3-4 were single-blind, placebo-controlled treated with placebo, SB, or NAC for 18 weeks. The primary end points were the correction of NTIS and the occurrence of end stage renal disease (ESRD). The secondary point was the change in estimated glomerular filtration rate (eGFR) after the follow-up. RESULTS: The Kaplan-Meier survival analysis showed significant lower correcting ratio of NTIS in control group compared with SB group [Hazard ratio (HR) 0.19, 95 % confidence interval (CI) 0.04-0.89, p = 0.035] and NAC group (HR 0.09, 95 % CI 0.02-0.38, p = 0.001), and increased ESRD risk in control group than in SB group (HR 1.97, 95 % CI 1.02 3.84, p = 0.045) and NAC group (HR 5.50, 95 % CI 2.23-13.57, p < 0.001). The Cox regression analysis demonstrated significantly different effectiveness of placebo, SB and NAC on NTIS correction and ESRD risk, p < 0.05, respectively. Variance analysis displayed a greater reduction in eGFR in controls than in SB (p = 0.044) and NAC group (p < 0.001). CONCLUSION: SB and NAC are effective in promoting the recovery from NTIS status and delaying the deterioration of renal function in advanced CKD patients. PMID- 27485005 TI - A proteomics approach reveals molecular manipulators of distinct cellular processes in the salivary glands of Glossina m. morsitans in response to Trypanosoma b. brucei infections. AB - BACKGROUND: Glossina m. morsitans is the primary vector of the Trypanosoma brucei group, one of the causative agents of African trypanosomoses. The parasites undergo metacyclogenesis, i.e. transformation into the mammalian-infective metacyclic trypomastigote (MT) parasites, in the salivary glands (SGs) of the tsetse vector. Since the MT-parasites are largely uncultivable in vitro, information on the molecular processes that facilitate metacyclogenesis is scanty. METHODS: To bridge this knowledge gap, we employed tandem mass spectrometry to investigate protein expression modulations in parasitized (T. b. brucei-infected) and unparasitized SGs of G. m. morsitans. We annotated the identified proteins into gene ontologies and mapped the up- and downregulated proteins within protein-protein interaction (PPI) networks. RESULTS: We identified 361 host proteins, of which 76.6 % (n = 276) and 22.3 % (n = 81) were up- and downregulated, respectively, in parasitized SGs compared to unparasitized SGs. Whilst 32 proteins were significantly upregulated (> 10-fold), only salivary secreted adenosine was significantly downregulated. Amongst the significantly upregulated proteins, there were proteins associated with blood feeding, immunity, cellular proliferation, homeostasis, cytoskeletal traffic and regulation of protein turnover. The significantly upregulated proteins formed major hubs in the PPI network including key regulators of the Ras/MAPK and Ca(2+)/cAMP signaling pathways, ubiquitin-proteasome system and mitochondrial respiratory chain. Moreover, we identified 158 trypanosome-specific proteins, notable of which were proteins in the families of the GPI-anchored surface glycoproteins, kinetoplastid calpains, peroxiredoxins, retrotransposon host spot multigene and molecular chaperones. Whilst immune-related trypanosome proteins were over-represented, membrane transporters and proteins involved in translation repression (e.g. ribosomal proteins) were under-represented, potentially reminiscent of the growth-arrested MT-parasites. CONCLUSIONS: Our data implicate the significantly upregulated proteins as manipulators of diverse cellular processes in response to T. b. brucei infection, potentially to prepare the MT parasites for invasion and evasion of the mammalian host immune defences. We discuss potential strategies to exploit our findings in enhancement of trypanosome refractoriness or reduce the vector competence of the tsetse vector. PMID- 27485007 TI - Comparative effectiveness of angiotensin receptor blockers vs. angiotensin converting enzyme inhibitors on cardiovascular outcomes in patients initiating peritoneal dialysis. AB - BACKGROUND: There is evidence that angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-II receptor blockers (ARB) may reduce cardiovascular (CV) risk in patients undergoing peritoneal dialysis (PD), but no studies have compared the effectiveness between these drug classes. In this observational cohort study, we compared the association of ARB vs. ACEI use on CV outcomes in patients initiating PD. METHODS: We identified from the US Renal Data System all adult patients who initiated PD from 2007 to 2011 and participated in Medicare Part D, a federal prescription drug benefits program, for the first 90 days of dialysis. Patients who filled a prescription for an ACEI or ARB in those 90 days were considered users. We excluded patients who used both ACEI and ARB. We applied Cox proportional hazards regression to an inverse probability of treatment-weighted cohort to estimate the hazard ratios (HR) for the combined outcome of all-cause death, ischemic stroke, or myocardial infarction; all-cause mortality; and CV death. RESULTS: Among 1892 patients using either drug class, 39 % were ARB users. We observed 624 events over 2,898 person-years of follow-up, for a composite event rate of 22 events per 100 person-years. We observed no differences between ARB vs. ACEI users: composite outcome HR 0.94, 95 % confidence interval (CI) 0.79-1.11; all-cause mortality HR 0.92, 95 % CI 0.76 1.10; CV death HR: 1.06, 95 % CI 0.80-1.41. CONCLUSION: We identified no significant difference in the risks of CV events or death between users of ARBs vs. ACEIs in patients initiating PD, thus supporting their mostly interchangeable use in this population. PMID- 27485008 TI - Substrate Factors Determine Roadside Vegetation Structure and Species Richness: A Case Study Along a Meridional Gradient in Fennoscandia. AB - This study assessed the effects of road-related alteration of substrate, including increased salinity, on vegetation along a meridional gradient in Fennoscandia. Vegetation community composition were surveyed in 29 randomly selected 1-m(2) sized roadside plots. Number of plant species and plant cover (%) on the plots were positively interrelated (p < 0.0001). Both variables also decreased towards the north and with increasing coarseness of the substrate. Canonical correspondence analysis (CCA) indicated that roadside vegetation diversity and composition were most related to the importance of the road (i.e. its size and traffic intensity) and substrate pH. Road importance affects plant dispersal, whereas substrate pH was found to be a factor limiting growth. CCA indicated also that vegetation composition was affected by the meridional gradient and by the substrate salinity; both substrate salinity pH and salinity were not related to meridional gradient. Our results indicate that roadside vegetation diversity and composition is driven by natural and anthropogenic factors. PMID- 27485009 TI - Continued Studies on the Effects of Simazine on the Liver Histological Structure and Metamorphosis in the Developing Xenopus laevis. AB - This study continued our previous work (Sai et al. in Bull Environ Contam Toxicol 95:157-163, 2015a) by analysing the effects of simazine on the liver histological structure and metamorphosis in the developing Xenopus laevis. Tadpoles (Nieuwkoop Faber stage 46) were exposed to simazine at 0.1, 1.2, 11.0 and 100.9 MUg/L for 100 days. When tadpoles were exposed to simazine at 11.0 and 100.9 ug/L, an increased mortality and damaged liver tissues were observed together with significant inhibition of percent of X. laevis completing metamorphosis on days 80 and 90 and prolonged time of completing metamorphosis. On the other hand, we found that simazine has no significant effects on liver weight and altered hepatosomatic index. Results of this study may be considered to inform risk assessment of the effects of simazine on the development of X. laevis. PMID- 27485010 TI - Prevalence and correlates of achieving recommended physical activity levels among children living in rural South Asia-A multi-centre study. AB - BACKGROUND: We report the prevalence of recommended physical activity levels (RPALs) and examine the correlates of achieving RPALs in rural South Asian children and analyse its association with anthropometric outcomes. METHODS: This analysis on rural South Asian children aged 5-14 years (n = 564) is a part of the Chronic Disease Risk Factor study conducted at three sites in India (Chennai n = 146; Goa n = 218) and Bangladesh (Matlab; n = 200). Data on socio-demographic and lifestyle factors (physical activity (PA); diet) were collected using an interviewer-administered questionnaires, along with objective anthropometric measurements. Multivariate logistic regression models were used to examine whether RPALs (active travel to school (yes/no); leisure-time PA >= 1 h/day; sedentary-activity <= 2 h/day) were associated with socio-demographic factors, diet and other forms of PA. Multivariate linear regression models were used to investigate associations between RPALs and anthropometrics (BMI- and waist z scores). RESULTS: The majority of children (71.8 %) belonged to households where a parent had at least a secondary education. Two-thirds (66.7 %) actively travelled to school; 74.6 % reported >=1 h/day of leisure-time PA and 55.7 % had <=2 h/day of sedentary-activity; 25.2 % of children reported RPALs in all three dimensions. Older (10-14 years, OR = 2.0; 95 % CI: 1.3, 3.0) and female (OR = 1.7; 95 % CI: 1.1, 2.5) children were more likely to travel actively to school. Leisure-time PA >= 1 h/day was more common among boys (OR = 2.5; 95 % CI: 1.5, 4.0), children in Matlab, Bangladesh (OR = 3.0; 95 % CI: 1.6, 5.5), and those with higher processed-food consumption (OR = 2.3; 95 % CI: 1.2, 4.1). Sedentary activity <= 2 h/day was associated with younger children (5-9 years, OR = 1.6; 95 % CI: 1.1, 2.4), children of Goa (OR = 3.5; 95 % CI: 2.1, 6.1) and Chennai (OR = 2.5; 95 % CI: 1.5, 4.3) and low household education (OR = 2.1; 95 % CI: 1.1, 4.1). In multivariate analyses, sedentary activity <= 2 h/day was associated with lower BMI-z-scores (beta = -0.3; 95 % CI: -0.5, -0.08) and lower waist-z-scores (beta = -1.1; 95 % CI: -2.2, -0.07). CONCLUSION: Only one quarter of children in these rural areas achieved RPAL in active travel, leisure and sedentary activity. Improved understanding of RPAL in rural South Asian children is important due to rapid socio-economic transition. PMID- 27485011 TI - Tolerogenic dendritic cells for reprogramming of lymphocyte responses in autoimmune diseases. AB - Dendritic cells (DCs) control immune responses by driving potent inflammatory actions against external and internal threats while generating tolerance to self and harmless components. This duality and their potential to reprogram immune responses in an antigen-specific fashion have made them an interesting target for immunotherapeutic strategies to control autoimmune diseases. Several protocols have been described for in vitro generation of tolerogenic DCs (tolDCs) capable of modulating adaptive immune responses and restoring tolerance through different mechanisms that involve anergy, generation of regulatory lymphocyte populations, or deletion of potentially harmful inflammatory T cell subsets. Recently, the capacity of tolDCs to induce interleukin (IL-10)-secreting regulatory B cells has been demonstrated. In vitro assays and rodent models of autoimmune diseases provide insights to the molecular regulators and pathways enabling tolDCs to control immune responses. Here we review mechanisms through which tolDCs modulate adaptive immune responses, particularly focusing on their suitability for reprogramming autoreactive CD4+ effector T cells. Furthermore, we discuss recent findings establishing that tolDCs also modulate B cell populations and discuss clinical trials applying tolDCs to patients with autoimmune diseases. PMID- 27485012 TI - Complement and thrombosis in the antiphospholipid syndrome. AB - The involvement of complement activation in the pathophysiology of antiphospholipid syndrome (APS) was first reported in murine models of antiphospholipid antibody (aPL)-related pregnancy morbidities. We previously reported that complement activation is prevalent and may function as a source of procoagulant cell activation in the sera of APS patients. Recently, autoantibodies against C1q, a component of complement 1, were reported to be correlated with complement activation in systemic lupus erythematosus. These antibodies target neoepitopes of deformed C1q bound to various molecules (i.e., anionic phospholipids) and induce accelerated complement activation. We found that anti-C1q antibodies are more frequently detected in primary APS patients than in control patients and in refractory APS patients with repeated thrombotic events. The titer of anti-C1q antibodies was significantly higher in refractory APS patients than in APS patients without flare. The binding of C1q to anionic phospholipids may be associated with the surge in complement activation in patients with anti-C1q antibodies when triggered by 'second-hit' biological stressors such as infection. Such stressors will induce overexpression of anionic phospholipids, with subsequent increases in deformed C1q that is targeted by anti C1q antibodies. PMID- 27485013 TI - From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time. AB - A wide variety of clinical syndromes has been associated with antibodies to voltage-gated potassium channels (VGKCs). Six years ago, it was discovered that patients do not truly have antibodies to potassium channels, but to associated proteins. This enabled the distinction of three VGKC-positive subgroups: anti LGI1 patients, anti-Caspr2 patients and VGKC-positive patients lacking both antibodies. Patients with LGI1-antibodies have a limbic encephalitis, often with hyponatremia, and about half of the patients have typical faciobrachial dystonic seizures. Caspr2-antibodies cause a more variable syndrome of peripheral or central nervous system symptoms, almost exclusively affecting older males. Immunotherapy seems to be beneficial in patients with antibodies to LGI1 or Caspr2, stressing the need for early diagnosis. Half of the VGKC-positive patients lack antibodies to both LGI1 and Caspr2. This is a heterogeneous group of patients with a wide variety of clinical syndromes, raising the question whether VGKC-positivity is truly a marker of disease in these patients. Data regarding this issue are limited, but a recent study did not show any clinical relevance of VGKC-positivity in the absence of antibodies to LGI1 and Caspr2. The three VGKC-positive subgroups are essentially different, therefore, the lumping term 'VGKC-complex antibodies' should be abolished. PMID- 27485014 TI - Science Signaling Podcast for 2 August 2016: Patient-specific protein complexes. AB - This Podcast features an interview with Adam Schrum and Steven Neier, authors of a Research Article that appears in the 2 August 2016 issue of Science Signaling, about a method for identifying protein-protein interactions in patient tissue samples. The authors used this method to compare signaling complexes downstream of the T cell receptor in T cells from healthy skin with those in T cells from the skin of patients with the autoimmune disease alopecia areata. The study revealed differences in the relative abundance of some protein complexes between T cells from the control and patient groups. This technique could be adapted for use as a diagnostic tool to stratify patients by molecular phenotype and predict the therapeutic strategy that is likely to work best for each patient.Listen to Podcast. PMID- 27485016 TI - Small heterodimer partner SHP mediates liver X receptor (LXR)-dependent suppression of inflammatory signaling by promoting LXR SUMOylation specifically in astrocytes. AB - Liver X receptors (LXRs) suppress the expression of inflammatory genes in a context-specific manner. In astrocytes, SUMOylation of LXRs promotes their anti inflammatory effects. We found that small heterodimer partner (SHP), also known as NR0B2 (nuclear receptor subfamily 0, group B, member 2), facilitates the anti inflammatory actions of LXRs by promoting their SUMOylation. Knockdown of SHP abrogated SUMOylation of LXRs, preventing their anti-inflammatory effects, in primary rat astrocytes but not macrophages. The underlying mechanisms differed according to LXR isoform. SHP promoted SUMO2 and SUMO3 attachment to LXRalpha by interacting directly with the histone deacetylase and E3 SUMO ligase HDAC4. In contrast, SHP promoted SUMO1 attachment to LXRbeta by stabilizing the E3 SUMO ligase PIAS1. SHP bound PIAS1 and disrupted its interaction with the E3 ubiquitin ligase SIAH1. Knocking down SIAH1 rescued LXRbeta SUMOylation in SHP-deficient astrocytes. Our data collectively suggested that SHP mediates the anti inflammatory actions of LXRs through differential regulation of receptor SUMOylation specifically in astrocytes, thereby revealing potential avenues for therapeutic development in diseases associated with brain inflammation. PMID- 27485015 TI - Peripheral motor neuropathy is associated with defective kinase regulation of the KCC3 cotransporter. AB - Using exome sequencing, we identified a de novo mutation (c.2971A>G; T991A) in SLC12A6, the gene encoding the K(+)-Cl(-) cotransporter KCC3, in a patient with an early-onset, progressive, and severe peripheral neuropathy primarily affecting motor neurons. Normally, the WNK kinase-dependent phosphorylation of T(991) tonically inhibits KCC3; however, cell swelling triggers Thr(991) dephosphorylation to activate the transporter and restore cell volume. KCC3 T991A mutation in patient cells abolished Thr(991) phosphorylation, resulted in constitutive KCC3 activity, and compromised cell volume homeostasis. KCC3(T991A/T991A) mutant mice exhibited constitutive KCC3 activity and recapitulated aspects of the clinical, electrophysiological, and histopathological findings of the patient. These results suggest that the function of the peripheral nervous system depends on finely tuned, kinase regulated KCC3 activity and implicate abnormal cell volume homeostasis as a previously unreported mechanism of axonal degeneration. PMID- 27485017 TI - Multiplex matrix network analysis of protein complexes in the human TCR signalosome. AB - Multiprotein complexes transduce cellular signals through extensive interaction networks, but the ability to analyze these networks in cells from small clinical biopsies is limited. To address this, we applied an adaptable multiplex matrix system to physiologically relevant signaling protein complexes isolated from a cell line or from human patient samples. Focusing on the proximal T cell receptor (TCR) signalosome, we assessed 210 pairs of PiSCES (proteins in shared complexes detected by exposed surface epitopes). Upon stimulation of Jurkat cells with superantigen-loaded antigen-presenting cells, this system produced high dimensional data that enabled visualization of network activity. A comprehensive analysis platform generated PiSCES biosignatures by applying unsupervised hierarchical clustering, principal component analysis, an adaptive nonparametric with empirical cutoff analysis, and weighted correlation network analysis. We generated PiSCES biosignatures from 4-mm skin punch biopsies from control patients or patients with the autoimmune skin disease alopecia areata. This analysis distinguished disease patients from the controls, detected enhanced basal TCR signaling in the autoimmune patients, and identified a potential signaling network signature that may be indicative of disease. Thus, generation of PiSCES biosignatures represents an approach that can provide information about the activity of protein signaling networks in samples including low-abundance primary cells from clinical biopsies. PMID- 27485018 TI - Development of an open-source web-based intervention for Brazilian smokers - Viva sem Tabaco. AB - BACKGROUND: Web-based interventions for smoking cessation available in Portuguese do not adhere to evidence-based treatment guidelines. Besides, all existing web based interventions are built on proprietary platforms that developing countries often cannot afford. We aimed to describe the development of "Viva sem Tabaco", an open-source web-based intervention. RESULTS: The development of the intervention included the selection of content from evidence-based guidelines for smoking cessation, the design of the first layout, conduction of 2 focus groups to identify potential features, refinement of the layout based on focus groups and correction of content based on feedback provided by specialists on smoking cessation. At the end, we released the source-code and intervention on the Internet and translated it into Spanish and English. CONCLUSIONS: The intervention developed fills gaps in the information available in Portuguese and the lack of open-source interventions for smoking cessation. The open-source licensing format and its translation system may help researchers from different countries deploying evidence-based interventions for smoking cessation. PMID- 27485020 TI - Biological maturity-associated variance in peak power output and momentum in academy rugby union players. AB - The study aimed to evaluate the mediating effect of biological maturation on anthropometrical measurements, performance indicators and subsequent selection in a group of academy rugby union players. Fifty-one male players 14-17 years of age were assessed for height, weight and BMI, and percentage of predicted mature status attained at the time of observation was used as an indicator of maturity status. Following this, initial sprint velocity (ISV), Wattbike peak power output (PPO) and initial sprint momentum (ISM) were assessed. A bias towards on-time (n = 44) and early (n = 7) maturers was evident in the total sample and magnified with age cohort. Relative to UK reference values, weight and height were above the 90th and 75th centiles, respectively. Significant (p <= .01) correlations were observed between maturity status and BMI (r = .48), weight (r = .63) and height (r = .48). Regression analysis (controlling for age) revealed that maturity status and height explained 68% of ISM variance; however, including BMI in the model attenuated the influence of maturity status below statistical significance (p = .72). Height and BMI explained 51% of PPO variance, while no initial significant predictors were identified for ISV. The sample consisted of players who were on-time and early in maturation with no late maturers represented. This was attributable, in part, to the mediating effect of maturation on body size, which, in turn, predicted performance variables. PMID- 27485019 TI - Resurgence of Schmallenberg Virus in Belgium after 3 Years of Epidemiological Silence. AB - In spring 2016, three years after the last reported outbreak of Schmallenberg virus (SBV) in Belgium, an abortion was notified in a two year old Holstein heifer that previously had not been vaccinated against SBV. The autopsy of the eight-month-old malformed foetus revealed hydrocephalus, torticollis and arthrogryposis. Foetal brain tissue and blood were found to be SBV-positive by RT PCR and ELISA tests, respectively. Evidencing the circulation of SBV in Belgium in the autumn 2015 is important to anticipate future outbreaks and advise veterinarians about the risks associated with calving, as more bovine foetuses might have been infected. PMID- 27485021 TI - Complex band structure of topological insulator Bi2Se3. AB - Topological insulators are very interesting from a fundamental point of view, and their unique properties may be useful for electronic and spintronic device applications. From the point of view of applications it is important to understand the decay behavior of carriers injected in the band gap of the topological insulator, which is determined by its complex band structure (CBS). Using first-principles calculations, we investigate the dispersion and symmetry of the complex bands of Bi2Se3 family of three-dimensional topological insulators. We compare the CBS of a band insulator and a topological insulator and follow the CBS evolution in both when the spin-orbit interaction is turned on. We find significant differences in the CBS linked to the topological band structure. In particular, our results demonstrate that the evanescent states in Bi2Se3 are non-trivially complex, i.e. contain both the real and imaginary contributions. This explains quantitatively the oscillatory behavior of the band gap obtained from Bi2Se3 (0 0 0 1) slab calculations. PMID- 27485022 TI - Hamostaseologie - Progress in Haemostasis. Recent achievements and future directions. PMID- 27485023 TI - Molecular complexity of the megakaryocyte-platelet system in health and disease. PMID- 27485024 TI - Cellular and molecular mechanisms of acute exposure to sulfur mustard: a systematic review. AB - CONTEXT: Mustard gas (e.g. sulfur mustard (SM)) has been used as a chemical agent in several battles and is still a potential worldwide menace. Besides local absorption, particularly in the skin, eyes and lungs, systemic spread of the agent also has detrimental effects on gonads, bone marrow and nervous system. Moreover, chronic exposure of SM to respiratory system causes death. Inducing oxidative stress, and disturbing DNA and tissue repair systems, inflammation and cell death signaling pathways have been introduced as molecular mechanisms of the injury. METHODS: In this systematic review, more than 1200 (2000-2014) articles focusing on gross or molecular pathological reports in the acute phase of the respiratory injury after SM exposure were reviewed, followed by two different layers of gross and molecular pathological data (clinic and laboratory) integrated together in a spatio-temporal order. Role of epithelial, neutrophil and macrophage cells and three signaling pathways of inflammation, oxidative stress and cell death are covered in details. RESULTS AND CONCLUSION: Our results propose a critical role of interleukin-17 producing cells in acute and chronic inflammatory responses. PMID- 27485025 TI - Moderate Humidity Delays Electron-Hole Recombination in Hybrid Organic-Inorganic Perovskites: Time-Domain Ab Initio Simulations Rationalize Experiments. AB - Experiments show both positive and negative changes in performance of hybrid organic-inorganic perovskite solar cells upon exposure to moisture. Ab initio nonadiabatic molecular dynamics reveals the influence of humidity on nonradiative electron-hole recombination. In small amounts, water molecules perturb perovskite surface and localize photoexcited electron close to the surface. Importantly, deep electron traps are avoided. The electron-hole overlap decreases, and the excited state lifetime increases. In large amounts, water forms stable hydrogen bonded networks, has a higher barrier to enter perovskite, and produces little impact on charge localization. At the same time, by contributing high frequency polar vibrations, water molecules increase nonadiabatic coupling and accelerate recombination. In general, short coherence between electron and hole benefits photovoltaic response of the perovskites. The calculated recombination time scales show excellent agreement with experiment. The time-domain atomistic simulations reveal the microscopic effects of humidity on perovskite excited state lifetimes and rationalize the conflicting experimental observations. PMID- 27485027 TI - Stress and Humoral Innate Immune Response of Gilthead Seabream Sparus aurata Cultured in Sea Cages. AB - Innate and acquired immune responses of Gilthead Seabream Sparus aurata was studied under normal culture and short-term stressful conditions for 18 months in offshore sea cages in Alghero Bay, Italy. Every 45 d, 50 fish were sampled and divided into two groups: fish in the first group (normal culture conditions) were bled after harvesting; fish in the second group were put into a tank under stressful conditions (crowding and confinement) and bled after 2 h. Innate humoral immunity, such as complement-like, hemagglutination, and lysozyme activities, was determined in the sera of both groups. Pathogen challenge was not performed, but the specific humoral immune response was assessed against the most common pathogens affecting cultured fish in Sardinia. Stressed fish, compared with the control, showed a lower lysozyme activity against Vibrio (Listonella) anguillarum, which was not clearly correlated with temperatures. Complement-like activity differed between the first and second half of the study and, at the end of the trial, a slightly higher activity was recorded in the controls than in the stressed fish. Hemagglutination activity was mainly higher in the stressed fish than in control fish. Confinement, crowding, and cold water temperature caused decreased lysozyme activity in short-term stressed Gilthead Seabream compared with those reared normally. The specific humoral immune response, against V. anguillarum, Tenacibaculum mesophilum, Enterococcus Seriolicida, and Aeromonas sobria, fluctuated during the rearing period, particularly during the first year of culture. Received October 12, 2015; accepted March 24, 2016. PMID- 27485026 TI - Notch signalling mediates reproductive constraint in the adult worker honeybee. AB - The hallmark of eusociality is the reproductive division of labour, in which one female caste reproduces, while reproduction is constrained in the subordinate caste. In adult worker honeybees (Apis mellifera) reproductive constraint is conditional: in the absence of the queen and brood, adult worker honeybees activate their ovaries and lay haploid male eggs. Here, we demonstrate that chemical inhibition of Notch signalling can overcome the repressive effect of queen pheromone and promote ovary activity in adult worker honeybees. We show that Notch signalling acts on the earliest stages of oogenesis and that the removal of the queen corresponds with a loss of Notch protein in the germarium. We conclude that the ancient and pleiotropic Notch signalling pathway has been co opted into constraining reproduction in worker honeybees and we provide the first molecular mechanism directly linking ovary activity in adult worker bees with the presence of the queen. PMID- 27485028 TI - The acute and temporary modulation of PERIOD genes by hydrocortisone in healthy subjects. AB - The physiological stress system and the circadian clock system communicate with each other at different signaling levels. The steroid hormone cortisol, the end effector of the hypothalamus-pituitary-adrenal axis, is released in response to stress and acts as a mediator in circadian rhythms. We determined the effect of escalating cortisol doses on the expression of PERIOD genes (PER1, PER2 and PER3) in healthy subjects and analyzed whether the glucocorticoid receptor (GR) is involved in the cortisol-mediated PERIOD gene expression. Forty participants (50% males and 50% females) were randomly assigned to groups receiving a saline placebo solution or 3 mg, 6 mg, 12 mg and 24 mg of hydrocortisone. Blood was drawn every 15 min to measure quantitative gene expression of PER1, PER2 and PER3. A potential role of the GR was determined by an ex vivo study stimulating whole blood with hydrocortisone and RU486 (a GR antagonist). As a result, moderate doses of hydrocortisone produced an acute and temporary induction of PER1 and PER3 mRNA levels, whereas PER2 was not responsive to the hormone administration. The cortisol-dependent induction of PER1 was blocked by the GR antagonist in whole blood after treatment with hydrocortisone and RU486 ex vivo. In conclusion, acute pharmacological stress modulated the expression of PER1 and PER3 in whole blood temporarily in our short-term sampling design, suggesting that these circadian genes mediate stable molecular mechanisms in the periphery. PMID- 27485030 TI - Development of an Allergy Immunotherapy Leads to a New Type of Hepatitis B Vaccine. PMID- 27485031 TI - Genetic variation in photosynthetic performance and tolerance to osmotic stress (desiccation, freezing, hyposalinity) in the rocky littoral foundation species Fucus vesiculosus (Fucales, Phaeophyceae). AB - Genetic diversity may play an analogous role to species diversity, as it can contribute to ecosystem function and stability, and provision of ecosystem services. In the Baltic Sea, perennial algal beds are often comprised of only Fucus vesiculosus and the amount of genetic variation in fitness-related traits (i.e., the ability of the alga to photosynthesize or withstand stress) will thus determine the alga's local persistence in a changing environment. To study genetic variation in the crucial traits behind persistence we grew replicate vegetative branches that came from the same genotype in common gardens. We quantified osmotic stress tolerance and recovery responses by exposing branches to desiccation, freezing, and hyposalinity regimens. Our results show that genetic variation among genotypes was apparent for some photosynthetic parameters (maximal electron transport rate, saturation irradiance for electron transport, nonphotochemical quenching) and growth. Algae tolerated freezing (1,440 min at 2.5 degrees C) and hyposalinity (1,560 min at 2.5) well, but did not recover from desiccation (70 min at 12 degrees C, causing ~94% water loss). Furthermore, we found very little if any evidence on genetic variation in tolerance to these stressors. Our results suggest that low salinity and cold winters in the northern marginal populations selected for hyposalinity and freezing tolerant genotypes, possibly eroding genetic variation in tolerance, but that tolerance to harsh desiccation has been lost, likely due to relaxed selection. The overall availability of genetic variation in fitness related traits might be supportive for F. vesiculosus during adaptation to gradual changes of its environment. PMID- 27485029 TI - Creation of a model to predict survival in patients with refractory coeliac disease using a multinational registry. AB - BACKGROUND: Refractory coeliac disease is a severe complication of coeliac disease with heterogeneous outcome. AIM: To create a prognostic model to estimate survival of patients with refractory coeliac disease. METHODS: We evaluated predictors of 5-year mortality using Cox proportional hazards regression on subjects from a multinational registry. Bootstrap resampling was used to internally validate the individual factors and overall model performance. The mean of the estimated regression coefficients from 400 bootstrap models was used to derive a risk score for 5-year mortality. RESULTS: The multinational cohort was composed of 232 patients diagnosed with refractory coeliac disease across seven centres (range of 11-63 cases per centre). The median age was 53 years and 150 (64%) were women. A total of 51 subjects died during a 5-year follow-up (cumulative 5-year all-cause mortality = 30%). From a multiple variable Cox proportional hazards model, the following variables were significantly associated with 5-year mortality: age at refractory coeliac disease diagnosis (per 20 year increase, hazard ratio = 2.21; 95% confidence interval, CI: 1.38-3.55), abnormal intraepithelial lymphocytes (hazard ratio = 2.85; 95% CI: 1.22-6.62), and albumin (per 0.5 unit increase, hazard ratio = 0.72; 95% CI: 0.61-0.85). A simple weighted three-factor risk score was created to estimate 5-year survival. CONCLUSIONS: Using data from a multinational registry and previously reported risk factors, we create a prognostic model to predict 5-year mortality among patients with refractory coeliac disease. This new model may help clinicians to guide treatment and follow-up. PMID- 27485032 TI - Mono- and multimeric ferrocene congeners of quinoline-based polyamines as potential antiparasitics. AB - A series of mono- and multimeric polyamine-containing ferrocenyl complexes containing a quinoline motif were prepared. The complexes were characterised by standard techniques. The molecular structure of the monomeric salicylaldimine derivative was elucidated using single crystal X-ray diffraction and was consistent with the proposed structure. The antiplasmodial activity of the compounds were evaluated in vitro against both the NF54 (chloroquine-sensitive) and K1 (chloroquine-resistant) strains of Plasmodium falciparum. The polyamine derivatives exhibit good resistance index values suggesting that these systems are beneficial in overcoming the resistance experienced by chloroquine. Mechanistic studies suggest that haemozoin formation may be the target of these quinoline complexes in the parasite. Some of the complexes exhibit moderate to high cytotoxicity against WHCO1 oesophageal cancer cells in vitro. The monomeric ferrocenyl-amine complexes exhibit potent activity against this particular cell line. The complexes were also screened against the G3 strain of Trichomonas vaginalis and the salicylaldimine complexes demonstrated promising activity at the tested concentration. All of these compounds show no inhibitory effect on several common normal flora bacteria, indicative of their selectivity for eukaryotic pathogens and cancer. PMID- 27485034 TI - Psychologists Should Help Curb the Wave of U. S. Gun Violence. PMID- 27485033 TI - Diffusion tensor imaging and histology of developing hearts. AB - Diffusion tensor imaging (DTI) has emerged as a promising method for noninvasive quantification of myocardial microstructure. However, the origin and behavior of DTI measurements during myocardial normal development and remodeling remain poorly understood. In this work, conventional and bicompartmental DTI in addition to three-dimensional histological correlation were performed in a sheep model of myocardial development from third trimester to postnatal 5 months of age. Comparing the earliest time points in the third trimester with the postnatal 5 month group, the scalar transverse diffusivities preferentially increased in both left ventricle (LV) and right ventricle (RV): secondary eigenvalues D2 increased by 54% (LV) and 36% (RV), whereas tertiary eigenvalues D3 increased by 85% (LV) and 67% (RV). The longitudinal diffusivity D1 changes were small, which led to a decrease in fractional anisotropy by 41% (LV) and 33% (RV) in 5 month versus fetal hearts. Histological analysis suggested that myocardial development is associated with hyperplasia in the early stages of the third trimester followed by myocyte growth in the later stages up to 5 months of age (increased average myocyte width by 198%, myocyte length by 128%, and decreased nucleus density by 70% between preterm and postnatal 5 month hearts.) In a few histological samples (N = 6), correlations were observed between DTI longitudinal diffusivity and myocyte length (r = 0.86, P < 0.05), and transverse diffusivity and myocyte width (r = 0.96, P < 0.01). Linear regression analysis showed that transverse diffusivities are more affected by changes in myocyte size and nucleus density changes than longitudinal diffusivities, which is consistent with predictions of classical models of diffusion in porous media. Furthermore, primary and secondary DTI eigenvectors during development changed significantly. Collectively, the findings demonstrate a role for DTI to monitor and quantify myocardial development, and potentially cardiac disease. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27485035 TI - Specific alleles at immune genes, rather than genome-wide heterozygosity, are related to immunity and survival in the critically endangered Attwater's prairie chicken. AB - The negative effects of inbreeding on fitness are serious concerns for populations of endangered species. Reduced fitness has been associated with lower genome-wide heterozygosity and immune gene diversity in the wild; however, it is rare that both types of genetic measures are included in the same study. Thus, it is often unclear whether the variation in fitness is due to the general effects of inbreeding, immunity-related genes or both. Here, we tested whether genome wide heterozygosity (20 990 SNPs) and diversity at nine immune genes were better predictors of two measures of fitness (immune response and survival) in the endangered Attwater's prairie-chicken (Tympanuchus cupido attwateri). We found that postrelease survival of captive-bred birds was related to alleles of the innate (Toll-like receptors, TLRs) and adaptive (major histocompatibility complex, MHC) immune systems, but not to genome-wide heterozygosity. Likewise, we found that the immune response at the time of release was related to TLR and MHC alleles, and not to genome-wide heterozygosity. Overall, this study demonstrates that immune genes may serve as important genetic markers when monitoring fitness in inbred populations and that in some populations specific functional genes may be better predictors of fitness than genome-wide heterozygosity. PMID- 27485036 TI - Genome-wide identification and gene expression profiling of ubiquitin ligases for endoplasmic reticulum protein degradation. AB - Endoplasmic reticulum (ER)-associated degradation (ERAD) is a mechanism by which unfolded proteins that accumulate in the ER are transported to the cytosol for ubiquitin-proteasome-mediated degradation. Ubiquitin ligases (E3s) are a group of enzymes responsible for substrate selectivity and ubiquitin chain formation. The purpose of this study was to identify novel E3s involved in ERAD. Thirty-seven candidate genes were selected by searches for proteins with RING-finger motifs and transmembrane regions, which are the major features of ERAD E3s. We performed gene expression profiling for the identified E3s in human and mouse tissues. Several genes were specifically or selectively expressed in both tissues; the expression of four genes (RNFT1, RNF185, CGRRF1 and RNF19B) was significantly upregulated by ER stress. To determine the involvement of the ER stress responsive genes in ERAD, we investigated their ER localisation, in vitro autoubiquitination activity and ER stress resistance. All were partially localised to the ER, whereas CGRRF1 did not possess E3 activity. RNFT1 and RNF185, but not CGRRF1 and RNF19B, exhibited significant resistance to ER stressor in an E3 activity-dependent manner. Thus, these genes are possible candidates for ERAD E3s. PMID- 27485038 TI - RBC omega-3 predicts risk for death. PMID- 27485037 TI - OpEx - a validated, automated pipeline optimised for clinical exome sequence analysis. AB - We present an easy-to-use, open-source Optimised Exome analysis tool, OpEx (http://icr.ac.uk/opex) that accurately detects small-scale variation, including indels, to clinical standards. We evaluated OpEx performance with an experimentally validated dataset (the ICR142 NGS validation series), a large 1000 exome dataset (the ICR1000 UK exome series), and a clinical proband-parent trio dataset. The performance of OpEx for high-quality base substitutions and short indels in both small and large datasets is excellent, with overall sensitivity of 95%, specificity of 97% and low false detection rate (FDR) of 3%. Depending on the individual performance requirements the OpEx output allows one to optimise the inevitable trade-offs between sensitivity and specificity. For example, in the clinical setting one could permit a higher FDR and lower specificity to maximise sensitivity. In contexts where experimental validation is not possible, minimising the FDR and improving specificity may be a preferable trade-off for slightly lower sensitivity. OpEx is simple to install and use; the whole pipeline is run from a single command. OpEx is therefore well suited to the increasing research and clinical laboratories undertaking exome sequencing, particularly those without in-house dedicated bioinformatics expertise. PMID- 27485039 TI - The sympathetic nervous system affects the susceptibility and course of Trypanosoma cruzi infection. AB - Trypanosoma cruzi (T. cruzi) is an intracellular parasite that causes Chagas' disease, a major health problem in Latin America. Using a murine model of infection with this parasite, we have previously shown that corticosterone blood levels are markedly elevated during the course of the disease in C57Bl/6 male mice and that this increase is protective for the host by restricting the production of pro-inflammatory cytokines. Since the hypothalamus-pituitary adrenal (HPA) axis usually operates in a concerted way with the sympathetic nervous system (SNS), we have now studied whether noradrenergic nerves can affect the course of T. cruzi infection and the sexual dimorphism observed in the disease. We found a decreased splenic noradrenaline concentration and content, paralleled by a reduction in noradrenergic nerve fibers in the spleen of infected mice, and increased HPA axis activity. These alterations were more marked in males than in females. When the spontaneous loss of noradrenergic nerve fibers was advanced by chemical sympathectomy prior to infection, males died earlier and mortality significantly increased in females. Chemical denervation did not significantly affect the concentration of specific IgM and IgG2a antibodies to T. cruzi, and did not worsen myocarditis, but resulted in increased parasitemia and IL-6 and IFN-gamma blood levels. The results obtained in this model of parasitic disease provide further indications of the relevance of interactions between the immune system and the SNS for host defense. PMID- 27485040 TI - beta-Adrenergic-stimulated macrophages: Comprehensive localization in the M1-M2 spectrum. AB - beta-Adrenergic signaling can regulate macrophage involvement in several diseases and often produces anti-inflammatory properties in macrophages, which are similar to M2 properties in a dichotomous M1 vs. M2 macrophage taxonomy. However, it is not clear that beta-adrenergic-stimulated macrophages may be classified strictly as M2. In this in vitro study, we utilized recently published criteria and transcriptome-wide bioinformatics methods to map the relative polarity of murine beta-adrenergic-stimulated macrophages within a wider M1-M2 spectrum. Results show that beta-adrenergic-stimulated macrophages did not fit entirely into any one pre-defined category of the M1-M2 spectrum but did express genes that are representative of some M2 side categories. Moreover, transcript origin analysis of genome-wide transcriptional profiles located beta-adrenergic-stimulated macrophages firmly on the M2 side of the M1-M2 spectrum and found active suppression of M1 side gene transcripts. The signal transduction pathways involved were mapped through blocking experiments and bioinformatics analysis of transcription factor binding motifs. M2-promoting effects were mediated specifically through beta2-adrenergic receptors and were associated with CREB, C/EBPbeta, and ATF transcription factor pathways but not with established M1-M2 STAT pathways. Thus, beta-adrenergic-signaling induces a macrophage transcriptome that locates on the M2 side of the M1-M2 spectrum but likely accomplishes this effect through a signaling pathway that is atypical for M2-spectrum macrophages. PMID- 27485041 TI - Prevalence of hand syndromes among patients with diabetes mellitus in Taiwan: A population-based study. AB - BACKGROUND: Population-based data for diabetic hand syndrome (DHS) are limited. The aim of the present epidemiological study was to estimate the overall and cause-specific prevalence and rate ratio (RR) of DHS in patients with diabetes. METHODS: The present study was a cross-sectional study based on a random sample of 57 093 diabetics and matched controls, both identified from Taiwan National Health Insurance claims in 2010. The DHS analyzed in the present study included carpal tunnel syndrome (CTS), stenosing flexor tenosynovitis (SFT), limited joint mobility (LJM), and Dupuytren's disease (DD). RESULTS: The prevalence of overall DHS was estimated at 2472 per 105 for the diabetics, compared with 1641 per 105 for the controls, representing a prevalence RR of 1.51 (95 % confidence interval [CI] 1.39-1.64). Stratified analyses further revealed that the significantly increased prevalence of overall DHS was more evident in females than males (1.59 vs 1.36) and was only noted in diabetics aged >=35 years. Cause-specific analysis suggested that patients with diabetes had the highest prevalence of CTS (1244 per 105 ), followed by SFT (1209 per 105 ), LJM (39 per 105 ), and DD (6 per 105 ). In addition, diabetes was only significantly associated with CTS (RR 1.34; 95 % CI 1.20-1.51) and SFT (1.74; 95 % CI 1.54-1.97). CONCLUSION: The prevalence of overall and certain cause-specific DHS was significantly elevated in patients with diabetes in Taiwan. PMID- 27485042 TI - Diagnostic mistakes of culturally diverse individuals when using North American neuropsychological tests. AB - Although the role of culture has increasingly gained acceptance in clinical neuropsychology, relatively minimal research exists regarding the actual impact on clinical activities. In this study, we assess how using North American neuropsychological tests affects diagnostic accuracy in cognitive disorders of culturally diverse individuals. To address this question, participants from Colombia, Morocco, and Spain were administered five commonly used neuropsychological tests and the test results were used to determine whether they would be classified as having the DSM-5 diagnostic criteria for Mild Cognitive and Major Cognitive Disorder. Results reveal that diagnostic error occurred up to 20% of the time, and that the frequency of misdiagnosis differed by nationality. These results provide evidence that using tests from one culture to assess individuals from other cultures produces significant false positives. Findings are discussed in terms of the foundations of neuropsychological assessment and its relationship to cultural variables. PMID- 27485043 TI - Apprehensive about retirement: Women, life transitions, and relationships. AB - Understanding women's attitudes toward retirement is crucial for being able to help women adjust to this transition. The present study uses interviews and questionnaires to understand retirement ambivalence and the role that close relationships play in women's retirement experiences. Findings indicate that women have mixed feelings about retirement; they are both excited and fearful. They particularly enjoy the freedom and control this transition brings but are also moderately fearful of retirement, especially about shifting relationships. A better-quality relationship correlates with greater satisfaction and less fear. Such insights can be used to help women prepare for this major transition. PMID- 27485044 TI - Regiodivergent Intermolecular [3+2] Cycloadditions of Vinyl Aziridines and Allenes: Stereospecific Synthesis of Chiral Pyrrolidines. AB - The first rhodium-catalyzed intermolecular [3+2] cycloaddition reaction of vinyl aziridines and allenes for the synthesis of enantioenriched functionalized pyrrolidines was realized. [3+2] cycloaddition with the proximal C=C bond of N allenamides gave 3-methylene-pyrrolidines in high regio- and diastereoselectivity, whereas, 2-methylene-pyrrolidines were obtained as the major products by the cycloadditions of vinyl aziridines with the distal C=C bond of allenes. Use of readily available starting materials, a broad substrate scope, high selectivity, mild reaction conditions, as well as versatile functionalization of the cycloadducts make this approach very practical and attractive. PMID- 27485045 TI - Anterior inferior cerebellar artery aneurysms: Segments and results of surgical and endovascular managements. AB - BACKGROUND: Anterior inferior cerebellar artery (AICA) aneurysms are rare and published clinical experience with these aneurysms is limited. OBJECTIVE: The objective of this article is to report angiographic characteristics and results associated with premeatal, meatal and postmeatal segments, surgical and endovascular therapies. METHODS: A literature review was performed through PubMed using "anterior inferior cerebellar artery aneurysm" through January 2016. Clinical data, angiograms, management techniques, and patient outcomes were reviewed for 47 collected cases in 30 previous reports. RESULTS: Of these aneurysms, 21 (44.7%) were associated with meatal segment, 10 (21.3%) were postmeatal and 16 (34.0%) were premeatal. Patients with meatal aneurysms are more likely to present with subarachnoid hemorrhage and hearing loss and facial palsy (77.8%). Patient outcomes of meatal aneurysms presented with more neuropathies (51.7%) and cerebellar symptoms (14.3%) (p = 0.049). Four cases of meatal aneurysm with preoperative cranial nerve deficits (two VII and two VIII) showed improvement after surgery. Endovascular treatment achieved outcomes similar to surgical treatment (p = 0.327). CONCLUSIONS: AICA aneurysms have a predilection for meatal segment. Patients with meatal aneurysms are more likely to present with subarachnoid hemorrhage and hearing loss and facial palsy. Patient outcomes of meatal aneurysms presented with more neuropathies and cerebellar symptoms. Endovascular treatment achieved outcomes similar to surgical treatment. PMID- 27485046 TI - Modification of cerebral vascular anatomy induced by Leo stent placement depending on the site of stenting: A series of 102 cases. AB - BACKGROUND AND PURPOSE: Recent studies demonstrated the capacity of stents to modify cerebral vascular anatomy. This study evaluates arterial anatomy deformation after Leo stent placement according to the stenting site and the impact on the immediate postoperative and six-month degree of aneurysmal occlusion. MATERIALS AND METHODS: A total of 102 stents were placed against the neck of aneurysms situated in the anterior cerebral circulation. Aneurysms were classified into two groups: The first was called the distal group (n = 62) and comprised aneurysms situated in the middle cerebral and anterior communicating arteries and the second was called the proximal group (n = 40) and comprised aneurysms in other sites. The stented arterial segment was classified as deformed or non-deformed by blinded review and superimposition of anonymised films before and after stenting. The degree of occlusion was determined immediately postoperatively and at six months. RESULTS: Significantly, anatomical deformity was observed in the distal group compared to the proximal group (85% vs 28%). No significant difference was observed between the two groups in terms of postoperative degree of occlusion. At six months, a significant difference was observed between the two groups: three recurrences in the distal group vs 10 recurrences in the proximal group. Two (3%) recurrences were observed in the deformed group vs 11 (31%) recurrences in the non-deformed group. CONCLUSIONS: Arterial deformity induced by stenting is even more marked for distal aneurysms. The recurrence rate is smaller when the stent placement results in an arterial anatomical change. The percentage of recurrence is lower when anatomy was amended by stent implantation. PMID- 27485047 TI - Rational approach, technique and selection criteria treating lumbar disk herniations by oxygen-ozone therapy. AB - Radicular lumbar back pain is an important public health problem not yet benefiting from a unequivocal treatment approach. Medical and physical therapies represent the first solution; however, when these fail, the second therapeutic step is still controversial and mini-invasive treatments may play an important role. In these cases oxygen-ozone therapy has been proved to be a very safe and effective option that is widely used with different modalities. This paper, by reviewing oxygen-ozone therapy literature data, aims to describe the rationale of oxygen-ozone therapy for the treatment of lumbar disk herniations, propose an effective procedural technique and clarify patient selection criteria; furthermore, complications and follow-up management are also considered. PMID- 27485048 TI - Large basilar perforator pseudoaneurysm: A case report. AB - Basilar perforator aneurysms are rare and a communication between a basilar perforator and a separate pseudoaneurysm cavity is extremely rare. We describe a case presenting with high grade subarachnoid hemorrhage which on further investigation delineated a 2-3 mm dissecting basilar perforator aneurysm communicating superiorly into a contained 6 mm pseudoaneurysm cavity. This case illustrates an unusual neurovascular pathology with low potential for successful endovascular treatment such as coil embolization or intracranial flow diverter stenting. Conservative medical management remains the main stay of treatment for such poor surgical candidates. PMID- 27485049 TI - The sense of body ownership relaxes temporal constraints for multisensory integration. AB - Experimental work on body ownership illusions showed how simple multisensory manipulation can generate the illusory experience of an artificial limb as being part of the own-body. This work highlighted how own-body perception relies on a plastic brain representation emerging from multisensory integration. The flexibility of this representation is reflected in the short-term modulations of physiological states and perceptual processing observed during these illusions. Here, we explore the impact of ownership illusions on the temporal dimension of multisensory integration. We show that, during the illusion, the temporal window for integrating touch on the physical body with touch seen on a virtual body representation, increases with respect to integration with visual events seen close but separated from the virtual body. We show that this effect is mediated by the ownership illusion. Crucially, the temporal window for visuotactile integration was positively correlated with participants' scores rating the illusory experience of owning the virtual body and touching the object seen in contact with it. Our results corroborate the recently proposed causal inference mechanism for illusory body ownership. As a novelty, they show that the ensuing illusory causal binding between stimuli from the real and fake body relaxes constraints for the integration of bodily signals. PMID- 27485051 TI - Secular trends in physical fitness and body size in Lithuanian children and adolescents between 1992 and 2012. AB - BACKGROUND AND METHODS: There is a paucity of data on contemporary secular trends on the different aspects of physical fitness in school-aged children and adolescents. This study presents the largest ever data set on changes in fitness between 1992, 2002 and 2012 for both genders of schoolchildren aged 11-18 years (n=16 199). Eurofit test battery was used to assess the balance, flexibility, muscular strength and power, agility and cardiorespiratory fitness. Anthropometrics were also measured and body mass index (BMI) was calculated. RESULTS: The study has shown loss of flexibility, leg muscle power, upper body strength and cardiorespiratory fitness between 1992 and 2012, although there was an improvement in abdominal muscle strength in girls, agility in boys and balance in both genders during the same period. At large, negative trends in aspects of fitness seen between 1992 and 2002 have not slowed down between 2002 and 2012. Positive trends in agility and abdominal muscle strength seen before 2002 have regressed or were reversed between 2002 and 2012, while balance continued to improve at increased pace. While the BMI continued to increase in all groups, analysis of covariance has shown that it was not the main cause of changes in fitness. CONCLUSIONS: The general decline in physical fitness in Lithuanian schoolchildren observed between 1992 and 2002 continued between 2002 and 2012, although some aspects of fitness showed a positive trend. If this general negative trend continues, it will compromise the well-being of future adults and create a serious economic burden on the society. PMID- 27485050 TI - Vitamin D levels and perinatal depressive symptoms in women at risk: a secondary analysis of the mothers, omega-3, and mental health study. AB - BACKGROUND: Vitamin D insufficiency may be associated with depressive symptoms in non-pregnant adults. We performed this study to evaluate whether low maternal vitamin D levels are associated with depressive symptoms in pregnancy. METHODS: This study was a secondary analysis of a randomized trial designed to assess whether prenatal omega-3 fatty acid supplementation would prevent depressive symptoms. Pregnant women from Michigan who were at risk for depression based on Edinburgh Postnatal Depression Scale Score or history of depression were enrolled. Participants completed the Beck Depression Inventory (BDI) and Mini International Neuropsychiatric Interview at 12-20 weeks, 26-28 weeks, 34-36 weeks, and 6-8 weeks postpartum. Vitamin D levels were measured at 12-20 weeks (N = 117) and 34-36 weeks (N = 112). Complete datasets were available on 105 subjects. Using regression analyses, we evaluated the relationship between vitamin D levels with BDI scores as well as with MINI diagnoses of major depressive disorder and generalized anxiety disorder. Our primary outcome measure was the association of maternal vitamin D levels with BDI scores during early and late pregnancy and postpartum. RESULTS: We found that vitamin D levels at 12-20 weeks were inversely associated with BDI scores both at 12-20 and at 34-36 weeks' gestation (P < 0.05, both). For every one unit increase in vitamin D in early pregnancy, the average decrease in the mean BDI score was .14 units. Vitamin D levels were not associated with diagnoses of major depressive disorder or generalized anxiety disorder. CONCLUSIONS: In women at risk for depression, early pregnancy low vitamin D levels are associated with higher depressive symptom scores in early and late pregnancy. Future investigations should study whether vitamin D supplementation in early pregnancy may prevent perinatal depressive symptoms. TRIAL REGISTRATION: https://clinicaltrials.gov/ REGISTRATION NUMBER: NCT00711971. PMID- 27485052 TI - Competing risk analysis of factors related to long-term incidence of CHD. AB - BACKGROUND: The 5-year follow-up results for the 1202 middle-aged men prospective study of coronary heart disease (CHD) incidence were published in 1980. This paper extends the follow-up, relating the development of CHD to 10 risk factors. METHODS: The population studied comprised all men born in the 10-year period 1909 1918 aged 45-64 years at baseline who were registered in 6 group practices in Belfast. Some 1202 CHD-free men entered the study. Study end points included: (a) the development of CHD, (b) the development of myocardial infarction, (c) the development of angina pectoris, (d) death from myocardial infarction and (e) death from other causes. The men were followed for an average of 6.9 years, and the influence of 10 risk factors was assessed by Cox's proportional hazards model in a competing risk framework. RESULTS: The analysis of first major CHD event identified four risk factors-diastolic blood pressure, serum cholesterol, T wave abnormality and tobacco index. First myocardial infarction depended on diastolic blood pressure, ST abnormality and tobacco index, while time to first angina pectoris depended on serum cholesterol, T abnormality, tobacco index and age at entry. These findings do not support the hypothesis of a common risk factor profile in the myocardial infarction and angina pectoris groups. The sensitivity of all models was poor. DISCUSSION: The study confirms the role of known risk factors in the development of first CHD event. It also suggests that the risk factors involved in developing myocardial infarction and angina pectoris differ. The poor sensitivity of models suggests the presence of unmeasured risk factors in the aetiology of CHD. PMID- 27485053 TI - Recent cohort effects in suicide in Scotland: a legacy of the 1980s? AB - BACKGROUND: Mortality rates are higher in Scotland relative to England and Wales, even after accounting for deprivation. This 'excess' mortality is partly due to higher mortality from alcohol-related and drug-related deaths, violence and suicide (particularly in young adults). This study investigated whether cohort effects from exposure to neoliberal politics from the 1980s might explain the recent trends in suicide in Scotland. METHODS: We analysed suicide deaths data from 1974 to 2013 by sex and deprivation using shaded contour plots and intrinsic estimator regression modelling to identify and quantify relative age, period and cohort effects. RESULTS: Suicide was most common in young adults (aged around 25 40 years) living in deprived areas, with a younger peak in men. The peak age for suicide fell around 1990, especially for men for whom it dropped quickly from around 50 to 30 years. There was evidence of an increased risk of suicide for the cohort born between 1960 and 1980, especially among men living in the most deprived areas (of around 30%). The cohort at highest risk occurred earlier in the most deprived areas, 1965-1969 compared with 1970-1974. CONCLUSIONS: The risk of suicide increased in Scotland for those born between 1960 and 1980, especially for men living in the most deprived areas, which resulted in a rise in age standardised rates for suicide among young adults during the 1990s. This is consistent with the hypothesis that exposure to neoliberal politics created a delayed negative health impact. PMID- 27485054 TI - Association between targeted somatic mutation (TSM) signatures and HGS-OvCa progression. AB - Evidence already exists that the activation-induced cytidine deaminase (AID/APOBEC) and the adenosine deaminase (ADAR) families of enzymes are implicated as powerful mutagens in oncogenic processes in many somatic tissues. Each deaminase is identified by the DNA or RNA nucleotide sequence ("motif") surrounding the nucleotide targeted for deamination. The primary objective of this study is to develop an in silico approach to identify nucleotide sequence changes of the target motifs of key deaminases during oncogenesis. If successful, a secondary objective is to investigate if such changes are associated with disease progression indicators that include disease stage and progression-free survival time. Using a discovery cohort of 194 high-grade serous ovarian adenocarcinoma (HGS-OvCa) exomes, the results confirm the ability of the novel in silico approach used to identify changes in the preferred target motifs for AID, APOBEC3G, APOBEC3B, and ADAR1 during oncogenesis. Using this approach, a set of new cancer-progression associated signatures (C-PASs) were identified. Furthermore, it was found that the C-PAS identified can be used to differentiate between the cohort of patients that remained progression-free for longer than 60 months, from those in which disease progressed within 60 months (sensitivity 95%, specificity 90%). The spectrum of outcomes observed here could provide a foundation for future clinical assessment of susceptibility variants in ovarian, and several other cancers as disease progresses. The ability of the in silico methodology used to identify changes in deaminase motifs during oncogenesis also suggests new links between immune system function and tumorigenesis. PMID- 27485056 TI - Hepatic resection for metastatic breast cancer: an exercise in selection bias. PMID- 27485055 TI - Visual Outcome and Related Factors in Bilateral Total Congenital Cataract Patients: A Prospective Cohort Study. AB - This study is to evaluate the visual outcome and identify its crucial related factors in children undergoing cataract surgery for bilateral total congenital cataract (CC). This prospective study included consecutive bilateral total cataract patients undergoing primary surgery at Zhongshan Ophthalmic Center (ZOC), Guangzhou, China from Jan 2010 to May 2014. Visual outcome was estimated by best-corrected visual acuity (BCVA) at last follow-up. Potential related factors, including gender, age at last follow-up, age at primary surgery, surgical procedure, postoperative complications (PCs), frequency of follow-up and changes in spectacles were evaluated. Eighty-eight children (176 eyes) were included in the cohort. The mean post-operative BCVA (logMAR) was 1.07 +/- 0.53 at the mean follow-up duration 31.07 +/- 19.36 months. Multivariable generalized estimating equations (GEEs) showed BCVA was significantly associated with PCs, age at last follow-up and age at primary surgery. Partial correlation analysis indicated age at primary surgery was positively correlated with BCVA controlling for the other factors, both for the whole age range (R = 0.415, P < 0.001) and age >6 months (R = 0.867, P < 0.001). Better visual acuity was related to early primary surgery and low PC occurrence in children with bilateral total CC. Timely surgical intervention and strict control of PCs would be potential steps to achieving better visual outcome. PMID- 27485057 TI - Positive para-aortic lymph nodes following pancreatectomy for pancreatic cancer. Systematic review and meta-analysis of impact on short term survival and association with clinicopathologic features. AB - BACKGROUND: The relation between para-aortic lymph nodes (PALN) involvement and pancreatic ductal adenocarcinoma (PDAC) survival, along with the optimal handling of this particular lymph node station remain unclear. A systematic review and meta-analysis was performed to assess this. METHODS: A search of Medline, Embase, Ovid and Cochrane databases was performed until July 2015 to identify studies reporting on the relation of PALN involvement and PDAC outcomes and a meta analysis was performed following data extraction. RESULTS: Ten retrospective studies and two prospective non randomized studies (2467 patients) were included. Patients with positive PALN had worse one (p < 0.00001) and two year (p < 0.00001) survival when compared with patients with negative PALN. Even when comparing only patients with positive lymph nodes (N1), patients with PALN involvement presented with a significant lower one (p = 0.03) and two (p = 0.002) year survival. PALN involvement was associated with an increased possibility of positive margin (R1) resection (p < 0.00001), stations' 12, 14 and 17 malignant infiltration (p < 0.00001), but not with tumour stage (p = 0.78). DISCUSSION: Involvement of PALN is associated with decreased survival in pancreatic cancer patients. However, existence of long term survivors among this subgroup of patients should be further evaluated, in order to identify factors associated with their favourable prognosis. PMID- 27485058 TI - Defining post-operative pancreatitis as a new pancreatic specific complication following pancreatic resection. AB - INTRODUCTION: Post-operative pancreatic fistula has been well defined. However the underlying aetiology remains poorly understood. The aim of this review was to investigate whether the underlying aetiology for a proportion of patients suffering from post-operative pancreatic fistula was due to post-operative pancreatitis. METHOD: A systematic literature review according to the PRISMA guidelines. The date range was from 2005 to 2016. The search strategy included the terms: post-operative pancreatitis, pathophysiology, post-operative pancreatic fistula, pancreaticoduodenectomy, ischaemic pancreatitis, microcirculation and pancreatitis, serum and drain amylase and lipase. The data was summarised without quantitative or qualitative analysis. RESULTS: There exists significant physiological, biochemical, clinical and histological evidence in the literature that a proportion of post-operative pancreatic fistula is due to post-operative pancreatitis. A new definition of post-operative pancreatitis based on the presence of biochemical evidence for pancreatic inflammation (urinary trypsinogen-2 >50 ug/L or serum amylase/lipase > upper limit of normal) between post-operative days 0-2. Predicted severity is based on C-reactive protein with a cut-off of 180 mg/L at post-operative day 2. The proposed grading of severity is in line with previous work by international study group of pancreatic surgery. CONCLUSION: Post-operative pancreatitis should be recognised as a separate pancreatic specific complication following pancreatic resection. Improved recognition may allow better understanding of potential methods of prevention, treatment and prediction of severity. PMID- 27485060 TI - Effects of Rowachol on prevention of postcholecystectomy pain after laparoscopic cholecystectomy: prospective multicenter randomized controlled trial. AB - BACKGROUND: Postcholecystectomy pain (PCP) is characterized by abdominal pain after cholecystectomy. However, prevention of PCP is not well known yet. The purpose of this study was to determine whether Rowachol might be useful in preventing PCP. METHODS: Between May 2013 and January 2014, a total of 138 patients with gallbladder disease who were scheduled to undergo laparoscopic cholecystectomy were randomly assigned to orally receive 100 mg Rowachol or placebo three times daily for 3 months after surgery. Abdominal pain was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. RESULTS: Incidence of PCP in the placebo group (n = 9, 14.3%) was higher than that in the Rowachol group (n = 3, 4.7%) with statistically marginal significance (P = 0.08). Risk factor analysis implicated PCP with increased difficulty in performing LC, more frequent pathology with acute cholecystitis, and absence of postoperative Rowachol treatment. Multivariate analysis revealed that greater difficulty of laparoscopic cholecystectomy (HR = 5.78, 95% CI 1.36 24.40, P < 0.05), and absence of postoperative Rowachol treatment (HR = 2.54, 95% CI 1.10-10.39, P < 0.05) were independent risk factors for development of PCP. CONCLUSION: Rowachol might be beneficial for prevention of PCP after laparoscopic cholecystectomy. PMID- 27485059 TI - Systematic review of peri-operative prognostic biomarkers in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) continues to be associated with a poor prognosis. This systematic review aimed to summarize the literature regarding potential prognostic biomarkers to facilitate validation studies and clinical application. METHODS: A systematic review was performed (2004-2014) according to PRISMA guidelines. Studies were ranked using REMARK criteria and the following outcomes were examined: overall/disease free survival, nodal involvement, tumour characteristics, metastasis, recurrence and resectability. RESULTS: 256 biomarkers were identified in 158 studies. 171 biomarkers were assessed with respect to overall survival: urokinase-type plasminogen activator receptor, atypical protein kinase C and HSP27 ranked the highest. 33 biomarkers were assessed for disease free survival: CD24 and S100A4 were the highest ranking. 17 biomarkers were identified for lymph node involvement: Smad4/Dpc4 and FOXC1 ranked highest. 13 biomarkers were examined for tumour grade: mesothelin and EGFR were the highest ranking biomarkers. 10 biomarkers were identified for metastasis: p16 and sCD40L were the highest ranking. 4 biomarkers were assessed resectability: sCD40L, s100a2, Ca 19-9, CEA. CONCLUSION: This review has identified and ranked specific biomarkers that should be a primary focus of ongoing validation and clinical translational work in PDAC. PMID- 27485061 TI - Early surgical bypass versus endoscopic stent placement in pancreatic cancer. AB - INTRODUCTION: The optimal treatment for biliary obstruction in pancreatic cancer remains controversial between surgical bypass and endoscopic stenting. METHODS: Retrospective analysis of unresected pancreatic cancer patients in the Healthcare Cost and Utilization Project Florida State Inpatient and Ambulatory Surgery databases (2007-2011). Propensity score matching by procedure. Primary outcome was reintervention, and secondary outcomes were readmission, overall length of stay (LOS), discharge home, death and cost. Multivariate analyses performed by logistic regression. RESULTS: In a matched cohort of 622, 20.3% (63) of endoscopic and 4.5% (14) of surgical patients underwent reintervention (p < 0.0001) and 56.0% (174) vs. 60.1% (187) were readmitted (p = 0.2909). Endoscopic patients had lower median LOS (10 vs. 19 days, p < 0.0001) and cost ($21,648 vs. $38,106, p < 0.0001) as well as increased discharge home (p = 0.0029). No difference in mortality on index admission. On multivariate analysis, initial procedure not predictive of readmission (p = 0.1406), but early surgical bypass associated with lower odds of reintervention (OR = 0.233, 95% CI 0.119, 0.434). DISCUSSION: Among propensity score-matched patients receiving bypass vs. stenting, readmission and mortality rates are similar. However, candidates for both techniques may experience fewer subsequent procedures if offered early biliary bypass with the caveats of decreased discharge home and increased cost/LOS. PMID- 27485062 TI - Evaluating the risk of hepatocellular carcinoma in patients with prominently elevated liver stiffness measurements by FibroScan: a multicentre study. AB - BACKGROUND AND AIMS: There are limited data on the significance of liver stiffness measurements (LSM) by transient elastography in the upper extreme end of the measurable spectrum. This multicentre retrospective observational study evaluated the risk of hepatocellular carcinoma (HCC) in patients with LSM >=20 kPa. METHODS: 432 cirrhosis patients with LSM >=20 kPa between June 2007 and October 2015 were retrospectively followed-up through electronic records. RESULTS: A minimum 1-year follow-up was available for 278 patients (177 men; average age 57, range 18-84). LSM ranged from 20.0 to 75.0 kPa (mean 34.6 kPa). Cumulative incidences of HCC were 19 (6.8%), 30 (10.8%) and 41 (14.7%) at 1, 2 and 3 years, respectively. HCC was associated with age (p = 0.003), higher LSM (p = 0.005) and viral aetiology (p = 0.007). Patients were divided into 4 groups based on LSM at entry: 20-25 kPa (n = 74); 25-30 kPa (n = 62); 30-40 kPa (n = 75); >40 kPa (n = 67). Compared to the 20-25 kPa group, the 30-40 kPa group had a hazard ratio (HR) of 3.0 (95% CI, 1.1-8.3; p = 0.037), and the >40 kPa group had a HR of 4.8 (95% CI, 1.7-13.4; p = 0.003). CONCLUSIONS: This study shows an association between LSM at the upper extreme and HCC risk. Physicians may find this beneficial as a non-invasive dynamic approach to assessing HCC risk in cirrhosis patients. PMID- 27485063 TI - Sequential transarterial chemoembolization and portal vein embolization before resection is a valid oncological strategy for unilobar hepatocellular carcinoma regardless of the tumor burden. AB - OBJECTIVE: To investigate the long-term oncological outcome of patients with resectable hepatocellular carcinoma (HCC) undergoing sequential transarterial chemoembolization (TACE) and portal vein embolization (PVE). METHODS: Analysis of all Child A HCC patients who underwent TACE-PVE before major liver resection from 2006 to 2012 was performed according to whether or not they underwent surgical resection as planned. RESULTS: 54 patients (50 men, 93% median 69-years (range 44 87)) were included. Thirty-nine (72%) patients underwent resection, including 19/25, 16/23, and 4/6 of patients with BCLC A, B, and C (p = 0.839). Twenty-two (56%) had tumor recurrence (median delay 10 months) including 9/19, 11/16, and 2/4 of the patients with BCLC A, B, and C (p = 0.430). Survival was significantly better in resected patients as compared to those who were not resected (median overall survival (OS): 44 vs. 18 months; p < 0.001). Recurrence was associated with a poorer prognosis as compared to patients without recurrence (median OS 43 months vs. not reached; p < 0.001). BCLC stage did not influence survival (p = 0.13). CONCLUSION: In patients with large unilobar HCC, TACE-PVE leads to resection in most patients, with a good oncological outcome regardless of the tumor burden. When this strategy fails, patients can be managed with TACE despite prior PVE. PMID- 27485064 TI - Liver function declines with increased age. AB - INTRODUCTION: Age itself is not considered a contraindication for high impact surgery. However, the aging process of the liver remains largely unknown. This study evaluates age-dependent changes in liver function using a quantitative liver function test. METHODS: Between January 2005 and December 2014, 508 patients underwent (99m)Tc-mebrofenin hepatobiliary scintigraphy (HBS) for the assessment of liver function. These included 203 patients with healthy livers (group A) and 57 patients with HCC and Child-Pugh A (group B). (99m)Tc-mebrofenin uptake-rate of the whole liver corrected for body surface area (cMUR) was calculated for all patients. Linear regression analysis was performed to assess the relationship between age and cMUR. RESULTS: The mean cMUR was 8.50 +/- 2.05%/min/m(2) and 6.94 +/- 2.03%/min/m(2) in group A and B, respectively. A negative linear correlation was found between patient's age and cMUR in group A, r = 0.244, p = 0.000. In group B, there was no correlation between age and cMUR, however, a trend in decline of liver function with age was noted. CONCLUSION: This study shows that liver function deteriorates with age. Since the regenerative capacity of the liver correlates with liver function, this finding should be taken into account when assessing surgical risk in patients considered for major liver resection. PMID- 27485065 TI - Trends in the scientific program of the Americas Hepato-Pancreato-Biliary Association (AHPBA) Annual Meeting over the past decade: the more things change, the more they stay the same. AB - BACKGROUND: Numerous clinical and basic science innovations have been presented at the AHPBA. The objective was to define changes in content and methodology of the scientific program over the past decade. METHODS: AHPBA abstracts from the past 10-years were reviewed by 2 investigators (volume, content, origin, methodology). RESULTS: Of 2194 total AHPBA abstracts (2005-2015), the volume per year decreased over time (2005 = 283; 2015 = 177; p < 0.05). Contribution from the United States increased (USA = 65% (41-76%); p < 0.05). Topic categories were consistent across years (liver = 38% (30-46%), pancreas = 29% (27-48%), biliary = 13% (5-16%); p > 0.05). Amongst liver topics, primary tumors increased in volume (13% (8-18%)). Colorectal metastases were stable (19% (15-28%)) but more frequent than primary hepatic tumors overall (p < 0.05). Amongst pancreas topics, cancer and cysts increased significantly (30% (18-39%) and 4% (0-5%) respectively). While transplantation topics decreased (7% (3-12%), education abstracts increased (1% (0-3%; p < 0.05). Retrospective methodology was consistent amongst 83% (75 91%) of abstracts despite a decrease in prospective studies (9% (3-17%; p < 0.05). Basic science (11% (4-15%)) topics decreased, while large registry/database (9% (0-23%)) abstracts increased (p < 0.05). DISCUSSION: Abstracts related to primary hepatic tumors, pancreatic cancer, pancreatic cystic neoplasms, and education have increased over the past decade of the AHPBA. The decrease in prospective methodology combined with few randomized trials remains concerning. PMID- 27485066 TI - The role of liver-directed surgery in patients with hepatic metastasis from primary breast cancer: a multi-institutional analysis. AB - BACKGROUND: Data on surgical management of breast liver metastasis are limited. We sought to determine the safety and long-term outcome of patients undergoing hepatic resection of breast cancer liver metastases (BCLM). METHODS: Using a multi-institutional, international database, 131 patients who underwent surgery for BCLM between 1980 and 2014 were identified. Clinicopathologic and outcome data were collected and analyzed. RESULTS: Median tumor size of the primary breast cancer was 2.5 cm (IQR: 2.0-3.2); 58 (59.8%) patients had primary tumor nodal metastasis. The median time from diagnosis of breast cancer to metastasectomy was 34 months (IQR: 16.8-61.3). The mean size of the largest liver lesion was 3.0 cm (2.0-5.0); half of patients (52.0%) had a solitary metastasis. An R0 resection was achieved in most cases (90.8%). Postoperative morbidity and mortality were 22.8% and 0%, respectively. Median and 3-year overall-survival was 53.4 months and 75.2%, respectively. On multivariable analysis, positive surgical margin (HR 3.57, 95% CI 1.40-9.16; p = 0.008) and diameter of the BCLM (HR 1.03, 95% CI 1.01-1.06; p = 0.002) remained associated with worse OS. DISCUSSION: In selected patients, resection of breast cancer liver metastases can be done safely and a subset of patients may derive a relatively long survival, especially from a margin negative resection. PMID- 27485069 TI - Scotopic vision in the monkey is modulated by the G protein-coupled receptor 55. AB - The endogenous cannabinoid system plays important roles in the retina of mice and monkeys via their classic CB1 and CB2 receptors. We have previously reported that the G protein-coupled receptor 55 (GPR55), a putative cannabinoid receptor, is exclusively expressed in rod photoreceptors in the monkey retina, suggesting its possible role in scotopic vision. To test this hypothesis, we recorded full-field electroretinograms (ERGs) after the intravitreal injection of the GPR55 agonist lysophosphatidylglucoside (LPG) or the selective GPR55 antagonist CID16020046 (CID), under light- and dark-adapted conditions. Thirteen vervet monkeys (Chlorocebus sabaeus) were used in this study: four controls (injected with the vehicle dimethyl sulfoxide, DMSO), four injected with LPG and five with CID. We analyzed amplitudes and latencies of the a-wave (photoreceptor responses) and the b-wave (rod and cone system responses) of the ERG. Our results showed that after injection of LPG, the amplitude of the scotopic b-wave was significantly higher, whereas after the injection of CID, it was significantly decreased, compared to the vehicle (DMSO). On the other hand, the a-wave amplitude, and the a-wave and b wave latencies, of the scotopic ERG responses were not significantly affected by the injection of either compound. Furthermore, the photopic ERG waveforms were not affected by either drug. These results support the hypothesis that GPR55 plays an instrumental role in mediating scotopic vision. PMID- 27485070 TI - The S-curve for forecasting waste generation in construction projects. AB - Forecasting construction waste generation is the yardstick of any effort by policy-makers, researchers, practitioners and the like to manage construction and demolition (C&D) waste. This paper develops and tests an S-curve model to indicate accumulative waste generation as a project progresses. Using 37,148 disposal records generated from 138 building projects in Hong Kong in four consecutive years from January 2011 to June 2015, a wide range of potential S curve models are examined, and as a result, the formula that best fits the historical data set is found. The S-curve model is then further linked to project characteristics using artificial neural networks (ANNs) so that it can be used to forecast waste generation in future construction projects. It was found that, among the S-curve models, cumulative logistic distribution is the best formula to fit the historical data. Meanwhile, contract sum, location, public-private nature, and duration can be used to forecast construction waste generation. The study provides contractors with not only an S-curve model to forecast overall waste generation before a project commences, but also with a detailed baseline to benchmark and manage waste during the course of construction. The major contribution of this paper is to the body of knowledge in the field of construction waste generation forecasting. By examining it with an S-curve model, the study elevates construction waste management to a level equivalent to project cost management where the model has already been readily accepted as a standard tool. PMID- 27485071 TI - Chimeric antigen receptor-engineered primary natural killer cells: a tool to improve adoptive tumor immunotherapy. PMID- 27485072 TI - Research progress in the field of immunotherapeutic vaccination in human TB and the way ahead. PMID- 27485073 TI - Self-administered hyaluronidase-facilitated subcutaneous immunoglobulin therapy in complicated primary antibody deficiencies. AB - Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIg) is a new immunoglobulin product for replacement therapy in patients with primary antibody deficiencies (PAD). The pre-administration of recombinant human hyaluronidase associated with 10% immunoglobulin allowed the infusion of larger (up to 600 ml) amounts of immunoglobulin at a single infusion site, enabling patients to receive the necessary treatment in a single monthly dose. Here, we report the effectiveness and the tolerability of fSCIg in patients with severe PAD-related comorbidities: refractory autoimmune thrombocytopenia; systemic granulomatous disease; severe enteropathy, and Type I diabetes. We conclude that fSCIg could be a feasible option to improve the adherence to replacement therapy also by patients with severe PAD. PMID- 27485074 TI - Cytokine-induced killer cell therapy-associated idiopathic thrombocytopenic purpura: rare but noteworthy. AB - Idiopathic thrombocytopenic purpura (ITP) is characterized by a diminished platelet count, an autoimmune condition with antibodies against platelets and an increased tendency to bleed. The association between ITP and solid tumors is uncommon. Cytokine-induced killer (CIK) cell therapy is a well tolerated and promising cancer treatment with minimal toxicity. For the first time, CIK cell therapy was reported to be followed by ITP. The mechanism through which CIK induces ITP remains unclear. Imbalanced ratio of Th cells, decreased numbers or impaired function of Treg cells and excessive secretion of cytokines inducing abnormal activation of B cells may be among the possible reasons. Therefore, a better understanding of this rare condition will require further investigation of these cases. PMID- 27485075 TI - A pooled analysis of nivolumab for the treatment of advanced non-small-cell lung cancer and the role of PD-L1 as a predictive biomarker. AB - BACKGROUND: Recent studies with nivolumab (a monoclonal antibody against programmed cell death 1 [PD-1] receptor) have shown promise non-small-cell lung cancer (NSCLC) treatment. METHODS: To review available clinical trials data in order to assess nivolumab efficacy and the role of tumoral PDL-1 expression as a biomarker. RESULTS: Nine eligible studies included 2102 patients. In the second line setting, nivolumab achieved a 1-year survival rate of 41%; and in the first line, a 1-year survival rate of 76%. For those with PD-L1 expression <1%, nivolumab showed a trend for improved survival compared with docetaxel. CONCLUSIONS: The available data reinforce nivolumab activity against NSCLC in first-line or subsequent lines. Although PD-L1 expression is related to greater response, PD-L1 negative patients had also some benefit. PMID- 27485076 TI - Use of LDH and autoimmune side effects to predict response to ipilimumab treatment. AB - BACKGROUND: Ipilimumab is a cytotoxic T-lymphocyte antigen-4 antibody that enhances T-cell activity and proliferation. METHODS: In a retrospective analysis of 86 patients the clinical benefits of ipilimumab treatment were correlated with laboratory and clinical data. RESULTS: A lactate dehydrogenase (LDH) value within the normal range before the start of therapy was significantly correlated with better OS (p <= 0.009). An increase in LDH level after two cycles was indicative of a poor outcome, and was significantly negatively correlated with treatment response and overall survival and progression-free survival. 42% of all patients suffered from autoimmune toxicity (CTCAE grades 2-4). The occurrence of autoimmune toxicity clearly correlated with clinical benefit. CONCLUSION: Changes in LDH level and side effects correlate with response to therapy and survival. PMID- 27485077 TI - A recombinant TGF-beta1 vaccine ameliorates diabetic nephropathy in OLETF rats. AB - AIM: The aim of this study was to investigate the potential of a recombinant vaccine encoding TGF-beta1 in OLETF rats with diabetic nephropathy (DN). METHODS: OLETF rats were treated with vehicle or TGF-beta1 vaccine. LETO rats were used as normal controls. At 42 weeks after immunization with vaccine, samples from blood, urine and kidney were collected for biochemical, histologic, immunohistochemical and molecular analyses. RESULTS: OLETF rats treated with the vaccine reduced blood glucose levels, improved renal pathological changes, and inhibited overexpression of TGF-beta1 and p-Smad3, as well as MCP-1, TNF-alpha and IL 1beta. CONCLUSION: TGF-beta1 vaccine attenuated diabetic nephropathy in OLETF rats through reduction of inflammation, improvement of kidney fibrosis and partial correction of glucose metabolism. PMID- 27485078 TI - Tumor-derived vaccines containing CD200 inhibit immune activation: implications for immunotherapy. AB - There are over 400 ongoing clinical trials using tumor-derived vaccines. This approach is especially attractive for many types of brain tumors, including glioblastoma, yet so far the clinical response is highly variable. One contributor to poor response is CD200, which acts as a checkpoint blockade, inducing immune tolerance. We demonstrate that, in response to vaccination, glioma-derived CD200 suppresses the anti-tumor immune response. In contrast, a CD200 peptide inhibitor that activates antigen-presenting cells overcomes immune tolerance. The addition of the CD200 inhibitor significantly increased leukocyte infiltration into the vaccine site, cytokine and chemokine production, and cytolytic activity. Our data therefore suggest that CD200 suppresses the immune system's response to vaccines, and that blocking CD200 could improve the efficacy of cancer immunotherapy. PMID- 27485079 TI - Current status of engineered T-cell therapy for synovial sarcoma. AB - Synovial sarcoma is a rare soft tissue sarcoma characterized by a t(X;18) translocation, which results in a SYT-SSX gene fusion. In the metastatic setting, chemotherapy has limited, durable efficacy prompting the necessity for new therapeutic modalities. One emerging new strategy involves T-cell-directed therapy such as tumor-infiltrating lymphocytes or the development of T cells that are genetically engineered to express a T-cell receptor against a cancer testis antigen. Of these approaches, engineered T cells that recognize NY-ESO-1 are the furthest along in development. Completed and on-going clinical trials have shown promise and there are efforts to continue to optimize the current approach. PMID- 27485080 TI - PD-L1 expression and outcome of advanced melanoma patients treated with anti-PD 1/PD-L1 agents: a meta-analysis. AB - AIM: This meta-analysis aims at assessing the correlation of PD-L1 levels and response PD-1/PD-L1 inhibitors in advanced malignant melanoma. METHODS: Eligible studies included those evaluating PD-1/PD-L1 inhibitors in advanced melanoma and correlating the outcomes to PD-L1 levels. RESULTS: After preclusion of ineligible studies, 11 studies were included. For PD-L1 >1% patients versus PD-L1 <1% patients treated with PD-1/PD-L1 targeted agents, the OR of ORR was 2.81 (95% CI: 1.64-4.82; p = 0.0002); while for PD-L1 >5% patients versus PD-L1 <5% patients, it was 2.22 (95% CI: 1.71-2.87; p < 0.00001). CONCLUSION: The current analysis indicates the value of PD-L1 positivity in predicting higher response from PD 1/PD-L1 agents. This molecular predictor - together with other predictors - may help further individualize treatment options for metastatic melanoma patients. PMID- 27485081 TI - Perspectives of ofatumumab as CD20 targeted therapy in rheumatoid arthritis and other autoimmune diseases. AB - Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune condition viewed as a severe destructive disease. The treatment strategies include anti-CD20 monoclonal antibody (mAb)-targeting B cells. Ofatumumab specifically targets a membrane-proximal epitope on the CD20 molecule distinct from other anti-CD20 antibodies including rituximab and ocrelizumab, and bind the epitope located on the large loop of CD20. This explains a more durable B-cell depletion and a different pharmacodynamic. We review the pharmacodynamic of B-cell depletion and analyze the results in RA and other B-cell-mediated autoimmune diseases. The randomized trial in RA showed clinical efficacy comparable to rituximab at week 24. However, structural impact has not been demonstrated. Studies including RA patients refractory to rituximab would be useful to define the optimal strategy of ofatumumab therapy. PMID- 27485083 TI - Tau-based therapeutics for Alzheimer's disease: active and passive immunotherapy. AB - Pharmacological manipulation of tau protein in Alzheimer's disease included microtubule-stabilizing agents, tau protein kinase inhibitors, tau aggregation inhibitors, active and passive immunotherapies and, more recently, inhibitors of tau acetylation. Animal studies have shown that both active and passive approaches can remove tau pathology and, in some cases, improve cognitive function. Two active vaccines targeting either nonphosphorylated (AAD-vac1) and phosphorylated tau (ACI-35) have entered Phase I testing. Notwithstanding, the recent discontinuation of the monoclonal antibody RG7345 for Alzheimer's disease, two other antitau antibodies, BMS-986168 and C2N-8E12, are also currently in Phase I testing for progressive supranuclear palsy. After the recent impressive results in animal studies obtained by salsalate, the dimer of salicylic acid, inhibitors of tau acetylation are being actively pursued. PMID- 27485084 TI - Strategies to control human cytomegalovirus infection in adult hematopoietic stem cell transplant recipients. AB - Human cytomegalovirus (HCMV) represents the major viral complication after hematopoietic stem cell transplantation. HCMV infection may be controlled by the reconstituting immune system and remain subclinical or can lead to severe systemic and/or organ disease (mainly pneumonia and gastroenteritis) when immune reconstitution is delayed or impaired. In order to prevent the occurrence of HCMV disease, a prompt diagnosis of HCMV infection is mandatory. The adoption of pre emptive therapy strategies guided by virological monitoring dramatically reduced the occurrence of HCMV disease. However, late-onset end-organ disease may occur in some patients with apparent immune reconstitution. In the near future, introduction of immunological monitoring and immunotherapies could markedly improve management of HCMV infection. PMID- 27485085 TI - Erratum. PMID- 27485082 TI - Anti-GD2 mAbs and next-generation mAb-based agents for cancer therapy. AB - Tumor-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the clinic, becoming an important approach for cancer immunotherapy. Due to its limited expression on normal tissue, the GD2 disialogangloside expressed on neuroblastoma cells is an excellent candidate for mAb therapy. In 2015, dinutuximab (an anti-GD2 mAb) was approved by the US FDA and is currently used in a combination immunotherapeutic regimen for the treatment of children with high risk neuroblastoma. Here, we review the extensive preclinical and clinical development of anti-GD2 mAbs and the different mechanisms by which they mediate tumor cell killing. In addition, we discuss different mAb-based strategies that capitalize on the targeting ability of anti-GD2 mAbs to potentially deliver, as monotherapy, or in combination with other treatments, improved antitumor efficacy. PMID- 27485086 TI - Evaluation of Giardia lamblia thioredoxin reductase as drug activating enzyme and as drug target. AB - The antioxidative enzyme thioredoxin reductase (TrxR) has been suggested to be a drug target in several pathogens, including the protist parasite Giardia lamblia. TrxR is also believed to catalyse the reduction of nitro drugs, e.g. metronidazole and furazolidone, a reaction required to render these compounds toxic to G. lamblia and other microaerophiles/anaerobes. It was the objective of this study to assess the potential of TrxR as a drug target in G. lamblia and to find direct evidence for the role of this enzyme in the activation of metronidazole and other nitro drugs. TrxR was overexpressed approximately 10-fold in G. lamblia WB C6 cells by placing the trxR gene behind the arginine deiminase (ADI) promoter on a plasmid. Likewise, a mutant TrxR with a defective disulphide reductase catalytic site was strongly expressed in another G. lamblia WB C6 cell line. Susceptibilities to five antigiardial drugs, i.e. metronidazole, furazolidone, nitazoxanide, albendazole and auranofin were determined in both transfectant cell lines and compared to wildtype. Further, the impact of all five drugs on TrxR activity in vivo was measured. Overexpression of TrxR rendered G. lamblia WB C6 more susceptible to metronidazole and furazolidone but not to nitazoxanide, albendazole, and auranofin. Of all five drugs tested, only auranofin had an appreciably negative effect on TrxR activity in vivo, albeit to a much smaller extent than expected. Overexpression of TrxR and mutant TrxR had hardly any impact on growth of G. lamblia WB C6, although the enzyme also exerts a strong NADPH oxidase activity which is a source of oxidative stress. Our results constitute first direct evidence for the notion that TrxR is an activator of metronidazole and furazolidone but rather question that it is a relevant drug target of presently used antigiardial drugs. PMID- 27485087 TI - High-throughput in vitro assay to evaluate the cytotoxicity of liberated platinum compounds for stimulating neural electrodes. AB - BACKGROUND: It is currently unclear how the platinum (Pt) species released from platinum-containing stimulating electrodes may affect the health of the surrounding tissue. This study develops an effective system to assess the cytotoxicity of any electrode-liberated Pt over a short duration, to screen systems before future in vivo testing. NEW METHOD: A platinum electrode was stimulated for two hours under physiologically relevant conditions to induce the liberation of Pt species. The total concentration of liberated Pt species was quantified and the concentration found was used to develop a range of Pt species for our model system comprised of microglia and neuron-like cells. RESULTS: Under our stimulation conditions (k=2.3, charge density of 57.7MUC/cm2), Pt was liberated to a concentration of 1ppm. Interestingly, after 24h of Pt exposure, the dose-dependent cytotoxicity plots revealed that cell death became statistically significant at 10ppm for microglia and 20ppm for neuronal cells. However, in neuron-like cell cultures, concentrations above 1ppm resulted in significant neurite loss after 24h. COMPARISON WITH EXISTING METHODS: To our knowledge, there does not exist a simple, in vitro assay system for assessing the cytotoxicity of Pt liberated from stimulating neural electrodes. CONCLUSIONS: This work describes a simple model assay that is designed to be applicable to almost any electrode and stimulation system where the electrode is directly juxtaposed to the neural target. Based on the application, the duration of stimulation and Pt exposure may be varied. PMID- 27485088 TI - Excitation Light Dose Engineering to Reduce Photo-bleaching and Photo-toxicity. AB - It is important to determine the most effective method of delivering light onto a specimen for minimal light induced damage. Assays are presented to measure photo bleaching of fluorophores and photo-toxicity to living cells under different illumination conditions. Turning the light off during part of the experimental time reduced photo-bleaching in a manner proportional to the time of light exposure. The rate of photo-bleaching of EGFP was reduced by 9-fold with light pulsing on the micro-second scale. Similarly, in living cells, rapid line scanning resulted in reduced cell stress as measured by mitochondrial potential, rapid cell protrusion and reduced cell retraction. This was achieved on a commercial confocal laser scanning microscope, without any compromise in image quality, by using rapid laser scan settings and line averaging. Therefore this technique can be implemented broadly without any software or hardware upgrades. Researchers can use the rapid line scanning option to immediately improve image quality on fixed samples, reduce photo-bleaching for large high resolution 3D datasets and improve cell health in live cell experiments. The assays developed here can be applied to other microscopy platforms to measure and optimize light delivery for minimal sample damage and photo-toxicity. PMID- 27485089 TI - Differing Philosophical Approaches to Treating Patients. PMID- 27485090 TI - Availability and Readability of Online Patient Education Materials Regarding Regional Anesthesia Techniques for Perioperative Pain Management. AB - Objective: Patient education materials (PEM) should be written at a sixth-grade reading level or lower. We evaluated the availability and readability of online PEM related to regional anesthesia and compared the readability and content of online PEM produced by fellowship and nonfellowship institutions. Methods: With IRB exemption, we constructed a cohort of online regional anesthesia PEM by searching Websites from North American academic medical centers supporting a regional anesthesiology and acute pain medicine fellowships and used a standardized Internet search engine protocol to identify additional nonfellowship Websites with regional anesthesia PEM based on relevant keywords. Readability metrics were calculated from PEM using the TextStat 0.1.4 textual analysis package for Python 2.7 and compared between institutions with and without a fellowship program. The presence of specific descriptive PEM elements related to regional anesthesia was also compared between groups. Results: PEM from 17 fellowship and 15 nonfellowship institutions were included in analyses. The mean (SD) Flesch-Kincaid Grade Level for PEM from the fellowship group was 13.8 (2.9) vs 10.8 (2.0) for the nonfellowship group (p = 0.002). We observed no other differences in readability metrics between fellowship and nonfellowship institutions. Fellowship-based PEM less commonly included descriptions of the following risks: local anesthetic systemic toxicity (p = 0.033) and injury due to an insensate extremity (p = 0.003). Conclusions: Available online PEM related to regional anesthesia are well above the recommended reading level. Further, fellowship-based PEM posted are at a higher reading level than PEM posted by nonfellowship institutions and are more likely to omit certain risk descriptions. PMID- 27485091 TI - Rationalising pKa shifts in Bacillus circulans xylanase with computational studies. AB - Bacillus circulans xylanase (BcX), a family 11 glycoside hydrolase, catalyses the hydrolysis of xylose polymers with a net retention of stereochemistry. Glu172 in BcX is believed to act as a general acid by protonating the aglycone during glycosylation, and then as a general base to facilitate the deglycosylation step. The key to the dual role of this general acid/base lies in its protonation states, which depend on its intrinsic pKa value and the specific environment which it resides within. To fully understand the detailed molecular features in BcX to establish the dual role of Glu172, we present a combined study based on both atomistic simulations and empirical models to calculate pKa shifts for the general acid/base Glu172 in BcX at different functional states. Its pKa values and those of nearby residues, obtained based on QM/MM free energy calculations, MCCE and PROPKA, show a good agreement with available experimental data. Additionally, our study provides additional insights into the effects of structural and electrostatic perturbations caused by mutations and chemical modifications, suggesting that the local solvation environment and mutagenesis of the residues adjacent to Glu172 establish its dual role during hydrolysis. The strengths and limitations of various methods for calculating pKas and pKa shifts have also been discussed. PMID- 27485092 TI - The Rainbow Scale for Assessing Breast Ptosis: Validation of Three Different Views. AB - BACKGROUND: Photographic scales have become an increasingly used tool in objectively assessing outcomes in aesthetic surgery. However, no online photographic scale for assessing breast ptosis has been developed yet that is readily available. OBJECTIVES: This study was designed to validate the online Rainbow Scale for the assessment of breast ptosis for the anterior-posterior (AP), lateral, and oblique views. METHODS: For the five grades of the Rainbow Scale format, standardized reference photographs were selected. Six plastic surgeons rated 15 photographs for each view three times. Intra- and inter observer agreements were calculated by using the weighted kappa coefficient and differences in intra- and inter-observer agreements between the three views were assessed for statistical significance using the Kruskal-Wallis test. RESULTS: The mean intra-observer agreements were 0.91 (range, 0.82-0.98) for the AP view, 0.88 (range, 0.77-1.00) for the oblique view, and 0.86 (range, 0.74-0.97) for the lateral view and did not vary significantly between all three views. The mean inter-observer agreements were 0.88 (range, 0.77-0.95) for the AP view, 0.84 (range, 0.72-0.94) for the oblique view, and 0.82 (range, 0.58-0.95) for the lateral view. The mean inter-observer agreements of the AP view varied significantly from the oblique view (P = .012) and the lateral view (P = .001). CONCLUSIONS: The Rainbow Scale for breast ptosis has been validated for the AP view, the lateral view, and the oblique view and is reproducible and reliable for the assessment of breast ptosis in three different views in an online setup. LEVEL OF EVIDENCE: 4 Diagnostic. PMID- 27485093 TI - Metabolic demand of the hepatic cell cycle. PMID- 27485094 TI - Repair of segmental radial defects in dogs using tailor-made titanium mesh cages with plates combined with calcium phosphate granules and basic fibroblast growth factor-binding ion complex gel. AB - Repair of large segmental defects of long bones are a tremendous challenge that calls for a novel approach to supporting immediate weight bearing and bone regeneration. This study investigated the functional and biological characteristics of a combination of a tailor-made titanium mesh cage with a plate (tTMCP) with tetrapod-shaped alpha tricalcium phosphate granules (TB) and basic fibroblast growth factor (bFGF)-binding ion complex gel (f-IC gel) to repair 20 mm segmental radial defects in dogs. The defects were created surgically in 18 adult beagle dogs and treated by implantation of tTMCPs with TB with (TB-gel group) or without (TB group) f-IC gel. Each tTMCP fitted the defect well, and all dogs could bear weight on the affected limb immediately after surgery. Dogs were euthanized 4, 8 and 24 weeks after implantation. Histomorphometry showed greater infiltration of new vessels and higher bone union rate in the TB-gel group than in the TB group. The lamellar bone volume and mineral apposition rate did not differ significantly between the groups, indicating that neovascularization may be the primary effect of f-IC gel on bone regeneration. This combination method which is tTMCP combined with TB and f-IC gel, would be useful for the treatment of segmental long bone defects. PMID- 27485095 TI - Cadmium Isotope Fractionation in Soil-Wheat Systems. AB - Analyses of stable metal isotope ratios constitute a novel tool in order to improve our understanding of biogeochemical processes in soil-plant systems. In this study, we used such measurements to assess Cd uptake and transport in wheat grown on three agricultural soils under controlled conditions. Isotope ratios of Cd were determined in the bulk C and A horizons, in the Ca(NO3)2-extractable Cd soil pool, and in roots, straw, and grains. The Ca(NO3)2-extractable Cd was isotopically heavier than the Cd in the bulk A horizon (Delta(114/110)Cdextract Ahorizon = 0.16 to 0.450/00). The wheat plants were slightly enriched in light isotopes relative to the Ca(NO3)2-extractable Cd or showed no significant difference (Delta(114/110)Cdwheat-extract = -0.21 to 0.030/00). Among the plant parts, Cd isotopes were markedly fractionated: straw was isotopically heavier than roots (Delta(114/110)Cdstraw-root = 0.21 to 0.410/00), and grains were heavier than straw (Delta(114/110)Cdgrain-straw = 0.10 to 0.510/00). We suggest that the enrichment of heavy isotopes in the wheat grains was caused by mechanisms avoiding the accumulation of Cd in grains, such as the chelation of light Cd isotopes by thiol-containing peptides in roots and straw. These results demonstrate that Cd isotopes are significantly and systematically fractionated in soil-wheat systems, and the fractionation patterns provide information on the biogeochemical processes in these systems. PMID- 27485096 TI - Cranium asymmetry in a modern Greek population sample of known age and sex. AB - The aim of this paper is to evaluate and quantify cranium asymmetry, sexual differences in the set of individual asymmetry scores, and the relationship between fluctuating asymmetry and age, in a modern Greek population sample. In addition, we test for the developmental origins of health and disease hypothesis by assessing the correlation between fluctuating asymmetry and cause of death. The study sample consisted of 173 crania of known sex and adult age (92 males, 81 females) belonging to individuals who lived in Greece during the twentieth century. The three-dimensional coordinates of 77 ectocranial landmarks were digitized using a Microscribe 3DX contact digitizer and landmark configurations were analyzed using the generalized least-squares Procrustes method. Regarding directional asymmetry, the results show that the human skull has a tendency for a left-side excess for the Greek population. No significant directional asymmetry differences between the sexes are found. The highest levels of fluctuating asymmetry for both sexes are located on the skull base. The levels of fluctuating asymmetry in all cranial regions appear higher for males than females. Nevertheless, these differences do not present any statistical significance between sexes. Additionally, there is no relationship between fluctuating asymmetry scores and age for both males and females. Finally, the results of this study could not confirm that early development has a significant impact on adult health outcomes. PMID- 27485097 TI - Study of genetic markers of CODIS and ESS systems in a population of individuals from Cabo Verde living in Lisboa. AB - Twenty-two autosomal short tandem repeats included in the PowerPlex(r) Fusion System Amplification kit (Promega Corporation) were genotyped in a population sample of 500 unrelated individuals from Cabo Verde living in Lisboa. Allelic frequency data and forensic and statistical parameters were calculated and evaluated in this work. The genetic relationship among immigrant population from Cabo Verde living in Lisboa and other populations, such as Brazilian and Angola immigrants living in Lisboa; Afro-Americans, Caucasians, Hispanics and Asians living in the USA and the population from Lisboa was assessed, and a multidimensional scaling plot was drown to show these results. PMID- 27485098 TI - Hyperbaric oxygen as an adjunctive therapy in treatment of malignancies, including brain tumours. AB - Hyperbaric oxygen (HBO) therapy is widely used as an adjunctive treatment for various pathological states, predominantly related to hypoxic and/or ischaemic conditions. It also holds promise as an approach to overcoming the problem of oxygen deficiency in the poorly oxygenated regions of the neoplastic tissue. Occurrence of local hypoxia within the central areas of solid tumours is one of the major issues contributing to ineffective medical treatment. However, in anti cancer therapy, HBO alone gives a limited curative effect and is typically not applied by itself. More often, HBO is used as an adjuvant treatment along with other therapeutic modalities, such as radio- and chemotherapy. This review outlines the existing data regarding the medical use of HBO in cancer treatment, with a particular focus on the use of HBO in the treatment of brain tumours. We conclude that the administration of HBO can provide many clinical benefits in the treatment of tumours, including management of highly malignant gliomas. Applied immediately before irradiation, it is safe and well tolerated by patients, causing rare and limited side effects. The results obtained with a combination of HBO/radiotherapy protocol proved to be especially favourable compared to radiation treatment alone. HBO can also increase the cytostatic effect of certain drugs, which may render standard chemotherapy more effective. The currently available data support the legitimacy of conducting further research on the use of HBO in the treatment of malignancies. PMID- 27485099 TI - Parenting Strategies to Deal with Children's Anxiety: Do Parents Do What They Say They Do? AB - Parents' perceptions about their strategies to deal with children's anxiety have been minimally explored. Based on a mixed-method approach, the current study compared the strategies that parents said they use more frequently to deal with their child's anxious behaviors and the strategies they actually used during two mildly anxiogenic interactions with their child. Forty-two parents of children with anxiety disorders, aged 9-12 years, participated in the study. Semi structured interviews were administered to identify parental perceptions about their strategies to deal with their children's anxiety. Subsequently dyadic interactions were observed and coded by two independent coders. We found discrepancies relating to four strategies. Significantly more parents used strategies based on overinvolvement and anxious behavior during the interactions than had been reported by them in the interviews. In contrast, reassurance and reinforcement of avoidance/dependence were used in interactions by fewer parents than would be expected, according to the interviews. Relevant implications for assessment and intervention with families of anxious children are suggested. PMID- 27485100 TI - Augmenting Cognitive Behavior Therapy for School Refusal with Fluoxetine: A Randomized Controlled Trial. AB - This study investigates whether the augmentation of cognitive behavior therapy (CBT) with fluoxetine improves outcomes in anxious school refusing adolescents (11-16.5 years). Sixty-two participants were randomly allocated to CBT alone, CBT + fluoxetine or CBT + placebo. All treatments were well tolerated; with one suicide-attempt in the CBT + placebo group. All groups improved significantly on primary (school attendance) and secondary outcome measures (anxiety, depression, self-efficacy and clinician-rated global functioning); with gains largely maintained at 6-months and 1-year. Few participants were anxiety disorder free after acute treatment. During the follow-up period anxiety and depressive disorders continued to decline whilst school attendance remained stable, at around 54 %. The only significant between-group difference was greater adolescent reported treatment satisfaction in the CBT + fluoxetine group than the CBT alone group. These results indicate the chronicity of school refusal, and the need for future research into how to best improve school attendance rates. PMID- 27485102 TI - Editorial. PMID- 27485101 TI - MicroRNA-26a protects against cardiac hypertrophy via inhibiting GATA4 in rat model and cultured cardiomyocytes. AB - Pathological cardiac hypertrophy is characterized by deleterious changes developed in cardiovascular diseases, whereas microRNAs (miRNAs) are involved in the mediation of cardiac hypertrophy. To investigate the role of microRNA-26a (miR-26a) in regulating cardiac hypertrophy and its functioning mechanisms, overexpression and suppression of miR-26a via its mimic and inhibitor in a transverse abdominal aortic constriction (TAAC)-induced rat model and in angiotensin II (Ang II)-induced cardiomyocytes (CMs) was performed. In the rat model, the heart weight (HW) compared with the body weight (BW), the CM area, and expression of the hypertrophy-associated factors, atrial natriuretic factor (ANF) and beta-myosin heavy chain (beta-MHC), were assessed. In CMs, the protein synthesis rate was determined using a leucine incorporation assay. Mutation of the GATA-binding protein 4 (GATA4) 3'-untranslated region (UTR) and overexpression of GATA4 were performed to confirm whether GATA4 is the target of miR-26a. The results indicated that miR-26a was significantly downregulated in the heart tissue of the rat model, as well as in Ang II-induced CMs (P<0.05). The TAAC-induced rat model exhibited a higher HW/BW ratio, a larger CM area, and higher expression levels of ANF and beta-MHC. CMs, upon Ang II treatment, also demonstrated a larger CM area, higher levels of ANF and beta-MHC, as well as accelerated protein synthesis. miR-26a was not able to regulate GATA4 with mutations in the 3'-UTR, indicating that GATA4 was the direct target of miR-26a. Overexpression of GATA4 abrogated the inhibitory functions of miR-26a in cardiac hypertrophy. Taken together, the present study suggested an anti-hypertrophic role of miR-26a in cardiac hypertrophy, possibly via inhibition of GATA4. These findings may be useful in terms of facilitating cardiac treatment, with potential therapeutic targets and strategies. PMID- 27485103 TI - Aspartate kinase involved in 4-hydroxy-3-nitrosobenzamide biosynthesis in Streptomyces murayamaensis. AB - Streptomyces murayamensis carries two aspartate kinase (AK) genes: one for the biosynthesis of lysine, threonine, and methionine, and the other (nspJ) contained in the biosynthetic gene cluster for the secondary metabolite, 4-hydroxy-3 nitrosobenzamide, for catalyzing the first reaction. AKs involved in the biosynthesis of amino acids are often regulated allosterically by the end products. In the present study, we characterized NspJ to investigate whether AKs involved in secondary metabolism were also allosterically regulated. NspJ was in alpha2beta2 and (alpha2beta2)2 heterooligomeric forms, and was insensitive to all the compounds tested including lysine, threonine, and methionine. The reduction in the activity following the removal of ammonium sulfate, which induced subunit dissociation, suggests that the beta subunit may be involved in stabilizing the structure of the alpha subunit in order to exhibit its activity. This study has provided the first example of a feedback-insensitive alpha2beta2-type AK, which is involved in the secondary metabolism. PMID- 27485104 TI - Two-Tension-Band Technique in Revision Surgery for Fixation Failure of Patellar Fractures. AB - BACKGROUND Failed patellar fracture fixation is rare, and is usually attributed to technical errors. There are no specific details available on how to address this problem. We present our two-tension-band technique for fixing patellar fractures. MATERIAL AND METHODS Between March 2010 and March 2013, 4 men and 2 women with failed fixation patellar fractures were treated in our department. Their average age was 34 years (range 23-49 years). The initial fracture type was C1 in 3, C2 in 1, and C3 in 2, according to the AO classification. The initial fracture patterns included 3 transverse and 3 comminuted fractures. There were no open fractures. All patients underwent internal fixation with a modified anterior tension band (MATB) supplemented with cerclage wiring. All failures were caused by tension bands sliding past the tip of the Kirschner wires. The mean time between the primary and revision operations was 16.2 months (range 2-63 months). We revised the fractures by two-separate-tension-band technique. RESULTS The mean follow-up was 52 months (range 31-67 months). All patients healed radiographically without complications at an average of 14.7 weeks (range 8-20 weeks). The Bostman knee score was excellent in 3 and good in 3. All patients regained full extension and the mean range of flexion was 147.5 degrees (135-155 degrees ). CONCLUSIONS Use of this two-tension-band technique can avoid technical errors and provide more secure fixation. We recommend it for both primary and revision surgery of patellar fractures. PMID- 27485105 TI - Effects of HeartWare ventricular assist device on the von Willebrand factor: results of an academic Belgian center. AB - BACKGROUND: Left Ventricular Assist Device (LVAD) is a promising therapy for patients with advanced heart failure (HF), but bleeding complications remain an important issue. Previous series show that acquired von Willebrand syndrome was present in up to 100 % of first generation LVAD recipients. We report the effects of new generation LVADs on vW factor (vWF) metabolism and activity in our center. METHODS: Fifteen LVAD recipients (HeartWare(r), Framingham, MA, USA) were compared to 12 HF patients, matched for age and body mass index. vWF antigen and activity, as well as D-dimers, were measured on hemostasis analyzers. A vWF LVAD induced alteration was evocated when the [vWF activity]/[vWF antigen] ratio was <0.6. ADAMTS13 and high molecular weight multimers of vWF were also assessed. RESULTS: LVAD recipients had similar levels of endothelial vWF production than the HF subjects (137 +/- 14.5 vs. 147 +/- 11.7 %; respectively, p = 0.611) but a decreased vWF activity (90 +/- 11 vs. 132.6 +/- 13 %; respectively, p = 0.017). [vWF activity]/[vWF antigen] ratio was 0.65 +/- 0.02 in the LVAD recipients and 0.92 +/- 0.06 in the subjects with HF (p = 0.001). ADAMTS13 activity was 80.3 +/- 4.7 % in LVAD recipients and 96.2 +/- 3.5 % in the HF patients (p = 0.016). LVAD patients disclosed markedly elevated D-dimers (3217.7 +/- 735 vs. 680.6 +/- 223.2 ng/mL FEU in the HF patients, p = 0.006). The LVAD patients experienced one major hemorrhagic event and one systemic thrombotic event during the median follow-up of 345 days. CONCLUSIONS: LVAD recipients achieved a new hemostatic equilibrium characterized by infrequent major hemorrhagic and thrombotic events, despite a mildly impaired vWF function and a markedly enhanced thrombin formation. TRIAL REGISTRATION: ISRCTN39517567. PMID- 27485107 TI - Use of a Simulated Model to Teach Male Adult Circumcision in Sub-Saharan Africa. AB - Male adult circumcision (MC) has been shown to reduce the risk of HIV transmission in men by 50-60 %. An upscaling in the training of providers to perform circumcision is necessary to meet demand since MC is a key component of essential surgery in the context of universal health coverage. We piloted a low cost, high-fidelity model for training adult circumcision. Multi-centre, multinational data were collected on 74 trainees and clinicians (trainers) in sub Saharan Africa. Both trainers and trainees gave excellent feedback for the model (content and face validity). The simulated model enables a safe and realistic simulation experience to perform MC. The model is quick to set up and easily transportable to multiple teaching sites. PMID- 27485108 TI - A new xyelotomid (Hymenoptera) from the Middle Jurassic of China displaying enigmatic venational asymmetry. AB - BACKGROUND: Pterygota insects typically have symmetric veins in left and right wings. For studying taxonomy and phylogeny of fossil insects, venational patterns are commonly used as diagnostic characters, in conjunction with preserved body characters. Some examples of asymmetrical venation are known among extant insects, but only a few fossil insects with asymmetric wings have been reported, among which a previously described xyelotomid of Hymenoptera, Xyelocerus diaphanous, displays an unusual, small cell of vein Rs in the left forewing, but not in the right. RESULTS: Herein we report a new sawfly of the family Xyelotomidae, Aethotoma aninomorpha gen. et sp. nov., from the late Middle Jurassic of China having a simple Sc in the forewing and Sc with two branches in the hind wing. In additional, the new specimen exhibits an enigmatic venational asymmetry. In the right forewing, crossvein 2r-rs of forms a loop, then forks into 2 long branches reaching Rs, while 2r-rs of the left forewing forks into 2 short branches reaching Rs, in contrast to a linear 2r-rs in typical fossil and extant sawflies. CONCLUSION: Such rare asymmetrical venation found from fossil sawflies provides a glance at early occurrences of venational variability and instability, or possibly aberrational development, for insects in the late Middle Jurassic. PMID- 27485106 TI - Robot-aided assessment of lower extremity functions: a review. AB - The assessment of sensorimotor functions is extremely important to understand the health status of a patient and its change over time. Assessments are necessary to plan and adjust the therapy in order to maximize the chances of individual recovery. Nowadays, however, assessments are seldom used in clinical practice due to administrative constraints or to inadequate validity, reliability and responsiveness. In clinical trials, more sensitive and reliable measurement scales could unmask changes in physiological variables that would not be visible with existing clinical scores.In the last decades robotic devices have become available for neurorehabilitation training in clinical centers. Besides training, robotic devices can overcome some of the limitations in traditional clinical assessments by providing more objective, sensitive, reliable and time-efficient measurements. However, it is necessary to understand the clinical needs to be able to develop novel robot-aided assessment methods that can be integrated in clinical practice.This paper aims at providing researchers and developers in the field of robotic neurorehabilitation with a comprehensive review of assessment methods for the lower extremities. Among the ICF domains, we included those related to lower extremities sensorimotor functions and walking; for each chapter we present and discuss existing assessments used in routine clinical practice and contrast those to state-of-the-art instrumented and robot-aided technologies. Based on the shortcomings of current assessments, on the identified clinical needs and on the opportunities offered by robotic devices, we propose future directions for research in rehabilitation robotics. The review and recommendations provided in this paper aim to guide the design of the next generation of robot-aided functional assessments, their validation and their translation to clinical practice. PMID- 27485109 TI - In chronic myeloid leukemia patients on second-line tyrosine kinase inhibitor therapy, deep sequencing of BCR-ABL1 at the time of warning may allow sensitive detection of emerging drug-resistant mutants. AB - BACKGROUND: Imatinib-resistant chronic myeloid leukemia (CML) patients receiving second-line tyrosine kinase inhibitor (TKI) therapy with dasatinib or nilotinib have a higher risk of disease relapse and progression and not infrequently BCR ABL1 kinase domain (KD) mutations are implicated in therapeutic failure. In this setting, earlier detection of emerging BCR-ABL1 KD mutations would offer greater chances of efficacy for subsequent salvage therapy and limit the biological consequences of full BCR-ABL1 kinase reactivation. Taking advantage of an already set up and validated next-generation deep amplicon sequencing (DS) assay, we aimed to assess whether DS may allow a larger window of detection of emerging BCR ABL1 KD mutants predicting for an impending relapse. METHODS: a total of 125 longitudinal samples from 51 CML patients who had acquired dasatinib- or nilotinib-resistant mutations during second-line therapy were analyzed by DS from the time of failure and mutation detection by conventional sequencing backwards. BCR-ABL1/ABL1%(IS) transcript levels were used to define whether the patient had 'optimal response', 'warning' or 'failure' at the time of first mutation detection by DS. RESULTS: DS was able to backtrack dasatinib- or nilotinib resistant mutations to the previous sample(s) in 23/51 (45 %) pts. Median mutation burden at the time of first detection by DS was 5.5 % (range, 1.5-17.5 %); median interval between detection by DS and detection by conventional sequencing was 3 months (range, 1-9 months). In 5 cases, the mutations were detectable at baseline. In the remaining cases, response level at the time mutations were first detected by DS could be defined as 'Warning' (according to the 2013 ELN definitions of response to 2nd-line therapy) in 13 cases, as 'Optimal response' in one case, as 'Failure' in 4 cases. No dasatinib- or nilotinib-resistant mutations were detected by DS in 15 randomly selected patients with 'warning' at various timepoints, that later turned into optimal responders with no treatment changes. CONCLUSIONS: DS enables a larger window of detection of emerging BCR-ABL1 KD mutations predicting for an impending relapse. A 'Warning' response may represent a rational trigger, besides 'Failure', for DS based mutation screening in CML patients undergoing second-line TKI therapy. PMID- 27485110 TI - The comprehensive profile of fermentation products during in situ CO2 recycling by Rubisco-based engineered Escherichia coli. AB - BACKGROUND: In our previous study, the feasibility of Rubisco-based engineered E. coli (that contains heterologous phosphoribulokinase (PrkA) and Rubisco) for in situ CO2 recycling during the fermentation of pentoses or hexoses was demonstrated. Nevertheless, it is perplexing to see that only roughly 70 % of the carbon fed to the bacterial culture could be accounted for in the standard metabolic products. This low carbon recovery during fermentation occurred even though CO2 emission was effectively reduced by Rubisco-based engineered pathway. RESULTS: In this study, the heterologous expression of form I Rubisco was found to enhance the accumulation of pyruvate in Escherichia coli MZLF [E. coli BL21(DE3) Deltazwf, Deltaldh, Deltafrd]. This may be attributed to the enhanced glycolytic reaction supported by the increased biomass and the ethanol/acetate ratio. Besides, it was found that the transcription of arcA (encodes the redox dependent transcriptional activators ArcA that positively regulates the transcription of pyruvate formate-lyase) was down-regulated in the presence of Rubisco. The enhanced accumulation of pyruvate also occurs when PrkA is co expressed with Rubisco in E. coli MZLF. Furthermore, E. coli containing Rubisco based engineered pathway has a distinct profile of the fermentation products, indicating CO2 was converted into fermentation products. By analyzing the ratio of total C-2 (2-carbon fermentation products) to total C-1 (1-carbon fermentation product) of MZLFB (MZLF containing Rubisco-based engineered pathway), it is estimated that 9 % of carbon is directed into Rubisco-based engineered pathway. CONCLUSIONS: Here, we report for the first time the complete profile of fermentation products using E. coli MZLF and its derived strains. It has been shown that the expression of Rubisco alone in MZLF enhances the accumulation of pyruvate. By including the contribution of pyruvate accumulation, the perplexing problem of low carbon recovery during fermentation by E. coli containing Rubisco based engineered pathway has been solved. 9 % of glucose consumption is directed from glycolysis to Rubisco-based engineered pathway in MZLFB. The principle characteristics of mixotroph MZLFB are the high bacterial growth and the low CO2 emission. PMID- 27485111 TI - A protocol for a systematic review of non-randomised evaluations of strategies to improve participant recruitment to randomised controlled trials. AB - BACKGROUND: Randomised controlled trials guard against selection bias and therefore offer the fairest way of evaluating healthcare interventions such as medicinal products, devices and services. Recruitment to trials can be extremely difficult, and poor recruitment can lead to extensions to both time and budget and may result in an underpowered study which does not satisfactorily answer the original research question. In the worst cases, a trial may be abandoned, causing huge waste. The evidence to support the choice of recruitment interventions is currently weak. Non-randomised evaluations of recruitment interventions are currently rejected on grounds of poor methodological quality, but systematic evaluation and assessment of this substantial body of work (using Grading of Recommendations Assessment, Development and Evaluation (GRADE) where possible) may provide useful information to support and inform the recruitment decisions of trialists and the research priorities of methodology researchers. METHODS: The following databases will be searched for relevant studies: Cochrane Methodology Register, MEDLINE, EMBASE, CINAHL and PsycINFO. Any non-randomised study that includes a comparison of two or more interventions to improve recruitment to randomised controlled trials will be included. We will not apply any restrictions on publication date, language or journal. The primary outcome will be the number of individuals or centres recruited into a randomised controlled trial. The secondary outcome will be cost per recruit. Two reviewers will independently screen abstracts for eligible studies, and then, full texts of potentially relevant records will be reviewed. Disagreements will be resolved through discussion. The methodological quality of studies will be assessed using the Cochrane risk of bias tool for non-randomised studies, and the GRADE system will be used if studies are pooled. DISCUSSION: This review aims to summarise the evidence on methods used to improve recruitment to randomised controlled trials. Carrying out a systematic review including only data from non-randomised studies is a novel approach, and one which some may argue is futile. However, we believe that the systematic evaluation of what is likely to be a substantial amount of research activity is necessary, worthwhile, and will yield valuable results for the clinical trials community regardless of whether the outcomes find in favour of one or more interventions. Should the results of this review suggest that non randomised evaluations do have something to offer trialists planning their recruitment strategies, the review may be combined in the future with the Cochrane review of randomised evaluations to produce a full review of recruitment strategies encompassing both randomised and non-randomised evaluation methods. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016037718. PMID- 27485112 TI - Tescalcin expression contributes to invasive and metastatic activity in colorectal cancer. AB - We reported previously that tescalcin (TESC) levels were higher in tissue and serum from colorectal cancer (CRC) patients and suggested that TESC was a potential oncotarget in CRC. The aim of this study was to investigate the function of TESC in CRC invasion and metastatic potential. TESC expression was knocked down in CRC cells using small interfering RNA (siRNA). The expression of TESC siRNA reduced cell migration and invasion by inhibiting matrix metalloprotease (MMP) and the epithelial-mesenchymal transition (EMT) pathway. RT PCR and Western blot analysis showed that TESC siRNA induced E-cadherin. Consistently, TESC overexpression in HCT116 (HCT/TESC) cells enhanced cell migration and invasion by activating MMP and the EMT pathway and reducing E cadherin. The formation of liver metastatic nodules in vivo was strongly increased in mice injected with HCT/TESC cells compared with that in mice injected with HCT/mock cells. This study demonstrates that TESC is involved in cell migration, invasion, and EMT during CRC tumor invasion. These results implicate TESC as a metastatic mediator and provide a biological rationale for the adverse prognosis associated with elevated TESC expression in human CRC. PMID- 27485114 TI - Construction and application of a lung cancer stem cell model: antitumor drug screening and molecular mechanism of the inhibitory effects of sanguinarine. AB - Lung cancer is a neoplasm with a 5-year survival rate of less than 15 % and a leading cause of death worldwide, despite recent progress in treatment and diagnostic methods. Lung cancer stem-like cells (CSCs) are pivotal in lung cancer metastasis and drug resistance. This study aimed to develop lung CSCs that stably express stem cell properties through transfection to further screen traditional Chinese herbal compounds. Lung adenocarcinoma stem cells, which include various phenotypic subgroups, are normally characterized by high expression levels of pluripotent stem cell genes, particularly Nanog and OCT4. Plasmids containing Nanog and OCT4 were constructed and transfected into cells, and lung CSCs were identified not only in vitro using RT-PCR, Western blotting, plate cloning, sphere formation, drug resistance, and transwell migration but also in vivo using a nude mouse tumorigenicity assay. Subsequently, sanguinarine, which is derived from the whole leaves of the traditional Chinese medicine celandine, was identified through the high-throughput screening of a small-molecule compound library. Investigation of the molecular mechanisms of the effects of sanguinarine revealed that it significantly inhibited lung CSC proliferation, invasion, and apoptosis, possibly via downregulation of the Wnt/beta-catenin signaling pathway. Our results indicate that lung CSCs established by gene transfection may provide a stable and effective method of constructing CSCs to effectively screen potential antitumor drugs. Furthermore, these results suggest that sanguinarine may be a natural antitumor compound that targets lung CSCs, laying a foundation for further clinical study. PMID- 27485113 TI - Identification of novel biomarkers associated with poor patient outcomes in invasive breast carcinoma. AB - Breast carcinoma (BC) corresponds to 23 % of all cancers in women, with 1.38 million new cases and 460,000 deaths worldwide annually. Despite the significant advances in the identification of molecular markers and different modalities of treatment for primary BC, the ability to predict its metastatic behavior is still limited. The purpose of this study was to identify novel molecular markers associated with distinct clinical outcomes in a Brazilian cohort of BC patients. We generated global gene expression profiles using tumor samples from 24 patients with invasive ductal BC who were followed for at least 5 years, including a group of 15 patients with favorable outcomes and another with nine patients who developed metastasis. We identified a set of 58 differentially expressed genes (p <= 0.01) between the two groups. The prognostic value of this metastasis signature was corroborated by its ability to stratify independent BC patient datasets according to disease-free survival and overall survival. The upregulation of B3GNT7, PPM1D, TNKS2, PHB, and GTSE1 in patients with poor outcomes was confirmed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in an independent sample of patients with BC (47 with good outcomes and eight that presented metastasis). The expression of BCL2-associated agonist of cell death (BAD) protein was determined in 1276 BC tissue samples by immunohistochemistry and was consistent with the reduced BAD mRNA expression levels in metastatic cases, as observed in the oligoarray data. These findings point to novel prognostic markers that can distinguish breast carcinomas with metastatic potential from those with favorable outcomes. PMID- 27485115 TI - Clinical significance of beta2-adrenergic receptor expression in patients with surgically resected gastric adenocarcinoma. AB - The beta2-adrenergic receptor (beta2-AR) is highly expressed in various human neoplasms and has been considered a novel therapeutic target of cancer treatment. However, the clinicopathological significance of beta2-AR expression in patients with gastric cancer (GC) remains unclear. The aim of this study was to explore beta2-AR expression and its prognostic significance. A total of 331 patients with surgically resected GC were evaluated. Tumor sections were stained immunohistochemically for beta2-AR. And, we confirmed beta2-AR expression in the GC cell lines by Western blot. beta2-AR was highly expressed in 30.5 % of GC patients. Expression was significantly associated with age, T factor, tumor differentiation, histology of non-signet cells, lymphatic permeation, and vascular invasion. And, all the GC cell lines expressed beta2-AR. On univariate analysis, age, disease stage, T factor, N factor, lymphatic permeation, vascular invasion, and beta2-AR expression were significantly associated with overall survival. Although the multivariate analysis did not indicate that beta2-AR expression was independently prognostic of survival, high-level beta2-AR expression was associated with significantly poorer survival of GC patients with well or moderately differentiated tumors. beta2-AR expression was a significant predictor of tumor aggressiveness in, and poorer survival of, patients with GC. PMID- 27485116 TI - Tumor suppressor Fbxw7 antagonizes WNT signaling by targeting beta-catenin for degradation in pancreatic cancer. AB - Pancreatic cancer is one of the deadliest solid malignancies associated with aberrant Wnt signaling activation. Fbxw7 mutations have been implicated in the development of pancreatic cancer, whereas the exact mechanism of this ubiquitin ligase as a tumor suppressor remains unclear in pancreatic carcinogenesis. Here, we describe that Fbxw7 is downregulated upon pancreatic cancer development. Depletion of Fbxw7 results in tumor suppression in pancreatic cancer cells, while Fbxw7 overexpression inhibits pancreatic cancer cell proliferation and invasion. Considering the negative correlation between Fbxw7 and beta-catenin, we find that Fbxw7 antagonizes Wnt signaling through targeting beta-catenin for its degradation. Moreover, the inhibitory effect of Fbxw7 on pancreatic cancer cell proliferation is mainly executed by the destruction of the Wnt/beta-catenin signaling pathway. We also reveal that c-myc, a widely accepted target of Fbxw7, is also transcriptionally regulated by the Fbxw7/beta-catenin axis in pancreatic cancer cells. Collectively, our results demonstrate that Fbxw7 is a novel regulator of Wnt/beta-catenin signaling-dependent regulation of pancreatic cancer cell growth and invasion, and inactivation of Fbxw7 in pancreatic cancer tissues might be the reason for the aberrant activation of Wnt signaling. PMID- 27485117 TI - Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model. AB - Astrocytes are key participants in various aspects of brain development and function, many of which are executed via secreted proteins. Defects in astrocyte signaling are implicated in neurodevelopmental disorders characterized by abnormal neural circuitry such as Fragile X syndrome (FXS). In animal models of FXS, the loss in expression of the Fragile X mental retardation 1 protein (FMRP) from astrocytes is associated with delayed dendrite maturation and improper synapse formation; however, the effect of astrocyte-derived factors on the development of neurons is not known. Thrombospondin-1 (TSP-1) is an important astrocyte-secreted protein that is involved in the regulation of spine development and synaptogenesis. In this study, we found that cultured astrocytes isolated from an Fmr1 knockout (Fmr1 KO) mouse model of FXS displayed a significant decrease in TSP-1 protein expression compared to the wildtype (WT) astrocytes. Correspondingly, Fmr1 KO hippocampal neurons exhibited morphological deficits in dendritic spines and alterations in excitatory synapse formation following long-term culture. All spine and synaptic abnormalities were prevented in the presence of either astrocyte-conditioned media or a feeder layer derived from FMRP-expressing astrocytes, or following the application of exogenous TSP-1. Importantly, this work demonstrates the integral role of astrocyte-secreted signals in the establishment of neuronal communication and identifies soluble TSP 1 as a potential therapeutic target for Fragile X syndrome. PMID- 27485118 TI - A rare cardiopulmonary parasite of the European badger, Meles meles: first description of the larvae, ultrastructure, pathological changes and molecular identification of Angiostrongylus daskalovi Janchev & Genov 1988. AB - BACKGROUND: Angiostrongylus daskalovi is a rare cardiopulmonary nematode infecting badgers. The parasite was described in 1988 and, since then, found only once in mustelids in Europe. The present study aims to report new cases of patent A. daskalovi infection in badgers from northern Romania and to provide new information on its ultrastructure, molecular diagnosis, and pathology. METHODS: Eight road-killed or hunted badgers originating from Maramures and Alba counties in Romania were collected and necropsied. Adults and larvae of cardio-pulmonary nematodes were collected and examined by light and scanning electron microscopy (SEM). Genomic DNA was extracted from adults and first-stage larvae (L1). PCR amplification of the internal transcribed spacer 2 (ITS2, ~500 bp) of the rRNA gene was performed. Amplicons were purified, sequenced, and compared to those available in the GenBank database. Histopathological examination of the lungs was performed and lesions described. RESULTS: The necropsy revealed the presence of nematodes in the pulmonary arteries of three animals. All parasites were mature adults and the coproscopic examination showed the presence of eggs and L1 larvae in all three positive animals. Light microscopy examination confirmed the morphological and morphometric similarity of parasites to Angiostrongylus daskalovi. SEM highlighted the typical angiostrongylid structure of the rays of the copulatory bursa and the anterior extremity, with the presence of six sensory papillae surrounding the mouth opening in which a triangular tooth was visible. The first-stage larva (L1) of A. daskalovi is described here for the first time. Histopathological examination of the lungs showed chronic interstitial verminous pneumonia due to the presence of adult parasites. Molecular analysis showed 100 % nucleotide similarity to an Angiostrongylus sp. isolate originating from a badger from Spain, tentatively identified as A. daskalovi. CONCLUSIONS: Our study unequivocally demonstrates the presence of A. daskalovi in European badgers from Romania, provides the first description of the larvae and reveals new data about the ultrastructure of adult parasites and their pathological impact, contributing to the understanding of the phylogenetic relationships with other congeneric species. PMID- 27485119 TI - Quality of life effects of androgen deprivation therapy in a prostate cancer cohort in New Zealand: can we minimize effects using a stratification based on the aldo-keto reductase family 1, member C3 rs12529 gene polymorphism? AB - BACKGROUND: Androgen deprivation therapy (ADT) is an effective palliation treatment in men with advanced prostate cancer (PC). However, ADT has well documented side effects that could alter the patient's health-related quality of life (HRQoL). The current study aims to test whether a genetic stratification could provide better knowledge for optimising ADT options to minimize HRQoL effects. METHODS: A cohort of 206 PC survivors (75 treated with and 131 without ADT) was recruited with written consent to collect patient characteristics, clinical data and HRQoL data related to PC management. The primary outcomes were the percentage scores under each HRQoL subscale assessed using the European Organisation for Research and Treatment of Cancer Quality of Life questionnaires (QLQ-C30 and PR25) and the Depression Anxiety Stress Scales developed by the University of Melbourne, Australia. Genotyping of these men was carried out for the aldo-keto reductase family 1, member C3 (AKR1C3) rs12529 single nucleotide polymorphism (SNP). Analysis of HRQoL scores were carried out against ADT duration and in association with the AKR1C3 rs12529 SNP using the generalised linear model. P-values <0 . 05 were considered significant, and were further tested for restriction with Bonferroni correction. RESULTS: Increase in hormone treatment-related effects were recorded with long-term ADT compared to no ADT. The C and G allele frequencies of the AKR1C3rs12529 SNP were 53.4 % and 46.6 % respectively. Hormone treatment-related symptoms showed an increase with ADT when associated with the AKR1C3 rs12529 G allele. Meanwhile, decreasing trends on cancer-specific symptoms and increased sexual interest were recorded with no ADT when associated with the AKR1C3 rs12529 G allele and reverse trends with the C allele. As higher incidence of cancer-specific symptoms relate to cancer retention it is possible that associated with the C allele there could be higher incidence of unresolved cancers under no ADT options. CONCLUSIONS: If these findings can be reproduced in larger homogeneous cohorts, a genetic stratification based on the AKR1C3 rs12529 SNP, can minimize ADT-related HRQoL effects in PC patients. Our data additionally show that with this stratification it could also be possible to identify men needing ADT for better oncological advantage. PMID- 27485120 TI - "Did you ever drink more?" A detailed description of pregnant women's drinking patterns. AB - BACKGROUND: This paper presents drinking patterns in a prospective study of a population-based cohort of 1570 pregnant women using a combination of dose and timing to give best estimates of prenatal alcohol exposure (PAE). Novel assessments include women's special occasion drinking and alcohol use prior to pregnancy recognition. METHODS: Information on up to nine types of alcoholic drink, with separate frequencies and volumes, including drinking on special occasions outside a 'usual' pattern, was collected for the periconceptional period and at four pregnancy time points. Weekly total and maximum alcohol consumption on any one occasion was calculated and categorised. Drinking patterns are described in the context of predictive maternal characteristics. RESULTS: 41.3 % of women did not drink during pregnancy, 27 % drank in first trimester only; most of whom stopped once they realised they were pregnant (87 %). When compared to women who abstained from alcohol when pregnant, those who drank in the first trimester only were more likely to have an unplanned pregnancy and not feel the effects of alcohol quickly. Almost a third of women continued to drink alcohol at some level throughout pregnancy (27 %), around half of whom never drank more than at low or moderate levels. When compared with abstainers and to women who only drank in trimester one, those who drank throughout pregnancy tended to be in their early to mid-thirties, smoke, have a higher income and educational attainment. Overall, almost one in five women (18.5 %) binge drank prior to pregnancy recognition, a third of whom were identified with a question about 'special occasion' drinking. Women whose age at first intoxication was less than 18 years (the legal drinking age in Australia), were significantly more likely to drink in pregnancy and at binge levels prior to pregnancy recognition. CONCLUSIONS: We have identified characteristics of pregnant women who either abstain, drink until pregnancy awareness or drink throughout pregnancy. These may assist in targeting strategies to enhance adherence to an abstinence policy and ultimately allow for appropriate follow-up and interpretation of adverse child outcomes. Our methodology also produced important information to reduce misclassification of occasional binge drinking episodes and ensure clearly defined comparison groups. PMID- 27485121 TI - LIMT is a novel metastasis inhibiting lncRNA suppressed by EGF and downregulated in aggressive breast cancer. AB - Long noncoding RNAs (lncRNAs) are emerging as regulators of gene expression in pathogenesis, including cancer. Recently, lncRNAs have been implicated in progression of specific subtypes of breast cancer. One aggressive, basal-like subtype associates with increased EGFR signaling, while another, the HER2 enriched subtype, engages a kin of EGFR Based on the premise that EGFR-regulated lncRNAs might control the aggressiveness of basal-like tumors, we identified multiple EGFR-inducible lncRNAs in basal-like normal cells and overlaid them with the transcriptomes of over 3,000 breast cancer patients. This led to the identification of 11 prognostic lncRNAs. Functional analyses of this group uncovered LINC01089 (here renamed LncRNA Inhibiting Metastasis; LIMT), a highly conserved lncRNA, which is depleted in basal-like and in HER2-positive tumors, and the low expression of which predicts poor patient prognosis. Interestingly, EGF rapidly downregulates LIMT expression by enhancing histone deacetylation at the respective promoter. We also find that LIMT inhibits extracellular matrix invasion of mammary cells in vitro and tumor metastasis in vivo In conclusion, lncRNAs dynamically regulated by growth factors might act as novel drivers of cancer progression and serve as prognostic biomarkers. PMID- 27485123 TI - MRI-based ACL graft maturity does not predict clinical and functional outcomes during the first year after ACL reconstruction. AB - PURPOSE: To determine whether magnetic resonance image (MRI)-based graft maturity predicts clinical and functional scores during the first year after ACL reconstruction. METHODS: Patients with unilateral ACL reconstruction were prospectively invited to participate in this study, and they were examined using a 3.0-T MRI scan at 3, 6, and 12 months after the operation. Clinical examinations were performed on the same day, including subjective functional examinations, physical examinations and the KT-1000 test. MRI measurements were focused on the graft signal intensity of the ACL graft using the signal/noise quotient value from a region of interest analysis. RESULTS: Finally, a total of 38 participants with ACL reconstruction were recruited for this study, including 21 with autograft tendons and 17 with allograft tendons. Generally, the signal/noise quotient values of the ACL grafts increased from 3 to 6 months and then decreased from 6 to 12 months. There was no significant association between graft signal/noise quotient value and IKDC, Lysholm, or Tegner scores at each time point. Graft signal/noise quotient value had a significant positive association with ATTD for the cohort (p = 0.002) and for the autograft group (p = 0.004) at 3 months. However, there was no significant association between graft signal/noise quotient value and ATTD at 6 or 12 months, respectively. CONCLUSION: The MRI-based graft maturity does not have the ability to predict clinical and functional outcomes in patients at the first-year follow-up. Graft maturity should not be used as an objective test to determine the appropriate time to return to sports during the first year after ACL reconstruction. The results from this study will allow clinicians to determine graft-specific health to determine whether the graft is healed enough to return to sports during the first postoperative year. LEVEL OF EVIDENCE: III. PMID- 27485122 TI - miR-132 loss de-represses ITPKB and aggravates amyloid and TAU pathology in Alzheimer's brain. AB - microRNA-132 (miR-132) is involved in prosurvival, anti-inflammatory and memory promoting functions in the nervous system and has been found consistently downregulated in Alzheimer's disease (AD). Whether and how miR-132 deficiency impacts AD pathology remains, however, unaddressed. We show here that miR-132 loss exacerbates both amyloid and TAU pathology via inositol 1,4,5-trisphosphate 3-kinase B (ITPKB) upregulation in an AD mouse model. This leads to increased ERK1/2 and BACE1 activity and elevated TAU phosphorylation. We confirm downregulation of miR-132 and upregulation of ITPKB in three distinct human AD patient cohorts, indicating the pathological relevance of this pathway in AD. PMID- 27485124 TI - Anteroposterior translation and range of motion after total knee arthroplasty using posterior cruciate ligament-retaining versus posterior cruciate ligament substituting prostheses. AB - PURPOSE: It is still controversial whether anteroposterior (AP) translation magnitude after total knee arthroplasty (TKA) affects clinical outcomes, particularly range of motion (ROM). This study examined the following two questions: (1) are AP translations at the mid- and long-term follow-up different for knees within the same patient treated with posterior cruciate ligament retaining (PCLR) versus posterior cruciate ligament-substituting (PCLS) mobile bearing TKA prosthesis designs? (2) Is the ROM at the mid- and long-term follow up for knees treated with PCLR and PCLS designs correlated with the AP translation? METHODS: Thirty-seven patients undergoing sequential bilateral TKA for osteoarthritis were prospectively enrolled. Patients received a PCLR implant in one knee and a PCLS implant in the other and were followed-up for an average 9.8 +/- 3.2 years. The AP translations at 30 degrees and 75 degrees of knee flexion and the ROM of both knees were assessed. RESULTS: The implant design (p < 0.001), but not flexion angle (n.s.), had a significant effect on AP translation. AP translation values were larger in PCLR knees than in PCLS knees at both flexion angles (p < 0.0001). The ROM at the final follow-up in the two implant designs was similar (both 115 degrees , n.s.). There was a weak correlation between ROM and AP translation at 30 degrees in the PCLR knees (r = 0.397, p = 0.015), but no correlation at 75 degrees or in the PCLS knees. CONCLUSIONS: Differently constrained prosthesis designs resulted in significantly different AP translational values within the same patient. This indicates that achieving good clinical outcomes and ROM after TKA may not be strongly influenced by the specifics of each patient's anatomical characteristics, but instead by knee constrainment. Clinically, this means that surgeons should familiarize themselves with the AP translation of the implant being used, as this may be the most important factor for optimizing outcomes after mobile-bearing TKA. Level of evidence II, prospective, comparative study. PMID- 27485125 TI - Comparison between cylindrical axis-reference and articular surface-reference femoral bone cut for total knee arthroplasty. AB - PURPOSE: Reproducing a functional flexion-extension axis (FEA) of the femur is key to achieving successful collateral ligament balance and joint line in total knee arthroplasty (TKA). This study compared the feasibility of cylindrical axis (CA)-reference bone cut and articular surface-reference bone cuts in reproducing the FEA for Japanese osteoarthritis patients. METHODS: The study enrolled 122 knees from 86 patients who underwent primary TKA due to grade III or IV osteoarthritis. Data from pre-operative CT were reconstructed into three dimensional (3D) models using 3D-planning software. Cylindrical radii of the condyles were measured, and femoral bone cut angles relative to anatomical landmarks were determined in the coronal and axial reference planes based on CA reference and articular surface-reference methods. RESULTS: Mean cylindrical radii for medial and lateral femoral condyles were 17.4 +/- 1.6 and 17.3 +/- 1.4 mm, respectively. Of the 122 knees, 46 exhibited >1 mm of difference between condyles. Fifty-three and 22 knees exhibited >2 degrees of angular difference between CA-reference and articular surface-reference bone cuts in the coronal and axial planes. Mean angle of the CA and surgical epicondylar axis in 3D space was 4.6 +/- 2.1 degrees . As practical parameters for TKA, the angle between CA and IM rod was significantly larger than that between the distal articular surface line and IM rod in the coronal plane (p < 0.0001), indicating that CA-reference involves a smaller valgus bone cut of the distal femur than articular surface reference. CONCLUSIONS: CA-reference bone cut of the femur is preferable to articular surface-reference bone cut for reproducing FEA in Japanese OA patients, in whom more than one-third of knees exhibited asymmetry of radii between medial and lateral condyles. In clinical practice, the CA-reference bone cut represents a good technical option for kinematically aligned TKA in the Japanese population. PMID- 27485126 TI - Natural history and risk stratification of patients undergoing non-invasive ventilation in a non-ICU setting for severe COPD exacerbations. PMID- 27485127 TI - Determinants of a successful problem list to support the implementation of the problem-oriented medical record according to recent literature. AB - BACKGROUND: A problem-oriented approach is one of the possibilities to organize a medical record. The problem-oriented medical record (POMR) - a structured organization of patient information per presented medical problem- was introduced at the end of the sixties by Dr. Lawrence Weed to aid dealing with the multiplicity of patient problems. The problem list as a precondition is the centerpiece of the problem-oriented medical record (POMR) also called problem oriented record (POR). Prior to the digital era, paper records presented a flat list of medical problems to the healthcare professional without the features that are possible with current technology. In modern EHRs a POMR based on a structured problem list can be used for clinical decision support, registries, order management, population health, and potentially other innovative functionality in the future, thereby providing a new incentive to the implementation and use of the POMR. METHODS: On both 12 May 2014 and 1 June 2015 a systematic literature search was conducted. From the retrieved articles statements regarding the POMR and related to successful or non-successful implementation, were categorized. Generic determinants were extracted from these statements. RESULTS: In this research 38 articles were included. The literature analysis led to 12 generic determinants: clinical practice/reasoning, complete and accurate problem list, data structure/content, efficiency, functionality, interoperability, multi disciplinary, overview of patient information, quality of care, system support, training of staff, and usability. CONCLUSIONS: Two main subjects can be distinguished in the determinants: the system that the problem list and POMR is integrated in and the organization using that system. The combination of the two requires a sociotechnical approach and both are equally important for successful implementation of a POMR. All the determinants have to be taken into account, but the weight given to each of the determinants depends on the organizationusing the problem list or POMR. PMID- 27485128 TI - Characterization and quantification of dissolved organic carbon releases from suspended and sedimented leaf fragments and of residual particulate organic matter. AB - Bank filtration is a powerful and established barrier for pathogens and organic pollutants. The aerobic degradation of the pollutants competes with the microbial respiration of dissolved and particulate organic matter (DOC and POC). The fate of terrestrial POC (tPOC) in bank filtration is currently not fully understood. In the present study, fallen leaves of different local trees were milled, characterized and investigated as tPOC in both batch and column experiments. The respective contents of carbon and nitrogen differed slightly, but the different leaves released significantly different DOC fractions as determined by size exclusion chromatography. While high molecular weight biopolymers were degraded by indigenous microorganisms, humic substances were not degraded within 96days in batch experiments. DOC release and POC wash-out in column experiments led to a slight decrease of tPOC depositions, but more than 80% of the initial tPOC remained after 54days thus representing a long-term organics reservoir for microbial respiration. The release of humic substances from autumnal leaf litter inputs is a plausible explanation for comparably high DOC concentrations (approximately 4.5mg/L) in Berlin drinking water that mainly originates from lake bank filtration. PMID- 27485129 TI - Engineered nanomaterial-mediated changes in the metabolism of terrestrial plants. AB - Engineered nanomaterials (ENMs) possess remarkable physicochemical characteristics suitable for different applications in medicine, pharmaceuticals, biotechnology, energy, cosmetics and electronics. Because of their ultrafine size and high surface reactivity, ENMs can enter plant cells and interact with intracellular structures and metabolic pathways which may produce toxicity or promote plant growth and development by diverse mechanisms. Depending on their type and concentration, ENMs can have positive or negative effects on photosynthesis, photochemical fluorescence and quantum yield as well as photosynthetic pigments status of the plants. Some studies have shown that ENMs can improve photosynthetic efficiency via increasing chlorophyll content and light absorption and also broadening the spectrum of captured light, suggesting that photosynthesis can be nano-engineered for harnessing more solar energy. Both up- and down-regulation of primary metabolites such as proteins and carbohydrates have been observed following exposure of plants to various ENMs. The potential capacity of ENMs for changing the rate of primary metabolites lies in their close relationship with activation and biosynthesis of the key enzymes. Several classes of secondary metabolites such as phenolics, flavonoids, and alkaloids have been shown to be induced (mostly accompanied by stress-related factors) in plants exposed to different ENMs, highlighting their great potential as elicitors to enhance both quantity and quality of biologically active secondary metabolites. Considering reports on both positive and negative effects of ENMs on plant metabolism, in-depth studies are warranted to figure out the most appropriate ENMs (type, size and optimal concentration) in order to achieve the desirable effect on specific metabolites in a given plant species. In this review, we summarize the studies performed on the impacts of ENMs on biosynthesis of plant primary and secondary metabolites and mention the research gaps that currently exist in this field. PMID- 27485130 TI - Evaluation of different approaches to describe the sorption and desorption of phosphorus in soils on experimental data. AB - Phosphorus is an essential element to enhance the needed increase in crop production in the forthcoming century. On the other hand environmental losses of phosphorus cause eutrophication of surface waters. Both problems call for reliable models to predict the behaviour of phosphorus in agricultural soils. In this study the performances of five different sorption approaches were evaluated. The ultimate aim was to identify the most suitable concept for large scale predictions of P dynamics in soils, in terms of a high comparability between observations and predictions with a minimum amount of input data. The model results were compared with unique data from long term (10-15years) experimental field studies of grassland including situations with P mining, equilibrium P fertilization and P surpluses and a pot experiment with P mining. The model performance was evaluated while using site specific constants and generic constants for adsorption and desorption. Three rate limited models (DPPS, INITIATOR and ANIMO) showed good performance when site specific constants were used but the performance of the equilibrium model (NEWS-Dynamic) was reasonably comparable. Model performance was better for experiments with a P surplus than for P mining and was also better for sandy soils as compared to clay and peat soils. However, long term desorption rates had to be calibrated for each application rate. The performance of all models declined when generic data were used. We conclude that none of the included models properly describe what happens when the soil changes its P status, considering that parameterization needs to be treatment-specific to obtain reliable predictions. Considering this flaw, models of intermediate complexity, including both equilibrium and rate limited sorption, and a limited data demand, like DPPS and INITIATOR, seem most suited for regional model application. PMID- 27485131 TI - Low-level environmental arsenic exposure correlates with unexplained male infertility risk. AB - Humans are exposed to arsenic via drinking water, dietary intake and inhaled particulates. Endemic chronic arsenic exposure related reproductive toxicity is well documented, but the effect of low-level general environmental arsenic exposure on unexplained male infertility (UMI) remains unclear. In this case control study, we aimed to investigate the relationship between non-geogenic environmental arsenic exposure and UMI risk. One hundred and one infertile men with normal semen as cases and sixty one fertile men as controls were recruited. Five urinary arsenic species: pentavalent arsenate (Asi(V)), trivalent arsenite (Asi(III)), methylated to monomethylarsonic acid (MMA(V)), dimethylarsinic acid (DMA(V)), arsenobetaine (AsB) were quantitatively measured by liquid chromatography-inductively coupled plasma-mass spectrometry (LC-ICP-MS). To assess the semen quality, semen volume, sperm concentration, total motility, and progressive motility were measured. The nonparametric Mann-Whitney U test was used to compare the differences of arsenic species and index between the case and the control group; we observed that concentrations of Asi(V), AsB, MMA(V), DMA(V), total inorganic As and total As were significantly higher in the cases than the controls. The urine Asi(V) level increased more than twenty folds in case group. Moreover, higher redox index (Asi(V)/Asi(III)) and lower primary arsenic methylation index (PMI=MMA(V)/Asi) were observed for case group. Furthermore, through the logistic regression analysis, we observed that the urine Asi(V) level and PMI were most significantly associated with UMI risk among the observations. Specifically, in comparison to the first quartile, the subjects with higher Asi(V) levels were more likely to exhibit UMI with increasing adjusted odds ratios (AORs) (adjusted by age, body mass index, drinking status and smoking status) of 8.39 [95% confidence interval (CI), 2.59-27.17], 13.12 (95% CI, 3.44-50.12) and 36.51 (95% CI, 8.25-161.66) at the second, third and fourth quartiles, respectively. Also a concentration-dependent decrease of AOR was also observed for PMI in comparison to the fourth quartile: 15.43 [95% CI, 4.28-55.69], 9.69 (95% CI, 2.78-33.78) and 6.93 (95% CI, 2.21-21.76) at the first, second and third quartiles, respectively. These findings provide evidences that low-level environmental arsenic exposure was positively associated with UMI risk. PMID- 27485132 TI - Playing Action Video Games Improves Visuomotor Control. AB - Can playing action video games improve visuomotor control? If so, can these games be used in training people to perform daily visuomotor-control tasks, such as driving? We found that action gamers have better lane-keeping and visuomotor control skills than do non-action gamers. We then trained non-action gamers with action or nonaction video games. After they played a driving or first-person shooter video game for 5 or 10 hr, their visuomotor control improved significantly. In contrast, non-action gamers showed no such improvement after they played a nonaction video game. Our model-driven analysis revealed that although different action video games have different effects on the sensorimotor system underlying visuomotor control, action gaming in general improves the responsiveness of the sensorimotor system to input error signals. The findings support a causal link between action gaming (for as little as 5 hr) and enhancement in visuomotor control, and suggest that action video games can be beneficial training tools for driving. PMID- 27485133 TI - Why Do People Tend to Infer "Ought" From "Is"? The Role of Biases in Explanation. AB - People tend to judge what is typical as also good and appropriate-as what ought to be. What accounts for the prevalence of these judgments, given that their validity is at best uncertain? We hypothesized that the tendency to reason from "is" to "ought" is due in part to a systematic bias in people's (nonmoral) explanations, whereby regularities (e.g., giving roses on Valentine's Day) are explained predominantly via inherent or intrinsic facts (e.g., roses are beautiful). In turn, these inherence-biased explanations lead to value-laden downstream conclusions (e.g., it is good to give roses). Consistent with this proposal, results from five studies (N = 629 children and adults) suggested that, from an early age, the bias toward inherence in explanations fosters inferences that imbue observed reality with value. Given that explanations fundamentally determine how people understand the world, the bias toward inherence in these judgments is likely to exert substantial influence over sociomoral understanding. PMID- 27485134 TI - The Bitter Truth About Sugar and Willpower: The Limited Evidential Value of the Glucose Model of Ego Depletion. AB - The idea behind ego depletion is that willpower draws on a limited mental resource, so that engaging in an act of self-control impairs self-control in subsequent tasks. To present ego depletion as more than a convenient metaphor, some researchers have proposed that glucose is the limited resource that becomes depleted with self-control. However, there have been theoretical challenges to the proposed glucose mechanism, and the experiments that have tested it have found mixed results. We used a new meta-analytic tool, p-curve analysis, to examine the reliability of the evidence from these experiments. We found that the effect sizes reported in this literature are possibly influenced by publication or reporting bias and that, even within studies yielding significant results, the evidential value of this research is weak. In light of these results, and pending further evidence, researchers and policymakers should refrain from drawing any conclusions about the role of glucose in self-control. PMID- 27485135 TI - Molecular Programming of Tumor-Infiltrating CD8+ T Cells and IL15 Resistance. AB - Despite clinical potential and recent advances, durable immunotherapeutic ablation of solid tumors is not routinely achieved. IL15 expands natural killer cell (NK), natural killer T cell (NKT) and CD8(+) T-cell numbers and engages the cytotoxic program, and thus is under evaluation for potentiation of cancer immunotherapy. We found that short-term therapy with IL15 bound to soluble IL15 receptor alpha-Fc (IL15cx; a form of IL15 with increased half-life and activity) was ineffective in the treatment of autochthonous PyMT murine mammary tumors, despite abundant CD8(+) T-cell infiltration. Probing of this poor responsiveness revealed that IL15cx only weakly activated intratumoral CD8(+) T cells, even though cells in the lung and spleen were activated and dramatically expanded. Tumor-infiltrating CD8(+) T cells exhibited cell-extrinsic and cell-intrinsic resistance to IL15. Our data showed that in the case of persistent viral or tumor antigen, single-agent systemic IL15cx treatment primarily expanded antigen irrelevant or extratumoral CD8(+) T cells. We identified exhaustion, tissue resident memory, and tumor-specific molecules expressed in tumor-infiltrating CD8(+) T cells, which may allow therapeutic targeting or programming of specific subsets to evade loss of function and cytokine resistance, and, in turn, increase the efficacy of IL2/15 adjuvant cytokine therapy. Cancer Immunol Res; 4(9); 799 811. (c)2016 AACR. PMID- 27485136 TI - Therapeutic HPV Cancer Vaccine Targeted to CD40 Elicits Effective CD8+ T-cell Immunity. AB - Human papillomavirus (HPV), particularly HPV16 and HPV18, can cause cancers in diverse anatomical sites, including the anogenital and oropharyngeal (throat) regions. Therefore, development of safe and clinically effective therapeutic vaccines is an important goal. Herein, we show that a recombinant fusion protein of a humanized antibody to CD40 fused to HPV16.E6/7 (alphaCD40-HPV16.E6/7) can evoke HPV16.E6/7-specific CD8+ and CD4+ T-cell responses in head-and-neck cancer patients in vitro and in human CD40 transgenic (hCD40Tg) mice in vivo The combination of alphaCD40-HPV16.E6/7 and poly(I:C) efficiently primed HPV16.E6/7 specific T cells, particularly CD8+ T cells, in hCD40Tg mice. Inclusion of montanide enhanced HPV16.E6/7-specific CD4+, but not CD8+, T-cell responses. Poly(I:C) plus alphaCD40-HPV16.E6/7 was sufficient to mount both preventative and therapeutic immunity against TC-1 tumors in hCD40Tg mice, significantly increasing the frequency of HPV16-specific CD8+ CTLs in the tumors, but not in peripheral blood. In line with this, tumor volume inversely correlated with the frequency of HPV16.E6/7-specific CD8+ T cells in tumors, but not in blood. These data suggest that CD40-targeting vaccines for HPV-associated malignancies can provide a highly immunogenic platform with a strong likelihood of clinical benefit. Data from this study offer strong support for the development of CD40 targeting vaccines for other cancers in the future. Cancer Immunol Res; 4(10); 823-34. (c)2016 AACR. PMID- 27485137 TI - Analyses of Pretherapy Peripheral Immunoscore and Response to Vaccine Therapy. AB - Tumor immunoscore analyses, especially for primary colorectal cancer and melanoma lesions, provide valuable prognostic information. Metastatic lesions of many carcinoma types, however, are often not easily accessible. We hypothesized that immune cells in peripheral blood may differ among individual patients with metastatic disease, which, in turn, may influence their response to immunotherapy. We thus analyzed immune cell subsets within peripheral blood mononuclear cells to determine if a "peripheral immunoscore" could have any prognostic significance for patients before receiving immunotherapy. Patients with metastatic breast cancer were randomly assigned to receive docetaxel +/- PANVAC vaccine. In another trial, prostate cancer patients with metastatic bone lesions were randomly assigned to receive a bone-seeking radionuclide +/- PROSTVAC vaccine. Predefined analyses of "classic" immune cell types (CD4, CD8, natural killer cells, regulatory T cells, myeloid-derived suppressor cells, and ratios) revealed no differences in progression-free survival (PFS) for either arm in both trials. Predefined analyses of refined immune cell subsets for which a biologic function had been previously reported also showed no significant prognostic value in PFS for patients receiving either docetaxel or radionuclide alone; however, in patients receiving these agents in combination with vaccine, the peripheral immunoscore of refined subsets revealed statistically significant differences in PFS (P < 0.001) for breast cancer patients receiving docetaxel plus vaccine, and in prostate cancer patients receiving radionuclide plus vaccine (P = 0.004). Larger randomized studies will be required to validate these findings. These studies, however, provide the rationale for the evaluation of refined immune cell subsets to help determine which patients may benefit most from immunotherapy. Cancer Immunol Res; 4(9); 755-65. (c)2016 AACR. PMID- 27485138 TI - Survival of neonates and predictors of their mortality in Tigray region, Northern Ethiopia: prospective cohort study. AB - BACKGROUND: Neonatal mortality accounts for an estimated 2.8 million deaths worldwide, which constitutes 44 % of under-5-mortality and 60 % of infant mortality. Neonatal mortality predictors vary by country with the availability and quality of health care. Therefore, aim of this study was to estimate survival time and identify predictors of neonatal mortality in Tigray region, northern Ethiopia. METHOD: A prospective cohort study design was carried out among a cohort of neonates delivered in seven hospitals of Tigray from April to July, 2014 and followed up for a total of 28 days. Data were collected by interviewing mothers using structured questionnaires and assessments of the neonate and mothers by midwives. Kaplan-Meier, Log rank test and Cox-proportional hazard regressions were used. STATA V-11 program was used for data entry, cleaning and analysis. RESULTS: From 1152 neonates, 68 died (neonatal mortality rate 62.5/1000 live births), 73.52 % of the neonates died within 7 days, 60 were lost to follow up and the percentage of survival at 28 days was 93.96 % (95 % CI: 92.4, 95.2 %). Predictors of neonatal mortality were: normal birth weight (AHR: 0.45, 95 % CI: 0.24, 0.84), not initiating exclusive breastfeeding (AHR: 7.5, 95 % CI: 3.77, 15.05), neonatal complications (AHR: 0.14, 95 % CI 0.07, 0.29), maternal complications (AHR: 0.37, 95 % CI: 0.22, 0.63) and proximity (AHR: 2.5, 95 % CI: 1.29, 4.91). CONCLUSION: Neonatal mortality is unacceptably very high. Managing complications and low birth weight, initiating exclusive breast feeding, improving quality of services and ensuring a continuum of care are recommended to increase survival of neonates. PMID- 27485139 TI - Neuroprotective effect of ginsenoside Rg1 prevents cognitive impairment induced by isoflurane anesthesia in aged rats via antioxidant, anti-inflammatory and anti apoptotic effects mediated by the PI3K/AKT/GSK-3beta pathway. AB - Ginsenoside Rg1 is the primary active substance in ginseng, and it has multiple pharmacological actions. Investigations on the pharmacologic action of ginsenoside Rg1 have developed, with a particular focus on the regulation of metabolism. The present study hypothesized that the neuroprotective effects of ginsenoside Rg1 prevent cognitive impairment induced by isoflurane anesthesia via antioxidant, anti-inflammatory and anti-apoptotic effects, mediated by the phosphoinositide 3-kinase (PI3K)/AKT/glycogen synthase kinase-3beta (GSK-3beta) pathway in aged rats. Sprague-Dawley rats were divided into isoflurane and ginsenoside Rg1 groups and were treated with 20 mg/kg ginsenoside Rg1 for 7 days. Morris water maze was performed to analyze the cognitive function of the rats. Enzyme-linked immunosorbent assays were used to analyze the levels of malondialdehyde, glutathione, interleukin (IL)-1beta, IL-6 and caspase 3. The protein expression levels of AKT, GSK 3beta, p21WAF1/CIP1 and p53 were measured using western blot analysis. Ginsenoside Rg1 significantly improved cognitive function, and exhibited antioxidant and anti-inflammatory effects, demonstrating the neuroprotective effects of ginsenoside Rg1 against the effect of isoflurane anesthesia in the rats. In addition, ginsenoside Rg1 significantly reduced caspase-3 activity, upregulated the expression of PI3K/AKT/GSK-3beta and downregulated the mRNA expression levels of p21WAF1/CIP1 and p53 in the aged rats exposed to isoflurane anesthesia. The data obtained in the present study provided evidence that the neuroprotective effects of ginsenoside Rg1 prevented the cognitive impairment induced by isoflurane anesthesia via antioxidant, anti inflammatory and anti-apoptotic effects, mediated by the PI3K/AKT/GSK-3beta pathway. PMID- 27485140 TI - Implications of different criteria for percutaneous coronary intervention-related myocardial infarction on study results of three large phase III clinical trials: The CHAMPION experience. AB - AIMS: The purpose of this study was to test whether different results between Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON (CHAMPION) PCI/PLATFORM and PHOENIX trials are due in part to different definitions of percutaneous coronary intervention (PCI)-related myocardial infarction (MI). METHODS AND RESULTS: In patients with acute coronary syndrome (ACS), the definition of MI was identical in CHAMPION PCI and PLATFORM and did not require an assessment of baseline cardiac biomarker status, while in PHOENIX specific MI criteria were associated with different patient presentations. The same MI criteria were used in PCI, PLATFORM, and PHOENIX for patients with stable angina. Logistic regression assessed the effect of cangrelor on MI (PCI- and non-PCI related) in the combined PCI/PLATFORM population and in PHOENIX. Consistency of cangrelor's effect in PCI/PLATFORM and in PHOENIX in patients with stable angina and in those with an ACS (with or without ST elevation) was evaluated. Overall, the incidence of PCI-related MI at 48 h was 6.3% in PCI/PLATFORM and 4.0% in PHOENIX. In patients with ACS, MI incidence was 6.4% in PCI/PLATFORM and 1.7% in PHOENIX, and 6.3% and 5.6%, respectively in stable angina patients. Cangrelor's effect on PCI-related MI differed between PCI/PLATFORM (odds ratio (OR) 1.03, 95% confidence interval (CI) 0.90-1.17) and PHOENIX (OR 0.80, 95% CI 0.66-0.98) with pINT=0.04. This difference was mostly evident in patients with ACS ( pINT= 0.06) while the effect was consistent in patients with stable angina ( pINT=0.81). Results were similar when all MIs were analyzed. CONCLUSIONS: The definition of PCI-related MI has important implications for event rates, treatment effect, and study results. This illustrates the importance of a rigorous assessment of PCI-related MI in clinical trials of patients with an ACS. PMID- 27485141 TI - Editor's Choice-Sex differences in young patients with acute myocardial infarction: A VIRGO study analysis. AB - AIMS: Young women with acute myocardial infarction (AMI) have a higher risk of adverse outcomes than men. However, it is unclear how young women with AMI are different from young men across a spectrum of characteristics. We sought to compare young women and men at the time of AMI on six domains of demographic and clinical factors in order to determine whether they have distinct profiles. METHODS AND RESULTS: Using data from Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO), a prospective cohort study of women and men aged ?55 years hospitalized for AMI ( n = 3501) in the United States and Spain, we evaluated sex differences in demographics, healthcare access, cardiovascular risk and psychosocial factors, symptoms and pre-hospital delay, clinical presentation, and hospital management for AMI. The study sample included 2349 (67%) women and 1152 (33%) men with a mean age of 47 years. Young women with AMI had higher rates of cardiovascular risk factors and comorbidities than men, including diabetes, congestive heart failure, chronic obstructive pulmonary disease, renal failure, and morbid obesity. They also exhibited higher levels of depression and stress, poorer physical and mental health status, and lower quality of life at baseline. Women had more delays in presentation and presented with higher clinical risk scores on average than men; however, men presented with higher levels of cardiac biomarkers and more classic electrocardiogram findings. Women were less likely to undergo revascularization procedures during hospitalization, and women with ST segment elevation myocardial infarction were less likely to receive timely primary reperfusion. CONCLUSIONS: Young women with AMI represent a distinct, higher-risk population that is different from young men. PMID- 27485142 TI - Age-related commonalities and differences in the relationship between executive functions and intelligence: Analysis of the NAB executive functions module and WAIS-IV scores. AB - Data from five subtests of the Executive Functions Module of the German Neuropsychological Assessment Battery (NAB) and all ten core subtests of the German Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) were used to examine the relationship between executive functions and intelligence in a comparison of two age groups: individuals aged 18-59 years and individuals aged 60-88 years. The NAB subtests Categories and Word Generation demonstrated a consistent correlation pattern for both age groups. However, the NAB Judgment subtest correlated more strongly with three WAIS-IV indices, the Full Scale IQ (FSIQ), and the General Ability Index (GAI) in the older adult group than in the younger group. Additionally, in the 60-88 age group, the Executive Functions Index (EFI) was more strongly correlated with the Verbal Comprehension Index (VCI) than with the Perceptual Reasoning Index (PRI). Both age groups demonstrated a strong association of the EFI with the FSIQ and the Working Memory Index (WMI). The results imply the potential diagnostic utility of the Judgment subtest and a significant relationship between executive functioning and crystallized intelligence at older ages. Furthermore, it may be concluded that there is a considerable age-independent overlap between the EFI and general intelligence, as well as between the EFI and working memory. PMID- 27485143 TI - Allantoin, a stress-related purine metabolite, can activate jasmonate signaling in a MYC2-regulated and abscisic acid-dependent manner. PMID- 27485144 TI - From nanoemulsions to self-nanoemulsions, with recent advances in self nanoemulsifying drug delivery systems (SNEDDS). AB - INTRODUCTION: Lipid-based drug delivery systems (LBDDS) are the most promising technique to formulate the poorly water soluble drugs. Nanotechnology strongly influences the therapeutic performance of hydrophobic drugs and has become an essential approach in drug delivery research. Self-nanoemulsifying drug delivery systems (SNEDDS) are a vital strategy that combines benefits of LBDDS and nanotechnology. SNEDDS are now preferred to improve the formulation of drugs with poor aqueous solubility. Areas covered: The review in its first part shortly describes the LBDDS, nanoemulsions and clarifies the ambiguity between nanoemulsions and microemulsions. In the second part, the review discusses SNEDDS and elaborates on the current developments and modifications in this area without discussing their associated preparation techniques and excipient properties. Expert opinion: SNEDDS have exhibit the potential to increase the bioavailability of poorly water soluble drugs. The stability of SNEDDS is further increased by solidification. Controlled release and supersaturation can be achieved, and are associated with increased patient compliance and improved drug loads, respectively. Presence of biodegradable ingredients and ease of large-scale manufacturing combined with a lot of 'drug-targeting opportunities' give SNEDDS a clear distinction and prominence over other solubility enhancement techniques. PMID- 27485146 TI - Field-induced dielectric response saturation in o-TaS3. AB - We investigated dependence of the dielectric properties on temperature and electric field below 50 K along the chain direction of o-TaS3. With external electric field increase, two threshold features could be identified. For electric fields somewhat larger than the lower threshold [Formula: see text], the dielectric constant starts to decrease whereas the conductivity increases due to the tunnelling of solitons. For higher external electric field we observe a saturation of dielectric response and analyze that the possible reasons may be related to the polarization behavior of charged solitons. With a decrease in temperature, the effect of external field on the dielectric response of the system weakens gradually and at 13 K it diminishes due to soliton freezing. PMID- 27485145 TI - Ten-year alcohol consumption typologies and trajectories of C-reactive protein, interleukin-6 and interleukin-1 receptor antagonist over the following 12 years: a prospective cohort study. AB - BACKGROUND: Moderate alcohol consumption is thought to confer cardiometabolic protective effects. Inflammatory pathways are hypothesized to partly underlie this association. OBJECTIVES: The aim of this study was to examine the association between typologies of alcohol consumption and markers of inflammation, and their rate of change over time. METHODS: Data were collected from 8209 participants [69% men; mean age, 50 years (SD 6.1)] of the British Whitehall II study. Alcohol consumption typologies were defined using up to three measures during an approximately 10-year period spanning from 1985 to 1994 as (i) stable nondrinkers, (ii) stable moderate drinkers (referent), (iii) stable heavy drinkers, (iv) nonstable drinkers and (v) former drinkers. C-reactive protein (CRP), interleukin (IL)-6 and IL-1 receptor antagonist (IL-1 RA) were measured up to three times in the following 12 years. RESULTS: Stable moderate drinkers had lower levels of CRP than stable nondrinkers, stable heavy drinkers, former drinkers and nonstable drinkers, but there were no differences in the rate of change in CRP over time between groups. Stable nondrinkers had higher levels of IL-6 as did stable heavy drinkers; rates of change in IL-6 over time were also increased in the latter group. Stable nondrinkers also had higher levels of IL-1 RA. These associations were robust to adjustment for confounding factors. CONCLUSION: Our novel investigation of 10-year drinking typologies shows that stable moderate alcohol consumption is associated with a long-term inflammatory marker profile that is consistent with conferring a reduced risk of developing coronary heart disease. PMID- 27485147 TI - Circadian variation in clinical features and outcome of intracerebral hemorrhage: The INTERACT studies. AB - Previous studies consistently reported a diurnal variation in the occurrence of intracerebral hemorrhage (ICH), with a morning peak. However, limited knowledge exists on the circadian pattern of ICH severity and outcome. This study aimed to determine possible associations between ICH onset time and admission severity and 90-day outcomes using the combined data set of the pilot and main-phase Intensive blood pressure (BP) reduction in an acute cerebral hemorrhage trial (INTERACT). The ICH onset time was categorized into three groups (1: 00:00-07:59; 2: 08:00 15:59; and 3: 16:00-23:59). We found an association between onset time and low Glasgow Coma Scale score: aOR (time 1: 1.72, 95% CI 1.12-2.66; time 3: 1.95, 95% CI 1.31-2.89, p = 0.003; in comparison to time 2). There was no association between onset time and volume of ICH (adjusted p = 0.354) or 90-day outcomes of death or major disability, and death and major disability separately (all adjusted p > 0.4). The results showed that more severe cases of ICH patients, defined by a reduced level of consciousness, had late afternoon to early morning stroke onset, but this was unrelated to baseline hematoma volume or location. There was no circadian influence on ICH clinical outcome. PMID- 27485148 TI - Electrokinetic supercharging in nonaqueous capillary electrophoresis for online preconcentration and determination of tamoxifen and its metabolites in human plasma. AB - An online preconcentration method, namely electrokinetic supercharging (EKS), was evaluated for the determination of tamoxifen and its metabolites in human plasma in nonaqueous capillary electrophoresis with ultraviolet detection (NACE-UV). This method was comprehensively optimized in terms of the leading electrolyte (LE) and terminating electrolyte (TE) injection lengths, as well as electrokinetic sample injection time. The optimized EKS conditions employed were as follows: hydrodynamic injection (HI) of 10mM potassium chloride as LE at 150mbar for 36s (4% of total capillary volume). The sample was injected at 10kV for 300s, followed by HI of 10mM pimozide as TE at 150mbar for 36s (4% of total capillary volume). Separation was performed in 7.5mM deoxycholic acid sodium salt, 15mM acetic acid and 1mM 18-crown-6 in 100% methanol at +25kV with UV detection at 205nm. Under optimized conditions, the sensitivity was enhanced between 160- and 600-fold when compared with our previously developed method based on HI at 150mbar for 12s. The detection limit of the method for tamoxifen and its metabolites were 0.05-0.25ng/mL, with RSDs between 2.1% and 3.5%. Recoveries in spiked human plasma were 95.6%-99.7%. A comparison was also made between the proposed EKS approach and the standard field-amplified sample injection (FASI) technique. EKS proved to be 3-5 times more sensitive than the FASI. The new EKS method was applied to the analysis of tamoxifen and its metabolites in plasma samples from breast cancer patients after liquid-liquid extraction. PMID- 27485149 TI - Pharmacokinetics of ketamine and three metabolites in Beagle dogs under sevoflurane vs. medetomidine comedication assessed by enantioselective capillary electrophoresis. AB - Ketamine is often used for anesthesia in veterinary medicine. One possible comedication is the sedative alpha2-agonist medetomidine. Advantages of that combination are the compensation of side effects of the two drugs and the anesthetic-sparing effect of medetomidine. In vitro studies showed that medetomidine has an inhibitive effect on the formation of norketamine. Norketamine is the first metabolite of ketamine and is also active. It is followed by others like 6-hydroxynorketamine and 5,6-dehydronorketamine (DHNK). In an in vivo pharmacokinetic study Beagle dogs under sevoflurane anesthesia (mean end-tidal concentration 3.0+/-0.2%) or following medetomidine sedation (450MUg/m2) received 4mg/kg racemic ketamine or 2mg/kg S-ketamine. Blood samples were collected between 0 and 900min after drug injection. 50MUL aliquots of plasma were pretreated by liquid-liquid extraction prior to analysis of the reconstituted extracts with a robust enantioselective capillary electrophoresis assay using highly sulfated gamma-cyclodextrin as chiral selector and electrokinetic sample injection of the analytes from the extract across a short buffer plug without chiral selector. Levels of S- and R-ketamine, S- and R norketamine, (2S,6S)- and (2R,6R)-hydroxynorketamine and S- and R-DHNK were determined. Data were analyzed with compartmental pharmacokinetic models which included two compartments for the ketamine and norketamine enantiomers and a single compartment for the DHNK and 6-hydroxynorketamine stereoisomers. Medetomidine showed an effect on the formation and elimination of all metabolites. Stereoselectivities were detected for 6-hydroxynorketamine and DHNK, but not for ketamine and norketamine. PMID- 27485150 TI - Development of tropine-salt aqueous two-phase systems and removal of hydrophilic ionic liquids from aqueous solution. AB - A novel aqueous two-phase systems (ATPS) composed of a small molecule organic compound tropine and an organic or inorganic salt aqueous solution has been developed for the first time. The phase behavior of tropine-salt ATPS was systemically investigated and the phase equilibrium data were measured in different temperatures and concentrations and correlated by the Merchuk equation with satisfactory results. The detection of the conductivity and particle size proved the formation of micelle in the process of forming tropine-salt ATPS. The separation application of the ATPS was assessed with the removal of hydrophilic benzothiazolium-based ionic liquids (ILs) from aqueous solution. The result showed that ILs were effectively extracted into the top tropine-rich phase. Finally, ILs in the top tropine-rich phase were further separated by the means of adsorption-desorption with DM301 macroporous resin and ethanol. The method of novel tropine-salt ATPS combined with adsorption-desorption is demonstrated a promising alternative thought and approach for the removal or recovery of hydrophilic compounds from aqueous media and also could provide a potential application for bio-separation. PMID- 27485151 TI - Gas chromatography fractionation platform featuring parallel flame-ionization detection and continuous high-resolution analyte collection in 384-well plates. AB - Gas chromatography (GC) is a superior separation technique for many compounds. However, fractionation of a GC eluate for analyte isolation and/or post-column off-line analysis is not straightforward, and existing platforms are limited in the number of fractions that can be collected. Moreover, aerosol formation may cause serious analyte losses. Previously, our group has developed a platform that resolved these limitations of GC fractionation by post-column infusion of a trap solvent prior to continuous small-volume fraction collection in a 96-wells plate (Pieke et al., 2013 [17]). Still, this GC fractionation set-up lacked a chemical detector for the on-line recording of chromatograms, and the introduction of trap solvent resulted in extensive peak broadening for late-eluting compounds. This paper reports advancements to the fractionation platform allowing flame ionization detection (FID) parallel to high-resolution collection of a full GC chromatograms in up to 384 nanofractions of 7s each. To this end, a post-column split was incorporated which directs part of the eluate towards FID. Furthermore, a solvent heating device was developed for stable delivery of preheated/vaporized trap solvent, which significantly reduced band broadening by post-column infusion. In order to achieve optimal analyte trapping, several solvents were tested at different flow rates. The repeatability of the optimized GC fraction collection process was assessed demonstrating the possibility of up-concentration of isolated analytes by repetitive analyses of the same sample. The feasibility of the improved GC fractionation platform for bioactivity screening of toxic compounds was studied by the analysis of a mixture of test pesticides, which after fractionation were subjected to a post-column acetylcholinesterase (AChE) assay. Fractions showing AChE inhibition could be unambiguously correlated with peaks from the parallel-recorded FID chromatogram. PMID- 27485153 TI - Influences of Sex and Age on the Hematological Profile of the Jundia (Silver Catfish) Rhamdia quelen. AB - In this study, sex and age influenced the hematological profiles of Jundia (Silver Catfish) Rhamdia quelen. Females showed lower levels of hemoglobin, young fish increased lymphocyte counts, and older fish increased hematocrit values. These results indicate that, depending on age and sex, the fish have disparate hematological profiles. For this reason, it is important to consider the sex and age of an R. quelen when examining the impact of environmental and management factors on this species in terms of their hematological profiles. Received May 24, 2015; accepted March 24, 2016. PMID- 27485152 TI - Prevalence of cardiovascular-related comorbidity in ankylosing spondylitis, psoriatic arthritis and psoriasis in primary care: a matched retrospective cohort study. AB - The aim of this study is to compare the prevalence of cardiovascular (CVD) related comorbidities in patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA) or psoriasis (Ps) in UK primary care against matched cohorts. Matched retrospective cohort study used a primary care consultation database. Three cohorts were constructed using all patients with a Read code diagnosis of AS, PsA or Ps between 1999 and 2009; each cohort was then compared in a 1:4 ratio to a matched cohort. The prevalence of CVD-related comorbidities (hypertension, ischaemic heart disease, hyperlipidaemia and diabetes mellitus) were identified by the first consultation of a comorbid Read code, in those with an inflammatory condition of interest. The prevalence of CVD-related comorbidities was compared between each inflammatory cohort and their matched cohort using Fisher's exact test. Ninety-four AS, 106 PsA and 290 Ps patients were identified. Compared with matched cohorts, the most prevalent CVD-related comorbidity in patients with AS was hypertension (35 (37.2 %) vs. 96 matched (25.5 %), p = 0.03); this was also the case for PsA (41 (38.7 %) vs. 114 matched (26.9 %), p = 0.02). No differences were seen in the prevalence of other CVD-related comorbidities in those with AS, PsA or Ps compared to their matched cohorts. Our findings provide UK comparisons of CVD-related comorbidities in patients with AS, PsA and Ps alone; specifically, demonstrating increased prevalence of hypertension in AS and PsA cohorts compared to their matched cohorts. This further supports the argument for more evidence in the need for screening and intervention around CVD comorbidities in inflammatory conditions. PMID- 27485154 TI - Effect of OATP-binding on the prediction of biliary excretion. AB - 1. Biliary excretion of compounds is dependant on several transporter proteins for the active uptake of compounds from the blood into the hepatocytes. Organic anion-transporting polypeptides (OATPs) are some of the most abundant transporter proteins in the sinusoidal membrane and have been shown to have substrate specificity similar to the structural characteristics of cholephilic compounds. 2. In this study, we sought to use measures of OATP binding as predictors of biliary excretion in conjunction with molecular descriptors in a quantitative structure-activity relationship (QSAR) study. Percentage inhibitions of three subtypes of OATPs were used as surrogate indicators of OATP substrates. Several statistical modelling techniques were incorporated including classification and regression trees, boosted trees, random forest and multivariate adaptive regression splines (MARS) in order to first develop QSARs for the prediction of OATP inhibition of compounds. The predicted OATP percentage inhibition using selected models were then used as features of the QSAR models for the prediction of biliary excretion of compounds in rat. 3. The results indicated that incorporation of predicted OATP inhibition improves accuracy of biliary excretion models. The best result was obtained from a simple regression tree that used predicted OATP1B1 percentage inhibition at the root node of the tree. PMID- 27485155 TI - "Knowing Your Status and Knowing Your Partner's Status Is Really Where It Starts": A Qualitative Exploration of the Process by Which a Sexual Partner's HIV Status Can Influence Sexual Decision Making. AB - Gay and bisexual men are at disproportionate risk for human immunodeficiency virus (HIV) infection. While prevention efforts often emphasize consistent condom use, there is growing evidence that men are using seroadaptive safer-sex strategies, such as serosorting and seropositioning. This qualitative analysis of 204 HIV-negative and HIV-positive gay and bisexual men explored the ways that a sexual partner's HIV status can influence safer-sex strategies and sexual decisions. The majority of the respondents reported that they were influenced by their partners' HIV status. Those respondents who reported no influence discussed adhering to safer-sex rules that were not dependent on partner status and a lack of concern about HIV. Conversely, respondents who reported influence identified three primary areas of influence: psychological impacts, partner preference and selection, and specific behavioral intentions and strategies. A conceptual model explicating a potential process by which respondents use partner serostatus information in shaping sexual decisions is presented. PMID- 27485156 TI - Phenotypic and genotypic characterization of enteroaggregative Escherichia coli isolates from pediatric population in Pakistan. AB - Enteroaggregative Escherichia coli (EAEC) are a leading cause of diarrhea among children. The objective of this study was to define the frequency of EAEC among diarrheal children from flood-affected areas as well as sporadic cases, determine multidrug resistance, and evaluation of virulence using an in vivo model of pathogenesis. Stool samples were collected from 225 diarrheal children from 2010 to 2011 from flood-affected areas as well as from sporadic cases in Pakistan. Identified EAEC isolates were characterized by phylogrouping, antibiotic resistance patterns including the extended-spectrum beta lactamase spectrum, single nucleotide polymorphism detection in gyrA and parC, and virulence potential using wax worm, G. mellonella. A total of 35 (12.5%) confirmed EAEC isolates were identified among 225 E. coli isolates. EAEC isolates displayed high resistance to tetracycline, ampicillin, and cefaclor. A total of 34.28% were ESBL positive. Single nucleotide polymorphism detection revealed 37.14% and 68.57% isolates were positive for SNPs in gyrA (A660 -T660 ) and parC (C330 -T330 ), respectively. Phylogrouping revealed that B2 phylogroup was more prevalent among all EAEC isolates tested followed by D, A, B1, and non-typeable (NT). Infection of G. mellonella with EAEC showed that killing infective dose was 100% higher than E. coli DH5 alpha control. EAEC are prevalent among Pakistani children with diarrhea, they are highly resistant to antibiotics, and predominantly fall into B2 phylogroup. Epidemiologic surveillance of EAEC and other E. coli pathotypes is critical to assess not only the role of these pathogens in diarrheal disease but also to determine the extent of multidrug resistance among the population. PMID- 27485157 TI - Combination of collagen and fibronectin to design biomimetic interfaces: Do these proteins form layer-by-layer assemblies? AB - Layer-by-layer (LbL) assembly is a surface modification method which may bring complexity to biointerfaces designed to control cell-material interactions. This work aims at investigating the LbL assembly of two extracellular matrix proteins, collagen (Col) and fibronectin (Fn), on polystyrene substrates. LbL assembly, which is widely applied to polyelectrolytes, is not easily transferred to proteins. Different buffers and conditions are tested, and LbL assembly is compared to the simultaneous adsorption of Fn and Col. Build-up and properties of the films are monitored using quartz crystal microbalance, ellipsometry, water contact angle measurements, and atomic force microscopy. Results show that denatured Col leads to smoother films, and that the addition of a polyethyleneimine anchoring layer increases film thickness. A more regular construction and thicker films are obtained with Hepes (pH 7.4) compared to other buffers. However, the LbL assembly is not sustainable and stops after the deposition of a few layers. Films obtained by simultaneous adsorption have lower water contact angles, different morphologies, lower water content and are as thick or thicker compared to the ones prepared by the LbL method. The present work shows that collagen and fibronectin are not involved in a true LbL assembly process. The obtained biointerfaces however exhibit different properties compared to those obtained by the one-step adsorption of these proteins. These differences could be exploited to control cell fate. PMID- 27485158 TI - Mental health and breast cancer screening utilization among older Hispanic women. AB - Considerable racial and ethnic differences exist in the way the burden of cancer is experienced in the United States for older Hispanic women. This study utilized data from the 2008 wave of the Health and Retirement Study to investigate the mental health factors associated with older Hispanic women's participation in breast cancer screening services. Logistic regression models were used. Findings indicated that anxiety and positive affect were associated with a greater likelihood of participating in breast cancer screening. Despite ongoing national conversations, evidence indicates there is agreement that underserved women need to be screened, particularly the older Hispanic population. PMID- 27485159 TI - Serum cell death biomarker mirrors liver cancer regression after transarterial chemoembolisation. AB - BACKGROUND: Hepatocellular carcinoma (HCC) represents an increasing health problem with limited therapeutic options. In patients with intermediate disease stage, transarterial chemoembolisation (TACE) is widely applied. Treatment response is routinely assessed by imaging techniques according to the international response evaluation criteria in solid tumours (RECIST), which consider tumour regression or additionally tumour necrosis (modified RECIST). Evaluation of treatment response, however, by these methods is time- and cost intensive and usually performed at earliest several months following TACE. AIM: To investigate the suitability of novel non-invasive cell death biomarkers for an earlier prediction of TACE response. METHODS: We analysed activation of pro apoptotic caspases and the proteolytic cleavage of the caspase substrate CK-18 in liver tissues and sera from HCC patients by immunohistochemistry, a luminometric substrate assay and ELISA. RESULTS: Both caspase activity and caspase-cleaved CK 18 fragments were elevated in HCC patients compared to healthy controls. CK-18 serum levels significantly increased during the first 3 days and peaked at day two following TACE. Interestingly, we found significant differences in CK-18 levels between patients with and without tumour regression. Detection of CK-18 fragments revealed a promising performance for the early prediction of TACE response with an area under the curve value of 0.76. CONCLUSIONS: Caspase-cleaved CK-18 levels mirror liver cancer regression and allow an earlier prediction of TACE response. The concordance with mRECIST suggests that the detection of CK-18 levels immediately after TACE might be used as a short-term decision guide to continue or change HCC therapy. PMID- 27485160 TI - Optimal Device Independent Quantum Key Distribution. AB - We consider an optimal quantum key distribution setup based on minimal number of measurement bases with binary yields used by parties against an eavesdropper limited only by the no-signaling principle. We note that in general, the maximal key rate can be achieved by determining the optimal tradeoff between measurements that attain the maximal Bell violation and those that maximise the bit correlation between the parties. We show that higher correlation between shared raw keys at the expense of maximal Bell violation provide for better key rates for low channel disturbance. PMID- 27485161 TI - More than meets the eye: Emergent properties of transcription factors networks in Arabidopsis. AB - Uncovering and mathematically modeling Transcription Factor Networks (TFNs) are the first steps in engineering plants with traits that are better equipped to respond to changing environments. Although several plant TFNs are well known, the framework for systematically modeling complex characteristics such as switch-like behavior, oscillations, and homeostasis that emerge from them remain elusive. This review highlights literature that provides, in part, experimental and computational techniques for characterizing TFNs. This review also outlines methodologies that have been used to mathematically model the dynamic characteristics of TFNs. We present several examples of TFNs in plants that are involved in developmental and stress response. In several cases, advanced algorithms capture or quantify emergent properties that serve as the basis for robustness and adaptability in plant responses. Increasing the use of mathematical approaches will shed new light on these regulatory properties that control plant growth and development, leading to mathematical models that predict plant behavior. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer. PMID- 27485162 TI - Early suppression effect in human primary visual cortex during Kanizsa illusion processing: A magnetoencephalographic evidence. AB - Detection of illusory contours (ICs) such as Kanizsa figures is known to depend primarily upon the lateral occipital complex. Yet there is no universal agreement on the role of the primary visual cortex in this process; some existing evidence hints that an early stage of the visual response in V1 may involve relative suppression to Kanizsa figures compared with controls. Iso-oriented luminance borders, which are responsible for Kanizsa illusion, may evoke surround suppression in V1 and adjacent areas leading to the reduction in the initial response to Kanizsa figures. We attempted to test the existence, as well as to find localization and timing of the early suppression effect produced by Kanizsa figures in adult nonclinical human participants. We used two sizes of visual stimuli (4.5 and 9.0 degrees ) in order to probe the effect at two different levels of eccentricity; the stimuli were presented centrally in passive viewing conditions. We recorded magnetoencephalogram, which is more sensitive than electroencephalogram to activity originating from V1 and V2 areas. We restricted our analysis to the medial occipital area and the occipital pole, and to a 40-120 ms time window after the stimulus onset. By applying threshold-free cluster enhancement technique in combination with permutation statistics, we were able to detect the inverted IC effect-a relative suppression of the response to the Kanizsa figures compared with the control stimuli. The current finding is highly compatible with the explanation involving surround suppression evoked by iso oriented collinear borders. The effect may be related to the principle of sparse coding, according to which V1 suppresses representations of inner parts of collinear assemblies as being informationally redundant. Such a mechanism is likely to be an important preliminary step preceding object contour detection. PMID- 27485163 TI - Branched Arylalkenes from Cinnamates: Selectivity Inversion in Heck Reactions by Carboxylates as Deciduous Directing Groups. AB - A decarboxylative Mizoroki-Heck coupling of aryl halides with cinnamic acids has been developed in which the carboxylate group directs the arylation into its beta position before being tracelessly removed through protodecarboxylation. In the presence of a copper/palladium catalyst, both electron-rich and electron deficient aryl bromides and chlorides bearing numerous functionalities were successfully coupled with broadly available cinnamates, with selective formation of 1,1-disubstituted alkenes. This reaction concept, in which the carboxylate acts as a deciduous directing group, ideally complements traditional 1,2 selective Heck reactions of styrenes. PMID- 27485164 TI - Acquired cold urticaria: Clinical features, particular phenotypes, and disease course in a tertiary care center cohort. AB - BACKGROUND: Data about special phenotypes, natural course, and prognostic variables of patients with acquired cold urticaria (ACU) are scarce. OBJECTIVES: We sought to describe the clinical features and disease course of patients with ACU, with special attention paid to particular phenotypes, and to examine possible parameters that could predict the evolution of the disease. METHODS: This study was a retrospective chart review of 74 patients with ACU who visited a tertiary referral center of urticaria between 2005 and 2015. RESULTS: Fourteen patients (18.9%) presented with life-threatening reactions after cold exposure, and 21 (28.4%) showed negative results after cold stimulation tests (classified as atypical ACU). Nineteen patients (25.7%) achieved complete symptoms resolution at the end of the surveillance period and had no subsequent recurrences. Higher rates of atypical ACU along with a lower likelihood of achieving complete symptom resolution was observed in patients who had an onset of symptoms during childhood (P < .05). In patients with atypical ACU, shorter disease duration and lower doses of antihistamines required for achieving disease control were detected (P < .05). Age at disease onset, symptom severity, and cold urticaria threshold values were found to be related to disease evolution (P < .05). LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: The knowledge of the clinical predictors of the disease evolution along with the clinical features of ACU phenotypes would allow for the establishment of an early and proper therapeutic strategy. PMID- 27485165 TI - MicroRNA-101 inhibits the proliferation and invasion of bladder cancer cells via targeting c-FOS. AB - MicroRNAs (miRs) have important roles in the parthenogenesis of malignancies. While it has been suggested that deregulation of miR-101 is involved in bladder cancer, the underlying mechanisms have remained largely elusive. The present study aimed to investigate the roles of miR-101 in the regulation of bladder cancer cell proliferation and invasion. Reverse-transcription quantitative polymerase chain reaction analysis revealed that the expression of miR-101 was significantly reduced in the HT-1376, BIU87, T24 and 5637 several human bladder cancer cell lines compared to that in the SV-HUC-1 normal bladder epithelial cell line. Furthermore, a Targetscan search and a luciferase assay were used to identify c-FOS as a novel target of miR-101, and western blot analysis indicated that the protein expression of c-FOS was shown to be negatively regulated by miR 101 in bladder cancer T24 cells; however, c-FOS mRNA expression was not affected. In addition, plasmid-mediated overexpression of miR-101 and small hairpin RNA mediated inhibition of c-FOS significantly inhibited the proliferation and invasive capacity of T24 cells, as indicated by an MTT and a Transwell assay, respectively. However, plasmid-mediated overexpression of c-FOS reversed the inhibitory effects of miR-101 overexpression on T24-cell proliferation and invasion. In conclusion, the present study demonstrated that miR-101 inhibits the proliferation and invasion of bladder cancer cells, at least partly via targeting c-FOS, suggesting that miR-101/c-FOS signaling may represent a potential therapeutic target for bladder cancer. PMID- 27485166 TI - Erratum: Pubertal development in healthy children is mirrored by DNA methylation patterns in peripheral blood. PMID- 27485167 TI - Pathology reporting of malignant pleural mesothelioma first diagnosis: A population-based approach. AB - Accurate pathologic diagnosis and reporting in malignant pleural mesothelioma are essential for clinical care, and cancer registration. Practical guidelines for pathologists are provided in publications and textbooks but it is unclear how these recommendations are applied in routine practice. We investigated the characteristics of pathology reports, and the extent to which they meet guideline standards. We reviewed 819 pathology reports relating to a first diagnosis of malignant pleural mesothelioma. Data sources were a regional section of the Italian network of the Mesothelioma Registry (2001-2014) and a pathology archive (1990-2000). We evaluated tumor characteristics, the diagnosis field including terminology and immunohistochemistry (IHC) workup, and report completeness (the proportion of items recorded). We investigated also two IHC panels identified by the most used markers in current practical guidelines, one best suited for epithelioid mesotheliomas (combinations of at least 2 positive and at least 2 negative mesothelioma markers) and the other best suited for sarcomatoid mesotheliomas (positive mesothelioma markers plus cytokeratins). Reports (753 histology, 66 cytology, IHC-confirmed 86%) were 74% complete and always narrative. Missing data were related to clinical history (76%), tumor laterality (61%), specimen size (38%), and histological subtype (23%). The proportion of cases with IHC was higher for epithelioid (90%) than sarcomatoid mesothelioma (87%). Compliance to IHC recommendations was higher for epithelioid (59%) than sarcomatoid mesothelioma (11%). The mean number of stains was significantly higher for sarcomatoid than epithelioid mesothelioma (p<0.000; Kruskal-Wallis test). Our findings show that although guidelines are designed to improve actual reporting practices, there is ample room for improvement in their application to standardize the diagnosis of mesothelioma. Synoptic pathology reporting needs to be implemented to better utilize pathology information. PMID- 27485168 TI - Charles Bonnet syndrome successfully treated with levetiracetam. PMID- 27485169 TI - Extensive bilateral striopallidodentate calcinosis: a 50 years history of hypoparathyroidism presenting like a parkinsonian syndrome. PMID- 27485170 TI - Higher frequencies of HLA DQB1*05:01 and anti-glycosphingolipid antibodies in a cluster of severe Guillain-Barre syndrome. AB - Few regional and seasonal Guillain-Barre syndrome (GBS) clusters have been reported so far. It is unknown whether patients suffering from sporadic GBS differ from GBS clusters with respect to clinical and paraclinical parameters, HLA association and antibody response to glycosphingolipids and Campylobacter jejuni (Cj). We examined 40 consecutive patients with GBS from the greater Munich area in Germany with 14 of those admitted within a period of 3 months in fall 2010 defining a cluster of GBS. Sequencing-based HLA typing of the HLA genes DRB1, DQB1, and DPB1 was performed, and ELISA for anti-glycosphingolipid antibodies was carried out. Clinical and paraclinical findings (Cj seroreactivity, cerebrospinal fluid parameters, and electrophysiology) were obtained and analyzed. GBS cluster patients were characterized by a more severe clinical phenotype with more patients requiring mechanical ventilation and higher frequencies of autoantibodies against sulfatide, GalC and certain ganglioside epitopes (54 %) as compared to sporadic GBS cases (13 %, p = 0.017). Cj seropositivity tended to be higher within GBS cluster patients (69 %) as compared to sporadic cases (46 %, p = 0.155). We noted higher frequencies of HLA class II allele DQB1*05:01 in the cluster cohort (23 %) as compared to sporadic GBS patients (3 %, p = 0.019). Cluster of severe GBS was defined by higher frequencies of autoantibodies against glycosphingolipids. HLA class II allele DQB1*05:01 might contribute to clinical worsening in the cluster patients. PMID- 27485171 TI - Cortical thinning in drug-naive Parkinson's disease patients with depression. AB - To shed more light on the contribution of brain structural changes to PD-related depressive symptoms, this study conducted cortical thickness analysis in drug naive PD patients with and without depression. We recruited 27 PD patients with depression (PD-Dep), 29 PD patients without depression (PD-NDep), and 56 normal controls. T1 weighted magnetic resonance imaging and surface-based morphometric analyses were performed to examine morphometric abnormalities in PD patients and their relationship to depression. We found decreased thickness in the left prefrontal cortex in PD-Dep group compared with PD-NDep group. No significant difference was found between PD patients and controls. In addition, we found there is a trend of inverse correlation between the structural changes and the score of depressive symptom in depressed PD patients. This study demonstrates that cortical thinning in prefrontal area in drug-naive PD patients with depression and highlights the critical role of prefrontal region in the depression associated with PD. PMID- 27485173 TI - The influence of pi-conjugation on competitive pathways: charge transfer or electron transfer in new D-pi-A and D-pi-Si-pi-A dyads. AB - In order to elucidate the influence of pi-conjugation on photoinduced electron transfer (PET) and intramolecular charge transfer processes, donor-pi-acceptor dyads (D-pi-A (1) and D-pi-Si-pi-A (2)) were newly synthesized. In these dyads, carbazole and triazine moieties acted as the electron donor and acceptor, respectively. The fluorescence of dyad 1 red-shifted as the solvent polarity was increased. The electron charge distribution of the excited state of dyad 1 was delocalized in the acceptor moiety, forming the charge transfer D(delta+)-pi A(delta-) dyad in the excited state. In the excited state of dyad 1, the pi conjugation acted as the linker for charge transfer between the donor and acceptor moieties. A large dipole moment change (DeltaMU = 45.6 D) between the ground and excited states was determined using the Lippert-Mataga plot. Furthermore, the fluorescence of dyad 1 was observed upon two-photon excitation. In contrast, dyad 2, in which the pi-conjugation is disconnected by a Si-atom in the linker, displayed weak dual-emission: a short-wavelength emission at around 350 nm arising from the monomeric species and a long-wavelength one assigned to the emission from an intramolecular exciplex between the donor and acceptor moieties. The weak emission of dyad 2 indicates that the D(+)-pi-Si-pi-A(-) species was generated through a PET process in the excited state. The cationic radical species of the carbazole and the anionic radical species of the triazine, which show transient absorption (TA) bands at around 780 and 530 nm, respectively, were characterized using the femtosecond TA method. PMID- 27485172 TI - Thalamic interictal epileptiform discharges in deep brain stimulated epilepsy patients. AB - The relationships between interictal epileptiform discharges (IEDs) in the anterior (ANT) and dorsomedial nuclei (DMNT) of the thalamus and electro-clinical parameters in pharmacoresistant focal epilepsy patients receiving intrathalamic electrodes for deep brain stimulation (DBS) were investigated. Thalamus-localized IEDs (LIEDs) and surface EEG (sEEG)-IEDs were evaluated in eight patients who underwent ANT-DBS. Occurrence and frequency of ANT- and DMNT-LIEDs and pre operative sEEG-IEDs were examined with respect to seizure onset location and seizure outcome following ANT-DBS. LIEDs were identified in all eight patients, in the ANT, DMNT, or both. ANT-LIEDs were observed in all patients with an unequivocal temporal seizure onset zone. The ANT-LIED frequency correlated with pre-surgical sEEG-IED frequency (rho = 0.76, p = 0.033) and predicted ANT-DBS responsiveness (T = -2.6; p = 0.0428). Of the five patients with bilateral sEEG IEDs, all had ANT-LIEDs, but only one patient had DMNT-LIEDs. All patients with no or unilateral sEEG-IEDs had DMNT-LIEDs. Observation of LIEDS in the ANT and DMNT supports the hypothesis that these nuclei are involved in propagation of focal epileptic activity. Their correspondence with differing electro-clinical features suggests that these nuclei are functionally distinguishable nodes within the epileptic networks of individual patients. PMID- 27485174 TI - Incidence, risk factors and outcomes of acute kidney injury (AKI) in patients with acute-on-chronic liver failure (ACLF) of underlying cirrhosis. AB - BACKGROUND AND AIMS: Acute kidney injury (AKI) is a life-threatening complication in patients with acute-on-chronic liver failure (ACLF) of underlying cirrhosis. However, the characteristics of AKI in these patients have not been clarified. Our aim was to determine the incidence and risk factors of AKI and the association between AKI severity and 180-day transplant-free survival. METHODS: We performed a retrospective cohort analysis of patients with ACLF of underlying cirrhosis in a single center from January 2009 through December 2014. AKI was defined by the criteria proposed by International Club of Ascites (ICA). The incidence and risk factors of AKI development and its relationship to 180-day transplant-free survival rates were evaluated. RESULTS: Of 1032 patients with ACLF of underlying cirrhosis, 121 (11.72 %) had AKI at admission, and 319 (30.9 %) developed AKI during hospitalization. We established a logistic regression model including four independent factors with AKI development: MELD score [odds ratio (OR), 1.1; 95 % confidence interval (CI), 1.07-1.14], presence of ascites (OR, 3.80; 95 % CI, 2.13-6.78), sepsis/infection (OR, 2.25; 95 % CI, 1.66-3.03) and acute variceal bleed (OR, 1.78; 95 % CI, 1.00-3.19). The area under receiver operating characteristics of the model in internal and external validations were 0.95 and 0.85, respectively. Patients with mild-A AKI had a higher 180-day transplant-free survival rate (23.8 %) than patients with mild-B AKI (19.0 %) or marked AKI (5.9 %) (all p < 0.001). AKI patients with a peak value of sCr <1.5 mg/dl had higher 180-day transplant-free survival rates compared to those with a peak value of sCr ?1.5 mg/dl (23.8 % vs. 14.7 %, p < 0.001). CONCLUSIONS: We developed a clinical risk model for predicting development of AKI with great accuracy. Combining the ICA-AKI criteria and the peak value of sCr with 1.5 mg/dl provides a good prognostic method for patients with ACLF of underlying cirrhosis. PMID- 27485176 TI - Mcm10: The glue at replication forks. PMID- 27485177 TI - Inter-disciplinarity in sport sciences: The neuroscience example. AB - Sport science is a relatively recent domain of research born from the interactions of different disciplines related to sport. According to the European College of sport science ( http://sport-science.org ): "scientific excellence in sport science is based on disciplinary competence embedded in the understanding that its essence lies in its multi- and interdisciplinary character". In this respect, the scientific domain of neuroscience has been developed within such a framework. Influenced by the apparent homogeneity of this scientific domain, the present paper reviews three important research topics in sport from a neuroscientific perspective. These topics concern the relationship between mind and motor action, the effects of cognition on motor performance, and the study of certain mental states (such as the "flow" effect, see below) and motor control issues to understand, for example, the neural substrates of the vertical squat jump. Based on the few extensive examples shown in this review, we argue that by adopting an interdisciplinary paradigm, sport science can emulate neuroscience in becoming a mono-discipline. PMID- 27485175 TI - Prognostic value of 5-microRNA based signature in T2-T3N0 colon cancer. AB - The role of adjuvant chemotherapy in stage T2-T3N0 colon cancer (CC) is controversial and there are currently no reliable factors allowing for individual selection of patients with high risk of relapse for such therapy. We searched for microRNA-based signature with prognostic significance in this group. We assessed by qRT-PCR expression of 754 microRNAs (miRNAs) in tumour samples from 85 stage pT2-3N0 CC patients treated with surgery alone. MiRNA expression was compared between two groups of patients: 40 and 45 patients who did and did not develop distant metastases after resection, respectively. Additionally, miRNA expression was compared between CC and normal colon mucosa samples and between the mismatch repair (MMR) competent and deficient tumours. Low expression of miR-1300 and miR 939 was significantly correlated with shorter distant metastasis-free survival (DMFS) in Cox univariate analysis (p.adjusted = 0.049). The expression signature of five miRNAs (miR-1296, miR-135b, miR-539, miR-572 and miR-185) was found to be prognostic [p = 1.28E-07, HR 8.4 (95 % CI: 3.81-18.52)] for DMFS and cross validated in a leave-one-out analysis, with the sensitivity and specificity of 74 and 78 %, respectively. The expression of miR-592 was significantly associated with the MMR status (p.adjusted <0.01). The expression of several novel miRNAs were found to be tumour specific, e.g. miR-888, miR-523, miR-18b, miR-302a, miR 423-5p, miR-582-3p (p < 0.05). We developed a miRNA expression signature that may be predictive for the risk of distant relapse in early stage CC and confirmed previously reported association between miR-592 expression and MMR status. PMID- 27485178 TI - Removal of oxytetracycline and determining its biosorption properties on aerobic granular sludge. AB - This study investigates biosorption of Oxytetracycline, a broad-spectrum antibiotic, using aerobic granular sludge as an adsorbent in aqueous solutions. A sequencing batch reactor fed by a synthetic wastewater was operated to create aerobic granular sludge. Primarily, the pore structure and surface area of granular sludge, the chemical structure and the molecular sizes of the pharmaceutical, operating conditions, such as pH, stirring rate, initial concentration of Oxytetracycline, during adsorption process was verified. Subsequently, thermodynamic and kinetic aspects of the adsorption were examined and adsorption isotherm studies were carried out. It was shown that the aerobic granular sludge was a good alternative for biosorption of this pharmaceutical. The pharmaceutical was adsorbed better at pH values of 6-8. The adsorption efficiency increased with rising ionic strength. Also, it was seen that the adsorption process was an exothermic process in terms of thermodynamics. The adsorption can be well explained by Langmuir isotherm model. PMID- 27485179 TI - Arsenate Accumulation, Distribution, and Toxicity Associated with Titanium Dioxide Nanoparticles in Daphnia magna. AB - Titanium dioxide nanoparticles (nano-TiO2) are widely used in consumer products. Nano-TiO2 dispersion could, however, interact with metals and modify their behavior and bioavailability in aquatic environments. In this study, we characterized and examined arsenate (As(V)) accumulation, distribution, and toxicity in Daphnia magna in the presence of nano-TiO2. Nano-TiO2 acts as a positive carrier, significantly facilitating D. magna's ability to uptake As(V). As nano-TiO2 concentrations increased from 2 to 20 mg-Ti/L, total As increased by a factor of 2.3 to 9.8 compared to the uptake from the dissolved phase. This is also supported by significant correlations between arsenic (As) and titanium (Ti) signal intensities at concentrations of 2.0 mg-Ti/L nano-TiO2 (R = 0.676, P < 0.01) and 20.0 mg-Ti/L nano-TiO2 (R = 0.776, P < 0.01), as determined by LA-ICP MS. Even though As accumulation increased with increasing nano-TiO2 concentrations in D. magna, As(V) toxicity associated with nano-TiO2 exhibited a dual effect. Compared to the control, the increased As was mainly distributed in BDM (biologically detoxified metal), but Ti was mainly distributed in MSF (metal sensitive fractions) with increasing nano-TiO2 levels. Differences in subcellular distribution demonstrated that adsorbed As(V) carried by nano-TiO2 could dissociate itself and be transported separately, which results in increased toxicity at higher nano-TiO2 concentrations. Decreased As(V) toxicity associated with lower nano-TiO2 concentrations results from unaffected As levels in MSFs (when compared to the control), where several As components continued to be adsorbed by nano-TiO2. Therefore, more attention should be paid to the potential influence of nano-TiO2 on bioavailability and toxicity of cocontaminants. PMID- 27485180 TI - miR-128 promoted adipogenic differentiation and inhibited osteogenic differentiation of human mesenchymal stem cells by suppression of VEGF pathway. AB - CONTEXT: MicroRNA-128 (miR-128), a brain-enriched microRNA, has been reported to participate in the regulation of cell differentiation, but its potential roles in adipogenic and osteogenic differentiation of human mesenchymal stem cells (hMSCs) have not been addressed. OBJECTIVE: The study was conducted to investigate the effects and mechanism of miR-128 on adipogenic and osteogenic differentiation of hMSCs. MATERIALS AND METHODS: Morphology of hMSCs, lipid droplets and calcium nodules were observed and photographed by LSM microscopy. Expression of CCAAT/enhancer binding protein-alpha (C/EBPalpha), peroxisome proliferator activated receptor-gamma (PPARgamma), miR-128, vascular endothelial growth factor (VEGF), osteocalcin (OCN) and Runt-related transcription factor 2 (RUNX2) was determined by RNA preparation and reverse transcription polymerase chain reaction (RT-PCR), protein expression of VEGF was analyzed by Western blot. RESULTS: It was suggested that miR-128 expression showed a 4.56-fold induction by adipogenic treatment and a 58.8% reduction by osteogenic treatment. Over-expression of miR 128, promoted adipogenic differentiation while inhibited osteogenic differentiation. In contrast, adipocyte formation was inhibited and osteogenesis was enhanced in cells slicing miR-128. Furthermore, over-expression of miR-128 down-regulated VEGF expression in adipogenically and osteogenically differentiated cells. We further identified VEGF as a key regulator in miR-128 induced adipogenic and osteogenic differentiation. Following knockdown of VEGF, the effects of over-expression of miR-128 on adipogenic and osteogenic differentiation of hMSCs were limited. CONCLUSION: It was indicated that miR-128 could regulate adipogenic and osteogenic differentiation of hMSCs significantly through the suppression of VEGF pathway. PMID- 27485182 TI - Human gut microbiota plays a role in the metabolism of drugs. AB - BACKGROUND AND AIMS: The gut microbiome, an aggregate genome of trillions of microorganisms residing in the human gastrointestinal tract, is now known to play a critical role in human health and predisposition to disease. It is also involved in the biotransformation of xenobiotics and several recent studies have shown that the gut microbiota can affect the pharmacokinetics of orally taken drugs with implications for their oral bioavailability. METHODS: Review of Pubmed, Web of Science and Science Direct databases for the years 1957-2016. RESULTS AND CONCLUSIONS: Recent studies make it clear that the human gut microbiota can play a major role in the metabolism of xenobiotics and, the stability and oral bioavailability of drugs. Over the past 50 years, more than 30 drugs have been identified as a substrate for intestinal bacteria. Questions concerning the impact of the gut microbiota on drug metabolism, remain unanswered or only partially answered, namely (i) what are the molecular mechanisms and which bacterial species are involved? (ii) What is the impact of host genotype and environmental factors on the composition and function of the gut microbiota, (iii) To what extent is the composition of the intestinal microbiome stable, transmissible, and resilient to perturbation? (iv) Has past exposure to a given drug any impact on future microbial response, and, if so, for how long? Answering such questions should be an integral part of pharmaceutical research and personalised health care. PMID- 27485181 TI - Executive function in children with prenatal cocaine exposure (12-15years). AB - PURPOSE: Prenatal exposure to cocaine (PCE) may alter areas of the brain dense with monoamine receptors such as the prefrontal cortex and negatively affect cognitive processes implicated in executive function (EF). This study investigated the effects of PCE on EF at 12 and 15years. METHODS: EF was examined in 189 PCE and 183 non-cocaine exposed (NCE) children who were primarily African American and of low socioeconomic status. Caregivers rated their child on the Behavior Rating Inventory of Executive Function (BRIEF) at ages 12 and 15. The BRIEF includes two summary scales and eight subscales: Behavioral Regulation Index (BRI) (Inhibit, Shift, and Emotion) and Metacognition Index (MI) (Monitor, Working Memory, Plan/Organize, Organization of Materials and Task Completion). Two additional measures were included at age 15 (BRIEF Self-Report and the CANTAB Stockings of Cambridge (SOC)). RESULTS: Girls with PCE were perceived by caregivers to have more behavioral regulation problems at age 12 (p<0.005) and more metacognitive problems at age 12 (p<0.003) than NCE females, but there was no association for males. PCE girls improved in behavioral regulation (p<0.05) and metacognition (p<0.04) from 12 to 15years compared to NCE girls based on caregiver report. By self-report PCE was associated with problems of inhibition (p<0.006). Girls with PCE performed more poorly on number of moves to complete the SOC, requiring planning and problem solving, than NCE girls. CONCLUSION: Prenatally cocaine exposed girls were perceived by caregivers as having problems of behavioral regulation, and by self-report, inhibitory control problems. Girls with PCE also performed more poorly on a task of planning and problem solving at age 15 which corresponded to caregiver report at age 12. Early assessment and remediation of these weaknesses in girls may improve school performance and behavior associated with poor EF. PMID- 27485183 TI - The impact of cardiovascular drugs on the efficacy of local anesthesia in dentistry. AB - BACKGROUND AND AIM: Drugs used chronically by patients with diseases of the cardiovascular system (group C of the ATC classification) may act on adrenergic receptors and/or certain ion channels, which gives them the potential to interact with the action of local dental anesthetics. The aim of the study was to investigate the effect of systemically administered chronic cardiovascular medication (oral route) on the efficacy of intraoral local anesthesia in patients with diseases of the cardiovascular system. PATIENTS AND METHODS: This was a prospective cohort study which analyzed the efficacy of local terminal anesthesia (onset of anesthesia, duration anesthetized area) in the upper jaw of 70 patients: 40 patients on medication for cardiovascular system disorders and 30 patients who were not using these drugs (the control group). The following cardiovascular drugs were used: beta blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, vasodilatators, diuretics, angiotensin receptor blockers, antiarrhythmics, statins and alfa blockers. RESULTS: The onset of anesthesia on the vestibular side was faster in those taking cardiovascular drugs (40.50+/-19.87 s) than the control patients (58.93+/-31.07 s; P = 0.004) and duration of anesthesia on this side was shorter. Although the difference was not significant, it was evident that on vestibular and palatal side the anesthetized area was more rapidly reduced in the patients taking cardiovascular drugs. The duration of cardiovascular therapy also had a significant impact on the anesthetized area. CONCLUSION: Drugs acting on cardiovascular system may influence the effect of local anesthetics used in dentistry, possibly through interaction with autonomic receptors and ion channels. PMID- 27485184 TI - Significant phenotype variability of congenital central hypoventilation syndrome in a family with polyalanine expansion mutation of the PHOX2B gene. AB - BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder resulting from mutations in the PHOX2B gene located on chromosome 4p12.3, characterized by hypoventilation secondary to missing responses to both hypercapnia and hypoxia. CASE REPORT: Proband. A girl, hospitalised 5 times for respiratory failure from 6 weeks old, presented at 4 years of age severe cyanosis related to pneumonia. Tracheostomy was done, and she was discharged home using a portable positive pressure ventilator during sleep. Proband's father: The father was retrospectively found out to suffer from severe headache and excessive daytime sleepiness. Molecular genetic evaluation of PHOX2B gene was performed and casual polyalanine repeat expansion mutation c.741_755dup15 in exon 3 was found both in proband and her father in heterozygous form. The proband's grandmother died of respiratory failure after administration of benzodiazepine at the age of fifty years. Considering the grandmother's history, she is highly suspected of having had CCHS as well. CONCLUSION: Repeated respiratory failure of girl was explained by PHOX2B mutation and Ondina curse. Proband's father has incompletely penetrated PHOX2B heterozygous mutation as well and proband's grandmother died probably from the consequences of drug interaction with PHOX2B mutated background as well. Both daughter and father currently require overnight mechanical ventilatory support. Although most PHOX2B mutations occur de novo, our case is a rare three generation family affected by autosomal dominant inheritance with incomplete penetrance manifested as the late-form of CCHS and proven PHOX2B mutation in two generations. PMID- 27485185 TI - SPECT/CT imaging in breast cancer - current status and challenges. AB - BACKGROUND: The increasing incidence of breast cancer worldwide raises the importance of improving imaging techniques for disease stratification after early lesion detection. SPECT/CT imaging is now widely available but its diagnostic potential is not fully utilized for more specific purposes including breast cancer patient stratification. METHODS AND RESULTS: A Pubmed search for both original and review articles related to the value of SPECT/CT in breast cancer patients and comparison to other diagnostic methods. 62 articles were found using the key words SPECT/CT, Fusion Image and Breast Cancer. Development of a new generation of SPECT/CT systems and their introduction into practice has changed the old diagnostic algorithm. The increasing importance of SPECT/CT in the detection of bone metastases is confirmed. The diagnostic accuracy of new SPECT/CT instruments in the diagnostics of bone metastases is nearly comparable to PET/CT scans. SPECT/CT is more widely available and costs less than PET. It is able not only to identify a sentinel lymph nodes in atypical localizations but also to detect sentinel lymph nodes non visualized on previous planar scans. SPECT/CT offers precise anatomic localization of sentinel lymph nodes, thereby facilitating surgery. Knowledge of precise sentinel lymph node localization can also be applied in radiotherapy. CONCLUSIONS: The role of hybrid SPECT/CT imaging in breast cancer patients is changing. It is a powerful modality for skeletal and nodal staging in breast cancer patients with important impact on therapy. PMID- 27485186 TI - Requirement of TLR4 signaling for the induction of a Th1 immune response elicited by oligomannose-coated liposomes. AB - We have previously demonstrated that administration of oligomannose-coated liposomes (OMLs), in which an antigen is encased, induce antigen-specific Th1 immune responses and CTLs. In the present study, we showed that TLR4 signaling is required for the induction of specific immune responses following OML administration. In C3H/HeJ mice, which express a dysfunctional TLR4, the antigen specific Th1 immune response could not be elicited following intraperitoneal administration of OVA-encased OMLs (OML/OVA). However, OML uptake by peritoneal cells, the subsequent production of IL-12 and the upregulation of co-stimulatory molecules and MHC class II on the cells in response to OML uptake occurred in C3H/HeJ mice to the same extent as in wild type C3H/HeN mice. In addition, peritoneal phagocytic cells from TLR4(-/-) mice that ingest OML/OVA can activate CD4(+) T cells from OT-II mice. On the other hand, the number of OML-ingesting peritoneal cells that migrated into mesenteric lymph nodes in C3H/HeJ mice was significantly less than that in C3H/HeN mice. Therefore, the chemotactic capability of OML-ingesting peritoneal phagocytes to the draining lymph nodes rather than the activation and maturation of the cells in response to OML uptake is impaired by lack of TLR4 signaling, and disorder of the Th1 immune response elicited by OMLs in mice, which lack TLR4 signaling, is due to the impairment of cell migration following OML uptake. PMID- 27485187 TI - Regulation of B cell functions by Toll-like receptors and complement. AB - B cell functions triggered by the clonally-rearranged antigen-specific B cell receptor (BCR) are regulated by several germ-line encoded receptors - including Toll-like receptors (TLRs) and complement receptors (CRs). Simultaneous or sequential engagement of these structures expressed either on the cell membrane or intracellularly, may fundamentally alter and fine tune activation, antibody and cytokine production of B cells. Here we review the expression and function of TLRs and various C3 fragment binding CRs on B cells, emphasizing their role in different human B cell subsets under physiological and pathological conditions. Studies underlining the importance of the crosstalk between TLRs and CRs in regulating B cell functions are also highlighted. PMID- 27485189 TI - Erratum to: Ethnic/Racial Disparities in the Fetal Growth Outcomes of Ecuadorian Newborns. PMID- 27485188 TI - Residential Environment for Outdoor Play Among Children in Latino Farmworker Families. AB - Child health and development benefit from physical activity. This analysis describes the residential play environment for children aged 2-4 years in farmworker families, their parent-reported levels of play and media time, and the association of residential environment with play and media time. Mothers with a child aged 2-4 years in farmworker families (n = 248) completed interviews over 2 years. Outcome measures were daily outdoor play time and media time. Measures of the residential environment included physical and social components. The mean min/day for outdoor play was 81.8 (SD 57.3) at baseline, 111.4 (SD 90.1) at year 1 follow-up, and 103.6 (SD 76.2) at year 2 follow-up. The mean media min/day at baseline was 83.8 (SD 64.3), 93.7 (SD 80.3) min/day at year 1 follow-up, and 59.9 min/day (SD (45.6) at year 2 follow-up. One additional person per bedroom was associated with 6 fewer min/day with media. The addition of each age appropriate toy was associated with an additional 12.3 min/day of outdoor play. An additional type of inappropriate media was associated with 6.8 more min/day with media. These results suggest changes to the residential environment to improve physical activity among children in Latino farmworker families. PMID- 27485190 TI - Coulomb Screening and Coherent Phonon in Methylammonium Lead Iodide Perovskites. AB - Methylammonium lead iodide (CH3NH3PbI3) hybrid perovskite in the tetragonal and orthorhombic phases have different exciton binding energies and demonstrate different excitation kinetics. Here, we explore the role that crystal structure plays in the kinetics via fluence dependent transient absorption spectroscopy. We observe stronger saturation of the free carrier concentration under high pump energy density in the orthorhombic phase relative to the tetragonal phase. We attribute this phenomenon to small dielectric constant, large exciton binding energy, and weak Coulomb screening, which results in difficult exciton dissociation under high light intensity in the orthorhombic phase. At higher excitation intensities, we observe a coherent phonon with an oscillation frequency of 23.4 cm(-1) at 77 K, whose amplitude tracks the increase of the first-order lifetime. PMID- 27485191 TI - Instructive percutaneous coronary intervention to avoid the risk of side branch occlusion at a lesion with a lotus root appearance: a case report. AB - BACKGROUND: A lotus root appearance is a rare entity, and there is little opportunity to perform coronary intervention for this kind of lesion. Because of its peculiar anatomical characteristics, one of the problems regarding percutaneous coronary intervention (PCI) for these lesions is related to the involvement of branch vessels. CASE PRESENTATION: We encountered a case of PCI for a stenotic lesion with a lotus root appearance in the mid-portion of the right coronary artery (RCA). To avoid the risk of right ventricular (RV) branch occlusion due to stent deployment in the main RCA, we re-crossed the third guidewire into the main RCA via the nearest point to the RV branch ostium through the communicating vascular lumen. Thereafter, we deployed a drug-eluting stent in the main RCA crossing over the RV branch, and the ostium of the RV branch remained intact, as we expected. CONCLUSIONS: This case is the first report in the world describing the details of how to maintain the patency of the side branch bifurcating from a lesion with a lotus root appearance under optical coherence tomography guidance. PMID- 27485193 TI - Molecular Informatics Going "Fully Online". PMID- 27485192 TI - Abdomen/pelvis computed tomography in staging of pediatric Hodgkin Lymphoma: is it always necessary? AB - The purpose of the study was to determine if abdomen/pelvis computed tomography (CT) can be safety omitted in the initial staging of a subgroup of children affected by Hodgkin Lymphoma (HL). Every participating center of A.I.E.O.P (Associazione Italiana di Ematologia ed Oncologia Pediatrica) sent local staging reports of 18F-fluorodeoxyglucose positron emission tomography (PET) and abdominal ultrasound (US) along with digital images of staging abdomen/pelvis CT to the investigation center where the CT scans were evaluated by an experienced pediatric radiologist. The local radiologist who performed the US was unaware of local CT and PET reports (both carried out after US), and the reviewer radiologist examining the CT images was unaware of local US, PET and CT reports. A new abdominal staging of 123 patients performed on the basis of local US report, local PET report, and centralized CT report was then compared to a simpler staging based on local US and PET. No additional lesion was discovered by CT in patients with abdomen/pelvis negativity in both US and PET or isolated spleen positivity in US (or US and PET), and so it seems that in the initial staging, abdomen/pelvis CT can be safety omitted in about 1/2 to 2/3 of children diagnosed with HL. PMID- 27485194 TI - Bilinear Model for the Size-Dependency of the CYP3A4 Inhibitory Activity of Structurally Diverse Compounds. AB - A quantitative structure-activity relationship analysis of the inhibitory activity of structurally diverse compounds on recombinant human CYP3A4 is presented using a bilinear approach based on our previously developed LinBiExp model. Using only two main descriptors, molecular size and an indicator variable for the presence of triazole/imidazole moieties, this approach can account for close to 65 % of the variability in the inhibitory activity of more than 70 compounds and provides clear evidence that molecular size plays an important, but nonlinear role. Strongest inhibitory activity is likely to occur for compounds close to an optimal size, which is roughly that of the well-know CYP3A4-inhibitor ketoconazole. The activity-limiting role of size was also confirmed on a large dataset of 3438 compounds (PubChem Bioassay AID 884). This model provides a simple, intuitive interpretation and can serve as the starting point for more complex descriptions of the CYP3A4 inhibitory activity. PMID- 27485195 TI - Pharmacophore Model Refinement for 11beta-Hydroxysteroid Dehydrogenase Inhibitors: Search for Modulators of Intracellular Glucocorticoid Concentrations. AB - 11beta-Hydroxysteroid dehydrogenases (11beta-HSD) control the intracellular concentrations of glucocorticoids: 11beta-HSD1 converts the inactive cortisone to the active cortisol, and 11beta-HSD2 is responsible for the opposite reaction. Inhibition of 11beta-HSD1 is beneficial in the treatment of metabolic syndrome, whereas 11beta-HSD2 inhibition leads to hypertension. Therefore, 11beta-HSD1 inhibitors should be selective over 11beta-HSD2. To support drug discovery and toxicological studies, we have previously reported pharmacophore models for 11beta-HSD1 and 2 inhibition. These models represent the common chemical features of 11beta-HSD inhibitors, which were used as virtual screening filter. Since new inhibitors are constantly discovered, the quality of the pharmacophore models has to be evaluated in order to maintain a good predictive power. In this study, we report a systematic evaluation and refinement of our pharmacophore model collection. We employed our models for virtual screening, especially focusing on the 11beta-HSD2 inhibition. In total, 42 compounds were biologically evaluated and among these we discovered 17 11beta-HSD inhibitors that decreased the residual enzyme activity to 50% or less at the concentration of 20 uM. The experimental 11beta-HSD1 and 2 readouts from these compounds were used for further model refinement. Evaluation metrics were applied for a quantitative comparison of the old and newly generated models which resulted in a set of improved pharmacophore models offering reliable in silico tools for the identification of novel and selective 11beta-HSD inhibitors. PMID- 27485196 TI - Applicability Domain Dependent Predictive Uncertainty in QSAR Regressions. AB - Predictive models used in decision making, such as QSARs in chemical regulation or drug discovery, call for evaluated approaches to quantitatively assess associated uncertainty in predictions. Uncertainty in less reliable predictions may be captured by locally varying predictive errors. In the current study, model based bootstrapping was combined with analogy reasoning to generate predictive distributions varying in magnitude over a model's domain of applicability. A resampling experiment based on PLS regressions on four QSAR data sets demonstrated that predictive errors assessed by k nearest neighbour or weighted PRedicted Error Sum of Squares (PRESS) on samples of external test data or by internal cross-validation improved the performance of the uncertainty assessment. Analogy using similarity defined by Euclidean distances, or differences in standard deviation in perturbed predictions, resulted in better performances than similarity defined by distance to, or density of, the training data. Locally assessed predictive distributions had on average at least as good coverage as Gaussian distribution with variance assessed from the PRESS. An R-code is provided that evaluates performances of the suggested algorithms to assess predictive error based on log likelihood scores and empirical coverage graphs, and which applies these to derive confidence intervals or samples from the predictive distributions of query compounds. PMID- 27485197 TI - Application of EMBM to Structure-Based Design of Warheads for Protease Inhibitors. AB - Most CADD tools handle non-covalent enzyme inhibitors, despite the growing interest of the pharma industry in covalent inhibitors. We have recently introduced an enzyme mechanism-based method, EMBM, as a computational tool for binding trend analysis and prediction of chemical sites (CS) of reversible covalent enzyme inhibitors. In the current study we demonstrate the utility of EMBM to structure-based applications. In this mode, the energy of the enzyme inhibitor covalent bond is accounted for by the W1 and W2 covalent descriptors we have developed, whereas the non-covalent interactions between the inhibitor CS and the enzyme active site can be estimated directly on the 3D structure of the enzyme-inhibitor complex. PMID- 27485198 TI - Integrating Computational Modeling and Experimental Assay to Discover New Potent ACE-Inhibitory Peptides. AB - Human angiotensin-I-converting enzyme (ACE) is an important target of antihypertensive therapy, which possesses a bulky, hydrophobic pocket that is physicochemically compatible with a wide variety of peptide substrates and small molecule ligands. Rational design of potent ACE inhibitors has long been an attractive topic in the chemical, biological and medical communities. In the present study, an integrative protocol is described to optimize and modify peptides bound with ACE based on their complex three-dimensional structures. The protocol combines a number of sophisticated computational methods including molecular dynamics (MD) simulation, quantitative structure-activity relationship (QSAR), molecular mechanics/Poisson-Boltzmann surface area (MM-PB/SA) and quantum mechanics/molecular mechanics (QM/MM) to discover new potent ACE-inhibitory peptides. With this strategy hundreds of potential peptides are generated virtually, from which several promising candidates are synthesized and assayed in vitro using a standard Fmoc -protected amino acid solid phase synthesis and spectrophotometric method, respectively. Six peptides are found to have potency against ACE, four of which (LVY, VLKP, MLPVY and LKIPLY) show satisfactory inhibitory capability (pIC50 =5.84, 5.27, 5.40 and 5.57, respectively). Subsequently, the complex structures of tripeptide LVY and hexapeptide LKIPLY with ACE are computationally modeled and their binding free energies are estimated as - 34.2 and - 57.8 kcal/mol, respectively, by using a rigorous QM/MM scheme. Intensive steric collisions are observed around the C-terminus of peptide ligands in the bound state. Based upon the findings the C-terminal residues of the two peptides are modified to small, hydrophobic amino acids Val and Ala, resulting in mutated peptides LVA and LKIPVA, respectively. Consequently, a significant improvement in ACE-inhibitory activity is observed for the LKIPVA mutant (pIC50 increases from 5.57 to 6.07), whereas only a modest activity change was associated with the LVA mutant (pIC50 decreases from 5.84 to 5.80). PMID- 27485199 TI - Alkylphosphocholines as Promising Antitumor Agents: Exploring the Role of Structural Features on the Hemolytic Potential. AB - Alkylphosphocholines (APC) are promising antitumor agents, which have the cellular membrane as primary target; however, red blood cell damage limits their wide therapeutic use. A variety of APC analogs has been synthesized and tested showing less hemolytic effect than the class prototype, Miltefosine (HePC). In this work, chemometric methods were applied to a set of 34 APC derivatives to identify the most relevant structural and molecular features of hemolytic activity. The APC derivatives were divided into three groups: (i) N methylpiperidine and N-methylmorpholine derivatives with a long alkyl chain or flexible cyclopentadecyl rings, displaying a hemolytic rate of 17 %; (ii) adamantyl and cyclopentadecyl derivatives, showing an average hemolysis of 39 %; and, N,N,N-trimethylammonium, trans-N,N,N-trimethylcyclohexanamine, and trans N,N,N-trimethylcyclopentanamine derivatives, whose average hemolysis was 41 %. The findings suggested that the presence of either bulky cationic head groups, or rings such as adamantyl and cyclohexyl, primarily increases the hemolysis of compounds with eleven atoms in the alkyl chain. Moreover, the macrocyclic cyclopentadecyl seems to be important to the hemolytic potential especially of compounds with five carbon atoms in the alkyl chain. Regarding linear carbon chain derivatives with no ring substitution, less bulky cationic head groups seem to favor hemolysis. Thus, in order to design more potent and less toxic APC antitumors, the reported structural/molecular patterns should not be included in their structure. PMID- 27485200 TI - Prediction of Protein?Protein Interaction Pocket Using L-Shaped PLS Approach and Its Visualizations by Generative Topographic Mapping. AB - Protein?protein interaction (PPI) pockets in a host?guest protein system were predicted using an L-shaped partial least squares (LPLS) method. LPLS is an extension of standard PLS regression, where, in addition to response vector y and regressor matrix X, an extra data matrix Z is constructed which summarizes the background information on X. The regressor matrix X is a similarity matrix of Tanimoto coefficients of the paired fingerprints of pockets, while the background information Z constitutes eleven physico-chemical and geometrical parameters for describing a pocket. The Boolean response vector y specifies whether each pocket is PPI or non-PPI (indicated by 1 and 0, respectively). Constructing two LPLS models, we successfully predicted the PPI pockets of two protein clusters. Clusters 1 and 2 comprised the X-ray crystal structures of protein-peptide complexes and protein-protein complexes, respectively. From the loading plots derived from each model, we could speculate the geometrical constraints of the PPI pockets. These two models are exclusively unique and it was validated by the cross-prediction simulations. The PPI pockets of cluster 1 were projected onto 2D maps by generative topographic mapping (GTM) and the molecular lipophilic potentials (MLP). Among three examples, the MLP distributions were highly similar because the specimens shared the same p53 guest peptides. Contribution to the Autumn School of Chemoinformatics in Nara, Japan, November 27-28, 2013. PMID- 27485201 TI - Modeling the Biodegradability of Chemical Compounds Using the Online CHEmical Modeling Environment (OCHEM). AB - Biodegradability describes the capacity of substances to be mineralized by free living bacteria. It is a crucial property in estimating a compound's long-term impact on the environment. The ability to reliably predict biodegradability would reduce the need for laborious experimental testing. However, this endpoint is difficult to model due to unavailability or inconsistency of experimental data. Our approach makes use of the Online Chemical Modeling Environment (OCHEM) and its rich supply of machine learning methods and descriptor sets to build classification models for ready biodegradability. These models were analyzed to determine the relationship between characteristic structural properties and biodegradation activity. The distinguishing feature of the developed models is their ability to estimate the accuracy of prediction for each individual compound. The models developed using seven individual descriptor sets were combined in a consensus model, which provided the highest accuracy. The identified overrepresented structural fragments can be used by chemists to improve the biodegradability of new chemical compounds. The consensus model, the datasets used, and the calculated structural fragments are publicly available at http://ochem.eu/article/31660. PMID- 27485202 TI - Effect of evodiamine on the proliferation and apoptosis of A549 human lung cancer cells. AB - Evodia rutaecarpa is a plant, which has antitumor activity. Evodiamine is an alkaloid with antitumor activity present in E. rutaecarpa and has potential to be developed into a therapeutic antitumor agent. The present study investigated the effect of evodiamine on the proliferation of A549 human lung cancer cells and the mechanism underlying these effects. The results indicated that evodiamine significantly inhibited proliferation, induced apoptosis and the expression of reactive oxygen species, arrested the cell cycle, regulated the expression of Survivin, Bcl-2 and Cyclin B1, regulated the activity of caspase-3/8 and glutathione in tumor cells, and decreased the activity of AKT/nuclear factor kappaB (NF-kappaB) and Sonic hedgehog/GLI family zinc finger 1 (SHH/GLI1) signaling pathways in A549 cells. In conclusion, the evodiamine-induced inhibition of the proliferation of A549 lung cancer cells may be attributable to its ability to promote oxidative injury in the cells, induce apoptosis, arrest the cell cycle and regulate the AKT/NF-kappaB and SHH/GLI1 signaling pathways, subsequently controlling the expression of tumor-associated genes. PMID- 27485203 TI - Delimitating cryptic species in the Gracilaria domingensis complex (Gracilariaceae, Rhodophyta) using molecular and morphological data. AB - Species in the genus Gracilaria that display conspicuously flattened vegetative morphologies are a taxonomically challenging group of marine benthic red algae. This is a result of their species richness, morphological similarity, and broad phenotypic plasticity. Within this group, the Gracilaria domingensis complex is one of the most common, conspicuous, and morphologically variable species along the tropical western Atlantic Ocean. Previous research has identified that members of this complex belong to two distantly related clades. However, despite this increased phylogentic resolution, species delimitations within each of these clades remain unclear. Our study assessed the species diversity within this difficult complex using morphological and molecular data from three genetic markers (cox1, UPA, and rbcL). We additionally applied six single-marker species delimitation methods (SDM: ABGD, GMYCs, GMYCm, SPN, bPTP, and PTP) to rbcL, which were largely in agreement regarding species delimitation. These results, combined with our analysis of morphology, indicate that the G. domingensis complex includes seven distinct species, each of which are not all most closely related: G. cervicornis; a ressurected G. ferox; G. apiculata subsp. apiculata; a new species, Gracilaria baiana sp. nov.; G. intermedia subsp. intermedia; G. venezuelensis; and G. domingensis sensu stricto, which includes the later heterotypic synonym, G. yoneshigueana. Our study demonstrates the value of multipronged strategies, including the use of both molecular and morphological approaches, to decipher cryptic species of red algae. PMID- 27485205 TI - A high-resolution map of the gut microbiota in Atlantic salmon (Salmo salar): A basis for comparative gut microbial research. AB - Gut health challenges, possibly related to alterations in gut microbiota, caused by plant ingredients in the diets, cause losses in Atlantic salmon production. To investigate the role of the microbiota for gut function and health, detailed characterization of the gut microbiota is needed. We present the first in-depth characterization of salmon gut microbiota based on high-throughput sequencing of the 16S rRNA gene's V1-V2 region. Samples were taken from five intestinal compartments: digesta from proximal, mid and distal intestine and of mucosa from mid and distal intestine of 67.3 g salmon kept in seawater (12-14 degrees C) and fed a commercial diet for 4 weeks. Microbial richness and diversity differed significantly and were higher in the digesta than the mucosa. In mucosa, Proteobacteria dominated the microbiota (90%), whereas in digesta both Proteobacteria (47%) and Firmicutes (38%) showed high abundance. Future studies of diet and environmental impacts on gut microbiota should therefore differentiate between effects on mucosa and digesta in the proximal, mid and the distal intestine. A core microbiota, represented by 22 OTUs, was found in 80% of the samples. The gut microbiota of Atlantic salmon showed similarities with that of mammals. PMID- 27485204 TI - PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis. AB - Many types of human tumour cells overexpress the dual-specificity phosphatase Cdc25A. Cdc25A dephosphorylates cyclin-dependent kinase and regulates the cell cycle, but other substrates of Cdc25A and their relevant cellular functions have yet to be identified. We demonstrate here that EGFR activation results in c-Src mediated Cdc25A phosphorylation at Y59, which interacts with nuclear pyruvate kinase M2 (PKM2). Cdc25A dephosphorylates PKM2 at S37, and promotes PKM2 dependent beta-catenin transactivation and c-Myc-upregulated expression of the glycolytic genes GLUT1, PKM2 and LDHA, and of CDC25A; thus, Cdc25A upregulates itself in a positive feedback loop. Cdc25A-mediated PKM2 dephosphorylation promotes the Warburg effect, cell proliferation and brain tumorigenesis. In addition, we identify positive correlations among Cdc25A Y59 phosphorylation, Cdc25A and PKM2 in human glioblastoma specimens. Furthermore, levels of Cdc25A Y59 phosphorylation correlate with grades of glioma malignancy and prognosis. These findings reveal an instrumental function of Cdc25A in controlling cell metabolism, which is essential for EGFR-promoted tumorigenesis. PMID- 27485206 TI - Polybrominated diphenylethers (PBDEs) and their hydroxylated metabolites (OH PBDEs) in female serum from Dalian, China. AB - Seven polybrominated diphenyl ethers (PBDEs) and eleven hydroxylated PBDEs (OH PBDEs) were selected to investigate their contamination status in 32 female serum samples from Dalian, China. These studied PBDEs and OH-PBDEs were found in most of the serum samples with the concentrations of SigmaPBDEs and SigmaOH-PBDEs ranging from 1.07 to 38.7ng/g lipid (median: 5.56ng/g lipid) and from 0.011 to 0.436ng/g lipid (median: 0.069ng/g lipid), respectively. More impressively, BDE 47 and OH-BDE-47 were the predominant congeners in female serum, accounting for 52% of SigmaPBDEs and 46% of SigmaOH-PBDEs, respectively. Correspondence analysis indicated that significant (p<0.05) positive correlations were observed between BDE-47 and its metabolites such as 6-OH-BDE-47, 3-OH-BDE-47 and 4'-OH-BDE-49. In addition, the positive significant (p<0.05) correlation was shown between ?PBDEs and lipid contents but between concentrations of ?PBDEs and ages or BMIs, as well as for ?OH-PBDEs. PMID- 27485208 TI - Pituitary response to thyrotropin releasing hormone in children with overweight and obesity. AB - Thyroid stimulating hormone (TSH) concentrations in the high normal range are common in children with overweight and obesity, and associated with increased cardiovascular disease risk. Prior studies aiming at unravelling the mechanisms underlying these high TSH concentrations mainly focused on factors promoting thyrotropin releasing hormone (TRH) production as a cause for high TSH concentrations. However, it is unknown whether TSH release of the pituitary in response to TRH is affected in children with overweight and obesity. Here we describe TSH release of the pituitary in response to exogenous TRH in 73 euthyroid children (39% males) with overweight or (morbid) obesity. Baseline TSH concentrations (0.9-5.5 mU/L) were not associated with BMI z score, whereas these concentrations were positively associated with TSH concentrations 20 minutes after TRH administration (r(2) = 0.484, p < 0.001) and the TSH incremental area under the curve during the TRH stimulation test (r(2) = 0.307, p < 0.001). These results suggest that pituitary TSH release in response to TRH stimulation might be an important factor contributing to high normal serum TSH concentrations, which is a regular finding in children with overweight and obesity. The clinical significance and the intermediate factors contributing to pituitary TSH release need to be elucidated in future studies. PMID- 27485209 TI - Tracking tool for frailty: ABCDEF. AB - The aging population leads to psychological, medical and social reflection for optimal care of the elderly, especially characterized by a frailty state. The frailty is the cause of morbi-mortality require screening to anticipate these complications. The objective was to evaluate the statistical performance and feasibility of the tool "ABCDEF" to screen frailty defined by Fried's criteria. A prospective multicenter study including 300 ambulatory elderly consultants was conducted. ABCDEF appears feasible without major prior training or special equipment by any doctor or caregiver during an assessment in 98% of consultants. His sensitivity to detect frailty, is of 75% and specificity of 64%. The frailty tracking threshold is 3 criteria (6). Its negative predictive value is interesting because it eliminates the hypothesis of frailty in 91% of cases. This tracking tool requires, when abnormal, further geriatric assessment. It provides a standardized and normative approach to describe frailty whose frequency is high in people older than 80 and whose consequences are major. PMID- 27485207 TI - Genetic analysis of variation in lifespan using a multiparental advanced intercross Drosophila mapping population. AB - BACKGROUND: Considerable natural variation for lifespan exists within human and animal populations. Genetically dissecting this variation can elucidate the pathways and genes involved in aging, and help uncover the genetic mechanisms underlying risk for age-related diseases. Studying aging in model systems is attractive due to their relatively short lifespan, and the ability to carry out programmed crosses under environmentally-controlled conditions. Here we investigate the genetic architecture of lifespan using the Drosophila Synthetic Population Resource (DSPR), a multiparental advanced intercross mapping population. RESULTS: We measured lifespan in females from 805 DSPR lines, mapping five QTL (Quantitative Trait Loci) that each contribute 4-5 % to among-line lifespan variation in the DSPR. Each of these QTL co-localizes with the position of at least one QTL mapped in 13 previous studies of lifespan variation in flies. However, given that these studies implicate >90 % of the genome in the control of lifespan, this level of overlap is unsurprising. DSPR QTL intervals harbor 11-155 protein-coding genes, and we used RNAseq on samples of young and old flies to help resolve pathways affecting lifespan, and identify potentially causative loci present within mapped QTL intervals. Broad age-related patterns of expression revealed by these data recapitulate results from previous work. For example, we see an increase in antimicrobial defense gene expression with age, and a decrease in expression of genes involved in the electron transport chain. Several genes within QTL intervals are highlighted by our RNAseq data, such as Relish, a critical immune response gene, that shows increased expression with age, and UQCR 14, a gene involved in mitochondrial electron transport, that has reduced expression in older flies. CONCLUSIONS: The five QTL we isolate collectively explain a considerable fraction of the genetic variation for female lifespan in the DSPR, and implicate modest numbers of genes. In several cases the candidate loci we highlight reside in biological pathways already implicated in the control of lifespan variation. Thus, our results provide further evidence that functional genetics tests targeting these genes will be fruitful, lead to the identification of natural sequence variants contributing to lifespan variation, and help uncover the mechanisms of aging. PMID- 27485210 TI - Highly Efficient Multiphoton-Pumped Frequency-Upconversion Stimulated Blue Emission with Ultralow Threshold from Highly Extended Ladder-Type Oligo(p phenylene)s. AB - A series of highly extended pi-conjugated ladder-type oligo(p-phenylene)s containing up to 10 phenyl rings with (L)-Ph(n)-NPh (n=7-10) or without diphenylamino endcaps (L)-Ph(n) (n=7 and 8) were synthesized and investigated for their multiphoton absorption properties for frequency upconverted blue ASE/lasing. Extremely large two-photon absorption (2PA) cross-sections and highly efficient 2PA ASE/lasing with ultralow threshold were achieved. (L)-Ph(10)-NPh exhibits the highest intrinsic 2PA cross-section of 3643 GM for a blue emissive organic fluorophore reported so far. The record-high 2PA pumped ASE/lasing efficiency of 2.06 % was obtained by un-endcapped oligomer, (L)-Ph(8) rather than that with larger sigma2 , suggesting that a molecule with larger sigma2 is not guaranteed to exhibit higher eta2 . All of these oligomers exhibit exceptionally ultralow 2PA pumped ASE/lasing thresholds, among which the lowest 2PA pumped threshold of circa 0.26 MUJ was achieved by (L)-Ph(10)-NPh. PMID- 27485211 TI - Low prevalence of dihydro folate reductase (dhfr) and dihydropteroate synthase (dhps) quadruple and quintuple mutant alleles associated with SP resistance in Plasmodium vivax isolates of West Bengal, India. AB - BACKGROUND: Emergence of chloroquine resistant Plasmodium vivax is a serious obstacle towards malaria control in India. This study elucidates the temporal pattern of antifolate [sulfadoxine-pyrimethamine (SP)] resistance in P. vivax infection by means of genetic polymorphisms, especially analysing the single nucleotide polymorphisms of dihydrofolate reductase (pvdhfr) and dihydropteroate synthase (pvdhps) gene among the field isolates of urban Kolkata Municipal Corporation and rural Purulia region of West Bengal, India. METHODS: Blood samples were collected from 99 microscopically diagnosed P. vivax patients (52 from Kolkata Municipal Corporation and 47 from Purulia). Parasitic DNA was extracted followed by polymerase chain reaction and sequencing of different codons of pvdhfr gene (15, 33, 50, 57, 58, 61, 64, 117, and 173 codons) and pvdhps gene (373, 380, 382, 383, 384, 512, 553, 585, and 601 codons) were performed to identify the mutations. RESULTS: Prevalence of double mutant dhfr A15P33N50F57 R 58 T61V64 N 117 I173 allele (53.85 %) was observed in Kolkata Municipal Corporation (KMC) whereas in Purulia, wild dhfr A15P33N50F57S58T61V64S117I173 allele was predominated (48.94 %). In pvdhps gene a significant number of isolates (17.31 %) in KMC contained the double mutant S373E380S382 G 383 P384K512 G 553 V585M601 allele. pvdhfr and pvdhps combination haplotype revealed the emergence of quadruple (13.46 %) and quintuple (3.84 %) mutant allele in KMC, which might result in poor clinical response against antifolate drugs. CONCLUSION: The study reveals that P. vivax parasites in rural Purulia may still be susceptible to SP but additional caution should be taken for treatment of vivax malaria in KMC to limit the blooming of quadruple and quintuple mutant allele in the remainder of the West Bengal, India. PMID- 27485212 TI - Acute upregulation of neuronal mitochondrial type-1 cannabinoid receptor and it's role in metabolic defects and neuronal apoptosis after TBI. AB - Metabolic defects and neuronal apoptosis initiated by traumatic brain injury (TBI) contribute to subsequent neurodegeneration. They are all regulated by mechanisms centered around mitochondrion. Type-1 cannabinoid receptor (CB1) is a G-protein coupled receptor (GPCR) enriched on neuronal plasma membrane. Recent evidences point to the substantial presence of CB1 receptors on neuronal mitochondrial outer membranes (mtCB1) and the activation of mtCB1 influences aerobic respiration via inhibiting mitochondrial cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/complex I pathway. The expression and role of neuronal mtCB1 under TBI are unknown. Using TBI models of cultured neurons, wild type and CB1 knockout mice, we found mtCB1 quickly upregulated after TBI. Activation of mtCB1 promoted metabolic defects accompanied with ATP shortage but protected neurons from apoptosis. Selective activation of plasma membrane CB1 showed no effects on neuronal metabolism and apoptosis. Activation of mtCB1 receptors inhibited mitochondrial cAMP/PKA/complex I and resulted in exacerbated metabolic defects accompanied with a higher ratio of ATP reduction to oxygen consumption decrease as well as neuronal apoptosis. Further research found the remarkable accumulation of protein kinase B (AKT) on neuronal mitochondria following TBI and the activation of mtCB1 upregulated mitochondrial AKT/complex V activity. Upregulation of mitochondrial AKT/complex V activity showed anti apoptosis effects and alleviated ATP shortage in metabolic defects. Taken together, we have identified mtCB1 quickly upregulate after TBI and a dual role the mtCB1 might play in metabolic defects and neuronal apoptosis initiated by TBI: the inhibition of mitochondrial cAMP/PKA/complex I aggravates metabolic defects, energy insufficiency as well as neuronal apoptosis, but the coactivation of mitochondrial AKT/complex V mitigates energy insufficiency and neuronal apoptosis. PMID- 27485213 TI - The impact of identifying carotid plaque on addressing cardiovascular risk in psoriatic arthritis. AB - BACKGROUND: Patients with psoriatic arthritis (PsA) are at an increased risk for cardiovascular (CV) disease. The aim of this study was to identify the frequency of carotid plaque in asymptomatic patients with psoriatic arthritis at baseline and follow-up screening, and to assess for the impact of demonstrating plaque on management of traditional cardiovascular risk factors. METHODS: Eighty-seven PsA patients underwent carotid duplex ultrasound screening. Repeat carotid duplex ultrasound was offered to all patients between 12 and 30 months. Preventive cardiology referrals were generated for all patients through the electronic health record. Traditional cardiovascular risk factors, medication use, and rates of utilization of preventive cardiology services were compared between patients with and without plaque. RESULTS: Carotid plaque was identified in 34/87 (39 %) of PsA patients. Age and triglyceride levels were predictors of plaque presence. Patients with plaque trended toward higher rates of smoking and diabetes, and higher low-density lipoprotein levels. Only 9/87 (10 %) patients completed at least one visit with preventive cardiology after enrollment despite referral. Low use of statin (21 %) and antiplatelet (27 %) medication was observed. Rates of biologic medication use for PsA were higher (75 %) than studies in similar cohorts of patients with carotid plaque. No association was seen between disease duration or activity and the presence of carotid plaque. CONCLUSION: Despite demonstration of high cardiac risk by the presence of carotid plaque, implementation of preventive cardiovascular services and rates of statin and antiplatelet use remained low. Age and triglyceride levels were significant variables in predicting plaque presence. There is no evidence that demonstration of plaque resulted in further evaluation or changes in treatment regimens to address heightened cardiovascular risk. PMID- 27485214 TI - Relative abdominal adiposity is associated with chronic low back pain: a preliminary explorative study. AB - BACKGROUND: Although previous research suggests a relationship between chronic low back pain (cLBP) and adiposity, this relationship is poorly understood. No research has explored the relationship between abdominal-specific subcutaneous and visceral adiposity with pain and disability in cLBP individuals. The aim of this study therefore was to examine the relationship of regional and total body adiposity to pain and disability in cLBP individuals. METHODS: A preliminary explorative study design of seventy (n = 70) adult men and women with cLBP was employed. Anthropometric and adiposity measures were collected, including body mass index, waist-to-hip ratio, total body adiposity and specific ultrasound based abdominal adiposity measurements. Self-reported pain and disability were measured using a Visual Analogue Scale (VAS) and the Oswestry Disability Index (ODI) questionnaires respectively. Relationships between anthropometric and adiposity measures with pain and disability were assessed using correlation and regression analyses. RESULTS: Significant correlations between abdominal to lumbar adiposity ratio (A-L) variables and the waist-to-hip ratio with self reported pain were observed. A-L variables were found to predict pain, with 9.1 30.5 % of the variance in pain across the three analysis models explained by these variables. No relationships between anthropometric or adiposity variables to self-reported disability were identified. CONCLUSIONS: The findings of this study indicated that regional distribution of adiposity via the A-L is associated with cLBP, providing a rationale for future research on adiposity and cLBP. PMID- 27485215 TI - 10-Year experience regarding the reliability and morbidity of radio guided lymph node biopsy in penile cancer patients and the associated radiation exposure of medical staff in this procedure. AB - BACKGROUND: The guidelines of the European Association of Urologists (EAU), of the German Society of Nuclear Medicine (DGN), and the European Society for Medical Oncology (ESMO) recommend sentinel lymph node biopsy (SLNB) for lymph node staging in penile cancer with non-palpable inguinal lymph nodes as one diagnostic method. Despite this, the method is neither widely nor regularly applied in Germany - the same applies to many other countries, which may be due to insecurity in dealing with open radioactive tracers. This study aims to assess the reliability and morbidity of this method, as well as the associated radioactive burden for clinical staff. METHODS: Between 2006 and 2016, 34 patients with an invasive penile carcinoma and inconspicuous inguinal lymph node status underwent SLNB in 57 groins after application of a radiotracer (Tc-99 m nanocolloid). We collected the results prospectively. The reliability of the method was assessed by determining the false-negative rate. In addition, we evaluated complication rates and determined the radioactive burden for the clinical staff both pre- and intraoperatively. RESULTS: SLNB was performed in 34 patients with penile cancer with non-palpable inguinal lymph nodes in 57 groins. In two patients inguinal lymph node metastases were detected by means of SLNB. In one patient recurrent inguinal lymph node disease was found after negative SLNB in both groins. Thus, the false negative rate was 3.13 % per patient (1/32 patients) and 3.51 % per groin (2/57 groins). The morbidity rate was 2.94 % per patient (1/34 patients) and 1.75 % per groin (1/57 groins). Radiation exposure for the clinical staff during this procedure was low at a maximum of ca. four MUSV per intervention. CONCLUSIONS: SLNB is a reliable method with low morbidity that is associated with a low radiation burden for clinical staff. Due to the enhanced methodological and logistic demands, this intervention should be performed in specialized centres and in an interdisciplinary approach. PMID- 27485216 TI - Molecular analysis of myocilin and optineurin genes in Korean primary glaucoma patients. AB - To investigate the underlying genetic influences of primary glaucoma in Korea, molecular analysis was performed in 112 sporadic cases, and results compared with healthy controls. The myocilin (MYOC) and optineurin (OPTN) genes were directly sequenced in 112 unrelated patients, including 17 with primary open-angle glaucoma, 19 with juvenile open-angle glaucoma, and 76 with normal tension glaucoma. Healthy unrelated Korean individuals (n=100) were used as the non selected population control. A total of three MYOC and four OPTN variants potentially associated with primary glaucoma were identified in 4 and 18 patients, respectively. A novel variant of MYOC, p.Leu255Pro, was predicted to be potentially pathogenic by in silico analysis. Another, p.Thr353Ile, has been previously reported. These two missense variants were detected in patients with a family history of glaucoma. Combined heterozygous variants p.[Thr123=;Ile288=] were identified in 2 of 112 (2%) patients but not in healthy controls. Among OPTN variants, a novel variant p.Arg271Cys was identified. Homozygous p.[Thr34=;Thr34=] (4/112, 4%), homozygous p.[Met98Lys;Met98Lys] (4/112, 4%), or combined heterozygous p.[Thr34=;Arg545Gln] (9/112, 8%) was significantly associated with the development of primary glaucoma [odds ratio (OR)=8.768, 95% confidence interval (CI)=1.972-38.988; relative risk=1.818, 95% CI=1.473-2.244; P=0.001]. The present study provides insight into the genetic or haplotype variants of MYOC and OPTN genes contributing to primary glaucoma. Haplotype variants identified in the present study may be regarded as potential contributing factors of primary glaucoma in Korea. Further studies, including those on additional genes, are required to elucidate the underlying pathogenic mechanism using a larger cohort to provide additional statistical power. PMID- 27485218 TI - Biosynthesis of Carotenoids in Plants: Enzymes and Color. AB - Carotenoids are the most important biocolor isoprenoids responsible for yellow, orange and red colors found in nature. In plants, they are synthesized in plastids of photosynthetic and sink organs and are essential molecules for photosynthesis, photo-oxidative damage protection and phytohormone synthesis. Carotenoids also play important roles in human health and nutrition acting as vitamin A precursors and antioxidants. Biochemical and biophysical approaches in different plants models have provided significant advances in understanding the structural and functional roles of carotenoids in plants as well as the key points of regulation in their biosynthesis. To date, different plant models have been used to characterize the key genes and their regulation, which has increased the knowledge of the carotenoid metabolic pathway in plants. In this chapter a description of each step in the carotenoid synthesis pathway is presented and discussed. PMID- 27485217 TI - Carotenoid Distribution in Nature. AB - Carotenoids are naturally occurring red, orange and yellow pigments that are synthesized by plants and some microorganisms and fulfill many important physiological functions. This chapter describes the distribution of carotenoid in microorganisms, including bacteria, archaea, microalgae, filamentous fungi and yeasts. We will also focus on their functional aspects and applications, such as their nutritional value, their benefits for human and animal health and their potential protection against free radicals. The central metabolic pathway leading to the synthesis of carotenoids is described as the three following principal steps: (i) the synthesis of isopentenyl pyrophosphate and the formation of dimethylallyl pyrophosphate, (ii) the synthesis of geranylgeranyl pyrophosphate and (iii) the synthesis of carotenoids per se, highlighting the differences that have been found in several carotenogenic organisms and providing an evolutionary perspective. Finally, as an example, the synthesis of the xanthophyll astaxanthin is discussed. PMID- 27485219 TI - Structures and Analysis of Carotenoid Molecules. AB - Modifications of the usual C40 linear and symmetrical carotenoid skeleton give rise to a wide array of structures of carotenes and xanthophylls in plant tissues. These include acyclic, monocyclic and dicyclic carotenoids, along with hydroxy and epoxy xanthophylls and apocarotenoids. Carotenols can be unesterified or esterified (monoester) in one or two (diester) hydroxyl groups with fatty acids. E-Z isomerization increases the array of possible plant carotenoids even further. Screening and especially quantitative analysis are being carried out worldwide. Visible absorption spectrometry and near infrared reflectance spectroscopy have been used for the initial estimation of the total carotenoid content or the principal carotenoid content when large numbers of samples needed to be analyzed within a short time, as would be the case in breeding programs. Although inherently difficult, quantitative analysis of the individual carotenoids is essential. Knowledge of the sources of errors and means to avoid them has led to a large body of reliable quantitative compositional data on carotenoids. Reverse-phase HPLC with a photodiode array detector has been the preferred analytical technique, but UHPLC is increasingly employed. HPLC-MS has been used mainly for identification and NMR has been useful in unequivocally identifying geometric isomers. PMID- 27485220 TI - Carotenoids and Photosynthesis. AB - Carotenoids are ubiquitous and essential pigments in photosynthesis. They absorb in the blue-green region of the solar spectrum and transfer the absorbed energy to (bacterio-)chlorophylls, and so expand the wavelength range of light that is able to drive photosynthesis. This is an example of singlet-singlet energy transfer, and so carotenoids serve to enhance the overall efficiency of photosynthetic light reactions. Carotenoids also act to protect photosynthetic organisms from the harmful effects of excess exposure to light. Triplet-triplet energy transfer from chlorophylls to carotenoids plays a key role in this photoprotective reaction. In the light-harvesting pigment-protein complexes from purple photosynthetic bacteria and chlorophytes, carotenoids have an additional role of structural stabilization of those complexes. In this article we review what is currently known about how carotenoids discharge these functions. The molecular architecture of photosynthetic systems will be outlined first to provide a basis from which to describe carotenoid photochemistry, which underlies most of their important functions in photosynthesis. PMID- 27485221 TI - Regulation of Carotenoid Biosynthesis in Photosynthetic Organs. AB - A substantial proportion of the dazzling diversity of colors displayed by living organisms throughout the tree of life is determined by the presence of carotenoids, which most often provide distinctive yellow, orange and red hues. These metabolites play fundamental roles in nature that extend far beyond their importance as pigments. In photosynthetic lineages, carotenoids are essential to sustain life, since they have been exploited to maximize light harvesting and protect the photosynthetic machinery from photooxidative stress. Consequently, photosynthetic organisms have evolved several mechanisms that adjust the carotenoid metabolism to efficiently cope with constantly fluctuating light environments. This chapter will focus on the current knowledge concerning the regulation of the carotenoid biosynthetic pathway in leaves, which are the primary photosynthetic organs of most land plants. PMID- 27485222 TI - Regulation of Carotenoid Biosynthesis During Fruit Development. AB - Carotenoids are recognized as the main pigments in most fruit crops, providing colours that range from yellow and pink to deep orange and red. Moreover, the edible portion of widely consumed fruits or their derived products represent a major dietary source of carotenoids for animals and humans. Therefore, these pigments are crucial compounds contributing to fruit aesthetic and nutritional quality but may also have protecting and ecophysiological functions in coloured fruits. Among plant organs, fruits display one of the most heterogeneous carotenoids patterns in terms of diversity and abundance. In this chapter a comprehensive list of the carotenoid content and profile in the most commonly cultivated fleshy fruits is reported. The proposed fruit classification systems attending to carotenoid composition are revised and discussed. The regulation of carotenoids in fruits can be rather complex due to the dramatic changes in content and composition during ripening, which are also dependent on the fruit tissue and the developmental stage. In addition, carotenoid accumulation is a dynamic process, associated with the development of chromoplasts during ripening. As a general rule, carotenoid accumulation is highly controlled at the transcriptional level of the structural and accessory proteins of the biosynthetic and degradation pathways, but other mechanisms such as post transcriptional modifications or the development of sink structures have been recently revealed as crucial factors in determining the levels and stability of these pigments. In this chapter common key metabolic reactions regulating carotenoid composition in fruit tissues are described in addition to others that are restricted to certain species and generate unique carotenoids patterns. The existence of fruit-specific isoforms for key steps such as the phytoene synthase, lycopene beta-cyclases or catabolic carotenoid cleavage dioxygenases has allowed an independent regulation of the pathway in fruit tissues and a source of variability to create novel activities or different catalytic properties. Besides key genes of the carotenoid pathway, changes in carotenoid accumulation could be also directly influenced by differences in gene expression or protein activity in the pathway of carotenoid precursors and some relevant examples are discussed. The objective of this chapter is to provide an updated review of the main carotenoid profiles in fleshy fruits, their pattern of changes during ripening and our current understanding of the different regulatory levels responsible for the diversity of carotenoid accumulation in fruit tissues. PMID- 27485223 TI - Carotenoid Biosynthesis in Daucus carota. AB - Carrot (Daucus carota) is one of the most important vegetable cultivated worldwide and the main source of dietary provitamin A. Contrary to other plants, almost all carrot varieties accumulate massive amounts of carotenoids in the root, resulting in a wide variety of colors, including those with purple, yellow, white, red and orange roots. During the first weeks of development the root, grown in darkness, is thin and pale and devoid of carotenoids. At the second month, the thickening of the root and the accumulation of carotenoids begins, and it reaches its highest level at 3 months of development. This normal root thickening and carotenoid accumulation can be completely altered when roots are grown in light, in which chromoplasts differentiation is redirected to chloroplasts development in accordance with an altered carotenoid profile. Here we discuss the current evidence on the biosynthesis of carotenoid in carrot roots in response to environmental cues that has contributed to our understanding of the mechanism that regulates the accumulation of carotenoids, as well as the carotenogenic gene expression and root development in D. carota. PMID- 27485224 TI - Carotenoids in Microalgae. AB - Carotenoids are a class of isoprenoids synthesized by all photosynthetic organisms as well as by some non-photosynthetic bacteria and fungi with broad applications in food, feed and cosmetics, and also in the nutraceutical and pharmaceutical industries. Microalgae represent an important source of high-value products, which include carotenoids, among others. Carotenoids play key roles in light harvesting and energy transfer during photosynthesis and in the protection of the photosynthetic apparatus against photooxidative damage. Carotenoids are generally divided into carotenes and xanthophyls, but accumulation in microalgae can also be classified as primary (essential for survival) and secondary (by exposure to specific stimuli).In this chapter, we outline the high value carotenoids produced by commercially important microalgae, their production pathways, the improved production rates that can be achieved by genetic engineering as well as their biotechnological applications. PMID- 27485226 TI - Plastids and Carotenoid Accumulation. AB - Plastids are ubiquitously present in plants and are the organelles for carotenoid biosynthesis and storage. Based on their morphology and function, plastids are classified into various types, i.e. proplastids, etioplasts, chloroplasts, amyloplasts, and chromoplasts. All plastids, except proplastids, can synthesize carotenoids. However, plastid types have a profound effect on carotenoid accumulation and stability. In this chapter, we discuss carotenoid biosynthesis and regulation in various plastids with a focus on carotenoids in chromoplasts. Plastid transition related to carotenoid biosynthesis and the different capacity of various plastids to sequester carotenoids and the associated effect on carotenoid stability are described in light of carotenoid accumulation in plants. PMID- 27485225 TI - Apocarotenoids: A New Carotenoid-Derived Pathway. AB - Carotenoids are precursors of carotenoid derived molecules termed apocarotenoids, which include isoprenoids with important functions in plant-environment interactions such as the attraction of pollinators and the defense against pathogens and herbivores. Apocarotenoids also include volatile aromatic compounds that act as repellents, chemoattractants, growth simulators and inhibitors, as well as the phytohormones abscisic acid and strigolactones. In plants, apocarotenoids can be found in several types of plastids (etioplast, leucoplast and chromoplast) and among different plant tissues such as flowers and roots. The structural similarity of some flower and spice isoprenoid volatile organic compounds (beta-ionone and safranal) to carotenoids has led to the recent discovery of carotenoid-specific cleavage oxygenases, including carotenoid cleavage dioxygenases and 9-cis-epoxydioxygenases, which tailor and transform carotenoids into apocarotenoids. The great diversity of apocarotenoids is a consequence of the huge amount of carotenoid precursors, the variations in specific cleavage sites and the modifications after cleavage. Lycopene, beta carotene and zeaxanthin are the precursors of the main apocarotenoids described to date, which include bixin, crocin, picrocrocin, abscisic acid, strigolactone and mycorradicin.The current chapter will give rise to an overview of the biosynthesis and function of the most important apocarotenoids in plants, as well as the current knowledge about the carotenoid cleavage oxygenase enzymes involved in these biosynthetic pathways. PMID- 27485227 TI - Evidence of Epigenetic Mechanisms Affecting Carotenoids. AB - Epigenetic mechanisms are able to regulate plant development by generating non Mendelian allelic interactions. An example of these are the responses to environmenal stimuli that result in phenotypic variability and transgression amongst important crop traits. The need to predict phenotypes from genotypes to understand the molecular basis of the genotype-by-environment interaction is a research priority. Today, with the recent discoveries in the field of epigenetics, this challenge goes beyond analyzing how DNA sequences change. Here we review examples of epigenetic regulation of genes involved in carotenoid synthesis and degradation, cases in which histone- and/or DNA-methylation, and RNA silencing at the posttranscriptional level affect carotenoids in plants. PMID- 27485228 TI - Manipulation of Carotenoid Content in Plants to Improve Human Health. AB - Carotenoids are essential components for human nutrition and health, mainly due to their antioxidant and pro-vitamin A activity. Foods with enhanced carotenoid content and composition are essential to ensure carotenoid feasibility in malnourished population of many countries around the world, which is critical to alleviate vitamin A deficiency and other health-related disorders. The pathway of carotenoid biosynthesis is currently well understood, key steps of the pathways in different plant species have been characterized and the corresponding genes identified, as well as other regulatory elements. This enables the manipulation and improvement of carotenoid content and composition in order to control the nutritional value of a number of agronomical important staple crops. Biotechnological and genetic engineering-based strategies to manipulate carotenoid metabolism have been successfully implemented in many crops, with Golden rice as the most relevant example of beta-carotene improvement in one of the more widely consumed foods. Conventional breeding strategies have been also adopted in the bio-fortification of carotenoid in staple foods that are highly consumed in developing countries, including maize, cassava and sweet potatoes, to alleviate nutrition-related problems. The objective of the chapter is to summarize major breakthroughs and advances in the enhancement of carotenoid content and composition in agronomical and nutritional important crops, with special emphasis to their potential impact and benefits in human nutrition and health. PMID- 27485229 TI - Modern Breeding and Biotechnological Approaches to Enhance Carotenoid Accumulation in Seeds. AB - There is an increasing demand for carotenoids, which are fundamental components of the human diet, for example as precursors of vitamin A. Carotenoids are also potent antioxidants and their health benefits are becoming increasingly evident. Protective effects against prostate cancer and age-related macular degeneration have been proposed for lycopene and lutein/zeaxanthin, respectively. Additionally, beta-carotene, astaxanthin and canthaxanthin are high-value carotenoids used by the food industry as feed supplements and colorants. The production and consumption of these carotenoids from natural sources, especially from seeds, constitutes an important step towards fortifying the diet of malnourished people in developing nations. Therefore, attempts to metabolically manipulate beta-carotene production in plants have received global attention, especially after the generation of Golden Rice (Oryza sativa). The endosperms of Golden Rice seeds synthesize and accumulate large quantities of beta-carotene (provitamin A), yielding a characteristic yellow color in the polished grains. Classical breeding efforts have also focused in the development of cultivars with elevated seed carotenoid content, with maize and other cereals leading the way. In this communication we will summarize transgenic efforts and modern breeding strategies to fortify various crop seeds with nutraceutical carotenoids. PMID- 27485230 TI - Carotenoids as a Source of Antioxidants in the Diet. AB - Carotenoids, widely distributed fat-soluble pigments, are responsible for the attractive colorations of several fruits and vegetables commonly present in our daily diet. They are particularly abundant in yellow-orange fruits (carrots, tomatoes, pumpkins, peppers, among others) and, although masked by chlorophylls, in dark green leafy vegetables. Several health benefits have been attributed to carotenoids or to foods rich in these pigments, by means of different mechanisms of-action, including the role as provitamin A of almost 50 different carotenoids and the antioxidant activity that protects cells and tissues from damage of free radicals and singlet oxygen, providing enhancement of the immune function, protection from sunburn reactions and delaying the onset of certain types of cancer. Common food sources and the efficiency of the absorption of carotenoids, analytical approaches used for measurement of their antioxidant effect and an overview of some epidemiological studies that have been performed to assess the beneficial impact of carotenoids in human health are outlined in this chapter. PMID- 27485231 TI - Carotenoids in Adipose Tissue Biology and Obesity. AB - Cell, animal and human studies dealing with carotenoids and carotenoid derivatives as nutritional regulators of adipose tissue biology with implications for the etiology and management of obesity and obesity-related metabolic diseases are reviewed. Most studied carotenoids in this context are beta-carotene, cryptoxanthin, astaxanthin and fucoxanthin, together with beta-carotene-derived retinoids and some other apocarotenoids. Studies indicate an impact of these compounds on essential aspects of adipose tissue biology including the control of adipocyte differentiation (adipogenesis), adipocyte metabolism, oxidative stress and the production of adipose tissue-derived regulatory signals and inflammatory mediators. Specific carotenoids and carotenoid derivatives restrain adipogenesis and adipocyte hypertrophy while enhancing fat oxidation and energy dissipation in brown and white adipocytes, and counteract obesity in animal models. Intake, blood levels and adipocyte content of carotenoids are reduced in human obesity. Specifically designed human intervention studies in the field, though still sparse, indicate a beneficial effect of carotenoid supplementation in the accrual of abdominal adiposity. In summary, studies support a role of specific carotenoids and carotenoid derivatives in the prevention of excess adiposity, and suggest that carotenoid requirements may be dependent on body composition. PMID- 27485232 TI - Absorption of Carotenoids and Mechanisms Involved in Their Health-Related Properties. AB - Carotenoids participate in the normal metabolism and function of the human body. They are involved in the prevention of several diseases, especially those related to the inflammation syndrome. Their main mechanisms of action are associated to their potent antioxidant activity and capacity to regulate the expression of specific genes and proteins. Recent findings suggest that carotenoid metabolites may explain several processes where the participation of their parent carotenoids was unclear. The health benefits of carotenoids strongly depend on their absorption and transformation during gastrointestinal digestion. The estimation of the 'bioaccessibility' of carotenoids through in vitro models have made possible the evaluation of the effect of a large number of factors on key stages of carotenoid digestion and intestinal absorption. The bioaccessibility of these compounds allows us to have a clear idea of their potential bioavailability, a term that implicitly involves the biological activity of these compounds. PMID- 27485233 TI - Transcriptome of the Caribbean stony coral Porites astreoides from three developmental stages. AB - BACKGROUND: Porites astreoides is a ubiquitous species of coral on modern Caribbean reefs that is resistant to increasing temperatures, overfishing, and other anthropogenic impacts that have threatened most other coral species. We assembled and annotated a transcriptome from this coral using Illumina sequences from three different developmental stages collected over several years: free swimming larvae, newly settled larvae, and adults (>10 cm in diameter). This resource will aid understanding of coral calcification, larval settlement, and host-symbiont interactions. FINDINGS: A de novo transcriptome for the P. astreoides holobiont (coral plus algal symbiont) was assembled using 594 Mbp of raw Illumina sequencing data generated from five age-specific cDNA libraries. The new transcriptome consists of 867 255 transcript elements with an average length of 685 bases. The isolated P. astreoides assembly consists of 129 718 transcript elements with an average length of 811 bases, and the isolated Symbiodinium sp. assembly had 186 177 transcript elements with an average length of 1105 bases. CONCLUSIONS: This contribution to coral transcriptome data provides a valuable resource for researchers studying the ontogeny of gene expression patterns within both the coral and its dinoflagellate symbiont. PMID- 27485234 TI - The Manchester procedure versus vaginal hysterectomy in the treatment of uterine prolapse: a review. AB - INTRODUCTION AND HYPOTHESIS: Uterine prolapse is a common health problem and the number of surgical procedures is increasing. No consensus regarding the surgical strategy for repair of uterine prolapse exists. Vaginal hysterectomy (VH) is the preferred surgical procedure worldwide, but uterus-preserving alternatives including the Manchester procedure (MP) are available. The objective was to evaluate if VH and the MP are equally efficient treatments for uterine prolapse with regard to anatomical and symptomatic outcome, quality of life score, functional outcome, re-operation and conservative re-intervention rate, complications and operative outcomes. METHODS: We systematically searched Embase, PubMed, the Cochrane databases, Clinicaltrials and Clinical trials register using the MeSh terms "uterine prolapse", "uterus prolapse", "vaginal prolapse" "pelvic organ prolapse", "prolapsed uterus", "Manchester procedure" and "vaginal hysterectomy". No limitations regarding language, study design or methodology were applied. In total, nine studies published from 1966 to 2014 comparing the MP to VH were included. RESULTS: The anatomical recurrence rate for the middle compartment was 4-7 % after VH, whereas recurrence was very rare after the MP. The re-operation rate because of symptomatic recurrence was higher after VH (9 13.1 %) compared with MP (3.3-9.5 %) and more patients needed conservative re intervention (14-15 %) than after MP (10-11 %). After VH, postoperative bleeding and blood loss tended to be greater, bladder lesions and infections more frequent and the operating time longer. CONCLUSIONS: This review is in favour of the MP, which seems to be an efficient and safe treatment for uterine prolapse. We suggest that the MP might be considered a durable alternative to VH in uterine prolapse repair. PMID- 27485235 TI - Is Immunomodulation a Principal Mechanism Underlying How Cell-Based Therapies Enhance Stroke Recovery? AB - Inflammation within the brain and in peripheral tissues contributes to brain injury following ischemic stroke. Therapeutic modulation of the inflammatory response has been actively pursued as a novel stroke treatment approach for decades, without success. In recent years, extensive studies support the high potential for cell-based therapies to become a new treatment modality for stroke and other neurological disorders. In this review, we explore different types of cellular therapies and discuss how they modulate central and peripheral inflammatory processes after stroke. Apart from identifying potential targets for cell therapy, we also discuss paracrine and immunomodulatory mechanisms of cell therapy. PMID- 27485236 TI - Prophylactic Antibiotic Therapy for Preventing Poststroke Infection. AB - Infections, in particular pneumonia, are common complications in patients with acute stroke and are associated with a less favorable neurologic and functional outcome. Patients with severe stroke and dysphagia are at highest risk of infection. Experimental and clinical data suggest stroke-induced immunodeficiency as a major factor contributing to the high incidence of infection after stroke. Preclinical studies support the potential benefit of preventive antibiotic therapy in acute stroke for lowering the incidence of infection and improving clinical outcome. Several smaller clinical trials on preventive antibiotic therapy in patients with stroke conducted during the last 10 years yielded inconclusive results. Recently, 2 large, open-label, controlled trials failed to demonstrate an improved clinical outcome after preventive antibiotic therapy in patients with acute stroke treated in specialized stroke units. In the "Preventive Antibiotics in Stroke Study", antibiotic therapy lowered the rate of infection but did not influence outcome. In the STROKE-INF study, performed in patients with dysphagia after stroke, antibiotic therapy did not lower the incidence of pneumonia and had no prognostic significance. At present, preventive antibiotic therapy cannot be recommended as a therapeutic option for acute stroke. PMID- 27485237 TI - Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy. AB - Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients with BMD, who often have mild cognitive impairment, and nNOS may be important for the regulation of the microvascular circulation in the brain. We hypothesized that treatment with sildenafil, a phosphodiesterase type 5 inhibitor that potentiates nitric oxide responses, would augment both the blood oxygen level-dependent (BOLD) response and cerebral blood flow (CBF) in patients with BMD. Seventeen patients (mean +/- SD age 38.5 +/- 10.8 years) with BMD were included in this randomized, double-blind, placebo-controlled, crossover trial. Twelve patients completed the entire study. Effects of sildenafil were assessed by 3 T magnetic resonance (MR) scanning, evoked potentials, somatosensory task-induced BOLD functional MR imaging, regional and global perfusion, and angiography before and after 4 weeks of sildenafil, 20 mg (Revatio in gelatine capsules, oral, 3 times daily), or placebo treatment. Sildenafil increased the event-related sensory and visual BOLD response compared with placebo (p < 0.01). However, sildenafil did not alter CBF, measured by MR phase contrast mapping, or the arterial diameter of the middle cerebral artery, measured by MR angiography. We conclude that nNOS may play a role in event-related neurovascular responses. Further studies in patients with BMD may help clarify the roles of dystrophin and nNOS in neurovascular coupling in general, and in patients with BMD in particular. PMID- 27485239 TI - Maternal Sleep Quality and Diurnal Cortisol Regulation Over Pregnancy. AB - Poor sleep in pregnancy is related to adverse neonatal health. Elevated maternal cortisol has been proposed as a pathway, yet the association in pregnancy is not well understood. The goals of the current study were to examine associations between (a) sleep and cortisol, (b) sleep, cortisol, and neonatal outcomes, and (c) variables that could explain these associations. Two hundred pregnant women completed the Pittsburgh Sleep Quality Index (PSQI; Buysse, Reynolds, Monk, Berman, & Kupfer, 1989) and provided diurnal salivary cortisol samples at two times over pregnancy. Poor sleep quality was associated with greater evening cortisol concentrations at 36 weeks' gestation. This association was mediated by anxiety symptoms. Higher evening cortisol at 36 weeks' gestation was associated with shorter gestation. PMID- 27485240 TI - Brief report on a systematic review of youth violence prevention through media campaigns: Does the limited yield of strong evidence imply methodological challenges or absence of effect? AB - BACKGROUND: We present a brief report on a systematic review which identified, assessed and synthesized the existing evidence of the effectiveness of media campaigns in reducing youth violence. METHODS: Search strategies made use of terms for youth, violence and a range of terms relating to the intervention. An array of academic databases and websites were searched. RESULTS: Although media campaigns to reduce violence are widespread, only six studies met the inclusion criteria. There is little strong evidence to support a direct link between media campaigns and a reduction in youth violence. Several studies measure proxies for violence such as empathy or opinions related to violence, but the link between these measures and violence perpetration is unclear. Nonetheless, some evidence suggests that a targeted and context-specific campaign, especially when combined with other measures, can reduce violence. However, such campaigns are less cost effective to replicate over large populations than generalised campaigns. CONCLUSIONS: It is unclear whether the paucity of evidence represents a null effect or methodological challenges with evaluating media campaigns. Future studies need to be carefully planned to accommodate for methodological difficulties as well as to identify the specific elements of campaigns that work, especially in lower and middle income countries. PMID- 27485241 TI - Antenatal care use in urban areas in two European countries: Predisposing, enabling and pregnancy-related determinants in Belgium and the Netherlands. AB - BACKGROUND: Examining determinants of antenatal care (ANC) is important to stimulate equitable distribution of ANC across Europe. This study (1) compares ANC utilisation in Belgium and the Netherlands and (2) identifies predisposing, enabling and pregnancy-related determinants. METHODS: Secondary data analysis is performed using data from Belgium, and the Netherlands. The content and timing of care during pregnancy (CTP) tool measured ANC use. Non-parametric tests and ordinal logistic regression are performed to gain insight in the determinants of health care use. RESULTS: Dutch women receive appropriate ANC more often than Belgian women. Multivariate analysis showed that lower education, unemployment, lower continuity of care and non-attendance of antenatal classes are associated with a lower likelihood of having more appropriate ANC. CONCLUSIONS: Predisposing and pregnancy related variables are most important to influence the content and timing of ANC, irrespective of the country women live in. Lower health literacy in socially vulnerable women might explain the predisposing determinants of health care use in both countries. Stimulating accessibility to antenatal courses or organising public education are recommendations for practice. Regarding pregnancy-related determinants, improving continuity of care can optimise ANC use in both countries. PMID- 27485238 TI - Microglia and Monocyte-Derived Macrophages in Stroke. AB - Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood-brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood-brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions. PMID- 27485243 TI - Weight-Related Goal Setting in a Telephone-Based Preventive Health-Coaching Program: Demonstration of Effectiveness. AB - PURPOSE: This study investigated whether participants in a 6-month telephone based coaching program, who set physical activity, nutrition, and weight loss goals had better outcomes in these domains. DESIGN: Quasi-experimental design. SETTING: The Australian Get Healthy Information and Coaching Service (GHS), a free population-wide telephone health-coaching service that includes goal setting as a key component of its coaching program. PARTICIPANTS: Consenting GHS coaching participants who had completed coaching between February 2009 and December 2012 (n = 4108). MEASURES: At baseline, participants select a goal for the coaching program, and sociodemographic variables are collected. Self-reported weight, height, waist circumference, physical activity, and nutrition-related behaviors are assessed at baseline and 6 months. ANALYSIS: Descriptive analysis was performed on key sociodemographic variables, and the relationship between goal type and change in health outcomes was assessed using a series of linear mixed models that modeled change from baseline to 6 months. RESULTS: Participants who set goals in relation to weight management and physical activity achieved better results in these areas than those who set alternate goals, losing more than those who set alternate goals (1.5 kg and 0.9 cm in waist circumference) and increasing walking per week (40 minutes), respectively. There was no difference in food related outcomes for those that set nutrition-related goals. CONCLUSION: Goal setting for weight management and increasing physical activity in the overweight and obese population, undertaken in a telephone-based coaching program, can be effective. PMID- 27485242 TI - The skin microbiome in allergen-induced canine atopic dermatitis. AB - BACKGROUND: Studies focusing on next-generation sequencing of the bacterial 16S rRNA gene have allowed detailed surveys of skin bacterial populations (microbiota) of the skin. HYPOTHESIS/OBJECTIVES: This study evaluated temporal changes in the skin microbiota in a canine model of atopic dermatitis. ANIMALS: Eight atopic dogs previously sensitized with house dust mites (HDM). METHODS: The dogs were topically challenged on the right groin with HDM allergens. Swabs were collected from the challenged and the contralateral nonchallenged sites prior to provocation (pre-challenge; baseline sample) and on days 1, 7, 14, 21 and 28 after allergen challenge. The 16S rRNA gene was amplified, sequenced and analysed. Staphylococcus spp. and Staphylococcus pseudintermedius were quantified with quantitative PCR (RT-qPCR). RESULTS: Skin lesions developed in all dogs on the challenged sites. Differences in bacterial groups were observed on the challenged site over time. Relatively lower abundances of Fusobacteriaceae on Day 7, and, based on LEfSe, increased abundances of Corynebacteriaceae on Day 1, and Staphylococcaceae on days 7, 14 and 21, were observed on the challenged site, compared to the contralateral site. Results of RT-qPCR correlated with those of next-generation sequencing, with significantly increased numbers of Staphylococcus spp. and S. pseudintermedius on Day 21, and days 7 and 21 on the challenged site compared to the contralateral site, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: This study demonstrates that an allergen challenge in sensitized dogs leads to bacterial dysbiosis with increased abundance of S. pseudintermedius at the site of lesion induction. PMID- 27485244 TI - Phenomenological theory of uniaxial relaxor ferroelectrics. AB - A phenomenological thermodynamic theory of uniaxial relaxor strontium barium niobate [Formula: see text] is developed using the Landau-Devonshire approach with two order parameters. The fourth-order thermodynamic potential allowed to explain the shape of the polarization hysteresis loops experimentally observed at different temperatures. We show that the broad maximum of the dielectric permittivity is not related to the phase transition and arise due to the coupling between polarization and true order parameter which has antiferroelectric nature. We found that the phase transition temperature is much higher than the maximum of the dielectric permittivity and very likely corresponds to so-called Burn's temperature. True order parameter has no simple relation with polar modes. PMID- 27485245 TI - Pulling it all together: The road to lasting bilingualism for children with developmental disabilities. AB - Children with DD must and do become bilingual, but the research reported in this special issue raises questions about equitable access to bilingual opportunities and provision of appropriate supports to ensure optimal bilingual growth in these children. The purpose of the present article was to apply the findings from our international collaboration to inform policy and practice on bilingualism in children with developmental disabilities (DD). To do this, we first overview the research presented in detail in other articles of this special issue: a narrative literature review, a review of site policies and practices related to special education and language education, a qualitative analysis of key informant interviews, and a quantitative analysis of surveys of practitioners. From these overviews emerge a complex set of contextual factors that impact bilingual development in children with DD. We then use the Bioecological Systems model of Bronfenbrenner and Morris (2007) and conceptual maps (C-maps) to examine the particular circumstances of three hypothetical children with DD who are in very different bilingual contexts. In so doing, areas of both positive and negative influence on lasting bilingualism are identified for each child. We end with recommendations for increasing access to and support for bilingualism in children with DD. PMID- 27485246 TI - Functional independence measure for elderly patients undergoing aortic valve replacement. AB - OBJECTIVE: This study aimed to evaluate the efficacy of the Functional Independence Measure to assess preoperative frailty for elderly patients undergoing surgical aortic valve replacement. METHODS: Eighty-five patients >65 years who survived elective isolated aortic valve replacement from January 2008 to October 2015 were included. The mean age at the operation was 78 +/- 6 years old (n = 28 males, n = 57 females). The patients were divided into two groups according to their status at discharge: impossible to discharge home or hospitalization for >30 days (compromised group, n = 8), or unaffected (unaffected group, n = 77). Preoperative frailty was evaluated with the Functional Independence Measure, which comprises 18 items divided into six domains: self-care, sphincter control, mobility, locomotion, communication, and social cognition. RESULTS: The preoperative total Functional Independence Measure score was significantly lower in the compromised group (79 +/- 32) than in the unaffected group (120 +/- 9, p < 0.01). The preoperative motor Functional Independence Measure score was significantly lower in the compromised group (45 +/- 24) than in the unaffected group (85 +/- 9, p = <0.01). The duration of postoperative intubation, intensive care unit stay, and postoperative hospitalization were significantly longer in the compromised group than in the unaffected group (48 +/- 67 vs 16 +/- 12 h, p < 0.01; 6.7 +/- 5.3 vs 3.4 +/- 2.0 days, p < 0.01; 34 +/- 27 vs 23 +/- 11 days, p = 0.02, respectively). CONCLUSIONS: The preoperative Functional Independence Measure is effective for assessing preoperative frailty in elderly patients undergoing aortic valve replacement in terms of predicting operative morbidity. PMID- 27485247 TI - Predictors of patent false lumen of the aortic arch after hemiarch replacement. AB - BACKGROUND: Hemiarch replacement for acute type A aortic dissection is less invasive than total arch replacement but involves increased risk of late aortic arch dilation because of patent false lumen of the aortic arch. If we can predict this risk, it may be a valuable prognostic indicator for selecting surgical procedures for acute type A aortic dissection. METHODS: We reviewed our surgical experience to predict patent false lumen. From January 2009 to November 2014, we performed 108 hemiarch replacement procedures for acute type A aortic dissection that had patent false lumen of the ascending aortic arch. We identified 56 patients who had preoperative and postoperative contrast-enhanced computed tomography. Patients' preoperative characteristics, preoperative and postoperative contrast-enhanced computed tomography findings, intraoperative findings and postoperative course were investigated. RESULTS: Of the 56 patients, 32 (57.1 %) were men and their mean age at surgery was 63.7 +/- 11.8 years. Overall in-hospital mortality rate was 7.1 % (4 patients). According to postoperative imaging findings, 56 patients were classified into two groups: group A (39 patients), with patent false lumen, and group B (17 patients), with thrombosed false lumen. Logistic regression analysis revealed that brachiocephalic artery dissection and no tear resection contributed to postoperative patent false lumen of the aortic arch more strongly than did other factors. CONCLUSIONS: Brachiocephalic artery dissection and no tear resection are potential predictors of patent false lumen of the aortic arch after hemiarch replacement. PMID- 27485248 TI - Preoperative simulation of minimally invasive aortic valve replacement using patient-specific replica. AB - Exposure of surgeons to minimally invasive cardiac surgery is typically limited. We developed a patient-specific aortic root silicon replica for simulating minimally invasive aortic valve replacement (MIAVR). From this 3D model, important anatomical information was obtained. To understand the best procedural option, different techniques were attempted without time limitation, leading to the complete planning of the operation. The patient-specific replica and simulated surgery were useful for preoperative training and planning for the MIAVR procedure. PMID- 27485249 TI - Impact of the size mismatch between saphenous vein graft and coronary artery on graft patency. AB - BACKGROUND: The saphenous vein graft (SVG) is widely used in coronary artery bypass grafting because of its availability and ease of use. However, the patency rate of the SVG grafted to the right coronary artery (RCA) is poor. Diameter mismatch between the coronary artery and SVG is an important cause of graft occlusion. In this study, we assessed how the degree of diameter mismatch affects SVG patency. METHODS: We reviewed the records of 123 patients who underwent aorto right coronary artery bypass grafting with an SVG. The patency rate of the SVG, SVG diameter, RCA diameter and SVG-RCA diameter ratio (SR ratio) was assessed based on angiography and CT. RESULTS: The mean SVG diameter was 3.61 +/- 0.72 mm, the mean RCA diameter was 1.57 +/- 0.32 mm and the mean SR ratio was 2.37 +/- 0.57. Cumulative patency rate of the SVG was 95.5 % at the early phase, 85.2 % at 1 year, and 70.2 % at 5 years. Multivariate analysis showed that the SR ratio was an independent predictor of SVG occlusion. The cutoff value of the SR ratio was 2.8, calculated from the point of maximal specificity (81.2 %) and sensitivity (64.7 %), and the area under the ROC curve was 0.734. When the SR ratio was <=2.8, the 3-year patency rate was 86.1 %. CONCLUSIONS: A mismatch between SVG diameter and RCA diameter has an impact on the patency rate of the SVG. Evaluation of the saphenous vein before surgery and selection of a graft to minimize mismatch should improve SVG patency. PMID- 27485250 TI - Premature mammary gland involution with repeated corticosterone injection in interleukin 10-deficient mice. AB - Recently, we found that maternal stress could induce premature mammary gland involution in interleukin 10 knock out (IL-10-/-) mice. To elucidate correlation between stress, IL-10, and mammary gland involution, corticosterone was injected into the lactating wild type and IL-10-deficient mice and assessed mammary gland phenotype. Repetitive corticosterone injection developed premature mammary gland involution only in B6.IL-10-/- mice; moreover, it induced alopecia in nursing pups. Corticosterone injection induced several typical changes such as mammary gland epithelial cell apoptosis, macrophage infiltration, fat deposition in adipocyte, STAT3 phosphorylation, and upregulation of tyrosine hydroxylase gene in adrenal gland. Overall incidence of pup alopecia and mammary gland involution was relatively high in corticosterone than control B6.IL-10-/- group (57% vs. 20%). Our finding demonstrates that IL-10 is important for stress modulation, and B6.Il-10-/- with corticosterone has several advantage such as simple to establish, well-defined onset of mammary gland involution, high incidence, and inducing pup alopecia. PMID- 27485251 TI - Minimally invasive microneedles for ocular drug delivery. AB - INTRODUCTION: Anterior and posterior segment eye diseases are highly challenging to treat, due to the barrier properties and relative inaccessibility of the ocular tissues. Topical eye drops and systemically delivered treatments result in low bioavailability. Alternatively, direct injection of medication into the ocular tissues is clinically employed to overcome the barrier properties, but injections cause significant tissue damage and are associated with a number of untoward side effects and poor patient compliance. Microneedles (MNs) has been recently introduced as a minimally invasive means for localizing drug formulation within the target ocular tissues with greater precision and accuracy than the hypodermic needles. Areas covered: This review article seeks to provide an overview of a range of challenges that are often faced to achieve efficient ocular drug levels within targeted tissue(s) of the eye. It also describes the problems encountered using conventional hypodermic needle-based ocular injections for anterior and posterior segment drug delivery. It discusses research carried out in the field of MNs, to date. Expert opinion: MNs can aid in localization of drug delivery systems within the selected ocular tissue. And, hold the potential to revolutionize the way drug formulations are administered to the eye. However, the current limitations and challenges of MNs application warrant further research in this field to enable its widespread clinical application. PMID- 27485252 TI - When less could be more: Investigating the effects of a brief internet-based imagery cognitive bias modification intervention in depression. AB - Depression is a highly prevalent condition worldwide, yet multiple barriers to treatments means that the development of low intensive and easily accessible psychological interventions is crucially needed. The current study sought to investigate the efficacy of a brief, self-administered imagery cognitive bias modification (imagery CBM) procedure delivered online to a sample of 101 individuals with depressive symptoms. Compared to a closely matched control condition or a waitlist condition, imagery CBM led to greater improvements in depressive symptoms (d = 0.86, 95% CI = [0.33, 1.3] and d = 1.17, 95% CI = [0.62, 1.65]) interpretation bias and anhedonia. Despite the limitation to a two week follow-up, the study findings highlight the potential of imagery CBM as a brief, easily accessible intervention for depression that can be delivered remotely in peoples' home. PMID- 27485253 TI - Evaluation of synergistic effects of sulforaphene with photodynamic therapy in human cervical cancer cell line. AB - Sulforaphene from cruciferous vegetable has shown to modulate various signaling pathways of apoptosis. But it has not yet been studied extensively for the cervical cancer treatment. Previous studies show the promising role of photodynamic therapy for cervical cancer. Here, we confirm that sulforaphene can synergistically enhance the efficacy of photodynamic therapy. Human cervical cancer cells HeLa were treated with a very low dose of sulforaphene (2.0 MUg/ml) and photodynamic therapy with radachlorin (0.5 MUg/ml) at a fluence of 27 J/cm2 (30 milliwatts/cm2, lambdamax ~ 670 +/- 3 nm). The combination treatment showed a synergistic effect to induce apoptosis. The mitochondrial apoptotic pathway was activated via caspase 3 and caspase 9. On the other hand, caspase 12 and C/EBP homologous protein (CHOP) were expressed that indicated endoplasmic reticulum stress. This combination treatment also activated death receptor pathway via activation of caspase 8 and inhibited cell proliferation via down-regulation of EGFR. Thus, several apoptotic pathways were simultaneously activated in this combination treatment which results in a synergistic efficacy of sulforaphene with photodynamic therapy. Therefore, this study could be useful in the improvement of therapies for human cervical and other types of cancers. PMID- 27485255 TI - Local thermal sensation modeling-a review on the necessity and availability of local clothing properties and local metabolic heat production. AB - Local thermal sensation modeling gained importance due to developments in personalized and locally applied heating and cooling systems in office environments. The accuracy of these models depends on skin temperature prediction by thermophysiological models, which in turn rely on accurate environmental and personal input data. Environmental parameters are measured or prescribed, but personal factors such as clothing properties and metabolic rates have to be estimated. Data for estimating the overall values of clothing properties and metabolic rates are available in several papers and standards. However, local values are more difficult to retrieve. For local clothing, this study revealed that full and consistent data sets are not available in the published literature for typical office clothing sets. Furthermore, the values for local heat production were not verified for characteristic office activities, but were adapted empirically. Further analyses showed that variations in input parameters can lead to local skin temperature differences (?Tskin,loc = 0.4-4.4 degrees C). These differences can affect the local sensation output, where ?Tskin,loc = 1 degrees C is approximately one step on a 9-point thermal sensation scale. In conclusion, future research should include a systematic study of local clothing properties and the development of feasible methods for measuring and validating local heat production. PMID- 27485254 TI - Rapid Detection of Cyprinid Herpesvirus 3 in Latently Infected Koi by Recombinase Polymerase Amplification. AB - Since the emergence of cyprinid herpesvirus 3 (CyHV-3), outbreaks have been devastating to Common Carp Cyprinus carpio and koi (a variant of Common Carp), leading to high economic losses. Current diagnostics for detecting CyHV-3 are limited in sensitivity and are further complicated by latency. Here we describe the detection of CyHV-3 by recombinase polymerase amplification (RPA). The RPA assay can detect as low as 10 copies of the CyHV-3 genome by an isothermal reaction and yields results in approximately 20 min. Using the RPA assay, the CyHV-3 genome can be detected in the total DNA of white blood cells isolated from koi latently infected with CyHV-3, while less than 10% of the latently infected koi can be detected by a real-time PCR assay in the total DNA of white blood cells. In addition, RPA products can be detected in a lateral flow device that is cheap and fast and can be used outside of the diagnostic lab. The RPA assay and lateral flow device provide for the rapid, sensitive, and specific amplification of CyHV-3 that with future modifications for field use and validation could lead to enhanced surveillance and early diagnosis of CyHV-3 in the laboratory and field. Received September 14, 2015; accepted April 9, 2016. PMID- 27485256 TI - Simple and rapid characterization of novel large germline deletions in SDHB, SDHC and SDHD-related paraganglioma. AB - Germline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with hereditary paraganglioma and pheochromocytoma. Although most mutations in SDHB, SDHC and SDHD are intraexonic variants, large germline deletions may represent up to 10% of all variants but are rarely characterized at the DNA sequence level. Additional phenotypic effects resulting from deletions that affect neighboring genes are also not understood. We performed multiplex ligation-dependent probe amplification, followed by a simple long-range PCR 'chromosome walking' protocol to characterize breakpoints in 20 SDHx-linked paraganglioma-pheochromocytoma patients. Breakpoints were confirmed by conventional PCR and Sanger sequencing. Heterozygous germline deletions of up to 104 kb in size were identified in SDHB, SDHC, SDHD and flanking genes in 20 paraganglioma-pheochromocytoma patients. The exact breakpoint could be determined in 16 paraganglioma-pheochromocytoma patients of which 15 were novel deletions. In six patients proximal genes were also deleted, including PADI2, MFAP2, ATP13A2 (PARK9), CFAP126, TIMM8B and C11orf57. These genes were either partially or completely deleted, but did not modify the phenotype. This study increases the number of known SDHx deletions by over 50% and demonstrates that a significant proportion of large gene deletions can be resolved at the nucleotide level using a simple and rapid method. PMID- 27485257 TI - Utilizing single- and double-transfected cell models expressing human organic anion transporter 1 and human cytochrome P450 1A2 to investigate the interactions with ingredients of herbal medicines. AB - 1. Cell models expressing human drug transporters and enzymes are useful tools to understand the process of drug disposition in vitro. However, no study on transfected cells stably co-expressing human organic anion transporter 1 (hOAT1) and/or human cytochrome P450 1A2 (hCYP1A2) is available. In this study, cell models stably expressing hOAT1 and/or hCYP1A2 were established, and were used to investigate the interactions of ingredients of herbal medicines (IHMs) with hOAT1 and/or hCYP1A2. 2. The MDCK cells were stable transfected with recombinant plasmids expressing hOAT1 and/or hCYP1A2. Cellular uptake assay and CYP450 activity assay showed that the transfected cells were available. A marked high expression of hOAT1 and hCYP1A2 mRNA was also validated by quantitative RT-PCR. Totally 6 IHMs which significantly inhibited the activity of hOAT1 were screened out by employing hOAT1 expressing cells. The contribution of hOAT1 and hCYP1A2 to the toxicity of aristolochic acid I (AAI) was further determined. Compared to mock cells, all transfected cells showed a decrease in viability after being treated with AAI. 3. A method to establish transfected cell expressing drug metabolism enzymes and/or transporters was provided in our study. Three IHMs (dihydrotanshinone I, cryptotanshinone, and tanshinone I) were confirmed as novel inhibitors of hOAT1. Furthermore, a synergistic effect of hOAT1 and hCYP1A2 on AAI-induced toxicity was also observed in this investigation. PMID- 27485259 TI - Long-term care in Spain: Difficulties in professionalizing services. AB - The aim of this article is to analyze the difficulties in professionalizing the long-term care system in Spain. Since 2006, the new Spanish law has recognized care as a subjective right, and regulations are being designed to create a framework for its professionalization. Nowadays, family remains the most important group of providers who care for their elders, and women remain the main informal caregivers. Why do families resist using public long-term care services and professional carers included in the new law? The hypothesis highlights sociocultural factors as an obstacle to professionalization of long-term care services in addition to political and economic factors. The results show qualitative data about expectations, preferences, and discourses that women caregivers have in relation to their responsibility. The empirical material includes 25 interviews with different profiles of caregivers and six focus groups with family caregivers. The article suggests that the Spanish ideal of care is a problem for the professionalization of services because the family remains as the main provider of care-without specific skills, knowledge, and abilities. PMID- 27485260 TI - Positive Feelings After Casual Sex: The Role of Gender and Traditional Gender Role Beliefs. AB - The purpose of this study was to identify predictors of positive and negative affect following casual sex. Specifically, the primary goal was to investigate how traditional gender-role beliefs, peer approval of casual sex, perceptions of others, sexual assertiveness, and sexual pleasure influence affective experiences. Second, we aimed to determine the extent to which these associations were comparable for men and women. Although we expected mean differences on many of these constructs (e.g., men perceiving more peer approval), we expected the relationships between these constructs to be comparable for women and men. Participants ages 18 to 35 (N = 585) were recruited from a large university and Amazon Mechanical Turk (MTurk) and described their most recent casual sex experience in a self-report questionnaire. Structural equation modeling (SEM) analyses indicated that gender-role beliefs were significantly associated with less sexual assertiveness and more negative perceptions of others; for women they were also associated with less peer approval of casual sex. For women and men, sexual assertiveness predicted sexual pleasure; and sexual pleasure was associated with affect. To decrease the gender discrepancy in positive affect and sexual pleasure, it is important to develop a comprehensive understanding of the interrelationships among norms, casual sex experiences, and affect. PMID- 27485261 TI - Role of physician perception of patient smile on pretest probability assessment for acute pulmonary embolism. AB - BACKGROUND: Many clinicians use a global visual interpretation of patient appearance to decide if a patient looks sick or not. For patients with suspected acute pulmonary embolism (PE), we tested the relationship between visual appearance of a happy patient facial affect and probability of PE+ on CT pulmonary angiography (CTPA). METHODS: Eligible patients were selected by usual care to undergo CTPA, the criterion standard for PE+ or PE-. Prior to CTPA result, trained study personnel obtained physician pretest probability using the gestalt method (visual analogue scale, 0%-100%), the Wells score (0-12) and physicians' impression of whether the patient smiled during the initial examination (smile+). Patients' faces were also video recorded and analysed with an automated neural network-based algorithm (Noldus FaceReader) for happy affect. RESULTS: Of the 208 patients enrolled, 27 were PE+ and smile+ was more frequent in patients with PE+ than PE-, a finding confirmed by the Noldus. The diagnostic sensitivity and specificity of smile was low, and physicians overestimated presence of an alternative diagnosis more likely to PE with smile+ than smile- patients in patients with true PE. As a result, the area under the receiver operating characteristic curve (AUROC) was lower for the Wells score in smile+ patients. However, the physicians' mean gestalt estimate of PE did not differ with smile status, nor did smile status affect the AUROC for gestalt. CONCLUSIONS: In patients with suspected PE, physician recollection of patients' smile+ was more common in PE+ patients, and was associated with a less accurate Wells score, primarily because physicians overestimated probability of alternative diagnosis. However, the overall diagnostic accuracy of physicians' gestalt did not differ with perceived smile status. These data suggest that the patients' smile had less effect on the numeric gestalt pretest probability assessment than on the binary decision about an alternative diagnosis. PMID- 27485262 TI - Out-of-hospital cardiac arrest attended by ambulance services in Ireland: first 2 years' results from a nationwide registry. AB - BACKGROUND: National data collection provides information on out-of-hospital cardiac arrest (OHCA) incidence, management and outcomes that may not be generalisable from smaller studies. This retrospective cohort study describes the first 2 years' results from the Irish National Out-of-Hospital Cardiac Arrest Register (OHCAR). METHODS: Data on OHCAs attended by emergency medical services (EMS) where resuscitation was attempted (EMS-treated) were collected from ambulance services and entered onto OHCAR. Descriptive analysis of the study population was performed, and regression analysis was performed on the subgroup of adult patients with a bystander-witnessed event of presumed cardiac aetiology and an initial shockable rhythm (Utstein group). RESULTS: 3701 EMS-treated OHCAs were recorded for the study period (1 January 2012-31 December 2013). Incidence was 39/100 000 population/year. In the Utstein group (n=577), compared with the overall group, there was a higher proportion of male patients, public event location, bystander cardiopulmonary resuscitation (CPR) and early defibrillation. Median EMS call-response interval was similar in both groups. A higher proportion of patients in the Utstein group achieved return of spontaneous circulation (35% vs 17%) and survival to hospital discharge (22% vs 6%). After multivariate adjustment for the Utstein group, the following variables were found to be independent predictors of the outcome survival to hospital discharge: public event location (OR 3.1 (95% CI 1.9 to 5.0)); bystander CPR (2.4 (95% CI 1.2 to 4.9)); EMS response of 8 min or less (2.2 (95% CI 1.3 to 3.6)). CONCLUSIONS: This study highlights the role of nationwide registries in quantifying, monitoring and benchmarking OHCA incidence and outcome, providing baseline data upon which service improvement effects can be measured. PMID- 27485263 TI - Structure-antiproliferative activity studies on l-proline- and homoproline-4-N pyrrolidine-3-thiosemicarbazone hybrids and their nickel(ii), palladium(ii) and copper(ii) complexes. AB - Two water-soluble thiosemicarbazone-proline (H2L(1)) and thiosemicarbazone homoproline hybrids (H2L(2)) were synthesised. By reaction of H2L(1) with NiCl2.6H2O, PdCl2 and CuCl2.2H2O in ethanol, the series of square-planar complexes [Ni(H2L(1))Cl]Cl.1.3H2O (1.1.3H2O), [Pd(H2L(1))Cl]Cl.H2O (2.H2O) and [Cu(H2L(1))Cl]Cl.0.7H2O (3.0.7H2O) was prepared, and starting from H2L(2) and CuCl2.2H2O in methanol, the complex [Cu(H2L(2))Cl2].H2O (4.H2O) was obtained. The compounds have been characterised by elemental analysis, spectroscopic methods (IR, UV-vis and NMR spectroscopy), ESI mass spectrometry and single crystal X-ray crystallography (H2L(1), 1, 2 and 4). As a solid, 1 is diamagnetic, while it is paramagnetic in methanolic solution. The effective magnetic moment of 3.26 B.M. at room temperature indicates the change in coordination geometry from square planar to octahedral upon dissolution. The in vitro anticancer potency of ligand precursors H2L(1) and H2L(2) and metal complexes 1-4 was studied in three human cancer cell lines (A549, CH1 and SW480) and in noncancerous murine embryonal fibroblasts (NIH/3T3), and the mechanism of cell death was also assayed by flow cytometry. Clear-cut structure-activity relationships have been established. The metal ions exert marked effects in a divergent manner: copper(ii) increases, whereas nickel(ii) and palladium(ii) decrease the cytotoxicity of the hybrids. The antiproliferative activity of H2L(1) and metal complexes 1-3 decreases in all three tumour cell lines in the following rank order: 3 > H2L(1) > 1 > 2. The role of square-planar geometry in the underlying mechanism of cytotoxicity of the metal complexes studied seems to be negligible, while structural modifications at the terminal amino group of thiosemicarbazide and proline moieties are significant for enhancing the antiproliferative activity of both hybrids and copper(ii) complexes. PMID- 27485265 TI - Ethnobotanical study of wild edible plants in Burji District, Segan Area Zone of Southern Nations, Nationalities and Peoples Region (SNNPR), Ethiopia. AB - BACKGROUND: An ethnobotanical study of wild edible plants was conducted in Burji District, Segan Area Zone of Southern Nations, Nationalities and Peoples Region, Ethiopia. The objective of the study was to identify and document wild edible plants and the associated ethnobotanical knowledge of the local people. METHODS: Relevant ethnobotanical data focused on wild edible plants were collected using guided field walk, semi-structured interview, and direct field observation. Informant consensus method and group discussion were conducted for crosschecking and verification of the information. Both descriptive statistics and quantitative ethnobotanical methods were used for data analysis. RESULTS: We documented 46 species distributed in 37 genera and 29 families based on local claims of use as food. Local users collect most of these plants from the wild. The common plant families that encompass more number of wild edible plant species were Anacardiaceae (five species) followed by Boraginaceae, Fabaceae and Solanaceae which contributed three species each. CONCLUSION: The study showed the existence of a number of wild edible plants which mitigate food insecurity situations during problematic times that the people of the area face occasionally. Informants stated that wild growing edible plants are under threat due to increased anthropogenic pressure and disturbed climatic conditions. This calls for urgent and collaborative actions to keep the balance between edible plants availability in the wild and their utilization by the community. Furthermore, the study attempted to prioritize very important wild edible plants as perceived by the local people for possible domestication and/or sustainable utilization. PMID- 27485264 TI - Fiberless multicolor neural optoelectrode for in vivo circuit analysis. AB - Maximizing the potential of optogenetic approaches in deep brain structures of intact animals requires optical manipulation of neurons at high spatial and temporal resolutions, while simultaneously recording electrical data from those neurons. Here, we present the first fiber-less optoelectrode with a monolithically integrated optical waveguide mixer that can deliver multicolor light at a common waveguide port to achieve multicolor modulation of the same neuronal population in vivo. We demonstrate successful device implementation by achieving efficient coupling between a side-emitting injection laser diode (ILD) and a dielectric optical waveguide mixer via a gradient-index (GRIN) lens. The use of GRIN lenses attains several design features, including high optical coupling and thermal isolation between ILDs and waveguides. We validated the packaged devices in the intact brain of anesthetized mice co-expressing Channelrhodopsin-2 and Archaerhodopsin in pyramidal cells in the hippocampal CA1 region, achieving high quality recording, activation and silencing of the exact same neurons in a given local region. This fully-integrated approach demonstrates the spatial precision and scalability needed to enable independent activation and silencing of the same or different groups of neurons in dense brain regions while simultaneously recording from them, thus considerably advancing the capabilities of currently available optogenetic toolsets. PMID- 27485266 TI - Lymphatic Leak Occurring After Surgical Lymph Node Dissection: A Preliminary Study Assessing the Feasibility and Outcome of Lymphatic Embolization. AB - PURPOSE: To analyze imaging findings of lymphatic leakage associated with surgical lymph node dissection on lymphangiography and assess the outcome of lymphatic embolization. MATERIALS AND METHODS: This retrospective study comprised 21 consecutive patients who were referred for lymphatic intervention between March 2014 and April 2015 due to postsurgical lymphatic leaks. Lymphangiography was performed through inguinal lymph nodes to identify the leak. When a leak was found, lymphatic embolization was performed by fine-needle injection of N-butyl cyanoacrylate into the site of leakage or into an inflow lymphatic vessel or into a pelvic lymph node located below the leakage. Electronic medical records and imaging studies were reviewed to assess the outcome. RESULT: Lymphangiography revealed single or multiple leaks in all but one patient. Lymphatic embolization was performed in 20 patients with leaks. Including the patient who did not undergo embolization, 17 patients (81.0 %) showed initial response to treatment. Three patients underwent repeated embolization with successful results. The overall success rate was 95.2 %. The mean duration of hospitalization after lymphatic intervention was 5.9 days. During a mean follow-up period of 11 months, two patients developed localized swelling in the groin following lipiodol injection. There were no complications related to lymphatic embolization. Three patients were found to have developed small, asymptomatic lymphoceles on CT or MRI that did not require further treatment. CONCLUSION: Lymphangiography is useful for detecting lymphatic leakage occurring after lymph node dissection. Furthermore, lymphatic embolization is feasible, effective, and safe for managing leaks demonstrated on lymphangiography. PMID- 27485267 TI - Transperineal Prostate Core Needle Biopsy: A Comparison of Coaxial Versus Noncoaxial Method in a Randomised Trial. AB - PURPOSE: To compare the procedural time and complication rate of coaxial technique with those of noncoaxial technique in transperineal prostate biopsy. MATERIALS AND METHODS: Transperineal prostate biopsy with coaxial (first group, n = 120) and noncoaxial (second group, n = 120) methods was performed randomly in 240 patients. The procedural time was recorded. The level of pain experienced during the procedure was assessed on a visual analogue scale (VAS), and the rate of complications was evaluated in comparison of the two methods. RESULTS: The procedural time was significantly shorter in the first group (p < 0.001). In the first group, pain occurred less frequently (p = 0.002), with a significantly lower VAS score being experienced (p < 0.002). No patient had post procedural fever. Haematuria (p = 0.029) and haemorrhage from the site of biopsy (p < 0.001) were seen less frequently in the first group. There was no significant difference in the rate of urethral haemorrhage between the two groups (p = 0.059). Urinary retention occurred less commonly in the first group (p = 0.029). No significant difference was seen in the rate of dysuria between the two groups (p = 0.078). CONCLUSIONS: Transperineal prostate biopsy using a coaxial needle is a faster and less painful method with a lower rate of complications compared with conventional noncoaxial technique. PMID- 27485268 TI - Quantitative Real-Time Fluoroscopy Analysis on Measurement of the Hepatic Arterial Flow During Transcatheter Arterial Chemoembolization of Hepatocellular Carcinoma: Comparison with Quantitative Digital Subtraction Angiography Analysis. AB - PURPOSE: To quantify the arterial flow change during transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) using digital subtraction angiography, quantitative color-coding analysis (d-QCA), and real time subtraction fluoroscopy QCA (f-QCA). MATERIALS AND METHODS: This prospective study enrolled 20 consecutive patients with HCC who had undergone TACE via a subsegmental approach between February 2014 and April 2015. The TACE endpoint was a sluggish antegrade tumor-feeding arterial flow. d-QCA and f-QCA were used for determining the relative maximal density time (rTmax) of the selected arteries. The rTmax of the selected arteries was analyzed in d-QCA and f-QCA before and after TACE, and its correlation in both analyses was evaluated. RESULTS: The pre- and post-TACE rTmax of the embolized segmental artery in d-QCA and f-QCA were 1.59 +/- 0.81 and 2.97 +/- 1.80 s (P < 0.001) and 1.44 +/- 0.52 and 2.28 +/- 1.02 s (P < 0.01), respectively. The rTmax of the proximal hepatic artery did not significantly change during TACE in d-QCA and f-QCA. The Spearman correlation coefficients of the pre- and post-TACE rTmax of the embolized segmental artery between d-QCA and f-QCA were 0.46 (P < 0.05) and 0.80 (P < 0.001). Radiation doses in one series of d-QCA and f-QCA were 140.7 +/- 51.5 milligray (mGy) and 2.5 +/- 0.7 mGy, respectively. CONCLUSIONS: f-QCA can quantify arterial flow changes with a higher temporal resolution and lower radiation dose. Flow quantification of the embolized segmental artery using f-QCA and d-QCA is highly correlated. PMID- 27485269 TI - Amine coupling versus biotin capture for the assessment of sulfonamide as ligands of hCA isoforms. AB - This work was dedicated to the development of a reliable SPR method allowing the simultaneous and quick determination of the affinity and selectivity of designed sulfonamide derivatives for hCAIX and hCAXII versus hCAII, in order to provide an efficient tool to discover drugs for anticancer therapy of solid tumors. We performed for the first time a comparison of two immobilization approaches of hCA isoforms. First one relies on the use of an amine coupling strategy, using a CM7 chip to obtain higher immobilization levels than with a CM5 chip and consequently the affinity with an higher precision (CV% < 10%). The second corresponds to a capture of proteins on a streptavidin chip, named CAP chip, after optimization of biotinylation conditions (amine versus carboxyl coupling, biotin to protein ratio). Thanks to the amine coupling approach, only hCAII and hCAXII isoforms were efficiently biotinylated to reach relevant immobilization (3000 RU and 2700 RU, respectively) to perform affinity studies. For hCAIX, despite a successful biotinylation, capture on the CAP chip was a failure. Finally, concordance between affinities obtained for the three derivatives to CAs isozymes on both chips has allowed to valid the approaches for a further screening of new derivatives. PMID- 27485270 TI - Development of a scintillation proximity binding assay for high-throughput screening of hematopoietic prostaglandin D2 synthase. AB - Prostaglandin D2 synthase (PGDS) catalyzes the isomerization of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2). PGD2 produced by hematopoietic prostaglandin D2 synthase (H-PGDS) in mast cells and Th2 cells is proposed to be a mediator of allergic and inflammatory responses. Consequently, inhibitors of H-PGDS represent potential therapeutic agents for the treatment of inflammatory diseases such as asthma. Due to the instability of the PGDS substrate PGH2, an in-vitro enzymatic assay is not feasible for large-scale screening of H-PGDS inhibitors. Herein, we report the development of a competition binding assay amenable to high-throughput screening (HTS) in a scintillation proximity assay (SPA) format. This assay was used to screen an in-house compound library of approximately 280,000 compounds for novel H-PGDS inhibitors. The hit rate of the H-PGDS primary screen was found to be 4%. This high hit rate suggests that the active site of H-PGDS can accommodate a large diversity of chemical scaffolds. For hit prioritization, these initial hits were rescreened at a lower concentration in SPA and tested in the LAD2 cell assay. 116 compounds were active in both assays with IC50s ranging from 6 to 807 nM in SPA and 82 nM to 10 MUM in the LAD2 cell assay. PMID- 27485271 TI - Type-specific photoreceptor loss in pigeons after disruption of parasympathetic control of choroidal blood flow by the medial subdivision of the nucleus of Edinger-Westphal. AB - The medial part of the nucleus of Edinger-Westphal (EWM) in birds mediates light regulated adaptive increases in choroidal blood flow (ChBF). We sought to characterize the effect of loss of EWM-mediated ChBF regulation on photoreceptor health in pigeons housed in either moderate intensity diurnal or constant light (CL). Photoreceptor abundance following complete EWM destruction was compared to that following a lesion in the pupil control circuit (as a control for spread of EWM lesions to the nearby pupil-controlling lateral EW) or following no EW damage. Birds were housed post-lesion in a 12 h 400 lux light/12 h dark light cycle for up to 16.5 months, or in constant 400 lux light for up to 3 weeks. Paraformaldehyde-glutaraldehyde fixed eyes were embedded in plastic, sectioned, slide-mounted, and stained with toluidine blue/azure II. Blinded analysis of photoreceptor outer segment abundance was performed, with outer segment types distinguished by oil droplet tint and laminar position. Brains were examined histologically to assess lesion accuracy. Disruption of pupil control had no adverse effect on photoreceptor outer segment abundance in either diurnal light or CL, but EWM destruction led to 50-60% loss of blue/violet cone outer segments in both light conditions, and a 42% loss of principal cone outer segments in CL. The findings indicate that adaptive regulation of ChBF by the EWM circuit plays a role in maintaining photoreceptor health and mitigates the harmful effect of light on photoreceptors, especially short wavelength-sensitive cone photoreceptors. PMID- 27485272 TI - Antioxidant status of serum bilirubin and uric acid in patients with polymyositis and dermatomyositis. AB - OBJECTIVE: Oxidative stress and variations in antioxidant status are implicated in the pathogenesis of inflammatory and autoimmune diseases. Polymyositis and dermatomyositis (PM/DM) are autoimmune diseases with inflammatory cells infiltrating into skeletal muscles, and the antioxidant status is still controversial. The aim of our study was to investigate the correlation between PM/DM and the antioxidant status of serum bilirubin (Tbil, Dbil and Ibil) and uric acid (UA). MATERIALS AND METHODS: We measured serum concentrations of bilirubin (Tbil, Dbil and Ibil) and uric acid in 384 individuals, including 110 PM/DM patients and 274 healthy controls. RESULTS: We found that PM/DM patients had significantly lower serum concentrations of bilirubin (Tbil and Ibil) and uric acid than healthy controls, whether male or female. Also, after separately adjusting the covariances of age and gender, Tbil, Dbil, Ibil and UA were all relevant factors for PM/DM. Moreover, there were no significant differences in serum antioxidant molecule levels between PM and DM subgroups. CONCLUSION: Our study demonstrated the low serum levels of bilirubin and uric acid in patients with PM/DM. This suggested low antioxidant status in PM/DM patients with excessive oxidative stress. PMID- 27485275 TI - Dissociative trance and spirit possession: Challenges for cultures in transition. AB - The cross-cultural validity of dissociative possession and trance disorders is a matter of some debate, limiting research and meaningful interpretation of prevalence data. Intimate to these concerns is the status of spirit possession categories studied in the social sciences, particularly anthropology. These two categories are phenomenologically related and display similar epidemiological associations. In India, dissociative and conversion disorders are fairly common in clinical settings. There is no doubt that there are true cultural variations in possession and trance disorders. A new framework may enable clinicians to better understand possession states and spirit possession. PMID- 27485274 TI - Population genomics reveals multiple drivers of population differentiation in a sex-role-reversed pipefish. AB - A major goal of molecular ecology is to identify the causes of genetic and phenotypic differentiation among populations. Population genomics is suitably poised to tackle these key questions by diagnosing the evolutionary mechanisms driving divergence in nature. Here, we set out to investigate the evolutionary processes underlying population differentiation in the Gulf pipefish, Syngnathus scovelli. We sampled approximately 50 fish from each of 12 populations distributed from the Gulf coast of Texas to the Atlantic coast of Florida and performed restriction-site-associated DNA sequencing to identify SNPs throughout the genome. After imposing quality and stringency filters, we selected a panel of 6348 SNPs present in all 12 populations, 1753 of which were not physically linked. We identified a genome-wide pattern of isolation by distance, in addition to a more substantial genetic break separating populations in the Gulf of Mexico from those in the Atlantic. We also used several divergence outlier approaches and tests for genotype-environment correlations to identify 400 SNPs putatively involved in local adaptation. Patterns of phenotypic differentiation and variation diverged from the overall genomic pattern, suggesting that selection, phenotypic plasticity or demographic factors may be shaping phenotypes in distinct populations. Overall, our results suggest that population divergence is driven by a variety of factors in S. scovelli, including neutral processes and selection on multiple traits. PMID- 27485273 TI - Evaluation of folate receptor 1 (FOLR1) mRNA expression, its specific promoter methylation and global DNA hypomethylation in type I and type II ovarian cancers. AB - BACKGROUND: In this retrospective study we evaluated the respective correlations and clinical relevance of FOLR1 mRNA expression, FOLR1 promoter specific methylation and global DNA hypomethylation in type I and type II ovarian cancer. METHODS: Two hundred fifty four ovarian cancers, 13 borderline tumours and 60 samples of healthy fallopian epithelium and normal ovarian epithelium were retrospectively analysed for FOLR1 expression with RT-PCR. FOLR1 DNA promoter methylation and global DNA hypomethylation (measured by means of LINE1 DNA hypomethylation) were evaluated with MethyLight technique. RESULTS: No correlation between FOLR1 mRNA expression and its specific promoter DNA methylation was found neither in type I nor in type II cancers, however, high FOLR1 mRNA expression was found to be correlated with global DNA hypomethylation in type II cancers (p = 0.033). Strong FOLR1 mRNA expression was revealed for Grades 2-3, FIGO stages III-IV, residual disease > 0, and serous histotype. High FOLR1 expression was found to predict increased platinum sensitivity in type I cancers (odds ratio = 3.288; 1.256-10.75; p = 0.020). One-year survival analysis showed in type I cancers an independent better outcome for strong expression of FOLR1 in FIGO stage III and IV. For the entire follow up period no significant independent outcome for FOLR1 expression was revealed. In type I cancers LINE 1 DNA hypomethylation was found to exhibit a worse PFS and OS which were confirmed to be independent in multivariate COX regression model for both PFS (p = 0.026) and OS (p = 0.012). CONCLUSION: No correlations were found between FOLR1 expression and its specific promoter methylation, however, high FOLR1 mRNA expression was associated with DNA hypomethylation in type II cancers. FOLR1 mRNA expression did not prove to predict clinical outcome in type II cancers, although strong FOLR1 expression generally denotes ovarian cancers with highly aggressive phenotype. In type I cancers, however, strong FOLR1 expression has been found to be a reliable indicator of improved platinum responsiveness reflecting a transient better one-year follow up outcome in highly FOLR1 expressing type I cancers. An independent prognostic role of global DNA hypomethylation was demonstrated in type I tumours. PMID- 27485276 TI - Coke Formation in a Zeolite Crystal During the Methanol-to-Hydrocarbons Reaction as Studied with Atom Probe Tomography. AB - Understanding the formation of carbon deposits in zeolites is vital to developing new, superior materials for various applications, including oil and gas conversion processes. Herein, atom probe tomography (APT) has been used to spatially resolve the 3D compositional changes at the sub-nm length scale in a single zeolite ZSM-5 crystal, which has been partially deactivated by the methanol-to-hydrocarbons reaction using (13) C-labeled methanol. The results reveal the formation of coke in agglomerates that span length scales from tens of nanometers to atomic clusters with a median size of 30-60 (13) C atoms. These clusters correlate with local increases in Bronsted acid site density, demonstrating that the formation of the first deactivating coke precursor molecules occurs in nanoscopic regions enriched in aluminum. This nanoscale correlation underscores the importance of carefully engineering materials to suppress detrimental coke formation. PMID- 27485277 TI - Controversies in Veterinary Nephrology: Renal Diets Are Indicated for Cats with International Renal Interest Society Chronic Kidney Disease Stages 2 to 4: The Pro View. AB - Renal diets have been the mainstay of therapy for cats with chronic kidney disease (CKD) for many decades. Clinical trials in cats with CKD have shown them to be effective in improving survival, reducing uremic crises, and improving serum urea nitrogen and phosphorous concentrations. It has shown that, when food intake is adequate, renal diets can maintain body weight and body condition scores for up to 2 years. Although some have questioned whether renal diets provide adequate protein and have advocated feeding higher-protein diets to cats with CKD, there is currently no convincing evidence in support of this proposal. PMID- 27485278 TI - Management of Proteinuria in Dogs and Cats with Chronic Kidney Disease. AB - Proteinuria is a negative prognostic indicator for dogs and cats with chronic kidney disease. A normal dog or cat should excrete very little protein and have a urine protein:creatinine ratio that is less than 0.4 or less than 0.2, respectively; persistent proteinuria above this magnitude warrants attention. Administration of angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers, blood pressure control and nutritional modification are considered a standard of care for renal proteinuria. Renal biopsy and administration of immunosuppressive agents should be considered in animals with glomerular proteinuria that have not responded to standard therapy. Targeted patient monitoring is essential when instituting management of proteinuria. PMID- 27485279 TI - Kidney Disease and the Nexus of Chronic Kidney Disease and Acute Kidney Injury: The Role of Novel Biomarkers as Early and Accurate Diagnostics. AB - Chronic kidney disease (CKD) and acute kidney injury (AKI) are interconnected and the presence of one is a risk for the other. CKD is an important predictor of AKI after exposure to nephrotoxic drugs or major surgery, whereas persistent or repetitive injury could result in the progression of CKD. This brings new perspectives to the diagnosis and monitoring of kidney diseases highlighting the need for a panel of kidney-specific biomarkers that reflect functional as well as structural damage and recovery, predict potential risk and provide prognosis. This article discusses the kidney-specific biomarkers, symmetric dimethylarginine (SDMA), clusterin, cystatin B, and inosine. PMID- 27485280 TI - Protective effects of ghrelin against oxidative stress, inducible nitric oxide synthase and inflammation in a mouse model of myocardial ischemia/reperfusion injury via the HMGB1 and TLR4/NF-kappaB pathway. AB - The present study aimed to investigate the protective effects of ghrelin against oxidative stress, inducible nitric oxide synthase (iNOS) and inflammation in a mouse model of myocardial ischemia/reperfusion injury (MIRI). In addition, the study aimed to determine its underlying mechanisms. A mouse model of MIRI was used in vivo, in order to ascertain the protective effects of ghrelin on MIRI. Commercial kits were used to measure the serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH) in MIRI mice. Furthermore, Evan's Blue triphenyltetrazolium chloride solution was used to analyze the protective effects of ghrelin against infarct size in MIRI mice. The underlying mechanisms were determined by measuring MIRI-induced tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, superoxide dismutase (SOD), glutathione (GSH), GSH-peroxidase (GSH-PX), malondialdehyde (MDA) and caspase-3/caspase-9 activities, and iNOS, high mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4) and nuclear factor (NF)-kappaB protein expression in MIRI mice. The results demonstrated that MIRI led to an increase in infarct size; CK, LDH, TNF-alpha, IL-6, MDA, caspase-3 and caspase-9 serum levels; and iNOS protein expression. MIRI resulted in inhibition of SOD, FSH and GSH-PX levels. Conversely, these alterations were significantly inhibited following treatment with ghrelin. In addition, the protective effects of ghrelin against MIRI suppressed HMGB1, TLR4 and NF-kappaB protein expression in MIRI mice. The present study revealed that ghrelin exerted protective effects against oxidative stress, iNOS and inflammation in MIRI mice via the HMGB1/TLR4/NF-kappaB pathway. PMID- 27485281 TI - Distribution of tetracycline resistance genes in anaerobic treatment of waste sludge: The role of pH in regulating tetracycline resistant bacteria and horizontal gene transfer. AB - Although pH value has been widely regarded as an important factor that affects resource recovery of waste sludge, the potential influence of diverse pHs on the distribution of tetracycline resistance genes (TRGs) during sludge anaerobic treatment is largely unknown. Here we reported that in the range of pH 4-10, 0.58 1.18 log unit increase of target TRGs was observed at pH 4, compared with that at pH 7, while 0.70-1.31 log unit further removal were obtained at pH 10. Mechanism study revealed that varied pHs not only altered the community structures of tetracycline resistant bacteria (TRB), but also changed their relative abundances, benefitting the propagation (acidic pHs) or attenuation (alkaline pHs) of TRB. Further investigation indicated that the amount and gene-possessing abilities of key genetic vectors for horizontal TRGs transfer were greatly promoted at acidic pHs but restricted under alkaline conditions. PMID- 27485282 TI - Glucose supplementation-induced changes in the Auxenochlorella protothecoides fatty acid composition suitable for biodiesel production. AB - This study evaluates the effect of different concentrations of glucose supplementation on growth, lipid accumulation, and the fatty acid profile in the Auxenochlorella protothecoides. Addition of glucose promoted the growth rate and decreased the chlorophyll content. Compared with photoautotrophic cells, an increase in the lipid content was observed in mixotrophic cells. The glucose addition induced changes in the fatty acid profile. Higher content of saturated fatty acids was found in the case of cells growing in the glucose-free medium. Oleic acid was the predominant component in mixotrophic cells supplemented with 5gL(-1) glucose, while linoleic acids dominated in cultures supplemented with both 1 and 3gL(-1) glucose. The use of glucose was associated with decreased levels of linolenic acid and PUFA. The changes in the fatty acid profile in mixotrophic cells are favourable for biodiesel production. PMID- 27485283 TI - Ion mobility spectrometry-mass spectrometry examination of the structures, stabilities, and extents of hydration of dimethylamine-sulfuric acid clusters. AB - We applied an atmospheric pressure differential mobility analyzer (DMA) coupled to a time-of-flight mass spectrometer to examine the stability, mass-mobility relationship, and extent of hydration of dimethylamine-sulfuric acid cluster ions, which are of relevance to nucleation in ambient air. Cluster ions were generated by electrospray ionization and were of the form: [H((CH3)2NH)x(H2SO4)y](+) and [(HSO4)((CH3)2NH)x(H2SO4)y](-), where 4 <= x <= 8, and 5 <= y <= 12. Under dry conditions, we find that positively charged cluster ions dissociated via loss of both multiple dimethylamine and sulfuric acid molecules after mobility analysis but prior to mass analysis, and few parent ions were detected in the mass spectrometer. Dissociation also occurred for negative ions, but to a lesser extent than for positive ions for the same mass spectrometer inlet conditions. Under humidified conditions (relative humidities up to 30% in the DMA), positively charged cluster ion dissociation in the mass spectrometer inlet was mitigated and occurred primarily by H2SO4 loss from ions containing excess acid molecules. DMA measurements were used to infer collision cross sections (CCSs) for all identifiable cluster ions. Stokes-Millikan equation and diffuse/inelastic gas molecule scattering predicted CCSs overestimate measured CCSs by more than 15%, while elastic-specular collision model predictions are in good agreement with measurements. Finally, cluster ion hydration was examined by monitoring changes in CCSs with increasing relative humidity. All examined cluster ions showed a modest amount of water molecule adsorption, with percentage increases in CCS smaller than 10%. The extent of hydration correlates directly with cluster ion acidity for positive ions. PMID- 27485284 TI - Long-Term, Prospective Performance of the MD Anderson Dysphagia Inventory in "Low Intermediate Risk" Oropharyngeal Carcinoma After Intensity Modulated Radiation Therapy. AB - PURPOSE: To characterize long-term MD Anderson Dysphagia Inventory (MDADI) results after primary intensity modulated radiation therapy (IMRT) for oropharyngeal carcinoma (OPC) among patients with "low-intermediate risk" OPC who would be eligible for current trials (eg, ECOG 3311, NRG HN002, CRUK PATHOS). METHODS AND MATERIALS: A retrospective pooled analysis combined data from 3 single-institution clinical trials for advanced-stage head and neck carcinoma. Inclusion criteria were clinical stage III/IV OPC (T1-2/N1-2b, T3/N0-2b) treated with definitive split-field IMRT and prospectively collected MDADI at baseline and at least 1 posttreatment interval available in trial databases. Patients were sampled to represent likely human papillomavirus (HPV)-associated disease (HPV+/p16+ or <10 pack-years if HPV/p16 unknown). The MDADI composite scores were collected at baseline and 6, 12, and 24 months after treatment. Pairwise tests were Bonferroni corrected for multiple comparisons. RESULTS: Forty-six patients were included. All received bilateral neck irradiation with a median dose of 70 Gy and systemic therapy (57% concurrent, 43% induction only). Overall the mean baseline MDADI composite score was 90.1, dropping to 74.6 at 6 months (P<.0001) and rising to 78.5 (P<.0001) and 83.1 (P=.002) by 12 and 24 months relative to baseline, respectively, representing a clinically meaningful drop in MDADI scores at 6 months that partially recovers by 24 months (6 vs 24 months, P=.05). Poor MDADI scores (composite <60) were reported in 4%, 11%, 15%, and 9% of patients at baseline and 6, 12, and 24 months, respectively. Fifteen percent of patients had a persistently depressed composite score by at least 20 points at the 24-month interval. CONCLUSION: "Low-intermediate risk" patients with OPC treated with laryngeal/esophageal inlet dose-optimized split-field IMRT are highly likely to report recovery of acceptable swallowing function in long-term follow-up. Only 15% report poor swallowing function and/or persistently depressed MDADI at 12 months or more after IMRT. These data serve as a benchmark future trial design and endpoint interpretation. PMID- 27485286 TI - MCM2-7 conformational changes in the presence of DNA. PMID- 27485285 TI - Identifying Urinary and Serum Exosome Biomarkers for Radiation Exposure Using a Data Dependent Acquisition and SWATH-MS Combined Workflow. AB - PURPOSE: Early and accurate assessment of radiation injury by radiation responsive biomarkers is critical for triage and early intervention. Biofluids such as urine and serum are convenient for such analysis. Recent research has also suggested that exosomes are a reliable source of biomarkers in disease progression. In the present study, we analyzed total urine proteome and exosomes isolated from urine or serum for potential biomarkers of acute and persistent radiation injury in mice exposed to lethal whole body irradiation (WBI). METHODS AND MATERIALS: For feasibility studies, the mice were irradiated at 10.4 Gy WBI, and urine and serum samples were collected 24 and 72 hours after irradiation. Exosomes were isolated and analyzed using liquid chromatography mass spectrometry/mass spectrometry-based workflow for radiation exposure signatures. A data dependent acquisition and SWATH-MS combined workflow approach was used to identify significantly exosome biomarkers indicative of acute or persistent radiation-induced responses. For the validation studies, mice were exposed to 3, 6, 8, or 10 Gy WBI, and samples were analyzed for comparison. RESULTS: A comparison between total urine proteomics and urine exosome proteomics demonstrated that exosome proteomic analysis was superior in identifying radiation signatures. Feasibility studies identified 23 biomarkers from urine and 24 biomarkers from serum exosomes after WBI. Urinary exosome signatures identified different physiological parameters than the ones obtained in serum exosomes. Exosome signatures from urine indicated injury to the liver, gastrointestinal, and genitourinary tracts. In contrast, serum showed vascular injuries and acute inflammation in response to radiation. Selected urinary exosomal biomarkers also showed changes at lower radiation doses in validation studies. CONCLUSIONS: Exosome proteomics revealed radiation- and time-dependent protein signatures after WBI. A total of 47 differentially secreted proteins were identified in urinary and serum exosomes. Together, these data showed the feasibility of defining biomarkers that could elucidate tissue-associated and systemic response caused by high-dose ionizing radiation. This is the first report using an exosome proteomics approach to identify radiation signatures. PMID- 27485288 TI - Effect of gear ratio on peak power and time to peak power in BMX cyclists. AB - The aim of this study was to ascertain if gear ratio selection would have an effect on peak power and time to peak power production in elite Bicycle Motocross (BMX) cyclists. Eight male elite BMX riders volunteered for the study. Each rider performed three, 10-s maximal sprints on an Olympic standard indoor BMX track. The riders' bicycles were fitted with a portable SRM power meter. Each rider performed the three sprints using gear ratios of 41/16, 43/16 and 45/16 tooth. The results from the 41/16 and 45/16 gear ratios were compared to the current standard 43/16 gear ratio. Statistically, significant differences were found between the gear ratios for peak power (F(2,14) = 6.448; p = .010) and peak torque (F(2,14) = 4.777; p = .026), but no significant difference was found for time to peak power (F(2,14) = 0.200; p = .821). When comparing gear ratios, the results showed a 45/16 gear ratio elicited the highest peak power,1658 +/- 221 W, compared to 1436 +/- 129 W and 1380 +/- 56 W, for the 43/16 and 41/16 ratios, respectively. The time to peak power showed a 41/16 tooth gear ratio attained peak power in -0.01 s and a 45/16 in 0.22 s compared to the 43/16. The findings of this study suggest that gear ratio choice has a significant effect on peak power production, though time to peak power output is not significantly affected. Therefore, selecting a higher gear ratio results in riders attaining higher power outputs without reducing their start time. PMID- 27485287 TI - Colorectal cancer in southern Israel: Comparison between Bedouin Arab and Jewish patients. AB - PURPOSE: Colorectal cancer (CRC) is the second most common malignancy and the third leading cause of cancer deaths in Israel; it is less common among the Arab than the Jewish population. This study compares the clinico-pathologic features, treatment, and prognosis between Bedouin-Arab (BA) and Jewish CRC patients treated at our medical centre. METHODS: The medical records of 56 BA patients with CRC were compared retrospectively to 115 Jewish patients. Collected data included age, gender, history of smoking, family history of cancer, presenting symptoms, laboratory tests, previous malignancy, tumor characteristics, surgery type, stoma formation and closure, types of adjuvant treatment, and outcome. RESULTS: BA patients were younger (mean age 68 versus 57 years, p < 0.001), showed a higher incidence in females (p = 0.045), and had a lower frequency of a family history of cancer (p = 0.005) compared to Jewish patients. BA patients had a higher presentation of rectal bleeding and a lower rate of anemia at tumor diagnosis (p = 0.05 and p = 0.004, respectively) with a more distal location of the tumor (p = 0.003). BA patients more often received chemotherapy and radiotherapy (p = 0.02 and p = 0.04, respectively). Disease-free survival was shorter among BA patients (p = 0.023); overall survival was similar in both groups. CONCLUSIONS: CRC in BAs is characterized by a higher proportion of female, younger age, and higher proportion of distal location compared to Jewish patients. These differences in biology may be related to differences in past lifestyles and diet of BA compared to Jewish patients, and are expected to decrease in the following years as the BA population continues to undergo "westernization" changes. PMID- 27485289 TI - Isotopic Composition of Atmospheric Mercury in China: New Evidence for Sources and Transformation Processes in Air and in Vegetation. AB - The isotopic composition of atmospheric total gaseous mercury (TGM) and particle bound mercury (PBM) and mercury (Hg) in litterfall samples have been determined at urban/industrialized and rural sites distributed over mainland China for identifying Hg sources and transformation processes. TGM and PBM near anthropogenic emission sources display negative delta(202)Hg and near-zero Delta(199)Hg in contrast to relatively positive delta(202)Hg and negative Delta(199)Hg observed in remote regions, suggesting that different sources and atmospheric processes force the mass-dependent fractionation (MDF) and mass independent fractionation (MIF) in the air samples. Both MDF and MIF occur during the uptake of atmospheric Hg by plants, resulting in negative delta(202)Hg and Delta(199)Hg observed in litter-bound Hg. The linear regression resulting from the scatter plot relating the delta(202)Hg to Delta(199)Hg data in the TGM samples indicates distinct anthropogenic or natural influences at the three study sites. A similar trend was also observed for Hg accumulated in broadleaved deciduous forest foliage grown in areas influenced by anthropogenic emissions. The relatively negative MIF in litter-bound Hg compared to TGM is likely a result of the photochemical reactions of Hg(2+) in foliage. This study demonstrates the diagnostic stable Hg isotopic composition characteristics for separating atmospheric Hg of different source origins in China and provides the isotopic fractionation clues for the study of Hg bioaccumulation. PMID- 27485290 TI - Tiron ameliorates oxidative stress and inflammation in a murine model of airway remodeling. AB - Airway remodeling includes lung structural changes that have a role in the irreversibility of pulmonary dysfunction shown in chronic bronchial asthmatics. The current experiment investigated the effect of the mitochondrial antioxidant, tiron in comparison with dexamethasone (DEXA) on airway remodeling in chronic asthma. Sensitized BALB/c mice were challenged with ovalbumin (OVA) aerosol for 8weeks, OVA sensitized-challenged mice were treated with either DEXA or tiron, respectively. After that, lung tissue and bronchoaveolar lavage fluid (BALF) were used for measurement of different biological markers. Lungs were examined for histopathological changes and immunohistochemistry. Upon comparing with vehicle treated animals, trion or DEXA treatment significantly reduced eosinophils, lymphocytes, neutrophils and macrophages count in the BALF. Both drugs significantly alleviated chronic OVA-induced oxidative stress as illustrated by decreased pulmonary malondialdenhyde (MDA) and increased glutathione (GSH) and superoxide dismutase (SOD) levels. Asthmatic mice exhibited elevated levels of NOx, IL-13 and TGF-beta1 that were reduced by DEXA and tiron. Histopathological changes and increased immunoreactivity of nuclear factor-Kappa B (NF-kappa B) in OVA-challenged mice were minimized by tiron and DEXA treatment. In conclusion, in this model of chronic asthma DEXA and tiron ameliorated airway remodeling and inflammation in experimental chronic asthma with no difference between the effect of tiron and DEXA. Tiron has a potential role as adjuvant treatment in chronic asthma. PMID- 27485292 TI - Calcium-induced conformational changes of Thrombospondin-1 signature domain: implications for vascular disease. AB - CONTEXT: Thrombospondin1 (TSP1) participates in numerous signaling pathways critical for vascular physiology and disease. The conserved signature domain of thrombospondin 1 (TSP1-Sig1) comprises three epidermal growth factor (EGF), 13 calcium-binding type 3 thrombospondin (T3) repeats, and one lectin-like module arranged in a stalk-wire-globe topology. TSP1 is known to be present in both calcium-replete (Holo-) and calcium-depleted (Apo-) state, each with distinct downstream signaling effects. OBJECTIVE: To prepare a homology model of TSP1-Sig1 and investigate the effect of calcium on its dynamic structure and interactions. METHODS: A homology model of Holo-TSP1-Sig1 was prepared with TSP2 as template in Swissmodel workspace. The Apo-form of the model was obtained by omitting the bound calcium ions from the homology model. Molecular dynamics (MD) simulation studies (100 ns) were performed on the Holo- and Apo- forms of TSP1 using Gromacs4.6.5. RESULTS AND DISCUSSION: After simulation, Holo-TSP1-Sig1 showed significant reorientation at the interface of the EGF1-2 and EGF2-3 modules. The T3 wire is predicted to show the maximum mobility and deviation from the initial model. In Apo-TSP1-Sig1 model, the T3 repeats unfolded and formed coils with predicted increase in flexibility. Apo-TSP1-Sig1model also predicted the exposure of the binding sites for neutrophil elastase, integrin and fibroblast growth factor 2. We present a structural model and hypothesis for the role of TSP1-Sig1 interactions in the development of vascular disorders. CONCLUSION: The simulated model of the fully calcium-loaded and calcium-depleted TSP1-Sig1 may enable the development of its interactions as a novel therapeutic target for the treatment of vascular diseases. PMID- 27485291 TI - The role of the CCN family of proteins in blood cancers. AB - Haematopoiesis is the term used to describe the production of blood cells. This is a tightly regulated hierarchical system in which mature circulating blood cells develop from a small population of haematopoietic stem (HSC) and progenitor cells within the microenvironment of the bone marrow. Molecular and genetic abnormalities arising in these stem cells lead to a block in the normal programme of proliferation and differentiation and result in the development of the blood cancers known as the leukaemias and lymphomas. Recently the regulatory role of the bone marrow microenvironment or niche has also become increasingly recognised. The interface between the bone and bone marrow (endosteum) and the region surrounding the blood vessels (perivascular) provide distinct niches harbouring quiescent HSC or proliferative HSC respectively. Current chemotherapeutic regimes can often successfully target the proliferative HSC but disease relapse occurs due to residual quiescent HSC. Understanding these developmental and regulatory processes and the associated cell communication mechanisms are thus crucial to the development of new treatment strategies. The CCN family of proteins have been recognised to play a key role in all aspects of haematopoiesis. PMID- 27485293 TI - The Moses-Littenberg meta-analytical method generates systematic differences in test accuracy compared to hierarchical meta-analytical models. AB - OBJECTIVE: To compare meta-analyses of diagnostic test accuracy using the Moses Littenberg summary receiver operating characteristic (SROC) approach with those of the hierarchical SROC (HSROC) model. STUDY DESIGN AND SETTING: Twenty-six data sets from existing test accuracy systematic reviews were reanalyzed with the Moses-Littenberg model, using equal weighting ("E-ML") and weighting by the inverse variance of the log DOR ("W-ML"), and with the HSROC model. The diagnostic odds ratios (DORs) were estimated and covariates added to both models to estimate relative DORs (RDORs) between subgroups. Models were compared by calculating the ratio of DORs, the ratio of RDORs, and P-values for detecting asymmetry and effects of covariates on DOR. RESULTS: Compared to the HSROC model, the Moses-Littenberg model DOR estimates were a median of 22% ("E-ML") and 47% ("W-ML") lower at Q*, and 7% and 42% lower at the central point in the data. Instances of the ML models giving estimates higher than the HSROC model also occurred. Investigations of heterogeneity also differed; the Moses-Littenberg models on average estimating smaller differences in RDOR. CONCLUSIONS: Moses Littenberg meta-analyses can generate lower estimates of test accuracy, and smaller differences in accuracy, compared to mathematically superior hierarchical models. This has implications for the usefulness of meta-analyses using this approach. We recommend meta-analysis of diagnostic test accuracy studies to be conducted using available hierarchical model-based approaches. PMID- 27485294 TI - Hydantoin: The mechanism of its in vitro anti-enterovirus activity revisited. AB - It has been generally accepted that hydantoin [5-(3,4 dichlorophenyl)methylhydantoin] exerts its anti-enterovirus activity by solely inhibiting viral assembly. However, we here show that hydantoin inhibits enteroviral RNA synthesis as well as subgenomic replication in a dose-dependent manner. We demonstrate that inhibition of RNA synthesis is the predominant mechanism of action at relatively high concentrations of hydantoin. However, at lower concentrations inhibition of viral morphogenesis is the main mechanism of action. Thus, hydantoin inhibits enteroviral replication by two distinct mechanisms. PMID- 27485295 TI - Tax on saturated fat-does it work? PMID- 27485296 TI - Evolution of Nonmirror Image Fluorescence Spectra in Conjugated Polymers and Oligomers. AB - The nonmirror image relationship between absorption and fluorescence spectra of conjugated polymers contrasts with most organic chromophores and is widely considered a signature of interchromopohore energy funneling. We apply broad-band ultrafast fluorescence spectroscopy to resolve the evolution of fluorescence spectra for dilute solutions of conjugated oligothiophenes, where no energy transfer is possible. Fluorescence spectra evolve from a mirror image of absorption, which lacks vibronic structure, toward a spectrally narrower and vibronically structured species on the hundreds of femtosecond to early picosecond time scale. Our analysis of this fluorescence spectral evolution shows that a broad distribution of torsional conformers is driven to rapidly planarize in the excited state, including in solid films, which is supported by Raman spectroscopy and quantum chemical modeling. Our data have important implications for understanding different energy-transfer regimes that are delineated by structural relaxation. PMID- 27485298 TI - Spiritual Factors Predict State and Trait Anxiety. AB - This research study was designed to examine the effect of spiritual well-being and spirituality on state and trait anxiety. Two hundred and thirty-eight adults in the USA were surveyed using the State-Trait Anxiety Inventory, Duke University Religion Index, Spiritual Well-Being Scale, and Participant Questionnaire. Results indicate that spiritual well-being can predict 39.1 % of an adult's state anxiety and 37.9 % of trait anxiety. Furthermore, frequency of religious attendance, frequency of private religious activity, and intrinsic religiosity can predict 6.2 % of an adult's state anxiety and 8.6 % of trait anxiety. Recommendations for researchers and implications for clinicians are discussed. PMID- 27485299 TI - Neuroprotection induced by post-conditioning following ischemia/reperfusion in mice is associated with altered microRNA expression. AB - Ischemic preconditioning and ischemic postconditioning (IPostC) represent promising strategies to reduce ischemia-reperfusion (I/R) injury and attenuate the lethal ischemic damage following stroke. However, the mechanism underlying this attenuation remains to be elucidated. It was hypothesized that alterations in microRNA (miRNA) expression in the cerebral cortex and hippocampus of mice following I/R is associated with the functional improvement induced by IPostC. Behavioral changes were assessed in a mouse model of I/R in the absence or presence of IPostC, followed by microarray analyses to investigate the expressional alterations of miRNAs in the cerebral cortex and hippocampus of mice. The results of the present study revealed that IPostC abrogated the neurological impairment and hippocampus-associated cognitive deficits induced by I/R, and upregulated or downregulated the expression levels of numerous miRNAs. Furthermore, the upregulation of miR-19a, and the downregulation of miR-1, let-7f and miR-124 expression levels following IPostC was confirmed utilizing reverse transcription-quantitative polymerase chain reaction. The results of the present study demonstrated that alterations in miRNA expression in the cerebral cortex and hippocampus of mice following I/R was associated with the neuroprotection induced by IPostC. PMID- 27485300 TI - 'Quasi-Mixture' Descriptors for QSPR Analysis of Molecular Macroscopic Properties. The Critical Properties of Organic Compounds. AB - Rational approach towards the QSAR/QSPR modeling requires the descriptors to be computationally efficient, yet physically and chemically meaningful. On the basis of existing simplex representation of molecular structure (SiRMS) the novel 'quasi-mixture' descriptors were developed in order to accomplish the goal of characterization molecules on 2D level (i.e. without explicit generation of 3D structure and exhaustive conformational search) with account for potential intermolecular interactions. The critical properties of organic compounds were chosen as target properties for the estimation of descriptors' efficacy because of their well-known physical nature, rigorously estimated experimental errors and large quantity of experimental data. Among described properties are critical temperature, pressure and volume. Obtained models have high statistical characteristics, therefore showing the efficacy of suggested 'quasi-mixture' approach. Moreover, 'quasi-mixture' approach, as a branch of the SiRMS, allows to interpret results in terms of simple basic molecular properties. The obtained picture of influences corresponds to the accepted theoretical views. PMID- 27485301 TI - Global Performance and Trend of QSAR/QSPR Research: A Bibliometric Analysis. AB - A bibliometric analysis based on the Science Citation Index Expanded was conducted to provide insights into the publication performance and research trend of quantitative structure-activity relationship (QSAR) and quantitative structure property relationship (QSPR) from 1993 to 2012. The results show that the number of articles per year quadrupled from 1993 to 2006 and plateaued since 2007. Journal of Chemical Information and Modeling was the most prolific journal. The internal methodological innovations in acquiring molecular descriptors and modeling stimulated the articles' increase in the research fields of drug design and synthesis, and chemoinformatics; while the external regulatory demands on model validation and reliability fueled the increase in environmental sciences. "Prediction endpoints", "statistical algorithms", and "molecular descriptors" were identified as three research hotspots. The articles from developed countries were larger in number and more influential in citation, whereas those from developing countries were higher in output growth rates. PMID- 27485297 TI - Impact of aerobic exercise on levels of IL-4 and IL-10: results from two randomized intervention trials. AB - The mechanisms whereby regular exercise reduces chronic inflammation remain unclear. We investigated whether regular aerobic exercise alters basal levels of interleukin (IL)-10 and IL-4 in two randomized trials of physical activity. The Alberta Physical Activity and Breast Cancer Prevention Trial (ALPHA, n = 320) and the Breast Cancer and Exercise Trial in Alberta (BETA, n = 400) were two-center, two-armed randomized trials in inactive, healthy, postmenopausal women. Both trials included an exercise intervention prescribed five times/week and no dietary changes. In ALPHA, the exercise group was prescribed 225 min/week versus no activity in the controls. BETA examined dose-response effects comparing 300 (HIGH) versus 150 (MODERATE) min/week. Plasma concentrations of IL-10 and IL-4 were measured at baseline, 6, and 12 months. Intention-to-treat (ITT) analysis was performed using linear mixed models adjusted for baseline biomarker concentrations. Circulating anti-inflammatory cytokine levels decreased among all groups, with percent change ranging from -3.4% (controls) to -8.2% (HIGH) for IL 4 and -1.6% (controls) to -7.5% (HIGH) for IL-10. No significant group differences were found for IL-4 (ALPHA P = 0.54; BETA P = 0.32) or IL-10 (ALPHA P = 0.84; BETA P = 0.68). Some evidence for moderation of the effect of exercise by baseline characteristics was found for IL-10 but not for IL-4. Results from these two large randomized aerobic exercise intervention trials suggest that aerobic exercise does not alter IL-10 or IL-4 in a manner consistent with chronic disease and cancer prevention. PMID- 27485302 TI - Computational Prediction of Drug?Target Interactions Using Chemical, Biological, and Network Features. AB - Drug?target interactions (DTIs) are central to current drug discovery processes. Efforts have been devoted to the development of methodology for predicting DTIs and drug?target interaction networks. Most existing methods mainly focus on the application of information about drug or protein structure features. In the present work, we proposed a computational method for DTI prediction by combining the information from chemical, biological and network properties. The method was developed based on a learning algorithm-random forest (RF) combined with integrated features for predicting DTIs. Four classes of drug?target interaction networks in humans involving enzymes, ion channels, G-protein-coupled receptors (GPCRs) and nuclear receptors, are independently used for establishing predictive models. The RF models gave prediction accuracy of 93.52 %, 94.84 %, 89.68 % and 84.72 % for four pharmaceutically useful datasets, respectively. The prediction ability of our approach is comparative to or even better than that of other DTI prediction methods. These comparative results demonstrated the relevance of the network topology as source of information for predicting DTIs. Further analysis confirmed that among our top ranked predictions of DTIs, several DTIs are supported by databases, while the others represent novel potential DTIs. We believe that our proposed approach can help to limit the search space of DTIs and provide a new way towards repositioning old drugs and identifying targets. PMID- 27485303 TI - Molecular Dynamics of Major Allergens from Alternaria, Birch Pollen and Peach. AB - In the search for factors that make a protein allergenic (an issue that remains so far elusive) some common features of allergens such as small size, high stability and lipid binding are recognized in spite of their structural diversity. Other relevant but still poorly understood feature is their capability to form homodimers. We investigated by means of Molecular Dynamics (MD) calculations the stability in solution of several dimers of three major allergens from Alternaria mold, birch pollen, and peach fruit known to play essential roles in allergic disease. By running 20 ns MD simulations we found essential properties on solution that provide information of interest on their dimerization, stability of their epitopes and dynamical features of ligand binding cavities. Our results show that three essential allergen proteins display a distinct behavior on their trends to form homodimers in solution. PMID- 27485304 TI - Interaction of Flaviviruses with Reproduction Inhibitors Binding in beta-OG Pocket: Insights from Molecular Dynamics Simulations. AB - Flaviviral diseases, including dengue fever, West Nile fever, yellow fever, tick borne encephalitis, Omsk haemorrhagic fever, and Powassan encephalitis, threaten human health all over the world. Lack of effective antivirals targeting replication cycle of flaviviruses makes the search of such compounds a challenging task. Recently we have identified a reproduction inhibitor effective against tick-borne encephalitis virus and Powassan virus (POWV) (ACS Med. Chem. Lett., 2013, 4, 869-874). To enable using this inhibitor as a template for 3D pharmacophore search, a biologically active conformation of this molecule should have been established. Here we performed molecular dynamics simulations of the complexes between the different enantiomers of the inhibitor and POWV envelope (E) proteins, putative targets of the inhibitor, in the different protonation states corresponding to the different stages of membrane fusion process. Several stable conformations of the inhibitor were identified, opening routes for further design of more advanced molecules. PMID- 27485305 TI - Erratum: Fractal Dimensions of Macromolecular Structures. PMID- 27485308 TI - Evidence that birds sleep in mid-flight. AB - Many birds fly non-stop for days or longer, but do they sleep in flight and if so, how? It is commonly assumed that flying birds maintain environmental awareness and aerodynamic control by sleeping with only one eye closed and one cerebral hemisphere at a time. However, sleep has never been demonstrated in flying birds. Here, using electroencephalogram recordings of great frigatebirds (Fregata minor) flying over the ocean for up to 10 days, we show that they can sleep with either one hemisphere at a time or both hemispheres simultaneously. Also unexpectedly, frigatebirds sleep for only 0.69 h d(-1) (7.4% of the time spent sleeping on land), indicating that ecological demands for attention usually exceed the attention afforded by sleeping unihemispherically. In addition to establishing that birds can sleep in flight, our results challenge the view that they sustain prolonged flights by obtaining normal amounts of sleep on the wing. PMID- 27485306 TI - Altered corticospinal function during movement preparation in humans with spinal cord injury. AB - KEY POINTS: In uninjured humans, transmission in the corticospinal pathway changes in a task-dependent manner during movement preparation. We investigated whether this ability is preserved in humans with incomplete chronic cervical spinal cord injury (SCI). Our results show that corticospinal excitability is altered in the preparatory phase of an upcoming movement when there is a need to suppress but not to execute rapid index finger voluntary contractions in individuals with SCI compared with controls. This is probably related to impaired transmission at a cortical and spinal level after SCI. Overall our findings indicate that deficits in corticospinal transmission in humans with chronic incomplete SCI are also present in the preparatory phase of upcoming movements. ABSTRACT: Corticospinal output is modulated in a task-dependent manner during the preparatory phase of upcoming movements in humans. Whether this ability is preserved after spinal cord injury (SCI) is unknown. In this study, we examined motor evoked potentials elicited by cortical (MEPs) and subcortical (CMEPs) stimulation of corticospinal axons and short-interval intracortical inhibition in the first dorsal interosseous muscle in the preparatory phase of a reaction time task where individuals with chronic incomplete cervical SCI and age-matched controls needed to suppress (NOGO) or initiate (GO) ballistic index finger isometric voluntary contractions. Reaction times were prolonged in SCI participants compared with control subjects and stimulation was provided ~90 ms prior to movement onset in each group. During NOGO trials, both MEPs and CMEPs remained unchanged compared to baseline in SCI participants but were suppressed in control subjects. Notably, during GO trials, MEPs increased to a similar extent in both groups but CMEPs increased only in controls. The magnitude of short-interval intracortical inhibition increased in controls but not in SCI subjects during NOGO trials and decreased in both groups in GO trials. These novel observations reveal that humans with incomplete cervical SCI have an altered ability to modulate corticospinal excitability during movement preparation when there is a need to suppress but not to execute upcoming rapid finger movements, which is probably related to impaired transmission at a cortical and spinal level. Thus, deficits in corticospinal transmission after human SCI extend to the preparatory phase of upcoming movements. PMID- 27485307 TI - Mortality among head trauma patients taking preinjury antithrombotic agents: a retrospective cohort analysis from a Level 1 trauma centre. AB - BACKGROUND: Bleeding represents the most well-known and the most feared complications caused by the use of antithrombotic agents. There is, however, limited documentation whether pre-injury use of antithrombotic agents affects outcome after head trauma. The aim of this study was to define the relationship between the use of preinjury antithrombotic agents and mortality among elderly people sustaining blunt head trauma. METHODS: A retrospective cohort analysis was performed on the hospital based trauma registry at Oslo University Hospital. Patients aged 55 years or older sustaining blunt head trauma between 2004 and 2006 were included. Multivariable logistic regression analyses were used to identify independent predictors of 30-day mortality. Separate analyses were performed for warfarin use and platelet inhibitor use. RESULTS: Of the 418 patients admitted with a diagnosis of head trauma, 137 (32.8 %) used pre-injury antithrombotic agents (53 warfarin, 80 platelet inhibitors, and 4 both). Seventy patients died (16.7 %); 15 (28.3 %) of the warfarin users, 12 (15.0 %) of the platelet inhibitor users, and two (50 %) with combined use of warfarin and platelet inhibitors, compared to 41 (14.6 %) of the non-users. There was a significant interaction effect between warfarin use and the Triage Revised Trauma Score collected upon the patients' arrival at the hospital. After adjusting for potential confounders, warfarin use was associated with increased 30-day mortality among patients with normal physiology (adjusted OR 8,3; 95 % CI, 2.0 to 34.8) on admission, but not among patients with physiological derangement on admission. Use of platelet inhibitors was not associated with increased mortality. CONCLUSIONS: The use of warfarin before trauma was associated with increased 30-day mortality among a subset of patients. Use of platelet inhibitors before trauma was not associated with increased mortality. These results indicate that patients on preinjury warfarin may need closer monitoring and follow up after trauma despite normal physiology on admission to the emergency department. PMID- 27485309 TI - Abundant immunoglobulin (Ig)G4-positive plasma cells in interstitial pneumonia without extrathoracic lesions of IgG4-related disease: is this finding specific to IgG4-related lung disease? AB - AIMS: There have been few reports on immunoglobulin-G4 (IgG4)-related interstitial pneumonia (IP), and its clinical features remain unclear. The objective of this study was to assess whether IP with marked IgG4-positive plasma cell infiltration without extrathoracic lesions of IgG4-related disease (RD) should be diagnosed as a subtype of IgG4-RD or a separate entity. METHODS AND RESULTS: All consecutive patients with surgical lung biopsy-proven idiopathic IP with an IgG4/IgG-positive cell ratio of >40% and >50 IgG4+ plasma cells in a high power field without extrathoracic lesions of IgG4-RD were reviewed retrospectively. Five patients were enrolled into this study. All patients were male with a history of smoking. Four patients met the comprehensive diagnostic criteria for IgG4-RD. The remaining patient lacked data related to the serum IgG4 level. Histologically, a non-specific IP pattern was observed in all patients. The key morphological features of IgG4-RD, such as storiform fibrosis and obliterative phlebitis with lymphoplasmacytic infiltration in a loose background texture, were absent in every patient. In contrast, venule obstruction by densely packed lymphoplasmacytic infiltration was observed in two patients. Marked scarring and remodelling of the lung were also noted, which is not seen typically in IgG4-RD. A favourable response to corticosteroid monotherapy was observed in all patients; however, two patients developed lung cancer during the course of observation. CONCLUSIONS: IP with marked IgG4-positive plasma cell infiltration without extrathoracic lesions of IgG4-RD had different pathological features from those of IgG4-RD, and it is appropriate to regard this as a separate entity. PMID- 27485311 TI - Commentary to "Effect of postoperative weight gain on the risk of channel revision following continent catheterizable urinary channel surgery". PMID- 27485310 TI - Rbfox2 function in RNA metabolism is impaired in hypoplastic left heart syndrome patient hearts. AB - Hypoplastic left heart syndrome (HLHS) is a fatal congenital heart disease in which the left side of the heart is underdeveloped, impairing the systemic circulation. Underdeveloped left ventricle exerts biomechanical stress on the right ventricle that can progress into heart failure. Genome-wide transcriptome changes have been identified at early stages in the right ventricle (RV) of infants with HLHS, although the molecular mechanisms remain unknown. Here, we demonstrate that the RNA binding protein Rbfox2, which is mutated in HLHS patients, is a contributor to transcriptome changes in HLHS patient RVs. Our results indicate that majority of transcripts differentially expressed in HLHS patient hearts have validated Rbfox2 binding sites. We show that Rbfox2 regulates mRNA levels of targets with 3'UTR binding sites contributing to aberrant gene expression in HLHS patients. Strikingly, the Rbfox2 nonsense mutation identified in HLHS patients truncates the protein, impairs its subcellular distribution and adversely affects its function in RNA metabolism. Overall, our findings uncover a novel role for Rbfox2 in controlling transcriptome in HLHS. PMID- 27485312 TI - Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations. AB - Tight regulation of kinesin activity is crucial and malfunction is linked to neurological diseases. Point mutations in the KIF21A gene cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by disrupting the autoinhibitory interaction between the motor domain and a regulatory region in the stalk. However, the molecular mechanism underlying the misregulation of KIF21A activity in CFEOM1 is not understood. Here, we show that the KIF21A regulatory domain containing all disease-associated substitutions in the stalk forms an intramolecular antiparallel coiled coil that inhibits the kinesin. CFEOM1 mutations lead to KIF21A hyperactivation by affecting either the structural integrity of the antiparallel coiled coil or the autoinhibitory binding interface, thereby reducing its affinity for the motor domain. Interaction of the KIF21A regulatory domain with the KIF21B motor domain and sequence similarities to KIF7 and KIF27 strongly suggest a conservation of this regulatory mechanism in other kinesin-4 family members. PMID- 27485313 TI - Label-free optical quantification of structural alterations in Alzheimer's disease. AB - We present a wide-field quantitative label-free imaging of mouse brain tissue slices with sub-micrometre resolution, employing holographic microscopy and an automated scanning platform. From the measured light field images, scattering coefficients and anisotropies are quantitatively retrieved by using the modified the scattering-phase theorem, which enables access to structural information about brain tissues. As a proof of principle, we demonstrate that these scattering parameters enable us to quantitatively address structural alteration in the brain tissues of mice with Alzheimer's disease. PMID- 27485314 TI - A Biodegradable Polydopamine-Derived Electrode Material for High-Capacity and Long-Life Lithium-Ion and Sodium-Ion Batteries. AB - Polydopamine (PDA), which is biodegradable and is derived from naturally occurring products, can be employed as an electrode material, wherein controllable partial oxidization plays a key role in balancing the proportion of redox-active carbonyl groups and the structural stability and conductivity. Unexpectedly, the optimized PDA derivative endows lithium-ion batteries (LIBs) or sodium-ion batteries (SIBs) with superior electrochemical performances, including high capacities (1818 mAh g(-1) for LIBs and 500 mAh g(-1) for SIBs) and good stable cyclabilities (93 % capacity retention after 580 cycles for LIBs; 100 % capacity retention after 1024 cycles for SIBs), which are much better than those of their counterparts with conventional binders. PMID- 27485315 TI - Social Network Behavior and Engagement Within a Smoking Cessation Facebook Page. AB - BACKGROUND: Social media platforms are increasingly being used to support individuals in behavior change attempts, including smoking cessation. Examining the interactions of participants in health-related social media groups can help inform our understanding of how these groups can best be leveraged to facilitate behavior change. OBJECTIVE: The aim of this study was to analyze patterns of participation, self-reported smoking cessation length, and interactions within the National Cancer Institutes' Facebook community for smoking cessation support. METHODS: Our sample consisted of approximately 4243 individuals who interacted (eg, posted, commented) on the public Smokefree Women Facebook page during the time of data collection. In Phase 1, social network visualizations and centrality measures were used to evaluate network structure and engagement. In Phase 2, an inductive, thematic qualitative content analysis was conducted with a subsample of 500 individuals, and correlational analysis was used to determine how participant engagement was associated with self-reported session length. RESULTS: Between February 2013 and March 2014, there were 875 posts and 4088 comments from approximately 4243 participants. Social network visualizations revealed the moderator's role in keeping the community together and distributing the most active participants. Correlation analyses suggest that engagement in the network was significantly inversely associated with cessation status (Spearman correlation coefficient = -0.14, P=.03, N=243). The content analysis of 1698 posts from 500 randomly selected participants identified the most frequent interactions in the community as providing support (43%, n=721) and announcing number of days smoke free (41%, n=689). CONCLUSIONS: These findings highlight the importance of the moderator for network engagement and provide helpful insights into the patterns and types of interactions participants are engaging in. This study adds knowledge of how the social network of a smoking cessation community behaves within the confines of a Facebook group. PMID- 27485316 TI - Relational categories are more mutable than entity categories. AB - Across three experiments, we explore differences between relational categories whose members share common relational patterns-and entity categories, whose members share common intrinsic properties. Specifically, we test the claim that relational concepts are more semantically mutable in context, and therefore less stable in memory, than entity concepts. We compared memory for entity nouns and relational nouns, tested either in the same context as at encoding or in a different context. We found that (a) participants show better recognition accuracy for entity nouns than for relational nouns, and (b) recognition of relational nouns is more impaired by a change in context than is recognition of entity nouns. We replicated these findings even when controlling for factors highly correlated with relationality, such as abstractness-concreteness. This suggests that the contextual mutability of relational concepts is due to the core semantic property of conveying relational structure and not simply to accompanying characteristics such as abstractness. We note parallels with the distinction between nouns and verbs and suggest implications for lexical and conceptual structure. Finally, we relate these patterns to proposals that a deep distinction exists between words with an essentially referential function and those with a predicate function. PMID- 27485317 TI - Estimation of genetic parameters and detection of chromosomal regions affecting the major milk proteins and their post translational modifications in Danish Holstein and Danish Jersey cattle. AB - BACKGROUND: In the Western world bovine milk products are an important protein source in human diet. The major proteins in bovine milk are the four caseins (CN), alphaS1-, alphaS2-, beta-, and k-CN and the two whey proteins, beta-LG and alpha-LA. It has been shown that both the amount of specific CN and their isoforms including post-translational modifications (PTM) influence technological properties of milk. Therefore, the aim of this study was to 1) estimate genetic parameters for individual proteins in Danish Holstein (DH) (n = 371) and Danish Jersey (DJ) (n = 321) milk, and 2) detect genomic regions associated with specific milk protein and their different PTM forms using a genome-wide association study (GWAS) approach. RESULTS: For DH, high heritability estimates were found for protein percentage (0.47), casein percentage (0.43), k-CN (0.77), beta-LG (0.58), and alpha-LA (0.40). For DJ, high heritability estimates were found for protein percentage (0.70), casein percentage (0.52), and alpha-LA (0.44). The heritability for G-k-CN, U-k-CN and GD was higher in the DH compared to the DJ, whereas the heritability for the PD of alphaS1-CN was lower in DH compared to DJ, whereas the PD for alphaS2-CN was higher in DH compared to DJ. The GWAS results for the main milk proteins were in line what has been earlier published. However, we showed that there were SNPs specifically regulating G-k-CN in DH. Some of these SNPs were assigned to casein protein kinase genes (CSNK1G3, PRKCQ). CONCLUSION: The genetic analysis of the major milk proteins and their PTM forms revealed that these were heritable in both DH and DJ. In DH, genomic regions specific for glycosylation of k-CN were detected. Furthermore, genomic regions for the major milk proteins confirmed the regions on BTA6 (casein cluster), BTA11 (PEAP), and BTA14 (DGAT1) as important regions influencing protein composition in milk. The results from this study provide confidence that it is possible to breed for specific milk protein including the different PTM forms. PMID- 27485318 TI - Influence of asthma status on sleep variability in overweight/obese youth. AB - OBJECTIVE: Pediatric asthma and overweight/obesity (OV/OB) frequently co-occur and youth with both conditions exhibit poor sleep/bedtime habits. This study assessed differences in week-to-weekend bedtime/wake time variability among OV/OB youth with/without comorbid asthma, and tested whether variability predicted weekday sleep. METHODS: OV/OB youth (n = 142; 28% comorbid asthma; 7-12 years) wore an Accelerometer for 5 days (2 weekend days), providing estimates of week-to weekend bedtime/wake-time variability, weekday Total Sleep Time (TST), weekday time in bed (TIB), and weekday wake after sleep onset (WASO). RESULTS: There were no demographic differences between groups beyond lower family income for the OV/OB+asthma group. The OV/OB+asthma group exhibited later weekday (mean OV/OB+asthma = 10:39 pm, mean OV/OB only = 10:30pm) and weekend (mean OV/OB+asthma = 11:41 pm, mean OV/OB only = 11:17pm) bedtimes, earlier weekday waketimes (mean OV/OB+asthma = 6:40 am, mean OV/OB only = 6:51 am), and similar weekend waketimes (mean OV/OB+asthma = 7:54 pm, mean OV/OB only = 7:52 pm. Univariate MANOVA follow-ups indicated a main effect of asthma group for week-to weekend bedtime and waketime variability, with the OV/OB+asthma group evidencing approximately 30 minutes greater bedtime (OV/OB+asthma mean = 90 minutes) and waketime (OV/OB+asthma mean = 108 minutes) variability. Within the OV/OB+asthma group, greater waketime variability predicted fewer minutes of weekday TIB and WASO. Within the OV/OB only group, wake time variability predicted fewer minutes of weekday TIB. CONCLUSION: Findings suggest that asthma status confers risk for more week-to-weekend variability among currently OV/OB youth, and that greater variability shortens the weekday sleep period. Further research on reasons for greater week-to-weekend sleep variability in asthma is needed. PMID- 27485319 TI - Prevalence of glutamine deficiency in ICU patients: a cross-sectional analytical study. AB - BACKGROUND: Not only is glutamine deficiency an independent predictor of mortality in intensive care unit (ICU) patients, but glutamine supplementation is also recommended for its proven outcome benefits. However, recent data suggest that early glutamine supplementation in certain patient groups increase mortality. The aim of this study was to investigate plasma glutamine levels of adult ICU patients in the South African setting and to determine relationships between glutamine levels, gender, diagnostic categories and selected inflammatory markers. The data from this study will be used as baseline measurement to support a large scale study that will be undertaken in the South African ICU population. METHODS: This cross-sectional, analytical study included 60 mixed adult ICU patients within 24 h post ICU admission. Plasma glutamine levels were determined on admission. The relationship between glutamine levels, Interleukin-6 (IL-6) and C-reactive protein (CRP); as well as gender- and diagnosis-related differences in glutamine levels were also investigated. A non-parametric ROC curve was computed to determine the CRP concentration cut-off point above which glutamine becomes deficient. RESULTS: The median plasma glutamine level (497 MUmol/L) was in the normal range; however, 38.3 % (n = 23) of patients had deficient (<420 MUmol/L) and 6.7 % (n = 4) had supra-normal glutamine levels (>930 MUmol/L). No significant difference could be detected between glutamine levels and gender or diagnosis categories as a group. When only the medical and surgical categories were compared, the median plasma glutamine level of the medical patients were significantly lower than that of the surgical patients (p = 0.042). Glutamine showed inverse associations with CRP levels (r = -0.44, p < 0.05) and IL-6 concentrations (r = -0.23, p = 0.08). A CRP cut-off value of 95.5 mg/L was determined above which glutamine levels became deficient. CONCLUSIONS: About a third of patients (38 %) were glutamine deficient on admission to ICU, whereas some presented with supra-normal levels. While glutamine levels correlated inversely with inflammatory markers, and a CRP value of above 95.5 mg/L indicated potential glutamine deficiency, the clinical application of this finding needs further investigation. PMID- 27485320 TI - Immunomodulatory effects of Longdan Xiegan Tang on CD4+/CD8+ T cells and associated inflammatory cytokines in rats with experimental autoimmune uveitis. AB - Longdan Xiegan Tang (LXT) is a mixture of herbal extracts commonly used in traditional Chinese medicine that may exert immunomodulatory effects for the treatment of autoimmune diseases. However, the detailed mechanisms that mediate the actions of LXT are unclear. The present study induced an experimental autoimmune uveitis (EAU) model in Lewis rats via injection of IRBP1177-1191 emulsion. The model was used to investigate the effects of LXT on EAU rats and assess the efficacy of LXT by measuring clinical manifestations and histopathological changes caused by EAU. Additionally, alterations in the ratio of CD4+/CD8+-T cells were determined by flow cytometry, and the expression of interferon (IFN)-gamma, interleukin (IL)-17, IL-10 and tumor necrosis factor (TNF)-alpha were measured using reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay analysis. The results of the present study demonstrate that LXT can efficiently alleviate the symptoms of EAU, inhibit the differentiation of uveitogenic CD4+ T cells and reduce the expression of proinflammatory cytokines, including IFN-gamma, IL-17 and TNF-alpha. Furthermore, LXT promotes the production of IL-10 and accelerates the recovery of EAU, indicating that the immunomodulatory effects of LXT may potentially be used for the treatment of uveitis. PMID- 27485321 TI - Synaptic plasticity and spatial working memory are impaired in the CD mouse model of Williams-Beuren syndrome. AB - Mice heterozygous for a complete deletion (CD) equivalent to the most common deletion found in individuals with Williams-Beuren syndrome (WBS) recapitulate relevant features of the neurocognitive phenotype, such as hypersociability, along with some neuroanatomical alterations in specific brain areas. However, the pathophysiological mechanisms underlying these phenotypes still remain largely unknown. We have studied the synaptic function and cognition in CD mice using hippocampal slices and a behavioral test sensitive to hippocampal function. We have found that long-term potentiation (LTP) elicited by theta burst stimulation (TBS) was significantly impaired in hippocampal field CA1 of CD animals. This deficit might be associated with the observed alterations in spatial working memory. However, we did not detect changes in presynaptic function, LTP induction mechanisms or AMPA and NMDA receptor function. Reduced levels of Brain-derived neurotrophic factor (BDNF) were present in the CA1-CA3 hippocampal region of CD mice, which could account for LTP deficits in these mice. Taken together, these results suggest a defect of CA1 synapses in CD mice to sustain synaptic strength after stimulation. These data represent the first description of synaptic functional deficits in CD mice and further highlights the utility of the CD model to study the mechanisms underlying the WBS neurocognitive profile. PMID- 27485322 TI - Precarious employment is a risk factor for poor mental health in young individuals in Sweden: a cohort study with multiple follow-ups. AB - BACKGROUND: The globalisation of the economy and the labour markets has resulted in a growing proportion of individuals who find themselves in a precarious labour market situation, especially among the young. This pertains also to the Nordic countries, despite their characterisation as well developed welfare states with active labour market policies. This should be viewed against the background of a number of studies, which have shown that several aspects of precarious employment are detrimental to mental health. However, longitudinal studies from the Nordic region that examine the impact of precarious labour market conditions on mental health in young individuals are currently lacking. The present study aims to examine this impact in a general cohort of Swedish young people. METHODS: Postal questionnaires were sent out in 1999/2000 to a stratified random sample of the Scania population, Sweden; the response rate was 58 %. All of those who responded at baseline were invited to follow-ups after 5 and 10 years. Employment precariousness was determined based on detailed questions about present employment, previous unemployment, and self-rated risk of future unemployment. Mental health was assessed by GHQ-12. For this study individuals in the age range of 18-34 years at baseline, who were active in the labour market (employed or seeking job) and had submitted complete data from 1999/2000, 2005, and 2010 on employment precariousness and mental health status, were selected (N = 1135). RESULTS: Forty-two percent of the participants had a precarious employment situation at baseline. Labour market trajectories that included precarious employment in 1999/2000 or 2005 predicted poor mental health in 2010: the incidence ratio ratio was 1.4 (95 % CI: 1.1-2.0) when excluding all individuals with mental health problems at baseline and adjusting for age, gender, social support, social capital, and economic difficulties in childhood. The population attributable fraction regarding poor mental health in the studied age group was 18 %. CONCLUSIONS: This study supported the hypothesis that precarious employment should be regarded as an important social determinant for subsequent development of mental health problems in previously mentally healthy young people. PMID- 27485323 TI - MRI-detected osteitis is not associated with the presence or level of ACPA alone, but with the combined presence of ACPA and RF. AB - BACKGROUND: In rheumatoid arthritis (RA) bone marrow edema (BME, osteitis) and anti-citrullinated protein antibodies (ACPA) are associated with radiographic progression. ACPA have been associated with BME, but it is unknown if this association is confined to ACPA and BME. We performed cross-sectional analysis of the association of ACPA, rheumatoid factor (RF) and anti-carbamylated protein (anti-CarP) antibodies with BME and other types of inflammation (synovitis, tenosynovitis) detected by magnetic resonance imaging (MRI). METHODS: Disease modifying antirheumatic drug (DMARD)-naive patients with early arthritis (n = 589), included in the Leiden Early Arthritis Clinic cohort, underwent contrast enhanced 1.5 T MRI of unilateral wrist, metacarpophalangeal and metatarsophalangeal-joints at baseline. BME, synovitis and tenosynovitis were scored by two readers. ACPA, rheumatoid factor (RF) and anti-CarP were determined at baseline. RESULTS: In univariable analyses ACPA-positive patients had higher BME scores than ACPA-negative patients (median 4.5 vs. 2.0, p < 0.001), but not more synovitis and tenosynovitis. Also RF (median 3.75 vs. 2.0, p < 0.001) and anti-CarP antibodies (median 3.5 vs. 2.5, p = 0.012) were associated with higher BME scores. Because the autoantibodies were concomitantly present, analyses were stratified for the presence of different autoantibody combinations. ACPA-positive (ACPA+), RF-negative (RF-), anti-CarP-negative (anti-CarP-) patients did not have higher BME-scores than ACPA-negative (ACPA-), RF-, anti-CarP- patients. However ACPA+, RF-positive (RF+), anti-CarP- patients and ACPA+, RF+, anti-CarP-positive (anti-CarP+) patients had higher BME scores than ACPA-, RF-, anti-CarP- patients (median 5.0 and 4.5 vs. 2.0, p < 0.001 and p < 0.001). ACPA levels were not associated with BME scores. Analyses within RA- and UA-patients revealed similar results. CONCLUSIONS: The presence of ACPA alone or ACPA level was not statistically significantly associated with BME scores, but the combined presence of ACPA and RF was associated with more BME. This suggests an additive role of RF to ACPA in mediating osteitis. PMID- 27485324 TI - Utility of repeat cytological assessment of thyroid nodules initially classified as benign: clinical insights from multidisciplinary care in an Irish tertiary referral centre. AB - BACKGROUND: Fine needle aspiration biopsy (FNAB) is the tool of choice for evaluating thyroid nodules with the majority classified as benign following initial assessment. However, concern remains about false negative results and some guidelines have recommended routine repeat aspirates. We aimed to assess the utility of routine repeat FNAB for nodules classified as benign on initial biopsy and to examine the impact of establishing a multidisciplinary team for the care of these patients. METHODS: We performed a retrospective review of 400 consecutive patients (413 nodules) who underwent FNAB of a thyroid nodule at our hospital between July 2008 and July 2011. Data recorded included demographic, clinical, histological and radiological variables. RESULTS: Three hundred and fifty seven patients (89 %) were female. Median follow-up was 5.5 years. Two hundred and fifty eight (63 %) nodules were diagnosed as benign. The rate of routine repeat biopsy increased significantly over the time course of the study (p for trend = 0.012). Nine Thy 2 nodules were classified differently on the basis of routine repeat biopsy; one patient was classified as malignant on repeat biopsy and was diagnosed with papillary thyroid carcinoma. Eight were classified as a follicular lesions on repeat biopsy-six diagnosed as benign following lobectomy; two declined lobectomy and were followed radiologically with no nodule size increase. CONCLUSIONS: The false negative rate of an initial benign cytology result, from a thyroid nodule aspirate, is low. In the setting of an experienced multidisciplinary thyroid team, routine repeat aspiration is not justified. PMID- 27485325 TI - Diagnostic Efficiency of Caregiver Report on the SCARED for Identifying Youth Anxiety Disorders in Outpatient Settings. AB - This study investigated the diagnostic and clinical utility of the parent-rated Screen for Child Anxiety Related Emotional Disorders (SCARED-P) for detecting youth anxiety disorders. Youth ages 6 to 12 years, 11 months were recruited from 9 outpatient mental health clinics (N = 707). Consensus diagnoses were based on semistructured interviews (Schedule for Affective Disorders and Schizophrenia for School-Age Children) with youth and caregivers; 31% were diagnosed with at least one anxiety disorder. Caregivers completed the SCARED-P to describe youth anxiety levels. SCARED-P scores were not considered during the consensus diagnoses. Areas under the curve (AUCs) from receiver operating characteristic analyses and diagnostic likelihood ratios (DLRs) quantified performance of the SCARED-P total score and subscale scores (generalized anxiety disorder and separation anxiety disorder). SCARED-P total scores had variable efficiency (AUCs = .69-.88), and Generalized Anxiety Disorder and Separation Anxiety subscale scores were excellent (AUCs = .86-.89) for identifying specific anxiety disorders. Optimal subscale cutoff scores were computed to help rule in (DLRs = 2.7-5.4) or rule out (DLRs < 1.0) anxiety disorders among youth. Results suggest that the Generalized Anxiety Disorder and Separation Anxiety SCARED-P subscales accurately identify their respective matched diagnoses. DLRs may aid clinicians in screening for youth anxiety disorders and improve accuracy of diagnosis. PMID- 27485326 TI - Cell-Free Production of Membrane Proteins in Escherichia coli Lysates for Functional and Structural Studies. AB - The complexity of membrane protein synthesis is largely reduced in cell-free systems and it results into high success rates of target expression. Protocols for the preparation of bacterial lysates have been optimized in order to ensure reliable efficiencies in membrane protein production that are even sufficient for structural applications. The open accessibility of the semisynthetic cell-free expression reactions allows to adjust membrane protein solubilization conditions according to the optimal folding requirements of individual targets. Two basic strategies will be exemplified. The post-translational solubilization of membrane proteins in detergent micelles is most straightforward for crystallization approaches. The co-translational integration of membrane proteins into preformed nanodiscs will enable their functional characterization in a variety of natural lipid environments. PMID- 27485327 TI - Membrane Protein Production in the Yeast, S. cerevisiae. AB - The first crystal structures of recombinant mammalian membrane proteins were solved in 2005 using protein that had been produced in yeast cells. One of these, the rabbit Ca(2+)-ATPase SERCA1a, was synthesized in Saccharomyces cerevisiae. All host systems have their specific advantages and disadvantages, but yeast has remained a consistently popular choice in the eukaryotic membrane protein field because it is quick, easy and cheap to culture, whilst being able to post translationally process eukaryotic membrane proteins. Very recent structures of recombinant membrane proteins produced in S. cerevisiae include those of the Arabidopsis thaliana NRT1.1 nitrate transporter and the fungal plant pathogen lipid scramblase, TMEM16. This chapter provides an overview of the methodological approaches underpinning these successes. PMID- 27485328 TI - Membrane Protein Production in Escherichia coli: Protocols and Rules. AB - Functional and structural studies on membrane proteins are limited by the difficulty to produce them in large amount and in a functional state. In this review, we provide protocols to achieve high-level expression of membrane proteins in Escherichia coli. The T7 RNA polymerase-based expression system is presented in detail and protocols to assess and improve its efficiency are discussed. Protocols to isolate either membrane or inclusion bodies and to perform an initial qualitative test to assess the solubility of the recombinant protein are also included. PMID- 27485329 TI - Codon Optimizing for Increased Membrane Protein Production: A Minimalist Approach. AB - Reengineering a gene with synonymous codons is a popular approach for increasing production levels of recombinant proteins. Here we present a minimalist alternative to this method, which samples synonymous codons only at the second and third positions rather than the entire coding sequence. As demonstrated with two membrane-embedded transporters in Escherichia coli, the method was more effective than optimizing the entire coding sequence. The method we present is PCR based and requires three simple steps: (1) the design of two PCR primers, one of which is degenerate; (2) the amplification of a mini-library by PCR; and (3) screening for high-expressing clones. PMID- 27485330 TI - Generation of Tetracycline-Inducible Mammalian Cell Lines by Flow Cytometry for Improved Overproduction of Membrane Proteins. AB - Overexpression of mammalian membrane proteins in mammalian cells is an effective strategy to produce sufficient protein for biophysical analyses and structural studies, because the cells generally express proteins in a correctly folded state. However, obtaining high levels of expression suitable for protein purification on a milligram scale can be challenging. As membrane protein overexpression often has a negative impact on cell viability, it is usual to make stable cell lines where the protein of interest is expressed from an inducible promoter. Here we describe a methodology for optimizing the inducible production of any membrane protein fused to GFP through the isolation of clonal cell lines. Flow cytometry is used to sort uninduced cells and the most fluorescent 5 % of the cell population are used to make clonal cell lines. PMID- 27485331 TI - Membrane Protein Production in Lactococcus lactis for Functional Studies. AB - Due to their unique properties, expression and study of membrane proteins in heterologous systems remains difficult. Among the bacterial systems available, the Gram-positive lactic bacterium, Lactococcus lactis, traditionally used in food fermentations, is nowadays widely used for large-scale production and functional characterization of bacterial and eukaryotic membrane proteins. The aim of this chapter is to describe the different possibilities for the functional characterization of peripheral or intrinsic membrane proteins expressed in Lactococcus lactis. PMID- 27485332 TI - Expression of Viral Envelope Glycoproteins in Drosophila melanogaster S2 Cells. AB - The expression of recombinant viral envelope glycoproteins in S2 (Drosophila melanogaster) has been performed with good results. This chapter contains protocols for the utilization of this system for the expression and analysis of proteins presented in cell plasma membrane. PMID- 27485333 TI - Leishmania tarentolae as a Promising Tool for Expressing Polytopic and Multi Transmembrane Spans Eukaryotic Membrane Proteins: The Case of the ABC Pump ABCG6. AB - This chapter includes a practical method of membrane protein production in Leishmania tarentolae cells. We routinely use it to express membrane proteins of the ABC (adenosine triphosphate-binding cassette) family, here exemplified with ABCG6 from L. braziliensis, implicated in phospholipid trafficking and drug efflux. The pLEXSY system used here allows membrane protein production with a mammalian-like N-glycosylation pattern, at high levels and at low costs. Also the effects of an N-terminal truncation of the protein are described. The method is described to allow any kind of membrane protein production. PMID- 27485334 TI - Overexpression, Membrane Preparation, and Purification of a Typical Multidrug ABC Transporter BmrA. AB - The production and purification is normally the first step in any biophysical or biochemical study of a new target protein. For membrane proteins, due to their generally low expression levels and hydrophobic properties this is often a major hurdle. Some multidrug transporters are members of one of the largest families of membrane proteins, the ABC ("ATP-binding cassette"), and are responsible for the uptake and export of a wide variety of molecules. This can lead to resistance when those molecules are antibiotics or chemotherapy drugs. To better understand their role in multidrug resistance pure and active protein is required. Here we outline a protocol to produce a highly pure and functionally active multidrug transporter BmrA that is suitable for use in biophysical and biochemical studies. We show that BmrA can be heterologously overexpressed in huge amount in E. coli and extracted from the membrane in a functionally active form. PMID- 27485335 TI - Expression of Eukaryotic Membrane Proteins in Pichia pastoris. AB - A key point when it comes to heterologous expression of eukaryotic membrane proteins (EMPs) is the choice of the best-suited expression platform. The yeast Pichia pastoris has proven to be a very versatile system showing promising results in a growing number of cases. Indeed, its particular methylotrophic characteristics combined to the very simple handling of a eukaryotic microorganism that possesses the majority of mammalian-like machineries make it a very competitive expression system for various complex proteins, in amounts compatible with functional and structural studies. This chapter describes a set of robust methodologies routinely used for the successful expression of a variety of EMPs, going from yeast transformation with the recombinant plasmid to the analysis of the quality and quantity of the proteins produced. PMID- 27485336 TI - Integral Membrane Protein Expression in Saccharomyces cerevisiae. AB - Eukaryotic integral membrane proteins are challenging targets for crystallography or functional characterization in a purified state. Since expression is often a limiting factor when studying this difficult class of biological macromolecules, the intent of this chapter is to focus on the expression of eukaryotic integral membrane proteins (IMPs) using the model organism Saccharomyces cerevisiae. S. cerevisiae is a prime candidate for the expression of eukaryotic IMPs because it offers the convenience of using episomal expression plasmids, selection of positive transformants, posttranslational modifications, and it can properly fold and target IMPs. Here we present a generalized protocol and insights based on our collective knowledge as an aid to overcoming the challenges faced when expressing eukaryotic IMPs in S. cerevisiae. PMID- 27485337 TI - High-Throughput Baculovirus Expression System for Membrane Protein Production. AB - The ease of use, robustness, cost-effectiveness, and posttranslational machinery make baculovirus expression system a popular choice for production of eukaryotic membrane proteins. This system can be readily adapted for high-throughput operations. This chapter outlines the techniques and procedures for cloning, transfection, small-scale production, and purification of membrane protein samples in a high-throughput manner. PMID- 27485338 TI - Small-Scale Screening to Large-Scale Over-Expression of Human Membrane Proteins for Structural Studies. AB - Membrane protein structural studies are frequently hampered by poor expression. The low natural abundance of these proteins implies a need for utilizing different heterologous expression systems. E. coli and yeast are commonly used expression systems due to rapid cell growth at high cell density, economical production, and ease of manipulation. Here we report a simplified, systematically developed robust strategy from small-scale screening to large-scale over expression of human integral membrane proteins in the mammalian expression system for structural studies. This methodology streamlines small-scale screening of several different constructs utilizing fluorescence size-exclusion chromatography (FSEC) towards optimization of buffer, additives, and detergents for achieving stability and homogeneity. This is followed by the generation of stable clonal cell lines expressing desired constructs, and lastly large-scale expression for crystallization. These techniques are designed to rapidly advance the structural studies of eukaryotic integral membrane proteins including that of human membrane proteins. PMID- 27485339 TI - Purification of Human and Mammalian Membrane Proteins Expressed in Xenopus laevis Frog Oocytes for Structural Studies. AB - This protocol describes the isolation of recombinant human and mammalian membrane proteins expressed in Xenopus laevis frog oocytes for structural studies. The cDNA-derived cRNA of the desired genes is injected into several hundreds of oocytes, which are incubated for several days to allow protein expression. Recombinant proteins are then purified via affinity chromatography. The novelty of this method comes from the design of a plasmid that produces multi-tagged proteins and, most importantly, the development of a protocol for efficiently discarding lipids, phospholipids, and lipoproteins from the oocyte egg yolk, which represent the major contaminants in protein purifications. Thus, the high protein purity and good yield obtained from this method allows protein structure determination by transmission electron microscopy of single detergent-solubilized protein particles and of 2D crystals of membrane protein embedded in lipid bilayers. Additionally, a radiotracer assay for functional analysis of the expressed target proteins in oocytes is described. Overall, this method is a valuable option for structural studies of mammalian and particularly human proteins, for which other expression systems often fail. PMID- 27485340 TI - Membrane Protein Solubilization and Composition of Protein Detergent Complexes. AB - Membrane proteins are typically expressed in heterologous systems with a view to in vitro characterization. A critical step in the preparation of membrane proteins after expression in any system is the solubilization of the protein in aqueous solution, typically using detergents and lipids, to obtain the protein in a form suitable for purification, structural or functional analysis. This process is particularly difficult as the objective is to prepare the protein in an unnatural environment, a protein detergent complex, separating it from its natural lipid partners while causing the minimum destabilization or modification of the structure. Although the process is difficult, and relatively hard to master, an increasing number of membrane proteins have been successfully isolated after expression in a wide variety of systems. In this chapter we give a general protocol for preparing protein detergent complexes that is aimed at guiding the reader through the different critical steps. In the second part of the chapter we illustrate how to analyze the composition of protein detergent complexes; this analysis is important as it has been found that compositional variation often causes irreproducible results. PMID- 27485341 TI - Detergent-Free Membrane Protein Purification. AB - Membrane proteins are localized within a lipid bilayer; in order to purify them for functional and structural studies the first step must involve solubilizing or extracting the protein from these lipids. To date this has been achieved using detergents which disrupt the bilayer and bind to the protein in the transmembrane region. However finding conditions for optimal extraction, without destabilizing protein structure, is time consuming and expensive. Here we present a recently developed method using a styrene-maleic acid (SMA) co-polymer instead of detergents. The SMA co-polymer extracts membrane proteins in a small disc of lipid bilayer which can be used for affinity chromatography purification, thus enabling the purification of membrane proteins while maintaining their native lipid bilayer environment. PMID- 27485342 TI - Conformational Dynamics and Interactions of Membrane Proteins by Hydrogen/Deuterium Mass Spectrometry. AB - Hydrogen/deuterium exchange associated with mass spectrometry has been recently used to characterize the dynamics and the interactions of membrane proteins. Here we describe experimental workflow enabling localization of the regions involved in conformational changes or interactions. PMID- 27485343 TI - Lessons from an alpha-Helical Membrane Enzyme: Expression, Purification, and Detergent Optimization for Biophysical and Structural Characterization. AB - This chapter outlines the protocol developed in our lab to produce a multipass alpha-helical membrane protein. We present our work flow, from ortholog selection to protein purification, including molecular biology for plasmid construction, protein expression in E. coli, membrane isolation and detergent solubilization, protein purification and tag removal, biophysical assessment of protein stability in different detergents, and detergent concentration determination using thin layer chromatography. We focus on results from our ongoing work with intramembrane aspartyl proteases from archaeal organisms. PMID- 27485344 TI - Method to Screen Multidrug Transport Inhibitors Using Yeast Overexpressing a Human MDR Transporter. AB - Multidrug resistance has appeared to mitigate the efficiency of anticancer drugs and the possibility of successful cancer chemotherapy. The Hedgehog receptor Patched is a multidrug transporter expressed in several cancers and as such it represents a new target to circumvent chemotherapy resistance. In this chapter, we describe the screening test developed to identify molecules able to inhibit the drug efflux activity of Patched. This screening test uses yeast overexpressing functional human Patched that have been shown to resist to chemotherapeutic agents. This test can be adapted to other MDR transporters. PMID- 27485345 TI - INC-Seq: accurate single molecule reads using nanopore sequencing. AB - BACKGROUND: Nanopore sequencing provides a rapid, cheap and portable real-time sequencing platform with the potential to revolutionize genomics. However, several applications are limited by relatively high single-read error rates (>10 %), including RNA-seq, haplotype sequencing and 16S sequencing. RESULTS: We developed the Intramolecular-ligated Nanopore Consensus Sequencing (INC-Seq) as a strategy for obtaining long and accurate nanopore reads, starting with low input DNA. Applying INC-Seq for 16S rRNA-based bacterial profiling generated full length amplicon sequences with a median accuracy >97 %. CONCLUSIONS: INC-Seq reads enabled accurate species-level classification, identification of species at 0.1 % abundance and robust quantification of relative abundances, providing a cheap and effective approach for pathogen detection and microbiome profiling on the MinION system. PMID- 27485346 TI - Humanizing the zebrafish liver shifts drug metabolic profiles and improves pharmacokinetics of CYP3A4 substrates. AB - Understanding and predicting whether new drug candidates will be safe in the clinic is a critical hurdle in pharmaceutical development, that relies in part on absorption, distribution, metabolism, excretion and toxicology studies in vivo. Zebrafish is a relatively new model system for drug metabolism and toxicity studies, offering whole organism screening coupled with small size and potential for high-throughput screening. Through toxicity and absorption analyses of a number of drugs, we find that zebrafish is generally predictive of drug toxicity, although assay outcomes are influenced by drug lipophilicity which alters drug uptake. In addition, liver microsome assays reveal specific differences in metabolism of compounds between human and zebrafish livers, likely resulting from the divergence of the cytochrome P450 superfamily between species. To reflect human metabolism more accurately, we generated a transgenic "humanized" zebrafish line that expresses the major human phase I detoxifying enzyme, CYP3A4, in the liver. Here, we show that this humanized line shows an elevated metabolism of CYP3A4-specific substrates compared to wild-type zebrafish. The generation of this first described humanized zebrafish liver suggests such approaches can enhance the accuracy of the zebrafish model for toxicity prediction. PMID- 27485347 TI - Influence of the Time of Intravenous Administration of Paracetamol on its Pharmacokinetics and Ocular Disposition in Rabbits. AB - BACKGROUND AND OBJECTIVES: Paracetamol is one of the most common analgesics and antipyretics applied in health care. The aim of the study was to investigate the influence of the time-of-day administration on the paracetamol pharmacokinetics and its penetration into aqueous humour (AH). METHODS: Rabbits were divided into three groups: I-receiving paracetamol at 08.00 h, II-receiving paracetamol at 16.00 h, and III-receiving paracetamol at 24.00 h. Paracetamol was administered intravenously at a single dose of 35 mg/kg. The concentrations of paracetamol and its metabolite (paracetamol glucuronide) in the plasma, as well as in AH were measured with the validated HPLC-UV method. RESULTS: No significant differences in the pharmacokinetic parameters of paracetamol was observed. When the drug was administered at 24.00 h, elimination half-life (t 1/2kel) of paracetamol glucuronide was longer than when the drug was administered 08.00 h (P = 0.0193). In addition, a statistically significant increase in the paracetamol glucuronide/paracetamol ratio was observed when the drug was administered at 08.00 vs. 16.00 h (P <= 0.0001) and 24.00 h (P <= 0.0001). CONCLUSIONS: There was no chronobiological effect on the pharmacokinetic parameters of paracetamol. PMID- 27485348 TI - CPP2-p16MIS treatment-induced colon carcinoma cell death in vitro and prolonged lifespan of tumor-bearing mice. AB - BACKGROUND: Cell-penetrating peptides (CPPs) are a research hotspot due to their noninvasive delivery ability. Among the identified CPPs, the TAT and R8 peptides have been preferentially applied to transduction into different cells. However, this process is nonselective among various cells. Recent research suggested that CPP2 could selectively penetrate human colorectal cancer (CRC) cells. METHODS: Using in vitro experiments, the mean fluorescence intensity of fluorescein isothiocyanate-labeled CPPs (CPPs-FITC) incubated with different cell lines was compared to corroborate the colon tumor targeting ability of CPP2. The targeting ability of CPP2 was determined in the same way in tumor-bearing mice. We synthesized antitumor peptides by fusing CPP2 to the minimal inhibitory sequence of p16 (p16MIS), which had the ability to restore the function of lost p16, the expression of which was absent in tumor cell lines of various origins. The antitumor effect of the combined peptide was tested in both CRC cell lines and tumor-bearing mice. RESULTS: In each CRC cell line, the mean fluorescence intensity of CPP2-FITC was higher than that of the TAT-FITC (p < 0.001) and R8 FITC (p < 0.001) groups. CPP2-p16MIS, the targeting carrier, showed a higher antitumor response in the in vitro cell research. CPP2-p16MIS showed a prolonged mean lifespan of tumor-bearing mice, further characterizing its role in specific tumor-targeting ability in vivo. Survival analysis showed that the mice treated with CPP2-p16MIS had significantly longer survival than the mice treated with phosphate-buffered saline (p < 0.05) or those treated with control peptides, including the CPP2 (p < 0.05) and p16MIS (p < 0.05) groups. CONCLUSION: CPP2 could more selectively penetrate CRC cells than TAT or R8 as well as effectively deliver the p16MIS to the tumor. PMID- 27485349 TI - The care center influences the management of lymphoma patients in a universal health care system: an observational cohort study. AB - BACKGROUND: Healthcare providers-related disparities in adherence to the treatment plan among lymphoma patients are found even in a universal healthcare system, but the mechanism remains unclear. We investigated the association between the type of care center and the relative dose intensity and determined whether it persists after adjustment for patients' recruitment differences. METHODS: Prospective observational cohort study of 294 patients treated with standard protocols for diffuse large B-cell lymphoma (DLBCL) in teaching or community public hospitals or in private centers in the French Midi-Pyrenees region from 2006-2013. To test our assumptions, we used multinomial and mixed effect logistic models progressively adjusted for patients' biomedical characteristics, socio-spatial characteristics and treatment-related toxicity events. RESULTS: Patients treated using standard protocols in the teaching hospital had more advanced stage and poorer initial prognosis without limitation regarding the distance from the residence to the care center. Patients' recruitment profile across the different types of care center failed to explain the difference in relative dose intensity. Low relative dose intensity was less often observed in teaching hospital than elsewhere. CONCLUSION: We showed that even in a universal healthcare system, disparities in the management of DLBCL patients' do exist according to the types of care center. A main issue may be to find and diffuse the reasons of this benefit in cancer management in the teaching hospital to the other centers. PMID- 27485350 TI - Ireland's contribution to urology and nephrology research in the new millennium: a bibliometric analysis. AB - INTRODUCTION: Bibliometrics is the statistical analysis of written publications. Bibliometric analyses have been performed across a range of biomedical disciplines. The aim of this study was to provide a comprehensive qualitative and quantitative analysis of Irish urology and nephrology research and to analyse how this compares internationally. METHODS: We performed a retrospective bibliometric analysis of the top 20 ranking journals in the field of "Urology and Nephrology" based on their 5 years impact factor, as obtained from the ISI Journal Citation Report database over the 15-year study period, 2000-2015. Utilising the Pubmed database, a search phrase was constructed using country of affiliation, year of publication and journal title. The abstracts of the Irish publications identified were analysed for their institution of origin, article theme and content. RESULTS: A total of 67,740 article abstracts were analysed over the 15 years study period. As anticipated, the USA accounted for the largest number of publications by a country [28,206 (41.64 % of all articles)]. Ireland contributed 347 articles in total (0.51 % of all articles); however, ranking according to population per million was 13th worldwide. Ireland's contribution to urology and nephrology research was highest in the BJUI-British Journal of Urology International [76 articles (21.90 % of Irish total)]. CONCLUSION: We believe this study to be the largest bibliometric analysis in the field of urology and nephrology internationally. This study provides a novel overview of the current Irish urology- and nephrology-related research, and examines how our results compare within the international community. PMID- 27485351 TI - Physiological mechanisms of QRS narrowing in bundle branch block patients undergoing permanent His bundle pacing. AB - His bundle pacing is increasingly used to avoid chronic right ventricular pacing, and electrically resynchronize ventricular activation by narrowing or normalizing the QRS interval in left and right bundle branch block. The mechanisms by which this occurs remain poorly understood. In this review, the proposed mechanisms and evidence supporting them are discussed. Also discussed are aspects of mechanisms that are not completely supported by the evidence. We also review the differences and physiological bases for direct vs. indirect His bundle capture, and the physiological mechanisms for QRS narrowing vs. normalization following His bundle pacing. PMID- 27485352 TI - Cervical reconstruction techniques. After adequate selection of the patient report of a series of 34 patients treated with winged expandable cages. AB - After single or multilevel cervical corpectomy for the treatment of different diseases, many surgical options have been proposed over the years. As a single device, a winged expandable titanium cage (WETC) has been developed. We report the use of this device and our clinical results at 24 months of follow-up in a prospective series of 34 patients who underwent single or multilevel corpectomy for the treatment of cervical spondylosis. Thirty-four consecutive patients underwent single or multilevel cervical corpectomy followed by the insertion of a WETC for the treatment of cervical spondylosis at Department of Neurology and Psychiatry "Sapienza" University of Rome, Italy, from May 2011 to May 2013. Patients affected by cervical spondylosis with cervical lordosis >0 degrees were included. Patients affected by cervical lordosis <0 degrees , osteoporosis, or other cervical diseases were excluded. The mean postsurgical Nurick's grade was significantly lower than the mean presurgical Nurick's grade (mean = 0.98 for postsurgical Nurick's grade and mean = 2.42 for presurgical Nurick's grade). Four patients (11.7 %) presented subsidence respectively of 1, 2, 2, and 3 mm at 24 months of radiological follow-up. Postoperative complications occurred in five patients (14.7 %). Our case series at 24 months of follow-up demonstrates that the use of a WETC obtains good clinical results after single or multiple corpectomy in patients not affected by osteoporosis who do not require cervical lordosis correction. During the insertion of the device, an adequate preparation of the end plates is suggested and their over distraction should be avoided. PMID- 27485353 TI - Cellular plasticity: 1712 to the present day. AB - Cell identity is a fundamental feature of cells. Tissues are often organized into cellular hierarchies characterized by progressive differentiation and developmental commitment. However, it is been historically evident that the cells of many organisms of various phyla, especially in the context of injury, exhibit remarkable plasticity in terms of their ability to convert into other cell types. Recent modern studies, using genetic lineage tracing, have demonstrated that many mature functional cells retain a potential to undergo lineage reversion (dedifferentiation) or to convert into cells of other more distant lineages (transdifferentiation) following injury. Similarly, mimicking progenitor cell transdetermination, stem cells can interconvert. These forms of plasticity may be essential for organismal survival, and are likely part and parcel of regeneration. PMID- 27485355 TI - The Order of Addition of Immunocompromise: The Effects of HIV Infection on Fibrosis Progression Among Hepatitis C Virus-Infected Patients. PMID- 27485354 TI - Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection. AB - BACKGROUND: Unlike tuberculosis, few studies have evaluated a host genetic basis for variability in susceptibility to latent Mycobacterium tuberculosis infection (LTBI). We performed a candidate gene association study of autophagy-related genes and LTBI. METHODS: We enrolled close contacts of individuals with pulmonary tuberculosis, assessed LTBI status, and determined clinical and sociodemographic risk factors for LTBI. In participants who self-identified as Asian or black, we compared haplotype-tagging single-nucleotide polymorphisms (SNPs) in ULK1 and GABARAP between cases (n = 143) and controls (n = 106). Using CRISPR/Cas9 in U937 monocytes, we investigated the effect of ULK1 deficiency on cytokine expression, autophagy, and M. tuberculosis replication. RESULTS: In Asian participants, we identified 2 ULK1 SNPs (rs12297124 and rs7300908) associated with LTBI. After adjustment for population admixture and clinical risk for LTBI, each rs12297124 minor allele conferred 80% reduction in LTBI risk (odds ratio, 0.18; 95% confidence interval, .07-.46). Compared with controls, ULK1-deficient cells exhibited decreased tumor necrosis factor secretion after stimulation with Toll like receptor ligands and M. tuberculosis whole-cell lysate, increased M. tuberculosis replication, and decreased selective autophagy. CONCLUSIONS: These results demonstrate a strong association of rs12297124, a noncoding ULK1 SNP, with LTBI and a role for ULK1 regulation of TNF secretion, nonspecific and M. tuberculosis-induced autophagy, and M. tuberculosis replication in monocytes. PMID- 27485356 TI - Fibrosis Progression in Patients With Chronic Hepatitis C Virus Infection. AB - BACKGROUND: Fibrosis progression varies markedly in hepatitis C virus (HCV) infected individuals. We investigated factors that influence fibrosis progression in chronic HCV infection. METHODS: HCV-infected patients who underwent at least 2 liver biopsies were included in this study. Associations between fibrosis progression and epidemiologic, virologic, and disease-associated factors were analyzed using logistic regression and multistate Markov modeling. RESULTS: We analyzed 936 biopsy specimens obtained from 378 individuals. Mean age (+/-SD) at first biopsy was 48.3 +/- 9.3 years, 59.3% of patients were male, 59.9% were white, and 86.7% were infected with HCV genotype 1. Fibrosis progression and cirrhosis occurred in 57.4% and 5.8%, respectively. Fibrosis progression between the first and last biopsies was associated with lower fibrosis in the first biopsy specimen (P < .001) and with the occurrence of at least 1 flare in the alanine aminotransferase (ALT) level (>200 U/L; P = .007). We found the highest fibrosis progression rate between stages 0 and 1 and the lowest between stages 2 and 3. Increased necroinflammation and higher ALT level were associated with faster progression. HCV genotype 3-infected patients were more likely to progress to cirrhosis (P < .001). CONCLUSIONS: Fibrosis progression in HCV is not linear but varies according to stage, with the highest progression in patients with the lowest fibrosis severity. Patients who experience flares in the ALT level are also more likely to progress. PMID- 27485358 TI - Armah et al (J Infect Dis 2016; 213:1678-85). PMID- 27485359 TI - Surgery for Benign Gynecological Disorders Improve Endometrium Receptivity. AB - Regardless of the anatomical locations, some benign gynecological disorders (BGDs) such as peritoneal endometriosis, ovarian endometrioma, adenomyosis, uterine leiomyomas, endometrial polyps, uterine septum, and hydrosalpinges may lead to implantation failure. Despite progress in medical therapies, surgery remains a mainstay of BGDs treatment. Although our knowledge of endometrial receptivity after BGDs surgery is limited, it has allowed for significant improvement in the treatment of female subfertility. Many researchers studied on pregnancy outcome following BGDs surgery, but they did not investigate the possible impact of surgery on endometrial receptivity. They, therefore, concluded that pregnancy rates improved after BGDs surgery based on clinical observations. Many of these clinicians believe that surgical resection of BGDs leads to removal of local mechanical effect over the endometrium. Moreover, they accept that BGDs surgery may inhibit the detrimental signaling and secretion of some molecules from the BGDSs into the endometrium that may lead to favorable effect on the endometrium. However, so far, data from randomized controlled trials or systematic review or meta-analyses to answer the question whether surgical treatment of BGDs can improve endometrial receptivity are lacking. The purpose of this systematic review was to evaluate the results of available publications dealing with the impact of reproductive surgery for BGDs on endometrial receptivity. PMID- 27485361 TI - Exposure to Zearalenone During Early Pregnancy Causes Estrogenic Multitoxic Effects in Mice. AB - Although zearalenone (ZEN; Sigma Chemicals, St Louis, Missouri) is a well-known mycotoxin with estrogenic activity, the toxic effects of ZEN during pregnancy are unknown. This study compared the effects of daily subcutaneous injections of ZEN (2, 4, or 8 mg/kg) with those of 17beta-estradiol (E2; [Sigma Chemicals] 0.8, 1.6, or 3.2 MUg/kg) in mice. Injections were administered on gestational days (GDs) 1 to 5, the period including implantation which is sensitive to hormonal balance. The effects of ZEN or E2 were evaluated by comparing the number of live fetuses, their weight, and absorbed conceptuses on GD 18, with those in vehicle treated controls. In addition, implantation, embryos in the oviducts and those in uteri without implantation sites were investigated on GD 5. In mice treated with the highest dose of ZEN or E2, decidual responses and plasma progesterone concentrations were measured on GDs 5 and 6, respectively, and delayed implantation was investigated on GDs 9 and 14. The results showed that treatment with ZEN, in a manner similar to that seen for E2, led to obstruction of essential processes for establishing and maintaining pregnancy, such as embryo migration from oviducts to uteri, the decidual response, and activation of luteal function. Zearalenone also induced delayed implantation and loss of conceptuses and at low doses caused a retarded growth of the fetuses after normal implantation. It was therefore concluded that ZEN causes multiple estrogenic toxic actions when administered during early pregnancy in mice. PMID- 27485360 TI - Panel of Autoimmune Markers for Noninvasive Diagnosis of Minimal-Mild Endometriosis. AB - Endometriosis, characterized by the presence of endometrial-like tissue at extrauterine sites, is a common, chronic, estrogen-dependent, inflammatory condition associated with pelvic pain, subfertility, dysmenorrhea, and dyspareunia, affecting about 10% of reproductive-age women in any population. The diagnosis of endometriosis is usually delayed on an average by 8 to 11 years leading to significant consequences in terms of disease progression. The current study was aimed to validate enzyme-linked immunosorbent assay based on the epitopes of stomatin-like protein 2, tropomodulin 3 (TMOD3), and tropomyosin 3 (TPM3) for diagnosis of minimal-mild endometriosis (revised American Fertility Society Classification (rAFS) stage I-II) and to compare the performance with the reported markers: cancer antigen (CA) 125, CA19-9, alpha-enolase, Serine/threonine-protein kinase (PDIK1L), and syntaxin 5. This was a cross sectional, multicenter study conducted during the year 2012 to 2015. Women with minimal-mild endometriosis (rAFS stage I-II [n = 133]) and healthy controls (n = 104) were screened for 11 novel autoimmune markers and reported markers alpha enolase, PDIK1L, syntaxin 5, CA-125, and CA19-9. The sensitivity and diagnostic accuracy of serum antibodies against all the 11 epitopes were higher than that of CA-125, CA19-9, alpha-enolase, PDIK1L, and syntaxin 5 for diagnosis of rAFS stage I to II endometriosis. The sensitivity of 6 biomarkers (anti-TMOD3b-autoAb, anti TMOD3c-autoAb, anti-TMOD3d-autoAb, anti-TPM3a-autoAb, anti-TPM3c-autoAb, and anti TPM3d-autoAb) was higher at the specificity of >=80% for diagnosis of rAFS stage I to II endometriosis as well as ultrasound-negative endometriosis. Further, logistic regression models of this panel of biomarkers showed increase in sensitivity, specificity, and diagnostic accuracy than individual biomarkers. The panel of 6 autoimmune biomarkers could be useful in setting up of noninvasive diagnostic test for detection of minimal-mild endometriosis. PMID- 27485362 TI - Ultrasound-Assisted Catheter-Directed Thrombolysis in High-Risk and Intermediate High-Risk Pulmonary Embolism: Results From a Single-Center Cohort. AB - We present our single-center results on ultrasound-assisted thrombolysis (USAT) in patients with pulmonary embolism (PE) at intermediate high risk (IHR) and high risk (HR). Our study consisted of 75 patients with PE who underwent USAT (60 at IHR and 15 at HR). The median time delay from symptoms to USAT was 5 days. Ultrasound-assisted thrombolysis resulted in improvements in tricuspid annular plane systolic excursion; pulmonary artery (PA) systolic and mean pressures; Qanadli score; right to left ventricle diameter ratio and right to left atrial diameter ratio; and diameters of main, right, and left PA regardless of the baseline risk status ( P < .0001 for all). Death was documented in 4 patients, and major and minor bleeding were noted in 2 and 5 of the patients, respectively. No PE-related event was noted during postdischarge follow-up period of median 310 days. Our study revealed that USAT facilitates the resolution of PA thrombotic burden, recovery of pulmonary hemodynamics, and right heart functions with acceptable rates of procedure-related complications in patients with PE, irrespective of the IHR or HR status. PMID- 27485357 TI - Renal Impairment and Cardiovascular Disease in HIV-Positive Individuals: The D:A:D Study. AB - BACKGROUND: While the association between renal impairment and cardiovascular disease (CVD) is well established in the general population, the association remains poorly understood in human immunodeficiency virus (HIV)-positive individuals. METHODS: Individuals with >=2 estimated glomerular filtration rate (eGFR) measurements after 1 February 2004 were followed until CVD, death, last visit plus 6 months, or 1 February 2015. CVD was defined as the occurrence of centrally validated myocardial infarction, stroke, invasive cardiovascular procedures, or sudden cardiac death. RESULTS: During a median follow-up duration of 8.0 years (interquartile range, 5.4-8.9 years) 1357 of 35 357 individuals developed CVD (incidence rate, 5.2 cases/1000 person-years [95% confidence interval {CI}, 5.0-5.5]). Confirmed baseline eGFR and CVD were closely related with 1.8% of individuals (95% CI, 1.6%-2.0%) with an eGFR > 90 mL/minute/1.73 m(2) estimated to develop CVD at 5 years, increasing to 21.1% (95% CI, 6.6% 35.6%) among those with an eGFR <= 30 mL/minute/1.73 m(2) The strong univariate relationship between low current eGFR and CVD was primarily explained by increasing age in adjusted analyses, although all eGFRs <= 80 mL/minute/1.73 m(2) remained associated with 30%-40% increased CVD rates, and particularly high CVD rates among individuals with an eGFR <= 30 mL/minute/1.73 m(2) (incidence rate ratio, 3.08 [95% CI, 2.04-4.65]). CONCLUSIONS: Among HIV-positive individuals in a large contemporary cohort, a strong relation between confirmed impaired eGFR and CVD was observed. This finding highlights the need for renal preventive measures and intensified monitoring for emerging CVD, particularly in older individuals with continuously low eGFRs. PMID- 27485363 TI - Strategies Preventing Contrast-Induced Nephropathy After Coronary Angiography: A Comprehensive Meta-Analysis and Systematic Review of 125 Randomized Controlled Trials. AB - This systematic review with meta-analysis sought to determine the strength of evidence for the effects of hydration (sodium bicarbonate [SB] and normal saline [NS]), supplementations ( N-acetylcysteine [NAC] and vitamin C), and some common drugs (adenosine antagonists [AAs], statins, loop diuretics, and angiotensin converting enzyme inhibitors [ACEIs]) on the incidence of contrast-induced nephropathy (CIN) and requirement for hemodialysis after coronary angiography. After screening, a total of 125 trials that reported outcomes were identified. Pooled analysis indicated beneficial effects of SB versus NS (odds ratio [OR] = 0.73; 95% confidence interval [CI]: 0.56-0.94; P = .01), NAC (OR = 0.79; 95% CI: 0.70-0.88; P = .001), vitamin C (OR = 0.64; 95% CI: 0.45-0.89; P = .01), statins (OR = 0.45; 95% CI: 0.35-0.57; P = .001), AA (OR = 0.28; 95% CI: 0.14-0.47; P = .001), loop diuretics (OR = 0.97; 95% CI: 0.33-2.85; P = .9), and ACEI (OR = 1.06; 95% CI: 0.69-1.61; P = .8). Overall, hydration with SB, use of supplements, such as NAC and vitamin C, and administration of statins and AA should always be considered for the prevention of CIN after coronary angiography. PMID- 27485364 TI - Patient and Therapist Agreement on Performance-Rated Ability Using the de Morton Mobility Index. AB - OBJECTIVE: To determine the level of agreement between patient self-report and therapist-assessed performance of mobility using the de Morton Mobility Index (DEMMI). DESIGN: Interrater agreement study. SETTING: Outpatient hospital clinic. PARTICIPANTS: Consecutive sample of patients (N=128) undergoing preoperative assessment for elective lower limb (LL) arthroplasty. INTERVENTIONS: Participants completed a therapist-directed assessment of the DEMMI followed by self-report of performance. A random subsample (n=62, 48%) also completed a self-report of anticipated performance before the therapist-directed assessment. Both raters (participant and therapist) were blinded to the scores obtained from the other rater. MAIN OUTCOME MEASURES: Interrater agreement between patient self-report and therapist-directed assessment of the total DEMMI scores was assessed using the intraclass correlation coefficient model 2,1 (ICC2,1) with a 95% confidence interval. The Bland-Altman plots were also used to illustrate the agreement between the 2 raters. RESULTS: The intraclass correlation coefficient (ICC) between patient self-report after performance and therapist-directed assessment of the total DEMMI score was .967 (95% confidence interval, .952-.977). The ICC between patient self-report of anticipated performance and therapist-directed assessment of the total DEMMI score was .830 (95% confidence interval, .730 .894). The Bland-Altman plots depicted higher levels of agreement among participants with impaired levels of mobility (<=74 out of 100) than did those with near-maximum DEMMI scores. CONCLUSIONS: Patient self-report of anticipated performance is an acceptable proxy for DEMMI scores derived from the therapist rating of performance. Caution should be exercised when interpreting self-report scores of patients with near-maximum levels of mobility. Further research is required to establish whether these results can be generalized across a range of patient populations and to clinicians with differing backgrounds and expertise. PMID- 27485365 TI - Social Isolation and Physical Barriers in the Houses of Stroke Survivors in Rural China. AB - OBJECTIVE: To describe the home barriers and social isolation of stroke survivors in the rural areas of China and to explore which home barriers are associated with social isolation. DESIGN: Cross-sectional survey. SETTING: Structured interviews and observation in the participants' homes. PARTICIPANTS: Community dwelling stroke survivors in the rural areas of China (N=818). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Physical barriers in rural homes were surveyed using a home fall hazards assessment. Social isolation was identified if >=2 of the following indicators were observed: low frequency of getting out of the home, lacking leisure activities, and living alone in the previous 3 months. RESULTS: The prevalence rates of 18 among 30 home barriers were >20%, and the highest was 93% (lack of handrails in the bathroom). The prevalence of social isolation was 30%. Three home barriers were independently related to social isolation. These were a distant toilet (odds ratio [OR], 2.363; 95% confidence interval [CI], 1.527-3.658; P<.001), unsuitable seating (OR, 1.571; 95% CI, 1.026-2.404; P=.038), and inaccessible light switches (OR, 1.572; 95% CI, 1.064-2.324; P=.023). CONCLUSIONS: Many barriers exist in the houses of stroke survivors in rural China. Some of them are related to social isolation. Eliminating or decreasing home barriers could be a feasible and effective approach to reducing social isolation. PMID- 27485366 TI - Gait Retraining With Real-Time Biofeedback to Reduce Knee Adduction Moment: Systematic Review of Effects and Methods Used. AB - OBJECTIVE: To review the current literature regarding methods and effects of real time biofeedback used as a method for gait retraining to reduce knee adduction moment (KAM), with intended application for patients with knee osteoarthritis (KOA). DATA SOURCES: Searches were conducted in MEDLINE, Embase, CINAHL, SPORTDiscus, Web of Science, and Cochrane Central Register of Controlled Trials with the keywords gait, feedback, and knee osteoarthritis from inception to May 2015. STUDY SELECTION: Titles and abstracts were screened by 1 individual for studies aiming to reduce KAM. Full-text articles were assessed by 2 individuals against predefined criteria. DATA EXTRACTION: Data were extracted by 1 individual according to a predefined list, including participant demographics and training methods and effects. DATA SYNTHESIS: Electronic searches resulted in 190 potentially eligible studies, from which 12 met all inclusion criteria. Within group standardized mean differences (SMDs) for reduction of KAM in healthy controls ranged from .44 to 2.47 and from .29 to .37 in patients with KOA. In patients with KOA, improvements were reported in pain and function, with SMDs ranging from .55 to 1.16. Methods of implementation of biofeedback training varied between studies, but in healthy controls increased KAM reduction was noted with implicit, rather than explicit, instructions. CONCLUSIONS: This review suggests that biofeedback gait training is effective primarily for reducing KAM but also for reducing pain and improving function in patients with KOA. The review was limited by the small number of studies featuring patients with KOA and the lack of controlled studies. The results suggest there is value and a need in further researching biofeedback training for reducing KAM. Future studies should include larger cohorts of patients, long-term follow-up, and controlled trials. PMID- 27485367 TI - Novel method using 3-dimensional segmentation in spectral domain-optical coherence tomography imaging in the chick reveals defocus-induced regional and time-sensitive asymmetries in the choroidal thickness. AB - Studies into the mechanisms underlying the active emmetropization process by which neonatal refractive errors are corrected, have described rapid, compensatory changes in the thickness of the choroidal layer in response to imposed optical defocus. While high frequency A-scan ultrasonography, as traditionally used to characterize such changes, offers good resolution of central (on-axis) changes, evidence of local retinal control mechanisms make it imperative that more peripheral, off-axis changes also be tracked. In this study, we used in vivo high resolution spectral domain-optical coherence tomography (SD OCT) imaging in combination with the Iowa Reference Algorithms for 3-dimensional segmentation, to more fully characterize these changes, both spatially and temporally, in young, 7-day old chicks (n = 15), which were fitted with monocular +15 D defocusing lenses to induce choroidal thickening. With these tools, we were also able to localize the retinal area centralis, which was used as a landmark along with the ocular pectin in standardizing the location of scans and aligning them for subsequent analyses of choroidal thickness (CT) changes across time and between eyes. Values were derived for each of four quadrants, centered on the area centralis, and global CT values were also derived for all eyes. Data were compared with on-axis changes measured using ultrasonography. There were significant on-axis choroidal thickening that was detected after just one day of lens wear (~190 um), and regional (quadrant-related) differences in choroidal responses were also found, as well as global thickness changes 1 day after treatment. The ratio of global to on-axis choroidal thicknesses, used as an index of regional variability in responses, was also found to change significantly, reflecting the significant central changes. In summary, we demonstrated in vivo high resolution SD-OCT imaging, used in combination with segmentation algorithms, to be a viable and informative approach for characterizing regional (spatial), time-sensitive changes in CT in small animals such as the chick. PMID- 27485368 TI - Comparison of results of graft uptake using tragal cartilage perichondrium composite graft versus temporalis fascia in patients undergoing surgery for chronic otitis media - squamous type. AB - BACKGROUND: To assess, analyze and compare the results of graft uptake using Tragal Cartilage-Perichondrium Composite (TCPC) graft with Temporalis Fascia (TF) graft in patients who undergoing surgery for chronic otitis media - squamous type. METHODS: Patients aged 13 years and above with diagnosis of chronic otitis media - squamous type undergoing modified radical mastoidectomy, either primary or revision surgery with grafting of tympanic membrane (TM) and patients undergoing excision of postero-superior retraction pocket (PSRP) were included in this study. Patients were divided in two groups: Group A-patients undergoing TCPC graft and Group B -patients undergoing TF graft. Graft uptake results were assessed between 8-12 weeks of surgery. RESULTS: In both Groups there were 30 patients each. In Group A successful graft uptake was seen in 27 patients (90 %) and failure of graft uptake was seen in 3 patients(10 %). In Group B successful graft uptake was seen in 28 patients (93.3 %) and failure in 2 patients (6.67 %).Out of the total 60 patients, 11 patients had PSRP. All 6 patients with PSRP in Group A had successful graft uptake and no retraction. Among the 5 patients with PSRP in Group B all patients had sucessful graft uptake, however, in 2 patients retraction of the tympanic membrane was seen similar to the preoperative findings. CONCLUSIONS: There was no statistical difference (p = 0.433) between the use of temporalis fascia or tragal cartilage perichondrium in patients undergoing surgery for chronic otitis media - squamous type. PMID- 27485369 TI - Variant origin and course of left circumflex coronary artery. AB - Variant origin of left circumflex coronary artery (LCx) from right aortic sinus is a well-recognized coronary variation, usually without any clinical consequences. However, the variant origin and trajectory of the artery may have major implications during percutaneous coronary intervention, coronary artery surgery, aortic and mitral valve replacement procedures. We observed a variant LCx in a heart specimen belonging to 45-year-female with no history of hypertension, diabetes mellitus and coronary artery disease. The artery arose along with the right coronary artery from a common ostium in right aortic sinus and depicted a retroaortic course. The vessel was located at the level of aortic annulus and 6.6 mm above mitral valve annulus. The degree of luminal stenosis in variant LCx was higher than that in right coronary artery (RCA) and left anterior descending artery (LAD). Appropriate anatomical knowledge of the location and course of variant LCx is important for successful coronary interventions and valve replacement procedures. PMID- 27485370 TI - 3D spin-flop transition in enhanced 2D layered structure single crystalline TlCo2Se2. AB - The enhanced 2D layered structure single crystalline TlCo2Se2 has been successfully fabricated, which exhibits field-induced 3D spin-flop phase transitions. In the case of the magnetic field parallel to the c-axis (B//c), the applied magnetic field induces the evolution of the noncollinear helical magnetic coupling into a ferromagnetic (FM) state with all the magnetization of the Co ion parallel to the c-axis. A striking variation of the field-induced strain within the ab-plane is noticed in the magnetic field region of 20-30 T. In the case of the magnetic field perpendicular to the c-axis (B ? c), the inter-layer helical antiferromagnetic (AFM) coupling may transform to an initial canted AFM coupling, and then part of it transforms to an intermediate metamagnetic phase with the alignment of two-up-one-down Co magnetic moments and finally to an ultimate FM coupling in higher magnetic fields. The robust noncollinear AFM magnetic coupling is completely destroyed above 30 T. In combination with the measurements of magnetization, magnetoresistance and field-induced strain, a complete magnetic phase diagram of the TlCo2Se2 single crystal has been depicted, demonstrating complex magnetic structures even though the crystal geometry itself gives no indication of the magnetic frustration. PMID- 27485371 TI - Biological effects of compressive forces exerted on particulate bone grafts during socket preservation: animal study. AB - OBJECTIVES: To compare different compressive forces exerted on a particulate graft material during socket preservation and their effects on bone regeneration. MATERIAL AND METHODS: Six male dogs were used. The second, third, and fourth premolars, and the first molar were extracted bilaterally at the lower jaws. A particulate synthetic biphasic grafting material (60% HA and 40% beta-tricalcium phosphate) was used. Three different standardized compressive forces were applied randomly during the socket preservation. The sample was divided into four experimental groups Test A (10 g), Test B (50 g), Test C (200 g), and Control (empty sockets). Collagen membranes were placed, and primary closure was obtained. Two months after the surgery the animals were sacrificed, and histomorphometric analysis of non-decalcified samples was performed at the coronal, middle, and apical thirds. RESULTS: Grafted sockets resulted in higher bony contour (3 +/- 0.43 mm2 ; P < 0.05). The particles penetrated up to the apical third in the group C but not in the other test groups and controls (P < 0.05). The percentage of new bone were higher at the coronal and apical thirds for Controls and group C compared to A and B groups (P < 0.05). The residual graft was higher for group C (53 +/- 1.4%), followed by group B (45 +/- 3.1%) and group A (35 +/- 1.9%; P < 0.05). The percentages of connective tissue were higher at the middle third without differences between groups (P > 0.05). CONCLUSIONS: Within the limitations of this experimental animal study, it might be concluded that grafted sockets compressed with 200 g force will have higher bony contours; higher compressive forces facilitate the penetration of the particulate graft material into the apical area of the socket and results in more bone formation at the coronal, middle, and apical thirds. PMID- 27485373 TI - Effect of cadmium on phenolic compounds, antioxidant enzyme activity and oxidative stress in blueberry (Vaccinium corymbosum L.) plantlets grown in vitro. AB - Cadmium (Cd(2+)) can affect plant growth due to its mobility and toxicity. We evaluated the effects of Cd(2+) on the production of phenolic compounds and antioxidant response of Vaccinium corymbosum L. Plantlets were exposed to Cd(2+) at 50 and 100uM for 7, 14 and 21 days. Accumulation of malondialdehyde (MDA), hydrogen peroxide (H2O2) and the antioxidant enzyme SOD was determined. The profile of phenolic compounds was evaluated using LC-MS. The antioxidant activity was measured using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and the ferric reducing antioxidant power test (FRAP). Cd(2+) increased the content of MDA, with the highest increase at 14 days. The presence of Cd(2+) resulted in changes in phenolic compounds. The main phenolic compound found in blueberry plantlets was chlorogenic acid, whose abundance increased with the addition of Cd(2+) to the medium. The changes in the composition of phenolic compounds showed a positive correlation with the antioxidant activity measured using FRAP. Our results suggest that blueberry plantlets produced phenolic compounds with reducing capacity as a selective mechanism triggered by the highest activity of Cd(2+). PMID- 27485372 TI - Prevalence of Sexual Aggression Victimization and Perpetration in a Sample of Female and Male College Students in Turkey. AB - In Turkey, there is a shortage of studies on the prevalence of sexual aggression among young adults. The present study examined sexual aggression victimization and perpetration since the age of 15 in a convenience sample of N = 1,376 college students (886 women) from four public universities in Ankara, Turkey. Prevalence rates for different coercive strategies, victim-perpetrator constellations, and sexual acts were measured with a Turkish version of the Sexual Aggression and Victimization Scale (SAV-S). Overall, 77.6% of women and 65.5% of men reported at least one instance of sexual aggression victimization, and 28.9% of men and 14.2% of women reported at least one instance of sexual aggression perpetration. Prevalence rates of sexual aggression victimization and perpetration were highest for current or former partners, followed by acquaintances/friends and strangers. Alcohol was involved in a substantial proportion of the reported incidents. The findings are the first to provide systematic evidence on sexual aggression perpetration and victimization among college students in Turkey, including both women and men. PMID- 27485374 TI - Emodin enhances cisplatin-induced cytotoxicity in human bladder cancer cells through ROS elevation and MRP1 downregulation. AB - BACKGROUND: Chemoresistance is one of the most leading causes for tumor progression and recurrence of bladder cancer. Reactive oxygen species (ROS) plays a key role in the chemosensitivity of cancer cells. In the present study, emodin (1,3,8-trihydroxy-6-methylanthraquinone) was applied as a ROS generator in combination with cisplatin in T24 and J82 human bladder cancer cells. METHODS: Cell viability and apoptosis rate of different treatment groups were detected by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry (FCM). The expression of transporters was measured at both the transcription and translation levels using PCR and western blotting. In vitro findings were confirmed by in vivo experiments using tumor-bearing mice. The expression of multidrug resistance-associated protein 1 (MRP1) in tumour tissue was measured using immunohistochemistry and side effects of the emodin/cisplatin co-treatment were investigated by histological examination. RESULTS: Emodin increased the cellular ROS level and effectively enhanced the cisplatin-induced cytotoxicity of T24 and J82 human bladder cancer cells through decreasing glutathione-cisplatin (GSH-cisplatin) conjugates. It blocked the chemoresistance of T24 and J82 cells to cisplatin through suppressing the expression of MRP1. This effect was specific in T24 and J82 cells but not in HCV-29 normal bladder epithelial cells. Consistent with in vitro experiments, emodin/cisplatin co treatment increased the cell apoptosis and repressed the MRP1 expression in xenograft tumors, and without obvious systemic toxicity. CONCLUSIONS: This study revealed that emodin could increase the cisplatin-induced cytotoxicity against T24 and J82 cells via elevating the cellular ROS level and downregulating MRP1 expression. We suggest that emodin could serve as an effective adjuvant agent for the cisplatin-based chemotherapy of bladder cancer. PMID- 27485375 TI - Assessing treatment barriers in eating disorders: A systematic review. AB - This systematic review evaluated methods used to assess treatment barriers among individuals with eating disorders or disordered eating. A total of 11 studies were identified and evaluated according to attributes considered important in the accurate assessment of treatment barriers. The majority of studies used qualitative methods, with five studies utilizing either a checklist or scale based instrument. Adequate psychometric investigation was lacking. This review highlights the paucity of research examining barriers to accessing and/or receiving treatment in disordered eating populations. There is a need for development of psychometrically sound instruments that assess the range and relative interference of specific barriers experienced in this population. PMID- 27485376 TI - A role for Rtt109 in buffering gene-dosage imbalance during DNA replication. AB - Chromatin can function as an integrator of DNA-related processes, allowing communication, for example, between DNA replication and gene transcription. Such communication is needed to overcome the gene-dosage imbalance introduced during DNA replication, when certain genes are replicated prior to others. Increased transcription of early replicating genes could alter regulatory balances. This does not occur, suggesting a mechanism that suppresses expression from newly replicated DNA. Critical to this buffering is Rtt109, which acetylates the internal K56 residue of newly synthesized histone H3 prior to incorporation onto DNA. H3K56ac distinguishes replicated from non-replicated DNA, communicating this information to the transcription machinery to ensure expression homeostasis during S phase. PMID- 27485377 TI - Bayesian adaptive patient enrollment restriction to identify a sensitive subpopulation using a continuous biomarker in a randomized phase 2 trial. AB - With the development of molecular targeted drugs, predictive biomarkers have played an increasingly important role in identifying patients who are likely to receive clinically meaningful benefits from experimental drugs (i.e., sensitive subpopulation) even in early clinical trials. For continuous biomarkers, such as mRNA levels, it is challenging to determine cutoff value for the sensitive subpopulation, and widely accepted study designs and statistical approaches are not currently available. In this paper, we propose the Bayesian adaptive patient enrollment restriction (BAPER) approach to identify the sensitive subpopulation while restricting enrollment of patients from the insensitive subpopulation based on the results of interim analyses, in a randomized phase 2 trial with time-to endpoint outcome and a single biomarker. Applying a four-parameter change-point model to the relationship between the biomarker and hazard ratio, we calculate the posterior distribution of the cutoff value that exhibits the target hazard ratio and use it for the restriction of the enrollment and the identification of the sensitive subpopulation. We also consider interim monitoring rules for termination because of futility or efficacy. Extensive simulations demonstrated that our proposed approach reduced the number of enrolled patients from the insensitive subpopulation, relative to an approach with no enrollment restriction, without reducing the likelihood of a correct decision for next trial (no-go, go with entire population, or go with sensitive subpopulation) or correct identification of the sensitive subpopulation. Additionally, the four-parameter change-point model had a better performance over a wide range of simulation scenarios than a commonly used dichotomization approach. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27485378 TI - Vigabatrin efficacy in GPR56-associated polymicrogyria: The role of GABAA receptor pathway. PMID- 27485379 TI - Commentary on clinical significance of CYP2C9-status-guided valproic acid therapy in children. PMID- 27485380 TI - In response: Commentary on clinical significance of CYP2C9-status-guided valproic acid therapy in children. PMID- 27485381 TI - RT-qPCR for the diagnosis of dermatophilosis in horses. AB - BACKGROUND: Dermatophilus congolensis causes a crusting dermatitis that affects horses. Diagnosis requires the identification of the organism with cytological evaluation of crust samples. This method can lack sensitivity in chronic cases. HYPOTHESIS/OBJECTIVES: To develop a probe-based real time quantitative polymerase chain reaction (RT-qPCR) test to assist with the diagnosis of dermatophilosis in horses. ANIMALS: Twenty six privately owned horses and seven horses from a research colony were used. METHODS: Crust samples, collected from 14 horses with suspected dermatophilosis and 12 horses with crusting skin disease not characteristic of dermatophilosis, were evaluated by cytological evaluation and RT-qPCR; the latter was also performed on hair samples collected from seven healthy horses. RESULTS: Cytological evaluation revealed organisms consistent with Dermatophilus congolensis from nine horses with suspected dermatophilosis, with only a few organisms seen from five samples. Cytological evaluation of all other crusts was negative for Dermatophilus. Other bacterial organisms were detected on cytological evaluation from 15 samples. RT-qPCR for Dermatophilus was positive from 11 crusts, whereas all other samples were negative. Two samples were cytologically negative but RT-qPCR positive for Dermatophilus. No samples were cytologically positive but RT-qPCR negative for Dermatophilus. CONCLUSION: Results of this study show that RT-qPCR may be a more sensitive and easier method than cytological evaluation for the diagnosis of dermatophilosis in horses. PMID- 27485382 TI - Effect of SO2 and steam on CO2 capture performance of biomass-templated calcium aluminate pellets. AB - Four types of synthetic sorbents were developed for high-temperature post combustion calcium looping CO2 capture using Longcal limestone. Pellets were prepared with: lime and cement (LC); lime and flour (LF); lime, cement and flour (LCF); and lime, cement and flour doped with seawater (LCFSW). Flour was used as a templating material. All samples underwent 20 cycles in a TGA under two different calcination conditions. Moreover, the prepared sorbents were tested for 10 carbonation/calcination cycles in a 68 mm-internal-diameter bubbling fluidized bed (BFB) in three environments: with no sulphur and no steam; in the presence of sulphur; and with steam. When compared to limestone, all the synthetic sorbents exhibited enhanced CO2 capture performance in the BFB experiments, with the exception of the sample doped with seawater. In the BFB tests, the addition of cement binder during the pelletisation process resulted in the increase of CO2 capture capacity from 0.08 g CO2 per g sorbent (LF) to 0.15 g CO2 per g sorbent (LCF) by the 10th cycle. The CO2 uptake in the presence of SO2 dramatically declined by the 10th cycle; for example, from 0.22 g CO2 per g sorbent to 0.05 g CO2 per g sorbent in the case of the untemplated material (LC). However, as expected all samples showed improved performance in the presence of steam, and the decay of reactivity during the cycles was less pronounced. Nevertheless, in the BFB environment, the templated pellets showed poorer CO2 capture performance. This is presumably because of material loss due to attrition under the FB conditions. By contrast, the templated materials performed better than untemplated materials under TGA conditions. This indicates that the reduction of attrition is critical when employing templated materials in realistic systems with FB reactors. PMID- 27485383 TI - Direct and quantitative evaluation of the human CYP3A4 contribution (fm) to drug clearance using the in vitro SILENSOMES model. AB - 1. Among the different in vitro studies recommended by the regulatory agencies, no gold-standard model can easily and directly measure the quantitative CYP450 contributions to drug biotransformation. In this article, we propose an original strategy, called SilensomesTM, to produce human liver microsomes silenced for one specific CYP450, thanks to specific mechanism-based inhibitors (MBI). 2. Using azamulin as a specific CYP3A4 MBI, we demonstrated the proof of concept that CYP3A4 can be totally, specifically (even against 3A5) and permanently (at least for six years) inhibited by our process. Thus, comparing clearance in control and CYP3A4-SilensomesTM, CYP3A4 contributions were determined for 11 CYP3A4 substrates which correlated with known in vivo contributions and revealed accuracy with less than 10% error. In comparison, contributions determined using recombinant human CYP450 (rhCYP450s) were less accurate (more than 10% error for 30% of the tested CYP3A4 substrates). 3. This easy and ready-to-use in vitro method combines the advantages of existing models (specificity of rhCYP450s and representativeness of HLM) without their drawbacks. The same strategy could be used to silence other major CYP450s one-by-one to provide a complete direct CYP450 quantitative phenotyping kit. PMID- 27485384 TI - Loss of coxsackie and adenovirus receptor expression in human colorectal cancer: A potential impact on the efficacy of adenovirus-mediated gene therapy in Chinese Han population. AB - The coxsackie and adenovirus receptor (CAR) is considered a tumor suppressor and critical factor for the efficacy of therapeutic strategies that employ the adenovirus. However, data on CAR expression levels in colorectal cancer are conflicting and its clinical relevance remains to be elucidated. Immunohistochemistry was performed on tissue microarrays containing 251 pairs of colon cancer and adjacent normal tissue samples from Chinese Han patients to assess the expression levels of CAR. Compared with healthy mucosa, decreased CAR expression (40.6% vs. 95.6%; P<0.001) was observed in colorectal cancer samples. The CAR immunopositivity in tumor tissues was not significantly associated with gender, age, tumor size, differentiation, TNM stage, lymph node metastasis or distant metastasis in patients with colon cancer. However, expression of CAR is present in 83.3% of the tumor tissues from patient with colorectal liver metastasis, which was significantly higher than those without liver metastasis (39.6%; P=0.042). At the plasma membrane, CAR was observed in 29.5% normal mucosa samples, which was significantly higher than in colorectal cancer samples (4.0%; P<0.001). In addition, the survival analysis demonstrated that the expression level of CAR has no association with the prognosis of colorectal cancer. CAR expression was observed to be downregulated in colorectal cancer, and it exerts complex effects during colorectal carcinogenesis, potentially depending on the stage of the cancer development and progression. High CAR expression may promote liver metastasis. With regard to oncolytic therapy, CAR expression analysis should be performed prior to adenoviral oncolytic treatment to stratify Chinese Han patients for treatment. PMID- 27485385 TI - A two-step strategy for the preparation of 6-deoxy-l-sorbose. AB - A two-step enzymatic strategy for the efficient and convenient synthesis of 6 deoxy-l-sorbose was reported herein. In the first reaction step, the isomerization of l-fucose (6-deoxy-l-galactose) to l-fuculose (6-deoxy-l tagatose) catalyzed by l-fucose isomerase (FucI), and the epimerization of l fuculose to 6-deoxy-l-sorbose catalyzed by d-tagatose 3-epimerase (DTE) were coupled with the targeted phosphorylation of 6-deoxy-l-sorbose by fructose kinase from human (HK) in a one-pot reaction. The resultant 6-deoxy-l-sorbose 1 phosphate was purified by silver nitrate precipitation method. In the second reaction step, the phosphate group of the 6-deoxy-l-sorbose 1-phosphate was hydrolyzed with acid phosphatase (AphA) to produce 6-deoxy-l-sorbose in 81% yield with regard to l-fucose. PMID- 27485386 TI - New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms. AB - A number of new nucleoside derivatives are disclosed as inhibitors of DOT1L activity. SARs established that DOT1L inhibition could be achieved through incorporation of polar groups and small heterocycles at the 5-position (5, 6, 12) or by the application of alternative nitrogenous bases (18). Based on these results, CN-SAH (19) was identified as a potent and selective inhibitor of DOT1L activity where the polar 5-nitrile group was shown by crystallography to bind in the hydrophobic pocket of DOT1L. In addition, we show that a polar nitrile group can be used as a non-traditional replacement for heavy halogen atoms. PMID- 27485387 TI - Cloning, expression, purification and sulfonamide inhibition profile of the complete domain of the eta-carbonic anhydrase from Plasmodium falciparum. AB - We report the cloning, purification and characterization of the full domain of carbonic anhydrase (CA, EC 4.2.1.1) from Plasmodium falciparum, which incorporates 358 amino acid residues (from 181 to 538, in the sequence of this 600 amino acid long protein), called PfCAdom. The enzyme, which belongs to the eta-CA class showed the following kinetic parameters: kcat of 3.8*10(5)s(-1) and kcat/Km of 7.2*10(7)M(-1)*s(-1), being 13.3 times more effective as a catalyst compared to the truncated form PfCA. PfCAdom is more effective than the human (h) isoform hCA I, being around 50% less effective compared to hCA II, one of the most catalytically efficient enzymes known so far. Intriguingly, the sulfonamides CA inhibitors generally showed much weaker inhibitory activity against PfCAdom compared to PfCA, prompting us to hypothesize that the 69 amino acid residues insertion present in the active site of this eta-CA is crucial for the active site architecture. The best sulfonamide inhibitors for PfCAdom were acetazolamide, methazolamide, metanilamide and sulfanilamide, with KIs in the range of 366-808nM. PMID- 27485388 TI - Unraveling gene function in agricultural species using gene co-expression networks. AB - Co-expression networks have been shown to be a powerful tool for inferring a gene's function when little is known about it. With the advent of next generation sequencing technologies, the construction and analysis of co-expression networks is now possible in non-model species, including those with agricultural importance. Here, we review fundamental concepts in the construction and application of co-expression networks with a focus on agricultural crops. We survey past and current applications of co-expression network analysis in several agricultural species and provide perspective on important considerations that arise when analyzing network relationships. We conclude with a perspective on future directions and potential challenges of utilizing this powerful approach in crops. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer. PMID- 27485389 TI - Effect of clonazepam and clonidine on primary sleep bruxism: a double-blind, crossover, placebo-controlled trial. AB - The aim of this study was to assess the acute effects of clonazepam and clonidine on rhythmic masticatory muscle activity in young adults with primary sleep bruxism, as well as accompanying effects on sleep architecture and cardiac activity. This study used a double-blind, crossover, placebo-controlled design. Polysomnography was performed on 19 subjects [nine men and 10 women; mean age (+/ SE): 25.4 +/- 2.7 years] for 5 nights. The first 2 nights were used for the habituation and diagnosis of sleep bruxism. The other 3 nights were randomly assigned for clonazepam (1.0 mg), clonidine (0.15 mg) or placebo (all administered 30 min before bedtime). Sleep, oromotor activity and cardiac activity variables were assessed and compared among the three drug conditions. Clonidine significantly reduced the median percentage of time spent in the rapid eye movement sleep stage compared with placebo and clonazepam. The number of rhythmic masticatory muscle activity episodes was reduced with clonidine by >30% compared with placebo and clonazepam. The reduction of rhythmic masticatory muscle activity index by clonidine was associated with an increase of mean RR intervals (slower heart rate) during quiet sleep periods and during a 70-s period before the onset of rhythmic masticatory muscle activity episodes. However, no changes in cardiac activity variables were observed for clonazepam. In young adults with primary sleep bruxism, clonidine was significantly more effective in suppressing sleep bruxism than clonazepam. The acute effects of clonidine on rhythmic masticatory muscle activity episodes may be mediated by suppression of autonomic nervous system activity and non-rapid eye movement-rapid eye movement sleep processes. PMID- 27485390 TI - Resident and family member perceptions of cultural diversity in aged care homes. AB - Similar to many developed nations, older people living in residential aged care homes in Australia and the staff who care for them have become increasingly multicultural. This cultural diversity adds challenges for residents in adapting to the care home. This study explores: (i) residents' and family members' perceptions about staff and cultural diversity, and (ii) culturally and linguistically diverse residents' and family members' experiences. An interpretive study design employing a thematic analysis was applied. Twenty-three residents and seven family members participated in interviews. Four themes were identified from interpreting residents and family members' perceptions of the impact of cultural diversity on their adaptation to aged care homes: (i) perceiving diversity as an attraction; (ii) adapting to cross-cultural communication; (iii) adjusting to diet in the residential care home; and (iv) anticipating individualized psychosocial interactions. The findings have implications for identifying strategies to support staff from all cultural backgrounds in order to create a caring environment that facilitates positive relationships with residents and supports residents to adjust to the care home. PMID- 27485391 TI - Bacterial IgA protease-mediated degradation of agIgA1 and agIgA1 immune complexes as a potential therapy for IgA Nephropathy. AB - Mesangial deposition of aberrantly glycosylated IgA1 (agIgA1) and its immune complexes is a key pathogenic mechanism of IgA nephropathy (IgAN). However, treatment of IgAN remains ineffective. We report here that bacteria-derived IgA proteases are capable of degrading these pathogenic agIgA1 and derived immune complexes in vitro and in vivo. By screening 14 different bacterial strains (6 species), we found that 4 bacterial IgA proteases from H. influenzae, N. gonorrhoeae and N. meningitidis exhibited high cleaving activities on serum agIgA1 and artificial galactose-depleted IgA1 in vitro and the deposited agIgA1 containing immune complexes in the mesangium of renal biopsy from IgAN patients and in a passive mouse model of IgAN in vitro. In the modified mouse model of passive IgAN with abundant in situ mesangial deposition of the agIgA-IgG immune complexes, a single intravenous delivery of IgA protease from H. influenzae was able to effectively degrade the deposited agIgA-IgG immune complexes within the glomerulus, demonstrating a therapeutic potential for IgAN. In conclusion, the bacteria-derived IgA proteases are biologically active enzymes capable of cleaving the circulating agIgA and the deposited agIgA-IgG immune complexes within the kidney of IgAN. Thus, the use of such IgA proteases may represent a novel therapy for IgAN. PMID- 27485393 TI - Montelukast, current indications and prospective future applications. AB - INTRODUCTION: Montelukast is recommended for the treatment of asthma, exercise induced bronchospasm and allergic rhinitis. Several trials demonstrated potential therapeutic effects in other respiratory conditions, and different animal-model based studies explored potential pharmacological actions in non-respiratory conditions. AREAS COVERED: Clinical investigations on the pharmacotherapeutic effects of montelukast, in addition to in-vivo studies on animal models of non respiratory diseases. The data discussed in this review were mainly obtained from clinical randomized trials, real-life studies, and studies based on animal models as approve of concept. As a condition, all of the discussed articles were published in journals cited by Pubmed. Expert commentary: The current clinical data are in favor of montelukast use in the management of chronic asthma as an add-on or alternative therapy to the inhaled corticosteroids. Further clinical trials are required to confirm the effectiveness and feasibility of montelukast for the treatment of conditions other than the current clinical indications. PMID- 27485394 TI - Stability of LAPONITE(r)-stabilized high internal phase Pickering emulsions under shear. AB - Colloidal particles are often used to make Pickering emulsions that are reported to be very stable. Commonly the stabilization is a combined effect of particle adsorbing at the fluid interface and a particle network in the continuous phase; the contribution of each to the overall stability is difficult to assess. We investigate the role of LAPONITE(r) particles on high internal phase emulsion stability by considering three different situations: emulsion stabilization by surfactant only, by surfactant plus clay particles, and finally clay particles only. To clarify the structure of the emulsion and the role of the clay particles, we have succeeded in fluorescently labelling the clay particles by adsorbing the dye onto the particle surfaces. This allows us to show directly using confocal microscopy, that the clay particles are not only located at the interface but also aggregate and form a gel in the continuous aqueous phase. We show that the emulsions in the presence of surfactant (with or without clay) are stable to coalescence and shear. Without surfactant (with only LAPONITE(r) as stabilizer) the emulsions are stable to coalescence for several weeks, however they destabilize rapidly under shear. Our results suggest that the formation of the emulsions is mostly due to gel formation of the clay particles in the continuous phase, rather than that the clay is an emulsifier. This gel formation also accounts for the instability of the emulsions to shear that we observe caused by shear thinning of the continuous gel and inability of the adsorbed particles to rearrange effectively around the droplets due to their attractive nature. PMID- 27485395 TI - Separation and analysis of mono-glucosylated lipids in brain and skin by hydrophilic interaction chromatography based on carbohydrate and lipid moiety. AB - Mono-glycosylated sphingolipids and glycerophospholipids play important roles in diverse biological processes and are linked to a variety of pathologies, such as Parkinson disease. The precise identification of the carbohydrate head group of these lipids is complicated by their isobaric nature and by substantial differences in concentration in different biological samples. To overcome these obstacles, we developed a zwitterionic (ZIC)-hydrophilic interaction chromatography (HILIC) electrospray ionization tandem mass spectrometry method. ZIC-HILIC preferentially retains inositol, followed by glucose- and galactose featuring lipids. Comparison with unmodified silica gel HILIC stationary phase revealed different retention specificity. To evaluate the precision of ZIC-HILIC, we quantified glucosyl- (GlcCer) and galactosylceramides (GalCer) in seven different regions of the mouse brain and discovered that GlcCer and GalCer concentrations are inversely related. The highest GalCer (lowest GlcCer) content was found in the medulla oblongata and hippocampus, whereas the highest GlcCer (lowest GalCer) content was found in other regions. With a neutral loss scan, ZIC HILIC resolved glucosylceramide species featuring non-hydroxylated fatty acid, hydroxylated fatty acid, and trihydroxy sphingoid bases in mouse epidermis samples. This demonstrates that our ZIC-HILIC-based approach is a valuable tool for characterizing the structural diversity of mono-glucosylated lipids in biological material and for quantifying these important lipids. PMID- 27485392 TI - Toward development of epigenetic drugs for central nervous system disorders: Modulating neuroplasticity via H3K4 methylation. AB - The mammalian brain dynamically activates or silences gene programs in response to environmental input and developmental cues. This neuroplasticity is controlled by signaling pathways that modify the activity, localization, and/or expression of transcriptional-regulatory enzymes in combination with alterations in chromatin structure in the nucleus. Consistent with this key neurobiological role, disruptions in the fine-tuning of epigenetic and transcriptional regulation have emerged as a recurrent theme in studies of the genetics of neurodevelopmental and neuropsychiatric disorders. Furthermore, environmental factors have been implicated in the increased risk of heterogeneous, multifactorial, neuropsychiatric disorders via epigenetic mechanisms. Aberrant epigenetic regulation of gene expression thus provides an attractive unifying model for understanding the complex risk architecture of mental illness. Here, we review emerging genetic evidence implicating dysregulation of histone lysine methylation in neuropsychiatric disease and outline advancements in small molecule probes targeting this chromatin modification. The emerging field of neuroepigenetic research is poised to provide insight into the biochemical basis of genetic risk for diverse neuropsychiatric disorders and to develop the highly selective chemical tools and imaging agents necessary to dissect dynamic transcriptional-regulatory mechanisms in the nervous system. On the basis of these findings, continued advances may lead to the validation of novel, disease modifying therapeutic targets for a range of disorders with aberrant chromatin mediated neuroplasticity. PMID- 27485396 TI - Elimination of biofilm and microbial contamination reservoirs in hospital washbasin U-bends by automated cleaning and disinfection with electrochemically activated solutions. AB - BACKGROUND: Washbasin U-bends are reservoirs of microbial contamination in healthcare environments. U-Bends are constantly full of water and harbour microbial biofilm. AIM: To develop an effective automated cleaning and disinfection system for U-bends using two solutions generated by electrochemical activation of brine including the disinfectant anolyte (predominantly hypochlorous acid) and catholyte (predominantly sodium hydroxide) with detergent properties. METHODS: Initially three washbasin U-bends were manually filled with catholyte followed by anolyte for 5min each once weekly for five weeks. A programmable system was then developed with one washbasin that automated this process. This U-bend had three cycles of 5min catholyte followed by 5min anolyte treatment per week for three months. Quantitative bacterial counts from treated and control U-bends were determined on blood agar (CBA), R2A, PAS, and PA agars following automated treatment and on CBA and R2A following manual treatment. FINDINGS: The average bacterial density from untreated U-bends throughout the study was >1*10(5) cfu/swab on all media with Pseudomonas aeruginosa accounting for ~50% of counts. Manual U-bend electrochemically activated (ECA) solution treatment reduced counts significantly (<100cfu/swab) (P<0.01 for CBA; P<0.005 for R2A). Similarly, counts from the automated ECA-treatment U-bend were significantly reduced with average counts for 35 cycles on CBA, R2A, PAS, and PA of 2.1+/-4.5 (P<0.0001), 13.1+/-30.1 (P<0.05), 0.7+/-2.8 (P<0.001), and 0 (P<0.05) cfu/swab, respectively. P. aeruginosa was eliminated from all treated U bends. CONCLUSION: Automated ECA treatment of washbasin U-bends consistently minimizes microbial contamination. PMID- 27485397 TI - Expression of cyclooxygenases and trophic and growth factors in epiretinal membranes at late stages of proliferative vitreoretinopathy. PMID- 27485398 TI - Preparation and preclinical evaluation of a freeze-dried formulation of a novel combined multivalent whole-cell/B-subunit oral vaccine against enterotoxigenic Escherichia coli diarrhea. AB - A promising liquid killed multivalent whole-cell plus enterotoxin B-subunit oral vaccine against enterotoxigenic Escherichia coli (ETEC), the primary cause of diarrhea among children in low-income countries and travelers to these areas, has recently been developed and tested in preclinical and phase-I and phase-II clinical studies. The vaccine contains killed E. coli bacteria over-expressing the main ETEC colonization factors (CFs) CFA/I, CS3, C5 and C6, and a recombinant enterotoxin B subunit protein (LCTBA) given together with a recently developed enterotoxin-derived adjuvant, dmLT. A dry-powder vaccine formulation should be advantageous especially for use in low-income countries. Here we describe a method to produce a dry-powder formulation by freeze-drying of the vaccine using inulin as stabilizer. Although not completely preventing aggregation of bacteria during freeze-drying, the stabilizer provided both improved overall bacterial morphology and almost complete recovery of the CF and B subunit antigens. Most importantly, oral-intragastric immunization of mice with the freeze-dried vaccine together with dmLT adjuvant elicited strong intestinal mucosal and serum antibody responses against all vaccine antigens, which were comparable to those achieved with the liquid vaccine. Our results indicate the feasibility to use freeze drying with inulin as stabilizer for preparing a dry-powder formulation of the novel ETEC vaccine with retained oral-mucosal immunogenicity compared to the liquid formulation. PMID- 27485399 TI - Novel virtual lead identification in the discovery of hematopoietic cell kinase (HCK) inhibitors: application of 3D QSAR and molecular dynamics simulation. AB - High level of hematopoietic cell kinase (Hck) is associated with drug resistance in chronic myeloid leukemia. Additionally, Hck activity has also been connected with the pathogenesis of HIV-1 and chronic obstructive pulmonary disease. In this study, three-dimensional (3D) QSAR pharmacophore models were generated for Hck based on experimentally known inhibitors. A best pharmacophore model, Hypo1, was developed with high correlation coefficient (0.975), Low RMS deviation (0.60) and large cost difference (49.31), containing three ring aromatic and one hydrophobic aliphatic feature. It was further validated by the test set (r = 0.96) and Fisher's randomization method (95%). Hypo 1 was used as a 3D query for screening the chemical databases, and the hits were further screened by applying Lipinski's rule of five and ADMET properties. Selected hit compounds were subjected to molecular docking to identify binding conformations in the active site. Finally, the appropriate binding modes of final hit compounds were revealed by molecular dynamics (MD) simulations and free energy calculation studies. Hence, we propose the final three hit compounds as virtual candidates for Hck inhibitors. PMID- 27485400 TI - Senescence: Adaptation to DNA repair targeting drugs? PMID- 27485401 TI - Interactive effects of attachment and FKBP5 genotype on school-aged children's emotion regulation and depressive symptoms. AB - Attachment insecurity is influenced by both environmental and genetic factors, but few studies have examined the effects of gene-environment interactions. In the context of environmental stress, a functional variant in the glucocorticoid receptor co-chaperone FKBP5 gene has been repeatedly shown to increase risk for psychiatric illness, including depression. We expand on prior work by exploring cross-sectional attachment by gene effects on both attachment insecurity and downstream physiological and behavioral measures in a diverse community sample of school-aged children (N=99, 49% girls, Mage=10.29years, 66.6% non-White) and their mothers. Specifically, we examined moderating effects of FKBP5 rs3800373 genotype on the links between parenting insensitivity (overcontrol) and child attachment. Further, we assessed whether FKBP5 moderates the links between maternal and child attachment and children's emotion regulation self-report, respiratory sinus arrhythmia (RSA) in response to a standardized laboratory stressor, and depressive symptoms. Higher levels of overcontrol predicted lower child attachment security only in FKBP5 minor allele carriers. Among children with two minor alleles (CC), attachment security was negatively associated with emotion suppression, rumination, depressive symptoms, and RSA reactivity; similarly, for these children, maternal attachment anxiety was positively associated with depressive symptoms. The findings can be conceptualized in a differential susceptibility framework, where the FKBP5 minor allele confers either risk or resilience, depending on the parenting environment. PMID- 27485402 TI - The lateral septum and anterior hypothalamus act in tandem to regulate burying in the shock-probe test but not open-arm avoidance in the elevated plus-maze. AB - Both the lateral septum (LS) and anterior hypothalamus (AHA) regulate behavioural defense. We tested whether those two interconnected structures act in serial in that regard. Infusions of the GABAA agonist muscimol into one side of the LS and the contralateral (but not ipsilateral) AHA suppressed rats' burying in the shock probe test whereas none of our muscimol infusion approaches altered their open arm avoidance in the elevated plus-maze. These results suggest that the LS-AHA circuit serves a specialized role in defensive responses towards discrete, localizable threat stimuli but not towards potential threats. PMID- 27485403 TI - Alternating Current Influences Anaerobic Electroactive Biofilm Activity. AB - Alternating current (AC) is known to inactivate microbial growth in suspension, but how AC influences anaerobic biofilm activities has not been systematically investigated. Using a Geobacter dominated anaerobic biofilm growing on the electrodes of microbial electrochemical reactors, we found that high frequency AC ranging from 1 MHz to 1 kHz (amplitude of 5 V, 30 min) showed only temporary inhibition to the biofilm activity. However, lower frequency (100 Hz, 1.2 or 5 V) treatment led to 47 +/- 19% permanent decrease in limiting current on the same biofilm, which is attributed to the action of electrohydrodynamic force that caused biofilm damage and loss of intercellular electron transfer network. Confocal microscopy images show such inactivation mainly occurred at the interface between the biofilm and the electrode. Reducing the frequency further to 1 Hz led to water electrolysis, which generated gas bubbles that flushed all attached cells out of the electrode. These findings provide new references on understanding and regulating biofilm growth, which has broader implications in biofouling control, anaerobic waste treatment, energy and product recovery, and general understanding of microbial ecology and physiology. PMID- 27485404 TI - Carbidopa-assisted 18F-fluorodihydroxyphenylalanine PET/CT for the localization and staging of non-functioning neuroendocrine pancreatic tumors. AB - OBJECTIVE: CD premedication was found to increase the value of 18F fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT imaging in the detection of adult insulinoma. The aim of this study was to evaluate the performance of CD-assisted 18F-FDOPA PET/CT in the diagnosis and staging of non-functioning pNETs. METHODS: Twenty consecutive patients with low-grade pNETs who underwent CD-assisted 18F FDOPA PET/CT imaging and 111In-somatostatin receptor scintigraphy (SRS) were evaluated. Histology was considered as the gold standard. In case where no surgical resection was performed, the diagnosis of pNET was made by the confrontation of the different available imaging modalities. RESULTS: CD-assisted 18F-FDOPA PET/CT was positive in 18/20 cases (90 %), whereas SRS was positive in 13/19 cases (68 %). When considered the 19 patients underwent both nuclear medicine examinations, 18F-FDOPA PET/CT was significantly more sensitive then SRS for primary tumor detection (p = 0.049). False-negative results of both 18F-FDOPA PET/CT and SRS were observed in 2 cystic pNETs. SRS failed to detect one additional cystic tumor and 3 pNETs of 10, 12 and 17 mm, respectively. 18F-FDOPA PET/CT correctly identified all patients with lymphatic, visceral and bone metastases. SRS failed to detect lymphatic spread and was falsely negative in one patient with splenic metastasis. CONCLUSIONS: Contrary to widely held assumptions, our study further expands the application of CD-assisted 18F-FDOPA PET/CT for non-functioning pNETs when 68Ga-radiolabeled somatostatin analogs are not available. PMID- 27485405 TI - Effects of left ventricular size on the accuracy of diastolic parameters derived from myocardial perfusion SPECT: comparison with tissue Doppler echocardiography. AB - BACKGROUND: Impaired left ventricular (LV) diastolic function is a sensitive and early sign of myocardial ischemia. We evaluated the effects of LV size on the accuracy of diastolic parameters derived from SPECT. METHODS: The study population consisted of 151 patients with known or suspected coronary artery disease who underwent both SPECT and transthoracic echocardiography. Peak filling rate (PFR), one-third mean filling rate (1/3 MFR) and the ratio of time to PFR to the RR interval (TPFR/RR) were calculated by quantitative gated SPECT. Peak early mitral annular velocity (e') was used as the reference standard of LV diastolic function. RESULTS: There were 43 patients with end-systolic volume (ESV) of <=10 ml, 43 patients with ESV of 11-20 ml and 65 patients with ESV of >20 ml. There were significant differences in PFR (p < 0.001), 1/3 MFR (p < 0.001) or TPFR/RR (p = 0.01) among the 3 groups. These diastolic parameters were increased with decreased LV size. In overall patients, PFR (r = 0.24, p = 0.003) and 1/3 MFR (r = 0.31, p < 0.001) were positively, and TPFR/RR (r = -0.23, p = 0.004) was inversely correlated with e'. Multivariate linear regression analyses showed that male gender (beta = -0.14, p = 0.07; beta = -0.16, p = 0.04), ESV (beta = -0.63, p < 0.001; beta = -0.45, p < 0.001) and e' (beta = 0.36, p < 0.001; beta = 0.40, p < 0.001) were significant factors associated with PFR or 1/3 MFR. Multivariate linear regression analysis also showed that ESV (beta = -0.17, p = 0.03) and e' (beta = -0.21, p = 0.01) were significant factors associated with TPFR/RR. CONCLUSIONS: Our data suggest that PFR, 1/3 MFR and TPFR/RR derived from SPECT are correlated with e' as the reference standard of LV diastolic function, but are overestimated in small-sized heart. LV size should be taken into consideration when interpreting these diastolic parameters. PMID- 27485406 TI - Cerebral hyperperfusion syndrome resulting in subarachnoid hemorrhage after carotid artery stenting. AB - A 64-year-old, right-handed man underwent endovascular treatment for internal carotid artery stenosis after experiencing a left-hemispheric transient ischemic attack. 15O-gas and H 215 O positron emission tomography revealed slightly reduced cerebral blood flow (CBF), elevated cerebral blood volume, and severely reduced cerebral vasoreactivity in the ipsilateral hemisphere as determined by an acetazolamide challenge test. The patient underwent left carotid artery stenting (CAS) via a prefemoral approach under local anesthesia without any complications. Follow-up examinations performed 20 h postoperatively showed subarachnoid hemorrhage (SAH) and cerebral hyperperfusion syndrome (CHS) in the left frontal lobe. Although it is a relatively rare phenomenon, SAH resulting from CHS was determined to be specifically caused by CAS. In this case, the causes of SAH may have been related to multiple factors including increased regional CBF, loss of cerebrovascular autoregulation, contrast agent-mediated disruption of major cerebral vessels, and strong antiplatelet therapy. PMID- 27485408 TI - A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency. AB - We describe a new early-onset neuromuscular disorder due to a homozygous loss-of function variant in the kyphoscoliosis peptidase gene (KY). A 7.5-year-old girl with walking difficulties from 2 years of age presented with generalized muscle weakness; mild contractures in the shoulders, hips and feet; cavus feet; and lordosis but no scoliosis. She had previously been operated with Achilles tendon elongation. Whole-body MRI showed atrophy and fatty infiltration in the calf muscles. Biopsy of the vastus lateralis muscle showed variability in fiber size, with some internalized nuclei and numerous very small fibers with variable expression of developmental myosin heavy chain isoforms. Some small fibers showed abnormal sarcomeres with thickened Z-discs and small nemaline rods. Whole-exome sequencing revealed a homozygous one-base deletion (c.1071delG, p.(Thr358Leufs*3)) in KY, predicted to result in a truncated protein. Analysis of an RNA panel showed that KY is predominantly expressed in skeletal muscle in humans. A recessive variant in the murine ortholog Ky was previously described in a spontaneously generated mouse mutant with kyphoscoliosis, which developed postnatally and was caused by dystrophy of postural muscles. The abnormal distribution of Xin and Ky-binding partner filamin C in the muscle fibers of our patient was highly similar to their altered localization in ky/ky mouse muscle fibers. We describe the first human case of disease associated with KY inactivation. As in the mouse model, the affected child showed a neuromuscular disorder - but in contrast, no kyphoscoliosis. PMID- 27485407 TI - Cadmium, lead and mercury concentrations in pathologically altered human kidneys. AB - Heavy metals, including cadmium (Cd), lead (Pb) and mercury (Hg) act as nephrotoxic agents, particularly in the renal cortex. The aim of the study was to determine the concentrations of Cd, Pb and Hg in kidneys removed from patients due to lesions of various etiologies and from patients after the rejection of transplanted kidneys. Additionally, we determined the influence of selected biological and environmental factors on the concentrations of toxic metals. The study material consisted of kidneys with tumor lesions (n = 27), without tumors (n = 7) and its extracted grafts (n = 10) obtained from patients belongs to the north-western areas of Poland. The determined metal concentrations in the renal cortex and medulla may be arranged in the following descending order: Cd > Pb > Hg. The highest concentrations of Cd and Hg were found in the cortex, while the maximum content Pb was observed in the medulla. Significant correlations were found in the concentrations of the same metals between cortex and medulla and between Pb and Hg in the renal medulla. Pb content was higher in the renal medulla of men than in the cortex of the elderly (above 60 years of age). The highest concentrations of Pb and Hg were found in the cortex and medulla, of the kidneys had not neoplastic changes, and lower content of these metals were found in the extracted kidney grafts. In summary, renal grafts accumulate less heavy metals than cancerous kidneys, what could have been caused by immunosuppressors taken by the graft recipients. Moreover, sex, age and smoking are key factors responsible for xenobiotics concentrations. PMID- 27485409 TI - Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit. AB - The mitochondrial inner membrane possesses distinct subdomains including cristae, which are lamellar structures invaginated into the mitochondrial matrix and contain the respiratory complexes. Generation of inner membrane domains requires the complex interplay between the respiratory complexes, mitochondrial lipids and the recently identified mitochondrial contact site and cristae organizing system (MICOS) complex. Proper organization of the mitochondrial inner membrane has recently been shown to be important for respiratory function in yeast. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with a neurodegenerative disorder accompanied by hyperlactatemia, 3-methylglutaconic aciduria, disturbed hepatocellular function with abnormal cristae morphology in liver and cerebellar and vermis atrophy, which suggest mitochondrial dysfunction. Using homozygosity mapping and exome sequencing the patients were found to be homozygous for the p.(Gly15Glufs*75) variant in the QIL1/MIC13 (C19orf70) gene. QIL1/MIC13 is a constituent of MICOS, a six subunit complex that helps to form and/or stabilize cristae junctions and determine the placement, distribution and number of cristae within mitochondria. In patient fibroblasts both MICOS subunits QIL1/MIC13 and MIC10 were absent whereas MIC60 was present in a comparable abundance to that of the control. We conclude that QIL1/MIC13 deficiency in human, is associated with disassembly of the MICOS complex, with the associated aberration of cristae morphology and mitochondrial respiratory dysfunction. 3-Methylglutaconic aciduria is associated with variants in genes encoding mitochondrial inner membrane organizing determinants, including TAZ, DNAJC19, SERAC1 and QIL1/MIC13. PMID- 27485410 TI - Clinical Utility Gene Card for: Familial partial lipodystrophy. PMID- 27485411 TI - Copy number variation of the REXO1L1 gene cluster; euchromatic deletion variant or susceptibility factor? PMID- 27485412 TI - Lack of gene-language correlation due to reciprocal female but directional male admixture in Austronesians and non-Austronesians of East Timor. AB - Nusa Tenggara, including East Timor, located at the crossroad between Island Southeast Asia, Near Oceania, and Australia, are characterized by a complex cultural structure harbouring speakers from two different major linguistic groups of different geographic origins (Austronesian (AN) and non-Austronesian (NAN)). This provides suitable possibilities to study gene-language relationship; however, previous studies from other parts of Nusa Tenggara reported conflicting evidence about gene-language correlation in this region. Aiming to investigate gene-language relationships including sex-mediated aspects in East Timor, we analysed the paternally inherited non-recombining part of the Y chromosome (NRY) and the maternally inherited mitochondrial (mt) DNA in a representative collection of AN- and NAN-speaking groups. Y-SNP (single-nucleotide polymorphism) data were newly generated for 273 samples and combined with previously established Y-STR (short tandem repeat) data of the same samples, and with previously established mtDNA data of 290 different samples with, however, very similar representation of geographic and linguistic coverage of the country. We found NRY and mtDNA haplogroups of previously described putative East/Southeast Asian (E/SEA) and Near Oceanian (NO) origins in both AN and NAN speakers of East Timor, albeit in different proportions, suggesting reciprocal genetic admixture between both linguistic groups for females, but directional admixture for males. Our data underline the dual genetic origin of East Timorese in E/SEA and NO, and highlight that substantial genetic admixture between the two major linguistic groups had occurred, more so via women than men. Our study therefore provides another example where languages and genes do not conform due to sex-biased genetic admixture across major linguistic groups. PMID- 27485413 TI - Searching Missing Proteins Based on the Optimization of Membrane Protein Enrichment and Digestion Process. AB - A membrane protein enrichment method composed of ultracentrifugation and detergent-based extraction was first developed based on MCF7 cell line. Then, in solution digestion with detergents and eFASP (enhanced filter-aided sample preparation) with detergents were compared with the time-consuming in-gel digestion method. Among the in-solution digestion strategies, the eFASP combined with RapiGest identified 1125 membrane proteins. Similarly, the eFASP combined with sodium deoxycholate identified 1069 membrane proteins; however, the in-gel digestion characterized 1091 membrane proteins. Totally, with the five digestion methods, 1390 membrane proteins were identified with >=1 unique peptides, among which 1345 membrane proteins contain unique peptides >=2. This is the biggest membrane protein data set for MCF7 cell line and even breast cancer tissue samples. Interestingly, we identified 13 unique peptides belonging to 8 missing proteins (MPs). Finally, eight unique peptides were validated by synthesized peptides. Two proteins were confirmed as MPs, and another two proteins were candidate detections. PMID- 27485414 TI - An analysis of the relationship between metastases and cachexia in lung cancer patients. AB - Weight loss and hematogenous metastases are poor prognosis factors in lung cancer patients that can but do not necessarily co-occur. We retrospectively investigated the clinical association between cachexia, tumor characteristics (such as metastatic burden and mutational status), and treatment in lung cancer patients. The medical records of 394 lung cancer patients from two institutions (Columbia University, USA and Tohoku University, Japan) were reviewed. Information collected included the presence of cachexia, histologic subtype, tumor stage, number of metastases, mutation status, treatment, and survival. Descriptive statistics were performed. Only stage IV patients exhibited >5% weight loss (0.8%, 2.2%, 3.6%, and 5.1%, for stages I to IV; P = 0.0001). Patients with metastases developed cachexia more often than patients without metastases independent of treatment (6.0% and 7.1% weight loss in patients with metastases vs. 2.5% and 2.0% in patients without metastases, before [P = 0.0001] and after [P < 0.0001] treatment, respectively). The change in number of metastatic sites over time correlated with increasing weight loss (5.2%, 10.6%, 13.4%, and 13.4%, for an increase of 0, 1, 2, and >=3 metastatic sites, from initial diagnosis to the endpoint; P < 0.0001). Patients with cachexia had worse survival than patients without cachexia (hazard ratio, 2.94; 95% confidence interval, 2.08-4.16; P < 0.0001). Tumors with mutated KRAS were associated with an increased risk of weight loss (11.4% weight loss in patients with mutated KRAS vs. 6.0% in patients with wild-type KRAS; P = 0.0011). Our findings suggest that the capabilities of lung cancer to metastasize and cause cachexia might be linked intrinsically and are independent of treatments administered. KRAS-mutated tumors were more commonly associated with cachexia. PMID- 27485415 TI - Nitidine chloride inhibits proliferation, induces apoptosis via the Akt pathway and exhibits a synergistic effect with doxorubicin in ovarian cancer cells. AB - Nitidine chloride (NC) exhibits anti-tumor properties in various types of tumor. However, to the best of our knowledge there is no previous evidence of NC involvement in the apoptosis or proliferation of ovarian cancer cells and the underlying molecular mechanisms. The present study aimed to investigate the influence of NC on the viability and apoptosis of ovarian cancer cells and the synergistic effect NC and doxorubicin (DOX) may have on ovarian cancer cells. The viability and proliferation of ovarian cancer cells were examined using a methyl thiazolyl tetrazolium assay and 3H-thymidine incorporation assay. The apoptotic rate of ovarian cancer cells was detected by flow cytometry. The expression of apoptosis-associated proteins and Akt serine/threonine kinase 1 (Akt) were determined by western blot analysis following NC treatment. The inhibitory effect of NC on the proliferation of ovarian cancer cells was demonstrated in a time and dose-dependent manner. The pro-apoptotic effect of NC on ovarian cancer cells was also observed. It was determined that NC significantly downregulated the protein expression levels of B-cell CLL/lymphoma 2 (Bcl-2) and upregulated the expression of Bcl-2-associated X protein, p53, caspase-3 and -9. NC suppressed Akt phosphorylation. Additionally, the present study demonstrated that the effect of NC on the proliferation and apoptosis of ovarian cancer cells was Akt-dependent by using the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt signaling pathway inhibitor, LY294002. NC exhibited a synergistic inhibitory effect on the viability of ovarian cancer cells when combined with DOX. The current study demonstrated that NC inhibited the proliferation and induced the apoptosis of ovarian cancer cells via the Akt signaling pathway and highlighted its potential clinical application for the treatment of ovarian cancer. PMID- 27485417 TI - Editorial: Chemoinformatics in Japan. PMID- 27485416 TI - Migration of a shotgun pellet into the L7-S1 intervertebral foramen of a hunting dog. PMID- 27485418 TI - Benchmarking a Wide Range of Chemical Descriptors for Drug-Target Interaction Prediction Using a Chemogenomic Approach. AB - The identification of drug-target interactions, or interactions between drug candidate compounds and target candidate proteins, is a crucial process in genomic drug discovery. In silico chemogenomic methods are recently recognized as a promising approach for genome-wide scale prediction of drug-target interactions, but the prediction performance depends heavily on the descriptors and similarity measures of drugs and proteins. In this paper, we investigated the performance of various descriptors and similarity measures of drugs and proteins for the drug-target interaction prediction using a chemogenomic approach. We compared the prediction accuracy of 18 chemical descriptors of drugs (e.g., ECFP, FCFP,E-state, CDK, Klekota?Roth, MACCS, PubChem, Dragon, KCF-S, and graph kernels) and 4 descriptors of proteins (e.g., amino acid composition, domain profile, local sequence similarity, and string kernel) on about one hundred thousand drug-target interactions. We examined the combinatorial effects of drug descriptors and protein descriptors using the same benchmark data under several experimental conditions. Large-scale experiments showed that our proposed KCF-S descriptor worked the best in terms of prediction accuracy. The comparative results are expected to be useful for selecting chemical descriptors in various pharmaceutical applications. PMID- 27485419 TI - Constructing a Foundational Platform Driven by Japan's K Supercomputer for Next Generation Drug Design. AB - The cost of pharmaceutical R&D has risen enormously, both worldwide and in Japan. However, Japan faces a particularly difficult situation in that its population is aging rapidly, and the cost of pharmaceutical R&D affects not only the industry but the entire medical system as well. To attempt to reduce costs, the newly launched K supercomputer is available for big data drug discovery and structural simulation-based drug discovery. We have implemented both primary (direct) and secondary (infrastructure, data processing) methods for the two types of drug discovery, custom tailored to maximally use the 88 128 compute nodes/CPUs of K, and evaluated the implementations. We present two types of results. In the first, we executed the virtual screening of nearly 19 billion compound-protein interactions, and calculated the accuracy of predictions against publicly available experimental data. In the second investigation, we implemented a very computationally intensive binding free energy algorithm, and found that comparison of our binding free energies was considerably accurate when validated against another type of publicly available experimental data. The common feature of both result types is the scale at which computations were executed. The frameworks presented in this article provide prospectives and applications that, while tuned to the computing resources available in Japan, are equally applicable to any equivalent large-scale infrastructure provided elsewhere. PMID- 27485421 TI - Data Mining of Chemogenomics Data Using Bi-Modal PLS Methods and Chemical Interpretation for Molecular Design. AB - Chemogenomics is a new strategy in drug discovery for interrogating all molecules capable of interacting with all biological targets. Because of the almost infinite number of drug-like organic molecules, bench-based experimental chemogenomics methods are not generally feasible. Several in silico chemogenomics models have therefore been developed for high-throughput screening of large numbers of drug candidate compounds and target proteins. In previous studies, we described two novel bi-modal PLS approaches. These methods provide a significant advantage in that they enable direct connections to be made between biological activities and ligand and protein descriptors. In this special issue, we review these two PLS-based approaches using two different chemogenomics datasets for illustration. We then compare the predictive and interpretive performance of the two methods using the same congeneric data set. PMID- 27485420 TI - In Silico Investigation of a HIV-1 Vpr Inhibitor Binding Site: Potential for Virtual Screening and anti-HIV Drug Design. AB - Present HIV antiviral therapy only targets structural proteins of HIV, but evidence shows that the targeting of accessory proteins will expand our options in combating HIV. HIV-1 Vpr, a multifunctional accessory protein involved in viral infection, replication and pathogenesis, is a potential target. Previously, we have shown that phenyl coumarin compounds can inhibit the growth arrest activity of Vpr in host cells and predicted that the inhibitors' binding site is a hydrophobic pocket on Vpr. To investigate our prediction of the inhibitors' binding site, we docked the coumarin inhibitors into the predicted hydrophobic binding pocket on a built model of Vpr and observed a linear trend between their calculated binding energies and prior experimentally determined potencies. Subsequently, to analyze the inhibitor-protein binding interactions in detail, we built homology models of Vpr mutants and performed docking studies on these models too. The results revealed that structural changes on the binding pocket that were caused by the mutations affected inhibitor binding. Overall, this study showed that the binding energies of the docked molecules are good indicators of the activity of the inhibitors. Thus, the model can be used in virtual screening to identify other Vpr inhibitors and for designing more potent inhibitors. PMID- 27485422 TI - Multivariate Analysis of Side Effects of Drug Molecules Based on Knowledge of Protein Bindings and Protein?Protein Interactions. AB - Here, we examined the relationships between 969 side effects associated with 658 drugs and their 1368 human protein targets using our hybrid approaches. Firstly, L-shaped PLS (LPLS) was used to construct a multivariate model of side effects and protein bindings of drug molecules. LPLS is an extension of standard PLS regression, where, in addition to the response matrix Y and the regressor matrix X, an extra data matrix Z is constructed that summarizes the background information of X. X and Y are matrices comprising drugs-target proteins, and drugs-side effects, respectively. The Z matrix is the protein?protein interaction data. From the loading plot of Y, we could identify two remarkable side effects (urinary incontinence and increased salivation) From the corresponding loading plot of X, the responsible protein targets causing each side effect could be estimated (sodium channels and gamma-aminobutyric acid (GABA) receptors). The loading plot of the Z matrix indicated that the GABA receptors interact with each other and they heavily influence the side effect of increased salivation. Secondly, Bayesian classifier methods were separately applied to the cases of the two side effects. That is, the Bayesian classifier method was used to classify drug molecules as binding or not binding to the responsible protein targets associated with each side effect. Using atom-coloring techniques, it was possible to estimate which fragments on the drug molecule might cause the specific side effects. This information is valuable for drug design to avoid specific side effects. PMID- 27485423 TI - Ring-System-Based Exhaustive Structure Generation for Inverse-QSPR/QSAR. AB - Inverse-QSPR/QSAR aims to solve the inverse problem of chemical structure generation based on QSPR/QSAR models, once the properties or activities are specified. To efficiently solve this problem, an exhaustive ring-system-based structure generation methodology was developed. The concept of the applicability domain (AD) is automatically acknowledged within the proposed strategy. The local AD is considered by introducing the probability distribution of a given data set, and the universal AD is considered using ring-system-based fragments in the training data set. Structures with desired properties or activities are enumerated by assembling fragments, including atomic elements, in a tree-like way. The usefulness of the proposed method is demonstrated through a case study of ligand design for the human alpha 2A adrenergic receptor (ADR2A_HUMAN). We succeeded in generating structures focusing only on a pre-defined region in chemical space, resulting in structures whose desired activity has a high likelihood being efficiently generated. In addition, the limitations of our proposed method and future challenges are discussed. PMID- 27485424 TI - Development of a New De Novo Design Algorithm for Exploring Chemical Space. AB - In the first stage of development of new drugs, various lead compounds with high activity are required. To design such compounds, we focus on chemical space defined by structural descriptors. New compounds close to areas where highly active compounds exist will show the same degree of activity. We have developed a new de novo design system to search a target area in chemical space. First, highly active compounds are manually selected as initial seeds. Then, the seeds are entered into our system, and structures slightly different from the seeds are generated and pooled. Next, seeds are selected from the new structure pool based on the distance from target coordinates on the map. To test the algorithm, we used two datasets of ligand binding affinity and showed that the proposed generator could produce diverse virtual compounds that had high activity in docking simulations. PMID- 27485425 TI - Clustering of 3D-Structure Similarity Based Network of Secondary Metabolites Reveals Their Relationships with Biological Activities. AB - Developing database systems connecting diverse species based on omics is the most important theme in big data biology. To attain this purpose, we have developed KNApSAcK Family Databases, which are utilized in a number of researches in metabolomics. In the present study, we have developed a network-based approach to analyze relationships between 3D structure and biological activity of metabolites consisting of four steps as follows: construction of a network of metabolites based on structural similarity (Step 1), classification of metabolites into structure groups (Step 2), assessment of statistically significant relations between structure groups and biological activities (Step 3), and 2-dimensional clustering of the constructed data matrix based on statistically significant relations between structure groups and biological activities (Step 4). Applying this method to a data set consisting of 2072 secondary metabolites and 140 biological activities reported in KNApSAcK Metabolite Activity DB, we obtained 983 statistically significant structure group-biological activity pairs. As a whole, we systematically analyzed the relationship between 3D-chemical structures of metabolites and biological activities. PMID- 27485426 TI - Connecting Classical QSAR and LERE Analyses Using Modern Molecular Calculations, LERE-QSAR (VI): Hydrolysis of Substituted Hippuric Acid Phenyl Esters by Trypsin. AB - The reaction mechanism of trypsin was studied by applying DFT and ab initio molecular orbital (MO) calculations to complexes of trypsin with a congeneric series of eight para-substituted hippuric acid phenyl esters, for which a previous quantitative structure?activity relationship (QSAR) study revealed nice linearity of Hammett substitution constant sigma(-) with logarithmic values of the Michaelis?Menten and catalytic rate constants. Based on the LERE procedure, we performed QSAR analyses on each elementary reaction step during the acylation process. The present calculations showed that the rate-determining step during the acylation process is the transition state (TS) between the enzyme?substrate complex (ES) and tetrahedral intermediate (TET), and that the proton transfer occurs from Ser195 to His57, not between His57 and Asp102. The LERE-QSAR analysis statistically suggested that the variation of overall free-energy changes leading to formation of TS is governed mostly by that of activation energies required to form TS from ES. In spite of a very limited number of congeneric ligands in the current work, it is critically essential to clarify and verify physicochemical meanings of a typical QSAR/Chemoinformatics parameter, Hammett sigma(-) based on quantum chemical calculations on the protein?ligand kinetics; how Hammett sigma( ) behaves in terms of protein?ligand interaction energies. PMID- 27485429 TI - Dose-response meta-analysis of differences in means. AB - BACKGROUND: Meta-analytical methods are frequently used to combine dose-response findings expressed in terms of relative risks. However, no methodology has been established when results are summarized in terms of differences in means of quantitative outcomes. METHODS: We proposed a two-stage approach. A flexible dose response model is estimated within each study (first stage) taking into account the covariance of the data points (mean differences, standardized mean differences). Parameters describing the study-specific curves are then combined using a multivariate random-effects model (second stage) to address heterogeneity across studies. RESULTS: The method is fairly general and can accommodate a variety of parametric functions. Compared to traditional non-linear models (e.g. E max, logistic), spline models do not assume any pre-specified dose-response curve. Spline models allow inclusion of studies with a small number of dose levels, and almost any shape, even non monotonic ones, can be estimated using only two parameters. We illustrated the method using dose-response data arising from five clinical trials on an antipsychotic drug, aripiprazole, and improvement in symptoms in shizoaffective patients. Using the Positive and Negative Syndrome Scale (PANSS), pooled results indicated a non-linear association with the maximum change in mean PANSS score equal to 10.40 (95 % confidence interval 7.48, 13.30) observed for 19.32 mg/day of aripiprazole. No substantial change in PANSS score was observed above this value. An estimated dose of 10.43 mg/day was found to produce 80 % of the maximum predicted response. CONCLUSION: The described approach should be adopted to combine correlated differences in means of quantitative outcomes arising from multiple studies. Sensitivity analysis can be a useful tool to assess the robustness of the overall dose-response curve to different modelling strategies. A user-friendly R package has been developed to facilitate applications by practitioners. PMID- 27485428 TI - Comparing Different Sequential Mediational Interpretations of Beck's Cognitive Model of Depression in Adolescents. AB - Depression is a developmental phenomenon with significantly increasing rates during adolescence. As Beck's cognitive model of depression has been commonly accepted to explain the development and maintenance of depression, it is crucial to understand how and when cognitive vulnerabilities predicted in this model begin to interact. Three sequential interpretations of this model were compared. The causal mediational interpretation identifies dysfunctional attitudes as most distal to depressive symptoms, followed by cognitive errors, cognitive triad, and negative automatic thoughts, with each construct successively more proximal to depressive symptoms. In the symptom model the causal chain is reversed, with depressive symptoms as the most distal construct, followed by negative automatic thoughts, the cognitive triad, cognitive errors, and then dysfunctional attitudes. The bidirectional model merges both interpretations in which the activation of cognitive constructs causes the development of depressive symptoms which in turn trigger and reinforce already existing dysfunctional attitudes. Further, while Beck's model of depression proposes full mediation, empirical studies identified repeatedly partial mediations. Thus, the causal meditational, the symptoms, and the bidirectional model were each tested as full and partial mediation models. Finally, sex differences in the associations between variables were studied. In the 3-wave longitudinal study, 518 high school students (62.7 % female, average age: 15.09 years) completed questionnaires measuring all mentioned elements of Beck's model. The bidirectional model with partial mediation fits the data best. Cognitive errors emerged as the main mediator in the bidirectional model with partial mediation and significant sex differences in the strengths of associations were identified. The findings demonstrate the relevance of adolescence as developmental period during which the examined associations develop into the network they form in adulthood. Further, psychological interventions focusing on cognitive errors promise to be most effective. PMID- 27485430 TI - Variant detection and runs of homozygosity in next generation sequencing data elucidate the genetic background of Lundehund syndrome. AB - BACKGROUND: The Lundehund is a highly specialized breed characterized by a unique flexibility of the joints and polydactyly in all four limbs. The extremely small population size and high inbreeding has promoted a high frequency of diseased dogs affected by the Lundehund syndrome (LS), a severe gastro-enteropathic disease. RESULTS: Comprehensive analysis of bead chip and whole-genome sequencing data for LS in the Lundehund resulted in a genome-wide association signal on CFA 34 and LS-specific runs of homozygosity (ROH) in this region. Filtering analysis for variants with predicted high or moderate effects revealed a missense mutation in LEPREL1 1.2 Mb proximal to the region of the genome-wide association, which was shown to be significantly associated with LS. LS-affected Lundehund harbored the mutant LEPREL1:g.139212C>G genotype A/A whereas all controls of other breeds showed the C/C wild type. In addition, ROH analysis for the Lundehund indicated a high enrichment of genes in potential signatures of selection affecting protein activation and immunoregulatory processes like NOD1 potentially involved in LS breed disposition. CONCLUSIONS: Sequencing results for Lundehund specific traits reveal a potential causative mutation for LS in the neuropeptide operating gene LEPREL1 and suggests it as a precursor of the inflammatory process. Analyses of ROH regions give an insight into the genetic background of characteristic traits in the Lundehund that remain to be elucidated in the future. PMID- 27485431 TI - Interprofessional and interdisciplinary simulation-based training leads to safe sedation procedures in the emergency department. AB - BACKGROUND: Sedation is a procedure required for many interventions in the Emergency department (ED) such as reductions, surgical procedures or cardioversions. However, especially under emergency conditions with high risk patients and rapidly changing interdisciplinary and interprofessional teams, the procedure caries important risks. It is thus vital but difficult to implement a standard operating procedure for sedation procedures in any ED. Reports on both, implementation strategies as well as their success are currently lacking. This study describes the development, implementation and clinical evaluation of an interprofessional and interdisciplinary simulation-based sedation training concept. METHODS: All physicians and nurses with specialised training in emergency medicine at the Berne University Department of Emergency Medicine participated in a mandatory interdisciplinary and interprofessional simulation based sedation training. The curriculum consisted of an individual self-learning module, an airway skill training course, three simulation-based team training cases, and a final practical learning course in the operating theatre. Before and after each training session, self-efficacy, awareness of emergency procedures, knowledge of sedation medication and crisis resource management were assessed with a questionnaire. Changes in these measures were compared via paired tests, separately for groups formed based on experience and profession. To assess the clinical effect of training, we collected patient and team satisfaction as well as duration and complications for all sedations in the ED within the year after implementation. We further compared time to beginning of procedure, time for duration of procedure and time until discharge after implementation with the one year period before the implementation. Cohen's d was calculated as effect size for all statistically significant tests. RESULTS: Fifty staff members (26 nurses and 24 physicians) participated in the training. In all subgroups, there is a significant increase in self-efficacy and knowledge with high effect size (d z = 1.8). The learning is independent of profession and experience level. In the clinical evaluation after implementation, we found no major complications among the sedations performed. Time to procedure significantly improved after the introduction of the training (d = 0.88). DISCUSSION: Learning is independent of previous working experience and equally effective in raising the self-efficacy and knowledge in all professional groups. Clinical outcome evaluation confirms the concepts safety and feasibility. CONCLUSION: An interprofessional and interdisciplinary simulation-based sedation training is an efficient way to implement a conscious sedation concept in an ED. PMID- 27485432 TI - Effectiveness of conventional treatment using bulk-fill composite resin versus Atraumatic Restorative Treatments in primary and permanent dentition: a pragmatic randomized clinical trial. AB - BACKGROUND: Clinical studies are being conducted in less strict conditions in order to establish an adequate scientific basis for decision making. The aim of this pragmatic randomized clinical trial is to evaluate the effectiveness of single and multiple-surfaces restorations performed following the Atraumatic Restorative Treatment (ART) premises compared with Conventional Treatment (CT) using bulk fill composite restorations in primary and permanent teeth. METHODS/DESIGN: A total of 1,214 5-to-13 year-old children with at least one single or multiple-surface dentin caries lesion in primary or permanent molars will be selected in public schools of Barueri-SP, Brazil. The participants will be randomly assigned into 2 groups: CT (caries removal with bur and restoration performed with ScotchbondTM Universal Adhesive system associated with Filtek Bulk Fill - 3 M/ESPE) and ART (Caries removal with hand instruments and restoration with high viscosity glass ionomer cement Ketac Molar Easy Mix - 3 M/ESPE). Ten untrained dentists will perform the treatment in in dental offices located at public schools. The restorations will be evaluated after 6, 12 and 24 months by an independent trained and calibrated examiner. The restoration and tooth survival, the cost-effectiveness analysis between the two groups and the operators' preferences regarding the techniques will be also evaluated. Kaplan Meier survival analysis and log-rank test will be applied for the restoration and tooth survival. All the average event rates in the two groups will be modelled and compared with a Cox proportional hazard shared frailty model since there is an operator-cluster effect. The significance level for all analyses will be 5 %. DISCUSSION: Our hypothesis is that despite similar expected effectiveness between ART using high viscosity GIC and conventional treatment using bulk fill composite resin when treating single or multiple-surface in posterior primary and permanent teeth, ART will present superior cost-effectiveness. The results of this trial will support decision-making by clinicians and policy makers. TRIAL REGISTRATION: NCT02568917 . Registered on May 10th 2015. PMID- 27485433 TI - The epidemiology of road traffic injury hotspots in Kigali, Rwanda from police data. AB - BACKGROUND: Road traffic injuries (RTIs) are the eighth-leading cause of death worldwide, with low- and middle-income countries sharing a disproportionate number of fatalities. African countries, like Rwanda, carry a higher burden of these fatalities and with increased economic growth, these numbers are expected to rise. We aim to describe the epidemiology of RTIs in Kigali Province, Rwanda and create a hotspot map of crashes from police data. METHODS: Road traffic crash (RTC) report data from January 1, 2013 to December 31, 2013 was collected from Kigali Traffic Police. In addition to analysis of descriptive data, locations of RTCs were mapped and analyzed through exploratory spatial data analysis to determine hotspots. RESULTS: A total of 2589 of RTCs were reported with 4689 total victims. The majority of victims were male (94.7 %) with an average age of 35.9 years. Cars were the most frequent vehicle involved (43.8 %), followed by motorcycles (14.5 %). Motorcycles had an increased risk of involvement in grievous crashes and pedestrians and cyclists were more likely to have grievous injuries. The hotspots identified were primarily located along the major roads crossing Kigali and the two busiest downtown areas. CONCLUSIONS: Despite significant headway by the government in RTC prevention, there continue to be high rates of RTIs in Rwanda, specifically with young males and a vulnerable road user population, such as pedestrians and motorcycle users. Improvements in police data and reporting by laypersons could prove valuable for further geographic information system analysis and efforts towards crash prevention and targeting education to motorcycle taxis could help reduce RTIs in a severely affected population. PMID- 27485436 TI - Retraction Note to: Meta-analysis of the associations between TNF-alpha or IL-6 gene polymorphisms and susceptibility to lung cancer. PMID- 27485434 TI - Evaluating the quality of shared decision making during the patient-carer encounter: a systematic review of tools. AB - BACKGROUND: The concept of shared decision making (SDM) has been developing in many countries since the 1990s. The main challenge of SDM, based on the principles of respect for the person's autonomy, is to improve patients' participation, should they so wish, in decisions concerning their personal health. To our knowledge, there is only one SDM evaluation tool validated in metropolitan French that does not measure the entire SDM construct. The aim of this review was to identify existing and validated SDM measurement tools to determine which of them could be adapted in French to cover all the dimensions of SDM. METHODS: A systematic literature review was conducted based on articles found in the PubMed and PsycINFO bibliographic databases and published between 2010 and 2014. Studies were included if the main goal of the article was the development and psychometric validation of an SDM measurement tool, not specific to any given disease or situation, in English, French and Spanish. We used the nine essential elements of the Makoul and Clayman's integrative model to describe the different existing tools. RESULTS: Nineteen studies were included. Seven new tools had been published since Scholl's previous review in 2011. We observed a recent spread of the multi-appraiser approach, which combines points of view of patients, healthcare professionals and sometimes external observers. Several models were used for the development of the seven newly identified tools. None of the identified tools assessed the nine elements of the Makoul's model. Three of these elements, however, were systematically measured in each of the new tools: "defining/explaining the problem", "patient values/preferences", and "checking/clarifying understanding". CONCLUSIONS: We identified several potentially interesting tools for the French context which could cover the whole elements of Makoul's model. The next step will be the development of a French language instrument based on these tools. PMID- 27485437 TI - Patient preferences in allergy immunotherapy (AIT) in Germany - a discrete-choice experiment. AB - BACKGROUND: Allergic Rhinitis (AR) is a common disorder in Europe with Allergic Asthma (AA) as a frequent comorbidity. Allergy immunotherapy (AIT) is the only causal therapy of AR and AA, and can be administered as subcutaneous injections at the physician or as sublingual drops or tablets at home. The usual treatment duration is 3 years. OBJECTIVE: This study aimed to elicit patient preferences to identify the AIT administration mode preferred by patients. METHODS: A discrete choice-experiment (DCE) was developed to determine how people weight different treatment options using a paper-based questionnaire from June to September 2014, including 16 study centres. Main inclusion criteria: >18 years, grass, birch and/or house dust mite AR with moderate to severe symptoms, AIT-naive and AIT indicated. DCE-attributes were: Administration form, number and duration of physician visits, frequency of life-threatening anaphylactic shocks, local side effects and co-payments. RESULTS: Two-hundred thirty-nine subjects participated, resulting in analysable 1842 choices. All attributes were significant predictors for the treatment-choice. Ranked by importance, the following first three attributes are most preferred by patients: 1(st) Number and duration of physician visits: Fewer visits with shorter duration preferred (0.658*) 2(nd) Frequency of life-threatening anaphylactic shocks: Lower risk of shocks preferred (0.285*) 3(rd) Local side-effects: Preference for rash/swelling on upper arm over itching/swelling under the tongue (0.210*) (*coefficient-size represents relative importance of the attributes) CONCLUSION: The most important attribute is the number and duration of visits to a physician. A lower risk of life-threatening anaphylactic shocks was ranked as the second whereas co-payments and administration form play a limited role. PMID- 27485438 TI - Benefit assessment in Germany: implications for price discounts. AB - BACKGROUND: The AMNOG regulation, introduced in 2011 in Germany, changed the game for new drugs. Now, the industry is required to submit a dossier to the GBA (the central decision body in the German sickness fund system) to show additional benefit. After granting the magnitude of the additional benefit by the GBA, the manufacturer is entitled to negotiate the reimbursement price with the GKV-SV (National Association of Statutory Health Insurance Funds). The reimbursement price is defined as a discount on the drug price at launch. As the price or discount negotiations between the manufacturers and the GKV-SV takes place behind closed doors, the factors influencing the results of the negotiation are not known. OBJECTIVES: The aim of this evaluation is to identify factors influencing the results of the AMNOG price negotiation process. METHODS: The analysis was based on a dataset containing detailed information on all assessments until the end of 2015. A descriptive analysis was followed by an econometric analysis of various potential factors (benefit rating, size of target population, deviating from appropriate comparative therapy and incorporation of HRQoL-data). RESULTS: Until December 2015, manufacturers and the GKV-SV finalized 96 negotiations in 193 therapeutic areas, based on assessment conducted by the GBA. The GBA has granted an additional benefit to 100/193 drug innovations. Negotiated discount was significantly higher for those drugs without additional benefit (p = 0.030) and non-orphan drugs (p = 0.015). Smaller population size, no deviation from recommended appropriate comparative therapy and the incorporation of HRQoL-data were associated with a lower discount on the price at launch. However, neither a uni- nor the multivariate linear regression showed enough power to predict the final discount. CONCLUSIONS: Although the AMNOG regulation implemented binding and strict rules for the benefit assessment itself, the outcome of the discount negotiations are still unpredictable. Obviously, negotiation tactics, the current political situation and soft factors seem to play a more influential role for the outcome of the negotiations than the five hard and known factors analyzed in this study. Further research is needed to evaluate additional factors. PMID- 27485435 TI - Antiretroviral medication treatment for all HIV-infected individuals: a protocol using innovative multilevel methodologies to evaluate New York City's universal ART policy among problem substance users. AB - BACKGROUND: The intersection of HIV-related health outcomes and problem substance use has been well documented. New York City continues to be a focal point of the U.S. HIV epidemic. In 2011, the NYC Department of Health and Mental Hygiene (NYC DOHMH) issued a recommendation that all HIV infected individuals should be offered antiretroviral therapy (ART) regardless of CD4 cell count or other indicators of disease progression. This policy is based in the concept of "treatment as prevention," in which providing ART to people living with HIV (PLWH) greatly reduces the likelihood of HIV transmission, while also improving individual health. The "ART for ALL" (AFA) study was designed to inform modifications to and identify gaps in the implementation of universal ART, and specifically to help guide allocation of resources to obtain local policy goals for increasing viral suppression among PLWH who have problem substance use. METHODS/DESIGN: The AFA Study is informed by two complementary frameworks: Glasgow and colleagues' RE-AIM model, a multi-level framework developed to guide the evaluation of implementation of new policies, and Bronfrenbrenner's ecological systems model, which conceptualizes the bi-directional interplay between people and their environment. Using multi-level data and mixed methods, the primary aims of the AFA Study are to assess rates of viral load suppression, using the NYC HIV Surveillance Registry, within 12 months of HIV diagnosis with (a) yearly cohorts of high-risk-to-transmit, difficult-to-treat, substance using patients recruited from NYC Sexually Transmitted Disease clinics and a large detoxification unit and (b) yearly cohorts of all newly HIV diagnosed people in NYC. Further goals include (c) recruiting cross-sectional samples of HIV/AIDS service providers to assess ART initiation with problem substance users and d) examining geographic factors that influence rates of viral load suppression. An Implementation Collaborative Board meets regularly to guide study procedures and interpret results. DISCUSSION: The AFA Study has the unique strength of accessing and analyzing data at multiple levels using mixed methodology, taking advantage of NYC DOHMH biomedical surveillance data. If successful, others may benefit from lessons learned to inform local and state policies to improve the health of PLWH and further reduce HIV transmission. PMID- 27485439 TI - Long noncoding RNA TUG1 is downregulated in non-small cell lung cancer and can regulate CELF1 on binding to PRC2. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis, and lncRNA taurine-upregulated gene 1 (TUG1) has been proven to be associated with several human cancers. However, the mechanisms of TUG1-involved regulation remain largely unknown. METHODS: We examined the expressions of TUG1 in a cohort of 89 patients with non-small cell lung cancer (NSCLC) to determine the association between TUG1 expression and clinical parameters. We used circular chromosome conformation capture (4C) coupled with next-generation sequencing to explore the genome regions that interact with TUG1 and the TUG1-mediated regulation. RESULTS: TUG1 was significantly downregulated, and the TUG1 downregulation correlated with sex (p = 0.006), smoking status (p = 0.016), and tumor differentiation grade (p = 0.001). Knockdown of TUG1 significantly promoted the proliferation of NSCLC cells. According to the bioinformatic analysis result of TUG1 4C sequencing data, 83 candidate genes and their interaction regions were identified. Among these candidate genes, CUGBP and Elav-like family member 1 (CELF1) are potential targets of TUG1 in-trans regulation. To confirm the interaction between TUG1 and CELF1, relative expressions of CELF1 were examined in TUG1 knockdown H520 cells; results showed that CELF1 was significantly upregulated in TUG1 knockdown H520 cells. RNA immunoprecipitation was then performed to examine whether TUG1 RNA was bound to PRC2, a TUG1-involved regulation mechanism reported in previous studies. The results demonstrated that TUG1 RNA was bound to enhancer of zeste protein 2/embryonic ectoderm development (EZH2/EED), which is essential for PRC2. Finally, our designed ChIP assay revealed that the EZH2/EED was bound to the promotor region of CELF1 within 992 bp upstream of the transcript start site. CONCLUSION: TUG1 is downregulated in NSCLC. Using TUG1 4C sequencing and bioinformatic analysis, we found CELF1 to be a potential target of TUG1 RNA in in-trans regulation. Moreover, subsequent experiments showed that TUG1 RNA could bind to PRC2 in the promotor region of CELF1 and negatively regulate CELF1 expressions in H520 cells. Our results may facilitate developing new treatment modalities targeting TUG1/PRC2/CELF1 interactions in patients with NSCLC. PMID- 27485442 TI - MetaCoMET: a web platform for discovery and visualization of the core microbiome. AB - MOTIVATION: A key component of the analysis of microbiome datasets is the identification of OTUs shared between multiple experimental conditions, commonly referred to as the core microbiome. RESULTS: We present a web platform named MetaCoMET that enables the discovery and visualization of the core microbiome and provides a comparison of the relative abundance and diversity patterns between subsets of samples within a microbiome dataset. MetaCoMET provides an efficient and interactive graphical interface for analyzing each subset defined by the union or disjunction of groups within the Venn diagram, and includes a graphical taxonomy summary, alpha diversity metrics, Principal Coordinate analysis, abundance-based heatmaps, and a chart indicating the geographic distribution of each sample. AVAILABILITY AND IMPLEMENTATION: MetaCoMET is a user-friendly and efficient web platform freely accessible at http://probes.pw.usda.gov/MetaCoMET or http://aegilops.wheat.ucdavis.edu/MetaCoMET CONTACT: devin.coleman derr@ars.usda.govSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27485441 TI - NET-GE: a web-server for NETwork-based human gene enrichment. AB - MOTIVATION: Gene enrichment is a requisite for the interpretation of biological complexity related to specific molecular pathways and biological processes. Furthermore, when interpreting NGS data and human variations, including those related to pathologies, gene enrichment allows the inclusion of other genes that in the human interactome space may also play important key roles in the emergency of the phenotype. Here, we describe NET-GE, a web server for associating biological processes and pathways to sets of human proteins involved in the same phenotype RESULTS: NET-GE is based on protein-protein interaction networks, following the notion that for a set of proteins, the context of their specific interactions can better define their function and the processes they can be related to in the biological complexity of the cell. Our method is suited to extract statistically validated enriched terms from Gene Ontology, KEGG and REACTOME annotation databases. Furthermore, NET-GE is effective even when the number of input proteins is small. AVAILABILITY AND IMPLEMENTATION: NET-GE web server is publicly available and accessible at http://net ge.biocomp.unibo.it/enrich CONTACT: gigi@biocomp.unibo.itSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27485440 TI - Role of bioactive fatty acids in nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is characterized by fat deposition in hepatocytes, and a strong association with nutritional factors. Dietary fatty acids are classified according to their biochemical properties, which confer their bioactive roles. Monounsaturated fatty acids have a dual role in various human and murine models. In contrast, polyunsaturated fatty acids exhibit antiobesity, anti steatosic and anti-inflammatory effects. The combination of these forms of fatty acids-according to dietary type, daily intake and the proportion of n-6 to n-3 fats-can compromise hepatic lipid metabolism. A chemosensory rather than a nutritional role makes bioactive fatty acids possible biomarkers for NAFLD. Bioactive fatty acids provide health benefits through modification of fatty acid composition and modulating the activity of liver cells during liver fibrosis. More and better evidence is necessary to elucidate the role of bioactive fatty acids in nutritional and clinical treatment strategies for patients with NAFLD. PMID- 27485443 TI - An efficient method to estimate the optimum regularization parameter in RLDA. AB - MOTIVATION: The biomarker discovery process in high-throughput genomic profiles has presented the statistical learning community with a challenging problem, namely learning when the number of variables is comparable or exceeding the sample size. In these settings, many classical techniques including linear discriminant analysis (LDA) falter. Poor performance of LDA is attributed to the ill-conditioned nature of sample covariance matrix when the dimension and sample size are comparable. To alleviate this problem, regularized LDA (RLDA) has been classically proposed in which the sample covariance matrix is replaced by its ridge estimate. However, the performance of RLDA depends heavily on the regularization parameter used in the ridge estimate of sample covariance matrix. RESULTS: We propose a range-search technique for efficient estimation of the optimum regularization parameter. Using an extensive set of simulations based on synthetic and gene expression microarray data, we demonstrate the robustness of the proposed technique to Gaussianity, an assumption used in developing the core estimator. We compare the performance of the technique in terms of accuracy and efficiency with classical techniques for estimating the regularization parameter. In terms of accuracy, the results indicate that the proposed method vastly improves on similar techniques that use classical plug-in estimator. In that respect, it is better or comparable to cross-validation-based search strategies while, depending on the sample size and dimensionality, being tens to hundreds of times faster to compute. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/danik0411/optimum-rlda CONTACT: amin.zollanvari@nu.edu.kzSupplementary information: Supplementary materials are available at Bioinformatics online. PMID- 27485444 TI - Predicting G protein-coupled receptor downstream signaling by tissue expression. AB - MOTIVATION: G protein-coupled receptors (GPCRs) are central to how cells respond to their environment and a major class of pharmacological targets. However, comprehensive knowledge of which pathways are activated and deactivated by these essential sensors is largely unknown. To better understand the mechanism of GPCR signaling system, we integrated five independent genome-wide expression datasets, representing 275 human tissues and cell lines, with protein-protein interactions and functional pathway data. RESULTS: We found that tissue-specificity plays a crucial part in the function of GPCR signaling system. Only a few GPCRs are expressed in each tissue, which are coupled by different combinations of G proteins or beta-arrestins to trigger specific downstream pathways. Based on this finding, we predicted the downstream pathways of GPCR in human tissues and validated our results with L1000 knockdown data. In total, we identified 154,988 connections between 294 GPCRs and 690 pathways in 240 tissues and cell types. AVAILABILITY AND IMPLEMENTATION: The source code and results supporting the conclusions of this article are available at http://tatonettilab.org/resources/GOTE/source_code/ CONTACT: nick.tatonetti@columbia.eduSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27485445 TI - NRGC: a novel referential genome compression algorithm. AB - MOTIVATION: Next-generation sequencing techniques produce millions to billions of short reads. The procedure is not only very cost effective but also can be done in laboratory environment. The state-of-the-art sequence assemblers then construct the whole genomic sequence from these reads. Current cutting edge computing technology makes it possible to build genomic sequences from the billions of reads within a minimal cost and time. As a consequence, we see an explosion of biological sequences in recent times. In turn, the cost of storing the sequences in physical memory or transmitting them over the internet is becoming a major bottleneck for research and future medical applications. Data compression techniques are one of the most important remedies in this context. We are in need of suitable data compression algorithms that can exploit the inherent structure of biological sequences. Although standard data compression algorithms are prevalent, they are not suitable to compress biological sequencing data effectively. In this article, we propose a novel referential genome compression algorithm (NRGC) to effectively and efficiently compress the genomic sequences. RESULTS: We have done rigorous experiments to evaluate NRGC by taking a set of real human genomes. The simulation results show that our algorithm is indeed an effective genome compression algorithm that performs better than the best-known algorithms in most of the cases. Compression and decompression times are also very impressive. AVAILABILITY AND IMPLEMENTATION: The implementations are freely available for non-commercial purposes. They can be downloaded from: http://www.engr.uconn.edu/~rajasek/NRGC.zip CONTACT: rajasek@engr.uconn.edu. PMID- 27485447 TI - ReactPRED: a tool to predict and analyze biochemical reactions. AB - MOTIVATION: Biochemical pathways engineering is often used to synthesize or degrade target chemicals. In silico screening of the biochemical transformation space allows predicting feasible reactions, constituting these pathways. Current enabling tools are customized to predict reactions based on pre-defined biochemical transformations or reaction rule sets. Reaction rule sets are usually curated manually and tailored to specific applications. They are not exhaustive. In addition, current systems are incapable of regulating and refining data with an aim to tune specificity and sensitivity. A robust and flexible tool that allows automated reaction rule set creation along with regulated pathway prediction and analyses is a need. ReactPRED aims to address the same. RESULTS: ReactPRED is an open source flexible and customizable tool enabling users to predict biochemical reactions and pathways. The tool allows automated reaction rule creation from a user defined reaction set. Additionally, reaction rule degree and rule tolerance features allow refinement of predicted data. It is available as a flexible graphical user interface and a console application. AVAILABILITY AND IMPLEMENTATION: ReactPRED is available at: https://sourceforge.net/projects/reactpred/ CONTACT: anirban.b@samsung.com or ty76.kim@samsung.comSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27485446 TI - HiPub: translating PubMed and PMC texts to networks for knowledge discovery. AB - We introduce HiPub, a seamless Chrome browser plug-in that automatically recognizes, annotates and translates biomedical entities from texts into networks for knowledge discovery. Using a combination of two different named-entity recognition resources, HiPub can recognize genes, proteins, diseases, drugs, mutations and cell lines in texts, and achieve high precision and recall. HiPub extracts biomedical entity-relationships from texts to construct context-specific networks, and integrates existing network data from external databases for knowledge discovery. It allows users to add additional entities from related articles, as well as user-defined entities for discovering new and unexpected entity-relationships. HiPub provides functional enrichment analysis on the biomedical entity network, and link-outs to external resources to assist users in learning new entities and relations. AVAILABILITY AND IMPLEMENTATION: HiPub and detailed user guide are available at http://hipub.korea.ac.kr CONTACT: kangj@korea.ac.kr, aikchoon.tan@ucdenver.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 27485448 TI - Erratum: Finite particle size drives defect-mediated domain structures in strongly confined colloidal liquid crystals. PMID- 27485449 TI - Amarogentin ameliorates diabetic disorders in animal models. AB - Amarogentin is a bitter-tasting secoiridoid glycoside isolated from an herb. Inhibition of aldose reductase by amarogentin has been documented as an antidiabetic action. However, the mechanisms of action of amarogentin in diabetic disorders remain unknown. The present study employed streptozotocin-induced type 1 diabetic (T1DM) rats to investigate the antihyperglycemic action of amarogentin. Changes in the protein expression of glucose transporter 4 (GLUT4) and phosphoenolpyruvate carboxykinase (PEPCK) in skeletal muscle and liver, respectively, were also detected by Western blotting. Additionally, a type 2 diabetes (T2DM) animal model induced using a fructose-rich diet was also applied to assess the effect of amarogentin on insulin resistance according to the homeostasis model assessment-insulin resistance (HOMA-IR). Amarogentin dose dependently attenuated hyperglycemia in the T1DM rats lacking insulin. The action of amarogentin was further supported in rats administered the oral glucose tolerance test. Western blotting showed that amarogentin reversed the decreased GLUT4 level in skeletal muscle and reduced the elevated PEPCK expression in livers isolated from the T1DM rats. Moreover, amarogentin decreased the HOMA-IR and increased insulin sensitivity in the T2DM rats. These data show that amarogentin may ameliorate glucose homeostasis in diabetic rats, indicating its potential for future development as an antidiabetic drug. PMID- 27485450 TI - Metastatic Progression of Prostate Cancer Is Mediated by Autonomous Binding of Galectin-4-O-Glycan to Cancer Cells. AB - Metastatic prostate cancer continues to pose a difficult therapeutic challenge. Prostate cancer progression is associated with aberrant O-glycosylation of cancer cell surface receptors, but the functional impact of such events is uncertain. Here we report spontaneous metastasis of human prostate cancer xenografts that express high levels of galectin-4 along with genetic signatures of EGFR-HER2 signaling and O-glycosylation. Galectin-4 expression in clinical specimens of prostate cancer correlated with poor patient survival. Galectin-4 binding to multiple receptor tyrosine kinases stimulated their autophosphorylation, activated expression of pERK, pAkt, fibronectin, and Twist1, and lowered expression of E-cadherin, thereby facilitating epithelial-mesenchymal transition, invasion, and metastasis. In vivo investigations established that galectin-4 expression enabled prostate cancer cells to repopulate tumors in orthotopic and heterotopic tissues. Notably, these effects of galectin-4 relied upon O glycosylation mediated by C1GALT1, a galactosyltransferase implicated in other cancers. Parallel changes in galectin-4 and O-glycosylation triggered aberrant receptor signaling and more aggressive invasive character in prostate cancer cells, which through better survival in the circulation also contributed to the bulk cell progeny of distal tumors. Our findings establish galectin-4 and C1GALT1 mediated glycosylation in a signaling axis that is activated during prostate cancer progression, with implications for therapeutic targeting of advanced metastatic disease. Cancer Res; 76(19); 5756-67. (c)2016 AACR. PMID- 27485451 TI - Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth. AB - Somatic missense mutations in the Ser/Thr protein phosphatase 2A (PP2A) Aalpha scaffold subunit gene PPP2R1A are among the few genomic alterations that occur frequently in serous endometrial carcinoma (EC) and carcinosarcoma, two clinically aggressive subtypes of uterine cancer with few therapeutic options. Previous studies reported that cancer-associated Aalpha mutants exhibit defects in binding to other PP2A subunits and contribute to cancer development by a mechanism of haploinsufficiency. Here we report on the functional significance of the most recurrent PPP2R1A mutations in human EC, which cluster in Aalpha HEAT repeats 5 and 7. Beyond predicted loss-of-function effects on the formation of a subset of PP2A holoenzymes, we discovered that Aalpha mutants behave in a dominant-negative manner due to gain-of-function interactions with the PP2A inhibitor TIPRL1. Dominant-negative Aalpha mutants retain binding to specific subunits of the B56/B' family and form substrate trapping complexes with impaired phosphatase activity via increased recruitment of TIPRL1. Accordingly, overexpression of the Aalpha mutants in EC cells harboring wild-type PPP2R1A increased anchorage-independent growth and tumor formation, and triggered hyperphosphorylation of oncogenic PP2A-B56/B' substrates in the GSK3beta, Akt, and mTOR/p70S6K signaling pathways. TIPRL1 silencing restored GSK3beta phosphorylation and rescued the EC cell growth advantage. Our results reveal how PPP2R1A mutations affect PP2A function and oncogenic signaling, illuminating the genetic basis for serous EC development and its potential control by rationally targeted therapies. Cancer Res; 76(19); 5719-31. (c)2016 AACR. PMID- 27485452 TI - Integrating evidence-based practices for increasing cancer screenings in safety net health systems: a multiple case study using the Consolidated Framework for Implementation Research. AB - BACKGROUND: Implementing evidence-based practices (EBPs) to increase cancer screenings in safety net primary care systems has great potential for reducing cancer disparities. Yet there is a gap in understanding the factors and mechanisms that influence EBP implementation within these high-priority systems. Guided by the Consolidated Framework for Implementation Research (CFIR), our study aims to fill this gap with a multiple case study of health care safety net systems that were funded by an American Cancer Society (ACS) grants program to increase breast and colorectal cancer screening rates. The initiative funded 68 safety net systems to increase cancer screening through implementation of evidence-based provider and client-oriented strategies. METHODS: Data are from a mixed-methods evaluation with nine purposively selected safety net systems. Fifty two interviews were conducted with project leaders, implementers, and ACS staff. Funded safety net systems were categorized into high-, medium-, and low performing cases based on the level of EBP implementation. Within- and cross-case analyses were performed to identify CFIR constructs that influenced level of EBP implementation. RESULTS: Of 39 CFIR constructs examined, six distinguished levels of implementation. Two constructs were from the intervention characteristics domain: adaptability and trialability. Three were from the inner setting domain: leadership engagement, tension for change, and access to information and knowledge. Engaging formally appointed internal implementation leaders, from the process domain, also distinguished level of implementation. No constructs from the outer setting or individual characteristics domain differentiated systems by level of implementation. CONCLUSIONS: Our study identified a number of influential CFIR constructs and illustrated how they impacted EBP implementation across a variety of safety net systems. Findings may inform future dissemination efforts of EBPs for increasing cancer screening in similar settings. Moreover, our analytic approach is similar to previous case studies using CFIR and hence could facilitate comparisons across studies. PMID- 27485453 TI - Cost analysis of a randomized stem cell mobilization study in multiple myeloma. AB - Upfront autologous stem cell transplantation (ASCT) is the standard therapy for younger multiple myeloma (MM) patients. MM patients usually undergo stem cell mobilization with cyclophosphamide (CY) followed by granulocyte colony stimulating factor (G-CSF), or with G-CSF alone. A limited number of randomized studies are available comparing costs of different mobilization strategies. Eighty transplant-eligible patients aged up to 70 years with untreated MM were included in this prospective study. The patients were treated with RVD induction for three 21-day cycles and randomized 1:1 at inclusion into one of the two mobilization arms CY 2 g/m(2) + G-CSF [arm A] vs. G-CSF alone [arm B]. Plerixafor was given according to a specific algorithm if needed. Sixty-nine patients who received mobilization followed by blood graft collection were included in the cost analysis. The median total costs of the mobilization phase were significantly higher in arm A than in arm B (3855 ? vs. 772 ?, p <= 0.001). The cumulative median cost of the mobilization and collection phases was significantly lower in arm B than in arm A (8524 ? vs. 11,622 ?, p = 0.012). There was no significant difference between the arms in the total median costs of ASCT (n = 59) (34,997 ? in arm A vs. 31,981 ? in arm B, p = 0.118). Mobilization with G-CSF alone seems to be a preferable mobilization method for MM patients in terms of mobilization and apheresis costs. In addition, it requires less hospital resource utilization. PMID- 27485454 TI - R-CVP regimen is active in frail elderly patients aged 80 or over with diffuse large B cell lymphoma. AB - Patients aged 80 or over with diffuse large B cell lymphoma (DLBCL) often have comorbidities that increase drug toxicity and prevent the use of otherwise optimal treatment. We performed a retrospective analysis of 43 patients aged 80 or over (median age: 83; range: 80-93) unable to receive treatment with anthracyclines, at diagnosis of DLBCL, treated with an R-CVP treatment (standard R-CHOP without doxorubicin). The patients had one or more comorbidities: 18 patients (41.9 %) had a performance status (PS) of 3; 23 patients (53.5 %) had low creatinine clearance; 12 patients (27.9 %) had low left ventricular ejection fraction; seven patients (16.3 %) had poor hepatic function; and 26 patients (60.5 %) had a Charlson index score >=4. Thirty patients (70 %) had two or three adverse factors according to the age-adjusted International Prognostic Index. Twenty-five patients (58.1 %) received eight cycles of R-CVP, but the full eight cycles could not be given to 18 patients (41.9 %). The OR rate was 58.1 % (CR 37.2 %). There were 34 deaths (79 %) during treatment and follow-up. Ten patients (23.3 %) died early from toxicity before interim evaluation; all had PS 3. The median follow-up of surviving patients was 52.6 months. The overall 2-year survival rate was 31.9 % and the median OS was 12.6 months. The median OS for patients who completed the entire treatment was 26.4 months. The median PFS was 11.2 months. In multivariate analyses, OS was only affected by performance status >=2 and Charlson index score >=4. The R-CVP regimen can be active in elderly frail patients aged 80 or more with DLBCL, but systematic geriatric assessment is required so that those unsuitable for chemotherapy are excluded. PMID- 27485455 TI - Clinical characteristics and risk factors of Intracranial hemorrhage in patients following allogeneic hematopoietic stem cell transplantation. AB - Intracranial hemorrhage (ICH) is one of the most life-threatening neurological complications after allogeneic hematopoietic stem cell transplantation. Although cerebral complications and its causes after allo-HSCT are well documented, assessment of the incidence and risk factors of intracranial hemorrhage following allo-HSCT are less discussed. A nested case-control study was conducted involving 160 subjects drawn from 2169 subjects who underwent HSCT at Peking University People's Hospital between 2004 and 2014. Thirty-two patients (1.5 %) with ICH were identified, and 128 controls were matched for age, gender, transplantation type, and time of transplantation. Intracranial hemorrhage was identified by CT scan and/or MRI by searching hospital records. Among the 32 ICH patients, 27 (82.9 %) developed intraparenchymal hemorrhages (IPH), 2 cases (5.7 %) suffered subdural hematomas (SDH), and 3 cases (8.6 %) had multiple hemorrhage lesions in the brain parenchyma. The median time of appearance for cerebral hemorrhages was 147.5 days. Multivariate analysis showed that systemic infections (hazard ratio 2.882, 95 % confidence interval 1.231-6.746), platelet count (5.894, 1.145 30.339), and fibrinogen levels (3.611, 1.528-8.532) were independent risk factors for intracranial hemorrhage among HSCT patients. The cumulative survival rate in the intracranial hemorrhage and control groups were 43.3 and 74.7 % (P = .001), respectively. Intracranial hemorrhage is associated with high mortality and a decreased overall survival rate. Systemic infections, platelet count, and fibrinogen levels were individual independent risk factors. PMID- 27485456 TI - Capsaicin for Rhinitis. AB - Rhinitis is a multifactorial disease characterized by symptoms of sneezing, rhinorrhea, postnasal drip, and nasal congestion. Non-allergic rhinitis is characterized by rhinitis symptoms without systemic sensitization of infectious etiology. Based on endotypes, we can categorize non-allergic rhinitis into an inflammatory endotype with usually eosinophilic inflammation encompassing at least NARES and LAR and part of the drug induced rhinitis (e.g., aspirin intolerance) and a neurogenic endotype encompassing idiopathic rhinitis, gustatory rhinitis, and rhinitis of the elderly. Patients with idiopathic rhinitis have a higher baseline TRPV1 expression in the nasal mucosa than healthy controls. Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the active component of chili peppers, plants of the genus Capsicum. Capsaicin is unique among naturally occurring irritant compounds because the initial neuronal excitation evoked by it is followed by a long-lasting refractory period, during which the previously excited neurons are no longer responsive to a broad range of stimuli. Patients with idiopathic rhinitis benefit from intranasal treatment with capsaicin. Expression of TRPV1 is reduced in patients with idiopathic rhinitis after capsaicin treatment. Recently, in a Cochrane review, the effectiveness of capsaicin in the management of idiopathic rhinitis was evaluated and the authors concluded that given that many other options do not work well in non-allergic rhinitis, capsaicin is a reasonable option to try under physician supervision. Capsaicin has not been shown to be effective in allergic rhinitis nor in other forms of non-allergic rhinitis like the inflammatory endotypes or other neurogenic endotypes like rhinitis of the elderly or smoking induced rhinitis. PMID- 27485457 TI - Nutritional care of cancer patients: a survey on patients' needs and medical care in reality. AB - PURPOSE: Cancer patients represent a patient group with a wide-range of nutrition related problems which are often under-recognized and undertreated. In order to assess the status quo of nutritional care in Germany, we conducted a survey among patients with different types of cancer. METHODS: A standardized questionnaire was distributed online by two national umbrella organizations for self-help groups. RESULTS: 1335 participants completed the questionnaire. 69 % of the participants reported having received information on nutrition and/or specific nutrition-related symptoms. Most often this information was derived from print media (68.5 %) or from within self-help groups (58.7 %). 57.0 % of participants reported having had questions concerning nutrition and/or problems with food intake. most frequently named topics of interest were "healthy diet" (35.0 %) weakness/fatigue (24.3 %), dietary supplements (21.3 %) and taste changes (19.8 %). Nutrition information was most often provided by dietitians (38.7 %) followed by physicians (9.8 %). Women reported receiving nutrition counseling in the hospital nearly twice as often as men (12.5 % versus 5.7 %; p < 0.001). A quarter of the patients (24.1 %) reported using dietary supplements and patients who had received some sort of nutrition information more often reported using supplements (p < 0.001). CONCLUSION: Nutrition is an essential element in cancer care and patients report a high interest and need: Yet, many patients do not have access to high quality nutrition therapy during and after cancer therapy. IMPLICATIONS FOR CANCER SURVIVORS: With respect to survival and quality of life, increasing the availability and resources for provision of evidence based nutrition information seems mandatory. PMID- 27485459 TI - Genetics of primary hyperaldosteronism. AB - Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8-13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5 This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights. PMID- 27485458 TI - Functional Recovery from Neural Stem/Progenitor Cell Transplantation Combined with Treadmill Training in Mice with Chronic Spinal Cord Injury. AB - Most studies targeting chronic spinal cord injury (SCI) have concluded that neural stem/progenitor cell (NS/PC) transplantation exerts only a subclinical recovery; this in contrast to its remarkable effect on acute and subacute SCI. To determine whether the addition of rehabilitative intervention enhances the effect of NS/PC transplantation for chronic SCI, we used thoracic SCI mouse models to compare manifestations secondary to both transplantation and treadmill training, and the two therapies combined, with a control group. Significant locomotor recovery in comparison with the control group was only achieved in the combined therapy group. Further investigation revealed that NS/PC transplantation improved spinal conductivity and central pattern generator activity, and that treadmill training promoted the appropriate inhibitory motor control. The combined therapy enhanced these independent effects of each single therapy, and facilitated neuronal differentiation of transplanted cells and maturation of central pattern generator activity synergistically. Our data suggest that rehabilitative treatment represents a therapeutic option for locomotor recovery after NS/PC transplantation, even in chronic SCI. PMID- 27485460 TI - Perspectives for immunotherapy in endocrine cancer. AB - The fight against cancer has seen major breakthroughs in recent years. More than a decade ago, tyrosine kinase inhibitors targeting constitutively activated signaling cascades within the tumor inaugurated a new era of oncological therapy. Recently, immunotherapy with immune checkpoint inhibitors has started to revolutionize the treatment of several malignancies, most notably malignant melanoma, leading to the renaissance and the long-awaited breakthrough of immunooncology. This review provides an overview of the basis of immunotherapy from its initial concepts of anti-tumor immunity and cell-based therapy to the development of immune checkpoint inhibitors and discusses published studies and the perspectives of immunooncology for the treatment of endocrine malignancies. PMID- 27485461 TI - A HELLP syndrome complicates a gestational trophoblastic neoplasia in a perimenopausal woman: a case report. AB - BACKGROUND: HELLP syndrome is a combination of symptoms described as hemolysis, elevated liver enzymes and low platelets, that complicates 0.01-0.6 % of pregnancies. HELLP syndrome has been scarcely reported associated with partial moles, another rare complication of pregnancy. This manuscript describes the only reported case of HELLP syndrome associated with a complete invasive hydatiform mole. CASE PRESENTATION: We report a perimenopausal patient in prolonged remission from an uncommon high-risk invasive complete mole. The diagnosis was set in a context of early onset preeclampsia and HELLP syndrome. The development of life-threatening complications required primary hysterectomy. Postoperative hCG quickly returned to normal with EMA/CO multi-agent chemotherapy. CONCLUSION: Our patient is in prolonged remission from a complete mole complicated with EOP and HELLP syndrome. This exceptional case of complicated gestational trophoblastic neoplasia reflects a very rare condition in which several risk factors for placental ischemia are associated. Emergency hysterectomy should be considered as salvage initial treatment in such life-threatening situations. PMID- 27485462 TI - Can I get me out of my head? Exploring strategies for controlling the self referential aspects of the mind-wandering state during reading. AB - Trying to focus on a piece of text and keep unrelated thoughts at bay can be a surprisingly futile experience. The current study explored the effects of different instructions on participants' capacity to control their mind-wandering and maximize reading comprehension, while reading. Participants were instructed to (a) enhance focus on what was read (external) or (b) enhance meta-awareness of mind-wandering (internal). To understand when these strategies were important, we induced a state of self-focus in half of our participants at the beginning of the experiment. Results replicated the negative association between mind-wandering and comprehension and demonstrated that both internal and external instructions impacted on the efficiency of reading following a period of induced self-focus. Techniques that foster meta-awareness improved task focus but did so at the detriment of reading comprehension, while promoting a deeper engagement while reading improved comprehension with no changes in reported mind-wandering. These data provide insight into how we can control mind-wandering and improve comprehension, and they underline that a state of self-focus is a condition under which they should be employed. Furthermore, these data support component process models that propose that the self-referent mental contents that arise during mind wandering are distinguishable from those processes that interfere with comprehension. PMID- 27485463 TI - Physical activity is associated with reduced fatigue in adults living with HIV/AIDS. AB - AIMS: The aim of this study was to describe the relationships among home-based physical activity, fatigue, sleep, gender and quality of life in people living with HIV/AIDS BACKGROUND: Fatigue is a common and distressing symptom among people living with HIV/AIDS. Few interventions exist that effectively reduce fatigue in this population. Physical activity has shown promise to reduce fatigue in other populations, but its impact on fatigue in HIV/AIDS has not yet been explored. DESIGN: This study was conducted using a prospective, descriptive cohort design. METHODS: Overall, 90 adults living with HIV/AIDS completed cross sectional measures. Home-based physical activity was measured using a 7-day self report diary. Fatigue was measured using the self-reported HIV-Related Fatigue Scale. Sleep was assessed using wrist actigraphy and quality of life was assessed using the HIV-Associated Quality of Life Scale. Data were collected from December 2012-April 2013 and analysed using correlations and multiple linear regression. RESULTS: The number of minutes of home-based physical activity was significantly associated with reduced fatigue among people living with HIV/AIDS. In addition, increased fatigue was associated with decreased quality of life. No associations were found among fatigue, sleep or gender. CONCLUSIONS: Our study demonstrates that physical activity in the home setting is an effective strategy to reduce fatigue among people living with HIV/AIDS. Future work developing and testing interventions to improve home-based physical activity in this population is needed. PMID- 27485464 TI - A Brief Community-Based Nutrition Education Intervention Combined With Food Baskets Can Increase Fruit and Vegetable Consumption Among Low-Income Latinos. AB - OBJECTIVE: To evaluate the impact of an 8-week community-based nutrition education program combined with food baskets on fruit and vegetable consumption (FVC) among Latinos. DESIGN: Pre-post intervention study assessing perceived barriers, knowledge, food efficacy, food outcomes, and FVC, using mixed methods (quantitative and qualitative). SETTING: Participants' recruitment and data collection took place in the Seattle Metropolitan area from September 2012 to July 2013. PARTICIPANTS: Participants' (n = 40) mean age was 37.8 (+/-10.5) years. Participants were mostly women, from Mexico, uninsured, low income, and overweight or obese. INTERVENTION: Nuestras Comidas was developed through the use of the Social Cognitive Theory and focused on increasing behavioral capability, food efficacy, food outcomes, and FVC. MAIN OUTCOME MEASURE: Dependent variables were knowledge, perceived barriers, food efficacy, food outcomes, and FVC. Independent variable was the intervention (pre-post). STATISTICAL ANALYSES: A McNemar exact test was computed for categorical variables and Wilcoxon signed rank test and paired t test for continuous variables. Focus group data were analyzed by identifying common themes. RESULTS: Participation in the intervention was significantly associated with increased knowledge, food efficacy, and vegetable consumption. CONCLUSIONS AND IMPLICATIONS: A brief nutrition education intervention combined with food baskets can improve healthy eating among Latinos. PMID- 27485466 TI - Maternal micronutrient consumption periconceptionally and during pregnancy: a prospective cohort study. AB - OBJECTIVE: To examine overall micronutrient intake periconceptionally and throughout pregnancy in a population-based cohort of Australian women. DESIGN: In a prospective cohort study, micronutrient dosages were extracted from self reported maternal supplement use, recorded pre-conception, and for each trimester of pregnancy. A food frequency scale (DQESv2) captured usual maternal diet for gestational weeks 14-26. The influence of sociodemographic and lifestyle factors associated with supplement use was examined using logistic regression, and changes in micronutrient intakes prior to and throughout pregnancy were assessed using repeated-measures ANOVA analyses. SETTING: Metropolitan hospital sites in Melbourne, Australia. SUBJECTS: Women with a viable singleton pregnancy were recruited at less than 19 weeks' gestation (n 2146). RESULTS: Compared with non users, women using supplements during pregnancy were more likely to have planned their pregnancy, be >25 years old, primiparous, Caucasian, non-smokers, have a tertiary education and be consuming a folate-rich diet. Intakes of folate, Fe and Zn were significantly lower in the periconceptional period, compared with other periods (P<0.001). Intakes below Recommended Daily Intake levels were common both periconceptionally and throughout pregnancy, with 19-46 % of women not meeting the Recommended Daily Intake for folate, 68-82 % for Fe and 17-36 % for Zn. Conversely, 15-19 % of women consumed beyond the recommended Upper Limit for folate and 11-24 % for Fe. CONCLUSIONS: The study highlights the need for improved public health education on nutritional needs during pregnancy, especially among women with lower educational achievements and income. PMID- 27485467 TI - Lessons learnt from the radiological measures performed by the Radiological Emergency Network of Extremadura in the International Emergency Exercise CURIEX 2013. AB - In late 2013 (5th-7th of November), the Caceres Urgent Response International Exercise (CURIEX 2013) took place to test the Nuclear Emergency Plan of Caceres (PENCA) with the collaboration of both national and international support teams. The theme of the exercise was the simulation of a nuclear accident at the Almaraz Nuclear Power Plant located in Extremadura (Spain) with release of radioactive plume. From the point of view of radioactive contamination, the CURIEX exercise objective was to assess the capability of the different radiological teams to quantify the radioactive impact that would occur in this environment, a goal in which the Radiological Emergency Network of Extremadura (RARE) is directly implicated. The present paper analyses in detail the environmental radiological and dosimetrical results obtained by the Radiological Emergency Network of Extremadura during the CURIEX exercise. The rapid radioactivity measurement techniques on air and soil samples performed by the RARE's mobile lab involves great uncertainties. However, the results show a relative good effectiveness both in dose rate car-borne measurements and gamma soil spectrometry with uncertainties over 40%. It also shows a good correlation between the dose rate values measured by car-borne apparatus and those calculated from gamma spectrometry measurements. The capability of the RARE's facilities are evaluated in both the measurements, showing whether or not there is a radiological problem, and the transmission of that data to the decision centres in the shortest time. Although the results were highly satisfactory, some shortcomings were detected and therefore some improvements are proposed in the paper, in order to achieve a greater capacity in response to an event with the characteristics simulated in the CURIEX exercise. PMID- 27485465 TI - ADHD and Sleep Quality: Longitudinal Analyses From Childhood to Early Adulthood in a Twin Cohort. AB - Attention-deficit/hyperactivity disorder (ADHD) is associated with poor sleep quality, but there is more to learn about the longitudinal association and aetiology of this association. We investigated the following: (a) Is there an association between childhood ADHD and poor sleep quality in young adulthood? (b) Is this driven by the long-term effects of childhood ADHD or concurrent associations with ADHD in young adulthood? (c) To what extent do genetic and environmental influences explain the overlap between symptoms of ADHD and poor sleep quality? Participants were from the Environmental Risk Longitudinal Twin Study of 2,232 twin children born in the United Kingdom in 1994-1995. We ascertained ADHD diagnoses at ages 5, 7, 10, 12, and 18. We assessed sleep quality using the Pittsburgh Sleep Quality Index at age 18. We used regression models to examine longitudinal associations and bivariate twin modelling to test genetic and environmental influences. Children with ADHD had poorer sleep quality in young adulthood, but only if their ADHD persisted. Adults with ADHD had more sleep problems than those without ADHD, over and above psychiatric comorbidity and maternal insomnia. ADHD and sleep problems in young adulthood were associated because of genetic (55%) and nonshared environmental influences (45%). Should ADHD remit, children with ADHD do not appear to have an increased risk of later sleep problems. Good quality sleep is important for multiple areas of functioning, and a better understanding of why adults with ADHD have poorer sleep quality will further the goal of improving treatments. PMID- 27485468 TI - Cardio-metabolic responses during horse riding at three different speeds. AB - PURPOSE: The purpose of the present investigation was to study the metabolic demand and cardiovascular response during a typical horse riding session. METHODS: To this aim, 19 (9 male, 10 female) riders, regularly participating in competitions, were enrolled. They underwent a preliminary, incremental exercise test on a cycle-ergometer to assess their anaerobic threshold (AT) and VO2max. Then, participants underwent a riding training session, which comprised periods of walking, trotting, and cantering for a total of 20 min. Oxygen uptake (VO2), carbon dioxide production (VCO2), and heart rate (HR) were obtained throughout the preliminary and riding test by means of a portable metabolic system. Moreover, excess of CO2 production (CO2excess) and oxygen pulse (OP) were also calculated to obtain an estimate of anaerobic glycolysis and stroke volume. RESULTS: The main result was that all collected parameters remained below the AT level throughout the riding session, with the exception of HR that approached the AT level only during cantering. In detail, during cantering, average VO2, VCO2, HR, CO2excess, and OP values were 1289 +/- 331 mL min(-1), 1326 +/- 266 mL min( 1), 158 +/- 22 bpm, 215 +/- 119 mL min(-1), and 7.8 +/- 1.6 mL/bpm, respectively. CONCLUSIONS: It was concluded that riding imposes only light to moderate stress on the aerobic and anaerobic energy systems. Moreover, cardiovascular reserve is only moderately recruited in terms of inotropism, while chronotropism can be stimulated more. PMID- 27485470 TI - A process to control light in a micro resonator through a coupling modulation by surface acoustic waves. AB - A novel process to control light through the coupling modulation by surface acoustic wave (SAW) is presented in an optical micro resonator. An optical waveguide modulator of a racetrack resonator on silicon-on-insulator (SOI) technology is took as an example to explore the mechanism. A finite-difference time-domain (FDTD) is developed to simulate the acousto-optical (AO) modulator using the mechanism. An analytical method is presented to verify our proposal. The results show that the process can work well as an optical modulator by SAW. PMID- 27485469 TI - No evidence of neural adaptations following chronic unilateral isometric training of the intrinsic muscles of the hand: a randomized controlled study. AB - PURPOSE: To test whether long-term cortical adaptations occur bilaterally following chronic unilateral training with a simple motor task. METHODS: Participants (n = 34) were randomly allocated to a training or control groups. Only the former completed a 4-week maximal-intensity isometric training of the right first dorsal interosseus muscle through key pinching. Maximal strength was assessed bilaterally in four different movements progressively less similar to the training task: key, tip and tripod pinches, and handgrip. Transcranial magnetic stimulation was used to probe, in the left and right primary hand motor cortices, a number of standard tests of cortical excitability, including thresholds, intra-cortical inhibition and facilitation, transcallosal inhibition, and sensory-motor integration. RESULTS: Training increased strength in the trained hand, but only for the tasks specifically involving the trained muscle (key +8.5 %; p < 0.0005; tip +7.2 %; p = 0.02). However, the effect size was small and below the cutoff for meaningful change. Handgrip and tripod pinch were instead unaffected. There was a similar improvement in strength in the untrained hand, i.e., a cross-education effect (key +6.4 %; p = 0.02; tip +4.7 %; p = 0.007). Despite these changes in strength, no significant variation was observed in any of the neurophysiological parameters describing cortico-spinal and intra cortical excitability, inter-hemispheric inhibition, and cortical sensory-motor integration. CONCLUSIONS: A 4-week maximal-intensity unilateral training induced bilaterally spatial- and task-specific strength gains, which were not associated to direct or crossed cortical adaptations. The observed long-term stability of neurophysiological parameters might result from homeostatic plasticity phenomena, aimed at restoring the physiological inter-hemispheric balance of neural activity levels perturbed by the exercise. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02010398. PMID- 27485471 TI - Abnormal histone acetylation of CD8+ T cells in patients with severe aplastic anemia. AB - Severe aplastic anemia (SAA) is a rare autoimmune disease characterized by severe pancytopenia and bone marrow failure, which is caused by activated T lymphocytes. In the present study, we evaluated histone H3 acetylation levels of bone marrow CD8+ T cells in SAA patients, and analyzed its correlation with clinical condition parameters. We found that the percentages of CD8+ T cell histone H3 acetylation in patients with untreated SAA, recovering SAA (R-SAA) and normal control, were 1.21 +/- 0.08, 1.05 +/- 0.36, and 1.00 +/- 0.41, respectively, with no significant statistical differences. However, the amount of CD8+ T cell histone H3 acetylation from untreated SAA was 176.21 +/- 32.22 MUg/mg protein, which was significantly higher than that of complete response (CR)-SAA (104.29 +/ 62.06 MUg/mg protein) and normal control (133.94 +/- 56.27 MUg/mg protein) (P < 0.05) groups. Moreover, histone H3 acetylation amount of CD8+ T cell was significantly and negatively correlated with absolute neutrophil count, proportion of reticulocytes, ratio of CD4+ to CD8+ T cell in peripheral blood, and percentage of bone marrow erythroid (P < 0.05). To some extent, it also negatively correlated with hemoglobin level, platelet count, percentage of bone marrow granulocyte, and megakaryocyte count. Abnormal histone H3 acetylation of CD8+ T cells may thus play a role in the immune pathogenesis of SAA. PMID- 27485472 TI - Panobinostat for the treatment of acute myelogenous leukemia. AB - INTRODUCTION: Therapeutic strategies in patients with acute myeloid leukemia (AML) have not changed significantly over the last decades. Appropriate strategies are ultimately driven by the assessment of patients' fitness to define suitability for intensive induction chemotherapy, which produces high initial remission rates but, increased likelihood of relapse. Old/unfit AML patients still represent an urgent and unmet therapeutic need. Epigenetic deregulation represents a strategic characteristic of AML pathophysiology whereby aberrant gene transcription provides an advantage to leukemic cell survival. Efforts to re establish impaired epigenetic regulation include hypomethylating agents and histone deacetylase inhibitors (HDACi). AREAS COVERED: The review discusses the underlying mechanisms leading to disruption of lysine acetyltransferases (KAT or HAT)/deacetylase (KDAC or HDAC) balance and the rationale for using the HDACi panobinostat (LBH-589) in AML. EXPERT OPINION: Although panobinostat has produced significant results in myeloma, its efficacy remains limited in AML. Panobinostat exerts pleiotropic activity and lack of specificity, which likely contributes to its inadequate safety in elderly AML patients. Phase I-II trials, utilizing panobinostat associated with well-known chemotherapeutic agents are ongoing and combinations with other druggable targets may likely be evaluated in future trials. The clinical use of this HDACi in AML the near future does not appearing promising. PMID- 27485473 TI - Jasmonic acid protects etiolated seedlings of Arabidopsis thaliana against herbivorous arthropods. AB - Seed predators can cause mass ingestion of larger seed populations. As well, herbivorous arthropods attempt to attack etiolated seedlings and chose the apical hook for ingestion, aimed at dropping the cotyledons for later consumption. Etiolated seedlings, as we show here, have established an efficient mechanism of protecting their Achilles' heel against these predators, however. Evidence is provided for a role of jasmonic acid (JA) in this largely uncharacterized plant herbivore interaction during skotomorphogenesis and that this comprises the temporally and spatially tightly controlled synthesis of a cysteine protease inhibitors of the Kunitz family. Interestingly, the same Kunitz protease inhibitor was found to be expressed in flowers of Arabidopsis where endogenous JA levels are high for fertility. Because both the apical hook and inflorescences were preferred isopod targets in JA-deficient plants that could be rescued by exogenously administered JA, our data identify a JA-dependent mechanism of plant arthropod deterrence that is recalled in different organs and at quite different times of plant development. PMID- 27485474 TI - Tissue-resident Eomes(hi) T-bet(lo) CD56(bright) NK cells with reduced proinflammatory potential are enriched in the adult human liver. AB - The adult human liver is enriched with natural killer (NK) cells, accounting for 30-50% of hepatic lymphocytes, which include tissue-resident hepatic NK-cell subpopulations, distinct from peripheral blood NK cells. In murine liver, a subset of liver-resident hepatic NK cells have altered expression of the two highly related T-box transcription factors, T-bet and eomesodermin (Eomes). Here, we investigate the heterogeneity of T-bet and Eomes expression in NK cells from healthy adult human liver with a view to identifying human liver-resident populations. Hepatic NK cells were isolated from donor liver perfusates and biopsies obtained during orthotopic liver transplantation (N = 28). Hepatic CD56(bright) NK cells were Eomes(hi) T-bet(lo) , a phenotype virtually absent from peripheral blood. These NK cells express the chemokine receptor CXCR6 (chemokine (C-X-C motif) receptor 6), a marker of tissue residency, which is absent from hepatic CD56(dim) and blood NK cells. Compared to blood populations, these hepatic CD56(bright) NK cells have increased expression of activatory receptors (NKp44, NKp46, and NKG2D). They show reduced ability to produce IFN gamma but enhanced degranulation in response to challenge with target cells. This functionally distinct population of hepatic NK cells constitutes 20-30% of the total hepatic lymphocyte repertoire and represents a tissue-resident immune cell population adapted to the tolerogenic liver microenvironment. PMID- 27485476 TI - The impact of dementia on women internationally: An integrative review. AB - Women are disproportionately affected by dementia, both in terms of developing dementia and becoming caregivers. We conducted an integrative review of English language literature focusing on the issues affecting women in relation to dementia from an international perspective. The majority of relevant studies were conducted in high-income countries, and none were from low-income countries. The effects of caregiving on health, well-being, and finances are greater for women; issues facing women, particularly in low- and middle-income countries, need to be better understood. Research should focus on building resilience to help people adjust and cope long term. PMID- 27485475 TI - Identifying fusion transcripts using next generation sequencing. AB - Fusion transcripts (i.e., chimeric RNAs) resulting from gene fusions have been used successfully for cancer diagnosis, prognosis, and therapeutic applications. In addition, many fusion transcripts are found in normal human cell lines and tissues, with some data supporting their role in normal physiology. Besides chromosomal rearrangement, intergenic splicing can generate them. Global identification of fusion transcripts becomes possible with the help of next generation sequencing technology like RNA-Seq. In the past decade, major advancements have been made for chimeric RNA discovery due to the development of advanced sequencing platform and software packages. However, current software tools behave differently in terms of specificity, sensitivity, time, and computational memory usage. Recent benchmarking studies showed that none of the tools are inclusive. The development of high performance (accurate and fast), and user-friendly fusion detection tool/pipeline is still an open quest. In this article, we review the existing software packages for fusion detection. We explain the methods of the tools, and discuss various factors that affect fusion detection. We summarize conclusions drawn from several comparative studies, and then discuss some of the pitfalls of these studies. We also describe the limitations of current tools, and suggest directions for future development. WIREs RNA 2016, 7:811-823. doi: 10.1002/wrna.1382 For further resources related to this article, please visit the WIREs website. PMID- 27485477 TI - Clinical risk factors associated with the post-transplant anemia in kidney transplant patients. AB - BACKGROUND: Anemia is a very common occurrence in post-renal transplant patients. Post-transplantation anemia (PTA) is associated with significant graft loss or cardiovascular morbidity. The objective of this study is to identify clinical risk factors associated with anemia after kidney transplantation. METHODS: Our retrospective cohort study included a total of 570 renal transplant recipients. For the definition of anemia, we adopted "the lower limit of normal for Hgb concentration of blood" proposed by Beutler E and Waalen J [14], which has adjustments for age, gender and ethnicity. Post-transplant anemia (PTA) was defined as anemia that arose between 30 and 180days after transplantation. Based on this definition, of the 570 renal transplant recipients, 344 patients (62.1%) experienced PTA. The patients were divided into anemic and non-anemic groups, and a total of 20 clinical factors were compared between the two groups. RESULTS: In the univariate analysis, age, race, multiple transplants, delayed graft function (DGF), and use of tacrolimus, sirolimus, thymoglobulin, ganciclovir, ACE inhibitors, and ARBs were associated with PTA. In the multivariate analysis, age (>60years old, OR=2.62, p=0.001), race (OR=2.54, p=0.001), and use of sirolimus (OR=2.01, p=0.019), antiviral agents (OR=1.96, p=0.015), thymoglobulin (OR=1.86, p=0.011), and DGF (OR=2.78, p=0.001) remained significant. CONCLUSION: The current results show that undergoing a transplant at age 60 or older, use of sirolimus, antiviral agents, and thymoglobulin are independent clinical risk factors associated with PTA. In terms of ethnicity, AA, MEA, or PI is higher risk for PTA and Hispanic is significantly lower risk for PTA compared to Caucasians. PMID- 27485478 TI - Multistimuli-Responsive Bilirubin Nanoparticles for Anticancer Therapy. AB - Although stimuli-responsive materials hold potential for use as drug-delivery carriers for treating cancers, their clinical translation has been limited. Ideally, materials used for the purpose should be biocompatible and nontoxic, provide "on-demand" drug release in response to internal or external stimuli, allow large-scale manufacturing, and exhibit intrinsic anticancer efficacy. We present multistimuli-responsive nanoparticles formed from bilirubin, a potent endogenous antioxidant that possesses intrinsic anticancer and anti-inflammatory activity. Exposure of the bilirubin nanoparticles (BRNPs) to either reactive oxygen species (ROS) or external laser light causes rapid disruption of the BRNP nanostructure as a result of a switch in bilirubin solubility, thereby releasing encapsulated drugs. In a xenograft tumor model, BRNPs loaded with the anticancer drug doxorubicin (DOX@BRNPs), when combined with laser irradiation of 650 nm, significantly inhibited tumor growth. This study suggests that BRNPs may be used as a drug-delivery carrier as well as a companion medicine for effectively treating cancers. PMID- 27485479 TI - In vivo strain in the deep and superficial regions of the human patellar tendon. AB - This study investigated strain differences within the patellar tendon (PT) mid region using an ultrasound-based digital image correlation (DIC) method. Six healthy young participants performed six knee extensions to 60% of maximal voluntary isometric contraction on 2 days. Sagittal ultrasound videos recorded during each contraction were analyzed using the DIC method to determine the strain-torque relationships of the superficial, deep, and whole PT mid-regions. Significantly greater strain was observed in the deep vs superficial layer of the PT mid-region for all contraction intensities, with peak strains of 5.8% (SD 1.7) and 4.5% (SD 1.5), respectively. DIC-based measures of peak tendon strain were repeatable within [intraclass coefficients (ICC) >0.97] and between sessions (ICCs >0.83) and agreed well with the conventional point-to-point method. This study confirmed that significant differences exist between deep and superficial layers of PT mid-region during ramped isometric extensions. These findings support the use of DIC to examine regional strain patterns within the PT mid region that may be important in the context of tendon injury and adaptation. PMID- 27485480 TI - Seminal fluid and fertility in women. AB - Seminal fluid is often viewed as simply a vehicle to carry sperm to fertilize the oocyte, but a more complex function in influencing female reproductive physiology is now evident. Remarkably, seminal fluid contains soluble and exosome-born signaling agents that interact with the female reproductive tract to prime the immune response, with consequences for fertility and pregnancy outcome. Experiments in rodent models demonstrate a key role for seminal fluid in enabling robust embryo implantation and optimal placental development. In particular, seminal fluid promotes leukocyte recruitment and generation of regulatory T cells, which facilitate embryo implantation by suppressing inflammation, assisting uterine vascular adaptation, and sustaining tolerance of fetal antigens. There is emerging evidence of comparable effects in women, where seminal fluid provokes an adaptive immune response in the cervical tissues after contact at intercourse, and spermatozoa accessing the higher tract potentially affect the endometrium directly. These biological responses may have clinical significance, explaining why [1] intercourse in IVF ET cycles improves the likelihood of pregnancy, [2] inflammatory disorders of gestation are more common in women who conceive after limited exposure to seminal fluid of the prospective father, and [3] preeclampsia incidence is elevated after use of donor oocytes or donor sperm where prior contact with conceptus alloantigens has not occurred. It will be important to define the mechanisms through which seminal fluid interacts with female reproductive tissues, to provide knowledge that may assist in preconception planning and infertility treatment. PMID- 27485481 TI - Synthesis and evaluation of an (18)F-labeled pyrimidine-pyridine amine for targeting CXCR4 receptors in gliomas. AB - INTRODUCTION: Chemokine receptor-4 (CXCR4, fusin, CD184) is expressed on several tissues involved in immune regulation and is upregulated in many diseases including malignant gliomas. A radiolabeled small molecule that readily crosses the blood-brain barrier can aid in identifying CXCR4-expressing gliomas and monitoring CXCR4-targeted therapy. In the current work, we have synthesized and evaluated an [(18)F]-labeled small molecule based on a pyrimidine-pyridine amine for its ability to target CXCR4. EXPERIMENTAL: The nonradioactive standards and the nitro precursor used in this study were prepared using established methods. An HPLC method was developed to separate the nitro-precursor from the nonradioactive standard and radioactive product. The nitro-precursor was radiolabeled with (18)F under inert, anhydrous conditions using the [(18)F] kryptofix 2.2.2 complex to form the desired N-(4-(((6-[(18)F]fluoropyridin-2 yl)amino)methyl)benzyl)pyrimidin-2-amine ([(18)F]-3). The purified radiolabeled compound was used in serum stability, partition coefficient, cellular uptake, and in vivo cancer targeting studies. RESULTS: [(18)F]-3 was synthesized in 4-10% decay-corrected yield (to start of synthesis). [(18)F]-3 (tR ~ 27 min) was separated from the precursor (tR ~ 30 min) using a pentafluorophenyl column with an isocratic solvent system. [(18)F]-3 displayed acceptable serum stability over 2 h. The amount of [(18)F]-3 bound to the plasma proteins was determined to be > 97%. The partition coefficient (LogD7.4) is 1.4 +/- 0.5. Competitive in vitro inhibition indicated 3 does not inhibit uptake of (67)Ga-pentixafor. Cell culture media incubation and ex vivo urine analysis indicate rapid metabolism of [(18)F] 3 into hydrophilic metabolites. Thus, in vitro uptake of [(18)F]-3 in CXCR4 overexpressing U87 cells (U87 CXCR4) and U87 WT indicated no specific binding. In vivo studies in mice bearing U87 CXCR4 and U87 WT tumors on the left and right shoulders were carried out using [(18)F]-3 and (68)Ga-pentixafor on consecutive days. The CXCR4 positive tumor was clearly visualized in the PET study using (68)Ga-pentixafor, but not with [(18)F]-3. CONCLUSIONS: We have successfully synthesized both a radiolabeled analog to previously reported CXCR4-targeting molecules and a nitro precursor. Our in vitro and in vivo studies indicate that [(18)F]-3 is rapidly metabolized and, therefore, does not target CXCR4-expressing tumors. Optimization of the structure to improve the in vivo (and in vitro) stability, binding, and solubility could lead to an appropriate CXCR4-targeted radiodiagnositic molecule. PMID- 27485482 TI - Incidence of advanced neoplasia during surveillance in high- and intermediate risk groups of the European colorectal cancer screening guidelines. AB - Background and study aims: The European guidelines for quality assurance in colorectal cancer (CRC) screening have established high-risk (>= 5 adenomas or an adenoma >= 20 mm) and intermediate-risk (3 - 4 adenomas or at least one adenoma 10 - 19 mm in size, or villous histology, or high grade dysplasia) groups with different endoscopic surveillance intervals. The aim of this study was to evaluate the difference in the incidence of advanced neoplasia (advanced adenoma or CRC) between the two risk groups. Patients and methods: This retrospective group study included patients meeting high- or intermediate-risk criteria for adenomas detected in CRC screening programs and the COLONPREV study before European guidelines were adopted in Spain (June 2011) with a 3-year surveillance recommendation according to Spanish guidelines. The primary outcome measure was the incidence of advanced neoplasia in patients undergoing surveillance. The secondary outcome measure was the CRC incidence. We used an adjusted proportional hazards regression model to control confounding variables. Results: The study included 5401 patients (3379 intermediate risk, 2022 high risk). Endoscopic surveillance was performed in 65.5 % of the patients (2.8 +/- 1 years). The incidence of advanced neoplasia in the high- and intermediate-risk groups was 16.0 % (59.0 cases/1000 patient-years) and 12.3 % (41.2 cases/1000 patient years), respectively. The CRC incidence was 0.5 % (1.4 cases/1000 patient-years) and 0.4 % (1 case/1000 patient-years), respectively. The advanced neoplasia and CRC attributable risk to the high risk group was of 3.7 % and 0.1 %, respectively. In the proportional hazards analysis, the risk of advanced neoplasia was greater in the high-risk group (hazard ratio [HR] 1.5, 95 % confidence interval [CI] 1.2 - 1.8), with no significant differences in the CRC incidence (HR 1.6, 95 %CI 0.6 - 3.8). Conclusions: Patients meeting high-risk criteria have a higher incidence of advanced neoplasia during endoscopic surveillance. No differences were found in the CRC incidence at a 3-year surveillance recommendation. PMID- 27485483 TI - European Society of Gastrointestinal Endoscopy - Establishing the key unanswered research questions within gastrointestinal endoscopy. AB - Background and study aim: Gastrointestinal endoscopy is a rapidly evolving research field. The European Society of Gastrointestinal Endoscopy (ESGE) plays a key role in shaping opinion and endoscopy activity throughout Europe and further afield. Establishing key unanswered questions within the field of endoscopy and prioritizing those that are important enables researchers and funders to appropriately allocate resources. Methods: Over 2 years, the ESGE Research Committee gathered information on research priorities and refined them through a modified Delphi approach. Consultations were held with the ESGE Governing Board and Quality Improvement Committee to identify important unanswered questions. Research workshops were held at the 21st United European Gastroenterology Week. Research questions were refined by the ESGE Research Committee and Governing Board, compiled into an online survey, and distributed to all ESGE members, who were invited to rank each question by priority. Results: The final questionnaire yielded 291 responses from over 60 countries. The three countries with the highest response rates were Spain, Italy, and United Kingdom. Most responders were from teaching hospitals (62 %) and were specialist endoscopists (51 %). Responses were analyzed with weighted rankings, resulting in prioritization of 26 key unanswered questions. The top ranked generic questions were: 1) How do we define the correct surveillance interval following endoscopic diagnosis? 2) How do we correctly utilize advanced endoscopic imaging? 3) What are the best markers of endoscopy quality? Conclusion: Following this comprehensive process, the ESGE has identified and ranked the key unanswered questions within the field of gastrointestinal endoscopy. Researchers, funders, and journals should prioritize studies that seek to answer these important questions. PMID- 27485484 TI - hiPSC-derived cardiomyocytes from Brugada Syndrome patients without identified mutations do not exhibit clear cellular electrophysiological abnormalities. AB - Brugada syndrome (BrS) is a rare cardiac rhythm disorder associated with sudden cardiac death. Mutations in the sodium channel gene SCN5A are found in ~20% of cases while mutations in other genes collectively account for <5%. In the remaining patients the genetic defect and the underlying pathogenic mechanism remain obscure. To provide insight into the mechanism of BrS in individuals without identified mutations, we here studied electrophysiological properties of cardiomyocytes (CMs) generated from human induced pluripotent stem cells (hiPSCs) from 3 BrS patients who tested negative for mutations in the known BrS-associated genes. Patch clamp studies revealed no differences in sodium current (INa) in hiPSC-CMs from the 3 BrS patients compared to 2 unrelated controls. Moreover, action potential upstroke velocity (Vmax), reflecting INa, was not different between hiPSC-CMs from the BrS patients and the controls. hiPSC-CMs harboring the BrS-associated SCN5A-1795insD mutation exhibited a reduction in both INa and Vmax, demonstrating our ability to detect reduced sodium channel function. hiPSC CMs from one of the BrS lines demonstrated a mildly reduced action potential duration, however, the transient outward potassium current (Ito) and the L-type calcium current (ICa,L), both implicated in BrS, were not different compared to the controls. Our findings indicate that ion channel dysfunction, in particular in the cardiac sodium channel, may not be a prerequisite for BrS. PMID- 27485485 TI - Umbilical cord-derived mesenchymal stem cells inhibit growth and promote apoptosis of HepG2 cells. AB - Hepatocellular carcinoma is the fifth most common type of cancer worldwide and remains difficult to treat. The aim of this study was to investigate the effects of mesenchymal stem cells (MSCs) derived from the umbilical cord (UC-MSCs) on HepG2 hepatocellular carcinoma cells. UC-MSCs were co-cultured with HepG2 cells and biomarkers of UC-MSCs were analyzed by flow cytometry. mRNA and protein expression of genes were determined by reverse transcription-polymerase chain reaction and flow cytometry, respectively. Passage three and seven UC-MSCs expressed CD29, CD44, CD90 and CD105, whereas CD34 and CD45 were absent on these cells. Co-culture with UC-MSCs inhibited proliferation and promoted apoptosis of HepG2 cells in a time-dependent manner. The initial seeding density of UC-MSCs also influenced the proliferation and apoptosis of HepG2 cells, with an increased number of UC-MSCs causing enhanced proliferation inhibition and cell apoptosis. Co-culture with UC-MSCs downregulated mRNA and protein expression of alpha fetoprotein (AFP), Bcl-2 and Survivin in HepG2 cells. Thus, UC-MSCs may inhibit growth and promote apoptosis of HepG2 cells through downregulation of AFP, Bcl-2 and Survivin. US-MSCs may be used as a novel therapy for treating hepatocellular carcinoma in the future. PMID- 27485486 TI - Capacity to improve fine motor skills in Williams syndrome. AB - BACKGROUND: Individuals with Williams syndrome (WS) are known to have difficulties in carrying out fine motor movements; however, a detailed behavioural profile of WS in this domain is still missing. It is also unknown how great the capacity to improve these skills with focused and extensive practice is. METHOD: We studied initial performance and learning capacity in a sequential finger tapping (FT) task in WS and in typical development. Improvement in the FT task has been shown to be sleep dependent. WS subjects participating in the current study have also participated in earlier polysomnography studies, although not directly related to learning. RESULTS: WS participants presented with great individual variability. In addition to generally poor initial performance, learning capacity was also greatly limited in WS. We found indications that reduced sleep efficiency might contribute to this limitation. CONCLUSIONS: Estimating motor learning capacity and the depth of sleep disorder in a larger sample of WS individuals might reveal important relationships between sleep and learning, and contribute to efficient intervention methods improving skill acquisition in WS. PMID- 27485487 TI - Spatiotemporal characteristics of the pharyngeal event-related potential in healthy subjects and older patients with oropharyngeal dysfunction. AB - BACKGROUND: Oropharyngeal dysphagia (OD) is a highly prevalent symptom in older people. Appropriate oropharyngeal sensory feedback is essential for safe and efficient swallowing. However, pharyngeal sensitivity decreases with advancing age and could play a fundamental role in the physiopathology of swallowing dysfunction associated with aging. We aimed to characterize pharyngeal sensitivity and cortical response to a pharyngeal electrical stimulus in healthy volunteers (HV) and older patients with and without OD. METHODS: Eight young HV, eight older HV without OD, and 14 older patients with OD were studied by electroencephalography through 32 scalp electrodes. Pharyngeal event-related potentials (ERP) were assessed following electrical stimulation of the pharynx. Sensory and tolerance thresholds to the electrical stimulus and latency, amplitude, and scalp current density of each ERP component were analyzed and compared. An ERP source localization study was also performed using the sLORETA software. KEY RESULTS: Older participants (with and without OD) presented an increased sensory threshold to pharyngeal electrical stimulation (10.2 +/- 1.7 mA and 11.5 +/- 1.9 mA respectively), compared with young HV (6.0 +/- 1.2 mA). The cortical activation of older HV in response to pharyngeal electrical stimulus was reduced compared with young HV (N2 amplitude: 0.22 +/- 0.79 vs -3.10 +/- 0.59, P<.05). Older patients with OD also presented disturbances to the pharyngo cortical connection together with disrupted pattern of cortical activation. CONCLUSIONS AND INFERENCES: Older people present a decline in pharyngeal sensory function, more severe in older patients with OD. This sensory impairment might be a critical pathophysiological element and a potential target for treatment of swallowing dysfunction in older patients. PMID- 27485488 TI - The differential effects of alprazolam and oxazepam on methamphetamine self administration in rats. AB - BACKGROUND: Methamphetamine is the second most commonly used illicit drug in the world, and despite recent attempts by the Drug Enforcement Administration to combat this epidemic, methamphetamine use is still on the rise. As methamphetamine use increases so does polydrug use, particularly that involving methamphetamine and benzodiazepines. The present study was designed to examine the effects of two benzodiazepines on methamphetamine self-administration. METHODS: Five doses of methamphetamine (0.0075, 0.015, 0.03, 0.09, and 0.12mg/kg/infusion) were tested, producing an inverted U-shaped dose-response curve. Rats were then pretreated with oxazepam, alprazolam, or vehicle prior to methamphetamine self-administration. To determine if the effects of these drugs were due to the GABAA receptor and/or translocator protein (TSPO), we also pretreated rats with an antagonist for the benzodiazepine-binding site on the GABAA receptor (i.e., flumazenil) and a TSPO antagonist (i.e., PK11195) prior to alprazolam or oxazepam administration. RESULTS: Oxazepam significantly reduced methamphetamine self-administration as demonstrated by a downward shift of the dose-response curve. In contrast, alprazolam significantly enhanced methamphetamine self-administration as evidenced by a leftward shift of the dose response curve. Flumazenil completely blocked the effects of alprazolam on methamphetamine self-administration. When administered individually, both flumazenil and PK11195 partially reversed the effects of oxazepam on methamphetamine self-administration. However, when these two antagonists were combined, the effects of oxazepam were completely reversed. CONCLUSIONS: The GABAA receptor is responsible for the alprazolam-induced enhancement of methamphetamine self-administration, while the activation of both the GABAA receptor and TSPO are responsible for the oxazepam-induced reduction of methamphetamine self-administration. PMID- 27485489 TI - Structural characterization, molecular modification and hepatoprotective effect of melanin from Lachnum YM226 on acute alcohol-induced liver injury in mice. AB - In this paper, the possible structural formula of the intracellular homogeneous melanin of Lachnum YM226 (LM) was concluded based on an elemental assay, ultraviolet-visible spectroscopy (UV-Vis), Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), mass spectrometry (MS) and equivalent series resistance (ESR). Meanwhile, a d-glucosamine melanin derivative (GLM) was also prepared and its cytotoxicity was evaluated using the MTT assay. The hepatoprotective effect of LM and GLM was evaluated in an acute alcohol induced liver injury model. The results showed that pretreatments with LM and GLM markedly decreased subsequent alcohol elicited acute hepatic oxidative and inflammatory stress via improving the activity of antioxidant enzymes (glutathione (GSH), catalase (CAT), glutathione peroxidase (GPX), and total superoxide dismutase (SOD)), reducing hepatic levels of nuclear transcription factor (NF-kappaB), cytokines related to its activation (interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and macrophage chemoattractant protein (MCP)-1) and hepatic activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2. The protection properties of alcoholic liver injury of GLM were more obvious than that of LM at the same dose. The present findings recommend that LM and GLM may be used as a prototype for the prevention of alcoholic liver injury. PMID- 27485490 TI - Comparing Weight-for-Length Status of Young Children in Two Infant Feeding Programs. AB - Objectives A cross-sectional study comparing weight-for-length status of children 6-24 months old who participated in Nurse-Family Partnership (NFP) or Special Supplemental Program for Women, Infants, and Children (WIC). Methods Secondary analysis of NFP (n = 44,980) and WIC (n = 31,294) national datasets was conducted to evaluate infant and toddler growth trajectories. Weight-for-length status was calculated at 6, 12, 18, and 24 months based on World Health Organization criteria. Demographics and breastfeeding rates were also evaluated. Binary logistic regression was used to calculate odds ratios for high weight-for-length (>=97.7 percentile) at each time point. Results At 6 months, approximately 10 % of WIC and NFP children were classified as high weight-for-length. High weight for-length rates increased for both groups similarly until 24 months. At 24 months, NFP children had significantly lower rates of excess weight (P = 0.03) than WIC children, 15.5 and 17.5 % respectively. At all time points, non-Hispanic white children had lower rates of high-weight for length than Hispanic and non Hispanic black children. NFP infants were also found to have higher rates of ever being breastfed than WIC infants (P < 0.0001). Conclusions for Practice Infant and toddler populations served by NFP or WIC were found to be at increased risk for high weight-for-length. This study found NFP participation was associated with a small, but significant, protective impact on weight-for-length status at 24 months. Continued efforts need to be made in addressing weight-related racial/ethnic and socioeconomic disparities during early childhood. PMID- 27485492 TI - Hurricane Charley Exposure and Hazard of Preterm Delivery, Florida 2004. AB - Objective Hurricanes are powerful tropical storm systems with high winds which influence many health effects. Few studies have examined whether hurricane exposure is associated with preterm delivery. We aimed to estimate associations between maternal hurricane exposure and hazard of preterm delivery. Methods We used data on 342,942 singleton births from Florida Vital Statistics Records 2004 2005 to capture pregnancies at risk of delivery during the 2004 hurricane season. Maternal exposure to Hurricane Charley was assigned based on maximum wind speed in maternal county of residence. We estimated hazards of overall preterm delivery (<37 gestational weeks) and extremely preterm delivery (<32 gestational weeks) in Cox regression models, adjusting for maternal/pregnancy characteristics. To evaluate heterogeneity among racial/ethnic subgroups, we performed analyses stratified by race/ethnicity. Additional models investigated whether exposure to multiples hurricanes increased hazard relative to exposure to one hurricane. Results Exposure to wind speeds >=39 mph from Hurricane Charley was associated with a 9 % (95 % CI 3, 16 %) increase in hazard of extremely preterm delivery, while exposure to wind speed >=74 mph was associated with a 21 % (95 % CI 6, 38 %) increase. Associations appeared greater for Hispanic mothers compared to non Hispanic white mothers. Hurricane exposure did not appear to be associated with hazard of overall preterm delivery. Exposure to multiple hurricanes did not appear more harmful than exposure to a single hurricane. Conclusions Hurricane exposure may increase hazard of extremely preterm delivery. As US coastal populations and hurricane severity increase, the associations between hurricane and preterm delivery should be further studied. PMID- 27485491 TI - The Impact of Perinatal Depression on Children's Social-Emotional Development: A Longitudinal Study. AB - Objectives This longitudinal population study aimed to investigate if maternal depression at different time points during the perinatal period impacts children's social-emotional development at 2 years of age. Methods Participants were women (n = 1235) who gave birth at Akershus University Hospital in Norway. Maternal depressive symptoms were assessed by using the Edinburgh Postnatal Depression Scale at pregnancy week 32 and at 8 weeks and 2 years postpartum, whereas children's social-emotional development at the age of 2 years was assessed by using the Ages and Stages Questionnaire: Social-Emotional. Bi- and multivariate logistic regression analyses were conducted to examine the linkage between maternal perinatal depression and children's early social-emotional development. Results Multivariate analyses showed that social-emotional problems in the child 2 years after birth were strongly associated with maternal depression at pregnancy week 32 (adjusted odds ratio (aOR) 3.4; 95 % CI 1.4-8.0), depression at 8 weeks postpartum (aOR 3.8; 95 % CI 1.7-8.6), and with depression at both time points (aOR 3.7; 95 % CI 1.5-10.1). Conclusion Findings indicate pre and postnatal depression each bears an independent, adverse impact on children's social-emotional development. PMID- 27485493 TI - Group Prenatal Care Attendance: Determinants and Relationship with Care Satisfaction. AB - Objectives Group prenatal care results in improved birth outcomes in randomized controlled trials, and better attendance at group prenatal care visits is associated with stronger clinical effects. This paper's objectives are to identify determinants of group prenatal care attendance, and to examine the association between proportion of prenatal care received in a group context and satisfaction with care. Methods We conducted a secondary data analysis of pregnant adolescents (n = 547) receiving group prenatal care in New York City (2008-2012). Multivariable linear regression models were used to test associations between patient characteristics and percent of group care sessions attended, and between the proportion of prenatal care visits that occurred in a group context and care satisfaction. Results Sixty-seven groups were established. Group sizes ranged from 3 to 15 women (mean = 8.16, SD = 3.08); 87 % of groups enrolled at least five women. Women enrolled in group prenatal care supplemented group sessions with individual care visits. However, the percent of women who attended each group session was relatively consistent, ranging from 56 to 63 %. Being born outside of the United States was significantly associated with higher group session attendance rates [B(SE) = 11.46 (3.46), p = 0.001], and women who received a higher proportion of care in groups reported higher levels of care satisfaction [B(SE) = 0.11 (0.02), p < 0.001]. Conclusions Future research should explore alternative implementation structures to improve pregnant women's ability to receive as much prenatal care as possible in a group setting, as well as value based reimbursement models and other incentives to encourage more widespread adoption of group prenatal care. PMID- 27485494 TI - Effect of Modifiable Risk Factors on Preterm Birth: A Population Based-Cohort. AB - Objectives The purpose of this study is to evaluate the prevalence, impact, and interaction of short interpregnancy interval (IPI), pre-pregnancy body mass index (BMI) category, and pregnancy weight gain (PWG) on the rate of preterm birth. Methods This is a population-based retrospective cohort study using vital statistics birth records from 2006 to 2011 in OH, US, analyzing singleton live births to multiparous mothers with recorded IPI (n = 393,441). Preterm birth rate at <37 weeks gestational age was compared between the referent pregnancy (defined as normal pre-pregnancy maternal BMI, IPI of 12-24 months, and Institute of Medicine (IOM) recommended PWG) and those with short or long IPI, abnormal BMI (underweight, overweight, and obese), and high or low PWG (under or exceeding IOM recommendations). Results Only 6 % of the women in this study had a referent pregnancy, with a preterm birth rate of 7.6 % for this group. Short IPIs of <6 and 6-12 months were associated with increased rates of preterm birth rate to 12.9 and 10.4 %, respectively. Low PWG compared to IOM recommendations for pre pregnancy BMI class was also associated with increased preterm birth rate of 13.2 % for all BMI classes combined. However, the highest rate of preterm birth of 25.2 % occurred in underweight women with short IPI and inadequate weight gain with adjOR 3.44 (95 % CI 2.80, 4.23). The fraction of preterm births observed in this cohort that can be attributed to short IPIs is 5.9 %, long IPIs is 8.3 %, inadequate PWG is 7.5 %, and low pre-pregnancy BMI is 2.2 %. Conclusions Our analysis indicates that a significant proportion of preterm births in Ohio are associated with potentially modifiable risk factors. These data suggest public health initiatives focused on preterm birth prevention could include counseling and interventions to optimize preconception health and prenatal nutrition. PMID- 27485495 TI - Sustained live poultry market surveillance contributes to early warnings for human infection with avian influenza viruses. AB - Sporadic human infections with the highly pathogenic avian influenza (HPAI) A (H5N6) virus have been reported in different provinces in China since April 2014. From June 2015 to January 2016, routine live poultry market (LPM) surveillance was conducted in Shenzhen, Guangdong Province. H5N6 viruses were not detected until November 2015. The H5N6 virus-positive rate increased markedly beginning in December 2015, and viruses were detected in LPMs in all districts of the city. Coincidently, two human cases with histories of poultry exposure developed symptoms and were diagnosed as H5N6-positive in Shenzhen during late December 2015 and early January 2016. Similar viruses were identified in environmental samples collected in the LPMs and the patients. In contrast to previously reported H5N6 viruses, viruses with six internal genes derived from the H9N2 or H7N9 viruses were detected in the present study. The increased H5N6 virus positive rate in the LPMs and the subsequent human infections demonstrated that sustained LPM surveillance for avian influenza viruses provides an early warning for human infections. Interventions, such as LPM closures, should be immediately implemented to reduce the risk of human infection with the H5N6 virus when the virus is widely detected during LPM surveillance. PMID- 27485496 TI - Prevalence of influenza A virus in live-captured North Atlantic gray seals: a possible wild reservoir. AB - Influenza A virus (IAV) has been associated with multiple unusual mortality events (UMEs) in North Atlantic pinnipeds, frequently attributed to spillover of virus from wild-bird reservoirs. To determine if endemic infection persists outside of UMEs, we undertook a multiyear investigation of IAV in healthy, live captured Northwest Atlantic gray seals (Halichoerus grypus). From 2013 to 2015, we sampled 345 pups and 57 adults from Cape Cod, MA, USA and Nova Scotia, Canada consistently detecting IAV infection across all groups. There was an overall viral prevalence of 9.0% (95% confidence interval (CI): 6.4%-12.5%) in weaned pups and 5.3% (CI: 1.2%-14.6%) in adults, with seroprevalences of 19.3% (CI: 15.0%-24.5%) and 50% (CI: 33.7%-66.4%), respectively. Positive sera showed a broad reactivity to diverse influenza subtypes. IAV status did not correlate with measures of animal health nor impact animal movement or foraging. This study demonstrated that Northwest Atlantic gray seals are both permissive to and tolerant of diverse IAV, possibly representing an endemically infected wild reservoir population. PMID- 27485497 TI - A combination of the QuantiFERON-TB Gold In-Tube assay and the detection of adenosine deaminase improves the diagnosis of tuberculous pleural effusion. AB - The differential diagnosis of tuberculous pleural effusion (TPE) and malignant pleural effusion (MPE) remains difficult despite the availability of numerous diagnostic tools. The current study aimed to evaluate the performance of the whole blood QuantiFERON-TB Gold In-Tube (QFT-GIT) assay and conventional laboratory biomarkers in differential diagnosis of TPE and MPE in high tuberculosis prevalence areas. A total of 117 patients with pleural effusions were recruited, including 91 with TPE and 26 with MPE. All of the patients were tested with QFT-GIT, and the conventional biomarkers in both blood and pleural effusion were detected. The level of antigen-stimulated QFT-GIT in the whole blood of TPE patients was significantly higher than that of MPE (2.89 vs 0.33 IU/mL, P<0.0001). The sensitivity and specificity of QFT-GIT for the diagnosis of TPE were 93.0% and 60.0%, respectively. Among the biomarkers in blood and pleural effusion, pleural adenosine deaminase (ADA) was the most prominent biomarker, with a cutoff value of 15.35 IU/L. The sensitivity and specificity for the diagnosis of TPE were 93.4% and 96.2%, respectively. The diagnostic classification tree from the combination of these two biomarkers was 97.8% sensitive and 92.3% specific. Ultimately, the combination of whole blood QFT-GIT with pleural ADA improved both the specificity and positive predictive value to 100%. Thus, QFT-GIT is not superior to pleural ADA in the differential diagnosis of TPE and MPE. Combined whole blood QFT-GIT and pleural ADA detection can improve the diagnosis of TPE. PMID- 27485499 TI - Testing for carryover effects after cessation of treatments: a design approach. AB - BACKGROUND: Recently, trials addressing noisy measurements with diagnosis occurring by exceeding thresholds (such as diabetes and hypertension) have been published which attempt to measure carryover - the impact that treatment has on an outcome after cessation. The design of these trials has been criticised and simulations have been conducted which suggest that the parallel-designs used are not adequate to test this hypothesis; two solutions are that either a differing parallel-design or a cross-over design could allow for diagnosis of carryover. METHODS: We undertook a systematic simulation study to determine the ability of a cross-over or a parallel-group trial design to detect carryover effects on incident hypertension in a population with prehypertension. We simulated blood pressure and focused on varying criteria to diagnose systolic hypertension. RESULTS: Using the difference in cumulative incidence hypertension to analyse parallel-group or cross-over trials resulted in none of the designs having acceptable Type I error rate. Under the null hypothesis of no carryover the difference is well above the nominal 5 % error rate. CONCLUSIONS: When a treatment is effective during the intervention period, reliable testing for a carryover effect is difficult. Neither parallel-group nor cross-over designs using the difference in cumulative incidence appear to be a feasible approach. Future trials should ensure their design and analysis is validated by simulation. PMID- 27485498 TI - flrA, flrB and flrC regulate adhesion by controlling the expression of critical virulence genes in Vibrio alginolyticus. AB - Adhesion is an important virulence trait of Vibrio alginolyticus. Bacterial adhesion is influenced by environmental conditions; however, the molecular mechanism underlying this effect remains unknown. The expression levels of flrA, flrB and flrC were significantly downregulated in adhesion-deficient V. alginolyticus strains cultured under Cu(2+), Pb(2+), Hg(2+) and low-pH stresses. Silencing these genes led to deficiencies in adhesion, motility, flagellar assembly, biofilm formation and exopolysaccharide (EPS) production. The expression levels of fliA, flgH, fliS, fliD, cheR, cheV and V12G01_22158 (Gene ID) were significantly downregulated in all of the RNAi groups, whereas the expression levels of toxT, ctxB, acfA, hlyA and tlh were upregulated in flrA- and flrC-silenced groups. These genes play a key role in the virulence mechanisms of most pathogenic Vibrio species. Furthermore, the expression of flrA, flrB and flrC was significantly influenced by temperature, salinity, starvation and pH. These results indicate that (1) flrA, flrB and flrC are important for V. alginolyticus adhesion; (2) flrA, flrB and flrC significantly influence bacterial adhesion, motility, biofilm formation and EPS production by controlling expression of key genes involved in those phenotypes; and (3) flrA, flrB and flrC regulate adhesion in the natural environment with different temperatures, pH levels, salinities and starvation time. PMID- 27485500 TI - Congenital primary adrenal insufficiency and selective aldosterone defects presenting as salt-wasting in infancy: a single center 10-year experience. AB - BACKGROUND: Salt-wasting represents a relatively common cause of emergency admission in infants and may result in life-threatening complications. Neonatal kidneys show low glomerular filtration rate and immaturity of the distal nephron leading to reduced ability to concentrate urine. METHODS: A retrospective chart review was conducted for infants hospitalized in a single Institution from 1(st) January 2006 to 31(st) December 2015. The selection criterion was represented by the referral to the Endocrinology Unit for hyponatremia (serum sodium <130 mEq/L) of suspected endocrine origin at admission. RESULTS: Fifty-one infants were identified. In nine infants (17.6 %) hyponatremia was related to unrecognized chronic gastrointestinal or renal salt losses or reduced sodium intake. In 10 infants (19.6 %) hyponatremia was related to central nervous system diseases. In 19 patients (37.3 %) the final diagnosis was congenital adrenal hyperplasia (CAH). CAH was related to 21-hydroxylase deficiency in 18 patients, and to 3beta Hydroxysteroid dehydrogenase (3betaHSD) deficiency in one patient. Thirteen patients (25.5 %) were affected by different non-CAH salt-wasting forms of adrenal origin. Four familial cases of X-linked adrenal hypoplasia congenita due to NROB1 gene mutation were identified. Two unrelated girls showed aldosterone synthase deficiency due to mutation of the CYP11B2 gene. Two unrelated infants were affected by familial glucocorticoid deficiency due to MC2R gene mutations. One girl showed pseudohypoaldosteronism related to mutations of the SCNN1G gene encoding for the epithelial sodium channel. Transient pseudohypoaldosteronism was identified in two patients with renal malformations. In two infants the genetic aetiology was not identified. CONCLUSIONS: Emergency management of infants presenting with salt wasting requires correction of water losses and treatment of electrolyte imbalances. Nevertheless, the differential diagnosis may be difficult in emergency settings, and sometimes hospitalized infants presenting with salt wasting are immediately started on steroid therapy to avoid life-threatening complications, before the correct diagnosis is reached. Physicians involved in the management of infants with salt-wasting of suspected hormonal origin should remember that, whenever practicable, a blood sample for the essential hormonal investigations should be collected before starting steroid therapy, to guide the subsequent diagnostic procedures and in particular to address the analysis of candidate genes. PMID- 27485501 TI - Synthesis and characterization of PEGylated bolaamphiphiles with enhanced retention in liposomes. AB - Long-circulating liposomes are typically prepared with poly(ethylene glycol)- (PEG-) modified lipids, where the lipid portion is inserted in the lipid bilayers as an anchor and the hydrophilic PEG coats the surface to prevent liposome aggregation and rapid clearance in vivo. However, these steric protection effects are compromised upon systemic administration due to low retention of PEGylated lipids within liposome membranes upon dilution. Hence, a series of PEGylated bolaamphiphiles (PEG-bolas) were for the first time developed to increase retention in the lipid bilayer, presumably leading to enhanced integrity of the PEG protective layer upon dilution. We hypothesized that PEG-bolas with a sufficiently long hydrophobic domain and rigid central group could predominantly adopt a membrane-spanning configuration, taking full advantage of steric protection offered by PEG and enhanced retention in liposomes enabled by the bola geometry. In this paper, liposomes stabilized by PEG-bolas comprised of a biphenyl core and twelve-carbon alkyl chain not only exhibited similar storage and biological stability compared to conventional PEGylated lipid stabilized liposomes, but also significantly improved retention upon dilution. Our findings facilitate new designs of liposome-stabilizing agents and can be applied to improve the delivery efficiency of liposomal delivery vehicles in vivo. PMID- 27485502 TI - Carboxymethylated lignins with low surface tension toward low viscosity and highly stable emulsions of crude bitumen and refined oils. AB - Kraft and organosolv lignins were subjected to carboxymethylation to produce fractions that were soluble in water, displayed a minimum surface tension as low as 34mN/m (25 degrees C) and a critical aggregation concentration of ~1.5wt%. The carboxymethylated lignins (CML), which were characterized in terms of their degree of substitution ((31)P NMR), elemental composition, and molecular weight (GPC), were found suitable in the formulation of emulsions with bitumens of ultra high viscosity, such as those from the Canadian oil sands. Remarkably, the interfacial features of the CML enabled fuel emulsions that were synthesized in a very broad range of internal phase content (30-70%). Cryo-replica transmission electron microscopy, which was used here the first time to assess the morphology of the lignin-based emulsions, revealed the droplets of the emulsion stabilized with the modified lignin. The observed drop size (diameters<2MUm) was confirmed by light scattering, which revealed a normal size distribution. Such characteristics led to stable emulsified systems that are amenable for a wide range of applications. Emulsification with CML afforded bitumen emulsions with very high colloidal stability (no change was noted for over one month) and with a strong shear thinning behavior. Both features indicate excellent prospects for storage, transport and spraying, which are relevant in operations for power generation, which also take advantage of the high heating value of the emulsion components. The ability of CML to stabilize emulsions and to contribute in their combustion was tested with light fuels (kerosene, diesel, and jet fuel) after formulation of high internal phase systems (70% oil) that enabled operation of a fuel engine. A significant finding is that under certain conditions and compared to the respective pure fuel, combustion of the O/W emulsions stabilized by CML presented lower NOx and CO emissions and maintained a relatively high combustion efficiency. The results highlight the possibilities in high volume application for lignin biomacromolecules. PMID- 27485503 TI - High-performance glucose biosensor based on chitosan-glucose oxidase immobilized polypyrrole/Nafion/functionalized multi-walled carbon nanotubes bio-nanohybrid film. AB - A highly electroactive bio-nanohybrid film of polypyrrole (PPy)-Nafion (Nf) functionalized multi-walled carbon nanotubes (fMWCNTs) nanocomposite was prepared on the glassy carbon electrode (GCE) by a facile one-step electrochemical polymerization technique followed by chitosan-glucose oxidase (CH-GOx) immobilization on its surface to achieve a high-performance glucose biosensor. The as-fabricated nanohybrid composite provides high surface area for GOx immobilization and thus enhances the enzyme-loading efficiency. The structural characterization revealed that the PPy-Nf-fMWCNTs nanocomposite films were uniformly formed on GCE and after GOx immobilization, the surface porosities of the film were decreased due to enzyme encapsulation inside the bio-nanohybrid composite materials. The electrochemical behavior of the fabricated biosensor was investigated by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and amperometry measurements. The results indicated an excellent catalytic property of bio-nanohybrid film for glucose detection with improved sensitivity of 2860.3MUAmM(-1)cm(-2), the linear range up to 4.7mM (R(2)=0.9992), and a low detection limit of 5MUM under a signal/noise (S/N) ratio of 3. Furthermore, the resulting biosensor presented reliable selectivity, better long-term stability, good repeatability, reproducibility, and acceptable measurement of glucose concentration in real serum samples. Thus, this fabricated biosensor provides an efficient and highly sensitive platform for glucose sensing and can open up new avenues for clinical applications. PMID- 27485504 TI - Effect of Cavitation Bubble Collapse on the Modification of Solids: Crystallization Aspects. AB - This review examines the concepts how cavitation bubble collapse affects crystalline structure, the crystallization of newly formed structures, and recrystallization. Although this subject can be discussed in a broad sense across the area of metastable crystallization, our main focus is discussing specific examples of the inorganic solids: metal, intermetallics, metal oxides, and silicon. First, the temperature up to which ultrasound heats solids is discussed. Cavitation-induced changes in the crystal size of intermetallic phases in binary AlNi (50 wt % of Ni) alloys allow an estimation of local temperatures on surfaces and in bulk material. The interplay between atomic solid-state diffusion and recrystallization during bubble collapses in heterogeneous systems is revealed. Furthermore, cavitation triggered red/ox processes at solid/liquid interfaces and their influence on recrystallization are discussed for copper aluminum nanocomposites, zinc, titanium, magnesium-based materials, and silicon. Cavitation-driven highly nonequilibrium conditions can affect the thermodynamics and kinetics of mesoscopic phase formation in heterogeneous systems and in many cases boost the macroscopic performance of composite materials, notably in catalytic alloy and photocatalytic semiconductor oxide properties, corrosion resistance, nanostructured surface biocompatibility, and optical properties. PMID- 27485505 TI - Ultrasound imaging of splenomegaly as a proxy to monitor colon tumor development in Apc(min716/+) mice. AB - Animal models of colon cancer are widely used to understand the molecular mechanisms and pathogenesis of the disease. These animal models require a substantial investment of time and traditionally necessitate the killing of the animal to measure the tumor progression. Several in vivo imaging techniques are being used in both human clinics and preclinical studies, albeit at high cost and requiring particular expertise. Here, we report that the progression of splenomegaly coincides with and positively correlates to colon tumor development in Apc(min716/+) mice expressing a mutant gene encoding an adenomatous polyposis coli protein truncated at amino acid 716. Ultrasound image-based spleen size measurement precisely mirrors splenomegaly development in vivo in the tumor-laden Apc(min716/+) mice. Moreover, the spleen dimensions extracted from the ultrasound sonograms are positively correlated with normalized spleen weight and the number and area of colon tumors. Hence, we propose measuring the spleen size in vivo by ultrasound imaging as a novel approach to estimate splenomegaly development and to indirectly monitor colon tumor development in Apc(min716/+) mice. The widespread use of ultrasound machines in the laboratory setting, coupled with the fact that it is a noninvasive method, make it a straightforward and useful tool for monitoring the experimental progress of colon cancer in mice and determining end points without killing animals strictly for diagnostics purposes. PMID- 27485506 TI - Comparison of Two Measures of Working Memory Impairments in 220 Adolescents and Adults With ADHD. AB - OBJECTIVE: This study tests the hypotheses that (a) adolescents and adults with ADHD score lower on two normed measures of verbal working memory, relative to their overall verbal abilities, than the general population and (b) a specific story memory test is a more sensitive and relevant measure of working memory impairment than a numerically based test. METHOD: Scores on normed story memory and numerical memory tests of 220 adolescents and adults with ADHD were corrected for the individual's verbal abilities and compared with each other and national norms. RESULTS: Participants with ADHD scored significantly below their verbal ability measure on both verbal and numerically based memory tests in comparison with national norms. Scores on verbal memory test were lower than scores for numerically based memory tests. CONCLUSION: This story memory test is a more sensitive measure of working memory impairments in adolescents and adults with ADHD than measures based on recall of numerical data. PMID- 27485507 TI - Profile of tuberculosis and its response to anti-TB drugs among tuberculosis patients treated under the TB control programme at Felege-Hiwot Referral Hospital, Ethiopia. AB - BACKGROUND: Tuberculosis (TB) is a global concern for both developing and developed countries. Currently it becomes more complex due to increasing levels of drug resistance and HIV co-infection. Delayed diagnosis and high case load are major factors contributing to continued transmission and failure to the treatment outcome. The study was conducted to determine the profile and treatment outcomes of TB patients at Felege-Hiwot Referral Hospital. METHODS: We analyzed the records of 1761 TB patients registered for treatment in Felege Hiwot Referral Hospital from July 2010 to June 2015. Data on patients' socio-demographic characteristics, type of TB, HIV status and treatment outcome were analysed. Descriptive statistics and binary logistic regression models were used to present data. The odds ratio and the 95 % confidence intervals were calculated. A p-value of < 0.05 was considered statistical significant. RESULTS: The proportion of smear positive, smear-negative and extra-pulmonary TB were 205 (11.6 %), 548 (31.1 %) and 1008 (57.2 %), respectively. The overall treatment success rate accounts 542(80.8 %) with unsuccessful treatment of 129(19.2 %). The treatment outcome varied by the years from 68.9 to 97.4 %. Among tuberculosis patients, 459(26.1 %) of them were HIV positive. Being HIV positive (AOR = 4.29, 95 % CI, 2.20-8.37 P = 0.001), retreatment (AOR = 5.32, 95 % CI, 1.92-14.3, P = 0.001), rural residency (AOR = 18.0, 95 % CI, 9.06-37.82, P = 0.001) and the age group of 15-24 years (AOR = 2.91, 95%CI, 1.00-8.45, P = 0.04) showed statistical significant association for poor treatment outcome. CONCLUSIONS: In the studied region, the overall treatment success rate was still below the WHO target of success rate, 85 %. However, the trend of treatment success rate showed a promising increment. Patients at high risk of unsuccessful treatment outcome should be identified early and given additional follow-up, medical intervention and social support. PMID- 27485508 TI - Pipeline for amplifying and analyzing amplicons of the V1-V3 region of the 16S rRNA gene. AB - BACKGROUND: Profiling of 16S rRNA gene sequences is an important tool for testing hypotheses in complex microbial communities, and analysis methods must be updated and validated as sequencing technologies advance. In host-associated bacterial communities, the V1-V3 region of the 16S rRNA gene is a valuable region to profile because it provides a useful level of taxonomic resolution; however, use of Illumina MiSeq data for experiments targeting this region needs validation. RESULTS: Using a MiSeq machine and the version 3 (300 * 2) chemistry, we sequenced the V1-V3 region of the 16S rRNA gene within a mock community. Nineteen bacteria and one archaeon comprised the mock community, and 12 replicate amplifications of the community were performed and sequenced. Sequencing the large fragment (490 bp) that encompasses V1-V3 yielded a higher error rate (3.6 %) than has been reported when using smaller fragment sizes. This higher error rate was due to a large number of sequences that occurred only one or two times among all mock community samples. Removing sequences that occurred one time among all samples (singletons) reduced the error rate to 1.4 %. Diversity estimates of the mock community containing all sequences were inflated, whereas estimates following singleton removal more closely reflected the actual mock community membership. A higher percentage of the sequences could be taxonomically assigned after singleton and doubleton sequences were removed, and the assignments reflected the membership of the input DNA. CONCLUSIONS: Sequencing the V1-V3 region of the 16S rRNA gene on the MiSeq platform may require additional sequence curation in silico, and improved error rates and diversity estimates show that removing low-frequency sequences is reasonable. When datasets have a high number of singletons, these singletons can be removed from the analysis without losing statistical power while reducing error and improving microbiota assessment. PMID- 27485509 TI - Intervention to Improve Quality of life for African-AmericaN lupus patients (IQAN): study protocol for a randomized controlled trial of a unique a la carte intervention approach to self-management of lupus in African Americans. AB - BACKGROUND: Systemic Lupus Erythematosus (lupus) is a chronic autoimmune disease that can impact any organ system and result in life-threatening complications. African-Americans are at increased risk for morbidity and mortality from lupus. Self-management programs have demonstrated significant improvements in health distress, self-reported global health, and activity limitation among people with lupus. Despite benefits, arthritis self-management education has reached only a limited number of people. Self-selection of program could improve such trends. The aim of the current study is to test a novel intervention to improve quality of life, decrease indicators of depression, and reduce perceived and biological indicators of stress in African-American lupus patients in South Carolina. METHODS/DESIGN: In a three armed randomized, wait list controlled trial, we will evaluate the effectiveness of a patient-centered 'a-la-carte' approach that offers subjects a variety of modes of interaction from which they can choose as many or few as they wish, compared to a 'set menu' approach and usual care. This unique 'a-la-carte' self-management program will be offered to 50 African American lupus patients participating in a longitudinal observational web-based SLE Database at the Medical University of South Carolina. Each individualized intervention plan will include 1-4 options, including a mail-delivered arthritis kit, addition and access to an online message board, participation in a support group, and enrollment in a local self-management program. A 'set menu' control group of 50 lupus patients will be offered a standardized chronic disease self management program only, and a control group of 50 lupus patients will receive usual care. Outcomes will include changes in (a) health behaviors, (b) health status, (c) health care utilization, and (d) biological markers (urinary catecholamines). DISCUSSION: Such a culturally sensitive educational intervention which includes self-selection of program components has the potential to improve disparate trends in quality of life, disease activity, depression, and stress among African-American lupus patients, as better outcomes have been documented when participants are able to choose/dictate the content and/or pace of the respective treatment/intervention program. Since there is currently no "gold standard" self-management program specifically for lupus, this project may have a considerable impact on future research and policy decisions. TRIAL REGISTRATION: NCT01837875 ; April 18, 2013. PMID- 27485510 TI - Genomic mechanisms for cold tolerance and production of exopolysaccharides in the Arctic cyanobacterium Phormidesmis priestleyi BC1401. AB - BACKGROUND: Cyanobacteria are major primary producers in extreme cold ecosystems. Many lineages of cyanobacteria thrive in these harsh environments, but it is not fully understood how they survive in these conditions and whether they have evolved specific mechanisms of cold adaptation. Phormidesmis priestleyi is a cyanobacterium found throughout the cold biosphere (Arctic, Antarctic and alpine habitats). Genome sequencing of P. priestleyi BC1401, an isolate from a cryoconite hole on the Greenland Ice Sheet, has allowed for the examination of genes involved in cold shock response and production of extracellular polymeric substances (EPS). EPSs likely enable cyanobacteria to buffer the effects of extreme cold and by identifying mechanisms for EPS production in P. priestleyi BC1401 this study lays the way for investigating transcription and regulation of EPS production in an ecologically important cold tolerant cyanobacterium. RESULTS: We sequenced the draft genome of P. priestleyi BC1401 and implemented a new de Bruijn graph visualisation approach combined with BLAST analysis to separate cyanobacterial contigs from a simple metagenome generated from non axenic cultures. Comparison of known cold adaptation genes in P. priestleyi BC1401 with three relatives from other environments revealed no clear differences between lineages. Genes involved in EPS biosynthesis were identified from the Wzy and ABC-dependent pathways. The numbers of genes involved in cell wall and membrane biogenesis in P. priestleyi BC1401 were typical relative to the genome size. A gene cluster implicated in biofilm formation was found homologous to the Wps system, although the intracellular signalling pathways by which this could be regulated remain unclear. CONCLUSIONS: Results show that the genomic characteristics and complement of known cold shock genes in P. priestleyi BC1401 are comparable to related lineages from a wide variety of habitats, although as yet uncharacterised cold shock genes in this organism may still exist. EPS production by P. priestleyi BC1401 likely contributes to its ability to survive efficiently in cold environments, yet this mechanism is widely distributed throughout the cyanobacterial phylum. Discovering how these EPS related mechanisms are regulated may help explain why P. priestleyi BC1401 is so successful in cold environments where related lineages are not. PMID- 27485511 TI - Gingival hyperplasia as first sign of recurrence of granulomatosis with polyangiitis (Wegener's granulomatosis): case report and review of the literature. AB - BACKGROUND: Granulomatosis with polyangiitis (GPA), formerly referred to as Wegener's granulomatosis, is a rare systemic disease of unknown etiology which can affect all areas of the body, including the oral cavity. The typical oral manifestations occur as nonspecific erosive/ulcerative lesions of the oral cavity or appear with hyperplastic gingivitis, a so called "strawberry gingivitis". CASE PRESENTATION: We report here about an extremely rare case with hyperplastic gingivitis as the first sign of recurrence of GPA in the absence of oral manifestations in the primary disease. A 72 year-old female was referred to our Department of Cranio-Maxillofacial Surgery with hyperplastic gingivitis. The patient was diagnosed with GPA already eight years before. We referred the patient to our Clinic of Internal Medicine where she was successfully treated with rituximab. At the follow-up visit, the patient showed complete remission of the hyperplastic gingiva. CONCLUSION: The often overlooked oral manifestation may be interpreted as the first evidence of resurgent GPA in general and therefore could be pathognostic for the disease. This case affirms the need of health professionals to be acquainted with orofacial manifestations of rare diseases such as GPA. As a consequence, dentists will be able to assist in diagnosing GPA more easily leading to a better prognosis for patients suffering from this disease. PMID- 27485512 TI - Making Quality Health Websites a National Public Health Priority: Toward Quality Standards. AB - BACKGROUND: Most US adults have limited health literacy skills. They struggle to understand complex health information and services and to make informed health decisions. The Internet has quickly become one of the most popular places for people to search for information about their health, thereby making access to quality information on the Web a priority. However, there are no standardized criteria for evaluating Web-based health information. Every 10 years, the US Department of Health and Human Services' Office of Disease Prevention and Health Promotion (ODPHP) develops a set of measurable objectives for improving the health of the nation over the coming decade, known as Healthy People. There are two objectives in Healthy People 2020 related to website quality. The first is objective Health Communication and Health Information Technology (HC/HIT) 8.1: increase the proportion of health-related websites that meet 3 or more evaluation criteria for disclosing information that can be used to assess information reliability. The second is objective HC/HIT-8.2: increase the proportion of health-related websites that follow established usability principles. OBJECTIVE: The ODPHP conducted a nationwide assessment of the quality of Web-based health information using the Healthy People 2020 objectives. The ODPHP aimed to establish (1) a standardized approach to defining and measuring the quality of health websites; (2) benchmarks for measurement; (3) baseline data points to capture the current status of website quality; and (4) targets to drive improvement. METHODS: The ODPHP developed the National Quality Health Website Survey instrument to assess the quality of health-related websites. The ODPHP used this survey to review 100 top-ranked health-related websites in order to set baseline data points for these two objectives. The ODPHP then set targets to drive improvement by 2020. RESULTS: This study reviewed 100 health-related websites. For objective HC/HIT-8.1, a total of 58 out of 100 (58.0%) websites met 3 or more out of 6 reliability criteria. For objective HC/HIT-8.2, a total of 42 out of 100 (42.0%) websites followed 10 or more out of 19 established usability principles. On the basis of these baseline data points, ODPHP set targets for the year 2020 that meet the minimal statistical significance-increasing objective HC/HIT-8.1 data point to 70.5% and objective HC/HIT-8.2 data point to 55.7%. CONCLUSIONS: This research is a critical first step in evaluating the quality of Web-based health information. The criteria proposed by ODPHP provide methods to assess website quality for professionals designing, developing, and managing health-related websites. The criteria, baseline data, and targets are valuable tools for driving quality improvement. PMID- 27485513 TI - Prevalence of pathogenic free-living amoeba and other protozoa in natural and communal piped tap water from Queen Elizabeth protected area, Uganda. AB - BACKGROUND: Pathogenic water dwelling protozoa such as Acanthamoeba spp., Hartmannella spp., Naegleria spp., Cryptosporidium spp. and Giardia spp. are often responsible for devastating illnesses especially in children and immunocompromised individuals, yet their presence and prevalence in certain environment in sub-Saharan Africa is still unknown to most researchers, public health officials and medical practitioners. The objective of this study was to establish the presence and prevalence of pathogenic free-living amoeba (FLA), Cryptosporidium and Giardia in Queen Elizabeth Protected Area (QEPA). METHODS: Samples were collected from communal taps and natural water sites in QEPA. Physical water parameters were measured in situ. The samples were processed to detect the presence of FLA trophozoites by xenic cultivation, Cryptosporidium oocysts by Ziehl-Neelsen stain and Giardia cysts by Zinc Sulphate floatation technique. Parasites were observed microscopically, identified, counted and recorded. For FLA, genomic DNA was extracted for amplification and sequencing. RESULTS: Both natural and tap water sources were contaminated with FLA, Cryptosporidium spp. and Giardia spp. All protozoan parasites were more abundant in the colder rainy season except for Harmannella spp. and Naegleria spp. which occurred more in the warmer months. The prevalence of all parasites was higher in tap water than in natural water samples. There was a strong negative correlation between the presence of Acanthamoeba spp., Hartmannella spp., Cryptosporidium spp. and Giardia spp. with Dissolved Oxygen (DO) (P < 0.05). The presence of Cryptosporidium spp. showed a significant positive correlation (P < 0.05) with conductivity, pH and Total Dissolved Solids (TDS); whereas the presence of Giardia spp. had only a strong positive correlation with TDS. Molecular genotyping of FLA produced 7 Acanthamoeba, 5 Echinamoeba, 2 Hartmannella, 1 Bodomorpha, 1 Nuclearia and 1 Cercomonas partial sequences. CONCLUSIONS: All water collection sites were found to be contaminated with pathogenic protozoa that could possibly be the cause of a number of silent morbidities and mortalities among rural households in QEPA. This implies that water used by communities in QEPA is of poor quality and predisposes them to a variety of protozoan infections including the FLA whose public health importance was never reported, thus necessitating adoption of proper water safety measures. PMID- 27485514 TI - A rational two-step approach to KRAS mutation testing in colorectal cancer using high resolution melting analysis and pyrosequencing. AB - BACKGROUND: KRAS mutation testing is mandatory in the management of metastatic colorectal cancer prior to treatment with anti-EGFR antibodies as patients whose tumors express mutant KRAS do not benefit from these agents. Although the U.S. Food and Drug Administration has recently approved two in-vitro diagnostics kits for determination of KRAS status, there is generally no consensus on the preferred method and new tests are continuously being developed. Most of these techniques focus on the hotspot mutations at codons 12 and 13 of the KRAS gene. METHODS: We describe a two-step approach to KRAS codon 12/13 mutation testing involving high resolution melting analysis (HRM) followed by pyrosequencing using the Therascreen KRAS Pyro kit (Qiagen) of only those samples that are not clearly identified as KRAS wildtype or mutant by HRM. First, we determined KRAS status in a panel of 61 colorectal cancer samples using both methods to compare technical performance and concordance of results. Subsequently, we evaluated practicability and costs of our concept in an independent set of 120 colorectal cancer samples in a routine diagnostic setting. RESULTS: HRM and pyrosequencing appeared to be equally sensitive, allowing for clear detection of mutant alleles at a mutant allele frequency >=12.5 %. Pyrosequencing yielded more exploitable results due to lower input requirements and a lower rate of analysis failures. KRAS codon 12/13 status was called concordantly for 98.2 % (56/57) of all samples that could be successfully analysed by both methods and 100 % (19/19) of samples that were identified mutant by HRM. Reviewing the actual effort and expenses for KRAS mutation testing in our laboratory revealed, that the selective use of pyrosequencing for only those samples that could not be analysed by HRM increased the fraction of valid results from 87.5 % for HRM alone to 99.2 % (119/120) while allowing for a net reduction of operational costs of >75 % compared to pyrosequencing alone. CONCLUSIONS: Combination of HRM and pyrosequencing in a two step diagnostic procedure constitutes a reliable and economic analysis platform for KRAS mutation testing in colorectal cancer in a clinical setting. PMID- 27485515 TI - Tumor Growth Suppression Induced by Biomimetic Silk Fibroin Hydrogels. AB - Protein-based hydrogels with distinct conformations which enable encapsulation or differentiation of cells are of great interest in 3D cancer research models. Conformational changes may cause macroscopic shifts in the hydrogels, allowing for its use as biosensors and drug carriers. In depth knowledge on how 3D conformational changes in proteins may affect cell fate and tumor formation is required. Thus, this study reports an enzymatically crosslinked silk fibroin (SF) hydrogel system that can undergo intrinsic conformation changes from random coil to beta-sheet conformation. In random coil status, the SF hydrogels are transparent, elastic, and present ionic strength and pH stimuli-responses. The random coil hydrogels become beta-sheet conformation after 10 days in vitro incubation and 14 days in vivo subcutaneous implantation in rat. When encapsulated with ATDC-5 cells, the random coil SF hydrogel promotes cell survival up to 7 days, whereas the subsequent beta-sheet transition induces cell apoptosis in vitro. HeLa cells are further incorporated in SF hydrogels and the constructs are investigated in vitro and in an in vivo chick chorioallantoic membrane model for tumor formation. In vivo, Angiogenesis and tumor formation are suppressed in SF hydrogels. Therefore, these hydrogels provide new insights for cancer research and uses of biomaterials. PMID- 27485516 TI - Transcriptomes of a xylose-utilizing industrial flocculating Saccharomyces cerevisiae strain cultured in media containing different sugar sources. AB - Lignocellulosic hydrolysates used for bioethanol production contain a mixture of sugars, with xylose being the second most abundant after glucose. Since xylose is not a natural substrate for Saccharomyces cerevisiae, recombinant S. cerevisiae strongly prefers glucose over xylose, and the fermentation rate and ethanol yield with xylose are both lower than those with glucose. To determine the molecular basis for glucose and xylose fermentation, we used microarrays to investigate the transcriptional difference of a xylose-utilizing industrial strain cultured in both single sugar media and a mixed sugar medium of glucose and xylose. The transcriptomes were nearly identical between glucose metabolizing cells in the glucose alone medium and those in the glucose fermentation phase in the mixed sugar medium. Whereas the transcriptomes highly differed between the xylose metabolizing cells in the xylose alone medium and those in the xylose fermentation phase in the mixed sugar medium, and the differences mainly involved sulfur metabolism. When the transcriptional profiles were compared between glucose fermentation state and xylose fermentation state, we found the expression patterns of hexose transporters and glucose signaling pathway differed in response to different sugar sources, and the expression levels of the genes involved in gluconeogenesis, the glyoxylate and tricarboxylic acid cycles and respiration increased with xylose, indicating that the xylose-metabolizing cells had high requirements for maintenance energy and lacked the carbon catabolite repression capability. The effect of carbon catabolite repression by glucose lasted after glucose depletion for specific genes to different extents. PMID- 27485517 TI - Kinetic studies on recombinant UDP-glucose: sterol 3-O-beta-glycosyltransferase from Micromonospora rhodorangea and its bioconversion potential. AB - Kinetics of a recombinant uridine diphosphate-glucose: sterol glycosyltransferase from Micromonospora rhodorangea ATCC 27932 (MrSGT) were studied using a number of sterols (including phytosterols) as glycosyl acceptors. The lowest K m value and the highest catalytical efficiency (k cat/K m) were found when beta-sitosterol was the glycosyl acceptor in the enzymatic reaction. In contrast to the enzyme's flexibility toward the glycosyl acceptor substrate, this recombinant enzyme was highly specific to uridine diphosphate (UDP)-glucose as the donor substrate. Besides, the UDP-glucose-dependent MrSGT was able to attach one glucose moiety specifically onto the C-3 hydroxyl group of other phytosterols such as fucosterol and gramisterol, yielding stereo-specific fucosterol-3-O-beta-D-glucoside and gramisterol-3-O-beta-D-glucoside, respectively. Based on kinetic data obtained from the enzyme's reactions using five different sterol substrates, the significance of the alkene (or ethylidene) side chains on the C-24 position in the sterol scaffolds was described and the possible relationship between the substrate structure and enzyme activity was discussed. This is the first report on the enzymatic bioconversion of the above two phytosteryl 3-O-beta-glucosides, as well as on the discovery of a stereospecific bacterial SGT which can attach a glucose moiety in beta-conformation at the C-3 hydroxyl group of diverse sterols, thus highlighting the catalytic potential of this promiscuous glycosyltransferase to expand the structural diversity of steryl glucosides. PMID- 27485518 TI - Process parameters and changes in the microbial community patterns during the first 240 days of an agricultural energy crop digester. AB - Commercial biogas production takes place by complex microbial communities enclosed in controlled "technical ecosystems". Once established, the communities tend to be resilient towards disturbances, although the relative abundance of their members may vary. The start-up phase, during which the community establishes itself, is therefore decisive for the later performance of the reactor. In this study, we followed the first 240 days of a standard agricultural energy crop digester consisting of a 400 m(3) plug flow fermenter and a 1000 m(3) agitated post digester, operated at 40-45 degrees C. The feed consisted of corn and later grass silage augmented by ground wheat. Changes in both the eubacterial and methanogenic archaeal communities were followed by automated ribosomal intergenic spacer analysis (ARISA). In addition the copy number of the methyl coenzyme reductase A (mcrA)-genes found in all known methanogens were followed by quantitative PCR, while selected samples from two phases-one early, one late-of the community structure development were subjected to high throughput sequencing. Biogas volume and composition (CH4, CO2, H2, H2S, O2), pH, ammonia-N, and volatile fatty acids (VFA), were measured as part of the routine process control. VFA/TIC values were calculated on this basis. Whereas the total gas production of the plant established itself at about 2500 m(3) biogas per day within the first months, the composition of the microbial communities showed distinct spatial and temporal differences over the investigated time period. Absolute values for DNA isolation procedures are difficult to certify, hence comparative results on community structures obtained using standardized ARISA with identical primers are of value. Moreover, ARISA patterns can be statistically analyzed to identify distinct subgroups and transitions between them as well as serial correlations. Thereby the microbial community and its structural development can be correlated with statistical relevance to changes in operational (feed) and process parameters (pH-value, biogas composition). In particular when augmented by deep sequencing data of judiciously chosen samples, this allows a hitherto unknown level of insight into the performance of technical biogas plants. PMID- 27485520 TI - Erratum. PMID- 27485521 TI - Influence of gamma radiation on the physical and sensory properties of two Brazilian rice cultivars. AB - BACKGROUND: Little has been reported about the effects of gamma radiation on the physical and sensory characteristics of rice. Samples were irradiated with 60 Co in doses 0, 1, 2 and 5 kGy, on a rate of 0.4 kGy h-1 . RESULTS: The evaluation of instrumental color showed that increasing doses promoted the yellowing (higher b* value) of the rice grains. Hardness was decreased and stickiness was increased in cooked rice with increasing doses. Sensory evaluation using quantitative descriptive analysis showed that increasing doses promoted higher occurrence of yellowish appearance, emergence of burnt aroma, and an increase of bitter and burnt taste. The sensory acceptance test by 9-point hedonic scale showed alteration of the samples irradiated with 5 kGy in all evaluated attributes (appearance, color, aroma, taste and texture). The lowest dose (1 kGy), however, had good acceptability by the panelists. CONCLUSION: Rice may be subjected to 1 kGy dose of gamma radiation without changes or with small changes in physical properties and with good overall acceptability. (c) 2016 Society of Chemical Industry. PMID- 27485519 TI - Physical activity and the risk of gestational diabetes mellitus: a systematic review and dose-response meta-analysis of epidemiological studies. AB - Physical activity has been inconsistently associated with risk of gestational diabetes mellitus in epidemiological studies, and questions remain about the strength and shape of the dose-response relationship between the two. We therefore conducted a systematic review and meta-analysis of cohort studies and randomized trials on physical activity and gestational diabetes mellitus. PubMed, Embase and Ovid databases were searched for cohort studies, and randomized controlled trials of physical activity and risk of gestational diabetes mellitus, up to August 5th 2015. Summary relative risks (RRs) were estimated using a random effects model. Twenty-five studies (26 publications) were included. For total physical activity the summary RR for high versus low activity was 0.62 (95 % CI 0.41-0.94, I2 = 0 %, n = 4) before pregnancy, and 0.66 (95 % CI 0.36-1.21, I2 = 0 %, n = 3) during pregnancy. For leisure-time physical activity the respective summary RRs for high versus low activity was 0.78 (95 % CI 0.61-1.00, I2 = 47 %, n = 8) before pregnancy, and it was 0.80 (95 % CI 0.64-1.00, I2 = 17 %, n = 17) during pregnancy. The summary RR for pre-pregnancy activity was 0.70 (95 % CI 0.49-1.01, I2 = 72.6 %, n = 3) per increment of 5 h/week and for activity during pregnancy was 0.98 (95 % CI 0.87-1.09, I2 = 0 %, n = 3) per 5 h/week. There was evidence of a nonlinear association between physical activity before pregnancy and the risk of gestational diabetes mellitus, pnonlinearity = 0.005, with a slightly steeper association at lower levels of activity although further reductions in risk were observed up to 10 h/week. There was also evidence of nonlinearity for physical activity in early pregnancy, pnonlinearity = 0.008, with no further reduction in risk above 8 h/week. There was some indication of inverse associations between walking (before and during pregnancy) and vigorous activity (before pregnancy) and the risk of gestational diabetes mellitus. This meta-analysis suggests that there is a significant inverse association between physical activity before pregnancy and in early pregnancy and the risk of gestational diabetes mellitus. Further studies are needed to clarify the association between specific types and intensities of activity and gestational diabetes mellitus. PMID- 27485522 TI - A generalized analytic solution to the win ratio to analyze a composite endpoint considering the clinical importance order among components. AB - A composite endpoint consists of multiple endpoints combined in one outcome. It is frequently used as the primary endpoint in randomized clinical trials. There are two main disadvantages associated with the use of composite endpoints: a) in conventional analyses, all components are treated equally important; and b) in time-to-event analyses, the first event considered may not be the most important component. Recently Pocock et al. (2012) introduced the win ratio method to address these disadvantages. This method has two alternative approaches: the matched pair approach and the unmatched pair approach. In the unmatched pair approach, the confidence interval is constructed based on bootstrap resampling, and the hypothesis testing is based on the non-parametric method by Finkelstein and Schoenfeld (1999). Luo et al. (2015) developed a close-form variance estimator of the win ratio for the unmatched pair approach, based on a composite endpoint with two components and a specific algorithm determining winners, losers and ties. We extend the unmatched pair approach to provide a generalized analytical solution to both hypothesis testing and confidence interval construction for the win ratio, based on its logarithmic asymptotic distribution. This asymptotic distribution is derived via U-statistics following Wei and Johnson (1985). We perform simulations assessing the confidence intervals constructed based on our approach versus those per the bootstrap resampling and per Luo et al. We have also applied our approach to a liver transplant Phase III study. This application and the simulation studies show that the win ratio can be a better statistical measure than the odds ratio when the importance order among components matters; and the method per our approach and that by Luo et al., although derived based on large sample theory, are not limited to a large sample, but are also good for relatively small sample sizes. Different from Pocock et al. and Luo et al., our approach is a generalized analytical method, which is valid for any algorithm determining winners, losers and ties. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27485523 TI - Ectopic Expression of DREB Transcription Factor, AtDREB1A, Confers Tolerance to Drought in Transgenic Salvia miltiorrhiza. AB - Drought decreases crop productivity more than any other type of environmental stress. Transcription factors (TFs) play crucial roles in regulating plant abiotic stress responses. The Arabidopsis thaliana gene DREB1A/CBF3, encoding a stress-inducible TF, was introduced into Salvia miltiorrhiza Ectopic expression of AtDREB1A resulted in increased drought tolerance, and transgenic lines had higher relative water content and Chl content, and exhibited an increased photosynthetic rate when subjected to drought stress. AtDREB1A transgenic plants generally displayed lower malondialdehyde (MDA), but higher superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) activities under drought stress. In particular, plants with ectopic AtDREB1A expression under the control of the stress-induced RD29A promoter exhibited more tolerance to drought compared with p35S::AtDREB1A transgenic plants, without growth inhibition or phenotypic aberrations. Differential gene expression profiling of wild-type and pRD29A::AtDREB1A transgenic plants following drought stress revealed that the expression levels of various genes associated with the stress response, photosynthesis, signaling, carbohydrate metabolism and protein protection were substantially higher in transgenic plants. In addition, the amount of salvianolic acids and tanshinones was significantly elevated in AtDREB1A transgenic S. miltiorrhiza roots, and most of the genes in the related biosynthetic pathways were up-regulated. Together, these results demonstrated that inducing the expression of a TF can effectively regulate multiple genes in the stress response pathways and significantly improve the resistance of plants to abiotic stresses. Our results also suggest that genetic manipulation of a TF can improve production of valuable secondary metabolites by regulating genes in associated pathways. PMID- 27485524 TI - Individual factors, neighborhood social context and asthma at age 5 years. AB - OBJECTIVE: Childhood asthma is a major public health problem and its development is multifactorial. We examined whether neighborhood cohesion and disorder were associated with caregiver-report of asthma at age 5 years. METHODS: This study is a secondary data analysis of the 2011-2012 United States National Survey of Children's Health. Data were available for 4680 children, age 5 years old born at term or preterm with birthweight >2500 g. Neighborhood disorder and cohesion were assessed based on caregivers' responses to validated questionnaires. Child asthma diagnosis was reported by the caregiver. Multivariable logistic regression was used to examine the relationship between these neighborhood factors and caregiver report of child asthma, while accounting for individual level covariates. RESULTS: Approximately two-thirds of the 4680 children were White and lived in households with income >400% of federal poverty line. Asthma was present in 399 (9%) children. Child female sex was associated with reduced risk of caregiver reported asthma while non-Hispanic Black race and having smokers in the household were independently associated with increased risk in multivariable models. In these models, neighborhood disorder was significantly associated with asthma (adjusted Odds Ratio [aOR] 1.70, 95% Confidence Interval [CI] 1.04-2.78), while neighborhood cohesion was not (aOR 0.93, 95% CI 0.51-1.68). CONCLUSION: Even after adjustment for several individual level factors, neighborhood disorder was associated with caregiver-report of asthma in this nationally representative sample of 5-year-old children. Further research is needed to better understand how risk factors at different levels of the socio-ecological framework may interact to affect childhood asthma development. PMID- 27485526 TI - Nanostructuration of PEDOT in Porous Coordination Polymers for Tunable Porosity and Conductivity. AB - A series of conductive porous composites were obtained by the polymerization of 3,4-ethylenedioxythiophene (EDOT) in the cavities of MIL-101(Cr). By controlling the amount of EDOT loaded into the host framework, it was possible to modulate the conductivity as well as the porosity of the composite. This approach yields materials with a reasonable electronic conductivity (1.1 * 10(-3) S.cm(-1)) while maintaining high porosity (SBET = 803 m(2)/g). This serves as a promising strategy for obtaining highly nanotextured conductive polymers with very high accessibility for small gas molecules, which are beneficial to the fabrication of a chemiresistive sensor for the detection of NO2. PMID- 27485525 TI - Assessing postural stability via the correlation patterns of vertical ground reaction force components. AB - BACKGROUND: Many methods have been proposed to assess the stability of human postural balance by using a force plate. While most of these approaches characterize postural stability by extracting features from the trajectory of the center of pressure (COP), this work develops stability measures derived from components of the ground reaction force (GRF). METHODS: In comparison with previous GRF-based approaches that extract stability features from the GRF resultant force, this study proposes three feature sets derived from the correlation patterns among the vertical GRF (VGRF) components. The first and second feature sets quantitatively assess the strength and changing speed of the correlation patterns, respectively. The third feature set is used to quantify the stabilizing effect of the GRF coordination patterns on the COP. RESULTS: In addition to experimentally demonstrating the reliability of the proposed features, the efficacy of the proposed features has also been tested by using them to classify two age groups (18-24 and 65-73 years) in quiet standing. The experimental results show that the proposed features are considerably more sensitive to aging than one of the most effective conventional COP features and two recently proposed COM features. CONCLUSIONS: By extracting information from the correlation patterns of the VGRF components, this study proposes three sets of features to assess human postural stability during quiet standing. As demonstrated by the experimental results, the proposed features are not only robust to inter-trial variability but also more accurate than the tested COP and COM features in classifying the older and younger age groups. An additional advantage of the proposed approach is that it reduces the force sensing requirement from 3D to 1D, substantially reducing the cost of the force plate measurement system. PMID- 27485527 TI - MicroRNA-610 is downregulated in glioma cells, and inhibits proliferation and motility by directly targeting MDM2. AB - The expression of microRNA (miR)-610 has previously been reported to be downregulated in gastric cancer and hepatocellular carcinoma. However, miR-610 has yet to be investigated in human glioma. In the present study, miR-610 expression was analyzed by reverse transcription-quantitative polymerase chain reaction. Post-transfection with miR-610 mimics and inhibitors, MTT assay, cell migration and invasion assays, western blot analysis and a luciferase assay were performed in glioma cell lines. The results demonstrated that miR-610 was downregulated in glioma tissues compared with their normal adjacent tissues and normal brain tissues (P<0.05). The reduced expression levels of miR-610 were associated with World Health Organization grade and the Karnofsky performance status of patients with glioma. Furthermore, the present study revealed that miR 610 inhibited cell growth, migration and invasion in glioma cells. To the best of our knowledge, the present study is the first to provide evidence suggesting that miR-610 directly targets MDM2 proto-oncogene E3 ubiquitin protein ligase to function as a tumor suppressor in glioma. These results indicate that miR-610 may be investigated as a target for therapeutic drugs designed to treat glioma. PMID- 27485528 TI - Operative Duration and Risk of Surgical Site Infection in Neurosurgery. AB - BACKGROUND: The association of surgical duration with the risk of surgical site infection (SSI) has not been quantified in neurosurgery. We investigated the association of operative duration in neurosurgical procedures with the incidence of SSI. METHODS: We performed a retrospective cohort study involving patients who underwent neurosurgical procedures from 2005 to 2012 and were registered in the American College of Surgeons National Quality Improvement Project registry. To control for confounding, we used multivariable regression models and propensity score conditioning. RESULTS: During the study period there were 94,744 patients who underwent a neurosurgical procedure and met the inclusion criteria. Of these patients, 4.1% developed a postoperative SSI within 30 days. Multivariable logistic regression showed an association between longer operative duration with higher incidence of SSI (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.16-1.20). Compared with procedures of moderate duration (third quintile, 40th 60th percentile), patients undergoing the longest procedures (>80th percentile) had higher odds (OR, 2.07; 95% CI, 1.86-2.31) of developing SSI. The shortest procedures (<20th percentile) were associated with decreased incidence of SSI (OR, 0.72; 95% CI, 0.61-0.83) compared with those of moderate duration. The same associations were present in propensity score adjusted models and models stratified by subgroups of cranial, spinal, peripheral nerve, and carotid procedures. CONCLUSIONS: In a cohort of patients from a national prospective surgical registry, longer operative duration was associated with increased incidence of SSI for neurosurgical procedures. These results can be used by neurosurgeons to inform operative management and to stratify patients with regard to SSI risk. PMID- 27485529 TI - Evaluation of the Predictive Value of Intraoperative Changes in Motor-Evoked Potentials of Caudal Cranial Nerves for the Postoperative Functional Outcome. AB - OBJECTIVE: The predictive value of changes in intraoperatively acquired motor evoked potentials (MEPs) of the lower cranial nerves (LCN) IX-X (glossopharyngeal vagus nerve) and CN XII (hypoglossal nerve) on operative outcomes was investigated. METHODS: MEPs of CN IX-X and CN XII were recorded intraoperatively in 63 patients undergoing surgery of the posterior cranial fossa. We correlated the changes of the MEPs with postoperative nerve function. RESULTS: For CN IX-X, we found a correlation between the amplitude of the MEP ratio and uvula deviation (P = 0.028) and the amplitude duration of the MEP and gag reflex function (P = 0.027). Patients with an MEP ratio of the glossopharyngeal-vagus amplitude <=1.47 MUV had a 3.4 times increased risk of developing a uvula deviation. Patients with a final MEP duration of the CN IX-X <=11.6 milliseconds had a 3.6 times increased risk for their gag reflex to become extinct. CONCLUSIONS: Our study greatly contributes to the current knowledge of intraoperative MEPs as a predictor for postoperative cranial nerve function. We were able to extent previous findings on MEP values of the facial nerve on postoperative nerve function to 3 additional cranial nerves. Finding reliable predictors for postoperative nerve function is of great importance to the overall quality of life for a patient undergoing surgery of the posterior cranial fossa. PMID- 27485530 TI - Analysis of Treatment Tolerance and Factors Associated with Overall Survival in Elderly Patients with Glioblastoma. AB - BACKGROUND: As the population ages, the proportion of elderly patients with glioblastomas has increased. Recently, many researchers have focused on the treatments available to and prognoses in elderly patients with glioblastomas. METHODS: We conducted a retrospective study of glioblastoma patients aged 60 years old or older who were treated at the Neurosurgery Center at Beijing Tiantan Hospital from 2012 to 2014. Their clinical features, immunohistochemical characteristics, treatments, and outcomes were evaluated to determine treatment tolerance and identify prognostic factors. RESULTS: Among the 70 included patients, the median survival time was 15 months. In the univariate analysis, patients who underwent a gross total resection had longer overall survival times than patients who had a subtotal resection (P < 0.05), and patients who received postoperative adjuvant therapy had longer overall survival times than those with no postoperative adjuvant therapy (P < 0.05). The expression of the p53 protein significantly affected overall survival. Patients with low p53 protein expression had a median survival of 17 months, whereas those who had high p53 protein expression had a median survival of 11.50 months (P < 0.05). Undergoing a gross total resection, receiving postoperative adjuvant therapy and having low p53 protein expression were factors that independently contributed to longer overall survival times in multivariate analysis. CONCLUSIONS: Maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide significantly prolonged overall survival times and was well tolerated in elderly patients with glioblastomas. In addition, low p53 protein expression was a significant favorable prognostic indicator in this population. PMID- 27485531 TI - Analysis of recruitment in a pragmatic observational study on C-reactive protein point-of-care testing in primary care. AB - INTRODUCTION: Failure to recruit all eligible study patients can lead to biased results. Little is known on selective patient recruitment in studies on implementation of diagnostic devices. OBJECTIVES: The aim of this observational study was to measure recruitment of patients in an implementation study in primary care on use of point-of-care (POC) C-reactive protein (CRP) and to evaluate recruitment bias and its impact on the study endpoint. METHODS: In a cross-sectional observational study on POC CRP implementation and related antibiotics prescribing, we compared included patients with all eligible patients to assess the representativeness of the included subjects. Eligible patients were adults presenting with acute cough in primary care between March and September 2012. The frequency of POC CRP testing and the proportion of prescribed antibiotics were compared between recruited and non-recruited patients. As measure of bias, odds ratios (ORs) with accompanying 95% confidence intervals (CIs) for the association between CRP level (<20 mg/l or not) and antibiotic prescribing were computed. RESULTS: Of all 1473 eligible patients 348 (24%) were recruited. In recruited patients, POC CRP tests were conducted and antibiotics prescribed more frequently as compared to non-recruited patients (81% versus 6% and 44% versus 29%, respectively). The ORs were 18.2 (95%CI: 9.6-34.3), 30.5 (95%CI: 13.2-70.3) and 3.8 (95%CI: 0.9-14.8) respectively in all eligible patients, the recruited and the non-recruited patients. CONCLUSION: Selective recruitment resulted in an overestimation of POC CRP test use and antibiotic prescribing. PMID- 27485532 TI - Anti-aging treatments slow propagation of synucleinopathy by restoring lysosomal function. AB - Aging is the major risk factor for neurodegenerative diseases that are also associated with impaired proteostasis, resulting in abnormal accumulation of protein aggregates. However, the role of aging in development and progression of disease remains elusive. Here, we used Caenorhabditis elegans models to show that aging-promoting genetic variations accelerated the rate of cell-to-cell transmission of SNCA/alpha-synuclein aggregates, hallmarks of Parkinson disease, and the progression of disease phenotypes, such as nerve degeneration, behavioral deficits, and reduced life span. Genetic and pharmacological anti-aging manipulations slowed the spread of aggregates and the associated phenotypes. Lysosomal degradation was significantly impaired in aging models, while anti aging treatments reduced the impairment. Transgenic expression of hlh-30p::hlh 30, the master controller of lysosomal biogenesis, alleviated intercellular transmission of aggregates in the aging model. Our results demonstrate that the rate of aging closely correlates with the rate of aggregate propagation and that general anti-aging treatments can slow aggregate propagation and associated disease progression by restoring lysosomal function. PMID- 27485534 TI - A quantile regression model for failure-time data with time-dependent covariates. AB - Since survival data occur over time, often important covariates that we wish to consider also change over time. Such covariates are referred as time-dependent covariates. Quantile regression offers flexible modeling of survival data by allowing the covariates to vary with quantiles. This article provides a novel quantile regression model accommodating time-dependent covariates, for analyzing survival data subject to right censoring. Our simple estimation technique assumes the existence of instrumental variables. In addition, we present a doubly-robust estimator in the sense of Robins and Rotnitzky (1992, Recovery of information and adjustment for dependent censoring using surrogate markers. In: Jewell, N. P., Dietz, K. and Farewell, V. T. (editors), AIDS Epidemiology. Boston: Birkhaauser, pp. 297-331.). The asymptotic properties of the estimators are rigorously studied. Finite-sample properties are demonstrated by a simulation study. The utility of the proposed methodology is demonstrated using the Stanford heart transplant dataset. PMID- 27485533 TI - Re-irradiation for locoregionally recurrent tumors of the thorax: a single institution, retrospective study. AB - BACKGROUND: Re-irradiation (re-RT) of the thorax is challenging due to the impact of prior therapies on normal tissues, and there are few reports of definitive re RT. The treatment toxicities and efficacy of re-RT are not well known. The aim of the present study was to assess the safety and efficacy of definitive re-RT of the thorax. METHODS: Patients who were treated with thoracic re-RT between March 2007 and December 2014 were retrospectively analyzed. Primary and re-irradiation plans were required to have an overlap of dose distributions for the 80 % isodose level. All doses were recalculated to an equivalent dose of 2 Gy per fraction (EQD2). When possible, analysis of dose accumulation was carried out using the medical image merge (MIM) ((r)) software program (version 6.5, MIM Software Inc., Cleveland, OH). Administration dosages for organs at risk were defined. RESULTS: Fourteen (67 %) and seven (33 %) patients with non-small cell carcinoma (NSCLC) and small cell carcinoma (SCLC), respectively, were identified. The patients' median age was 72 (range 53-85) years. Fifteen patients (71 %) had "proximal" tumors, defined as tumors at the distal 2 cm of the trachea, carina, and main bronchi. The median interval from initial RT to re-RT was 26.8 (range 11.4-92.3) months. Re-RT was delivered by X-ray beam and proton beam therapy in 20 (95 %) patients and 1 (5 %) patient, respectively. The median radiation dose of re-RT was 60 (range 54-87.5) Gy10 and 50 (range 50.0-87.5) Gy10 for patients with NSCLC and SCLC, respectively. Grade 3 acute radiation pneumonitis occurred in only one patient. There were no other serious complications. The median follow-up time was 22.1 (range 2.3-56.4) months. The median local progression-free survival time (LPFS) and overall survival time (OS) were 12.9 (95 % confidence interval (CI): 8.9-27.9) months and 31.4 (95 % CI: 16.9-45.9) months, respectively. Patients receiving >= 60 Gy10 at re-RT had longer LPFS (p = 0.04). CONCLUSIONS: Good safety with longer OS than in previous reports was demonstrated. Re-RT seems to be a promising treatment option. Further study to define the risk-benefit ratios is necessary. PMID- 27485535 TI - Evidence for the Absence of Stimulus Quality Differences in Tests of the Accuracy of Sexual Orientation Judgments: A Reply to Cox, Devine, Bischmann, and Hyde (2016). AB - An article recently published in this journal (Cox, Devine, Bischmann, & Hyde, 2016) questioned the validity of existing research on the accurate judgment of sexual orientation from photographs of faces. Specifically, those authors reported a confound in their stimuli whereby the photos of sexual minorities (gay men and lesbians) were of higher quality than the photos of heterosexuals. Based on this finding, they concluded that the accuracy in judging sexual orientation from faces demonstrated in the broader literature is an artifact of stimulus quality differences. Here, we addressed this claim by systematically testing the numerous photo sets that we have used in 61 studies documenting accurate judgments of sexual orientation from facial cues published since 2007. Contrary to their claim, the overwhelming majority of studies (93%) showed no significant differences in photo quality according to sexual orientation. Of those that did show differences, most revealed that heterosexual targets' photos were actually of higher quality than sexual minority targets' photos - opposite of what Cox et al. found. In addition, we highlight additional research using stimuli equated for quality differences overlooked in the recent article by Cox et al., lending further support to the conclusion that sexual orientation is legible from multiple sensory cues. PMID- 27485536 TI - Unilateral hippocampal inactivation or lesion selectively impairs remote contextual fear memory. AB - RATIONALE: Contextual fear memory depends on the hippocampus, but the role of unilateral hippocampus in this type of memory remains unclear. OBJECTIVES: Herein, pharmacological inactivation or excitotoxic lesions were used to study the role of unilateral hippocampus in the stages of contextual fear memory. RESULTS: The pharmacological experiments revealed that compared with the control groups, unilateral hippocampal blockade did not impair 1-day recent memory following learning, whereas bilateral hippocampal blockade significantly impaired this memory. The lesion experiments showed that compared with the control groups, the formed contextual fear memory was retained for 7 days and that 30-day remote memory was markedly reduced in unilateral hippocampal lesion groups. CONCLUSIONS: These results indicate that an intact bilateral hippocampus is required for the formation of remote memory and that unilateral hippocampus is sufficient for recent contextual fear memory. PMID- 27485537 TI - BSA and ABCB1 polymorphism affect the pharmacokinetics of sunitinib and its active metabolite in Asian mRCC patients receiving an attenuated sunitinib dosing regimen. AB - PURPOSE: An attenuated dosing (AD) sunitinib regimen of 37.5 mg daily has been suggested to reduce the toxicity reported with the standard dosing regimen to metastatic renal cell carcinoma (mRCC) patients. The aim of this study was to characterize the population pharmacokinetic (PK) properties of sunitinib and SU12662, the active metabolite, in patients receiving the AD regimen and to ascertain significant covariates influencing PK parameters. METHODS: Thirty-one mRCC patients receiving AD sunitinib regimen were included. Plasma samples were collected on day 29 of each treatment cycle after the start of the therapy. Nonlinear mixed-effects modeling was applied to estimate the population PK properties of sunitinib and SU12662 as well as the effect of covariates on PK parameters. Monte Carlo simulation was also performed to predict the total trough level (TTL) of sunitinib and SU12662. RESULTS: Sunitinib population means for CL/F and V d /F central were 13.8 L/h and 1720 L, respectively. SU12662 population means for CL/F and V d /F were 42.1 L/h and 1410 L, respectively. Body surface area (BSA) and ABCB1 polymorphism significantly influenced the CL/F variability of sunitinib: CL/F parent = 13.8 * exp((BSA - 1.75) * 2.08 + (ABCB1 genotype - 0.67) * 0.61), ABCB1-0: wild genotype, 1: mutant genotype. The effect size of ABCB1 mutant genotype and BSA greater than 1.75 m(2) in relation to sunitinib clearance was 31.14 % (p = 0.006) and 22.11 % (p = 0.011), respectively, relative to the reference group. CONCLUSIONS: Adjusting doses of sunitinib according to BSA and ABCB1 polymorphism in Asian mRCC patients may be recommended for sufficient attainment of a target TTL of sunitinib and its metabolite. PMID- 27485538 TI - Myelosuppression by chemotherapy in obese patients with gynecological cancers. AB - PURPOSE: The American Society of Clinical Oncology provides clinical practice guidelines for appropriate cytotoxic chemotherapy dosing for obese adult patients with cancer. The panel recommends that actual body weight should be used when selecting cytotoxic chemotherapy doses regardless of obesity status. However, there have been no reports regarding the appropriate cytotoxic chemotherapy dosing for obese Japanese patients with cancer. PATIENTS AND METHODS: We collected data from 216 gynecological cancer patients who were treated with at least one course of a paclitaxel and carboplatin (TC) regimen or a docetaxel and carboplatin (DC) regimen at Niigata University Medical and Dental Hospital from July 2006 to April 2014. Patients were divided into three groups according to body mass index (BMI): obese (BMI >= 25), normal (BMI 18.5-24.9), and underweight (BMI < 18.5), as defined by the Japan Society for the Study of Obesity. We analyzed hematological toxicities by full weight-based chemotherapy in each group. RESULTS: The rates of grade 3/4 leukocytopenia, neutropenia, and thrombocytopenia were not significantly different among the three BMI groups on all patient analyses. For the TC regimen, the obese and normal groups had significantly lower leukocytopenia (grade 3/4) rates than did the underweight group. Also, significant positive correlations between BMI and the nadirs of leukocytes, neutrophils, platelets, and hemoglobin were observed. For the DC regimen, no significant difference was observed among the BMI groups and the rate of grade 3/4 hematological toxicities. CONCLUSIONS: We did not observe stronger myelosuppression in obese cancer patients compared with non-obese cancer patients. Therefore, the cytotoxic chemotherapy dose should be calculated by the actual body weight and unnecessary dose reduction should be avoided. PMID- 27485539 TI - KLF4: A new player in plasma cell development. PMID- 27485541 TI - Corrigendum to "Nonmuscle Myosin-Dependent Synthesis of Type I Collagen..." [J Mol Biol. 27;401(4):2010: 564-578]. PMID- 27485540 TI - The Role of Intracoronary Plaque Imaging with Intravascular Ultrasound, Optical Coherence Tomography, and Near-Infrared Spectroscopy in Patients with Coronary Artery Disease. AB - The development of multiple diagnostic intracoronary imaging modalities has increased our understanding of coronary atherosclerotic disease. These imaging modalities, intravascular ultrasound (IVUS), optical coherence tomography (OCT), and near-infrared spectroscopy (NIRS), have provided a method to study plaques and introduced the concept of plaque vulnerability. They are being increasingly used for percutaneous coronary intervention (PCI) optimization and are invaluable tools in research studying the pathophysiology of acute coronary syndrome (ACS), in-stent thrombosis and in-stent restenosis. IVUS has the ability to visualize the intracoronary lumen and the vessel wall and can be used to detect early atherosclerotic disease even in the setting of positive arterial remodeling. Studies supporting the use of IVUS to optimize stent deployment and apposition have shown a significant reduction in cardiovascular events. OCT provides even higher resolution imaging and near microscopic detail of plaques, restenoses, and thromboses; thus, it can identify the etiology of ACS. Ongoing trials are evaluating the role of OCT in PCI and using OCT to study stent endothelialization and neointimal proliferation. NIRS is a modality capable of localizing and quantifying lipid core burden. It is usually combined with IVUS and is used to characterize plaque composition. The benefits of NIRS in the setting of ACS have been limited to case reports and series. The utilization of all these intracoronary imaging modalities will continue to expand as their indications for clinical use and research grow. Studies to support their use for PCI optimization resulting in improved outcomes with potential to prevent downstream events are ongoing. PMID- 27485542 TI - Timing of initiation of renal replacement therapy for acute kidney injury: a systematic review and meta-analysis of randomized-controlled trials. AB - BACKGROUND: The effects of early renal replacement therapy (RRT) on mortality and renal recovery in patients with acute kidney injury (AKI) remain controversial. A systematic review and meta-analysis of randomized-controlled trials (RCTs) was performed. METHODS: MEDLINE, EMBASE and the Cochrane Library database (Cochrane Central Register of Controlled Trials) were searched to identify RCTs, investigating the effects of early RRT on patients with AKI. RESULTS: Six studies with a total of 1257 participants were included in this meta-analysis. Compared to late RRT, early RRT did not reduce the risk of mortality (RR 0.93, 95 % CI 0.68-1.26) or affect renal recovery (RR 0.88, 95 % CI 0.48-1.62) or composite endpoint (death or dialysis dependence) (RR 0.91, 95 % CI 0.71-1.17). There was no significant difference in adverse events in the analysis, between the early RRT and late RRT arms. CONCLUSIONS: Early initiation of RRT for patients with AKI is not associated with decreased overall mortality or a delayed renal recovery rate. The optimal time to initiate RRT remains uncertain. Large scale and adequately powered RCTs are needed to detect the effects of early initiation of RRT in AKI patients. PMID- 27485543 TI - MicroRNA-363 and GATA-1 are regulated by HIF-1alpha in K562 cells under hypoxia. AB - The aim of the present study was to investigate regulatory relationships among hypoxia-inducible factor-1alpha (HIF-1alpha), microRNA and erythroid transcription factors. K562 cells were transfected with HIF-1alpha knockout or with overexpression lentivirus of plasmid (MOI 10). The cells were divided into 3 groups: the negative control, overexpressing and interference groups. The cells were cultured under normoxia and hypoxia. Expression of miR-17*, miR-363 and miR 574-5p in the three groups was determined by quantitative PCR. Expression levels of erythroid transcription factor mRNAs such as GATA-1/GATA-2 and nuclear factor erythroid 2 (NF-E2) were measured using RT-qPCR while the protein expression was studied using western blot analysis. Under normoxia or hypoxia, the levels of miR 17*, miR-363 and miR-574-5p in the overexpression group were higher than those in the other groups. Differences were statistically significant (P<0.05). Under hypoxia, the level of miR-363 in the interference group was less than that in the negative control group and difference was statistically significant (P<0.05). The level of GATA-1 mRNA in the overexpression group was higher than that in the negative control group, however, in the interference group the level was lower than that in the overexpression group under both normoxic and hypoxic conditions. The level of GATA-2 mRNA in the interference group was higher than that in other two groups under normoxic or hypoxic conditions. The NF-E2 mRNA was reversely related to GATA-2. The levels of HIF-1alpha, GATA-1 and NF-E2 mRNAs in the negative control under hypoxia were higher than those of normoxia. The level of HIF-1alpha mRNA in the overexpression group in hypoxia was lower than that in normoxia, while the GATA-1 and GATA-2 mRNA showed a reverse association. The levels of HIF-1alpha and GATA-2 mRNA in the interference group under hypoxia were higher compared to those of normoxia. Differences were statistically significant (P<0.05). Western blot results suggested that GATA-1, GATA-2 and NF-E2 protein expression correlated with changes in their respective mRNA transcription levels. The results therefore suggested that GATA-l and miR-363 were involved in the regulation of hematopoiesis via the HIF-1alpha pathway in K562 cells under hypoxic condition. The hsa-miR-17* and hsa-miR-574-5p were not entirely dependent on HIF-1alpha, suggesting possible complex regulatory mechanisms involved in hypoxia. PMID- 27485545 TI - Awareness of and compliance with healthy oral habits reported by children and their parents in Democratic People's Republic of Korea after a preventive programme. AB - OBJECTIVE: The study aimed to examine awareness of and compliance with healthy oral habits reported by children and their parents in Pyongyang, Democratic People's Republic of Korea (DPRK), after a preventive programme. MATERIALS AND METHODS: The data were collected in 2013 with self-completed, partly structured questionnaires from 1994 children aged 10 and 13 years and from 200 parents. Association between awareness of and compliance with healthy oral habits reported by the children and their parents was evaluated using Chi square tests and multivariate logistic regression analyses, children's oral health habits according to themselves and their parents were analysed using McNemar's test. RESULTS: Both children and their parents seemed to be familiar with healthy oral habits, although the awareness was not directly related to the reports of the children's oral practices. Most of the children reported brushing their teeth at least twice a day, using fluoride toothpaste and drinking water for thirst but frequent sweet snacking was common. Children's and their parents' reports were consistent with regard to sweet snacking frequency (p = 0.736) and the main thirst quencher (p = 0.349). CONCLUSIONS: Awareness of healthy oral habits appeared to be good among children and their parents. Unhealthy oral habits seemed to coincide with one another. PMID- 27485544 TI - Quantitative proteomic analysis for novel biomarkers of buccal squamous cell carcinoma arising in background of oral submucous fibrosis. AB - BACKGROUND: In South and Southeast Asian, the majority of buccal squamous cell carcinoma (BSCC) can arise from oral submucous fibrosis (OSF). BSCCs develop in OSF that are often not completely resected, causing local relapse. The aim of our study was to find candidate protein biomarkers to detect OSF and predict prognosis in BSCCs by quantitative proteomics approaches. METHODS: We compared normal oral mucosa (NBM) and paired biopsies of BSCC and OSF by quantitative proteomics using isobaric tags for relative and absolute quantification (iTRAQ) to discover proteins with differential expression. Gene Ontology and KEGG networks were analyzed. The prognostic value of biomarkers was evaluated in 94 BSCCs accompanied with OSF. Significant associations were assessed by Kaplan Meier survival and Cox-proportional hazards analysis. RESULTS: In total 30 proteins were identified with significantly different expression (false discovery rate < 0.05) among three tissues. Two consistently upregulated proteins, ANXA4 and FLNA, were validated. The disease-free survival was negatively associated with the expression of ANXA4 (hazard ratio, 3.4; P = 0.000), FLNA (hazard ratio, 2.1; P = 0.000) and their combination (hazard ratio, 8.8; P = 0.002) in BSCCs. CONCLUSION: The present study indicates that iTRAQ quantitative proteomics analysis for tissues of BSCC and OSF is a reliable strategy. A significantly up regulated ANXA4 and FLNA could be not only candidate biomarkers for BSCC prognosis but also potential targets for its therapy. PMID- 27485546 TI - Recurrent Brown's Syndrome after Superior Oblique Tendon Recession Treated by Silicone Spacer. AB - INTRODUCTION: Undercorrections have been reported after a number of surgical procedures for Brown's syndrome. The reason for late undercorrections is not clear but may be related to the heterogeneous etiology of Brown's syndrome. PURPOSE: We report a patient with late undercorrection after superior oblique tendon recession for Brown's syndrome that was partially relieved by a silicone spacer placed nasally. RESULTS: We noted on surgical exploration that the superior oblique tendon had attached to the sclera under the nasal border of the superior rectus. Further weakening of the tendon was achieved by a No. 240 band expander that resulted in improvement of adduction in elevation. CONCLUSION: Undercorrections following surgery for Brown's syndrome can be relieved by further weakening the superior oblique muscle. However, as late undercorrections have been reported, the optimal timing of surgery is not certain. PMID- 27485547 TI - Mitochondrial Ca2+ handling in Huntington's and Alzheimer's diseases - Role of ER mitochondria crosstalk. AB - Mitochondria play a relevant role in Ca2+ buffering, governing energy metabolism and neuronal function. Huntington's disease (HD) and Alzheimer's disease (AD) are two neurodegenerative disorders that, although clinically distinct, share pathological features linked to selective brain damage. These include mitochondrial dysfunction, intracellular Ca2+ deregulation and mitochondrial Ca2+ handling deficits. Both diseases are associated with misfolding and aggregation of specific proteins that physically interact with mitochondria and interfere with endoplasmic reticulum (ER)/mitochondria-contact sites. Cumulating evidences indicate that impairment of mitochondrial Ca2+ homeostasis underlies the susceptibility to selective neuronal death observed in HD and AD; however data obtained with different models and experimental approaches are not always consistent. In this review, we explore the recent literature on deregulation of mitochondrial Ca2+ handling underlying the interplay between mitochondria and ER in HD and AD-associated neurodegeneration. PMID- 27485548 TI - Bronchial colonization and complications after lung cancer surgery. AB - PURPOSE: Infectious complications occur following pulmonary resections preceded or not by induction chemoradiotherapy. We aimed to investigate whether bacterial colonization of the bronchial tree at the time of surgery was associated with postoperative complications. PATIENTS AND METHODS: A retrospective analysis of all patients who underwent open anatomical pulmonary resections for malignancies at a single center was performed. Demographical data of the included patients, intraoperative data, and data on the postoperative course of patients were collected. Outcome of patients with a positive intraoperative bronchial culture was compared to patients with a negative bronchial culture. Relations between the presence of potential bacterial pathogens in the bronchial tree and other possible risk factors for the development of postoperative infectious and non infectious complications, were analyzed using uni- and multivariate analysis. RESULTS: Between January 2010 and January 2012, a total of 121 consecutive patients underwent open anatomical pulmonary resections for malignancy, of whom 45 were preceded by induction chemoradiotherapy and 5 by induction chemotherapy. Intraoperative bronchial cultures were taken from 58 patients (48 %). Patients with a positive bronchial culture developed significantly more infectious (88 % vs. 20 %, p < 0.001) and non-infectious complications (63 % vs. 12 %, p = 0.001). Positive intraoperative bronchial cultures showed the strongest association with the development of infectious and non-infectious postoperative complications (OR 24.8 and 12.2, respectively). After multivariate analysis, only BMI less than 20 kg/m(2) and the presence of a positive intraoperative bronchial culture were found to be independent risk factors for the development of infectious complications. Chemoradiotherapy was not associated with postoperative complications in the present study. CONCLUSIONS: Bacterial colonization of the bronchial tree assessed intraoperatively, appears to be associated with higher rates of infectious and non-infectious complications after pulmonary resection. Whether early starting of appropriate antibiotics based on intraoperative-taken culture findings will reduce the infectious complication rate in a subcategory of patients needs to be investigated. PMID- 27485550 TI - Theoretical investigation of the broad one-photon absorption line-shape of a flexible symmetric carbazole derivative. AB - The one-photon absorption spectrum of a carbazole derivative has been studied by employing density functional response theory combined with a mixed quantum/classical (QC) approach to simulate the spectral shape. In a first step of our analysis we employed the vertical gradient (VG) vibronic model to investigate the role of Franck-Condon (FC) profiles of the first ten electronic excited states of the system, underlying most of the range of the experimental spectrum. We then focussed on the first six excited states covering the low energy region of the spectrum, and investigated the effect of inter-state electronic couplings on the spectral shapes within Herzberg-Teller (HT) theory. Furthermore, in order to introduce the broadening effects due to the two inter ring torsions, we employed a QC approach, adopting VG vibronic models for high frequency modes and computing the contribution of the torsions to the spectrum from the distribution of the excitation energies along a two-dimensional relaxed potential energy. Finally, we estimated the solvent inhomogeneous broadening by computing the solvent reorganization energy using a polarizable continuum model. Our calculations allow us to obtain a non-phenomenological description of the low energy part of the spectrum in semi-quantitative agreement with experiment and to dissect the relative importance of solvent, torsional flexibility, FC vibronic progressions, and inter-state couplings in determining its broad spectral shapes and the modulation of its intensity. Our analysis also clearly highlights that the investigated carbazole represents a big challenge for available methodologies due to the existence of many close-lying excited electronic states coupled by internal low-frequency and high-frequency motions and by solvent fluctuations. The study of their impact on the spectra at the HT level is only approximate and more refined treatments would require a fully quantum-dynamical calculation on the manifold of the coupled states. PMID- 27485549 TI - Role of frailty and nutritional status in predicting complications following total gastrectomy with D2 lymphadenectomy in patients with gastric cancer: a prospective study. AB - PURPOSE: This study was performed to determine the association of frailty and nutritional status with postoperative complications after total gastrectomy (TG) with D2 lymphadenectomy in patients with gastric cancer. METHODS: Patients undergoing TG with D2 lymphadenectomy for gastric cancer between August 2014 and February 2016 were enrolled. Frailty was evaluated by sarcopenia which was diagnosed by a combination of third lumbar vertebra muscle index (L3 MI), handgrip strength, and 6-m usual gait speed. Nutritional status was evaluated by the nutritional risk screening 2002 (NRS 2002) score. Univariate and multivariate analyses evaluating the risk factors for postoperative complications were performed. RESULTS: A total of 158 patients were analyzed, and 27.2 % developed complications within 30 days of surgery. One patient died within 30 days of the operation. In the univariate analyses, NRS 2002 score >=3 (OR = 2.468, P = 0.012), sarcopenia (OR = 2.764, P = 0.008), and tumor located at the cardia (OR = 2.072, P = 0.046) were associated with the postoperative complications. Multivariable analysis revealed that sarcopenia (OR = 3.084, P = 0.005) and tumor located at the cardia (OR = 2.347, P = 0.026) were independent predictors of postoperative complications. CONCLUSIONS: This study showed a significant relationship between postoperative complications and geriatric frailty using sarcopenia in patients with gastric cancer after TG with D2 lymphadenectomy. Frailty should be integrated into preoperative risk assessment and may have implications in preoperative decisionmaking. PMID- 27485551 TI - Detection of selected periodontal bacteria in preschool children affected by early childhood caries. AB - The aim of this study was to compare the detection frequency of periodontal bacteria in dental plaque in children with early childhood caries (ECC) with and without gingival inflammation. A convenience sample of 25 preschool children (mean age 3.61 years, SD 1.42) was recruited. Dental plaque was taken from periodontal areas with and without visible signs of inflammation and processed using the StomaGene(r) (Protean s.r.o. Czech Republic) and ParoCheck(r) 20 (Greiner Bio-one GmbH, Germany) detection kits. The two sample t tests between percents for differences between inflammatory and healthy sites and kappa statistics for the agreement of both systems were used. At the inflammatory sites, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were significantly more frequently detected by StomaGene(r) while Fusobacterium nucleatum, A. actinomycetemcomitans, Tanarella forsythia and Prevotella intermedia were significantly more frequently identified by ParoCheck(r) test. The agreement between the two detection systems was substantial for A. actinomycetemcomitans and F. nucleatum in the samples collected from inflamed sites and only for F. nucleatum from clinically healthy sites. Therefore, we recommend that the same system should be used when the same patient is examined repeatedly. PMID- 27485552 TI - Stochastic Induction of Long-Term Potentiation and Long-Term Depression. AB - Long-term depression (LTD) and long-term potentiation (LTP) of granule-Purkinje cell synapses are persistent synaptic alterations induced by high and low rises of the intracellular calcium ion concentration ([Ca(2+)]), respectively. The occurrence of LTD involves the activation of a positive feedback loop formed by protein kinase C, phospholipase A2, and the extracellular signal-regulated protein kinase pathway, and its expression comprises the reduction of the population of synaptic AMPA receptors. Recently, a stochastic computational model of these signalling processes demonstrated that, in single synapses, LTD is probabilistic and bistable. Here, we expanded this model to simulate LTP, which requires protein phosphatases and the increase in the population of synaptic AMPA receptors. Our results indicated that, in single synapses, while LTD is bistable, LTP is gradual. Ca(2+) induced both processes stochastically. The magnitudes of the Ca(2+) signals and the states of the signalling network regulated the likelihood of LTP and LTD and defined dynamic macroscopic Ca(2+) thresholds for the synaptic modifications in populations of synapses according to an inverse Bienenstock, Cooper and Munro (BCM) rule or a sigmoidal function. In conclusion, our model presents a unifying mechanism that explains the macroscopic properties of LTP and LTD from their dynamics in single synapses. PMID- 27485553 TI - Aunting as a Call to Public Intellectualism: The Roles of (In)Visibility in Health Communication Research and Service. AB - In this essay, the author identifies the theme of (in)visibility permeating her research on fathers of children with a rare genetic condition, Sturge-Weber syndrome. The tension between physical visibility of the condition and lack of awareness is explored, alongside issues of (in)visibility in coping and support seeking strategies of fathers. Finally, the author examines her own experiences in the research process through the lens of (in)visibility, in both managing her own emotions and exploring her roles as a researcher, an aunt, and a public intellectual. PMID- 27485554 TI - Role of cysteine residues in the redox-regulated oligomerization and nucleotide binding to EhRabX3. AB - The enteric protozoan parasite, Entamoeba histolytica, an etiological agent of amebiasis, is involved in the adhesion and destruction of human tissues. Worldwide, the parasite causes about 50 million cases of amebiasis and 100,000 deaths annually. EhRabX3, a unique amoebic Rab GTPase with tandem G-domains, possesses an unusually large number of cysteine residues in its N-terminal domain. Crystal structure of EhRabX3 revealed an intra-molecular disulfide bond between C39 and C163 which is critical for maintaining the 3-dimensional architecture and biochemical function of this protein. The remaining six cysteine residues were found to be surface exposed and predicted to be involved in inter molecular disulfide bonds. In the current study, using biophysical and mutational approaches, we have investigated the role of the cysteine residues in the assembly of EhRabX3 oligomer. The self-association of EhRabX3 is found to be redox sensitive, in vitro. Furthermore, the oligomeric conformation of EhRabX3 failed to bind and exchange the guanine nucleotide, indicating structural re organization of the active site. Altogether, our results provide valuable insights into the redox-dependent oligomerization of EhRabX3 and its implication on nucleotide binding. PMID- 27485555 TI - Transcription of the apicoplast genome. AB - Many members of the Apicomplexa contain a remnant chloroplast, known as an apicoplast. The apicoplast encodes numerous genes, and loss of the organelle is lethal. Here, we present a summary of what is known about apicoplast transcription. Unlike plant chloroplasts, there is a single RNA polymerase, and initial transcription is polycistronic. RNA is then cleaved into tRNA, mRNA and rRNA molecules. Significant levels of antisense transcription have been reported, together with a single case of RNA editing. Polycistronic transcription is also observed in the related algae Chromera and Vitrella, which retain a photosynthetic chloroplast. Surprisingly, a polyU tail is added to Chromera and Vitrella transcripts which encode proteins involved in photosynthesis. No such tail is added to Plasmodium transcripts. Transcription in the Apicomplexa is remarkably similar to that seen in the chloroplast of the related peridinin dinoflagellate algae, reflecting the common evolutionary origins of the organelle. PMID- 27485556 TI - Schistosoma bovis-host interplay: Proteomics for knowing and acting. AB - Schistosoma bovis is a parasite of ruminants that causes significant economic losses to farmers throughout Africa, Southwestern Asia and the Mediterranean. Additionally, recent studies have reported its zoonotic potential through the formation of S. bovis*Schistosoma haematobium hybrids. As observed in the Schistosoma species infecting humans, it is assumed that S. bovis has also evolved host regulatory molecules that ensure its long-term survival in the bloodstream of its host. Since these molecules could be potential targets for the development of new drugs and anti-schistosome vaccines, their identification and functional characterization were undertaken. With this aim in mind, the molecular interface between S. bovis and its vertebrate host was subjected to a series of proteomic studies, which started with the analysis of the proteomes of the S. bovis moieties exposed to the host, namely, the excretory/secretory products and the tegument surface. Thus, a wealth of novel molecular information of S. bovis was obtained, which in turn allowed the identification of several parasite proteins with fibrinolytic and anticoagulant activities that could be used by S. bovis to regulate the host defensive systems. Following on, the host interface was investigated by studying the proteome of the host vascular endothelium surface at two points along the infection: in the lung vessels during the schistosomula migration and in the portal vein after the parasites have reached adulthood and sexual maturity. These studies have provided original data regarding the proteomes of the endothelial cell surface of pulmonary vasculature and portal vein in S. bovis-infected animals, and have shown significant changes in these proteomes associated with infection. This review compiles current information and the analyses of all the proteomic data from S. bovis and the S. bovis-host interface, including the molecular and functional characterization of S. bovis proteins that were found to participate in the regulation of the host coagulation and fibrinolysis systems. PMID- 27485557 TI - Order information in verbal working memory shifts the subjective midpoint in both the line bisection and the landmark tasks. AB - A largely substantiated view in the domain of working memory is that the maintenance of serial order is achieved by generating associations of each item with an independent representation of its position, so-called position markers. Recent studies reported that the ordinal position of an item in verbal working memory interacts with spatial processing. This suggests that position markers might be spatial in nature. However, these interactions were so far observed in tasks implying a clear binary categorization of space (i.e., with left and right responses or targets). Such binary categorizations leave room for alternative interpretations, such as congruency between non-spatial categorical codes for ordinal position (e.g., begin and end) and spatial categorical codes for response (e.g., left and right). Here we discard this interpretation by providing evidence that this interaction can also be observed in a task that draws upon a continuous processing of space, the line bisection task. Specifically, bisections are modulated by ordinal position in verbal working memory, with lines bisected more towards the right after retrieving items from the end compared to the beginning of the memorized sequence. This supports the idea that position markers are intrinsically spatial in nature. PMID- 27485558 TI - Diverging P waves after convergent procedures: What do they mean? PMID- 27485559 TI - Change in P wave morphology after convergent atrial fibrillation ablation. AB - Convergent atrial fibrillation ablation involves extensive epicardial as well as endocardial ablation of the left atrium. We examined whether it changes the morphology of the surface P wave. We reviewed electrocardiograms of 29 patients who underwent convergent ablation for atrial fibrillation. In leads V1, II and III, we measured P wave duration, area and amplitude before ablation, and at 1, 3 and 6 months from ablation. After ablation, there were no significant changes in P wave amplitude, area, or duration in leads II and III. There was a significant reduction in the area of the terminal negative deflection of the P wave in V1 from 0.38 mm(2) to 0.13 mm(2) (p = 0.03). There is also an acute increase in the amplitude and duration of the positive component of the P wave in V1 followed by a reduction in both by 6 months. Before ablation, 62.5% of the patients had biphasic P waves in V1. In 6 months, only 39.2% of them had biphasic P waves. Hybrid ablation causes a reduction of the terminal negative deflection of the P wave in V1 as well as temporal changes in the duration and amplitude of the positive component of the P wave in V1. This likely reflects the reduced electrical contribution of the posterior left atrium after ablation as well as anatomical and autonomic remodeling. Recognition of this altered sinus P wave morphology is useful in the diagnosis of atrial arrhythmias in this patient population. PMID- 27485560 TI - Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes. AB - BACKGROUND: Long QT syndromes (LQTS) are characterized by prolonged QTc interval on electrocardiogram (ECG) and manifest with syncope, seizures or sudden cardiac death. Long QT 1-3 constitute about 75% of all inherited LQTS. We classified a cohort of Indian patients for the common LQTS based on T wave morphology and triggering factors to prioritize the gene to be tested. We sought to identify the causative mutations and mutation spectrum, perform genotype-phenotype correlation and screen family members. METHODS: Thirty patients who fulfilled the criteria were enrolled. The most probable candidate gene among KCNQ1, KCNH2 and SCN5A were sequenced. RESULTS: Of the 30 patients, 22 were classified at LQT1, two as LQT2 and six as LQT3. Mutations in KCNQ1 were identified in 17 (77%) of 22 LQT1 patients, KCNH2 mutation in one of two LQT2 and SCN5A mutations in two of six LQT3 patients. We correlated the presence of the specific ECG morphology in all mutation positive cases. Eight mutations in KCNQ1 and one in SCN5A were novel and predicted to be pathogenic by in-silico analysis. Of all parents with heterozygous mutations, 24 (92%) of 26 were asymptomatic. Ten available siblings of nine probands were screened and three were homozygous and symptomatic, five heterozygous and asymptomatic. CONCLUSIONS: This study in a cohort of Asian Indian patients highlights the mutation spectrum of common Long QT syndromes. The clinical utility for prevention of unexplained sudden cardiac deaths is an important sequel to identification of the mutation in at-risk family members. PMID- 27485562 TI - Extreme bradycardia and transient asystole after massive gastric air entrapment. PMID- 27485563 TI - Deceptive intracardiac electrograms during an ICD interrogation. A clinical challenge. AB - We present a case of a patient with significant structural heart disease from previous cardiac surgeries who presented for an electrophysiology study and radiofrequency ablation. The case highlights the significance of intra-atrial conduction delays in such patients and potential pitfalls it can present while interpreting intra-cardiac electrograms especially during implantable cardioverter defibrillator (ICD) interrogations. PMID- 27485561 TI - Ventricular pacing - Electromechanical consequences and valvular function. AB - Although great strides have been made in the areas of ventricular pacing, it is still appreciated that dyssynchrony can be malignant, and that appropriately placed pacing leads may ameliorate mechanical dyssynchrony. However, the unknowns at present include: 1. The mechanisms by which ventricular pacing itself can induce dyssynchrony; 2. Whether or not various pacing locations can decrease the deleterious effects caused by ventricular pacing; 3. The impact of novel methods of pacing, such as atrioventricular septal, lead-less, and far-field surface stimulation; 4. The utility of ECG and echocardiography in predicting response to therapy and/or development of dyssynchrony in the setting of cardiac resynchronization therapy (CRT) lead placement; 5. The impact of ventricular pacing-induced dyssynchrony on valvular function, and how lead position correlates to potential improvement. This review examines the existing literature to put these issues into context, to provide a basis for understanding how electrical, mechanical, and functional aspects of the heart can be distorted with ventricular pacing. We highlight the central role of the mitral valve and its function as it relates to pacing strategies, especially in the setting of CRT. We also provide future directions for improved pacing modalities via alternative pacing sites and speculate over mechanisms on how lead position may affect the critical function of the mitral valve and thus overall efficacy of CRT. PMID- 27485564 TI - Incessant tachycardia in a patient with advanced heart failure and left ventricular assist device: What is the mechanism? AB - We present a case of incessant wide-complex tachycardia in a patient with left ventricular assist device, and discuss the differential diagnosis with an in depth analysis of the intracardiac tracings during the invasive electrophysiologic study, including interpretation of the relative timing of the fascicular signals during tachycardia and in sinus rhythm, and interpretation of pacing and entrainment maneuvers. PMID- 27485565 TI - Use of a novel pacing mode to achieve biventricular pacing in a patient with recurrent atrial lead dislodgement after CRT-D implantation. AB - Cardiac resynchronization therapy device (CRT-P and CRT-D) implantation has increased tremendously with increasing operator experience, eligible patients and expansion of indications. Refinements in devices and algorithms now aid physicians to improve biventricular pacing and optimize CRT. We report a case in which an interesting device program was used to achieve biventricular pacing after repeated dislodgement of the atrial lead in a patient implanted with CRT-D. PMID- 27485566 TI - Development of Monopole Interaction Models for Ionic Compounds. Part I: Estimation of Aqueous Henry's Law Constants for Ions and Gas Phase pKa Values for Acidic Compounds. AB - The SPARC (SPARC Performs Automated Reasoning in Chemistry) physicochemical mechanistic models for neutral compounds have been extended to estimate Henry's Law Constant (HLC) for charged species by incorporating ionic electrostatic interaction models. Combinations of absolute aqueous pKa values, relative pKa values in the gas phase, and aqueous HLC for neutral compounds have been used to develop monopole interaction models that quantify the energy differences upon moving an ionic solute molecule from the gas phase to the liquid phase. Inter molecular interaction energies were factored into mechanistic contributions of monopoles with polarizability, dipole, H-bonding, and resonance. The monopole ionic models were validated by a wide range of measured gas phase pKa data for 450 acidic compounds. The RMS deviation error and R(2) for the ?OH, ?SH, ?CO2 H, ?CH3 and ?NR2 acidic reaction centers (C) were 16.9 kcal/mol and 0.87, respectively. The calculated HLCs of ions were compared to the HLCs of 142 ions calculated by quantum mechanics. Effects of inter-molecular interaction of the monopoles with polarizability, dipole, H-bonding, and resonance on acidity of the solutes in the gas phase are discussed. PMID- 27485567 TI - The Complexation of the Anticancer Drug ThioTEPA with Methylated DNA Base Guanine: Combined Ab Initio and QTAIM Investigation. AB - Non-covalent complexes of methylated nitrogenous DNA base guanine (m(9) Gua) with 1 to 6 molecules of anticancer drug ThioTEPA (1,1',1'' phosphorothioyltriaziridine) have been investigated by molecular modeling techniques (molecular docking and DFT geometry optimization), ab initio wavefunction calculations and the quantum theory of atoms in molecules (QTAIM). The accuracy of complex structures predicted by standard molecular docking techniques have been assessed by comparing them with ab initio calculations, and the most important differences have been discussed. Obtained stabilization enthalpies (kcal/mol) for the m(9) Gua???(ThioTEPA)n complexes with n=1...6 have been found to be -15.6, -26.5, -38.4, -49.6, -60.5 and -69.3 respectively. The non-covalent interactions revealed by the QTAIM method have been shown to be a dominating factor responsible for the complex stability, with hydrogen bonds of NH???N type being the most important interactions in small (n=1 to 4) and CH???N bonds - in large (n=5, 6) complexes. The obtained results may help to understand ThioTEPA-DNA interactions and clarify the mechanism of the drug action. PMID- 27485568 TI - Development of a New Decision Tree to Rapidly Screen Chemical Estrogenic Activities of Xenopus laevis. AB - During the last past decades, there is an increasing number of studies about estrogenic activities of the environmental pollutants on amphibians and many determination methods have been proposed. However, these determination methods are time-consuming and expensive, and a rapid and simple method to screen and test the chemicals for estrogenic activities to amphibians is therefore imperative. Herein is proposed a new decision tree formulated not only with physicochemical parameters but also a biological parameter that was successfully used to screen estrogenic activities of the chemicals on amphibians. The biological parameter, CDOCKER interaction energy (Ebinding ) between chemicals and the target proteins was calculated based on the method of molecular docking, and it was used to revise the decision tree formulated by Hong only with physicochemical parameters for screening estrogenic activity of chemicals in rat. According to the correlation between Ebinding of rat and Xenopus laevis, a new decision tree for estrogenic activities in Xenopus laevis is finally proposed. Then it was validated by using the randomly 8 chemicals which can be frequently exposed to Xenopus laevis, and the agreement between the results from the new decision tree and the ones from experiments is generally satisfactory. Consequently, the new decision tree can be used to screen the estrogenic activities of the chemicals, and combinational use of the Ebinding and classical physicochemical parameters can greatly improves Hong's decision tree. PMID- 27485569 TI - Pharmacophore Mapping, In Silico Screening and Molecular Docking to Identify Selective Trypanosoma brucei Pteridine Reductase Inhibitors. AB - Trypanosoma brucei Pteridine reductase (TbPTR1) is of vital importance and is an established drug target for dreaded Human African trypanosomiasis (HAT). Pharmacophore perception strategy has been employed to identify key chemical features responsible for the biological activity for TbPTR1. The findings suggest that three different pharmacophore features can be associated with T. brucei anti PTR1 activity namely: H-bond donors (D), Hydrophobic aromatic (H) and Ring aromatic (R). The resulting hypothesis is able to predict the activity of other existing TbPTR1 inhibitors with a correlation coefficient (r) of 0.89. An in silico database screening, based on the best hypothesis, has been used to identify some potential nanomolar range TbPTR1 inhibitors. These compounds were then checked by molecular docking and subjected to ADMET analysis. Further, a detailed comparison of the pharmacophore behavior and differential analysis of binding pockets of T. brucei and L. major was made which revealed subtle differences in terms of their shape and charge properties. This investigation can form the basis for tweaking the specificity of compounds for generating new improved species specific inhibitor molecules for Pteridine reductase in these different parasitic protozoans. PMID- 27485570 TI - eFindSite: Enhanced Fingerprint-Based Virtual Screening Against Predicted Ligand Binding Sites in Protein Models. AB - A standard practice for lead identification in drug discovery is ligand virtual screening, which utilizes computing technologies to detect small compounds that likely bind to target proteins prior to experimental screens. A high accuracy is often achieved when the target protein has a resolved crystal structure; however, using protein models still renders significant challenges. Towards this goal, we recently developed eFindSite that predicts ligand binding sites using a collection of effective algorithms, including meta-threading, machine learning and reliable confidence estimation systems. Here, we incorporate fingerprint based virtual screening capabilities in eFindSite in addition to its flagship role as a ligand binding pocket predictor. Virtual screening benchmarks using the enhanced Directory of Useful Decoys demonstrate that eFindSite significantly outperforms AutoDock Vina as assessed by several evaluation metrics. Importantly, this holds true regardless of the quality of target protein structures. As a first genome-wide application of eFindSite, we conduct large-scale virtual screening of the entire proteome of Escherichia coli with encouraging results. In the new approach to fingerprint-based virtual screening using remote protein homology, eFindSite demonstrates its compelling proficiency offering a high ranking accuracy and low susceptibility to target structure deformations. The enhanced version of eFindSite is freely available to the academic community at http://www.brylinski.org/efindsite. PMID- 27485571 TI - Easy Identification of Residues Involved on Structural Differences Between Nonphosphorylated and Phosphorylated CDK2?Cyclin A Complexes Using Two Dimensional Networks. AB - The structures of proteins in Protein Data Bank (PDB) contain a lot of information that can be revealed through the use of tools to facilitate their organization and analysis. The increase in available structural data of nonphosphorylated and phosphorylated CDK2?cyclin A (npCDK2?cycA and pCDK2?cycA) complexes has enabled a more realistic description of the fine structural details of the interface residues of these proteins. This work reports the application of two-dimensional network representations (TDNRs) to the structures deposited in PDB to distinguish the differences in the surface between both complexes due to phosphorylation. As a result, a detailed map of the hydrogen bonds (HBs) and hydrophobic interactions between the T-loop residues of CDK2 and the residues of cycA that are different among nonphosphorylated and phosphorylated complexes were described. In addition, we found some interesting subtle differences in the CDK2?cycA interface between nonphosphorylated and phosphorylated complexes due to residues that are not located at the T-loop of CDK2. We noted that some HB interactions in CDK2?cycA complex are reinforced when the CDK2 is phosphorylated. PMID- 27485572 TI - A case of recurrent swimming-induced pulmonary edema in a triathlete: the need for awareness. AB - This report discusses a rare case of a 55-year-old female triathlete who developed recurrent episodes of swimming-induced pulmonary edema (SIPE). She had two hospital admissions with pulmonary edema after developing breathlessness while swimming, including a near-drowning experience in an open water swim. With increasing popularity of triathlon and open water sports, this case highlights the importance of a greater awareness of SIPE among health professionals, event organizers, and athletes. This report explores the previous reported cases in triathletes and those who have suffered recurrent episodes. It is paramount that an accurate diagnosis is made as these individuals may be at an increased risk of future life-threatening episodes. PMID- 27485573 TI - Microchemical Study of Pigments and Binders in Polychrome Relics from Maiji Mountain Grottoes in Northwestern China. AB - In this study, an integrated analytical method was developed to investigate the composition of both the inorganic pigments and organic binders of polychrome relics in Maiji Mountain Grottoes in northwestern China. Cross-sections of each sample were prepared at the beginning of the study, and all experiments were carried out on these cross-sections. Polychromic structures were revealed by optical microscopy and scanning electron microscopy-backscattered electron imaging. Inorganic materials were determined by using SEM coupled with an energy dispersive spectrometer and MU-Raman spectrometer, whereas organic materials were identified by staining techniques and highly sensitive and specific immunofluorescence microscopy. Data showed that the red colors are attributed to one or two pigments of red ochre, cinnabar, and minium; the blue pigment is natural lazurite; the green pigment is ascribed to atacamite; the white color is attributed to potassium feldspar; and the black surface is formed by the discoloration of minium to plattnerite under the influence of environmental factors. Regarding organic binders used in painting and preparation layers, mammalian animal glue and chicken egg white were both found alone or in mixture. Finally, the conclusion is made that the Secco technique is employed in polychrome relics from Maiji Mountain Grottoes. PMID- 27485574 TI - Enhancing the quality of oral nutrition support for hospitalized patients: a mixed methods knowledge translation study (The EQONS study). AB - AIM: The aim of this study was to report a multifaceted knowledge translation intervention to facilitate use of the Malnutrition Universal Screening Tool and innovation in nutritional care for patients at risk of malnutrition. BACKGROUND: Malnutrition among hospitalized patients is a widespread problem leading to adverse health outcomes. Despite evidence of the benefits of malnutrition screening and recommendations for achieving good nutrition, shortfalls in practice continue. DESIGN: A mixed method integrated knowledge translation study. METHODS: The knowledge translation intervention comprised nutrition champions supported by knowledge translation facilitators and an action planning process. Data collection was undertaken over 18 months between 2011-2012 in a hospital in England. Data comprised observation of mealtimes, audit of patient records, survey of nurses and semi-structured interviews with nutrition champions, knowledge translation facilitators, senior ward nurses and nurse managers. FINDINGS: Statistically significant relationships (Chi Square) were observed between self-reported confidence of nurses (a) to assess patients using the Malnutrition Universal Screening Tool, (b) to teach colleagues how to use the Malnutrition Universal Screening Tool and (c) to ensure that patients were assessed within 24 hours of admission. Ward-based nutrition champions facilitated successful innovation in nutrition support. Contextual factors operating at micro (ward), meso (organization) and macro (healthcare system) levels acted as barriers and enablers for change. CONCLUSION: Nutrition champions were successful in increasing the timely assessment of patients at risk of malnutrition and promoting innovation in nutritional care. Support from knowledge translation facilitators helped nutrition champions develop their role and work collaboratively with senior ward nurses to implement action plans for improving nutrition. PMID- 27485576 TI - Do we need intracardiac echo to guide ablation of ventricular arrhythmias from the papillary muscles? PMID- 27485575 TI - Secreted Isoform of Human Lynx1 (SLURP-2): Spatial Structure and Pharmacology of Interactions with Different Types of Acetylcholine Receptors. AB - Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the alpha3beta2 subtype of the nicotinic acetylcholine receptors (nAChRs). Here, we describe the structure and pharmacology of a recombinant analogue of SLURP-2. Nuclear magnetic resonance spectroscopy revealed a 'three-finger' fold of SLURP-2 with a conserved beta-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the alpha3, alpha4, alpha5, alpha7, beta2, and beta4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at alpha4beta2 and alpha3beta2-nAChRs (IC50 ~0.17 and >3 MUM, respectively) expressed in Xenopus oocytes. In contrast, at alpha7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 MUM but induces inhibition at higher concentrations. SLURP-2 allosterically interacts with human M1 and M3 muscarinic acetylcholine receptors (mAChRs) that are overexpressed in CHO cells. SLURP-2 was found to promote the proliferation of human oral keratinocytes via interactions with alpha3beta2-nAChRs, while it inhibited cell growth via alpha7-nAChRs. SLURP-2/mAChRs interactions are also probably involved in the control of keratinocyte growth. Computer modeling revealed possible SLURP-2 binding to the 'classical' orthosteric agonist/antagonist binding sites at alpha7 and alpha3beta2-nAChRs. PMID- 27485577 TI - Different impact of long-detection interval and anti-tachycardia pacing in reducing unnecessary shocks: data from the ADVANCE III trial. AB - AIMS: A long-detection interval (LDI) (30/40 intervals) has been proved to be superior to a standard-detection interval (SDI) (18/24 intervals) in terms of reducing unnecessary implantable cardioverter defibrillator (ICD) therapies. To better evaluate the different impact of LDI and anti-tachycardia pacing (ATP) on reducing painful shocks, we assessed all treated episodes in the ADVANCE III trial. METHODS AND RESULTS: A total of 452 fast (200 ms < cycle length <= 320 ms) arrhythmic episodes were recorded: 284 in 138 patients in the SDI arm and 168 in 82 patients in the LDI arm (106/452 inappropriate detections). A total of 346 fast ventricular tachycardias (FVT) were detected in 169 patients: 208 in 105 patients with SDI and 138 in 64 patients with LDI. Setting LDI determined a significant reduction in appropriate but unnecessary therapies [208 in SDI vs. 138 in LDI; incidence rate ratio (IRR): 0.61 (95% CI 0.45-0.83), P = 0.002]. Anti tachycardia pacing determined another 52% reduction in unnecessary shocks [208 in SDI with hypothetical shock-only programming vs. 66 in LDI with ATP; IRR: 0.37 (95% CI 0.25-0.53, P < 0.001)]. The efficacy of ATP in terminating FVT was 63% in SDI and 52% in LDI (P = 0.022). No difference in the safety profile (acceleration/degeneration and death/cardiovascular hospitalizations) was observed between the two groups. CONCLUSION: The combination of LDI and ATP during charging is extremely effective and significantly reduces appropriate but unnecessary therapies. The use of LDI alone yielded a 39% reduction in appropriate but unnecessary therapies; ATP on top of LDI determined another 52% reduction in unnecessary shocks. The strategy of associating ATP and LDI could be considered in the majority of ICD recipients. PMID- 27485578 TI - Intracardiac echo-facilitated 3D electroanatomical mapping of ventricular arrhythmias from the papillary muscles: assessing the 'fourth dimension' during ablation. AB - AIMS: Ventricular arrhythmias (VA) originating from a papillary muscle (PM) have recently been described as a distinct clinical entity with peculiar features that make its treatment with catheter ablation challenging. Here, we report our experience using an intracardiac echo-facilitated 3D electroanatomical mapping approach in a case series of patients undergoing ablation for PM VA. METHODS AND RESULTS: Sixteen patients who underwent catheter ablation for ventricular tachycardia (VT) or symptomatic premature ventricular contractions originating from left ventricular PMs were included in the study. A total of 24 procedures (mean 1.5 per patient) were performed: 15 using a retrograde aortic approach and 9 using a transseptal approach. Integrated intracardiac ultrasound for 3D electroanatomical mapping was used in 15 of the 24 procedures. The posteromedial PM was the most frequent culprit for the clinical arrhythmia, and the body was the part of the PM most likely to be the successful site for ablation. The site of ablation was identified based on the best pace map matching the clinical arrhythmia and the site of earliest the activation. At a mean follow-up of 10.5 +/- 7 months, only two patients had recurrent arrhythmias following a repeat ablation procedure. CONCLUSION: An echo-facilitated 3D electroanatomical mapping allows for real-time creation of precise geometries of cardiac chambers and endocavitary structures. This is useful during procedures such as catheter ablation of VAs originating from PMs, which require detailed representation of anatomical landmarks. Routine adoption of this technique should be considered to improve outcomes of PM VA ablation. PMID- 27485579 TI - Template-Directed Synthesis of Porous and Protective Core-Shell Bionanoparticles. AB - Metal-organic frameworks (MOFs) are promising high surface area coordination polymers with tunable pore structures and functionality; however, a lack of good size and morphological control over the as-prepared MOFs has persisted as an issue in their application. Herein, we show how a robust protein template, tobacco mosaic virus (TMV), can be used to regulate the size and shape of as fabricated MOF materials. We were able to obtain discrete rod-shaped TMV@MOF core shell hybrids with good uniformity, and their diameters could be tuned by adjusting the synthetic conditions, which can also significantly impact the stability of the core-shell composite. More interestingly, the virus particle underneath the MOF shell can be chemically modified using a standard bioconjugation reaction, showing mass transportation within the MOF shell. PMID- 27485580 TI - Keep nanotechnology in mind. PMID- 27485581 TI - Correction. PMID- 27485582 TI - Hopes and anxieties. PMID- 27485584 TI - Origin and control of blinking in quantum dots. AB - Semiconductor nanocrystals offer an enormous diversity of potential device applications, based on their size-tunable photoluminescence, high optical stability and 'bottom-up' chemical approaches to self-assembly. However, the promise of such applications can be seriously limited by photoluminescence intermittency in nanocrystal emission, that is, 'blinking', arising from the escape of either one or both of the photoexcited carriers to the nanocrystal surface. In the first scenario, the remaining nanocrystal charge quenches photoluminescence via non-radiative Auger recombination, whereas for the other, the exciton is thought to be intercepted before thermalization and does not contribute to the photoluminescence. This Review summarizes the current understanding of the mechanisms responsible for nanocrystal blinking kinetics as well as core-shell engineering efforts to control such phenomena. In particular, 'softening' of the core-shell confinement potential strongly suppresses non radiative Auger processes in charged nanocrystals, with successful non-blinking implementations demonstrated in CdSe-CdS core-thick-shell nanocrystals and their modifications. PMID- 27485585 TI - Erratum: Additive interfacial chiral interaction in multilayers for stabilization of small individual skyrmions at room temperature. PMID- 27485586 TI - A tale of two disciplines. PMID- 27485587 TI - Re: Prediction of adverse perinatal outcome of small-for-gestational-age pregnancy using size centiles and conditional growth centiles. H. O. Karlsen, S. L. Johnsen, S. Rasmussen and T. Kiserud. Ultrasound Obstet Gynecol 2016; 48: 217 223. PMID- 27485588 TI - Re: Warping of the levator hiatus: how significant is it? H. P. Dietz, I. Severino, I. Kamisan Atan, K. L. Shek and R. Guzman Rojas. Ultrasound Obstet Gynecol 2016; 48: 239-242. PMID- 27485589 TI - ISUOG Practice Guidelines: invasive procedures for prenatal diagnosis. PMID- 27485590 TI - Repeated Hospital Transfers and Associated Outcomes by Residency Time Among Nursing Home Residents in Taiwan. AB - BACKGROUND: Nursing home residents' repeated transfers to hospital are costly and can lead to in-hospital complications and high mortality for frail residents. However, no research has examined the trajectory of residents' symptoms over their nursing home residency and its relationship to hospital transfer. AIM: The purpose of this retrospective chart-review study was to examine associations between nursing home residents' characteristics, including length of residency, and repeated hospital transfers as well as the trajectory of transfers during residency. DESIGN: For this retrospective study, we reviewed 583 residents' charts in 6 randomly selected nursing homes from northern Taiwan. Data were analyzed by descriptive statistics, chi-squared tests, and 1-way analysis of variance. RESULTS: About half of nursing home residents who had been transferred to hospital (n = 320) were transferred more than twice during their residency (50.97%). Residents who had been transferred 1, 2, 3, or >=4 times differed significantly in length of residency (F = 3.85, P = .01), physical status (F = 2.65, P = .05), medical history of pneumonia (chi2 = 13.03, P = .01), and fractures (chi2 = 8.52, P = .04). Residents with different numbers of transfers differed significantly in their reasons for transfer, that is, falls (chi2 = 13.01, P = .01) and tube problems (chi2 = 8.87, P = .03). Among 705 total transfers, fever was the top reason for transfer, and transfer prevalence increased with nursing home residency. CONCLUSION: To decrease the chance of residents' hospital transfer, nursing home staff should be educated about recognizing and managing fever symptoms, infection-control programs such as influenza vaccination should be initiated, and fall-prevention/education programs should be started when residents first relocate to nursing homes. PMID- 27485591 TI - Intensity of Occupational Therapy Utilization in Nursing Home Residents: The Role of Sensory Impairments. AB - OBJECTIVES: Unaddressed functional limitations in nursing home (NH) residents can lead to unnecessary, excess disability that negatively affects residents' quality of life. In order to enhance functioning, NH residents can receive rehabilitation such as occupational therapy (OT). However, little is known about factors that may aid or hinder full therapy utilization in NH residents. Hence, our study investigated sensory impairments (vision and hearing) and other important health related variables (eg, cognitive functioning) as predictors of intensity of OT utilization. DESIGN: Retrospective study with data extraction from electronic medical records (EMRs). SETTING: Skilled nursing facility. PARTICIPANTS: A sample of newly admitted NH residents (N = 121). MEASUREMENTS: Single items for sociodemographic variables and clinician-rated extent of sensory difficulties (hearing and vision) as well as pain presence based on Minimum Data Set (MDS 3.0) assessments in EMRs. MDS 3.0 scales assess cognitive functioning, depressive symptoms, and functional dependency. Total hours of OT received during 90 days postadmission to the NH were extracted from the EMRs. RESULTS: A regression analysis demonstrated that better admission hearing and cognitive functioning, fewer admission depressive symptoms, and higher admission functional dependence were associated with more intense OT utilization-more hours used-over a 90-day period. CONCLUSION: This study emphasizes the importance of assessing and addressing hearing difficulties and depression in NH residents in order to optimize utilization of beneficial OT services and to promote most optimal independent functioning and quality of life. PMID- 27485592 TI - Novel polymorphic microsatellite loci for distinguishing rock bass (Ambloplites rupestris), Roanoke bass (Ambloplites cavifrons), and their hybrids. AB - The rock bass (Ambloplites rupestris) is a popular sport-fish native to the Mississippi and Great Lakes basins of North America. The species has been widely introduced outside its native range, including into Atlantic-slope streams of Virginia where it may hybridize with an imperiled, similar-looking congener, the Roanoke bass (Ambloplites cavifrons). In this study, we identified and evaluated novel molecular markers to facilitate identification of these species and study the extent of hybridization. Using molecular libraries developed from A. rupestris, we identified a suite of candidate nuclear microsatellite loci, synthesized primer sets, and tested these markers for amplification and polymorphism in populations of both species. We then calculated standard diversity statistics within and differentiation statistics between species, the latter providing an indication of marker power for distinguishing the species and their hybrids. Additionally, we evaluated our efficiency for identifying hybrids by classifying simulated genotypes of known ancestry. Eleven loci were polymorphic (2-22 alleles per locus) and reliably amplified in both species. Multilocus genetic differentiation between A. cavifrons and A. rupestris was quite high (F ST = 0.66; D LR = 19.3), indicating the high statistical power of this marker set for species and hybrid identification. Analyses of simulated data suggested these markers reliably distinguish between hybrids and non-hybrids, as well as between F1 hybrids and backcrossed individuals. This panel of 11 loci should prove useful for understanding patterns of hybridization between A. rupestris and A. cavifrons. As the first microsatellite markers developed for Ambloplites, these markers also should prove broadly useful for population genetic studies of this genus. PMID- 27485595 TI - Minimax and admissible adaptive two-stage designs in phase II clinical trials. AB - BACKGROUND: Simon's two-stage design is the most widely implemented among multi stage designs in phase II clinical trials to assess the activity of a new treatment in a single-arm study. In this two-stage design, the sample size from the second stage is fixed regardless of the number of responses observed in the first stage. METHODS: We develop a new minimax adaptive design for phase II clinical trials, by using the branch-and-bound intelligent algorithm based on conditional error functions. RESULTS: We compare the performance of the proposed design and competitors, including Simon's minimax design, and a modified Simon's design that allows early stopping for futility or efficacy. The maximum sample size of the proposed minimax adaptive design is guaranteed to be less than or equal to those from other existing designs. When the proposed design has the same maximum sample size as others, it always has the smallest expected sample size. In addition to the minimax adaptive design, we also introduce admissible adaptive designs determined from a Bayesian perspective. CONCLUSIONS: The proposed adaptive minimax design can save sample sizes for a clinical trial. The minimum required sample size is critical to reduce the cost of a project. PMID- 27485596 TI - Individualizing endpoints in randomized clinical trials to better inform individual patient care: the TARGET proposal. AB - In practice, critical care practitioners individualize treatments and goals of care for each patient in light of that patient's acute and chronic pathophysiology, as well as their beliefs and values. Yet critical care researchers routinely measure one endpoint for all patients during randomized clinical trials (RCTs), eschewing any such individualization. More recent methodology work has explored the possibility that enrollment criteria in RCTs can be individualized, as can data analysis plans. Here we propose that the specific endpoints of a RCT can be individualized-that is, different patients within a single RCT might have different secondary endpoints measured. If done rigorously and objectively, based on pre-randomization data, such individualization of endpoints may improve the bedside usefulness of information obtained during a RCT, while perhaps also improving the power and efficiency of any RCT. We discuss the theoretical underpinnings of this proposal in light of related innovations in RCT design such as sliding dichotomies. We discuss what a full elaboration of such individualization would require, and outline a pragmatic initial step towards the use of "individualized secondary endpoints" in a large RCT evaluating optimal enteral nutrition targets in the critically ill. PMID- 27485597 TI - Methodological concerns related to response bias in migrant and seasonal farmworkers. AB - BACKGROUND: The original objective was to measure the impact of kneepads on musculoskeletal pain in migrant and seasonal farmworkers (MSFWs). Secondary analyses were conducted to quantify the extent to which response bias may have skewed the study's results. METHODS: Surveys were used to collect data on baseline pain and post-intervention pain, the amount of time participants spent wearing kneepads, and their overall ratings of the intervention. RESULTS: Participants did not experience significantly less pain with kneepads, and wore them for considerably less than the prescribed amount of time. However, subjects rated them very favorably. Given the strong suspicion of response bias, no firm conclusions could be drawn regarding the intervention. CONCLUSIONS: Unique survey methodologies must be used with MSFWs, who tend to have low research literacy and are particularly susceptible to response bias. Objective study outcomes are particularly favorable in this population in order to minimize dependence on self reported measures. Am. J. Ind. Med. 59:1112-1119, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27485599 TI - Serum-based microRNA signatures in early diagnosis and prognosis prediction of colon cancer. AB - Early detection of colorectal cancer is the main prerequisite for successful treatment and reduction of mortality. Circulating microRNAs were previously identified as promising diagnostic, prognostic and predictive biomarkers. The purpose of this study was to identify serum microRNAs enabling early diagnosis and prognosis prediction of colon cancer. In total, serum samples from 427 colon cancer patients and 276 healthy donors were included in three-phase biomarker study. Large-scale microRNA expression profiling was performed using Illumina small RNA sequencing. Diagnostic and prognostic potential of identified microRNAs was validated on independent training and validation sets of samples using RT qPCR. Fifty-four microRNAs were found to be significantly deregulated in serum of colon cancer patients compared to healthy donors (P < 0.01). A diagnostic four microRNA signature consisting of miR-23a-3p, miR-27a-3p, miR-142-5p and miR-376c 3p was established (AUC = 0.917), distinguishing colon cancer patients from healthy donors with sensitivity of 89% and specificity of 81% (AUC = 0.922). This panel of microRNAs exhibited high diagnostic performance also when analyzed separately in colon cancer patients in early stages of the disease (T1-4N0M0; AUC = 0.877). Further, a prognostic panel based on the expression of miR-23a-3p and miR-376c-3p independent of TNM stage was established (HR 2.30; 95% CI 1.44-3.66; P < 0.0004). In summary, highly sensitive signatures of circulating microRNAs enabling non-invasive early detection and prognosis prediction of colon cancer were identified. PMID- 27485598 TI - Genetic variations in the Hippo signaling pathway and breast cancer risk in African American women in the AMBER Consortium. AB - The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. Dysfunction of the Hippo pathway components has been linked with breast cancer stem cell regulation, as well as breast tumor progression and metastasis. TAZ, a key component of the Hippo pathway, is highly expressed in triple negative breast cancer; however, the associations of genetic variations in this important pathway with breast cancer risk remain largely unexplored. Here, we analyzed 8309 germline variants in 15 genes from the Hippo pathway with a total of 3663 cases and 4687 controls from the African American Breast Cancer Epidemiology and Risk Consortium. Odds ratios (ORs) were estimated using logistic regression for overall breast cancer, by estrogen receptor (ER) status (1983 ER positive and 1098 ER negative), and for case-only analyses by ER status. The Hippo signaling pathway was significantly associated with ER-negative breast cancer (pathway level P = 0.02). Gene-based analyses revealed that CDH1 was responsible for the pathway association (P < 0.01), with rs4783673 in CDH1 statistically significant after gene-level adjustment for multiple comparisons (P = 9.2*10(-5), corrected P = 0.02). rs142697907 in PTPN14 was associated with ER-positive breast cancer and rs2456773 in CDK1 with ER-negativity in case-only analysis after gene-level correction for multiple comparisons (corrected P < 0.05). In conclusion, common genetic variations in the Hippo signaling pathway may contribute to both ER negative and ER+ breast cancer risk in AA women. PMID- 27485600 TI - Design, synthesis and anti-P. falciparum activity of pyrazolopyridine-sulfonamide derivatives. AB - Ten 1-phenyl-1H-pyrazolo[3,4-b]pyridine derivatives connected by a linker group to benzenesulfonamide moieties with different substituents in the 4-position were synthesized and assayed against Plasmodium falciparum. These ten compounds exhibited activity in vitro against the chloroquine-resistant clone W2 with IC50 values ranging from 3.46 to 9.30MUM. The most active derivatives with substituent R2=Cl or CH3 at the benzenesulfonamide moiety exhibited the lowest IC50. Compounds with an R1=CO2Et substituent at the 5-position of the 1H-pyrazolo[3,4 b]pyridine ring presented lower activity than those with a CN substituent. The 1H pyrazolo[3,4-b]pyridine system appears to be promising for further studies as an antimalarial for overcoming the burden of resistance in P. falciparum. PMID- 27485601 TI - Identification of the minimum pharmacophore of lipid-phosphatidylserine (PS) binding peptide-peptoid hybrid PPS1D1. AB - We previously reported a unique peptide-peptoid hybrid, PPS1 that specifically recognizes lipid-phosphatidylserine (PS) and a few other negatively charged phospholipids, but not neutral phospholipids, on the cell membrane. The dimeric version of PPS1, i.e., PPS1D1 triggers strong cancer cell cytotoxicity and has been validated in lung cancer models both in vitro and in vivo. Given that PS and other negatively charged phospholipids are abundant in almost all tumor microenvironments, PPS1D1 is an attractive drug lead that can be developed into a globally applicable anti-cancer agent. Therefore, it is extremely important to identify the minimum pharmacophore of PPS1D1. In this study, we have synthesized alanine/sarcosine derivatives as well as truncated derivatives of PPS1D1. We performed ELISA-like competitive binding assay to evaluate the PS-recognition potential and standard MTS cell viability assay on HCC4017 lung cancer cells to validate the cell cytotoxicity effects of these derivatives. Our studies indicate that positively charged residues at the second and third positions, as well as four hydrophobic residues at the fifth through eighth positions, are imperative for the binding and activity of PPS1D1. Methionine at the first position was not essential, whereas the positively charged Nlys at the fourth position was minimally needed, as two derivatives that were synthesized replacing this residue were almost as active as PPS1D1. PMID- 27485602 TI - Similarities and differences in affinity and binding modes of tricyclic pyrimido- and pyrazinoxanthines at human and rat adenosine receptors. AB - A new series of 32 pyrimido- and 5 tetrahydropyrazino[2,1-f]purinediones was obtained and evaluated for their adenosine receptors (ARs) affinities. The 1,3 dibutyl derivative of 9-(4-(2-(dimethylamino)ethoxy)phenyl)-6,7,8,9 tetrahydropyrimido[1,2-f]purine-2,4(1H,3H)-dione was found to be the most potent A1 AR antagonist of the present series, showing selectivity over the other AR subtypes. The structure-activity for the obtained purinediones was established. Docking experiments of the investigated library to homology models of the human and rat A1 and A2A ARs allowed to compare the expected binding modes for selected compounds. The detailed analysis of binding cavities within individual AR subtypes indicated small but significant structural variations that may underlie the observed differences in binding affinities of purinediones at particular subtypes and species. PMID- 27485604 TI - Blinded predictions of binding modes and energies of HSP90-alpha ligands for the 2015 D3R grand challenge. AB - In the framework of the 2015 D3R inaugural grand challenge, blind binding pose and affinity predictions were performed for a set of 180 ligands of the Heat Shock Protein HSP90-alpha protein, a relevant cancer target. Spectral clustering was used to rapidly identify alternative binding site conformations in publicly available crystallographic HSP90-alpha structures. Subsequently, multiple docking and scoring protocols employing the software Autodock Vina and rDock were applied to predict binding modes and rank order ligands. Alchemical free energy calculations were performed with the software FESetup and Sire/OpenMM to predict binding affinities for three congeneric series subsets. Some of the protocols used here were ranked among the top submissions according to most of the evaluation metrics. Docking performance was excellent, but the scoring results were disappointing. A critical assessment of the results is reported, as well as suggestions for future similar competitions. PMID- 27485603 TI - Computer-aided discovery of anti-HIV agents. AB - A review is provided on efforts in our laboratory over the last decade to discover anti-HIV agents. The work has focused on computer-aided design and synthesis of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) with collaborative efforts on biological assaying and protein crystallography. Numerous design issues were successfully addressed including the need for potency against a wide range of viral variants, good aqueous solubility, and avoidance of electrophilic substructures. Computational methods including docking, de novo design, and free-energy perturbation (FEP) calculations made essential contributions. The result is novel NNRTIs with picomolar and low-nanomolar activities against wild-type HIV-1 and key variants that also show much improved solubility and lower cytotoxicity than recently approved drugs in the class. PMID- 27485605 TI - Improving drug safety: From adverse drug reaction knowledge discovery to clinical implementation. AB - Adverse drug reactions (ADRs) are a major public health concern, causing over 100,000 fatalities in the United States every year with an annual cost of $136 billion. Early detection and accurate prediction of ADRs is thus vital for drug development and patient safety. Multiple scientific disciplines, namely pharmacology, pharmacovigilance, and pharmacoinformatics, have been addressing the ADR problem from different perspectives. With the same goal of improving drug safety, this article summarizes and links the research efforts in the multiple disciplines into a single framework from comprehensive understanding of the interactions between drugs and biological system and the identification of genetic and phenotypic predispositions of patients susceptible to higher ADR risks and finally to the current state of implementation of medication-related decision support systems. We start by describing available computational resources for building drug-target interaction networks with biological annotations, which provides a fundamental knowledge for ADR prediction. Databases are classified by functions to help users in selection. Post-marketing surveillance is then introduced where data-driven approach can not only enhance the prediction accuracy of ADRs but also enables the discovery of genetic and phenotypic risk factors of ADRs. Understanding genetic risk factors for ADR requires well organized patient genetics information and analysis by pharmacogenomic approaches. Finally, current state of clinical decision support systems is presented and described how clinicians can be assisted with the integrated knowledgebase to minimize the risk of ADR. This review ends with a discussion of existing challenges in each of disciplines with potential solutions and future directions. PMID- 27485606 TI - Exploring the threshold premium for viable community based health insurance schemes in Nigeria. AB - BACKGROUND: The national health insurance scheme of Nigeria recently proposed a national premium for community based insurance scheme. This study determined the capacity of households in the rural and urban areas in Nigeria to pay for the premium and different hypothetical health insurance schemes namely national health insurance scheme, national urban health insurance scheme, national rural health insurance scheme and regional health insurance schemes. It determined the likely impact of different premiums on membership across socio-economic status quintiles, and then determined the threshold premium affordable to rural and urban households. RESULTS: The results show that the mean capacity to pay for the households in different regions ranged from US$194 +/- 100 to US$986 +/- 907. The threshold premiums of the national health insurance scheme, urban national health insurance and rural health insurance schemes were US$66, US$154 and US$53 respectively. CONCLUSIONS: Overall, the threshold premium for rural national health insurance scheme and national health insurance schemes were affordable to the lowest socio economic group. Hence, it is recommended that threshold premium for rural national health insurance scheme be adopted as the maximum premium not to be exceeded in the proposed national health insurance scheme. PMID- 27485607 TI - Associations between physical activity patterns and dietary patterns in a representative sample of Polish girls aged 13-21 years: a cross-sectional study (GEBaHealth Project). AB - BACKGROUND: Similar to other countries, trends of decreasing levels of physical activity (PA) and an increasing prevalence of unhealthy dietary patterns are observed among girls in Poland. Better understanding of potentially inter-related behaviours within this population can help to design tailored interventions. The purpose of this study was to determine associations between PA patterns and dietary patterns in a representative sample of Polish girls. METHODS: Girls aged 13-21 years (n = 1107) were randomly selected for the study. PA was assessed using International Physical Activity Questionnaire - Long (IPAQ-L). Dietary data were collected with food frequency questionnaires. PA patterns and dietary patterns were drawn separately by Principal Component Analysis (PCA). Logistic regression was used to find the associations between PA patterns and dietary patterns. RESULTS: Four major PA patterns ('School/work activity', 'Active recreation', 'Yard activity' and 'Walking and domestic activity') and four dietary patterns ('Traditional Polish', 'Fruit & vegetables', 'Fast food & sweets' and 'Dairy & fats') were identified. Level of PA was the highest in the upper tertile of 'School/work activity' pattern (mean 1372.2 MET-minutes/week, 95 % Confidence Intervals [CI]: 1285.9-1458.5). Girls in upper tertiles of 'Yard activity', 'Active recreation' and 'School/work activity' patterns had significantly higher chances of being in the upper tertile of the 'Fruit and vegetables' dietary pattern (odds ratio [OR] 2.17, 95 % CI: 1.50-3.14, p < 0.0001; OR 2.02, 95 % CI: 1.41-2.91; p < 0.001 and OR 1.76, 95 % CI: 1.24-2.51, p < 0.01 respectively; all adjusted for confounders) in comparison to bottom tertiles. Weak, but significant inverse associations were found between upper tertiles of 'Active recreation' and 'Yard activity' patterns and unhealthy dietary patterns. CONCLUSIONS: We found associations between PA patterns and dietary patterns in the population of Polish girls. Girls with the highest adherence to the 'School/work activity' pattern had the highest levels of PA and presented pro-healthy dietary behaviours. School should be recognised as potentially efficient and important setting to maximise girls' PA potential. The after-school time is the area that should also be targeted to increase daily PA or to at least sustain the level of PA after completing education. PMID- 27485608 TI - Genome-wide characterization of non-reference transposons in crops suggests non random insertion. AB - BACKGROUND: Transposons (transposable elements or TEs) are DNA sequences that can change their position within the genome. A large number of TEs have been identified in reference genome of each crop(named accumulated TEs), which are the important part of genome. However, whether there existed TEs with different insert positions in resequenced crop accession genomes from those of reference genome (named non-reference transposable elements, non-ref TEs), and what the characteristics (such as the number, type and distribution) are. To identify and characterize crop non-ref TEs, we analyzed non-ref TEs in more than 125 accessions from rice (Oryza sativa), maize (Zea mays) and sorghum (Sorghum bicolor) using resequenced data with paired-end mapping methods. RESULTS: We identified 13,066, 23,866 and 35,679 non-ref TEs in rice, maize and sorghum, respectively. Genome-wide characterization analysis shows that most of non-ref TEs were unique and non-ref TE classes shows different among rice, maize and sorghum. We found that non-ref TEs have a strong positive correlation with gene number and have a bias toward insertion near genes, but with a preference for avoiding coding regions in maize and sorghum. The genes affected by non-ref TE insertion were functionally enriched for stress response mechanisms in all three crops. CONCLUSIONS: These observations suggest that transposon insertion is not a random event and it makes genomic diversity, which may affect the intraspecific adaption and evolution of crops. PMID- 27485609 TI - Providing mental health first aid in the workplace: a Delphi consensus study. AB - BACKGROUND: Mental health problems are common in the workplace, but workers affected by such problems are not always well supported by managers and co workers. Guidelines exist for the public on how to provide mental health first aid, but not specifically on how to tailor one's approach if the person of concern is a co-worker or employee. A Delphi consensus study was carried out to develop guidelines on additional considerations required when offering mental health first aid in a workplace context. METHODS: A systematic search of websites, books and journal articles was conducted to develop a questionnaire with 246 items containing actions that someone may use to offer mental health first aid to a co-worker or employee. Three panels of experts from English speaking countries were recruited (23 consumers, 26 managers and 38 workplace mental health professionals), who independently rated the items over three rounds for inclusion in the guidelines. RESULTS: The retention rate of the expert panellists across the three rounds was 61.7 %. Of the 246 items, 201 items were agreed to be important or very important by at least 80 % of panellists. These 201 endorsed items included actions on how to approach and offer support to a co worker, and additional considerations where the person assisting is a supervisor or manager, or is assisting in crisis situations such as acute distress. CONCLUSIONS: The guidelines outline strategies for a worker to use when they are concerned about the mental health of a co-worker or employee. They will be used to inform future tailoring of Mental Health First Aid training when it is delivered in workplace settings and could influence organisational policies and procedures. PMID- 27485610 TI - "Talk with me": perspectives on services for men with problem gambling and housing instability. AB - BACKGROUND: Problem gambling and homelessness are recognized as important public health concerns that significantly impact individuals, their friends and families, communities and broader society. We aimed to explore the experiences with health and social services of men who had histories of problem gambling and housing instability in Toronto, Ontario. METHODS: We used a community-based participatory approach with a multi-service agency serving low-income individuals. We conducted qualitative interviews with men (n = 30) who had experienced problem gambling and housing instability. Our interviews employed open-ended questions to elicit men's perceptions of services related to housing instability, problem gambling and other comorbid conditions (e.g., mental illness, substance use). We reviewed relevant themes related to experiences with services (e.g., Use of and feedback on: health and social services, housing services, justice/legal aid services, substance use services, gambling services; stigma; goals; triggers; physical health; coping strategies; finances; relationships; barriers to services and recommendations for services). RESULTS: The concept of person-centred engagement was identified as a main overarching theme, and seemed to be lacking in most of the men's experiences of services. Person-centred engagement for these men entailed empowerment and autonomy; empathy, compassion and sincerity; respectful communication; and tailored and holistic life plans. While there was a strong emphasis placed on independence, the men identified the importance of positive therapeutic relationships as being critical aspects of the recovery process. Based on our analyses, several recommendations were identified: 1) Increasing general awareness of services for problem gambling; 2) Delivering integrated services in a one-stop-shop; 3) Addressing mental health with psychotherapy and pharmacotherapy; 4) Providing timely access to prevention and recovery services; and 5) Enhancing life skills with peer support. CONCLUSIONS: Our study highlighted that most of the men we interviewed were not having their health and social needs met. Services need to address the intersection of problem gambling, housing instability, and other comorbidities. Ensuring services are grounded in person-centred engagement appears to be critical for optimal service delivery. PMID- 27485611 TI - Analysis of RTEL1 and PCDHGB6 promoter methylation in circulating-free DNA of lung cancer patients using liquid biopsy: A pilot study. AB - BACKGROUND: Analysis of epigenetic alterations such as methylation of circulating free DNA (cf-DNA) expression significantly broadened perspectives of lung cancer (LC) screening. Moreover, methylation of tumor suppressor genes may be analyzed with non-invasive manner in patients' blood samples (liquid biopsy), what underline necessity of detailed investigation of tumor cf-DNA. MATERIAL AND METHODS: The purpose of current study was to assess methylation of RTEL1 and PCDHGB6 promoter regions in cf-DNA of 70 LC patients and 80 healthy individuals using qMSP-PCR technique. Methylation status of both genes has not been investigated in cf-DNA of LC patients before. RESULTS: PCDHGB6 promoter methylation was found in 41.4% of LC patients and in 1.3% of healthy individuals, whereas promoter of RTEL1 was found methylated in 51.4% of LC patients and in 8.8% of healthy individuals. Combined analysis of two markers improved test sensitivity up to 62.9% and specificity up to 90% with area under the curve (AUC) in receiver operating curve (ROC) of 0.755. CONCLUSIONS: The evaluation of RTEL1 and PCDHGB6 promoter methylation may be an useful tool for non-invasive diagnosis of LC in liquid biopsy. PMID- 27485612 TI - Atomic resolution mechanistic studies of ribocil: A highly selective unnatural ligand mimic of the E. coli FMN riboswitch. AB - Bacterial riboswitches are non-coding RNA structural elements that direct gene expression in numerous metabolic pathways. The key regulatory roles of riboswitches, and the urgent need for new classes of antibiotics to treat multi drug resistant bacteria, has led to efforts to develop small-molecules that mimic natural riboswitch ligands to inhibit metabolic pathways and bacterial growth. Recently, we reported the results of a phenotypic screen targeting the riboflavin biosynthesis pathway in the Gram-negative bacteria Escherichia coli that led to the identification of ribocil, a small molecule inhibitor of the flavin mononucleotide (FMN) riboswitch controlling expression of this biosynthetic pathway. Although ribocil is structurally distinct from FMN, ribocil functions as a potent and highly selective synthetic mimic of the natural ligand to repress riboswitch-mediated ribB gene expression and inhibit bacterial growth both in vitro and in vivo. Herein, we expand our analysis of ribocil; including mode of binding in the FMN binding pocket of the riboswitch, mechanisms of resistance and structure-activity relationship guided efforts to generate more potent analogs. PMID- 27485613 TI - Setting up computed tomography automatic tube current modulation systems. AB - Automatic tube current modulation (ATCM) on CT scanners can yield significant reductions in patient doses. Modulation is based on x-ray beam attenuation in body tissues obtained from scan projection radiographs (SPRs) and aims to maintain the same level of image quality throughout a scan. Noise level is important in judging image quality, but tissues in larger patients exhibit higher contrast resulting from the presence of fat. CT scanner manufacturers use different metrics to assess image quality. Some employ a simple measure of image noise, while others adopt a measure related to a reference image that accepts higher noise levels in more attenuating parts with higher contrast. At the present time there is no standard method for testing ATCM. This paper reviews the operation of different ATCM systems, considers options for testing, and sets out a framework that could be used for optimizing clinical protocols. If dose and image quality can be established for a reference phantom, the modulation performed by ATCM systems can be characterised using anatomical phantoms or geometrical elliptical phantoms which may be conical or include sections of varying dimension. For scanners using a reference image or mAs, selection of the image quality reference determines other factors. However, for scanners using a noise reference, a higher noise level should be selected for larger patients to avoid high doses, and the operator should ensure that appropriate limits are set for mA modulation. Other factors that need to be considered include the SPRs used to plan the ATCM and image thickness. Users should be aware of the mode of operation of the ATCM system on their CT scanner, and be familiar with the effects of changing different protocol parameters. The behaviour of ATCM systems should be established through testing of each CT scanner with suitable phantoms during commissioning. PMID- 27485614 TI - Indicative role of urban tree vegetation in the assessment of natural and man made complex in Akhtubinsk and its local areas. AB - The study was conducted as a part of the selection of the objects of phytomonitoring for the environmental assessment on the value of fluctuating asymmetry of bilateral morphological parameters. The territorial structure of flora of tree layer in Akhtubinsk and its local areas was determined as of 2013. The living conditions and species and quantitative composition of the tree layer of urban landscape were examined. The vital status of trees was assessed on a ten point scale of the categories: good condition; satisfactory; weakened plants (Bukharina and Dvoeglazova 2010). The quantitative assessment of biodiversity of tree layer was made on the basis of conventional indices of individual dominance and dominating structures, as well as the method of multivariate statistical analysis. This is an objective method that has been used by other authors in a variety of the environmental studies for a long time, but it has not been actively used in the studies of the Astrakhan area vegetation yet. The results of the study make it possible to believe that the most appropriate indicator of tree vegetation for biomonitoring of intact floodplain, residential and recreational areas in the urban territory in the arid climate of the Volga-Akhtuba floodplain is the Chinese elm (Ulmus parvifolia Jacq.),as the most widespread, numerous and sensitive. It is noted that the tree vegetation cannot be a universal bioindicator of the urban environment in Akhtubinsk and its local areas by fluctuating asymmetry of bilateral morphological parameters. PMID- 27485615 TI - Impact assessment of PM10 cement plants emissions on urban air quality using the SCIPUFF dispersion model. AB - The Second-order Closure Integrated Puff (SCIPUFF) model was used to study the impact on urban air quality caused by two cement plants emissions located near the city of Caserta, Italy, during the entire year of 2015. The simulated and observed PM10 concentrations were compared using three monitoring stations located in urban and sub-urban area of Caserta city. Both simulated and observed concentrations are shown to be highest in winter, lower in autumn and spring and lowest in summer. Model results generally follow the pattern of the observed concentrations but have a systematic under-prediction of the concentration values. Measures of the bias, NMSE and RMSE indicate a good correlation between observed and estimated values. The SCIPUFF model data analysis suggest that the cement plants are major sources for the measured PM10 values and are responsible for the deterioration of the urban air quality in the city of Caserta. PMID- 27485616 TI - Bioaccumulation of heavy metals in crop plants grown near Almeda Textile Factory, Adwa, Ethiopia. AB - The contents of heavy metals cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), manganese (Mn), nickel (Ni), lead (Pb), and zinc (Zn) present in water (wastewater and wetland), soils, and food crops collected from the vicinity of Almeda Textile Factory were quantified using Flame Atomic Absorption Spectrometer (FAAS) in order to assess the environmental impact of the textile factory. The contents of heavy metals determined in the wastewater were found below the recommended limit set by WHO and United States Environmental Protection Agency (US EPA) except for Cr, which was found slightly higher than WHO permissible limit. Besides, the contents of the heavy metals determined in soils were below the permissible level of FAO/WHO and Canada maximum allowable limits. Moreover, only the concentrations of Cd and Pb were found above the permissible level set by FAO/WHO in the crop plants studied. Generally, the mean concentrations of heavy metals in the plants were in the decreasing order of: Mn > Zn > Cu > Pb > Ni > Co > Cr > Cd. Nevertheless, higher bioconcentration factor (BCF) was found for Cd (0.108-1.156) followed by Zn (0.081-0.499). In conclusion, comparison of heavy metal concentrations with the permissible limits in all collected sample types i.e. water, soil, and crop plants did not show significant pollution from the factory. PMID- 27485617 TI - In vitro characterization of an osteoinductive biphasic calcium phosphate in combination with recombinant BMP2. AB - BACKGROUND: The repair of alveolar bone defects with growth factors and bone grafting materials has played a pivotal role in modern dentistry. Recombinant human bone morphogenetic protein-2 (rhBMP2), an osteoinductive growth factor capable of cell recruitment and differentiation towards the osteoblast lineage, has been utilized in combination with various biomaterials to further enhance new bone formation. Recently, a group of novel biphasic calcium phosphate (BCP) bone grafting materials have been demonstrated to possess osteoinductive properties by demonstrating signs of ectopic bone formation. The aim of the present study was to study the effects of rhBMP2 in combination with osteoinductive BCP bone grafts on osteoblast cell behaviour. METHODS: MC3T3-E1 pre-osteoblasts were seeded on 1) control tissue culture plastic, 2) 10 mg of BCP alone, 3) 100 ng rhBMP2, and 4) 100 ng rhBMP2+ 10 mg of BCP and analyzed for cell recruitment via a Transwell chamber, proliferation via an MTS assay and differentiation as assessed by alkaline phosphatase (ALP) activity, alizarin red staining and real-time PCR for osteoblast differentiation markers including Runx2, collagen1, ALP, and osteocalcin (OCN). RESULTS: rhBMP2 was able to significantly upregulate cell recruitment whereas the addition of BCP as well as BCP alone had no additional ability to improve osteoblast recruitment. Both BCP and rhBMP2 were able to significantly increase cell proliferation at 3 and 5 days post seeding and cell number was further enhanced when rhBMP2 was combined with BCP. In addition, the combination of rhBMP2 with BCP significantly improved ALP activity at 7 and 14 days post seeding, alizarin red staining at 14 days, and mRNA levels of Runx2, ALP and osteocalcin when compared to cells seeded with rhBMP2 alone or BCP alone. CONCLUSIONS: The results from the present study demonstrate that 1) the osteoinductive potential of BCP bone particles is equally as osteopromotive as rhBMP2 on in vitro osteoblast differentiation and 2) BCP particles in combination with rhBMP2 is able to further increase the osteopromotive differentiation of osteoblasts in vitro when compared to either rhBMP2 alone or BCP alone. Future animal testing is further required to investigate this combination approach on new bone formation. PMID- 27485619 TI - What socioeconomic factors are associated with different levels of antenatal care visits in Bangladesh? A behavioral model. AB - We identify the socioeconomic determinants of three levels of antenatal care (ANC) visits (no, intermediate [1-3], and recommended [>=4]) in Bangladesh using a behavior model framework for health care utilization. Using multinomial logistic regression, we found that different levels of visits had different determinants; for example, media exposure increased the likelihood of intermediate compared with no visits while desire for pregnancy increased the likelihood of recommended compared with intermediate visits. We therefore highlight that ANC policies or interventions should be target-group specific because determinants differ depending on level of ANC visits. PMID- 27485618 TI - Health services research of integrative oncology in palliative care of patients with advanced pancreatic cancer. AB - BACKGROUND: Pancreatic cancer has a dire prognosis and is associated with a high mortality. Palliative patients have special needs and often seek help in integrative oncological concepts (IO) that combine conventional and complementary therapies. Nevertheless there are few recommendations regarding IO in current cancer guidelines. The aims of this study were to report on implementation of IO in everyday palliative care and to analyze patient survival in advanced pancreatic cancer. METHODS: This multicenter observational study investigates the implementation of IO and length of survival of patients suffering from advanced pancreatic cancer (stage IV). We analyzed patient's survival by employing multivariable proportional hazard models using different parametric distribution functions and compared patients receiving chemotherapy only, a combination of chemotherapy and Viscum album (VA) treatment, and VA treatment only. RESULTS: Records of 240 patients were analyzed. Complementary therapy showed high acceptance (93 %). Most frequent therapy was VA treatment (74 %) that was often administered concomitantly to chemotherapy (64 %). Both therapies had positive effects on patient survival as they had significant negative effects on the hazard in our log-normal model. A second analysis showed that patients with combined chemotherapy and VA therapy performed significantly better than patients receiving only chemotherapy (12.1 to 7.3 month). Patients receiving only VA therapy showed longer survival than those receiving neither chemotherapy nor VA therapy (5.4 to 2.5 months). Our data demonstrates that IO can be implemented in the everyday care of patients without disregarding conventional treatment. Patients combining VA with chemotherapy showed longest survival. CONCLUSIONS: Our data demonstrate the importance and potential of health services research showing that IO treatment can be successfully implemented in the every-day care of patients suffering from advanced pancreatic cancer. Patients combining VA with chemotherapy showed longest survival. To address patients' needs adequately, future cancer guidelines might increasingly include comments on complementary treatment options in addition to conventional therapies. Further studies should investigate the effect of complementary treatments on survival and quality of life in more detail. PMID- 27485620 TI - Interactive effects of phosphorus and Pseudomonas putida on chickpea (Cicer arietinum L.) growth, nutrient uptake, antioxidant enzymes and organic acids exudation. AB - Phosphorus (P) availability in alkaline soils of arid and semi-arid regions is a major constraint for decreased crop productivity. Use of plant growth promoting rhizobacteria (PGPR) may enhance plant growth through the increased plant antioxidation activity. Additionally, PGPR may increase nutrient uptake by plants as a result of induced root exudation and rhizosphere acidification. The current study was aimed to investigate combined effects of P and Pesudomonas putida (PGPR) on chickpea growth with reference to antioxidative enzymatic activity and root exudation mediated plant nutrient uptake, particularly P. Half of the seeds were soaked in PGPR solution, whereas others in sterile water and latter sown in soils. Plants were harvested 8 weeks after onset of experiment and analyzed for leaf nutrient contents, antioxidant enzymes activities and organic acids concentrations. Without PGPR, P application (+P) increased various plant growth attributes, plant uptake of P and Ca, soil pH, citric acid and oxalic acid concentrations, whereas decreased the leaf POD enzymatic activity as compared to the P-deficiency. PGPR supply both under -P and +P improved the plant growth, plant uptake of N, P, and K, antioxidative activity of SOD and POD enzymes and concentrations of organic acids, whereas reduced the rhizosphere soil pH. Growth enhancement by PGPR supply was related to higher plant antioxidation activity as well as nutrient uptake of chickpea including P as a result of root exudation mediated rhizosphere acidification. PMID- 27485621 TI - Sleep problems and temperament in young children with Down syndrome and typically developing controls. AB - BACKGROUND: Although group differences have been found between children with Down syndrome (DS) and typically developing (TD) children when considering sleep problems and temperament independently, none of the research conducted to date has examined sleep-temperament associations in children with DS. The present research was conducted to determine (1) whether the sleep problems experienced by children with DS are associated with temperament or (2) if the demonstrated relations between sleep and temperament differ from those that are observed in TD children. METHOD: The present study included examination of relations between parent-reported sleep problems and temperament in 19 children with DS and 20 TD controls matched on developmental age. RESULTS: The results revealed group differences in temperament and sleep problems. Mediation models indicated that temperament (effortful control and inhibitory control) mediated the association between group and sleep problems; sleep problems also mediated the association between group and temperament (effortful and inhibitory control). CONCLUSION: Findings indicated that sleep problems may serve as both cause and consequence of variability in effortful and inhibitory control and provide insight as to future experimental studies that should be conducted to better elucidate these relations. PMID- 27485622 TI - Dual-immuno-MS technique for improved differentiation power in heterodimeric protein biomarker analysis: determination and differentiation of human chorionic gonadotropin variants in serum. AB - If the biomarker potential of intact heteromers and their free subunits is different, differentiation between these forms may reveal important clinical information. Such differentiation may however be analytically challenging. One possible way of circumventing this challenge is by performing a dual-immuno-MS approach. In the present paper, a two-step immunoaffinity sample preparation step is succeeded by digestion and subsequent LC-MS analysis to provide high sensitivity quantification and differentiation between the heterodimer human chorionic gonadotropin (hCG) and its free beta-subunit in serum. Intact and free variants are captured in two separate immunoextraction steps in order to increase the differentiation power of the method. Intact heterodimer variants were depleted prior to free subunit variants in order to incorporate a method quality control. The method was optimized for serum samples. A fully validated immuno-MS method was used as foundation, and partial validation according to the European Medicines Agency's (EMA) guidelines on validation of bioanalytical methods was performed for the dual approach. An accelerated digestion step was incorporated making batch processing of samples within 1 day possible (approx. 3.5 h of sample preparation including digestion). Acceptable linearity (R (2) >= 0.990 for four variants and R (2) of 0.920 and 0.966 for the remaining two) and specificity were demonstrated, and the method was robust toward varying levels of intact heterodimer versus free subunit. The method was also successfully tested on realistic samples, demonstrating both the differences in total hCG and the distribution between intact hCG and its free beta-subunit in real samples. Graphical abstract Schematic overview of the dual immuno-MS process. PMID- 27485623 TI - An approach to optimize sample preparation for MALDI imaging MS of FFPE sections using fractional factorial design of experiments. AB - A standardized workflow for matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI imaging MS) is a prerequisite for the routine use of this promising technology in clinical applications. We present an approach to develop standard operating procedures for MALDI imaging MS sample preparation of formalin-fixed and paraffin-embedded (FFPE) tissue sections based on a novel quantitative measure of dataset quality. To cover many parts of the complex workflow and simultaneously test several parameters, experiments were planned according to a fractional factorial design of experiments (DoE). The effect of ten different experiment parameters was investigated in two distinct DoE sets, each consisting of eight experiments. FFPE rat brain sections were used as standard material because of low biological variance. The mean peak intensity and a recently proposed spatial complexity measure were calculated for a list of 26 predefined peptides obtained by in silico digestion of five different proteins and served as quality criteria. A five-way analysis of variance (ANOVA) was applied on the final scores to retrieve a ranking of experiment parameters with increasing impact on data variance. Graphical abstract MALDI imaging experiments were planned according to fractional factorial design of experiments for the parameters under study. Selected peptide images were evaluated by the chosen quality metric (structure and intensity for a given peak list), and the calculated values were used as an input for the ANOVA. The parameters with the highest impact on the quality were deduced and SOPs recommended. PMID- 27485624 TI - Sensitive and specific detection of miRNA using an isothermal exponential amplification method using fluorescence-labeled LNA/DNA chimera primers. AB - MicroRNAs (miRNAs) are currently considered as potential biomarkers for various human diseases. In the present study, miRNA-triggered real-time fluorescent isothermal reaction with exponential amplification (ReFIRE) with or without Thermus aquaticus MutS (Taq MutS) was developed to analyze miRNAs using DNA polymerase, a nicking endonuclease, and fluorescently labeled primers. In the absence of Taq MutS, the ReFIRE system permitted the detection of 100 ymol of targeted miRNA in 80 min. However, this system enabled limited differentiation between homologous miRNA family members. Upon addition of Taq MutS to the ReFIRE system, non-specific amplification generated from the mishybridization between primers and primer dimers or primers and the template duplex was eliminated. The addition of Taq MutS enabled the ultrasensitive detection of as little as 10 ymol of targeted miRNAs in 50 min, which corresponds to less than 10 copies of miRNAs in a total volume of 20 MUl. Additionally, the assay exhibited a dynamic range of up to 12 orders of magnitude. The ReFIRE system also showed high specificity, enabling differentiation between homologous miRNA family members exhibiting only single-base differences. The sensitivity, specificity, and dynamic range associated with this system were greater than most currently available miRNA isothermal amplification assays. Moreover, when target-specific primers were labeled with different fluorescent reporters, multiplex analysis was easily performed in a single tube, permitting accurate normalization of miRNA expression. This simple, fast, ultrasensitive, highly specific, and easy-to multiplex method could significantly contribute to research investigations pertaining to the biological roles of miRNA, as well as clinical diagnosis of various diseases that involve miRNA disruptions. Graphical Abstract The principle of ReFIRE system. PMID- 27485625 TI - A novel carbon material with nanopores prepared using a metal-organic framework as precursor for highly selective enrichment of N-linked glycans. AB - Protein glycosylation plays a key role in many biological processes. In this study, a novel carbon material with nanopores was prepared by carbonization of metal-organic framework (MOF) Mil-101(Cr). The parent MOF assembled from metal ions with bridging organic linkers had many fascinating properties, such as ultrahigh surface area, suitable nanopore structure, and especially a large amount of carbon after being calcined. Due to the strong interactions between carbon and glycans as well as the size-exclusion effect of pore against protein, the N-linked glycans from standard glycoprotein or complex human serum proteins could be identified with high efficiency. The simple synthesis method as well as good enrichment efficiency made this novel carbon material a promising tool for glycosylation research. PMID- 27485626 TI - Recent advances and progress in the detection of bisphenol A. AB - Bisphenol A (BPA) is an important industrial chemical used as a plasticizer in polycarbonate and epoxy resins in the plastic and paper industries. Because of its estrogenic properties, BPA has attracted increasing attention from many researchers. This review focuses primarily on analytical methods for BPA detection that have emerged in recent years. We present and discuss the advantages and disadvantages of sample preparation techniques (e.g., solvent extraction, solid-phase extraction, molecularly imprinted polymer solid-phase extraction, and micro-extraction techniques) and analytical methods (e.g., liquid chromatography, liquid chromatography-mass spectrometry, gas chromatography-mass spectrometry, capillary electrophoresis, immunoassay, and several novel sensors). We also discuss expected future developments for the detection of BPA. Graphical Abstract This review focuses primarily on the recent development in the detection of bisphenol A including sample pre-treatment and analytical methods. PMID- 27485627 TI - Exploring the flexible chemistry of 4-fluoro-3-nitrophenyl azide for biomolecule immobilization and bioconjugation. AB - Bioconjugation and functionalization of polymer surfaces are two major tasks in materials chemistry which are accomplished using a variety of coupling agents. Immobilization of biomolecules onto polymer surfaces and the construction of bioconjugates are essential requirements of many biochemical assays and chemical syntheses. Different linkers with a variety of functional groups are used for these purposes. Among them, the benzophenones, aryldiazirines, and arylazides represent the most commonly used photolinker to produce the desired chemical linkage upon their photo-irradiation. In this review, we describe the versatile applications of 4-fluoro-3-nitrophenyl azide, one of the oldest photolinkers used for photoaffinity labeling in the late 1960s. Surprisingly, this photolinker, historically known as 1-fluoro-2-nitro-4-azidobenzene (FNAB), has remained unexplored for a long time because of apprehension that FNAB forms ring-expanded dehydroazepine as a major product and hence cannot activate an inert polymer. The first evidence of photochemical activation of an inert surface by FNAB through nitrene insertion reaction was reported in 2001, and the FNAB-activated surface was found to conjugate a biomolecule without any catalyst, reagent, or modification. FNAB has distinct advantages over perfluorophenyl azide derivatives, which are contemporary nitrene-generating photolinkers, because of its simple, single-step preparation and ease of thermochemical and photochemical reactions with versatile polymers and biomolecules. Covering these aspects, the present review highlights the flexible chemistry of FNAB and its applications in the field of surface engineering, immobilization of biomolecules such as antibodies, enzymes, cells, carbohydrates, oligonucleotides, and DNA aptamers, and rapid diagnostics. Graphical Abstract An overview of the FNAB-engineered activated polymer surfaces for covalent ligation of versatile biomolecules. PMID- 27485628 TI - Some ruminations on graduate students. PMID- 27485629 TI - Investigation of Growth Phase-Dependent Acid Tolerance in Bifidobacteria longum BBMN68. AB - The underlying mechanisms imparting the growth phase-dependent acid tolerance have not been extensively investigated. In this study, we compared the acid resistance of the Bifidobacterium longum strain BBMN68 from different growth phases at lethal pH values (pH 2.5, 3.0, and 3.5), and analyzed the activity of H(+)-ATPase, the composition of fatty acids, and the mRNA abundance of ffh, uvrA, recA, lexA, groES, and dnaK in cells from different growth phases. The results indicated that the survival rates of cells from early stationary (ES) and late stationary (LS) growth phases at lethal pH values were significantly higher than those of exponential growth phase cells. Our findings indicated that by inducing a continuously auto-acidizing environment during cell growth, the acid resistance of ES and LS cells was strengthened. The higher activity of H(+)-ATPase, the decrease in unsaturated fatty acids, and the increased expression of genes involved in DNA repair and protein protection in the cells in stationary growth phase were all implicated in the significantly increased acid resistance of ES and LS cells compared with exponential growth phase cells of the B. longum strain BBMN68. PMID- 27485630 TI - Is Stem Cell Transplantation Ready for Prime Time in Diabetic Polyneuropathy? AB - Diabetic polyneuropathy (DPN) is the most common complication that emerges early in patients who have diabetes. Curative treatment for overt or symptomatic DPN has not been established, requiring much effort to explore new modalities. Thus, the use of various kinds of stem cells as a potential therapeutic option for DPN is of particular interest. The beneficial effects were proposed to be attributed to either cytokine released from transplanted stem cells or the differentiation of stem cells to substitute the damaged peripheral nerve. Furthermore, based on the concept that humoral factors secreted from stem cells play a pivotal role in tissue regeneration, the utilization of conditioned medium derived from the stem cell culture serves as a novel tool for regenerative therapy. However, many questions have not been yet answered to determine whether stem cell therapy is essential in clinical application of DPN. In this report, we review the current status of preclinical studies on stem cell therapy for DPN and discuss future prospects. PMID- 27485631 TI - Aggregatibacter aphrophilus chronic lacrimal canaliculitis: a case report. AB - BACKGROUND: Chronic canaliculitis is often misdiagnosed as conjunctivitis, delaying proper documentation and management. Aggregatibacter aphrophillus has not been implicated in chronic canaliculitis. CASE PRESENTATION: We report a case of unilateral chronic epiphora associated with chronic lacrimal canaliculitis resistant to prolonged topical antibiotic treatment in a 65-year-old woman without notable medical history. Canaculotomy, curettage with removal of concretions and tubing with silicone stent for six weeks resolved this chronic infection. Culturing lacrimal secretions and concretions yielded Aggregatibacter aphrophilus in pure culture. Histological analyses showed elongated seed clusters surrounded by neutrophils. Fluorescence in Situ Hybridization confirmed the presence of bacteria in two distinctive concretions. CONCLUSION: This first documented case of A. aphrophilus chronic lacrimal canaliculitis illustrates that optimal surgical management of chronic lacrimal canaliculitis allows for both accurate microbiological diagnosis and treatment. PMID- 27485632 TI - Dual pharmacological inhibition of glutathione and thioredoxin systems synergizes to kill colorectal carcinoma stem cells. AB - NRF2 stabilizes redox potential through genes for glutathione and thioredoxin antioxidant systems. Whether blockade of glutathione and thioredoxin is useful in eliminating cancer stem cells remain unknown. We used xenografts derived from colorectal carcinoma patients to investigate the pharmacological inhibition of glutathione and thioredoxin systems. Higher expression of five glutathione S transferase isoforms (GSTA1, A2, M4, O2, and P1) was observed in xenograft derived spheroids than in fibroblasts. Piperlongumine (2.5-10 MUmol/L) and auranofin (0.25-4 MUmol/L) were used to inhibit glutathione S-transferase pi and thioredoxin reductase, respectively. Piperlongumine or auranofin alone up regulated the expression of NRF2 target genes, but not TP53 targets. While piperlongumine showed modest cancer-specific cell killing (IC50 difference between cancer spheroids and fibroblasts: P = 0.052), auranofin appeared more toxic to fibroblasts (IC50 difference between cancer spheroids and fibroblasts: P = 0.002). The synergism of dual inhibition was evaluated by determining the Combination Index, based on the number of surviving cells with combination treatments. Molar ratios indicated synergism in cancer spheroids, but not in fibroblasts: (auranofin:piperlongumine) = 2:5, 1:5, 1:10, and 1:20. Cancer specific cell killing was achieved at the following drug concentrations (auranofin:piperlongumine): 0.25:2.5 MUmol/L, 0.5:2.5 MUmol/L, or 0.25:5 MUmol/L. The dual inhibition successfully decreased CD44v9 surface presentation and delayed tumor emergence in nude mouse. However, a small subpopulation persistently survived and accumulated phosphorylated histone H2A. Such "persisters" still retained lesser but significant tumorigenicity. Thus, dual inhibition of glutathione S-transferase pi and thioredoxin reductase could be a feasible option for decreasing the tumor mass and CD44v9-positive fraction by disrupting redox regulation. PMID- 27485633 TI - Access to health for refugees in Greece: lessons in inequalities. AB - Eastern Greek islands have been direct passageways of (mainly Syrian) refugees to the European continent over the past year. However, basic medical care has been insufficient. Despite calls for reform, the Greek healthcare system has for many years been costly and dysfunctional, lacking universal equity of access. Thus, mainly volunteers look after the refugee camps in the Greek islands under adverse conditions. Communicable diseases, trauma related injuries and mental health problems are the most common issues facing the refugees. The rapid changes in the epidemiology of multiple conditions that are seen in countries with high immigration rates, like Greece, demand pragmatic solutions. Best available knowledge should be used in delivering health interventions. So far, Greece is failed by international aid, and cross-border policies have not effectively tackled underlying reasons for ill-health in this context, like poverty, conflict and equity of access. PMID- 27485635 TI - Sex allocation conflict between queens and workers in Formica pratensis wood ants predicts seasonal sex ratio variation. AB - Sex allocation theory predicts parents should adjust their investment in male and female offspring in a way that increases parental fitness. This has been shown in several species and selective contexts. Yet, seasonal sex ratio variation within species and its underlying causes are poorly understood. Here, we study sex allocation variation in the wood ant Formica pratensis. This species displays conflict over colony sex ratio as workers and queens prefer different investment in male and female offspring, owing to haplodiploidy and relatedness asymmetries. It is unique among Formica ants because it produces two separate sexual offspring cohorts per season. We predict sex ratios to be closer to queen optimum in the early cohort but more female-biased and closer to worker optimum in the later one. This is because the power of workers to manipulate colony sex ratio varies seasonally with the availability of diploid eggs. Consistently, more female biased sex ratios in the later offspring cohort over a three-year sampling period from 93 colonies clearly support our prediction. The resulting seasonal alternation of sex ratios between queen and worker optima is a novel demonstration how understanding constraints of sex ratio adjustment increases our ability to predict sex ratio variation. PMID- 27485634 TI - Mitofusin-2 is required for mouse oocyte meiotic maturation. AB - Mitofusin-2 (Mfn2) is essential for embryonic development, anti-apoptotic events, protection against free radical-induced lesions, and mitochondrial fusion in many cells. However, little is known about its mechanism and function during oocyte maturation. In this study, we found that Mfn2 was expressed in the cytoplasm during different stages of mouse oocyte maturation. Mfn2 was mainly associated with alpha-tubulin during oocyte maturation. Knockdown of Mfn2 by specific siRNA injection into oocytes caused the mitochondrial morphology and quantity to change, resulting in severely defective spindles and misaligned chromosomes. This led to metaphase I arrest and the failure of first polar body extrusion. Furthermore, Mfn2 depletion from GV stage oocytes caused the redistribution of p38 MAPK in oocyte cytoplasm. These findings provide insights into potential mechanisms of Mfn2-mediated cellular alterations, which may have significant implications for oocyte maturation. PMID- 27485636 TI - Bilberry extract, its major polyphenolic compounds, and the soy isoflavone genistein antagonize the cytostatic drug erlotinib in human epithelial cells. AB - Erlotinib (Tarceva(r)) is a chemotherapeutic drug approved for the treatment of pancreatic cancer and non-small cell lung cancer. Its primary mode of action is the inhibition of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK). Recently, RTK-inhibiting polyphenols have been reported to interact synergistically with erlotinib. Furthermore some anthocyanidins and anthocyanin-rich berry extracts have been reported to inhibit tyrosine kinases, including the EGFR, which raises the question of potential interactions with erlotinib. Polyphenol-rich preparations such as berry- or soy-based products are commercially available as food supplements. In the present study we tested a bilberry extract, its major anthocyanin and potential intestinal degradation products, as well as genistein, with respect to possible interactions with erlotinib. Cell growth inhibition was assessed using the sulforhodamine B assay, while interactions with EGFR phosphorylation were analyzed by SDS-PAGE/western blotting with subsequent immunodetection. Genistein, bilberry extract, delphinidin-3-O-glucoside and delphinidin were found to antagonize erlotinib whereas phloroglucinol aldehyde was found to enhance cytostatic effects of the drug on human epithelial A431 cells. Genistein also antagonized the EGFR inhibitory effects of erlotinib, whereas bilberry anthocyanins showed no significant interactions in this regard. Our data indicate that different polyphenols are potentially able to impair the cytostatic effect of erlotinib in vitro. Genistein interacts via the modulation of erlotinib-mediated EGFR inhibition whereas bilberry anthocyanins modulated the growth-inhibitory effect of erlotinib without affecting EGFR phosphorylation, thus indicating a different mechanism of interference. PMID- 27485637 TI - Dosimetric impact of different bladder and rectum filling during prostate cancer radiotherapy. AB - BACKGROUND: The aim of this study was to analyze the influence of volumetric changes of bladder and rectum filling on the 3D dose distribution in prostate cancer radiotherapy. METHODS: A total of 314 cone-beam CT (CBCT) image data sets from 19 patients were enrolled in this study. For each CBCT, the bladder and rectum were contoured and volume sizes were normalized to those on their original CT. The daily delivered dose was recalculated on the CBCT images and the doses to bladder and rectum were investigated. Linear regression analysis was performed to identify the mean dose change of the volume change using SPSS 19. RESULTS: The data show that the variances of the normalized volume of the bladder and the rectum are 0.13-0.58 and 0.12-0.50 respectively. The variances of V70Gy, V60Gy, V50Gy, V40Gy and V30Gy of bladder are bigger than those of rectum for 17 patients. The linear regression analysis indicates a 10 % increase in bladder volume will cause a 5.6 % (+/-4.9 %) reduction in mean dose (p <0.05). CONCLUSIONS: The bladder's volume change is more significant than that of the rectum for the prostate cancer patient. The rectum volume variations are not significant except for air bubbles, which change the shape and the position of the rectum. The bladder volume variations may cause dose changes proportionately. Monitoring the bladder's volume before fractional treatment delivery will be crucial for accurate dose delivery. PMID- 27485638 TI - Resistant mechanisms and molecular epidemiology of imipenem-resistant Acinetobacter baumannii. AB - The aim of the study was to investigate the resistant mechanisms and homology of imipenem-resistant Acinetobacter baumannii (A. baumannii). A total of 46 non duplicate imipenem-resistant A. baumannii clinical isolates were collected from three tertiary hospitals between July, 2011 and June, 2012. The minimal inhibitory concentrations (MICs) of antimicrobial agents were determined using the agar dilution method. Phenylalanine-arginine beta-naphthylamide was used to detect the presence of the efflux pump-mediated resistant mechanism. Polymerase chain reaction was employed to amplify genes associated with drug resistance, including beta-lactamase genes, efflux pump genes and outer membrane protein gene CarO. A few amplicons were randomly selected and sequenced. Multilocus sequence analysis (MLST) was employed in typing A. baumanni. A. baumannii was resistant to imipenem, simultaneously showing resistance to several other antimicrobials. In addtition, 13 A. baumannii were found to mediate drug resistance through operation of the efflux pump. Of the various drug resistance genes tested, blaOXA 51 was present in 46 isolates, blaOXA-23 gene was present in 44 isolates and blaNDM gene was found in only one strain. Other drug resistant-associated genes, including blaKPC, blaIMP, blaOXA-24, blaOXA-58, blaSHV, blaGIM and blaVIM were not detected. Mutation of adeS and outer membrane protein gene CarO were found in a few of the imipenem-resistant isolates. The MLST analysis revealed that all 46 clinical isolates were clustered into 11 genotypes and the most frequent genotype was ST208. In conclusion, beta-lactamase genes, genes involved in efflux pump and mutation of outer membrane protein encoding gene may be important in mediating imipenem resistance in A. baumannii. Of the 11 different genotypes, ST11 was shared by the majority of A. baumannii, which may be due to horizontal transfer of patients from hospitals. PMID- 27485639 TI - Fungal biofilm composition and opportunities in drug discovery. AB - Biofilm infections are exceptionally recalcitrant to antimicrobial treatment or clearance by host immune responses. Within biofilms, microbes form adherent multicellular communities that are embedded in an extracellular matrix. Many prescribed antifungal drugs are not effective against biofilm infections owing to several protective factors including poor diffusion of drugs through biofilms as well as specific drug-matrix interactions. Despite the key roles that biofilms play in infections, there is little quantitative information about their composition and structural complexity because of the analytical challenge of studying these dense networks using traditional techniques. Within this review, recent work to elucidate fungal biofilm composition is discussed, with particular attention given to the challenges of annotation and quantification of matrix composition. PMID- 27485640 TI - Vismodegib and risk of cholestatic injury: should we screen candidate patients? PMID- 27485641 TI - LrABCF1, a GCN-type ATP-binding cassette transporter from Lilium regale, is involved in defense responses against viral and fungal pathogens. AB - MAIN CONCLUSION: The L. regale ATP-binding cassette transporter gene, LrABCF1 belonging to GCN subfamily, functions as a positive regulator of plant defense against Cucumber mosaic virus, Tobacco rattle virus , and Botrytis cinerea in petunia. ATP-binding cassette (ABC) transporters are essential for membrane translocation in diverse biological processes, such as plant development and defense response. Here, a general control non-derepressible (GCN)-type ABC transporter gene, designated LrABCF1, was identified from Cucumber mosaic virus (CMV)-induced cDNA library of L. regale. LrABCF1 was up-regulated upon inoculation with CMV and Lily mottle virus (LMoV). Salicylic acid (SA) and ethylene (ET) application and treatments with abiotic stresses such as cold, high salinity, and wounding increased the transcript abundances of LrABCF1. Constitutive overexpression of LrABCF1 in petunia (Petunia * hybrida) resulted in an impairment of plant growth and development. LrABCF1 overexpression conferred reduced susceptibility to CMV, Tobacco rattle virus (TRV), and B. cinerea infection in transgenic petunia plants, accompanying by elevated transcripts of PhGCN2 and a few defense-related genes in SA-signaling pathway. Our data indicate that LrABCF1 positively modulates viral and fungal resistance. PMID- 27485643 TI - The chronology of third molar mineralization by digital orthopantomography. AB - The present study was designed to determine the chronology of third molar mineralization to establish Indian reference data and to observe the advantages of digital orthopantomography. Therefore, a cross-sectional study was undertaken by evaluating 167 digital orthopantomographs in order to assess the mineralization status of the mandibular third molar of Caucasian individuals (85 males and 82 females) between the age of 14 and 24. The evaluation was carried out using the 8-stage developmental scheme of Demirjian et al (1973). The range, mean age, standard deviation and Student t-test are presented for each stage of mineralization in all four quadrants. Statistically significant differences between males and females were not found for all four third molars. All the individuals in this study with mature third molar were at least 18 years of age. For medicolegal purposes, the likelihood of whether an Indian is older than 18 years or not was determined. The advantage of digital orthopantomography in the interpretation of the tooth mineralization over the traditional method was acknowledged. PMID- 27485642 TI - Development of a Flow-Through USP-4 Apparatus Drug Release Assay to Evaluate Doxorubicin Liposomes. AB - Doxil(r) is a complex parenteral doxorubicin (DOX) liposome formulation approved by the FDA. For generic doxorubicin liposomes, analyzing the release profile of DOX is important for quality control and comparability studies. However, there is no robust standard drug release assay available for doxorubicin liposomes. In this study, we describe a USP-4 apparatus assay capable of discriminating DOX liposomal formulations based on release profile. Establishment of the assay was hindered by limited DOX release from liposomes in physiological conditions at 37 degrees C. The addition of NH4HCO3 to the release media facilitated DOX release proportionally to the salt concentration added but caused precipitation of released drug in USP-4 apparatus. Precipitation of DOX was avoided by adding hydroxypropyl-cyclodextrin (HP-CD) to the release medium. We optimized conditions for DOX release by varying a number of parameters such as: concentration of HP CD, testing temperature, and concentration of tested samples. The optimized release medium contained: 100 mM NH4HCO3, 75 mM 2-(N-morpholino) ethanesulfonic acid (MES) and 5% w/v HP-CD, 5% w/v sucrose, 0.02% w/v NaN3 (pH 6). The drug release assay was performed at 45 degrees C. The optimized release assay can discriminate between DOX liposomal formulations of different compositions, physicochemical properties, and prepared by different manufacturing methods. This indicates that the assay could be used to compare DOX release from generic DOX formulations to the innovator product Doxil(r). PMID- 27485645 TI - Complications and Anesthesia for Colonoscopy: Culprit or Accomplice? PMID- 27485646 TI - Limitations to an Important Study on the Risks of Colonoscopy With Anesthesia Services. PMID- 27485647 TI - Long-term Retention of Plastic Bread Bag Clip That Grips and Perforates the Colonic Mucosa. PMID- 27485648 TI - Rectal Indomethacin for the Prevention of Post-ERCP Pancreatitis. PMID- 27485649 TI - Rectal Indomethacin for Post-ERCP Pancreatitis Prophylaxis in Average Risk Patients: Too Early to Terminate and Too Early to Conclude. PMID- 27485650 TI - Painful Anterior Chest Wall Mass, Compatible With Abscess on Computed Tomography and Possible Osteomyelitis in a Man With Ulcerative Colitis. PMID- 27485651 TI - Forward Progress of Sedation for Gastrointestinal Endoscopy Requires Taking a Step Back. PMID- 27485652 TI - A Rare Cause of Gastrointestinal Ulcers. PMID- 27485653 TI - Anesthesia Services Increase Risk Of Complications After Colonoscopy: We Are Not Sure! PMID- 27485654 TI - Anesthesia's Impact on Outcomes After Endoscopy: More Research Is Needed. PMID- 27485655 TI - Anesthesia Services Are Beneficial for Colonoscopy in Interventional Gastroenterology. PMID- 27485656 TI - Protein glycation and aggregation inhibitory potency of biomolecules from black gram milled by-product. AB - BACKGROUND: Persistent hyperglycaemia causes increased advanced glycation end products (AGEs), which contribute to the pathogenesis of diabetic complication. Therefore, effect of black gram milled by-product (BGBP) extract on inhibition of AGE formation in a bovine serum albumin (BSA)/glucose system was investigated. RESULTS: BGBP extract had a total polyphenol content of 82 mg GAE g-1 and flavonoid content of 46 mg CE g-1 . Ferulic acid, protocatechuic acid, gallic acid, gentisic acid, isovitexin, vitexin and epicatechin were the major bioactives in the extract. BGBP extract exhibited an effective Fe2+ chelating activity. Size exclusion-high-performance liquid chromatographic studies indicated that upon BSA-AGE formation the BSA monomer content was 38%; however, in the presence of BGBP extract at 50 and 100 ug levels, the monomer content increased and it was found to be 48% and 73%, respectively. BGBP extract at 50 and 100 ug levels decreased the protein carbonyl and fructosamine contents, and quenched the fluorescence intensity of glycated BSA in a dose-dependent manner. Further, fluorescence and transmission electron microscopic studies confirmed the decrease in formation of AGEs by BGBP extract. CONCLUSION: As BGBP extract inhibited the formation of AGEs, the extract can be used as a nutraceutical or it can be incorporated into food products to obtain functional foods. (c) 2016 Society of Chemical Industry. PMID- 27485657 TI - Nicotine produces long-term increases in cocaine reinforcement in adolescent but not adult rats. AB - Studies have shown that many smokers begin using nicotine during adolescence, yet the influence of early nicotine use on the response to other drugs of abuse in adulthood is not fully understood. In the current study, nicotine was administered to adolescent and adult rats for seven days. Thirty days later, cocaine-induced locomotor activity and cocaine self-administration were examined when the rats pretreated as adolescents were adults. Rats exposed to nicotine during early adolescence were sensitized thirty days later to the locomotor activating effects of cocaine and self-administered a greater number of cocaine infusions than adolescent rats pretreated with vehicle. As a result of this increased intake, the cocaine self-administration dose-response curve was shifted upward indicating an increase in cocaine reinforcement. Rats pretreated with nicotine as adults, however, did not show a difference in locomotor activity or cocaine self-administration thirty days later compared to adult rats pretreated with vehicle. These findings suggest that early exposure to nicotine has long term consequences on cocaine use. These data further suggest that nicotine use may carry a greater risk during adolescence than adulthood and adolescents who smoke may be particularly vulnerable to stimulant use. This article is part of a Special Issue entitled SI: Adolescent plasticity. PMID- 27485658 TI - Anxiety modulates cognitive deficits in a perinatal glutathione deficit animal model of schizophrenia. AB - In this study, we investigated long-term repercussion of early glutathione deficit by l-buthionine-(S,R)-sulfoximine (BSO) injections as a rat model of schizophrenia. BSO rats were tested through various behavioral tasks requiring animals to take into account previously delivered information. We showed that relative to controls, BSO rats (1) were less active and more anxious in an Elevated Plus Maze test, allowing us to split them into two subgroups with high and low anxiety levels; (2) demonstrated normal abilities of behavioral flexibility tested with a rat-adapted version of the Wisconsin Card Sorting Test (WCST), with even higher abilities in anxious BSO rats suggesting reduced interference of previously acquired rules; (3) did not forage normally in radial arm mazes and mainly used clockwise strategies; (4) exhibited a lack of habituation during a startle response task; and (5) showed a normal prepulse inhibition of the startle response (PPI) and a normal conditioned taste aversion (CTA). All these results indicate that early glutathione deficit provokes persistent changes in adulthood and improves the validity of this animal model of schizophrenia. They further suggest difficulties binding temporally separated events (WCST), except when the salience of this information is very strong (CTA). We propose that the transient glutathione deficit during cerebral development could alter a "cognitive binding" process in interaction with the emotional state that could possibly account for the disruption of integrative function that characterizes schizophrenia. PMID- 27485659 TI - Cognitive MMN and P300 in mild cognitive impairment and Alzheimer's disease: A high density EEG-3D vector field tomography approach. AB - Precise preclinical detection of dementia for effective treatment and stage monitoring is of great importance. Miscellaneous types of biomarkers, e.g., biochemical, genetic, neuroimaging, and physiological, have been proposed to diagnose Alzheimer's disease (AD), the usual suspect behind manifested cognitive decline, and mild cognitive impairment (MCI), a neuropathology prior to AD that does not affect cognitive functions. Event related potential (ERP) methods constitute a non-invasive, inexpensive means of analysis and have been proposed as sensitive biomarkers of cognitive impairment; besides, various ERP components are strongly linked with working memory, attention, sensory processing and motor responses. In this study, an auditory oddball task is employed, to acquire high density electroencephalograhy recordings from healthy elderly controls, MCI and AD patients. The mismatch negativity (MMN) and P300 ERP components are then extracted and their relationship with neurodegeneration is examined. Then, the neural activation at these components is reconstructed using the 3D vector field tomography (3D-VFT) inverse solution. The results reveal a decline of both ERPs amplitude, and a statistically significant prolongation of their latency as cognitive impairment advances. For the MMN, higher brain activation is usually localized in the inferior frontal and superior temporal gyri in the controls. However, in AD, parietal sites exhibit strong activity. Stronger P300 generators are mostly found in the frontal lobe for the controls, but in AD they often shift to the temporal lobe. Reduction in inferior frontal source strength and the switch of the maximum intensity area to parietal and superior temporal sites suggest that these areas, especially the former, are of particular significance when neurodegenerative disorders are investigated. The modulation of MMN and P300 can serve to produce biomarkers of dementia and its progression, and brain imaging can further contribute to the diagnostic efficiency of ERPs. PMID- 27485661 TI - Lack of Dependence of Indian Summer Monsoon Rainfall Extremes on Temperature: An Observational Evidence. AB - The intensification of precipitation extremes in a warming world has been reported on a global scale and is traditionally explained with the Clausius Clapeyron (C-C) relation. The relationship is observed to be valid in mid latitudes; however, the debate persists in tropical monsoon regions, with the extremes of the Indian Summer Monsoon Rainfall (ISMR) being a prime example. Here, we present a comprehensive study on the dependence of ISMR extremes on both the 2 m surface air temperature over India and on the sea surface temperature over the tropical Indian Ocean. Remarkably, the ISMR extremes exhibit no significant association with temperature at either spatial scale: neither aggregated over the entire India/Tropical Indian Ocean area nor at the grid levels. We find that the theoretical C-C relation overestimates the positive changes in precipitation extremes, which is also reflected in the Coupled Model Intercomparison Project 5 (CMIP5) simulations. We emphasize that the changing patterns of extremes over the Indian subcontinent need a scientific re evaluation, which is possible due to availability of the unique long-term in-situ data. This can aid bias correction of model projections of extremes whose value for climate adaptation can hardly be overemphasized, especially for the developing tropical countries. PMID- 27485660 TI - Incubation of food craving is independent of macronutrient composition. AB - Cues previously paired with rewarding stimuli induce a time-dependent increase in the motivational craving state (incubation of craving). Whether there is an increase in craving for high-fat (HF) food over time, which may contribute to overeating and obesity, has not been determined. We hypothesized that cues paired with HF pellets would elicit a greater incubation of craving effect than those paired with standard chow (SC) pellets. Rats exposed to cues associated with either HF or SC pellets demonstrated equivalent levels of craving over an abstinence period of 30 days. Diet preference tests between SC pellets and LabDiet revealed that SC pellets were preferred over LabDiet. Rats reared on SC pellets exclusively, did not display incubation of craving for SC pellets, suggesting that prior history with the food plays an important role in cue induced seeking behavior. Results identified cues previously associated with food undergo a comparable magnitude of incubation of craving. When ingestive behavior was measured after 30 days of abstinence, rats significantly increased their consumption of HF pellets. Our results indicate that food cues gain importance over time, trigger increased approach behaviors, and increased consumption of HF food following abstinence. This may contribute to overeating and the development of obesity. PMID- 27485663 TI - Using Marginal Structural Modeling for Grade Retention Effects. AB - Vandecandelaere, Vansteelandt, De Fraine, and Van Damme (this issue) described marginal structural modeling (MSM) and used it to estimate the effects of a time varying intervention, retention (holding back) in school grades, on students' math achievement. This commentary supplements Vandecandelaere et al. (this issue) and discusses several topics in retention studies and MSM. First, we discuss the importance of equating time-varying confounders in retention studies. Second, we discuss same-grade and same-age comparisons in retention studies. Third, we discuss one important section in the authors' overview of MSM: why standard methods (e.g., ANCOVA, propensity score analysis) cannot properly adjust for time varying confounders. Finally, using the grade retention analyses in Vandecandelaere et al. (this issue) as an example, we provide our insights on four aspects of MSM: (a) covariate selection, (b) estimation of weights, PMID- 27485665 TI - Proceedings of the International Summit on Emergency Medicine and Trauma 2014. PMID- 27485662 TI - Intracellular Salmonella induces aggrephagy of host endomembranes in persistent infections. AB - Xenophagy has been studied in epithelial cells infected with Salmonella enterica serovar Typhimurium (S. Typhimurium). Distinct autophagy receptors target this pathogen to degradation after interacting with ubiquitin on the surface of cytosolic bacteria, and the phagophore- and autophagosome-associated protein MAP1LC3/LC3. Glycans exposed in damaged phagosomal membranes and diacylglycerol accumulation in the phagosomal membrane also trigger S. Typhimurium xenophagy. How these responses control intraphagosomal and cytosolic bacteria remains poorly understood. Here, we examined S. Typhimurium interaction with autophagy in fibroblasts, in which the pathogen displays limited growth and does not escape into the cytosol. Live-cell imaging microscopy revealed that S. Typhimurium recruits late endosomal or lysosomal compartments that evolve into a membranous aggregate connected to the phagosome. Active dynamics and integrity of the phagosomal membrane are requisite to induce such aggregates. This membranous structure increases over time to become an aggresome that engages autophagy machinery at late infection times (> 6 h postentry). The newly formed autophagosome harbors LC3 and the autophagy receptor SQSTM1/p62 but is devoid of ubiquitin and the receptor CALCOCO2/NDP52. Live-cell imaging showed that this autophagosome captures and digests within the same vacuole the aggresome and some apposed intraphagosomal bacteria. Other phagosomes move away from the aggresome and avoid destruction. Thus, host endomembrane accumulation resulting from activity of intracellular S. Typhimurium stimulates a novel type of aggrephagy that acts independently of ubiquitin and CALCOCO2, and destroys only a few bacteria. Such selective degradation might allow the pathogen to reduce its progeny and, as a consequence, to establish persistent infections. PMID- 27485664 TI - A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population. AB - BACKGROUND: Gastroesophageal reflux disease (GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism (SNP) genotypes. METHODS: We performed a GWAS meta analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis (GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map (cMap). KEY RESULTS: We identified 30 GERD suggestive risk loci (P<=5*10-5 ), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti inflammatory drugs scored highest among the repurposed compounds. CONCLUSIONS: We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities. PMID- 27485666 TI - A Semi-Supervised Learning Approach to Enhance Health Care Community-Based Question Answering: A Case Study in Alcoholism. AB - BACKGROUND: Community-based question answering (CQA) sites play an important role in addressing health information needs. However, a significant number of posted questions remain unanswered. Automatically answering the posted questions can provide a useful source of information for Web-based health communities. OBJECTIVE: In this study, we developed an algorithm to automatically answer health-related questions based on past questions and answers (QA). We also aimed to understand information embedded within Web-based health content that are good features in identifying valid answers. METHODS: Our proposed algorithm uses information retrieval techniques to identify candidate answers from resolved QA. To rank these candidates, we implemented a semi-supervised leaning algorithm that extracts the best answer to a question. We assessed this approach on a curated corpus from Yahoo! Answers and compared against a rule-based string similarity baseline. RESULTS: On our dataset, the semi-supervised learning algorithm has an accuracy of 86.2%. Unified medical language system-based (health related) features used in the model enhance the algorithm's performance by proximately 8%. A reasonably high rate of accuracy is obtained given that the data are considerably noisy. Important features distinguishing a valid answer from an invalid answer include text length, number of stop words contained in a test question, a distance between the test question and other questions in the corpus, and a number of overlapping health-related terms between questions. CONCLUSIONS: Overall, our automated QA system based on historical QA pairs is shown to be effective according to the dataset in this case study. It is developed for general use in the health care domain, which can also be applied to other CQA sites. PMID- 27485667 TI - The sex locus is tightly linked to factors conferring sex-specific lethal effects in the mosquito Aedes aegypti. AB - In many taxa, sex chromosomes are heteromorphic and largely non-recombining. Evolutionary models predict that spread of recombination suppression on the Y chromosome is fueled by the accumulation of sexually antagonistic alleles in close linkage to the sex determination region. However, empirical evidence for the existence of sexually antagonistic alleles is scarce. In the mosquito Aedes aegypti, the sex-determining chromosomes are homomorphic. The region of suppressed recombination, which surrounds the male-specific sex-determining gene, remains very small, despite ancient origin of the sex chromosomes in the Aedes lineage. We conducted a genetic analysis of the A. aegypti chromosome region tightly linked to the sex locus. We used a strain with an enhanced green fluorescent protein (EGFP)-tagged transgene inserted near the male-determining gene to monitor crossing-over events close to the boundary of the sex-determining region (SDR), and to trace the inheritance pattern of the transgene in relation to sex. In a series of crossing experiments involving individuals with a recombinant sex chromosome we found developmental abnormalities leading to 1:2 sex biases, caused by lethality of half of the male or female progeny. Our results suggest that various factors causing sex-specific lethal effects are clustered within the neighborhood of the SDR, which in the affected sex are likely lost or gained through recombination, leading to death. These may include genes that are recessive lethal, vital for development and/or sexually antagonistic. The sex chromosome fragment in question represents a fascinating test case for the analysis of processes that shape stable boundaries of a non recombining region. PMID- 27485668 TI - Genome-wide SNP data suggest complex ancestry of sympatric North Pacific killer whale ecotypes. AB - Three ecotypes of killer whale occur in partial sympatry in the North Pacific. Individuals assortatively mate within the same ecotype, resulting in correlated ecological and genetic differentiation. A key question is whether this pattern of evolutionary divergence is an example of incipient sympatric speciation from a single panmictic ancestral population, or whether sympatry could have resulted from multiple colonisations of the North Pacific and secondary contact between ecotypes. Here, we infer multilocus coalescent trees from >1000 nuclear single nucleotide polymorphisms (SNPs) and find evidence of incomplete lineage sorting so that the genealogies of SNPs do not all conform to a single topology. To disentangle whether uncertainty in the phylogenetic inference of the relationships among ecotypes could also result from ancestral admixture events we reconstructed the relationship among the ecotypes as an admixture graph and estimated f4-statistics using TreeMix. The results were consistent with episodes of admixture between two of the North Pacific ecotypes and the two outgroups (populations from the Southern Ocean and the North Atlantic). Gene flow may have occurred via unsampled 'ghost' populations rather than directly between the populations sampled here. Our results indicate that because of ancestral admixture events and incomplete lineage sorting, a single bifurcating tree does not fully describe the relationship among these populations. The data are therefore most consistent with the genomic variation among North Pacific killer whale ecotypes resulting from multiple colonisation events, and secondary contact may have facilitated evolutionary divergence. Thus, the present-day populations of North Pacific killer whale ecotypes have a complex ancestry, confounding the tree-based inference of ancestral geography. PMID- 27485669 TI - Relaxed selective constraints drove functional modifications in peripheral photoreception of the cavefish P. andruzzii and provide insight into the time of cave colonization. AB - The genetic basis of phenotypic changes in extreme environments is a key but rather unexplored topic in animal evolution. Here we provide an exemplar case of evolution by relaxed selection in the Somalian cavefish Phreatichthys andruzzii that has evolved in the complete absence of light for at least 2.8 million years. This has resulted in extreme degenerative phenotypes, including complete eye loss and partial degeneration of the circadian clock. We have investigated the molecular evolution of the nonvisual photoreceptor melanopsin opn4m2, whose mutation contributes to the inability of peripheral clocks to respond to light. Our intra- and inter-species analyses suggest that the 'blind' clock in P. andruzzii evolved because of the loss of selective constraints on a trait that was no longer adaptive. Based on this change in selective regime, we estimate that the functional constraint on cavefish opn4m2 was relaxed at ~5.3 Myr. This implies a long subterranean history, about half in complete isolation from the surface. The visual photoreceptor rhodopsin, expressed in the brain and implicated in photophobic behavior, shows similar evolutionary patterns, suggesting that extreme isolation in darkness led to a general weakening of evolutionary constraints on light-responsive mechanisms. Conversely, the same genes are still conserved in Garra barreimiae, a cavefish from Oman, that independently and more recently colonized subterranean waters and evolved troglomorphic traits. Our results contribute substantially to the open debate on the genetic bases of regressive evolution. PMID- 27485670 TI - "It's Like Moving the Titanic:" Community Organizing to Address Food (In)Security. AB - Health communication scholars are uniquely positioned to examine the ways in which individuals organize to address current and future exigencies related to social ills. In particular, organizations are key sites in understanding our health decisions related to food choice. From a young age, children develop habits of eating that stay with them throughout their life. More specifically, food insecurity impacts childhood nutrition. Children from low-income homes experience disproportional negative health outcomes. Appalachian Ohio is an area within the United States that experiences severe poverty. In 2013, community members in a small public school district in Appalachian Ohio formed the Appalachian Nutrition Advisory Council to address the nutritional needs of students in schools. This project stories the ways in which community members creatively organized to supplement existing structures in place designed to address school nutrition and food security. PMID- 27485671 TI - Direct observation of slow intersystem crossing in an aromatic ketone, fluorenone. AB - Direct measurements of Single vibronic Level InterSystem Crossing (SLISC) have been performed on the fluorenone molecule in the gas phase, by time resolved photoelectron and photoion spectroscopy. Vibronic transitions above the S1 npi* origin were excited in the 432-420 nm region and the decay of S1 and growth of T1(3)pipi* could be observed within a 10 ns time domain. The ionization potential is measured as 8.33 +/- 0.04 eV. The energy of the first excited triplet state of fluorenone, T1 has been characterized directly at 18 640 +/- 250 cm(-1). The internal conversion of S1 to S0 is found to amount to ~15% of the population decay, thus ISC is the dominant electronic relaxation process. ISC, although favored by the S1(1)npi*-T1(3)pipi* coupling scheme, is 3 orders of magnitude less efficient than in the similar molecule benzophenone. Thus, the planarity of the fluorenone molecule disfavors the exploration of the configuration space where surface crossings would create high ISC probability, which occurs in benzophenone through surface crossings. The time evolution of S1 fluorenone is well accounted for by the statistical decay of individual levels into a quasi continuum of T1 vibronic levels. PMID- 27485672 TI - MCRS1: Not only ran. PMID- 27485673 TI - Metal Oleate Induced Etching and Growth of Semiconductor Nanocrystals, Nanorods, and Their Heterostructures. AB - Unexpected etching of nanocrystals, nanorods, and their heterostructures by one of the most commonly used metal precursors, metal oleates, is reported. Zn oleate is shown to etch CdS nanorods anisotropically, where the length decreases without a significant change in the diameter. Sodium oleate enhances the etch rate, whereas oleic acid alone does not cause etching, indicating the importance of the countercation on the rate of oleate induced etching. Subsequent addition of Se precursors to the partially etched nanorods in Zn oleate solution can lead to epitaxial growth of CdSe particles rather than the expected ZnSe growth, despite an excess amount of Zn precursors being present. The composition of this epitaxial growth can be varied from CdSe to ZnSe, depending on the amount of excess oleic acid or the reaction temperature. Similar tuning of composition can be observed when starting with collinear CdSe/CdS/CdSe rod/rod/rod heterostructures and spherical CdS (or CdSe/CdS core/shell) nanocrystals. Conversion of collinear rod/rod/rod structures to barbells and interesting rod growth from nearly spherical particles among other structures can also result due to the initial etching effect of metal oleates. These observations have important implications on our understanding of nanocrystal heterostructure synthesis and open up new routes to varying the composition and morphology of these materials. PMID- 27485674 TI - Risk Factors for Falls in People With a Lower Limb Amputation: A Systematic Review. AB - OBJECTIVE: To review the evidence connecting risk factors to falls in adults with a lower limb amputation (LLA) across the continuum of care settings. DESIGN: Systematic review. LITERATURE SURVEY: Electronic database searches were conducted in MEDLINE, Pubmed, CINAHL, and EMBASE covering January 1988 to January 2016. Noninterventional studies, including cohort and cross-sectional studies, were included. Two reviewers independently completed data extraction and quality evaluation. METHODOLOGY: Twelve studies met the inclusion criteria and quality of reporting was evaluated using the criteria by Tooth et al. SYNTHESIS: The average quality of reporting score was 19.8, scores ranged from 16 to 29. Studies covered the acute hospital stay after the amputation, inpatient rehabilitation, and community living. Falls were a common occurrence, with the cohort studies reporting 20.8% for acute hospital stay to 58% in the community years after the amputation. Injurious falls also were common, with an occurrence ranging from 40% to 60%. Risk factors that increase falls and are shared with the general population of older adults include lower extremity muscle weakness, increasing age, comorbidities, and number of prescription medications. Risk factors for falls that are unique to adults with LLA are dysvascular etiology of the amputation, transtibial level of amputation in the postoperative period and transfemoral level postrehabilitation, and reduced sense of vibration. CONCLUSIONS: Falls in adults with an LLA are common from the time of the amputation to years later living in the community. Risk factors vary across care settings after the amputation, which has implications for safety and fall prevention strategies. LEVEL OF EVIDENCE: III. PMID- 27485675 TI - Relationships Between Age at Menarche, Walking Gait Base of Support, and Stance Phase Frontal Plane Knee Biomechanics in Adolescent Girls. AB - BACKGROUND: Age at menarche impacts patterns of pubertal growth and skeletal development. These effects may carry over into variation in biomechanical profiles involved in sports-related traumatic and overuse knee injuries. The present study investigated whether age at menarche is a potential indicator of knee injury risk through its influence on knee biomechanics during normal walking. OBJECTIVE: To test the hypothesis that earlier menarche is related to postpubertal biomechanical risk factors for knee injuries, including a wider, more immature gait base of support, and greater valgus knee angles and moments. DESIGN: Cross-sectional observational study. SETTING: University research facility. PARTICIPANTS: Healthy, postmenarcheal, adolescent girls. METHODS: Age at menarche was obtained by recall questionnaire. Pubertal growth and anthropometric data were collected by using standard methods. Biomechanical data were taken from tests of walking gait at self-selected speed. Reflective marker position data were collected with a 3-dimensional quantitative motion analysis system, and 3 force plates recorded kinetic data. MAIN OUTCOME MEASURES: Age at menarche; growth and anthropometric measurements; base of support; static knee frontal plane angle; and dynamic knee frontal plane angles and moments during stance. RESULTS: Earlier menarche was correlated significantly with abbreviated pubertal growth and postpubertal retention of immature traits, including a wider base of support. Earlier menarche and wider base of support were both correlated with more valgus static knee angles, more valgus knee abduction angles and moments at foot-strike, and a more valgus peak knee abduction angle during stance. Peak knee abduction moment during stance was not correlated with age at menarche or base of support. CONCLUSIONS: Earlier menarche and its effects on growth are associated with retention of a relatively immature gait base of support and a tendency for static and dynamic valgus knee alignment. This biomechanical profile may put girls with earlier menarche at greater risk for sports-related knee injuries. LEVEL OF EVIDENCE: Not applicable. PMID- 27485676 TI - Melorheostosis: A Retrospective Clinical Analysis of 24 Patients at the Mayo Clinic. AB - BACKGROUND: Current understanding of the clinical features of persons with melorheostosis is restricted primarily to individual case reports and small case series. OBJECTIVE: To assess the clinical features of patients with melorheostosis treated at our institution from 1972 through 2010. DESIGN: Chart review. SETTING: Tertiary academic medical center. PARTICIPANTS: Twenty-three patients with "definite" and one patient with "probable" melorheostosis based on radiographic criteria. METHODS: The eligible study cohort was identified through the Rochester Medical Index database. Further diagnostic confirmation of patients with melorheostosis was performed by radiographic review. MAIN OUTCOME MEASUREMENTS: We evaluated age at first visit to our institution, gender, affected body area, number of bones affected, presenting symptoms, surgical evaluation, and therapies provided. RESULTS: The average age at first evaluation at our clinic was 36.5 years (median 41.5 years, range 3-68 years). The female to male ratio was 4:1. The lower extremity was most commonly affected (66.6%), followed by upper extremity (33.3%), spine (16.6%), and head (8.3%). One-third of patients had involvement of a single bone; two-thirds had multiple bone involvement. Pain was the most common presenting concern (83.3%), followed by deformity (54.1%), limitation of movement (45.8%), numbness (37.5%), and weakness (25.0%). Most patients had a physician evaluation (87.5%); patients also underwent orthopedic surgery (45.8%), physical therapy (33.3%), and occupational therapy (12.5%). CONCLUSIONS: Melorheostosis is a rare sclerotic bone disease resulting in pain, deformity, and dysfunction. An interdisciplinary approach to care should include nonoperative and operative evaluation, as well as appropriate therapies. A prospective approach to evaluation, including imaging and physical examinations, would provide valuable longitudinal data. LEVEL OF EVIDENCE: IV. PMID- 27485677 TI - Insights from complex aortic surgery with a Streamliner device for aortic arch repair (STAR). AB - OBJECTIVE: Aortic arch aneurysms and thoracoabdominal aortic arch aneurysms are technically challenging to manage by established surgical and endovascular methods. The Streamliner Multilayer Flow Modulator device (Cardiatis, Isnes, Brussels, Belgium) offers an unorthodox option for these high-risk cases. The Streamliner device for aortic arch repair (STAR) study investigated complex aneurysm cases managed by the Streamliner Multilayer Flow Modulator device and offers an analytic solution for a clinical dilemma. METHODS: Six cases were included, with a 1-year follow-up, comprising 4 pure arch aneurysms and 2 thoracoabdominal aortic arch aneurysms Crawford type I, from a multicenter database hosted by the Streamliner Multilayer Flow Modulator Global Registry. A total of 50% of cases were performed under instructions for use. All were American Society of Anesthesiology IV and originated from zone 0. All cases were computationally analyzed, which consisted of (1) simulating the treatment on the basis of the postoperative data, (2) repositioning the stents for the failed technical cases, and (3) assessing the effects of overlapping devices on branch patency. RESULTS: Correct device placement induced aneurysm flow streamlining, which reduced the dynamic pressure by 23% to 66%, whereas incorrect placements promoted Failure Mode I with 58% and 16% dynamic pressure increases and aneurysm volume expansion up to 23%. Overlapped devices improved distal perfusion by increasing arch branch outflows from 5% to 24%. The Streamliner Multilayer Flow Modulator device does not benefit a sac volume greater than 400 cm3. CONCLUSIONS: The Streamliner Multilayer Flow Modulator device is a new technology that can manage complex aortic arch aneurysms and thoracoabdominal aortic arch aneurysms with favorable clinical outcomes if it is performed under instructions for use. Careful procedure planning and perioperative virtual stent placement will avoid foreshortening, prevent inadequate stent overlap lengths, and provide insight into the sufficient numbers of required implanted devices. PMID- 27485678 TI - Off-pump coronary artery bypass grafting: Do it often, do it well, and do it completely-or don't do it at all. PMID- 27485679 TI - Stapled aortic graft-to-graft anastomoses: Is automation optimization? PMID- 27485680 TI - The latissimus dorsi flap continues to play an important role in cardiothoracic surgery. PMID- 27485681 TI - Oilfield water treatment by electrocoagulation-reverse osmosis for agricultural use: effects on germination and early growth characteristics of sunflower. AB - This study aims to evaluate the effects of oilfield water (OW), treated by a hybrid process of electrocoagulation and reverse osmosis (EC-RO), on seed germination and early growth characteristics of sunflower (Heliantus annus L.). In the EC step, tests were conducted with 28.6 A m-2 current density and 4 min. reaction time. In the RO step, the system was operated with 1 L min-1 constant flow and 2 MPa, 2.5 MPa and 3 MPa feed pressures. In all feed pressures, RO polymeric membranes achieved very high removals of chemical oxygen demand (up to 89%) and oils and greases (100%) from EC-treated effluent. In best feed pressure (2.5 MPa), turbidity, total dissolved salts, electrical conductivity, salinity, toxic ions and sodium adsorption ratio values attained internationally recognized standards for irrigation water. Using EC-RO (feed pressure:2.5 MPa) treated OW, germinated sunflower seeds percentage (86 +/- 6%), speed of germination (30 +/- 2) and biomass production (49 +/- 5 mg) were statistically similar to control (distilled water) results. Vigor index average values obtained using OW treated by EC-RO (3871)were higher than that obtained by OW water treated by EC (3300). The results of this study indicate that EC-RO seems to be a promising alternative for treatment of OW aiming sunflower crops irrigation, since the use of this treated effluent did not affect adversely seed germination and seedling development, and improved seedling vigor. Furthermore, OW treatment by EC-RO reduces sodium levels into acceptable standards values avoiding soil degradation. PMID- 27485682 TI - Path to health asthma study: A survey of pediatric asthma in an urban community. AB - OBJECTIVE: Minority children with asthma who live in low-income urban communities bear a disproportionate burden of the disease. This study explores the perceived health care needs related to asthma care, identifies asthma triggers, potential barriers to care, and assesses the need for additional community resources. METHODS: We conducted a cross-sectional survey of Hispanic and African American adults (n = 53) who take care of a child with asthma and live in an urban community of North Philadelphia. Input from community leaders was obtained in the development the survey tool resulting in a unique 'community-centric' questionnaire. The survey was also available in Spanish. All surveys were conducted in the community setting. RESULTS: Variables were used to measure asthma severity and triggers. Children were categorized with intermittent (n = 24, 45.3%), mild persistent (n = 13, 24.5%), or moderate-to-severe persistent asthma (n = 16, 30.2%). Most children with persistent asthma were enrolled under Medicaid or CHIP (n = 24, p = 0.011) and reflected a low-income socioeconomic status. Persistent asthma was found to be associated with most triggers: pets, dust mites, mice, mold, and cockroaches. There was no significant association between environmental tobacco smoke and persistent asthma. Children with persistent asthma and 2 or more triggers were more likely to be hospitalized and go to the Emergency Department. CONCLUSION: Urban minority children living in low income communities face neighborhood-specific asthma triggers and challenges to care. Studies conducted in urban neighborhoods, with collaboration from community members, will highlight the need of comprehensive services to account for community-centric social determinants. PMID- 27485683 TI - Distinct beneficial effects of continuous vs accumulated exercise training on cardiovascular risk factors in Wistar rats. AB - We compared the effects of continuous exercise (CE) vs accumulated exercise (AE) training on CVD risk factors and heart of young male Wistar rats. The exercise training (ET) was performed in a swimming pool for 30-60 min/day, 5 days/week over 15 weeks. CE group performed the ET in a single long daily session (30-60 min), while AE group performed the ET at the same frequency, intensity, and duration of CE rats, but in three short bouts over the course of a day (10-20 min in three daily sessions). AE training was more efficient than CE in attenuating body and fat weight gain and inhibiting visceral adipocyte hypertrophy at the same food intake level. CE training was more efficient in improving systolic blood pressure, LDL/HDL cholesterol, and serum triglyceride. Both ET protocols increased heart function, decreased lipid peroxidation, and increased intracellular Hsp72 content in the heart. This work shows distinct beneficial effects of CE vs AE training suggesting that the prescription of one or other may be preferred to prevent the increase of a specific CVD risk factor. PMID- 27485684 TI - Comparative thermal unfolding study of psychrophilic and mesophilic subtilisin like serine proteases by molecular dynamics simulations. AB - Molecular dynamics (MD) simulations of a subtilisin-like serine protease VPR from the psychrophilic marine bacterium Vibrio sp. PA-44 and its mesophilic homologue, proteinase K (PRK), have been performed for 20 ns at four different temperatures (300, 373, 473, and 573 K). The comparative analyses of MD trajectories reveal that at almost all temperatures, VPR exhibits greater structural fluctuations/deviations, more unstable regular secondary structural elements, and higher global flexibility than PRK. Although these two proteases follow similar unfolding pathways at high temperatures, VPR initiates unfolding at a lower temperature and unfolds faster at the same high temperatures than PRK. These observations collectively indicate that VPR is less stable and more heat-labile than PRK. Analyses of the structural/geometrical properties reveal that, when compared to PRK, VPR has larger radius of gyration (Rg), less intramolecular contacts and hydrogen bonds (HBs), more protein-solvent HBs, and smaller burial of nonpolar area and larger exposure of polar area. These suggest that the increased flexibility of VPR would be most likely caused by its reduced intramolecular interactions and more favourable protein-solvent interactions arising from the larger exposure of the polar area, whereas the enhanced stability of PRK could be ascribed to its increased intramolecular interactions arising from the better optimized hydrophobicity. The factors responsible for the significant differences in local flexibility between these two proteases were also analyzed and ascertained. This study provides insights into molecular basis of thermostability of homologous serine proteases adapted to different temperatures. PMID- 27485685 TI - Stress and resilience in a post-Francis world - a qualitative study of executive nurse directors. AB - AIMS: The aim of this study was to explore the role stressors experienced by executive nurse directors and strategies employed to maintain resilience. BACKGROUND: Recent financial pressures on and care quality scandals in the UK NHS impact on the work of executive nurse directors. The short length of tenure and the high number of vacancies for these posts point to the exacting demands of the role and raise questions about the support mechanisms available for the most senior nurses in NHS organizations. DESIGN: A grounded constructivist study. METHODS: Semi-structured telephone interviews conducted between February-July, 2014. RESULTS: Stressors were both chronic (workload, lack of corporate responsibility for quality, reductions in quality team staffing, tensions between financial solvency and care quality and personal vulnerability) and acute (dealing with complaints and major incidents). Resilience required the support of fellow executives, peers, family and mentors and could be enhanced by self discipline, good preparation for the post and ongoing coaching. CONCLUSION: Recent fiscal austerity and scandals relating to quality of care have increased pressure on executive nurse directors. Increasing size of organizations, limited resources devoted to quality combined with poorly defined limits of responsibility are all major stressors and executive nurse directors, both in the United Kingdom and internationally, need clear strategies to maintain resilience. Repetitive demands for data by oversight organizations may detract from more important quality assurance strategies. PMID- 27485687 TI - Cross-talk Between Host, Microbiome and Probiotics: A Systems Biology Approach for Analyzing the Effects of Probiotic Enterococcus faecium NCIMB 10415 in Piglets. AB - A comprehensive data-set from a multidisciplinary feeding experiment with the probiotic Enterococcus faecium was analyzed to elucidate effects of the probiotic on growing piglets. Sixty-two piglets were randomly assigned to a control (no probiotic treatment) and a treatment group (E. faecium supplementation). Piglets were weaned at 26 d. Age-matched piglets were sacrificed for the collection of tissue samples at 12, 26, 34 and 54 d. In addition to zootechnical data, the composition and activity of intestinal microbiota, immune cell types, and intestinal responses were determined. Our systems analysis revealed clear effects on several measured variables in 26 and 34 days old animals, while response patterns varied between piglets from different age groups. Correlation analyses identified reduced associations between intestinal microbial communities and immune system reactions in the probiotic group. In conclusion, the developed model is useful for comparative analyses to unravel systems effects of dietary components and their time resolution. The model identified that effects of E. faecium supplementation most prominently affected the interplay between intestinal microbiota and the intestinal immune system. These effects, as well as effects in other subsystems, clustered around weaning, which is the age where piglets are most prone to diarrhea. PMID- 27485688 TI - Theoretical Studies on Pyrazolo[3,4-d]pyrimidine Derivatives as Potent Dual c Src/Abl Inhibitors Using 3D-QSAR and Docking Approaches. AB - In recent years, the development of dual or multi-targeted inhibitors has captured extensive attention of research for treating of malignancies. In this paper, three-dimensional quantitative structure-activity relationship and docking studies were performed on 87 pyrazolo[3,4-d]pyrimidines as dual Src/Abl inhibitors. The appropriate binding orientations and conformations of these compounds interacting with both Src and Abl kinases were revealed by docking studies, and the established optimum CoMFA models yielded q(2) =0.856, R(2) =0.966 for Src and q(2) =0.869, R(2) =0.974 for Abl, and the best CoMSIA models gave q(2) =0.877, R(2) =0.979 for Src and q(2) =0.885, R(2) =0.982 for Abl. Systemic external validations further confirm the satisfactory predictive power of these models, producing R(2) pred values of 0.872 and 0.865 for Src, 0.876 and 0.867 for Abl, r(2) m values of 0.832 and 0.928 for Src, 0.838 and 0.904 for Abl, respectively. In addition, through a comparison between 3D-QSAR contour maps and docking results, it is revealed that the hydrophobic and electrostatic interactions of compounds play significant roles for the inhibitory activity against both Src and Abl kinases. Some structural factors influencing the activities of these compounds were discussed in detail. The key amino acids impacting the receptor-ligand interactions have been identified. These theoretical results can offer useful references for designing novel potential dual Src/Abl inhibitors. PMID- 27485686 TI - Neuronal Deletion of Kmt2a/Mll1 Histone Methyltransferase in Ventral Striatum is Associated with Defective Spike-Timing-Dependent Striatal Synaptic Plasticity, Altered Response to Dopaminergic Drugs, and Increased Anxiety. AB - Lysine (K) methyltransferase 2a (Kmt2a) and other regulators of H3 lysine 4 methylation, a histone modification enriched at promoters and enhancers, are widely expressed throughout the brain, but molecular and cellular phenotypes in subcortical areas remain poorly explored. We report that Kmt2a conditional deletion in postnatal forebrain is associated with excessive nocturnal activity and with absent or blunted responses to stimulant and dopaminergic agonist drugs, in conjunction with near-complete loss of spike-timing-dependent long-term potentiation in medium spiny neurons (MSNs). Selective ablation of Kmt2a, but not the ortholog Kmt2b, in adult ventral striatum/nucleus accumbens neurons markedly increased anxiety scores in multiple behavioral paradigms. Striatal transcriptome sequencing in adult mutants identified 262 Kmt2a-sensitive genes, mostly downregulated in Kmt2a-deficient mice. Transcriptional repression includes the 5 Htr2a serotonin receptor, strongly associated with anxiety- and depression related disorders in human and animal models. Consistent with the role of Kmt2a in promoting gene expression, the transcriptional regulators Bahcc1, Isl1, and Sp9 were downregulated and affected by H3K4 promoter hypomethylation. Therefore, Kmt2a regulates synaptic plasticity in striatal neurons and provides an epigenetic drug target for anxiety and dopamine-mediated behaviors. PMID- 27485689 TI - The Development of Novel Chemical Fragment-Based Descriptors Using Frequent Common Subgraph Mining Approach and Their Application in QSAR Modeling. AB - We present a novel approach to generating fragment-based molecular descriptors. The molecules are represented by labeled undirected chemical graph. Fast Frequent Subgraph Mining (FFSM) is used to find chemical-fragments (subgraphs) that occur in at least a subset of all molecules in a dataset. The collection of frequent subgraphs (FSG) forms a dataset-specific descriptors whose values for each molecule are defined by the number of times each frequent fragment occurs in this molecule. We have employed the FSG descriptors to develop variable selection k Nearest Neighbor (kNN) QSAR models of several datasets with binary target property including Maximum Recommended Therapeutic Dose (MRTD), Salmonella Mutagenicity (Ames Genotoxicity), and P-Glycoprotein (PGP) data. Each dataset was divided into training, test, and validation sets to establish the statistical figures of merit reflecting the model validated predictive power. The classification accuracies of models for both training and test sets for all datasets exceeded 75 %, and the accuracy for the external validation sets exceeded 72 %. The model accuracies were comparable or better than those reported earlier in the literature for the same datasets. Furthermore, the use of fragment based descriptors affords mechanistic interpretation of validated QSAR models in terms of essential chemical fragments responsible for the compounds' target property. PMID- 27485690 TI - Computational Search for Possible Mechanisms of 4-Thiazolidinones Anticancer Activity: The Power of Visualization. AB - Public databases of NCI-60 tumor cell line screen results and measurements of molecular targets in the NCI-60 panel give the opportunity to assign possible anticancer mechanism to compounds with positive outcome from antitumor assay. Here, the novel protocol of NCI databases mining where inferences are based on the visualization is presented and utilized with the aim to identify putative biological routes of 4-thiazolidinones anticancer effect. As a result, highly potent 4-thiazolidinone-pyrazoline-isatin conjugates show the similarity of activity patterns with puromycin and CBU-028 and their pattern is also highly correlated with fraction of methylated CpG sites in CD34, AF5q31 and SYK. Several compounds from this group show strong negative correlation with fraction of methylated CpG sites in HOXA5. Thiopyrano[2,3-d][1,3]thiazol-2-ones bearing naphtoquinone fragment were found to possess the same activity pattern as fusarubin does. But none of the studied 4-thiazolidinone derivatives has activity fingerprint similar to standard anticancer agents. The obtained results bring medicinal chemistry closer to the understanding of basic nature of 4 thiazolidinones effect on cancer cells. PMID- 27485691 TI - Prediction of Signal Peptide Cleavage Sites with Subsite-Coupled and Template Matching Fusion Algorithm. AB - Fast and effective prediction of signal peptides (SP) and their cleavage sites is of great importance in computational biology. The approaches developed to predict signal peptide can be roughly divided into machine learning based, and sliding windows based. In order to further increase the prediction accuracy and coverage of organism for SP cleavage sites, we propose a novel method for predicting SP cleavage sites called Signal-CTF that utilizes machine learning and sliding windows, and is designed for N-termial secretory proteins in a large variety of organisms including human, animal, plant, virus, bacteria, fungi and archaea. Signal-CTF consists of three distinct elements: (1) a subsite-coupled and regularization function with a scaled window of fixed width that selects a set of candidates of possible secretion-cleavable segment for a query secretory protein; (2) a sum fusion system that integrates the outcomes from aligning the cleavage site template sequence with each of the aforementioned candidates in a scaled window of fixed width to determine the best candidate cleavage sites for the query secretory protein; (3) a voting system that identifies the ultimate signal peptide cleavage site among all possible results derived from using scaled windows of different width. When compared with Signal-3L and SignalP 4.0 predictors, the prediction accuracy of Signal-CTF is 4-12 %, 10-25 % higher than that of Signal-3L for human, animal and eukaryote, and SignalP 4.0 for eukaryota, Gram-positive bacteria and Gram-negative bacteria, respectively. Comparing with PRED-SIGNAL and SignalP 4.0 predictors on the 32 archaea secretory proteins of used in Bagos's paper, the prediction accuracy of Signal-CTF is 12.5 %, 25 % higher than that of PRED-SIGNAL and SignalP 4.0, respectively. The predicting results of several long signal peptides show that the Signal-CTF can better predict cleavage sites for long signal peptides than SignalP, Phobius, Philius, SPOCTOPUS, Signal-CF and Signal-3L. These results show that Signal-CTF is more accurate and flexible in predicting signal peptides of different characteristics for many organisms. Signal-CTF is freely available as a web-server at http://darwin2.cbi.utsa.edu/minniweb/index.html. PMID- 27485692 TI - Insights from QM/MM Modeling the 3D Structure of the 2009 H1N1 Influenza A Virus Neuraminidase and Its Binding Interactions with Antiviral Drugs. AB - Control of drug release through the inhibition of neuraminidase-1 has been identified as a potential target for the treatment of H1N1 influenza; however, the drug binding mode of neuraminidase is not yet completely understood. In this work, we propose a model for a neuraminidase-1 complex based on four known X-ray structures of drug/neuraminidase-1 complexes. Specifically, H1N1 neuraminidase-1 complexed with 4 drugs (zanamivir, laninamivir, laninamivir octanoate and oseltamivir) was first investigated using a combined quantum mechanical and molecular mechanical (QM/MM) approach. Based on these structures, a model for the H1N1 neuraminidase-1 complex was proposed and simulated using the same computational protocol. Implications to drug/H1N1 neuraminidase-1 binding modes are discussed. From our simulations, the predicted binding free energies of the four drugs are in good agreement with the experimental results, with the correlation coefficient being 0.84. PMID- 27485693 TI - Downregulation of AATK mediates microRNA-558-induced resistance of A549 cells to radiotherapy. AB - The deregulation of microRNAs (miRNAs) is often implicated in the control of sensitivity to radiotherapy. The objective of the present study was to identify the association between miR-558 and apoptosis-associated tyrosine kinase (AATK), and their importance in regulating the development of resistance to radiotherapy. The current study demonstrated that AATK, a radiosensitization-associated gene, is a target of miR-558 in lung cancer cells, using in silico analysis and a luciferase reporter system. Furthermore, it was determined that transfection of 30 or 50 nM miR-558 mimics and AATK specific siRNA markedly suppressed the mRNA and protein expression of AATK. To determine whether miR-558 was required for lung cancer cell radioresistance, A549 cells were treated with different doses of ionizing radiation, from 0 to 10 Gy, following transfection with miR-558 mimics or AATK specific siRNA. It was determined that the administration of miR-558 mimics or AATK specific siRNA alone did not significantly alter the survival rate of the cells. By contrast, in the cells exposed to 4, 6 or 8 Gy, the administration of miR-558 mimics or AATK specific siRNA significantly promoted cell survival rate and overexpression of AATK reversed this effect. In conclusion, these data demonstrate that the miR-558/AATK cascade is important for the radiosensitization of lung cancer cells and may be a potential radiotherapy target. PMID- 27485694 TI - Relationships between milks differentiated on native milk fat globule characteristics and fat, protein and calcium compositions. AB - Many studies have shown that milk fat globule (MFG) diameter varies in dairy cows in relation to diet and/or breed. However, the mechanisms governing the size of the fat globules remain hypothetical. Our objective was to determine the variable biochemical characteristics (fat, protein, fatty acids (FA), casein and calcium (Ca) contents) between individual milk which differed in both MFG diameter and membrane content, in order to speculate about the links between milk synthesis and MFG secretion. With this aim, we built five databases of individual milk samples from 21 experiments performed between 2003 and 2011. Three of them grouped data from trials dealing with breed/diet effects and included information about: (i) MFG size/membrane, fat and protein contents (n=982), (ii) previous parameters plus FA profile (n=529) and (iii) previous parameters plus true protein composition and calcium contents (n=101). A hierarchical clustering analysis performed on these three databases yielded four groups differing in the MFG characteristics. We observed significant differences among groups for the following parameters: (i) fat content and fat : protein ratio; (ii) de novo and polyunsaturated FA contents; (iii) Ca contents. These relationships could result from potential process regulating the synthesis and secretion of MFG: (i) the apical membrane turnover for MFG secretion and (ii) cytoplasmic lipid droplet formation in the lactocyte during its migration from the basal to the apical pole. The two other databases grouped data from trials dealing with milking frequency (n=211), milking kinetics and milk type (residual v. cisternal) (n=224). They were used to study the relationships between the size of the MFG and milk composition for high native fat contents (from 60 up to 100 g/kg in residual milks). We observed curvilinear relationships between the size of the MFG and fat content, as well as with the fat : protein ratio. This result suggests that MFG diameter reaches a threshold but mechanisms are still unknown. PMID- 27485695 TI - Spinal Cord Infarction in Hemoglobin SC Disease as an Amusement Park Accident. AB - Spinal cord infarction (SCI) is extremely rare in children, and only 2 other reports have described the occurrence of SCI in patients with hemoglobin SC disease (HbSC). Amusement park accidents are serious injuries. Patients with preexisting conditions, such as hypertension, cardiac disease, and recent back or neck injuries, may be at an increased risk. We report the case of a 12-year-old girl with HbSC with a past history of only 2 admissions for pain crises, who presented to the emergency department with symptoms of SCI after riding a roller coaster. Fibrocartilaginous embolism (FCE) is an increasingly recognized cause of SCI after events that put strain on the axial skeleton, such as many amusement park rides. Although radiologic criteria for FCE have been proposed, FCE remains a diagnosis of exclusion. To the best of our knowledge, this is the first documented case of SCI in a patient with HbSC and the first case of FCE after an amusement park accident. This case report highlights that HbSC may confound the differential diagnosis of SCI and aims to document an association with FCE in pediatric patients. PMID- 27485697 TI - 30th Anniversary of Pediatric Research in Office Settings (PROS): An Invitation to Become Engaged. PMID- 27485698 TI - Observations of disorganized behaviour yield no magic wand: response to Shemmings. PMID- 27485696 TI - Parent Experience With False-Positive Newborn Screening Results for Cystic Fibrosis. AB - BACKGROUND: The risk of psychosocial harm in families of infants with false positive (FP) newborn bloodspot screening (NBS) results for cystic fibrosis (CF) is a longstanding concern. Whether well designed retrieval and confirmatory testing systems can mitigate risks remains unknown. METHODS: Using a mixed methods cohort design, we obtained prospective self-report data from mothers of infants with FP CF NBS results 2 to 3 months after confirmatory testing at Ontario's largest follow-up center, and from a randomly selected control sample of mothers of screen negative infants from the same region. Mothers completed a questionnaire assessing experience and psychosocial response. A sample of mothers of FP infants completed qualitative interviews. RESULTS: One hundred thirty-four mothers of FP infants (response rate, 55%) and 411 controls (response rate, 47%) completed questionnaires; 54 mothers of FP infants were interviewed. Selected psychosocial response measures did not detect psychosocial distress in newborns or 1 year later (P > .05). Mothers recalled distress during notification of the positive result and in the follow-up testing period related to fear of chronic illness, but valued the screening system of care in mitigating concerns. CONCLUSIONS: Although immediate distress was reported among mothers of FP infants, selected psychometric tools did not detect these concerns. The NBS center from which mothers were recruited minimizes delay between notification and confirmatory testing and ensures trained professionals are communicating results and facilitating follow-up. These factors may explain the presence of minimal psychosocial burden. The screening system reflected herein may be a model for NBS programs working to minimize FP-related psychosocial harm. PMID- 27485699 TI - Labilizing the Photoinert: Extraordinarily Facile Photochemical Ligand Ejection in an [Os(N^N)3 ](2+) Complex. AB - Whilst [Os(N^N)3 ](2+) complexes are supposed to be photochemically inert to ligand loss, the complex [Os(btz)3 ](2+) (btz=1,1'-dibenzyl-4,4'-bi-1,2,3 triazolyl) undergoes unprecedented photolytic reactivity to liberate free btz (Phi363 ~1.2 %). Further, both cis and trans isomers of the photodechelated ligand-loss solvento intermediate [Os(kappa(2) -btz)2 (kappa(1) -btz)(NCMe)](2+) are unambiguously observed and characterized by NMR spectroscopy and mass spectrometry. PMID- 27485700 TI - The Importance of Innate Immunity in Acne. PMID- 27485701 TI - Interference in transcription of overexpressed genes by promoter-proximal downstream sequences. AB - Despite a high sequence homology among four human RNAi-effectors Argonaute proteins and their coding sequences, the efficiency of ectopic overexpression of AGO3 and AGO4 coding sequences in human cells is greatly reduced as compared to AGO1 and AGO2. While investigating this phenomenon, we documented the existence of previously uncharacterized mechanism of gene expression regulation, which is manifested in greatly varying basal transcription levels from the RNApolII promoters depending on the promoter-proximal downstream sequences. Specifically, we show that distinct overexpression of Argonaute coding sequences cannot be explained by mRNA degradation in the cytoplasm or nucleus, and exhibits on transcriptional level. Furthermore, the first 1000-2000 nt located immediately downstream the promoter had the most critical influence on ectopic gene overexpression. The transcription inhibiting effect, associated with those downstream sequences, subsided with increasing distance to the promoter and positively correlated with promoter strength. We hypothesize that the same mechanism, which we named promoter proximal inhibition (PPI), could generally contribute to basal transcription levels of genes, and could be mainly responsible for the essence of difficult-to-express recombinant proteins. Finally, our data reveal that expression of recombinant proteins in human cells can be greatly enhanced by using more permissive promoter adjacent downstream sequences. PMID- 27485702 TI - The Association between Diabetes and Herpes Simplex Eye Disease. AB - PURPOSE: To evaluate the association between diabetes mellitus (DM) and presence and severity of Herpes simplex eye disease (HSED). METHODS: We conducted two sub studies. We included the patients seen on the Cornea Service of the Wills Eye Hospital from January 2008 to August 2012. Study 1 included 541 patients with HSED and 3226 controls. Study 2 involved 40 diabetic and 120 non-diabetic ocular surface HSED patients. Severity of ocular surface HSED was graded as mild, moderate, or severe, based on best-corrected visual acuity (BCVA). Patients were excluded if they had fewer than two office visits or had non-Herpes simplex related vision-threatening conditions. Diabetes was graded as: diet group (DM controlled with diet), oral group (DM controlled with oral medications), and insulin group (DM control required insulin). RESULTS: Five of 541 (0.93%) HSED patients had type 1 DM, similar to 19/3246 (0.59%) controls (p = 0.375); 48 of 541 (8.88%) HSED patients had type 2 DM, similar to 287/3246 (8.84%) controls (p = 0.981). Using multinomial logistic regression analyses, the probability/risk of being in the severe ocular surface HSED group as opposed to the mild ocular surface HSED group were not statistically significantly different between DM patients and those without DM (p = 0.120; OR, 1.900; 95% CI, 0.846-4.266). CONCLUSIONS: There may not be a positive association between type 2 DM and HSED. PMID- 27485703 TI - Postpartum unconscious dynamics emerging from the Luscher color test in Ethiopian women. AB - The aim of this study was to explore the feasibility of the Luscher color test (LCT), a psychological instrument based on theory that colors are selected in unconscious way and that the color sensory perception of color is objective and universal. The research has involved 24 Ethiopian women, which delivered at the Getche Health Center in Gurage. It seemed to be relevant for the majority of Ethiopian women identify the rejected color (58.66%), the gray, than the favorite color, the yellow 33.33%). The yellow color suggests that they better express their personality in a physical context, while the gray color indicates that they want to live this experience intensely. This exploratory work lays the foundations for further studies in disadvantaged women, both in developing low income Countries as well as in industrialized Countries characterized by an high level of emigration, and for clinical applications by the complete LCT version. PMID- 27485704 TI - Intrapartum transvaginal sonographic imaging of mentum posterior presentation at 39 weeks' gestation. PMID- 27485705 TI - Strabismus and Near Point of Convergence and Amblyopia in 4-6 Year-Old Children. AB - PURPOSE: To determine the prevalence of strabismus and amblyopia, and the distribution of the near point of convergence (NPC), in a population of children aged 4 to 6 years. METHODS: In this cross-sectional study, preschoolers in Mashhad were sampled using a random multistage cluster sampling approach. Examinations were done after obtaining parental consent. All participants had measurements of uncorrected visual acuity, corrected visual acuity, and non cycloplegic refraction, and they had near and far cover tests to determine tropia and phoria. RESULTS: Of the 3765 selected children, 3701 participated in the study. The prevalence of tropia was 1.21% (95% confidence interval [CI]: 0.86 1.57). Near and near/far tropia was observed in 0.83% (95% CI: 0.53-1.12) and 0.39% (95% CI: 0.18-0.59), respectively. Tropia was significantly more prevalent in boys (P=0.005). The most common type of tropia was esotropia, 0.22% (95% CI: 0.07-0.37). Among participants, 63.92% (95% CI: 62.36-65.48) had phoria; prevalence of far, near, and near/far phoria was 0.22% (95% CI: 0.07-0.37), 60.47% (95% CI: 58.88-62.07), and 3.22% (95% CI: 2.65-3.8), respectively. Mean NPC was 5.1 cm (95% CI: 5.05-5.14). NPC increased by 0.08 cm per month of age (P=0.033) and was 0.10 cm higher in boys compared to girls (P=0.027). Based on NPC, 61.58% (95% CI: 59.99-63.17) were symptomatic. The prevalence of amblyopia was 0.41% (95% CI: 0.20-0.61). The type of amblyopia was anisometropic, strabismic, and isoametropic in 75%, 11.1%, and 8.5%, respectively. CONCLUSION: The prevalence of amblyopia in this study population was not high; however, the prevalence of tropia was average compared to previous studies in Iran. Describing NPC in a 4- to 6-year-old Iranian population for the first time, we found that NPC increased with age in this sample. PMID- 27485706 TI - Elevated DRD4 promoter methylation increases the risk of Alzheimer's disease in males. AB - Aberrant promoter methylation of multiple genes is associated with various diseases, including Alzheimer's disease (AD). The goal of the present study was to determine whether dopamine receptor D4 (DRD4) promoter methylation is associated with AD. In the current study, the methylation levels of the DRD4 promoter were measured in 46 AD patients and 61 controls using bisulfite pyrosequencing technology. The results of the present study demonstrated that DRD4 promoter methylation was significantly higher in AD patients than in controls. A further breakdown analysis by gender revealed that there was a significant association of DRD4 promoter methylation with AD in males (23 patients and 45 controls). In conclusion, the results of the present study demonstrated that elevated DRD4 promoter methylation was associated with AD risk in males. PMID- 27485707 TI - The role of IGF-1 and the distribution of body fat in decreasing the number of prostate rebiopsies. AB - OBJECTIVE: To assess the usefulness of IGF-1 and internal organ fat measured by bioelectrical impedance audiometry to avoid rebiopsies in patients with persistently high prostate-specific antigen (PSA) levels. MATERIAL AND METHOD: A prospective study was conducted with 92 patients who underwent prostate rebiopsy due to high PSA levels with negative results in the rectal examination and a lack of preneoplastic lesions. The patients previously had their IGF-1 levels measured and had undergone an impedance audiometry test using the abdominal Fat Analyser AB-140 TANITA system. We calculated the receiver operating characteristic (ROC) curves for the PSA levels, %PSA, internal organ fat and IGF-1 and PSA density. RESULTS: Twenty-five patients were diagnosed with prostate cancer. These patients had significantly higher PSA, PSAd and IGF-1 values and a tendency towards higher internal organ fat levels and lower %PSA readings (p=.001, p=.003, p=.001, p=.24 and P=0.28, respectively). The ROC curve showed an area under the curve for IGF-1 and PSA of .82 and .81, respectively. Using the cutoff points for 95% sensitivity and using the 3 criteria as an indication of rebiopsy, 74% of the biopsies would have been spared, leaving undiagnosed only 1 patient with clinically significant cancer -Gleason score>7 (4+3)-. The positive and negative predictive values for the set of variables were higher than for each one separately (PPV: 66/NPV: 63). The cost of both determinations was 82 euros. CONCLUSIONS: Our results suggest that measuring IGF-1 could significantly decrease the number of unnecessary rebiopsies in an inexpensive and safe manner. PMID- 27485708 TI - A review of current methods using bacteriophages in live animals, food and animal products intended for human consumption. AB - Bacteriophages are utilised in the food industry as biocontrol agents to reduce the load of bacteria, and thus reduce potential for human infection. This review focuses on current methods using bacteriophages within the food chain. Limitations of research will be discussed, and the potential for future food based bacteriophage research. PMID- 27485709 TI - Evaluation of real-time PCR assays and standard curve optimisation for enhanced accuracy in quantification of Campylobacter environmental water isolates. AB - Campylobacter is a major public health and economic burden in developed and developing countries. This study evaluated published real-time PCR (qPCR) assays for detection of Campylobacter to enable selection of the best assays for quantification of C. spp. and C. jejuni in environmental water samples. A total of 9 assays were compared: three for thermotolerant C. spp. targeting the 16S rRNA and six for C. jejuni targeting different genes. These assays were tested in the wet-lab for specificity and sensitivity against a collection of 60, genetically diverse, Campylobacter isolates from environmental water. All three qPCR assays targeting C. spp. were positive when tested against the 60 isolates, whereas, assays targeting C. jejuni differed among each other in terms of specificity and sensitivity. Three C. jejuni-specific assays that demonstrated good specificity and sensitivity when tested in the wet-lab showed concordant results with in silico-predicted results obtained against a set of 211 C. jejuni and C. coli genome sequences. Two of the assays targeting C. spp. and C. jejuni were selected to compare DNA concentration estimation, using spectrophotometry and digital PCR (dPCR), in order to calibrate standard curves (SC) for greater accuracy of qPCR-based quantification. Average differences of 0.56+/-0.12 and 0.51+/-0.11 log fold copies were observed between the spectrophotometry-based SC preparation and the dPCR preparation for C. spp. and C. jejuni, respectively, demonstrating an over-estimation of Campylobacter concentration when spectrophotometry was used to calibrate the DNA SCs. Our work showed differences in quantification of aquatic environmental isolates of Campylobacter between qPCR assays and method-specific bias in SC preparation. This study provided an objective analysis of qPCR assays targeting Campylobacter in the literature and provides a framework for evaluating novel assays. PMID- 27485710 TI - Kostmann syndrome: oral aspects and 10-year follow-up case report. AB - Kostmann syndrome (KS) is an autosomal recessive disorder characterized by a low neutrophil count and recurrent bacterial infections, including periodontal disease. This report describes the case of a 5-year-old female KS patient treated with regular infusions of granulocyte stimulating factor (granulokine), with primary complaint of gingival bleeding and tooth mobility, and followed up for 10 years. Conventional periodontal treatment and some extractions were performed, after neutrophil function tests using flow cytometry. The invasive procedures were carried out at an outpatient clinic under antibiotic prophylaxis due to a low neutrophil count and an impaired neutrophil function presented. During the 10 year follow-up period, despite episodes of recurrent gingivitis and periodontitis the present report describes the positive outcome of dental treatment of a patient with KS. PMID- 27485711 TI - [Algorithm for Choosing the Study Design in Systematic Reviews]. AB - Background: The Federal Joint Committee (Gemeinsamer Bundesausschuss) assigns the highest evidence level of Ia to systematic reviews of randomized controlled trials in evaluating the benefit of therapeutic interventions. Contradictory results among randomized and non-randomized studies may not always be caused by the study design. Methods: The objective of the study was to identify statements in systematic or non-systematic reviews about the choice of study designs in systematic reviews. Another objective was to develop an algorithm to facilitate the choice of appropriate study designs in systematic reviews. Results: The inclusion of non-randomized in addition to randomized study designs was supported by 85% of the 42 identified articles. A strong reason was the need to evaluate the possible treatment-associated harm. The developed algorithm included the 4 decision points of length of follow-up, frequency of events, outcomes, and study designs. Conclusions: If the benefit and the harm of a therapeutic intervention is planned to be evaluated, then often multiple study designs are required to be included. The algorithm provides guidance on which study designs should be considered for inclusion in systematic reviews. PMID- 27485712 TI - The Red Nucleus Interleukin-6 Participates in the Maintenance of Neuropathic Pain Induced by Spared Nerve Injury. AB - Previous studies have demonstrated that the red nucleus (RN) is involved in the regulation of neuropathic pain and plays both facilitated and inhibitory roles through different cytokines. Here, we aim to investigate the expression changes and roles of interleukin-6 (IL-6), a pleiotropic cytokine, as well as its receptor (IL-6R) in the RN of rats with neuropathic pain induced by spared nerve injury (SNI). Immunohistochemistry indicated that IL-6 and IL-6R were weakly expressed in the RN of normal rats, and were mainly co-localized with neurons and oligodendrocytes. Following SNI, the expression levels of IL-6 and IL-6R in the RN did not show obvious changes at 1 week and 2 weeks postinjury. However, both of them were significantly increased in the RN contralateral (but not ipsilateral) to the nerve ligation side at 3 weeks postinjury, and co-localized not only with neurons and oligodendrocytes, but also with numerous astrocytes. Injection of different doses of anti-IL-6 antibody (100, 250, 500 ng) into the RN contralateral to the nerve ligation side at 3 weeks postinjury dose-dependently increased the paw withdrawal threshold (PWT) of rats and alleviated SNI-induced mechanical allodynia. Conversely, injection of different doses of recombinant rat IL-6 (5.0, 10, 20 ng) into the unilateral RN of normal rats dose-dependently decreased the PWT of contralateral (but not ipsilateral) hind paw and evoked significant mechanical allodynia, which was similar to SNI-induced neuropathic allodynia. These results further support the conclusion that the RN is involved in the modulation of neuropathic pain, and suggest that IL-6 and IL-6R in the RN play a facilitated role in the later maintenance of SNI-induced neuropathic pain. PMID- 27485713 TI - Uptake and Toxicity of Copper Oxide Nanoparticles in C6 Glioma Cells. AB - Copper oxide nanoparticles (CuO-NPs) are frequently used for many technical applications, but are also known for their cell toxic potential. In order to investigate a potential use of CuO-NPs as a therapeutic drug for glioma treatment, we have investigated the consequences of an application of CuO-NPs on the cellular copper content and cell viability of C6 glioma cells. CuO-NPs were synthesized by a wet-chemical method and were coated with dimercaptosuccinic acid and bovine serum albumin to improve colloidal stability in physiological media. Application of these protein-coated nanoparticles (pCuO-NPs) to C6 cells caused a strong time-, concentration- and temperature-dependent copper accumulation and severe cell death. The observed loss in cellular MTT-reduction capacity, the loss in cellular LDH activity and the increase in the number of propidium iodide positive cells correlated well with the specific cellular copper content. C6 glioma cells were less vulnerable to pCuO-NPs compared to primary astrocytes and toxicity of pCuO-NPs to C6 cells was only observed for incubation conditions that increased specific cellular copper contents above 20 nmol copper per mg protein. Both cellular copper accumulation as well as the pCuO-NP-induced toxicity in C6 cells were prevented by application of copper chelators, but not by endocytosis inhibitors, suggesting that liberation of copper ions from the pCuO-NPs is the first step leading to the observed toxicity of pCuO-NP-treated glioma cells. PMID- 27485714 TI - Protective Effect of Hyperbaric Oxygen on Cognitive Impairment Induced by D Galactose in Mice. AB - Memory decline is characteristic of aging and age-related neurodegenerative disorders. This study was designed to investigate the protective effect of hyperbaric oxygen (HBO) against cognitive impairment induced by D-galactose (D gal) in mice. D-gal was intraperitoneally injected into mice daily for 8 weeks to establish the aging model. HBO was simultaneously administered once daily. The results indicate that HBO significantly reversed D-gal-induced learning and memory impairments. Studies on the potential mechanisms of this action showed that HBO significantly reduced oxidative stress by increasing superoxide dismutase, glutathione peroxidase, and catalase levels, as well as the total anti oxidation capability, while decreasing the content of malondialdehyde, nitric oxide, and nitric oxide synthase in the hippocampal CA1 region. HBO also inhibited advanced glycation end-product formation and decreased levels of tumor necrosis factor-alpha and interleukin-6. Moreover, HBO significantly attenuated D gal-induced pathological injury in the hippocampus, as well as beta-amyloid protein1-42 expression and retained BDNF expression. Furthermore, HBO decreased p16, p21 and p53 gene and protein expression in the hippocampus of D-gal-treated mice. In conclusion, the protective effect of HBO against D-gal-induced cognitive impairment was mainly due to its ability to reduce oxidative damage, suppress inflammatory responses, and regulate aging-related gene expression. PMID- 27485715 TI - Colonic polyp histopathology and location in a community-based sample of older adults. AB - BACKGROUND: Colorectal cancer and its precursors are highly prevalent in developed countries. Estimates in the available literature for prevalence of right-sided-only lesions vary between 20.5 and 48.1 %, with association with female gender and advancing age. Since the original polyp studies, premalignant potential of sessile serrated adenomas has been described and screening utilization of colonoscopy in men, women, and older adults has increased. This study describes the histopathology and distribution of colorectal polyps by age and gender in the post-screening era. METHODS: A registry of biopsies performed during colonoscopy for adults aged 50+ years in 2002-2012 was created using pathology reports from an independent, regional laboratory. Age, histopathology, and polyp location(s) were included. A subgroup analysis was performed for sessile serrated adenomas for 2007-2012. Distributions of histopathology and polyp location were described by age and gender. Statistical comparisons are made using chi-square tests. RESULTS: 13,881 patients (55.5 % male, 44.5 % female), aged 50-95 years (median = 62) were identified. Most patients (59.9 %) had adenomas. Single and multiple adenomas were more common in men than women (57.7 % vs 42.3 %, p < .0001 and 62.2 % vs 37.8 %, p < .001), and with advancing age (60.4 % for ages 50- < 60, 63.4 % for ages 60- < 70, 65 % for ages 70- < 80, and 68.9 % for ages >80). Villous adenomas (n = 545; 3.6 %), dysplasia (n = 49; 0.4 %), and invasive carcinoma (n = 22; 0.2 %) were rare. Sessile serrated adenomas were uncommon (n = 417, 4.5 %), with greater prevalence in women than men (5.1 % vs 4 %, p = 0.02). Patients aged 70- < 80 were more likely to have multiple polyps than those aged 50- < 60 (OR 1.17, 95 % CI 1.03-1.32, p = 0.018 and OR 1.27, 95 % CI 1.10-1.46, p = .001). Most polyps were from ascending and/or transverse colon (n = 8095; 58.3 %). When location was stratified by sex only, men had more polyps than women at each location except the sigmoid and rectum. Further stratification by age of location and sex revealed statistically significant differences (age 50- < 60, p < .0001, age 60- < 70, p = .0227, age 70 < 80, p = .0298, age 80+, p = .0018). CONCLUSIONS: This large community-based sample contributes to understanding of colonic neoplasia. The high prevalence of right and transverse lesions supports ongoing use of colonoscopy over sigmoidoscopy for screening examinations. PMID- 27485716 TI - Erratum to: CoMEt: a statistical approach to identify combinations of mutually exclusive alterations in cancer. PMID- 27485717 TI - Facebook use and its effects on the life of health science students in a private medical college of Nepal. AB - BACKGROUND: Facebook, a popular social networking site, has been used by people of different ages and professions for various purposes. Its use in the field of medical education is increasing dramatically. At the same time, the pros and cons of facebook use among the health science students has attracted the attention of educators. The data regarding its use and the effect on the life of Nepalese health science students has not yet been documented. Therefore, this study is carried out to evaluate the effect of facebook use on social interactions, behaviour, academics, and the health of students in a medical college of Nepal. RESULTS: A cross-sectional descriptive study conducted among medical, dental, nursing and allied health science students using self-administered questionnaire. The study showed that 98.2 % of participants were facebook users. Among 452 respondents, 224 and 228 were male and female respectively, with a mean age of 20.2 +/- 1.2 years. The main reason for using facebook was to remain in contact with family and friend (32 %), while its use for the academic purpose was only 5 %. However, 80.8 % of students acknowledged ease in acquiring academic materials from others, through facebook. One-fourth of the students acknowledged that they are using facebook late at night on a regular basis, while surprisingly 4.2 % of the students admitted accessing facebook during the classroom lectures. Almost two-third of the users, further admitted that facebook has had a negative impact on their studies. Burning eyes (21 %), disturbed sleep (19 %), and headache (16 %) were the most common adverse health effects reported by the facebook users. Many students (71.4 %) tried and most of them (68.7 %) succeeded, in reducing time spent on facebook, to allow for increased time devoted to their studies. CONCLUSION: The widespread use of facebook among the health science students, was found to have both positive and negative effects on their academics, social life, and health. PMID- 27485718 TI - Parameters and outcomes in 525 patients operated on for oral squamous cell carcinoma. AB - PURPOSE: This report analyzed the outcomes of patients undergoing surgery for oral squamous cell carcinoma (OSCC) to identify the value of prognostic factors. MATERIAL AND METHODS: A total of 525 patients were studied who had undergone surgery for oral squamous cell carcinoma (OSCC) between 2000 and 2011, of whom 222 had received postoperative radiation-therapy (PORT) and or chemoradiation therapy (PORTC). For each patient, personal data, histological findings, treatment and outcome were recorded and analyzed statistically. Survival curves were calculated using the Kaplan-Meier algorithm, and the difference in survival among subgroups was examined. RESULTS: The overall survival (OS) and disease specific survival (DSS) 5-year survival rate in the 525 patients were respectively 71.38% and 73.18%. The differences in the overall survival and disease-specific 5-year survival were significant (p < 0.05) for age < 40 years, site of origin, N status, staging, grading, osseous medullar infiltration, and perineural invasion. In patients undergoing radiation therapy, only perineural invasion negatively influenced the survival prognosis. In 150 pT1 cases of tongue and floor-of-mouth cancer, an infiltration depth (ID) > 4 mm was statistically correlated with poorer prognosis. CONCLUSIONS: The results demonstrate an improvement in the 5-year OS and DSS rates during the past decade compared with the previous decade. Univariate analysis revealed that age, tumor staging, and lymph node involvement, extracapsular spread, grading, perineurial invasion, infiltration depth, and osseus medullary invasion were associated significantly with overall survival and disease-specific survival. PMID- 27485719 TI - Task shifting from physicians to nurses in primary care in 39 countries: a cross country comparative study. AB - BACKGROUND: Primary care is in short supply in many countries. Task shifting from physicians to nurses is one strategy to improve access, but international research is scarce. We analysed the extent of task shifting in primary care and policy reforms in 39 countries. METHODS: Cross-country comparative research, based on an international expert survey, plus literature scoping review. A total of 93 country experts participated, covering Europe, USA, Canada, Australia and New Zealand (response rate: 85.3%). Experts were selected according to pre defined criteria. Survey responses were triangulated with the literature and analysed using policy, thematic and descriptive methods to assess developments in country-specific contexts. RESULTS: Task shifting, where nurses take up advanced roles from physicians, was implemented in two-thirds of countries (N = 27, 69%), yet its extent varied. Three clusters emerged: 11 countries with extensive (Australia, Canada, England, Northern Ireland, Scotland, Wales, Finland, Ireland, Netherlands, New Zealand and USA), 16 countries with limited and 12 countries with no task shifting. The high number of policy, regulatory and educational reforms, such as on nurse prescribing, demonstrate an evolving trend internationally toward expanding nurses' scope-of-practice in primary care. CONCLUSIONS: Many countries have implemented task-shifting reforms to maximise workforce capacity. Reforms have focused on removing regulatory and to a lower extent, financial barriers, yet were often lengthy and controversial. Countries early on in the process are primarily reforming their education. From an international and particularly European Union perspective, developing standardised definitions, minimum educational and practice requirements would facilitate recognition procedures in increasingly connected labour markets. PMID- 27485721 TI - En face choroidal vascular feature imaging in acute and chronic central serous chorioretinopathy using swept source optical coherence tomography. AB - AIMS: To evaluate the variable depth tomographic features of choroidal vasculature in acute and chronic central serous chorioretinopathy (CSC) using swept source optical coherence tomography (SS-OCT) en face imaging. METHODS: We retrospectively reviewed the en face SS-OCT images of 29 patients that presented with acute (12 eyes) or chronic (17 eyes) CSC. All of the patient eyes underwent 6*6 macular scans with SS-OCT (DRI OCT-1, Topcon, Tokyo, Japan), fluorescein angiography and indocyanine green angiography. The en face image was used to investigate the choroidal vasculature of each layer. Moreover, we determined that some parts corresponded to choriocapillaris and Sattler's layer attenuation, whereas choroidal vessel dilatation was associated with Haller's layer. RESULTS: At Haller's layer level, choroidal vessel dilatation was observed in 11 of 12 acute CSC (91.7%) and 15 of 17 chronic CSC (88.2%). In acute CSC, choroidal vessel dilatation was divided into focal (9/11; 81.8%) and diffuse (2/11; 18.2%) patterns. The chronic CSC cases demonstrated different patterns of choroidal vessel dilatation: focal (5/15; 33.3%) and diffuse (10/15; 66.6%). Ten of the acute CSC eyes (83.3%) and 14 of the chronic CSC eyes (82.4%) were found to have obscured choriocapillaris and Sattler's layers on en face imaging. CONCLUSIONS: En face imaging of SS-OCT is useful when combined with angiography in CSC for evaluating choroidal vessel dilatation at Haller's layer and to identify obscured upper layers. We identified different choroidal vessel dilatation patterns between acute and chronic CSC. These findings might be useful for pathophysiological understanding of CSC. PMID- 27485720 TI - Factors for successful implementation of population-based expanded carrier screening: learning from existing initiatives. AB - Background: Carrier screening for autosomal recessive disorders aims to facilitate reproductive decision-making by identifying couples with a 1-in-4 risk in every pregnancy of having an affected child. Except for a few countries or regions, carrier screening is not widely offered and is mostly ancestry-based. Technological advances enable carrier screening for multiple diseases simultaneously allowing universal screening regardless of ancestry (population based expanded carrier screening). It is important to study how this can be successfully implemented. This study therefore aims to identify critical factors involved in successful implementation, from a user perspective, by learning from already implemented initiatives. Methods: Factors associated with successful implementation were identified by: (i) a literature review and (ii) two case studies; studying experiences with carrier screening in two high-risk communities (a Dutch founder population and the Ashkenazi Jewish population), including a survey among community members. Results: Factors identified were familiarity with (specific) genetic diseases and its availability, high perceived benefits of screening (e.g. screening avoids much suffering), acceptance of reproductive options, perceived risk of being a carrier and low perceived social barriers (e.g. stigmatization). In contrast to the Jewish community, the initial demand for screening in the Dutch founder population did not entirely come from the community itself. However, the large social cohesion of the community facilitated the implementation process. Conclusion: To ensure successful implementation of population-based expanded carrier screening, efforts should be made to increase knowledge about genetic diseases, create awareness and address personal benefits of screening in a non-directive way. PMID- 27485722 TI - The impact of typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy on vision-related quality of life in Asian patients. AB - AIMS: To determine the impact of neovascular age-related macular degeneration (nAMD) on vision-related quality of life (VRQoL) in an Asian population. METHODS: In this cross-sectional study, 162 subjects with nAMD from the Asian AMD Phenotyping Study and 105 randomly sampled age-matched and gender-matched controls from the population-based Singapore Chinese Eye Study were recruited. nAMD was categorised as either polypoidal choroidal vasculopathy (PCV) or 'typical' AMD (tAMD). The reading, mobility and emotional well-being subscales of the impact of vision impairment (IVI) scale were validated using Rasch analysis and used as the main outcome measures and collectively referred to as VRQoL. Multivariate linear regression analyses were performed to assess the impact of nAMD overall, and PCV and tAMD subtypes, on the three IVI domains. RESULTS: Of the 162 with nAMD, 103 (63.6%) had PCV and 59 (36.4%) had tAMD. In multivariate models, nAMD overall was independently associated with a 21% reduction in reading (beta=-1.08; CI -1.58 to -0.57); 16% reduction in mobility (beta=-0.74; -1.14 to 0.33) and 44% reduction in emotional well-being (beta=-2.15; -2.83 to -1.47) compared with controls. There were significant VRQoL deficits (p<0.05) associated with both PCV and tAMD; these deficits were similar and not statistically different between the two nAMD subtypes (p>0.05). CONCLUSIONS: Neovascular AMD, including both PCV and tAMD subtypes, has a detrimental impact on VRQoL in Asian subjects independent of level of vision impairment. Interventions to increase reading capacity, enhance mobility and independence and improve mental health outcomes for subjects with neovascular AMD further address the impact of the condition on VRQoL in addition to pharmacological therapies. PMID- 27485723 TI - Is prophylactic laser peripheral iridotomy for primary angle closure suspects a risk factor for cataract progression? The Chennai Eye Disease Incidence Study. AB - BACKGROUND: To report the risk of cataract progression among primary angle closure suspects (PACS) 6 years after they underwent laser peripheral iridotomy (LPI). METHODS: In the Chennai Eye Disease Incidence Study, 6 years after their baseline evaluation, 4421 subjects were examined again. As part of a detailed evaluation cataract was graded using the Lens Opacities Classification System II; progression was defined as change of cataract by two or more grades or history of cataract surgery in the 6-year period. Only bilaterally phakic subjects with less than N2 or C2 or P2 cataract at baseline with no history of any form of glaucoma, primary angle closure and pseudoexfoliation were included. RESULTS: There were 3205 eligible subjects. Of these, 190 had undergone LPI for PACS. In comparison to the study population, they were significantly older (p<0.001), female (p=0.008), urban residents (p=0.001) and patients with hypertension (p<0.001). During the intervening period, 53 subjects had undergone cataract surgery. The cataract progression rate was significantly greater (OR 1.7, 95% CI 1.3 to 2.4, p<0.001) in those who had undergone LPI. For the study population the baseline risk factors for progression of cataract were age (p<0.001), female gender (p=0.01), diabetes (p<0.001) and LPI (p<0.001). Diabetes and female gender were significant risk factors for nuclear and cortical cataract progression; LPI was a risk factor only for cortical cataract (OR 1.6, 95% CI 1.1 to 2.3, p=0.007). CONCLUSIONS: There was significant cataract progression in 6 years following LPI for PACS. PMID- 27485724 TI - Individual, social, and environmental influences on the transitions in physical activity among emerging adults. AB - BACKGROUND: Youth's physical activity (PA) may change across developmental periods. Although previous studies have observed a decline in levels of PA during adolescence, few studies have explored trends in PA during the transition from adolescence to young adulthood and what factors may impact the transitional change. The purpose of this study was to examine changes and predictors of change over time in PA from 10(th) grade to post-high school. METHODS: The NEXT Generation Health Study recruited a nationally-representative cohort of US 10(th) graders, and administered longitudinal surveys in four waves (years) to follow up the participants to their first year after high school. Using transition models, the self-reported outcomes, moderate-to-vigorous PA (MVPA) and vigorous PA (VPA) each of which was repeatedly measured by one question, were modelled in association with wave-4 environmental-status variables and time-varying covariates. RESULTS: There was a continuous decline in the proportion of respondents who met or exceeded the minimum recommended level for either MVPA (from 55.97 to 34.33 %) or VPA (from 65.96 to 54.90 %) from W1 to W4. Higher scores of peer PA, family support and VPA planning were prospectively associated with higher likelihood of meeting the MVPA/VPA recommendations. At wave 4, compared to those not working, attending 4-year colleges, or living on campus, participants working full/part time, not attending school or attending community college level schools, and living at home or in own place were more likely to engage in MVPA. CONCLUSIONS: Peer PA, family support, self-regulatory skills, and environmental status after high school are critical factors that can promote MVPA/VPA among adolescents and emerging adults. PMID- 27485726 TI - Comparison of survival between radiation therapy and trans-oral laser microsurgery for early glottic cancer patients; a retrospective cohort study. AB - BACKGROUND: The literature reports various treatment methodologies, such as trans oral laser microsurgery, radiation therapy, total/partial laryngectomies, and concurrent radiation chemotherapy for patients with early larynx cancer. However, at the forefront of early glottis treatment is trans-oral laser microsurgery and radiation therapy, likely due to better functional and survival outcomes. Here we conduct the largest Canadian head-to-head comparison of consecutive patients treated with either radiation therapy or trans-oral laser microsurgery. Additionally, we compare these two treatments and their 5-year survival rates post treatment to add to the existing literature. METHODS: Charts of patients who were diagnosed with early glottic cancer between 2006 and 2013 were reviewed. Seventy-five patients were identified, and split into 2 groups based on their primary treatment, trans-oral laser microsurgery and radiation therapy. Kaplan Meier survival curves, life-tables, and the log-rank statistic were reported to determine if there was a difference between the two treatment groups and their disease-specific survival, disease-free survival, and total laryngectomy-free survival. Additionally, each different survival analysis was stratified by potential confounding variables, to help conclude which treatment is more efficacious in this population. RESULTS: The 5-year disease-specific survival rate is 93.3 % sigma = 0.063 and 90.8 % sigma = 0.056 for patients treated with trans-oral laser microsurgery and radiation therapy, respectively (chi (2) < 0.001, p = 0.983). The disease free survival rate is 60.0 % (sigma =0.121) for patients treated with trans-oral laser microsurgery, and 67.2 % (sigma = 0.074) for those who received RT (chi (2) = 0.19, p = 0.663). Additionally, the total laryngectomy-free survival rate is 84.1 % (sigma = 0.1) and 79.1 % (sigma = 0.072) for patients' early glottic cancer treated by trans-oral laser microsurgery and radiation therapy, respectively (chi (2) = 0.235, p = 0.628). Chi-square analysis of age-group versus treatment group (chi (2) = 6.455, p = 0.04) and T-stage versus treatment group (chi (2) = 11.3, p = 0.001) revealed a statistically significant relationship, suggesting survival analysis should be stratified by these variables. However, after stratification, there was no statistically significant difference between the trans-oral laser microsurgery and radiation therapy groups in any of the survival analyses. CONCLUSION: No difference was demonstrated in the 5-year disease-specific survival, disease-free survival, and total laryngectomy-free survival, between the RT and TLM treatment groups. Additionally, both groups showed similar 5-year survival after stratifying by confounding variables. PMID- 27485725 TI - MicroRNA-mRNA regulatory networking fine-tunes the porcine muscle fiber type, muscular mitochondrial respiratory and metabolic enzyme activities. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in diverse biological processes via regulation of gene expression including in skeletal muscles. In the current study, miRNA expression profile was investigated in longissimus muscle biopsies of malignant hyperthermia syndrome-negative Duroc and Pietrain pigs with distinct muscle metabolic properties in order to explore the regulatory role of miRNAs related to mitochondrial respiratory activity and metabolic enzyme activity in skeletal muscle. RESULTS: A comparative analysis of the miRNA expression profile between Duroc and Pietrain pigs was performed, followed by integration with mRNA profiles based on their pairwise correlation and computational target prediction. The identified target genes were enriched in protein ubiquitination pathway, stem cell pluripotency and geranylgeranyl diphosphate biosynthesis, as well as skeletal and muscular system development. Next, we analyzed the correlation between individual miRNAs and phenotypical traits including muscle fiber type, mitochondrial respiratory activity, metabolic enzyme activity and adenosine phosphate concentrations, and constructed the regulatory miRNA-mRNA networks associated with energy metabolism. It is noteworthy that miR-25 targeting BMPR2 and IRS1, miR-363 targeting USP24, miR-28 targeting HECW2 and miR-210 targeting ATP5I, ME3, MTCH1 and CPT2 were highly associated with slow-twitch oxidative fibers, fast-twitch oxidative fibers, ADP and ATP concentration suggesting an essential role of the miRNA-mRNA regulatory networking in modulating the mitochondrial energy expenditure in the porcine muscle. In the identified miRNA-mRNA network, a tight relationship between mitochondrial and ubiquitin proteasome system at the level of gene expression was observed. It revealed a link between these two systems contributing to energy metabolism of skeletal muscle under physiological conditions. CONCLUSIONS: We assembled miRNA-mRNA regulatory networks based on divergent muscle properties between different pig breeds and further with the correlation analysis of expressed genes and phenotypic measurements. These complex networks relate to muscle fiber type, metabolic enzyme activity and ATP production and may contribute to divergent muscle phenotypes by fine-tuning the expression of genes. Altogether, the results provide an insight into a regulatory role of miRNAs in muscular energy metabolisms and may have an implication on meat quality and production. PMID- 27485727 TI - Theory-based modifications of an advanced notification letter improves screening for bowel cancer in men: A randomised controlled trial. AB - RATIONALE: Male participation in screening for bowel cancer is sub-optimal. Theory-based interventions provide a means of improving screening uptake. OBJECTIVE: To test the efficacy of modifying consumer invitation material in line with continuum and stage theories of health behaviour on screening participation. METHODS: N = 9216 Australian men aged 50-74 years were randomised to one of four trial arms in a 2 * 2 factorial design randomised controlled trial. Participants received either standard invitation material (control group), or combinations of modified advance-notification and invitation letters. A subsample completed baseline and endpoint behavioural surveys. RESULTS: Participants who received the modified advance notification letter were 12% more likely to screen than those who received the standard version (RR = 1.12, chi(2)(1) = 10.38, p = 0.001). The modified invitation letter did not impact screening uptake (RR = 0.97, chi(2)(1) = 0.63, p = 0.424). No significant changes in psychological variables due to the intervention were observed. CONCLUSION: Modifications to advance notification letters in line with health behaviour theories significantly improves screening uptake in men. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12612001122842 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362688. PMID- 27485728 TI - What health plans do people prefer? The trade-off between premium and provider choice. AB - Within a healthcare system with managed competition, health insurers are expected to act as prudent buyers of care on behalf of their customers. To fulfil this role adequately, understanding consumer preferences for health plan characteristics is of vital importance. Little is known, however, about these preferences and how they vary across consumers. Using a discrete choice experiment (DCE) we quantified trade-offs between basic health plan characteristics and analysed whether there are differences in preferences according to age, health status and income. We selected four health plan characteristics to be included in the DCE: (i) the level of provider choice and associated level of reimbursement, (ii) the primary focus of provider contracting (price, quality, social responsibility), (iii) the level of service benefits, and (iv) the monthly premium. This selection was based on a literature study, expert interviews and focus group discussions. The DCE consisted of 17 choice sets, each comprising two hypothetical health plan alternatives. A representative sample (n = 533) of the Dutch adult population, based on age, gender and educational level, completed the online questionnaire during the annual open enrolment period for 2015. The final model with four latent classes showed that being able to choose a care provider freely was by far the most decisive characteristic for respondents aged over 45, those with chronic conditions, and those with a gross income over ?3000/month. Monthly premium was the most important choice determinant for young, healthy, and lower income respondents. We conclude that it would be very unlikely for half of the sample to opt for health plans with restricted provider choice. However, a premium discount up to ?15/month by restricted health plans might motivate especially younger, healthier, and less wealthy consumers to choose these plans. PMID- 27485729 TI - Mediating pathways between parental socio-economic position and allostatic load in mid-life: Findings from the 1958 British birth cohort. AB - Understanding how human environments affect our health by "getting under the skin" and penetrating the cells, organs and physiological systems of our bodies is a key tenet in public health research. Here, we examine the idea that early life socioeconomic position (SEP) can be biologically embodied, potentially leading to the production of health inequalities across population groups. Allostatic load (AL), a composite measure of overall physiological wear-and-tear, could allow for a better understanding of the potential biological pathways playing a role in the construction of the social gradient in adult health. We investigate the factors mediating the link between two components of parental SEP, maternal education (ME) and parental occupation (PO), and AL at 44 years. Data was used from 7573 members of the 1958 British birth cohort follow-up to age 44. AL was constructed using 14 biomarkers representing four physiological systems. We assessed the contribution of financial/materialist, psychological/psychosocial, educational, and health behaviors/BMI pathways over the life course, in mediating the associations between ME, PO and AL. ME and PO were mediated by three pathways: educational, material/financial, and health behaviors, for both men and women. A better understanding of embodiment processes leading to disease development may contribute to developing adapted public policies aiming to reduce health inequalities. PMID- 27485730 TI - Affective health bias in older adults: Considering positive and negative affect in a general health context. AB - RATIONALE: Because subjective health reports are a primary source of health information in a number of medical and research-based contexts, much research has been devoted to establishing the extent to which these self-reports of health correspond to health information from more objective sources. One of the key factors considered in this area is trait affect, with most studies emphasizing the impact of negative affect (negative emotions) over positive affect (positive emotions), and focusing on high-arousal affect (e.g., anger, excitement) over moderate- or low-arousal affect (e.g., relaxed, depressed). OBJECTIVES: The present study examines the impact of both Positive and Negative Affect (PA/NA) measured by items of both high and low arousal-on the correspondence between objective health information and subjective health reports. Another limitation of existing literature in the area is the focus on samples suffering from a particular diagnosis or on specific symptom reports; here, these effects are investigated in a sample of community-dwelling older adults representing a broader spectrum of health. METHOD: 153 older adults (Mage = 71.2) took surveys assessing Perceived Health and Affect and underwent an objective physical health assessment. Structural equation modeling was used to investigate the extent to which the relationship between Objective Health and Perceived Health was moderated by PA or NA, which would indicate the presence of affective health bias. RESULTS: Results reveal a significant moderation effect for NA, but not for PA; PA appeared to serve a more mediational function, indicating that NA and PA operate on health perceptions in distinct ways. CONCLUSIONS: These findings provide evidence that in our high-functioning, community-dwelling sample of older adults, a) affective health bias is present within a general health context, and not only within specific symptom or diagnostic categories; and b) that both PA and NA play important roles in the process. PMID- 27485731 TI - Variation of partial transferrin sequences and phylogenetic relationships among hares (Lepus capensis, Lagomorpha) from Tunisia. AB - North African hares are currently included in cape hares, Lepus capensis sensu lato, a taxon that may be considered a superspecies or a complex of closely related species. The existing molecular data, however, are not unequivocal, with mtDNA control region sequences suggesting a separate species status and nuclear loci (allozymes, microsatellites) revealing conspecificity of L. capensis and L. europaeus. Here, we study sequence variation in the intron 6 (468 bp) of the transferrin nuclear gene, of 105 hares with different coat colour from different regions in Tunisia with respect to genetic diversity and differentiation, as well as their phylogenetic status. Forty-six haplotypes (alleles) were revealed and compared phylogenetically to all available TF haplotypes of various Lepus species retrieved from GenBank. Maximum Likelihood, neighbor joining and median joining network analyses concordantly grouped all currently obtained haplotypes together with haplotypes belonging to six different Chinese hare species and the African scrub hare L. saxatilis. Moreover, two Tunisian haploypes were shared with L. capensis, L timidus, L. sinensis, L. yarkandensis, and L. hainanus from China. These results indicated the evolutionary complexity of the genus Lepus with the mixing of nuclear gene haplotypes resulting from introgressive hybridization or/and shared ancestral polymorphism. We report the presence of shared ancestral polymorphism between North African and Chinese hares. This has not been detected earlier in the mtDNA sequences of the same individuals. Genetic diversity of the TF sequences from the Tunisian populations was relatively high compared to other hare populations. However, genetic differentiation and gene flow analyses (AMOVA, FST, Nm) indicated little divergence with the absence of geographically meaningful phylogroups and lack of clustering with coat colour types. These results confirm the presence of a single hare species in Tunisia, but a sound inference on its phylogenetic position would require additional nuclear markers and numerous geographically meaningful samples from Africa and Eurasia. PMID- 27485732 TI - Parallel study about the effects of psychotherapy on patients with dental phobia determined by anxiety scores and saliva secretion and composition. AB - BACKGROUND: The aim of this study was to determine the success of psychotherapeutic treatment for dental phobia by measurement of anxiety using the dental anxiety score (DAS), the state trait anxiety score (STAI state), salivary cortisol and protein concentrations and the salivary secretion rate. Primary endpoint of the study was the comparison of the data before and after psychotherapeutic treatment. METHODS: Forty patients were included into the study. Twenty-four were allocated to the phobic group, 16 to the control group. Saliva was collected upon entering the dental clinic and again after three weeks of psychotherapy. The results were compared with those of a control group. The DAS and STAI questionnaires were completed at each visit. RESULTS: A reduction in DAS values was found after psychotherapy. However, the values remained significantly higher in the phobic group than in the controls. Similar results were found for STAI scores. A slightly higher salivary cortisol level was found in the phobic group. No changes occurred in cortisol or protein concentrations. The salivary secretion rate increased in the phobic patients after psychotherapy. CONCLUSIONS: It could be concluded that psychotherapy is effective in the treatment of dental phobic patients. TRIAL REGISTRATION: This study has been retrospectively registered in the German Clinical Trials Register (# DRKS00009552 ) on 10/19/15. PMID- 27485733 TI - "Safety and utility of percutaneous liver biopsy in hematopoietic stem cell transplant pediatric recipients: a retrospective study". AB - BACKGROUND: Liver biopsies in pediatric hematopoietic stem cell transplantation (HSCT) patients are as and effective when performed at bedside in the Bone Marrow Transplant Unit (BMTU) than in the Day Surgery Unit (DSU), with better patient compliance and lower emotional distress for these children. METHODS: The study group consisted of 45 children who underwent allogeneic HSCT. We reviewed 68 liver biopsies performed between April 2006 and September 2015. 12 (17.6 %) biopsies were performed in the DSU and 56 (82.3 %) in the BMTU; nine (13.2 %) prior to HSCT and 59 (86.7 %) after HSCT. Pre-procedural behavioral status (subjective score) was evaluated by pediatric transplant physicians by filling in a questionnaire employing a three-point scale: "calm and cooperative", "agitated and non-cooperative" or "frightened and suffering". Objective score was obtained measuring patient's heart rate before the procedure and comparing it with mean heart rate. RESULTS: Patients who underwent the procedure at the BMTU experienced less emotional distress than those who underwent it in the DSU: 58.3 % of patients treated at the DSU were agitated as compared with 16.1 % of those treated at the BMTU (p < 0.01). Among the 59 biopsies performed after HSCT, 41 (69.5 %) were taken from symptomatic patients for a diagnostic purpose and 18 (30.5 %) in asymptomatic ones in order to rule out hepatic GVHD. Among these 18 procedures, GVHD was diagnosed in 16 (88.9 %) cases. Minor complications occurred in about 17 % of procedures (12 biopsies), at a rate of 25 % for the DSU location compared with 16 % for the BMTU location. Only two major complications were reported, one in the DSU and one in the BMTU. CONCLUSION: Liver biopsy performed at bedside in HSCT patients does not carry a higher risk of adverse events than the same procedure performed in the DSU and has lower emotional distress associated with better patient compliance, thus contributing significantly to a higher standard of care. PMID- 27485734 TI - Primate superior colliculus neurons activated by unexpected sensation. AB - Midbrain superior colliculus (SC) contains a variety of neuronal types, influencing a rich spectrum of functions beyond gaze orienting. Here, we report on a novel class of SC neurons in the rhesus monkey (Macaca mulatta) that are activated by an unexpected perturbation in a goal-directed arm-movement task. One monkey subject reached for and pressed an illuminated target on a working panel upon a visual go-signal, while maintaining visual fixation elsewhere. On 50 % of trials, a task perturbation occurred-the working panel abruptly and unexpectedly moved against the subject's hand after he pressed the target. During the performance, we recorded single SC neurons and found neurons activated exclusively for the task perturbation. These perturbation neurons were localized in the deep lateral zone of the SC, were silent during non-perturbed trials, did not appear to respond to task-irrelevant stimuli, and they had intriguingly long neuronal latencies. If the perturbation neurons' activity relates to the hand target contact, it may reflect the saliency of an unexpected sensation, i.e. a sensation that is not self-induced and thus cannot be predicted on a basis of the monkey's motor program. PMID- 27485736 TI - Erratum to: Variable-Internal-Stores models of microbial growth and metabolism with dynamic allocation of cellular resources. PMID- 27485735 TI - STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis. AB - Among the diverse cytokines involved in osteoclast differentiation, interleukin (IL)-3 inhibits RANKL-induced osteoclastogenesis. However, the mechanism underlying IL-3-mediated inhibition of osteoclast differentiation is not fully understood. Here we demonstrate that the activation of signal transducers and activators of transcription 5 (STAT5) by IL-3 inhibits RANKL-induced osteoclastogenesis through the induction of the expression of Id genes. We found that STAT5 overexpression inhibited RANKL-induced osteoclastogenesis. However, RANKL did not regulate the expression or activation of STAT5 during osteoclast differentiation. STAT5 deficiency prevented IL-3-mediated inhibition of osteoclastogenesis, suggesting a key role of STAT5 in IL-3-mediated inhibition of osteoclast differentiation. In addition, IL-3-induced STAT5 activation upregulated the expression of Id1 and Id2, which are negative regulators of osteoclastogenesis. Overexpression of ID1 or ID2 in STAT5-deficient cells reversed osteoclast development recovered from IL-3-mediated inhibition. Importantly, microcomputed tomography and histomorphometric analysis revealed that STAT5 conditional knockout mice showed reduced bone mass, with an increased number of osteoclasts. Furthermore, IL-3 inhibited RANKL-induced osteoclast differentiation less effectively in the STAT5 conditional knockout mice than in the wild-type mice after RANKL injection. Taken together, our findings indicate that STAT5 contributes to the remarkable IL-3-mediated inhibition of RANKL induced osteoclastogenesis by activating Id genes and their associated pathways. PMID- 27485737 TI - Burden of Heart Failure in Adults with Congenital Heart Disease. AB - Patients born with congenital heart disease (CHD) have benefited from remarkable advances in surgical and catheter-based interventions. As a result, the majority of children born with even the most complex forms of CHD live into adulthood. The specialized field of adult CHD (ACHD) was born out of the necessity to care for this new population of survivors of childhood CHD and their distinctive features. In this review, relevant aspects of ACHD that lead to, and are affected by, heart failure will be examined along with the increasing prevalence of HF in the burgeoning population of ACHD. We also highlight the challenges in defining HF in this particular group of patients. PMID- 27485738 TI - From ZikV genome to vaccine: in silico approach for the epitope-based peptide vaccine against Zika virus envelope glycoprotein. AB - Zika virus (ZikV) has emerged as a potential threat to human health worldwide. A member of the Flaviviridae, ZikV is transmitted to humans by mosquitoes. It is related to other pathogenic vector-borne flaviviruses including dengue, West Nile and Japanese encephalitis viruses, but produces a comparatively mild disease in humans. As a result of its epidemic outbreak and the lack of potential medication, there is a need for improved vaccine/drugs. Computational techniques will provide further information about this virus. Comparative analysis of ZikV genomes should lead to the identification of the core characteristics that define a virus family, as well as its unique properties, while phylogenetic analysis will show the evolutionary relationships and provide clues about the protein's ancestry. Envelope glycoprotein of ZikV was obtained from a protein database and the most immunogenic epitope for T cells and B cells involved in cell-mediated immunity, whereas B cells are primarily responsible for humoral immunity. We mainly focused on MHC class I potential peptides. YRIMLSVHG, VLIFLSTAV and MMLELDPPF, GLDFSDLYY are the most potent peptides predicted as epitopes for CD4+ and CD8+ T cells, respectively, whereas MMLELDPPF and GLDFSDLYY had the highest pMHC-I immunogenicity score and these are further tested for interaction against the HLA molecules, using in silico docking techniques to verify the binding cleft epitope. However, this is an introductory approach to design an epitope-based peptide vaccine against ZikV; we hope that this model will be helpful in designing and predicting novel vaccine candidates. PMID- 27485739 TI - Level of adherence to ocular hypotensive agents and its determinant factors among glaucoma patients in Menelik II Referral Hospital, Ethiopia. AB - BACKGROUND: Good adherence to ocular hypotensive agents is important to control intraocular pressure and hence to prevent progressive glaucomatous optic nerve head damage. Periodic investigation of adherence is crucial in glaucoma treatment. The purpose of this study was to assess level of adherence to ocular hypotensive agents and to identify factors affecting adherence among glaucoma patients at a tertiary public eye care center. METHODS: The study was a hospital based cross-sectional study that was conducted in Menelik II Referral Hospital from June 1, 2015 to July 31, 2015. A systematic random sampling technique was used to select 359 study participants from the source population. The study patients were interviewed and their medical charts were reviewed using a pretested structured questionnaire. Adherence was assessed using Morisky Medication Adherence Scale - 8 and adherence determinant factors were identified using multivariate binary logistic regression analysis. The association was declared statistically significant at p < 0.05. RESULTS: Among the 359 study glaucoma patients, 42.6 % were adherent to their prescribed hypotensive agents. Higher educational level (AOR = 4.60, 95 % CI: 1.01-21.03, p < 0.049), being self - employed (AOR = 6.14, 95 % CI: 1.37-27.50, p < 0.018) and taking lesser frequency of drops (AOR = 2.89, 95 % CI: 1.25-6.66, p < 0.013) were significantly associated with adherence, whereas being a farmer (AOR = 0.07, 95 % CI: 0.01 0.75, p < 0.028), having very low monthly family income (AOR = 0.22, 95 % CI: 0.06-0.77, p < 0.019) and self - purchasing of medications (AOR = 0.30, 95 % CI: 0.10-0.93, p < 0.036) were significantly associated with non-adherence. CONCLUSIONS: The study has identified the adherence level to the prescribed ocular hypotensive agents to be sub-optimal and is influenced by different factors among glaucoma patients of the public tertiary center. We recommend glaucoma care providers to pay due attention on the importance of adherence. PMID- 27485740 TI - Assessment of the spatial accessibility to health professionals at French census block level. AB - BACKGROUND: The evaluation of geographical healthcare accessibility in residential areas provides crucial information to public policy. Traditional methods - such as Physician Population Ratios (PPR) or shortest travel time - offer only a one-dimensional view of accessibility. This paper developed an improved indicator: the Index of Spatial Accessibility (ISA) to measure geographical healthcare accessibility at the smallest available infra-urban level, that is, the Ilot Regroupe pour des Indicateurs Statistiques. METHODS: This study was carried out in the department of Nord, France. Healthcare professionals are geolocalized using postal addresses available on the French state health insurance website. ISA is derived from an Enhanced Two-Step Floating Catchment Area (E2FCA). We have constructed a catchment for each healthcare provider, by taking into account residential building centroids, car travel time as calculated by Google Maps and the edge effect. Principal Component Analyses (PCA) were used to build a composite ISA to describe the global accessibility of different kinds of health professionals. RESULTS: We applied our method to studying geographical healthcare accessibility for pregnant women, by selecting three types of healthcare provider: general practitioners, gynecologists and midwives. A total of 3587 healthcare providers are potentially able to provide care for inhabitants of the department of Nord. On average there are 92 general practitioners, 22 midwives and 21 gynecologists per 100,000 residents. The composite ISA for the three types of healthcare provider is 39 per 100,000 residents. A comparative analysis between ISA and physician-population ratios indicates that ISA represents a more even distribution whereas the physician population ratios show an 'all-or-nothing' approach. CONCLUSION: ISA is a multidimensional and improved measure, which combines the volume of services relative to population size with the proximity of services relative to the population's location, available at the smallest feasible geographical scale. It could guide policy makers towards highlighting critical areas in need of more healthcare providers, and these areas should be earmarked for further knowledge based policy making. PMID- 27485741 TI - Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma. AB - INTRODUCTION: Advanced melanoma is a devastating disease that has propelled research in therapeutics beyond chemotherapy and radiotherapy. Being highly immunogenic, melanoma is a model tumor for immunotherapy and has highlighted the therapeutic potential of the immune checkpoint inhibitors. AREAS COVERED: This review discusses the pharmacologic properties, clinical efficacy, and safety profile of pembrolizumab, an IgG4-kappa humanized monoclonal antibody against the programmed cell death protein 1 (PD-1) receptor, for the treatment of unresectable or metastatic melanoma. EXPERT OPINION: Pembrolizumab was the first PD-1 inhibitor to be approved by the U.S. Food and Drug Administration (FDA). Remarkably, this accelerated approval for the treatment of advanced, heavily pretreated melanoma was based on response rates alone from a phase I trial. As anticipated, pembrolizumab confirmed a survival advantage in phase II and III trials and has led the way for the study of other drugs that share its mechanism of action. Defining disease and patient characteristics associated with a response remains amongst the most pressing priorities. PMID- 27485742 TI - High turnover rates of aerobic anoxygenic phototrophs in European freshwater lakes. AB - Aerobic Anoxygenic Phototrophic (AAP) bacteria are bacteriochlorophyll (BChl) a containing organisms which use light energy to supplement their predominantly heterotrophic metabolism. Here, we investigated mortality and growth rates of AAP bacteria in three different freshwater lakes in Central Europe: the mountain lake Plesne, the oligo-mesotrophic Lake Stechlin and the forest pond Huntov. The mortality of AAP bacteria was estimated from diel changes of BChl a fluorescence. Net and gross growth rates were calculated from the increases in AAP cell numbers. The gross growth rates of AAP bacteria ranged from 0.38 to 5.6 d-1 , with the highest values observed during summer months. Simultaneously, the rapidly growing AAP cells have to cope with an intense grazing pressure by both zooplankton and protists. The presented results document that during the day, gross growth usually surpased mortality. Our results indicate that AAP bacteria utilize light energy under natural conditions to maintain rapid growth rates, which are balanced by a generally intense grazing pressure. PMID- 27485743 TI - Dysregulated function of normal human epidermal keratinocytes in the absence of filaggrin. AB - The aim of the present study was to investigate the impact of filaggrin knockdown on the function of normal human epidermal keratinocytes (NHEKs). Filaggrin expression levels in NHEKs were knocked down by lentivirus (LV) encoding small hairpin RNA (shRNA), with control cells infected with nonsense shRNA or not infected. Cell migration and invasion were assayed using Transwell inserts, cell adhesion and proliferation by the Cell Counting kit-8 assay, and apoptosis and cell cycle progression by flow cytometry. shRNA efficiently suppressed expression of filaggrin protein. The LV group had significantly decreased cell migration, adhesion and proliferation, and increased apoptosis compared with the control groups (P=0.027). In addition, the proportion of cells in G1 and G2 phases were significantly increased in the LV group compared with control groups (P=0.018). The results of the present study demonstrate that filaggrin knockdown inhibits NHEK migration, adhesion and proliferation, promotes apoptosis and disturbs cell cycle progression. PMID- 27485744 TI - Chemoinformatic expedition of the chemical space of fungal products. AB - AIM: Fungi are valuable resources for bioactive secondary metabolites. However, the chemical space of fungal secondary metabolites has been studied only on a limited basis. Herein, we report a comprehensive chemoinformatic analysis of a unique set of 207 fungal metabolites isolated and characterized in a USA National Cancer Institute funded drug discovery project. RESULTS: Comparison of the molecular complexity of the 207 fungal metabolites with approved anticancer and nonanticancer drugs, compounds in clinical studies, general screening compounds and molecules Generally Recognized as Safe revealed that fungal metabolites have high degree of complexity. Molecular fingerprints showed that fungal metabolites are as structurally diverse as other natural products and have, in general, drug like physicochemical properties. CONCLUSION: Fungal products represent promising candidates to expand the medicinally relevant chemical space. This work is a significant expansion of an analysis reported years ago for a smaller set of compounds (less than half of the ones included in the present work) from filamentous fungi using different structural properties. PMID- 27485745 TI - Effects of chronic sleep deprivation on bone mass and bone metabolism in rats. AB - BACKGROUND: This study aimed to assess the effects of chronic sleep deprivation (CSD) on bone mass and bone metabolism in rats. METHODS: Twenty-four rats were randomly divided into CSD and control (CON) groups. Rats were subjected to CSD by using the modified multiple platform method (MMPM) to establish an animal model of CSD. Biochemical parameters such as levels of serum N-terminal propeptide of type I procollagen (PINP), N-terminal cross-linking telopeptide of type I collagen (NTX), growth hormone (GH), estradiol (E2), serum 25(OH)D, and calcium (Ca) were evaluated at 0, 1, 2, and 3 months. After 3 months, each fourth lumbar vertebra and the distal femoral metaphysis of the left extremity of rats were harvested for micro-computed tomography scans and histological analysis, respectively, after the rats were sacrificed under an overdose of pentobarbital sodium. RESULTS: Compared with rats from the CON group, rats from the CSD group showed significant decreases in bone mineral density (BMD), bone volume over total volume, trabecular bone thickness, and trabecular bone number and significant increases in bone surface area over bone volume and trabecular bone separations (P < 0.05). Bone histomorphology studies showed that rats in the CSD group had decreased osteogenesis, impaired mineralization of newly formed bones, and deteriorative trabecular bone in the secondary spongiosa zone. In addition, they showed significantly decreased levels of serum PINP (1 month later) and NTX (3 months later) (P < 0.05). The serum 25(OH)D level of rats from the CSD group was lower than that of rats from the CON group after 1 month (P < 0.05). CONCLUSIONS: CSD markedly affects bone health by decreasing BMD and 25(OH)D, deteriorating the bone microarchitecture, and decreasing bone formation and bone resorption markers. PMID- 27485746 TI - Foraging strategies of black-fronted titi monkeys (Callicebus nigrifrons) in relation to food availability in a seasonal tropical forest. AB - Many primates have to cope with a temporal scarcity in food availability that shapes their foraging strategies. Here we investigated the changes in diet, activity, and ranging behavior of a group of black-fronted titi monkeys (Callicebus nigrifrons) according to the availability of the main high nutritional-density item in their diet and the foraging strategy adopted when this food is scarce. We monitored one habituated group using instantaneous scan sampling over 1 year (533 h of observation, 61 days) in a seasonal tropical forest fragment (245 ha). We simultaneously collected data on food availability with fruit traps. The titi monkeys consumed fleshy fruits, the main high nutritional-density item of their diet, in accordance with its availability, and the availability of this item modulated the ingestion of vegetative plant parts, a relatively low-nutritional-density food. During high fleshy fruit availability, the titi monkeys consumed more fleshy fruits, flowers, and invertebrates. They also traveled more, but concentrated their activity in a central area of their home range. Conversely, during fleshy fruit scarcity, they increased the breadth of their diet, switching to one richer in seeds and vegetative plant parts, and with greater plant diversity. At the same time, they reduced most energy demanding activities, traveling less and over shorter distances, but using their home range more broadly. Corroborating the optimal foraging theory, titi monkeys altered foraging strategies according to temporal food fluctuations and responded to low fleshy fruit availability by changing their diet, activity, and ranging behavior. The adoption of a low-cost/low-yield strategy allowed us to classify them as energy minimizers. PMID- 27485747 TI - Predatory threat of harpy eagles for yellow-breasted capuchin monkeys in the Atlantic Forest. AB - We describe seven encounters between different harpy eagle individuals (Harpia harpyja) and a group of yellow-breasted capuchin monkeys (Sapajus xanthosternos) in Una Biological Reserve. These interactions lasted 58 min on average. In each of those encounters, the capuchin monkeys used particular behavioral strategies against the harpy eagle that were not employed in reaction to other aerial predators. We did not observe any successful predation events, but after one of those encounters an infant disappeared from the capuchin group. As a whole, these observations indicate that the presence of harpy eagles in the group's home range increases predation risk for capuchin monkeys. The present report also suggests a reoccupation by H. harpyja of this area, as no previous recent records identify harpy eagle occurrence in Una Biological Reserve. PMID- 27485748 TI - The first smile: spontaneous smiles in newborn Japanese macaques (Macaca fuscata). AB - Spontaneous smiles are facial movements that are characterized by lip corner raises that occur during irregular sleep or drowsiness without known external or internal causes. They are shown by human infants and infant chimpanzees. These smiles are considered to be the developmental origin of smiling and laughter. There are some case studies showing that spontaneous smiles occur in Japanese macaques. The goals of this study were to investigate whether newborn Japanese macaques show a considerable number of spontaneous smiles thus to examine the mechanism of them. Seven newborn Japanese macaques were observed in a room for an average of 44 min, and incidental sleeping situations were monitored twice. All seven participants showed spontaneous smiles at least once during the observation. They showed 8.29 spontaneous smiles in average (SD = 10.89; 58 smiles in total), all found in the state of REM sleep. Thirty-nine of the 58 smiles were produced on the left side of the mouth. These characteristics were similar to those of spontaneous smiles in human infants. This is the first evidence that macaques as well as hominoids show a considerable number of spontaneous smiles. These phenomena may facilitate the development of the zygomaticus major muscle, which is implicated in smiling-like facial expressions. PMID- 27485749 TI - Adenosine A2A receptors in the olfactory bulb suppress rapid eye movement sleep in rodents. AB - Rapid eye movement (REM) sleep behavior disorder in humans is often accompanied by a reduced ability to smell and detect odors, and olfactory bulbectomized rats exhibit increased REM sleep, suggesting that the olfactory bulb (OB) is involved in REM-sleep regulation. However, the molecular mechanism of REM-sleep regulation by the OB is unknown. Adenosine promotes sleep and its A2A receptors (A2AR) are expressed in the OB. We hypothesized that A2AR in the OB regulate REM sleep. Bilateral microinjections of the A2AR antagonist SCH58261 into the rat OB increased REM sleep, whereas microinjections of the A2AR agonist CGS21680 decreased REM sleep. Similar to the A2AR antagonist, selective A2AR knockdown by adeno-associated virus carrying short-hairpin RNA for A2AR in the rat OB increased REM sleep. Using chemogenetics on the basis of designer receptors exclusively activated by designer drugs, we demonstrated that the inhibition of A2AR neurons increased REM sleep, whereas the activation of these neurons decreased REM sleep. Moreover, using a conditional anterograde axonal tract tracing approach, we found that OB A2AR neurons innervate the piriform cortex and olfactory tubercle. These novel findings indicate that adenosine suppresses REM sleep via A2AR in the OB of rodents. PMID- 27485750 TI - Mapping the connectivity of serotonin transporter immunoreactive axons to excitatory and inhibitory neurochemical synapses in the mouse limbic brain. AB - Serotonin neurons arise from the brainstem raphe nuclei and send their projections throughout the brain to release 5-HT which acts as a modulator of several neuronal populations. Previous electron microscopy studies in rats have morphologically determined the distribution of 5-HT release sites (boutons) in certain brain regions and have shown that 5-HT containing boutons form synaptic contacts that are either symmetric or asymmetric. In addition, 5-HT boutons can form synaptic triads with the pre- and postsynaptic specializations of either symmetrical or asymmetrical synapses. However, due to the labor intensive processing of serial sections required by electron microscopy, little is known about the neurochemical properties or the quantitative distribution of 5-HT triads within whole brain or discrete subregions. Therefore, we used a semi automated approach that combines immunohistochemistry and high-resolution confocal microscopy to label serotonin transporter (SERT) immunoreactive axons and reconstruct in 3D their distribution within limbic brain regions. We also used antibodies against key pre- (synaptophysin) and postsynaptic components of excitatory (PSD95) or inhibitory (gephyrin) synapses to (1) identify putative 5 HTergic boutons within SERT immunoreactive axons and, (2) quantify their close apposition to neurochemical excitatory or inhibitory synapses. We provide a 5 HTergic axon density map and have determined the ratio of synaptic triads consisting of a 5-HT bouton in close proximity to either neurochemical excitatory or inhibitory synapses within different limbic brain areas. The ability to model and map changes in 5-HTergic axonal density and the formation of triadic connectivity within whole brain regions using this rapid and quantitative approach offers new possibilities for studying neuroplastic changes in the 5 HTergic pathway. PMID- 27485752 TI - Estimating functional brain networks by incorporating a modularity prior. AB - Functional brain network analysis has become one principled way of revealing informative organization architectures in healthy brains, and providing sensitive biomarkers for diagnosis of neurological disorders. Prior to any post hoc analysis, however, a natural issue is how to construct "ideal" brain networks given, for example, a set of functional magnetic resonance imaging (fMRI) time series associated with different brain regions. Although many methods have been developed, it is currently still an open field to estimate biologically meaningful and statistically robust brain networks due to our limited understanding of the human brain as well as complex noises in the observed data. Motivated by the fact that the brain is organized with modular structures, in this paper, we propose a novel functional brain network modeling scheme by encoding a modularity prior under a matrix-regularized network learning framework, and further formulate it as a sparse low-rank graph learning problem, which can be solved by an efficient optimization algorithm. Then, we apply the learned brain networks to identify patients with mild cognitive impairment (MCI) from normal controls. We achieved 89.01% classification accuracy even with a simple feature selection and classification pipeline, which significantly outperforms the conventional brain network construction methods. Moreover, we further explore brain network features that contributed to MCI identification, and discovered potential biomarkers for personalized diagnosis. PMID- 27485751 TI - Overall satisfaction of health care users with the quality of and access to health care services: a cross-sectional study in six Central and Eastern European countries. AB - BACKGROUND: The measurement of consumer satisfaction is an essential part of the assessment of health care services in terms of service quality and health care system responsiveness. Studies across Europe have described various strategies health care users employ to secure services with good quality and quick access. In Central and Eastern European countries, such strategies also include informal payments to health care providers. This paper analyzes the satisfaction of health care users with the quality of and access to health care services. The study focuses on six Central and Eastern European countries (Bulgaria, Hungary, Lithuania, Poland, Romania and Ukraine). METHODS: We use data on past experience with health care use collected in 2010 through uniform national surveys in these countries. Based on these data, we carry out a multi-country analysis to investigate factors associated with the satisfaction of health care users in the six countries. RESULTS: The results indicate that about 10-14 % of the service users are not satisfied with the quality of, or access to health care services they used in the preceding year. However, significant differences across countries and services are observed, e.g. the highest level of dissatisfaction with access to outpatient services (16.4 %) is observed among patients in Lithuania, while in Poland, the level of dissatisfaction with quality of outpatient and inpatient services are much lower than dissatisfaction with access. The study also analyses the association of users' satisfaction with factors such as making informal payments, inability to pay and relative importance of service attributes stated by the service users. CONCLUSIONS: These multi-country findings provide evidence for health policy making in the Central and Eastern European countries. Although the average rates of satisfactions per country are relatively high, the results suggest that there is ample room for improvements. Specifically, many service-users still report dissatisfaction especially those who pay informally and those unable to pay. The high shares of informal payments and inability of users to deal with the health expenditures lead to doubts about the fairness of the health care provision in Central and Eastern Europe. There is an urgent need for policy makers in the region to not only acknowledge but also to effectively address this key problem. PMID- 27485754 TI - Analytical and empirical fluctuation functions of the EEG microstate random walk Short-range vs. long-range correlations. AB - We analyze temporal autocorrelations and the scaling behaviour of EEG microstate sequences during wakeful rest. We use the recently introduced random walk approach and compute its fluctuation function analytically under the null hypothesis of a short-range correlated, first-order Markov process. The empirical fluctuation function and the Hurst parameter H as a surrogate parameter of long range correlations are computed from 32 resting state EEG recordings and for a set of first-order Markov surrogate data sets with equilibrium distribution and transition matrices identical to the empirical data. In order to distinguish short-range correlations (H ~ 0.5) from previously reported long-range correlations (H > 0.5) statistically, confidence intervals for H and the fluctuation functions are constructed under the null hypothesis. Comparing three different estimation methods for H, we find that only one data set consistently shows H > 0.5, compatible with long-range correlations, whereas the majority of experimental data sets cannot be consistently distinguished from Markovian scaling behaviour. Our analysis suggests that the scaling behaviour of resting state EEG microstate sequences, though markedly different from uncorrelated, zero order Markov processes, can often not be distinguished from a short-range correlated, first-order Markov process. Our results do not prove the microstate process to be Markovian, but challenge the approach to parametrize resting state EEG by single parameter models. PMID- 27485753 TI - Down but not out in posterior cingulate cortex: Deactivation yet functional coupling with prefrontal cortex during demanding semantic cognition. AB - The posterior cingulate cortex (pCC) often deactivates during complex tasks, and at rest is often only weakly correlated with regions that play a general role in the control of cognition. These observations led to the hypothesis that pCC contributes to automatic aspects of memory retrieval and cognition. Recent work, however, has suggested that the pCC may support both automatic and controlled forms of memory processing and may do so by changing its communication with regions that are important in the control of cognition across multiple domains. The current study examined these alternative views by characterising the functional coupling of the pCC in easy semantic decisions (based on strong global associations) and in harder semantic tasks (matching words on the basis of specific non-dominant features). Increasingly difficult semantic decisions led to the expected pattern of deactivation in the pCC; however, psychophysiological interaction analysis revealed that, under these conditions, the pCC exhibited greater connectivity with dorsolateral prefrontal cortex (PFC), relative to both easier semantic decisions and to a period of rest. In a second experiment using different participants, we found that functional coupling at rest between the pCC and the same region of dorsolateral PFC was stronger for participants who were more efficient at semantic tasks when assessed in a subsequent laboratory session. Thus, although overall levels of activity in the pCC are reduced during external tasks, this region may show greater coupling with executive control regions when information is retrieved from memory in a goal-directed manner. PMID- 27485755 TI - Feasibility and potential limitations of abbreviated breast MRI: an observer study using an enriched cohort. AB - BACKGROUND: Breast cancer screening using magnetic resonance imaging (MRI) has been introduced in Western countries primarily for populations with an elevated risk of breast cancer. We conducted an observer study involving an experimental abbreviated MRI interpretation by Japanese radiologists, using an enriched cohort, to evaluate its feasibility in a screening setting. METHODS: Eighty-eight breast MRI examinations including 28 cases with breast cancer were enrolled as study subjects. Two radiologists independently reviewed the MR images, first with only two sequences (abbreviated series), and then with all of the images provided for clinical care (full diagnostic series). The difference in sensitivity and specificity was evaluated using McNemar's test. Interobserver agreement was assessed by calculating kappa values. RESULTS: A total of 176 breasts including 31 cancers (3 cases with bilateral disease) were included. No significant difference in sensitivity or specificity for either observer was observed between the abbreviated series and the full diagnostic series (observer 1: sensitivity 87.1 vs 87.1 %, p = 1.00, specificity 91.7 vs 90.3 %, p = 0.791; observer 2: sensitivity 93.5 vs 96.8 %, p = 1.00, specificity 83.4 vs 89.7 %, p = 0.064). Moderate interobserver agreement (kappa = 0.56) was observed for the abbreviated series, whereas substantial agreement (kappa = 0.69) was observed for the full diagnostic series. CONCLUSIONS: The diagnostic accuracy of the abbreviated breast MRI was not inferior to that of the conventional full diagnostic interpretation, although a slight decline in interobserver agreement was observed. PMID- 27485756 TI - Therapeutic play to prepare children for invasive procedures: a systematic review. AB - OBJECTIVE: To analyze the available evidence regarding the efficacy of using therapeutic play on behavior and anxiety in children undergoing invasive procedures. DATA SOURCE: The systematic review search was performed in the MEDLINE, LILACS, CENTRAL and CINAHL databases. There was no limitation on the year or language. SYNTHESIS OF DATA: The literature search found 1892 articles and selected 22 for full reading. Eight articles were excluded, as they did not address the objectives assessed in this review. Twelve studies, representing 14 articles, were included. The studies were conducted between 1983 and 2015, five in Brazil, one in the United States, five in China, one in Lebanon, one in Taiwan, and one in Iran. Most studies showed that intervention with therapeutic play promotes reduction in the level of anxiety and promotes collaborative behavior and acceptance of the invasive procedure. CONCLUSIONS: Evidence related to the use of therapeutic play on anxiety and behavior of children undergoing invasive procedures is still questionable. The absence, in most studies, of the creation of a random sequence to assign the subjects to either the control or the experimental group, as well as allocation concealment, are factors that contribute to these questions. Another issue that characterizes an important source of bias is the absence of blinded evaluators. It is necessary to perform further studies that will take into account greater methodological stringency. PMID- 27485757 TI - The influence of home-rearing environment on children's behavioral problems 3 years' later. AB - Reduction of children's behavioral problems has the potential to ameliorate parental stress, mental health problems, and family dysfunction. The current study was designed as a 3-year longitudinal study with secondary data. A total of 99 caregivers with preschool aged children were required to complete two self reported questionnaires: the Index of Child Care Environment and Strengths and Difficulties Questionnaire. It demonstrated that a positive home-rearing environment had a positive influence on children's behavioral problem 3 years' later. Our study suggests that we may reduce behavioral problems in children's later development by providing a positive home rearing environment. PMID- 27485758 TI - Grafting of mesenchymal stem cell-seeded small intestinal submucosa to repair the deep partial-thickness burns. AB - PURPOSE: Regenerative medicine provides many treatments for burn wounds, of which cell-seeded substitutes are encouraging for large and deep burns. To assess the feasibility of mesenchymal stem cell (MSC)-seeded small intestinal submucosa (SIS) to repair the deep partial-thickness burns, a rat study was performed. MATERIALS & METHODS: The burn model was created by contacting the dorsal surface directly with boiled water for 10 seconds. MSCs at passage 3 were seeded on the SIS before implantation. Three days after burn injury, the grafts were implanted onto the burn area. At 3, 7, 14 and 21 days post implantation, gross observation and histological assessments were performed. RESULTS: SIS alone and MSC-seeded SIS were able to accelerate the burn wound closure by enhancing granulation tissue formation, increasing wound maturity, improving revascularization, and inducing the proliferation of neo-epidermal cells. Additionally, MSC-seeded SIS was much more effective than SIS alone for the repair of deep partial-thickness burns. CONCLUSION: Both SIS and MSC-seeded SIS were able to repair the large and deep burn wounds and the loaded MSCs possessed positive effects to accelerate the wound closure in a rat model. PMID- 27485759 TI - Combinatorial fabrication of composite nanorods using oblique angle co deposition. AB - We demonstrate that oblique angle co-deposition can be used as a versatile combinatory nanofabrication technique to generate a library of nanomaterials. Using the Cu-Fe2O3 system as an example, by carefully characterizing the vapor plumes of the source materials, a composition map can be generated, which is used to design the locations of all the substrate holders. The resulting nanostructures at different locations show different thickness, morphology, crystallinity, composition, as well as inhomogeneity in microstructures, and material maps of all these structural parameters are established. By further oxidizing or reducing the composite nanostructures, their properties-such as band gap, photocatalytic performance, and magnetic properties-can be easily linked to their composition and other structural parameters. Optimal materials for photocatalytic and magnetic applications are efficiently identified. It is expected that oblique angle co-deposition and its variations could become the most powerful combinatory nanofabrication technique for nanomaterial survey. PMID- 27485760 TI - Diagnosis of bacterial pathogens in the dialysate of peritoneal dialysis patients with peritonitis using surface-enhanced Raman spectroscopy. AB - BACKGROUND: Bacterial peritonitis is the most common cause of peritoneal dialysis (PD) therapy drop-out. A quick and accurate diagnosis of the bacterial pathogen can reduce the PD drop-out rate. Surface-enhanced Raman spectroscopy (SERS) can rapidly identify bacteria using chips coated with nano-sized metal particles. METHODS: Known bacteria were loaded in the SERS-chips and illuminated with laser light to establish a reference Raman spectra library. Dialysate from PD peritonitis patients was concentrated by centrifuge and examined with the same SERS, and the resulting Raman spectra were compared with library spectra for bacteria identification. Principal component analysis was used for further confirmation. The same batches of dialysate were sent to routine culture as a reference bacteria identification method. The results of the 2 identification methods were compared. RESULTS: A total of 43 paired-samples were sent for study. There were 37 samples with bacteria identified but 6 were culture-negative by the reference method. 31 bacteria were identified in paired-samples by SERS, among which, 29 bacteria were exactly the same as those identified by the reference method. Bacteria not included in the reference library spectra cannot be identified. CONCLUSIONS: SERS techniques can rapidly identify bacterial pathogens in the dialysate of PD peritonitis patients. PMID- 27485761 TI - A novel MSX1 intronic mutation associated with autosomal dominant non-syndromic oligodontia in a large Chinese family pedigree. AB - BACKGROUND: Tooth agenesis is a common developmental dental anomaly. The aim of the study was to identify the causal genetic mutation in a four-generation Chinese family affected with non-syndromic autosomal dominant tooth agenesis. METHODS: Genome-wide scanning was performed using the Illumina Linkage-12 array. Genotyping of short tandem repeat markers was used to finely map the causative locus. Haplotype analysis and Sanger sequencing was performed to precisely locate the position and nature of the gene defect. RESULTS: Clinical examination of the available 23 family members showed variable tooth agenesis in 10 subjects, ranging from oligodontia to mild hypodontia. Genome-wide scanning and haplotype analyses identified the 4p16.1-p16.3 region with a maximum multi-point LOD score of 3.50, which overlapped with the MSX1 gene. A single heterozygous point mutation IVS1-5 G>A in the MSX1 gene was exclusively detected in the 10 family members affected with tooth agenesis. Sequencing of MSX1 cDNA revealed that the intronic mutation did not affect the normal splicing pattern of the pre-mRNA. However, real-time qPCR analysis of lymphocyte RNA showed that the level of MSX1 mRNA was significantly decreased in individuals heterozygous for the mutation. CONCLUSIONS: We identified and characterized a novel intronic mutation in the MSX1 gene in a large Chinese pedigree, adding to the small repertoire of MSX1 mutations associated with autosomal dominant tooth agenesis. We hypothesize that the variable degree of tooth agenesis observed in each affected individual may be due to sub-optimal levels of MSX1 expression during critical stages tooth development. PMID- 27485762 TI - "That Should Be Left to Doctors, That's What They are There For!"-Exploring the Reflexivity and Trust of Young Adults When Seeking Health Information. AB - This paper explores the health information-seeking practices of healthy young adults and how they assess and rank sources of information through a qualitative study. The findings show that participants (a) are strongly committed to searching for information about health and lifestyle, especially via the Internet; (b) healthcare professionals were perceived as the most reliable source of health information and advice; (c) online health information, although frequently accessed and experienced as empowering, is seen as a potentially unreliable source. Findings evidence how becoming better informed about health related topics plays a pivotal role in individuals' lives, most notably by using the Internet. Participants were able to reflect about what it means to know about health. The construction of trust regarding health information involved a heuristic process vis-a-vis source reliability and perceived credibility that places doctors as the most trustworthy medium of medical advice and health information. We conclude that participants' trust toward professionals suggests the preference and need for more personalized care; and it is a response to the ambiguity and uncertainty that permeates the health information landscape, particularly that which is web-based. PMID- 27485763 TI - A Bayesian Power Analysis Procedure Considering Uncertainty in Effect Size Estimates from a Meta-analysis. AB - In conventional frequentist power analysis, one often uses an effect size estimate, treats it as if it were the true value, and ignores uncertainty in the effect size estimate for the analysis. The resulting sample sizes can vary dramatically depending on the chosen effect size value. To resolve the problem, we propose a hybrid Bayesian power analysis procedure that models uncertainty in the effect size estimates from a meta-analysis. We use observed effect sizes and prior distributions to obtain the posterior distribution of the effect size and model parameters. Then, we simulate effect sizes from the obtained posterior distribution. For each simulated effect size, we obtain a power value. With an estimated power distribution for a given sample size, we can estimate the probability of reaching a power level or higher and the expected power. With a range of planned sample sizes, we can generate a power assurance curve. Both the conventional frequentist and our Bayesian procedures were applied to conduct prospective power analyses for two meta-analysis examples (testing standardized mean differences in example 1 and Pearson's correlations in example 2). The advantages of our proposed procedure are demonstrated and discussed. PMID- 27485765 TI - Intrapair Comparison of Life-Course Appetite and Physical Activity in Elderly Danish Twins: Reliability and Association With Subsequent Survival. AB - Avoiding overeating and being physically active is associated with healthy aging, but methodological issues challenge the quantification of the association. Intrapair comparison of twins is a study design that attempts to minimize social norm-driven biased self-reporting of lifestyle factors. We aimed to investigate the association between self-reported lifestyle factors and subsequent survival in 347 Danish twin pairs aged 70 years and older and, additionally, to investigate the reliability of these self-reports. The twins were interviewed in 2003 and followed for mortality until 2015. They were asked to compare their appetite and physical activity to that of their co-twins in different stages of life. On an individual level, we found a positive association between current self-reported physical activity and late-life survival for elderly twins. This was supported by the intrapair analyses, which revealed a positive association between midlife and current physical activity and late-life survival. A positive association between lower appetite and late-life survival was found generally over the life course in the individual level analyses but not in the intrapair analyses. Kappa values for the inter-twin agreement on who ate the most were 0.16 to 0.34 in different life stages, and for physical activity 0.19 to 0.26, corresponding to a slight-to-fair agreement. Approximately, 50% of the twin pairs were not in agreement regarding physical activity, and of these twins 75% (95% CI: 67-82%) considered themselves the most active twin. These findings indicate a still-existing tendency of answering according to social norms, even in a twin study designed to minimize this. PMID- 27485766 TI - Tendon reflex is suppressed during whole-body vibration. AB - In this study we have investigated the effect of whole body vibration (WBV) on the tendon reflex (T-reflex) amplitude. Fifteen young adult healthy volunteer males were included in this study. Records of surface EMG of the right soleus muscle and accelerometer taped onto the right Achilles tendon were obtained while participant stood upright with the knees in extension, on the vibration platform. Tendon reflex was elicited before and during WBV. Subjects completed a set of WBV. Each WBV set consisted of six vibration sessions using different frequencies (25, 30, 35, 40, 45, 50Hz) applied randomly. In each WBV session the Achilles tendon was tapped five times with a custom-made reflex hammer. The mean peak-to peak (PP) amplitude of T-reflex was 1139.11+/-498.99uV before vibration. It decreased significantly during WBV (p<0.0001). The maximum PP amplitude of T reflex was 1333+/-515MUV before vibration. It decreased significantly during WBV (p<0.0001). No significant differences were obtained in the mean acceleration values of Achilles tendon with tapping between before and during vibration sessions. This study showed that T-reflex is suppressed during WBV. T-reflex suppression indicates that the spindle primary afferents must have been pre synaptically inhibited during WBV similar to the findings in high frequency tendon vibration studies. PMID- 27485764 TI - TGF-beta1 promotes acinar to ductal metaplasia of human pancreatic acinar cells. AB - Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-beta1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases. PMID- 27485767 TI - Women's experiences with HIV-related stigma from health care providers in Lima, Peru: "I would rather die than go back for care". AB - In Peru, HIV/AIDS is increasing among heterosexual women. In this qualitative study researchers examined HIV-related stigma among 14 women in Lima, Peru, who were HIV positive and at least 18 years of age. Data were analyzed using thematic analysis and indicated that women experienced stigma from health care providers. Two broad themes emerged from the data: forms of stigma and response to stigma. Within these themes, subthemes included maltreatment during care, neglect of patients' rights to confidentiality and privacy, and the process of women speaking out. Stigma from health care providers had a long-term, negative impact on women's willingness to seek treatment. Future stigma reduction initiatives, on a global level, should include health care workers. PMID- 27485768 TI - Variation of excited-state dynamics in trifluoromethyl functionalized C60 fullerenes. AB - We report on electronically excited-state dynamics of three different trifluoromethyl C60 fullerenes (TMFs, C60(CF3)n: C60/4-1, C60/6-2, and C60/10-1, featuring four, six, and ten trifluoromethyl groups, respectively) using steady state and time-resolved optical spectroscopy as well as ultrafast pump/probe transient absorption spectroscopy. C60/4-1 and C60/6-2 dissolved in toluene solvent show near-unity S1 -> T1 intersystem crossing quantum yield (PhiISC), ca. 1 ns S1-state lifetimes, and microsecond-timescale T1-state lifetimes, which are typical of the fullerene class. On the other hand, C60/10-1 exhibits a dominant sub-nanosecond nonradiative S1 -> S0 relaxation mechanism and negligible PhiISC, therefore decreasing the average excited-state lifetime (tauavg) by about 5 orders of magnitude compared to that of C60/4-1 and C60/6-2 (tauavg ~ 17 MUs and 54 MUs for C60/4-1 and C60/6-2, respectively, whereas tauavg ~ 100 ps for C60/10 1). These excited-state characteristics of C60/4-1 and C60/6-2 are preserved in polymer matrix, suggesting that fullerene/polymer interactions do not modulate intrinsic photophysics of trifluoromethyl-substituted fullerenes. The contrasting excited-state study results of C60/4-1 and C60/6-2 to that of C60/10-1 infer that intrinsic optical properties and excited-state dynamics can be affected by the substitution on the fullerene. PMID- 27485769 TI - 5-Hydroxymethylcytosine in E-box motifs ACAT|GTG and ACAC|GTG increases DNA binding of the B-HLH transcription factor TCF4. AB - We evaluated DNA binding of the B-HLH family members TCF4 and USF1 using protein binding microarrays (PBMs) containing double-stranded DNA probes with cytosine on both strands or 5-methylcytosine (5mC) or 5-hydroxymethylcytosine (5hmC) on one DNA strand and cytosine on the second strand. TCF4 preferentially bound the E-box motif (CAN|NTG) with strongest binding to the 8-mer CAG|GTGGT. 5mC uniformly decreases DNA binding of both TCF4 and USF1. The bulkier 5hmC also inhibited USF1 binding to DNA. In contrast, 5hmC dramatically enhanced TCF4 binding to E-box motifs ACAT|GTG and ACAC|GTG, being better bound than any 8-mer containing cytosine. Examination of X-ray structures of the closely related TCF3 and USF1 bound to DNA suggests TCF3 can undergo a conformational shift to preferentially bind to 5hmC while the USF1 basic region is bulkier and rigid precluding a conformation shift to bind 5hmC. These results greatly expand the regulatory DNA sequence landscape bound by TCF4. PMID- 27485770 TI - Stakeholder analysis for the development of a community pharmacy service aimed at preventing cardiovascular disease. AB - BACKGROUND: Participatory approaches involving stakeholders across the health care system can help enhance the development, implementation and evaluation of health services. These approaches may be particularly useful in planning community pharmacy services and so overcome challenges in their implementation into practice. Conducting a stakeholder analysis is a key first step since it allows relevant stakeholders to be identified, as well as providing planners a better understanding of the complexity of the health care system. OBJECTIVES: The main aim of this study was to conduct a stakeholder analysis to identify those individuals and organizations that could be part of a leading planning group for the development of a community pharmacy service (CPS) to prevent cardiovascular disease (CVD) in Australia. METHODS: An experienced facilitator conducted a workshop with 8 key informants of the Australian health care system. Two structured activities were undertaken. The first explored current needs and gaps in cardiovascular care and the role of community pharmacists. The second was a stakeholder analysis, using both ex-ante and ad-hoc approaches. Identified stakeholders were then classified into three groups according to their relative influence on the development of the pharmacy service. The information gathered was analyzed using qualitative content analysis. RESULTS: The key informants identified 46 stakeholders, including (1) patient/consumers and their representative organizations, (2) health care providers and their professional organizations and (3) institutions and organizations that do not directly interact with patients but organize and manage the health care system, develop and implement health policies, pay for health care, influence funding for health service research or promote new health initiatives. From the 46 stakeholders, a core group of 12 stakeholders was defined. These were considered crucial to the service's development because they held positions that could drive or inhibit progress. Secondary results of the workshop included: a list of needs and gaps in cardiovascular care (n = 6), a list of roles for community pharmacists in cardiovascular prevention (n = 12) and a list of potential factors (n = 7) that can hinder the integration of community pharmacy services into practice. CONCLUSIONS: This stakeholder analysis provided a detailed picture of the wide range of stakeholders across the entire health care system that have a stake in the development of a community pharmacy service aimed at preventing CVD. Of these, a core group of key stakeholders, with complementary roles, can then be approached for further planning of the service. The results of this analysis highlight the relevance of establishing multilevel stakeholder groups for CPS planning. PMID- 27485771 TI - Systematic Identification of Matching Molecular Series and Mapping of Screening Hits. AB - Matching molecular series (MMS) have originally been introduced as an extension of the matched molecular pair (MMP) concept to facilitate the design of substructure-based structure-activity relationship (SAR) networks. An MMP is defined as a pair of compounds that only differ by a structural change at a single site. In addition, an MMS is defined as an MMP-based series of compounds that have a conserved structural core and are distinguished by modifications at a single site. Systematic generation of MMS from specifically active compounds generalizes the search for series of structural analogs. Potency-ordered MMS provide series associated with SAR information. We have systematically extracted MMS from publicly available compounds with well-defined activity measurements and generated a large database with approx. 40 000 single- and 13 600 multi-target series, which provide a rich source of SAR information. As an application, we introduce MMP-based mapping of screening hits to MMS to search for initial SAR information and determine all SAR environments available for such hits. The MMS database is made freely available to the scientific community. PMID- 27485772 TI - Identification of Novel Histamine H4 Ligands by Virtual Screening on Molecular Dynamics Ensembles. AB - We report the identification of novel histamine H4 receptor ligands by ensemble docking on homology model conformers derived from molecular dynamics simulations. Selected receptor models from the trajectories demonstrated superior virtual screening performance compared to the initial models. The ensemble of the best models was able to retrieve a diverse set of known H4 ligands. Prospective virtual screening against these models and subsequent in vitro experimental validation identified novel H4 ligands. Compound 3 showing highest affinity and ligand efficiency represents an interesting scaffold for further medicinal chemistry exploration. PMID- 27485773 TI - Topological Fingerprints as an Aid in Finding Structural Patterns for LRRK2 Inhibition. AB - Multiplet-based fingerprint mapping has been used to analyse the relationship between the structural features of potential drug candidates and the enzyme LRRK2 inhibition expressed as the inhibition constant (pKi ). For 198 structurally diverse compounds 4195 dimensional fingerprints were generated and mathematically manipulated using partial least squares (PLS) regression. A variation of PLS-BETA technique was developed for the reduction of noise by eliminating excess variables that resulted in a 636 dimensional fingerprint related to pKi . The QSAR model for the training set of 170 compounds (R(2) =0.87, Q(2) =0.77 and SDEC=0.42) had four latent variables (PLS components) and it was validated by the external test set of 28 compounds (Qext (2) =0.63). The proposed model of LRRK2 inhibitory activity can be helpful in designing focused libraries enriched in LRRK2 inhibitors and identifying new active chemotypes in compound databases. PMID- 27485774 TI - LECTINPred: web Server that Uses Complex Networks of Protein Structure for Prediction of Lectins with Potential Use as Cancer Biomarkers or in Parasite Vaccine Design. AB - Lectins (Ls) play an important role in many diseases such as different types of cancer, parasitic infections and other diseases. Interestingly, the Protein Data Bank (PDB) contains +3000 protein 3D structures with unknown function. Thus, we can in principle, discover new Ls mining non-annotated structures from PDB or other sources. However, there are no general models to predict new biologically relevant Ls based on 3D chemical structures. We used the MARCH-INSIDE software to calculate the Markov-Shannon 3D electrostatic entropy parameters for the complex networks of protein structure of 2200 different protein 3D structures, including 1200 Ls. We have performed a Linear Discriminant Analysis (LDA) using these parameters as inputs in order to seek a new Quantitative Structure-Activity Relationship (QSAR) model, which is able to discriminate 3D structure of Ls from other proteins. We implemented this predictor in the web server named LECTINPred, freely available at http://bio-aims.udc.es/LECTINPred.php. This web server showed the following goodness-of-fit statistics: Sensitivity=96.7 % (for Ls), Specificity=87.6 % (non-active proteins), and Accuracy=92.5 % (for all proteins), considering altogether both the training and external prediction series. In mode 2, users can carry out an automatic retrieval of protein structures from PDB. We illustrated the use of this server, in operation mode 1, performing a data mining of PDB. We predicted Ls scores for +2000 proteins with unknown function and selected the top-scored ones as possible lectins. In operation mode 2, LECTINPred can also upload 3D structural models generated with structure-prediction tools like LOMETS or PHYRE2. The new Ls are expected to be of relevance as cancer biomarkers or useful in parasite vaccine design. PMID- 27485775 TI - Global Model for Octanol-Water Partition Coefficients from Proton Nuclear Magnetic Resonance Spectra. AB - The ability to estimate chemical and physical properties from experimental spectra is highly desirable, as it eliminates the need for a priori knowledge of exact chemical structure and allows the property estimation of mixtures. Here we report the proof of principle that a predictive method for octanol-water partition coefficient (logP) based on (1) H-NMR spectra in d(3) -chloroform is feasible and can yield accuracy comparable to in silico logP models. The Spectrometric Data-Activity Relationship (QSDAR) reported predicts logP of neutral organic chemicals using descriptors derived only from (1) H-NMR chemical shifts, integrations and peak widths. Proton NMR spectra of 140 compounds with diverse structures were used to construct a Multiple Linear Regression (MLR) and a Partial Least Squares (PLS) model that predicts logP. The optimized models were internally validated by K-fold cross validation and leave-one-out validation, and externally with a test set of 28 chemicals. The squared regression coefficients of prediction for the MLR and PLS regression models were 0.970 and 0.971 respectively, showing that the method allows accurate prediction of logP values exclusively from predicted (1) H NMR spectra. PMID- 27485776 TI - Discovery and Bioevaluation of Novel Pyrazolopyrimidine Analogs as Competitive Hsp90 Inhibitors Through Shape-Based Similarity Screening. AB - Hsp90 as a promising therapeutic target for the treatment of cancer has received great attention. Many Hsp90 inhibitors such as BIIB021 and CUDC-305 have been in clinical. In this paper shape-based similarity screening through ROCS overlays on the basis of CUDC-305, BIIB021, PU-H71 and PU-3 were performed to discover HSP90 inhibitors. A set of 19 novel pyrazolopyrimidine analogues was identified and evaluated on enzyme level and cell-based level as Hsp90 inhibitors. The compound HDI4-04 with IC50 0.35 uM in the Hsp90 ATP hydrolysis assay exhibited potent cytotoxicity against five human cancer cell lines. Western blot analysis and Hsp70 luciferase reporter assay further confirmed that HDI4-04 targeted the Hsp90 protein folding machinery. And according to the biological assay, the SAR was discussed and summarized, which will guide us for further optimization of these compounds. PMID- 27485777 TI - External Evaluation of QSAR Models, in Addition to Cross-Validation: Verification of Predictive Capability on Totally New Chemicals. PMID- 27485778 TI - PRDM5 promotes the proliferation and invasion of murine melanoma cells through up regulating JNK expression. AB - PRDM (PRDI-BF1 and RIZ domain-containing) proteins constitute a family of zinc finger proteins and play important roles in multiple cellular processes by acting as epigenetic modifiers. PRDM5 is a recently identified member of the PRDM family and may function as a tumor suppressor in several types of cancer. However, the role of PRDM5 in murine melanoma remains largely unknown. In our study, effect of PRDM5 on murine melanoma cells was determined and results showed that PRDM5 overexpression significantly promoted proliferation, migration, and invasion of murine melanoma B16F10 cells. Consistently, silencing of PRDM5 expression significantly inhibited proliferation, invasion, and migration of B16F10 cells. In vivo study also showed that PRDM5 silencing significantly inhibited the growth and metastasis of melanoma in mice. PRDM5 was then found to increase the expression and activation of JNK in B16F10 cells. JNK silencing significantly reduced PRDM5-mediated up-regulation of JNK expression and blocked the PRDM5 induced proliferation and invasion of B16F10 cells. To further verify the involvement of JNK signaling in PRDM5-induced progression of B16F10 cells, a specific JNK inhibitor was employed to inhibit the JNK signaling pathway, and results showed that PRDM5-induced proliferation and invasion of B16F10 cells were abolished. We conclude that PRDM5 promotes the proliferation and invasion of murine melanoma cells through up-regulating JNK expression and strategies targeting PRDM5 may be promising for the therapy of melanoma. PMID- 27485779 TI - Engineering Intracellular Delivery Nanocarriers and Nanoreactors from Oxidation Responsive Polymersomes via Synchronized Bilayer Cross-Linking and Permeabilizing Inside Live Cells. AB - Reactive oxygen species (ROS) and oxidative stress are implicated in various physiological and pathological processes, and this feature provides a vital biochemical basis for designing novel therapeutic and diagnostic nanomedicines. Among them, oxidation-responsive micelles and vesicles (polymersomes) of amphiphilic block copolymers have been extensively explored; however, in previous works, oxidation by ROS including H2O2 exclusively leads to microstructural destruction of polymeric assemblies. For oxidation-responsive polymersomes, fast release of encapsulated hydrophilic drugs and bioactive macromolecules will occur upon microstructural disintegration. Under certain application circumstances, this does not meet design requirements for sustained-release drug nanocarriers and long-acting in vivo nanoreactors. Also note that conventional polymersomes possess thick hydrophobic bilayers and compromised membrane permeability, rendering them as ineffective nanocarriers and nanoreactors. We herein report the fabrication of oxidation-responsive multifunctional polymersomes exhibiting intracellular milieu-triggered vesicle bilayer cross-linking, permeability switching, and enhanced imaging/drug release features. Mitochondria-targeted H2O2 reactive polymersomes were obtained through the self-assembly of amphiphilic block copolymers containing arylboronate ester-capped self-immolative side linkages in the hydrophobic block, followed by surface functionalization with targeting peptides. Upon cellular uptake, intracellular H2O2 triggers cascade decaging reactions and generates primary amine moieties; prominent amidation reaction then occurs within hydrophobic bilayer membranes, resulting in concurrent cross-linking and hydrophobic-to-hydrophilic transition of polymersome bilayers inside live cells. This process was further utilized to achieve integrated functions such as sustained drug release, (combination) chemotherapy monitored by fluorescence and magnetic resonance (MR) imaging turn-on, and to construct intracellular fluorogenic nanoreactors for cytosolic thiol-containing bioactive molecules. PMID- 27485781 TI - Polycyclic aromatic hydrocarbons (PAHs) in surface sediments from the intertidal zone of Bohai Bay, Northeast China: Spatial distribution, composition, sources and ecological risk assessment. AB - Polycyclic aromatic hydrocarbons (PAHs) can enter intertidal zones by various pathways and pose potential threats to intertidal ecosystem. We investigated distribution, composition, sources and risk assessment of PAHs in intertidal surface sediments of Bohai Bay. Total PAH concentrations ranged from 37.2ng.g-1 to 206.6ng.g-1, among which high values occurred near Nanpaishuihe River Estuary and Haihe River Estuary. The composition patterns of PAHs were characterized by the predominance of 3-ring and 4-ring PAHs, and acenaphthylene was the most dominant component. Diagnostic ratios and principal component analysis have confirmed that PAH contaminants originated from mixed sources, and the major was local combustion. The mean benzo(a)pyrene equivalent concentration of total PAHs in intertidal sediments was 15.67ng.g-1, which was mostly contributed by seven carcinogenic PAHs. According to ecological risk assessment, negative effects related to acenaphthylene would occur occasionally in partial survey regions of the study. PMID- 27485780 TI - The Microbiome of Aseptically Collected Human Breast Tissue in Benign and Malignant Disease. AB - Globally breast cancer is the leading cause of cancer death among women. The breast consists of epithelium, stroma and a mucosal immune system that make up a complex microenvironment. Growing awareness of the role of microbes in the microenvironment recently has led to a series of findings important for human health. The microbiome has been implicated in cancer development and progression at a variety of body sites including stomach, colon, liver, lung, and skin. In this study, we assessed breast tissue microbial signatures in intraoperatively obtained samples using 16S rDNA hypervariable tag sequencing. Our results indicate a distinct breast tissue microbiome that is different from the microbiota of breast skin tissue, breast skin swabs, and buccal swabs. Furthermore, we identify distinct microbial communities in breast tissues from women with cancer as compared to women with benign breast disease. Malignancy correlated with enrichment in taxa of lower abundance including the genera Fusobacterium, Atopobium, Gluconacetobacter, Hydrogenophaga and Lactobacillus. This work confirms the existence of a distinct breast microbiome and differences between the breast tissue microbiome in benign and malignant disease. These data provide a foundation for future investigation on the role of the breast microbiome in breast carcinogenesis and breast cancer prevention. PMID- 27485782 TI - Microbial community structure shifts are associated with temperature, dispersants and nutrients in crude oil-contaminated seawaters. AB - This study tracked structure shifts of bacterial compositions before, during and after invading by crude oil to determine the microbial response and explore how temperature, dispersants and nutrients affect the composition of microbial communities or their activities of biodegradation in artificial marine environment. During petroleum hydrocarbons exposed, the composition and functional dynamics of marine microbial communities were altered, favoring bacteria that could utilize this rich carbon source such as the Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes phyla. Low temperature as a dominant factor decreased bacterial richness and catabolic diversity due to abated enzymes activities in correlation with the process of biodegradation. Dispersants exerted no negative consequences on microbial composition, however, bacterial composition by the Chloroflexi, TM6, OP8, Cyanobacteria and Gemmatimonadetes phyla increased. It seemed that more frequent fertilizer application could be equally safe to bacteria and increased significantly the abundance of bacterial strains but Actinobacteria phyla decreased. PMID- 27485783 TI - Impact on water surface due to deepwater gas blowouts. AB - This paper presents a study on the impact of underwater gas blowouts near the ocean surface, which has a greater relevance to assess Health, Safety, and Environmental risks. In this analysis the gas flux near the surface, reduction of bulk density, and gas surfacing area are studied for different scenarios. The simulations include a matrix of scenarios for different release depths, release rates, and initial bubble size distributions. The simulations are carried out using the MEGADEEP model, for a location in East China Sea. Significant changes in bulk density and gas surface flux near the surface are observed under different release conditions, which can pose a potential threat for cleanup and rescue operations. Furthermore, the effect of hydrate formation on gas surfacing is studied for much greater release depths. The type of outcomes of this study is important to conduct prior risk assessments and contingency planning for underwater gas blowouts. PMID- 27485784 TI - Viral hepatitis: The global burden of viral hepatitis is increasing. PMID- 27485785 TI - Viral hepatitis: beginning of the end? PMID- 27485787 TI - Obesity: Childhood obesity: time bomb for future burden of chronic liver disease. PMID- 27485788 TI - Gut microbiota: Microbiota and behaviour: visiting the sins of the mother. PMID- 27485789 TI - Colorectal cancer: Engineered colons for cancer research. PMID- 27485786 TI - Adult and paediatric GERD: diagnosis, phenotypes and avoidance of excess treatments. AB - Detailed investigations and objective measurements in patients with symptoms of gastro-oesophageal reflux should be performed with the intent of making the correct diagnosis, thus enabling choice of appropriate therapy. Establishing the most effective therapy is particularly important in adults who do not respond to standard treatment and in children. The use of PPIs for suspected GERD has increased substantially over the past decade, providing great relief in patients with acid-related symptoms, but also leading to adverse effects and a considerable economic burden. Adults with functional heartburn do not benefit from PPIs, while prolonged PPI use in patients with extraoesophageal symptoms remains a controversial area. Moreover, PPIs are not indicated in infants with GERD unless symptoms are proven to be acid-related. With regard to antireflux surgery, patients must be carefully selected to avoid the need for ongoing PPI treatment postoperatively. Correct diagnosis and phenotyping of patients with symptoms attributed to gastro-oesophageal reflux through detailed investigations is therefore imperative, leading to improved patient outcomes and rationalized use of available treatment options. In this Review, we outline currently available diagnostic tests and discuss approaches to limit any unnecessary medical or surgical interventions. PMID- 27485790 TI - Immunology: A glia-ILC3 axis. PMID- 27485791 TI - Downregulation of thrombospondin-1 by DNA hypermethylation is associated with tumor progression in laryngeal squamous cell carcinoma. AB - Thrombospondin-1 (THBS-1) has been demonstrated to have a complicated role in human cancer and to exert stimulatory and inhibitory effects in different types of tumors. DNA methylation, as the most frequent mechanism for gene silencing, has been widely investigated in regards to the development of tumors. However, the expression levels and methylation status of THBS-1, and their roles in laryngeal squamous cell carcinoma (LSCC) remain to be elucidated. The present study detected downregulated THBS-1 mRNA and protein expression levels in LSCC by using reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting, while decreased expression levels of THBS-1 mRNA and protein were significantly associated with lymph node metastasis and tumor-node metastasis (TNM) stage. Furthermore, aberrant methylation of THBS-1 was frequently observed in LSCC by methylation-specific PCR, particularly in tumor tissues from lymph node metastasis or samples from cancer with advanced TNM stage. Furthermore, the current study demonstrated that downregulated expression of THBS-1 in LSCC was consistent with aberrant methylation of this gene. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxy-cytidine in Hep 2 cells induced demethylation of THBS-1, enhanced THBS-1 expression, and inhibited the proliferative and invasive ability of Hep-2 cells. Collectively, the results of the present study suggest that THBS-1 may exert an inhibitory effect in the development of LSCC. Aberrant methylation was an important reason for the downregulation of THBS-1 and was involved in the invasion and metastasis of LSCC. Demethylating agents may be effective candidates for the treatment of LSCC. PMID- 27485792 TI - Primary cilium and autophagy: The avengers of cell-size regulation. AB - The maintenance of cellular homeostasis in response to extracellular stresses by autophagy is vital for the health of various tissues. Extracellular stimuli may include nutrient starvation, endoplasmic reticulum stress, hypoxia, cytotoxic agents, or mechanical stress. The primary cilium (PC) is a microtubule-based sensory organelle that regulates the integration of various extracellular stimuli. The interconnection between macroautophagy/autophagy and the PC is beginning to be illuminated. In this punctum, we discuss our recent study of PC dependent autophagy in response to fluid flow in kidney epithelial cells. Urinary flow in kidney tubules creates a shear stress that regulates epithelial cell volume. PC-mediated autophagy is necessary for the regulation of cell size. The signal from the PC is transduced by the activation of STK11/LKB1 and by MTOR inhibition. Our results clarify the physiological role of PC-dependent autophagy in the kidney and suggest that autophagy manipulation may provide a route to the treatment of ciliopathies. PMID- 27485793 TI - Epileptic phenotype of FGFR3-related bilateral medial temporal lobe dysgenesis. AB - Hypochondroplasia (HCH) is a skeletal dysplasia, characterized by short stature and macrocephaly. Clinical symptoms and radiological and histopathological features of HCH are similar, but milder than those seen in achondroplasia. Particularly, HCH patients with Asn540Lys mutation in the FGFR3 gene are reported to have medial temporal lobe dysgenesis and epilepsy. We report a 3-year-old girl who developed recurrent epileptic apnea, which started immediately after birth. The apneic seizures were refractory to antiepileptic medications; ictal electroencephalography showed rhythmic activity originating from the left or right temporal areas and rarely from the right frontal area. Macrocephaly was noted since birth. Neuroimaging revealed bilateral dysgenesis and hypometabolism of the medial temporal structures as well as perfusion changes in the left lateral temporofrontal areas during the ictal period. Clonazepam was initiated and acetazolamide dosage was increased at 6months, resulting in complete seizure control after 8months of age. Genetic analysis identified an Asn540Lys (c.1620 C>A) mutation in the FGFR3 gene. Characteristic bone findings on the lumbar spine, iliac bone, and femur were retrospectively confirmed on X-rays during infancy. This was the first report that delineated the epilepsy phenotype in FGFR3-related bilateral medial temporal lobe dysgenesis; such findings would lead to an early diagnosis and better epilepsy management. PMID- 27485795 TI - Abstracts from EMCON 2014: International Conference on Emergency Medicine; 16th Annual Conference by the Society for Emergency Medicine in India (SEMI). PMID- 27485794 TI - Polyphenol, antioxidant and antimicrobial potential of six different white and red wine grape processing leftovers. AB - BACKGROUND: During winemaking, grape polyphenols are only partly extracted, and consequently unexploited. The main aim was to characterize the phenolic content of freeze-dried grape skin and seed (FDSS) extracts obtained from Slovenian and international grape varieties and to evaluate their antioxidant, antimicrobial and anti-adhesive activities. RESULTS: FDSS of six Vitis vinifera L. grapevine cultivars from Vipava Valley region (Slovenia) underwent extraction and sonification under different conditions. Flavonols were the predominant content of extracts from white 'Zelen' and 'Sauvignon Blanc' grape varieties, with strong antimicrobial activities against Gram-negative bacteria. 'Pinot Noir' FDSS extracted with 50% aqueous ethanol extraction produced a high phenolic content in the final extract, which was further associated with strong antioxidant and antimicrobial activities against all tested bacteria. Bacterial adhesion to stainless steel surfaces with minimal and maximal surface roughness was significantly inhibited (up to 60%) across a wide FDSS concentration range, with lower concentrations also effective with two types of stainless steel surfaces. CONCLUSION: FDSS extracts from winery by-products show interesting phenolic profiles that include flavonols, catechins, anthocyanins and hydroxycinnamic acids, with yields influenced by grapevine cultivar and extraction conditions. The antioxidant, antimicrobial and anti-adhesive activities of 50% aqueous ethanol 'Pinot Noir' FDSS extract reveals potential applications in food, pharmaceutical and cosmetic industries for these bioactive residues. (c) 2016 Society of Chemical Industry. PMID- 27485797 TI - A two-component nonphotochemical fluorescence quenching in eustigmatophyte algae. AB - Eustigmatophyte algae represent an interesting model system for the study of the regulation of the excitation energy flow due to their use of violaxanthin both as a major light-harvesting pigment and as the basis of xanthophyll cycle. Fluorescence induction kinetics was studied in an oleaginous marine alga Nannochloropsis oceanica. Nonphotochemical fluorescence quenching was analyzed in detail with respect to the state of the cellular xanthophyll pool. Two components of nonphotochemical fluorescence quenching (NPQ), both dependent on the presence of zeaxanthin, were clearly resolved, denoted as slow and fast NPQ based on kinetics of their formation. The slow component was shown to be in direct proportion to the amount of zeaxanthin, while the fast NPQ component was transiently induced in the presence of membrane potential on subsecond timescales. The applicability of these observations to other eustigmatophyte species is demonstrated by measurements of other representatives of this algal group, both marine and freshwater. PMID- 27485796 TI - Sexual transmission-risk behaviour among HIV-positive persons: a multisite study using social action theory. AB - AIM: Sexual risk behaviour was explored and described using Social Action Theory. BACKGROUND: The sexual transmission of HIV is complex and multi-factorial. Social Action Theory provides a framework for viewing self-regulation of modifiable behaviour such as condom use. Condom use is viewed within the context of social interaction and interdependence. DESIGN: Cross-sectional survey. METHODS: Self report questionnaire administered to adults living with HIV/AIDS, recruited from clinics, service organizations and by active outreach, between 2010 - 2011. FINDINGS: Having multiple sex partners with inconsistent condom use during a 3 month recall period was associated with being male, younger age, having more years of education,substance use frequency and men having sex with men being a mode of acquiring HIV. In addition, lower self-efficacy for condom use scores were associated with having multiple sex partners and inconsistent condom use. CONCLUSION: Social Action Theory provided a framework for organizing data from an international sample of seropositive persons. Interventions for sexually active, younger, HIV positive men who have sex with men, that strengthen perceived efficacy for condom use, and reduce the frequency of substance use, may contribute to reducing HIV-transmission risk. PMID- 27485798 TI - Relationship between physico-chemical characteristics and potential toxicity of PM10. AB - PM10 was sampled at a suburban location affected by traffic and industry in the north of Spain. The samples were analysed to determine the chemical components of PM10 (organic and elemental carbon, soluble chemical species and metals). The aim of this study was to assess the toxicity of PM10 in terms of the bulk analysis and the physico-chemical properties of the particles. Total carbon, sulphates, ammonium, chlorides and nitrates were found to be the major constituents of PM10. The contribution of the last of these was found to increase significantly with PM10 concentration (Pearson coefficient correlation of 0.7, p-value < 0.001). Individual airborne particles were characterised morphologically and chemically via a combination of Scanning Electron Microscopy and Energy-Dispersive X-ray spectroscopy (SEM-EDX). The subsequent image analysis revealed C-rich particles with shapes that pointed to combustion processes. Moreover, carbonaceous particles seemed to act as vehicles for sulphur compounds and metals (S, Na, Fe, Ca, Mg, K, Al, Mn, Zn and Cu). Coarse particles were found to be mainly constituted by crustal material and marine and carbonaceous particles. Although most of the studied individual particles in PM10 samples (86.0%) had a diameter within the 0.1-2.5 MUm range, 1.8% of them had sizes lower than 0.1 MUm 40.2% of the total studied particles were estimated to be inhaled and deposited in the human respiratory tract; 12.3% of these particles would reach the deepest zones, thereby posing a major risk to human health. PMID- 27485799 TI - Pollution status of polycyclic aromatic hydrocarbons in surface sediments from the Yangtze River Estuary and its adjacent coastal zone. AB - Polycyclic aromatic hydrocarbons (PAHs) are mainly produced by incomplete combustion and are used as indicators of anthropogenic activities on the environment. This study analyses the PAHs level in the Yangtze River Estuary (YRE), an important component of Yangtze River and a developed and populated region in China. Surface sediments were collected from 77 sites at the YRE and its adjacent coastal zone (IACZ) for a comprehensive study of PAHs. Kriging interpolation technology and Positive matrix factorization (PMF) model were applied to explore the spatial distribution and sources of PAHs. Concentrations of 16 PAHs (SigmaPAHs) varied from 27.2 ng g(-1) to 621.6 ng g(-1) dry weight, with an average value of 158.2 ng g(-1). Spatially, SigmaPAHs exhibited wide fluctuation and exhibited an increasing tendency from north to south. In addition, SigmaPAHs exhibited a decreasing trend with increasing distance between the estuary and IACZ. The deposition flux of PAHs indicated that more than 107.8 t a(-1) PAHs was deposited in the study area annually. The results of the PMF model revealed that anthropogenic activities were the main sources of PAHs in the study area. Vehicle emissions and marine engines were the most important sources and accounted for 40.9% of the pollution. Coal combustion, petrogenic sources, and wood combustion were other sources that contributed 23.9%, 23.6%, and 11.5%, respectively. The distribution patterns of PAHs in the YRE and IACZ were influenced by many complicated factors such as sediment grain size, hydrodynamics and so on. PMID- 27485800 TI - News from the editors of Neurogastroenterology and Motility. PMID- 27485801 TI - Functional and genetic characterization of hydrocarbon biodegrader and exopolymer producing clones from a petroleum reservoir metagenomic library. AB - Microbial degradation of petroleum is a worldwide issue, which causes physico chemical changes in its compounds, diminishing its commercial value. Biosurfactants are chemically diverse molecules that can be produced by several microorganisms and can enable microbial access to hydrocarbons. In order to investigate both microbial activities, function-driven screening assays for biosurfactant production and hydrocarbon biodegradation were carried out from a metagenomic fosmid library. It was constructed from the total DNA extracted from aerobic and anaerobic enrichments from a Brazilian biodegraded petroleum sample. A sum of 10 clones were selected in order to evaluate their ability to produce exopolymers (EPS) with emulsifying activity, as well as to characterize the gene sequences, harbored by the fosmid clones, through 454 pyrosequencing. Functional analyses confirmed the ability of some clones to produce surfactant compounds. Regarding hydrocarbon as microbial carbon sources, n-alkane (in mixture or not) and naphthalene were preferentially consumed as substrates. Analysis of sequence data set revealed the presence of genes related to xenobiotics biodegradation and carbohydrate metabolism. These data were corroborated by the results of hydrocarbon biodegradation and biosurfactant production detected in the evaluated clones. PMID- 27485802 TI - Perioperative non-invasive haemodynamic monitoring: Yes or not yet? PMID- 27485803 TI - The efficacy of intra-articular lidocaine administration in chronic knee pain due to osteoarthritis: A randomized, double-blind, controlled study. AB - BACKGROUND: Intra-articular injections for the treatment of knee pain due to osteoarthritis are performed when conservative therapies have failed. The intra articular injection of lidocaine may be an effective treatment modality due to its neuronal membrane-stabilizing effect and long-lasting anti-inflammatory action. In this study, we compared the efficacy of intra-articular 0.5% lidocaine versus saline injection on pain, stiffness and physical function in patients with osteoarthritis. METHODS: Patients with osteoarthritis were randomly allocated to two groups. Group I (n=26) received 7mL 0.5% lidocaine and group II (n=26) received 7mL saline into the painful knee for a series of three injections spaced by 1 week intervals under ultrasound guidance. Knee pain was measured with a numeric rating score (NRS) at baseline and 3 months after the 3rd injection. WOMAC scales, including pain (WOMAC-P), stiffness (WOMAC-S) and physical function (WOMAC-F), were assessed and recorded at baseline, 30minutes after the 1st injection, immediately prior to the 2nd and 3rd injections and 3 months after the 3rd injection. RESULTS: Demographic data were comparable between groups. The NRS after 3 months was significantly lower in group I (P=0.001). The WOMAC-P, immediately prior to the 3rd injection and 3 months afterwards, was significantly lower in group I (P=0.006, P=0.001, respectively). The WOMAC-S was improved prior to the 3rd injection and sustained until 3 months in group I (P=0.035, P=0.004, respectively). The WOMAC-F was improved after the 1st injection and sustained until 3 months in group I (P=0.002, P<0.0001 and P<0.0001, respectively). CONCLUSIONS: Intra-articular 0.5% lidocaine injection under ultrasound guidance has a potential role in the management of chronic knee pain due to osteoarthritis for a 3-month period. PMID- 27485804 TI - The risk of atrial fibrillation after pneumonectomy is not impaired by preoperative administration of dexamethasone. A cohort study. AB - INTRODUCTION: Atrial fibrillation (AF) is one of the most frequent complications occurring after thoracic surgery especially after lung resection. It is associated with an increase in postoperative morbidity and mortality. Recent data having documented the preventive role of corticosteroids on the occurrence of AF in cardiac surgery, we sought to evaluate the effect of preoperative administration of dexamethasone on the incidence of AF after pneumonectomy. METHODS: We reviewed the files of all consecutive patients who underwent a pneumonectomy in one single centre between July 2004 and July 2012. For each patient, demographics, medical status, the surgical procedure and treatments administered including dexamethasone, were recorded. The data were analysed using a univariate analysis and a multivariate logistic regression. RESULTS: Among them, 153 patients were included and analysed; 35 (23%) presented with at least one episode of AF occurring within 48hours after surgery. Mortality was higher in these patients (26.5% versus 12.1%, P=0.06). The univariate analysis indicated that patients who had a postoperative course complicated by the occurrence of AF were older (P=0.003), had a higher SAPS2 score (P=0.002) and a higher CHADS score (P=0.05). Older age (OR=1.08; P=0.048) and preoperative treatment by anti arrhythmics (OR=3.9; P=0.029) were documented as independent risk factors in the multivariate analysis. Preoperative administration of dexamethasone 8-12mg did not impair the incidence of AF. DISCUSSION: AF is a frequent complication after pneumonectomy associated with increased mortality. Whereas corticosteroids have been documented as preventing AF following cardiac surgery, no such effect was found after pneumonectomy. PMID- 27485805 TI - Large vein injection alleviates rocuronium-induced pain in gynaecologic patients. AB - BACKGROUND: Rocuronium-induced pain upon injection is very common in the clinical setting. Using the antecubital rather than the hand vein can avoid pain due to propofol injection. We aimed to investigate whether the use of the antecubital vein for injection would alleviate rocuronium-induced pain in a similar fashion. METHODS: Sixty patients (ASA classes I and II) scheduled for gynaecologic laparoscopy were randomised into two groups. Rocuronium (0.6mg/kg) was injected either into the vein on the dorsum of the hand (group D) or a large vein in the antecubital fossa (group A). Pain was assessed and recorded using a four-point scale. RESULTS: Compared with group D, the incidence of pain and severe pain was lower in group A patients. The rate of no pain was also higher in group A patients. CONCLUSION: The incidence and severity of rocuronium-induced injection pain were significantly alleviated via use of a large vein for rocuronium injection. PMID- 27485806 TI - Intrathoracic small bowel obstruction with cardiac compression. PMID- 27485808 TI - Effect of floorball training on blood lipids, body composition, muscle strength, and functional capacity of elderly men. AB - Floorball training consists of intense repeated exercise and may offer a motivating and social stimulating team activity in elderly individuals. However, the effect of floorball training in elderly adults on physiological adaptations important for health is not known. Thus, this study examined the effect of floorball training on blood lipids, muscle strength, body composition, and functional capacity of men aged 65-76 years. Thirty-nine recreational active men were randomized into a floorball group (FG; n = 22) or petanque group (PG; n = 17), in which training was performed 1 h twice a week for 12 weeks. In FG and PG, average heart rate (HR) during training was 80% and 57%, respectively, of maximal HR. In FG, plasma low-density lipoprotein (LDL) cholesterol and triglycerides were 11% and 8% lower (P < 0.05), respectively. Insulin resistance determined by homeostatic model assessment (HOMA-IR) was reduced (P < 0.05) by 18%. HR during submaximal cycling was 5% lower (P < 0.05), and maximal voluntary contraction force was 8% higher (P < 0.05). Total and visceral fat content was lowered (P < 0.05) by 5% and 14%, respectively, HR at rest was 8% lower (P < 0.05) and performance in four different functional capacity tests were better (P < 0.05) after compared to before the training period. No changes were observed in PG. In conclusion, 12 weeks of floorball training resulted in a number of favorable effects important for health and functional capacity, suggesting that floorball training can be used as a health-promoting activity in elderly men. PMID- 27485807 TI - Utilization of different anti-viral mechanisms by mammalian embryonic stem cells and differentiated cells. AB - Embryonic stem cells (ESCs) have received tremendous attention because of their potential applications in regenerative medicine. Over the past two decades, intensive research has not only led to the generation of various types of cells from ESCs that can be potentially used for the treatment of human diseases but also led to the formation of new concepts and breakthroughs that have significantly impacted our understanding of basic cell biology and developmental biology. Recent studies have revealed that ESCs and other types of pluripotent cells do not have a functional interferon (IFN)-based anti-viral mechanism, challenging the idea that the IFN system is developed as the central component of anti-viral innate immunity in all types of cells in vertebrates. This finding also provided important insight into a question that has been uncertain for a long time: whether or not the RNA interference (RNAi) anti-viral mechanism operates in mammalian cells. An emerging paradigm is that mammals may have adapted distinct anti-viral mechanisms at different stages of organismal development; the IFN-based system is mainly used by differentiated somatic cells, while the RNAi anti-viral mechanism may be used in ESCs. This paper discusses the molecular basis and biological implications for mammals to have different anti viral mechanisms during development. PMID- 27485809 TI - Importance of a Fluorine Substituent for the Preparation of meta- and para Pentafluoro-lambda(6) -sulfanyl-Substituted Pyridines. AB - Although there are ways to synthesize ortho-pentafluoro-lambda(6) -sulfanyl (SF5 ) pyridines, meta- and para-SF5 -substituted pyridines are rare. We disclose herein a general route for their synthesis. The fundamental synthetic approach is the same as reported methods for ortho-SF5 -substituted pyridines and SF5 substituted arenes, that is, oxidative chlorotetrafluorination of the corresponding disulfides to give pyridylsulfur chlorotetrafluorides (SF4 Cl pyridines), followed by chloride/fluoride exchange with fluorides. However, the trick in this case is the presence on the pyridine ring of at least one fluorine atom, which is essential for the successful transformation of the disulfides into m-and p-SF5 -pyridines. After enabling the synthesis of an SF5 -substituted pyridine, ortho-F groups can be efficiently substituted by C, N, S, and O nucleophiles through an SN Ar pathway. This methodology provides access to a variety of previously unavailable SF5 -substituted pyridine building blocks. PMID- 27485810 TI - Bull's eye and pigment maculopathy are further retinal manifestations of an abnormal Bruch's membrane in Alport syndrome. AB - BACKGROUND AND OBJECTIVES: The retinal features of Alport syndrome include a central and peripheral fleck retinopathy, temporal retinal thinning, and a macular hole. Here we describe further retinal abnormalities. METHODS: We identified a case of bull's eye maculopathy 20 years previously in a 68-year-old female, and reviewed archived retinal images from our cohort of X-linked (28 males, 28 females) or autosomal recessive (n = 13) Alport syndrome. All individuals had Alport syndrome confirmed on genetic testing or renal biopsy, were examined by an ophthalmologist, and underwent retinal imaging (KOWA non mydriatic camera, Japan). RESULTS: The index case had the p.Q379X variant in COL4A5 and currently had renal impairment, (eGFR = 45 ml/min/1.73 m2), bilateral hearing loss, and central and peripheral retinopathies. Her maculopathy had deteriorated, and she had a bilateral central visual field loss. Optical coherence tomography (Heidelberg Spectralis) demonstrated a disrupted retinal pigment epithelium and retinal atrophy. We identified a further early bull's eye maculopathy (1/69, 1.4%) from a female with autosomal recessive disease and normal renal function. We also noted a subtle pigment maculopathy associated with an abnormal retinal pigment epithelium in 27 (27/69, 39%) subjects with Alport syndrome, in both males (8/28, 29%) and females (13/28, 46%) with X-linked disease, and in autosomal recessive disease (6/13, 38%). CONCLUSIONS: The bull's eye and pigment maculopathies in Alport syndrome result mainly from the damaged Bruch's membrane and overlying retinal pigment epithelium. Bull's eye maculopathy affects vision and patients should undergo regular monitoring for retinal complications. PMID- 27485811 TI - In situ microscopy for online monitoring of cell concentration in Pichia pastoris cultivations. AB - In situ Microscopy (ISM) is an optical non-invasive technique to monitor cells in bioprocesses in real-time. Pichia pastoris is one of the most promising protein expression systems. This yeast combines fast growth on simple media and important eukaryotic features such as glycosylation. In this work, the ISM technology was applied to Pichia pastoris cultivations for online monitoring of the cell concentration during cultivation. Different ISM settings were tested. The acquired images were analyzed with two image processing algorithms. In seven cultivations the cell concentration was monitored by the applied algorithms and offline samples were taken to determine optical density (OD) and dry cell mass (DCM). Cell concentrations up to 74g/L dry cell mass could be analyzed via the ISM. Depending on the algorithm and the ISM settings, an accuracy between 0.3 % and 12 % was achieved. The overall results show that for a robust measurement a combination of the two described algorithms is required. PMID- 27485812 TI - Production of a polar fish antimicrobial peptide in Escherichia coli using an ELP intein tag. AB - An important aspect related to infectious pathogens is their exceptional adaptability in developing resistance, which leads to a perpetual challenge in the discovery of antimicrobial drugs with novel mechanisms of action. Among them, antimicrobial peptides (AMPs) stand out as promising anti-infective molecules. In order to overcome the high costs associated with isolation from natural sources or chemical synthesis of AMPs we propose the expression of Pa-MAP 2, a polyalanine AMP. Pa-MAP 2 was fused to an ELP-intein tag where the ELP (Elastin like polypeptide) was used to promote aggregation and fast and cost-effective isolation after expression, and the intein was used to stimulate a controlled AMP release. For these, the vector pET21a was used to produce Pa-MAP 2 fused to the N termini region of a modified Mxe GyrA intein followed by 60 repetitions of ELP. Purified Pa-MAP 2 showed a MIC of 25MUM against E. coli ATCC 8739. Batch fermentation demonstrated that Pa-MAP-2 can be produced in both rich and defined media at yields 50-fold higher than reported for other AMPs produced by the ELP intein system, and in comparable yields to expression systems with protease or chemical cleavage. PMID- 27485813 TI - Characterization of nanobodies binding human fibrinogen selected by E. coli display. AB - Abnormal levels of fibrinogen (Fib) in blood plasma are associated with several pathological conditions and hence methods for its detection in blood and body fluids are essential. Nanobodies (Nbs) or (VHHs) are single domain antibodies derived from camelids with excellent biophysical and antigen-binding properties, showing great promise in diagnostics and therapy. In this work, we select and characterize high affinity Nbs binding human Fib employing an E. coli cell surface display system based on the fusion of an immune library of VHH domains with the beta-domain of Intimin. Bacteria displaying high-affinity Nbs against Fib were selected using magnetic cell sorting (MACS). Specific binding of the selected clones to Fib was confirmed by flow cytometry of E. coli bacteria, as well as by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) with the purified Nbs. E. coli display also provided an excellent estimation of the affinity of the selected Nbs by flow cytometry analysis under equilibrium conditions, with equilibrium constant (KD) values very similar to those obtained by SPR analysis. Finally, pairwise epitope-scouting studies revealed that the selected Nbs bound distinct epitopes on Fib. The selected Nbs are promising diagnostic tools for determination of human Fib levels. PMID- 27485815 TI - Editorial. PMID- 27485814 TI - Biosorption of aluminum through the use of non-viable biomass of Pseudomonas putida. AB - Living and non-living biomass of Pseudomonas putida A (ATCC 12633) was used as biosorbent for the removing of Al(3+) from aqueous solutions. The process was stable with time, efficient at pH 4.3 and between 15 degrees C and 42 degrees C. Two isotherms models were applied to describe the interaction between the biosorbent and Al(3+). Non-living biomass of P. putida A (ATCC 12633) was found to be the most efficient at adsorbing Al(3+) with a maximum sorption capacity of 0.55mg Al(3+)/gr adsorbent and with 36*10(5) binding sites of Al(3+)/microorganisms. Infrared spectroscopy analysis shows that the biosorbent present some vibrational band of functional groups that change in presence of Al(3+): hydroxyl, carboxyl and phosphate. Considering that Al(3+) binds to the phosphate group of phosphatidylcholine, non-viable biomass of P. putida PB01 (mutant lacking phosphatidylcholine) was used. Aluminum adsorption of the parental strain was 30 times higher than values registered in P. putida PB01 (36*10(5) sites/microorganism vs 1.2*10(5) sites/microorganism, respectively). This result evidenced that the absence of phosphatidylcholine significantly affected the availability of the binding sites and consequently the efficiency of the biomass to adsorb Al(3+). PMID- 27485816 TI - In Vitro Metabolism Evaluation of the Ergot Alkaloid Dihydroergotamine: Application of Microsomal and Biomimetic Oxidative Model. AB - Dihydroergotamine is a semisynthetic natural product derived from ergotamine, an ergot alkaloid. It is used to treat migraines, a neurological disease characterized by recurrent moderate to severe headaches. In this work, the in vitro metabolism of dihydroergotamine was evaluated in a biomimetic phase I reaction, aiming to verify all possible formed metabolites. Dihydroergotamine was submitted to an in vitro metabolism assay using rat liver microsomes, and the metabolites were analyzed by HPLC-MS/MS. The biomimetic reactions were performed with Jacobsen catalyst for scaling up production of oxidized metabolites. Two hydroxylated metabolites were isolated and characterized by MS/MS and 1H NMR analysis. PMID- 27485817 TI - Left atrial enlargement is an independent predictor of stroke and systemic embolism in patients with non-valvular atrial fibrillation. AB - Controversy exists regarding whether left atrial enlargement (LAE) is a predictor of stroke/systemic embolism (SE) in atrial fibrillation (AF) patients. The Fushimi AF Registry, a community-based prospective survey, enrolled all AF patients in Fushmi-ku, Japan, from March 2011. Follow-up data and baseline echocardiographic data were available for 2,713 patients by August 2015. We compared backgrounds and incidence of events over a median follow-up of 976.5 days between patients with LAE (left atrial diameter > 45 mm; LAE group) and those without in the Fushimi AF Registry. The LAE group accounted for 39% (n = 1,049) of cohort. The LAE group was older and had longer AF duration, with more prevalent non-paroxysmal AF, higher CHADS2/CHA2DS2-VASc score, and oral anticoagulant (OAC) use. A higher risk of stroke/SE during follow-up in the LAE group was found (entire cohort; hazard ratio (HR): 1.92, 95% confidence interval (CI): 1.40-2.64; p < 0.01; without OAC; HR: 1.97, 95% CI: 1.18-3.25; p < 0.01; with OAC; HR: 1.83, 95% CI: 1.21-2.82; p < 0.01). LAE was independently associated with increased risk of stroke/SE (HR: 1.74, 95% CI: 1.25-2.42; p < 0.01) after adjustment by the components of CHA2DS2-VASc score and OAC use. In conclusion, LAE was an independent predictor of stroke/SE in large community cohort of AF patients. PMID- 27485818 TI - Mammary epithelial morphogenesis and early breast cancer. Evidence of involvement of basal components of the RNA Polymerase I transcription machinery. AB - Upregulation of RNA Polymerase (Pol I)-mediated transcription of rRNA and increased ribogenesis are hallmarks of breast cancer. According to several datasets, including The Cancer Genome Atlas (TCGA), amplification/upregulation of genes encoding for basal components of the Pol I transcriptional machinery is frequent at different breast cancer stages. Here we show that knock down of the RNA polymerase I-specific transcription initiation factor RRN3 (TIF-IA) in breast cancer cells is sufficient to reduce rRNA synthesis and inhibit cell proliferation, and second that stable ectopic expression of RRN3 in human mammary epithelial (HME1) cells, by increasing rRNA transcription, confers increased sensitivity to the anti-proliferative effects of a selective Pol I inhibitor. Further, RRN3-overexpressing HME1 cells, when grown in in vitro 3-dimensional (3D) culture, develop into morphologically aberrant acinar structures lacking a lumen and filled with proliferative cells, thus acquiring a morphology resembling in situ ductal breast cancer lesions (DCIS). Consequently, interference with RRN3 control of Pol I transcription seems capable of both compromising mammary epithelial morphogenetic processes at early breast cancer stages, and driving breast cancer progression by fostering proliferation. PMID- 27485819 TI - Multifocal Surgically Induced Necrotizing Scleritis Following Strabismus Surgery: A Case Report. AB - PURPOSE: To present clinical findings of a 28-year-old woman with multifocal surgically induced necrotizing scleritis following uncomplicated strabismus surgery. METHOD: A 28-year-old woman underwent uncomplicated strabismus surgery of her right eye for sensory exotropia under general anesthesia (6 mm right medial rectus muscle resection and 8 mm right lateral rectus muscle recession). DESIGN: Retrospective, observational case report and literature review. RESULTS: One month after strabismus surgery, the patient presented with surgically induced necrotizing scleritis in the nasal aspect of sclera. Bacterial culture of the bed of the scleral melt showed no growth and all laboratory evaluation was normal. The scleritis completely resolved after initiation of systemic corticosteroids and oral azathioprine. Three weeks later (after tapering dose of systemic medication), the patient returned with large area of necrotizing scleritis in the same eye, but this time in the temporal aspect of sclera. CONCLUSION: To our knowledge, this is the first documented case of multifocal surgically induced necrotizing scleritis occurring after strabismus surgery. This study also highlights the fact that scleritis may recur even in an area distant from the site of surgery, despite initial control. It seems that maybe with a longer course of treatment it is less likely to recur, and tapering medications should be carefully managed. PMID- 27485820 TI - PPARalpha-ATGL pathway improves muscle mitochondrial metabolism: implication in aging. AB - Adipose triglyceride lipase (ATGL) maintains an optimum mitochondrial function putatively by generating cognate ligands for peroxisome proliferator-activated receptor alpha (PPARalpha), which, together with PPARgamma coactivator-1alpha (PGC1alpha), regulate muscle mitochondrial biogenesis. However, the cross-talk between ATGL and PPARalpha in skeletal muscle mitochondrial metabolism and its implication in chronological aging is poorly understood. The role of ATGL in muscle mitochondrial metabolism was studied by overexpressing and depleting the gene and studying its downstream effect in cultured myotubes and in murine skeletal muscle. We found that PPARalpha directly induces ATGL expression during myogenesis. Overexpression of ATGL significantly enhanced while depletion of ATGL attenuated mitochondrial oxidative phosphorylation and fatty acid oxidation without alteration in mitochondrial content, and it rendered PPARalpha and PGC1alpha redundant in promoting mitochondrial oxidative function. However, ATGL did not alter PPARalpha-dependent lipid accumulation and insulin sensitivity. In middle-aged rats, ATGL expression was higher and correlated with PPARalpha expression and sustained fatty acid oxidation in oxidative soleus muscle. Fenofibrate feeding further induced ATGL expression selectively in this muscle compartment. These findings illustrate that PPARalpha and ATGL constitute a regulatory pathway in skeletal muscle, suggesting their role as a mitochondrial metabolic reserve.-Biswas, D., Ghosh, M., Kumar, S., Chakrabarti, P. PPARalpha ATGL pathway improves muscle mitochondrial metabolism: implication in aging. PMID- 27485821 TI - Maternal serum ADAMTS-9 levels in gestational diabetes: a pilot study. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) is characterized with insulin resistance which is diagnosed during pregnancy. Although pregnancy is a diabetogenic state, not all women develop GDM. Genetic factors together with enviromental factors cause the maladaptation of maternal pancreas to this diabetogenic state and GDM develops. ADAMTS-9 is a recently recognized molecule whose genetic variants have risk of GDM. Decreased levels have already been shown in fetal membranes. Maternal serum levels of this protein have not been studied yet. We hypothesized that the alteration of ADAMTS-9 expression should cause changes in maternal serum levels which further could help to identify the disease and develop new treatment strategies. MATERIALS AND METHODS: This prospective case-control study is consisted of 27 pregnancies with GDM and 30 healthy singleton pregnancies matched for matenal age, gestational week, and maternal weight. GDM diagnosis was made with 2-h 75 g oral glucose tolerance test. ADAMTS 9 levels were compared between groups. RESULTS: ADAMTS levels were 3.62 +/- 0.33 ng/dL (range: 3.04-4.23) in GDM group and 4.65 +/- 1.70 ng/dL (range: 3.07-8.21) in control group (p < 0.001). ADAMTS levels were not affected by maternal age, gestational age, and maternal weight. CONCLUSION: ADAMTS-9 levels were significantly lower in GDM pregnancies. This may help to understand the mechanism of GDM pathogenesis. In future, target treatments with ADAMTS proteins may help to improve the severity of diabetes pathogenesis. PMID- 27485822 TI - The Empowering Role of Mobile Apps in Behavior Change Interventions: The Gray Matters Randomized Controlled Trial. AB - BACKGROUND: Health education and behavior change programs targeting specific risk factors have demonstrated their effectiveness in reducing the development of future diseases. Alzheimer disease (AD) shares many of the same risk factors, most of which can be addressed via behavior change. It is therefore theorized that a behavior change intervention targeting these risk factors would likely result in favorable rates of AD prevention. OBJECTIVE: The objective of this study was to reduce the future risk of developing AD, while in the short term promoting vascular health, through behavior change. METHODS: The study was an interventional randomized controlled trial consisting of subjects who were randomly assigned into either treatment (n=102) or control group (n=42). Outcome measures included various blood-based biomarkers, anthropometric measures, and behaviors related to AD risk. The treatment group was provided with a bespoke "Gray Matters" mobile phone app designed to encourage and facilitate behavior change. The app presented evidence-based educational material relating to AD risk and prevention strategies, facilitated self-reporting of behaviors across 6 behavioral domains, and presented feedback on the user's performance, calculated from reported behaviors against recommended guidelines. RESULTS: This paper explores the rationale for a mobile phone-led intervention and details the app's effect on behavior change and subsequent clinical outcomes. Via the app, the average participant submitted 7.3 (SD 3.2) behavioral logs/day (n=122,719). Analysis of these logs against primary outcome measures revealed that participants who improved their high-density lipoprotein cholesterol levels during the study duration answered a statistically significant higher number of questions per day (mean 8.30, SD 2.29) than those with no improvement (mean 6.52, SD 3.612), t97.74=-3.051, P=.003. Participants who decreased their body mass index (BMI) performed significantly better in attaining their recommended daily goals (mean 56.21 SD 30.4%) than those who increased their BMI (mean 40.12 SD 29.1%), t80 = -2.449, P=.017. In total, 69.2% (n=18) of those who achieved a mean performance percentage of 60% or higher, across all domains, reduced their BMI during the study, whereas 60.7% (n=34) who did not, increased their BMI. One-way analysis of variance of systolic blood pressure category changes showed a significant correlation between reported efforts to reduce stress and category change as a whole, P=.035. An exit survey highlighted that respondents (n=83) reported that the app motivated them to perform physical activity (85.4%) and make healthier food choices (87.5%). CONCLUSIONS: In this study, the ubiquitous nature of the mobile phone excelled as a delivery platform for the intervention, enabling the dissemination of educational intervention material while simultaneously monitoring and encouraging positive behavior change, resulting in desirable clinical effects. Sustained effort to maintain the achieved behaviors is expected to mitigate future AD risk. TRIAL REGISTRATION: ClinicalTrails.gov NCT02290912; https://clinicaltrials.gov/ct2/show/NCT02290912 (Archived by WebCite at http://www.webcitation.org/6ictUEwnm). PMID- 27485823 TI - Adjunctive Role of Glucagon-Like Peptide-1 Receptor Agonists in the Management of Type 1 Diabetes Mellitus. AB - Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used in combination with insulin to manage type 2 diabetes mellitus, and four agents are currently approved for this indication: exenatide, liraglutide, dulaglutide, and albiglutide. The distinctive properties of GLP-1 RAs-potential hemoglobin A1c (A1C) reduction, weight loss, potential to reduce insulin doses, and lower hypoglycemia risk-have made these agents potential treatment options for patients with type 1 diabetes mellitus (T1DM) as well. These positive effects are due to glucose-dependent insulin secretion, reduced glucagon secretion, increased satiety, and delayed gastric emptying. Patients with T1DM are unable to suppress glucagon during meals, which contributes to postprandial hyperglycemia and may be improved with GLP-1 therapy. In this review, we evaluated the available literature on the clinical efficacy and safety of GLP-1 RAs in patients with T1DM. We conducted a search of the PubMed (1966-May 2016) and Ovid (1946-May 2016) databases. Abstracts presented at the scientific and clinical sessions of the American Diabetes Association and the American Association of Clinical Endocrinologists were also searched. The references of the published articles were also reviewed to identify additional studies appropriate for inclusion. All identified articles published in English were evaluated. Studies were included if they evaluated the clinical use or safety of GLP-1 RAs in patients with T1DM. Twelve studies were included, with four evaluating exenatide, one evaluating exenatide extended release, and seven evaluating liraglutide. Both exenatide and liraglutide showed significant reductions in hemoglobin A1C, plasma glucose concentration, body weight, and insulin doses when administered to patients with T1DM already receiving insulin therapy, without increasing the occurrence of hypoglycemia. Adverse effects were mostly gastrointestinal in nature but were mild and transient. Patients who may benefit most are those experiencing adverse effects from insulin, those not at their A1C goal but hypoglycemia prevents insulin titration, and those who may benefit from weight loss. PMID- 27485824 TI - Ophthalmic artery Doppler analysis: a window into the cerebrovasculature of women with pre-eclampsia. PMID- 27485825 TI - Synergy between von Hippel-Lindau and P53 contributes to chemosensitivity of clear cell renal cell carcinoma. AB - The von Hippel-Lindau tumor suppressor (VHL; E3 ubiquitin ligase gene) is frequently mutated or undetectable in clear cell renal cell carcinoma (CCRCC), and therefore these tumors are highly resistant to chemotherapeutic agents, including adriamycin (ADM) and sunitinib. A mutation in the tumor protein p53 (TP53) also leads to chemoresistance in tumors; however, in CCRCC, TP53 is frequently functional, yet the tumors remain highly insensitive to chemotherapy. This indicates the possibility of a synergistic effect of VHL and P53 in CCRCC. The present study aimed to detect the chemosensitivity of CCRCC. The expression of VHL in the MZ1257 cell line sensitized these cells to ADM and sunitinib, and a knockdown of VHL in the ACHN cells increased their chemoresistance. To confirm that VHL and P53 are both required for chemosensitivity, VHL and P53 were co expressed in 786-O cells. The results of the functional antagonist assay (which assessed the IC50 values, i.e. the half maximal inhibitory concentration) confirmed that VHL and P53 act in synergy to promote chemosensitivity. Cell cycle arrest was measured by propidium iodide staining following treatment with ADM or sunitinib. Further analysis indicated that co-expression of VHL and P53 inhibited cell proliferation by completely inhibiting the cell cycle at the G0/G1 phase, and promoted apoptosis following treatment with ADM or sunitinib. These findings demonstrated that VHL and P53 act synergistically in the regulation of cell proliferation and apoptosis in CCRCC. Overall, VHL and P53 have important roles in the regulation of cell proliferation and apoptosis in CCRCC. Furthermore, the regulatory role of VHL is dependant on the activation P53. PMID- 27485826 TI - Genome-wide association study of aggressive behaviour in chicken. AB - In the poultry industry, aggressive behaviour is a large animal welfare issue all over the world. To date, little is known about the underlying genetics of the aggressive behaviour. Here, we performed a genome-wide association study (GWAS) to explore the genetic mechanism associated with aggressive behaviour in chickens. The GWAS results showed that a total of 33 SNPs were associated with aggressive behaviour traits (P < 4.6E-6). rs312463697 on chromosome 4 was significantly associated with aggression (P = 2.10905E-07), and it was in the intron region of the sortilin-related VPS10 domain containing receptor 2 (SORCS2) gene. In addition, biological function analysis of the nearest 26 genes around the significant SNPs was performed with Ingenuity Pathway Analysis. An interaction network contained 17 genes was obtained and SORCS2 was involved in this network, interacted with nerve growth factor (NGF), nerve growth factor receptor (NGFR), dopa decarboxylase (L-dopa) and dopamine. After knockdown of SORCS2, the mRNA levels of NGF, L-dopa and dopamine receptor genes DRD1, DRD2, DRD3 and DRD4 were significantly decreased (P < 0.05). In summary, our data indicated that SORCS2 might play an important role in chicken aggressive behaviour through the regulation of dopaminergic pathways and NGF. PMID- 27485829 TI - Palliative stenting of a jejunal stricture secondary to malignant compression using single-balloon enteroscopy. PMID- 27485830 TI - Erratum to: AGE-RAGE interaction in the TGFbeta2-mediated epithelial to mesenchymal transition of human lens epithelial cells. PMID- 27485827 TI - miR-146b antagomir-treated human Tregs acquire increased GVHD inhibitory potency. AB - CD4(+)CD25(+)FoxP3(+) thymic-derived regulatory T cells (tTregs) are indispensable for maintaining immune system equilibrium. Adoptive transfer of tTregs is an effective means of suppressing graft-versus-host disease (GVHD) in murine models and in early human clinical trials. Tumor necrosis factor receptor associated factor 6 (TRAF6), an ubiquitin-conjugating enzyme that mediates nuclear factor kappaB (NF-kappaB) activation, plays an essential role in modulating regulatory T cell survival and function. MicroRNAs (miRNAs) are noncoding RNAs, which mediate RNA silencing and posttranscriptional gene repression. By performing comprehensive TaqMan Low Density Array miRNA assays, we identified 10 miRNAs differentially regulated in human tTreg compared with control T cells. One candidate, miR-146b, is preferentially and highly expressed in human naive tTregs compared with naive CD4 T cells. miRNA prediction software revealed that TRAF6 was the one of the top 10 scored mRNAs involved tTreg function with the highest probability as a potential miR-146b target. Antagomir mediated knockdown of miRNA-146b, but not another miRNA-146 family member (miRNA 146a), enhanced TRAF6 expression. TRAF6, in turn, increases NF-kappaB activation, which is essential for tTreg function as well as Foxp3 protein and antiapoptotic gene expression, and downregulates proapoptotic gene expression. miR-146b knockdown increased the nuclear localization and expression of genes regulated by NF-kappaB, which was associated with enhanced tTreg survival, proliferation, and suppressive function measured in vitro and in vivo. TRAF6 inhibition had the opposite effects. We conclude that an miR-146b-TRAF6-NF-kappaB-FoxP3 signaling pathway restrains regulatory T cell survival, proliferation, and suppressor function. In vitro exposure of human tTregs to miR-146b antagomirs can be exploited to improve the clinical efficacy of human adoptive tTreg transfer in a GVHD setting. PMID- 27485828 TI - Genome of Rhizobium leucaenae strains CFN 299(T) and CPAO 29.8: searching for genes related to a successful symbiotic performance under stressful conditions. AB - BACKGROUND: Common bean (Phaseolus vulgaris L.) is the most important legume cropped worldwide for food production and its agronomic performance can be greatly improved if the benefits from symbiotic nitrogen fixation are maximized. The legume is known for its high promiscuity in nodulating with several Rhizobium species, but those belonging to the Rhizobium tropici "group" are the most successful and efficient in fixing nitrogen in tropical acid soils. Rhizobium leucaenae belongs to this group, which is abundant in the Brazilian "Cerrados" soils and frequently submitted to several environmental stresses. Here we present the first high-quality genome drafts of R. leucaenae, including the type strain CFN 299(T) and the very efficient strain CPAO 29.8. Our main objective was to identify features that explain the successful capacity of R. leucaenae in nodulating common bean under stressful environmental conditions. RESULTS: The genomes of R. leucaenae strains CFN 299(T) and CPAO 29.8 were estimated at 6.7 6.8 Mbp; 7015 and 6899 coding sequences (CDS) were predicted, respectively, 6264 of which are common to both strains. The genomes of both strains present a large number of CDS that may confer tolerance of high temperatures, acid soils, salinity and water deficiency. Types I, II, IV-pili, IV and V secretion systems were present in both strains and might help soil and host colonization as well as the symbiotic performance under stressful conditions. The symbiotic plasmid of CPAO 29.8 is highly similar to already described tropici pSyms, including five copies of nodD and three of nodA genes. R. leucaenae CFN 299(T) is capable of synthesizing Nod factors in the absence of flavonoids when submitted to osmotic stress, indicating that under abiotic stress the regulation of nod genes might be different. CONCLUSION: A detailed study of the genes putatively related to stress tolerance in R. leucaenae highlighted an intricate pattern comprising a variety of mechanisms that are probably orchestrated to tolerate the stressful conditions to which the strains are submitted on a daily basis. The capacity to synthesize Nod factors under abiotic stress might follow the same regulatory pathways as in CIAT 899(T) and may help both to improve bacterial survival and to expand host range to guarantee the perpetuation of the symbiosis. PMID- 27485831 TI - Cross-validation of cultural tightness and looseness measures. AB - The goal of the present study was to cross-validate two measures of cultural tightness and looseness, CTL: one used in a comparison within the United States, and the other used in a cross-country comparison. The former was based mainly on aggregation of state laws on controversial issues and religiosity and the latter on assessment of homogeneity in moral values among representative samples across countries. To cross-validate these two measures, both were recomputed at the US divisional level. Despite the differences in their methods of computation, the two measures of CTL correlated highly with each other, r = .92, and with theoretical variables of interest. Further, when the two measures of CTL were used simultaneously to predict theoretical variables of interest, neither remained significant suggesting that they were substitutable with each other. Convergence of results with measures computed via maximally different methods increases the confidence in the validity of these two CTL measures. PMID- 27485832 TI - What is the appropriate therapy for asymptomatic gonorrhoea in men who have sex with men? PMID- 27485834 TI - [Not Available]. PMID- 27485833 TI - Bipartite graph analyses reveal interdomain LGT involving ultrasmall prokaryotes and their divergent, membrane-related proteins. AB - Based on their small size and genomic properties, ultrasmall prokaryotic groups like the Candidate Phyla Radiation have been proposed as possible symbionts dependent on other bacteria or archaea. In this study, we use a bipartite graph analysis to examine patterns of sequence similarity between draft and complete genomes from ultrasmall bacteria and other complete prokaryotic genomes, assessing whether the former group might engage in significant gene transfer (or even endosymbioses) with other community members. Our results provide preliminary evidence for many lateral gene transfers with other prokaryotes, including members of the archaea, and report the presence of divergent, membrane-associated proteins among these ultrasmall taxa. In particular, these divergent genes were found in TM6 relatives of the intracellular parasite Babela massiliensis. PMID- 27485835 TI - Telocytes as potential targets in a cyclophosphamide-induced animal model of premature ovarian failure. AB - Premature ovarian failure (POF) refers to the presence of ovarian atrophic permanent amenorrhea in women under the age of 40. The pathogenesis of POF remains to be fully elucidated. Telocytes are a group of specialized cells with a small cell volume and very long cytoplasmic prolongations with dichotomous branching. Previous studies have indicated that telocytes function to support the trachea and serve as stem cell niches. Although it has been confirmed that telocytes are present in numerous organs in mammals, it remains to be determined whether they are present in ovarian tissues and whether they are involved in the development of POF. The present study used a cyclophosphamide-induced mouse model of POF. Hematoxylin and eosin staining and an enzyme-linked immunosorbent assay revealed that cyclophosphamide induced edema and apoptosis of ovarian stromal and granulosa cells and increased atretic follicles. In addition, cyclophosphamide induced abnormal peripheral blood FSH and E2 levels in mice. Transmission electron microscopy revealed a small number of telocyte-like cell structures in the ovarian stroma of wild-type mice. In addition, flow cytometry and immunohistochemical staining results suggested that the number of cluster of differentiation (CD)34/platelet-derived growth factor receptor (PDGFR)alpha, CD34/PDGFRbeta and CD34/vimentin double-positive cells in the ovaries of POF mice was significantly decreased compared with wild-type mice. In conclusion, mouse ovarian tissues appear to contain telocytes, and cyclophosphamide treatment significantly reduced the number of ovarian telocytes. Therefore, telocytes may serve as a potential novel marker of POF induced by cyclophosphamide. PMID- 27485836 TI - Laboratory Innovation Towards Quality Program Sustainability. AB - Laboratory innovation significantly affects program sustainability of HIV programs in low and middle income countries (LMICs) far beyond its immediate sphere of impact. Innovation in rapid development of diagnostic technologies, improved quality management systems, strengthened laboratory management, affordable external quality assurance and accreditation schemes, and building local capacity have reduced costs, brought quality improvement to point-of-care testing, increased access to testing services, reduced treatment and prevention costs and opened the door to the real possibility of ending the AIDS epidemic. However, for effectively implemented laboratory innovation to contribute to HIV quality program sustainability, it must be implemented within the overall context of the national strategic plan and HIV treatment programs. The high quality of HIV rapid diagnostic test was a breakthrough that made it possible for more persons to learn their HIV status, receive counseling, and if infected to receive treatment. Likewise, the use of dried blood spots made the shipment of samples easier for the assessment of different variables of HIV infection-molecular diagnosis, CD4+ cell counts, HIV antibodies, drug resistance surveillance, and even antiretroviral drug level measurements. Such advancement is critical for to reaching the UNAIDS target of 90-90-90 and for bringing the AIDS epidemic to an end, especially in LMICs. PMID- 27485837 TI - Past and Future Performance: PEPFAR in the Landscape of Foreign Aid for Health. AB - This review traces the course of the US President's Emergency Plan for AIDS Relief (PEPFAR) as a foreign aid program. It illustrates how the epidemiologic and geopolitical environments of the early 2000s influenced PEPFAR's early directions and contributed to its successes. In addition to scaling up infrastructure and care delivery platforms, PEPFAR led to large increases in the number of people receiving antiretroviral therapy and reductions in mortality. These successes, in turn, have brought its principal challenges-its outsized budget, narrow focus, and problem of entitlement-into sharp relief. PEPFAR's recent evolution, then, has been in response to these challenges. This review suggests that PEPFAR's early formulation as an emergency response relieved it from a need to articulate clear goals, and that this freedom is now leading to new challenges as it struggles to identify priorities in the face of expectations to do more with a flat budget. PMID- 27485839 TI - The fungal resistome: a risk and an opportunity for the development of novel antifungal therapies. AB - The risks for toxicity of novel antifungal compounds, together with the emergence of resistance, makes the use of inhibitors of resistance, in combination with antifungal compounds, a suitable strategy for developing novel antifungal formulations. Among them, inhibitors of efflux pumps are suitable candidates. Increasing drug influx or interfering with the stress response may also improve the efficacy of antifungals. Therapies as induction of fungal apoptosis or immunostimulation are also good strategies for reducing the risks for resistance and to improve antifungals' efficacy. Understanding the effect of the acquisition of resistance on the fungal physiology and determining the collateral sensitivity networks are useful for the development of novel strategies based on combination of antifungals for improving the efficacy of the therapy. PMID- 27485838 TI - Use of Non-invasive Testing to Stage Liver Fibrosis in Patients with HIV. AB - Patients with HIV have a proclivity to develop liver fibrosis, especially when associated with other conditions such as HCV, HBV, and NAFLD. Identifying HIV infected patients with significant fibrosis or cirrhosis plays an important role in clinical and therapeutic decision-making. Liver biopsy is currently considered as the gold standard for fibrosis assessment but carries many shortcomings (cost, invasiveness, complications, false negative rate of 20 %). Multiple non-invasive methods of liver fibrosis assessment have been developed, but not all have been studied in HIV-infected individuals. Non-invasive liver fibrosis tools include both serologic-based testing scores (rely on direct and/or indirect markers) such as APRI, FIB4, FibroTest, FibroSpect II, HepaScore, or imaging-based methods such as vibration controlled liver elastography. There is validated data to support the use of non-invasive modalities of fibrosis assessment in HIV-HCV co-infected individuals for the exclusion of cirrhosis, but may be poorly reliable or not enough data exists for the assessment of other co-morbid disease processes. PMID- 27485840 TI - [Percutaneous endoscopic gastrostomy: analysis of practice at the endoscopic center of tertiary medical care]. AB - INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) is a minimally invasive routine procedure used to provide long-term enteral nutrition in selected patients with impaired oral intake. The knowledge of clinical, technical and safety features of PEG is an important issue in clinical practice.The aim of this study was to evaluate the popu-lation of patients selected for PEG insertion, describe certain aspects of the insertion procedure, assess the service life of PEG, as well as account for the number of complications and patient mortality in the six-month period following the procedure. METHODS: We used a retrospective analysis of data from medical database. The data were collected in a single endoscopic tertiary-referral center for a period of seven and a half years. RESULTS: We evaluated 326 PEG insertions performed on 292 patients with a median age of 63 years (IQR 55-70). Mortality in the six-month period following PEG insertion was 26 %. Prevailing indications for PEG insertion were oncological (53 %) and neurological (40 %) diseases, with certain fluctuation of these numbers during the observed period according to changing demands of the two medical specialties. Local anesthesia alone was applied in 56 % of patients, 38 % underwent analgosedation and 6 % required general anesthesia. Median duration of the procedure (from insertion of endoscope to its final extraction) in 68 consecutive procedures was 6 minutes (IQR 5-8). Median interval between PEG introduction and its first replacement in 21 patients was 22 months (IQR 14-31, range 4-76). 61 patients underwent PEG extraction during the observed period, 66 % of whom had oncological disease. Periprocedural complications were seen in 5.8 % of patients, of these one patient (0.3 %) suffered a serious complication. The buried bumper syndrome was observed in four patients (1.2 %), all of whom had neurological disease. CONCLUSIONS: PEG is a relatively safe procedure and can be performed in a short time using local anesthesia or analgosedation in a majority of patients. The population of patients indicated for PEG insertion reflects primarily the current needs of neurological and oncological departments. Most patients within the observed group benefit from PEG insertion for more than six months. KEY WORDS: analgosedation - complications - mortality - percutaneous endoscopic gastrostomy. PMID- 27485841 TI - [Diabetic Kidney Disease 3rd stage - laboratory markers of mineral bone disorder]. AB - BACKGROUND: Diabetes mellitus is the most common cause of end stage kidney disease in the developed countries. Chronic kidney disease-mineral and bone disorder (CKD-MBD) develops with deteriorating of the renal functions. Diabetic patients on hemodialysis are characterized by low bone turnover, higher prevalence of severe and progressive vascular calcification with increased cardiovascular morbidity and mortality. The main factor which causes vascular calcification in patients with diabetic kidney disease (DKD) is poor glycemic control. The recent trial findings describe an inverse correlation between intact parathyroid hormone (iPTH) serum levels and glycemic control in a group of diabetic patients on hemodialysis. AIM: The objective of the proposed project is to access the difference of the laboratory markers MBD in the group of patients with 3rd stage DKD depending on glycemic control. We focused on the relationship between the glycemic compensation of diabetes (HbA1c) and iPTH serum level. PATIENTS AND METHOD: Ninety one patients with 3rd stage DKD were investigated. There were 46 women (50.5 %) and 45 men (49.5 %), average age of patients was 71.2 +/- 7.0 years, with creatinine level 128 +/- 30 MUmol/l and estimated glomerular filtration (eGF, MDRD) 0.82 +/- 0.16 ml/s. There were 60 patients with better glycemic control of diabetes (HbA1c < 7 %) vs 29 patients with poorly controlled diabetes (HbA1c > 7 %). MBD markers were compared in both groups. Patients were further stratified into subgroups based on the serum level of iPTH (iPTH < 35 pg/ml vs iPTH > 35 pg/ml) and MBD markers compared. Statistical analysis was performed using and Mann-Whitney test. RESULTS: We have found the statistical significance in the serum phosphate and proteinuria levels in between groups with HbA1c < 7 % vs patients with HbA1c > 7 %. Diabetics with better glycemic control had significant reduction in serum phosphate level (1.14 +/- 0.20 vs 1.23 +/- 0.18 mmol/l, p = 0.038) and in 24 hrs proteinuria level (0.56 +/ 1.35 vs 1.30 +/- 1.61 g/day, p = 0.007). In the group of presumed low bone turnover (iPTH < 35 pg/ml) we have found the trend towards increased serum calcium level (2.49 +/- 0.12 vs 2.43 +/- 0.10 mmol/l, p = 0.063) and increased HbA1c value (7.5 +/- 1.8 vs 6.4 +/- 1.6 %, p = 0.023). CONCLUSION: Our results suggest the closer relationship between glycemic control of diabetes and mineral bone disorder in earlier stages of DKD. KEY WORDS: diabetes mellitus type 2 (DM2T) - chronic kidney disease (CKD) - mineral and bone disorder (MBD). PMID- 27485842 TI - [Long-term treatment of venous thromboembolism in patients with cancer]. AB - BACKGROUND: The treatment with low-molecular-weight heparin (LMWH) is recommended for patients with cancer associated thrombosis (CAT) during the first 6 months; the initial therapeutic dose can be reduced to 60-75 % after one month. The therapy should be reevaluated after 6 month and subsequent therapy using LMWH or warfarin is recommended indefinitely, unless the cancer is resolved or any major contraindications arise. AIMS: To analyze the usage of various treatment modalities in CAT patients after the initial 6 month period according to the course of cancer. PATIENTS AND METHODS: 87 patients with CAT were followed prospectively during the treatment period. The proportion of patients, in whom LMWH was replaced by warfarin during the first 6 months and during the entire follow up, was analyzed in relation to the course of the cancer. The chi2 test and chi2 test with Yates correction were used for the statistical evaluation. RESULTS: The median follow-up was 445 days, mean duration of follow up was 743 days. 6 months after the diagnosis of thrombosis 9/30 (31.0 %) patients with complete remission (CR) of the cancer were treated with warfarin, while only 3/12 (25 %), 0/9 (0 %) and 1/13 (7.7 %) of the patients with partial remission (PR), stable disease (SD) and progression, respectively, were treated with warfarin. Patients with CR and PR were more frequently treated with warfarin than patients with SD or progression (P = 0.02). 13 patients died during the first 6 months, and 8 patients were followed less than 6 months. During the entire follow up, 25/30 (83.3 %) patients with CR switched to warfarin, while only 5/12 (41.7 %), 1/9 (11.1 %) and 1/13 (7.7 %) patients with PR, SD, and progression, respectively, were treated with warfarin. The proportion of patients with CR which switched to warfarin was higher, than the proportion of patients with PR (P = 0.007), with SD (P = 0.0003), and with progression (P < 0.0001). Median time from thrombosis onset to the switch from LMWH to warfarin was 219 days in patients in complete remission after 6 months and was not reached in patients in PR,SD, and progression. CONCLUSIONS: The course of malignant disease is important for the choice of appropriate therapy of CAT after the initial period of LMWH therapy. The patients achieving complete remission are more prone to switch from LMWH to warfarin. KEY WORDS: cancer - low-molecular-weight-heparin - venous thromboembolism - warfarin. PMID- 27485843 TI - [Annual monitoring of side effects of administering sitagliptin in patients with type 2 diabetes mellitus]. AB - We present the results of an independent, drug company-unsupported follow-up of patients with type 2 diabetes mellitus (T2DM) treated with the dipeptidyl peptidase 4 inhibitor sitagliptin. 29 patients (16 men, 13 women) used sitagliptin 100 mg daily for one year as an add-on to their chronic antidiabetic therapy. 16 type diabetic patients formed a control group - they used their chronic antidiabetic therapy without sitagliptin. 10 additional patients (6 men and 4 women) were enrolled in the study and treated with sitagliptin for one month. Body weight, BMI, glycaemia, glycated hemoglobin (HbA1c), cholesterolemia, triacylglycerolemia and serum amylases were determined and abdominal ultrasonography was performed. Because significant changes in immunological tests had been found especially after one month of treatment, 10 additional patients (6 men and 4 women) were enrolled in the study and treated with sitagliptin for one month. Sitagliptin treatment led to a significant body weight loss of 1 kg per year. In the control group, no significant change was observed. Similar results were noticed in HbA1c level and fasting glycaemia - mild but statisticaly significant reduction in the sitagliptin group both after one month and one year (not in HbA1c), no difference in the control group. There was no change in cholesterolemia, or in triacylglycerolemia. In 33% of patients in the sitagliptin group, the level of liver steatosis decreased by ultrasonographic evaluation. This was not found in any of the patients case in the control group. The serum amylase levels increased slightly over the upper limit in two sitagliptin treated patients. In the other sitagliptin treated patients serum amylase remained within the laboratory limits, but slight, statistically significant elevation of serum amylases was observed in the intervened group. This result was not found in the control group. There were not differences in the frequency between occurence of mild respiratory infections in the sitagliptin and control group. Marginally significant decrease was observed in the intervened group. KEY WORDS: sitagliptin - type 2 diabetes mellitus - side effects. PMID- 27485844 TI - [Acute causes of sudden deaths in patients with severe hypoglycemia]. AB - Hypoglycemia is a serious event, which is associated with the neurological and cardiovascular events. Hypoglycemia can be also associated with sudden death, however, the prevalence of these sudden deaths is not exactly known. Hypoglycemia is associated with the risk of sudden death in patients with type 1. and 2. type diabetes mellitus and also in critically ill patients. Sudden death can occure due to cardiovascular, neurological or metabolic disorders associated with hypoglycemia. The article provides a review of current knowledge about the prevalence of severe hypoglycemia, the association between hypoglycemia and sudden deaths and about the causes of sudden death in patients with severe hypoglycemia. KEY WORDS: hypoglycemia - prevalence of these sudden deaths - severe hypoglycemia. PMID- 27485845 TI - [Cardiomyopathy in MR image]. AB - The purpose of this article is to summarize some general information about the most common types of cardio-myopathies with an emphasis on a use of cardiac magnetic resonance imaging (CMR) in its diagnosis. Although characteristic CMR findings of the cardiomyopathy are generally revealed, the establishing of a clear diagnosis could be difficult. The assessment of structural myocardial abnormalities allows determination of the degree of changes in the myocardium and the prognosis of the disease. The wide range of information about the heart structure and function is feasible to achieve due to advanced techniques of magnetic resonance imaging and the ima-ging is not limited by acoustic windows as it is in case of echocardiography. The role of CMR in diagnostics of the cardiomyopathies tends to be increasingly important, cardiologists increasingly favour this examination and it is consequently becoming a standard part of a diagnostic algorithm. KEY WORDS: amyloidosis - cardiac magnetic resonance - cardiomyopathy - myocardial hypertrophy. PMID- 27485846 TI - [Komentar ke clanku HOPE-3: Statins Lower CV Events in Intermediate-CHD-Risk Patients]. AB - The HOPE-3 study focused on identifying the significance of the polypill and mini polypill in broad clinical practice, including individuals of different gender without cardiovascular diseases with an intermediate risk of cardiovascular diseases. The authors were interested in the question whether people from various antropologhy groups including not only white people but also other antropologhy groups - the blacks, people of Asian and South American origin and more covering 6 continents, would respond in a similar way. The study mainly examined the significance of the mini-polypill, comprising the use of antihypertensive treatment (16 mg candesartan per day + 12.5 mg hydrochlorothiazide), treatment with statins (10 mg rosuvastatin per day), and their combination. The study presents a new way forward in the prevention of cardiovascular diseases, but it also entails some weaknesses which consist in rather rare medical checkups including laboratory tests. Owing to that the concept of mini-polypill has met with some reservation. But it also brings with it reduction of healthcare costs. KEY WORDS: mini-polypill - prevention of cardiovascular diseases - relevance of statins also to primary prevention. PMID- 27485847 TI - [microRNA and internal medicine: from pathophysiology to the new diagnostic and therapeutic procedures]. AB - microRNAs (abbreviated miRNAs or miRs) represents one of the group of so called small non-coding RNAs which participate in the negative post-transcriptional regulation of gene expression. According to the base complementarity they target molecules of messenger RNAs (mRNAs) which results either in translational blockade or in degradation of target mRNA. One miRNA usually targets more mRNA and one mRNA is usually targeted by more than one miRNA - complicated and interconnected regulatory networks are thus created and their disruption leads to the abnormalities in development or results in the development of diseases. Within the past two decades, novel mechanisms were described that enable us to modulate miRNA levels (either causing upregulation or downregulation) - miRNAs can thus be considered as a novel potential group of therapeutic targets. First clinical trials using the blockade of liver specific miR-122 showed very promising results in the treatment of chronic hepatitis C virus infection. Results of preclinical and animal studies are also promising providing future rationale for the development of new therapeutics for various internal diseases including heart failure, bronchial asthma or inflammatory bowel diseases. Moreover, miRNAs are not only affecting the pathophysiology of internal diseases, but they can also reflect their presence - there is a group of miRNAs called extracellular, or circulating miRNAs, i.e. miRNAs that are present in extracellular space including all known body fluids such as plasma, serum, urine, saliva or sweat. Circulating miRNAs are stable; their levels are constant among the individuals of one species, methods determining their levels are reproducible and last but not least - levels of extracellular miRNAs differ between healthy and diseased individuals. They are released into the circulation either after the cell necrosis or by active transport. Except of being potential novel biomarkers, these miRNAs represent a novel mean of intercellular communication. Their levels thus reflect not only the organ damage but also the changes of the homeostasis during various illnesses. The aim of the current study is to provide the first insight into the miRNA world to clinicians, especially to internal medicine specialists. Using simple examples from clinical praxis or clinical pathophysiology, we are trying to present diagnostic and therapeutic potential that is hidden within these tiny interesting molecules. KEY WORDS: circulating microRNA - diagnostics - internal diseases - microRNA - therapy. PMID- 27485848 TI - [Insulin application techniques in adult patients with diabetes]. AB - Treatment of diabetes mellitus with insulin is associated with a large number of subcutaneous injections. Incorrect insulin application technique can lead to complications both local (lipohypertrophy, scars) and systemic (high variability of insulin absorption and action, unexpected hypoglycemia or hyperglycemia, suboptimal overall glucose control). Regarding insulin application, we need to pay particular attention to the risk of intramuscular application and consequent less expectable insulin effect. The risk of accidental intramuscular administration of insulin is reduced when shorter 4 mm insulin pen needles are used. Repeated application of insulin in the same locations may cause changes in the subcutaneous tissue (lipohypertrophy, inflammation). Application sites should be examined during routine checks at diabetes clinics. Patients should also be repeatedly advised to rotate the injection sites as a prevention of lipohypertrophy formation and not to inject any more injections into pathologically changed subcutaneous tissue. At the same time, patients should be advised that their total insulin dose may be decreased, and that they are temporarily at higher risk of hypoglycemia, if they switch injecting from lipohypertrophy changed tissue into healthy tissue. KEY WORDS: glucose variability - insulin application - lipohypertrophy - needles. PMID- 27485849 TI - [Sinus histiocytosis with massive lymphadenopathy: FDG-PET/CT documented partial remission after treatment with 2-chlorodeoxyadenosine]. AB - Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) is a very rare disease belonging to a group of histiocytoses (more precisely non Langerhans cell histiocytoses). Rosai-Dorfman disease is characterised by the presence of atypical histiocytic cells in the sinuses of lymph nodes or in the extranodal lymphoid tissue, absorbing lymphocytes and plasma cells. The structure and function of the absorbed cells is not impaired and they can leave histiocytes as viable cells. This effect is called emperipolesis, whereas ingestion of cells with their destruction is called phagocytosis. In our text we describe a patient with this disease located, characteristically, in supraclavicular lymph nodes, but also in mediastinal lymph nodes. Along with lymphadenopathy skin alterations appeared which were both clinically and histologically described as eczema dermatitis. At the same time as lymphadenopathy also strong headaches started which the patient had never suffered before. Within the first-line treatment prednisone was administered, but no effect was achieved. 2-chlorodeoxyadenosine in 5 mg/m2 s. c. dose was used in the second-line treatment, for 5 successive days in monthly intervals. There were four cycles of this treatment administered overall. Therapy was tolerated without any manifestations of toxicity. Already after the 1st cycle skin alterations as well as headaches entirely disappeared. To assess the effect of treatment the PET/CT examination with 18F fluorodeoxyglucose (FDG-PET/CT) was made. After 4 cycles of treatment the mediastinal lymph nodes diminished to a physiological size and the accumulation of fluorodeoxyglucose in them was assessed as physiological. Lymphadenopathy in the neck area also significantly diminished by 50-75 % and the accumulation of fluorodeoxyglucose was reduced as well, though it did not reach the norm. Therefore we evaluate the effect of treatment as a partial remission with complete disappearance of skin alterations and headaches. The cause of the eczema and headaches has not been clarified, however considering the same time of their arising and then disappearance after the application of 2-chlorodeoxyadenosine the causal connection with Rosai-Dorfman disease is likely. KEY WORDS: Castlemans disease - lenalidomide - Rosai-Dorfman disease - rituximab - sinus lymphadenopathy with massive lymphadenopathy - thalidomide - 2 chlorodeoxyadenosine. PMID- 27485850 TI - Synovial incorporation of polyacrylamide hydrogel after injection into normal and osteoarthritic animal joints. AB - OBJECTIVE: Polyacrylamide hydrogel (PAAG) is a non-toxic, non-degradable synthetic product, used for years in the augmentation of soft tissues. Preliminary results in animals and humans have suggested long-lasting beneficial effects on symptoms of osteoarthritis (OA). The aim of this histopathological study was to investigate whether intra-articular injection of PAAG is integrated into synovial tissue in normal and OA animal joints, and if this integration is sustained. METHODS: (A) A prospective, controlled, longitudinal study of normal knee joints injected with PAAG was performed in 10 rabbits, following the animals up to 1 year, and (B) a post mortem examination was carried out up to 2 years post-injection on 18 horse joints which had previously been treated with 1-2 injections of 2 ml PAAG for clinically and radiologically diagnosed OA. RESULTS: Integration of the injected gel was evident at day 10 in the rabbit and by day 14 in the horse, with proliferation and invasion of synovial cells into the gel. By day 90 in rabbit joints and day 30 in horse joints, the gel had formed a sub synovial layer, which was traversed by thin strands of connective tissue with vessels and covered by a synovial lining facing the joint cavity. This histological appearance persisted up to 2 years post-injection in horse joints. CONCLUSION: Intra-articular injection of PAAG results in a stable, long-lasting sub-synovial layer of gel traversed with thin strands of connective tissue. Further studies to explore potential effects on synovial inflammation and pain are warranted. PMID- 27485852 TI - Assessment of response rates and yields for Two opportunistic Tools for Early detection of Non-diabetic hyperglycaemia and Diabetes (ATTEND). A randomised controlled trial and cost-effectiveness analysis. AB - AIMS: To assess the opportunistic use in primary care of a computer risk score versus a self-assessment risk score for undiagnosed type 2 diabetes. METHODS: We conducted a randomised controlled trial in 11 primary care practices in the UK. 577 patients aged 40-75years with no current diagnosis of type 2 diabetes were recruited to a computer based risk score (Leicester Practice Computer Risk Score (LPCRS)) or a patient self-assessment score (Leicester Self-Assessment Score (LSAS)). RESULTS: The rate of self-referral blood tests was significantly higher for the LPCRS compared to the LSAS, 118.98 (95% CI: 102.85, 137.64) per 1000 high risk patient years of follow-up compared to 92.14 (95% CI: 78.25, 108.49), p=0.022. Combined rate of diagnosis of type 2 diabetes and those at risk of developing the disease (i.e. impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)) was similar between the two arms, 15.12 (95% CI: 9.11, 25.08) per 1000 high-risk patient years for LPCRS compared to 14.72 (95% CI: 9.59, 22.57) for the LSAS, p=0.699. For the base case scenario the cost per new case of type 2 diabetes diagnosed was lower for the LPCRS compared to the LSAS, L168 (95% Credible Interval (CrI): 76, 364), and L352 (95% CrI: 109, 1148), respectively. CONCLUSIONS: Compared to a self-assessment risk score, a computer based risk score resulted in greater attendance to an initial blood test and is potentially more cost-effective. PMID- 27485851 TI - Diabetes mellitus in Zambia and the Western Cape province of South Africa: Prevalence, risk factors, diagnosis and management. AB - AIMS: To determine the prevalence of and risk factors for diabetes mellitus and examine its diagnosis and management in the study communities. METHODS: This is a population-based cross-sectional study among adults in 24 communities from Zambia and the Western Cape (WC) province of South Africa. Diabetes is defined as a random blood glucose concentration (RBG)?11.1mmol/L, or RBG<11.1mmol/L but with a self-reported prior diabetes diagnosis. For individuals with a prior diagnosis of diabetes, RBG<7.8mmol/L was considered to be an acceptable level of glycaemia. RESULTS: Among 45,767 Zambian and 12,496 WC participants the age-standardised prevalence of diabetes was 3.5% and 7.2% respectively. The highest risk groups identified were those of older age and those with obesity. Of those identified to have diabetes, 34.5% in Zambia and 12.7% in WC were previously unaware of their diagnosis. Among Zambian participants with diabetes, this proportion was lower among individuals with better education or with higher household socio-economic position. Of all those with previously diagnosed diabetes, 66.0% in Zambia and 59.4% in WC were not on any diabetes treatment, and 34.4% in Zambia and 32.7% in WC had a RBG concentration beyond the recommended level, ?7.8mmol/L. CONCLUSIONS: The diabetes risk factor profile for our study communities is similar to that seen in high-income populations. A high proportion of individuals with diabetes are not on diabetes treatment and of those on treatment a high proportion have high glycaemic concentrations. Such data may assist in healthcare planning to ensure timely diagnosis and management of diabetes. PMID- 27485853 TI - Improved diastolic function in type 2 diabetes after a six month liraglutide treatment. AB - AIMS: To investigate whether liraglutide improves diastolic function in type 2 diabetes. METHODS: Thirty-seven patients with type 2 diabetes who began liraglutide therapy between June 2013 and May 2014 were enrolled in this observational, prospective study. 26 patients received liraglutide therapy for at least 6months. The remaining 11 patients withdrew from liraglutide therapy during the first month, were started on other hypoglycaemic therapies and formed the control group. Anthropometric, metabolic and echocardiographic parameters including pulsed wave tissue Doppler imaging were evaluated at baseline and at 6months. RESULTS: In the liraglutide group the early diastolic mitral annulus velocity on the lateral (e-lat) and medial (e-med) sides of the mitral annulus increased from 9.2+/-3.4 to 11.6+/-4.7cm/s (p<0.001) and from 6.9+/-1.7 to 8.4+/ 2.6cm/s (p<0.003), respectively. The ratio of early-to-late velocities on the lateral and medial sides of the mitral annulus increased from 0.7+/-0.3 to 0.9+/ 0.4 (p<0.001) and from 0.5+/-0.1 to 0.6+/-0.1 (p<0.02), respectively. The ratio of early diastolic mitral inflow velocity to early diastolic myocardial relaxation velocity decreased from 10.7+/-4.3 to 8.5+/-2.5 (p<0.005). No improvements in diastolic function was detected in the control group. Glucose control improved similarly in both groups: HA1bc -1.5% (-17mmol/mol) vs -1.3% ( 14mmol/mol), p=0.67. CONCLUSIONS: In patients with type 2 diabetes, 6months liraglutide treatment was associated with a significant improvement in diastolic function. PMID- 27485854 TI - Application of the limited-memory quasi-Newton algorithm for multi-dimensional, large flip-angle RF pulses at 7T. AB - OBJECTIVE: Ultrahigh field MRI provides great opportunities for medical diagnostics and research. However, ultrahigh field MRI also brings challenges, such as larger magnetic susceptibility induced field changes. Parallel-transmit radio-frequency pulses can ameliorate these complications while performing advanced tasks in routine applications. To address one class of such pulses, we propose an optimal-control algorithm as a tool for designing advanced multi dimensional, large flip-angle, radio-frequency pulses. We contrast initial conditions, constraints, and field correction abilities against increasing pulse trajectory acceleration factors. MATERIALS AND METHODS: On an 8-channel 7T system, we demonstrate the quasi-Newton algorithm with pulse designs for reduced field-of-view imaging with an oil phantom and in vivo with scans of the human brain stem. We used echo-planar imaging with 2D spatial-selective pulses. Pulses are computed sufficiently rapid for routine applications. RESULTS: Our dataset was quantitatively analyzed with the conventional mean-square-error metric and the structural-similarity index from image processing. Analysis of both full and reduced field-of-view scans benefit from utilizing both complementary measures. CONCLUSION: We obtained excellent outer-volume suppression with our proposed method, thus enabling reduced field-of-view imaging using pulse trajectory acceleration factors up to 4. PMID- 27485856 TI - Corrigendum. PMID- 27485855 TI - Rhizophagus irregularis as an elicitor of rosmarinic acid and antioxidant production by transformed roots of Ocimum basilicum in an in vitro co-culture system. AB - Arbuscular mycorrhiza is a symbiotic association formed between plant roots and soil borne fungi that alter and at times improve the production of secondary metabolites. Detailed information is available on mycorrhizal development and its influence on plants grown under various edapho-climatic conditions, however, very little is known about their influence on transformed roots that are rich reserves of secondary metabolites. This raises the question of how mycorrhizal colonization progresses in transformed roots grown in vitro and whether the mycorrhizal fungus presence influences the production of secondary metabolites. To fully understand mycorrhizal ontogenesis and its effect on root morphology, root biomass, total phenolics, rosmarinic acid, caffeic acid and antioxidant production under in vitro conditions, a co-culture was developed between three Agrobacterium rhizogenes-derived, elite-transformed root lines of Ocimum basilicum and Rhizophagus irregularis. We found that mycorrhizal ontogenesis in transformed roots was similar to mycorrhizal roots obtained from an in planta system. Mycorrhizal establishment was also found to be transformed root line specific. Colonization of transformed roots increased the concentration of rosmarinic acid, caffeic acid and antioxidant production while no effect was observed on root morphological traits and biomass. Enhancement of total phenolics and rosmarinic acid in the three mycorrhizal transformed root lines was found to be transformed root line-specific and age dependent. We reveal the potential of R. irregularis as a biotic elicitor in vitro and propose its incorporation into commercial in vitro secondary metabolite production via transformed roots. PMID- 27485857 TI - Nano-structured interface of graphene and h-BN for sensing applications. AB - The atomically-precise controlled synthesis of graphene stripes embedded in hexagonal boron nitride opens up new possibilities for the construction of nanodevices with applications in sensing. Here, we explore properties related to the electronic structure and quantum transport of a graphene nanoroad embedded in hexagonal boron nitride, using a combination of density functional theory and the non-equilibrium Green's functions method to calculate the electric conductance. We find that the graphene nanoribbon signature is preserved in the transmission spectra and that the local current is mainly confined to the graphene domain. When a properly sized nanopore is created in the graphene part of the system, the electronic current becomes restricted to a carbon chain running along the border with hexagonal boron nitride. This circumstance could allow the hypothetical nanodevice to become highly sensitive to the electronic nature of molecules passing through the nanopore, thus opening up ways to detect gas molecules, amino acids, or even DNA sequences based on a measurement of the real-time conductance modulation in the graphene nanoroad. PMID- 27485858 TI - Chemical conversion of mouse fibroblasts into functional dopaminergic neurons. AB - Ectopic expression of lineage-specific transcription factors facilitates the conversion of mammalian somatic cells into dopaminergic (DA) neurons, which is a promising strategy for cell therapy of Parkinson's disease (PD). However, this approach still has some drawbacks limiting its clinical application due to the potential risks of integrating vectors into the host genome. Therefore, it is critical to seek a more desired approach to generate DA neurons derived from mammalian somatic cells. Here, we report that mouse embryonic fibroblasts (MEFs) can be efficiently converted into DA neurons by using small molecules along with specific growth factors. These neuron-like cells generate DA neuronal morphology, and acquire immunocytochemical and calcium imaging special for neuronal electrophysiological profile. More importantly, these converted cells can secrete dopamine, indicating that they are functionally similar to DA neurons. Taken together, our study might provide a promising cell source for treating PD by using chemical approach without introduction of exogenous transcription factors. PMID- 27485859 TI - A review on architecture of the gag-pol ribosomal frameshifting RNA in human immunodeficiency virus: a variability survey of virus genotypes. AB - Programmed '-1' ribosomal frameshifting is necessary for expressing the pol gene overlapped from a gag of human immunodeficiency virus. A viral RNA structure that requires base pairing across the overlapping sequence region suggests a mechanism of regulating ribosome and helicase traffic during expression. To get precise roles of an element around the frameshift site, a review on architecture of the frameshifting RNA is performed in combination of reported information with augments of a representative set of 19 viral samples. In spite of a different length for the viral RNAs, a canonical comparison on the element sequence allocation is performed for viewing variability associations between virus genotypes. Additionally, recent and historical insights recognized in frameshifting regulation are looked back as for indel and single nucleotide polymorphism of RNA. As specially noted, structural changes at a frameshift site, the spacer sequence, and a three-helix junction element, as well as two Watson Crick base pairs near a bulge and a C-G pair close a loop, are the most vital strategies for the virus frameshifting regulations. All of structural changes, which are dependent upon specific sequence variations, facilitate an elucidation about the RNA element conformation-dependent mechanism for frameshifting. These facts on disrupting base pair interactions also allow solving the problem of competition between ribosome and helicase on a same RNA template, common to single-stranded RNA viruses. In a broad perspective, each new insight of frameshifting regulation in the competition systems introduced by the RNA element construct changes will offer a compelling target for antiviral therapy. PMID- 27485860 TI - Communication and Exchange of Specialized Health-Related Support Among People With Experiential Similarity on Facebook. AB - Social support is an important factor that shapes how people cope with illness, and health-related communication among peers managing the same illness (network ties with experiential similarity) offers specialized information, resources, and emotional support. Facebook has become a ubiquitous part of many Americans' lives, and may offer a way for patients and caregivers experiencing a similar illness to exchange specialized health-related support. However, little is known about the content of communication among people who have coped with the same illness on personal Facebook pages. We conducted a content analysis of 12 months of data from 18 publicly available Facebook pages hosted by parents of children with acute lymphoblastic leukemia, focusing on communication between users who self-identified as parents of pediatric cancer patients. Support exchanges between users with experiential similarity contained highly specialized health related information, including information about health services use, symptom recognition, compliance, medication use, treatment protocols, and medical procedures. Parents also exchanged tailored emotional support through comparison, empathy, encouragement, and hope. Building upon previous research documenting that social media use can widen and diversify support networks, our findings show that cancer caregivers access specialized health-related informational and emotional support through communication with others who have experienced the same illness on personal Facebook pages. These findings have implications for health communication practice and offer evidence to tailor M-Health interventions that leverage existing social media platforms to enhance peer support for patients and caregivers. PMID- 27485861 TI - Association Between Nutritional Status, Inflammatory Condition, and Prognostic Indexes with Postoperative Complications and Clinical Outcome of Patients with Gastrointestinal Neoplasia. AB - The aim of this study is to describe and relate nutritional and inflammatory status and prognostic indexes with postoperative complications and clinical outcome of patients with gastrointestinal malignancies. Twenty-nine patients were evaluated; nutritional assessment was carried out by subjective and objective parameters; albumin, pre-albumin, C-reactive protein (CRP), and alpha-1-acid glycoprotein (AGP) were determined. To assess prognosis, the Glasgow scale, the Prognostic Inflammatory Nutritional Index (PINI), and CRP/albumin ratio were used; the clinical outcomes considered were hospital discharge and death. A high Subjective Global Assessment (SGA) score was associated with the occurrence of postoperative complications: 73% of the patients with postoperative complications had the highest SGA score, but only 6% of those without postoperative complications had the highest SGA score (P < 0.001). Greater occurrence of death was observed in patients with a high SGA score, low serum albumin, increased CRP, PINI > 1, and Glasgow score 2. There was a positive correlation between weight loss percentage with serum CRP levels (P = 0.002), CRP/albumin (P = 0.002), PINI (P = 0.002), and Glasgow score (P = 0.000). This study provides evidence that the assessment of the nutritional status and the use of prognostic indexes are good tools for predicting postoperative complications and clinical outcome in patients with gastrointestinal neoplasia. PMID- 27485863 TI - [A brief introduction to the disease-syndrome names in bamboo slips of Qin Dynasty]. AB - There are plenty of names of disease-syndrome from the four kinds of unearthed Qin bamboo slips, namely Fangmatan, Shuihudi, Zhoujiatai, and Liye. Altogether, these names number to 85. According to statistics, nomenclature of 34 disease syndromes are derived from the location of the lesion, 8 from symptoms, 1 from etiology, 12 from location of lesion plus symptom, 3 from location plus etiology, and 25 are for special diseases. Through comparison of these names, with those from oracle bones and Han bamboo slips, Prescriptions for Hundred Kinds of Disease, it is summarized that, as time passes, nomenclature simply named by the location of the lesion was gradually reduced, and named by etiology and special diseases gradually increased. To some extent, it reflects the historical process of knowledge of the disease gradually deepened in ancient times. PMID- 27485864 TI - [Evolution of the Origin of Herba Schizonepetae]. AB - Herba Schizonepetae was firstly recorded in the Sheng nong ben caojing (Shennong's Materia Medica) with the title Jiasu. It could be sure that the original plant of Jiasu is Ocimumbasilicum L. ofLabiatae based on the record of Jiasu's name, morphology, edible property before the Song Dynasty. Beginning from the Ben cao tu jing (Illustrated Classic of Materia Medica) in the Song Dynasty, the source of this drug evolved as SchizonepetatenuisfoliaBriq. ofLabiatae, and it has been in use until now. Hence, the sources of Jiasu should be both O. basilicum L. and the co-existence of S. tenuisfolia Briq in the Qing Dynasty. It is claimed that the hometowns of those herb writers who considered the source ofOcimumbasilicum L. to be the producing areas of cultivation of the edible Ocimumbasilicum L. It was found that the source of Jiasu recorded in the Sheng nong ben cao jing should be O. basilicum L. , hence, it is suggested the title Jiasu should be recorded for the source of O. basilicum L, and the original plant of Herba Schizonepetae was Schizonepetatenuisfolia Briq. of Labiatae, and this medicine should be separately recorded. In fact, Jiasu and Herba Schizonepetae were two different kinds of medicines. PMID- 27485862 TI - Fusion to a homo-oligomeric scaffold allows cryo-EM analysis of a small protein. AB - Recent technical advances have revolutionized the field of cryo-electron microscopy (cryo-EM). However, most monomeric proteins remain too small (<100 kDa) for cryo-EM analysis. To overcome this limitation, we explored a strategy whereby a monomeric target protein is genetically fused to a homo-oligomeric scaffold protein and the junction optimized to allow the target to adopt the scaffold symmetry, thereby generating a chimeric particle suitable for cryo-EM. To demonstrate the concept, we fused maltose-binding protein (MBP), a 40 kDa monomer, to glutamine synthetase, a dodecamer formed by two hexameric rings. Chimeric constructs with different junction lengths were screened by biophysical analysis and negative-stain EM. The optimal construct yielded a cryo-EM reconstruction that revealed the MBP structure at sub-nanometre resolution. These findings illustrate the feasibility of using homo-oligomeric scaffolds to enable cryo-EM analysis of monomeric proteins, paving the way for applying this strategy to challenging structures resistant to crystallographic and NMR analysis. PMID- 27485865 TI - [A brief history of traditional Chinese medicinal pills]. AB - Traditional Chinese medicine pill, an archaic medicinal preparation form, is a kind of spherical or spherical-like preparation form produced by medicinal powders or extracts mixed with appropriate excipient or other accessories. It was originated in the Pre-Qin Dynasty, developed and enriched from the Han Dynasty to the Ming and Qing Dynasties. With the improvement of preparing process, honeyed pill, waxed pill, coating pill and wax-coating pill etc. appeared in succession. In modern times, with the progress of pharmaceutical machine, the medicinal pill is innovated constantly, and at present, it becomes the main form of Chinese patent medicine with batch production. PMID- 27485866 TI - [Historical textual research on Shan biandou with discussion on the misnaming of plant title]. AB - The original plants of Shan biandou, first seen in Jiu huang ben cao (Materia Medica for Relief of Famines), include the plants of Astragalusgenus, such as A. scaberrimus and/or A. complanatus in the Ming and Qing Dynasties. But Cassia mimosoides was named as Shan biandou by Japanese scholars in the 19th century. This mistaken identification and misnaming, still in use today in Chinese and Japanese circles of botany and materia medica, did cause some confusion. The merits and demerits of using the plant names in Chinese characters from the Japanese language by Chinese botanists were analyzed, the disadvantages of which should be well avoided. Because of the vicissitude in the names of plants and Chinese herbs, it is necessary to strengthen the study and develop the significant value of A. complanatus and C. mimosoides in health care so as to promote its contributions to the cause of TCM. PMID- 27485867 TI - [Military medical and health care system in the Song Dynasty]. AB - The military medical and health care system in the Song Dynasty manifested as two aspects, namely disease prevention and medical treatment. Disease prevention included ensuring food and drink safety, avoiding dangerous stations and enjoying regular vacations, etc. Medical treatment included sending medical officials to patrol, stationing military physicians to follow up, applying emergency programs, establishing military medical and pharmacy centers, dispensing required medicines, and accommodating and nursing sick and injured personnel, etc. Meanwhile, the imperial court also supervised the implementation of military medical mechanism, in order to check the soldiers' foods, check and restrict the military physicians' responsibilities, etc., which did play a positive role in protecting soldier's health, guaranteeing the military combat effectiveness, and maintaining national security. PMID- 27485868 TI - [Using Guangming (GB37) acupoint to treat eye diseases: from historical suspense to modern clinical experiments]. AB - Guangming (GB37) gained its name before the writing of Huang di Ming Tang Jing (The Yellow Emperor's Mingtang Classic), the earliest work of the art of acupuncture point. However, in acupuncture and moxibustion works before the Song Dynasty, this acupoint was not used to treat eye diseases. In Dou Hanqing's Zhen jiu biao you fu (Song to Elucidate Mysteries in Acupuncture Moxibustion), Guangming was used to treat oculopathy as an alias of Cuanzhu (BL2). Influenced by this, the alias "Guangming" was mistaken as Guangming (GB37) of the Gallbladder Meridian in the Bian que shen ying zhen jiu yu long jing (Bian Que Acupuncture and Moxibustion Jade Dragon Classic) of the Yuan Dynasty, and the symptom of eye itch was added to the indications of Guangming (GB37). This was wrongly informed in the later acupuncture and moxibustion works, and the modern scholars also accepted it and confirmed its effect by the clinical and experimental research. PMID- 27485869 TI - [Changes of career of traditional Chinese medicine in Hong Kong Donghua Hospital in modern times]. AB - Founded in 1872, the Hong Kong Donghua Hospital (Tung Wah Group of Hospitals later) was the earliest traditional Chinese hospital in modern times, which has made positive contributions in exploring the shape and structure of TCM hospital and promoting science of TCM in Hong Kong. Unfortunately, TCM didn't acquire a legal status in Hong Kong, the practice of TCM in Donghua Hospital was thus restricted by the government, and ultimately, it changed into a comprehensive hospital mainly use western medicine. The change of TCM business in Hong Kong Donghua Hospital reflected the problems and situation of traditional Chinese medicine encountered in modern times. PMID- 27485870 TI - [Health Station, a product of combining the ideas of public health with the modern Chinese national conditions]. AB - The Health Station was a local health organization founded by the pioneers of the public health in modern China under the national conditions of "poverty, ignorance, illness and selfishness" , being the result of combining the ideas of public health with the Chinese national conditions of modern times. Though this organization appeared in backward modern China, it was advanced all over the world. John Grant was the planner of the Peiping First Health Station, whereas Li Ting'an, its builder. PMID- 27485871 TI - [Decipherment and annotation of a manuscript of Tibetan medicine in Dunhuang scroll (Part I)-on pulse-taking]. AB - A manuscript of Tibetan medicine, P. t.1054 is recorded in the Volume 10 of Dunhuang Tibetan Manuscripts Preserved in France, which is written in 4 pattra leaf-like rectangular papers connected together. The content in the front side is the pulse-taking of Tibetan medicine, and the back, on prescription. For the pulse-taking, it deals with the manifestations, time and position for pulse taking, paradoxical and death pulse. There is no information about the title, author, editor, translator, copyist or collector. PMID- 27485872 TI - [Review and reflection of the research of history of plague in modern China in recent 25 years]. AB - Influenced by the research on history of disease abroad, the research on the history of plague in modern China began in 1989. For the recent 25 years, the related researches on plague mainly took place in Guangzhou, Hong Kong, the Northeast and Shanxi, supplemented by other places, showing its clear regional characteristic, with diversified research views, methods and application of materials. As an important content of research on disease history, the research of history of plague in modern China revealed obvious defects, viz. mainly traditional and one-way or linear research, reflecting the research was still at the borderland. Of late years, some scholars began to break through the limitation of traditional historical concept and method, and try to apply the interdisciplinary view for widening the research scope. With the promotion of this academic concept, the research of plague history began " to regard history by a bottom-up approach" , and paid more attention to the living space. PMID- 27485873 TI - Remote care of a patient with stroke in rural Trinidad: use of telemedicine to optimise global neurological care. AB - We report a patient driven home care system that successfully assisted 24/7 with the management of a 68-year-old woman after a stroke-a global illness. The patient's caregiver and physician used computer devices, smartphones and internet access for information exchange. Patient, caregiver, family and physician satisfaction, coupled with outcome and cost were indictors of quality of care. The novelty of this basic model of teleneurology is characterised by implementing a patient/caregiver driven system designed to improve access to cost-efficient neurological care, which has potential for use in primary, secondary and tertiary levels of healthcare in rural and underserved regions of the world. We suggest involvement of healthcare stakeholders in teleneurology to address this global problem of limited access to neurological care. This model can facilitate the management of neurological diseases, impact on outcome, reduce frequency of consultations and hospitalisations, facilitate teaching of healthcare workers and promote research. PMID- 27485874 TI - Factors affecting illness in the developing world: chronic disease, mental health and traditional medicine cures. AB - This is a case report of a 24-year-old Ethiopian woman with a medical history of hepatosplenic schistosomiasis. She suffers from chronic liver failure and portal hypertension. She has been hospitalised for 'hysteria' in the past but did not receive follow-up, outpatient treatment or psychiatric evaluation. After discontinuing her medications and leaving her family to use holy water, a religious medicine used by many Ethiopians, she was found at a nearby monastery. She was non-communicative and difficult to arouse. The patient was rushed to nearby University of Gondar Hospital where she received treatment for hepatic encephalopathy and spontaneous bacterial peritonitis. Her illness is the result of neglected tropical disease, reliance on traditional medicine as opposed to biomedical services and the poor state of psychiatric care in the developing world. PMID- 27485875 TI - Graft-versus-host disease: unexpected presentation with simultaneous hepatitis and pancreatitis. AB - We report the case of a 37-year-old man with a previous bone marrow transplantation presenting with abdominal pain, diarrhoea and jaundice. Laboratory evaluation showed marked elevated liver enzymes, amylase and lipase with ultrasonographic evidence of acute alithiasic pancreatitis. Liver biopsy was compatible with graft-versus-host disease and toxic hepatitis. The patient rapidly improved after increasing immunosuppression. Although gastrointestinal manifestations are common in graft-versus-host disease, clinical acute pancreatitis is rarely seen. Patients with graft versus host are seldom managed by gastroenterologists and hepatologists. An awareness of this condition is essential for the experienced clinician. PMID- 27485876 TI - Jejunal intussusception caused by metastasis of a giant cell carcinoma of the lung. AB - A 55-year-old woman was admitted to our hospital reporting of nausea, vomiting and anorexia. One month before admission, she had been diagnosed with lung cancer with intestinal metastasis. A CT scan confirmed intussusception due to intestinal metastasis and she underwent emergency laparoscopic surgery followed by resection of the primary lung cancer. Histopathological findings of the intestinal specimen suggested the metastasis was from a giant cell carcinoma of the lung, which had extensive necrosis. She was still alive without recurrence 11 months after the first surgery. Giant cell carcinoma of the lung is a rare type of non-small cell carcinoma and intestinal metastasis is one of the unique features. This type of tumour has such aggressive characteristics that oncological prognosis is reported to be extremely poor. In our case, however, complete surgical resection of both primary and metastatic tumours might result in a better outcome than has been reported. PMID- 27485877 TI - Ultrastructural pathology of human liver in Rift Valley fever. AB - Rift Valley fever (RVF) is a zoonotic disease that primarily affects ruminant animals and can also cause fatal disease in humans. In the current report, we present the ultrastructural changes in the liver of a man aged 60 years who died from RVF in the Aseer Central Hospital, Abha, Saudi Arabia. The main hepatic changes by transmission electron microscopy included the presence of 95-115 nm electron-dense particles consistent with RVF virions, nuclear condensation, vacuolar degeneration, lipid droplet accumulation and mitochondrial damage and dilation. There were also viral inclusion bodies with electron-dense aggregates, dilation of intercellular spaces, damage of sinusoidal microvilli with widening of space of Disse, dilation of bile canaliculi and increasing number of phagolysosomes. PMID- 27485878 TI - Recurrent SDSE bacteraemia resulting in streptococcal toxic shock syndrome in a patient with Noonan syndrome. AB - A 19-year-old man with chronic lymphoedema due to Noonan syndrome presented at our hospital with septic shock and pain in his lower leg. Blood cultures were positive for Streptococcus dysgalactiae subsp equisimilis (SDSE), resulting in a diagnosis of cellulitis with toxic involvement. He was treated with ampicillin for 3 weeks. Although he did well for 6 weeks, septic shock recurred. Blood culture again revealed SDSE, with the strain being identical to the first episode, suggesting that this infection had relapsed. He was treated with ampicillin for 6 weeks and prophylactically with trimethoprim-sulfamethoxazole for 12 months. Although SDSE bacteraemia occurs commonly in elderly patients, findings in this patient showed that it can also develop in younger persons with predisposing factors. This case also indicates that SDSE has the potential to recur, despite generally sufficient antibiotic administration, and that patients who experience recurrent episodes may require prolonged treatment with antibiotics, including prophylaxis. PMID- 27485879 TI - Ileal perforation associated with dengue in the paediatric age group: an uncommon presentation. AB - Acute abdomen in dengue, a common arboviral disease found in tropical and subtropical countries, is not uncommon and can occasionally present as acute surgical emergency requiring urgent surgical intervention. The spectrum of acute abdomen presenting as surgical emergency in dengue infection that raises suspicion of an abdominal catastrophe includes acute appendicitis, acute cholecystitis, appendicitis and, rarely, intestinal perforation. All cases of intestinal perforation including appendicular, gastric and jejunal perforation have been reported in adult patients during the course of dengue infection. However, intestinal perforation during the course of dengue infection in the paediatric age group has never been reported. We report two cases of ileal perforation in children occurring during the course of dengue infection. PMID- 27485880 TI - Idelalisib-induced pneumonitis. PMID- 27485881 TI - Chemical Genetics Uncovers Novel Inhibitors of Lignification, Including p Iodobenzoic Acid Targeting CINNAMATE-4-HYDROXYLASE. AB - Plant secondary-thickened cell walls are characterized by the presence of lignin, a recalcitrant and hydrophobic polymer that provides mechanical strength and ensures long-distance water transport. Exactly the recalcitrance and hydrophobicity of lignin put a burden on the industrial processing efficiency of lignocellulosic biomass. Both forward and reverse genetic strategies have been used intensively to unravel the molecular mechanism of lignin deposition. As an alternative strategy, we introduce here a forward chemical genetic approach to find candidate inhibitors of lignification. A high-throughput assay to assess lignification in Arabidopsis (Arabidopsis thaliana) seedlings was developed and used to screen a 10-k library of structurally diverse, synthetic molecules. Of the 73 compounds that reduced lignin deposition, 39 that had a major impact were retained and classified into five clusters based on the shift they induced in the phenolic profile of Arabidopsis seedlings. One representative compound of each cluster was selected for further lignin-specific assays, leading to the identification of an aromatic compound that is processed in the plant into two fragments, both having inhibitory activity against lignification. One fragment, p iodobenzoic acid, was further characterized as a new inhibitor of CINNAMATE 4 HYDROXYLASE, a key enzyme of the phenylpropanoid pathway synthesizing the building blocks of the lignin polymer. As such, we provide proof of concept of this chemical biology approach to screen for inhibitors of lignification and present a broad array of putative inhibitors of lignin deposition for further characterization. PMID- 27485884 TI - Appropriate methods to study health treatment outcomes, policies, and practices. PMID- 27485883 TI - Evolutionary Fates and Dynamic Functionalization of Young Duplicate Genes in Arabidopsis Genomes. AB - Gene duplication is a primary means to generate genomic novelties, playing an essential role in speciation and adaptation. Particularly in plants, a high abundance of duplicate genes has been maintained for significantly long periods of evolutionary time. To address the manner in which young duplicate genes were derived primarily from small-scale gene duplication and preserved in plant genomes and to determine the underlying driving mechanisms, we generated transcriptomes to produce the expression profiles of five tissues in Arabidopsis thaliana and the closely related species Arabidopsis lyrata and Capsella rubella Based on the quantitative analysis metrics, we investigated the evolutionary processes of young duplicate genes in Arabidopsis. We determined that conservation, neofunctionalization, and specialization are three main evolutionary processes for Arabidopsis young duplicate genes. We explicitly demonstrated the dynamic functionalization of duplicate genes along the evolutionary time scale. Upon origination, duplicates tend to maintain their ancestral functions; but as they survive longer, they might be likely to develop distinct and novel functions. The temporal evolutionary processes and functionalization of plant duplicate genes are associated with their ancestral functions, dynamic DNA methylation levels, and histone modification abundances. Furthermore, duplicate genes tend to be initially expressed in pollen and then to gain more interaction partners over time. Altogether, our study provides novel insights into the dynamic retention processes of young duplicate genes in plant genomes. PMID- 27485882 TI - Auxin Is Rapidly Induced by Herbivore Attack and Regulates a Subset of Systemic, Jasmonate-Dependent Defenses. AB - Plant responses to herbivore attack are regulated by phytohormonal networks. To date, the role of the auxin indole-3-acetic acid (IAA) in this context is not well understood. We quantified and manipulated the spatiotemporal patterns of IAA accumulation in herbivore-attacked Nicotiana attenuata plants to unravel its role in the regulation of plant secondary metabolism. We found that IAA is strongly, rapidly, and specifically induced by herbivore attack. IAA is elicited by herbivore oral secretions and fatty acid conjugate elicitors and is accompanied by a rapid transcriptional increase of auxin biosynthetic YUCCA-like genes. IAA accumulation starts 30 to 60 s after local induction and peaks within 5 min after induction, thereby preceding the jasmonate (JA) burst. IAA accumulation does not require JA signaling and spreads rapidly from the wound site to systemic tissues. Complementation and transport inhibition experiments reveal that IAA is required for the herbivore-specific, JA-dependent accumulation of anthocyanins and phenolamides in the stems. In contrast, IAA does not affect the accumulation of nicotine or 7-hydroxygeranyllinalool diterpene glycosides in the same tissue. Taken together, our results uncover IAA as a rapid and specific signal that regulates a subset of systemic, JA-dependent secondary metabolites in herbivore attacked plants. PMID- 27485885 TI - Sex and gender matters: The health of women and girls determines the health of our modern world. PMID- 27485886 TI - Origins of Dirac cones and parity dependent electronic structures of alpha graphyne derivatives and silagraphynes. AB - Compared with graphene, graphyne and its derivatives possess more diversified atomic configurations and richer electronic structures including Dirac cones (DCs) and metallic features depending on the parity of the number of sp carbon atoms of graphynes. This report described conceptually the process of DC formation of alpha-graphyne within a tight-binding framework parameterized from density functional calculations. We propose a "triple coupling" mechanism elucidating the DC formation and some flat bands of alpha-graphynes where the couplings among the three sp carbon chain atoms are critical. The extension of this mechanism further explains the origins of DCs of silagraphynes and the parity dependent electronic structures of alpha-graphyne derivatives with extended sp carbon chains. Understanding these origins helps in tuning electronic properties in the design of C or C-Si based nanoelectronic devices. PMID- 27485888 TI - In Memoriam: Prof. Dr. Joachim K. Seydel. PMID- 27485887 TI - Effect of long-range interactions on nanoparticle-induced aggregation. AB - The process of attaching liquid media molecules to dispersed nanoparticles is studied by numerically investigating the time evolution of the size distribution of the emerging aggregates. Within the considered mechanism of aggregation, both the primary particles and the resulting aggregates are assumed to connect freely dispersing molecules, but the particles and aggregates are not allowed to self link or self-assemble at each evolution stage of the system, due to, e.g., repulsive interactions. The process of random attachment of dispersing molecules to immersed nanoparticles and aggregates is considered to be driven by attractive long-range interactions of the van der Waals type. The molecule binding rate is, in consequence, modeled as being dependent not only on the size and surface morphology of the existing aggregates, but also on the van der Waals forces, whose strength is itself treated as dependent on the aggregate size. It is demonstrated that these forces diminish, in general, the inhomogeneity of aggregate size. Such an effect is shown to be especially distinct when the interaction strength is relatively large but does not increase as aggregates increase in size, i.e., when strongly attracted media molecules functionalize the resultant aggregates to prevent the increase of the interaction strength. This result can be helpful to construct stable complex substances containing aggregates with low size dispersion. Surprisingly, the evolution of aggregating systems toward more significant inhomogeneity takes place when the interaction strength is initially large and increases fast enough with the size of aggregates. PMID- 27485889 TI - BCRP Inhibition: from Data Collection to Ligand-Based Modeling. AB - Breast Cancer Resistance Protein (BCRP, gene ABCG2) is an efflux transporter from the ABC transporters family. It is known to be responsible for the multidrug resistance phenomenon observed in some cancers and is also involved in drug-drug interactions in the liver. Prediction and assessment of inhibition of BCRP is of great interest in the drug development process. This paper presents the largest open dataset currently available for BCRP inhibition, along with the methodology used to compile it. It contains 978 unique compounds with corresponding bioactivities, extracted from 47 studies. The presence of duplicates allowed us to set up thresholds on reported activities to obtain a labelled dataset suitable for learning classification models. Exploratory data analysis and predictive modelling lead to the identification of substructures important for inhibition. We find that the substructures that characterize inhibitors are in line with known SAR relationships of BCRP inhibitors, while the substructures characterizing the non-inhibitors are novel. PMID- 27485890 TI - Mining Molecular Pharmacological Effects from Biomedical Text: a Case Study for Eliciting Anti-Obesity/Diabetes Effects of Chemical Compounds. AB - In the pharmaceutical industry, efficiently mining pharmacological data from the rapidly increasing scientific literature is very crucial for many aspects of the drug discovery process such as target validation, tool compound selection etc. A quick and reliable way is needed to collect literature assertions of selected compounds' biological and pharmacological effects in order to assist the hypothesis generation and decision-making of drug developers. INFUSIS, the text mining system presented here, extracts data on chemical compounds from PubMed abstracts. It involves an extensive use of customized natural language processing besides a co-occurrence analysis. As a proof-of-concept study, INFUSIS was used to search in abstract texts for several obesity/diabetes related pharmacological effects of the compounds included in a compound dictionary. The system extracts assertions regarding the pharmacological effects of each given compound and scores them by the relevance. For each selected pharmacological effect, the highest scoring assertions in 100 abstracts were manually evaluated, i.e. 800 abstracts in total. The overall accuracy for the inferred assertions was over 90 percent. PMID- 27485891 TI - Discrete Derivatives for Atom-Pairs as a Novel Graph-Theoretical Invariant for Generating New Molecular Descriptors: Orthogonality, Interpretation and QSARs/QSPRs on Benchmark Databases. AB - This report presents a new mathematical method based on the concept of the derivative of a molecular graph (G) with respect to a given event (S) to codify chemical structure information. The derivate over each pair of atoms in the molecule is defined as ?G/?S(vi , vj )=(fi -2fij +fj )/fij , where fi (or fj ) and fij are the individual frequency of atom i (or j) and the reciprocal frequency of the atoms i and j, respectively. These frequencies characterize the participation intensity of atom pairs in S. Here, the event space is composed of molecular sub-graphs which participate in the formation of the G skeleton that could be complete (representing all possible connected sub-graphs) or comprised of sub-graphs of certain orders or types or combinations of these. The atom level graph derivative index, Deltai , is expressed as a linear combination of all atom pair derivatives that include the atomic nuclei i. Global [total or local (group or atom-type)] indices are obtained by applying the so called invariants over a vector of Deltai values. The novel MDs are validated using a data set of 28 alkyl alcohols and other benchmark data sets proposed by the International Academy of Mathematical Chemistry. Also, the boiling point for the alcohols, the adrenergic blocking activity of N,N-dimethyl-2-halo-phenethylamines and physicochemical properties of polychlorinated biphenyls and octanes are modeled. These models exhibit satisfactory predictive power compared with other 0-3D indices implemented successfully by other researchers. In addition, tendencies of the proposed indices are investigated using examples of various types of molecular structures, including chain-lengthening, branching, heteroatoms-content, and multiple bonds. On the other hand, the relation of atom-based derivative indices with (17) O NMR of a series of ethers and carbonyls reflects that the new MDs encode electronic, topological and steric information. Linear independence between the graph derivative indices and other 0-3D MDs is demonstrated by using principal component analysis on a dataset of 41 heterogeneous molecules. It is concluded that the graph derivative indices are independent indices containing important structural information to be used in QSPR/QSAR and drug design studies, and permit obtaining easier, more interpretable and robust mathematical models than the majority of those reported in the literature. PMID- 27485892 TI - Identification of Aurora-A Inhibitors by Ligand and Structure-Based Virtual Screening. AB - Aurora kinase A has been identified as one of the most attractive targets for cancer therapy because of its critical role in the regulation of the cell cycle. In order to identify active compounds with structural diversity we performed virtual screening. 3D-QSAR pharmacophore models were developed and the best model was used as a query for screening the databases. Ligand and structure-based virtual screening protocol was conducted sequentially by applying the common feature pharmacophore and molecular docking to discover potent Aurora-A inhibitors. A total of eighty-eight compounds were selected for the in vitro activities against various human cancer cell lines (DU145 and HT29). Considering the activity data, we have identified seven compounds to be considered for the next step, among which four compounds had high inhibition rate (above 50 %) at 10 uM with GI50 lower than 10 uM. Based on the cell line and enzyme assay (Aurora-A & B) result, these four compounds were used as template/query molecule for similarity search. The best result was obtained for similarity hit SH3. It had IC50 of 0.578 and 11.77 uM for Aurora-A and B respectively, which implies 20-fold selectivity over Aurora-B. The hits obtained from this screening scheme could be potential drug candidates after further optimization. PMID- 27485893 TI - TriClust: A Tool for Cross-Species Analysis of Gene Regulation. AB - We present a software tool, called TriClust, for multi-way analysis of gene expression data from paired conditions of multiple organisms. The analysis is based on a new concept called triclustering, which is an extension of biclustering over a third dimension that represents the organism where the microarray experiment is performed. TriClust provides a comprehensive analysis of co-regulated genes under a subset of experimental conditions over multiple organisms. The results are visualized using heat-maps and the Gene Ontology (GO) term enrichment statistics. The experimental results indicate that TriClust can successfully identify biologically significant triclusters and promote a useful tool for cross species analysis of gene regulation from microarray expression data. The statistical results suggest that, when available, triclustering on multi-organism data can result in better gene clusters in comparison to biclustering on single-organism data. The TriClust software is publicly available as a standalone program. PMID- 27485894 TI - Soluble Metal-Nanoparticle-Decorated Porous Coordination Polymers for the Homogenization of Heterogeneous Catalysis. AB - Ultrasmall metal nanoparticles (MNPs) were decorated on soluble porous coordination polymers (PCPs) with high metal loadings. The solubility of the composite and the size of the MNPs can be controlled by varying the ratio of the precursors to the supports. The soluble PCPs can serve as a platform to homogenize heterogeneous MNPs catalysts, which exhibited excellent activity and recyclability in C-H activation and Suzuki reactions. This strategy combines the advantages of homogeneous and heterogeneous catalysis and may bring new inspiration to catalysis. PMID- 27485895 TI - Adult orthodontics: a quality assessment of Internet information. AB - OBJECTIVES: This study evaluated the quality, reliability and readability of information on the Internet on adult orthodontics. DESIGN: A quality assessment of adult orthodontic websites. SETTING: Postgraduate Orthodontic Unit, Cork University Dental School and Hospital, Cork, Ireland. METHOD: An Internet search using three search engines (Google, Yahoo and Bing) was conducted using the terms ('adult orthodontics' and 'adult braces'). The first 50 websites from each engine and under each search term were screened and exclusion criteria applied. Included websites were then assessed for quality using four methods: the HON seal, JAMA benchmarks, the DISCERN instrument and the LIDA tool. Readability of included websites was assessed using the Flesch Reading Ease Score (FRES). RESULTS: Only 13 websites met the inclusion criteria. Most were of US origin (n = 8; 61%). The authors of the websites were dentists (n = 5; 39%), professional organizations (n = 2; 15%), past patients (n = 2; 15%) and unspecified (n = 4; 31%). Only 1 website displayed the HON seal and three websites contained all JAMA benchmarks. The mean overall score for DISCERN was 3.9/5 and the mean total LIDA score was 115/144. The average FRES score was 63.1/100. CONCLUSIONS: The number of informative websites on adult orthodontics is low and these are of moderate quality. More accurate, high-quality Internet resources are required on adult orthodontics. Recommendations are made as to how this may be achieved. PMID- 27485897 TI - Physical Activity Level and Colorectal Cancer Mortality. AB - Physical activity has been shown to reduce colorectal cancer risk. However, the association of physical activity levels separately with colon and rectum cancer mortality is less clear. We included 226 089 Korean in a large prospective cohort study. We assessed the associations of physical activity levels (length, frequency, and intensity) with colon and rectum cancer mortality using Cox proportional hazards model. Men, but not women, who had regular physical activity showed a lower risk of death from colon cancer. The association for high intensity of physical activity was borderline significant in men (hazard ratio 0.67; 95% CI = 0.45-1.00 for >17.5 MET-hour/week). The associations were largely consistent among those aged <55 years, body mass index <25 kg/m2, low high density lipoprotein cholesterol, current smoker, and without hypertension or history of cardiovascular disease. In conclusion, higher length or intensity of physical activity decreased colon, but not rectum cancer mortality in men. Regular physical activity may have beneficial effects on colon cancer survival. PMID- 27485896 TI - Effects of carbon sources on the enrichment of halophilic polyhydroxyalkanoate storing mixed microbial culture in an aerobic dynamic feeding process. AB - Microbial polyhydroxyalkanoate (PHA) production serves as a substitute for petroleum-based plastics. Enriching mixed microbial cultures (MMCs) with the capacity to store PHA is a key precursor for low-cost PHA production. This study investigated the impact of carbon types on enrichment outcomes. Three MMCs were separately fed by acetate sodium, glucose, and starch as an enriching carbon source, and were exposed to long-term aerobic dynamic feeding (ADF) periods. The PHA production capacity, kinetics and stoichiometry of the enrichments, the PHA composition, and the microbial diversity and community composition were explored to determine carbon and enrichment correlations. After 350-cycle enriching periods under feast-famine (F-F) regimes, the MMCs enriched by acetate sodium and glucose contained a maximum PHA content of 64.7% and 60.5% cell dry weight (CDW). The starch-enriched MMC only had 27.3% CDW of PHA. High-throughput sequencing revealed that non-PHA bacteria survived alongside PHA storing bacteria, even under severe F-F selective pressure. Genus of Pseudomonas and Stappia were the possible PHA accumulating bacteria in acetate-enriched MMC. Genus of Oceanicella, Piscicoccus and Vibrio were found as PHA accumulating bacteria in glucose enriched MMC. Vibrio genus was the only PHA accumulating bacteria in starch enriched MMC. The community diversity and composition were regulated by the substrate types. PMID- 27485898 TI - Diarrheal Diseases and Climate Change in Cambodia. AB - The DRIP-SWICCH (Developing Research and Innovative Policies Specific to the Water-related Impacts of Climate Change on Health) project aimed to increase the resilience of Cambodian communities to the health risks posed by climate change related impacts on water. This article follows a review of climate change and water-related diseases in Cambodia and presents the results of a time series analysis of monthly weather and diarrheal disease data for 11 provinces. In addition, correlations of diarrheal disease incidence with selected demographic, socioeconomic, and water and sanitation indicators are described, with results suggesting education and literacy may be most protective against disease. The potential impact of climate change on the burden of diarrheal disease in Cambodia is considered, along with the implications of these findings for health systems adaptation. PMID- 27485900 TI - Photoprotective properties of 20(S)-protopanaxatriol, an aglycone of ginseng saponins: Protection from ultraviolet-B radiation-induced oxidative stress in human epidermal keratinocytes. AB - Ginsenosides are responsible for diverse pharmacological properties ascribed to ginseng, a plant used in traditional medicine. Ginsenosides are classified into three categories: Protopanaxadiol, protopanaxatriol (PPT) and oleanolic acid. As an aglycone of PPT-type ginsenosides, PPT exists in two stereoisomeric forms, 20(S)-PPT and 20(R)-PPT. The 20(S)-PPT stereoisomer is a major metabolic product of PPT-type ginsenosides produced in the gastrointestinal tract. In the present study, 20(S)-PPT suppressed the elevation of reactive oxygen species in HaCaT cells following irradiation with ultraviolet (UV)-B. In addition, 20(S)-PPT inhibited UV-B-induced gelatinase activities of matrix metalloproteinase-2 and -9 in HaCaT cells, and suppressed UV-B-induced expression and secretion of these proteins. Accordingly, 20(S)-PPT restored the total glutathione levels in UV-B irradiated keratinocytes. Taken together, these data indicated that 20(S)-PPT may possess photoprotective properties that combat the effects of UV-B radiation. PMID- 27485901 TI - Connecting polyphosphate translocation and hyphal water transport points to a key of mycorrhizal functioning. PMID- 27485899 TI - Structural insights into the catalysis and regulation of E3 ubiquitin ligases. AB - Covalent attachment (conjugation) of one or more ubiquitin molecules to protein substrates governs numerous eukaryotic cellular processes, including apoptosis, cell division and immune responses. Ubiquitylation was originally associated with protein degradation, but it is now clear that ubiquitylation also mediates processes such as protein-protein interactions and cell signalling depending on the type of ubiquitin conjugation. Ubiquitin ligases (E3s) catalyse the final step of ubiquitin conjugation by transferring ubiquitin from ubiquitin conjugating enzymes (E2s) to substrates. In humans, more than 600 E3s contribute to determining the fates of thousands of substrates; hence, E3s need to be tightly regulated to ensure accurate substrate ubiquitylation. Recent findings illustrate how E3s function on a structural level and how they coordinate with E2s and substrates to meticulously conjugate ubiquitin. Insights regarding the mechanisms of E3 regulation, including structural aspects of their autoinhibition and activation are also emerging. PMID- 27485902 TI - 'Hide and seek' is no game in a specialized ant-plant interaction. PMID- 27485903 TI - Diversity of Frankia in soil assessed by Illumina sequencing of nifH gene fragments. AB - Targeted Illumina sequencing of nitrogenase reductase (nifH) gene fragments and analyses of pair-end reads through a modified QIIME pipeline were used to assess the diversity of the actinomyceteous genus Frankia in three soils. Soils were vegetated with host or non-host plants, and included locations in Illinois (ABA, host), Colorado (CoMt, non-host), and Wisconsin (FMWI, non-host). After filtering, seven unique sequences were recovered for soil ABA, six for CoMt, and four sequences for FMWI. These sequences were included in a Bayesian topology anchored by published sequence data from pure cultures of Frankia. Sequences from all three soils showed affinities to Frankia strains from both the Alnus and Elaeagnus host infection groups. Reads representing Casuarina-infective strains were not detected. Four sequences from soil CoMt and five sequences from soil ABA did not cluster, at 97% similarity, into a shared OTU that contained a cultured relative. These results demonstrate that targeted Illumina sequencing provides an efficient and economical method for assessing haplotype diversity of ecofunctional genes (e.g. nifH) at the genus level in microorganisms that perform important ecosystem functions. PMID- 27485904 TI - Diffuse subarachnoid and intraventricular hemorrhage as the presenting sign of a conus medullaris arteriovenous malformation: Case report. AB - Spinal arteriovenous malformations (AVMs) are rare vascular lesions that usually present with progressive myelopathy or less frequently, with acute neurological deficit due to hematomyelia or spinal subarachnoid hemorrhage (SAH). There are few reports of concomitant cerebral SAH and intraventricular hemorrhage (IVH) following rupture of a spinal AVM. Herein, we present a rare case of conus medullaris arteriovenous malformation, out-breaking with loss of consciousness due to SAH and IVH. PMID- 27485905 TI - Lysosome calcium in ROS regulation of autophagy. AB - Lysosomes, the cell's recycling center, undergo nutrient-sensitive adaptive changes in function and biogenesis, i.e., lysosomal adaptation. We recently discovered that lysosomes also mediate the cell's "survival" response (i.e., autophagy) to oxidative stress through the activation of TFEB (transcription factor EB), a master regulator of lysosome biogenesis and autophagy. MCOLN1/TRPML1, the principal Ca2+ release channel on the lysosomal membrane, serves as the redox sensor in this process. Increasing reactive oxygen species (ROS) levels, either endogenously by mitochondrial damage or exogenously, directly activates MCOLN1 to induce lysosomal Ca2+ release, triggering PPP3/calcineurin-dependent TFEB nuclear translocation to enhance autophagy. Hence, ROS may induce autophagy by activating the MCOLN1-lysosome Ca2+-TFEB pathway, facilitating the removal of damaged mitochondria and excess ROS. Our findings have revealed a lysosomal signaling mechanism for cells to respond to oxidative bursts and adapt to oxidative stress. PMID- 27485907 TI - 10th WINFOCUS World Congress on Ultrasound in Emergency and Critical Care. PMID- 27485906 TI - Nonsuicidal Self-Injury and Suicidal Risk Among Emerging Adults. AB - PURPOSE: Although nonsuicidal self-injury (NSSI) has been differentiated from suicidal behavior on the basis of nonlethal intent in the Diagnostic and Statistical Manual of Mental Disorders, NSSI often is associated with increased suicidal risk. However, there is a paucity of large-scale longitudinal examinations on the associations among NSSI, suicidal ideation, and suicidal attempts, particularly among community-based samples. In the present study, we examined whether NSSI in first-year university was associated with increased risk for later suicidal ideation and attempts over time among students. METHODS: Participants included 940 emerging adults (70.8% female, mean age = 19.05 years) from a mid-sized Canadian university who volunteered to participate in a longitudinal research project starting in first-year university (participants were surveyed annually over five waves). RESULTS: Binary logistic regression analyses revealed that the odds of experiencing suicidal ideation across times 2 5 were 2.04 times as high for emerging adults who engaged in NSSI at baseline (even after controlling for suicidal ideation and attempts at baseline) as for individuals who did not engage in NSSI. Furthermore, the odds of attempting suicide across times 2-5 were 3.46 times as high for emerging adults who engaged in NSSI at baseline (even after controlling for suicidal ideation and attempts at baseline) as for individuals who did not engage in NSSI. CONCLUSIONS: Findings suggest that the presence of NSSI in first-year university may be an important marker of later suicidal risk, reflecting increased risk for both suicidal ideation and attempts across the university years among emerging adults. PMID- 27485908 TI - JAN Classic article: Mental illness, mental handicap and the nursing service establishment - an alternative approach. PMID- 27485909 TI - Atmospheric thorium pollution and inhalation exposure in the largest rare earth mining and smelting area in China. AB - Exposure to radionuclide thorium (Th) has generated widespread public concerns, mainly because of its radiological effects on human health. Activity levels of airborne 232Th in total suspended particulate (TSP) were measured in the vicinity of the largest rare earth mine in China in August 2012 and March 2013. The mean activity concentrations of 232Th in TSP ranged from 820MUBqm-3 in a mining area in August 2012 to 39,720MUBqm-3 in a smelting area in March 2013, much higher than the world reference of 0.5MUBqm-3. Multistatistical analysis and Kohonen's self-organizing maps suggested that 232Th in TSP was mainly derived from rare earth mining and smelting practices. In addition, personal inhalation exposures to 232Th associated with respirable particulate (PM10) were also measured among local dwellers via personal monitoring. The mean dose values for different age groups in the smelting and mining areas ranged from 97.86 to 417MUSvyear-1 and from 101.03 to 430.83MUSvyear-1, respectively. These results indicate that people living in the study areas are exposed to high levels of widespread 232Th. PMID- 27485910 TI - Exposure to polybrominated diphenyl ethers and female reproductive function: A study in the production area of Shandong, China. AB - Polybrominated diphenyl ethers (PBDEs) are widely used in commercial and household products. Few human studies have examined the effects of PBDE exposure on female reproductive function. We recruited 207 pregnant women when they were admitted for labor from September 2010 to February 2012 as part of a birth cohort study, the Laizhou Wan Birth Cohort study. Maternal sera were analyzed for eight PBDE congeners (BDE-28, -47, -85, -99, -100, -153, -154, and -183) and four sex hormones. BDE-153 exhibited the highest serum level (median 4.67ng/g lipid), followed by BDE-99 (median 3.45ng/g lipid) and BDE-28, -47, and -100 (medians near 2ng/g lipid). BDE-28, -47, -99, -100, and -153 were the most frequently detected (>90%) congeners. Follicle-stimulating hormone (FSH) levels were negatively associated with PBDE exposure. For each natural log unit increase in BDE-47, 100, and ?5PBDEs, FSH levels changed -1.19IU/L (95% confidence interval [CI]: -1.32, -1.02), -1.17IU/L (95%CI: -1.36, -1.01) and -1.26IU/L (95%CI: -1.55, -1.02) respectively. BDE-85, -153, and -183 were associated with adverse reproductive effects, including an increased risk of threatened abortion (odds ratio [OR] [95% CI]: 1.30 [1.03, 1.62], 1.04 [1.01, 1.08], and 1.03 [1.01, 1.06], respectively). BDE-153 was associated with an increased risk of premature birth (adjusted OR [95% CI]:1.05 [1.01, 1.09]), and BDE-28 was associated with longer time to pregnancy (adjusted OR [95% CI]: 1.34 [1.03, 1.76]). These findings suggest that maternal PBDE exposure may be inversely associated with female reproductive function. PMID- 27485911 TI - Loneliness and related factors among people with schizophrenia in Japan: a cross sectional study. AB - WHAT IS KNOWN ABOUT THE SUBJECT?: Loneliness among people diagnosed with schizophrenia is a serious problem. Recent studies have focused on the loneliness; however, no study has examined the relationships between loneliness and both individual and environmental factors comprehensively. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: The main results indicated that the community dwelling people diagnosed with schizophrenia in Japan as well as in other countries experienced higher levels of loneliness. Both individual and environmental factors were related to loneliness. Increasing the self-efficacy for community life and self-esteem of individual factors, and not being socially isolated and increasing community integration of environmental factors would improve their loneliness. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Health practitioners, in particular, public health nurses in mental health care, should work to develop a partnership with people diagnosed with schizophrenia, their family members, friends and other community-dwelling people in order to decrease and prevent loneliness. For individuals diagnosed with schizophrenia, interventions by cooperating with community resources and using the technique of nurses to assist them with continuous community activity could be useful. For environmental interventions, population approach such as developing daily programmes which family members can participate in, and cooperating with educational institutions and community events could have a positive effects. ABSTRACT: Introduction Loneliness among people diagnosed with schizophrenia living in communities can decrease quality of life and may contribute to suicide. Aim The aim of this study was to examine the levels of loneliness among Japanese people diagnosed with schizophrenia and to identify individual and environmental factors related to their loneliness. Method A cross-sectional survey was conducted with 264 people diagnosed with schizophrenia who use local activity support centres in urban areas. The self-administered questionnaires included questions on loneliness, demographic characteristics, individual factors including self-efficacy for community life and self-esteem, and environmental factors including social isolation, community integration and service use. Results The study results indicated that people diagnosed with schizophrenia in Japan experience higher levels of loneliness, corroborating results from other countries. Multiple regression analysis showed that a lower level of self efficacy for community life, self-esteem, community integration and social isolation predicted a higher level of loneliness, accounting for 55.3% of variance. Implications for Practice Public health nurses in mental health care in Japan can work with individuals diagnosed with schizophrenia and communities using the technique to assist them with continuous activity and cooperating with community resources and educational institutions in order to decrease and prevent loneliness. PMID- 27485912 TI - Graphene oxide/ferroferric oxide/polyethylenimine nanocomposites for Congo red adsorption from water. AB - Graphene oxide/ferroferric oxide/polyethylenimine (GO/Fe3O4/PEI) nanocomposites were synthesized by an in situ growth of Fe3O4 nanoparticles on GO sheets, and then modified by PEI. The GO/Fe3O4/PEI nanocomposites showed extremely high removal efficiency for anionic dye Congo Red (CR) due to the positively charged PEI molecules (methylene blue was also tested but with low adsorption capacity due to its cationic property). The CR removal capacity was 574.7 mg g-1, higher than most of reported results. The adsorption kinetics could be well described by a pseudo-second-order model. Furthermore, GO/Fe3O4/PEI nanocomposites could be easily recycled by magnetic separation. The removal efficiency remained above 70% after five cycles. PMID- 27485914 TI - Regional three-dimensional deformation of human Achilles tendon during conditioning. AB - Our understanding of in vivo Achilles tendon (AT) conditioning is limited to two dimensional ultrasound measures of longitudinal deformation of the whole tendon. This study investigated the regional three-dimensional (3D) deformation of the AT during conditioning. Eighteen ATs were scanned using 3D freehand ultrasound during 10 successive 25 s submaximal (50%) voluntary isometric plantarflexion contractions. Longitudinal strain was assessed for the whole AT, aponeurosis, and free AT and transverse strain was assessed for the proximal-, mid-, and distal portions of the free AT. Longitudinal conditioning of the whole AT was primarily driven by creep response of the free AT and transverse conditioning was greatest for the mid-portion of the free AT. Whole and free AT longitudinal strain increased up to the third contraction and were accompanied by a corresponding reduction in free AT cross-sectional area (CSA) strain in proximal-, mid-, and distal-portions. No significant changes in aponeurosis strain or tendon volume were detected between contractions. These findings suggest that conditioning alters free AT shape, with increased tendon length attained at the expense of reduction in free AT CSA. Although AT experiences different amounts of strain in different regions, the number of contractions required to reach steady-state strain during conditioning is uniform throughout the tendon. PMID- 27485913 TI - Differences in fairness and trust between lean and corpulent men. AB - BACKGROUND: Employment disparities are known to exist between lean and corpulent people, for example, corpulent people are less likely to be hired and get lower wages. The reasons for these disparities between weight groups are not completely understood. We hypothesize (i) that economic decision making differs between lean and corpulent subjects, (ii) that these differences are influenced by peoples' blood glucose concentrations and (iii) by the body weight of their opponents. METHODS: A total of 20 lean and 20 corpulent men were examined, who performed a large set of economic games (ultimatum game, trust game and risk game) under euglycemic and hypoglycemic conditions induced by the glucose clamp technique. RESULTS: In the ultimatum game, lean men made less fair decisions and offered 16% less money than corpulent men during euglycemia (P=0.042). During hypoglycemia, study participants of both weight groups accepted smaller amounts of money than during euglycemia (P=0.031), indicating that a lack of energy makes subjects to behave more like a Homo Economicus. In the trust game, lean men allocated twice as much money to lean than to corpulent trustees during hypoglycemia (P<0.001). Risk-seeking behavior did not differ between lean and corpulent men. CONCLUSION: Our data show that economic decision making is affected by both, the body weight of the participants and the body weight of their opponents, and that blood glucose concentrations should be taken into consideration when analyzing economic decision making. When relating these results to the working environment, the weight bias in economic decision making may be also relevant for employment disparities. PMID- 27485915 TI - Mapping painDETECT, a neuropathic pain screening tool, to the EuroQol (EQ-5D-3L). AB - PURPOSE: To map relationships between painDETECT, a neuropathic pain (NeP) screening tool, and EQ-5D-3L health status in a real-world setting. METHODS: Patients with physician-confirmed NeP and painDETECT score classifications of nociceptive (n = 79), transitional (n = 141), and NeP (n = 386) completed the EuroQol (EQ-5D-3L), which evaluates Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression with three ordinal response levels ("no problem," "some problems," or "extreme problems/unable to do"), and has a health status thermometer (0 = worst health, 100 = perfect health). Multiple linear and logistic regressions were performed (adjusted for age, gender, race, ethnicity, time since NeP diagnosis, number of comorbidities, NeP conditions). RESULTS: Unadjusted mean (+/-SD) EQ-5D-3L thermometer scores showed poorer health status across painDETECT classifications from nociceptive (67.3 +/- 22.1) to transitional (62.3 +/- 20.9) to NeP (53.7 +/- 21.8), as did utility scores, 0.695 +/- 0.206, 0.615 +/- 0.216, and 0.506 +/- 0.216. In general, the highest odds of health problems were observed for NeP and the lowest for nociceptive, e.g., the NeP group was 6.2 (95 % confidence interval 3.4-11.4) times as likely to have a more severe problem of Usual Activities compared with the nociceptive group. Relative to nociceptive and transitional, NeP had lower adjusted mean thermometer scores, by 12.1 (P < 0.0001) and 7.8 (P = 0.0004) points, respectively, and lower mean utility scores by 0.157 (P < 0.0001) and 0.092 points (P < 0.0001). CONCLUSIONS: This study, the first to map relationships between painDETECT and the EQ-5D-3L in a real-world setting, indicates that the patient burden with respect to pain classification can be characterized and quantified by decrements in health status overall and in specific domains. These data support the psychometric soundness of painDETECT, enhancing its use in pain management. PMID- 27485916 TI - Autism spectrum disorder: family quality of life while waiting for intervention services. AB - PURPOSE: Families of children with autism spectrum disorder (ASD) often experience high levels of stress; it is important to investigate the family quality of life (FQOL) to understand how to serve the entire family, not just the child. The purpose of this investigation was to determine: (a) how families with a child with ASD view their overall FQOL and (b) what aspects of everyday life have the greatest influence on the FQOL? METHODS: A survey designed to asses FQOL was mailed to all families (n = 454) of children with ASD (0-18 years) waiting for government-funded services. Results from 151 surveys were examined (31 % response rate). Descriptive on all variables, ordinal logistic regression, and t tests were used to analyze the data. RESULTS: The most influential factors on FQOL were whether the child with ASD had a major health concern, whether the family's needs were met by disability-related services, and whether there were opportunities to engage in leisure and recreation activities. CONCLUSIONS: Families on waitlists experience challenges in FQOL influenced by the health of the family members; this is implicitly important for service agencies and providers. Future research should continue to explore how access to disability related services impacts FQOL; and how these associations may be moderated by contextual factors such as socioeconomic status, health of child and family members, access and engagement in recreation, and severity of the child's needs. PMID- 27485917 TI - Chemical Twinning of Salt and Metal in the Subnitridometalates Ba23 Na11 (MN4 )4 with M=V, Nb, Ta. AB - The subnitridometalates Ba23 Na11 (MN4 )4 (M=V, Nb, Ta) crystallize in a new structure type, which shows ionic ortho-nitridometalate anions and motifs from simple (inter)metallic packings: Na-centered [Na8 ] cubes as cutouts of the bcc structure of elemental Na and Na-centered [Ba10 Na2 ] icosahedra as found in Laves phases, for example. Single-crystal and powder X-ray diffraction studies in combination with quantum-chemical calculations of the electronic structure and Raman spectroscopy support the characterization of the subnitridometalates as "chemical twins". They consist of independent building units with locally prevalent ionic or metallic bonding in an overall metallic compound. PMID- 27485918 TI - Novel variant in the TP63 gene associated to ankyloblepharon-ectodermal dysplasia cleft lip/palate (AEC) syndrome. AB - BACKGROUND: Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome is a disorder resulting from anomalous embryonic development of ectodermal tissues. There is evidence that AEC syndrome is caused by mutations in the TP63 gene, which encodes the p63 protein. This is an important regulatory protein involved in epidermal proliferation and differentiation. MATERIALS AND METHODS: Genome sequencing was performed in DNA from peripheral blood leukocytes of a newborn with AEC syndrome and her parents. Variants were searched in all coding exons and intron-exon boundaries of the TP63 gene. RESULTS: A heterozygous missense variant (NM_003722.4:c.1063G>C (p.Asp355His) was found in the newborn patient. No variants were found in either of the parents. CONCLUSIONS: We identified a previously unreported variant in TP63 gene which seems to be involved in the somatic malformations found in the AEC syndrome. The absence of this variant in both parents suggests that the variant appeared de novo. PMID- 27485919 TI - Effect of Astaxanthin, Vitamin E, and Vitamin C in Combination with Calorie Restriction on Sperm Quality and Quantity in Male Rats. AB - The aim of this study was to investigate the effect of calorie restriction and dietary antioxidant supplementation, separately or in combination, on the quality and quantity of sperm in male rats. Forty male rats were randomly allocated to four groups of 10 animals each, and fed for at least 86 days with an ad libitum diet (group 1), a restricted diet (group 2), an ad libitum diet and astaxanthin, vitamin E, and vitamin C supplements (group 3), or a restricted diet with astaxanthin, vitamin E, and vitamin C supplements (group 4). At the end of the study period, sperm count and motility were determined with a hemocytometer, and differences between the groups were analyzed by analysis of variance. In addition, total antioxidant capacity and 8-epi prostaglandin F2 alpha were measured at the beginning and end of the study period with an enzyme-linked immunosorbent assay method. After 86 days, a significantly higher sperm count was seen in group 4 compared to other groups. The percentage of immotile sperm was significantly decreased in groups 2, 3, and 4 compared to group 1. A significant increase in total antioxidant capacity was observed in group 3 (p = 0.02) and group 4 (p = 0.02) compared to groups 1 and 2. Antioxidant supplementation with or without calorie restriction had no significant effect on the serum isoprostane level in any group. Astaxanthinin, combined with vitamin E, vitamin C, and calorie restriction, was able to ameliorate, in part, infertility in male rats. PMID- 27485920 TI - Analysis of adaptive mutations selected during the consecutive passages of hepatitis E virus produced from an infectious cDNA clone. AB - To characterize the genomic mutations of hepatitis E virus (HEV) during consecutive passages associated with adaptation to growth in cell culture, a cloned genotype 3 HEV [pJE03-1760F/wt, starting virus (SV)] was passaged 10 times in A549 cells, and the entire genomic sequence of the passage 10 (P10) progeny was determined. Compared to SV, P10 virus possessed two non-synonymous (T2808C and A5054G) and four synonymous mutations (C1213T, T2557C, C3118T and C4435T) in the ORF1. Full-length infectious cDNA clones with a single, double (T2808C and A5054G), or all six mutations, identical to P10, were constructed, and their replication capacity was compared. Four (C1213T, T2557C, T2808C and A5054G) of the six viruses with a single mutation grew more efficiently than SV. The P10 virus propagated more rapidly and grew more efficiently than SV and T2808C+A5054G and reached a higher viral load (95.1- and 8.5-fold, respectively) at 20days post inoculation. An immunofluorescence analysis revealed that a high percentage (>80%) of cells inoculated with the P10 virus expressed ORF2 proteins, while relatively low percentages (nearly 30% or 5%) inoculated with T2808C+A5054G or SV, respectively, expressed ORF2 proteins. We found that not only non-synonymous but also synonymous HEV mutations are independently associated with increased virus production. PMID- 27485921 TI - Cyclophilin and enolase are the most prevalent conidial antigens of Lomentospora prolificans recognized by healthy human salivary IgA and cross-react with Aspergillus fumigatus. AB - PURPOSE: The study of the immunocompetent airways immune response may provide important information to improve the therapeutic efficacy against Lomentospora (Scedosporium) prolificans. So, this study aimed to identify the most prevalent conidial antigens of this multiresistant fungus recognized by healthy human salivary immunoglobulin A, and to study their expression and cross-reactivity with other fungal species. EXPERIMENTAL DESIGN: Twenty saliva from immunocompetent donors were used to detect and identify the immunoreactive proteins by 2D immunoblotting and LC-MS/MS. Moreover, anti-Aspergillus antibodies were purified to study their cross-reactivity. RESULTS: Ten proteins of L. prolificans conidia showed reactivity with more than 50% of the saliva samples. Among them, cyclophilin and enolase were the most prevalent antigens recognized by 85 and 80% of the samples, respectively. These enzymes were also identified on the cell wall surface of L. prolificans and on the immunomes of Scedosporium apiospermum and Scedosporium aurantiacum. Additionally, they showed cross reactivity with the most common pathogenic filamentous fungus Aspergillus fumigatus. CONCLUSION AND CLINICAL RELEVANCE: These results show that the immunocompetent immune response might offer a pan-fungal recognition of conserved antigens such as enolase and cyclophilins, making them potential candidates for study as therapeutic targets. PMID- 27485922 TI - Effect of WC/Co coherency phase boundaries on Fracture toughness of the nanocrystalline cemented carbides. AB - The effect of coherency WC/Co phase boundaries on the fracture toughness of the nanocrystalline WC-Co cemented carbides is studied by MD simulation method. The simulation results show that the nanocrystalline WC-Co cemented carbides with coherency WC/Co phase boundaries has higher fracture toughness than that without coherency WC/Co phase boundaries. Moreover, the mechanism of why coherency WC/Co phase boundaries can improve the fracture toughness of the nanocrystalline cemented carbides is also investigated. It is found the fact that the separation energy of the coherent WC/Co phase boundary is larger than that of the incoherent WC/Co phase boundaries is the main reason for this excellent mechanical property. PMID- 27485923 TI - Regulatory Factors Influencing Usage of Retinal Pharmaceuticals: A Look Both Home and Abroad. PMID- 27485924 TI - [Not Available]. PMID- 27485925 TI - [Not Available]. PMID- 27485926 TI - [Joint Conference of the German Society for Medical Sociology and the German Society for Medical Psychology from September 28 - 30, 2016]. PMID- 27485927 TI - [On the Relationship between EMDR and Eye Movements - An Analysis of the Current State of Neurobiological Research]. AB - EMDR is an effective treatment for people diagnosed with posttraumatic stress disorder. The traditional technique of EMDR combines the activation of distressing reminders with guided rhythmic eye movements. The present article reviews the current state of research on the neurobiological correlates of the eye movements occurring during EMDR. The distinction between saccades and smooth pursuit eye movements allows for detailed analyses of ocular motor connections with cerebral networks of attention, memory and emotion. Possible consequences for research and clinical practice with EMDR are discussed. PMID- 27485928 TI - [Evaluation of the One-Year Multimodal Weight Loss Program DOC WEIGHT(r) 1.0 for Obesity Class II and III]. AB - According to treatment guidelines, treatment for obesity (body mass index [BMI]>=30.0 kg/m(2)) comprises nutritional, physical, and behavioral interventions. However, evidence-based programs for the treatment of severe obesity are rare. In an uncontrolled study, a total of 190 participants (BMI>=35.0 kg/m(2)) of the one-year multimodal treatment program DOC WEIGHT((r)) 1.0 were assessed at pre- (t0) and post-intervention (t1) as well as at 1-year follow-up (t2). Results revealed significant improvements from t0 to t1 in body weight, waist circumference, eating disorder psychopathology, and quality of life that persisted to t2. Long-term multimodal outpatient treatment for severe obesity focusing on behavior modification is promising, however, high rates of loss to follow-up limit explanatory power. To improve evidence, consecutive evaluation is intended. PMID- 27485929 TI - [Feedback on Cognitive Remediation Therapy from Adolescents with Anorexia Nervosa - A Qualitative Study]. AB - BACKGROUND: Cognitive remediation therapy (CRT) is a relatively new therapy for patients with anorexia nervosa (AN). There is an increased demand to include the patient view during the evaluation of treatment programs. So far, there is no structured evaluation of the subjective view of adolescents with AN on CRT available. METHODS: 20 patients with AN between the ages of 12 and 18 years completed 10 CRT sessions. 19 patients (age: 15.6+/-1.3; BMI-percentile: 2.4+/ 3.5) filled out a feedback questionnaire on their subjective CRT experience. The positive and negative aspects of CRT from a patient's perspective were inducted from the feedback material using the 'Qualitative content analysis' from Mayring, allowing the data to be summarized into different categories. The software program MAXQDA 11 was used for the data analysis. RESULTS: The final category system consisted of 6 general categories, which in turn were summarized into 4 main categories: "general therapy perception", "content specific therapy perception", "relationship to everyday life" and "relationship with CRT therapist". 10 patients described CRT (53%) as 'fun'. 12 patients (63%) noticed positive changes in their everyday lives, which they attributed to their participation in CRT. 4 patients (21%) were not able to notice any changes in their everyday lives. 3 patients (16%) valued the good atmosphere during the CRT sessions and 6 patients (32%) found CRT to be a welcome distraction from their daily lives on the ward. 5 patients (26%) mentioned that CRT was too demanding and that difficulties arose during their reflection on thinking styles. DISCUSSION: Overall, CRT is evaluated positively by adolescent patients with AN. A small number of patients reports difficulties with CRT and experiences CRT as strenuous. This positive evaluation of CRT is in line with results from the few qualitative studies in adults with AN. Due to a potential social desirability bias, the patient's perspective should be interpreted with slight caution. CONCLUSION: CRT is received well by adolescents with AN and poses an interesting, new therapy module in the eating disorder field. PMID- 27485930 TI - [A Cognitive Behavioural Group Therapy Manual for Elderly People with Type 2 Diabetes and Minor Depression]. AB - Diabetes in the elderly is often associated with depressive symptoms. This comorbidity leads to a higher risk for diabetes related complications, disability and mortality and can be observed not only in major depression but also in subthreshold or minor depression. Specific psychological interventions for this high-risk patient group were not available yet. Therefore, we developed a diabetes specific cognitive behavioral group intervention for elderly outpatients with subthreshold or minor depression and type 2 diabetes within a randomized controlled trial. The treatment goals focus on improvement in health related quality of life, depression symptoms, glycemic control and cost effectiveness. In this article we give an overview of the manualized treatment program. PMID- 27485931 TI - [Psychosocial Therapies in Severe Mental Illness: Outlook on the Update of the DGPPN-S3-Guideline]. AB - The Psychiatry Enquete turned 40 years old last year. The S3 guideline "Psychosocial therapies for severe mental illness" is considered to be the last milestone of the reform to date. This paper highlights new impulses resulting from the S3 guideline for psychiatric care and provides an outlook on the update, expected in 2017. Many of the interventions reported in the S3 guideline are now supported by a broader evidence base. PMID- 27485932 TI - Transformation by different oncogenes relies on specific metabolic adaptations. AB - Metabolic adaptations are emerging as common traits of cancer cells and tumor progression. In vitro transformation of NIH 3T3 cells allows the analysis of the metabolic changes triggered by a single oncogene. In this work, we have compared the metabolic changes induced by H-RAS and by the nuclear resident mutant of histone deacetylase 4 (HDAC4). RAS-transformed cells exhibit a dominant aerobic glycolytic phenotype characterized by up-regulation of glycolytic enzymes, reduced oxygen consumption and a defect in complex I activity. In this model of transformation, glycolysis is strictly required for sustaining the ATP levels and the robust cellular proliferation. By contrast, in HDAC4/TM transformed cells, glycolysis is only modestly up-regulated, lactate secretion is not augmented and, instead, mitochondrial oxygen consumption is increased. Our results demonstrate that cellular transformation can be accomplished through different metabolic adaptations and HDAC4/TM cells can represent a useful model to investigate oncogene-driven metabolic changes besides the Warburg effect. PMID- 27485933 TI - Prevalence and risk factors associated with the patency of ductus arteriosus in premature neonates: a prospective observational study from Iran. AB - BACKGROUND: Patent ductus arteriosus (PDA) is a common problem in the preterm infants. The frequency of PDA varies with the time of study, and the characteristics of the population included in the trial. AIMS AND OBJECTIVE: To determine the prevalence and prenatal risk factor associated with PDA. METHODS AND MATERIAL: This prospective cross-sectional observational study was carried out on neonates who had gestational age below 37 weeks during the period of February 2014 to September 2014. Echocardiography was done at 4-7 days of postnatal age. The association between prenatal risk factors of the infants and the PDA was studied. RESULTS: From a total population of 200 enrolled infants 22.5% had PDA. The mean gestational age and birth weight were 32.1 +/- 2.65 (weeks) and 1741 +/- 622.85 (g), respectively. Maternal antepartum hemorrhage, respiratory distress syndrome (RDS), need for surfactant, birth weights, female gender, gestational age, Apgar scores at 1 and 5 min of the infants were found to be associated with the prevalence of PDA. CONCLUSION: Several prenatal factors make preterm newborns susceptible to PDA. These risk factors should be identified as soon as possible for early commencement of PDA management. PMID- 27485934 TI - A Social Media Peer Group Intervention for Mothers to Prevent Obesity and Promote Healthy Growth from Infancy: Development and Pilot Trial. AB - BACKGROUND: Evidence increasingly indicates that childhood obesity prevention efforts should begin as early as infancy. However, few interventions meet the needs of families whose infants are at increased obesity risk due to factors including income and maternal body mass index (BMI). Social media peer groups may offer a promising new way to provide these families with the knowledge, strategies, and support they need to adopt obesity prevention behaviors. OBJECTIVE: The aim of this study is to develop and pilot test a Facebook-based peer group intervention for mothers, designed to prevent pediatric obesity and promote health beginning in infancy. METHODS: We conducted in-depth semi structured interviews with 29 mothers of infants and focus groups with 30 pediatric clinicians, to inform the development of a theory-based intervention. We then conducted a single-group pilot trial with 8 mothers to assess its feasibility and acceptability. All participants were recruited offline at pediatric primary care practices. Participants in the pilot trial joined a private Facebook group, moderated by a psychologist, with a weekly video-based curriculum, and also had the option to meet at a face-to-face event. Within the Facebook group, mothers were encouraged to chat, ask questions, and share photos and videos of themselves and babies practicing healthy behaviors. Consistent with the literature on obesity prevention, the curriculum addressed infant feeding, sleep, activity, and maternal well-being. Feasibility was assessed using the frequency and content of group participation by mothers, and acceptability was measured using online surveys and phone interviews. RESULTS: Based on preferences of mothers interviewed (mean BMI 35 kg/m(2), all Medicaid-insured, mean age 27, all Black), we designed the intervention to include frequent posts with new information, videos showing parents of infants demonstrating healthy behaviors, and an optional face-to-face meeting. We developed a privacy and safety plan that met the needs of participants as well as the requirements of the local institutional review board (IRB), which included use of a "secret" group and frequent screening of participant posts. Clinicians, 97% (29/30) women and 87% (26/30) pediatricians, preferred no direct involvement in the intervention, but were supportive of their patients' participation. In our 8-week, single group pilot trial, all participants (mean BMI 35 kg/m(2), all Medicaid-insured, mean age 28, all Black) viewed every weekly video post, and interacted frequently, with a weekly average of 4.4 posts/comments from each participant. All participant posts were related to parenting topics. Participants initiated conversations about behaviors related to healthy infant growth including solid food introduction, feeding volume, and managing stress. All 8 pilot group participants reported that they found the group helpful and would recommend it to others. CONCLUSIONS: Our methodology was feasible and acceptable to low-income mothers of infants at high risk of obesity, and could be adapted to implement peer groups through social media for underserved populations in varied settings. CLINICALTRIAL: ClinicalTrials.gov NCT01977105; https://clinicaltrials.gov/ct2/show/NCT01977105 (Archived by WebCite at http://www.webcitation.org/6iMFfOBat). PMID- 27485935 TI - (1)H NMR metabolomic study of auxotrophic starvation in yeast using Multivariate Curve Resolution-Alternating Least Squares for Pathway Analysis. AB - Disruption of specific metabolic pathways constitutes the mode of action of many known toxicants and it is responsible for the adverse phenotypes associated to human genetic defects. Conversely, many industrial applications rely on metabolic alterations of diverse microorganisms, whereas many therapeutic drugs aim to selectively disrupt pathogens' metabolism. In this work we analyzed metabolic changes induced by auxotrophic starvation conditions in yeast in a non-targeted approach, using one-dimensional proton Nuclear Magnetic Resonance spectroscopy ((1)H NMR) and chemometric analyses. Analysis of the raw spectral datasets showed specific changes linked to the different stages during unrestricted yeast growth, as well as specific changes linked to each of the four tested starvation conditions (L-methionine, L-histidine, L-leucine and uracil). Analysis of changes in concentrations of more than 40 metabolites by Multivariate Curve Resolution - Alternating Least Squares (MCR-ALS) showed the normal progression of key metabolites during lag, exponential and stationary unrestricted growth phases, while reflecting the metabolic blockage induced by the starvation conditions. In this case, different metabolic intermediates accumulated over time, allowing identification of the different metabolic pathways specifically affected by each gene disruption. This synergy between NMR metabolomics and molecular biology may have clear implications for both genetic diagnostics and drug development. PMID- 27485936 TI - Characteristics and clinical outcomes of patients undergoing fertility treatment by double gamete donation. AB - The number of women receiving in vitro fertilization cycles with both oocyte and sperm donation (double donation; DD) has grown globally in the last decade. The aim of this retrospective study, which included 1139 DD cycles, was to describe the characteristics of patients receiving DD and the outcomes of this assisted reproductive treatment. A cluster analysis identified couple 'status' as the main variable in dividing patients into categories. Three such status groups were identified for further analysis: (i) single women (SW), that is women without a partner either male or female; (ii) women with a male partner (MP); (iii) women with a female partner (FP). SW were significantly older (43.9) than patients with a MP (40.4) and a FP (41.3). Women with a male or FP comprised fewer patients with no previous assisted reproductive technology cycles (18.4% and 25.7%, respectively) compared to SW (43.5%). The proportion of patients without children before treatment was significantly different between SW (94.7%) and women with a MP (87.2%). There were no differences in clinical outcomes among the three groups studied. Biochemical pregnancy rate was 58.2% in SW, 58.4% in women with a MP and 64.9% in women with a FP. For the same groups, clinical pregnancy rates were 50.2%, 49.4% and 55.4%, while 'take-home baby' rates were 36.6%, 38.9% and 40.3%. Multiple birth and caesarean section rates were not different among the groups, with twinning rates 21.1%, 30.4% and 36%, and caesarean section rates 25.6%, 24% and 26.4% for SW, women with MP and women with FP, respectively. PMID- 27485937 TI - Paediatric Eye Services: How Much of the Workload Is Amblyopia-Related? AB - AIMS: The proportion of patients seen by the paediatric eye service that attend for reasons related to amblyopia has not been quantified. The purpose of this study was to quantify the proportion of patients seen in the paediatric eye service attending for reasons related to amblyopia. METHODS: Records of all eye appointments of children attending the Hillingdon Hospitals NHS Foundation Trust and St Mary's Hospital Imperial College Healthcare NHS Trust over one month in 2009 were examined to determine the diagnosis and reason for attendance. RESULTS: Seven hundred and four patients had appointments booked at St Mary's and Hillingdon in March 2009. The fail-to-attend rates were not significantly different at the 2 sites (19% at St Mary's and 9% at Hillingdon; P=0.75). Of the 704 patients, 533 (St Mary's, 252 [75%]; Hillingdon, 281 [76%]) were attending for amblyopia-related reasons. Of the overall 982 booked appointments, 770 (79%) were amblyopia-related. CONCLUSIONS: Amblyopia diagnosis and management is clearly the most common cause of attendance to the paediatric eye service, accounting for over three-quarters of outpatient visits. PMID- 27485938 TI - Low-dose testosterone alleviates vascular damage caused by castration in male rats in puberty via modulation of the PI3K/AKT signaling pathway. AB - The aim of the present study was to investigate the effect of testosterone on glucolipid metabolism and vascular injury in male rats, and examine the underlying molecular mechanisms. A total of 40 male Sprague-Dawley rats were divided into a control group (n=10), high-fat-diet + castration group (n=10), high-fat-diet + castration + low dose testosterone group (n=10), and high-fat diet + castration + high dose testosterone group (n=10). Hematoxylin and eosin staining was performed to evaluate the morphology of the thoracic aortic tissues. Immunohistochemical staining was used to detect biomarkers of the phosphoinositide 3-kinase (PI3K) signaling pathway. The mRNA and protein expression levels of PI3K, AKT, insulin receptor substrate-1 (IRS-1), glucose transporter type 4 (GLUT-4), nuclear factor (NF)-kappaB and tumor necrosis factor (TNF)-alpha in the aortas were determined using quantitative polymerase chain reaction and Western blot analyses, respectively. Apoptosis in the aortic tissues was detected using a TUNEL assay. Castration induced apoptosis in the animals fed a high-fat-diet, whereas low dose testosterone replacement ameliorated the apoptosis in the aorta. However, the levels of apoptosis was more severe following high-dose testosterone treatment. Low-dose testosterone induced upregulation in the levels of IRS-1, AKT, GLUT-4 protein, NF-kappaB, TNF-alpha and PI3K, compared with those in the animals fed a high-fat diet following castration. A high dose of testosterone resulted in a significant decrease in the levels of IRS-1, AKT, GLUT-4, NF-kappaB, TNF-alpha and PI3K. Compared with the rats in the high-fat diet + castration group, a low dose of testosterone induced upregulation in the mRNA levels of IRS-1, AKT and GLUT-4, and downregulation of the mRNA levels of NF-kappaB, TNF-alpha and PI3K. A high dose of testosterone resulted in a significant decrease in the levels of IRS-1, AKT and GLUT-4, and marked increases in the mRNA levels of NF-kappaB, TNF-alpha and PI3K, compared with the low dose group. Castration induced marked disorders of glucolipid metabolism and vascular injuries in the pubescent male rats. Low-dose testosterone treatment was found to ameliorate the vascular damage caused by castration via the PI3K/AKT signaling pathway. PMID- 27485939 TI - Co-expression of autophagic markers following photodynamic therapy in SW620 human colon adenocarcinoma cells. AB - Photodynamic therapy (PDT) is a minimally invasive cancer treatment. It involves the combination of a photosensitizer and light of a specific wavelength to generate singlet oxygen and other reactive oxygen species that lead to tumor cell death. Autophagy is one of the pathways that tumor cells undergo during photodamage and it is common in photodynamic therapy. The aim of this study was to examine the effect of in vitro PDT on the expression of autophagy-related proteins, autophagy related 7 (Atg7), light chain 3 (LC3) and Beclin-1. Human SW620 colon carcinoma cells were treated with 5-aminolevulinic acid (ALA)-based PDT at a dose of 3 mM. The irradiation was performed using 4.5 J/cm2 total light and a fluence rate of 60 mW/cm2. Autophagy was evaluated by immunocytochemistry using specific antibodies to Atg7, Beclin-1 and LC3. The evaluation was repeated at several time points (0, 4, 8 and 24 h) following irradiation. The induction of autophagy was observed directly following the 5-ALA-mediated PDT procedure with the strongest expression of autophagy-related proteins at 4 and 8 h after irradiation as demonstrated using immunocytochemistry. It was characterized by significantly increased expression of Beclin-1, Atg7 and LC3. To the best of our knowledge this is the first study to analyze Beclin-1, Atg7 and LC3 expression in a PDT-related experiment. This study enhances the understanding of the role of autophagy in PDT, which may contribute to better and more effective tumor responses to this therapy. PMID- 27485941 TI - Patient Variables Associated with Nafcillin Plasma Concentrations and Toxicity. AB - OBJECTIVES: PRIMARY OBJECTIVE: To retrospectively review nafcillin plasma concentrations (CNAF ) and determine nafcillin clearance (CLNAF ) in a diverse sample of patients treated with nafcillin administered as a continuous infusion. SECONDARY OBJECTIVE: To identify clinical variables associated with CLNAF and nafcillin-related adverse drug reactions (ADRs). METHODS: Retrospective chart review of patients receiving nafcillin via continuous infusion at University of Utah Health Care from 2006 to 2013 who had at least one steady-state CNAF measured. CLNAF was determined by dividing the nafcillin rate of infusion by CNAF . Adverse drug reactions (ADRs) were defined using the National Institutes of Health, Division of Microbiology and Infectious Diseases criteria and scored for probability of association with nafcillin by using Naranjo criteria. Multivariate models were constructed to identify independent variables associated with CLNAF and ADRs. MAIN RESULTS: Seventy-six CNAF from 54 patients were included. Median CLNAF was 13.9 L/hour (range <= 4.2 to 36.9 L/hr). Congestive heart failure (p=0.007), hyperbilirubinemia (p<0.0001), and serum creatinine (p<0.0001) were associated with reduced CLNAF , and Hispanic race (p=0.002) was associated with increased CLNAF by multivariate analysis. Twenty patients (37.0%) experienced an ADR. CNAF were significantly higher between patients that experienced an ADR and those that did not (66.0 vs 25.5 mg/L, p<0.001). Individual ADRs associated with CNAF included hepatotoxicity (62.8 vs 27.0 mg/L, p=0.001), nausea/vomiting (80.0 vs 28.5 mg/L, p=0.01), and diarrhea (66.5 vs 26.5 mg/L, p<0.001). Multivariate analysis identified CNAF as being independently associated with ADRs. A putative toxicity relationship between CNAF and predicted probability of ADR was established. CONCLUSIONS: Several patient variables were associated with impaired CLNAF , and elevated CNAF were associated with ADRs. Additional studies assessing the utility of nafcillin therapeutic drug monitoring to minimize toxicity are warranted. PMID- 27485942 TI - A Study of Hmong Immigrants' Experience With Diabetes Education: A Community Engaged Qualitative Study. AB - PURPOSE: The prevalence of diabetes is increasing in Hmong Americans, an understudied ethnic minority group. This research sought to identify barriers and facilitators related to the diabetes education experience of Hmong Americans with type 2 diabetes, living in central California. METHOD: This qualitative study employed a hybrid design to identify barriers and facilitators to diabetes education. Two focus group interviews were conducted among 16 participants. FINDINGS: The three barriers identified are language, self-management, and stress; the three facilitators are focused culturally specific education, use of media, and peer support group. A priori elements of the Study of Access framework were confirmed. DISCUSSION/CONCLUSION: There is a need for diabetes education in Hmong Americans. Health care access and education should incorporate culturally appropriate strategies that could improve health outcomes for the Hmong. IMPLICATION: To improve diabetes care in the Hmong population, health educators should consider the use of cultural competency, language assistance, and culturally appropriate education to achieve better clinical outcomes. PMID- 27485944 TI - Impact of Infection on Stroke Morbidity and Outcomes. AB - Each year, millions of persons worldwide are disabled by stroke. The burden of stroke is expected to increase as a consequence of growth in our elderly population. Outcome is dependent upon limitation of secondary medical processes in the acute setting that lead to deterioration and increased long-term disability. The prevalence of infection after stroke is greater that seen in other medical conditions with similar acuity and its impact upon morbidity and mortality is substantial. Physical impairment and immune modulation are chief determinants in rate of infection after stroke. Each of these factors has been a target for therapeutic intervention. Current best practices for acute stroke management implement strategies for prevention, prompt identification, and treatment of infection. Novel therapies are currently being explored which have the opportunity to greatly minimize infectious complications following stroke. Fever commonly accompanies infection and independently influences stroke outcome. Targeted temperature management provides an additional chance to improve stroke recovery. PMID- 27485943 TI - Multiprotein-bridging factor 1 regulates vegetative growth, osmotic stress, and virulence in Magnaporthe oryzae. AB - Multiprotein bridging factor 1 (MBF1) is a transcriptional co-activator that mediates transcriptional activation by bridging sequence-specific activator like proteins and the TATA-box binding protein (TBP). MBF1 has been well-studied in Arabidopsis thaliana, Saccharomyces cerevisiae, Drosophila melanogaster, and Homo sapiens, but it is not well understood in filamentous fungi. In this study, we report the identification and characterization of a MBF1 ortholog (MoMBF1) in the rice blast fungus Magnaporthe oryzae), which causes the devastating rice blast disease and is an ideal model for studying the growth, development and pathogenic mechanisms of filamentous fungi. MoMBF1 encodes a 161 amino acid protein with a typical MBF1 domain and HTH domain. Bioinformatics were used to analyze the structural domains in MoMBF1 and its phylogenetic relationship to other homologs from different organisms. We have generated MoMBF1 deletion mutants (DeltaMoMBF1) and functional complementation transformants, and found that the deletion mutants showed significant defects in vegetative growth and tolerance to exogenous stresses, such as 1 M sorbitol, 0.5 M NaCl, and 5 mM H2O2. Moreover, DeltaMoMBF1 showed reduced pathogenicity with smaller infection lesions than wild type and the complementation strain, and decreased response to the accumulation of ROS (reactive oxygen species) in planta at the initial infection stage. Taken together, our data indicate that MoMBF1 is required for vegetative growth, pathogenicity and stress response in M. oryzae. PMID- 27485945 TI - Alemtuzumab for Multiple Sclerosis. AB - Alemtuzumab is a humanised anti-CD52 monoclonal antibody approved for use in active, relapsing multiple sclerosis (MS). Administration results in a rapid depletion of circulating lymphocytes with a subsequent beneficial immune reconstitution. Early open-label experience and recent clinical trials have demonstrated a dramatic effect on relapse rates as well as a positive effect on radiological disease outcomes and disability measures. Despite a mechanism of action that results in profound lymphopaenia, opportunistic infections are rarely seen and no excess association with malignancy has been identified. However, acquired autoimmune disease (AID) is a common adverse event following treatment, necessitating rigorous monitoring in order to facilitate prompt detection and management. Despite this issue, a unique dosing schedule and durability of effect make alemtuzumab a welcome addition to currently available treatment options for MS. PMID- 27485947 TI - Geometric morphometrics reveals restrictions on the shape of the female os coxae. AB - The methodology for sex determination in human skeletal remains depends on the different bone morphologies presented by men and women. Due to their direct implications in reproduction, the whole pelvis, particularly the os coxae, shows different characteristics in either sex. The sacrum and the os coxae constitute the birth canal. In this research study, the os coxae shape is analyzed using geometric morphometrics, providing information on morphology, regardless of size or any other factor beyond the geometry itself. A total of 46 adult ossa coxae from a Spanish archaeological collection were studied using geometric morphometrics. The results show that there is a restriction on the shape of female os coxae. In contrast, male os coxae presents a greater range of variation. The biological reason for this difference is the obstetrical dilemma; a concept defined as the anatomical conflict between bipedalism and the full-term birth of a neonate whose large head requires greater dimensions in the pelvic cavity. Our experimental data reinforce the validity of the obstetrical dilemma as source of the restriction on the shape of female ossa coxae. Additionally, according to the results obtained, size itself does not represent a condition for belonging to one sex or another. PMID- 27485946 TI - Sleep Disturbances in Frontotemporal Dementia. AB - Sleep disorders appear to be frequent comorbidities in patients with frontotemporal dementia (FTD). Insomnia and excessive daytime sleepiness commonly occur in patients with FTD and significantly contribute to caregiver burden and burnout. Sleep is severely fragmented in FTD patients, likely secondary to behavioral disturbances, other primary sleep disorders such as sleep disordered breathing and restless leg syndrome, and neurodegeneration of nuclei involved in sleep and wakefulness. Treatment of primary sleep disorders may improve excessive daytime sleepiness and sleep quality and may improve daytime cognitive functioning. Rapid eye movement (REM) sleep behavior disorder is rare in FTD and may be confused with excessive nocturnal activity due to disturbed circadian rhythm. The relationship between FTD, sleep quality, and sleep disorders requires further study to better understand the contribution of disturbed sleep to daytime neurocognitive functioning and quality of life in FTD. Further, future studies should focus on comparing sleep disturbances between different FTD syndromes, especially behavioral variant FTD and primary progressive aphasia. Comorbid sleep disorders should be promptly sought and treated in patients with FTD to improve patient and caregiver quality of life. PMID- 27485948 TI - Challenges in the development of novel anticryptococcal agents. PMID- 27485949 TI - Properties of Life: Toward a Coherent Understanding of the Organism. AB - The question of specific properties of life compared to nonliving things accompanied biology throughout its history. At times this question generated major controversies with largely diverging opinions. Basically, mechanistic thinkers, who tried to understand organismic functions in terms of nonliving machines, were opposed by those who tried to describe specific properties or even special forces being active within living entities. As this question included the human body, these controversies always have been of special relevance to our self image and also touched practical issues of medicine. During the second half of the twentieth century, it seemed to be resolved that organisms are explainable basically as physicochemical machines. Especially from the perspective of molecular biology, it seemed to be clear that organisms need to be explained solely by the chemical functions of their component parts, although some resistance to this view never ceased. This research program has been working quite successfully, so that science today knows a lot about the physiological and chemical processes within organisms. However, again new doubts arise questioning whether the mere continuation of this analytical approach will finally generate a fundamental understanding of living entities. At the beginning of the twenty first century the quest for a new synthesis actually comes from analytical empiricists themselves. The hypothesis of the present paper is that empirical research has been developed far enough today, that it reveals by itself the materials and the prerequisites to understand more of the specific properties of life. Without recourse to mysterious forces, it is possible to generate answers to this age-old question, just using recent, empirically generated knowledge. This view does not contradict the results of reductionistic research, but rather grants them meaning within the context of organismic systems and also may increase their practical usefulness. Although several of these properties have been discussed before, different authors usually concentrated on a single one or some of them. The paper describes ten specific properties of living entities as they can be deduced from contemporary science. The aim is to demonstrate that the results of empirical research show both the necessity as well as the possibility of the development of a new conception of life to build a coherent understanding of organismic functions. PMID- 27485950 TI - Memory deficits with intact cognitive control in the methylazoxymethanol acetate (MAM) exposure model of neurodevelopmental insult. AB - Cognitive impairments are amongst the most debilitating deficits of schizophrenia and the best predictor of functional outcome. Schizophrenia is hypothesized to have a neurodevelopmental origin, making animal models of neurodevelopmental insult important for testing predictions that early insults will impair cognitive function. Rats exposed to methylazoxymethanol acetate (MAM) at gestational day 17 display morphological, physiological and behavioral abnormalities relevant to schizophrenia. Here we investigate the cognitive abilities of adult MAM rats. We examined brain activity in MAM rats by histochemically assessing cytochrome oxidase enzyme activity, a metabolic marker of neuronal activity. To assess cognition, we used a hippocampus-dependent two-frame active place avoidance paradigm to examine learning and spatial memory, as well as cognitive control and flexibility using the same environment and evaluating the same set of behaviors. We confirmed that adult MAM rats have altered hippocampal morphology and brain function, and that they are hyperactive in an open field. The latter likely indicates MAM rats have a sensorimotor gating deficit that is common to many animal models used for schizophrenia research. On first inspection, cognitive control seems impaired in MAM rats, indicated by more errors during the two-frame active place avoidance task. Because MAM rats are hyperactive throughout place avoidance training, we considered the possibility that the hyperlocomotion may account for the apparent cognitive deficits. These deficits were reduced on the basis of measures of cognitive performance that account for motor activity differences. However, though other aspects of memory are intact, the ability of MAM rats to express trial-to-trial memory is delayed compared to control rats. These findings suggest that spatial learning and cognitive abilities are largely intact, that the most prominent cognitive deficit is specific to acquiring memory in the MAM neurodevelopmental model, and that hyperactivity can confound assessments of cognition in animal models of mental dysfunction. PMID- 27485951 TI - Floating lumbar spine: proposed mechanism with review of literature. AB - Hyperextension injuries of lumbar spine resulting in lumbosacral dislocation are a rare entity. We report a case of a 60-year-old male who presented to us in outpatient department with history of trivial fall from bicycle with fracture through the pedicles extending from L2 to L5 with lumbosacral dislocation with free floating posterior elements with intact neurology. This is the first case report of 4 level extension compression injury with lumbosacral dislocation leading to floating lumbar spine to the best of author's knowledge. Treatment consists of reduction of the lumbosacral dislocation first and fusion of the disc space followed by reduction of the other fractures proximally. These injuries may present with a trivial trauma in spondylotic spine in elderly patients. MRI and CT scan should be done early to identify it, reduce and fix it, as in many cases with trivial trauma there may be no neural deficit. PMID- 27485953 TI - In situ thiolated alginate hydrogel: Instant formation and its application in hemostasis. AB - An in situ formed hydrogel was synthesized by sodium alginate and cysteine methyl ester, which turned the sodium alginate into thiolated alginate (SA-SH). SA-SH can in situ formed into hydrogel (SA-SS-SA) with a large amount of water through covalent bond in less than 20 s. The structure characterization showed that the mechanism of SA-SH gelation was thiol-disulfide transformation. The rheology and cytotoxicity experiments of SA-SS-SA hydrogel were also investigated, which indicated that SA-SS-SA hydrogel had an appropriate mechanical strength as well as an excellent biocompatibility. The SA-SS-SA hydrogel would degrade under certain conditions after a few days and its mechanism was disulfide alkaline reduction. Finally, the hemostatic property of SA-SH was tested by rat tail amputation experiment. The time to hemostasis of rat reduced from 8.26 min to 3.24 min, which proved that SA-SH had an excellent hemostatic property. PMID- 27485954 TI - Mechanical properties, biological behaviour and drug release capability of nano TiO2-HAp-Alginate composite scaffolds for potential application as bone implant material. AB - Nanocomposite scaffolds of TiO2 and hydroxyapatite nanoparticles with alginate as the binding agent were fabricated using the freeze drying technique. TiO2, hydroxyapatite and alginate were used in the ratio of 1:1:4. The scaffolds were characterized using X-ray diffraction, fourier transform infrared spectroscopy, and scanning electron microscopy. The biocompatibility of the scaffolds was evaluated using cell adhesion and MTT assay on osteosarcoma (MG-63) cells. Scanning electron microscopy analysis revealed that cells adhered to the surface of the scaffolds with good spreading. The mechanical properties of the scaffolds were investigated using dynamic mechanical analysis. The swelling ability, porosity, in vitro degradation, and biomineralization of the scaffolds were also evaluated. The results indicated controlled swelling, limited degradation, and enhanced biomineralization. Further, drug delivery studies of the scaffolds using the chemotherapeutic drug methotrexate exhibited an ideal drug release profile. These scaffolds are proposed as potential candidates for bone tissue engineering and drug delivery applications. PMID- 27485955 TI - Persistent maternal Zika viremia: a marker of fetal infection. PMID- 27485969 TI - Analysis of Gambierdiscus transcriptome data supports ancient origins of mixotrophic pathways in dinoflagellates. AB - Toxic dinoflagellates pose serious threats to human health and to fisheries. The genus Gambierdiscus is significant in this respect because its members produce ciguatoxin that accumulates in predominantly tropical marine food webs and leads to ciguatera fish poisoning. Understanding the biology of toxic dinoflagellates is crucial to developing control strategies. To this end, we generated a de novo transcriptome library from G. caribaeus and studied its growth under different culture conditions to elucidate pathways of carbon (C) and nitrogen (N) utilization. We also gathered available dinoflagellate transcriptome data to trace the evolutionary history of C and N pathways in this phylum. We find that rather than being specific adaptations to the epiphytic lifestyle in G. caribaeus, the majority of dinoflagellates share a large array of genes that putatively confer mixotrophy and the ability to use N via the ornithine-urea cycle and nitric oxide synthase production. These results suggest that prior to plastid endosymbiosis, the dinoflagellate ancestor possessed complex pathways that linked metabolism, intercellular signaling, and stress responses to environmental cues that have been maintained by extant photosynthetic species. This metabolic flexibility likely explains the success of dinoflagellates in marine ecosystems and may presage difficulties in controlling the spread of toxic species. PMID- 27485952 TI - Consensus Paper: Cerebellum and Emotion. AB - Over the past three decades, insights into the role of the cerebellum in emotional processing have substantially increased. Indeed, methodological refinements in cerebellar lesion studies and major technological advancements in the field of neuroscience are in particular responsible to an exponential growth of knowledge on the topic. It is timely to review the available data and to critically evaluate the current status of the role of the cerebellum in emotion and related domains. The main aim of this article is to present an overview of current facts and ongoing debates relating to clinical, neuroimaging, and neurophysiological findings on the role of the cerebellum in key aspects of emotion. Experts in the field of cerebellar research discuss the range of cerebellar contributions to emotion in nine topics. Topics include the role of the cerebellum in perception and recognition, forwarding and encoding of emotional information, and the experience and regulation of emotional states in relation to motor, cognitive, and social behaviors. In addition, perspectives including cerebellar involvement in emotional learning, pain, emotional aspects of speech, and neuropsychiatric aspects of the cerebellum in mood disorders are briefly discussed. Results of this consensus paper illustrate how theory and empirical research have converged to produce a composite picture of brain topography, physiology, and function that establishes the role of the cerebellum in many aspects of emotional processing. PMID- 27485970 TI - Psychometric Validation of the Parental Bonding Instrument in a U.K. Population Based Sample: Role of Gender and Association With Mental Health in Mid-Late Life. AB - The factorial structure of the Parental Bonding Instrument (PBI) has been frequently studied in diverse samples but no study has examined its psychometric properties from large, population-based samples. In particular, important questions have not been addressed such as the measurement invariance properties across parental and offspring gender. We evaluated the PBI based on responses from a large, representative population-based sample, using an exploratory structural equation modeling method appropriate for categorical data. Analysis revealed a three-factor structure representing "care," "overprotection," and "autonomy" parenting styles. In terms of psychometric measurement validity, our results supported the complete invariance of the PBI ratings across sons and daughters for their mothers and fathers. The PBI ratings were also robust in relation to personality and mental health status. In terms of predictive value, paternal care showed a protective effect on mental health at age 43 in sons. The PBI is a sound instrument for capturing perceived parenting styles, and is predictive of mental health in middle adulthood. PMID- 27485971 TI - Comment on "Cellular and molecular aspects of diabetic nephropathy; the role of VEGF-A". PMID- 27485972 TI - Treating refractory mental illness with closed-loop brain stimulation: Progress towards a patient-specific transdiagnostic approach. AB - Mental disorders are a leading cause of disability, morbidity, and mortality among civilian and military populations. Most available treatments have limited efficacy, particularly in disorders where symptoms vary over relatively short time scales. Targeted modulation of neural circuits, particularly through open loop deep brain stimulation (DBS), showed initial promise but has failed in blinded clinical trials. We propose a new approach, based on targeting neural circuits linked to functional domains that cut across diagnoses. Through that framework, which includes measurement of patients using six psychophysical tasks, we seek to develop a closed-loop DBS system that corrects dysfunctional activity in brain circuits underlying those domains. We present convergent preliminary evidence from functional neuroimaging, invasive human electrophysiology, and human brain stimulation experiments suggesting that this approach is feasible. Using the Emotional Conflict Resolution (ECR) task as an example, we show that emotion-related networks can be identified and modulated in individual patients. Invasive and non-invasive methodologies both identify a network between prefrontal cortex, cingulate cortex, insula, and amygdala. Further, stimulation in cingulate and amygdala changes patients' performance in ways that are linked to the task's emotional content. We present preliminary statistical models that predict this change and allow us to track it at a single-trial level. As these diagnostic and modeling strategies are refined and embodied in an implantable device, they offer the prospect of a new approach to psychiatric treatment and its accompanying neuroscience. PMID- 27485973 TI - Role of extracellular matrix protein CabA in resistance of Vibrio vulnificus biofilms to decontamination strategies. AB - Biofilms are recalcitrant and raise safety problems in the food industry. In this study, the role of CabA, an extracellular matrix protein, in the resistance of the biofilms of Vibrio vulnificus, a foodborne pathogen, to decontamination strategies was investigated. Biofilms of the cabA mutant revealed reduced resistance to detachment by vibration and disinfection by sodium hypochlorite compared to the biofilms of the parental wild type in vitro. The reduced resistance of the cabA mutant biofilms was complemented by introducing a recombinant cabA, indicating that the reduced resistance of the cabA mutant biofilms is caused by the inactivation of cabA. The expression of cabA was induced in cells bound to oyster, the primary vehicle of the pathogen. The cabA mutant biofilms on oyster are defective in biomass and resistance to detachment and disinfection. The bacterial cells in the wild-type biofilms are clustered by filaments which are not apparent in the cabA mutant biofilms. The combined results indicated that CabA contributes to the structural integrity of V. vulnificus biofilms possibly by forming filaments in the matrix and thus rendering the biofilms robust, suggesting that CabA could be a target to control V. vulnificus biofilms on oyster. PMID- 27485976 TI - A Summer School for Structuring the Chemoinformatics Community. PMID- 27485974 TI - A novel approach to study the structure-property relationships and applications in living systems of modular Cu(2+) fluorescent probes. AB - A series of Cu(2+) probe which contains 9 probes have been synthesized and established. All the probes were synthesized using Rhodamine B as the fluorophore, conjugated to various differently substituted cinnamyl aldehyde with C=N Schiff base structural motif as their core moiety. The structure-property relationships of these probes have been investigated. The change of optical properties, caused by different electronic effect and steric effect of the recognition group, has been analyzed systematically. DFT calculation simulation of the Ring-Close and Ring-Open form of all the probes have been employed to illuminate, summarize and confirm these correlations between optical properties and molecular structures. In addition, biological experiment demonstrated that all the probes have a high potential for both sensitive and selective detection, mapping of adsorbed Cu(2+) both in vivo and environmental microbial systems. This approach provides a significant strategy for studying structure-property relationships and guiding the synthesis of probes with various optical properties. PMID- 27485975 TI - Protein-Anchoring Therapy of Biglycan for Mdx Mouse Model of Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by loss of-function mutations in DMD encoding dystrophin. No rational therapy is currently available. Utrophin is a paralog of dystrophin and is highly expressed at the neuromuscular junction. In mdx mice, utrophin is naturally upregulated throughout the muscle fibers, which mitigates muscular dystrophy. Protein anchoring therapy was previously reported, in which a recombinant extracellular matrix (ECM) protein is delivered to and anchored to a specific target using its proprietary binding domains. Being prompted by a report that intramuscular and intraperitoneal injection of an ECM protein, biglycan, upregulates expression of utrophin and ameliorates muscle pathology in mdx mice, protein-anchoring therapy was applied to mdx mice. Recombinant adeno-associated virus serotype 8 (rAAV8) carrying hBGN encoding human biglycan was intravenously injected into 5-week-old mdx mice. The rAAV8-hBGN treatment improved motor deficits and decreased plasma creatine kinase activities. In muscle sections of treated mice, the number of central myonuclei and the distribution of myofiber sizes were improved. The treated mice increased gene expressions of utrophin and beta1-syntrophin, as well as protein expressions of biglycan, utrophin, gamma-sarcoglycan, dystrobrevin, and alpha1-syntrophin. The expression of hBGN in the skeletal muscle of the treated mice was 1.34-fold higher than that of the native mouse Bgn (mBgn). The low transduction efficiency and improved motor functions suggest that biglycan expressed in a small number of muscle fibers was likely to have been secreted and anchored to the cell surface throughout the whole muscular fibers. It is proposed that the protein-anchoring strategy can be applied not only to deficiency of an ECM protein as previously reported, but also to augmentation of a naturally induced ECM protein. PMID- 27485977 TI - Future De Novo Drug Design. AB - The computer-assisted generation of new chemical entities (NCEs) has matured into solid technology supporting early drug discovery. Both ligand- and receptor-based methods are increasingly used for designing small lead- and druglike molecules with anticipated multi-target activities. Advanced "polypharmacology" prediction tools are essential pillars of these endeavors. In addition, it has been realized that iterative design-synthesis-test cycles facilitate the rapid identification of NCEs with the desired activity profile. Lab-on-a-chip platforms integrating synthesis, analytics and bioactivity determination and controlled by adaptive, chemistry-driven de novo design software will play an important role for future drug discovery. PMID- 27485978 TI - The Calculation of Molecular Structural Similarity: Principles and Practice. AB - Measures of structural similarity play an important role in chemoinformatics for applications such as similarity searching, database clustering and molecular diversity analysis. A similarity measure comprises three components: a structure representation; a weighting scheme; and a similarity coefficient. The paper introduces these components and describes methods for comparing different measures. The use of similarity measures in chemoinformatics research is illustrated by recent projects in the author's laboratory on: the interactions between a weighting scheme and a similarity coefficient; the design of comparative studies of similarity measures; the use of 2D fingerprints for scaffold-hopping searches; and the registration of orphan drugs for rare diseases. PMID- 27485979 TI - Exploring Activity Cliffs from a Chemoinformatics Perspective. AB - The activity cliff concept experiences considerable interest in medicinal chemistry and chemoinformatics. Activity cliffs are defined as pairs or groups of structurally similar or analogous active compounds having large differences in potency. Depending on the research field, views of activity cliffs partly differ. While interpretability and utility of activity cliff information is considered to be of critical importance in medicinal chemistry, large-scale exploration and prediction of activity cliffs are of special interest in chemoinformatics. Much emphasis has recently been put on making activity cliff information accessible for medicinal chemistry applications. Herein, different approaches to the analysis and prediction of activity cliffs are discussed that are of particular relevance from a chemoinformatics viewpoint. PMID- 27485980 TI - Investigating and Predicting how Biology Changes Molecules and Their Properties. AB - Most molecules are transformed and transported by specific metabolising enzymes and transporters resulting in changes in their bioactivities, pharmacokinetics and toxicity profiles. This is a key consideration in the design of drugs. Ideally, when medicines have performed their task, they need to fade away gracefully, and not introduce unexpected or untoward biological effects. Some examples of predictive metabolism, transport and interesting design considerations of drugs are described. PMID- 27485981 TI - BioGPS: The Music for the Chemo- and Bioinformatics Walzer. AB - Identifying cross-relationships among protein binding sites is becoming increasingly important in the chemo- and bioinformatics field; indeed, protein structural similarity might provide the right answer to a number of questions including Is a drug repurposable for another target? What is the molecular mechanism of a drug side-effect? How can we improve the ligand selectivity? The comparison of protein binding sites in terms of their three-dimensional structure molecular interaction fields can be a useful technique to approach all of these problems. Here, we report a semi-automated method for comparing and clustering protein pockets, called BioGPS, that combines the GRID Molecular Interactions Fields (MIFs) with FLAP pharmacophoric fingerprints. BioGPS identifies and compares protein binding sites by aligning them each other and directly comparing their MIFs. The strengths of this approach are that it is MIF-based, and therefore describes molecular interactions from a ligand perspective, and it is independent of protein superposition or sequence alignment. This approach enables protein-protein virtual screening (drug repurposing, polypharmacology, off-target effects), and also clustering to relate sequence-based similarities to structure based differences among protein binding sites. PMID- 27485982 TI - Solved and Unsolved Problems of Chemoinformatics. AB - From humble beginnings in the Sixties chemoinformatics evolved into a scientific field of its own. Without the achievements of chemoinformatics the flood of information in chemistry would simply not be manageable and modern research in chemistry and related fields would be inconceivable. However, there are still a host of problems waiting for solutions to be found or to be improved. The impact of chemicals on human health and on the environment presents both challenges and concerns. Research in chemoinformatics could help in better understanding these topics and thus contribute to a better living. PMID- 27485983 TI - Bioisosteres and Scaffold Hopping in Medicinal Chemistry. AB - The twin concepts of bioisosteric replacement and scaffold hopping are increasingly becoming important in modern drug design. The concepts of isosterism stretch back over a century, but only recently have systematic and data-intensive methods been used to explore appropriate replacements. Here, a summary of the history of bioisosterism is presented to provide context to the methods applied. Molecular similarity and data mining methods are introduced as approaches to introduce these replacements to rationalise the space of synthetic targets to consider in a medicinal chemistry project. Lastly, an outlook of the field is given of potential future improvements and areas of focus that should be considered to anyone interested in the field. PMID- 27485984 TI - Attractor Structures of Signaling Networks: Consequences of Different Conformational Barcode Dynamics and Their Relations to Network-Based Drug Design. AB - Conformational barcodes tag functional sites of proteins and are decoded by interacting molecules transmitting the incoming signal. Conformational barcodes are modified by all co-occurring allosteric events induced by post-translational modifications, pathogen, drug binding, etc. We argue that fuzziness (plasticity) of conformational barcodes may be increased by disordered protein structures, by integrative plasticity of multi-phosphorylation events, by increased intracellular water content (decreased molecular crowding) and by increased action of molecular chaperones. This leads to increased plasticity of signaling and cellular networks. Increased plasticity is both substantiated by and inducing an increased noise level. Using the versatile network dynamics tool, Turbine (www.turbine.linkgroup.hu), here we show that the 10 % noise level expected in cellular systems shifts a cancer-related signaling network of human cells from its proliferative attractors to its largest, apoptotic attractor representing their health-preserving response in the carcinogen containing and tumor suppressor deficient environment modeled in our study. Thus, fuzzy conformational barcodes may not only make the cellular system more plastic, and therefore more adaptable, but may also stabilize the complex system allowing better access to its largest attractor. PMID- 27485985 TI - A Short Review of Chemical Reaction Database Systems, Computer-Aided Synthesis Design, Reaction Prediction and Synthetic Feasibility. AB - This article is the text for a pedagogical lecture to be given at the Strasbourg Summer School in Chemoinformatics in June 2104. It covers a very wide range of reaction topics including structure and reaction representation, reaction centers, atom-to-atom mapping, reaction retrieval systems, computer-aided synthesis design, retrosynthesis, reaction prediction and synthetic feasibility. In the time available the coverage of each topic can only be cursory; the main usefulness of this article to the research community is the extensive bibliography. PMID- 27485986 TI - Individual Hydrogen-Bond Strength QSPR Modelling with ISIDA Local Descriptors: a Step Towards Polyfunctional Molecules. AB - Here, we introduce new ISIDA fragment descriptors able to describe "local" properties related to selected atoms or molecular fragments. These descriptors have been applied for QSPR modelling of the H-bond basicity scale pKBHX , measured by the 1 : 1 complexation constant of a series of organic acceptors (H bond bases) with 4-fluorophenol as the reference H-bond donor in CCl4 at 298 K. Unlike previous QSPR studies of H-bond complexation, the models based on these new descriptors are able to predict the H-bond basicity of different acceptor centres on the same polyfunctional molecule. QSPR models were obtained using support vector machine and ensemble multiple linear regression methods on a set of 537 organic compounds including 5 bifunctional molecules. They were validated with cross-validation procedures and with two external test sets. The best model displays good predictive performance on a large test set of 451 mono- and bifunctional molecules: a root-mean squared error RMSE=0.26 and a determination coefficient R(2) =0.91. It is implemented on our website (http://infochim.u strasbg.fr/webserv/VSEngine.html) together with the estimation of its applicability domain and an automatic detection of potential H-bond acceptors. PMID- 27485988 TI - An experimental and theoretical study of the aggregate structure of calix[6]arenes in Langmuir films at the water/air interface. AB - In this paper, the aggregate formation of para-tert-butylcalix[6]arene molecules (Calix6) in dimeric structures was investigated at the water/air interface using experimental and theoretical studies. A specific orientation for such Calix6 molecules was observed with an average area of 133 A(2), which corresponds to a flat-on orientation with the OH groups parallel to the interface. By varying the pressure on the Calix6 monolayer, the molecules tend to organize at the water/air interface and subsequently, at higher pressures, aggregates were formed atop the monolayer as cluster structures. Morphological characterization by the Brewster Angle Microscopy technique showed the formation of larger domains at lower pressures. Based on such experimental evidence, molecular dynamics (MD) simulations were performed to investigate possible dimeric structures for aggregated Calix6 molecules, which are localized at the water/air interface, where one molecule remains in the water phase and the other remains in the air phase. By increasing surface pressure, experimental and theoretical results corroborate the intermolecular interactions among Calix6 molecules. These results are relevant because a dimeric structure has a molecular cavity, which is a candidate for host-guest chemistry, an ion receptor or a drug-delivery system. PMID- 27485987 TI - Substance Use among a Sample of Healthcare Workers in Kenya: A Cross-Sectional Study. AB - This study describes reported substance use among Kenyan healthcare workers (HCWs), as it has implications for HCWs' health, productivity, and their ability and likelihood to intervene on substance use. The Alcohol Smoking and Substance Involvement Screening Test (ASSIST) was administered to a convenience sample of HCWs (n = 206) in 15 health facilities. Reported lifetime use was 35.8% for alcohol, 23.5% for tobacco, 9.3% for cannabis, 9.3% for sedatives, 8.8% for cocaine, 6.4% for amphetamine-like stimulants, 5.4% for hallucinogens, 3.4% for inhalants, and 3.9% for opioids. Tobacco and alcohol were also the two most commonly used substances in the previous three months. Male gender and other substance use were key predictors of both lifetime and previous three months' use rates. HCWs' substance use rates appear generally higher than those seen in the general population in Kenya, though lower than those reported among many HCWs globally. This pattern of use has implications for both HCWs and their clients. PMID- 27485989 TI - Confronting the Problem of Obesity in Dogs and Cats. PMID- 27485990 TI - Can dispersion modeling of air pollution be improved by land-use regression? An example from Stockholm, Sweden. AB - Both dispersion modeling (DM) and land-use regression modeling (LUR) are often used for assessment of long-term air pollution exposure in epidemiological studies, but seldom in combination. We developed a hybrid DM-LUR model using 93 biweekly observations of NOx at 31 sites in greater Stockholm (Sweden). The DM was based on spatially resolved topographic, physiographic and emission data, and hourly meteorological data from a diagnostic wind model. Other data were from land use, meteorology and routine monitoring of NOx. We built a linear regression model for NOx, using a stepwise forward selection of covariates. The resulting model predicted observed NOx (R2=0.89) better than the DM without covariates (R2=0.68, P-interaction <0.001) and with minimal apparent bias. The model included (in descending order of importance) DM, traffic intensity on the nearest street, population (number of inhabitants) within 100 m radius, global radiation (direct sunlight plus diffuse or scattered light) and urban contribution to NOx levels (routine urban NOx, less routine rural NOx). Our results indicate that there is a potential for improving estimates of air pollutant concentrations based on DM, by incorporating further spatial characteristics of the immediate surroundings, possibly accounting for imperfections in the emission data. PMID- 27485991 TI - Non-smoking pregnant women and their fetuses are exposed to environmental tobacco smoke as a result of living in multiunit housing. AB - This study investigates whether pregnant women and their fetuses are exposed to environmental tobacco smoke (ETS) as a result of living in apartments. We measured cotinine concentrations in serum, a biomarker of exposure to ETS, in non smoking women's umbilical cord blood collected at delivery and in maternal blood drawn shortly after delivering a baby. Concurrently, information was collected regarding the women's housing situation, whether family members or co-workers smoked, and other potential exposure factors. Newborns whose non-smoking mothers lived in an apartment during pregnancy were more than three times (OR 3.17, 95% CI 1.62-6.21) more likely to have detectable levels of cotinine in their cord blood serum than babies whose mothers lived in a detached house. There is a strong association between detectable concentrations of cotinine in cord blood serum and living in an apartment, even after adjusting for confounders, such as exposure at home or at work. A similar association was observed between the detectable levels of cotinine in maternal serum and living in an apartment (OR 1.95, 95% CI 1.03-3.71). PMID- 27485993 TI - Effects of damping and stiffness of AFM cantilever on the imaging of fine surfaces. AB - In this paper, by applying the differential quadrature (DQ) method, a semi analytical model has been developed for atomic force microscope cantilever, and then by using the interfacial forces between the cantilever tip and imaged surfaces, a 2D model has been extracted for imaging nano-sized fine samples. By employing the present model, several simple and standard samples have been imaged, and finally the effects of the microcantilever's structural damping and its stiffness on the imaging results have been investigated. It has been observed that, through the control of damping, the quality of the acquired images is considerably improved. It has also been shown that the self-softening and self hardening properties of cantilever have serious effects on the obtained images. The present model can be used to study the effects of different parameters on the process of imaging small-scale samples. Also, as one of its most important applications, this model can be used in common multiscale models for simulating and predicting the effects of large and small fields on each other. PMID- 27485992 TI - Exposure science in an age of rapidly changing climate: challenges and opportunities. AB - Climate change is anticipated to alter the production, use, release, and fate of environmental chemicals, likely leading to increased uncertainty in exposure and human health risk predictions. Exposure science provides a key connection between changes in climate and associated health outcomes. The theme of the 2015 Annual Meeting of the International Society of Exposure Science-Exposures in an Evolving Environment-brought this issue to the fore. By directing attention to questions that may affect society in profound ways, exposure scientists have an opportunity to conduct "consequential science"-doing science that matters, using our tools for the greater good and to answer key policy questions, and identifying causes leading to implementation of solutions. Understanding the implications of changing exposures on public health may be one of the most consequential areas of study in which exposure scientists could currently be engaged. In this paper, we use a series of case studies to identify exposure data gaps and research paths that will enable us to capture the information necessary for understanding climate change-related human exposures and consequent health impacts. We hope that paper will focus attention on under-developed areas of exposure science that will likely have broad implications for public health. PMID- 27485995 TI - Hepatoprotective Effect of Low Doses of Caffeine on CCl4-Induced Liver Damage in Rats. AB - Several studies have shown the hepatoprotective effect of the consumption of coffee and tea, which is mainly attributed to caffeine. Many experimental studies have demonstrated this effect; however, these studies used high caffeine doses that are not related to human consumption. The aim of this study was to evaluate the hepatoprotective effect of low doses of caffeine on carbon tetrachloride (CCl4)-treated rats. Low doses of caffeine (CAFF) 5 and 10 mg/kg (CAFF5 and CAFF10) were evaluated in chronic liver damage induced by CCl4 (0.75 mL/kg) in rats. CAFF treatment was administered once a day and CCl4 administration was twice weekly for 10 weeks. Liver function tests (biochemical markers) and functional (sleeping time) and histological (hematoxylin-eosin and Masson trichrome stains) parameters were carried out at the end of damage treatment. Daily treatments of CAFF5 and CAFF10 exhibited a hepatoprotective effect supported by a decrease of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AP) serum activities and bilirubin serum levels compared with control and also restored serum albumin levels and liver glutathione (GSH). Moreover, CAFF prevented CCl4-induced prolongation in pentobarbital sleeping time and a decrease of liver fibrosis and cell death. Our results demonstrated that low doses of CAFF exert a hepatoprotective effect against CCl4 -induced liver damage in rats. PMID- 27485996 TI - Talking about sex, relationships and intimacy: new guidance and standards for nurses and other health and social care professionals working with young people with life-limiting and life-threatening conditions: Publication of Sexuality Standards and Guidance for nurses and other health and social care professionals working with life-limited young adults, care staff and their families (December 2015 and July 2016). PMID- 27485994 TI - Dynamics and genetics of a disease-driven species decline to near extinction: lessons for conservation. AB - Amphibian chytridiomycosis has caused precipitous declines in hundreds of species worldwide. By tracking mountain chicken (Leptodactylus fallax) populations before, during and after the emergence of chytridiomycosis, we quantified the real-time species level impacts of this disease. We report a range-wide species decline amongst the fastest ever recorded, with a loss of over 85% of the population in fewer than 18 months on Dominica and near extinction on Montserrat. Genetic diversity declined in the wild, but emergency measures to establish a captive assurance population captured a representative sample of genetic diversity from Montserrat. If the Convention on Biological Diversity's targets are to be met, it is important to evaluate the reasons why they appear consistently unattainable. The emergence of chytridiomycosis in the mountain chicken was predictable, but the decline could not be prevented. There is an urgent need to build mitigation capacity where amphibians are at risk from chytridiomycosis. PMID- 27485997 TI - Cannabis Hyperemesis Syndrome in the Emergency Department: How Can a Specialized Addiction Team Be Useful? A Pilot Study. AB - BACKGROUND: Chronic cannabis users may experience cyclical episodes of nausea and vomiting and learned behavior of hot bathing. This clinical condition, known as cannabis hyperemesis syndrome, was first reported in 2004. OBJECTIVE: Our aim was to promote early recognition of this syndrome in emergency departments (EDs) and to increase referral to addiction specialists. METHODS: Cannabis abusers were admitted to the ED for vomiting or abdominal pain from June 1, 2014 to January 1, 2015 and diagnosed with cannabis hyperemesis syndrome by a specialized addiction team. Then, medical records were examined retrospectively. RESULTS: Seven young adults were included. Their mean age was 24.7 years (range 17-39 years) and the majority were men (male-to-female ratio 1.2). Biological and toxicological blood samples were taken in all patients. Tetrahydrocannabinol blood level was measured in 4 patients, with a mean blood concentration of 11.6 ng/mL. Radiographic examination including abdominal computed tomography and brain imaging were negative, as was upper endoscopy. Five patients compulsively took hot baths in an attempt to decrease the symptoms. Treatment was symptomatic. Five patients have started follow-up with the specialized addiction team. CONCLUSIONS: Cannabis hyperemesis syndrome is still under-diagnosed 10 years after it was first described. Physicians should be aware of this syndrome to avoid repeated hospitalizations or esophageal complications. Greater awareness should lead to prompt treatment and prevention of future recurrence through cannabis cessation. Addiction specialists, as well as medical toxicologists, are experts in the management of cannabis abusers and can help re-establish the role of medical care in this population in collaboration with emergency physicians. PMID- 27485998 TI - Evaluation of US prescription patterns: Are treatment guidelines for cancer associated venous thromboembolism being followed? AB - INTRODUCTION: Venous thromboembolism (VTE) is a common complication of cancer. Clinical practice guidelines recommend low-molecular-weight heparin (LMWH) for treatment of cancer-associated VTE, but it is unclear how frequently these are followed. This study assessed anticoagulation treatment patterns for VTE in newly diagnosed cancer patients in the United States. MATERIALS AND METHODS: MarketScan(r) claims records of more than 80 million insured members between January 1, 2009 and July 31, 2014 were retrospectively analyzed. Subjects were included if they were 18years of age or older, and had a diagnosis of cancer (9 solid tumor types) and VTE. Data were included for LMWH, warfarin, and other anticoagulants (fondaparinux and direct oral anticoagulants [DOACs]). Patients with anticoagulant treatment prior to cancer diagnosis were excluded. RESULTS: VTE developed in 6.2% of cancer patients (median, 181days after cancer diagnosis). VTE rates were highest for pancreatic (17.5%) and lung (12.6%) cancer and lowest for breast (4.2%) and prostate (4.1%) cancer. For patients for whom outpatient prescription data were available, warfarin was most commonly used (50.0%), followed by LMWH (40.0%) and other anticoagulants (10.0%). Over 6months, 13% of patients who initiated injectable anticoagulants remained on them compared with 30% of those who initiated oral anticoagulants. More patients switched from LMWH to warfarin and other anticoagulants (44%) versus those who switched from warfarin (28%). CONCLUSIONS: Warfarin was the most utilized anticoagulant for cancer-associated VTE despite guideline recommendations for LMWH. More patients remained on oral versus injectable agents, which may be related to self-injection burden and costs. PMID- 27485999 TI - Reply to: Early mobilization in abdominal and thoracic surgery. PMID- 27486000 TI - Application of an individualized operative strategy for wedge resection of gastric gastrointestinal stromal tumors: Effectiveness for tumors in difficult locations. AB - BACKGROUND: There is some concern that wedge resection of gastric gastrointestinal stromal tumors is not feasible in certain anatomic locations, such as the cardia or antrum. We sought to review our experience with treatment of gastric gastrointestinal stromal tumors with a particular focus on nonanatomic wedge resections in these challenging locations. METHODS: Patients undergoing resection of gastrointestinal stromal tumors from 2000-2014 at the Montreal General Hospital were identified from a prospectively collected database, and outcomes were tabulated. An individualized operative strategy was used to guide resection based on tumor location, size, and characteristics. Disease-free survival and overall survival analyzed using the Kaplan-Meier method. Data are presented as median (range). RESULTS: We identified 59 patients who underwent operative resection for gastric gastrointestinal stromal tumors. Tumor location was fundus/body/greater curvature in 35 (59%) patients, lesser curvature in 8 (14%) patients, antrum in 8 (14%) patients, and cardia in 8 (14%) patients. Median tumor size was 4.5 cm (1.4-25 cm). The majority of cardia and antral lesions were removed with wedge resections (14/16, 87%). For cardial and antral tumors, on-table gastroscopy was used to guide the operative approach and prevent narrowing of the Gastroesophageal junction or pylorus in all patients undergoing wedge resection. Negative pathologic margins were achieved in all patients. The 5 year disease-free survival was 91% and 5-year overall survival was 95%. CONCLUSION: When selected appropriately, and under the guidance of on-table gastroscopy, laparoscopic nonanatomic wedge resection can be performed successfully in the majority of cases, even for gastrointestinal stromal tumors near the GEJ or pylorus, with excellent oncologic outcomes. PMID- 27486001 TI - Propensity scores for comparative effectiveness research: Finding the right match. PMID- 27486002 TI - Perioperative and oncologic outcomes of minimally invasive liver resection for colorectal metastases: A case-control study of 130 patients. AB - BACKGROUND: Our aim was to compare the perioperative and oncologic outcomes of open liver resection and minimally invasive liver resection in the management of colorectal liver metastases. METHODS: Patients who underwent minimally invasive liver resection for colorectal liver metastases between January 2006 and June 2015 at a single center were identified and matched by extent of resection to consecutive open liver resection patients from the same period. Clinicopathologic characteristics, perioperative data, recurrence, and survival outcomes were collected and analyzed based on intention-to-treat. RESULTS: Sixty-five patients underwent minimally invasive liver resection during this period and were matched to 65 consecutive open liver resection patients, with similar baseline demographic, tumor, and chemotherapy parameters. Conversion to open occurred in 5 (7.7%) minimally invasive liver resection patients. R0 resection rates and operative times were comparable, but the estimated blood loss was less in the minimally invasive liver resection group (median 200 mL vs 400 mL, P < .001), as were perioperative transfusion rates (4.6% vs 15.4%, P = .04). The duration of stay was shorter after minimally invasive liver resection (median 4 days vs 6 days, P < .001), while major and minor complication rates were similar and no perioperative mortality was recorded. At a median follow-up of 28 months, there was no difference regarding disease-free (P = .90) or overall survival (P = .37). CONCLUSION: In selected patients with colorectal liver metastases, minimally invasive liver resection resulted in similar oncologic outcomes, with decreased blood loss and shorter duration of stay compared to patients who underwent open liver resection. PMID- 27486004 TI - Discussion. PMID- 27486003 TI - Differential access to care: The role of age, insurance, and income on race/ethnicity-related disparities in adult perforated appendix admission rates. AB - BACKGROUND: Differences in perforated appendix admission rates (PAAR) are an ambulatory-sensitive measure of access to care. While pediatric studies report disparities in PAAR, initial adult investigations suggest a lack of racial/ethnic inequity. The objectives of this study were to (1) assess for risk-adjusted, racial/ethnic differences in PAAR among adults on a national scale, (2) consider the extent to which variations (or lack thereof) are explained by age, insurance, and income, and (3) compare results within the United States population to a national segment of the population who are completely insured. METHODS: According to the Agency for Healthcare Research and Quality definition of PAAR, adults (aged 18-64 years) in the 2006-2010 Nationwide Inpatient Sample were queried for the occurrence and perforation of acute appendicitis. Risk-adjusted differences were compared by race/ethnicity over 5-year age increments using logistic regression with reweighted estimating equations. Noting disparate outcomes between younger (aged 18-34 years) versus older (aged 35-64 years) adults, age stratified variations were further considered. Results were compared relative to differences among national military/civilian-dependent patients with universal insurance and were assessed for the extent to which disparities could be explained by variations in insurance and income. RESULTS: A total of 129,257 (weighted: 638,452) patients were included. Despite a lack of differences overall, significantly worse outcomes among younger (odds ratio point-estimates ranged from 1.11-1.32) and better outcomes among older (0.78-0.93) minority patients were found. This observation contrasted a lack of differences among completely insured military/civilian-dependent patients (n = 12,154). A total of 22.4% (non-Hispanic black versus non-Hispanic white) and 39.0% (Hispanic versus non-Hispanic white) of younger adult differences were explained by insurance 12.2% and 13.6% by income, 29.8% and 44.0% combined. CONCLUSION: This national assessment of differences in access to care among adults with acute appendicitis demonstrated the existence of racial/ethnic disparities in PAAR that varied with age and were partially, although incompletely, explained by variations in insurance and income. PMID- 27486005 TI - Pilot Assessment of the Repeatability of Indocyanine Green Fluorescence Imaging and Correlation with Traditional Foot Perfusion Assessments. AB - BACKGROUND: Ankle brachial index (ABI), toe pressures (TP), and transcutaneous oxygen pressure (TcPO2) are traditionally used in the assessment of critical limb ischemia (CLI). Indocyanine green (ICG) fluorescence imaging can be used to evaluate local circulation in the foot and to evaluate the severity of ischemia. This prospective study analyzed the suitability of a fluorescence imaging system (photodynamic eye [PDE]) in CLI. MATERIAL AND METHODS: Forty-one patients with CLI were included. Of the patients, 66% had diabetes and there was an ischemic tissue lesion in 70% of the limbs. ABI, toe pressures, TcPO2 and ICG-fluorescence imaging (ICG-FI) were measured in each leg. To study the repeatability of the ICG FI, each patient underwent the study twice. After the procedure, foot circulation was measured using a time-intensity curve, where T1/2 (the time needed to achieve half of the maximum fluorescence intensity) and PDE10 (increase of the intensity during the first 10 s) were determined. A time-intensity curve was plotted using the same areas as for the TcPO2 probes (n=123). RESULTS: The mean ABI was 0.43, TP 21 mmHg, TcPO2 23 mmHg, T1/2 38 s, and PDE10 19 AU. Time-intensity curves were repeatable. In a Bland-Altman scatter plot, the 95% limits of agreement of PDE10 was 9.9 AU and the corresponding value of T1/2 was 14 s. Correlation between ABI and TP was significant (R=.73, p<.001), and it was weaker in diabetic patients (R=.47, p=.048) compared with non-diabetic patients (R=.89, p=.002). Correlations between ABI and TcPO2 and TP and TcPO2 were weak (R=.37, p=.05 and R=.43, p=.037, respectively). Correlation between TcPO2 and PDE10 was strong in diabetic patients (R=.70, p=.003). CONCLUSIONS: According to this pilot study, ICG-FI with PDE can be used in the assessment of blood supply in the ischemic foot. PMID- 27486006 TI - Alkyne Metathesis with Silica-Supported and Molecular Catalysts at Parts-per Million Loadings. AB - Improvement of the activity, stability, and chemoselectivity of alkyne-metathesis catalysts is necessary before this promising methodology can become a routine method to construct C=C triple bonds. Herein, we show that grafting of the known molecular catalyst [MesC=Mo(OtBuF6 )3 ] (1, Mes=2,4,6-trimethylphenyl, OtBuF6 =hexafluoro-tert-butoxy) onto partially dehydroxylated silica gave a well-defined silica-supported active alkyne-metathesis catalyst [(=SiO)Mo(=CMes)(OtBuF6 )2 ] (1/SiO2-700 ). Both 1 and 1/SiO2-700 showed very high activity, selectivity, and stability in the self-metathesis of a variety of carefully purified alkynes, even at parts-per-million catalyst loadings. Remarkably, the lower turnover frequencies observed for 1/SiO2-700 by comparison to 1 do not prevent the achievement of high turnover numbers. We attribute the lower reactivity of 1/SiO2 700 to the rigidity of the surface Mo species owing to the strong interaction of the metal site with the silica surface. PMID- 27486007 TI - Exploratory factor analysis of the reintegration to normal living index in a stroke population. AB - BACKGROUND: The reintegration to normal living index (RNLI) is a global assessment of patient quality of life often utilized in stroke populations. Previous studies in various general disability samples have consistently reported a two-factor solution for the RNLI. Despite its common use with stroke patients, the RNLI has not been psychometrically evaluated in an exclusively stroke sample. This study is believed to represent the first factor analysis of the RNLI using a sample comprised exclusively of individuals who have survived cerebral infarct. OBJECTIVE: The aim of this study is to evaluate the psychometric properties of the RNLI in assessing quality of life of stroke survivors. METHODS: We retrospectively examined RNLI scores of 928 adults with strokes of varying severities as part of a multidisciplinary, interinstitutional collaboration across an academic medical center, acute care hospital, and rehabilitation center. We utilized a principal component factor analysis to evaluate the factor structure of the RNLI. RESULTS: Mean RNLI scores +/-SD for the sample were 75.26 +/- 19.85, ranging between 20 and 100. The Cronbach alpha was .94. A scree test for factor retention strongly suggested a single factor solution, explaining 64.50% of the total variance. CONCLUSIONS: Previous factor analyses on the RNLI utilizing general disability samples commonly report a two-factor solution. Our data support the presence of a single factor solution across the RNLI within a large sample comprised exclusively of stroke survivors. This suggests that the RNLI acts as more of a unitary measure of quality of life within a stroke sample relative to other disabled samples. PMID- 27486008 TI - Response to Wiewel-Verschueren S et al.: gynaecological and obstetrical bleeding in women with factor XI deficiency - a systematic review. PMID- 27486009 TI - Predictors for prolonged interval from premature rupture of membranes to spontaneous onset of labor at term. AB - OBJECTIVE: To identify predictors for prolonged interval from premature rupture of membranes (PROM) to spontaneous onset of labor in women presenting with PROM and low Bishop score at term. METHODS: A retrospective study of women presenting with PROM and Bishop score < 7 at term (>=37weeks) in a tertiary hospital (2013 14). Spontaneous onset of labor was defined as presence of regular uterine contractions and Bishop score >= 7. Women with interval from PROM to spontaneous onset of labor of <24hours (short interval group) were compared to those with interval >= 24 hours (prolonged interval group). Women who underwent induction of labor at < 24 hours from PROM were excluded. RESULTS: Among 625 women who met inclusion criteria, 155 (24.8%) had a prolonged interval to onset of labor. In multivariate analysis, prolonged PROM was associated with (OR, 95%CI) cervical dilatation (0.35, 0.24-0.52, p < 0.001), effacement (0.97, 0.96-0.99, p < 0.001) and uterine contraction (0.51, 0.32-0.80, p = 0.004). A multivariable prediction model including maternal age, parity, cervical dilatation and effacement, gestational age and neonatal birthweight was associated with an AUC of receiver operator characteristic curve of 0.739 (0.631-0.847, p < 0.001) for predicting prolonged PROM. CONCLUSION: Uterine contractions and cervical examination parameters can be used for prediction of prolonged interval to spontaneous onset of labor in women with term PROM. PMID- 27486011 TI - Running injuries in novice runners enrolled in different training interventions: a pilot randomized controlled trial. AB - : The purpose of this trial was to evaluate injury risk in novice runners participating in different strength training interventions. This was a pilot randomized controlled trial. Novice runners (n = 129, 18-60 years old, <2 years recent running experience) were block randomized to one of three groups: a "resistance" strength training group, a "functional" strength training group, or a stretching "control" group. The primary outcome was running related injury. The number of participants with complaints and the injury rate (IR = no. injuries/1000 running hours) were quantified for each intervention group. For the first 8 weeks, participants were instructed to complete their training intervention three to five times a week. The remaining 4 months was a maintenance period. TRIAL REGISTRATION: NCT01900262. A total of 52 of the 129 (40%) novice runners experienced at least one running related injury: 21 in the functional strength training program, 16 in the resistance strength training program and 15 in the control stretching program. Injury rates did not differ between study groups [IR = 32.9 (95% CI 20.8, 49.3) in the functional group, IR = 31.6 (95% CI 18.4, 50.5) in the resistance group, and IR = 26.7 (95% CI 15.2, 43.2)] in the control group. Although this was a pilot assessment, home-based strength training did not appear to alter injury rates compared to stretching. Future studies should consider methods to minimize participant drop out to allow for the assessment of injury risk. Injury risk in novice runners based on this pilot study will inform the development of future larger studies investigating the impact of injury prevention interventions. PMID- 27486012 TI - Ocular morphology and function in juvenile neuronal ceroid lipofuscinosis (CLN3) in the first decade of life. AB - PURPOSE: CLN3 is a rare lysosomal storage disorder. The majority of the patients suffer from neurological degeneration in the first decade of life leading to death in the second or third decade. One of the first symptoms is a rapid visual decline from retinal degeneration. The aim of this study was to correlate the retinal changes in CLN3 as seen with spectral domain optical coherence tomography (SD-OCT) with functional data in patients in the first years after the subjective onset of ocular symptoms. METHODS: Three unrelated children aged from 5.6 to 8.8 years, and with molecularly confirmed CLN3, underwent a comprehensive ophthalmological examination including visual acuity, fundus photography, fundus autofluorescence (FAF), electrophysiology (multifocal ERG), Goldmann visual fields, and SD-OCT. RESULTS: A predominant loss of the first and second neuron retinal layers progressing from the macula to the periphery was identifed. The retinal nerve fibre layer (RNFL) displayed gliosis and an irregular lining of the inner limiting membrane. Compared to the preferential reduction of photoreceptor layer thickness in other maculopathies with pan-retinal involvement, the thickness of the first and second neuron layers was reduced simultaneously in CLN3. Functional testing by multifocal ERG reflected the degenerative progress. Semiquantitative evaluation revealed a generally reduced FAF. CONCLUSION: This is the first detailed morphological evaluation of CLN3 patients in the first years after the subjective onset of ocular symptoms. CLN3 is characterized by an early degeneration predominant of the first and second neuron compared to other macular and generalized retinal dystrophies. Imaging is instrumental for early diagnosis and gene-directed molecular analysis of this fatal disorder. PMID- 27486010 TI - NAFLD and liver transplantation: Current burden and expected challenges. AB - Because of global epidemics of obesity and type 2 diabetes, the prevalence of non alcoholic fatty liver disease (NAFLD) is increasing both in Europe and the United States, becoming one of the most frequent causes of chronic liver disease and predictably, one of the leading causes of liver transplantation both for end stage liver disease and hepatocellular carcinoma. For most transplant teams around the world this will raise many challenges in terms of pre- and post transplant management. Here we review the multifaceted impact of NAFLD on liver transplantation and will discuss: (1) NAFLD as a frequent cause of cryptogenic cirrhosis, end-stage chronic liver disease, and hepatocellular carcinoma; (2) prevalence of NAFLD as an indication for liver transplantation both in Europe and the United States; (3) the impact of NAFLD on the donor pool; (4) the access of NAFLD patients to liver transplantation and their management on the waiting list in regard to metabolic, renal and vascular comorbidities; (5) the prevalence and consequences of post-transplant metabolic syndrome, recurrent and de novo NAFLD; (6) the alternative management and therapeutic options to improve the long-term outcomes with particular emphasis on the correction and control of metabolic comorbidities. PMID- 27486013 TI - A current snapshot of common genomic variants contribution in psychiatric disorders. AB - In the past decade, numerous advances were achieved in psychiatric genetics. Particularly, the genome wide association studies (GWAS) have contributed to uncovering new genes and pathways associated to psychiatric disorders (PDs). At the same time, with increasing sample sizes in the GWAS, the polygenic risk score (PRS) promoted an additional tool for identification and evaluation the genetic risk quantitatively in PDs. This concept review presents the state of the art GWAS analysis and PRS focusing on the genetic underpinnings of PDs. (c) 2016 Wiley Periodicals, Inc. PMID- 27486014 TI - 10 weeks of heavy strength training improves performance-related measurements in elite cyclists. AB - Elite cyclists have often a limited period of time available during their short preparation phase to focus on development of maximal strength; therefore, the purpose of the present study was to investigate the effect of 10-week heavy strength training on lean lower-body mass, leg strength, determinants of cycling performance and cycling performance in elite cyclists. Twelve cyclists performed heavy strength training and normal endurance training (E&S) while 8 other cyclists performed normal endurance training only (E). Following the intervention period E&S had a larger increase in maximal isometric half squat, mean power output during a 30-s Wingate sprint (P < 0.05) and a tendency towards larger improvement in power output at 4 mmol ? L-1 [la-] than E (P = 0.068). There were no significant difference between E&S and E in changes in 40-min all-out trial (4 +/- 6% vs. -1 +/- 6%, respectively, P = 0.13). These beneficial effects may encourage elite cyclists to perform heavy strength training and the short period of only 10 weeks should make it executable even in the compressed training and competition schedule of elite cyclists. PMID- 27486016 TI - Implementation of an Educational Cartoon ("the Patchbook") and Other Compliance Enhancing Measures by Orthoptists in Occlusion Treatment of Amblyopia. AB - PURPOSE: This implementation study evaluated orthoptists' use of an educational cartoon ("the Patchbook") and other measures to improve compliance with occlusion therapy for amblyopia. METHODS: Participating orthoptists provided standard orthoptic care for one year, adding the Patchbook in the second year. They attended courses on compliance and intercultural communication by communication skills training. Many other compliance-enhancing measures were initiated. Orthoptists' awareness, attitude, and activities regarding noncompliance were assessed through interviews, questionnaires, and observations. Their use of the Patchbook was measured. The study was performed in low socio-economic status (SES) areas and in other areas in the Netherlands. It was attempted to integrate education on compliance into basic and continuing orthoptic training. RESULTS: The Patchbook was used by all 9 orthoptists who participated in low-SES areas and 17 of 23 orthoptists in other areas. Courses changed awareness and attitude about compliance, but this was not sustained. Although orthoptists estimated compliance during patching at 70%, three-quarters never suspected noncompliance during a full day of observation in any of their patients. Explanations to parents who spoke Dutch poorly were short. In the second year, explanations to children were longer. Implementation of all 7 additional compliance-enhancing measures failed. Education on compliance was not integrated into orthoptists' training. CONCLUSION: Almost all orthoptists used the Patchbook and, as another study demonstrated, it proved to be very effective, especially in low-SES areas. Duration of explanation was inversely proportional to parents' fluency in Dutch. Noncompliance was rarely suspected by orthoptists. Although 7 additional compliance-enhancing measures had been conceived and planned with the best intentions, they were not realized. These required extra, unpaid time from the orthoptists, which is especially scarce in hospitals in low-SES areas where the educational cartoon is most needed. PMID- 27486015 TI - Dynamic mRNA and miRNA expression analysis in response to intermuscular bone development of blunt snout bream (Megalobrama amblycephala). AB - Intermuscular bone (IB), which occurs only in the myosepta of lower teleosts, is attracting more attention because they are difficult to remove and make the fish unpleasant to eat. By gaining a better understanding of the genetic regulation of IB development, an integrated analysis of miRNAs and mRNAs expression profiling was performed on Megalobrama amblycephala. Four key development stages were selected for transcriptome and small RNA sequencing. A number of significantly differentially expressed miRNAs/genes associated with bone formation and differentiation were identified and the functional characteristics of these miRNAs/genes were revealed by GO function and KEGG pathway analysis. These were involved in TGF-beta, ERK and osteoclast differentiation pathways known in the literature to affect bone formation and differentiation. MiRNA-mRNA interaction pairs were detected from comparison of expression between different stages. The function annotation results also showed that many miRNA-mRNA interaction pairs were likely to be involved in regulating bone development and differentiation. A negative regulation effect of two miRNAs was verified through dual luciferase reporter assay. As a unique public resource for gene expression and regulation during the IB development, this study is expected to provide forwards ideas and resources for further biological researches to understand the IBs' development. PMID- 27486017 TI - Effects of intermittent pneumatic compression of the thigh on blood flow velocity in the femoral and popliteal veins: developing a new physical prophylaxis for deep vein thrombosis in patients with plaster-cast immobilization of the leg. AB - Patients with plaster-cast immobilization of the lower limb have an estimated venous thromboembolism rate of 2.5 % without prophylaxis, which includes many fatal cases. However, there is no practical physical prophylaxis for deep-vein thrombosis (DVT) in these patients. The aim of this study was to examine the effects of intermittent pneumatic compression on the thigh alone (IPC to the thigh) on peak blood velocity (PBV) in the legs and to consider the possibility that IPC of the thigh could be used as physical prophylaxis for DVT in patients with plaster-cast immobilization of the lower leg. Nine healthy male volunteers and eighteen elderly males were recruited. We immobilized each subject's right lower leg and ankle with a plaster splint, and applied the ActiveCare+S.F.T.((r)) (Medical Compression Systems, Inc.) device to each subject's right thigh. The PBV in the superficial femoral vein (PBVFV) and the popliteal vein (PBVPV) were measured using duplex Doppler ultrasonography. IPC to the thigh resulted in a 2.3 fold increase in PBVFV and a 3.0-fold increase in PBVPV compared with resting at supine in the elderly group. Although IPC to the thigh also increased PBVFV and PBVPV significantly in the sitting position, the change ratios of PBV in the supine and sitting positions were equal (2.6-fold increase in PBVFV and 2.9-fold increase in PBVPV). IPC to the thigh in supine and sitting positions significantly increased PBVFV and PBVPV, and could be a useful prophylaxis for DVT in patients with plaster-cast immobilization of the lower leg. PMID- 27486018 TI - Effect of infertility on quality of life of women: a validation study of the Turkish FertiQoL. AB - The fertility quality of life (FertiQoL) measure specifically evaluates the impact of fertility problems in various life areas. The aim of this study was to examine the relationship between FertiQoL and the hospital anxiety and depression scale (HADS) in the Turkish population. All female patients who underwent various fertility treatments in our infertility clinic from May 2011 to May 2014 were approached to participate in the study and 389 completed the questionnaires. Our results showed that the four core scales of the FertiQoL measure had a Cronbach's alpha value that was between 0.70 and 0.89. Two scales (anxiety and depression) of HADS both had a Cronbach's alpha value of 0.80. These values present a reliable usage of FertiQoL and HADS measures (alpha > 0.60). Significant negative correlations were found between the FertiQoL scales and HADS scales, ranging from -0.27 (between relational scale of FertiQoL and anxiety scale of HADS) to -0.65 (between mind-body scale of FertiQoL and depression scale of HADS). The results of this study provide supportive data to confirm that the Turkish version of FertiQol can accurately evaluate QoL in women who seek fertility treatment in Turkey. PMID- 27486019 TI - Rare Variation in TET2 Is Associated with Clinically Relevant Prostate Carcinoma in African Americans. AB - BACKGROUND: Common variants have been associated with prostate cancer risk. Unfortunately, few are reproducibly linked to aggressive disease, the phenotype of greatest clinical relevance. One possible explanation is that rare genetic variants underlie a significant proportion of the risk for aggressive disease. METHOD: To identify such variants, we performed a two-stage approach using whole exome sequencing followed by targeted sequencing of 800 genes in 652 aggressive prostate cancer patients and 752 disease-free controls in both African and European Americans. In each population, we tested rare variants for association using two gene-based aggregation tests. We established a study-wide significance threshold of 3.125 * 10-5 to correct for multiple testing. RESULTS: TET2 in African Americans was associated with aggressive disease, with 24.4% of cases harboring a rare deleterious variant compared with 9.6% of controls (FET P = 1.84 * 10-5, OR = 3.0; SKAT-O P = 2.74 * 10-5). We report 8 additional genes with suggestive evidence of association, including the DNA repair genes PARP2 and MSH6 Finally, we observed an excess of rare truncation variants in 5 genes, including the DNA repair genes MSH6, BRCA1, and BRCA2 This adds to the growing body of evidence that DNA repair pathway defects may influence susceptibility to aggressive prostate cancer. CONCLUSIONS: Our findings suggest that rare variants influence risk of clinically relevant prostate cancer and, if validated, could serve to identify men for screening, prophylaxis, and treatment. IMPACT: This study provides evidence that rare variants in TET2 may help identify African American men at increased risk for clinically relevant prostate cancer. Cancer Epidemiol Biomarkers Prev; 25(11); 1456-63. (c)2016 AACR. PMID- 27486020 TI - Missing the Target for Routine Human Papillomavirus Vaccination: Consistent and Strong Physician Recommendations Are Lacking for 11- to 12-Year-Old Males. AB - BACKGROUND: Rates of routine human papillomavirus (HPV) vaccination of adolescent males in the United States are low. Leading health organizations advocate consistent and strong physician recommendations to improve HPV vaccine dissemination. This study describes the prevalence and correlates of consistent and strong physician recommendations for HPV vaccination of adolescent males. METHODS: We surveyed pediatric and family medicine physicians in Florida about their HPV vaccine recommendations for male vaccine-eligible age groups (11-12, 13 17, 18-21 years). Descriptive statistics compared consistency and strength of HPV recommendations across age groups. Multivariable logistic regression examined factors associated with consistent and strong recommendations for 11- to 12-year olds. RESULTS: We received 367 completed surveys (51% response rate). Physicians most often consistently and strongly recommended HPV vaccine to males ages 13 to 17 (39%) compared with ages 11 to 12 (31%) and 18 to 21 (31%). Consistent and strong recommendation for 11- to 12-year-old males was more likely to be delivered by Vaccine for Children providers and less likely among physicians who reported more personal barriers to vaccination, particularly concerns about vaccine safety, concerns about adding vaccines to the vaccine schedule, and difficulty in remembering to discuss HPV vaccination. CONCLUSIONS: Physicians' current consistency and strength of HPV vaccine recommendations do not align with national recommendations. Interventions to improve HPV vaccine recommendations must also consider the influence of physicians' personal barriers to HPV vaccine delivery. IMPACT: As one of the first studies to examine both consistency and strength of physicians' HPV vaccine recommendations for males, our findings can inform future interventions focused on facilitating physicians' recommendations. Cancer Epidemiol Biomarkers Prev; 25(10); 1435-46. (c)2016 AACR. PMID- 27486021 TI - Neuregulin-1 (Nrg1) signaling has a preventive role and is altered in the frontal cortex under the pathological conditions of Alzheimer's disease. AB - Alzheimer's disease (AD), one of the neurodegenerative disorders that may develop in the elderly, is characterized by the deposition of beta-amyloid protein (Abeta) and extensive neuronal cell death in the brain. Neuregulin-1 (Nrg1) mediated intercellular and intracellular communication via binding to ErbB receptors regulates a diverse set of biological processes involved in the development of the nervous system. In the present study, a linear correlation was identified between Nrg1 and phosphorylated ErbB (pNeu and pErbB4) receptors in a human cortical tissue microarray. In addition, increased expression levels of Nrg1, but reduced pErbB receptor levels, were detected in the frontal lobe of a patient with AD. Western blotting and immunofluorescence staining were subsequently performed to uncover the potential preventive role of Nrg1 in cortical neurons affected by the neurodegenerative processes of AD. It was observed that the expression of Nrg1 increased as the culture time of the cortical neurons progressed. In addition, H2O2 and Abeta1-42, two inducers of oxidative stress and neuronal damage, led to a dose-dependent decrease in Nrg1 expression. Recombinant Nrg1beta, however, was revealed to exert a pivotal role in preventing oxidative stress and neuronal damage from occurring in the mouse cortical neurons. Taken together, these results suggest that changes in Nrg1 signaling may influence the pathological development of AD, and exogenous Nrg1 may serve as a potential candidate for the prevention and treatment of AD. PMID- 27486022 TI - Comparative evaluation of outcomes of phacoemulsification in vitrectomized eyes: silicone oil versus air/gas group. AB - The purpose of this study is to comparatively evaluate the morphology of cataract, intraoperative and postoperative complications (IPC), and surgical outcomes of phacoemulsification in post 23G vitrectomized eyes in silicone oil versus air/gas group. This prospective interventional clinical study took place in the Dr. RP Centre for Ophthalmic Sciences, AIIMS, New Delhi, India. Eighty nine eyes of 89 consecutive vitrectomized patients with cataract were included. All underwent phacoemulsification and evaluated for cataract morphology, surgical difficulties, IPC, visual acuity, and specular count. Mean age of patients was 50.24 +/- 15.19 years. There were 65 males and 24 females and 48 eyes in silicone oil group and 41 in air/gas group. Combination type was the commonest morphology seen in both silicone oil (52.08 %) and air/gas group (70.33 %) followed by posterior subcapsular cataract (PSC) in 31.25 % silicone group and 12.2 % air/gas group. Posterior capsular plaque (PCP) was seen in 41.67 % of silicone oil versus 7.32 % air/gas group; p < 0.005. Pupillary abnormalities were significantly more in oil (31.25 %) than in air/gas group (9.76 %); p = 0.014. Mean duration between vitrectomy and phacoemulsification in oil group versus air/gas group was 8.39 +/- 4.7 months and 10.9 +/- 5.22 months, respectively; p < 0.005. Mean postoperative logMAR visual acuity was better in air/gas (0.43 +/- 0.25) than in oil (0.66 +/- 0.29) group, p < 0.005. There was no significant difference in mean endothelial cell loss postoperatively in either groups (p = 0.25). Morphology of cataract differs in the two groups with PSC being more common in oil group. The mean time of cataract onset was significantly less in patients with oil group, and poor visual outcome in oil group may be attributable to the increased PCP noted. PMID- 27486023 TI - Enhanced depth imaging is less suited than indocyanine green angiography for close monitoring of primary stromal choroiditis: a pilot report. AB - The purpose of this study is to investigate the performance, utility, and precision of enhanced depth imaging optical coherence tomography (EDI-OCT) versus indocyanine green angiography (ICGA) in tracking any fluctuation in the activity of stromal choroiditis in response to therapeutic interventions during long-term follow-up. Patients with a diagnosis of Vogt-Koyanagi-Harada (VKH) disease or birdshot retinochoroiditis (BRC), with untreated initial disease, and having had long-term follow-up, including both ICGA and EDI-OCT, were recruited at the Centre for Ophthalmic Specialised care, Lausanne, Switzerland. Angiography signs were quantified according to established dual fluorescein angiography (FA) and ICGA scoring systems for uveitis. Changes in ICGA score and EDI choroidal thickness, in response to therapeutic intervention, were assessed. In the four eyes analysed (2 BRC and 2 VKH), mean EDI-OCT choroidal thickness decreased from 672 +/- 101 um at presentation to 358.5 +/- 44.5 um in a mean of 26.5 months, i.e. the time taken to stabilize the disease. Mean ICGA scores decreased from 28 +/- 4.2 at presentation to 5 +/- 7 at stabilization. Only ICGA was sufficiently sensitive and reactive having the ability to detect disease recurrences and efficacy or the absence of effect of successive treatment changes, detected in seven instances during follow-up, not recorded by EDI-OCT. This pilot study showed that ICGA was a more sensitive methodology, which promptly identifies evolving subclinical and occult choroidal disease, and flag occult recurrence and/or therapeutic responses that were otherwise missed by EDI-OCT. Although choroidal thickness was proportional to treatment course, demonstrating a linear decrease, these changes were too sluggish to be relied upon for close follow-up and timely adjustment of therapy. PMID- 27486024 TI - Opening of the inward rectifier potassium channel alleviates maladaptive tissue repair following myocardial infarction. AB - Activation of the inward rectifier potassium current (IK1) channel has been reported to be associated with suppression of ventricular arrhythmias. In this study, we tested the hypothesis that opening of the IK1 channel with zacopride (ZAC) was involved in the modulation of tissue repair after myocardial infarction. Sprague-Dawley rats were subject to coronary artery ligation and ZAC was administered intraperitoneally (15 ug/kg/day) for 28 days. Compared with the ischemia group, treatment with ZAC significantly reduced the ratio of heart/body weight and the cross-sectional area of cardiomyocytes, suggesting less cardiac hypertrophy. ZAC reduced the accumulation of collagen types I and III, accompanied with decrease of collagen area, which were associated with a reduction of collagen deposition in the fibrotic myocardium. Echocardiography showed improved cardiac function, evidenced by the reduced left ventricular end diastolic dimension and left ventricular end-systolic dimension, and the increased ejection fraction and fractional shortening in ZAC-treated animals (all P < 0.05 vs. ischemia group). In coincidence with these changes, ZAC up-regulated the protein level of the IK1 channel and down-regulated the phosphorylation of mammalian target of rapamycin (mTOR) and 70-kDa ribosomal protein S6 (p70S6) kinase. Administration of chloroquine alone, an IK1 channel antagonist, had no effect on all the parameters measured, but significantly blocked the beneficial effects of ZAC on cardiac repair. In conclusion, opening of the IK1 channel with ZAC inhibits maladaptive tissue repair and improves cardiac function, potentially mediated by the inhibition of ischemia-activated mTOR-p70S6 signaling pathway via the IK1 channel. So the development of pharmacological agents specifically targeting the activation of the IK1 channel may protect the heart against myocardial ischemia-induced cardiac dysfunction. PMID- 27486025 TI - Haplotype distribution and association of candidate genes with salt tolerance in Indian wild rice germplasm. AB - KEY MESSAGE: The association of natural genetic variations of salt-responsive candidate genes belonging to different gene families with salt-tolerance phenotype and their haplotype variation in different geographic regions. Soil salinity covers a large part of the arable land of the world and is a major factor for yield losses in salt-sensitive crops, such as rice. Different gene families that respond to salinity have been identified in rice, but limited success has been achieved in developing salt-tolerant cultivars. Therefore, 21 salt stress-responsive candidate genes belonging to different gene families were re-sequenced to analyse their genetic variation and association with salt tolerance. The average single nucleotide polymorphism (SNP) density was 16 SNPs per kbp amongst these genes. The identified nucleotide and haplotype diversity showed comparatively higher genetic variation in the transporter family genes. Linkage disequilibrium (LD) analysis showed significant associations of SNPs in BADH2, HsfC1B, MIPS1, MIPS2, MYB2, NHX1, NHX2, NHX3, P5CS1, P5CS2, PIP1, SIK1, SOS1, and SOS2 genes with the salt-tolerant phenotype. A combined analysis of SNPs in the 21 candidate genes and eight other HKT transporter genes produced two separate clusters of tolerant genotypes, carrying unique SNPs in the ion transporter and osmoticum-related genes. Haplotype network analysis showed all the major and few minor alleles distributed over distant geographic regions. Minor haplotypes may be recently evolved alleles which migrated to distant geographic regions and may represent recent expansion of Indian wild rice. The analysis of genetic variation in different gene families identified the relationship between adaptive variations and functional significance of the genes. Introgression of the identified alleles from wild relatives may enhance the salt tolerance and consequently rice production in the salinity-affected areas. PMID- 27486027 TI - Fertility Awareness Counseling for Adolescent Girls; Guiding Conception: The Right Time, Right Weight, and Right Way. AB - STUDY OBJECTIVE: To provide a detailed summary of fertility awareness counseling pearls for healthy teens and those with fertility-relevant comorbidities, and to assist providers in offering such counseling to adolescents and young adult women. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Comprehensive literature review of English-language studies relating to fertility in pediatric and adolescent female patients (ages 13-21 years), and evidence based dialogue guide. RESULTS: The literature indicates that although adolescents are interested in discussing sexuality and reproduction, this is commonly overlooked during the standard office medical visit. As a result, adolescents often turn to less reliable sources and hold a variety of reproductive misconceptions and a sense of lack of control over future fertility. We found no studies that examined the routine provision of fertility awareness counseling with healthy adolescents. There are a multitude of specific gynecologic and medical conditions that have ramifications for fertility. We detail these comprehensively, and provide a dialogue guide to assist with fertility awareness counseling for the female adolescent, containing specific information and indications for referral. CONCLUSION: Providers caring for adolescent girls have the opportunity to enhance fertility awareness as part of a larger reproductive health conversation that adolescents desire, and from which they might benefit. Identifying potential future fertility issues, understanding age-related fertility decline, and aiding in health optimization before future conception might empower the adolescent to make informed reproductive decisions. We provide an algorithm to use with adolescents to discuss the "right time, right weight, right way" to pursue childbearing. PMID- 27486028 TI - Service users' expectations of treatment and support at the Community Mental Health Centre in their recovery. AB - BACKGROUND: Focus on service users' needs, coping and empowerment, user involvement, and comprehensiveness are supposed to be key elements of the Community Mental Health Centres in Norway. Taking a user-oriented approach means acknowledging the individual's own expectations, aims and hopes. However, studies that have investigated service users' expectations of treatment and support at Community Mental Health Centres are hard to find. OBJECTIVE: The aim of the study was therefore to explore service users' expectations at the start of treatment at a Community Mental Health Centre. METHOD: Within a collaborative framework, taking a hermeneutic-phenomenological approach, ten service users participated in in-depth interviews about their expectations, hopes and aims for treatment and recovery. The participants sought help due to various mental health issues that had interfered with their lives and created disability and suffering. A data driven stepwise approach in line with thematic analysis was used. The study was approved by the Norwegian Social Science Data Services. RESULTS: The following four main themes representing participants' expectations at the start of treatment were elicited: hope for recovery, developing understanding, finding tools for coping and receiving counselling and practical assistance. Participants' expectations about treatment were tightly interwoven with their personal aims and hopes for their future life, and expectations were often related to practical and financial problems, the solution of which being deemed necessary to gain a safe basis for recovery in the long run. LIMITATIONS: The transferability of the results may be limited by the small number of participants. CONCLUSIONS: The study emphasises how important it is that service users' personal aims and expectations guide the collaborative treatment process. In addition to providing treatment aimed at improving symptoms, Community Mental Health Centres should take a more comprehensive approach than today by providing more support with family issues, social life, education, work and financial issues. PMID- 27486029 TI - A case of endocarditis mimicking Crimean-Congo haemorrhagic fever. AB - Infective endocarditis (IE) is life-threatening condition with a highly variable clinical presentation. We report a case of acute IE with delayed diagnosis which resulted due to an initial misdiagnosis of Crimean Congo Hemorrhagic Fever (CCHF) in an endemic area. A case was due to Staphylococcus aureus and requiring valve replacement. They serve to emphasize the importance of careful history taking, physical examination and a broad range of different diagnostic techniques in the context of suspected viral hemorrhagic fever. PMID- 27486031 TI - Diagnostic accuracy of individual antenatal tools for prediction of small-for gestational age at birth. AB - OBJECTIVE: To determine the accuracy of fetal and newborn growth charts for the prediction of small-for-gestational age (SGA) at birth (birth weight < 10th centile). METHODS: This was a prospective cohort study performed within a UK specialist fetal growth clinic. A total of 105 consecutive pregnant women referred for a suspected SGA fetus were included. All pregnancies were managed according to a standard protocol using estimated fetal weight (EFW) plotted on customized Gestation Related Optimal Weight (GROW) charts. The last antenatal estimates of EFW (according to charts of GROW, Hadlock et al. and Mikolajczyk et al.), abdominal circumference (AC) (according to charts of Hadlock et al., INTERGROWTH-21st Project and Chitty et al.) or change in AC over time (calculated according to Pregnancy Outcome Prediction (POP) study) were compared against four birth-weight charts (GROW, INTERGROWTH-21st , Mikolajczyk et al. and World Health Organization (WHO)). The ability of each antenatal test to predict adverse perinatal outcome (APO) was assessed. RESULTS: Birth weight < 10th centile was assigned in 62 (59%) neonates using the GROW chart, 57 (54%) using the Mikolajczyk et al. chart, 55 (52%) using the INTERGROWTH-21st chart and 51 (49%) using the WHO chart. AC-Hadlock had the best negative likelihood ratio (range, 0.3-0.4) and sensitivity (range, 74%-82%) for predicting SGA as defined by all four postnatal birth-weight charts. AC-INTERGROWTH-21st had the best positive likelihood ratio (range, 5.9-10.9) and specificity (94%-96%). For prediction of APO, AC-Hadlock and EFW-GROW had the best sensitivities (57% and 52%, respectively), whereas AC-POP had the best positive likelihood ratio (2.2) and specificity (88%). Antenatal prediction of APO increased to a sensitivity of 61% when AC-POP and EFW-GROW were combined; however, specificity was only 56%. CONCLUSIONS: We have identified wide variation in the diagnostic accuracy of various antenatal tools for the prediction of both SGA and APO, dependent on the choice of chart. Suboptimal diagnostic accuracy of commonly used antenatal tests may lead to increasing medicalization without prevention of APO. Researchers should focus their attention on a combination of fetal biometry and biomarkers for better prediction of SGA and prevention of APO. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27486032 TI - Desulfovibrio vulgaris CbiKP cobaltochelatase: evolution of a haem binding protein orchestrated by the incorporation of two histidine residues. AB - The sulfate-reducing bacteria of the Desulfovibrio genus make three distinct modified tetrapyrroles, haem, sirohaem and adenosylcobamide, where sirohydrochlorin acts as the last common biosynthetic intermediate along the branched tetrapyrrole pathway. Intriguingly, D. vulgaris encodes two sirohydrochlorin chelatases, CbiKP and CbiKC , that insert cobalt/iron into the tetrapyrrole macrocycle but are thought to be distinctly located in the periplasm and cytoplasm respectively. Fusing GFP onto the C-terminus of CbiKP confirmed that the protein is transported to the periplasm. The structure-function relationship of CbiKP was studied by constructing eleven site-directed mutants and determining their chelatase activities, oligomeric status and haem binding abilities. Residues His154 and His216 were identified as essential for metal chelation of sirohydrochlorin. The tetrameric form of the protein is stabilized by Arg54 and Glu76, which form hydrogen bonds between two subunits. His96 is responsible for the binding of two haem groups within the main central cavity of the tetramer. Unexpectedly, CbiKP is shown to bind two additional haem groups through interaction with His103. Thus, although still retaining cobaltochelatase activity, the presence of His96 and His103 in CbiKP , which are absent from all other known bacterial cobaltochelatases, has evolved CbiKP a new function as a haem binding protein permitting it to act as a potential haem chaperone or transporter. PMID- 27486033 TI - Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Hepatitis C Virus Genotype 2, 3, 4, or 6 Infections in an Open-Label, Phase 2 Trial. AB - BACKGROUND & AIMS: Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections whose prior course of antiviral therapy has failed, and the feasibility of shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS 9857 in these patients. METHODS: We performed a multicenter, open-label trial at 32 sites in the United States and 2 sites in New Zealand from March 3, 2015 to April 27, 2015. Our study included 128 treatment-naive and treatment-experienced patients (1 with HCV genotype 1b; 33 with HCV genotype 2; 74 with HCV genotype 3; 17 with genotype HCV 4; and 3 with HCV genotype 6), with or without compensated cirrhosis. All patients received sofosbuvir-velpatasvir (400 mg/100 mg fixed-dose combination tablet) and GS-9857 (100 mg) once daily for 6-12 weeks. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: After 6 weeks of treatment, SVR12s were achieved by 88% of treatment naive patients without cirrhosis (29 of 33; 95% confidence interval, 72%-97%). After 8 weeks of treatment, SVR12s were achieved by 93% of treatment-naive patients with cirrhosis (28 of 30; 95% CI, 78%-99%). After 12 weeks of treatment, SVR12s were achieved by all treatment-experienced patients without cirrhosis (36 of 36; 95% CI, 90%-100%) and 97% of treatment-experienced patients with cirrhosis (28 of 29; 95% CI, 82%-100%). The most common adverse events were headache, diarrhea, fatigue, and nausea. Three patients (1%) discontinued treatment due to adverse events. CONCLUSIONS: In a phase 2 open-label trial, we found sofosbuvir velpatasvir plus GS-9857 (8 weeks in treatment-naive patients or 12 weeks in treatment-experienced patients) to be safe and effective for patients with HCV genotype 2, 3, 4, or 6 infections, with or without compensated cirrhosis. ClinicalTrials.gov ID: NCT02378961. PMID- 27486034 TI - Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Genotype 1 Hepatitis C Virus Infection in an Open-Label, Phase 2 Trial. AB - BACKGROUND & AIMS: The best regimen to re-treat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus genotype 1 infection. METHODS: We performed an open-label trial at 32 sites in the United States and at 2 sites in New Zealand of 197 patients with genotype 1 hepatitis C virus infection, with or without compensated cirrhosis, who were treatment-naive or were treated previously with a DAA. Between March 2, 2015, and September 1, 2015, patients received sofosbuvir-velpatasvir (400 mg/100 mg in a fixed-dose combination) plus GS-9857 (100 mg) once daily for 6-12 weeks, plus ribavirin for 1 treatment group consisting of treatment-naive patients with cirrhosis. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: Among treatment-naive patients without cirrhosis, 71% (24 of 34; 95% confidence interval [CI], 53-85) achieved SVR12 after 6 weeks of treatment and 100% (36 of 36; 95% CI, 90%-100%) achieved SVR12 after 8 weeks of treatment. Among treatment-naive patients with cirrhosis, 94% (31 of 33; 95% CI, 80-99) achieved SVR12 after 8 weeks of treatment and 81% (25 of 31; 95% CI, 63 93) achieved SVR12 after 8 weeks of treatment with ribavirin. Among DAA experienced patients treated for 12 weeks, 100% without cirrhosis (31 of 31; 95% CI, 89-100) and 100% with cirrhosis (32 of 32; 95% CI, 89-100) achieved SVR12. The most common adverse events were headache, diarrhea, fatigue, and nausea. One patient (<1%) discontinued treatment because of adverse events. CONCLUSIONS: In a phase 2 open-label trial, we found 8 weeks of treatment with sofosbuvir velpatasvir plus GS-9857 to be safe and effective in treatment-naive patients; 12 weeks was safe and effective in patients previously treated with DAAs. The combination was safe and effective in patients with or without compensated cirrhosis. Clinicaltrials.gov no: NCT02378935. PMID- 27486036 TI - Hybrids of the Benzofuran Core from Natural Products and the 2,4-Dihydroxy-5 isopropylbenzene Fragment as Potent Hsp90 Inhibitors: Design, Synthesis and Bioevaluation. AB - Several chemical fragments have been confirmed as highly efficient cores for the design of Hsp90 inhibitors. Molecular hybridization of potent fragments has been widely used as a rational drug discovery strategy. In this study, a novel class of hybrids of benzofuran, a privileged core from natural products, and 2,4 dihydroxy-5-isopropyl phenyl, an efficient fragment in Hsp90 inhibitors, were designed and synthesized. Subsequent evaluation confirmed they inhibited cell proliferation and regulated the level of client proteins through Hsp90 inhibition. Some of the hybrids can serve as leads to obtain novel chemotypes of Hsp90 inhibitors. The methods reported here may expand the range of known structural types accommodated by the ATP binding site of Hsp90. PMID- 27486035 TI - [Characteristics of potentially inappropriate prescribing of drugs in elderly polypathological patients]. AB - OBJECTIVE: To analyse potentially inappropriate prescribing (PIP) in elderly polypathological patients (PP). METHOD: Multicentre observational, prospective study of 672 patients aged 75 years and older hospitalised in Internal Medicine between April 2011 and March 2012. The Beers, STOPP-START and ACOVE criteria were used to detect potentially inappropriate prescribing and the results of PP and non-PP patients were compared. RESULTS: Of the 672 patients included, 419 (62%) were polypathological, of which 89.3% met PIP criteria versus 79.4% of non polypathological patients (p <0.01). 40.3% of polypathological patients met at least one Beers criteria, 62.8% at least one STOPP criteria, 62.3% at least one START criteria and 65.6% at least one ACOVE criteria. The rate of potentially inappropriate prescribing was higher in polypathological patients regardless of the tool used. CONCLUSIONS: Given the high rate of potentially inappropriate prescribing in polypathological patients, strategies to improve prescribing adequacy must be developed. PMID- 27486037 TI - A Combinational Strategy of Model Disturbance and Outlier Comparison to Define Applicability Domain in Quantitative Structural Activity Relationship. AB - In order to define an applicability domain for quantitative structure-activity relationship modeling, a combinational strategy of model disturbance and outlier comparison is developed. An indicator named model disturbance index was defined to estimate the prediction error. Moreover, the information of the outliers in the training set was used to filter the unreliable samples in the test set based on "structural similarity". Chromatography retention indices data were used to investigate this approach. The relationship between model disturbance index and prediction error can be found. Also, the comparison between the outlier set and the test set could provide additional information about which unknown samples should be paid more attentions. A novel technique based on model population analysis was used to evaluate the validity of applicability domain. Finally, three commonly used methods, i.e. Leverage, descriptor range-based and model perturbation method, were compared with the proposed approach. PMID- 27486038 TI - Network Analysis of Publications on Topological Indices from the Web of Science. AB - In this paper we analyze a collection of bibliographic networks, constructed from the data from the Web of Science on works (papers, books, etc.) on the topic of topological indices and on relating scientific fields. We present the general outlook and more specific findings about authors, works and journals, subtopics and keywords and also important relations between them based on scientometric approaches like the strongest and main citation paths, the main themes on citation path based on keywords, results of co-authorship analysis in form of the most prominent islands of citing authors, groups of collaborating authors, two mode cores of authors and works. We investigate the nature of citing of authors, important journals and citing of works between them, journals preferred by authors and expose hierarchy of similar collaborating authors, based on keywords they use. We perform temporal analysis on one important journal as well. We give a comprehensive scientometric insight into the field of topological indices. PMID- 27486039 TI - Design Some New Type-I c-met Inhibitors Based on Molecular Docking and Topomer CoMFA Research. AB - In this paper, a specific design strategy targeting c-met kinase was reported based on docking modeling and topomer comparative molecular field analysis (Topomer CoMFA). A novel U-shape conformation which is distinct from the literature was demonstrated by molecular docking among 68 U-shape c-met inhibitors. According to the docking results, two Topomer CoMFA models with high predictive ability were established based on the two fragment rule. The results from both docking and topomer CoMFA showed that the pi-pi stacking interaction with Tyr1230 and the hydrogen bond with hinge region play an important role in inhibitory activity. Furthermore, the flexible linker and the adjacent solvent group would be favorable to stabilize the conformation and to enhance the two interactions mentioned above. Based on our patent, 14 new compounds were designed by our design strategy. The binding mode exhibited as expected and their activities were predicted by topomer CoMFA model. The preliminary biological tests showed most of them have potent activity to c-met kinase. Our study would provide guidelines to design some new U-shaped c-met inhibitors with new scaffolds and optimize the current molecules. PMID- 27486040 TI - Compound Structure-Independent Activity Prediction in High-Dimensional Target Space. AB - Profiling of compound libraries against arrays of targets has become an important approach in pharmaceutical research. The prediction of multi-target compound activities also represents an attractive task for machine learning with potential for drug discovery applications. Herein, we have explored activity prediction in high-dimensional target space. Different types of models were derived to predict multi-target activities. The models included naive Bayesian (NB) and support vector machine (SVM) classifiers based upon compound structure information and NB models derived on the basis of activity profiles, without considering compound structure. Because the latter approach can be applied to incomplete training data and principally depends on the feature independence assumption, SVM modeling was not applicable in this case. Furthermore, iterative hybrid NB models making use of both activity profiles and compound structure information were built. In high dimensional target space, NB models utilizing activity profile data were found to yield more accurate activity predictions than structure-based NB and SVM models or hybrid models. An in-depth analysis of activity profile-based models revealed the presence of correlation effects across different targets and rationalized prediction accuracy. Taken together, the results indicate that activity profile information can be effectively used to predict the activity of test compounds against novel targets. PMID- 27486041 TI - Discovery of Potential, Non-Toxic Influenza Virus Inhibitor by Computational Techniques. AB - Influenza infection continues to be a major problem in many parts of the world. Rimantadine is a first-line drug used to treat the influenza infection by targeting M2 proton channel. However, S31N mutation in M2 proton channel diminishes the efficiency of rimantadine and creates resistance. To address this issue, the present study was aimed to screen the effective lead candidate against drug resistance strain of influenza from DrugBank database. Initially, the lead molecules were filtered using Lipinski rule of five and the drug likeliness property. Subsequently, the data reduction was carried out by employing molecular docking study. Finally, molecular dynamics simulations techniques were performed to validate the lead compound. Most importantly, the -p LD50 of the screened lead molecule was calculated using CORAL software to estimate the Rat oral toxicity. Accordingly, memantine may possibly become a promising lead compound of rimantadine-resistant influenza virus strain. PMID- 27486042 TI - Young-of-the-year fish as a prospective bioindicator for aquatic environmental contamination monitoring. AB - Toxic metals (Hg, Cd, Pb) and fifteen perfluoroalkyl substances (PFASs) were determined in different fish samples at two locations on the Elbe River in the Czech Republic. The muscle tissue of the two adult fish species most commonly used as bioindicators in central Europe and whole body homogenates of various species of young-of-the-year (YOY) fish were used. The purpose of this study was to evaluate the potential to replace adult fish muscle tissue with YOY fish for contamination monitoring. All of the toxic metals and five of the fifteen PFASs were found in the YOY fish samples while only mercury and PFOS were detected in the muscle tissue of adults. The concentration of total mercury (THg) in the YOY fish homogenates ranged between 0.014 and 0.062 MUg g(-1). Of the spectrum of analysed pollutants, only the THg concentrations were lower in YOY fish homogenates than in adult muscle tissue. The cadmium concentration varied from 0.004 to 0.024 MUg g(-1) and the lead concentration varied from 0.032 to 0.396 MUg g(-1) in YOY fish homogenates, while in most of the adult samples, Cd and Pb were below the detection limit of the analytical methods employed. The PFOS concentrations in YOY fish homogenates were comparable to the concentrations frequently found in adult liver tissue. These results show that mixed shoals of YOY fish can be successfully used for aquatic bio-monitoring. Interspecific variability in the concentrations of the target pollutants in YOY fish whole body homogenates is usually lower than the intraspecific variability of the concentrations of the pollutants in adult fish muscle. YOY fish were found to be a suitable bioindicator and have several advantages compared to adult fish. PMID- 27486043 TI - Occurrence and partitioning of bisphenol analogues in water and sediment from Liaohe River Basin and Taihu Lake, China. AB - Bisphenol analogues are widely used in the manufacture of polycarbonate plastics and epoxy resins, and the demand and production capacity of these compounds are growing rapidly in China. The occurrence and distribution of bisphenol analogues other than bisphenol A (BPA) in the aquatic environment is still poorly understood. In this study, nine bisphenol analogues were measured in water and sediment samples from Taihu Lake (TL), Liaohe River basin, including Liaohe River (LR) and Hunhe River (HR), China. Water samples from LR and HR contained much higher total bisphenols (?BPs) concentrations. BPA and bisphenol S (BPS) were predominant with a summed contribution of 55, 75, and 75% to the ?BPs in TL, LR, and HR waters, respectively. This suggests that BPA and BPS were the most widely used and manufactured bisphenols in these regions. In sediment, BPA was always predominant, with the next abundant compound bisphenol F (BPF) in TL and HR sediment, but BPS in LR sediment. The average field sediment-water partitioning coefficients (log Koc) were calculated for the first time for certain bisphenols and were determined to be 4.7, 4.6, 3.8, 3.7, and 3.5 mL/g for BPF, BPAP, BPA, BPAF, and BPS, respectively. PMID- 27486044 TI - High flux and antifouling properties of negatively charged membrane for dyeing wastewater treatment by membrane distillation. AB - This study investigated the applicability of membrane distillation (MD) to treat dyeing wastewater discharged by the textile industry. Four different dyes containing methylene blue (MB), crystal violet (CV), acid red 18 (AR18), and acid yellow 36 (AY36) were tested. Two types of hydrophobic membranes made of polytetrafluoroethylene (PTFE) and polyvinylidene fluoride (PVDF) were used. The membranes were characterized by testing against each dye (foulant-foulant) and the membrane-dye (membrane-foulant) interfacial interactions and their mechanisms were identified. The MD membranes possessed negative charges, which facilitated the treatment of acid and azo dyes of the same charge and showed higher fluxes. In addition, PTFE membrane reduced the wettability with higher hydrophobicity of the membrane surface. The PTFE membrane evidenced especially its resistant to dye absorption, as its strong negative charge and chemical structure caused a flake like (loose) dye-dye structure to form on the membrane surface rather than in the membrane pores. This also enabled the recovery of flux and membrane properties by water flushing (WF), thereby direct-contact MD with PTFE membrane treating 100 mg/L of dye mixtures showed stable flux and superior color removal during five days operation. Thus, MD shows a potential for stable long-term operation in conjunction with a simple membrane cleaning process, and its suitability in dyeing wastewater treatment. PMID- 27486045 TI - Targeting CDK5 post-stroke provides long-term neuroprotection and rescues synaptic plasticity. AB - Post-stroke cognitive impairment is a major cause of long-term neurological disability. The prevalence of post-stroke cognitive deficits varies between 20% and 80% depending on brain region, country, and diagnostic criteria. The biochemical mechanisms underlying post-stroke cognitive impairment are not known in detail. Cyclin-dependent kinase 5 is involved in neurodegeneration, and its dysregulation contributes to cognitive disorders and dementia. Here, we administered cyclin-dependent kinase 5-targeting gene therapy to the right hippocampus of ischemic rats after transient right middle cerebral artery occlusion. Cyclin-dependent kinase 5 RNA interference prevented the impairment of reversal learning four months after ischemia as well as neuronal loss, tauopathy, and microglial hyperreactivity. Additionally, cyclin-dependent kinase 5 silencing increased the expression of brain-derived neurotrophic factor in the hippocampus. Furthermore, deficits in hippocampal long-term potentiation produced by excitotoxic stimulation were rescued by pharmacological blockade of cyclin dependent kinase 5. This recovery was blocked by inhibition of the TRKB receptor. In summary, these findings demonstrate the beneficial impact of cyclin-dependent kinase 5 reduction in preventing long-term post-ischemic neurodegeneration and cognitive impairment as well as the role of brain-derived neurotrophic factor/TRKB in the maintenance of normal synaptic plasticity. PMID- 27486047 TI - Nonalcoholic steatohepatitis heralding olmesartan-induced sprue-like enteropathy. PMID- 27486049 TI - Acute pancreatitis: An unusual cause of esophageal stricture. PMID- 27486048 TI - FOLFOX4 or sorafenib as the first-line treatments for advanced hepatocellular carcinoma: A cost-effectiveness analysis. AB - BACKGROUND: This study aimed to investigate the pharmaco-economic implications of FOLFOX4 or sorafenib for advanced hepatocellular carcinoma in China. METHODS: To conduct the analysis, we performed a Markov model to simulate the process of advanced HCC treated with sorafenib or FOLFOX4. Clinical data were obtained from the ORIENTAL trial and the EACH trial. Incremental cost-effectiveness ratio was regarded as the primary outcome in the analysis. One-way sensitivity analysis as well as probabilistic sensitivity analysis was performed to explore the impact of essential variables on the results of the analysis. RESULTS: Treatment with sorafenib provided an effectiveness gain of 0.3935 quality-adjusted life year at an average cost of $18,748.00, whereas chemotherapy of FOLFOX4 brought 0.3808 quality-adjusted life year at a cost of $6876.02. The incremental cost effectiveness ratio of FOLFOX4 versus sorafenib was $934,801.57/QALY. In a probabilistic sensitivity analysis based on a Monte Carlo simulation of 1000 items, the probabilities of FOLFOX4 and sorafenib being cost-effective were 100% and 0% using a willingness-to-pay threshold of $20,301.00 per quality-adjusted life year. CONCLUSIONS: FOLFOX4 chemotherapy is likely to be a cost-effective option compared with sorafenib in the treatment of advanced hepatocellular carcinoma in China. PMID- 27486050 TI - The power of the patient question: A secret shopper study. AB - OBJECTIVES: To examine the effect of one standardized patient question on the length, number and type of new topics pharmacists addressed. To explore how community pharmacists counsel secret shoppers on two types of over-the-counter (OTC) medications-ibuprofen (IB) and emergency contraceptives (EC). METHODS: 25 pharmacists from 7 independent, midwestern community pharmacies consented to have secret shoppers purchase an OTC medication and to have their consultations audio recorded. Following standardized scenarios, 5 secret shoppers audio-recorded 73 encounters. At the end of 36 encounters secret shoppers asked one standard question, "What else should I know before taking this product?" Role Theory informed the study design with apriori hypotheses that topics assessed, topics discussed, and consultation length would vary by the OTC medication (IB or EC) and whether secret shoppers asked a question. Audio-recording coding had high inter-rater reliability (kappa=0.94). RESULTS: Length of encounter was significantly associated with patients asking the question (p<0.05), but not type of OTC medication. On average 1.22 new topics were discussed with a patient question. New topics included information about safe and efficacious use of the OTC's. CONCLUSION: Results highlight the importance of encouraging patients to ask pharmacists their questions about OTC products for safe use and thorough consultations. PMID- 27486051 TI - Evaluation of individualized quality of life and illness perceptions in low back pain. A patient education cluster randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of a cognitive patient education intervention compared with usual care on secondary outcomes of individual quality of life and psychological outcomes of illness perceptions and pain catastrophizing in patients with low back pain. METHODS: A pragmatic cluster randomized controlled trial in which 16 general practitioners (GPs) and 20 physiotherapists (PTs) in primary care were randomly assigned to provide either a cognitive patient education intervention or usual treatment. Patients were followed up at 4 weeks and 12 months after treatment. Linear mixed models were used with group, time, type of clinician and interaction effects of group*time as fixed effects. RESULTS: A total of 203 patients provided data at baseline, 86% responded at 4 weeks and 74% at 12 months. For all the outcome measures there was a statistically significant effect of time (p<0.001) and type of clinician (p<0.05) during the follow-up year. There was a significant interaction effect of group*time on illness perceptions (p=0.003), however not for the other outcome measures. CONCLUSION: The cognitive patient education intervention initiated a faster improvement in illness perceptions but not in the other outcomes. PRACTICE IMPLICATIONS: A patient education intervention can be beneficial to improve illness perceptions, however more research is needed. PMID- 27486046 TI - Inflammasomes link vascular disease with neuroinflammation and brain disorders. AB - The role of inflammation in neurological disorders is increasingly recognised. Inflammatory processes are associated with the aetiology and clinical progression of migraine, psychiatric conditions, epilepsy, cerebrovascular diseases, dementia and neurodegeneration, such as seen in Alzheimer's or Parkinson's disease. Both central and systemic inflammatory actions have been linked with the development of brain diseases, suggesting that complex neuro-immune interactions could contribute to pathological changes in the brain across multiple temporal and spatial scales. However, the mechanisms through which inflammation impacts on neurological disease are improperly defined. To develop effective therapeutic approaches, it is imperative to understand how detrimental inflammatory processes could be blocked selectively, or controlled for prolonged periods, without compromising essential immune defence mechanisms. Increasing evidence indicates that common risk factors for brain disorders, such as atherosclerosis, diabetes, hypertension, obesity or infection involve the activation of NLRP3, NLRP1, NLRC4 or AIM2 inflammasomes, which are also associated with various neurological diseases. This review focuses on the mechanisms whereby inflammasomes, which integrate diverse inflammatory signals in response to pathogen-driven stimuli, tissue injury or metabolic alterations in multiple cell types and different organs of the body, could functionally link vascular- and neurological diseases and hence represent a promising therapeutic target. PMID- 27486052 TI - Shared decision making within goal setting in rehabilitation settings: A systematic review. AB - OBJECTIVE: To map out and synthesise literature that considers the extent of shared decision-making (SDM) within goal-setting in rehabilitation settings and explore participants' views of this approach within goal-setting. METHODS: Four databases were systematically searched between January 2005-September 2015. All articles addressing SDM within goal-setting involving adult rehabilitation patients were included. The literature was critically appraised followed by a thematic synthesis. RESULTS: The search output identified 3129 studies and 15 articles met the inclusion criteria. Themes that emerged related to methods of SDM within goal-setting, participants' views on SDM, perceived benefits of SDM, barriers and facilitators to using SDM and suggestions to improve involvement of patients resulting in a better process of goal-setting. CONCLUSIONS: The literature showed various levels of patient involvement existing within goal setting however few teams adopted an entirely patient-centred approach. However, since the review has identified clear value to consider SDM within goal-setting for rehabilitation, further research is required and practice should consider educating both clinicians and patients about this approach. PRACTICE IMPLICATIONS: To enhance the use of SDM within goal-setting in rehabilitation it is likely clinicians and patients will require further education on this approach. For clinicians this could commence during their training at undergraduate level. PMID- 27486053 TI - Functional Vegetable Guar (Cyamopsis tetragonoloba L. Taub.) Accessions for Improving Flavonoid Concentrations in Immature Pods. AB - Dry guar (Cyamopsis tetragonoloba L. Taub) seeds are primarily used to extract galactomannan gum for oil fracking, however, the immature pods are used as a vegetable in India and sold in ethnic grocery stores in the Atlanta, Georgia area. Nineteen guar genotypes were grown in the field at Griffin, GA, USA for two years (2010-2011). Since the determination of flavonoid concentration would add value to the guar accessions for use as a functional food vegetable, immature guar pods were evaluated for flavonoid concentration. In this study, the immature pods from these 19 guar accessions were analyzed for flavonoid concentration using high-performance liquid chromatography. Several accessions including PI 253182, PI 262152, PI 263698, and PI 288357 showed significantly greater daidzein concentration than all three controls based on seed production in 2010. However, PI 179926, PI 180434, PI 182969, PI 183400, PI 253182, PI 262152, PI 263882, and PI 263897 exhibited significantly greater genistein concentration than the second and third best controls in 2011. Both PI 180434 and PI 288359 produced significantly higher kaempferol concentration than the third best control. Daidzein concentration was significantly correlated with genistein concentration (r2 = 0.47*) for both years. Luteolin concentration showed a significant negative correlation with genistein (r2 = -0.45*). Quercetin concentration significantly correlated with kaempferol (r2 = 0.854***) and genistein (r2 = 0.455*) concentrations. The accession, PI 542608 was observed to contain high concentrations of kaempferol and quercetin in the cluster analyses. These results will help plant breeders develop guar cultivars with superior flavonoid concentrations. PMID- 27486055 TI - Five (bad) reasons to publish your research in predatory journals. PMID- 27486054 TI - Sphingosine-1-phosphate-enhanced Wnt5a promotes osteogenic differentiation in C3H10T1/2 cells. AB - In this study, we investigated the involvement of Wnt signaling in sphingosine-1 phosphate (S1P)-enhanced osteogenic differentiation of C3H10T1/2 pluripotent stem cells. We found that S1P enhanced the expression of Wnt5a and low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6) during osteogenic differentiation. Wnt5a-neutralizing antibody inhibited S1P-enhanced expression of LRP5/6 and alkaline phosphatase, which are essential for osteogenic differentiation. Conversely, S1P did not affect endogenous canonical Wnt signaling. Taken together, S1P-enhanced Wnt5a promotes LRP5/6 expression, resulting in the trigger of osteogenic differentiation of C3H10T1/2 cells. These findings suggest a potential beneficial role for S1P in bone regeneration. PMID- 27486056 TI - Olfactory Dysfunction in IgG4-Related Disease. AB - IgG4-related disease is a newly recognized systemic disease, and its elucidation is progressing. However, little is known about its sinonasal manifestations. The aim of this study was to assess the olfaction of patients with IgG4-related disease. Twenty-five patients with IgG4-related disease underwent T&T olfactometry to measure olfactory function. We analyzed the clinical features, including serum IgG4 and IgE levels, involved organs, and sinonasal computed tomography scores to explore the etiology of olfactory dysfunction. Thirteen patients with IgG4-related disease were found to have moderate to severe olfactory dysfunction (52%). There were no differences in the clinical features between the olfactory dysfunction group and the normal group. In 7 patients, the inferior turbinate was biopsied to study the correlation between olfaction score and the number of IgG4-positive cells, but no such correlation was found. Six hyposmia patients recovered to a normal state. Five patients recovered after corticosteroid treatment and 1 recovered spontaneously. We found that the prevalence of olfactory dysfunction was high in patients with IgG4-related disease and that it could be reversed. Olfactory dysfunction appears to be a novel important manifestation of IgG4-related disease. PMID- 27486057 TI - Neutrons in proton pencil beam scanning: parameterization of energy, quality factors and RBE. AB - The biological effectiveness of neutrons produced during proton therapy in inducing cancer is unknown, but potentially large. In particular, since neutron biological effectiveness is energy dependent, it is necessary to estimate, besides the dose, also the energy spectra, in order to obtain quantities which could be a measure of the biological effectiveness and test current models and new approaches against epidemiological studies on cancer induction after proton therapy. For patients treated with proton pencil beam scanning, this work aims to predict the spatially localized neutron energies, the effective quality factor, the weighting factor according to ICRP, and two RBE values, the first obtained from the saturation corrected dose mean lineal energy and the second from DSB cluster induction. A proton pencil beam was Monte Carlo simulated using GEANT. Based on the simulated neutron spectra for three different proton beam energies a parameterization of energy, quality factors and RBE was calculated. The pencil beam algorithm used for treatment planning at PSI has been extended using the developed parameterizations in order to calculate the spatially localized neutron energy, quality factors and RBE for each treated patient. The parameterization represents the simple quantification of neutron energy in two energy bins and the quality factors and RBE with a satisfying precision up to 85 cm away from the proton pencil beam when compared to the results based on 3D Monte Carlo simulations. The root mean square error of the energy estimate between Monte Carlo simulation based results and the parameterization is 3.9%. For the quality factors and RBE estimates it is smaller than 0.9%. The model was successfully integrated into the PSI treatment planning system. It was found that the parameterizations for neutron energy, quality factors and RBE were independent of proton energy in the investigated energy range of interest for proton therapy. The pencil beam algorithm has been extended using the developed parameterizations in order to calculate the neutron energy, quality factor and RBE. PMID- 27486059 TI - Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin. AB - In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona based-squaramide-catalyzed enantioselective Mannich reactions of diverse imines or alpha-amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl alpha-amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling-reagent-free synthesis of the antidiabetic drug (-)-(R)-sitagliptin. PMID- 27486058 TI - The pro-oxidant gene p66shc increases nicotine exposure-induced lipotoxic oxidative stress in renal proximal tubule cells. AB - Nicotine (NIC) exposure augments free fatty acid (FFA) deposition and oxidative stress, with a concomitant increase in the expression of the pro-oxidant p66shc. In addition, a decrease in the antioxidant manganese superoxide dismutase (MnSOD) has been observed in the kidneys of mice fed a high-fat diet. The present study aimed to determine whether the pro-oxidant p66shc mediates NIC-dependent increases in renal oxidative stress by augmenting the production of reactive oxygen species (ROS) and suppressing the FFA-induced antioxidant response in cultured NRK52E renal proximal tubule cells. Briefly, NRK52E renal proximal tubule cells were treated with 200 uM NIC, 100 uM oleic acid (OA), or a combination of NIC and OA. The expression levels of p66shc and MnSOD were modulated according to genetic methods. ROS production and cell injury, in the form of lactate dehydrogenase release, were subsequently detected. Promoter activity of p66shc and MnSOD, as well as forkhead box (FOXO)-dependent transcription, was investigated using reporter luciferase assays. The results demonstrated that NIC exacerbated OA-mediated intracellular ROS production and cell injury through the transcriptional activation of p66shc. NIC also suppressed OA-mediated induction of the antioxidant MnSOD promoter activity through p66shc dependent inactivation of FOXO activity. Overexpression of p66shc and knockdown of MnSOD had the same effect as treatment with NIC on OA-mediated lipotoxicity. These data may be used to generate a therapeutic means to ameliorate renal lipotoxicity in obese smokers. PMID- 27486060 TI - Efficacy and safety of point-of-care ultrasound-guided intra-articular corticosteroid joint injections in patients with haemophilic arthropathy. AB - INTRODUCTION AND OBJECTIVES: Intra-articular corticosteroid injections are standard of care for managing joint pain secondary to osteoarthritis or rheumatoid arthritis but are rarely used in haemophilic arthropathy. We have introduced and evaluated the efficacy and safety of ultrasound-guided corticosteroid injections for pain relief in patients with haemophilic arthropathy. PATIENTS AND METHODS: Ultrasound-guided intra-articular injections performed on haemophilia patients at UCSD between March 2012 and January 2016 were analysed. Needle placement and injection (40 mg triamcinolone; 3-5 mL lidocaine) were performed with musculoskeletal ultrasound and Power Doppler. Analysis included patient demographics, joint-specific parameters such as tissue hypervascularity and effusions, pain relief, and procedure-associated complications. RESULTS: Forty-five injections (14 ankles, 13 elbows, 18 knees) were administered in 25 patients. Advanced arthropathy with hypervascularity and/or effusions was present in 91% and 61% of joints, respectively. Ninety-one per cent of injections resulted in pain relief which was significant in 84% (>30% reduction). Median pain score was reduced from 7 of 10 to 1 of 10 (P < 0.001), usually within 24 h. Median duration of pain relief was 8 weeks (range 1-16 weeks). Haemophilia B patients experienced longer periods of relief, and high Pettersson scores were associated with shorter duration of relief. There were no procedure-associated complications. Repeat ultrasound of eight joints within 4 weeks of injection demonstrated nearly complete resolution of hypervascularity. CONCLUSIONS: Point-of-care ultrasound enabled intra-articular corticosteroid injections that provided highly effective, safe, and relatively long-lasting pain relief in haemophilic arthropathy. This approach should be used to improve pain management in haemophilic arthropathy. PMID- 27486061 TI - Extended-Spectrum beta-lactam Resistance in the Enteric Flora of Patients at a Tertiary Care Medical Centre. AB - The dissemination of Enterobacteriaceae expressing resistance to extended spectrum cephalosporins, which are therapeutically used in both human and veterinary medicine, is of critical concern. The normal commensal flora of food animals may serve as an important reservoir for the zoonotic food-borne transmission of Enterobacteriaceae harbouring beta-lactam resistance. We hypothesized that the predominant AmpC and ESBL genes reported in US livestock and fresh retail meat products, blaCMY-2 and blaCTX-M , would also be predominant in human enteric flora. We recovered enteric flora from a convenience sample of patients included in a large tertiary medical centre's Clostridium difficile surveillance programme to screen for and estimate the frequency of carriage of AmpC and ESBL resistance genes. In- and outpatient diarrhoeic submissions (n = 692) received for C. difficile testing at the medical centre's clinical diagnostic laboratory from July to December, 2013, were included. Aliquoted to a transport swab, each submission was inoculated to MacConkey broth with cefotaxime, incubated at 37 degrees C and then inoculated to MacConkey agars supplemented with cefoxitin and cefepime to select for the AmpC and ESBL phenotypes, with blaCMY and blaCTX-M genotypes confirmed by PCR and sequencing. From the 692 diarrhoeic submissions, our selective culture yielded 184 isolates (26.6%) with reduced susceptibility to cefotaxime. Of these, 46 (6.7%) samples harboured commensal isolates carrying the AmpC blaCMY . Another 21 (3.0%) samples produced isolates harbouring the ESBL blaCTX-M : 19 carrying CTX-M-15 and 2 with CTX-M-27. Our results indicate that beta-lactam resistance genes likely acquired through zoonotic food-borne transmission are present in the enteric flora of this hospital-associated population at lower levels than reported in livestock and fresh food products. PMID- 27486063 TI - Plasma functionalization procedure for antibody immobilization for SU-8 based sensor. AB - In this paper, we report the study on a new protocol for the immobilization process of antigen/antibody assay on SU-8 layers by oxygen plasma treatment. Plasma treatments, at different plasma powers and for different duration times, are performed and their effects on immobilization efficiency are studied. The chemical properties and the surface morphology of SU-8 before and after the functionalization and immobilization of (IgG) are then verified by Raman spectroscopy and atomic force microscopy (AFM). An increase of the surface roughness of SU-8 layers is observed after the oxygen plasma treatment and an intensity variation of functional groups is also evidenced. To demonstrate the validity of the process the distribution of IgG immobilized on SU-8 surfaces is detected by fluorescence microscopy measurement after incubation with fluorescein isothiocyanate (FITC)-tagged anti-human IgG. An increase of the amount of the adsorbed protein of about 20% and a good repeatability on antigen/antibody distribution on the surface are detected for IgG on plasma treated substrates. Finally, label free measurements are performed by SU-8 optical ring resonators reaching detection limits of 0.86ngcm(-2). The proposed approach offers a smart protocol for IgG immobilization on SU-8 substrate that can be easily extended to different antigen/antibody assay and polymeric materials for the realization of high performance immunosensors. PMID- 27486062 TI - TLE4 regulation of wnt-mediated inflammation underlies its role as a tumor suppressor in myeloid leukemia. AB - The presence of AML1-ETO (RUNX1-CBF2T1), a fusion oncoprotein resulting from a t(8;21) chromosomal translocation, has been implicated as a necessary but insufficient event in the development of a subset of acute myeloid leukemias (AML). While AML1-ETO prolongs survival and inhibits differentiation of hematopoietic stem cells (HSC), other contributory events are needed for cell proliferation and leukemogenesis. We have postulated that specific tumor suppressor genes keep the leukemic potential of AML1-ETO in check. In studying del(9q), one of the most common concomitant chromosomal abnormalities with t(8;21), we identified the loss of an apparent tumor suppressor, TLE4, that appears to cooperate with AML1-ETO to confer a leukemic phenotype. This study sought to identify the molecular basis of this cooperation. We show that the loss of TLE4 confers proliferative advantage to leukemic cells, simultaneous with an upregulation of a pro- inflammatory signature mediated through aberrant increases in Wnt signaling activity. We further demonstrate that inhibition of cyclooxygenase (COX) activity partly reverses the pro-leukemic phenotype due to TLE4 knockdown, pointing towards a novel therapeutic approach for myeloid leukemia. PMID- 27486064 TI - Pharmacists caring for transgender persons. PMID- 27486065 TI - Ambiguity: A new way of thinking about responses to climate change. AB - Diversity, interdisciplinarity and transdisciplinarity are now recognized as vital to tackling wicked problems such as those presented by a changing climate (Nature editorial 2015, Ledford 2015; Dick et al., 2016). Including diverse disciplines in science projects enables a range of different views which often facilitate the creation of innovative solutions. Supporting multiple views and options requires a different way of working beyond traditional reductionist approaches to science, communication and decision-making. To embrace diversity in scientific project teams in order to tackle complex, integrated and urgent issues but to expect singular and linear pathways forward is paradoxical. Much has been written about the need for the scientific community to embrace uncertainty (e.g. Popper, Lempert & Bankes 2005; Lempert et al., 2004; Nelson, Howden & Hayman 2013; Bammer & Smithson 2008). We argue that this in itself will not suffice, and that there is also a need to embrace ambiguity in certain situations. Thus, in this article we explore: (1) what ambiguity is, including the benefits it can offer to climate adaptation in particular, using existing approaches to ambiguity in the arts and humanities as examples (2), we discuss practical meanings of ambiguity in relation to climate change, (3) we propose possible next steps for bringing ambiguity into interdisciplinary practice, and (4) we identify some challenges and necessary preconditions to successfully and appropriately embracing ambiguity. PMID- 27486066 TI - Fungus-associated bacteriome in charge of their host behavior. AB - Bacterial-fungal interactions are widespread in nature and there is a growing number of studies reporting distinct fungus-associated bacteria. However, little is known so far about how shifts in the fungus-associated bacteriome will affect the fungal host's lifestyle. In the present study, we describe for the first time the bacterial community associated with the saprotrophic fungus Mucor hiemalis, commonly found in soil and rhizosphere. Two broad-spectrum antibiotics that strongly altered the bacterial community associated with the fungus were applied. Our results revealed that the antibiotic treatment did not significantly reduce the amount of bacteria associated to the fungus but rather changed the community composition by shifting from initially dominating Alpha-Proteobacteria to dominance of Gamma-Proteobacteria. A novel approach was applied for the isolation of fungal-associated bacteria which also revealed differences between bacterial isolates obtained from the original and the antibiotic-treated M. hiemalis. The shift in the composition of the fungal-associated bacterial community led to significantly reduced fungal growth, changes in fungal morphology, behavior and secondary-metabolites production. Furthermore, our results showed that the antibiotic-treated isolate was more attractive and susceptible to mycophagous bacteria as compared to the original isolate. Overall, our study highlights the importance of the fungus-associated bacteriome for the host's lifestyle and interactions and indicate that isolation with antibacterials is not sufficient to eradicate the associated bacteria. PMID- 27486067 TI - Three alcohol dehydrogenase genes and one acetyl-CoA synthetase gene are responsible for ethanol utilization in Yarrowia lipolytica. AB - The non-conventional yeast Yarrowia lipolytica is able to utilize a wide range of different substrates like glucose, glycerol, ethanol, acetate, proteins and various hydrophobic molecules. Although most metabolic pathways for the utilization of these substrates have been clarified by now, it was not clear whether ethanol is oxidized by alcohol dehydrogenases or by an alternative oxidation system inside the cell. In order to detect the genes that are required for ethanol utilization in Y. lipolytica, eight alcohol dehydrogenase (ADH) genes and one alcohol oxidase gene (FAO1) have been identified and respective deletion strains were tested for their ability to metabolize ethanol. As a result of this, we found that the availability of ADH1, ADH2 or ADH3 is required for ethanol utilization in Y. lipolytica. A strain with deletions in all three genes is lacking the ability to utilize ethanol as sole carbon source. Although Adh2p showed by far the highest enzyme activity in an in vitro assay, the availability of any of the three genes was sufficient to enable a decent growth. In addition to ADH1, ADH2 and ADH3, an acetyl-CoA synthetase encoding gene (ACS1) was found to be essential for ethanol utilization. As Y. lipolytica is a non-fermenting yeast, it is neither able to grow under anaerobic conditions nor to produce ethanol. To investigate whether Y. lipolytica may produce ethanol, the key genes of alcoholic fermentation in S. cerevisiae, ScADH1 and ScPDC1, were overexpressed in an ADH and an ACS1 deletion strain. However, instead of producing ethanol, the respective strains regained the ability to use ethanol as single carbon source and were still not able to grow under anaerobic conditions. PMID- 27486068 TI - Ultrashort cationic lipopeptides and lipopeptoids: Evaluation and mechanistic insights against epithelial cancer cells. AB - Peptides present an attractive scaffold for the development of new anticancer lead agents due to their accessibility and ease of modification. Synthetic ultrashort cationic lipopeptides, with four amino acids or less conjugated to a fatty acid, were developed to retain the biological activity of longer peptides in a smaller molecular size. Herein, we report the activity of amphiphilic lipotripeptides, lipotripeptoids and lipotetrapeptides against breast (MDA-MB 231, JIMT-1), prostate (DU145) and pancreas (MiaPaCa2) epithelial cancer cell lines. The lipotripeptide C16-KKK-NH2 and lipotetrapeptide C16-PCatPHexPHexPCat NH2 were identified to possess anticancer activity. The latter lipotetrapeptide possess a short polyproline scaffold consisting of only two L-4R-aminoproline (PCat) and two L-4R-hexyloxyproline (PHex). However, all the prepared lipotripeptoids lack anticancer activity. The amphiphilic C16-PCatPHexPHexPCat NH2 exhibited similar anticancer potency to the surfactant benzethonium chloride while superior activity was observed in comparison to myristylamine. Mechanistic studies revealed that the peptides do not lyse ovine erythrocytes nor epithelial cancer cells, thus ruling out necrosis as the mechanism of cell death. Surprisingly, the two lipopeptides exhibit different mechanisms of action that result in cancer cell death. The lipotripeptide C16-KKK-NH2 was found to induce caspase-mediated apoptosis while C16-PCatPHexPHexPCat-NH2 kills tumor cells independent of caspases. PMID- 27486069 TI - p21(CIP1/WAF1)-dependent inhibition of cardiac hypertrophy in response to Angiotensin II involves Akt/Myc and pRb signaling. AB - The cyclin-dependent kinase inhibitor p21(CIP1/WAF1) (p21) is highly expressed in the adult heart. However, in response to stress, its expression is downregulated. Therefore, we investigated the role of p21 in the regulation of cardiac hypertrophic growth. At 2 months of age, p21 knockout mice (p21KO) lack an overt cardiac phenotype. In contrast, by 10 months of age, p21KO developed age dependent cardiac hypertrophy and heart failure. After 3 weeks of trans-aortic banding (TAB), the heart/body weight ratio in 11 week old p21KO mice increased by 57%, as compared to 42% in wild type mice indicating that p21KO have a higher susceptibility to pressure overload-induced cardiac hypertrophy. We then chronically infused 8 week old wild type mice with Angiotensin II (2.0mg/kg/min) or saline subcutaneously by osmotic pumps for 14 days. Recombinant TAT conjugated p21 protein variants (10mg/kg body weight) or saline were intraperitoneally injected once daily for 14 days into Angiotensin II and saline-infused animals. Angiotensin II treated mice developed pathological cardiac hypertrophy with an average increase of 38% in heart/body weight ratios, as compared to saline treated controls. Reconstitution of p21 function by TAT.p21 protein transduction prevented Angiotensin II-dependent development of cardiac hypertrophy and failure. Taken together, our genetic and biochemical data show an important function of p21 in the regulation of growth-related processes in the heart. PMID- 27486070 TI - Effects of increasing levothyroxine on pregnancy outcomes in women with uncontrolled hypothyroidism. AB - OBJECTIVE: Uncontrolled hypothyroidism has been associated with an increased risk of adverse pregnancy outcomes. We aimed to assess the effectiveness of increasing levothyroxine (LT4) dose on reducing the risk of adverse outcomes for pregnant women with TSH level greater than the recommended 1st trimester limit. DESIGN, PATIENTS, MEASUREMENTS: We reviewed the electronic medical records of pregnant women evaluated from January 2011 to December 2013, who had history of LT4 treated hypothyroidism and were found to have TSH > 2.5 mIU/l in 1st trimester. Women were divided into two groups: group A - LT4 dose was increased within two weeks from the TSH test, group B - LT4 dose remained stable. We compared the frequency of pregnancy loss (primary outcome) and other prespecified pregnancy related adverse outcomes between groups. RESULTS: There were 85 women in group A (median TSH: 5.0, interquartile range 3.8-6.8 mIU/l) and 11 women in group B (median TSH: 4.5, interquartile range 3.2-4.9 mIU/l). The groups were not different in baseline clinical and socioeconomic characteristics. The mean interval between TSH test and LT4 dose increase was 4.5 (SD 4.6) days. Pregnancy loss was significantly lower in group A (2/85, 2.4%) vs group B (4/11, 36.4%) (P = 0.001). Other pregnancy-related adverse outcomes were similar between groups. CONCLUSIONS: Increasing LT4 dose for women with uncontrolled hypothyroidism in the 1st trimester of pregnancy was associated with a decreased risk of pregnancy loss. Given the limitations of our study, this association awaits further confirmation from larger studies. PMID- 27486071 TI - Semen characteristics and biochemical composition of cloacal foam of male Japanese quails (Coturnix coturnix Japonica) fed diet incorporated with selenium. AB - An attempt was made to investigate the effect of dietary selenium (Se) on physical and cloacal gland size, foam production, biochemical composition of foam and semen biochemical characteristics of male Japanese quail (Coturnix coturnix Japonica). Two hundred twenty-five (225)-day-old male Japanese quail were randomly distributed to three dietary treatment groups for a period of 20 weeks. Each treatment comprised of three replicates, each containing 25 chicks. Three experimental diets were supplemented with 0, 0.5 and 1.0 mg Se/kg (T1 , T2 and T3, respectively), and diet T1 was considered as control. Sodium selenite was used as the source of selenium. All the birds were provided with feed and water ad libitum. Cloacal foam characteristics, that is cloacal gland index and foam weight, were significantly higher in T2 group. However, body weight, frequency of foam discharge and testes weight (left and right) did not differ significantly (p > 0.05). Physical characteristics of semen, that is semen volume and sperm concentration, did not differ (p > 0.05) among the Se-treated groups. The sperm motility, live-dead count and abnormality improved significantly (p < 0.05) in 0.5 mg/Se-supplemented group compared to 0 or 1.0 mg/Se-supplemented groups. Similarly, fertility and hatchability percentages were higher (p < 0.05) in 0.5 mg/Se-supplemented group than in control or 1.0 mg/Se-supplemented counterparts. The biochemical characteristics of foam in terms of total protein, acid phosphatase (ACP) and nitric oxide did not differ (p > 0.05), while the concentration of glucose was higher (p < 0.05) in 0.5 mg/Se-supplemented diet. On the other hand, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were lower (p < 0.05) in 0.5 mg/Se-supplemented group compared to control or 1.0 mg/Se-supplemented groups. From this study, it was concluded that supplementation of 0.5 mg Se/kg diet was beneficial for foam variables, biochemical composition of foam, semen characteristics and fertility in male Japanese quail. PMID- 27486072 TI - Prenatal diagnosis of double aortic arch: can we predict airway obstruction (pseudo-CHAOS) and need for airway EXIT? PMID- 27486073 TI - Two-step crystal growth mechanism during crystallization of an undercooled Ni50Al50 alloy. AB - Crystallization processes are always accompanied by the emergence of multiple intermediate states, of which the structures and transition dynamics are far from clarity, since it is difficult to experimentally observe the microscopic pathway. To insight the structural evolution and the crystallization dynamics, we perform large-scale molecular dynamics simulations to investigate the time-dependent crystallization behavior of the NiAl intermetallic upon rapid solidification. The simulation results reveal that the crystallization process occurs via a two-step growth mechanism, involving the formation of initial non-equilibrium long range order (NLRO) regions and of the subsequent equilibrium long range order (ELRO) regions. The formation of the NLRO regions makes the grains rather inhomogeneous, while the rearrangement of the NLRO regions into the ELRO regions makes the grains more ordered and compact. This two-step growth mechanism is actually controlled by the evolution of the coordination polyhedra, which are characterized predominantly by the transformation from five-fold symmetry to four fold and six-fold symmetry. From liquids to NLRO and further to ELRO, the five fold symmetry of these polyhedra gradually fades, and finally vanishes when B2 structure is distributed throughout the grain bulk. The energy decrease along the pathway further implies the reliability of the proposed crystallization processes. PMID- 27486074 TI - Direct-geneFISH: tuning up microscopic and molecular methodologies for targeted cell visualization. PMID- 27486075 TI - The host specificity of ape malaria parasites can be broken in confined environments. AB - Recent studies have revealed a large diversity of Plasmodium spp. among African great apes. Some of these species are related to Plasmodium falciparum, the most virulent agent of human malaria (subgenus Laverania), and others to Plasmodium ovale, Plasmodium malariae and Plasmodium vivax (subgenus Plasmodium), three other human malaria agents. Laverania parasites exhibit strict host specificity in their natural environment. Plasmodium reichenowi, Plasmodium billcollinsi, Plasmodium billbrayi and Plasmodium gaboni infect only chimpanzees, while Plasmodium praefalciparum, Plasmodium blacklocki and Plasmodium adleri are restricted to gorillas and Plasmodium falciparum is pandemic in humans. This host specificity may be due to genetic and/or environmental factors. Infrastructures hosting captive primates, such as sanctuaries and health centres, usually concentrate different primate species, thus favouring pathogen exchanges. Using molecular tools, we analysed blood samples from captive non-human primates living in Gabon to evaluate the risk of Plasmodium spp. transfers between host species. We also included blood samples from workers taking care of primates to assess whether primate-human parasite transfers occurred. We detected four transfers of Plasmodium from gorillas towards chimpanzees, one from chimpanzees to gorillas, three from humans towards chimpanzees and one from humans to mandrills. No simian Plasmodium was found in the blood samples from humans working with primates. These findings demonstrate that the genetic barrier that determines the apparent host specificity of Laverania is not completely impermeable and that parasite exchanges between gorillas and chimpanzees are possible in confined environments. PMID- 27486077 TI - Streamlining ethical review of data intensive research. PMID- 27486076 TI - Protein aggregation and neurodegenerative diseases: From theory to therapy. AB - The study of protein misfolding and aggregation saw resurgence in the last decade. Aggregation is the main cause of several human neurodegenerative diseases which makes this field as the leading edge in the science today. Protein aggregation is a highly complex process resulting in formation of a variety of aggregates with different structures and morphologies. Many of them are highly cytotoxic. In-depth knowledge about structure, mechanism of formation, and physiological effects of aggregates will shed new light on the aggregation mediated cell toxicity, and helps in deciphering new target for drug design and development. This review summarizes the existing information on the molecular mechanism of protein misfolding and aggregation involved in neurodegeneration stressing on the possible therapeutic intervention in neurodegenerative diseases. As our knowledge about the relation between the protein misfolding and disease pathogenesis will be enhanced, more specific and promising treatment opportunities will come into existence. PMID- 27486078 TI - Predicting Novel Antitumor Agents: 3D-Pharmacophore Mapping of beta-N-biaryl Ether Sulfonamide-Based Hydroxamates as Potentially MMP-2 Inhibitors. AB - Matrix metalloproteinases (MMP) are a group of enzymes related to extracelular matrix remodeling. Some types of MMP are overexpressed by malignant tumors, mainly the MMP-2 subtype, and have been associated to cancer invasiveness and metastasis. A receptor-independent (RI) 4D-QSAR formalism was applied, herein, to a set of forty beta-N-biaryl ether sulfonamide hydroxamates, previously reported as potent MMP-2 inhibitors, in order to map 3D-pharmacophore models and predict novel antitumor agents. The best RI 4D-QSAR model was statistically significant (N=30, r(2) =0.93, q(2) =0.88, five occupancy descriptors (GCOD), LSE=0.04, LOF=0.11, outliers=0), robust and not obtained by chance. The external predictability was 75 % (test set; N=8). A different orientation (binding mode) in the MMP-2 catalytic site was suggested regarding the most hydrophobic portion (R1 ) of the compounds' structure. Compounds were predicted and their inhibitory activity against MMP-2 was calculated by using the optimum RI 4D-QSAR model. The findings have provided interesting information to drive the designing and synthesis of novel potentially MMP-2 inhibitors against melanoma invasion. PMID- 27486079 TI - Discovery of Novel Mycobacterial DNA Gyrase B Inhibitors: In Silico and In Vitro Biological Evaluation. AB - DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase that ensures the regulation of DNA topology and has been genetically demonstrated to be a bactericidal drug target. Availability of crystal structure of M. smegmatics GyrB in complex with one of the aminopyrazinamides facilitated us to employ structure-based virtual screening approach to obtain new hits from a commercial library of Asinex database using energy-optimized pharmacophore modeling. Further the model was validated using enrichment calculations, and finally three models were employed for high-throughput virtual screening and docking to identify novel DNA gyrase B inhibitors. This study led to the identification of fifteen potential compounds with IC50 values in the range of 1.5-45.5 uM against M. smegmatics GyrB and 1.16-25 uM in MTB supercoiling assay. Lead 11 emerged as the most potential compound, exhibiting inhibition of MTB DNA gyrase supercoiling with an IC50 of 1.16+/-0.25 uM, and M. smegmatics GyrB IC50 of 1.5+/-0.12 uM and hence could be further developed as novel inhibitor for mycobacterial GyrB. PMID- 27486080 TI - Pharmacophore Modeling, Ensemble Docking, Virtual Screening, and Biological Evaluation on Glycogen Synthase Kinase-3beta. AB - Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine protein kinase which is engaged in a variety of signaling pathways, regulating a wide range of cellular processes. GSK-3beta, also known as tau protein kinase I (TPK I), is one of the most important kinases implicated in the hyperphosphorylation of tau that leads to neurodegenerative diseases. Hence, GSK-3beta has emerged as an important therapeutic target. To identify compounds that are structurally novel and diverse compared to previously reported ATP-competitive GSK-3beta inhibitors, we performed virtual screening by implementing a mixed ligand/structure-based approach, which included pharmacophore modeling, diversity analysis, and ensemble docking. The sensitivities of different docking protocols to induced-fit effects were explored. An enrichment study was employed to verify the robustness of ensemble docking, using 13 X-ray structures of GSK-3beta, compared to individual docking in terms of retrieving active compounds from a decoy dataset. A total of 24 structurally diverse compounds obtained from the virtual screening underwent biological validation. The bioassay results showed that 15 out of the 24 hit compounds are indeed GSK-3beta inhibitors, and among them, one compound exhibiting sub-micromolar inhibitory activity is a reasonable starting point for further optimization. PMID- 27486081 TI - Quantitative Structure-Activity Relationship Analysis and a Combined Ligand Based/Structure-Based Virtual Screening Study for Glycogen Synthase Kinase-3. AB - Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine protein kinase which regulates a wide range of cellular processes, involving various signalling pathways. GSK-3beta has emerged as an important therapeutic target for diabetes and Alzheimer's disease. To identify structurally novel GSK-3beta inhibitors, we performed virtual screening by implementing a combined ligand based/structure-based approach, which included quantitative structure-activity relationship (QSAR) analysis and docking prediction. To integrate and analyze complex data sets from multiple experimental sources, we drafted and validated a hierarchical QSAR method, which adopts a two-level structure to take data heterogeneity into account. A collection of 728 GSK-3 inhibitors with diverse structural scaffolds was obtained from published papers that used different experimental assay protocols. Support vector machines and random forests were implemented with wrapper-based feature selection algorithms to construct predictive learning models. The best models for each single group of compounds were then used to build the final hierarchical QSAR model, with an overall R(2) of 0.752 for the 141 compounds in the test set. The compounds obtained from the virtual screening experiment were tested for GSK-3beta inhibition. The bioassay results confirmed that 2 hit compounds are indeed GSK-3beta inhibitors exhibiting sub-micromolar inhibitory activity, and therefore validated our combined ligand based/structure-based approach as effective for virtual screening experiments. PMID- 27486083 TI - Effects of salinity on short-term waterborne zinc uptake, accumulation and sub lethal toxicity in the green shore crab (Carcinus maenas). AB - Waterborne zinc (Zn) is known to cause toxicity to freshwater animals primarily by disrupting calcium (Ca) homeostasis during acute exposure, but its effects in marine and estuarine animals are not well characterized. The present study investigated the effects of salinity on short-term Zn accumulation and sub-lethal toxicity in the euryhaline green shore crab, Carcinus maenas. The kinetic and pharmacological properties of short-term branchial Zn uptake were also examined. Green crabs (n=10) were exposed to control (no added Zn) and 50MUM (3.25mgL(-1)) of waterborne Zn (~25% of 96h LC50 in 100 seawater) for 96h at 3 different salinity regimes (100%, 60% and 20% seawater). Exposure to waterborne Zn increased tissue-specific Zn accumulation across different salinities. However, the maximum accumulation occurred in 20% seawater and no difference was recorded between 60% and 100% seawater. Gills appeared to be the primary site of Zn accumulation, since the accumulation was significantly higher in the gills relative to the hepatopancreas, haemolymph and muscle. Waterborne Zn exposure induced a slight increase in haemolymph osmolality and chloride levels irrespective of salinity. In contrast, Zn exposure elicited marked increases in both haemolymph and gill Ca levels, and these changes were more pronounced in 20% seawater relative to that in 60% or 100% seawater. An in vitro gill perfusion technique was used to examine the characteristics of short-term (1-4h) branchial Zn uptake over an exposure concentration range of 3-12MUM (200-800MUgL(-1)). The rate of short-term branchial Zn uptake did not change significantly after 2h, and no difference was recorded in the rate of uptake between the anterior (respiratory) and posterior (ion transporting) gills. The in vitro branchial Zn uptake occurred in a concentration-dependent manner across different salinities. However, the rate of uptake was consistently higher in 20% seawater relative to 60% or 100% seawater - similar to the trend observed with tissue Zn accumulation during in vivo exposure. The short-term branchial Zn uptake was found to be inhibited by lanthanum (a blocker of voltage-independent Ca channels), suggesting that branchial Zn uptake occurs via the Ca transporting pathways, at least in part. Overall, our findings indicate that acute exposure to waterborne Zn leads to the disruption of Zn and Ca homeostasis in green crab, and these effects are exacerbated at the lower salinity. PMID- 27486082 TI - Single-cell analyses of X Chromosome inactivation dynamics and pluripotency during differentiation. AB - Pluripotency, differentiation, and X Chromosome inactivation (XCI) are key aspects of embryonic development. However, the underlying relationship and mechanisms among these processes remain unclear. Here, we systematically dissected these features along developmental progression using mouse embryonic stem cells (mESCs) and single-cell RNA sequencing with allelic resolution. We found that mESCs grown in a ground state 2i condition displayed transcriptomic profiles diffused from preimplantation mouse embryonic cells, whereas EpiStem cells closely resembled the post-implantation epiblast. Sex-related gene expression varied greatly across distinct developmental states. We also identified novel markers that were highly enriched in each developmental state. Moreover, we revealed that several novel pathways, including PluriNetWork and Focal Adhesion, were responsible for the delayed progression of female EpiStem cells. Importantly, we "digitalized" XCI progression using allelic expression of active and inactive X Chromosomes and surprisingly found that XCI states exhibited profound variability in each developmental state, including the 2i condition. XCI progression was not tightly synchronized with loss of pluripotency and increase of differentiation at the single-cell level, although these processes were globally correlated. In addition, highly expressed genes, including core pluripotency factors, were in general biallelically expressed. Taken together, our study sheds light on the dynamics of XCI progression and the asynchronicity between pluripotency, differentiation, and XCI. PMID- 27486085 TI - Amorphous Li2 O2 : Chemical Synthesis and Electrochemical Properties. AB - When aprotic Li-O2 batteries discharge, the product phase formed in the cathode often contains two different morphologies, that is, crystalline and amorphous Li2 O2 . The morphology of Li2 O2 impacts strongly on the electrochemical performance of Li-O2 cells in terms of energy efficiency and rate capability. Crystalline Li2 O2 is readily available and its properties have been studied in depth for Li-O2 batteries. However, little is known about the amorphous Li2 O2 because of its rarity in high purity. Herein, amorphous Li2 O2 has been synthesized by a rapid reaction of tetramethylammonium superoxide and LiClO4 in solution, and its amorphous nature has been confirmed by a range of techniques. Compared with its crystalline siblings, amorphous Li2 O2 demonstrates enhanced charge-transport properties and increased electro-oxidation kinetics, manifesting itself a desirable discharge phase for high-performance Li-O2 batteries. PMID- 27486084 TI - Smoking and Posttraumatic Stress Disorder Symptomatology in Orofacial Pain. AB - To explore the impact of interactions between smoking and symptoms of posttraumatic stress disorder (PTSD) on pain intensity, psychological distress, and pain-related functioning in patients with orofacial pain, a retrospective review was conducted of data obtained during evaluations of 610 new patients with a temporomandibular disorder who also reported a history of a traumatic event. Pain-related outcomes included measures of pain intensity, psychological distress, and pain-related functioning. Main effects of smoking status and PTSD symptom severity on pain-related outcomes were evaluated with linear regression analyses. Further analyses tested interactions between smoking status and PTSD symptom severity on pain-related outcomes. PTSD symptom severity and smoking predicted worse pain-related outcomes. Interaction analyses between PTSD symptom severity and smoking status revealed that smoking attenuated the impact of PTSD symptom severity on affective distress, although this effect was not found at high levels of PTSD symptom severity. No other significant interactions were found, but the present results identifying smoking as an ineffective coping mechanism and the likely role of inaccurate outcome expectancies support the importance of smoking cessation efforts in patients with orofacial pain. Smoking is a maladaptive mechanism for coping with pain that carries significant health- and pain-related risks while failing to fulfill smokers' expectations of affect regulation, particularly among persons with orofacial pain who also have high levels of PTSD symptom severity. Addressing smoking cessation is a critical component of comprehensive treatment. Further research is needed to develop more effective ways to help patients with pain and/or PTSD to replace smoking with more effective coping strategies. PMID- 27486086 TI - In-line phase-contrast breast tomosynthesis: a phantom feasibility study at a synchrotron radiation facility. AB - The major objective is to adopt, apply and test developed in-house algorithms for volumetric breast reconstructions from projection images, obtained in in-line phase-contrast mode. Four angular sets, each consisting of 17 projection images obtained from four physical phantoms, were acquired at beamline ID17, European Synchroton Radiation Facility, Grenoble, France. The tomosynthesis arc was +/-32 degrees . The physical phantoms differed in complexity of texture and introduced features of interest. Three of the used phantoms were in-house developed, and made of epoxy resin, polymethyl-methacrylate and paraffin wax, while the fourth phantom was the CIRS BR3D. The projection images had a pixel size of 47 um * 47 um. Tomosynthesis images were reconstructed with standard shift-and-add (SAA) and filtered backprojection (FBP) algorithms. It was found that the edge enhancement observed in planar x-ray images is preserved in tomosynthesis images from both phantoms with homogeneous and highly heterogeneous backgrounds. In case of BR3D, it was found that features not visible in the planar case were well outlined in the tomosynthesis slices. In addition, the edge enhancement index calculated for features of interest was found to be much higher in tomosynthesis images reconstructed with FBP than in planar images and tomosynthesis images reconstructed with SAA. The comparison between images reconstructed by the two reconstruction algorithms shows an advantage for the FBP method in terms of better edge enhancement. Phase-contrast breast tomosynthesis realized in in-line mode benefits the detection of suspicious areas in mammography images by adding the edge enhancement effect to the reconstructed slices. PMID- 27486087 TI - Factoring in the missing link. PMID- 27486088 TI - Re-Evaluation of the Psychometric Properties of the Maternal-Fetal Attachment Scale in a Hungarian Sample. AB - OBJECTIVE: To explore the factor structure of the Maternal-Fetal Attachment Scale (MFAS) and investigate its psychosocial and demographic correlates in a Hungarian sample. DESIGN: Cross-sectional survey. SETTING: Sonography clinic in a metropolitan area. PARTICIPANTS: One hundred fourteen women over the age of 18 years in the second or third trimesters of pregnancy. METHODS: Participants completed the Hungarian version of the MFAS and provided information on demographic, socioeconomic, and pregnancy-related factors. RESULTS: The internal consistency of the MFAS total scale was acceptable (Cronbach's alpha = .87). However, the reliability of the five subscales was low (alpha coefficients between .57 and .74), and the original five-factor model was not supported by the factor analyses. Married mothers had higher scores on the MFAS than participants who were unmarried, and uncertainty about the sex of the fetus was associated with lower attachment scores. Furthermore, gestational age showed a positive correlation with MFAS scores. No significant association was found between the total score on the MFAS and such factors as age, income, or education of the parents; whether the pregnancy was planned; method of conception; number of children born previously; prior perinatal losses; and circumstances of the mother's own birth. CONCLUSION: Our study showed that marital status, uncertainty about the sex of the fetus, and gestational age were associated with maternal fetal attachment; however, more detailed analysis was not possible because of the instability of the subscales of the instrument. Further research is warranted on the underlying factors related to maternal-fetal attachment. PMID- 27486089 TI - Case Report of Sepsis in Neonates Fed Expressed Mother's Milk. AB - Mother's milk is the recommended food for premature infants cared for in the NICU. In the cases presented in this article, mothers pumped their milk into food grade aseptic plastic containers. Milk was refrigerated before use. In Case 1, an infant developed Pseudomonas aeruginosa sepsis. In Case 2, an infant developed methicillin-resistant Staphylococcus aureus. Both cases were attributed to contaminated mother's milk. Proper cleaning and sterilization of pump parts is essential to prevent milk contamination. PMID- 27486091 TI - Academics should leave research credentials behind when they move, Stern report says. PMID- 27486090 TI - Fructose sensitizes Jurkat cells oxidative stress-induced apoptosis via caspase dependent and caspase-independent mechanisms. AB - Whether fructose (FRU), as the sole energy source, confers a metabolic advantage on cancer cells against noxious stimuli is unknown. The aim of this study was to evaluate the effects of low (11 mM), moderate (25 mM), and high (55 mM) FRU concentrations alone or in combination with rotenone (ROT) or doxorubicin (DOX) in Jurkat cells, an acute lymphoblastic leukemia cell model. Glucose (GLU) was used as a control. Using different cell analysis techniques, we demonstrated that FRU was predominantly metabolized via oxidative phosphorylation (~95%) (i.e., lactate production was reduced >120-fold), resulting in endogenous oxidative stress-induced conditions. The cells were characterized by generation of O2*- (43%)/ H2 O2 (40%) and activation of NF-kappaB (~95-fold increase, fi), c-Jun-N terminal kinase (JNK), p53 (40-fi), and c-Jun (9-fi). In addition, we observed a loss of DeltaPsim (10%), activation of caspase-3 (50-fi) and apoptosis-inducing factor (AIF, 2-fi), and condensation and fragmentation of the nuclei [20% by acridine orange/ethidium bromide/Hoechst (AO/EB/H) staining, 15% by flow cytometry] compared to those of GLU 11 at 24 h. Although DOX killed Jurkat cells independent of sugar content in the culture medium, leukemic cells in low, but not high, FRU were extremely sensitive to ROT. Taken together, our findings suggest that Jurkat cells are more susceptible to cell death if forced to shift from GLU metabolism (i.e., aerobic glycolysis) to FRU metabolism (i.e., oxidative phosphorylation) after treatment with mitochondria-targeting molecules. These observations may help elucidate the cell death mechanism of leukemic cells cultured in FRU. PMID- 27486092 TI - Role of muscular eNOS in skeletal arteries: Endothelium-independent hypoxic vasoconstriction of the femoral artery is impaired in eNOS-deficient mice. AB - We previously reported that hypoxia augments alpha-adrenergic contraction (hypoxic vasoconstriction, HVC) of skeletal arteries in rats. The underlying mechanism may involve hypoxic inhibition of endothelial nitric oxide synthase (eNOS) expressed in skeletal arterial myocytes (16). To further explore the novel role of muscular eNOS in the skeletal artery, we compared HVC in femoral arteries (FAs) from eNOS knockout (KO) mice with that from wild-type (WT) and heterozygous (HZ) mice. Immunohistochemical assays revealed that, in addition to endothelia, eNOS is also expressed in the medial layer of FAs, albeit at a much lower level. However, the medial eNOS signal was not evident in HZ FAs, despite strong expression in the endothelium; similar observations were made in WT carotid arteries (CAs). The amplitude of contraction induced by 1 MUM phenylephrine (PhE) was greater in HZ than in WT FAs. Hypoxia (3% Po2) significantly augmented PhE induced contraction in WT FAs but not in HZ or KO FAs. No HVC was observed in PhE pretreated WT CAs. The NOS inhibitor nitro-l-arginine methyl ester (0.1 mM) also augmented PhE contraction in endothelium-denuded WT FAs but not in WT CAs. Inhibitors specific to neuronal NOS and inducible NOS did not augment PhE-induced contraction of WT FAs. NADPH oxidase 4 (NOX4) inhibitor (GKT137831, 5 MUM), but not NOX2 inhibitor (apocynin, 100 MUM), suppressed HVC. Consistent with the role of reactive oxygen species (ROS), HVC was also inhibited by pretreatment with tiron or polyethylene glycol-catalase. Taken together, these data suggest that the eNOS expressed in smooth muscle cells in FAs attenuates alpha-adrenergic vasoconstriction; this suppression is alleviated under hypoxia, which potentiates vasoconstriction in a NOX4/ROS-dependent mechanism. PMID- 27486095 TI - Erratum. PMID- 27486093 TI - Control of human energy expenditure by cytochrome c oxidase subunit IV-2. AB - Resting metabolic rate (RMR) in humans shows pronounced individual variations, but the underlying molecular mechanism remains elusive. Cytochrome c oxidase (COX) plays a key role in control of metabolic rate, and recent studies of the subunit 4 isoform 2 (COX IV-2) indicate involvement in the cellular response to hypoxia and oxidative stress. We evaluated whether the COX subunit IV isoform composition may explain the pronounced individual variations in resting metabolic rate (RMR). RMR was determined in healthy humans by indirect calorimetry and correlated to levels of COX IV-2 and COX IV-1 in vastus lateralis. Overexpression and knock down of the COX IV isoforms were performed in primary myotubes followed by evaluation of the cell respiration and production of reactive oxygen species. Here we show that COX IV-2 protein is constitutively expressed in human skeletal muscle and strongly correlated to RMR. Primary human myotubes overexpressing COX IV-2 displayed markedly (>60%) lower respiration, reduced (>50%) cellular H2O2 production, higher resistance toward both oxidative stress, and severe hypoxia compared with control cells. These results suggest an important role of isoform COX IV-2 in the control of energy expenditure, hypoxic tolerance, and mitochondrial ROS homeostasis in humans. PMID- 27486094 TI - Intensification with pegylated interferon during treatment with tenofovir in HIV hepatitis B virus co-infected patients. AB - In hepatitis B "e" antigen (HBeAg) positive patients with hepatitis B virus (HBV) mono-infection, intensification of nucleos(t)ide analogue treatment with pegylated interferon (PegIFN) could help induce higher HBeAg seroclearance rates. Our aim was to determine the long-term effect of adding PegIFN to tenofovir (TDF) containing antiretroviral therapy on seroclearance in HBeAg-positive patients co infected with the human immunodeficiency virus (HIV) and HBV. In this prospective matched cohort study, 46 patients with 1-year PegIFN intensification during TDF containing antiretroviral therapy (TDF+PegIFN) were matched 1:1 to controls undergoing TDF without PegIFN (TDF) using a time-dependent propensity score based on age, CD4+ count and liver cirrhosis status. Kinetics of HBeAg quantification (qHBeAg) and hepatitis B surface antigen quantification (qHBsAg) were estimated using mixed-effect linear regression and time to HBeAg seroclearance or HBsAg seroclearance was modelled using proportional hazards regression. At baseline, previous TDF exposure was a median 39.8 months (IQR=21.4-59.4) and median qHBeAg and qHBsAg levels were 6.9 PEIU/mL and 3.72 log10 IU/mL, respectively (P>.5 between groups). Median follow-up was 33.4 months (IQR=19.0-36.3). During intensification, faster average declines of qHBeAg (-0.066 vs -0.027 PEIU/mL/month, P=.001) and qHBsAg (-0.049 vs -0.026 log10 IU/mL/month, P=.09) were observed in patients undergoing TDF+PegIFN vs TDF, respectively. After intensification, qHBeAg and qHBsAg decline was no different between groups (P=.7 and P=.9, respectively). Overall, no differences were observed in HBeAg seroclearance (TDF+PegIFN=13.2 vs TDF=12.6/100 person.years, P=.5) or HBsAg seroclearance rates (TDF+PegIFN=1.8 vs TDF=1.3/100 person.years, P=.7). In conclusion, PegIFN intensification in HBeAg-positive co-infected patients did not lead to increased rates of HBeAg or HBsAg clearance, despite faster declines of antigen levels while on PegIFN. PMID- 27486096 TI - Accelerated Stability Studies on Dried Extracts of Centella asiatica Through Chemical, HPLC, HPTLC, and Biological Activity Analyses. AB - Regulatory guidelines recommend systematic stability studies on a herbal product to establish its shelf life. In the present study, commercial extracts (Types I and II) and freshly prepared extract (Type III) of Centella asiatica were subjected to accelerated stability testing for 6 months. Control and stability samples were evaluated for organoleptics, pH, moisture, total phenolic content (TPC), asiatic acid, kaempherol, and high-performance thin layer chromatography fingerprints, and for antioxidant and acetylcholinesterase inhibitory activities. Markers and TPC and both the activities of each extract decreased in stability samples with respect to control. These losses were maximum in Type I extract and minimum in Type III extract. Higher stability of Type III extract than others might be attributed to the additional phytoconstituents and/or preservatives in it. Pearson correlation analysis of the results suggested that TPC, asiatic acid, and kaempferol can be taken as chemical markers to assess chemical and therapeutic shelf lives of herbal products containing Centella asiatica. PMID- 27486098 TI - NHS England to appeal against ruling that it can fund PrEP to prevent HIV. PMID- 27486099 TI - Dozens of Turkish doctors are among those detained after coup. PMID- 27486100 TI - Assessing the effects of 35 European-derived BMI-associated SNPs in Mexican children. AB - OBJECTIVE: The prevalence of obesity in Mexico has increased at an alarming rate in both adults and children. This study was undertaken to test in Mexican children the effects of single nucleotide polymorphisms (SNP) that have been associated with body mass index (BMI) and obesity in Europeans. METHODS: School age children (N = 1,559, 5-17 years) were recruited in Mexico City. Thirty-five SNPs with established effects on BMI and obesity were genotyped and analyzed individually and as a combined gene score (GS). RESULTS: SNPs in FAIM2 (rs7138803), GPRC5BB (rs12444979), MTIF3 (rs4771122), TFAP2B (rs987237), TMEM18 (rs7561317), and the GS were significantly associated with BMI. The GS explained 0.9% of the variance of BMI. Also, SNPs in LRRN6C (rs10968576) and MC4R (rs17782313) were significantly associated with overweight and obesity categories, respectively. Importantly, the effect allele frequency of 26/35 SNPs (74.3%) differed significantly between Mexican children and European adults. No significant gene * environment or gene * gene interactions were detected after Bonferroni adjustment. CONCLUSIONS: Several SNPs first associated with BMI/obesity in European adults replicated well in Mexican children, and investigating differences in the distribution of effect alleles across ethnic populations may shed light on genetic susceptibilities of different populations to obesity. PMID- 27486097 TI - Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma. AB - OBJECTIVE: Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. DESIGN: We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-kappaB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. RESULTS: We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5*10-5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk. CONCLUSIONS: This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility. PMID- 27486101 TI - Velocity dependence of vestibular information for postural control on tilting surfaces. AB - Vestibular information is known to be important for postural stability on tilting surfaces, but the relative importance of vestibular information across a wide range of surface tilt velocities is less clear. We compared how tilt velocity influences postural orientation and stability in nine subjects with bilateral vestibular loss and nine age-matched, control subjects. Subjects stood on a force platform that tilted 6 deg, toes-up at eight velocities (0.25 to 32 deg/s), with and without vision. Results showed that visual information effectively compensated for lack of vestibular information at all tilt velocities. However, with eyes closed, subjects with vestibular loss were most unstable within a critical tilt velocity range of 2 to 8 deg/s. Subjects with vestibular deficiency lost their balance in more than 90% of trials during the 4 deg/s condition, but never fell during slower tilts (0.25-1 deg/s) and fell only very rarely during faster tilts (16-32 deg/s). At the critical velocity range in which falls occurred, the body center of mass stayed aligned with respect to the surface, onset of ankle dorsiflexion was delayed, and there was delayed or absent gastrocnemius inhibition, suggesting that subjects were attempting to actively align their upper bodies with respect to the moving surface instead of to gravity. Vestibular information may be critical for stability at velocities of 2 to 8 deg/s because postural sway above 2 deg/s may be too fast to elicit stabilizing responses through the graviceptive somatosensory system, and postural sway below 8 deg/s may be too slow for somatosensory-triggered responses or passive stabilization from trunk inertia. PMID- 27486102 TI - Air-Track: a real-world floating environment for active sensing in head-fixed mice. AB - Natural behavior occurs in multiple sensory and motor modalities and in particular is dependent on sensory feedback that constantly adjusts behavior. To investigate the underlying neuronal correlates of natural behavior, it is useful to have access to state-of-the-art recording equipment (e.g., 2-photon imaging, patch recordings, etc.) that frequently requires head fixation. This limitation has been addressed with various approaches such as virtual reality/air ball or treadmill systems. However, achieving multimodal realistic behavior in these systems can be challenging. These systems are often also complex and expensive to implement. Here we present "Air-Track," an easy-to-build head-fixed behavioral environment that requires only minimal computational processing. The Air-Track is a lightweight physical maze floating on an air table that has all the properties of the "real" world, including multiple sensory modalities tightly coupled to motor actions. To test this system, we trained mice in Go/No-Go and two alternative forced choice tasks in a plus maze. Mice chose lanes and discriminated apertures or textures by moving the Air-Track back and forth and rotating it around themselves. Mice rapidly adapted to moving the track and used visual, auditory, and tactile cues to guide them in performing the tasks. A custom-controlled camera system monitored animal location and generated data that could be used to calculate reaction times in the visual and somatosensory discrimination tasks. We conclude that the Air-Track system is ideal for eliciting natural behavior in concert with virtually any system for monitoring or manipulating brain activity. PMID- 27486103 TI - Perimovement decrease of alpha/beta oscillations in the human nucleus accumbens. AB - The human nucleus accumbens is thought to play an important role in guiding future action selection via an evaluation of current action outcomes. Here we provide electrophysiological evidence for a more direct, i.e., online, role during action preparation. We recorded local field potentials from the nucleus accumbens in patients with epilepsy undergoing surgery for deep brain stimulation. We found a consistent decrease in the power of alpha/beta oscillations (10-30 Hz) before and around the time of movements. This perimovement alpha/beta desynchronization was observed in seven of eight patients and was present both before instructed movements in a serial reaction time task as well as before self-paced, deliberate choices in a decision making task. A similar beta decrease over sensorimotor cortex and in the subthalamic nucleus has been directly related to movement preparation and execution. Our results support the idea of a direct role of the human nucleus accumbens in action preparation and execution. PMID- 27486104 TI - Firing characteristics of deep dorsal horn neurons after acute spinal transection during administration of agonists for 5-HT1B/1D and NMDA receptors. AB - Spinal cord injury (SCI) results in a loss of serotonin (5-HT) to the spinal cord and a loss of inhibition to deep dorsal horn (DDH) neurons, which produces an exaggerated excitatory drive to motoneurons. The mechanism of this excitatory drive could involve the DDH neurons triggering long excitatory postsynaptic potentials in motoneurons, which may ultimately drive muscle spasms. Modifying the activity of DDH neurons with drugs such as NMDA or the 5-HT1B/1D receptor agonist zolmitriptan could have a large effect on motoneuron activity and, therefore, on muscle spasms. In this study, we characterize the firing properties of DDH neurons after acute spinal transection in adult mice during administration of zolmitriptan and NMDA, using the in vitro sacral cord preparation and extracellular electrophysiology. DDH neurons can be categorized into three major types with distinct evoked and spontaneous firing characteristics: burst (bursting), simple (single spiking), and tonic (spontaneously tonic firing) neurons. The burst neurons likely contribute to muscle spasm mechanisms because of their bursting behavior. Only the burst neurons show significant changes in their firing characteristics during zolmitriptan and NMDA administration. Zolmitriptan suppresses the burst neurons by reducing their evoked spikes, burst duration, and spontaneous firing rate. Conversely, NMDA facilitates them by enhancing their burst duration and spontaneous firing rate. These results suggest that zolmitriptan may exert its antispastic effect on the burst neurons via activation of 5-HT1B/1D receptors, whereas activation of NMDA receptors may facilitate the burst neurons in contributing to muscle spasm mechanisms following SCI. PMID- 27486105 TI - Live interaction distinctively shapes social gaze dynamics in rhesus macaques. AB - The dynamic interaction of gaze between individuals is a hallmark of social cognition. However, very few studies have examined social gaze dynamics after mutual eye contact during real-time interactions. We used a highly quantifiable paradigm to assess social gaze dynamics between pairs of monkeys and modeled these dynamics using an exponential decay function to investigate sustained attention after mutual eye contact. When monkeys were interacting with real partners compared with static images and movies of the same monkeys, we found a significant increase in the proportion of fixations to the eyes and a smaller dispersion of fixations around the eyes, indicating enhanced focal attention to the eye region. Notably, dominance and familiarity between the interacting pairs induced separable components of gaze dynamics that were unique to live interactions. Gaze dynamics of dominant monkeys after mutual eye contact were associated with a greater number of fixations to the eyes, whereas those of familiar pairs were associated with a faster rate of decrease in this eye directed attention. Our findings endorse the notion that certain key aspects of social cognition are only captured during interactive social contexts and dependent on the elapsed time relative to socially meaningful events. PMID- 27486106 TI - Initial information prior to movement onset influences kinematics of upward arm pointing movements. AB - To elaborate a motor plan and perform online control in the gravity field, the brain relies on priors and multisensory integration of information. In particular, afferent and efferent inputs related to the initial state are thought to convey sensorimotor information to plan the upcoming action. Yet it is still unclear to what extent these cues impact motor planning. Here we examined the role of initial information on the planning and execution of arm movements. Participants performed upward arm movements around the shoulder at three speeds and in two arm conditions. In the first condition, the arm was outstretched horizontally and required a significant muscular command to compensate for the gravitational shoulder torque before movement onset. In contrast, in the second condition the arm was passively maintained in the same position with a cushioned support and did not require any muscle contraction before movement execution. We quantified differences in motor performance by comparing shoulder velocity profiles. Previous studies showed that asymmetric velocity profiles reflect an optimal integration of the effects of gravity on upward movements. Consistent with this, we found decreased acceleration durations in both arm conditions. However, early differences in kinematic asymmetries and EMG patterns between the two conditions signaled a change of the motor plan. This different behavior carried on through trials when the arm was at rest before movement onset and may reveal a distinct motor strategy chosen in the context of uncertainty. Altogether, we suggest that the information available online must be complemented by accurate initial information. PMID- 27486107 TI - The antiepileptic and ictogenic effects of optogenetic neurostimulation of PV expressing interneurons. AB - Parvalbumin (PV)-expressing interneurons exert powerful inhibitory effects on the normal cortical network; thus optogenetic activation of PV interneurons may also possess antiepileptic properties. To investigate this possibility we expressed channelrhodopsin 2 in PV interneurons by locally injecting the Cre-dependent viral vector AAV2/1-EF1a-DIO-ChETA-EYFP into the S1 barrel cortex of PV-Cre mice. Approximately 3-4 wk later recurrent electrographic seizures were evoked by local application of the chemoconvulsant 4-aminopyridine (4-AP); the ECoG and unit activity were monitored with extracellular silicone electrodes; and PV interneurons were activated optogenetically during the ictal and interictal phases. Five- to ten-second optogenetic activation of PV interneurons applied during electrographic seizures (ictal phase) terminated 33.7% of electrographic seizures compared with only 6% during sham stimulation, and the average electrographic seizure duration shortened by 38.7 +/- 34.2% compared with sham stimulation. In contrast, interictal optogenetic activation of PV interneurons showed powerful and robust ictogenic effects. Approximately 60% of interictal optogenetic stimuli resulted in electrographic seizure initiation. Single-unit recordings revealed that presumptive PV-expressing interneurons markedly increased their firing during optogenetic stimulation, while many presumptive excitatory pyramidal neurons showed a biphasic response, with initial suppression of firing during the optogenetic pulse followed by a synchronized rebound increase in firing at the end of the laser pulse. Our findings indicated that ictal activation of PV-expressing interneurons possesses antiepileptic properties probably due to suppression of firing in pyramidal neurons during the laser pulse. However, in addition interictal activation of PV-expressing interneurons possesses powerful ictogenic properties, probably due to synchronized postinhibition rebound firing of pyramidal neurons. PMID- 27486108 TI - Growth restriction induced by chronic prenatal hypoxia affects breathing rhythm and its pontine catecholaminergic modulation. AB - Impaired transplacental supply of oxygen leads to intrauterine growth restriction, one of the most important causes of perinatal mortality and respiratory morbidity. Breathing rhythm depends on the central respiratory network modulated by catecholamines. We investigated the impact of growth restriction, using prenatal hypoxia, on respiratory frequency, on central respiratory-like rhythm, and on its catecholaminergic modulation after birth. At birth, respiratory frequency was increased and confirmed in en bloc medullary preparations, where the frequency of the fourth cervical (C4) ventral root discharge was increased, and in slice preparations containing the pre-Botzinger complex with an increased inspiratory rhythm. The inhibition of C4 burst discharge observed in pontomedullary preparations was stronger in the growth restricted group. These results cannot be directly linked by the tyrosine hydroxylase activity increase of A1/C1 and A2/C2 cell groups in the medulla since blockade of alpha1- and alpha2-adrenergic receptors did not abolish the difference between both groups. However, in pontomedullary preparations, the stronger inhibition of C4 burst discharge is probably supported by an increased inhibition of A5, a respiratory rhythm inhibitor pontine group of neurons displaying increased tyrosine hydroxylase activity, because blockade of alpha2 adrenergic receptors abolished the difference between the two groups. Taken together, these results indicate that growth restriction leads to a perturbation of the breathing frequency, which finds, at least in part, its origin in the modification of catecholaminergic modulation of the central breathing network. PMID- 27486109 TI - Savings for visuomotor adaptation require prior history of error, not prior repetition of successful actions. AB - When we move, perturbations to our body or the environment can elicit discrepancies between predicted and actual outcomes. We readily adapt movements to compensate for such discrepancies, and the retention of this learning is evident as savings, or faster readaptation to a previously encountered perturbation. The mechanistic processes contributing to savings, or even the necessary conditions for savings, are not fully understood. One theory suggests that savings requires increased sensitivity to previously experienced errors: when perturbations evoke a sequence of correlated errors, we increase our sensitivity to the errors experienced, which subsequently improves error correction (Herzfeld et al. 2014). An alternative theory suggests that a memory of actions is necessary for savings: when an action becomes associated with successful target acquisition through repetition, that action is more rapidly retrieved at subsequent learning (Huang et al. 2011). In the present study, to better understand the necessary conditions for savings, we tested how savings is affected by prior experience of similar errors and prior repetition of the action required to eliminate errors using a factorial design. Prior experience of errors induced by a visuomotor rotation in the savings block was either prevented at initial learning by gradually removing an oppositely signed perturbation or enforced by abruptly removing the perturbation. Prior repetition of the action required to eliminate errors in the savings block was either deprived or enforced by manipulating target location in preceding trials. The data suggest that prior experience of errors is both necessary and sufficient for savings, whereas prior repetition of a successful action is neither necessary nor sufficient for savings. PMID- 27486110 TI - Subretinal electrical stimulation reveals intact network activity in the blind mouse retina. AB - Retinal degeneration (rd) leads to progressive photoreceptor cell death, resulting in vision loss. Stimulation of the inner-retinal neurons by neuroprosthetic implants is one of the clinically approved vision-restoration strategies, providing basic visual percepts to blind patients. However, little is understood as to what degree the degenerating retinal circuitry and the resulting aberrant hyperactivity may prevent the stimulation of physiological electrical activity. Therefore, we electrically stimulated ex vivo retinas from wild-type (wt; C57BL/6J) and blind (rd10 and rd1) mice using an implantable subretinal microchip and simultaneously recorded and analyzed the retinal ganglion cell (RGC) output with a flexible microelectrode array. We found that subretinal anodal stimulation of the rd10 retina and wt retina evoked similar spatiotemporal RGC-spiking patterns. In both retinas, electrically stimulated ON and a small percentage of OFF RGC responses were detected. The spatial selectivity of the retinal network to electrical stimuli reveals an intact underlying network with a median receptive-field center of 350 MUm in both retinas. An antagonistic surround is activated by stimulation with large electrode fields. However, in rd10 and to a higher percentage, in rd1 retinas, rhythmic and spatially unconfined RGC patterns were evoked by anodal or by cathodal electrical stimuli. Our findings demonstrate that the surviving retinal circuitry in photoreceptor degenerated retinas is preserved in a way allowing for the stimulation of temporally diverse and spatially confined RGC activity. Future vision restoration strategies can build on these results but need to avoid evoking the easily inducible rhythmic activity in some retinal circuits. PMID- 27486111 TI - Spike synchrony generated by modulatory common input through NMDA-type synapses. AB - Common excitatory input to neurons increases their firing rates and the strength of the spike correlation (synchrony) between them. Little is known, however, about the synchronizing effects of modulatory common input. Here, we show that modulatory common input with the slow synaptic kinetics of N-methyl-d-aspartate (NMDA) receptors enhances firing rates and also produces synchrony. Tight synchrony (correlations on the order of milliseconds) always increases with modulatory strength. Unexpectedly, the relationship between strength of modulation and strength of loose synchrony (tens of milliseconds) is not monotonic: The strongest loose synchrony is obtained for intermediate modulatory amplitudes. This finding explains recent neurophysiological results showing that in cortical areas V1 and V2, presumed modulatory top-down input due to contour grouping increases (loose and tight) synchrony but that additional modulatory input due to top-down attention does not change tight synchrony and actually decreases loose synchrony. These neurophysiological findings are understood from our model of integrate-and-fire neurons under the assumption that contour grouping as well as attention lead to additive modulatory common input through NMDA-type synapses. In contrast, circuits with common projections through model alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors did not exhibit the paradoxical decrease of synchrony with increased input. Our results suggest that NMDA receptors play a critical role in top-down response modulation in the visual cortex. PMID- 27486113 TI - Editorial Commentary: Sliding Down the Cascade of Care for Chronic Hepatitis B Virus Infection. PMID- 27486112 TI - No Evidence of Reactivation of Hepatitis B Virus Among Patients Treated With Ledipasvir-Sofosbuvir for Hepatitis C Virus Infection. AB - Postmarketing cases of hepatitis B virus (HBV) reactivation during hepatitis C treatment have been reported. We analyzed serum samples from patients in a clinical trial of ledipasvir-sofosbuvir in Taiwan and Korea. Of the 173 patients enrolled, 103 (60%) had been previously infected with HBV. None showed evidence of HBV reactivation. PMID- 27486114 TI - Case-Control Study of Vaccine Effectiveness in Preventing Laboratory-Confirmed Influenza Hospitalizations in Older Adults, United States, 2010-2011. AB - BACKGROUND: Older adults are at increased risk of influenza-associated complications, including hospitalization, but influenza vaccine effectiveness (VE) data are limited for this population. We conducted a case-control study to estimate VE to prevent laboratory-confirmed influenza hospitalizations among adults aged >=50 years in 11 US Emerging Infections Program hospitalization surveillance sites. METHODS: Cases were influenza infections (confirmed by reverse-transcription polymerase chain reaction) in adults aged >=50 years hospitalized during the 2010-2011 influenza season, identified through Emerging Infections Program surveillance. Community controls, identified through home telephone lists, were matched by age group (+/-5 years), county, and month of hospitalization for case patients. Vaccination status was determined by self report (with location and date) or medical records. Conditional logistic regression models were used to calculate adjusted VE (aVE) estimates (100 * [1 - adjusted odds ratio]), adjusting for sex, race, socioeconomic factors, smoking, chronic medical conditions, recent hospitalization for a respiratory condition, and functional status. RESULTS: Among case patients, 205 of 368 (55%) were vaccinated, compared with 489 of 773 controls (63%). Case patients were more likely to be of nonwhite race and more likely to have >=2 chronic health conditions, a recent hospitalization for a respiratory condition, an income <$35 000, and a lower functional status score (P < .01 for all). The aVE was 56.8% (95% confidence interval, 34.1%-71.7%) and was similar across age groups, including adults >=75 years (aVE, 57.3%; 15.9%-78.4%). CONCLUSIONS: During 2010 2011, influenza vaccination was associated with a significant reduction in the risk of laboratory-confirmed influenza hospitalization among adults aged >=50 years, regardless of age group. PMID- 27486115 TI - Infrequent Clinical Assessment of Chronic Hepatitis B Patients in United States General Healthcare Settings. AB - Among 2338 chronic hepatitis B patients followed during 2006-2013 in the Chronic Hepatitis Cohort Study, 78% had >=1 alanine aminotransferase and 37% had >=1 hepatitis B virus DNA level assessed annually. Among cirrhotic patients, 46% never had hepatic imaging. Patients in this cohort were insufficiently monitored for disease activity and hepatocellular carcinoma. PMID- 27486116 TI - Spread of Carbapenem-Resistant Enterobacteriaceae Among Illinois Healthcare Facilities: The Role of Patient Sharing. AB - BACKGROUND: Carbapenem-resistant Enterobacteriaceae (CRE) spread regionally throughout healthcare facilities through patient transfer and cause difficult-to treat infections. We developed a state-wide patient-sharing matrix and applied social network analyses to determine whether greater connectedness (centrality) to other healthcare facilities and greater patient sharing with long-term acute care hospitals (LTACHs) predicted higher facility CRE rates. METHODS: We combined CRE case information from the Illinois extensively drug-resistant organism registry with measures of centrality calculated from a state-wide hospital discharge dataset to predict facility-level CRE rates, adjusting for hospital size and geographic characteristics. RESULTS: Higher CRE rates were observed among facilities with greater patient sharing, as measured by degree centrality. Each additional hospital connection (unit of degree) conferred a 6% increase in CRE rate in rural facilities (relative risk [RR] = 1.056; 95% confidence interval [CI], 1.030-1.082) and a 3% increase among Chicagoland and non-Chicago urban facilities (RR = 1.027; 95% CI, 1.002-1.052 and RR = 1.025; 95% CI, 1.002-1.048, respectively). Sharing 4 or more patients with LTACHs was associated with higher CRE rates, but this association may have been due to chance (RR = 2.08; 95% CI, .85-5.08; P = .11). CONCLUSIONS: Hospitals with greater connectedness to other hospitals in a statewide patient-sharing network had higher CRE burden. Centrality had a greater effect on CRE rates in rural counties, which do not have LTACHs. Social network analysis likely identifies hospitals at higher risk of CRE exposure, enabling focused clinical and public health interventions. PMID- 27486118 TI - Seo YB et al (Clin Infect Dis 2016; 62:755-60). PMID- 27486117 TI - Karanika S et al (Clin Infect Dis 2016; 63:310-18). PMID- 27486119 TI - Editorial Commentary: Network Models, Patient Transfers, and Infection Control. PMID- 27486120 TI - Zoophthora radicans (Entomophthorales), a fungal pathogen of Bagrada hilaris and Bactericera cockerelli (Hemiptera: Pentatomidae and Triozidae): Prevalence, pathogenicity, and interplay of environmental influence, morphology, and sequence data on fungal identification. AB - The exotic bagrada bug or painted bug, Bagrada hilaris, and the native potato/tomato psyllid, Bactericera (=Paratrioza) cockerelli, are key pests of horticulture in western North America. In 2014-2015, adult and juvenile B. hilaris and B. cockerelli killed by fungi in the genus Zoophthora were detected near Saltillo, northeastern Mexico. We report the field prevalence and observations of Zoophthora on these hosts. The morphology and growth characteristics of field-collected specimens and pure in vitro cultures, as well as molecular markers (ITS1 and ITS4) were analyzed to identify these Zoophthora populations. Although there were morphological spore differences detected among field collections from both insect hosts, the fungi causing these mycoses can be identified as the same species (Zoophthora radicans), according to morphometric data from in vitro cultures (where differences observed in field material were attenuated) and sequence data (96-99% identity for ITS1 and 4). These results underscore the plasticity of field collections and in vitro cultures, and the relevance of comprehensive morphological and molecular analysis from cultures under standard conditions. Dose-response bioassays were conducted with one Z. radicans strain against bagrada bug nymphs. Exposure to conidial showers from cultures induced 30-90% mortality. This is the first report of a natural enemy of bagrada bug in Mexico, and the first published report of entomophthoralean fungi naturally attacking bagrada bugs and potato psyllids. Z. radicans should be further investigated as a tool in the biological control of hemipterans. PMID- 27486121 TI - Revisiting protein structure, function, and evolution in the genomic era. AB - The expansion of genomic data, three-dimensional structures of proteins, and computing power continues to improve our understanding of the evolution of protein structure and function relationships. As of June 2016, publically available databases contain more than 60 million unique protein sequences that group into 16,295 protein families that adopt ~1400 different three-dimensional folds. This data supports the exploration of evolutionary relationships on protein structure and function to answer a basic question - how do changes in gene sequence lead to alterations in protein structure and to the tailoring of biological and chemical function? This mini-review aims to provide a primer on the basics of protein structure, how evolution of sequence leads to diversity in protein structure and function, how these changes occur, and the role of domains in protein evolution. Understanding how to use the vast amount of sequence and structural information may also aid in assessing if changes in protein sequence and/or structure are relevant for safety assessments of new commercial biotechnology products. PMID- 27486122 TI - Supplementation of vitamin B12 or folic acid on hemoglobin concentration in children 6-36 months of age: A randomized placebo controlled trial. AB - BACKGROUND & AIMS: The main objective of this report is to measure to what extent folate or vitamin B12 given daily for 6 months to young North Indian Children improves hemoglobin (Hb) concentration. METHODS: In a randomized placebo controlled trial in low-to-middle income neighborhoods in New Delhi, India, children were randomized into four groups in a 1:1:1:1 ratio and supplemented daily for 6 months with 2 RDAs of vitamin B12, folic acid, both, or placebo. All children with anemia at baseline were given iron supplementation daily for 2 months. We measured the plasma concentrations of soluble transferrin receptor (sTfR), folate, vitamin B12, total homocysteine (tHcy) and Hb in 262 children. RESULTS: Mean Hb concentration decreased in all four study groups during the six months of follow up and supplementation of either or both of the vitamins did not improve the Hb concentration. Iron supplements for the initial 2 mo had limited effect on anemia at 6 mo as almost 90% were still anemic at study end. CONCLUSION: Supplementation of folic acid and/or vitamin B12 for 6 months does not improve Hb concentration in young children. Our findings do not argue for widespread vitamin B12 or folic acid supplementation to combat anemia. Our results also call for alternative strategies to improve iron status and treat iron deficiency anemia. CLINICAL TRIAL REGISTRY: NCT00717730 at www.clinicaltrials.gov, CTRI No.: CTRI/2010/091/001090 at www.ctri.nic.in. PMID- 27486123 TI - Feasibility of nephrinuria as a screening tool for the risk of pre-eclampsia: prospective observational study. AB - OBJECTIVES: To investigate the possibility of nephrinuria as a screening tool for the risk of pre-eclampsia (PE). DESIGN: Prospective observational study. SETTING: A single university hospital. Changes in urinary nephrin:creatinine ratio (NCR, ng/mg) and protein:creatinine ratio (PCR, mg/mg) in pregnancy were determined. Significant proteinuria in pregnancy (SPIP) was defined as PCR>0.27. PE was diagnosed in women with both SPIP and hypertension. PARTICIPANTS: 89 pregnant women in whom neither hypertension nor SPIP was present at enrolment, providing 31, 125 and 93 random urine samples during first, second and third trimesters, respectively. RESULTS: PE developed in 14 of the 89 women. NCR increased with increasing PCR in 14 women with PE (correlation coefficient, 0.862; p<0.0001). In contrast, NCR did not change significantly despite significant increases in PCR in 75 women with normotensive pregnancies defined as neither SPIP nor hypertension, indicating that there was little increase in nephrinuria over the physiological range of proteinuria in pregnancy. Relative risk of later development of PE among asymptomatic second and third trimester women with NCR (ng/mg) >122 (95th centile value for 75 women with normotensive pregnancies) was 5.93 (95% CI 2.59 to 13.6; 60% (6/10) vs 10% (8/79)) and 13.5 (95% CI 3.31 to 55.0; 75% (6/8) vs 5.5% (2/36)), respectively, compared with women with NCR<=122 at that time. CONCLUSIONS: Nephrinuria was unlikely to increase in normal pregnancy. A certain NCR cut-off may efficiently differentiate women at higher risk of PE. PMID- 27486125 TI - Lipid changes during basal insulin peglispro, insulin glargine, or NPH treatment in six IMAGINE trials. AB - Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action resulting from reduced peripheral effects. This report provides an integrated summary of lipid changes at 26 weeks with BIL and comparator insulins (glargine, NPH) from phase III studies in type 1 diabetes (T1D), insulin-naive patients with type 2 diabetes (T2D), patients with T2D on basal insulin only and patients with T2D on basal-bolus therapy. BIL treatment had little effect on HDL cholesterol and LDL cholesterol in all patients. The effect of both BIL and glargine treatment on triglycerides (TG) depended on whether patients had been previously treated with insulin. When BIL replaced conventional insulin glargine or NPH treatments, increases in TG levels were observed. When BIL or comparator insulins were given for 26 weeks to insulin-naive patients with T2D, TG levels were unchanged from baseline with BIL but decreased with either glargine or NPH. The decreased peripheral action of BIL may reduce suppression of lipolysis in peripheral adipose tissue resulting in increased free fatty acid delivery to the liver and, hence, increased hepatic TG synthesis and secretion. PMID- 27486126 TI - Women's Empowerment as a Protective Factor Against Intimate Partner Violence in Bangladesh: A Qualitative Exploration of the Process and Limitations of Its Influence. AB - Literature on the relationship between intimate partner violence (IPV) against women and women's empowerment is contradictory. Findings from a recent survey in rural Bangladesh suggest that empowerment is becoming protective even though IPV rates remain high. We construct qualitative case studies exploring factors and social processes underlying relationships between empowerment and IPV in four villages. Empowerment may be protective against IPV in the aggregate, but this relationship can be subverted at the micro level. Interventions are needed to reinforce the potential of empowerment to reduce IPV and counteract factors such as geographic isolation and limited employment opportunities that inhibit empowerment. PMID- 27486124 TI - Visually Impaired OLder people's Exercise programme for falls prevenTion (VIOLET): a feasibility study protocol. AB - INTRODUCTION: In the UK, 1 in 5 people aged 75 and over live with sight loss. Visually impaired older people (VIOP) have an above average incidence of falls and 1.3-1.9 times more likely to experience hip fractures, than the general population. Older people with eye diseases are ~3 times more likely than those with good vision, to limit activities due to fear of falling. This feasibility study aims to adapt the group-based Falls Management Exercise (FaME) programme to the needs of VIOP and carry out an external pilot trial to inform the design of a future definitive randomised controlled trial. METHODS AND DESIGN: A UK based 2 centre mixed methods, randomised, feasibility study will be conducted over 28 months. Stakeholder panels, including VIOP, will make recommendations for adaptations to an existing exercise programme (FaME), to meet the needs of VIOP, promoting uptake and adherence, while retaining required effective components of the exercise programme. 80 VIOP aged 60 and over, living at home, ambulant with or without a walking aid, will be recruited in Newcastle (n=40) and Glasgow (n=40) through National Health Service (NHS) Trusts and third sector partners. Participants randomised into the intervention arm will receive the adapted FaME programme. Participants randomised into the control arm will continue with usual activity. Outcomes are, recruitment rate, adherence and validated measures including fear of falling and quality of life. Postintervention in-depth qualitative interviews will be conducted with a purposive sample of VIOP (N=10). Postural stability instructors will be interviewed, before trial-specific training and following the intervention. ETHICS AND DISSEMINATION: Ethics approval was secured through the National Research Ethics Service (NRES) Committee North East, Newcastle and North Tyneside 2. Glasgow Caledonian University was approved as a non-NHS site with local ethics approval. Findings will be disseminated through peer-reviewed journals, national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN16949845. PMID- 27486127 TI - Differences in Mental Health and Sexual Outcomes Based on Type of Nonconsensual Sexual Penetration. AB - Little is known based on the stratification and localization of penetration type of rape: oral, vaginal, and/or anal. The current study examined associations between type of rape and mental and sexual health symptoms in 865 community women. All penetration types were positively associated with negative mental and sexual health symptoms. Oral and/or anal rape accounted for additional variance in anxiety, depression, some trauma-related symptoms, and dysfunctional sexual behavior than the association with vaginal rape alone. Findings suggest that penetration type can be an important facet of a rape experience and may be useful to assess in research and clinical settings. PMID- 27486128 TI - Calling the Shots: How Family Courts Address the Firearms Ban in Protection Orders. AB - Access to firearms increases the risk of a batterer killing his partner. Moreover, firearms may be more common in homes where intimate partner abuse has occurred. The Violence Against Women Act of 1994 banned possession of firearms by individuals subject to civil protection orders. Yet little research has focused on how this ban is communicated to survivors and batterers. Drawing on systematic observations of protection order hearings, the current study explores factors related to judicial discussion of the ban in court. Implications for improving protection orders and for increasing battered women's safety are discussed. PMID- 27486129 TI - Comment on 'A new method to measure electron density and effective atomic number using dual-energy CT images'. PMID- 27486130 TI - Effect of race/ethnicity on risk of complete and partial molar pregnancy after adjustment for age. AB - OBJECTIVE: To quantify the effect of race/ethnicity on risk of complete and partial molar pregnancy. METHODS: We conducted a cross-sectional study including women who were followed for complete or partial mole and those who had a live singleton birth in a teaching hospital in the northeastern United States between 2000 and 2013. We calculated race/ethnicity-specific risk of complete and partial mole per 10,000 live births, and used logistic regression to estimate crude and age-adjusted relative risks (RR) of complete and partial mole. RESULTS: We identified 140 cases of complete mole, 115 cases of partial mole, and 105,942 live births. The risk of complete mole was 13 cases per 10,000 live births (95% confidence interval [CI] 11-16) and that of partial mole was 11 cases per 10,000 live births (95% CI 9-13). After age-adjustment, Asians were more likely to develop complete mole (RR 2.3 95% CI 1.4-3.8, p<0.001) but less likely to develop partial mole (RR 0.2; 95% CI 0.04-0.7, p=0.02) than whites. Blacks were significantly less likely than whites to develop partial mole (RR 0.4; 95% CI 0.2 0.8, p=0.01) but only marginally less likely to develop complete mole (RR 0.6; 95% CI 0.3-1.0, p=0.07). Hispanics were less likely than whites to develop complete mole (RR 0.4; 95% CI 0.2-0.7, p=0.002) and partial mole (RR 0.4; 95% CI 0.2-0.9, p=0.02). CONCLUSION: Race/ethnicity is a significant risk factor for both complete and partial molar pregnancy in the northeastern United States. PMID- 27486131 TI - Impact of postoperative intensity-modulated radiation therapy (IMRT) on the rate of bowel obstruction in gynecologic malignancy. AB - OBJECTIVE: The purpose was to determine the potential impact of IMRT on the rate of bowel obstruction (BO), in patients with gynecologic malignancies undergoing postoperative pelvic RT. METHODS: We performed a retrospective review of all patients with endometrial or cervical cancer who received postoperative pelvic RT at our institution from 2000 to 2012. Patients who received definitive or palliative RT, or those with BO due to disease progression, were excluded. Standard two-sided statistical tests were used to evaluate for associated risk factors. Kaplan-Meier, Log rank and Cox proportional hazards regression analysis tests were performed for actuarial analysis. RESULTS: A total of 224 patients were identified, 120 (54%) received postoperative pelvic IMRT and 104 (46%) 3 dimentional (3-D) RT. Median follow-up time was 67months. BO was grade 1 (asymptomatic) in 2/228 (0.9%), grade 2 (conservative management) in 4 (1.8%), and grade 3>= in 4 (1.8%). Overall, the 5-year actuarial rate of BO was 4.8%. The 5-year rate of BO in the IMRT group was 0.9% compared to 9.3% for 3-D RT (p=0.006). Patients with BMI>=30kg/m(2) were less likely to develop BO (2.6% vs. 8.3; p=0.03). On multivariate analysis, only IMRT retained its significance as an independent predictor of less BO (p=0.022). CONCLUSIONS: The use of postoperative IMRT for cervical and endometrial cancer was associated with significant reduction in the rate of bowel obstruction. This difference maintained its statistical significance on multivariate analysis. Such finding if confirmed by others will help further solidify the benefit of IMRT in gynecologic cancers. PMID- 27486132 TI - Boari flap ureteroneocystostomy in an oncological patient. AB - OBJECTIVE: Demonstration of surgical steps of a Boari Flap ureteroneocystostomy in an oncological context. METHODS: Clinical case of a 66-year-old woman diagnosed with a left-pelvic recurrence of a high-grade serous ovarian carcinoma, involving the left ureter. After transection of 5cm of ureteral length, up to the level of the bifurcation of common iliac vessels, it was decided to perform a Boari Flap for ureteral reimplantation. RESULTS: Through the tubularization of a bladder flap, the extension of the ureter to the bladder is possible. After mobilization and psoas fixation, the bladder is opened on its anterior surface, in a rhomboid incision, and a full thickness bladder flap is extended cranially and tubularized for anastomosis of the proximal ureteral segment. The ureter is reimplanted after creation of an anti-reflux system with a submucosal tunnel between the mucosa and the detrusor. To finish the procedure, the bladder is closed in two layers with a running monofilament absorbable suture. CONCLUSIONS: Boari Flap ureteroneocystostomy is an uncommon urinary reconstruction, useful to correct distal ureteric defects caused by traumatic, oncological or iatrogenic injuries [1]. The success rate of ureteral reimplantation can be higher than 85% [2]. This technique is suitable for anastomosis of lumbar ureteral segments, allowing the better correction of higher and more extensive defects than the Psoas-Hitch technique. The flap length should compensate the ureteric defect and enable a tension free anastomosis. PMID- 27486133 TI - Emergency department imaging: are weather and calendar factors associated with imaging volume? AB - AIM: To identify weather and calendar factors that would enable prediction of daily emergency department (ED) imaging volume to aid appropriate scheduling of imaging resources for efficient ED function. MATERIALS AND METHODS: Daily ED triage and imaging volumes for radiography, computed tomography (CT), and ultrasound were obtained from hospital databases for the period between January 2011 and December 2013 at a large tertiary urban hospital with a Level II trauma centre. These data were tabulated alongside daily weather conditions (temperature, wind and precipitation), day of week, season, and holidays. Multivariate analysis was performed. Pearson correlations were used to measure the association between number of imaging studies performed and ED triage volume. RESULTS: For every additional 50 triaged patients, the odds of having high (imaging volume >=90th percentile) radiography, CT, and ultrasound volume increased by 4.3 times (p<0.001), 1.5 times (p=0.02), and 1.4 times (p=0.02), respectively. Tuesday was an independent predictor of high radiography volume (odds ratio=2.8) and Monday was an independent predictor of high CT volume (odds ratio=3.0). Weekday status was an independent factor increasing the odds of a high US volume compared to Saturday (odds ratios ranging from 5.6-9.8). Weather factors and other calendar variables were not independent predictors of high imaging volume. Using Pearson correlations, ED triage volume correlated with number of radiographs, CT, and ultrasound examinations with r=0.73, 0.37, and 0.41, respectively (p<0.0001). CONCLUSION: As ED triage volume was found to be the only factor associated with imaging volume for all techniques, analysis of predictors of ED triage volumes at a particular healthcare facility would be useful to determine imaging needs. Although calendar and weather factors were found to be minor or non-significant independent predictors of ED imaging utilisation, these may be important in influencing the actual number of ED triages. PMID- 27486135 TI - The impact of intestinal resection on the immune function of short bowel syndrome patients. AB - Short bowel syndrome (SBS) is characterized by a massive intestinal loss after surgery resection. Likewise, disturbances involving the intestine, which represents a complex immune environment, may result in breakdown of homeostasis and altered responses, thus leading to unpredictable clinical outcomes. However, the consequences of bowel resection were poorly investigated until now. Therefore, this study aimed to evaluate the immunological status of SBS-patients. For this purpose, ten subjects and nine healthy controls were evaluated. Along with some metabolic disturbances, the main results showed higher levels of the inflammatory cytokine IL-6 in plasma among SBS-patients. However, there were no differences in the frequency of CD3+, CD3+CD4+ or CD3+CD8+ T lymphocytes. An augmented frequency in CD4+ and CD8+ cells producing IFN-gamma was also observed in peripheral blood mononuclear cells (PBMC), together with elevated percentage of CD4+ cells producing IL-10. No differences were observed in the frequency of total CD4+CD25-, CD4+CD25+ lymphocytes nor in the expression of FoxP3 or GITR. Nevertheless, SBS-patients showed higher frequency of the regulatory T cell population CD4+CD25+CD39+ cells in PBMC. In conclusion, these data pointed to SBS as an important disturbance that compromises not only the intestinal environment but also negatively influences systemic immune components. PMID- 27486134 TI - Amyloid-beta Precursor Protein Modulates the Sorting of Testican-1 and Contributes to Its Accumulation in Brain Tissue and Cerebrospinal Fluid from Patients with Alzheimer Disease. AB - The mechanisms leading to amyloid-beta (Abeta) accumulation in sporadic Alzheimer disease (AD) are unknown but both increased production or impaired clearance likely contribute to aggregation. To understand the potential roles of the extracellular matrix proteoglycan Testican-1 in the pathophysiology of AD, we used samples from AD patients and controls and an in vitro approach. Protein expression analysis showed increased levels of Testican-1 in frontal and temporal cortex of AD patients; histological analysis showed that Testican-1 accumulates and co-aggregates with Abeta plaques in the frontal, temporal and entorhinal cortices of AD patients. Proteomic analysis identified 10 fragments of Testican-1 in cerebrospinal fluid (CSF) from AD patients. HEK293T cells expressing human wild type or mutant Abeta precursor protein (APP) were transfected with Testican 1. The co-expression of both proteins modified the sorting of Testican-1 into the endocytic pathway leading to its transient accumulation in Golgi, which seemed to affect APP processing, as indicated by reduced Abeta40 and Abeta42 levels in APP mutant cells. In conclusion, patient data reflect a clearance impairment that may favor Abeta accumulation in AD brains and our in vitro model supports the notion that the interaction between APP and Testican-1 may be a key step in the production and aggregation of Abeta species. PMID- 27486136 TI - Paradoxical Response to Enzyme Replacement Therapy of Fabry Disease Cardiomyopathy. PMID- 27486137 TI - Understanding the Personality and Behavioral Mechanisms Defining Hypersexuality in Men Who Have Sex With Men. AB - INTRODUCTION: Hypersexuality has been conceptualized as sexual addiction, compulsivity, and impulsivity, among others, in the absence of strong empirical data in support of any specific conceptualization. AIM: To investigate personality factors and behavioral mechanisms that are relevant to hypersexuality in men who have sex with men. METHODS: A sample of 242 men who have sex with men was recruited from various sites in a moderate-size mid-western city. Participants were assigned to a hypersexuality group or a control group using an interview similar to the Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition. Self-report inventories were administered that measured the broad personality constructs of positive emotionality, negative emotionality, and constraint and more narrow constructs related to sexual behavioral control, behavioral activation, behavioral inhibition, sexual excitation, sexual inhibition, impulsivity, attention deficit/hyperactivity disorder, and sexual behavior. MAIN OUTCOME MEASURES: Hierarchical logistic regression was used to determine the relation between these personality and behavioral variables and group membership. RESULTS: A hierarchical logistic regression controlling for age showed a significant positive relation between hypersexuality and negative emotionality and a negative relation with constraint. None of the behavioral mechanism variables entered this equation. However, a hierarchical multiple regression analysis predicting sexual behavioral control indicated that lack of such control was positively related to sexual excitation and sexual inhibition owing to the threat of performance failure and negatively related to sexual inhibition owing to the threat of performance consequences and general behavioral inhibition CONCLUSION: Hypersexuality was found to be related to two broad personality factors that are characterized by emotional reactivity, risk taking, and impulsivity. The associated lack of sexual behavior control is influenced by sexual excitatory and inhibitory mechanisms, but not by general behavioral activation and inhibitory mechanisms. PMID- 27486139 TI - Hyperplastic stomatitis and esophagitis in a tortoise (Testudo graeca) associated with an adenovirus infection. AB - A 2-year-old female, spur-thighed tortoise (Testudo graeca) was presented with poor body condition (1/5) and weakness. Fecal analysis revealed large numbers of oxyurid-like eggs, and radiographs were compatible with gastrointestinal obstruction. Despite supportive medical treatment, the animal died. At gross examination, an intestinal obstruction was confirmed. Histopathology revealed severe hyperplastic esophagitis and stomatitis with marked epithelial cytomegaly and enormous basophilic intranuclear inclusion bodies. Electron microscopy examination revealed a large number of 60-80 nm, nonenveloped, icosahedral virions arranged in crystalline arrays within nuclear inclusions of esophageal epithelial cells, morphologically compatible with adenovirus-like particles. PCR for virus identification was performed with DNA extracted from formalin-fixed, paraffin-embedded tissues. A nested, consensus pan-adenovirus PCR and sequencing analysis showed a novel adenovirus. According to phylogenetic calculations, it clustered to genus Atadenovirus in contrast with all other chelonian adenoviruses described to date. The present report details the pathologic findings associated with an adenovirus infection restricted to the upper digestive tract. PMID- 27486140 TI - Incidence, Determinants, and Outcomes of Coronary Perforation During Percutaneous Coronary Intervention in the United Kingdom Between 2006 and 2013: An Analysis of 527 121 Cases From the British Cardiovascular Intervention Society Database. AB - BACKGROUND: As coronary perforation (CP) is a rare but serious complication of percutaneous coronary intervention (PCI) the current evidence base is limited to small series. Using a national PCI database, the incidence, predictors, and outcomes of CP as a complication of PCI were defined. METHODS AND RESULTS: Data were prospectively collected and retrospectively analyzed from the British Cardiovascular Intervention Society data set on all PCI procedures performed in England and Wales between 2006 and 2013. Multivariate logistic regressions and propensity scores were used to identify predictors of CP and its association with outcomes. In total, 1762 CPs were recorded from 527 121 PCI procedures (incidence of 0.33%). Patients with CP were more often women or older, with a greater burden of comorbidity and underwent more complex PCI procedures. Factors predictive of CP included age per year (odds ratio [OR], 1.03; 95% confidence intervals, 1.02 1.03; P<0.001), previous coronary artery bypass graft (OR, 1.44; 95% confidence intervals, 1.17-1.77; P<0.001), left main (OR, 1.54; 95% confidence intervals, 1.21-1.96; P<0.001), use of rotational atherectomy (OR, 2.37; 95% confidence intervals, 1.80-3.11; P<0.001), and chronic total occlusions intervention (OR, 3.96; 95% confidence intervals, 3.28-4.78; P<0.001). Adjusted odds of adverse outcomes were higher in patients with CP for all major adverse coronary events, including stroke, bleeding, and mortality. Emergency surgery was required in 3% of cases. Predictors of mortality in patients with CP included age, diabetes mellitus, previous myocardial infarction, renal disease, ventilatory support, use of circulatory support, glycoprotein inhibitor use, and stent type. CONCLUSIONS: Using a national PCI database for the first time, the incidence, predictors, and outcomes of CP were defined. Although CP as a complication of PCI occurred rarely, it was strongly associated with poor outcomes. PMID- 27486138 TI - Mendelian Randomization as an Approach to Assess Causality Using Observational Data. AB - Mendelian randomization refers to an analytic approach to assess the causality of an observed association between a modifiable exposure or risk factor and a clinically relevant outcome. It presents a valuable tool, especially when randomized controlled trials to examine causality are not feasible and observational studies provide biased associations because of confounding or reverse causality. These issues are addressed by using genetic variants as instrumental variables for the tested exposure: the alleles of this exposure associated genetic variant are randomly allocated and not subject to reverse causation. This, together with the wide availability of published genetic associations to screen for suitable genetic instrumental variables make Mendelian randomization a time- and cost-efficient approach and contribute to its increasing popularity for assessing and screening for potentially causal associations. An observed association between the genetic instrumental variable and the outcome supports the hypothesis that the exposure in question is causally related to the outcome. This review provides an overview of the Mendelian randomization method, addresses assumptions and implications, and includes illustrative examples. We also discuss special issues in nephrology, such as inverse risk factor associations in advanced disease, and outline opportunities to design Mendelian randomization studies around kidney function and disease. PMID- 27486141 TI - Promising effects of oxytocin on social and food-related behaviour in young children with Prader-Willi syndrome: a randomized, double-blind, controlled crossover trial. AB - BACKGROUND: Prader-Willi syndrome (PWS) is known for hyperphagia with impaired satiety and a specific behavioural phenotype with stubbornness, temper tantrums, manipulative and controlling behaviour and obsessive-compulsive features. PWS is associated with hypothalamic and oxytocinergic dysfunction. In humans without PWS, intranasal oxytocin administration had positive effects on social and eating behaviour, and weight balance. OBJECTIVE AND HYPOTHESES: To evaluate the effects of intranasal oxytocin compared to placebo administration on social behaviour and hyperphagia in children with PWS. DESIGN: Randomized, double-blind, placebo controlled, crossover study in a PWS Reference Center in the Netherlands. METHOD: Crossover intervention with twice daily intranasal oxytocin (dose range 24-48 IU/day) and placebo administration, both during 4 weeks, in 25 children with PWS (aged 6 to 14 years). RESULTS: In the total group, no significant effects of oxytocin on social behaviour or hyperphagia were found, but in the 17 children younger than 11 years, parents reported significantly less anger (P = 0.001), sadness (P = 0.005), conflicts (P = 0.010) and food-related behaviour (P = 0.011), and improvement of social behaviour (P = 0.018) during oxytocin treatment compared with placebo. In the eight children older than 11 years, the items happiness (P = 0.039), anger (P = 0.042) and sadness (P = 0.042) were negatively influenced by oxytocin treatment compared to placebo. There were no side effects or adverse events. CONCLUSIONS: This randomized, double-blind, placebo-controlled study suggests that intranasal oxytocin administration has beneficial effects on social behaviour and food-related behaviour in children with PWS younger than 11 years of age, but not in those older than 11 years of age. PMID- 27486142 TI - Improvements in ECG accuracy for diagnosis of left ventricular hypertrophy in obesity. AB - OBJECTIVES: The electrocardiogram (ECG) is the most commonly used tool to screen for left ventricular hypertrophy (LVH), and yet current diagnostic criteria are insensitive in modern increasingly overweight society. We propose a simple adjustment to improve diagnostic accuracy in different body weights and improve the sensitivity of this universally available technique. METHODS: Overall, 1295 participants were included-821 with a wide range of body mass index (BMI 17.1 53.3 kg/m(2)) initially underwent cardiac magnetic resonance evaluation of anatomical left ventricular (LV) axis, LV mass and 12-lead surface ECG in order to generate an adjustment factor applied to the Sokolow-Lyon criteria. This factor was then validated in a second cohort (n=520, BMI 15.9-63.2 kg/m(2)). RESULTS: When matched for LV mass, the combination of leftward anatomical axis deviation and increased BMI resulted in a reduction of the Sokolow-Lyon index, by 4 mm in overweight and 8 mm in obesity. After adjusting for this in the initial cohort, the sensitivity of the Sokolow-Lyon index increased (overweight: 12.8% to 30.8%, obese: 3.1% to 27.2%) approaching that seen in normal weight (37.8%). Similar results were achieved in the validation cohort (specificity increased in overweight: 8.3% to 39.1%, obese: 9.4% to 25.0%) again approaching normal weight (39.0%). Importantly, specificity remained excellent (>93.1%). CONCLUSIONS: Adjusting the Sokolow-Lyon index for BMI (overweight +4 mm, obesity +8 mm) improves the diagnostic accuracy for detecting LVH. As the ECG, worldwide, remains the most widely used screening tool for LVH, implementing these findings should translate into significant clinical benefit. PMID- 27486143 TI - An algorithm for rule-in and rule-out of acute myocardial infarction using a novel troponin I assay. AB - OBJECTIVE: To derive and validate a hybrid algorithm for rule-out and rule-in of acute myocardial infarction based on measurements at presentation and after 2 hours with a novel cardiac troponin I (cTnI) assay. METHODS: The algorithm was derived and validated in two cohorts (605 and 592 patients) from multicentre studies enrolling chest pain patients presenting to the emergency department (ED) with onset of last episode within 12 hours. The index diagnosis and cardiovascular events up to 30 days were adjudicated by independent reviewers. RESULTS: In the validation cohort, 32.6% of the patients were ruled out on ED presentation, 6.1% were ruled in and 61.3% remained undetermined. A further 22% could be ruled out and 9.8% ruled in, after 2 hours. In total, 54.6% of the patients were ruled out with a negative predictive value (NPV) of 99.4% (95% CI 97.8% to 99.9%) and a sensitivity of 97.7% (95% CI 91.9% to 99.7%); 15.8% were ruled in with a positive predictive value (PPV) of 74.5% (95% CI 64.8% to 82.2%) and a specificity of 95.2% (95% CI 93.0% to 96.9%); and 29.6% remained undetermined after 2 hours. No patient in the rule-out group died during the 30 day follow-up in the two cohorts. CONCLUSIONS: This novel two-step algorithm based on cTnI measurements enabled just over a third of the patients with acute chest pain to be ruled in or ruled out already at presentation and an additional third after 2 hours. This strategy maximises the speed of rule-out and rule-in while maintaining a high NPV and PPV, respectively. PMID- 27486145 TI - Medical students writing on death, dying and palliative care: a qualitative analysis of reflective essays. AB - BACKGROUND: Medical students and doctors are becoming better prepared to care for patients with palliative care needs and support patients at the end of life. This preparation needs to start at medical school. OBJECTIVE: To assess how medical students learn about death, dying and palliative care during a clinical placement using reflective essays and to provide insights to improve medical education about end-of-life care and/or palliative care. METHODS: Qualitative study in which all reflective essays written by third-year medical students in 1 year from a UK medical school were searched electronically for those that included 'death', 'dying' and 'palliative care'. The anonymised data were managed using QSR NVivo 10 software, and a systematic analysis was conducted in three distinct phases: (1) open coding; (2) axial coding and (3) selective coding. Ethical approval was received. RESULTS: 54 essays met the inclusion criteria from 241 essays screened for the terms 'death', 'dying' or 'palliative'; 22 students gave consent for participation and their 24 essays were included. Saturation of themes was reached. Three overarching themes were identified: emotions, empathy and experiential and reflective learning. Students emphasised trying to develop a balance between showing empathy and their emotional state. Students learnt a lot from clinical encounters and watching doctors manage difficult situations, as well as from their refection during and after the experience. CONCLUSIONS: Reflective essays give insights into the way students learn about death, dying and palliative care and how it affects them personally as well as the preparation that is needed to be better equipped to deal with these kinds of experiences. Analysis of the essays enabled the proposal of new strategies to help make them more effective learning tools and to optimise students' learning from a palliative care attachment. PMID- 27486146 TI - International palliative care research in the context of global development: a systematic mapping review. AB - CONTEXT: An increasing amount of health policy is formulated at global level. At this global level, palliative care has attracted support primarily from normative institutions (WHO), not funding agencies. To attract greater global attention from policymakers, it has been argued that an international approach to research is required. However, the extent to which an international approach is being undertaken is unknown. OBJECTIVES: To systematically identify and thematically synthesise all international palliative care research, defined as research involving two or more countries, or focused on the global level. METHODS: Five bibliographic databases (CINAHL, Cochrane Library, ASSIA, Web of Knowledge, Psychinfo) were searched for journal articles relevant to international and global palliative care and end-of-life care. Data were extracted using a piloted extraction form and findings were synthesised. RESULTS: 184 studies were included, published across 75 different academic journals. Research emanates from and focuses on all world regions and there is increasing focus on the global level. Thematically, there is a high focus on Evaluation (n=53) and views of Stakeholders (n=38). The review revealed a predominantly observational research approach and few interventional studies were identified. CONCLUSIONS: International palliative care research is a relatively new, but growing field. However, many gaps in the evidence base remain and palliative care research continues to take place outside broader discourses of international development. The relative absence of interventional research demonstrating the effectiveness and cost-effectiveness of palliative care risks limiting the tools with which advocates can engage with international policymakers on this topic. PMID- 27486144 TI - Left ventricular hypertrophy by ECG versus cardiac MRI as a predictor for heart failure. AB - OBJECTIVE: To determine if there is a significant difference in the predictive abilities of left ventricular hypertrophy (LVH) detected by ECG-LVH versus LVH ascertained by cardiac MRI-LVH in a model similar to the Framingham Heart Failure Risk Score (FHFRS). METHODS: This study included 4745 (mean age 61+/-10 years, 53.5% women, 61.7% non-whites) participants in the Multi-Ethnic Study of Atherosclerosis. ECG-LVH was defined using Cornell voltage product while MRI-LVH was derived from left ventricular mass. Cox proportional hazard regression was used to examine the association between ECG-LVH and MRI-LVH with incident heart failure (HF). Harrell's concordance C-index was used to estimate the predictive ability of the model when either ECG-LVH or MRI-LVH was included as one of its components. RESULTS: ECG-LVH was present in 291 (6.1%), while MRI-LVH was present in 499 (10.5%) of the participants. Both ECG-LVH (HR 2.25, 95% CI 1.38 to 3.69) and MRI-LVH (HR 3.80, 95% CI 1.56 to 5.63) were predictive of HF. The absolute risk of developing HF was 8.81% for MRI-LVH versus 2.26% for absence of MRI-LVH with a relative risk of 3.9. With ECG-LVH, the absolute risk of developing HF 6.87% compared with 2.69% for absence of ECG-LVH with a relative risk of 2.55. The ability of the model to predict HF was better with MRI-LVH (C-index 0.871, 95% CI 0.842 to 0.899) than with ECG-LVH (C-index 0.860, 95% CI 0.833 to 0.888) (p<0.0001). CONCLUSIONS: ECG-LVH and MRI-LVH are predictive of HF. Substituting MRI-LVH for ECG-LVH improves the predictive ability of a model similar to the FHFRS. PMID- 27486147 TI - Rasip1-Mediated Rho GTPase Signaling Regulates Blood Vessel Tubulogenesis via Nonmuscle Myosin II. AB - RATIONALE: Vascular tubulogenesis is essential to cardiovascular development. Within initial vascular cords of endothelial cells, apical membranes are established and become cleared of cell-cell junctions, thereby allowing continuous central lumens to open. Rasip1 (Ras-interacting protein 1) is required for apical junction clearance, as well as for regulation of Rho GTPase (enzyme that hydrolyzes GTP) activity. However, it remains unknown how activities of different Rho GTPases are coordinated by Rasip1 to direct tubulogenesis. OBJECTIVE: The aim of this study is to determine the mechanisms downstream of Rasip1 that drive vascular tubulogenesis. METHODS AND RESULTS: Using conditional mouse mutant models and pharmacological approaches, we dissect GTPase pathways downstream of Rasip1. We show that clearance of endothelial cell apical junctions during vascular tubulogenesis depends on Rasip1, as well as the GTPase Cdc42 (cell division control protein 42 homolog) and the kinase Pak4 (serine/threonine protein kinase 4). Genetic deletion of Rasip1 or Cdc42, or inhibition of Pak4, all blocks endothelial cell tubulogenesis. By contrast, inactivation of RhoA (Ras homologue gene family member A) signaling leads to vessel overexpansion, implicating actomyosin contractility in control of lumen diameter. Interestingly, blocking activity of NMII (nonmuscle myosin II) either before, or after, lumen morphogenesis results in dramatically different tubulogenesis phenotypes, suggesting time-dependent roles. CONCLUSIONS: Rasip1 controls different pools of GTPases, which in turn regulate different pools of NMII to coordinate junction clearance (remodeling) and actomyosin contractility during vascular tubulogenesis. Rasip1 promotes activity of Cdc42 to activate Pak4, which in turn activates NMII, clearing apical junctions. Once lumens open, Rasip1 suppresses actomyosin contractility via inhibition of RhoA by Arhgap29, allowing controlled expansion of vessel lumens during embryonic growth. These findings elucidate the stepwise processes regulated by Rasip1 through downstream Rho GTPases and NMII. PMID- 27486148 TI - Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments. AB - BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. METHODS: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Pharmacological Treatments" is the third of six sections of the 2016 guidelines. With little new information on older medications, treatment recommendations focus on second-generation antidepressants. RESULTS: Evidence-informed responses are given for 21 questions under 4 broad categories: 1) principles of pharmacological management, including individualized assessment of patient and medication factors for antidepressant selection, regular and frequent monitoring, and assessing clinical and functional outcomes with measurement-based care; 2) comparative aspects of antidepressant medications based on efficacy, tolerability, and safety, including summaries of newly approved drugs since 2009; 3) practical approaches to pharmacological management, including drug-drug interactions and maintenance recommendations; and 4) managing inadequate response and treatment resistance, with a focus on switching antidepressants, applying adjunctive treatments, and new and emerging agents. CONCLUSIONS: Evidence-based pharmacological treatments are available for first-line treatment of MDD and for management of inadequate response. However, given the limitations of the evidence base, pharmacological management of MDD still depends on tailoring treatments to the patient. PMID- 27486149 TI - Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 6. Special Populations: Youth, Women, and the Elderly. AB - BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. METHODS: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. This section on "Special Populations" is the sixth of six guidelines articles. RESULTS: Recent studies inform the treatment of MDD in children and adolescents, pregnant and breastfeeding women, women in perimenopause or menopause, and the elderly. Evidence for efficacy of treatments in these populations is more limited than for the general adult population, however, and risks of treatment in these groups are often poorly studied and reported. CONCLUSIONS: Despite the limited evidence base, extant data and clinical experience suggest that each of these special populations can benefit from the systematic application of treatment guidelines for treatment of MDD. PMID- 27486152 TI - Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Introduction and Methods. PMID- 27486150 TI - Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 2. Psychological Treatments. AB - BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) has revised its 2009 guidelines for the management of major depressive disorder (MDD) in adults by updating the evidence and recommendations. The target audiences for these 2016 guidelines are psychiatrists and other mental health professionals. METHODS: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Psychological Treatments" is the second of six sections of the 2016 guidelines. RESULTS: Evidence-informed responses were developed for 25 questions under 5 broad categories: 1) patient characteristics relevant to using psychological interventions; 2) therapist and health system characteristics associated with optimizing outcomes; 3) descriptions of major psychotherapies and their efficacy; 4) additional psychological interventions, such as peer interventions and computer- and technology-delivered interventions; and 5) combining and/or sequencing psychological and pharmacological interventions. CONCLUSIONS: First line psychological treatment recommendations for acute MDD include cognitive behavioural therapy (CBT), interpersonal therapy (IPT), and behavioural activation (BA). Second-line recommendations include computer-based and telephone delivered psychotherapy. Where feasible, combining psychological treatment (CBT or IPT) with antidepressant treatment is recommended because combined treatment is superior to either treatment alone. First-line psychological treatments for maintenance include CBT and mindfulness-based cognitive therapy (MBCT). Patient preference, in combination with evidence-based treatments and clinician/system capacity, will yield the optimal treatment strategies for improving individual outcomes in MDD. PMID- 27486151 TI - Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 1. Disease Burden and Principles of Care. AB - BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. METHODS: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. This section is the first of six guidelines articles. RESULTS: In Canada, the annual and lifetime prevalence of MDD was 4.7% and 11.3%, respectively. MDD represents the second leading cause of global disability, with high occupational and economic impact mainly attributable to indirect costs. DSM-5 criteria for depressive disorders remain relatively unchanged, but other clinical dimensions (sleep, cognition, physical symptoms) may have implications for depression management. e-Mental health is increasingly used to support clinical and self-management of MDD. In the 2-phase (acute and maintenance) treatment model, specific goals address symptom remission, functional recovery, improved quality of life, and prevention of recurrence. CONCLUSIONS: The burden attributed to MDD remains high, whether from individual distress, functional and relationship impairment, reduced quality of life, or societal economic cost. Applying core principles of care, including comprehensive assessment, therapeutic alliance, support of self-management, evidence-informed treatment, and measurement-based care, will optimize clinical, quality of life, and functional outcomes in MDD. PMID- 27486153 TI - Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 5. Complementary and Alternative Medicine Treatments. AB - BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. METHODS: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Complementary and Alternative Medicine Treatments" is the fifth of six sections of the 2016 guidelines. RESULTS: Evidence-informed responses were developed for 12 questions for 2 broad categories of complementary and alternative medicine (CAM) interventions: 1) physical and meditative treatments (light therapy, sleep deprivation, exercise, yoga, and acupuncture) and 2) natural health products (St. John's wort, omega-3 fatty acids; S-adenosyl-L-methionine [SAM-e], dehydroepiandrosterone, folate, Crocus sativus, and others). Recommendations were based on available data on efficacy, tolerability, and safety. CONCLUSIONS: For MDD of mild to moderate severity, exercise, light therapy, St. John's wort, omega-3 fatty acids, SAM-e, and yoga are recommended as first- or second-line treatments. Adjunctive exercise and adjunctive St. John's wort are second-line recommendations for moderate to severe MDD. Other physical treatments and natural health products have less evidence but may be considered as third-line treatments. CAM treatments are generally well tolerated. Caveats include methodological limitations of studies and paucity of data on long-term outcomes and drug interactions. PMID- 27486155 TI - Association between naturally occurring antiamyloid beta autoantibodies and medial temporal lobe atrophy in Alzheimer's disease. PMID- 27486156 TI - Assessment of different pre-treatment methods for the removal of limonene in citrus waste and their effect on methane potential and methane production rate. AB - The objective of this study was to assess the limonene removal efficiency of three pre-treatment methods when applied to citrus waste and to evaluate their effects on the biochemical methane potential and the methane production rate using batch anaerobic tests. The methods tested were based on removal (biological pretreatment by fungi) or recovery (steam distillation and ethanol extraction) of limonene. All the treatments decreased the concentration of limonene in orange peel, with average efficiencies of 22%, 44% and 100% for the biological treatment, steam distillation and ethanol extraction, respectively. By-products from limonene biodegradation by fungi exhibited an inhibitory effect also, not making interesting the biological pretreatment. The methane potential and production rate of the treated orange peel increased significantly after applying the recovery strategies, which separated and recovered simultaneously other inhibitory components of the citrus essential oil. Apart from the high recovery efficiency of the ethanol extraction process, it presented a favourable energy balance. PMID- 27486154 TI - Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 4. Neurostimulation Treatments. AB - BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. METHODS: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Neurostimulation Treatments" is the fourth of six sections of the 2016 guidelines. RESULTS: Evidence-informed responses were developed for 31 questions for 6 neurostimulation modalities: 1) transcranial direct current stimulation (tDCS), 2) repetitive transcranial magnetic stimulation (rTMS), 3) electroconvulsive therapy (ECT), 4) magnetic seizure therapy (MST), 5) vagus nerve stimulation (VNS), and 6) deep brain stimulation (DBS). Most of the neurostimulation treatments have been investigated in patients with varying degrees of treatment resistance. CONCLUSIONS: There is increasing evidence for efficacy, tolerability, and safety of neurostimulation treatments. rTMS is now a first-line recommendation for patients with MDD who have failed at least 1 antidepressant. ECT remains a second-line treatment for patients with treatment-resistant depression, although in some situations, it may be considered first line. Third-line recommendations include tDCS and VNS. MST and DBS are still considered investigational treatments. PMID- 27486157 TI - Evaluation of a buried vertical well leachate recirculation system for municipal solid waste landfills. AB - Vertical liquids addition systems have been used at municipal landfills as a leachate management method and to enhance biostabilization of waste. Drawbacks of these systems include a limitation on pressurized injection and the occurrence of seepage. A novel vertical well system that employed buried wells constructed below a lift of compacted waste was operated for 153 days at a landfill in Florida, USA. The system included 54 wells installed in six clusters of nine wells connected with a horizontally-oriented manifold system. A cumulative volume of 8430 m3 of leachate was added intermittently into the well clusters over the duration of the project with no incidence of surface seeps. Achievable average flow rates ranged from 9.3 * 10-4 m3 s-1 to 14.2 * 10-4 m3 s-1, which was similar to or greater than flow rates achieved in a previous study using traditional vertical wells at the same landfill site. The results demonstrated that pressurized liquids addition in vertical wells at municipal solid waste landfills can be achieved while avoiding typical operational and maintenance issues associated with seeps. PMID- 27486158 TI - How Melanoma Resists PD-1 Blockade. AB - Researchers at the University of California, Los Angeles, have shed light on mechanisms by which melanoma cells become resistant to PD-1 blockade with pembrolizumab. One mechanism involves loss-of-function mutations in JAK1 or JAK2 that abolish interferon-gamma signaling; the other involves a truncating mutation in B2M that results in defective antigen presentation. PMID- 27486159 TI - Vascular age calculation and equivalent risk factors in HIV-infected patients obtained from the D:A:D risk equation. AB - BACKGROUND: Vascular age is a concept that represents the hypothetical age of the cardiovascular system and might be an alternative way of expressing the cardiovascular risk of a patient. The Data Collection on Adverse Effects of Anti HIV Drugs Study (D:A:D) developed a cardiovascular risk equation from a population of HIV-infected patients, incorporating exposure to individual antiretroviral therapy drugs and traditional classic cardiovascular risk factors. OBJECTIVES: The aim of this study was to determine the vascular age calculated from the D:A:D equation, for HIV infected patients. METHODS: Vascular age was calculated according to its definition by using the D:A:D equation. The Poisson regression model used in the D:A:D equation is an exponential model to calculate the vascular age to match the exponent of the equation with the factors of a patient with the exponent of a subject with controlled risk factors. RESULTS: We obtained an equation that allows calculating the vascular age of a patient considering cardiovascular risk factors listed in the same D:A:D equation. From the equation, we have built a table for easy calculation of the vascular age and a table of cardiovascular risk equivalents. CONCLUSIONS: Vascular age is a new concept derived from Framingham risk tables that can be calculated with other risk scales, such as D:A:D for HIV patients. The calculation of vascular age in HIV patients could be a useful tool for communicating cardiovascular risk and to improve the control of modifiable risk factors. PMID- 27486160 TI - Assessment of Fever Advisory Cards (FACs) as an Initiative to Improve Febrile Neutropenia Management in a Regional Cancer Center Emergency Department. AB - PURPOSE: We aimed to improve the time to antibiotics (TTA) for patients treated with chemotherapy who present to the emergency department (ED) with febrile neutropenia (FN) by using standardized fever advisory cards (FACs). METHODS: Patients treated with chemotherapy who visited the ED at the Peel Regional Cancer Center in Ontario, Canada, with suspected FN were identified, before (April 2012 to March 2013) and after (October 2013 to March 2014) FAC implementation. The primary outcome of interest was TTA. Additional process measures included Canadian Triage and Acuity Scale score, time to physician assessment, and FAC compliance. Outcomes were analyzed with descriptive statistics and control charts to determine whether the change in primary measures were within statistical control over time. RESULTS: Between the pre-FAC cohort (n = 239) and post-FAC cohort (n = 69), TTA did not change significantly post-FACs (195 v 244 min, P = .09), with monthly averages demonstrating normal variation by statistical process control methodology. The introduction of FACs increased the percentage of patients with correctly assigned Canadian Triage and Acuity Scale scores (87% v 100%) but did not affect time to physician assessment. Compliance with FACs among patients was not ideal, with only 62.5% using them as intended. CONCLUSION: The distribution of FACs was associated with an improved incidence of correct FN triaging but did not demonstrate a meaningful improvement in the quality of FN management. This may be explained by FAC use among patients not being ideal. Next steps in the continued effort toward high-quality FN care include redesign of FACs, reinforcement of provider and patient education, and ED outreach. PMID- 27486161 TI - Biochemistry, function, and deficiency of vitamin B12 in Caenorhabditis elegans. AB - Caenorhabditis elegans is a nematode that has been widely used as an animal for investigation of diverse biological phenomena. Vitamin B12 is essential for the growth of this worm, which contains two cobalamin-dependent enzymes, methylmalonyl-CoA mutase and methionine synthase. A full complement of gene homologs encoding the enzymes associated with the mammalian intercellular metabolic processes of vitamin B12 is identified in the genome of C elegans However, this worm has no orthologs of the vitamin B12-binders that participate in human intestinal absorption and blood circulation. When the worm is treated with a vitamin B12-deficient diet for five generations (15 days), it readily develops vitamin B12 deficiency, which induces worm phenotypes (infertility, delayed growth, and shorter lifespan) that resemble the symptoms of mammalian vitamin B12 deficiency. Such phenotypes associated with vitamin B12 deficiency were readily induced in the worm. PMID- 27486163 TI - Management of Hypertension in Patients With Mild to Moderate Aortic Stenosis: Navigating the SEAS. PMID- 27486162 TI - Peptidomimetic Targeting of Cavbeta2 Overcomes Dysregulation of the L-Type Calcium Channel Density and Recovers Cardiac Function. AB - BACKGROUND: L-type calcium channels (LTCCs) play important roles in regulating cardiomyocyte physiology, which is governed by appropriate LTCC trafficking to and density at the cell surface. Factors influencing the expression, half-life, subcellular trafficking, and gating of LTCCs are therefore critically involved in conditions of cardiac physiology and disease. METHODS: Yeast 2-hybrid screenings, biochemical and molecular evaluations, protein interaction assays, fluorescence microscopy, structural molecular modeling, and functional studies were used to investigate the molecular mechanisms through which the LTCC Cavbeta2 chaperone regulates channel density at the plasma membrane. RESULTS: On the basis of our previous results, we found a direct linear correlation between the total amount of the LTCC pore-forming Cavalpha1.2 and the Akt-dependent phosphorylation status of Cavbeta2 both in a mouse model of diabetic cardiac disease and in 6 diabetic and 7 nondiabetic cardiomyopathy patients with aortic stenosis undergoing aortic valve replacement. Mechanistically, we demonstrate that a conformational change in Cavbeta2 triggered by Akt phosphorylation increases LTCC density at the cardiac plasma membrane, and thus the inward calcium current, through a complex pathway involving reduction of Cavalpha1.2 retrograde trafficking and protein degradation through the prevention of dynamin-mediated LTCC endocytosis; promotion of Cavalpha1.2 anterograde trafficking by blocking Kir/Gem-dependent sequestration of Cavbeta2, thus facilitating the chaperoning of Cavalpha1.2; and promotion of Cavalpha1.2 transcription by the prevention of Kir/Gem-mediated shuttling of Cavbeta2 to the nucleus, where it limits the transcription of Cavalpha1.2 through recruitment of the heterochromatin protein 1gamma epigenetic repressor to the Cacna1c promoter. On the basis of this mechanism, we developed a novel mimetic peptide that, through targeting of Cavbeta2, corrects LTCC life cycle alterations, facilitating the proper function of cardiac cells. Delivery of mimetic peptide into a mouse model of diabetic cardiac disease associated with LTCC abnormalities restored impaired calcium balance and recovered cardiac function. CONCLUSIONS: We have uncovered novel mechanisms modulating LTCC trafficking and life cycle and provide proof of concept for the use of Cavbeta2 mimetic peptide as a novel therapeutic tool for the improvement of cardiac conditions correlated with alterations in LTCC levels and function. PMID- 27486165 TI - Advanced Practice Nursing: A Special Issue. PMID- 27486166 TI - Try-It-On: Experiential Learning of Holistic Stress Management in a Graduate Nursing Curriculum. PMID- 27486164 TI - Assessing Optimal Blood Pressure in Patients With Asymptomatic Aortic Valve Stenosis: The Simvastatin Ezetimibe in Aortic Stenosis Study (SEAS). AB - BACKGROUND: Evidence for treating hypertension in patients with asymptomatic aortic valve stenosis is scarce. We used data from the SEAS trial (Simvastatin Ezetimibe in Aortic Stenosis) to assess what blood pressure (BP) would be optimal. METHODS: A total of 1767 patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease were analyzed. Outcomes were all-cause mortality, cardiovascular death, heart failure, stroke, myocardial infarction, and aortic valve replacement. BP was analyzed in Cox models as the cumulative average of serially measured BP and a time-varying covariate. RESULTS: The incidence of all-cause mortality was highest for average follow-up systolic BP >=160 mm Hg (4.3 per 100 person-years; 95% confidence interval [CI], 3.1-6.0) and lowest for average systolic BP of 120 to 139 mm Hg (2.0 per 100 person-years; 95% CI, 1.6-2.6). In multivariable analysis, all-cause mortality was associated with average systolic BP <120 mm Hg (hazard ratio [HR], 3.4; 95% CI, 1.9-6.1), diastolic BP >=90 mm Hg (HR, 1.8; 95% CI, 1.1-2.9), and pulse pressure <50 mm Hg (HR, 1.8; 95% CI, 1.1-2.9), with systolic BP of 120 to 139 mm Hg, diastolic BP of 70 to 79 mm Hg, and pulse pressure of 60 to 69 mm Hg taken as reference. Low systolic and diastolic BPs increased risk in patients with moderate aortic stenosis. With a time-varying systolic BP from 130 to 139 mm Hg used as reference, mortality was increased for systolic BP >=160 mm Hg (HR, 1.7; P=0.033) and BP of 120 to 129 mm Hg (HR, 1.6; P=0.039). CONCLUSIONS: Optimal BP seems to be systolic BP of 130 to 139 mm Hg and diastolic BP of 70 to 90 mm Hg in these patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease or diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00092677. PMID- 27486167 TI - Antidepressant Use After Aneurysmal Subarachnoid Hemorrhage: A Population-Based Case-Control Study. AB - BACKGROUND AND PURPOSE: To elucidate the predictors of antidepressant use after subarachnoid hemorrhage from saccular intracranial aneurysm (sIA-SAH) in a population-based cohort with matched controls. METHODS: The Kuopio sIA database includes all unruptured and ruptured sIA cases admitted to the Kuopio University Hospital from its defined catchment population in Eastern Finland, with 3 matched controls for each patient. The use of all prescribed medicines has been fused from the Finnish national registry of prescribed medicines. In the present study, 2 or more purchases of antidepressant medication indicated antidepressant use. The risk factors of the antidepressant use were analyzed in 940 patients alive 12 months after sIA-SAH, and the classification tree analysis was used to create a predicting model for antidepressant use after sIA-SAH. RESULTS: The 940 12-month survivors of sIA-SAH had significantly more antidepressant use (odds ratio, 2.6; 95% confidence interval, 2.2-3.1) than their 2676 matched controls (29% versus 14%). Classification tree analysis, based on independent risk factors, was used for the best prediction model of antidepressant use after sIA-SAH. Modified Rankin Scale until 12 months was the most potent predictor, followed by condition (Hunt and Hess Scale) and age on admission for sIA-SAH. CONCLUSIONS: The sIA-SAH survivors use significantly more often antidepressants, indicative of depression, than their matched population controls. Even with a seemingly good recovery (modified Rankin Scale score, 0) at 12 months after sIA-SAH, there is a significant risk of depression requiring antidepressant medication. PMID- 27486168 TI - Response by Hastrup and Andersen to Letter Regarding Article, "Prehospital Acute Stroke Severity Scale to Predict Large Artery Occlusion: Design and Comparison With Other Scales". PMID- 27486169 TI - Letter by Hastrup et al Regarding Article, "Clinical Scales Do Not Reliably Identify Acute Ischemic Stroke Patients With Large-Artery Occlusion". PMID- 27486170 TI - Homozygous ALDH2*2 Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men. AB - BACKGROUND AND PURPOSE: The *2 allele of the aldehyde dehydrogenase 2 gene (ALDH2) is the most common variant in Asian populations. The variant resulting in enzyme dysfunction was highly related to coronary artery disease. Recently, genome-wide association studies also discovered that the 12q24 locus near ALDH2 gene was associated with hypertension and ischemic stroke. This study intended to further investigate whether the above variant of ALDH2 increases the risk for ischemic stroke in Taiwanese. METHODS: A case-control study was conducted on 914 patients with acute ischemic stroke and 746 nonstroke controls. Polymerase chain reaction and sequencing were used to identify the ALDH2 genotype. Vascular risk factors, stroke subtypes, vascular stenosis, and stroke outcomes were analyzed. RESULTS: ALDH2 genotypes differed significantly between male controls (*1/*1 versus *1/*2 versus *2/*2=53.8% versus 39.9% versus 6.4%) and male patients with ischemic stroke (*1/*1 versus *1/*2 versus *2/*2=51.5% versus 37.3% versus 11.2%; P=0.048). No significant difference was found between groups for female patients (P=0.228). Multivariate logistic regression analysis revealed that the ALDH2*2/*2 genotype was an independent risk factor for ischemic stroke in male patients (odds ratio, 1.93 [95% confidence interval, 1.07-3.46]; P=0.028). Further analysis of men with ischemic stroke demonstrated that the polymorphism of ALDH2 was not related to vascular risk factors, severity of vascular atherosclerosis, stroke subtypes, and stroke functional outcomes. CONCLUSIONS: The study demonstrated that ALDH2*2/*2 may be an independent risk factor for ischemic stroke in Taiwanese men, but not in Taiwanese women. PMID- 27486171 TI - Response by Maier and Turc to Letter Regarding Article, "Clinical Scales Do Not Reliably Identify Acute Ischemic Stroke Patients With Large-Artery Occlusion". PMID- 27486172 TI - Letter by Heldner et al Regarding Article, "Prehospital Acute Stroke Severity Scale to Predict Large Artery Occlusion: Design and Comparison With Other Scales". PMID- 27486173 TI - Aspiration Thrombectomy After Intravenous Alteplase Versus Intravenous Alteplase Alone. AB - BACKGROUND AND PURPOSE: Thrombectomy, primarily with stent retrievers with or without adjunctive aspiration, provided clinical benefit across multiple prospective randomized trials. Whether this benefit is exclusive to stent retrievers is unclear. METHODS: THERAPY (The Randomized, Concurrent Controlled Trial to Assess the Penumbra System's Safety and Effectiveness in the Treatment of Acute Stroke; NCT01429350) was an international, multicenter, prospective, randomized (1:1), open label, blinded end point evaluation, concurrent controlled clinical trial of aspiration thrombectomy after intravenous alteplase (IAT) administration compared with intravenous-alteplase alone in patients with large vessel ischemic stroke because of a thrombus length of >=8 mm. The primary efficacy end point was the percent of patients achieving independence at 90 days (modified Rankin Scale score, 0-2; intention-to-treat analysis). The primary safety end point was the rate of severe adverse events (SAEs) by 90 days (as treated analysis). Patients were randomized 1:1 across 36 centers in 2 countries (United States and Germany). RESULTS: Enrollment was halted after 108 (55 IAT and 53 intravenous) patients (of 692 planned) because of external evidence of the added benefit of endovascular therapy to intravenous-alteplase alone. Functional independence was achieved in 38% IAT and 30% intravenous intention-to-treat groups (P=0.52). Intention-to-treat ordinal modified Rankin Scale odds ratio was 1.76 (95% confidence interval, 0.86-3.59; P=0.12) in favor of IAT. Secondary efficacy analyses all demonstrated a consistent direction of effect toward benefit of IAT. No differences in symptomatic intracranial hemorrhage rates (9.3% IAT versus 9.7% intravenous, P=1.0) or 90-day mortality (IAT: 12% versus intravenous: 23.9%, P=0.18) were observed. CONCLUSIONS: THERAPY did not achieve its primary end point in this underpowered sample. Directions of effect for all prespecified outcomes were both internally and externally consistent toward benefit. It is possible that an alternate method of thrombectomy, primary aspiration, will benefit selected patients harboring large vessel occlusions. Further study on this topic is indicated. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01429350. PMID- 27486174 TI - The Dual Inhibition of RNA Pol I Transcription and PIM Kinase as a New Therapeutic Approach to Treat Advanced Prostate Cancer. AB - PURPOSE: The MYC oncogene is frequently overexpressed in prostate cancer. Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. In addition, PIM kinases activate MYC signaling and mRNA translation in prostate cancer and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer. EXPERIMENTAL DESIGN: The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective, and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription, has been successfully exploited therapeutically but only in models of hematologic malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in prostate cancer cell lines, in Hi-MYC- and PTEN-deficient mouse models and in patient-derived xenografts (PDX) of metastatic tissue obtained from a patient with castration-resistant prostate cancer. RESULTS: CX 5461 inhibited anchorage-independent growth and induced cell-cycle arrest in prostate cancer cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced TP53 expression and activity and reduced proliferation (MKI67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of prostate cancer. CONCLUSIONS: Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of prostate cancer. Clin Cancer Res; 22(22); 5539-52. (c)2016 AACR. PMID- 27486176 TI - Regression of Chemotherapy-Resistant Polymerase epsilon (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab. AB - PURPOSE: The management of endometrial carcinoma no longer amenable to treatment with surgery or radiotherapy has not improved significantly with modern chemotherapy. Alternative therapeutic options are desperately needed. EXPERIMENTAL DESIGN: We describe 2 heavily pretreated patients with recurrent disease refractory to surgery, radiotherapy, and chemotherapy who were treated with the anti-PD-1 immune checkpoint inhibitor nivolumab. RESULTS: Patient #1 harbored an ultra-mutated tumor (mutation load/MB = 117.3, total mutations = 4,660) driven by mutation in the exonuclease domain of the DNA polymerase epsilon gene. Patient #2 harbored a hyper-mutated tumor (mutation load/MB = 33.5, total mutations = 1,037) due to a germinal MSH6 gene mutation. Both patients demonstrated a remarkable clinical response to the anti-PD-1 immune checkpoint inhibitor nivolumab. Patients' clinical responses remain unchanged at the time of the writing of this report, with no grade 3 or higher side effects reported to date. CONCLUSIONS: Anti-PD-1 inhibitors represent a novel treatment option for recurrent/metastatic, ultra/hyper-mutated human tumors refractory to salvage treatment. Clin Cancer Res; 22(23); 5682-7. (c)2016 AACRSee related commentary by Piulats and Matias-Guiu, p. 5623. PMID- 27486175 TI - Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-1-Associated Adult T-cell Leukemia/lymphoma. AB - PURPOSE: Therapeutic regimens for adult T-cell leukemia/lymphoma (ATL) are limited with unsatisfactory results, thereby warranting development of novel therapies. This study investigated antitumor activity and toxicity of alemtuzumab with regard to response, duration of response, progression-free survival, and overall survival in patients with human T-cell lymphotropic virus-1 (HTLV-1) associated ATL. EXPERIMENTAL DESIGN: Twenty-nine patients with chronic, acute, and lymphomatous types of ATL were enrolled in a single-institution, nonrandomized, open-label phase II trial wherein patients received intravenous alemtuzumab 30 mg three times weekly for a maximum of 12 weeks. RESULTS: Twenty nine patients were evaluable for response and toxicity. The overall objective response was 15 of 29 patients [95% confidence interval (CI), 32.5%-70.6%]. The 15 patients who responded manifested a median time to response of 1.1 months. Median response duration was 1.4 months for the whole group and 14.5 months among responders. Median progression-free survival was 2.0 months. Median overall survival was 5.9 months. The most common adverse events were 2 with vasovagal episodes (7%) and 3 with hypotensive episodes (10%), leukopenia (41%) grade 3 and (17%) grade 4, lymphocytopenia (59%) grade 3, neutropenia (31%) grade 3, anemia (24%), and thrombocytopenia (10%). All patients developed cytomegalovirus antigenemia (CMV). Three were symptomatic and all responded to antiviral therapy. Grade 3 or 4 infections were reported in 4 (14%) of patients. CONCLUSIONS: Alemtuzumab induced responses in patients with acute HTLV-1-associated ATL with acceptable toxicity, but with short duration of responses. These studies support inclusion of alemtuzumab in novel multidrug therapies for ATL. Clin Cancer Res; 23(1); 35-42. (c)2016 AACR. PMID- 27486178 TI - Evidence That Classroom-Based Behavioral Interventions Reduce Pregnancy-Related School Dropout Among Nairobi Adolescents. AB - PURPOSE: To evaluate the effect of behavioral, empowerment-focused interventions on the incidence of pregnancy-related school dropout among girls in Nairobi's informal settlements. METHOD: Retrospective data on pregnancy-related school dropout from two cohorts were analyzed using a matched-pairs quasi-experimental design. The primary outcome was the change in the number of school dropouts due to pregnancy from 1 year before to 1 year after the interventions. RESULTS: Annual incidence of school dropout due to pregnancy decreased by 46% in the intervention schools (from 3.9% at baseline to 2.1% at follow-up), whereas the comparison schools remained essentially unchanged ( p < .029). Sensitivity analysis shows that the findings are robust to small levels of unobserved bias. CONCLUSIONS: Results suggest that these behavioral interventions significantly reduced the number of school dropouts due to pregnancy. As there are limited promising studies on behavioral interventions that decrease adolescent pregnancy in low-income settings, this intervention may be an important addition to this toolkit. PMID- 27486177 TI - Evaluating Acetate Metabolism for Imaging and Targeting in Multiple Myeloma. AB - PURPOSE: We hypothesized that in multiple myeloma cells (MMC), high membrane biosynthesis will induce acetate uptake in vitro and in vivo Here, we studied acetate metabolism and targeting in MMC in vitro and tested the efficacy of 11C acetate-positron emission tomography (PET) to detect and quantitatively image myeloma treatment response in vivo EXPERIMENTAL DESIGN: Acetate fate tracking using 13C-edited-1H NMR (nuclear magnetic resonance) was performed to study in vitro acetate uptake and metabolism in MMC. Effects of pharmacological modulation of acetate transport or acetate incorporation into lipids on MMC cell survival and viability were assessed. Preclinical mouse MM models of subcutaneous and bone tumors were evaluated using 11C-acetate-PET/CT imaging and tissue biodistribution. RESULTS: In vitro, NMR showed significant uptake of acetate by MMC and acetate incorporation into intracellular metabolites and membrane lipids. Inhibition of lipid synthesis and acetate transport was toxic to MMC, while sparing resident bone cells or normal B cells. In vivo, 11C-acetate uptake by PET imaging was significantly enhanced in subcutaneous and bone MMC tumors compared with unaffected bone or muscle tissue. Likewise, 11C-acetate uptake was significantly reduced in MM tumors after treatment. CONCLUSIONS: Uptake of acetate from the extracellular environment was enhanced in MMC and was critical to cellular viability. 11C-Acetate-PET detected the presence of myeloma cells in vivo, including uptake in intramedullary bone disease. 11C-Acetate-PET also detected response to therapy in vivo Our data suggested that acetate metabolism and incorporation into lipids was crucial to MM cell biology and that 11C-acetate PET is a promising imaging modality for MM. Clin Cancer Res; 23(2); 416-29. (c)2016 AACR. PMID- 27486180 TI - Maximum Likelihood Implementation of an Isolation-with-Migration Model for Three Species. AB - We develop a maximum likelihood (ML) method for estimating migration rates between species using genomic sequence data. A species tree is used to accommodate the phylogenetic relationships among three species, allowing for migration between the two sister species, while the third species is used as an out-group. A Markov chain characterization of the genealogical process of coalescence and migration is used to integrate out the migration histories at each locus analytically, whereas Gaussian quadrature is used to integrate over the coalescent times on each genealogical tree numerically. This is an extension of our early implementation of the symmetrical isolation-with-migration model for three species to accommodate arbitrary loci with two or three sequences per locus and to allow asymmetrical migration rates. Our implementation can accommodate tens of thousands of loci, making it feasible to analyze genome-scale data sets to test for gene flow. We calculate the posterior probabilities of gene trees at individual loci to identify genomic regions that are likely to have been transferred between species due to gene flow. We conduct a simulation study to examine the statistical properties of the likelihood ratio test for gene flow between the two in-group species and of the ML estimates of model parameters such as the migration rate. Inclusion of data from a third out-group species is found to increase dramatically the power of the test and the precision of parameter estimation. We compiled and analyzed several genomic data sets from the Drosophila fruit flies. Our analyses suggest no migration from D. melanogaster to D. simulans, and a significant amount of gene flow from D. simulans to D. melanogaster, at the rate of ~0.02 migrant individuals per generation. We discuss the utility of the multispecies coalescent model for species tree estimation, accounting for incomplete lineage sorting and migration. PMID- 27486179 TI - Development of the System for Observing Student Movement in Academic Routines and Transitions (SOSMART). AB - National attention on whole-of-school approaches to decrease children's sedentary behavior and increase physical activity includes movement integration (MI) in classrooms. The purpose of this study was to describe instrument development, reliability, and validity of the System for Observing Student Movement in Academic Routines and Transitions (SOSMART), designed to assess MI in elementary classrooms. An a priori conceptual framework was developed based on existing literature. The framework was expanded/refined using videos from elementary classrooms and a Delphi survey. The survey, sent to 85 experts, yielded a 38% response rate. The final system includes 11 MI variables (three categories of teacher variables, two categories of student variables) and uses a 20-second continuous interval recording format. Reliability and validity data were collected in 12 classrooms across four elementary schools. Instrument reliability was tested using interval-by-interval percentage agreement for each category. Construct validity was tested by estimating multilevel random effects logistic regression models comparing student accelerometer derived activity with the presence/absence of each MI variable. Intraobserver reliability resulted in 97.5% agreement and exceeded 80% on all variables. Construct validity was supported for 8 out of 11 MI variables. SOSMART can provide valid, reliable, and objective data about MI in elementary schools. PMID- 27486181 TI - SpeciesGeoCoder: Fast Categorization of Species Occurrences for Analyses of Biodiversity, Biogeography, Ecology, and Evolution. AB - Understanding the patterns and processes underlying the uneven distribution of biodiversity across space constitutes a major scientific challenge in systematic biology and biogeography, which largely relies on effectively mapping and making sense of rapidly increasing species occurrence data. There is thus an urgent need for making the process of coding species into spatial units faster, automated, transparent, and reproducible. Here we present SpeciesGeoCoder, an open-source software package written in Python and R, that allows for easy coding of species into user-defined operational units. These units may be of any size and be purely spatial (i.e., polygons) such as countries and states, conservation areas, biomes, islands, biodiversity hotspots, and areas of endemism, but may also include elevation ranges. This flexibility allows scoring species into complex categories, such as those encountered in topographically and ecologically heterogeneous landscapes. In addition, SpeciesGeoCoder can be used to facilitate sorting and cleaning of occurrence data obtained from online databases, and for testing the impact of incorrect identification of specimens on the spatial coding of species. The various outputs of SpeciesGeoCoder include quantitative biodiversity statistics, global and local distribution maps, and files that can be used directly in many phylogeny-based applications for ancestral range reconstruction, investigations of biome evolution, and other comparative methods. Our simulations indicate that even datasets containing hundreds of millions of records can be analyzed in relatively short time using a standard computer. We exemplify the use of SpeciesGeoCoder by inferring the historical dispersal of birds across the Isthmus of Panama, showing that lowland species crossed the Isthmus about twice as frequently as montane species with a marked increase in the number of dispersals during the last 10 million years. [ancestral area reconstruction; biodiversity patterns; ecology; evolution; point in polygon; species distribution data.]. PMID- 27486183 TI - The design and application of an e-health readiness assessment tool. AB - BACKGROUND: To date, several models have been developed to evaluate e-health readiness in healthcare organisations; however, no specific tool has been designed to assess or measure e-health readiness. OBJECTIVE: The aim of this research was to design an e-health readiness assessment tool and to apply this tool to two Iranian hospitals to assess their readiness for the implementation of e-health. METHOD: The study, which was undertaken in 2012, consisted of three phases: (i) review of existing models of e-health; (ii) design of an e-health readiness assessment tool; and (iii) trial of the assessment tool in two Iranian hospitals. Phase 1 consisted of a literature review that informed the development of the tool. In phase 2, we developed an e-health readiness assessment tool with feedback using two questionnaires from 40 employees from two teaching hospitals in Iran. In phase 3, we applied the tool to the same two Iranian teaching hospitals. Participants who completed the questionnaires were from management, health information technology, medical and nursing backgrounds and were familiar with e-health. A purposive sampling method was used to invite them to take part in the study. Data from the questionnaires were analysed using factor analysis and descriptive statistics. RESULTS: Five dimensions and twenty-one indices were selected to be included in the e-health readiness tool. The 5 dimensions and their relative importance were e-health readiness (16%), information and communication technology (ICT) functions (15%), environmental readiness (20%), human resources readiness (29%) and ICT readiness (20%). The total e-health readiness scores for hospital A and hospital B were 0.22 and 0.4, respectively (a score of 1 is the ideal). CONCLUSION: It is important to assess the e-health readiness of hospitals to save time and money and be able to better prepare for ICT implementations. The e-health readiness assessment tool provides a relatively simple method for assessing hospitals and provides essential information to assist healthcare facilities focus preparations and planning for e-health implementations. PMID- 27486184 TI - Patient perspectives on a personally controlled electronic health record used in regional Australia. AB - BACKGROUND: Personally controlled electronic health records (PCEHRs) are being implemented throughout Australia; yet few studies have investigated patients' experiences of using a PCEHR. AIM: To explore patients' experiences and perspectives of using a locally developed PCEHR implemented in an Australian health service. METHOD: Twelve patients completed individual semi-structured telephone interviews, which underwent inductive analysis. RESULTS: Participants described two main interdependent advantages of PCEHRs: improved quality of healthcare through better information sharing and enhanced patient capacity for self-management. To realise these advantages, widespread acceptance and use of PCEHRs by healthcare providers is required, and PCEHRs need to be simple to use and accessible. CONCLUSION: PCEHRs can produce tangible benefits for patients. However, maximum benefits will be realised when PCEHRs contain a complete collection of relevant health information and are carefully designed for easy use. PMID- 27486185 TI - Utilizing health records to characterize obesity, comorbidities, and health-care services in one human service agency in the United States. AB - US surveys report higher prevalence of obesity in adults with intellectual disability. Health records of 40 adults with intellectual disability were retrospectively reviewed for data on health status, problem lists with International Classification of Diseases, Ninth Revision codes, medication lists, and health encounters over 18 months. Mean age was 49.5 years, 53% were males. Prevalence of overweight, obese, and morbidly obese was 28%, 58%, and 23%, respectively. Primary diagnosis was intellectual disability (50% mild, 33% moderate, 10% severe, and 8% profound), 85% had mental health disorders (67.5% with affective or mood and 42.5% had anxiety disorders). On average, residents consumed 2.63 psychotropic medications daily with additional 5.75 medications for axis 3 diagnoses and made 39.2 health visits over past 18 months. Our analysis supports increased prevalence of overweight/obesity, higher comorbidities, dual psychiatric diagnosis, substantial medication consumption, and higher utilization of health-care services in adults with intellectual disabilities. Targeted health interventions are therefore essential to improve their health and quality of life. PMID- 27486186 TI - All voices matter in experience design: A commitment to action in engaging patient and family voice. AB - This article intends to frame the broader concept of experience design and the engagement of patient and family voice, reinforcing how truly aligned healthcare professionals are not only on the value of this work but also in understanding the benefits of it. When addressing the idea of design, it is important to look at the broadest possible construct and consider the engagement of patient and family voices in healthcare operational efforts, not as passive advisors but as active participants in data gathering, providing input, and with actual decision making. The article offers engagement is not just part of process, facility, or experience design but must be part of the decisions made in how organizations in healthcare today are built, led, and sustained, fundamentally reinforcing our opportunity in healthcare is to focus on overall experience with purpose and intention. This commitment is what will lead to the outcomes all ultimately hope to achieve. PMID- 27486187 TI - DamX Controls Reversible Cell Morphology Switching in Uropathogenic Escherichia coli. AB - The ability to change cell morphology is an advantageous characteristic adopted by multiple pathogenic bacteria in order to evade host immune detection and assault during infection. Uropathogenic Escherichia coli (UPEC) exhibits such cellular dynamics and has been shown to transition through a series of distinct morphological phenotypes during a urinary tract infection. Here, we report the first systematic spatio-temporal gene expression analysis of the UPEC transition through these phenotypes by using a flow chamber-based in vitro infection model that simulates conditions in the bladder. This analysis revealed a novel association between the cell division gene damX and reversible UPEC filamentation. We demonstrate a lack of reversible bacterial filamentation in a damX deletion mutant in vitro and absence of a filamentous response by this mutant in a murine model of cystitis. While deletion of damX abrogated UPEC filamentation and secondary surface colonization in tissue culture and in mouse infections, transient overexpression of damX resulted in reversible UPEC filamentation. In this study, we identify a hitherto-unknown damX-mediated mechanism underlying UPEC morphotypical switching. Murine infection studies showed that DamX is essential for establishment of a robust urinary tract infection, thus emphasizing its role as a mediator of virulence. Our study demonstrates the value of an in vitro methodology, in which uroepithelium infection is closely simulated, when undertaking targeted investigations that are challenging to perform in animal infection models. IMPORTANCE: Urinary tract infections (UTIs) are most often caused by uropathogenic Escherichia coli (UPEC) and account for a considerable health care burden. UPEC exhibits a dynamic lifestyle in the course of infection, in which the bacterium transiently adopts alternative morphologies ranging from rod shaped to coccoid and filamentous, rendering it better at immune evasion and host epithelium adhesion. This penchant for morphotype switching might in large measure account for UPEC's success as a pathogen. In aiming to uncover genes underlying the phenomenon of UPEC morphotype switching, this study identifies damX, a cell division gene, as a mediator of reversible filamentation during UTI. DamX-mediated filamentation represents an additional pathway for bacterial cell shape control, an alternative to SulA mediated FtsZ sequestration during E. coli uropathogenesis, and hence represents a potential target for combating UTI. PMID- 27486188 TI - Heteroresistance to Fluconazole Is a Continuously Distributed Phenotype among Candida glabrata Clinical Strains Associated with In Vivo Persistence. AB - Candida glabrata causes persistent infections in patients treated with fluconazole and often acquires resistance following exposure to the drug. Here we found that clinical strains of C. glabrata exhibit cell-to-cell variation in drug response (heteroresistance). We used population analysis profiling (PAP) to assess fluconazole heteroresistance (FLC(HR)) and to ask if it is a binary trait or a continuous phenotype. Thirty (57.6%) of 52 fluconazole-sensitive clinical C. glabrata isolates met accepted dichotomous criteria for FLC(HR) However, quantitative grading of FLC(HR) by using the area under the PAP curve (AUC) revealed a continuous distribution across a wide range of values, suggesting that all isolates exhibit some degree of heteroresistance. The AUC correlated with rhodamine 6G efflux and was associated with upregulation of the CDR1 and PDH1 genes, encoding ATP-binding cassette (ABC) transmembrane transporters, implying that HetR populations exhibit higher levels of drug efflux. Highly FLC(HR) C. glabrata was recovered more frequently than nonheteroresistant C. glabrata from hematogenously infected immunocompetent mice following treatment with high-dose fluconazole (45.8% versus 15%, P = 0.029). Phylogenetic analysis revealed some phenotypic clustering but also variations in FLC(HR) within clonal groups, suggesting both genetic and epigenetic determinants of heteroresistance. Collectively, these results establish heteroresistance to fluconazole as a graded phenotype associated with ABC transporter upregulation and fluconazole efflux. Heteroresistance may explain the propensity of C. glabrata for persistent infection and the emergence of breakthrough resistance to fluconazole. IMPORTANCE: Heteroresistance refers to variability in the response to a drug within a clonal cell population. This phenomenon may have crucial importance for the way we look at antimicrobial resistance, as heteroresistant strains are not detected by standard laboratory susceptibility testing and may be associated with failure of antimicrobial therapy. We describe for the first time heteroresistance to fluconazole in C. glabrata, a finding that may explain the propensity of this pathogen to acquire resistance following exposure to fluconazole and to persist despite treatment. We found that, rather than being a binary all-or-none trait, heteroresistance was a continuously distributed phenotype associated with increased expression of genes that encode energy-dependent drug efflux transporters. Moreover, we show that heteroresistance is associated with failure of fluconazole to clear infection with C. glabrata Together, these findings provide an empirical framework for determining and quantifying heteroresistance in C. glabrata. PMID- 27486189 TI - Ablation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency In Vivo. AB - A challenging property of gammaherpesviruses is their ability to establish lifelong persistence. The establishment of latency in B cells is thought to involve active virus engagement of host signaling pathways. Pathogenic effects of these viruses during latency or following reactivation can be devastating to the host. Many cancers, including those associated with members of the gammaherpesvirus family, Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, express elevated levels of active host signal transducer and activator of transcription-3 (STAT3). STAT3 is activated by tyrosine phosphorylation in response to many cytokines and can orchestrate effector responses that include proliferation, inflammation, metastasis, and developmental programming. However, the contribution of STAT3 to gammaherpesvirus pathogenesis remains to be completely understood. This is the first study to have identified STAT3 as a critical host determinant of the ability of gammaherpesvirus to establish long term latency in an animal model of disease. Following an acute infection, murine gammaherpesvirus 68 (MHV68) established latency in resident B cells, but establishment of latency was dramatically reduced in animals with a B cell specific STAT3 deletion. The lack of STAT3 in B cells did not impair germinal center responses for immunoglobulin (Ig) class switching in the spleen and did not reduce either total or virus-specific IgG titers. Although ablation of STAT3 in B cells did not have a global effect on these assays of B cell function, it had long-term consequences for the viral load of the host, since virus latency was reduced at 6 to 8 weeks postinfection. Our findings establish host STAT3 as a mediator of gammaherpesvirus persistence. IMPORTANCE: The insidious ability of gammaherpesviruses to establish latent infections can have detrimental consequences for the host. Identification of host factors that promote viral latency is essential for understanding latency mechanisms and for therapeutic interventions. We provide the first evidence that STAT3 expression is needed for murine gammaherpesvirus 68 to establish latency in primary B cells during an active immune response to infection. STAT3 deletion in B cells does not impair adaptive immune control of the virus, but loss of STAT3 in B cells has a long lasting impact on viral persistence. These results indicate a potential therapeutic benefit of STAT3 inhibitors for combating gammaherpesvirus latency and, thereby, associated pathologies. PMID- 27486190 TI - In Vivo Biotinylation of the Toxoplasma Parasitophorous Vacuole Reveals Novel Dense Granule Proteins Important for Parasite Growth and Pathogenesis. AB - Toxoplasma gondii is an obligate intracellular parasite that invades host cells and replicates within a unique parasitophorous vacuole. To maintain this intracellular niche, the parasite secretes an array of dense granule proteins (GRAs) into the nascent parasitophorous vacuole. These GRAs are believed to play key roles in vacuolar remodeling, nutrient uptake, and immune evasion while the parasite is replicating within the host cell. Despite the central role of GRAs in the Toxoplasma life cycle, only a subset of these proteins have been identified, and many of their roles have not been fully elucidated. In this report, we utilize the promiscuous biotin ligase BirA* to biotinylate GRA proteins secreted into the vacuole and then identify those proteins by affinity purification and mass spectrometry. Using GRA-BirA* fusion proteins as bait, we have identified a large number of known and candidate GRAs and verified localization of 13 novel GRA proteins by endogenous gene tagging. We proceeded to functionally characterize three related GRAs from this group (GRA38, GRA39, and GRA40) by gene knockout. While Deltagra38 and Deltagra40 parasites showed no altered phenotype, disruption of GRA39 results in slow-growing parasites that contain striking lipid deposits in the parasitophorous vacuole, suggesting a role in lipid regulation that is important for parasite growth. In addition, parasites lacking GRA39 showed dramatically reduced virulence and a lower tissue cyst burden in vivo Together, the findings from this work reveal a partial vacuolar proteome of T. gondii and identify a novel GRA that plays a key role in parasite replication and pathogenesis. IMPORTANCE: Most intracellular pathogens reside inside a membrane bound vacuole within their host cell that is extensively modified by the pathogen to optimize intracellular growth and avoid host defenses. In Toxoplasma, this vacuole is modified by a host of secretory GRA proteins, many of which remain unidentified. Here we demonstrate that in vivo biotinylation of proximal and interacting proteins using the promiscuous biotin ligase BirA* is a powerful approach to rapidly identify vacuolar GRA proteins. We further demonstrate that one factor identified by this approach, GRA39, plays an important role in the ability of the parasite to replicate within its host cell and cause disease. PMID- 27486191 TI - Effect of Shear Stress on Pseudomonas aeruginosa Isolated from the Cystic Fibrosis Lung. AB - Chronic colonization of the lungs by Pseudomonas aeruginosa is one of the major causes of morbidity and mortality in cystic fibrosis (CF) patients. To gain insights into the characteristic biofilm phenotype of P. aeruginosa in the CF lungs, mimicking the CF lung environment is critical. We previously showed that growth of the non-CF-adapted P. aeruginosa PAO1 strain in a rotating wall vessel, a device that simulates the low fluid shear (LS) conditions present in the CF lung, leads to the formation of in-suspension, self-aggregating biofilms. In the present study, we determined the phenotypic and transcriptomic changes associated with the growth of a highly adapted, transmissible P. aeruginosa CF strain in artificial sputum medium under LS conditions. Robust self-aggregating biofilms were observed only under LS conditions. Growth under LS conditions resulted in the upregulation of genes involved in stress response, alginate biosynthesis, denitrification, glycine betaine biosynthesis, glycerol metabolism, and cell shape maintenance, while genes involved in phenazine biosynthesis, type VI secretion, and multidrug efflux were downregulated. In addition, a number of small RNAs appeared to be involved in the response to shear stress. Finally, quorum sensing was found to be slightly but significantly affected by shear stress, resulting in higher production of autoinducer molecules during growth under high fluid shear (HS) conditions. In summary, our study revealed a way to modulate the behavior of a highly adapted P. aeruginosa CF strain by means of introducing shear stress, driving it from a biofilm lifestyle to a more planktonic lifestyle. IMPORTANCE: Biofilm formation by Pseudomonas aeruginosa is one of the hallmarks of chronic cystic fibrosis (CF) lung infections. The biofilm matrix protects this bacterium from antibiotics as well as from the immune system. Hence, the prevention or reversion of biofilm formation is believed to have a great impact on treatment of chronic P. aeruginosa CF lung infections. In the present study, we showed that it is possible to modulate the behavior of a highly adapted transmissible P. aeruginosa CF isolate at both the transcriptomic and phenotypic levels by introducing shear stress in a CF-like environment, driving it from a biofilm to a planktonic lifestyle. Consequently, the results obtained in this study are of great importance with regard to therapeutic applications that introduce shear stress in the lungs of CF patients. PMID- 27486192 TI - Lcp1 Is a Phosphotransferase Responsible for Ligating Arabinogalactan to Peptidoglycan in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB), has a unique cell envelope which accounts for its unusual low permeability and contributes to resistance against common antibiotics. The main structural elements of the cell wall consist of a cross-linked network of peptidoglycan (PG) in which some of the muramic acid residues are covalently attached to a complex polysaccharide, arabinogalactan (AG), via a unique alpha-l-rhamnopyranose-(1->3) alpha-d-GlcNAc-(1->P) linker unit. While the molecular genetics associated with PG and AG biosynthetic pathways have been largely delineated, the mechanism by which these two major pathways converge has remained elusive. In Gram-positive organisms, the LytR-CpsA-Psr (LCP) family of proteins are responsible for ligating cell wall teichoic acids to peptidoglycan, through a linker unit that bears a striking resemblance to that found in mycobacterial arabinogalactan. In this study, we have identified Rv3267 as a mycobacterial LCP homolog gene that encodes a phosphotransferase which we have named Lcp1. We demonstrate that lcp1 is an essential gene required for cell viability and show that recombinant Lcp1 is capable of ligating AG to PG in a cell-free radiolabeling assay. IMPORTANCE: Tuberculosis is an infectious disease caused by the bacterial organism Mycobacterium tuberculosis Survival of M. tuberculosis rests critically on the integrity of its unique cell wall; therefore, a better understanding of how the genes and enzymes involved in cell wall assembly work is fundamental for us to develop new drugs to treat this disease. In this study, we have identified Lcp1 as an essential phosphotransferase that ligates together arabinogalactan and peptidoglycan, two crucial cell wall macromolecules found within the mycobacterial cell wall. The discovery of Lcp1 sheds new light on the final stages of mycobacterial cell wall assembly and represents a key biosynthetic step that could be exploited for new anti-TB drug discovery. PMID- 27486193 TI - The Double-Stranded DNA Virosphere as a Modular Hierarchical Network of Gene Sharing. AB - Virus genomes are prone to extensive gene loss, gain, and exchange and share no universal genes. Therefore, in a broad-scale study of virus evolution, gene and genome network analyses can complement traditional phylogenetics. We performed an exhaustive comparative analysis of the genomes of double-stranded DNA (dsDNA) viruses by using the bipartite network approach and found a robust hierarchical modularity in the dsDNA virosphere. Bipartite networks consist of two classes of nodes, with nodes in one class, in this case genomes, being connected via nodes of the second class, in this case genes. Such a network can be partitioned into modules that combine nodes from both classes. The bipartite network of dsDNA viruses includes 19 modules that form 5 major and 3 minor supermodules. Of these modules, 11 include tailed bacteriophages, reflecting the diversity of this largest group of viruses. The module analysis quantitatively validates and refines previously proposed nontrivial evolutionary relationships. An expansive supermodule combines the large and giant viruses of the putative order "Megavirales" with diverse moderate-sized viruses and related mobile elements. All viruses in this supermodule share a distinct morphogenetic tool kit with a double jelly roll major capsid protein. Herpesviruses and tailed bacteriophages comprise another supermodule, held together by a distinct set of morphogenetic proteins centered on the HK97-like major capsid protein. Together, these two supermodules cover the great majority of currently known dsDNA viruses. We formally identify a set of 14 viral hallmark genes that comprise the hubs of the network and account for most of the intermodule connections. IMPORTANCE: Viruses and related mobile genetic elements are the dominant biological entities on earth, but their evolution is not sufficiently understood and their classification is not adequately developed. The key reason is the characteristic high rate of virus evolution that involves not only sequence change but also extensive gene loss, gain, and exchange. Therefore, in the study of virus evolution on a large scale, traditional phylogenetic approaches have limited applicability and have to be complemented by gene and genome network analyses. We applied state-of-the art methods of such analysis to reveal robust hierarchical modularity in the genomes of double-stranded DNA viruses. Some of the identified modules combine highly diverse viruses infecting bacteria, archaea, and eukaryotes, in support of previous hypotheses on direct evolutionary relationships between viruses from the three domains of cellular life. We formally identify a set of 14 viral hallmark genes that hold together the genomic network. PMID- 27486194 TI - Identification of Multiple Cryptococcal Fungicidal Drug Targets by Combined Gene Dosing and Drug Affinity Responsive Target Stability Screening. AB - Cryptococcus neoformans is a pathogenic fungus that is responsible for up to half a million cases of meningitis globally, especially in immunocompromised individuals. Common fungistatic drugs, such as fluconazole, are less toxic for patients but have low efficacy for initial therapy of the disease. Effective therapy against the disease is provided by the fungicidal drug amphotericin B; however, due to its high toxicity and the difficulty in administering its intravenous formulation, it is imperative to find new therapies targeting the fungus. The antiparasitic drug bithionol has been recently identified as having potent fungicidal activity. In this study, we used a combined gene dosing and drug affinity responsive target stability (GD-DARTS) screen as well as protein modeling to identify a common drug binding site of bithionol within multiple NAD dependent dehydrogenase drug targets. This combination genetic and proteomic method thus provides a powerful method for identifying novel fungicidal drug targets for further development. IMPORTANCE: Cryptococcosis is a neglected fungal meningitis that causes approximately half a million deaths annually. The most effective antifungal agent, amphotericin B, was developed in the 1950s, and no effective medicine has been developed for this disease since that time. A key aspect of amphotericin B's effectiveness is thought to be because of its ability to kill the fungus (fungicidal activity), rather than just stop or slow its growth. The present study utilized a recently identified fungicidal agent, bithionol, to identify potential fungicidal drug targets that can be used in developing modern fungicidal agents. A combined protein and genetic analysis approach was used to identify a class of enzymes, dehydrogenases, that the fungus uses to maintain homeostasis with regard to sugar nutrients. Similarities in the drug target site were found that resulted in simultaneous inhibition and killing of the fungus by bithionol. These studies thus identify a common, multitarget site for antifungal development. PMID- 27486195 TI - A LuxR Homolog in a Cottonwood Tree Endophyte That Activates Gene Expression in Response to a Plant Signal or Specific Peptides. AB - Homologs of the LuxR acyl-homoserine lactone (AHL) quorum-sensing signal receptor are prevalent in Proteobacteria isolated from roots of the Eastern cottonwood tree, Populus deltoides Many of these isolates possess an orphan LuxR homolog, closely related to OryR from the rice pathogen Xanthomonas oryzae OryR does not respond to AHL signals but, instead, responds to an unknown plant compound. We discovered an OryR homolog, PipR, in the cottonwood endophyte Pseudomonas sp. strain GM79. The genes adjacent to pipR encode a predicted ATP-binding cassette (ABC) peptide transporter and peptidases. We purified the putative peptidases, PipA and AapA, and confirmed their predicted activities. A transcriptional pipA gfp reporter was responsive to PipR in the presence of plant leaf macerates, but it was not influenced by AHLs, similar to findings with OryR. We found that PipR also responded to protein hydrolysates to activate pipA-gfp expression. Among many peptides tested, the tripeptide Ser-His-Ser showed inducer activity but at relatively high concentrations. An ABC peptide transporter mutant failed to respond to leaf macerates, peptone, or Ser-His-Ser, while peptidase mutants expressed higher-than-wild-type levels of pipA-gfp in response to any of these signals. Our studies are consistent with a model where active transport of a peptidelike signal is required for the signal to interact with PipR, which then activates peptidase gene expression. The identification of a peptide ligand for PipR sets the stage to identify plant-derived signals for the OryR family of orphan LuxR proteins. IMPORTANCE: We describe the transcription factor PipR from a Pseudomonas strain isolated as a cottonwood tree endophyte. PipR is a member of the LuxR family of transcriptional factors. LuxR family members are generally thought of as quorum-sensing signal receptors, but PipR is one of an emerging subfamily of LuxR family members that respond to compounds produced by plants. We found that PipR responds to a peptidelike compound, and we present a model for Pip system signal transduction. A better understanding of plant-responsive LuxR homologs and the compounds to which they respond is of general importance, as they occur in dozens of bacterial species that are associated with economically important plants and, as we report here, they also occur in members of certain root endophyte communities. PMID- 27486196 TI - Obesity Outweighs Protection Conferred by Adjuvanted Influenza Vaccination. AB - Obesity is a risk factor for developing severe influenza virus infection, making vaccination of utmost importance for this high-risk population. However, vaccinated obese animals and adults have decreased neutralizing antibody responses. In these studies, we tested the hypothesis that the addition of either alum or a squalene-based adjuvant (AS03) to an influenza vaccine would improve neutralizing antibody responses and protect obese mice from challenge. Our studies demonstrate that adjuvanted vaccine does increase both neutralizing and nonneutralizing antibody levels compared to vaccine alone. Although obese mice mount significantly decreased virus-specific antibody responses, both the breadth and the magnitude of the responses against hemagglutinin (HA) and neuraminidase (NA) are decreased compared to the responses in lean mice. Importantly, even with a greater than fourfold increase in neutralizing antibody levels, obese mice are not protected against influenza virus challenge and viral loads remain elevated in the respiratory tract. Increasing the antigen dose affords no added protection, and a decreasing viral dose did not fully mitigate the increased mortality seen in obese mice. Overall, these studies highlight that, while the use of an adjuvant does improve seroconversion, vaccination does not fully protect obese mice from influenza virus challenge, possibly due to the increased sensitivity of obese animals to infection. Given the continued increase in the global obesity epidemic, our findings have important implications for public health. IMPORTANCE: Vaccination is the most effective strategy for preventing influenza virus infection and is a key component for pandemic preparedness. However, vaccines may fail to provide optimal protection in high-risk groups, including overweight and obese individuals. Given the worldwide obesity epidemic, it is imperative that we understand and improve vaccine efficacy. No work to date has investigated whether adjuvants increase the protective capacity of influenza vaccines in the obese host. In these studies, we show that adjuvants increased the neutralizing and nonneutralizing antibody responses during vaccination of lean and obese mice to levels considered "protective," and yet, obese mice still succumbed to infection. This vulnerability is likely due to a combination of factors, including the increased susceptibility of obese animals to develop severe and even lethal disease when infected with very low viral titers. Our studies highlight the critical public health need to translate these findings and better understand vaccination in this increasing population. PMID- 27486197 TI - Comprehensive Identification of Meningococcal Genes and Small Noncoding RNAs Required for Host Cell Colonization. AB - Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia, affecting infants and adults worldwide. N. meningitidis is also a common inhabitant of the human nasopharynx and, as such, is highly adapted to its niche. During bacteremia, N. meningitidis gains access to the blood compartment, where it adheres to endothelial cells of blood vessels and causes dramatic vascular damage. Colonization of the nasopharyngeal niche and communication with the different human cell types is a major issue of the N. meningitidis life cycle that is poorly understood. Here, highly saturated random transposon insertion libraries of N. meningitidis were engineered, and the fitness of mutations during routine growth and that of colonization of endothelial and epithelial cells in a flow device were assessed in a transposon insertion site sequencing (Tn-seq) analysis. This allowed the identification of genes essential for bacterial growth and genes specifically required for host cell colonization. In addition, after having identified the small noncoding RNAs (sRNAs) located in intergenic regions, the phenotypes associated with mutations in those sRNAs were defined. A total of 383 genes and 8 intergenic regions containing sRNA candidates were identified to be essential for growth, while 288 genes and 33 intergenic regions containing sRNA candidates were found to be specifically required for host cell colonization. IMPORTANCE: Meningococcal meningitis is a common cause of meningitis in infants and adults. Neisseria meningitidis (meningococcus) is also a commensal bacterium of the nasopharynx and is carried by 3 to 30% of healthy humans. Under some unknown circumstances, N. meningitidis is able to invade the bloodstream and cause either meningitis or a fatal septicemia known as purpura fulminans. The onset of symptoms is sudden, and death can follow within hours. Although many meningococcal virulence factors have been identified, the mechanisms that allow the bacterium to switch from the commensal to pathogen state remain unknown. Therefore, we used a Tn-seq strategy coupled to high throughput DNA sequencing technologies to find genes for proteins used by N. meningitidis to specifically colonize epithelial cells and primary brain endothelial cells. We identified 383 genes and 8 intergenic regions containing sRNAs essential for growth and 288 genes and 33 intergenic regions containing sRNAs required specifically for host cell colonization. PMID- 27486198 TI - A culturally tailored Internet cancer support group for Asian American breast cancer survivors: A randomized controlled pilot intervention study. AB - Introduction The necessity of culturally competent Internet Cancer Support Groups (ICSGs) for ethnic minorities has recently been highlighted in order to increase its attractiveness and usage. The purpose of this study was to determine the preliminary efficacy of a culturally tailored registered-nurse-moderated ICSG for Asian American breast cancer survivors in enhancing the women's breast cancer survivorship experience. Methods The study included two phases: (a) a usability test and an expert review; and (b) a randomized controlled pilot intervention study. The usability test was conducted among five Asian American breast cancer survivors using a one-month online forum, and the expert review was conducted among five experts using the Cognitive Walkthrough method. The randomized controlled pilot intervention study (a pre-test and post-test design) was conducted among 65 Asian American breast cancer survivors. The data were analysed using content analysis and descriptive and inferential statistics including the repeated ANOVA. Results All users and experts positively evaluated the program and provided their suggestions for the display, educational contents, and user friendly structure. There were significant positive changes in the support care needs and physical and psychological symptoms ( p < 0.05) of the control group. There were significant negative changes in the uncertainty level of the intervention group ( p < 0.10). Controlling for background and disease factors, the intervention group showed significantly greater improvements than the control group in physical and psychological symptoms and quality of life ( p < 0.10). Discussion The findings supported the positive effects of ICSGs on support care needs, psychological and physical symptoms, and quality of life. PMID- 27486200 TI - Ionophore Antibiotics as Cancer Stem Cell-Selective Drugs: Open Questions. PMID- 27486199 TI - Phosphoproteomics to Characterize Host Response During Influenza A Virus Infection of Human Macrophages. AB - Influenza A viruses cause infections in the human respiratory tract and give rise to annual seasonal outbreaks, as well as more rarely dreaded pandemics. Influenza A viruses become quickly resistant to the virus-directed antiviral treatments, which are the current main treatment options. A promising alternative approach is to target host cell factors that are exploited by influenza viruses. To this end, we characterized the phosphoproteome of influenza A virus infected primary human macrophages to elucidate the intracellular signaling pathways and critical host factors activated upon influenza infection. We identified 1675 phosphoproteins, 4004 phosphopeptides and 4146 nonredundant phosphosites. The phosphorylation of 1113 proteins (66%) was regulated upon infection, highlighting the importance of such global phosphoproteomic profiling in primary cells. Notably, 285 of the identified phosphorylation sites have not been previously described in publicly available phosphorylation databases, despite many published large-scale phosphoproteome studies using human and mouse cell lines. Systematic bioinformatics analysis of the phosphoproteome data indicated that the phosphorylation of proteins involved in the ubiquitin/proteasome pathway (such as TRIM22 and TRIM25) and antiviral responses (such as MAVS) changed in infected macrophages. Proteins known to play roles in small GTPase-, mitogen-activated protein kinase-, and cyclin-dependent kinase- signaling were also regulated by phosphorylation upon infection. In particular, the influenza infection had a major influence on the phosphorylation profiles of a large number of cyclin dependent kinase substrates. Functional studies using cyclin-dependent kinase inhibitors showed that the cyclin-dependent kinase activity is required for efficient viral replication and for activation of the host antiviral responses. In addition, we show that cyclin-dependent kinase inhibitors protect IAV-infected mice from death. In conclusion, we provide the first comprehensive phosphoproteome characterization of influenza A virus infection in primary human macrophages, and provide evidence that cyclin-dependent kinases represent potential therapeutic targets for more effective treatment of influenza infections. PMID- 27486201 TI - Long-Term Responders After Brentuximab Vedotin: Single-Center Experience on Relapsed and Refractory Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma Patients. AB - BACKGROUND: Brentuximab vedotin (BV) has shown high overall response rate in refractory/relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) with reported long-term response duration in clinical trials, but few data are available regarding its role in long-term outcomes in real life. PATIENTS AND METHODS: A single-center observational study was conducted on patients treated with BV in daily clinical practice to evaluate the long-term effectiveness of BV in HL and sALCL patients and to check whether clinical trial results are confirmed in a real-life context. RESULTS: The best response rate in the treated 53 patients (43 HL and 10 sALCL) was 69.8% (with 46.5% complete response [CR]) in HL and 100% (80% CR) for sALCL, respectively. With a median patient follow-up of 36.8 months, the estimated median duration of response was 31.5 months for HL and 17.8 for sALCL, respectively. At the latest available follow-up, 75% of patients were still in response, with 43% without any consolidation. Toxicity was primarily neurological and it was rarely so serious to require dose reduction or interruption. In addition, it always reversed completely after the end of treatment. CONCLUSION: Our data showed that 51% of patients treated with BV can be regarded as "long-term responders." Among these cases, for all patients who underwent stem cell transplantation immediately after BV, the procedure was consolidative. For patients who have remained in continuous CR without any consolidation after therapy, BV can induce prolonged disease control. IMPLICATIONS FOR PRACTICE: Brentuximab vedotin (BV) has shown a high overall response rate in refractory/relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma, with reported long-term response duration in clinical trials, whereas few data are available regarding its role in long-term outcomes in real life. The data reported in this study suggest that BV can induce the same results in daily clinical practice. The data showed that 51% of patients treated with BV can be regarded as "long-term responders." Among these cases, BV can induce prolonged disease control in patients who have remained in continuous complete response without any consolidation after the drug. PMID- 27486202 TI - Is Salvage Liver Resection Necessary for Initially Unresectable Hepatocellular Carcinoma Patients Downstaged by Transarterial Chemoembolization? Ten Years of Experience. AB - INTRODUCTION: This study evaluated long-term outcomes of salvage surgery as additional therapy following downstaging of hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) in patients with initially unresectable HCC. METHODS: A retrospective analysis was performed of 831 consecutive patients with unresectable HCC who underwent TACE as initial treatment between June 2004 and December 2014. Of these, 82 patients with downstaged resectable HCC were enrolled in this study: 43 received salvage surgery (S group) and the remaining 39, who refused salvage resection, were the control group (T group). The primary endpoint was overall survival (OS). RESULTS: The median OS in the S and T groups was 49 and 31 months, respectively (p = .027). The 2-, 4-, and 5-year survival rates were 93%, 47%, and 26% in the S group and 74%, 18%, and 10% in the T group, respectively (p = .019). Treatment modality (hazard ratio [HR], 0.337; 95% confidential interval [CI], 0.184-0.616; p < .001) and response to TACE (complete vs. partial; HR, 3.154; 95% CI, 1.709-5.822; p < .001) were independent prognostic factors for survival. The median OS for patients in the complete response and partial response (PR) subgroups was 50 and 49 months, respectively, in the S group and 54 and 24 months, respectively, in the T group (p = .699 and p < .001, respectively). The median OS for HCC patients with macroscopic vascular invasion (MVI) was 58 and 30 months in the S and T groups, respectively (p = .024). CONCLUSION: Salvage surgery after downstaging of unresectable HCC had a survival benefit only for patients with MVI or a PR to TACE. IMPLICATIONS FOR PRACTICE: The results of this study suggest that salvage liver resection after downstaging of unresectable hepatocellular carcinoma in patients with a complete response to transarterial chemoembolization (TACE) has a comparable long-term outcome in this good-prognosis group. Salvage liver resection may provide a better long-term outcome compared with TACE alone, but only in patients with macroscopic vascular invasion or those with a partial response to TACE. PMID- 27486203 TI - Analysis of Real-World Data on Overall Survival in Multiple Myeloma Patients With >=3 Prior Lines of Therapy Including a Proteasome Inhibitor (PI) and an Immunomodulatory Drug (IMiD), or Double Refractory to a PI and an IMiD. AB - BACKGROUND: This retrospective study evaluated the treatment patterns in and overall survival (OS) of multiple myeloma (MM) patients who were refractory to a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) or who had received three or more prior lines of therapy (LOTs) including a PI and an IMiD. METHODS: Electronic health records in the IMS LifeLink and OPTUM databases were screened for indexing periods of 2000-2014 and 2007-2014, respectively. Patients who were refractory to both a PI and an IMiD (criterion 1) or who received three or more prior LOTs (including a PI and an IMiD) and showed disease progression within 60 days of their most recent regimen (criterion 2) comprised the eligible population. Median OS from time of last LOT was assessed for the full cohort, cohorts meeting criteria 1 and 2, and clinically important subgroups. RESULTS: Of 3,929 and 3,837 patients with MM diagnoses evaluated in the IMS LifeLink and OPTUM databases, 500 and 162 met the eligibility criteria, respectively. Similar median OS was observed for eligible patients in the IMS LifeLink and OPTUM databases (7.9 vs. 7.9 months; p = .5358). In subgroup analyses of the IMS LifeLink data set, median OS was longer in patients <65 years of age than it was for those >=65 years at eligibility (9.5 vs 6.7 months; p < .01) and in patients with good or unreported versus poor performance status at last claim (7.8 or 8.8 vs. 2.9 months; p < .0001). CONCLUSION: The findings of this survival analysis suggest that outcomes for these patients remain poor despite the availability of newer agents. IMPLICATIONS FOR PRACTICE: This real-world retrospective study of electronic health records examines the survival outcomes of patients with multiple myeloma who are heavily pretreated or highly refractory to currently approved treatments, including recently approved proteasome inhibitors and immunomodulatory drugs. This survival analysis showed that outcomes for these patients remain poor despite the availability of newer agents, with median overall survival of approximately 8 months. These findings highlight a critical need to develop novel therapies for these patients and also serve as a reference point against which emerging agents for heavily pretreated or highly refractory disease may be evaluated. PMID- 27486206 TI - Time enough for tears? PMID- 27486204 TI - Randomised, double-blind, placebo-controlled trial with azithromycin selects for anti-inflammatory microbial metabolites in the emphysematous lung. AB - INTRODUCTION: Azithromycin (AZM) reduces pulmonary inflammation and exacerbations in patients with COPD having emphysema. The antimicrobial effects of AZM on the lower airway microbiome are not known and may contribute to its beneficial effects. Here we tested whether AZM treatment affects the lung microbiome and bacterial metabolites that might contribute to changes in levels of inflammatory cytokines in the airways. METHODS: 20 smokers (current or ex-smokers) with emphysema were randomised to receive AZM 250 mg or placebo daily for 8 weeks. Bronchoalveolar lavage (BAL) was performed at baseline and after treatment. Measurements performed in acellular BAL fluid included 16S rRNA gene sequences and quantity; 39 cytokines, chemokines and growth factors and 119 identified metabolites. The response to lipopolysaccharide (LPS) by alveolar macrophages after ex-vivo treatment with AZM or bacterial metabolites was assessed. RESULTS: Compared with placebo, AZM did not alter bacterial burden but reduced alpha diversity, decreasing 11 low abundance taxa, none of which are classical pulmonary pathogens. Compared with placebo, AZM treatment led to reduced in-vivo levels of chemokine (C-X-C) ligand 1 (CXCL1), tumour necrosis factor (TNF)-alpha, interleukin (IL)-13 and IL-12p40 in BAL, but increased bacterial metabolites including glycolic acid, indol-3-acetate and linoleic acid. Glycolic acid and indol-3-acetate, but not AZM, blunted ex-vivo LPS-induced alveolar macrophage generation of CXCL1, TNF-alpha, IL-13 and IL-12p40. CONCLUSION: AZM treatment altered both lung microbiota and metabolome, affecting anti-inflammatory bacterial metabolites that may contribute to its therapeutic effects. TRIAL REGISTRATION NUMBER: NCT02557958. PMID- 27486205 TI - Individualized prediction of lung-function decline in chronic obstructive pulmonary disease. AB - BACKGROUND: The rate of lung-function decline in chronic obstructive pulmonary disease (COPD) varies substantially among individuals. We sought to develop and validate an individualized prediction model for forced expiratory volume at 1 second (FEV1) in current smokers with mild-to-moderate COPD. METHODS: Using data from a large long-term clinical trial (the Lung Health Study), we derived mixed effects regression models to predict future FEV1 values over 11 years according to clinical traits. We modelled heterogeneity by allowing regression coefficients to vary across individuals. Two independent cohorts with COPD were used for validating the equations. RESULTS: We used data from 5594 patients (mean age 48.4 yr, 63% men, mean baseline FEV1 2.75 L) to create the individualized prediction equations. There was significant between-individual variability in the rate of FEV1 decline, with the interval for the annual rate of decline that contained 95% of individuals being -124 to -15 mL/yr for smokers and -83 to 15 mL/yr for sustained quitters. Clinical variables in the final model explained 88% of variation around follow-up FEV1. The C statistic for predicting severity grades was 0.90. Prediction equations performed robustly in the 2 external data sets. INTERPRETATION: A substantial part of individual variation in FEV1 decline can be explained by easily measured clinical variables. The model developed in this work can be used for prediction of future lung health in patients with mild-to moderate COPD. TRIAL REGISTRATION: Lung Health Study - ClinicalTrials.gov, no. NCT00000568; Pan-Canadian Early Detection of Lung Cancer Study - ClinicalTrials.gov, no. NCT00751660. PMID- 27486207 TI - Kounis syndrome and systemic mastocytosis in a 52-year-old man having surgery. PMID- 27486208 TI - Metastatic pulmonary calcification in end-stage renal failure. PMID- 27486210 TI - Older doctors under increasing regulatory scrutiny. PMID- 27486209 TI - Inuit suicide prevention strategy strives to save lives. PMID- 27486211 TI - Infoway calls for e-prescribing proposals. PMID- 27486212 TI - Predicting individual lung-function trajectories: An opportunity for prevention? PMID- 27486213 TI - (1,3) beta-D-Glucan in Bronchoalveolar Lavage of Lung Transplant Recipients for the Diagnosis of Invasive Pulmonary Aspergillosis. AB - (1,3) beta-D-Glucan (BDG) is present in the cell wall of most fungi. Its detection in serum has been useful in the diagnosis of invasive aspergillosis (IA) in patients with hematologic malignancies. However, assaying for BDG did not perform well in the serum of lung transplant recipients. We undertook to study the performance of BDG in the bronchoalveolar lavage (BAL) of lung transplant recipients for the diagnosis of invasive pulmonary aspergillosis (IPA). Available and stored BAL samples from lung transplant recipients at the Toronto General Hospital between October 2007 and April 2013 were tested for BDG using the Fungitell kit from the Associates of Cape Cod Inc, Falmouth, MA, USA : The International Society for Heart and Lung transplantation (ISHLT) criteria was used for the diagnosis of IA. Of 195 samples, there were ten episodes of IA. The sensitivity and specificity of the test were 80% and 53% and 60% and 70% at 41 pg/ml and 108 pg/ml cut-offs, respectively. On excluding 52 bronchoscopies due to receipt of anti-Aspergillus therapy during specimen collection, the sensitivity and specificity improved to 75% and 91%, respectively, at a 524 pg/ml cut-off. However, only four episodes of IA remained in this analysis. Using BDG in BAL of lung transplant recipients for the diagnosis of IA, our study demonstrated moderate sensitivity and specificity. PMID- 27486214 TI - Trichophyton erinacei in pet hedgehogs in Spain: Occurrence and revision of its taxonomic status. AB - Hedgehogs have increased in popularity as pets in Spain but there are no data of infection rates of this exotic animal with dermatophytes in our country. During the period of 2008-2011 a total of 20 pet hedgehogs (19 African pygmy hedgehogs and 1 Egyptian long-eared hedgehog) suspected of having dermatophytoses were studied. This is the first survey of the occurrence of T. erinacei in household hedgehogs in Spain. The T. erinacei infection rate was 50% (9 out of 19 African pygmy hedgehogs, and the one Egyptian long-eared hedgehog surveyed). Morphological identification of the isolates was confirmed by molecular analysis. All the strains had the same ITS sequence and showed 100% sequence similarity to T. erinacei type strain CBS 511.73 (AB 105793). The Spanish isolates were confirmed as T. erinacei urease positive. On the basis of ITS sequences, T. erinacei is a species close to but separate from the taxa included in the A. benhamiae complex. Review of the current literature on DNA-based methods for identification of species included in this complex has highlighted the urgent need to reach a consensus in species circumscription and classification system accepted by all mycologists. PMID- 27486215 TI - A subdose of fluconazole alters the virulence of Cryptococcus gattii during murine cryptococcosis and modulates type I interferon expression. AB - Cryptococcosis is an invasive infection caused by yeast-like fungus of the genera Cryptococcus spp. The antifungal therapy for this disease provides some toxicity and the incidence of infections caused by resistant strains increased. Thus, we aimed to assess the consequences of fluconazole subdoses during the treatment of cryptococcosis in the murine inflammatory response and in the virulence factors of Cryptococcus gattii. Mice infected with Cryptococcus gattii were treated with subdoses of fluconazole. We determined the behavior of mice and type 1 interferon expression during the treatment; we also studied the virulence factors and susceptibility to fluconazole for the colonies recovered from the animals. A subdose of fluconazole prolonged the survival of mice, but the morbidity of cryptococcosis was higher in treated animals. These data were linked to the increase in: (i) fluconazole minimum inhibitory concentration, (ii) capsule size and (iii) melanization of C. gattii, which probably led to the increased expression of type I interferons in the brains of mice but not in the lungs. In conclusion, a subdose of fluconazole altered fungal virulence factors and susceptibility to this azole, leading to an altered inflammatory host response and increased morbidity. PMID- 27486216 TI - Quantification of A. fumigatus-specific CD154+ T-cells-preanalytic considerations. AB - Fungal specific CD154+ T-cells have been described as a biomarker in invasive aspergillosis. The influence of sample storage on the detection of these cells was assessed. Six-hour delay prior to PBMC isolation is associated with an 18% decrease of cell viability and alterations of the cellular composition of the sample. This results in 87% reduction of CD154+ A. fumigatus specific cells due to reduced assay sensitivity and increased background values in unstimulated samples. If prompt cell measurement is not feasible, isolated PBMCs can be frozen (at -20 degrees C and -80 degrees C) and processed later with comparable assay reliability (mean value fresh vs. thawing: 0.126, 0.133; Pearson-Coefficient: 0.962). PMID- 27486217 TI - Stories of MDM: It Only Takes One. PMID- 27486218 TI - Development of a Conceptual Model of Disease Progression for Use in Economic Modeling of Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: To develop and validate a new conceptual model (CM) of chronic obstructive pulmonary disease (COPD) for use in disease progression and economic modeling. The CM identifies and describes qualitative associations between disease attributes, progression and outcomes. METHODS: A literature review was performed to identify any published CMs or literature reporting the impact and association of COPD disease attributes with outcomes. After critical analysis of the literature, a Steering Group of experts from the disciplines of health economics, epidemiology and clinical medicine was convened to develop a draft CM, which was refined using a Delphi process. The refined CM was validated by testing for associations between attributes using data from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). RESULTS: Disease progression attributes included in the final CM were history and occurrence of exacerbations, lung function, exercise capacity, signs and symptoms (cough, sputum, dyspnea), cardiovascular disease comorbidities, 'other' comorbidities (including depression), body composition (body mass index), fibrinogen as a biomarker, smoking and demographic characteristics (age, gender). Mortality and health-related quality of life were determined to be the most relevant final outcome measures for this model, intended to be the foundation of an economic model of COPD. CONCLUSION: The CM is being used as the foundation for developing a new COPD model of disease progression and to provide a framework for the analysis of patient-level data. The CM is available as a reference for the implementation of further disease progression and economic models. PMID- 27486219 TI - Does robot-assisted gait training improve ambulation in highly disabled multiple sclerosis people? A pilot randomized control trial. AB - BACKGROUND: Robotic training is commonly used to assist walking training in patients affected by multiple sclerosis (MS) with non-conclusive results. OBJECTIVE: To compare the effect of robot-assisted gait training (RAGT) with that of conventional walking training (CWT) on gait competencies, global ability, fatigue and spasticity in a group of severely affected patients with MS. METHODS: A pilot, single-blind randomized controlled trial was conducted in 43 severe (Expanded Disability Status Scale (EDSS) score of 6-7.5) and non-autonomous ambulant in-patients with MS. Experimental group performed 12 sessions of RAGT, whereas control group performed the same amount of CWT. Primary outcome measures were gait ability assessed by 2 minutes walking test and Functional Ambulatory Category; secondary outcomes were global ability (modified Barthel Index), global mobility (Rivermead Mobility Index), severity of disease (EDSS) and subjectively perceived fatigue (Fatigue Severity Scale). RESULTS: The number of subjects who achieved a clinical significant improvement was significantly higher in RAGT than in CWT ( p < 0.05 for both primary outcome measures). RAGT also led to an improvement in all the other clinical parameters (global ability: p < 0.001, global mobility: p < 0.001, EDSS: p = 0.014 and fatigue: p = 0.001). CONCLUSIONS: RAGT improved the walking competencies in non-autonomous ambulant patients with MS, with benefits in terms of perceived fatigue. PMID- 27486220 TI - Is Mutation Random or Targeted?: No Evidence for Hypermutability in Snail Toxin Genes. AB - Ever since Luria and Delbruck, the notion that mutation is random with respect to fitness has been foundational to modern biology. However, various studies have claimed striking exceptions to this rule. One influential case involves toxin encoding genes in snails of the genus Conus, termed conotoxins, a large gene family that undergoes rapid diversification of their protein-coding sequences by positive selection. Previous reconstructions of the sequence evolution of conotoxin genes claimed striking patterns: (1) elevated synonymous change, interpreted as being due to targeted "hypermutation" in this region; (2) elevated transversion-to-transition ratios, interpreted as reflective of the particular mechanism of hypermutation; and (3) much lower rates of synonymous change in the codons encoding several highly conserved cysteine residues, interpreted as strong position-specific codon bias. This work has spawned a variety of studies on the potential mechanisms of hypermutation and on causes for cysteine codon bias, and has inspired hypermutation hypotheses for various other fast-evolving genes. Here, I show that all three findings are likely to be artifacts of statistical reconstruction. First, by simulating nonsynonymous change I show that high rates of dN can lead to overestimation of dS. Second, I show that there is no evidence for any of these three patterns in comparisons of closely related conotoxin sequences, suggesting that the reported findings are due to breakdown of statistical methods at high levels of sequence divergence. The current findings suggest that mutation and codon bias in conotoxin genes may not be atypical, and that random mutation and selection can explain the evolution of even these exceptional loci. PMID- 27486221 TI - PoPoolationTE2: Comparative Population Genomics of Transposable Elements Using Pool-Seq. AB - The evolutionary dynamics of transposable elements (TEs) are still poorly understood. One reason is that TE abundance needs to be studied at the population level, but sequencing individuals on a population scale is still too expensive to characterize TE abundance in multiple populations. Although sequencing pools of individuals dramatically reduces sequencing costs, a comparison of TE abundance between pooled samples has been difficult, if not impossible, due to various biases. Here, we introduce a novel bioinformatic tool, PoPoolationTE2, which is specifically tailored for the comparison of TE abundance among pooled population samples or different tissues. Using computer simulations, we demonstrate that PoPoolationTE2 not only faithfully recovers TE insertion frequencies and positions but, by homogenizing the power to identify TEs across samples, it provides an unbiased comparison of TE abundance between pooled population samples. We anticipate that PoPoolationTE2 will greatly facilitate the analysis of TE insertion patterns in a broad range of applications. PMID- 27486222 TI - Smoothed Bootstrap Aggregation for Assessing Selection Pressure at Amino Acid Sites. AB - To detect positive selection at individual amino acid sites, most methods use an empirical Bayes approach. After parameters of a Markov process of codon evolution are estimated via maximum likelihood, they are passed to Bayes formula to compute the posterior probability that a site evolved under positive selection. A difficulty with this approach is that parameter estimates with large errors can negatively impact Bayesian classification. By assigning priors to some parameters, Bayes Empirical Bayes (BEB) mitigates this problem. However, as implemented, it imposes uniform priors, which causes it to be overly conservative in some cases. When standard regularity conditions are not met and parameter estimates are unstable, inference, even under BEB, can be negatively impacted. We present an alternative to BEB called smoothed bootstrap aggregation (SBA), which bootstraps site patterns from an alignment of protein coding DNA sequences to accommodate the uncertainty in the parameter estimates. We show that deriving the correction for parameter uncertainty from the data in hand, in combination with kernel smoothing techniques, improves site specific inference of positive selection. We compare BEB to SBA by simulation and real data analysis. Simulation results show that SBA balances accuracy and power at least as well as BEB, and when parameter estimates are unstable, the performance gap between BEB and SBA can widen in favor of SBA. SBA is applicable to a wide variety of other inference problems in molecular evolution. PMID- 27486223 TI - Divergent Ah Receptor Ligand Selectivity during Hominin Evolution. AB - We have identified a fixed nonsynonymous sequence difference between humans (Val381; derived variant) and Neandertals (Ala381; ancestral variant) in the ligand-binding domain of the aryl hydrocarbon receptor (AHR) gene. In an exome sequence analysis of four Neandertal and Denisovan individuals compared with nine modern humans, there are only 90 total nucleotide sites genome-wide for which archaic hominins are fixed for the ancestral nonsynonymous variant and the modern humans are fixed for the derived variant. Of those sites, only 27, including Val381 in the AHR, also have no reported variability in the human dbSNP database, further suggesting that this highly conserved functional variant is a rare event. Functional analysis of the amino acid variant Ala381 within the AHR carried by Neandertals and nonhuman primates indicate enhanced polycyclic aromatic hydrocarbon (PAH) binding, DNA binding capacity, and AHR mediated transcriptional activity compared with the human AHR. Also relative to human AHR, the Neandertal AHR exhibited 150-1000 times greater sensitivity to induction of Cyp1a1 and Cyp1b1 expression by PAHs (e.g., benzo(a)pyrene). The resulting CYP1A1/CYP1B1 enzymes are responsible for PAH first pass metabolism, which can result in the generation of toxic intermediates and perhaps AHR-associated toxicities. In contrast, the human AHR retains the ancestral sensitivity observed in primates to nontoxic endogenous AHR ligands (e.g., indole, indoxyl sulfate). Our findings reveal that a functionally significant change in the AHR occurred uniquely in humans, relative to other primates, that would attenuate the response to many environmental pollutants, including chemicals present in smoke from fire use during cooking. PMID- 27486224 TI - Development and Application of a Novel Model System to Study "Active" and "Passive" Tumor Targeting. AB - Macromolecular reagents can be targeted to tumors through active and passive mechanisms. "Active" targeting involves moieties, such as receptor ligands, to direct tumor cell binding, whereas "passive" targeting relies on long reagent circulating half-life, abnormal tumor vasculature, and poor lymphatic drainage for tumor entrapment. Here, we sought to study the impact of reagent circulating half-life on "active" and "passive" tumor uptake. The humanized prostate-specific membrane antigen (PSMA)-targeting antibody HuJ591 was used as the "active" targeting agent. HuJ591 was labeled with a Near Infrared (NIR) dye and its circulating half-life was modified by conjugation to high-molecular-weight Polyethylene Glycol (PEG). PEGylation did not negatively impact PSMA-binding specificity. "Active" and "passive" tumor targeting of intravenously injected antibody conjugates were then quantified by NIR fluorescent imaging of immunocompromised mice bearing bilateral isogenic PSMA-positive and PSMA-negative human tumor xenografts. Two isogenic tumor pairs were applied, PC3 +/- PSMA (PC3 PIP/PC3-Flu) or LMD-MDA-MB-231 +/- PSMA (LMD-PSMA/LMD). This study provided a unique model system to simultaneously observe "active" and "passive" tumor targeting within a single animal. "Passive" targeting was observed in all PSMA negative tumors, and was not enhanced by increased HuJ591 size or extended circulating half-life. Interestingly, "active" targeting was only successful in some situations. Both PSMA-positive tumor models could be actively targeted with J591-IR800 and J591-PEG10K. However, the larger J591-PEG30K enhanced "active" targeting in the PC-3 tumor models, but inhibited "active" targeting the LMD-MDA MB-231 tumor model. Successful "active" targeting was associated with higher PSMA expression. These results support the potential for "active" targeting to enhance overall macromolecular reagent uptake within tumors. Mol Cancer Ther; 15(10); 2541-50. (c)2016 AACR. PMID- 27486225 TI - A Novel Small Molecule Activator of Nuclear Receptor SHP Inhibits HCC Cell Migration via Suppressing Ccl2. AB - Small heterodimer partner (SHP, NR0B2) is a nuclear orphan receptor without endogenous ligands. Due to its crucial inhibitory role in liver cancer, it is of importance to identify small molecule agonists of SHP. As such, we initiated a probe discovery effort to identify compounds capable of modulating SHP function. First, we performed binding assays using small molecule microarrays (SMM) and discovered 5-(diethylsulfamoyl)-3-hydroxynaphthalene-2-carboxylic acid (DSHN) as a novel activator of SHP. DSHN transcriptionally activated Shp mRNA, but also stabilized the SHP protein by preventing its ubiquitination and degradation. Second, we identified Ccl2 as a new SHP target gene by RNA-seq. We showed that activation of SHP by DSHN repressed Ccl2 expression and secretion by inhibiting p65 activation of CCL2 promoter activity, as demonstrated in vivo in Shp-/- mice and in vitro in HCC cells with SHP overexpression and knockdown. Third, we elucidated a strong inhibitory effect of SHP and DSHN on HCC cell migration and invasion by antagonizing the effect of CCL2. Lastly, by interrogating a publicly available database to retrieve SHP expression profiles from multiple types of human cancers, we established a negative association of SHP expression with human cancer metastasis and patient survival. In summary, the discovery of a novel small molecule activator of SHP provides a therapeutic perspective for future translational and preclinical studies to inhibit HCC metastasis by blocking Ccl2 signaling. Mol Cancer Ther; 15(10); 2294-301. (c)2016 AACR. PMID- 27486226 TI - Cardiac Emergency Response Planning for Schools: A Policy Statement. AB - A sudden cardiac arrest in school or at a school event is potentially devastating to families and communities. An appropriate response to such an event-as promoted by developing, implementing, and practicing a cardiac emergency response plan (CERP)-can increase survival rates. Understanding that a trained lay-responder team within the school can make a difference in the crucial minutes between the time when the victim collapses and when emergency medical services arrive empowers school staff and can save lives. In 2015, the American Heart Association convened a group of stakeholders to develop tools to assist schools in developing CERPs. This article reviews the critical components of a CERP and a CERP team, the factors that should be taken into account when implementing the CERP, and recommendations for policy makers to support CERPs in schools. PMID- 27486227 TI - Asthma and Vocal Cord Dysfunction: Can You Tell the Difference? AB - School nurses care for students with asthma on a daily basis, but what happens when the asthma medication is administered and symptoms persist? As a part of care coordination, the school nurse provides ongoing assessment and care for students with asthma. When symptoms persist despite treatment, school nurses need to consider other issues such as Vocal Cord Dysfunction (VCD). The purpose of this article is to highlight the similarities and differences in the pathophysiology and treatment of both asthma and VCD. PMID- 27486228 TI - Moving toward Light in Response to a Gas: A Novel Cyanobacterial Ethylene Receptor. PMID- 27486229 TI - Size regulation blossoms in Kobe. AB - Coincident with the blossoming of the sakura was the 14th annual CDB Symposium hosted by the RIKEN Center for Developmental Biology in Kobe, Japan. This year's meeting, 'Size in Development: Growth, Shape and Allometry' focused on the molecular and cellular mechanisms underlying differences in size and shape and how they have evolved. On display was the power of using diverse approaches ranging from the study of organoids to whole organisms. PMID- 27486231 TI - Blood vessel formation and function in bone. AB - In addition to their conventional role as a conduit system for gases, nutrients, waste products or cells, blood vessels in the skeletal system play active roles in controlling multiple aspects of bone formation and provide niches for hematopoietic stem cells that reside within the bone marrow. In addition, recent studies have highlighted roles for blood vessels during bone healing. Here, we provide an overview of the architecture of the bone vasculature and discuss how blood vessels form within bone, how their formation is modulated, and how they function during development and fracture repair. PMID- 27486230 TI - Direct lineage reprogramming via pioneer factors; a detour through developmental gene regulatory networks. AB - Although many approaches have been employed to generate defined fate in vitro, the resultant cells often appear developmentally immature or incompletely specified, limiting their utility. Growing evidence suggests that current methods of direct lineage conversion may rely on the transition through a developmental intermediate. Here, I hypothesize that complete conversion between cell fates is more probable and feasible via reversion to a developmentally immature state. I posit that this is due to the role of pioneer transcription factors in engaging silent, unmarked chromatin and activating hierarchical gene regulatory networks responsible for embryonic patterning. Understanding these developmental contexts will be essential for the precise engineering of cell identity. PMID- 27486234 TI - The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes. AB - HNF4A mutations cause increased birth weight, transient neonatal hypoglycemia, and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W), but functional studies have shown inconsistent results; there is a lack of cosegregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI 9.79-125, P = 2 * 10( 21)) for diabetes in our MODY cohort compared with control subjects. p.R114W heterozygotes did not have the increased birth weight of patients with other HNF4A mutations (3,476 g vs. 4,147 g, P = 0.0004), and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P = 0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 years compared with 71% for other HNF4A mutations. We redefine p.R114W as a pathogenic mutation that causes a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment, and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy, and predictive testing of at-risk relatives. The increasing availability of large scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations. PMID- 27486235 TI - Acute Effects of Oral Dehydroepiandrosterone on Counterregulatory Responses During Repeated Hypoglycemia in Healthy Humans. AB - We tested the hypothesis that acute administration of oral dehydroepiandrosterone (DHEA) during episodes of repeated hypoglycemia can prevent the development of hypoglycemia-associated neuroendocrine and autonomic failure in healthy humans. Twenty-seven individuals (16 men, 11 women) participated in two separate randomized, single-blind, 2-day protocols. Day 1 consisted of morning and afternoon 2-h hypoglycemic clamps (2.9 mmol/L) with 800 mg of DHEA or placebo administered before each clamp. Day 2 consisted of a single 2-h hypoglycemic clamp (2.9 mmol/L) following either DHEA (1,600 mg) or placebo. A 3-tritiated glucose was used to determine glucose kinetics during hypoglycemia on day 2. Antecedent hypoglycemia with placebo resulted in significant reductions of epinephrine, norepinephrine, glucagon, growth hormone, cortisol, endogenous glucose production, and lipolytic and symptom responses. During hypoglycemia on day 2, DHEA prevented blunting of all neuroendocrine, autonomic nervous system (ANS), metabolic, and symptom counterregulatory responses following hypoglycemia on day 1. In summary, DHEA can acutely preserve a wide range of key neuroendocrine, ANS, and metabolic counterregulatory homeostatic responses during repeated hypoglycemia. We conclude that DHEA may have acute effects to protect against hypoglycemia-associated neuroendocrine and autonomic failure in healthy humans. PMID- 27486236 TI - Heme-Regulated eIF2alpha Kinase Modulates Hepatic FGF21 and Is Activated by PPARbeta/delta Deficiency. AB - Fibroblast growth factor 21 (FGF21), a peptide hormone with pleiotropic effects on carbohydrate and lipid metabolism, is considered a target for the treatment of diabetes. We investigated the role of peroxisome proliferator-activated receptor (PPAR) beta/delta deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARbeta/delta-null mice and in mouse primary hepatocytes when this receptor was knocked down by small interfering RNA (siRNA). Increased Fgf21 was associated with enhanced protein levels in the heme regulated eukaryotic translation initiation factor 2alpha (eIF2alpha) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2alpha and activating transcription factor (ATF) 4, which is essential for Fgf21-induced expression. siRNA analysis demonstrated that HRI regulates Fgf21 expression in primary hepatocytes. Enhanced Fgf21 expression attenuated tunicamycin-induced endoplasmic reticulum stress, as demonstrated by using a neutralizing antibody against FGF21. Of note, increased Fgf21 expression in mice fed a high-fat diet or hepatocytes exposed to palmitate was accompanied by reduced PPARbeta/delta and activation of the HRI-eIF2alpha-ATF4 pathway. Moreover, pharmacological activation of HRI increased Fgf21 expression and reduced lipid-induced hepatic steatosis and glucose intolerance, but these effects were not observed in Fgf21 null mice. Overall, these findings suggest that HRI is a potential target for regulating hepatic FGF21 levels. PMID- 27486238 TI - Utilization of Stable Isotope Labeling to Facilitate the Identification of Polar Metabolites of KAF156, an Antimalarial Agent. AB - Identification of polar metabolites of drug candidates during development is often challenging. Several prominent polar metabolites of 2-amino-1-(2-(4 fluorophenyl)-3-((4-fluorophenyl)amino)-8,8-dimethyl-5,6-dihydroimidazo[1,2 a]pyrazin-7(8H)-yl)ethanone ([(14)C]KAF156), an antimalarial agent, were detected in rat urine from an absorption, distribution, metabolism, and excretion study but could not be characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS) because of low ionization efficiency. In such instances, a strategy often chosen by investigators is to use a radiolabeled compound with high specific activity, having an isotopic mass ratio (i.e., [(12)C]/[(14)C]) and mass difference that serve as the basis for a mass filter using accurate mass spectrometry. Unfortunately, [(14)C]KAF156-1 was uniformly labeled (n = 1-6) with the mass ratio of ~0.1. This ratio was insufficient to be useful as a mass filter despite the high specific activity (120 MUCi/mg). At this stage in development, stable isotope labeled [(13)C6]KAF156-1 was available as the internal standard for the quantification of KAF156. We were thus able to design an oral dose as a mixture of [(14)C]KAF156-1 (specific activity 3.65 MUCi/mg) and [(13)C6]KAF156-1 with a mass ratio of [(12)C]/[(13)C6] as 0.9 and the mass difference as 6.0202. By using this mass filter strategy, four polar metabolites were successfully identified in rat urine. Subsequently, using a similar dual labeling approach, [(14)C]KAF156-2 and [(13)C2]KAF156-2 were synthesized to allow the detection of any putative polar metabolites that may have lost labeling during biotransformations using the previous [(14)C]KAF156-1. Three polar metabolites were thereby identified and M43, a less polar metabolite, was proposed as the key intermediate metabolite leading to the formation of a total of seven polar metabolites. Overall this dual labeling approach proved practical and valuable for the identification of polar metabolites by LC-MS/MS. PMID- 27486240 TI - News Feature: Prehistoric animals, in living color. PMID- 27486237 TI - Youth-Onset Type 2 Diabetes Consensus Report: Current Status, Challenges, and Priorities. AB - Type 2 diabetes is a significant and increasing burden in adolescents and young adults. Clear strategies for research, prevention, and treatment of the disease in these vulnerable patients are needed. Evidence suggests that type 2 diabetes in children is different not only from type 1 but also from type 2 diabetes in adults. Understanding the unique pathophysiology of type 2 diabetes in youth, as well as the risk of complications and the psychosocial impact, will enable industry, academia, funding agencies, advocacy groups, and regulators to collectively evaluate both current and future research, treatment, and prevention approaches. This Consensus Report characterizes type 2 diabetes in children, evaluates the fundamental differences between childhood and adult disease, describes the current therapeutic options, and discusses challenges to and approaches for developing new treatments. PMID- 27486242 TI - Reply to Marom et al.: Mitochondrial panmixia in dromedaries predates ancient caravan trading. PMID- 27486243 TI - Note on the contribution of genetics to understanding the organization of camel caravans in antiquity. PMID- 27486244 TI - Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins. AB - Dishevelled (DVL) is a key scaffolding protein and a branching point in Wnt signaling pathways. Here, we present conclusive evidence that DVL regulates the centrosomal cycle. We demonstrate that DVL dishevelled and axin (DIX) domain, but not DIX domain-mediated multimerization, is essential for DVL's centrosomal localization. DVL accumulates during the cell cycle and associates with NIMA related kinase 2 (NEK2), which is able to phosphorylate DVL at a multitude of residues, as detected by a set of novel phospho-specific antibodies. This creates interfaces for efficient binding to CDK5 regulatory subunit-associated protein 2 (CDK5RAP2) and centrosomal Nek2-associated protein 1 (C-NAP1), two proteins of the centrosomal linker. Displacement of DVL from the centrosome and its release into the cytoplasm on NEK2 phosphorylation is coupled to the removal of linker proteins, an event necessary for centrosomal separation and proper formation of the mitotic spindle. Lack of DVL prevents NEK2-controlled dissolution of loose centrosomal linker and subsequent centrosomal separation. Increased DVL levels, in contrast, sequester centrosomal NEK2 and mimic monopolar spindle defects induced by a dominant negative version of this kinase. Our study thus uncovers molecular crosstalk between centrosome and Wnt signaling. PMID- 27486245 TI - Intratumoral oxygen gradients mediate sarcoma cell invasion. AB - Hypoxia is a critical factor in the progression and metastasis of many cancers, including soft tissue sarcomas. Frequently, oxygen (O2) gradients develop in tumors as they grow beyond their vascular supply, leading to heterogeneous areas of O2 depletion. Here, we report the impact of hypoxic O2 gradients on sarcoma cell invasion and migration. O2 gradient measurements showed that large sarcoma mouse tumors (>300 mm(3)) contain a severely hypoxic core [<=0.1% partial pressure of O2 (pO2)] whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1-6% pO2). To analyze tumor invasion, we used O2 controllable hydrogels to recreate the physiopathological O2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer distance in the hypoxic hydrogels compared with nonhypoxic hydrogels. To model the effect of the O2 gradient accurately, we examined individual sarcoma cells embedded in the O2-controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through hypoxia-inducible factor-1alpha (HIF-1alpha) activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O2 tension. Treatment with minoxidil, an inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Overall, we show that O2 acts as a 3D physicotactic agent during sarcoma tumor invasion and propose the O2-controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets. PMID- 27486246 TI - Spatial organization of bacterial transcription and translation. AB - In bacteria such as Escherichia coli, DNA is compacted into a nucleoid near the cell center, whereas ribosomes-molecular complexes that translate mRNAs into proteins-are mainly localized to the poles. We study the impact of this spatial organization using a minimal reaction-diffusion model for the cellular transcriptional-translational machinery. Although genome-wide mRNA-nucleoid segregation still lacks experimental validation, our model predicts that [Formula: see text] of mRNAs are segregated to the poles. In addition, our analysis reveals a "circulation" of ribosomes driven by the flux of mRNAs, from synthesis in the nucleoid to degradation at the poles. We show that our results are robust with respect to multiple, biologically relevant factors, such as mRNA degradation by RNase enzymes, different phases of the cell division cycle and growth rates, and the existence of nonspecific, transient interactions between ribosomes and mRNAs. Finally, we confirm that the observed nucleoid size stems from a balance between the forces that the chromosome and mRNAs exert on each other. This suggests a potential global feedback circuit in which gene expression feeds back on itself via nucleoid compaction. PMID- 27486247 TI - The stringent response regulates adaptation to darkness in the cyanobacterium Synechococcus elongatus. AB - The cyanobacterium Synechococcus elongatus relies upon photosynthesis to drive metabolism and growth. During darkness, Synechococcus stops growing, derives energy from its glycogen stores, and greatly decreases rates of macromolecular synthesis via unknown mechanisms. Here, we show that the stringent response, a stress response pathway whose genes are conserved across bacteria and plant plastids, contributes to this dark adaptation. Levels of the stringent response alarmone guanosine 3'-diphosphate 5'-diphosphate (ppGpp) rise after a shift from light to dark, indicating that darkness triggers the same response in cyanobacteria as starvation in heterotrophic bacteria. High levels of ppGpp are sufficient to stop growth and dramatically alter many aspects of cellular physiology, including levels of photosynthetic pigments and polyphosphate, DNA content, and the rate of translation. Cells unable to synthesize ppGpp display pronounced growth defects after exposure to darkness. The stringent response regulates expression of a number of genes in Synechococcus, including ribosomal hibernation promoting factor (hpf), which causes ribosomes to dimerize in the dark and may contribute to decreased translation. Although the metabolism of Synechococcus differentiates it from other model bacterial systems, the logic of the stringent response remains remarkably conserved, while at the same time having adapted to the unique stresses of the photosynthetic lifestyle. PMID- 27486248 TI - Wavy membranes and the growth rate of a planar chemical garden: Enhanced diffusion and bioenergetics. AB - To model ion transport across protocell membranes in Hadean hydrothermal vents, we consider both theoretically and experimentally the planar growth of a precipitate membrane formed at the interface between two parallel fluid streams in a 2D microfluidic reactor. The growth rate of the precipitate is found to be proportional to the square root of time, which is characteristic of diffusive transport. However, the dependence of the growth rate on the concentrations of hydroxide and metal ions is approximately linear and quadratic, respectively. We show that such a difference in ionic transport dynamics arises from the enhanced transport of metal ions across a thin gel layer present at the surface of the precipitate. The fluctuations in transverse velocity in this wavy porous gel layer allow an enhanced transport of the cation, so that the effective diffusivity is about one order of magnitude higher than that expected from molecular diffusion alone. Our theoretical predictions are in excellent agreement with our laboratory measurements of the growth of a manganese hydroxide membrane in a microfluidic channel, and this enhanced transport is thought to have been needed to account for the bioenergetics of the first single-celled organisms. PMID- 27486250 TI - Is the learning value of workplace-based assessment being realised? A qualitative study of trainer and trainee perceptions and experiences. AB - PURPOSE: Workplace-based assessments (WBAs) were originally intended to inform learning and development by structuring effective observation-based feedback. The success of this innovation has not yet been established due in part to the widely varied tools, implementation strategies and research approaches. Using a conceptual framework of experience, trajectories and reifications in workplace learning, we aimed to explore trainer and trainee experiences and perceptions of the learning value of WBAs. STUDY DESIGN: Trainers and trainees who had used at least one WBA in the previous year were invited to participate in semistructured interviews for this phenomenological study. We used a template analysis method to explore and compare the experiences of the two groups, using the emergent themes to develop an understanding of the impact of these experiences on perceptions of learning value. RESULTS: Nine trainers and eight trainees participated in the study. Common themes emerged among the two groups around issues of responsibility and engagement along with (mis)understandings of the purpose of the individual tools. Trainer-specific themes emerged related to the concurrent implementation of a new e-portfolio and perceptions of increased workload. Trainees associated WBA with a training structure support value but could not translate experiences into learning values. CONCLUSIONS: WBAs provide trainees with a justified reason to approach trainers for feedback. WBAs, however, are not being reified as the formative assessments originally intended. A culture change may be required to change the focus of WBA research and reconceptualise this set of tools and methods as a workplace learning practice. PMID- 27486251 TI - Dietary non-phytate phosphorus requirement of broilers fed a conventional corn soybean meal diet from 1 to 21 d of age. AB - An experiment was conducted to investigate the effect of dietary non-phytate phosphorus (NPP) level on growth performance, bone characteristics and phosphorus metabolism-related gene expressions, so as to evaluate the dietary NPP requirement of broiler chicks fed a conventional corn-soybean meal diet from 1 to 21 d of age. A total of 540 day-old Arbor Acres male chicks were randomly allocated to one of nine treatments with six replicate cages of 10 birds per cage in a completely randomized design, and fed a basal corn-soybean meal diet (containing 0.08% of NPP) supplemented with 0.10, 0.15, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50% of inorganic phosphorus in the form of CaHPO4.2H2O, respectively. Each diet contained the constant calcium content of about 1.0%. The results showed that daily weight gain, serum inorganic P, tibia bone strength, tibia ash percentage, tibia bone mineral content (BMC) and density (BMD), middle toe ash percentage, middle toe BMC and BMD were affected (P < 0.0001) by dietary NPP level, and increased linearly (P < 0.0001) and quadraticly (P < 0.004) as dietary NPP levels increased. The gene expression of type IIb sodium-phosphate cotransporter (NaPi-IIb) in the duodenum was affected (P < 0.03) and decreased linearly (P < 0.002) as dietary NPP levels increased. Dietary NPP requirements estimated based on fitted broken-line models (P < 0.0001) of the sensitive indices including daily weight gain, tibia bone strength, tibia ash percentage, tibia BMC and BMD as well as middle toe ash percentage were 0.34~0.39%. The results from this study indicate that tibia BMC and BMD might be new, sensitive, and noninvasive criteria to evaluate the dietary NPP requirements of broilers, and the dietary NPP requirement is 0.39% for broiler chicks fed a conventional corn-soybean meal diet from 1 to 21 d of age. PMID- 27486249 TI - Erasure of DNA methylation, genomic imprints, and epimutations in a primordial germ-cell model derived from mouse pluripotent stem cells. AB - The genome-wide depletion of 5-methylcytosines (5meCs) caused by passive dilution through DNA synthesis without daughter strand methylation and active enzymatic processes resulting in replacement of 5meCs with unmethylated cytosines is a hallmark of primordial germ cells (PGCs). Although recent studies have shown that in vitro differentiation of pluripotent stem cells (PSCs) to PGC-like cells (PGCLCs) mimics the in vivo differentiation of epiblast cells to PGCs, how DNA methylation status of PGCLCs resembles the dynamics of 5meC erasure in embryonic PGCs remains controversial. Here, by differential detection of genome-wide 5meC and 5-hydroxymethylcytosine (5hmeC) distributions by deep sequencing, we show that PGCLCs derived from mouse PSCs recapitulated the process of genome-wide DNA demethylation in embryonic PGCs, including significant demethylation of imprint control regions (ICRs) associated with increased mRNA expression of the corresponding imprinted genes. Although 5hmeCs were also significantly diminished in PGCLCs, they retained greater amounts of 5hmeCs than intragonadal PGCs. The genomes of both PGCLCs and PGCs selectively retained both 5meCs and 5hmeCs at a small number of repeat sequences such as GSAT_MM, of which the significant retention of bisulfite-resistant cytosines was corroborated by reanalysis of previously published whole-genome bisulfite sequencing data for intragonadal PGCs. PSCs harboring abnormal hypermethylation at ICRs of the Dlk1-Gtl2-Dio3 imprinting cluster diminished these 5meCs upon differentiation to PGCLCs, resulting in transcriptional reactivation of the Gtl2 gene. These observations support the usefulness of PGCLCs in studying the germline epigenetic erasure including imprinted genes, epimutations, and erasure-resistant loci, which may be involved in transgenerational epigenetic inheritance. PMID- 27486252 TI - Technological quality, mineral profile, and sensory attributes of broiler chicken breasts affected by White Striping and Wooden Breast myopathies. AB - The aim of the research was to study the impact of white striping and wooden breast myopathies on the technological quality, mineral, and sensory profile of poultry meat. With this purpose, a total of 138 breasts were selected for a control group with normal breasts (N), a group of breasts characterised by white striping (WS) myopathy, and a group of breasts having both white striping and wooden breast myopathies (WSWB). Data revealed that the simultaneous presence of the two myopathies, with respect to the WS lesion individually considered, had a further detrimental effect on pH (6.04 vs. 5.96; P < 0.05), yellowness (11.4 vs. 10.3; P < 0.01), cooking losses (30.4 vs. 27.6%; P < 0.05), toughness instrumental values (22.8 vs. 20.0 N; P < 0.01), and perception (6.22 vs. 5.56; P < 0.01). In addition, mineral contents suggest that a defective ions regulation is also present in white striping and wooden breast myopathies. PMID- 27486253 TI - Effects of free-range access on production parameters and meat quality, composition and taste in slow-growing broiler chickens. AB - Demand for meat from free-range broiler chickens is increasing in several countries. Consumers are motivated by better animal welfare and other product attributes such as quality and taste. However, scientific literature is not unanimous about whether free-range access influences quality, composition, and taste of the meat. Because chickens normally do not use free-range areas optimally, it is possible that provision of more suitable shelter will lead to more pronounced differences between chickens raised indoors and outdoors. In this study, an experiment with 2 production rounds of 600 slow-growing broilers each was performed. In each round, 200 chickens were raised indoors (IN), 200 had free range access to grassland with artificial shelter (AS), and 200 had free-range access to short-rotation coppice with willow (SRC). Free-range use, feed intake, and growth were monitored, and after slaughter (d72) meat quality, composition, and taste were assessed. Free-range use was higher in SRC than in AS chickens (42.8 vs. 35.1%, P < 0.001). IN chickens were heavier at d70 than AS and SRC chickens (2.79 vs. 2.66 and 2.68 kg, P = 0.005). However, feed intake and conversion did not differ. Breast meat of chickens with free-range access was darker (P = 0.021) and yellower (P = 0.001) than that of IN chickens. Ultimate pH was lower (5.73 vs. 5.79; P = 0.006) and drip loss higher (1.29 vs. 1.09%; P = 0.05) in IN versus AS chickens. The percentage of polyunsaturated fatty acids was higher in AS than in IN meat (35.84 vs. 34.59%; P = 0.021). The taste panel judged breast meat of SRC chickens to be more tender (P = 0.003) and less fibrous (P = 0.013) compared to that of AS and IN chickens, and juicier compared to the IN chickens (P = 0.017). Overall, free-range access negatively affected slaughter weight, but positively affected meat quality, taste, and composition. Only a few differences between AS and SRC were found, possibly due to limited differences in free-range use. PMID- 27486254 TI - Gluconeogenesis, non-essential amino acid synthesis and substrate partitioning in chicken embryos during later development. AB - We aimed to quantify the rate of gluconeogenesis (GNG), non-essential amino-acid (NEAA) synthesis, and substrate partitioning to the Krebs cycle in embryonic (e) day e14 and e19 chicken embryos. An in ovo continuous tracer infusion approach was employed to test the hypotheses that GNG and NEAA synthesis in developing chicken embryo increases from e14 to e19. [13C6]Glucose or [13C3]glycerol was continuously infused (8 h) into the chorio-allantoic compartment of eggs on e14 and e19. Glucose entry rate, Cori cycling, and GNG were higher (P < 0.05) in e19 compared to e14 embryos, presumably to support higher glycogen deposition in liver and muscle. Whereas de novo synthesis of alanine, aspartate, and glutamate via glycolysis and the Krebs cycle was higher (P < 0.01) in e14 embryos, synthesis of these NEAA from glycerol was higher (P < 0.05) in e19 compared to e14 embryos. These patterns of glucose and glycerol utilization suggest a metabolic shift to conserve glucose for glycogen synthesis and an increased utilization of yolk glycerol (from triacylglyceride) after e14. Although the contribution of glycerol to GNG in e19 embryos was higher (P < 0.05) than that in e14 embryos, the contribution of glycerol to GNG (1.3 to 6.0%) was minor. Based on [13C6]glucose tracer kinetics, the activities of both pyruvate carboxylase (PC) and pyruvate dehydrogenase (PDH) in the liver were higher (P < 0.05) in e19 embryos; whereas the higher (P < 0.01) relative activity of liver PC compared to PDH in e14 embryos suggests a greater anaplerotic flux into the Krebs cycle. In summary, the in ovo continuous tracer infusion approach allowed for a measurement of chicken embryo whole body and liver metabolism over a shorter window of development. This study provided quantitative estimates of the developmental shifts in substrate utilization, GNG, and NEAA synthesis by chicken embryos, as well as qualitative estimates of the activities of enzymes central to the Krebs cycle, glucose, and fatty acid metabolism. PMID- 27486256 TI - Cooled perch effects on performance and well-being traits in caged White Leghorn hens. AB - We assessed the effects of chilled water cooling perches on hen performance and physiological and behavioral parameters under "natural" high temperatures during the 2013 summer with a 4-hour acute heating episode. White Leghorns at 16 wk of age (N = 162) were randomly assigned to 18 cages (n = 9) arranged into 3 units. Each unit was assigned to one of the 3 treatments through 32 wk of age: 1) cooled perches, 2) air perches, and 3) no perches. Chilled water (10 degrees C) was circulated through the cooled perches when cage ambient temperature exceeded 25 degrees C. At the age of 27.6 wk, hens were subjected to a 4-hour acute heating episode of 33.3 degrees C and plasma corticosterone was determined within 2 hours. Egg production was recorded daily. Feed intake and egg and shell quality were measured at 5-week intervals. Feather condition, foot health, adrenal and liver weights, plasma corticosterone, and heat shock protein 70 mRNA were determined at the end of the study at 32 wk of age. The proportion of hens per cage perching, feeding, drinking, panting, and wing spreading was evaluated over one d every 5 wks and on the d of acute heat stress. There were no treatment effects on the measured physiological and production traits except for nail length. Nails were shorter for cooled perch hens than control (P = 0.002) but not air perch hens. Panting and wing spread were observed only on the day of acute heat stress. The onset of both behaviors was delayed for cooled perch hens, and they perched more than air perch hens following acute heat stress (P = 0.001) and at the age 21.4 wk (P = 0.023). Cooled perch hens drank less than control (P = 0.019) but not air perch hens at the age 21.4 wk. These results indicate that thermally cooled perches reduced thermoregulatory behaviors during acute heat stress, but did not affect their performance and physiological parameters under the ambient temperature imposed during this study. PMID- 27486257 TI - Supplemental effects of probiotic Bacillus subtilis fmbJ on growth performance, antioxidant capacity, and meat quality of broiler chickens. AB - This study aimed to investigate the supplemental effects of probiotic Bacillus subtilis fmbJ (BS fmbJ) on growth performance, antioxidant capacity, and meat quality of broiler chickens. A total of 240 day-old male Arbor Acres (AA) broiler chickens were randomly allotted to 4 treatments and raised for 6 wk. Each treatment had 6 replicate pens with ten birds per replicate. Birds in the control group (CON) were fed diets without BS fmbJ and antibiotics. The BS groups were fed the basal diets with BS fmbJ at 2 * 1010 cfu/kg (BS-1 group), BS fmbJ at 3 * 1010 cfu/kg (BS-2 group), BS fmbJ at 4 * 1010 cfu/kg (BS-3 group) without antibiotics for 42 d. In the study, dietary supplementation with BS fmbJ significantly improved (P < 0.05) the average daily gain (ADG), average daily feed intake (ADFI), and feed conversion ratio (FCR) of broilers from 21 to 42 d and 1 to 42 d. At 42 d, the final body weight was increased (P < 0.05) in BS-2 group compared with that in CON. Dietary BS fmbJ significantly increased (P < 0.05) serum IgA and IgG concentrations of broilers after 42 days raising. The glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activity of serum and liver were increased (P < 0.05), and methane dicarboxylic aldehyde (MDA) contents in serum and liver were decreased (P < 0.05) by BS fmbJ added into the broiler diets. Dietary supplementation with BS fmbJ significantly decreased (P < 0.05) reactive oxygen species (ROS) contents in liver mitochondria of broilers. Additionally, the expression of antioxidant enzyme gene including nuclear factor erythroid 2 related factor 2 (Nrf2), heme oxygenase 1 (HO-1), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were improved (P < 0.05) by BS fmbJ added into the broiler diets. Among measuring items of chicken breast meat quality, the drip loss, cooking loss, shear force, L*24 h, a*24 h, b*45 min, and b*24 h values were influenced (P < 0.05) by BS fmbJ provided in the diet. Based on these results, Bacillus subtilis fmbJ could be acted as a beneficial feed additive with antioxidant capacity in broiler diets. PMID- 27486255 TI - ALV-J strain SCAU-HN06 induces innate immune responses in chicken primary monocyte-derived macrophages. AB - Avian leucosis virus subgroup J (ALV-J) can cause lifelong infection and can escape from the host immune defenses in chickens. Since macrophages act as the important defense line against invading pathogens in host innate immunity, we investigated the function and innate immune responses of chicken primary monocyte derived macrophages (MDM) after ALV-J infection in this study. Our results indicated that ALV-J was stably maintained in MDM cells but that the viral growth rate was significantly lower than that in DF-1 cells. We also found that ALV-J infection significantly increased nitric oxide (NO) production, but had no effect on MDM phagocytic capacity. Interestingly, infection with ALV-J rapidly promoted the expression levels of Myxovirus resistance 1 (Mx) (3 h, 6 h), ISG12 (6 h), and interleukin-1beta (IL-1beta) (3 h, 12 h) at an early infection stage, whereas it sharply decreased the expression of Mx (24 h, 36 h), ISG12 (36 h), and made little change on IL-1beta (24 h, 36 h) production at a late infection stage in MDM cells. Moreover, the protein levels of interferon-beta (IFN-beta) and interleukin-6 (IL-6) had sharply increased in infected MDM cells from 3 to 36 h post infection (hpi) of ALV-J. And, the protein level of interleukin-10 (IL-10) was dramatically decreased at 36 hpi in MDM cells infected with ALV-J. These results demonstrate that ALV-J can induce host innate immune responses and we hypothesize that macrophages play an important role in host innate immune attack and ALV-J immune escape. PMID- 27486258 TI - Intermolecular disulfide bond influences unphosphorylated STAT3 dimerization and function. AB - Signal transducer and activator of transcription 3 (STAT3) is a transcription factor activated by the phosphorylation of tyrosine 705 in response to many cytokines and growth factors. Recently, the roles for unphosphorylated STAT3 (U STAT3) have been described in response to cytokine stimulation, in cancers, and in the maintenance of heterochromatin stability. It has been reported that U STAT3 dimerizes, shuttles between the cytoplasm and nucleus, and binds to DNA, thereby driving genes transcription. Although many reports describe the active role of U-STAT3 in oncogenesis in addition to phosphorylated STAT3, the U-STAT3 functional pathway remains elusive.In this report, we describe the molecular mechanism of U-STAT3 dimerization, and we identify the presence of two intermolecular disulfide bridges between Cys367 and Cys542 and Cys418 and Cys426, respectively. Recently, we reported that the same cysteines contribute to the redox regulation of STAT3 signaling pathway both in vitro and in vivo The presence of these disulfides is here demonstrated to largely contribute to the structure and the stability of U-STAT3 dimer as the dimeric form rapidly dissociates upon reduction in the S-S bonds. In particular, the Cys367-Cys542 disulfide bridge is shown to be critical for U-STAT3 DNA-binding activity. Mutation of the two Cys residues completely abolishes the DNA-binding capability of U-STAT3. Spectroscopic investigations confirm that the noncovalent interactions are sufficient for proper folding and dimer formation, but that the interchain disulfide bonds are crucial to preserve the functional dimer. Finally, we propose a reaction scheme of U-STAT3 dimerization with a first common step followed by stabilization through the formation of interchain disulfide bonds. PMID- 27486259 TI - Triggering safer general practice care. PMID- 27486260 TI - Novel folliculin (FLCN) mutation and familial spontaneous pneumothorax. AB - BACKGROUND: Familial spontaneous pneumothorax is one of the characteristics of Birt-Hogg-Dube syndrome (BHDS), which is an autosomal dominant disease caused by the mutation of folliculin (FLCN). AIM: To investigate the mutation of FLCN gene in a familial spontaneous pneumothorax. DESIGN: Prospective case study. METHODS: Clinical and genetic data of a Chinese family with four patients who presented spontaneous pneumothorax in the absence of skin lesions or renal tumors were collected. CT scan of patient's lung was applied for observation of pneumothorax. DNA sequencing of the coding exons (4-14 exons) of FLCN was performed for all 11 members of the family and 100 unrelated healthy controls. RESULTS: CT scan of patient's lung showed spontaneous pneumothorax. A mutation (c. 510C > G) that leads to a premature stop codon (p. Y170X) was found in the proband using DNA sequencing of coding exons (4-14 exons) of FLCN. This mutation was also observed in the other affected members of the family. CONCLUSIONS: A nonsense mutation of FLCN was found in a spontaneous pneumothorax family. Our results expand the mutational spectrum of FLCN in patients with BHDS. PMID- 27486261 TI - 'The old guessing tube': 200 years of the stethoscope. PMID- 27486262 TI - Dementia in the acute hospital: the prevalence and clinical outcomes of acutely unwell patients with dementia. AB - BACKGROUND: Studies have demonstrated that a significant minority of older persons presenting to acute hospital services are cognitively impaired; however, the impact of dementia on long-term outcomes is less clear. AIM: To evaluate the prevalence of dementia, both formally diagnosed and hitherto unrecognised in a cohort of acutely unwell older adults, as well as its impact on both immediate outcomes (length of stay and in-hospital mortality) and 12-month outcomes including readmission, institutionalisation and death. DESIGN: Prospective observational study. METHODS: 190 patients aged 70 years and over, presenting to acute hospital services underwent a detailed health assessment including cognitive assessment (standardised Mini Mental State Examination, AD8 and Confusion Assessment Method for the Intensive Care Unit). Patients or informants were contacted directly 12 months later to compile 1-year outcome data. Dementia was defined as a score of 2 or more on the AD8 screening test. RESULTS: Dementia was present in over one-third of patients (73/190). Of these patients, 36% (26/73) had a prior documented diagnosis of dementia with the remaining undiagnosed before presentation. The composite outcome of death or readmission to hospital within the following 12 months was more likely to occur in patients with dementia (73% (53/73) vs. 58% (68/117), P = 0.043). This finding persisted after controlling for age, gender, frailty status and medical comorbidities, including stroke and heart disease. CONCLUSION: A diagnosis of dementia confers an increased risk of either death or further admission within the following 12 months, highlighting the need for better cognitive screening in the acute setting, as well as targeted intervention such as comprehensive geriatric assessment. PMID- 27486263 TI - Using routine blood test results to predict the risk of death for emergency medical admissions to hospital: an external model validation study. AB - BACKGROUND: The Biochemistry and Haematology Outcome Model (BHOM) relies on the results from routine index blood tests to predict the patient risk of death. We aimed to externally validate the BHOM model. METHOD: We considered all emergency adult medical patients who were discharged from Northern Lincolnshire and Goole (NLAG) hospital in 2014. We compared patient characteristics between NLAG (the validation sample) and the hospital where BHOM was developed. We evaluated the predictive performance, according to discriminative ability (with a concordance statistic, c), and calibration (agreement between observed and predicted risk). RESULT: There were 29 834 emergency discharges of which 24 696 (83%) had complete data. In comparison with the development sample, the NLAG sample was similar in age, blood test results, but experienced a lower mortality (4.7 vs. 8.7%). When applied to NLAG, the BHOM model had good discrimination (c-statistic 0.83 [95% CI 0.823-0.842]). Calibration was good overall, although the BHOM model overpredicted for lowest (<5%, observed = 229, predicted = 286) and highest (>=50%, observed = 31, predicted = 49) risk groups, even after recalibrating for the differences in baseline risk of death. CONCLUSION: Differences in patient case-mix profile and baseline risk of death need to be considered before the BHOM model can be used in another hospital. After re-calibrating for the baseline difference in risk the BHOM model had good discrimination but less adequate calibration. PMID- 27486264 TI - The role of syncytins in human reproduction and reproductive organ cancers. AB - Human life begins with sperm and oocyte fusion. After fertilization, various fusion events occur during human embryogenesis and morphogenesis. For example, the fusion of trophoblastic cells constitutes a key process for normal placental development. Fusion in the placenta is facilitated by syncytin 1 and syncytin 2. These syncytins arose from retroviral sequences that entered the primate genome 25 million and more than 40 million years ago respectively. About 8% of the human genome consists of similar human endogenous retroviral (HERVs) sequences. Many are inactive because of mutations or deletions. However, the role of the few that remain transcriptionally active has not been fully elucidated. Syncytin proteins maintain cell-cell fusogenic activity based on ENV: gene-mediated viral cell entry. In this review, we summarize how syncytins and their receptors are involved in fusion events during human reproduction. The significance of syncytins in tumorigenesis is also discussed. PMID- 27486265 TI - The evolution of the placenta. AB - The very apt definition of a placenta is coined by Mossman, namely apposition or fusion of the fetal membranes to the uterine mucosa for physiological exchange. As such, it is a specialized organ whose purpose is to provide continuing support to the developing young. By this definition, placentas have evolved within every vertebrate class other than birds. They have evolved on multiple occasions, often within quite narrow taxonomic groups. As the placenta and the maternal system associate more intimately, such that the conceptus relies extensively on maternal support, the relationship leads to increased conflict that drives adaptive changes on both sides. The story of vertebrate placentation, therefore, is one of convergent evolution at both the macromolecular and molecular levels. In this short review, we first describe the emergence of placental-like structures in nonmammalian vertebrates and then transition to mammals themselves. We close the review by discussing the mechanisms that might have favored diversity and hence evolution of the morphology and physiology of the placentas of eutherian mammals. PMID- 27486266 TI - Seminal vesicle proteins SVS3 and SVS4 facilitate SVS2 effect on sperm capacitation. AB - Mammalian spermatozoa acquire their fertilizing ability in the female reproductive tract (sperm capacitation). On the other hand, seminal vesicle secretion, which is a major component of seminal plasma, inhibits the initiation of sperm capacitation (capacitation inhibition) and reduces the fertility of the capacitated spermatozoa (decapacitation). There are seven major proteins involved in murine seminal vesicle secretion (SVS1-7), and we have previously shown that SVS2 acts as both a capacitation inhibitor and a decapacitation factor, and is indispensable for in vivo fertilization. However, the effects of SVSs other than SVS2 on the sperm have not been elucidated. Since mouse Svs2-Svs6 genes evolved by gene duplication belong to the same gene family, it is possible that SVSs other than SVS2 also have some effects on sperm capacitation. In this study, we examined the effects of SVS3 and SVS4 on sperm capacitation. Our results showed that both SVS3 and SVS4 are able to bind to spermatozoa, but SVS3 alone showed no effects on sperm capacitation. On the other hand, SVS4 acted as a capacitation inhibitor, although it did not show decapacitation abilities. Interestingly, SVS3 showed an affinity for SVS2 and it facilitated the effects of SVS2. Interaction of SVS2 and spermatozoa is mediated by the ganglioside GM1 in the sperm membrane; however, both SVS3 and SVS4 had weaker affinities for GM1 than SVS2. Therefore, we suggest that separate processes may cause capacitation inhibition and decapacitation, and SVS3 and SVS4 act on sperm capacitation cooperatively with SVS2. PMID- 27486268 TI - BMP2, 4 and 6 and BMPR1B are altered from early stages of bovine cystic ovarian disease development. AB - Cystic ovarian disease (COD) is an important cause of subfertility in dairy cattle. Bone morphogenetic proteins (BMPs), mainly BMP2, BMP4 and BMP6, play a key role in female fertility. In this study, we hypothesized that an altered BMP system is associated with ovarian alterations contributing to COD pathogenesis. Therefore, we examined the expression of BMP2, BMP4 and BMP6 and BMP receptor 1B (BMPR1B) in the ovaries of animals with spontaneous or ACTH-induced COD, as well as during the development of the disease, in a model of follicular persistence induced by low doses of progesterone (at 5, 10 and 15 days of follicular persistence). Results showed changes in BMP2, BMP4 and BMP6 expression during folliculogenesis, in granulosa and theca cells in the COD groups, as well as at different stages of follicular persistence. Results also showed changes in BMPR1B expression in developing follicles in animals with COD, and at the initial stages of follicular persistence (P5). Comparison between groups showed significant differences, mainly in BMP4 and BMP6 expression, in granulosa and theca cells of different follicular categories. The expression of these BMPs also increased in cystic and persistent follicles, in relation to antral follicles of the control group. BMPR1B showed high expression in cystic follicles. Together, these results may indicate an alteration in BMPs, especially in BMP4 and BMP6, as well as in BMPR1B, which occurs early in folliculogenesis and incipiently during the development of COD, which could be a major cause of recurrence of this disease in cattle.Free Spanish abstract: A Spanish translation of this abstract is freely available at http://www.reproduction-online.org/content/early/2016/08/01/REP-15 0315/suppl/DC1. PMID- 27486267 TI - Ectopic POU5F1 in the male germ lineage disrupts differentiation and spermatogenesis in mice. AB - Expression levels of the pluripotency determinant, POU5F1, are tightly regulated to ensure appropriate differentiation during early embryogenesis. POU5F1 is also present in the spermatogonial stem cell/progenitor cell population in mice and it is downregulated as spermatogenesis progresses. To test if POU5F1 downregulation is required for SSCs to differentiate, we produced transgenic mice that ubiquitously express POU5F1 in Cre-expressing lineages. Using a Vasa-Cre driver to produce ectopic POU5F1 in all postnatal germ cells, we found that POU5F1 downregulation was necessary for spermatogonial expansion during the first wave of spermatogenesis and for the production of differentiated spermatogonia capable of undergoing meiosis. In contrast, undifferentiated spermatogonia were maintained throughout adulthood, consistent with a normal presence of POU5F1 in these cells. The results suggest that POU5F1 downregulation in differentiating spermatogonia is a necessary step for the progression of spermatogenesis. Further, the creation of a transgenic mouse model for conditional ectopic expression of POU5F1 may be a useful resource for studies of POU5F1 in other cell lineages, during tumorogenesis and cell fate reprogramming. PMID- 27486270 TI - Endometrial stem cells repair injured endometrium and induce angiogenesis via AKT and ERK pathways. AB - Intrauterine adhesions are common acquired endometrial syndromes secondary to endometrial injury, with limited effective therapies. Recently, several studies have reported that bone marrow stem cells (BMSCs) could repair injured endometrium in animal experiments. However, the role of stem cells in endometrial injury repair and its therapeutic mechanisms remain unclear. Here, we established mouse endometrial injury model and examined the benefit of human endometrial mesenchymal stem cells derived from menstrual blood (MenSCs) in restoration of injured endometrium. Injured endometrium exhibited significantly accelerated restoration at Day 7 after MenSCs transplantation, with increased endometrial thickness and microvessel density. Moreover, the fertility of mice with injured endometrium was improved, with higher conception rate (53.57% vs 14.29%, P = 0.014) and larger embryo number (3.1 +/- 0.6 vs 0.9 +/- 0.7, P = 0.030) in MenSCs group than control group, while no difference was found in undamaged horns between two groups. Conditioned medium from MenSCs (MenSCs-CM) could decrease H2O2-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and promote proliferation, migration and angiogenesis. Angiogenesis effect of MenSCs CM was also confirmed in Matrigel plug assay in mice. Furthermore, we discovered that MenSCs-CM could activate AKT and ERK pathways and induce the overexpression of eNOS, VEGFA, VEGFR1, VEGFR2 and TIE2 in HUVECs, which are critical in MenSCs CM-induced angiogenesis. Angiogenesis induced by MenSCs-CM could be reversed by inhibitors of AKT and/or ERK. Taken together, we concluded that MenSCs could restore injured endometrium and improve the fertility of the endometrial injury mice, which was partially attributed to angiogenesis induced by MenSCs. PMID- 27486269 TI - Rhox13 is required for a quantitatively normal first wave of spermatogenesis in mice. AB - We previously described a novel germ cell-specific X-linked reproductive homeobox gene (Rhox13) that is upregulated at the level of translation in response to retinoic acid (RA) in differentiating spermatogonia and preleptotene spermatocytes. We hypothesize that RHOX13 plays an essential role in male germ cell differentiation, and have tested this by creating a Rhox13 gene knockout (KO) mouse. Rhox13 KO mice are born in expected Mendelian ratios, and adults have slightly reduced testis weights, yet a full complement of spermatogenic cell types. Young KO mice (at ~7-8 weeks of age) have a ~50% reduction in epididymal sperm counts, but numbers increased to WT levels as the mice reach ~17 weeks of age. Histological analysis of testes from juvenile KO mice reveals a number of defects during the first wave of spermatogenesis. These include increased apoptosis, delayed appearance of round spermatids and disruption of the precise stage-specific association of germ cells within the seminiferous tubules. Breeding studies reveal that both young and aged KO males produce normal-sized litters. Taken together, our results indicate that RHOX13 is not essential for mouse fertility in a controlled laboratory setting, but that it is required for optimal development of differentiating germ cells and progression of the first wave of spermatogenesis. PMID- 27486271 TI - Effects of neonatal exposure to a glyphosate-based herbicide on female rat reproduction. AB - In this study, we investigated whether neonatal exposure to a glyphosate-based herbicide (GBH) alters the reproductive performance and the molecular mechanisms involved in the decidualization process in adult rats. Newborn female rats received vehicle or 2 mg/kg/day of a GBH on postnatal days (PND) 1, 3, 5 and 7. On PND90, the rats were mated to evaluate (i) the reproductive performance on gestational day (GD) 19 and (ii) the ovarian steroid levels, uterine morphology, endometrial cell proliferation, apoptosis and cell cycle regulators, and endocrine pathways that regulate uterine decidualization (steroid receptors/COUP TFII/Bmp2/Hoxa10) at the implantation sites (IS) on GD9. The GBH-exposed group showed a significant increase in the number of resorption sites on GD19, associated with an altered decidualization response. In fact, on GD9, the GBH treated rats showed morphological changes at the IS, associated with a decreased expression of estrogen and progesterone receptors, a downregulation of COUP-TFII (Nr2f2) and Bmp2 mRNA and an increased expression of HOXA10 and the proliferation marker Ki67(Mki67) at the IS. We concluded that alterations in endometrial decidualization might be the mechanism of GBH-induced post-implantation embryo loss. PMID- 27486272 TI - Uterine flushing proteome of the tammar wallaby after reactivation from diapause. AB - The marsupial tammar wallaby has the longest period of embryonic diapause of any mammal, up to 11 months, during which there is no cell division or blastocyst growth. Since the blastocyst in diapause is surrounded by acellular coats, the signals that maintain or terminate diapause involve factors that reside in uterine secretions. The nature of such factors remains to be resolved. In this study, uterine flushings (UFs) were used to assess changes in uterine secretions of tammars using liquid chromatography-mass spectrometry (LC-MS/MS) during diapause (day 0 and 3) and reactivation days (d) 4, 5, 6, 8, 9, 11 and 24 after removal of pouch young (RPY), which initiates embryonic development. This study supports earlier suggestions that the presence of specific factors stimulate reactivation, early embryonic growth and cell proliferation. A mitogen, hepatoma derived growth factor and soluble epidermal growth factor receptors were observed from d3 until at least d11 RPY when these secreted proteins constituted 21% of the UF proteome. Binding of these factors to specific cellular receptors or growth factors may directly stimulate DNA synthesis and division in endometrial gland cells. Proteins involved in the p53/CDKN1A (p21) cell cycle inhibition pathway were also observed in the diapause samples. Progesterone and most of the oestrogen-regulated proteins were present in the UF after d3, which is concomitant with the start of blastocyst mitoses at d4. We propose that once the p21 inhibition of the cell cycle is lost, growth factors including HDGF and EGFR are responsible for reactivation of the diapausing blastocyst via the uterine secretions. PMID- 27486273 TI - Getting Older Women Pregnant: Contemporary Thoughts. AB - For women of advanced age with abnormally increased FSH levels, standardized hormonal stimulation often represents a cost-intensive procedure with a low success rate. It is well established now that with mild ovarian stimulation, there is a greater percentage of good-quality eggs (although a smaller number) than with higher-dose conventional stimulation. Mild stimulation protocols reduce the mean number of days of stimulation, the total amount of gonadotropins used and the mean number of oocytes retrieved. The proportion of high-quality and euploid embryos seems to be higher compared with conventional stimulation protocols, and the pregnancy rate per embryo transfer is comparable. Moreover, the reduced costs, the better tolerability for patients and the less time needed to complete an IVF cycle make mild approaches clinically and cost-effective over a given period of time. The low number of embryos available for transfer poses a great challenge in the management of older women going in for IVF. A potential management of these older women is to create a sufficient pool of embryos by accumulating vitrified good-grade embryos over several minimal stimulation and natural cycles. At the end of the accumulation process, these embryos can be subjected to a preimplantation genetic screening using next-generation sequencing and then the pool would have only chromosomal normal embryos with maximal chances of implantation. This would potentially make the chances of success for older women similar to normal responders. This management, however, is unthinkable without an outstanding vitrification program. The option of accumulating embryos has become a promising reality with the advent of vitrification technologies. PMID- 27486274 TI - An Epidemiology Study to Determine the Prevalence and Risk Factors Associated with Recurrent Spontaneous Miscarriage in India. AB - BACKGROUND: The data on the prevalence of recurrent spontaneous miscarriage (RSM) in India are scarce. This study aimed to determine the prevalence of RSM in Indian females. METHODS: Female patients aged between 18 and 45 years with history of at least one spontaneous miscarriage were enrolled in the study. The probability of a subsequent miscarriage after the first, second, and third miscarriage was determined. The prevalence of RSM (defined as loss of >=3 pregnancies of <=20 weeks gestation each) between different age groups was compared using chi (2) test. Binary logistic regression analysis was applied to determine any association between RSM and the presence of risk factors. RESULTS: Of the 2398 patients screened for eligibility, 767 (32 %) had a history of at least one spontaneous miscarriage. The prevalence of RSM among the 753 enrolled patients who satisfied the eligibility criteria in the study was 7.46 %. RSM was mostly recorded in the age group of >=33 years (14.68 %, n = 32). In patients with RSM, the second and third miscarriages were more prevalent during 7th week to end of 11th week of gestation. The probability of having a subsequent miscarriage after the first, second, and third miscarriage was 0.25, 0.34, and 0.22, respectively. There was a significant association (p < 0.05) between RSM and clotting disorders, immunological factors, infections, and genetic disorders. CONCLUSION: The study revealed a higher prevalence of RSM among the Indian women as compared to western data. Age, clotting disorders, immunological factors, infections, and genetic disorders were the significant risk factors associated with RSM. PMID- 27486275 TI - Types and Outcome of Fetal Urinary Anomalies in Low Resource Setting Countries: A Retrospective Study. AB - BACKGROUND: Congenital anomalies of the kidney and urinary tract in the developing countries have a poor prognosis due to limited experience in antenatal and postnatal management. PATIENTS AND METHODS: A 3-year retrospective study was carried out from January 2011 to December 2013. The following data were collected and analyzed: maternal age, gravidity, parity, gestational age at diagnosis, and ultrasonography findings. Final diagnosis after birth, the performed surgeries, follow-up data, as well as survival at one year were also analyzed. RESULTS: The mean age of the included patients was 28 years (range 20-35 years). The mean parity was 1.7 (range 0-4). The mean gestational age at diagnosis was 26 weeks (range 15-36 weeks). Consanguinity was reported in 10 cases (24.4 %). There were 25 males and 16 females. Bilateral renal agenesis was the commonest type (19.5 %). The anomalies of kidneys and urinary tract in our cases were associated with other anomalies in 8 cases (19.5 %). Oligohydramnios was detected in bilateral renal agenesis and posterior urethral valve. Surgical interference during the first 6 months was performed in 6 cases; pyeloplasty for unilateral or bilateral hydronephrosis was performed in 5 cases; and excision of solitary renal cyst performed in one case. By the end of the first year, two of the three cases with chronic renal disease, who were under peritoneal dialysis, died, and three cases who had undergone pyeloplasty were lost to follow-up. CONCLUSION: Among the 41 cases with antenatally diagnosed renal and urinary malformations; bilateral renal agenesis was the commonest anomaly (19.5 %). There were high rates of induction of abortion, IUFD, and neonatal deaths. The poor outcome may be due to lack of experience in performing invasive therapeutic fetal procedures. PMID- 27486276 TI - Pregnancy Outcome in Women with Mechanical Prosthetic Heart Valves Treated with Unfractionated Heparin (UFH) or Enoxaparin. AB - OBJECTIVE: This study was carried out to determine the maternal (including thromboembolic and hemorrhagic complications) and fetal outcomes (including miscarriage, stillbirth, baby death, and live birth) in women with mechanical heart valves managed with therapeutic doses of unfractionated heparin (UFH) versus enoxaparin during pregnancy. METHODS: This is a prospective comparative, nonrandomized study. Pregnant women with mechanical heart valves presenting to high-risk pregnancy unit of Benha University Hospital, Egypt were treated with UFH 15,000 U/12 h versus enoxaparin (Clexane) 1 mg/kg SC/12 h during pregnancy and the results were analyzed. RESULTS: 40 pregnant women were included in the study. In 20 pregnant women, anticoagulation was with UFH, and 20 pregnant women received enoxaparin. One (3 %) thrombotic complication occurred with enoxaparin treatment. Noncompliance or subtherapeutic levels contributed to this outcome in this case. Antenatal hemorrhage occurred in 4 (10 %) and postpartum hemorrhagic complications in 5 (12.5 %) pregnancies. Of the 32 pregnant women who continued after 20 weeks' gestation, 100 % (17/17) of the women taking predominantly UFH had a surviving infant compared with 93 % (14/15) of the women taking primarily enoxaparin (p = 0.25). One intrauterine fetal death occurred in the enoxaparin group. There was no significant difference in the live birth rates between the two groups (p = 0.31). CONCLUSIONS: Compliance with therapeutic dose of UFH during pregnancy in women with mechanical heart valves is associated with a low risk of valve thrombosis and good fetal outcomes, but meticulous monitoring is essential. PMID- 27486277 TI - The Paraoxonase 1 Arylesterase Activity, Total Oxidative Stress, Nitric Oxide and Vitamin C Levels in Maternal Serum, and Their Relation to Birth Weight of Newborn. AB - AIM: Aim of this study is to find out clinical relevance of estimating PON1 arylesterase activity, total oxidative stress (TOS), nitric oxide (NO), and vitamin C levels in maternal serum for prediction of birth weight of newborn. METHODS: We have investigated the PON1 arylesterase activity, TOS, NO, vitamin C, total protein, and albumin levels in 56 postnatal clinic patients having newborn weighing <2500 gm (low birth weight) and compared with 56 postnatal clinic patients having newborn weighing >2500 gm. Samples were collected immediately after delivery. RESULTS: PON1 arylesterase activity levels show significant decrease in cases as compared to controls (93.27 +/- 13.76 kU/l vs. 112.77 +/- 9.42 kU/l). Nitric oxide (nitrate + nitrite) levels are also found to be significantly decreased in cases with respect to controls (22.89 +/- 2.65 umol/l vs. 24.73 +/- 3.80 umol/l). Total oxidative stress is significantly increased in cases than in control subjects (23.34 +/- 2.64 MUmol H2O2 equiv./l vs. +/- 21.43 +/- 2.47 MUmol H2O2 equiv/l). Vitamin C levels are also significantly decreased in cases as compared to controls (1.23 +/- 0.25 mg/dl vs. 1.34 +/- 0.28 mg/dl). Positive correlation between neonatal birth weight and maternal serum PON1 arylesterase activity (r = 0.682, p < 0.05) while negative correlation is obtained between neonatal birth weight and maternal serum oxidative stress (r = 0.478, p < 0.05). Logistic regression analysis is applied for assessing predictive utility which demonstrated a significant association of birth weight with PON1 arylesterase activity (AUC = 0.960, Naglekerke's R (2) = 0.793, p < 0.05). CONCLUSION: Decreased arylesterase activity and antioxidant vitamin C levels with increased total oxidative stress in maternal serum may be considered as the additional risk factors for the development of low birth weight newborn. PMID- 27486278 TI - Gonadotropin Alone is a Better Drug for Ovarian Stimulation than in Combination with Clomiphene in Intrauterine Insemination. AB - OBJECTIVE: This study compares the efficacy of sequential clomiphene citrate (CC) + Gonadotropin to that of Gonadotropin alone with ultrasound monitoring. METHODS: It is a retrospective analytic study done on a total of 100 couples to compare two groups receiving CC + Gonadotropin and Gonadotropin alone for ovarian stimulation followed by intrauterine Insemination (IUI). We studied the cycle performance parameters. Cumulative pregnancy rates and ovulation rates were the primary outcomes. Results were analyzed following the intention-to-treat principle. RESULTS: There were no significant differences with respect to indications and the numbers of dominant follicles recruited. The endometrial thickness was significantly better in Gonadotropin-alone group (P < 0.05). Ovulation rate was better for CC + Gonadotropin at 95.91 %. Nine pregnancies were in the CC + Gonadotropin group (18.36 %) and 17 in Gonadotropin-alone group (33.3 %). CONCLUSIONS: Significant differences in pregnancy rates and endometrial thickness were seen. Gonadotropin alone thus appears to give better results, but CC + Gonadotropin seems to be a cost-effective drug. PMID- 27486279 TI - Role of PET-CT Scan in Gynaeconcology. AB - THE PURPOSE OF THIS STUDY: This study was undertaken to evaluate the role of positron emission tomography-CT (PET-CT) in diagnosis and management of gynecological malignancies in primary and recurrent settings and also to investigate its role in inappropriately treated patients, for pretreatment evaluation (staging) to help in proper therapeutic management. METHOD: This is a retrospective study of 56 patients of gynecological malignancy registered in Gujarat Cancer Research Institute from June 2011 to December 2013. RESULTS: Out of 56 cases where PET was done, the results were as follows: carcinoma cervix-23, carcinoma ovary-20, carcinoma endometrium-9, carcinoma vulva-1, carcinoma vagina 2, and GTN-1. PET scan was negative in 37 % of patients where CT scan was suspicious, which changed the therapeutic modality and prevented further unnecessary interventions. In cases where clinical suspicion of recurrence was high based on rising tumor marker and CT scan was negative, subsequent PET-CT was able to pick up malignancy in 75 % cases. Eleven patients (25 %) with suspected recurrence with inconclusive CT scan and negative PET-CT scan were kept on follow up, thus reducing further morbidity and cost. CONCLUSION: Addition of PET-CT, a noninvasive method to the oncologist's imaging armamentarium may ultimately improve both outcomes and costs by altering management strategies in primary and recurrent settings. The potential use of PET-CT appears promising in several decision-making steps in the management of patients with gynecological malignancy. It defines the extent of metastatic disease which enables the clinician to decide regarding salvageable surgical intervention or palliative measures. PMID- 27486281 TI - Defining the Role of Neoadjuvant Chemotherapy Followed by Surgery in Locally Advanced Cancer Cervix: A Meta-analysis of Phase III Trials. AB - STUDY OBJECTIVES: This meta-analysis was performed to compare the outcomes between NACT-S and RT for locally advanced cancer cervix. The primary end points were survival benefits. SEARCHING METHOD: The data sources for the search included medline, national library of medicine, and the embase search engines. Inclusion criteria included studies published between 2000 and 2012, and FIGO stages IB2 to IVA. Studies had to be properly randomized, prospective, or retrospective and only phase III. Further, the studies had to be with two arms, including one arm for neoadjuvant chemotherapy then-surgery (NACT-S), and the other arm for radiotherapy (RT). RESULTS: Data were collected from 1171 patients enrolled in seven phase III trials. The 5-year PFS (progression-free survival) for NACT-S and RT were 62 and 45.5 %, respectively. The 5-year OS for NACT-S and RT were 66 and 49 %, respectively. NACT-S was associated with better late toxicities compared to RT. CONCLUSION: NACT-S is a reasonable treatment option for locally advanced cancer cervix. It achieved better results than RT, especially for stages from IB2 to IIB. PMID- 27486280 TI - Outcome Analysis of Day-3 Frozen Embryo Transfer v/s Fresh Embryo Transfer in Infertility: A Prospective Therapeutic Study in Indian Scenario. AB - INTRODUCTION: Advanced fertilization techniques like frozen embryo transfer (FET) and assisted reproductive technology have become popular and commonly used methods to treat patients suffering from infertility. Incidences of infertility are on a rise due to increased representation of females in the work place, delay in marriages, stress, and ignorance. METHODS: We performed this prospective therapeutic study to compare FET and fresh embryo transfer in the treatment of infertility in terms of conception rate, patient acceptance, complications, and patient's compliance. A prospective screening therapeutic study on 108 patients, from September 2013 to September 2014 in Karnataka, India, randomized the patients into 2 groups (n = 54), Group-I treated with day-3 FET while Group-II was treated with fresh embryo transfer, after performing ICSI. RESULTS: In 108 patients, 45 % patients were within 35 years of age, 35 % were in the age group 35-39. Significantly, 22 (40.75 %) patients treated with FET conceived (P = 0.022), whereas 16 (29.63 %) patients treated with fresh embryo transfer conceived (P = 0.59). DISCUSSION: There is limited published literature from the subcontinent, comparing techniques like FET and embryo transfers in the treatment of infertility. Awareness and economic reforms must be formulated in India to facilitate individuals facing infertility problems to conceive. CONCLUSION: FET has better and significant conception rates compared to fresh embryo transfers. FET shares an advantage of providing good quality embryos for future and subsequent implantations in cases of failure. Patient counseling and motivation play a pivotal role in the success of therapeutic procedure. PMID- 27486282 TI - Unusual Metastasis from Carcinoma Cervix. AB - INTRODUCTION: Although the incidence of cancer cervix has reduced in India during the last two decades, still most of the patients presenting in tertiary care centers are in advanced stages. MATERIAL AND METHODS: At this center, we see 6% of cancer cervix cases every year, and most of these cases are in stage III and IVa. All these patients have squamous cell carcinoma and were treated with a combination of external and intracavitary radiotherapy along with concurrent cisplatin given once weekly. Eighty-nine point nine % patients had achieved a complete response. RESULTS: Local recurrence was seen in 17.9% at a median duration of 10.5 months, and 8.17% developed distant metastasis involving lung, liver, bone, and supraclavicular lymph nodes. Three patients developed metastasis at unusual sites involving breast, paraspinal muscles, and duodenum which are very rarely involved. These patients were treated with chemotherapy using carboplatin and Paclitaxel combination but succumbed within 8-10 months of development of metastasis. CONCLUSION: The cause of involvement of these unusual sites is not clear, but it may be hematological spread, and we want to share these reports such that these sites are seen during follow-up of patients of cancer cervix. PMID- 27486283 TI - Prognostic Factors in Primary Vaginal Cancer: A Single Institute Experience and Review of Literature. AB - BACKGROUND: Primary vaginal carcinoma is rare, accounting for 1-2 % of all gynecological malignancies. Being rare, most observations are based on retrospective and comparative analyses. This study was aimed to retrospectively analyze the prognostic factors and its relevance in the outcomes of primary vaginal cancers. MATERIALS: Medical records of all cases of primary vaginal cancers, presented to Department of Oncology, from 2004 to 2012, at a tertiary care center in southern India, were retrieved from electronic medical records, and were analyzed. RESULTS: The total number of cases was 32. Median age at presentation was 64.28 years. Squamous histology accounted for 84.4 %, with the rest being adenocarcinoma. Surgery was offered for five (15.6 %), and concurrent chemotherapy for 14 (43.8 %) patients. Three patients had only surgery. All others received radiotherapy. Twenty received external beam radiation (EBRT) and vaginal brachytherapy (VBT); seven only EBRT and two, adjuvant radiation. Five patients had residual disease; two, stage III, and three stage IV. Median follow up was 55.83 months. Twelve patients were alive at last follow-up (37.5 %), while 14 were dead (43.8 %-8 of disease and 6 of other causes). Six patients were lost to follow-up (18.8 %). Twenty patients were disease free. Seven had recurrence, three loco-regional and four distant. Median overall survival (OS) was 86.1 months, disease-free survival (DFS) 90.17 months, and disease-specific survival (DSS) 97.13 months. When well and moderately differentiated tumors were taken together, the 5-year OS, DFS, and DSS rates were, 56.6, 64.3, and 82.3 %. For poorly differentiated tumors, median OS, DFS, and DSS were, 20.9, 14.6, and 20.9 months, with statistically significant advantage for better grade tumors, for DSS (p 0.050). Better 5-year OS, DFS, and DSS rates were observed for stage I + II group, with 54.9, 79.8, and 78.9 %, compared with advanced stage where the same were 54.8, 38.2, and 68.6 % (DFS-p 0.003, DSS-p 0.009). Grade and stage of tumor had statistically significant predictive value over the outcomes, while tumor size showed a significant trend. Patients treated with combination of EBRT and VBT fared well. CONCLUSION: Our study could conclude that grade of differentiation was a significant predictor of poor survival as was stage of disease. Combination of VBT and external beam radiotherapy provides good DFS. PMID- 27486284 TI - Induction Chemotherapy Followed by Concurrent Chemoradiation in the Management of Different Stages of Cervical Carcinoma: 5-year Retrospective Study. AB - AIM: The data of survival for Indian cervical cancer patients treated by indigenous modifications of the protocol are scarce. The objective of this retrospective study was to analyze the efficacy and tolerability in patients of cervical carcinoma treated by neoadjuvant chemotherapy followed by concurrent chemoradiation. MATERIALS AND METHODS: Three hundred and thirty two cases of squamous cell carcinoma of cervix who received 3 cycles of neoadjuvant chemotherapy followed concurrent chemoradiation were retrospectively analyzed for overall survival (OS), disease-free survival (DFS), and local pelvic control rate. RESULTS: The 3-year OS and DFS were 93.7 % for stage I-B, 88.0 and 84.0 % for stage II-A, 82.8 and 79.7 % for stage II-B, 70.0 and 64.9 % for stage III-A, 59.3 and 52.4 % for stage III-B, and 53.6 and 32.1 % for stage IV-A disease. The 5-year OS and DFS rates were 93.7 and 87.5 % for stage I-B, 84.0 % for Stage II A, 79.7 and 76.6 % for stage II-B, 67.6 and 59.5 % for stage III-A, 48.4 and 41.9 % for stage III-B, and 28.6 and 14.3 % for stage IV-A disease. CONCLUSION: Neoadjuvant chemotherapy followed by concurrent chemoradiation is feasible and produces impressive disease-free and overall survival. This protocol is especially helpful for busy cancer centers with long waiting lists on radiotherapy machines. PMID- 27486285 TI - Risks and Benefits of Total Laparoscopic Hysterectomy and the Effect of Learning Curve on Them. AB - STUDY OBJECTIVE: The objective of this study was to prospectively analyze the risks and benefits of total laparoscopic hysterectomy (TLH) compared with total abdominal hysterectomy (TAH) and the effects of learning curve on them over 4 years (March 2010-April 2014). DESIGN: It was a prospective randomized study. SETTING: The study was conducted in Delhi government hospital which had no staff with previous experience of advanced laparoscopic surgeries. PATIENTS: Two hundred fifty patients were operated on for benign gynecological conditions (35 65 years). The numbers of cases operated laparoscopically were as follows-22 in 2010, 25 in 2011, 32 in 2012, and 46 in 2013. Equal number. of patients operated by open surgery were taken in the study during the same time period. RESULTS: Two hundred fifty cases were operated since March 2010, by either laparoscopic or open surgery. Incidence of major complications was-1.6 % for TLH compared to 4 % in TAH. After the first year of surgery, this incidence has fallen to 0 % in subsequent years in TLH group. The incidence of minor complications declined from 14 to 4.5 % in the third year of study. Total rate of conversion to laparotomy was 9.7 %, which again had a significant decline after the first year. TLH also clearly showed superior benefits of less intraoperative blood loss, early postoperative ambulance, and shorter period of hospital stay in comparison with TAH. CONCLUSION: The study has led us to conclude that TLH is a safe, effective, and reproducible technique after the completion of a period of training necessary to standardize the procedure. This approach must be established in our real, day to-day clinical practice. PMID- 27486287 TI - Pulseless Disease in Pregnancy: A Rare Case. PMID- 27486286 TI - Pros and Cons of Adding of Neoadjuvant Chemotherapy to Standard Concurrent Chemoradiotherapy in Cervical Cancer: A Regional Cancer Center Experience. AB - BACKGROUND: The present study summarizes the results of treatment in the form of disease-free survival and overall survival in bulky stage IB2 and locally advanced (stages II-IVA) squamous cell carcinoma of the uterine cervix. The treatment has been given in the form of NACT followed by CCRT in one arm and CCRT in the other arm. MATERIALS AND METHODS: This retrospective study analyzed 713 cervical cancer patients who were treated at our center during 2007 and 2008; out of 713 patients, data of 612 patients have been compared. The patients' data were analyzed retrospectively. Patients had undergone PF 28.6 %, TPF 21.5 %, and only CCRT 49.9 %. Majority of patients were in the age group 41-50 years, while stage wise, mainly stage IIIb and IIb. Disease-free survival was observed on the basis of stage and NACT. The survival analyses were performed using the Kaplan-Meier method. All statistical calculations were done with SPSS Statistics version 20.0. RESULTS: For cancer cervix NACT versus CCRT, the DFS rate was at 5 years (58.3 vs. 41.8 % p = 0.001). NACT followed by CCRT demonstrated significantly superior DFS as compared to definitive CCRT, respectively, TPF (hazard ratio (HR) = 0.248, 95 % confidence interval (CI) 0.123-0.500; p < 0.001), PF (HR = 0.445, 95 % CI 0.266-0.722; p = 0.002). The results of univariate stage, age, and multivariate study show that stage hemoglobin level, interval between external-intracavitary radiation, and type of neoadjuvant chemotherapy were the factors affected survival cervical patients treated with radiation. The grade 3/4 hematologic toxicities were more in the NACT group than CCRT (p < 0.001) while the non hematological toxicity was not significant; the TPF group experienced more toxicity than PF (p = 0.029). This treatment regimen is feasible as evidenced by the acceptable toxicity of NACT and by the high compliance to radiotherapy. The grade 3/4 hematologic toxicities were more in NACT groups than CCRT (p < 0.001); the TPF group experienced more toxicity than PF (p = 0.029). CONCLUSION: TPF/PF as NACT is feasible and produces impressive responses in cancer cervix. PMID- 27486288 TI - Malignant Melanoma of Vagina: A Report and Review of Literature. PMID- 27486289 TI - Clinical outcomes and prognostic factors depending on implant design in the treatment of proximal humeral fractures: A retrospective study. AB - PURPOSE: We aimed to examine the clinical outcomes of proximal humeral fractures treated with different intramedullary nail shapes. METHODS: Thirty-seven patients were divided into two groups depending on the implant shape. We also defined F group as a subgroup of fracture classification. RESULTS: In the F group, the flexion of the shoulder joint was significantly greater in S (mean, 134.6 degrees ) than in C groups (mean, 109 degrees ) (p = 0.04). The complication rate was significantly larger in the C group (p = 0.04). CONCLUSIONS: Patients with one kind of fracture and who were treated with straight nails had better outcomes. PMID- 27486290 TI - Toxin yet not toxic: Botulinum toxin in dentistry. AB - Paracelsus contrasted poisons from nonpoisons, stating that "All things are poisons, and there is nothing that is harmless; the dose alone decides that something is a poison". Living organisms, such as plants, animals, and microorganisms, constitute a huge source of pharmaceutically useful medicines and toxins. Depending on their source, toxins can be categorized as phytotoxins, mycotoxins, or zootoxins, which include venoms and bacterial toxins. Any toxin can be harmful or beneficial. Within the last 100 years, the perception of botulinum neurotoxin (BTX) has evolved from that of a poison to a versatile clinical agent with various uses. BTX plays a key role in the management of many orofacial and dental disorders. Its indications are rapidly expanding, with ongoing trials for further applications. However, despite its clinical use, what BTX specifically does in each condition is still not clear. The main aim of this review is to describe some of the unclear aspects of this potentially useful agent, with a focus on the current research in dentistry. PMID- 27486291 TI - Association between anterior alveolar dimensions and vertical facial pattern among Saudi adults. AB - OBJECTIVE: To establish the anterior alveolar dimensions among a sample of Saudi subjects with different vertical facial heights. MATERIALS AND METHODS: Lateral cephalometric radiographs of 63 Saudi subjects (30 males and 33 females) were included in this retrospective study. The sample was divided into high angle (SN MP ? 39 degrees ), low angle (SN-MP ? 28 degrees ) and average angle (30 degrees < SN-MP < 37 degrees ) groups. The anteroposterior and vertical dimensions of the alveolus surrounding the root apex of upper and lower incisors were calculated. RESULTS: The anterior alveolar dimensions exhibited significant differences (p < 0.05) between the different vertical facial height groups. The males and females demonstrated significant differences (p < 0.05) in the anterior alveolar dimensions for the same vertical jaw relationship. CONCLUSIONS: Both gender and the vertical jaw relationship can be factors for different height and thickness of the anterior alveolus. Clinicians must be aware of differences in the anterior alveolar dimensions for safe and sound orthodontic tooth movement. PMID- 27486292 TI - Neurogenic tumors and tumor-like lesions of the oral and maxillofacial region: A clinicopathological study. AB - OBJECTIVE: Oral and maxillofacial lesions of neural origin are rare soft tissue neoplasms. The aim of the present study is to review the epidemiological data of oral and maxillofacial neurogenic lesions submitted for diagnosis to our laboratory over a 31-year period (August 1984-March 2015). MATERIALS AND METHODS: The available formalin-fixed embedded specimens, Hematoxylin and Eosin slides, demographic and clinical data were retrieved. RESULTS: Thirty-one cases were included in this study, representing 0.6% of the 5161 biopsies submitted. Most of the diagnosed cases 11 (35.5%) were traumatic neuromas. The other cases included 2 (6.5%) solitary circumscribed neuromas, 2 (6.5%) melanotic neuroectodermal tumors of infancy, 2 (6.5%) Schwannomas, 5 (16.1%) granular cell tumors, and 9 (29%) neurofibromas. The patients' ages ranged from 5 months to 78 years. Among these cases, 16 were males (51.61%) and 15 were females (48.38%). CONCLUSION: This analysis showed that neural lesions affecting the oral and maxillofacial region were rare and mostly benign in nature. Such lesions should be carefully diagnosed because of their association with life-threatening syndromes and the possibility of malignant transformation. PMID- 27486293 TI - A randomized control trial comparing the visual and verbal communication methods for reducing fear and anxiety during tooth extraction. AB - PURPOSE: To evaluate the value of using the visual information for reducing the level of dental fear and anxiety in patients undergoing teeth extraction under LA. METHODS: A total of 64 patients were indiscriminately allotted to solitary of the study groups following reading the information sheet and signing the formal consent. If patient was in the control group, only verbal information and routine warnings were provided. If patient was in the study group, tooth extraction video was showed. The level of dental fear and anxiety was detailed by the patients on customary 100 mm visual analog scales (VAS), with "no dental fear and anxiety" (0 mm) and "severe dental distress and unease" (100 mm). Evaluation of dental apprehension and fretfulness was made pre-operatively, following visual/verbal information and post-extraction. RESULTS: There was a substantial variance among the mean dental fear and anxiety scores for both groups post-extraction (p-value < 0.05). Patients in tooth extraction video group were more comfortable after dental extraction than verbal information and routine warning group. For tooth extraction video group there were major decreases in dental distress and anxiety scores between the pre-operative and either post video information scores or postoperative scores (p-values < 0.05). Younger patients recorded higher dental fear and anxiety scores than older ones (P < 0.05). CONCLUSION: Dental fear and anxiety associated with dental extractions under local anesthesia can be reduced by showing a tooth extraction video to the patients preoperatively. PMID- 27486294 TI - A 22 year comparison survey of dental knowledge in Al-Jubail antenatal clinic population. AB - OBJECTIVE: To analyze and compare dental knowledge between two generations of pregnant women attending the same antenatal clinic in Al-Jubail, Saudi Arabia. METHODS: A cross sectional self administered questionnaire was conducted among 252 pregnant women in three different antenatal clinics. Data were analyzed using SPSS (v. 21), p value <0.05 was considered statistically significant. RESULTS: Most surveyed women were knowledgeable about dental health issues, although a large percentage did not visit dental clinics regularly during pregnancy. Results showed a decline in dental knowledge, compared with data collected 22 years ago. Pregnant women participating in the current survey had more dental problems and underwent more dental procedures than did those participating in the previous survey. CONCLUSIONS: Results of this study show a decline in dental knowledge and oral health in pregnant women of the current generation, compared with those of the previous generation. Antenatal clinics should educate pregnant women more about the relationship between good oral and fetal health. PMID- 27486295 TI - Experimentation and correlates of electronic nicotine delivery system (electronic cigarettes) among university students - A cross sectional study. AB - OBJECTIVE: E-cigarettes are becoming popular among youth as safe nicotine delivery systems. Many have expressed concern, however, that e-cigarettes may serve as a gateway to future smoking, given their low perceived risk, or that their use may prevent regular smokers from quitting by maintaining their nicotine addiction. The aim of this study was to assess experimentation with and correlates of e-cigarette use among university students. MATERIAL AND METHODS: A cross-sectional study was carried out among 480 university students from four faculties at a university in Riyadh in August-October 2014. A modified version of the World Health Organization's Global Adult Tobacco Survey was used, and multinomial logistic regression was carried out to assess correlations with e cigarette variables in the whole study sample and among smokers. RESULTS: Almost all students, including the majority of ex-smokers (96.3%) and smokers (94.4%), reported having heard about e-cigarettes. In addition, about one-quarter of the sample (54.2% of smokers, 24.7% of ex-smokers, 6% of never smokers) had experimented with e-cigarettes at least once during their lifetime. Curiosity and peer influence were reported as the main reasons for the use of e-cigarettes. Factors found to be correlated significantly with e-cigarette use were male gender, being a traditional cigarette smoker, having friends who have tried e cigarettes, and having a strong belief that e-cigarettes could aid smoking cessation. CONCLUSION: E-cigarettes are popular among Saudi youth, especially among smokers and ex-smokers. Well-designed health education programs and regulatory interventions are required to address this issue. PMID- 27486297 TI - Notes on the Statistical Power of the Binary State Speciation and Extinction (BiSSE) Model. AB - The Binary State Speciation and Extinction (BiSSE) method is one of the most popular tools for investigating the rates of diversification and character evolution. Yet, based on previous simulation studies, it is commonly held that the BiSSE method requires phylogenetic trees of fairly large sample sizes (>300 taxa) in order to distinguish between the different models of speciation, extinction, or transition rate asymmetry. Here, the power of the BiSSE method is reevaluated by simulating trees of both small and large sample sizes (30, 60, 90, and 300 taxa) under various asymmetry models and root state assumptions. Results show that the power of the BiSSE method can be much higher, also in trees of small sample size, for detecting differences in speciation rate asymmetry than anticipated earlier. This, however, is not a consequence of any conceptual or mathematical flaw in the method per se but rather of assumptions about the character state at the root of the simulated trees and thus the underlying macroevolutionary model, which led to biased results and conclusions in earlier power assessments. As such, these earlier simulation studies used to determine the power of BiSSE were not incorrect but biased, leading to an overestimation of type-II statistical error for detecting differences in speciation rate but not for extinction and transition rates. PMID- 27486296 TI - The range of diagnoses for oral soft-tissue biopsies of geriatric patients in a Saudi Arabian teaching hospital. AB - INTRODUCTION: The increased life expectancy being observed worldwide necessitates careful planning for future geriatric oral health care needs, which should be based on epidemiologic surveys to identify these needs. We aimed to survey the range of lesions diagnosed in soft-tissue biopsies of patients over age 60 over a 30-year period in a Saudi Arabian teaching hospital. METHODS: The histopathology records of geriatric patients with complete demographic data who were diagnosed between 1984 and 2013 at the College of Dentistry, King Saud University, were reviewed. The lesions were then classified into eight broad categories. Associations between variables were evaluated using Pearson's Chi square test. RESULTS: There were 231 soft-tissue biopsies obtained from geriatric patients whose complete records were available. The male to female ratio was 1.1:1, and the mean age was 66.7 years. Most lesions (69%) occurred in patents aged 60-69 years. Although reactive lesions were generally the most common, the most common lesions were squamous cell carcinoma and fibroma. Lesions were most commonly located on the buccal mucosa and the alveolar ridge/gingivae. CONCLUSIONS: The range of lesions seen in Saudi geriatric patients were similar to those reported for other parts of the world, although the lesions were more similar to those reported from developing countries. The very high rate of oral cancer, however, is expected to take the majority of the resources allocated to geriatric oral health care, except if a strong, population-based prevention program is initiated immediately. PMID- 27486298 TI - Normalized lmQCM: An Algorithm for Detecting Weak Quasi-Cliques in Weighted Graph with Applications in Gene Co-Expression Module Discovery in Cancers. AB - In this paper, we present a new approach for mining weighted networks to identify densely connected modules such as quasi-cliques. Quasi-cliques are densely connected subnetworks in a network. Detecting quasi-cliques is an important topic in data mining, with applications such as social network study and biomedicine. Our approach has two major improvements upon previous work. The first is the use of local maximum edges to initialize the search in order to avoid excessive overlaps among the modules, thereby greatly reducing the computing time. The second is the inclusion of a weight normalization procedure to enable discovery of "subtle" modules with more balanced sizes. We carried out careful tests on multiple parameters and settings using two large cancer datasets. This approach allowed us to identify a large number of gene modules enriched in both biological functions and chromosomal bands in cancer data, suggesting potential roles of copy number variations (CNVs) involved in the cancer development. We then tested the genes in selected modules with enriched chromosomal bands using The Cancer Genome Atlas data, and the results strongly support our hypothesis that the coexpression in these modules are associated with CNVs. While gene coexpression network analyses have been widely adopted in disease studies, most of them focus on the functional relationships of coexpressed genes. The relationship between coexpression gene modules and CNVs are much less investigated despite the potential advantage that we can infer from such relationship without genotyping data. Our new approach thus provides a means to carry out deep mining of the gene coexpression network to obtain both functional and genetic information from the expression data. PMID- 27486299 TI - Pathway-Informed Classification System (PICS) for Cancer Analysis Using Gene Expression Data. AB - We introduce Pathway-Informed Classification System (PICS) for classifying cancers based on tumor sample gene expression levels. PICS is a computational method capable of expeditiously elucidating both known and novel biological pathway involvement specific to various cancers and uses that learned pathway information to separate patients into distinct classes. The method clearly separates a pan-cancer dataset by tissue of origin and also sub-classifies individual cancer datasets into distinct survival classes. Gene expression values are collapsed into pathway scores that reveal which biological activities are most useful for clustering cancer cohorts into subtypes. Variants of the method allow it to be used on datasets that do and do not contain noncancerous samples. Activity levels of all types of pathways, broadly grouped into metabolic, cellular processes and signaling, and immune system, are useful for separating the pan-cancer cohort. In the clustering of specific cancer types, certain pathway types become more valuable depending on the site being studied. For lung cancer, signaling pathways dominate; for pancreatic cancer, signaling and metabolic pathways dominate; and for melanoma, immune system pathways are the most useful. This work suggests the utility of pathway-level genomic analysis and points in the direction of using pathway classification for predicting the efficacy and side effects of drugs and radiation. PMID- 27486300 TI - Recursive Partitioning Method on Competing Risk Outcomes. AB - In some cancer clinical studies, researchers have interests to explore the risk factors associated with competing risk outcomes such as recurrence-free survival. We develop a novel recursive partitioning framework on competing risk data for both prognostic and predictive model constructions. We define specific splitting rules, pruning algorithm, and final tree selection algorithm for the competing risk tree models. This methodology is quite flexible that it can corporate both semiparametric method using Cox proportional hazards model and parametric competing risk model. Both prognostic and predictive tree models are developed to adjust for potential confounding factors. Extensive simulations show that our methods have well-controlled type I error and robust power performance. Finally, we apply both Cox proportional hazards model and flexible parametric model for prognostic tree development on a retrospective clinical study on oropharyngeal cancer patients. PMID- 27486301 TI - Transzonular vitreous injection vs a single drop compounded topical pharmaceutical regimen after cataract surgery. AB - PURPOSE: To compare the relative effectiveness of a Tri-Moxi-Vanc intraocular solution injected transzonularly into the vitreous with the topical formulation of Pred-Moxi-Ketor (given for the first week postoperatively) followed by Pred Ketor (given for weeks 2-4 after surgery). PATIENTS AND METHODS: This was a single-site, single-surgeon, prospective, randomized, subject-masked contralateral eye study with an active comparator and was approved by an appropriate ethics committee. Twenty-five subjects with uncomplicated cataract who were scheduled for cataract surgery were enrolled. If surgery was uneventful, subjects received either an injection in that eye or followed a minimum drop postoperative pharmaceutical regimen. The second eye surgery was performed with the opposite treatment. Subjects were followed for 1 month. Measures of interest were the changes in intraocular pressure (IOP) from baseline and the changes in corneal and macular thickness. Subjects were also asked to evaluate pain perception, visual quality, and overall satisfaction with surgery. They were also asked which regimen they preferred. RESULTS: IOP was not statistically significantly different between the groups (P=0.81); there was also no statistically significant difference in IOP over time (P=0.74). There was no statistically significant difference in central macular thickness at 1 week and 1 month between the groups (P=0.18). The central corneal thickness was significantly greater 1 day postoperatively relative to baseline, but there was no statistically significant difference between the groups at any time point (P=0.92). The difference in reported pain was also not statistically significantly different between the groups (P=0.67). Satisfaction with surgery was similar for both groups, but significantly more subjects preferred the injection for overall experience (P<0.01). CONCLUSION: Cataract surgery completed with the two pharmaceutical regimens was similar in outcome. Significantly more subjects preferred the injection, presumably as a function of the greater convenience with no apparent difference in the therapeutic effect. PMID- 27486302 TI - Optical coherence tomography parameters predictive of visual outcome after anti VEGF therapy for retinal vein occlusion. AB - PURPOSE: To determine the optical coherence tomography (OCT) parameters that are predictive of visual outcome after anti-VEGF therapy for a retinal vein occlusion (RVO). METHODS: Fifty-seven eyes with macular edema (ME) secondary to a central or branch RVO treated with bevacizumab or ranibizumab were studied. Spectral domain OCT and microperimetry were performed before, 1, 3, and 6 months after the treatment and at the final visit. Central retinal thickness (CRT), macular volume (MV), integrity of the external limiting membrane (ELM), ellipsoid zone (EZ), and foveal bulge (FB), and photoreceptor outer segment (PROS) length were determined. RESULTS: The mean follow-up period was 17.8+/-11.5 months. In 46 of the 57 eyes, a resolution of the ME was achieved. The pretreatment CRT and MV, presence of intact ELM, EZ, and FB, and PROS length at the time of ME resolution were significantly correlated with the best-corrected visual acuity and retinal sensitivity at the final visit (P<0.050). Multiple regression analyses showed that the pretreatment MV had the highest correlation with the posttreatment best corrected visual acuity and retinal sensitivity (P<0.050). CONCLUSION: The CRT, MV, ELM, EZ, FB, and PROS length are predictive factors for the visual outcome after anti-VEGF therapy for RVO. PMID- 27486303 TI - Inter-eye comparison of retinal oximetry and vessel caliber between eyes with asymmetrical glaucoma severity in different glaucoma subtypes. AB - BACKGROUND: To compare retinal vessel oxygenation and vessel caliber in primary angle-closure glaucoma (PACG), primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), and normal controls, as well as between eyes of asymmetrical glaucoma severity. METHODS: This was a prospective, cross-sectional study. The 159 subjects (PACG, n=39; POAG, n=41; NTG, n=41; normal controls, n=38) underwent retinal oxygen saturation measurements using the Oxymap T1 Retinal Oximeter, optical coherence tomography, and Humphrey visual field testing. Retinal oxygen saturation and vessel diameter were compared between the glaucoma groups and normal controls, as well as between eyes of asymmetrical glaucoma severity. Kruskal-Wallis test was performed for comparison among different subtypes of glaucoma. Wilcoxon signed-rank test was used to compare the inter-eye differences. RESULTS: Compared to normal controls, arteriolar oxygen saturation was increased in PACG eyes (P=0.048) but not in POAG or NTG eyes. There were no significant differences in oxygen saturation in venules or arteriovenous (AV) difference in all three glaucoma groups. Venular diameter was significantly reduced in all glaucoma groups compared to normal controls (P<0.001), but no such change was observed in arteriolar diameter (P=0.10). When comparing between eyes of asymmetrical glaucoma severity, arteriolar oxygen saturation (P=0.03) and AV difference (P=0.04) were significantly higher, while arteriolar diameter was significantly lower (P=0.001) in the worse eye in PACG group. There were no significant differences in oximetric parameters or vessel calibers between the worse and the better eyes in POAG and NTG groups. CONCLUSION: Eyes with PACG showed increased arteriolar oxygen saturation and increased AV difference. This was not observed in POAG and NTG eyes. Arteriolar diameter in PACG and venular diameter in all three glaucoma groups were reduced. The difference observed in PACG eyes may be due to an increased metabolic demand in the disease process compared to open-angle glaucoma. PMID- 27486304 TI - Endothelial Nitric Oxide Synthase (-786T>C) and Endothelin-1 (5665G>T) Gene Polymorphisms as Vascular Dysfunction Risk Factors in Sickle Cell Anemia. AB - Sickle cell anemia (SCA) patients have vascular complications, and polymorphisms in endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) genes were associated with ET-1 and nitric oxide disturbance. We investigate the association of ET-1 5665G>T and eNOS -786T>C polymorphisms with soluble adhesion molecules (sVCAM-1 and sICAM-1), biochemical markers, and medical history. We studied 101 SCA patients; carriers of eNOS minor allele (C) had the highest levels of sVCAM 1, and carriers of ET-1 minor allele had more occurrence of acute chest syndrome (ACS). The multivariate analysis suggested the influence of the ET-1 gene on ACS outcome and an association of the eNOS gene with upper respiratory tract infection. We suggest that eNOS and ET-1 gene polymorphisms can influence SCA pathophysiology and that eNOS variant in SCA patients might be important to nitric oxide activity and vascular alteration. We found an association of the ET 1 minor allele in ACS, showing the importance of genetic screening in SCA. PMID- 27486305 TI - Sitagliptin/metformin fixed-dose combination in type 2 diabetes mellitus: an evidence-based review of its place in therapy. AB - Type 2 diabetes mellitus is a progressive disease associated with significant morbidity and mortality. There is good evidence showing that intensive glycemic control reduces the development and progression of complications. In order to achieve glycemic targets, patients often require a combination of oral therapy and/or insulin in addition to lifestyle modification. Unfortunately, many of the traditional therapies for type 2 diabetes are associated with weight gain and hypoglycemia, resulting in poor compliance and subsequent worsening of glycemic control. The dipeptidyl peptidase-4 inhibitor sitagliptin is a therapy for type 2 diabetes and is available as a fixed-dose combination with metformin. Phase III clinical trials have demonstrated beneficial effects on glycemic control and minimal untoward effects with this combination. In this article, we provide an overview of the pharmacology, efficacy, and safety and examine the role of this combination within current practice. PMID- 27486307 TI - Rational design and synthesis of novel diphenyl ether derivatives as antitubercular agents. AB - A series of triclosan mimic diphenyl ether derivatives have been synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The binding mode of the compounds at the active site of enoyl acyl carrier protein reductase of M. tuberculosis has been explored. Among them, compound 10b was found to possess antitubercular activity (minimum inhibitory concentration =12.5 ug/mL) comparable to triclosan. All the synthesized compounds exhibited low levels of cytotoxicity against Vero and HepG2 cell lines, and three compounds 10a, 10b, and 10c had a selectivity index more than 10. Compound 10b was also evaluated for log P, pKa, human liver microsomal stability, and % protein binding, in order to probe its druglikeness. Based on the antitubercular activity and druglikeness profile, it may be concluded that compound 10b could be a lead for future development of antitubercular drugs. PMID- 27486306 TI - Galeterone for the treatment of advanced prostate cancer: the evidence to date. AB - Major advances have been achieved recently in the treatment of metastatic castration-resistant prostate cancer, resulting in significant improvements in quality of life and survival with the use of several new agents, including the next-generation androgen receptor (AR)-targeted drugs abiraterone and enzalutamide. However, virtually all patients will eventually progress on these therapies and most will ultimately die of treatment-refractory metastatic disease. Recently, several mechanisms of resistance to AR-directed therapies have been uncovered, including the AR splice variant 7 (AR-V7), which is a ligand independent constitutionally-active form of the AR that has been associated with poor outcomes to abiraterone and enzalutamide. Galeterone, a potent anti-androgen with three modes of action (CYP17 lyase inhibition, AR antagonism, and AR degradation), is a novel agent under clinical development that could potentially target both full-length AR and aberrant AR, including AR-V7. In this manuscript, we will first discuss the biological mechanisms of action of galeterone and then review the safety and efficacy data from Phase I and II clinical studies of galeterone in patients with metastatic castration-resistant prostate cancer. A Phase III study of galeterone (compared against enzalutamide) in AR-V7-positive patients is currently underway, and represents the first pivotal trial using a biomarker-selection design in this disease. PMID- 27486308 TI - SPOCK1 promotes tumor growth and metastasis in human prostate cancer. AB - Prostate cancer is the most diagnosed noncutaneous cancer and ranks as the second leading cause of cancer-related deaths in American males. Metastasis is the primary cause of prostate cancer mortality. Survival rate is only 28% for metastatic patients, but is nearly 100% for patients with localized prostate cancers. Molecular mechanisms that underlie this malignancy remain obscure, and this study investigated the role of SPARC/osteonectin, cwcv, and kazal-like domain proteoglycan 1 (SPOCK1) in prostate cancer progression. Initially, we found that SPOCK1 expression was significantly higher in prostate cancer tissues relative to noncancerous tissues. In particular, SPOCK1 expression was also markedly high in metastatic tissues compared with nonmetastatic cancerous tissues. SPOCK1 expression knockdown by specific short hairpin RNA in PC3 cells was significantly inhibited, whereas SPOCK1 overexpression in RWPE-1 cells promoted cell viability, colony formation in vitro, and tumor growth in vivo. Moreover, the SPOCK1 knockdown in PC3 cells was associated with cell cycle arrest in G0/G1 phase, while the SPOCK1 overexpression in RWPE-1 cells induced cell cycle arrest in S phase. The SPOCK1 knockdown in PC3 cells even increased cell apoptosis. SPOCK1 modulation was also observed to affect cancerous cell proliferation and apoptotic processes in the mouse model of prostate cancer. Additionally, the SPOCK1 knockdown decreased, whereas the SPOCK1 overexpression increased cell migration and invasion abilities in vitro. Injection of SPOCK1 depleted PC3 cells significantly decreased metastatic nodules in mouse lungs. These findings suggest that SPOCK1 is a critical mediator of tumor growth and metastasis in prostate cancer. PMID- 27486309 TI - Prediction of selective estrogen receptor beta agonist using open data and machine learning approach. AB - BACKGROUND: Estrogen receptors (ERs) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. ERs have been validated as important drug targets for the treatment of various diseases, including breast cancer, ovarian cancer, osteoporosis, and cardiovascular disease. ERs have two subtypes, ER-alpha and ER-beta. Emerging data suggest that the development of subtype-selective ligands that specifically target ER-beta could be a more optimal approach to elicit beneficial estrogen like activities and reduce side effects. METHODS: Herein, we focused on ER-beta and developed its in silico quantitative structure-activity relationship models using machine learning (ML) methods. RESULTS: The chemical structures and ER-beta bioactivity data were extracted from public chemogenomics databases. Four types of popular fingerprint generation methods including MACCS fingerprint, PubChem fingerprint, 2D atom pairs, and Chemistry Development Kit extended fingerprint were used as descriptors. Four ML methods including Naive Bayesian classifier, k nearest neighbor, random forest, and support vector machine were used to train the models. The range of classification accuracies was 77.10% to 88.34%, and the range of area under the ROC (receiver operating characteristic) curve values was 0.8151 to 0.9475, evaluated by the 5-fold cross-validation. Comparison analysis suggests that both the random forest and the support vector machine are superior for the classification of selective ER-beta agonists. Chemistry Development Kit extended fingerprints and MACCS fingerprint performed better in structural representation between active and inactive agonists. CONCLUSION: These results demonstrate that combining the fingerprint and ML approaches leads to robust ER beta agonist prediction models, which are potentially applicable to the identification of selective ER-beta agonists. PMID- 27486310 TI - Voiding dysfunction in patients with nasal congestion treated with pseudoephedrine: a prospective study. AB - BACKGROUND: Pseudoephedrine is a sympathomimetic drug widely used as a nasal decongestant. However, it can cause adverse effects, such as voiding dysfunction. The risk of voiding dysfunction remains uncertain in patients without subjective voiding problems. METHODOLOGY: We prospectively enrolled patients with nasal congestion who required treatment with pseudoephedrine from May to August 2015. All patients denied concomitant subjective voiding problem. The International Prostate Symptom Score (IPSS) questionnaire was used to evaluate voiding function before and 1 week after the pseudoephedrine treatment. The results of the IPSS questionnaire were analyzed as the total (IPSS-T), voiding (IPSS-V), storage (IPSS-S), and quality of life due to urinary symptom scores. RESULTS: We enrolled 131 males with a mean age of 42.0+/-14.3 years. The IPSS-T, IPSS-V, and IPSS-S scores slightly increased after the medication (IPSS-T increased from 6.49 to 6.77, IPSS-V from 3.33 to 3.53, and IPSS-S from 3.17 to 3.24). The quality of life due to urinary symptom score nonsignificantly decreased from 2.02 to 1.87. We observed that older age and a higher premedication IPSS-V score yielded significant differences (P<0.05) for subclinical voiding dysfunction and unchanged voiding function. In patients aged >=50 years, the IPSS-T, IPSS-V, and IPSS-S scores significantly increased after the pseudoephedrine treatment (IPSS-T increased from 9.95 to 11.45, IPSS-V from 5.38 to 6.07, and IPSS-S 4.57 to 5.38), whereas the quality of life due to urinary symptom score nonsignificantly decreased from 2.71 to 2.48 (P=0.057). In patients aged <50 years, all scores did not significantly differ. CONCLUSION: Pseudoephedrine treatment for nasal congestion requires extra precautions in males >50 years, even without subjective voiding symptoms. PMID- 27486311 TI - Simultaneous surgery in patients with both cardiac and noncardiac diseases. AB - BACKGROUND: To investigate the possibility and feasibility of simultaneous cardiac and noncardiac surgery. METHODS: From August 2000 to March 2015, 64 patients suffering from cardiac and noncardiac diseases have been treated by simultaneous surgeries. RESULTS: Two patients died after operations in hospital; thus, the hospital mortality rate was 3.1%. One patient with coronary heart disease, acute myocardial infarction, and a recurrence of bladder cancer accepted emergency simultaneous coronary artery bypass grafting (CABG), bladder cystectomy, and ureterostomy. He died of acute cerebral infarction complicated with multiple organ failure on the 153rd day after operation. The other patient with chronic constrictive pericarditis and right lung cancer underwent pericardial stripping and right lung lower lobectomy, which resulted in multiple organ failure, and the patient died on the tenth day postoperatively. The remaining 62 patients recovered and were discharged. The total operative morbidity was 17.2%: postoperative hemorrhage (n, % [1, 1.6%]), pulmonary infection and hypoxemia (2, 3.1%), hemorrhage of upper digestive tract (1, 1.6%), incisional infection (3, 4.7%), subphrenic abscess (1, 1.6%), and postoperative acute renal failure and hemofiltration (3, 4.7%). Of the 62 patients discharged, 61 patients were followed up. Eleven patients died with 10 months to 10 years during the follow-up. The mean survival time is 116.2+/-12.4 months. The cumulative survival rate is 50.8%. CONCLUSION: Simultaneous surgeries in patients suffering from both cardiac and noncardiac benign or malignant diseases are safe and possible with satisfactory short-term and long-term survival. PMID- 27486312 TI - Cardiovascular risk prediction: a comparative study of Framingham and quantum neural network based approach. AB - PURPOSE: Currently cardiovascular diseases (CVDs) are the main cause of death worldwide. Disease risk estimates can be used as prognostic information and support for treating CVDs. The commonly used Framingham risk score (FRS) for CVD prediction is outdated for the modern population, so FRS may not be accurate enough. In this paper, a novel CVD prediction system based on machine learning is proposed. METHODS: This study has been conducted with the data of 689 patients showing symptoms of CVD. Furthermore, the dataset of 5,209 CVD patients of the famous Framingham study has been used for validation purposes. Each patient's parameters have been analyzed by physicians in order to make a diagnosis. The proposed system uses the quantum neural network for machine learning. This system learns and recognizes the pattern of CVD. The proposed system has been experimentally evaluated and compared with FRS. RESULTS: During testing, patients' data in combination with the doctors' diagnosis (predictions) are used for evaluation and validation. The proposed system achieved 98.57% accuracy in predicting the CVD risk. The CVD risk predictions by the proposed system, using the dataset of the Framingham study, confirmed the potential risk of death, deaths which actually occurred and had been recorded as due to myocardial infarction and coronary heart disease in the dataset of the Framingham study. The accuracy of the proposed system is significantly higher than FRS and other existing approaches. CONCLUSION: The proposed system will serve as an excellent tool for a medical practitioner in predicting the risk of CVD. This system will be serving as an aid to medical practitioners for planning better medication and treatment strategies. An early diagnosis may be effectively made by using this system. An overall accuracy of 98.57% has been achieved in predicting the risk level. The accuracy is considerably higher compared to the other existing approaches. Thus, this system must be used instead of the well-known FRS. PMID- 27486313 TI - A role of ZnO nanoparticle electrostatic properties in cancer cell cytotoxicity. AB - ZnO nanoparticles (NPs) have previously been shown to exhibit selective cytotoxicity against certain types of cancerous cells suggesting their potential use in biomedical applications. In this study, we investigate the effect of surface modification of ZnO NPs on their cytotoxicity to both cancerous and primary T cells. Our results show that polyacrylic acid capping produces negatively charged ZnO NPs that are significantly more toxic compared to uncapped positively charged NPs of identical size and composition. In contrast, the greatest selectivity against cancerous cells relative to normal cells is observed with cationic NPs. In addition, differences in NP cytotoxicity inversely correlate with NP hydrodynamic size, propensity for aggregation, and dissolution profiles. The generation of reactive oxygen species (ROS) was also observed in the toxicity mechanism with anionic NPs generating higher levels of mitochondrial superoxide without appreciably affecting glutathione levels. Additional experiments evaluated the combined effects of charged ZnO NPs and nontoxic cationic or anionic CeO2 NPs. Results show that the CeO2 NPs offer protective effects against cytotoxicity from anionic ZnO NPs via antioxidant properties. Altogether, study data indicate that surface modification of NPs and resulting changes in their surface charge affect the level of intracellular ROS production, which can be ameliorated by the CeO2 ROS scavenger, suggesting that ROS generation is a dominant mechanism of ZnO NP cytotoxicity. These findings demonstrate the importance of surface electrostatic properties for controlling NP toxicity and illustrate an approach for engineering NPs with desired properties for potential use in biological applications. PMID- 27486314 TI - Phylogenetic and Structural Analysis of the Pluripotency Factor Sex-Determining Region Y box2 Gene of Camelus dromedarius (cSox2). AB - Although the sequencing information of Sox2 cDNA for many mammalian is available, the Sox2 cDNA of Camelus dromedaries has not yet been characterized. The objective of this study was to sequence and characterize Sox2 cDNA from the brain of C. dromedarius (also known as Arabian camel). A full coding sequence of the Sox2 gene from the brain of C. dromedarius was amplified by reverse transcription PCRjmc and then sequenced using the 3730XL series platform Sequencer (Applied Biosystem) for the first time. The cDNA sequence displayed an open reading frame of 822 nucleotides, encoding a protein of 273 amino acids. The molecular weight and the isoelectric point of the translated protein were calculated as 29.825 kDa and 10.11, respectively, using bioinformatics analysis. The predicted cSox2 protein sequence exhibited high identity: 99% for Homo sapiens, Mus musculus, Bos taurus, and Vicugna pacos; 98% for Sus scrofa and 93% for Camelus ferus. A 3D structure was built based on the available crystal structure of the HMG-box domain of human stem cell transcription factor Sox2 (PDB: 2 LE4) with 81 residues and predicting bioinformatics software for 273 amino acid residues. The comparison confirms the presence of the HMG-box domain in the cSox2 protein. The orthologous phylogenetic analysis showed that the Sox2 isoform from C. dromedarius was grouped with humans, alpacas, cattle, and pigs. We believe that this genetic and structural information will be a helpful source for the annotation. Furthermore, Sox2 is one of the transcription factors that contributes to the generation-induced pluripotent stem cells (iPSCs), which in turn will probably help generate camel induced pluripotent stem cells (CiPSCs). PMID- 27486315 TI - Daily home gardening improved survival for older people with mobility limitations: an 11-year follow-up study in Taiwan. AB - AIMS: To test the hypothesis that gardening is beneficial for survival after taking time-dependent comorbidities, mobility, and depression into account in a longitudinal middle-aged (50-64 years) and older (>=65 years) cohort in Taiwan. METHODS: The cohort contained 5,058 nationally sampled adults >=50 years old from the Taiwan Longitudinal Study on Aging (1996-2007). Gardening was defined as growing flowers, gardening, or cultivating potted plants for pleasure with five different frequencies. We calculated hazard ratios for the mortality risks of gardening and adjusted the analysis for socioeconomic status, health behaviors and conditions, depression, mobility limitations, and comorbidities. Survival models also examined time-dependent effects and risks in each stratum contingent upon baseline mobility and depression. Sensitivity analyses used imputation methods for missing values. RESULTS: Daily home gardening was associated with a high survival rate (hazard ratio: 0.82; 95% confidence interval: 0.71-0.94). The benefits were robust for those with mobility limitations, but without depression at baseline (hazard ratio: 0.64, 95% confidence interval: 0.48-0.87) when adjusted for time-dependent comorbidities, mobility limitations, and depression. Chronic or relapsed depression weakened the protection of gardening. For those without mobility limitations and not depressed at baseline, gardening had no effect. Sensitivity analyses using different imputation methods yielded similar results and corroborated the hypothesis. CONCLUSION: Daily gardening for pleasure was associated with reduced mortality for Taiwanese >50 years old with mobility limitations but without depression. PMID- 27486316 TI - Predicting Gleason score using the initial serum total prostate-specific antigen in Black men with symptomatic prostate adenocarcinoma in Nigeria. AB - BACKGROUND: Men of Black African descent are known to have the highest incidence of prostate cancer. The disease is also more aggressive in this group possibly due to biologically more aggressive tumor or late presentation. Currently, serum prostate-specific antigen (PSA) assay plays a significant role in making the diagnosis of prostate cancer. However, the obtained value of serum PSA may not directly relate with the Gleason score (GS), a measure of tumor aggression in prostate cancer. This study explores the relationship between serum total PSA at presentation (iPSA) and GS. PATIENTS AND METHODS: The iPSA of patients with histologically confirmed prostate cancer was compared with the obtained GS of the prostate biopsy specimens. The age of the patients at presentation and the prostate volumes were also analyzed with respect to the iPSA and GS. The data were analyzed retrospectively using IBM SPSS Version 20. Pearson correlation was used for numeric variables, whereas Fisher's exact test was used for categorical variables. Significance was set at P<=0.05. RESULTS: There were 205 patients from January 2010 to November 2013 who satisfied the inclusion criteria. iPSA as well as age at presentation and prostate volume were not found to significantly correlate with the primary Gleason grade, the secondary Gleason grade, or the GS. However, the presence of distant metastasis was identified to significantly correlate positively with GS. CONCLUSION: GS may not be confidently predicted by the iPSA. Higher iPSA does not correlate with higher GS and vice versa. PMID- 27486317 TI - Colorectal cancer development and advances in screening. AB - Most colon tumors develop via a multistep process involving a series of histological, morphological, and genetic changes that accumulate over time. This has allowed for screening and detection of early-stage precancerous polyps before they become cancerous in individuals at average risk for colorectal cancer (CRC), which may lead to substantial decreases in the incidence of CRC. Despite the known benefits of early screening, CRC remains the second leading cause of cancer related deaths in the United States. Hence, it is important for health care providers to have an understanding of the risk factors for CRC and various stages of disease development in order to recommend appropriate screening strategies. This article provides an overview of the histological/molecular changes that characterize the development of CRC. It describes the available CRC screening methods and their advantages and limitations and highlights the stages of CRC development in which each screening method is most effective. PMID- 27486318 TI - Effects of biomass smoke on pulmonary functions: a case control study. AB - BACKGROUND: Biomass smoke is the leading cause of COPD in developing countries such as Turkey. In rural areas of Turkey, females are more exposed to biomass smoke because of traditional lifestyles. AIM: The aim of this study was to determine the adverse effects of biomass smoke on pulmonary functions and define the relationship between duration in years and an index (cumulative exposure index) with altered pulmonary function test results. PARTICIPANTS AND METHODS: A total of 115 females who lived in the village of Kagizman (a borough of Kars located in the eastern part of Turkey) and were exposed to biomass smoke were included in the study. The control group was generated with 73 individuals living in the same area who were never exposed to biomass smoke. RESULTS: Twenty-seven (23.8%) females in the study group and four (5.5%) in the control group had small airway disease (P=0.038). Twenty-two (19.1%) females in the study group and ten (13.7%) in the control group had obstruction (P=0.223). Twenty (17.3%) females in the study group who were exposed to biomass smoke had restriction compared with ten (13%) in the control group (P=0.189). The duration needed for the existence of small airway disease was 16 years, for obstructive airway disease was 17 years, and for restrictive airway disease was 17 years. The intensity of biomass smoke was defined in terms of cumulative exposure index; it was calculated by multiplying hours per day, weeks per month, and total years of smoke exposure and dividing the result by three. CONCLUSION: Exposure to biomass smoke is a serious public health problem, especially in rural areas of developing countries, because of its negative effects on pulmonary functions. As the duration and the intensity of exposure increase, the probability of having altered pulmonary function test results is higher. PMID- 27486319 TI - Increased cutaneous wound healing effect of biodegradable liposomes containing madecassoside: preparation optimization, in vitro dermal permeation, and in vivo bioevaluation. AB - Madecassoside (MA) is highly potent in treating skin disorders such as wounds and psoriasis. However, the topical wound healing effect of MA was hampered by its poor membrane permeability. In order to overcome this shortcoming, MA liposomes were designed and prepared by a double-emulsion method to enhance transdermal and wound healing effects. In this study, response surface methodology was adopted to yield the optimal preparation conditions of MA double-emulsion liposomes with average particle size of 151 nm and encapsulation efficiency of 70.14%. Moreover, MA double-emulsion liposomes demonstrated superior stability and homogeneous appearance in 5 months; their leakage rate was <12% even at 37 degrees C and <5% at 4 degrees C within 1 month. In vitro skin permeation, skin distribution, and burn wound healing of MA liposomal formulations were conducted for the first time to evaluate MA delivery efficiency and wound healing effect. The transdermal property and wound cure effect of MA double-emulsion liposomes were superior to those of MA film dispersion liposomes, and both the methods were endowed with an excellent performance by polyethylene glycol modification. In conclusion, double emulsion liposome formulation was an applicable and promising pharmaceutical preparation for enhancing MA delivery toward wound healing effect and improving wound-healing progress. PMID- 27486320 TI - Cerium oxide nanoparticles inhibit the migration and proliferation of gastric cancer by increasing DHX15 expression. AB - Gastric cancer is one of the leading causes of tumor-related deaths in the world. Current treatment options do not satisfy doctors and patients, and new therapies are therefore needed. Cerium oxide nanoparticles (CNPs) have been studied as a potential therapeutic approach for treating many diseases. However, their effects on human gastric cancer are currently unknown. Therefore, in this study, we aimed to characterize the effects of CNPs on human gastric cancer cell lines (MKN28 and BGC823). Gastric cancer cells were cocultured with different concentrations of CNPs, and proliferation and migration were measured both in vitro and in vivo. We found that CNPs inhibited the migration of gastric cancer cells when applied at different concentrations, but only a relatively high concentration (10 ug/mL) of CNPs suppressed proliferation. Furthermore, we found that CNPs increased the expression of DHX15 and its downstream signaling pathways. We therefore provide evidence showing that CNPs may be a promising approach to suppress malignant activity of gastric cancer by increasing the expression of DHX15. PMID- 27486322 TI - Synthesis, characterization, and efficacy of antituberculosis isoniazid zinc aluminum-layered double hydroxide based nanocomposites. AB - The chemotherapy for tuberculosis (TB) is complicated by its long-term treatment, its frequent drug dosing, and the adverse effects of anti-TB drugs. In this study, we have developed two nanocomposites (A and B) by intercalating the anti TB drug isoniazid (INH) into Zn/Al-layered double hydroxides. The average size of the nanocomposites was found to be164 nm. The efficacy of the Zn/Al-layered double hydroxides intercalated INH against Mycobacterium tuberculosis was increased by approximately three times more than free INH. The nanocomposites were also found to be active against Gram-positive and -negative bacteria. Compared to the free INH, the nanodelivery formulation was determined to be three times more biocompatible with human normal lung fibroblast MRC-5 cells and 3T3 fibroblast cells at a very high concentration of 50 ug/mL for up to 72 hours. The in vitro release of INH from the Zn/Al-layered double hydroxides was found to be sustained in human body-simulated buffer solutions of pH 4.8 and 7.4. This research is a step forward in making the TB chemotherapy patient friendly. PMID- 27486321 TI - Remote magnetic targeting of iron oxide nanoparticles for cardiovascular diagnosis and therapeutic drug delivery: where are we now? AB - Magnetic resonance imaging (MRI) allows for an accurate assessment of both functional and structural cardiac parameters, and thereby appropriate diagnosis and validation of cardiovascular diseases. The diagnostic yield of cardiovascular MRI examinations is often increased by the use of contrast agents that are almost exclusively based on gadolinium compounds. Another clinically approved contrast medium is composed of superparamagnetic iron oxide nanoparticles (IONs). These particles may expand the field of contrast-enhanced cardiovascular MRI as recently shown in clinical studies focusing on acute myocardial infarction (AMI) and atherosclerosis. Furthermore, IONs open up new research opportunities such as remote magnetic drug targeting (MDT). The approach of MDT relies on the coupling of bioactive molecules and magnetic nanoparticles to form an injectable complex. This complex, in turn, can be attracted to and retained at a desired target inside the body with the help of applied magnetic fields. In comparison to common systemic drug applications, MDT techniques promise both higher concentrations at the target site and lower concentrations elsewhere in the body. Moreover, concurrent or subsequent MRI can be used for noninvasive monitoring of drug distribution and successful delivery to the desired organ in vivo. This review does not only illustrate the basic conceptual and biophysical principles of IONs, but also focuses on new research activities and achievements in the cardiovascular field, mainly in the management of AMI. Based on the presentation of successful MDT applications in preclinical models of AMI, novel approaches and the translational potential of MDT are discussed. PMID- 27486323 TI - Annonaceous acetogenins nanosuspensions stabilized by PCL-PEG block polymer: significantly improved antitumor efficacy. AB - Annonaceous acetogenins (ACGs) have shown superior antitumor activity against a variety of cancer cell lines, but their clinical application has been limited by their poor solubility. In this study, ACGs-nanosuspensions (NSps) were successfully prepared by a precipitation ultrasonic method using monomethoxypoly (ethylene glycol)2000-poly (epsilon-caprolactone)2000 (mPEG2000-PCL2000) as a stabilizer. The resultant ACGs-NSps had a mean particle size of 123.2 nm, a zeta potential of -20.17 mV, and a high drug payload of 73.68%. ACGs-NSps were quite stable in various physiological solutions, and they exhibited sustained drug release. Compared to free drug, ACGs-NSps exhibited stronger cytotoxicity against 4T1, MCF-7, and HeLa cells. An in vivo real-time biodistribution investigation after labeling with 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide, a noninvasive near-infrared fluorescence probe, demonstrated that ACGs-NSps could effectively accumulate in tumor. An in vivo antitumor activity study in 4T1 tumor bearing mice revealed that ACGs-NSps achieved much better therapeutic efficacy than the traditional dosage form (oil solution) even at 1/10 of the dose (74.83% vs 45.53%, P<0.05), demonstrating that NSp was a good dosage form for ACGs to treat cancer. PMID- 27486324 TI - Controlled release hydrogen sulfide delivery system based on mesoporous silica nanoparticles protects graft endothelium from ischemia-reperfusion injury. AB - Hydrogen sulfide (H2S) functions as a protective gas transmitter in various physiological and pathological processes, but the lack of ideal donors severely hampers the clinical application of H2S. This study aims to construct a controlled release H2S donor and evaluate its protective effect on graft endothelium. Mesoporous silica nanoparticles (MSNs) were synthesized using the sol-gel method and loaded with diallyl trisulfide (DATS), an H2S-releasing agent named DATS-MSN. In vitro experiments showed that DATS-MSN could alleviate endothelial cell inflammation and enhance endothelial cell proliferation and migration. In vivo experiments demonstrated that the apoptosis of graft endothelium was mitigated in the presence of DATS-MSN. Our results indicated that DATS-MSN, releasing H2S in a controlled release fashion, could serve as an ideal H2S donor. PMID- 27486325 TI - A clinician's guide to recurrent isolated sleep paralysis. AB - This review summarizes the empirical and clinical literature on sleep paralysis most relevant to practitioners. During episodes of sleep paralysis, the sufferer awakens to rapid eye movement sleep-based atonia combined with conscious awareness. This is usually a frightening event often accompanied by vivid, waking dreams (ie, hallucinations). When sleep paralysis occurs independently of narcolepsy and other medical conditions, it is termed "isolated" sleep paralysis. Although the more specific diagnostic syndrome of "recurrent isolated sleep paralysis" is a recognized sleep-wake disorder, it is not widely known to nonsleep specialists. This is likely due to the unusual nature of the condition, patient reluctance to disclose episodes for fear of embarrassment, and a lack of training during medical residencies and graduate education. In fact, a growing literature base has accrued on the prevalence, risk factors, and clinical impact of this condition, and a number of assessment instruments are currently available in both self-report and interview formats. After discussing these and providing suggestions for accurate diagnosis, differential diagnosis, and patient selection, the available treatment options are discussed. These consist of both pharmacological and psychotherapeutic interventions which, although promising, require more empirical support and larger, well-controlled trials. PMID- 27486326 TI - Parenting, identity development, internalizing symptoms, and alcohol use: a cross sectional study in a group of Italian adolescents. AB - BACKGROUND: Literature has demonstrated the adaptive function of identity development and parenting toward manifestation of problem behaviors in adolescence. These dimensions act on both internalizing and externalizing symptoms. METHODS: The objective is to investigate the relationship between identity status, parenting, and adolescent problems, which may manifest through internalized (phobias, obsessions, depression, eating disorders, entropy) and externalized modes (alcohol use and school discomfort). The research involved 198 Italian students (104 males and 94 females) in the 4th year (mean =16.94 years, standard deviation =0.35) and 5th year (mean =17.94 years, standard deviation =0.43) of senior secondary schools, who live in Caltanissetta, a town located in Sicily, Italy. The research lasted for 1 school year. The general group consisted of 225 students with a mortality rate of 12%. They completed an anamnestic questionnaire to provide 1) basic information, 2) alcohol consumption attitude in the past 30 days, and 3) their beliefs about alcohol; the "Ego Identity Process Questionnaire" to investigate identity development; the "Parental Bonding Instrument" to measure the perception of parenting during childhood; and the "Constraints of Mind" to value the presence of internalizing symptoms. RESULTS: Data show that identity status influences alcohol consumption. Low-profile identity and excessive maternal control affect the relational dependence and the tendency to perfectionism in adolescents. Among the predictors of alcohol use, there are socioeconomic status, parental control, and the presence of internalizing symptoms. CONCLUSION: Family is the favored context of learning beliefs, patterns, and values that affect the broader regulatory social environment, and for this reason, it is considered the privileged context on which to intervene to reduce the adolescents' behavior problems. This deviance could be an external manifestation of the difficulty in management of internalizing symptoms in adolescence. PMID- 27486327 TI - Association of brain-derived neurotrophic factor and nerve growth factor gene polymorphisms with susceptibility to migraine. AB - Migraine is one of the most common neurological diseases worldwide. Migraine pathophysiology is very complex. Genetic factors play a major role in migraine. Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), play an important role in central nervous system functioning, development, and modulation of pain. This study investigates whether polymorphisms in the BDNF and NGF genes are associated with migraine disease in a Turkish case-control population. Overall, 576 subjects were investigated (288 patients with migraine and 288 healthy controls) for the following polymorphisms: rs6265(G/A), rs8192466(C/T), rs925946(G/T), rs2049046(A/T), and rs12273363(T/C) in the BDNF gene, and rs6330(C/T), rs11466112(C/T), rs11102930(C/A), and rs4839435(G/A) in the NGF gene using 5'-exonuclease allelic discrimination assays. We found no differences in frequency of the analyzed eight polymorphisms between migraine and control groups. However, the frequency of minor A alleles of rs6265 in BDNF gene was borderline significant in the patients compared with the healthy controls (P=0.049; odds ratios [ORs] [95% confidence intervals {CIs}] =0.723 [0.523-0.999]). Moreover, when the migraine patients were divided into two subgroups, migraine with aura (MA) and migraine without aura (MO), the minor TT genotype of rs6330 in NGF was significantly higher in MA patients than in MO patients (P=0.036) or healthy controls (P=0.026), and this disappeared after correction for multiple testing. Also, the rs6330*T minor allele was more common in the MA group than in the MO group or controls (P=0.011, ORs [95% CIs] =1.626 [1.117-2.365] or P=0.007, ORs [95% CIs] =1.610 [1.140-2.274], respectively). In conclusion, this is the first clinical study to evaluate the association between BDNF and NGF polymorphisms in migraine patients compared with health controls. Our findings suggest that the NGF rs6330*T minor allele might be nominated as a risk factor for developing aura in migraine disease. Our results should be considered as preliminary, and they need to be confirmed by future studies. PMID- 27486328 TI - An overview of the effect of sodium glucose cotransporter 2 inhibitor monotherapy on glycemic and other clinical laboratory parameters in type 2 diabetes patients. AB - OBJECTIVES: We aimed to determine the effect of sodium glucose cotransporter 2 (SGLT2) inhibitor monotherapy on glycemic and other clinical laboratory parameters versus other antidiabetic medications or placebo therapy in patients with type 2 diabetes mellitus. In addition, we aimed to investigate the risk of diabetic ketoacidosis associated with SGLT2 inhibitor therapy and evaluate its weight-sparing ability. DESIGN: Meta-analysis. MATERIALS AND METHODS: PubMed and MEDLINE were searched to identify eligible studies up to December 2015. Randomized controlled trials that assessed the efficacy and safety of SGLT2 inhibitor monotherapy versus placebo therapy or active control were considered. The Cochrane Collaboration Risk of Bias Tool was used to evaluate quality and bias. The mean difference was used to evaluate the glycemic and other clinical laboratory parameters for SGLT2 inhibitor intervention versus control by drugs or placebo. Similarly, the risk ratio was used to assess adverse events, and the I (2) was used to evaluate heterogeneity. RESULTS: SGLT2 inhibitors significantly decreased glycated hemoglobin (HbA1c) (P<0.001), weight (P<0.001), and the low density lipoprotein/high-density lipoprotein ratio (P=0.03) compared with placebo therapy. No statistically significant changes were found in fasting plasma glucose, 2-hour postprandial glucose, or lipid parameters. Significant changes in the uric acid level were found for SGLT2 inhibitors versus placebo therapy (P=0.005) or active control (P<0.001). Although no significant change in levels of ketones occurred (P=0.93), patients receiving SGLT2 inhibitors were at greater risk of increased ketone bodies. Events suggestive of urinary tract infection and pollakiuria presented the greatest risk for patients receiving SGLT2 inhibitors versus active control or placebo therapy. CONCLUSION: SGLT2 inhibitors significantly decreased HbA1c, body weight, and the low-density lipoprotein/high density lipoprotein ratio and were found to be safe and well tolerated in type 2 diabetes mellitus patients. Further randomized control trials are required to establish their risk for ketoacidosis. PMID- 27486330 TI - Prevalence and perception of smoking habits among the Palestinian population in the Gaza Strip. AB - BACKGROUND: The Gaza Strip is a densely populated place with ~2 million inhabitants in an area of 365 km(2). The aim of this study was to determine the smoking prevalence in the Gaza Strip and to identify the perception of the Palestinian population on smoking. METHOD: A cross-sectional study was conducted in the Gaza Strip, Palestinian territories, during the period from June to September 2014. Convenient sampling method was adopted. A structured pretested questionnaire was used. RESULTS: A total of 600 adults aged 15 years or older completed the questionnaires with a response rate of 83.3%. The prevalence rate of smoking was 26.3%, with a significantly higher rate among males (31%) than females (6.9%) (P<0.001). The mean starting age was 17.4+/-3.9 years. The study revealed that influence of friends is the major reason for initiation of smoking and the most influential factor in convincing smokers to quit was the family. Smokers' knowledge about smoking risks motivates them to try stop smoking (64.9%) or desire to stop smoking (65.2%). CONCLUSION: The study revealed that tobacco use is significantly prevalent in the Gaza Strip. The author recommends rapid antismoking campaigns with stress on the family role and massive intervention programs to encourage young people to change their behavior toward smoking. PMID- 27486329 TI - Biomarkers and the prediction of atrial fibrillation: state of the art. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, and it places a substantial burden on the health care system. Despite improvements in our understanding of AF pathophysiology, we have yet to develop targeted preventive therapies. Recently, numerous biological markers have been identified to aid in the prediction of future AF events. Subclinical markers of atrial stress, inflammation, endothelial dysfunction, kidney dysfunction, and atherosclerosis have been linked to AF. The connection between these markers and AF is the identification of subclinical states in which AF propagation is likely to occur, as these conditions are associated with abnormal atrial remodeling and fibrosis. Additionally, several risk scores have been developed to aid in the identification of at-risk patients. The practicing clinician should be aware of these subclinical markers, as several of these markers improve the predictive abilities of current AF risk scores. Knowledge of these subclinical markers also provides clinicians with a better understanding of AF risk factors, and the opportunity to reduce the occurrence of AF by incorporating well-known cardiovascular disease risk factor modification strategies. In this review, we highlight several novel biological markers that have improved our understanding of AF pathophysiology and appraise the utility of these markers to improve our ability to predict future AF events. PMID- 27486331 TI - Clinical study on the influence of motion and other factors on stereotactic radiotherapy in the treatment of adrenal gland tumor. AB - BACKGROUND: The aim of this study was to investigate the adrenal tumor motion law and influence factors in the treatment of adrenal gland tumor and provide a reference value basis for determining the planning target volume margins for therapy. MATERIALS AND METHODS: The subjects considered in this study were 38 adrenal tumor patients treated with CyberKnife with the placement of 45 gold fiducials. Fiducials were implanted into each adrenal tumor using beta-ultrasonic guidance. Motion amplitudes of gold fiducials were measured with a Philips SLS simulator and motion data in the left-right, anterior-posterior, and cranio caudal directions were obtained. Multiple linear regression models were used to analyze influencing factors. t-Test was used for motion amplitude comparison of different tumor locations along the z-axis. RESULTS: The motion distances were 0.1-0.4 cm (0.27+/-0.07 cm), 0.1-0.5 cm (0.31+/-0.11 cm), and 0.5-1.2 cm (0.87+/ 0.21 cm) along the x-, y-, and z-axes, respectively. Motion amplitude along the z axis may be affected by tumor location, but movement along the other axes was not affected by age, height, body mass, location, and size. CONCLUSION: The maximum motion distance was along the z-axis. Therefore, this should be the main consideration when defining the planning target volume safety margin. Due to the proximity of the liver, adrenal gland tumor motion amplitude was smaller on the right than the left. This study analyzed adrenal tumor motion amplitude data to evaluate how motion and other factors influence the treatment of adrenal tumor with a goal of providing a reference for stereotactic radiotherapy boundary determination. PMID- 27486332 TI - Lung cancer with concurrent EGFR mutation and ROS1 rearrangement: a case report and review of the literature. AB - ROS1 rearrangement has recently emerged as a new molecular subtype in non-small cell lung cancer, and is predominantly found in lung adenocarcinomas compared with other oncogenes such as EGFR, KRAS, or ALK. Patients who have both mutations are extremely rare. Here we report a 50-year-old female diagnosed with adenocarcinoma with sarcomatoid differentiation, who was shown to have EGFR and ROS1 mutations. The patient was treated surgically and received three cycles of adjuvant postoperative chemotherapy. In addition, we reviewed the previously reported cases and related literature. This presentation will provide further understanding of the underlying molecular biology and optimal treatment for non small cell lung cancer patients with more than one driver mutation. PMID- 27486333 TI - MicroRNA-194 promotes the growth, migration, and invasion of ovarian carcinoma cells by targeting protein tyrosine phosphatase nonreceptor type 12. AB - Ovarian carcinoma is the most lethal gynecologic malignancy among women. Ovarian cancer metastasis is the main reason for poor prognosis. MicroRNAs (miRNAs) have been shown to play an important role in tumorigenesis and metastasis in various cancers by affecting the expression of their targets. In this study, we explored the role of miR-194 in ovarian cancer. Real-time polymerase chain reaction assays showed that miR-194 was significantly upregulated in ovarian cancer tissues. Overexpression of miR-194 in ovarian cancer cells promotes cell proliferation, migration, and invasion; in contrast, inhibition of the expression of miR-194 has the opposite effects. Meanwhile, bioinformatics tools were used to identify protein tyrosine phosphatase nonreceptor type 12 (PTPN12) as a potential target of miR-194. The luciferase assay showed that miR-194 directly binds to the 3' untranslated region of PTPN12. Western blot analysis and quantitative real-time polymerase chain reaction assay revealed that PTPN12 expression was negatively associated with miR-194 expression in both ovarian cancer tissues and cells. Thus, we conclude that miR-194 targets PTPN12 and functions as an oncogene in ovarian cancer cells. This novel pathway may provide a new insight to explain ovarian cancer development and metastasis. PMID- 27486334 TI - Ectopic micronodular thymoma with lymphoid stroma in the cervical region: a rare case associated with Langerhans cells proliferation. AB - Micronodular thymoma (MNT) with lymphoid stroma is a rare thymic epithelial neoplasm with the characteristics of multiple nodules separated by abundant lymphoid stroma. MNTs mainly arise in the anterior mediastinum and thymus, while ectopic MNTs are extremely rarely seen. Here, we report an ectopic MNT that occurred in the neck of a 62-year-old woman. There were also scattered eosinophilic granulocytes and S100(+)/CD1a(+) Langerhans cells within the tumor. This case provides a better understanding of such rare, poorly understood cases. PMID- 27486336 TI - Association between CD14 SNP -159 C/T and gastric cancer: an independent case control study and an updated meta-analysis. AB - PURPOSE: The association between CD14 -159C/T polymorphism and the susceptibility to gastric cancer (GC) has been reported. However, the results were inconclusive. In the present study, a case-control study and a meta-analysis were performed to assess the possible association between -159C/T in the CD14 gene and GC risk. PATIENTS AND METHODS: Relevant studies were searched in several databases including PubMed, Web of Science, EMBASE, Chinese National Knowledge Infrastructure database, and Wanfang database (last search was performed on December 30, 2015). In addition, a case-control study involving 164 GC cases and 169 controls was also performed in the analysis. Statistical analysis was performed by the software Revman5.3. RESULTS: A total of ten published studies and the present case-control study involving 2,844 GC and 3,983 controls were included for the meta-analysis. The analysis result indicated that the T allele of CD14 -159C/T polymorphism did not confer risk for GC (in our study: [P=0.93]; in the meta-analysis: T vs 2N odds ratio =1.28 and 95% confidence interval (CI) =0.95-1.24, [P=0.24]). However, we found a significant association in the recessive model (in our study: TT vs TC+CC [P=0.04]; in the meta-analysis: TT vs TC+CC odds ratio =1.12 and 95% CI =1.01-1.26, [P=0.04]). Furthermore, a subgroup analysis by ethnicity showed that TT genotype was significantly associated with GC in Asian (odds ratio =1.17 and 95% CI =1.02-1.34, [P=0.02]) but not in Caucasian. CONCLUSION: Our results highlight the TT genotype of CD14 -159C/T as a genetic susceptibility factor for gastric cancer, particularly, in Asians and population-based controls. PMID- 27486337 TI - Evaluation of MMP-9 and MMP-2 and their suppressor TIMP-1 and TIMP-2 in adenocarcinoma of esophagogastric junction. AB - OBJECTIVE: Adenocarcinoma of esophagogastric junction (AEG) is a lethal malignancy featured with early metastasis, poor prognosis, and few treatment options. Matrix metalloproteinase (MMP) and metalloproteinase suppressor (TIMP) have been considered to be associated with cancer invasion and metastasis. In our study, we evaluated expressions of MMP-9, MMP-2, TIMP-1, and TIMP-2 in AEG and their correlation with clinicopathological parameters and the overall survival rate. METHODS: Expressions of MMP-9, MMP-2, TIMP-1, and TIMP-2 in specimens from 120 AEGs were detected by immunohistochemistry. The correlations between expressions of these four proteins and clinicopathological characters were analyzed by chi-square test. Moreover, the prognostic value of these four biomarkers was evaluated by univariate analysis with Kaplan-Meier method and multivariate analysis with Cox regression model. RESULTS: The positive expression rate of MMP-9, MMP-2, TIMP-1, and TIMP-2 was 65%, 53%, 70%, and 49%, respectively, in the detected 120 AEG samples. MMP-9 was significantly associated with poorly histological differentiation (P=0.001), lymph node metastasis (P=0.007), and UICC stage (P=0.008). TIMP-1 showed significantly reversed correlations with histological differentiation (P=0.001), lymph node metastasis (P=0.007), and Union for International Cancer Control stage (P=0.008). Univariate analysis revealed that lymph node metastasis (P=0.002), depth of invasion (P=0.050), and MMP-9+/TIMP-1 phonotype (P<0.001) were significantly associated with the overall survival rate. Multivariate analyses demonstrated that MMP 9+/TIMP-1-phenotype was an independent prognostic factor in AEGs. CONCLUSION: Detection of MMP-9 and TIMP-1 expression allows stratification of AEG patients into different survival categories and can be useful for precise individual evaluation and survival prediction. PMID- 27486335 TI - Endocannabinoid system as a regulator of tumor cell malignancy - biological pathways and clinical significance. AB - The endocannabinoid system (ECS) comprises cannabinoid receptors (CBs), endogenous cannabinoids, and enzymes responsible for their synthesis, transport, and degradation of (endo)cannabinoids. To date, two CBs, CB1 and CB2, have been characterized; however, orphan G-protein-coupled receptor GPR55 has been suggested to be the third putative CB. Several different types of cancer present abnormal expression of CBs, as well as other components of ECS, and this has been shown to correlate with the clinical outcome. Although most effects of (endo)cannabinoids are mediated through stimulation of classical CBs, they also interact with several molecules, either prosurvival or proapoptotic molecules. It should be noted that the mode of action of exogenous cannabinoids differs significantly from that of endocannabinoid and results from the studies on their activity both in vivo and in vitro could not be easily compared. This review highlights the main signaling pathways involved in the antitumor activity of cannabinoids and the influence of their activation on cancer cell biology. We also discuss changes in the expression pattern of the ECS in various cancer types that have an impact on disease progression and patient survival. A growing amount of experimental data imply possible exploitation of cannabinoids in cancer therapy. PMID- 27486338 TI - Smartphone applications to aid weight loss and management: current perspectives. AB - The development and dissemination of smart devices has cultivated a global environment of hyperconnectivity and increased our access to information. The paralleled launch and success of the Mobile Health industry has created a market of commercially available applications or "apps" along with tools or sensors, which allow the user to receive and collect personal health information. Apps and accompanying tools now allow an individual to "self-digitize" and, pertaining to weight management, monitor their body weight, caloric intake, physical activity, and more. These products possess the ability to improve the scalability of traditional in-person weight management services considering their near ubiquity, affordability, and capability to deliver information directly and personally to the user. However, similar to the dietary supplement market, the anecdotal value of these products has driven their popularity and acceptance by the general public without requirement of scientific validation or, in the area of weight management or diet/exercise, validation of the safety and efficacy by the Food and Drug Administration prior to market launch. By conducting a literature and clinical trial search, we found remarkably few active, completed, or published studies testing the efficacy of smart device applications using randomized controlled trials. Research efforts must be focused on illuminating the efficacy of behavioral interventions and remote self-monitoring for weight loss/maintenance treatment with true, randomized controlled trials. PMID- 27486339 TI - Real-world glycemic outcomes in patients with type 2 diabetes initiating exenatide once weekly and liraglutide once daily: a retrospective cohort study. AB - AIM: The glucagon-like peptide-1 receptor agonists exenatide once weekly (QW) and liraglutide once daily (QD) have demonstrated improvements in glycemic outcomes in patients with type 2 diabetes mellitus in randomized clinical trials. However, little is known about their real-world comparative effectiveness. This retrospective cohort study used the Quintiles Electronic Medical Record database to evaluate the 6-month change in glycated hemoglobin (A1C) for patients initiating exenatide QW or liraglutide QD. METHODS: Patients with type 2 diabetes mellitus prescribed exenatide QW (n=664) or liraglutide QD (n=3,283) between February 1, 2012 and May 31, 2013 were identified. Baseline A1C measures were from 75 days before to 15 days after initiating exenatide QW or liraglutide QD, with follow-up measures documented at 6 months (+/-45 days). Adjusted linear regression models compared the difference in mean A1C change. A priori defined sensitivity analysis was performed in the subgroup of patients with baseline A1C >=7.0% and no prescription for insulin during the 12-month pre-index period. RESULTS: For exenatide QW and liraglutide QD, respectively, mean (SD) age of the main study cohort was 58.01 (10.97) and 58.12 (11.05) years, mean (SD) baseline A1C was 8.4% (1.6) and 8.4% (1.6), and 48.2% and 54.2% of patients were women. In adjusted models, change in A1C did not differ between exenatide QW and liraglutide QD during 6 months of follow-up. Results were consistent in the subgroup analyses. CONCLUSION: In a real-world setting, A1C similarly improves in patients initiating exenatide QW or liraglutide QD. PMID- 27486340 TI - Safety of polyethylene glycol 3350 solution in chronic constipation: randomized, placebo-controlled trial. AB - PURPOSE: To evaluate the safety and tolerability of aqueous solution concentrate (ASC) of polyethylene glycol (PEG) 3350 in patients with functional constipation. PATIENTS AND METHODS: The patients who met Rome III diagnostic criteria for functional constipation were randomized in this multicenter, randomized, placebo controlled, single-blind study to receive once daily dose of PEG 3350 (17 g) ASC or placebo solution for 14 days. The study comprised a screening period (visit 1), endoscopy procedure (visits 2 and 3), and followup telephone calls 30 days post-treatment. Safety end points included adverse events (AEs), clinical laboratory evaluations, vital signs, and others. The primary end points were the proportion of patients with abnormalities of the oral and esophageal mucosa, detected by visual and endoscopic examination of the oral cavity and esophagus, respectively, compared with placebo. A secondary objective was to compare the safety and tolerability of ASC by evaluating AEs or adverse drug reactions. RESULTS: A total of 65 patients were enrolled in this study, 31 were randomized to PEG 3350 ASC and 34 were randomized to placebo, of which 62 patients completed the study. No patients in either group showed abnormalities in inflammation of the oral mucosa during visit 2 (before treatment) or visit 3 (after treatment). Fewer abnormalities of the esophageal mucosa were observed in the PEG 3350 ASC group than in the placebo group on visit 3, with no significant difference in the proportion of abnormalities between the treatment groups. Overall, 40 treatment emergent AEs were observed in 48.4% of patients treated with PEG 3350 ASC, and 41 treatment-emergent AEs were observed in 55.9% of patients treated with placebo - nonsignificant difference of -7.5% (95% CI: -21.3, 6.3) between treatment groups. No serious AEs or deaths were reported, and no patient discontinued because of an AE. CONCLUSION: PEG 3350 ASC is safe and well tolerated in patients with functional constipation (NCT01885104). PMID- 27486342 TI - A systematic review and meta-analysis of Harmonic technology compared with conventional techniques in mastectomy and breast-conserving surgery with lymphadenectomy for breast cancer. AB - BACKGROUND: Mastectomy and breast-conserving surgery (BCS) are important treatment options for breast cancer patients. A previous meta-analysis demonstrated that the risk of certain complications can be reduced with the Harmonic technology compared with conventional methods in mastectomy. However, the meta-analysis did not include studies of BCS patients and focused on a subset of surgical complications. The objective of this study was to compare Harmonic technology and conventional techniques for a range of clinical outcomes and complications in both mastectomy and BCS patients, including axillary lymph node dissection. METHODS: A comprehensive literature search was performed for randomized controlled trials comparing Harmonic technology and conventional methods in breast cancer surgery. Outcome measures included blood loss, drainage volume, total complications, seroma, necrosis, wound infections, ecchymosis, hematoma, hospital length of stay, and operating time. Risk of bias was analyzed for all studies. Meta-analysis was performed using random-effects models for mean differences of continuous variables and a fixed-effects model for risk ratios of dichotomous variables. RESULTS: Twelve studies met the inclusion criteria. Across surgery types, compared to conventional techniques, Harmonic technology reduced total complications by 52% (P=0.002), seroma by 46% (P<0.0001), necrosis by 49% (P=0.04), postoperative chest wall drainage by 46% (P=0.0005), blood loss by 38% (P=0.0005), and length of stay by 22% (P=0.007). Although benefits generally appeared greatest in mastectomy patients with lymph node dissection, Harmonic technology showed significant reductions in complications in the BCS study subgroup. CONCLUSION: In this meta-analysis of both mastectomy and BCS procedures, the use of Harmonic technology reduced the risk of most complications by about half across breast cancer surgery patients. These benefits may be due to superior hemostatic capabilities of Harmonic technology and better dissection, particularly lymph node dissection. Reduction in complications and other resource outcomes may engender lower downstream health care costs. PMID- 27486341 TI - Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements. AB - Serum albumin concentration (CP) is a remarkably strong prognostic indicator of morbidity and mortality in both sick and seemingly healthy subjects. Surprisingly, the specifics of the pathophysiology underlying the relationship between CP and ill-health are poorly understood. This review provides a summary that is not previously available in the literature, concerning how synthesis, catabolism, and renal and gastrointestinal clearance of albumin interact to bring about albumin homeostasis, with a focus on the clinical factors that influence this homeostasis. In normal humans, the albumin turnover time of about 25 days reflects a liver albumin synthesis rate of about 10.5 g/day balanced by renal (~6%), gastrointestinal (~10%), and catabolic (~84%) clearances. The acute development of hypoalbuminemia with sepsis or trauma results from increased albumin capillary permeability leading to redistribution of albumin from the vascular to interstitial space. The best understood mechanism of chronic hypoalbuminemia is the decreased albumin synthesis observed in liver disease. Decreased albumin production also accounts for hypoalbuminemia observed with a low-protein and normal caloric diet. However, a calorie- and protein-deficient diet does not reduce albumin synthesis and is not associated with hypoalbuminemia, and CP is not a useful marker of malnutrition. In most disease states other than liver disease, albumin synthesis is normal or increased, and hypoalbuminemia reflects an enhanced rate of albumin turnover resulting either from an increased rate of catabolism (a poorly understood phenomenon) or enhanced loss of albumin into the urine (nephrosis) or intestine (protein-losing enteropathy). The latter may occur with subtle intestinal pathology and hence may be more prevalent than commonly appreciated. Clinically, reduced CP appears to be a result rather than a cause of ill-health, and therapy designed to increase CP has limited benefit. The ubiquitous occurrence of hypoalbuminemia in disease states limits the diagnostic utility of the CP measurement. PMID- 27486343 TI - One-year assessment of physical activity level in adult Qatari females: a pedometer-based longitudinal study. AB - BACKGROUND: Physical inactivity is a growing health concern and has been identified as the fourth leading risk factor for global mortality. The Arab region includes countries with some of the world's highest physical inactivity levels, such as Qatar, more specifically the Qatari female population. OBJECTIVE: The objective of this study is to assess the physical activity levels of Qatari national female adults during a 1-year pedometer-based program. MATERIALS AND METHODS: A total of 549 Qatari national females aged between 18 years and 64 years were included. Data extracted from "Step into Health" program web database in Qatar were used for analyses. Daily habitual physical activity (daily total step count and aerobic steps) was assessed through the Omron HJ-324U pedometer. Step counts were classified as follows: <5,000 steps/d, sedentary; 5,000-7,499 steps/d, low active; and >=7,500 steps/d, physically active. Statistical significance was set at P-value <=0.05. Descriptive statistics were used, and habitual physical activity was calculated through repeated measures analysis of variance to determine the difference across the monitored days. RESULTS: Mean age was 37.4+/-11.7 years, and median body mass index of 28.8 kg/m(2) (interquartile range 24.8-33.5). Daily steps for the overall population ranged from 3,505 steps/d to 10,010 steps/d, with a median of 6,008 steps/d. A total of 242 (44.1%) females were sedentary, 178 (32.4%) were low active, and 129 (23.5%) were physically active. The physically active group showed a median of 927 aerobic steps/d (interquartile range 0-4,248). CONCLUSION: Based on the results of this study, Qatari females are not meeting the global recommendations of physical activity. Future research might need to consider barriers to physical activity as well as social, cultural, and environmental factors. PMID- 27486344 TI - Administration of palmitoylethanolamide in combination with topiramate in the preventive treatment of nummular headache. AB - Nummular headache has been recently described as a primary disorder characterized by head pain exclusively felt in a small rounded area typically 2-6 cm in diameter, not attributed to another disorder. Both size and shape of the painful area remain constant since the onset of symptoms. A 57-year-old woman presented with a history of focal episodic pain in a circumscribed area on the right parietal region. The administration of standard oral doses of palmitoylethanolamide and topiramate in combination showed an improvement in pain symptoms and on pain measuring scales. PMID- 27486345 TI - Computed tomography and magnetic resonance imaging contrast media injectors: technical feature review - what is really needed? AB - There has been little technical innovation over the last few years for contrast media (CM) injectors that are used for diagnostic imaging (computed tomography [CT], magnetic resonance imaging [MRI], and hybrid imaging systems, such as positron emission tomography-CT or magnetic resonance-positron emission tomography) examinations. The medical need of CM for the enhancement of diagnostic images has been around for a long time, but the application of the CM into the blood stream comes with potential medical complications for the patient and requires a lot of operator experience and training. Most power injector systems that are currently used can do significantly more than what is typically required; this complexity however, adds error potential and cost. This paper focuses on the main features that CM injector systems should have and highlights the technical developments that are useful to have but which add complexity and cost, increase setup time, and require intensive training for safe use. CM injection protocols are very different between CT and MRI, with CT requiring many more variances, has a need for multiphase protocols, and requires a higher timing accuracy. A CM injector used in the MRI suite, on the other-hand, could only need a relatively time insensitive injection with a standard injection flow rate and a volume that is dependent on the patients' weight. This would make easy and lightweight systems possible, which are able to safely and accurately perform the injection task, while allowing full MRI compatibility with relatively low cost investment and consumable costs. PMID- 27486346 TI - Clinical applications of therapeutic phlebotomy. AB - Phlebotomy is the removal of blood from the body, and therapeutic phlebotomy is the preferred treatment for blood disorders in which the removal of red blood cells or serum iron is the most efficient method for managing the symptoms and complications. Therapeutic phlebotomy is currently indicated for the treatment of hemochromatosis, polycythemia vera, porphyria cutanea tarda, sickle cell disease, and nonalcoholic fatty liver disease with hyperferritinemia. This review discusses therapeutic phlebotomy and the related disorders and also offers guidelines for establishing a therapeutic phlebotomy program. PMID- 27486348 TI - Computational Representations of Myocardial Infarct Scars and Implications for Arrhythmogenesis. AB - Image-based computational modeling is becoming an increasingly used clinical tool to provide insight into the mechanisms of reentrant arrhythmias. In the context of ischemic heart disease, faithful representation of the electrophysiological properties of the infarct region within models is essential, due to the scars known for arrhythmic properties. Here, we review the different computational representations of the infarcted region, summarizing the experimental measurements upon which they are based. We then focus on the two most common representations of the scar core (complete insulator or electrically passive tissue) and perform simulations of electrical propagation around idealized infarct geometries. Our simulations highlight significant differences in action potential duration and focal effective refractory period (ERP) around the scar, driven by differences in electrotonic loading, depending on the choice of scar representation. Finally, a novel mechanism for arrhythmia induction, following a focal ectopic beat, is demonstrated, which relies on localized gradients in ERP directly caused by the electrotonic sink effects of the neighboring passive scar. PMID- 27486347 TI - Oncogenes: The Passport for Viral Oncolysis Through PKR Inhibition. AB - The transforming properties of oncogenes are derived from gain-of-function mutations, shifting cell signaling from highly regulated homeostatic to an uncontrolled oncogenic state, with the contribution of the inactivating mutations in tumor suppressor genes P53 and RB, leading to tumor resistance to conventional and target-directed therapy. On the other hand, this scenario fulfills two requirements for oncolytic virus infection in tumor cells: inactivation of tumor suppressors and presence of oncoproteins, also the requirements to engage malignancy. Several of these oncogenes have a negative impact on the main interferon antiviral defense, the double-stranded RNA-activated protein kinase (PKR), which helps viruses to spontaneously target tumor cells instead of normal cells. This review is focused on the negative impact of overexpression of oncogenes on conventional and targeted therapy and their positive impact on viral oncolysis due to their ability to inhibit PKR-induced translation blockage, allowing virion release and cell death. PMID- 27486349 TI - No Postoperative Adrenal Insufficiency in a Patient with Unilateral Cortisol Secreting Adenomas Treated with Mifepristone Before Surgery. AB - BACKGROUND: Glucocorticoid replacement is commonly required to treat secondary adrenal insufficiency after surgical resection of unilateral cortisol-secreting adrenocortical adenomas. Here, we describe a patient with unilateral cortisol secreting adenomas in which the preoperative use of mifepristone therapy was associated with recovery of the hypothalamic-pituitary-adrenal (HPA) axis, eliminating the need for postoperative glucocorticoid replacement. CASE PRESENTATION: A 66-year-old Caucasian man with type 2 diabetes mellitus, hyperlipidemia, hypertension, and obesity was hospitalized for Fournier's gangrene and methicillin-resistant Staphylococcus aureus sepsis. Abdominal computed tomography scan revealed three left adrenal adenomas measuring 1.4, 2.1, and 1.2 cm and an atrophic right adrenal gland. Twenty-four-hour urinary free cortisol level was elevated (237 ug/24 hours, reference range 0-50 ug/24 hours). Hormonal evaluation after resolution of the infection showed an abnormal 8 mg overnight dexamethasone suppression test (cortisol postdexamethasone 14.5 ug/dL), suppressed adrenocorticotropic hormone (ACTH; <5 pg/mL, reference range 7.2-63.3 pg/mL), and low-normal dehydroepiandrosterone sulfate (50.5 ug/dL, male reference range 30.9-295.6 ug/dL). Because of his poor medical condition and uncontrolled diabetes, his Cushing's syndrome was treated with medical therapy before surgery. Mifepristone therapy was started and, within five months, his diabetes was controlled and insulin discontinued. The previously suppressed ACTH increased to above normal range accompanied by an increase in dehydroepiandrosterone sulfate levels, indicating recovery of the HPA axis and atrophic contralateral adrenal gland. The patient received one precautionary intraoperative dose of hydrocortisone and none thereafter. Two days postoperatively, ACTH (843 pg/mL) and cortisol levels (44.8 ug/dL) were significantly elevated, reflecting an appropriate HPA axis response to the stress of surgery, and two weeks postoperatively, ACTH was within normal range and a repeat dexamethasone suppression test was normal. Six months postoperatively, ACTH was within normal limits and cortisol was approaching normal. The patient has exhibited no postoperative signs or symptoms of adrenal insufficiency in 12 months. CONCLUSION: Preoperative mifepristone therapy was associated with apparent recovery of the HPA axis prior to unilateral adrenalectomy in a patient with unilateral adrenal adenomas. Postoperatively, the patient experienced no signs or symptoms of adrenal insufficiency and no glucocorticoid replacement was required. PMID- 27486352 TI - Benefits of simulation training in medical education. PMID- 27486351 TI - Developing a competency-based medical education curriculum for the core basic medical sciences in an African Medical School. AB - The College of Medicine of the University of Ibadan recently revised its MBBS and BDS curricula to a competency-based medical education method of instruction. This paper reports the process of revising the methods of instruction and assessment in the core basic medical sciences directed at producing medical and dental graduates with a sound knowledge of the subjects sufficient for medical and dental practice and for future postgraduate efforts in the field or related disciplines. The health needs of the community and views of stakeholders in the Ibadan medical and dental schools were determined, and the "old" curriculum was reviewed. This process was directed at identifying the strengths and weaknesses of the old curricula and the newer competences required for modern-day medical/dental practice. The admission criteria and processes and the learning methods of the students were also studied. At the end of the review, an integrated, system-based, community-oriented, person-centered, and competency driven curriculum was produced and approved for implementation. Four sets of students have been admitted into the curriculum. There have been challenges to the implementation process, but these have been overcome by continuous faculty development and reorientation programs for the nonteaching staff and students. Two sets of students have crossed over to the clinical school, and the consensus among the clinical teachers is that their knowledge and application of the basic medical sciences are satisfactory. The Ibadan medical and dental schools are implementing their competency-based medical education curricula successfully. The modifications to the teaching and assessment of the core basic medical science subjects have resulted in improved learning and performance at the final examinations. PMID- 27486350 TI - Elderly Onset Celiac Disease: A Narrative Review. AB - Celiac sprue is a chronic disease, which usually occurs in children and young adults. However, it can develop in any age group, and the prevalence is increasing even in the elderly population. The atypical patterns of clinical presentation in this age group sometimes can cause a delay in diagnosis. Given the lower sensitivity and specificity of serological tests in the aged population, clinical suspect often arises in the presence of complications (autoimmune disorders, fractures, and finally, malignancy) and must be supported by endoscopic and imaging tools. In this review, we highlight the incidence and prevalence of celiac disease in the elderly, the patterns of clinical presentation, diagnosis, and the most frequent complications, with the aim of increasing awareness and reducing the diagnostic delay of celiac disease even in the elderly population. PMID- 27486353 TI - Dose-dependent effect of N'-Nitrosodiethylamine on hepatic architecture, RBC rheology and polypeptide repertoire in Wistar rats. AB - N'-Nitrosodiethylamine (NDEA) is an effective hepatotoxicant, carcinogen and mutagen. NDEA-induced hepatic necrosis, through metabolic activation by CYP2E1, is an extensively used experimental model. In the present study, we analysed the dose- and time-dependent effect of NDEA on hepatic damage, RBC rheology and proteomic profile in male Wistar rats. The rats, 5-6 weeks old, were divided into four groups: Group-1 served as control and received normal saline, Group-2 received a single dose of 200 mg/kg body weight NDEA intraperitoneally (i.p.) and the animals were sacrificed after one week; the rats of Group-3 received a single dose of 100 mg/kg body weight NDEA and were sacrificed after one week; Group-4 received 100 mg/kg body weight/wk NDEA for two weeks and were then sacrificed. Various biochemical parameters such as ALT, AST, ALP and bilirubin were determined. Further, RBC rheology, histopathology (H&E staining) of liver biopsies and polypeptide profiling (SDS-PAGE) in sera and liver sections were also carried out both in control and NDEA treated groups. Our results showed a significant increase in all the biochemical parameters of the liver function test (p<0.05). In NDEA treated categories dacryocytes (tear drop cells), schistocytes (fragmented cells), codocytes (target cells), acanthocytes (spur cells) and ovalocytes (oval cells) were observed. H & E stained liver biopsies treated with NDEA showed abnormal liver architecture with severe haemorrhage, neutrophilic infiltration and dysplastic hepatocytes manifested in a dose-dependent manner. Software analysis of SDS-PAGE of control and NDEA treated rat sera and liver revealed qualitative and quantitative differences in polypeptide composition. Based on the presence/absence, polypeptides were classified in three different categories: (1) house-keeping, present in all the groups investigated; (2) novel, present in either control or NDEA treated group at any given time; (3) differential expression, showing quantitative differences. Our study indicates a dose and time-dependent hepatocellular damage and proteome profile which is likely due to NDEA-mediated oxidative stress in rats. PMID- 27486354 TI - Antioxidant modulation of nevirapine induced hepatotoxicity in rats. AB - HIV/AIDS related mortality has been dramatically reduced by the advent of antiretroviral therapy (ART). However, ART presents with associated adverse effects. One of such adverse effects is hepatotoxicity observed with nevirapine (NVP) containing ART. Since previous studies showed that NVP hepatotoxicity may be due to oxidative stress via generation of oxidative radicals, this study sought to evaluate the protective effects of antioxidants in alleviating NVP induced hepatotoxicity. Rats were divided into 6 groups with 8 animals per group and received doses of the antioxidants jobelyn (10.7 mg/kg/day), vitamin C (8 mg/kg/day), vitamin E (5 mg/kg/day) and/or NVP (6 mg/kg/day) for 60 days. The animals were sacrificed on day 61 by cervical dislocation, blood samples were collected for biochemical and hematological examination. The liver of the sacrificed animals was weighed and subjected to histopathological examination. There was a statistically significant (p<0.05) elevation in MDA level observed in the NVP group as compared with control. The results further showed non significant decreases in the levels of MDA in the NVP plus antioxidant groups, except vitamin C, when compared with the NVP alone group. Vitamin E and Vitamin E plus C treated groups showed significantly (p<0.05) higher levels of SOD, CAT and GSH. The results also showed statistically significantly (p<0.05) lower levels of ALT and AST in the antioxidant treated groups There was an observed significantly (p<0.05) higher level of TP and urea in the antioxidant treated rats. A significantly (p<0.05) higher white blood cell count was observed in the antioxidant groups. Histopathological assessment of the liver extracted from the rats showed no visible pathology across the groups. Observations from this study suggest a potentially positive modulatory effect of antioxidants and may be indicative for the inclusion of antioxidants in nevirapine containing ART. PMID- 27486355 TI - Physiochemical basis of human degenerative disease. AB - The onset of human degenerative diseases in humans, including type 2 diabetes, cardiovascular disease, neurological disorders, neurodevelopmental disease and neurodegenerative disease has been shown to be related to exposures to persistent organic pollutants, including polychlorinated biphenyls, chlorinated pesticides, polybrominated diphenyl ethers and others, as well as to polynuclear aromatic hydrocarbons, phthalates, bisphenol-A and other aromatic lipophilic species. The onset of these diseases has also been related to exposures to transition metal ions. A physiochemical mechanism for the onset of degenerative environmental disease dependent upon exposure to a combination of lipophilic aromatic hydrocarbons and transition metal ions is proposed here. The findings reported here also, for the first time, explain why aromatic hydrocarbons exhibit greater toxicity than aliphatic hydrocarbons of equal carbon numbers. PMID- 27486356 TI - Effects of teicoplanin on cell number of cultured cell lines. AB - Teicoplanin is a glycopeptide antibiotic with a wide variation in human serum half-life. It is also a valuable alternative of vancomycin. There is however no study on its effect on cultured cells. The aim of the present study was to test the effect of teicoplanin on cultured cell lines CHO, Jurkat E6.1 and MCF-7. The cultured cells were exposed to teicoplanin at final concentrations of 0-11000 MUg/ml for 24 hours. To determine cell viability, the 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) test was performed. At low concentrations of teicoplanin the numbers of cultured cells (due to cell proliferation) were increased in the three cell lines examined. The maximum cell proliferation rates were observed at concentrations of 1000, 400, and 200 MUg/ml of teicoplanin for CHO, MCF-7 and Jurkat cell lines, respectively. Cell toxicity was observed at final concentrations over 2000, 6000, and 400 MUg/ml of teicoplanin for CHO, MCF-7 and Jurkat cell lines, respectively. A dose-dependent manner of cell toxicity was observed. Our present findings indicated that teicoplanin at clinically used concentrations induced cell proliferation. It should therefore be used cautiously, particularly in children, pregnant women and patients with cancer. PMID- 27486357 TI - Protective effect of Cupressus sempervirens extract against indomethacin-induced gastric ulcer in rats. AB - Cupressus sempervirens (C. sempervirens) belongs to the family Cupressaceae. It is widspread in Northern Africa, Greece, Turkey, North America, Cyprus and Syria. Cupressuflavone is the major ingredient of the plant leave extract. The aim of the present study was to evaluate the antiulcerogenic activity of the extract of C. sempervirens leaves in gastric ulcer tissues induced by indomethacin. The results of the present study revealed that indomethacin significantly decreased glutathione S-transferase (GST), glutathione peroxidase (GPx), catalase (CAT), reduced glutathione (GSH), glutathione reductase (GR) and superoxide dismutase (SOD) levels, while it increased significantly lipid peroxidation (MDA), nitric oxide (NO) and protein carbonyl (PC) levels in gastric tissue. Furthermore, indomethacin decreased p53 expression, while it increased bcl-2 expression in gastric tissue. Pretreatment with 5%, 10% & 20% of the LD50 of C. sempervirens and cupressuflavone of indomethacin-treated rats restored all the above parameters to approach normal values. C. sempervirens at the highest dose was more effective than the two lower doses. C. sempervirens proved more potent than cupressuflavone. In conclusion, C. sempervirens exerted antiulcerogenic activity and the effect was dose-dependent and related to the cupressuflavone ingredient of the plant leave extract. PMID- 27486358 TI - Probit analysis of comparative assays on toxicities of lead chloride and lead acetate to in vitro cultured human umbilical cord blood lymphocytes. AB - This work describes that cytotoxicity of lead chloride and lead acetate to in vitro cultured lymphocytes from human umbilical cord blood, using four monitoring methods namely, trypan blue staining, acridine orange/ethidium bromide staining, 3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyl tetrazolium bromide (MTT) and neutral red uptake assays; lead genotoxicity to lymphocytes was monitored by comet assay. The MIC value in each method was invariably 300 mg/L for PbCl2. Lethal concentration25 (LC25) values were almost in an agreeable range: 691.83 to 831.76 mg/L; LC50 values in each method were almost in the range: 1174.9 to 1348.9 mg/L; LC100 values were in the range: 3000 to 3300 mg/L, for lead chloride. Similarly, The MIC value in each method were invariably 150 mg/L; LC25 values were almost in the range: 295.12 to 371.53 mg/L; LC50 values were in the range: 501.18 to 588.84 mg/L; LC100 value was 1500 mg/L in all assays, for lead acetate. The comet assay also indicated that the LC100 values were 3300 mg/L lead chloride and 1500 mg/L lead acetate. Thus, both cytotoxicity and genotoxicity were recorded at 3300 mg/L lead chloride and 1500 mg/L lead acetate with lymphocytes. PMID- 27486359 TI - Endothelium and the effect of activated neutrophils on arterial smooth muscle. AB - The aim of the study was to analyze the involvement of the endothelium in the effects of neutrophils (PMNL) on phenylephrine-precontracted isolated rings of the rat thoracic aorta and to compare their effects with those of peroxynitrite (ONOO(-)) and hypochlorous acid (HOCl). Activated PMNL-induced contraction of the precontracted aorta was prevented by the blockade of NO-synthase and by endothelium removal. In the endothelium-free preparations, the effect of PMNL reappeared in the presence of sodium nitroprusside. The effect of ONOO(-) and HOCl significantly differed from that of activated PMNL both in the presence and absence of the endothelium. It is therefore likely that neither ONOO(-) nor HOCl generated by transformation of superoxide anion radical (O2 (*-)) produced by PMNL is involved in their action. Reduction of the relaxant effect of nitric oxide derived from the endothelium by O2 (*-) seems to be the keystone mechanism in generation of PMNL-induced contraction. PMID- 27486360 TI - Toxicological studies of aqueous extract of Acacia nilotica root. AB - Acacia nilotica is a widely used plant in traditional medical practice in Northern Nigeria and many African countries. The aim of this study was to determine the toxicological effects of a single dose (acute) and of repeated doses (sub-acute) administration of aqueous extract of A. nilotica root in rodents, following our earlier study on antiplasmodial activity. In the acute toxicity test, three groups of Swiss albino mice were orally administered aqueous extract of A. nilotica (50, 300 and 2000 mg/kg body weight) and signs of toxicity were observed daily for 14 days. In the sub-acute toxicity study, four groups of 12 rats (6 male and 6 female) were used. Group 1 received 10 ml/kg b.w distilled water (control), while groups 2, 3 and 4 received 125, 250 and 500 mg/kg b.w of the extract, respectively, for 28 consecutive days by oral gavage. Signs of toxicity/mortality, food and water intake and body weight changes were observed. Biochemical parameters were analysed in both plasma and liver homogenate. In the acute and sub-acute toxicity studies, the extract did not cause mortality. A significant reduction in the activity of lactate dehydrogenase was observed at 250 and 500 mg/kg b.w, while alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase activities were significantly higher than control values at 500 mg/kg b.w. The aqueous extract of A. nilotica was found to be safe in single dose administration in mice but repeated administration of doses higher than 250 mg/kg b.w of the extract for 28 days in rats may cause hepatotoxicity. PMID- 27486361 TI - Lead toxicity: a review. AB - Lead toxicity is an important environmental disease and its effects on the human body are devastating. There is almost no function in the human body which is not affected by lead toxicity. Though in countries like US and Canada the use of lead has been controlled up to a certain extent, it is still used vehemently in the developing countries. This is primarily because lead bears unique physical and chemical properties that make it suitable for a large number of applications for which humans have exploited its benefits from historical times and thus it has become a common environmental pollutant. Lead is highly persistent in the environment and because of its continuous use its levels rise in almost every country, posing serious threats. This article reviews the works listed in the literature with recent updates regarding the toxicity of lead. Focus is also on toxic effects of lead on the renal, reproductive and nervous system. Finally the techniques available for treating lead toxicity are presented with some recent updates. PMID- 27486362 TI - Fatal aluminium phosphide poisoning. AB - Aluminium phosphide (AlP) is a cheap solid fumigant and a highly toxic pesticide which is commonly used for grain preservation. AlP has currently aroused interest with a rising number of cases in the past four decades due to increased use for agricultural and non-agricultural purposes. Its easy availability in the markets has increased also its misuse for committing suicide. Phosphine inhibits cellular oxygen utilization and can induce lipid peroxidation. Poisoning with AlP has often occurred in attempts to commit suicide, and that more often in adults than in teenagers. This is a case of suicidal consumption of aluminium phosphide by a 32-year-old young medical anesthetist. Toxicological analyses detected aluminium phosphide. We believe that free access of celphos tablets in grain markets should be prohibited by law. PMID- 27486363 TI - Thimerosal exposure and increased risk for diagnosed tic disorder in the United States: a case-control study. AB - A hypothesis testing, case-control study evaluated automated medical records for exposure to organic-Hg from Thimerosal-containing hepatitis B vaccines (TM-HepB) administered at specific intervals in the first six-months-of-life among cases diagnosed with a tic disorder (TD) or cerebral degeneration (CD) (an outcome not biologically plausibly linked to TM exposure) in comparison to controls; both cases and controls were continuously enrolled from birth (born from 1991-2000) within the Vaccine Safety Datalink (VSD) database. TD cases were significantly more likely than controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (odds ratio (OR)=1.59, p<0.00001), first two-months-of-life (OR=1.59, p<0.00001), and first six-months-of-life (OR=2.97, p<0.00001). Male TD cases were significantly more likely than male controls to have received increased organic-Hg from TM-HepB administered within the first month-of-life (OR =1.65, p<0.0001), first two-months-of-life (OR=1.64, p<0.0001), and first six months-of-life (OR=2.47, p<0.05), where as female TD were significantly more likely than female controls to have received increased organic-Hg from TM-HepB administered within the first six-months-of-life (OR=4.97, p<0.05). By contrast, CD cases were no more likely than controls to have received increased organic-Hg exposure from TM-HepB administered at any period studied within the first six-months-of-life. Although routine childhood vaccination is considered an important public health tool to combat infectious diseases, the present study associates increasing organic-Hg exposure from TM HepB and the subsequent risk of a TD diagnosis. PMID- 27486364 TI - Plasma cadmium and zinc and their interrelationship in adult Nigerians: potential health implications. AB - Zinc (an essential trace element) and cadmium (a ubiquitous environmental pollutant with acclaimed toxicity) have been found to occur together in nature, with reported antagonism between the two elements. The present study aimed at determination of plasma levels of zinc (Zn) and cadmium (Cd) and their interrelationship in adult Nigerians. The series comprised adults (n=443) aged >=18 yrs (mean +/- SD 38.4+/-13.7 yrs), consisting of 117 males, 184 non-pregnant and 140 pregnant females. Sociodemographic data were collected by questionnaire while anthropometrics were determined using standard methods. Plasma Cd and Zn were determined by using an atomic absorption spectrophotometer. The mean plasma zinc and cadmium were 94.7+/-18.1 MUg/dl and 0.150+/-0.548 MUg/dl, respectively. Age, sex, pregnancy, and parity had no effect on either plasma Zn or Cd. Although educational level had no effect on plasma Zn, it had a significant effect on Cd; subjects possessing either secondary or tertiary education had significantly lower plasma Cd than subjects without formal education. Moreover, there seemed to be an inverse relationship between Cd and Zn, but this was not statistically significant (r=-0.089; p=0.061). Although plasma Zn was not related to BMI (r=0.037; p=0.432), Cd was significantly negatively correlated with BMI (r= 0.124; p=0.009). It may be concluded that adult Nigerians in Ebonyi State have elevated plasma levels of Cd, with apparent impact on the levels of plasma Zn. This has important public health implications considering the essential roles of Zn in the protection of Cd mediated adverse health effects. While food diversification is recommended to improve plasma Zn, efforts should be made to reduce exposure to Cd to mitigate partially its possible adverse effects. PMID- 27486365 TI - Altered differential hemocyte count in 3rd instar larvae of Drosophila melanogaster as a response to chronic exposure of Acephate. AB - Acephate, an organophosphate (OP) pesticide, was used to investigate the effects of its chronic exposure on hemocyte abundance in a non-target dipteran insect Drosophila melanogaster. For this purpose, six graded concentrations ranging from 1 to 6 MUg/ml were selected, which are below the reported residual values (up to 14 MUg/ml) of the chemical. 1(st) instar larvae were fed with these concentrations up to the 3(rd) instar stage and accordingly hemolymph smears from these larvae were prepared for differential hemocyte count. Three types of cells are found in Drosophila hemolymph, namely, plasmatocytes, lamellocytes and crystal cells. Plasmatocyte count was found to decrease with successive increase in treatment concentrations. Crystal cells showed an increasing trend in their number. Though the number of lamellocytes was very low, a bimodal response was noticed. Lamellocyte number was found to increase with the initial three concentrations, followed by a dose dependent reduction in their number. As hemocytes are directly linked to the immune system of fruit flies, fluctuations in normal titer of these cells may affect insect immunity. Hemocytes share homologies in their origin and mode of action with the immune cells of higher organisms including man. Thus the present findings suggest that immune cells of humans and other organisms may be affected adversely under chronic exposure to Acephate. PMID- 27486366 TI - Toxicological evaluation of the aqueous stem bark extract of Bridelia ferruginea (Euphorbiaceae) in rodents. AB - Bridelia ferruginea is a woody shrub that grows in the Savannah or rain forests of Africa and has traditionally been used to treat diabetes, arthritis and boils. Despite all these uses, extensive toxicological evaluation has not been carried out. The aim of the present investigation was to evaluate the sub-chronic toxicological effects of the stem bark aqueous extract of Bridelia ferruginea in rats. The lethal dose (LD50) was determined using probit analysis and graded doses of the extract (250-4000 mg/kg) were administered to the animals via oral and intraperitoneal routes and observed for mortality, behavioral changes and signs of toxicity. Sub-chronic toxicity study was carried out at doses of 1 000, 2 000 and 4 000 mg/kg administered daily for 60 days. The animals were sacrificed after 60 days. Blood was collected for biochemical (renal and hepatic), hematological, oxidative stress, sperm and histopathological examinations, using standard methods. LD50 of the extract was estimated as >4 000 mg/kg orally; neither significant visible signs of toxicity nor mortality were observed. There were no significant differences in the animals and organ weights, hematological and biochemical parameters in the treated groups compared to the control group. However, a significant increase (p<0.05) in the level of lipid peroxidation and a significant (p<0.05) decrease in sperm count were observed in the treated animals compared with the control group. The stem-bark aqueous extract of Bridelia ferruginea was found to be relatively safe, though it has the potential to cause lipid peroxidation and damage sperm quality and should thus be used with caution. PMID- 27486367 TI - Chemopreventive role of Coriandrum sativum against gentamicin-induced renal histopathological damage in rats. AB - Drug induced nephrotoxicity is one of the most common causes of renal failure. Gentamicin belongs to aminoglycosides, which elicit nephrotoxic potential. Natural antioxidants from plants demonstrate a number of biotherapeutic activities. Coriander is an important medicinal plant known for its hepatoprotective, diuretic, carminative, digestive and antihelminthic potential. This study was designed to investigate whether the extract of Coriandrum sativum ameliorates the nephrotoxicity induced by gentamicin in rats. Dried coriander powder was coarsely grinded and subjected to defatting by petroleum ether and further with ethyl acetate. The extract was filtered and subjected to phytochemical and phytoanalytical studies. Acute toxicity in Wistar rats was determined by the OECD Guideline (423). Animals were divided into four groups. The first group served as positive control, while the second group was toxic control (gentamicin treated). The third and fourth group were treated with the extract (200 and 400 mg/kg gentamicin). After 8 days, the animals were sacrificed and biochemical and histopathological studies were carried out. Phytochemical screening of the extract demonstrated Coriandrum sativum to be rich in flavonoids, polyphenolics and alkaloids. Results of acute toxicity suggested the use of 200 mg/kg and 400 mg/kg for Coriandrum sativum in the study. Coriandrum sativum extract at the dose of 400 mg/kg significantly (p<0.01) decreased creatinine levels in the animals, along with a decrease in serum urea and blood urea nitrogen. Treatment with Coriandrum sativum extract ameliorated renal histological lesions. It is concluded that Coriandrum sativum is a potential source of nephroprotective phytochemical activity, with flavonoids and polyphenols as the major components. PMID- 27486369 TI - The neurochemical profile of the hippocampus in isoflurane-treated and unanesthetized rat pups. AB - In vivo study of cerebral metabolism in neonatal animals by high-resolution magnetic resonance spectroscopy (MRS) is an important tool for deciphering the developmental origins of adult diseases. Up to date, all in vivo spectrum acquisition procedures have been performed in neonatal rodents under anesthesia. However, it is still unknown if the inhaled anesthetic isoflurane, which is commonly used in magnetic resonance imaging studies, could affect metabolite levels in the brain of neonatal rats. Moreover, the unanesthetized MRS preparation that uses neonatal rodent pups is still lacking. Here, a novel restraint protocol was developed for neonatal rats in accordance with the European Directive 2010/63/EU. This protocol shares the same gradation of severity as the protocol for non-invasive magnetic resonance imaging of animals with appropriate sedation or anesthesia. Such immobilization of neonatal rats without anesthesia can be implemented for MRS studies when an interaction between anesthetic and target drugs is expected. Short-term isoflurane treatment did not affect the levels of key metabolites in the hippocampi of anesthetized pups and, in contrast to juvenile and adult rodents, it is suitable for MRS studies in neonatal rats when the interaction between anesthetic and target drugs is not expected. PMID- 27486370 TI - Damascenine induced hepatotoxicity and nephrotoxicity in mice and in vitro assessed human erythrocyte toxicity. AB - Nigella damascena seed is characterized by the presence of the major alkaloid, damascenine and its related metabolites. To our knowledge, no detailed subchronic toxicological assessment of damascenine (DA) has been reported. The present study evaluated the potential toxicity of DA in vivo after sub-chronic intraperitoneal (i.p) administration in mice and in vitro following human erythrocyte hemolysis. In vivo, a total of 48 adult male and female Swiss albino mice were used in a sub chronic toxicity study. The mice received intraperitoneally two doses of DA (20 and 100 mg/kg) for 28 days. Food intake, body weight and central body temperature were measured during the experiment. After completion of drug treatment, biochemical and histological analyses were performed. No mortality was observed in any of the treatment groups of mice, showing no toxic effects during the study. Neither were biochemical parameters altered; no significant differences were observed concerning glucose, bilirubin, aspartate transaminase (AST), alanine aminotransferase (ALT), urea, and creatinine parameters. No histopathological alterations were found in kidney and liver structures. In vitro, we focused on the human erythrocyte hemolytic process in the presence of several concentrations of DA. High level concentration of 1 000 MUg/ml of DA revealed normal cell shapes and absence of hemolysis and deformation. PMID- 27486368 TI - Protective efficacy of folic acid and vitamin B12 against nicotine-induced toxicity in pancreatic islets of the rat. AB - Although cigarette smoking is associated with insulin resistance and an increased risk for type 2 diabetes, few studies have examined the effect of nicotine on the adult endocrine pancreas. In this study, male Wister rats were treated with nicotine (3 mg/kg body weight/ day) with or without supplementation of folic acid (36 MUg/kg body weight/day) or vitamin B12 (0.63 MUg/kg body weight/day) alone or in combination. Fasting blood glucose, insulin and HBA1C level and different oxidative and anti-oxidative stress parameters were measured and pancreatic tissue sections were stained with eosin-haematoxylene. Data were analysed by nonparametric statistics. The results revealed that nicotine induced prediabetes condition with subsequent damage to pancreatic islets in rats. Nicotine also caused oxidative stress in pancreatic tissue as evidenced by increased nitric oxide and malondialdehyde level and decreased superoxide dismutase, catalase and reduced glutathione level. Compared to vitamin B12 supplementation, folic acid blunted the nicotine-induced toxicity in pancreatic islets with higher efficacy. Further, folic acid and vitamin B12 in combination were able to confer significant protection on pancreatic islets against nicotine induced toxicity. These results suggest that supplementation of folic acid and vitamin B12 in combination may be a possible strategy of detoxification against nicotine-induced toxicity in pancreatic islets of the rat. PMID- 27486371 TI - Antitumor activity and antioxidant status of Streblus asper bark against Dalton's ascitic lymphoma in mice. AB - Streblus asper Lour (Moraceae), commonly known as Siamee Rough Brush in English is widely distributed in subtropical Asia and traditionally used for several medicinal purposes. In the present study, the ethyl acetate fraction of the methanol extract from Streblus asper bark (EASA) was evaluated for antitumor effect against Dalton's ascitic lymphoma (DAL) in Swiss albino mice. Twenty-four hours after intraperitoneal inoculation of DAL cells in mice, EASA was administered intraperitoneally at 200 and 400 mg/kg body weight for 9 consecutive days. On the 10th day, half of the mice were sacrificed to determine the tumor growth parameters, and the rest were kept alive for survival assessment. Hematological, serum biochemical and tissue (liver, kidney) antioxidant profiles were also determined. EASA exhibited significant and dose dependent decrease in tumor growth parameters and increased survival of DAL bearing animals. EASA significantly and dose-dependently normalized the altered hematological, serum biochemical and tissue antioxidant parameters as compared with the DAL control mice. From the present study it may be concluded that S. asper bark possesses remarkable antitumor efficacy mediated by amelioration of oxidative stress by multiple mechanisms. PMID- 27486372 TI - Zinc asparaginate supplementation induces redistribution of toxic trace elements in rat tissues and organs. AB - The primary objective of the current study was the investigation of the influence of zinc asparaginate supplementation for 7 and 14 days on toxic metal and metalloid content in rat organs and tissues. Rats obtained zinc asparaginate in doses of 5 and 15 mg/kg/day for 7 and 14 days. At the end of the experiment rat tissues and organs (liver, kidney, heart, m. gastrocnemius, serum, and hair) were collected for subsequent analysis. Estimation of Zn, Al, As, Li, Ni, Sn, Sr content in the harvested organs was performed using inductively coupled plasma mass spectrometry at NexION 300D. The obtained data showed that intragastric administration of zinc significantly increased liver, kidney and serum zinc concentrations. Seven-day zinc treatment significantly affected the toxic trace element content in the animals' organs. Zinc supplementation significantly decreased particularly liver aluminium, nickel, and tin content, whereas lead tended to increase. Zinc-induced changes in kidney metal content were characterized by elevated lithium and decreased nickel concentration. Zinc induced alteration of myocardical toxic element content was multidirectional. Muscle aluminium and lead concentration were reduced in response to zinc supplementation. At the same time, serum and hair toxic element concentrations remained relatively stable after 7-day zinc treatment. Zinc asparaginate treatment of 14 days significantly depressed liver and elevated kidney lithium content, whereas a significant zinc-associated decrease was detected in kidney strontium content. Zinc supplementation for 14 days resulted also in multidirectional changes in the content of heart toxic elements. At the same time, significant zinc-associated decrease in muscle lithium and nickel levels was observed. Fourteen-day zinc treatment resulted in significantly increased serum arsenic and tin concentrations, whereas hair trace element content remained relatively stable. Generally, the obtained data indicate a significant redistribution of toxic metals in the animal organism under zinc supplementation. PMID- 27486373 TI - Local salt substitutes "Obu-otoyo" activate acetylcholinesterase and butyrylcholinesterase and induce lipid peroxidation in rat brain. AB - Evidence has shown that ingestion of heavy metals can lead to neurodegenerative diseases. This study aimed to investigate the neurotoxic potential of salt substitutes (Obu-Otoyo); salt A (made by burning palm kernel shaft then soaked in water overnight and the extract from the resulting residue is used as the salt substitute) and salt B (an unrefined salt mined from a local site at Ilobu town, Osun-State, Nigeria) by assessing their effect on some key enzymes linked with neurodegenerative disease [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities] as well as on malondialdehyde (MDA) content of the rat brain. Salt substitutes were fed to normal rats as dietary inclusion at doses of 0.5 and 1.0% for 30 days. Thereafter, the effect of the salt substitutes on AChE and BChE activities as well as on MDA level in the rat brain was determined. The results revealed that the salt substitutes caused a significant (p<0.05) increase in both AChE and BChE activity and also induced lipid peroxidation in the brain of rats in vivo as well as under in vitro condition in a dose-dependent manner. The effect of the salt substitutes on AChE and BChE activities could be attributed to the presence of some toxic heavy metals. Therefore, the ability of the salt substitutes to induce lipid peroxidation and activate AChE and BChE activities could provide some possible mechanism for their neurotoxic effect. PMID- 27486374 TI - Blood level of cadmium and lead in occupationally exposed persons in Gwagwalada, Abuja, Nigeria. AB - This study was designed to assess the blood levels of cadmium and lead in some occupationally exposed individuals and compare the values with non-exposed individuals, with the aim of increasing the awareness of health risk caused by these heavy metals. A total of 120 subjects (64 occupationally exposed and 56 non exposed subjects) with the age range of 15-40 years were studied in cross sectional study conducted between September 2012 and February 2013 in Gwagwalada area of Abuja, Nigeria. Blood cadmium and lead were analyzed using an atomic absorption spectrophotometer (AAS). The respective mean blood levels of cadmium and lead were 11.63+/-1.73 MUg/dl and 45.43+/-6.93 MUg/dl in occupationally exposed subjects, while in non-exposed subjects 2.03+/-0.55 MUg/dl and 12.08+/ 2.87 MUg/dl. The results show that occupational exposure increases the blood level of cadmium and lead, which consequently increases the health risk of the exposed individuals. PMID- 27486375 TI - Effect of chronic exposure to cadmium on serum lipid, lipoprotein and oxidative stress indices in male rats. AB - Cadmium (Cd) is an environmental toxic metal implicated in lipid abnormalities. The present study was designed to elucidate the possible association between chronic exposure to Cd concentration and alterations in plasma lipid, lipoprotein, and oxidative stress indices in rats. Sixteen male rats were assigned to 2 groups of 8 rats each (test and control). The Cd-exposed group obtained drinking water containing cadmium chloride (CdCl2) in the concentration of 2.0 mg Cd/L in drinking water for 3 months. At the end of the experimental period, blood samples were obtained to determine the changes of serum triglycerides (TG), total cholesterol (TC), highdensity lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), reduced glutathione (GSH), malondialdehyde (MDA) and also serum Cd contents. The results of the present study indicated that Cd administration significantly increased the serum levels of TG, TC, LDL-C, MDA and Cd with reduction in the HDL-C and GSH levels. In conclusion, evidence is presented that chronic exposure to low Cd concentration can adversely affect the lipid and lipoprotein profile via lipid peroxidation. PMID- 27486376 TI - Expression of calmodulin-related genes in lead-exposed mice. AB - The toxic metal lead is a widespread environmental polutant that can adversely affect human health. However, the underlying mechanisms of lead-induced toxicity are still largely unknown. The mechanism of lead toxicity was presumed to involve cross reaction between Pb(2+) and Ca(2+) with calmodulin dependent systems. The aim of the present study was thus to identify differential expression of calmodulin-related genes in the spleen of lead-exposed mice. We performed microarray analysis to identify differentially expressed genes. RNAs from spleen tissue of lead exposed animals (n=6) and controls (n=6) were converted to labeled cRNA and hybridized to Illumina mouse WG-6_v2_Bead Chip. Expression profiles were analyzed using Illumina BeadStudio Application. Real-time RT-PCR was conducted to validate the microarray data. By microarray analysis 5 calmodulin-related genes (MAP2K6, CAMKK2, CXCR4, PHKA2, MYLK) were found to be differently expressed in lead exposed compared with control mice (p<0.05). The results of Real-time RT-PCR showed that MAP2K6 and CAMKK2 were up-regulated and CXCR4 was down-regulated in lead exposure, but there were no significant differences in PHKA2 and MYLK expression between the lead exposed and control group. These results show that lead exposure produced significant changes in expression of a variety of genes in the spleen and can affect calmodulin-related gene expression. PMID- 27486377 TI - Long-term changes in brain cholinergic system and behavior in rats following gestational exposure to lead: protective effect of calcium supplement. AB - Our earlier studies showed that lactational exposure to lead (Pb) caused irreversible neurochemical alterations in rats. The present study was carried out to examine whether gestational exposure to Pb can cause long-term changes in the brain cholinergic system and behavior of rats. The protective effect of calcium (Ca) supplementation against Pb toxicity was also examined. Pregnant rats were exposed to 0.2% Pb (Pb acetate in drinking water) from gestational day (GD) 6 to GD 21. The results showed decrease in body weight gain (GD 6-21) of dams, whereas no changes were observed in offspring body weight at different postnatal days following Pb exposure. Male offspring treated with Pb showed marginal alterations in developmental landmarks such as unfolding of pinnae, lower and upper incisor eruption, fur development, eye slit formation and eye opening on postnatal day (PND) 1, whereas significant alterations were found in the righting reflex (PNDs 4-7), slant board behavior (PNDs 8-10) and forelimb hang performance (PNDs 12 16). Biochemical analysis showed decrease in synaptosomal acetylcholinesterase (AChE) activity and an increase in acetylcholine (ACh) levels in the cortex, cerebellum and hippocampus on PND 14, PND 21, PND 28 and in the four-month age group of rats following Pb exposure. Significant deficits were also observed in total locomotor activity, exploratory behavior and open field behavior in selected age groups of Pb-exposed rats. These alterations were found to be maximal on PND 28, corresponding with the greater blood lead levels observed on PND 28. Addition of 0.02% Ca to Pb reversed the Pb-induced impairments in the cholinergic system as well as in behavioral parameters of rats. In conclusion, these data suggest that gestational exposure to Pb is able to induce long-term changes in neurological functions of offspring. Maternal Ca administration reversed these neurological effects of Pb later in life, suggesting a protective effect of calcium in Pb-exposed animals. PMID- 27486378 TI - Evaluation of miR-9 and miR-143 expression in urine specimens of sulfur mustard exposed patients. AB - Sulfur mustard (SM) or mustard gas is a chemical alkylating agent that causes blisters in the skin (blister gas), burns the eyes and causes lung injury. Some major cellular pathways are involved in the damage caused by mustard gas such as NF-kappab signaling, TGF-beta signaling, WNT pathway, inflammation, DNA repair and apoptosis. MicroRNAs are non-coding small RNAs (19-25 nucleotides) that are involved in the regulation of gene expression and are found in two forms, extracellular and intracellular. Changes in the levels of extracellular microRNAs are directly associated with many diseases, it is thus common to study the level of extracellular microRNAs as a biomarker to determine the pathophysiologic status. In this study, 32 mustard gas injured patients and 32healthy subjects participated. Comparative evaluation of miR-9 and miR-143 expression in urine samples was performed by Real Time PCR and Graph Pad software. The Mann Whitney t test analysis of data showed that the expression level of miR-143 and miR-9 had a significant decrease in sulfur mustard individuals with the respective p-value of 0.0480 and 0.0272 compared to normal samples, with an imbalance of several above mentioned pathways. It seems that reducing the expression level of these genes has a very important role in the pathogenicity of mustard gas injured patients. PMID- 27486379 TI - Modulatory effect of Mangifera indica against carbon tetrachloride induced kidney damage in rats. AB - There is little scientific evidence on the local use of Mangifera indica in kidney diseases. This study investigated the reno-modulatory roles of the aqueous stem bark extract of Mangifera indica (MIASE) against CCl4-induced renal damage. Rats were treated intragastrically with 125, 250 and 500 mg/kg/day MIASE for 7 days before and after the administration of CCl4 (3 ml/kg of 30% CCl4, i.p.). Serum levels of electrolytes (Na+, K+, Cl(-), HCO3(-)), urea and creatinine were determined. Renal tissue reduced glutathione (GSH), malondialdehyde (MDA), catalase (CAT), superoxide (SOD) activities were also assessed. The histopathological changes in kidneys were determined using standard methods. In CCl4 treated rats the results showed significant (p<0.05) increases in serum Na+, K+, Cl(-), urea and creatinine. CCl4 also caused significant (p<0.05) decreases in renal tissue SOD, CAT and GSH and significant (p<0.05) increases in MDA. The oral MIASE treatment (125-500 mg/kg) was found to significantly (p<0.05) attenuate the increase in serum electrolytes, urea and creatinine. Similarly, MIASE significantly (p<0.05) attenuated the decrease in SOD, CAT and GSH levels and correspondingly attenuated increases in MDA. Mangifera indica may present a great prospect for drug development in the management of kidney disease with lipid peroxidation as its etiology. PMID- 27486380 TI - Genotoxicity and antigenotoxicity study of aqueous and hydro-methanol extracts of Spondias mombin L., Nymphaea lotus L. and Luffa cylindrical L. using animal bioassays. AB - Spondias mombin (Linn), Nymphaea lotus (Linn) and Luffa cylindrica (Linn) (syn Luffa aegyptiaca Mill) are plants traditionally used as food ingredients and in the management of diseases, including cancer, in Nigeria. Despite the therapeutic potentials attributed to these plants, reports on their genotoxicity are scanty. In this study, the genotoxicity of the aqueous and hydro-methanol extract of these plants was evaluated using mouse bone marrow micronucleus and sperm morphology assays. Antigenotoxicity was assessed by the bone marrow micronucleus test. The highest attainable dose of 5 000 mg/kg according to OECD guidelines was first used to assess acute toxicity of the aqueous and hydro-methanol extracts in Swiss albino mice. For each extract, there were five groups of mice (n=4/group) treated with different concentrations of the extract as against the negative and positive control group for the genotoxicity study. In the antigenotoxicity study, five groups of mice were exposed to five different concentrations of the extracts along with 60 mg/kg of methyl methane sulfonate (MMS), which was used to induce genotoxicity. The mice were administered 0.2 mL of extract per day for 10 days in the genotoxicity and antigenotoxicity groups. Administration of each of the extracts at the concentration of 5 000 mg/kg did not induce acute toxicity in mice. At the concentrations tested, all the extracts, except aqueous S. mombin, increased micronucleated polychromatic erythrocytes. The aqueous and hydro methanol extracts of N. lotus increased the frequency of aberrant sperm cells. All the extracts were also able to ameliorate MMS induced genotoxicity in bone marrow cells of the exposed mice. The results showed the potential of the extracts to induce somatic and germ cell mutation in male mice. The extracts also ameliorated the genotoxic effect of MMS. PMID- 27486381 TI - Toxicological assessment of polyhexamethylene biguanide for water treatment. AB - Polyhexamethylene biguanide (PHMB) is an antiseptic with antiviral and antibacterial properties used in a variety of products including wound care dressings, contact lens cleaning solutions, perioperative cleansing products, and swimming pool cleaners. There are regulatory concerns with regard to its safety in humans for water treatment. We decided to assess the safety of this chemical in Sprague-Dawley rats. PHMB was administered in a single dose by gavage via a stomach tube as per the manufacturer's instruction within a dose range of 2 mg/kg to 40 mg/kg. Subchronic toxicity studies were also conducted at doses of 2 mg/kg, 8 mg/kg and 32 mg/kg body weight and hematological, biochemical and histopathological findings of the major organs were assessed. Administration of a dose of 25.6 mg/kg, i.e. 1.6 mL of 0.4% PHMB solution (equivalent to 6.4x10(3) mg/L of 0.1% solution) resulted in 50% mortality. Histopathological analysis in the acute toxicity studies showed that no histopathological lesions were observed in the heart and kidney samples but 30% of the animals had mild hydropic changes in zone 1 of their liver samples, while at a dosage of 32 mg/kg in the subchronic toxicity studies, 50% of the animals showed either mild hepatocyte cytolysis with or without lymphocyte infiltration and feathery degeneration. Lymphocyte infiltration was, for the first time, observed in one heart sample, whereas one kidney sample showed mild tubular damage. The acute studies showed that the median lethal dose (LD50) is 25.6 mg/kg (LC50 of 1.6 mL of 0.4% PHMB. Subchronic toxicological studies also revealed few deleterious effects on the internal organs examined, as seen from the results of the biochemical parameters evaluated. These results have implications for the use of PHMB to make water potable. PMID- 27486382 TI - Resistance to receptor tyrosine kinase inhibitors in solid tumors: can we improve the cancer fighting strategy by blocking autophagy? AB - A growing field of evidence suggests the involvement of oncogenic receptor tyrosine kinases (RTKs) in the transformation of malignant cells. Constitutive and abnormal activation of RTKs may occur in tumors either through hyperactivation of mutated RTKs or via functional upregulation by RTK-coding gene amplification. In several types of cancer prognosis and therapeutic responses were found to be associated with deregulated activation of one or more RTKs. Therefore, targeting various RTKs remains a significant challenge in the treatment of patients with diverse malignancies. However, a frequent issue with the use of RTK inhibitors is drug resistance. Autophagy activation during treatment with RTK inhibitors has been commonly observed as an obstacle to more efficacious therapy and has been associated with the limited efficacy of RTK inhibitors. In the present review, we discuss autophagy activation after the administration of RTK inhibitors and summarize the achievements of combination RTK/autophagy inhibitor therapy in overcoming the reported resistance to RTK inhibitors in a growing number of cancers. PMID- 27486383 TI - miRNA-135a promotes hepatocellular carcinoma cell migration and invasion by targeting forkhead box O1. AB - AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Many microRNAs (miRNAs), small non-coding RNAs, are involved in regulating cancer cell proliferation, metastasis, migration, invasion and apoptosis. MAIN METHODS: We investigated the expression of miR-135a in HCC cell lines and clinical tissues. The effect of miR-135a on migration and invasion of HepG2 and MHCC-97L were examined using wound healing and Transwell assay. We determined the expression of miR-135a, forkhead box O1 (FOXO1), matrix metalloproteinase-2 (MMP-2) and Snail using real-time PCR and western blotting. KEY FINDINGS: We found miR-135a was upregulated in HCC cell lines and tissues. miR-135a overexpression promoted HCC cells migration and invasion, whereas miR 135a inhibition suppressed HCC cells migration and invasion. miR-135a overexpression could upregulate the expression of MMP2, Snail and the phosphorylation of AKT, but decreased FOXO3a phosporylation. Tumor suppressor FOXO1 was the direct target for miR-135a. SIGNIFICANCE: Our results suggested that miR-135a might play an important role in promoting migration and invasion in HCC and presents a novel mechanism of miRNA-mediated direct suppression of FOXO1 in HCC cells. PMID- 27486384 TI - Apolipoprotein A-I gene transfer exerts immunomodulatory effects and reduces vascular inflammation and fibrosis in ob/ob mice. AB - BACKGROUND: Obesity is associated with vascular inflammation, fibrosis and reduced high-density lipoproteins (HDL)-cholesterol. We aimed to investigate whether adenoviral gene transfer with human apolipoprotein (apo) A-I (Ad.A-I), the main apo of HDL, could exert immunomodulatory effects and counteract vascular inflammation and fibrosis in ob/ob mice. METHODS: Ad.A-I transfer was performed in 8 weeks (w) old ob/ob mice, which were sacrificed 7 w later. The aorta was excised for mRNA analysis and the spleen for splenocyte isolation for subsequent flow cytometry and co-culture with murine fibroblasts. HDL was added to mononuclear cells (MNC) and fibroblasts to assess their impact on adhesion capacity and collagen deposition, respectively. RESULTS: Ad.A-I led to a 1.8-fold (p < 0.05) increase in HDL-cholesterol versus control ob/ob mice at the day of sacrifice, which was paralleled by a decrease in aortic TNF-alpha and VCAM-1 mRNA expression. Pre-culture of MNC with HDL decreased their adhesion to TNF-alpha activated HAEC. Ad.A-I exerted immunomodulatory effects as evidenced by a downregulation of aortic NOD2 and NLRP3 mRNA expression and by a 12 %, 6.9 %, and 15 % decrease of the induced proliferation/activity of total splenic MNC, CD4+, and CD8+ cells in ob/ob Ad.A-I versus control ob/ob mice, respectively (p < 0.05). Ad.A-I further reduced aortic collagen I and III mRNA expression by 62 % and 66 %, respectively (p < 0.0005), and abrogated the potential of ob/ob splenocytes to induce the collagen content in murine fibroblasts upon co-culture. Finally, HDL decreased the TGF-beta1-induced collagen deposition of murine fibroblasts in vitro. CONCLUSIONS: Apo A-I transfer counteracts vascular inflammation and fibrosis in ob/ob mice. PMID- 27486385 TI - Comparative approaches for assessing access to alcohol outlets: exploring the utility of a gravity potential approach. AB - BACKGROUND: A growing body of research recommends controlling alcohol availability to reduce harm. Various common approaches, however, provide dramatically different pictures of the physical availability of alcohol. This limits our understanding of the distribution of alcohol access, the causes and consequences of this distribution, and how best to reduce harm. The aim of this study is to introduce both a gravity potential measure of access to alcohol outlets, comparing its strengths and weaknesses to other popular approaches, and an empirically-derived taxonomy of neighborhoods based on the type of alcohol access they exhibit. METHODS: We obtained geospatial data on Seattle, including the location of 2402 alcohol outlets, United States Census Bureau estimates on 567 block groups, and a comprehensive street network. We used exploratory spatial data analysis and employed a measure of inter-rater agreement to capture differences in our taxonomy of alcohol availability measures. RESULTS: Significant statistical and spatial variability exists between measures of alcohol access, and these differences have meaningful practical implications. In particular, standard measures of outlet density (e.g., spatial, per capita, roadway miles) can lead to biased estimates of physical availability that over emphasize the influence of the control variables. Employing a gravity potential approach provides a more balanced, geographically-sensitive measure of access to alcohol outlets. CONCLUSIONS: Accurately measuring the physical availability of alcohol is critical for understanding the causes and consequences of its distribution and for developing effective evidence-based policy to manage the alcohol outlet licensing process. A gravity potential model provides a superior measure of alcohol access, and the alcohol access-based taxonomy a helpful evidence-based heuristic for scholars and local policymakers. PMID- 27486386 TI - Manual-Protocol Inspired Technique for Improving Automated MR Image Segmentation during Label Fusion. AB - Recent advances in multi-atlas based algorithms address many of the previous limitations in model-based and probabilistic segmentation methods. However, at the label fusion stage, a majority of algorithms focus primarily on optimizing weight-maps associated with the atlas library based on a theoretical objective function that approximates the segmentation error. In contrast, we propose a novel method-Autocorrecting Walks over Localized Markov Random Fields (AWoL-MRF) that aims at mimicking the sequential process of manual segmentation, which is the gold-standard for virtually all the segmentation methods. AWoL-MRF begins with a set of candidate labels generated by a multi-atlas segmentation pipeline as an initial label distribution and refines low confidence regions based on a localized Markov random field (L-MRF) model using a novel sequential inference process (walks). We show that AWoL-MRF produces state-of-the-art results with superior accuracy and robustness with a small atlas library compared to existing methods. We validate the proposed approach by performing hippocampal segmentations on three independent datasets: (1) Alzheimer's Disease Neuroimaging Database (ADNI); (2) First Episode Psychosis patient cohort; and (3) A cohort of preterm neonates scanned early in life and at term-equivalent age. We assess the improvement in the performance qualitatively as well as quantitatively by comparing AWoL-MRF with majority vote, STAPLE, and Joint Label Fusion methods. AWoL-MRF reaches a maximum accuracy of 0.881 (dataset 1), 0.897 (dataset 2), and 0.807 (dataset 3) based on Dice similarity coefficient metric, offering significant performance improvements with a smaller atlas library (< 10) over compared methods. We also evaluate the diagnostic utility of AWoL-MRF by analyzing the volume differences per disease category in the ADNI1: Complete Screening dataset. We have made the source code for AWoL-MRF public at: https://github.com/CobraLab/AWoL-MRF. PMID- 27486387 TI - Mitochondrial Dynamics Decrease Prior to Axon Degeneration Induced by Vincristine and are Partially Rescued by Overexpressed cytNmnat1. AB - Axon degeneration is a prominent feature of various neurodegenerative diseases, such as Parkinson's and Alzheimer's, and is often characterized by aberrant mitochondrial dynamics. Mitochondrial fission, fusion, and motility have been shown to be particularly important in progressive neurodegeneration. Thus we investigated these imperative dynamics, as well as mitochondrial fragmentation in vincristine induced axon degradation in cultured dorsal root ganglia (DRG) neurons. CytNmnat1 inhibits axon degeneration in various paradigms including vincristine toxicity. The mechanism of its protection is not yet fully understood; therefore, we also investigated the effect of cytNmnat1 on mitochondrial dynamics in vincristine treated neurons. We observed that vincristine treatment decreases the rate of mitochondrial fission, fusion and motility and induces mitochondrial fragmentation. These mitochondrial events precede visible axon degeneration. Overexpression of cytNmnat1 inhibits axon degeneration and preserves the normal mitochondrial dynamics and motility in vincristine treated neurons. We suggest the alterations in mitochondrial structure and dynamics are early events which lead to axon degeneration and cytNmnat1 blocks axon degeneration by halting the vincristine induced changes to mitochondrial structure and dynamics. PMID- 27486388 TI - A Pair of Pharyngeal Gustatory Receptor Neurons Regulates Caffeine-Dependent Ingestion in Drosophila Larvae. AB - The sense of taste is an essential chemosensory modality that enables animals to identify appropriate food sources and control feeding behavior. In particular, the recognition of bitter taste prevents animals from feeding on harmful substances. Feeding is a complex behavior comprised of multiple steps, and food quality is continuously assessed. We here examined the role of pharyngeal gustatory organs in ingestion behavior. As a first step, we constructed a gustatory receptor-to-neuron map of the larval pharyngeal sense organs, and examined corresponding gustatory receptor neuron (GRN) projections in the larval brain. Out of 22 candidate bitter compounds, we found 14 bitter compounds that elicit inhibition of ingestion in a dose-dependent manner. We provide evidence that certain pharyngeal GRNs are necessary and sufficient for the ingestion response of larvae to caffeine. Additionally, we show that a specific pair of pharyngeal GRNs, DP1, responds to caffeine by calcium imaging. In this study we show that a specific pair of GRNs in the pharyngeal sense organs coordinates caffeine sensing with regulation of behavioral responses such as ingestion. Our results indicate that in Drosophila larvae, the pharyngeal GRNs have a major role in sensing food palatability to regulate ingestion behavior. The pharyngeal sense organs are prime candidates to influence ingestion due to their position in the pharynx, and they may act as first level sensors of ingested food. PMID- 27486390 TI - Whisking Kinematics Enables Object Localization in Head-Centered Coordinates Based on Tactile Information from a Single Vibrissa. AB - During active tactile exploration with their whiskers (vibrissae), rodents can rapidly orient to an object even though there are very few proprioceptors in the whisker muscles. Thus a long-standing question in the study of the vibrissal system is how the rat can localize an object in head-centered coordinates without muscle-based proprioception. We used a three-dimensional model of whisker bending to simulate whisking motions against a peg to investigate the possibility that the 3D mechanics of contact from a single whisker are sufficient for localization in head-centered coordinates. Results show that for nearly all whiskers in the array, purely tactile signals at the whisker base - as would be measured by mechanoreceptors, in whisker-centered coordinates - could be used to determine the location of a vertical peg in head-centered coordinates. Both the "roll" and the "elevation" components of whisking kinematics contribute to the uniqueness and resolution of the localization. These results offer an explanation for a behavioral study showing that rats can more accurately determine the horizontal angle of an object if one column, rather than one row, of whiskers is spared. PMID- 27486391 TI - Intermittent Theta Burst Over M1 May Increase Peak Power of a Wingate Anaerobic Test and Prevent the Reduction of Voluntary Activation Measured with Transcranial Magnetic Stimulation. AB - Despite the potential of repetitive transcranial magnetic stimulation (rTMS) to improve performances in patients suffering from motor neuronal afflictions, its effect on motor performance enhancement in healthy subjects during a specific sport task is still unknown. We hypothesized that after an intermittent theta burst (iTBS) treatment, performance during the Wingate Anaerobic Test (WAnT) will increase and supraspinal fatigue following the exercise will be lower in comparison to a control treatment. Ten subjects participated in two randomized experiments consisting of a WAnT 5 min after either an iTBS or a control treatment. We determined voluntary activation (VA) of the right knee extensors with TMS (VATMS) and with peripheral nerve stimulation (VAPNS) of the femoral nerve, before and after the WAnT. T-tests were applied to the WAnT results and a two way within subject ANOVA was applied to VA results. The iTBS treatment increased the peak power and the maximum pedalling cadence and suppressed the reduction of VATMS following the WAnT compared to the control treatment. No behavioral changes related to fatigue (mean power and fatigue index) were observed. These results indicate for the first time that iTBS could be used as a potential intervention to improve anaerobic performance in a sport specific task. PMID- 27486389 TI - Horizontal Cells, the Odd Ones Out in the Retina, Give Insights into Development and Disease. AB - Thorough investigation of a neuronal population can help reveal key aspects regarding the nervous system and its development. The retinal horizontal cells have several extraordinary features making them particularly interesting for addressing questions regarding fate assignment and subtype specification. In this review we discuss and summarize data concerning the formation and diversity of horizontal cells, how morphology is correlated to molecular markers, and how fate assignment separates the horizontal lineage from the lineages of other retinal cell types. We discuss the novel and unique features of the final cell cycle of horizontal cell progenitors and how they may relate to retinoblastoma carcinogenesis. PMID- 27486392 TI - Oxytocin and Social Sensitivity: Gene Polymorphisms in Relation to Depressive Symptoms and Suicidal Ideation. AB - Although the neuropeptide oxytocin has been associated with enhanced prosocial behaviors, it has also been linked to aggression and mental health disorders. Thus, it was suggested that oxytocin might act by increasing the salience of social stimuli, irrespective of whether these are positive or negative, thus increasing vulnerability to negative mental health outcomes. The current study (N = 243), conducted among white university students, examined the relation of trauma, depressive symptoms including suicidal ideation in relation to a single nucleotide polymorphism (SNP) within the oxytocin receptor gene (OXTR), rs53576, and a SNP on the CD38 gene that controls oxytocin release, rs3796863. Individuals with the polymorphism on both alleles (AA genotype) of the CD38 SNP had previously been linked to elevated plasma oxytocin levels. Consistent with the social sensitivity perspective, however, in the current study, individuals carrying the AA genotype displayed elevated feelings of alienation from parents and peers as well as increased levels of suicidal ideation. Moreover, they tended to report elevated depressive symptoms compared to CC homozygotes. It was also observed that the CD38 genotype moderated the relation between trauma and suicidal ideation scores, such that high levels of trauma were associated with elevated suicidal ideation among all CD38 genotypes, but this relationship was stronger among individuals with the AA genotype. In contrast, there was no relationship between the OXTR SNP, rs53576, depression or suicidal ideation. These findings support a social sensitivity hypothesis of oxytocin, wherein the AA genotype of the CD38 SNP, which has been considered the "protective allele" was associated with increased sensitivity and susceptibility to disturbed social relations and suicidal ideation. PMID- 27486395 TI - A Comprehensive Account of Sound Sequence Imitation in the Songbird. AB - The amazing imitation capabilities of songbirds show that they can memorize sensory sequences and transform them into motor activities which in turn generate the original sound sequences. This suggests that the bird's brain can learn (1) to reliably reproduce spatio-temporal sensory representations and (2) to transform them into corresponding spatio-temporal motor activations by using an inverse mapping. Neither the synaptic mechanisms nor the network architecture enabling these two fundamental aspects of imitation learning are known. We propose an architecture of coupled neuronal modules that mimick areas in the song bird and show that a unique synaptic plasticity mechanism can serve to learn both, sensory sequences in a recurrent neuronal network, as well as an inverse model that transforms the sensory memories into the corresponding motor activations. The proposed membrane potential dependent learning rule together with the architecture that includes basic features of the bird's brain represents the first comprehensive account of bird imitation learning based on spiking neurons. PMID- 27486393 TI - Spared Primary Motor Cortex and The Presence of MEP in Cerebral Palsy Dictate the Responsiveness to tDCS during Gait Training. AB - The current priority of investigations involving transcranial direct current stimulation (tDCS) and neurorehabilitation is to identify biomarkers associated with the positive results of the interventions such that respondent and non respondent patients can be identified in the early phases of treatment. The aims were to determine whether: (1) present motor evoked potential (MEP); and (2) injuries involving the primary motor cortex, are associated with tDCS-enhancement in functional outcome following gait training in children with cerebral palsy (CP). We reviewed the data from our parallel, randomized, sham-controlled, double blind studies. Fifty-six children with spastic CP received gait training (either treadmill training or virtual reality training) and tDCS (active or sham). Univariate and multivariate logistic regression analyses were employed to identify clinical, neurophysiologic and neuroanatomic predictors associated with the responsiveness to treatment with tDCS. MEP presence during the initial evaluation and the subcortical injury were associated with positive effects in the functional results. The logistic regression revealed that present MEP was a significant predictor for the six-minute walk test (6MWT; p = 0.003) and gait speed (p = 0.028), whereas the subcortical injury was a significant predictor of gait kinematics (p = 0.013) and gross motor function (p = 0.021). In this preliminary study involving children with CP, two important prediction factors of good responses to anodal tDCS combined with gait training were identified. Apparently, MEP (integrity of the corticospinal tract) and subcortical location of the brain injury exerted different influences on aspects related to gait, such as velocity and kinematics. PMID- 27486396 TI - Coding Properties of Mouse Retinal Ganglion Cells with Dual-Peak Patterns with Respect to Stimulus Intervals. AB - How visual information is encoded in spikes of retinal ganglion cells (RGCs) is essential in visual neuroscience. In the present study, we investigated the coding properties of mouse RGCs with dual-peak patterns with respect to visual stimulus intervals. We first analyzed the response properties, and observed that the latencies and spike counts of the two response peaks in the dual-peak pattern exhibited systematic changes with the preceding light-OFF interval. We then applied linear discriminant analysis (LDA) to assess the relative contributions of response characteristics of both peaks in information coding regarding the preceding stimulus interval. It was found that for each peak, the discrimination results were far better than chance level based on either latency or spike count, and were further improved by using the combination of the two parameters. Furthermore, the best discrimination results were obtained when latencies and spike counts of both peaks were considered in combination. In addition, the correct rate for stimulation discrimination was higher when RGC population activity was considered as compare to single neuron's activity, and the correct rate was increased with the group size. These results suggest that rate coding, temporal coding, and population coding are all involved in encoding the different stimulus-interval patterns, and the two response peaks in the dual-peak pattern carry complementary information about stimulus interval. PMID- 27486397 TI - Handling Metadata in a Neurophysiology Laboratory. AB - To date, non-reproducibility of neurophysiological research is a matter of intense discussion in the scientific community. A crucial component to enhance reproducibility is to comprehensively collect and store metadata, that is, all information about the experiment, the data, and the applied preprocessing steps on the data, such that they can be accessed and shared in a consistent and simple manner. However, the complexity of experiments, the highly specialized analysis workflows and a lack of knowledge on how to make use of supporting software tools often overburden researchers to perform such a detailed documentation. For this reason, the collected metadata are often incomplete, incomprehensible for outsiders or ambiguous. Based on our research experience in dealing with diverse datasets, we here provide conceptual and technical guidance to overcome the challenges associated with the collection, organization, and storage of metadata in a neurophysiology laboratory. Through the concrete example of managing the metadata of a complex experiment that yields multi-channel recordings from monkeys performing a behavioral motor task, we practically demonstrate the implementation of these approaches and solutions with the intention that they may be generalized to other projects. Moreover, we detail five use cases that demonstrate the resulting benefits of constructing a well-organized metadata collection when processing or analyzing the recorded data, in particular when these are shared between laboratories in a modern scientific collaboration. Finally, we suggest an adaptable workflow to accumulate, structure and store metadata from different sources using, by way of example, the odML metadata framework. PMID- 27486394 TI - Higher Precision in Pointing Movements of the Preferred vs. Non-Preferred Hand Is Associated with an Earlier Occurrence of Anticipatory Postural Adjustments. AB - It is a common experience to exhibit a greater dexterity when performing a pointing movement with the preferred limb (PREF) vs. the non-preferred (NON-PREF) one. Here we provide evidence that the higher precision in pointing movements of the PREF vs. NON-PREF hand is associated with an earlier occurrence of the anticipatory postural adjustments (APAs). In this aim, we compared the APAs which stabilize the left or the right arm when performing a pen-pointing movement (prime mover flexor carpi radialis (FCR)). Moreover, we analyzed the elbow and wrist kinematics as well as the precision of the pointing movement. The mean kinematics of wrist movement and its latency, with respect to prime mover recruitment, were similar in the two sides, while APAs in triceps brachii (TB), biceps brachii (BB) and anterior deltoid (AD) were more anticipated when movements were performed with the PREF than with the NON-PREF hand (60-70 vs. 20 30 ms). APAs amplitudes were comparable in the muscles of the two sides. Earlier APAs in the preferred limb were associated with a better fixation of the elbow, which showed a lower excursion, and with a less scattered pointing error (PREF: 10.1 +/- 0.8 mm; NON-PREF: 16.3 +/- 1.7). Present results suggest that, by securing the more proximal joints dynamics, an appropriate timing of the intra limb APAs is necessary for refining the voluntary movement precision, which is known to be scarce on the NON-PREF side. PMID- 27486398 TI - Proposed Training to Meet Challenges of Large-Scale Data in Neuroscience. AB - The scale of data being produced in neuroscience at present and in the future creates new and unheralded challenges, outstripping conventional ways of handling, considering, and analyzing data. As neuroinformatics enters into this big data era, a need for a highly trained and perhaps unique workforce is emerging. To determine the staffing needs created by the impending era of big data, a workshop (iNeuro Project) was convened November 13-14, 2014. Participants included data resource providers, bioinformatics/analytics trainers, computer scientists, library scientists, and neuroscience educators. These individuals provided perspectives on the challenges of big data, the preparation of a workforce to meet these challenges, and the present state of training programs. Participants discussed whether suitable training programs will need to be constructed from scratch or if existing programs can serve as models. Currently, most programs at the undergraduate and graduate levels are located in Europe participants knew of none in the United States. The skill sets that training programs would need to provide as well as the curriculum necessary to teach them were also discussed. Consistent with Vision and Change in Undergraduate Biology Education: A Call to Action, proposed curricula included authentic, hands-on research experiences. Further discussions revolved around the logistics and barriers to creating such programs. The full white paper, iNeuro Project Workshop Report, is available from iNeuro Project. PMID- 27486399 TI - Mechanosensory Neuron Aging: Differential Trajectories with Lifespan-Extending Alaskan Berry and Fungal Treatments in Caenorhabditis elegans. AB - Many nutritional interventions that increase lifespan are also proposed to postpone age-related declines in motor and cognitive function. Potential sources of anti-aging compounds are the plants and fungi that have adapted to extreme environments. We studied the effects of four commonly consumed and culturally relevant Interior Alaska berry and fungus species (bog blueberry, lowbush cranberry, crowberry, and chaga) on the decline in overall health and neuron function and changes in touch receptor neuron morphology associated with aging. We observed increased wild-type Caenorhabditis elegans lifespan and improved markers of healthspan upon treatment with Alaskan blueberry, lowbush cranberry, and chaga extracts. Interestingly, although all three treatments increased lifespan, they differentially affected the development of aberrant morphologies in touch receptor neurons. Blueberry treatments decreased anterior mechanosensory neuron (ALM) aberrations (i.e., extended outgrowths and abnormal cell bodies) while lowbush cranberry treatment increased posterior mechanosensory neuron (PLM) aberrations, namely process branching. Chaga treatment both decreased ALM aberrations (i.e., extended outgrowths) and increased PLM aberrations (i.e., process branching and loops). These results support the large body of knowledge positing that there are multiple cellular strategies and mechanisms for promoting health with age. Importantly, these results also demonstrate that although an accumulation of abnormal neuron morphologies is associated with aging and decreased health, not all of these morphologies are detrimental to neuronal and organismal health. PMID- 27486400 TI - Statistical Approaches for the Study of Cognitive and Brain Aging. AB - Neuroimaging studies of cognitive and brain aging often yield massive datasets that create many analytic and statistical challenges. In this paper, we discuss and address several limitations in the existing work. (1) Linear models are often used to model the age effects on neuroimaging markers, which may be inadequate in capturing the potential nonlinear age effects. (2) Marginal correlations are often used in brain network analysis, which are not efficient in characterizing a complex brain network. (3) Due to the challenge of high-dimensionality, only a small subset of the regional neuroimaging markers is considered in a prediction model, which could miss important regional markers. To overcome those obstacles, we introduce several advanced statistical methods for analyzing data from cognitive and brain aging studies. Specifically, we introduce semiparametric models for modeling age effects, graphical models for brain network analysis, and penalized regression methods for selecting the most important markers in predicting cognitive outcomes. We illustrate these methods using the healthy aging data from the Active Brain Study. PMID- 27486401 TI - HLA-B (*) 58:01 for Allopurinol-Induced Cutaneous Adverse Drug Reactions: Implication for Clinical Interpretation in Thailand. AB - BACKGROUND: The aim of this study was to investigate the predisposition to different types of allopurinol-induced cutaneous adverse drug reactions (CADR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN; SJS TEN, n = 13), drug reaction with eosinophilia and systemic symptoms (DRESS, n = 10) and Maculopapular eruption (MPE; n = 7), conferred by HLA-B (*) 58:01 in a Thai population. METHODS: This case-control association study compares 30 patients with allopurinol-induced CADR, allopurinol-tolerant control patients (n = 100), and a Thai general population (n = 1095). Patients' human leukocyte antigen type B (HLA-B) alleles were genotyped by using a two-stage sequence specific oligonucleotide probe system. RESULTS: Of a total 30 patients with CADR due to allopurinol, 29 (96.7%) patients were found to be at least heterozygous for HLA-B (*) 58:01, compared to only 4.0% in allopurinol-tolerant patients (p < 0.001). Odds ratio (OR) for the association of HLA-B (*) 58:01 with allopurinol induced CADR in this population was 696.0 (95% CI: 74.8-6475.0). The HLA-B (*) 58:01 allele was present in all patients with allopurinol-induced SJS-TEN (OR = 579.0, 95%CI: 29.5-11362.7, p < 0.001) and DRESS (OR 430.3, 95%CI: 22.6-8958.9, p < 0.001). Additionally, OR of HLA-B (*) 58:01 was highly significant in the allopurinol-induced MPE patients (OR 144.0, 95%CI: 13.9-1497.0, p < 0.001). CONCLUSION: In this study we confirmed the association between HLAB (*) 58:01 and allopurinol-induced SJS-TEN in a Thai population. In addition, we identified an association between HLA-B (*) 58:01 and allopurinol-induced DRESS and MPE in this population. Therefore, HLA-B (*) 58:01 can be used as a pharmacogenetic marker for allopurinol-induced CADR including SJS-TEN, DRESS and MPE. These results suggest that screening for HLA-B (*) 58:01 alleles in patients who will be treated with allopurinol would be clinically helpful in preventing the risk of developing CARD in a Thai patients. Summary Regardless of phenotype, this is the first pharmacogenetic study of allopurinol-induced CADR in patients of Thai ancestry.In this study we confirmed the association between HLA-B (*) 58:01 and allopurinol-induced SJS-TEN, DRESS, and MPE in Thai population.Regarding to our findings, the pharmacogenetic interpretation could be generalized to drug hypersensitivity including DRESS, SJS-TEN, and MPE. PMID- 27486402 TI - Orthodontic Forces Induce the Cytoprotective Enzyme Heme Oxygenase-1 in Rats. AB - Orthodontic forces disturb the microenvironment of the periodontal ligament (PDL), and induce craniofacial bone remodeling which is necessary for tooth movement. Unfortunately, orthodontic tooth movement is often hampered by ischemic injury and cell death within the PDL (hyalinization) and root resorption. Large inter-individual differences in hyalinization and root resorption have been observed, and may be explained by differential protection against hyalinization. Heme oxygenase-1 (HO-1) forms an important protective mechanism by breaking down heme into the strong anti-oxidants biliverdin/bilirubin and the signaling molecule carbon monoxide. These versatile HO-1 products protect against ischemic and inflammatory injury. We postulate that orthodontic forces induce HO-1 expression in the PDL during experimental tooth movement. Twenty-five 6-week-old male Wistar rats were used in this study. The upper three molars at one side were moved mesially using a Nickel-Titanium coil spring, providing a continuous orthodontic force of 10 cN. The contralateral side served as control. After 6, 12, 72, 96, and 120 h groups of rats were killed. On parasagittal sections immunohistochemical staining was performed for analysis of HO-1 expression and quantification of osteoclasts. Orthodontic force induced a significant time dependent HO-1 expression in mononuclear cells within the PDL at both the apposition- and resorption side. Shortly after placement of the orthodontic appliance HO-1 expression was highly induced in PDL cells but dropped to control levels within 72 h. Some osteoclasts were also HO-1 positive but this induction was shown to be independent of time- and mechanical stress. It is tempting to speculate that differential induction of tissue protecting- and osteoclast activating genes in the PDL determine the level of bone resorption and hyalinization and, subsequently, "fast" and "slow" tooth movers during orthodontic treatment. PMID- 27486403 TI - Cloning, Characteristics, and Functional Analysis of Rabbit NADPH Oxidase 5. AB - BACKGROUND: Nox5 was the last member of the Nox enzyme family to be identified. Functionally distinct from the other Nox isoforms, our understanding of its physiological significance has been hampered by the absence of Nox5 in mouse and rat genomes. Nox5 is present in the genomes of other species such as the rabbit that have broad utility as models of cardiovascular disease. However, the mRNA sequence, characteristics, and functional analysis of rabbit Nox5 has not been fully defined and were the goals of the current study. METHODS: Rabbit Nox5 was amplified from rabbit tissue, cloned, and sequenced. COS-7 cells were employed for expression and functional analysis via Western blotting and measurements of superoxide. We designed and synthesized miRNAs selectively targeting rabbit Nox5. The nucleotide and amino acid sequences of rabbit Nox5 were aligned with those of putative rabbit isoforms (X1, X2, X3, and X4). A phylogenetic tree was generated based on the mRNA sequence for Nox5 from rabbit and other species. RESULTS: Sequence alignment revealed that the identified rabbit Nox5 was highly conserved with the predicted sequence of rabbit Nox5. Cell based experiments reveal that rabbit Nox5 was robustly expressed and produced superoxide at rest and in a calcium and PMA-dependent manner that was susceptible to superoxide dismutase and the flavoprotein inhibitor, DPI. miRNA-1 was shown to be most effective in down regulating the expression of rabbit Nox5. Phylogenetic analysis revealed a close relationship between rabbit and armadillo Nox5. Rabbit Nox5 was relatively closely related to human Nox5, but lies in a distinct cluster. CONCLUSION: Our study establishes the suitability of the rabbit as a model organism to further our understanding of the role of Nox5 in cardiovascular and other diseases and provides new information on the genetic relationship of Nox5 genes in different species. PMID- 27486404 TI - Fast Regulation of Vertical Squat Jump during Push-Off in Skilled Jumpers. AB - The height of a maximum Vertical Squat Jump (VSJ) reflects the useful power produced by a jumper during the push-off phase. In turn this partly depends on the coordination of the jumper's segmental rotations at each instant. The physical system constituted by the jumper has been shown to be very sensitive to perturbations and furthermore the movement is realized in a very short time (ca. 300 ms), compared to the timing of known feedback loops. However, the dynamics of the segmental coordination and its efficiency in relation to energetics at each instant of the push-off phase still remained to be clarified. Their study was the main purpose of the present research. Eight young adult volunteers (males) performed maximal VSJ. They were skilled in jumping according to their sport activities (track and field or volleyball). A video analysis on the kinematics of the jump determined the influence of the jumpers' segments rotation on the vertical velocity and acceleration of the body mass center (MC). The efficiency in the production of useful power at the jumpers' MC level, by the rotation of the segments, was measured in consequence. The results showed a great variability in the segmental movements of the eight jumpers, but homogeneity in the overall evolution of these movements with three consecutive types of coordination in the second part of the push-off (lasting roughly 0.16 s). Further analyses gave insights on the regulation of the push-off, suggesting that very fast regulation(s) of the VSJ may be supported by: (a) the adaptation of the motor cerebral programming to the jumper's physical characteristics; (b) the control of the initial posture; and PMID- 27486405 TI - Altered Differential Control of Sympathetic Outflow Following Sedentary Conditions: Role of Subregional Neuroplasticity in the RVLM. AB - Despite the classically held belief of an "all-or-none" activation of the sympathetic nervous system, differential responses in sympathetic nerve activity (SNA) can occur acutely at varying magnitudes and in opposing directions. Sympathetic nerves also appear to contribute differentially to various disease states including hypertension and heart failure. Previously we have reported that sedentary conditions enhanced responses of splanchnic SNA (SSNA) but not lumbar SNA (LSNA) to activation of the rostral ventrolateral medulla (RVLM) in rats. Bulbospinal RVLM neurons from sedentary rats also exhibit increased dendritic branching in rostral regions of the RVLM. We hypothesized that regionally specific structural neuroplasticity would manifest as enhanced SSNA but not LSNA following activation of the rostral RVLM. To test this hypothesis, groups of physically active (10-12 weeks on running wheels) or sedentary, male Sprague Dawley rats were instrumented to record mean arterial pressure, LSNA and SSNA under Inactin anesthesia and during microinjections of glutamate (30 nl, 10 mM) into multiple sites within the RVLM. Sedentary conditions enhanced SSNA but not LSNA responses and SSNA responses were enhanced at more central and rostral sites. Results suggest that enhanced SSNA responses in rostral RVLM coincide with enhanced dendritic branching in rostral RVLM observed previously. Identifying structural and functional neuroplasticity in specific populations of RVLM neurons may help identify new treatments for cardiovascular diseases, known to be more prevalent in sedentary individuals. PMID- 27486406 TI - A Guide to Transient Expression of Membrane Proteins in HEK-293 Cells for Functional Characterization. AB - The human embryonic kidney 293 (HEK-293) cells are commonly used as host for the heterologous expression of membrane proteins not least because they have a high transfection efficiency and faithfully translate and process proteins. In addition, their cell size, morphology and division rate, and low expression of native channels are traits that are particularly attractive for current-voltage measurements. Nevertheless, the heterologous expression of complex membrane proteins such as receptors and ion channels for biological characterization and in particular for single-cell applications such as electrophysiology remains a challenge. Expression of functional proteins depends largely on careful step-by step optimization that includes the design of expression vectors with suitable identification tags, as well as the selection of transfection methods and detection parameters appropriate for the application. Here, we use the heterologous expression of a plant potassium channel, the Arabidopsis thaliana guard cell outward-rectifying K(+) channel, AtGORK (At5G37500) in HEK-293 cells as an example, to evaluate commonly used transfection reagents and fluorescent detection methods, and provide a detailed methodology for optimized transient transfection and expression of membrane proteins for in vivo studies in general and for single-cell applications in particular. This optimized protocol will facilitate the physiological and cellular characterization of complex membrane proteins. PMID- 27486407 TI - Ectotherms in Variable Thermal Landscapes: A Physiological Evaluation of the Invasive Potential of Fruit Flies Species. AB - Climate change and biological invasions pose one of the greatest threats to biodiversity. Most analyses of the potential biological impacts have focused on changes in mean temperature, but changes in thermal variance may also impact native and invasive organisms, although differentially. We assessed the combined effects of the mean and the variance of temperature on the expression of heat shock protein (hsp90) in adults of the invasive fruit fly Drosophila melanogaster and the native Drosophila gaucha in Mediterranean habitats of central Chile. We observed that, under these experimental conditions, hsp90 mRNA expression was higher in the invasive species but absent in the native one. Apparently, the biogeographic origin and niche conservatisms are playing a role in the heat shock response of these species under different putative scenarios of climate change. We suggest that in order to develop more realistic predictions about the biological impact of climate change and biological invasions, one must consider the interactions between the mean and variance of climatic variables, as well as the evolutionary original conditions of the native and invasive species. PMID- 27486408 TI - Cognitive Neuroscience and Causal Inference: Implications for Psychiatry. AB - In this paper, we investigate to what extent it is justified to draw conclusions about causal relations between brain states and mental states from cognitive neuroscience studies. We first explain the views of two prominent proponents of the interventionist account of causation: Woodward and Baumgartner. We then discuss the implications of their views in the context of traditional cognitive neuroscience studies in which the effect of changes in mental state on changes in brain states is investigated. After this, we turn to brain stimulation studies in which brain states are manipulated to investigate the effects on mental states. We argue that, depending on whether one sides with Woodward or Baumgartner, it is possible to draw causal conclusions from both types of studies (Woodward) or from brain stimulation studies only (Baumgartner). We show what happens to these conclusions if we adopt different views of the relation between mental states and brain states. Finally, we discuss the implications of our findings for psychiatry and the treatment of psychiatric disorders. PMID- 27486409 TI - Imitated Prosodic Fluency Predicts Reading Comprehension Ability in Good and Poor High School Readers. AB - Researchers have established a relationship between beginning readers' silent comprehension ability and their prosodic fluency, such that readers who read aloud with appropriate prosody tend to have higher scores on silent reading comprehension assessments. The current study was designed to investigate this relationship in two groups of high school readers: Specifically Poor Comprehenders (SPCs), who have adequate word level and phonological skills but poor reading comprehension ability, and a group of age- and decoding skill matched controls. We compared the prosodic fluency of the two groups by determining how effectively they produced prosodic cues to syntactic and semantic structure in imitations of a model speaker's production of syntactically and semantically varied sentences. Analyses of pitch and duration patterns revealed that speakers in both groups produced the expected prosodic patterns; however, controls provided stronger durational cues to syntactic structure. These results demonstrate that the relationship between prosodic fluency and reading comprehension continues past the stage of early reading instruction. Moreover, they suggest that prosodically fluent speakers may also generate more fluent implicit prosodic representations during silent reading, leading to more effective comprehension. PMID- 27486410 TI - Do Our Means of Inquiry Match our Intentions? AB - A key stage of the scientific method is the analysis of data, yet despite the variety of methods that are available to researchers they are most frequently distilled to a model that focuses on the average relation between variables. Although research questions are frequently conceived with broad inquiry in mind, most regression methods are limited in comprehensively evaluating how observed behaviors are related to each other. Quantile regression is a largely unknown yet well-suited analytic technique similar to traditional regression analysis, but allows for a more systematic approach to understanding complex associations among observed phenomena in the psychological sciences. Data from the National Education Longitudinal Study of 1988/2000 are used to illustrate how quantile regression overcomes the limitations of average associations in linear regression by showing that psychological well-being and sex each differentially relate to reading achievement depending on one's level of reading achievement. PMID- 27486411 TI - The Feeling of "Face" in Confucian Society: From a Perspective of Psychosocial Equilibrium. AB - Previous research on the feeling of "face" has long described "face" as a complicated phenomenon in Confucian societies. Indeed, the feeling of face is highly context dependent. One may have very different (having or losing) face perception if the same face event occurs in a different context. To better capture the features of how face is felt, effects on possible responses need to be considered. Therefore, this article adopts a perspective of psychosocial equilibrium to elaborate people's feeling of face in Taiwan, a Confucian society. The first section illustrates the concept of psychosocial equilibrium and its psychodynamic effects on people's feeling of face. Then, the second section of this article takes positive social situations (having face events) as backdrop to exhibit how people balance their psychosocial equilibrium with different relationships. Following the positive social situations, the third section of this article then focuses on the negative situations (losing face events) to explain how losing face is felt due to unbalance of psychosocial equilibrium with one's relation in that specific context. PMID- 27486412 TI - Familiality of Co-existing ADHD and Tic Disorders: Evidence from a Large Sibling Study. AB - BACKGROUND: The association of attention-deficit/hyperactivity disorder (ADHD) and tic disorder (TD) is frequent and clinically important. Very few and inconclusive attempts have been made to clarify if and how the combination of ADHD+TD runs in families. AIM: To determine the first time in a large-scale ADHD sample whether ADHD+TD increases the risk of ADHD+TD in siblings and, also the first time, if this is independent of their psychopathological vulnerability in general. METHODS: The study is based on the International Multicenter ADHD Genetics (IMAGE) study. The present sub-sample of 2815 individuals included ADHD index patients with co-existing TD (ADHD+TD, n = 262) and without TD (ADHD-TD, n = 947) as well as their 1606 full siblings (n = 358 of the ADHD+TD index patients and n = 1248 of the ADHD-TD index patients). We assessed psychopathological symptoms in index patients and siblings by using the Strength and Difficulties Questionnaire (SDQ) and the parent and teacher Conners' long version Rating Scales (CRS). For disorder classification the Parental Account of Childhood Symptoms (PACS-Interview) was applied in n = 271 children. Odds ratio with the GENMOD procedure (PROCGENMOD) was used to test if the risk for ADHD, TD, and ADHD+TD in siblings was associated with the related index patients' diagnoses. In order to get an estimate for specificity we compared the four groups for general psychopathological symptoms. RESULTS: Co-existing ADHD+TD in index patients increased the risk of both comorbid ADHD+TD and TD in the siblings of these index patients. These effects did not extend to general psychopathology. INTERPRETATION: Co-existence of ADHD+TD may segregate in families. The same holds true for TD (without ADHD). Hence, the segregation of TD (included in both groups) seems to be the determining factor, independent of further behavioral problems. This close relationship between ADHD and TD supports the clinical approach to carefully assess ADHD in any case of TD. PMID- 27486413 TI - Untangling the Contribution of the Subcomponents of Working Memory to Mathematical Proficiency as Measured by the National Tests: A Study among Swedish Third Graders. AB - The aim with the present study was to examine the relationship between the subcomponents in working memory (WM) and mathematical performance, as measured by the National tests in a sample of 597 Swedish third-grade pupils. In line with compelling evidence of other studies, individual differences in WM capacity significantly predicted mathematical performance. Dividing the sample into four groups, based on their mathematical performance, revealed that mathematical ability can be conceptualized in terms of different WM profiles. Pupils categorized as High-math performers particularly differed from the other three groups in having a significant higher phonological ability. In contrast, pupils categorized as Low-math performers were particularly characterized by having a significant lower visuo-spatial ability. Findings suggest that it is important for educators to recognize and acknowledge individual differences in WM to support mathematical achievement at an individual level. PMID- 27486414 TI - Get Your Facts Right: Preschoolers Systematically Extend Both Object Names and Category-Relevant Facts. AB - There is an ongoing debate over the extent to which language development shares common processing mechanisms with other domains of learning. It is well established that toddlers will systematically extend object labels to similarly shaped category exemplars (e.g., Markman and Hutchinson, 1984; Landau et al., 1988). However, previous research is inconclusive as to whether young children will similarly extend factual information about an object to other category members. We explicitly contrast facts varying in category relevance, and test for extension using two different tasks. Three- to four-year-olds (N = 61) were provided with one of three types of information about a single novel object: a category-relevant fact ('it's from a place called Modi'), a category-irrelevant fact ('my uncle gave it to me'), or an object label ('it's called a Modi'). At test, children provided with the object name or category-relevant fact were significantly more likely to display systematic category extension than children who learnt the category-irrelevant fact. Our findings contribute to a growing body of evidence that the mechanisms responsible for word learning may be domain general in nature. PMID- 27486416 TI - Can We Talk through a Robot As if Face-to-Face? Long-Term Fieldwork Using Teleoperated Robot for Seniors with Alzheimer's Disease. AB - This work presents a case study on fieldwork in a group home for the elderly with dementia using a teleoperated robot called Telenoid. We compared Telenoid mediated and face-to-face conditions with three residents with Alzheimer's disease (AD). The result indicates that two of the three residents with moderate AD showed a positive reaction to Telenoid. Both became less nervous while communicating with Telenoid from the time they were first introduced to it. Moreover, they started to use more body gestures in the face-to-face condition and more physical interactions in the Telenoid-mediated condition. In this work, we present all the results and discuss the possibilities of using Telenoid as a tool to provide opportunities for seniors to communicate over the long term. PMID- 27486415 TI - Bayesian Analysis of Individual Level Personality Dynamics. AB - A Bayesian technique with analyses of within-person processes at the level of the individual is presented. The approach is used to examine whether the patterns of within-person responses on a 12-trial simulation task are consistent with the predictions of ITA theory (Dweck, 1999). ITA theory states that the performance of an individual with an entity theory of ability is more likely to spiral down following a failure experience than the performance of an individual with an incremental theory of ability. This is because entity theorists interpret failure experiences as evidence of a lack of ability which they believe is largely innate and therefore relatively fixed; whilst incremental theorists believe in the malleability of abilities and interpret failure experiences as evidence of more controllable factors such as poor strategy or lack of effort. The results of our analyses support ITA theory at both the within- and between-person levels of analyses and demonstrate the benefits of Bayesian techniques for the analysis of within-person processes. These include more formal specification of the theory and the ability to draw inferences about each individual, which allows for more nuanced interpretations of individuals within a personality category, such as differences in the individual probabilities of spiraling. While Bayesian techniques have many potential advantages for the analyses of processes at the level of the individual, ease of use is not one of them for psychologists trained in traditional frequentist statistical techniques. PMID- 27486417 TI - The Association among Difficulties in Emotion Regulation, Hostility, and Empathy in a Sample of Young Italian Adults. AB - The aim of the present study was to assess the role of empathy in mediating the association between difficulties in emotion regulation and hostility. Three hundred and sixty young Italian adults (220 women and 140 men) were enrolled in the study. Psychopathological assessments included the Difficulties in Emotion Regulation Scale (DERS), the Interpersonal Reactivity Index and the Buss-Durkee Hostility Inventory (BDHI). Perspective taking (PT) and Personal distress (PD) are significantly associated with both DERS total score and BDHI total score. A mediational model analyzing the direct and indirect effects of DERS on BDHI through the mediating role of PT and PD showed that the relation between DERS and BDHI was partially mediated by PT total score (b = 0.16; se = 0.01; p = 0.02). Taken together our findings support the possibility that PT skills could play a crucial role in inhibiting hostility behaviors. PMID- 27486418 TI - The Experience of Depression during the Careers of Elite Male Athletes. AB - The topic of depression during the career of elite male athletes has been the subject of much public interest and attention in recent years. Despite numerous debates and personal disclosures within the media, there is a dearth of published research directly exploring the phenomenon. This study sought to explore how elite male athletes experience depression during their sporting careers. Eight former/current elite male athletes who had previously publically self-identified as having experienced depression while participating in sport were recruited for this study. A qualitative methodology was employed and each participant was interviewed using semi-structured interviews. Data analysis which was conducted using descriptive and interpretive thematic analysis uncovered three domains: (1) The emergence of depression, (2) The manifestation of symptoms of depression, and (3) Adaptive and Maladaptive proceesses of recovery. Findings from the current study reveal the nature of how male athletes experience, express, and respond to depression during their careers. Additionally, this is influenced by a myriad of factors embedded in the masculine elite sport environment. Implications are discussed particularly in relation to atypical expressions of depression not necessarily reflected on or in standard diagnostic criteria. Future research is encouraged to examine in depth moderating factors (e.g., athletic sense of identity and masculine elite sport environments) for the relationship between depression and participation in elite sport. PMID- 27486420 TI - A Multidisciplinary Approach to Research in Small-Scale Societies: Studying Emotions and Facial Expressions in the Field. AB - Although cognitive science was multidisciplinary from the start, an under emphasis on anthropology has left the field with limited research in small scale, indigenous societies. Neglecting the anthropological perspective is risky, given that once-canonical cognitive science findings have often been shown to be artifacts of enculturation rather than cognitive universals. This imbalance has become more problematic as the increased use of Western theory-driven approaches, many of which assume human uniformity ("universality"), confronts the absence of a robust descriptive base that might provide clarifying or even contrary evidence. We highlight the need for remedies to such shortcomings by suggesting a two-fold methodological shift. First, studies conducted in indigenous societies can benefit by relying on multidisciplinary research groups to diminish ethnocentrism and enhance the quality of the data. Second, studies devised for Western societies can readily be adapted to the changing settings encountered in the field. Here, we provide examples, drawn from the areas of emotion and facial expressions, to illustrate potential solutions to recurrent problems in enhancing the quality of data collection, hypothesis testing, and the interpretation of results. PMID- 27486419 TI - Can We Predict Burnout among Student Nurses? An Exploration of the ICWR-1 Model of Individual Psychological Resilience. AB - The nature of nursing work is demanding and can be stressful. Previous studies have shown a high rate of burnout among employed nurses. Recently, efforts have been made to understand the role of resilience in determining the psychological adjustment of employed nurses. A theoretical model of resilience was proposed recently that includes several constructs identified in the literature related to resilience and to psychological functioning. As nursing students are the future of the nursing workforce it is important to advance our understanding of the determinants of resilience in this population. Student nurses who had completed their final practicum were invited to participate in an online survey measuring the key constructs of the ICWR-1 model. 422 students from across Australia and Canada completed the survey between July 2014 and July 2015. As well as several key demographics, trait negative affect, mindfulness, self-efficacy, coping, resilience, and burnout were measured. We used structural equation modeling and found support for the major pathways of the model; namely that resilience had a significant influence on the relationship between mindfulness, self-efficacy and coping, and psychological adjustment (burnout scores). Furthermore, as predicted, Neuroticism moderated the relationship between coping and burnout. Results are discussed in terms of potential approaches to supporting nursing students who may be at risk of burnout. PMID- 27486421 TI - Young Children Learning from Touch Screens: Taking a Wider View. AB - Touch screen devices such as smartphones and tablets are now ubiquitous in the lives of American children. These devices permit very young children to engage interactively in an intuitive fashion with actions as simple as touching, swiping and pinching. Yet, we know little about the role these devices play in very young children's lives or their impact on early learning and development. Here we focus on two areas in which existing research sheds some light on these issues with children under 3 years of age. The first measures transfer of learning, or how well children use information learned from screens to reason about events off screen, using object retrieval and word learning tasks. The second measures the impact of interactive screens on parent-child interactions and story comprehension during reading time. More research is required to clarify the pedagogical potential and pitfalls of touch screens for infants and very young children, especially research focused on capabilities unique to touch screens and on the social and cultural contexts in which young children use them. PMID- 27486422 TI - The Impact of Early Bilingualism on Face Recognition Processes. AB - Early linguistic experience has an impact on the way we decode audiovisual speech in face-to-face communication. The present study examined whether differences in visual speech decoding could be linked to a broader difference in face processing. To identify a phoneme we have to do an analysis of the speaker's face to focus on the relevant cues for speech decoding (e.g., locating the mouth with respect to the eyes). Face recognition processes were investigated through two classic effects in face recognition studies: the Other-Race Effect (ORE) and the Inversion Effect. Bilingual and monolingual participants did a face recognition task with Caucasian faces (own race), Chinese faces (other race), and cars that were presented in an Upright or Inverted position. The results revealed that monolinguals exhibited the classic ORE. Bilinguals did not. Overall, bilinguals were slower than monolinguals. These results suggest that bilinguals' face processing abilities differ from monolinguals'. Early exposure to more than one language may lead to a perceptual organization that goes beyond language processing and could extend to face analysis. We hypothesize that these differences could be due to the fact that bilinguals focus on different parts of the face than monolinguals, making them more efficient in other race face processing but slower. However, more studies using eye-tracking techniques are necessary to confirm this explanation. PMID- 27486424 TI - Editorial: Color Vision Sensation and Perception. PMID- 27486423 TI - Affective Norms for 4900 Polish Words Reload (ANPW_R): Assessments for Valence, Arousal, Dominance, Origin, Significance, Concreteness, Imageability and, Age of Acquisition. AB - In studies that combine understanding of emotions and language, there is growing demand for good-quality experimental materials. To meet this expectation, a large number of 4905 Polish words was assessed by 400 participants in order to provide a well-established research method for everyone interested in emotional word processing. The Affective Norms for Polish Words Reloaded (ANPW_R) is designed as an extension to the previously introduced the ANPW dataset and provides assessments for eight different affective and psycholinguistic measures of Valence, Arousal, Dominance, Origin, Significance, Concreteness, Imageability, and subjective Age of Acquisition. The ANPW_R is now the largest available dataset of affective words for Polish, including affective scores that have not been measured in any other dataset (concreteness and age of acquisition scales). Additionally, the ANPW_R allows for testing hypotheses concerning dual-mind models of emotion and activation (origin and subjective significance scales). Participants in the current study assessed all 4905 words in the list within 1 week, at their own pace in home sessions, using eight different Self-assessment Manikin (SAM) scales. Each measured dimension was evaluated by 25 women and 25 men. The ANPW_R norms appeared to be reliable in split-half estimation and congruent with previous normative studies in Polish. The quadratic relation between valence and arousal was found to be in line with previous findings. In addition, nine other relations appeared to be better described by quadratic instead of linear function. The ANPW_R provides well-established research materials for use in psycholinguistic and affective studies in Polish-speaking samples. PMID- 27486425 TI - Study Protocol on Ecological Momentary Assessment of Health-Related Quality of Life Using a Smartphone Application. AB - Health-Related Quality of Life (HRQoL) is a construct of increasing importance in modern healthcare, and has typically been assessed using retrospective instruments. While such measures have been shown to have predictive utility for clinical outcomes, several cognitive biases associated with human recall and current mood state may undermine their validity and reliability. Retrospective tools can be further criticized for their lack of ecology, as individuals are usually assessed in less natural settings such as hospitals and health centers, and may be obliged to spend time and money traveling to receive assessment. Ecological momentary assessment (EMA) is an alternative, as mobile assessment using mobile health (mHealth) technology has the potential to minimize biases and overcome many of these limitations. Employing an EMA methodology, we will use a smartphone application to collect data on real-time HRQoL, with an adapted version of the widely used WHOQOL-BREF questionnaire. We aim to recruit a total of 450 healthy participants. Participants will be prompted by the application to report their real-time HRQoL over 2 weeks together with information on mood and current activities. At the end of 2 weeks, they will complete a retrospective assessment of their HRQoL and they will provide information about their sleep quality and perceived stress. The psychometric properties of real-time HRQoL will be assessed, including analysis of the factorial structure, reliability and validity of the measure, and compared with retrospective HRQoL responses for the same 2-week testing period. Further, we aim to identify factors associated with real-time HRQoL (e.g., mood, activities), the feasibility of the application, and within- and between-person variability in real-time HRQoL. We expect real-time HRQoL to have adequate validity and reliability, and positive responses on the feasibility of using a smartphone application for routine HRQoL assessment. The direct comparison of real-time and retrospective measures in this study will provide important novel insight into the efficacy of mHealth applications for HRQoL assessment. If shown to be valid, reliable and feasible for the collection of HRQoL data, mHealth applications may have future potential for facilitating clinical assessment, patient-physician communication, and monitoring individual HRQoL over course of treatment. PMID- 27486427 TI - The Causal Effect of Student Mobility on Standardized Test Performance: A Case Study with Possible Implications for Accountability Mandates within the Elementary and Secondary Education Act. AB - This paper presents a limited case study examining the causal inference of student mobility on standardized test performance, within one middle-class high school in suburban Connecticut. Administrative data were used from a district public high school enrolling 319 10th graders in 2010. Propensity score methods were used to estimate the causal effect of student mobility on Math, Science, Reading, and Writing portions of the Connecticut Academic Performance Test (CAPT), after matching mobile vs. stable students on gender, race/ethnicity, eligibility for free/reduced lunches, and special education status. Analyses showed that mobility was associated with lower performance in the CAPT Writing exam. Follow-up analyses revealed that this trend was only significant among those who were ineligible for free/reduced lunches, but not among eligible students. Additionally, mobile students who were ineligible for free/reduced lunches had lower performance in the CAPT Science exam according to some analyses. Large numbers of students transferring into a school district may adversely affect standardized test performance. This is especially relevant for policies that affect student mobility in schools, given the accountability measures in the No Child Left Behind that are currently being re-considered in the recent Every Student Succeeds Act. PMID- 27486426 TI - Subjective Social Status and Cardiovascular Reactivity: An Experimental Examination. AB - The present experiment examined the causal influence of subjective social status (SSS) on variables related to cardiovascular health [i.e., blood pressure, heart rate variability (HRV)]. Participants were randomly assigned to one of two conditions involving a social comparison that either induced a temporary shift toward high SSS or toward low SSS. Cardiovascular variables were measured before (baseline), throughout, and after the manipulation (recovery). Participants in the low SSS condition had a significantly lower HRV during experimental manipulation than at baseline (p = 0.001). They also showed a significantly stronger HRV reactivity compared to participants in the high SSS condition (p = 0.027). Our results suggest that already temporary shifts of one's SSS have measureable effects on cardiovascular variables. They support the notion that social status plays a causal role in the development of cardiovascular disease. PMID- 27486428 TI - Bringing Formal and Informal Reasoning Together-A New Era of Assessment? PMID- 27486429 TI - The Emergence of Tool Use in Preterm Infants. AB - Preterm born children without neurological impairments have been shown to present some visual-manual coordination deficits, more or less depending on their tonicity and the degree of prematurity. In this paper, we compare the development of tool use in 15-23-month-old preterm infants born after 33-36 weeks of gestation without neurological complications with that of full-term infants according to corrected age. Understanding the affordance of a tool is an important cognitive milestone in early sensorimotor period. Using a tool to bring within reach an out-of-reach object, for instance, has been shown to develop during the 2nd year in full-term infants. Here we presented preterm infants with an attractive toy out of reach and with a rake-like tool within reach in five conditions of spatial relationships between the toy and the tool. Like full terms, preterm infants used the tool with success in conditions of spatial contiguity around 15-17 months. In conditions of a spatial gap between tool and toy, i.e., the only conditions which shows without ambiguity that the infant understands the affordance of the tool, preterm infants as a group showed no delay for tool use: the frequency of spontaneous successes started to increase after 18 months, and demonstration became effective after that age. However, further analyses showed that only the preterm infants without hypotonia and born after 36 weeks of pregnancy developed tool use without delay. Hypotonic preterm infants were still largely unsuccessful in the conditions of spatial gap, even at the end of the study. The degree of prematurity also influenced the performance at tool use. These results, following the observation of a delay in the development of bimanual coordination and of handedness in the same infants at 10 12 months in a previous study, show that low risk preterm infants can still be impaired for the development of new manual skills beyond the 1st year. Thus, hypotonic preterm infants and infants born before 36 weeks of pregnancy should be followed and might benefit from early intervention programs. PMID- 27486430 TI - Aging Increases Compensatory Saccade Amplitude in the Video Head Impulse Test. AB - OBJECTIVE: Rotational vestibular function declines with age resulting in saccades as a compensatory mechanism to improve impaired gaze stability. Small reductions in rotational vestibulo-ocular reflex (VOR) gain that would be considered clinically normal have been associated with compensatory saccades. We evaluated whether compensatory saccade characteristics varied as a function of age, independent of semicircular canal function as quantified by VOR gain. METHODS: Horizontal VOR gain was measured in 243 participants age 27-93 from the Baltimore Longitudinal Study of Aging using video head impulse testing. Latency and amplitude of the first saccade (either covert - occurring during head impulse, or overt - occurring following head impulse) were measured for head impulses with compensatory saccades (n = 2230 head impulses). The relationship between age and saccade latency, as well as the relationship between age and saccade amplitude, were evaluated using regression analyses adjusting for VOR gain, gender, and race. RESULTS: Older adults (mean age 75.9) made significantly larger compensatory saccades relative to younger adults (mean age 45.0). In analyses adjusted for VOR gain, there was a significant association between age and amplitude of the first compensatory covert saccade (beta = 0.015, p = 0.008). In analyses adjusted for VOR gain, there was a significant association between age and amplitude of the first compensatory overt saccade (beta = 0.02, p < 0.001). Compensatory saccade latencies did not vary significantly by age. CONCLUSION: We observed that aging increases the compensatory catch-up saccade amplitude in healthy adults after controlling for VOR gain. Size of compensatory saccades may be useful in addition to VOR gain for characterizing vestibular function in aging adults. PMID- 27486431 TI - Intrusive Thoughts Elicited by Direct Electrical Stimulation during Stereo Electroencephalography. AB - Cortical direct electrical stimulation (DES) is a method of brain mapping used during invasive presurgical evaluation of patients with intractable epilepsy. Intellectual auras like intrusive thoughts, also known as forced thinking (FT), have been reported during frontal seizures. However, there are few reports on FT obtained during DES in frontal cortex. We report three cases in which we obtained intrusive thoughts while stimulating the dorsolateral prefrontal cortex and the white matter in the prefrontal region. In order to highlight the effective connectivity that might explain this clinical response, we have analyzed cortico cortical potentials evoked by single pulse electrical stimulation. PMID- 27486433 TI - Association Studies of the GPR103 and BCL2L15 Genes in Autoimmune Thyroid Disease in the Japanese Population. AB - While the past genome-wide association study (GWAS) for autoimmune thyroid diseases (AITDs) was done in Caucasians, a recent GWAS in Caucasian patients with both AITD and type 1 diabetes [a variant of autoimmune polyglandular syndrome type 3 (APS3v)] identified five non-HLA genes: BCL2L15, MAGI3, PHTF1, PTPN22, and GPR103. The aim of our study was to replicate these associations with AITD in a Japanese population. Since analyzing the rs2476601 single-nucleotide polymorphism (SNP) within the PTPN22 gene revealed no polymorphism in the Japanese, we analyzed four SNPs, rs2358994 (in BCL2L15), rs2153977 (in MAGI3), rs1111695 (in PHTF1), and rs7679475 (in GPR103) genotypes in a case-control study based on 447 Japanese AITD patients [277 Graves' disease (GD) and 170 Hashimoto's thyroiditis (HT) patients] and 225 matched Japanese controls using the high-resolution melting and unlabeled probe methods. Case-control association studies were performed using the chi(2) and Fisher's exact tests with Yates correction. The G allele of rs7679475 (A/G) was associated with HT compared with controls [P = 0.022, odds ratio (OR) = 0.69]. GD showed no significant associations with any SNPs. However, when patients with GD were stratified according to Graves' ophthalmopathy (GO), the G allele of rs2358994 (A/G) was associated with GO vs. controls (P = 0.018, OR = 1.52). These findings suggest that in the Japanese population the GPR103 gene may contribute to the pathogenesis of HT. Moreover, this study demonstrated that the SNP rs2358994 within BCL2L15 gene is associated with GO in the Japanese population. PMID- 27486432 TI - An Abbreviated Diagnostic Maneuver for Posterior Benign Positional Paroxysmal Vertigo. AB - INTRODUCTION: Benign paroxysmal positional vertigo (BPPV) secondary to canalolithiasis of the posterior semicircular canal is perhaps the most frequent cause of vertigo and dizziness. One of its properties is a high response rate to canalith repositioning maneuvers. However, delays in the diagnosis and treatment of this entity can range from days to years, depending on the setting. Here, we present an abbreviated variation of the Dix-Hallpike maneuver, which can be used to diagnose this disease. It is similar to the standard maneuver but can be performed without an examination bed/table and requires only a backed chair (a difference that we feel is very important in settings where a clinical bed/table is not readily available). METHODS: A diagnostic assessment study was conducted in 163 patients who presented with vertigo or dizziness. RESULTS: The abbreviated test had fairly good sensitivity (80%) and high specificity (95%) for diagnosing posterior BPPV. DISCUSSION: This new diagnostic maneuver may serve as a screening procedure for quickly identifying this pathology. This will allow patients to be more directly treated, without requiring unnecessary referrals or full vestibular testing, and will be especially useful in primary care settings or heavily overloaded otolaryngology or neurology departments. PMID- 27486434 TI - Statin Therapy Alters Lipid Storage in Diabetic Skeletal Muscle. AB - While statins significantly reduce cholesterol levels and thereby reduce the risk of cardiovascular disease, the development of myopathy with statin use is a significant clinical side effect. Recent guidelines recommend increasing inclusion criteria for statin treatment in diabetic individuals; however, the impact of statins on skeletal muscle health in those with diabetes (who already suffer from impairments in muscle health) is ill defined. Here, we investigate the effects of fluvastatin treatment on muscle health in wild type (WT) and streptozotocin (STZ)-induced diabetic mice. WT and STZ-diabetic mice received diet enriched with 600 mg/kg fluvastatin or control chow for 24 days. Muscle morphology, intra and extracellular lipid levels, and lipid transporter content were investigated. Our findings indicate that short-term fluvastatin administration induced a myopathy that was not exacerbated by the presence of STZ induced diabetes. Fluvastatin significantly increased ectopic lipid deposition within the muscle of STZ-diabetic animals, findings that were not seen with diabetes or statin treatment alone. Consistent with this observation, only fluvastatin-treated diabetic mice downregulated protein expression of lipid transporters FAT/CD36 and FABPpm in their skeletal muscle. No differences in FAT/CD36 or FABPpm mRNA content were observed. Altered lipid compartmentalization resultant of a downregulation in lipid transporter content in STZ-induced diabetic skeletal muscle was apparent in the current investigation. Given the association between ectopic lipid deposition in skeletal muscle and the development of insulin-resistance, our findings highlight the necessity for more thorough investigations into the impact of statins in humans with diabetes. PMID- 27486435 TI - Dual Topology of the Melanocortin-2 Receptor Accessory Protein Is Stable. AB - Melanocortin 2 receptor accessory protein (MRAP) facilitates trafficking of melanocortin 2 (MC2) receptors and is essential for ACTH binding and signaling. MRAP is a single transmembrane domain protein that forms antiparallel homodimers. These studies ask when MRAP first acquires this dual topology, whether MRAP architecture is static or stable, and whether the accessory protein undergoes rapid turnover. To answer these questions, we developed an approach that capitalizes on the specificity of bacterial biotin ligase, which adds biotin to lysine in a short acceptor peptide sequence; the distinct mobility of MRAP protomers of opposite orientations based on their N-linked glycosylation; and the ease of identifying biotin-labeled proteins. We inserted biotin ligase acceptor peptides at the N- or C-terminal ends of MRAP and expressed the modified proteins in mammalian cells together with either cytoplasmic or endoplasmic reticulum targeted biotin ligase. MRAP assumed dual topology early in biosynthesis in both CHO and OS3 adrenal cells. Once established, MRAP orientation was stable. Despite its conformational stability, MRAP displayed a half-life of under 2 h in CHO cells. The amount of MRAP was increased by the proteasome inhibitor MG132 and MRAP underwent ubiquitylation on lysine and other amino acids. Nonetheless, when protein synthesis was blocked with cycloheximide, MRAP was rapidly degraded even when MG132 was included and all lysines were replaced by arginines, implicating non-proteasomal degradation pathways. The results show that although MRAP does not change orientations during trafficking, its synthesis and degradation are dynamically regulated. PMID- 27486436 TI - Microbial Community Responses to Increased Water and Organic Matter in the Arid Soils of the McMurdo Dry Valleys, Antarctica. AB - The soils of the McMurdo Dry Valleys, Antarctica are an extreme polar desert, inhabited exclusively by microscopic taxa. This region is on the threshold of anticipated climate change, with glacial melt, permafrost thaw, and the melting of massive buried ice increasing liquid water availability and mobilizing soil nutrients. Experimental water and organic matter (OM) amendments were applied to investigate how these climate change effects may impact the soil communities. To identify active taxa and their functions, total community RNA transcripts were sequenced and annotated, and amended soils were compared with unamended control soils using differential abundance and expression analyses. Overall, taxonomic diversity declined with amendments of water and OM. The domain Bacteria increased with both amendments while Eukaryota declined from 38% of all taxa in control soils to 8 and 11% in water and OM amended soils, respectively. Among bacterial phyla, Actinobacteria (59%) dominated water-amended soils and Firmicutes (45%) dominated OM amended soils. Three bacterial phyla (Actinobacteria, Proteobacteria, and Firmicutes) were primarily responsible for the observed positive functional responses, while eukaryotic taxa experienced the majority (27 of 34) of significant transcript losses. These results indicated that as climate changes in this region, a replacement of endemic taxa adapted to dry, oligotrophic conditions by generalist, copiotrophic taxa is likely. PMID- 27486437 TI - Devices for In situ Development of Non-disturbed Oral Biofilm. A Systematic Review. AB - OBJECTIVE: The aim of this review was to assess the types of devices used for in situ development of oral biofilm analyzed microbiologically. MATERIALS AND METHODS: A systematic search of the literature was conducted to identify all in situ studies of oral biofilm which used an oral device; the Ovid MEDLINE and EMBASE databases complemented with manual search were used. Specific devices used to microbiologically analyze oral biofilm in adults were included. After reading of the selected full texts, devices were identified and classified according to the oral cavity zone and manufacturing material. The "ideal" characteristics were analyzed in every group. RESULTS: The search provided 787 abstracts, of which 111 papers were included. The devices used in these studies were classified as palatal, lingual or buccal. The last group was sub-classified in six groups based on the material of the device. Considering the analyzed characteristics, the thermoplastic devices and the Intraoral Device of Overlaid Disk-holding Splints (IDODS) presented more advantages than limitations. CONCLUSIONS: Buccal devices were the most commonly used for the study of in situ biofilm. The majority of buccal devices seemed to slightly affect the volunteer's comfort, the IDODS being the closest to the "ideal" model. CLINICAL RELEVANCE: New devices for in situ oral biofilm microbiological studies should take into account the possible effect of their design on the volunteer's comfort and biofilm formation. PMID- 27486438 TI - Metatranscriptional Response of Chemoautotrophic Ifremeria nautilei Endosymbionts to Differing Sulfur Regimes. AB - Endosymbioses between animals and chemoautotrophic bacteria are ubiquitous at hydrothermal vents. These environments are distinguished by high physico-chemical variability, yet we know little about how these symbioses respond to environmental fluctuations. We therefore examined how the gamma-proteobacterial symbionts of the vent snail Ifremeria nautilei respond to changes in sulfur geochemistry. Via shipboard high-pressure incubations, we subjected snails to 105 MUM hydrogen sulfide (LS), 350 MUM hydrogen sulfide (HS), 300 MUM thiosulfate (TS) and seawater without any added inorganic electron donor (ND). While transcript levels of sulfur oxidation genes were largely consistent across treatments, HS and TS treatments stimulated genes for denitrification, nitrogen assimilation, and CO2 fixation, coincident with previously reported enhanced rates of inorganic carbon incorporation and sulfur oxidation in these treatments. Transcripts for genes mediating oxidative damage were enriched in the ND and LS treatments, potentially due to a reduction in O2 scavenging when electron donors were scarce. Oxidative TCA cycle gene transcripts were also more abundant in ND and LS treatments, suggesting that I. nautilei symbionts may be mixotrophic when inorganic electron donors are limiting. These data reveal the extent to which I. nautilei symbionts respond to changes in sulfur concentration and species, and, interpreted alongside coupled biochemical metabolic rates, identify gene targets whose expression patterns may be predictive of holobiont physiology in environmental samples. PMID- 27486439 TI - Hantavirus Infection Suppresses Thrombospondin-1 Expression in Cultured Endothelial Cells in a Strain-Specific Manner. AB - Hantavirus infection is associated with two frequently fatal diseases in humans: Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The pathogenesis of hantavirus infection is complex and not fully understood; however, it is believed to involve virus-induced hyperinflammatory immune responses. Thrombospondin-1 (THBS1) is a large homotrimeric protein that plays a putative role in regulating blood homeostasis. Hyperresponsiveness to inflammatory stimuli has also been associated with defects in the THBS1 gene. Our data suggest that hantavirus infection of human umbilical cord vein endothelial cells (HUVEC) suppress the accumulation of THBS1 in the extracellular matrix. Additionally, this suppression is dependent on virus replication, implying a direct mechanism of action. Our data also imply that the pathogenic Andes and Hantaan strains inhibit THBS1 expression while the non-pathogenic Prospect Hill strain showed little inhibition. These observations suggest that a dysregulation of THBS1 may contribute to the pathogenesis of hantavirus infection. PMID- 27486440 TI - Genome and Transcriptome Sequences Reveal the Specific Parasitism of the Nematophagous Purpureocillium lilacinum 36-1. AB - Purpureocillium lilacinum is a promising nematophagous ascomycete able to adapt diverse environments and it is also an opportunistic fungus that infects humans. A microbial inoculant of P. lilacinum has been registered to control plant parasitic nematodes. However, the molecular mechanism of the toxicological processes is still unclear because of the relatively few reports on the subject. In this study, using Illumina paired-end sequencing, the draft genome sequence and the transcriptome of P. lilacinum strain 36-1 infecting nematode-eggs were determined. Whole genome alignment indicated that P. lilacinum 36-1 possessed a more dynamic genome in comparison with P. lilacinum India strain. Moreover, a phylogenetic analysis showed that the P. lilacinum 36-1 had a closer relation to entomophagous fungi. The protein-coding genes in P. lilacinum 36-1 occurred much more frequently than they did in other fungi, which was a result of the depletion of repeat-induced point mutations (RIP). Comparative genome and transcriptome analyses revealed the genes that were involved in pathogenicity, particularly in the recognition, adhesion of nematode-eggs, downstream signal transduction pathways and hydrolase genes. By contrast, certain numbers of cellulose and xylan degradation genes and a lack of polysaccharide lyase genes showed the potential of P. lilacinum 36-1 as an endophyte. Notably, the expression of appressorium formation and antioxidants-related genes exhibited similar infection patterns in P. lilacinum strain 36-1 to those of the model entomophagous fungi Metarhizium spp. These results uncovered the specific parasitism of P. lilacinum and presented the genes responsible for the infection of nematode-eggs. PMID- 27486441 TI - Analysis of Plant Growth-Promoting Effects of Fluorescent Pseudomonas Strains Isolated from Mentha piperita Rhizosphere and Effects of Their Volatile Organic Compounds on Essential Oil Composition. AB - Many species or strains of the genus Pseudomonas have been characterized as plant growth promoting rhizobacteria (PGPR). We used a combination of phenotypic and genotypic techniques to analyze the community of fluorescent Pseudomonas strains in the rhizosphere of commercially grown Mentha piperita (peppermint). Biochemical techniques, Amplified rDNA Restriction Analysis (ARDRA), and 16S rRNA gene sequence analysis revealed that the majority of the isolated native fluorescent strains were P. putida. Use of two Repetitive Sequence-based PCR (rep PCR) techniques, BOX-PCR and ERIC-PCR, allowed us to evaluate diversity among the native strains and to more effectively distinguish among them. PGPR activity was tested for the native strains and reference strain P. fluorescens WCS417r. Micropropagated M. piperita plantlets were exposed to microbial volatile organic compounds (mVOCs) emitted by the bacterial strains, and plant biomass parameters and production of essential oils (EOs) were measured. mVOCs from 11 of the native strains caused an increase in shoot fresh weight. mVOCs from three native strains (SJ04, SJ25, SJ48) induced changes in M. pierita EO composition. The mVOCs caused a reduction of metabolites in the monoterpene pathway, for example menthofuran, and an increase in menthol production. Menthol production is the primary indicator of EO quality. The mVOCs produced by native strains SJ04, SJ25, SJ48, and strain WCS417r were analyzed. The obtained mVOC chromatographic profiles were unique for each of the three native strains analyzed, containing varying hydrocarbon, aromatic, and alogenic compounds. The differential effects of the strains were most likely due to the specific mixtures of mVOCs emitted by each strain, suggesting a synergistic effect occurs among the compounds present. PMID- 27486442 TI - The Interaction between Arbuscular Mycorrhizal Fungi and Endophytic Bacteria Enhances Plant Growth of Acacia gerrardii under Salt Stress. AB - Microbes living symbiotically in plant tissues mutually cooperate with each other by providing nutrients for proliferation of the partner organism and have a beneficial effect on plant growth. However, few studies thus far have examined the interactive effect of endophytic bacteria and arbuscular mycorrhizal fungi (AMF) in hostile conditions and their potential to improve plant stress tolerance. In this study, we investigated how the synergistic interactions of endophytic bacteria and AMF affect plant growth, nodulation, nutrient acquisition and stress tolerance of Acacia gerrardii under salt stress. Plant growth varied between the treatments with both single inoculants and was higher in plants inoculated with the endophytic B. subtilis strain than with AMF. Co-inoculated A. gerrardii had a significantly greater shoot and root dry weight, nodule number, and leghemoglobin content than those inoculated with AMF or B. subtilis alone under salt stress. The endophytic B. subtilis could alleviate the adverse effect of salt on AMF colonization. The differences in nitrate and nitrite reductase and nitrogenase activities between uninoculated plants and those inoculated with AMF and B. subtilis together under stress were significant. Both inoculation treatments, either B. subtilis alone or combined with AMF, enhanced the N, P, K, Mg, and Ca contents and phosphatase activities in salt-stressed A. gerrardii tissues and reduced Na and Cl concentration, thereby protecting salt-stressed plants from ionic and osmotic stress-induced changes. In conclusion, our results indicate that endophytic bacteria and AMF contribute to a tripartite mutualistic symbiosis in A. gerrardii and are coordinately involved in the plant adaptation to salt stress tolerance. PMID- 27486443 TI - Recovery of Heat Treated Bacillus cereus Spores Is Affected by Matrix Composition and Factors with Putative Functions in Damage Repair. AB - The ability of spores to recover and grow out after food processing is affected by cellular factors and by the outgrowth conditions. In the current communication we studied the recovery and outgrowth of individually sorted spores in BHI and rice broth media and on agar plates using flow cytometry. We show that recovery of wet heat treated Bacillus cereus ATCC 14579 spores is affected by matrix composition with highest recovery in BHI broth or on rice agar plates, compared to BHI agar plates and rice broth. Data show that not only media composition but also its liquid or solid state affect the recovery of heat treated spores. To determine the impact of factors with putative roles in recovery of heat treated spores, specific genes previously shown to be highly expressed in outgrowing heat treated spores were selected for mutant construction. Spores of nine B. cereus ATCC 14579 deletion mutants were obtained and their recovery from wet heat treatment was evaluated using BHI and rice broth and agar plates. Deletion mutant spores showed different capacity to recover from heat treatment compared to wild type with the most pronounced effect for a mutant lacking BC5242, a gene encoding a membrane protein with C2C2 zinc finger which resulted in over 95% reduction in recovery compared to the wild type in BHI broth. Notably, similar relative performance of wild type and mutants was observed using the other recovery conditions. We obtained insights on the impact of matrix composition and state on recovery of individually sorted heat treated spores and identified cellular factors with putative roles in this process. These results may provide leads for future developments in design of more efficient combined preservation treatments. PMID- 27486444 TI - The Resilience of Microbial Community under Drying and Rewetting Cycles of Three Forest Soils. AB - Forest soil ecosystems are associated with large pools and fluxes of carbon (C) and nitrogen (N), which could be strongly affected by variation in rainfall events under current climate change. Understanding how dry and wet cycle events might influence the metabolic state of indigenous soil microbes is crucial for predicting forest soil responses to environmental change. We used 454 pyrosequencing and quantitative PCR to address how present (DNA-based) and potentially active (RNA-based) soil bacterial communities might response to the changes in water availability across three different forest types located in two continents (Africa and Asia) under controlled drying and rewetting cycles. Sequencing of rRNA gene and transcript indicated that Proteobacteria, Actinobacteria, and Acidobacteria were the most responsive phyla to changes in water availability. We defined the ratio of rRNA transcript to rRNA gene abundance as a key indicator of potential microbial activity and we found that this ratio was increased following soil dry-down process whereas it decreased after soil rewetting. Following rewetting Crenarchaeota-like 16S rRNA gene transcript increased in some forest soils and this was linked to increases in soil nitrate levels suggesting greater nitrification rates under higher soil water availability. Changes in the relative abundance of (1) different microbial phyla and classes, and (2) 16S and amoA genes were found to be site- and taxa specific and might have been driven by different life-strategies. Overall, we found that, after rewetting, the structure of the present and potentially active bacterial community structure as well as the abundance of bacterial (16S), archaeal (16S) and ammonia oxidizers (amoA), all returned to pre-dry-down levels. This suggests that microbial taxa have the ability to recover from desiccation, a critical response, which will contribute to maintaining microbial biodiversity in harsh ecosystems under environmental perturbations, such as significant changes in water availability. PMID- 27486445 TI - Interaction of Bovine Peripheral Blood Polymorphonuclear Cells and Leptospira Species; Innate Responses in the Natural Bovine Reservoir Host. AB - Cattle are the reservoir hosts of Leptospira borgpetersenii serovar Hardjo, and can also be reservoir hosts of other Leptospira species such as L. kirschneri, and Leptospira interrogans. As a reservoir host, cattle shed Leptospira, infecting other animals, including humans. Previous studies with human and murine neutrophils have shown activation of neutrophil extracellular trap or NET formation, and upregulation of inflammatory mediators by neutrophils in the presence of Leptospira. Humans, companion animals and most widely studied models of Leptospirosis are of acute infection, hallmarked by systemic inflammatory response, neutrophilia, and septicemia. In contrast, cattle exhibit chronic infection with few outward clinical signs aside from reproductive failure. Taking into consideration that there is host species variation in innate immunity, especially in pathogen recognition and response, the interaction of bovine peripheral blood polymorphonuclear cells (PMNs) and several Leptospira strains was evaluated. Studies including bovine-adapted strains, human pathogen strains, a saprophyte and inactivated organisms. Incubation of PMNs with Leptospira did induce slight activation of neutrophil NETs, greater than unstimulated cells but less than the quantity from E. coli P4 stimulated PMNs. Very low but significant from non-stimulated, levels of reactive oxygen peroxides were produced in the presence of all Leptospira strains and E. coli P4. Similarly, significant levels of reactive nitrogen intermediaries (NO2) was produced from PMNs when incubated with the Leptospira strains and greater quantities in the presence of E. coli P4. PMNs incubated with Leptospira induced RNA transcripts of IL-1beta, MIP-1alpha, and TNF-alpha, with greater amounts induced by live organisms when compared to heat-inactivated leptospires. Transcript for inflammatory cytokine IL-8 was also induced, at similar levels regardless of Leptospira strain or viability. However, incubation of Leptospira strains with bovine PMNs did not affect Leptospira viability as measured by limiting dilution culture. This is in contrast to previously reported results of innate inflammatory activation by Leptospira in human and other animal models, or the activation and interaction of bovine PMNs with Escherichia coli and other bacterial pathogens. While it could be hypothesized that variations in innate receptor recognition, specifically variance in toll-like receptor 2, could underlie the observed reduction of activation in bovine PMNs, additional studies would be needed to explore this possibility. Reduction in neutrophil responses may help to establish nearly asymptomatic chronic Leptospira infection of cattle. This study emphasizes the importance of studying host-pathogen relationships in the appropriate species as extrapolation from other animal models may be incorrect and confounded by differences in the host responses. PMID- 27486447 TI - Thusin, a Novel Two-Component Lantibiotic with Potent Antimicrobial Activity against Several Gram-Positive Pathogens. AB - Due to the rapidly increasing prevalence of multidrug-resistant bacterial strains, the need for new antimicrobial drugs to treat infections has become urgent. Bacteriocins, which are antimicrobial peptides of bacterial origin, are considered potential alternatives to conventional antibiotics and have attracted widespread attention in recent years. Among these bacteriocins, lantibiotics, especially two-component lantibiotics, exhibit potent antimicrobial activity against some clinically relevant Gram-positive pathogens and have potential applications in the pharmaceutical industry. In this study, we characterized a novel two-component lantibiotic termed thusin that consists of Thsalpha, Thsbeta, and Thsbeta' (mutation of Thsbeta, A14G) and that was isolated from a B. thuringiensis strain BGSC 4BT1. Thsalpha and Thsbeta (or Thsbeta') exhibit optimal antimicrobial activity at a 1:1 ratio and act sequentially to affect target cells, and they are all highly thermostable (100 degrees C for 30 min) and pH tolerant (pH 2.0 to 9.0). Thusin shows remarkable efficacy against all tested Gram-positive bacteria and greater activities than two known lantibiotics thuricin 4A-4 and ticin A4, and one antibiotic vancomycin against various bacterial pathogens (Bacillus cereus, Listeria monocytogenes, Staphylococcus aureus (MRSA), Staphylococcus sciuri, Enterococcus faecalis, and Streptococcus pneumoniae). Moreover, thusin is also able to inhibit the outgrowth of B. cereus spores. The potent antimicrobial activity of thusin against some Gram-positive pathogens indicates that it has potential for the development of new drugs. PMID- 27486446 TI - Insights into Bacteriophage Application in Controlling Vibrio Species. AB - Bacterial infections from various organisms including Vibrio sp. pose a serious hazard to humans in many forms from clinical infection to affecting the yield of agriculture and aquaculture via infection of livestock. Vibrio sp. is one of the main foodborne pathogens causing human infection and is also a common cause of losses in the aquaculture industry. Prophylactic and therapeutic usage of antibiotics has become the mainstay of managing this problem, however, this in turn led to the emergence of multidrug resistant strains of bacteria in the environment; which has raised awareness of the critical need for alternative non antibiotic based methods of preventing and treating bacterial infections. Bacteriophages - viruses that infect and result in the death of bacteria - are currently of great interest as a highly viable alternative to antibiotics. This article provides an insight into bacteriophage application in controlling Vibrio species as well underlining the advantages and drawbacks of phage therapy. PMID- 27486448 TI - Transfer of a Catabolic Pathway for Chloromethane in Methylobacterium Strains Highlights Different Limitations for Growth with Chloromethane or with Dichloromethane. AB - Chloromethane (CM) is an ozone-depleting gas, produced predominantly from natural sources, that provides an important carbon source for microbes capable of consuming it. CM catabolism has been difficult to study owing to the challenging genetics of its native microbial hosts. Since the pathways for CM catabolism show evidence of horizontal gene transfer, we reproduced this transfer process in the laboratory to generate new CM-catabolizing strains in tractable hosts. We demonstrate that six putative accessory genes improve CM catabolism, though heterologous expression of only one of the six is strictly necessary for growth on CM. In contrast to growth of Methylobacterium strains with the closely related compound dichloromethane (DCM), we find that chloride export does not limit growth on CM and, in general that the ability of a strain to grow on DCM is uncorrelated with its ability to grow on CM. This heterologous expression system allows us to investigate the components required for effective CM catabolism and the factors that limit effective catabolism after horizontal transfer. PMID- 27486449 TI - Complete Sequence of pEC012, a Multidrug-Resistant IncI1 ST71 Plasmid Carrying bla CTX-M-65, rmtB, fosA3, floR, and oqxAB in an Avian Escherichia coli ST117 Strain. AB - A 139,622-bp IncI1 ST71 conjugative plasmid pEC012 from an avian Escherichia coli D-ST117 strain was sequenced, which carried five IS26-bracketed resistance modules: IS26-fosA3-orf1-orf2-Deltaorf3-IS26, IS26-fip-DeltaISEcp1-bla CTX-M-65 IS903D-iroN-IS26, IS26-DeltatnpR-bla TEM-1-rmtB-IS26, IS26-oqxAB-IS26, and IS26 floR-aac(3)-IV-IS26. The backbone of pEC012 was similar to that of several other IncI1 ST71 plasmids: pV408, pM105, and pC271, but these plasmids had different arrangements of multidrug resistance region. In addition, the novel ISEc57 element was identified, which is in the IS21 family. The stepwise emergence of multi-resistance regions demonstrated the accumulation of different resistance determinants through homologous recombination. To the best of our knowledge, this is the first study to identify a multidrug-resistant IncI1 ST71 plasmid carrying bla CTX-M-65, rmtB, fosA3, floR, and oqxAB in an avian E. coli ST117 strain. PMID- 27486450 TI - The Lp_3561 and Lp_3562 Enzymes Support a Functional Divergence Process in the Lipase/Esterase Toolkit from Lactobacillus plantarum. AB - Lactobacillus plantarum species is a good source of esterases since both lipolytic and esterase activities have been described for strains of this species. No fundamental biochemical difference exists among esterases and lipases since both share a common catalytic mechanism. L. plantarum WCFS1 possesses a protein, Lp_3561, which is 44% identical to a previously described lipase, Lp_3562. In contrast to Lp_3562, Lp_3561 was unable to degrade esters possessing a chain length higher than C4 and the triglyceride tributyrin. As in other L. plantarum esterases, the electrostatic potential surface around the active site in Lp_3561 is predicted to be basic, whereas it is essentially neutral in the Lp_3562 lipase. The fact that the genes encoding both proteins were located contiguously in the L. plantarum WCFS1 genome, suggests that they originated by tandem duplication, and therefore are paralogs as new functions have arisen during evolution. The presence of the contiguous lp_3561 and lp_3562 genes was studied among L. plantarum strains. They are located in a 8,903 bp DNA fragment that encodes proteins involved in the catabolism of sialic acid and are predicted to increase bacterial adaptability under certain growth conditions. PMID- 27486451 TI - Characterization of a New Cold-Adapted and Salt-Activated Polysaccharide Lyase Family 7 Alginate Lyase from Pseudoalteromonas sp. SM0524. AB - Marine bacterial alginate lyases play a role in marine alginate degradation and carbon cycling. Although a large number of alginate lyases have been characterized, reports on alginate lyases with special characteristics are still rather less. Here, a gene alyPM encoding an alginate lyase of polysaccharide lyase family 7 (PL7) was cloned from marine Pseudoalteromonas sp. SM0524 and expressed in Escherichia coli. AlyPM shows 41% sequence identity to characterized alginate lyases, indicating that AlyPM is a new PL7 enzyme. The optimal pH for AlyPM activity was 8.5. AlyPM showed the highest activity at 30 degrees C and remained 19% of the highest activity at 5 degrees C. AlyPM was unstable at temperatures above 30 degrees C and had a low T m of 37 degrees C. These data indicate that AlyPM is a cold-adapted enzyme. Moreover, AlyPM is a salt-activated enzyme. AlyPM activity in 0.5-1.2 M NaCl was sixfolds higher than that in 0 M NaCl, probably caused by a significant increase in substrate affinity, because the K m of AlyPM in 0.5 M NaCl decreased more than 20-folds than that in 0 M NaCl. AlyPM preferably degraded polymannuronate and mainly released dimers and trimers. These data indicate that AlyPM is a new PL7 endo-alginate lyase with special characteristics. PMID- 27486452 TI - Methane Inhibition Alters the Microbial Community, Hydrogen Flow, and Fermentation Response in the Rumen of Cattle. AB - Management of metabolic hydrogen ([H]) in the rumen has been identified as an important consideration when reducing ruminant CH4 emissions. However, little is known about hydrogen flux and microbial rumen population responses to CH4 inhibition when animals are fed with slowly degradable diets. The effects of the anti-methanogenic compound, chloroform, on rumen fermentation, microbial ecology, and H2/CH4 production were investigated in vivo. Eight rumen fistulated Brahman steers were fed a roughage hay diet (Rhode grass hay) or roughage hay:concentrate diet (60:40) with increasing levels (low, mid, and high) of chloroform in a cyclodextrin matrix. The increasing levels of chloroform resulted in an increase in H2 expelled as CH4 production decreased with no effect on dry matter intakes. The amount of expelled H2 per mole of decreased methane, was lower for the hay diet suggesting a more efficient redirection of hydrogen into other microbial products compared with hay:concentrate diet. A shift in rumen fermentation toward propionate and branched-chain fatty acids was observed for both diets. Animals fed with the hay:concentrate diet had both higher formate concentration and H2 expelled than those fed only roughage hay. Metabolomic analyses revealed an increase in the concentration of amino acids, organic, and nucleic acids in the fluid phase for both diets when methanogenesis was inhibited. These changes in the rumen metabolism were accompanied by a shift in the microbiota with an increase in Bacteroidetes:Firmicutes ratio and a decrease in Archaea and Synergistetes for both diets. Within the Bacteroidetes family, some OTUs assigned to Prevotella were promoted under chloroform treatment. These bacteria may be partly responsible for the increase in amino acids and propionate in the rumen. No significant changes were observed for abundance of fibrolytic bacteria, protozoa, and fungi, which suggests that fiber degradation was not impaired. The observed 30% decrease in methanogenesis did not adversely affect rumen metabolism and the rumen microbiota was able to adapt and redirect [H] into other microbial end-products for both diets. However, it is also required dietary supplements or microbial treatments to capture the additional H2 expelled by the animal to further improve rumen digestive efficiency. PMID- 27486453 TI - Stress Conditions Induced by Carvacrol and Cinnamaldehyde on Acinetobacter baumannii. AB - Acinetobacter baumannii has emerged as a major cause of nosocomial infections. The ability of A. baumannii to display various resistance mechanisms against antibiotics has transformed it into a successful nosocomial pathogen. The limited number of antibiotics in development and the disengagement of the pharmaceutical industry have prompted the development of innovative strategies. One of these strategies is the use of essential oils, especially aromatic compounds that are potent antibacterial molecules. Among them, the combination of carvacrol and cinnamaldehyde has already demonstrated antibacterial efficacy against A. baumannii. The aim of this study was to determine the biological effects of these two compounds in A. baumannii, describing their effect on the rRNA and gene regulation under environmental stress conditions. Results demonstrated rRNA degradation by the carvacrol/cinnamaldehyde mixture, and this effect was due to carvacrol. Degradation was conserved after encapsulation of the mixture in lipid nanocapsules. Results showed an upregulation of the genes coding for heat shock proteins, such as groES, groEL, dnaK, clpB, and the catalase katE, after exposure to carvacrol/cinnamaldehyde mixture. The catalase was upregulated after carvacrol exposure wich is related to an oxidative stress. The combination of thiourea (hydroxyl radical scavenger) and carvacrol demonstrated a potent bactericidal effect. These results underline the development of defense strategies of the bacteria by synthesis of reactive oxygen species in response to environmental stress conditions, such as carvacrol. PMID- 27486454 TI - Probing Synechocystis-Arsenic Interactions through Extracellular Nanowires. AB - Microbial nanowires (MNWs) can play an important role in the transformation and mobility of toxic metals/metalloids in environment. The potential role of MNWs in cell-arsenic (As) interactions has not been reported in microorganisms and thus we explored this interaction using Synechocystis PCC 6803 as a model system. The effect of half maximal inhibitory concentration (IC50) [~300 mM As (V) and ~4 mM As (III)] and non-inhibitory [4X lower than IC50, i.e., 75 mM As (V) and 1 mM As (III)] of As was studied on Synechocystis cells in relation to its effect on Chlorophyll (Chl) a, type IV pili (TFP)-As interaction and intracellular/extracellular presence of As. In silico analysis showed that subunit PilA1 of electrically conductive TFP, i.e., microbial nanowires of Synechocystis have putative binding sites for As. In agreement with in silico analysis, transmission electron microscopy analysis showed that As was deposited on Synechocystis nanowires at all tested concentrations. The potential of Synechocystis nanowires to immobilize As can be further enhanced and evaluated on a large scale and thus can be applied for bioremediation studies. PMID- 27486455 TI - Exploring the Diversity and Antimicrobial Potential of Marine Actinobacteria from the Comau Fjord in Northern Patagonia, Chile. AB - Bioprospecting natural products in marine bacteria from fjord environments are attractive due to their unique geographical features. Although, Actinobacteria are well known for producing a myriad of bioactive compounds, investigations regarding fjord-derived marine Actinobacteria are scarce. In this study, the diversity and biotechnological potential of Actinobacteria isolated from marine sediments within the Comau fjord, in Northern Chilean Patagonia, were assessed by culture-based approaches. The 16S rRNA gene sequences revealed that members phylogenetically related to the Micrococcaceae, Dermabacteraceae, Brevibacteriaceae, Corynebacteriaceae, Microbacteriaceae, Dietziaceae, Nocardiaceae, and Streptomycetaceae families were present at the Comau fjord. A high diversity of cultivable Actinobacteria (10 genera) was retrieved by using only five different isolation media. Four isolates belonging to Arthrobacter, Brevibacterium, Corynebacterium and Kocuria genera showed 16S rRNA gene identity <98.7% suggesting that they are novel species. Physiological features such as salt tolerance, artificial sea water requirement, growth temperature, pigmentation and antimicrobial activity were evaluated. Arthrobacter, Brachybacterium, Curtobacterium, Rhodococcus, and Streptomyces isolates showed strong inhibition against both Gram-negative Pseudomonas aeruginosa, Escherichia coli and Salmonella enterica and Gram-positive Staphylococcus aureus, Listeria monocytogenes. Antimicrobial activities in Brachybacterium, Curtobacterium, and Rhodococcus have been scarcely reported, suggesting that non-mycelial strains are a suitable source of bioactive compounds. In addition, all strains bear at least one of the biosynthetic genes coding for NRPS (91%), PKS I (18%), and PKS II (73%). Our results indicate that the Comau fjord is a promising source of novel Actinobacteria with biotechnological potential for producing biologically active compounds. PMID- 27486456 TI - Factors Determining Staphylococcus aureus Susceptibility to Photoantimicrobial Chemotherapy: RsbU Activity, Staphyloxanthin Level, and Membrane Fluidity. AB - Photoantimicrobial chemotherapy (PACT) constitutes a particular type of stress condition, in which bacterial cells induce a pleiotropic and as yet unexplored effect. In light of this, the key master regulators are of putative significance to the overall phototoxic outcome. In Staphylococcus aureus, the alternative sigma factor sigma(B) controls the expression of genes involved in the response to environmental stress. We show that aberration of any sigB operon genes in S. aureus USA300 isogenic mutants causes a pronounced sensitization (>5 log10 reduction in CFU drop) to PACT with selected photosensitizers, namely protoporphyrin diarginate, zinc phthalocyanine and rose bengal. This effect is partly due to aberration-coupled staphyloxanthin synthesis inhibition. We identified frequent mutations in RsbU, a sigma(B) activator, in PACT-vulnerable clinical isolates of S. aureus, resulting in sigma(B) activity impairment. Locations of significant changes in protein structure (IS256 insertion, early STOP codon occurrence, substitutions A230T and A276D) were shown in a theoretical model of S. aureus RsbU. As a phenotypic hallmark of PACT-vulnerable S. aureus strains, we observed an increased fluidity of bacterial cell membrane, which is a result of staphyloxanthin content and other yet unidentified factors. Our research indicates sigma(B) as a promising target of adjunctive antimicrobial therapy and suggests that enhanced cell membrane fluidity may be an adjuvant strategy in PACT. PMID- 27486457 TI - Three CoA Transferases Involved in the Production of Short Chain Fatty Acids in Porphyromonas gingivalis. AB - Butyryl-CoA:acetate CoA transferase, which produces butyrate and acetyl-CoA from butyryl-CoA and acetate, is responsible for the final step of butyrate production in bacteria. This study demonstrates that in the periodontopathogenic bacterium Porphyromonas gingivalis this reaction is not catalyzed by PGN_1171, previously annotated as butyryl-CoA:acetate CoA transferase, but by three distinct CoA transferases, PGN_0725, PGN_1341, and PGN_1888. Gas chromatography/mass spectrometry (GC-MS) and spectrophotometric analyses were performed using crude enzyme extracts from deletion mutant strains and purified recombinant proteins. The experiments revealed that, in the presence of acetate, PGN_0725 preferentially utilized butyryl-CoA rather than propionyl-CoA. By contrast, this preference was reversed in PGN_1888. The only butyryl-CoA:acetate CoA transferase activity was observed in PGN_1341. Double reciprocal plots revealed that all the reactions catalyzed by these enzymes follow a ternary-complex mechanism, in contrast to previously characterized CoA transferases. GC-MS analysis to determine the concentrations of short chain fatty acids (SCFAs) in culture supernatants of P. gingivalis wild type and mutant strains revealed that PGN_0725 and PGN_1888 play a major role in the production of butyrate and propionate, respectively. Interestingly, a triple deletion mutant lacking PGN_0725, PGN_1341, and PGN_1888 produced low levels of SCFAs, suggesting that the microorganism contains CoA transferase(s) in addition to these three enzymes. Growth rates of the mutant strains were mostly slower than that of the wild type, indicating that many carbon compounds produced in the SCFA synthesis appear to be important for the biological activity of this microorganism. PMID- 27486458 TI - Antimicrobial Activity of Mast Cells: Role and Relevance of Extracellular DNA Traps. AB - Mast cells (MCs) have been shown to release their nuclear DNA and subsequently form mast cell extracellular traps (MCETs) comparable to neutrophil extracellular traps, which are able to entrap and kill various microbes. The formation of extracellular traps is associated with the disruption of the nuclear membrane, which leads to mixing of nuclear compounds with granule components and causes the death of the cell, a process called ETosis. The question arises why do MCs release MCETs although they are very well known as multifunctional long-living sentinel cells? MCs are known to play a role during allergic reactions and certain parasitic infections. Nonetheless, they are also critical components of the early host innate immune response to bacterial and fungal pathogens: MCs contribute to the initiation of the early immune response by recruiting effector cells including neutrophils and macrophages by locally releasing inflammatory mediators, such as TNF-alpha. Moreover, various studies demonstrate that MCs are able to eliminate microbes through intracellular as well as extracellular antimicrobial mechanisms, including MCET formation similar to that of professional phagocytes. Recent literature leads to the suggestion that MCET formation is not the result of a passive release of DNA and granule proteins during cellular disintegration, but rather an active and controlled process in response to specific stimulation, which contributes to the innate host defense. This review will discuss the different known aspects of the antimicrobial activities of MCs with a special focus on MCETs, and their role and relevance during infection and inflammation. PMID- 27486460 TI - M1- and M2-Type Macrophage Responses Are Predictive of Adverse Outcomes in Human Atherosclerosis. AB - Atherosclerosis is an inflammatory disease caused by endothelial injury, lipid deposition, and oxidative stress. This progressive disease can be converted into an acute clinical event by plaque rupture and thrombosis. In the context of atherosclerosis, the underlying cause of myocardial infarction and stroke, macrophages uniquely possess a dual functionality, regulating lipid accumulation and metabolism and sustaining the chronic inflammatory response, two of the most well-documented pathways associated with the pathogenesis of the disease. Macrophages are heterogeneous cell populations and it is hypothesized that, during the pathogenesis of atherosclerosis, macrophages in the developing plaque can switch from a pro-inflammatory (MPhi1) to an anti-inflammatory (MPhi2) phenotype and vice versa, depending on the microenvironment. The aim of this study was to identify changes in macrophage subpopulations in the progression of human atherosclerotic disease. Established atherosclerotic plaques from symptomatic and asymptomatic patients with existing coronary artery disease undergoing carotid endarterectomy were recruited to the study. Comprehensive histological and immunohistochemical analyses were performed to quantify the cellular content and macrophage subsets of atherosclerotic lesion. In parallel, expression of MPhi1 and MPhi2 macrophage markers were analyzed by real-time PCR and Western blot analysis. Gross analysis and histological staining demonstrated that symptomatic plaques presented greater hemorrhagic activity and the internal carotid was the most diseased segment, based on the predominant prevalence of fibrotic and necrotic tissue, calcifications, and hemorrhagic events. Immunohistochemical analysis showed that both MPhi1 and MPhi2 macrophages are present in human plaques. However, MPhi2 macrophages are localized to more stable locations within the lesion. Importantly, gene and protein expression analysis of MPhi1/MPhi2 markers evidenced that MPhi1 markers and Th1-associated cytokines are highly expressed in symptomatic plaques, whereas expression of the MPhi2 markers, mannose receptor (MR), and CD163 and Th2 cytokines are inversely related with disease progression. These data increase the understanding of atherosclerosis development, identifying the cellular content of lesions during disease progression, and characterizing macrophage subpopulation within human atherosclerotic plaques. PMID- 27486459 TI - Transcriptome Analysis of B Cell Immune Functions in Periodontitis: Mucosal Tissue Responses to the Oral Microbiome in Aging. AB - Evidence has shown activation of T and B cells in gingival tissues in experimental models and in humans diagnosed with periodontitis. The results of this adaptive immune response are noted both locally and systemically with antigenic specificity for an array of oral bacteria, including periodontopathic species, e.g., Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. It has been recognized through epidemiological studies and clinical observations that the prevalence of periodontitis increases with age. This report describes our studies evaluating gingival tissue transcriptomes in humans and specifically exploiting the use of a non-human primate model of naturally occurring periodontitis to delineate gingival mucosal tissue gene expression profiles focusing on cells/genes critical for the development of humoral adaptive immune responses. Patterns of B cell and plasmacyte genes were altered in aging healthy gingival tissues. Substantial increases in a large number of genes reflecting antigen-dependent activation, B cell activation, B cell proliferation, and B cell differentiation/maturation were observed in periodontitis in adults and aged animals. Finally, evaluation of the relationship of these gene expression patterns with those of various tissue destructive molecules (MMP2, MMP9, CTSK, TNFalpha, and RANKL) showed a greater frequency of positive correlations in healthy tissues versus periodontitis tissues, with only MMP9 correlations similar between the two tissue types. These results are consistent with B cell response activities in healthy tissues potentially contributing to muting the effects of the tissue destructive biomolecules, whereas with periodontitis this relationship is adversely affected and enabling a progression of tissue destructive events. PMID- 27486461 TI - Transforming Growth Factor-beta-Activated Kinase 1 Is Required for Human FcgammaRIIIb-Induced Neutrophil Extracellular Trap Formation. AB - Neutrophils (PMNs) are the most abundant leukocytes in the blood. PMN migrates from the circulation to sites of infection where they are responsible for antimicrobial functions. PMN uses phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs) to kill microbes. Several stimuli, including bacteria, fungi, and parasites, and some pharmacological compounds, such as Phorbol 12-myristate 13-acetate (PMA), are efficient inducers of NETs. Antigen-antibody complexes are also capable of inducing NET formation. Recently, it was reported that FcgammaRIIIb cross-linking induced NET formation similarly to PMA stimulation. Direct cross-linking of FcgammaRIIA or integrins did not promote NET formation. FcgammaRIIIb-induced NET formation presented different kinetics from PMA-induced NET formation, suggesting differences in signaling. Because FcgammaRIIIb also induces a strong activation of extracellular signal regulated kinase (ERK) and nuclear factor Elk-1, and the transforming growth factor-beta-activated kinase 1 (TAK1) has recently been implicated in ERK signaling, in the present report, we explored the role of TAK1 in the signaling pathway activated by FcgammaRIIIb leading to NET formation. FcgammaRIIIb was stimulated by specific monoclonal antibodies, and NET formation was evaluated in the presence or absence of pharmacological inhibitors. The antibiotic LL Z1640-2, a selective inhibitor of TAK1 prevented FcgammaRIIIb-induced, but not PMA-induced NET formation. Both PMA and FcgammaRIIIb cross-linking induced phosphorylation of ERK. But, LL Z1640-2 only inhibited the FcgammaRIIIb-mediated activation of ERK. Also, only FcgammaRIIIb, similarly to transforming growth factor-beta-induced TAK1 phosphorylation. A MEK (ERK kinase)-specific inhibitor was able to prevent ERK phosphorylation induced by both PMA and FcgammaRIIIb. These data show for the first time that FcgammaRIIIb cross-linking activates TAK1, and that this kinase is required for triggering the MEK/ERK signaling pathway to NETosis. PMID- 27486462 TI - Remodeling of Leaf Cellular Glycerolipid Composition under Drought and Re hydration Conditions in Grasses from the Lolium-Festuca Complex. AB - Drought tolerant plant genotypes are able to maintain stability and integrity of cellular membranes in unfavorable conditions, and to regenerate damaged membranes after stress cessation. The profiling of cellular glycerolipids during drought stress performed on model species such as Arabidopsis thaliana does not fully cover the picture of lipidome in monocots, including grasses. Herein, two closely related introgression genotypes of Lolium multiflorum (Italian ryegrass) * Festuca arundinacea (tall fescue) were used as a model for other grass species to describe lipid rearrangements during drought and re-hydration. The genotypes differed in their level of photosynthetic capacity during drought, and in their capacity for membrane regeneration after stress cessation. A total of 120 lipids, comprising the classes of monogalactosyldiacyloglycerol, digalactosyldiacyloglycerol, sulfoquinovosyldiacylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, diacylglicerol, and triacylglicerol, were analyzed. The results clearly showed that water deficit had a significant impact on lipid metabolism in studied forage grasses. It was revealed that structural and metabolic lipid species changed their abundance during drought and re-watering periods and some crucial genotype-dependent differences were also observed. The introgression genotype characterized by an ability to regenerate membranes after re-hydration demonstrated a higher accumulation level of most chloroplast and numerous extra-chloroplast membrane lipid species at the beginning of drought. Furthermore, this genotype also revealed a significant reduction in the accumulation of most chloroplast lipids after re-hydration, compared with the other introgression genotype without the capacity for membrane regeneration. The potential influence of observed lipidomic alterations on a cellular membrane stability and photosynthetic capacity, are discussed. HIGHLIGHTS A higher drought tolerance of grasses could be associated with an earlier lipidome response to a stress signal and with a membrane regeneration after stress cessation accompanied by a turnover of chloroplast lipids. PMID- 27486463 TI - New Insights on Eggplant/Tomato/Pepper Synteny and Identification of Eggplant and Pepper Orthologous QTL. AB - Eggplant, pepper, and tomato are the most exploited berry-producing vegetables within the Solanaceae family. Their genomes differ in size, but each has 12 chromosomes which have undergone rearrangements causing a redistribution of loci. The genome sequences of all three species are available but differ in coverage, assembly quality and percentage of anchorage. Determining their syntenic relationship and QTL orthology will contribute to exploit genomic resources and genetic data for key agronomic traits. The syntenic analysis between tomato and pepper based on the alignment of 34,727 tomato CDS to the pepper genome sequence, identified 19,734 unique hits. The resulting synteny map confirmed the 14 inversions and 10 translocations previously documented, but also highlighted 3 new translocations and 4 major new inversions. Furthermore, each of the 12 chromosomes exhibited a number of rearrangements involving small regions of 0.5 0.7 Mbp. Due to high fragmentation of the publicly available eggplant genome sequence, physical localization of most eggplant QTL was not possible, thus, we compared the organization of the eggplant genetic map with the genome sequence of both tomato and pepper. The eggplant/tomato syntenic map confirmed all the 10 translocations but only 9 of the 14 known inversions; on the other hand, a newly detected inversion was recognized while another one was not confirmed. The eggplant/pepper syntenic map confirmed 10 translocations and 8 inversions already detected and suggested a putative new translocation. In order to perform the assessment of eggplant and pepper QTL orthology, the eggplant and pepper sequence based markers located in their respective genetic map were aligned onto the pepper genome. GBrowse in pepper was used as reference platform for QTL positioning. A set of 151 pepper QTL were located as well as 212 eggplant QTL, including 76 major QTL (PVE >= 10%) affecting key agronomic traits. Most were confirmed to cluster in orthologous chromosomal regions. Our results highlight that the availability of genome sequences for an increasing number of crop species and the development of "ultra-dense" physical maps provide new and key tools for detailed syntenic and orthology studies between related plant species. PMID- 27486464 TI - Genome-Wide QTL Mapping for Wheat Processing Quality Parameters in a Gaocheng 8901/Zhoumai 16 Recombinant Inbred Line Population. AB - Dough rheological and starch pasting properties play an important role in determining processing quality in bread wheat (Triticum aestivum L.). In the present study, a recombinant inbred line (RIL) population derived from a Gaocheng 8901/Zhoumai 16 cross grown in three environments was used to identify quantitative trait loci (QTLs) for dough rheological and starch pasting properties evaluated by Mixograph, Rapid Visco-Analyzer (RVA), and Mixolab parameters using the wheat 90 and 660 K single nucleotide polymorphism (SNP) chip assays. A high-density linkage map constructed with 46,961 polymorphic SNP markers from the wheat 90 and 660 K SNP assays spanned a total length of 4121 cM, with an average chromosome length of 196.2 cM and marker density of 0.09 cM/marker; 6596 new SNP markers were anchored to the bread wheat linkage map, with 1046 and 5550 markers from the 90 and 660 K SNP assays, respectively. Composite interval mapping identified 119 additive QTLs on 20 chromosomes except 4D; among them, 15 accounted for more than 10% of the phenotypic variation across two or three environments. Twelve QTLs for Mixograph parameters, 17 for RVA parameters and 55 for Mixolab parameters were new. Eleven QTL clusters were identified. The closely linked SNP markers can be used in marker-assisted wheat breeding in combination with the Kompetitive Allele Specific PCR (KASP) technique for improvement of processing quality in bread wheat. PMID- 27486465 TI - Plant Recycling for Molecular Biofarming to Produce Recombinant Anti-Cancer mAb. AB - The expression and glycosylation patterns of anti-colorectal cancer therapeutic monoclonal antibody (mAb) CO17-1A recognizing the tumor-associated antigen GA733 2, expressed in human colorectal carcinoma cells, were observed in the leaf and stem tissues of primary (0 cycle), secondary (1 cycle), and tertiary (2 cycle) growths of seedlings obtained from the stem cut of T2 plants. The bottom portion of the stem of T2 seedlings was cut to induce the 1 cycle shoot growth, which was again cut to induce the 2 cycle shoot growth. In the 1 and 2 cycle growths, the periods for floral organ formation (35 days) was shorter than that (100 days) for the 0 cycle growth. The genes of heavy and light chains of mAb CO17-1A existed at the top, middle, and basal portions of the leaves and stem obtained from the 0, 1, and 2 cycle plants. The protein levels in the leaves and stem tissues from the 1 and 2 cycles were similar to those in the tissues from the 0 cycle. The glycosylation level and pattern in the leaf and stem did not alter dramatically over the different cycles. Surface plasmon resonance (SPR) confirmed that mAbs CO17-1A obtained from leaf and stem tissues of the 0, 1, and 2 cycles had similar binding affinity for the GA733-2 antigen. These data suggest that the shoot growth by bottom stem cutting is applicable to speed up the growth of plant biomass expressing anti-colorectal cancer mAb without variation of expression, glycosylation, and functionality. PMID- 27486466 TI - Identification and Comparative Analysis of Differential Gene Expression in Soybean Leaf Tissue under Drought and Flooding Stress Revealed by RNA-Seq. AB - Drought and flooding are two major causes of severe yield loss in soybean worldwide. A lack of knowledge of the molecular mechanisms involved in drought and flood stress has been a limiting factor for the effective management of soybeans; therefore, it is imperative to assess the expression of genes involved in response to flood and drought stress. In this study, differentially expressed genes (DEGs) under drought and flooding conditions were investigated using Illumina RNA-Seq transcriptome profiling. A total of 2724 and 3498 DEGs were identified under drought and flooding treatments, respectively. These genes comprise 289 Transcription Factors (TFs) representing Basic Helix-loop Helix (bHLH), Ethylene Response Factors (ERFs), myeloblastosis (MYB), No apical meristem (NAC), and WRKY amino acid motif (WRKY) type major families known to be involved in the mechanism of stress tolerance. The expression of photosynthesis and chlorophyll synthesis related genes were significantly reduced under both types of stresses, which limit the metabolic processes and thus help prolong survival under extreme conditions. However, cell wall synthesis related genes were up-regulated under drought stress and down-regulated under flooding stress. Transcript profiles involved in the starch and sugar metabolism pathways were also affected under both stress conditions. The changes in expression of genes involved in regulating the flux of cell wall precursors and starch/sugar content can serve as an adaptive mechanism for soybean survival under stress conditions. This study has revealed the involvement of TFs, transporters, and photosynthetic genes, and has also given a glimpse of hormonal cross talk under the extreme water regimes, which will aid as an important resource for soybean crop improvement. PMID- 27486467 TI - Application of the Ribosomal DNA ITS2 Region of Physalis (Solanaceae): DNA Barcoding and Phylogenetic Study. AB - Recently, commercial interest in Physalis species has grown worldwide due to their high nutritional value, edible fruit, and potential medicinal properties. However, many Physalis species have similar shapes and are easily confused, and consequently the phylogenetic relationships between Physalis species are poorly understood. This hinders their safe utilization and genetic resource conservation. In this study, the nuclear ribosomal ITS2 region was used to identify species and phylogenetically examine Physalis. Eighty-six ITS2 regions from 45 Physalis species were analyzed. The ITS2 sequences were aligned using Clustal W and genetic distances were calculated using MEGA V6.0. The results showed that ITS2 regions have significant intra- and inter-specific divergences, obvious barcoding gaps, and higher species discrimination rates (82.2% for both the BLASTA1 and nearest distance methods). In addition, the secondary structure of ITS2 provided another way to differentiate species. Cluster analysis based on ITS2 regions largely concurred with the relationships among Physalis species established by many previous molecular analyses, and showed that most sections of Physalis appear to be polyphyletic. Our results demonstrated that ITS2 can be used as an efficient and powerful marker in the identification and phylogenetic study of Physalis species. The technique provides a scientific basis for the conservation of Physalis plants and for utilization of resources. PMID- 27486468 TI - Leaf Treatments with a Protein-Based Resistance Inducer Partially Modify Phyllosphere Microbial Communities of Grapevine. AB - Protein derivatives and carbohydrates can stimulate plant growth, increase stress tolerance, and activate plant defense mechanisms. However, these molecules can also act as a nutritional substrate for microbial communities living on the plant phyllosphere and possibly affect their biocontrol activity against pathogens. We investigated the mechanisms of action of a protein derivative (nutrient broth, NB) against grapevine downy mildew, specifically focusing on the effects of foliar treatments on plant defense stimulation and on the composition and biocontrol features of the phyllosphere microbial populations. NB reduced downy mildew symptoms and induced the expression of defense-related genes in greenhouse and in vitro-grown plants, indicating the activation of grapevine resistance mechanisms. Furthermore, NB increased the number of culturable phyllosphere bacteria and altered the composition of bacterial and fungal populations on leaves of greenhouse-grown plants. Although, NB-induced changes on microbial populations were affected by the structure of indigenous communities originally residing on grapevine leaves, degrees of disease reduction and defense gene modulation were consistent among the experiments. Thus, modifications in the structure of phyllosphere populations caused by NB application could partially contribute to downy mildew control by competition for space or other biocontrol strategies. Particularly, changes in the abundance of phyllosphere microorganisms may provide a contribution to resistance induction, partially affecting the hormone-mediated signaling pathways involved. Modifying phyllosphere populations by increasing natural biocontrol agents with the application of selected nutritional factors can open new opportunities in terms of sustainable plant protection strategies. PMID- 27486469 TI - Phytochrome and Ethylene Signaling Integration in Arabidopsis Occurs via the Transcriptional Regulation of Genes Co-targeted by PIFs and EIN3. AB - Plant seedlings germinating under the soil are challenged by rough soil grains that can induce physical damage and sudden exposure to light, which can induce photobleaching. Seedlings overcome these challenges by developing apical hooks and by suppressing chlorophyll precursor biosynthesis. These adaptive responses are, respectively, regulated by the phytochrome and ethylene signaling pathways via the PHYTOCHROME-INTERACTING FACTORs (PIFs) and the ETHYLENE INSENSITIVE 3 (EIN3)/EIN3-LIKE transcription factors. Although many processes downstream of phytochrome and ethylene signaling are similar, it remains unclear if and where these pathways converge. Here, we show PIFs and EIN3 induce similar changes in the transcriptome without robustly regulating each other's signaling pathways. PIFs and EIN3 target highly overlapped gene promoters and activate subsets of the co-target genes either interdependently or additively to induce plant responses. For chlorophyll biosynthesis, PIFs and EIN3 target and interdependently activate the expression of HOOKLESS1. HOOKLESS1, in turn, represses chlorophyll synthesis genes to prevent photobleaching. Thus, our results indicate an integration of the phytochrome and ethylene signaling pathways at the level of transcriptional gene regulation by two core groups of transcription factors, PIFs and EIN3. PMID- 27486470 TI - Corrigendum: Digital Gene Expression Analysis of Populus simonii * P. nigra Pollen Germination and Tube Growth. AB - [This corrects the article on p. 825 in vol. 7, PMID: 27379121.]. PMID- 27486471 TI - Rice Stress Associated Protein 1 (OsSAP1) Interacts with Aminotransferase (OsAMTR1) and Pathogenesis-Related 1a Protein (OsSCP) and Regulates Abiotic Stress Responses. AB - Stress associated proteins (SAPs) are the A20/AN1 zinc-finger containing proteins which can regulate the stress signaling in plants. The rice SAP protein, OsSAP1 has been shown to confer abiotic stress tolerance to plants, when overexpressed, by modulating the expression of endogenous stress-related genes. To further understand the mechanism of OsSAP1-mediated stress signaling, OsSAP1 interacting proteins were identified using yeast two-hybrid analysis. Two novel proteins, aminotransferase (OsAMTR1) and a SCP/TAPS or pathogenesis-related 1 class of protein (OsSCP) were found to interact with OsSAP1. The genes encoding OsAMTR1 and OsSCP were stress-responsive and showed higher expression upon abiotic stress treatments. The role of OsAMTR1 and OsSCP under stress was analyzed by overexpressing them constitutively in Arabidopsis and responses of transgenic plants were assessed under salt and water-deficit stress. The OsAMTR1 and OsSCP overexpressing plants showed higher seed germination, root growth and fresh weight than wild-type plants under stress conditions. Overexpression of OsAMTR1 and OsSCP affected the expression of many known stress-responsive genes which were not affected by the overexpression of OsSAP1. Moreover, the transcript levels of OsSCP and OsAMTR1 were also unaffected by the overexpression of OsSAP1. Hence, it was concluded that OsSAP1 regulates the stress responsive signaling by interacting with these proteins which further regulate the downstream stress responsive gene expression. PMID- 27486472 TI - Genome-Wide Association Mapping in the Global Diversity Set Reveals New QTL Controlling Root System and Related Shoot Variation in Barley. AB - The fibrous root system is a visible sign of ecological adaptation among barley natural populations. In the present study, we utilized rich barley diversity to dissect the genetic basis of root system variation and its link with shoot attributes under well-water and drought conditions. Genome-wide association mapping of phenotype data using a dense genetic map (5892 SNP markers) revealed 17 putative QTL for root and shoot traits. Among these, at 14 loci the preeminence of exotic QTL alleles resulted in trait improvements. The most promising QTL were quantified using haplotype analysis at local and global genome levels. The strongest QTL was found on chromosome 1H which accounted for root dry weight and tiller number simultaneously. Candidate gene analysis across the targeted region detected a crucial amino acid substitution mutation in the conserved domain of a WRKY29 transcription factor among genotypes bearing major and minor QTL alleles. Similarly, the drought inducible QTL QRdw.5H (5H, 95.0 cM) seems to underlie 37 amino acid deletion and substitution mutations in the conserved domain of two related genes CBF10B and CBF10A, respectively. The identification and further characterization of these candidate genes will be essential to decipher genetics behind developmental and natural adaptation mechanisms of barley. PMID- 27486473 TI - Sustained Diurnal Stimulation of Cyclic Electron Flow in Two Tropical Tree Species Erythrophleum guineense and Khaya ivorensis. AB - The photosystem II (PSII) activity of C3 plants is usually inhibited at noon associated with high light but can be repaired fast in the afternoon. However, the diurnal variation of photosystem I (PSI) activity is unknown. Although, cyclic electron flow (CEF) has been documented as an important mechanism for photosynthesis, the diurnal variation of CEF in sun leaves is little known. We determined the diurnal changes in PSI and PSII activities, light energy dissipation in PSII and the P700 redox state in two tropical tree species Erythrophleum guineense and Khaya ivorensis grown in an open field. The PSI activity (as indicated by the maximum quantity of photo-oxidizable P700) was maintained stable during the daytime. CEF was strongly activated under high light at noon, accompanying with high levels of non-photochemical quenching (NPQ) and PSI oxidation ratio. In the afternoon, CEF was maintained at a relatively high level under low light, which was accompanied with low levels of NPQ and P700 oxidation ratio. These results indicated that CEF was flexibly modulated during daytime under fluctuating light conditions. Under high light at noon, CEF dependent generation of proton gradient across the thylakoid membranes (DeltapH) mainly contributed to photoprotection for PSI and PSII. By comparison, at low light in the afternoon, the CEF-dependent formation of DeltapH may be important for PSII repair via an additional ATP synthesis. PMID- 27486474 TI - The Role of Silicon in Higher Plants under Salinity and Drought Stress. AB - Although deemed a "non-essential" mineral nutrient, silicon (Si) is clearly beneficial to plant growth and development, particularly under stress conditions, including salinity and drought. Here, we review recent research on the physiological, biochemical, and molecular mechanisms underlying Si-induced alleviation of osmotic and ionic stresses associated with salinity and drought. We distinguish between changes observed in the apoplast (i.e., suberization, lignification, and silicification of the extracellular matrix; transpirational bypass flow of solutes and water), and those of the symplast (i.e., transmembrane transport of solutes and water; gene expression; oxidative stress; metabolism), and discuss these features in the context of Si biogeochemistry and bioavailability in agricultural soils, evaluating the prospect of using Si fertilization to increase crop yield and stress tolerance under salinity and drought conditions. PMID- 27486475 TI - Dual Function of NAC072 in ABF3-Mediated ABA-Responsive Gene Regulation in Arabidopsis. AB - The NAM, ATAF1/2, and CUC2 (NAC) domain proteins play various roles in plant growth and stress responses. Arabidopsis NAC transcription factor NAC072 has been reported as a transcriptional activator in Abscisic acid (ABA)-responsive gene expression. However, the exact function of NAC072 in ABA signaling is still elusive. In this study, we present evidence for the interrelation between NAC072 and ABA-responsive element binding factor 3 (ABF3) that act as a positive regulator of ABA-responsive gene expression in Arabidopsis. The transcript of NAC072 is up-regulated by ABF3 in ABA response, and NAC072 protein interacts with ABF3. Enhanced ABA sensitivity occurs in nac072 mutant plants that overexpressed ABF3. However, overexpression of NAC072 weakened the ABA sensitivity in the abf3 mutant plants, but instead of recovering the ABA sensitivity of abf3. NAC072 and ABF3 cooperate to regulate RD29A expression, but are antagonistic when regulating RD29B expression. Therefore, NAC072 displays a dual function in ABF3-mediated ABA responsive gene regulation. PMID- 27486477 TI - Erratum to: Evaluation of a surgical service in the chronic phase of a refugee camp: an example from the Thai-Myanmar border. AB - [This corrects the article DOI: 10.1186/1752-1505-6-5.]. PMID- 27486476 TI - Interferon gamma-induced apoptosis of head and neck squamous cell carcinoma is connected to indoleamine-2,3-dioxygenase via mitochondrial and ER stress associated pathways. AB - BACKGROUND: Tumor response to immunotherapy is the consequence of a concerted crosstalk between cytokines and effector cells. Interferon gamma (IFNgamma) is one of the common cytokines coordinating tumor immune response and the associated biological consequences. Although the role of IFNgamma in the modulation of tumor immunity has been widely documented, the mechanisms regulating IFNgamma-induced cell death, during the course of immune therapy, is not described in detail. RESULTS: IFNgamma triggered apoptosis of CLS-354 and RPMI 2650 cells, enhanced the protein expression and activation of indoleamine 2,3-dioxygenase (IDO), and suppressed the basal expression of heme oxygenase-1(HO-1). Interestingly, IFNgamma induced the loss of mitochondrial membrane potential (Deltapsim) and increased accumulation of reactive oxygen species (ROS). The cytokine also induced the activation of Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT)1, apoptosis signal-regulating kinase 1 (ASK1), p38, c-jun-N terminal kinase (JNK) and NF-kappaB pathways and the transcription factors STAT1, interferon regulatory factor 1 (IRF1), AP-1, ATF-2, NF-kappaB and p53, and expression of Noxa protein. Furthermore, IFNgamma was found to trigger endoplasmic reticulum (ER) stress as evidenced by the cleavage of caspase-4 and activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring-1alpha (IRE1alpha) pathways. Using specific inhibitors, we identified a potential role for IDO as apoptotic mediator in the regulation of IFNgamma-induced apoptosis of head and neck squamous cell carcinoma (HNSCC) cells via Noxa-mediated mitochondrial dysregulation and ER stress. CONCLUSION: In addition to the elucidation of the role of IDO in the modulation of apoptosis, our study provides new insights into the molecular mechanisms of IFNgamma-induced apoptosis of HNSCC cells during the course of immune therapy. PMID- 27486478 TI - Screening for antioxidant and antibacterial activities of phenolics from Golden Delicious apple pomace. AB - BACKGROUND: Synthetic antioxidants and antimicrobials are losing ground to their natural counterparts and therefore, the food industry has motivated to seek other natural alternatives. Apple pomace, a by-product in the processing of apples, is rich in polyphenols, and plant polyphenols have been used as food additives owing to their strong antioxidant and antimicrobial properties. The goal of this study was to screen the individual polyphenols with antioxidant and antimicrobial activities from the extracts (methanol, ethanol, acetone, ethyl acetate, and chloroform) of Golden Delicious pomace. RESULTS: First, the polyphenolic compounds (total phenol content, TPC; total flavonoids, TFD; total flavanols, TFL) and antioxidant activities (AAs) with four assays (ferric reducing antioxidant power, FRAP; 1,1-diphenyl-2-picryhydrazyl radical scavenging capacity assay, DRSC; hydroxyl radical averting capacity assay, HORAC; oxygen radical absorbance capacity assay, ORAC) were analyzed. The results showed a significant positive correlation (P < 0.05) between AAs and TFD. Ethyl acetate extract (EAE) exhibited the highest TFD with a concentration of 1.85 mg RE/g powder (expressed as rutin equivalents), and the highest AAs (expressed as butylated hydroxytoluene (BHT) equivalents) with 2.07 mg BHT/g powder for FRAP, 3.05 mg BHT/g powder for DRSC, 5.42 mg BHT/g powder for HORAC, and 8.89 mg BHT/g powder for ORAC. Composition and AA assays of individual polyphenols from the EAE were then performed. Phloridzin and phloretin accounted for 46.70 and 41.94 % of TFD, respectively. Phloretin displayed the highest AA, followed by phloridzin. Finally, the antimicrobial activities of the EAE, phloridzin, and phloretin were evaluated. EAE displayed good inhibitory activities against Staphylococcus aureus with a minimum inhibition concentration (MIC) of 1.25 mg/ml and against Escherichia coli with a MIC of 2.50 mg/ml. Phloridzin and phloretin showed better inhibitory activities than the EAE, which were MICs of 0.50 and 0.10 mg/ml, respectively, against S. aureus and MICs of 1.50 and 0.75 mg/ml, respectively, against E. coli. CONCLUSIONS: Ethyl acetate was the best solvent of choice to extract natural products to obtain the maximum antioxidant and antibacterial benefits. Phloridzin and phloretin have the potential to be used as natural alternatives to synthetic antioxidants and antimicrobials. PMID- 27486479 TI - Activation of lignocellulosic biomass for higher sugar yields using aqueous ionic liquid at low severity process conditions. AB - BACKGROUND: Concerns around greenhouse gas emissions necessitate the development of sustainable processes for the production of chemicals, materials, and fuels from alternative renewable sources. The lignocellulosic plant cell walls are one of the most abundant sources of carbon for renewable bioenergy production. Certain ionic liquids (ILs) are very effective at disrupting the plant cell walls of lignocellulose, and generate a substrate that is effectively hydrolyzed into fermentable sugars. Conventional ILs are relatively expensive in terms of purchase price, and the most effective imidazolium-based ILs also require energy intensive processing conditions (>140 degrees C, 3 h) to release >90 % fermentable sugar yields after saccharification. RESULTS: We have developed a highly effective pretreatment technology utilizing the relatively inexpensive IL comprised tetrabutylammonium [TBA](+) and hydroxide [OH](-) ions that generate high glucose yields (~95 %) after pretreatment at very mild processing conditions (50 degrees C). The efficiency of [TBA][OH] pretreatment of lignocellulose was further studied by analyzing chemical composition, powder X-ray diffraction for cellulose structure, NMR and SEC for lignin dissolution/depolymerization, and glycome profiling for cell wall modifications. Glycome profiling experiments and computational results indicate that removal of the noncellulosic polysaccharides occurs due to the ionic mobility of [TBA][OH] and is the key factor in determining pretreatment efficiency. Process modeling and energy demand analysis suggests that this [TBA][OH] pretreatment could potentially reduce the energy required in the pretreatment unit operation by more than 75 %. CONCLUSIONS: By leveraging the benefits of ILs that are effective at very mild processing conditions, such as [TBA][OH], lignocellulosic biomass can be pretreated at similar efficiency as top performing conventional ILs, such as 1-ethyl-3 methylimidazolium acetate [C2C1Im][OAc], but at much lower temperatures, and with less than half the IL normally required to be effective. [TBA][OH] IL is more reactive in terms of ionic mobility which extends removal of lignin and noncellulosic components of biomass at the lower temperature pretreatment. This approach to biomass pretreatment at lower temperatures could be transformative in the affordability and energy efficiency of lignocellulosic biorefineries. PMID- 27486480 TI - Partial monosomy14q involving FOXG1 and NOVA1 in an infant with microcephaly, seizures and severe developmental delay. AB - BACKGROUND: FOXG1 gene mutations have been associated with the congenital variant of Rett syndrome (RTT) since the initial description of two patients in 2008. The on-going accumulation of clinical data suggests that the FOXG1-variant of RTT forms a distinguishable phenotype, consisting mainly of postnatal microcephaly, seizures, hypotonia, developmental delay and corpus callosum agenesis. CASE PRESENTATION: We report a 6-month-old female infant, born at 38 weeks of gestation after in vitro fertilization, who presented with feeding difficulties, irritability and developmental delay from the first months of life. Microcephaly with bitemporal narrowing, dyspraxia, poor eye contact and strabismus were also noted. At 10 months, the proband exhibited focal seizures and required valproic acid treatment. Array-Comparative Genomic Hybridization revealed a 4.09 Mb deletion in 14q12 region, encompassing the FOXG1 and NOVA1 genes. The proband presented similar feature with patients with 14q12 deletions except for dysgenesis of corpus callosum. Disruption of the NOVA1 gene which promotes the motor neurons apoptosis has not yet been linked to any human phenotypes and it is uncertain if it affects our patient's phenotype. CONCLUSIONS: Since our patient is the first reported case with deletion of both genes (FOXG1-NOVA1), thorough clinical follow up would further delineate the Congenital Rett-Variant phenotypes. PMID- 27486481 TI - A de novo 1.6Mb microdeletion at 19q13.2 in a boy with Diamond-Blackfan anemia, global developmental delay and multiple congenital anomalies. AB - BACKGROUD: Microdeletions at 19q13.2 are very rare. Only two cases have been previously described. Here we report a 2-year-2-month old boy with Diamond Blackfan anemia, global developmental delay, cognitive impairments, distinctive facial features, behavior problems, skeletal and genital dysplasia. CASE PRESENTATION: A de novo 1.6 Mb microdeletion at 19q13.2q13.31 was detected by chromosomal microarray analysis. Haploinsufficiency of the RPS19 gene is known to cause Diamond-Blackfan anemia, other features in this patient are likely due to the deletion of other candidate genes such as PAFAH1B3, ERF, LIPE and GSK3A. CONCLUSION: The deletion detected in our patient overlapped and was significantly smaller than the ones previously reported, which offered the opportunity to further define the critical region for this proposed contiguous gene deletion syndrome. PMID- 27486482 TI - A pilot investigation of the prevalence of US-detectable forefoot joint pathology and reported foot-related disability in participants with systemic lupus erythematosus. AB - BACKGROUND: The main aim of this study was to determine the prevalence of US detectable forefoot bursae, metatarsophalangeal (MTP) joint and metacarpophalangeal (MCP) joint synovial hypertrophy (SH), Power Doppler (PD) signal or erosion in participants with systemic lupus erythematosus (SLE). A secondary aim was to determine the strength of potential association between patient reported foot-related disability and US-detected forefoot bursae, MTP joint SH, PD signal or erosion in participants with SLE. METHOD: A cross sectional observational study of 20 participants with SLE was completed to determine the prevalence of US-detected forefoot bursal, MTP and MCP joint pathology. Patient-reported foot-related impairment and activity limitation (accumulatively referred to as disability) were also recorded. Spearmans' Rank Correlation analyses were completed to determine the potential strength of association between US-detected pathology and patient report disability. RESULTS: The prevalence of MTP joint SH and PD was 80 % (16/20) and 10 % (2/20), respectively. The prevalence of MCP joint SH and PD was 60 % (12/20) and 30 % (6/20) respectively. A significant association was noted between PD scores for the MTP joints and MCP joints (r = 0.556; p = 0.011) although this was not demonstrated for SH scores (r = 0.176; p = 0.459). Significant associations between forefoot bursal prevalence and MTP joint PD were noted (r = 0.467; p = 0.038). The prevalence of bursae and bursal PD (grade 2 or above) was 100 % (20/20) and 10 % (2/20), respectively. Moderate foot-related impairment and activity limitation was reported by 95 and 85 % of participants respectively. CONCLUSION: This pilot study suggests that US-detected MTP, MCP joint and forefoot bursal abnormalities may be prevalent in participants with SLE and they may experience a moderate level of foot-related disability. Further research is required to substantiate these preliminary findings. PMID- 27486483 TI - A quantitative measure of restricted and repetitive behaviors for early childhood. AB - BACKGROUND: Restricted and repetitive behaviors are characteristic phenotypic features of many neurodevelopmental, psychiatric, and neurological conditions. During early childhood, such behaviors are considered normative. More research is needed to delineate the dimensions of restricted and repetitive behavior across typical and atypical development during this period. METHODS: We developed the 34 item parent-rated Repetitive Behavior Scale for Early Childhood (RBS-EC) to capture quantitative, dimensional features across a broad range of behaviors contributing to this domain. We evaluated its psychometric properties and factor structure in a community sample of 914 toddlers. RESULTS: The RBS-EC showed excellent overall internal consistency (alpha = 0.90), strong test-retest reliability (ICC = 0.87 for topographies and 0.90 for frequency) and evidence of convergent and discriminative validity. Using a split-half approach to factor analysis, we identified that a three- or four-factor structure best fit the data and confirmatory factor analysis indicated acceptable fit for both models. The empirically derived four-factor model was consistent with our conceptual model and included repetitive motor, restricted interests and behavior, ritual and routine, and self-directed behavior. CONCLUSIONS: This initial study indicates that the RBS-EC is a reliable and valid instrument for characterizing quantitative, dimensional aspects of restricted and repetitive behaviors in young children. PMID- 27486485 TI - Draft genome sequence of Mycobacterium rufum JS14(T), a polycyclic-aromatic hydrocarbon-degrading bacterium from petroleum-contaminated soil in Hawaii. AB - Mycobacterium rufum JS14(T) (=ATCC BAA-1377(T), CIP 109273(T), JCM 16372(T), DSM 45406(T)), a type strain of the species Mycobacterium rufum sp. . belonging to the family Mycobacteriaceae, was isolated from polycyclic aromatic hydrocarbon (PAH)-contaminated soil in Hilo (HI, USA) because it harbors the capability of degrading PAH. Here, we describe the first genome sequence of strain JS14(T), with brief phenotypic characteristics. The genome is composed of 6,176,413 bp with 69.25 % G + C content and contains 5810 protein-coding genes with 54 RNA genes. The genome information on M. rufum JS14(T) will provide a better understanding of the complexity of bacterial catabolic pathways for degradation of specific chemicals. PMID- 27486486 TI - Dr. Alfred A. Bove Lends Expertise on the Impact of Exercise on Cardiovascular Disease for the Methodist Debakey Cardiovascular Journal. PMID- 27486484 TI - Prevention of fatigue and insomnia in shift workers-a review of non pharmacological measures. AB - BACKGROUND: Excessive fatigue and insomnia are common among shift workers and can lead to negative effects such as reduced work performance, processing errors, accidents at work, absenteeism, reduced quality of life, and symptoms of depression. Moreover, work in rotating shifts can be a risk factor for different somatic and psychiatric diseases and may contribute to poor health, especially in elder adults and women. This review aims to show non-pharmacological preventive measures against fatigue and insomnia in shift workers. METHOD: Computerized literature searches in MedLine and in the Cochrane Library were performed with the following key words: shift work disorder, fatigue, insomnia, shift work, measures, treatment, therapy, strategies and coping. The search was limited to non-pharmacological studies that were conducted on human subjects and published as English-language articles in peer-reviewed journals since 1970. Additional studies were identified through the reference sections of relevant articles. Eighteen articles on fatigue in shift workers, including six original research articles with a total sample size of 3504 probands consisting of industrial workers, office employees, aircraft maintenance engineers, and non-shift workers working in simulated shifts, were analyzed, as well as seven articles on insomnia, including an original research article with a sample size of 26 media workers. Also, 4 reviews on shift work disorder were analyzed. MAIN: The occurrence of fatigue and insomnia in shift workers associated with a working period is described as shift work disorder. Estimations on the prevalence of shift work disorder in shift workers vary between 5 % and about 20 %; about one in three shift workers is affected by insomnia and up to 90 % of shift workers report regular fatigue and sleepiness at the workplace. We concluded that there is a necessity for treatments to improve the sleep quality of the shift working population. The most common non-pharmacological recommendations to improve sleep quality and to reduce insomnia and fatigue were scheduling, bright light exposure, napping, psychoeducation for sleep hygiene, and cognitive-behavioral measures. CONCLUSION: Some important preventive coping strategies for fatigue associated with shift work such as napping and exposure to bright light have already been investigated and are generally approved. A few studies also provide good evidence for the efficacy of cognitive-behavioral techniques in the treatment of chronic primary and comorbid insomnia. These coping strategies summarized in this paper should be considered in the workplace health promotion programs of each work environment to improve working conditions for shift workers and to save money. PMID- 27486487 TI - Exercise and Heart Disease. PMID- 27486489 TI - Electrocardiographic Evaluation in Athletes and Use of the Seattle Criteria to Improve Specificity. AB - The screening of athletes for cardiovascular disease prior to participation can be challenging. Sustained training often leads to anatomical changes in the heart that can translate into electrocardiographic (ECG) abnormalities. This can lead to a high false-positive rate that excludes healthy participants or results in costly workups. The Seattle Criteria applied to ECG interpretation has resulted in improved specificity without sacrificing sensitivity. At the Houston Methodist DeBakey Heart & Vascular Center in Houston, we have had much success using this tool to screen thousands of athletes ranging across all age groups and levels of expertise-from the middle school level to the professional athlete. PMID- 27486488 TI - Sudden Cardiac Death in Athletes. AB - There are clear health benefits to exercise; even so, patients with cardiac conditions who engage in exercise and athletic competition may on rare occasion experience sudden cardiac death (SCD). This article reviews the epidemiology and common causes of SCD in specific athlete populations. There is ongoing debate about the optimal mechanism for SCD prevention, specifically regarding the inclusion of the ECG and/or cardiac imaging in routine preparticipation sports evaluation. This controversy and contemporary screening recommendations are also reviewed. PMID- 27486490 TI - Cardiac Imaging In Athletes. AB - Athletic heart syndrome refers to the physiological and morphological changes that occur in a human heart after repetitive strenuous physical exercise. Examples of exercise-induced changes in the heart include increases in heart cavity dimensions, augmentation of cardiac output, and increases in heart muscle mass. These cardiac adaptations vary based on the type of exercise performed and are often referred to as sport-specific cardiac remodeling. The hemodynamic effects of endurance and strength training exercise lead to these adaptations. Any abnormalities in chamber dilatation and left ventricular function usually normalize with cessation of exercise. Athletic heart syndrome is rare and should be differentiated from pathologic conditions such as hypertrophic cardiomyopathy, left ventricular noncompaction, and arrhythmogenic right ventricular dysplasia when assessing a patient for athletic heart syndrome. This paper describes specific adaptations that occur in athletic heart syndrome and tools to distinguish between healthy alterations versus underlying pathology. PMID- 27486491 TI - Pulmonary Aspects of Exercise and Sports. AB - Although the lungs are a critical component of exercise performance, their response to exercise and other environmental stresses is often overlooked when evaluating pulmonary performance during high workloads. Exercise can produce capillary leakage, particularly when left atrial pressure increases related to left ventricular (LV) systolic or diastolic failure. Diastolic LV dysfunction that results in elevated left atrial pressure during exercise is particularly likely to result in pulmonary edema and capillary hemorrhage. Data from race horses, endurance athletes, and triathletes support the concept that the lungs can react to exercise and immersion stress with pulmonary edema and pulmonary hemorrhage. Immersion in water by swimmers and divers can also increase stress on pulmonary capillaries and result in pulmonary edema. Swimming-induced pulmonary edema and immersion pulmonary edema in scuba divers are well-documented events caused by the fluid shifts that occur with immersion, elevated pulmonary venous pressure during extreme exercise, and negative alveolar pressure due to inhalation resistance. Prevention strategies include avoiding extreme exercise, avoiding over hydration, and assuring that inspiratory resistance is minimized. PMID- 27486492 TI - Coming of Age: Considerations in the Prescription of Exercise for Older Adults. AB - Older adults represent the fastest-growing age demographic of the population. Physiological changes associated with primary aging and concurrent chronic disease adversely impact functional capacity, health outcomes, and quality of life. For these reasons, there is a national emphasis for healthcare providers to improve the health, function, and quality of life of older adults to preserve independent living and psychological well-being. The benefits of regular physical activity or exercise with regard to aging and disease are indisputable, yet many clinicians do not prescribe exercise to older adults. This reluctance may be attributable to a lack of knowledge regarding appropriate exercise prescription for older adults in light of the potential risks and benefits of various doses and types of exercise. In addition, clinicians and patients may have concerns about potential health considerations relevant to older adults such as comprehensive pre-exercise screening and exercise-drug interactions. In light of this, the following review presents (1) guidelines for exercise prescription in older adults and modification of these guidelines for patients with the most common age-associated comorbidities; (2) recommendations for pre-exercise screening prior to initiating an exercise program in older adults; (3) considerations for older adults on one or more medications; and (4) common barriers to adopting and maintaining exercise in an older population. Our goal is to provide a framework that clinicians can follow when prescribing exercise in older adults while considering the unique characteristics and concerns present in this population. PMID- 27486493 TI - Exercise Intolerance In Heart Failure With Preserved Ejection Fraction. AB - More than 50% of Americans with heart failure have preserved ejection fraction (HFpEF). Exercise intolerance is a hallmark of HFpEF, but the pathophysiology is not well understood. Diverse etiologies and incomplete mechanistic understanding have resulted in ineffective management strategies to improve the outcomes of HFpEF. Traditional therapies that have been beneficial in the treatment of heart failure with reduced ejection fraction (HFrEF), neurohormonal blockade in particular, have not been effective in treating HFpEF. In this review, we address underlying mechanisms of HFpEF and present the rationale supporting exercise as a component of comprehensive management. PMID- 27486494 TI - Exercise And Heart Failure: Advancing Knowledge And Improving Care. AB - Exercise limitation is the hallmark of heart failure, and an increasing degree of intolerance is associated with poor prognosis. Objective evaluation of functional class (e.g., cardiopulmonary exercise testing) is essential for adequate prognostication in patients with advanced heart failure and for implementing an appropriate exercise training program. A graded exercise program has been shown to be beneficial in patients with heart failure and has become an essential component of comprehensive cardiac rehabilitation in these patients. An exercise program tailored to the patient's preferences, possibilities, and physiologic reserve has the greatest chance of being successful. Despite being safe, effective, and a guideline-recommended treatment to improve quality of life, exercise training remains grossly underutilized. Patient, physician, insurance and practice barriers need to be addressed to improve this quality gap. PMID- 27486495 TI - Case Report: Cardiac Tumor Resection And Repair With Porcine Xenograft. AB - Primary cardiac sarcomas are rare and carry a grave prognosis. Improved survival requires a complete margin negative resection of the tumor. These surgical resections are often large and complex, requiring extensive reconstructive procedures. The appropriate material for cardiac reconstruction is not known. We have used glutaraldehyde-fixed bovine pericardium in our early series but have recently employed the MatriStem((r)) Surgical Matrix PSMX membrane (ACell((r)), Inc.; Columbia, MD), a unique proprietary urinary bladder matrix derived from porcine urinary bladder with the potential for viability and tissue ingrowth. In our study of six patients at this institution, all six underwent successful surgical resection and repair with the MatriStem acellular porcine urinary bladder membrane (ACell). The postoperative course was uncomplicated in all patients, and they are still alive at this time. An aggressive surgical approach to cardiac tumors can possibly lead to complete resection but often requires reconstruction of the cardiac tissue with a membrane. We were able to achieve acceptable results in our cardiac reconstruction by using the ACell extracellular matrix to reconstruct the defect following tumor resection. Longer-term follow-up in these patients, including imaging studies, will be necessary to demonstrate the durability and integrity of the reconstruction. PMID- 27486496 TI - Chylous Ascites Following Open Abdominal Aortic Aneurysm Repair: An Unusual Complication. AB - Chylous ascites is a rare complication after abdominal aortic aneurysm repair. Accumulation of chyle within the close space of the peritoneal cavity may cause severe discomfort to the patient, complicating the postoperative course. Prompt diagnosis is needed to adopt measures for reducing lymph leakage and contributing to lymphatic fistula closure. Fortunately, conservative treatment is successful in the majority of cases. In the rare cases that do not respond to conservative treatment, surgery becomes mandatory. Accurate preoperative localization of lymph leakage is a prerequisite for a successful outcome. Postoperative chyloperitoneum has a benign course and an excellent prognosis. PMID- 27486497 TI - Contained Rupture of Ventricular Wall And Ventricular Septal Defect In the Same Patient Following Myocardial Infarction. PMID- 27486498 TI - Wall of Honor. PMID- 27486499 TI - Cardiac Consequences Of Electrolyte Imbalance. PMID- 27486500 TI - Two Poems Introducing Don Quixote. PMID- 27486501 TI - Bullseye. PMID- 27486502 TI - Lighting the Way. PMID- 27486503 TI - Letter to the Editor. PMID- 27486504 TI - Qualitative evaluation of the adesive interface between lithium disilicate, luting composite and natural tooth. AB - Aim of this work was to qualitatively evaluate the interface between tooth, luting composite and lithium disilicate surface using a scanning electron microscope (SEM). An extracted restoration-free human molar was stored in physiological solution until it was embedded in an autopolimerysing acrylic resin. A standard preparation for overlay was completed and after preparation an anatomic overlay was waxed on the tooth and then hot pressed using lithium disilicate ceramic. After cementation the sample was dissected and the section was analysed using an Automatic Micromet (Remet s.a.s) and the section was analyzed using a scanning electron microscope (SEM). SEM evaluation of the tooth showed the three layers seamlessly; by increasing the enlargement the interface did not change. PMID- 27486505 TI - Fracture resistance of endodontically treated teeth restored with a bulkfill flowable material and a resin composite. AB - AIM: To determine and compare the fracture resistance of endodontically treated teeth restored with a bulk fill flowable material (SDR) and a traditional resin composite. METHODS: Thirty maxillary and 30 mandibular first molars were selected based on similar dimensions. After cleaning, shaping and filling of the root canals and adhesive procedures, specimens were assigned to 3 subgroups for each tooth type (n=10): Group A: control group, including intact teeth; Group B: access cavities were restored with a traditional resin composite (EsthetX; Dentsply-Italy, Rome, Italy); Group C: access cavities were restored with a bulk fill flowable composite (SDR; Dentsply-Italy), except 1.5 mm layer of the occlusal surface that was restored with the same resin composite as Group B. The specimens were subjected to compressive force in a material static-testing machine until fracture occurred, the maximum fracture load of the specimens was measured (N) and the type of fracture was recorded as favorable or unfavorable. Data were statistically analyzed with one-way analysis of variance (ANOVA) and Bonferroni tests (P<0.05). RESULTS: No statistically significant differences were found among groups (P<0.05). Fracture resistance of endodontically treated teeth restored with a traditional resin composite and with a bulk fill flowable composite (SDR) was similar in both maxillary and mandibular molars and showed no significant decrease in fracture resistance compared to intact specimens. CONCLUSIONS: No significant difference was observed in the mechanical fracture resistance of endodontically treated molars restored with traditional resin composite restorations compared to bulk fill flowable composite restorations. PMID- 27486506 TI - In vitro evaluation of carrier based obturation technique: a CBCT study. AB - AIM: The goal of the study was to compare the ability of two different carrier based obturation (CBO) techniques to reach working length and fill in three dimensions root canal systems, by using CBCT. MATERIALS AND METHODS: Twenty-six extracted molars were scanned with CBCT and 40 curved canals were selected (between 30 degrees and 90 degrees ) and divided in two similar groups (n=20). All canals were prepared up to size 25 taper .06 using nickel-titanium instrumentation. The canals in the Group SC were obturated using Soft-Core obturators (Kerr, Romulus, Mi, USA), while Group TH canals (n= 20) were obturated using Thermafil Endodontic Obturators (Tulsa Dental Products, Tulsa, OK, USA), strictly following manufacturers' instructions for use. The obturations were analyzed by means of CBCT to measure the distance from the apical limit of obturation to the apical foramen and the presence of voids inside root canals. RESULTS: There was no significant difference between the two groups in the mean distance of the apical extent of the obturation (t test, p>0.05). Overfilling occurred in only 3 cases (2 in Group TH and 1 in Group SC). The percentages of voids in both groups were very low with no significant difference (Z test, p>0.05). CONCLUSIONS: The two tested CBO techniques showed similar positive results in terms of performance, even if, after checking with verifiers, in most cases the size of the selected Soft-Core obturator was one size smaller than Thermafil. PMID- 27486507 TI - Biomimetic hydroxyapatite used in the treatment of periodontal intrabony pockets: clinical and radiological analysis. AB - AIM: Hydroxyapatite (PA) has a chemical composition and physical structure very similar to natural bone and therefore it has been considered to be the ideal biomaterial able to ensure a biomimetic scaffold to use in bone tissue engineering. The aim of this study is to clinically test hydroxyapatite used as osteoconductive biomaterial in the treatment of periodontal bone defects. Clinical and radiological evaluations were conducted at 6, 12 and 18 months after the surgery. MATERIALS AND METHODS: Forty patients with 2- and 3-wall intrabony pockets were enrolled in this study. PPD, CAL, radiographic depth (RD) and angular defects were preoperatively measured. After surgery, patients were re evaluated every 6 months for 18 months. Statistical analyses were also performed to investigate any differences between preoperative and postoperative measurements. RESULTS: Paired t-test samples conducted on the data obtained at baseline and 18 months after, showed significant (p<0.01) differences in each measurement performed. The role of preoperative RD was demonstrated to be a significant key factor (p<0.01). A relevant correlation between preoperative PPD and CAL gain was also found. CONCLUSIONS: Within the limitations of this study, the absence of anatomical variables, except the morphology of the bone defect, emphasizes the importance of the proper surgical approach and the graft material used. PMID- 27486509 TI - Histone acetyl transferase GCN5 promotes human hepatocellular carcinoma progression by enhancing AIB1 expression. AB - BACKGROUND: General control non-depressible 5 (GCN5) is a crucial catalytic component of a transcriptional regulatory complex that plays important roles in cellular functions from cell cycle regulation to DNA damage repair. Although GCN5 has recently been implicated in certain oncogenic roles, its role in liver cancer progression remains vague. RESULTS: In this study, we report that GCN5 was overexpressed in 17 (54.8 %) of 31 human hepatocellular carcinoma (HCC) specimens. Down-regulation of GCN5 inhibited HCC cell proliferation and xenograft tumor formation. GCN5 knockdown decreased the protein levels of the proliferation marker proliferating cell nuclear antigen (PCNA) and amplified in breast cancer 1 (AIB1), but increased the protein levels of cell cycle inhibitor p21(Cip1/Waf1) in HepG2 cells. GCN5 regulated AIB1 expression, at least in part, by cooperating with E2F1 to enhance AIB1 transcription. Consistently, GCN5 expression was positively correlated with AIB1 expression in human HCC specimens in two GEO profile datasets. CONCLUSION: Since AIB1 plays a promoting role in HCC progression, our results propose that GCN5 promotes HCC progression at least partially by regulating AIB1 expression. This study implicates that GCN5 might be a potential molecular target for HCC diagnosis and treatment. PMID- 27486508 TI - Muscle-specific loss of Bmal1 leads to disrupted tissue glucose metabolism and systemic glucose homeostasis. AB - BACKGROUND: Diabetes is the seventh leading cause of death in the USA, and disruption of circadian rhythms is gaining recognition as a contributing factor to disease prevalence. This disease is characterized by hyperglycemia and glucose intolerance and symptoms caused by failure to produce and/or respond to insulin. The skeletal muscle is a key insulin-sensitive metabolic tissue, taking up ~80 % of postprandial glucose. To address the role of the skeletal muscle molecular clock to insulin sensitivity and glucose tolerance, we generated an inducible skeletal muscle-specific Bmal1 (-/-) mouse (iMSBmal1 (-/-)). RESULTS: Progressive changes in body composition (decreases in percent fat) were seen in the iMSBmal1 (-/-) mice from 3 to 12 weeks post-treatment as well as glucose intolerance and non-fasting hyperglycemia. Ex vivo analysis of glucose uptake revealed that the extensor digitorum longus (EDL) muscles did not respond to either insulin or 5 aminoimidazole-4-carboxamide ribonucleotide (AICAR) stimulation. RT-PCR and Western blot analyses demonstrated a significant decrease in mRNA expression and protein content of the muscle glucose transporter (Glut4). We also found that both mRNA expression and activity of two key rate-limiting enzymes of glycolysis, hexokinase 2 (Hk2) and phosphofructokinase 1 (Pfk1), were significantly reduced in the iMSBmal1 (-/-) muscle. Lastly, results from metabolomics analyses provided evidence of decreased glycolytic flux and uncovered decreases in some tricarboxylic acid (TCA) intermediates with increases in amino acid levels in the iMSBmal1 (-/-) muscle. These findings suggest that the muscle is relying predominantly on fat as a fuel with increased protein breakdown to support the TCA cycle. CONCLUSIONS: These data support a fundamental role for Bmal1, the endogenous circadian clock, in glucose metabolism in the skeletal muscle. Our findings have implicated altered molecular clock dictating significant changes in altered substrate metabolism in the absence of feeding or activity changes. The changes in body composition in our model also highlight the important role that changes in skeletal muscle carbohydrate, and fat metabolism can play in systemic metabolism. PMID- 27486511 TI - Expression of matrix metalloproteinase 2 (MMP-2), E-cadherin and Ki-67 in metastatic and non-metastatic canine mammary carcinomas. AB - BACKGROUND: The aim of the study was to demonstrate the immunohistochemical expression of proteins that affect the metastatic potential of a tumour, including matrix metalloproteinase 2 (MMP-2) and E-cadherin. Another objective was to determine their correlation with the expression of the Ki-67 antigen in metastasizing and non-metastasizing mammary carcinomas in female dogs. The study was conducted on 32 canine mammary carcinomas (12 metastatic and 20 non metastatic), classified as simple tubular and tubulopapillary carcinomas. Immunohistochemistry was performed to evaluate the expression of MMP-2, E cadherin and Ki-67 antigen. RESULTS: MMP-2 was expressed in 85 % of the non metastatic tumours and in all the metastatic tumours, while E-cadherin was expressed in 85 % of the non-metastatic tumours and in 66 % of the metastatic tumours. The Ki-67 antigen was expressed in 65 % of the non-metastatic tumours and in 91 % of the metastatic tumours. The mean Ki-67 expression was slightly higher in tumours that had metastasized (1.5 +/- 0.90 vs 1.1 +/- 0.94; p = 0.22). A similar relationship was found in terms of the intensity of the MMP-2 expression (2.9 +/- 1.9 vs 2.7 +/- 2.4; p = 0.50). A decrease in the expression of E-cadherin (2.8 +/- 2.5) was found in metastatic tumours compared to the expression in non-metastatic tumours (3.2 +/- 2.3). However, these differences were not statistically significant (p = 0.63). CONCLUSION: We did not show significant differences in MMP-2, E-cadherin and Ki-67 expression between metastatic and non-metastatic tumours due to low number of cases studied, however further experiments are necessary to assess the role of these antigens in the process of canine mammary tumours metastasis. PMID- 27486510 TI - The effectiveness and feasibility of an online educational program for improving evidence-based practice literacy: an exploratory randomized study of US chiropractors. AB - BACKGROUND: Online education programs are becoming a popular means to disseminate knowledge about evidence-based practice (EBP) among healthcare practitioners. This mode of delivery also offers a viable and potentially sustainable solution for teaching consistent EBP content to learners over time and across multiple geographical locations. We conducted a study with 3 main aims: 1) develop an online distance-learning program about the principles of evidence-based practice (EBP) for chiropractic providers; 2) test the effectiveness of the online program on the attitudes, skills, and use of EBP in a sample of chiropractors; and 3) determine the feasibility of expanding the program for broader-scale implementation. This study was conducted from January 2013 to September 2014. METHODS: This was an exploratory randomized trial in which 293 chiropractors were allocated to either an online EBP education intervention or a waitlist control. The online EBP program consisted of 3 courses and 4 booster lessons, and was developed using educational resources created in previous EBP educational programs at 4 chiropractic institutions. Participants were surveyed using a validated EBP instrument (EBASE) with 3 rescaled (0 to 100) subscores: Attitudes, Skills, and Use of EBP. Multiple regression was used to compare groups, adjusting for personal and practice characteristics. Satisfaction and compliance with the program was evaluated to assess feasibility. RESULTS: The Training Group showed modest improvement compared to the Waitlist Group in attitudes (Delta =6.2, p < .001) and skills (Delta =10.0, p < .001) subscores, but not the use subscore (Delta = -2.3, p = .470). The majority of participants agreed that the educational program was 'relevant to their profession' (84 %) and 'was worthwhile' (82 %). Overall, engagement in the online program was less than optimal, with 48 % of the Training Group, and 42 % of the Waitlist Group completing all 3 of the program courses. CONCLUSIONS: Online EBP training leads to modest improvements in chiropractors' EBP attitudes and skill, but not their use of EBP. This online program can be delivered to a wide national audience, but requires modification to enable greater individualization and peer-to-peer interaction. Our results indicate that it is feasible to deliver an online EBP education on a broad scale, but that this mode of education alone is not sufficient for making large changes in chiropractors' use of EBP. PMID- 27486512 TI - Postoperative respiratory failure necessitating transfer to the intensive care unit in orthopedic surgery patients: risk factors, costs, and outcomes. AB - BACKGROUND: Postoperative pulmonary complications in orthopedic surgery patients have been associated with worse clinical outcomes. Identifying patients with respiratory risk factors requiring enhanced monitoring and management modifications is an important part of postoperative care. Patients with unanticipated respiratory decompensation requiring transfer to the intensive care unit (ICU) have not been studied in sufficient detail. METHODS: A retrospective case-control study of elective orthopedic surgery patients (knee, hip, shoulder, or spine, n = 51) who developed unanticipated respiratory failure (RF) necessitating transfer to the ICU over a 3-year period was conducted. Controls (n = 153) were frequency matched to cases by gender, age, and surgical procedure. Patient and perioperative care factors, clinical outcomes, and cost of care were examined. RESULTS: Transfer to the ICU occurred within 48 h of surgery in 73 % of the cases, 31 % required non-invasive ventilation, and 18 % required mechanical ventilation. Cases had a higher prevalence of chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), and regular psychotropic medication use than controls. Cases received more intravenous opioids during the first 24 postoperative hours, were hospitalized 4 days longer, had higher in hospital mortality, and had excess hospitalization costs of US$26,571. COPD, OSA, preoperative psychotropic medications, and anesthesia time were associated with risk of RF in a multivariate analysis. CONCLUSIONS: Unanticipated RF after orthopedic surgery is associated with extended hospitalization, increased mortality, and higher cost of care. Hospital protocols that include risk factor assessment, enhanced monitoring, and a cautious approach to opioid use in high risk patients may reduce the frequency of this complication. PMID- 27486513 TI - Matched-pair analysis: identification of factors with independent influence on the development of PTLD after kidney or liver transplantation. AB - BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) adversely affects patients' long-term outcome. METHODS: The paired t test and McNemar's test were applied in a retrospective 1:1 matched-pair analysis including 36 patients with PTLD and 36 patients without PTLD after kidney or liver transplantation. Matching criteria were age, gender, indication, type of transplantation, and duration of follow-up. All investigated PTLD specimen were histologically positive for EBV. Risk-adjusted multivariable regression analysis was used to identify independence of risk factors for PTLD detected in matched-pair analysis. The resultant prognostic model was assessed with ROC-curve analysis. RESULTS: Patients suffering with PTLD had shorter mean survival (p = 0.004), more episodes of CMV infections or reactivations (p = 0.042), and fewer recipient HLA A2 haplotypes (p = 0.007), a tacrolimus-based immunosuppressive regimen (p = 0.052) and higher dosages of tacrolimus at hospital discharge (Tac dosage) (p = 0.052). Significant independent risk factors for PTLD were recipient HLA A2 (OR = 0.07, 95 % CI = 0.01-0.55, p = 0.011), higher Tac dosages (OR = 1.29, 95 % CI = 1.01-1.64, p = 0.040), and higher numbers of graft rejection episodes (OR = 0.38, 95 % CI = 0.17 0.87, p = 0.023). The following prognostic model for the prediction of PTLD demonstrated good model fit and a large area under the ROC curve (0.823): PTLD probability in % = Exp(y)/(1 + Exp(y)) with y = 0.671 - 1.096 * HLA A2-positive recipient + 0.151 * Tac dosage - 0.805 * number of graft rejection episodes. CONCLUSIONS: This study suggests prognostic relevance for recipient HLA A2, CMV, and EBV infections or reactivations and strong initial tacrolimus-based immunosuppression. Patients with risk factors may benefit from intensified screening for PTLD. PMID- 27486514 TI - Dietary supplementation with a high dose of daidzein enhances the antioxidant capacity in swine muscle but experts pro-oxidant function in liver and fat tissues. AB - BACKGROUND: Although isoflavones are natural dietary antioxidants, they may have toxicological effects. This study aimed to evaluate the redox system in tissues of finishing pigs by supplementation with high dose of daidzein (640 mg/kg). RESULTS: The supplementation of high dose of daidzein for 64 d increased the activity of superoxide dismutase and total antioxidant capacity in longissimus muscle but down-regulated the expression of reactive oxygen species (ROS) producing enzyme NADPH oxidase-2 and cyclooxygenase-2. In contrast, high-level supplementation with daidzein exerted pro-oxidant changes in back fat, abdominal fat, liver, and plasma, as reflected by increased contents of malondialdehyde, a lipid peroxidation product, in these tissues. Furthermore, daidzein supplementation resulted in higher expression of ROS-producing enzymes, including NADPH oxidase-1 and cyclooxygenase-1 in liver, 5-lipoxygenase (5-LOX) in backfat and NADPH oxidase-2 both in abdominal fat and backfat. The supplementation of daidzein did not affect meat quality parameters in longissimus muscle, including marbling score, eye muscle areas, intramuscular fat, shear force, drip loss, pH and meat color. CONCLUSIONS: This experiment suggests that dietary supplementation of finishing pigs with daidzein at a high dose level improves redox status in muscle but exerts pro-oxidant effect in liver and fat tissues. PMID- 27486515 TI - Morphometrics and stable isotopes differentiate wintering populations of a migratory bird. AB - BACKGROUND: Describing migratory connectivity in mobile animals is crucial for understanding the selective pressures acting on different populations throughout their life cycle. Tracking single individuals has provided valuable data, but for most species the data available are still spurious and usually limited to a few individuals. Since different populations of migratory birds can be distinguished by a combination of morphometric measurements and the isotopic composition of their feathers, it is possible to measure these parameters on a large sample to differentiate populations. METHODS: We studied northern wheatears, Oenanthe oenanthe, captured in their African wintering range and applied discriminant analyses on morphometric measurements and stable isotope signatures to determine whether birds found in different areas were distinguishable from each other. RESULTS: Morphometric and isotopic measurements alone were not sufficient to discriminate between the birds of ssp. oenanthe from different areas in Africa. When combining the two measurements, however, assignment to the different groups became substantially more accurate. Following the discriminant analysis of morphometrics and delta(2)H, delta(13)C, and delta(15)N isotopes signatures, 19 of 20 oenanthe from Kenya, 15 of 20 oenanthe from Mali/Mauritania, and 19 of 20 oenanthe from Niger were assigned correctly to their wintering area. CONCLUSIONS: Our results show that birds at different wintering sites can be distinguished from each other when using a combination of markers. We discuss the possible breeding origins of these wintering birds. PMID- 27486516 TI - Factors associated with suicide ideation among subway drivers in Korea. AB - BACKGROUND: There were several suicide events of subway drivers in Korea. The aim of this study is to explore work-related factors associated with suicide ideation among subway drivers. METHODS: We analyzed data from 980 male subway drivers. A section of the Korean version of the Composite International Diagnostic Interview (K-CIDI 2.1) was administered by trained interviewers to judge whether a driver has suicide ideation and to diagnose psychiatric disorders. A questionnaire was also administered to collect data on sociodemographic characteristics, work environments, occupational stress, person under train (PUT) experience, and work related problems. Occupational stress was examined by using the Korean Occupational Stress Scale (KOSS). Logistic regression was applied to evaluate the association between work-related factors and suicide ideation among subway drivers. RESULTS: Regarding work-related problems, conflict with passengers and sudden stops due to the emergency bell were significantly associated with suicide ideation. MDD, PTSD, and panic disorder were strongly associated with suicide ideation. In the analysis of occupational stress, insufficient job control (OR 2.34) and lack of reward (OR 2.52) were associated with suicide ideation even after being adjusted for psychiatric disorders and other work-related factors. CONCLUSIONS: Insufficient job control and lack of reward were associated with suicide ideation among subway drivers. Strategies for drivers to have autonomy while working and to achieve effort-reward balance should be implemented. Furthermore, drivers who have experienced negative work-related problems should be managed appropriately. PMID- 27486517 TI - The association between perceived discrimination and depression/anxiety disorders among Korean workers: analysis of the third Korean Working Conditions Survey. AB - BACKGROUND: Discrimination is a long-standing social problem, and interest in the health effects of discrimination has been increasing. Unfortunately, Korean workers experience various types and combinations of discrimination. This study aimed to examine the association between perceived discrimination and depression/anxiety disorders among Korean workers. METHODS: Data from 33,530 paid workers were extracted from the third Korean Working Conditions Survey. The data included general characteristics, occupational characteristics, perceived discrimination, and depression/anxiety disorders. To examine the relationship between perceived discrimination and depression/anxiety disorders, multiple logistic regression analysis was used to evaluate depression/anxiety disorders as the dependent variable and perceived discrimination as the independent variable, after adjusting for relevant general and occupational characteristics. RESULTS: After adjusting for the relevant general and occupational characteristics, we observed that male and female workers who had experienced perceived discrimination exhibited a significantly higher likelihood of having depression/anxiety disorders. The odds ratios among male and female workers were 3.25 (95 % confidence interval: 2.45-4.32) and 4.56 (95 % confidence interval: 3.45-6.03), respectively. CONCLUSIONS: Perceived discrimination was significantly related to depression or anxiety disorders among Korean workers. The risk of depression or anxiety was higher among female workers, compared to male workers. PMID- 27486518 TI - Impact of obesity on hospital complications and mortality in hospitalized patients with hyperglycemia and diabetes. AB - OBJECTIVE: Obesity is associated with increased risk of diabetes, hypertension and cardiovascular mortality. Several studies have reported increased length of hospital stay and complications; however, there are also reports of obesity having a protective effect on health, a phenomenon coined the 'obesity paradox'. We aimed to investigate the impact of overweight and obesity on complications and mortality in hospitalized patients with hyperglycemia and diabetes. RESEARCH DESIGN AND METHODS: This retrospective analysis was conducted on 29 623 patients admitted to two academic hospitals in Atlanta, Georgia, between January 2012 and December 2013. Patients were subdivided by body mass index into underweight (body mass index <18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)) and obese (>30 kg/m(2)). Hyperglycemia was defined as a blood glucose >10 mmol/L during hospitalization. Hospital complications included a composite of pneumonia, acute myocardial infarction, respiratory failure, acute kidney injury, bacteremia and death. RESULTS: A total of 4.2% were underweight, 29.6% had normal weight, 30.2% were overweight, and 36% were obese. 27.2% of patients had diabetes and 72.8% did not have diabetes (of which 75% had hyperglycemia and 25% had normoglycemia during hospitalization). A J-shaped curve with higher rates of complications was observed in underweight patients in all glycemic groups; however, there was no significant difference in the rate of complications among normal weight, overweight, or obese patients, with and without diabetes or hyperglycemia. CONCLUSIONS: Underweight is an independent predictor for hospital complications. In contrast, increasing body mass index was not associated with higher morbidity or mortality, regardless of glycemic status. There was no evidence of an obesity paradox among inpatients with diabetes and hyperglycemia. PMID- 27486519 TI - PERS&O (PERsistent Sitagliptin treatment & Outcomes): observational retrospective study on cardiovascular risk evolution in patients with type 2 diabetes on persistent sitagliptin treatment. AB - OBJECTIVES: The UK Prospective Diabetes Study (UKPDS) Risk Engine (RE) provides the best risk estimates available for people with type 2 diabetes (T2D), so it was applied to patients on persistent sitagliptin treatment. DESIGN: A 'real world' retrospective, observational, single-center study. SETTING: The study was performed in a general hospital in Northern Italy in order: (1) to validate UKPDS RE in a cohort of Italian participants with T2D without prespecified diabetes duration, with/without cardiovascular (CV) disease, treated with sitagliptin; (2) to confirm CV risk gender difference; (3) to evaluate the effect on metabolic control and on CV risk evolution obtained by 'add-on' persistent sitagliptin treatment. PARTICIPANTS: Sitagliptin 100 mg once a day was taken by 462 participants with T2D: 170 of them (males: 106; age: 63.6+/-8.8; T2D duration: 11.58+/-7.33; females: 64; age: 65.6+/-7.95; T2D duration 13.5+/-7.9) were treated for 48 months with the same dosage. INTERVENTIONS: An analysis of normality was performed both for continuous, and for groups variables on UKPDS RE percentage values, defining the requirement of a base log10 transformation to normalize risk factor values for analysis validation. RESULTS: The evaluation of CV risk evolution by gender (t-test) confirmed the expected statistical difference (p<0.0001). Sitagliptin obtained significant results after 12 months, and at the end of the observation, both on metabolic control (expressed by glycated hemoglobin) and on UKPDS RE. Analysis of variance test revealed a significant effect on CV risk after 12 months (p=0.003), and after 48 months (p=0.04). A bivariate correlation analysis revealed a correlation index (r)=0.2 between the two variables (p<0.05). CONCLUSIONS: These 'real-world' data obtained applying UKPDS RE may reflect patients' and clinicians' interest in realizing individual CV risk, and its evolution. Sitagliptin-persistent treatment for a medium-long period obtained an improvement on metabolic control, as well as a reduction on CV risk. PMID- 27486520 TI - Peripheral sensory neuropathy is associated with altered postocclusive reactive hyperemia in the diabetic foot. AB - OBJECTIVE: This study examined whether the presence of peripheral sensory neuropathy or cardiac autonomic deficits is associated with postocclusive reactive hyperemia (reflective of microvascular function) in the diabetic foot. RESEARCH DESIGN AND METHODS: 99 participants with type 2 diabetes were recruited into this cross-sectional study. The presence of peripheral sensory neuropathy was determined with standard clinical tests and cardiac autonomic function was assessed with heart rate variation testing. Postocclusive reactive hyperemia was measured with laser Doppler in the hallux. Multiple hierarchical regression was performed to examine relationships between neuropathy and the peak perfusion following occlusion and the time to reach this peak. RESULTS: Peripheral sensory neuropathy predicted 22% of the variance in time to peak following occlusion (p<0.05), being associated with a slower time to peak but was not associated with the magnitude of the peak. Heart rate variation was not associated with the postocclusive reactive hyperemia response. CONCLUSIONS: This study found an association between the presence of peripheral sensory neuropathy in people with diabetes and altered microvascular reactivity in the lower limb. PMID- 27486521 TI - Persistent constipation and abdominal adverse events with newer treatments for constipation. AB - BACKGROUND: Clinical trials of several new treatments for opioid-induced constipation (OIC), chronic idiopathic constipation (CIC) and constipation predominant irritable bowel syndrome (IBS-C) have focused on differences between subjects relieved of constipation with placebo and active treatment. Patients and clinicians however, are more interested in the probability these treatments provide actual relief of constipation and its associated symptoms. METHODS: We searched the medical literature using MEDLINE and Cochrane central register of controlled trials. Randomised, placebo-controlled trials that examined the use of methylnaltrexone, naloxegol, lubiprostone, prucalopride or linaclotide in adults with OIC, CIC and IBS-C were eligible for inclusion. The primary efficacy measure was relief of constipation. Adverse event data for abdominal symptoms were also analysed. KEY RESULTS AND FINDINGS: 25 publications were included in our analyses. The proportion of constipated individuals with active treatment was significantly lower than the proportion with placebo; however, in 15 of these 20 trials analysed, a majority of patients remained constipated with active treatment. Analyses of adverse event data revealed that the percentage of participants who experienced abdominal pain, diarrhoea and flatulence with active treatment was higher than that with placebo in the majority of trials analysed. CONCLUSIONS: Newer pharmacological treatments for constipation are superior to placebo in relieving constipation, but many patients receiving active treatment may remain constipated. In addition, all 5 of the treatments studied are accompanied by no change or a possible increase in the prevalence of abdominal symptoms, such as abdominal pain, diarrhoea and flatulence. PMID- 27486522 TI - Percutaneous endoscopic transgastric jejunostomy (PEG-J): a retrospective analysis on its utility in maintaining enteral nutrition after unsuccessful gastric feeding. AB - BACKGROUND/AIMS: Although percutaneous endoscopic gastrostomy (PEG) is the method of choice for long-term enteral nutrition, feeding-related adverse events such as aspiration pneumonia and peristomal leakage can impede the use of PEG. Percutaneous endoscopic transgastric jejunostomy (PEG-J) using large-bore jejunal tubes may help by circumventing gastric passage during enteral nutrition and improving drainage of gastric secretions. METHODS: 20 patients (12 males and 8 females) who received PEG-J after unsuccessful PEG feeding during a 6-year period in our institution were analysed retrospectively to evaluate the efficacy of large-bore jejunal feeding tubes in maintaining enteral nutrition. RESULTS: The median age was 83.5 (71-96) years. The median period between PEG and PEG-J was 33 (14-280) days. Indications were aspiration due to gastro-oesophageal reflux in 18 patients and severe peristomal leakage in 2 patients. Tube placements were successful in all patients. There were 6 (30%) in-hospital mortalities, with 3 (15%) occurring within 30 days after procedure. CONCLUSIONS: PEG-J can be performed safely in patients with PEG and may facilitate the maintenance of enteral nutrition in most of the patients. Patients with unsuccessful PEG feeding can be offered the option of jejunal feeding before considering termination of enteral nutrition. PMID- 27486523 TI - The first cases of collagenous sprue successfully treated with thioguanine. AB - OBJECTIVE: Collagenous sprue (CS) is a rare form of small bowel enteropathy characterised by a thickened basement membrane and is, in most of the literature, reported as part of coeliac disease. Multiple treatment strategies are suggested in CS, but there is no standardised therapy. The aim of this series is to describe 4 cases of CS and to propose thioguanine (6-TG) treatment. DESIGN: We reviewed 4 cases of CS. Data were obtained from our prospective database of patients referred to our coeliac centre. Evaluation of small bowel biopsies was performed by an expert pathologist. RESULTS: None of the patients had ever had coeliac-specific antibodies, and all were negative for HLA-DQ2 and HLA-DQ8 phenotype. Three patients were treated with a combination of 6-TG and budesonide, and 1 patient received 6-TG only. All patients improved remarkably. Normalisation of the thickened basement membrane was found in 2 patients and complete histological improvement including full recovery of villi was found in 1 patient. In the third patient, the thickened basement membrane was only very focally recognised. The thickened membrane persisted in the last patient, probably because of the short time of follow-up. CONCLUSIONS: CS should be separated from coeliac disease. Based on the lack of typical HLA phenotyping and the absence of coeliac-specific antibodies, there seems to be no relation with coeliac disease in these 4 cases. A promising treatment option might be 6-TG with or without budesonide. Research in a larger cohort is needed to standardise treatment for CS. PMID- 27486524 TI - Impact of etanercept tapering on work productivity in patients with early rheumatoid arthritis: results from the PRIZE study. AB - OBJECTIVE: To assess changes in work productivity in patients who have achieved response using etanercept (ETN) 50 mg+methotrexate (MTX) (phase I) are randomised to ETN 25 mg+MTX versus MTX versus placebo (phase II) and then withdrawn from treatment (phase III). METHODS: Patients included in the analysis were in employment entering phase II of the PRIZE trial and had one or more follow-ups. Phase II was a 39-week, randomised and double-blind comparison of the 3 dose reduction treatments. Phase III was a 26-week observational study where treatment was withdrawn. The Valuation of Lost Productivity was completed approximately every 13 weeks to estimate productivity impacts from a societal perspective. RESULTS: A total of 120 participants were included in our analyses. During phase II, ETN25+MTX or MTX improved paid work productivity by over 100 hours compared with placebo, amounting to a gain of ?1752 or ?1503, respectively. ETN25+MTX compared with placebo gains ?1862 in total paid/unpaid productivity. At week 52, the 3-month paid work productivity loss was 21.8, 12.8 and 14.0 hours, respectively. The productivity loss increased at week 64 from week 52, dropped at week 76 for all treatment groups and then continued rising after week 76 for the placebo group (71.9 hours at week 91) but not for the other 2 groups (21.9 hours for ETX25+MTX and 27.6 hours for MTX). CONCLUSIONS: The work productivity gain in phase I as a result of ETN50+MTX was marginally lost in the dose-reduction treatment groups, ETN25+MTX and MTX, but substantially lost in the placebo group during phase II. TRIAL REGISTRATION NUMBER: NCT00913458; Results. PMID- 27486525 TI - Responsiveness of a simple RAPID-3-like index compared to disease-specific BASDAI and ASDAS indices in patients with axial spondyloarthritis. AB - OBJECTIVE: To evaluate the responsiveness of a simple routine assessment of patient index data (RAPID3)-like index that includes only 3 patient self-report measures (physical function, pain and patient global estimate) compared to that of traditional composite indices to assess change in patients with axial spondyloarthritis (Ax-SpA). METHODS: Devenir des Spondylarthropathies Indifferenciees Recentes (DESIR) is a prospective cohort of patients with inflammatory back pain suggestive of Ax-SpA. The study included 461 patients, who met the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for Ax-SpA. A simple RAPID3-like index was compared with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the AS Disease Activity Score (ASDAS) scores for responsiveness over 6 months. Construct validity was also evaluated through Pearson correlations and discrimination of disease activity through standardised mean differences for the 3 indices. RESULTS: The RAPID3-like index was correlated significantly with BASDAI (r=0.84, p<0.005) and ASDAS-C-reactive protein (CRP) (r=0.74, p<0.005), similar to correlations of BASDAI with ASDAS-CRP (r=0.76, p<0.005). The percentage of patients with inactive disease ranged from 9% to 25% and with high activity from 10% to 45%, according to various measures. The capacity to discriminate between high and low disease activity was similar for the 3 indices. The strength of agreement of RAPID3 with ASDAS-CRP was moderate (0.44) and lower with BASDAI (0.37). Responsiveness over 6 months was slightly higher for ASDAS-CRP and the RAPID3-like index than that for BASDAI. CONCLUSIONS: The RAPID3-like index provides similar information to BASDAI and ASDAS-CRP concerning responsiveness over 6 months. RAPID3 appears feasible to assess patients with Ax-SpA quantitatively over time in busy clinical settings. PMID- 27486526 TI - Osteoporosis prevention among chronic glucocorticoid users: results from a public health insurance database. AB - INTRODUCTION: Long-term glucocorticoid therapy is the leading cause of secondary osteoporosis. The management of glucocorticoid-induced osteoporosis (GIOP) seems to be inadequate in many European countries. OBJECTIVE: To evaluate the rate of screening and treatment of GIOP. DESIGN: Information was collected from a national public health-insurance database in our geographic area of Provence Alpes-Cote-d'Azur and in Corsica, from September 2009 through August 2011. PATIENTS: We identified participants aged 15 years and over starting glucocorticoid therapy (>=7.5 mg of prednisone equivalent per day during at least 90 days consecutive). This cohort was compared with an age-matched and sex matched population that did not receive glucocorticoids. MAIN OUTCOME MEASURES: Bone mass, prescription of bone antiresorptive medication and use of calcium and/or vitamin D treatment. RESULTS: We identified 32 812 patients who were prescribed glucocorticoid therapy, yielding 1% prevalence. Incidence of glucocorticoid therapy was 2.8/1000 inhabitants/year. Males represented 44%, the mean age was 58 years. The median prednisone-equivalent dose was 11 mg/day (IQR 9 18 mg/day). 8% underwent bone mass measurement. Calcium and/or vitamin D, and bisphosphonates were prescribed in 18% and 12%, respectively. Results were lower for the control population: 3% underwent bone mass measurement and 3% received bisphosphonate therapy. The rates of osteodensitometry and treatments were higher in women over 55 years of age than in men and women 55 years of age and younger, and also when glucocorticoid therapy was initiated by a rheumatologist versus other physician specialty. CONCLUSIONS: The management of GIOP remains very inadequate, despite the availability of a statutory health insurance system. Targeted interventions are needed to improve the management of GIOP. PMID- 27486527 TI - Treatment of systemic sclerosis: is there any hope for the future? PMID- 27486528 TI - Average symptom trajectories following incident radiographic knee osteoarthritis: data from the Osteoarthritis Initiative. AB - INTRODUCTION: Previous research has identified the existence of a prodromal phase of symptom worsening beginning on average 2-3 years prior to the first appearance of radiographic knee osteoarthritis (OA). The current study extends these observations to investigate the trajectory of self-reported pain, stiffness, function and other symptoms following the incidence of radiographic OA. METHODS: Data were from the incidence cohort of the Osteoarthritis Initiative public use data sets. Cases were defined as knees without symptoms at enrolment, which developed incident radiographic OA (Kellgren and Lawrence grade >=2) at any of the first 4 annual follow-up visits. Symptoms investigated were knee-specific Western Ontario & McMaster Universities Osteoarthritis Index and Knee injury and Osteoarthritis Outcome Score subscale scores and individual items, available up to 3 years before and 5 years after the incidence of radiographic OA. Trajectories of having at least one of the symptoms from a subscale, and for each individual symptom over time, were fitted using multilevel logistic regression models. RESULTS: The probability of symptoms following the initial prodromal phase generally stabilised, whereas the probability of moderate, severe or extreme symptoms was consistently low. Two exceptions were pain frequency, which increased greatly in the lead up to incidence, then decreased slightly, and audible joint sounds, which had a much higher overall probability, and after increasing prior to incident radiographic OA, stabilised then started to increase again at 5 years. CONCLUSIONS: Following an increase in the risk of symptoms during the prodromal phase, this risk does not continue to increase in the period up to 5 years after the incidence of radiographic OA. PMID- 27486529 TI - Irritability in Pediatric Patients: Normal or Not? AB - The goal of this article is to describe the concept of irritability in children and youth, which has been revisited in the DSM-5. Traditionally, this behavior has been more commonly associated with mood disorders, which may account for the rising incidence of bipolar disorder diagnosis and overuse of mood-stabilizing medications in pediatric patients. While not predictive of mania, persistent nonepisodic irritability, if undetected, may escalate to violent behavior with potentially serious outcomes. It is therefore important to educate clinicians about how to accurately assess irritability in pediatric patients. PMID- 27486530 TI - Intravenous Methylprednisolone-Induced Nocturnal Sinus Bradycardia in a Multiple Sclerosis Patient. PMID- 27486531 TI - Cerebellar Cognitive Affective Syndrome: A Case Report. PMID- 27486532 TI - A Case of Risperidone Overdose in a 4-Year-Old Boy. PMID- 27486533 TI - New-Onset Visual Hallucinations With Eszopiclone. PMID- 27486534 TI - A Retrospective Snapshot of Patients Prescribed Acute Versus Chronic Narcotic Therapy in a Resident-Provider Internal Medicine Outpatient Clinic. PMID- 27486535 TI - Cotard Syndrome: "I'm Dead, So Why Do I Need to Eat?". PMID- 27486536 TI - Will Adding Methadone to Controlled Substance Monitoring Programs Help Psychiatrists Prevent Prescription Drug Overdoses? PMID- 27486537 TI - Postpartum Eclampsia Associated With Changes of Mood Symptoms. PMID- 27486538 TI - A Survey of Same-Sex Sexual Experiences Among Psychiatric Inpatients With and Without Borderline Personality Symptomatology. PMID- 27486539 TI - Delusional Infestation: A Case of Ekbom Syndrome in an HIV-Infected Patient. PMID- 27486540 TI - Mania Induced by Garcinia cambogia: A Case Series. PMID- 27486541 TI - Pattern of Care Before Presentation Among the Psychiatric Emergency Cases at a Tertiary Health Care Center in Nigeria. AB - OBJECTIVE: To determine the pattern of care sought in cases of psychiatric emergency before presentation to a tertiary health care center. METHOD: Consecutive recruitment of 180 emergency psychiatric cases, which comprised a total of 156 patients, presenting to the accident and emergency unit of the University of Benin Teaching Hospital (UBTH), Edo State, Nigeria, was conducted from June 2008 to January 2009. A structured instrument was used to gather the patients' information including their sociodemographic characteristics, their care before presentation, and the relations accompanying them to the hospital. RESULTS: The mean +/- SD patient age was 33.82 +/- 12.64 years, with an age range of 18-73 years and a modal age of 23 years. The male to female ratio was 1:1.05. Of the patients, 121 (77.6%) were not married, while 35 (22.4%) were married. Most identified as Christian (96.2%). The majority of the patients (70.0%) presented to the hospital through self-referral. Eighty (44.4%) of the patients had not sought any treatment before coming to UBTH. Forty-seven patients (26.1%) had sought care in churches, 39 (21.7%) had sought treatment in other hospitals, and 12 (6.7%) had sought traditional care before presenting to UBTH. Seventy-four patients (41.1%) were accompanied by parents and 44 (24.4%) were accompanied by siblings, while the spouse accompanied 23 (12.8%) patients. CONCLUSIONS: Most patients with psychiatric emergencies at UBTH prefer to present directly to the tertiary health care center in Benin City, and they are usually supported by their immediate family members. PMID- 27486542 TI - Development of the 7-Item Binge-Eating Disorder Screener (BEDS-7). AB - OBJECTIVE: Develop a brief, patient-reported screening tool designed to identify individuals with probable binge-eating disorder (BED) for further evaluation or referral to specialists. METHODS: Items were developed on the basis of the DSM-5 diagnostic criteria, existing tools, and input from 3 clinical experts (January 2014). Items were then refined in cognitive debriefing interviews with participants self-reporting BED characteristics (March 2014) and piloted in a multisite, cross-sectional, prospective, noninterventional study consisting of a semistructured diagnostic interview (to diagnose BED) and administration of the pilot Binge-Eating Disorder Screener (BEDS), Binge Eating Scale (BES), and RAND 36-Item Short-Form Health Survey (RAND-36) (June 2014-July 2014). The sensitivity and specificity of classification algorithms (formed from the pilot BEDS item level responses) in predicting BED diagnosis were evaluated. The final algorithm was selected to minimize false negatives and false positives, while utilizing the fewest number of BEDS items. RESULTS: Starting with the initial BEDS item pool (20 items), the 13-item pilot BEDS resulted from the cognitive debriefing interviews (n = 13). Of the 97 participants in the noninterventional study, 16 were diagnosed with BED (10/62 female, 16%; 6/35 male, 17%). Seven BEDS items (BEDS-7) yielded 100% sensitivity and 38.7% specificity. Participants correctly identified (true positives) had poorer BES scores and RAND-36 scores than participants identified as true negatives. CONCLUSIONS: Implementation of the brief, patient-reported BEDS-7 in real-world clinical practice is expected to promote better understanding of BED characteristics and help physicians identify patients who may have BED. PMID- 27486543 TI - Factors Differentiating Childhood-Onset and Adolescent-Onset Schizophrenia:A Claims Database Study. AB - BACKGROUND: The greater severity and burden of illness in individuals with early onset schizophrenia (ie, before age 18 years) deserves further investigation, specifically regarding its prevalence in community-based treatment and its association with other psychiatric or medical conditions. METHOD: A retrospective cohort design was employed using the South Carolina Medicaid claims database covering outpatient and inpatient medical services from January 1, 1999, through December 31, 2013, to identify patients aged <= 17 years with a diagnosis of schizophrenia spectrum disorders (ICD-9-CM). Logistic regression was used to examine the factors differentiating childhood- versus adolescent-onset schizophrenia in a community-based system of care. RESULTS: Early onset schizophrenia was diagnosed in 613 child and adolescent cases during the study epoch or 0.2% of this population-based cohort. The early onset cohort was primarily male (64%) and black (48%). The mean length of time followed in the Medicaid dataset was 12.6 years. Within the early onset cohort, 22.5% were diagnosed at age <= 12 years and 77.5% were diagnosed as adolescents. The childhood-onset subgroup was twice as likely to have speech, language, or educational disabilities and an attention-deficit/hyperactivity disorder diagnosis but significantly less likely to have schizophrenia or schizoaffective disorder, an organic brain disorder or mental retardation/intellectual disability, or a substance use disorder (adjusted OR = 2.01, 2.26, 0.38, 0.31, 0.47, and 0.32, respectively) compared to the adolescent-onset subgroup. CONCLUSION: Primary care providers should identify and maintain surveillance of cases of pediatric neurodevelopmental disorders, which appear to be highly comorbid and genetically related, and refer them early and promptly for specialized treatment. PMID- 27486545 TI - Managing Depression Among Homeless Mothers: Pilot Testing an Adapted Collaborative Care Intervention. AB - OBJECTIVE: Although depression is common among homeless mothers, little progress has been made in testing treatment strategies for this group. We describe pilot test results of an adapted collaborative care model for homeless mothers with depression. METHOD: We conducted a pilot intervention study of mothers screening positive for depression in 2 randomly selected shelter-based primary care clinics in New York over 18 months in 2010-2012. Study participants completed a psychosocial, health, and mental health assessment at baseline, 3 months, and 6 months. RESULTS: One-third of women screened positive for depression (123 of 328 women). Sixty-seven women (63.2% of the eligible sample) enrolled in the intervention. At 6 months, compared to usual-care women, intervention group women were more likely to be receiving depression treatment (40.0% vs 5.9%, P = .01) and antidepressant medication (73.3% vs 5.9%, P = .001, respectively) and had more primary care physician and care manager visits at both 3 months (74.3% vs 53.3%, P = .009 and 91.4% vs 26.7%, P < .001, respectively) and 6 months (46.7% vs 23.5%, P = .003 and 70% vs 17.7%, P = .001, respectively). More women in the intervention group compared to usual-care women reported >= 50% improvement in depression symptoms at 6 months (30% vs 5.9%, P = .07). CONCLUSIONS: This pilot study found that implementing an adapted collaborative care intervention was feasible in a shelter-based primary care clinic and had promising results that require further testing. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02723058. PMID- 27486544 TI - Post Hoc Analyses of Anxiety Measures in Adult Patients With Generalized Anxiety Disorder Treated With Vilazodone. AB - OBJECTIVE: To investigate vilazodone, currently approved for major depressive disorder in adults, for generalized anxiety disorder (GAD). METHOD: Three randomized, double-blind, placebo-controlled studies showing positive results for vilazodone (2,040 mg/d) in adult patients with GAD (DSM-IV-TR) were pooled for analyses; data were collected from June 2012 to March 2014. Post hoc outcomes in the pooled intent-to-treat population (n = 1,462) included mean change from baseline to week 8 in Hamilton Anxiety Rating Scale (HARS) total score, psychic and somatic anxiety subscale scores, and individual item scores; HARS response (>= 50% total score improvement) and remission (total score <= 7) at week 8; and category shifts, defined as HARS item score >= 2 at baseline (moderate to very severe symptoms) and score of 0 at week 8 (no symptoms). RESULTS: The least squares mean difference was statistically significant for vilazodone versus placebo in change from baseline to week 8 in HARS total score (-1.83, P < .0001) and in psychic anxiety (-1.21, P < .0001) and somatic anxiety (-0.63, P < .01) subscale scores; differences from placebo were significant on 11 of 14 HARS items (P < .05). Response rates were higher with vilazodone than placebo (48% vs 39%, P < .001), as were remission rates (27% vs 21%, P < .01). The percentage of patients who shifted to no symptoms was significant for vilazodone on several items: anxious mood, tension, intellectual, depressed mood, somatic-muscular, somatic-sensory, cardiovascular, respiratory, and autonomic symptoms (P < .05). CONCLUSIONS: Treatment with vilazodone versus placebo was effective in adult GAD patients, with significant differences between treatment groups found on both psychic and somatic HARS items. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01629966, NCT01766401, NCT01844115. PMID- 27486546 TI - A Cross-Sectional Study on the Prevalence, Risk Factors, and Ill Effects of Internet Addiction Among Medical Students in Northeastern India. AB - OBJECTIVE: To evaluate Internet addiction among medical students in northeastern India and gain detailed knowledge about the prevalence, risk factors, and ill effects commonly associated with the disorder. METHOD: The cross-sectional study sample comprised 188 medical students from Silchar Medical College and Hospital (Silchar, Assam, India). Students completed a sociodemographic form and an Internet use questionnaire, both created for this study, and the Young's 20-Item Internet Addiction Test after they received brief instructions. Data were collected during a10-day period in June 2015. RESULTS: Of the 188 medical students, 46.8% were at increased risk of Internet addiction. Those who were found to be at increased risk had longer years of Internet exposure (P = .046) and always online status (P = .033). Also, among this group, the men were more prone to develop an online relationship. Excessive Internet usage also led to poor performance in college (P < .0001) and feeling moody, anxious, and depressed (P < .0001). CONCLUSIONS: The ill effects of Internet addiction include withdrawal from real-life relationships, deterioration in academic activities, and a depressed and nervous mood. Internet use for nonacademic purposes is increasing among students, thus there is an immediate need for strict supervision and monitoring at the institutional level. The possibility of becoming addicted to the Internet should be emphasized to students and their parents through awareness campaigns so that interventions and restrictions can be implemented at the individual and family levels. PMID- 27486547 TI - Pharmacotherapy for Insomnia in Primary Care. AB - Pharmacotherapy for insomnia in primary care settings can be challenging. Frequently, there are multiple coexisting medical and psychiatric conditions, drug interactions, concern regarding use of habit-forming sleep aids, and paucity of time in office visits to discuss management of sleep difficulties. This article reports the results of a literature search related to pharmacotherapy for insomnia and presents 4 clinical vignettes with corresponding treatment options. PMID- 27486548 TI - Two For the Road. PMID- 27486549 TI - Psychosis Resulting From Herbs Rather Than Nutrients. PMID- 27486550 TI - Dietary Supplement Nomenclature. PMID- 27486551 TI - Improvement of sensitivity in continuous wave near infra-red spectroscopy systems by using silicon photomultipliers. AB - We experimentally analyze the signal-to-noise ratio of continuous wave (CW) near infrared spectroscopy (NIRS) reflectance systems based on light emitting diodes and silicon photomultipliers for high performance low cost NIRS biomedical systems. We show that under suitable experimental conditions such systems exhibit a high SNR, which allows an SDS of 7 cm, to our knowledge the largest ever demonstrated in a CW-NIRs system. PMID- 27486552 TI - Beyond Contact Tracing: Community-Based Early Detection for Ebola Response. AB - INTRODUCTION: The 2014 Ebola outbreak in West Africa raised many questions about the control of infectious disease in an increasingly connected global society. Limited availability of contact information made contact tracing diffcult or impractical in combating the outbreak. METHODS: We consider the development of multi-scale public health strategies that act on individual and community levels. We simulate policies for community-level response aimed at early screening all members of a community, as well as travel restrictions to prevent inter-community transmission. RESULTS: Our analysis shows the policies to be effective even at a relatively low level of compliance and for a variety of local and long range contact transmission networks. In our simulations, 40% of individuals conforming to these policies is enough to stop the outbreak. Simulations with a 50% compliance rate are consistent with the case counts in Liberia during the period of rapid decline after mid September, 2014. We also find the travel restriction to be effective at reducing the risks associated with compliance substantially below the 40% level, shortening the outbreak and enabling efforts to be focused on affected areas. DISCUSSION: Our results suggest that the multi-scale approach can be used to further evolve public health strategy for defeating emerging epidemics. PMID- 27486553 TI - Validation of a Tablet as a Tangent Perimeter. AB - PURPOSE: To describe a tangent perimeter developed on an Apple iPad (Melbourne Rapid Field, MRF). METHODS: The MRF assays 66 locations over 28 degrees * 18 degrees by having the patient vary fixation. Spot size and background luminance are paired to yield constant thresholds across the field. Spot locations were selected after analysis of 360 patient records. The capacity of the MRF to detect defects was verified in five participants (age 22-28 years) by simulating four common losses: central, arcuate, quadrant, and hemianopia. We also consider the effect of: myosis, blur (+3 DS), viewing distance (25-75 cm), ambient light (4 600 lux), and retest repeatability (1-week apart) on thresholds. Group means [SEM] are compared by Student's t-test and repeatability returned from Bland Altman analysis. RESULTS: We found a 5 cd.m-2 background replicates the Weber fraction produced by a Humphrey spot shown at 35 dB. Our variable size gives constant thresholds (29.6 [0.2] dB) across all locations. Altering viewing distance (25 cm = 29.8 [0.9] dB; 75 cm = 28.9 [0.6] dB) and ambient lighting (4 lux, 29.8 [0.8] dB; 600 lux, 29.5 [1.0] dB) did not affect threshold although screen reflections must be avoided. Myosis (-1.2 dB) and blur (-1.5 dB) will reduce sensitivity (P < 0.05). Simulated defects with a mean defect (MD) of -3.3 dB are detected by the MRF. The Coefficient of repeatability was 9.6% (SD ~2.9 dB) in normal regions and 48.1% (SD ~8.0 dB) in areas of simulated scotoma. CONCLUSIONS: Tablet technology can return efficient and reliable thresholds to 30 degrees as a tangent perimeter. TRANSLATIONAL RELEVANCE: The MRF will allow testing at a bedside, at home, in rural or remote areas, or where equipment cannot be financed. PMID- 27486554 TI - Comparison of Peristat Online Perimetry with the Humphrey Perimetry in a Clinic Based Setting. AB - PURPOSE: We determined the receiver operating characteristic (ROC) curves for Peristat online perimetry at detecting varying degrees of glaucoma and the correlation between Peristat online perimetry and Humphrey visual field. METHODS: A prospective, comparative study of Peristat online perimetry (an achromatic static computer threshold testing program) and Humphrey visual field (HVF) 24-2 SITA standard testing was performed by 63 glaucoma patients and 30 healthy controls in random order. The number of total adjacent abnormal test points were identified for each test, and compared with Spearman correlation. Receive operating characteristic curves were generated for Peristat online perimetry detection of mild and moderate-severe glaucoma patients using contrast sensitivity thresholds of -16.7, -21.7, and -26.7 dB. RESULTS: The area under the ROC curve for glaucoma detection ranged from 0.77 to 0.81 for mild disease (mean deviation [MD], >-6 dB on HVF) and 0.85 to 0.87 for moderate to severe disease (MD, <-6 dB on HVF) depending on contrast threshold. Peristat online perimetry and Humphrey visual field abnormal points were highly correlated with Spearman rank correlations ranging from 0.55 to 0.77 (all P < 0.001). CONCLUSIONS: Peristat online perimetry exhibits a reasonable ROC curve without specialized equipment and exhibited significant correlation with the conventional 24 degrees Humphrey visual field test. TRANSLATIONAL RELEVANCE: Low cost widely available internet-based visual fields may complement traditional office-based visual field testing. PMID- 27486555 TI - Local Variability of Macular Thickness Measurements With SD-OCT and Influencing Factors. AB - PURPOSE: To compare the intrasession variability of spectral-domain optical coherence tomography (SD-OCT)-derived local macular thickness measures and explore influencing factors. METHODS: One hundred two glaucomatous eyes (102 patients) and 21 healthy eyes (21 subjects) with three good quality macular images during the same session were enrolled. Thickness measurements were calculated for 3 degrees superpixels for the inner plexiform (IPL), ganglion cell (GCL), or retinal nerve fiber layers (mRNFL), GC/IPL, ganglion cell complex, and full macular thickness. Spatial distribution and magnitude of measurement errors (ME; differences between the 3 individual superpixel values and their mean) and association between MEs and thickness, age, axial length, and image quality were explored. RESULTS: MEs had a normal distribution with mostly random noise along with a small fraction of outliers (1.2%-6.6%; highest variability in mRNFL and on the nasal border) based on M-estimation. Boundaries of 95% prediction intervals for variability reached a maximum of 3 MUm for all layers and diagnostic groups after exclusion of outliers. Correlation between proportion of outliers and thickness measures varied among various parameters. Age, axial length, or image quality did not influence MEs (P > 0.05 for both groups). CONCLUSIONS: Local variability of macular SD-OCT measurements is low and uniform across the macula. The relationship between superpixel thickness and outlier proportion varied as a function of the parameter of interest. TRANSLATIONAL RELEVANCE: Given the low and uniform variability within and across eyes, definition of an individualized 'variability space' seems unnecessary. The variability measurements from this study could be used for designing algorithms for detection of glaucoma progression. PMID- 27486557 TI - Sun protection practices in New Zealand secondary schools: a 2014 baseline study. AB - OBJECTIVE: Guided by the established primary school SunSmart programme, a survey of secondary schools' sun protection policies, planning, behavioural expectations, curriculum content and environment was undertaken in order to establish a baseline to inform advocacy and secondary level programme development. METHODS: All 448 principals of state or state integrated public secondary schools identified from the Ministry of Education database were mailed a hard copy questionnaire. School sun protection practices were assessed and a summative, non-weighted, 11-item Total Sun Protection Score (TSPS) was created. Associations between TSPS and socio-demographic factors, as well as school sun protection policy, were investigated using unadjusted and multiple linear regressions. RESULTS: Usable responses received from 211 of the 448 schools (47% participation) indicated reasonable representativeness of eligible schools, but under-representation of low socioeconomic decile institutions (p = 0.003) and those with the smallest roll size (p = 0.004). Only 50% of schools reported having a sun protection policy. The least attained TSPS components were outdoor event planning (17.1%), student breaks (16.6%), sun-protective clothing (8.5%) and shade provision (6.2%). The mean (SD) TSPS was 4.58 (2.06). In multivariable analysis, TSPS was statistically significantly positively associated with having a sun protection policy (p < 0.001) and the presence of primary level classes (p < 0.001) - the latter suggesting a possible influence of programme continuity, but negatively associated with integrated school status (p = 0.036). CONCLUSION: A standard SunSmart programme could be promoted to all schools, irrespective of socioeconomic decile, overall roll size, gender status or regional population density. Low attainment of some TSPS components indicates targeting priorities. PMID- 27486556 TI - Efficacy and Safety of Human Retinal Progenitor Cells. AB - PURPOSE: We assessed the long-term efficacy and safety of human retinal progenitor cells (hRPC) using established rodent models. METHODS: Efficacy of hRPC was tested initially in Royal College of Surgeons (RCS) dystrophic rats immunosuppressed with cyclosporine/dexamethasone. Due to adverse effects of dexamethasone, this drug was omitted from a subsequent dose-ranging study, where different hRPC doses were tested for their ability to preserve visual function (measured by optokinetic head tracking) and retinal structure in RCS rats at 3 to 6 months after grafting. Safety of hRPC was assessed by subretinal transplantation into wild type (WT) rats and NIH-III nude mice, with analysis at 3 to 6 and 9 months after grafting, respectively. RESULTS: The optimal dose of hRPC for preserving visual function/retinal structure in dystrophic rats was 50,000 to 100,000 cells. Human retinal progenitor cells integrated/survived in dystrophic and WT rat retina up to 6 months after grafting and expressed nestin, vimentin, GFAP, and betaIII tubulin. Vision and retinal structure remained normal in WT rats injected with hRPC and there was no evidence of tumors. A comparison between dexamethasone-treated and untreated dystrophic rats at 3 months after grafting revealed an unexpected reduction in the baseline visual acuity of dexamethasone-treated animals. CONCLUSIONS: Human retinal progenitor cells appear safe and efficacious in the preclinical models used here. TRANSLATIONAL RELEVANCE: Human retinal progenitor cells could be deployed during early stages of retinal degeneration or in regions of intact retina, without adverse effects on visual function. The ability of dexamethasone to reduce baseline visual acuity in RCS dystrophic rats has important implications for the interpretation of preclinical and clinical cell transplant studies. PMID- 27486558 TI - Racial and ethnic minority patients report different weight-related care experiences than non-Hispanic Whites. AB - Our objective was to compare patients' health care experiences, related to their weight, across racial and ethnic groups. In Summer 2015, we distributed a written survey with telephone follow-up to a random sample of 5400 racially/ethnically and geographically diverse U.S. adult health plan members with overweight or obesity. The survey assessed members' perceptions of their weight-related healthcare experiences, including their perception of their primary care provider, and the type of weight management services they had been offered, or were interested in. We used multivariable multinomial logistic regression to examine the relationship between race/ethnicity and responses to questions about care experience. Overall, 2811 members (53%) responded to the survey and we included 2725 with complete data in the analysis. Mean age was 52.7 years (SD 15.0), with 61.7% female and 48.3% from minority racial/ethnic groups. Mean BMI was 37.1 kg/m(2) (SD 8.0). Most (68.2%) respondents reported having previous discussions of weight with their provider, but interest in such counseling varied by race/ethnicity. Non-Hispanic blacks were significantly less likely to frequently avoid care (for fear of discussing weight/being weighed) than whites (OR 0.49, 95% CI 0.26-0.90). Relative to whites, respondents of other race/ethnicities were more likely to want weight-related discussions with their providers. Race/ethnicity correlates with patients' perception of discussions of weight in healthcare encounters. Clinicians should capitalize on opportunities to discuss weight loss with high-risk minority patients who may desire these conversations. PMID- 27486559 TI - Electronic health record-based assessment of cardiovascular health: The stroke prevention in healthcare delivery environments (SPHERE) study. AB - < 3% of Americans have ideal cardiovascular health (CVH). The primary care encounter provides a setting in which to conduct patient-provider discussions of CVH. We implemented a CVH risk assessment, visualization, and decision-making tool that automatically populates with electronic health record (EHR) data during the encounter in order to encourage patient-centered CVH discussions among at risk, yet under-treated, populations. We quantified five of the seven CVH behaviors and factors that were available in The Ohio State University Wexner Medical Center's EHR at baseline (May-July 2013) and compared values to those ascertained at one-year (May-July 2014) among intervention (n = 109) and control (n = 42) patients. The CVH of women in the intervention clinic improved relative to the metrics of body mass index (16% to 21% ideal) and diabetes (62% to 68% ideal), but not for smoking, total cholesterol, or blood pressure. Meanwhile, the CVH of women in the control clinic either held constant or worsened slightly as measured using those same metrics. Providers need easy-to-use tools at the point of-care to help patients improve CVH. We demonstrated that the EHR could deliver such a tool using an existing American Heart Association framework, and we noted small improvements in CVH in our patient population. Future work is needed to assess how to best harness the potential of such tools in order to have the greatest impact on the CVH of a larger patient population. PMID- 27486560 TI - Smokers' and e-cigarette users' perceptions of modified risk warnings for e cigarettes. AB - The 2009 Family Smoking Prevention and Tobacco Control Act opened the possibility for tobacco companies to apply to market their products as having "modified" or reduced risks. However, research on how to communicate comparative tobacco risks and how such messages are interpreted is limited. This study aimed to qualitatively examine perceptions of potential modified risk statements presented as warning labels for e-cigarettes. We conducted six focus groups between 2014 and 2015 with 27 adult e-cigarette users and cigarette-only smokers who provided comments on two versions of a modified risk warning for e-cigarettes: 1) "WARNING: No tobacco product is safe, but this product presents substantially lower risks to health than cigarettes" (as proposed by two companies for their smokeless tobacco products) and 2) "WARNING: This product may be harmful to health, but is substantially less harmful than cigarettes" (an alternative developed by our team). Although most personally believed that e-cigarettes are safer than cigarettes and some thought the messages were true and accurate, many were skeptical and uncomfortable with the warnings because they did not "seem like a warning" and because use of the phrase "substantially lower risks" could be misleading and difficult to understand. Several thought the second warning was stronger (e.g., more active, more specific). Modified risk messages about e cigarettes may impact perceptions and use of the product. More research is needed to identify the framing, wording and placement (e.g. within or in addition to a warning) that could potentially increase population-level benefits and minimize harms. PMID- 27486561 TI - Testing the theory of holism: A study of family systems and adolescent health. AB - Holism is an ancient theory that can be applied contemporarily to adolescent health and its determinants. This theory suggests that there is value in considering factors that influence health together as integrated wholes, in addition to consideration of individual components. Characteristics of families are fundamental determinants of health and provide opportunity for exploration of this theory. In a "proof-of-concept" analysis we therefore: (1) developed a multidimensional, composite (holistic) measure to be used to characterize family systems; and (2) related this measure and its individual components to adolescent health outcomes, in order to test the theory of holism. Cross-sectional analyses of survey reports from the 2014 Canadian Health Behaviour in School-aged Children study (weighted n = 19,333) were performed. Factor analysis was used to confirm the psychometric properties of the holistic measure to describe a family system (the "holistic measure"). Associations between this holistic measure, its individual components, and various indicators of health were examined descriptively and using binomial regression. The holistic measure (4 items, alpha = 0.62; RMSEA = .04; SRMR = 0.01; AGFI = 0.99) included components describing family: material wealth, meal practices, neighbourhood social capital, and social connections. It was consistently associated with various health behaviours, and social and emotional health outcomes. In 22/24 comparisons, this holistic measure related to positive health outcomes more strongly than did its individual components; for negative health outcomes this occurred in 20/24 comparisons. Study findings suggest that it is possible to assess family systems holistically. Such systems are strongly associated with adolescent health outcomes, and there is etiological and theoretical value in considering family systems as integrated wholes. PMID- 27486562 TI - Change in settings for early-season influenza vaccination among US adults, 2012 to 2013. AB - Vaccination in non-medical settings is recommended as a strategy to increase access to seasonal influenza vaccine. To evaluate change in early-season influenza vaccination setting, we analyzed data from the National Internet Flu Survey. Bivariate comparison of respondent characteristics by location of vaccination was assessed using chi-square tests. Multinomial logistic regression was performed to compare the predicted probability of being vaccinated in medical, retail, and mobile settings in 2012 vs 2013. In both 2012 and 2013, vaccination in medical settings was more likely among elderly adults, those with chronic conditions, and adults with a high school education or less. Adults 18-64 without a chronic condition had a lower probability of vaccination in the medical setting, and higher probability of vaccination in a retail or mobile setting, in 2013 compared to 2012. Adults 18-64 with a chronic condition had no change in their location of flu vaccination. Elderly adults had a lower probability of vaccination in the medical setting, and higher probability of vaccination in a retail setting, in 2013 compared to 2012. Non-medical settings continue to play an increasing role in influenza vaccination of adults, particularly for adults without a chronic condition and elderly adults. Retail and mobile settings should continue to be viewed as important mechanisms to ensure broad access to influenza vaccination. PMID- 27486564 TI - Educational gradients in five Asian immigrant populations: Do country of origin, duration and generational status moderate the education-health relationship? AB - Education usually shows a relationship with self-rated health such that those with highest education have the best health and those with lowest education have the worst health. We examine these educational gradients among Asian immigrants and whether they differ by country of origin, duration in the United States, and generational status. Migration theories suggest that recent immigrants from poorer countries should show a weaker relationship between education and health than US-born Whites. Acculturation theory further suggests that differences in gradients across country of origin should diminish for longer-term immigrants and the US-born and that these groups should display gradients similar to US-born Whites. We use the March Current Population Survey (2000 - 2010) to examine educational gradients in self-rated health among recent immigrants (<= 15 years duration), longer-term immigrants (> 15 years duration), and second generation US born Asians from China (n = 4473), India (n = 4,307), the Philippines (n = 5746), South Korea (n = 2760), and Japan (n = 1265). We find weak or non-significant educational gradients among recent Asian immigrants across the five countries of origin. There is no indication that longer-term immigrants display significant differences across educational status. Only second generation Chinese and Filipinos show significant differences by educational status. Overall, Asians show an attenuated relationship between education and self-rated health compared to US-Whites that persists over duration in the US and generational status. Our findings show shortcomings in migration and acculturation theories to explain these gradient patterns. Future research could use binational data or explore psychosocial factors to identify potential suppressors of educational gradients. PMID- 27486565 TI - Transcriptional profiling of immortalized and K-ras-transformed mouse fibroblasts upon PKA stimulation by forskolin in low glucose availability. AB - Forskolin (FSK) induces activation of protein kinase A (PKA). This activation protects specifically some cancer cells from death induced by glucose starvation. Cell effects upon FSK treatment prompted us to investigate in detail the physiological role of PKA in the activation of pro-survival mechanisms in glucose starvation. In this regard we performed a microarray analysis of normal NIH3T3 and transformed NIH3T3-K-ras mouse fibroblasts cultured at 1 mM glucose and daily treated or not with 10 MUM FSK until 72 h of growth, when the samples were collected. The microarray is deposited into Gene Expression Omnibus under Series GSE68266. The microarray data revealed that the activation of PKA regulates the expression of genes involved in metabolic, stress-response and pro-survival processes, like glutamine metabolism, autophagy and unfolded protein response, preventing cancer cell death in glucose starvation. Altogether these findings suggest that PKA activation, by inducing a complex transcriptional program, leads to cancer survival in nutrient stress, a typical feature of developing tumor. These transcriptional data, identifying this important role of PKA, will be useful to identify novel target in cancer therapy. PMID- 27486563 TI - Smoking status and abdominal obesity among normal- and overweight/obese adults: Population-based FINRISK study. AB - Several studies have reported direct associations of smoking with body mass index (BMI) and abdominal obesity. However, the interplay between them is poorly understood. Our first aim was to investigate the interaction between smoking status and BMI on abdominal obesity (waist circumference, WC). Our second aim was to examine how the association of smoking status with WC varies among normal and overweight/obese men and women. We examined 5833 participants from the National FINRISK 2007 Study. The interactions between smoking and BMI on WC were analyzed. Participants were categorized into eight groups according to BMI (normal weight vs. overweight/obese) and smoking status (never smoker, ex-smoker, occasional/light/moderate daily smoker, heavy daily smoker). The associations between each BMI/smoking status -group and WC were analyzed by multiple regressions, the normal-weight never smokers as the reference group. The smoking status by BMI-interaction on WC was significant for women, but not for men. Among the overweight/obese women, ex-smokers (beta = 2.73; 1.99, 3.46) and heavy daily smokers (beta = 4.90; 3.35, 6.44) had the highest estimates for WC when adjusted for age, BMI, alcohol consumption and physical activity. In comparison to never smoking overweight/obese women, the beta-coefficients of ex-smokers and heavy daily smokers were significantly higher. Among men and normal weight women the beta -coefficients did not significantly differ by smoking status. An interaction between smoking status and BMI on abdominal obesity was observed in women: overweight/obese heavy daily smokers were particularly vulnerable for abdominal obesity. This risk group should be targeted for cardiovascular disease prevention. PMID- 27486566 TI - De novo sequencing of Eucommia ulmoides flower bud transcriptomes for identification of genes related to floral development. AB - Eucommia ulmoides Oliver is a woody perennial dioecious species native to China and has great economic value. However, little is known about flower bud development in this species. In this study, the transcriptomes of female and male flower buds were sequenced using the Illumina platform, a next-generation sequencing technology that provides cost-effective, highly efficient transcriptome profiling. In total, 11,558,188,080 clean reads were assembled into 75,065 unigenes with an average length of 1011 bp by de novo assembly using Trinity software. Through similarity comparisons with known protein databases, 47,071 unigenes were annotated, 146 of which were putatively related to the floral development of E. ulmoides. Fifteen of the 146 unigenes had significantly different expression levels between the two samples. Additionally, 24,346 simple sequence repeats were identified in 18,565 unigenes with 12,793 sequences suitable for the designed primers. In total, 67,447 and 58,236 single nucleotide polymorphisms were identified in male and female buds, respectively. This study provides a valuable resource for further conservation genetics and functional genomics research on E. ulmoides. PMID- 27486567 TI - Neuroendocrine Tumors of the Large Intestine: Clinicopathological Features and Predictive Factors of Lymph Node Metastasis. AB - A new histological classification of neuroendocrine tumors (NETs) was established in WHO 2010. ENET and NCCN proposed treatment algorithms for colorectal NET. Retrospective study of NET of the large intestine (colorectal and appendiceal NET) was performed among institutions allied with the Japanese Society for Cancer of the Colon and Rectum, and 760 neuroendocrine tumors from 2001 to 2011 were re assessed using WHO 2010 criteria to elucidate the clinicopathological features of NET in the large intestine. Next, the clinicopathological relationship with lymph node metastasis was analyzed to predict lymph node metastasis in locally resected rectal NET. The primary site was rectum in 718/760 cases (94.5%), colon in 30/760 cases (3.9%), and appendix in 12/760 cases (1.6%). Patients were predominantly men (61.6%) with a mean age of 58.7 years. Tumor size was <10 mm in 65.4% of cases. Proportions of NET G1, G2, G3, and mixed adeno-neuroendocrine carcinoma (MANEC) were 88.4, 6.3, 3.9, and 1.3%, respectively. Of the 760 tumors, 468 were locally resected, and 292 were surgically resected with lymph node dissection. Rectal NET showed a higher proportion of NET G1, and colonic and appendiceal NET was more commonly G3 and MANEC. Of the 292 surgically resected cases, 233 NET G1 and G2 located in the rectum were used for the prediction of lymph node metastasis. Lymphatic and blood vessel invasion were independent predictive factors of lymph node metastasis. NET G2 cases showed more frequent lymph node metastasis than that seen in NET G1 cases, but this was not an independent predictor of lymph node metastasis. Of the 98 surgically resected cases <10 mm in size, we found 9 cases with lymph node metastasis (9.2%). All cases were NET G1, and eight of the nine cases were positive either for lymphatic invasion or blood vessel invasion. Using the WHO classification, we found NET in the large intestine showed a tumor-site-dependent variety of histological and clinicopathological features. Risk of lymph node metastasis in rectal NET was confirmed even in lesions smaller than 10 mm. Concordant assessment of vascular invasion will be required to estimate lymph node metastasis in small lesions. PMID- 27486568 TI - Effectiveness of sulphonylureas in the therapy of diabetes mellitus type 2 patients: an observational cohort study. AB - BACKGROUND: We compared all-cause mortality, major macrovascular events (MACE) and diabetes-related hospitalizations in T2DM-incident patients newly treated with metformin (MET) versus sulphonylureas (SU) monotherapy and in T2DM-prevalent patients newly treated with MET+SU versus MET+DPP4-inhibitor combination therapy. METHODS: We analysed anonymized data obtained from a German health fund. Patients were included when they had started MET versus SU therapy or MET+SU versus MET+DPP4 therapy between 01/07/2010 and 31/12/2011. Observation started with the first MET/SU prescription or the first prescription of the second agent of a MET+SU/MET+DPP4 combination therapy. Follow-up time lasted until the end of data availability (a minimum of 12 months), death or therapy discontinuation. RESULTS: In total, 434,291 T2DM-prevalent and 35,661 T2DM-incident patients were identified. Of the identified T2DM-incident patients, 904/7,874 started SU/MET monotherapy, respectively, with a mean age of 70.1/61.4 years (54.6/50.3 % female; Charlson Comorbidity Index (CCI) 1.4/2.2; 933/7,350 observed SU/MET patient years). 4,157/1,793 SU+MET/DPP4+MET therapy starters had a mean age of 68.1/62.2 years (53.4/50.8 % female; CCI 2.8/2.6; 4,556/1,752 observed SU+MET/ DPP4+MET patient years). In a propensity score matched (PSM) comparison, the HRs (95 % CIs) associated with SU monotherapy compared to MET monotherapy exposure were 1.4 (0.9-2.3) for mortality, 1.4 (0.9-2.2) for MACE, 4.1 (1.5-10.9) for T2DM hospitalizations and 1.6 (1.2-2.3) for composite event risk. In a multivariable Cox regression model, SU monotherapy was associated with higher mortality (aHR 2.0; 1.5-2.6), higher MACE (aHR 1.3; 1.0-1.7) and higher T2DM hospitalizations (aHR 2.8; 1.8-4.4), which corresponded with a higher composite event risk (aHR 1.8; 1.5-2.1). No significant differences in event rates were observed in the PSM comparison between DPP4+MET/SU+MET combination therapy starters and in the multivariable Cox regression analysis. CONCLUSIONS: Our results show that SU monotherapy may be associated with increased mortality, MACE and T2DM hospitalizations, compared to MET monotherapy. When considering SU therapy, the associated cardiovascular risk should also be taken into account. PMID- 27486569 TI - Vasectomy and prostate cancer risk: a historical synopsis of undulating false causality. AB - The potential influence of vasectomy being a risk factor for the development of prostate cancer is not a new concept, with more than 30 publications addressing the topic. Given the global frequency of vasectomy and the prevalence of prostate cancer, this subject justifiably deserves scrutiny. Several articles have claimed that vasectomy puts men at risk for future development of prostate cancer. We explore articles that have shown the contrary (no link), explore the studies' strengths and weaknesses, describe possible prostate cancer pathophysiologic mechanisms, and apply Bradford Hill criteria to help discern correlation with causation. The risk and interest of association of prostate cancer with vasectomy has waxed and waned over the last three decades. Based on our review, vasectomy remains a safe form of sterilization and does not increase prostate cancer risk. PMID- 27486570 TI - Prevalence, psychological impact, and risk factors of erectile dysfunction in patients with Peyronie's disease: a retrospective analysis of 309 cases. AB - Peyronie's disease (PD) is a chronic inflammatory disease involving the tunica albuginea of the penis. Erectile dysfunction (ED) is a possible invalidating symptom of PD. The aim of this study was to evaluate the prevalence, psychological impact, and risk factors of ED in patients with PD. The study was conducted by carrying out a retrospective analysis of the clinical records of 309 patients with PD who visited our andrology clinic. All patients underwent the following tests: body mass index, common blood tests and hormone assays, questionnaire for erectile function assessment, dynamic penile color Doppler ultrasonography, imaging of the penis at maximum erection with photographic poses according to Kelami, psychosexual impact evaluation with PD Questionnaire (symptom bother score), evaluation of depression symptoms with the Patient Health Questionnaire-9, and evaluation of the intensity of penile pain with the pain intensity numeric rating scale. ED was observed in 37.5% of the cases. We divided the cases into two groups: group A (PD + ED), 116 cases, and group B (PD without ED), 193 cases. After multivariate analysis, we concluded that the following comorbidities are independent risk factors for ED: dyslipidemia, obesity, chronic prostatitis, benign prostatic hyperplasia, and autoimmune diseases. A depressive disorder was observed in 62.4%, and it was more frequent in patients with PD + ED (91.37% versus 45.07% group B). Sexual bother was greater in group A compared with group B (9.7 versus 7.6). Intensities of depressive symptoms and sexual bother were significantly higher compared with cases with no curvature when the bend angle was >=30 degrees . Our study confirms that an integrated psychological support with medical treatment is needed in patients with PD. PMID- 27486572 TI - Spatial-Temporal Analysis of Air Pollution, Climate Change, and Total Mortality in 120 Cities of China, 2012-2013. AB - China has had a rapid increase in its economy over the past three decades. However, the economic boom came at a certain cost of depleting air quality. In the study, we aimed to examine the burden of air pollution and its association with climatic factors and health outcomes using data from Chinese national and city-level air quality and public health surveillance systems. City-level daily air pollution index (API, a sum weighted index of SO2, NO2, PM10, CO, and Ozone) in 120 cities in 2012 and 2013, and its association with climate factors were analyzed using multiple linear regression analysis, spatial autocorrelation analysis, and panel fixed models. City-level ecological association between annual average API and total mortality were examined using univariate and partial correlation analysis. Sensitivity analysis was conducted by taking the consideration of time-lag effect between exposures and outcomes. The results show that among the 120 cities, annual average API significantly increased from 2012 to 2013 (65.05 vs. 75.99, p < 0.0001). The highest average API was in winter, and the lowest in summer. A significantly spatial clustering of elevated API was observed, with the highest API in northwest China in 2012 and with the highest in east China in 2013. In 2012, 5 (4%) of the 120 cities had >=60 days with API >100 (defined as "slightly polluted"), however, it increased to 21 cities (18%) that experienced API >100 for >=60 days in 2013. Furthermore, 16 cities (13%) in 2012 and 35 (29%) in 2013 experienced a maximum API >300 (defined as "severely polluted"). API was negatively and significantly correlated with heat index, precipitation, and sunshine hours, but positively with air pressure. Cities with higher API concentrations had significantly higher total mortality rates than those with lower API. About a 4-7% of the variation in total mortality could be explained by the difference in API across the nation. In conclusion, the study highlights an increased trend of air pollution from 2012 to 2013 in China. The magnitude of air pollution varied by seasons and regions and correlated with climatic factors and total mortality across the country. PMID- 27486571 TI - Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates: Design of a Retrospective Cohort Study. AB - INTRODUCTION: Acute kidney injury (AKI) affects ~30% of hospitalized neonates. Critical to advancing our understanding of neonatal AKI is collaborative research among neonatologists and nephrologists. The Neonatal Kidney Collaborative (NKC) is an international, multidisciplinary group dedicated to investigating neonatal AKI. The AWAKEN study (Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates) was designed to describe the epidemiology of neonatal AKI, validate the definition of neonatal AKI, identify primary risk factors for neonatal AKI, and investigate the contribution of fluid management to AKI events and short-term outcomes. METHODS AND ANALYSIS: The NKC was established with at least one pediatric nephrologist and neonatologist from 24 institutions in 4 countries (USA, Canada, Australia, and India). A Steering Committee and four subcommittees were created. The database subcommittee oversaw the development of the web-based database (MediData RaveTM) that captured all NICU admissions from 1/1/14 to 3/31/14. Inclusion and exclusion criteria were applied to eliminate neonates with a low likelihood of AKI. Data collection included: (1) baseline demographic information; (2) daily physiologic parameters and care received during the first week of life; (3) weekly "snapshots"; (4) discharge information including growth parameters, final diagnoses, discharge medications, and need for renal replacement therapy; and (5) all serum creatinine values. ETHICS AND DISSEMINATION: AWAKEN was proposed as human subjects research. The study design allowed for a waiver of informed consent/parental permission. NKC investigators will disseminate data through peer-reviewed publications and educational conferences. DISCUSSION: The purpose of this publication is to describe the formation of the NKC, the establishment of the AWAKEN cohort and database, future directions, and a few "lessons learned." The AWAKEN database includes ~325 unique variables and >4 million discrete data points. AWAKEN will be the largest, most inclusive neonatal AKI study to date. In addition to validating the neonatal AKI definition and identifying risk factors for AKI, this study will uncover variations in practice patterns related to fluid provision, renal function monitoring, and involvement of pediatric nephrologists during hospitalization. The AWAKEN study will position the NKC to achieve the long-term goal of improving the lives, health, and well-being of newborns at risk for kidney disease. PMID- 27486574 TI - Using Virtual Reality in the Inference-Based Treatment of Compulsive Hoarding. AB - The present study evaluated the efficacy of adding a virtual reality (VR) component to the treatment of compulsive hoarding (CH), following inference-based therapy (IBT). Participants were randomly assigned to either an experimental or a control condition. Seven participants received the experimental and seven received the control condition. Five sessions of 1 h were administered weekly. A significant difference indicated that the level of clutter in the bedroom tended to diminish more in the experimental group as compared to the control group F(2,24) = 2.28, p = 0.10. In addition, the results demonstrated that both groups were immersed and present in the environment. The results on posttreatment measures of CH (Saving Inventory revised, Saving Cognition Inventory and Clutter Image Rating scale) demonstrate the efficacy of IBT in terms of symptom reduction. Overall, these results suggest that the creation of a virtual environment may be effective in the treatment of CH by helping the compulsive hoarders take action over their clutter. PMID- 27486573 TI - Chemical Pesticides and Human Health: The Urgent Need for a New Concept in Agriculture. AB - The industrialization of the agricultural sector has increased the chemical burden on natural ecosystems. Pesticides are agrochemicals used in agricultural lands, public health programs, and urban green areas in order to protect plants and humans from various diseases. However, due to their known ability to cause a large number of negative health and environmental effects, their side effects can be an important environmental health risk factor. The urgent need for a more sustainable and ecological approach has produced many innovative ideas, among them agriculture reforms and food production implementing sustainable practice evolving to food sovereignty. It is more obvious than ever that the society needs the implementation of a new agricultural concept regarding food production, which is safer for man and the environment, and to this end, steps such as the declaration of Nyeleni have been taken. PMID- 27486575 TI - Compensating for Electrode Polarization in Dielectric Spectroscopy Studies of Colloidal Suspensions: Theoretical Assessment of Existing Methods. AB - Dielectric spectroscopy can be used to determine the dipole moment of colloidal particles from which important interfacial electrokinetic properties, for instance their zeta potential, can be deduced. Unfortunately, dielectric spectroscopy measurements are hampered by electrode polarization (EP). In this article, we review several procedures to compensate for this effect. First EP in electrolyte solutions is described: the complex conductivity is derived as function of frequency, for two cell geometries (planar and cylindrical) with blocking electrodes. The corresponding equivalent circuit for the electrolyte solution is given for each geometry. This equivalent circuit model is extended to suspensions. The complex conductivity of a suspension, in the presence of EP, is then calculated from the impedance. Different methods for compensating for EP are critically assessed, with the help of the theoretical findings. Their limit of validity is given in terms of characteristic frequencies. We can identify with one of these frequencies the frequency range within which data uncorrected for EP may be used to assess the dipole moment of colloidal particles. In order to extract this dipole moment from the measured data, two methods are reviewed: one is based on the use of existing models for the complex conductivity of suspensions, the other is the logarithmic derivative method. An extension to multiple relaxations of the logarithmic derivative method is proposed. PMID- 27486576 TI - Quantifying Dynamic Changes in Plantar Pressure Gradient in Diabetics with Peripheral Neuropathy. AB - Diabetic foot ulcers remain one of the most serious complications of diabetes. Peak plantar pressure (PPP) and peak pressure gradient (PPG) during walking have been shown to be associated with the development of diabetic foot ulcers. To gain further insight into the mechanical etiology of diabetic foot ulcers, examination of the pressure gradient angle (PGA) has been recently proposed. The PGA quantifies directional variation or orientation of the pressure gradient during walking and provides a measure of whether pressure gradient patterns are concentrated or dispersed along the plantar surface. We hypothesized that diabetics at risk of foot ulceration would have smaller PGA in key plantar regions, suggesting less movement of the pressure gradient over time. A total of 27 participants were studied, including 19 diabetics with peripheral neuropathy and 8 non-diabetic control subjects. A foot pressure measurement system was used to measure plantar pressures during walking. PPP, PPG, and PGA were calculated for four foot regions - first toe (T1), first metatarsal head (M1), second metatarsal head (M2), and heel (HL). Consistent with prior studies, PPP and PPG were significantly larger in the diabetic group compared with non-diabetic controls in the T1 and M1 regions, but not M2 or HL. For example, PPP was 165% (P = 0.02) and PPG was 214% (P < 0.001) larger in T1. PGA was found to be significantly smaller in the diabetic group in T1 (46%, P = 0.04), suggesting a more concentrated pressure gradient pattern under the toe. The proposed PGA may improve our understanding of the role of pressure gradient on the risk of diabetic foot ulcers. PMID- 27486579 TI - Editorial: Metabolome Informatics and Statistics: Current State and Emerging Trends. PMID- 27486577 TI - Expression of S-adenosylmethionine Hydrolase in Tissues Synthesizing Secondary Cell Walls Alters Specific Methylated Cell Wall Fractions and Improves Biomass Digestibility. AB - Plant biomass is a large source of fermentable sugars for the synthesis of bioproducts using engineered microbes. These sugars are stored as cell wall polymers, mainly cellulose and hemicellulose, and are embedded with lignin, which makes their enzymatic hydrolysis challenging. One of the strategies to reduce cell wall recalcitrance is the modification of lignin content and composition. Lignin is a phenolic polymer of methylated aromatic alcohols and its synthesis in tissues developing secondary cell walls is a significant sink for the consumption of the methyl donor S-adenosylmethionine (AdoMet). In this study, we demonstrate in Arabidopsis stems that targeted expression of AdoMet hydrolase (AdoMetase, E.C. 3.3.1.2) in secondary cell wall synthesizing tissues reduces the AdoMet pool and impacts lignin content and composition. In particular, both NMR analysis and pyrolysis gas chromatography mass spectrometry of lignin in engineered biomass showed relative enrichment of non-methylated p-hydroxycinnamyl (H) units and a reduction of dimethylated syringyl (S) units. This indicates a lower degree of methylation compared to that in wild-type lignin. Quantification of cell wall bound hydroxycinnamates revealed a reduction of ferulate in AdoMetase transgenic lines. Biomass from transgenic lines, in contrast to that in control plants, exhibits an enrichment of glucose content and a reduction in the degree of hemicellulose glucuronoxylan methylation. We also show that these modifications resulted in a reduction of cell wall recalcitrance, because sugar yield generated by enzymatic biomass saccharification was greater than that of wild-type plants. Considering that transgenic plants show no important diminution of biomass yields, and that heterologous expression of AdoMetase protein can be spatiotemporally optimized, this novel approach provides a valuable option for the improvement of lignocellulosic biomass feedstock. PMID- 27486578 TI - How Biomaterials Can Influence Various Cell Types in the Repair and Regeneration of the Heart after Myocardial Infarction. AB - The healthy heart comprises many different cell types that work together to preserve optimal function. However, in a diseased heart the function of one or more cell types is compromised which can lead to many adverse events, one of which is myocardial infarction (MI). Immediately after MI, the cardiac environment is characterized by excessive cardiomyocyte death and inflammatory signals leading to the recruitment of macrophages to clear the debris. Proliferating fibroblasts then invade, and a collagenous scar is formed to prevent rupture. Better functional restoration of the heart is not achieved due to the limited regenerative capacity of cardiac tissue. To address this, biomaterial therapy is being investigated as an approach to improve regeneration in the infarcted heart, as they can possess the potential to control cell function in the infarct environment and limit the adverse compensatory changes that occur post-MI. Over the past decade, there has been considerable research into the development of biomaterials for cardiac regeneration post-MI; and various effects have been observed on different cell types depending on the biomaterial that is applied. Biomaterial treatment has been shown to enhance survival, improve function, promote proliferation, and guide the mobilization and recruitment of different cells in the post-MI heart. This review will provide a summary on the biomaterials developed to enhance cardiac regeneration and remodeling post-MI with a focus on how they control macrophages, cardiomyocytes, fibroblasts, and endothelial cells. A better understanding of how a biomaterial interacts with the different cell types in the heart may lead to the development of a more optimized biomaterial therapy for cardiac regeneration. PMID- 27486581 TI - Next Step in Cost Containment of Public Hospital Economy Could Be Merging of Anesthesia and Surgery Budgets. PMID- 27486580 TI - Achiasmy: Male Fruit Flies Are Not Ready to Mix. AB - Maintenance of the chromosomal copy number over generations and recombination between homologous chromosomes are hallmarks of meiotic cell division. This genetic exchange that take place during gamete formation leads to genetic diversity, the main driving force behind natural selection. Formation of chiasmata, the physical link between homologous chromosomes during meiosis, is a requisite for recombination. In addition, chiasmata also aid in proper segregation of homologous chromosomes and has a major impact on reproductive fitness. Given these facts it is intriguing that many insect species have forgone the need for genetic exchange between homologous chromosomes during meiosis. Geneticists for several decades knew that meiotic crossover and recombination is absent in Drosophila males and some female lepidopterans, a condition termed achiasmy. However, a good understanding of the mechanisms that cause achiasmy and the evolutionary benefits of achiasmy is currently lacking. In this article we will discuss possible genetic and molecular basis of achiasmy in male Drosophila. PMID- 27486582 TI - Conjugative DNA Transfer Is Enhanced by Plasmid R1 Partitioning Proteins. AB - Bacterial conjugation is a form of type IV secretion used to transport protein and DNA directly to recipient bacteria. The process is cell contact-dependent, yet the mechanisms enabling extracellular events to trigger plasmid transfer to begin inside the cell remain obscure. In this study of plasmid R1 we investigated the role of plasmid proteins in the initiation of gene transfer. We find that TraI, the central regulator of conjugative DNA processing, interacts physically, and functionally with the plasmid partitioning proteins ParM and ParR. These interactions stimulate TraI catalyzed relaxation of plasmid DNA in vivo and in vitro and increase ParM ATPase activity. ParM also binds the coupling protein TraD and VirB4-like channel ATPase TraC. Together, these protein-protein interactions probably act to co-localize the transfer components intracellularly and promote assembly of the conjugation machinery. Importantly these data also indicate that the continued association of ParM and ParR at the conjugative pore is necessary for plasmid transfer to start efficiently. Moreover, the conjugative pilus and underlying secretion machinery assembled in the absence of Par proteins mediate poor biofilm formation and are completely dysfunctional for pilus specific R17 bacteriophage uptake. Thus, functional integration of Par components at the interface of relaxosome, coupling protein, and channel ATPases appears important for an optimal conformation and effective activation of the transfer machinery. We conclude that low copy plasmid R1 has evolved an active segregation system that optimizes both its vertical and lateral modes of dissemination. PMID- 27486583 TI - Age-Dependent Effects of Haptoglobin Deletion in Neurobehavioral and Anatomical Outcomes Following Traumatic Brain Injury. AB - Cerebral hemorrhages are common features of traumatic brain injury (TBI) and their presence is associated with chronic disabilities. Recent clinical and experimental evidence suggests that haptoglobin (Hp), an endogenous hemoglobin binding protein most abundant in blood plasma, is involved in the intrinsic molecular defensive mechanism, though its role in TBI is poorly understood. The aim of this study was to investigate the effects of Hp deletion on the anatomical and behavioral outcomes in the controlled cortical impact model using wildtype (WT) C57BL/6 mice and genetically modified mice lacking the Hp gene (Hp(-/-)) in two age cohorts [2-4 mo-old (young adult) and 7-8 mo-old (older adult)]. The data obtained suggest age-dependent significant effects on behavioral and anatomical TBI outcomes and recovery from injury. Moreover, in the adult cohort, neurological deficits in Hp(-/-) mice at 24 h were significantly improved compared to WT, whereas there were no significant differences in brain pathology between these genotypes. In contrast, in the older adult cohort, Hp(-/-) mice had significantly larger lesion volumes compared to WT, but neurological deficits were not significantly different. Immunohistochemistry for ionized calcium binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) revealed significant differences in microglial and astrocytic reactivity between Hp(-/-) and WT in selected brain regions of the adult but not the older adult aged cohort. In conclusion, the data obtained in the study provide clarification on the age-dependent aspects of the intrinsic defensive mechanisms involving Hp that might be involved in complex pathways differentially affecting acute brain trauma outcomes. PMID- 27486585 TI - Another milestone: Stem Cell Investigation is indexed in PubMed/PMC. PMID- 27486584 TI - Therapeutic Management of Feline Chronic Gingivostomatitis: A Systematic Review of the Literature. AB - Feline chronic gingivostomatitis (FCGS) is a disease characterized by protracted and potentially debilitating oral inflammation in cats, the etiology of which is currently unknown. The purpose of this review is to apply an evidence-based medicine approach to systematically review and critically evaluate the scientific literature reporting the outcome of medical and surgical management of FCGS. Those articles meeting inclusion criteria were reviewed and assigned an "Experimental Design Grade" (EDG) and an "Evidence Grade" (EG) in order to score relative strength of study design and produced data. Studies were evaluated and compared, especially highlighting the treatments, the outcomes, and the therapeutic success rates. This review found a lack of consistency between articles' data, rendering direct comparison of results unreliable. The field of FCGS research, and ultimately patient care, would benefit from standardizing studies by adopting use of a consistent semi-quantitative scoring system and extending follow-up duration. Future researchers should commit to large prospective studies that compare existing treatments and demonstrate the promise of new treatments. PMID- 27486586 TI - Inflammation-induced emergency megakaryopoiesis: inflammation paves the way for platelets. PMID- 27486587 TI - A rare case of the upper extremity diffuse large B-cell lymphoma mimicking soft tissue sarcoma in an elderly patient. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, with about 30% of new cases presenting with extranodal disease. Lesions originating from soft tissues of the upper extremities are extremely rare and may mimic other malignancies like sarcoma. We present a case of an elderly patient with right upper extremity (RUE) mass which was proven to be DLBCL instead of sarcoma. We emphasize the increasing need for investigating new therapeutic options for patients of extreme age and/or with underlying heart disease. PMID- 27486588 TI - Treatment of symptomatic epidermolysis bullosa simplex with botulinum toxin in a pediatric patient. PMID- 27486589 TI - Romidepsin-induced neutrophilic urticaria. PMID- 27486590 TI - Immune-related sarcoidosis observed in combination ipilimumab and nivolumab therapy. PMID- 27486591 TI - Systemic methotrexate for prurigo nodularis and keratoacanthomas in actinically damaged skin. PMID- 27486592 TI - Bowel-associated dermatosis-arthritis syndrome (BADAS) in a pediatric patient. PMID- 27486593 TI - Purpuric and cream-colored plaques in an immunocompromised person: A case of disseminated trichosporonosis. PMID- 27486594 TI - Exuberant inflammatory reaction to occlusion of topical 5-fluorouracil (FU) under a continuous positive airway pressure (CPAP) mask: A warning to dermatologists and patients. PMID- 27486595 TI - A silicon nitride ISFET based immunosensor for Ag85B detection of tuberculosis. AB - A silicon nitride Ion Sensitive Field Effect Transistor (ISFET) based immunosensor was developed as a low-cost and label-free electrical detection for the detection of antigen 85 complex B (Ag85B). The sensing membrane of the ISFET was modified with 3-aminopropyltriethoxysilane (APTES) followed by glutaraldehyde (GA), yielding an aldehyde-terminated surface. This group is available for immobilization of a monoclonal antibody against a recombinant Ag85B protein (anti Ag85B antibody). The optimal concentration for anti-Ag85B antibody immobilization onto the modified ISFET was 100 MUg ml-1. This optimal condition provided the maximal binding capability and minimal non-specific background signal. The binding event between the recombinant Ag85B antigen and anti-Ag85B antibody on the ISFET surface is presented by monitoring the gate potential change at a constant drain current. The dose response for the recombinant Ag85B protein showed a linear response between 0.12 and 1 MUg ml-1 without significant interference from other recombinant proteins. The analytical imprecision (CV%) and accuracy of this Ag85B protein biosensor were 9.73-10.99% and 95.29%, respectively. In addition, an irrelevant antibody and other recombinant proteins were employed as a negative control to demonstrate the non-specific interaction of the antigen and antibody. The success of this immunosensor system for Ag85B protein detection facilitates the construction of a promising device which can shorten the turnaround time for the diagnosis of tuberculosis compared to a standard culture method. Furthermore, this device could also be applied for real time growth monitoring of Mycobacterium tuberculosis in a mycobacterial culture system. PMID- 27486596 TI - Dyneon THV, a fluorinated thermoplastic as a novel material for microchip capillary electrophoresis. AB - In this work, we have investigated Dyneon THV, a fluorinated material, as a new material to afford electrokinetic separations in microfluidic devices. To overcome protein adsorption, two poly(ethylene oxide) (PEO)-based coatings have been investigated: Pluronic F127 and PEO stearate 40. The best results were obtained with the PEO stearate 40 coating which allowed decreasing the surface contact angle from 91 +/- 3 to 76 degrees +/- 3. With this surface treatment, a 66% reduction of the electroosmotic mobility at pH 8.0 and a marked suppression of protein adsorption were observed compared to a native Dyneon THV microchip. Finally, a separation of fluorescently labeled proteins (bovine serum albumin and trypsin inhibitor), well-known for their strong tendency to adsorb on hydrophobic surfaces, was successfully achieved in an HEPES buffer with a PEO stearate 40 treated microchip by capillary zone electrophoresis. Furthermore, we demonstrated the possibility to perform non-aqueous capillary electrophoresis analysis of hydrophobic dyes using various solvents in untreated microchips. The overall results demonstrated not only the suitability of the Dyneon THV microchip for electrokinetic separations, but also its versatility allowing different separation modes to be implemented with the same microchip material. PMID- 27486597 TI - Macro-to-micro interfacing to microfluidic channels using 3D-printed templates: application to time-resolved secretion sampling of endocrine tissue. AB - Employing 3D-printed templates for macro-to-micro interfacing, a passively operated polydimethysiloxane (PDMS) microfluidic device was designed for time resolved secretion sampling from primary murine islets and epidiymal white adipose tissue explants. Interfacing in similar devices is typically accomplished through manually punched or drilled fluidic reservoirs. We previously introduced the concept of using hand fabricated polymer inserts to template cell culture and sampling reservoirs into PDMS devices, allowing rapid stimulation and sampling of endocrine tissue. However, fabrication of the fluidic reservoirs was time consuming, tedious, and was prone to errors during device curing. Here, we have implemented computer-aided design and 3D printing to circumvent these fabrication obstacles. In addition to rapid prototyping and design iteration advantages, the ability to match these 3D-printed interface templates with channel patterns is highly beneficial. By digitizing the template fabrication process, more robust components can be produced with reduced fabrication variability. Herein, 3D printed templates were used for sculpting millimetre-scale reservoirs into the above-channel, bulk PDMS in passively-operated, eight-channel devices designed for time-resolved secretion sampling of murine tissue. Devices were proven functional by temporally assaying glucose-stimulated insulin secretion from <10 pancreatic islets and glycerol secretion from 2 mm adipose tissue explants, suggesting that 3D-printed interface templates could be applicable to a variety of cells and tissue types. More generally, this work validates desktop 3D printers as versatile interfacing tools in microfluidic laboratories. PMID- 27486598 TI - Kirsten Jackson: Aussie equine vet shares her passion for welfare. PMID- 27486599 TI - Trust and transparency in the veterinary profession. PMID- 27486601 TI - One of your SIGs is under threat. PMID- 27486600 TI - Looking like leaders. PMID- 27486602 TI - Red kite feeding at Rhayader. PMID- 27486603 TI - International Veterinary Epilepsy Task Force consensus reports. PMID- 27486604 TI - Employment and remuneration trends in 2016. PMID- 27486605 TI - New koala chlamydia vaccine trialed. PMID- 27486606 TI - Fleams added to AVA's historical collection. PMID- 27486607 TI - Leadership qualities. PMID- 27486608 TI - Australia Day Honours 2016. PMID- 27486609 TI - Highlights of our media program. PMID- 27486610 TI - Distinguished academic welcomed to senior UQ veterinary science role. PMID- 27486611 TI - Stress and non-communicable disease: a multi-pronged approach to building healthier coping skills. PMID- 27486612 TI - Conceptual review article. PMID- 27486613 TI - What qualitative research has taught us about occupational stress. AB - While many reviews of job stress and the stressor-strain relationship have been conducted, such reviews typically focus exclusively on quantitative data. In the current paper, we review qualitative studies on occupational stress that met two criteria: (1) the studies employed qualitative methods; (2) the stressors, strains and/or coping strategies were grouped into identifiable, higher-order categories. Results indicated that the nature of the stressors experienced varied by (a) occupation, (b) country, (c) seniority and (d) gender. The review further revealed that organizational constraints, work overload and interpersonal conflict were relatively universal stressors. Anger and annoyance were the most frequently reported psychological strains in the United States and the United Kingdom, while Chinese workers exhibited tension and anxiety and Indian workers exhibited acceptance. Coping strategies also varied by gender, occupation and country. Research on gender differences suggested that, compared to men, women tended to report more interpersonal stressors. Differences in the ways in which the two types of methodologies are applied, as well as their relative strengths and weaknesses, underline the value of qualitative approaches to the study of occupational stress, especially when used in conjunction with quantitative methods in mixed-methods studies. PMID- 27486614 TI - Predicting employees' well-being using work-family conflict and job strain models. AB - The present study examined the effects of two models of work-family conflict (WFC) and job-strain on the job-related and context-free well-being of employees. The participants of the study consisted of Iranian employees from a variety of organizations. The effects of three dimensions of the job-strain model and six forms of WFC on affective well-being were assessed. The results of hierarchical multiple regression analysis revealed that the number of working hours, strain based work interfering with family life (WIF) along with job characteristic variables (i.e. supervisory support, job demands and job control) all make a significant contribution to the prediction of job-related well-being. On the other hand, strain-based WIF and family interfering with work (FIW) significantly predicted context-free well-being. Implications are drawn and recommendations made regarding future research and interventions in the workplace. PMID- 27486615 TI - Coping with coping strategies: how distributed teams and their members deal with the stress of distance, time zones and culture. AB - The changing world of work is increasing demands on workers through greater need for flexibility in global collaboration. This multiple-case study uses a qualitative research approach to study context-specific job stressors and coping in ten geographically distributed work teams. Results demonstrate the complex and dynamic nature of the stress-coping process and how coping strategies, adapted to manage stress-evoking uncertainty and ambiguity in distributed work, created secondary sources of psychological strain to individuals. The main strategies for managing the uncertainty and ambiguity in the studied teams were extensive emailing, travelling to face-to-face meetings and extending workdays to collaborate simultaneously across time zones. Continuously used, these coping strategies created work overload and strain. Experienced workers, who had good self-management skills, succeeded in coping with these secondary sources of strain by prioritizing and setting clear limits for workload. Less-experienced workers were overloaded and needed more social support from their leaders and teammates. The study proposes that distributed team members rely heavily on individual coping resources, because spatial and temporal distance hinders or even precludes the mobilization of social resources related to emotional, instrumental and informational social support. PMID- 27486616 TI - Linking household income and work-family conflict: a moderated mediation study. AB - Research on the work-family interface has not often explored the role of structural characteristics such as income in the associations among work stressors, work-family conflict and family stressors. The goal of this study was to examine household income as a moderator of the relations among these variables. Results from a nationally (US) representative sample of 1472 employed individuals who were married with children indicate that the relations between work-to-family interference and family strain were stronger for individuals with lower household incomes than for those with higher household incomes. Furthermore, family strain was more strongly associated with family-to-work interference for individuals in low-income households. Household income did not moderate other relations examined in the study. Potential explanations for these moderating effects are discussed, along with their implications for the generalizability of findings in the work-family literature across contexts. PMID- 27486617 TI - Authors' Response. PMID- 27486618 TI - Social capital and psychological distress of elderly in Japanese rural communities. AB - The growing recognition of the social determinants of health has stimulated research on social capital and mental health. We explored new empirical evidence regarding whether social capital was a determinant of psychological distress. Baseline surveys examining psychological distress were conducted in two towns in 2006-2007 (participation rates for those aged 20 or over were 27.6 per cent, 6.1 per cent). We also conducted follow-up surveys in 2008 to capture the social capital measured by trust. By linking these data and excluding the missing data, 141 males and 234 females remained as the subjects of our study. Results showed that the odds ratios of psychological distress was higher in groups with low social capital measured by trust (odds ratio 2.17; 95 per cent CI, 1.40-3.36), than those in groups with high social capital. Further, we examined the interaction effect of social capital and social support. The odds ratios of psychological distress was higher in groups with some social support/lower trust (odds ratio 2.21; 95 per cent CI, 1.36-3.58) or no social support/lower trust (odds ratio 2.07; 95 per cent CI, 1.06-4.05), than those in groups with some social support/higher trust. These findings reinforce the hypothesized discussion regarding pathways from social capital to psychological distress via supportive relationships. PMID- 27486619 TI - Immobilization stress responses in adult rats exposed in utero to immobilization. AB - The present study investigated the influence of immobilization prenatal stress on adult male rats, with the same postnatal stress, on the immune parameters and its relation with plasma corticosterone (COR) and glucose levels. To study the immunity parameters, profiles of the leucocytes, size of spleen and number of the mononuclear cells of this organ were determined. Basal levels of COR and glucose were higher in prenatally stressed animals. When the adult animals were exposed to immobilization stress, COR increased but the increase was less than that for the control group, and glucose was equal in both groups. Although postnatal acute stress decreased the number of leucocytes and lymphocytes and increased the number of neutrophils, the effect was lower in prenatally stressed animals; for that reason, the ratio neutrophil/lymphocyte increased less. The number of mononuclear cells were higher in the spleen of prenatally stressed animals. This effect was probably due to retention of blood lymphocytes in the spleen. There seemed to be an alteration in the redistribution of leucocytes, both in basal conditions and under postnatal stress. The alteration of the immunological function may be partly due to an alteration in the functionality of the hypothalamic-pituitary-adrenal axis, which was hyperactive in basal conditions but appeared to suffer habituation to the same stress. PMID- 27486620 TI - Cortisol variability and self-reports in the measurement of work-related stress. AB - We examined whether a high cortisol awakening response (CAR) and low cortisol decline over the day (CDD) are related to self-reported work stress and well being, and whether there are gender differences in these relationships. Three hundred eighty-three working men and women responded to a survey measuring job stress factors, mastery at work, symptoms and well-being. Salivary cortisol was sampled at awakening, after 45 min and at 21:00, from which the variables CAR and CDD were defined. A high CAR was associated with lower perceived job control and work mastery, and poorer well-being. Low CDD was associated only with higher job demands, but the self-report scores showed a number of interactions between cortisol group and gender. Among women, those showing a low CDD, compared with those with a higher CDD, had more favourable scores on a number of job stress factors and symptom load. In contrast, among men, a similar comparison showed those with low CDD to have poorer scores on job stress factors and symptom load. We conclude that individuals displaying high CAR or low CDD differ from those not displaying these cortisol profiles in self-report of work stress and well-being, and that gender differences appear in these relationships. PMID- 27486621 TI - Lecturing to 200 students and its effects on cytokine concentration and salivary markers of adrenal activation. AB - Stress not only activates the SAM system and the hypothalamic-pituitary-adrenal axes, but also the immune system. The aims of this study are to assess the physiological variations in saliva (cytokines, cortisol and alpha-amylase) and perceived stress in professors when they had to lecture to 200 students. A total of eight unstimulated saliva samples were collected from nine professors: four on a working day that included the lecture and four controls on a working day without a lecture. The professors also rated subjective stress on a seven-point scale 5 min before the lecture, immediately after the lecture and at the same times on the control day. The lecture elicited substantial increases in subjective stress ratings, with the values on the lecture day significantly higher than those on the control day. Lecturing resulted in significant increases in Tumor Necrosis Factor (TNF)-alpha, Interleukin (IL)-2 and IL-4 concentrations, but did not affect the IL-10 values. These changes appeared to be concomitant with changes in the concentrations of the stress markers, alpha-amylase and cortisol. The mechanisms by which psychosocial stress can induce cytokine changes and modify the activity of salivary alpha-amylase are not entirely understood, and further research is thus warranted. PMID- 27486622 TI - Patient and nurse perceptions of stressors in the intensive care unit. AB - The objective of the study was to determine the perceptions of a group of patients on intensive care units' (ICUs) stressors and the perceptions of nurses on ICU patients' stressors in Turkey, and compare the differences in patients' and nurses' perception of the stressors in ICUs. In this descriptive study, 155 patients who were admitted to medical or surgical ICUs and 152 nurses who are employed in the same units of two training and research hospitals in Turkey were enrolled in this study. The ICU Environmental Stressor Scale (ICUESS) was used to determine intensive care stressors. According to total ICUESS mean scores, patients (91.41 +/- 34.91) perceived significantly less stress than the ICU nurses (133.23 +/- 32.20) perceived them to have. Both patients and nurses ranked 'fear of death' as the greatest stressor. Physiological stressors were identified as the most important stressors by both patients and nurses. Patients and nurses in medical ICUs were more affected by stressors than their counterparts in surgical ICUs. Patients with unplanned or emergency admissions perceived higher stress than that of patients with planned admissions. Several factors could help reduce these stressors, such as having familiar arrangements, humane ICU environment, individual patient assessments and appropriate nursing interventions. PMID- 27486623 TI - Age differences in strain and emotional reactivity to stressors in professional careers. AB - While age differences of workers gain increasing importance because of demographic changes in most industrialized countries, age differences in stress experience and resistance have been rarely addressed. In this initial empirical study, we explore the general relationship of age and strain as a function of three processes: (1) older workers might experience less strain because of better coping strategies; (2) older workers might experience more strain because of higher vulnerability; or (3) age and strain might be curvilinearly related with highest strain reported by middle-age workers. Using both general and experience based measures, strain and emotional reactivity to stressful job events were reported by 274 workers aged between 18 and 65 years. Results showed an inverted U-shaped relationship between age and strain experience. PMID- 27486624 TI - Adolescent girls' experiences of underlying social processes triggering stress in their everyday life: a grounded theory study. AB - The aim of this study was to generate a theoretical model of underlying social processes that trigger stress in adolescent girls' everyday life. In-depth interviews regarding the experiences of stress at home, school and during leisure time were conducted with 14 17-year-old schoolgirls. Data were analysed by means of the grounded theory method. Stress was triggered in the interaction between responsibility and the way in which the girls were encountered. Triggered emotional reactions took the form of four dimensions of stress included ambivalence, frustration, despair and downheartedness. These reactions were dependent on whether the girls voluntary assumed responsibility for various situations or whether they were forced, or felt they were being forced, to assume responsibility in interaction with an encounter characterized by closeness or distance. These forms of stress reactions could appear in one dimension and subsequently shift to another. From the public health perspective, the generated stress model can be used in the planning and implementation of future actions to prevent stress and promote well-being related to stress in adolescent girls. PMID- 27486625 TI - Work stressors and impaired sleep: rumination as a mediator. AB - An association between stress at work and impaired sleep is theoretically plausible and supported by empirical evidence. The current study's main aim was to investigate how the influence of stressors is carried over into the evening and the night. We assume that this relationship is mediated by perseverative cognitions. We tested this assumption in two cross-sectional samples with structural equation modeling, using bootstrapped standard errors to test for significance. Effort-reward imbalance and time pressure were used as stressors, and rumination as a measure for perseverative cognitions. Results show that the stressors are related to perseverative cognitions, and these are related to impaired sleep in both samples. Indirect effects are significant in both samples. With rumination controlled, direct effects of stressors on sleep are only significant in one out of four cases. Thus, there is full mediation in three out of four cases, and partial mediation in the fourth one. Our results underscore the notion that perseverative cognitions are crucial for transferring negative effects of work stressors into private life, including sleep, thus hindering individuals to successfully recover. PMID- 27486626 TI - General job performance of first-line supervisors: the role of conscientiousness in determining its effects on subordinate exhaustion. AB - In an integrated test of the job demands-resources model and trait activation theory, we predicted that the general job performance of employees who also hold supervisory roles may act as a demand to subordinates, depending on levels of subordinate conscientiousness. In a sample of 313 customer service call centre employees, we found that high-conscientiousness individuals were more likely to experience emotional exhaustion, and low-conscientiousness individuals were less likely as the general job performance of their supervisor improved. The results were curvilinear, such that high-conscientiousness individuals' exhaustion levelled off with very high supervisor performance (two standard deviations above the mean), and low-conscientiousness individuals' exhaustion levelled off as supervisor performance improved from moderate to high. These findings suggest high-conscientiousness employees may efficiently handle demands presented by a low-performing coworker who is their boss, but when performance expectations are high (i.e. high-performing boss), these achievement-oriented employees may direct their resources (i.e. energy and time) towards performance-related efforts at the expense of their well-being. Conversely, low-conscientiousness employees suffer when paired with a low-performing boss, but benefit from a supervisor who demonstrates at least moderate job performance. PMID- 27486627 TI - Mediating effects of emotional exhaustion on the relationship between job demand control model and mental health. AB - This study attempted to investigate the role of emotional exhaustion as a mediator on the relationship between job demands-control (JDC) model and mental health. Three-wave data from 297 employees were collected. The results showed that job demands were positively related to emotional exhaustion, and increasing job demands will increase the level of emotional exhaustion. Job control was negatively associated with emotional exhaustion; therefore, increasing job control will decrease the level of emotional exhaustion. Emotional exhaustion was negatively related to mental health. Emotional exhaustion fully mediated the relationship between job demands and mental health, and partially mediated the positive relationship between job control and mental health. In addition, job control was positively associated with mental health directly. The remarkable finding of the present study was that emotional exhaustion served as the key mediator between the JDC model and mental health. Theoretical and managerial implications and limitations were discussed. PMID- 27486628 TI - Gastrointestinal Tumors. PMID- 27486630 TI - WHO publishes an implementation framework on active tuberculosis drug-safety monitoring and management (ADSM). PMID- 27486629 TI - Integration of Trastuzumab, with or without Pertuzumab, into Perioperative Chemotherapy of HER2- Positive Stomach Cancer: The INNOVATION Trial (EORTC-1203 GITCG). PMID- 27486631 TI - Obituary: Professor Armando Sabbadin. PMID- 27486633 TI - Overview and Summary: Societal Violence: What is Our Response? PMID- 27486634 TI - Most important best practice? Readers say partnerships targeting readmissions. PMID- 27486632 TI - Nucleus and gene regulation. PMID- 27486635 TI - Largest business graduate schools for physician-executives. Ranked by number of full-time students; data collected January-April 2016 for the 2015-16 school year. PMID- 27486636 TI - Top Medicare supplier organizations. Ranked by 2014 Medicare payments through Part B. PMID- 27486637 TI - 2016 Dentist of the Year Dr. Andy Brown. PMID- 27486638 TI - Health Care Cyberliabilty Threats: What Email Scams Look Like and How to Avoid Them. PMID- 27486639 TI - The drug pricing racket. PMID- 27486640 TI - Empagliflozin (Jardiance). Type 2 diabetes: no rush to use this drug. AB - * In early 2016, metformin monotherapy remains the treatment of choice for most patients with type 2 diabetes. There are several alternatives for patients in whom metformin is poorly tolerated or ineffective. However, dapagliflozin and canagiflozin have an unfavourable harm-benefit balance and should not be used to enhance the action of metformin. Empagliflozin is the third glifozin to be authorised in the European Union for the treatment of type 2 diabetes. A randomised, double-blind, placebo-controlled trial of empaglifloznin, in combination with other glucose-lowering drugs, involved 7020 patients with type 2 diabetes, an average glycated haemoglobin (HbA1c) concentration of about 8%, and a history of at least one cardiovascular event. After about 3 years of follow-up, overall mortality was lower with empagliflozin (5.7% versus 8.3%, p < 0.001), mainly due to a reduction in cardiovascular mortality, particularly due to heart failure. This benefit does not seem due to efficacy in preventing the cardiovascular complications of diabetes, as there was no difference between the groups in terms of myocardial infarction or stroke. The most likely explanation is an effect in preventing other cardiovascular disorders, such as heart failure, in patients with a history of cardiovascular disorders. This is consistent with the diuretic effect of empagliflozin and its rapid impact on mortality (within a matter of months in the trial), as well as with lower exposure to cardiovascular drugs and reduction in the risk of hospital admission for heart failure. In seven comparative trials, empagliflozin had only a moderate glucose-lowering action: among patients with an average baseline HbA1c of about 8%, the HbA1c fell by about 0.5% more with empagliflozin than with placebo. An even smaller effect was reported in patients with renal impairment. Empagliflozin shares the adverse effects of other gliflozins, including genital infections, kidney failure, and diabetic ketoacidosis. Empagliflozin may also be hepatotoxic. A risk of cancer (especially bladder cancer) cannot be ruled out. Empagliflozin interacts with nephrotoxic drugs, which aggravate its adverse effects and decrease its hypoglycaemic potency. The diuretic action of empagliflozin can lead to volume depletion and a fail in blood pressure, especially during co-administration with other diuretics or antihypertensive drugs. In practice, empagliflozin was found to reduce mortality in a clinical trial involving patients with type 2 diabetes and significant cardiovascular risk factors. This benefit does not seem to be related to the hypoglycaemic effect of empagliflozin or to prevention of the cardiovascular complications of diabetes, but rather to prevention of heart failure in patients with history of cardiovascular disease. In early 2016, it is unclear which patients are most likely to derive a concrete benefit from empagliflozin therapy. Comparative evaluation must continue, especially in patients with heart failure. PMID- 27486641 TI - Apremilast (Otezla). No progress in plaque psoriasis or psoriatic arthritis. AB - When PUVA therapy and immunosuppressants such as methotrexate are ineffective, TNF alpha antagonists are an option for patients with severe plaque psoriasis, in the absence of a better alternative. This is also the case for patients with psoriatic arthritis after failure of a "disease-modifying" antirheumatic drug. Apremilast, an oral immunosuppressant that inhibits phosphodiesterase type 4, has been authorised in the European Union for use in these settings. In patients with plaque psoriasis, oral apremilast was compared with subcutaneous etanercept, aTNF alpha antagonist, in a randomised, doubleblind, placebo-controlled trial lasting 16 weeks and involving 250 patients in whom other treatments had failed or were inappropriate. This trial failed to show that apremilast was more effective than etanercept. And about one-quarter more patients experienced symptom relief compared with placebo. In patients with psoriatic arthritis, there are no clinical trials comparing apremilast with TNF alpha antagonists, and no interpretable trials of apremilast after failure of a TNF alpha antagonist. In three randomised, double-blind trials including a total of 1493 patients treated for 16 weeks, at least a modest improvement in joint status was reported in about 35% of patients treated with apremilast versus 19% with placebo. This would suggest that apremilast is less effective than a TNF alpha antagonist. In the trial versus etanercept, serious adverse events occurred in 3.6% of patients treated with apremilast versus 1.2% of those treated with the TNF alpha antagonist. The main adverse effects of apremilast are diarrhoea, nausea and vomiting, headache, sometimes marked weight loss, and infections. A risk of depression and cardiac arrhythmia must also be taken into account. A risk of cancer in the long-term is likely, given the immunosuppressive action of apremilast. Apremilast is a substrate of cytochrome P450 isoenzyme 3A4 and accumulates in patients with renal failure. This creates a risk of multiple pharmacokinetic interactions. PMID- 27486643 TI - COMMON STEM. -astine. PMID- 27486642 TI - Efavirenz in children. Minimal evaluation. PMID- 27486645 TI - Azithromycin: pyloric stenosis in neonates. PMID- 27486644 TI - Sympathomimetic decongestants during pregnancy: risks for the unborn child. AB - In addition to the risk of cardiovascular events and neurological disorders, sympathomimetic decongestants have teratogenic potential, albeit weak, when taken during the first trimester of pregnancy, probably through disruption of the vascular system of the embryo and the pregnant woman. In the second and third trimesters of pregnancy, the fetus is exposed to the same adverse effects as the mother. PMID- 27486646 TI - Sofosbuvir: bradycardia. PMID- 27486647 TI - Bisphosphonates: osteonecrosis of the external auditory canal. PMID- 27486648 TI - Oral mucositis associated with cancer therapy. Guide to first-choice treatments. PMID- 27486650 TI - Pulmonary embolism and thrombolysis. AB - A meta-analysis of studies including about 2000 patients with pulmonary embolism suggests that thrombolysis slightly reduces overall mortality at one month in patients under 65 but increases the number of major bleeding events, including intracranial haemorrhage. PMID- 27486649 TI - Pneumococcal conjugate vaccine: do not routinely vaccinate adults aged 65 years and older. AB - A randomised placebo-controlled trial of 13-valent pneumococcal conjugate vaccine was conducted in about 84 500 adults aged 65 years and older, with no particular risk factors. Four years on average after vaccination, there was no reduction in either mortality or the overall incidence of community-acquired pneumonia. It was necessary to vaccinate about 1000 individuals in order to prevent one case of vaccine-type pneumococcal pneumonia during the 4-year follow-up period. PMID- 27486651 TI - Drug packaging in 2015: risky industry choices and lax regulation. AB - Prescrire examined the packaging quality of 240 drugs in 2015. No new advances were identified, but drug packaging continues to expose patients to a variety of dangers. Some past advances persist: for example, INNs are often more legible, and recent patient leaflets tend to be clearer and more informative. But these measures are not applied to all drugs, and are rarely applied retroactively to older drugs. The overall picture in 2015 is that many drugs are difficult to identify, risky or downright dangerous to prepare, or supplied with patient leaflets that fail to correctly inform patients about their medication. And measures to prevent drug poisoning in children need to be completely rethought. It is high time for regulators and policy makers to take the issue of drug packaging seriously, so blatant are the signs of their failure to do so: the increasing use of bulk bottles for new drugs; failure to implement guidelines on safe drug packaging (unit-dose presentations, appropriate dosing devices, etc.); and expanding umbrella brands which, given the dangers they pose to patients, should be banned instead. All things considered, healthcare professionals and patients must remain vigilant and report any dangers they identify. A major European initiative on drug packaging is becoming increasingly necessary. PMID- 27486652 TI - Patient leaflet for Harvoni (sofosbuvir + ledipasvir): almost no information on adverse effects. PMID- 27486653 TI - Andrew Herxheimer: medicine for the people. PMID- 27486654 TI - The finances of Association Mieux Prescrire: 2015 Prescrire annual report. PMID- 27486655 TI - Fetoscopic Endoluminal Tracheal Occlusion in Fetuses with Severe Diaphragmatic Hernia: A Three-Year Single-Center Experience. AB - OBJECTIVE: To report on our experience in the prenatal treatment of severe congenital diaphragmatic hernia (CDH) by fetoscopic endoluminal tracheal occlusion (FETO). METHODS: Between 2012 and 2014, FETO was performed at our center in 21 cases of CDH considered to be severe based on sonographic measurement of observed/expected lung-to-head ratio (O/E LHR) and side of the defect. We reported pre- and postoperative ultrasound findings, procedure-related complications, pregnancy outcome and survival at 1-3 years of age. RESULTS: The median gestational age (GA) at balloon insertion was 28.1 weeks (range 26.0-31.1) and the median GA at delivery 34.7 weeks (range 31.6-39.0); delivery before 32 and 34 weeks occurred in 2 (9.5%) and 7 (33.3%) cases, respectively. Postnatal survival at 1-3 years of age in the 17 cases with isolated unilateral CDH was 47.1%. The percentage difference between pre-balloon removal O/E LHR and pre-FETO O/E LHR was significantly higher in survivors compared to neonates who died (40.8 vs. 21.2%, respectively; p < 0.05). CONCLUSIONS: In this study, FETO was associated with an infant survival of 47% in cases with isolated unilateral severe CDH. The post-FETO increase in O/E LHR was higher in fetuses that survived compared to those who died. PMID- 27486656 TI - Induction of Connective Tissue Growth Factor Expression by Hypoxia in Human Lung Fibroblasts via the MEKK1/MEK1/ERK1/GLI-1/GLI-2 and AP-1 Pathways. AB - Several reports have indicated that hypoxia, GLI, and connective tissue growth factor (CTGF) contribute to pulmonary fibrosis in idiopathic pulmonary fibrosis. We investigated the participation of mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1)/MEK1/ERK1/GLI-1/2 and activator protein-1 (AP-1) signaling in hypoxia-induced CTGF expression in human lung fibroblasts. Hypoxia time dependently increased CTGF expression, which was attenuated by the small interfering RNA (siRNA) of GLI-1 (GLI-1 siRNA) and GLI-2 (GLI-2 siRNA) in both human lung fibroblast cell line (WI-38) and primary human lung fibroblasts (NHLFs). Moreover, GLI-1 siRNA and GLI-2 siRNA attenuated hypoxia-induced CTGF luciferase activity, and the treatment of cells with hypoxia induced GLI-1 and GLI-2 translocation. Furthermore, hypoxia-induced CTGF expression was reduced by an MEK inhibitor (PD98059), MEK1 siRNA, ERK inhibitor (U0126), ERK1 siRNA, and MEKK1 siRNA. Both PD98059 and U0126 significantly attenuated hypoxia-induced CTGF luciferase activity. Hypoxia time-dependently increased MEKK1, ERK, and p38 MAPK phosphorylation. Moreover, SB203580 (a p38 MAPK inhibitor) also apparently inhibited hypoxia-induced CTGF expression. The treatment of cells with hypoxia induced ERK, GLI-1, or GLI-2 complex formation. Hypoxia-induced GLI-1 and GLI-2 translocation into the nucleus was significantly attenuated by U0126. In addition, hypoxia-induced ERK Tyr204 phosphorylation was impeded by MEKK1 siRNA. Moreover, hypoxia-induced CTGF-luciferase activity was attenuated by cells transfected with AP-1 site mutation in a CTGF construct. Exposure to hypoxia caused a time-dependent phosphorylation of c-Jun, but not of c-Fos. Chromatin immunoprecipitation (ChIP) revealed that hypoxia induced the recruitment of c Jun, GLI-1, and GLI-2 to the AP-1 promoter region of CTGF. Hypoxia-treated cells exhibited an increase in alpha-smooth muscle actin (alpha-SMA) and collagen production, which was blocked by GLI-1 siRNA and GLI-2 siRNA. Overall, these data implied that the MEKK1/MEK1/ERK1/GLI-1/GLI-2, and AP-1 pathways mediated hypoxia induced CTGF expression in human lung fibroblasts. Furthermore, GLI-1 and GLI-2 found to be involved in hypoxia-induced alpha-SMA and collagen expression. PMID- 27486657 TI - Increased Echogenicity and Radiodense Foci on Echocardiogram and MicroCT in Murine Myocarditis. AB - OBJECTIVES: To address the question as to whether echocardiographic and/or microcomputed tomography (microCT) analysis can be utilized to assess the extent of Coxsackie B virus (CVB) induced myocarditis in the absence of left ventricular dysfunction in the mouse. BACKGROUND: Viral myocarditis is a significant clinical problem with associated inflammation of the myocardium and myocardial injury. Murine models of myocarditis are commonly used to study the pathophysiology of the disease, but methods for imaging the mouse myocardium have been limited to echocardiographic assessment of ventricular dysfunction and, to a lesser extent, MRI imaging. METHODS: Using a murine model of myocarditis, we used both echocardiography and microCT to assess the extent of myocardial involvement in murine myocarditis using both wild-type mice and CVB cleavage-resistant dystrophin knock-in mice. RESULTS: Areas of increased echogenicity were only observed in the myocardium of Coxsackie B virus infected mice. These echocardiographic abnormalities correlated with the extent of von Kossa staining (a marker of membrane permeability), inflammation, and fibrosis. Given that calcium phosphate uptake as imaged by von Kossa staining might also be visualized using microCT, we utilized microCT imaging which allowed for high-resolution, 3 dimensional images of radiodensities that likely represent calcium phosphate uptake. As with echocardiography, only mice infected with Coxsackie B virus displayed abnormal accumulation of calcium within individual myocytes indicating increased membrane permeability only upon exposure to virus. CONCLUSIONS: These studies demonstrate new, quantitative, and semi-quantitative imaging approaches for the assessment of myocardial involvement in the setting of viral myocarditis in the commonly utilized mouse model of viral myocarditis. PMID- 27486659 TI - The Distribution of Climate Change Public Opinion in Canada. AB - While climate scientists have developed high resolution data sets on the distribution of climate risks, we still lack comparable data on the local distribution of public climate change opinions. This paper provides the first effort to estimate local climate and energy opinion variability outside the United States. Using a multi-level regression and post-stratification (MRP) approach, we estimate opinion in federal electoral districts and provinces. We demonstrate that a majority of the Canadian public consistently believes that climate change is happening. Belief in climate change's causes varies geographically, with more people attributing it to human activity in urban as opposed to rural areas. Most prominently, we find majority support for carbon cap and trade policy in every province and district. By contrast, support for carbon taxation is more heterogeneous. Compared to the distribution of US climate opinions, Canadians believe climate change is happening at higher levels. This new opinion data set will support climate policy analysis and climate policy decision making at national, provincial and local levels. PMID- 27486658 TI - Natalizumab Affects T-Cell Phenotype in Multiple Sclerosis: Implications for JCV Reactivation. AB - The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects. PMID- 27486660 TI - Effect of Novel, School-Based High-Intensity Interval Training (HIT) on Cardiometabolic Health in Adolescents: Project FFAB (Fun Fast Activity Blasts) - An Exploratory Controlled Before-And-After Trial. AB - BACKGROUND: Low-volume high-intensity interval training holds promise for cardiometabolic health promotion in adolescents, but sustainable interventions must be practical and engaging. We examined the effect of a school-based multi activity low-volume high-intensity interval training intervention on adolescents' cardiometabolic health. METHODS: In an exploratory controlled before-and-after design, 101 adolescents (mean age +/- standard deviation [SD] 14.0 +/- 0.3 years) were recruited from four schools; two were designated as intervention sites (n = 41), and two as control (n = 60). The intervention comprised 4 to 7 repetitions of 45 s maximal effort exercise (basketball, boxing, dance and soccer drills) interspersed with 90-s rest, thrice weekly for 10 weeks. Outcomes were non fasting blood lipids and glucose, waist circumference, high sensitivity C reactive protein, resting blood pressure, physical activity, twenty-metre shuttle run test performance and carotid artery intima-media thickness. The difference in the change from baseline (intervention minus control) was estimated for each outcome. Using magnitude-based inferences, we calculated the probability that the true population effect was beneficial, trivial, and harmful against a threshold for the minimum clinically important difference of 0.2 between-subject SDs. RESULTS AND DISCUSSION: Mean (+/- SD) attendance for the intervention (expressed as percentage of available intervention sessions [n = 30]) was 77 +/- 13%. Post intervention, there were likely beneficial effects for triglycerides (-26%; 90% confidence interval -46% to 0%), waist circumference (-3.9 cm; -6.1 cm to -1.6 cm) and moderate-to-vigorous physical activity (+16 min; -5 to 38 min), and a possibly beneficial effect for twenty-metre shuttle-run test performance (+5 shuttles; -1 to 11 shuttles) in intervention participants (vs controls). The role of elevated triglycerides and waist circumference in cardiovascular disease and metabolic syndrome development underlines the importance of our findings. We also demonstrated that school-based low-volume high-intensity interval training can be delivered as intended, thus representing a novel and scalable means of improving aspects of adolescents' cardiometabolic health. TRIAL REGISTRATION: ClinicalTrials.gov NCT02626767. PMID- 27486661 TI - Tourniquet Test for Dengue Diagnosis: Systematic Review and Meta-analysis of Diagnostic Test Accuracy. AB - BACKGROUND: Dengue fever is a ubiquitous arboviral infection in tropical and sub tropical regions, whose incidence has increased over recent decades. In the absence of a rapid point of care test, the clinical diagnosis of dengue is complex. The World Health Organisation has outlined diagnostic criteria for making the diagnosis of dengue infection, which includes the use of the tourniquet test (TT). PURPOSE: To assess the quality of the evidence supporting the use of the TT and perform a diagnostic accuracy meta-analysis comparing the TT to antibody response measured by ELISA. DATA SOURCES: A comprehensive literature search was conducted in the following databases to April, 2016: MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials, BIOSIS, Web of Science, SCOPUS. STUDY SELECTION: Studies comparing the diagnostic accuracy of the tourniquet test with ELISA for the diagnosis of dengue were included. DATA EXTRACTION: Two independent authors extracted data using a standardized form. DATA SYNTHESIS: A total of 16 studies with 28,739 participants were included in the meta-analysis. Pooled sensitivity for dengue diagnosis by TT was 58% (95% Confidence Interval (CI), 43%-71%) and the specificity was 71% (95% CI, 60%-80%). In the subgroup analysis sensitivity for non-severe dengue diagnosis was 55% (95% CI, 52%-59%) and the specificity was 63% (95% CI, 60% 66%), whilst sensitivity for dengue hemorrhagic fever diagnosis was 62% (95% CI, 53%-71%) and the specificity was 60% (95% CI, 48%-70%). Receiver-operator characteristics demonstrated a test accuracy (AUC) of 0.70 (95% CI, 0.66-0.74). CONCLUSION: The tourniquet test is widely used in resource poor settings despite currently available evidence demonstrating only a marginal benefit in making a diagnosis of dengue infection alone. REGISTRATION: The protocol for this systematic review was registered at PROSPERO: CRD42015020323. PMID- 27486662 TI - Focal and Generalized Patterns of Cerebral Cortical Veins Due to Non-Convulsive Status Epilepticus or Prolonged Seizure Episode after Convulsive Status Epilepticus - A MRI Study Using Susceptibility Weighted Imaging. AB - OBJECTIVE: The aim of this study was to investigate variant patterns of cortical venous oxygenation during status epilepticus (SE) using susceptibility-weighted imaging (SWI). METHODS: We analyzed magnetic resonance imaging (MRI) scans of 26 patients with clinically witnessed prolonged seizures and/or EEG-confirmed SE. All MRI exams encompassed SWI, dynamic susceptibility contrast perfusion MRI (MRI DSC) and diffusion-weighted imaging (DWI). We aimed to identify distinct patterns of SWI signal alterations that revealed regional or global increases of cerebral blood flow (CBF) and DWI restrictions. We hypothesized that SWI-related oxygenation patterns reflect ictal or postictal patterns that resemble SE or sequelae of seizures. RESULTS: Sixteen patients were examined during nonconvulsive status epilepticus (NCSE) as confirmed by EEG, a further ten patients suffered from witnessed and prolonged seizure episode ahead of imaging without initial EEG. MRI patterns of 15 of the 26 patients revealed generalized hyperoxygenation by SWI in keeping with either global or multifocal cortical hyperperfusion. Eight patients revealed a focal hyperoxygenation pattern related to focal CBF increase and three patients showed a focal deoxygenation pattern related to focal CBF decrease. CONCLUSIONS: SWI-related hyper- and deoxygenation patterns resemble ictal and postictal CBF changes within a range from globally increased to focally decreased perfusion. In all 26 patients the SWI patterns were in keeping with ictal hyperperfusion (hyperoxygenation patterns) or postictal hypoperfusion (deoxygenation patterns) respectively. A new finding of this study is that cortical venous patterns in SWI can be not only focally, but globally attenuated. SWI may thus be considered as an alternative contrast-free MR sequence to identify perfusion changes related to ictal or postictal conditions. PMID- 27486663 TI - Kinetic Study of Acetone-Butanol-Ethanol Fermentation in Continuous Culture. AB - Acetone-butanol-ethanol (ABE) fermentation by clostridia has shown promise for industrial-scale production of biobutanol. However, the continuous ABE fermentation suffers from low product yield, titer, and productivity. Systems analysis of the continuous ABE fermentation will offer insights into its metabolic pathway as well as into optimal fermentation design and operation. For the ABE fermentation in continuous Clostridium acetobutylicum culture, this paper presents a kinetic model that includes the effects of key metabolic intermediates and enzymes as well as culture pH, product inhibition, and glucose inhibition. The kinetic model is used for elucidating the behavior of the ABE fermentation under the conditions that are most relevant to continuous cultures. To this end, dynamic sensitivity analysis is performed to systematically investigate the effects of culture conditions, reaction kinetics, and enzymes on the dynamics of the ABE production pathway. The analysis provides guidance for future metabolic engineering and fermentation optimization studies. PMID- 27486664 TI - Detection and Characterization of Low Temperature Peat Fires during the 2015 Fire Catastrophe in Indonesia Using a New High-Sensitivity Fire Monitoring Satellite Sensor (FireBird). AB - Vast and disastrous fires occurred on Borneo during the 2015 dry season, pushing Indonesia into the top five carbon emitting countries. The region was affected by a very strong El Nino-Southern Oscillation (ENSO) climate phenomenon, on par with the last severe event in 1997/98. Fire dynamics in Central Kalimantan were investigated using an innovative sensor offering higher sensitivity to a wider range of fire intensities at a finer spatial resolution (160 m) than heretofore available. The sensor is onboard the TET-1 satellite, part of the German Aerospace Center (DLR) FireBird mission. TET-1 images (acquired every 2-3 days) from the middle infrared were used to detect fires continuously burning for almost three weeks in the protected peatlands of Sebangau National Park as well as surrounding areas with active logging and oil palm concessions. TET-1 detection capabilities were compared with MODIS active fire detection and Landsat burned area algorithms. Fire dynamics, including fire front propagation speed and area burned, were investigated. We show that TET-1 has improved detection capabilities over MODIS in monitoring low-intensity peatland fire fronts through thick smoke and haze. Analysis of fire dynamics revealed that the largest burned areas resulted from fire front lines started from multiple locations, and the highest propagation speeds were in excess of 500 m/day (all over peat > 2m deep). Fires were found to occur most often in concessions that contained drainage infrastructure but were not cleared prior to the fire season. Benefits of implementing this sensor system to improve current fire management techniques are discussed. Near real-time fire detection together with enhanced fire behavior monitoring capabilities would not only improve firefighting efforts, but also benefit analysis of fire impact on tropical peatlands, greenhouse gas emission estimations as well as mitigation measures to reduce severe fire events in the future. PMID- 27486666 TI - Nd:YAG Laser Treatment for Extranasal Telangiectasias: A Retrospective Analysis of 38 Patients with Hereditary Hemorrhagic Telangiectasia and Review of the Literature. AB - BACKGROUND/AIMS: Extranasal telangiectasias are common amongst hereditary hemorrhagic telangiectasia (HHT) patients. Telangiectasias can be found at sites like the external nose, lips, oral cavity and fingers. Although not life threatening, they can be annoying for patients and lead to bleeding in some cases, necessitating treatment. METHODS: The data of 38 HHT patients treated for extranasal telangiectasias during a period of 10 years by means of Nd:YAG laser were retrospectively analyzed. RESULTS: The telangiectasias treated affected predominantly the tongue, facial skin and lips. During a minimum follow-up of 3 years, only 7 patients required a revision of surgery. CONCLUSION: This study shows that Nd:YAG laser constitutes a fast, safe and efficient therapeutic modality for the treatment of extranasal telangiectasias. PMID- 27486667 TI - Significant Association between Toll-Like Receptor Gene Polymorphisms and Posttransplantation Diabetes Mellitus. AB - BACKGROUND: Posttransplantation diabetes mellitus (PTDM) is an important metabolic complication after renal transplantation. Activation of the innate immune system via toll-like receptors (TLRs) is implicated in the pathogenesis of insulin resistance and deficiency. Although links between diabetes, dysregulated innate immune responses, and the TLR signaling pathway have been reported, no study so far has investigated their associations with PTDM. In this study, we ascertained whether single nucleotide polymorphisms (SNPs) in TLRs are associated with PTDM in the Korea population. METHODS: A total of 305 patients who received renal transplants without previously diagnosed diabetes were included. We analyzed the association between PTDM development and 6 SNPs within 2 genes of TLR2, 1 gene of TLR4, and 3 genes of TRL6. RESULTS: Of 305 patients, PTDM developed in 51 patients (16.6%). Patients in the PTDM group were older than those in the non-PTDM group (45.56 +/- 1.28 vs. 38.28 +/- 0.71 years). Patients with PTDM had significantly higher allele frequency compared to those without PTDM for the TLR4 rs1927914*T, TLR6 rs3775073*A, TLR6 rs3821985*C, and TLR6 rs1039559*C alleles. Of the 6 SNPs, rs1927914 in the TLR4 gene and rs1039559 in the TLR6 gene were significantly associated with the development of PTDM after adjustment for age, gender, and tacrolimus usage. CONCLUSIONS: Our study demonstrates a significant association between SNPs rs1927914 in TLR4 and rs1039559 in TLR6 and PTDM in the renal transplantation recipient group. These data suggest that the activation of the innate immune system and inflammation via TLR activation might have an essential role in the pathogenesis of PTDM in renal transplantation. PMID- 27486665 TI - Temporal Dynamics of CD8+ T Cell Effector Responses during Primary HIV Infection. AB - The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution. Selective expression of the effector-associated transcription factors T-bet and eomesodermin in cytokine-producing HIV-specific CD8+ T cells differentiated HIV-specific from bulk memory CD8+ T cell effector expansion. As infection progressed expression of perforin was maintained in HIV specific CD8+ T cells with high levels of T-bet, but not necessarily in the population of T-betLo HIV-specific CD8+ T cells that expand as infection progresses. Together, these data demonstrate that while HIV-specific CD8+ T cells in acute HIV infection initially possess cytolytic potential, progressive transcriptional dysregulation leads to the reduced CD8+ T cell perforin expression characteristic of chronic HIV infection. PMID- 27486668 TI - Is It Desirable that I Must Disclose My Genetic Data to Swiss Private Medical Insurances? AB - Genetic testing has far-reaching consequences, not only in terms of immediate patient management and the wider implications for the patient and their families, but also with respect to disclosure to insurance companies. The focus of this review is the controversial but important topic of the use of genetic data in private medical insurance. We discuss the current legal regulation of genetic data in the context of Swiss insurance, what type(s) of information is relevant to insurance companies, and why 'genetic exceptionalism' (the notion that genetic data has special status) persists. Furthermore, we discuss the sensitive area of handling genetic data from children. The consequences of legal regulation of disclosure of genetic information are considered, particularly from the economic perspective. Finally, we examine how legal conditions correspond to current insurance practice and contrast the Swiss system with the handling of genetic data in other countries in the context of private insurance. Switzerland has adopted fairly 'laissez-faire' regulations compared to other countries, and the public need education on the potential effects of genetic testing on their insurance, especially with respect to direct-to-consumer genetic testing, where there is no consultation from a qualified doctor, or when minors are involved. PMID- 27486670 TI - Deep-Red and Near-Infrared Xanthene Dyes for Rapid Live Cell Imaging. AB - In this work, two xanthene dyes (H-hNR and TF-hNR) have been synthesized by a convenient and efficient method. These two dyes exhibited deep-red and near infrared emissions, high fluorescence quantum yields, and good photostability. Their structure-optical properties were investigated by X-ray crystal structure analysis and density functional theory calculations. Live cell imaging data revealed that H-hNR and TF-hNR could rapidly stain both A549 and HeLa cells with low concentrations. The excellent photophysical and imaging properties render them as promising candidates for use in live cell imaging. PMID- 27486671 TI - Relationship between mechanical properties and crystal structure in cocrystals and salt of paracetamol. AB - Objectives were to study mechanical properties of various solid forms of paracetamol and relate to their crystal structures. Paracetamol form I (PRA), its cocrystals with oxalic acid (PRA-OXA) and 4,4-bipyridine (PRA-BPY) and hydrochloride salt (PRA-HCL) were selected. Cocrystals and salt were scaled-up using rational crystallization methods. The resulting materials were subjected to different solid-state characterizations. The powders were sieved and 90-360 um sieve fraction was considered. These powders were examined by scanning electron microscopy (SEM) and densities were determined. Tablets were made at applied pressures of 35-180 MPa under controlled conditions and the tablet height, diameter and hardness were measured. Tensile strength and porosity of the tablets were estimated using well known models. Crystal structures of these systems were visualized and slip planes were identified. Cocrystal and salt of PRA were physically pure. Sieved powders had comparable morphologies and particle size. The apparent and theoretical densities of powders were similar, but no clear trends were observed. The tensile strengths of these compacts were increased with increasing pressure whereas tabletability decreased in the order oxalic acid > PRA-HCL ~ PRA-OXA > BPY > PRA-BPY. Tablet tensile strength decreases exponentially with increasing porosity with the exception of PRY-BPY and BPY. Slip plane prediction based on attachment energies may not be independently considered. However, it was possible to explain the improved mechanical properties of powders based on the crystal structure. Cocrystallization and salt formation have introduced structural features that are responsible for improved tableting properties of PRA. PMID- 27486669 TI - Risk of Invasive Meningococcal Disease in Men Who Have Sex with Men: Lessons Learned from an Outbreak in Germany, 2012-2013. AB - BACKGROUND: We undertook investigations in response to an invasive meningococcal disease (IMD) outbreak in men who have sex with men (MSM) in Berlin 2012-2013 to better understand meningococcal transmission and IMD risk in MSM. METHODS: We retrospectively searched for further IMD cases in MSM in Germany through local health departments and undertook exploratory interviews. We performed antigen sequence typing, characterized fHbp and aniA genes of strains with the outbreak finetype and reviewed epidemiologically or spatiotemporally linked cases from 2002-2014. RESULTS: Among the 148 IMD-cases notified from 01.01.2012-30.09.2013 in 18-59 year-old men we identified 13 MSM in 6 federal states: 11 serogroup C (MenC, all finetype C:P1.5-1,10-8:F3-6), 2 MenB. Interviews with 7 MSM revealed frequent meeting of multiple partners online or via mobile apps and illicit drug use as potential risk factors. MenC incidence was 13-fold higher in MSM than non MSM. MenC isolates from 9/11 MSM had a novel fHbp allele 766. All C:P1.5-1,10 8:F3-6 strains from MSM versus 16/23 from non-MSM had intact aniA genes (p = 0.04). Although definitive evidence for transmission among MSM in epidemiological or spatiotemporal clusters in 2002-2014 was lacking, clusters were more frequent in men aged 20-49 years. Molecular analysis of C:P1.5-1,10-8:F3-6 strains revealed cases with intact aniA since 2007, mainly associated with fHbp361, fHbp766 and fHbp813, all involving one or more MSM. CONCLUSIONS: MenC incidence was elevated in MSM during the study period. Multiple casual sexual contacts and illicit drug use were common in affected MSM. In all strains from MSM we detected an intact aniA gene coding for a nitrite reductase, which permits survival in microanaerobic environments and could play a role in meningococcal transmission in MSM through urogenital colonization. Furthermore, meningococcal transmission among MSM may be sustained over large areas and thus require modified spatiotemporal scanning algorithms for timely detection and control. PMID- 27486672 TI - Active Somatic and Psychic Ear Acupuncture Points in Newborn Infants with Neonatal Abstinence Syndrome. AB - BACKGROUND: Neonatal abstinence syndrome (NAS) occurs within the first days after birth in newborns of mothers with a history of drug abuse. It may also occur in newborns whose mothers are undergoing substitution therapy. OBJECTIVE: To determine the presence of active ear acupuncture points in newborn infants with NAS. METHODS: Among newborn infants with NAS admitted to the Division of Neonatology at the University Hospital Graz between March 2009 and November 2014, an acupuncture-point detector (PS3 Silberbauer, Vienna, Austria) was used to identify active ear acupuncture points. An integrated optical and acoustical signal detects the ear points, which were then assigned to the ear map. A total of 31 newborn infants were assessed; 1 infant was excluded, however, because the mother had already weaned herself off opiates before admission. RESULTS: The excluded infant did not develop signs of NAS, had a low Finnegan score (3 points), and did not present any detectable active psychic ear acupuncture points. In all included newborn infants with NAS, active ear acupuncture points were identified: The psychovegetative rim was the most common active somatic area in each infant, followed by a few somatic and psychic ear acupuncture points. In all infants with symptoms of NAS, active psychic ear points were identified, of which the most frequently found points were the Frustration point and the R point. CONCLUSION: The activity of psychic ear acupuncture points may be specific for neonates with NAS. PMID- 27486673 TI - Pyclen Tri-n-butylphosphonate Ester as Potential Chelator for Targeted Radiotherapy: From Yttrium(III) Complexation to (90)Y Radiolabeling. AB - The Y(3+) complex of PCTMB, the tri-n-butyl phosphonate ester of pyclen (3,6,9,15 tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene), was synthesized as well as its Ho(3+) and Lu(3+) analogues. X-ray diffraction analyses revealed isomorphous dimeric M2(PCTMB)2.9H2O (M = Y, Ho, Lu) structures that crystallize in the centrosymmetric P1 triclinic space group. (1)H NMR and UV studies in aqueous solutions indicated that Y(3+) complexation is fast, being quantitative in 167 min at pH 3.8 and in 13 min at pH 5.5 (25 degrees C, acetate buffer, I = 0.150 M, [Y(3+)] = [PCTMB] = 0.2 mM). (1)H NMR DOSY and photon correlation spectroscopy experiments evidenced the formation of aggregates in chloroform with a bimodal distribution that changes slightly with concentration (11-24 and 240-258 nm). The behavior of the acid-assisted dissociation of the complex of Y(3+) with PCTMB was studied under pseudo-first-order conditions, and the half-life of the [Y(PCTMB)] complex in 0.5 M HCl at 25 degrees C was found to be 37 min, a value that decreases to 2.6 min in 5 M HCl. The Y(3+) complex of PCTMB is thermodynamically very stable, with a stability constant of log KY-PCTMB = 19.49 and pY = 16.7 measured by potentiometry. (90)Y complexation studies revealed fast radiolabeling kinetics; optimal radiolabeling conditions were obtained for (90)Y in acetate medium, PCTMB at 10(-4) to 10(-2) M in acetate buffer pH = 4.75, 15 min at 45-60 degrees C. In vitro stability studies in human serum showed that [(90)Y(PCTMB)] is quite stable, with about 90% of the activity still in the form of the radiotracer at 24 h and 80% from 48 h to 72 h. A comparison with other ligands such as PCTA, DOTA, and DTPA already used for in vivo application shows that [(90)Y(PCTMB)] is an interesting lipophilic and neutral analogue of these reference chelates for therapeutic applications in aqueous and nonaqueous media. PMID- 27486674 TI - Total Synthesis of Leupyrrin B1: A Potent Inhibitor of Human Leukocyte Elastase. AB - The total synthesis of leupyrrin B1 was accomplished by an expedient strategy that involves an optimized HATU-mediated amide coupling protocol of elaborate substrates. The generally useful procedure was also successfully applied in an improved total synthesis of leupyrrin A1. Finally, leupyrrins A1 and B1 were evaluated toward a panel of proteases, and human leukocyte elastase was discovered as a molecular target of the leupyrrins. PMID- 27486675 TI - Influence of Water on the Interfacial Nanostructure and Wetting of [Rmim][NTf2] Ionic Liquids at Mica Surfaces. AB - The effect of water concentration on the interfacial nanostructure and wetting behavior of a family of ionic liquids (ILs), 1-alkyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide, [Rmim][NTf2], at the surface of mica was investigated by contact angle measurement and atomic force microscopy (AFM). AFM reveals that interfacial layers of ILs observed at the surface of mica for "dry" ILs are not present for water-saturated ILs. The interaction of the IL ions of [Rmim][NTf2] with water molecules through hydrogen bonding is suspected to disrupt IL ion layering and precursor film growth on mica. Without the IL precursor film, contact angle relaxation of "wet" ILs on mica is less significant and ambient vapor adsorption becomes more important in determining the macroscopic wetting behavior. PMID- 27486676 TI - Neuroprotection by intravenous transplantation of bone marrow mononuclear cells from 5-fluorouracil pre-treated rats in a model of ischemic stroke. AB - Our previous studies showed that bone marrow mononuclear cells (BMMNCs) from 5 fluorouracil (5-FU) pre-treated rats (named BMRMNCs) had a better therapeutic efficacy in ischemia/reperfusion rats as compared to BMMNCs from untreated rats. This study was undertaken to further explore the potential mechanisms underlying the neuroprotective effects of BMRMNCs in the same model. Rats were intravenously pre-treated with 5-FU, and BMRMNCs were collected 7 days later and subjected to flow cytometry for detection of CD34, CD45 and CD90. Middle cerebral artery occlusion (MCAO) was induced in rats, and BMMNCs and BMRMNCs were independently transplanted via the tail vein at 24 h after MCAO. NISSL staining was performed 14 days after cell transplantation and the viable cells in the hippocampus were counted. Stromal cell-derived factor 1 (SDF-1) mRNA expression was detected in the penumbra at 7 and 14 days after treatment. The contents of pro-inflammatory cytokines and growth factors as well as microvessel density (MVD) were determined at 14 days. Results showed more BMRMNCs were positive for CD34, CD45 and CD90. After transplantation, more viable cells were observed in the hippocampus of BMRMNCs treated rats. In addition, BMRMNCs transplantation significantly increased MVD, reduced pro-inflammatory cytokines and raised growth factors in the penumbra. However, the SDF-1 mRNA expression was comparable between BMRMNCs group and BMMNCs group. Our results indicate that BMRMNCs are likely to more effectively improve the local microenvironment to increase viable cells and elevate angiogenesis, exerting neuroprotective effects on cerebral ischemia in rats. PMID- 27486677 TI - An evaluation of the effectiveness of self-management interventions for people with type 2 diabetes after an acute coronary syndrome: a systematic review. AB - BACKGROUND: Type 2 diabetes is highly prevalent in patients with acute coronary syndrome and impacts negatively on health outcomes and self-management. Both conditions share similar risk factors. However, there is insufficient evidence on the effectiveness of combined interventions to promote self-management behaviour for people with diabetes and cardiac problems. Identifying critical features of successful interventions will inform future integrated self-management programmes for patients with both conditions. OBJECTIVES: To assess the evidence on the effectiveness of existing interventions to promote self-management behaviour for patients presenting with acute coronary syndrome and type 2 diabetes in secondary care settings and postdischarge. DESIGN: We searched MEDLINE, PubMed, CINAHL Plus, PsycInfo, Cochrane Library and AMED for randomised controlled trials published between January 2005-December 2014. The search was performed using the following search terms of 'acute coronary syndrome', 'type 2 diabetes' and 'self management intervention' and their substitutes combined. RESULTS: Of 4275 articles that were retrieved, only four trials met all the inclusion criteria (population, intervention, comparison and outcome) and were analysed. Overall, the results show that providing combined interventions for patients with both conditions including educational sessions supported by multimedia or telecommunication technologies was partially successful in promoting self management behaviours. Implementation of these combined interventions during patient's hospitalisation and postdischarge was feasible. Intervention group subjects reported a significant improvement in self-efficacy, level of knowledge, glycated haemoglobin, blood pressure and fasting glucose test. However, there are many threats have been noticed around internal validity of included studies that could compromise the conclusions drawn. CONCLUSION: With limited research in this area, there was no final evidence to support effectiveness of combined interventions to promote self-management behaviour for patients with type 2 diabetes and acute coronary syndrome. Sufficiently powered, good quality, well conducted and reported randomised controlled trials are required. PMID- 27486679 TI - Writing Out Loud: To Computers, Patients, and Burnout, 2016. PMID- 27486680 TI - Cutting the cost of carbon capture: a case for carbon capture and utilization. AB - A significant part of the cost for carbon capture and storage (CCS) is related to the compression of captured CO2 to its supercritical state, at 150 bar and typically 99% purity. These stringent conditions may however not always be necessary for specific cases of carbon capture and utilization (CCU). In this manuscript, we investigate how much the parasitic energy of an adsorbent-based carbon capture process may be lowered by utilizing CO2 at 1 bar and adapting the final purity requirement for CO2 from 99% to 70% or 50%. We compare different CO2 sources: the flue gases of coal-fired or natural gas-fired power plants and ambient air. We evaluate the carbon capture performance of over 60 nanoporous materials and determine the influence of the initial and final CO2 purity on the parasitic energy of the carbon capture process. Moreover, we demonstrate the underlying principles of the parasitic energy minimization in more detail using the commercially available NaX zeolite. Finally, the calculated utilization cost of CO2 is compared with the reported prices for CO2 and published costs for CCS. PMID- 27486678 TI - Gender and Alcohol Use Disorders Diagnostic Criteria in Emergency Department Patients of Argentina. AB - BACKGROUND: Alcohol consumption and its related consequences are not equal for women and men, although related studies do not frequently include gender analysis. OBJECTIVE: Our aim was to characterize differences in endorsement of ICD-10 and DSM 5 alcohol use disorder (AUD) criteria by gender in an Argentinean emergency department population. METHODS: A probability sample of patients (N = 923) from the largest emergency department in the city of Mar del Plata, Argentina (44% were females, aged 16 to 86, M (SD) = 37.31(15.20) was collected. Using a structured questionnaire, diagnostic criteria for alcohol use disorders, alcohol consumption, and socio-demographic variables were obtained. Bivariate and multivariate analyses were used to assess differences in the endorsement of each diagnostic criterion by gender. RESULTS: Women were less likely to endorse each of the criteria for each of the diagnostic schemes. Even after controlling alcohol consumption, socio-demographic variables, severity of alcohol use disorders and adjusting for multiple comparisons females had a lower probability than males of endorsing withdrawal and impaired control. CONCLUSIONS: gender differences in the endorsement of diagnostic criteria for both the DSM 5 and ICD 10 were found. Some differences in endorsement but not all, might be partially explained by alcohol consumption patterns and socio-demographic factors, and same remained after controlling severity of the AUD. Results also suggest a differential functioning of DSM 5 and ICD-10 AUD criteria for women and men. PMID- 27486681 TI - Exercise therapy in patients with hip osteoarthritis: Effect on hip muscle strength and safety aspects of exercise-results of a randomized controlled trial. AB - PURPOSE: To evaluate the effect of an exercise therapy concept (the Tubingen exercise therapy approach THuKo) for increasing hip muscle strength (HMS) in patients with hip osteoarthritis (OA), and to investigate whether patients do adhere to the intervention and if there are any adverse events related to the intervention. METHODS: A total of 210 hip OA patients (89 females, 121 males) were randomized into a 12-week exercise intervention (THuKo) including group sessions (1/week) and home exercising (2/week), a placebo ultrasound group (1/week) or a control group (no treatment). HMS was measured as isometric peak torque of hip abduction, adduction, flexion, and extension. Adherence to exercise and safety aspects were monitored as additional outcomes. RESULTS: Baseline adjusted post intervention HMS of the THuKo group were higher compared to the control group (differences of 0.11-0.27 Nm/kg, p < 0.01) and to the placebo ultrasound group (differences of 0.09-0.19 Nm/kg, p < 0.01). Adherence to exercise was high (about 90%). No subject had to refuse from training because of an exercise related adverse event and exercise related pain was only of intermittent nature without sustainable adverse effects. CONCLUSIONS: The Tubingen exercise therapy approach has shown to have a significant positive effect on HMS. Its implementation has shown to be feasible and safe according to the percentage of exercise participation and the absence of sustainable adverse events. PMID- 27486682 TI - Hematopoiesis in Bivalvia larvae: Cellular origin, differentiation of hemocytes, and neoplasia. AB - Hemocytes play vital roles in the immune response. Despite progress in the characterization of molluscan hemocytes and immune cells, including their cellular receptors and signal transduction pathways, the processes that lead to their differentiation in bivalve larvae remain unknown. Furthermore, the molecular mechanisms of that decide hemocyte stem cell fate and self-renewal during development remain poorly characterized. Similar to adult mollusks, the larvae are filter feeders and are highly susceptible to pathogens and biotoxins; therefore, it is important to understand the development and function of their immune system. This review summarizes the current data on the appearance of elements of the immune system in bivalve larvae. I have discussed why the immune cells emerge before the circular blood vessel system, which differentiates at the late stages of development. I also discuss how molluscan hemocytes are involved in the development of disseminated neoplasia. PMID- 27486683 TI - Leukocyte susceptibility and immune response against Vibrio parahaemolyticus in Totoaba macdonaldi. AB - Vibrio parahaemolyticus is a serious pathogen that affects aquaculture. Nonetheless, to the best of our knowledge, no studies have focused on its immunological implications in Totoaba macdonaldi. Thus, the early immune response to V. parahaemolyticus in juveniles of totoaba was studied at 24 h post-infection with an in vivo study. In addition, changes in cellular innate immune parameters phagocytosis, respiratory burst activity and viability (annexin V/propidium iodide) - were evaluated in vitro in head-kidney, spleen and thymus leukocytes at 6 and 24 h after bacterial stimulation by flow cytometry. Simultaneously, the expression levels of two immune-relevant genes (IL-1beta and IL-8) were measured by using real time PCR. During in vivo study, mRNA transcripts of IL-1beta were highly expressed in spleen, thymus and intestine and down-regulated in liver after 24 h post-infection. IL-8 gene expression was upregulated in spleen, intestine and liver compared to that of non-infected fish and down-regulated in thymus after 24 h post-infection. Generally, the results showed a significant decrease in cellular immune responses during the infection, principally in phagocytic ability and respiratory burst. The survival or viability of stimulated leukocytes was significantly reduced causing necrosis and apoptosis, indicating a robust killing response by V. parahaemolyticus. Finally the in vitro analysis showed that transcript levels of IL-1beta and IL-8 were up-regulated during stimulation with V. parahaemolyticus in head-kidney, spleen and intestine and down-regulated in thymus at any time of the experiment. Although V. parahaemolyticus has been reported to be an important pathogen for many aquatic organisms, to our knowledge this might be the first report of early-immune response in juvenile totoaba and these immune parameters may be reliable indicators and can be useful in the health control of this species. PMID- 27486684 TI - Origin of the Enhancement of the Second Hyperpolarizabilities of Metal-Carbon Bonds. AB - The spin-unrestricted coupled-cluster method was employed to investigate the origin of the second hyperpolarizabilities (gamma) in model systems involving metal-carbon bonds with various bond lengths as a function of their diradical character (y) and charge transfer (CT). These systems exhibit unique features: (i) sigma electrons give the dominant contribution to gamma, (ii) the pi electrons contribution to gamma is negative, (iii) when the bond length increases, gamma exhibits two positive extrema, which are associated with the CT nature and the intermediate diradical character, respectively, (iv) and one negative extremum corresponding to intermediate CT and diradical character, and (v) in the bond stretching process, the maximum gamma amplitude per sigma bond is about 7 times larger than that per pi bond. These features are significantly different from those observed in pure organic systems. PMID- 27486685 TI - An expanded framework for biomolecular visualization in the classroom: Learning goals and competencies. AB - A thorough understanding of the molecular biosciences requires the ability to visualize and manipulate molecules in order to interpret results or to generate hypotheses. While many instructors in biochemistry and molecular biology use visual representations, few indicate that they explicitly teach visual literacy. One reason is the need for a list of core content and competencies to guide a more deliberate instruction in visual literacy. We offer here the second stage in the development of one such resource for biomolecular three-dimensional visual literacy. We present this work with the goal of building a community for online resource development and use. In the first stage, overarching themes were identified and submitted to the biosciences community for comment: atomic geometry; alternate renderings; construction/annotation; het group recognition; molecular dynamics; molecular interactions; monomer recognition; symmetry/asymmetry recognition; structure-function relationships; structural model skepticism; and topology and connectivity. Herein, the overarching themes have been expanded to include a 12th theme (macromolecular assemblies), 27 learning goals, and more than 200 corresponding objectives, many of which cut across multiple overarching themes. The learning goals and objectives offered here provide educators with a framework on which to map the use of molecular visualization in their classrooms. In addition, the framework may also be used by biochemistry and molecular biology educators to identify gaps in coverage and drive the creation of new activities to improve visual literacy. This work represents the first attempt, to our knowledge, to catalog a comprehensive list of explicit learning goals and objectives in visual literacy. (c) 2016 by The International Union of Biochemistry and Molecular Biology, 45(1):69-75, 2017. PMID- 27486688 TI - Spike gene deletion quasispecies in serum of patient with acute MERS-CoV infection. AB - The spike glycoprotein of the Middle East respiratory coronavirus (MERS-CoV) facilitates receptor binding and cell entry. During investigation of a multi facility outbreak of MERS-CoV in Taif, Saudi Arabia, we identified a mixed population of wild-type and variant sequences with a large 530 nucleotide deletion in the spike gene from the serum of one patient. The out of frame deletion predicted loss of most of the S2 subunit of the spike protein leaving the S1 subunit with an intact receptor binding domain. This finding documents human infection with a novel genetic variant of MERS-CoV present as a quasispecies. J. Med. Virol. 89:542-545, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27486689 TI - APS - Diagnostics and challenges for the future. AB - Diagnosis of antiphospholipid syndrome (APS) is essentially based on the detection of circulating antiphospholipid (aPL) antibodies. Progress have been made on the standardization of tests exploring the presence of aPL as guidelines on coagulation and immunological tests were recently published in the literature. Clinical relevance of aPL profile has come from prospective cohort studies in populations with a homogeneous antibody profile supporting the view that triple positivity is a high risk pattern in patients and carriers. In addition to the classic ones, several other tests have been proposed for the diagnosis of APS. The detection of antibodies directed to domain 1 and 4/5 of beta2-Glycoprotein I (beta2GP1) were found to be particularly sound. Several issues remain to be addressed. We do not yet know what is the physiological function of beta2GP1 and the pathophysiology of thrombosis and pregnancy loss in these patients. Moreover, treatment is poorly defined especially in the case of feared catastrophic APS. PMID- 27486687 TI - FBXW7 is involved in the acquisition of the malignant phenotype in epithelial ovarian tumors. AB - FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, such as c-Myc, cyclin E, Notch and c-Jun. FBXW7 is a known tumor-suppressor gene, and mutations in FBXW7 have been reported in various human malignancies. In this study, we examined the sequences of the FBXW7 and p53 genes in 57 ovarian cancer clinical samples. Interestingly, we found no FBXW7 mutations associated with amino acid changes. We also investigated FBXW7 expression levels in 126 epithelial ovarian tumors. FBXW7 expression was negatively correlated with the malignant potential of ovarian tumors. That is to say, FBXW7 expression levels in ovarian cancer samples were significantly lower than those in borderline and benign tumors (P < 0.01). FBXW7 expression levels in serous carcinoma samples were the lowest among four major histological subtypes. In addition, p53-mutated ovarian cancer samples showed significantly lower levels of FBXW7 expression compared with p53 wild-type cancer samples (P < 0.001). DNA methylation arrays and bisulfite PCR sequencing experiments revealed that 5'-upstream regions of FBXW7 gene in p53-mutated samples were significantly higher methylated compared with those in p53 wild-type samples (P < 0.01). This data indicates that p53 mutations might suppress FBXW7 expression through DNA hypermethylation of FBXW7 5'-upstream regions. Thus, FBXW7 expression was downregulated in ovarian cancers, and was associated with p53 mutations and the DNA methylation status of the 5' upstream regions of FBXW7. PMID- 27486686 TI - Quantitative Proteomic Analysis Reveals Similarities between Huntington's Disease (HD) and Huntington's Disease-Like 2 (HDL2) Human Brains. AB - The pathogenesis of HD and HDL2, similar progressive neurodegenerative disorders caused by expansion mutations, remains incompletely understood. No systematic quantitative proteomics studies, assessing global changes in HD or HDL2 human brain, were reported. To address this deficit, we used a stable isotope labeling based approach to quantify the changes in protein abundances in the cortex of 12 HD and 12 control cases and, separately, of 6 HDL2 and 6 control cases. The quality of the tissues was assessed to minimize variability due to post mortem autolysis. We applied a robust median sweep algorithm to quantify protein abundance and performed statistical inference using moderated test statistics. 1211 proteins showed statistically significant fold changes between HD and control tissues; the differences in selected proteins were verified by Western blotting. Differentially abundant proteins were enriched in cellular pathways previously implicated in HD, including Rho-mediated, actin cytoskeleton and integrin signaling, mitochondrial dysfunction, endocytosis, axonal guidance, DNA/RNA processing, and protein transport. The abundance of 717 proteins significantly differed between control and HDL2 brain. Comparative analysis of the disease-associated changes in the HD and HDL2 proteomes revealed that similar pathways were altered, suggesting the commonality of pathogenesis between the two disorders. PMID- 27486690 TI - Proliferative Nodules vs Melanoma Arising in Giant Congenital Melanocytic Nevi During Childhood. AB - Importance: The differential diagnosis between proliferative nodules (PNs) and melanoma arising in congenital melanocytic nevi (CMN) is crucial, as patients with PNs most often experience no increased risk of melanoma with metastases and death. Objective: To analyze the utility of immunohistochemistry and fluorescence in situ hybridization (FISH) in distinguishing PNs from childhood and adult-onset melanoma arising in CMN. Design, Setting, and Participants: A case series was conducted from June 29, 1989, to November 12, 2009, of 13 children with PNs arising in CMN in childhood and 5 children with melanomas arising in CMN in childhood. Five patients with giant CMN with no nodules were included as negative controls, and 6 patients with melanomas arising in CMN in adulthood were included as positive controls. Follow-up ranged from 3 to 21 years in all children (mean, 9.9 years) and from 3 months to 7 years in adults. Specimens were selected for immunohistochemistry and FISH. All histopathologic sections were reviewed by 2 dermatopathologists who examined all nodules arising at different ages in the same patient and, in the case of melanoma, all locations. Data analysis was performed from January 1, 2013, to January 31, 2015. Main Outcomes and Measures: The ability to distinguish melanoma from PN using immunohistochemistry and/or FISH. Results: Of the 13 patients (5 boys and 8 girls) with PNs present at birth, all PNs were stable (mean follow-up, 9 years). Eight patients with PNs and 4 of 5 patients with childhood-onset melanoma showed homogeneous staining for HMB45, while heterogeneous staining for HMB45 was seen in 3 of 6 patients with adult onset melanoma. Expression of p16 was strongly positive in most patients with childhood-onset PNs (10 of 11 patients) and melanoma (all patients) but negative in 4 patients with adult-onset melanoma. Patients with PNs and the 5 patients with childhood-onset melanoma had numerical chromosomal aberrations never observed in the adjacent CMN. The 2 children with FISH-positive PNs are melanoma free after 7 and 4 years. Only 1 patient with childhood-onset melanoma had a FISH aberration compared with 4 patients with adult-onset melanoma. Conclusions and Relevance: Immunohistochemistry and the 4-probe FISH melanoma analysis are not useful for distinguishing PN from childhood-onset melanoma as opposed to adult onset melanoma. Numerical anomalies seen in PNs but not in the adjacent CMN could be the result of a chromosomal segregation malfunction resulting in the development of nodules. PMID- 27486691 TI - Phenolic content, antioxidant capacity and antimicrobial activity of leaf extracts from Pistacia atlantica. AB - The aim of this study was to investigate the secondary metabolites related to Pistacia atlantica Desf as well as their biological activities. Results show that using ethanol as a solvent exhibited the highest content of total phenolics and flavonoids (68.23 mg GAE g-1 of DW and 44 mg RE g-1 of DW), followed by aqueous one (20.07 mg GAE g-1 of DW and 15 mg RE g-1 of DW). Good correlation (Data not shown) was obtained between the DPPH radical-scavenging activities and total phenolics contents. Many similarities were observed between the results of the DPPH (IC50 = 32 and 200 MUg mL-1) and ABTS (IC50 = 42 and 300 MUg mL-1) assays. All tested extracts contained phenolic compounds exhibited an antimicrobial effect against Gram-positive and Gram-negative bacteria. Further, researches for identification and purification of phenolic compounds are required. PMID- 27486692 TI - ? PMID- 27486693 TI - ? PMID- 27486694 TI - ? PMID- 27486695 TI - Phage display as a tool to discover blood-brain barrier (BBB)-shuttle peptides: panning against a human BBB cellular model. AB - Most potential drugs for the treatment of central nervous system disorders do not cross the blood-brain barrier (BBB). Much research effort has been devoted to the discovery of new BBB-shuttle peptides-most of which have been identified by phage display. Here we report for the first time on the use of phage display against a human BBB cellular model which mimics the characteristics of the BBB. From the panning experiment of a 12-mer library, the SGVYKVAYDWQH (SGV) peptide sequence was selected and its permeability validated in the aforementioned model. Furthermore, internalization studies suggested that SGV internalizes through a clathrin-mediated mechanism and that it increases the uptake of a cargo in endothelial cells. These results highlight the usefulness of in vitro BBB models for the discovery of BBB-shuttle peptides through phage display libraries. PMID- 27486696 TI - Optimizing Venous Thromboembolic Prophylaxis: Is Thromboelastography the Answer? PMID- 27486697 TI - Polynanocrystalline Graphite: A New Carbon Anode with Superior Cycling Performance for K-Ion Batteries. AB - We synthesized a new type of carbon-polynanocrystalline graphite-by chemical vapor deposition on a nanoporous graphenic carbon as an epitaxial template. This carbon is composed of nanodomains being highly graphitic along c-axis and very graphenic along ab plane directions, where the nanodomains are randomly packed to form micron-sized particles, thus forming a polynanocrystalline structure. The polynanocrystalline graphite is very unique, structurally different from low dimensional nanocrystalline carbon materials, e.g., fullerenes, carbon nanotubes, and graphene, nanoporous carbon, amorphous carbon and graphite, where it has a relatively low specific surface area of 91 m2/g as well as a low Archimedes density of 0.92 g/cm3. The structure is essentially hollow to a certain extent with randomly arranged nanosized graphite building blocks. This novel structure with disorder at nanometric scales but strict order at atomic scales enables substantially superior long-term cycling life for K-ion storage as an anode, where it exhibits 50% capacity retention over 240 cycles, whereas for graphite, it is only 6% retention over 140 cycles. PMID- 27486698 TI - Worse quality of life in young and recently diagnosed breast cancer survivors compared with female survivors of other cancers: A cross-sectional study. AB - Literature focusing on health-related quality of life (HRQoL) by cancer site among women only is scarce. This study examines HRQoL of breast cancer (BC) survivors compared with female survivors of other cancers, and to understand which subgroups of BC survivors were particularly at risk of reduced HRQoL. We placed emphasis on young (<50 years) and recently diagnosed (<=5 years) survivors, where the deficits in HRQoL were most pronounced. The cross-sectional study consisted of 2,224 BC survivors, 8,504 non-cancer controls and 2,205 other cancer survivors in the Karma study. We examined HRQoL differences using linear regression analyses in the whole cohort and in a subset of young and recently diagnosed BC survivors (n = 242) and female survivors of other cancers (n = 140) with comparable ages at diagnosis (43.6 vs 43.6, p = 0.917) and time since diagnosis (2.3 vs 2.8 years, p < 0.001). HRQoL was assessed using the EORTC QLQ C30 questionnaire. While only cognitive functioning was significantly compromised in BC survivors compared with survivors of other cancers when women of all ages were included, young BC survivors reported significantly lower HRQoL on multiple functional scales (global quality of life, emotional, role, social and cognitive functioning) and experienced more fatigue and insomnia. BC survivors with any prior medical history of mental disorders reported poorer HRQoL than those without such a history. We also observed a close-knit relationship between tumor and treatment characteristics. BC survivors perform poorly in HRQoL in comparison with female survivors of other cancers. Our results emphasize the importance of age- and gender-appropriate comparison groups. PMID- 27486700 TI - Addressing the stroke evidence-treatment gap. PMID- 27486699 TI - Predicting unfolding thermodynamics and stable intermediates for alanine-rich helical peptides with the aid of coarse-grained molecular simulation. AB - This report focuses on the molecular-level processes and thermodynamics of unfolding of a series of helical peptides using a coarse-grained (CG) molecular model. The CG model was refined to capture thermodynamics and structural changes as a function of temperature for a set of published peptide sequences. Circular dichroism spectroscopy (CD) was used to experimentally monitor the temperature dependent conformational changes and stability of published peptides and new sequences introduced here. The model predictions were quantitatively or semi quantitatively accurate in all cases. The simulations and CD results showed that, as expected, in most cases the unfolding of helical peptides is well described by a simply 2-state model, and conformational stability increased with increased length of the helices. A notable exception in a 19-residue helix was when two Ala residues were each replaced with Phe. This stabilized a partly unfolded intermediate state via hydrophobic contacts, and also promoted aggregates at higher peptide concentrations. PMID- 27486701 TI - Effect of improved contact on reliability of sub-60 nm carbon nanotube vias. AB - Advances in semiconductor technology due to the aggressive downward scaling of on chip feature sizes have led to rapid rises in the resistivity and current density of interconnect conductors. As a result, current interconnect materials, Cu and W, are subject to performance and reliability constraints approaching or exceeding their physical limits. Therefore, alternative materials are being actively considered as potential replacements to meet such constraints. The carbon nanotube (CNT) is among the leading replacement candidates for on-chip interconnect vias due to its high aspect-ratio nanostructure and superior current carrying capacity to Cu and W, as well as other potential candidates. Based on the results for 40 nm and 60 nm top-contact metallized CNT vias, we demonstrate that not only are their current-carrying capacities two orders of magnitude higher than their Cu and W counterparts, they are enhanced by reduced via resistance due to contact engineering facilitated by the first reported contact resistance extraction scheme for a 40 nm linewidth. PMID- 27486702 TI - Cerebrospinal fluid cytokines in the diagnosis of bacterial meningitis in infants. AB - BACKGROUND: Bacterial meningitis poses diagnostic challenges in infants. Antibiotic pretreatment and low bacterial density diminish cerebrospinal fluid (CSF) culture yield, while laboratory parameters do not reliably identify bacterial meningitis. Pro and anti-inflammatory cytokines are elevated in bacterial meningitis and may be useful diagnostic adjuncts when CSF cultures are negative. METHODS: In a prospective cohort study of infants, we used cytometric bead arrays to measure tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL 1), IL-6, IL-8, IL-10, and IL-12 in CSF. Receiver operating characteristic (ROC) analyses and Principal component analysis (PCA) were used to determine cytokine combinations that identified bacterial meningitis. RESULTS: Six hundred and eighty four infants < 6 mo were included; 11 had culture-proven bacterial meningitis. IL-6 and IL-10 were the individual cytokines possessing greatest accuracy in diagnosis of culture proven bacterial meningitis (ROC analyses; area under the concentration-time curve (AUC) 0.91; 0.9103 respectively), and performed as well as, or better than combinations identified using ROC and PCA. CSF cytokines were highly correlated with each other and with CSF white blood cell count (WBC) counts in infants with meningitis. A subset of antibiotic pretreated culture-negative subjects demonstrated cytokine patterns similar to culture positive subjects. CONCLUSION: CSF cytokine levels may aid diagnosis of bacterial meningitis, and facilitate decision-making regarding treatment for culture negative meningitis. PMID- 27486703 TI - Altered Treg and cytokine responses in RSV-infected infants. AB - BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in children under 1 y of age in the USA. The host immune response is believed to contribute to RSV-induced disease. We hypothesize that severe RSV infection in infants is mediated by insufficient regulation of the host immune response of regulatory T cells (Tregs) resulting in immunopathology. METHODS: Blood and nasal aspirates from 23 RSV-infected and 17 control infants under 1 y of age were collected. Treg frequencies were determined by flow cytometry from peripheral blood mononuclear cells. Analysis of 24 cytokines was measured by multiplex assay on nasal aspirates. RESULTS: We demonstrate that the frequency of activated Tregs is significantly reduced in the peripheral blood of RSV-infected infants compared with age-matched controls. Surprisingly, T helper (Th)17 related cytokines including interleukin (IL)-1beta, IL-17A, and IL-23 were associated with a reduction in clinical symptoms of respiratory distress. In addition, the amount of IL-33 protein in nasal washes, a cytokine important in maintaining Treg homeostasis in mucosal tissues, was decreased in RSV-infected children. CONCLUSION: These results suggest that decreased Treg numbers and an inability to properly control the host inflammatory response results in severe RSV infection. PMID- 27486704 TI - Assessment of pedometer accuracy in capturing habitual types of physical activities in overweight and obese children. AB - BACKGROUND: Currently, there is a limited amount of research exploring physical activity measurement tools in overweight and obese (OW/OB) children using pedometers. Thus, our objective was to determine the accuracy of one spring levered (SC-T2) and two piezoelectric pedometers (NL-1000 and Piezo) in OW/OB children. METHODS: A total of 26 boys and 34 girls (n = 60) participated. Pedometer step-counts were compared to observed step counts for walking (walking, stair ascent and decent) and hopping tests. Pedometer accuracies were compared with Friedman tests while Bland-Altman plots were used to establish the accuracy of each pedometer against direct observations. RESULTS: Boys (n = 26) and females (n = 34) were 96 and 91% OB, respectively. The two piezoelectric pedometers (NL 1000 and Piezo) were accurate for walking and stair climbing tasks, however all pedometers were inaccurate for hopping tests. Averaged over all three walking activities, the NL-1000 was the most accurate with 6.7% median error (interquartile range (IQR): 0.0-13.3); followed by the Piezo with 10.0% median error (IQR: 3.3-18.1); SC-T2 was the least accurate with -14.7% median error (IQR: -54.8-3.5). CONCLUSION: These results support the use of the piezoelectric pedometers for walking and stair climbing types of activities, which are typical for OW/OB children in a nonlaboratory setting. PMID- 27486705 TI - Colitis, independent of macronutrient intake, compromises bone structure and strength in growing piglets. AB - BACKGROUND: Deterioration in bone health is a concern in managing pediatric inflammatory bowel diseases, but clear understanding of the independent contributions of disease and nutrition is lacking. This study aimed to ascertain whether bone health could be conserved during colitis by maintaining adequate nutritional intake in growing piglets. METHODS: The effect of colitis on bone structure and strength was determined in piglets with dextran sulphate sodium induced colitis. Piglets received either 100% macro/micronutrient requirements or 50% macro/100% micronutrient requirements. Femurs were analyzed for dual-energy x ray absorptiometry, peripheral quantitative computed tomography, microcomputed tomography, and 3-point bending tests. RESULTS: Colitis, regardless of a well nourished or malnourished diet, compromised areal bone mineral density (-17%) and volumetric bone mineral density (-20%) in cortical and trabecular bone. Structural integrity at mid-diaphysis was maintained during colitis; however, lower cortical area, trabecular area, and bone mineral content resulted in lower energy to break. CONCLUSION: Colitis compromises both bone structure and strength of long bones in piglets, independent of macronutrient intakes. Although confirmation of these findings in pediatric cohorts is needed, these data identify aspects of bone health that may be affected by inflammatory bowel disease. PMID- 27486706 TI - Workplace wellness using online learning tools in a healthcare setting. AB - The aim was to develop and evaluate an online learning tool for use with UK healthcare employees, healthcare educators and healthcare students, to increase knowledge of workplace wellness as an important public health issue. A 'Workplace Wellness' e-learning tool was developed and peer-reviewed by 14 topic experts. This focused on six key areas relating to workplace wellness: work-related stress, musculoskeletal disorders, diet and nutrition, physical activity, smoking and alcohol consumption. Each key area provided current evidence-based information on causes and consequences, access to UK government reports and national statistics, and guidance on actions that could be taken to improve health within a workplace setting. 188 users (93.1% female, age 18-60) completed online knowledge questionnaires before (n = 188) and after (n = 88) exposure to the online learning tool. Baseline knowledge of workplace wellness was poor (n = 188; mean accuracy 47.6%, s.d. 11.94). Knowledge significantly improved from baseline to post-intervention (mean accuracy = 77.5%, s.d. 13.71) (t(75) = 14.801, p < 0.0005) with knowledge increases evident for all included topics areas. Usability evaluation showed that participants perceived the tool to be useful (96.4%), engaging (73.8%) and would recommend it to others (86.9%). Healthcare professionals, healthcare educators and pre-registered healthcare students held positive attitudes towards online learning, indicating scope for development of further online packages relating to other important health parameters. PMID- 27486707 TI - Care Transitions in Childhood Cancer Survivorship: Providers' Perspectives. AB - PURPOSE: Most adolescent and young adult (AYA)-aged childhood cancer survivors develop physical and/or psychosocial sequelae; however, many do not receive long term follow-up (LTF) critical for screening, prevention, and treatment of late effects. To develop a health services research agenda to optimize care models, we conducted qualitative research with LTF providers examining existing models, and successes and challenges in maintaining survivors' connections to care across their transition to adulthood. METHODS: We interviewed 20 LTF experts (MDs, RNs, social workers, education specialists, psychologists) from 10 Children's Oncology Group-affiliated institutions, and analyzed data using grounded theory and content analysis techniques. RESULTS: Participants described the complexity of survivors' healthcare transitions. Survivors had pressing educational needs in multiple domains, and imparting the need for prevention was challenging. Multidisciplinary LTF teams focused on prevention and self-management. Care and decisions about transfer were individualized based on survivors' health risks, developmental issues, and family contexts. An interplay of provider and institutional factors, some of which were potentially modifiable, also influenced how transitions were managed. Interviewees rarely collaborated with community primary care providers to comanage patients. Communication systems and collective norms about sharing care limited comanagement capacity. Interviewees described staffing practices, policies, and informal initiatives they found reduced attrition. CONCLUSIONS: Results suggest that survivors will benefit from care models that better connect patients, survivorship experts, and community providers for uninterrupted LTF across transitions. We propose research priorities, framing attrition from LTF as a public health concern, transition as the central challenge in LTF, and transition readiness as a multilevel concept. PMID- 27486708 TI - Screening of Toxic Effects of Bisphenol A and Products of Its Degradation: Zebrafish (Danio rerio) Embryo Test and Molecular Docking. AB - Bisphenol A (BPA) acts as an endocrine-disrupting compound even at a low concentration. Degradation of BPA could lead to the formation of toxic products. In this study, we compare the toxicity of BPA and seven intermediate products of its degradation. The accuracy of three molecular docking programs (Surflex, Autodock, and Autodock Vina) in predicting the binding affinities of selected compounds to human (ERalpha, ERbeta, and ERRgamma) and zebrafish (ERalpha, ERRgammaA, and ERRgammaB) estrogen and estrogen-related receptors was evaluated. The docking experiments showed that 4-isopropylphenol could have similar toxicity to that of BPA due to its high affinity to ERRgamma and ERRgammaB and high octanol-water partitioning coefficient. The least toxic compounds were hydroquinone and phenol. Those compounds as well as BPA were screened in the zebrafish (Danio rerio) embryo test. 4-isopropylphenol had the strongest toxic effect on zebrafish embryos and caused 100% lethality shortly after exposure. BPA caused the delay in development, multiple deformations, and low heartbeats (30 bps), whereas hydroquinone had no impact on the development of the zebrafish embryo. Thus, the results of zebrafish screening are in good agreement with our docking experiment. The molecular docking could be used to screen the toxicity of other xenoestrogens and their products of degradation. PMID- 27486709 TI - [Polonia Medyczna: struktura, wspolczesnosc i przyszlosc]. AB - It is estimated that approximately 20-25 000 polish physicians practice medicine in different countries outside of Poland, enriching medical workforces in their newly elected countries. The composition of this group, known as "Medical Polonia", has been changing from post Second World War emigration, resulting from the war and its political consequences, thru the next large wave of physicians leaving the communist country in 1980's. The last large group of Polish physicians has taken advantage of training opportunities or have started practices in the European Union, having departed Poland permanently or temporarily, after the country joined the European Union in 2004. The first organizations of Polish physicians outside of Poland were founded almost immediately after WWII in London, Chicago, New York, Paris, Lille, and later in Stockholm. Decades later, re-invigorated by their native country gaining independence after 1989, they organized the first World Congress of Medical Polonia in 1991 (in collaboration with physicians' organization from Poland). The World Federation of Polish Medical Organization Abroad was then established in 1994. Subsequently, many organizations joined the Federation, including several from newly liberated countries of former Soviet Union. The Federation of Polish Medical Organizations and its member societies actively promotes medical education, collaboration between polish doctors all over the world, and the exchange of ideas-sharing experiences with significant emphasis on the quality of care and patient safety. PMID- 27486710 TI - Genetics of Parkinson's disease: a review of SNCA and LRRK2. AB - Parkinson's disease (PD) is a common neurodegenerative disorder that usually affects the elderly. Resting tremor, rigidity, bradykinesia, and postural instability are the main symptoms of PD. The loss of dopaminergic neurons in the substantia nigra and Lewy bodies in remaining neurons are pathological characteristics of PD. To combat these symptoms, dopaminergic therapy can benefit PD patients; however, it is only symptomatic therapy. Although the pathogenesis of PD has yet to be elucidated, approximately 10% of PD patients have familial history of PD. Since the first discovery of a causative gene of PD, SNCA, in 1997, 18 other genes have been identified in familial PD. These discoveries make it possible to begin to understand the pathogenesis of PD and can lead to the development of curative therapies. Here, we describe the clinical and pathological features of PD caused by mutations in two major PD-associated genes, SNCA and LRRK2. Mutations in SNCA revealed the pathological association between alpha-synuclein and PD, while LRRK2 is the most common genetic cause of PD. The patients with LRRK2 mutations present with relatively typical PD phenotypes, but heterogeneous pathologies including alpha-synuclein, tau, and occasionaly transactive response DNA-binding protein 43. PMID- 27486711 TI - [Dehumanizacja wspolczesnej medycyny: przyczyny i przeciwdzialanie]. AB - A discussion of causes of dehumanisation in contemporary medicine and possible methods of preventing this situation. The causes can be divided into external, associated with the influence of the environment of civilisation, and internal, which constitute a form of aunwanted side effects" of the rapid progress of civilisation. The latter include reductionist thinking and axiological neutrality typical of natural sciences, increased import_ance of technology, and excessive specialisation combined with poor coordination of diagnostic work-up and treatment or the lack of such coordination. Possible preventive measures include a change in the model of medical education, consisting for instance in the inclusion of humanistic elements and a more holistic view of the patient, as well as a change in the health care model so that the diagnostic work-up and treatment would be coordinated mainly by the primary health care doctor. PMID- 27486712 TI - [Masywne krwawienie z jelita malego: nowa opcja terapeutyczna z lokalizacja microcoil i laparoskopowa resekcja]. AB - Masywne krwawienie z przewodu pokarmowego prezentuje kompleksowy problem diagnostyczny i terapeutyczny. Dokladna identyfikacja miejsca krwawienia jest skomplikowana i chirurgiczna resekcja miejsca krwawienia jest trudne. Angiografii uzywanej do lokalizacji i embolizacji miejscu krwawienia w krazeniu krezkowym brakuje skutecznosci ze wzgledu na skomplikowana siec zespolenia naczyn krwionosnych zaopatrujacych jelito cienkie. Przedoperacyjnie umieszczenie microcoil dla fluoroskopowo kierowanej laparoskopowej resekcji jelita cienkiego zostalo wykorzystane w przypadku 58-letniej kobiety leczonej chemioterapia z uzyciem idarubicyny i cytarabiny. Pacjentka miala krwawienie z przewodu pokarmowego, ktore nie reagowalo na leczenie zachowawcze i wymagalo masywnych transfuzji produktow krwi. PMID- 27486713 TI - [Laryngotracheitis, recurrent laryngotracheitis and asthma in children: features of ontogenesis and feeding in the first months of life]. AB - Objective of research was to study features of ontogenesis and feeding in the first months of life in children with laryngotracheitis (LT), recurrent laryngotracheitis (RLT) and asthma. METHODS: Questionnaire-based survey was performed to collect data on anamnesis of 1004 children aged 6-14 years (575 children with a history of LT, 60 children with asthma, and 369 children of control group) pertaining to preeclampsia in mothers, history of birth asphyxia, preterm birth and feeding during the first months of life in children. Children with LT were divided into two groups: 458 children with 1-3 episodes of LT and 117 children with RLT (4 or more episodes of LT). RESULTS: The frequency of preeclampsia among mothers of children with RLT exceeded the corresponding frequency among mothers of children with 1-3 episodes of LT and children of control group in 2.1 and 2.8 times, respectively. The frequency of birth asphyxia or preterm birth among children with RLT exceeded the corresponding frequency among children with 1-3 episodes of LT and children of control group by a factor of 2. The frequency of breastfeeding initiation after 24 hours of birth among children with asthma or RLT exceeded the corresponding frequency among children with 1-3 episodes of LT (in 1.4 and 1.5 times, respectively) and among children of control group (in 2.4 and 2.6 times, respectively). CONCLUSION: The frequency of preeclampsia in mothers, birth asphyxia, preterm birth and late initiation of breastfeeding among children with RLT exceeded the corresponding frequency among children with 1-3 episodes of LT and children of control group. There was no significant difference between the frequency of preeclampsia in mothers, birth asphyxia, initiation of breastfeeding among children with RLT and children with asthma. Formula feeding in the first months of life was equally often observed among children with LT, RLT and asthma and significantly exceeded the corresponding percentage among children in control group. PMID- 27486714 TI - [Jak obnizyc umieralnosc kobiet z powodu krwotokow poporodowych?]. AB - Postpartum hemorrhage (PPH) is still a common obstetrical complication and is believed to be the leading cause of peripartum maternal mortality in Poland. PPH prevention is though the main aim of contemporary obstetrics. It might be obtained by careful screening for high risk of PPH gravidas and active management of the third stage of labor. Postpartum hemorrhage requires aggressive measures, accurate diagnosis and precise management. The knowledge of algorithms of PPH management is essential and required for all physicians working in the Delivery Room. PMID- 27486715 TI - Why parents refuse immunization? AB - Rates of child immunization are falling in many countries, leading to the increase of morbidity and mortality from diseases controlled by vaccinations. The simplified model of the natural history of immunization follows a sequence of fear of the disease before vaccination, followed by acceptance of the vaccination until plateau, where the population forgets the morbidity and mortality of pre immunization. Historical factors including withdrawals of vaccines, and publications regarding the true or falsified dangers of vaccines still resonate with parents. Building on these historical factors, unscientific sources such as naturopaths, homeopaths, chiropractors, celebrities and lay-people with anecdotal evidence and even scientific sources such as some universities and some medical doctors push their views on anti-vaccination, which proves to make the decision to vaccinate more difficult on parents. The main reason that parents refuse vaccination is a desire to protect their children. These parents believe that vaccination is harmful, or that not vaccinated children are healthier than vaccinated children. Scientific data often will lose with pseudoscientific, false or anecdotal data that have higher sensational and emotional impact on parents. With so many sources giving so many factors which sometimes contradict themselves, it is indeed difficult for a parent to make a clear decision for their child. PMID- 27486716 TI - An investigation of the auditory perception of western lowland gorillas in an enrichment study. AB - Previous research has highlighted the varied effects of auditory enrichment on different captive animals. This study investigated how manipulating musical components can influence the behavior of a group of captive western lowland gorillas (Gorilla gorilla gorilla) at Bristol Zoo. The gorillas were observed during exposure to classical music, rock-and-roll music, and rainforest sounds. The two music conditions were modified to create five further conditions: unmanipulated, decreased pitch, increased pitch, decreased tempo, and increased tempo. We compared the prevalence of activity, anxiety, and social behaviors between the standard conditions. We also compared the prevalence of each of these behaviors across the manipulated conditions of each type of music independently and collectively. Control observations with no sound exposure were regularly scheduled between the observations of the 12 auditory conditions. The results suggest that naturalistic rainforest sounds had no influence on the anxiety of captive gorillas, contrary to past research. The tempo of music appears to be significantly associated with activity levels among this group, and social behavior may be affected by pitch. Low tempo music also may be effective at reducing anxiety behavior in captive gorillas. Regulated auditory enrichment may provide effective means of calming gorillas, or for facilitating active behavior. Zoo Biol. 35:398-408, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27486717 TI - The Influence of Zeolites on Radical Formation During Lignin Pyrolysis. AB - Lignin from lignocellulosic biomass is a promising source of energy, fuels, and chemicals. The conversion of the polymeric lignin to fuels and chemicals can be achieved by catalytic and noncatalytic pyrolysis. The influence of nonporous silica and zeolite catalysts, such as silicalite, HZSM5, and HUSY, on the radical and volatile product formation during lignin pyrolysis was studied by in situ high-temperature electron paramagnetic resonance spectroscopy (HTEPR) as well as GC-MS. Higher radical concentrations were observed in the samples containing zeolite compared to the sample containing only lignin, which suggests that there is a stabilizing effect by the inorganic surfaces on the formed radical fragments. This effect was observed for nonporous silica as well as for HUSY, HZSM5, and silicalite zeolite catalysts. However, the effect is far larger for the zeolites owing to their higher specific surface area. The zeolites also showed an effect on the volatile product yield and the product distribution within the volatile phase. Although silicalite showed no effect on the product selectivity, the acidic zeolites such as HZSM5 or HUSY increased the formation of deoxygenated products such as benzene, toluene, xylene (BTX), and naphthalene. PMID- 27486718 TI - Preventing recurrence of diffuse malignant peritoneal mesothelioma. AB - INTRODUCTION: Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive malignancy with a poor prognosis when treated with systemic therapy. Cytoreductive surgery (CRS) with intraperitoneal chemotherapy (IPC) is considered the best therapy in DMPM, but a high risk of locoregional recurrence remains. AREAS COVERED: This review describes patient selection and operative goals with CRS and IPC, the reported outcomes with this approach, and the data supporting platinum-based IPC. We assess the pharmacokinetics supporting the use of dwell IPC. We outline clinical, imaging and laboratory surveillance for recurrence. In addition, we highlight the role of re-operation, both as a planned second procedure and in the context of disease recurrence. Literature review was performed via Medline search. Expert commentary: CRS/IPC offers survival benefit in selected patients with DMPM, but given the high rate of recurrence, close surveillance is needed post-operatively. Strategies to prevent and treat recurrent disease include dwell IPC and second CRS/IPC. PMID- 27486719 TI - Nursing students' spiritual talks with patients - evaluation of a partnership learning programme in clinical practice. AB - AIMS AND OBJECTIVES: To evaluate the impact of a partnership learning programme designed to support undergraduate nursing students' competence in speaking with patients about spiritual issues. BACKGROUND: Spiritual care is an oft-neglected and underexposed area of nursing practice. Despite the increasing amount of research on spiritual care in educational programmes, little is known about nursing students' experiences with existential/spiritual talks and the process of learning about spiritual care in the clinical placement. DESIGN: The project used a qualitative evaluation design to evaluate the impact of a partnership-initiated intervention focusing on student learning of spiritual care in a hospital ward. METHODS: Data were collected through three focus group interviews with bachelor of nursing students from one Norwegian university college and supplemented with notes. Data were analysed by means of qualitative interpretative content analysis. RESULTS: The intervention was found to enhance students' competence in spiritual talks. The students developed an extended understanding of spirituality, became more confident in speaking with patients about spiritual issues and more active in grasping opportunities to provide spiritual care. Participating nurses significantly contributed to the students' learning process by being role models, mentoring the students and challenging them to overcome barriers in speaking with patients about spiritual issues. CONCLUSIONS: The partnership learning programme proved to be a useful model in terms of enhancing students' confidence in speaking with patients about spiritual concerns. RELEVANCE TO CLINICAL PRACTICE: Collaboration between nursing university colleges and clinical placements could help nursing students and clinical nurses to develop competencies in spiritual care and bridge the gap between academic education and clinical education, to the benefit of both. PMID- 27486720 TI - The Biological Basis for Nonunions. AB - Fracture nonunion is a failure of the biological processes of fracture-healing. Critical cellular events in fracture-healing include the inflammatory response, differentiation and proliferation of progenitor cells, formation of fibrocartilage callus, angiogenesis and subsequent mineralization of the callus, vascular union (restoration of normal medullary circulation), and conversion of woven bone to lamellar bone. All critical events are closely regulated and coordinated by numerous cytokines and growth factors, which are expressed in complex spatial and temporal patterns throughout the repair process. At all phases of fracture-healing, poor cellular and metabolic capacity (e.g., chronic disease), excessive instability, and poor vascularity inhibit cellular responses and healing. Many biological treatments to prevent or treat nonunions are emerging in clinical use, including stem-cell and bone-marrow-aspirate preparations, various progenitor cells and growth factors (e.g., recombinant human bone morphogenetic proteins), and gene therapy. PMID- 27486721 TI - Current Controversies in Reverse Total Shoulder Arthroplasty. AB - Reverse total shoulder arthroplasty can restore forward elevation in pseudoparalytic shoulders, can reduce pain, and can increase quality of life for patients; however, there are a number of issues with regard to the design and ideal implantation technique of reverse total shoulder arthroplasties that remain controversial. Glenospheres with a Grammont, medialized center of rotation and designs with a more lateralized center of rotation have specific pros and cons. Medialized designs have historically decreased glenosphere loosening but increase scapular notching, and lateralized designs decrease notching and improve range of motion but historically have resulted in increased baseplate failure. As such, a concrete conclusion with regard to medialization or lateralization of the glenosphere cannot be made at this time. Caudal, inferior placement of the glenosphere increases internal rotation, external rotation, abduction, and adduction while reducing notching. Superior baseplate positioning and tilt are correlated with baseplate failure and therefore should be avoided. It remains unclear whether neutral or slightly inferior tilt is preferred. The ideal humerosocket inclination angle remains unclear. The 135[degrees] designs appear to have a lower rate of scapular notching than the Grammont-style 155[degrees] humerosockets. The implications of this angle for instability remain unclear as, to our knowledge, there have been no randomized comparisons and the largest meta analysis was confounded by other implant variables. PMID- 27486722 TI - Biological Treatments for Tendon and Ligament Abnormalities: A Critical Analysis Review. AB - The poor intrinsic healing potential of tendon and ligamentous tissue has driven the search for biological agents that can improve healing, most notably platelet rich plasma (PRP) and autologous stem cells. Current evidence best supports the use of PRP as treatment for chronic, degenerative tendinopathies such as lateral epicondylitis of the elbow or patellar tendinopathy. It does not support the use of PRP to promote tendon or ligament-to-bone healing in rotator cuff repair or anterior cruciate ligament (ACL) reconstruction. Clinical evidence regarding the use of autologous stem cells as treatment for tendon and ligament abnormalities is currently limited. However, the initial results appear to be promising, particularly following rotator cuff repair. A major limitation in the evaluation of current data is the lack of standardization in the preparation and composition of PRP, which are often not reported. Future investigators should make an effort to report the method of preparation and final composition of PRP used. Autologous stem cells were most often harvested from bone marrow aspirate but were occasionally derived from dermal tenocyte cells. Recent studies have explored new sources for stem cells, including adipose tissue, peripheral blood, and human amniotic tissue. We expect that clinical data evaluating these treatments will soon emerge. PMID- 27486723 TI - Instrumented Gait Analysis: A Tool in the Treatment of Spastic Gait Dysfunction. AB - Spasticity is a term commonly used to describe a collection of muscle overactivity patterns associated with the upper motor neuron syndrome including actual spasticity, clonus, dystonia, co-contraction, associated reactions, and flexor or extensor spasms. Gait dysfunction in the upper motor neuron syndrome can be due to a combination of paresis, impaired coordination and balance, and muscle overactivity and contracture. Treatment options include physiotherapy, assistive devices, orthotic devices, oral and intrathecal medications, intramuscular chemodenervation, neurolysis, and/or neuro-orthopaedic surgical procedures. The objective evaluation of walking and its underlying muscle activation patterns can be performed by the simultaneous collection of joint kinematics, kinetics, and dynamic electromyography (EMG) data that serve as an extension of the physical examination to better discern primary gait deviations from compensatory gait deviations as well as underlying muscle overactivity from contracture. Despite the science behind instrumented three-dimensional gait analysis, its specific contribution to clinical and surgical decision-making is not well utilized because of its associated cost, the incorrect view by some insurance companies of gait analysis being a research technique, the dearth of qualified clinical gait and motion analysis laboratories accessible to adult patients, and limited access to orthopaedic surgeons who have experience in the treatment of neurological disorders for this patient population. PMID- 27486724 TI - Endoscopic Compared with Open Operative Treatment of Carpal Tunnel Syndrome. AB - Carpal tunnel syndrome is the most common peripheral nerve compression syndrome. Treatment options include wrist-neutral bracing, corticosteroid injections, operative release of the transverse carpal ligament, and symptom-relief options. Endoscopic carpal tunnel release may give patients a faster recovery compared with traditional open release, but there are no ultimate differences in outcome among the various surgical options. PMID- 27486725 TI - Microfracture of Articular Cartilage. AB - Microfracture is a treatment option for symptomatic, full-thickness cartilage defects. Microfracture is most likely to be successful when performed in nonobese patients under the age of thirty years for small (<2 to 4-cm2) femoral condylar defects that have been symptomatic for a short time (less than twelve to twenty four months). Microfracture has acceptable short-term clinical results, but results can be expected to decline over time. Long-term studies that compare microfracture with advanced cartilage restoration techniques are required to ascertain whether these newer techniques provide longer-lasting results. PMID- 27486726 TI - Variability in Response to Bilateral Medial Rectus Recessions in Infantile Esotropia. AB - PURPOSE: To evaluate factors associated with surgical success in bilateral medial rectus recessions in infantile esotropia. METHODS: The results of 97 patients with infantile esotropia undergoing surgical correction from January 2010 through December 2013 at Children's Medical Center of Dallas were reviewed. Multivariate logistic regression analysis of risk factors for success and evaluation of the relationship of surgical responses to baseline characteristics were performed. RESULTS: The authors achieved an overall success rate of 59% (57 of 97 patients) with one surgery. At the time of surgery, preoperative angle, refraction, amblyopia, and simultaneous inferior oblique surgery were not significantly related to success or failure. The mean dose response was 3.61 +/- 1.45 prism diopters per millimeter of surgery and was modestly correlated only with the preoperative deviation (r(2) = 0.32). Failure was associated with variability in dose-response, not inadequate or inconsistent with surgical dosing. CONCLUSIONS: Surgical success with bilateral medial rectus recessions in infantile esotropia is limited by the high variability in surgical dose-response. [J Pediatr Ophthalmol Strabismus. 2016;53(5):305-310.]. PMID- 27486727 TI - Congenital Nasolacrimal Duct Obstruction: Comparison of Two Different Treatment Algorithms. AB - PURPOSE: To clarify the most appropriate treatment regimen for congenital nasolacrimal duct obstruction (CNLDO). METHODS: A retrospective observational analysis was performed of patients undergoing probing with or without intubation to treat CNLDO in a single institution (Royal Victoria Hospital, Belfast) from 2006 to 2011. RESULTS: Based on exclusion criteria, 246 eyes of 177 patients (aged 0 to 9.8 years with a mean age of 2.1 years) were included in this study: 187 (76%) eyes had successful outcome at first intervention with primary probing, whereas 56 (23%) eyes underwent secondary intervention. There were no significant differences by gender, age, or obstruction complexity between the successful and unsuccessful patients with first intervention. For those patients requiring secondary intervention, 16 of 24 (67%) eyes had successful probing, whereas 22 of 24 (92%) had successful intubation. Patients with intubation as a secondary procedure were significantly more likely to have a successful outcome (P = .037). Statistical analysis was performed using the Fisher's exact test and Barnard's exact test. CONCLUSIONS: Primary probing for CNLDO has a high success rate that is not adversely affected by increasing age. This study also indicates that if initial probing is unsuccessful, nasolacrimal intubation rather than repeat probing yields a significantly higher success rate. [J Pediatr Ophthalmol Strabismus. 2016;53(5):285-291.]. PMID- 27486728 TI - Retinoblastoma Control With Primary Intra-arterial Chemotherapy: Outcomes Before and During the Intravitreal Chemotherapy Era. AB - PURPOSE: To compare outcomes of intra-arterial chemotherapy for retinoblastoma as primary therapy before (Era I) and during (Era II) the intravitreal chemotherapy era. METHODS: In this retrospective interventional case series at a tertiary referral center, 66 eyes of 66 patients with untreated unilateral retinoblastoma were used. intraarterial chemotherapy into the ophthalmic artery under fluoroscopic guidance was performed using melphalan in every case, with additional topotecan as necessary. Intravitreal chemotherapy using melphalan and/or topotecan was employed as needed for active vitreous seeding. Globe salvage was measured based on the International Classification of Retinoblastoma (ICRB) during two eras. RESULTS: The two eras encompassed 2008 to 2012 (intraarterial chemotherapy alone, Era I) and 2012 to 2015 (intraarterial chemotherapy plus intravitreal chemotherapy, Era II). Over this period, there were 66 patients with unilateral untreated retinoblastoma treated with primary intra-arterial chemotherapy. A comparison of features (Era I vs Era II) revealed no significant difference in mean patient age (24 vs 24 months), ICRB groups, mean largest tumor diameter (19 vs 17 mm), mean largest tumor thickness (10 vs 10 mm), vitreous seed presence (56% vs 59%), subretinal seed presence (67% vs 62%), retinal detachment (70% vs 66%), or vitreous hemorrhage (0% vs 5%). There was no significant difference in mean number of intra-arterial chemotherapy cycles (3 vs 3.1) or intraarterial chemotherapy dosages. Following therapy, there was a significant difference (Era I vs Era II) in the need for enucleation overall (44% vs 15%, P = .012), especially for group E eyes (75% vs 27%, P = .039). Four of the eyes that initiated therapy in Era I later required intravitreal chemotherapy during Era II. The enucleation rate was 0% for groups B and C in both eras and non-significant for group D (23% vs 13%). There were no patients with stroke, seizure, limb ischemia, extraocular tumor extension, secondary leukemia, metastasis, or death. CONCLUSIONS: The current era of retinoblastoma management using intra-arterial chemotherapy plus additional intravitreal chemotherapy (as needed for vitreous seeding) has improved globe salvage in eyes with advanced retinoblastoma. [J Pediatr Ophthalmol Strabismus. 2016;53(5):275-284.]. PMID- 27486729 TI - The Effectiveness of a Mobile Clinic in Improving Follow-up Eye Care for At-Risk Children. AB - PURPOSE: To investigate the potential of a mobile ophthalmic unit in the schoolyard to improve the follow-up rate for children who have failed an optometric in-school screening program. Previously, the optometric program made referrals to the center and only 53% of students attended the desired ophthalmology consultation. METHODS: This was a cohort study of students conducted in elementary school lots in socioeconomically disadvantaged communities. The mobile ophthalmic unit visited schools where students with parental consent who needed examination had been identified by an in-school optometric vision care program. RESULTS: A total of 132 students were referred by the optometric program, of whom 95 (72%) had complete signed consent forms. Eighty-two patients (62%, confidence interval: 54% to 70%) were successfully seen by the mobile unit. Compared to the historical rate of successful completion of ophthalmology consultation (53%), a statistically significant improvement in follow-up was noted (P = .036). On a Likert scale of 1 to 5, the mean school nurse satisfaction rating was 4.8. CONCLUSIONS: The findings demonstrate the potential impact of mobile eye clinics at schools in connecting children with ophthalmic care. [J Pediatr Ophthalmol Strabismus. 2016;53(6):344-348.]. PMID- 27486730 TI - Respiratory Viral Infections. PMID- 27486731 TI - Human Influenza Virus Infections. AB - Seasonal and pandemic influenza are the two faces of respiratory infections caused by influenza viruses in humans. As seasonal influenza occurs on an annual basis, the circulating virus strains are closely monitored and a yearly updated vaccination is provided, especially to identified risk populations. Nonetheless, influenza virus infection may result in pneumonia and acute respiratory failure, frequently complicated by bacterial coinfection. Pandemics are, in contrary, unexpected rare events related to the emergence of a reassorted human-pathogenic influenza A virus (IAV) strains that often causes increased morbidity and spreads extremely rapidly in the immunologically naive human population, with huge clinical and economic impact. Accordingly, particular efforts are made to advance our knowledge on the disease biology and pathology and recent studies have brought new insights into IAV adaptation mechanisms to the human host, as well as into the key players in disease pathogenesis on the host side. Current antiviral strategies are only efficient at the early stages of the disease and are challenged by the genomic instability of the virus, highlighting the need for novel antiviral therapies targeting the pulmonary host response to improve viral clearance, reduce the risk of bacterial coinfection, and prevent or attenuate acute lung injury. This review article summarizes our current knowledge on the molecular basis of influenza infection and disease progression, the key players in pathogenesis driving severe disease and progression to lung failure, as well as available and envisioned prevention and treatment strategies against influenza virus infection. PMID- 27486732 TI - Avian Influenza A Viruses: Evolution and Zoonotic Infection. AB - Although efficient human-to-human transmission of avian influenza virus has yet to be seen, in the past two decades avian-to-human transmission of influenza A viruses has been reported. Influenza A/H5N1, in particular, has repeatedly caused human infections associated with high mortality, and since 1998 the virus has evolved into many clades of variants with significant antigenic diversity. In 2013, three (A/H7N9, A/H6N1, and A/H10N8) novel avian influenza viruses (AIVs) breached the animal-human host species barrier in Asia. In humans, roughly 35% of A/H7N9-infected patients succumbed to the zoonotic infection, and two of three A/H10N8 human infections were also lethal; however, neither of these viruses cause influenza-like symptoms in poultry. While most of these cases were associated with direct contact with infected poultry, some involved sustained human-to-human transmission. Thus, these events elicited concern regarding potential AIV pandemics. This article reviews the human incursions associated with AIV variants and the potential role of pigs as an intermediate host that may hasten AIV evolution. In addition, we discuss the known influenza A virus virulence and transmission factors and their evaluation in animal models. With the growing number of human AIV infections, constant vigilance for the emergence of novel viruses is of utmost importance. In addition, careful characterization and pathobiological assessment of these novel variants will help to identify strains of particular concern for future pandemics. PMID- 27486733 TI - Metapneumovirus Infections and Respiratory Complications. AB - Acute respiratory tract infections (ARTIs) are the most common illnesses experienced by people of all ages worldwide. In 2001, a new respiratory pathogen called human metapneumovirus (hMPV) was identified in respiratory secretions. hMPV is an RNA virus of the Paramyxoviridae family, and it has been isolated on every continent and from individuals of all ages. hMPV causes 7 to 19% of all cases of ARTIs in both hospitalized and outpatient children, and the rate of detection in adults is approximately 3%. Symptoms of hMPV infection range from a mild cold to a severe disease requiring a ventilator and cardiovascular support. The main risk factors for severe disease upon hMPV infection are the presence of a high viral load, coinfection with other agents (especially human respiratory syncytial virus), being between 0 and 5 months old or older than 65 years, and immunodeficiency. Currently, available treatments for hMPV infections are only supportive, and antiviral drugs are employed in cases of severe disease as a last resort. Ribavirin and immunoglobulins have been used in some patients, but the real efficacy of these treatments is unclear. At present, the direction of research on therapy for hMPV infection is toward the development of new approaches, and a variety of vaccination strategies are being explored and tested in animal models. However, further studies are required to define the best treatment and prevention strategies. PMID- 27486734 TI - Human Respiratory Syncytial Virus: Infection and Pathology. AB - The human respiratory syncytial virus (hRSV) is by far the major cause of acute lower respiratory tract infections (ALRTIs) worldwide in infants and children younger than 2 years. The overwhelming number of hospitalizations due to hRSV induced ALRTI each year is due, at least in part, to the lack of licensed vaccines against this virus. Thus, hRSV infection is considered a major public health problem and economic burden in most countries. The lung pathology developed in hRSV-infected individuals is characterized by an exacerbated proinflammatory and unbalanced Th2-type immune response. In addition to the adverse effects in airway tissues, hRSV infection can also cause neurologic manifestations in the host, such as seizures and encephalopathy. Although the origins of these extrapulmonary symptoms remain unclear, studies with patients suffering from neurological alterations suggest an involvement of the inflammatory response against hRSV. Furthermore, hRSV has evolved numerous mechanisms to modulate and evade the immune response in the host. Several studies have focused on elucidating the interactions between hRSV virulence factors and the host immune system, to rationally design new vaccines and therapies against this virus. Here, we discuss about the infection, pathology, and immune response triggered by hRSV in the host. PMID- 27486735 TI - Parainfluenza Virus Infection. AB - Human parainfluenza viruses (HPIVs) are single-stranded, enveloped RNA viruses of the Paramyoviridaie family. There are four serotypes which cause respiratory illnesses in children and adults. HPIVs bind and replicate in the ciliated epithelial cells of the upper and lower respiratory tract and the extent of the infection correlates with the location involved. Seasonal HPIV epidemics result in a significant burden of disease in children and account for 40% of pediatric hospitalizations for lower respiratory tract illnesses (LRTIs) and 75% of croup cases. Parainfluenza viruses are associated with a wide spectrum of illnesses which include otitis media, pharyngitis, conjunctivitis, croup, tracheobronchitis, and pneumonia. Uncommon respiratory manifestations include apnea, bradycardia, parotitis, and respiratory distress syndrome and rarely disseminated infection. Immunity resulting from disease in childhood is incomplete and reinfection with HPIV accounts for 15% of respiratory illnesses in adults. Severe disease and fatal pneumonia may occur in elderly and immunocompromised adults. HPIV pneumonia in recipients of hematopoietic stem cell transplant (HSCT) is associated with 50% acute mortality and 75% mortality at 6 months. Though sensitive molecular diagnostics are available to rapidly diagnose HPIV infection, effective antiviral therapies are not available. Currently, treatment for HPIV infection is supportive with the exception of croup where the use of corticosteroids has been found to be beneficial. Several novel drugs including DAS181 appear promising in efforts to treat severe disease in immunocompromised patients, and vaccines to decrease the burden of disease in young children are in development. PMID- 27486736 TI - Update on Human Rhinovirus and Coronavirus Infections. AB - Human rhinovirus (HRV) and coronavirus (HCoV) infections are associated with both upper respiratory tract illness ("the common cold") and lower respiratory tract illness (pneumonia). New species of HRVs and HCoVs have been diagnosed in the past decade. More sensitive diagnostic tests such as reverse transcription polymerase chain reaction have expanded our understanding of the role these viruses play in both immunocompetent and immunosuppressed hosts. Recent identification of severe acute respiratory syndrome and Middle East respiratory syndrome viruses causing serious respiratory illnesses has led to renewed efforts for vaccine development. The role these viruses play in patients with chronic lung disease such as asthma makes the search for antiviral agents of increased importance. PMID- 27486737 TI - Middle East Respiratory Syndrome Virus Pathogenesis. AB - Coronaviruses (CoVs) are enveloped RNA viruses that infect birds, mammals, and humans. Infections caused by human coronaviruses (hCoVs) are mostly associated with the respiratory, enteric, and nervous systems. The hCoVs only occasionally induce lower respiratory tract disease, including bronchitis, bronchiolitis, and pneumonia. In 2002 to 2003, a global outbreak of severe acute respiratory syndrome (SARS) was the seminal detection of a novel CoV (SARS-CoV). A decade later (June 2012), another novel CoV was implicated as the cause of Middle East respiratory syndrome (MERS) in Saudi Arabia. Although bats might serve as a reservoir of MERS-CoV, it is unlikely that they are the direct source for most human cases. Severe lines of evidence suggest that dromedary camels have been the major cause of transmission to humans. The emergence of MERS-CoV has triggered serious concerns about the potential for a widespread outbreak. All MERS cases were linked directly or indirectly to the Middle East region including Saudi Arabia, Jordan, Qatar, Oman, Kuwait, and UAE. MERS cases have also been reported in the later phases in the United Kingdom, France, Germany, Italy, Spain, and Tunisia. Most of these MERS cases were linked with the Middle East. The high mortality rates in family-based and hospital-based outbreaks were reported among patients with comorbidities such as diabetes and renal failure. MERS-CoV causes an acute, highly lethal pneumonia and renal dysfunction. The major complications reported in fatal cases are hyperkalemia with associated ventricular tachycardia, disseminated intravascular coagulation, pericarditis, and multiorgan failure. The case-fatality rate seems to be higher for MERS-CoV (around 30%) than for SARS-CoV (9.6%). The combination regimen of type 1 interferon + lopinavir/ritonavir is considered as the first-line therapy for MERS. Antiviral treatment is generally recommended for 10 to 14 days in patients with MERS-CoV infection. Convalescent plasma therapy has shown some efficacy among patients refractory to antiviral drugs if administered within 2 weeks of the onset of the disease. PMID- 27486738 TI - Enterovirus D68 and Human Respiratory Infections. AB - Enterovirus D68 (EV-D68) is a member of the species Enterovirus D in the genus Enterovirus of the Picornaviridae family. EV-D68 was first isolated in the United States in 1962 and is primarily an agent of respiratory disease. Infections with EV-D68 have been rarely reported until recently, when reports of EV-D68 associated with respiratory disease increased notably worldwide. An outbreak in 2014 in the United States, for example, involved more than 1,000 cases of severe respiratory disease that occurred across almost all states. Phylogenetic analysis of all EV-D68 sequences indicates that the circulating strains of EV-D68 can be classified into two lineages, lineage 1 and lineage 2. In contrast to the prototype Fermon strain, all circulating strains have deletions in their genomes. Respiratory illness associated with EV-D68 infection ranges from mild illness that just needs outpatient service to severe illness requiring intensive care and mechanical ventilation. To date, there are no specific medicines and vaccines to treat or prevent EV-D68 infection. This review provides a detailed overview about our current understanding of EV-D68-related virology, epidemiology and clinical syndromes, pathogenesis, and laboratory diagnostics. PMID- 27486739 TI - Adenovirus: Epidemiology, Global Spread of Novel Serotypes, and Advances in Treatment and Prevention. AB - Adenoviruses (AdVs) are DNA viruses that typically cause mild infections involving the upper or lower respiratory tract, gastrointestinal tract, or conjunctiva. Rare manifestations of AdV infections include hemorrhagic cystitis, hepatitis, hemorrhagic colitis, pancreatitis, nephritis, or meningoencephalitis. AdV infections are more common in young children, due to lack of humoral immunity. Epidemics of AdV infection may occur in healthy children or adults in closed or crowded settings (particularly military recruits). The disease is more severe and dissemination is more likely in patients with impaired immunity (e.g., organ transplant recipients, human immunodeficiency virus infection). Fatality rates for untreated severe AdV pneumonia or disseminated disease may exceed 50%. More than 50 serotypes of AdV have been identified. Different serotypes display different tissue tropisms that correlate with clinical manifestations of infection. The predominant serotypes circulating at a given time differ among countries or regions, and change over time. Transmission of novel strains between countries or across continents and replacement of dominant viruses by new strains may occur. Treatment of AdV infections is controversial, as prospective, randomized therapeutic trials have not been conducted. Cidofovir is the drug of choice for severe AdV infections, but not all patients require treatment. Live oral vaccines are highly efficacious in reducing the risk of respiratory AdV infection and are in routine use in the military in the United States, but currently are not available to civilians. PMID- 27486740 TI - Herpesvirus Respiratory Infections in Immunocompromised Patients: Epidemiology, Management, and Outcomes. AB - Among immunocompromised individuals, members of the human Herpesviridae family are frequently encountered pathogens. Cytomegalovirus, herpes simplex virus 1 and 2, varicella zoster virus, Epstein-Barr virus, and human herpesvirus-6, -7, and 8 all establish latency after infection and can reactivate during periods of immunosuppression, leading to both direct and indirect adverse effects on the host including severe organ dysfunction as well as allograft rejection and loss after transplantation. While not all herpesviruses are primary respiratory pathogens, many of their manifestations include involvement of the respiratory tract. This article discusses the individual viruses, their epidemiology, and clinical manifestations as well as recommended treatment and preventive strategies. PMID- 27486741 TI - Control Measures for Human Respiratory Viral Infection. AB - New viral respiratory pathogens are emerging with increasing frequency and have potentially devastating impacts on the population worldwide. Recent examples of newly emerged threats include severe acute respiratory syndrome coronavirus, the 2009 H1N1 influenza pandemic, and Middle East respiratory syndrome coronavirus. Experiences with these pathogens have shown up major deficiencies in how we deal globally with emerging pathogens and taught us salient lessons in what needs to be addressed for future pandemics. This article reviews the lessons learnt from past experience and current knowledge on the range of measures required to limit the impact of emerging respiratory infections from public health responses down to individual patient management. Key areas of interest are surveillance programs, political limitations on our ability to respond quickly enough to emerging threats, media management, public information dissemination, infection control, prophylaxis, and individual patient management. Respiratory physicians have a crucial role to play in many of these areas and need to be aware of how to respond as new viral pathogens emerge. PMID- 27486742 TI - Antivirals for Respiratory Viral Infections: Problems and Prospects. AB - In the past two decades, several newly emerging and reemerging viral respiratory pathogens including several influenza viruses (avian influenza and pandemic influenza), severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV), have continued to challenge medical and public health systems. Thereafter, the development of cost-effective, broad-spectrum antiviral agents is the urgent mission of both virologists and pharmacologists. Current antiviral developments have focused targets on viral entry, replication, release, and intercellular pathways essential for viral life cycle. Here, we review the current literature on challenges and prospects in the development of these antivirals. PMID- 27486743 TI - Distinct Skeletal Muscle Gene Regulation from Active Contraction, Passive Vibration, and Whole Body Heat Stress in Humans. AB - Skeletal muscle exercise regulates several important metabolic genes in humans. We know little about the effects of environmental stress (heat) and mechanical stress (vibration) on skeletal muscle. Passive mechanical stress or systemic heat stress are often used in combination with many active exercise programs. We designed a method to deliver a vibration stress and systemic heat stress to compare the effects with active skeletal muscle contraction. PURPOSE: The purpose of this study is to examine whether active mechanical stress (muscle contraction), passive mechanical stress (vibration), or systemic whole body heat stress regulates key gene signatures associated with muscle metabolism, hypertrophy/atrophy, and inflammation/repair. METHODS: Eleven subjects, six able bodied and five with chronic spinal cord injury (SCI) participated in the study. The six able-bodied subjects sat in a heat stress chamber for 30 minutes. Five subjects with SCI received a single dose of limb-segment vibration or a dose of repetitive electrically induced muscle contractions. Three hours after the completion of each stress, we performed a muscle biopsy (vastus lateralis or soleus) to analyze mRNA gene expression. RESULTS: We discovered repetitive active muscle contractions up regulated metabolic transcription factors NR4A3 (12.45 fold), PGC-1alpha (5.46 fold), and ABRA (5.98 fold); and repressed MSTN (0.56 fold). Heat stress repressed PGC-1alpha (0.74 fold change; p < 0.05); while vibration induced FOXK2 (2.36 fold change; p < 0.05). Vibration similarly caused a down regulation of MSTN (0.74 fold change; p < 0.05), but to a lesser extent than active muscle contraction. Vibration induced FOXK2 (p < 0.05) while heat stress repressed PGC-1alpha (0.74 fold) and ANKRD1 genes (0.51 fold; p < 0.05). CONCLUSION: These findings support a distinct gene regulation in response to heat stress, vibration, and muscle contractions. Understanding these responses may assist in developing regenerative rehabilitation interventions to improve muscle cell development, growth, and repair. PMID- 27486744 TI - Rabies in Kazakhstan. AB - BACKGROUND: Rabies is a neglected zoonotic disease. There is a sparsity of data on this disease with regard to the incidence of human and animal disease in many low and middle income countries. Furthermore, rabies results in a large economic impact and a high human burden of disease. Kazakhstan is a large landlocked middle income country that gained independence from the Soviet Union in 1991 and is endemic for rabies. METHODOLOGY/PRINCIPAL FINDINGS: We used detailed public health and veterinary surveillance data from 2003 to 2015 to map where livestock rabies is occurring. We also estimate the economic impact and human burden of rabies. Livestock and canine rabies occurred over most of Kazakhstan, but there were regional variations in disease distribution. There were a mean of 7.1 officially recorded human fatalities due to rabies per year resulting in approximately 457 Disability Adjusted Life Years (DALYs). A mean of 64,289 individuals per annum underwent post exposure prophylaxis (PEP) which may have resulted in an additional 1140 DALYs annually. PEP is preventing at least 118 cases of human rabies each year or possibly as many as 1184 at an estimated cost of $1193 or $119 per DALY averted respectively. The estimated economic impact of rabies in Kazakhstan is $20.9 million per annum, with nearly half of this cost being attributed to the cost of PEP and the loss of income whilst being treated. A further $5.4 million per annum was estimated to be the life time loss of income for fatal cases. Animal vaccination programmes and animal control programmes also contributed substantially to the economic losses. The direct costs due to rabies fatalities of agricultural animals was relatively low. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that in Kazakhstan there is a substantial economic cost and health impact of rabies. These costs could be reduced by modifying the vaccination programme that is now practised. The study also fills some data gaps on the epidemiology and economic effects of rabies in respect to Kazakhstan. PMID- 27486745 TI - Referrals between Public Sector Health Institutions for Women with Obstetric High Risk, Complications, or Emergencies in India - A Systematic Review. AB - Emergency obstetric care (EmOC) within primary health care systems requires a linked referral system to be effective in reducing maternal death. This systematic review aimed to summarize evidence on the proportion of referrals between institutions during pregnancy and delivery, and the factors affecting referrals, in India. We searched 6 electronic databases, reviewed four regional databases and repositories, and relevant program reports from India published between 1994 and 2013. All types of study or reports (except editorials, comments and letters) which reported on institution-referrals (out-referral or in referral) for obstetric care were included. Results were synthesized on the proportion and the reasons for referral, and factors affecting referrals. Of the 11,346 articles identified by the search, we included 232 articles in the full text review and extracted data from 16 studies that met our inclusion criteria Of the 16, one was RCT, seven intervention cohort (without controls), six cross sectional, and three qualitative studies. Bias and quality of studies were reported. Between 25% and 52% of all pregnancies were referred from Sub-centres for antenatal high-risk, 14% to 36% from nurse run delivery or basic EmOC centres for complications or emergencies, and 2 to 7% were referred from doctor run basic EmOC centres for specialist care at comprehensive EmOC centres. Problems identified with referrals from peripheral health centres included low skills and confidence of staff, reluctance to induce labour, confusion over the clinical criteria for referral, non-uniform standards of care at referral institutions, a tendency to by-pass middle level institutions, a lack of referral communication and supervision, and poor compliance. The high proportion of referrals from peripheral health centers reflects the lack of appropriate clinical guidelines, processes, and skills for obstetric care and referral in India. This, combined with inadequate referral communication and low compliance, is likely to contribute to gaps and delays in the provision of emergency obstetric care. PMID- 27486746 TI - Host Biomarkers for Distinguishing Bacterial from Non-Bacterial Causes of Acute Febrile Illness: A Comprehensive Review. AB - BACKGROUND: In resource limited settings acute febrile illnesses are often treated empirically due to a lack of reliable, rapid point-of-care diagnostics. This contributes to the indiscriminate use of antimicrobial drugs and poor treatment outcomes. The aim of this comprehensive review was to summarize the diagnostic performance of host biomarkers capable of differentiating bacterial from non-bacterial infections to guide the use of antibiotics. METHODS: Online databases of published literature were searched from January 2010 through April 2015. English language studies that evaluated the performance of one or more host biomarker in differentiating bacterial from non-bacterial infection in patients were included. Key information extracted included author information, study methods, population, pathogens, clinical information, and biomarker performance data. Study quality was assessed using a combination of validated criteria from the QUADAS and Lijmer checklists. Biomarkers were categorized as hematologic factors, inflammatory molecules, cytokines, cell surface or metabolic markers, other host biomarkers, host transcripts, clinical biometrics, and combinations of markers. FINDINGS: Of the 193 citations identified, 59 studies that evaluated over 112 host biomarkers were selected. Most studies involved patient populations from high-income countries, while 19% involved populations from low- and middle income countries. The most frequently evaluated host biomarkers were C-reactive protein (61%), white blood cell count (44%) and procalcitonin (34%). Study quality scores ranged from 23.1% to 92.3%. There were 9 high performance host biomarkers or combinations, with sensitivity and specificity of >=85% or either sensitivity or specificity was reported to be 100%. Five host biomarkers were considered weak markers as they lacked statistically significant performance in discriminating between bacterial and non-bacterial infections. DISCUSSION: This manuscript provides a summary of host biomarkers to differentiate bacterial from non-bacterial infections in patients with acute febrile illness. Findings provide a basis for prioritizing efforts for further research, assay development and eventual commercialization of rapid point-of-care tests to guide use of antimicrobials. This review also highlights gaps in current knowledge that should be addressed to further improve management of febrile patients. PMID- 27486747 TI - Skeletal Muscle Regeneration and Oxidative Stress Are Altered in Chronic Kidney Disease. AB - Skeletal muscle atrophy and impaired muscle function are associated with lower health-related quality of life, and greater disability and mortality risk in those with chronic kidney disease (CKD). However, the pathogenesis of skeletal dysfunction in CKD is unknown. We used a slow progressing, naturally occurring, CKD rat model (Cy/+ rat) with hormonal abnormalities consistent with clinical presentations of CKD to study skeletal muscle signaling. The CKD rats demonstrated augmented skeletal muscle regeneration with higher activation and differentiation signals in muscle cells (i.e. lower Pax-7; higher MyoD and myogenin RNA expression). However, there was also higher expression of proteolytic markers (Atrogin-1 and MuRF-1) in CKD muscle relative to normal. CKD animals had higher indices of oxidative stress compared to normal, evident by elevated plasma levels of an oxidative stress marker, 8-hydroxy-2' deoxyguanosine (8-OHdG), increased muscle expression of succinate dehydrogenase (SDH) and Nox4 and altered mitochondria morphology. Furthermore, we show significantly higher serum levels of myostatin and expression of myostatin in skeletal muscle of CKD animals compared to normal. Taken together, these data show aberrant regeneration and proteolytic signaling that is associated with oxidative stress and high levels of myostatin in the setting of CKD. These changes likely play a role in the compromised skeletal muscle function that exists in CKD. PMID- 27486748 TI - Hypnotizability and Placebo Analgesia in Waking and Hypnosis as Modulators of Auditory Startle Responses in Healthy Women: An ERP Study. AB - We evaluated the influence of hypnotizability, pain expectation, placebo analgesia in waking and hypnosis on tonic pain relief. We also investigated how placebo analgesia affects somatic responses (eye blink) and N100 and P200 waves of event-related potentials (ERPs) elicited by auditory startle probes. Although expectation plays an important role in placebo and hypnotic analgesia, the neural mechanisms underlying these treatments are still poorly understood. We used the cold cup test (CCT) to induce tonic pain in 53 healthy women. Placebo analgesia was initially produced by manipulation, in which the intensity of pain induced by the CCT was surreptitiously reduced after the administration of a sham analgesic cream. Participants were then tested in waking and hypnosis under three treatments: (1) resting (Baseline); (2) CCT-alone (Pain); and (3) CCT plus placebo cream for pain relief (Placebo). For each painful treatment, we assessed pain and distress ratings, eye blink responses, N100 and P200 amplitudes. We used LORETA analysis of N100 and P200 waves, as elicited by auditory startle, to identify cortical regions sensitive to pain reduction through placebo and hypnotic analgesia. Higher pain expectation was associated with higher pain reductions. In highly hypnotizable participants placebo treatment produced significant reductions of pain and distress perception in both waking and hypnosis condition. P200 wave, during placebo analgesia, was larger in the frontal left hemisphere while placebo analgesia, during hypnosis, involved the activity of the left hemisphere including the occipital region. These findings demonstrate that hypnosis and placebo analgesia are different processes of top down regulation. Pain reduction was associated with larger EMG startle amplitudes, N100 and P200 responses, and enhanced activity within the frontal, parietal, and anterior and posterior cingulate gyres. LORETA results showed that placebo analgesia modulated pain-responsive areas known to reflect the ongoing pain experience. PMID- 27486750 TI - Risk Factors and Relationship of Cutaneous and Uveal Melanocytic Lesions in Monozygotic and Dizygotic Twin Pairs. AB - BACKGROUND: The similar genetic background of a pair of twins, and the similar environmental impacts to which they are exposed allow an exact and objective investigation of various constitutional and environmental factors in naevus development. As far as we are aware, this is the first published survey that simultaneously examines cutaneous and ocular pigmented lesions in an appreciable sample of identical and non-identical twins. METHODS: 172 pairs of twins of Caucasian origin were included in this study. A whole-body skin examination and a detailed ophthalmological examination were performed to determine the density of melanocytic lesions. A standardized questionnaire was used to assess the data relating to constitutional, sun exposure and other variables. RESULTS: A notably high proportion of the subjects (36.78%) manifested one or more clinically atypical melanocytic naevi (CAMNs), and approximately one-third (31.4%) of them at least one benign uveal pigmented lesion (BUPL). The incidence of iris freckles (IFs), iris naevi (INs) and choroidal naevi (CHNs) proved to be 25.35%, 5.98% and 3.52%, respectively. The interclass correlation coefficients for common melanocytic naevi (CMNs), CAMNs, and INs were 0.77, 0.76 and 0.86 in monozygotic twins, as compared with 0.5, 0.27 and 0.25 in dizygotic twin pairs, respectively. A statistically significant correlation was found between the prevalence of CAMNs and that of INs. CONCLUSIONS: This significant correlation suggests the existence of a subgroup of Caucasian people with an increased susceptibility to both cutaneous and ocular naevus formation. There is accumulating evidence that, besides the presence of cutaneous atypical naevi, INs can serve as a marker of a predisposed phenotype at risk of uveal melanoma. The correlation between cutaneous and ocular pigmented lesions underlines the need for the adequate ophthalmological screening of subjects with CAMNs and INs. PMID- 27486749 TI - In Vitro Inhibition of NFAT5-Mediated Induction of CCL2 in Hyperosmotic Conditions by Cyclosporine and Dexamethasone on Human HeLa-Modified Conjunctiva Derived Cells. AB - PURPOSE: To investigate the pro-inflammatory intracellular mechanisms induced by an in vitro model of dry eye disease (DED) on a Hela-modified conjunctiva-derived cells in hyperosmolarity (HO) stress conditions. This study focused on CCL2 induction and explored the implications of the nuclear factor of activated T cells 5 (NFAT5) as well as mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NFKB). This work was completed by an analysis of the effects of cyclosporine A (CsA), dexamethasone (Dex) and doxycycline (Dox) on HO-induced CCL2 and NFAT5 induction. METHODS: A human HeLa-modified conjunctiva-derived cell line was cultured in NaCl-hyperosmolar medium for various exposure times. Cellular viability, CCL2 secretion, NFAT5 and CCL2 gene expression, and intracytoplasmic NFAT5 were assessed using the Cell Titer Blue(r) assay, enzyme linked immunosorbent assay (ELISA), RT-qPCR and immunostaining, respectively. In selected experiments, inhibitors of MAPKs or NFkappaB, therapeutic agents or NFAT5 siRNAs were added before the hyperosmolar stimulations. RESULTS: HO induced CCL2 secretion and expression as well as NFAT5 gene expression and translocation. Adding NFAT5-siRNA before hyperosmolar stimulation led to a complete inhibition of CCL2 induction and to a decrease in cellular viability. p38 MAPK (p38), c-Jun NH2-terminal kinase (JNK) and NFKB inhibitors, CsA and Dex induced a partial inhibition of HO-induced CCL2, while Dox and extracellular signal-regulated kinase (ERK) inhibitor did not. Dex also induced a partial inhibition of HO induced NFAT5 gene expression but not CsA or Dox. CONCLUSIONS: These in vitro results suggest a potential role of CCL2 in DED and highlight the crucial role of NFAT5 in the pro-inflammatory effect of HO on HeLa-modified conjunctiva-derived cells, a rarely studied cellular type. This inflammatory pathway involving NFAT5 and CCL2 could offer a promising target for developing new therapies to treat DED, warranting further investigations to fully grasp the complete intracellular mechanisms. PMID- 27486751 TI - Exopolysaccharide Production by Sinorhizobium fredii HH103 Is Repressed by Genistein in a NodD1-Dependent Manner. AB - In the rhizobia-legume symbiotic interaction, bacterial surface polysaccharides, such as exopolysaccharide (EPS), lipopolysaccharide (LPS), K-antigen polysaccharide (KPS) or cyclic glucans (CG), appear to play crucial roles either acting as signals required for the progression of the interaction and/or preventing host defence mechanisms. The symbiotic significance of each of these polysaccharides varies depending on the specific rhizobia-legume couple. In this work we show that the production of exopolysaccharide by Sinorhizobium fredii HH103, but not by other S. fredii strains such as USDA257 or NGR234, is repressed by nod gene inducing flavonoids such as genistein and that this repression is dependent on the presence of a functional NodD1 protein. In agreement with the importance of EPS for bacterial biofilms, this reduced EPS production upon treatment with flavonoids correlates with decreased biofilm formation ability. By using quantitative RT-PCR analysis we show that expression of the exoY2 and exoK genes is repressed in late stationary cultures of S. fredii HH103 upon treatment with genistein. Results presented in this work show that in S. fredii HH103 EPS production is regulated just in the opposite way than other bacterial signals such as Nod factors and type 3 secreted effectors: it is repressed by flavonoids and NodD1 and enhanced by the nod repressor NolR. These results are in agreement with our previous observations showing that lack of EPS production by S. fredii HH103 is not only non-detrimental but even beneficial for symbiosis with soybean. PMID- 27486752 TI - Personality and Body-Mass-Index in School-Age Children: An Exploration of Mediating and Moderating Variables. AB - This study explored longitudinal associations between personality and body-mass index (BMI) in school-age children, including the potential mediating role of screen time and physical activity, and the potential moderating roles of child demographics and neighbourhood socioeconomic position. Participants were the parents (and teachers) of 3857 ten-year-old children, who completed questionnaires at baseline with a two-year follow-up. After controlling for child demographics (e.g., sex, pubertal status), we found that personality was unimportant for concurrent BMI, but was important for subsequent BMI and change in BMI over two years. Low levels of introversion and persistence at baseline, and decreases in persistence over time, were associated with a higher BMI at follow-up and a greater increase in BMI over time. Moderator analyses showed that introversion was more strongly related to subsequent BMI for children listed as aboriginal or Torres Strait Islander. The relationship between personality and change in BMI was mediated by screen time, but not by physical activity. To conclude, findings demonstrate that personality is important for change in body mass in Australian children (particularly indigenous children), and that screen based sedentary behaviour features an important role in this association. PMID- 27486753 TI - Mechanism of BRG1 silencing in primary cancers. AB - BRG1 (SMARCA4) is a documented tumor suppressor and a key subunit of the SWI/SNF chromatin remodeling complex that is silenced in many cancer types. Studies have shown that BRG1 is mutated in cancer-derived cell lines, which led to the assertion that BRG1 is also mutated in primary human tumors. However, the sequencing of BRG1-deficient tumors has revealed a paucity of mutations; hence, the cause of BRG1 silencing in tumors remains an enigma. We conducted immunohistochemistry (IHC) on a number of tumor microarrays to characterize the frequency of BRG1 loss in different tumor types. We also analyzed BRG1-deficient tumors by sequencing the genomic DNA and the mRNA. We then tested if BRG1 expression could be induced in BRG1-negative cell lines (i.e., that lack mutations in BRG1) after the application of several different epigenetic agents, including drugs that inhibit the AKT pathway. We found that a subset of BRG1 negative cell lines also demonstrated aberrant splicing of BRG1, and in at least 30% of BRG1-deficient tumors, BRG1 expression appeared to be suppressed due to aberrant BRG1 splicing. As the majority of BRG1-deficient tumors lack mutations or splicing defects that could drive BRG1 loss of expression, this suggests that other mechanisms underlie BRG1 silencing. To this end, we analyzed 3 BRG1 deficient nonmutated cancer cell lines and found that BRG1 was inducible in these cell lines upon inhibition of the AKT pathway. We show that the loss of BRG1 is associated with the loss of E-cadherin and up-regulation of Vimentin in primary tumors, which explains why BRG1 loss is associated with a poor prognosis in multiple tumor types. PMID- 27486754 TI - Inhibition of cyclin dependent kinase 9 by dinaciclib suppresses cyclin B1 expression and tumor growth in triple negative breast cancer. AB - Cyclin-dependent kinases (CDKs) are potential cancer therapeutic targets because of their critical role in promoting cell growth. Dinaciclib is a novel CDK inhibitor currently under clinical evaluation for the treatment of advanced malignancies. In this study, we demonstrated the anti-tumor activity of dinaciclib in triple negative breast cancer (TNBC) patient derived xenograft (PDX) and cell lines in vitro and in vivo. Treatment with dinaciclib induced cell cycle arrest at G2/M phase and marked apoptosis. These changes were accompanied by reduced phosphorylation of CDK1 and retinoblastoma (Rb) protein and decreased protein levels of cyclin B1, cMYC and survivin. We further demonstrated that siRNA knockdown of CDK9, the kinase subunit of positive transcription elongation factor b (P-TEFb), instead of CDK1 or CDK2, reduced the levels of cyclin B1 and MYC in TNBC cell lines. These data support the importance of CDK9, in addition to CDK1, in mediating the growth inhibitory effect of dinaciclib in TNBC. Further investigation of CDK9 as a therapeutic target in TNBC is needed. PMID- 27486755 TI - Fulvestrant inhibits growth of triple negative breast cancer and synergizes with tamoxifen in ERalpha positive breast cancer by up-regulation of ERbeta. AB - The estrogen receptor-alpha (ERalpha) is used as a predictive marker for anti estrogen therapy in breast cancer patients. In addition to aromatase inhibitors, ERalpha can be targeted at the receptor level using the receptor modulator tamoxifen or by the pure anti-estrogen fulvestrant. The role of the second ER, ER beta (ERbeta), as a therapeutic target or prognostic marker in breast cancer is still elusive. Hitherto, it is not known if ERalpha+/ERbeta+ breast cancers would benefit from a treatment strategy combining tamoxifen and fulvestrant or if fulvestrant exert any therapeutic effects in ERalpha-/ERbeta+ breast cancer. Here, we report that fulvestrant up-regulated ERbeta in ERalpha+/ERbeta+ breast cancer and in triple negative ERbeta+ breast cancers (ERalpha-/ERbeta+). In ERalpha+/ERbeta+ breast cancer, a combination therapy of tamoxifen and fulvestrant significantly reduced tumor growth compared to either treatment alone both in vivo and in vitro. In ERalpha-/ERbeta+ breast cancer fulvestrant had potent effects on cancer growth, in vivo as well as in vitro, and this effect was dependent on intrinsically expressed levels of ERbeta. The role of ERbeta was further confirmed in cells where ERbeta was knocked-in or knocked-down. Inhibition of DNA methyltransferase (DNMT) increased the levels of ERbeta and fulvestrant exerted similar potency on DNMT activity as the DNMT inhibitor decitabine. We conclude that fulvestrant may have therapeutic potential in additional groups of breast cancer patients; i) in ERalpha+/ERbeta+ breast cancer where fulvestrant synergizes with tamoxifen and ii) in triple negative/ERbeta+ breast cancer patients, a subgroup of breast cancer patients with poor prognosis. PMID- 27486756 TI - Simultaneous activation and inhibition of autophagy sensitizes cancer cells to chemotherapy. AB - While combined chemotherapy (CT) with an autophagy inducer and an autophagy inhibitor appears paradoxical, it may provide a more effective perturbation of autophagy pathways. We used two dissimilar cell lines to test the hypothesis that autophagy is the common denominator of cell fate after CT. HA22T cells are characterized by CT-induced apoptosis and use autophagy to prevent cell death, while Huh7.5.1 cells exhibit sustained autophagic morphology after CT. Combined CT and rapamycin treatment resulted in a better combination index (CI) in Huh7.5.1 cells than combined CT and chloroquine, while the reverse was true in HA22T cells. The combination of 3 drugs (triplet drug treatment) had the best CI. After triplet drug treatment, HA22T cells switched from protective autophagy to mitochondrial membrane permeabilization and endoplasmic reticulum stress response induced apoptosis, while Huh7.5.1 cells intensified autophagic lethality. Most importantly, both cell lines showed activation of Akt after CT, while the triplet combination blocked Akt activation through inhibition of phospholipid lipase D activity. This novel finding warrants further investigation as a broad chemosensitization strategy. PMID- 27486758 TI - Circulating tumor cells: A promising marker of predicting tumor response in rectal cancer patients receiving neoadjuvant chemo-radiation therapy. AB - PURPOSE: The aim of this study was to investigate the role of circulating tumor cells (CTCs) in assessing and predicting tumor response to neoadjuvant chemoradiotherapy (CRT) for patients with locally advanced rectal cancer (LARC). METHODS: A total of 115 patients with T3-4 and/or N+ rectal cancer were enrolled. All patients received neoadjuvant CRT followed by radical surgery after 6-8 weeks. The pathological results after surgery were evaluated according to tumor regression grade (TRG) classification. RESULTS: Based on TRG score, patients were classified as responders (TRG3-4) and non-responders (TRG0-2). The baseline CTC counts of responders were significantly higher than those of non-responders (44.50+/-11.94 vs. 37.67+/-15.45, P=0.012). By contrast, the post-CRT CTC counts of responders were significantly lower than those of non-responders (3.61+/-2.90 vs. 12.08+/-7.40, P<0.001). According to ROC analysis, Delta%CTC (percentage difference in CTC counts between baseline and post-CRT) was identified as the stronger predictor to discriminate responders from non-responders (AUC: 0.860). The results of multivariate analysis also indicated that post-CRT CTC counts and Delta%CTC were significantly and independently associated with tumor response to CRT. CONCLUSIONS: The detection of CTCs is a powerful and promising tool for evaluating and predicting responses to neoadjuvant CRT in LARC patients. PMID- 27486757 TI - The breast cancer susceptibility-related polymorphisms at the TOX3/LOC643714 locus associated with lung cancer risk in a Han Chinese population. AB - It has been well established that besides environmental factors, genetic factors are also associated with lung cancer risk. However, to date, the prior identified genetic variants and loci only explain a small fraction of the familial risk of lung cancer. Hence it is vital to investigate the remaining missing heritability to understand the development and process of lung cancer. In the study, to test our hypothesis that the previously identified breast cancer risk-associated genetic polymorphisms at the TOX3/LOC643714 locus might contribute to lung cancer risk, 16 SNPs at the TOX3/LOC643714 locus were evaluated in a Han Chinese population based on a case-control study. Pearson's chi-square test or Fisher's exact test revealed that rs9933638, rs12443621, and rs3104746 were significantly associated with lung cancer risk (P < 0.001, P < 0.001, and P = 0.005, respectively). Logistic regression analyses displayed that lung cancer risk of individuals with rs9933638(GG+GA) were 1.89 times higher than that of rs9933638AA carriers (OR = 1.893, 95% CI = 1.308-2.741, P = 0.001). Similar findings were manifested for rs12443621 (OR = 1.824, 95% CI = 1.272-2.616, P = 0.001, rs12443621(GG+GA) carriers vs. rs12443621AA carriers) and rs3104746 (OR = 1.665, 95% CI = 1.243-2.230, P = 0.001, rs3104746TT carriers vs. rs3104746(TA+AA) carriers). The study discovered for the first time that three SNPs (rs9933638, rs12443621, and rs3104746) at the TOX3/LOC643714 locus contributed to lung cancer risk, providing new evidences that lung cancer and breast cancer are linked at the molecular and genetic level to a certain extent. PMID- 27486759 TI - Chemo-immunotherapy induces tumor regression in a mouse model of spontaneous mammary carcinogenesis. AB - Tumor-specific immune tolerance represents an obstacle for the development of effective anti-tumor immune responses through cancer vaccines. We here evaluated the efficacy of chemo-immunotherapy in breaking tumor-specific immune tolerance in an almost incurable mouse model of spontaneous carcinogenesis.Transgenic HER 2/neu mice bearing large mammary tumors received the adoptive transfer of splenocytes and serum isolated from immune donors, with or without pre conditioning with cyclophosphamide. Treatment efficacy was assessed by monitoring tumor growth by manual inspection and by magnetic resonance imaging. The same chemo-immunotherapy protocol was tested on tumor-free HER-2/neu mice, to evaluate the effects on tumor emergence.Our data show that chemo-immunotherapy hampered carcinogenesis and caused the regression of large mammary tumor lesions in tumor bearing HER-2/neu mice. The complete eradication of a significant number of tumor lesions occurred only in mice receiving cyclophosphamide shortly before immunotherapy, and was associated with increased serum anti HER-2/p185 antibodies and tumor leukocyte infiltration. The same protocol significantly delayed the appearance of mammary tumors when administered to tumor-free HER-2/neu mice, indicating that this chemo-immunotherapy approach acted through the elicitation of an effective anti-tumor immune response. Overall, our data support the immune modulatory role of chemotherapy in overcoming cancer immune tolerance when administered at lymphodepleting non-myeloablative doses shortly before transfer of antigen-specific immune cells and immunoglobulins. These findings open new perspectives on combining immune-modulatory chemotherapy and immunotherapy to overcome immune tolerance in cancer patients. PMID- 27486760 TI - Combining GRP78 suppression and MK2206-induced Akt inhibition decreases doxorubicin-induced P-glycoprotein expression and mitigates chemoresistance in human osteosarcoma. AB - P-glycoprotein (P-gp) overexpression is associated with poor prognosis and drug resistance in osteosarcoma (OS), but the underlying mechanisms remain incompletely understood. Here, we examined the regulation of P-gp, GRP78, and phospho-Akt in doxorubicin (DOX)-treated OS cells. DOX induced P-gp expression, which was associated with increased GRP78 levels and Akt activation in vitro and in vivo. Functional analysis showed that Akt induces P-gp and GRP78 expression, which contributes to the DOX-induced Akt activation. Examination of the relationship between Akt and GRP78 demonstrated that GRP78 suppression attenuates the Akt activity in OS parental sensitive and resistant cells, indicating that GRP78 is required for full Akt activity. Inhibition of Akt activity using MK2206 decreased GRP78 expression in OS cells, which enhanced the inhibitory effect of MK2206 on P-gp expression. GRP78 knockdown combined with MK2206 suppressed the development of DOX resistance in OS cells and inhibited the in vivo tumor growth in the presence of DOX. These results support the development of novel therapeutic strategies that target GRP78 and Akt to sensitize OS cells for chemotherapy. PMID- 27486761 TI - Intratumoral heterogeneity of the therapeutical response to gemcitabine and metformin. AB - Cancer heterogeneity and microenvironmental aspects within a tumor are considered key factors influencing resistance of carcinoma cells to distinct chemotherapeutical agents. We evaluated a high concentration of metformin in combination with gemcitabine on a syngeneic orthotopic mouse model using 6606PDA cells. We observed reduced tumor size and reduced cancer cell proliferation after three weeks of chemotherapy with either compound and noticed an additive effect between gemcitabine and metformin on tumor weight. Interestingly, distinct areas of the carcinoma responded differently to either compound. Metformin inhibited the proliferation of cancer cells close to the desmoplastic reaction, whereas gemcitabine inhibited the proliferation of cancer cells mainly 360-570 MUm distant to the desmoplastic reaction. Indeed, co-culture of pancreatic stellate cells with 6606PDA, 7265PDA or MIA PaCa-2 cells increased gemcitabine resistance. Metformin resistance, however, was increased by high glucose concentration in the medium. Other factors such as hypoxia or the pH of the medium had no influence on gemcitabine or metformin induced inhibition of cancer cell proliferation. These data demonstrate a spatial heterogeneity in drug resistance within pancreatic adenocarcinomas and that microenvironmental aspects such as supply of glucose and the presence of pancreatic stellate cells regulate cancer cell sensitivity towards metformin or gemcitabine. PMID- 27486763 TI - Inhibition of the colony-stimulating-factor-1 receptor affects the resistance of lung cancer cells to cisplatin. AB - In the present work we show that multiple lung cancer cell lines contain cisplatin resistant cell subpopulations expressing the Colony-Stimulating-Factor Receptor-1 (CSF-1R) and surviving chemotherapy-induced stress. By exploiting siRNA-mediated knock down in vitro and the use of an investigational CSF-1R TKI (JNJ-40346527) in vitro and in vivo, we show that expression and function of the receptor are required for the clonogenicity and chemoresistance of the cell lines. Thus, inhibition of the kinase activity of the receptor reduced the levels of EMT-associated genes, stem cell markers and chemoresistance genes. Additionally, the number of high aldehyde dehydrogenase (ALDH) expressing cells was reduced, consequent to the lack of cisplatin-induced increase of ALDH isoforms. This affected the collective chemoresistance of the treated cultures. Treatment of tumor bearing mice with JNJ-40346527, at pharmacologically relevant doses, produced strong chemo-sensitizing effects in vivo. These anticancer effects correlated with a reduced number of CSF-1Rpos cells, in tumors excised from the treated mice. Depletion of the CD45pos cells within the treated tumors did not, apparently, play a major role in mediating the therapeutic response to the TKI. Thus, lung cancer cells express a functional CSF-1 and CSF-1R duo which mediates pro-tumorigenic effects in vivo and in vitro and can be targeted in a therapeutically relevant way. These observations complement the already known role for the CSF-1R at mediating the pro-tumorigenic properties of tumor infiltrating immune components. PMID- 27486764 TI - C-Myc functions as a competing endogenous RNA in acute promyelocytic leukemia. AB - Recent reports have described a new post-transcriptional regulation that RNA transcripts can crosstalk with each other by competing for their common microRNAs. These RNA transcripts termed competing endogenous RNAs (ceRNAs) regulate the distribution of miRNAs on their targets. One corollary from ceRNA interaction is that chromosomal translocation in acute promyelocytic leukemia (APL) would perturb ceRNA regulation due to altered expression of 3'UTRs. In our study, we demonstrate that expression of PML/RARalpha, the APL-associated fusion oncogene is repressed by c-Myc mRNA transcript independent of protein-coding function but dependent upon microRNA. Attenuation of c-Myc transcript results in PML/RARalpha-degraded cellular phenotypes in APL cells, but these Myc reduction associated cell phenotypes are sufficient to abrogate in a microRNA dependent manner. We also show that let-7 microRNA family members promote differentiation of All-Trans-Retinoic Acid (ATRA)-induced NB4 cells and their activities are affected by expression levels of both c-Myc and PML/RARalpha through altering miRNA targets. These results indicate that c-Myc mRNA represses PML/RARalpha expression via altering the distribution of let-7 miRNAs on their targets. Our findings reveal a previously unrecognized role of c-Myc as a potential ceRNA for PML/RARalpha in APL. PMID- 27486766 TI - Loss of ARID1A expression leads to sensitivity to ROS-inducing agent elesclomol in gynecologic cancer cells. AB - Inactivating mutations in ARID1A are found in a broad spectrum of cancer types, with the highest frequency in gynecologic cancers. However, therapeutic strategies targeting ARID1A-mutant cancer cells remain limited. In this study, we aimed to identify drugs sensitivities in ARID1A-mutant cancer cell lines. By analyzing the Genomics of Drug Sensitivity in Cancer database, we found that ARID1A-mutant cancer cell lines were more sensitive to treatment with the reactive oxygen species (ROS)-inducing agent elesclomol. In a panel of 14 gynecologic cancer cell lines, treatment with elesclomol inhibited growth and induced apoptosis more potently in ARID1A-mutant cells. Knockdown of ARID1A in RMG1 and OVCA432 ovarian cancer cells resulted in increased sensitivity to elesclomol, whereas restoration of ARID1A expression in TOV21G ovarian cancer cells resulted in increased resistance to elesclomol. Furthermore, we found that knockdown of ARID1A expression resulted in increased intracellular ROS levels. In ovarian clear cell carcinoma patient samples, low expression of ARID1A correlated with high expression of 8-hydroxyguanosine, a marker for oxidative stress. In summary, we demonstrate for the first time that loss of ARID1A leads to accumulation of ROS and suggest that elesclomol may be used to target ARID1A mutant gynecologic cancer cells. PMID- 27486767 TI - Identification of genetic variants predictive of early onset pancreatic cancer through a population science analysis of functional genomic datasets. AB - Biomarkers are critically needed for the early detection of pancreatic cancer (PC) are urgently needed. Our purpose was to identify a panel of genetic variants that, combined, can predict increased risk for early-onset PC and thereby identify individuals who should begin screening at an early age. Previously, we identified genes using a functional genomic approach that were aberrantly expressed in early pathways to PC tumorigenesis. We now report the discovery of single nucleotide polymorphisms (SNPs) in these genes associated with early age at diagnosis of PC using a two-phase study design. In silico and bioinformatics tools were used to examine functional relevance of the identified SNPs. Eight SNPs were consistently associated with age at diagnosis in the discovery phase, validation phase and pooled analysis. Further analysis of the joint effects of these 8 SNPs showed that, compared to participants carrying none of these unfavorable genotypes (median age at PC diagnosis 70 years), those carrying 1-2, 3-4, or 5 or more unfavorable genotypes had median ages at diagnosis of 64, 63, and 62 years, respectively (P = 3.0E-04). A gene-dosage effect was observed, with age at diagnosis inversely related to number of unfavorable genotypes (Ptrend = 1.0E-04). Using bioinformatics tools, we found that all of the 8 SNPs were predicted to play functional roles in the disruption of transcription factor and/or enhancer binding sites and most of them were expression quantitative trait loci (eQTL) of the target genes. The panel of genetic markers identified may serve as susceptibility markers for earlier PC diagnosis. PMID- 27486768 TI - Functional intratumoral lymphatics in patient-derived xenograft models of squamous cell carcinoma of the uterine cervix: implications for lymph node metastasis. AB - Studies of cell line-derived human tumor xenografts have suggested that the lymphatics seen in immunohistochemical preparations from non-peripheral regions of tumors are nonfunctional. In this investigation, lymphangiogenesis, hemangiogenesis, and lymph node metastasis were studied in patient-derived xenograft (PDX) models of carcinoma of the uterine cervix. Lymph vessel density (LVD) and blood vessel density (BVD) were measured in immunohistochemical preparations. The expression of angiogenesis-related genes was investigated by quantitative PCR. Lymphatic functionality was assessed with the ferritin assay, and tumor interstitial fluid pressure (IFP) was measured with a Millar catheter. The PDX models mirrored the angiogenesis and aggressiveness of the donor patients' tumors, and two highly aggressive models developed functional lymphatics within the tumor mass. Tumors with functional intratumoral lymphatics showed low IFP, high LVD, high BVD, high expression of a large number of angiogenesis-related genes, and high incidence of lymph node metastases. LVD correlated with BVD, and lymph node metastasis was associated with high LVD and high BVD. Nine angiogenesis-related genes associated with the development of functional intratumoral lymhatics were identified. High expression of these genes, high LVD, and high BVD may be important biomarkers for poor outcome in cervix carcinoma. PMID- 27486769 TI - Radio-frequency plasma polymerized biodegradable carrier for in vivo release of cis-platinum. AB - A low pressure plasma process based on plasma deposition has been used to develop a drug delivery strategy. In this study, a drug delivery system based on different layers of plasma co-polymerized Poly epsilon-caprolactone-Polyethylene glycol (PCL-PEG) co-polymers was deposited on biocompatible substrates. Cis platinum (118 MUgm/cm2) was used as an anti-cancer drug and incorporated for local delivery of the chemotherapeutic agent. The co-polymer layers and their interaction with cancer cells were analyzed by scanning electron microscopy. Our study showed that the plasma-PCL-PEG coated cellophane membranes, in which the drug, was included did not modify the flexibility and appearance of the membranes. This system was actively investigated as an alternative method of controlling localized delivery of drug in vivo. The loading of the anti-cancer drug was investigated by UV-VIS spectroscopy and its release from plasma deposited implants against BALB/c mice liver tissues were analyzed through histological examination and apoptosis by TUNEL assay. The histological examination of liver tissues revealed that when the plasma-modified membranes encapsulated the cis-platinum, the Glisson's capsule and liver parenchyma were damaged. In all cases, inflammatory tissues and fibrosis cells were observed in contact zones between the implant and the liver parenchyma. In conclusion, low pressure plasma deposited uniform nano-layers of the co-polymers can be used for controlled release of the drug in vivo. PMID- 27486770 TI - A retrospective analysis in patients with EGFR-mutant lung adenocarcinoma: is EGFR mutation associated with a higher incidence of brain metastasis? AB - Lung adenocarcinomas are more commonly associated with brain metastases (BM). Epidermal growth factor receptor (EGFR) mutations have been demonstrated to be both predictive and prognostic for patients with lung adenocarcinoma. We aimed to explore the potential association between EGFR mutation and the risk of BM in pulmonary adenocarcinoma patients. Data of 234 patients from 2007 to 2014 were retrospectively reviewed. A total of 108 patients had EGFR mutations in the entire cohort. Among them, 76 patients developed BM during their disease course. The incidence of BM was statistically higher in patients with EGFR mutations both at initial diagnosis (P=0.014) and at last follow-up (P<0.001). Multivariate logistic regression analysis revealed that EGFR mutation significantly increased the risk of BM at initial diagnosis (OR=2.515, P=0.022). In patients without BM at initial diagnosis, the accumulative rate of subsequent BM was significantly higher with EGFR mutations (P=0.001). Multivariate Cox regression analysis identified EGFR mutation as the only independent risk factor for subsequent BM (HR=3.036, P=0.001). Patients with EGFR mutations demonstrated longer overall survival (OS) after BM diagnosis than patients with wild-type EGFR (P=0.028). Our data suggest that EGFR mutation is an independent predictive and prognostic risk factor for BM and a positive predictive factor for OS in patients with BM. PMID- 27486771 TI - The underlying mechanism of proinflammatory NF-kappaB activation by the mTORC2/Akt/IKKalpha pathway during skin aging. AB - Mammalian target of rapamycin complex 2 (mTORC2), one of two different enzymatic complexes of mTOR, regulates a diverse set of substrates including Akt. mTOR pathway is one of well-known mediators of aging process, however, its role in skin aging has not been determined. Skin aging can be induced by physical age and ultraviolet (UV) irradiation which are intrinsic and extrinsic factors, respectively. Here, we report increased mTORC2 pathway in intrinsic and photo induced skin aging, which is implicated in the activation of nuclear factor kappaB (NF-kappaB). UVB-irradiated or aged mice skin revealed that mTORC2 activity and its component, rictor were significantly upregulated which in turn increased Akt activation and Akt-dependent IkappaB kinase alpha (IKKalpha) phosphorylation at Thr23 in vivo. We also confirmed that UVB induced the mTORC2/Akt/IKKalpha signaling pathway with HaCaT human normal keratinocytes. The increased mTORC2 signaling pathway during skin aging were associated to NF-kappaB activation. Suppression of mTORC2 activity by the treatment of a mTOR small inhibitor or knockdown of RICTOR partially rescued UVB-induced NF-kappaB activation through the downregulation of Akt/IKKalpha activity. Our data demonstrated the upregulation of mTORC2 pathway in intrinsic and photo-induced skin aging and its role in IKKalpha/NF-kappaB activation. These data not only expanded the functions of mTOR to skin aging but also revealed the therapeutic potential of inhibiting mTORC2 in ameliorating both intrinsic skin aging and photoaging. PMID- 27486773 TI - Integrated analysis miRNA and mRNA profiling in patients with severe oligozoospermia reveals miR-34c-3p downregulates PLCXD3 expression. AB - Our previous research suggested that an integrated analysis of microRNA (miRNA) and messenger RNA (mRNA) expression is helpful to explore miRNA-mRNA interactions and to uncover the molecular mechanisms of male infertility. In this study, microarrays were used to compare the differences in the miRNA and mRNA expression profiles in the testicular tissues of severe oligozoospermia (SO) patients with obstructive azoospermia (OA) controls with normal spermatogenesis. Four miRNAs (miR-1246, miR-375, miR-410, and miR-758) and six mRNAs (SLC1A3, PRKAR2B, HYDIN, WDR65, PRDX1, and ADATMS5) were selected to validate the microarray data using quantitative real-time PCR. Using statistical calculations and bioinformatics predictions, we identified 33 differentially expressed miRNAs and 1,239 differentially expressed mRNAs, among which one potential miRNA-target gene pair, miR-34c-3p and PLCXD3 (Phosphatidylinositol-Specific Phospholipase C, X Domain Containing 3), was identified. Immunohistochemical analysis indicated that PLCXD3 was located within the germ cells of the mouse and human testis. Moreover, we found that miR-34c-3p was able to decrease PLCXD3 expression in mouse (GC-1 and TM4) and human (NCM460) cell lines, presumably indicating the possibility that miR-34c-3p acts as an intracellular mediator in germinal lineage differentiation. Notably, we reported the expression of the PLCXD3 protein in a man with normal spermatogenesis and the lack of the PLCXD3 protein in a man with SO. Therefore, the identified miRNA and mRNA may represent a potentially novel molecular regulatory network and therapeutic targets for the study or treatment of SO, which might provide a better understanding of the molecular basis of spermatogenesis dysfunction. PMID- 27486772 TI - Decellularized scaffolds in regenerative medicine. AB - Allogeneic organ transplantation remains the ultimate solution for end-stage organ failure. Yet, the clinical application is limited by the shortage of donor organs and the need for lifelong immunosuppression, highlighting the importance of developing effective therapeutic strategies. In the field of regenerative medicine, various regenerative technologies have lately been developed using various biomaterials to address these limitations. Decellularized scaffolds, derived mainly from various non-autologous organs, have been proved a regenerative capability in vivo and in vitro and become an emerging treatment approach. However, this regenerative capability varies between scaffolds as a result of the diversity of anatomical structure and cellular composition of organs used for decellularization. Herein, recent advances in scaffolds based on organ regeneration in vivo and in vitro are highlighted along with aspects where further investigations and analyses are needed. PMID- 27486777 TI - Constrained Score Statistics Identify Genetic Variants Interacting with Multiple Risk Factors in Barrett's Esophagus. AB - Few gene-environment interactions (G * E) have been discovered in cancer epidemiology thus far, in part due to the large number of possible G * E to be investigated and inherent low statistical power of traditional analytic methods for discovering G * E. We consider simultaneously testing for interactions between several related exposures and a genetic variant in a genome-wide study. To improve power, constrained testing strategies are proposed for multivariate gene-environment interactions at two levels: interactions that have the same direction (one-sided or bidirectional hypotheses) or are proportional to respective exposure main effects (a variant of Tukey's one-degree test). Score statistics were developed to expedite the genome-wide computation. We conducted extensive simulations to evaluate validity and power performance of the proposed statistics, applied them to the genetic and environmental exposure data for esophageal adenocarcinoma and Barrett's esophagus from the Barretts Esophagus and Esophageal Adenocarcinoma Consortium (BEACON), and discovered three loci simultaneously interacting with gastresophageal reflux, obesity, and tobacco smoking with genome-wide significance. These findings deepen understanding of the genetic and environmental architecture of Barrett's esophagus and esophageal adenocarcinoma. PMID- 27486776 TI - Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome. AB - Bardet-Biedl syndrome (BBS) is a defining ciliopathy, notable for extensive allelic and genetic heterogeneity, almost all of which has been identified through sequencing. Recent data have suggested that copy-number variants (CNVs) also contribute to BBS. We used a custom oligonucleotide array comparative genomic hybridization (aCGH) covering 20 genes that encode intraflagellar transport (IFT) components and 74 ciliopathy loci to screen 92 unrelated individuals with BBS, irrespective of their known mutational burden. We identified 17 individuals with exon-disruptive CNVs (18.5%), including 13 different deletions in eight BBS genes (BBS1, BBS2, ARL6/BBS3, BBS4, BBS5, BBS7, BBS9, and NPHP1) and a deletion and a duplication in other ciliopathy-associated genes (ALMS1 and NPHP4, respectively). By contrast, we found a single heterozygous exon-disruptive event in a BBS-associated gene (BBS9) in 229 control subjects. Superimposing these data with resequencing revealed CNVs to (1) be sufficient to cause disease, (2) Mendelize heterozygous deleterious alleles, and (3) contribute oligogenic alleles by combining point mutations and exonic CNVs in multiple genes. Finally, we report a deletion and a splice site mutation in IFT74, inherited under a recessive paradigm, defining a candidate BBS locus. Our data suggest that CNVs contribute pathogenic alleles to a substantial fraction of BBS-affected individuals and highlight how either deletions or point mutations in discrete splice isoforms can induce hypomorphic mutations in genes otherwise intolerant to deleterious variation. Our data also suggest that CNV analyses and resequencing studies unbiased for previous mutational burden is necessary to delineate the complexity of disease architecture. PMID- 27486774 TI - Ubc13: the Lys63 ubiquitin chain building machine. AB - Ubc13 is an ubiquitin E2 conjugating enzyme that participates with many different E3 ligases to form lysine 63-linked (Lys63) ubiquitin chains that are critical to signaling in inflammatory and DNA damage response pathways. Recent studies have suggested Ubc13 as a potential therapeutic target for intervention in various human diseases including several different cancers, alleviation of anti-cancer drug resistance, chronic inflammation, and viral infections. Understanding a potential therapeutic target from different angles is important to assess its usefulness and potential pitfalls. Here we present a global review of Ubc13 from its structure, function, and cellular activities, to its natural and chemical inhibition. The aim of this article is to review the literature that directly implicates Ubc13 in a biological function, and to integrate structural and mechanistic insights into the larger role of this critical E2 enzyme. We discuss observations of multiple Ubc13 structures that suggest a novel mechanism for activation of Ubc13 that involves conformational change of the active site loop. PMID- 27486778 TI - Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis. AB - Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 * 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping. PMID- 27486779 TI - Defining KIR and HLA Class I Genotypes at Highest Resolution via High-Throughput Sequencing. AB - The physiological functions of natural killer (NK) cells in human immunity and reproduction depend upon diverse interactions between killer cell immunoglobulin like receptors (KIRs) and their HLA class I ligands: HLA-A, HLA-B, and HLA-C. The genomic regions containing the KIR and HLA class I genes are unlinked, structurally complex, and highly polymorphic. They are also strongly associated with a wide spectrum of diseases, including infections, autoimmune disorders, cancers, and pregnancy disorders, as well as the efficacy of transplantation and other immunotherapies. To facilitate study of these extraordinary genes, we developed a method that captures, sequences, and analyzes the 13 KIR genes and HLA-A, HLA-B, and HLA-C from genomic DNA. We also devised a bioinformatics pipeline that attributes sequencing reads to specific KIR genes, determines copy number by read depth, and calls high-resolution genotypes for each KIR gene. We validated this method by using DNA from well-characterized cell lines, comparing it to established methods of HLA and KIR genotyping, and determining KIR genotypes from 1000 Genomes sequence data. This identified 116 previously uncharacterized KIR alleles, which were all demonstrated to be authentic by sequencing from source DNA via standard methods. Analysis of just two KIR genes showed that 22% of the 1000 Genomes individuals have a previously uncharacterized allele or a structural variant. The method we describe is suited to the large scale analyses that are needed for characterizing human populations and defining the precise HLA and KIR factors associated with disease. The methods are applicable to other highly polymorphic genes. PMID- 27486780 TI - TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization. AB - Multiprotein complexes referred to as outer dynein arms (ODAs) develop the main mechanical force to generate the ciliary and flagellar beat. ODA defects are the most common cause of primary ciliary dyskinesia (PCD), a congenital disorder of ciliary beating, characterized by recurrent infections of the upper and lower airways, as well as by progressive lung failure and randomization of left-right body asymmetry. Using a whole-exome sequencing approach, we identified recessive loss-of-function mutations within TTC25 in three individuals from two unrelated families affected by PCD. Mice generated by CRISPR/Cas9 technology and carrying a deletion of exons 2 and 3 in Ttc25 presented with laterality defects. Consistently, we observed immotile nodal cilia and missing leftward flow via particle image velocimetry. Furthermore, transmission electron microscopy (TEM) analysis in TTC25-deficient mice revealed an absence of ODAs. Consistent with our findings in mice, we were able to show loss of the ciliary ODAs in humans via TEM and immunofluorescence (IF) analyses. Additionally, IF analyses revealed an absence of the ODA docking complex (ODA-DC), along with its known components CCDC114, CCDC151, and ARMC4. Co-immunoprecipitation revealed interaction between the ODA-DC component CCDC114 and TTC25. Thus, here we report TTC25 as a new member of the ODA-DC machinery in humans and mice. PMID- 27486781 TI - Isolated and Syndromic Retinal Dystrophy Caused by Biallelic Mutations in RCBTB1, a Gene Implicated in Ubiquitination. AB - Inherited retinal dystrophies (iRDs) are a group of genetically and clinically heterogeneous conditions resulting from mutations in over 250 genes. Here, homozygosity mapping and whole-exome sequencing (WES) in a consanguineous family revealed a homozygous missense mutation, c.973C>T (p.His325Tyr), in RCBTB1. In affected individuals, it was found to segregate with retinitis pigmentosa (RP), goiter, primary ovarian insufficiency, and mild intellectual disability. Subsequent analysis of WES data in different cohorts uncovered four additional homozygous missense mutations in five unrelated families in whom iRD segregates with or without syndromic features. Ocular phenotypes ranged from typical RP starting in the second decade to chorioretinal dystrophy with a later age of onset. The five missense mutations affect highly conserved residues either in the sixth repeat of the RCC1 domain or in the BTB1 domain. A founder haplotype was identified for mutation c.919G>A (p.Val307Met), occurring in two families of Mediterranean origin. We showed ubiquitous mRNA expression of RCBTB1 and demonstrated predominant RCBTB1 localization in human inner retina. RCBTB1 was very recently shown to be involved in ubiquitination, more specifically as a CUL3 substrate adaptor. Therefore, the effect on different components of the CUL3 and NFE2L2 (NRF2) pathway was assessed in affected individuals' lymphocytes, revealing decreased mRNA expression of NFE2L2 and several NFE2L2 target genes. In conclusion, our study puts forward mutations in RCBTB1 as a cause of autosomal recessive non-syndromic and syndromic iRD. Finally, our data support a role for impaired ubiquitination in the pathogenetic mechanism of RCBTB1 mutations. PMID- 27486784 TI - Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10, a Manganese Transporter in Man. PMID- 27486783 TI - Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility. AB - Primary ciliary dyskinesia (PCD) is an autosomal-recessive disease due to functional or ultra-structural defects of motile cilia. Affected individuals display recurrent respiratory-tract infections; most males are infertile as a result of sperm flagellar dysfunction. The great majority of the PCD-associated genes identified so far encode either components of dynein arms (DAs), which are multiprotein-ATPase complexes essential for ciliary motility, or proteins involved in DA assembly. To identify the molecular basis of a PCD phenotype characterized by central complex (CC) defects but normal DA structure, a phenotype found in ~15% of cases, we performed whole-exome sequencing in a male individual with PCD and unexplained CC defects. This analysis, combined with whole-genome SNP genotyping, identified a homozygous mutation in DNAJB13 (c.833T>G), a gene encoding a HSP40 co-chaperone whose ortholog in the flagellated alga Chlamydomonas localizes to the radial spokes. In vitro studies showed that this missense substitution (p.Met278Arg), which involves a highly conserved residue of several HSP40 family members, leads to protein instability and triggers proteasomal degradation, a result confirmed by the absence of endogenous DNAJB13 in cilia and sperm from this individual. Subsequent DNAJB13 analyses identified another homozygous mutation in a second family; the study of DNAJB13 transcripts obtained from airway cells showed that this mutation (c.68+1G>C) results in a splicing defect consistent with a loss-of-function mutation. Overall, this study, which establishes mutations in DNAJB13 as a cause of PCD, unveils the key role played by DNAJB13 in the proper formation and function of ciliary and flagellar axonemes in humans. PMID- 27486782 TI - Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis. AB - Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0.33, discovery + replication p = 6.38 * 10(-10)) and a rare synonymous variant in GFI1B (rs150813342, MAF = 0.009, discovery + replication p = 1.79 * 10(-27)). By performing CRISPR/Cas9 genome editing in hematopoietic cell lines and follow-up targeted knockdown experiments in primary human hematopoietic stem and progenitor cells, we demonstrate an alternative splicing mechanism by which the GFI1B rs150813342 variant suppresses formation of a GFI1B isoform that preferentially promotes megakaryocyte differentiation and platelet production. These results demonstrate how unbiased studies of natural variation in blood cell traits can provide insight into the regulation of human hematopoiesis. PMID- 27486786 TI - In Silico Design of Halogen-Bonding-Based Organocatalyst for Diels-Alder Reaction, Claisen Rearrangement, and Cope-Type Hydroamination. AB - Using DFT calculations, we investigated the use of halogen bonding (XB) interactions to accelerate and control organic reactions, namely Diels-Alder reaction, Claisen rearrangement, and Cope-type hydroamination. Our designed triarylbenzene tripodal organocatalyst is characterized by three halogen bond donors, perfluoro-iodophenyl groups. The calculated transition states unravel multiple halogen bonds between the iodine atoms and various types of halogen bond acceptors (lone pair, pi and sigma bonds). These cooperative noncovalent interactions provide efficient binding between the catalyst and substrate (~15 kcal/mol binding energy) and are the key factors for transition-state stabilization and molecular recognition. On the basis of our DFT calculations and calculated turnover frequencies, the XB-catalyzed reactions are found to be competitive with the corresponding hydrogen bonding catalysis reported in literature. PMID- 27486785 TI - Microfluidic Synthesis and Biological Evaluation of Photothermal Biodegradable Copper Sulfide Nanoparticles. AB - The continuous synthesis of biodegradable photothermal copper sulfide nanoparticles has been carried out with the aid of a microfluidic platform. A comparative physicochemical characterization of the resulting products from the microreactor and from a conventional batch reactor has been performed. The microreactor is able to operate in a continuous manner and with a 4-fold reduction in the synthesis times compared to that of the conventional batch reactor producing nanoparticles with the same physicochemical requirements. Biodegradation subproducts obtained under simulated physiological conditions have been identified, and a complete cytotoxicological analysis on different cell lines was performed. The photothermal effect of those nanomaterials has been demonstrated in vitro as well as their ability to generate reactive oxygen species. PMID- 27486787 TI - Correction to Discovery of a Potent and Selective Coactivator Associated Arginine Methyltransferase 1 (CARM1) Inhibitor by Virtual Screening. PMID- 27486788 TI - Chiral Perylene Materials by Ionic Self-Assembly. AB - Two chiral complexes (1-SDS and 1-SDBS) were prepared via the ionic self-assembly of a chiral perylene diimide tecton with oppositely charged surfactants. The effect of surfactant tail architecture on the self-assembly properties and supramolecular structure was investigated in detail using UV-vis, IR, circular dichroism, light microscopy, X-ray diffraction studies, and electron microscopy. The results obtained revealed the molecular chirality of the parent perylene tecton could be translated into supramolecular helical chirality of the resulting complexes via primary ionic interactions through careful choice of solvent and concentration. Differing solvent-dependent aggregation behavior was observed for these complexes as a result of the different possible noncovalent interactions via the surfactant alkyl tails. The results presented in this study demonstrate that ionic self-assembly (ISA) is a facile strategy for the production of chiral supramolecular materials based on perylene diimides. The structure-function relationship is easily explored here due to the wide selection and easy availability of common surfactants. PMID- 27486789 TI - State-to-State Mode Specificity in F + CHD3 -> HF/DF + CD3/CHD2 Reaction. AB - The F + CHD3 -> HF/DF + CD3/CHD2 reaction is studied using a state-to-state quasi classical trajectory method on a recently developed ab initio based full dimensional potential energy surface. Consistent with sudden vector projection model predictions, the HF/DF products are highly excited in both vibrational and rotational modes, while the CD3/CHD2 product internal excitation is mostly in the umbrella/out-of-plane mode. Furthermore, the C-H stretching vibration in the CHD3 reactant is found to behave as an active mode for the HF + CD3 channel, leading to additional excitation in the HF product but having almost no impact on CD3 vibrational state distributions. On the other hand, this mode acts as a spectator for the DF + CHD2 channel, exerting little influence on the DF and other CHD2 vibrational modes except an extra quantum excitation in the C-H stretching mode. The calculated vibrational state resolved differential cross sections are in good agreement with available experimental results at Ec = 9.00 kcal/mol. PMID- 27486790 TI - Construction of Covalent Organic Nanotubes by Light-Induced Cross-Linking of Diacetylene-Based Helical Polymers. AB - Organic nanotubes (ONTs) are tubular nanostructures composed of small molecules or macromolecules that have found various applications including ion sensor/channels, gas absorption, and photovoltaics. While most ONTs are constructed by self-assembly processes based on weak noncovalent interactions, this unique property gives rise to the inherent instability of their tubular structures. Herein, we report a simple "helix-to-tube" strategy to construct robust, covalent ONTs from easily accessible poly(m-phenylene diethynylene)s (poly-PDEs) possessing chiral amide side chains that can adopt a helical conformation through hydrogen-bonding interactions. The helically folded poly PDEs subsequently undergo light-induced cross-linking at longitudinally aligned 1,3-butadiyne moieties across the whole helix to form covalent tubes (ONTs) both in solution and solid phases. The structures of poly-PDEs and covalent ONTs were characterized by spectroscopic analyses, diffraction analysis, and microscopic analyses. We envisage that this simple yet powerful "helix-to-tube" strategy will generate a range of ONT-based materials by introducing functional moieties into a monomer. PMID- 27486791 TI - Unexpected Ring Expansion of a Four-Membered Cyclophosphazane. AB - Nucleophilic substitution reactions of the N(R),N(R)-spiro-bridged octachlorobis(cyclotriphosphazene), N3P3Cl4[N(CH2)5CH3]2N3P3Cl4 (1), with sodium salts of alcohols (1,3-propanediol, 2,2,3,3,4,4-hexafluoro-1,5-pentanediol, and phenol) give ansa products (2-4) via an unexpected rearrangement. These products were characterized by elemental analysis, mass spectrometry, and (1)H and (31)P NMR spectroscopy. The molecular structures of compounds 3 and 4 were also established by X-ray crystallography. This new class of phosphazene structures consists of three fused P3N3 rings that arise from expansion of the four-membered phosphazane ring in 1 to a six-membered N3P3 ring during alcoholysis reactions. PMID- 27486792 TI - Aryne Compatible Solvents are not Always Innocent. AB - Arynes are important and versatile intermediates in a variety of transformations. Commonly used solvents for aryne chemistry include acetonitrile and dichloromethane. Although rarely reported, the reactive nature of aryne intermediates makes them prone to side reactions, which sometimes involve solvent participation. Acetonitrile and dichloromethane are not always innocent solvents and can participate in aryne-based reactions. These results are presented in the context of ongoing mechanistic investigations of the triple aryne-tetrazine reaction. PMID- 27486793 TI - LI-RADS-CEUS - Proposal for a Contrast-Enhanced Ultrasound Algorithm for the Diagnosis of Hepatocellular Carcinoma in High-Risk Populations. AB - Purpose: To develop a contrast-enhanced ultrasound algorithm (LI-RADS-CEUS = liver imaging reporting and data system with contrast-enhanced ultrasound) for the diagnosis of hepatocellular carcinoma (HCC) in patients at risk. Materials and Methods: A CEUS algorithm (LI-RADS-CEUS) was designed analogously to CT- and MRI-based LI-RADS. LI-RADS-CEUS was evaluated retrospectively in 50 patients at risk with confirmed HCC or non-HCC lesions (test group) with subsequent validation in a prospective cohort of 50 patients (validation group). Results were compared to histology, CE-CT and CE-MRI as reference standards. Results: Tumor diagnosis in the test group/validation group (n = 50/50) were 46/41 HCCs, 3/3 intrahepatic cholangiocellular carcinomas (ICCs) and 1/6 benign lesions. The diagnostic accuracy of LI-RADS-CEUS for HCC, ICC and non-HCC-non-ICC-lesions was 89 %. For the diagnosis of HCC, the diagnostic accuracy was 93.5 % (43/46 cases) in the test group and 95.1 % (39/41 cases) in the validation group. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 94.3 %, 66.6 %, 94.3 % and 66.6 %, respectively (mean values from both cohorts). Histological findings of HCC were available in 40 versus 23 cases (in total: G1 / G2/G3: 15/35/13). Arterial hyperenhancement was seen in 68/87 (78.2 %) of HCCs. Arterial hyperenhancement with subsequent portal venous or late phase hypoenhancement was seen in 66 % of HCCs. Conclusion: LI-RADS-CEUS offers a CEUS algorithm for standardized assessment and reporting of focal liver lesions in patients at risk for HCC. Arterial hyperenhancement in CEUS is the key feature for the diagnosis of HCC in patients at risk, whereas washout is not a necessary prerequisite. PMID- 27486794 TI - High Spatial Inhomogeneity in the Intima-Media Thickness of the Common Carotid Artery is Associated with a Larger Degree of Stenosis in the Internal Carotid Artery: The PARISK Study. AB - Purpose Inhomogeneity of arterial wall thickness may be indicative of distal plaques. This study investigates the intra-subject association between relative spatial intima-media thickness (IMT) inhomogeneity of the common carotid artery (CCA) and the degree of stenosis of plaques in the internal carotid artery (ICA). Materials and Methods We included 240 patients with a recent ischemic stroke or transient ischemic attack and mild-to-moderate stenosis in the ipsilateral ICA. IMT inhomogeneity was extracted from B-mode ultrasound recordings. The degree of ICA stenosis was assessed on CT angiography according to the European Carotid Surgery Trial method. Patients were divided into groups with a low (<= 2 %) and a high (> 2 %) IMT inhomogeneity scaled with respect to the local end-diastolic diameter. Results 182 patients had suitable CT and ultrasound measurements. Relative CCA-IMT inhomogeneity was similar for the symptomatic and asymptomatic side (difference: 0.02 %, p = 0.85). High relative IMT inhomogeneity was associated with a larger IMT (difference: 235 um, p < 0.001) and larger degree of ICA stenosis (difference: 5 %, p = 0.023) which remained significant (p = 0.016) after adjustment for common risk factors. Conclusion Regardless of common risk factors, high relative CCA-IMT inhomogeneity is associated with a greater degree of ICA stenosis and is therefore indicative of atherosclerotic disease. The predictive value of CCA-IMT inhomogeneity for plaque progression and recurrence of cerebrovascular symptoms will be determined in the follow-up phase of PARISK. PMID- 27486795 TI - Transcranial Sonography of the Insula: Digitized Image Analysis of Fusion Images with Magnetic Resonance. AB - Purpose: Transcranial B-mode sonography (TCS) of brain parenchyma is increasingly used as a diagnostic tool for movement disorders. Accordingly, experimental B Mode Assist software was developed to enable digitized analysis of the echogenicity of predefined brain regions. The aim of the study was to assess the reproducibility of digitized TCS image analysis of the insula. Materials and Methods: A total of 130 patients with an indication for neurosonological examination were screened for participation in the study. The insula was imaged from the right temporal bone window using Virtual Navigator and TCS-MRI (magnetic resonance imaging) fusion imaging. All subjects were examined three times by two experienced sonographers. Corresponding images of the insula in the axial thalamic plane were encoded and digitally analyzed. Interclass correlation coefficient (ICC) and Spearman's rank correlation coefficient were used for the assessment of intra- and inter-reader as well as intra- and inter-investigator reliabilities. Results: TCS images of 114 patients were evaluated (21 patients with TIA, 53 patients with headache, 18 patients with essential tremor, 22 patients with neurodegerative disease). 16 patients were excluded from analysis due to insufficient bone window. The intra-reader, inter-reader, intra investigator and inter-investigator ICCs/Spearman's rank correlation coefficients were 0.995/0.993, 0.937/0.921, 0.969/0.961 and 0.875/0.858, resp. Conclusion: The present study demonstrates a high reliability to reproduce echogenicity values of the insula using digitized image analysis and TCS-MRI fusion images with almost perfect intra-reader, inter-reader, intra-investigator and inter-investigator agreement. PMID- 27486796 TI - Live-Cell Bioorthogonal Chemical Imaging: Stimulated Raman Scattering Microscopy of Vibrational Probes. AB - Innovations in light microscopy have tremendously revolutionized the way researchers study biological systems with subcellular resolution. In particular, fluorescence microscopy with the expanding choices of fluorescent probes has provided a comprehensive toolkit to tag and visualize various molecules of interest with exquisite specificity and high sensitivity. Although fluorescence microscopy is currently the method of choice for cellular imaging, it faces fundamental limitations for studying the vast number of small biomolecules. This is because common fluorescent labels, which are relatively bulky, could introduce considerable perturbation to or even completely alter the native functions of vital small biomolecules. Hence, despite their immense functional importance, these small biomolecules remain largely undetectable by fluorescence microscopy. To address this challenge, a bioorthogonal chemical imaging platform has recently been introduced. By coupling stimulated Raman scattering (SRS) microscopy, an emerging nonlinear Raman microscopy technique, with tiny and Raman-active vibrational probes (e.g., alkynes and stable isotopes), bioorthogonal chemical imaging exhibits superb sensitivity, specificity, and biocompatibility for imaging small biomolecules in live systems. In this Account, we review recent technical achievements for visualizing a broad spectrum of small biomolecules, including ribonucleosides and deoxyribonucleosides, amino acids, fatty acids, choline, glucose, cholesterol, and small-molecule drugs in live biological systems ranging from individual cells to animal tissues and model organisms. Importantly, this platform is compatible with live-cell biology, thus allowing real-time imaging of small-molecule dynamics. Moreover, we discuss further chemical and spectroscopic strategies for multicolor bioorthogonal chemical imaging, a valuable technique in the era of "omics". As a unique tool for biological discovery, this platform has been applied to studying various metabolic processes under both physiological and pathological states, including protein synthesis activity of neuronal systems, protein aggregations in Huntington disease models, glucose uptake in tumor xenografts, and drug penetration through skin tissues. We envision that the coupling of SRS microscopy with vibrational probes would do for small biomolecules what fluorescence microscopy of fluorophores has done for larger molecular species. PMID- 27486797 TI - NMR Study Reveals the Receiver Domain of Arabidopsis ETHYLENE RESPONSE1 Ethylene Receptor as an Atypical Type Response Regulator. AB - The gaseous plant hormone ethylene, recognized by plant ethylene receptors, plays a pivotal role in various aspects of plant growth and development. ETHYLENE RESPONSE1 (ETR1) is an ethylene receptor isolated from Arabidopsis and has a structure characteristic of prokaryotic two-component histidine kinase (HK) and receiver domain (RD), where the RD structurally resembles bacteria response regulators (RRs). The ETR1 HK domain has autophosphorylation activity, and little is known if the HK can transfer the phosphoryl group to the RD for receptor signaling. Unveiling the correlation of the receptor structure and phosphorylation status would advance the studies towards the underlying mechanisms of ETR1 receptor signaling. In this study, using the nuclear magnetic resonance technique, our data suggested that the ETR1-RD is monomeric in solution and the rigid structure of the RD prevents the conserved aspartate residue phosphorylation. Comparing the backbone dynamics with other RRs, we propose that backbone flexibility is critical to the RR phosphorylation. Besides the limited flexibility, ETR1-RD has a unique gamma loop conformation of opposite orientation, which makes ETR1-RD unfavorable for phosphorylation. These two features explain why ETR1-RD cannot be phosphorylated and is classified as an atypical type RR. As a control, phosphorylation of the ETR1-RD was also impaired when the sequence was swapped to the fragment of the bacterial typical type RR, CheY. Here, we suggest a molecule insight that the ETR1-RD already exists as an active formation and executes its function through binding with the downstream factors without phosphorylation. PMID- 27486798 TI - Molecular Identification of Hookworm Isolates in Humans, Dogs and Soil in a Tribal Area in Tamil Nadu, India. AB - BACKGROUND: Hookworms (Necator americanus and Ancylostoma duodenale) remain a major public health problem worldwide. Infections with hookworms (e.g., A. caninum, A. ceylanicum and A. braziliense) are also prevalent in dogs, but the role of dogs as a reservoir for zoonotic hookworm infections in humans needs to be further explored. METHODOLOGY/PRINCIPAL FINDINGS: As part of an open-label community based cluster-randomized trial in a tribal area in Tamil Nadu (India; 2013-2015), a total of 143 isolates of hookworm eggs from human stool were speciated based on a previously described PCR-RFLP methodology. The presence of hookworm DNA was confirmed in 119 of 143 human samples. N. americanus (100%) was the most prevalent species, followed by A. caninum (16.8%) and A. duodenale (8.4%). Because of the high prevalence of A. caninum in humans, dog samples were also collected to assess the prevalence of A. caninum in dogs. In 68 out of 77 canine stool samples the presence of hookworms was confirmed using PCR-RFLP. In dogs, both A. caninum (76.4%) and A. ceylanicum (27.9%) were identified. Additionally, to determine the contamination of soil with zoonotic hookworm larvae, topsoil was collected from defecating areas. Hookworm DNA was detected in 72 out of 78 soil samples that revealed presence of hookworm-like nematode larvae. In soil, different hookworm species were identified, with animal hookworms being more prevalent (A. ceylanicum: 60.2%, A. caninum: 29.4%, A. duodenale: 16.6%, N. americanus: 1.4%, A. braziliense: 1.4%). CONCLUSIONS/SIGNIFICANCE: In our study we regularly detected the presence of A. caninum DNA in the stool of humans. Whether this is the result of infection is currently unknown but it does warrant a closer look at dogs as a potential reservoir. PMID- 27486799 TI - Dearth and Delayed Maturation of Testicular Germ Cells in Fanconi Anemia E Mutant Male Mice. AB - After using a self-inactivating lentivirus for non-targeted insertional mutagenesis in mice, we identified a transgenic family with a recessive mutation that resulted in reduced fertility in homozygous transgenic mice. The lentiviral integration site was amplified by inverse PCR. Sequencing revealed that integration had occurred in intron 8 of the mouse Fance gene, which encodes the Fanconi anemia E (Fance) protein. Fanconi anemia (FA) proteins play pivotal roles in cellular responses to DNA damage and Fance acts as a molecular bridge between the FA core complex and Fancd2. To investigate the reduced fertility in the mutant males, we analyzed postnatal development of testicular germ cells. At one week after birth, most tubules in the mutant testes contained few or no germ cells. Over the next 2-3 weeks, germ cells accumulated in a limited number of tubules, so that some tubules contained germ cells around the full periphery of the tubule. Once sufficient numbers of germ cells had accumulated, they began to undergo the later stages of spermatogenesis. Immunoassays revealed that the Fancd2 protein accumulated around the periphery of the nucleus in normal developing spermatocytes, but we did not detect a similar localization of Fancd2 in the Fance mutant testes. Our assays indicate that although Fance mutant males are germ cell deficient at birth, the extant germ cells can proliferate and, if they reach a threshold density, can differentiate into mature sperm. Analogous to previous studies of FA genes in mice, our results show that the Fance protein plays an important, but not absolutely essential, role in the initial developmental expansion of the male germ line. PMID- 27486800 TI - Transcriptome Analysis of Storage Roots and Fibrous Roots of the Traditional Medicinal Herb Callerya speciosa (Champ.) ScHot. AB - Callerya speciosa (Champ.) ScHot is a woody perennial plant in Fabaceae, the roots of which are used medicinally. The storage roots of C. speciosa are derived from fibrous roots, but not all fibrous roots can develop into storage roots. To detect key genes involved in storage roots formation, we performed Illumina sequencing of the C. speciosa storage roots and fibrous roots. De novo assembly resulted in 161,926 unigenes, which were subsequently annotated by BLAST, GO and KEGG analyses. After expression profiling, 4538 differentially expressed genes were identified. The KEGG pathway enrichment analysis revealed changes in the biosynthesis of cytokinin, phenylpropanoid, starch, sucrose, flavone and other secondary metabolites. Transcription factor-related differentially expressed genes (DEGs) were also identified, including such gene families as GRAS, COL, MIKC, ERF, LBD, and NAC. The DEGs related to light signaling, starch, sugar, photohormones and cell wall-loosening might be involved in the formation of storage roots. This study provides the first transcriptome profiling of C. speciosa roots, data that will facilitate future research of root development and metabolites with medicinal value as well as the breeding of C. speciosa. PMID- 27486801 TI - Frequency- and Phase Encoded SSVEP Using Spatiotemporal Beamforming. AB - In brain-computer interfaces (BCIs) based on steady-state visual evoked potentials (SSVEPs) the number of selectable targets is rather limited when each target has its own stimulation frequency. One way to remedy this is by combining frequency- with phase encoding. We introduce a new multivariate spatiotemporal filter, based on Linearly Constrained Minimum Variance (LCMV) beamforming, for discriminating between frequency-phase encoded targets more accurately, even when using short signal lengths than with (extended) Canonical Correlation Analysis (CCA), which is traditionally posited for this stimulation paradigm. PMID- 27486802 TI - Does Grammatical Structure Accelerate Number Word Learning? Evidence from Learners of Dual and Non-Dual Dialects of Slovenian. AB - How does linguistic structure affect children's acquisition of early number word meanings? Previous studies have tested this question by comparing how children learning languages with different grammatical representations of number learn the meanings of labels for small numbers, like 1, 2, and 3. For example, children who acquire a language with singular-plural marking, like English, are faster to learn the word for 1 than children learning a language that lacks the singular plural distinction, perhaps because the word for 1 is always used in singular contexts, highlighting its meaning. These studies are problematic, however, because reported differences in number word learning may be due to unmeasured cross-cultural differences rather than specific linguistic differences. To address this problem, we investigated number word learning in four groups of children from a single culture who spoke different dialects of the same language that differed chiefly with respect to how they grammatically mark number. We found that learning a dialect which features "dual" morphology (marking of pairs) accelerated children's acquisition of the number word two relative to learning a "non-dual" dialect of the same language. PMID- 27486803 TI - Two New Mylagaulid Rodents from the Early Miocene of China. AB - Mylagaulid fossorial rodents are a common component of North American Miocene fossil faunas. However outside of North America, only three species are known from Asia. Here we report two new mylagaulids, Irtyshogaulus minor gen. et sp. nov. and Irtyshogaulus major gen. et sp. nov., recovered from early Miocene sediments in the Junggar Basin in northwestern China. The two new taxa are small sized, high-crowned promylagauline rodents. Their lower molars possess high metastylid crests, small mesostylids, broad and posterolingually expanded labial inflections, and transversely extending metalophid IIs. The mesoconid is absent in both species. The anterior and posterior fossettids are large and equally developed. Their upper M1-2s possess a square occlusal surface with five deep fossettes. The two new taxa are distinguished from each other mainly by their size, the morphology of fossettes and fossettids, development of mesial and distal lophs, posterior reduction of M3, and the orientation of m2 hypolophid. Our phylogenetic analysis indicates that Irtyshogaulus and Lamugaulus (another early Miocene Asian mylagaulid) are sister taxa. The two genera are nested among the North American promylagaulines, and share a common ancestor from North America, indicating early Miocene intercontinental dispersal within this clade of rodents. PMID- 27486804 TI - The Incremental Prognostic Value of Cardiac Computed Tomography in Comparison with Single-Photon Emission Computed Tomography in Patients with Suspected Coronary Artery Disease. AB - BACKGROUND: Coronary computed tomographic angiography (CCTA) facilitates comprehensive evaluation of coronary artery disease (CAD), including plaque characterization, and can provide additive diagnostic value to single-photon emission computed tomography (SPECT). However, data regarding the incremental prognostic value of CCTA to SPECT remain sparse. We evaluated the independent and incremental prognostic value of CCTA, as compared with clinical risk factors and SPECT. MATERIALS AND METHODS: A total of 1,077 patients with suspected CAD who underwent both SPECT and cardiac CT between 2004 and 2012 were enrolled retrospectively. Presence of reversible or fixed perfusion defect (PD) and summed stress score were evaluated on SPECT. Presence, extent of coronary atherosclerosis and diameter stenosis (DS) were evaluated on CCTA. Plaque composition was categorized as non-calcified, mixed, or calcified according to the volume of calcified component (>130 Hounsfield Units). Patients were followed up for the occurrence of adverse cardiac events including cardiac death, non fatal myocardial infarction, unstable angina, and late revascularization (>90 days after imaging studies). RESULTS: During follow-up (median 23 months), adverse cardiac events were observed in 71 patients (6.6%). When adjusted for clinical risk factors and SPECT findings, the presence of any coronary plaque, any plaque in >=3 segments, coronary artery calcium score (CACS) >=400, a plaque >=50% DS, presence of non-calcified plaque (NCP) or mixed plaque (MP), and NCP/MP in >=2 segments were independent predictors of adverse cardiac events; however, the presence of calcified plaque (CP) was not. Conventional CCTA findings, including CACS >=400 and a plaque >=50% DS, demonstrated incremental prognostic value over clinical risk factors and SPECT (chi2 54.19 to 101.03; p <0.001). Addition of NCP/MP in >=2 segments resulted in further significantly improved prediction (chi2 101.03 to 113.29; p <0.001). CONCLUSION: Comprehensive CCTA evaluation of coronary atherosclerosis provides independent and incremental prognostic value in relation to SPECT evaluation of myocardial ischemia. Specifically, segmentally-analyzed plaque composition with CCTA provides further risk stratification in addition to CACS and DS. PMID- 27486805 TI - Regulatory Cytokine Expression and Preterm Birth: Case-Control Study Nested in a Cohort. AB - BACKGROUND: Currently known risk factors explain only a small fraction of preterm birth (PTB). Previous PTB is one of the most important predictors. However, this information is not available in primiparous women. Few studies have looked at associations between regulatory cytokine expression (RCE) and PTB and the results are conflicting. OBJECTIVE: To investigate the association of RCE-Interleukin 10 (IL-10) and Transforming Growth Factor beta (TGF-beta)-with PTB, and to assess whether bacterial vaginosis (BV) is involved in this relationship. METHODS: This was a case-control study nested in a prospective cohort-called BRISA. Women with singleton pregnancies were interviewed from 22 to 25 weeks of gestational age (GA). Women were recruited from health services in Sao Luis, Brazil. A blood sample was collected and gynecological examination was performed. Serum IL-10 and TGF-beta were determined using cytometric bead array. Nugent score >7 and/or the presence of clue cells were used for BV diagnosis. All PTB estimated by ultrasound dating performed before 20 weeks of gestational age were considered cases. Controls were selected by simple random sampling from the rest of the cohort, at a 2:1 ratio. Different models were tested, according to the main independent variable. Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated by regression analyses. RESULTS: The study included 327 pregnant women, 109 cases and 218 controls. No associations were found between BV and PTB (P = 1.44; 95%CI: 0.51-3.77). Low levels of IL-10 (OR = 2.92 95%CI: 1.38-6.16) or TGF beta (OR = 16.90 95%CI: 6.42-44.51) or both simultaneously (OR = 77.16 95%CI: 7.99-744.88) were associated with increasing odds of PTB, even after adjustment for confounding. CONCLUSION: Decreased RCE is a risk factor for PTB. This relationship, however, is not triggered by the presence of BV. Low IL-10/TGF-beta levels from 22 to 25 weeks of GA could be used as early predictors of PTB. We suggest monitoring of these RCE, especially among primiparous women, for whom history of previous PTB is not available. PMID- 27486807 TI - Preparation and evaluation of enteric coated tablets of hot-melt extruded lansoprazole. AB - The objective of this work was to use hot-melt extrusion (HME) technology to improve the physiochemical properties of lansoprazole (LNS) to prepare stable enteric coated LNS tablets. For the extrusion process, we chose Kollidon(r) 12 PF (K12) polymeric matrix. Lutrol(r) F 68 was selected as the plasticizer and magnesium oxide (MgO) as the alkalizer. With or without the alkalizer, LNS at 10% drug load was extruded with K12 and F68. LNS changed to the amorphous phase and showed better release compared to that of the pure crystalline drug. Inclusion of MgO improved LNS extrudability and release and resulted in over 80% drug release in the buffer stage. Hot-melt extruded LNS was physically and chemically stable after 12 months of storage. Both formulations were studied for compatibility with Eudragit(r) L100-55. The optimized formulation was compressed into a tablet followed by coating process utilizing a pan coater using L100-55 as an enteric coating polymer. In a two-step dissolution study, the release profile of the enteric coated LNS tablets in the acidic stage was less than 10% of the LNS, while that in the buffer stage was more than 80%. Drug content analysis revealed the LNS content to be 97%, indicating the chemical stability of the enteric coated tablet after storage for six months. HME, which has not been previously used for LNS, is a valuable technique to reduce processing time in the manufacture of enteric coated formulations of an acid-sensitive active pharmaceutical ingredient as compared to the existing methods. PMID- 27486808 TI - Rapid Intracranial Response to Osimertinib in a Patient with Epidermal Growth Factor Receptor T790M-Positive Adenocarcinoma of the Lung. AB - BACKGROUND: Osimertinib (AZD9291, Tagrisso) is a potent, irreversible third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). CASE REPORT: Our report demonstrates that osimertinib is able to inhibit the growth of a radiotherapy- and surgery-refractory EGFR T790M-positive brain metastasis in a patient with lung adenocarcinoma. CONCLUSION: These data show that re-biopsy in EGFR-mutated non-small cell lung cancer patients with acquired TKI resistance should be performed. PMID- 27486806 TI - New Biochemical Insights into the Mechanisms of Pulmonary Arterial Hypertension in Humans. AB - Diagnosis of pulmonary arterial hypertension (PAH) is difficult due to the lack of specific clinical symptoms and biomarkers, especially at early stages. We compared plasma metabolic fingerprints of PAH patients (n = 20) with matched healthy volunteers (n = 20) using, for the first time, untargeted multiplatform metabolomics approach consisting of high-performance liquid and gas chromatography coupled with mass spectrometry. Multivariate statistical analyses were performed to select metabolites that contribute most to groups' classification (21 from liquid in both ionization modes and 9 from gas chromatography-mass spectrometry). We found metabolites related to energy imbalance, such as glycolysis-derived metabolites, as well as metabolites involved in fatty acid, lipid and amino acid metabolism. We observed statistically significant changes in threitol and aminomalonic acid in PAH patients, which could provide new biochemical insights into the pathogenesis of the disease. The results were externally validated on independent case and control cohorts, confirming up to 16 metabolites as statistically significant in the validation study. Multiplatform metabolomics, followed by multivariate chemometric data analysis has a huge potential for explaining pathogenesis of PAH and for searching potential and new more specific and less invasive markers of the disease. PMID- 27486809 TI - Possible Underlying Mechanisms of the Renoprotective Effect of Remote Limb Ischemic Preconditioning Against Renal Ischemia/Reperfusion Injury: A Role of Osteopontin, Transforming Growth Factor-Beta and Survivin. AB - BACKGROUND: It has been documented that remote limb ischemic preconditioning (rIPC) protect kidneys against renal ischemia/reperfusion (I/R). We hypothesized that osteopontin (OPN), transforming growth factor beta (TGF-beta), apoptotic proteins (survivin and caspase-3) and oxidative stress play role in the renoprotective effects of rIPC. MATERIALS AND METHODS: Fifty-four male Sprague Dawley rats were randomized into 3 equal groups: sham group, I/R group (left renal 45 min ischemia) and rIPC group (as I/R group with 3 cycles of left hind limb ischemia just before renal ischemia). Each group was subdivided into 24, 48 and 72 h groups according to the time of sacrifice. We measured serum creatinine and blood urea nitrogen (BUN) at the baseline and end points. Also, left kidney was harvested at study end points for assessment of the expression of OPN, TGF beta, apoptotic proteins (survivin and caspase-3) and oxidative stress markers (malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD)) in kidney tissues and histopathological examination. RESULTS: Serum creatinine and BUN levels and histopathological damage score were significantly lower in rIPC group than I/R group (p < 0.005). Also, compared to I/R group, the levels of MDA and the expression of OPN, TGF-beta and caspase-3 in kidney tissues were significantly lower in rIPC group, while the levels of SOD and GSH and the expression of survivin in kidney tissues were significantly higher in rIPC group at all time points (p <= 0.05). CONCLUSIONS: rIPC exhibited protective effects against renal I/R injury which might be due to inhibition of OPN expression, inflammatory cytokine TGF-beta and caspase-3 and activation of anti-apoptotic protein survivin as well as improvement of oxidative stress in kidney tissues. PMID- 27486810 TI - Bilateral optic nerve edema presenting as initial manifestation of thyroid eye disease. AB - A 48-year-old smoker with a history of hyperthyroidism treated 10 years prior to presentation with radioactive iodine ablation of the thyroid gland presented to his ophthalmologist with a 2-week history of transient loss of vision in the right eye occurring for 1 to 2 hours each morning. He denied ocular pain, diplopia or change in the prominence of one or both eyes. Examination revealed 2 mm of relative proptosis on the right, bilateral temporal flare and lower lid retraction. There was minimal upper lid retraction and no evidence of lid lag. Ocular motility was full. Dilated fundoscopic examination revealed bilateral optic nerve edema, right more than left. CT of the orbit demonstrated enlargement of the extraocular muscles bilaterally with marked enlargement of the right medial rectus and left inferior rectus muscles resulting in crowding at the orbital apex bilaterally. Laboratory testing revealed the patient to be hyperthyroid. The patient was treated with high dose oral steroids followed by orbital radiation. Hyperthyroidism was managed by the patient's primary care physician. Visual symptoms rapidly improved with oral steroids and orbital radiation. Optic nerve edema completely resolved. Repeat CT imaging demonstrated a reduction in the enlargement of the extraocular muscles with relief of bilateral optic nerve compression. PMID- 27486811 TI - Longitudinal Association between Child Emotion Regulation and Aggression, and the Role of Parenting: A Comparison of Three Cultures. AB - BACKGROUND: The ability to regulate emotions is a key developmental achievement acquired during social interactions and associated with better behavioral and social outcomes. We examined the influence of culture on child emotion regulation (ER) and aggression and on early parenting practices, and the role of parenting in child ER. METHODS: We assessed 48 mother-infant dyads from three cultures (1 UK, 2 South African) at infant age of 3 months for maternal sensitivity during face-to-face interactions and responses to infant distress during daily life, and at 2 years for child ER strategies and maternally reported aggression. RESULTS: There were cultural differences in child ER, and these were associated with differences in levels of aggression. Maternal strategies in response to early infant distress also differed by culture and predicted later child ER. Maternal sensitivity during face-to-face interactions was not associated with culture and showed no clear relationship with child ER. CONCLUSION: Cultural differences in maternal responses to infant distress mediated differences in child ER that are, in turn, related to differences in child aggression. PMID- 27486812 TI - A Meta-Analysis for Effects of Elevated Pre-Transplantation Serum Ferritin on the Outcomes in Patients Undergoing Hematopoietic Stem Cell Transplantation. AB - The level of pre-transplantation serum ferritin (SF) is one of the factors related to outcome for patients undergoing allogeneic hematopoietic stem cell transplantation. We searched PubMed and Cochrane Library databases from 2000 to 2014. The primary efficacy outcome was overall survival rate and non-relapse mortality. Twenty clinical trials were selected from 189 studies identified. The combined hazard ratio indicated a significantly lower overall survival rate and a higher non-relapse mortality rate in patients with elevated SF before transplantation. This indicates that elevated pre-transplantation SF affects outcome in patients undergoing allogeneic hematopoietic stem cell transplantation. PMID- 27486814 TI - Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development. AB - Nucleophosmin (NPM1) is a ubiquitous multifunctional phosphoprotein with both oncogenic and tumor suppressor functions. Mutations of the NPM1 gene are the most frequent genetic alterations in acute myeloid leukemia (AML) and result in the expression of a mutant protein with aberrant cytoplasmic localization, NPMc+. Although NPMc+ causes myeloproliferation and AML in animal models, its mechanism of action remains largely unknown. Here we report that NPMc+ activates canonical Wnt signaling during the early phases of zebrafish development and determines a Wnt-dependent increase in the number of progenitor cells during primitive hematopoiesis. Coherently, the canonical Wnt pathway is active in AML blasts bearing NPMc+ and depletion of the mutant protein in the patient derived OCI-AML3 cell line leads to a decrease in the levels of active beta-catenin and of Wnt target genes. Our results reveal a novel function of NPMc+ and provide insight into the molecular pathogenesis of AML bearing NPM1 mutations. PMID- 27486815 TI - The human Smoothened inhibitor PF-04449913 induces exit from quiescence and loss of multipotent Drosophila hematopoietic progenitor cells. AB - The efficient treatment of hematological malignancies as Acute Myeloid Leukemia, myelofibrosis and Chronic Myeloid Leukemia, requires the elimination of cancer initiating cells and the prevention of disease relapse through targeting pathways that stimulate generation and maintenance of these cells. In mammals, inhibition of Smoothened, the key mediator of the Hedgehog signaling pathway, reduces Chronic Myeloid Leukemia progression and propagation. These findings make Smo a candidate target to inhibit maintenance of leukemia-initiating cells. In Drosophila melanogaster the same pathway maintains the hematopoietic precursor cells of the lymph gland, the hematopoietic organ that develops in the larva. Using Drosophila as an in vivo model, we investigated the mode of action of PF 04449913, a small-molecule inhibitor of the human Smo protein. Drosophila larvae fed with PF-04449913 showed traits of altered hematopoietic homeostasis. These include the development of melanotic nodules, increase of circulating hemocytes, the size increase of the lymph gland and accelerated differentiation of blood cells likely due to the exit of multi-potent precursors from quiescence. Importantly, the Smo inhibition can lead to the complete loss of hematopoietic precursors. We conclude that PF-04449913 inhibits Drosophila Smo blocking the Hh signaling pathway and causing the loss of hematopoietic precursor cells. Interestingly, this is the effect expected in patients treated with PF-04449913: number decrease of cancer initiating cells in the bone marrow to reduce the risk of leukemia relapse. Altogether our results indicate that Drosophila comprises a model system for the in vivo study of molecules that target evolutionary conserved pathways implicated in human hematological malignancies. PMID- 27486817 TI - Samarium-153-EDTMP (Quadramet(r)) with or without vaccine in metastatic castration-resistant prostate cancer: A randomized Phase 2 trial. AB - PSA-TRICOM is a therapeutic vaccine in late stage clinical testing in metastatic castration-resistant prostate cancer (mCRPC). Samarium-153-ethylene diamine tetramethylene phosphonate (Sm-153-EDTMP; Quadramet(r)), a radiopharmaceutical, binds osteoblastic bone lesions and emits beta particles causing local tumor cell destruction. Preclinically, Sm-153-EDTMP alters tumor cell phenotype facilitating immune-mediated killing. This phase 2 multi-center trial randomized patients to Sm-153-EDTMP alone or with PSA-TRICOM vaccine. Eligibility required mCRPC, bone metastases, prior docetaxel and no visceral disease. The primary endpoint was the proportion of patients without radiographic disease progression at 4 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and immune responses. Forty-four patients enrolled. Eighteen and 21 patients were evaluable for the primary endpoint in Sm-153-EDTMP alone and combination arms, respectively. There was no statistical difference in the primary endpoint, with two of 18 (11.1%) and five of 21 (23.8%) in Sm-153-EDTMP alone and combination arms, respectively, having stable disease at approximately the 4-month evaluation time point (P = 0.27). Median PFS was 1.7 vs. 3.7 months in the Sm-153-EDTMP alone and combination arms (P = 0.041, HR = 0.51, P = 0.046). No patient in the Sm-153-EDTMP alone arm achieved prostate-specific antigen (PSA) decline > 30% compared with four patients (of 21) in the combination arm, including three with PSA decline > 50%. Toxicities were similar between arms and related to number of Sm-153-EDTMP doses administered. These results provide the rationale for clinical evaluation of new radiopharmaceuticals, such as Ra-223, in combination with PSA-TRICOM. PMID- 27486820 TI - TAM receptors Tyro3 and Mer as novel targets in colorectal cancer. AB - PURPOSE: CRC remains the third most common cancer worldwide with a high 5-year mortality rate in advanced cases. Combined with chemotherapy, targeted therapy is an additional treatment option. However as CRC still escapes targeted therapy the vigorous search for new targets is warranted to increase patients' overall survival. RESULTS: In this study we describe a new role for Gas6/protein S-TAM receptor interaction in CRC. Gas6, expressed by tumor-infiltrating M2-like macrophages, enhances malignant properties of tumor cells including proliferation, invasion and colony formation. Upon chemotherapy macrophages increase Gas6 synthesis, which significantly attenuates the cytotoxic effect of 5 FU chemotherapy on tumor cells. The anti-coagulant protein S has similar effects as Gas6.In CRC patient samples Tyro3 was overexpressed within the tumor. In-vitro inhibition of Tyro3 and Mer reduces tumor cell proliferation and sensitizes tumor cells to chemotherapy. Moreover high expression of Tyro3 and Mer in tumor tissue significantly shortens CRC patients' survival. EXPERIMENTAL DESIGN: Various in vitro models were used to investigate the role of Gas6 and its TAM receptors in human CRC cells, by stimulation (rhGas6) and knockdown (siRNA) of Axl, Tyro3 and Mer. In terms of a translational research, we additionally performed an expression analysis in human CRC tissue and analyzed the medical record of these patients. CONCLUSIONS: Tyro3 and Mer represent novel therapeutic targets in CRC and warrant further preclinical and clinical investigation in the future. PMID- 27486821 TI - Repurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma. AB - Glioblastoma (GBM) is the most aggressive primary brain tumor with poor prognosis. Here, we studied the effects of phenformin, a mitochondrial complex I inhibitor and more potent chemical analog of the diabetes drug metformin on the inhibition of cell growth and induction of apoptosis of glioma stem cells (GSCs) using both in vitro and in vivo models. Phenformin inhibited the self-renewal of GSCs, decreased the expression of stemness and mesenchymal markers and increased the expression of miR-124, 137 and let-7. Silencing of let-7 abrogated phenformin effects on the self-renewal of GSCs via a pathway associated with inhibition of H19 and HMGA2 expression. Moreover, we demonstrate that phenformin inhibited tumor growth and prolonged the overall survival of mice orthotopically transplanted with GSCs. Combined treatments of phenformin and temozolomide exerted an increased antitumor effect on GSCs in vitro and in vivo. In addition, dichloroacetate, an inhibitor of the glycolysis enzyme pyruvate dehydrogenase kinase, that decreases lactic acidosis induced by biguanides, enhanced phenformin effects on the induction of cell death in GSCs and prolonged the survival of xenograft-bearing mice. Our results demonstrate for the first time that phenformin targets GSCs and can be efficiently combined with current therapies for GBM treatment and GSC eradication. PMID- 27486822 TI - Bone marrow involvement identifies a subgroup of advanced Ewing sarcoma patients with fatal outcome irrespective of therapy in contrast to curable patients with multiple bone metastases but unaffected marrow. AB - PURPOSE: Advanced Ewing sarcomas have poor prognosis. They are defined by early relapse (<24 months after diagnosis) and/or by metastasis to multiple bones or bone marrow (BM). We analyzed risk factors, toxicity and survival in advanced Ewing sarcoma patients treated with the MetaEICESS vs. EICESS92 protocols. DESIGN: Of 44 patients, 18 patients were enrolled into two subsequent MetaEICESS protocols between 1992 and 2014, and compared to outcomes of 26 advanced Ewing sarcoma patients treated with EICESS 1992 between 1992 and 1996. MetaEICESS 1992 consisted of induction chemotherapy, whole body imaging directed radiotherapy to the primary tumor and metastases, tandem high-dose chemotherapy and autologous rescue. In MetaEICESS 2007 this treatment was complemented by allogeneic stem cell transplantation. EICESS 1992 comprised induction chemotherapy, local therapy to the primary tumor only followed by consolidation chemotherapy. RESULTS: In MetaEICESS 8/18 patients survived in complete remission vs. 2/26 in EICESS 1992 (p<0.05). Survival did not differ between MetaEICESS 2007 and MetaEICESS 1992. Three MetaEICESS patients died of complications, all in MetaEICESS 1992. After exclusion of patients succumbing to treatment related complications (n=3), 7/10 patients survived without BM involvement, in contrast to 0/5 patients with BM involvement. This was confirmed in a multivariate analysis. There was no correlation between BM involvement and the number of metastases at diagnosis. CONCLUSION: The MetaEICESS protocols yield long-term disease-free survival in patients with advanced Ewing sarcoma. Allogeneic stem cell transplantation was not associated with increased death of complications. Bone marrow involvement is a risk factor distinct from multiple bone metastases. PMID- 27486824 TI - Ionofore antibiotic polynactin produced by Streptomyces sp. 156A isolated from Lake Baikal. AB - The potential antibacterial activity of secondary metabolites produced by Streptomyces sp. 156A isolated from Lake Baikal was investigated. The selective liquid-liquid extraction method was applied to obtain a mixture of nactins (polynactin) produced by the strain. The polynactin consisted of nonactin (3%), monactin (18%), dinactin (36%), trinactin (31%) and tetranactin (12%). The compounds were identified by MS/MS, 1H and 13C NMR methods. The loss of neutral 184 and 198 Da fragments from a sodiated molecular ion, [M + Na]+, of nactins was observed in the MS/MS spectrum. The polynactin was shown to possess the antibiotic activity against Gram-positive strains including opportunistic strains and strains isolated from various ecosystems of Lake Baikal. PMID- 27486823 TI - The lncRNA MALAT1 is a novel biomarker for gastric cancer metastasis. AB - The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is frequently over-expressed and serves as a prognostic marker in human cancers. However, little is known about the role of MALAT1 in gastric cancer. Here, we reported that the tissue and plasma MALAT1 levels were significantly higher in gastric cancer patients with distant metastasis (P<0.01) than patients without distant metastasis and the healthy controls. In addition, high levels of plasma MALAT1 independently correlated to a poor prognosis for gastric cancer patients (hazard ratio, 0.242; 95% CI, 0.154-0.836; P=0.036; Cox regression analysis). Functional studies revealed that knockdown of MALAT1 could inhibit cell proliferation, cell cycle progression, migration and invasion, and promote apoptosis in gastric cancer cells. Furthermore, the miR-122-IGF-1R signaling correlated with the dysregulated MALAT1 expression in gastric cancer. These data suggest that MALAT1 could function as an oncogene in gastric cancer, and high MALAT1 level could serve as a potential biomarker for the distant metastasis of gastric cancer. PMID- 27486825 TI - Prevalence of Psychoactive Substance Consumption in People With Obesity. AB - OBJECTIVE: The aim of this study was to evaluate the prevalence and the kind of psychoactive substances consumed by people with obesity. METHODS: Patients were included at their first visit for bariatric surgery. Socio-demographic characteristics, anxiety, depressive disorders and psychoactive substance consumption were assessed. The prevalence of psychoactive substance consumption was compared to that of the general population reported by the French National Institute of Prevention and Health Education. RESULTS: One hundred (100) patients were consecutively recruited: 60 women (mean age 41 +/- 14 years) and 40 men (mean age 46 +/- 13 years). Sixty-seven percent of subjects consumed alcohol. Consumption rates of cannabis (21% vs. 10%), cocaine (7.0% vs. 0.8%) and amphetamine (6.0% vs. 0.3%) were significantly (p < .0001) higher in people with obesity than in the general population. CONCLUSIONS: People with obesity have an excess risk of amphetamine, cocaine and cannabis consumption. This consumption may increase the risk of cardiovascular and psychiatric morbidity and should therefore be detected before surgery. PMID- 27486826 TI - l-Alpha Glycerylphosphorylcholine as a Potential Radioprotective Agent in Zebrafish Embryo Model. AB - This work establishes the zebrafish embryo model for ionizing radiation (IR) modifier research and also evaluates the protective effect of l-alpha glycerylphosphorylcholine (GPC). Embryos were exposed to a single-fraction whole body gamma irradiation (5, 10, 15, and 20 Gy) at different postfertilization time points and were serially assessed for viability and macro- and micromorphologic abnormalities. After toxicity evaluation, 194 MUM of GPC was added for certain groups with 3-h incubation before the radiation. Nuclear factor kappa B (NF kappaB) and interleukin-1beta (IL-1beta) expression changes were measured using quantitative real-time polymerase chain reaction. A higher sensitivity could be observed at earlier stages of the embryogenesis. The lethal dose (LD50) for 6 hours postfertilization (hpf) embryos was 15 Gy and for 24 hpf was 20 Gy on day 7, respectively. GPC administration resulted in a significant improvement in both the distortion rate and survival of the 24 hpf embryos. Qualitative evaluation of the histological changes confirmed the protective effect of GPC. IL-1beta and NF kappaB overexpression due to 10 Gy irradiation was also reduced by GPC. GPC exhibited promising radioprotective effects in our zebrafish embryo model, decreasing the irradiation-induced morphological damage and lethality with significant reduction of IR-caused pro-inflammatory activation. PMID- 27486827 TI - Multitask Imidazolium Salt Additives for Innovative Poly(l-lactide) Biomaterials: Morphology Control, Candida spp. Biofilm Inhibition, Human Mesenchymal Stem Cell Biocompatibility, and Skin Tolerance. AB - Candida species have great ability to colonize and form biofilms on medical devices, causing infections in human hosts. In this study, poly(l-lactide) films with different imidazolium salt (1-n-hexadecyl-3-methylimidazolium chloride (C16MImCl) and 1-n-hexadecyl-3-methylimidazolium methanesulfonate (C16MImMeS)) contents were prepared, using the solvent casting process. Poly(l-lactide) imidazolium salt films were obtained with different surface morphologies (spherical and directional), and the presence of the imidazolium salt in the surface was confirmed. These films with different concentrations of the imidazolium salts C16MImCl and C16MImMeS presented antibiofilm activity against isolates of Candida tropicalis, Candida parapsilosis, and Candida albicans. The minor antibiofilm concentration assay enabled one to determine that an increasing imidazolium salt content promoted, in general, an increase in the inhibition percentage of biofilm formation. Scanning electron microscopy micrographs confirmed the effective prevention of biofilm formation on the imidazolium salt containing biomaterials. Lower concentrations of the imidazolium salts showed no cytotoxicity, and the poly(l-lactide)-imidazolium salt films presented good cell adhesion and proliferation percentages with human mesenchymal stem cells. Furthermore, no acute microscopic lesions were identified in the histopathological evaluation after contact between the films and pig ear skin. In combination with the good morphological, physicochemical, and mechanical properties, these poly(l-lactide)-based materials with imidazolium salt additives can be considered as promising biomaterials for use in the manufacturing of medical devices. PMID- 27486828 TI - Experimental and Quantum Chemical Calculations of Imidazolium Appended Naphthalene Hybrid in Different Biomimicking Aqueous Interfaces. AB - The effect of solvent polarity and micellar headgroup on a newly designed imidazolium based ionic liquid (IL) conjugated with naphthalene, 1,2-dimethyl-3 ((6-(octyloxy)naphthalen-2-yl)methyl)-1H-imidazol-3-ium chloride (IN-O8-Cl), was studied using steady state and time-resolved fluorescence techniques. We observed that the dipole moment in the excited state is remarkably higher than the ground state. The effect of micellar surface charge on the photophysics of IN-O8-Cl in aqueous phase at room temperature was investigated. Formation of premicellar aggregates in sodium dodecylsulfate (SDS) was perceived; further the microenvironment of IN-O8-Cl was examined using steady-state fluorescence spectroscopy. Micropolarity of the micellar environment of SDS was found to be lower than that of cetyltrimethylammonium bromide (CTAB) and triton X-100 (TX100) following the order SDS < TX-100 < CTAB. The binding constant (Kb) and edge excitation red shift (EERS) from the emission maximum suggest that the probe binds strongly to the micelles. Multiexponential behavior was observed in time resolved fluorescence lifetime studies in all micellar environments. We have observed an increase in rotational correlation time as we move from pure aqueous phase to solution containing surfactants of different head charge. Varieties of spectral parameters were used to justify the region in which the probe is present. The experimentally obtained dipole moment data were justified and explained by the DFT calculations of the electronic properties of IN-O8-Cl molecules in gas phase and in selected solvents. PMID- 27486829 TI - Mechanism and Selectivity in the Pd-Catalyzed Difunctionalization of Isoprene. AB - The three-component coupling of isoprene, an alkenyl triflate, and styrenylboronic acid catalyzed by a palladium pyrox complex affords access to skipped dienes from simple chemical feedstocks. Unfortunately, the transformation proceeds with only moderate selectivity and yields. The reaction mechanism and factors responsible for the resulting regioselectivity were elucidated using M06/SDD/6-311++G(d,p) + SMD calculations. Distortion of the palladium coordination sphere in the transition structure of the migratory insertion step is found to control the 4,1- vs 1,x-selectivity. The calculated DeltaDeltaG? of 1.0 kcal/mol for this step is in excellent agreement with the experimentally observed selectivity of 1:9.9 disfavoring the 4,1-product. The transmetalation was found to be the regioselectivity determining step for the formation of the 1,2- vs 1,4-addition products. Systematic conformational searches for the transmetalation transition structure revealed a series of steric interactions between the t-Bu substituent on the ligand and the substrates in the model system that are balanced by additional repulsive interactions between the substrates and the pyridyl portion of the ligand. The combination of these effects leads to the low to moderate 1,2- vs 1,4-selectivity in the experimentally studied system. PMID- 27486830 TI - Ceramide-Induced Lamellar Gel Phases in Fluid Cell Lipid Extracts. AB - The effects of increasing amounts of palmitoylceramide (pCer) on human red blood cell lipid membranes have been studied using atomic force microscopy of supported lipid bilayers, in both imaging (bilayer thickness) and force-spectroscopy (nanomechanical resistance) modes. Membranes appeared homogeneous with pCer concentrations up to 10 mol % because of the high concentration of cholesterol (Chol) present in the membrane (~45 mol %). However, the presence of pCer at 30 mol % gave rise to a clearly distinguishable segregated phase with a nanomechanical resistance 7-fold higher than the continuous phase. These experiments were validated using differential scanning calorimetry. Furthermore, Chol depletion of the bilayers caused lipid domain generation in the originally homogeneous samples, and Chol-depleted domain stiffness significantly increased with higher amounts of pCer. These results point to the possibility of different kinds of transient and noncompositionally constant, complex gel-like phases present in RBC lipid membranes rich in both pCer and Chol, in contrast to the widespread opinion about the displacements between pCer-enriched "gel-like" domains and liquid-ordered "raft-like" Chol-enriched phases. Changes in the biophysical properties of these complex gel-like phases governed by local modulation of pCer:Chol ratios could be a cell mechanism for fine-tuning the properties of membranes as required. PMID- 27486831 TI - Lewis Acid Catalyzed Displacement of Trichloroacetimidates in the Synthesis of Functionalized Pyrroloindolines. AB - The pyrroloindoline core is found in many natural products. These structures often differ at the C3a position, which may be substituted with an oxygen, nitrogen, or sp(3)- or sp(2)-hybridized carbon. Utilizing a trichloroacetimidate leaving group, a diversity-oriented approach to these structures has been developed. The trichloroacetimidate intermediate allows for the rapid incorporation of anilines, alcohols, thiols, and carbon nucleophiles. This method was applied in the synthesis of arundinine and a formal synthesis of psychotriasine. PMID- 27486832 TI - Effects of Rate-Limited Mass Transfer on Modeling Vapor Intrusion with Aerobic Biodegradation. AB - Most of the models for simulating vapor intrusion accept the local equilibrium assumption for multiphase concentration distributions, that is, concentrations in solid, liquid and vapor phases are in equilibrium. For simulating vapor transport with aerobic biodegradation controlled by counter-diffusion processes, the local equilibrium assumption combined with dual-Monod kinetics and biomass decay may yield near-instantaneous behavior at steady state. The present research investigates how predicted concentration profiles and fluxes change as interphase mass transfer resistances are increased for vapor intrusion with aerobic biodegradation. Our modeling results indicate that the attenuation coefficients for cases with and without mass transfer limitations can be significantly different by orders of magnitude. Rate-limited mass transfer may lead to larger overlaps of contaminant vapor and oxygen concentrations, which cannot be simulated by instantaneous reaction models with local equilibrium mass transfer. In addition, the contaminant flux with rate-limited mass transfer is much smaller than that with local equilibrium mass transfer, indicating that local equilibrium mass transfer assumption may significantly overestimate the biodegradation rate and capacity for mitigating vapor intrusion through the unsaturated zone. Our results indicate a strong research need for field tests to examine the validity of local equilibrium mass transfer, a widely accepted assumption in modeling vapor intrusion. PMID- 27486833 TI - Discovery of (R)-2-(6-Methoxynaphthalen-2-yl)butanoic Acid as a Potent and Selective Aldo-keto Reductase 1C3 Inhibitor. AB - Type 5 17beta-hydroxysteroid dehydrogenase, aldo-keto reductase 1C3 (AKR1C3) converts Delta(4)-androstene-3,17-dione and 5alpha-androstane-3,17-dione to testosterone (T) and 5alpha-dihydrotestosterone, respectively, in castration resistant prostate cancer (CRPC). In CRPC, AKR1C3 is implicated in drug resistance, and enzalutamide drug resistance can be surmounted by indomethacin a potent inhibitor of AKR1C3. We examined a series of naproxen analogues and find that (R)-2-(6-methoxynaphthalen-2-yl)butanoic acid (in which the methyl group of R-naproxen was replaced by an ethyl group) acts as a potent AKR1C3 inhibitor that displays selectivity for AKR1C3 over other AKR1C enzymes. This compound was devoid of inhibitory activity on COX isozymes and blocked AKR1C3 mediated production of T and induction of PSA in LNCaP-AKR1C3 cells as a model of a CRPC cell line. R-Profens are substrate selective COX-2 inhibitors and block the oxygenation of endocannabinoids and in the context of advanced prostate cancer R profens could inhibit intratumoral androgen synthesis and act as analgesics for metastatic disease. PMID- 27486834 TI - Characterization of Key Aroma Compounds in Raw and Thermally Processed Prawns and Thermally Processed Lobsters by Application of Aroma Extract Dilution Analysis. AB - Application of aroma extract dilution analysis (AEDA) to an aroma distillate of blanched prawn meat (Litopenaeus vannamei) (BPM) revealed 40 odorants in the flavor dilution (FD) factor range from 4 to 1024. The highest FD factors were assigned to 2-acetyl-1-pyrroline, 3-(methylthio)propanal, (Z)-1,5-octadien-3-one, trans-4,5-epoxy-(E)-2-decenal, (E)-3-heptenoic acid, and 2-aminoacetophenone. To understand the influence of different processing conditions on odorant formation, fried prawn meat was investigated by means of AEDA in the same way, revealing 31 odorants with FD factors between 4 and 2048. Also, the highest FD factors were determined for 2-acetyl-1-pyrroline, 3-(methylthio)propanal, and (Z)-1,5-octadien 3-one, followed by 4-hydroxy-2,5-dimethyl-3(2H)-furanone, (E)-3-heptenoic acid, and 2-aminoacetophenone. As a source of the typical marine, sea breeze-like odor attribute of the seafood, 2,4,6-tribromoanisole was identified in raw prawn meat as one of the contributors. Additionally, the aroma of blanched prawn meat was compared to that of blanched Norway and American lobster meat, respectively (Nephrops norvegicus and Homarus americanus). Identification experiments revealed the same set of odorants, however, with differing FD factors. In particular, 3 hydroxy-4,5-dimethyl-2(5H)-furanone was found as the key aroma compound in blanched Norway lobster, whereas American lobster contained 3-methylindole with a high FD factor. PMID- 27486835 TI - Xylitol for preventing acute otitis media in children up to 12 years of age. AB - BACKGROUND: Acute otitis media (AOM) is the most common bacterial infection among young children in the United States. There are limitations and concerns over its treatment with antibiotics and surgery and so effective preventative measures are attractive. A potential preventative measure is xylitol, a natural sugar substitute that reduces the risk of dental decay. Xylitol can reduce the adherence of Streptococcus pneumoniae (S pneumoniae) and Haemophilus influenzae (H influenzae) to nasopharyngeal cells in vitro. This is an update of a review first published in 2011. OBJECTIVES: To assess the efficacy and safety of xylitol to prevent AOM in children aged up to 12 years. SEARCH METHODS: We searched CENTRAL (to Issue 12, 2015), MEDLINE (1950 to January 2016), Embase (1974 to January 2016), CINAHL (1981 to January 2016), LILACS (1982 to January 2016), Web of Science (2011 to January 2016) and International Pharmaceutical Abstracts (2000 to January 2016). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs of children aged 12 years or younger where xylitol supplementation was compared with placebo or no treatment to prevent AOM. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials from search results, assessed and rated study quality and extracted relevant data for inclusion in the review. We contacted trial authors to request missing data. We noted data on any adverse events of xylitol. We extracted data on relevant outcomes and estimated the effect size by calculating risk ratio (RR), risk difference (RD) and associated 95% confidence intervals (CI). MAIN RESULTS: We identified five clinical trials that involved 3405 children for inclusion. For this 2016 update, we identified one new trial for inclusion. This trial was systematically reviewed but due to several sources of heterogeneity, was not included in the meta analysis. The remaining four trials were of adequate methodological quality. In three RCTs that involved a total of 1826 healthy Finnish children attending daycare, there is moderate quality evidence that xylitol (in any form) can reduce the risk of AOM from 30% to around 22% compared with the control group (RR 0.75, 95% CI 0.65 to 0.88). Among the reasons for dropouts, there were no significant differences in abdominal discomfort and rash between the xylitol and the control groups. Xylitol was not effective in reducing AOM among healthy children during a respiratory infection (RR 1.13, 95% CI 0.83 to 1.53; moderate quality evidence) or among otitis-prone healthy children (RR 0.90, 95% CI 0.67 to 1.21; low-quality evidence). AUTHORS' CONCLUSIONS: There is moderate quality evidence showing that the prophylactic administration of xylitol among healthy children attending daycare centres can reduce the occurrence of AOM. There is inconclusive evidence with regard to the efficacy of xylitol in preventing AOM among children with respiratory infection, or among otitis-prone children. The meta-analysis was limited because data came from a small number of studies, and most were from the same research group. PMID- 27486836 TI - Home telemonitoring and remote feedback between clinic visits for asthma. AB - BACKGROUND: Asthma is a chronic disease that causes reversible narrowing of the airways due to bronchoconstriction, inflammation and mucus production. Asthma continues to be associated with significant avoidable morbidity and mortality. Self management facilitated by a healthcare professional is important to keep symptoms controlled and to prevent exacerbations.Telephone and Internet technologies can now be used by patients to measure lung function and asthma symptoms at home. Patients can then share this information electronically with their healthcare provider, who can provide feedback between clinic visits. Technology can be used in this manner to improve health outcomes and prevent the need for emergency treatment for people with asthma and other long-term health conditions. OBJECTIVES: To assess the efficacy and safety of home telemonitoring with healthcare professional feedback between clinic visits, compared with usual care. SEARCH METHODS: We identified trials from the Cochrane Airways Review Group Specialised Register (CAGR) up to May 2016. We also searched www.clinicaltrials.gov, the World Health Organization (WHO) trials portal and reference lists of other reviews, and we contacted trial authors to ask for additional information. SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs) of adults or children with asthma in which any form of technology was used to measure and share asthma monitoring data with a healthcare provider between clinic visits, compared with other monitoring or usual care. We excluded trials in which technologies were used for monitoring with no input from a doctor or nurse. We included studies reported as full-text articles, those published as abstracts only and unpublished data. DATA COLLECTION AND ANALYSIS: Two review authors screened the search and independently extracted risk of bias and numerical data, resolving disagreements by consensus.We analysed dichotomous data as odds ratios (ORs) while using study participants as the unit of analysis, and continuous data as mean differences (MDs) while using random-effects models. We rated evidence for all outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation Working Group) approach. MAIN RESULTS: We found 18 studies including 2268 participants: 12 in adults, 5 in children and one in individuals from both age groups. Studies generally recruited people with mild to moderate persistent asthma and followed them for between three and 12 months. People in the intervention group were given one of a variety of technologies to record and share their symptoms (text messaging, Web systems or phone calls), compared with a group of people who received usual care or a control intervention.Evidence from these studies did not show clearly whether asthma telemonitoring with feedback from a healthcare professional increases or decreases the odds of exacerbations that require a course of oral steroids (OR 0.93, 95% confidence Interval (CI) 0.60 to 1.44; 466 participants; four studies), a visit to the emergency department (OR 0.75, 95% CI 0.36 to 1.58; 1018 participants; eight studies) or a stay in hospital (OR 0.56, 95% CI 0.21 to 1.49; 1042 participants; 10 studies) compared with usual care. Our confidence was limited by imprecision in all three primary outcomes. Evidence quality ratings ranged from moderate to very low. None of the studies recorded serious or non serious adverse events separately from asthma exacerbations.Evidence for measures of asthma control was imprecise and inconsistent, revealing possible benefit over usual care for quality of life (MD 0.23, 95% CI 0.01 to 0.45; 796 participants; six studies; I(2) = 54%), but the effect was small and study results varied. Telemonitoring interventions may provide additional benefit for two measures of lung function. AUTHORS' CONCLUSIONS: Current evidence does not support the widespread implementation of telemonitoring with healthcare provider feedback between asthma clinic visits. Studies have not yet proven that additional telemonitoring strategies lead to better symptom control or reduced need for oral steroids over usual asthma care, nor have they ruled out unintended harms. Investigators noted small benefits for quality of life, but these are subject to risk of bias, as the studies were unblinded. Similarly, some benefits for lung function are uncertain owing to possible attrition bias.Larger pragmatic studies in children and adults could better determine the real-world benefits of these interventions for preventing exacerbations and avoiding harms; it is difficult to generalise results from this review because benefits may be explained at least in part by the increased attention participants receive by taking part in clinical trials. Qualitative studies could inform future research by focusing on patient and provider preferences, or by identifying subgroups of patients who are more likely to attain benefit from closer monitoring, such as those who have frequent asthma attacks. PMID- 27486837 TI - Psychosocial Interventions for Adolescents and Young Adults Diagnosed with Cancer During Adolescence: A Critical Review. AB - Adolescents and young adults (AYA) face individual and social challenges different to other age groups that shape their experience of cancer and the associated psychological distress. This critical review examined the availability of AYA-specific psychosocial interventions to assess the impact they have and identify elements that make them successful. Five literature databases were searched for psychosocial intervention studies involving AYAs with cancer, on and off treatment, aged 10-30 years, published between 1980 and 2016. Eleven out of 42 identified studies were included in the final review after quality assessment. All but two interventions showed positive results on at least one measure of psychosocial well-being. A distinctive difference between the supportive needs of those on and off treatment was noted, and differences in intervention design and delivery formats were identified between the two subgroups. Analysis of specific intervention characteristics that achieved the successful outcomes was more challenging due to the large variation in outcome measures used. This review demonstrates that psychosocial intervention research for AYA with cancer is increasing and the results show a potential benefit of intervention participation. Further work is needed to validate whether the benefits achieved by intervention participation remain over time. PMID- 27486838 TI - Variation in stiffness regulates cardiac myocyte hypertrophy via signaling pathways. AB - Much diseased human myocardial tissue is fibrotic and stiff, which increases the work that the ventricular myocytes must perform to maintain cardiac output. The hypothesis tested is that the increased load due to greater stiffness of the substrata drives sarcomere assembly of cells, thus strengthening them. Neonatal rat ventricular myocytes (NRVM) were cultured on polyacrylamide or polydimethylsiloxane substrates with stiffness of 10 kPa, 100 kPa, or 400 kPa, or glass with stiffness of 61.9 GPa. Cell size increased with stiffness. Two signaling pathways were explored, phosphorylation of focal adhesion kinase (p FAK) and lipids by phosphatidylinositol 4,5-bisphosphate (PIP2). Subcellular distributions of both were determined in the sarcomeric fraction by antibody localization, and total amounts were measured by Western or dot blotting, respectively. More p-FAK and PIP2 distributed to the sarcomeres of NRVM grown on stiffer substrates. Actin assembly involves the actin capping protein Z (CapZ). Both actin and CapZ dynamic exchange were significantly increased on stiffer substrates when assessed by fluorescence recovery after photobleaching (FRAP) of green fluorescent protein tags. Blunting of actin FRAP by FAK inhibition implicates linkage from mechano-signalling pathways to cell growth. Thus, increased stiffness of cardiac disease can be modeled with polymeric materials to understand how the microenvironment regulates cardiac hypertrophy. PMID- 27486840 TI - Correction to: Thyroid 2016;26:189-196. PMID- 27486841 TI - Thiocyanate-Ligated Heterobimetallic {PtM} Lantern Complexes Including a Ferromagnetically Coupled 1D Coordination Polymer. AB - A series of heterobimetallic lantern complexes with the central unit {PtM(SAc)4(NCS)} have been prepared and thoroughly characterized. The {Na(15C5)}[PtM(SAc)4(NCS)] series, 1 (Co), 2 (Ni), 3 (Zn), are discrete compounds in the solid state, whereas the {Na(12C4)2)}[PtM(SAc)4(NCS)] series, 4 (Co), 5 (Ni), 6 (Zn), and 7 (Mn), are ion-separated species. Compound 7 is the first {PtMn} lantern of any bridging ligand (carboxylate, amide, etc.). Monomeric 1-7 have M(2+), necessitating counter cations that have been prepared as {(15C5)Na}(+) and {(12C4)2Na}(+) variants, none of which form extended structures. In contrast, neutral [PtCr(tba)4(NCS)]infinity 8 forms a coordination polymer of {PtCr}(+) units linked by (NCS)(-) in a zigzag chain. All eight compounds have been thoroughly characterized and analyzed in comparison to a previously reported family of compounds. Crystal structures are presented for compounds 1-6 and 8, and solution magnetic susceptibility measurements are presented for compounds 1, 2, 4, 5, and 7. Further structural analysis of dimerized {PtM} units reinforces the empirical observation that greater charge density along the Pt-M vector leads to more Pt...Pt interactions in the solid state. Four structural classes, one new, of {MPt}...{PtM} units are presented. Solid state magnetic characterization of 8 reveals a ferromagnetic interaction in the {PtCr(NCS)} chain between the Cr centers of J/kB = 1.7(4) K. PMID- 27486842 TI - Passivation of hematite nanorod photoanodes with a phosphorus overlayer for enhanced photoelectrochemical water oxidation. AB - Hematite (i.e., alpha-Fe2O3) nanorod photoanodes passivated with a phosphorus overlayer have been fabricated by decomposing sodium hypophosphite (NaH2PO2) at a low temperature over the hematite nanorod surface. Extensive scanning electron microscopy, transmission electron microscopy, x-ray diffractometry and UV-vis spectroscopy characterizations confirm that conformal deposition of an amorphous phosphorus overlayer does not change the crystal structure, morphology, and optical absorption properties of hematite photoanodes. X-ray photoelectron spectroscopy reveals that phosphorus in the deposited overlayer exists in an oxidized state. Comprehensive steady-state polarization, transient photocurrent response, and impedance spectroscopy measurements as well as Mott-Schottky analysis manifest that the phosphorus overlayer is able to effectively passivate surface states and suppress electron-hole recombination, substantially enhancing the photocurrent for water oxidation. Combining the phosphorization treatment with two-step thermal activation, a photocurrent density of 1.1 mA cm(-2) is achieved at 1.23 V versus reversible hydrogen electrode under illumination of 100 mW cm(-2), ca 55 times higher than that of the non-activated pristine hematite photoanode measured under the same conditions. The simple and fast phosphorization strategy we present here can be readily applied to passivate surfaces of other semiconductor photoelectrodes to improve their photoelectrochemical performance. PMID- 27486843 TI - Pain Intensity and Pain Interference in Older Adults: Role of Gender, Obesity and High-Sensitivity C-Reactive Protein. AB - BACKGROUND: Among older adults, pain intensity and pain interference are more common in women than men and associated with obesity and inflammatory markers. OBJECTIVE: We examined whether the obesity and pain relationship is mediated by the high-sensitivity C-reactive protein (hsCRP), a nonspecific marker of systemic inflammation, and whether this relationship differs by sex. METHODS: Items from Medical Outcomes Study Short Form-36 were used to measure pain intensity and pain interference in daily life. Ordinal logistic regression was used to assess the cross-sectional association among body mass index (BMI), hsCRP levels, pain intensity and pain interference using gender-stratified models adjusted for demographic variables. RESULTS: Participants included 667 community-residing adults over the age of 70 years, free of dementia, enrolled in the Einstein Aging Study (EAS). In women (n = 410), pain intensity was associated with obesity [BMI >=30 vs. normal, odds ratio (OR) = 2.29, 95% confidence interval (CI) 1.43-3.68] and higher hsCRP (OR = 1.28, 95% CI 1.08-1.51). In a model with obesity and hsCRP, both remained significant, but the association between hsCRP and pain intensity was somewhat attenuated. Obesity (OR = 3.04, 95% CI 1.81-5.11) and higher hsCRP levels (OR = 1.30, 95% CI 1.08-1.56) were also independently associated with greater pain interference in women. After adjustment for pain intensity and BMI, hsCRP was no longer associated with pain interference in women. Greater pain intensity and being overweight or obese continued to be significantly associated with pain interference in women. In men (n = 257), obesity and hsCRP were not associated with pain intensity or pain interference. CONCLUSIONS: In women, the relationship between obesity and higher levels of pain intensity or interference may be accounted for by factors related to hsCRP. PMID- 27486844 TI - A Novel Role for Banana MaASR in the Regulation of Flowering Time in Transgenic Arabidopsis. AB - The abscisic acid (ABA)-, stress-, and ripening-induced (ASR) protein is a plant specific hydrophilic transcriptional factor involved in fruit ripening and the abiotic stress response. To date, there have been no studies on the role of ASR genes in delayed flowering time. Here, we found that the ASR from banana, designated as MaASR, was preferentially expressed in the banana female flowers from the eighth, fourth, and first cluster of the inflorescence. MaASR transgenic lines (L14 and L38) had a clear delayed-flowering phenotype. The number of rosette leaves, sepals, and pedicel trichomes in L14 and L38 was greater than in the wild type (WT) under long day (LD) conditions. The period of buds, mid flowers, and full bloom of L14 and L38 appeared later than the WT. cDNA microarray and quantitative real-time PCR (qRT-PCR) analyses revealed that overexpression of MaASR delays flowering through reduced expression of several genes, including photoperiod pathway genes, vernalization pathway genes, gibberellic acid pathway genes, and floral integrator genes, under short days (SD) for 28 d (from vegetative to reproductive transition stage); however, the expression of the autonomous pathway genes was not affected. This study provides the first evidence of a role for ASR genes in delayed flowering time in plants. PMID- 27486845 TI - Relocating the Active-Site Lysine in Rhodopsin: 2. Evolutionary Intermediates. AB - The visual pigment rhodopsin is a G protein-coupled receptor that covalently binds its retinal chromophore via a Schiff base linkage to an active-site Lys residue in the seventh transmembrane helix. Although this residue is strictly conserved among all type II retinylidene proteins, we found previously that the active-site Lys in bovine rhodopsin (Lys296) can be moved to three other locations (G90K, T94K, S186K) while retaining the ability to form a pigment with retinal and to activate transducin in a light-dependent manner [ Devine et al. ( 2013 ) Proc. Natl. Acad. Sci. USA 110 , 13351 - 13355 ]. Because the active-site Lys is not functionally constrained to be in helix seven, it is possible that it could relocate within the protein, most likely via an evolutionary intermediate with two active-site Lys. Therefore, in this study we characterized potential evolutionary intermediates with two Lys in the active site. Four mutant rhodopsins were prepared in which the original Lys296 was left untouched and a second Lys residue was substituted for G90K, T94K, S186K, or F293K. All four constructs covalently bind 11-cis-retinal, form a pigment, and activate transducin in a light-dependent manner. These results demonstrate that rhodopsin can tolerate a second Lys in the retinal binding pocket and suggest that an evolutionary intermediate with two Lys could allow migration of the Schiff base Lys to a position other than the observed, highly conserved location in the seventh TM helix. From sequence-based searches, we identified two groups of natural opsins, insect UV cones and neuropsins, that contain Lys residues at two positions in their active sites and also have intriguing spectral similarities to the mutant rhodopsins studied here. PMID- 27486846 TI - Seeing for themselves - healthcare professionals' views about the presence of family members during brainstem death testing. AB - AIMS AND OBJECTIVES: To provide an insight into the views of healthcare professionals on the presence of family members during brainstem death testing. BACKGROUND: Brainstem death presents families with a paradoxical death that can be difficult to define. International research suggests families should be given the choice to be present at brainstem death testing, yet it appears few units offer families the choice to be present and little attention has been paid to developing practice to enable effective facilitation of choice. DESIGN: A qualitative, exploratory design was adopted to understand the perceptions of healthcare professionals. Individual semi-structured interviews were audio-taped and carried out over two months. METHODS: A purposive sample of 10 nurses and 10 doctors from two tertiary intensive care units in the United Kingdom was interviewed, and transcripts were analysed using content analysis to identify emergent categories and themes. RESULTS: Healthcare professionals indicated different perceptions of death in the context of catastrophic brainstem injury. The majority of participants favoured offering families the choice to be present while acknowledging the influence of organisational culture. Identified benefits included acceptance, closure and better understanding. Suggested challenges involved the assumption of trauma or disruption and sense of obligation for families to accept if choice was offered. Key issues involved improving knowledge and communication skills to individually tailor support for families involved. CONCLUSIONS: If families are to be offered the choice of witnessing brainstem death testing, considering that needs and conventions will differ according to global cultural backgrounds, then key needs must be met to ensure that effective care and support is provided to families and clinicians. RELEVANCE TO CLINICAL PRACTICE: A proactive approach to facilitating family choice to be present at testing requires the development of guidelines that accommodate cultural and professional variations to provide excellence in end-of-life care. PMID- 27486847 TI - The Role of Temporal Trends in Growing Networks. AB - The rich get richer principle, manifested by the Preferential attachment (PA) mechanism, is widely considered one of the major factors in the growth of real world networks. PA stipulates that popular nodes are bound to be more attractive than less popular nodes; for example, highly cited papers are more likely to garner further citations. However, it overlooks the transient nature of popularity, which is often governed by trends. Here, we show that in a wide range of real-world networks the recent popularity of a node, i.e., the extent by which it accumulated links recently, significantly influences its attractiveness and ability to accumulate further links. We proceed to model this observation with a natural extension to PA, named Trending Preferential Attachment (TPA), in which edges become less influential as they age. TPA quantitatively parametrizes a fundamental network property, namely the network's tendency to trends. Through TPA, we find that real-world networks tend to be moderately to highly trendy. Networks are characterized by different susceptibilities to trends, which determine their structure to a large extent. Trendy networks display complex structural traits, such as modular community structure and degree-assortativity, occurring regularly in real-world networks. In summary, this work addresses an inherent trait of complex networks, which greatly affects their growth and structure, and develops a unified model to address its interaction with preferential attachment. PMID- 27486848 TI - Emerging biological therapies for the treatment of myelodysplastic syndromes. AB - INTRODUCTION: No drug has resulted in a survival advantage in patients with lower risk myelodysplastic syndromes (MDS). While hypomethylating agents (HMA) have revolutionized treatment options for patients with higher-risk MDS, the prognosis remains dismal after HMA treatment failure. Novel effective therapies are urgently needed especially after HMA failure. AREAS COVERED: This review covers the current approach to disease prognostication and risk-adaptive therapy, as well as novel therapeutic approaches. We discuss the recent advancements in the understanding of MDS disease biology as a basis of targeted drug development. Several classes of novel agents are reviewed including drugs targeting dysregulated epigenetic control mechanisms, signaling pathways, abnormal splicing, as well as agents that target the immune system and the MDS bone marrow niche. EXPERT OPINION: Significant advancements in the understanding of the underlying biology of MDS are only starting to be translated into novel treatment options for MDS. Epigenetic therapy has shown significant clinical activity with HMA but the results of clinical trials combining HMAs with histone deacetylase inhibitors (HDACi) have been disappointing to date. Similarly, targeting several aberrant pathways in MDS has not resulted in significant improvements in therapy. Future therapies will focus both on synergic combination of existing drugs as well as novel agents targeting dysregulated immune responses and abnormal RNA splicing in MDS. PMID- 27486849 TI - Design of cyclic peptides with biological activities from biologically active peptides: the case of peptide modulators of melanocortin receptors. AB - Design of biologically active peptides is of critical importance for the development of potent, selective, nontoxic bioavailable drugs. A major approach that has been developed to accomplish this is the development of methods for the design and synthesis of a wide variety of cyclic peptides and peptidomimetics. In this short and general review, we outline the methods that have been developed for cyclization of peptides and how these have been used for peptide and peptidomimetic design using the melanotropin peptides and melanocortin receptors MC1R, MC3R, MC4R, and MC5R to illustrate aspects of this approach. PMID- 27486850 TI - Effects of infant massage on state anxiety in mothers of preterm infants prior to hospital discharge. AB - AIMS AND OBJECTIVES: This study evaluated the effect of infant massage on anxiety in mothers of preterm infants who discharged from the neonatal intensive care unit. BACKGROUND: Birth of preterm infants commonly leads to great levels of distress and anxiety in mothers. Although various methods have been suggested to help mothers cope with such stressful conditions, the effects of infant massage have not been adequately studied in mothers. DESIGN: This was a quasi experimental clinical trial. METHODS: Overall, in 70 mothers and their preterm infants who scheduled to be discharged within 24 hours, State-Trait Anxiety Inventory scale (Spielberger) was completed for mothers in both groups in the morning of the day before discharge. The experimental group received eight minutes of massage including two standard similar parts (each part four minutes). The massage was repeated in two parts on the day of discharge, and then, state anxiety was re-measured using Spielberg's scale for all mothers. The control group received no intervention. RESULTS: The results showed that on the day of discharge, there was a significant difference in the overall mean score of maternal state anxiety between the two groups (p < 0.002), although not in the severity of maternal state anxiety. In both groups, the mean score of maternal state anxiety was significantly decreased on the day of discharge (p < 0.001). CONCLUSIONS: The findings provide evidence that infant massage by mother has an effect on the state anxiety of mothers of preterm infants, so it is recommended that mothers apply massage for preterm infants to improve their mental health. RELEVANCE TO CLINICAL PRACTICE: Mothers of preterm infants can promote mental health by continuing massage of their infants at home. PMID- 27486851 TI - Recommendations of Common Data Elements to Advance the Science of Self-Management of Chronic Conditions. AB - PURPOSE: Common data elements (CDEs) are increasingly being used by researchers to promote data sharing across studies. The purposes of this article are to (a) describe the theoretical, conceptual, and definition issues in the development of a set of CDEs for research addressing self-management of chronic conditions; (b) propose an initial set of CDEs and their measures to advance the science of self management; and (c) recommend implications for future research and dissemination. DESIGN AND METHODS: Between July 2014 and December 2015 the directors of the National Institute of Nursing Research (NINR)-funded P20 and P30 centers of excellence and NINR staff met in a series of telephone calls and a face-to-face NINR-sponsored meeting to select a set of recommended CDEs to be used in self management research. A list of potential CDEs was developed from examination of common constructs in current self-management frameworks, as well as identification of variables frequently used in studies conducted in the centers of excellence. FINDINGS: The recommended CDEs include measures of three self management processes: activation, self-regulation, and self-efficacy for managing chronic conditions, and one measure of a self-management outcome, global health. CONCLUSIONS: The self-management of chronic conditions, which encompasses a considerable number of processes, behaviors, and outcomes across a broad range of chronic conditions, presents several challenges in the identification of a parsimonious set of CDEs. This initial list of recommended CDEs for use in self management research is provisional in that it is expected that over time it will be refined. Comment and recommended revisions are sought from the research and practice communities. CLINICAL RELEVANCE: The use of CDEs can facilitate generalizability of research findings across diverse population and interventions. PMID- 27486852 TI - Tiron Inhibits UVB-Induced AP-1 Binding Sites Transcriptional Activation on MMP-1 and MMP-3 Promoters by MAPK Signaling Pathway in Human Dermal Fibroblasts. AB - Recent research found that Tiron was an effective antioxidant that could act as the intracellular reactive oxygen species (ROS) scavenger or alleviate the acute toxic metal overload in vivo. In this study, we investigated the inhibitory effect of Tiron on matrix metalloproteinase (MMP)-1 and MMP-3 expression in human dermal fibroblast cells. Western blot and ELISA analysis revealed that Tiron inhibited ultraviolet B (UVB)-induced protein expression of MMP-1 and MMP-3. Real time quantitative PCR confirmed that Tiron could inhibit UVB-induced mRNA expression of MMP-1 and MMP-3. Furthermore, Tiron significantly blocked UVB induced activation of the MAPK signaling pathway and activator protein (AP)-1 in the downstream of this transduction pathway in fibroblasts. Through the AP-1 binding site mutation, it was found that Tiron could inhibit AP-1-induced upregulation of MMP-1 and MMP-3 expression through blocking AP-1 binding to the AP-1 binding sites in the MMP-1 and MMP-3 promoter region. In conclusion, Tiron may be a novel antioxidant for preventing and treating skin photoaging UV induced. PMID- 27486853 TI - Oncolytic virus therapy: A new era of cancer treatment at dawn. AB - Oncolytic virus therapy is perhaps the next major breakthrough in cancer treatment following the success in immunotherapy using immune checkpoint inhibitors. Oncolytic viruses are defined as genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells without harming the normal tissues. T-Vec (talimogene laherparepvec), a second-generation oncolytic herpes simplex virus type 1 (HSV-1) armed with GM-CSF, was recently approved as the first oncolytic virus drug in the USA and Europe. The phase III trial proved that local intralesional injections with T-Vec in advanced malignant melanoma patients can not only suppress the growth of injected tumors but also act systemically and prolong overall survival. Other oncolytic viruses that are closing in on drug approval in North America and Europe include vaccinia virus JX 594 (pexastimogene devacirepvec) for hepatocellular carcinoma, GM-CSF-expressing adenovirus CG0070 for bladder cancer, and Reolysin (pelareorep), a wild-type variant of reovirus, for head and neck cancer. In Japan, a phase II clinical trial of G47?, a third-generation oncolytic HSV-1, is ongoing in glioblastoma patients. G47? was recently designated as a "Sakigake" breakthrough therapy drug in Japan. This new system by the Japanese government should provide G47? with priority reviews and a fast-track drug approval by the regulatory authorities. Whereas numerous oncolytic viruses have been subjected to clinical trials, the common feature that is expected to play a major role in prolonging the survival of cancer patients is an induction of specific antitumor immunity in the course of tumor-specific viral replication. It appears that it will not be long before oncolytic virus therapy becomes a standard therapeutic option for all cancer patients. PMID- 27486854 TI - Mutation in the S gene a determinant of the hepatitis B virus associated with concomitant HBsAg and anti-HBs in a population in Northeastern Brazil. AB - Mutations in the a determinant of S gene may develop co-existence of hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) in the serum of infected hepatitis B virus (HBV) individuals. Mutations in this region may change the antigenicity of HBsAg, which in turn, lead to escape of neutralizing action of anti-HBs antibodies. This study identified individuals with concomitant HBsAg and anti-HBs serological markers in individuals of Maranhao, Northeastern Brazil. Samples from a population-based study were evaluated for HBsAg, anti-HBs, and anti-HBc, and those that tested positive for simultaneous HBsAg and anti-HBs were submitted to HBV DNA quantification and S gene characterization by Sanger sequencing. Mutations were investigated in the a determinant located in major hydrophilic region (MHR) of the S gene. Among 3,984 samples analyzed, 92 (2.3%) were positive for HBsAg and three had the atypical HBsAg and anti-HBs-positive profile (3.26%). The frequency of HBsAg and anti-HBs co-existence was similar to previous studies. Only one individual harbored mutation in the S gene a determinant associated with this profile. Little is known about this phenomenon; however, studies as ours may contribute for future enlightenment of this important issue. J. Med. Virol. 89:458-462, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27486855 TI - Nutrient Starvation Sensitizes Human Ovarian Cancer SKOV3 Cells to BH3 Mimetic via Modulation of Mitochondrial Dynamics. AB - The aberrant proliferation of tumor cells necessitates compensatory changes in tumor metabolic processes. Previous studies on tumor growth and metabolism have established a relationship between nutrient stress and Bcl-2 anti-apoptotic proteins, although the mechanisms connecting these processes remain unclear. We induced nutrient deprivation in human ovarian cancer SKOV3 cells by culturing cells in Earle's balanced salt solution (EBSS) as a starvation model. We used EBSS treatment with the BH3 domain of Bcl-2 family proteins (BH3) mimetic ABT737, which targets Bcl-2/Bcl-xL, to examine mitochondrial dynamics and the interactive regulatory mechanisms between nutrition and Bcl-2 proteins. We found that EBSS combined with ABT737 can promote SKOV3 cells to undergo apoptosis and convert tubular mitochondria into small, fragmented morphologies. Bcl-2 family proteins participated in the regulation of mitochondrial fusion and fission through apoptosis, and the decrease of Mcl-1 expression was the key to ABT737 sensitization. Our findings showed that nutrient stress could sensitize SKOV3 cells to ABT737 via regulation of the mitochondrial dynamic balance and interaction of Bcl-2 family proteins. Our data suggest that nutrient starvation combined with the BH3 mimetic ABT737 could reduce the required effective dose of ABT737, and that inhibition of Bcl-2 and Mcl-1 together with nutrient starvation could serve as an effective strategy for the treatment of human ovarian cancer. Anat Rec, 300:326-339, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27486856 TI - Differential Expression of Complement Markers in Normal and AMD Transmitochondrial Cybrids. AB - PURPOSE: Variations in mitochondrial DNA (mtDNA) and abnormalities in the complement pathways have been implicated in the pathogenesis of age-related macular degeneration (AMD). This study was designed to determine the effects of mtDNA from AMD subjects on the complement pathway. METHODS: Transmitochondrial cybrids were prepared by fusing platelets from AMD and age-matched Normal subjects with Rho0 (lacking mtDNA) human ARPE-19 cells. Quantitative PCR and Western blotting were performed to examine gene and protein expression profiles, respectively, of complement markers in these cybrids. Bioenergetic profiles of Normal and AMD cybrids were examined using the Seahorse XF24 flux analyzer. RESULTS: Significant decreases in the gene and protein expression of complement inhibitors, along with significantly higher levels of complement activators, were found in AMD cybrids compared to Older-Normal cybrids. Seahorse flux data demonstrated that the bioenergetic profiles for Older-Normal and Older-AMD cybrid samples were similar to each other but were lower compared to Young-Normal cybrid samples. CONCLUSION: In summary, since all cybrids had identical nuclei and differed only in mtDNA content, the observed changes in components of complement pathways can be attributed to mtDNA variations in the AMD subjects, suggesting that mitochondrial genome and retrograde signaling play critical roles in this disease. Furthermore, the similar bioenergetic profiles of AMD and Older-Normal cybrids indicate that the signaling between mitochondria and nuclei are probably not via a respiratory pathway. PMID- 27486857 TI - Informing Investment to Reduce Inequalities: A Modelling Approach. AB - BACKGROUND: Reducing health inequalities is an important policy objective but there is limited quantitative information about the impact of specific interventions. OBJECTIVES: To provide estimates of the impact of a range of interventions on health and health inequalities. MATERIALS AND METHODS: Literature reviews were conducted to identify the best evidence linking interventions to mortality and hospital admissions. We examined interventions across the determinants of health: a 'living wage'; changes to benefits, taxation and employment; active travel; tobacco taxation; smoking cessation, alcohol brief interventions, and weight management services. A model was developed to estimate mortality and years of life lost (YLL) in intervention and comparison populations over a 20-year time period following interventions delivered only in the first year. We estimated changes in inequalities using the relative index of inequality (RII). RESULTS: Introduction of a 'living wage' generated the largest beneficial health impact, with modest reductions in health inequalities. Benefits increases had modest positive impacts on health and health inequalities. Income tax increases had negative impacts on population health but reduced inequalities, while council tax increases worsened both health and health inequalities. Active travel increases had minimally positive effects on population health but widened health inequalities. Increases in employment reduced inequalities only when targeted to the most deprived groups. Tobacco taxation had modestly positive impacts on health but little impact on health inequalities. Alcohol brief interventions had modestly positive impacts on health and health inequalities only when strongly socially targeted, while smoking cessation and weight reduction programmes had minimal impacts on health and health inequalities even when socially targeted. CONCLUSIONS: Interventions have markedly different effects on mortality, hospitalisations and inequalities. The most effective (and likely cost-effective) interventions for reducing inequalities were regulatory and tax options. Interventions focused on individual agency were much less likely to impact on inequalities, even when targeted at the most deprived communities. PMID- 27486858 TI - Infant Respiratory Outcomes Associated with Prenatal Exposure to Maternal 2009 A/H1N1 Influenza Vaccination. AB - BACKGROUND: Infants are at high risk for influenza illness, but are ineligible for vaccination before 6 months. Transfer of maternal antibodies to the fetus has been demonstrated for 2009 A/H1N1 pandemic vaccines; however, clinical effectiveness is unknown. Our objective was to evaluate the association between 2009 A/H1N1 pandemic vaccination during pregnancy and rates of infant influenza and pneumonia. METHODS: We linked a population-based birth cohort to administrative databases to measure rates of influenza and pneumonia diagnosed during ambulatory physician visits, hospitalizations and emergency department visits during one year of follow-up. We estimated incidence rate ratios and 95% confidence intervals (95% CI) using Poisson regression, comparing infants born to A/H1N1-vaccinated women (vaccine-exposed infants) with unexposed infants, adjusted for confounding using high-dimensional propensity scores. RESULTS: Among 117,335 infants in the study, 36,033 (31%) were born to A/H1N1-vaccinated women. Crude rates of influenza during the pandemic (per 100,000 infant-days) for vaccine-exposed and unexposed infants were similar (2.19, 95% CI: 1.27-3.76 and 3.60, 95% CI: 2.51-5.14, respectively), as were crude rates of influenza and pneumonia combined. We did not observe any significant differences in rates of study outcomes between study groups during the second wave of the 2009 A/H1N1 pandemic, nor during any post-pandemic time period. CONCLUSION: We observed no difference in rates of study outcomes among infants born to A/H1N1-vaccinated mothers relative to unexposed infants born during the second A/H1N1 pandemic wave; however, due to late availability of the pandemic vaccine, the available follow-up time during the pandemic time period was very limited. PMID- 27486859 TI - Structure and biochemical properties of recombinant human dimethylglycine dehydrogenase and comparison to the disease-related H109R variant. AB - : The human dimethylglycine dehydrogenase (hDMGDH) is a flavin adenine dinucleotide (FAD)- and tetrahydrofolate (THF)-dependent, mitochondrial matrix enzyme taking part in choline degradation, one-carbon metabolism and electron transfer to the respiratory chain. The rare natural variant H109R causes dimethylglycine dehydrogenase deficiency leading to increased blood and urinary dimethylglycine concentrations. A detailed biochemical and structural characterization of hDMGDH was thus far hampered by insufficient heterologous expression of the protein. In the present study, we report the development of an intracellular, heterologous expression system in Komagataella phaffii (formerly known as Pichia pastoris) providing the opportunity to determine kinetic parameters, spectroscopic properties, thermostability, and the redox potential of hDMGDH. Moreover, we have successfully crystallized the wild-type enzyme and determined the structure to 3.1-A resolution. The structure-based analysis of our biochemical data provided new insights into the kinetic properties of the enzyme in particular with respect to oxygen reactivity. A comparative study with the H109R variant demonstrated that the variant suffers from decreased protein stability, cofactor saturation, and substrate affinity. DATABASE: Structural data are available in the PDB database under the accession number 5L46. PMID- 27486860 TI - Retrospective characterisation of solitary cutaneous histiocytoma with lymph node metastasis in eight dogs. AB - OBJECTIVES: To describe a small subset of canine solitary cutaneous histiocytoma in which lymph node metastasis has been documented. METHODS: Cases of dogs with solitary cutaneous histiocytoma lesions and regional lymph node metastasis diagnosed via histopathology were found through a retrospective search of the databases of IDEXX Laboratories and the University of California, Davis Veterinary Medical Teaching Hospital Clinical Diagnostic Laboratories. Information on signalment, history and clinical follow-up was obtained from the submittal form and/or via a questionnaire to the submitting veterinarian. Slides were available for review in seven cases and when possible immunohistochemistry was reviewed or performed by a single pathologist. RESULTS: Eight cases met the inclusion criteria. The neoplasms had the typical appearance of histiocytomas. All tested samples were immunoreactive for CD18 and lacked immunoreactivity for other lymphocyte markers and CD11d. Immunoreactivity for E-cadherin varied among the neoplasms tested. Outcome was known for five dogs and at the time of manuscript preparation three of those dogs were alive 1682 days, 570 days and 318 days post-diagnosis. Of the other two dogs with known outcome, one was euthanased shortly after diagnosis and another was hit by a car. Of the dogs that were eventually lost to follow-up, one was reported to be disease-free 1003 days after diagnosis. CLINICAL SIGNIFICANCE: Metastatic histiocytoma is rarely reported and distinction from aggressive disease processes such as histiocytic sarcoma may be difficult. Based upon a small number of cases with known outcomes, some dogs with solitary metastatic histiocytoma may experience favourable outcomes. PMID- 27486862 TI - Husbandry and enclosure influences on penguin behavior and conservation breeding. AB - Multi-zoo comparisons of animal welfare are rare, and yet vital for ensuring continued improvement of zoo enclosures and husbandry. Methods are not standardized for the development of zoo enclosures based on multiple indicators, and case study species are required. This study compares behavior and breeding success to various enclosure and husbandry parameters for the Humboldt penguin, Spheniscus humboldti, for the development of improved enclosure design. Behavioral sampling was completed at Flamingo Land over a period of 8 months. Further data on behavior, enclosure design, and breeding success were collected via questionnaires, visits to zoos, and literature review. Breeding success was primarily influenced by colony age and number of breeding pairs, suggesting an important social influence on reproduction. Across zoos, there was also significant variation in behavior. The proportion of time spent in water varied between zoos (2-23%) and was used as an indicator of physical activity and natural behavior. Regression models revealed that water-use was best predicted by total enclosure area per penguin, followed by land area, with some evidence for positive influence of pool surface area per penguin. Predominantly linear/curvilinear increases in our biological indicators with enclosure parameters suggest that optimal conditions for S. humboldti were not met among the selected zoos. We propose revised minimum conditions for S. humboldti enclosure design, which exceed those in the existing husbandry guidelines. We present a framework for the evaluation of zoo enclosures and suggest that a rigorous scientific protocol be established for the design of new enclosures, based on multivariate methods. Zoo Biol. 35:385-397, 2016. (c) Wiley Periodicals, Inc. PMID- 27486861 TI - LAT1 is a putative therapeutic target in endometrioid endometrial carcinoma. AB - l-type amino acid transporters (LAT1-4) are expressed in various cancer types and are involved in the uptake of essential amino acids such as leucine. Here we investigated the expression of LAT1-4 in endometrial adenocarcinoma and evaluated the contribution of LATs to endometrial cancer cell growth. Analysis of human gene expression data showed that all four LAT family members are expressed in endometrial adenocarcinomas. LAT1 was the most highly expressed, and showed a significant increase in both serous and endometrioid subtypes compared to normal endometrium. Endometrioid patients with the highest LAT1 levels exhibited the lowest disease-free survival. The pan-LAT inhibitor BCH led to a significant decrease in cell growth and spheroid area in four endometrial cancer cell lines tested in vitro. Knockdown of LAT1 by shRNA inhibited cell growth in HEC1A and Ishikawa cells, as well as inhibiting spheroid area in HEC1A cells. These data show that LAT1 plays an important role in regulating the uptake of essential amino acids such as leucine into endometrial cancer cells. Increased ability of BCH compared to LAT1 shRNA at inhibiting Ishikawa spheroid area suggests that other LAT family members may also contribute to cell growth. LAT1 inhibition may offer an effective therapeutic strategy in endometrial cancer patients whose tumours exhibit high LAT1 expression. PMID- 27486863 TI - The Phenotypic Effects of Royal Jelly on Wild-Type D. melanogaster Are Strain Specific. AB - The role for royal jelly (RJ) in promoting caste differentiation of honeybee larvae into queens rather than workers is well characterized. A recent study demonstrated that this poorly understood complex nutrition drives strikingly similar phenotypic effects in Drosophila melanogaster, such as increased body size and reduced developmental time, making possible the use of D. melanogaster as a model system for the genetic analysis of the cellular mechanisms underlying RJ and caste differentiation. We demonstrate here that RJ increases the body size of some wild-type strains of D. melanogaster but not others, and report significant delays in developmental time in all flies reared on RJ. These findings suggest that cryptic genetic variation may be a factor in the D. melanogaster response to RJ, and should be considered when attempting to elucidate response mechanisms to environmental changes in non-honeybee species. PMID- 27486864 TI - Bone marrow stem cells and their niche components are adversely affected in advanced cirrhosis of the liver. AB - Bone marrow (BM) is a reservoir for immune and hematopoietic cells and critical for tissue repair and regeneration. All of these functions are severely altered in cirrhosis. We investigated the cellular and functional state of BM in cirrhosis patients. We studied the histological, cellular, and molecular changes in BM of cirrhosis patients (n = 168) and controls (n = 44). Hematopoietic stem cells (HSCs) and associated niche cells, mesenchymal stem cells, Schwann cells, neural fibers, and endothelial cells were evaluated by immunohistochemistry. Cytokines and growth factors were analyzed in peripheral blood and BM plasma. Cirrhotic BM showed an inverse correlation between cluster of differentiation 34+HSCs and Model of End-Stage Liver Disease (rho = -0.582, P < 0.001) and Child's scores (P < 0.038). BMs of cirrhosis patients with higher Model of End Stage Liver Disease (>15) showed significantly decreased HSCs, mesenchymal stem cells, Schwann cells, and neural fibers; increased interleukin-1beta (P = 0.004), tumor necrosis factor-alpha (P = 0.040), and interferon-gamma (P = 0.03); and decreased oncostatin M (P = 0.04), stem cell factor (P = 0.05), and stromal cell derived factor 1 (P = 0.03) compared to those with lower Model of End-Stage Liver Disease scores (<=15). The cluster of differentiation 34+ cell population was a predictor for the development of sepsis (P < 0.001), and per unit loss increased the probability of sepsis by 16%. Cirrhosis patients with fewer HSCs had lower hemoglobin (P = 0.05) and platelet counts (P = 0.05) and showed early graft dysfunction. CONCLUSIONS: Increasing severity of cirrhosis causes derangement of the hematopoietic niche and loss of HSCs, contributing to the hematological and immunological dysfunctions and reduced potential for regeneration; restoring BM functions could provide new therapeutic options in cirrhosis. (Hepatology 2016;64:1273-1288). PMID- 27486865 TI - The subperiosteal, drill hole, midface lift. AB - This article describes a surgical technique using drill holes through the inferior orbital rim and fixation with permanent sutures as a functional subperiosteal midface lift and compares it to other standard midface elevation techniques. This was a retrospective, comparative, non-randomized study. Charts of all patients undergoing midface elevation between 2009 and 2013 were reviewed. Pre- and post-operative photos were graded on a scale 0 to 3 with 0 representing normal lower lid position and lid/cheek junction and 3 representing the most severe malposition. Twenty-seven patients (35 sides) underwent midface lift. Twelve sides had the subperiosteal drill hole midface lift; 9 preperiosteal with Vicryl suture fixation to periosteum; 14 subperiosteal with Endotine midface B device. All groups had similar demographics and indications for surgery. Average follow-up time was greater than 4 months in all groups. No significant complications were seen in any of the patients. The average post-operative grade of the drill hole group was 0.65 compared to 0.75 of the preperiosteal Vicryl group and 0.7 of the Endotine group. The drill hole group had the most severe pre operative malposition. Overall, the drill hole group demonstrated the largest improvement score. The subperiosteal drill hole technique proved to be an effective method for functional midface elevation. This technique achieves adequate and durable vertical elevation without relying on the strength of the periosteum or use of a commercial device. PMID- 27486866 TI - Longitudinal Erythronychia of the Fingernail. PMID- 27486867 TI - The Role of a Vascular Surgeon. PMID- 27486868 TI - Association between Elevated Hemoglobin A1c Levels and the Outcomes of Patients with Small-Artery Occlusion: A Hospital-Based Study. AB - INTRODUCTION: Abnormal glucose metabolism is an independent risk factor for poor outcome following acute ischemic stroke. However, the relationship between initial hemoglobin A1c level and functional outcome (defined by modified Rankin Scale scores) following small-artery occlusion, a subtype of ischemic stroke, is unknown. The aim of the present study was to evaluate this association among patients diagnosed with small-artery occlusion. MATERIALS AND METHODS: Data on 793 patients diagnosed with small-artery occlusion from October 25, 2012 to June 30, 2015 were collected from the stroke registry of the Department of Neurorehabilitation of HuanHu Hospital. Hemoglobin A1c values at admission were classified into three groups according to tertiles (<5.9,5.9to<6.7, and>=6.7). We used receiver operating characteristics curves to investigate the predictive value of hemoglobin A1c and examined the relationship between hemoglobin A1c levels at admission and modified Rankin Scale scores using univariate and multivariate analyses. RESULTS: The area under the curve was 0.570 (95%CI, 0.509 0.631; P = 0.023). Patients in the highest HbA1c stratification (>=6.7) had a significantly higher risk of an unfavorable outcome than patients in the lowest stratification (<5.9; adjusted odds ratio, 2.099; 95%CI, 1.160-3.798; P = 0.014). However, a significant association was not seen in the middle stratification (5.9 to <6.7; P = 0.115). CONCLUSIONS: Elevated hemoglobin A1c level on admission was adversely associated with functional outcomes 3 months after stroke onset among patients presenting with small-artery occlusion. PMID- 27486869 TI - The Emerging Role of Tyrosine Kinase Inhibitors in Ovarian Cancer Treatment: A Systematic Review. AB - The present systematic review summarizes current evidence regarding the mechanisms of action, the efficacy, and the adverse effects of tyrosine kinase inhibitors (TKIs) in ovarian cancer patients. Phase II and III clinical trials were sought in the PubMed database and in the Clinical Trials.gov registry through September 30, 2015. Seventy-five clinical trials regarding TKIs targeting mainly vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, and sarcoma tyrosine kinase (Src) were yielded. The most promising results were noted with cediranib, nintedanib, and pazopanib. However, drawing universal conclusions about the potential integration of TKIs in ovarian cancer therapy remains elusive. Furthermore, emerging challenges and directions for the future research are critically discussed. PMID- 27486871 TI - The Miraprep: A Protocol that Uses a Miniprep Kit and Provides Maxiprep Yields. AB - Plasmid purification is a basic tool of molecular biologists. Although the development of plasmid isolation kits utilizing silica spin columns reduced the time and labor spent on plasmid purification, achieving large plasmid DNA yields still requires significant time and effort. Here we introduce the Miraprep, a rapid protocol that allows isolation of plasmid DNA using commercial Miniprep kits, but with DNA yields comparable to commercial Maxiprep plasmid purifications. Combining ethanol precipitation with spin column purification, we created a DNA isolation protocol that yields highly concentrated plasmid DNA samples in less than 30 minutes. We show that Miraprep isolated plasmids are as stable as plasmids isolated by standard procedures, can be used for standard molecular biology procedures including DNA sequencing, and can be efficiently transfected into mammalian cells. This new plasmid DNA isolation protocol will significantly reduce time and labor without increasing costs. PMID- 27486872 TI - Global DNA Methylation Changes in Nile Tilapia Gonads during High Temperature Induced Masculinization. AB - In some fish species, high or low temperature can switch the sex determination mechanisms and induce fish sex reversal when the gonads are undifferentiated. During this high or low temperature-induced sex reversal, the expressions of many genes are altered. However, genome-wide DNA methylation changes in fish gonads after high or low temperature treatment are unclear. Herein, we compared the global DNA methylation changes in the gonads from control females (CF), control males (CM), high temperature-treated females (TF), and high temperature-induced males (IM) from the F8 family of Nile tilapia (Oreochromis niloticus) using methylated DNA immunoprecipitation sequencing. The DNA methylation level in CF was higher than that in CM for various chromosomes. Both females and males showed an increase in methylation levels on various chromosomes after high-temperature induction. We identified 64,438 (CF/CM), 63,437 (TF/IM), 98,675 (TF/CF), 235,270 (IM/CM) and 119,958 (IM/CF) differentially methylated regions (DMRs) in Nile tilapia gonads, representing approximately 0.70% (CF/CM), 0.69% (TF/IM), 1.07% (TF/CF), 2.56% (IM/CM), and 1.30% (IM/CF)of the length of the genome. A total of 89 and 65 genes that exhibited DMRs in their gene bodies and promoters were mapped to the Nile tilapia genome. Furthermore, more than half of the genes with DMRs in the gene body in CF/CM were also included in the IM/CM, TF/CF, TF/IM, and IM/CF groups. Additionally, many important pathways, including neuroactive ligand receptor interaction, extracellular matrix-receptor interaction, and biosynthesis of unsaturated fatty acids were identified. This study provided an important foundation to investigate the molecular mechanism of high temperature-induced sex reversal in fish species. PMID- 27486873 TI - CONIFER - Non-Interventional Study to Evaluate Therapy Monitoring During Deferasirox Treatment of Iron Toxicity in Myelodysplastic Syndrome Patients with Transfusional Iron Overload. AB - BACKGROUND: The non-interventional study CONIFER was designed to assess the safety and clinical practicability of deferasirox for the treatment of transfusional iron overload in myelodysplastic syndrome (MDS) patients. METHODS: Patients included in the study were diagnosed with MDS and received at least 1 treatment with deferasirox. The observation period covered the time from the initial visit until the last follow-up. RESULTS: The data of 99 patients with MDS scored mainly as International Prognostic Scoring System (IPSS) low and intermediate 1 were evaluated. The mean age of the participants was 75 years and 58% of the patients were male. Iron overload was assessed by serum ferritin level (mean baseline serum ferritin 2,080 +/- 1,244 ug/l). Patients were treated for a mean duration of 16 months (mean daily dose at baseline 11.8 +/- 7.0 mg/kg). Stratification of serum ferritin levels by deferasirox dose showed a reduction at the higher but no reduction at the lower dose (< 15 mg/kg vs. >= 15 mg/kg and < 20 mg/kg vs. >= 20 mg/kg). The majority of patients (81%) were affected by at least 1 adverse event, with decreased renal creatinine clearance being the most frequent. CONCLUSION: Higher doses (>= 15 mg/kg) of deferasirox effectively and safely reduced serum ferritin levels in MDS patients with transfusional iron overload. PMID- 27486874 TI - ENETS Newsletter. PMID- 27486876 TI - Predictive value of pedicle involvement with MRI in spine metastases. AB - OBJECTIVES: The study aimed to retrospectively evaluate the accuracy and value of magnetic resonance imaging (MRI) in predicting pedicle involvement for patients with spine metastases. METHODS: Forty-five patients with a vertebral metastasis encroaching at least one pedicle were studied using MRI before surgery and regularly after surgery. Patients were categorized on the basis of their numbers of pedicle involvement (Group 1: one pedicle was involved, n = 23; Group 2: two pedicles were involved, n = 22). The diagnostic accuracy was calculated, and comparisons of intraoperative blood loss and recurrence rate between the two groups were performed. RESULTS: The overall performance of MRI in predicting the pedicle involvement was as follows: accuracy, 94.4%; sensitivity, 95.5%; and specificity, 91.3%. Less intraoperative blood loss was observed for Group 1 compared with Group 2 (1,661 +/- 672 ml and 2,173 +/- 790 ml, respectively, P = 0.024). Tumor relapse occurred in 8.7% (2/23) of Group 1 and in 22.7% (5/22) of Group 2 with median recurrence free survival time 14 and 9 months, respectively. CONCLUSIONS: MRI is a reliable approach to assess pedicle involvement. It has potential for use in the evaluation of the clinical characteristics of patients with spine metastases. PMID- 27486877 TI - A three-dimensional collagen scaffold cell culture system for screening anti glioma therapeutics. AB - Three-dimensional (3D) culture, which can simulate in vivo microenvironments, has been increasingly used to study tumor cell biology. Since most preclinical anti glioma drug tests still rely on conventional 2D cell culture, we established a collagen scaffold for 3D glioma cell culture. Glioma cells cultured on these 3D scaffolds showed greater degree of dedifferentiation and quiescence than cells in 2D culture. 3D-cultured cells also exhibited enhanced resistance to chemotherapeutic alkylating agents, with a much higher proportion of glioma stem cells and upregulation of O6-methylguanine DNA methyltransferase (MGMT). Importantly, tumor cells in 3D culture showed chemotherapy resistance patterns similar to those observed in glioma patients. Our results suggest that 3D collagen scaffolds are promising in vitro research platforms for screening new anti-glioma therapeutics. PMID- 27486880 TI - Overexpressed LAPTM4B-35 is a risk factor for cancer recurrence and poor prognosis in non-small-cell lung cancer. AB - BACKGROUND: The expression levels and clinical significances of Lysosomal associated protein transmembrane-4beta-35 (LAPTM4B-35) protein are unknown in the non-small-cell lung cancer (NSCLC). This study aimed to explore the expression and prognostic value of LAPTM4B-35 in NSCLC patients. METHODS: The clinicopathological and survival data of 107 NSCLC patients who received radical surgery from 2007 and 2011 were reviewed. The LAPTM4B-35 expression of the paired tumors and adjacent normal specimens were detected, and the association between LAPTM4B-35 and clinical variables was explored. Kaplan-Meier analysis and Cox regression (Proportional hazard model) were performed to investigate the prognostic significance for NSCLC. RESULTS: LAPTM4B-35 was over expressed in NSCLC tissues. The elevated LAPTM4B-35 expression was associated with cancer recurrence (P = 0.031). The 5-year median OS and PFS were significantly worse in the LAPTM4B-35 overexpressed group. Multivariate Cox analysis showed that LAPTM4B 35 over-expression was an independent factor for OS and PFS in NSCLC(P = 0.018, P = 0.026, respectively). CONCLUSIONS: The overexpressed LAPTM4B-35 was an independent prognostic biomarker for NSCLC, which could predict cancer recurrence and poor over survival. And that may be applied as potential target for NSCLC treatment. PMID- 27486879 TI - Consumption of pomegranates improves synaptic function in a transgenic mice model of Alzheimer's disease. AB - Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by extracellular plaques containing abnormal Amyloid Beta (Abeta) aggregates, intracellular neurofibrillary tangles containing hyperphosphorylated tau protein, microglia-dominated neuroinflammation, and impairments in synaptic plasticity underlying cognitive deficits. Therapeutic strategies for the treatment of AD are currently limited. In this study, we investigated the effects of dietary supplementation of 4% pomegranate extract to a standard chow diet on neuroinflammation, and synaptic plasticity in APPsw/Tg2576 mice brain. Treatment with a custom mixed diet (pellets) containing 4% pomegranate for 15 months ameliorated the loss of synaptic structure proteins, namely PSD-95, Munc18-1, and SNAP25, synaptophysin, phosphorylation of Calcium/Calmodulin Dependent Protein Kinase IIalpha (p-CaMKIIalpha/ CaMKIIalpha), and phosphorylation of Cyclic AMP Response Element Binding Protein (pCREB/CREB), inhibited neuroinflammatory activity, and enhanced autophagy, and activation of the phophoinositide-3-kinase Akt-mammalian target of rapamycin signaling pathway. These neuroprotective effects were associated with reduced beta-site cleavage of Amyloid Precursor Protein in APPsw/Tg2576 mice. Therefore, long-term supplementation with pomegranates can attenuate AD pathology by reducing inflammation, and altering APP-dependent processes. PMID- 27486881 TI - The effect of radiotherapy in liver-confined but non-resectable Barcelona Clinic Liver Cancer stage C large hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Clinical trials to determine the efficacy of radiotherapy (RT) in liver-confined but non-resectable Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) are scarce. We aimed to determine the benefit of RT in such tumors and investigated large HCC tumors. METHODS: HCC data from the Korea Central Cancer Registry recorded from 2008 to 2010 were used. A total of 593 patients met our inclusion criteria; 67 were treated with RT while the remainder made up the non-RT group. Fifty-two RT recipients underwent combination treatments within 4 weeks after the first RT treatment, and were defined as the combination RT group. We performed propensity score matching (PSM) to compare the RT or combination RT groups with the non-RT group. The endpoint was overall survival (OS). RESULTS: Median follow-up time for surviving patients was 48 months. After PSM, there was no difference in OS between the RT and non-RT groups or between the combination RT and non-RT groups. However, the combination RT group had a longer median survival time (MST) (10.7 vs. 6.9 months, respectively). Next, we conducted PSM between the combination RT and non-RT groups in patients with tumor sizes >=10 cm; MST was significantly longer in the former group (10.1 vs. 5.4 months, respectively; bootstrap 95% confidence interval of the difference in MST: 0.2-11.8). CONCLUSIONS: As a combined modality, RT is a plausible therapeutic option for liver-confined but non resectable BCLC stage C large HCC patients. PMID- 27486882 TI - Occult HBV infection in HCC and cirrhotic tissue of HBsAg-negative patients: a virological and clinical study. AB - AIM: To evaluate the virological and clinical characteristics of occult HBV infection (OBI) in 68 consecutive HBsAg-negative patients with biopsy-proven cirrhosis and HCC. METHODS: HBV DNA was sought and sequenced in plasma, HCC tissue and non-HCC liver tissue by PCRs using primers for HBV core, surface and x regions. OBI was identified by the presence of HBV DNA in at least two different PCRs. RESULTS: OBI was detected in HCC tissue of 13 (20%) patients and in non-HCC liver tissue of 3 of these 13. OBI was detected in HCC tissue of 54.5% of 11 anti HBs- negative/anti-HBc-positive patients, in 29.4% of 17 anti-HBs/anti-HBc positive and in 5% of 40 anti-HBs/anti-HBc-negative (p < 0.0005). The 13 patients with OBI in HCC tissue more frequently than the 55 without showed Child-B or -C cirrhosis (53.9% vs. 5.5%, p < 0.0001) and BCLC-B or -C stages (46.1% vs. 1.8%, p < 0.0001). The pre-S1, pre-S2 and S region sequences in HCC tissue showed amino acid (AA) substitutions (F19L, P24L, S59F, T131I, Q129H) and deletions (in positions 4,8, 17 and 86) in the S region, AA substitutions (T40S, P124K, L54P, G76A, N222T and I273L) in pre-S1 region and AA substitutions in pre-S2 region (P41H and P66L). In the 3 patients showing OBI also in non-HCC liver tissue the S, pre-S1 and pre-S2 sequencing displayed patterns of mutations different. CONCLUSIONS: The study showed a significant correlation between OBI and the severity of liver damage, several patterns of mutations in the S, pre-S1 and pre S2 regions in HCC tissue, some at their first description. PMID- 27486883 TI - Validation of prognostic scoring and assessment of clinical benefit for patients with bone sarcomas enrolled in phase I clinical trials. AB - BACKGROUND: We sought to validate the Royal Marsden Hospital (RMH) and MD Anderson Cancer Center (MDACC) prognostic scoring systems for the selection of bone sarcoma patients for phase I clinical trials and to identify additional risk factors related to survival. PATIENTS AND METHODS: We retrospectively reviewed the baseline characteristics and outcomes of 92 bone sarcoma patients who were referred to MDACC's Phase I Clinical Trials Program. RESULTS: Ninety-two patients with Ewing sarcoma (N = 47), osteosarcoma (N = 22), chondrosarcoma (N = 16), and other tumors (N = 7) were evaluated; 78 were enrolled in at least 1 of 43 different phase I trials. The median overall survival (OS) was 8.8 months (95% confidence interval [CI] = 6.8-13.7 months). Independent factors that predicted shorter survival were male sex, >2 metastatic sites, >3 previous therapies, hemoglobin level <10.5 g/dL, platelet count >200 x103/L, creatinine level >=1.3 mg/dL, and lactate dehydrogenase level >ULN. Patients with good RMH scores (0-1) had longer OS than patients with poor RMH scores (2-3) (HR = 5.8, 95% CI = 2.9 11.0; P < 0.0001), as did patients with low MDACC scores (0-1) as compared to patients with higher MDACC scores (2-4) (HR = 3.2, 95% CI = 1.9-5.6; P < 0.0001). CONCLUSION: The RMH prognostic score can be used to predict the OS of bone cancer patients referred for phase I trials. The MDACC score added no value to the RMH score and therefore does not have a role in assessment of patients with bone tumors. Patients with advanced bone sarcomas should be considered for phase I trials. PMID- 27486885 TI - Inherent low Erk and p38 activity reduce Fas Ligand expression and degranulation in T helper 17 cells leading to activation induced cell death resistance. AB - Activation Induced Cell Death of T helper cells is central to maintaining immune homeostasis and a perturbation often manifests in aberrant T helper cells that is associated with immunopathologies. Significant presence of T cells positive for IL-17A (Th17) and dual positive for IFN-gamma/IL-17A (Th1/Th17) in both effector (CD45RA+RO+) and memory (CD45RA-RO+) compartments with differential FasL protein in RA peripheral blood suggested their differential TCR AICD sensitivity. Lowered active caspase-3 in Th17 and Th1/Th17 over Th1 cells confirmed their capability to resist AICD and pointed to early upstream events. Differential MAPK activities, FasL protein and downstream caspase-3 activities in murine Th1 and Th17 cells established distinct TCR mediated signaling pathways and suggested low Erk and p38 activity as pivotal for AICD sensitivity. We extrapolated our mouse and human data and report that Fas-FasL is the preferred death pathway for both Th1 and Th17 and that inherently low Erk2 activity protected Th17 cells from TCR AICD. The presence of significantly higher numbers of aberrant T helper cells in RA also suggest an inflammatory cytokine milieu and AICD insensitive T cell link to sustained inflammation. Re sensitization to apoptosis by targeting MAPK activity especially Erk2 in RA might be of therapeutic value. PMID- 27486887 TI - Differences in Patient Characteristics among Men Choosing Open or Robot-Assisted Radical Prostatectomy in Contemporary Practice - Analysis of Surveillance, Epidemiology, and End Results Database. AB - OBJECTIVE: To examine characteristics of robot-assisted (RARP) and open radical prostatectomy (ORP) patients. PATIENTS AND METHODS: We relied on the Surveillance, Epidemiology, and End Results-Medicare-linked database and focused on prostate cancer patients between 2008 and 2009. In multivariable logistic regression analyses, we predicted RARP. RESULTS: Of 5,915 patients, 3,476 (58.8%) underwent RARP and 2,439 (41.2%) ORP. Patients within intermediate (OR 1.4, p = 0.01) or highest (OR 1.5, p = 0.02) education strata and those treated by surgeons with a high volume (OR 2.2, p < 0.001) were more likely to undergo RARP. Conversely, those residing in rural areas (OR 0.7, p = 0.005) and those with clinical stage T2 or higher (OR 0.7, p = 0.006) were less likely to undergo RARP. Additionally, patients from the Southwest were less likely to undergo RARP (OR 0.4, p < 0.001), but those from the Northern Plains were more likely to undergo RARP (OR 1.4, p = 0.02) than their counterparts from the East. Finally, RARP patients were neither younger nor healthier than ORP patients. CONCLUSIONS: Several patient characteristics such as education, region of residence and population density affect the likelihood of RARP vs. ORP treatment. Similarly, clinical stage and surgeon characteristics also affect the assignment to one or other treatment modality. PMID- 27486888 TI - Screening of Variations in CD22 Gene in Children with B-Precursor Acute Lymphoblastic Leukemia. AB - BACKGROUND: CD22 is expressed on the surface of B-cell lineage cells from the early progenitor stage of pro-B cell until terminal differentiation to mature B cells. It plays a role in signal transduction and as a regulator of B-cell receptor signaling in B-cell development. OBJECTIVES: We aimed to screen exons 9 14 of the CD22 gene, which is a mutational hot spot region in B-precursor acute lymphoblastic leukemia (pre-B ALL) patients, to find possible genetic variants that could play role in the pathogenesis of pre-B ALL in Turkish children. METHODS: This study included 109 Turkish children with pre-B ALL who were diagnosed at Losante Hospital for Children with Leukemia. Genomic DNA was extracted from both peripheral blood and bone marrow leukocytes. Gene amplification was performed with PCR, and all samples were screened for the variants by single strand conformation polymorphism. Samples showing band shifts were sequenced on an automated sequencer. RESULTS: In our patient group a total of 9 variants were identified in the CD22 gene by sequencing: a novel variant in intron 10 (T2199G); a missense variant in exon 12; 5 intronic variants between exon 12 and intron 13; a novel intronic variant (C2424T); and a synonymous in exon 13. Thirteen of 109 children (11.9%) carried the T2199G novel intronic variant located in intron 10, and 17 of 109 children (15.6%) carried the C2424T novel intronic variant. CONCLUSION: Novel variants in the CD22 gene in children with pre-B ALL in Turkey that are not present, in the Human Gene Mutation Database or NCBI SNP database, were found. PMID- 27486890 TI - Unidirectional Fast Growth and Forced Jumping of Stretched Droplets on Nanostructured Microporous Surfaces. AB - Superhydrophobic nanostructured surfaces have demonstrated outstanding capability in energy and water applications by promoting dropwise condensation, where fast droplet growth and efficient condensate removal are two key parameters. However, these parameters remain contradictory. Although efficient droplet removal is easily obtained through coalescence jumping on uniform superhydrophobic surfaces, simultaneously achieving fast droplet growth is still challenging. Also, on such surfaces droplets can grow to larger sizes without restriction if there is no coalescence. In this work, we show that superhydrophobic nanostructured microporous surfaces can manipulate the droplet growth and jumping. Microporous surface morphology effectively enhances the growth of droplets in pores owing to large solid-liquid contact area. At low supersaturations, the upward growth rate (1-1.5 MUm/s) of these droplets in pores is observed to be around 15-25 times that of the droplets outside the pores. Meanwhile, their top curvature radius increases relatively slowly (~0.25 MUm/s) due to pore confinement, which results in a highly stretched droplet surface. We also observed forced jumping of stretched droplets in pores either through coalescence with spherical droplets outside pores or through self-pulling without coalescence. Both experimental observation and theoretical modeling reveal that excess surface free energy stored in the stretched droplet surface and micropore confinement are responsible for this pore-scale-forced jumping. These findings reveal the insightful physics of stretched droplet dynamics and offer guidelines for the design and fabrication of novel super-repellent surfaces with microporous morphology. PMID- 27486889 TI - The Criminal Justice Experience of African American Cocaine Users in Arkansas. AB - BACKGROUND: African Americans are incarcerated at rates much higher than other racial and ethnic groups in the United States. OBJECTIVES: We sought to qualitatively explore the relationships between ongoing involvement in the criminal justice system and continued drug use in a population of urban and rural African American cocaine users in a southern state. METHODS: Semi-structured qualitative interviews were conducted among African American cocaine users in Arkansas between 2010 and 2012. Participants resided in both rural (two counties located in the eastern Arkansas Mississippi delta region) and urban (the county including the capital city of Little Rock) areas. RESULTS: Numerous important themes emerged from participants' narratives, including chronic involvement with the criminal justice system (being a "career criminal"), continued access to drugs while incarcerated, relapse, and reincarceration and lack of access to effective drug treatment. Conclusion/Importance: The themes which emerged from our data speak to the collective experience that many substance using populations in the United States face in dealing with the criminal justice system. Our findings highlight the need to better, more holistic ways of engaging African American substance users in community based substance use treatment and supportive services. PMID- 27486891 TI - Micellar Effects on Photoinduced Electron Transfer in Aqueous Solutions Revisited: Dramatic Enhancement of Cage Escape Yields in Surfactant Ru(II) Diimine Complex/[Ru(NH3)6](2+) Systems. AB - The effect of cationic micelle incorporation on light induced electron transfer, charge separation and back electron transfer between an aqueous electron donor, [Ru(NH3)6](2+), and a series of Ru(II) diimine complex chromophores/acceptors, is presented. The chromophores have the general formula [(bpy)2Ru(LL)](2+) (LL = bpy; 4-R-4'-methyl-2,2'-bpy, R = pentyl (MC5), terdecyl (MC13), heptadecyl (MC17); 4,4'-di(heptadecyl)-2,2'-bpy (DC17)). Of the five chromophores, the MC13, MC17, and DC17 complexes associate with the added micelle forming surfactant, cetyltrimethylammonium bromide (CTAB). Quenching of the luminescence of the bpy and MC5 complexes by [Ru(NH3)6](2+) is unaffected by addition of surfactant, while rate constants for quenching of the MC13 and MC17 complexes are decreased. Cage escape yields following photoinduced electron transfer to generate [(bpy)2Ru(LL)](+) and [Ru(NH3)6](3+) are approximately 0.1 for all the water soluble chromophores (excluding DC17) in the absence of added CTAB. In the presence of surfactant, the cage escape yields dramatically increase for the MC13 (0.4) and MC17 (0.6) complexes, while remaining unchanged for [Ru(bpy)3](2+) and the MC5 complex. Back electron transfer of the solvent separated ions is also strongly influenced by the presence of surfactant. For the MC13 and MC17 complexes, back electron transfer rate constants decrease by factors of 270 and 190, respectively. The MC5 complex exhibits two component back electron transfer, with the fast component having a rate constant close to that in the absence of surfactant and a slow component nearly 200 times smaller. Results are interpreted in terms of the partitioning of the 2+ and 1+ forms of the chromophores between aqueous and micellar phases. The extended lifetimes of the radical ions may prove useful in coupling the strong reductants formed to kinetically facile catalysts for reduction of water to hydrogen. PMID- 27486892 TI - Isolated Bilateral Lacrimal Gland Agenesis. AB - A 5-year-old boy presented to the ophthalmology department complaining of absent tearing while crying. Slit-lamp examination showed decreased tear margin film with normal punctae. Orbit magnetic resonance imaging was done and showed bilateral absent lacrimal glands. This is the third case of isolated bilateral lacrimal gland agenesis in the literature. [J Pediatr Ophthalmol Strabismus. 2016;53:e35-e38.]. PMID- 27486893 TI - Familial Exudative Vitreoretinopathy With a Novel LRP5 Mutation. AB - This report reviews the genetics of familial exudative vitreoretinopathy (FEVR) and describes the identification of a novel variant in the LRP5 gene. A 20-month old boy presented with reduced visual acuity in the right eye from exudative retinal detachment with mild retinal traction. Fluorescein angiography in the right eye disclosed extensive peripheral retinal non-perfusion and telangiectatic vessels and the left eye showed minimal peripheral non-perfusion. These features were suggestive of FEVR. Treatment with laser photocoagulation and cryotherapy to the region of non-perfusion was performed with resolution of the exudative retinal detachment. Fundus examination of the father revealed mild signs of FEVR, such as hyperacute retinal vascular branching and slight retinal vascular traction, whereas the mother's fundus examination was unremarkable. Genetic testing revealed that the affected boy was negative for mutations in the FZD4, NDP, and TSPAN12 genes and heterozygous for a previously unreported A745V variant in the LRP5 gene. The father was also heterozygous for the A745V variant in the LRP5 gene and the unaffected mother showed no mutation. A genetic evaluation of the known genes associated with FEVR revealed a novel variant in the LRP5 gene that co-segregated with the phenotype in the family. [J Pediatr Ophthalmol Strabismus. 2016;53:e39-e42.]. PMID- 27486894 TI - Intra-arterial Chemotherapy for Adult Onset Retinoblastoma in a 32-Year-Old Man. AB - A 32-year-old man with active unilateral group D retinoblastoma that was recurrent following external beam radiotherapy was treated with intra-arterial chemotherapy, leading to tumor regression. Additional plaque radiotherapy and intravitreal chemotherapy were required for complete control. Final visual acuity was 20/40. In selected cases, adult-onset retinoblastoma can be managed with intra-arterial chemotherapy. [J Pediatr Ophthalmol Strabismus. 2016;53:e43-e46.]. PMID- 27486895 TI - Trends in Receipt of Mental Health Treatments Among Adults in the United States, 2008-2013. AB - OBJECTIVE: This study examined trends in the 12-month prevalence of receiving mental health treatments among adults 18 years or older and among different generational cohorts in the United States between 2008 and 2013. METHODS: We examined data from 274,900 persons 18 years or older who participated in the 2008 2013 National Surveys on Drug Use and Health (then linked to the 2011-2014 Area Health Resources Files at the county level). Multivariable logistic regressions were applied to assess trends in the model-adjusted prevalence of receiving mental health treatments. RESULTS: Between 2008 and 2013, the 12-month prevalence of mental illness (MI) remained stable in adults 18 years or older in the United States and in each of the examined generational cohorts. Receipt of psychotropic medications without inpatient or outpatient treatment increased in the overall adult population, baby boomers with MI, and Generation X with MI. The increase was 23.8% (6.3% to 7.8%, P < .001) among all adults, 28.4% (20.4% to 26.2%, P = .010) among baby boomers with MI, and 34.7% (14.7% to 19.8%, P = .001) among Generation X with MI. Among the Silent Generation with MI, receipt of mental health treatments remained unchanged. CONCLUSIONS: The prevalence of receiving psychotropic medications without inpatient or outpatient treatment increased among the overall adult population, baby boomers with MI, and Generation X with MI between 2008 and 2013. With the ongoing mental health parity and health reform efforts, further studies are warranted to monitor trends in mental health treatment in these populations. PMID- 27486896 TI - Correction: Durations and Delays in Care Seeking, Diagnosis and Treatment Initiation in Uncomplicated Pulmonary Tuberculosis Patients in Mumbai, India. AB - [This corrects the article DOI: 10.1371/journal.pone.0152287.]. PMID- 27486897 TI - Identification of temporal factors related to shot performance for indoor recurve archery. AB - The purpose of this study was to investigate the temporal phases of the archery shot cycle that distinguish the arrows distance from centre, in an attempt to understand critical factors that affect performance. Fifteen archers of varying ability each performed 30 shots at 18 m. Fourteen potential predictor variables were measured for statistical modelling by stepwise multiple linear regression. The results show that pre-shot time (pre-performance routine), follow-through time (post-performance routine), aiming time, speed of the arrow and the %variation in clicker-release time, account for 7.7% of the variation in predicting shot performance. The results have implications for practice demonstrating factors that coaches should focus on to develop their athletes. Further work on pre-, but more importantly, post-performance routines are needed generally within sport research as they are lacking and have been shown to be important contributing factors in a number of sports. PMID- 27486898 TI - Apolipoprotein E Genotype Linked to Spatial Gait Characteristics: Predictors of Cognitive Dual Task Gait Change. AB - BACKGROUND: Developing measures to detect preclinical Alzheimer's Disease is vital, as prodromal stage interventions may prove more efficacious in altering the disease's trajectory. Gait changes may serve as a useful clinical heuristic that precedes cognitive decline. This study provides the first systematic investigation of gait characteristics relationship with relevant demographic, physical, genetic (Apolipoprotein E genotype), and health risk factors in non demented older adults during a cognitive-load dual task walking condition. METHODS: The GAITRite system provided objective measurement of gait characteristics in APOE-e4 "carriers" (n = 75) and "non-carriers" (n = 224). Analyses examined stride length and step time gait characteristics during simple and dual-task (spelling five-letter words backwards) conditions in relation to demographic, physical, genetic, and health risk factors. RESULTS: Slower step time and shorter stride length associated with older age, greater health risk, and worse physical performance (ps < .05). Men and women differed in height, gait characteristics, health risk factors and global cognition (ps < .05). APOE-e4 associated with a higher likelihood of hypercholesterolemia and overall illness index scores (ps < .05). No genotype-sex interactions on gait were found. APOE-e4 was linked to shorter stride length and greater dual-task related disturbances in stride length. CONCLUSIONS: Stride length has been linked to heightened fall risk, attention decrements and structural brain changes in older adults. Our results indicate that stride length is a useful behavioral marker of cognitive change that is associated with genetic risk for AD. Sex disparities in motor decline may be a function of health risk factors. PMID- 27486900 TI - Synthesis of a Small-Molecule Library with Skeletal Diversity from Hemslecin A via the Reaction-Discovery Strategy. AB - An efficient reaction tool box was developed for the synthesis of skeletally diverse and stereochemically complex templates for a small-molecule library based on the common synthon Q, which was prepared from hemslecin A in four steps. The reaction tool box comprises three acid-promoted rearrangements: semipinacol, Wagner-Meerwein, and cyclopropylmethyl cation rearrangements. More importantly, a Mn-mediated C-H oxidation was developed to achieve a high level of complexity, which provides a new entry for C-H functionalization of inert angular methyl groups in the chemistry of triterpenes. Our reaction-discovery strategy based on hemslecin A provides a basis for the inherent chemistry of triterpenes and could be applied for the further transformation of triterpenes. PMID- 27486899 TI - The Association between the Cross-Sectional Area of the Dural Sac and Low Back Pain in a Large Population: The Wakayama Spine Study. AB - OBJECTIVE: The purpose of this study was to evaluate the relations between the degree of encroachment, measured as the cross-sectional area of the dural sac, and low back pain in a large population. METHODS: In this cross-sectional study, data from 802 participants (247 men, 555 women; mean age, 63.5 years) were analyzed. The measurement of the cross-sectional area of the dural sac from the level of L1/2 to L4/5 was taken using axial T2-weighted images. The minimum cross sectional area was defined as the cross-sectional area of the dural sac at the most constricted level in the examined spine. Participants were divided into three groups according to minimum cross-sectional area measurement quartiles (less than the first quartile, between the first and third quartiles, and greater than the third quartile). A multivariate logistic regression analysis was used to estimate the association between the minimum cross-sectional area and the prevalence of low back pain. RESULTS: The mean minimum cross-sectional area was 117.3 mm2 (men: 114.4 mm2; women: 118.6 mm2). A logistic regression analysis adjusted for age, sex, body mass index, and other confounding factors, including disc degeneration, showed that a narrow minimum cross-sectional area (smaller than the first quartile) was significantly associated with low back pain (odds ratio, 1.78; 95% confidence interval, 1.13-2.80 compared to the wide minimum cross-sectional area group: minimum cross-sectional area greater than the third quartile measured). CONCLUSION: This study showed that a narrow dural sac cross sectional area was significantly associated with the presence of low back pain after adjustment for age, sex, and body mass index. Further investigations that include additional radiographic findings and psychological factors will continue to elucidate the causes of low back pain. PMID- 27486901 TI - HMGA1 silencing reduces stemness and temozolomide resistance in glioblastoma stem cells. AB - OBJECTIVE: Glioblastoma multiforme (GBM) develops from a small subpopulation of stem-like cells, which are endowed with the ability to self-renew, proliferate and give rise to progeny of multiple neuroepithelial lineages. These cells are resistant to conventional chemo- and radiotherapy and are hence also responsible for tumor recurrence. HMGA1 overexpression has been shown to correlate with proliferation, invasion, and angiogenesis of GBMs and to affect self-renewal of cancer stem cells from colon cancer. The role of HMGA1 in GBM tumor stem cells is not completely understood. RESEARCH DESIGN AND METHODS: We have investigated the role of HMGA1 in brain tumor stem cell (BTSC) self-renewal, stemness and resistance to temozolomide by shRNA- mediated HMGA1 silencing. RESULTS: We first report that HMGA1 is overexpressed in a subset of BTSC lines from human GBMs. Then, we show that HMGA1 knockdown reduces self-renewal, sphere forming efficiency and stemness, and sensitizes BTSCs to temozolomide. Interestingly, HMGA1 silencing also leads to reduced tumor initiation ability in vivo. CONCLUSIONS: These results demonstrate a pivotal role of HMGA1 in cancer stem cell gliomagenesis and endorse HMGA1 as a suitable target for CSC-specific GBM therapy. PMID- 27486902 TI - Comparison of Keyes Punch Biopsy Instrument with Cervical Punch Biopsy Forceps for Diagnosing Cervical Lesions. AB - OBJECTIVE: To assess the feasibility and efficacy of Keyes punch biopsy instrument (KP) in diagnosing cervical lesions and compare it with cervical punch biopsy forceps (CP). METHODS: 75 women having satisfactory colposcopy with abnormal transformation zone were included and paired colposcopic directed biopsies were taken using KP followed by CP from the same target area. RESULTS: It was feasible in all cases to take cervical biopsy with KP after increasing its effective length. The volume of gross specimen obtained by KP was less than CP (0.076 +/- 0.097 vs. 0.101 +/- 0.156 cm3, p = 0.061), however on microscopic examination, mean length and mean depth of tissue in KP was greater than CP by 0.06 mm (p = 0.810) and 0.14 mm (p = 0.634) respectively. Exact agreement was found with the final surgical specimen in 42% of cases in both the biopsy forceps. CONCLUSION: KP is almost at par with CP for diagnosing preinvasive cervical lesions and is a useful adjunct to the existing armamentarium of biopsy forceps. PMID- 27486904 TI - Biomechanical Factors in the Adaptations of Insect Tibia Cuticle. AB - Insects are among the most diverse groups of animals on Earth. Their cuticle exoskeletons vary greatly in terms of size and shape, and are subjected to different applied forces during daily activities. We investigated the biomechanics of the tibiae of three different insect species: the desert locust (Schistocerca gregaria), American cockroach (Periplaneta americana) and Death's Head cockroach (Blaberus discoidalis). In a previous work, we showed that these tibiae vary not only in geometry (length, radius and thickness) but also in material quality (Young's modulus) and in the applied stress required to cause failure when loaded in bending. In the present work we used kinematic data from the literature to estimate the forces and stresses arising in vivo for various different activities, and thus calculated factors of safety defined as the ratio between the failure stress and the in vivo stress, adjusting the failure stress to a lower value to allow for fatigue failure in the case of frequently repeated activities. Factors of safety were found to vary considerably, being as little as 1.7 for the most strenuous activities, such as jumping or escaping from tight spaces. Our results show that these limbs have evolved to the point where they are close to optimal, and that instantaneous failure during high-stress activities is more critical than long-term fatigue failure. This work contributes to the discussion on how form and material properties have evolved in response to the mechanical functions of the same body part in different insects. PMID- 27486903 TI - White Adipose Tissue Browning in the R6/2 Mouse Model of Huntington's Disease. AB - Huntington's disease (HD) is a fatal, autosomal dominantly inherited neurodegenerative disorder, characterised not only by progressive cognitive, motor and psychiatric impairments, but also of peripheral pathology. In both human HD and in mouse models of HD there is evidence of increased energy expenditure and weight loss, alongside altered body composition. Unlike white adipose tissue (WAT), brown adipose tissue (BAT), as well as brown-like cells within WAT, expresses the mitochondrial protein, uncoupling protein 1 (UCP1). UCP1 enables dissociation of cellular respiration from ATP utilization, resulting in the release of stored energy as heat. Hyperplasia of brown/beige cells in WAT has been suggested to enhance energy expenditure. In this study, we therefore investigated the gene expression profile, histological appearance, response to cold challenge and functional aspects of WAT in the R6/2 HD mouse model and selected WAT gene expression in the full-length Q175 mouse model of HD. WAT from R6/2 mice contained significantly more brown-like adipocyte regions and had a gene profile suggestive of the presence of brown-like adipocytes, such as higher Ucp1 expression. Cold exposure induced Ucp1 expression in R6/2 inguinal WAT to a markedly higher degree as compared to the thermogenic response in WT WAT. Alongside this, gene expression of transcription factors (Zfp516 and Pparalpha), important inducers of WAT browning, were increased in R6/2 inguinal WAT, and Creb1 was highlighted as a key transcription factor in HD. In addition to increased WAT Ucp1 expression, a trend towards increased mitochondrial oxygen consumption due to enhanced uncoupling activity was found in inguinal R6/2 WAT. Key gene expressional changes (increased expression of (Zfp516 and Pparalpha)) were replicated in inguinal WAT obtained from Q175 mice. In summary, for the first time, we here show that HD mouse WAT undergoes a process of browning, resulting in molecular and functional alterations that may contribute to the weight loss and altered metabolism observed with disease progression. PMID- 27486905 TI - Olsalazine-Based Metal-Organic Frameworks as Biocompatible Platforms for H2 Adsorption and Drug Delivery. AB - The drug olsalazine (H4olz) was employed as a ligand to synthesize a new series of mesoporous metal-organic frameworks that are expanded analogues of the well known M2(dobdc) materials (dobdc(4-) = 2,5-dioxido-1,4-benzenedicarboxylate; M MOF-74). The M2(olz) frameworks (M = Mg, Fe, Co, Ni, and Zn) exhibit high surface areas with large hexagonal pore apertures that are approximately 27 A in diameter. Variable temperature H2 adsorption isotherms revealed strong adsorption at the open metal sites, and in situ infrared spectroscopy experiments on Mg2(olz) and Ni2(olz) were used to determine site-specific H2 binding enthalpies. In addition to its capabilities for gas sorption, the highly biocompatible Mg2(olz) framework was also evaluated as a platform for the delivery of olsalazine and other encapsulated therapeutics. The Mg2(olz) material (86 wt % olsalazine) was shown to release the therapeutic linker through dissolution of the framework under simulated physiological conditions. Furthermore, Mg2(olz) was used to encapsulate phenethylamine (PEA), a model drug for a broad class of bioactive compounds. Under simulated physiological conditions, Mg2(olz)(PEA)2 disassembled to release PEA from the pores and olsalazine from the framework itself, demonstrating that multiple therapeutic components can be delivered together at different rates. The low toxicity, high surface areas, and coordinatively unsaturated metal sites make these M2(olz) materials promising for a range of potential applications, including drug delivery in the treatment of gastrointestinal diseases. PMID- 27486906 TI - Platinum-induced hearing loss after treatment for childhood cancer. AB - BACKGROUND: Platinum-based therapy, including cisplatin, carboplatin, oxaliplatin or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. There is a wide variation in the reported prevalence of platinum-induced ototoxicity and the associated risk factors. More insight into the prevalence of and risk factors for platinum-induced hearing loss is essential in order to develop less ototoxic treatment protocols for the future treatment of children with cancer and to develop adequate follow-up protocols for childhood cancer survivors treated with platinum-based therapy. OBJECTIVES: To evaluate the existing evidence on the association between childhood cancer treatment including platinum analogues and the occurrence of hearing loss. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 8), MEDLINE (PubMed) (1945 to 23 September 2015) and EMBASE (Ovid) (1980 to 23 September 2015). In addition, we searched reference lists of relevant articles and the conference proceedings of the International Society for Paediatric Oncology (2008 to 2014), the American Society of Pediatric Hematology/Oncology (2008 to 2015) and the International Conference on Long-Term Complications of Treatment of Children and Adolescents for Cancer (2010 to 2015). Experts in the field provided information on additional studies. SELECTION CRITERIA: All study designs, except case reports, case series (i.e. a description of non-consecutive participants) and studies including fewer than 100 participants treated with platinum-based therapy who had an ototoxicity assessment, examining the association between childhood cancer treatment including platinum analogues and the occurrence of hearing loss. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection. One review author performed data extraction and risk of bias assessment, which was checked by another review author. MAIN RESULTS: We identified 13 eligible cohort studies including 2837 participants with a hearing test after treatment with a platinum analogue for different types of childhood cancers. All studies had methodological limitations, with regard to both internal (risk of bias) and external validity. Participants were treated with cisplatin, carboplatin or both, in varying doses. The reported prevalence of hearing loss varied considerably between 0% and 90.1%; none of the studies provided data on tinnitus. Three studies reported a prevalence of 0%, but none of these studies provided a definition for hearing loss and there might be substantial or even complete overlap in included participants between these three studies. When only studies that did provide a definition for hearing loss were included, the prevalence of hearing loss still varied widely between 1.7% and 90.1%. All studies were very heterogeneous with regard to, for example, definitions of hearing loss, used diagnostic tests, participant characteristics, (prior) anti-tumour treatment, other ototoxic drugs and length of follow-up. Therefore, pooling of results was not possible.Only two studies included a control group of people who had not received platinum treatment. In one study, the prevalence of hearing loss was 67.1% (95% confidence interval (CI) 59.3% to 74.1%) in platinum-treated participants, while in the control participants it was 7.4% (95% CI 6.2% to 8.8%). However, hearing loss was detected by screening in survivors treated with platinum analogues and by clinical presentation in control participants. It is uncertain what the effect of this difference in follow-up/diagnostic testing was. In the other study, the prevalence of hearing loss was 20.1% (95% CI 17.4% to 23.2%) in platinum-treated participants and 0.4% (95% CI 0.12% to 1.6%) in control participants. As neither study was a randomized controlled trial or controlled clinical trial, the calculation of a risk ratio was not feasible as it is very likely that both groups differed more than only the platinum treatment.Only two studies evaluated possible risk factors using multivariable analysis. One study identified a significantly higher risk of hearing loss in people treated with cisplatin 400 mg/m(2) plus carboplatin 1700 mg/m(2) as compared to treatment with cisplatin 400 mg/m(2) or less, irrespective of the definition of hearing loss. They also identified a significantly higher risk of hearing loss in people treated with non-anthracycline aminoglycosides antibiotics (using a surrogate marker) as compared to people not treated with them, for three out of four definitions of hearing loss. The other study reported that age at treatment (odds ratio less than 1 for each single-unit increase) and single maximum cisplatin dose (odds ratio greater than 1 for each single-unit increase) were significant predictors for hearing loss, while gender was not. AUTHORS' CONCLUSIONS: This systematic review shows that children treated with platinum analogues are at risk for developing hearing loss, but the exact prevalence and risk factors remain unclear. There were no data available for tinnitus. Based on the currently available evidence we can only advise that children treated with platinum analogues are screened for ototoxicity in order to make it possible to diagnose hearing loss early and to take appropriate measures. However, we are unable to give recommendations for specific follow-up protocols including frequency of testing. Counselling regarding the prevention of noise pollution can be considered, such as the use of noise-limiting equipment, avoiding careers with excess noise and ototoxic medication. Before definitive conclusions on the prevalence and associated risk factors of platinum-induced ototoxicity can be made, more high-quality research is needed. Accurate and transparent reporting of findings will make it possible for readers to appraise the results of these studies critically. PMID- 27486907 TI - Spirometry reference values for a Kyrgyz population. PMID- 27486908 TI - Increased Airport Scrutiny by the Transportation Security Administration of a Patient-Passenger Carrying Ammonium Lactate-Containing Moisturizer. PMID- 27486909 TI - Identification of Rosmarinic Acid-Adducted Sites in Meat Proteins in a Gel Model under Oxidative Stress by Triple TOF MS/MS. AB - Triple TOF MS/MS was used to identify adducts between rosmarinic acid (RosA) derived quinones and meat proteins in a gel model under oxidative stress. Seventy five RosA-modified peptides responded to 67 proteins with adduction of RosA. RosA conjugated with different amino acids in proteins, and His, Arg, and Lys adducts with RosA were identified for the first time in meat. A total of 8 peptides containing Cys, 14 peptides containing His, 48 peptides containing Arg, 64 peptides containing Lys, and 5 peptides containing N-termini that which participated in adduction reaction with RosA were identified, respectively. Seventy-seven adduction sites were subdivided into all adducted proteins including 2 N-terminal adduction sites, 3 Cys adduction sites, 4 His adduction sites, 29 Arg adduction sites, and 39 Lys adduction sites. Site occupancy analyses showed that approximately 80.597% of the proteins carried a single RosA modified site, 14.925% retained two sites, 1.492% contained three sites, and the rest 2.985% had four or more sites. Large-scale triple TOF MS/MS mapping of RosA adducted sites reveals the adduction regulations of quinone and different amino acids as well as the adduction ratios, which clarify phenol-protein adductions and pave the way for industrial meat processing and preservation. PMID- 27486910 TI - Cost-Benefit Analysis of Three-Dimensional Craniofacial Models for Midfacial Distraction: A Pilot Study. AB - OBJECTIVE: Patient-specific three-dimensional (3D) models are increasingly used to virtually plan rare surgical procedures, providing opportunity for preoperative preparation, better understanding of individual anatomy, and implant prefabrication. The purpose of this study was to assess the benefit of 3D models related to patient safety, operative time, and cost. DESIGN: Retrospective review. SETTING: Academic, tertiary care hospital. PATIENTS, PARTICIPANTS: Midfacial distraction was studied as a representative craniofacial operation. A consecutive series of 29 patients who underwent a single type of midfacial distraction was included. INTERVENTION: For a subset of patients, computed tomography-derived 3D models were used to study patient-specific anatomy and precontour hardware. MAIN OUTCOME MEASURES: Complications, operative time, blood loss, and estimated cost. RESULTS: Twenty patients underwent midfacial distraction without and nine with preoperative use of a 3D model. Seven complications occurred in six patients without model use, including premature consolidation (3), cerebrospinal fluid leak (2), and hardware malfunction (2). No complications were reported in the model group. Controlling for surgeon variation, model use resulted in a 31.3-minute (7.8%) reduction in operative time. Time-based cost savings were estimated to be $1036. CONCLUSIONS: Three dimensional models are valuable for preoperative planning and hardware precontouring in craniofacial surgery, with potential positive effects on complications and operative time. Savings related to operative time and complications may offset much of the cost of the model. PMID- 27486912 TI - The Proteasome: More Than a Means to an End. AB - The proteasome regulates timed degradation of proteins using both intrinsic and extrinsic receptors that recognize polyubiquitin chains on targets. In this issue of Structure, Chen et al. (2016) outline the structural basis of how intrinsic receptors prefer ubiquitin-like domains rather than ubiquitin, to bind extrinsic co-receptors. PMID- 27486911 TI - Glycogen synthase kinase-3beta is a pivotal mediator of cancer invasion and resistance to therapy. AB - Tumor cell invasion and resistance to therapy are the most intractable biological characteristics of cancer and, therefore, the most challenging for current cancer research and treatment paradigms. Refractory cancers, including pancreatic cancer and glioblastoma, show an inextricable association between the highly invasive behavior of tumor cells and their resistance to chemotherapy, radiotherapy and targeted therapies. These aggressive properties of cancer share distinct cellular pathways that are connected to each other by several molecular hubs. There is increasing evidence to show that glycogen synthase kinase (GSK)-3beta is aberrantly activated in various cancer types and this has emerged as a potential therapeutic target. In many but not all cancer types, aberrant GSK3beta sustains the survival, immortalization, proliferation and invasion of tumor cells, while also rendering them insensitive or resistant to chemotherapeutic agents and radiation. Here we review studies that describe associations between therapeutic stimuli/resistance and the induction of pro-invasive phenotypes in various cancer types. Such cancers are largely responsive to treatment that targets GSK3beta. This review focuses on the role of GSK3beta as a molecular hub that connects pathways responsible for tumor invasion and resistance to therapy, thus highlighting its potential as a major cancer therapeutic target. We also discuss the putative involvement of GSK3beta in determining tumor cell stemness that underpins both tumor invasion and therapy resistance, leading to intractable and refractory cancer with dismal patient outcomes. PMID- 27486913 TI - Forcing FAK into Transcriptional Activity. AB - Focal adhesion kinase (FAK) has known signaling roles in cytoplasmic adhesion structures, but was recently shown to act as a transcriptional regulator in the nucleus. In this issue of Structure, Cardoso et al. (2016) report that mechanical forces translocate FAK to the nucleus of cardiomyocytes, and provide structural insights into how FAK interacts with the MEF2 transcription factor to control cardiac hypertrophy. PMID- 27486914 TI - Drug Discovery Gets a Boost from Data Science. AB - In this issue of Structure, Schiebel et al. (2016) describe a workflow-driven approach to high-throughput X-ray crystallographic fragment screening and refinement. In doing so, they extend the applicability of X-ray crystallography as a primary fragment-screening tool and show how data science techniques can favorably impact drug discovery efforts. PMID- 27486915 TI - Structural Mechanism of Allosteric Activity Regulation in a Ribonucleotide Reductase with Double ATP Cones. PMID- 27486916 TI - Job stress dimension and work-related musculoskeletal disorders among southeast Nigerian physiotherapists. AB - BACKGROUND: Although publications describe physical demands of the job in the physiotherapy profession, there is a dearth of literature on job stress dimensions (JSDs), and their relationship to work-related musculoskeletal disorders (WMSDs). OBJECTIVE: To investigate JSDs and their relationship to WMSDs among physiotherapists currently practicing in southeast Nigeria. METHOD: A cross sectional study using items related to the Job Content Questionnaire and the Nordic musculoskeletal questionnaire. Data were summarized with descriptive statistics, and the relationship between WMSDs and JSDs was analyzed with the Mann-Whitney U test. RESULTS: A total of 126 physiotherapists responded. There were high levels of stress in most of the job dimensions investigated: 82.1% and 22.8% of the physiotherapists had WMSDs in at least one body region in the last 12 months and the last 7 days respectively. The lower back was the most commonly affected in both periods. No specific domain was related to development of WMSDs. CONCLUSION: Over 80% of physiotherapists in southeast Nigeria have WMSDs. However, despite high levels of physical demands on the job, physiotherapists have job control and good social support. Intervention programs aimed at reducing WMSDs in physiotherapists should focus on risk factors that target the physical demands of the job. PMID- 27486917 TI - Growth of single-layer boron nitride dome-shaped nanostructures catalysed by iron clusters. AB - We report on the growth and formation of single-layer boron nitride dome-shaped nanostructures mediated by small iron clusters located on flakes of hexagonal boron nitride. The nanostructures were synthesized in situ at high temperature inside a transmission electron microscope while the e-beam was blanked. The formation process, typically originating at defective step-edges on the boron nitride support, was investigated using a combination of transmission electron microscopy, electron energy loss spectroscopy and computational modelling. Computational modelling showed that the domes exhibit a nanotube-like structure with flat circular caps and that their stability was comparable to that of a single boron nitride layer. PMID- 27486918 TI - Prediction of whelping date in large and giant canine breeds by ultrasonography foetal biometry. AB - OBJECTIVES: To derive the growth curves of the inner chorionic cavity and the biparietal diameter in large and giant dog breeds by ultrasonographic foetal biometry. To evaluate their accuracy in the prediction of whelping date and the effect of litter size and foetal sex ratio. METHODS: Foetal biometry parameters were obtained using serial ultrasonographic examinations in eight large (26 to 40 kg) and nine giant (>40 kg) pregnant bitches with known breeding dates and concentrations of serum progesterone during oestrus. The relationship between inner chorionic cavity or biparietal diameter growth and days to parturition were analysed by linear regression and the equations derived from the growth curves were applied to predict the whelping day. The accuracy of the prediction (whelping day +/-1 day and +/-2 days) and the litter size and sex ratio were recorded. RESULTS: The results showed a significant relationship between days before parturition and inner chorionic cavity or biparietal diameter. The overall accuracy at +/-2 days was greater, than that at +/-1 day. In giant breed bitches, the accuracy of the prediction by biparietal diameter was significantly lower in small, than normal litter size. No effect of foetal sex ratio was observed. CLINICAL SIGNIFICANCE: Foetal biometry parameters obtained by ultrasonography can be used to predict whelping dates in large and giant dog breeds. PMID- 27486919 TI - Hypothetical orchestrated cooperation between dopaminergic and kinin receptors for the regulation of common functions. AB - The G protein-coupled receptors (GPCRs), one of the largest protein families, are essential components of the most commonly used signal-transduction systems in cells. These receptors, often using common pathways, may cooperate in the regulation of signal transmission to the cell nucleus. Recent scientific interests increasingly focus on the cooperation between these receptors, particularly in a context of their oligomerization, e.g. the formation of dimers that are able to change characteristic signaling of each receptor. Numerous studies on kinin and dopamine receptors which belong to this family of receptors have shown new facts demonstrating their direct interactions with other GPCRs. In this review, current knowledge on signaling pathways and oligomerization of these receptors has been summarized. Owing to the fact that kinin and dopamine receptors are widely expressed in cell membranes where they act as mediators of numerous common physiological processes, the information presented here sheds new light on a putative crosstalk of these receptors and provides more comprehensive understanding of possible direct interactions that may change their functions. The determination of such interactions may be useful for the development of new targeted therapeutic strategies against many disorders in which kinin and dopamine receptors are involved. PMID- 27486920 TI - Column chromatography as a useful step in purification of diatom pigments. AB - Fucoxanthin, diadinoxanthin and diatoxanthin are carotenoids found in brown algae and most other heterokonts. These pigments are involved in photosynthetic and photoprotective reactions, and they have many potential health benefits. They can be extracted from diatom Phaeodactylum tricornutum by sonication, extraction with chloroform : methanol and preparative thin layer chromatography. We assessed the utility of an additional column chromatography step in purification of these pigments. This novel addition to the isolation protocol increased the purity of fucoxanthin and allowed for concentration of diadinoxanthin and diatoxanthin before HPLC separation. The enhanced protocol is useful for obtaining high purity pigments for biochemical studies. PMID- 27486921 TI - Abscisic acid and blue light signaling pathways in chloroplast movements in Arabidopsis mesophyll. AB - Abscisic acid (ABA) and phototropins act antagonistically to control stomatal movements. Here, we investigated the role of ABA in phototropin-directed chloroplast movements in mesophyll cells of Arabidopsis thaliana. We analyzed the expression of phototropins at mRNA and protein level under the influence of ABA. PHOT1 mRNA level was decreased by ABA in the dark while it was insensitive to ABA in light. PHOT2 mRNA level was independent of the hormone treatment. The levels of phototropin proteins were down-regulated by ABA, both in darkness and light. No impact of exogenous ABA on amplitudes and kinetics of chloroplast movements was detected. Chloroplast responses in wild type Arabidopsis and three mutants, abi4, abi2 (abscisic acid insensitive4, 2) and aba1 (abscisic acid1), were measured to account for endogenous ABA signaling. The chloroplast responses were slightly reduced in abi2 and aba1 mutants in strong light. To further investigate the effect, abi2 and aba1 mutants were supplemented with exogenous ABA. In the aba1 mutant, the reaction was rescued but in abi2 it was unaffected. Our results show that ABA is not directly involved in phototropin-controlled chloroplast responses in mature leaves of Arabidopsis. However, the disturbance of ABA biosynthesis and signaling in mutants affects some elements of the chloroplast movement mechanism. In line with its role as a stress hormone, ABA appears to enhance plant sensitivity to light and promote the chloroplast avoidance response. PMID- 27486922 TI - Prison officers' views about hepatitis C testing and treatment: a qualitative enquiry. AB - AIMS AND OBJECTIVES: To explore the views of prison officers in an English category B male prison about people in prison being tested and treated for hepatitis C. BACKGROUND: Hepatitis C testing and treatment in English prisons remain low with the reasons being poorly understood. Prison officers are in continuous contact with prisoners so might observe factors that may influence people in prisons' choice in whether to accept hepatitis C testing and treatment. DESIGN: A qualitative design within an interpretative framework was employed. METHODS: Semistructured interviews were conducted with 10 prison officers at an English male category B prison. The interviews were audiorecorded and transcribed at the prison. RESULTS: Four themes emerged Safeguarding, Stigma, Confidentiality and Education. Hepatitis C testing and treatment were supported in principle but if a person in prison poses a threat to the overall security of a prison, any health issues that are not immediately life threatening will be overridden, irrespective of the financial or health consequences. The prison officers respected people in prisons' confidentiality regarding health matters, but this could be compromised during violent incidents. All of the prison officers displayed limited knowledge about hepatitis C. CONCLUSIONS: This qualitative enquiry illustrates that prison security transcends health. This suggests that health providers may need to offer greater flexibility and collaboration across the network of National Health Service hospitals to maintain continuity in treatment if a prisoner is moved to a different establishment or liberated. RELEVANCE TO CLINICAL PRACTICE: This study introduces the notion that prison security staff may have a potential role in promoting or discouraging hepatitis C testing and treatment by the ways in which their knowledge impacts on their interactions with people in prison. Engaging this staff group in educational opportunities should be a component of commissioned hepatitis service delivery in prisons. PMID- 27486923 TI - Piezophototronic Effect in Single-Atomic-Layer MoS2 for Strain-Gated Flexible Optoelectronics. AB - Strain-gated flexible optoelectronics are reported based on monolayer MoS2 . Utilizing the piezoelectric polarization created at the metal-MoS2 interface to modulate the separation/transport of photogenerated carriers, the piezophototronic effect is applied to implement atomic-layer-thick phototransistor. Coupling between piezoelectricity and photogenerated carriers may enable the development of novel optoelectronics. PMID- 27486924 TI - Molecular self-assembly using peptide nucleic acids. AB - Peptide nucleic acids (PNAs) are extensively studied for the control of genetic expression since their design in the 1990s. However, the application of PNAs in nanotechnology is much more recent. PNAs share the specific base-pair recognition characteristic of DNA together with material-like properties of polyamides, both proteins and synthetic polymers, such as Kevlar and Nylon. The first application of PNA was in the form of PNA-amphiphiles, resulting in the formation of either lipid integrated structures, hydrogels or fibrillary assemblies. Heteroduplex DNA PNA assemblies allow the formation of hybrid structures with higher stability as compared with pure DNA. A systematic screen for minimal PNA building blocks resulted in the identification of guanine-containing di-PNA assemblies and protected guanine-PNA monomer spheres showing unique optical properties. Finally, the co-assembly of PNA with thymine-like three-faced cyanuric acid allowed the assembly of poly-adenine PNA into fibers. In summary, we believe that PNAs represent a new and important family of building blocks which converges the advantages of both DNA- and peptide-nanotechnologies. PMID- 27465247 TI - Exenatide Alters Gene Expression of Neural Cell Adhesion Molecule (NCAM), Intercellular Cell Adhesion Molecule (ICAM), and Vascular Cell Adhesion Molecule (VCAM) in the Hippocampus of Type 2 Diabetic Model Mice. AB - BACKGROUND Glucagon-like peptide-1 (GLP-1), a potent and selective agonist for the GLP-1 receptor, ameliorates the symptoms of diabetes through stimulation of insulin secretion. Exenatide is a potent and selective agonist for the GLP-1 receptor. Cell adhesion molecules are members of the immunoglobulin superfamily and are involved in synaptic rearrangements in the mature brain. MATERIAL AND METHODS The present study demonstrated the effects of exenatide treatment (0.1 ug/kg, subcutaneously, twice daily for 2 weeks) on the gene expression levels of cell adhesion molecules, neural cell adhesion molecule (NCAM), intercellular cell adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) in the brain tissue of diabetic BALB/c male mice by real-time quantitative polymerase chain reaction (PCR). Diabetes was induced by streptozotocin/nicotinamide (STZ-NA) injection to male mice. RESULTS The results of this study revealed that hippocampal gene expression of NCAM, ICAM, and VCAM were found to be up-regulated in STZ-NA-induced diabetic mice compared to those of controls. A significant decrease in the gene expression levels of NCAM, ICAM, and VCAM were determined after 2 weeks of exenatide administration. CONCLUSIONS Cell adhesion molecules may be involved in the molecular mechanism of diabetes. Exenatide has a strong beneficial action in managing diabetes induced by STZ/NA by altering gene expression of NCAM, ICAM, and VCAM. PMID- 27486926 TI - Directive and non-directive food-related parenting practices: Associations between an expanded conceptualization of food-related parenting practices and child dietary intake and weight outcomes. AB - : This study examines associations between an expanded conceptualization of food related parenting practices, specifically, directive and non-directive control, and child weight (BMI z-score) and dietary outcomes [Healthy Eating Index (HEI) 2010, daily servings fruits/vegetables] within a sample of parent-child dyads (8 12 years old; n = 160). Baseline data from the Healthy Home Offerings via the Mealtime Environment (HOME Plus) randomized controlled trial was used to test associations between directive and non-directive control and child dietary outcomes and weight using multiple regression analyses adjusted for parental education. Overall variance explained by directive and non-directive control constructs was also calculated. Markers of directive control included pressure-to eat and food restriction, assessed using subscales from the Child Feeding Questionnaire; markers of non-directive control were assessed with a parental role modeling scale and a home food availability inventory in which an obesogenic home food environment score was assigned based on the types and number of unhealthful foods available within the child's home food environment. DIRECTIVE CONTROL: Food restriction and pressure-to-eat were positively and negatively associated with BMI z-scores, respectively, but not with dietary outcomes. NON DIRECTIVE CONTROL: An obesogenic home food environment was inversely associated with both dietary outcomes; parental role modeling of healthful eating was positively associated with both dietary outcomes. Neither non-directive behavioral construct was significantly associated with BMI z-scores. TOTAL VARIANCE: Greater total variance in BMI-z was explained by directive control; greater total variance in dietary outcomes was explained by non-directive control. Including a construct of food-related parenting practices with separate markers for directive and non-directive control should be considered for future research. These concepts address different forms of parental control and, in the present study, yielded unique associations with child dietary and weight outcomes. PMID- 27486928 TI - Biodegradation Kinetics of 1,4-Dioxane in Chlorinated Solvent Mixtures. AB - This study investigated the impacts of individual chlorinated solvents and their mixtures on aerobic 1,4-dioxane biodegradation by Pseudonocardia dioxanivorans CB1190. The established association of these co-occurring compounds suggests important considerations for their respective biodegradation processes. Our kinetics and mechanistic studies demonstrated that individual solvents inhibited biodegradation of 1,4-dioxane in the following order: 1,1-dichloroethene (1,1 DCE) > cis-1,2-diochloroethene (cDCE) > trichloroethene (TCE) > 1,1,1 trichloroethane (TCA). The presence of 5 mg L(-1) 1,1-DCE completely inhibited 1,4-dioxane biodegradation. Subsequently, we determined that 1,1-DCE was the strongest inhibitor of 1,4-dioxane biodegradation by bacterial pure cultures exposed to chlorinated solvent mixtures as well as in environmental samples collected from a site contaminated with chlorinated solvents and 1,4-dioxane. Inhibition of 1,4-dioxane biodegradation rates by chlorinated solvents was attributed to delayed ATP production and down-regulation of both 1,4-dioxane monooxygenase (dxmB) and aldehyde dehydrogenase (aldH) genes. Moreover, increasing concentrations of 1,1-DCE and cis-1,2-DCE to 50 mg L(-1) respectively increased 5.0-fold and 3.5-fold the expression of the uspA gene encoding a universal stress protein. In situ natural attenuation or enhanced biodegradation of 1,4-dioxane is being considered for contaminated groundwater and industrial wastewater, so these results will have implications for selecting 1,4-dioxane bioremediation strategies at sites where chlorinated solvents are present as co contaminants. PMID- 27486927 TI - Driving Structure-Based Drug Discovery through Cosolvent Molecular Dynamics. AB - Identifying binding hotspots on protein surfaces is of prime interest in structure-based drug discovery, either to assess the tractability of pursuing a protein target or to drive improved potency of lead compounds. Computational approaches to detect such regions have traditionally relied on energy minimization of probe molecules onto static protein conformations in the absence of the natural aqueous environment. Advances in high performance computing now allow us to assess hotspots using molecular dynamics (MD) simulations. MD simulations integrate protein flexibility and the complicated role of water, thereby providing a more realistic assessment of the complex kinetics and thermodynamics at play. In this review, we describe the evolution of various cosolvent-based MD techniques and highlight a myriad of potential applications for such technologies in computational drug development. PMID- 27486929 TI - Towards sustainable and safe apparel cleaning methods: A review. AB - Perchloroethylene (PERC) is a compound commonly used as a solvent in dry cleaning, despite its severe health and environmental impacts. In recent times chemicals such as hydrocarbons, GreenEarth((r)), acetal and liquid carbon dioxide have emerged as less damaging substitutes for PERC, and an even more sustainable water-based wet cleaning process has been developed. We employed a systematic review approach to provide a comprehensive overview of the existing research evidence in the area of sustainable and safe apparel cleaning methods and care. Our review describes traditional professional dry cleaning methods, as well as those that utilise solvents other than PERC, and their ecological attributes. In addition, the new professional wet cleaning process is discussed. Finally, we address the health hazards of the various solvents used in dry cleaning and state of-the-art solvent residue trace analysis techniques. PMID- 27486930 TI - Biosorption and biodegradation of a sulfur dye in high-strength dyeing wastewater by Acidithiobacillus thiooxidans. AB - The ability of the bacterial strain Acidithiobacillus thiooxidans to remove sulfur blue 15 (SB15) dye from water samples was examined. This bacterium could not only oxidize sulfur compounds to sulfuric acid but also promote the attachment of the cells to the surface of sulfidic particles, therefore serving as an efficient biosorbent. The biosorption isotherms were better described by the Langmuir equation than by the Freundlich or Dubinin-Radushkevich equation. Also, the biosorption process followed the pseudo-second-order kinetics. At pH 8.3 and SB15 concentrations up to 2000 mg L(-1) in the biomass/mineral salt solution, the dye removal and decolorization were 87.5% and 91.4%, respectively, following the biosorption process. Biodegradation was proposed as a subsequent process for the remaining dye (250-350 mg L(-1)). A central composite design was used to analyze independent variables in the response surface methodology study. Under the optimal conditions (i.e., initial dye concentration of 300 mg L(-1), initial biomass concentration of 1.0 g L(-1), initial pH of 11.7, and yeast extract dose of 60 mg L(-1)), up to 50% of SB15 was removed after 4 days of biodegradation. PMID- 27486931 TI - Taxonomy and Phylogeny of Polyporus Group Melanopus (Polyporales, Basidiomycota) from China. AB - Melanopus is a morphological group of Polyporus which contains species with a black cuticle on the stipe. In this article, taxonomic and phylogenetic studies on Melanopus group were carried out on the basis of morphological characters and phylogenetic evidence of DNA sequences of multiple loci including the internal transcribed spacer (ITS) regions, the large subunit nuclear ribosomal RNA gene (nLSU), the small subunit nuclear ribosomal RNA gene (nSSU), the small subunit mitochondrial rRNA gene sequences (mtSSU), the translation elongation factor 1 alpha gene (EF1-alpha), the largest subunit of RNA polymerase II (RPB1), the second largest subunit of RNA polymerase II (RPB2), and beta-tubulin gene sequences (beta-tubulin). The phylogenetic result confirmed that the previously so-called Melanopus group is not a monophyletic assemblage, and species in this group distribute into two distinct clades: the Picipes clade and the Squamosus clade. Four new species of Picipes are described, and nine new combinations are proposed. A key to species of Picipes is provided. PMID- 27486932 TI - VIP Family Members Prevent Outer Blood Retinal Barrier Damage in a Model of Diabetic Macular Edema. AB - Diabetic macular edema (DME), characterized by an increase of thickness in the eye macular area, is due to breakdown of the blood-retinal barrier (BRB). Hypoxia plays a key role in the progression of this pathology by activating the hypoxia inducible factors. In the last years, various studies have put their attention on the role of pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) in retinal dysfunction. However, until now, no study has investigated their protective role against the harmful combined effect of both hyperglycemia and hypoxia on outer BRB. Therefore, in the present study, we have analyzed the role of these peptides on permeability, restoration of tight junctions expression and inhibition of hyperglycemia/hypoxia-induced apoptosis, in an experimental in vitro model of outer BRB. Our results have demonstrated that the peptides' treatment have restored the integrity of outer BRB induced by cell exposure to hyperglycemia/hypoxia. Their effect is mediated through the activation of phosphoinositide 3 kinase (PI3K)/Akt and mammalian mitogen activated protein kinase/Erk kinase (MAPK/ERK) signaling pathways. In conclusion, our study further clarifies the mechanism through which PACAP and VIP perform the beneficial effect on retinal damage induced by hyperglycemic/hypoxic insult, responsible of DME progression. J. Cell. Physiol. 232: 1079-1085, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27486933 TI - Asymmetric and Upper Body Parkinsonism in Patients with Idiopathic Normal Pressure Hydrocephalus. AB - BACKGROUND AND PURPOSE: Our aims were to analyze the characteristics of parkinsonian features and to characterize changes in parkinsonian motor symptoms before and after the cerebrospinal fluid tap test (CSFTT) in idiopathic normal pressure hydrocephalus (INPH) patients. METHODS: INPH subjects were selected in consecutive order from a prospectively enrolled INPH registry. Fifty-five INPH patients (37 males) having a positive response to the CSFTT constituted the final sample for analysis. The mean age was 73.7+/-4.7 years. The pre-tap mean Unified Parkinson's Disease Rating Scale motor (UPDRS-III) score was 24.5+/-10.2. RESULTS: There was no significant difference between the upper and lower body UPDRS-III scores (p=0.174). The parkinsonian signs were asymmetrical in 32 of 55 patients (58.2%). At baseline, the Timed Up and Go Test and 10-meter walking test scores were positively correlated with the total motor score, global bradykinesia score, global rigidity score, upper body score, lower body score, and postural instability/gait difficulties score of UPDRS-III. After the CSFTT, the total motor score, global bradykinesia score, upper body score, and lower body score of UPDRS-III significantly improved (p<0.01). There was a significant decrease in the number of patients with asymmetric parkinsonism (p<0.05). CONCLUSIONS: In the differential diagnosis of elderly patients presenting with asymmetric and upper body parkinsonism, we need to consider a diagnosis of INPH. The association between gait function and parkinsonism severity suggests the involvement of similar circuits producing gait and parkinsonian symptoms in INPH. PMID- 27486934 TI - Clinical Considerations of Obstructive Sleep Apnea with Little REM Sleep. AB - BACKGROUND AND PURPOSE: Obstructive sleep apnea (OSA) is more severe during rapid eye movement (REM) sleep than during non-REM sleep. We aimed to determine the features of patients with OSA who experience little REM sleep. METHODS: Patients with a chief complaint of sleep-disordered breathing were enrolled. All subjects underwent overnight polysomnography (PSG) and completed questionnaires on sleep quality. Patients were divided into the following three groups according to the proportion of REM sleep detected in overnight PSG: little REM sleep [REM sleep <20% of total sleep time (TST)], normal REM sleep (20-25% of TST), and excessive REM sleep (>25% of TST). Multiple logistic regression analyses were applied to the data. The success rate of continuous positive airway pressure (CPAP) titration was estimated in these groups. RESULTS: The age and body mass index of the patients were 47.9+/-15.9 years (mean+/-SD) and 25.2+/-4.1 kg/m2, respectively. The 902 patients comprised 684 (76%) men and 218 (24%) women. The apnea-hypopnea index (AHI) in the little-REM-sleep group was 22.1+/-24.4 events/hour, which was significantly higher than those in the other two groups (p<0.05). Multiple logistic regression showed that a higher AHI (p<0.001; odds ratio, 1.512; 95% confidence interval, 1.020-1.812) was independently predictive of little REM sleep. The titration success rate was lower in the little-REM-sleep group than in the normal-REM-sleep group (p=0.038). CONCLUSIONS: The AHI is higher and the success rate of CPAP titration is lower in OSA patients with little REM sleep than those with normal REM sleep. PMID- 27486935 TI - Detection of Listeria monocytogenes in CSF from Three Patients with Meningoencephalitis by Next-Generation Sequencing. AB - BACKGROUND AND PURPOSE: Encephalitis caused by Listeria monocytogenes (L. monocytogenes) is rare but sometimes fatal. Early diagnosis is difficult using routine cerebrospinal fluid (CSF) tests, while next-generation sequencing (NGS) is increasingly being used for the detection and characterization of pathogens. METHODS: This study set up and applied unbiased NGS to detect L. monocytogenes in CSF collected from three cases of clinically suspected listeria meningoencephalitis. RESULTS: Three cases of patients with acute/subacute meningoencephalitis are reported. Magnetic resonance imaging and blood cultures led to a suspected diagnosis of L. monocytogenes, while the CSF cultures were negative. Unbiased NGS of CSF identified and sequenced reads corresponding to L. monocytogenes in all three cases. CONCLUSIONS: This is the first report highlighting the feasibility of applying NGS of CSF as a diagnostic method for central nervous system (CNS) L. monocytogenes infection. Routine application of this technology in clinical microbiology will significantly improve diagnostic methods for CNS infectious diseases. PMID- 27486936 TI - Projected Numbers of Ischemic Strokes Recorded in the Austrian Stroke-Unit Registry from 2012 to 2075. AB - BACKGROUND AND PURPOSE: This study analyzed the number of patients with ischemic strokes recorded in the Austrian Stroke-Unit Registry with the aim of projecting this number from 2012 to 2075 and to highlight that the Austrian health system will face a dramatic increase in older patients within the next few decades. METHODS: Current demographic information was obtained from EUROSTAT, and information on age- and sex-stratified 1-year incidence rates of ischemic stroke were obtained from the Austrian Stroke-Unit Registry. Sensitivity analysis was performed by analyzing the projections based on predicted ageing, main, and growth population scenarios, and with stratification by age and gender. RESULTS: The total number of ischemic strokes recorded in the Austrian Stroke-Unit Registry was 8,690 in 2012 and is expected to increase to 15,826, 15,626, or 18,134 in 2075 according to the ageing, main, and growth scenarios, respectively. The corresponding numbers of patients are projected to increase or decrease within different age strata as follows (100%=number of registered ischemic strokes in 2012): 0-40 years, 100%/99% (males/females); 40-50 years, 83%/83%; 50 60 years, 98%/97%; 60-70 years, 126%/119%; 70-80 years, 159%/139%; 80-90 years, 307%/199%; and 90+ years, 894%/413%. CONCLUSIONS: The ageing population in Austria will result in the number of patients increasing considerably from 2012 to 2075, to 182%, 180%, or 208% (relative to 100% in 2012) according to the ageing, main, and growth scenarios, respectively; the corresponding value among those aged 80+ years is 315%, 290%, or 347%. These figures demonstrated the importance of improving primary preventive measures. The results of this study should provide a basis for discussions among health-care professionals and economists to face the future large financial burden of ischemic stroke on the Austrian health system. PMID- 27486938 TI - Optic Neuritis in a Patient with Bickerstaff's Brainstem Encephalitis. PMID- 27486937 TI - Effects of Regular Treadmill Exercise on a DNA Oxidative-Damage Marker and Total Antioxidant Capacity in Rat Hippocampal Tissue. AB - BACKGROUND AND PURPOSE: Regular exercise can result in changes in the levels of oxidative stress in the hippocampus; however, little attention has been paid to physical-activity-induced neuronal protection to exposure to lead compounds. This study investigated the effects of regular treadmill exercise on a DNA oxidative damage marker [8-hydroxy-2'-deoxyguanosine (8-OHdG)] and the total antioxidant capacity (TAC) of hippocampal tissue in lead-acetate exposed rats. METHODS: This study investigated the effects of 8 weeks of regular treadmill exercise on 8-OHdG and the TAC of hippocampal tissue in lead-acetate-exposed rats. Wistar rats were randomly divided into four groups: baseline, sham (control), lead, and exercise+lead. The exercise program involved running on a treadmill with increasing intensity five times a week for 8 weeks. Animals in the lead and exercise+lead groups received lead acetate at 20 mg/kg body weight intraperitoneally three times weekly for 8 weeks. Animals in the sham group received solvent (ethyl oleate) at 30 mg/kg body weight three times weekly for 8 weeks. TAC and 8-OHdG were measured by spectrophotometric and ELISA techniques, respectively. Data were analyzed by ANOVA and Tukey's post-hoc test with a significance cutoff of p<=0.05. RESULTS: The level of 8-OHdG and the TAC were significantly higher and lower, respectively, in the lead group than in the baseline and sham groups (p<0.01). However, the 8-OHdG level and TAC value in hippocampal tissue were significantly decreased and increased, respectively, in the exercise+lead group relative to the lead group (p<0.05). CONCLUSIONS: The TAC of hippocampal tissue may be directly associated with neural protection mechanisms of exercise following lead acetate injection, and the beneficial effects of regular exercise in preventing hippocampal neuronal damage could be due to decreased hippocampal oxidative stress such as reflected by a lower 8-OHdG level and increased TAC. PMID- 27486939 TI - Leber's 'Plus' in a Korean Patient with 14484/ND6 Mutation. PMID- 27486940 TI - A Large Dominant Myotonia Congenita Family with a V1293I Mutation in SCN4A. PMID- 27486944 TI - Response, Letter to the Editor. PMID- 27486943 TI - Letter to the Editor: Sex Steroids and Vascular Calcification. PMID- 27486945 TI - Letter to the Editor: The Value of Molecular Testing for Effective Management of Patients With Indeterminate Thyroid Nodules. PMID- 27486946 TI - Response to the Letter to the Editor. PMID- 27486947 TI - Letter to the Editor: Combination Treatment With Teriparatide and Denosumab in Osteoporosis. PMID- 27486948 TI - An innovative approach for sequential extraction of phosphorus in sediments: Ferrous iron P as an independent P fraction. AB - Accurate identification of phosphorus (P) forms is crucially important for understanding the geochemical cycle of P; however, until now the role of ferrous iron P (Fe(II)-P) buried in sediments has been completely ignored in nearly all sequential extraction procedures developed. Using sediment cores sampled from Donghu Lake in Wuhan, China, this study explored a modified version of widely used sequential P extraction method (SEDEX; Ruttenberg, 1992) in which Fe(II)-P was identified as an independent fraction. Based on the high selectivity of the extractant (0.2% 2,2'-bipyridine+0.1 M KCl) and the dissolution equilibrium of P, procedures for extracting Fe(II)-P were optimized using a 1:100 solid:liquid ratio and extraction at 50 +/- 1 degrees C for 24 h. The sedimentary P extracted was divided into five fractions: loosely-bound P, Fe(II)-P, CDB-P, Ca-P and O-P. Fe(II)-P was the predominant fraction in fresh sediments in Donghu Lake, accounting for 15.7-49.9% of TP, with a mean of 31.6%. The mean values of Ca-P, O P, CDB-P and loosely-bound P were 28.4%, 22.7%, 17.1% and 4.3%, respectively. Combined with component analysis of extracts and recovery experiments of standard reference minerals (vivianite, Fe3(PO4)2.8H2O) in natural sediments, extraction of Fe(II)-P with 0.2% 2,2-bipridine and 0.1 M KCl was robust, with a good recovery rate (88.7-100.6%) and little of the Ca-P dissolved. It is possible to use this innovative SEDEX not only to distinguish the contribution of different P matrices in fresh sediments, but also to investigate the transformation of sedimentary P under different redox conditions. Therefore, greater focus on Fe(II)-P is necessary, because it is a major sink for the geochemical process of sedimentary P. PMID- 27486949 TI - Microbial community adaptation influences long-chain fatty acid conversion during anaerobic codigestion of fats, oils, and grease with municipal sludge. AB - Codigesting fats, oils, and greases with municipal wastewater sludge can greatly improve biomethane recovery at wastewater treatment facilities. Process loading rates of fats, oils, and greases have been previously tested with little knowledge of the digester microbial community structure, and high transient fat loadings have led to long chain fatty acid (LCFA) accumulation and digester upsets. This study utilized recently-developed quantitative PCR assays for syntrophic LCFA-degrading bacteria along with 16S amplicon sequencing to relate changes in microbial community structure to LCFA accumulation during transient loading increases to an anaerobic codigester receiving waste restaurant oil and municipal wastewater sludge. The 16S rRNA gene concentration of the syntrophic beta-oxidizing genus Syntrophomonas increased to ~15% of the Bacteria community in the codigester, but stayed below 3% in the control digester that was fed only wastewater sludge. Methanosaeta and Methanospirillum were the dominant methanogenic genera enriched in the codigester, and together comprised over 80% of the Archaea community by the end of the experimental period. Constrained ordination showed that changes in the codigester Bacteria and Archaea community structures were related to measures of digester performance. Notably, the effluent LCFA concentration in the codigester was positively correlated to the specific loading rate of waste oil normalized to the Syntrophomonas 16S rRNA concentration. Specific loading rates of 0-1.5 * 10(-12) g VS oil/16S gene copies day resulted in LCFA concentrations below 30 mg/g TS, whereas LCFA accumulated up to 104 mg/g TS at higher transient loading rates. Based on the community dependent loading limitations found, enhanced biomethane production from high loadings of fats, oils and greases can be achieved by promoting a higher biomass of slow-growing syntrophic consortia, such as with longer digester solids retention times. This work also demonstrates the potential for controlling the loading rate of fats, oils, and greases based on the analysis of the codigester community structure, such as with quantitative PCR measurements of syntrophic LCFA-degrading bacteria abundance. PMID- 27486950 TI - Simultaneous bioremediation and biodetection of mercury ion through surface display of carboxylesterase E2 from Pseudomonas aeruginosa PA1. AB - Mercury is a toxic heavy metal and presents significant threats to organisms and natural ecosystems. Recently, the mercury remediation as well as its detection by environmental-friendly biotechnology has received increasing attention. In this study, carboxylesterase E2 from mercury-resistant strain Pseudomonas aeruginosa PA1 has been successfully displayed on the outer membrane of Escherichia coli Top10 bacteria to simultaneously adsorb and detect mercury ion (Hg(2+)). The transmission electron microscopy analysis shows that Hg(2+) can be absorbed by carboxylesterase E2 and accumulated on the outer membrane of surface-displayed E. coli bacteria. The adsorption of Hg(2+) followed a physicochemical, equilibrated and saturatable mechanism, which well fits the traditional Langmuir adsorption model. The surface-displayed system can be regenerated through regulating pH values. As its activity can be inhibited by Hg(2+), carboxylesterase E2 has been used to detect the concentration of Hg(2+) in water samples. The developed surface display system will be of great potential in the simultaneous bioremediation and biodetection of environmental mercury pollution. PMID- 27486951 TI - Impact of algal organic matter released from Microcystis aeruginosa and Chlorella sp. on the fouling of a ceramic microfiltration membrane. AB - Algal blooms lead to the secretion of algal organic matter (AOM) from different algal species into water treatment systems, and there is very limited information regarding the impact of AOM from different species on the fouling of ceramic microfiltration (MF) membranes. The impact of soluble AOM released from Microcystis aeruginosa and Chlorella sp. separately and together in feedwater on the fouling of a tubular ceramic microfiltration membrane (alumina, 0.1 MUm) was studied at lab scale. Multi-cycle MF tests operated in constant pressure mode showed that the AOM (3 mg DOC L(-1)) extracted from the cultures of the two algae in early log phase of growth (12 days) resulted in less flux decline compared with the AOM from stationary phase (35 days), due to the latter containing significantly greater amounts of high fouling potential components (protein and humic-like substances). The AOM released from Chlorella sp. at stationary phase led to considerably greater flux decline and irreversible fouling resistance compared with that from M. aeruginosa. The mixture of the AOM (1:1, 3 mg DOC L( 1)) from the two algal species showed more similar flux decline and irreversible fouling resistance to the AOM from M. aeruginosa than Chlorella sp. This was due to the characteristics of the AOM mixture being more similar to those for M. aeruginosa than Chlorella sp. The extent of the flux decline for the AOM mixture after conventional coagulation with aluminium chlorohydrate or alum was reduced by 70%. PMID- 27486952 TI - European longitudinal study on the relationship between adolescents' alcohol marketing exposure and alcohol use. AB - BACKGROUND AND AIMS: This is the first study to examine the effect of alcohol marketing exposure on adolescents' drinking in a cross-national context. The aim was to examine reciprocal processes between exposure to a wide range of alcohol marketing types and adolescent drinking, controlled for non-alcohol branded media exposure. DESIGN: Prospective observational study (11-12- and 14-17-month intervals), using a three-wave autoregressive cross-lagged model. SETTING: School based sample in 181 state-funded schools in Germany, Italy, Netherlands, Poland. PARTICIPANTS: A total of 9075 eligible respondents participated in the survey (mean age 14 years, 49.5% male. MEASUREMENTS: Adolescents reported their frequency of past-month drinking and binge drinking. Alcohol marketing exposure was measured by a latent variable with 13 items measuring exposure to online alcohol marketing, televised alcohol advertising, alcohol sport sponsorship, music event/festival sponsorship, ownership alcohol-branded promotional items, reception of free samples and exposure to price offers. Confounders were age, gender, education, country, internet use, exposure to non-alcohol sponsored football championships and television programmes without alcohol commercials. FINDINGS: The analyses showed one-directional long-term effects of alcohol marketing exposure on drinking (exposure T1 on drinking T2: beta = 0.420 (0.058), P < 0.001, 95% confidence interval (CI) = 0.324-0.515; exposure T2 on drinking T3: beta = 0.200 (0.044), P < 0.001, 95% CI = 0.127-0.272; drinking T1 and drinking T2 on exposure: P > 0.05). Similar results were found in the binge drinking model (exposure T1 on binge T2: beta = 0.409 (0.054), P < 0.001, 95% CI = 0.320-0.499; exposure T2 on binge T3: beta = 0.168 (0.050), P = 0.001, 95% CI = 0.086-0.250; binge T1 and binge T2 on exposure: P > 0.05). CONCLUSIONS: There appears to be a one-way effect of alcohol marketing exposure on adolescents' alcohol use over time, which cannot be explained by either previous drinking or exposure to non-alcohol-branded marketing. PMID- 27486953 TI - Comparison of semiologies between tilt-induced psychogenic nonsyncopal collapse and psychogenic nonepileptic seizures. AB - We sought to characterize the clinical features of tilt-induced psychogenic nonsyncopal collapse (PNSC) from a cohort of young patients and to compare the semiologies between PNSC and EEG-confirmed psychogenic nonepileptic seizures (PNES). A PNSC diagnosis was made if a clinical event occurred during tilt-table testing that the patient regarded as fainting, but neither hypotension nor EEG changes were present. A diagnosis of PNSC was made in 17.6% of all patients referred during the 15-month study period. Cohorts with psychogenic nonsyncopal collapse (n=40) and PNES (n=40) did not differ in age (15.5+/-2.2 versus 14.6+/ 2.7, p=.11) or female gender (80% versus 72.5%, p=.43). Psychogenic nonsyncopal collapse events were briefer than PNES events (median: 45 versus 201.5s, p<.001). Negative motor signs (head drop, body limpness) predominated in PNSC (85% versus 20%, p<.001), while the positive motor signs of convulsion occurred more often with PNES (90% versus 30%, p<.001). Behavioral arrest (25% versus 32.5%, p=.46) and eye closure (85% versus 72.5%, p=.21) did not differ between PNSC and PNES. Patients with PNSC were more likely to be tearful before (30% versus 7.5%, p=.02) and after (62.5% versus 7.5%, p<.001) an event. In conclusion, although overlap exists, the features of PNSC generally appear similar to neurally mediated syncope, while the features of PNES generally appear similar to epileptic seizures. Psychogenic nonsyncopal collapse and PNES likely represent similar disorders that differ primarily by clinical semiologies and referral patterns. PMID- 27486954 TI - Highly Conserved Testicular Localization of Claudin-11 in Normal and Impaired Spermatogenesis. AB - In this study we tested expression of tight junction proteins in human, mouse and rat and analyzed the localization of claudin-11 in testis of patients with normal and impaired spermatogenesis. Recent concepts generated in mice suggest that the stage-specifically expressed claudin-3 acts as a basal barrier, sealing the seminiferous epithelium during migration of spermatocytes. Corresponding mechanisms have never been demonstrated in humans. Testicular biopsies (n = 103) from five distinct groups were analyzed: normal spermatogenesis (NSP, n = 28), hypospermatogenesis (Hyp, n = 24), maturation arrest at the level of primary spermatocytes (MA, n = 24), Sertoli cell only syndrome (SCO, n = 19), and spermatogonial arrest (SGA, n = 8). Protein expression of claudin-3, -11 and occludin was analyzed. Human, mice and rat testis robustly express claudin-11 protein. Occludin was detected in mouse and rat and claudin-3 was found only in mice. Thus, we selected claudin-11 for further analysis of localization. In NSP, claudin-11 is located at Sertoli-Sertoli junctions and in Sertoli cell contacts towards spermatogonia. Typically, claudin-11 patches do not reach the basal membrane, unless flanked by the Sertoli cell body or patches between two Sertoli cell bodies. The amount of basal claudin-11 patches was found to be increased in impaired spermatogenesis. Only claudin-11 is expressed in all three species examined. The claudin-11 pattern is robust in man with impaired spermatogenesis, but the proportion of localization is altered in SCO and MA. We conclude that claudin-11 might represent the essential component of the BTB in human. PMID- 27486955 TI - A wearable, highly stable, strain and bending sensor based on high aspect ratio graphite nanobelts. AB - A simple and scalable method was developed for the fabrication of wearable strain and bending sensors, based on high aspect ratio (length/thickness ~10(3)) graphite nanobelt thin films deposited by a modified Langmuir-Blodgett technique onto flexible polymer substrates. The sensing mechanism is based on the changes in contact resistance between individual nanobelts upon substrate deformation. Very high sensor response stability for more than 5000 strain-release cycles and a device power consumption as low as 1 nW were achieved. The device maximum stretchability is limited by the metal electrodes and the polymer substrate; the maximum strain that could be applied to the polymer used in this work was 40%. Bending tests carried out for various radii of curvature demonstrated distinct sensor responses for positive and negative curvatures. The graphite nanobelt thin flexible films were successfully tested for acoustic vibration and heartbeat sensing. PMID- 27486956 TI - Optimal dehydrothermal processing conditions to improve biocompatibility and durability of a weakly denatured collagen scaffold. AB - Collagen scaffolds are essential for tissue regeneration; however, preprocessing of these scaffolds is necessary because of their poor mechanical properties. The aim of this study was to determine the optimal condition for preparing a collagen scaffold with biocompatibility and durability. An atelocollagen fiber suspension was made and stored at -10 degrees C in a container that could be cooled from the bottom to provide an orientation perpendicular to the collagen fiber and facilitate cell infiltration into the scaffold. After freeze-drying the frozen suspension, various collagen scaffolds were made by dehydrothermal (DHT) treatment under different conditions (processing temperature: 120-160 degrees C for 0-28 h). Sections of the obtained materials were embedded under the back skin of rats, and the thickness and biocompatibility of the residual scaffold were evaluated after 2 weeks. The number of foreign body giant cells was counted to evaluate biocompatibility. Although the residual scaffold was thick, excessive DHT treatment caused a strong foreign body reaction. Weak DHT treatment resulted in a collagen scaffold with good biocompatibility but with reduced thickness. Overall, these results showed the restricted optimal conditions to make a collagen scaffold with good biocompatibility and ability to maintain sufficient space for tissue regeneration. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2301-2307, 2017. PMID- 27486957 TI - The end of the hepatitis C burden: Really? PMID- 27486958 TI - A procedure for sensory detection of androstenone in meat and meat products from entire male pigs: Development of a panel training. AB - This study represents a proposal for training sensory panels in androstenone (AND) perception in meat and meat products. The procedure consists of four main parts: (1) selection and training of a sensory panel (11 panelists) using standards with Vaseline oil media as carriers of AND and skatole (SKA); (2) developing a training method AND detection in meat; (3) dry cured meat product and (4) cooked meat product. All candidates were able to distinguish between AND, SKA and AND+SKA in Vaseline oil, order AND solutions with different concentrations and classify them in the three categories: low, medium and high. The panel was able to differentiate the meat in the three categories, but only the high level in meat products. Due to the individual features in AND perception, specific training for each type of product is required. PMID- 27486959 TI - Effect of preservative addition on sensory and dynamic profile of Lucanian dry sausages as assessed by quantitative descriptive analysis and temporal dominance of sensations. AB - The quantitative descriptive analysis (QDA) was combined with temporal dominance of sensations (TDS) to assess the sensory properties of Lucanian dry-sausages either added with nitrate, nitrite and l-ascorbic acid (NS), or not (NNS). Both QDA and TDS differentiated the two groups of sausages. NNS products were perceived with higher intensity of hardness (P<0.05) and tended to be perceived with higher intensities of flavor (P<0.10), pepper (P<0.20), and oiliness (P<0.20), while resulting lower in chewiness (P<0.20). TDS showed that in all the sausages hardness was the first dominant attribute; then, in NNS products flavor remained dominant until the end of tasting, whereas in NS products oiliness prevailed. In conclusion, TDS showed that the perception of some textural parameters, such as oiliness, during mastication was more dominant in NS products, whereas using conventional QDA this attribute appeared higher in sausages manufactured without preservatives. Therefore, TDS provided additional information for the description and differentiation of Lucanian sausages. PMID- 27486960 TI - Characterising variation in five genetic loci of cytomegalovirus during treatment for congenital infection. AB - Cytomegalovirus (CMV) is the most common congenital infection in humans and a leading cause of sensorineural hearing loss. Ganciclovir (6 mg/kg twice daily for 42 days) has been shown to reduce hearing deterioration and is used in clinical practice. Vaccines and passive administration of antibody are being evaluated in randomized controlled trials in allograft candidates, women of childbearing age, and pregnant women with primary CMV infection. To help define genetic variation in each of the targets of these therapeutic interventions, we amplified and sequenced genes UL97 (site utilised for ganciclovir phosphorylation), UL55 (glycoprotein B (gB) vaccine target) and UL128, UL130, and UL131a (specific monoclonal antibody targets). Serial blood, saliva, and urine samples (total 120) obtained from nine infants with symptomatic congenital CMV treated with 42 days' ganciclovir were analyzed. All samples tested were UL97 wild type at baseline and none developed mutations during treatment, showing no selection of resistance. The prevalences of UL55 genotypes were 28% gB1, 22% gB2, 1% gB3, and mixed in 20% samples. No mutations were noted in UL128-131a. Phylogenetic tree analysis showed that sequences with variations were found in multiple body sites of individual patients, so there was no evidence of body site compartmentalization of particular strains of CMV. The significance of these results for changes in diagnostic practices and therapeutic interventions against CMV are discussed. J. Med. Virol. 89:502-507, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27486963 TI - Role of Operative Complexity Variables in Risk Adjustment for Patients With Cancer. PMID- 27486965 TI - The safety and efficacy of Diphoterine for ocular and cutaneous burns in humans. AB - CONTEXT: Diphoterine, developed by the French company Prevor, is a polyvalent, chelating, amphoteric and slightly hypertonic solution used in the management of chemical cutaneous and ocular burns. While used extensively in Europe and Canada, it is has not been approved by the United States Occupational Safety and Health Administration (OSHA) as an alternative to the water-rinse method due to a lack of evidence of its safety and efficacy on human subjects. An unbiased and extensive systematic review was undertaken in order to better understand Diphoterine's safety and efficaciousness on humans. OBJECTIVE: Review the safety and efficacy of Diphoterine for treating chemical burns of the skin and eyes in humans. METHODS: Data sources: Information sources included Pubmed, the National Library of Medicine's Medline Database and the "Publications" sections of the Prevor website. Search terms included Diphoterine, chemical burn, ocular burn and cutaneous burn. STUDY SELECTION: Any study type published through a peer-reviewed journal up to May 2016 was considered eligible. Published data must have included Diphoterine in the treatment of chemical burns on the skin or eyes as well as meet other specified criteria. Acceptable studies had to use either a quantitative (e.g. number of work days lost) or qualitative (e.g. level of erythema) approach when measuring cutaneous or ocular lesion outcomes. DATA EXTRACTION: Independent assessment of article inclusion by two authors using predefined criteria. RESULTS AND CONCLUSION: Diphoterine is safe and highly effective in improving healing time, healing sequelae and pain management of chemical burns on the skin and eyes of humans. Outcomes are significantly improved when compared to water or a physiologic solution equivalent. We recommend that this product be readily available to emergency responders and companies that expose their employees to hazardous chemical substances in order to improve healing sequelae, pain management and lost work days from these types of burns. PMID- 27486964 TI - Protein Kinase Czeta Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury. AB - Protein kinase Czeta (PKCzeta) is highly expressed in the lung, where it plays several regulating roles in the pathogenesis of acute lung injury (ALI). Proliferation and differentiation of integrin beta4+ distal lung epithelial progenitor cells seem to play a key role in proper lung regeneration. We investigated the effects of a myristoylated PKCzeta inhibitor (PKCzetai) in a murine model of bleomycin-induced ALI. After intratracheal injury, we treated mice three times a week with PKCzetai or its vehicle, DMSO. We found that mice injured with bleomycin and then treated with PKCzetai for one week showed decreased activation of PKCzeta, improved lung compliance, and decreased lung protein permeability compared to injured mice treated with DMSO. Mice treated continuously with PKCzetai for 6 weeks showed reduced evidence of lung fibrosis by computed tomographic images, decreased lung collagen deposition, and decreased active transforming growth factor-beta in the bronchoalveolar lavage fluid. In addition, we found an increased number of lung beta4+ cells compared to DMSO at Week 6. Therefore, we grew isolated integrin beta4+ lung progenitor cells in the presence of PKCzetai or DMSO and found that beta4+ cells treated with PKCzetai proliferated more in vitro compared to DMSO. We conclude that the use of a PKCzetai promotes resolution of lung fibrosis in a bleomycin ALI model and increases the number of beta4+ progenitor cells with regenerative potential in the lung. PMID- 27486966 TI - Imagery Rescripting: The Impact of Conceptual and Perceptual Changes on Aversive Autobiographical Memories. AB - BACKGROUND: Imagery rescripting (ImRs) is a process by which aversive autobiographical memories are rendered less unpleasant or emotional. ImRs is thought only to be effective if a change in the meaning-relevant (semantic) content of the mental image is produced, according to a cognitive hypothesis of ImRs. We propose an additional hypothesis: that ImRs can also be effective by the manipulation of perceptual features of the memory, without explicitly targeting meaning-relevant content. METHODS: In two experiments using a within-subjects design (both N = 48, community samples), both Conceptual-ImRs-focusing on changing meaning-relevant content-and Perceptual-ImRs-focusing on changing perceptual features-were compared to Recall-only of aversive autobiographical image-based memories. An active control condition, Recall + Attentional Breathing (Recall+AB) was added in the first experiment. In the second experiment, a Positive-ImRs condition was added-changing the aversive image into a positive image that was unrelated to the aversive autobiographical memory. Effects on the aversive memory's unpleasantness, vividness and emotionality were investigated. RESULTS: In Experiment 1, compared to Recall-only, both Conceptual-ImRs and Perceptual-ImRs led to greater decreases in unpleasantness, and Perceptual-ImRs led to greater decreases in emotionality of memories. In Experiment 2, the effects on unpleasantness were not replicated, and both Conceptual-ImRs and Perceptual-ImRs led to greater decreases in emotionality, compared to Recall only, as did Positive-ImRs. There were no effects on vividness, and the ImRs conditions did not differ significantly from Recall+AB. CONCLUSIONS: Results suggest that, in addition to traditional forms of ImRs, targeting the meaning relevant content of an image during ImRs, relatively simple techniques focusing on perceptual aspects or positive imagery might also yield benefits. Findings require replication and extension to clinical samples. PMID- 27486967 TI - Two-dimensional versus three-dimensional laparoscopy in surgical efficacy: a systematic review and meta-analysis. AB - BACKGROUND: Laparoscopy is a revolutionary technique in modern surgery. However, the comparative efficacy between two-dimensional laparoscopy and three dimensional laparoscopy remains in uncertainty. Therefore we performed this systematic review and meta-analysis in order to seek for answers. METHODS: Databases of PubMed, Web of Science, EMBASE and Cochrane Library were carefully screened. Clinical trials comparing two-dimensional versus three-dimensional laparoscopy were included for pooled analysis. Observational and randomized trials were methodologically appraised by Newcastle-Ottawa Scale and Revised Jadad's Scale respectively. Subgroup analyses were additionally conducted to clarify the potential confounding elements. Outcome stability was examined by sensitivity analysis, and publication bias was analyzed by Begg's test and Egger's test. RESULTS: 21 trials were screened out from the preliminary 3126 records. All included studies were high-quality in methodology, except for Bilgen 2013 and Ruan 2015. Three-dimensional laparoscopy was superior to two-dimensional laparoscopy in terms of surgical time (P < 0.00001), blood loss (P = 0.01), perioperative complications (P = 0.04) and hospital stay (P = 0.03). Additionally, both techniques demonstrated comparable results of secondary endpoints, including drainage volume (P = 0.74), drainage time (P = 0.26), numbers of retrieved lymphnodes (P = 0.85), hospital expenses (P = 0.49), anastomosis time in prostatectomy (P=0.15) and 6-month continence rate (P = 0.61). The pooled outcomes of primary endopoints were verified to be stable by sensitivity analysis. Although Begg's test (P = 0.215) and Egger's test (P = 0.003) revealed that there was publication bias across included studies, Trim-and Fill method confirmed that the results remained stable. CONCLUSION: Three dimensional laparoscopy is a preferably surgical option against two-dimensional laparoscopy due to its better surgical efficacy. PMID- 27486968 TI - Association between dietary nitrate and nitrite intake and sitespecific cancer risk: evidence from observational studies. AB - Epidemiological studies have reported inconsistent findings on the association between dietary nitrate and nitrite intake and cancer risk. We performed a meta analysis of epidemiological studies to summarize available evidence on the association between dietary nitrate and nitrite intake and cancer risk from published prospective and case-control studies. PubMed database was searched to identify eligible publications through April 30th, 2016. Study-specific relative risks (RRs) with corresponding 95% confidence interval (CI) from individual studies were pooled by using random- or fixed- model, and heterogeneity and publication bias analyses were conducted. Data from 62 observational studies, 49 studies for nitrates and 51 studies for nitrites, including a total of 60,627 cancer cases were analyzed. Comparing the highest vs. lowest levels, dietary nitrate intake was inversely associated with gastric cancer risk (RR = 0.78; 95%CI = 0.67-0.91) with moderate heterogeneity (I2 = 42.3%). In contrast, dietary nitrite intake was positively associated with adult glioma and thyroid cancer risk with pooled RR of 1.21 (95%CI = 1.03-1.42) and 1.52 (95%CI = 1.12-2.05), respectively. No significant associations were found between dietary nitrate/nitrite and cancers of the breast, bladder, colorectal, esophagus, renal cell, non-Hodgkin lymphoma, ovarian, and pancreas. The present meta-analysis provided modest evidence that positive associations of dietary nitrate and negative associations of dietary nitrite with certain cancers. PMID- 27486969 TI - CRISPR Cas9-guided chromatin immunoprecipitation identifies miR483 as an epigenetic modulator of IGF2 imprinting in tumors. AB - The normally imprinted insulin-like growth factor II (IGF2) gene is aberrantly upregulated in a variety of human malignancies, yet the mechanisms underlying this dysregulation are still poorly defined. In this report, we used a CRISPR Cas9-guided chromatin immunoprecipitation assay to characterize the molecular components that participate in the control of IGF2 gene expression in human tumor cells. We found that miR483, an oncogenic intronic miRNA, binds to the most upstream imprinted IGF2 promoter, P2. Ectopic expression of miR483 induced upregulation of IGF2 expression, in parallel with an increase in tumor cell proliferation, migration, invasion, and tumor colony formation. miR483 induced loss of IGF2 imprinting by altering the epigenotype at P2, with reduction in histone H3K27 methylation and a decrease in chromatin binding of two imprinting regulatory factors, CTCF and SUZ12. This study identifies a new role for miR483 in the regulation of IGF2 gene expression through the alteration of the promoter epigenotype. PMID- 27486970 TI - IGF-II induced by hepatitis B virus X protein regulates EMT via SUMO mediated loss of E-cadherin in mice. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer mortality. Prognosis of this disease largely depends on its stage. An Enlarged liver, due to dysplasia, may be a critical point in the multi step progression to HCC. The mechanism underlying hepatomegaly in human and mouse models are poorly understood. We previously reported we observed enlarged liver in hepatitis B virus X protein (HBx) expressing mice (HBx mice). Here we identify the critical role of HBx induced IGF-II in hepatomegaly in mice and abnormal cell growth in human hepatoma cells. We found that HBx induced IGF-II is essential to induce epithelial-mesenchymal transition (EMT) through loss of E-cadherin. In mouse liver, loss of E-cadherin was mediated by post-translational regulation, at least in part, by protease and SUMOylation not by transcriptional regulation. In contrast, in hepatoma cell line (HepG2 cells) Akt signal pathway controls the mRNA expression level of EMT-related transcription factors, especially Twist, in addition to post- translational modification through SUMOylation. Thus, IGF-II mediated loss of E-cadherin is central in developing hepatomegaly in mice and abnormal cell growth in the hepatoma cell line. HBx induced IGF-II represents a potential biomarker, which is also a therapeutic target in HCC. PMID- 27486971 TI - IRES-dependent translation of the long non coding RNA meloe in melanoma cells produces the most immunogenic MELOE antigens. AB - MELOE-1 and MELOE-2, two highly specific melanoma antigens involved in T cell immunosurveillance are produced by IRES-dependent translation of the long " non coding " and polycistronic RNA, meloe. In the present study, we document the expression of an additional ORF, MELOE-3, located in the 5' region of meloe. Data from in vitro translation experiments and transfection of melanoma cells with bicistronic vectors documented that MELOE-3 is exclusively translated by the classical cap-dependent pathway. Using a sensitive tandem mass spectrometry technique, we detected the presence of MELOE-3 in total lysates of both melanoma cells and normal melanocytes. This contrasts with our previous observation of the melanoma-restricted expression of MELOE-1 and MELOE-2. Furthermore, in vitro stimulation of PBMC from 6 healthy donors with overlapping peptides from MELOE-1 or MELOE-3 revealed a very scarce MELOE-3 specific T cell repertoire as compared to the abundant repertoire observed against MELOE-1. The poor immunogenicity of MELOE-3 and its expression in melanocytes is consistent with an immune tolerance towards a physiologically expressed protein. In contrast, melanoma-restricted expression of IRES-dependent MELOE-1 may explain its high immunogenicity. In conclusion, within the MELOE family, IRES-dependent antigens represent the best T cell targets for immunotherapy of melanoma. PMID- 27486972 TI - A role for activated Cdc42 in glioblastoma multiforme invasion. AB - Cdc42 is a Rho-GTPase which plays a major role in regulating cell polarity and migration by specifying the localization of filopodia. However, the role of Cdc42 in GBM invasion has not been thoroughly investigated. We generated stable doxycycline-inducible clones expressing wild type (WT)-, constitutively active (CA)-, and dominant negative (DN)-Cdc42 in three different human glioma cell lines. Expression of CA-Cdc42 significantly increased the migration and invasive properties of malignant glioma cells compared to WT and DN-Cdc42 cell clones, and this was accompanied by a greater number of filopodia and focal adhesion structures which co-localize with phosphorylated focal adhesion kinase (FAK). By mass spectrometry and immunoprecipitation studies, we demonstrated that activated Cdc42 binds to IQGAP1. When implanted orthotopically in mice, the CA-Cdc42 expressing glioma cells exhibited enhanced local migration and invasion, and led to larger tumors, which significantly reduced survival. Using the Cancer Genome Atlas dataset, we determined that high Cdc42 expression is associated with poorer progression free survival, and that Cdc42 expression is highest in the proneural and neural subgroups of GBM. In summary, our studies demonstrate that activated Cdc42 is a critical determinant of the migratory and invasive phenotype of malignant gliomas, and that its effect may be mediated, at least in part, through its interaction with IQGAP1 and phosphorylated FAK. PMID- 27486973 TI - Critical role of androgen receptor level in prostate cancer cell resistance to new generation antiandrogen enzalutamide. AB - Enzalutamide is an androgen receptor (AR) inhibitor approved for therapy of metastatic castration resistant prostate cancer. However, clinical application revealed that 30 to 40% of patients acquire resistance after a short period of treatment. Currently, the molecular mechanisms underlying such resistances are not completely understood, partly due to a lack of model systems. In the present study we established three different cellular models of enzalutamide resistance including a cell line with wild type AR (LAPC4), DuCaP cells which overexpress wild-type AR, as well as a cell which has been adapted to long term androgen ablation (LNCaP Abl) and harbors the AR T878A mutation. After 10 months of cultivation, sustained growth in the presence of enzalutamide was achieved. When compared to controls, resistant cells exhibit significantly decreased sensitivity to enzalutamide as measured with 3[H]thymidine incorporation and WST assay. Moreover, these cell models exhibit partly re-activated AR signaling despite presence of enzalutamide. In addition, we show that enzalutamide resistant cells are insensitive to bicalutamide but retain considerable sensitivity to abiraterone. Mechanistically, enzalutamide resistance was accompanied by increased AR and AR-V7 mRNA and protein expression as well as AR gene amplification, while no additional AR mutations have been identified. PMID- 27486974 TI - Telomere status in chronic lymphocytic leukemia with TP53 disruption. AB - In chronic lymphocytic leukemia (CLL), telomere dysfunction is associated with poor outcomes. TP53 is involved in cellular responses to dysfunctional telomeres, and its inactivation is the strongest adverse prognostic factor for CLL. Given the biological relationship between TP53 and telomeres, and their prognostic value, it is important to improve our understanding of the impact of TP53 alterations on telomeres. We performed a comprehensive study of the deletions and mutations of the TP53 gene and telomere parameters, including hTERT and the shelterin complex, in 115 CLL patients. We found that any type of TP53 alteration was associated with very short telomeres and high hTERT expression, independently of other biological CLL features. Patients with disrupted TP53 showed telomere deletions and chromosomal end-to-end fusions in cells with complex karyotypes. TP53 disruption was characterized by downregulation of shelterin genes. Interestingly, low expression of POT1, TPP1 and TIN2 was also found in some patients with wild-type TP53 and had an adverse impact on progression-free survival after standard genotoxic therapy. In conclusion, we have demonstrated that patients with disrupted TP53 have severe telomere dysfunction and high genomic instability. Thus, the telomeric profile could be tested as a biomarker in CLL patients treated with new therapeutic agents. PMID- 27486975 TI - Poor recognition of O6-isopropyl dG by MGMT triggers double strand break-mediated cell death and micronucleus induction in FANC-deficient cells. AB - Isopropyl methanesulfonate (IPMS) is the most potent genotoxic compound among methanesulfonic acid esters. The genotoxic potential of alkyl sulfonate esters is believed to be due to their alkylating ability of the O6 position of guanine. Understanding the primary repair pathway activated in response to IPMS-induced DNA damage is important to profile the genotoxic potential of IPMS. In the present study, both chicken DT40 and human TK6 cell-based DNA damage response (DDR) assays revealed that dysfunction of the FANC pathway resulted in higher sensitivity to IPMS compared to EMS or MMS. O6-alkyl dG is primarily repaired by methyl guanine methyltransferase (MGMT), while isopropyl dG is less likely to be a substrate for MGMT. Comparison of the cytotoxic potential of IPMS and its isomer n-propyl methanesulfonate (nPMS) revealed that the isopropyl moiety avoids recognition by MGMT and leads to higher cytotoxicity. Next, the micronucleus (MN) assay showed that FANC deficiency increases the sensitivity of DT40 cells to MN induction by IPMS. Pretreatment with O6-benzyl guanine (OBG), an inhibitor of MGMT, increased the MN frequency in DT40 cells treated with nPMS, but not IPMS. Lastly, IPMS induced more double strand breaks in FANC-deficient cells compared to wild-type cells in a time-dependent manner. All together, these results suggest that IPMS-derived O6-isopropyl dG escapes recognition by MGMT, and the unrepaired DNA damage leads to double strand breaks, resulting in MN induction. FANC, therefore, plays a pivotal role in preventing MN induction and cell death caused by IPMS. PMID- 27486976 TI - Neuropilin-1 is a receptor for extracellular miRNA and AGO2/miRNA complexes and mediates the internalization of miRNAs that modulate cell function. AB - Extracellular miRNAs are increasingly studied as markers for specific diseases. They are released in biological fluids in a remarkably stable form, and may play a role in intercellular communication. They are thought to be protected against degradation by either encapsulation within microparticles, or by binding to proteins (mostly AGO2). The particulate forms may be internalized by endocytosis or membrane fusion, but the protein-bound forms require a receptor mechanism for their uptake. A major question is whether there are natural cell-membrane receptors that capture and internalize protein-bound functional miRNAs. We examined neuropilin-1 (NRP1), in view of its properties as a receptor for many ligands, including growth factors such as vascular endothelial growth factor (VEGF), and efficiency at mediating ligand internalization. It is expressed by endothelial cells, many other normal cell types, and cancer cells. Here, we report that NRP1 binds miRNAs with high affinity, and promotes their entry into the cell. Furthermore, the internalized miRNAs remain functional, as they specifically regulate proliferation and migration of cancer cells, as well as tube formation by human endothelial cells. Anti-NRP1 antibodies or NRP1 siRNA knockdown block miRNA effects, further confirming NRP1-mediated uptake. VEGF does not compete with miRNAs for binding to NRP1. In addition, NRP1 binds extracellular AGO2 (carrying miRNA or not), and internalizes AGO2/miRNA complexes. Because miRNA bound to AGO2 appears to the most abundant form in body fluids, this may have important physiological and pathological effects. PMID- 27486977 TI - Improved survival of patients with hepatocellular carcinoma and disparities by age, race, and socioeconomic status by decade, 1983-2012. AB - Hepatocellular carcinoma (HCC), accounting for the majority of liver cancer, is a highly aggressive malignancy with poor prognosis and therefore adds up the financial burden. Incidence data of HCC in three decades during 1983-2012 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database with incidence rates of 1.9, 3.1 and 4.9 per 100,000 respectively. In addition, to evaluate the survival changes in the same period, a total of 63,640 HCC cancer cases were accessed from SEER database. The six-month relative survival rates improved each decade from 31.0% to 42.9% to 57.2% and the higher increase can be seen in the last two decades. More importantly, the disparities of survival among different racial groups and socioeconomic status (SES) were confirmed by the inferiority of survival in Black race and high-poverty group respectively. This research analyzed the incidence and survival data of HCC in the past three decades and may help predict the future trends of incidence and survival. Furthermore, this study may help better design healthcare policies and clinical management programs to balance the disparities of survival between SES groups, races, ages and sexes confirmed in this study and thereby improve the clinical management of HCC. PMID- 27486978 TI - Metformin use and cervical cancer risk in female patients with type 2 diabetes. AB - This study evaluated whether metformin may affect the risk of cervical cancer. The reimbursement databases of the Taiwan's National Health Insurance were used. Female patients with type 2 diabetes at an onset age of 25-74 years during 1999 2005 and newly treated with metformin (n=132971, "ever users of metformin") or other antidiabetic drugs (n=6940, "never users of metformin") were followed for at least 6 months until December 31, 2011. The treatment effect of metformin (for ever versus never users, and for tertiles of cumulative duration of therapy) was estimated by Cox regression incorporated with the inverse probability of treatment weighting using propensity score. Analyses were also conducted in a 1:1 matched pair cohort based on 8 digits of propensity score. Results showed that the respective numbers of incident cervical cancer in ever users and never users were 438 (0.33%) and 38 (0.55%), with respective incidences of 68.29 and 121.38 per 100,000 person-years. The overall hazard ratio suggested a significantly lower risk in metformin users (0.558, 95% confidence intervals: 0.401-0.778). In tertile analyses, the hazard ratios (95% confidence intervals) for the first (<23.0 months), second (23.0-47.9 months) and third (>47.9 months) tertile of cumulative duration were 1.272 (0.904-1.790), 0.523 (0.366-0.747) and 0.109 (0.070-0.172), respectively. Findings were supported by the analyses in the matched cohort. In conclusion, metformin may significantly reduce the risk of cervical cancer, especially when the cumulative duration is more than 2 years. PMID- 27486980 TI - Association of lncRNA H19 rs217727 polymorphism and cancer risk in the Chinese population: a meta-analysis. AB - Reports on the relationship between the lncRNA H19 rs217727 polymorphism and the risk of cancer in the Chinese population have been inconsistent. Therefore, we performed a meta-analysis to evaluate this association, by searching the Embase, PubMed, Web of Science, Wanfang, and CNKI databases. Four case-control studies with 3,157 cases and 3,564 controls were selected for this meta-analysis. The odds ratios with 95% confidence intervals were examined using the random effect model. Allelic (A vs. G), dominant (AA + GA vs. GG), recessive (AA vs. GA + GG), and additive (AA vs. GG) genetic models were used to determine the association. Overall, no significant association was observed between the rs217727 polymorphism and cancer susceptibility in any of the four genetic models. Sensitivity analysis revealed that the results were stable in the allelic and dominant genetic models, but those from the recessive and additive models were unstable, which should be treated with caution. Our meta-analysis suggests that the lncRNA H19 rs217727 polymorphism might not be associated with overall cancer risk. However, well-designed, large-scale studies with different ethnic populations need to be conducted in the future to elucidate the potential association. PMID- 27486981 TI - Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features. AB - Clonal cytogenetic abnormalities are found in 20-30% of patients with chronic myelomonocytic leukemia (CMML), while gene mutations are present in >90% of cases. Patients with low risk cytogenetic features account for 80% of CMML cases and often fall into the low risk categories of CMML prognostic scoring systems, but the outcome differs considerably among them. We performed targeted deep sequencing of 83 myeloid-related genes in 56 CMML patients with low risk cytogenetic features or uninformative conventional cytogenetics (CC) at diagnosis, with the aim to identify the genetic characteristics of patients with a more aggressive disease. Targeted sequencing was also performed in a subset of these patients at time of acute myeloid leukemia (AML) transformation. Overall, 98% of patients harbored at least one mutation. Mutations in cell signaling genes were acquired at time of AML progression. Mutations in ASXL1, EZH2 and NRAS correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS). Patients with SRSF2 mutations associated with poorer OS, while absence of TET2 mutations (TET2wt) was predictive of shorter PFS. A decrease in OS and PFS was observed as the number of adverse risk gene mutations (ASXL1, EZH2, NRAS and SRSF2) increased. On multivariate analyses, CMML specific scoring system (CPSS) and presence of adverse risk gene mutations remained significant for OS, while CPSS and TET2wt were predictive of PFS. These results confirm that mutation analysis can add prognostic value to patients with CMML and low risk cytogenetic features or uninformative CC. PMID- 27486979 TI - Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk. AB - The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01 1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk. PMID- 27486982 TI - Oncostatin M suppresses metastasis of lung adenocarcinoma by inhibiting SLUG expression through coordination of STATs and PIASs signalings. AB - Oncostatin M (OSM) is linked with multiple biological responses including growth and differentiation. Previous reports showed inhibitory effects of OSM in tumor progression while others showed promoting effects. The dual role of OSM in the development of various cancers is still unclear. We previously described OSM mediated SLUG suppression, leading to repressed metastasis of lung adenocarcinoma (LAC) cells. However, the underlying mechanism remains elusive. Here, we showed that OSM suppresses SLUG express in LAC cells through a STAT1-dependent transcriptional inhibition. Knockdown of STAT1 reversed the OSM-suppressed SLUG expression and rescued the OSM-mediated inhibition of cell proliferation, migration, and invasion in vitro, as well as pulmonary metastasis in vivo. STAT1 suppressed SLUG transcription through binding to its promoter region in response to OSM. Furthermore, PIAS4, a co-repressor of STAT, and HDAC1 were able to bind to STAT1 on SLUG promoter region, resulting in reduced H3K9 acetylation and suppressed SLUG expression upon OSM treatment. In contrast, PIAS3 bound to activated STAT3, another effector of OSM, in response to OSM and blocked the binding of STAT3 to SLUG promoter region, preventing STAT3-dependent activation of SLUG transcription. Our findings suggested that OSM suppresses SLUG expression and tumor metastasis of LAC through inducing the inhibitory effect of the STAT1 dependent pathway and suppressing the activating effect of STAT3-dependent signaling. These results can serve as a scientific basis for the potential therapeutic intervention of OSM in cancer cells. PMID- 27486984 TI - Age is associated with time in therapeutic range for warfarin therapy in patients with atrial fibrillation. AB - BACKGROUND: Warfarin is the most prescribed oral anticoagulant used for preventing stroke in patients with atrial fibrillation. Time in the therapeutic range (TTR) has been accepted as the best method to evaluate the quality of warfarin therapy. The main aim of the present study was to evaluate the impact of variables on the time in the therapeutic range for warfarin therapy in patients with atrial fibrillation from a referral cardiovascular hospital. METHODS: This retrospective study included 443 patients were included (190 patients with age < 65 years and 253 patients with age >=65 years) from 2011 to 2014 and TTR was computed according to Rosendaal's method. RESULTS: Patients with age >=65 years had higher TTR value (67+/-22%) compared with patients with < 65 years (60+/-24%) (p = 0.004). In a linear regression model, only age >=65 years emerged as a significant predictor of greater TTR values. In multivariate logistic regression model, the variable age >=65 years was associated with higher OR for having a TTR higher than the median value (OR = 2.17, p < 0.001). CONCLUSION: We suggest that the age influenced TTR through greater drug adherence. Strategies for increasing drug adherence might improve quality of warfarin anticoagulation. PMID- 27486983 TI - Targeting signal transduction pathways of cancer stem cells for therapeutic opportunities of metastasis. AB - Tumor comprises of heterogeneous population of cells where not all the disseminated cancer cells have the prerogative and "in-build genetic cues" to form secondary tumors. Cells with stem like properties complemented by key signaling molecules clearly have shown to exhibit selective growth advantage to form tumors at distant metastatic sites. Thus, defining the role of cancer stem cells (CSC) in tumorigenesis and metastasis is emerging as a major thrust area for therapeutic intervention. Precise relationship and regulatory mechanisms operating in various signal transduction pathways during cancer dissemination, extravasation and angiogenesis still remain largely enigmatic. How the crosstalk amongst circulating tumor cells (CTC), epithelial mesenchymal transition (EMT) process and CSC is coordinated for initiating the metastasis at secondary tissues, and during cancer relapse could be of great therapeutic interest. The signal transduction mechanisms facilitating the dissemination, infiltration of CSC into blood stream, extravasations, progression of metastasis phenotype and angiogenesis, at distant organs, are the key pathologically important vulnerabilities being elucidated. Therefore, current new drug discovery focus has shifted towards finding "key driver genes" operating in parallel signaling pathways, during quiescence, survival and maintenance of stemness in CSC. Understanding these mechanisms could open new horizons for tackling the issue of cancer recurrence and metastasis-the cause of ~90% cancer associated mortality. To design futuristic & targeted therapies, we propose a multi-pronged strategy involving small molecules, RNA interference, vaccines, antibodies and other biotechnological modalities against CSC and the metastatic signal transduction cascade. PMID- 27486985 TI - Combination of specific allergen and probiotics induces specific regulatory B cells and enhances specific immunotherapy effect on allergic rhinitis. AB - The therapeutic efficacy of allergen specific immunotherapy (SIT) on allergic diseases is to be improved. Probiotics can regulate immune response. This study aims to promote the effect of SIT on allergic rhinitis (AR) by co-administration with Clostridium butyricum (Cb). In this study, patients with AR sensitized to mite allergens were enrolled to this study, and treated with SIT or/and Cb. The therapeutic efficacy was evaluated by the total nasal symptom scores (NSS), medication scores, serum specific IgE levels and T helper (Th)2 cytokine levels. The improvement of immune regulation in the AR patients was assessed by immunologic approaches. The results showed that treating AR patients with SIT alone markedly reduced NSS and medication scores; but did not alter the serum specific IgE, Th2 cytokines and skin prick test (SPT) index. The clinical symptoms on AR in SIT group relapsed one month after stopping SIT. Co administration of Cb significantly enhanced the efficacy of SIT on AR as shown by suppression of NSS, medication scores, serum specific IgE, Th2 cytokines and SPT index; the regulatory B cell frequency was also markedly increased. Such an effect on AR was maintained throughout the observation period even after stopping the treatment. Butyrate blocked the activation of histone deacetylase-1, the downstream activities of epsilon chain promoter activation, and the IgE production in the antigen specific B cells. On the other hand, butyrate induced the IL-10 expression in B cells with a premise of the B cell receptor activation by specific antigens. In conclusion, administration with Cb can markedly enhance the efficacy of SIT on AR. PMID- 27486986 TI - miRNA-193a-5p repression of p73 controls Cisplatin chemoresistance in primary bone tumors. AB - Osteosarcoma and Ewing Sarcoma are the two most common types of Bone Sarcomas, principally localized at the long bones of the extremities and mainly affecting adolescents and young adults. Cisplatin is one of the current options in the therapeutic arsenal of drugs available to cure these aggressive cancers. Unfortunately, chemoresistance against this agent is still a major cause of patient relapse. Thus, a better understanding of the molecular pathways by which these drugs induce cancer cell death, together with a better delineation of the origins of chemoresistance are required to improve the success rate of current treatments. Furthermore, as p53 is frequently mutated in Bone Sarcomas, other pathways in these cancers must mediate drug-induced cell death. Here, we demonstrate for the first time that TAp73beta, a p53-family protein, is implicated in Cisplatin-induced apoptosis of Bone Sarcomas'. Furthermore, while acquired resistance developed by cancer cells against such drugs can have multiple origins, it is now well accepted that epigenetic mechanisms involving microRNAs (miRNAs) are one of them. We show that miRNA-193a-5p modulates the viability, the clonogenic capacity and the Cisplatin-induced apoptosis of the Bone Sarcoma cells through inhibition of TAp73beta. Collectively, these results shed light on the involvement of miR-193a-5p in Cisplatin chemoresistance of Bone Sarcomas', and they open the road to new therapeutic opportunities provided by targeting the miR-193a-5p/TAp73beta axis in the context of these malignancies. PMID- 27486989 TI - The Associations of IL-6, IFN-gamma, TNF-alpha, IL-10, and TGF-beta1 Functional Variants with Acute Myeloid Leukemia in Turkish Patients. AB - AIM: It has been suggested that cytokine dysregulation could be associated with pathogenesis, progression, and survival in acute myeloid leukemia (AML). The purpose of this study was to evaluate the relationship of functional single nucleotide polymorphisms (SNPs) in cytokine gene and cytokine expression levels with AML. MATERIALS AND METHODS: Peripheral blood samples were collected from 42 patients with AML and 85 healthy individuals. Eight SNPs in five cytokine genes, including interleukin 6 (IL-6), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), and transforming growth factor beta 1 (TGF-beta1), were analyzed using the polymerase chain reaction sequence specific primer method. RESULTS: We found that the frequencies of the TNF-alpha ( 308) GG genotype and G allele were significantly higher in the patients with AML compared to the healthy control group (p = 0.020 and 0.014). The AML patients had significantly lower frequencies of the CC genotype and C allele of the IL-10 ( 819 SNP), the G allele of the IL-10 (-1082 SNP), the CC genotype and C allele of the IL-10 (-592 SNP), and the codon 25 GC genotype of TGF-beta1, (p = 0.024, p = 0.012, p = 0.038, p = 0.024, p = 0.012, p = 0.028, respectively). However, no significant differences were found between AML and healthy control groups with respect to the distributions of genotypes in IL-6, IFN-gamma, IL-10 (-1082), TGF beta1 (codon 10), and haplotypes of IL-10, TGF-beta1 gene. CONCLUSION: Our results suggest that functional variants of the TNF-alpha, IL-10, and TGF-beta1 genes may have a significant association with the etiopathogenesis of AML. Further studies with larger groups and different ethnicities are needed to determine the impact of cytokine variants on the risk of developing AML. PMID- 27486987 TI - Coexistence of JAK2 and CALR mutations and their clinical implications in patients with essential thrombocythemia. AB - Janus kinase 2 (JAK2) and calreticulin (CALR) constitute the two most frequent mutations in essential thrombocythemia (ET), and both are reported to be mutually exclusive. Hence, we examined a cohort of 123 myeloproliferative neoplasm (MPN) patients without BCR-ABL1 rearrangement and additional ET patients (n=96) for coexistence of JAK2 and CALR mutations. The frequency of CALR mutations was 20.3% in 123 MPN patients; 31.1% in ET (n=74), 25% in primary myelofibrosis (n=4) and 2.2% in polycythemia vera (n=45). JAK2 and CALR mutations coexisted in 7 (4.2%) of 167 ET patients. Clinical characteristics, progression-free survival (PFS), and elapsed time to achieve partial remission across 4 groups (JAK2+/CALR+, JAK2+/CALR-, JAK2-/CALR+, JAK2-/CALR-) were reviewed. The JAK2+/CALR- group had higher leukocyte counts and hemoglobin levels and more frequent thrombotic events than JAK2-/CALR- group. JAK2 mutations have a greater effect on the disease phenotype and the clinical features of MPN patients rather than do CALR mutation. JAK2+ groups showed a tendency of poor PFS than JAK2- groups regardless of CALR mutation. CALR+ was a predictor of late response to the treatment. Our study also showed that thrombosis was more frequent in ET patients with type 2 CALR mutations than in those with type 1 CALR mutations. PMID- 27486988 TI - Epigenetic reprogramming and aberrant expression of PRAME are associated with increased metastatic risk in Class 1 and Class 2 uveal melanomas. AB - BACKGROUND: We previously identified PRAME as a biomarker for metastatic risk in Class 1 uveal melanomas. In this study, we sought to define a threshold value for positive PRAME expression (PRAME+) in a large dataset, identify factors associated with PRAME expression, evaluate the prognostic value of PRAME in Class 2 uveal melanomas, and determine whether PRAME expression is associated with aberrant hypomethylation of the PRAME promoter. RESULTS: Among 678 samples analyzed by qPCR, 498 (73.5%) were PRAME- and 180 (26.5%) were PRAME+. Class 1 tumors were more likely to be PRAME-, whereas Class 2 tumors were more likely to be PRAME+ (P < 0.0001). PRAME expression was associated with shorter time to metastasis and melanoma specific mortality in Class 2 tumors (P = 0.01 and P = 0.02, respectively). In Class 1 tumors, PRAME expression was directly associated with SF3B1 mutations (P < 0.0001) and inversely associated with EIF1AX mutations (P = 0.004). PRAME expression was strongly associated with hypomethylation at 12 CpG sites near the PRAME promoter. MATERIALS AND METHODS: Analyses included PRAME mRNA expression, Class 1 versus Class 2 status, chromosomal copy number, mutation status of BAP1, EIF1AX, GNA11, GNAQ and SF3B1, and genomic DNA methylation status. Analyses were performed on 555 de-identified samples from Castle Biosciences, 123 samples from our center, and 80 samples from the TCGA. CONCLUSIONS: PRAME is aberrantly hypomethylated and activated in Class 1 and Class 2 uveal melanomas and is associated with increased metastatic risk in both classes. Since PRAME has been successfully targeted for immunotherapy, it may prove to be a companion prognostic biomarker. PMID- 27486990 TI - Host Nectin-1 Promotes Chlamydial Infection in the Female Mouse Genital Tract, but Is Not Required for Infection in a Novel Male Murine Rectal Infection Model. AB - Chlamydia trachomatis is the most common bacterial sexually transmitted pathogen, but more than 70% of patients fail to seek treatment due to the asymptomatic nature of these infections. Women suffer from numerous complications from chronic chlamydial infections, which include pelvic inflammatory disease and infertility. We previously demonstrated in culture that host cell nectin-1 knockdown significantly reduced chlamydial titers and inclusion size. Here, we sought to determine whether nectin-1 was required for chlamydial development in vivo by intravaginally infecting nectin-1-/- mice with Chlamydia muridarum and monitoring chlamydial shedding by chlamydial titer assay. We observed a significant reduction in chlamydial shedding in female nectin-1-/- mice compared to nectin 1+/+ control mice, an observation that was confirmed by PCR. Immunohistochemical staining in mouse cervical tissue confirmed that there are fewer chlamydial inclusions in Chlamydia-infected nectin-1-/- mice. Notably, anorectal chlamydial infections are becoming a substantial health burden, though little is known regarding the pathogenesis of these infections. We therefore established a novel male murine model of rectal chlamydial infection, which we used to determine whether nectin-1 is required for anorectal chlamydial infection in male mice. In contrast to the data from vaginal infection, no difference in rectal chlamydial shedding was observed when male nectin-1+/+ and nectin-1-/- mice were compared. Through the use of these two models, we have demonstrated that nectin-1 promotes chlamydial infection in the female genital tract but does not appear to contribute to rectal infection in male mice. These models could be used to further characterize tissue and sex related differences in chlamydial infection. PMID- 27486991 TI - Correlates of Concurrent Khat and Tobacco Use in Yemen. AB - BACKGROUND: Habitual substance use poses public health threat. This is a growing concern in countries where one or more substances are commonly used. Many individuals in Middle Eastern and East African countries use khat (Catha edulis), a stimulant often accompanied by smoking. However, few systematic attempts have been made to characterize patterns of concurrent khat and tobacco use. OBJECTIVES: To examine correlates such as gender and patterns of khat and tobacco use in concurrent users and khat-only users. METHODS: This study used a cross sectional design with a face-to-face interview method including 151 (74 women) concurrent users of khat and tobacco and 141 (76 women) khat-only users in Yemen. Data collection was completed in 2012. Analysis of variance (ANOVA) and logistic regressions were conducted to examine gender and khat use group differences in use patterns. RESULTS: Reported frequency and intensity of khat use were greater in men than in women. Men and women khat users used different tobacco products and beverages while using khat. Khat use was more frequent in concurrent users relative to khat-only users. Earlier age of onset of khat use was associated with greater number of cigarettes smoked during a typical khat session. Approximately 70% of concurrent users reported initiating khat use prior to tobacco use. Conclusions/Importance: The results provide support for gender differences in khat and tobacco use, differences in khat use pattern between concurrent users of khat and tobacco and khat-only users, and positive associations between khat and tobacco use. PMID- 27486992 TI - Salespeople in the Surgical Suite: Relationships between Surgeons and Medical Device Representatives. AB - BACKGROUND: Industry payments to surgeons have received public attention, but little is known about the relationships between surgeons and medical device representatives. Medical device representatives ("device reps") have become an integral part of operating room personnel. The effect of their presence on patient care deserves discussion. STUDY DESIGN: We conducted a qualitative, ethnographic study to explore relationships between surgeons and medical device representatives, and characterize industry involvement in the training of surgeons. We used group and individual open-ended interviews to gain insight into the beliefs, values, and perspectives of surgeons and device reps. We conducted two focus groups, one with ear, nose, and throat surgeons, and one with hospital based attending orthopedic surgeons. We also conducted individual interviews with three former or current medical device representatives, a director of a surgical residency program at an academic medical center, and a medical assistant for a multi-physician orthopedic practice. RESULTS: While surgeons view themselves as indisputably in charge, device reps work hard to make themselves unobtrusively indispensable in order to establish and maintain influence, and to imbue the products they provide with personalized services that foster a surgeon's loyalty to the reps and their companies. Surgeons view industry-funded training opportunities as a necessary service. Device reps and some surgeons believe that reps benefit patient care, by increasing efficiency and mitigating deficiencies among operating room personnel (including the surgeons themselves). CONCLUSIONS: Our study raises ethical questions about the reliance of surgeons on device reps and device companies for education and surgical assistance and practical concerns regarding existing levels of competence among OR personnel. PMID- 27486993 TI - Separation of Water from Ultralow Sulfur Diesel Using Novel Polymer Nanofiber Coated Glass Fiber Media. AB - Polymer nanofibers with interpenetrating network (IPN) morphology are used in this work for the development of composite, hydrophobic filter media in conjunction with glass fibers for removal of water droplets from ultralow sulfur diesel (ULSD). The nanofibers are produced from hydrophobic polyvinyl acetate (PVAc) and hydrophilic polyvinylpyrrolidone (PVP) by spinning the polymer solutions using gas jet fiber (GJF) method. The nanofibers coat the individual glass fibers due to polar-polar interactions during the spinning process and render the filter media highly hydrophobic with a water contact angle approaching 150 degrees . The efficiency of the resultant filter media is evaluated in terms of separation of water droplets of average size 20 MUm from the suspensions in ULSD. PMID- 27486994 TI - Guideline Adherence Regarding the Use of Expensive Drugs in Daily Practice: The Examples of Trastuzumab in Breast Cancer and Bortezomib in Multiple Myeloma. AB - BACKGROUND: The present study was designed to obtain insights into guideline adherence regarding the use of expensive drugs in The Netherlands in daily practice and into the patients' perspective on the decision-making process. MATERIAL AND METHODS: A retrospective review of medical charts regarding the use of trastuzumab in early and metastatic breast cancer (EBC/MBC) and bortezomib in multiple myeloma (MM) was conducted. Prescription according to clinical practice guidelines was assessed. The review was supplemented with patient interviews. RESULTS: Of 702 adjuvant-treated EBC patients, 97% had a documented human epidermal growth factor receptor 2 (HER2) testing (23% HER2 positive). 92% (147/160) of the HER2-positive EBC patients were treated with trastuzumab. Of 594 MBC patients, 81% had a documented HER2 testing (19% HER2 positive). 82% (75/91) of the HER2-positive MBC patients were treated with trastuzumab. Of 68 MM patients, 50% were treated with bortezomib. Reasons not to treat were consistent with the guidelines. Patients were generally satisfied with the decision-making process; improvements in patient education were suggested (e.g., repeating the information given, adding information on side effects). CONCLUSIONS: Guidelines were generally well followed with respect to trastuzumab and bortezomib, indicating that funding did not influence the treatment decisions of physicians. In view of the growing numbers of both cancer patients and expensive new anticancer drugs, and increasing budget constraints, it is unclear whether the present-day policies will guarantee a similar level of guideline adherence. Patient involvement in decision-making could be increased by improving the patient education on treatment. PMID- 27486995 TI - Early Cord Metabolite Index and Outcome in Perinatal Asphyxia and Hypoxic Ischaemic Encephalopathy. AB - BACKGROUND: A 1H-NMR-derived metabolomic index based on early umbilical cord blood alterations of succinate, glycerol, 3-hydroxybutyrate and O-phosphocholine has shown potential for the prediction of hypoxic-ischaemic encephalopathy (HIE) severity. OBJECTIVE: To evaluate whether this metabolite score can predict 3-year neurodevelopmental outcome in infants with perinatal asphyxia and HIE, compared with current standard biochemical and clinical markers. METHODS: From September 2009 to June 2011, infants at risk of perinatal asphyxia were recruited from a single maternity hospital. Cord blood was drawn and biobanked at delivery. Neonates were monitored for development of encephalopathy both clinically and electrographically. Neurodevelopmental outcome was assessed at 36-42 months using the Bayley Scales of Infant and Toddler Development, ed. III (BSID-III). Death and cerebral palsy were also considered as abnormal end points. RESULTS: Thirty one infants had both metabolomic analysis and neurodevelopmental outcome at 36-42 months. No child had a severely abnormal BSID-III result. The metabolite index significantly correlated with outcome (rho2 = 0.30, p < 0.01), which is robust to predict both severe outcome (area under the receiver operating characteristic curve: 0.92, p < 0.01) and intact survival (0.80, p = 0.01). There was no correlation between the index score and performance in the individual BSID-III subscales (cognitive, language, motor). CONCLUSIONS: The metabolite index outperformed other standard biochemical markers at birth for prediction of outcome at 3 years, but was not superior to EEG or the Sarnat score. PMID- 27486996 TI - Role of the Electrostatic Interactions in the Stabilization of Ionic Liquid Crystals: Insights from Coarse-Grained MD Simulations of an Imidazolium Model. AB - In order to investigate the role of the electrostatic interactions in stabilizing various phases of ionic liquids, especially smectic ionic liquid crystals, we have employed a coarse-grained model of 1-hexadecyl-3-methylimidazolium nitrate, [C16mim][NO3], to perform molecular dynamics simulations with the partial charges artificially rescaled by a factor from 0.7 to 1.2. The simulated systems have been characterized by means of orientational and translational order parameters and by distribution functions. We have found that increasing the total charge of the ions strongly stabilizes the ionic smectic phase by shifting the clearing point (melting into the isotropic liquid phase) to higher temperatures, while a smaller effect is observed on the stability of the crystal phase. Our results highlight the importance of the electrostatic interactions in promoting the formation of ionic liquid crystals through microphase segregation. Moreover, as the total charge of the model is increased, we observe a transformation from a homogeneous to a nanosegregated isotropic structure typical of ionic liquids. Therefore, a connection can be established between the degree of nanosegregation of ILs and the stability of ILC phases. All the above can be understood by the competition among electrostatic interactions between charged groups (cationic head groups and anions), van der Waals interactions between nonpolar cationic tail groups, and thermal fluctuations. PMID- 27486997 TI - Diversity of Bacterial Urine and Prostate Gland Tissue Cultures in Patients Undergoing Transurethral Prostate Gland Resection. AB - INTRODUCTION: The objective of this study was to identify the types of bacterial colonization of the prostate gland tissue and urine pre- and postoperatively in patients undergoing a transurethral resection (TUR) of the prostate gland. In addition, clinical symptoms and histopathological findings were included. MATERIAL AND METHODS: Forty three patients were investigated. Urine test strips and urine cultures were taken pre- and postoperatively and intraoperatively prostate resection chips were taken for culture. RESULTS: A positive bacterial culture was found in 20 of 43 (46.5%) patients. Preoperatively, a positive bacterial culture was found in 12 patients and postoperatively in 7 patients. Thirteen patients showed a positive culture of the prostate gland tissue. No patient showed the same bacterial isolates in all 3 samples. Postinterventionally, 6 patients of the group with positive bacterial cultures developed complications. From the group of patients without bacterial growth, only one patient developed a postoperative complication. CONCLUSION: The bacterial colonization in the 3 different cultures showed an inhomogeneous spectrum of bacteria without a reproducible pattern. Nevertheless, it clearly demonstrates that the group with a positive culture is at great risk to develop postoperative complications. PMID- 27486998 TI - Intracellular Availability of pDNA and mRNA after Transfection: A Comparative Study among Polyplexes, Lipoplexes, and Lipopolyplexes. AB - Intracellular availability of nucleic acids from synthetic vectors is critical and directly influences the transfection efficiency (TE). Herein, we evaluated the TE of polymer- and lipid-based nanoplexes (polyplexes, lipoplexes and lipopolyplexes) of EGFP-encoding mRNA and pDNA. To determine the translation and transcription efficiency of each nucleic acid nanoplex, in vitro expression was measured in HEK293T7 cells that permit gene expression in the cytoplasmic region. Globally, mRNA transfection profile was well corroborative with cytoplasmic transfection of pT7-pDNA as well as with nuclear transfection of pCMV-DNA. Irrespective of the nucleic acid, high TE was observed with histidinylated l polyethylenimine (His-lPEI) polyplexes and dioleyl succinyl paromomycin/O,O dioleyl-N-histamine phosphoramidate (DOPS/MM27) lipoplexes. Moreover, His-lPEI polyplexes yielded higher in vitro expression of EGFP for pDNA than for mRNA. Furthermore, a significant enhancement in the TE in the presence of an excess of His-lPEI was observed indicating that this polymer promotes cytosolic delivery. Compared to other nanoplexes, His-lPEI polyplex showed high intracellular availability of DNA and mRNA along with low cytotoxicity, owing to its rapid (complete or partial) unpacking in the cytosol and/or endosomes. This study gives an insight that, whether with mRNA or pDNA, enhancing nanoplex unpacking in the endosomes and cytosol would improve the delivery of nucleic acid in the cytosol and particularly in the case of pDNA where a sufficient available amount of pDNA in the cytoplasm would definitely improve its transport toward the nucleus. PMID- 27486999 TI - Correction: Detecting Causality by Combined Use of Multiple Methods: Climate and Brain Examples. AB - [This corrects the article DOI: 10.1371/journal.pone.0158572.]. PMID- 27487000 TI - The Use of Cognitive Cues for Anticipatory Strategies in a Dynamic Postural Control Task - Validation of a Novel Approach to Dual-Task Testing. AB - INTRODUCTION: Dual-task testing is relevant in the assessment of postural control. A combination of a primary (motor) and a secondary (distracting cognitive) tasks is most often used. It remains a challenge however, to standardize and monitor the cognitive task. In this study a new dual-task testing approach with a facilitating, rather than distracting, cognitive component was evaluated. METHODS: Thirty-one community-dwelling elderly and fifteen young people were tested with respect to their ability to use anticipatory postural control strategies. The motor task consisted of twenty-five repetitive tasks in which the participants needed to exceed their limit of stability in order to touch one out of eight lights. The participants performed three tests. In two of the tests the color cues of the lights allowed the participants to utilize cognitive strategies to plan their next movement and improve their performance time. RESULTS: The young performed the baseline motor task test in an average of 29 seconds, while the average time for the elderly was 44 seconds. When comparing the performance time with a leading cue to the time with no cue, the young group improved their performance time significantly better than the elderly did: young: 17% (5), elderly: 5% (8); p<0.001. Similar differences were seen with a more complicated leading cue: young: 12% (5), elderly: 4% (9); p<0.01. The reliability of the test showed moderate to substantial agreement (ICC = 0.74), with a small learning effect between two sessions. CONCLUSION: The dual-task test was sensitive enough to discriminate between elderly and young people. It revealed that the elderly did not utilize cognitive cues for their anticipatory postural control strategies as well as the young were able to. The test procedure was feasible and comprehensible for the participants, and it may be relevant to standardize a similar test for an alternative dual-task approach in the clinical setting. PMID- 27487001 TI - Hemodiafiltration Decreases Serum Levels of Inflammatory Mediators in Severe Leptospirosis: A Prospective Study. AB - BACKGROUND: Leptospirosis is a health problem worldwide. Its most severe form is a classic model of sepsis, provoking acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), with associated mortality that remains unacceptably high. We previously demonstrated that early initiation of sustained low-efficiency dialysis (SLED) followed by daily SLED significantly decreases mortality. However, the mode of clearance can also affect dialysis patient outcomes. Therefore, the objective of this study was to compare the effects of SLED with traditional (diffusive) clearance, via hemodialysis, and SLED with convective clearance, via hemodiafiltration (SLEDf), in patients with severe leptospirosis. METHODS: In this prospective study, conducted in the intensive care unit (ICU) from 2009 through 2012, we compared two groups-SLED (n = 19) and SLEDf (n = 20)-evaluating demographic, clinical, and biochemical parameters, as well as serum levels of interleukins, up to the third day after admission. All patients received dialysis early and daily thereafter. RESULTS: During the study period, 138 patients were admitted to our ICU with a diagnosis of leptospirosis; 39 (36 males/3 females) met the criteria for ARDS and AKI. All patients were on mechanical ventilation and were comparable in terms of respiratory parameters. Mortality did not differ between the SLEDf and SLED groups. However, post admission decreases in the serum levels of interleukin (IL)-17, IL-7, and monocyte chemoattractant protein-1 were significantly greater in the SLEDf group. Direct bilirubin and the arterial oxygen tension/fraction of inspired oxygen ratio were significantly higher in the SLED group. We identified the following risk factors (sensitivities/specificities) for mortality in severe leptospirosis: age >= 55 years (67%/91%); serum urea >= 204 mg/dl (100%/70%); creatinine >= 5.2 mg/dl (100%/58%); Acute Physiology and Chronic Health Evaluation II score >= 39.5 (67%/88%); Sequential Organ Failure Assessment score >= 20.5 (67%/85%); and inspiratory pressure >= 31 mmHg (84%/85%). CONCLUSIONS: The mode of dialysis clearance might not affect outcomes in severe leptospirosis. PMID- 27487002 TI - Association between X-Ray Repair Cross-Complementing Group 1 Arg399Gln Polymorphism and Cervical Cancer Risk: A Meta-Analysis in the Chinese Population. AB - BACKGROUND: Many studies have examined the association of X-ray repair cross complementing group 1 (XRCC1) Arg399Gln polymorphism with cervical cancer susceptibility. However, the results of these studies are inconsistent. To further assess the effects of XRCC1 Arg399Gln polymorphism on the risk of cervical cancer in the Chinese population, a meta-analysis was performed. METHODS: Relevant studies were identified using PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure, and Chinese Biology Medicine through December 2015. Pooled ORs and 95% CIs were used to assess the strength of the associations. RESULTS: This meta-analysis identified 7 studies, including 1,589 cases and 2,235 controls. In the total analyses, a significantly elevated risk of cervical cancer was associated with variants of XRCC1 Arg399Gln (GA vs. GG: OR 1.30, 95% CI 1.13 1.49; AA + GA vs. GG: OR 1.27, 95% CI 1.02-1.58). In the subgroup analyses stratified by geographic areas and histopathology type, it revealed the significant result in South China. CONCLUSIONS: This meta-analysis showed that the XRCC1 Arg399Gln GA variant might be risk alleles for cervical cancer susceptibility in the Chinese population, and further studies in other ethnic groups are required to arrive at definite conclusions. PMID- 27487003 TI - The Effect of Background Music in Shark Documentaries on Viewers' Perceptions of Sharks. AB - Despite the ongoing need for shark conservation and management, prevailing negative sentiments marginalize these animals and legitimize permissive exploitation. These negative attitudes arise from an instinctive, yet exaggerated fear, which is validated and reinforced by disproportionate and sensationalistic news coverage of shark 'attacks' and by highlighting shark-on-human violence in popular movies and documentaries. In this study, we investigate another subtler, yet powerful factor that contributes to this fear: the ominous background music that often accompanies shark footage in documentaries. Using three experiments, we show that participants rated sharks more negatively and less positively after viewing a 60-second video clip of swimming sharks set to ominous background music, compared to participants who watched the same video clip set to uplifting background music, or silence. This finding was not an artifact of soundtrack alone because attitudes toward sharks did not differ among participants assigned to audio-only control treatments. This is the first study to demonstrate empirically that the connotative attributes of background music accompanying shark footage affect viewers' attitudes toward sharks. Given that nature documentaries are often regarded as objective and authoritative sources of information, it is critical that documentary filmmakers and viewers are aware of how the soundtrack can affect the interpretation of the educational content. PMID- 27487004 TI - Selective Serotonin Reuptake Inhibitors Decrease Pancreatic Insulin Secretion in Older Adults and Increase the Risk of Insulin Dependence in Type 2 Diabetes Patients. AB - OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) may decrease insulin secretion, but evidence from population studies is scarce. We investigated the association between SSRIs and markers for glucose-insulin homeostasis in a nondiabetic older population. Furthermore, we studied the association between SSRI use and insulin dependence in a diabetic population of older adults. METHODS: This study was embedded in the prospective population-based Rotterdam Study cohort (1991-2012). In nondiabetic participants, fasting glucose and insulin levels and the homeostasis model assessment for insulin sensitivity and secretion were compared between participants using SSRIs and participants using no antidepressant. In diabetic patients using oral glucose-lowering agents, the risk of insulin dependence, defined as the start of insulin treatment, was compared between participants using SSRIs and participants using no antidepressant. RESULTS: In nondiabetic participants, SSRI users (n = 87) had, compared with participants using no antidepressants (n = 5,505), a significantly (P < .05) lower level of insulin (8.8 mU/L and 9.9 mU/L, respectively), a lower degree of insulin resistance (2.2% and 2.4%, respectively), and less insulin secretion (89.1% and 100.4%, respectively), but a similar glucose level. Furthermore, > 90 days of consecutive use of SSRIs in diabetic patients was associated with a 2.17 times higher risk (95% confidence interval, 1.02-4.60) of starting insulin treatment than that of participants using no antidepressants. CONCLUSIONS: Use of SSRIs was associated with lower insulin secretion in nondiabetic participants and an increased risk of insulin dependence in type 2 diabetics in older adults. However, additional studies are required to confirm our results. PMID- 27487005 TI - Mathematical modelling as a tool to assessment of loads in volleyball player's shoulder joint during spike. AB - This article deals with kinematic and kinetic conditions in volleyball attack and identifies loads in the shoulder joint. Joint angles and velocities of individual segments of upper limb were measured with the use of the motion capture system XSENS. Muscle forces and loads in skeletal system were calculated by means of mathematical model elaborated in AnyBody system. Spikes performed by players in the best and worst way were compared with each other. The relationships were found between reactions in shoulder joint and flexion/extension, abduction/adduction and rotation angles in the same joint and flexion/extension in the elbow joint. Reactions in shoulder joint varied from 591 N to 2001 N (in relation to body weight [BW] 83-328%). The analysis proved that hand velocity at the moment of the ball hit (which varied between 6.8 and 13.3 m s-1) influences on the value of reaction in joints, but positions of individual segments relative to each other are also crucial. It was also proved in objective way, that position of the upper limb during spike can be more or less harmful assuming that bigger reaction increases possibility of injury, what can be an indication for trainers and physiotherapists how to improve injury prevention. PMID- 27487006 TI - Changes in Disparity in County-Level Diagnosed Diabetes Prevalence and Incidence in the United States, between 2004 and 2012. AB - BACKGROUND: In recent decades, the United States experienced increasing prevalence and incidence of diabetes, accompanied by large disparities in county level diabetes prevalence and incidence. However, whether these disparities are widening, narrowing, or staying the same has not been studied. We examined changes in disparity among U.S. counties in diagnosed diabetes prevalence and incidence between 2004 and 2012. METHODS: We used 2004 and 2012 county-level diabetes (type 1 and type 2) prevalence and incidence data, along with demographic, socio-economic, and risk factor data from various sources. To determine whether disparities widened or narrowed over the time period, we used a regression-based beta-convergence approach, accounting for spatial autocorrelation. We calculated diabetes prevalence/incidence percentage point (ppt) changes between 2004 and 2012 and modeled these changes as a function of baseline diabetes prevalence/incidence in 2004. Covariates included county-level demographic and, socio-economic data, and known type 2 diabetes risk factors (obesity and leisure-time physical inactivity). RESULTS: For each county-level ppt increase in diabetes prevalence in 2004 there was an annual average increase of 0.02 ppt (p<0.001) in diabetes prevalence between 2004 and 2012, indicating a widening of disparities. However, after accounting for covariates, diabetes prevalence decreased by an annual average of 0.04 ppt (p<0.001). In contrast, changes in diabetes incidence decreased by an average of 0.04 ppt (unadjusted) and 0.09 ppt (adjusted) for each ppt increase in diabetes incidence in 2004, indicating a narrowing of county-level disparities. CONCLUSIONS: County-level disparities in diagnosed diabetes prevalence in the United States widened between 2004 and 2012, while disparities in incidence narrowed. Accounting for demographic and, socio-economic characteristics and risk factors for type 2 diabetes narrowed the disparities, suggesting that these factors are strongly associated with changes in disparities. Public health interventions that target modifiable risk factors, such as obesity and physical inactivity, in high burden counties might further reduce disparities in incidence and, over time, in prevalence. PMID- 27487007 TI - High-Throughput, Automated Protein A Purification Platform with Multiattribute LC MS Analysis for Advanced Cell Culture Process Monitoring. AB - The levels of many product related variants observed during the production of monoclonal antibodies are dependent on control of the manufacturing process, especially the cell culture process. However, it is difficult to characterize samples pulled from the bioreactor due to the low levels of product during the early stages of the process and the high levels of interfering reagents. Furthermore, analytical results are often not available for several days, which slows the process development cycle and prevents "real time" adjustments to the manufacturing process. To reduce the delay and enhance our ability to achieve quality targets, we have developed a low-volume, high-throughput, and high content analytical platform for at-line product quality analysis. This workflow includes an automated, 96-well plate protein A purification step to isolate antibody product from the cell culture fermentation broth, followed by rapid, multiattribute LC-MS analysis. We have demonstrated quantitative correlations between particular process parameters with the levels of glycosylated and glycated species in a series of small scale experiments, but the platform could be used to monitor other attributes and applied across the biopharmaceutical industry. PMID- 27487008 TI - Synthesis of C60-Fused Tetrahydrocarbazole/Dibenzothiophene/Benzothiophene and Dibenzofuran Derivatives via Metal-Free Oxidative Dehydrogenative Carboannulation. AB - A transition-metal-free oxidative dehydrogenative coupling reaction has been developed for the direct construction of novel C60-fused tetrahydrocarbazoles, dibenzothiophenes, benzothiophenes, and dibenzofurans. This new carboannulation reaction features high atom economy, operational simplicity, broad substrate scope, and excellent functional-group tolerance and provides a convenient access to a scarce class of fullerene derivatives. PMID- 27487009 TI - Oral Health Status Is Associated with Common Medical Comorbidities in Older Hospital Inpatients. AB - OBJECTIVES: To investigate oral health status and abnormalities in older adults admitted acutely to the hospital and explore the association with common medical comorbidities. DESIGN: Cross-sectional study. SETTING: Hospital. PARTICIPANTS: All individuals aged 70 and older (mean age 84.4, 61.4% female) admitted to a geriatric service over 3 months (N = 202). MEASUREMENTS: In-person assessment using the Oral Health Assessment Tool (OHAT) (range 0-2, 2 = poorest) for lips, tongue, gums and soft tissue, saliva, teeth, dentures, oral cleanliness, and dental pain. Comorbidities and medications were also recorded. RESULTS: One hundred twenty-eight (63%) participants had full or partial dentures, and 31 (15%) were edentulous. Median OHAT score was 6 (interquartile range 5-8). Of the eight domains, saliva scored worst, with 53% scoring 2. On univariate analysis, the highest (poorest) tertile of OHAT (score >=8) was associated with dementia (odds ratio (OR) = 2.41, 95% confidence interval (CI) = 1.13-5.12, P = .02), moderate to severe renal impairment (estimated glomerular filtration rate <30 mL/min per 1.73 m(2) at discharge) (OR = 5.52, 95% CI = 1.54-19.69, P = .009), recent anticholinergic medication burden (P = .02), and low oral pH (P = .05). On multivariate analysis adjusted for oral pH and anticholinergic medication burden, dementia (OR = 2.29, P = .02) and moderate to severe renal impairment (OR = 5.64, P = .01) were independently associated with the highest tertile of OHAT. Charlson Comorbidity Index (includes renal disease, dementia) was associated with OHAT on univariate analysis (Spearman rho = 0.19, P = .01) but not when adjusted for oral pH (P = .10). CONCLUSION: Poorer oral health was not uncommon and was associated with dementia and renal impairment even after adjustment for anticholinergic medication and oral pH. Oral health screening should be considered for vulnerable populations. PMID- 27487010 TI - Decomposition nitrogen is better retained than simulated deposition from mineral amendments in a temperate forest. AB - Nitrogen (N) deposition (NDEP ) drives forest carbon (C) sequestration but the size of this effect is still uncertain. In the field, an estimate of these effects can be obtained by applying mineral N fertilizers over the soil or forest canopy. A 15 N label in the fertilizer can be then used to trace the movement of the added N into ecosystem pools and deduce a C effect. However, N recycling via litter decomposition provides most of the nutrition for trees, even under heavy NDEP inputs. If this recycled litter nitrogen is retained in ecosystem pools differently to added mineral N, then estimates of the effects of NDEP on the relative change in C (?C/?N) based on short-term isotope-labelled mineral fertilizer additions should be questioned. We used 15 N labelled litter to track decomposed N in the soil system (litter, soils, microbes, and roots) over 18 months in a Sitka spruce plantation and directly compared the fate of this 15 N to an equivalent amount in simulated NDEP treatments. By the end of the experiment, three times as much 15 N was retained in the O and A soil layers when N was derived from litter decomposition than from mineral N additions (60% and 20%, respectively), primarily because of increased recovery in the O layer. Roots expressed slightly more 15 N tracer from litter decomposition than from simulated mineral NDEP (7.5% and 4.5%) and compared to soil recovery, expressed proportionally more 15 N in the A layer than the O layer, potentially indicating uptake of organic N from decomposition. These results suggest effects of NDEP on forest ?C/?N may not be apparent from mineral 15 N tracer experiments alone. Given the importance of N recycling, an important but underestimated effect of NDEP is its influence on the rate of N release from litter. PMID- 27487011 TI - Surface-Based fMRI-Driven Diffusion Tractography in the Presence of Significant Brain Pathology: A Study Linking Structure and Function in Cerebral Palsy. AB - Diffusion MRI (dMRI) tractography analyses are difficult to perform in the presence of brain pathology. Automated methods that rely on cortical parcellation for structural connectivity studies often fail, while manually defining regions is extremely time consuming and can introduce human error. Both methods also make assumptions about structure-function relationships that may not hold after cortical reorganisation. Seeding tractography with functional-MRI (fMRI) activation is an emerging method that reduces these confounds, but inherent smoothing of fMRI signal may result in the inclusion of irrelevant pathways. This paper describes a novel fMRI-seeded dMRI-analysis pipeline based on surface meshes that reduces these issues and utilises machine-learning to generate task specific white matter pathways, minimising the requirement for manually-drawn ROIs. We directly compared this new strategy to a standard voxelwise fMRI-dMRI approach, by investigating correlations between clinical scores and dMRI metrics of thalamocortical and corticomotor tracts in 31 children with unilateral cerebral palsy. The surface-based approach successfully processed more participants (87%) than the voxel-based approach (65%), and provided significantly more-coherent tractography. Significant correlations between dMRI metrics and five clinical scores of function were found for the more superior regions of these tracts. These significant correlations were stronger and more frequently found with the surface-based method (15/20 investigated were significant; R2 = 0.43-0.73) than the voxelwise analysis (2 sig. correlations; 0.38 & 0.49). More restricted fMRI signal, better-constrained tractography, and the novel track-classification method all appeared to contribute toward these differences. PMID- 27487012 TI - Ozone mediators effect on "in vitro" scratch wound closure. AB - The beneficial effect of low doses of ozone on wound healing has been well documented and attributed mainly to its bactericidal and pro-oxidant properties. Because ozone itself does not penetrate the cells but immediately reacts with polyunsaturated fatty acids, its effects are the results of oxidative mediators. Among the molecule produces by the interaction of ozone with biological systems, there are HNE and H2O2. At today, the cellular mechanisms accounting for the positive effects of mild ozonization on wound closure are still largely unexplored. The aim of the present study was to evaluate the effect of different non-toxic doses of ozonated saline ranging from 2 to 300 MUM, in an in vitro wound scratch model by the use of human keratinocytes. The results showed that ozonated saline is able to improve in vitro wound healing by stimulating cell proliferation as measured by BrdU assay and PCNA protein levels. In order to better elucidate the molecules that play the main role in the beneficial effect of ozonated saline in wound healing, HNE and H2O2 were used alone or in combination to mimic ozonated saline effect. Surprisingly, keratinocytes treated with different doses of HNE and H2O2 did not significantly improve the wound closure, while the combination of the two compounds was able to improve wound closure. In addition, Nrf2 pathways were also activated as determined by its translocation to the nucleus and the increased HO1 gene expression. The present work suggests that ozonated saline effect on wound closure is the results of the combination of more molecules among which HNE and H2O2 play a key role. PMID- 27487013 TI - Contemporary methodological issues in drug development: the functionality of blinding is poorly studied. AB - Blinding is an important methodological principle in drug development. This article reviews the functionality of blinding within the context of bias minimizing structures of randomized clinical trials. Blinding is not well understood and not well studied. The risk of bias domain 'blinding' is commonly assumed to be 'low-risk' whenever readers come across randomized clinical trials labeled as 'blinded'. However, empirical evidence has shown that this assumption cannot be taken for granted. The functionality of blinding techniques in preventing bias requires further studies. PMID- 27487014 TI - High temperature homogenization improves impact toughness of vitamin E-diffused, irradiated UHMWPE. AB - Diffusion of vitamin E into radiation cross-linked ultrahigh molecular weight polyethylene (UHMWPE) is used to increase stability against oxidation of total joint implant components. The dispersion of vitamin E throughout implant preforms has been optimized by a two-step process of doping and homogenization. Both of these steps are performed below the peak melting point of the cross-linked polymer (<140 degrees C) to avoid loss of crystallinity and strength. Recently, it was discovered that the exposure of UHMWPE to elevated temperatures, around 300 degrees C, for a limited amount of time in nitrogen, could improve the toughness without sacrificing wear resistance. We hypothesized that high temperature homogenization of antioxidant-doped, radiation cross-linked UHMWPE could improve its toughness. We found that homogenization at 300 degrees C for 8 h resulted in an increase in the impact toughness (74 kJ/m2 compared to 67 kJ/m2 ), the ultimate tensile strength (50 MPa compared to 43 MPa) and elongation at break (271% compared to 236%). The high temperature treatment did not compromise the wear resistance or the oxidative stability as measured by oxidation induction time. In addition, the desired homogeneity was achieved at a much shorter duration (8 h compared to >240 h) by using high temperature homogenization. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1343-1347, 2017. PMID- 27487015 TI - All-Trans Retinoic Acid-Induced Craniofacial Malformation Model: A Prenatal and Postnatal Morphological Analysis. AB - OBJECTIVE: To characterize the prenatal and postnatal craniofacial bone development in mouse model of all-trans retinoic acid (ATRA) exposure at different ages by a quantitative and morphological analysis of skull morphology. METHODS: Pregnant mice were exposed to ATRA at embryonic day 10 (E10) and 13 (E13) by oral gavage. Skulls of mice embryos at E19.5 and adult mice at postnatal day 35 (P35) were collected for high-resolution microcomputed tomography (microCT) imaging scanning and section HE staining. Reconstruction and measurement of mouse skulls were performed for prenatal and postnatal analysis of the control and ATRA-exposed mice. RESULTS: Craniofacial malformations in mouse models caused by ATRA exposure were age dependent. ATRA exposure at E10 induced cleft palate in 81.8% of the fetuses, whereas the palatine bone of E13-exposed mice was intact. Inhibitions of maxilla and mandible development with craniofacial asymmetry induced were observed at E19.5 and P35. Compared with control and E13-exposed mice, the palatine bones of E10-exposed mice were not elevated and were smaller in dimension. Some E10-exposed mice exhibited other craniofacial abnormalities, including premature fusion of mandibular symphysis with a missing mandibular incisor and a smaller mandible. Severe deviated snouts and amorphous craniofacial suture were detected in E13-exposed mice at P35. CONCLUSION: These morphological variations in E10- and E13-exposed mice suggested that ATRA was teratogenic in craniofacial bone development in mice and the effect was age dependent. PMID- 27487016 TI - Incidence and Mortality of Solid Cancers in People Exposed In Utero to Ionizing Radiation: Pooled Analyses of Two Cohorts from the Southern Urals, Russia. AB - BACKGROUND: Previous studies have shown that acute external in utero exposure to ionizing radiation can increase cancer risk. It is not known whether chronic exposure at low dose rates, including due to radionuclide intake, influences the lifetime risk of solid cancers in the offspring. The objective of this study was to investigate solid cancer risk after in utero irradiation. METHODS: Cancer incidence and mortality over a 60-year period (from January 1950 to December 2009) were analyzed in the Urals Prenatally Exposed Cohort (UPEC). The cohort comprised in utero exposed offspring of Mayak Production Association female workers and of female residents of Techa River villages. Some of the offspring also received postnatal exposure, either due to becoming radiation workers themselves or due to continuing to live in the contaminated areas of the Techa River. The mortality analyses comprised 16,821 subjects (601,372 person-years), and the incidence analyses comprised 15,813 subjects (554,411 person-years). Poisson regression was used to quantify the relative risk as a function of the in utero soft tissue dose (with cumulative doses up to 944.9 mGy, mean dose of 14.1 mGy in the pooled cohort) and the postnatal stomach dose for solid cancer incidence and mortality. RESULTS: When a log-linear model was used, relative risk of cancer per 10 mGy of in utero dose was 0.99 (95% confidence interval (CI) = 0.96 to 1.01) based on incidence data and 0.98 (CI = 0.94 to 1.01) based on mortality data. Postnatal exposure to ionizing radiation was positively associated with the solid cancer risk in members of the UPEC, with a relative risk of 1.02 per 10mGy CI = 1.00 to 1.04). CONCLUSIONS: No strong evidence was found that chronic low-dose-rate exposure of the embryo and fetus increased the risk of solid cancers in childhood or in adulthood. For both incidence and mortality, a tendency towards a decreased relative risk was noted with increasing doses to soft tissues of the fetus. Further follow-up will provide more precise radiation risk estimates of solid cancer as cohort members are approaching their 60s and cancer becomes more common. PMID- 27487017 TI - Polyglandular endocrinopathy type II (Schmidt's syndrome) in a Dobermann pinscher. AB - A three-year-old, female neutered, Dobermann pinscher was presented for investigation of lethargy, episodic collapse, ataxia and myxoedema. Primary hypothyroidism and primary cortisol-deficient hypoadrenocorticism were diagnosed based on history, physical examination and compatible hormonal analysis. Increased serum concentrations of thyroglobulin autoantibodies and 21-hydroxylase autoantibodies indicated an immune-mediated aetiology. The case was complicated by lymphadenopathy with hand-mirror lymphocytes, classically identified in lymphoma. A polymerase chain reaction test for antigen receptor rearrangement indicated polyclonality and therefore reactive lymphadenopathy. The dog's clinical signs resolved following introduction of levothyroxine and prednisolone. Prioritising the problem-based approach in this case facilitated the diagnosis of hypoadrenocorticism in addition to hypothyroidism due to the persistence of clinical signs despite thyroxine replacement. Importantly, atypical adrenal gland dysfunction was not misinterpreted as inadequate therapeutic response to thyroxine supplementation. The observation that polyglandular endocrinopathy type II can occur in dogs suggests that in dogs with a suboptimal response to treatment for hypothyroidism or hypoadrenocorticism comorbid endocrinopathies should be investigated. PMID- 27487018 TI - Factors Influencing the Timeliness of Emergency Medical Service Response to Time Critical Emergencies. AB - OBJECTIVE: While emergency medical service (EMS) response times (ERT) remain a leading measure of system performance in many developed countries, relatively few studies have explored the factors associated with meeting benchmark performance for potentially time critical incidents. The purpose of this study was to identify system-level and patient-level factors associated with ERT, which are readily available at the time of ambulance dispatch. METHODS: Between July 2009 and June 2014, we included data from 1,000,458 EMS responses to time critical "lights and sirens" incidents in Melbourne, Australia. The primary outcome measure was ERT, defined as the time from emergency call to the arrival of the first EMS team on scene. Quantile regression models were used to identify system level and patient-level factors associated with 10-percentile intervals of ERT. RESULTS: The median ERT was 10.6 minutes (IQR: 8.1-14.0), increasing from 9.6 minutes (IQR: 7.6-12.5) in 2009/10 to 11.0 minutes (IQR: 8.4-14.7) in 2013/14 (p < 0.001). System-level factors independently associated with the 90th percentile ERT were distance to scene, activation time, turnout time, case upgrade, hour of day, day of week, workload in the previous hour, ambulance skill set, priority zero case (e.g., suspected cardiac or respiratory arrest), and average hospital delay time in the previous hour. Patient-level factors such as age, gender, chief medical complaint, and severity of complaint were also significantly associated with ERT. CONCLUSIONS: System-level and patient-level factors available at the time of ambulance dispatch are useful predictors of ERT performance, which could be used to improve the timeliness of EMS response. PMID- 27487019 TI - Cryptic, Sympatric Diversity in Tegu Lizards of the Tupinambis teguixin Group (Squamata, Sauria, Teiidae) and the Description of Three New Species. AB - Tegus of the genera Tupinambis and Salvator are the largest Neotropical lizards and the most exploited clade of Neotropical reptiles. For three decades more than 34 million tegu skins were in trade, about 1.02 million per year. The genus Tupinambis is distributed in South America east of the Andes, and currently contains four recognized species, three of which are found only in Brazil. However, the type species of the genus, T. teguixin, is known from Bolivia, Brazil, Colombia, Ecuador, French Guyana, Guyana, Peru, Suriname, Trinidad and Tobago, and Venezuela (including the Isla de Margarita). Here we present molecular and morphological evidence that this species is genetically divergent across its range and identify four distinct clades some of which are sympatric. The occurrence of cryptic sympatric species undoubtedly exacerbated the nomenclatural problems of the past. We discuss the species supported by molecular and morphological evidence and increase the number of species in the genus Tupinambis to seven. The four members of the T. teguixin group continue to be confused with Salvator merianae, despite having a distinctly different morphology and reproductive mode. All members of the genus Tupinambis are CITES Appendix II. Yet, they continue to be heavily exploited, under studied, and confused in the minds of the public, conservationists, and scientists. PMID- 27487020 TI - The Effectiveness of Bacteriophages against Methicillin-Resistant Staphylococcus aureus ST398 Nasal Colonization in Pigs. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important colonizer in animals and an opportunistic pathogen in humans. In humans, MRSA can cause infections that might be difficult to treat because of antimicrobial resistance. The use of bacteriophages has been suggested as a potential approach for the control of MRSA colonization to minimize the-often occupational-exposure of humans. The aim of this study was to assess the efficacy of bacteriophage treatment on porcine nasal colonization with MRSA in vitro, in vivo, and ex vivo. The effectiveness of a bacteriophage combination of phage K*710 and P68 was assessed in vitro by incubating them with MRSA V0608892/1 (ST398) measuring the OD600 hourly. To study the in vivo effect, bacteriophages were administered in a gel developed for human application, which contain 109 plaque-forming units (pfu)/mL (K and P68 in a 19.25:1 ratio) for 5 days to piglets (N = 8) that were experimentally colonized with the MRSA strain. Eight piglets experimentally colonized were used as a negative control. The MRSA strain was also used to colonize porcine nasal mucosa explants and bacteriophages were applied to assess the ex vivo efficacy of treatment. Bacteriophages were effective in vitro. In vivo, sixteen piglets were colonized with MRSA but the number of CFU recovered after the application of the bacteriophages in 8 piglets was not reduced compared to the control animals (approx. 105 CFU/swab). In the ex vivo model, 108 CFU were used to establish colonization with MRSA; a reduction of colonization was not observed after application of bacteriophages. However, application of mupirocin both in vivo and ex vivo resulted in a near eradication of MRSA. IN CONCLUSION: i) The MRSA strain was killed in the presence of the bacteriophages phage K*710 and P68 in vitro. ii) Bacteriophages did not reduce porcine nasal colonization in vivo or ex vivo. Physiological in vivo and ex vivo conditions may explain these observations. Efficacy in the ex vivo model matched that of the in vivo system. PMID- 27487026 TI - A Molecular Rotor that Measures Dynamic Changes of Lipid Bilayer Viscosity Caused by Oxidative Stress. AB - Oxidation of cellular structures is typically an undesirable process that can be a hallmark of certain diseases. On the other hand, photooxidation is a necessary step of photodynamic therapy (PDT), a cancer treatment causing cell death upon light irradiation. Here, the effect of photooxidation on the microscopic viscosity of model lipid bilayers constructed of 1,2-dioleoyl-sn-glycero-3 phosphocholine has been studied. A molecular rotor has been employed that displays a viscosity-dependent fluorescence lifetime as a quantitative probe of the bilayer's viscosity. Thus, spatially-resolved viscosity maps of lipid photooxidation in giant unilamellar vesicles (GUVs) were obtained, testing the effect of the positioning of the oxidant relative to the rotor in the bilayer. It was found that PDT has a strong impact on viscoelastic properties of lipid bilayers, which 'travels' through the bilayer to areas that have not been irradiated directly. A dramatic difference in viscoelastic properties of oxidized GUVs by Type I (electron transfer) and Type II (singlet oxygen-based) photosensitisers was also detected. PMID- 27487027 TI - Lipid lowering: PCSK9 inhibitors - new kids on the block target their breakthrough. PMID- 27487028 TI - Effects of Conjugated Linoleic Acid Associated With Endurance Exercise on Muscle Fibres and Peroxisome Proliferator-Activated Receptor gamma Coactivator 1 alpha Isoforms. AB - Conjugated linoleic acid (CLA) has been reported to improve muscle hypertrophy, steroidogenesis, physical activity, and endurance capacity in mice, although the molecular mechanisms of its actions are not completely understood. The aim of the present study was to identify whether CLA alters the expression of any of the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC1alpha) isoforms, and to evaluate the possible existence of fibre-type-specific hypertrophy in the gastrocnemius and plantaris muscles. Mice were randomly assigned to one of four groups: placebo sedentary, CLA sedentary, placebo trained, or CLA trained. The CLA groups were gavaged with 35 MUl per day of Tonalin(r) FFA 80 food supplement containing CLA throughout the 6-week experimental period, whereas the placebo groups were gavaged with 35 MUl sunflower oil each day. Each administered dose of CLA corresponded to approximately 0.7 g/kg or 0.5%, of the dietary daily intake. Trained groups ran 5 days per week on a Rota-Rod for 6 weeks at increasing speeds and durations. Mice were sacrificed by cervical dislocation and hind limb posterior muscle groups were dissected and used for histological and molecular analyses. Endurance training stimulated mitochondrial biogenesis by PGC1alpha isoforms (tot, alpha1, alpha2, and alpha3) but CLA supplementation did not stimulate PGC1alpha isoforms or mitochondrial biogenesis in trained or sedentary mice. In the plantaris muscle, CLA supplementation induced a fibre-type-specific hypertrophy of type IIx muscle fibres, which was associated with increased capillary density and was different from the fibre-type-specific hypertrophy induced by endurance exercise (of types I and IIb muscle fibres). J. Cell. Physiol. 232: 1086-1094, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27487030 TI - Correction: A Pilot Study Examining Physical and Social Warmth: Higher (Non Febrile) Oral Temperature Is Associated with Greater Feelings of Social Connection. AB - [This corrects the article DOI: 10.1371/journal.pone.0156873.]. PMID- 27487031 TI - Overexpression of AhpC enhances stress tolerance and N2-fixation in Anabaena by upregulating stress responsive genes. AB - The study explores the significance of peroxides in regulating the CO2- and N2 fixation capacities in Anabaena sp. PCC7120. To this end Anabaena strains were generated carrying an extra copy of ahpC (An+ahpC) or by deleting from their endogenous functional ahpC (AnDeltaahpC). AhpC levels were 2.2- to 6.0-fold higher in An+ahpC than in wild type. An+ahpC revealed 1.4- to 2-fold upregulation of photosystems I and II, nitrogenase, superoxide dismutase and catalase activities while same activities were 1.3- to 2.5-fold downregulated in the insertional mutant (AnDeltaahpC) compared to the wild type. Peroxide, superoxide and malondialdehyde contents were low in An+ahpC and high in AnDeltaahpC. Growth was inhibited in AnDeltaahpC by approximately 40-60% compared to a 33-40% enhanced growth in An+ahpC under selected stresses. Most interestingly, heterocyst frequency was increased in An+ahpC. In order to address transcriptional and posttranscriptional effects, transcripts of genes including groEL, fld, kat, gor, gst, dps, bfr, tf, sodA, dnaK, prx, uspA, pcs and apx were quantified and found to be increased 1.33- to 7.70-fold in unstressed and 1.76- to 13.80-fold in stressed An+ahpC. In a converse manner, they were downregulated by 1.20- to 7.50-fold in unstressed and 1.23 to 10.20-fold in stressed AnDeltaahpC. It is concluded that the level of AhpC controls a major set of metabolic and developmental genes in normal and stress conditions and thus likely is in the core of the redox regulatory system of Anabaena. PMID- 27487032 TI - Systems genetics - deciphering the complex disease with a systems approach. PMID- 27487029 TI - RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord. AB - ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned >50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG's). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFalpha-induced protein 2 (TNFAIP2) as a major network "hub" gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF's involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFalpha signaling may be helpful in ALS patients. PMID- 27487033 TI - Comparison of Sterile vs Nonsterile Gloves in Cutaneous Surgery and Common Outpatient Dental Procedures: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Whether the use of sterile vs nonsterile gloves in outpatient cutaneous procedures affects the rate of postoperative wound infection is unknown. OBJECTIVE: To explore rates of surgical site infection (SSI) with the use of sterile vs nonsterile gloves in outpatient cutaneous surgical procedures. DATA SOURCES: This systematic review and meta-analysis identified studies from Ovid MEDLINE (1946 to present), Ovid Cochrane Central Register of Controlled Trials (1991 to present), Ovid EMBASE (1988 to present), EBSCO Cumulative Index to Nursing and Allied Health Literature (1980 to present), Scopus (1996 to present), and Web of Science (1975 to present). STUDY SELECTION: Studies with information on sterile vs nonsterile gloves in outpatient surgical procedures were retrieved. Only randomized clinical trials and comparative studies were included for final analysis. DATA EXTRACTION: Data of trial design, surgery characteristics, and outcomes from published manuscripts and unpublished data were independently extracted. MAIN OUTCOMES AND MEASURES: Randomized clinical trials were considered high quality if randomization, allocation concealment, blinding, and follow-up completeness were appropriate. Relative risk and 95% CIs were derived for postoperative wound infections. RESULTS: Fourteen articles met eligibility and inclusion criteria for systematic review; they included 12 275 unique patients who had undergone 12 275 unique outpatient procedures with sterile or nonsterile gloves and had follow-up regarding SSI. With the exclusion of 1 single-arm observational study of 1204 patients, 11 071 patients from 13 studies remained in the meta-analysis. Of these, 228 patients were documented as having postoperative SSI (2.1%), including 107 of 5031 patients in the nonsterile glove group (2.1%) and 121 of 6040 patients in the sterile glove group (2.0%). Overall relative risk for SSI with nonsterile glove use was 1.06 (95% CI, 0.81 1.39). CONCLUSIONS AND RELEVANCE: No difference was found in the rate of postoperative SSI between outpatient surgical procedures performed with sterile vs nonsterile gloves. PMID- 27487034 TI - Structure-activity relationships and action mechanisms of collagen-like antimicrobial peptides. AB - An antimicrobial triple-helical peptide, R3, was previously obtained from a collagen-like combinatorial peptide library. In this research, based on structure activity relationship studies of R3, a more potent peptide, RR4, with increased positive net charge and charge density relative to R3, was developed. RR4 exhibited antimicrobial activity against both Gram-negative and Gram-positive bacterial strains, including multidrug-resistant strains. Its action could be attributed to entry into cells and interactions with intercellular molecules such as DNA/RNA that inhibited cell division rather than increasing bacterial membrane permeability. Furthermore, RR4 exhibited remarkable stability in serum and low cytotoxicity. PMID- 27487035 TI - Life-Threatening Hemolytic Anemia after Intrapleural Instillation of OK-432 for Treatment of Congenital Chylothorax. AB - Recent reports have advocated treatment of congenital chylothorax with chemical pleurodesis via intrapleural administration of OK-432. Severe complications have not been reported, but recently we have encountered a life-threatening case of massive hemolysis after the procedure. The hemoglobin of the infant decreased from 8.7 to 3.1 g/dl within 48 h, with concomitant severe hyperbilirubinemia (472 MUmol/l) requiring exchange transfusion. Frontline neonatologists should be aware of this rare but potentially life-threatening adverse reaction. In addition, it is possible that a longer indwelling time (3.5 vs. 0.5 h) for OK-432 pleurodesis may alter the therapeutic response. PMID- 27487036 TI - Transformation of Flame Retardant Tetrabromobisphenol A by Aqueous Chlorine and the Effect of Humic Acid. AB - In this work, it was found that the most widely used brominated flame retardant tetrabromobisphenol A (TBrBPA) could be transformed by free chlorine over a wide pH range from 5 to 10 with apparent second-order rate constants from 138 to 3210 M(-1).s(-1). A total of eight products, including one quinone-like compound (i.e., 2,6-dibromoquinone), two dimers, and several simple halogenated phenols (e.g., 4-(2-hydroxyisopropyl)-2,6-dibromophenol, 2,6-dibromohydroquinone, and 2,4,6-tribromophenol), were detected by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) using a novel precursor ion scan (PIS) approach. A tentative reaction pathway was proposed: chlorine initially oxidized TBrBPA leading to the formation of a phenoxy radical, and then this primary radical and its secondary intermediates (e.g., 2,6-dibromo-4-isopropylphenol carbocation) formed via beta-scission subsequently underwent substitution, dimerization, and oxidation reactions. Humic acid (HA) considerably inhibited the degradation rates of TBrBPA by chlorine even accounting for oxidant consumption. A similar inhibitory effect of HA was also observed in permanganate and ferrate oxidation. This inhibitory effect was possibly attributed to the fact that HA competitively reacted with the phenoxy radical of TBrBPA and reversed it back to parent TBrBPA. This study confirms that chlorine can transform phenolic compounds (e.g., TBrBPA) via electron transfer rather than the well-documented electrophilic substitution, which also have implications on the formation pathway of halo-benzoquinones during chlorine disinfection. These findings can improve the understanding of chlorine chemistry in water and wastewater treatment. PMID- 27487037 TI - Microbes on a Bottle: Substrate, Season and Geography Influence Community Composition of Microbes Colonizing Marine Plastic Debris. AB - Plastic debris pervades in our oceans and freshwater systems and the potential ecosystem-level impacts of this anthropogenic litter require urgent evaluation. Microbes readily colonize aquatic plastic debris and members of these biofilm communities are speculated to include pathogenic, toxic, invasive or plastic degrading-species. The influence of plastic-colonizing microorganisms on the fate of plastic debris is largely unknown, as is the role of plastic in selecting for unique microbial communities. This work aimed to characterize microbial biofilm communities colonizing single-use poly(ethylene terephthalate) (PET) drinking bottles, determine their plastic-specificity in contrast with seawater and glass colonizing communities, and identify seasonal and geographical influences on the communities. A substrate recruitment experiment was established in which PET bottles were deployed for 5-6 weeks at three stations in the North Sea in three different seasons. The structure and composition of the PET-colonizing bacterial/archaeal and eukaryotic communities varied with season and station. Abundant PET-colonizing taxa belonged to the phylum Bacteroidetes (e.g. Flavobacteriaceae, Cryomorphaceae, Saprospiraceae-all known to degrade complex carbon substrates) and diatoms (e.g. Coscinodiscophytina, Bacillariophytina). The PET-colonizing microbial communities differed significantly from free-living communities, but from particle-associated (>3 MUm) communities or those inhabiting glass substrates. These data suggest that microbial community assembly on plastics is driven by conventional marine biofilm processes, with the plastic surface serving as raft for attachment, rather than selecting for recruitment of plastic-specific microbial colonizers. A small proportion of taxa, notably, members of the Cryomorphaceae and Alcanivoraceae, were significantly discriminant of PET but not glass surfaces, conjuring the possibility that these groups may directly interact with the PET substrate. Future research is required to investigate microscale functional interactions at the plastic surface. PMID- 27487038 TI - Long-term Recall of Time to Pregnancy. AB - BACKGROUND: Despite the widespread use of retrospectively reported time to pregnancy to evaluate fertility either as an outcome or as a risk factor for chronic disease, only two small studies have directly compared prospective data with later recall. METHODS: The North Carolina Early Pregnancy Study (1982-1986) collected prospective time-to-pregnancy data from the beginning of participants' pregnancy attempt. In 2010, (24-28 years later) women were sent a questionnaire including lifetime reproductive history that asked about all prior times to pregnancy. Of the 202 women with prospective time-to-pregnancy data, 76% provided recalled time to pregnancy. RESULTS: A lower proportion of women with times to pregnancy >=3 cycles provided a recalled time to pregnancy than women with times to pregnancy <3 cycles. Also, high gravidity or parity was associated with a lower likelihood of providing a recalled time to pregnancy. Women with very short or very long times to pregnancy (1 cycle or >=13 cycles) had good recall of time to pregnancy. Positive predictive values of 1 or >=13 cycles were 73% and 68%, respectively, while positive predictive values for other categories of time to pregnancy ranged from 38% to 58%. The weighted kappa statistic for recalled versus prospective time to pregnancy was 0.72 (95% confidence interval: 0.65, 0.79). CONCLUSIONS: Recalled time to pregnancy showed good agreement with prospective time to pregnancy. Informative missingness must be considered when imputing recalled time to pregnancy. Associations observed in future studies can be corrected for misclassification. PMID- 27487039 TI - The Authors Respond: Erratum. PMID- 27487040 TI - Erratum: A Unification of Mediation and Interaction: A 4-Way Decomposition. PMID- 27487041 TI - Association between Food Insecurity and Procurement Methods among People Living with HIV in a High Resource Setting. AB - OBJECTIVE: People living with HIV in high-resource settings suffer severe levels of food insecurity; however, limited evidence exists regarding dietary intake and sub-components that characterize food insecurity (i.e. food quantity, quality, safety or procurement) in this population. We examined the prevalence and characteristics of food insecurity among people living with HIV across British Columbia, Canada. DESIGN: This cross-sectional analysis was conducted within a national community-based research initiative. METHODS: Food security was measured using the Health Canada Household Food Security Scale Module. Logistic regression was used to determine key independent predictors of food insecurity, controlling for potential confounders. RESULTS: Of 262 participants, 192 (73%) reported food insecurity. Sub-components associated with food insecurity in bivariate analysis included: < RDI consumption of protein (p = 0.046); being sick from spoiled/unsafe food in the past six months (p = 0.010); and procurement of food using non-traditional methods (p <0.05). In multivariable analyses, factors significantly associated with food insecurity included: procurement of food using non-traditional methods [AOR = 11.11, 95% CI: 4.79-25.68, p = <0.001]; younger age [AOR = 0.92, 95% CI: 0.86-0.96, p = <0.001]; unstable housing [AOR = 4.46, 95% CI: 1.15-17.36, p = 0.031]; household gross annual income [AOR = 4.49, 95% CI: 1.74-11.60, p = 0.002]; and symptoms of depression [AOR = 2.73, 95% CI: 1.25 5.96, p = 0.012]. CONCLUSIONS: Food insecurity among people living with HIV in British Columbia is characterized by poor dietary quality and food procurement methods. Notably, participants who reported procuring in non-traditional manners were over 10 times more likely to be food insecure. These findings suggest a need for tailored food security and social support interventions in this setting. PMID- 27487042 TI - Drug-Induced- or Rheumatic- Valvular Heart Disease in Patients Exposed to Benfluorex? AB - There is a risk of misdiagnosis between benfluorex-induced VHD and acute rheumatic fever (ARF)-related VHD due to common characteristics of both etiologies. We aimed at estimating the probability for a patient exposed to benfluorex presenting with VHD to have, at the same time, a history of ARF related VHD. Such epidemiological approach could help at reducing the risk of misdiagnosis. We used INSEE data and related literature as well as various modeling hypotheses to drive and test a formula for calculating the probability of a patient presenting with VHD and a history of benfluorex intake to have a prior history of ARF-related VHD. Different scenarios were estimated by a Markov model on the life course of people born in France between 1940 and 1960. Sensitivity analyses were performed under these scenarios. According to the different scenarios and gender, the probability that a patient born between 1940 and 1960 presenting with VHD and a history of benfluorex intake would have had a prior history of ARF-related VHD varied from 0.2% to 2.7%. The probabilities by the year of birth were as follows: 0.8%-2.7% for a patient born in 1940, < 0.5% in all scenarios for patients born after 1955, and < 0.2% in all scenarios for patients, born in 1960. Our results indicate that the burden of ARF-related VHD is low in the patient population exposed to benfluorex. The probability of ARF related VHD should not be over-estimated in the diagnostic procedure of VHD. PMID- 27487044 TI - Land Use Affects Carbon Sources to the Pelagic Food Web in a Small Boreal Lake. AB - Small humic forest lakes often have high contributions of methane-derived carbon in their food webs but little is known about the temporal stability of this carbon pathway and how it responds to environmental changes on longer time scales. We reconstructed past variations in the contribution of methanogenic carbon in the pelagic food web of a small boreal lake in Finland by analyzing the stable carbon isotopic composition (delta13C values) of chitinous fossils of planktivorous invertebrates in sediments from the lake. The delta13C values of zooplankton remains show several marked shifts (approx. 10 0/00), consistent with changes in the proportional contribution of carbon from methane-oxidizing bacteria in zooplankton diets. The results indicate that the lake only recently (1950s) obtained its present state with a high contribution of methanogenic carbon to the pelagic food web. A comparison with historical and palaeobotanical evidence indicates that this most recent shift coincided with agricultural land use changes and forestation of the lake catchment and implies that earlier shifts may also have been related to changes in forest and land use. Our study demonstrates the sensitivity of the carbon cycle in small forest lakes to external forcing and that the effects of past changes in local land use on lacustrine carbon cycling have to be taken into account when defining environmental and ecological reference conditions in boreal headwater lakes. PMID- 27487043 TI - Human CST Facilitates Genome-wide RAD51 Recruitment to GC-Rich Repetitive Sequences in Response to Replication Stress. AB - The telomeric CTC1/STN1/TEN1 (CST) complex has been implicated in promoting replication recovery under replication stress at genomic regions, yet its precise role is unclear. Here, we report that STN1 is enriched at GC-rich repetitive sequences genome-wide in response to hydroxyurea (HU)-induced replication stress. STN1 deficiency exacerbates the fragility of these sequences under replication stress, resulting in chromosome fragmentation. We find that upon fork stalling, CST proteins form distinct nuclear foci that colocalize with RAD51. Furthermore, replication stress induces physical association of CST with RAD51 in an ATR dependent manner. Strikingly, CST deficiency diminishes HU-induced RAD51 foci formation and reduces RAD51 recruitment to telomeres and non-telomeric GC-rich fragile sequences. Collectively, our findings establish that CST promotes RAD51 recruitment to GC-rich repetitive sequences in response to replication stress to facilitate replication restart, thereby providing insights into the mechanism underlying genome stability maintenance. PMID- 27487045 TI - Anti-Zinc Transporter Protein 8 Antibody Testing Is Not Informative in Routine Prediabetes Screening in Young Patients with Autoimmune Thyroiditis and Celiac Disease. AB - BACKGROUND/AIMS: Patients with type 1 diabetes mellitus (T1DM), autoimmune thyroiditis (ATD), and celiac disease (CD) are at increased risk for developing other autoimmune diseases. We evaluated zinc transporter 8 (ZnT8) prevalence in patients with ATD and/or CD in order to define the usefulness of ZnT8 autoantibodies for prediabetes screening. METHODS: Eighty-one young patients with ATD and/or CD were included in the study; 32 subjects with clinical onset of T1DM were enrolled as a control group. GAD65, IA-2, and ZnT8 antibodies were measured. An intravenous glucose tolerance test, C-peptide, glycosylated hemoglobin levels, and genomic analysis of HLA-DQA1* and -DQB1* were also considered in patients positive for autoantibodies. RESULTS: The ZnT8 prevalence was higher in T1DM patients than in patients with other autoimmune diseases (p < 0.001); positive ZnT8 detection was found in 2 ATD (p = 0.004) and 3 ATD + CD (p = 0.04) patients. Positive ZnT8 was associated with GAD65 (p = 0.01) but not with IA-2 positivity. No correlation between ZnT8 detection and the number of T1DM-susceptible HLA-DQ heterodimers was found. Pathological C-peptide levels and insulin response were found in subjects with islet autoimmunity and genetic susceptibility. CONCLUSION: ZnT8 autoantibodies detection in ATD and/or CD patients is low, and routine ZnT8 screening is not justified. ZnT8 evaluation may be recommended in subjects with autoimmune diseases as a marker for predicting compromised insulin secretion. PMID- 27487046 TI - The Joint Action of Sesquiterpene Lactones from Leaves as an Explanation for the Activity of Cynara cardunculus. AB - The work described herein is a continuation of a previous study centered on the bioprospect of cardoon (Cynara cardunculus) leaf extracts through the isolation of secondary metabolites with phytotoxic activity. Chromatographic fractionations of the ethyl acetate extract and spectroscopic analysis showed that the majority of the components were sesquiterpene lactones. Of these compounds, aguerin B, grosheimin, and cynaropicrin were very active on etiolated wheat coleoptile, standard target species, and weed growth. The joint action of binary mixtures of these three active sesquiterpene lactones and one nonactive compound (11,13 dihydroxy-8-desoxygrosheimin) was studied. The activities of fixed-ratio mixtures were assessed on wheat coleoptile. The results can be interpreted with respect to a reference model by considering dose-response analyses and isobolograms with linear regression analyses. A total of 17 binary mixtures at different levels of inhibition (ED25, ED50, and ED75) were studied, and predominantly they responded additively (25). Deviations from additivity included seven synergistic responses and two antagonistic responses. The joint action of major sesquiterpene lactones isolated from C. cardunculus can explain the activities observed in extracts and fractions. The results reported here reiterate the utility of the wheat coleoptile bioassay as a quick tool to detect potential synergistic effects in binary mixtures. PMID- 27487047 TI - Risk Factors for Parametrial Involvement in Early-Stage Cervical Cancer and Identification of Patients Suitable for Less Radical Surgery. AB - BACKGROUND: The aim of this study was to determine risk factors associated with parametrial involvement (PI) and to identify the subgroup of patients at low risk for PI. METHODS: The study comprised 565 patients with early-stage cervical cancer, who underwent radical hysterectomy with pelvic node dissection at Songklanagarind Hospital between 1987 and 2011. Analysis was performed to determine factors associated with PI. RESULTS: Overall, 24 (4.25%) women had PI. PI was more common in patients with non-squamous cell carcinoma, deep stromal invasion (DSI), tumor size > 2 cm, lymphovascular space invasion (LVSI), and pelvic node involvement. Multivariate analysis showed that DSI (p < 0.001) and tumor size > 2 cm (p < 0.001) were independently associated with PI. PI was linked with decreased recurrence-free (p < 0.001) and overall (p = 0.002) survival. Of 347 patients with tumor size <= 2 cm and no DSI, only 1 (0.29%) had PI. CONCLUSION: These findings confirm that PI in early-stage cervical cancer is uncommon. Risk factors associated with PI were DSI and tumor size > 2 cm. PI is a predictor of cervical cancer recurrence and decreased survival. Less radical surgery may be considered in low-risk patients. PMID- 27487048 TI - Sex Outside the Lines: Authentic Sexuality in a Sexually Dysfunctional Culture. PMID- 27487049 TI - Treating Out of Control Sexual Behavior: Rethinking Sex Addiction. PMID- 27487050 TI - Couple Resilience: Emerging Perspectives. PMID- 27487052 TI - Fostering resilience in the medical community. PMID- 27487051 TI - Antidepressants in unipolar major depression: what we need to know. PMID- 27487053 TI - Clinical News. PMID- 27487054 TI - When deep vein thrombosis occurs in the upper limb. AB - Upper extremity deep vein thrombosis is a relatively rare condition which has thus far not attracted much interest in the literature. The differences in its aetiopathology, different diagnostic modalities and the current standard of care are discussed in this article. PMID- 27487055 TI - Female gender and cardiovascular disease. AB - Despite a generalized belief that women are protected from cardiovascular disease, this remains the leading cause of death in women. This review focuses on differences in symptomatology, diagnostic modalities and therapeutic strategies in women with regard to cardiovascular disease. PMID- 27487056 TI - Management of atrial fibrillation: when are invasive approaches useful? AB - The management of atrial fibrillation extends from stroke prevention to rate or rhythm control strategies. The role of an invasive strategy is expanding and it remains important to identify suitable candidates early in the disease process. PMID- 27487057 TI - Smartphone and mobile phone security for the clinician. AB - Smartphones are near ubiquitous and widely used by doctors in discussing patients. In all communication doctors should take steps to protect confidentiality, yet there is a paucity of available information on how clinicians can bolster cyber security and minimize risk when using their mobile phone. PMID- 27487058 TI - Vertical leadership in highly complex and unpredictable health systems. AB - This article explores how the concept of vertical leadership development might help health organizations cope with and thrive within highly complex and unpredictable health systems, looking at concepts of VUCA (volatility, uncertainty, complexity and ambiguity) and RUPT (rapid, unpredictable, paradoxical and tangled). PMID- 27487059 TI - Guidance on feedback of outcome data to improve performance in vascular surgery. AB - Feedback of performance data is a well-established method of performance improvement in the health-care setting, although guidance has been limited in the context of surgical performance. This article outlines how optimal feedback can be achieved using surgeon outcome data. PMID- 27487060 TI - Improving the non-technical ward round skills of medical students. PMID- 27487061 TI - The birth of the antibiotic era. PMID- 27487062 TI - Tuberculous lymphadenitis in a patient with Good syndrome. PMID- 27487063 TI - Wrong side oculomotor nerve palsy. PMID- 27487064 TI - An unusual cause of acute kidney injury. PMID- 27487066 TI - Errata. PMID- 27487067 TI - 'Whippits': nitrous oxide gas inhalation as recreational drug use. PMID- 27487065 TI - Lingual tumour in a 6-year-old boy. PMID- 27487069 TI - Interscalene vs suprascapular nerve block for shoulder surgery. PMID- 27487070 TI - Interventional oncology. PMID- 27487071 TI - Cervical intraepithelial neoplasia: screening and management. PMID- 27487072 TI - Obstetric complications after treatment of cervical intraepithelial neoplasia. PMID- 27487073 TI - Nine years of a single referral center management of Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). AB - CONTEXT: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) corresponds to a rare and acute life-threatening mucocutaneous reactions characterized by extensive necrosis and epidermal detachment. There are no efficacious pharmaceutical interventions proven through large clinical trials. OBJECTIVE: We sought to study clinical cases admitted in our institution in order to determine which drugs and medical comorbidities or treatments impacted the mortality. MATERIAL AND METHODS: In a retrospective study over 9 years we evaluated all patients presenting biopsy-proven SJS or TEN for age, gender, total body surface area involved, causing agents, SCORTEN score, blood transfusion, steroid administration, intubation, length of intensive care stay and death rate. Statistical analysis was done using SPSS statistical software. RESULTS: The highest incidence of SJS and TEN was in age group of 71-80 years. Of the 30 patients, 30% died from SJS/TEN, mainly due sepsis. For each subgroup SJS/TEN overlap had the highest mortality. The highest mortality was from antibiotic treatment as causing agent. Step-wise regression analysis identified mechanical ventilation requirement and age over 65 years as mortality high-risk factors. DISCUSSION: The most crucial interventions are discontinuation of the offending drug and prompt referral to a burn unit, which helps in early diagnosis and decrease mortality in these diseases. CONCLUSION: When SJS/TEN is caused by antibiotics suspicion of developing fatal sepsis should be high, independently of patients' medical condition. PMID- 27487074 TI - Strongly Confined HgTe 2D Nanoplatelets as Narrow Near-Infrared Emitters. AB - Two-dimensional colloidal nanoplatelets (NPLs), owing to the atomic-level control of their confined direction (i.e., no inhomogeneous broadening), have demonstrated improved photoluminescence (PL) line widths for cadmium chalcogenide based nanocrystals. Here we use cation exchange to synthesize mercury chalcogenide NPLs. Appropriate control of reaction kinetics enables the 2D morphology of the NPLs to be maintained during the cation exchange. HgTe and HgSe NPLs have significantly improved optical features compared to existing materials with similar band gaps. The PL line width of HgTe NPLs (40 nm full width at half maximum, centered at 880 nm) is a factor of 2 smaller than typical PbS nanocrystals (NCs) emitting at the same wavelength. The PL has a lifetime of 50 ns, almost 2 orders of magnitude shorter than small PbS colloidal quantum dots (CQDs), and a quantum yield of ~10%, almost 2 orders of magnitude shorter than small PbS colloidal quantum dots (CQDs). These materials are promising for a large variety of applications spanning from telecommunications to the design of colloidal topological insulators. PMID- 27487075 TI - Dose-Dependent Effect of Granulocyte Transfusions in Hematological Patients with Febrile Neutropenia. AB - It is still under debate whether granulocyte transfusions (GTs) substantially increase survival in patients with febrile neutropenia. We retrospectively examined data relative to 96 patients with hematological malignancies receiving 491 GTs during 114 infectious episodes (IE). Patients were grouped according to the median doses of granulocytes transfused during the infectious episode (low dose group: <1.5-x108 cells/Kg; standard-dose group: 1.5-3.0x108 cells/Kg and high-dose group: >3.0x108 cells/Kg). The impact of clinical, microbiological and GT-related variables on the infection-related mortality (IRM) was investigated. The IRM was not influenced by the number of GTs or by the total amount of granulocytes received, whereas a dose-related effect of the median dose received for IE was detected at univariate analysis (IRM of 18.4% in the standard-dose group, 44.4% in the low-dose group and 48.4% in the high-dose group, p = 0.040) and confirmed at multivariate analysis (OR 3.7, IC 95% 1.5-8.9; 0.004 for patients not receiving standard doses of GTs). Moreover, patients receiving GTs at doses lower or greater than standard had increased risk for subsequent ICU admission and reduced overall survival. The dose-related effect of GTs was confirmed in bacterial but not in fungal infections. Preliminary findings obtained from a subgroup of patients candidate to GTs revealed that levels of inflammatory response mediators increase in a dose-related manner after GTs, providing a possible explanation for the detrimental effect exerted by high-dose transfusions. GTs can constitute a valuable tool to improve the outcome of infections in neutropenic patients, provided that adequate recipient-tailored doses are supplied. Further investigations of the immunomodulatory effects of GTs are recommended. PMID- 27487076 TI - Outer Membrane Vesicles from the Probiotic Escherichia coli Nissle 1917 and the Commensal ECOR12 Enter Intestinal Epithelial Cells via Clathrin-Dependent Endocytosis and Elicit Differential Effects on DNA Damage. AB - Interactions between intestinal microbiota and the human host are complex. The gut mucosal surface is covered by a mucin layer that prevents bacteria from accessing the epithelial cells. Thus, the crosstalk between microbiota and the host mainly rely on secreted factors that can go through the mucus layer and reach the epithelium. In this context, vesicles released by commensal strains are seen as key players in signaling processes in the intestinal mucosa. Studies with Gram-negative pathogens showed that outer membrane vesicles (OMVs) are internalized into the host cell by endocytosis, but the entry mechanism for microbiota-derived vesicles is unknown. Escherichia coli strains are found as part of normal human gut microbiota. In this work, we elucidate the pathway that mediate internalization of OMVs from the probiotic E.coli Nissle 1917 (EcN) and the commensal ECOR12 strains in several human intestinal epithelial cell lines. Time course measurement of fluorescence and microscopy analysis performed with rhodamine B-R18-labeled OMVs in the presence of endocytosis inhibitors showed that OMVs from these strains enter epithelial cells via clathrin-mediated endocytosis. Vesicles use the same endocytosis pathway in polarized epithelial monolayers. Internalized OMVs are sorted to lysosomal compartments as shown by their colocalization with clathrin and specific markers of endosomes and lysosomes. OMVs from both strains did not affect cell viability, but reduce proliferation of HT-29 cells. Labeling of 8-oxo-dG adducts in DNA revealed that neither OMVs from EcN nor from ECOR12 promoted oxidative DNA damage. In contrast, flow cytometry analysis of phosphorylated gammaH2AX evidenced that OMVs from the probiotic EcN significantly produced more double strand breaks in DNA than ECOR12 OMVs. The EcN genotoxic effects have been attributed to the synthesis of colibactin. However, it is not known how colibactin is exported and delivered into host cells. Whether colibactin is secreted via OMVs is an open question that needs further study. PMID- 27487077 TI - Examining the Role of Source Credibility and Reference Group Proximity on Personalized Normative Feedback Interventions for College Student Alcohol Use: A Randomized Laboratory Experiment. AB - BACKGROUND: Personalized normative feedback (PNF) interventions are designed to reduce misperceived drinking norms by delivering feedback regarding the actual drinking behavior of college students, thereby leading to subsequent reductions in one's own drinking. OBJECTIVE: We examined the roles of data source credibility and reference group proximity in the effectiveness of a laboratory based PNF intervention to reduce perceived drinking norms and thereby decrease intentions to drink. METHOD: Following completion of an online preintervention survey and using a 2 (highly credible data source/low credible data source) * 2 (proximal reference group/distal reference group) between-subjects factorial design, 104 college student drinkers were randomly assigned to condition. Participants then completed a postintervention questionnaire to assess for changes in various aspects of drinking. RESULTS: Highly credible feedback was associated with greater reductions in perceived weekly drinking by American college students compared to feedback with low credibility. Similarly, more proximal than distal reference group feedback led to greater reductions in perceived weekly drinking by a same-gender/same-class year students at one's university. No condition effects emerged for intended drinks per week. CONCLUSIONS: PNF interventions may benefit from considering data source credibility and reference group proximity to reduce misperceptions of college student drinking, depending on the goals and resources of practitioners implementing such programs. Even the use of such a distal reference group as American college students can indeed lead to a reduction of normative perceptions provided there is an emphasis on the credibility of the data source. PMID- 27487078 TI - Occupational Risk Factors for COPD: A Case-Control Study. AB - OBJECTIVES: The aim of this research was to examine the occupational risk factors for Chronic Obstructive Pulmonary Diseases (COPD) in a range of occupations. METHODS: Eleven occupations involving different types of exposure were observed in this multicenter case-control study. Controls and cases were matched for sex, age and smoking. Multiple logistic regression analyses were used to estimate odds ratios (ORs). RESULTS: A total of 1,519 participants were initially recruited between September 2004 and September 2012. After matching, 547 pairs were obtained. The mean age was 56.3 +/- 10.4 years. Smelter workers were the only ones with an increased risk of COPD in this study (OR = 7.6, p < 0.0001, 95% CI [4.5, 12.9]). Physical activity was protective (OR = 0.7), while living in the city was a risk (OR = 1.6). The main used metals were cast iron, aluminum and alloys. Molds and cores were mainly made from sand and synthetic resins. Machine maintenance (65.2%), molding (49.6%), finishing (41.1%) and casting (41.0%) were the most common activities. Almost all workers (95.1%) cleaned the floors and machines with a brush or compressed air. CONCLUSIONS: This study demonstrates the importance of occupational factors in the genesis of COPD, especially among smelter workers. As with the fight against smoking-related disease, the removal or substitution of recognized hazardous agents is the best way of preventing the onset of COPD. This is why it is essential to continue research on its occupational risk factors. PMID- 27487080 TI - A Thermodynamic Study of Adenine and Thymine Substitutions in the Loops of the Oligodeoxyribonucleotide HTel. AB - Guanine-rich DNA oligodeoxyribonucleotides (ODN) can form four-stranded structures named quadruplexes (G4s), which are stabilized via the association of four guanine bases. Quadruplexes have a high level of conformational diversity depending on the molecularity, sequence, and the cation conditions of the G4 formation. Monomolecular G4 structures have nonguanine loops that usually consist of between one and four adenine and thymine residues. In the work reported here, we systematically modified the nucleotides in the loops of the 22 nucleotide ODN, HTel, which contains four repeats of the human telomeric sequence, GGGTTA. We studied the effect of different types of bases in the loops on the stability and topology of the G4s formed. We show that lower steric hindrance of pyrimidine residues increases the stability of G4s with a major enthalpic contribution. Stacking of the loop bases onto tetrads could compensate for the loss of rotational freedom. In addition, in the presence of sodium, the stabilities of the G4s are loop dependent. In the presence of potassium, the stability of G4 depend on the sequences of each loop. Lastly, in the presence of potassium ions, the modified HTel ODNs may exist in equilibrium of the two types of the hybrid topology, and these structures are stabilized by the second loop. Modifications of the bases in this loop change the topology and stability of the folded structures. PMID- 27487079 TI - Co-Evolution of Social Learning and Evolutionary Preparedness in Dangerous Environments. AB - Danger is a fundamental aspect of the lives of most animals. Adaptive behavior therefore requires avoiding actions, objects, and environments associated with danger. Previous research has shown that humans and non-human animals can avoid such dangers through two types of behavioral adaptions, (i) genetic preparedness to avoid certain stimuli or actions, and (ii) social learning. These adaptive mechanisms reduce the fitness costs associated with danger but still allow flexible behavior. Despite the empirical prevalence and importance of both these mechanisms, it is unclear when they evolve and how they interact. We used evolutionary agent-based simulations, incorporating empirically based learning mechanisms, to clarify if preparedness and social learning typically both evolve in dangerous environments, and if these mechanisms generally interact synergistically or antagonistically. Our simulations showed that preparedness and social learning often co-evolve because they provide complimentary benefits: genetic preparedness reduced foraging efficiency, but resulted in a higher rate of survival in dangerous environments, while social learning generally came to dominate the population, especially when the environment was stochastic. However, even in this case, genetic preparedness reliably evolved. Broadly, our results indicate that the relationship between preparedness and social learning is important as it can result in trade-offs between behavioral flexibility and safety, which can lead to seemingly suboptimal behavior if the evolutionary environment of the organism is not taken into account. PMID- 27487081 TI - Comparative Proteomic Analysis of Extracellular Vesicles Isolated by Acoustic Trapping or Differential Centrifugation. AB - Extracellular vesicles (ECVs), including microparticles and exosomes, are submicrometer membrane vesicles released by diverse cell types upon activation or stress. Circulating ECVs are potential reservoirs of disease biomarkers, and the complexity of these vesicles is significantly lower compared to their source, blood plasma, which makes ECV-based biomarker studies more promising. Proteomic profiling of ECVs is important not only to discover new diagnostic or prognostic markers but also to understand their roles in biological function. In the current study, we investigated the protein composition of plasma-derived ECVs isolated by acoustic seed trapping. Additionally, the protein composition of ECVs isolated with acoustic trapping was compared to that isolated with a conventional differential centrifugation protocol. Finally, the proteome of ECVs originating from ST-elevation myocardial infarction patients was compared with that of healthy controls using label-free LC-MS quantification. The acoustic trapping platform allows rapid and automated preparation of ECVs from small sample volumes, which are therefore well-suited for biobank repositories. We found that the protein composition of trapped ECVs is very similar to that isolated by the conventional differential centrifugation method. PMID- 27487082 TI - Quit interest influences smoking cue-reactivity. AB - Interest in quitting smoking is important to model in cue-reactivity studies, because the craving elicited by cue exposure likely requires different self regulation efforts for smokers who are interested in quitting compared to those without any quit interest. The objective of the current study was to evaluate the role of quit interest in how cigarette cue exposure influences self-control efforts. Smokers interested in quitting (n=37) and smokers with no interest in quitting (n=53) were randomly assigned to a cigarette or neutral cue exposure task. Following the cue exposure, all participants completed two self-control tasks, a measure of risky gambling (the Iowa Gambling Task) and a cold pressor tolerance task. Results indicated that smokers interested in quitting had worse performance on the gambling task when exposed to a cigarette cue compared to neutral cue exposure. We also found that people interested in quitting tolerated the cold pressor task for a shorter amount of time than people not interested in quitting. Finally, we found that for people interested in quitting, exposure to a cigarette cue was associated with increased motivation to take steps toward decreasing use. Overall these results suggest that including quit interest in studies of cue reactivity is valuable, as quit interest influenced smoking cue reactivity responses. PMID- 27487083 TI - Older women, intimate partner violence and mental health: a consideration of the particular issues for health and healthcare practice. AB - AIMS AND OBJECTIVES: To explore qualitative evidence in older women with a history of intimate partner violence and their accounts and experiences of mental health. BACKGROUND: Intimate partner violence significantly impacts the health and well-being of women who experience it. However, women who experience intimate partner violence do not form a homogenous group and the effect on older women has not been adequately distinguished. While there is a growing body of evidence to address this deficit, studies to date have tended to concentrate on older women's experiences of intimate partner violence in totality and as such mental health issues have been subsumed as a part of the whole. DESIGN: Meta-ethnographic synthesis of qualitative evidence. METHODS: A systematic search of PUBMED, Cumulative Index to Nursing and Allied Health Literature, COCHRANE, Medline and PsycInfo, Sci was completed. The search included articles published up until the end of December 2015. RESULTS: The review identified that intimate partner violence exerts a significant impact on the mental health of older women. Intimate partner violence for women in later life is inherently complex, especially where the boundaries of violence and vulnerability have been blurred historically both within the intimate partner violence discourse and through provision and practice. CONCLUSIONS: This study adds to the developing knowledge and understanding of intimate partner violence for older women as a part of the growing body of evidence of the impact of intimate partner violence on the health and well-being of those who experience abuse more generally. When age and gender intersect with intimate partner violence, there are specific implications and health professionals and service providers need to be aware of these. RELEVANCE TO CLINICAL PRACTICE: urses and healthcare professionals are professionally accountable for the effective management and support of women who have experienced abuse. It is therefore crucial that they are able to understand and identify the possible complexity of presentations of abuse and this includes older women. PMID- 27487084 TI - An Optimized Method for Quantification of Pathogenic Leptospira in Environmental Water Samples. AB - Leptospirosis is a zoonotic disease usually acquired by contact with water contaminated with urine of infected animals. However, few molecular methods have been used to monitor or quantify pathogenic Leptospira in environmental water samples. Here we optimized a DNA extraction method for the quantification of leptospires using a previously described Taqman-based qPCR method targeting lipL32, a gene unique to and highly conserved in pathogenic Leptospira. QIAamp DNA mini, MO BIO PowerWater DNA and PowerSoil DNA Isolation kits were evaluated to extract DNA from sewage, pond, river and ultrapure water samples spiked with leptospires. Performance of each kit varied with sample type. Sample processing methods were further evaluated and optimized using the PowerSoil DNA kit due to its performance on turbid water samples and reproducibility. Centrifugation speeds, water volumes and use of Escherichia coli as a carrier were compared to improve DNA recovery. All matrices showed a strong linearity in a range of concentrations from 106 to 10 degrees leptospires/mL and lower limits of detection ranging from <1 cell /ml for river water to 36 cells/mL for ultrapure water with E. coli as a carrier. In conclusion, we optimized a method to quantify pathogenic Leptospira in environmental waters (river, pond and sewage) which consists of the concentration of 40 mL samples by centrifugation at 15,000*g for 20 minutes at 4 degrees C, followed by DNA extraction with the PowerSoil DNA Isolation kit. Although the method described herein needs to be validated in environmental studies, it potentially provides the opportunity for effective, timely and sensitive assessment of environmental leptospiral burden. PMID- 27487085 TI - Beneficial effect of arterial embolization with warmed miriplatin for multiple hepatocellular carcinoma. AB - AIM: The effect of transcatheter arterial chemoembolization (TACE) is not necessarily sufficient in patients with multiple hepatocellular carcinoma (HCC). We evaluated the antitumor activity and adverse events of TACE using warmed miriplatin suspension for multiple HCC. METHODS: Seventy patients with multiple HCC received TACE using warmed miriplatin/lipiodol suspension, including patients who were TACE-naive (group A, n = 5), those undergoing initial TACE after radical therapies (group B, n = 31), and those with a history of repeated TACE (group C, n = 34). Median tumor size was 19.5 mm and a median of four nodules. RESULTS: Complete necrosis (TE 4) and partial necrosis (TE 3) of 50% or more were attained in 24 and 19 patients at 3 months after TACE, respectively. Response rates (TE 4 + TE 3) were 60.0% in group A, 83.9% in group B, and 41.2% in group C (P = 0.038). Survival rates of all patients after TACE were 82.6% after 1 year, 65.6% after 2 years, and 47.7% after 3 years. Three-year survival rates of patients in groups A, B, and C were 53.3%, 78.8%, and 29.7%, respectively (P = 0.0029). CONCLUSION: Transcatheter arterial chemoembolization using warmed miriplatin induced high response rate in multiple HCC, and the rate was significantly high in those patients with recurrent multiple HCCs after curative therapies. PMID- 27487086 TI - Thermostability of Well-Ordered HIV Spikes Correlates with the Elicitation of Autologous Tier 2 Neutralizing Antibodies. AB - In the context of HIV vaccine design and development, HIV-1 spike mimetics displaying a range of stabilities were evaluated to determine whether more stable, well-ordered trimers would more efficiently elicit neutralizing antibodies. To begin, in vitro analysis of trimers derived from the cysteine stabilized SOSIP platform or the uncleaved, covalently linked NFL platform were evaluated. These native-like trimers, derived from HIV subtypes A, B, and C, displayed a range of thermostabilities, and were "stress-tested" at varying temperatures as a prelude to in vivo immunogenicity. Analysis was performed both in the absence and in the presence of two different adjuvants. Since partial trimer degradation was detected at 37 degrees C before or after formulation with adjuvant, we sought to remedy such an undesirable outcome. Cross-linking (fixing) of the well-ordered trimers with glutaraldehyde increased overall thermostability, maintenance of well-ordered trimer integrity without or with adjuvant, and increased resistance to solid phase-associated trimer unfolding. Immunization of unfixed and fixed well-ordered trimers into animals revealed that the elicited tier 2 autologous neutralizing activity correlated with overall trimer thermostability, or melting temperature (Tm). Glutaraldehyde fixation also led to higher tier 2 autologous neutralization titers. These results link retention of trimer quaternary packing with elicitation of tier 2 autologous neutralizing activity, providing important insights for HIV-1 vaccine design. PMID- 27487088 TI - Tuning Cationic Block Copolymer Micelle Size by pH and Ionic Strength. AB - The formation, morphology, and pH and ionic strength responses of cationic block copolymer micelles in aqueous solutions have been examined in detail to provide insight into the future development of cationic micelles for complexation with polyanions such as DNA. Diblock polymers composed of a hydrophilic/cationic block of N,N-dimethylaminoethyl methacrylate (DMAEMA) and a hydrophobic/nonionic block of n-butyl methacrylate (BMA) were synthesized [denoted as DMAEMA-b-BMA (X-Y), where X = DMAEMA molecular weight and Y = molecular weight of BMA in kDa]. Four variants were created with block molecular weights of 14-13, 14-23, 27-14, 27-29 kDa and low dispersities less than 1.10. The amphiphilic polymers self-assembled in aqueous conditions into core-shell micelles that ranged in size from 25-80 nm. These cationic micelles were extensively characterized in terms of size and net charge in different buffers over a wide range of ionic strength (0.02-1 M) and pH (5-10) conditions. The micelle core is kinetically trapped, and the corona contracts with increasing pH and ionic strength, consistent with previous work on micelles with glassy polystyrene cores, indicating that the corona properties are independent of the dynamics of the micelle core. The contraction and extension of the corona scales with solution ionic strength and charge fraction of the amine groups. The aggregation numbers of the micelles were obtained by static light scattering, and the Rg/Rh ratios are close to that of a hard sphere. The zeta potentials of the micelles were positive up to two pH units above the corona pKa, suggesting that applications relying on micelle charge for stability should be viable over a wide range of solution conditions. PMID- 27487087 TI - Chemistry of Renieramycins. 15. Synthesis of 22-O-Ester Derivatives of Jorunnamycin A and Their Cytotoxicity against Non-Small-Cell Lung Cancer Cells. AB - Eighteen 22-O-ester derivatives of jorunnamycin A (2) were prepared via 2, and their cytotoxicity against human non-small-cell lung cancer (NSCLC) cells was evaluated. Preliminary study of the structure-cytotoxicity relationship revealed that the ester part containing a nitrogen-heterocyclic ring elevated the cytotoxicity of the 22-O-ester derivatives. Among them, 22-O-(4-pyridinecarbonyl) ester 6a is the most potent compound (IC50 1.1 and 1.6 nM), exhibiting 21-fold and 5-fold increases in cytotoxicity against the H292 and H460 NSCLC cell lines, respectively, relative to renieramycin M (1), the major cytotoxic bistetrahydroisoquinolinequinone alkaloid of the Thai blue sponge Xestospongia sp. PMID- 27487089 TI - Noble-metal Ag nanoparticle chains: annealing Ag/Bi superlattice nanowires in vacuum. AB - One-dimensional noble-metal Ag nanoparticle chains have been prepared by electrodepositing Ag/Bi superlattice nanowires in a porous anodic alumina oxide (AAO) template and following an annealing process in vacuum. It is found that Bi, as a sacrificial metal, can be removed completely after annealing at 450 degrees C with a vacuum degree of 10(-5) Torr. The regulation of particle size, shape and interparticle spacing of Ag NP chains has been realized by adjusting the segment length of the Ag/Bi superlattice nanowires and the annealing condition. With an extension of the annealing time, it is observed that Ag particles display the transform trend from ellipsoid to sphere. Our findings could inspire further investigation on the design and fabrication of metal nanoparticle chains. PMID- 27487090 TI - Extent, Awareness and Perception of Dissemination Bias in Qualitative Research: An Explorative Survey. AB - BACKGROUND: Qualitative research findings are increasingly used to inform decision-making. Research has indicated that not all quantitative research on the effects of interventions is disseminated or published. The extent to which qualitative researchers also systematically underreport or fail to publish certain types of research findings, and the impact this may have, has received little attention. METHODS: A survey was delivered online to gather data regarding non-dissemination and dissemination bias in qualitative research. We invited relevant stakeholders through our professional networks, authors of qualitative research identified through a systematic literature search, and further via snowball sampling. RESULTS: 1032 people took part in the survey of whom 859 participants identified as researchers, 133 as editors and 682 as peer reviewers. 68.1% of the researchers said that they had conducted at least one qualitative study that they had not published in a peer-reviewed journal. The main reasons for non-dissemination were that a publication was still intended (35.7%), resource constraints (35.4%), and that the authors gave up after the paper was rejected by one or more journals (32.5%). A majority of the editors and peer reviewers "(strongly) agreed" that the main reasons for rejecting a manuscript of a qualitative study were inadequate study quality (59.5%; 68.5%) and inadequate reporting quality (59.1%; 57.5%). Of 800 respondents, 83.1% "(strongly) agreed" that non-dissemination and possible resulting dissemination bias might undermine the willingness of funders to support qualitative research. 72.6% and 71.2%, respectively, "(strongly) agreed" that non-dissemination might lead to inappropriate health policy and health care. CONCLUSIONS: The proportion of non dissemination in qualitative research is substantial. Researchers, editors and peer reviewers play an important role in this. Non-dissemination and resulting dissemination bias may impact on health care research, practice and policy. More detailed investigations on patterns and causes of the non-dissemination of qualitative research are needed. PMID- 27487091 TI - Determining mean fractional anisotropy using DDCOSY: preliminary results in biological tissues. AB - Complex materials are ubiquitous in science, engineering and nature. One important parameter for characterising their morphology is the degree of anisotropy. Magnetic resonance imaging offers non-invasive methods for quantitative measurements of the materials anisotropy, most commonly via diffusion tensor imaging and the subsequent extraction of the spatially resolved fractional anisotropy (FA) value. Here, we propose an alternative way of determining the FA as a sample average for cases where spatially resolved methods are not needed or not applicable. It is based on a particular diffusion-diffusion correlation spectroscopy protocol, allowing for the extraction of the mean (i.e. sample averaged) FA value. We demonstrate that mean FA values obtained from three anisotropic biological tissues are consistent with those extracted using diffusion tensor imaging. Moreover, we show that differences of mean FA values in healthy and tumour-bearing mouse brains allow to distinguish these tissue types. We anticipate that the proposed method will be beneficial in the wider context of medical and material science. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27487092 TI - Risk-Reduction Program for Cardiovascular and Limb Events in Patients With Peripheral Arterial Disease. PMID- 27487093 TI - A model assessment of the ability of lake water in Terra Nova Bay, Antarctica, to induce the photochemical degradation of emerging contaminants. AB - The shallow lakes located in Terra Nova Bay, Antarctica, are free from ice for only up to a couple of months (mid December to early/mid February) during the austral summer. In the rest of the year, the ice cover shields the light and inhibits the photochemical processes in the water columns. Previous work has shown that chromophoric dissolved organic matter (CDOM) in these lakes is very reactive photochemically. A model assessment is here provided of lake-water photoreactivity in field conditions, based on experimental data of lake water absorption spectra, chemistry and photochemistry obtained previously, taking into account the water depth and the irradiation conditions of the Antarctic summer. The chosen sample contaminants were the solar filter benzophenone-3 and the antimicrobial agent triclosan, which have very well known photoreactivity and have been found in a variety of environmental matrices in the Antarctic continent. The two compounds would have a half-life time of just a few days or less in the lake water during the Antarctic summertime, largely due to reaction with CDOM triplet states ((3)CDOM*). In general, pollutants that occur in the ice and could be released to lake water upon ice melting (around or soon after the December solstice) would be quickly photodegraded if they undergo fast reaction with (3)CDOM*. With some compounds, the important (3)CDOM* reactions might favour the production of harmful secondary pollutants, such as 2,8-dichlorodibenzodioxin from the basic (anionic) form of triclosan. PMID- 27487094 TI - Photoelectrochemical removal of 17beta-estradiol using a RuO2-graphene electrode. AB - A new electrode for the photoelectrochemical removal of 17beta-estradiol from water using ruthenium oxide nanoparticles supported on reduced graphene oxide is proposed in this study. The morphology, microstructure and the electrochemical performance of the material were characterized using HRTEM, XRD and Raman spectroscopy. The characterization showed the formation of reduced graphene oxide from a micro-wave assisted hydrothermal method with a particle size of 5.0 nm + 2.4 nm. The electrochemical measurements point to a high performance of the electrode in the presence of a white light source. The hormone removal efficiency in water containing 50 MUmol L(-1) of 17beta-estradiol was evaluated using chronoamperometry at +1.0 V and the process was monitored using liquid chromatography. The reaction is pseudo first order with the removal of 92.2% of 17beta-estradiol after 60 min of photoelectrocatalytic treatment. PMID- 27487095 TI - Prospects for arbuscular mycorrhizal fungi (AMF) to assist in phytoremediation of soil hydrocarbon contaminants. AB - Arbuscular mycorrhizal fungi (AMF) form mutualistic associations with the roots of 80-90% of vascular plant species and may constitute up to 50% of the total soil microbial biomass. AMF have been considered to be a tool to enhance phytoremediation, as their mycelium create a widespread underground network that acts as a bridge between plant roots, soil and rhizosphere microorganisms. Abundant extramatrical hyphae extend the rhizosphere thus creating the hyphosphere, which significantly increases the area of a plant's access to nutrients and contaminants. The paper presents and evaluates the role and significance of AMF in phytoremediation of hydrocarbon contaminated sites. We focused on (1) an impact of hydrocarbons on arbuscular mycorrhizal symbiosis, (2) a potential of AMF to enhance phytoremediation, (3) determinants that influence effectiveness of hydrocarbon removal from contaminated soils. This knowledge may be useful for selection of proper plant and fungal symbionts and crucial to optimize environmental conditions for effective AMF-mediated phytoremediation. It has been concluded that three-component phytoremediation systems based on synergistic interactions between plant roots, AMF and hydrocarbon-degrading microorganisms demonstrated high effectiveness in dissipation of organic pollutants in soil. PMID- 27487096 TI - Role of Janus-Kinases in Major Depressive Disorder. AB - BACKGROUND/AIMS: Major depressive disorder is a severe, common and often chronic disease with a significant mortality due to suicide. The pathogenesis of major depression is still unknown. It is assumed that a reduction of neurogenesis in the hippocampus plays an important role in the development of major depressive disorder. However, the mechanisms that control proliferation of neuronal stem cells in the hippocampus require definition. Here, we investigated the role of Janus-Kinase 3 (Jak-3) for stress-induced inhibition of neurogenesis and the induction of major depression symptoms in mice. METHODS: Stress was induced by the application of glucocorticosterone. Brain sections were stained with phospho specific antibodies and analysed by confocal microscopy to measure phosphorylation of Jak-3 specifically in the hippocampus. Jak-3 inhibitors and the antidepressant amitriptyline were applied to counteract stress. The effects of the inhibitors were determined by a set of behavioural tests and analysis of Jak-3 phosphorylation in brain sections. Acid sphingomyelinase-deficient mice were employed to test whether Jak3 is downstream of ceramide. RESULTS: The data show that stress reduces neurogenesis, which is restored by simultaneous application of Jak-3 inhibitors. Inhibition of neurogenesis correlated with an anxious-depressive behaviour that was also normalized upon application of a Jak-3 inhibitor. Confocal microscopy data revealed that stress triggers a phosphorylation and thereby activation of Jak-3 in the hippocampus. Amitriptyline, a commonly used antidepressant that blocks the acid sphingomyelinase, or acid sphingomyelinase-deficiency reduced stress-induced phosphorylation of Jak-3. CONCLUSION: Our data show that Jak-3 is activated by stress at least partially via the acid sphingomyelinase and is involved in the mediation of stress-induced major depression. PMID- 27487098 TI - Letter from the editor: the campaign button. PMID- 27487097 TI - Long-Term Outcomes, Genetics, and Pituitary Morphology in Patients with Isolated Growth Hormone Deficiency and Multiple Pituitary Hormone Deficiencies: A Single Centre Experience of Four Decades of Growth Hormone Replacement. AB - BACKGROUND: Growth hormone (GH) has been used to treat children with GH deficiency (GHD) since 1966. AIMS: Using a combined retrospective and cross sectional approach, we explored the long-term outcomes of patients with GHD, analysed factors influencing therapeutic response, determined persistence into adulthood, investigated pituitary morphology, and screened for mutations in causative genes. METHODS: The files of 96 GH-deficient children were reviewed. In a subset of 50 patients, re-assessment in adulthood was performed, including GHRH arginine testing, pituitary magnetic resonance imaging (MRI), and mutational screening for the growth hormone-1 gene (GH1) and the GHRH receptor gene (GHRHR) in isolated GHD (IGHD), and HESX1, PROP1, POU1F1, LHX3, LHX4, and GLI2 in multiple pituitary hormone deficiency (MPHD) patients. RESULTS: GH was started at a height SDS of -3.2 +/- 1.4 in IGHD patients and of -4.1 +/- 2.1 in MPHD patients. Relative height gain was 0.3 SDS/year, absolute gain 1.6 SDS, and 1.2/2.6 SDS in IGHD/MPHD, respectively. Mid-parental target height was reached in 77%. Initial height SDS, bone age retardation and duration of GH replacement were correlated with height SDS gain. GHD persisted into adulthood in 19 and 89% of subjects with IGHD and MPHD, respectively. In 1/42 IGHD patients a GH1 mutation was detected; PROP1 mutations were found in 3/7 MPHD subjects. Anterior pituitary hypoplasia, combined with posterior pituitary ectopy and pituitary stalk invisibility on MRI, was an exclusive finding in MPHD patients. CONCLUSIONS: GH replacement successfully corrects the growth deficit in children with GHD. While the genetic aetiology remains undefined in most cases of IGHD, PROP1 mutations constitute a major cause for MPHD. Persistence of GHD into adulthood is related to abnormal pituitary morphology. PMID- 27487099 TI - The role of talimogene laherparepvec (T-VEC) in the age of checkpoint inhibitors. PMID- 27487100 TI - Are we ready for precision medicine in acute myeloid leukemia? PMID- 27487101 TI - Sorafenib in combination with transarterial chemoembolization for the treatment of hepatocellular carcinoma. PMID- 27487102 TI - Highlights in kidney cancer from the 2016 American Society of Clinical Oncology Annual Meeting. PMID- 27487103 TI - Recent advances in the management of myelofibrosis. PMID- 27487104 TI - Improving clinical trial design through quantitative pharmacology. PMID- 27487105 TI - Moving beyond monotherapy in the immunotherapeutic arena: prospects for combination therapies in lung cancer. PMID- 27487106 TI - The status of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in ovarian cancer, part 1: olaparib. AB - Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown promising clinical activity in epithelial ovarian cancer. Following the observation in vitro that PARP inhibition is synthetically lethal in tumors with BRCA mutations, PARP inhibition has become the first genotype-directed therapy for BRCA1- and BRCA2-associated ovarian cancer. However, it is becoming clear that PARP inhibition also may have clinical utility in cancers associated with defects or aberrations in DNA repair that are unrelated to BRCA mutations. Deficient DNA repair mechanisms are present in approximately 30% to 50% of high grade serous ovarian cancers, the most common histologic subtype. Olaparib is the best-studied PARP inhibitor to date, and a number of phase 3 trials with this agent are underway. This article reviews the development of olaparib for ovarian cancer and discusses the current evidence for its use, ongoing studies, future research directions, and the challenges ahead. PMID- 27487107 TI - Trifluridine/tipiracil and regorafenib: new weapons in the war against metastatic colorectal cancer. AB - Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States. Approximately 20% of patients have metastatic disease at diagnosis, and a vast number of these patients die within 5 years. The advent of modern chemotherapeutics has improved median overall survival for these patients; nonetheless, we must keep striving for better outcomes. Trifluridine/tipiracil (TAS-102) and regorafenib are agents newly approved by the US Food and Drug Administration that show promise in the treatment of metastatic colorectal cancer. These drugs have the benefit of being formulated for oral administration and have different side effect profiles. These differences are important in the selection of the best therapy for each patient, especially if the patient is prone to a side effect that is unique to just one of the treatments. In this review, we discuss the mechanism of action, side effect profile, and clinical efficacy of trifluridine/tipiracil, and compare them with those of regorafenib. Future trials will evaluate the use of these drugs in earlier lines of therapy, alone and in combination with other agents. We now have 2 more agents in the arsenal against metastatic colorectal cancer and the future is looking brighter for patients, although we still have a long way to go. PMID- 27487108 TI - Impact of XRCC1, GSTP1, and GSTM1 Polymorphisms on the Survival of Ovarian Carcinoma Patients Treated with Chemotherapy. AB - BACKGROUND: Single nucleotide polymorphic variants of DNA repair genes may improve drug efficacy through altering expression levels of the encoded proteins. This study evaluated the influence of genetic polymorphism GSTP1 Ile105Val, GSTM1 (null/non-null) and 2 XRCC1 polymorphisms (Arg194Trp and Arg399Gln) on the survival of ovarian carcinoma patients treated with chemotherapy. METHODS: 106 patients received treatment with a carboplatin-based or alternative chemotherapy. Polymorphisms were genotyped by pyrosequencing. RESULTS: The genotypes XRCC1 194Arg/Trp and XRCC1 194Trp/Trp conferred no significant risk of death when compared to 194Arg/Arg (hazard ratio (HR) 1.01, 95% confidence interval (CI) 0.33 3.09, and HR 0.89, 95% CI 0.31-2.57, respectively). Similarly, those carrying the XRCC1 399Arg/Gln genotype had no increased risk of death compared to the XRCC1 399Arg/Arg (HR 0.85, 95% CI 0.39-1.86); no homozygous carriers of the glutamine allele (XRCC1 399 Gln/Gln) were detected. The GSTP1 105Ile/Val had no increased risk of death compared to the GSTP1 105Ile/Ile (HR = 1.20, 95% CI = 0.55-2.63) and no homozygous carriers of the valine allele (GSTP1 105Val/Val) were detected in the study. Compared to the non-null genotype of GSTM1, the mortality rate was nonsignificantly reduced in patients with the null genotype (HR 1.07, 95% CI 0.48 2.42). However, overall survival of the patients treated with the carboplatin based regimen was significantly longer than for those treated with alternative chemotherapy (plog-rank = 0.006). CONCLUSIONS: The present findings suggest that there are no correlations between genotypes and survival. PMID- 27487109 TI - Post-Operative Infection Is an Independent Risk Factor for Worse Long-Term Survival after Colorectal Cancer Surgery. AB - BACKGROUND: Colorectal cancer surgery is associated with a high incidence of post operative infections, the outcome of which may be improved if diagnosed and treated early enough. We compared white blood cell (WBC) count, C-reactive protein (CRP), and procalcitonin (PCT) as predictors of post-operative infections and analyzed their impact on long-term survival. METHODS: This retrospective study included 186 patients undergoing colorectal surgery. Post-operative values of WBC, CRP, and PCT were analyzed by the receiver operating characteristic (ROC) analysis. We followed infections 30 d after the surgery. A five-year survival was analyzed by Kaplan-Meier method and prognostic factors by Cox regression model. RESULTS: Fifty-five patients (29.5%) developed post-operative infection, the most frequent of which was surgical site infection (SSI). C-reactive protein on post operative day three and PCT on post-operative day two demonstrated the highest diagnostic accuracy for infection (area under the curve [AUC] 0.739 and 0.735). C reactive protein on post-operative day three was an independent predictor of infection. Five-year survival was higher in the non-infected group (70.8%), compared with the infected group (52.1%). The worst survival (40.9%) was identified in patients with organ/space SSI. Post-operative infection and tumor stage III-IV were independent predictors of a worse five-year survival. CONCLUSIONS: C-reactive protein on post-operative day three and PCT on post operative day two may be early predictors of infection after colorectal cancer surgery. Post-operative infections in particular organ/space SSI have a negative impact on long-term survival. PMID- 27487110 TI - Veterinary Student Confidence after Practicing with a New Surgical Training Model for Feline Ovariohysterectomy. AB - Lack of confidence and self-efficacy are the main causes of negative emotions experienced by veterinary students when performing surgery. A surgical training model (STM) was developed to test the hypothesis that practical training on an STM before performing live surgery would enhance the students' confidence. In addition, low-cost and easily accessible materials were used for the construction. In the STM, neodymium magnets that were detached if too much traction was applied were used to ensure careful tissue handling during ligation of the ovarian pedicles and cervix. A pilot study was performed to evaluate veterinary undergraduate students' confidence when using the STM before performing their first live feline ovariohysterectomy (OHE) as lead surgeon. The results showed that the students rated their confidence level higher after performing feline OHE if they had practiced with the STM before surgery. Voluntary written comments revealed that live surgery as a learning situation could have a very negative emotional impact on some students. PMID- 27487111 TI - Assessing Professionalism: A Theoretical Framework for Defining Clinical Rotation Assessment Criteria. AB - Although widely accepted as an important graduate competence, professionalism is a challenging outcome to define and assess. Clinical rotations provide an excellent opportunity to develop student professionalism through the use of experiential learning and effective feedback, but without appropriate theoretical frameworks, clinical teachers may find it difficult to identify appropriate learning outcomes. The adage "I know it when I see it" is unhelpful in providing feedback and guidance for student improvement, and criteria that are more specifically defined would help students direct their own development. This study sought first to identify how clinical faculty in one institution currently assess professionalism, using retrospective analysis of material obtained in undergraduate teaching and faculty development sessions. Subsequently, a faculty workshop was held in which a round-table type discussion sought to develop these ideas and identify how professionalism assessment could be improved. The output of this session was a theoretical framework for teaching and assessing professionalism, providing example assessment criteria and ideas for clinical teaching. This includes categories such as client and colleague interaction, respect and trust, recognition of limitations, and understanding of different professional identities. Each category includes detailed descriptions of the knowledge, skills, and behaviors expected of students in these areas. The criteria were determined by engaging faculty in the development of the framework, and therefore they should represent a focused development of criteria already used to assess professionalism, and not a novel and unfamiliar set of assessment guidelines. The faculty-led nature of this framework is expected to facilitate implementation in clinical teaching. PMID- 27487112 TI - A Guide for Making Valid Interpretations of Student Evaluation of Teaching (SET) Results. AB - Student evaluations of teaching (SETs) are conducted in virtually every veterinary medical school in the world. Results of these evaluations are typically used to evaluate faculty performance and often serve as the primary basis for promotion and tenure decisions. However, given the high-stakes nature of these evaluations, it is critical that stakeholders (faculty, curriculum committees, department chairs, deans, etc.) be able to identify the extent to which the scores are likely to be valid or not. Thus, the purpose of this article was to develop a guide for faculty and administrators to assess the interpretative validity of SET scores given an array of sample size, response rate, and score standard deviation possibilities. PMID- 27487113 TI - Use of Examination Wrappers to Direct Student Self-Assessment of Examination Preparation: A Pilot Study. AB - Metacognition is the act of thinking about one's own thought processes. There are long-term gains in learning among students who are trained to understand how the brain works and how they can control their own learning. Wrappers are short questionnaires provided at or near the time of completion of a lecture, assignment, or assessment to coach the student in thinking through the steps of metacognition (planning, monitoring, and adapting). As students completed the second and third of four examinations in a first-year veterinary anatomy course, they were invited to fill out an examination wrapper that asked them questions about examination preparation, where they felt they had had the most trouble with the examination, and what they might do differently before the next examination. Neither percentage change in scores from the second to the third and from the third to the fourth lecture or laboratory examination nor final grade for the course varied between the group of students who completed an examination wrapper and the group that did not. Students did not appear to change their behavior from one examination to the next. This was most likely because students lacked formal training in metacognition and therefore did not understand the value of completing the examination wrapper or the potential benefits of using their reflections. Future work will describe outcomes when learning objectives specific to metacognition are included in coursework in the veterinary curriculum. PMID- 27487114 TI - Prohibiting Students from Asking Questions during Exams: A Guideline for Promoting Fairness and Preserving Score Validity. AB - Many medical and professional programs implement policies that prohibit students from asking questions during examinations. The reasoning behind these policies remains unclear to some, as there is a lack of literature addressing this topic. The purpose of this article is to present the rationale behind such policies and to discuss why these policies may help promote fairness and preserve score validity. PMID- 27487115 TI - Micro-mechanical modelling of cellulose aerogels from molten salt hydrates. AB - In this paper, a generalised micro-mechanical model capable of capturing the mechanical behaviour of polysaccharidic aerogels, in particular cellulose aerogels, is proposed. To this end, first the mechanical structure and properties of these highly nanoporous cellulose aerogels prepared from aqueous salt hydrate melts (calcium thiocyanate, Ca(SCN)2.6H2O and zinc chloride, ZnCl2.4H2O) are studied. The cellulose content within these aerogels is found to have a direct relation to the microstructural quantities such as the fibril length and diameter. This, along with porosity, appears to influence the resulting mechanical properties. Furthermore, experimental characterisation of cellulose aerogels was done using scanning electron microscopy (SEM), pore-size data analysis, and compression tests. Cellulose aerogels are of a characteristic cellular microstructures and accordingly a network formed by square shaped cells is considered in the micro-mechanical model proposed in this paper. This model is based on the non-linear bending and collapse of such cells of varying pore sizes. The extended Euler-Bernoulli beam theory for large deflections is used to describe the bending in the cell walls. The proposed model is physically motivated and demonstrates a good agreement with our experimental data of both ZnCl2 and Ca(SCN)2 based cellulose aerogels with different cellulose contents. PMID- 27487116 TI - Effectiveness and Economic Evaluation of Chiropractic Care for the Treatment of Low Back Pain: A Systematic Review of Pragmatic Studies. AB - BACKGROUND CONTEXT: Low back pain (LBP) is one of the leading causes of disability worldwide and among the most common reasons for seeking primary sector care. Chiropractors, physical therapists and general practitioners are among those providers that treat LBP patients, but there is only limited evidence regarding the effectiveness and economic evaluation of care offered by these provider groups. PURPOSE: To estimate the clinical effectiveness and to systematically review the literature of full economic evaluation of chiropractic care compared to other commonly used care approaches among adult patients with non-specific LBP. STUDY DESIGN: Systematic reviews of interventions and economic evaluations. METHODS: A comprehensive search strategy was conducted to identify 1) pragmatic randomized controlled trials (RCTs) and/or 2) full economic evaluations of chiropractic care for low back pain compared to standard care delivered by other healthcare providers. Studies published between 1990 and 4th June 2015 were considered. Primary outcomes included pain, functional status and global improvement. Study selection, critical quality appraisal and data extraction were conducted by two independent reviewers. Data from RCTs with low risk of bias were included in a meta-analysis to determine effect estimates. Cost estimates of full economic evaluations were converted to 2015 USD and results summarized using Slavin's qualitative best-evidence synthesis. RESULTS: Six RCTs and three full economic evaluations were scientifically admissible. Five RCTs with low risk of bias compared chiropractic care to exercise therapy (n = 1), physical therapy (n = 3) and medical care (n = 1). Overall, we found similar effects for chiropractic care and the other types of care and no reports of serious adverse events. Three low to high quality full economic evaluations studies (one cost-effectiveness, one cost-minimization and one cost-benefit) compared chiropractic to medical care. Given the divergent conclusions (favours chiropractic, favours medical care, equivalent options), mixed-evidence was found for economic evaluations of chiropractic care compared to medical care. CONCLUSION: Moderate evidence suggests that chiropractic care for LBP appears to be equally effective as physical therapy. Limited evidence suggests the same conclusion when chiropractic care is compared to exercise therapy and medical care although no firm conclusion can be reached at this time. No serious adverse events were reported for any type of care. Our review was also unable to clarify whether chiropractic or medical care is more cost-effective. Given the limited available evidence, the decision to seek or to refer patients for chiropractic care should be based on patient preference and values. Future studies are likely to have an important impact on our estimates as these were based on only a few admissible studies. PMID- 27487117 TI - The Influence of Climate Change Efficacy Messages and Efficacy Beliefs on Intended Political Participation. AB - Using an online survey experiment with a national sample, this study examined how changing the type and valence of efficacy information in news stories discussing global climate change may impact intended political participation through the mediators of perceived internal, external, and response efficacy. Overall, the results revealed that after a single exposure to a news story, stories including positive internal efficacy content increased perceived internal efficacy, while stories including negative external efficacy content lowered perceived external efficacy. There were limited impacts of other types of efficacy content on perceived efficacy. Perceived internal, external, and response efficacy all offered unique, positive associations with intentions to engage in climate change related political participation. The results suggest that news stories including positive internal efficacy information in particular have the potential to increase public engagement around climate change. The implications for science communication are discussed. PMID- 27487119 TI - Correction to Direct Tracking of Amyloid and Tau Dynamics in Neuroblastoma Cells Using Nanoplasmonic Fiber Tip Probes. PMID- 27487118 TI - Pancreatic Fibroblasts Stimulate the Motility of Pancreatic Cancer Cells through IGF1/IGF1R Signaling under Hypoxia. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by its hypovascularity, with an extremely poor prognosis because of its highly invasive nature. PDAC proliferates with abundant stromal cells, suggesting that its invasive activity might be controlled by intercellular interactions between cancer cells and fibroblasts. Using four PDAC cell lines and two pancreas cancer-associated fibroblasts (CAFs), the expression of insulin-like growth factor-1 (IGF1) and IGF1 receptor (IGF1R) was evaluated by RT-PCR, FACScan, western blot, or ELISA. Correlation between IGF1R and the hypoxia marker carbonic anhydrase 9 (CA9) was examined by immunohistochemical staining of 120 pancreatic specimens. The effects of CAFs, IGF1, and IGF1R inhibitors on the motility of cancer cells were examined by wound-healing assay or invasion assay under normoxia (20% O2) and hypoxia (1% O2). IGF1R expression was significantly higher in RWP-1, MiaPaCa-2, and OCUP-AT cells than in Panc-1 cells. Hypoxia increased the expression level of IGF1R in RWP-1, MiaPaCa-2, and OCUP-AT cells. CA9 expression was correlated with IGF1R expression in pancreatic specimens. CAFs produced IGF1 under hypoxia, but PDAC cells did not. A conditioned medium from CAFs, which expressed alphaSMA, stimulated the migration and invasion ability of MiaPaCa-2, RWP-1, and OCUP-AT cells. The motility of all PDAC cells was greater under hypoxia than under normoxia. The motility-stimulating ability of CAFs was decreased by IGF1R inhibitors. These findings might suggest that pancreas CAFs stimulate the invasion activity of PDAC cells through paracrine IGF1/IGF1R signaling, especially under hypoxia. Therefore the targeting of IGF1R signaling might represent a promising therapeutic approach in IGF1R-dependent PDAC. PMID- 27487120 TI - Siderophores in Cloud Waters and Potential Impact on Atmospheric Chemistry: Photoreactivity of Iron Complexes under Sun-Simulated Conditions. AB - In the present work, the photoreactivity of a mixture of iron(III)-pyoverdin (Fe(III)-Pyo) complexes was investigated under simulated cloud conditions. Pyoverdins are expected to complex ferric ions naturally present in cloudwater, thus modifying their availability and photoreactivity. The spectroscopic properties and photoreactivity of Fe(III)-Pyo were investigated, with particular attention to their fate under solar irradiation, also studied through simulations. The photolysis of the Fe(III)-Pyo complex leads to the generation of Fe(II), with rates of formation (RFe(II)f) of 6.98 and 3.96 * 10-9 M s-1 at pH 4.0 and 6.0, respectively. Interestingly, acetate formation was observed during the iron-complex photolysis, suggesting that fragmentation can occur after the ligand-to-metal charge transfer (LMCT) via a complex reaction mechanism. Moreover, photogenerated Fe(II) represent an important source of hydroxyl radical via the Fenton reaction in cloudwater. This reactivity might be relevant for the estimation of the rates of formation and steady-state concentrations of the hydroxyl radical by cloud chemistry models and for organic matter speciation in the cloud aqueous phase. In fact, the conventional models, which describe the iron photoreactivity in terms of iron-aqua and oxalate complexes, are not in accordance with our results. PMID- 27487121 TI - Effect of the Chronic Use of Lithium Carbonate on Induced Tooth Movement in Wistar Rats. AB - Patients who seek dental treatment may have bipolar disorder, and lithium carbonate (LC) is the drug of choice used in the treatment of this disorder. Taking into consideration the controversial results found in the literature, and the possible influence of LC on induced tooth movement, the objective was to evaluate tooth movement induced in rats after administration of lithium carbonate. One hundred and ninety-two rats were divided into 3 groups. In the L group, the animals received daily 60mg/kg of LC, they were not subjected to orthodontic movement, and they were euthanized after 33, 37, 44 or 51 days. In the LM group, the LC was administered for 30 days and during the subsequent 3, 7, 14 and 21 days, corresponding to the period of induced tooth movement, and they received a spring that produced a 30cN force. In the SM group, saline solution was applied. Measurements were made of tooth displacement, the numbers of osteoclasts and serum lithium phosphate (PO4), alkaline phosphatase (ALP) and creatinine levels. The tooth displacement was lower in the LM group compared to the SM group at 44 days. A tendency toward reduction in the number of osteoclasts was observed in the LM group compared to the SM group at 44 days. The average lithium were higher in the L and LM groups compared to the SM group. The opposite was observed for the PO4 group. A higher value for the ALP was found in the L group. The average creatinine level was lower in the LM group. LC inhibited tooth movement for 14 days, possibly due to the reduction in the number of osteoclasts. PMID- 27487122 TI - Interleukin-11 promotes epithelial-mesenchymal transition in anaplastic thyroid carcinoma cells through PI3K/Akt/GSK3beta signaling pathway activation. AB - Metastasis is the major cause of treatment failure in anaplastic thyroid carcinoma (ATC) patients. In the preliminary study, we demonstrated that interleukin (IL)-11 expression is positively correlated with distant metastasis in ATC. However, the mechanisms underlying remain largely unknown. Here, we found that cobalt chloride (a hypoxia mimetic) promoted IL-11 expression via HIF-1alpha activation. Furthermore, the resultant increase in IL-11 expression significantly induced epithelial-mesenchymal transition (EMT) in ATC cells, accompanied by Akt/GSK3beta pathway activation and increased invasive and migratory abilities. Conversely, HIF-1alpha or IL-11 knockdown, or treating cells with a neutralizing antibody against IL-11, a PI3K inhibitor, or Akt inhibitor V, significantly suppressed the induction of EMT and counteracted the enhancements in invasive and migratory abilities. These results indicate that hypoxia increases IL-11 secretion in ATC cells via HIF-1alpha induction and that IL-11 then induces EMT in these cells via the PI3K/Akt/GSK3beta pathway, ultimately improving their invasive and migratory potential. This study elucidates the prometastatic role played by IL-11 in ATC metastasis and indicates it as a potential target for the treatment of cancer metastasis. However, many questions remain to be explored. PMID- 27487123 TI - KDM4B-mediated epigenetic silencing of miRNA-615-5p augments RAB24 to facilitate malignancy of hepatoma cells. AB - Emerging evidence indicates that dysregulation of microRNAs (miRNAs) contributes to hepatocellular carcinoma (HCC) tumorigenesis and development. Here, we found that miR-615-5p was obviously downregulated in HCC. Furthermore, the deficiency of demethylase KDM4B stimulated the CpG methylation of miR-615-5p promoter and then decreased the miR-615-5p expression. The Ras-related protein RAB24 was found to be downregulated by miR-615-5p. The low level of miR-615-5p increased the expression of RAB24 and facilitated HCC growth and metastasis in vitro and in vivo. Moreover, miR-615-5p suppresses HCC cell growth by influencing cell cycle progression and apoptosis. Downregulation of miR-615-5p and upregulation of RAB24 promotes the epithelial-mesenchymal transition (EMT), adhesion and vasculogenic mimicry (VM) of HCC cells, all of which contribute to cell motility and metastasis. Thus, miR-615-5p, who is downregulated by KDM4B-mediated hypermethylation in its promoter, functions as a tumor suppressor by inhibiting RAB24 expression in HCC. In conclusion, our findings characterize miR-615-5p as an important epigenetically silenced miRNA involved in the Rab-Ras pathway in hepatocellular carcinoma and expand our understanding of the molecular mechanism underlying hepatocarcinogenesis and metastasis. PMID- 27487124 TI - Downregulated pseudogene CTNNAP1 promote tumor growth in human cancer by downregulating its cognate gene CTNNA1 expression. AB - Accumulating evidence indicates that deregulation of cancer-associated pseudogene is involved in the pathogenesis of cancer. In the study, we demonstrated that pseudogene CTNNAP1, for the CTNNA1 gene, was dysregulated in colorectal cancer and the degree of dysregulation was remarkably associated with tumor node metastasis (TNM) stage (P<0.05). The mechanistic experiments revealed that pseudogene CTNNAP1 played a pivotal role in the regulation of its cognate gene CTNNA1 by competition for microRNA-141. Moreover, gain-of-function approaches showed that overexpression of CTNNAP1 or CTNNA1 significantly inhibited cell proliferation and tumor growth in vitro and in vivo by inducing G0/G1 cell cycle arrest. Our findings add a new regulatory circuit via competing endogenous RNA (ceRNA) cross-talk between pseudogene CTNNAP1 and its cognate gene CTNNA1, and provide new insights into potential diagnostic biomarker for monitoring human colorectal cancer. PMID- 27487125 TI - The application of mRNA-based gene transfer in mesenchymal stem cell-mediated cytotoxicity of glioma cells. AB - Since the tumor-oriented homing capacity of mesenchymal stem cells (MSCs) was discovered, MSCs have attracted great interest in the research field of cancer therapy mainly focused on their use as carries for anticancer agents. Differing from DNA-based vectors, the use of mRNA-based antituor gene delivery benefits from readily transfection and mutagenesis-free. However, it is essential to verify if mRNA transfection interferes with MSCs' tropism and their antitumor properties. TRAIL- and PTEN-mRNAs were synthesized and studied in an in vitro model of MSC-mediated indirect co-culture with DBTRG human glioma cells. The expression of TRAIL and PTEN in transfected MSCs was verified by immunoblotting analysis, and the migration ability of MSCs after anticancer gene transfection was demonstrated using transwell co-cultures. The viability of DBTRG cells was determined with bioluminescence, live/dead staining and real time cell analyzer. An in vivo model of DBTRG cell-derived xenografted tumors was used to verify the antitumor effects of TRAIL- and PTEN-engineered MSCs. With regard to the effect of mRNA transfection on MSCs' migration toward glioma cells, an enhanced migration rate was observed with MSCs transfected with all tested mRNAs compared to non-transfected MSCs (p<0.05). TRAIL- and PTEN-mRNA-induced cytotoxicity of DBTRG glioma cells was proportionally correlated with the ratio of conditioned medium from transfected MSCs. A synergistic action of TRAIL and PTEN was demonstrated in the current co-culture model. The immunoblotting analysis revealed the apoptotic nature of the cells death in the present study. The growth of the xenografted tumors was significantly inhibited by the application of MSCPTEN or MSCTRAIL/PTEN on day 14 and MSCTRAIL on day 28 (p<0.05). The results suggested that anticancer gene-bearing mRNAs synthesized in vitro are capable of being applied for MSC-mediated anticancer modality. This study provides an experimental base for further clinical anticancer studies using synthesized mRNAs. PMID- 27487126 TI - LncRNA RSU1P2 contributes to tumorigenesis by acting as a ceRNA against let-7a in cervical cancer cells. AB - Long non-coding RNAs (lncRNAs) can regulate gene expression at different levels and are widely participate in various physiological and pathological processes. Emerging evidences suggests that a number of differentially expressed lncRNAs are involved in tumorigenesis. However, the function and expression regulation of a vast majority of these unique RNAs is little known. Here, we found that the lncRNA Ras suppressor protein 1 pseudogene 2 (RSU1P2) is upregulateded in cervical cancer tissues and has a tumour-promoting role. We revealed that RSU1P2 acts as a competitive endogenous RNA (ceRNA) through regulating the expression of IGF1R, N-myc and EphA4. The mechanism of this regulation is via competition for the shared microRNA let-7a. This competition promotes the malignant phenotype of cervical carcinoma cells. The transcription factor N-myc forms a positive feedback loop with RSU1P2 by in turn activating its expression, thereby enhancing its oncogenic capacity. Hence, cancer-selective targeting of RSU1P2 could have strong benefits. PMID- 27487127 TI - miR-145 sensitizes breast cancer to doxorubicin by targeting multidrug resistance associated protein-1. AB - Multidrug resistance-associated protein 1 (MRP1) is an important efflux transporter and overexpression of MRP1 usually leads to chemoresistance in breast cancer. Here, we found MRP1 overexpressed in human breast cancer tissues and breast cancer cell lines (compared with normal breast tissues and cell line, respectively). And MRP1 level increased in doxorubicin resistant MCF-7 cells compared with parental MCF-7 cells. Increasing evidences suggest microRNAs (miRNAs) influence chemotherapy response. We found miR-145 level decreased in human breast cancer tissues, breast cancer cell lines and doxorubicin resistant MCF-7 cells, and inversely correlated with MRP1 expression level. In the process of constructing MCF-7 doxorubicin resistant cell line, escalating doxorubicin markedly decreased miR-145 level, following by increased MRP1 level. Further study showed, miR-145 suppressed MRP1 expression by directly targeting MRP1 3' untranslated regions. Overexpression of miR-145 sensitized breast cancer cells to doxorubicin in vitro and enhanced to doxorubicin chemotherapy in vivo through inducing intracellular doxorubicin accumulation via inhibiting MRP1. Taken together, our study revealed miR-145 sensitizes breast cancer to doxorubicin by targeting MRP1 and indicated the potential application in developing MRP1 inhibitor. PMID- 27487128 TI - Ethacrynic acid improves the antitumor effects of irreversible epidermal growth factor receptor tyrosine kinase inhibitors in breast cancer. AB - Prolonged treatment of breast cancer with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often results in acquired resistance and a narrow therapeutic index. One strategy to improve the therapeutic effects of EGFR TKIs is to combine them with drugs used for other clinical indications. Ethacrynic acid (EA) is an FDA approved drug that may have antitumor effects and may enhance the cytotoxicity of chemotherapeutic agents by binding to glutathione and inhibiting WNT signaling. While the alpha,beta-unsaturated-keto structure of EA is similar to that of irreversible TKIs, the mechanism of action of EA when combined with irreversible EGFR TKIs in breast cancer remains unknown. We therefore investigated the combination of irreversible EGFR TKIs and EA. We found that irreversible EGFR TKIs and EA synergistically inhibit breast cancer both in vitro and in vivo. The combination of EGFR TKIs and EA induces necrosis and cell cycle arrest and represses WNT/beta-catenin signaling as well as MAPK-ERK1/2 signaling. We conclude that EA synergistically enhances the antitumor effects of irreversible EGFR TKIs in breast cancer. PMID- 27487129 TI - Bortezomib-induced heat shock response protects multiple myeloma cells and is activated by heat shock factor 1 serine 326 phosphorylation. AB - Proteasome inhibitors such as bortezomib are highly active in multiple myeloma by affecting signaling cascades and leading to a toxic buildup of misfolded proteins. Bortezomib-treated cells activate the cytoprotective heat shock response (HSR), including upregulation of heat shock proteins (HSPs). Here we inhibited the bortezomib-induced HSR by silencing its master regulator, Heat Shock Factor 1 (HSF1). HSF1 silencing led to bortezomib sensitization. In contrast, silencing of individual and combination HSPs, except HSP40beta, did not result in significant bortezomib sensitization. However, HSP40beta did not entirely account for increased bortezomib sensitivity upon HSF1 silencing. To determine the mechanism of HSF1 activation, we assessed phosphorylation and observed bortezomib-inducible phosphorylation in cell lines and patient samples. We determined that this bortezomib-inducible event is phosphorylation at serine 326. Prior clinical use of HSP inhibitors in combination with bortezomib has been disappointing in multiple myeloma therapy. Our results provide a rationale for targeting HSF1 activation in combination with bortezomib to enhance multiple myeloma treatment efficacy. PMID- 27487130 TI - Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling. AB - The overall survival remains undesirable in clinical glioma treatment. Inhibition of DNA-PKcs activity by its inhibitors suppresses tumor growth and enhances chemosensitivity of several tumors to chemotherapy. However, whether DNA-PKcs could be a potential target in glioma therapy remains unknown. In this study, we reported that the hyperactivated DNA-PKcs was profoundly correlated with glioma malignancy and observe a significant association between DNA-PKcs activation and survival of the glioma patients. Our data also found that inhibition of DNA-PKcs by its inhibitor KU0060648 sensitized glioma cells to TMZ in vitro. Specifically, we demonstrated that KU0060648 interrupted the formation of DNA-PKcs/AKT complex, leading to suppression of AKT signaling and resultantly enhanced TMZ efficacy. Combination of KU0060648 and TMZ substantially inhibited downstream effectors of AKT. The in vivo results were similar to those obtained in vitro. In conclusion, this study indicated that inhibition of DNA-PKcs activity could suppress glioma malignancies and increase TMZ efficacy, which was mainly through regulation of the of AKT signaling. Therefore, DNA-PKcs/AKT axis may be a promising target for improving current glioma therapy. PMID- 27487131 TI - Integrin beta3 and CD44 levels determine the effects of the OPN-a splicing variant on lung cancer cell growth. AB - Osteopontin (OPN), a phosphorylated glycoprotein, is frequently overexpressed in cancer. Among the three OPN isoforms, OPN-a is the most highly expressed in lung cancer cell lines and lung tumors. Overexpression of OPN-a greatly reduced CL1-5 lung adenocarcinoma cell growth, but had no effect on growth in A549 lung adenocarcinoma cells. Examination of the expression of integrins and CD44, which are possible OPN-a receptors, revealed that differences in integrin beta3 levels might explain this discrepancy between CL1-5 and A549 cells. When integrin beta3 was ectopically expressed in A549 cells, OPN-a inhibited their growth, whereas OPN-a increased cell growth following integrin beta3 knockdown in CL1-5 cells. This OPN-a-induced increase in growth appeared to result from activation of the CD44/NFkappaB pathway. Our results demonstrated that OPN-a inhibits growth of cells with high integrin beta3 levels and increases growth via activation of the CD44/NFkappaB pathway in cells with low integrin beta3 levels. Thus, OPN-a, integrin beta3, and CD44 interact to affect lung cancer cell growth, and this study may aid in the development of cancer treatment strategies involving these molecules. PMID- 27487132 TI - YMO1 suppresses invasion and metastasis by inhibiting RhoC signaling and predicts favorable prognosis in hepatocellular carcinoma. AB - Previous studies have shown that 4.1 proteins, which are deregulated in many cancers, contribute to cell adhesion and motility. Yurt/Mosaic eyes-like 1 (YMO1) is a member of 4.1 protein family but it is unclear whether YMO1 plays a role in tumor invasion. This study aimed to investigate the effects of YMO1 on hepatocellular carcinoma (HCC) and attempted to elucidate the underlying molecular mechanisms. YMO1 expression in HCC tissues and its correlation with clinicopathological features and postoperative prognosis was analyzed. The results showed that YMO1 was down-regulated in the highly metastatic HCC cell line and in human tumor tissues. Underexpression of YMO1 indicated poor prognosis of HCC patients. Restoration of YMO1 expression caused a significant decrease in cell migration and invasiveness in vitro. In vivo study showed that YMO1 reduced liver tumor invasion and metastasis in xenograft mice. YMO1 directly inhibited RhoC activation. YMO1 expression in HCC was regulated by PAX5. Analysis of YMO1 expression levels in human HCC patients revealed a significant correlation of YMO1 expression with PAX5 and RhoC. Our findings revealed that YMO1 predicts favorable prognosis and the data suggest that YMO1 suppresses tumor invasion and metastasis by inhibiting RhoC activity. PMID- 27487134 TI - Overcoming chemoresistance in prostate cancer with Chinese medicine Tripterygium wilfordii via multiple mechanisms. AB - A leading cause of cancer chemotherapy failure is chemoresistance, which often involves multiple mechanisms. Chinese medicines (CM) usually contain multiple components which could potentially target many mechanisms simultaneously and may offer an advantage over single compounds that target one mechanism at a time. The purpose of this study was to investigate the chemosensitizing effect (CE) of a specific CM, Tripterygium wilfordii (TW), on prostate cancer cells resistant to docetaxel (Dtx) and identify the potential mechanisms. The CE of TW (in combination with Dtx) was evaluated in two Dtx resistant prostate cancer cell lines (PC3-TxR and DU145-TxR) and the efficacy of the combination for resistant PC3-TxR tumor was investigated using a xenograft mouse model. For mechanistic study, the inhibitory effect of TW on P-glycoprotein activity was assessed. In addition, novel gene targets of TW were identified using DNA microarray and quantitative PCR. Results showed that TW induced a CE of 8 and >38 folds in PC3 TxR and DU145-TxR cells, respectively with Dtx IC50 reversed back to that of the sensitive parent cells. An optimum dose of TW+Dtx significantly retarded tumor growth in mice compared to TW or Dtx alone. TW inhibited P-glycoprotein activity and induced a significant gene expression changes in genes related to angiogenesis, cell cycle regulation and differentiation. Our in vitro and in vivo studies demonstrate that TW in combination with Dtx was able to overcome the chemoresistance and suppress resistant prostate tumor growth via multi mechanisms. PMID- 27487135 TI - Tumor exosome-mediated promotion of adhesion to mesothelial cells in gastric cancer cells. AB - BACKGROUND: Peritoneal metastasis consists of a highly complex series of steps, and the details of the underlying molecular mechanism remain largely unclear. In this study, the effects of tumor-derived exosomes (TEX) on the progression of gastric cancers were investigated in peritoneal metastasis. RESULTS: TEX were internalized in both mesothelial and gastric cancer cells in a cellular origin non-specific manner. Internalization of TEX into mesothelial cells promoted significant adhesion between mesothelial and gastric cancer cells, and TEX internalization into gastric cancer cells significantly promoted migratory ability, while internalization of mesothelial cell-derived exosomes did not. Expression of adhesion-related molecules, such as fibronectin 1 (FN1) and laminin gamma 1 (LAMC1), were increased in mesothelial cells after internalization of TEX from gastric cancer cell line and malignant pleural effusion. METHODS: TEX were extracted from cell-conditioned medium by ultracentrifugation. The effects of TEX on the malignant potential of gastric cancer were investigated in adhesion, invasion, and proliferation assays. PCR array as well as western blotting were performed to determine the underlying molecular mechanisms. The molecular changes in mesothelial cell after internalization of TEX derived from malignant pleural effusion were also confirmed. CONCLUSIONS: TEX may play a critical role in the development of peritoneal metastasis of gastric cancer, which may be partially due to inducing increased expression of adhesion molecules in mesothelial cells. PMID- 27487136 TI - Caveolin-1 promotes Ewing sarcoma metastasis regulating MMP-9 expression through MAPK/ERK pathway. AB - Ewing sarcoma (ES) is a bone and soft tissue sarcoma affecting mostly children and young adults. Caveolin-1 (CAV1) is a well-known target of EWS/FLI1, the main driver of ES, with an oncogenic role in ES. We have previously described how CAV1 is able to induce metastasis in ES via matrix metalloproteinase-9 (MMP-9). In the present study we showed how CAV1 silencing in ES reduced MEK1/2 and ERK1/2 phosphorylation. Accordingly, chemical inhibition of MEK1/2 resulted in reduction in MMP-9 expression and activity that correlated with reduced migration and invasion. IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) silencing reduced MEK1/2 and ERK1/2 phosphorylation and MMP-9 expression. Furthermore, IQGAP1 silenced cells showed a marked decrease in their migratory and invasive capacity. We demonstrated that CAV1 and IQGAP1 localize in close proximity at the cellular edge, thus IQGAP1 could be the connecting node between CAV1 and MEK/ERK in ES metastatic phenotype. Analysis of the phosphorylation profile of CAV1 silenced cells showed a decrease of p-ribosomal protein S6 (RPS6). RPS6 can be phosphorylated by p90 ribosomal S6 kinases (RSK) proteins. CAV1-silenced cells showed reduced levels of p-RSK1 and treatment with U0126 provoked the same effect. Despite not affecting ERK1/2 and RPS6 phosphorylation status neither MMP 9 expression nor activity, RSK1 silencing resulted in a reduced migratory and invasive capacity in vitro and reduced incidence of metastases in vivo in a novel orthotopic model. The present work provides new insights into CAV1-driven metastatic process in ES unveiling novel key nodes. PMID- 27487137 TI - Decreased expression of FOXF2 as new predictor of poor prognosis in stage I non small cell lung cancer. AB - BACKGROUND: Forkhead box F2 (FOXF2) is relatively limited to the adult lung, but its contribution to non-small cell lung cancer (NSCLC) prognosis is unclear. RESULTS: FOXF2 mRNA levels in NSCLC were lower than that in paired normal lung tissues (P = 0.012). The FOXF2low patients had shorter survival time than the FOXF2high patients (P = 0.024) especially in stage I (P = 0.002), chemotherapy (P = 0.018) and < 60 age groups (P = 0.002). Lower FOXF2 mRNA levels could independently predict poorer survival for patients with NSCLC (HR = 2.384, 95% CI = 1.241-4.577; P = 0.009), especially in stage I (HR =4.367, 95% CI =1.599 11.925; P = 0.004). The two independent datasets confirmed our findings. METHODS: We examined FOXF2 mRNA levels in 84 primary NSCLC and 8 normal lung tissues using qRT-PCR. Rank-sum tests and chi-square tests were used to assess the differences among groups with various clinicopathological factors. Kaplan-Meier tests were used to compare survival status in patients with different FOXF2 mRNA levels. Cox proportional hazards regression model was used to evaluate the predictive value of FOXF2 mRNA level in NSCLC patients. Independent validation was performed using an independent dataset (98 samples) and an online survival analysis software Kaplan-Meier plotter (1928 samples). CONCLUSIONS: Our results demonstrated that decreased FOXF2 expression is an independent predictive factor for poor prognosis of patients with NSCLC, especially in stage I NSCLC. PMID- 27487138 TI - The microRNA signature of patients with sunitinib failure: regulation of UHRF1 pathways by microRNA-101 in renal cell carcinoma. AB - Molecular targeted therapy is a standard treatment for patients with advanced renal cell carcinoma (RCC). Sunitinib is one of the most common molecular targeted drugs for metastatic RCC. Molecular mechanisms of sunitinib resistance in RCC cells is still ambiguous. The microRNA (miRNA) expression signature of patients with sunitinib failure in RCC was constructed using a polymerase chain reaction (PCR)-based array. Several miRNAs that were aberrantly expressed in RCC tissues from patients treated with sunitinib were identified in this analysis. MicroRNA-101 (miR- 101) was markedly suppressed in sunitinib treated RCC tissues. Restoration of miR-101 significantly inhibited cell migration and invasion in Caki-1 and 786-O cells. Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) was directly suppressed by miR-101 in RCC cells, and overexpression of UHRF1 was confirmed in sunitinib-treated RCC tissues. The pathways of nucleotide excision repair and mismatch repair were significantly suppressed by knockdown of UHRF1. Our findings showed that antitumor miR-101- mediated UHRF1 pathways may be suppressed by sunitinib treatment. PMID- 27487139 TI - Construction and analysis of dysregulated lncRNA-associated ceRNA network identified novel lncRNA biomarkers for early diagnosis of human pancreatic cancer. AB - It is increasing evidence that ceRNA activity of long non-coding RNAs (lncRNAs) played critical roles in both normal physiology and tumorigenesis. However, functional roles and regulatory mechanisms of lncRNAs as ceRNAs in pancreatic ductal adenocarcinoma (PDAC), and their potential implications for early diagnosis remain unclear. In this study, we performed a genome-wide analysis to investigate potential lncRNA-mediated ceRNA interplay based on "ceRNA hypothesis". A dysregulated lncRNA-associated ceRNA network (DLCN) was constructed by utilizing sample-matched miRNA, lncRNA and mRNA expression profiles in PDAC and normal samples in combination with miRNA regulatory network. The results of network analysis uncovered seven novel lncRNAs as functional ceRNAs whose aberrant expression will result in the extensive variation in tumorigenic or tumor-suppressive gene expression through DLCN at the post transcriptional level contributing to PDAC. Therefore, we developed a 7-lncRNA signature (termed LncRisk-7) based on the expression data of seven lncRNAs and SVM algorithm as a novel diagnostic tool to improve early diagnosis of PDAC. The LncRisk-7 achieved high performance in distinguishing PDAC patients from nonmalignant pancreas samples in the discovery cohort and was further confirmed in another two independent validation cohorts. Functional analysis demonstrated that seven lncRNA biomarkers act as ceRNAs involving the regulation of cell death, cell adhesion and cell cycle. This study will help to improve our understanding of the lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of PDAC and provide novel lncRNAs as candidate diagnostic biomarkers or potential therapeutic targets. PMID- 27487140 TI - High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer. AB - We studied the changes of intratumoral stromal proteins including THBS1, TNC, FN, SPARC and alpha-SMA, following neoadjuvant chemotherapy. The underlying mechanisms by which THBS1 and TNC regulated resistance to docetaxel were further studied using functional studies. 100 patients with newly diagnosed breast cancer were treated with alternating sequential doxorubicin and docetaxel. Immunohistochemistry (IHC) staining for stromal proteins was performed on pre- and post-treatment core biopsies respectively. THBS1 and TNC were further validated with IHC in an independent cohort of 31 patients. A high baseline combined expression score of the 5 stromal proteins predicted independently for poor progression-free (HRadjusted 2.22, 95% CI 1.06-4.64) and overall survival (HRadjusted 5.94, 95% CI 2.25-15.71). After 1-2 cycles of chemotherapy, increased expression of THBS1, TNC, FN, SPARC and alpha-SMA was seen in patients with subsequent pathological lymph node involvement at surgery. Increased expression of THBS1 and TNC compared to baseline was also seen in intrinsically resistant tumors, but not in sensitive ones. Both THBS1 and TNC-associated chemoresistance were confirmed in an independent validation cohort. Exogenous THBS1 and TNC protected MCF-7 cells against proliferation inhibition induced by docetaxel through activating integrin beta1/mTOR pathway. Thus, up-regulation of THBS1, TNC, FN, SPARC and alpha-SMA following neoadjuvant chemotherapy was associated with chemotherapy resistance in breast cancer patients. Functional studies showed THBS1 and TNC to mediate chemoresistance through the integrin beta1/mTOR pathway, suggesting that therapies targeting integrin beta1/mTOR pathway may be a promising strategy to overcome chemotherapy resistance. PMID- 27487141 TI - Integrin alphaVbeta3 silencing sensitizes malignant glioma cells to temozolomide by suppression of homologous recombination repair. AB - Integrins have been suggested as possible targets in anticancer therapy. Here we show that knockdown of integrins alphaVbeta3, alphaVbeta5, alpha3beta1 and alpha4beta1 and pharmacological inhibition using a cyclo-RGD integrin alphaVbeta3/alphaVbeta5 antagonist sensitized multiple high-grade glioma cell lines to temozolomide (TMZ)-induced cytotoxicity. The greatest effect was observed in LN229 cells upon integrin beta3 silencing, which led to inhibition of the FAK/Src/Akt/NFkappaB signaling pathway and increased formation of gammaH2AX foci. The integrin beta3 knockdown led to the proteasomal degradation of Rad51, reduction of Rad51 foci and reduced repair of TMZ-induced DNA double-strand breaks by impairing homologous recombination efficiency. The down-regulation of beta3 in Rad51 knockdown (LN229-Rad51kd) cells neither further sensitized them to TMZ nor increased the number of gammaH2AX foci, confirming causality between beta3 silencing and Rad51 reduction. RIP1 was found cleaved and IkappaBalpha significantly less degraded in beta3-silenced/TMZ-exposed cells, indicating inactivation of NFkappaB signaling. The anti-apoptotic proteins Bcl-xL, survivin and XIAP were proteasomally degraded and caspase-3/-2 cleaved. Increased H2AX phosphorylation, caspase-3 cleavage, reduced Rad51 and RIP1 expression, as well as sustained IkappaBalpha expression were also observed in mouse glioma xenografts treated with the cyclo-RGD inhibitor and TMZ, confirming the molecular mechanism in vivo. Our data indicates that beta3 silencing in glioma cells represents a promising strategy to sensitize high-grade gliomas to TMZ therapy. PMID- 27487142 TI - Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma. AB - Bevacizumab is used to treat glioblastoma; however, no current biomarker predicts its efficacy. We used an exploratory cohort of patients treated with the radiochemotherapy then bevacizumab or chemotherapy at recurrence (N = 265). Bevacizumab use increased median overall survival (OS) 18.7 vs 11.3 months, p = 0.0014). In multivariate analysis, age, initial surgery, neutrophil count, Karnofsky status >70% and bevacizumab administration were independent prognostic factors of survival. We found an interaction between bevacizumab use and baseline neutrophil count. The cut-off value for the neutrophil count was set at 6000/mm3. Only patients with a high neutrophil count benefited from the bevacizumab treatment (17.3 vs 8.8 months p < 0.0001). We validated this result using data from the TEMAVIR trial, which tested the efficacy of neoadjuvant bevacizumab plus irinotecan versus radiochemotherapy in the first-line treatment of glioblastoma. Transcriptomic data from TCGA underlined that CSF3 expression, the gene encoding G-CSF, the growth factor for neutrophils, correlated with VEGF-A-dependent angiogenesis. In another independent cohort (BELOB trial), which compared lomustine versus lomustine plus bevacizumab at recurrence, bevacizumab only benefited patients with high CSF3 expression in the tumor. These data suggest that only patients with a high peripheral neutrophil count before bevacizumab treatment benefited from this therapy. PMID- 27487143 TI - Targeting Zfp148 activates p53 and reduces tumor initiation in the gut. AB - The transcription factor Zinc finger protein 148 (Zfp148, ZBP-89, BFCOL, BERF1, htbeta) interacts physically with the tumor suppressor p53, but the significance of this interaction is not known. We recently showed that knockout of Zfp148 in mice leads to ectopic activation of p53 in some tissues and cultured fibroblasts, suggesting that Zfp148 represses p53 activity. Here we hypothesize that targeting Zfp148 would unleash p53 activity and protect against cancer development, and test this idea in the APCMin/+ mouse model of intestinal adenomas. Loss of one copy of Zfp148 markedly reduced tumor numbers and tumor-associated intestinal bleedings, and improved survival. Furthermore, after activation of beta-catenin the initiating event in colorectal cancer-Zfp148 deficiency activated p53 and induced apoptosis in intestinal explants of APCMin/+ mice. The anti-tumor effect of targeting Zfp148 depended on p53, as Zfp148 deficiency did not affect tumor numbers in APCMin/+ mice lacking one or both copies of Trp53. The results suggest that Zfp148 controls the fate of newly transformed intestinal tumor cells by repressing p53 and that targeting Zfp148 might be useful in the treatment of colorectal cancer. PMID- 27487145 TI - Repair of UVB-induced DNA damage is reduced in melanoma due to low XPC and global genome repair. AB - UVB exposure leads to DNA damage, which when unrepaired induces C>T transitions. These mutations are found throughout the melanoma genome, particularly in non transcribed regions. The global genome repair (GGR) branch of nucleotide excision repair (NER) is responsible for repairing UV-induced DNA damage across non transcribed and silent regions of the genome. This study aimed to examine the relationship between UVB and GGR in melanoma. DNA repair capacity and relative expression of NER in melanocytes and melanoma cell lines before and after treatment with UVB was quantified. Transcript expression from 196 melanomas was compared to clinical parameters including solar elastosis and whole transcriptome data collected. Melanoma cell lines showed significantly reduced DNA repair when compared to melanocytes, most significantly in the S phase of the cell cycle. Expression of GGR components XPC, DDB1 and DDB2 was significantly lower in melanoma after UVB. In the melanoma tumours, XPC expression correlated with age of diagnosis and low XPC conferred significantly poorer survival. The same trend was seen in the TCGA melanoma dataset. Reduced GGR in melanoma may contribute to the UV mutation spectrum of the melanoma genome and adds further to the growing evidence of the link between UV, NER and melanoma. PMID- 27487144 TI - Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer. AB - Prostate cancer (PCa) is the most widely diagnosed male cancer in the Western World and while low- and intermediate-risk PCa patients have a variety of treatment options, metastatic patients are limited to androgen deprivation therapy (ADT). This treatment paradigm has been in place for 75 years due to the unique role of androgens in promoting growth of prostatic epithelial cells via the transcription factor androgen receptor (AR) and downstream signaling pathways. Within 2 to 3 years of ADT, disease recurs-at which time, patients are considered to have castration-recurrent PCa (CR-PCa). A universal mechanism by which PCa becomes resistant to ADT has yet to be discovered. In this review article, we discuss underlying molecular mechanisms by which PCa evades ADT. Several major resistance pathways center on androgen signaling, including intratumoral and adrenal androgen production, AR-overexpression and amplification, expression of AR mutants, and constitutively-active AR splice variants. Other ADT resistance mechanisms, including activation of glucocorticoid receptor and impairment of DNA repair pathways are also discussed. New therapies have been approved for treatment of CR-PCa, but increase median survival by only 2-8 months. We discuss possible mechanisms of resistance to these new ADT agents. Finally, the practicality of the application of "precision oncology" to this continuing challenge of therapy resistance in metastatic or CR-PCa is examined. Empirical validation and clinical-based evidence are definitely needed to prove the superiority of "precision" treatment in providing a more targeted approach and curative therapies over the existing practices that are based on biological "cause-and-effect" relationship. PMID- 27487146 TI - Nomogram and recursive partitioning analysis to predict overall survival in patients with stage IIB-III thoracic esophageal squamous cell carcinoma after esophagectomy. AB - We have developed statistical models for predicting survival in patients with stage IIB-III thoracic esophageal squamous cell carcinoma (ESCC) and assessing the efficacy of adjuvant treatment. From a retrospective review of 3,636 patients, we created a database of 1,004 patients with stage IIB-III thoracic ESCC who underwent esophagectomy with or without postoperative radiation. Using a multivariate Cox regression model, we assessed the prognostic impact of clinical and histological factors on overall survival (OS). Logistic analysis was performed to identify factors to include in a recursive partitioning analysis (RPA) to predict 5-year OS. The nomogram was evaluated internally based on the concordance index (C-index) and a calibration plot. The median survival time in the training dataset was 30.9 months, and the 5-year survival rate was 33.9%. T stage, differentiated grade, adjuvant treatment, tumor location, lymph node metastatic ratio (LNMR), and the presence of vascular carcinomatous thrombi were statistically significant predictors of 5-year OS. The C-index of the nomogram was 0.70 (95% CI 0.67-0.73). RPA resulted in a three-class stratification: class 1, LNMR <= 0.15 with adjuvant treatment; class 2, LNMR <= 0.15 without adjuvant treatment and LNMR > 0.15 with adjuvant treatment; and class 3, LNMR > 0.15 without adjuvant treatment. The three classes were statistically significant for OS (P < 0.001). Thus, the nomogram and RPA models predicted the prognosis of stage IIB-III ESCC patients and could be used in decision-making and clinical trials. PMID- 27487147 TI - Significant impact of amount of PCR input templates on various PCR-based DNA methylation analysis and countermeasure. AB - Methylation changes of CpG islands can be determined using PCR-based assays. However, the exact impact of the amount of input templates (TAIT) on DNA methylation analysis has not been previously recognized. Using COL2A1 gene as an input reference, TAIT difference between human tissues with methylation-positive and -negative detection was calculated for two representative genes GFRA1 and P16. Results revealed that TAIT in GFRA1 methylation-positive frozen samples (n = 332) was significantly higher than the methylation-negative ones (n = 44) (P < 0.001). Similar difference was found in P16 methylation analysis. The TAIT related effect was also observed in methylation-specific PCR (MSP) and denatured high performance liquid chromatography (DHPLC) analysis. Further study showed that the minimum TAIT for a successful MethyLight PCR reaction should be >= 9.4 ng (CtCOL2A1 <= 29.3), when the cutoff value of the methylated-GFRA1 proportion for methylation-positive detection was set at 1.6%. After TAIT of the methylation non-informative frozen samples (n = 94; CtCOL2A1 > 29.3) was increased above the minimum TAIT, the methylation-positive rate increased from 72.3% to 95.7% for GFRA1 and 26.6% to 54.3% for P16, respectively (Ps < 0.001). Similar results were observed in the FFPE samples. In conclusion, TAIT critically affects results of various PCR-based DNA methylation analyses. Characterization of the minimum TAIT for target CpG islands is essential to avoid false-negative results. PMID- 27487149 TI - Intra-tumoral delivery of functional ID4 protein via PCL/maltodextrin nano particle inhibits prostate cancer growth. AB - ID4, a helix loop helix transcriptional regulator has emerged as a tumor suppressor in prostate cancer. Epigenetic silencing of ID4 promotes prostate cancer whereas ectopic expression in prostate cancer cell lines blocks cancer phenotype. To directly investigate the anti-tumor property, full length human recombinant ID4 encapsulated in biodegradable Polycaprolactone/Maltodextrin (PCL MD) nano-carrier was delivered to LNCaP cells in which the native ID4 was stably silenced (LNCaP(-)ID4). The cellular uptake of ID4 resulted in increased apoptosis, decreased proliferation and colony formation. Intratumoral delivery of PCL-MD ID4 into growing LNCaP(-)ID4 tumors in SCID mice significantly reduced the tumor volume compared to the tumors treated with chemotherapeutic Docetaxel. The study supports the feasibility of using nano-carrier encapsulated ID4 protein as a therapeutic. Mechanistically, ID4 may assimilate multiple regulatory pathways for example epigenetic re-programming, integration of multiple AR co-regulators or signaling pathways resulting in tumor suppressor activity of ID4. PMID- 27487151 TI - ABCC2-24C > T polymorphism is associated with the response to platinum/5-Fu-based neoadjuvant chemotherapy and better clinical outcomes in advanced gastric cancer patients. AB - Several studies have evaluated the efficacy of neoadjuvant treatment using oxaliplatin and fluoropyrimidines in advanced gastric cancer (GC). However, preoperative biomarkers predictive of clinical outcome remain lacking. We examined polymorphisms in the MTHFR, DPYD, UMPS, ABCB1, ABCC2, GSTP1, ERCC1, and XRCC1 genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 103 GC patients treated with preoperative chemotherapy. DNA was extracted from peripheral blood cells, and the genotypes were analyzed using a SNaPShotTM assay, polymerase chain reaction amplification, and sequencing. The ABCC2-24C > T (rs717620) genotype was associated with pathologic response to neoadjuvant chemotherapy. Patients with the TT and TC genotypes responded to neoadjuvant chemotherapy 3.80 times more often than those with the CC genotype (95% CI: 1.27 11.32). Patients with the CC genotype also had poorer outcomes than those with other genotypes. Thus, ABCC2-24C > T polymorphism may help to predict the response to preoperative chemotherapy in GC patients. PMID- 27487152 TI - Thromboxane A2 receptor (TBXA2R) is a potent survival factor for triple negative breast cancers (TNBCs). AB - Triple Negative Breast Cancer (TNBC) is defined by the lack of ERalpha, PR expression and HER2 overexpression and is the breast cancer subtype with the poorest clinical outcomes. Our aim was to identify genes driving TNBC proliferation and/or survival which could represent novel therapeutic targets.We performed microarray profiling of primary TNBCs and generated differential genelists based on clinical outcomes following the chemotherapy regimen FEC (5 Fluorouracil/Epirubicin/Cyclophosphamide -'good' outcome no relapse > 3 years; 'poor' outcome relapse < 3 years). Elevated expression of thromboxane A2 receptor (TBXA2R) was observed in 'good' outcome TNBCs. TBXA2R expression was higher specifically in TNBC cell lines and TBXA2R knockdowns consistently showed dramatic cell killing in TNBC cells. TBXA2R mRNA and promoter activities were up regulated following BRCA1 knockdown, with c-Myc being required for BRCA1-mediated transcriptional repression.We demonstrated that TBXA2R enhanced TNBC cell migration, invasion and activated Rho signalling, phenotypes which could be reversed using Rho-associated Kinase (ROCK) inhibitors. TBXA2R also protected TNBC cells from DNA damage by negatively regulating reactive oxygen species levels. In summary, TBXA2R is a novel breast cancer-associated gene required for the survival and migratory behaviour of a subset of TNBCs and could provide opportunities to develop novel, more effective treatments. PMID- 27487153 TI - Novel functions of Fanconi anemia proteins in selective autophagy and inflammation. PMID- 27487155 TI - Incipient periodontitis and salivary molecules among Korean adults: association and screening ability. AB - AIM: This study aims to evaluate the association of salivary matrix metalloproteinase-9 (MMP-9) and interleukin-8 (IL-8) with periodontitis and its screening ability on periodontitis. MATERIAL AND METHODS: We selected 693 participants from the Yanypyeong Cohort: 577 participants with periodontitis and 116 participants without periodontitis. Periodontitis was assessed by dentists using a panoramic radiograph. Salivary MMP-9 and IL-8 were assayed using multiplexed bead immunoassay (Luminex). MMP-9 and IL-8 were categorized into low, medium and high. Age, sex, income, smoking, drinking, exercise, obesity and metabolic syndrome were confounders. Logistic regression analysis was applied to evaluate the association between MMP-9, IL-8 and periodontitis. Receiver operating characteristic curve was applied for sensitivity, specificity and c statistics. RESULTS: High MMP-9 and medium IL-8 were associated with periodontitis: adjusted odds ratio were 2.2 [95% confidence interval (CI): 1.3 3.7] for MMP-9 and 1.9 (95% CI: 1.1-3.4) for IL-8. The final screening model using salivary MMP-9 for periodontitis had a sensitivity of 0.46, specificity of 0.77 and c-statistic of 0.63 (p < 0.001). CONCLUSIONS: Our data show that salivary MMP-9 and IL-8 could be potential markers for periodontitis. The screening model for periodontitis could be useful in clinics and home. A future prospective study is indicated for predicting the occurrence of periodontitis. PMID- 27487154 TI - Monocyte-derived factors including PLA2G7 induced by macrophage-nasopharyngeal carcinoma cell interaction promote tumor cell invasiveness. AB - The non-keratinizing undifferentiated subtype of nasopharyngeal carcinoma (NPC) is a malignancy characterized by an intimate relationship between neoplastic cells and a non-neoplastic lymphoid component. Tumor-associated macrophages (TAMs) foster tumor progression through production of soluble mediators that support proliferation, angiogenesis, survival and invasion of malignant cells. However, the role of macrophages in the progression of NPC remains poorly understood. This study aims to investigate the functional and phenotypic changes that occur to macrophages in macrophage-NPC cell co-culture systems, and how these changes influence tumor cells. We found that monocytes, including THP-1 cells and primary human monocytes, co-cultured with C666-1 NPC cells upregulate expression of pro-inflammatory cytokines at the early stages, followed by the induction of metastasis-related genes and interferon-stimulated genes at the later stage of coculture, indicating that TAMs are "educated" by NPC cells for cancer progression. Importantly, the induction of these factors from the TAMs was also found to enhance the migratory capabilities of the NPC cells. We have also identified one of these macrophage-derived factor, phospholipase A2 Group 7 (PLA2G7), to be important in regulating tumor cell migration and a novel tumor promoting factor in NPC. Further studies to characterize the role of PLA2G7 in tumor metastasis may help determine its potential as a therapeutic target in NPC. PMID- 27487156 TI - Non-Esterified Fatty Acids Profiling in Rheumatoid Arthritis: Associations with Clinical Features and Th1 Response. AB - OBJECTIVES: Since lipid compounds are known to modulate the function of CD4+ T cells and macrophages, we hypothesize that altered levels of serum non-esterified fatty acids (NEFA) may underlie rheumatoid arthritis (RA) pathogenesis. METHODS: Serum levels of NEFA (palmitic, stearic, palmitoleic, oleic, linoleic, gamma linoleic, arachidonic -AA-, linolenic, eicosapentaenoic -EPA- and docosahexaenoic -DHA-) were quantified by LC-MS/MS after methyl-tert-butylether (MTBE)-extraction in 124 RA patients and 56 healthy controls (HC). CD4+ phenotype was studied by flow cytometry. TNFalpha, IL-8, VEGF, GM-CSF, IFNgamma, IL-17, CCL2, CXCL10, leptin and resistin serum levels were quantified by immunoassays. The effect of FA on IFNgamma production by PBMC was evaluated in vitro. RESULTS: Lower levels of palmitic (p<0.0001), palmitoleic (p = 0.002), oleic (p = 0.010), arachidonic (p = 0.027), EPA (p<0.0001) and DHA (p<0.0001) were found in RA patients, some NEFA being altered at onset. Cluster analysis identified a NEFA profile (hallmarked by increased stearic and decreased EPA and DHA) overrepresented in RA patients compared to HC (p = 0.002), being associated with clinical features (RF, shared epitope and erosions), increased IFNgamma expression in CD4+ T-cells (p = 0.002) and a Th1-enriched serum milieu (IFNgamma, CCL2 and CXCL10, all p<0.005). In vitro assays demonstrated that imbalanced FA could underlie IFNgamma production by CD4+ T-cells. Finally, changes on NEFA levels were associated with clinical response upon TNFalpha-blockade. CONCLUSION: An altered NEFA profile can be found in RA patients associated with clinical characteristics of aggressive disease and enhanced Th1 response. These results support the relevance of lipidomic studies in RA and provide a rationale for new therapeutic targets. PMID- 27487157 TI - B Cell Receptor Activation Predominantly Regulates AKT-mTORC1/2 Substrates Functionally Related to RNA Processing. AB - Protein kinase B (AKT) phosphorylates numerous substrates on the consensus motif RXRXXpS/T, a docking site for 14-3-3 interactions. To identify novel AKT-induced phosphorylation events following B cell receptor (BCR) activation, we performed proteomics, biochemical and bioinformatics analyses. Phosphorylated consensus motif-specific antibody enrichment, followed by tandem mass spectrometry, identified 446 proteins, containing 186 novel phosphorylation events. Moreover, we found 85 proteins with up regulated phosphorylation, while in 277 it was down regulated following stimulation. Up regulation was mainly in proteins involved in ribosomal and translational regulation, DNA binding and transcription regulation. Conversely, down regulation was preferentially in RNA binding, mRNA splicing and mRNP export proteins. Immunoblotting of two identified RNA regulatory proteins, RBM25 and MEF-2D, confirmed the proteomics data. Consistent with these findings, the AKT-inhibitor (MK-2206) dramatically reduced, while the mTORC-inhibitor PP242 totally blocked phosphorylation on the RXRXXpS/T motif. This demonstrates that this motif, previously suggested as an AKT target sequence, also is a substrate for mTORC1/2. Proteins with PDZ, PH and/or SH3 domains contained the consensus motif, whereas in those with an HMG-box, H15 domains and/or NF-X1-zinc-fingers, the motif was absent. Proteins carrying the consensus motif were found in all eukaryotic clades indicating that they regulate a phylogenetically conserved set of proteins. PMID- 27487159 TI - Variation in the use of point-of-care ultrasound in general practice in various European countries. Results of a survey among experts. AB - BACKGROUND: Before implementing point-of-care ultrasound in general practice in Denmark, we sought inspiration from other countries/regions. OBJECTIVES: To collect information about the use and organizational aspects of point-of-care ultrasound in general practice in different European countries/regions. METHODS: Fifteen key persons with knowledge about the use of ultrasound in general practice in Austria, Catalonia, Denmark, Finland, Germany, Greenland, Iceland, the Netherlands, Norway, Scotland, Sweden, and Switzerland were included. Participants received a link to a web-based questionnaire. The primary outcome measures were educational aspects regarding the use of point-of-care ultrasound; clinical application and use; financial aspects; and main barriers to using ultrasound in general practice. RESULTS: In eight out of 12 countries/regions there were national societies for the use of ultrasound in general practice. The respondents from three countries/regions reported that the use of ultrasound was integrated into undergraduate medical education. In nine of the countries/regions, there was formalized training for general practitioners, but only three reported this to be part of the specialization to become a general practitioner. In seven out of 12 countries/regions, general practitioners received payment for ultrasound scans. However, the payment and the requirements for reimbursement differed between countries. Lack of time, lack of training, and financial aspects were important common barriers across countries/regions. CONCLUSION: There were significant differences regarding the use and organizational aspects of point-of-care ultrasound in general practice in Europe. Lack of time and training as well as financial aspects were important barriers to the use of point-of-care ultrasound in general practice.[Box: see text]. PMID- 27487158 TI - New Initiation of Long-Acting Opioids in Long-Stay Nursing Home Residents. AB - OBJECTIVES: To estimate the prevalence of new initiation of long-acting opioids since introduction of national efforts to increase prescriber and public awareness on safe use of transdermal fentanyl patches. DESIGN: Cross-sectional. SETTING: U.S. nursing homes (NHs). PARTICIPANTS: Medicare-enrolled long-stay NH residents (N = 22,253). MEASUREMENTS: Minimum Data Set 3.0 was linked with Medicare enrollment, hospital claims, and prescription drug transaction data (January-December 2011) and used to determine the prevalence of new initiation of a long-acting opioid prescribed to residents in NHs. RESULTS: Of NH residents prescribed a long-acting opioid within 30 days of NH admission (n = 12,278), 9.4% (95% confidence interval = 8.9-9.9%) lacked a prescription drug claim for a short acting opioid in the previous 60 days. The most common initial prescriptions of long-acting opioids were fentanyl patch (51.9% of opioid-naive NH residents), morphine sulfate (28.1%), and oxycodone (17.2%). CONCLUSION: New initiation of long-acting opioids-especially fentanyl patches, which have been the subject of safety communications-persists in NHs. PMID- 27487160 TI - Ethnic Differences in Mental Illness Severity: A Population-Based Study of Chinese and South Asian Patients in Ontario, Canada. AB - OBJECTIVE: Little is known about the sociocultural determinants of mental illness at hospital presentation. Our objective was to examine ethnic differences in illness severity at hospital admission among Chinese, South Asian, and the general population living in Ontario, Canada. METHODS: We conducted a large, population-based, cross-sectional study of psychiatric inpatients aged from 19 to 105 years who were discharged between 2006 and 2014. A total of 133,588 patients were classified as Chinese (n = 2,582), South Asian (n = 2,452), or the reference group (n = 128,554) using a validated surnames algorithm (specificity: 99.7%). Diagnoses were based on DSM-IV criteria. We examined the association between ethnicity and 4 measures of disease severity: involuntary admissions, aggressive behaviors, and the number and frequency of positive symptoms (ie, hallucinations, command hallucinations, delusions, and abnormal thought process) (Positive Symptoms Scale, Resident Assessment Instrument-Mental Health [RAI-MH]). RESULTS: After adjusting for sociodemographic characteristics, immigration status, and discharge diagnosis, Chinese patients had greater odds of involuntary admissions (odds ratio [OR] = 1.79; 95% CI, 1.64-1.95) and exhibiting severe aggressive behaviors (OR = 1.36; 95% CI, 1.23-1.51) and >= 3 positive symptoms (OR = 1.39; 95% CI, 1.24-1.56) compared to the general population. South Asian ethnicity was also an independent predictor of most illness severity measures. The association between Chinese ethnicity and illness severity was consistent across sex, diagnostic and immigrant categories, and first-episode hospitalization. CONCLUSIONS: Chinese and South Asian ethnicities are independent predictors of illness severity at hospital presentation. Understanding the role of patient, family, and health system factors in determining the threshold for hospitalization is an important future step in informing culturally specific care for these large and growing populations worldwide. PMID- 27487161 TI - Comparison of two apheresis systems during hematopoietic progenitor stem cell collections at a tertiary medical center. AB - BACKGROUND: The Spectra Optia is a newer apheresis system developed based on the COBE Spectra platform. COBE Spectra requires more manual control, while Spectra Optia offers greater automation. The purpose of this study was to compare the two systems during hematopoietic progenitor stem cell (HPSC) collections. STUDY DESIGN AND METHODS: A retrospective review of 41 collections performed in 26 subjects at a tertiary medical center between June 1, 2013, and December 31, 2013, was conducted, 11 with the Spectra Optia and 30 with the COBE Spectra. Six patients underwent two consecutive daily collections, first on the Spectra Optia followed by the COBE Spectra. RESULTS: Procedure run time with the Spectra Optia was considerably longer than with the COBE Spectra (283 +/- 11 min vs. 217 +/- 2 min, respectively; p < 0.01). Mean CD34+ cell yields with the Spectra Optia were comparable with those of the COBE Spectra. Products collected with the Spectra Optia had less red blood cell contamination. However, platelet (PLT) attrition was greater with the Spectra Optia. Similar results were obtained in patients who were collected on consecutive days in both systems. CONCLUSION: Collections with the Spectra Optia take longer and lead to greater PLT losses during HPSC collections. PMID- 27487162 TI - Disentangling the Causal Association of Plasma Lipid Traits and Type 2 Diabetes Using Human Genetics. PMID- 27487164 TI - Peripartum Depression, Traditional Culture, and Israeli Society. AB - Although it is known that culture affects psychopathology, the nature of the relationship between culture and peripartum depression (PPD) is not fully understood. Here we report on 2 cases of Israeli women who are affiliated with traditional cultural groups that emphasize reproduction but developed PPD after childbirth. The first woman is an ultra-Orthodox Israeli Jew and the second is an Israeli Arab. The 2 cases illustrate the effect of cultural beliefs and rituals on the conceptualization, treatment, and trajectory of PPD. The cases suggest a complex relationship between traditional cultures and PPD, including the possibility that cultural factors may have both adaptive and maladaptive consequences. Future qualitative and quantitative studies are needed to further clarify this relationship. PMID- 27487163 TI - Increased Lung Expression of Anti-Angiogenic Factors in Down Syndrome: Potential Role in Abnormal Lung Vascular Growth and the Risk for Pulmonary Hypertension. AB - BACKGROUND AND AIMS: Infants with Down syndrome (DS) or Trisomy 21, are at high risk for developing pulmonary arterial hypertension (PAH), but mechanisms that increase susceptibility are poorly understood. Laboratory studies have shown that early disruption of angiogenesis during development impairs vascular and alveolar growth and causes PAH. Human chromosome 21 encodes known anti-angiogenic factors, including collagen18a1 (endostatin, ES), beta-amyloid peptide (BAP) and Down Syndrome Critical Region 1 (DSCR-1). Therefore, we hypothesized that fetal lungs from subjects with DS are characterized by early over-expression of anti angiogenic factors and have abnormal lung vascular growth in utero. METHODS: Human fetal lung tissue from DS and non-DS subjects were obtained from a biorepository. Quantitative reverse transcriptase PCR (qRT-PCR) was performed to assay 84 angiogenesis-associated genes and individual qRT-PCR was performed for ES, amyloid protein precursor (APP) and DSCR1. Western blot analysis (WBA) was used to assay lung ES, APP and DSCR-1 protein contents. Lung vessel density and wall thickness were determined by morphometric analysis. RESULTS: The angiogenesis array identified up-regulation of three anti-angiogenic genes: COL18A1 (ES), COL4A3 (tumstatin) and TIMP3 (tissue inhibitor of metallopeptidase 3) in DS lungs. Single qRT-PCR and WBA showed striking elevations of ES and APP mRNA (p = 0.022 and p = 0.001) and protein (p = 0.040 and p = 0.002; respectively). Vessel density was reduced (p = 0.041) and vessel wall thickness was increased in DS lung tissue (p = 0.033) when compared to non-DS subjects. CONCLUSIONS: We conclude that lung anti-angiogenic factors, including COL18A1 (ES), COL4A3, TIMP3 and APP are over-expressed and fetal lung vessel growth is decreased in subjects with DS. We speculate that increased fetal lung anti angiogenic factor expression due to trisomy 21 impairs lung vascular growth and signaling, which impairs alveolarization and contributes to high risk for PAH during infancy. PMID- 27487165 TI - Rhizosphere selection of Pseudomonas putida KT2440 variants with increased fitness associated to changes in gene expression. AB - As the interface between plant roots and soil, the rhizosphere is a complex environment where nutrients released by the plant promote microbial growth. Increasing evidences indicate that the plant also exerts a selective pressure on microbial populations in the rhizosphere, favouring colonization by certain groups. In this work, we have designed an experimental setup to begin analysing the evolution of a specific bacterial population in the rhizosphere, using Pseudomonas putida KT2440 as model organism. After several rounds of selection without passage through laboratory growth conditions, derivatives of this strain with increased fitness in the rhizosphere were isolated. Detailed analysis of one of these clones indicated that this effect is specific for rhizosphere conditions and derives from changes in its transcriptional profile in this environment, with 43 genes being differentially expressed with respect to the parental strain. Several of these genes belong to functional categories which could affect stress adaptation and availability of particular nutrients. By inactivating two genes identified as upregulated in the selected clone (coding for a stress-response protein and a rRNA modifying protein), these functions were shown to contribute to rhizosphere fitness. Our data also suggest the existence of different evolutionary pathways leading to increased rhizosphere fitness. PMID- 27487166 TI - Construction of Electrochemical Chiral Interfaces with Integrated Polysaccharides via Amidation. AB - Polysaccharides of sodium carboxymethyl cellulose (CMC) and chitosan (CS) were integrated together via amidation reactions between the carboxyl groups on sodium CMC and the amino groups on CS. Compared with individual sodium CMC and CS, the integrated polysaccharides with a mass ratio of 1:1, CMC-CS (1:1), exhibited a three-dimensional (3D) porous network structure, resulting in a significantly enhanced hydrophility due to the exposed polar functional groups in the CMC-CS (1:1). Chiral interfaces were constructed with the integrated polysaccharides and used for electrochemical enantiorecognition of tryptophan (Trp) isomers. The CMC CS (1:1) chiral interfaces exhibited excellent selectivity toward the Trp isomers owing to the highly hydrophilic feature of CMC-CS (1:1) and the different steric hindrance during the formation of H bonds between Trp isomers and CMC-CS (1:1). Also, the optimization in the preparation of integrated polysaccharides such as mass ratio and combination mode (amidation or electrostatic interactions) was investigated. The CMC-CS (1:1) presented the ability of determining the percentage of d-Trp in racemic mixtures, and thus, the proposed electrochemical chiral interfaces could be regarded as a potential biosensing platform for enantiorecognition of chiral compounds. PMID- 27487167 TI - Triacetonide of Glucoheptonic Acid in the Scalable Syntheses of d-Gulose, 6-Deoxy d-gulose, l-Glucose, 6-Deoxy-l-glucose, and Related Sugars. AB - Ease of separation of petrol-soluble acetonides derived from the triacetonide of methyl glucoheptonate allows scalable syntheses of rare sugars containing the l gluco or d-gulo structural motif with any oxidation level at the C6 or C1 position of the hexose, usually without chromatography: meso-d-glycero-d guloheptitol available in two steps is an ideal entry point for the study of the biotechnological production of heptoses. PMID- 27487168 TI - Life dissatisfaction is associated with depression and poorer surgical outcomes among lumbar spinal stenosis patients: a 10-year follow-up study. AB - Life satisfaction is associated with overall somatic health and the short-term surgical outcome in lumbar spinal stenosis (LSS) patients. In this study, the long-term relationship between life satisfaction and the surgical outcome in LSS patients was investigated in a 10-year follow-up. This prospective clinical study included 102 LSS patients who underwent decompressive surgery. They completed a set of questionnaires first preoperatively and then 6 times postoperatively (at 3 and 6 months, and at 1, 2, 5 and 10 years). The final study population at the 10 year follow-up comprised 72 patients. A four-item life satisfaction scale was used to measure global life satisfaction. The sum of all seven life satisfaction scores provided a measure of the life dissatisfaction burden over the entire 10 year follow-up. Depression was measured using the Beck Depression Inventory. The surgical outcome was evaluated using the Oswestry Disability Index, pain evaluation (visual analogue scale), self-reported walking capacity and overall satisfaction with the surgery. Both preoperative life dissatisfaction and the long-term life dissatisfaction burden were associated with poorer 10-year surgical outcomes (i.e. Oswestry Disability Index and visual analogue scale) in logistic regression analyses. Life dissatisfaction was also associated with symptoms of depression. Monitoring subjective well-being, especially life satisfaction and mood, in LSS patients before and after surgery may help in detecting those at risk of a poorer long-term surgical outcome. PMID- 27487169 TI - Rectal Indomethacin to Prevent Post-ERCP Pancreatitis. PMID- 27487170 TI - Should We Still Administer Prophylactic Rectal NSAIDs to Average-Risk Patients Undergoing ERCP? PMID- 27487172 TI - Iron-Catalyzed Ortho C-H Methylation of Aromatics Bearing a Simple Carbonyl Group with Methylaluminum and Tridentate Phosphine Ligand. AB - Iron-catalyzed C-H functionalization of aromatics has attracted widespread attention from chemists in recent years, while the requirement of an elaborate directing group on the substrate has so far hampered the use of simple aromatic carbonyl compounds such as benzoic acid and ketones, much reducing its synthetic utility. We describe here a combination of a mildly reactive methylaluminum reagent and a new tridentate phosphine ligand for metal catalysis, 4-(bis(2 (diphenylphosphanyl)phenyl)phosphanyl)-N,N-dimethylaniline (Me2N-TP), that allows us to convert an ortho C-H bond to a C-CH3 bond in aromatics and heteroaromatics bearing simple carbonyl groups under mild oxidative conditions. The reaction is powerful enough to methylate all four ortho C-H bonds in benzophenone. The reaction tolerates a variety of functional groups, such as boronic ester, halide, sulfide, heterocycles, and enolizable ketones. PMID- 27487171 TI - Production of Plasmodium vivax enolase in Escherichia coli and its protective properties. AB - Plasmodium vivax predominates in South-East Asia and the American continent, causes significant morbidity and inflicts a huge socioeconomic burden. Sequencing completion of the Plasmodium vivax genome and transcriptome provides the chance to identify antigens. Enolase is the eighth enzyme in the glycolytic pathway, which, apart from its glycolytic function, also possess antigenic properties and is present on the cell wall of many invasive organisms, such as Candida albicans. In order to assess whether enolase of Plasmodium vivax is also antigenic, in this study, we first reported the expression and purification of recombinant Plasmodium vivax enolase (r-Pven) in Escherichia coli, using prokaryotic expression vector. The r-Pven was expressed in soluble form in E. coli, and the expression was verified by SDS-PAGE and western blotting analysis. The r-Pven was purified to 90% purity by nickel-nitrilotriacetic acid (Ni2+-NTA) resin chromatography. For reactivity with r-Pven, compared with the average values of the reactivity of control serum samples, the average values of the reactivity of 99 individual serums from vivax malaria patients appeared higher, and there was significant difference between them (p=0.0117<0.05). Mice anti-r-Pven antibodies inhibited the growth of in vitro cultures of P. falciparum. Mice immunized with r Pven showed protection against a challenge with the mouse malarial parasite Plasmodium berghei. The antibodies raised against r-Pven were specific for Plasmodium and did not react to the host tissues. These observations established Plasmodium vivax enolase to be a potential protective antigen. PMID- 27487173 TI - Human papillomavirus in oropharyngeal cancer: The changing face of a disease. AB - The last decade has brought about an unexpected rise in oropharyngeal squamous cell carcinoma (OPSCC) primarily in white males from the ages of 40-55years, with limited exposure to alcohol and tobacco. This subset of squamous cell carcinoma (SCC) has been found to be associated with human papillomavirus infection (HPV). Other Head and Neck Squamous Cell carcinoma (HNSCC) subtypes include oral cavity, hypopharyngeal, nasopharyngeal, and laryngeal SCC which tend to be HPV negative. HPV associated oropharyngeal cancer has proven to differ from alcohol and tobacco associated oropharyngeal carcinoma in regards to the molecular pathophysiology, presentation, epidemiology, prognosis, and improved response to chemoradiation therapy. Given the improved survival of patients with HPV associated SCC, efforts to de-intensify treatment to decrease treatment related morbidity are at the forefront of clinical research. This review will focus on the important differences between HPV and tobacco related oropharyngeal cancer. We will review the molecular pathogenesis of HPV related oropharyngeal cancer with an emphasis on new paradigms for screening and treating this disease. PMID- 27487174 TI - An update on pharmacotherapy for personality disorders. PMID- 27487175 TI - Red-Green-Blue Trichromophoric Nanoparticles with Dual Fluorescence Resonance Energy Transfer: Highly Sensitive Fluorogenic Response Toward Polyanions. AB - A red-green-blue (RGB) trichromophoric fluorescent organic nanoparticle exhibiting multi-colour emission was constructed; the blue-emitting cationic oligofluorene nanoparticle acted as an energy-donor scaffold to undergo fluorescence resonance energy transfer (FRET) to a red-emitting dye embedded in the nanoparticle (interior FRET) and to a green-emitting dye adsorbed on the surface through electrostatic interactions (exterior FRET). Each FRET event occurs independently and is free from sequential FRET, thus the resultant dual FRET system exhibits multi-colour emission, including white, in aqueous solution and film state. A characteristic white-emissive nanoparticle showed visible responses upon perturbation of the exterior FRET efficiency by acceptor displacement, leading to highly sensitive responses toward polyanions in a ratiometric manner. Specifically, our system exhibits high sensitivity toward heparin with an extremely low detection limit. PMID- 27487176 TI - Exploratory Study of Heart Rate Variability and Sleep among Emergency Medical Services Shift Workers. AB - OBJECTIVES: To characterize the continuity and duration of sleep, and to measure nocturnal cardiac autonomic balance via heart rate variability (HRV) in a group of emergency medical technicians (EMTs) on and off duty. METHODS: Fourteen EMTs completed an online, daily sleep log that recorded total sleep duration, bedtime, rise time, and the number of alarms that caused awakening. HRV was captured using a physiological status monitor (PSM) affixed to a chest strap during sleep. RESULTS: For the 7-day trial, each of the 14 EMTs logged three work days (WDs) and four non-work days (NWDs). They reported sleeping significantly fewer hours per night on WDs (6.4 +/- 2.1) than on NWDs (7.9 +/- 0.5; P < 0.05), and experienced more sleep disruptions on WDs (4.4 +/- 2.8) than on NWDs (1.3 +/- 2.2; P < 0.001) as measured by the number of alarms. Global and vagal indices of HRV during sleep were significantly reduced during WDs (Standard Deviation of Normal R-R Intervals (SDNN) = 43.4 +/- 2.0 ms and High Frequency (HF) = 24.3 +/- 1.2 ms2) when compared to NWDs (SDNN = 61.1 +/- 1.0 ms and HF = 42.7 +/- 1.5 ms2; P < 0.001). CONCLUSION: EMTs who worked 24-hour shifts had shorter, more fragmented sleep associated with greater cumulative exposure to increased sympathetic and decreased parasympathetic activity as measured via sleep HRV. These changes in cardiac autonomic tone constitute one plausible pathway through which sleep deprivation may increase risk for cardiovascular disease. PMID- 27487177 TI - Data-Driven Derivation of an "Informer Compound Set" for Improved Selection of Active Compounds in High-Throughput Screening. AB - Despite the usefulness of high-throughput screening (HTS) in drug discovery, for some systems, low assay throughput or high screening cost can prohibit the screening of large numbers of compounds. In such cases, iterative cycles of screening involving active learning (AL) are employed, creating the need for smaller "informer sets" that can be routinely screened to build predictive models for selecting compounds from the screening collection for follow-up screens. Here, we present a data-driven derivation of an informer compound set with improved predictivity of active compounds in HTS, and we validate its benefit over randomly selected training sets on 46 PubChem assays comprising at least 300,000 compounds and covering a wide range of assay biology. The informer compound set showed improvement in BEDROC(alpha = 100), PRAUC, and ROCAUC values averaged over all assays of 0.024, 0.014, and 0.016, respectively, compared to randomly selected training sets, all with paired t-test p-values <10(-15). A per assay assessment showed that the BEDROC(alpha = 100), which is of particular relevance for early retrieval of actives, improved for 38 out of 46 assays, increasing the success rate of smaller follow-up screens. Overall, we showed that an informer set derived from historical HTS activity data can be employed for routine small-scale exploratory screening in an assay-agnostic fashion. This approach led to a consistent improvement in hit rates in follow-up screens without compromising scaffold retrieval. The informer set is adjustable in size depending on the number of compounds one intends to screen, as performance gains are realized for sets with more than 3,000 compounds, and this set is therefore applicable to a variety of situations. Finally, our results indicate that random sampling may not adequately cover descriptor space, drawing attention to the importance of the composition of the training set for predicting actives. PMID- 27487178 TI - The Molecular Bronchoscope: A Tool for Measurement of Spatially Dependent CO2 Concentrations in the Lungs. AB - Respiratory physicians use bronchoscopy for visual assessment of the lungs' topography and collecting tissue samples for external analysis. We propose a novel bronchoscope tool that would enable spatially dependent measurements of the functioning of the lungs by determining local concentrations of carbon dioxide, which will be produced by healthy parts of the lung at rates that are higher than from portions where gas exchange is impaired. The gas analyzer is based on a compact laser absorption spectrometer making use of fiber optics for delivery and return of low intensity diode laser radiation to and from the measurement chamber at the distal end of a flexible conduit. The appropriate optical wavelength was chosen such that light is selectively absorbed only by gaseous CO2. The optical absorption takes place over a short path (8.8 mm) within a rigid, 12 mm long, perforated probe tip. Wavelength modulation spectroscopy was adopted as the analytical technique to reduce the noise on the optical signal and yield measurements of relative CO2 concentration every 180 ms with a precision as low as 600 part-per-million by volume. The primary objective of such a device is to see if additional spatial information about the lungs functionality can be gathered, which will complement visual observation. PMID- 27487179 TI - Improved method for assembly of hemeprotein neuronal NO-synthase heterodimers. AB - The assembly of mutated and wild type monomers into functional heterodimeric hemeproteins has provided important mechanistic insights. As in the case of NO synthase (NOS), the existing methods to make such heterodimeric NOSs are inefficient and labor intensive with typical yields of about 5%. We have found that expression of neuronal NOS heterodimers in insect cells, where we take advantage of an exogenous heme-triggered chaperone-assisted assembly process, provides an approximately 43% yield in heterodimeric NOS. In contrast, in Escherichia coli little heterodimerization occurred. Thus, insect cells are preferred and may represent a valuable method for assembly of other dimeric hemeproteins. PMID- 27487180 TI - Rate and predictors of human papillomavirus vaccine uptake among women who have sex with women in the United States, the National Health and Nutrition Examination Survey, 2009-2012. AB - AIMS AND OBJECTIVES: To examine rates and associated correlates of human papilloma virus vaccine uptake in women who have sex with women in the United States, and to determine whether they differ from those in women who do not have sex with women. BACKGROUND: Women who have sex with women are at risk for human papilloma virus infection but are less likely to receive preventive gynaecological services. Little research has been carried out to evaluate human papilloma virus vaccination rates and associated predictors of vaccination uptake in this population. DESIGN: Cross-sectional descriptive study. METHODS: Data from two consecutive cohorts of the National Health and Nutrition Examination Survey conducted by the United States' Centers for Disease Control were analysed. RESULTS: The sample (N = 1105) consisted of women aged 18-26 years. There was no difference in human papilloma virus vaccine uptake between women who have sex with women and women who do not have sex with women. Overall, the vaccination rate was low (32.5%). Having health insurance and more education were significant predictors of vaccine uptake in women who have sex with women. Higher education and younger age were predictors in women who do not have sex with women. CONCLUSIONS: Vaccination rates of women are far lower than the national target of 80%. The predictors of vaccine uptake were different in women who have sex with women than for women who do not have sex with women. RELEVANCE TO CLINICAL PRACTICE: Women in their 20s (regardless of their sexual orientation) should be recognised as an undervaccinated population and require targeted interventions to improve vaccination uptake. PMID- 27487181 TI - Diagnostic Potential of Novel Salivary Host Biomarkers as Candidates for the Immunological Diagnosis of Tuberculosis Disease and Monitoring of Tuberculosis Treatment Response. AB - BACKGROUND: There is an urgent need for new tools for the early diagnosis of TB disease and monitoring of the response to treatment, especially in resource constrained settings. We investigated the usefulness of host markers detected in saliva as candidate biomarkers for the immunological diagnosis of TB disease and monitoring of treatment response. METHODS: We prospectively collected saliva samples from 51 individuals that presented with signs and symptoms suggestive of TB disease at a health centre in Cape Town, South Africa, prior to the establishment of a clinical diagnosis. Patients were later classified as having TB disease or other respiratory disease (ORD), using a combination of clinical, radiological and laboratory findings. We evaluated the concentrations of 69 host markers in saliva samples using a multiplex cytokine platform, and assessed the diagnostic potentials of these markers by receiver operator characteristics (ROC) curve analysis, and general discriminant analysis. RESULTS: Out of the 51 study participants, 18 (35.4%) were diagnosed with TB disease and 12 (23.5%) were HIV infected. Only two of the 69 host markers that were evaluated (IL-16 and IL-23) diagnosed TB disease individually with area under the ROC curve >=0.70. A five marker biosignature comprising of IL-1beta, IL-23, ECM-1, HCC1 and fibrinogen diagnosed TB disease with a sensitivity of 88.9% (95% CI,76.7-99.9%) and specificity of 89.7% (95% CI, 60.4-96.6%) after leave-one-out cross validation, regardless of HIV infection status. Eight-marker biosignatures performed with a sensitivity of 100% (95% CI, 83.2-100%) and specificity of 95% (95% CI, 68.1 99.9%) in the absence of HIV infection. Furthermore, the concentrations of 11 of the markers changed during treatment, indicating that they may be useful in monitoring of TB treatment response. CONCLUSION: We have identified novel salivary biosignatures which may be useful in the diagnosis of TB disease and monitoring of the response to TB treatment. Our findings require further validation in larger studies before these biosignatures could be considered for point-of-care screening test development. PMID- 27487182 TI - TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control TH2 Mediated Immunopathology. AB - Persistent TH2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of TH2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated TH2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, TH2 cell responses and exacerbated fibrosis in Map3k8-/-mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit TH2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8-/-M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated TH2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing TH2 cell expansion and downstream immunopathology and fibrosis. PMID- 27487184 TI - Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media. AB - The effects of different formulations and processes on inducing and maintaining the supersaturation of ternary solid dispersions of ezetimibe (EZ) in two biorelevant media fasted-state simulated intestinal fluid (FaSSIF) and fasted state simulated gastric fluid (FaSSGF) at different temperatures (25 degrees C and 37 degrees C) were investigated in this work. Ternary solid dispersions of EZ were prepared by adding polymer PVP-K30 and surfactant poloxamer 188 using melt-quenching and spray-drying methods. The resulting solid dispersions were characterized using scanning electron microscopy, differential scanning calorimetry (DSC), modulated DSC, powder X-ray diffraction and Fourier transformation infrared spectroscopy. The dissolution of all the ternary solid dispersions was tested in vitro under non-sink conditions. All the prepared solid dispersions were amorphous in nature. In FaSSIF at 25 degrees C, the melt quenched (MQ) solid dispersions of EZ were more soluble than the spray-dried (SD) solid dispersions and supersaturation was maintained. However, at 37 degrees C, rapid and variable precipitation behavior was observed for all the MQ and SD formulations. In FaSSGF, the melting method resulted in better solubility than the spray-drying method at both temperatures. Ternary solid dispersions show potential for improving solubility and supersaturation. However, powder dissolution experiments of these solid dispersions of EZ at 25 degrees C may not predict the supersaturation behavior at physiologically relevant temperatures. PMID- 27487183 TI - Self-Reported Health Experiences of Children Living with Congenital Heart Defects: Including Patient-Reported Outcomes in a National Cohort Study. AB - BACKGROUND: Understanding children's views about living with congenital heart defects (CHDs) is fundamental to supporting their successful participation in daily life, school and peer relationships. As an adjunct to a health and quality of life outcomes questionnaire, we asked school-age children who survived infant heart procedures to describe their experiences of living with CHDs. METHODS: In a UK-wide cohort study, children aged 10 to 14 years with CHDs self-completed postal questionnaires that included an open question about having a 'heart problem'. We compared the characteristics of children with more and less severe cardiac diagnoses and, through collaborative inductive content analysis, investigated the subjective experiences and coping strategies described by children in both clinical severity groups. RESULTS: Text and/or drawings were returned by 436 children (246 boys [56%], mean age 12.1 years [SD 1.0; range 10 14]); 313 had less severe (LS) and 123 more severe (MS) cardiac diagnoses. At the most recent hospital visit, a higher proportion of the MS group were underweight (more than two standard deviations below the mean for age) or cyanosed (underweight: MS 20.0%, LS 9.9%; cyanosed: MS 26.2%, LS 3.5%). Children in the MS group described concerns about social isolation and feeling 'different', whereas children with less severe diagnoses often characterised their CHD as 'not a big thing'. Some coping strategies were common to both severity groups, including managing health information to avoid social exclusion, however only children in the LS group considered their CHD 'in the past' or experienced a sense of survivorship. CONCLUSIONS: Children's reported experiences were not dependent on their cardiac diagnosis, although there were clear qualitative differences by clinical severity group. Children's concerns emphasised social participation and our findings imply a need to shift the clinical focus from monitoring cardiac function to optimising participation. We highlight the potential for informing and evaluating clinical practice and service provision through seeking patient reported outcomes in paediatric care. PMID- 27487186 TI - Ongoing Clinical Trials in Prostate Cancer: The STAMPEDE Trial. PMID- 27487185 TI - Errors and Nonadherence in Pediatric Oral Chemotherapy Use. AB - BACKGROUND: Nonadherence and medication error both limit the effectiveness of oral chemotherapy. The overlap between nonadherence and medication error is not well studied in children, and interventions strategies differ for each. Our objective was to describe nonadherence and errors in children with cancer to inform future interventions. METHODS: Nonadherence was measured using two self report tools. Medication error was measured using medication review and observation of administration at home. Two clinicians made judgments about whether each error also represented an episode of nonadherence. RESULTS: Of 72 errors detected in 92 home visits, 27 were also instances of nonadherence. For example, parents gave a child 1 tablet of mercaptopurine every day rather than the prescribed 1 tablet 5 days a week and 1/2 tablet on weekends. Clinician reviewers judged that family interventions and health system interventions would be most effective in preventing the errors and nonadherence identified in this population of children with cancer. DISCUSSION: The relationship between medication errors and nonadherence is not well described in the literature. Our data indicate that medication error and nonadherence coexist in the same population and in the same patient. Interventions should address both to most effectively support self-management. PMID- 27487188 TI - Evidence for Ventilation through Collective Respiratory Movements in Giant Honeybee (Apis dorsata) Nests. AB - The Asian giant honeybees (Apis dorsata) build single-comb nests in the open, which makes this species particularly susceptible to environmental strains. Long term infrared (IR) records documented cool nest regions (CNR) at the bee curtain (nCNR = 207, nnests > 20) distinguished by marked negative gradients (DeltaTCNR/d < -3 degrees C / 5 cm) at their margins. CNRs develop and recede within minutes, predominantly at higher ambient temperatures in the early afternoon. The differential size (DeltaACNR) and temperature (DeltaTCNR) values per time unit correlated mostly positively (RAT > 0) displaying the Venturi effect, which evidences funnel properties of CNRs. The air flows inwards through CNRs, which is verified by the negative spatial gradient DeltaTCNR/d, by the positive grading of TCNR with Tamb and lastly by fanners which have directed their abdomens towards CNRs. Rare cases of RAT < 0 (< 3%) document closing processes (for DeltaACNR/Deltat < -0.4 cm2/s) but also suggest ventilation of the bee curtain (for DeltaACNR/Deltat > +0.4 cm2/s) displaying "inhalation" and "exhalation" cycling. "Inhalation" could be boosted by bees at the inner curtain layers, which stretch their extremities against the comb enlarging the inner nest lumen and thus causing a pressure fall which drives ambient air inwards through CNR funnels. The relaxing of the formerly "activated" bees could then trigger the "exhalation" process, which brings the bee curtain, passively by gravity, close to the comb again. That way, warm, CO2-enriched nest-borne air is pressed outwards through the leaking mesh of the bee curtain. This ventilation hypothesis is supported by IR imaging and laser vibrometry depicting CNRs in at least four aspects as low-resistance convection funnels for maintaining thermoregulation and restoring fresh air in the nest. PMID- 27487187 TI - Comparison of the Non-VKA Oral Anticoagulants Apixaban, Dabigatran, and Rivaroxaban in the Extended Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis. AB - BACKGROUND: Historically, warfarin or aspirin have been the recommended therapeutic options for the extended treatment (>3 months) of VTE. Data from Phase III randomised controlled trials (RCTs) are now available for non-VKA oral anticoagulants (NOACs) in this indication. The current systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of anticoagulants for the extended treatment of VTE. METHODS: Electronic databases (accessed July 2014 and updated April 2016) were systematically searched to identify RCTs evaluating apixaban, aspirin, dabigatran, edoxaban, rivaroxaban, and warfarin for the extended treatment of VTE. Eligible studies included adults with an objectively confirmed deep vein thrombosis, pulmonary embolism or both. A fixed-effect Bayesian NMA was conducted, and results were presented as relative risks (RRs). Sensitivity analyses examining (i) the dataset employed according to the time frame for outcome assessment (ii) the model used for the NMA were conducted. RESULTS: Eleven Phase III RCTs (examining apixaban, aspirin, dabigatran, rivaroxaban, warfarin and placebo) were included. The risk of the composite efficacy outcome (VTE and VTE-related death) was statistically significantly lower with the NOACs and warfarin INR 2.0-3.0 compared with aspirin, with no significant differences between the NOACs. Treatment with apixaban (RR 0.23, 95% CrI 0.10, 0.55) or dabigatran (RR 0.55, 95% Crl 0.43, 0.71) was associated with a statistically significantly reduced risk of 'major or clinically relevant non-major bleed' compared with warfarin INR 2.0-3.0. Apixaban also showed a significantly reduced risk compared with dabigatran (RR 0.42, 95% Crl 0.18, 0.97) and rivaroxaban (RR 0.23, 95% Crl 0.09, 0.59). Sensitivity analyses indicate that results were dependent on the dataset, but not on the type of NMA model employed. CONCLUSIONS: Results from the NMA indicate that NOACs are an effective treatment for prevention of VTE or VTE-related death) in the extended treatment setting. However, bleeding risk differs between potential treatments, with apixaban reporting the most favourable profile compared with other NOACs, warfarin INR 2.0-3.0, and aspirin. PMID- 27487189 TI - Factors Associated with Fatality during the Intensive Phase of Anti-Tuberculosis Treatment. AB - OBJECTIVE: To determine the case-fatality rate (CFR) at the end of the intensive phase of tuberculosis (TB) treatment, and factors associated with fatality. METHODS: TB patients diagnosed between 2006 and 2013 were followed-up during treatment. We computed the CFR at the end of the intensive phase of TB treatment, and the incidence of death per 100 person-days (pd) of follow-up. We performed survival analysis using the Kaplan-Meier method and Cox regression, and calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: A total of 5,182 patients were included, of whom 180 (3.5%) died; 87 of these deaths (48.3%) occurred during the intensive phase of treatment, with a CFR of 1.7%. The incidence of death was 0.028/100 pd. The following factors were associated with death during the intensive phase: being >50 years (HR = 36.9;CI:4.8-283.4); being retired (HR = 2.4;CI:1.1-5.1); having visited the emergency department (HR = 3.1;CI:1.2-7.7); HIV infection (HR = 3.4;CI:1.6-7.2); initial standard treatment with 3 drugs (HR = 2.0;CI:1.2-3.3) or non-standard treatments (HR = 2.68;CI:1.36 5.25); comprehension difficulties (HR = 2.8;CI:1.3-6.1); and smear-positive sputum (HR = 2.3-CI:1.0-4.8). CONCLUSION: There is a non-negligible CFR during the intensive phase of TB, whose reduction should be prioritised. The CFR could be a useful indicator for evaluating TB programs. PMID- 27487190 TI - Quality Improvement in Acute Ischemic Stroke Care in Taiwan: The Breakthrough Collaborative in Stroke. AB - In the management of acute ischemic stroke, guideline adherence is often suboptimal, particularly for intravenous thrombolysis or anticoagulation for atrial fibrillation. We sought to improve stroke care quality via a collaborative model, the Breakthrough Series (BTS)-Stroke activity, in a nationwide, multi center activity in Taiwan. A BTS Collaborative, a short-term learning system for a large number of multidisciplinary teams from hospitals, was applied to enhance acute ischemic stroke care quality. Twenty-four hospitals participated in and submitted data for this stroke quality improvement campaign in 2010-2011. Totally, 14 stroke quality measures, adopted from the Get With The Guideline (GWTG)-Stroke program, were used to evaluate the performance and outcome of the ischemic stroke patients. Data for a one-year period from 24 hospitals with 13,181 acute ischemic stroke patients were analyzed. In 14 hospitals, most stroke quality measures improved significantly during the BTS-activity compared with a pre-BTS-Stroke activity period (2006-08). The rate of intravenous thrombolysis increased from 1.2% to 4.6%, door-to-needle time <=60 minutes improved from 7.1% to 50.8%, symptomatic hemorrhage after intravenous thrombolysis decreased from 11.0% to 5.6%, and anticoagulation therapy for atrial fibrillation increased from 32.1% to 64.1%. The yearly composite measures of five stroke quality measures revealed significant improvements from 2006 to 2011 (75% to 86.3%, p<0.001). The quarterly composite measures also improved significantly during the BTS-Stroke activity. In conclusion, a BTS collaborative model is associated with improved guideline adherence for patients with acute ischemic stroke. GWTG-Stroke recommendations can be successfully applied in countries besides the United States. PMID- 27487191 TI - Risk-Reduction Program for Cardiovascular and Limb Events in Patients With Peripheral Arterial Disease-Reply. PMID- 27487192 TI - Field-induced doping-mediated tunability in work function of Al-doped ZnO: Kelvin probe force microscopy and first-principle theory. AB - We demonstrate that the work function of Al-doped ZnO (AZO) can be tuned externally by applying an electric field. Our experimental investigations using Kelvin probe force microscopy show that by applying a positive or negative tip bias, the work function of AZO film can be enhanced or reduced, which corroborates well with the observed charge transport using conductive atomic force microscopy. These findings are further confirmed by calculations based on first-principles theory. Tuning the work function of AZO by applying an external electric field is not only important to control the charge transport across it, but also to design an Ohmic contact for advanced functional devices. PMID- 27487193 TI - Randomized, 6-Week, Placebo-Controlled Study of Treatment for Adult Attention Deficit/Hyperactivity Disorder: Individualized Dosing of Osmotic-Release Oral System (OROS) Methylphenidate With a Goal of Symptom Remission. AB - OBJECTIVE: To evaluate the efficacy and safety of individualized dosing within the approved dose range for osmotic-release oral system (OROS) methylphenidate hydrochloride in adults with attention-deficit/hyperactivity disorder (ADHD). METHODS: A double-blind, 6-week trial was conducted between July 2009 and February 2010 at 35 US sites. Adults with ADHD (DSM-IV diagnostic criteria) and a screening ADHD Investigator Symptom Rating Scale (AISRS) score > 24 were randomly assigned to OROS methylphenidate 18 mg or matching placebo. Treatment dose could be increased at 18 mg increments, up to 72 mg/d, until an optimal dose was achieved. AISRS score changes from baseline to end point (primary outcome) were analyzed using analysis of covariance. RESULTS: At baseline, the intent-to-treat population of 169 OROS methylphenidate and 172 placebo subjects (mean age = 35.8 years) had mean (standard deviation [SD]) AISRS scores of 37.8 (6.94) and 37.0 (7.51), respectively. OROS methylphenidate-treated subjects exhibited a significantly greater mean (SD) AISRS score improvement than placebo subjects ( 17.1 [12.44] vs -11.7 [13.30]; P < .001). In general, OROS methylphenidate treated subjects experienced greater improvements than placebo subjects in secondary measures of symptom frequency, cognitive function, work productivity, and quality-of-life. Little effect of OROS methylphenidate was observed in exploratory sleep assessments. The adverse event pattern was similar to previous reports of stimulants in adults with ADHD. CONCLUSIONS: OROS methylphenidate treatment with individualized doses titrated to achieve symptom remission demonstrated greater ADHD symptom reduction than placebo treatment. These data support the overall efficacy of OROS methylphenidate treatment in the management of adults with ADHD and provide new possibilities for additional intervention. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00937040. PMID- 27487194 TI - What Is True Halving in the Payoff Matrix of Game Theory? AB - In game theory, there are two social interpretations of rewards (payoffs) for decision-making strategies: (1) the interpretation based on the utility criterion derived from expected utility theory and (2) the interpretation based on the quantitative criterion (amount of gain) derived from validity in the empirical context. A dynamic decision theory has recently been developed in which dynamic utility is a conditional (state) variable that is a function of the current wealth of a decision maker. We applied dynamic utility to the equal division in dove-dove contests in the hawk-dove game. Our results indicate that under the utility criterion, the half-share of utility becomes proportional to a player's current wealth. Our results are consistent with studies of the sense of fairness in animals, which indicate that the quantitative criterion has greater validity than the utility criterion. We also find that traditional analyses of repeated games must be reevaluated. PMID- 27487195 TI - Effect of Inorganic and Organic Carbon Enrichments (DIC and DOC) on the Photosynthesis and Calcification Rates of Two Calcifying Green Algae from a Caribbean Reef Lagoon. AB - Coral reefs worldwide are affected by increasing dissolved inorganic carbon (DIC) and organic carbon (DOC) concentrations due to ocean acidification (OA) and coastal eutrophication. These two stressors can occur simultaneously, particularly in near-shore reef environments with increasing anthropogenic pressure. However, experimental studies on how elevated DIC and DOC interact are scarce and fundamental to understanding potential synergistic effects and foreseeing future changes in coral reef function. Using an open mesocosm experiment, the present study investigated the impact of elevated DIC (pHNBS: 8.2 and 7.8; pCO2: 377 and 1076 MUatm) and DOC (added as 833 MUmol L-1 of glucose) on calcification and photosynthesis rates of two common calcifying green algae, Halimeda incrassata and Udotea flabellum, in a shallow reef environment. Our results revealed that under elevated DIC, algal photosynthesis decreased similarly for both species, but calcification was more affected in H. incrassata, which also showed carbonate dissolution rates. Elevated DOC reduced photosynthesis and calcification rates in H. incrassata, while in U. flabellum photosynthesis was unaffected and thalus calcification was severely impaired. The combined treatment showed an antagonistic effect of elevated DIC and DOC on the photosynthesis and calcification rates of H. incrassata, and an additive effect in U. flabellum. We conclude that the dominant sand dweller H. incrassata is more negatively affected by both DIC and DOC enrichments, but that their impact could be mitigated when they occur simultaneously. In contrast, U. flabellum can be less affected in coastal eutrophic waters by elevated DIC, but its contribution to reef carbonate sediment production could be further reduced. Accordingly, while the capacity of environmental eutrophication to exacerbate the impact of OA on algal-derived carbonate sand production seems to be species-specific, significant reductions can be expected under future OA scenarios, with important consequences for beach erosion and coastal sediment dynamics. PMID- 27487196 TI - Diurnal changes in the histone H3 signature H3K9ac|H3K27ac|H3S28p are associated with diurnal gene expression in Arabidopsis. AB - Post-translational chromatin modifications are an important regulatory mechanism in light signalling and circadian clock function. The regulation of diurnal transcript level changes requires fine-tuning of the expression of generally active genes depending on the prevailing environmental conditions. We investigated the association of histone modifications H3K4me3, H3K9ac, H3K9me2, H3S10p, H3K27ac, H3K27me3 and H3S28p with diurnal changes in transcript expression using chromatin immunoprecipitations followed by sequencing (ChIP-Seq) in fully expanded leaves 6 of Arabidopsis thaliana grown in short-day optimal and water-deficit conditions. We identified a differential H3K9ac, H3K27ac and H3S28p signature between end-of-day and end-of-night that is correlated with changes in diurnal transcript levels. Genes with this signature have particular over represented promoter elements and encode proteins that are significantly enriched for transcription factors, circadian clock and starch catabolic process. Additional activating modifications were prevalent in optimally watered (H3S10p) and in water-deficit (H3K4me3) plants. The data suggest a mechanism for diurnal transcript level regulation in which reduced binding of repressive transcription factors facilitates activating H3K9ac, H3K27ac and H3S28p chromatin modifications. The presence of activating chromatin modification patterns on genes only at times of the day when their expression is required can explain why some genes are differentially inducible during the diurnal cycle. PMID- 27487197 TI - Alcohol Use Severity and Sexual Risk Behavior Among Female Substance Users. AB - BACKGROUND: Substance use has been identified as one of the leading factors related to HIV transmission in the United States. The association of problematic drinking with sexual risk behavior puts individuals at greater risk for HIV transmission. This may be of particular concern for women given that approximately 66% of new HIV infections occurring through heterosexual transmission are female. OBJECTIVES: To investigate alcohol use severity and sexual risk behavior among females who use heavy, illicit drugs. METHODS: Female substances users (N = 251; Mage = 31.90, SD = 7.67; 63.7% Black) self-reported past month alcohol use and lifetime sexual risk behaviors with both casual and steady sex partners. RESULTS: Problematic alcohol users were more likely to use noninjection drugs and less likely to use injection drugs than abstainers and more likely than moderate alcohol users to use alcohol before/during sex with a steady partner. White problematic alcohol users were less likely to use injection drugs before/during sex with a steady partner than abstainers. Black problematic alcohol users were more likely to use non-injection and alcohol than moderate alcohol users before/during sex with steady partners. CONCLUSIONS: The current study extends the existing literature by taking a closer look at the role of alcohol use severity in sexual risk taking behavior of Black and White female substance users, a particularly vulnerable group for HIV transmission. PMID- 27487198 TI - Single-Molecule Observation Reveals Spontaneous Protein Dynamics in the Nucleosome. AB - Structural dynamics of a protein molecule is often critical to its function. Single-molecule methods provide efficient ways to investigate protein dynamics, although it is very challenging to achieve a millisecond or higher temporal resolution. Here we report spontaneous structural dynamics of the histone protein core in the nucleosome based on a single-molecule method that can reveal submillisecond dynamics by combining maximum likelihood estimation and fluorescence correlation spectroscopy. The nucleosome, comprising ~147 bp DNA and an octameric histone protein core consisting of H2A, H2B, H3, and H4, is the fundamental packing unit of the eukaryotic genome. The nucleosome imposes a physical barrier that should be overcome during various DNA-templated processes. Structural fluctuation of the nucleosome in the histone core has been hypothesized to be required for nucleosome disassembly but has yet to be directly probed. Our results indicate that at 100 mM NaCl the histone H2A-H2B dimer dissociates from the histone core transiently once every 3.6 +/- 0.6 ms and returns to its position within 2.0 +/- 0.3 ms. We also found that the motion is facilitated upon H3K56 acetylation and inhibited upon replacing H2A with H2A.Z. These results provide the first direct examples of how a localized post translational modification or an epigenetic variation affects the kinetic and thermodynamic stabilities of a macromolecular protein complex, which may directly contribute to its functions. PMID- 27487199 TI - Targeting CYP51 for drug design by the contributions of molecular modeling. AB - CYP51 is an enzyme of sterol biosynthesis pathway present in animals, plants, protozoa and fungi. This enzyme is described as an important drug target that is still of interest. Therefore, in this work, we reviewed the structure and function of CYP51 and explored the molecular modeling approaches for the development of new antifungal and antiprotozoans that target this enzyme. Crystallographic structures of CYP51 of some organisms have already been described in the literature, which enable the construction of homology models of other organisms' enzymes and molecular docking studies of new ligands. The binding mode and interactions of some new series of azoles with antifungal or antiprotozoan activities has been studied and showed important residues of the active site. Molecular modeling is an important tool to be explored for the discovery and optimization of CYP51 inhibitors with better activities, pharmacokinetics, and toxicological profiles. PMID- 27487200 TI - Proteasomal Dysfunction Induced By Diclofenac Engenders Apoptosis Through Mitochondrial Pathway. AB - Diclofenac is the most commonly used phenylacetic acid derivative non-steroidal anti-inflammatory drug (NSAID) that demonstrates significant analgesic, antipyretic, and anti-inflammatory effects. Several epidemiological studies have demonstrated anti-proliferative activity of NSAIDs and examined their apoptotic induction effects in different cancer cell lines. However, the precise molecular mechanisms by which these pharmacological agents induce apoptosis and exert anti carcinogenic properties are not well known. Here, we have observed that diclofenac treatment induces proteasome malfunction and promotes accumulation of different critical proteasome substrates, including few pro-apoptotic proteins in cells. Exposure of diclofenac consequently elevates aggregation of various ubiquitylated misfolded proteins. Finally, we have shown that diclofenac treatment promotes apoptosis in cells, which could be because of mitochondrial membrane depolarization and cytochrome c release into cytosol. This study suggests possible beneficial insights of NSAIDs-induced apoptosis that may improve our existing knowledge in anti-proliferative interspecific strategies development. J. Cell. Biochem. 118: 1014-1027, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27487201 TI - [Not Available]. PMID- 27487202 TI - Airborne PCB patterns and urban scale in the Southern Rio de la Plata Basin, Argentina. AB - Atmospheric Polychlorinated Biphenyls (PCBs: ? 42 congeners) collected by polyurethane passive samplers (PAS-PUFs) in 29 stations from July 2010 to February 2014 (n=141) in the most productive and populated Southern Rio de la Plata area in Argentina were evaluated to assess concentration gradients, potential sources and compositional profiles related to different land use and urbanization. On a global scale, total airborne PCBs concentrations are low/very low (below detection limit to 937pgm-3) and show a significant potential correlation with urban scale increasing 2.5 times each 10 times increase of population reflecting the primary role of urbanization controlling PCB emissions. Compositional patterns evaluated by principal component analysis (PCA) of individual congeners indicated that highly populated atmospheres are enriched in lighter, more volatile tri, tetra and penta chlorine congeners of lighter Aroclor mixtures (from 1242 to 1254) suggesting actual emission of fresh PCBs signatures from sealants, combustion and/or electrical equipment. Sub urban and rural sites show a gradual transition to heavier Aroclor mixtures (from 1254 to 1260) with predominance of more persistent hexa and hepta PCBs indicating an aged background signal resulting from long range transport and/or re-emission from historic reservoirs such as soils. PMID- 27487203 TI - Mechanistic Insights into Catalytic Ethanol Steam Reforming Using Isotope-Labeled Reactants. AB - The low-temperature ethanol steam reforming (ESR) reaction mechanism over a supported Rh/Pt catalyst has been investigated using isotope-labeled EtOH and H2 O. Through strategic isotope labeling, all nonhydrogen atoms were distinct from one another, and allowed an unprecedented level of understanding of the dominant reaction pathways. All combinations of isotope- and non-isotope-labeled atoms were detected in the products, thus there are multiple pathways involved in H2 , CO, CO2 , CH4 , C2 H4 , and C2 H6 product formation. Both the recombination of C species on the surface of the catalyst and preservation of the C-C bond within ethanol are responsible for C2 product formation. Ethylene is not detected until conversion drops below 100 % at t=1.25 h. Also, quantitatively, 57 % of the observed ethylene is formed directly through ethanol dehydration. Finally there is clear evidence to show that oxygen in the SiO2 -ZrO2 support constitutes 10 % of the CO formed during the reaction. PMID- 27487204 TI - Recombinant expression of porcine lactoferrin peptide LF-6 with intein technology and its immunomodulatory function in ETEC K88-infected mice. AB - LF-6 is a modified antibacterial peptide derived from LFP-20, a major active ingredient of porcine lactoferrin, whose antibacterial activity is 200 times higher than its native protein counterpart. Moreover, LF-6 displays even higher antibacterial activity than LFP-20 and negligible toxic adverse effects, make it a potential therapeutic agent for antibacterial purposes. Escherichia coli expression system has been a preferred choice and workhorse for most recombinant proteins. However, LF-6 must be coexpressed with a fusion partner to avoid its potentially fatal toxicity which would threat E. coli expression system. In this study, we successfully introduced intein system to solve this problem, which LF-6 was N-terminally fused to dithiothreitol (DTT)-induced self-cleavable intein, and it conduct cleavage when the intein-fusion peptide passing through a chromatography column filled with chitin, then the spliced peptide was purified with RP-HPLC and identified with mass spectroscopy. A bacteriostatic test showed that the recombinant LF-6 displayed nearly the same antibacterial activity as the chemically synthetized LF-6, and an in vivo immunoprotection analysis showed that the recombinant LF-6 exerted protective effects on Escherichia coli (ETEC)-K88 infected mice, which significantly reduced the pro-inflammatory cytokines level in plasma and intestine, and resistant to intestinal mucosal injury compared to the infective alone groups. Our study indicates that the intein system allows a safe and efficient method to produce recombinant LF-6, which not only has antibacterial activity, but more importantly, has an immunomodulatory function. PMID- 27487205 TI - MRI evaluation of benign prostatic hyperplasia: Correlation with international prostate symptom score. AB - PURPOSE: To investigate the correlation between magnetic resonance imaging (MRI) derived prostate parameters and benign prostatic hyperplasia (BPH) type with the International Prostate Symptom Score (IPSS). MATERIALS AND METHODS: In all, 61 patients (median age, 60; range, 41-81 years) who underwent preoperative MRI and prostatectomy were included in this retrospective study. The MRI-based parameters including total prostate volume (TPV), transition zone (TZ) volume (TZV), TZ index, intravesical prostatic protrusion (IPP), the anterior fibromuscular stroma (AFMS) distance, prostatic urethral angle, bladder wall thickness, urethral wall thickness, urethral compression, urethral wall changes, and BPH type were correlated with total IPSS, IPSS-storage symptom (IPSS-ss), IPSS-voiding symptom (IPSS-vs), and responses to the individual IPSS questions using Spearman (rho) or Pearson (r) correlation coefficients, one-way analysis of variance (ANOVA), and multiple linear regression. RESULTS: TPV (r = 0.414, P = 0.001), TZV (r = 0.405, P = 0.001), IPP (r = 0.270, P = 0.04), and AFMS distance (r = 0.363, P = 0.004) correlated with total IPSS. In multiple linear regression analysis, TZV was the only predictor for total IPSS (P = 0.001), IPSS-ss (P < 0.001), IPSS-vs (P = 0.03), and the scores for the IPSS questions 1 (P = 0.03) and 4 (P = 0.001). TPV was a predictor of the scores for questions 2 (P = 0.003), 3 (P = 0.009), and 7 (P < 0.001). CONCLUSION: Several MRI-derived prostate measurements (TPV, TZV, IPP, AFMS distance) correlated with total IPSS. TZV was the only predictor for total IPSS based on multiple regression analysis. LEVEL OF EVIDENCE: 3 J. Magn. Reson. Imaging 2017;45:917-925. PMID- 27487206 TI - Heat Generation and Efficiency of a New Modified Phaco Tip and Sleeve. AB - PURPOSE: To compare a modified phacoemulsification tip with the established micro tip, in terms of temperature at the corneal wound, efficiency, and chatter events, using the Centurion(r) Vision system. METHODS: Eighty porcine eyes were randomized into 4 groups: 1)sleeveless conventional 45D MiniFlared ABS(r) Kelman tip (1.1-mm incision); 2)sleeveless new modified 45D ABS(r) INTREPID(r) balanced tip(1.1-mm incision); 3) Kelman tip with own sleeve (2.2-mm incision); 4)Balanced tip with modified 4-rib sleeve (2.2-mm incision). Measurements were taken with 2 settings: longitudinal(power 40% and 70%) and torsional mode (power 40% and 100%). Peak temperatures were measured 0, 10, 30, and 60 seconds after continuous ultrasound power. For the efficiency test, porcine lens nuclei were formalin soaked and cut into 2.0 mm3 cubes. Efficiency and chatter were examined. RESULTS: In all longitudinal settings, the sleeveless groups(1 and 2) showed lower temperatures than the sleeved groups(3 and 4) (P = 0.003). In 100% torsional mode, groups 3 and 4 produced significantly different temperatures(37.13 +/- 1.44 and 35.14 +/- 0.54, respectively; P = 0.007).The efficiency, in a 100% power torsional setting, was13.52 +/- 2.60 sec for group 4, and 44.45+/- 14.75 sec for group 3 (P<0.001). CONCLUSIONS: The two different bare tips show no significant differences in thermogenesis. However, the balanced tip with sleeve produces lower temperaturesat100% torsional power and better efficiency than the Kelman tip. PMID- 27487208 TI - Cancer: Fat and the fate of pancreatic tumours. PMID- 27487207 TI - SAR11 bacteria linked to ocean anoxia and nitrogen loss. AB - Bacteria of the SAR11 clade constitute up to one half of all microbial cells in the oxygen-rich surface ocean. SAR11 bacteria are also abundant in oxygen minimum zones (OMZs), where oxygen falls below detection and anaerobic microbes have vital roles in converting bioavailable nitrogen to N2 gas. Anaerobic metabolism has not yet been observed in SAR11, and it remains unknown how these bacteria contribute to OMZ biogeochemical cycling. Here, genomic analysis of single cells from the world's largest OMZ revealed previously uncharacterized SAR11 lineages with adaptations for life without oxygen, including genes for respiratory nitrate reductases (Nar). SAR11 nar genes were experimentally verified to encode proteins catalysing the nitrite-producing first step of denitrification and constituted ~40% of OMZ nar transcripts, with transcription peaking in the anoxic zone of maximum nitrate reduction activity. These results link SAR11 to pathways of ocean nitrogen loss, redefining the ecological niche of Earth's most abundant organismal group. PMID- 27487209 TI - Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility. AB - Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. Here we reconstruct the evolutionary history of the locus and identify bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95-kilobase-pair segment containing BOLA2 duplicated across the critical region approximately 282 thousand years ago (ka), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carried one or more copies of the duplication, which nearly fixed early in the human lineage--a pattern unlikely to have arisen so rapidly in the absence of selection (P < 0.0097). We show that the duplication of BOLA2 led to a novel, human-specific in-frame fusion transcript and that BOLA2 copy number correlates with both RNA expression (r = 0.36) and protein level (r = 0.65), with the greatest expression difference between human and chimpanzee in experimentally derived stem cells. Analyses of 152 patients carrying a chromosome 16p11. rearrangement show that more than 96% of breakpoints occur within the H. sapiens specific duplication. In summary, the duplicative transposition of BOLA2 at the root of the H. sapiens lineage about 282 ka simultaneously increased copy number of a gene associated with iron homeostasis and predisposed our species to recurrent rearrangements associated with disease. PMID- 27487210 TI - Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. AB - The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4, 5, 6, 7). Arginine activates mTORC1 upstream of the Rag family of GTPases, through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting Cellular Arginine Sensor for mTORC1 (CASTOR1). However, the mechanism by which the mTORC1 pathway detects and transmits this arginine signal has been elusive. Here, we present the 1.8 A crystal structure of arginine-bound CASTOR1. Homodimeric CASTOR1 binds arginine at the interface of two Aspartate kinase, Chorismate mutase, TyrA (ACT) domains, enabling allosteric control of the adjacent GATOR2-binding site to trigger dissociation from GATOR2 and downstream activation of mTORC1. Our data reveal that CASTOR1 shares substantial structural homology with the lysine-binding regulatory domain of prokaryotic aspartate kinases, suggesting that the mTORC1 pathway exploited an ancient, amino-acid-dependent allosteric mechanism to acquire arginine sensitivity. Together, these results establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor. PMID- 27487211 TI - Thirst neurons anticipate the homeostatic consequences of eating and drinking. AB - Thirst motivates animals to drink in order to maintain fluid balance. Thirst has conventionally been viewed as a homeostatic response to changes in blood volume or tonicity. However, most drinking behaviour is regulated too rapidly to be controlled by blood composition directly, and instead seems to anticipate homeostatic imbalances before they arise. How this is achieved remains unknown. Here we reveal an unexpected role for the subfornical organ (SFO) in the anticipatory regulation of thirst in mice. By monitoring deep-brain calcium dynamics, we show that thirst-promoting SFO neurons respond to inputs from the oral cavity during eating and drinking and then integrate these inputs with information about the composition of the blood. This integration allows SFO neurons to predict how ongoing food and water consumption will alter fluid balance in the future and then to adjust behaviour pre-emptively. Complementary optogenetic manipulations show that this anticipatory modulation is necessary for drinking in several contexts. These findings provide a neural mechanism to explain longstanding behavioural observations, including the prevalence of drinking during meals, the rapid satiation of thirst, and the fact that oral cooling is thirst-quenching. PMID- 27487212 TI - Global profiling of SRP interaction with nascent polypeptides. AB - Signal recognition particle (SRP) is a universally conserved protein-RNA complex that mediates co-translational protein translocation and membrane insertion by targeting translating ribosomes to membrane translocons. The existence of parallel co- and post-translational transport pathways, however, raises the question of the cellular substrate pool of SRP and the molecular basis of substrate selection. Here we determine the binding sites of bacterial SRP within the nascent proteome of Escherichia coli at amino acid resolution, by sequencing messenger RNA footprints of ribosome-nascent-chain complexes associated with SRP. SRP, on the basis of its strong preference for hydrophobic transmembrane domains (TMDs), constitutes a compartment-specific targeting factor for nascent inner membrane proteins (IMPs) that efficiently excludes signal-sequence-containing precursors of periplasmic and outer membrane proteins. SRP associates with hydrophobic TMDs enriched in consecutive stretches of hydrophobic and bulky aromatic amino acids immediately on their emergence from the ribosomal exit tunnel. By contrast with current models, N-terminal TMDs are frequently skipped and TMDs internal to the polypeptide sequence are selectively recognized. Furthermore, SRP binds several TMDs in many multi-spanning membrane proteins, suggesting cycles of SRP-mediated membrane targeting. SRP-mediated targeting is not accompanied by a transient slowdown of translation and is not influenced by the ribosome-associated chaperone trigger factor (TF), which has a distinct substrate pool and acts at different stages during translation. Overall, our proteome-wide data set of SRP-binding sites reveals the underlying principles of pathway decisions for nascent chains in bacteria, with SRP acting as the dominant triaging factor, sufficient to separate IMPs from substrates of the SecA-SecB post-translational translocation and TF-assisted cytosolic protein folding pathways. PMID- 27487213 TI - Cotranslational signal-independent SRP preloading during membrane targeting. AB - Ribosome-associated factors must properly decode the limited information available in nascent polypeptides to direct them to their correct cellular fate. It is unclear how the low complexity information exposed by the nascent chain suffices for accurate recognition by the many factors competing for the limited surface near the ribosomal exit site. Questions remain even for the well-studied cotranslational targeting cycle to the endoplasmic reticulum, involving recognition of linear hydrophobic signal sequences or transmembrane domains by the signal recognition particle (SRP). Notably, the SRP has low abundance relative to the large number of ribosome-nascent-chain complexes (RNCs), yet it accurately selects those destined for the endoplasmic reticulum. Despite their overlapping specificities, the SRP and the cotranslationally acting Hsp70 display precise mutually exclusive selectivity in vivo for their cognate RNCs. To understand cotranslational nascent chain recognition in vivo, here we investigate the cotranslational membrane-targeting cycle using ribosome profiling in yeast cells coupled with biochemical fractionation of ribosome populations. We show that the SRP preferentially binds secretory RNCs before their targeting signals are translated. Non-coding mRNA elements can promote this signal-independent pre recruitment of SRP. Our study defines the complex kinetic interaction between elongation in the cytosol and determinants in the polypeptide and mRNA that modulate SRP-substrate selection and membrane targeting. PMID- 27487214 TI - Mammalian development: Mechanics drives cell differentiation. PMID- 27487215 TI - Reconstruction of bacterial transcription-coupled repair at single-molecule resolution. AB - Escherichia coli Mfd translocase enables transcription-coupled repair by displacing RNA polymerase (RNAP) stalled on a DNA lesion and then coordinating assembly of the UvrAB(C) components at the damage site. Recent studies have shown that after binding to and dislodging stalled RNAP, Mfd remains on the DNA in the form of a stable, slowly translocating complex with evicted RNAP attached. Here we find, using a series of single-molecule assays, that recruitment of UvrA and UvrAB to Mfd-RNAP arrests the translocating complex and causes its dissolution. Correlative single-molecule nanomanipulation and fluorescence measurements show that dissolution of the complex leads to loss of both RNAP and Mfd. Subsequent DNA incision by UvrC is faster than when only UvrAB(C) are available, in part because UvrAB binds 20-200 times more strongly to Mfd-RNAP than to DNA damage. These observations provide a quantitative framework for comparing complementary DNA repair pathways in vivo. PMID- 27487216 TI - Operation of a homeostatic sleep switch. AB - Sleep disconnects animals from the external world, at considerable risks and costs that must be offset by a vital benefit. Insight into this mysterious benefit will come from understanding sleep homeostasis: to monitor sleep need, an internal bookkeeper must track physiological changes that are linked to the core function of sleep. In Drosophila, a crucial component of the machinery for sleep homeostasis is a cluster of neurons innervating the dorsal fan-shaped body (dFB) of the central complex. Artificial activation of these cells induces sleep, whereas reductions in excitability cause insomnia. dFB neurons in sleep-deprived flies tend to be electrically active, with high input resistances and long membrane time constants, while neurons in rested flies tend to be electrically silent. Correlative evidence thus supports the simple view that homeostatic sleep control works by switching sleep-promoting neurons between active and quiescent states. Here we demonstrate state switching by dFB neurons, identify dopamine as a neuromodulator that operates the switch, and delineate the switching mechanism. Arousing dopamine caused transient hyperpolarization of dFB neurons within tens of milliseconds and lasting excitability suppression within minutes. Both effects were transduced by Dop1R2 receptors and mediated by potassium conductances. The switch to electrical silence involved the downregulation of voltage-gated A-type currents carried by Shaker and Shab, and the upregulation of voltage-independent leak currents through a two-pore-domain potassium channel that we term Sandman. Sandman is encoded by the CG8713 gene and translocates to the plasma membrane in response to dopamine. dFB-restricted interference with the expression of Shaker or Sandman decreased or increased sleep, respectively, by slowing the repetitive discharge of dFB neurons in the ON state or blocking their entry into the OFF state. Biophysical changes in a small population of neurons are thus linked to the control of sleep-wake state. PMID- 27487217 TI - Asymmetric division of contractile domains couples cell positioning and fate specification. AB - During pre-implantation development, the mammalian embryo self-organizes into the blastocyst, which consists of an epithelial layer encapsulating the inner-cell mass (ICM) giving rise to all embryonic tissues. In mice, oriented cell division, apicobasal polarity and actomyosin contractility are thought to contribute to the formation of the ICM. However, how these processes work together remains unclear. Here we show that asymmetric segregation of the apical domain generates blastomeres with different contractilities, which triggers their sorting into inner and outer positions. Three-dimensional physical modelling of embryo morphogenesis reveals that cells internalize only when differences in surface contractility exceed a predictable threshold. We validate this prediction using biophysical measurements, and successfully redirect cell sorting within the developing blastocyst using maternal myosin (Myh9)-knockout chimaeric embryos. Finally, we find that loss of contractility causes blastomeres to show ICM-like markers, regardless of their position. In particular, contractility controls Yap subcellular localization, raising the possibility that mechanosensing occurs during blastocyst lineage specification. We conclude that contractility couples the positioning and fate specification of blastomeres. We propose that this ensures the robust self-organization of blastomeres into the blastocyst, which confers remarkable regulative capacities to mammalian embryos. PMID- 27487218 TI - Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. AB - Metastasis is the leading cause of cancer-related death in humans. It is a complex multistep process during which individual tumour cells spread primarily through the circulatory system to colonize distant organs. Once in the circulation, tumour cells remain vulnerable, and their metastatic potential largely depends on a rapid and efficient way to escape from the blood stream by passing the endothelial barrier. Evidence has been provided that tumour cell extravasation resembles leukocyte transendothelial migration. However, it remains unclear how tumour cells interact with endothelial cells during extravasation and how these processes are regulated on a molecular level. Here we show that human and murine tumour cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumour cell extravasation and metastasis. Treatment of mice with the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-inhibitor necrostatin-1 or endothelial-cell-specific deletion of RIPK3 reduced tumour-cell induced endothelial necroptosis, tumour cell extravasation and metastasis. In contrast, pharmacological caspase inhibition or endothelial-cell-specific loss of caspase-8 promoted these processes. We furthermore show in vitro and in vivo that tumour-cell-induced endothelial necroptosis leading to extravasation and metastasis requires amyloid precursor protein expressed by tumour cells and its receptor, death receptor 6 (DR6), on endothelial cells as the primary mediators of these effects. Our data identify a new mechanism underlying tumour cell extravasation and metastasis, and suggest endothelial DR6-mediated necroptotic signalling pathways as targets for anti-metastatic therapies. PMID- 27487219 TI - A partially differentiated interior for (1) Ceres deduced from its gravity field and shape. AB - Remote observations of the asteroid (1) Ceres from ground- and space-based telescopes have provided its approximate density and shape, leading to a range of models for the interior of Ceres, from homogeneous to fully differentiated. A previously missing parameter that can place a strong constraint on the interior of Ceres is its moment of inertia, which requires the measurement of its gravitational variation together with either precession rate or a validated assumption of hydrostatic equilibrium. However, Earth-based remote observations cannot measure gravity variations and the magnitude of the precession rate is too small to be detected. Here we report gravity and shape measurements of Ceres obtained from the Dawn spacecraft, showing that it is in hydrostatic equilibrium with its inferred normalized mean moment of inertia of 0.37. These data show that Ceres is a partially differentiated body, with a rocky core overlaid by a volatile-rich shell, as predicted in some studies. Furthermore, we show that the gravity signal is strongly suppressed compared to that predicted by the topographic variation. This indicates that Ceres is isostatically compensated, such that topographic highs are supported by displacement of a denser interior. In contrast to the asteroid (4) Vesta, this strong compensation points to the presence of a lower-viscosity layer at depth, probably reflecting a thermal rather than compositional gradient. To further investigate the interior structure, we assume a two-layer model for the interior of Ceres with a core density of 2,460-2,900 kilograms per cubic metre (that is, composed of CI and CM chondrites), which yields an outer-shell thickness of 70-190 kilometres. The density of this outer shell is 1,680-1,950 kilograms per cubic metre, indicating a mixture of volatiles and denser materials such as silicates and salts. Although the gravity and shape data confirm that the interior of Ceres evolved thermally, its partially differentiated interior indicates an evolution more complex than has been envisioned for mid-sized (less than 1,000 kilometres across) ice-rich rocky bodies. PMID- 27487220 TI - Enhanced electrocatalytic CO2 reduction via field-induced reagent concentration. AB - Electrochemical reduction of carbon dioxide (CO2) to carbon monoxide (CO) is the first step in the synthesis of more complex carbon-based fuels and feedstocks using renewable electricity. Unfortunately, the reaction suffers from slow kinetics owing to the low local concentration of CO2 surrounding typical CO2 reduction reaction catalysts. Alkali metal cations are known to overcome this limitation through non-covalent interactions with adsorbed reagent species, but the effect is restricted by the solubility of relevant salts. Large applied electrode potentials can also enhance CO2 adsorption, but this comes at the cost of increased hydrogen (H2) evolution. Here we report that nanostructured electrodes produce, at low applied overpotentials, local high electric fields that concentrate electrolyte cations, which in turn leads to a high local concentration of CO2 close to the active CO2 reduction reaction surface. Simulations reveal tenfold higher electric fields associated with metallic nanometre-sized tips compared to quasi-planar electrode regions, and measurements using gold nanoneedles confirm a field-induced reagent concentration that enables the CO2 reduction reaction to proceed with a geometric current density for CO of 22 milliamperes per square centimetre at -0.35 volts (overpotential of 0.24 volts). This performance surpasses by an order of magnitude the performance of the best gold nanorods, nanoparticles and oxide-derived noble metal catalysts. Similarly designed palladium nanoneedle electrocatalysts produce formate with a Faradaic efficiency of more than 90 per cent and an unprecedented geometric current density for formate of 10 milliamperes per square centimetre at -0.2 volts, demonstrating the wider applicability of the field-induced reagent concentration concept. PMID- 27487221 TI - Corrigendum: Concerted nucleophilic aromatic substitution with 19F- and 18F. PMID- 27487222 TI - Addendum: Non-Joulian magnetostriction. PMID- 27487223 TI - Neuroscience: Flipping the sleep switch. PMID- 27487224 TI - Cancer: Endothelial-cell killing promotes metastasis. PMID- 27487225 TI - Multivalence Charge Transfer in Doped and Codoped Photocatalytic TiO2. AB - The present work reports data for the mineralogical and chemical properties of anatase thin films individually doped or codoped with chromium and vanadium, fabricated by sol-gel spin coating on glass substrates and annealing at 450 degrees C for 2 h. X-ray photoelectron spectroscopy data indicated the presence of Ti(4+), Ti(3+), Cr(3+), and possibly Cr(4+) in the Cr-doped thin films; Ti(4+), Ti(3+), V(3+), V(4+), and possibly V(5+) in the V-doped thin films; and Ti(4+), Ti(3+), Cr(3+), Cr(4+), V(3+), V(4+), and possibly V(5+) in the codoped thin films. While the thermodynamically stable valences Ti(4+), Cr(3+), and V(5+) would be expected to have formed, the presence of the nonequilibrium valences Ti(3+), Cr(4+), V(3+), and V(4+) is considered to have resulted from intervalence charge transfer for the Cr-doped and V-doped systems but from multivalence charge transfer (MVCT) for the codoped system. The latter phenomenon, which is introduced as a new conceptual term, describes the nature of the mutual exchange of electrons during valence changes of both dopant (Cr, V) and matrix (Ti) ions during annealing. In the present case, MVCT appears to be a transient metastable condition that acts during annealing, but subsequent UV irradiation can alter its effects. PMID- 27487226 TI - Normal-Pressure Hydrocephalus, Sleep Apnea Syndrome, and Quality of Life in an Octagenarian. PMID- 27487228 TI - Prepregnancy Weight in Women with Type I Diabetes Mellitus: Effect on Pregnancy Outcomes. AB - Objective This study aims to evaluate the association between prepregnancy body mass index (BMI) and adverse pregnancy outcomes in women with type 1 diabetes mellitus (DM). Methods This is a secondary analysis of a cohort of 426 pregnancies in women with type 1 DM recruited before 20 weeks gestation. Women were categorized according to prepregnancy BMI: low BMI (< 20 kg/m2), normal BMI (20 to < 25 kg/m2), and high BMI (>= 25 kg/m2). The outcomes of interest were: spontaneous abortion (delivery < 20 weeks gestation); preeclampsia; emergent delivery for maternal indications (hypertension or placental abruption); and preterm delivery (< 37 weeks gestation). Analyses included proportional hazards and multiple logistic regression models with covariates: age, age at diagnosis of type 1 DM, previous spontaneous abortion, microvascular disease (nephropathy or retinopathy), and glycohemoglobin A1 concentrations. Results Low BMI was associated with preterm delivery. High BMI was associated with emergent delivery for maternal indications. Glycemic control as measured by glycohemoglobin A1 was associated with increased risk of spontaneous abortion, attenuating the association with low prepregnancy weight. Conclusion Prepregnancy BMI is a risk factor to be considered when caring for women with type 1 DM, in particular for preterm delivery (low BMI) and emergent delivery for maternal indications (high BMI). PMID- 27487230 TI - Association between Breast Milk and Bronchopulmonary Dysplasia: A Single Center Observational Study. AB - Introduction Bronchopulmonary dysplasia (BPD) is a frequent, long-term complication in very low-birth-weight (VLBW) newborns. Its etiology is multifactorial and the oxidative stress is one of its main causes. Breast milk (BM) reduces oxidative stress and provides antioxidant protection, therefore, BM may have a protective effect against BPD. Objectives This study aims to assess the possible protective effects of BM on BPD. Methods This is a cohort study including infants with a birth weight below 1,500 g and/or gestational age of less than 32 weeks, born between January 2011 and October 2014. BPD was defined as the need for supplementary oxygen for 28 days or more. Results The incidence of BPD was 29.1%. The median amount of BM received by the patients in the first 6 weeks of life was significantly higher in patients without BPD (10.8 mL/kg/day) than in those with BPD (2.3 mL/kg/day). The amount of BM received was inversely associated with the incidence of BPD, even after multivariate analysis. The cutoff point at which the protective effect emerged was an average amount of 7 mL/kg/day of BM during the first 42 days of life. Conclusion Feeding VLBW infants with BM is associated with a lower risk of developing BPD. PMID- 27487229 TI - Windows of Opportunity for Lifestyle Interventions to Prevent Gestational Diabetes Mellitus. AB - Gestational diabetes mellitus (GDM) is linked with several acute maternal health risks and long-term development of type 2 diabetes, metabolic syndrome, and cardiovascular disease. Intrauterine exposure to GDM similarly increases offspring risk of early-life health complications and later disease. GDM recurrence is common, affecting 40 to 73% of women, and augments associated maternal/fetal/child health risks. Modifiable and independent risk factors for GDM include maternal excessive gestational weight gain and prepregnancy overweight and obesity. Lifestyle interventions that target diet, activity, and behavioral strategies can effectively modify body weight. Randomized clinical trials testing the effects of lifestyle interventions during pregnancy to reduce excessive gestational weight gain have generally shown mixed effects on reducing GDM incidence. Trials testing the effects of postpartum lifestyle interventions among women with a history of GDM have shown reduced incidence of diabetes and improved cardiovascular disease risk factors. However, the long-term effects of interpregnancy or prepregnancy lifestyle interventions on subsequent GDM remain unknown. Future adequately powered and well-controlled clinical trials are needed to determine the effects of lifestyle interventions to prevent GDM and identify pathways to effectively reach reproductive-aged women across all levels of society, before, during, and after pregnancy. PMID- 27487231 TI - Relationship of Hospital Staff Coverage and Delivery Room Resuscitation Practices to Birth Asphyxia. AB - Objective The objective of this study was to assess utilization of specialist coverage and checklists in perinatal settings and to examine utilization by birth asphyxia rates. Design This is a survey study of California maternity hospitals concerning checklist use to prepare for delivery room resuscitation and 24-hour in-house specialist coverage (pediatrician/neonatologist, obstetrician, and obstetric anesthesiologist) and results linked to hospital birth asphyxia rates (preterm and low weight births were excluded). Results Of 253 maternity hospitals, 138 responded (55%); 59 (43%) indicated checklist use, and in-house specialist coverage ranged from 38% (pediatrician/neonatologist) to 54% (anesthesiology). In-house coverage was more common in urban versus rural hospitals for all specialties (p < 0.0001), but checklist use was not significantly different (p = 0.88). Higher birth volume hospitals had more specialist coverage (p < 0.0001), whereas checklist use did not differ (p = 0.3). In-house obstetric coverage was associated with lower asphyxia rates (odds ratio: 0.34; 95% confidence interval [CI]: 0.20, 0.58) in a regression model accounting for other providers. Checklist use was not associated with birth asphyxia (odds ratio: 1.12; 95% CI: 0.75, 1.68). Conclusion Higher birth volume and urban hospitals demonstrated greater in-house specialist coverage, but checklist use was similar across all hospitals. Current data suggest that in-house obstetric coverage has greater impact on asphyxia than other specialist coverage or checklist use. PMID- 27487233 TI - Exploring the Potential Benefits and Risks of Anticoagulation for Atrial Fibrillation During Hospitalization for Sepsis. PMID- 27487232 TI - Interferon Alpha Induces Sustained Changes in NK Cell Responsiveness to Hepatitis B Viral Load Suppression In Vivo. AB - NK cells are important antiviral effectors, highly enriched in the liver, with the potential to regulate immunopathogenesis in persistent viral infections. Here we examined whether changes in the NK pool are induced when patients with eAg positive CHB are 'primed' with PegIFNalpha and importantly, whether these changes are sustained or further modulated long-term after switching to nucleos(t)ides (sequential NUC therapy), an approach currently tested in the clinic. Longitudinal sampling of a prospectively recruited cohort of patients with eAg+CHB showed that the cumulative expansion of CD56bright NK cells driven by 48 weeks of PegIFNalpha was maintained at higher than baseline levels throughout the subsequent 9 months of sequential NUCs. Unexpectedly, PegIFNalpha-expanded NK cells showed further augmentation in their expression of the activating NK cell receptors NKp30 and NKp46 during sequential NUCs. The expansion in proliferating, functional NK cells was more pronounced following sequential NUCs than in comparison cohorts of patients treated with de novo NUCs or PegIFNalpha only. Reduction in circulating HBsAg concentrations, a key goal in the path towards functional cure of CHB, was only achieved in those patients with enhancement of NK cell IFNgamma and cytotoxicity but decrease in their expression of the death ligand TRAIL. In summary, we conclude that PegIFNalpha priming can expand a population of functional NK cells with an altered responsiveness to subsequent antiviral suppression by NUCs. Patients on sequential NUCs with a distinct NK cell profile show a decline in HBsAg, providing mechanistic insights for the further optimisation of treatment strategies to achieve sustained responses in CHB. PMID- 27487234 TI - Construction and Nanoscale Detection of Interfacial Charge Transfer of Elegant Z Scheme WO3/Au/In2S3 Nanowire Arrays. AB - Elegant Z-scheme WO3/Au/In2S3 nanowire arrays were precisely constructed through a facile step-by-step route. Surface potential change on pristine or In2S3-Au coated WO3 single nanowire under dark and illumination detected through a Kelvin probe force microscopy (KPFM) technique indicates that the vectorial holes transfer of In2S3 -> Au -> WO3 should occur upon the excitation of both WO3 and In2S3. In such charge transfer processes, the embedded Au nanoparticles in the heterojunction systems act as a charge mediator for electrons in the conduction band of WO3 and holes in the valence band of In2S3. The strong charge carrier separation ability of this structure will finally enhance the oxidation ability of WO3 with high concertation of photogenerated holes and, further, leave the free electrons in the In2S3 with long surviving time. Therefore, the unique Z scheme WO3/Au/In2S3 heterostructure shows great visible-light activity toward photocatalytic reduction of CO2 in the presence of water vapor into renewable hydrocarbon fuel (methane: CH4). PMID- 27487235 TI - PREVALENCE OF ANTIBODY TO AND DNA OF LAWSONIA INTRACELLULARIS IN SAMPLES FROM WILD ANIMALS IN KOREA. AB - We evaluated the prevalence of Lawsonia intracellularis infection in three wild animal species in Korea; the Korean water deer ( Hydropotes inermis ), Siberian roe deer ( Capreolus pygargus ), and raccoon dogs ( Nyctereutes procyonoides ). We collected 136 sera and 109 fecal samples from individuals in 10 Wildlife Rescue and Conservation Centers. Serum samples were tested for anti- L. intracellularis antibodies using a blocking enzyme-linked immunosorbent assay (bELISA), and fecal samples were subjected to a real-time PCR assay for L. intracellularis . Thirty-five (25.7%) sera and 36 (33.0%) fecal samples were positive. We found a higher proportion of positive sera (64.7%, chi2=15.439, P<0.01) and feces (58.8%, chi2=6.126, P<0.05) in raccoon dogs (chi2=11.855, P<0.01) than in the other species (20% positive sera and 29% positive feces in Korean water deer; 20% positive sera and 25% positive feces in Siberian roe deer). Our data indicate infection by L. intracellularis in Korean water deer, Siberian roe deer, and raccoon dogs throughout the country. It is imperative to know whether these infected animal species are natural hosts for L. intracellularis in addition to domestic pigs ( Sus scrofa domesticus). PMID- 27487236 TI - Safety of Denosumab Versus Zoledronic Acid in Patients with Bone Metastases: A Meta-Analysis of Randomized Controlled Trials. AB - INTRODUCTION: Bone metastases lead to local bone destruction and skeletal complications. Bisphosphonates, particlulaly zoledronic acid (ZA), play a central role in the treatment of bone metastases. Some studies have shown that denosumab may delay and prevent SREs in metastatic bone disease more effectively than ZA; therefore, we systematically reviewed and assessed the safety of denosumab and ZA. METHODS: The PubMed, EMBASE, Cochrane Library, Web of Science with Conference Proceedings, Elsevier, and China National Knowledge Infrastructure (CNKI) databases were searched up to October 2015. 2 independent reviewers extracted data from each eligible study using a standard protocol, and both fixed-effects and random-effects models were used to analyze and evaluate the data extracted from eligible articles. RESULTS: 6 randomized controlled trials enrolling 13,733 patients were included. Occurrences of adverse events were generally similar between the denosumab and ZA groups except anemia and anorexia in patients with bone metastases and back pain and bone pain. However, occurrences of serious adverse events such as hypocalcaemia , renal adverse events , and new primary malignancy were significantly different between the denosumab and ZA groups. Only the occurrence of osteonecrosis of the jaw showed no significant difference between the denosumab and ZA groups in patients with bone metastases. CONCLUSION: Denosumab was safer in delaying or preventing skeletal-related events in patients with bone metastases and prevented pain progression compared to ZA in this meta analysis. PMID- 27487237 TI - Identification of Differentially-Expressed Genes in Response to Mycosphaerella fijiensis in the Resistant Musa Accession 'Calcutta-4' Using Suppression Subtractive Hybridization. AB - Bananas and plantains are considered an important crop around the world. Banana production is affected by several constraints, of which Black Sigatoka Disease, caused by the fungus Mycosphaerella fijiensis, is considered one of the most important diseases in banana plantations. The banana accession 'Calcutta-4' has a natural resistance to Black Sigatoka; however, the fruit is not valuable for commercialization. Gene identification and expression studies in 'Calcutta-4' might reveal possible gene candidates for resistant to the disease and elucidate mechanisms for resistance. A subtracted cDNA library was generated from leaves after 6, 9 and 12 days inoculated with M. fijiensis conidia on greenhouse banana plants of the accession 'Calcutta-4'. Bioinformatic analysis revealed 99 good quality sequences. Blast2go analysis revealed that 31% of the sequences could not be categorized and, according to the Biological Process Category, 32 and 28 ESTs are related to general metabolic and cellular processes, respectively; while 10 ESTs response to stimulus. Seven sequences were redundant and one was similar to genes that may be involved in pathogen resistance including the putative disease resistance protein RGA1. Genes encoding zinc finger domains were identified and may play an important role in pathogen resistance by inducing the expression of downstream genes. Expression analysis of four selected genes was performed using RT-qPCR during the early stage of the disease development at 6, 9, 12 and 15 days post inoculation showing a peak of up regulation at 9 or 12 days post inoculation. Three of the four genes showed an up-regulation of expression in 'Calcutta-4' when compared to 'Williams' after inoculation with M. fijiensis, suggesting a fine regulation of specific gene candidates that may lead to a resistance response. The genes identified in early responses in a plant-pathogen interaction may be relevant for the resistance response of 'Calcutta-4' to Black Sigatoka. Genes with different functions may play a role in plant response to the disease. The present study suggests a fine up regulation of these genes that might be needed to perform an incompatible interaction. Further gene functional studies need to be performed to validate their use as candidate resistance genes in susceptible banana cultivars. PMID- 27487238 TI - Remotely Sensed Data Informs Red List Evaluations and Conservation Priorities in Southeast Asia. AB - The IUCN Red List has assessed the global distributions of the majority of the world's amphibians, birds and mammals. Yet these assessments lack explicit reference to widely available, remotely-sensed data that can sensibly inform a species' risk of extinction. Our first goal is to add additional quantitative data to the existing standardised process that IUCN employs. Secondly, we ask: do our results suggest species of concern-those at considerably greater risk than hitherto appreciated? Thirdly, these assessments are not only important on a species-by-species basis. By combining distributions of species of concern, we map conservation priorities. We ask to what degree these areas are currently protected and how might knowledge from remote sensing modify the priorities? Finally, we develop a quick and simple method to identify and modify the priority setting in a landscape where natural habitats are disappearing rapidly and so where conventional species' assessments might be too slow to respond. Tropical, mainland Southeast Asia is under exceptional threat, yet relatively poorly known. Here, additional quantitative measures may be particularly helpful. This region contains over 122, 183, and 214 endemic mammals, birds, and amphibians, respectively, of which the IUCN considers 37, 21, and 37 threatened. When corrected for the amount of remaining natural habitats within the known elevation preferences of species, the average sizes of species ranges shrink to <40% of their published ranges. Some 79 mammal, 49 bird, and 184 amphibian ranges are <20,000km2-an area at which IUCN considers most other species to be threatened. Moreover, these species are not better protected by the existing network of protected areas than are species that IUCN accepts as threatened. Simply, there appear to be considerably more species at risk than hitherto appreciated. Furthermore, incorporating remote sensing data showing where habitat loss is prevalent changes the locations of conservation priorities. PMID- 27487239 TI - A passenger strand variant in miR-196a2 contributes to asthma severity in children and adolescents: A preliminary study. AB - There is emerging evidence to support the role of microRNAs in allergic airway diseases and inflammation. Genetic variants in microRNA genes might affect microRNA-mediated cell regulation. This preliminary study was designed to investigate the association of the microRNA-196a2 rs11614913 (C/T) polymorphism with susceptibility to asthma and clinical outcomes in children and adolescents. Genotyping of rs11614913 polymorphism was determined in 96 patients with bronchial asthma (6-18 years of age) and 96 unrelated controls, using real-time polymerase chain reaction technology. In-silico target prediction and network core analyses were performed. The asthmatics did not show significant differences in genotype distribution (p = 0.609) and allele frequencies (p = 0.428) compared with the controls. There were also no associations with disease duration, age at onset, asthma phenotype, asthma control, therapeutic level, airway hyper responsiveness, or biochemical parameters in the blood. However, the CC genotype was associated with a more severe degree of asthma (p = 0. 023) and higher frequency of nocturnal asthma (p = 0.002). Carriers for CC were 17 times more likely to develop nocturnal asthma, and had a more than 2.5-fold increased risk for poor disease outcome compared with CT and TT individuals. In conclusion, microRNA-196a2 rs11614913 polymorphism might be associated with asthma severity in our sample of the Egyptian population. Further investigations in studies with a larger sample size and functional tests are needed to validate our findings and to explore the detailed biological mechanisms. PMID- 27487240 TI - MR Image Analytics to Characterize the Upper Airway Structure in Obese Children with Obstructive Sleep Apnea Syndrome. AB - PURPOSE: Quantitative image analysis in previous research in obstructive sleep apnea syndrome (OSAS) has focused on the upper airway or several objects in its immediate vicinity and measures of object size. In this paper, we take a more general approach of considering all major objects in the upper airway region and measures pertaining to their individual morphological properties, their tissue characteristics revealed by image intensities, and the 3D architecture of the object assembly. We propose a novel methodology to select a small set of salient features from this large collection of measures and demonstrate the ability of these features to discriminate with very high prediction accuracy between obese OSAS and obese non-OSAS groups. MATERIALS AND METHODS: Thirty children were involved in this study with 15 in the obese OSAS group with an apnea-hypopnea index (AHI) = 14.4 +/- 10.7) and 15 in the obese non-OSAS group with an AHI = 1.0 +/- 1.0 (p<0.001). Subjects were between 8-17 years and underwent T1- and T2 weighted magnetic resonance imaging (MRI) of the upper airway during wakefulness. Fourteen objects in the vicinity of the upper airways were segmented in these images and a total of 159 measurements were derived from each subject image which included object size, surface area, volume, sphericity, standardized T2-weighted image intensity value, and inter-object distances. A small set of discriminating features was identified from this set in several steps. First, a subset of measures that have a low level of correlation among the measures was determined. A heat map visualization technique that allows grouping of parameters based on correlations among them was used for this purpose. Then, through T-tests, another subset of measures which are capable of separating the two groups was identified. The intersection of these subsets yielded the final feature set. The accuracy of these features to perform classification of unseen images into the two patient groups was tested by using logistic regression and multi-fold cross validation. RESULTS: A set of 16 features identified with low inter-feature correlation (< 0.36) yielded a high classification accuracy of 96% with sensitivity and specificity of 97.8% and 94.4%, respectively. In addition to the previously observed increase in linear size, surface area, and volume of adenoid, tonsils, and fat pad in OSAS, the following new markers have been found. Standardized T2 weighted image intensities differed between the two groups for the entire neck body region, pharynx, and nasopharynx, possibly indicating changes in object tissue characteristics. Fat pad and oropharynx become less round or more complex in shape in OSAS. Fat pad and tongue move closer in OSAS, and so also oropharynx and tonsils and fat pad and tonsils. In contrast, fat pad and oropharynx move farther apart from the skin object. CONCLUSIONS: The study has found several new anatomic bio-markers of OSAS. Changes in standardized T2-weighted image intensities in objects may imply that intrinsic tissue composition undergoes changes in OSAS. The results on inter-object distances imply that treatment methods should respect the relationships that exist among objects and not just their size. The proposed method of analysis may lead to an improved understanding of the mechanisms underlying OSAS. PMID- 27487241 TI - Neoadjuvant Chemotherapy in Advanced Ovarian Cancer: A Single-Institution Experience and a Review of the Literature. AB - OBJECTIVES: The aim of this study was to evaluate the role of neoadjuvant chemotherapy (NACT) in advanced ovarian carcinoma patients unable to undergo a complete resection during primary debulking surgery. METHODS: From February 2005 to October 2015, all consecutive cases of advanced-stage epithelial ovarian carcinoma at the University of Bari were retrospectively recorded. Of them, patients treated with NACT were collected. Kaplan-Meier and Cox proportional hazards analyses were used to determine the predictors of survival. RESULTS: Seventy-eight women with advanced-stage epithelial ovarian carcinoma were treated with NACT. On univariate analysis, age (p = 0.003), CA-125 serum level (0.001), response to NACT (p < 0.0001), stage of disease (p = 0.011) and optimal debulking surgery (p < 0.0001) were found to be important prognostic factors related to survival. However, on multivariate analysis, age, response to NACT, CA-125 serum level and optimal debulking surgery remained as independent poor prognostic factors for survival. The median overall and disease-free survival were 31 and 12 months, respectively. CONCLUSIONS: NACT does not compromise survival in patients with stage IIIC and IV ovarian cancer compared to patients treated with primary surgery. Prospective randomized trials comparing NACT to conventional treatment are needed to determine the quality of life and cost/benefit outcomes for women presenting advanced epithelial ovarian cancer. PMID- 27487242 TI - Research on B Cell Algorithm for Learning to Rank Method Based on Parallel Strategy. AB - For the purposes of information retrieval, users must find highly relevant documents from within a system (and often a quite large one comprised of many individual documents) based on input query. Ranking the documents according to their relevance within the system to meet user needs is a challenging endeavor, and a hot research topic-there already exist several rank-learning methods based on machine learning techniques which can generate ranking functions automatically. This paper proposes a parallel B cell algorithm, RankBCA, for rank learning which utilizes a clonal selection mechanism based on biological immunity. The novel algorithm is compared with traditional rank-learning algorithms through experimentation and shown to outperform the others in respect to accuracy, learning time, and convergence rate; taken together, the experimental results show that the proposed algorithm indeed effectively and rapidly identifies optimal ranking functions. PMID- 27487243 TI - Locating and Activating Molecular 'Time Bombs': Induction of Mycolata Prophages. AB - Little is known about the prevalence, functionality and ecological roles of temperate phages for members of the mycolic acid producing bacteria, the Mycolata. While many lytic phages infective for these organisms have been isolated, and assessed for their suitability for use as biological control agents of activated sludge foaming, no studies have investigated how temperate phages might be induced for this purpose. Bioinformatic analysis using the PHAge Search Tool (PHAST) on Mycolata whole genome sequence data in GenBank for members of the genera Gordonia, Mycobacterium, Nocardia, Rhodococcus, and Tsukamurella revealed 83% contained putative prophage DNA sequences. Subsequent prophage inductions using mitomycin C were conducted on 17 Mycolata strains. This led to the isolation and genome characterization of three novel Caudovirales temperate phages, namely GAL1, GMA1, and TPA4, induced from Gordonia alkanivorans, Gordonia malaquae, and Tsukamurella paurometabola, respectively. All possessed highly distinctive dsDNA genome sequences. PMID- 27487244 TI - Tableting Properties and Compression Models of Labisia pumila Tablets. AB - The tableting properties of Labisia pumila herbal powder, which is well known for its therapeutic benefits was investigated. The herbal powder was compressed into tablets using a stainless steel cylindrical uniaxial die of 13-mm- diameter with compaction pressures ranging from 7 to 25 MPa. Two feed weights, 0.5 and 1.0 g were used to form tablets. Some empirical models were used to describe the compressibility behavior of Labisia pumila tablets. The strength and density of tablets increased with increase in compaction pressure and resulted in reduction in porosity of the tablets. Smaller feeds, higher forces and increase in compaction pressure, contributed to more coherent tablets. These findings can be used to enhance the approach and understanding of tableting properties of Labisia pumila herbal powder tablets. PMID- 27487246 TI - Photochemical Deposition of Silver Nanoparticles on Clays and Exploring Their Antibacterial Activity. AB - Photochemical method was used to synthesize silver nanoparticles (AgNPs) in the presence of citrate or clay (SWy-1, SYn-1, and Laponite B) as stabilizers and Lucirin TPO as photoinitiator. During the photochemical synthesis, an appearance of the plasmon absorption band was seen around 400 nm, indicating the formation of AgNPs. X-ray diffraction results suggested that AgNPs prepared in SWy-1 were adsorbed into interlamellar space, and moreover, showed some clay exfoliation. In the case of SYn-1, AgNPs was not intercalated. For the AgNP/Lap B sample, the formation of an exfoliated structure occurred. Transmission electron microscopy revealed the spherical shape of AgNPs for all samples. The particle sizes obtained for AgNP/SWy-1, AgNP/SYn-1, and AgNP/Lap B were 2.6, 5.1, and 3.8 nm, respectively. AgNPs adsorbed on SYn-1 reveal nonuniform size and aggregation of some particles. However, AgNP/SWy-1 and AgNP/Lap B samples are more uniform and have diameters smaller than those prepared with SYn-1. This behavior is due to the ability to exfoliate these clays. The antibacterial activities of pure clays, AgNP/citrate, and AgNP/clays were investigated against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). AgNPs in the presence of clays (AgNPs/SYn 1 and AgNPs/SWy-1) showed a lower survival index percentage compared to those obtained for pure clays and AgNPs. The AgNP/SWy-1 sample showed good antibacterial activity against both tested species and the lowest survival index of 3.9 and 4.3 against E. coli and S. aureus, respectively. AgNPs are located in the interlayer region of the SWy-1, which has acid sites. These acidic sites may contribute to the release of Ag(+) ions from the surface of AgNPs. On the other hand, Laponite B and AgNP/Lap B samples did not demonstrate any bactericidal activity. PMID- 27487247 TI - Variability of nitrifying communities in surface coastal waters of the Eastern South Pacific (~36 degrees S). AB - We report the seasonal and single-diurnal variability of potentially active members of the prokaryote community in coastal surface waters off central Chile and the relationship between nitrifiers and solar radiation by combining 16S cDNA based pyrosequencing, RT-qPCR of specific gene markers for nitrifiers (amoA, for general AOA, AOA-A, AOA-B, Nitrosopumilus maritimus and beta-AOB; and 16S rRNA gene for Nitrospina-like NOB), and solar irradiance measurements. We also evaluated the effects of artificial UVA-PAR and PAR spectra on nitrifiers by RT qPCR. All nitrifiers (except AOA-B ecotype) were detected via RT-qPCR but AOA was the only group detected by pyrosequencing. Results showed high variability in their transcriptional levels during the day which could be associated to sunlight intensity thresholds in winter although AOA and Nitrospina-like NOB transcript number were also potentially related with environmental substrate availability. Only N. maritimus amoA transcripts showed a significant negative correlation with solar irradiances in both periods. During spring-summer, Nitrospina transcripts decreased at higher sunlight intensities, whereas the opposite was found during winter under natural (in situ) and artificial light experiments. In summary, a nitrifying community with variable tolerance to solar radiation is responsible for daily nitrification, and was particularly diverse during winter in the study area. PMID- 27487245 TI - CLIMP: Clustering Motifs via Maximal Cliques with Parallel Computing Design. AB - A set of conserved binding sites recognized by a transcription factor is called a motif, which can be found by many applications of comparative genomics for identifying over-represented segments. Moreover, when numerous putative motifs are predicted from a collection of genome-wide data, their similarity data can be represented as a large graph, where these motifs are connected to one another. However, an efficient clustering algorithm is desired for clustering the motifs that belong to the same groups and separating the motifs that belong to different groups, or even deleting an amount of spurious ones. In this work, a new motif clustering algorithm, CLIMP, is proposed by using maximal cliques and sped up by parallelizing its program. When a synthetic motif dataset from the database JASPAR, a set of putative motifs from a phylogenetic foot-printing dataset, and a set of putative motifs from a ChIP dataset are used to compare the performances of CLIMP and two other high-performance algorithms, the results demonstrate that CLIMP mostly outperforms the two algorithms on the three datasets for motif clustering, so that it can be a useful complement of the clustering procedures in some genome-wide motif prediction pipelines. CLIMP is available at http://sqzhang.cn/climp.html. PMID- 27487248 TI - Maternal PTSD and Children's Adjustment: Parenting Stress and Emotional Availability as Proposed Mediators. AB - OBJECTIVES: Maternal posttraumatic stress disorder (PTSD) is a risk factor for negative child adjustment, but it is unclear whether this association is direct (e.g., a mother's PTSD symptoms are observed, learned, and internalized by children which results in behavioral and emotional problems) or indirect, through parent-child relationship difficulties or parenting stress. We hypothesized that parenting stress and maternal emotional availability would exhibit indirect effects on relationships between maternal PTSD and children's functioning. METHOD: Participants were 52 trauma-exposed mothers and their children (aged 7-12 years). Mothers completed measures of PTSD and parenting stress and reported on their children's functioning. Emotional availability was assessed through observer-rated mother-child interactions. RESULTS: Emotional availability was not related to PTSD or child outcomes. Parenting stress had a substantial indirect effect on the relationships between maternal PTSD and child emotion regulation, internalizing, and externalizing behaviors. CONCLUSIONS: Results highlight the need to target parenting stress in interventions with trauma-exposed families. PMID- 27487249 TI - The use of micro-electro mechanical systems in vascular monitoring: implications for clinical use. AB - INTRODUCTION: BioMEMS relates to the implementation of Micro-Electro-Mechanical Systems (MEMS), in the biological and medical sphere. BioMEMS sensors are being utilized for many clinical applications, including a wireless urinary pressure system, right heart pressure sensor, and measurements on shearing force on the vascular system An important application of BioMEMS is on Heart failure (HF), a common disease, with a prevalence of 10% or more in persons 70 years of age or older, associated with high morbidity and mortality. HF affects over 5 million people and contributes to over 200,000 deaths a year in the United States alone. AREAS COVERED: The purpose of this paper is to provide a short overview on the successful implementation of BioMEMS sensors in heart failure and vascular medicine. Expert commentary: BioMEMS devices have overcome current limitations in pharmacotherapies for resistant hypertension by electrical modulation of the baroreceeptors. This represents a step towards the development of biomedical micro-devices for those conditions in which pharmacotherapies result poorly effective or elicit unacceptable toxicity. PMID- 27487251 TI - Optimization of a Digital Medicine System in Psychiatry. AB - BACKGROUND: Nonadherence to medication compromises the effectiveness of psychiatric treatments in patients with serious mental illness (SMI). A newly developed digital medicine system (DMS) offers an opportunity to objectively assess and report patient medication adherence. DMS includes a wearable sensor that receives a data signal from a medication tablet with an embedded ingestible sensor after ingestion of the medication and transmits that data to the patient's mobile device to display health care information for the patient and treatment team. METHODS/RESULTS: Development of a DMS requires a program that investigates safety, tolerability, and usability of the system in patients with SMI. It necessitates rapid design adaptation of the individual components and the integrated system and human factors studies with the intended users. This article describes the program's methodology and shows results from 3 early studies, conducted in 2013 and 2014, to illustrate diversity of the programs' methodology. First, a standard 28-day study showed minimal skin irritation and demonstrated acceptable wearability of the wearable sensor. Second, a 16-week study provided usability feedback from patients with SMI and caregivers to improve the mobile application. Third, end-to-end bench-level integrated system testing led to multiple substudies of a master protocol (ClinicalTrials.gov identifier: NCT02091882) to investigate various aspects of the system (eg, ingestible sensor detection and latency). CONCLUSIONS: To develop a DMS in psychiatry, the system's multiple components must be considered simultaneously using various methodologies. A focus on usability, along with agile evaluation and feedback across studies, provides an optimal strategy for ensuring patient acceptance and successful regulatory review. PMID- 27487253 TI - Thrombelastography-Based Dosing of Enoxaparin for Thromboprophylaxis in Trauma and Surgical Patients: A Randomized Clinical Trial. AB - Importance: Prophylactic enoxaparin is used to prevent venous thromboembolism (VTE) in surgical and trauma patients. However, VTE remains an important source of morbidity and mortality, potentially exacerbated by antithrombin III or anti Factor Xa deficiencies and missed enoxaparin doses. Recent data suggest that a difference in reaction time (time to initial fibrin formation) greater than 1 minute between heparinase and standard thrombelastogram (TEG) is associated with a decreased risk of VTE. Objective: To evaluate the effectiveness of TEG-adjusted prophylactic enoxaparin dosing among trauma and surgical patients. Design, Setting, and Participants: This randomized clinical trial, conducted from October 2012 to May 2015, compared standard dosing (30 mg twice daily) with TEG-adjusted enoxaparin dosing (35 mg twice daily) for 185 surgical and trauma patients screened for VTE at 3 level I trauma centers in the United States. Main Outcomes and Measures: The incidence of VTE, bleeding complications, anti-Factor Xa deficiency, and antithrombin III deficiency. Results: Of the 185 trial participants, 89 were randomized to the control group (median age, 44.0 years; 55.1% male) and 96 to the intervention group (median age, 48.5 years; 74.0% male). Patients in the intervention group received a higher median enoxaparin dose than control patients (35 mg vs 30 mg twice daily; P < .001). Anti-Factor Xa levels in intervention patients were not higher than levels in control patients until day 6 (0.4 U/mL vs 0.21 U/mL; P < .001). Only 22 patients (11.9%) achieved a difference in reaction time greater than 1 minute, which was similar between the control and intervention groups (10.4% vs 13.5%; P = .68). The time to enoxaparin initiation was similar between the control and intervention groups (median [range] days, 1.0 [0.0-2.0] vs 1.0 [1.0-2.0]; P = .39), and the number of patients who missed at least 1 dose was also similar (43 [48.3%] vs 54 [56.3%]; P = .30). Rates of VTE (6 [6.7%] vs 6 [6.3%]; P > .99) were similar, but the difference in bleeding complications (5 [5.6%] vs 13 [13.5%]; P = .08) was not statistically significant. Antithrombin III and anti-Factor Xa deficiencies and hypercoagulable TEG parameters, including elevated coagulation index (>3), maximum amplitude (>74 mm), and G value (>12.4 dynes/cm2), were prevalent in both groups. Identified risk factors for VTE included older age (61.0 years vs 46.0 years; P = .04), higher body mass index (calculated as weight in kilograms divided by height in meters squared; 30.6 vs 27.1; P = .03), increased Acute Physiology and Chronic Health Evaluation II score (8.5 vs 7.0; P = .03), and increased percentage of missed doses per patient (14.8% vs 2.5%; P = .05). Conclusions and Relevance: The incidence of VTE was low and similar between groups; however, few patients achieved a difference in reaction time greater than 1 minute. Antithrombin III deficiencies and hypercoagulable TEG parameters were prevalent among patients with VTE. Low VTE incidence may be due to an early time to enoxaparin initiation and an overall healthier and less severely injured study population than previously reported. Trial Registration: clinicaltrials.gov Identifier: NCT00990236. PMID- 27487250 TI - Metabolite transport and associated sugar signalling systems underpinning source/sink interactions. AB - Metabolite transport between organelles, cells and source and sink tissues not only enables pathway co-ordination but it also facilitates whole plant communication, particularly in the transmission of information concerning resource availability. Carbon assimilation is co-ordinated with nitrogen assimilation to ensure that the building blocks of biomass production, amino acids and carbon skeletons, are available at the required amounts and stoichiometry, with associated transport processes making certain that these essential resources are transported from their sites of synthesis to those of utilisation. Of the many possible posttranslational mechanisms that might participate in efficient co-ordination of metabolism and transport only reversible thiol-disulphide exchange mechanisms have been described in detail. Sucrose and trehalose metabolism are intertwined in the signalling hub that ensures appropriate resource allocation to drive growth and development under optimal and stress conditions, with trehalose-6-phosphate acting as an important signal for sucrose availability. The formidable suite of plant metabolite transporters provides enormous flexibility and adaptability in inter-pathway coordination and source-sink interactions. Focussing on the carbon metabolism network, we highlight the functions of different transporter families, and the important of thioredoxins in the metabolic dialogue between source and sink tissues. In addition, we address how these systems can be tailored for crop improvement. PMID- 27487254 TI - Supercharging Reagent for Enhanced Liquid Chromatographic Separation and Charging of Sialylated and High-Molecular-Weight Glycopeptides for NanoHPLC-ESI-MS/MS Analysis. AB - Recent developments in proteomic techniques have led to the development of mass spectrometry (MS)-based methods to characterize site-specific glycosylation of proteins. However, appropriate analytical tools to characterize acidic and high molecular-weight (hMW) glycopeptides are still lacking. In this study, we demonstrate that the addition of supercharging reagent, m-nitrobenzyl alcohol (m NBA), into mobile phases greatly facilitates the analysis of acidic and hMW glycopeptides. Using commercial glycoproteins, we demonstrated that in the presence of m-NBA the charge state of sialylated glycopeptides increased and the chromatographic separation of neutral and acidic glycopeptides revealed a remarkable improvement. Next, we applied this system to the characterization of a glycoconjugate vaccine candidate consisting of a genetically detoxified exotoxin A of Pseudomonas aeruginosa covalently linked to Shigella flexneri type 2a O antigen (Sf2E) produced by engineered Escherichia coli. The addition of m-NBA, allowed us to identify peptides with glycan chains of unprecedented size, up to 20 repeat units (98 monosaccharides). Our results indicated that incorporation of m-NBA into reversed-phase liquid chromatography (LC) solvents improves sensitivity, charging, and chromatographic resolution for acidic and hMW glycopeptides. PMID- 27487252 TI - Azoreductases in drug metabolism. AB - : Azoreductases are flavoenzymes that have been characterized in a range of prokaryotes and eukaryotes. Bacterial azoreductases are associated with the activation of two classes of drug, azo drugs for the treatment of inflammatory bowel disease and nitrofuran antibiotics. The mechanism of reduction of azo compounds is presented; it requires tautomerisation of the azo compound to a quinoneimine and provides a unifying mechanism for the reduction of azo and quinone substrates by azoreductases. The importance of further work in the characterization of azoreductases from enteric bacteria is highlighted to aid in the development of novel drugs for the treatment of colon related disorders. Human azoreductases are known to play a crucial role in the metabolism of a number of quinone-containing cancer chemotherapeutic drugs. The mechanism of hydride transfer to quinones, which is shared not only between eukaryotic and prokaryotic azoreductases but also the wider family of NAD(P)H quinone oxidoreductases, is outlined. The importance of common single nucleotide polymorphisms (SNPs) in human azoreductases is described not only in cancer prognosis but also with regard to their effects on the efficacy of quinone drug based cancer chemotherapeutic regimens. This highlights the need to screen patients for azoreductase SNPs ahead of treatment with these regimens. LINKED ARTICLES: This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc. PMID- 27487255 TI - Investigating nurse practitioners in the private sector: a theoretically informed research protocol. AB - AIMS AND OBJECTIVES: To report a study protocol and the theoretical framework normalisation process theory that informs this protocol for a case study investigation of private sector nurse practitioners. BACKGROUND: Most research evaluating nurse practitioner service is focused on public, mainly acute care environments where nurse practitioner service is well established with strong structures for governance and sustainability. Conversely, there is lack of clarity in governance for emerging models in the private sector. In a climate of healthcare reform, nurse practitioner service is extending beyond the familiar public health sector. Further research is required to inform knowledge of the practice, operational framework and governance of new nurse practitioner models. DESIGN: The proposed research will use a multiple exploratory case study design to examine private sector nurse practitioner service. METHODS: Data collection includes interviews, surveys and audits. A sequential mixed method approach to analysis of each case will be conducted. Findings from within-case analysis will lead to a meta-synthesis across all four cases to gain a holistic understanding of the cases under study, private sector nurse practitioner service. Normalisation process theory will be used to guide the research process, specifically coding and analysis of data using theory constructs and the relevant components associated with those constructs. CONCLUSIONS: This article provides a blueprint for the research and describes a theoretical framework, normalisation process theory in terms of its flexibility as an analytical framework. RELEVANCE TO CLINICAL PRACTICE: Consistent with the goals of best research practice, this study protocol will inform the research community in the field of primary health care about emerging research in this field. Publishing a study protocol ensures researcher fidelity to the analysis plan and supports research collaboration across teams. PMID- 27487256 TI - Tyrosine-Coordinated P-Cluster in G. diazotrophicus Nitrogenase: Evidence for the Importance of O-Based Ligands in Conformationally Gated Electron Transfer. AB - The P-cluster is a unique iron-sulfur center that likely functions as a dynamic electron (e(-)) relay site between the Fe-protein and the catalytic FeMo-cofactor in nitrogenase. The P-cluster has been shown to undergo large conformational changes upon 2-e(-) oxidation which entail the coordination of two of the Fe centers to a Ser side chain and a backbone amide N, respectively. Yet, how and if this 2-e(-) oxidized state (P(OX)) is involved in catalysis by nitrogenase is not well established. Here, we present the crystal structures of reduced and oxidized MoFe-protein (MoFeP) from Gluconacetobacter diazotrophicus (Gd), which natively possesses an Ala residue in the position of the Ser ligand to the P-cluster. While reduced Gd-MoFeP is structurally identical to previously characterized counterparts around the FeMo-cofactor, oxidized Gd-MoFeP features an unusual Tyr coordination to its P-cluster along with ligation by a backbone amide nitrogen. EPR analysis of the oxidized Gd-MoFeP P-cluster confirmed that it is a 2-e(-) oxidized, integer-spin species. Importantly, we have found that the sequence positions corresponding to the Ser and Tyr ligands are almost completely covariant among Group I nitrogenases. These findings strongly support the possibility that the P(OX) state is functionally relevant in nitrogenase catalysis and that a hard, O-based anionic ligand serves to stabilize this state in a switchable fashion. PMID- 27487257 TI - The genetic architecture of freezing tolerance varies across the range of Arabidopsis thaliana. AB - The capacity to tolerate freezing temperatures limits the geographical distribution of many plants, including several species of agricultural importance. However, the genes involved in freezing tolerance remain largely unknown. Here, we describe the variation in constitutive freezing tolerance that occurs among worldwide accessions of Arabidopsis thaliana. We found that although plants from high latitudes tend to be more freezing tolerant than plants from low latitudes, the environmental factors that shape cold adaptation differ across the species range. Consistent with this, we found that the genetic architecture of freezing tolerance also differs across its range. Conventional genome-wide association studies helped identify a priori and other promising candidate genes. However, simultaneously modelling climate variables and freezing tolerance together pinpointed other excellent a priori candidate genes. This suggests that if the selective factor underlying phenotypic variation is known, multi-trait mixed models may aid in identifying the genes that underlie adaptation. PMID- 27487258 TI - Understanding Substance Use and Addiction Through the Lyrics of Black Sabbath: A Content Analysis. AB - BACKGROUND: Heavy metal music is distinguished for its deep sound and lyrical fixation with dark themes including war, destruction, doom, and misery. Such subjects permeate the music of Black Sabbath, the band generally considered the pioneers of heavy metal. One theme-substance use-is recurrent in Black Sabbath's songs and personal lives of its members. OBJECTIVE/METHODS: This study explored the band's relationship with substance use though a content analysis of all songs containing lyrics written and recorded in studio by Black Sabbath. The analysis included 156 songs across 19 albums recorded from 1970 to 2013. RESULTS: Three key findings emerged. First, a minority of songs (13%) contained substance references. Second, the songs with substance references were overwhelmingly (60%) negative, a pattern that increased over time. Third, despite many line-up changes over the band's 43-year period, every song referencing substance use except one featured vocalist Ozzy Osbourne and lyricist Geezer Butler. CONCLUSION: Contrary to the notion that heavy metal music glorifies or encourages substance use (Record Labeling, United States Senate, 1985), Black Sabbath's lyrics as a whole weave a cautionary tale of how persistent substance use can hijack free will, become the dominant focus of the affected individual, and produce myriad forms of human misery. The insidiousness of chronic substance use depicted by the lyrics mirrors findings from natural-history studies of individuals with substance use disorders and aligns with neurobiological heuristics of addiction. PMID- 27487260 TI - Measuring citalopram in blood and central nervous system: revealing a distribution pattern that differs from other antidepressants: Erratum. PMID- 27487259 TI - Effects of switching to aripiprazole from current atypical antipsychotics on subsyndromal symptoms and tolerability in patients with bipolar disorder. AB - We evaluated the effectiveness of aripiprazole among bipolar patients who had switched to this medication as a result of difficulty maintaining on their prestudy atypical antipsychotics (AAPs) because of subsyndromal mood symptoms or intolerance. This study included 77 bipolar patients who were in syndromal remission with an AAP as monotherapy or with an AAP combined with a mood stabilizer(s) who needed to switch from their present AAP because of subsyndromal symptoms or intolerance. At 24 weeks after switching to aripiprazole, the remission rates on the Montgomery-Asberg Depression Rating Scale (MADRS) and on both the MADRS and the Young Mania Rating Scale were increased significantly in the full sample and in the inefficacy subgroup. In the inefficacy subgroup, the MADRS score change was significant during the 24 weeks of study. Total cholesterol and prolactin decreased significantly after switching to aripiprazole. The proportion of patients who had abnormal values for central obesity and hypercholesterolemia decreased significantly from baseline to week 24. These findings suggest that a change from the current AAP to aripiprazole was associated with improvement in subsyndromal mood symptoms and several lipid/metabolic or safety profile parameters in patients with bipolar disorder with tolerability concerns or subsyndromal mood symptoms. PMID- 27487261 TI - Development, optimization and in vitro evaluation of norcantharidin loadedself nanoemulsifying drug delivery systems (NCTD-SNEDDS). AB - This study focused on developing a self-nanoemulsifying drug delivery system (SNEDDS) containing bioactive surfactants under an efficient screening approach for overcoming problems associated with the delivery of norcantharidin (NCTD), a high dose chemotherapy agent having pH dependent solubility. Preliminary screening was implemented to select proper components combination. Besides the solubility of NCTD in the oil phase, emulsifying efficiency, droplet size and size distribution were also employed to select components of the SNEDDS. Moreover, the influence of surfactant and co-surfactant on the interfacial tension and droplets of nanoemulsions were investigated to further understand the mechanism of spontaneous emulsification. Co-surfactant addition promoted the emulsification via reducing the water/oil interfacial tension and viscosity. Ternary phase diagrams were constructed to investigate the phase behavior and designate the optimum systems. The alternative formulations were characterized for cloud point, dilution robustness, droplet size, polydispersity index (PDI) and transmission electron microscopy (TEM). In vitro dissolution study showed that the dissolution rate of optimized formulation (NCTD 10 mg/g, EO 50 wt.%, Cremophor EL 35 wt.%, ethylene glycol 15 wt.%) was slower than drug suspension under the same conditions, confirming that the developed SNEDDS formulation would exhibit sustained release potential. PMID- 27487262 TI - The Relationship between Obesity, Prostate Tumor Infiltrating Lymphocytes and Macrophages, and Biochemical Failure. AB - BACKGROUND: Obesity reflects a chronic inflammatory environment that may contribute to prostate cancer progression and poor treatment outcomes. However, it is not clear which mechanisms drive this association within the tumor microenvironment. The aim of this pilot study was to examine prostatic inflammation via tumor infiltrating lymphocytes and macrophages characterized by obesity and cancer severity. METHODS: We studied paraffin-embedded prostatectomy tissue from 99 participants (63 non-obese and 36 obese) from the Study of Clinical Outcomes, Risk and Ethnicity (University of Pennsylvania). Pathologists analyzed the tissue for type and count of lymphocytes and macrophages, including CD3, CD8, FOXP3, and CD68. Pathology data were linked to clinical and demographic variables. Statistical analyses included frequency tables, Kruskal-Wallis tests, Spearman correlations, and multivariable models. RESULTS: We observed positive univariate associations between the number of CD68 cells and tumor grade (p = 0.019). In multivariable analysis, CD8 counts were associated with time to biochemical failure (HR = 1.09, 95% CI = 1.004-1.192, p-value = 0.041.) There were no differences in lymphocytes or macrophages by obesity status or BMI. CONCLUSIONS: The number of lymphocytes and macrophages in the tumor microenvironment did not differ by obesity status. However, these inflammation markers were associated with poor prostate cancer outcomes. Further examination of underlying mechanisms that influence obesity-related effects on prostate cancer outcomes is warranted. Such research will guide immunotherapy protocols and weight management as they apply to diverse patient populations and phenotypes. PMID- 27487263 TI - Association Between Depression and Hospital Admission in Older Men with Prostate Cancer. PMID- 27487264 TI - Preparation of benznidazole pellets for immediate drug delivery using the extrusion spheronization technique. AB - Recent advances in the treatment of Chagas disease have followed combinations of drugs that act synergistically against infection, predominantly including benznidazole (BNZ) and azoles derivatives. Possible incompatibilities between these drugs, slow dissolution of BNZ and dose adjustment difficulties are technological obstacles to the development of multidrug formulations. Thus, in the present study, BNZ pellets were developed using extrusion spheronization for immediate drug delivery. Preformulation studies were then performed using thermal analysis and infrared spectroscopy and compatibility between the drug and selected excipients (polyethylene glycol 6000, sodium starch glycolate, microcrystalline cellulose and sodium croscarmellose) was investigated. No chemical decomposition of BNZ was observed, even in samples submitted to wet granulation and thermal stress. Subsequently, formulations were elaborated according to a simplex lattice experimental design using polyethylene glycol, sodium starch glycolate and sodium croscarmellose as disintegrating agents. In these experiments, BNZ pellets showed appropriate physicochemical characteristics, including high drug load capacity and excellent flow properties. The mixture experimental design allowed identification of adequate compositions of disintegrating agents and achieved rapid disintegration and dissolution of pellets. Optimum performance was achieved using polyethylene glycol and sodium croscarmellose at 5.0% w/w each. The present BNZ pellets are versatile alternatives to treat Chagas disease and provide insights into the preparation of multidrug systems. PMID- 27487265 TI - Liquid Marbles Based on Magnetic Upconversion Nanoparticles as Magnetically and Optically Responsive Miniature Reactors for Photocatalysis and Photodynamic Therapy. AB - Magnetic liquid marbles have recently attracted extensive attention for various potential applications. However, conventional liquid marbles based on iron oxide nanoparticles are opaque and inadequate for photo-related applications. Herein, we report the first development of liquid marbles coated with magnetic lanthanide doped upconversion nanoparticles (UCNPs) that can convert near-infrared light into visible light. Apart from their excellent magnetic and mechanical properties, which are attractive for repeatable tip opening and magnetically directed movements, the resultant UCNP-based liquid marbles can act as ideal miniature reactors for photodynamic therapy of cancer cells. This work opens new ways for the development of liquid marbles, and shows great promise for liquid marbles based on UCNPs to be used in a large variety of potential applications, such as photodynamic therapy for accelerated drug screening, magnetically guided controlled drug delivery and release, and multifunctional actuation. PMID- 27487266 TI - Network ethnopharmacological evaluation of the immunomodulatory activity of Withania somnifera. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera (L.) Dunal (Ashwagandha, WS) is one of the extensively explored Ayurvedic botanicals. Several properties including immunomodulation, anti-cancer and neuro-protection of the botanical have been reported. Even though, in indigenous medicine, WS is well known for its immunomodulatory activity, the molecular mechanism of immunomodulation has not been elucidated. AIM OF THE STUDY: This study aimed the evaluation of the immunomodulatory effect of WS using network ethnopharmacology technique to elucidate the in silico molecular mechanism. MATERIALS AND METHODS: Databases- DPED, UNPD, PubChem, Binding DB, ChEMBL, KEGG and STRING were used to gather information to develop the networks. The networks were constructed using Cytoscape 3.2.1. Data analysis was performed with the help of Excel pivot table and Cytoscape network analyzer tool. RESULTS: Investigation for WS immune modulation mechanism identified five bioactives that are capable of regulating 15 immune system pathways through 16 target proteins by bioactive-target and protein protein interactions. The study also unveils the potential of withanolide phytosterol combination to achieve effective immunomodulation and seven novel bioactive-immune target combinations. CONCLUSION: The study elucidated an in silico molecular mechanism of immunomodulation of WS. It unveils the potential of withanolide-phytosterol combination to achieve a better immunomodulation. Experimental validation of the network findings would aid in understanding the rationale behind WS immunomodulation as well as aid in bioactive formulation based drug discovery. PMID- 27487267 TI - Effects of platelet-rich plasma on cartilage regeneration after costal cartilage resection: a stereological and histopathological study. AB - BACKGROUND: In cases of congenital chest wall deformities, it is important to maintain the flexibility of the chest wall after rib cartilage resection. In this study, we aimed to determine the regeneration capability of cartilage and the effects of platelet-rich plasma (PRP) on the regeneration process. METHODS: A total of 16 four-week-old New Zealand rabbits were used in this study. In the 4th 5th right costal cartilages, the perichondrial sheaths were dissected and costal cartilages were excised. Then, the perichondrial sheaths were closed with absorbable material in the sham group (n = 8), and this was done after replacing PRP in the PRP group (n = 8). The left costal cartilages of the animals were used as controls. The volumes of the costal cartilages and their perichondrial sheaths were estimated using Cavalieri's principle. In addition, the mean numerical densities of the chondroblasts and chondrocytes per square millimetre were estimated using unbiased counting frames. RESULTS: In the PRP and sham groups, the volumes of the cartilages and perichondrial sheaths were higher than those of the control group (p < 0.05). The numerical densities of the chondroblasts and chondrocytes increased more in the PRP group than in the sham group (p < 0.05). CONCLUSIONS: Applying PRP after resection may provide better healing and faster regeneration of cartilage. PMID- 27487268 TI - Developing and sustaining human resources in the health supply chain in Ethiopia: barriers and enablers. AB - INTRODUCTION: The health supply chain is often the weakest link in achieving the health-related Millennium Development Goals and universal health coverage, requiring trained professionals who are often unavailable. In Ethiopia there have been recent developments in the area of health supply chain management. The aim of this study was to explore the current status of the development of human resources in health supply chain management in Ethiopia and to identify important factors affecting this development. METHODS: A series of face-to-face interviews with key stakeholders was carried out in 2014. The interviews were conducted using a semi-structured interview guide. The interview guide comprised 51 questions. A qualitative analysis of transcripts was made. RESULTS: A total of 25 interviews were conducted. Three themes were identified: General changes: recognition, commitment and resources, Education and training, and Barriers and enablers. Results confirm the development of human resources in health supply chain management in many areas. However, several problems were identified including lack of coordination, partly due to the large number of stakeholders; reported high staff mobility; and a lack of overall strategy regarding the job/career structures necessary for maintaining human resources. Rural areas have a particular set of problems, including in transportation of goods and personnel, attracting and keeping personnel, and in communication and access to information. CONCLUSIONS: Ethiopia is on the way to developing a nationwide viable system for health supply chain management. However, there are still challenges. Short-term challenges include the importance of highlighting strategies and programs for human resources in health supply chain management. In the long term, commitments to financial support must be obtained. A strategy is needed for the further development and sustainability of human resources in the health supply chain in Ethiopia. PMID- 27487269 TI - Exploring the Motivations for Punishment: Framing and Country-Level Effects. AB - Identifying the motives underpinning punishment is crucial for understanding its evolved function. In principle, punishment of distributional inequality could be motivated by the desire to reciprocate losses ('revenge') or by the desire to reduce payoff asymmetries between the punisher and the target ('inequality aversion'). By separating these two possible motivations, recent work suggests that punishment is more likely to be motivated by disadvantageous inequality aversion than by a desire for revenge. Nevertheless, these findings have not consistently replicated across different studies. Here, we suggest that considering country of origin-previously overlooked as a possible source of variation in responses-is important for understanding when and why individuals punish one another. We conducted a two-player stealing game with punishment, using data from 2,400 subjects recruited from the USA and India. US-based subjects punished in response to losses and disadvantageous inequality, but seldom invested in antisocial punishment (defined here as punishment of non stealing partners). India-based subjects, on the other hand, punished at higher levels than US-based subjects and, so long as they did not experience disadvantageous inequality, punished stealing and non-stealing partners indiscriminately. Nevertheless, as in the USA, when stealing resulted in disadvantageous inequality, India-based subjects punished stealing partners more than non-stealing partners. These results are consistent with the hypothesis that variation in punitive behavior varies across societies, and support the idea that punishment might sometimes function to improve relative status, rather than to enforce cooperation. PMID- 27487270 TI - Thermoelectric properties of monolayer MSe2 (M = Zr, Hf): low lattice thermal conductivity and a promising figure of merit. AB - Monolayer transition-metal dichalcogenides (TMDCs) MX2 (M = Mo, W, Zr, Hf, etc; X = S, Se, Te) have become well-known in recent times for their promising applications in thermoelectrics and field effect transistors. In this work, we perform a systematic study on the thermoelectric properties of monolayer ZrSe2 and HfSe2 using first-principles calculations combined with Boltzmann transport equations. Our results point to a competitive thermoelectric figure of merit (close to 1 at optimal doping) in both monolayer ZrSe2 and HfSe2, which is markedly higher than previous explored monolayer TMDCs such as MoS2 and MoSe2. We also reveal that the higher figure of merits arise mainly from their low lattice thermal conductivity, and this is partly due to the strong coupling of acoustic modes with low frequency optical modes. It is found that the figure of merits can be better optimized in n-type than in p-type. In particular, the performance of HfSe2 is superior to ZrSe2 at a higher temperature. Our results suggest that monolayer ZrSe2 and HfSe2 with lower lattice thermal conductivity than usual monolayer TMDCs are promising candidates for thermoelectric applications. PMID- 27487271 TI - Differential Effects of E2 on MAPK Activity in the Brain and Heart of Aged Female Rats. AB - Aging and the coincident loss of circulating estrogens at menopause lead to increased risks for neurological and cardiovascular pathologies. Clinical studies show that estrogen therapy (ET) can be beneficial in mitigating these negative effects, in both the brain and heart, when it is initiated shortly after the perimenopausal transition. However, this same therapy is detrimental when initiated >10 years postmenopause. Importantly, the molecular mechanisms underlying this age-related switch in ET efficacy are unknown. Estrogen receptors (ERs) mediate the neuroprotective and cardioprotective functions of estrogens by modulating gene transcription or, non-genomically, by activating second messenger signaling pathways, such as mitogen activated protein kinases (MAPK). These kinases are critical regulators of cell signaling pathways and have widespread downstream effects. Our hypothesis is that age and estrogen deprivation following menopause alters the expression and activation of the MAPK family members p38 and ERK in the brain and heart. To test this hypothesis, we used a surgically induced model of menopause in 18 month old rats through bilateral ovariectomy (OVX) followed by an acute dose of 17beta-estradiol (E2) administered at varying time points post-OVX (1 week, 4 weeks, 8 weeks, or 12 weeks). Age and E2 treatment differentially regulated kinase activity in both the brain and heart, and the effects were also brain region specific. MAPK signaling plays an integral role in aging, and the aberrant regulation of those signaling pathways might be involved in age-related disorders. Clinical studies show benefits of ET during early menopause but detrimental effects later, which might be reflective of changes in kinase expression and activation status. PMID- 27487275 TI - DNA Methyltransferase 1: A Potential Gene Therapy Target for Hepatocellular Carcinoma? AB - BACKGROUND: DNA methyltransferase 1 (DNMT1) mutants display altered methylation patterns that may contribute to oncogenesis. We hypothesized that the silencing or inhibition of DNMT1 may affect the malignancy of hepatocellular carcinoma (HCC) cells. METHODS: The HCC cell line KYN2 was used to construct 3 experimental groups: i) a DNMT1-siRNA group transfected with a green fluorescent protein (GFP) lentiviral vector to silence endogenous DNMT1 gene expression, which was confirmed by real-time quantitative polymerase chain reaction, ii) a 5-Aza-CdR group transfected with a null GFP lentiviral vector and treated with the DNMT1 inhibitor 5-aza-2'-deoxycytidine (5-Aza-CdR), and iii) a control group transfected with a null GFP lentiviral vector. Cellomics ArrayScan VTI imaging and MTT assays were conducted to assess cell proliferation. Cell cycle phase arrest and apoptosis were assayed by flow cytometry. Colony formation was assessed by fluorescence microscopy. RESULTS: DNMT1 mRNA expression was significantly inhibited in DNMT1-silenced cells relative to control cells (p < 0.05), indicating successful transfection and gene expression knockdown. Cell proliferation was significantly inhibited in DNMT1-siRNA and 5-Aza-CdR cells relative to control cells (p < 0.05). G1-to-S phase shifts were significantly increased in DNMT1-siRNA and 5-Aza-CdR cells relative to control cells (p < 0.05). Apoptosis was significantly increased in DMNT1-siRNA and 5-Aza-CdR cells relative to control cells (p < 0.05). DMNT1-siRNA and 5-Aza-CdR cells displayed significantly reduced colony formation relative to control cells (p < 0.05). Notably, 5-Aza-CdR had more pronounced effects upon all these parameters than DNMT1 silencing. CONCLUSION: DNMT1 activity appears to positively contribute to the malignancy of HCC cells. PMID- 27487272 TI - Body Mass Index as a Measure of Obesity: Racial Differences in Predictive Value for Health Parameters During Pregnancy. AB - BACKGROUND: As a measure of obesity, body mass index (BMI; kg/m2) is an imperfect predictor of health outcomes, particularly among African Americans. However, BMI is used to guide prenatal care. We examined racial differences in the predictive value of maternal BMI for physiologic correlates of obesity, serum interleukin (IL)-6 and C-reactive protein (CRP), as well as cesarean section and infant birth weight. METHODS: One hundred five pregnant women (40 European American, 65 African American) were assessed during the second trimester. BMI was defined as per prepregnancy weight. Electrochemiluminescence and enzyme-linked immunosorbent assays were used to quantify IL-6 and CRP, respectively. Birth outcomes were determined by medical record review. RESULTS: Women of both races classified as obese had higher serum IL-6 and CRP than their normal-weight counterparts (ps <= 0.01). However, among women with overweight, elevations in IL-6 (p < 0.01) and CRP (p = 0.06) were observed among European Americans, but not African Americans (ps >= 0.61). Maternal obesity was a significantly better predictor of cesarean section among European Americans versus African Americans (p = 0.03) and BMI was associated with infant birth weight among European Americans (p < 0.01), but not African Americans (p = 0.94). Effects remained after controlling for gestational age at delivery, gestational diabetes, and gestational weight gain as appropriate. CONCLUSIONS: BMI may be a less valid predictor of correlates of overweight/obesity among African Americans versus European Americans during pregnancy. This should be considered in epidemiological studies of maternal-child health. In addition, studies examining the comparative validity of alternative/complementary measures to define obesity in pregnancy are warranted to inform clinical care. PMID- 27487276 TI - Quantitative analysis of lymph nodes in neck dissection specimens. Morphologic study. AB - PURPOSE: To quantify the amount of lymph nodes harvested in modified radical neck dissection. METHODS: Cross-sectional anatomical study conducted in 28 non preserved cadavers. RESULTS: The mean number of lymph nodes found in each nodal level of the 56 modified radical neck dissections performed were: level IA - 1.5 (95% CI: 1.1 - 1.8), level IB - 2.5 (95% CI: 2.1 - 2.9), level IIA - 7.2 (95% CI: 6.0 - 8.5), IIB level - 6.5 (95% CI: 5.5 - 7.4), level III - 6.6 (95% CI: 5.7 - 7.4), level IV - 8.6 (95% CI: 7.1 - 10.1), level V - 11 (95% CI: 9.2 - 12.7), totalizing 43.8 lymph nodes (95% CI: 40.3 - 47.4). CONCLUSION: The results defined a parameter in relation to the minimum recommended nodal yield in a modified radical neck dissection, as well as the number of lymph nodes in each level of this dissection, performed in clinical practice. PMID- 27487277 TI - Serum concentrations and renal expressions of IL-1 and TNF-a early after hemorrhage in rats under the effect of glibenclamide. AB - PURPOSE: To investigate changes in the serum concentration and renal expression of IL-1 and TNF-alpha cytokines in rats that received sevoflurane and glibenclamide prior to hemorrhage. METHODS: Two groups of sevoflurane anesthetized Wistar rats (n=10): G1 (control) and G2 (glibenclamide, 1 ug/g i.v.); hemorrhage of 30% blood volume (10% every 10 min), with replacement using Ringer solution, 5 ml/kg/h. Serum concentrations of IL-1 and TNF-alpha were studied in the first hemorrhage (T1) and 50 min later (T2), renal expression, at T2. RESULTS: In serum, G1 TNF-alpha (pg/mL) was T1=178.6+/-33.5, T2=509.2+/-118.8 (p<0.05); IL-1 (pg/mL) was T1=148.8+/-31.3, T2=322.6+/-115.4 (p<0.05); in G2, TNF alpha was T1=486.2+/-83.6, T2=261.8+/-79.5 (p<0.05); IL-1 was T1=347.0+/-72.0, T2= 327.3+/-90.9 (p>0.05). The expression of TNF-alpha and IL-1 in the glomerular and tubular cells was significantly higher in the G2 group. CONCLUSIONS: Hemorrhage and glibenclamide elevated TNF-alpha and IL-1 concentrations in serum and kidneys. High levels of TNF-alpha already present before the hemorrhage in the glibenclamide group may have attenuated the damages found in the kidneys after the ischemia event. PMID- 27487278 TI - Surgical approach to the thyroarytenoid branch of the inferior laryngeal nerve through the thyroid cartilage. AB - PURPOSE: To describe the anatomical course of the intralaryngeal portion of the inferior laryngeal nerve (ILN) and to standardize the surgical access to its thyroarytenoid branch (TAb) through the thyroid cartilage. METHODS: Under surgical microscopy, 33 adult human excised larynges were dissected, to expose the intralaryngeal portion of ILN. The point of entry of TAb, ILN's terminal branch, in the thyroarytenoid (TA) muscle was determined and correlated with thyroid cartilage dimensions. RESULTS: After entering the larynx, the ILN consistently traveled between the thyroid cartilage and the lateral cricoarytenoid muscle in an anterior and slightly cranial course. The distance from the point of entry of the TAb in the TA muscle to the midline (TAb-H) and to the inferior border (TAb-V) of the thyroid cartilage differed according to gender. In females, mean distances of TAb-H and TAb-V were 20.5mm and 5.2mm and in males, 22.3mm and 5.9mm, respectively. CONCLUSION: The intralaryngeal course of the inferior laryngeal nerve presents low variability and measures from landmarks in the thyroid cartilage help to estimate the point of entry of thyroarytenoid branch in thyroarytenoid muscle. PMID- 27487279 TI - Toll-like receptor 7 involves the injury in acute kidney ischemia/reperfusion of STZ-induced diabetic rats. AB - PURPOSE: To determine whether Toll-like receptor 7 (TLR7) is the potential targets of prevention or progression in the renal ischemia/reperfusion (I/R) injury of STZ-induced diabetic rats. METHODS: Thirty six Sprague-Dawley rats were randomly arranged to the nondiabetic (ND) or diabetic group (DM), with each group further divided into sham (no I/R injury), I/R (ischemia-reperfusion) and CD (given by Chloroquine) group. Preoperatively, Chloroquine (40 mg/kg, intraperitoneal injection.) was administrated 6 days for treatment group. I/R animals were subjected to 25 min of bilateral renal ischemia. Renal function, histology, apoptosis, cytokines, expression of TLR7, MyD88 and NF-kappaB were detected. RESULTS: The serum levels of blood urea nitrogen, creatinine, IL-6 and TNF-alpha, apoptotic tubular epithelial cells, expression of TLR7, MyD88 and NF kappaB were significantly increased in DM+I/R group, compared with ND+I/R group (p<0.05). All these changes were further improved by TLR7 inhibition Chloroquine except Paller scores (p<0.05). CONCLUSION: Toll-like receptor 7 inhibition attenuates the acute renal ischemia/reperfusion injury of STZ-induced diabetic in SD rats. PMID- 27487280 TI - The protective cardiac effects of Beta-myrcene after global cerebral ischemia/reperfusion in C57BL/J6 mouse. AB - PURPOSE: To investigate the protective effect of beta-myrcene (MYR) on oxidative and histological damage in mice heart tissue caused global cerebral ischemia/reperfusion (IR) in C57BL/J6 mice. METHODS: Animals(n=40) were randomly divided into four groups: (1)control, (2)IR, (3)MYR and (4)MYR+IR. The control group was received 0.1% carboxymethyl cellulose as a vehicle following a medial incision without carotid occlusion. In the IR group, the bilateral carotid arteries were clipped for 15min, and treated with the vehicle intraperitoneally(ip) for 10 days. MYR (200mg/kg) was received dissolved in 0.1%CMC for 10 days. In the MYR+IR group, the IR model was applied exactly as in the IR group, and then they were treated with MYR 10 days. RESULTS: The cerebral IR caused oxidative damage (increase TBARS, decrease antioxidant parameters). Treatment of MYR was increased in GSH,GPx,CAT,SOD activity while TBARS level was decreased. In addition, degenerative changes in I/R group heart tissue were ameliorated by MYR administration. CONCLUSION: The administration of beta-myrcene protects oxidative and histological damage in the heart tissue after global ischemia-reperfusion and may be useful safe alternative treatment for cardiac tissue after ischemic stroke. PMID- 27487281 TI - Low intensity ultrasound therapy induces angiogenesis and persistent inflammation in the chronic phase of the healing process of third degree burn wounds experimentally induced in diabetic and non-diabetic rats. AB - PURPOSE: To evaluate the effects of low intensity ultrasound on the healing process of third degree burn wounds in experimentally induced diabetic Wistar rats. METHODS: One hundred rats were divided into: control group; non-diabetic treated group; diabetic control group; diabetic treated group. The therapy was performed with a 3MHz ultrasound application, pulsed emission at 100Hz frequency, modulated at 20% with a dosage of 0.5W/cm2 during three minutes throughout 30 days. The surgical debridement of the wound was performed once at day 2. The wounds were morphometrically, macroscopically and microscopically evaluated at 3, 7, 14, 21 and 30 days. RESULTS: The wound contraction and collagen quantification were higher in all treated groups. Macroscopically, necrosis was higher in the diabetic control group. Granulation tissue was higher in treated groups during the proliferative and remodeling phase. Microscopically, there were greater mononuclear inflammatory infiltration, angiogenesis and fibroblast quantification in treated groups during the proliferative and remodeling phases. CONCLUSIONS: therapeutic ultrasound is beneficial in the inflammatory and proliferative phases of the healing process because it controlled the necrotic tissue, increased the granulation tissue and wound contraction. However in the remodeling phase it is not beneficial because of the continued angiogenesis and a mononuclear inflammatory infiltration. PMID- 27487282 TI - The acute effects of preoperative ozone theraphy on surgical wound healing. AB - PURPOSE: To investigate the effects of preoperative rectal ozone insufflation on surgical wound healing over the proinflammatory cytokines and histopathological changes. METHODS: Twenty one rabbits were divided into 3 groups. Sham, surgical wound, and ozone applied (6 sessions, every other day 70 ug/mL in 12 mL O2-O3 mixture rectally) surgical wound groups were created. TNF-alpha and IL-6 levels from all rabbits were studied at the basal, 24th hour, and 72nd hour. The histopathological examination was done by removing the surgical scar tissue at the end of 72nd hour. RESULTS: TNF-alfa and IL-6 levels were significantly lower compared to the control group, in the rabbits treated with ozone. The increase in angiogenesis, the decrease in the number of inflammatory cells, epidermal and dermal regeneration, better collagen deposition, and increased keratinisation in stratum corneum were observed in the histopathological examination. It was determined that the wound healing noticeably accelerated in the ozone group. CONCLUSION: Preoperative rectal ozone insufflation had a positive effect on surgical wound healing in acute period. PMID- 27487283 TI - Measurement of testicular volume in Wistar rats using a caliper and ultrasonography in experimental surgery. AB - PURPOSE: To compare the measurement of the testicular volume of Wistar rats using a caliper and ultrasonography. METHODS: Forty Wistar rats were randomly assigned into four groups. A tensile force of 1.6 Newton (N) and 1.0 N was applied to the right spermatic cord in group I and group II, respectively. Group III was the sham group, and group IV served as a control. The initial and final testicular volumes were measured using a caliper and ultrasonography and compared. A significance level of 5% was used. RESULTS: The Kappa coefficient was equal to 0.292 (p = 0.006). The Pearson correlation coefficient obtained for the percent reduction in the right testicular volume using ultrasonography and a caliper was equal to 0.696 (p < 0.001). CONCLUSION: There was reasonable agreement and a significant positive correlation between the percent reduction in the right testicular volume using ultrasonography and a caliper. PMID- 27487284 TI - Association between levobupivacaine and pancuronium. Interference in neuromuscular transmission and blockade in rats. AB - PURPOSE: To evaluate the effects of levobupivacaine on neuromuscular transmission and neuromuscular blockade produced by pancuronium in vitro. METHODS: Thirty rats were distributed into groups (n = 5) according to the drug used alone or in combination: Group I - levobupivacaine (5 ug.mL-1); Group II - pancuronium (2 ug.mL-1); Group III - pancuronium (2 ug.mL-1) + levobupivacaine (5ug.mL-1). The following parameters were evaluated: 1) amplitude of diaphragmatic response to indirect stimulation, before and 60 minutes after the addition of levobupivacaine and pancuronium alone, and after the addition of levobupivacaine combined with pancuronium; 2) membrane potentials (MP) and miniature endplate potentials (MEPP). RESULTS: Levobupivacaine alone did not alter the amplitude of muscle response and MP. In preparations previoulsy exposed to levobupivacaine, the block with pancuronium was significantly denser (90.2 +/- 15.2%), showing a significant difference (p=0.031) in comparison to the block produced by pancuronium alone (48.9% +/- 9.8%). There was a decrease in the frequency and amplitude of MEPPs. CONCLUSION: Levobupivacaine potentiated the neuromuscular blockade produced by pancuronium, confirming a presynaptic action by a decrease in miniature endplate potentials. PMID- 27487285 TI - Contamination index. A novel parameter for metal and pesticide analyses in maternal blood and umbilical cord. AB - PURPOSE: To evaluate the contamination index of metals and pesticides in pregnant women, and to relate this to perinatal outcomes. METHODS: Descriptive, retrospective, exploratory study, developed from existing secondary data analyses at Level III maternity center. A total of 40 mothers with their newborns (NB), living in a rural area in Botucatu- Brazil and surrounding region. Blood samples from mothers and newborn were collected to determine the total contamination index for metals and pesticides. The concentrations of each metal and each pesticide were determined in blood samples of mothers and their newborns by Rudge's results. After obtaining these concentrations, the total contamination index in mother and NB was calculated, along with its correlation with clinical parameters of NB. RESULTS: There was no correlation (p> 0.05) between maternal contamination index with NB clinical parameters, and NB contamination index versus NB clinical parameters. CONCLUSION: The maternal contamination index of metals and pesticides was not related to perinatal outcomes, but it could be used as baseline parameter in future toxicological studies, regarding to long-term toxic characteristics as persistent organic pollutants, its long half-lives, bioacumulative, and expected to impose serious health effects on humans. PMID- 27487286 TI - Morphological and Genetic Diversity of Opisthosporidia: New Aphelid Paraphelidium tribonemae gen. et sp. nov. AB - Aphelids are a poorly known group of parasitoids of algae that have raised considerable interest due to their pivotal phylogenetic position. Together with Cryptomycota and the highly derived Microsporidia, they have been recently re classified as the Opisthosporidia, which constitute the sister group to the fungi within the Holomycota. Despite their huge diversity, as revealed by molecular environmental studies, and their phylogenetic interest, only three genera have been described (Aphelidium, Amoeboaphelidium, and Pseudaphelidium), from which 18S rRNA gene sequences exist only for Amoeboaphelidium and Aphelidium species. Here, we describe the life cycle and ultrastructure of a new representative of Aphelida, Paraphelidium tribonemae gen. et sp. nov., and provide the first 18S rRNA gene sequence obtained for this genus. Molecular phylogenetic analysis indicates that Paraphelidium is distantly related to both Aphelidium and Amoebaphelidium, highlighting the wide genetic diversity of aphelids. Paraphelidium tribonemae has amoeboflagellate zoospores containing a lipid microbody complex, dictyosomes, and mitochondria with rhomboid cristae, which are also present in trophonts and plasmodia. The amoeboid trophont uses pseudopodia to feed from the host cytoplasm. Although genetically distinct, the genus Paraphelidium is morphologically indistinguishable from other aphelid genera and has zoospores able to produce lamellipodia with subfilopodia like those of Amoeboaphelidium. PMID- 27487287 TI - Missing Protein Landscape of Human Chromosomes 2 and 14: Progress and Current Status. AB - Within the C-HPP, the Swiss and French teams are responsible for the annotation of proteins from chromosomes 2 and 14, respectively. neXtProt currently reports 1231 entries on chromosome 2 and 624 entries on chromosome 14; of these, 134 and 93 entries are still not experimentally validated and are thus considered as "missing proteins" (PE2-4), respectively. Among these entries, some may never be validated by conventional MS/MS approaches because of incompatible biochemical features. Others have already been validated but are still awaiting annotation. On the basis of information retrieved from the literature and from three of the main C-HPP resources (Human Protein Atlas, PeptideAtlas, and neXtProt), a subset of 40 theoretically detectable missing proteins (25 on chromosome 2 and 15 on chromosome 14) was defined for upcoming targeted studies in sperm samples. This list is proposed as a roadmap for the French and Swiss teams in the near future. PMID- 27487288 TI - Injustice Experience Questionnaire, Japanese Version: Cross-Cultural Factor Structure Comparison and Demographics Associated with Perceived Injustice. AB - OBJECTIVE: The Injustice Experience Questionnaire (IEQ) assesses injury-related perceived injustice. This study aimed to (1) develop a Japanese version (IEQ-J), (2) examine its factor structure, validity, and reliability, and (3) discover which demographic variable(s) positively contributed to prediction of IEQ-J scores. METHODS: Data from 71 patients (33 male, 38 female; age = 20+) with injury pain were employed to investigate factor structure by exploratory and confirmatory factor analyses. Concurrent validity was examined by Pearson correlation coefficients among the IEQ-J, Brief Pain Inventory (BPI), and Pain Catastrophizing Scale (PCS). Internal consistency was investigated by Cronbach's alpha, and test-retest reliability was indicated with intra-class correlations (ICCs) in 42 of 71 patients within four weeks. Relations between demographic variables and IEQ-J scores were examined by covariance analysis and linear regression models. RESULTS: IEQ-J factor structure differed from the original two factor model. A three-factor model with Severity/irreparability, Blame/unfairness, and Perceived lack of empathy was extracted. The three-factor model showed goodness-of-fit with the data and sufficient reliability (Cronbach's alpha of 0.90 for total IEQ-J; ICCs = 0.96). Pearson correlation coefficients among IEQ-J, BPI, and PCS ranged from 0.38 to 0.73. Pain duration over a year (regression coefficient, 11.92, 95%CI; 5.95-17.89) and liability for injury on another (regression coefficient, 12.17, 95%CI; 6.38-17.96) predicted IEQ-J total scores. CONCLUSIONS: This study evidenced the IEQ-J's sound psychometric properties. The three-factor model was the latter distinctive in the Japanese version. Pain duration over a year and injury liability by another statistically significantly increased IEQ-J scores. PMID- 27487289 TI - Third metal stent for revision of malignant hilar biliary strictures. AB - Background and study aim: Endoscopic stent-in-stent (SIS) placement of multiple metal stents is technically demanding. In the present study, we explored the technical feasibility and efficacy of endoscopic deployment of a third metal stent to create a triple SIS placement in patients with a bilateral SIS configuration for inoperable high grade malignant hilar biliary stricture (HBS) that had failed clinically. Methods: Eighteen patients with histologically proven inoperable HBS underwent deployment of an additional third metal stent as a revisionary method after early clinical failure following technically successful bilateral SIS placement using cross-wired metal stents. The main outcome measures were the technical and clinical success rates, and adverse events. Results: The overall technical and clinical success rates were 88.9 % (16/18) and 87.5 % (14/16), respectively. The early and late complications were cholangitis (n = 2) and cholecystitis (n = 1). Stent occlusion developed in 35.7 % (5/14) of patients in whom a third metal stent for revision of a bilateral SIS configuration was clinically successful. The median (range) times for stent patency and patient survival were 176 days (49 - 372) and 216 days (52 - 384), respectively. Conclusions: Endoscopic deployment of an additional third metal stent into a bilateral SIS configuration was technically feasible and effective in patients with inoperable high grade malignant HBS in whom bilateral SIS placement had failed clinically. PMID- 27487290 TI - Synthesis of Surface-Modified Iron Oxides for the Solvent-Free Recovery of Bacterial Bioactive Compound Prodigiosin and Its Algicidal Activity. AB - Prodigiosin (PG) is a bioactive compound produced by several bacterial species. Currently, many technologies are being developed for the production of PG by fermentation processes. However, new challenges are being faced with regard to the production of PG in terms of the recovery and purification steps, owing to the labile nature of PG molecules and the cost of the purification steps. Conventional methods have limitations due to high cost, low reusability, and health hazards. Hence, the present investigation was focused on the development of surface-functionalized magnetic iron oxide ([Fe3O4]F) for solvent-free extraction of bioactive PG from the bacterial fermented medium. Fe3O4 was functionalized with diethanolamine and characterized by FT-IR, diffuse reflectance spectroscopy, thermogravimetric analysis, scanning electron microscopy, and confocal microscopy. The various process parameters, such as contact time, temperature, pH, and mass of Fe3O4, were optimized for the extraction of PG using functionalized Fe3O4. Instrumental analyses confirmed that the PG molecules were cross-linked with functional groups on [Fe3O4]F through van der Waals forces of attraction. PG extracted through Fe3O4 or [Fe3O4]F was separated from the fermentation medium by applying an external electromagnetic field and regenerated for successive reuse cycles. The purity of the extracted PG was characterized by high-performance liquid chromatography, FT-IR, and UV visible spectroscopy. The iron oxide-diethanolamine-PG cross-linked ([Fe3O4]F-PG) composite matrix effectively deactivates harmful fouling by cyanobacterial growth in water-treatment plants. The present investigation provides the possibility of solvent-free extraction of bacterial bioactive PG from a fermented medium using functionalized magnetic iron oxide. PMID- 27487291 TI - Synthesis of 2-Vinylindole-3-Acetic Acid Derivatives via Cyanide-Catalyzed Imino Stetter Reaction. AB - A new method for the synthesis of 2-vinylindole-3-acetic acid derivatives from aldimines, which are derived from 2-aminocinnamic acid derivatives and alpha,beta unsaturated aldehydes, via a cyanide-catalyzed imino-Stetter reaction is described. Various types of 2-aminocinnamic acid derivatives and alpha,beta unsaturated aldehydes could be used in this protocol, and the desired 2-vinyl substituted indole-3-acetic acid derivatives were obtained in high yields. This cyanide-catalyzed imino-Stetter reaction was further extended to the preparation of indole-3-acetic acid derivatives bearing a carboxylic acid functionality at the 2-position, using aldimines obtained from glyoxylates and 2-aminocinnamic acid derivatives. PMID- 27487292 TI - Diphenyl Diselenide Reduces Oxidative Stress and Toxicity Caused by HSV-2 Infection in Mice. AB - Herpes simplex viruses can cause uncommon systemic complications as acute liver failure (ALT) or urinary tract dysfunctions. Diphenyl diselenide, (PhSe)2 , a classical studied organic selenium compound, has a novel antiviral action against HSV-2 infection and well-known antioxidant and anti-inflammatory properties. This study aimed to investigate if (PhSe)2 reduces oxidative stress and systemic toxicity caused by HSV-2 infection in mice. Adult BALB/c mice were pre-treated with (PhSe)2 (5 mg kg-1 /day, intragastric, i.g.) during 5 days; at day 6 mice were infected with HSV-2 (10 MUl-105 PFU/mL-1 ) and post-treated with (PhSe)2 for more 5 days. At day 11, they were killed and samples of liver and kidney were obtained to determine: reactive species (RS); malondialdehyde (MDA), and non protein thiols (NPSH) levels; the activities of antioxidant enzymes, superoxide dismutase (SOD), and catalase (CAT). The activities of adenosine deaminase (ADA), Na+ /K+ -ATPase (liver and kidney); alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the levels of urea (plasma) were determined as markers of hepatic and renal toxicity. The results revealed that (PhSe)2 treatment was effective against the increase of renal and hepatic oxidative stress in infected mice and also normalized hepatic and renal ADA activity. It recovered the activity of Na+ /K+ - and was not effective against the increase in urea levels in infected mice. Different from (PhSe)2 , acyclovir (positive control), caused an increase in ADA activity and a decrease in hepatic CAT activity. Considering the interest of alternative therapies to treat HSV-2 infections and secondary complications, (PhSe)2 become a notable candidate. J. Cell. Biochem. 118: 1028-1037, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27487293 TI - First-line sunitinib versus pazopanib in metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. AB - BACKGROUND: Sunitinib (SU) and pazopanib (PZ) are standards of care for first line treatment of metastatic renal cell carcinoma (mRCC). However, how the efficacy of these drugs translates into effectiveness on a population-based level is unknown. PATIENTS AND METHODS: We used the International mRCC Database Consortium (IMDC) to assess overall survival (OS), progression-free survival (PFS), response rate (RR) and performed proportional hazard regression adjusting for IMDC prognostic groups. Second-line OS (OS2) and second-line PFS (PFS2) were also evaluated. RESULTS: We obtained data from 7438 patients with mRCC treated with either first-line SU (n = 6519) or PZ (n = 919) with an overall median follow-up of 40.4 months (95% confidence interval [CI] 39.2-42.1). There were no significant differences in IMDC prognostic groups (p = 0.36). There was no OS difference between SU and PZ (22.3 versus 22.6 months, respectively, p = 0.65). When adjusted for IMDC criteria, the hazard ratio (HR) of death for PZ versus SU was 1.03 (95% CI 0.92-1.17, p = 0.58). There was no PFS difference between SU and PZ (8.4 versus 8.3 months, respectively, p = 0.17). When adjusted for IMDC criteria, the HR for PFS for PZ versus SU was 1.08 (95% CI 0.981-1.19, p = 0.12). There was no difference in RR between SU and PZ (30% versus 28%, respectively, p = 0.15). We also found no difference in any second-line treatment between either post-SU or post-PZ groups for OS2 (13.1 versus 11 months, p = 0.27) and PFS2 (3.7 versus 5.0 months, p = 0.07). CONCLUSIONS: We confirmed in real-world practice that SU and PZ have similar efficacy in the first-line setting for mRCC and do not affect outcomes with subsequent second-line treatment. PMID- 27487294 TI - Metformin and Angiogenesis in Cancer - Revisited. AB - Several clinical studies demonstrated that diabetic patients treated with metformin were less likely to develop vascular complications, independent of glycemic control. It was also demonstrated that the large variety of metformin's vascular actions can be seen in nondiabetic conditions. Metformin has an interesting potential to treat vascular dysfunction and tumor angiogenesis in conditions beyond diabetes. Since metformin's use in cancer as a single antiangiogenic agent appears to be a therapeutic disappointment, the use of the drug as part of combination anticancer modality represents a therapeutic challenge. The normalization of vascular dysfunction as a new therapeutic strategy may provide better delivery of conventional anticancer agents to the tumor and disrupted tumor environment. In this review, we will outline the available information from the literature regarding metformin and tumor angiogenesis and suggest eventual experimental and clinical approaches. PMID- 27487295 TI - Fructated apolipoprotein A-I exacerbates cellular senescence in human umbilical vein endothelial cells accompanied by impaired insulin secretion activity and embryo toxicity. AB - Glycation of apolipoproteins is a major feature of the production of dysfunctional high-density lipoprotein (HDL), which is associated with the incidence of several metabolic diseases such as coronary artery disease and diabetes. In this report, fructated apoA-I (fA-I) induced by fructose treatment showed a covalently multimerized band without cross-linking, and lysine residues were irreversibly modified to prevent crosslinking. Using pancreatic beta-cells, insulin secretion was impaired by fA-I in the lipid-free and reconstituted HDL (rHDL) states, by up to 35%, and 40%, respectively, under hyperglycemic conditions (25 mmol/L glucose). Treatment of human umbilical vein endothelial cells (HUVECs) with fA-I and HDL from elderly patients caused a 1.8-fold and 1.5 fold increased cellular senescence, respectively, along with increased lysosomal enlargement. In the lipid-free and rHDL states, fA-I increased embryo death by 1.5-fold and 2.5-fold, respectively, along with the production of oxidized species. Furthermore, rHDL containing fA-I (fA-I-rHDL) showed a higher isoelectric point (pI, approximately 8.5), whereas rHDL containing nA-I (nA-I rHDL) showed a narrow band range with lower pI (around 8.0) as well as a much smaller particle size than that of nA-I-rHDL. In conclusion, fructose-mediated apoA-I fructation resulted in the severe loss of several beneficial functions of apoA-I and HDL, including anti-senescence and insulin secretion activities, accompanied with increased susceptibility to protein degradation and structural modification. PMID- 27487296 TI - Implementation of the Affordable Care Act and Solid-Organ Transplantation Listings in the United States. PMID- 27487297 TI - The salt-regulated element in the promoter of lycopene beta-cyclase gene confers a salt regulatory pattern in carotenogenesis of Dunaliella bardawil. AB - In the carotenoid biosynthesis, lycopene beta-cyclase (LCYb) is a key regulatory enzyme involved in the conversion of lycopene into beta-carotene. Under stress conditions, such as high salinity, high light, and nutrient deprivation, large amounts of beta-carotene can be accumulated in Dunaliella bardawil. To study on the molecular responses of salt stress in D. bardawil is of great significance to reveal the mechanisms of salt tolerance and engineer crop plants to be salt tolerant. In this study, the full-length coding sequence of lcyb from D. bardawil (Dblcyb, GenBank: KX218392) was isolated by transcriptome sequencing. Then the genomic sequence, promoter and terminator regions of Dblcyb were isolated by genome walking. The Dblcyb promoter (GenBank: KX218393) contained several typical transcription boxes, multiple light response elements, and a salt-regulated element (SRE, GT1GMSCAM4). Dbpsy and Dblcyb responsible for beta-carotene biosynthesis in D. bardawil was shown to be up-regulated under salt stress, and their promoters contained the common SRE. By element deletion analysis and using Ble-EGFP as the reporter, the salt-inducible SRE was confirmed to confer salt induced expression of Dblcyb promoter. It was indicated that the salt-regulated expression of Dblcyb may be attributed to the salt-responsive element (GT1GMSCAM4) and the GT-rich region in its genomic sequence. This article is protected by copyright. All rights reserved. PMID- 27487298 TI - Could Borophene Be Used as a Promising Anode Material for High-Performance Lithium Ion Battery? AB - The rapid development of electronic products has inspired scientists to design and explore novel electrode materials with an ultrahigh rate of charging/discharging capability, such as two-dimensional (2-D) nanostructures of graphene and MoS2. In this study, another 2-D nanosheet, that is a borophene layer, has been predicted to be utilized as a promising anode material for high performance Li ion battery based on density functional theory calculations. Our study has revealed that Li atom can combine strongly with borophene surface strongly and easily, and exist as a pure Li(+) state. A rather small energy barrier (0.007 eV) of Li diffusion leads to an ultrahigh diffusivity along an uncorrugated direction of borophene, which is estimated to be 10(4) (10(5)) times faster than that on MoS2 (graphene) at room temperature. A high Li storage capacity of 1239 mA.h/g can be achieved when Li content reaches 0.5. A low average operating voltage of 0.466 V and metallic properties result in that the borophene can be used as a possible anode material. Moreover, the properties of Li adsorption and diffusion on the borophene affected by Ag (111) substrate have been studied. It has been found that the influence of Ag (111) substrate is very weak. Li atom can still bind on the borophene with a strong binding energy of 2.648 eV. A small energy barrier of 0.033 eV can be retained for Li diffusion along the uncorrugated direction, which can give rise to a high Li diffusivity. Besides, the performances of borophene-based Na ion battery have been explored. Our results suggest that an extremely high rate capability could be expected in borophene-based Li ion battery. PMID- 27487299 TI - C-Reactive Protein and Inflammatory Cytokines during Percutaneous Coronary Intervention. AB - BACKGROUND: C-reactive protein (CRP) is significantly associated with cardiovascular diseases; however, whether CRP plays a causal role in coronary artery disease has yet to be determined. In addition, the relationship between CRP, atherosclerosis, and inflammation remains controversial. METHODS AND RESULTS: Serum interleukin (IL)-6, IL-1beta, and CRP levels were determined in 160 patients at time points around percutaneous coronary intervention (PCI) with drug-eluting stent implantation. The levels were found to be at peak at 24 h post PCI and gradually declined to the level before PCI at day 30 post-PCI. These inflammation markers around PCI have no statistical difference in the different postdilation pressures (<=14, 14-18, and >=18 atm) and stent number (1 and >=2 stents) groups. Treatment of cultured human vascular smooth muscle cells (VSMCs) with a combination of IL-6 and IL-1beta at concentrations associated with PCI did not result in any significant change in the CRP mRNA levels. The IL-6-augmented CRP expression in human internal mammary arteries (IMAs) stretched with a mechanical strength of 3 g was blocked by the nuclear factor-kappaB (NF-kappaB) peptide inhibitor SN50 and not by the inactive SN50 analog SN50M. IL-6 treatment increased NF-kappaB activity in human IMAs stretched with 3 g, and this effect was further blocked by stretch-activated channel (SAC) inhibitors (streptomycin or GdCl3) and SN50. CONCLUSIONS: The current study provides evidence that increased serum IL-6, IL-1beta, and CRP levels around PCI are not different between different postdilation pressure and stent number groups. The combination of IL-6 and IL-1beta at concentrations associated with PCI cannot induce CRP expression in human VSMCs, but they can augment mechanical strain-induced CRP synthesis via the SAC-NF-kappaB pathway in human IMAs. PMID- 27487300 TI - Effectiveness of Mindfulness-Based Stress Reduction Bibliotherapy: A Preliminary Randomized Controlled Trial. AB - OBJECTIVE: This randomized controlled investigation examined the effectiveness of a self-help bibliotherapy format of the evidence-based mindfulness-based stress reduction (MBSR) intervention. METHOD: College students seeking stress reduction were randomly assigned to a 10-week MBSR bibliotherapy intervention group (n = 47) or a no-treatment control group (n = 45). Self-report measures were collected at baseline and postintervention. RESULTS: A total of 25 bibliotherapy and 43 control group participants provided final data following the intervention period. Compared to the control group, bibliotherapy participants reported increased mindfulness following the intervention. Significant decreases on measures of depression, anxiety, stress, perceived stress, and anxiety sensitivity also were reported postintervention as well as increased quality of life in physical health, psychological, and environmental domains. No statistically significant group effects were found for social relationships quality of life domain, worry, and experiential avoidance measures. CONCLUSION: This MBSR workbook may provide an acceptable and effective alternative for motivated individuals seeking to reduce stress, at least for a select group of individuals who are willing and able to sustain participation in the intervention. PMID- 27487301 TI - Corrigendum. PMID- 27487302 TI - Prior stressor exposure delays the recovery of surgery-induced cognitive impairment and prolongs neuroinflammation in aged rats. AB - Increasing evidence indicates that stress potentiates pro-inflammatory response to a subsequent peripheral immune challenge. The present study investigated if prior exposure to inescapable tailshock (IS) delayed the recovery of surgery induced spatial learning and memory impairment and prolonged hippocampus interleukin (IL)-1beta and IL-6 expression. METHODS: A total of 192 aged rats were trained with Morris water-maze (MWM) for 6 consecutive days. A single session of inescapable tailshock was performed on day 6 after training. Then, the rats subjected to partial hepatectomy. Hippocampal-dependent spatial learning and memory were assessed on postoperative days 1, 3 and 7. The cytokines IL-1beta and IL-6 and ionized calcium binding adaptor protein (Iba)-1 were measured at each time point. Cluster of differentiation 200 (CD200) was also measured to explore potential mechanisms of glial cell activation. RESULTS: Exposure of IS alone failed to affect the latency to platform and increase hippocampal cytokine levels at each time point. However, IS alone significantly increased the expression levels of Iba-1. A prolonged latency and additional significant increase in hippocampal levels of IL-1beta and IL-6 were observed when partial hepatectomy was performed in aged rats exposed to IS 24h later. The combination of IS and surgical trauma dramatically upregulated the levels of Iba-1 and significantly decreased the expression of CD200. CONCLUSION: IS alone failed to induce cognitive deficits and increase pro-inflammatory cytokines expression. However, IS delayed the recovery of surgery-induced spatial learning and memory impairment and prolonged pro-inflammatory response to the subsequent surgery challenge. PMID- 27487303 TI - How Structured Is the Entangled Bank? The Surprisingly Simple Organization of Multiplex Ecological Networks Leads to Increased Persistence and Resilience. AB - Species are linked to each other by a myriad of positive and negative interactions. This complex spectrum of interactions constitutes a network of links that mediates ecological communities' response to perturbations, such as exploitation and climate change. In the last decades, there have been great advances in the study of intricate ecological networks. We have, nonetheless, lacked both the data and the tools to more rigorously understand the patterning of multiple interaction types between species (i.e., "multiplex networks"), as well as their consequences for community dynamics. Using network statistical modeling applied to a comprehensive ecological network, which includes trophic and diverse non-trophic links, we provide a first glimpse at what the full "entangled bank" of species looks like. The community exhibits clear multidimensional structure, which is taxonomically coherent and broadly predictable from species traits. Moreover, dynamic simulations suggest that this non-random patterning of how diverse non-trophic interactions map onto the food web could allow for higher species persistence and higher total biomass than expected by chance and tends to promote a higher robustness to extinctions. PMID- 27487305 TI - Size-specific imprinted polymer embedded carbon nanodots modified magnetic nanoparticle for specific recognition of titanium nanoparticle: The round versus round. AB - Like the two sides of a coin, any new invention or discovery also possess their two faces. Similarly, while nanomaterials were identified as a boon in several fields like industrial, medicinal or agriculture; some of them have been also validated as a risk to the environment and living organisms. In this report, we addressed an efficient optical method for the detection of popularly used titanium dioxide nanoparticle (TiO2) by a size-specific imprinted polymer embedded heteroatom-doped carbon nanodots (CNDs) decorated at the surface of the water-soluble magnetic nanoparticle. The CNDs were prepared by an economic and eco-friendly one-step hydrothermal method using a series of Brassicaceae family members (i.e. radish, cabbage, broccoli, and cauliflower). The as prepared CNDs shows very good production (12.8%) and quantum yields (40.7%). The size-specific imprinted polymer is biocompatible and biodegradable in nature and was able to detect the TiO2 nanoparticles with a high selectivity i.e. limit of detection (LOD)=6.88ngL(-1) (S/N=3) and remove the nanoparticle very efficiently. Furthermore, the method was successfully applied for the detection of TiO2 nanoparticles in wastewater, human sera, and cosmetic samples. PMID- 27487304 TI - Implications of Intraoperative Vascular Surgery Assistance for Hospitals and Vascular Surgery Trainees. AB - Importance: Vascular surgeons possess a skill set that allows them to assist nonvascular surgeons in the operating room. Existing studies on this topic are limited in their scope to specific procedures or clinical settings. Objective: To describe the broad spectrum of cases that require intraoperative vascular surgery assistance. Design, Setting, and Participants: A retrospective medical record review of patients undergoing nonvascular surgery procedures that required intraoperative vascular surgery assistance between January 2010 and June 2014 at a single urban academic medical center (Northwestern Memorial Hospital, Chicago, Illinois). Trauma patients and inferior vena cava filter placements were excluded. Exposures: Intraoperative vascular surgery assistance stratified by need for vascular reconstruction, anatomic location, urgency of consultation, and timing of consultation. Main Outcomes and Measures: A composite primary end point of death, myocardial infarction, or unplanned return to the operating room within 30 days of the index operation. Results: We identified 299 patients involving 12 different surgical subspecialties that met the study criteria. The cohort included 148 men (49.5%) and had a mean (SD) age of 56.4 (15) years. Most consultations occurred preoperatively (n = 224; 74.9%; odds ratio, 0.04; 95% CI, 0.02-0.08; P < .001) and were elective (n = 212; 70.9%; odds ratio, 0.06; 95% CI, 0.03-0.12; P < .001 ). The indications for vascular surgery assistance were 156 spine exposure (52%), 43 vascular control without hemorrhage (14.4%), 43 control of hemorrhage (14.4%), and 57 vascular reconstruction (19%). Vascular repairs consisted of 13 bypasses (4.3%), 18 patch angioplasties (6.0%), and 79 primary repairs (26.4%). All procedures required open surgical exposure by the vascular surgeon. The incidence of death, myocardial infarction, or unplanned return to the operating room was 11.4% for the cohort with a mortality rate of 1.7%. Patients who required vascular repair had a higher incidence of death, myocardial infarction, or unplanned return to the operating room (17.4% vs 7.9%; P = .01). These cases resulted in an additional 1371.46 work relative value units per year. Conclusions and Relevance: Vascular surgeons provide crucial operative support across multiple specialties. Although vascular reconstruction is not needed in most patients, it may be associated with increased risk of death, myocardial infarction, or unplanned return to the operating room. The high proportion of emergent cases that require vascular repair demonstrates the importance of having vascular surgeons immediately available at the hospital. To continue providing this valuable service, vascular surgery trainees need to continue to learn the full breadth of open anatomic exposures and vascular reconstruction. PMID- 27487306 TI - Finding New Components of the Mammalian Immune System. AB - The use of forward genetics to analyze mammalian biology has been dramatically accelerated by methods that make it possible instantly to determine which mutation causes a phenotype. Now it is possible to discover gene function as rapidly as mutations can be created and screened: approximately 1,000 coding changes per week are interrogated in our laboratory. Moreover, it is possible to know approximately how much damage has been done to the genome over time. We estimate that we have damaged or destroyed about one-quarter of all protein encoding genes and tested the effects of variant alleles within these genes three times or more in a set of phenotypic assays that interest us. Only about two years were required to reach this level of saturation. PMID- 27487307 TI - For Better Orchiopexy, Processus Vaginalis Should Be Dissected and a High Ligation Should Be Performed. AB - OBJECTIVE: Data on the prevalence of patent processus vaginalis (PPV) and hernia in patients with cryptorchidism are controversial. While some pediatric surgeons do not dissect the processus vaginalis (PV), most prefer to do so to prevent hernia formation and to achieve an effective orchiopexy outcome. This study was performed to evaluate the importance of dissection and high ligation of the PV during treatment of undescended testis (UT). METHODS: The clinical findings and surgical procedures of 55 patients with UT were retrospectively investigated. RESULTS: The mean patient age was 2.5 (range 1.0-12.0) years. Non-palpable testis (NPT) was located on the right and left side in 39 and 16 patients, respectively. Ultrasonography revealed no testis in 10 patients and an atrophic testis in 7 patients. Seven patients had a parent with an inguinal hernia, and the silk sign or a PPV was detected during inguinoscrotal examination in 22 patients. Undescended testis repair was performed by an inguinal approach in all patients. The inguinal canal was opened in all patients; 42 patients had a wider-than normal internal ring (>2.5 cm), and the posterior wall of the inguinal canal was consequently weakened. Two-stage orchiopexy was performed in 2 patients, and 15 underwent the Prentiss maneuver. In the remaining patients, the dissection was easily done, and the orchiopexy was performed without any difficulty. Scrotal edema and wound infection occurred in five and two patients, respectively. One patient presented with an atrophic testis, and three had recurrent UT. Inguinal hernia was not observed in any of the patients during the study period, and all procedures were performed on an outpatient basis. CONCLUSION: High ligation of the PV is an effective method for successful orchiopexy and prevention of inguinal hernia in patients with NPT and UT. PMID- 27487308 TI - Remembering More Jewish Physicians. AB - The history of medicine has been an intriguing topic for both authors. The modern relevance of past discoveries led both authors to take a closer look at the lives and contributions of persecuted physicians. The Jewish physicians who died in the Holocaust stand out as a stark example of those who merit being remembered. Many made important contributions to medicine which remain relevant to this day. Hence, this paper reviews the lives and important contributions of two persecuted Jewish physicians: Arthur Kessler (1903-2000) and Bronislawa Fejgin (1883-1943). PMID- 27487309 TI - Acrolein-an alpha,beta-Unsaturated Aldehyde: A Review of Oral Cavity Exposure and Oral Pathology Effects. AB - Acrolein is a highly reactive unsaturated aldehyde widely present in the environment, particularly as a product of tobacco smoke. Our previous studies indicated the adverse consequences of even short-term acrolein exposure and proposed a molecular mechanism of its potential harmful effect on oral cavity keratinocytic cells. In this paper we chose to review the broad spectrum of acrolein sources such as pollution, food, and smoking. Consequently, in this paper we consider a high level of oral exposure to acrolein through these sources and discuss the noxious effects it has on the oral cavity including on salivary quality and contents, oral resistance to oxidative stress, and stress mechanism activation in a variety of oral cells. PMID- 27487310 TI - Effectiveness of Inferior Vena Cava Filters without Anticoagulation Therapy for Prophylaxis of Recurrent Pulmonary Embolism. AB - OBJECTIVE: The optimal treatment of deep vein thrombosis (DVT) is anticoagulation therapy. Inferior vena cava filter (IVC) placement is another option for the prevention of pulmonary embolism (PE) in patients with deep vein thrombosis. This is used mostly in patients with a contraindication to anticoagulant therapy. The purpose of the present study was to compare the two options. METHODS: A retrospective cohort study of two groups of patients with DVT: patients who received an IVC filter and did not receive anticoagulation due to contraindications; and patients with DVT and similar burden of comorbidity treated with anticoagulation without IVC insertion. To adjust for a potential misbalance in baseline characteristics between the two groups, we performed matching for age, gender, and Charlson's index, which is used to compute the burden of comorbid conditions. The primary outcome was an occurrence of a PE. RESULTS: We studied 1,742 patients hospitalized with the diagnosis of DVT in our hospital;93 patients from this population received IVC filters. Charlson's score index was significantly higher in the IVC filter group compared with the anticoagulation group. After matching of the groups of patients according to Charlson's score index there were no significant differences in primary outcomes. CONCLUSION: Inferior vena cava filter without anticoagulation may be an alternative option for prevention of PE in patients with contraindications to anticoagulant therapy. PMID- 27487311 TI - Transversus Abdominis Plane Versus Ilioinguinal and Iliohypogastric Nerve Blocks for Analgesia Following Open Inguinal Herniorrhaphy. AB - OBJECTIVES: We hypothesized that preoperative (pre-op) ultrasound (US)-guided posterior transversus abdominis plane block (TAP) and US-guided ilioinguinal and iliohypogastric nerve block (ILI+IHG) will produce a comparable analgesia after Lichtenstein patch tension-free method of open inguinal hernia repair in adult men. The genital branch of the genitofemoral nerve will be blocked separately. METHODS: This is a prospective, randomized, controlled, and observer-blinded clinical study. A total of 166 adult men were randomly assigned to one of three groups: a pre-op TAP group, a pre-op ILI+IHG group, and a control group. An intraoperative block of the genital branch of the genitofemoral nerve was performed in all patients in all three groups, followed by postoperative patient controlled intravenous analgesia with morphine. The pain intensity and morphine consumption immediately after surgery and during the 24 hours after surgery were compared between the groups. RESULTS: A total of 149 patients completed the study protocol. The intensity of pain immediately after surgery and morphine consumption were similar in the two "block" groups; however, they were significantly decreased compared with the control group. During the 24 hours after surgery, morphine consumption in the ILI+IHG group decreased compared with the TAP group, as well as in each "block" group versus the control group. Twenty four hours after surgery, all evaluated parameters were similar. CONCLUSION: Ultrasound-guided ILI+IHG provided better pain control than US-guided posterior TAP following the Lichtenstein patch tension-free method of open inguinal hernia repair in men during 24 hours after surgery. (ClinicalTrials.gov number: NCT01429480.). PMID- 27487312 TI - Safety of Completion Thyroidectomy for Initially Misdiagnosed Thyroid Carcinoma. AB - INTRODUCTION: Completion thyroidectomy is defined as the surgical removal of the remnant thyroid tissue following procedures of less than total or near-total thyroidectomy. Whether thyroid reoperations are associated with an increased complication risk is controversial. OBJECTIVE: A retrospective analysis was done of patients undergoing completion thyroidectomy for cancer of the thyroid who had undergone surgery elsewhere for solitary thyroid nodule. The incidence of surgical complications in these patients after reoperation was investigated in this study. MATERIAL AND METHODS: The study included a total of 53 patients who had undergone thyroid lobectomy for a solitary nodule as initial surgery elsewhere and were referred to our institute for completion thyroidectomy when the histopathology revealed malignancy. RESULTS: There were 53 patients, 43 females and 10 males. Their mean age was 34.7+/-12.12 years (range 19-65 years). After initial surgery, the histopathology revealed papillary carcinoma in 46 patients (86.8%), follicular carcinoma in 7 (13.2%). Fourteen out of 53 patients had recurrent laryngeal nerve palsy after initial surgery (26.4%). None of the patients had clinical hypocalcemia after the first surgery. One or more parathyroid glands were identified and preserved in 52 patients (98.1%) in the process of completion thyroidectomy. No patient had additional recurrent nerve injury at the second surgery. The mean serum calcium value preoperatively was 8.96+/-0.39 mg/dL, and six months after surgery serum calcium was 8.74+/-0.56 mg/dL. Mean follow-up was 18 months. Transient hypoparathyroidism occurred in 24.5% patients. Five patients were lost to follow-up. Permanent and symptomatic hyperparathyroidism occurred in eight patients (16.67%). CONCLUSIONS: Completion thyroidectomy is a safe and appropriate option in the management of well differentiated thyroid cancer. It removes disease on the ipsilateral and contralateral side of the thyroid and carries a low risk of recurrent laryngeal nerve damage, but a higher risk of permanent hypoparathyroidism. PMID- 27487313 TI - Cancer of the Throat: A Physician's Experience as a Patient. AB - The author, a practicing physician, was diagnosed with throat cancer and lost his vocal cords. He endured the side effects of radiation, repeated surgeries, and the effects of prolonged hospitalizations; confronted medical mistakes and discrimination after losing his vocal cords; and struggled to regain his speech and find new meaning and purpose for his life. Facing the hardship and trials of becoming a laryngectomee illustrated to him how dependent and helpless a patient can become. Being unable to speak, eat, and breathe normally, while dealing with a potentially terminal illness, makes the patient very vulnerable, both physically and emotionally. A skillful, competent, error-free, empathetic, and caring approach that recognizes what the patient is experiencing can expedite recovery and well-being and help the patient return to a productive and meaningful life. PMID- 27487314 TI - Should Sabbath Prohibitions Be Overridden to Provide Emotional Support to a Sick Relative? AB - BACKGROUND: There is a consensus among the halachic authorities that life-saving actions override Sabbath prohibitions. They are painstaking in securing that the sanctity of the Sabbath is maintained but that not a single life be lost. OBJECTIVE: This manuscript examines if and when a relative's presence at the bedside of a seriously ill individual is potentially life-saving against the backdrop of the scientific literature. It specifically addresses the permissibility of traveling in a motorized vehicle, generally prohibited on the Sabbath, to be with one's relative in hospital for the provision of emotional support. METHODS: Discourse of the halachic issues in the context of the scientific literature. RESULTS: Stress, mental or physical, has been determined as a potentially life-threatening condition in many disease entities. The literature attests to both the patient's and the professionals' perception of the curative potential of the presence of loved ones by advocating for the patient and relieving stress in the hospital experience. Emotional support from a loved one is perceived by some patients as vital to survival. There is halachic consensus that a patient's perception of the emotional need for a relative's presence is sufficient to permit overriding rabbinic prohibitions. Torah prohibitions, which may be overridden for medical needs, may be overridden for emotional support, providing a health professional or family member attests to the fulfilment of this specific need as diminishing the danger to the patient's life. In certain cases, the latter contingency is unnecessary. CONCLUSIONS: Emotional support has an impact on the patient's health status; the degree to which its impact is strong enough to save life is still being studied. As more data from scientific studies emerge, they may be relevant to sharpening the halachic rulings with respect to the issue at hand. PMID- 27487315 TI - The profiles of students with significant cognitive disabilities and complex communication needs. AB - Understanding the characteristics of students with complex communication needs and significant cognitive disabilities is an important first step toward creating the kinds of supports and services required to help them successfully access the general education curriculum, achieve grade-level standards, and improve overall communication competence. The First Contact Survey was designed to collect important information about students with significant cognitive disabilities who were eligible to take the Dynamic Learning MapsTM (DLM((r))) alternate assessment based on alternate achievement standards. From November 2012-May 2013, the survey was used to gather information regarding more than 44,787 students. At that time, the goal was to use the data to inform the development of the DLM assessment. Although the survey includes a wealth of information regarding this large sample of students, the reanalysis of the data reported in the current study focused on the motor, sensory, language, reading, and writing skills of students with significant cognitive disabilities, based on their speech production abilities. Significant differences were identified across each of the domains between students who do and do not use speech with or without aided augmentative and alternative communication. PMID- 27487316 TI - The Indirect Effect of Perceived Criticism on Suicide Ideation and Attempts. AB - The effect of perceived criticism from others is one potentially important risk factor for suicide that has received scant attention, despite decades of research on the role of criticism in the treatment and course of mental illnesses such as schizophrenia and mood disorders. This study analyzed the effect of perceived criticism's association with suicidal ideation and attempts as well as its connection with the suicide related constructs thwarted belongingness and perceived burdensomeness as described in the Interpersonal Theory of Suicide. Fifty participants (66% female, MAge = 18.7), 18 of whom had previously made one or more suicide attempts, completed a battery of self-report assessments as well as two in-person, structured clinical interviews. Analyses demonstrated that perceived parental criticism is a significant indicator of suicide ideation (beta = .297, p = .003) and attempts (beta = .373, p < .001) and that perceived criticism from close friends is a significant indicator of suicide attempts (beta = .297, p = .006). Perceived criticism has a strong indirect effect on suicide ideation and attempts through its effect on thwarted belongingness, but not perceived burdensomeness, while controlling for mental illnesses. Some limitations of this study include the cross-sectional design and the use of a relatively small, restricted age sample. Treatment designed to mitigate perceived criticism and thwarted belongingness may be an important component in combatting suicidal ideation and attempts, particularly among young adults. PMID- 27487317 TI - Comparison of the National Early Warning Score in non-elective medical and surgical patients. AB - BACKGROUND: The National Early Warning Score (NEWS) is used to identify deteriorating patients in hospital. NEWS is a better discriminator of outcomes than other early warning scores in acute medical admissions, but it has not been evaluated in a surgical population. The study aims were to evaluate the ability of NEWS to discriminate cardiac arrest, death and unanticipated ICU admission in patients admitted to surgical specialties, and to compare the performance of NEWS in admissions to medical and surgical specialties. METHODS: Hospitalwide data over 31 months, from adult inpatients who stayed at least one night or died on the day of admission, were analysed. The data were categorized as elective or non elective surgical or medical admissions. The ability of NEWS to discriminate the outcomes above in these different groups was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: There were too few outcomes to permit meaningful comparison of elective admissions, so the analysis was constrained to comparison of non-elective admissions. NEWS performed equally well, or better, for surgical as for medical patients. For death within 24 h the AUROC for surgical admissions was 0.914 (95 per cent c.i. 0.907 to 0.922), compared with 0.902 (0.898 to 0.905) for medical admissions. For the combined outcome of any of death, cardiac arrest or unanticipated ICU admission, the AUROC was 0.874 (0.868 to 0.880) for surgical admissions and 0.874 (0.871 to 0.877) for medical admissions. CONCLUSION: NEWS discriminated deterioration in non-elective surgical patients at least as well as in non-elective medical patients. PMID- 27487318 TI - Violence and depression in a community sample. AB - AIMS AND OBJECTIVES: To understand the relation between the experience of violence and sociodemographic and clinical factors, and to determine whether diagnosed depression and the presence of anxiety and stress are related to having experienced workplace and domestic violence in different genders and age groups. BACKGROUND: Previous studies indicate that domestic and workplace violence increase the risk of suffering from depression. However, no studies have evaluated these two types of violence in a same cohort. DESIGN AND METHODS: We designed a descriptive cross-sectional study from 317 individuals randomly selected from the population in southern Catalonia (Spain). Sociodemographic and Goldberg anxiety-depression questionnaires were administered by telephone survey to 160 men and 157 women in December 2008. The data obtained were analysed by a logistic regression model. RESULTS: A quarter of the individuals had suffered from violence: 48.29% of them had experienced domestic violence and 32.9% had experienced workplace violence. Nearly half of the individuals with depression had experienced violence. No statistical difference has been observed between domestic and workplace violence regarding diagnosed depression. Women were twice as likely as men to have suffered from violence. People working outside their home and those who claimed to have no social support had a greater risk of suffering from violence. A greater consumption of medication, above all of psychotropic drugs, is associated with experiencing violence and with greater comorbidity. Predictive factors for suffering from depression are being women, having experienced violence, having suffered stress or anxiety, having little or no social support, having overload of task or having no secondary education and no tertiary education. CONCLUSIONS: This study suggests that when considering depression, anxiety and stress, especially in women, we must take into account whether an individual has suffered violence. RELEVANCE TO CLINICAL PRACTICE: Identifying violence can help health professionals, managers and researchers improve care and reduce suffering in families and communities. PMID- 27487319 TI - Synthetic Lipid-Containing Scaffolds Enhance Production by Colocalizing Enzymes. AB - Subcellular organization is critical for isolating, concentrating, and protecting biological activities. Natural subcellular organization is often achieved using colocalization of proteins on scaffold molecules, thereby enhancing metabolic fluxes and enabling coregulation. Synthetic scaffolds extend these benefits to new biological processes and are typically constructed from proteins or nucleic acids. To expand the range of available building materials, we use a minimal set of components from the lipid-encapsulated bacteriophage phi6 to form synthetic lipid-containing scaffolds (SLSs) in E. coli. Analysis of diffusive behavior by particle tracking in live cells indicates that SLSs are >20 nm in diameter; furthermore, density measurements demonstrate that SLSs contain a mixture of lipids and proteins. The fluorescent proteins mCitrine and mCerulean can be colocalized to SLSs. To test for effects on enzymatic production, we localized two enzymes involved in indigo biosynthesis to SLSs. We observed a scaffold dependent increase in indigo production, showing that SLSs can enhance the production of a commercially relevant metabolite. PMID- 27487320 TI - Reversal of Tetracycline Resistance in Escherichia coli by Noncytotoxic bis(Tryptophan)s. AB - Nine bis(tryptophan) derivatives (BTs) and two control compounds were synthesized and tested for antimicrobial activity against two Escherichia coli strains and a Staphylococcus aureus strain. The effects of linker type, shape, and conformational rigidity were manifested in dramatic differences in altering tetracycline potency when coadministered with that antibiotic. A reversal of resistance was observed for an E. coli strain having a TetA efflux pump. Survival of mammalian cells was assayed with good result. PMID- 27487321 TI - A GDI/GDF-like system for sorting and shuttling ciliary proteins. AB - Post/co-translational modifications by the addition of lipids take place in a vast number of proteins. Rab and Rho are small G proteins which are prenylated and targeted to membranes in complex with solubilizing factors called guanosine dissociation inhibitors (GDIs). The release of Rab and Rho at the correct destination from their cognate GDI has been proposed to be mediated through GDI displacement factors. However this mechanism is yet to be established and it has been shown that loading of Rab proteins with GTP at the destination can be sufficient for their correct targeting. PDE6D shares structural homology with Rho GDI and solubilises several prenylated proteins and mediate their targeting to different destinations including cilia. In a paper published by Fansa et al, the authors propose that sorting of cargo is dependent on the differential release by bona fide GDFs, Arl2 and Arl3, and the localization of the active Arl3GTP in cilia. PMID- 27487322 TI - Structural Basis of the Disorder in the Tandem Zinc Finger Domain of the RNA Binding Protein Tristetraprolin. AB - Tristetraprolin (TTP) and TIS11d are two human RNA-binding proteins that belong to the CCCH-type tandem zinc finger family. In the RNA-free state, TIS11d coordinates a zinc ion in each of its two fingers, while TTP coordinates a single zinc ion with the N-terminal zinc finger. We have previously identified three residues, located in the C-terminal half of a short alpha-helix in the second zinc finger, that control how structured the RNA-binding domain is in these two proteins: Y151, L152, and Q153 in TTP and H201, T202, and I203 in TIS11d. Here, we have used molecular dynamics, NMR spectroscopy, and other biochemical methods to investigate the role of these three residues in the stability of the RNA binding domain. We found that the intrahelical hydrogen bond formed by the T202 hydroxyl group in the C-terminal zinc finger of TIS11d is necessary to allow for pi-pi stacking between the side chains of a conserved phenylalanine and the zinc coordinating histidine. We demonstrated that the lack of this hydrogen bond in TTP is responsible for the reduced zinc affinity of the C-terminal zinc finger. PMID- 27487323 TI - Community Pharmacists' Perspectives on Dispensing Medications With the Potential for Misuse, Diversion, and Intentional Overdose: Results of a Province-Wide Survey of Community Pharmacists in Canada. AB - BACKGROUND: Community pharmacists frequently encounter patients at risk of medication misuse, diversion, and intentional overdose. However, few studies have examined the perspective of the pharmacist on the identification and management of these patients. OBJECTIVE: To understand the perspective of community pharmacists on the dispensing of select medications commonly associated with misuse, diversion, and overdose. METHODS: An online survey was disseminated by electronic mail to community pharmacists listed in the College of Pharmacists of Manitoba directory. The survey was open from July to September 2014. Descriptive statistics were used to describe demographic information of the pharmacist and practice setting, and pharmacists' perceptions on the dispensing of select medications. RESULTS: A total of 82 community pharmacists completed the survey. Most pharmacists considered a one-month supply appropriate for a psychotropic agent; but a 7-10 day-supply was considered appropriate for an opioid for acute pain. Factors that aid pharmacist decisions on providing select medications to patients include familiarity with the patient, ease of access to medical history information, and ease of access to the prescribing physician. Only 10.3%, 16.2%, and 32.4% felt they have received adequate training on the management of patients at risk for suicide, drug diversion, and medication misuse, respectively. CONCLUSION: Findings from this study demonstrated a need for improved systems for managing patients at risk for medication misuse, diversion, and overdose. Strategies that warrant further attention for limiting the means of medication misuse include increased access to electronic medical records and providing additional continuing education support for community pharmacists. PMID- 27487324 TI - Comparison of Verisyse and Veriflex Phakic Intraocular Lenses for Treatment of Moderate to High Myopia 36 Months after Surgery. AB - PURPOSE: To compare refractive stability, endothelial cell count (ECC), incidence of complications, and patients' satisfaction between a rigid Verisyse (group I, n = 198) and foldable Veriflex (group II, n = 212) phakic intraocular lenses (pIOL) over 36 months postop. MATERIALS AND METHODS: This was a retrospective study. Patients' satisfaction and incidence of photic phenomena were evaluated at one month and one year postop. Data were analyzed to determine difference between groups for astigmatism, mean spherical equivalent (MRSE), uncorrected (UDVA) and corrected (CDVA) monocular distance visual acuity, complication rate (acute and chronic), and ECC. Differences were considered statistically significant when p < 0.05. RESULTS: Group II cases had significantly higher UDVA, CDVA, and lower astigmatism during the entire follow-up. There was no significant difference in mean MRSE or mean ECC postoperatively. In both groups, mean ECC reduced significantly at one month postop, followed by a gradual linear decline between 1 and 36 months of 22.4 cells/mm2/annum (group I) and 13.32 cells/mm2/annum (group II). Overall complication rates were <= 10% with no significant inter-group differences. Group I patients reported lower incidence of halos at one month but more problems with night vision at one year compared with group II. Overall satisfaction was high and total incidence of reported photic phenomena was low. CONCLUSION: Both Verisyse and Veriflex pIOLs are effective in correcting myopia. The Veriflex lens demonstrated better refractive outcome; however, subclinical inflammation observed in the Veriflex group and potential influence of inflammation on ECC loss require further investigation. PMID- 27487325 TI - Effects of a Single Water Molecule on the Reaction Barrier of Interstellar CO2 Formation Reaction. AB - The mechanism by which CO2 is formed in the interstellar space remains a mystery. The most likely reaction is collision between CO and OH; however, previous theoretical works have shown that the activation barrier for CO2 formation is high enough to prevent the reaction at the low thermal conditions of space (~10 K). The effects of single water molecule on the reaction barrier of CO2 formation from reaction between CO and OH have been investigated here by means of ab initio calculation. The barrier height along the lowest-energy pathway in the reaction between CO and OH in the absence of the H2O molecule was calculated to be 2.3 kcal/mol when CCSD(T) energy corrections are combined with the MP2 basis set limit. In the case of the hydrated (H2O-CO-OH) system, the inclusion of a single H2O molecule into the system significantly decreased the barrier height to 0.2 kcal/mol. This suggests that CO2 can be formed when CO and OH react in the presence of H2O, even under thermal conditions as low as 10 K. PMID- 27487326 TI - Computational design strategy: an approach to enhancing the transdermal delivery of optimal capsaicin-loaded transinvasomes. AB - The aim of this study was to design and develop simultaneous optimal transinvasome formulations (OTV) to enhance the transdermal delivery of capsaicin. Using a central composite experimental design with duplicate centroids, 10 model formulations of transinvasomes (TVs) were demonstrated. The lipid compositions of the TV formulations were determined as formulation factors (Xn) and response variables (Yn), respectively. TV formulations containing a constant concentration of phosphatidylcholine, cholesterol, 0.15% capsaicin, and various percentages of d-limonene (X1) and cocamide diethanolamine (X2) were prepared. The physicochemical characteristics, e.g. the vesicle size, size distribution, zeta potential, entrapment efficiency, and skin permeability, of the TV formulations were experimentally investigated. The relationship among the formulation factor, the response variables, and the OTV was predicted using Design Expert(r) software. The accuracy and reliability of the OTV predicted using computer software were experimentally confirmed and investigated as an experimental transinvasome formulation (ETV). The results indicated that the skin permeability of the ETV was close to the OTV and was significantly higher than that of conventional liposomes and commercial products. The response surfaces estimated by the computer software were helpful in understanding the complicated relationship among the formulation factor, the response variables, and the stability of the TV formulation. PMID- 27487327 TI - Photoinduced Multicomponent Reactions. AB - The combination of multicomponent approaches with light-driven processes opens up new scenarios in the area of synthetic organic chemistry, where the need for sustainable, atom- and energy-efficient reactions is increasingly urgent. Photoinduced multicomponent reactions are still in their infancy, but significant developments in this area are expected in the near future. PMID- 27487328 TI - A genetic assay for gene essentiality in Clostridium. AB - Essential genes of pathogens are potential therapeutic targets, but are difficult to verify. Here, gene essentiality was determined by targeted knockout following engineered gene duplication. Null mutants of candidate essential genes of Clostridium difficile were viable only in the presence of a stable second copy of the gene. PMID- 27487329 TI - Structural and functional characterization of chimeric cyclotides from the Mobius and trypsin inhibitor subfamilies. AB - Cyclotides are plant-derived host defense peptides displaying exceptional stability due to their cyclic cystine knot comprising three intertwined disulfide bonds and a cyclic backbone. Their six conserved cysteine residues are separated by backbone loops with diverse sequences. Prototypical cyclotides from the Mobius (kalata B1) and trypsin inhibitor (MCoTI-II) subfamilies lack sequence homology with one another, but both are able to penetrate cells, apparently via different mechanisms. To delineate the influence of the sequences of the loops on the structure and cell internalization of these two cyclotide subfamilies, a series of Mobius/trypsin inhibitor loop-chimeras of kalata B1 and MCoTI-II were synthesized, and structurally and functionally characterized. NMR analysis showed that the structural fold of the majority of chimeric peptides was minimally affected by the loop substitutions. Substituting loops 3, 5, or 6 of MCoTI-II into the corresponding loops of kalata B1 attenuated its hemolytic and cytotoxic activities, and greatly reduced its cell-penetrating properties. On the other hand, replacing loops of MCoTI-II with the corresponding loops of kalata B1 did not introduce cytotoxicity into the chimeras. Loops 2, 3, and 4 of MCoTI-II were found to contribute little to cell-penetrating properties. Overall, this study provides valuable insights into the structural basis for the hemolytic, cytotoxic, and cell-penetrating properties of kalata B1 and MCoTI-II, which could be useful for future engineering of cyclotides to carry bioactive epitopes to intracellular targets. PMID- 27487331 TI - Asymmetric Assembly of All-Carbon Tertiary/Quaternary Nonadjacent Stereocenters through Organocatalytic Conjugate Addition of alpha-Cyanoacetates to a Methacrylate Equivalent. AB - An efficient, highly diastereo- and enantioselective assembly of acyclic carbonyl fragments possessing nonadjacent all-carbon tertiary/quaternary stereoarrays is reported based on a Bronsted base catalyzed Michael addition/alpha-protonation sequence involving alpha-cyanoacetates and 2,4-dimethyl-4-hydroxypenten-3-one as novel methacrylate equivalent. PMID- 27487332 TI - Opening of Carborane Cages by Metal Cluster Complexes: The Reaction of a Thiolate Substituted Carborane with Triosmium Carbonyl Cluster Complexes. AB - The reaction of Os3(CO)10(NCMe)2 with closo-o-(1-SCH3)C2B10H11 has yielded the complex Os3(CO)9[MU3-eta(3)-C2B10H9(SCH3)](MU-H)2, 1, by the loss of the two NCMe ligands and one CO ligand from the Os3 cluster and the coordination of the sulfur atom and the activation of two B-H bonds with transfer of the hydrogen atoms to the cluster. Reaction of 1 with a second equivalent of Os3(CO)10(NCMe)2 yielded the complex Os3(CO)9(MU-H)[(MU3-eta(3)-1,4,5-MU3-eta(3)-6,10,11 C2B10H8S(CH3)]Os3(CO)9(MU-H)2, 2, that contains two triosmium triangles attached to the same carborane cage. The carborane cage was opened by cleavage of two B-C bonds and one B-B bond. The B-H group that was pulled out of the cage became a triply bridging group on one of the Os3 triangles but remains bonded to the cage by two B-B bonds. When heated to 150 degrees C, 2 was transformed into the complex Os3(CO)9(MU-H)[(MU3-eta(3)-MU3-eta(3)-C2B10H7S(CH3)]Os3(CO)9(MU-H), 3, by the loss of two hydrogen atoms and a rearrangement that led to further opening of the carborane cage. Reaction of 1 with a second equivalent of closo-o-(1 SCH3)C2B10H11 has yielded the complex Os3(CO)6)(MU3-eta(3)-C2B10H9-R-SCH3) (MU3 eta(3)-C2B10H10-S-SCH3)(MU-H)3, 4a, containing two carborane cages coordinated to one Os3 cluster. Compound 4a was isomerized to the compound Os3(CO)6(MU3-eta(3) C2B10H9-R-SCH3)(MU3-eta(3)-C2B10H10-R-SCH3)(MU-H)3, 4b, by an inversion of stereochemistry at one of the sulfur atoms by heating to 174 degrees C. PMID- 27487333 TI - Designing a heterotrinuclear Cu(II)-Ni(II)-Cu(II) complex from a mononuclear Cu(II) Schiff base precursor with dicyanamide as a coligand: synthesis, crystal structure, thermal and photoluminescence properties. AB - Schiff bases are considered 'versatile ligands' in coordination chemistry. The design of polynuclear complexes has become of interest due to their facile preparations and varied synthetic, structural and magnetic properties. The reaction of the 'ligand complex' [CuL] {H2L is 2,2'-[propane-1,3 diylbis(nitrilomethanylylidene)]diphenol} with Ni(OAc)2.4H2O (OAc is acetate) in the presence of dicyanamide (dca) leads to the formation of bis(dicyanamido 1kappaN(1))bis(dimethyl sulfoxide)-2kappaO,3kappaO-bis{MU-2,2'-[propane-1,3 diylbis(nitrilomethanylylidene)]diphenolato} 1:2kappa(6)O,O':O,N,N',O';1:3kappa(6)O,O':O,N,N',O'-dicopper(II)nickel(II), [Cu2Ni(C17H16N2O2)2(C2N3)2(C2H6OS)2]. The complex shows strong absorption bands in the frequency region 2155-2269 cm(-1), which clearly proves the presence of terminal bonding dca groups. A single-crystal X-ray study revealed that two [CuL] units coordinate to an Ni(II) atom through the phenolate O atoms, with double phenolate bridges between Cu(II) and Ni(II) atoms. Two terminal dca groups complete the distorted octahedral geometry around the central Ni(II) atom. According to differential thermal analysis-thermogravimetric analysis (DTA-TGA), the title complex is stable up to 423 K and thermal decomposition starts with the release of two coordinated dimethyl sulfoxide molecules. Free H2L exhibits photoluminescence properties originating from intraligand (pi-pi*) transitions and fluorescence quenching is observed on complexation of H2L with Cu(II). PMID- 27487334 TI - Synthesis of 2-(2-hydroxyethyl)-1-(2-hydroxyphenyl)-6,7-dimethoxy-1,2,3,4 tetrahydroisoquinoline and pseudosymmetry in its crystal structure. AB - Natural and synthetic isoquinoline alkaloids display a wide variety of potent biological activities. The title 1-aryl-2-hydroxyethyl-1,2,3,4 tetrahydroisoquinoline, C19H23NO4, crystallizes with two molecules in the asymmetric unit related by pseudo-translation but differing only slightly in conformation. The pseudosymmetry is also reflected in the diffraction pattern. The subset of reflections corresponding to the smaller cell and average structure are on average twice as intense as those subtending the larger cell. Tentative refinement in the subcell leads to a disordered structural model with satisfactory agreement factors and, after appropriate use of restraints, acceptable molecular geometry but significantly larger and more anisotropic displacement parameters. In the correct unit cell, the independent molecules differ with respect to the orientation of the hydroxyethyl group. Intramolecular hydrogen bonding occurs between the hydroxyphenyl group and the N atom. PMID- 27487330 TI - CXCR5(+) follicular cytotoxic T cells control viral infection in B cell follicles. AB - During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies. PMID- 27487335 TI - Different acid-base behaviour of a pyrazole and an isoxazole with organic acids: crystal and molecular structures of the salt 3-(4-fluorophenyl)-1H-pyrazolium 2,4,6-trinitrophenolate and of the cocrystal 4-amino-N-(3,4-dimethyl-1,2-oxazol-5 yl)benzenesulfonamide-3,5-dinitrobenzoic acid (1/1). AB - Pyrazole and isoxazole rings differ only in the notional replacement of a potential hydrogen-bond-donor NH unit in pyrazole by a potential hydrogen-bond acceptor O atom in isoxazole. It is thus of interest to compare the hydrogen bonding characteristics of these rings. (4-Fluorophenyl)pyrazole undergoes protonation in the presence of 2,4,6-trinitrophenol to yield the salt 3-(4 fluorophenyl)-1H-pyrazolium 2,4,6-trinitrophenolate, C9H8FN2(+).C6H2N3O7(-), (I), whereas there is no proton transfer between 4-amino-N-(3,4-dimethyl-1,2-oxazol-5 yl)benzenesulfonamide and 3,5-dinitrobenzoic acid, whose reaction gives the 1:1 cocrystal, C11H13N3O3S.C7H4N2O6, (II). The bond lengths in salt (I) provide evidence for aromatic-type delocalization in the pyrazolium ring and for extensive delocalization of the negative charge into the ring of the trinitrophenolate anion. The O atoms of one of the nitro groups in the trinitrophenolate anion are disordered over two sets of atomic sites having occupancies of 0.571 (6) and 0.429 (6), but all of the other substituents on the carbocyclic rings are fully ordered. The ions in salt (I) are linked by an extensive series of N-H...O hydrogen bonds to form a three-dimensional framework structure, and in cocrystal (II), the molecular components are linked by a combination of O-H...N and N-H...O hydrogen bonds to form complex bilayers. Comparisons are made with some related compounds. PMID- 27487336 TI - Unexpected ring-closure products derived from 3-(2-allylanilino)-3-phenylacrylate esters: crystal and molecular structures of 3-acetyl-8-allyl-6-methyl-2 phenylquinolin-4-yl acetate and (2RS)-2,8-dimethyl-4-phenyl-1,2-dihydro-6H pyrrolo[3,2,1-ij]quinolin-6-one. AB - The reactions of two 3-(2-allylanilino)-3-phenylacrylate esters with acetic anhydride and with strong acids has revealed a richly diverse reactivity providing a number of unexpected products. Thus, acetylation of ethyl 3-(2 allylanilino)-3-phenylacrylate, (Ia), or ethyl 3-(2-allyl-4-methylanilino)-3 phenylacrylate, (Ib), with acetic anhydride yields not only the expected acetylated esters, (II), as the major products but also the unexpected polysubstituted quinolines 3-acetyl-8-allyl-2-phenylquinolin-4-yl acetate, (IIIa), and 3-acetyl-8-allyl-6-methyl-2-phenylquinolin-4-yl acetate, (IIIb), as minor products. Subsequent reaction of the major product ethyl 2-[(2-allyl-4 methylanilino)(phenyl)methylidene]-3-oxobutanoate, (IIb), with concentrated sulfuric acid did not provide the expected 3-acetylquinoline derivative, but instead two unexpected products, namely ethyl 4-ethyl-2-phenyl-1,4 dihydroquinoline-3-carboxylate, (IV), and ethyl 3-acetyl-4-ethyl-2-phenyl-3,4 dihydroquinoline-3-carboxylate, (V), in yields of 39 and 22%, respectively. The reaction of (Ib) with Eaton's reagent gave both the quinoline (Z)-6-methyl-2 phenyl-8-(prop-1-en-1-yl)quinolin-4(1H)-one, (VI), and the unexpected tricyclic product (2RS)-2,8-dimethyl-4-phenyl-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinolin-6 one, (VII), in yields of 71 and 12%, respectively. The products (II)-(VII) have all been fully characterized spectroscopically and the crystal structures of two of the unexpected products, i.e. (IIIb) (C23H21NO3) and (VII) (C19H17NO), are reported here. The formation of compounds (IV), (V) and (VII) all require an isomerization of the initial allyl substituent, with migration of the C=C double bond from the terminal site to the internal site. In (IIIb), the two acetyl substituents are oriented such that the intramolecular distance between the two carbonyl O atoms is only 3.243 (2) A, and in (VII), the five-membered ring adopts a twisted half-chair conformation. The molecules of compound (IIIb) are linked by two independent hydrogen bonds to form sheets built from R4(3)(20) rings and the sheets are linked by a pi-pi stacking interaction to form a three-dimensional framework structure. The molecules of compound (VII) are linked by a single type of C-H...O hydrogen bond to form centrosymmetric R2(2)(14) dimers. The molecules of compound (V), which crystallizes with Z' = 2, are linked by two N-H...O and two C-H...O hydrogen bonds, forming a chain of rings. PMID- 27487337 TI - The structure of a valinomycin-hexaaquamagnesium trifluoromethanesulfonate compound. AB - Valinomycin is a naturally occurring cyclic dodecadepsipeptide with the formula cyclo-[D-HiVA->L-Val ->L-LA->L-Val]3 (D-HiVA is D-alpha-hydroxyisovaleic acid, Val is valine and LA is lactic acid), which binds a K(+) ion with high selectively. In the past, several cation-binding modes have been revealed by X ray crystallography. In the K(+), Rb(+) and Cs(+) complexes, the ester O atoms coordinate the cation with a trigonal antiprismatic geometry, while the six amide groups form intramolecular hydrogen bonds and the network that is formed has a bracelet-like conformation (Type 1 binding). Type 2 binding is seen with the Na(+) cation, in which the valinomycin molecule retains the bracelet conformation but the cations are coordinated by only three ester carbonyl groups and are not centrally located. In addition, a picrate counter-ion and a water molecule is found at the center of the valinomycin bracelet. Type 3 binding is observed with divalent Ba(2+), in which two cations are incorporated, bridged by two anions, and coordinated by amide carbonyl groups, and there are no intramolecular amide hydrogen bonds. In this paper, we present a new Type 4 cation-binding mode, observed in valinomycin hexaaquamagnesium bis(trifluoromethanesulfonate) trihydrate, C54H90N6O18.[Mg(H2O)6](CF3SO3)2.3H2O, in which the valinomycin molecule incorporates a whole hexaaquamagnesium ion, [Mg(H2O)6](2+), via hydrogen bonding between the amide carbonyl groups and the hydrate water H atoms. In this complex, valinomycin retains the threefold symmetry observed in Type 1 binding, but the amide hydrogen-bond network is lost; the hexaaquamagnesium cation is hydrogen bonded by six amide carbonyl groups. (1)H NMR titration data is consistent with the 1:1 binding stoichiometry in acetonitrile solution. This new cation-binding mode of binding a whole hexaaquamagnesium ion by a cyclic polypeptide is likely to have important implications for the study of metal binding with biological models under physiological conditions. PMID- 27487338 TI - 6-Propyl-2-thiouracil versus 6-methoxymethyl-2-thiouracil: enhancing the hydrogen bonded synthon motif by replacement of a methylene group with an O atom. AB - The understanding of intermolecular interactions is a key objective of crystal engineering in order to exploit the derived knowledge for the rational design of new molecular solids with tailored physical and chemical properties. The tools and theories of crystal engineering are indispensable for the rational design of (pharmaceutical) cocrystals. The results of cocrystallization experiments of the antithyroid drug 6-propyl-2-thiouracil (PTU) with 2,4-diaminopyrimidine (DAPY), and of 6-methoxymethyl-2-thiouracil (MOMTU) with DAPY and 2,4,6 triaminopyrimidine (TAPY), respectively, are reported. PTU and MOMTU show a high structural similarity and differ only in the replacement of a methylene group ( CH2-) with an O atom in the side chain, thus introducing an additional hydrogen bond acceptor in MOMTU. Both molecules contain an ADA hydrogen-bonding site (A = acceptor and D = donor), while the coformers DAPY and TAPY both show complementary DAD sites and therefore should be capable of forming a mixed ADA/DAD synthon with each other, i.e. N-H...O, N-H...N and N-H...S hydrogen bonds. The experiments yielded one solvated cocrystal salt of PTU with DAPY, four different solvates of MOMTU, one ionic cocrystal of MOMTU with DAPY and one cocrystal salt of MOMTU with TAPY, namely 2,4-diaminopyrimidinium 6-propyl-2 thiouracilate-2,4-diaminopyrimidine-N,N-dimethylacetamide-water (1/1/1/1) (the systematic name for 6-propyl-2-thiouracilate is 6-oxo-4-propyl-2-sulfanylidene 1,2,3,6-tetrahydropyrimidin-1-ide), C4H7N4(+).C7H9N2OS(-).C4H6N4.C4H9NO.H2O, (I), 6-methoxymethyl-2-thiouracil-N,N-dimethylformamide (1/1), C6H8N2O2S.C3H7NO, (II), 6-methoxymethyl-2-thiouracil-N,N-dimethylacetamide (1/1), C6H8N2O2S.C4H9NO, (III), 6-methoxymethyl-2-thiouracil-dimethyl sulfoxide (1/1), C6H8N2O2S.C2H6OS, (IV), 6-methoxymethyl-2-thiouracil-1-methylpyrrolidin-2-one (1/1), C6H8N2O2S.C5H9NO, (V), 2,4-diaminopyrimidinium 6-methoxymethyl-2-thiouracilate (the systematic name for 6-methoxymethyl-2-thiouracilate is 4-methoxymethyl-6-oxo 2-sulfanylidene-1,2,3,6-tetrahydropyrimidin-1-ide), C4H7N4(+).C6H7N2O2S(-), (VI), and 2,4,6-triaminopyrimidinium 6-methoxymethyl-2-thiouracilate-6-methoxymethyl-2 thiouracil (1/1), C4H8N5(+).C6H7N2O2S(-).C6H8N2O2S, (VII). Whereas in (I) only an AA/DD hydrogen-bonding interaction was formed, the structures of (VI) and (VII) both display the desired ADA/DAD synthon. Conformational studies on the side chains of PTU and MOMTU also revealed a significant deviation for cocrystals (VI) and (VII), leading to the desired enhancement of the hydrogen-bond pattern within the crystal. PMID- 27487339 TI - A new one-dimensional strontium vanadium tellurite, Sr7V4Te12O41. AB - Vanadium tellurites display a rich structural chemistry with interesting physical properties, such as second harmonic generation (SHG). Tellurites, i.e. Te(4+)Ox, are often observed in unusual structures and form various structural motifs, including isolated clusters, chains, layers, and three-dimensional networks. Similarly, vanadates, i.e. V(5+)Ox, show rich structural features, such as VO4 tetrahedra, VO5 square pyramids or trigonal bipyramids, and VO6 octahedra. Strontium vanadium tellurite, Sr7V4Te12O41, was obtained from the melt of the solid-state reaction of SrTeO4 and VO2 in a sealed quartz tube as it cooled from 973 K. The crystal structure exhibits a one-dimensional latticework along the a axis comprised of paired Sr3Te3Ox units, namely Sr6Te6O2x+1, with corner-shared TeO4 polyhedra - and specifically the Te lone-pair electrons - facing outward in the bc plane. The Sr6Te6O2x+1 latticework is helical and is layered in the b-axis direction against sheets of corner-shared VO4 tetrahedra, and is linked in the c axis direction via individual corner-shared SrO8 square prisms. PMID- 27487340 TI - A two-dimensional mixed-valence Cu(II)/Cu(I) coordination polymer constructed from 2-(pyridin-3-yl)-1H-imidazole-4,5-dicarboxylate. AB - Coordination polymers are a thriving class of functional solid-state materials and there have been noticeable efforts and progress toward designing periodic functional structures with desired geometrical attributes and chemical properties for targeted applications. Self-assembly of metal ions and organic ligands is one of the most efficient and widely utilized methods for the construction of CPs under hydro(solvo)thermal conditions. 2-(Pyridin-3-yl)-1H-imidazole-4,5 dicarboxylate (HPIDC(2-)) has been proven to be an excellent multidentate ligand due to its multiple deprotonation and coordination modes. Crystals of poly[aquabis[MU3-5-carboxy-2-(pyridin-3-yl)-1H-imidazole-4-carboxylato kappa(5)N(1),O(5):N(3),O(4):N(2)]copper(II)dicopper(I)], [Cu(II)Cu(I)2(C10H5N3O4)2(H2O)]n, (I), were obtained from 2-(pyridin-3-yl)-1H imidazole-4,5-dicarboxylic acid (H3PIDC) and copper(II) chloride under hydrothermal conditions. The asymmetric unit consists of one independent Cu(II) ion, two Cu(I) ions, two HPIDC(2-) ligands and one coordinated water molecule. The Cu(II) centre displays a square-pyramidal geometry (CuN2O3), with two N,O chelating HPIDC(2-) ligands occupying the basal plane in a trans geometry and one O atom from a coordinated water molecule in the axial position. The Cu(I) atoms adopt three-coordinated Y-shaped coordinations. In each [CuN2O] unit, deprotonated HPIDC(2-) acts as an N,O-chelating ligand, and a symmetry-equivalent HPIDC(2-) ligand acts as an N-atom donor via the pyridine group. The HPIDC(2-) ligands in the polymer serve as T-shaped 3-connectors and adopt a MU3 kappa(2)N,O:kappa(2)N',O':kappaN''-coordination mode, linking one Cu(II) and two Cu(I) cations. The Cu cations are arranged in one-dimensional -Cu1-Cu2-Cu3- chains along the [001] direction. Further crosslinking of these chains by HPIDC(2 ) ligands along the b axis in a -Cu2-HPIDC(2-)-Cu3-HPIDC(2-)-Cu1- sequence results in a two-dimensional polymer in the (100) plane. The resulting (2,3) connected net has a (12(3))2(12)3 topology. Powder X-ray diffraction confirmed the phase purity for (I), and susceptibilty measurements indicated a very weak ferromagnetic behaviour. A thermogravimetric analysis shows the loss of the apical aqua ligand before decomposition of the title compound. PMID- 27487341 TI - A More Accurate Approach to Amyloid Detection and Subtyping: Combining in situ Congo Red Staining and Immunohistochemistry. AB - Amyloidosis is the result of various, differently approachable diseases. It is vital to subtype the amyloid deposits in order to establish and finally treat the underlying disease properly. Besides the classical staining with Congo red, further procedures like immunohistochemical staining are needed for classification. Here, we present a more accurate approach using Congo red/immunohistochemical double staining easily applicable in routine diagnostics. Modifications of the Congo red staining technique and the immunohistochemical procedures were needed in order to combine both staining procedures on one slide. The evaluation was done using conventional light and fluorescence microscopy. By shortening the staining time for Congo red to 10 s and by modification regarding endogenous peroxidase blockage, accurate results could be obtained for evaluating the Congo red/immunohistochemistry double staining using a fluorescence microscope. Sections of 2 MUm instead of 4 MUm thickness were superior for evaluation, since they increased staining specificity. The combination of Congo red and immunohistochemistry as in situ double staining on one slide is a feasible approach in the diagnosis of amyloidosis. It allows focusing on the fluorescent Congo red-positive areas when evaluating immunohistochemistry, thus avoiding signing out false-positive results. Additionally, it increases the signal-to-noise ratio of the immunohistochemically stained sections on conventional microscopy. PMID- 27487342 TI - Pharmacokinetic and Pharmacodynamic Characteristics of Subcutaneously Applied PTH 1-37. AB - BACKGROUND/AIMS: Parathyroid hormone (PTH) derivatives exert pronounced renal and osteoanabolic properties when given intermittently. The current study was performed to assess the pharmacokinetic and pharmacodynamic properties as well as safety of subcutaneously applied PTH-1-37 after repeated dosing in healthy subjects. METHODS: This randomized, double-blind, dose-escalating, placebo and active comparator controlled study was conducted in 33 healthy postmenopausal women. Subjects were allocated to one of five treatment options: 10, 20, or 40 ug PTH-1-37, 20 ug PTH-1-34 or placebo, administered as once daily subcutaneous doses for three days. Plasma drug concentrations and serum levels of endogenous PTH-1-84, and calcium as markers of biological activity were monitored during the treatment. RESULTS: PTH was absorbed rapidly from the subcutaneous tissue with a median tmax of 30 minutes for 20 and 40 ug of PTH-1-37. tmax was 45 minutes for 20 ug PTH-1-34. Elimination half-lives were estimated as 76 +/- 34 min and 70 +/- 13 min for 20 ug and 40 ug PTH-1-37 (mean +/- SD), and 78 +/- 34 for 20 ug PTH-1 34. Both PTH fragments (PTH-1-37 and PTH-1-34) increased serum calcium. For PTH-1 37 the effect on serum calcium was dose-dependent. Suppression of endogenous PTH 1-84 was seen after the application of both PTH-1-37 and PTH-1-34. During the study period, the subjects experienced no unexpected or serious adverse events. CONCLUSIONS: PTH-1-37 is rapidly absorbed after s.c. injection, has a short plasma elimination half-life, and does not accumulate during multiple dosing. Biological activity was demonstrated by rising serum calcium and decreasing endogenous PTH-1-84 in blood plasma. The study drugs were well tolerated and safe. Our investigation presents data that PTH-1-37 is an excellent drug candidate for intervening with syndromes of dysregulation of calcium metabolism. PMID- 27487343 TI - Funduscopic versus HRT III Confocal Scanner Vertical Cup-Disc Ratio Assessment in Normal Tension and Primary Open Angle Glaucoma (The Leuven Eye Study). AB - PURPOSE: To compare funduscopic and confocal scanning vertical cup-disc ratio (VCDR) assessments and their respective predictive value for estimating functional glaucomatous damage. METHODS: Data from a single eye of open angle glaucoma patients from the Leuven Eye Study were included: age, gender, intra ocular pressure, visual acuity, refractive error, visual field mean deviation and pattern standard deviation, funduscopic and HRT III VCDRs as well as mean retinal nerve fibre layer thickness. Non-parametric tests to compare differences within and between diagnostic groups were used, and receiver-operating characteristic curves as well as Bland-Altman plots constructed. RESULTS: Three hundred and one eyes of 301 subjects with primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) were included. The average VCDR assessed with HRT III was significantly smaller than the funduscopic measurement (0.69 +/- 0.16 vs. 0.81 +/ 0.14, respectively; p < 0.001). The predictive value of both measurement techniques did not differ in NTG patients, but the funduscopic estimate yielded a significantly larger predictive power in patients with severe POAG. CONCLUSION: Funduscopic and confocal scanner estimates of VCDR differ significantly and should not be used interchangeably. In POAG patients with severe glaucoma, a subjective VCDR predicts functional glaucomatous damage significantly better. PMID- 27487344 TI - Glioblastoma Multiforme with Hypodipsic Hypernatremia in a Seven-Month-Old Golden Retriever. AB - Primary hypodipsic hypernatremia is a rarely reported disease in dogs. Reported underlying causes associated with this disease in dogs include congenital malformations, encephalitis, intracranial neoplasia, and pressure atrophy of the hypothalamus secondary to hydrocephalus. The dog in this report had an infiltrative neoplastic disorder, likely causing damage to the hypothalamic osmoreceptors responsible for the thirst generation. The neoplastic process was identified histopathologically as glioblastoma multiforme, an unusual tumor to occur in a dog this young. A tumor of the central nervous system causing physical destruction of the osmoreceptors has rarely been reported in dogs and none of the previously reported cases involved a glial cell tumor. PMID- 27487345 TI - Evaluation of Dogs with Border Collie Collapse, Including Response to Two Standardized Strenuous Exercise Protocols. AB - Clinical and metabolic variables were evaluated in 13 dogs with border collie collapse (BCC) before, during, and following completion of standardized strenuous exercise protocols. Six dogs participated in a ball-retrieving protocol, and seven dogs participated in a sheep-herding protocol. Findings were compared with 16 normal border collies participating in the same exercise protocols (11 retrieving, five herding). Twelve dogs with BCC developed abnormal mentation and/or an abnormal gait during evaluation. All dogs had post-exercise elevations in rectal temperature, pulse rate, arterial blood pH, PaO2, and lactate, and decreased PaCO2 and bicarbonate, as expected with strenuous exercise, but there were no significant differences between BCC dogs and normal dogs. Electrocardiography demonstrated sinus tachycardia in all dogs following exercise. Needle electromyography was normal, and evaluation of muscle biopsy cryosections using a standard panel of histochemical stains and reactions did not reveal a reason for collapse in 10 dogs with BCC in which these tests were performed. Genetic testing excluded the dynamin-1 related exercise-induced collapse mutation and the V547A malignant hyperthermia mutation as the cause of BCC. Common reasons for exercise intolerance were eliminated. Although a genetic basis is suspected, the cause of collapse in BCC was not determined. PMID- 27487346 TI - Perioperative Cefovecin to Reduce the Incidence of Urinary Tract Infection in Dogs Undergoing Hemilaminectomy. AB - The prevalence of urinary tract infections (UTIs) in dogs with Type I intervertebral disc extrusion has been reported as high as 38% within 6 wk of surgery. Proper treatment of a UTI is important with myelopathy because it is a risk factor for persistent infection and reinfection in dogs. The study authors' investigated the incidence of UTIs in dogs having received either cefovecin or cefazolin as a preoperative prophylactic antibiotic for thoracolumbar hemilaminectomy. Thirty-nine dogs were retrospectively identified and assigned to groups based on preoperative antibiotic administration and postoperative urinary tract management. Urinalysis and urine culture performed preoperatively, at 2 wk, and at 6 wk, were reviewed to determine the incidence of UTIs. Urinary tract management, grade of neurologic deficit, time to ambulation, and time to voluntary urination were identified to evaluate for additional risk factors. No significant prevalence of UTI incidence was appreciated between the cefovecin and cefazolin groups. Patients with higher grades of neurologic deficit and that took longer to regain ambulation and voluntary urination were at significantly greater risk for UTIs throughout the postoperative period. This study reemphasizes the importance of continued surveillance for UTIs in patients with prolonged neurologic recovery. PMID- 27487347 TI - Diagnosis and Outcome of Periosteal Chondrosarcoma in Two Cats. AB - Two cats, both over 10 yr old, were presented for evaluation of non-painful bony proliferations on the appendicular skeleton. These proliferations were identifiable via palpation. Radiographs showed a smooth, proliferative bony lesion of the distal femur (case 1) and tarsus (case 2) with mild soft tissue swelling. Surgical debulking with incomplete resection was performed in each cat. Subsequent histopathology resulted in a diagnosis of periosteal chondrosarcoma (PC). Although both cats have experienced local recurrence, both are still alive more than 2.5 yr after mass debulking. Periosteal chondrosarcoma is a differential diagnosis in proliferative cortical bony lesions near an articular surface in older cats. Partial resection of these masses can lead to an excellent quality of life, and proper diagnosis can avoid amputation or even euthanasia. PMID- 27487348 TI - Evaluation of Commonly Used Products for Disinfecting Clipper Blades in Veterinary Practices: A Pilot Study. AB - Nosocomial infections are a concern of growing interest in veterinary medicine. Clipper blades have been confirmed as fomites for numerous potential pathogens and, as such, may be associated with wound and surgical site infections. The goal of this study was to evaluate the disinfectant capabilities of several commonly used clipper blade cleaning products. Seventy sterile clipper blades were inoculated with strains of Pseudomonas aeruginosa , Escherichia coli , and Staphylococcus aureus . Blades were then subjected to one of seven treatment groups for disinfecting. Quantitative cultures of remaining bacteria were performed. All blades in the control group showed large amounts of bacterial recovery. Culture results showed no recovery in blades soaked in alcohol or chlorhexidine or those sprayed with an ethanol/o-phenylphenol product, while moderate recovery was seen with all other treatments. These results show that persistent contamination of clipper blades can occur with the use of several commonly used disinfectant products. Further research is necessary to evaluate fungicidal capabilities as well as the effect of disinfection on clipper blade maintenance. PMID- 27487349 TI - Chronic Vomiting in Cats: Etiology and Diagnostic Testing. AB - Chronic vomiting in cats is a common presenting problem seen in veterinary practice today. The initial step when presented with a vomiting patient is to differentiate between vomiting and regurgitation or dysphagia. There are numerous causes for chronic vomiting in cats, and therefore a detailed and comprehensive patient history and a systematic diagnostic approach are key steps in determining the cause for vomiting and the most appropriate treatment plan. Common causes for chronic vomiting in cats may include inflammatory bowel disease, food allergy, gastrointestinal motility disorders, neoplasia, and extra-gastrointestinal diseases, such as renal disease, hepatobiliary disease, and hyperthyroidism. PMID- 27487350 TI - Seminal Vesiculitis in Three Pet Rabbits ( Oryctolagus cuniculus ). AB - To date, descriptions of pathologic conditions of the seminal vesicle in rabbits are scarce and limited to the laboratory animals in experimental conditions. The present article describes three cases of strangury, abdominal pain, and anorexia associated with seminal vesiculitis in pet rabbits. Three non-neutered male pet rabbits aged 3.6, 1.5, and 2.1 yrs were presented with strangury, abdominal pain, and anorexia. Seminal vesiculitis was diagnosed based on clinical signs and ultrasonography findings. Vesiculectomy was performed in two cases that presented strangury refractory to medical treatment, and diagnosis was confirmed by histopathology. In the third case, the patient received medical treatment, and a sequela in the form of lithiasis of the seminal vesicle was detected 3 yrs later. Plain radiographs were nearly unremarkable, and results from complete blood analysis and urinalysis were not specific in all three cases. Contrast radiography was performed in one case, showing a dilated seminal vesicle. Ultrasound and surgical biopsy seem to be the most sensitive techniques in the diagnosis of this pathology. Seminal vesiculitis must be included in the differential diagnosis of acute or chronic strangury in male pet rabbits. PMID- 27487351 TI - Palliative Epineurotomy for Focal Radial Malignant Peripheral Nerve Sheath Tumor in a Dog. AB - This case report describes the diagnosis of a peripheral nerve sheath tumor of the deep branch of the radial nerve distal to the elbow in a dog. The lesion was identified using computed tomography and ultrasonography and confirmed as sarcoma on histopathological analysis of incisional biopsies. Clinical signs dramatically improved following surgical biopsy before recurring three months later. Repeat epineurotomy of the deep branch of the radial nerve resulted in clinical improvement for a further month before signs once again returned. Epineurotomy as a palliative treatment for peripheral nerve sheath tumors has not been previously described, but may have a place in palliation of clinical signs in specific cases of peripheral nerve sheath tumors in which limb amputation is not an option. PMID- 27487352 TI - Hemothorax in Three Dogs with Intrathoracic Extracardiac Hemangiosarcoma. AB - Intrathoracic extracardiac hemangiosarcoma (HSA) is rare in dogs. This report describes three dogs with acute onset dyspnea due to hemorrhagic pleural effusion resulting from intrathoracic extracardiac masses, which were confirmed as HSA by histopathology. The dogs were stabilized with thoracocentesis and intravascular fluid resuscitation. Computed tomography identified intrathoracic masses, which were not originating from the heart or pulmonary parenchyma. Surgical exploration was performed in all cases. Case 1 was euthanized intraoperatively as the tumor could not be dissected from the aorta. In cases 2 and 3, hemostasis and resection of the tumors was successful. Case 2 was euthanized 1 mo after surgery and case 3 was alive at the time of writing, 5 mo postoperatively. Intrathoracic extracardiac HSA should be considered as a differential for nontraumatic hemothorax and surgical treatment can be palliative. PMID- 27487353 TI - Modern Spirometry Supports Anesthetic Management in Small Animal Clinical Practice: A Case Series. AB - Modern spirometry, like no other monitoring technique, allows insight into breath to-breath respiratory mechanics. Spirometers continuously measure volume, airway pressure, and flow while calculating and continuously displaying respiratory system compliance and resistance in the form of loops. The aim of this case series is to show how observation of spirometric loops, similar to electrocardiogram or CO2 curve monitoring, can improve safety of anesthetic management in small animals. Spirometric monitoring cases described in this case series are based on use of the anaesthesia monitor Capnomac Ultima with a side stream spirometry sensor. The cases illustrate how recognition and understanding of spirometric loops allows for easy diagnosis of iatrogenic pneumothorax, incorrect ventilator settings, leaks in the system, kinked or partially obstructed endotracheal tube, and spontaneous breathing interfering with intermittent positive-pressure ventilation. The case series demonstrates the potential of spirometry to improve the quality and safety of anesthetic management, and, hence, its use can be recommended during intermittent positive pressure ventilation and procedures in which interference with ventilation can be expected. PMID- 27487354 TI - Upper Airway Injury in Dogs Secondary to Trauma: 10 Dogs (2000-2011). AB - Ten dogs that presented with trauma-induced upper airway rupture or stenosis were reviewed. Tracheal rupture was seen in seven dogs, tracheal stenosis in one dog, and laryngeal rupture in two dogs. Clinical abnormalities included respiratory distress in five dogs, subcutaneous emphysema in eight, air leakage through the cervical wound in seven, stridor in three dogs, pneumomediastinum in four and pneumothorax in one dog. Reconstruction with simple interrupted sutures was performed in four dogs, tracheal resection and end-to-end anastomosis in five dogs, and one dog was euthanized intraoperatively. Complications were seen in three dogs including aspiration pneumonia in one and vocalization alterations in two dogs. PMID- 27487355 TI - Copeptin levels and kidney function in ADPKD: case-control study. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Studies have suggested a possible prognostic role of copeptin in determining the rate of progressive kidney function decline in ADPKD patients. However, it remains unresolved whether the changes in copeptin levels are specific for ADPKD or merely reflect a decline in glomerular filtration rate (GFR) regardless of the etiology of chronic kidney disease (CKD). METHODS: We performed a case-control study in ADPKD and non-ADPKD (control) patients. Patients were categorized based on the GFR-category (G-stage, KDIGO). We evaluated urea, creatinine, cystatin C, and copeptin in plasma and correlated these levels with estimated glomerular filtration rate (eGFR) (CKD-EPI). All p values were two sided, and p < 0.05 was considered as statistically significant. RESULTS: We enrolled 112 ADPKD and 112 control patients. The median copeptin level was 10.72 (interquartile range (IQR) 5.21 - 26.21) pmol/L in the ADPKD group and 12.32 (IQR 4.47 - 30.73) pmol/L in the control group. The median copeptin level increased according to the G-stage in a progressive fashion and remained statistically significant across all G-stages and in both groups. Copeptin levels were not significantly different between ADPKD and control groups. We found a significant inverse correlation between copeptin level and eGFR (Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) in the ADPKD, r = -0.81 (p < 0.001), and in the control group, r = -0.76 (p < 0.001). CONCLUSIONS: Copeptin levels seem to be strongly correlated with renal function rather than the presence of ADPKD. Further prospective studies need to evaluate its role as a prognostic marker in the early stage of CKD for ADPKD progression. PMID- 27487358 TI - Intrusion of a Liquid Droplet into a Powder under Gravity. AB - Intrusion of a liquid droplet into a hexagonal close-packed array of spheres under gravity is investigated using analytical methods and volume-of-fluid simulations. Four regimes of ultimate fluid behavior are identified: (A) no liquid imbibition into the bed, (B) trapping of liquid high in the bed, (C) liquid descending to the bottom of the bed, and (D) liquid spreading around the surface of all particles. These regimes are mapped based on the contact angle and Bond number of the system. Many aspects of the dynamics and ultimate liquid behavior are captured using a simplified model of a mass of liquid moving under gravity in a vertical capillary of undulating cross-sectional area. This simplified model is used to form momentum transport equations with four forms of nondimensional time, which are shown to collapse the simulation data with different fluid parameters in different regimes. PMID- 27487357 TI - Medication Intervention for Chronic Kidney Disease Patients Transitioning from Hospital to Home: Study Design and Baseline Characteristics. AB - BACKGROUND: The hospital readmission rate in the population with chronic kidney disease (CKD) is high and strategies to reduce this risk are urgently needed. METHODS: The CKD-Medication Intervention Trial (CKD-MIT; www.clinicaltrials.gov; NCTO1459770) is a single-blind (investigators), randomized, clinical trial conducted at Providence Health Care in Spokane, Washington. Study participants are hospitalized patients with CKD stages 3-5 (not treated with kidney replacement therapy) and acute illness. The study intervention is a pharmacist led, home-based, medication management intervention delivered within 7 days after hospital discharge. The primary outcome is a composite of hospital readmissions and visits to emergency departments and urgent care centers for 90 days following hospital discharge. Secondary outcomes are achievements of guideline-based targets for CKD risk factors and complications. RESULTS: Enrollment began in February 2012 and ended in May 2015. At baseline, the age of participants was 69 +/- 11 years (mean +/- SD), 50% (77 of 155) were women, 83% (117 of 141) had hypertension and 56% (79 of 141) had diabetes. At baseline, the estimated glomerular filtration rate was 41 +/- 14 ml/min/1.73 m2 and urine albumin-to creatinine ratio was 43 mg/g (interquartile range 8-528 mg/g). The most frequent diagnosis category for the index hospital admission was cardiovascular diseases at 34% (53 of 155), but the most common single diagnosis for admission was community-acquired acute kidney injury at 10% (16 of 155). CONCLUSION: Participants in CKD-MIT are typical of acutely ill hospitalized patients with CKD. A medication management intervention after hospital discharge is under study to reduce post-hospitalization acute care utilization and to improve CKD management. PMID- 27487356 TI - Downstream Antisense Transcription Predicts Genomic Features That Define the Specific Chromatin Environment at Mammalian Promoters. AB - Antisense transcription is a prevalent feature at mammalian promoters. Previous studies have primarily focused on antisense transcription initiating upstream of genes. Here, we characterize promoter-proximal antisense transcription downstream of gene transcription starts sites in human breast cancer cells, investigating the genomic context of downstream antisense transcription. We find extensive correlations between antisense transcription and features associated with the chromatin environment at gene promoters. Antisense transcription downstream of promoters is widespread, with antisense transcription initiation observed within 2 kb of 28% of gene transcription start sites. Antisense transcription initiates between nucleosomes regularly positioned downstream of these promoters. The nucleosomes between gene and downstream antisense transcription start sites carry histone modifications associated with active promoters, such as H3K4me3 and H3K27ac. This region is bound by chromatin remodeling and histone modifying complexes including SWI/SNF subunits and HDACs, suggesting that antisense transcription or resulting RNA transcripts contribute to the creation and maintenance of a promoter-associated chromatin environment. Downstream antisense transcription overlays additional regulatory features, such as transcription factor binding, DNA accessibility, and the downstream edge of promoter-associated CpG islands. These features suggest an important role for antisense transcription in the regulation of gene expression and the maintenance of a promoter-associated chromatin environment. PMID- 27487359 TI - Potential Curative Role of Hypericum Perforatum in an Experimental Rat Model of Tympanic Membrane Perforation. AB - OBJECTIVE: Our aim was to investigate the curative role of topical Hypericum perforatum (HP) in a rat model of tympanic membrane perforation in a histopathological manner. MATERIALS AND METHODS: This study was conducted on 30 female Sprague-Dawley rats. An HP extract was prepared as a suspension in pure olive oil. In all rats, the right and left tympanic membranes were perforated by a fine puncture under a microscope. Rats were randomly assigned to three groups. The HP extract was given as drops on a daily basis in Group 1, while olive oil alone was given on a daily basis in Group 2. In Group 3, the rats were allowed spontaneous recovery without any intervention. Three rats from each group were sacrificed on days 7, 14, and 21. Temporal bullae were removed for histopathological examination to evaluate fibroblast proliferation, leukocyte infiltration, neovascularization, and subepithelial thickness and to compare these among the groups. RESULTS: In histopathological examination of the rats from each group on days 7, 14, and 21, there were significant differences in leukocyte infiltration, fibroblast proliferation, and subepithelial thickness. No significant difference was observed in neovascularization among the groups. CONCLUSION: Compared with the spontaneous recovery group, HP was found to be more effective in a wound-healing model of the tympanic membrane. HP may be applied in clinical practice if it is shown to be safe with regard to ototoxicity. PMID- 27487360 TI - Protective Effect of Korean Red Ginseng on Cisplatin Ototoxicity: Is It Effective Enough? AB - OBJECTIVE: The aim of our study was to investigate the effects Korean Red Ginseng (KRG) on cisplatin (CDDP) ototoxicity in vivo and in vitro. MATERIALS AND METHODS: The first part of the study was conducted on the House Ear Institute Organ of Corti 1 (HEI-OC1) cell line. Cells were treated with CDDP, KRG, and their combination for 24 h. Cell viability, apoptosis, and the expression of 84 apoptosis-related genes were analyzed. In the second part of the study, 30 Wistar albino rats were divided into five groups. Baseline distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) measurements were obtained. In groups I, II, and III, only saline, KRG, and CDDP, respectively, were given. In group IV, 500 mg/kg KRG and in group V, 150 mg/kg of KRG were administered for 10 days. In groups III, IV, and V, 16 mg/kg CDDP injections were administered on day 11. On day 14, final DPOAEs and ABR measurements were completed. The rats were then sacrificed, and their inner ear structures were evaluated by transmission electron microscopy. RESULTS: In the first part of the study, pretreatment with 1 mg/mL KRG protected cells from CDDP ototoxicity. This protection was mainly due to a decline in apoptotic gene expression and an increase in antiapoptotic gene expression. In the in vivo part of the study, we found that both KRG doses had otoprotective effects. This protection was more prominent at the lower dose, especially on the spiral ganglion and the brainstem. CONCLUSION: KRG was shown to be an otoprotective agent against CDDP-induced ototoxicity both in vivo and in vitro. PMID- 27487361 TI - Neurofibroma around the Ear Canal: Report of Three Cases. AB - Facial nerve neurofibromas are an uncommon entity, particularly in the intraparotid region. Three cases are presented herein, including the first reported case of both an intratemporal and intraparotid facial nerve malignant neurofibroma. To the best of our knowledge, this is the first medical publication to describe a neurofibroma involving both the intratemporal and intraparotid regions. The aim of this clinical record was to present the surgical experiences in three cases of intratemporal and intraparotid facial neurofibroma. Of the three cases of neurofibroma included in this report, the first case was a 30-year old male who initially presented with a parotid mass without facial dysfunction. The other two cases were intratemporal neurofibromas, one of which was confirmed as a plexiform neurofibroma by pathology. These tumors often involve two or more segments of the facial nerve. The outcomes of these tumors are closely related to nerve integrity, preoperative facial nerve function level, and the follow-up period. Neurofibromas are most commonly found with neurofibromatosis type 1 and are characterized by incorporation of the nerve fibers within their matrix. Presentation of the intratemporal facial neurofibromas is variable, with facial palsy most common. Furthermore, the incidence of a solitary neurofibroma of the facial nerve originating in the parotid region is extremely low. PMID- 27487362 TI - Cochlear Implantation in Patient with Cochlear Nerve Deficiency: A Case Report. AB - Diagnostic imaging methods are very important for patients with bilateral sensourinoural hearing loss. Magnetic resonance imaging (MRI) is able to demonstrate the vestibulocochlear nerve and facial nerve in the internal acoustic canal. Also computed tomography can be helpful to determination of the deficiency of the cochlear nerve. Cochlear nerve anomalies are classified into three group according to the magnetic resonance imagings. Patients who have cochlear nerve deficiency may not hear with cochlear amplifications. Auditory brain stem implant (ABI) is most suitable for these cases. In this case report, we presented a 3 years old girls with bilateral totally hearing loss who performed cochlear implantation despite of cochlear nerve deficiency on magnetic resonance imaging (MRI) and computed tomography (CT). PMID- 27487364 TI - Ceruminous Adenocarcinoma of External Auditory Canal: A Case Report. AB - The external auditory canal contains ceruminous glands, which are modified apocrine sweat glands, along with sebaceous glands. Tumors that originate from ceruminous glands are very rare; thus, the classification, clinical behavior, and management of these tumors remain debatable. Here we present a case of ceruminous adenocarcinoma arising from the external auditory canal. Although most authors advise more aggressive therapy, our patient was treated with local en bloc resection of the tumor followed by intensity modulated radiotherapy and had no recurrence for 3 years. We suggest that limited surgery with safe margins followed by radiotherapy is an alternative choice of treatment in selected patients with ceruminous adenocarcinoma. Further reports are required to support this outcome. PMID- 27487363 TI - An Unusual Presentation of Gout: Tophi in the Middle Ear. AB - Gout is a common metabolic disease and is characterized by episodic acute and chronic arthritis caused by the deposition of monosodium urate (MSU) crystals in joints and connective tissues. The most commonly involved joint is the first metatarsophalangeal joint. It may also present with nonspecific complaints caused by gouty tophi in unusual sites of the body such as the spine, bone, and middle ear. Such involvements can be disabling and impair the quality of life. In this report, we describe the case of a patient who had complaints of hearing loss and otorrhea. A 34 year-old male patient presented with complaints of recurrent otorrhea and hearing loss for several months. He had no history of joint pain or constitutional symptoms at the time of admission. An otoscopic examination of the left ear revealed subtotal tympanic membrane perforation, and white middle ear plaques were detected. The patient underwent intact canal mastoidectomy under general anesthesia, and middle ear sclerosis was determined as Wieling Kerr classification type 2. Postoperative histopathologic examination of the specimen revealed amorphous eosinophilic deposits within fibrous stroma and tophi containing negatively birefringent MSU crystals by polarized light. After the histopathologic diagnosis of gout, the patient was assessed for peripheral joint involvement. He had no radiographic abnormalities. The patient was administered a serum urate-lowering therapy, given a low purine diet, and followed with the diagnosis of tophaceous gout. Unusual localizations of gouty tophi have been reported in the literature. Gouty tophi should also be considered in the differential diagnosis of middle ear masses alongside common pathologies. PMID- 27487366 TI - Comparative analysis of the efficacy of low- and moderate-intensity statins in Korea. AB - PURPOSE: The American College of Cardiology/American Heart Association (ACC/AHA) guidelines are based on studies with a limited number of Asian subjects; therefore, they are difficult to apply to Asian patients, including Korean patients. MATERIALS AND METHODS: Data were extracted from the clinical data warehouse system of Seoul St. Mary's hospital (January 2010 - December 2012) to determine the percent change in low-density lipoprotein cholesterol (LDL-C) levels at an average 3 and 6 months from baseline. Statins with statistically similar lowering effects were placed in one group (group A, B, or C). The proportions of patients who achieved LDL-C < 100 mg/dL were compared between baseline LDL-C levels: low (< 130 mg/dL), medium (130 - 160 mg/dL), and high (> 160 mg/dL). RESULTS: The majority of the 9 statins of various doses (2,349 patients) were effective at 3 months, with additional, smaller decreases at 6 months. The LDL-C lowering effect of group A (atorvastatin (20 mg), rosuvastatin (10 mg)) was ~ 45%; that of group B (atorvastatin (10 mg), pitavastatin (2 mg), pravastatin (40 mg), simvastatin (20 mg)) was 35 - 37%. groups A and B contained only moderate-intensity statins (ACC/AHA guidelines). With baseline LDL-C >= 130 mg/dL, greater proportions of patients achieved LDL-C < 100 mg with atorvastatin (20 mg) and rosuvastatin (10 mg). CONCLUSION: Because of the demonstrated LDL-C lowering effects and target achievement rates, the ACC/AHA guidelines might not apply to Korean patients. Korean treatment guidelines should consider statins with relatively low potency. Additional studies regarding appropriate statin doses should be conducted with Asian populations. PMID- 27487365 TI - Cell-Autonomous and Non-Cell-Autonomous Regulation of a Feeding State-Dependent Chemoreceptor Gene via MEF-2 and bHLH Transcription Factors. AB - Food and feeding-state dependent changes in chemoreceptor gene expression may allow Caenorhabditis elegans to modify their chemosensory behavior, but the mechanisms essential for these expression changes remain poorly characterized. We had previously shown that expression of a feeding state-dependent chemoreceptor gene, srh-234, in the ADL sensory neuron of C. elegans is regulated via the MEF-2 transcription factor. Here, we show that MEF-2 acts together with basic helix loop-helix (bHLH) transcription factors to regulate srh-234 expression as a function of feeding state. We identify a cis-regulatory MEF2 binding site that is necessary and sufficient for the starvation-induced down regulation of srh-234 expression, while an E-box site known to bind bHLH factors is required to drive srh-234 expression in ADL. We show that HLH-2 (E/Daughterless), HLH-3 and HLH-4 (Achaete-scute homologs) act in ADL neurons to regulate srh-234 expression. We further demonstrate that the expression levels of srh-234 in ADL neurons are regulated remotely by MXL-3 (Max-like 3 homolog) and HLH-30 (TFEB ortholog) acting in the intestine, which is dependent on insulin signaling functioning specifically in ADL neurons. We also show that this intestine-to-neuron feeding state regulation of srh-234 involves a subset of insulin-like peptides. These results combined suggest that chemoreceptor gene expression is regulated by both cell-autonomous and non-cell-autonomous transcriptional mechanisms mediated by MEF2 and bHLH factors, which may allow animals to fine-tune their chemosensory responses in response to changes in their feeding state. PMID- 27487367 TI - Expert consensus on the use of liraglutide in the treatment of diabetes in internal medicine. AB - BACKGROUND: Type 2 diabetes mellitus (DM2) is a disease of epidemic proportions. In the adult Spanish population, prevalence of DM2 is nearly 14%, which makes its monitoring and treatment imperative. Liraglutide has achieved relevance due to its efficacy and safety in DM treatment. The aim of this study is to gather expert opinion on diabetes to assess the current role of liraglutide in DM2. MATERIALS/METHODS: The survey was performed by 57 internal medicine specialists using the Delphi method. The questionnaire had 56 items regarding liraglutide in DM treatment. RESULTS: Consensus was reached in 71.4% of items. Panelists stated agreement regarding liraglutide suitability in the treatment of patients with DM2, high cardiovascular risk, and with pathologies related to obesity, highlighting its role in weight loss, low risk of hypoglycemia, and improvement of vascular risks. Moreover, consensus was not reached regarding the suitability of liraglutide in patients with special situations, mainly due to minimal experience caused by the small number of patients. CONCLUSIONS: Due to its safety and hypoglycemic efficacy, liraglutide is an excellent choice for DM treatment in combination with other drugs. Its effects on the reduction of weight and other cardiovascular risk factors, make it an optimal treatment, especially in overweight or obese patients. PMID- 27487368 TI - Persistence with antipsychotics in dementia patients in Germany?. AB - BACKGROUND/AIMS: To analyze the duration of treatment with antipsychotics in German dementia patients. METHODS: This study included patients aged 60 years and over with dementia who received a first-time antipsychotic prescription by psychiatrists between 2009 and 2013. The main outcome measure was the treatment rate for more than 6 months following the index date. RESULTS: A total of 12,979 patients with dementia (mean age 82 years, 52.1% living in nursing homes) were included. After 2 years of follow-up, 54.8%, 57.2%, 61.1%, and 65.4% of patients aged 60 - 69, 70 - 79, 80 - 89, and 90 - 99 years, respectively, received antipsychotic prescriptions. 63.9% of subjects living in nursing homes and 55.0% of subjects living at home also continued their treatment (p-value < 0.001). CONCLUSION: The percentage of dementia patients treated with antipsychotics is very high.?. PMID- 27487369 TI - Neurodegeneration with brain iron accumulation. PMID- 27487370 TI - Postural instability and falls are more frequent in Parkinson's disease patients with worse trunk mobility. AB - OBJECTIVE: Correlate the occurrence of falls and the activity of rolling over in bed with performance on the Trunk Mobility Scale (TMS) in patients with PD, and determine whether this instrument score can predict the risk of falls. METHOD: This is a cross-sectional study. Assessed patients reported the frequency of falls in the previous year and whether they had difficulties rolling over in bed. Then, the following scales were applied: TMS, Hoehn and Yahr, Unified Parkinson's Disease Rating Scale-III and Schwab and England Activities of Daily Living. RESULTS: Eighty-five patients were analyzed. Patients with a history of falling showed worse performance in the TMS (p < 0.01). There is a significant correlation between TMS and the activity of rolling over in bed (p < 0.01). CONCLUSION: PD fallers present worse scores in TMS, and there is a significant correlation between difficulty rolling over in bed and TMS score. PMID- 27487371 TI - Household task demands for quiet and focused behavior facilitate performance by ADHD youth. AB - This study evaluated the associations among symptoms of attention deficit/hyperactivity disorder (ADHD) and of oppositional defiant disorder (ODD) in children and adolescents' performance in household tasks and assistance provided by caregivers. Parents of children from 6 to 14 years old with ADHD (n = 67) were interviewed with the Children Helping Out: Responsibilities, Expectations, and Supports (CHORES) instrument. Significant correlations were found between symptoms of ODD and assistance in self-care tasks (r = -0.31; p = 0.01); symptoms of hyperactivity correlated with assistance in self-care (r = 0.30, p = 0.01); and family-care (r = -0.25, p = 0.04) tasks. Age was directly associated with the number of tasks performed by children and inversely related to the assistance provided by caregivers. A greater number of ODD symptoms resulted in more household assistance from caregivers. Characteristics of ODD symptoms, such as disobedience and hostility in the face of authority, may limit these children in accessing household tasks by their own initiative, requiring assistance from caregivers. PMID- 27487372 TI - Relationship between muscle strength and motor function in Duchenne muscular dystrophy. AB - OBJECTIVE: To investigate the relationship between muscle strength and motor function and between these variables and age. METHOD: Muscle strength was measured by Medical Research Council (MRC) scale and motor function, by Motor Function Measure (MFM), in 40 non-ambulatory patients. Spearman tests investigated the relationships between muscle strength, motor function and age. RESULTS: Total MRC and MFM scores were strongly related to each other (r = 0.94; p < 0.001), but not to age (r = -0.19, r = -0.31, respectively; p > 0.05). Strong and moderate relationships between partial muscle strength and motor function scores were found. Higher correlation coefficients were found between total scores and Dimensions 2 (axial/ proximal control) and 3 (distal control) of MFM. CONCLUSION: Muscle strength and motor function are strongly correlated and seem to decrease proportionally in DMD. PMID- 27487373 TI - Clinical electroencephalogram (EEG) evaluation is improved by the amplitude asymmetry index. AB - OBJECTIVE: Better definition of normal amplitude asymmetry values on the classical EEG frequency bands. RESULTS: EEG amplitude asymmetry index (AAI) is physiologically low in normal adults, differences usually lesser than 7%. CONCLUSION: Persistent or intermittent amplitude asymmetry regional differences higher than 7% may be suggestive of pathology after adequate correlation with clinical data and EEG classical visual analysis. PMID- 27487374 TI - Prolactinomas may have unusual presentations resulting from massive extrasellar tumor extension. AB - The purpose of this case series is to report eight patients with giant prolactinomas emphasizing presentations and a treatment complication. The study group included six men and two women. The median age was 29 years (18-54 years); median serum prolactin level was 4,562 ng/ml (1,543-18,690 ng/ml); three patients (37.5%) had panhypopituitarism; median tumor diameter was 50 mm (41-60 mm). Five patients (62.5%) had visual field defects and three had improvement during treatment; six patients (75%) reached prolactin normalization, with a median time of 10.5 months (7-84 months) and median dose of 2.0 mg/week (1.0 to 3.0 mg/week). One patient presented as a true incidentaloma. One patient presented a cerebrospinal fluid leakage during medical treatment and refused surgery, however this resolved with conservative measures. This case series illustrate a rare subtype of macroprolactinomas, the importance of considering unusual presentations at the diagnosis, the effectiveness of pharmacological treatment and its possible complications. PMID- 27487375 TI - Assessment of impairment in activities of daily living in mild cognitive impairment using an individualized scale. AB - Mild impairment in activities of daily living (ADL) can occur in Mild Cognitive Impairment (MCI), but the nature and extent of these difficulties need to be further explored. The Canadian occupational performance measure (COPM) is one of the few individualized scales designed to identify self-perceived difficulties in ADL. The present study investigated impairments in ADL using the COPM in elderly with MCI. A total of 58 MCI patients were submitted to the COPM for studies of its validity and reliability. The COPM proved a valid and consistent instrument for evaluating ADL in elderly MCI patients. A total of 74.6% of the MCI patients reported difficulties in ADL. Of these problems, 41.2% involved self-care, 31.4% productivity and 27.4% leisure. This data further corroborates recent reports of possible functional impairment in complex ADL in MCI. PMID- 27487377 TI - Sudden cardiac death in epilepsy disappoints, but epileptologists keep faith. AB - Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death in people with intractable epilepsy. Probably, optimization of seizure control will prevent some of these deaths. Briefly, we integrated in this paper some data about the epidemiology, risk factors, etiology, and preventative measures in the management of SUDEP. PMID- 27487376 TI - Translation and cross cultural adaptation of the Pediatric Motor Activity Log Revised scale. AB - OBJECTIVES: To translate PMAL-R and adapt for the Brazilian culture; analyze the reliability and the internal consistency of the Brazilian version. METHOD: Translation of PMAL-R to the Portuguese-Brazil and back translation. The back translated version was revised by the authors of the scale. The final version was administered to a sample of 24 patients with spastic hemiparesis CP between 2-8 years. RESULTS: The reliability intra and inter-rater were suitable (how often = 0.97 and 0.98, how well = 0.98 and 0.99 respectively) and so the internal consistency (0.98). CONCLUSION: The Brazilian version of PMAL-R has adequate internal consistency, reliability intra and inter raters and can be used to assess the spontaneous use of the upper limb of children with CP type spastic hemiparesis, aged 2-8 years. PMID- 27487378 TI - Currents issues in cardiorespiratory care of patients with post-polio syndrome. AB - METHOD: A search for papers was made in the databases Bireme, Scielo and Pubmed with the following keywords: post polio syndrome, cardiorespiratory and rehabilitation in English, French and Spanish languages. Although we targeted only seek current studies on the topic in question, only the relevant (double blind, randomized-controlled and consensus articles) were considered. RESULTS AND DISCUSSION: Certain features of PPS such as generalized fatigue, generalized and specific muscle weakness, joint and/or muscle pain may result in physical inactivity deconditioning obesity and dyslipidemia. Respiratory difficulties are common and may result in hypoxemia. CONCLUSION: Only when evaluated and treated promptly, somE patients can obtain the full benefits of the use of respiratory muscles aids as far as quality of life is concerned. PMID- 27487379 TI - Endoscopic endonasal management of cerebrospinal fluid rhinorrhea after anterior clinoidectomy for aneurysm surgery: changing the paradigm of complication management. AB - Resection of the anterior clinoid process results in the creation of the clinoid space, an important surgical step in the exposure and clipping of clinoidal and supraclinoidal internal carotid artery aneurysms. Cerebrospinal fluid rhinorrhea is an undesired and potentially serious complication. Conservative measures may be unsuccesful, and there is no consensus on the most appropriate surgical treatment. Two patients with persistent transclinoidal CSF rhinorrhea after aneurysm surgery were successfully treated with a combined endoscopic transnasal/transeptal binostril approach using a fat graft and ipsilateral mucosal nasal septal flap. Anatomical considerations and details of the surgical technique employed are discussed, and a management plan is proposed. PMID- 27487380 TI - A diagnostic approach for neurodegeneration with brain iron accumulation: clinical features, genetics and brain imaging. AB - Neurodegeneration with brain iron accumulation (NBIA) represents a heterogeneous and complex group of inherited neurodegenerative diseases, characterized by excessive iron accumulation, particularly in the basal ganglia. Common clinical features of NBIA include movement disorders, particularly parkinsonism and dystonia, cognitive dysfunction, pyramidal signs, and retinal abnormalities. The forms of NBIA described to date include pantothenase kinase-associated neurodegeneration (PKAN), phospholipase A2 associated neurodegeneration (PLAN), neuroferritinopathy, aceruloplasminemia, beta-propeller protein-associated neurodegeneration (BPAN), Kufor-Rakeb syndrome, mitochondrial membrane protein associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), coenzyme A synthase protein-associated neurodegeneration (CoPAN) and Woodhouse-Sakati syndrome. This review is a diagnostic approach for NBIA cases, from clinical features and brain imaging findings to the genetic etiology. PMID- 27487381 TI - Lumbago and alopecia in a patient with leukodystrophy: think on CARASIL. PMID- 27487382 TI - Electronically Pure Single-Chirality Semiconducting Single-Walled Carbon Nanotube for Large-Scale Electronic Devices. AB - Single-walled carbon nanotube (SWCNT) networks deposited from a purple single chirality (6,5) SWCNT aqueous solution were electrically characterized as pure semiconductors based on metal/semiconductor/metal Schottky contacts using both complex instruments and a portable device. Both air-stable PMOS (p-type metal oxide-semiconductor) and NMOS (n-type metal-oxide-semiconductor, resembling amorphous silicon) thin film transistors were fabricated on (6,5) SWCNT in large scale showing the characteristics of fA off current and ION/IOFF ratio of >1 * 10(8). CMOS (complementary metal-oxide-semiconductor) SWCNT inverter was demonstrated by wire-bonding PMOS (6,5) SWCNT TFT and NMOS (6,5) SWCNT TFT together to achieve the voltage gain as large as 52. PMID- 27487383 TI - HRMS in DMPK. PMID- 27487384 TI - HRMS or HRAMS? PMID- 27487385 TI - Unconjugated payload quantification and DAR characterization of antibody-drug conjugates using high-resolution MS. AB - AIM: The application of high-resolution MS to antibody-drug conjugate (ADC) drug development may provide insight into their safety and efficacy. Quantification of unconjugated cytotoxic drug (payload) and characterization of drug-to-antibody ratio distribution were determined in plasma using orthogonal acceleration quadrupole-time-of-flight MS. RESULTS: Unconjugated payload quantification determined by quadrupole-time-of-flight-based MRM(highresolution) and triple quadrupole-based multiple reaction monitoring were comparable and achieved detection limits of 0.030 and 0.015 ng/ml, respectively. As determined by immunocapture and TOF-MS, drug-to-antibody ratio remained unchanged up to 3-weeks postdose for an ADC containing engineered glutamine linkers, but declined from four to three over 2 weeks in an ADC containing engineered cysteine linkers. CONCLUSION: The use of high-resolution MS in ADC drug discovery confirms its utility within the bioanalytical discipline. PMID- 27487386 TI - A workflow for absolute quantitation of large therapeutic proteins in biological samples at intact level using LC-HRMS. AB - AIM: The commonly used LC-MS workflow to quantify protein therapeutics in biological samples is 'bottom-up' approach. In this study, the aim is to establish 'top-down' approach for absolute quantitation of therapeutic antibodies or proteins of similar sizes in biological samples at intact level. MATERIALS & METHODS: Using a recombinant human monoclonal antibody as the model molecule, we present a workflow to measure large therapeutic proteins in plasma at intact level based on deconvoluted high-resolution MS (HRMS) peaks. A novel MultiQuantTM software function was developed to automatically deconvolute the peaks and process the data. RESULTS & CONCLUSION: The workflow showed satisfying performance. This is a proof of concept study demonstrating the feasibility of bioanalysis of large therapeutic proteins at intact level using LC-HRMS. PMID- 27487387 TI - Recent developments in software tools for high-throughput in vitro ADME support with high-resolution MS. AB - The last several years have seen the rapid adoption of the high-resolution MS (HRMS) for bioanalytical support of high throughput in vitro ADME profiling. Many capable software tools have been developed and refined to process quantitative HRMS bioanalysis data for ADME samples with excellent performance. Additionally, new software applications specifically designed for quan/qual soft spot identification workflows using HRMS have greatly enhanced the quality and efficiency of the structure elucidation process for high throughput metabolite ID in early in vitro ADME profiling. Finally, novel approaches in data acquisition and compression, as well as tools for transferring, archiving and retrieving HRMS data, are being continuously refined to tackle the issue of large data file size typical for HRMS analyses. PMID- 27487388 TI - Structure-function analyses of microsomal triglyceride transfer protein missense mutations in abetalipoproteinemia and hypobetalipoproteinemia subjects. AB - We describe two new hypolipidemic patients with very low plasma triglyceride and apolipoprotein B (apoB) levels with plasma lipid profiles similar to abetalipoproteinemia (ABL) patients. In these patients, we identified two previously uncharacterized missense mutations in the microsomal triglyceride transfer protein (MTP) gene, R46G and D361Y, and studied their functional effects. We also characterized three missense mutations (H297Q, D384A, and G661A) reported earlier in a familial hypobetalipoproteinemia patient. R46G had no effect on MTP expression or function and supported apoB secretion. H297Q, D384A, and G661A mutants also supported apoB secretion similarly to WT MTP. Contrary to these four missense mutations, D361Y was unable to support apoB secretion. Functional analysis revealed that this mutant was unable to bind protein disulfide isomerase (PDI) or transfer lipids. The negative charge at residue 361 was critical for MTP function as D361E was able to support apoB secretion and transfer lipids. D361Y most likely disrupts the tightly packed middle alpha helical region of MTP, mitigates PDI binding, abolishes lipid transfer activity, and causes ABL. On the other hand, the hypolipidemia in the other two patients was not due to MTP dysfunction. Thus, in this study of five missense mutations spread throughout MTP's three structural domains found in three hypolipidemic patients, we found that four of the mutations did not affect MTP function. Thus, novel mutations that cause severe hypolipidemia probably exist in other genes in these patients, and their recognition may identify novel proteins involved in the synthesis and/or catabolism of plasma lipoproteins. PMID- 27487389 TI - Women's knowledge and use of prenatal screening tests. AB - AIMS AND OBJECTIVES: The aim of the study was to determine the rate of use of prenatal screening tests and the factors affecting the decision to have a prenatal screening test in pregnant women in Turkey. BACKGROUND: Prenatal genetic screening as an optional service is commonly used to determine a level of risk for genetic conditions in the foetus. DESIGN: A quantitative cross-sectional survey. METHODS: Pregnant women (n = 274) who sought prenatal care from one hospital in Turkey were recruited and asked to complete questionnaires that were developed by the researchers. Descriptive and inferential statistics were used to analyse the data. RESULTS: Almost half (44.2) % of the women were primiparas, and the majority (97.8%) were in the third trimester of pregnancy. Only 36.1% of the women reported that they had prenatal screening by either the double test or triple test. Women had a low level of knowledge regarding prenatal screening: the mean knowledge score was 3.43 +/- 3.21 of a possible score of 10. Having consanguineous marriage, a history of spontaneous abortion, a child with genetic disorder, multiparity or a longer marriage duration were positively correlated with accepting a prenatal screening test. CONCLUSIONS: This study has provided baseline data on the uptake and reasons for accepting or declining a prenatal screening in a cohort of Turkish women. There is evidence to suggest that more education is needed to improve knowledge and provide comprehensive nursing care to promote informed consent in this context. RELEVANCE TO CLINICAL PRACTICE: Perinatal nurses are ideally situated to inform pregnant women about prenatal screening tests to improve access to healthcare services and to ensure informed decisions are made by pregnant women and their partners. PMID- 27487391 TI - Multimodal Spectroscopic Study of Amyloid Fibril Polymorphism. AB - Amyloid fibrils are a large class of self-assembled protein aggregates that are formed from unstructured peptides and unfolded proteins. The fibrils are characterized by a universal beta-sheet core stabilized by hydrogen bonds, but the molecular structure of the peptide subunits exposed on the fibril surface is variable. Here we show that multimodal spectroscopy using a range of bulk- and surface-sensitive techniques provides a powerful way to dissect variations in the molecular structure of polymorphic amyloid fibrils. As a model system, we use fibrils formed by the milk protein beta-lactoglobulin, whose morphology can be tuned by varying the protein concentration during formation. We investigate the differences in the molecular structure and composition between long, straight fibrils versus short, wormlike fibrils. We show using mass spectrometry that the peptide composition of the two fibril types is similar. The overall molecular structure of the fibrils probed with various bulk-sensitive spectroscopic techniques shows a dominant contribution of the beta-sheet core but no difference in structure between straight and wormlike fibrils. However, when probing specifically the surface of the fibrils with nanometer resolution using tip enhanced Raman spectroscopy (TERS), we find that both fibril types exhibit a heterogeneous surface structure with mainly unordered or alpha-helical structures and that the surface of long, straight fibrils contains markedly more beta-sheet structure than the surface of short, wormlike fibrils. This finding is consistent with previous surface-specific vibrational sum-frequency generation (VSFG) spectroscopic results ( VandenAkker et al. J. Am. Chem. Soc. , 2011 , 133 , 18030 - 18033 , DOI: 10.1021/ja206513r ). In conclusion, only advanced vibrational spectroscopic techniques sensitive to surface structure such as TERS and VSFG are able to reveal the difference in structure that underlies the distinct morphology and rigidity of different amyloid fibril polymorphs that have been observed for a large range of food and disease-related proteins. PMID- 27487392 TI - More end resection is not merrier. PMID- 27487390 TI - TBC1D20 mediates autophagy as a key regulator of autophagosome maturation. AB - In humans, loss of TBC1D20 (TBC1 domain family, member 20) protein function causes Warburg Micro syndrome 4 (WARBM4), an autosomal recessive disorder characterized by congenital eye, brain, and genital abnormalities. TBC1D20 deficient mice exhibit ocular abnormalities and male infertility. TBC1D20 is a ubiquitously expressed member of the family of GTPase-activating proteins (GAPs) that increase the intrinsically slow GTP-hydrolysis rate of small RAB-GTPases when bound to GTP. Biochemical studies have established TBC1D20 as a GAP for RAB1B and RAB2A. However, the cellular role of TBC1D20 still remains elusive, and there is little information about how the functional loss of TBC1D20 causes clinical manifestations in WARBM4-affected children. Here we evaluate the role of TBC1D20 in cells carrying a null mutant allele, as well as TBC1D20-deficient mice, which display eye and testicular abnormalities. We demonstrate that TBC1D20, via its RAB1B GAP function, is a key regulator of autophagosome maturation, a process required for maintenance of autophagic flux and degradation of autophagic cargo. Our results provide evidence that TBC1D20-mediated autophagosome maturation maintains lens transparency by mediating the removal of damaged proteins and organelles from lens fiber cells. Additionally, our results show that in the testes TBC1D20-mediated maturation of autophagosomes is required for autophagic flux, but is also required for the formation of acrosomes. Furthermore TBC1D20-deficient mice, while not mimicking severe developmental brain abnormalities identified in WARBM4 affected children, display disrupted neuronal autophagic flux resulting in adult-onset motor dysfunction. In summary, we show that TBC1D20 has an essential role in the maturation of autophagosomes and a defect in TBC1D20 function results in eye, testicular, and neuronal abnormalities in mice implicating disrupted autophagy as a mechanism that contributes to WARBM4 pathogenesis. PMID- 27487393 TI - A route to new cancer therapies: the FA pathway is essential in BRCA1- or BRCA2 deficient cells. PMID- 27487394 TI - Catch me if you can: trapping scanning ribosomes in their footsteps. PMID- 27487395 TI - Thermal Expansion Anomaly in TTB Ferroelectrics: The Interplay between Framework Structure and Electric Polarization. AB - Tetragonal tungsten bronze (TTB) makes up a large family of functional materials with fascinating dielectric, piezoelectric, or ferroelectric properties. Understanding the thermal expansion mechanisms associated with their physical properties is important for their practical applications as well as theoretical investigations. Fortunately, the appearance of anomalous thermal expansion in functional materials offers a chance to capture the physics behind them. Herein, we report an investigation of the thermal expansion anomalies in TTBs that are related to ferroelectric transitions and summarize recent progress in this field. The special role of Pb(2+) cation is elucidated. The interplay between the thermal expansion anomaly, electric polarization, and framework structure provides new insight into the structure-property relationships in functional materials. PMID- 27487396 TI - Sperm chromatin maturity and integrity correlated to zygote development in ICSI program. AB - This study aimed to evaluate sperm chromatin maturity and integrity of that injected into good-quality oocytes in an in vitro fertilization-intra cytoplasmic sperm injection (IVF-ICSI) program. A cut-off value of sperm chromatin maturity and integrity was developed as a function of their correlation to the zygote development, i.e., embryo formation and cleavage rate. The study assessed sperm chromatin maturity using aniline blue (AB) staining, whereas toluidine blue (TB) staining was used to assess sperm chromatin integrity. Ejaculates from 59 patients undergoing ICSI and 46 fertile normozoospermic donors for determination of normal values of sperm chromatin status were used in this study. Embryo formation and cleavage rates were observed for the period of 3 days after ICSI. There was a significant difference in the percentage of sperm with mature chromatin between ejaculate from ICSI patients and fertile donor (p=0.020); while there was no significant difference in sperm chromatin integrity of both samples (p=0.120). There was no significant correlation between sperm chromatin maturity and either embryo formation or cleavage rate; as well as sperm chromatin integrity to both parameters of zygote development (p>0.05). Furthermore, we found that the cut-off value of sperm chromatin maturity and integrity of the fertile normozoospermic ejaculates were 87.2% and 80.2%, respectively. Using the cut-offs, we found that low sperm chromatin maturity at the level of <87% correlated significantly with the cleavage rate of the zygote (p=0.022; r=0.371); whereas poor sperm chromatin integrity at the level of <80% correlated with embryo formation (p=0.048; r=0,485). In conclusion, this study showed that poor maturity and integrity of sperm chromatin (AB<87% and TB<80%, respectively), could affect zygote development following ICSI. ABBREVIATIONS: AB: aniline blue; CMA3: chromomycin A3; ICSI: intra cytoplasmic sperm injection; IVF: in vitro fertilization; PBS: phosphate buffer saline; SPSS: Statistical Package for Social Science; TB: toluidine blue; WHO: World Health Organization. PMID- 27487397 TI - Fecal Fermentation in Irritable Bowel Syndrome: Influence of Dietary Restriction of Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols. AB - BACKGROUND/AIMS: Dietary restriction of fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) may relieve symptoms in patients with irritable bowel syndrome (IBS). We investigated whether this diet alters microbial fermentation, a process that may be involved in IBS symptom generation. METHODS: Patients with IBS were included consecutively to participate in a 4-week FODMAP restricted diet. IBS symptoms were evaluated by using the IBS severity scoring system (IBS-SSS). Short-chain fatty acids (SCFAs) were analyzed in fecal samples before and after the dietary intervention, both at baseline and after in vitro fermentation for 24 h. RESULTS: Sixty-three patients completed the study. Following the dietary intervention, IBS-SSS scores improved significantly (p < 0.0001). Total SCFA levels were reduced in fecal samples analyzed both at baseline (p = 0.005) and after in vitro fermentation for 24 h (p = 0.013). Following diet, baseline levels of acetic (p = 0.003) and n-butyric acids (p = 0.009) decreased, whereas 24 h levels of i-butyric (p = 0.003) and i-valeric acids (p = 0.003) increased. Fecal SCFA levels and IBS symptom scores were not correlated. CONCLUSION: Dietary FODMAP restriction markedly modulated fecal fermentation in patients with IBS. Saccharolytic fermentation decreased, while proteolytic fermentation increased, apparently independent of symptoms. PMID- 27487398 TI - Leptospira Seroprevalence and Risk Factors in Health Centre Patients in Hoima District, Western Uganda. AB - BACKGROUND: The burden of human leptospirosis in Uganda is unknown. We estimated the seroprevalence of Leptospira antibodies, probable acute/recent leptospirosis, and risk factors for seropositivity in humans in rural Western Uganda. METHODOLOGY AND PRINCIPAL FINDINGS: 359 non-pregnant adults visiting the Kikuube and Kigorobya Health Centers were sequentially recruited during March and April 2014. A health history survey and serum were collected from consented participants. Overall, 69% reported having fever in the past year, with 49% reporting malaria, 14% malaria relapse, 6% typhoid fever, 3% brucellosis, and 0% leptospirosis. We tested sera by microscopic agglutination test (MAT) against eight Leptospira serovars representing seven serogroups. Leptospira seroprevalence was 35% (126/359; 95%CI 30.2-40.3%) defined as MAT titer >= 1:100 for any serovar. The highest prevalence was against L. borgpetersenii Nigeria (serogroup Pyrogenes) at 19.8% (71/359; 95%CI 15.9-24.4%). The prevalence of probable recent leptospirosis (MAT titer >=1:800) was 1.9% (95%CI 0.9-4.2%) and uniquely related to serovar Nigeria (serogroup Pyrogenes). Probable recent leptospirosis was associated with having self-reported malaria within the past year (p = 0.048). Higher risk activities included skinning cattle (n = 6) with 12.3 higher odds (95%CI 1.4-108.6; p = 0.024) of Leptospira seropositivity compared with those who had not. Participants living in close proximity to monkeys (n = 229) had 1.92 higher odds (95%CI 1.2-3.1; p = 0.009) of seropositivity compared with participants without monkeys nearby. CONCLUSIONS/SIGNIFICANCE: The 35% prevalence of Leptospira antibodies suggests that exposure to leptospirosis is common in rural Uganda, in particular the Nigeria serovar (Pyrogenes serogroup). Leptospirosis should be a diagnostic consideration in febrile illness and "smear-negative malaria" in rural East Africa. PMID- 27487399 TI - Epidural spinal cavernous hemangioma and hybrid vascular subtype. AB - AIM: To demonstrate less common pathologies of purely epidural spinal tumors that should be considered when noted on MRI prior to surgery. To expand the differential diagnosis of purely epidural spinal tumors and comment on their surgical implications. MATERIAL AND METHODS: We report on two patients from our institution with rare pathology. We also utilized PubMed to concisely review the literature concerning purely epidural vascular lesions akin to the cavernous hemangioma. RESULTS: We describe common clinical presentations, radiographic findings, histopathologic characteristics and treatment algorithms relevant to the rare pure spinal epidural cavernous hemangioma and a newly described compound hemangioma subtype. CONCLUSION: Epidural spinal tumors are relatively common entities, though lesions isolated to the epidural space without origination in the vertebral body or as part of neurologic presentation of metastatic disease, are much less common. Less common pathologies may be missed in the initial differential diagnosis with treatment implications at surgery. PMID- 27487400 TI - The adaptor protein p40phox as a positive regulator of the superoxide-producing phagocyte oxidase. PMID- 27487401 TI - Association of Lipid Fractions With Risks for Coronary Artery Disease and Diabetes. AB - IMPORTANCE: Low-density lipoprotein cholesterol (LDL-C) is causally related to coronary artery disease (CAD), but the relevance of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) is uncertain. Lowering of LDL-C levels by statin therapy modestly increases the risk of type 2 diabetes, but it is unknown whether this effect is specific to statins. OBJECTIVE: To investigate the associations of 3 routinely measured lipid fractions with CAD and diabetes through mendelian randomization (MR) using conventional MR and making use of newer approaches, such as multivariate MR and MR-Egger, that address the pleiotropy of genetic instruments where relevant. DESIGN, SETTING, AND PARTICIPANTS: Published data from genome-wide association studies were used to construct genetic instruments and then applied to investigate associations between lipid fractions and the risk of CAD and diabetes using MR approaches that took into account pleiotropy of genetic instruments. The study was conducted from March 12 to December 31, 2015. MAIN OUTCOMES AND MEASURES: Coronary artery disease and diabetes. RESULTS: Genetic instruments composed of 130 single nucleotide polymorphisms (SNPs) were used for LDL-C (explaining 7.9% of its variance), 140 SNPs for HDL-C (6.6% of variance), and 140 SNPs for TGs (5.9% of variance). A 1-SD genetically instrumented elevation in LDL-C levels (equivalent to 38 mg/dL) and TG levels (equivalent to 89 mg/dL) was associated with higher CAD risk; odds ratios (ORs) were 1.68 (95% CI, 1.51-1.87) for LDL-C and 1.28 (95% CI, 1.13-1.45) for TGs. The corresponding OR for HDL-C (equivalent to a 16-mg/dL increase) was 0.95 (95% CI, 0.85-1.06). All 3 lipid traits were associated with a lower risk of type 2 diabetes. The ORs were 0.79 (95% CI, 0.71-0.88) for LDL-C and 0.83 (95% CI, 0.76-0.90) for HDL-C per 1-SD elevation. For TG, the MR estimates for diabetes were inconsistent, with MR-Egger giving an OR of 0.83 (95%CI, 0.72-0.95) per 1-SD elevation. CONCLUSIONS AND RELEVANCE: Routinely measured lipid fractions exhibit contrasting associations with the risk of CAD and diabetes. Increased LDL-C, HDL-C, and possibly TG levels are associated with a lower risk of diabetes. This information will be relevant to the design of clinical trials of lipid-modifying agents, which should carefully monitor participants for dysglycemia and the incidence of diabetes. PMID- 27487402 TI - Alkylation of Sulfonamides with Trichloroacetimidates under Thermal Conditions. AB - An intermolecular alkylation of sulfonamides with trichloroacetimidates is reported. This transformation does not require an exogenous acid, base, or transition metal catalyst; instead the addition occurs in refluxing toluene without additives. The sulfonamide alkylation partner appears to be only limited by sterics, with unsubstituted sulfonamides providing better yields than more encumbered N-alkyl sulfonamides. The trichloroacetimidate alkylating agent must be a stable cation precursor for the substitution reaction to proceed under these conditions. PMID- 27487403 TI - Charge Transfer States in Dilute Donor-Acceptor Blend Organic Heterojunctions. AB - We study the charge transfer (CT) states in small-molecule blend heterojunctions comprising the nonpolar donor, tetraphenyldibenzoperiflanthene (DBP), and the acceptor, C70, using electroluminescence and steady-state and time-resolved photoluminescence spectroscopy along with density functional theory calculations. We find that the CT exciton energy blue shifts as the C70 concentration in the blend is either decreased or increased away from 50 vol %. At 20 K, the increase in CT state lifetime is correlated with the increasing diameter of C70 nanocrystallites in the blends. A quantum confinement model is used to quantitatively describe the dependence of both CT energy and lifetime on the C70 or DBP domain size. Two discrete CT emission peaks are observed for blends whose C70 concentration is >65%, at which point C70 nanocrystallites with diameters >4 nm appear in high-resolution transmission electron micrographs. The presence of two CT states is attributed to coexistence of crystalline C70 and amorphous phases in the blends. Furthermore, analysis of CT dissociation efficiency versus photon energy suggests that the >90% dissociation efficiency of delocalized CT2 states from the crystalline phase significantly contributes to surprisingly efficient photogeneration in highly dilute (>80% C70) DBP/C70 heterojunctions. PMID- 27487404 TI - An Electrocardiogram-Based Risk Equation for Incident Cardiovascular Disease From the National Health and Nutrition Examination Survey. AB - Importance: Electrocardiography (ECG) may detect subclinical cardiovascular disease (CVD) in asymptomatic individuals, but its role in assessing adverse events beyond traditional risk factors is not clear. Interval and vector data that are commonly available on modern ECGs may offer independent prognostic information that improves risk classification. Objectives: To derive and validate a CVD risk equation based on ECG metrics and to determine its incremental benefit in addition to the Framingham risk score (FRS). Design, Setting, and Participants: This study included 3640 randomly selected community-based adults aged 40 to 74 years without known CVD from the First National Health and Nutrition Examination Survey (NHANES I) cohort (1971-1975) and 6329 from the NHANES III cohort (1988-1994). Participants were sampled from across the United States. A risk score to assess incident nonfatal and fatal CVD events was derived based on computer-generated ECG data, including frontal P, R, and T axes; heart rate; and PR, QRS, and QT intervals from NHANES I. The most prognostic variables, along with age and sex, were incorporated into the NHANES ECG risk equation. The equation was evaluated in the NHANES III cohort for an independent validation. Follow-up in the NHANES III cohort was completed on December 31, 2006. Data for this study were analyzed from August 11, 2015, to May 20, 2016. Main Outcomes and Measures: The primary end point was CVD death. Secondary outcomes included 10 year ischemic heart disease and all-cause death. Results: The final study sample included 9969 participants (4714 men [47.3%]; 5255 women [52.7%]; mean [SD] age, 55.3 [10.1] years) from both cohorts. Frontal T axis, heart rate, and heart rate corrected QT interval were the most significant ECG factors in the NHANES I cohort. In the validation cohort (NHANES III), the equation provided for prognostic information for fatal CVD with a hazard ratio (HR) of 3.23 (95% CI, 2.82-3.72); the C statistic was 0.79 (95% CI, 0.76-0.81). When added to the FRS in Cox proportional hazards regression models, the categorical (1%, 5%, and 10% cutoffs) net reclassification improvement was 24%. When the FRS and ECG scores were combined in a single model, the C statistic improved by 0.04 (95% CI, 0.02 0.06) to 0.80 (95% CI, 0.77-0.82). Similar improvements were noted when the ECG score was added to the pooled cohort equation. When the equation for prognostic information about ischemic heart disease and all-cause death was evaluated, the results were similar. Conclusions and Relevance: An ECG risk score based on age, sex, heart rate, frontal T axis, and QT interval assesses the risk for CVD and compares favorably with the FRS alone in an independent cohort of asymptomatic individuals. Although the ECG risk equation is low cost, further research is needed to ascertain whether this additional step in risk stratification may improve prevention efforts and reduce CVD events. PMID- 27487405 TI - Antenatal corticosteroid treatment: factors other than lung maturation. AB - Antenatal corticosteroid (CS) therapy improves both fetal lung mechanism and gas exchange due to accelerated morphologic development of type one and two pneumocytes. This therapy also enhances the production of surfactant binding proteins and fetal lung antioxidant enzymes. In women with threatening preterm delivery, a single course is advocated between 24 and 34 weeks' gestation with either betamethasone (two doses of 12 mg 24 h apart) or dexamethasone (four doses of 6 mg at 12-h intervals). Such treatment reduces the rate of respiratory distress syndrome, comorbidity, and mortality in neonates in the first 48 h of life. The optimal time interval between CS administration and delivery is reported to be 1-7 days. Weekly repeat courses reduce the occurrences and severity of respiratory diseases but are associated with reduce fetal growth. Multiple courses should be avoided. However, a repeat course should be considered in women at risk of preterm birth 7 or more days after an initial course in women who remain at risk of preterm birth <34 weeks' gestation. CS may be harmful in growth restricted fetuses associated with an absent or reversed end-diastolic UA flow since they are at increased risk of acidosis and perinatal death. The purpose of this publication is to update and highlight antenatal CS therapy. PMID- 27487406 TI - The Effects of Oscillatory Biofield Therapy on Pain and Functional Limitations Associated with Carpal Tunnel Syndrome: Randomized, Placebo-Controlled, Double Blind Study. AB - OBJECTIVES: Biofield treatments have been used for pain control in patients with cancer and chronic pain. However, research on the effect of biofield treatment on specific somatic disorders is lacking. This study intends to investigate the effect of oscillating biofield therapy (OBFT) on symptoms of carpal tunnel syndrome. DESIGN: Randomized, placebo-controlled, double-blind study. PARTICIPANTS: Thirty patients with chronic carpal tunnel syndrome participated in the study. INTERVENTION: Patients were randomly assigned to active or placebo treatment groups. Those in the treatment group received six sessions of OBFT with intention to treat during a period of 2 weeks. Patients in the placebo group had the same number of treatment sessions with mock OBFT treatment. OUTCOME MEASURE: The Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire; Symptom Severity Scale (SSS); and Functional Status Scale (FSS) were used for outcome assessment. RESULTS: Both clinically and statistically significant changes in intensity of pain with activity (95% confidence interval [CI], 2.5-4.2; p = 0.000), night pain (p = 0.000, 95% CI, 3.2-5.7), DASH questionnaire (95% CI, 12.0 21.9; p = 0.000), SSS (95% CI, 0.64-1.15; p = 0.003), and FSS (95% CI, 0.41-0.97; p = 0.029) were found between the treatment and placebo groups. Statistically significant reduction in number of patients with positive results on the Phalen test (87%; p = 0.000), Tinel sign (73%; p = 0.000), and hand paresthesia (80%; p = 0.000) was noted in the treatment group. During 6-month follow-up, 86% of patients in the treatment group remained pain free and had no functional limitations. CONCLUSION: OBFT can be a viable and effective treatment for improving symptoms and functional limitations associated with chronic carpal tunnel syndrome. PMID- 27487408 TI - Effects of Live and Educational Music Therapy on Working Alliance and Trust With Patients on Detoxification Unit: A Four-Group Cluster-Randomized Trial. AB - BACKGROUND: Lyric analysis is a commonly utilized music therapy intervention for clients in substance abuse rehabilitation wherein participants interpret song lyrics related to their clinical objectives. For these patients, working alliance and trust in the therapist represent consequential factors that may influence outcomes. However, there is a lack of randomized controlled music therapy studies investigating working alliance and trust in the therapist within lyric analysis interventions for patients with addictions. OBJECTIVE: The purpose of this study was to quantitatively differentiate live versus recorded and educational versus recreational music therapy interventions via measures of working alliance and trust with patients on a detoxification unit. METHOD: Participants (N = 130) were cluster randomized in a single-session posttest-only design to one of four conditions: Live educational music therapy, recorded educational music therapy, education without music, or recreational music therapy. Dependent measures included working alliance and trust in the therapist. Educational music therapy interventions were scripted lyric analyses. RESULTS: There was no statistically significant between-group difference in any of the measures. Although not significant, a greater number of patients and research participants attended live educational music therapy sessions. CONCLUSIONS: Between-group descriptive data were consistently similar but attendance trends may have implications for engaging patients and billing. Implications for clinical practice, limitations of the study, and suggestions for future research are provided. PMID- 27487407 TI - Metrics for the Human Proteome Project 2016: Progress on Identifying and Characterizing the Human Proteome, Including Post-Translational Modifications. AB - The HUPO Human Proteome Project (HPP) has two overall goals: (1) stepwise completion of the protein parts list-the draft human proteome including confidently identifying and characterizing at least one protein product from each protein-coding gene, with increasing emphasis on sequence variants, post translational modifications (PTMs), and splice isoforms of those proteins; and (2) making proteomics an integrated counterpart to genomics throughout the biomedical and life sciences community. PeptideAtlas and GPMDB reanalyze all major human mass spectrometry data sets available through ProteomeXchange with standardized protocols and stringent quality filters; neXtProt curates and integrates mass spectrometry and other findings to present the most up to date authorative compendium of the human proteome. The HPP Guidelines for Mass Spectrometry Data Interpretation version 2.1 were applied to manuscripts submitted for this 2016 C-HPP-led special issue [ www.thehpp.org/guidelines ]. The Human Proteome presented as neXtProt version 2016-02 has 16,518 confident protein identifications (Protein Existence [PE] Level 1), up from 13,664 at 2012 12, 15,646 at 2013-09, and 16,491 at 2014-10. There are 485 proteins that would have been PE1 under the Guidelines v1.0 from 2012 but now have insufficient evidence due to the agreed-upon more stringent Guidelines v2.0 to reduce false positives. neXtProt and PeptideAtlas now both require two non-nested, uniquely mapping (proteotypic) peptides of at least 9 aa in length. There are 2,949 missing proteins (PE2+3+4) as the baseline for submissions for this fourth annual C-HPP special issue of Journal of Proteome Research. PeptideAtlas has 14,629 canonical (plus 1187 uncertain and 1755 redundant) entries. GPMDB has 16,190 EC4 entries, and the Human Protein Atlas has 10,475 entries with supportive evidence. neXtProt, PeptideAtlas, and GPMDB are rich resources of information about post translational modifications (PTMs), single amino acid variants (SAAVSs), and splice isoforms. Meanwhile, the Biology- and Disease-driven (B/D)-HPP has created comprehensive SRM resources, generated popular protein lists to guide targeted proteomics assays for specific diseases, and launched an Early Career Researchers initiative. PMID- 27487409 TI - Toward Inexpensive Photocatalytic Hydrogen Evolution: A Nickel Sulfide Catalyst Supported on a High-Stability Metal-Organic Framework. AB - Few-atom clusters composed of nickel and sulfur have been successfully installed into the Zr(IV)-based metal-organic framework (MOF) NU-1000 via ALD-like chemistry (ALD = atomic layer deposition). X-ray photoelectron spectroscopy and Raman spectroscopy are used to determine that primarily Ni(2+) and S(2-) sites are deposited within the MOF. In a pH 7 buffered aqueous solution, the porous catalyst is able to produce H2 gas at a rate of 3.1 mmol g(-1) h(-1) upon UV irradiation, whereas no H2 is generated by irradiating bare NU-1000. Upon visible light irradiation, little H2 generation was observed; however, with the addition of an organic dye, rose bengal, NiS-AIM can catalyze the production of H2 at an enhanced rate of 4.8 mmol g(-1) h(-1). These results indicate that ALD in MOFs (AIM) can engender reactivity within high surface area supports for applications in the solar fuels field. PMID- 27487410 TI - Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5 phosphate Reductoisomerase with beta-Arylpropyl Analogues of Fosmidomycin. AB - Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the beta position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency. PMID- 27487411 TI - Spinal Cord Infarction in Clinical Neurology: A Review of Characteristics and Long-Term Prognosis in Comparison to Cerebral Infarction. AB - Spinal cord stroke is rare accounting for 0.3-1% of all strokes and is classified into upper (cervical) and lower (thoracolumbar) strokes. Patients present with severe deficits but later often show good functional improvement. On admission, younger age, male gender, hypertension, diabetes mellitus and elevated blood glucose indicate more severe spinal cord strokes. Treatment of these risk factors is essential in the acute phase. Biphasic spinal cord strokes are seen in one fifth of the patients. These present with acute or transient sensory spinal cord deficits often preceded by radiating pain between the shoulders, and should be considered and treated as imminent spinal cord strokes. Spinal cord infarction patients are younger and more often women compared to cerebral infarction patients. Traditional cerebrovascular risk factors are less relevant in spinal cord infarction. Spinal cord infarction patients are more likely to be discharged home and show better improvement after initial treatment compared to cerebral infarction patients. On long-term follow-up, spinal cord infarction patients have lower mortality and higher emotional well-being scores than cerebral infarction patients. Despite more chronic pain, the frequency of re-employment is higher among spinal cord infarction patients compared to cerebral infarction patients who are more often afflicted with cognitive function deficits. PMID- 27487412 TI - Strongly Coupled Nanotube Electromechanical Resonators. AB - Coupling an electromechanical resonator with carbon-nanotube quantum dots is a significant method to control both the electronic charge and the spin quantum states. By exploiting a novel microtransfer technique, we fabricate two separate strongly coupled and electrically tunable mechanical resonators for the first time. The frequency of the two resonators can be individually tuned by the bottom gates, and in each resonator, the electron transport through the quantum dot can be strongly affected by the phonon mode and vice versa. Furthermore, the conductance of either resonator can be nonlocally modulated by the other resonator through phonon-phonon interaction between the two resonators. Strong coupling is observed between the phonon modes of the two resonators, where the coupling strength larger than 200 kHz can be reached. This strongly coupled nanotube electromechanical resonator array provides an experimental platform for future studies of the coherent electron-phonon interaction, the phonon-mediated long-distance electron interaction, and entanglement state generation. PMID- 27487413 TI - Failure of Density Functional Dispersion Correction in Metallic Systems and Its Possible Solution Using a Modified Many-Body Dispersion Correction. AB - Previous density functional dispersion corrections to density functional theory lead to an unphysical description of metallic systems, as exemplified by alkali and alkaline earth compounds. We demonstrate that it is possible to remedy this limitation by including screening effects into the form of interacting smeared out dipoles in the many-body expansion of the interaction. Our new approach, called the coupled fluctuating smeared dipole model, describes equally well noncovalent systems, such as molecular pairs and crystals, and metallic systems. PMID- 27487414 TI - The role of Rho kinase (Rock) in re-epithelialization of adult zebrafish skin wounds. AB - Complete re-epithelialization of full-thickness skin wounds in adult mammals takes days to complete and relies on numerous signaling cues and multiple overlapping cellular processes that take place both within the epidermis itself and in other participating tissues. We have previously shown that re epithelialization of full-thickness skin wounds of adult zebrafish, however, is extremely rapid and largely independent of the other processes of wound healing allowing for the dissection of specific processes that occur in, or have a direct effect on, re-epithelializing keratinocytes. Recently, we have shown that, in addition to lamellipodial crawling at the leading edge, re-epithelialization of zebrafish partial- and full-thickness wounds requires long-range epithelial rearrangements including radial intercalations, flattening and directed elongation and that each of these processes involves Rho kinase (Rock) signaling. Our studies demonstrate how these coordinated signaling events allow for the rapid collective cell migration observed in adult zebrafish wound healing. Here we discuss the particular contribution of Rock to each of these processes. PMID- 27487415 TI - Rotavirus epidemiology and surveillance before vaccine introduction in Argentina, 2012-2014. AB - Group A Rotavirus has been widely described as one of the most important infantile diarrheal pathogens worldwide. In Argentina, it is responsible for over 200,000 acute diarrhea cases and from 30 to 50 deaths annually in children under 5 years. The aim of this study is to analyze frequency, seasonality, age group distribution, and circulating genotypes based on data notified in the 2012-2014 period and in turn to assess the pre-vaccine scenario, considering that rotavirus vaccine was introduced in 2015. Data were taken from the Viral Diarrhea Notification module of the Argentine SNVS-SIVILA surveillance tool. Analyses of circulating genotypes were performed on rotavirus-positive stool specimens by conventional binary characterization of the outermost capsid genes. Overall data showed rotavirus detection in about 25% of samples tested, and higher rates in children under 2 years old were observed. Rotavirus positive cases were distributed according to a typical winter seasonal pattern. A heterogeneous regional pattern of prevalence was also observed, with higher rates detected in the North region. Genotype co-circulation and annual fluctuation were observed. In general, G1P[8], G2P[4], G3P[8], and G12P[8] were the most frequently detected genotypes. This study represents the last survey taken of a population considered to be naive. J. Med. Virol. 89:423-428, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27487417 TI - Retraction. PMID- 27487416 TI - Behavioral consequences of exposure to a high fat diet during the post-weaning period in rats. AB - We explored the impact of exposure to an obesogenic diet (High Fat-High Sucrose; HFS) during the post-weaning period on sweet preference and behaviors linked to reward and anxiety. All rats were fed chow. In addition a HFS-transient group had access to this diet for 10days from post-natal (PN) day 22 and a HFS-continuous group continued access until adult. Behavioral tests were conducted immediately after PN 32 (adolescence) or after PN 60 (adult) and included: the condition place preference (CPP) test for chocolate, sugar and saccharin preference (anhedonia), the elevated plus maze (anxiety-like behavior) and the locomotor response to quinpirole in the open field. Behavior was unaltered in adult rats in the HFS-transient group, suggesting that a short exposure to this obesogenic food does not induce long-term effects in food preferences, reward perception and value of palatable food, anxiety or locomotor activity. Nevertheless, rats that continued to have access to HFS ate less chocolate during CPP training and consumed less saccharin and sucrose when tested in adolescence, effects that were attenuated when these rats became adult. Moreover, behavioral effects linked to transient HFS exposure in adolescence were not sustained if the rats did not remain on that diet until adult. Collectively our data demonstrate that exposure to fat and sucrose in adolescence can induce immediate reward hypofunction after only 10days on the diet. Moreover, this effect is attenuated when the diet is extended until the adult period, and completely reversed when the HFS diet is removed. PMID- 27487418 TI - Oxygen uptake, respiratory exchange ratio, or total distance: a comparison of methods to equalize exercise volume in Wistar rats. AB - This study compared strategies to equalize the volume of aerobic exercise performed with different intensities by Wistar rats, based on the distance covered during exercise bouts and energy expenditure (EE, isocaloric sessions) obtained from oxygen uptake (VO2) or respiratory exchange ratio (RER). Thirty three male rats (270.5+/-12.8 g) underwent maximal exercise tests to determine VO2 reserve (VO2R), being randomly assigned to three groups: moderate-intensity continuous exercise at speed corresponding to 50% VO2R (MIC; n=11); high intensity continuous exercise at 80% VO2R (HIC; n=11); and high-intensity intermittent exercise (HII; n=11) at 60% VO2R (3 min) and 80% VO2R (4 min). Exercise duration was calculated individually to elicit EE of 5 kcal in each session. No difference between groups was found for total running distance (MIC: 801+/-46, HIC: 734+/-42, HII: 885+/-64 m; P=0.13). Total EE measured by RER was systematically underestimated compared to values obtained from VO2 (HII: 4.5% and MIC: 6.2%, P<0.05). Total EE (calculated from VO2), and duration of HIC bouts (2.8 kcal and 30.8+/-2.2 min) were lower (P<0.0001) than in MIC (4.9 kcal and 64.7+/-1.8 min) and HII (4.7 kcal and 46.9+/-2.2 min). Predicted and actual values of total VO2, total EE, and duration of isocaloric sessions were similar in MIC and HII (P>0.05), which were both higher than in HIC (P<0.0001). In conclusion, the time to achieve a given EE in exercise bouts with different intensities did not correspond to the total distance. Therefore, the volume of aerobic exercise in protocols involving Wistar rats should be equalized using EE rather than total covered distance. PMID- 27487419 TI - Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro. AB - Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a beta-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (-19% of maximal response and -60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (-19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients. PMID- 27487420 TI - Water-Mediated Interactions between Hydrophilic and Hydrophobic Surfaces. AB - All surfaces in water experience at short separations hydration repulsion or hydrophobic attraction, depending on the surface polarity. These interactions dominate the more long-ranged electrostatic and van der Waals interactions and are ubiquitous in biological and colloidal systems. Despite their importance in all scenarios where the surface separation is in the nanometer range, the origin of these hydration interactions is still unclear. Using atomistic solvent explicit molecular dynamics simulations, we analyze the interaction free energies of charge-neutral model surfaces with different elastic and water-binding properties. The surface polarity is shown to be the most important parameter that not only determines the hydration properties and thereby the water contact angle of a single surface but also the surface-surface interaction and whether two surfaces attract or repel. Elastic properties of the surfaces are less important. On the basis of surface contact angles and surface-surface binding affinities, we construct a universal interaction diagram featuring three different interaction regimes-hydration repulsion, cavitation-induced attraction-and for intermediate surface polarities-dry adhesion. On the basis of scaling arguments and perturbation theory, we establish simple combination rules that predict the interaction behavior for combinations of dissimilar surfaces. PMID- 27487421 TI - Polycystic Ovary Syndrome and Obsessive-Compulsive Disorder: Interactions and Psychopharmacological Considerations. PMID- 27487422 TI - Direct and Indirect Measurements and Modeling of Methane Emissions in Indianapolis, Indiana. AB - This paper describes process-based estimation of CH4 emissions from sources in Indianapolis, IN and compares these with atmospheric inferences of whole city emissions. Emissions from the natural gas distribution system were estimated from measurements at metering and regulating stations and from pipeline leaks. Tracer methods and inverse plume modeling were used to estimate emissions from the major landfill and wastewater treatment plant. These direct source measurements informed the compilation of a methane emission inventory for the city equal to 29 Gg/yr (5% to 95% confidence limits, 15 to 54 Gg/yr). Emission estimates for the whole city based on an aircraft mass balance method and from inverse modeling of CH4 tower observations were 41 +/- 12 Gg/yr and 81 +/- 11 Gg/yr, respectively. Footprint modeling using 11 days of ethane/methane tower data indicated that landfills, wastewater treatment, wetlands, and other biological sources contribute 48% while natural gas usage and other fossil fuel sources contribute 52% of the city total. With the biogenic CH4 emissions omitted, the top-down estimates are 3.5-6.9 times the nonbiogenic city inventory. Mobile mapping of CH4 concentrations showed low level enhancement of CH4 throughout the city reflecting diffuse natural gas leakage and downstream usage as possible sources for the missing residual in the inventory. PMID- 27487423 TI - Bona Fide Psychotherapy Models Are Equally Effective for Major Depressive Disorder: Future Research Directions. PMID- 27487424 TI - Nightmares in cardiology: Sudden cardiac death in a patient with apparently healthy heart and "benign" outflow tract extrasystoles. PMID- 27487425 TI - Viscosupplementation in Knee Osteoarthritis: Evidence Revisited. AB - The body of evidence surrounding the use of viscosupplementation in knee osteoarthritis is extensive and fraught with heterogeneous trials with conflicting conclusions. Attempts to aggregate the evidence through systematic reviews, meta-analyses, and guidelines have also resulted in unclear, discordant recommendations. Closer examination reveals that the evidence around viscosupplementation favors clinically important reductions in pain among higher molecular-weight and cross-linked formulations and is a safe option in patients with knee osteoarthritis. Further large trials assessing the use of viscosupplementation across various formulations in knee osteoarthritis may confirm subgroup findings from meta-analyses; however, immediate focus on improved knowledge translation is required to ensure evidence-based approaches to the treatment of knee osteoarthritis. PMID- 27487426 TI - Arthroscopic Management of the Stiff Shoulder. AB - Shoulder stiffness affects a diverse population of patients suffering a decrease in function and shoulder pain. Arthroscopic management of this debilitating spectrum of pathology is a safe and effective course of action in cases recalcitrant to nonoperative therapy. Arthroscopic management of the stiff shoulder has been reported to be effective in the treatment of stiffness due to adhesive capsulitis, birth palsy, stiffness in the setting of rotator cuff tears, and osteoarthritis in the posttraumatic patient, in the postoperative patient, and in the throwing athlete. Arthroscopic management is most effective in treating the stiff shoulder in the setting of adhesive capsulitis recalcitrant to nonoperative therapy or posttraumatic stiffness. Results are more guarded in the treatment of postoperative stiffness. Excessive force and trauma to the shoulder, including fracture of the humerus, can be avoided with a 360[degrees] capsular release for shoulder stiffness rather than manipulation under anesthesia. PMID- 27487427 TI - Posterior Tibial Slope: Effect on, and Interaction with, Knee Kinematics. AB - Posterior tibial slope should be measured on a long lateral or an expanded lateral radiograph. Posterior tibial slope decreases the quadriceps force needed to exert knee extension moment. Posterior tibial slope parallel to natural tibial slope minimizes tibial component subsidence. Posterior tibial slope should be increased rather than releasing the posterior cruciate ligament (PCL) to restore normal kinematics in a knee that is tight in flexion. Larger tibial slope widens the flexion gap in posterior stabilized total knee replacement. PMID- 27487428 TI - Scapholunate Ligament Reconstruction: A Critical Analysis Review. AB - Scapholunate reconstruction procedures are best stratified according to preoperative stages of dissociative instability, injury chronicity, and arthrosis. In general, procedures aimed at correcting scapholunate instability focus on reestablishing ligament continuity in order to normalize carpal biomechanics; however, many existing interventions have shown differential success when performed on patients with varying stages of instability and degrees of carpal malalignment. The Mayo dorsal intercarpal ligament capsulodesis has proven most effective for preserving range of motion, whereas the Blatt capsulodesis has been associated with substantial improvements in terms of the postoperative pain rating and perceived functional capacity. PMID- 27487429 TI - Challenging the Conventional Standard for Thoracic Spine Range of Motion: A Systematic Review. AB - BACKGROUND: Segmental motion is a fundamental characteristic of the thoracic spine; however, studies of segmental ranges of motion have not been summarized or analyzed. The purpose of the present study was to present a summary of the literature on intact cadaveric thoracic spine segmental range of motion in each anatomical plane. METHODS: A systematic MEDLINE search was performed with use of the terms "thoracic spine," "motion," and "cadaver." Reports that included data on the range of motion of intact thoracic human cadaveric spines were included. Independent variables included experimental details (e.g., specimen age), type of loading (e.g., pure moments), and applied moment. Dependent variables included the ranges of motion in flexion-extension, lateral bending, and axial rotation. RESULTS: Thirty-three unique articles were identified and included. Twenty-three applied pure moments to thoracic spine specimens, with applied moments ranging from 1.5 to 8 Nm. Estimated segmental range of motion pooled means ranged from 1.9 degrees to 3.8 degrees in flexion-extension, from 2.1 degrees to 4.4 degrees in lateral bending, and from 2.4 degrees to 5.2 degrees in axial rotation. The sums of the range of motion pooled means (T1 to T12) were 28 degrees in flexion-extension, 36 degrees in lateral bending, and 45 degrees in axial rotation. CONCLUSIONS: The pooled ranges of motion were similar to reported in vivo motions but were considerably smaller in magnitude than the frequently referenced values reported prior to the widespread use of biomechanical testing standards. Improved reporting of biomechanical testing methods, as well as specimen health, may be beneficial for improving on these estimations of segmental cadaveric thoracic spine range of motion. PMID- 27487430 TI - The Present and Future of Genomics in Adult Reconstructive Orthopaedic Surgery. AB - As of 2015, members of the "baby boomer generation" comprise 75 million people in the growing United States population. Many of these individuals will be facing the need for total hip or knee replacement. Currently, the age of onset of osteoarthritis continues to decrease and the need for total joint replacements continues to increase. In current practice, nearly all patients undergoing joint replacement receive similar preoperative, intraoperative, and postoperative management strategies. However, wide variability in outcomes and satisfaction with total joint replacement still remain. The key to understanding the cause for such varied outcomes may lie in our understanding of the genetic basis of degenerative joint disease. The future of "orthogenomic" research should be centered on clinical application focusing on early preoperative identification of at-risk patients. The goal is to establish twenty-first-century patient-specific strategies for optimizing results and expectations after adult reconstructive surgery. PMID- 27487431 TI - Gastrointestinal stability, physicochemical characterization and oral bioavailability of chitosan or its derivative-modified solid lipid nanoparticles loading docetaxel. AB - OBJECTIVE: The purpose of this study was to prepare the positively charged chitosan (CS)- or hydroxypropyl trimethyl ammonium chloride chitosan (HACC) modified solid lipid nanoparticles (SLNs) loading docetaxel (DTX), and to evaluate their properties in vitro and in vivo. METHODS: The DTX-loaded SLNs (DTX SLNs) were prepared through an emulsion solvent evaporation method and further modified with CS or HACC (CS-DTX-SLNs or HACC-DTX-SLNs) via noncovalent interactions. The gastrointestinal (GI) stability, dissolution rate, physicochemical properties and cytotoxicities of SLNs were investigated. In addition, the GI mucosa irritation and oral bioavailability of SLNs were also evaluated in rats. RESULTS: The HACC-DTX-SLNs were highly stable in simulated gastric and intestinal fluids (SGF and SIF). By contrast, the CS-DTX-SLNs were less stable in SIF than in SGF. The drug dissolution remarkably increased when DTX was incorporated into the SLNs, which may be attributed to the change in the crystallinity of DTX and some molecular interactions that occurred between DTX and the carriers. The SLNs showed low toxicity in Caco-2 cells and no GI mucosa irritations were observed in rats. A 2.45-fold increase in the area under the curve of DTX was found in the HACC-DTX-SLN group compared with the DTX group after the modified SLNs were orally administered to rats. However, the oral absorption of DTX-SLN or CS-DTX-SLN group showed no significant difference compared with that of DTX group. CONCLUSIONS: The positively charged HACC-DTX SLNs with a stable particle size could provide the enhanced oral bioavailability of DTX in rats. PMID- 27487432 TI - Change in Driving Performance following Arthroscopic Shoulder Surgery. AB - The current study aimed to measure perioperative changes in driving performance following arthroscopic shoulder surgery using a validated driving simulator.21 patients who underwent arthroscopic surgery for rotator cuff or labral pathology were tested on a driving simulator preoperatively, and 6 and 12 weeks postoperatively. An additional 21 subjects were tested to establish driving data in a control cohort. The number of collisions, centerline crossings, and off-road excursions were recorded for each trial. VAS and SPADI scores were obtained at each visit.The mean number of collisions in the study group significantly increased from 2.05 preoperatively to 3.75 at 6 weeks (p<0.001), and significantly decreased to 1.95 at 12 weeks (p<0.001). Centerline crossings and off-road excursions did not significantly change from preoperative through 12 weeks, although centerline crossings were statistically different from the controls at each time point (p<0.001). Surgery on the dominant driving arm resulted in greater collisions at 6 weeks than surgery on the non-dominant driving arm (p<0.001).Preliminary data shows that driving performance is impaired for at least 6 weeks postoperatively, with a return to normal driving by 12 weeks. Driving is more profoundly affected in conditions that require avoiding a collision and when the dominant driving arm is involved. PMID- 27487433 TI - Effects of nitrogen plasma treatment on the surface characteristics of olive stone-based activated carbon. AB - Nitrogen plasma treatment (NPT) of activated carbon (AC) at different conditions was carried out to introduce nitrogen-containing groups onto olive stone activated carbon (OSAC) surfaces. Textural characteristics of raw and irradiated samples were analyzed by N2 and CO2 adsorption. Surface chemical functional groups were analyzed by X-ray photoelectron spectrometry (XPS) and Fourier Transformed Infrared spectroscopy. The results showed that after NPT, the surface textural properties of irradiated OSAC were slightly damaged, and a gradual decrease in surface area and pore volume was observed during the irradiation. XPS revealed that NPT could change the distribution of oxygen functional groups on the OSAC surface and there were more nitrogen atoms incorporated into the aromatic ring. A tentative explanation for the modification process is proposed. Phenol adsorption was enhanced from 110 mg/g for untreated AC to 635 mg/g for 30 min plasma-treated OSAC. PMID- 27487434 TI - The impact of single and shared rooms on family-centred care in children's hospitals. AB - AIMS AND OBJECTIVES: To explore whether and how spatial aspects of children's hospital wards (single and shared rooms) impact upon family-centred care. BACKGROUND: Family-centred care has been widely adopted in paediatric hospitals internationally. Recent hospital building programmes in many countries have prioritised the provision of single rooms over shared rooms. Limited attention has, however, been paid to the potential impact of spatial aspects of paediatric wards on family-centred care. DESIGN: Qualitative, ethnographic. METHODS: Phase 1; observation within four wards of a specialist children's hospital. Phase 2; interviews with 17 children aged 5-16 years and 60 parents/carers. Sixty nursing and support staff also took part in interviews and focus group discussions. All data were subjected to thematic analysis. RESULTS: Two themes emerged from the data analysis: 'role expectations' and 'family-nurse interactions'. The latter theme comprised three subthemes: 'family support needs', 'monitoring children's well-being' and 'survey-assess-interact within spatial contexts'. CONCLUSION: Spatial configurations within hospital wards significantly impacted upon the relationships and interactions between children, parents and nurses, which played out differently in single and shared rooms. Increasing the provision of single rooms within wards is therefore likely to directly affect how family-centred care manifests in practice. RELEVANCE TO CLINICAL PRACTICE: Nurses need to be sensitive to the impact of spatial characteristics, and particularly of single and shared rooms, on families' experiences of children's hospital wards. Nurses' contribution to and experience of family-centred care can be expected to change significantly when spatial characteristics of wards change and, as is currently the vogue, hospitals maximise the provision of single rather than shared rooms. PMID- 27487435 TI - Factors contributing to the low physical activity level for Hong Kong Chinese children hospitalised with cancer: an exploratory study. AB - AIMS AND OBJECTIVES: To explore the factors contributing to the low physical activity level for Hong Kong Chinese children hospitalised with cancer. BACKGROUND: Notwithstanding the fact that regular physical activity can ameliorate cancer-related fatigue and other adverse effect of cancer treatment on children's physical and psychological well-being, physical inactivity is a common problem among children undergoing cancer treatment. Understanding the factors that affect their physical activity level is an important step towards planning and evaluating an appropriate intervention that promotes the adoption and maintenance of regular physical activity. DESIGN: A phenomenological design was used in this qualitative study. METHODS: A purposive sample of 25 children with cancer was recruited in a paediatric oncology unit of an acute care public hospital in Hong Kong. They were asked to participate in a semistructured interview by their bedside lasting about 30 minutes. All the interviews were tape recorded and immediately transcribed. Content analysis was used to analyse the qualitative data. RESULTS: The findings revealed that the patients' physical condition, misunderstanding about physical activity by children, parents and healthcare professionals, emotional disturbances and social influences are four important factors impeding children from engaging in regular physical activity during cancer treatment. CONCLUSION: This study addresses a gap in the literature by identifying the factors that negatively influence the physical activity levels of Hong Kong Chinese children hospitalised with cancer. RELEVANCE TO CLINICAL PRACTICE: Understanding these factors, nurses can explore interventions that target on correcting the misunderstanding and providing relevant information about the importance of physical activity, eventually promoting the adoption and maintenance of regular physical activity and enhancing the quality of life. PMID- 27487436 TI - Enhanced surveillance of Clostridium difficile infection occurring outside hospital, England, 2011 to 2013. AB - There are limited national epidemiological data for community-associated (CA) Clostridium difficile infections (CDIs). Between March 2011 and March 2013, laboratories in England submitted to the Clostridium difficile Ribotyping Network (CDRN) up to 10 diarrhoeal faecal samples from successive patients with CA-CDI, defined here as C. difficile toxin-positive diarrhoea commencing outside hospital (or less than 48 hours after hospital admission), including those cases associated with community-based residential care, with no discharge from hospital within the previous 12 weeks. Patient demographics and C. difficile PCR ribotypes were compared for CA-CDIs in our study and presumed healthcare-associated (HA) CDIs via CDRN. Ribotype diversity indices, ranking and relative prevalences were very similar in CA- vs HA-CDIs, although ribotypes 002 (p <= 0.0001),020 (p = 0.009) and 056 (p < 0.0001) predominated in CA-CDIs; ribotype 027 (p = 0.01) predominated in HA-CDIs. Epidemic ribotypes 027 and 078 predominated in institutional residents with CDI (including care/nursing homes) compared with people with CDI living at home. Ribotype diversity decreased with increasing age in HA-CDIs, but not in CA-CDIs. Ribotype 078 CA-CDIs were significantly more common in elderly people (3.4% (6/174) vs 8.7% (45/519) in those aged < 65 and >= 65 years, respectively; p = 0.019). No antibiotics were prescribed in the previous four weeks in about twofold more CA-CDI vs HAs (38.6% (129/334) vs 20.3% (1,226/6,028); p < 0.0001). We found very similar ribotype distributions in CA- and HA-CDIs, although a few ribotypes significantly predominated in one setting. These national data emphasise the close interplay between, and likely common reservoirs for, CDIs, particularly when epidemic strains are not dominant. PMID- 27487437 TI - Qigong Yi Jinjing Promotes Pulmonary Function, Physical Activity, Quality of Life and Emotion Regulation Self-Efficacy in Patients with Chronic Obstructive Pulmonary Disease: A Pilot Study. AB - PURPOSE: The purpose of this pilot study was to examine the effect of a Chinese traditional exercise program, Qigong Yi Jinjing (QYJJ), on patients with chronic obstructive pulmonary disease (COPD). METHODS: One hundred and thirty eligible COPD patients were randomly divided into three groups: the QYJJ group (n = 42), the self-management exercise group (n = 43), and the control group (n = 45). Data were collected and analyzed at baseline and again at one, three, and six months. A pulmonary rehabilitation index, consisting of pulmonary function, six-minute walk test, Regulatory Emotion Self-Efficacy questionnaire, and exercise of the COPD Assessment Test widely used to evaluate health-related quality of life (HRQL) in participants with COPD, was measured. RESULTS: Compared with the other groups, participants in QYJJ group had significantly better lung function (forced expiratory volume in one second: F = 8.96, p = 0.000; forced expiratory volume in one second/forced vital capacity: F = 11.55, p = 0.000; the percentage of forced expiratory volume in one second in prediction: F = 24.27, p = 0.000); walked a longer distance (F = 152.52, p = 0.000), and had more satisfactory HRQL (F = 14.08, p = 0.000). QYJJ training also contributed to improving the ability of emotion regulation (F = 36.56, p = 0.000). There were significant positive changes in expressing positive affect (F = 56.25, p = 0.000) and managing despondency/distress (F = 21.58, p = 0.000), apart from the ability to regulate anger/irritation (F = 1.20, p = 0.305). The longer QYJJ is practiced, the more effective the influence is on the pulmonary rehabilitation-related index measures. CONCLUSIONS: These results indicate that QYJJ exercise produced positive effects on pulmonary function, physical activity, emotion regulation self-efficiency (modulating the expression of despondency or distress and experiencing and expressing positive affect), and HRQL in patients with COPD. PMID- 27487438 TI - Two isoforms of Serpent containing either one or two GATA zinc fingers have different roles in Drosophila haematopoiesis. PMID- 27487439 TI - [Violence against women in transnational communities in San Luis Potosi, Mexico: a public health problem]. AB - Violence against women is a worldwide problem due to its impact on quality of life for those living under the complicity of a patriarchal culture and a state that makes such violence invisible. This article aims to give visibility to the contexts of violence affecting female "partners of migrants" in their places of origin, problematizing how such violence assaults their physical and mental health. This was a qualitative study with an interpretative anthropological focus, drawing on a sample of 21 women from rural and urban areas in San Luis Potosi, Mexico. Interviews were based on daily life history and discourse analysis. According to the results, women experience more violence when their spouses migrate, new forms of violence are committed against them, and the violence occurs in both the household and the community. Violence against women is a public health problem that should be treated through a framework that is sensitive to the social and cultural dynamics characterizing the contexts in which health programs are implemented. PMID- 27487440 TI - [Perception, knowledge, and use of generic drugs in southern Brazil: what changed from 2002 to 2012?]. AB - This study compared the perception, knowledge, and use of generic drugs by adults in Pelotas, Rio Grande do Sul State, Brazil, using two cross-sectional population based studies from 2002 and 2012. Study outcomes were: (a) prevalence of use of generics; (b) generics as a proportion of all medication; (c) users' perceptions of prices and quality; (d) users' knowledge of generics; and (e) strategies for acquisition of medicines. Prevalence of generics use increased from 3.6% (95%CI: 3.0-4.3) to 26.1% (95%CI: 24.5-27.7) in the 10-year period. Perceptions of prices and quality of generics remained stable, identification of characteristics that distinguish generics from other drugs improved (p < 0.001), and drug classification errors decreased (p < 0.001). There was a significant increase in acquiring medication by replacing prescribed drugs with generics. Between 2002 and 2012 there was an increase in knowledge and use of generics, while perception of lower prices and equivalent quality remained high. PMID- 27487441 TI - Preparedness for the Rio 2016 Olympic Games: hospital treatment capacity in georeferenced areas. AB - Recently, Brazil has hosted mass events with recognized international relevance. The 2014 FIFA World Cup was held in 12 Brazilian state capitals and health sector preparedness drew on the history of other World Cups and Brazil's own experience with the 2013 FIFA Confederations Cup. The current article aims to analyze the treatment capacity of hospital facilities in georeferenced areas for sports events in the 2016 Olympic Games in the city of Rio de Janeiro, based on a model built drawing on references from the literature. Source of data were Brazilian health databases and the Rio 2016 website. Sports venues for the Olympic Games and surrounding hospitals in a 10km radius were located by geoprocessing and designated a "health area" referring to the probable inflow of persons to be treated in case of hospital referral. Six different factors were used to calculate needs for surge and one was used to calculate needs in case of disasters (20/1,000). Hospital treatment capacity is defined by the coincidence of beds and life support equipment, namely the number of cardiac monitors (electrocardiographs) and ventilators in each hospital unit. Maracana followed by the Olympic Stadium (Engenhao) and the Sambodromo would have the highest single demand for hospitalizations (1,572, 1,200 and 600, respectively). Hospital treatment capacity proved capable of accommodating surges, but insufficient in cases of mass casualties. In mass events most treatments involve easy clinical management, it is expected that the current capacity will not have negative consequences for participants. PMID- 27487442 TI - [Smoking prevalence and associated factors among tobacco farmers in southern Brazil]. AB - This study aimed to describe the prevalence of smoking and associated factors in a cross-sectional population-based sample of 2,464 tobacco farmers in 2011. Multivariate analysis in men assessed the association between smoking and socioeconomic, behavioral, and occupational variables. Some 31.2% of men and 3.1% of women were current smokers. In men, smoking was directly associated with age, schooling, income, heavy drinking, time at work in tobacco farming, and time of exposure to pesticides. Employment relationship was a risk factor for smoking, and participation in religious activities was a protective factor. Male tobacco farmers showed multiple risk behaviors and higher smoking prevalence than other farmers. Ignoring the risk and cultural legacy may be common factors for these behaviors and suggest combined approaches. PMID- 27487443 TI - Frequency of self-reported sexual aggression and victimization in Brazil: a literature review. AB - The lack of official data on rape has been a challenge for researchers in Brazil. Two recently published studies were based on law enforcement and medical records. Although these studies represent important progress in research on rape in the country, they have several limitations. In order to obtain more realistic rates, the current article reviews Brazilian studies on self-reported sexual aggression and victimization in individuals over 14 years of age. Forty-one studies were identified through electronic searches and reference verification. From 1% to 40% of women and 1% to 35% of men reported some form of victimization in the previous year. The male perpetration incidence ranged from 2% to 44%. Despite the wide variability, these rates were much higher than those provided by official data. The results suggest that sexual orientation is associated with vulnerability. Mixed findings were found concerning race. Most studies were based on convenience samples and focused on female victimization. Male victimization has received increasing attention, but studies on self-reported perpetration are still limited. PMID- 27487444 TI - [Mapping stakeholders' preferences in prioritization criteria for horizon scanning in healthcare technologies]. AB - Filtration and prioritization are two basics steps in horizon scanning systems. This article aimed to map stakeholders' preferences in the Brazilian Unified National Health System (SUS) regarding filtration and prioritization criteria. Two filtration criteria (time horizon and innovation) and eight prioritization criteria (relevance to epidemiology, health policies, and clinical practice; potential impact on SUS budget, healthcare providers' costs, and mortality; safety; and legal, ethical, and social aspects) were selected. Multiple correspondence analysis was used to map stakeholders' preferences within and between groups. Two groups were more homogeneous and determinant for selection of prioritization criteria. Stakeholders' professional experience had more influence than institutional affiliations. The approach showed transparent criteria selection and analysis of stakeholders' individual preferences. PMID- 27487445 TI - [Equations for the evaluation of body composition in children and adolescents]. AB - Body mass index (BMI) is widely used in the world, despite caveats concerning its interpretation in relation to gender, age, and race. BMI reading is normally standardized, potentially producing error in the results and classification of nutritional status. Body composition provides more relevant information than BMI: fat mass and lean mass are the main indices. This paper reviews existing equations and proposes the simplest ones and those with the lowest estimation error to replace or complement BMI and improve interpretation of nutritional status and physical activity. PMID- 27487446 TI - Thiol oxidation by nitrosative stress: Cellular localization in human spermatozoa. AB - Peroxynitrite is a highly reactive nitrogen species and when it is generated at high levels it causes nitrosative stress, an important cause of impaired sperm function. High levels of peroxynitrite have been shown to correlate with decreased semen quality in infertile men. Thiol groups in sperm are mainly found in enzymes, antioxidant molecules, and structural proteins in the axoneme. Peroxynitrite primarily reacts with thiol groups of cysteine-containing proteins. Although it is well known that peroxynitrite oxidizes sulfhydryl groups in sperm, the subcellular localization of this oxidation remains unknown. The main objective of this study was to establish the subcellular localization of peroxynitrite-induced nitrosative stress in thiol groups and its relation to sperm motility in human spermatozoa. For this purpose, spermatozoa from healthy donors were exposed in vitro to 3-morpholinosydnonimine (SIN-1), a compound which generates peroxynitrite. In order to detect peroxynitrite and reduced thiol groups, the fluorescent probes, dihydrorhodamine 123 and monobromobimane (mBBr), were used respectively. Sperm viability was analyzed by propidium iodide staining. Peroxynitrite generation and thiol redox state were monitored by confocal microscopy whereas sperm viability was evaluated by flow cytometry. Sperm motility was analyzed by CASA using the ISAS((r)) system. The results showed that exposure of human spermatozoa to peroxynitrite results in increased thiol oxidation which is mainly localized in the sperm head and principal piece regions. Thiol oxidation was associated with motility loss. The high susceptibility of thiol groups to peroxynitrite-induced oxidation could explain, at least in part, the negative effect of reactive nitrogen species on sperm motility. ABBREVIATIONS: DHR: dihydrorhodamine 123; mBBr: monobromobimane ONOO( ): peroxynitrite RNS: reactive nitrogen species RFI: relative fluorescence intensity SIN-1: 3-morpholinosydnonimine CASA: Computer-Aided Sperm Analysis PARP: poli ADP ribose polimerasa VCL: curvilinear velocity VSL: straight-line velocity VAP: average path velocity PRDXs: peroxiredoxins ODF: outer dense fiber ODF1: outer dense fiber 1 PI: propidium iodide DMSO: dimethyl sulfoxide SD: standard deviation ANOVA: analysis of variance. PMID- 27487447 TI - Nitrogen deposition does not enhance Sphagnum decomposition. AB - Long-term additions of nitrogen (N) to peatlands have altered bryophyte growth, species dominance, N content in peat and peat water, and often resulted in enhanced Sphagnum decomposition rate. However, these results have mainly been derived from experiments in which N was applied as ammonium nitrate (NH4NO3), neglecting the fact that in polluted areas, wet deposition may be dominated either by NO3(-) or NH4(+). We studied effects of elevated wet deposition of NO3( ) vs. NH4(+) alone (8 or 56kgNha(-1)yr(-1) over and above the background of 8kgNha(-1)yr(-1) for 5 to 11years) or combined with phosphorus (P) and potassium (K) on Sphagnum quality for decomposers, mass loss, and associated changes in hummock pore water in an ombrotrophic bog (Whim). Adding N, especially as NH4(+), increased N concentration in Sphagnum, but did not enhance mass loss from Sphagnum. Mass loss seemed to depend mainly on moss species and climatic factors. Only high applications of N affected hummock pore water chemistry, which varied considerably over time. Overall, C and N cycling in this N treated bog appeared to be decoupled. We conclude that moss species, seasonal and annual variation in climatic factors, direct negative effects of N (NH4(+) toxicity) on Sphagnum production, and indirect effects (increase in pH and changes in plant species dominance under elevated NO3(-) alone and with PK) drive Sphagnum decomposition and hummock C and N dynamics at Whim. PMID- 27487448 TI - PCDD, PCDF, dl-PCB and organochlorine pesticides monitoring in Sao Paulo City using passive air sampler as part of the Global Monitoring Plan. AB - The persistent organic pollutants (POPs), such as organochlorine pesticides and PCBs, are ordinarily monitored in the aquatic environment or in soil in the environmental quality monitoring programs in Sao Paulo, Brazil. One of the core matrices proposed in the POPs Global Monitoring Plan (GMP) from the Stockholm Convention list is the ambient air, which is not a usual matrix for POPs monitoring in the country. In this study POP levels were evaluated in the air samples from an urban site in Sao Paulo City over five years, starting in 2010 as a capacity building project for Latin America and the Caribbean region for POP monitoring in ambient air using passive samplers. Furthermore, after the end of the Project in 2012, the monitoring continued in the same sampling site as means to improving the analytical capacity building and contribute to the GMP data. The POPs monitored were 17 congeners of 2,3,7,8 chloro-substituted PCDDs and PCDFs, dioxin-like PCBs, indicator PCBs, organochlorine pesticides and toxaphene. The results show a slight decrease in PCDD/F, dl-PCBs and indicator PCBs levels along the five years. The organochlorine pesticide endosulfan was present at its highest concentration at the beginning of the monitoring period, but it was below detection level in the last year of the monitoring. Some other organochlorine pesticides were detected close to or below quantitation limits. The compounds identified were dieldrin, chlordane, alpha-HCH, gamma-HCH, heptachlor, heptachlor epoxide, hexachlorobenzene and DDTs. Toxaphene congeners were not detected. These results have confirmed the efficacy of passive sampling for POP monitoring and the capacity building for POP analysis and monitoring was established. However more needs to be done, including expansion of sampling sites, new POPs and studies on sampling rates to be considered in calculating the concentration of POPs in ambient air using a passive sampler. PMID- 27487449 TI - Epigenetic and transcriptional regulation of autophagy. AB - Macroautophagy (hereafter referred to as autophagy) is an essential self digestion process to maintain homeostasis and promote survival in response to starvation. Although the components of autophagy in the cytoplasm have been well studied, little has been known about the fine-tuning mechanism of autophagy through epigenetic regulations. Recently, we identified the histone arginine methyltransferase CARM1 as a new component and followed histone H3R17 dimethylation as a critical epigenetic mark in starvation-induced autophagy. Upon nutrient starvation, CARM1 is stabilized in the nucleus, but not in the cytoplasm, whereas it is constantly degraded under nutrient-rich conditions by the SKP2-containing SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase. We further showed that nutrient starvation induces the protein levels and activity of AMPK in the nucleus. Activated AMPK then phosphorylates FOXO3, leading to SKP2 downregulation and increased CARM1 protein levels in the nucleus. Stabilized CARM1 in turn functions as an essential co-activator of TFEB and regulates the expression of autophagy and lysosomal genes. Our findings provide a conceptual advance that activation of specific epigenetic programs is indispensable for a sustained autophagic response, and shed light on a potential therapeutic targeting of the newly identified AMPK-SKP2-CARM1 signaling axis in autophagy related diseases. PMID- 27487450 TI - Development and validation of a new serum standard for the measurement of anti HEV antibodies in animals. AB - Although hepatitis E virus (HEV) infection is a zoonosis, there is, currently, no standardized assay for quantitatively measuring anti-HEV antibody levels in HEV animal reservoirs. In this study, anti-HEV antibody positive serum from a rabbit (RS26) was calibrated by dose-response parallel line assay using the World Health Organization (WHO) reference standard for anti-HEV antibodies. After evaluating the stability of the RS26 serum, a quantification assay of anti-HEV antibodies using RS26 as a standard was developed and evaluated for both reproducibility and suitability to field studies. The anti-HEV antibody level of RS26 was calculated to be 39.54 IU/ml. A series of standard working serum for anti-HEV antibodies consisted of five serum dilutions (3.950 IU/ml, 1.975 IU/ml, 0.986 IU/ml, 0.494 IU/ml, and 0.247 IU/ml). The quantitative assay using RS26 showed good range and reproducibility, effectively measuring the dynamics of anti-HEV antibody concentrations in pigs and rabbits. In conclusion, we have developed a a stable and reproducible serum standard for the quantitation of anti-HEV antibodies. J. Med. Virol. 89:497-501, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27487451 TI - Action of Caffeine as an Amyloid Inhibitor in the Aggregation of Abeta16-22 Peptides. AB - Alzheimer's disease (AD) is a neurodegenerative disease caused due to aggregation of Abeta peptides in the brain tissues. Recently, several studies on AD transgenic mice have shown the effect of caffeine in significantly reducing the Abeta amyloid level in their brains. However, the mechanism and mode of caffeine action on amyloid aggregation are not known. Therefore, in this study, we have carried out molecular dynamics simulations of five amyloid-forming Abeta16-22 peptides in pure water and in a regime of caffeine solutions, with different caffeine/peptide stoichiometric ratios. The secondary structure analyses of peptides in pure water show the formation of beta-sheet conformations, whereas on addition of caffeine, these ordered conformations become negligible. The radial distribution function, contact map, nonbonding interaction energy, hydrogen bonding, potential of mean force, and hydration analyses show that there is less interpeptide interaction in the presence of caffeine, and the effect is greater with an increasing caffeine ratio. The interaction of aromatic phenylalanine residues of peptides with caffeine restricts the interpeptide interaction tendency. Upon increasing the number of caffeine molecules, interaction of caffeine with other hydrophobic residues also increases. Thus, the hydrophobic core-recognition motif of amyloid formation of peptides is physically blocked by caffeine, thereby abolishing the self-assembly formation. PMID- 27487452 TI - The CREB-binding protein affects the circadian regulation of behaviour. AB - Rhythmic changes in light and temperature conditions form the primary environmental cues that synchronize the molecular circadian clock of most species with the external cycles of day and night. Previous studies established a role for the CREB-binding protein (CBP) in molecular clock function by coactivation of circadian transcription. Here, we report that moderately increased levels of CBP strongly dampen circadian behavioural rhythms without affecting molecular oscillations of circadian transcription. Interestingly, light-dark cycles as well as high temperature facilitated a circadian control of behavioural activity. Based on these observations we propose that in addition to its coactivator function for circadian transcription, CBP is involved in the regulation of circadian behaviour down-stream of the circadian clock. PMID- 27487453 TI - van der Waals Heteroepitaxy of Germanene Islands on Graphite. AB - We fabricated flat, two-dimensional germanium sheets showing a honeycomb lattice that matches that of germanene by depositing submonolayers of Ge on graphite at room temperature and subsequent annealing to 350 degrees C. Scanning tunneling microscopy shows that the germanene islands have a small buckling with no atomic reconstruction and does not give any hints for alloy formation and hybridization with the substrate. Our density functional theory calculations of the structural properties agree well with our experimental findings and indicate that the germanene sheet interacts only weakly with the substrate underneath. Our band structure calculations confirm that the Dirac cone of free-standing germanene is preserved for layers supported on graphite. The germanene islands show a small but characteristic charge transfer with the graphite substrate which is predicted by our ab initio simulations in excellent agreement with scanning tunneling spectroscopy measurements. PMID- 27487455 TI - Natural Compounds as Inhibitors of Tyrosyl-tRNA Synthetase. AB - Tyrosyl-tRNA synthetases (TyrRSs) as essential enzymes for all living organisms are good candidates for therapeutic target in the prevention and therapy of microbial infection. We examined the effect of various polyphenols, alkaloids, and terpenes-secondary metabolites produced by higher plants showing many beneficial properties for the human organism, on bacterial aminoacylation reaction. The most potent inhibitors of Escherichia coli TyrRS are epigallocatechin gallate, acacetin, kaempferide, and chrysin, whereas the enzymes from Staphylococcus aureus and Pseudomonas aeruginosa are inhibited mainly by acacetin and chrysin. Most of them act as competitive inhibitors. Structure activity relationship showed that the most potent flavonoid inhibitors contain hydroxyl group at position 5 and 7 of A ring and OCH3 group at position 4' of B ring. PMID- 27487454 TI - Visceral Adipose Tissue Is Associated With Bone Microarchitecture in the Framingham Osteoporosis Study. AB - Obesity has been traditionally considered to protect the skeleton against osteoporosis and fracture. Recently, body fat, specifically visceral adipose tissue (VAT), has been associated with lower bone mineral density (BMD) and increased risk for some types of fractures. We studied VAT and bone microarchitecture in 710 participants (58% women, age 61.3 +/- 7.7 years) from the Framingham Offspring cohort to determine whether cortical and trabecular BMD and microarchitecture differ according to the amount of VAT. VAT was measured from CT imaging of the abdomen. Cortical and trabecular BMD and microarchitecture were measured at the distal tibia and radius using high-resolution peripheral quantitative computed tomography (HR-pQCT). We focused on 10 bone parameters: cortical BMD (Ct.BMD), cortical tissue mineral density (Ct.TMD), cortical porosity (Ct.Po), cortical thickness (Ct.Th), cortical bone area fraction (Ct.A/Tt.A), trabecular density (Tb.BMD), trabecular number (Tb.N), trabecular thickness (Tb.Th), total area (Tt.Ar), and failure load (FL) from micro-finite element analysis. We assessed the association between sex-specific quartiles of VAT and BMD, microarchitecture, and strength in all participants and stratified by sex. All analyses were adjusted for age, sex, and in women, menopausal status, then repeated adjusting for body mass index (BMI) or weight. At the radius and tibia, Ct.Th, Ct.A/Tt.A, Tb.BMD, Tb.N, and FL were positively associated with VAT (all p-trend <0.05), but no other associations were statistically significant except for higher levels of cortical porosity with higher VAT in the radius. Most of these associations were only observed in women, and were no longer significant when adjusting for BMI or weight. Higher amounts of VAT are associated with greater BMD and better microstructure of the peripheral skeleton despite some suggestions of significant deleterious changes in cortical measures in the non weight bearing radius. Associations were no longer significant after adjustment for BMI or weight, suggesting that the effects of VAT may not have a substantial effect on the skeleton independent of BMI or weight. (c) 2016 American Society for Bone and Mineral Research. PMID- 27487456 TI - Practice Patterns and Outcomes Associated With Use of Anticoagulation Among Patients With Atrial Fibrillation During Sepsis. AB - IMPORTANCE: Atrial fibrillation (AF) during sepsis is associated with an increased risk of ischemic stroke during hospitalization, but risks and benefits associated with anticoagulation for AF during sepsis are unclear. OBJECTIVE: To determine clinician practice patterns and patient risk of stroke and bleeding associated with use of anticoagulation for AF during sepsis. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study using enhanced administrative claims data from approximately 20% of patients hospitalized in the United States July 1, 2010, to June 30, 2013, examined patients with AF during sepsis who did not have additional indications for therapeutic anticoagulation. Propensity score and instrumental variable analyses were used to evaluate risks of in-hospital stroke and bleeding associated with anticoagulation during sepsis. EXPOSURES: Parenteral anticoagulants administered in doses greater than those used for prophylaxis of venous thromboembolism. MAIN OUTCOMES AND MEASURES: Ischemic stroke and clinically significant bleeding events during hospitalization. RESULTS: Of 113 511 patients hospitalized with AF and sepsis, 38 582 were included in our primary analysis (18 976 men and 19 606 women; mean [SD] age, 74.9 [11.7] years). A total of 13 611 patients (35.3%) received parenteral anticoagulants, while 24 971 (64.7%) did not. Hospital utilization rates of parenteral anticoagulants for AF during sepsis varied (median, 33%; 25th-75th percentile, 25%-43%). CHA2DS2VASc scores (congestive heart failure, hypertension, age >=75 years [doubled], type 1 or type 2 diabetes, stroke or transient ischemic attack or thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) poorly discriminated the risk of ischemic stroke during sepsis (C statistic, 0.526). Among 27 010 propensity score-matched patients, rates of in-hospital ischemic stroke events did not differ significantly between patients who did (174 of 13 505 [1.3%]) and did not (185 of 13 505 [1.4%]) receive parenteral anticoagulation (relative risk [RR], 0.94; 95% CI, 0.77-1.15). Clinically significant bleeding occurred more often among patients who received parenteral anticoagulation (1163 of 13 505 [8.6%]) than patients who did not receive parenteral anticoagulation (979 of 13 505 [7.2%]; RR, 1.21; 95% CI, 1.10-1.32). Risk of ischemic stroke associated with parenteral anticoagulation did not differ significantly between patients with preexisting (RR, 1.12; 95% CI, 0.86-1.44) or newly diagnosed AF (RR, 0.85; 95% CI 0.57-1.27; P = .31 for interaction). Results were robust to multiple sensitivity analyses, including hospital utilization rates of parenteral anticoagulation for AF as an instrument for anticoagulation exposure (RR for stroke, 1.08; 95% CI, 0.62-1.90; RR for bleeding, 1.23; 95% CI, 0.88-1.72). CONCLUSIONS AND RELEVANCE: Among patients with AF during sepsis, parenteral anticoagulation was not associated with reduced risk of ischemic stroke and was associated with higher bleeding rates. PMID- 27487457 TI - Gene-regulatory networks controlling inflorescence and flower development in Arabidopsis thaliana. AB - Reproductive development in plants is controlled by complex and intricate gene regulatory networks of transcription factors. These networks integrate the information from endogenous, hormonal and environmental regulatory pathways. Many of the key players have been identified in Arabidopsis and other flowering plant species, and their interactions and molecular modes of action are being elucidated. An emerging theme is that there is extensive crosstalk between different pathways, which can be accomplished at the molecular level by modulation of transcription factor activity or of their downstream targets. In this review, we aim to summarize current knowledge on transcription factors and epigenetic regulators that control basic developmental programs during inflorescence and flower morphogenesis in the model plant Arabidopsis thaliana. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer. PMID- 27487458 TI - Plant responses to abiotic stress: The chromatin context of transcriptional regulation. AB - The ability of plants to cope with abiotic environmental stresses such as drought, salinity, heat, cold or flooding relies on flexible mechanisms for re programming gene expression. Over recent years it has become apparent that transcriptional regulation needs to be understood within its structural context. Chromatin, the assembly of DNA with histone proteins, generates a local higher order structure that impacts on the accessibility and effectiveness of the transcriptional machinery, as well as providing a hub for multiple protein interactions. Several studies have shown that chromatin features such as histone variants and post-translational histone modifications are altered by environmental stress, and they could therefore be primary stress targets that initiate transcriptional stress responses. Alternatively, they could act downstream of stress-induced transcription factors as an integral part of transcriptional activity. A few experimental studies have addressed this 'chicken and-egg' problem in plants and other systems, but to date the causal relationship between dynamic chromatin changes and transcriptional responses under stress is still unclear. In this review we have collated the existing information on concurrent epigenetic and transcriptional responses of plants to abiotic stress, and we have assessed the evidence using a simple theoretical framework of causality scenarios. This article is part of a Special Issue entitled: Plant Gene Regulatory Mechanisms and Networks, edited by Dr. Erich Grotewold and Dr. Nathan Springer. PMID- 27487459 TI - Pericyclic Cascade toward Isochromenes: Application to the Synthesis of Alkaloid Benzosimuline. AB - The synthesis of biologically active alkaloid benzosimuline, isolated from the shrub Zanthoxylum simulans, is reported. Key transformation involves an oxa-6pi electrocyclic ring-opening/hetero-Diels-Alder pericyclic cascade. Although the last aromatization step proved to be cumbersome, this work unfolds a unique route to access interesting molecules from simple precursors. PMID- 27487460 TI - High Efficiency Organic Solar Cells Achieved by the Simultaneous Plasmon-Optical and Plasmon-Electrical Effects from Plasmonic Asymmetric Modes of Gold Nanostars. AB - The plasmon-optical effects have been utilized to optically enhance active layer absorption in organic solar cells (OSCs). The exploited plasmonic resonances of metal nanomaterials are typically from the fundamental dipole/high-order modes with narrow spectral widths for regional OSC absorption improvement. The conventional broadband absorption enhancement (using plasmonic effects) needs linear-superposition of plasmonic resonances. In this work, through strategic incorporation of gold nanostars (Au NSs) in between hole transport layer (HTL) and active layer, the excited plasmonic asymmetric modes offer a new approach toward broadband enhancement. Remarkably, the improvement is explained by energy transfer of plasmonic asymmetric modes of Au NS. In more detail, after incorporation of Au NSs, the optical power in electron transport layer transfers to active layer for improving OSC absorption, which otherwise will become dissipation or leakage as the role of carrier transport layer is not for photon absorption induced carrier generation. Moreover, Au NSs simultaneously deliver plasmon-electrical effects which shorten transport path length of the typically low-mobility holes and lengthen that of high-mobility electrons for better balanced carrier collection. Meanwhile, the resistance of HTL is reduced by Au NSs. Consequently, power conversion efficiency of 10.5% has been achieved through cooperatively plasmon-optical and plasmon-electrical effects of Au NSs. PMID- 27487461 TI - Mechanistically Inspired Route toward Hexahydro-2H-chromenes via Consecutive [4 + 2] Cycloadditions. AB - Utilizing two robust C-C bond-forming reactions, the Baylis-Hillman reaction and the Diels-Alder reaction, we report a highly enantio-, regio-, and diastereoselective synthesis of hexahydro-2H-chromenes via two sequential [4 + 2] cycloadditions. These tandem and formal cycloadditions have also been performed as a "one-pot" sequence to access the corresponding heterocycles constituting up to five contiguous stereocenters in excellent yields and stereoselectivity. PMID- 27487462 TI - Cancer Survivors Who Play Recreational Computer Games: Motivations for Playing and Associations with Beneficial Psychological Outcomes. AB - OBJECTIVE: Playing recreational videogames is a common activity, yet little is known about its role in the lives of people who are coping with serious illness. These individuals may experience depression and isolation and may turn to games to help alleviate negative experiences and support well-being. We explored these possibilities in the context of cancer survivors. The study aimed to discover motivations underlying game play and the extent to which motivations are associated with psychological health and well-being. METHODS: We conducted a cross-sectional online survey of survivors who play recreational games (N = 794). Key variables were motivations and indicators of psychological health, including self-efficacy in cancer communications, resilient coping, and beliefs that one is living a fulfilling and meaningful life (flourishing). RESULTS: Participants were most likely to be motivated to play for stimulation and a sense of accomplishment (intrinsic rewards), followed by development of self, sense of community, and personal affirmation. Multiple regression analyses revealed positive associations between playing for intrinsic rewards and all three psychological health outcomes. Playing for a sense of community was also positively associated with coping and flourishing. CONCLUSION: Playing recreational videogames, particularly to receive intrinsic rewards and to connect with others, may play a supportive role in the psychological health of survivors. Findings suggest future areas for research and implications for development of serious games. PMID- 27487463 TI - Efficacy of Topical Ofloxacin 0.3 % Administration on Conjunctival Bacterial Flora in Diabetic Patients Undergoing Intravitreal Injections. AB - PURPOSE: This prospective, randomized case series study aims to evaluate the efficacy of ofloxacin 0.3% eye drops in eradication of conjunctival bacterial flora in diabetic patients undergoing intravitreal injections (IVI). METHODS: Ninety-two diabetic patients (92 eyes) scheduled to undergo intravitreal injection of ranibizumab due to diabetic macular edema were enrolled in the study. Patients were randomly assigned to three different groups. Group 1 (n=32) received ofloxacin eye drops the day before before IVI (four times); patients in Group 2 (n=29) were administered ofloxacin one hour before IVI (every 15 minutes), while Group 3 (n=31) comprised patients that received combined administration of ofloxacin both one day and one hour before IVI (eight doses). Samples were collected from the injection site before and after antibiotic administration. Culture results from BACTEC broth and positive cultures in blood agar and Sabouraud's dextrose agar plates were measured. RESULTS: In Group 1, BACTEC broth positive cultures decreased from 84.4% at baseline to 50% after ofloxacin administration (p=0.007), and blood agar positive cultures reduced from 65.63% to 34.38% (p=0.02). In Group 2, positive cultures significantly decreased in BACTEC broth (from 79.3% at baseline to 48.28%; p=0.027) and in blood agar (from 68.97% to 37.13%; p=0.034). In Group 3, positive cultures decreased from 77.42% at baseline to 32.26% (p=0.0008) and from 58.06% at baseline to 22.58% (p=0.009) in BACTEC broth and blood agar, respectively. No microorganisms were isolated from Sabouraud's dextrose agar plates. CONCLUSIONS: The combined one day/one hour (eight doses) ofloxacin administration in diabetic patients is extremely effective in reducing conjunctival bacterial flora. The application of topical ofloxacin for one day or one hour before IVI is also significantly effective. PMID- 27487464 TI - Why is preconception health and care important? PMID- 27487465 TI - Effect of phosphonate monolayer adsorbate on the microwave photoresponse of TiO2 nanotube membranes mounted on a planar double ring resonator. AB - In this study, the effects of a phosphonate molecular monolayer adsorbed on the surface of a free-standing self-organized TiO2 nanotube membrane, on the microwave photoresponse of the membrane are presented. This phenomenon is monitored using planar microwave sensors. A double ring resonator is utilized to monitor the permittivity and conductivity variation on the monolayer coated membrane and the sensor environment separately. It is shown that the rise time and subsequent decay of the amplitude (A), resonance frequency (f 0) and quality factor (Q) of the resonator depend on the existence and the type of the monolayer coating the membrane. Three different monolayers of n-decylphosphonic acid (DPA), 1H, 1H', 2H, 2H'-perfluorodecyl phosphonic acid (PFDPA) and 16 phosphonohexadecanoic acid adsorbed on the titania nanotube membrane are investigated while monitoring their microwave properties during the illumination time period and in the relaxation period, which demonstrate different behavior in comparison to each other and to the bare nanotube membrane layer. The effect of humidity on the TiO2 nanotube membrane with and without different monolayers is also studied and the results demonstrate distinguishable microwave responses. While each of the monolayer-coated membranes exhibited an attenuation of the photo-induced change in A, f 0 and Q with respect to the bare membrane, PFDPA coated membranes showed the smallest relative change in the monitored microwave parameters upon ultraviolet illumination and upon the introduction of different levels of humidity. These effects are explained on the basis of surface trap passivation by the monolayers as well as the hydrophobicity of the monolayers. Our work also shows how the interactions of self-assembled monolayers with charge carriers and surface states on metal oxides may be used to indirectly sense their presence through measurement of the microwave response. PMID- 27487467 TI - The formation and characteristics of the i-motif structure within the promoter of the c-myb proto-oncogene. AB - C-myb proto-oncogene is a potential therapeutic target for some human solid tumors and leukemias. A long cytosine-rich sequence, which locates the downstream of the transcription initiation site, is demonstrated to fold into an intramolecular i-motif DNA using electrospray ionization mass spectrometry (ESI MS) and circular dichroism (CD) spectroscopy. Effects of factors, including the pH value, the number of C:C(+) dimers, the concentration of buffer, the molecular crowding condition, and the coexistence of the complementary DNA, on the formation and the structural stability of the i-motif DNA are systematically studied. We have demonstrated that the i-motif folding in the c-myb promoter could be accelerated upon synergistic physiological stimuli including intracellular molecular crowding and low pH values, as well as the large number of the i-motif C:C(+) dimers. Meanwhile, various inputs, such as acids/bases and metal ions, have exhibited their abilities in controlling the conformational switch of the c-myb GC-rich DNA. Acidic pH values and the presence of K(+) ions can induce the dissociation of the double helix. Our present strategy can greatly extend the potential usages of i-motif DNA molecules with specific sequences as conformational switch-controlled devices. Moreover, this work demonstrates the superiority of CD spectroscopy associated with ESI-MS as a rapid, more cost effective and sensitive structural change responsive method in the research of DNA conformational switching. PMID- 27487468 TI - A hermeneutic phenomenological study exploring the experience health practitioners have when working with families to safeguard children and the invisibility of the emotions work involved. AB - AIMS AND OBJECTIVES: To explore the emotions work undertaken by practitioners with responsibility for the safeguarding of child well-being and establish whether there is a relationship between emotion work, role visibility, professional well-being and effectiveness of supportive frameworks. BACKGROUND: Protecting children is the responsibility of everyone in society with health, social care and public health services leading this worldwide. To safeguard children effectively, it is known that practitioners build relationships with families in sometimes challenging situations, which involve the management of emotions. However, irrespective of this current knowledge; health practitioners who work in this area suggest that their child safeguarding role is not recognised, respected or valued in professional and societal settings. The purpose of this study was to report on a qualitative study which set out to explore the relationship between the known relational-based emotions work of practitioners' and the reported lack of visibility. METHODS: Hermeneutic phenomenology underpinned the study. Semistructured interviews were employed for data collection. Ten participants actively working with preschool children and families in healthcare organisations were recruited. RESULTS: The emotional-, relationship- and communicative-based work crucial to effectively safeguard children may influence the visibility of the role. Poor role visibility influences the morale of practitioners and the support they receive. CONCLUSION: In conclusion this study proposes that when there is poor role recognition; there is ineffective clinical support. This reduces professional well-being, which in turn will impact practitioner abilities to safeguard children. RELEVANCE TO CLINICAL PRACTICE: This study highlights that to sustain safe and effective health and social care practice, organisational leads require an understanding of the impact emotional- and relational-based work can have on practitioners and provide supportive frameworks that will effectively promote professional well being. PMID- 27487471 TI - Ab Initio Benchmark Study of Nonadiabatic S1-S2 Photodynamics of cis- and trans Hexatriene. AB - The dynamics of the nonadiabatically coupled lowest singlet excited states of cis and trans-hexatriene are studied theoretically, in a comprehensive electronic structure and quantum dynamical investigation. At the ground state equilibrium geometry the relevant S2 and S1 states carry the A1 (Ag) and B2 (Bu) symmetry labels, for the cis (trans) isomer. Various high-level electronic structure methods are used, including the recently reparametrized DFT/MRCI method, and the results are critically compared. Key parameters of interest are the vertical energy gap and the strength of vibronic coupling between the interacting electronic states. To estimate their influence, suitable comparison calculations are performed. The results are used as the basis for quantum dynamical calculations on the UV absorption spectrum and electronic population transfer involving the S1 and S2 states. Up to nine nonseparable degrees of freedom are included in the calculations. The experimental UV absorption spectrum in the 5 5.2 eV energy range can be very well reproduced. The time-dependent wavepacket propagations reveal a population transfer on the order of 30-50 fs, which becomes increasingly complete with more degrees of freedom included in the calculation. The results are briefly compared with analogous data for the s-trans-butadiene system treated by some of us recently. PMID- 27487469 TI - Migratory and adhesive cues controlling innate-like lymphocyte surveillance of the pathogen-exposed surface of the lymph node. AB - Lymph nodes (LNs) contain innate-like lymphocytes that survey the subcapsular sinus (SCS) and associated macrophages for pathogen entry. The factors promoting this surveillance behavior have not been defined. Here, we report that IL7R(hi)Ccr6(+) lymphocytes in mouse LNs rapidly produce IL17 upon bacterial and fungal challenge. We show that these innate-like lymphocytes are mostly LN resident. Ccr6 is required for their accumulation near the SCS and for efficient IL17 induction. Migration into the SCS intrinsically requires S1pr1, whereas movement from the sinus into the parenchyma involves the integrin LFA1 and its ligand ICAM1. CD169, a sialic acid-binding lectin, helps retain the cells within the sinus, preventing their loss in lymph flow. These findings establish a role for Ccr6 in augmenting innate-like lymphocyte responses to lymph-borne pathogens, and they define requirements for cell movement between parenchyma and SCS in what we speculate is a program of immune surveillance that helps achieve LN barrier immunity. PMID- 27487470 TI - Gating of reafference in the external cuneate nucleus during self-generated movements in wake but not sleep. AB - Nervous systems distinguish between self- and other-generated movements by monitoring discrepancies between planned and performed actions. To do so, corollary discharges are conveyed to sensory areas and gate expected reafference. Such gating is observed in neonatal rats during wake-related movements. In contrast, twitches, which are self-generated movements produced during active (or REM) sleep, differ from wake movements in that they reliably trigger robust neural activity. Accordingly, we hypothesized that the gating actions of corollary discharge are absent during twitching. Here, we identify the external cuneate nucleus (ECN), which processes sensory input from the forelimbs, as a site of movement-dependent sensory gating during wake. Whereas pharmacological disinhibition of the ECN unmasked wake-related reafference, twitch-related reafference was unaffected. This is the first demonstration of a neural comparator that is differentially engaged depending on the kind of movement produced. This mechanism explains how twitches, although self-generated, trigger abundant reafferent activation of sensorimotor circuits in the developing brain. PMID- 27487472 TI - Evaluation of Motivational Interviewing to Improve Psychotropic Medication Adherence in Adolescents. AB - PROBLEM: Medication adherence rates in adolescents are poor. The World Health Organization identified that those at greatest risk were nonwhite adolescents with depression. Medication nonadherence results in poorer mental health outcomes. OBJECTIVE: The first aim of the study was to investigate if two motivational interviewing (MI) sessions would improve medication adherence in adolescents taking antidepressants and mood stabilizers. The second aim was to evaluate if attitudes toward medication correlated with adherence. The third aim was to determine if self-reported adherence scores were similar to electronic adherence data collected. METHODS: The quasi-experimental study contained an MI intervention, including a baseline and postintervention assessment of adherence over 30 days. A total of 48 adolescents, ranging in age from 12 to 18 years, were recruited from a university mental health center to participate in the study; 41 completed the study. Four nurse practitioners and two child psychiatrists mastered the MI techniques evaluated with standardized measures. The Medication Electronic Monitoring System (MEMS) was the primary measure of medication adherence. The Drug Attitude Inventory (DAI) was used as a secondary measure. Finally, participants completed the client evaluation of MI and a satisfaction survey of MI. RESULTS: At endpoint, 70.7% of the participants were taking their medications between 80% and 100% of the time, as measured over 30 days, compared with 43.9% of participants at baseline. Mean adherence scores significantly improved by 17% after two MI sessions. Mean baseline adherence scores were 63.7%, whereas mean endpoint adherence scores were 80.6% (p < 0.0001). The effect size was 0.65, demonstrating moderate effect. Participants (n = 29) who demonstrated 80% or greater adherence had DAI mean scores of 16.48, whereas those below 80% had a DAI mean of 15.5 (p = 0.73), demonstrating no significant difference on drug attitudes between the two groups at endpoint. DAI baseline mean scores were 14.2, whereas endpoint mean scores were 16.2. There was a significant difference between self-rated adherence and objective data collected from the MEMS caps as participants over-reported medication adherence by an average of 18.4% at baseline (t = 6.84, df = 40, p < 0.001). Participants reported a high degree of satisfaction with MI. CONCLUSIONS: MI is a promising intervention for adolescents to improve psychotropic medication adherence. PMID- 27487473 TI - Rupture of the pregnant uterus - a 20-year review. AB - OBJECTIVES: To examine the incidence, causative factors, maternal and foetal outcomes and subsequent fertility in cases of uterine rupture in scarred and unscarred uteri. METHODS: A 20 years' retrospective review was carried out where relevant data were collected from the medical records. Outcome measures included labour characteristics, operative procedures, maternal and perinatal outcome in addition to subsequent fertility. RESULTS: Forty-nine cases of complete uterine rupture were identified. Women in the unscarred group were older, had higher parity and heavier babies (p values < 0.05). Alternatively, the scarred group cases were associated with more silent rupture discovered at time of surgery, recession of the presenting part and more visceral involvement in particularly the urinary bladder. Admission to NICU and birth asphyxia were more frequent in the scarred group while stillbirth and early neonatal death were more common in the unscarred one. Twenty-four out of 49 cases had repair with no bilateral tubal ligation and out of these, 13 patients subsequently conceived and had 22 babies. CONCLUSION: Physicians should be vigilant to the risk factors and clinical presentations of uterine rupture during pregnancy. Cautious attempts to repair the ruptured uterus should be tried for patients' wellbeing and to help maintain fertility. PMID- 27487475 TI - MiR-329 suppresses osteosarcoma development by downregulating Rab10. AB - MiR-329 has been proved to be a tumor suppressor gene in various malignancies, however, its role in osteosarcoma remains elusive. We found that miR-329 is remarkably downregulated in osteosarcoma tissues and relates to advanced stages. MiR-329 is able to inhibit osteosarcoma cell proliferation, promote apoptosis, and induce G0/G1 cell cycle arrest. In addition, miR-329 also suppresses wound healing and migration ability of osteosarcoma cells and inhibits tumorigenicity in vivo. Rab10 was identified as a target of miR-329 in osteosarcoma and mediates its biofunction. These findings may shed light to the understanding of tumor development in osteosarcoma. PMID- 27487474 TI - Selective endosomal microautophagy is starvation-inducible in Drosophila. AB - Autophagy delivers cytosolic components to lysosomes for degradation and is thus essential for cellular homeostasis and to cope with different stressors. As such, autophagy counteracts various human diseases and its reduction leads to aging like phenotypes. Macroautophagy (MA) can selectively degrade organelles or aggregated proteins, whereas selective degradation of single proteins has only been described for chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI). These 2 autophagic pathways are specific for proteins containing KFERQ-related targeting motifs. Using a KFERQ-tagged fluorescent biosensor, we have identified an eMI-like pathway in Drosophila melanogaster. We show that this biosensor localizes to late endosomes and lysosomes upon prolonged starvation in a KFERQ- and Hsc70-4- dependent manner. Furthermore, fly eMI requires endosomal multivesicular body formation mediated by ESCRT complex components. Importantly, induction of Drosophila eMI requires longer starvation than the induction of MA and is independent of the critical MA genes atg5, atg7, and atg12. Furthermore, inhibition of Tor signaling induces eMI in flies under nutrient rich conditions, and, as eMI in Drosophila also requires atg1 and atg13, our data suggest that these genes may have a novel, additional role in regulating eMI in flies. Overall, our data provide the first evidence for a novel, starvation-inducible, catabolic process resembling endosomal microautophagy in the Drosophila fat body. PMID- 27487476 TI - Light energy attenuation through orthodontic ceramic brackets at different irradiation times. AB - OBJECTIVE: To evaluate the total light energy (TLE) transmission through three types of ceramic brackets with, bracket alone and with the addition of orthodontic adhesive, at different exposure durations, and to compare the microhardness of the cured adhesive. MATERIALS AND METHODS: Three different makes of ceramic brackets, Pure Sapphire(M), ClarityTM ADVANCED(P) and Dual Ceramic(P) were used. Eighteen specimens of each make were prepared and allocated to three groups (n = 6). MARC((r))-resin calibrator was used to determine the light curing unit (LCU) tip irradiance (mW/cm(2)) and TLE (J/cm(2)) transmitted through the ceramic brackets, and through ceramic bracket plus TransbondTM XT Light Cure Adhesive, for 5, 10 and 20 s. Vickers-hardness values at the bottom of the cured adhesive were determined. Statistical analysis used one-way analysis of variance (ANOVA); P = 0.05. RESULTS: TLE transmission rose significantly among all samples with increasing exposure durations. TLE reaching the adhesive- enamel interface was less than 10 J/cm(2), and through monocrystalline and polycrystalline ceramic brackets was significantly different (P < 0.05). Pure Sapphire(M) showed the highest amount of TLE transmission and Vickers-hardness values for 5, 10 and 20 s. CONCLUSION: Following manufacturer's recommendations, insufficient TLE may be delivered to the adhesive: increasing the exposure durations may be required when adhesive is cured through ceramic brackets. Clinicians are advised to measure the tip irradiance of their LCUs and increase curing time beyond 5 s. Orthodontic clinicians should understand the type of light curing device and the orthodontic adhesive used in their practice. PMID- 27487477 TI - H2O2/DMSO-Promoted Regioselective Synthesis of 3,3'-Bisimidazopyridinylmethanes via Intermolecular Oxidative C(sp(2))-H Bond Activation of Imidazoheterocycles. AB - In the past decade, metal-free approaches for C-C bond formation have attracted a great deal of attention due to their ease of use and low cost. This report represents a novel and metal-free synthesis of 3,3'-bisimidazopyridinylmethanes via intermolecular oxidative C(sp(2))-H bond functionalization of imidazo[1,2 a]pyridines with dimethyl sulfoxide as the carbon synthon (CH2) using H2O2 as a mild oxidant under air. A library of 3,3'-bis(2-arylimidazo[1,2-a]pyridin-3 yl)methanes has been achieved in good to excellent yields. The present methodology has been successfully applied to imidazo[2,1-b]thiazoles and imidazo[2,1-b]benzothiazoles. Furthermore, the current approach was also extended for the synthesis of unsymmetrical 3,3'-bisimidazopyridinylmethanes under optimized reaction conditions. A mechanistic pathway is proposed on the basis of experiments with radical scavengers and DMSO-d6 and ESI-MS observations. PMID- 27487478 TI - Assessing patient outcomes and cost-effectiveness of nurse-led follow-up for women with breast cancer - have relevant and sensitive evaluation measures been used? AB - AIMS AND OBJECTIVES: To explore how interventions using nurse-led follow-up in breast cancer care have been evaluated with a focus on patient outcomes and cost effectiveness. BACKGROUND: As part of the advancement of breast care, nurse-led follow-up is increasingly used as an alternative to routine hospital follow-up in outpatient clinics. There is evidence suggesting that patients appear to be satisfied with the nurse-led follow-up, but there is a lack of evidence of whether this perception equates to patients' satisfaction with the model of physician-led follow-up. DESIGN: Systematic review. METHOD: Three databases were searched, and 29 RCT were initially screened. Finally, 13 articles were critically appraised. Searches included articles between 2005-2013. The quality of appraisal assessment was inspired by the GRADE system. RESULTS: The results show that there are many different instruments used when evaluating nurse-led follow-up, which makes it difficult to compare the studies. Several of the studies used QoL as an outcome measure; this is a broad concept that includes several aspects ranging from social role and psychosocial issues to symptoms and therefore difficult to use as an outcome measure. Only two of the studies made any cost-effective analyses, and the results are hard to interpret. CONCLUSIONS: Nurse-led follow-up can potentially result in better continuity of care and the availability of more time to provide psychosocial support and address patients' information needs. However, more well-conducted research is needed before equivalence to physician-led follow-up can be assessed in terms of survival, recurrence, patient well-being and cost-effectiveness. RELEVANCE TO CLINICAL PRACTICE: Results from well-conducted evaluation studies of nurse-led services based on theory are needed so that relevant interventions can be implemented in clinical practice. There is a need to in future studies include cost effectiveness analyses to compare nurse-led services with other types of follow up. PMID- 27487479 TI - Age-Dependent Effects of Methylphenidate on the Human Dopaminergic System in Young vs Adult Patients With Attention-Deficit/Hyperactivity Disorder: A Randomized Clinical Trial. AB - IMPORTANCE: Although numerous children receive methylphenidate hydrochloride for the treatment of attention-deficit/hyperactivity disorder (ADHD), little is known about age-dependent and possibly lasting effects of methylphenidate on the human dopaminergic system. OBJECTIVES: To determine whether the effects of methylphenidate on the dopaminergic system are modified by age and to test the hypothesis that methylphenidate treatment of young but not adult patients with ADHD induces lasting effects on the cerebral blood flow response to dopamine challenge, a noninvasive probe for dopamine function. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled trial (Effects of Psychotropic Drugs on Developing Brain-Methylphenidate) among ADHD referral centers in the greater Amsterdam area in the Netherlands between June 1, 2011, and June 15, 2015. Additional inclusion criteria were male sex, age 10 to 12 years or 23 to 40 years, and stimulant treatment-naive status. INTERVENTIONS: Treatment with either methylphenidate or a matched placebo for 16 weeks. MAIN OUTCOMES AND MEASURES: Change in the cerebral blood flow response to an acute challenge with methylphenidate, noninvasively assessed using pharmacological magnetic resonance imaging, between baseline and 1 week after treatment. Data were analyzed using intent-to-treat analyses. RESULTS: Among 131 individuals screened for eligibility, 99 patients met DSM-IV criteria for ADHD, and 50 participants were randomized to receive methylphenidate and 49 to placebo. Sixteen weeks of methylphenidate treatment increased the cerebral blood flow response to methylphenidate within the thalamus (mean difference, 6.5; 95% CI, 0.4-12.6; P = .04) of children aged 10 to 12 years old but not in adults or in the placebo group. In the striatum, the methylphenidate condition differed significantly from placebo in children but not in adults (mean difference, 7.7; 95% CI, 0.7-14.8; P = .03). CONCLUSIONS AND RELEVANCE: We confirm preclinical data and demonstrate age-dependent effects of methylphenidate treatment on human extracellular dopamine striatal-thalamic circuitry. Given its societal relevance, these data warrant replication in larger groups with longer follow-up. TRIAL REGISTRATION: identifier: NL34509.000.10 and trialregister.nl identifier: NTR3103. PMID- 27487480 TI - In vitro and in vivo effects of morin on the intestinal absorption and pharmacokinetics of olmesartan medoxomil solid dispersions. AB - PURPOSE: In-situ evaluation to corroborate morin effects on the intestinal absorption and pharmacokinetic behavior of freeze-dried OLM-loaded solid dispersions with Caco-2 and in-vivo studies Methods: Intestinal transport and absorption studies were examined by Caco-2 permeability, in-situ single pass perfusion and closed-loop models along with in-vivo pharmacokinetic studies to evaluate and confirm the effect of P-gp-mediated activity of morin. We evaluated the intestinal membrane damage in the presence of morin by measuring the release of protein and lactate dehydrogenase (LDH) followed by using qualitative and quantitative morphometric analysis to describe the surface characteristics of intestinal epithelium. RESULTS: Morin showed the highest Peff value 13.8 +/- 0.34 * 10-6 cm/s in jejunum than ileum (p < .01) at 100 uM with absorption enhancement of 1.31-fold together with enhanced (p < .01) secretory transport of 6.27 +/- 0.27 * 10 -6 cm/s in Caco-2 monolayer cells. Our findings noticed 2.37 (in-situ); 2.39 (in-vivo) and 1.43 (in-situ); 1.36 (in-vivo) fold increase in AUC0-t with elevated Cmax and shortened Tmax for freeze-dried solid dispersion in the presence of morin as compared to pure OLM and freeze-dried solid dispersions without morin, respectively. CONCLUSIONS: Our study demonstrated that increased solubilization through freeze-dried OLM-loaded solid dispersion together with efflux inhibition improved intestinal permeability to one system that might lead to novel solubilization and efflux pump inhibition as a novel alternative potential to increase oral absorption and bioavailability of OLM. PMID- 27487482 TI - Crystal Structure of the Apicoplast DNA Polymerase from Plasmodium falciparum: The First Look at a Plastidic A-Family DNA Polymerase. AB - Plasmodium falciparum, the primary cause of malaria, contains a non photosynthetic plastid called the apicoplast. The apicoplast exists in most members of the phylum Apicomplexa and has its own genome along with organelle specific enzymes for its replication. The only DNA polymerase found in the apicoplast (apPOL) was putatively acquired through horizontal gene transfer from a bacteriophage and is classified as an atypical A-family polymerase. Here, we present its crystal structure at a resolution of 2.9A. P. falciparum apPOL, the first structural representative of a plastidic A-family polymerase, diverges from typical A-family members in two of three previously identified signature motifs and in a region not implicated by sequence. Moreover, apPOL has an additional N terminal subdomain, the absence of which severely diminishes its 3' to 5' exonuclease activity. A compound known to be toxic to Plasmodium is a potent inhibitor of apPOL, suggesting that apPOL is a viable drug target. The structure provides new insights into the structural diversity of A-family polymerases and may facilitate structurally guided antimalarial drug design. PMID- 27487481 TI - Molecular Mechanisms of Innate Immune Inhibition by Non-Segmented Negative-Sense RNA Viruses. AB - The host innate immune system serves as the first line of defense against viral infections. Germline-encoded pattern recognition receptors detect molecular patterns associated with pathogens and activate innate immune responses. Of particular relevance to viral infections are those pattern recognition receptors that activate type I interferon responses, which establish an antiviral state. The order Mononegavirales is composed of viruses that possess single-stranded, non-segmented negative-sense (NNS) RNA genomes and are important human pathogens that consistently antagonize signaling related to type I interferon responses. NNS viruses have limited encoding capacity compared to many DNA viruses, and as a likely consequence, most open reading frames encode multifunctional viral proteins that interact with host factors in order to evade host cell defenses while promoting viral replication. In this review, we will discuss the molecular mechanisms of innate immune evasion by select NNS viruses. A greater understanding of these interactions will be critical in facilitating the development of effective therapeutics and viral countermeasures. PMID- 27487483 TI - Phosphoinositide Binding Inhibits Actin Crosslinking and Polymerization by Palladin. AB - Actin cytoskeleton remodeling requires the coordinated action of a large number of actin binding proteins that reorganize the actin cytoskeleton by promoting polymerization, stabilizing filaments, causing branching, or crosslinking filaments. Palladin is a key cytoskeletal actin binding protein whose normal function is to enable cell motility during development of tissues and organs of the embryo and in wound healing, but palladin is also responsible for regulating the ability of cancer cells to become invasive and metastatic. The membrane phosphoinositide phosphatidylinositol (PI) 4,5-bisphosphate [PI(4,5)P2] is a well known precursor for intracellular signaling and a bona fide regulator of actin cytoskeleton reorganization. Our results show that two palladin domains [immunoglobulin (Ig) 3 and 34] interact with the head group of PI(4,5)P2 with moderate affinity (apparent Kd=17MUM). Interactions with PI(4,5)P2 decrease the actin polymerizing activity of Ig domain 3 of palladin (Palld-Ig3). Furthermore, NMR titration and docking studies show that residues K38 and K51, which are present on the beta-sheet C and D, form salt bridges with the head group of PI(4,5)P2. Moreover, charge neutralization at lysine 38 in the Palld-Ig3 domain severely limits the actin polymerizing and bundling activity of Palld-Ig3. Our results provide biochemical proof that PI(4,5)P2 functions as a moderator of palladin activity and have also identified residues directly involved in the crosslinking activity of palladin. PMID- 27487484 TI - A Vesicle Supra-Assembly Approach to Synthesize Amine-Functionalized Hollow Dendritic Mesoporous Silica Nanospheres for Protein Delivery. AB - Intracellular delivery of proteins is a promising strategy of intervention in disease, which relies heavily on the development of efficient delivery platforms due to the cell membrane impermeability of native proteins, particularly for negatively charged large proteins. This work reports a vesicle supra-assembly approach to synthesize novel amine-functionalized hollow dendritic mesoporous silica nanospheres (A-HDMSN). An amine silica source is introduced into a water oil reaction solution prior to the addition of conventional silica source tetraethylorthosilicate. This strategy favors the formation of composite vesicles as the building blocks which further assemble into the final product. The obtained A-HDMSN have a cavity core of ~170 nm, large dendritic mesopores of 20.7 nm in the shell and high pore volume of 2.67 cm3 g-1 . Compared to the calcined counterpart without amine groups (C-HDMSN), A-HDMSN possess enhanced loading capacity to large negative proteins (IgG and beta-galactosidase) and improved cellular uptake performance, contributed by the cationic groups. A-HDMSN enhance the intracellular uptake of beta-galactosidase by up to 5-fold and 40-fold compared to C-HDMSN and free beta-galactosidase, respectively. The active form of beta-galactosidase delivered by A-HDMSN retains its intracellular catalytic functions. PMID- 27487485 TI - Indocyanine Green Lymphographic Evidence of Surgical Efficacy Following Microsurgical and Supermicrosurgical Lymphedema Reconstructions. AB - Background Microsurgical vascularized lymph node transfer (VLNT) and supermicrosurgical lymphaticovenular anastomosis (LVA) are increasingly performed to treat lymphedema. The surgical outcome is commonly assessed by volume-based measurement (VBM), a method that is not consistently reliable. We describe indocyanine green (ICG) lymphography as an alternative postoperative tracking modality after lymphatic reconstruction with VLNT and LVA. Methods VLNT and LVA were performed in patients with therapy-refractory lymphedema. Patients were evaluated qualitatively by clinical assessment, quantitatively with VBM, and lymphographically using ICG lymphography. The evaluation was performed preoperatively, and at 3, 6, and 12-month postoperatively. Results Overall, 21 patients underwent lymphatic reconstruction with either VLNT or LVA. All reported prompt and durable relief of symptoms during the study period. All experienced disease regression based on the Campisi criteria. Out of the 21 patients, 20 (95%) demonstrated lymphographic down staging of disease severity. Out of the 21 patients, 3 (14%) developed a paradoxical increase in limb volume based on VBM despite clinical improvement. Conclusions ICG lymphography correlated highly with patient self-assessment and clinical examination, and is an effective postoperative tracking modality after lymphatic reconstruction. PMID- 27487487 TI - Hormonally active agents in the environment: a state-of-the-art review. AB - After the Second World War, infatuation with modern products has exponentially widened the spectrum of chemicals used. Some of them are capable of hijacking the endocrine system by blocking or imitating a hormone and are referred to as hormonally active chemicals or endocrine disruptors. These are chemicals that the body was not designed for evolutionarily and they are present in every matrix of the environment. We are living in a chemical world where the exposures are ubiquitous and take place in combinations that can interact with the endocrine system and some other metabolic activities in unexpected ways. The complexity of interaction of these compounds can be understood by the fact that they interfere with gene expression at extremely low levels, consequently harming an individual life form, its offspring or population. As the endocrine system plays a critical role in many biological or physiological functions, by interfering body's endocrine system, endocrine disrupting compounds (EDCs) have various adverse effects on human health, starting from birth defects to developmental disorders, deadly deseases like cancer and even immunological disorders. Most of these compounds have not been tested yet for safety and their effects cannot be assessed by the available techniques. The establishment of proper exposure measurement techniques and integrating correlation is yet to be achieved to completely understand the impacts at various levels of the endocrine axis. PMID- 27487486 TI - Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer stromal interactions in a mouse xenograft model. AB - Desmoplasia contributes to the aggressive behavior of pancreatic cancer. However, recent clinical trials testing several antifibrotic agents on pancreatic cancer have not shown clear efficacy. Therefore, further investigation of desmoplasia targeting antifibrotic agents by another mechanism is needed. Calpeptin, an inhibitor of calpains, suppressed fibroblast function and inhibited fibrosis. In this study, we investigated the anticancer effects of calpeptin on pancreatic cancer. We investigated whether calpeptin inhibited tumor progression using a mouse xenograft model. We used quantitative RT-PCR to evaluate the expression of calpain-1 and calpain-2 mRNA in pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs). We also undertook functional assays, including proliferation, migration, and invasion, to evaluate the inhibitory effects of calpeptin on PCCs and PSCs. Quantitative RT-PCR indicated that PCCs and PSCs expressed calpain-2 mRNA. Calpeptin reduced tumor volume (P = 0.0473) and tumor weight (P = 0.0471) and inhibited the tumor desmoplastic reaction (P < 0.001) in xenograft tumors in nude mice. Calpeptin also inhibited the biologic functions of PCCs and PSCs including proliferation (P = 0.017), migration (P = 0.027), and invasion (P = 0.035) in vitro. Furthermore, calpeptin reduced the migration of PCCs and PSCs by disrupting the cancer-stromal interaction (P = 0.0002). Our findings indicate that calpeptin is a promising antitumor agent for pancreatic cancer, due not only to its suppressive effect on PCCs and PSCs but also its disruption of the cancer-stromal interaction. PMID- 27487488 TI - Prevalence and awareness of functional and structural foot abnormalities in children and adolescents with type 1 diabetes. AB - BACKGROUND: The ISPAD guideline 2011/2014 advises annual podiatric screening to detect foot complications and identify other possible risk factors such as functional and structural foot abnormalities. The aim of this study was to assess the prevalence and awareness of neurovascular, functional and structural foot abnormalities in children and adolescents with type 1 diabetes mellitus (T1DM). METHODS: All patients aged 0-18 years with T1DM were invited for a foot examination and structured questionnaire by a certified podiatrist. RESULTS: Three of the examined patients (n=128) showed signs of possible long-term complications. Structural and functional foot problems were observed in 71.9% (n=92). Of all patients, 38.3% (n=49) required further treatment by a podiatrist. CONCLUSIONS: Functional and structural foot abnormalities are a frequent problem in children with T1DM in the southern part of the Netherlands. These abnormalities are an additional risk factor for developing long-term foot complications. Education in and implementation of the guideline are necessary. PMID- 27487489 TI - Novel homozygous likely-pathogenic intronic variant in INS causing permanent neonatal diabetes in siblings. AB - Permanent neonatal diabetes (PNDM) is a rare genetic condition characterized by hyperglycemia, insulinopenia, and failure to thrive beginning in the first 6 months of life. Recessive mutations in INS lead to decreased production of insulin via a variety of mechanisms. We present a case of two brothers, born to consanguineous parents, with a novel homozygous intronic variant in the INS gene. Each patient presented with intrauterine growth restriction (IUGR) and significant hyperglycemia within the first 24 h of life. All the grandparents have a diagnosis of diabetes, one of them requiring insulin treatment and the parents currently deny personal histories of diabetes. Although this mutation has not previously been described, given the segregation of the mutation, absence of heterozygosity (AOH) in the genomic region encompassing the INS locus, documented insulinopenia, and high neonatal insulin requirements, we suspect that this variant is pathogenic. Possible implications for personalized treatment of the underlying molecular etiology for an individual's diabetes are discussed. PMID- 27487490 TI - Tanshinones and mental diseases: from chemistry to medicine. AB - The prevalence of mental diseases, especially neurodegenerative disorders, is ever-increasing, while treatment options for such disorders are limited and insufficient. In this scarcity of available medication, it is a feasible strategy to search for potential drugs among natural compounds, such as those found in plants. One such plant source is the root of Chinese sage, Salvia miltiorrhiza Bunge (Labiatae), which contains several compounds reported to possess neuroprotective activities. The most important of these compounds are tanshinones, which have been reported to possess ameliorative activity against a myriad of mental diseases such as Alzheimer's disease, cerebral ischemia/reperfusion injury, and glioma, along with promoting neuronal differentiation and manifesting antinociceptive and anticonvulsant outcomes. This review offers a critical evaluation of the utility of tanshinones to treat mental illnesses, and sheds light on the underlying mechanisms through which these naturally occurring compounds confer neuroprotection. PMID- 27487491 TI - Correlative study of peripheral ATP1A1 gene expression level to anxiety severity score on major depressive disorder patients. AB - BACKGROUND: Major depressive disorder (MDD) frequently co-occurs with other psychiatric problems. Our previous study showed that ATP1A1 gene expression level was significantly decreased in MDD patients. This research explores the potential correlations between the ATP1A1 expression level reduction and MDD patients' clinical manifestation. METHODS: All participant patients were diagnosed by Diagnostic and Statistical Manual of Mental Disorders - 4th edition (DSM-IV). Hamilton rating scale for depression (HAM-D) and anxiety (HAM-A) were applied to group patients into different categories. ATP1A1 expression level was measured by reverse transcript real-time polymerase chain reaction. RESULTS: ATP1A1 expression levels of all MDD subgroups showed significant reduction compared to the control group (p<0.01). Further, the trend of ATP1A1 expression level reduction is significantly related to MDD patients' HAM-A scores (p<0.01). However, there was no significance between ATP1A1 level and HAM-D scores (p>0.05). CONCLUSIONS: ATP1A1 expression level reduction is related to MDD anxiety score, which may be an explanation for the clinical manifestations and the underlining physiological mechanisms. PMID- 27487492 TI - Comparative pre-emptive analgesic efficacy study of novel antiepileptic agents gabapentin, lamotrigine and topiramate in patients undergoing major surgeries at a tertiary care hospital: a randomized double blind clinical trial. AB - BACKGROUND: Surgical injury leads to postoperative pain hypersensitivity preceded by central nervous sensitization, due to lowered pain threshold in peripheral nociceptors and increased excitability of the spinal neurons. Pre-emptive analgesia is intended to decrease pain perception and overall analgesic need by use of drug regimen seizing central nervous system sensitization before exposure to painful stimuli. Earlier, few studies support pre-emptive analgesic efficacy of novel antiepileptic agent gabapentin. But topiramate and lamotrigine though proven analgesic in animal models of chronic pain and clinical studies of gabapentin resistant neuropathic pain; literature search revealed scarce data on its pre-emptive analgesic efficacy. The present study is designed to study and compare the pre-emptive analgesic efficacy of lamotrigine, topiramate and gabapentin (as control) in postoperative pain control. METHODS: This randomized clinical trial included 90 patients of either sex, between 18 and 70 years undergoing major surgeries. Patients were randomly allocated into control and test groups and received respective treatment 30 min before induction of anesthesia. Aldrete's score and pain score were recorded using visual analogue scale and facial and behavioral rating scales at awakening and at 1, 2, 4, 6 and 24 h. Postoperative rescue analgesic consumption for 24 h was recorded. Data were analyzed using OpenEpi and SciStatCalc statistical softwares. RESULTS: Significantly higher pain scores were observed in the topiramate group postoperatively for 2 h on all pain scales (p<0.05). Lamotrigine-treated patients were more comfortable throughout the study with significantly less (p<0.05) postoperative analgesic requirement comparable to gabapentin. CONCLUSIONS: Study results are strongly suggestive of pre-emptive analgesic efficacy of single oral dose lamotrigine comparable to gabapentin and superior to topiramate in postoperative pain control. PMID- 27487493 TI - Anti-inflammatory, anti-diarrheal, thrombolytic and cytotoxic activities of an ornamental medicinal plant: Persicaria orientalis. AB - BACKGROUND: Persicaria orientalis, an ornamental medicinal plant, has been used in traditional medicine for the treatment of various diseases. Although the plant is reported to have some important pharmacological effects, many medicinal values remain unidentified. Our objective was to evaluate the anti-inflammatory, anti diarrheal, thrombolytic, and cytotoxic properties of the methanol extract of P. orientalis leaves (Po-MeOH). METHODS: Anti-inflammatory activity was measured by the inhibition of hypotonicity-induced human red blood cell hemolysis and albumin denaturation technique in vitro of Po-MeOH. Diarrheal episodes were examined in mice with castor oil-induced diarrhea. The clot lysis and brine shrimp lethality bioassay in vitro were used to evaluate the thrombolytic and cytotoxic activities of the plant extract, respectively. RESULTS: Using in vitro anti-inflammatory models, the results demonstrated that Po-MeOH at the five different dose ranges from 31.25 to 500 MUg/mL significantly (p<0.05) protected (0.98%-50.71%) the erythrocyte membrane against lysis induced by hypotonic medium solution and protein denaturation (38.27%-79.22%) of bovine albumin, respectively. The extract exhibited a significant reduction of severity (75.17%) of castor oil-induced diarrhea in mice at the highest dose of 400 mg/kg compared to loperamide (82.06%) at 5 mg/kg. Po-MeOH also showed 33.14% clot lytic activity in the thrombolytic test and cytotoxicity with LC50 value 58.91 MUg/mL in the brine shrimp bioassay. CONCLUSIONS: These findings suggest that Po-MeOH has significant anti inflammatory and anti-diarrheal effects along with moderate thrombolytic and lower cytotoxic properties that may warrant the further exploration. PMID- 27487494 TI - Genetic modification of tomato with the tobacco lycopene beta-cyclase gene produces high beta-carotene and lycopene fruit. AB - Transgenic Solanum lycopersicum plants expressing an additional copy of the lycopene beta-cyclase gene (LCYB) from Nicotiana tabacum, under the control of the Arabidopsis polyubiquitin promoter (UBQ3), have been generated. Expression of LCYB was increased some 10-fold in ripening fruit compared to vegetative tissues. The ripe fruit showed an orange pigmentation, due to increased levels (up to 5 fold) of beta-carotene, with negligible changes to other carotenoids, including lycopene. Phenotypic changes in carotenoids were found in vegetative tissues, but levels of biosynthetically related isoprenoids such as tocopherols, ubiquinone and plastoquinone were barely altered. Transformants showed tolerance to the bleaching herbicide beta-cyclase inhibitor, 2-(4-chlorophenylthio) triethylamine. The phenotype was inherited for at least three generations. PMID- 27487495 TI - Commutability of proficiency testing material containing tobramycin: a study within the framework of the Dutch Calibration 2.000 project. AB - BACKGROUND: Results from external quality assessment schemes (EQASs) can provide information about accuracy and comparability of different measurement methods, provided that the material used in these schemes behave identical to patient samples among the different methods, a characteristic also known as commutability. The aim of this study was to assess the commutability of different matrices for the material used in an EQAS for tobramycin. METHODS: Proficiency testing material (PTM) and patient samples containing tobramycin were prepared, collected, pooled, and distributed to participating laboratories for analysis. Low, medium, and high tobramycin concentrations in liquid human, liquid bovine and lyophilized bovine serum were tested in this study. The patient serum results of every laboratory were plotted against each of the other laboratories, and the distances of the PTM results to the patient serum regression line were calculated. For comparison, these distances were divided by the average within laboratory standard deviation (SDwl) of the results reported in the official EQAS for tobramycin, resulting in a relative residual. The commutability decision limit was set at 3 SDwl. RESULTS: With 10 laboratories participating in this study, 45 laboratory couples were formed. For human serum, only one relative residual for high concentrations of tobramycin was found outside the commutability decision limit. For liquid and lyophilized bovine sera, the number of relative residuals outside the decision limit was between 15 and 18 for low, medium, and high tobramycin concentrations. CONCLUSIONS: The PTM used for tobramycin is preferably prepared with human serum. PMID- 27487496 TI - Detection of gastric Helicobacter spp. in stool samples of dogs with gastritis. AB - The aim of this study was to determine the prevalence and identify the species of gastric Helicobacter in the stool of dogs with gastritis. The study was carried out on thirty dogs of different breeds, of both genders and of various ages, diagnosed with gastritis. Helicobacter spp. was detected in stool samples using the nested-PCR method. Helicobacter bacteria were identified in stool samples from seven (23.3%) dogs. Helicobacter heilmannii was found to be the most common species of gastric Helicobacter. Helicobacter salomonis was identified much less frequently, while Helicobacter felis, Helicobacter pylori and Helicobacter bizzozeronii were not detected in any of the samples. PMID- 27487497 TI - Effects of boldenone undecylenate on growth performance, maintenance behaviour, reproductive hormones and carcass traits of growing rabbits. AB - The present study was done to evaluate the effect of boldenone undecylenate (BOL) on growth performance, maintenance behaviour, reproductive hormones and carcass traits of male rabbits. Sixty apparently healthy New Zealand White male rabbits, 5 weeks of age, were allotted to 3 equal groups. Each group was subdivided into 5 replicates, where the first group is control. The second group (B1) comprised rabbits that received 2 intramuscular injections of BOL (5 mg/kg) with 3 week intervals (9 and 12 weeks of age), while the third group (B2) included rabbits that received 3 intramuscular injections of BOL (5 mg/kg) with 2 week intervals (8, 10 and 12 weeks of age). The end of the trial was after 4 weeks from the last injection (16 weeks of age). The results revealed that the treated groups had a significant increase in total body weight, daily gain and feed efficiency, with a significant decrease in feed conversion ratio (FCR). Ingestive, locomotion and grooming behaviors were significantly higher in treated groups. Lateral pasture and exploratory behaviors were significantly higher in the control group. Administration of BOL resulted in a significant increase in dressing % and a significant decrease in testes %. Groups treated with BOL had a significantly (P<0.05) decreased serum testosterone level, simultaneously with a significantly increased estradiol level. The results indicate that BOL improves performance and carcass traits. Furthermore, there are hormonal-behavioral correlations through enhancement of ingestive and locomotion behaviors of treated animals. PMID- 27487498 TI - Tumor necrosis factor-alpha alters integrins and metalloprotease ADAM12 levels and signaling in differentiating myoblasts. AB - The extracellular matrix (ECM) is important in the regulation of myogenesis. We hypothesized that tumor necrosis factor-alpha (TNF-alpha) modifies ECM during differentiation of mouse C2C12 myoblasts. Exogenous TNF-alpha (1 ng/ml) stimulated myoblast fusion on the 3rd day (by 160% vs control) but not on the 5th day of myogenesis. The level of integrin alpha5 was significantly augmented by TNF-alpha during 5 day-differentiation; however, integrin beta1 was higher than control only on the 3rd day of cytokine treatment. Both the abundance of integrin alpha5 bound to actin and the level of integrin beta1 complexed with integrin alpha5 increased in the presence of TNF-alpha, especially on the 3rd day of differentiation. Similarly, the stimulatory effects of TNF-alpha on integrin alpha3, metalloprotease ADAM12 and kinases related to integrins, FAK and ILK, were limited to the 3rd day of differentiation. We concluded that TNF-alpha induced changes in ECM components in differentiating myogenic cells, i.e. i) increased expression of integrin alpha5, beta1, alpha3, and metalloprotease ADAM12, ii) enhanced formation of alpha5beta1 integrin receptors and interaction of integrin alpha5-cytoskeleton, and iii) increased expression of kinases associated with integrin signaling, FAK and ILK, were temporarily associated with the onset of myocyte fusion. PMID- 27487499 TI - The relationship between basal and luminal cytokeratins with histopathologic characteristics of canine mammary gland cancer. AB - Neoplasia occurs mostly in mammary glands in female dogs and mammary gland cancer is one of the causes of death in these animals cytokeratins are one of the most important of tumor markers for identification of tumor prognosis. In this study, 120 canine malignant tumor samples of mammary glands were studied. From each sample, a section was taken for hematoxylin-eosin staining and two sections for immunohistochemical staining of markers CK5/6 and CK7. Histopathology slides was evaluated by light microscope. The results show that the presence of markers CK7 and CK5/6 had no significant relationship with tumor grade and type (p<0.05). However, it seems that unlike humans, CK5/6 and CK7 is not an independent prognostic factor in canine mammary gland tumors. PMID- 27487500 TI - Production and characterization of egg yolk antibody (IgY) against recombinant VP8-S2 antigen. AB - Bovine Rotavirus and Bovine Coronavirus are the most important causes of diarrhea in newborn calves and in some other species such as pigs and sheep. VP8 subunit of rotavirus is the major determinant of the viral infectivity and neutralization. Spike glycoprotein of coronavirus is responsible for induction of neutralizing antibody response. Studies showed that immunoglobulin of egg yolk (IgY) from immunized hens has been identified to be a convenient source for specific antibodies for using in immunotherapy and immunodiagnostic to limit the infections. In this study, chimeric VP8-S2 gene was designed using by computational techniques. The chimeric VP8-S2 gene was cloned and sub-cloned into pGH and pET32a (+) vectors. Then, recombinant pET32a-VP8-S2 vector was transferred into E. coli BL21 CodonPlus (DE3). The expressed protein was purified by Ni-NTA chromatography column. Hens were immunized with the purified VP8-S2 protein three times. IgY was purified from egg yolks using polyethylene glycol precipitation method. Activity and specificity of anti-VP8-S2 IgY were detected by dot-blotting, Western-blotting and indirect ELISA. We obtained anti-VP8-S2 IgY by immunizing hens with the recombinant VP8-S2 protein. The anti-VP8-S2 IgY was showed to bind specifically to the chimeric VP8-S2 protein by dot-blotting, Western-blotting analyses and indirect ELISA. The result of this study indicated that such construction can be useful to investigate as candidates for development of detection methods for simultaneous diagnosis of both infections. Specific IgY against the recombinant VP8-S2 could be recommended as a candidate for passive immunization against bovine rotavirus and bovine coronavirus. PMID- 27487501 TI - Identification of point mutations in exon 2 of GDF9 gene in Kermani sheep. AB - Screening the fertile ewes from national herds to detect the major genes for prolificacy is an effective way to create the fertile flocks. Growth differentiation factor (GDF) 9 is a member of the transforming growth factor beta superfamily that is essential for folliculogenesis and female fertility. The aim of this study was to detect single nucleotide polymorphisms (SNPs) in exon 2 of GDF9 gene in Kermani sheep breed using PCR-SSCP. Genomic DNA was extracted from whole blood of collected samples using salting-out method. Whole exon 2 of GDF9 gene was amplified (634 bp and 647 bp fragments) using designed specific primers. The single stranded conformation polymorphism (SSCP) patterns of PCR products were studied using electrophoresis on acrylamide gel and silver-nitrate staining method. Finally, 4 banding patterns for the first primer pair and 4 banding patterns for the second primer pair were obtained. Also, indices of population genetic per SNP were calculated using Gen Alex 6.41 software. The sequencing results showed the presence of 3 mutations (SNP) (443, 477 and 721 positions) in the studied population. PMID- 27487502 TI - Lawsonia intracellularis and Porcine Circovirus type-2 infection in Estonia. AB - The present study describes the reasons of post-weaning distress in Estonian pig herds. Here we examined the natural cases of Lawsonia intracellularis and porcine circovirus 2 (PCV2) infection and co-infections. The presence of L. intracellularis in swine herds were tested by PCR and by histopathological methods, whereas PCV2 was detected by real-time-PCR and immunohistochemical stainings. Seven of the 11 investigated herds with signs of post-weaning wasting were infected with L. intracellularis and all 11 herds with PCV2. From the analysed samples 22.2% were infected with L. intracellularis and 25% with PCV2. The results of microbiological studies suggested that the piglets suffered from enteritis and pneumonia. Escherichia coli and Pasteurella multocida often aggravated the process of illness. The frequency of L. intracellularis was high in pigs 7-12 weeks old (18.5-42.7%) and PCV2 infection was too high in pigs 7-12 weeks old (24.8-32.7%). E. coli was often a co-factor with L. intracellularis and PCV2. The primary reasons of post weaning wasting were PCV2 and E. coli, later aggravated by L. intracellularis and other pathogens. Our results indicated that different pathogens have an important role in developing post-weaning wasting. Proliferative intestinal inflammation caused by L. intracellularis is mainly characterised by its localization and morphological findings. The main gross lesions were the enlargement of mesenteric lymph nodes and thickening of the wall of ileum. In post-weaning multi-systemic wasting syndrome there are characteristic histological lesions in lymphoid tissues. They consist of a variable degree of lymphocyte depletion, together with histiocytic and/or multinucleate giant cell infiltration. This basic lymphoid lesions is observable in almost all tissues of a single severely affected animal, including lymph nodes, Peyer's patches and spleen. Sporadically, multifocal coagulative necrosis may be observed. PMID- 27487503 TI - Differential expression of Toll-like receptor 4 signaling pathway genes in Escherichia coli F18-resistant and - sensitive Meishan piglets. AB - The Toll-like receptor 4 (TLR4) signaling pathway is an important inflammatory pathways associated with the progression of numerous diseases. The aim of the present study was to investigate the relationship between TLR4 signaling and resistance to Escherichia coli F18 in locally weaned Meishan piglets. Using a real-time PCR approach, expression profiles were determined for key TLR4 signaling pathway genes TLR4, MyD88, CD14, IFN-alpha, IL-1beta and TNF-alpha in the spleen, thymus, lymph nodes, duodenum and jejunum of E. coli F18-resistant and -sensitive animals. TLR4 signaling pathway genes were expressed in all the immune organs and intestinal tissues, and the expression was generally higher in the spleen and lymph nodes. TLR4 transcription was higher in the spleen of sensitive piglets (p<0.05), but there was no significant difference in TLR4 mRNA levels in other tissues. Similarly, CD14 transcription was higher in lymph nodes of sensitive animals (p<0.05) but not in other tissues. IL-1beta expression was higher in the spleen and in the duodenum of resistant piglets (p<0.05, p<0.01, respectively), and there were no significant differences in other tissues. There were also no significant differences in the expression of MyD88, TNF-alpha and IFN-alpha between sensitive and resistant piglets (p>0.05). These results further confirm the involvement of the TLR4 signaling pathway in resistance to E. coli F18 in Meishan weaned piglets. The resistance appeared to be mediated via downregulation of TLR4 and CD14, and upregulation of MyD88 that may promote the release of cytokines TNF-alpha, IL-1beta, IFN-alpha and other inflammatory mediators which help to fight against E. coli F18 infection. PMID- 27487505 TI - Modeling the effect of temperature on survival rate of Listeria monocytogenes in yogurt. AB - The aim of the study was to (i) evaluate the behavior of Listeria monocytogenes in a commercially produced yogurt, (ii) determine the survival/inactivation rates of L. monocytogenes during cold storage of yogurt and (iii) to generate primary and secondary mathematical models to predict the behavior of these bacteria during storage at different temperatures. The samples of yogurt were inoculated with the mixture of three L. monocytogenes strains and stored at 3, 6, 9, 12 and 15 degrees C for 16 days. The number of listeriae was determined after 0, 1, 2, 3, 5, 7, 9, 12, 14 and 16 days of storage. From each sample a series of decimal dilutions were prepared and plated onto ALOA agar (agar for Listeria according to Ottaviani and Agosti). It was found that applied temperature and storage time significantly influenced the survival rate of listeriae (p<0.01). The number of L. monocytogenes in all the samples decreased linearly with storage time. The slowest decrease in the number of the bacteria was found in the samples stored at 6 degrees C (D-10 value = 243.9 h), whereas the highest reduction in the number of the bacteria was observed in the samples stored at 15 degrees C (D-10 value = 87.0 h). The number of L. monocytogenes was correlated with the pH value of the samples (p<0.01). The natural logarithm of the mean survival/inactivation rates of L. monocytogenes calculated from the primary model was fitted to two secondary models, namely linear and polynomial. Mathematical equations obtained from both secondary models can be applied as a tool for the prediction of the survival/inactivation rate of L. monocytogenes in yogurt stored under temperature range from 3 to 15 degrees C, however, the polynomial model gave a better fit to the experimental data. PMID- 27487504 TI - Microbiological and parasitological survey of zoonotic agents in apparently healthy feral pigeons. AB - Microbiological and parasitological investigation was carried out on a colony of feral pigeons, located in a green area near the main hospital of a Central Italy city. One hundred pigeons were submitted to clinical examination. Cloacal swabs, grouped in pool of 4 samples, were analyzed to detect the presence of Coxiella burnetii, Chlamydia psittaci, Chlamydophila spp. using a biomolecular procedure, while individual cloacal samples were examined for Salmonella spp., Campylobacter spp., and yeasts by means of a specific culture media. An ELISA test was used to determine the presence of Giardia spp., and Cryptosporidium spp. coproantigens. Individual serological samples were also tested with the modified agglutination test (MAT) in order to detect antibodies against Toxoplasma gondii. The pigeons did not show any clinical signs. The cloacal pools proved to be negative for C. burnetii DNA while three pools were positive for C. psittaci or Chlamydophila spp. DNAs. Salmonella spp. was not detected. C. jejuni and C. coli were found in 13% and 4% of the samples, respectively. No Giardia spp. and Cryptosporidium spp. were detected. Thirty-three out of 100 samples (33%) were positive for yeast colonies. The seroprevalence for T. gondii was 8%. Although with moderate incidence, potentially zoonotic agents were present thus highlighting the need for sanitary surveillance on feral pigeon colonies. PMID- 27487506 TI - Morphology of immune organs after very virulent plus strain of Marek's disease virus infection in vaccinated hens. AB - Marek's disease (MD) outbreaks in poultry flocks may be associated with overriding of vaccine immune protection by very virulent (vvMDV) or very virulent plus (vv+MDV) strains. This paper presents the study on lymphoid organ morphology in the latent phase of MD caused by vv+MDV which break post-vaccinal protection in hens. We also immunohistochemically examined B and T populations as well as B/T and CD4+/CD8+ ratio of lymphocytes in lymphatic organs and, as a background, in MD lymphomas from non-lymphatic organs. The number of antigen expressed cells was evaluated as a percentage of positive cells in the one power field. Organ samples were collected from 24 dead reproductive hens (Ross 308 line) in age between 35-56 weeks, infected with vv+MDV. The hens originated from farms with MD outbreaks, despite earlier routine vaccination with CVI988/Rispens + HVT. The control organ samples originated from 15 clinically healthy hens at the same age and line, subjected to the same vaccination schedule. The number of CD3+, CD8+ and TCRgammadelta+ cells was significantly lower in MDV infected thymus, spleen and cecal tonsils in comparison to that found in the control organs. The proportion of CD4+ was also distinctly reduced in the thymus and limited in the spleen of MDV infected hens. This study revealed that infection with field vv+MDV isolates might break post-vaccinal protection and influence the central and peripheral immune system. The decrease in CD8+ and TCRgammadelta+ cell number in the thymus, spleen and cecal tonsils suggests that primarily these cells are involved in cell-mediated cytotoxicity against MDV transformed cells during latency. PMID- 27487507 TI - Safety of the long-term application of QuikClot Combat Gauze, ChitoGauze PRO and Celox Gauze in a femoral artery injury model in swine - a preliminary study. AB - The purpose of this study was to examine the safety of the long-term application of QuikClot Combat Gauze, ChitoGauze PRO and Celox Gauze using a swine model. The study was conducted on nine pigs weighing approximately 30 kg, which were randomly divided into three groups. Under deep anesthesia, the pigs underwent complete transverse cutting of the femoral artery in the groin region. Hemostatic dressings were left in the wound for 24 hours. The animals were euthanized 24 hours after dressing application. In each group, macroscopic and microscopic severe changes and shock symptoms were observed in the lungs, liver, kidneys and heart. Fibrino-gaseous embolic material was found in the pulmonary artery of each group and in the lung vessels of the animals from the ChitoGauze PRO and Celox Gauze groups. In conclusion, the long-term application of the evaluated hemostatic dressings has the risk of coagulopathy and reaching the progressive stage of shock. The residues from the hemostatic dressings can ingress into the systemic circulation, thereby increasing the risk of embolus formation. Because of these harmful effects, the evaluated hemostatic dressings are not appropriate for long-term use. Future studies are needed on the consequences of the long-term application of these hemostatic agents. PMID- 27487508 TI - Morphology and immunoreactivity of canine and feline extramedullary plasmacytomas. AB - The aim of the study was the evaluation of morphology and immunophenotype of canine (19 cases) and feline (7 cases) extramedullary plasmacytomas. Tumours, located in skin, oral cavity and spleen were surgically excised, fixed and processed for histopathology and immunohistochemistry (CD79alpha, CD18, proliferating cell nuclear antigen, metallothionein). Histologically, tumours were classified into mature, cleaved, asynchronous, polymorphous blastic, hyalin, or monomorphous blastic type. All evaluated tumours showed cytoplasmic expression of CD79alpha antigen. The expression of CD18 was observed in canine cutaneous and splenic tumours. In canine tumours expression of metallothionein was low to moderate, while in feline plasmacytomas - absent or low. In canine tumours, the mitotic index and proliferating cell nuclear antigen index were positively correlated with the expression of metallothionein. In feline tumours no correlation between mitotic index, proliferating cell nuclear antigen and metallothionein was found. This is the first study describing expression of metallothionein in canine and feline extramedullary plasmacytoma. PMID- 27487509 TI - Occurence of Bordetella bronchiseptica in domestic cats with upper respiratory tract infections. AB - Bordetella bronchiseptica is a widespread Gram-negative pathogen occurring in different mammal species. It is known to play a role in the etiology of infectious atrophic rhinitis of swine, canine kennel cough, respiratory syndromes of cats, rabbits and guinea pigs, and sporadic human cases have also been reported. The aim of this article is to present the occurrence of infections caused by these bacteria in domestic cats with respiratory symptoms, as well as to conduct a molecular analysis of the flaA gene B. bronchiseptica for the purpose of ascertaining whether cats become infected with one or more bacteria strains. B. bronchiseptica was isolated from the respiratory system of 16 out of 35 domestic cats with symptoms of respiratory tract infections. Polymorphism analysis of polymerase chain reaction products of B. bronchiseptica flaA was performed to reveal the possible differences in nucleotide sequences of the flagellin gene. The phylogenetic analysis of nucleotide sequences obtained during PCR indicated that the isolates of bacteria from our own studies are characterised by 100% homology of the analysed fragment of the flaA gene, which suggests maintenance of a single genotype of these microorganisms in the cat population. Moreover, the bacteria revealed full homology with reference strain B. bronchiseptica ATCC 4617, and 99.4% homology with strain B. parapertussis ATCC 15311. This indicates that the PCR optimised for the Bordetella spp. flaA gene, combined with sequencing of amplicons obtained in PCR, is an effective diagnostic method allowing differentiation of Bordetella spp. type microorganisms. PMID- 27487510 TI - Evaluation of bone marrow with particular consideration of the megakaryocyte lineage and coagulation profile in the pregnant fallow deer (Dama dama). AB - The aim of the study was to evaluate the megakaryocyte lineage of bone marrow and coagulation parameters in fallow deer during the last month of pregnancy. The animals were managed in the barn-feeding system. Twenty female fallow deer, aged 2-3 years, divided into 2 groups were used in the study. Group 1 comprised the females in the last month of pregnancy, and the non-pregnant females were used as the control. All the animals were clinically healthy. Coagulation parameters were measured in all the deer: thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), and plasma concentrations of fibrinogen, D dimer, and antithrombin III. A quantitative assessment of bone marrow was carried out for the erythroblastic, myeloid, lymphoid, monocyte-macrophage, and megakaryopoietic cell lines. A detailed analysis of megakaryocyte lineage was performed after whole blood and platelet count. There were no significant differences in the erythroblast, granulocyte, monocyte-macrophage and lymphoid systems between the animal groups. Thrombocyte count in the pregnant deer was lower than that found in the control group. Bone marrow smears revealed a slightly decreased megakaryocyte count, while the megakaryoblast and promegakaryocyte counts were unchanged. The analysis of coagulation parameters showed increased levels of fibrinogen, thrombin time, prothrombin time and activated partial thromboplastin time in the pregnant animals. The study suggested a hyperactivation of the coagulation system with a slight reduction in the megakaryocyte count in bone marrow, and a reduction in platelet count in peripheral blood at the end of pregnancy. PMID- 27487511 TI - Serum concentrations of PIIINP aminopeptide in dogs with liver fibrosis. AB - The aim of the study was to evaluate the serum concentration of the type III procollagen aminopeptide in dogs, and to assess its utility in the diagnosis of liver fibrosis. The study was carried out on 20 dogs of different breeds and of both genders, between 7 and 15 years old. Based on the results of the histopathological examination and the evaluation of the degree of liver fibrosis, the dogs were divided into five groups. The mean serum PIIINP concentration in the group of dogs with stage 1 and 2 liver fibrosis (groups 2 and 3) was five fold higher than in healthy dogs (group 1). In turn, the mean PIIINP concentration in the group of dogs with stage 3 (group 4) and stage 4 (group 5) fibrosis was 10-fold higher than that of the control group (group 1). Based on the results, we found that the serum PIIINP concentration correlated with the degree of liver fibrosis, assessed based on a histopathological examination. Therefore, PIIINP serum concentration tests may be a promising non-invasive diagnostic technique that could be used in veterinary hepatology to assess the degree of liver fibrosis. PMID- 27487512 TI - Concentration of hepatic vitamins A and E in rats exposed to chlorpyrifos and/or enrofloxacin. AB - The aim of the study was to determine the level of antioxidant vitamins A and E in the liver of rats exposed to chlorpyrifos and/or enrofloxacin. Chlorpyrifos (Group I) was administered at a dose of 0.04 LD50 (6 mg/kg b.w.) for 28 days, and enrofloxacin (Group II) at a dose of 5 mg/kg b.w. for 5 consecutive days. The animals of group III were given both of the mentioned above compounds at the same manner as groups I and II, but enrofloxacin was applied to rats for the last 5 days of chlorpyrifos exposure (i.e. on day 24, 25, 26, 27 and 28). Chlorpyrifos and enrofloxacin were administered to rats intragastrically via a gastric tube. The quantitative determination of vitamins was made by the HPLC method. The results of this study indicated a reduction in the hepatic concentrations of vitamins A and E, compared to the control, which sustained for the entire period of the experiment. The four-week administration of chlorpyrifos to rats resulted in a significant decrease of vitamins in the initial period of the experiment, i.e. up to 24 hours after exposure. For vitamin A the maximum drop was observed after 24 hours (19.24%) and for vitamin E after 6 hours (23.19%). Enrofloxacin caused a slight (3-9%) reduction in the level of the analysed vitamins. In the chlorpyrifos-enrofloxacin co-exposure group reduced vitamins A and E levels were also noted, but changes in this group were less pronounced in comparison to the animals intoxicated with chlorpyrifos only. The decrease in the antioxidant vitamin levels, particularly noticeable in the chlorpyrifos- and the chlorpyrifos combined with enrofloxacin-treated groups, may result not only from the increase in the concentration of free radicals, but also from the intensification of the secondary stages of lipid peroxidation. PMID- 27487513 TI - Effect of neonatal or adult heat acclimation on plasma fT3 level, testicular thyroid receptors expression in male rats and testicular steroidogenesis in vitro in response to triiodothyronine treatment. AB - This study aimed to evaluate the effect of heat acclimation of neonatal and adult rats on their testes response to in vitro treatment with triiodothyronine (T3). Four groups of rats were housed from birth as: 1) control (CR) at 20 degrees C for 90 days, 2) neonatal heat-acclimated (NHA) at 34 degrees C for 90 days, 3) adult heat-acclimated (AHA) at 20 degrees C for 45 days followed by 45 days at 34 degrees C and 4) de-acclimated (DA) at 34 degrees C for 45 days followed by 45 days at 20 degrees C. Blood plasma and both testes were harvested from 90-day old rats. Testicular slices were then submitted to in vitro treatment with T3 (100 ng/ml) for 8 h. Plasma fT3 level was lower in AHA, NHA and DA groups than in CR group. Basal thyroid hormone receptor alpha1 (Thra1) expression was higher in testes of NHA and DA and beta1 receptor (Thrb1) in DA rats vs. other groups. In the in vitro experiment, T3: 1) decreased Thra1 expression in all groups and Thrb1 in DA group, 2) increased Star expression in CR, NHA and DA groups, and Hsd17b3 expression in NHA group, 3) decreased the expression of Cyp11a1 in NHA and DA groups, and Cyp19a1 in all the groups, 4) did not affect the activity of steroidogenic enzymes and steroid secretion (A4, T, E2) in all the groups. These results indicate, that heat acclimation of rats, depending on their age, mainly affects the testicular expression of steroidogenic enzymes in response to short lasting treatment with T3. PMID- 27487514 TI - Influence of various carbohydrate sources on postprandial glucose, insulin and NEFA concentrations in obese cats. AB - Carbohydrate is an important source of energy, which can significantly affect postprandial blood glucose and insulin levels in cats. In healthy animals, this is not a big concern; however, in obese and diabetic animals, this is an important detail. In the present study, the impact of four different carbohydrate sources (glucose, maltose, corn starch, and trehalose) on short-term post prandial serum glucose, insulin, and non-esterified fatty acid (NEFA) concentrations was investigated with four obese cats. Each of the carbohydrate sources was added to a commercial wet food diet for feeding the animals. A significant difference was observed in postprandial glucose, insulin, and NEFA area under the curve (AUC) values between each carbohydrate source in obese cats. Furthermore, glucose and maltose induced the highest postprandial glucose and insulin AUC values, whereas trehalose induced the lowest postprandial glucose and insulin AUC value amongst all carbohydrate sources, respectively, in obese cats. However, trehalose has a higher risk of inducing side effects, such as diarrhea, as compared to other carbohydrate sources. As such, different carbohydrate sources appear to have a very significant impact on post-prandial glycemia and subsequent insulin requirement levels in obese cats. These results might be useful when selecting a prescription diet for obese or diabetic cats. In addition, maltose appears to be capable of inducing experimentally evoked postprandial hyperglycemia in obese cats, which may serve as a good tool for use to check the impact and effectiveness of newly developed oral hypoglycemic drugs or supplements for cats in future experiments. PMID- 27487515 TI - Acute phase response in the primiparous dairy cows after repeated percutaneous liver biopsy during the transition period. AB - The aim of this study was to evaluate the acute phase response of dairy cows to repeated liver biopsy in order to estimate the safety of this procedure during the transition period. Liver biopsies (up to 1000 mg of liver tissue) were conducted twice a day, 7 days before expected parturition and 3 days after calving. The number of needle insertions for each biopsy was recorded and was dependent on the amount of obtained tissue. Blood samples were taken on day 7 before expected parturition, then on days 3, 4, 7 and 14 after calving. Body temperature was measured daily in all 30 cows from day 3 until day 14 after calving. The concentrations of haptoglobin, serum amyloid A, fibrinogen and interleukin-6 were determined in serum and plasma. In 16.7% of cows, the rectal body temperature rose by >= 0.5 degrees C on the day after liver biopsy. Although the concentrations of haptoglobin, serum amyloid A and fibrinogen increased significantly after calving (p<0.01), there was no influence of the number of biopsies on the acute phase reaction and repeated biopsy during the transition period had no effect on body temperature. Therefore, the procedure may be regarded as safe for cows during the transition period. PMID- 27487516 TI - The effects of freezing on long-term storage of canine erythrocytes. AB - Human medicine studies have so far demonstrated that erythrocytes may be preserved and stored at low temperatures for decades retaining their metabolic and biochemical properties. However, detailed studies regarding this problem are not yet available in veterinary medicine. Therefore, the objective of the current study was to investigate time-dependent effects of long-term frozen storage of canine red blood cells. Twelve healthy adult dogs meeting the criteria for blood transfusion were used in the study. Whole blood samples (450 +/- 45 ml) collected from each dog were centrifuged by a cryogenic microcentrifuge and packed RBC suspensions were obtained. The samples were prewashed three times in 0.9% NaCl solution and were allocated into three groups to be evaluated at three different time points (day 0 and month 4 and 6). The samples to be frozen were subjected to glycerolization and then stored at -80 degrees C for 4 and 6-month periods. At the end of this period the packed RBC samples were thawed, centrifuged and then washed in a consecutive series of dextrose solutions. 2,3-Diphosphoglycerate (2,3 DPG), Adenosin triphosphate (ATP), supernatant hemoglobin (SupHb), sodium (Na+) and potassium (K+) levels, residual glycerol concentrations and hemograms were evaluated and compared. Sterility tests were performed on all samples for bacterial contamination. A statistically significant decrease was noted in potassium levels, which was the natural outcome of deglycerolization process. No significant change was observed in terms of other parameters due based on different time points. In conclusion, long-term frozen storage had no negative effect on the quality parameters of canine erythrocytes. PMID- 27487517 TI - Flow cytometric assessment of activation of peripheral blood platelets in dogs with normal platelet count and asymptomatic thrombocytopenia. AB - Platelets play a crucial role in hemostasis. Their activation has not yet been evaluated in healthy dogs with a normal and low platelet count. The aim of this study was to determine the influence of activators on platelet activation in dogs with a normal platelet count and asymptomatic thrombocytopenia. 72 clinically healthy dogs were enrolled. Patients were allocated into three groups. Group 1 consisted of 30 dogs with a normal platelet count, group 2 included 22 dogs with a platelet count between 100 and 200*109/l and group 3 consisted of 20 dogs with a platelet count lower than 100*109/l. Platelet rich-plasma (PRP) was obtained from peripheral blood samples using tripotassium ethylenediaminetetraacetic acid (K3-EDTA) as anticoagulant. Next, platelets were stimulated using phorbol-12 myristate-13-acetate or thrombin, stabilized using procaine or left unstimulated. The expression of CD51 and CD41/CD61 was evaluated. Co-expression of CD41/CD61 and Annexin V served as a marker of platelet activation. The expression of CD41/CD61 and CD51 did not differ between the 3 groups. Thrombin-stimulated platelets had a significantly higher activity in dogs with a normal platelet count than in dogs with asymptomatic thrombocytopenia. Procaine inhibited platelet activity in all groups. In conclusion, activation of platelets of healthy dogs in vitro varied depending on the platelet count and platelet activator. PMID- 27487518 TI - Escherichia coli strains from ostriches and their sensitivity to antimicrobial substances. AB - Ostriches are bred especially for their high-quality meat. There is a lack of knowledge concerning the ostrich's microflora. Escherichia coli is a commensal microorganism of the poultry intestine, ostriches included. However, some strains may become pathogenic. This study was therefore undertaken to detect coliform bacteria in ostrich faeces and to test their antibiotic profile and sensitivity to enterocins. Faeces (n=54, 18 mixture samples from 3 different age groups of 140 ostriches) were sampled to isolate coliform bacteria. The counts of coliform bacteria varied from 5.69 +/- 2.4 log10 CFU/g to 5.73 +/- 2.4 CFU/g. Pure colonies were identified using MALDI-TOF MS mass spectrometry and confirmed by phenotypization. Seventy-one strains were allotted to the species E. coli. Sixty four of those 71 strains caused hemolysis. They were mostly polyresistant to antibiotics. Thirty-two poly-resistant strains of E. coli were sensitive to enterocins. These strains were most sensitive to Ent 9296 (26 strains). Moreover, Ent EM41 produced by E. faecium EM41 (isolated from ostrich faeces) inhibited the growth of 20 strains, reaching activity of 100 AU/ml. Our results indicate the possibility of enterocins being used for prevention/reduction of coliforms. Of course, in vivo studies are also being processed. PMID- 27487519 TI - Practical aspects of estimation of optimal time for vaccination of chicken against IBD with use of "Deventer formula". AB - One of the most commonly applied vaccination strategies against chicken infectious bursal disease (IBD) is the use of live vaccines at the optimal time estimated with the use of Deventer formula. The present study investigated the impact of different factors on maternally derived antibodies decline and therefore on the vaccination schedule against IBD. Our results suggest that blood collection from birds older than 3 days is more reliable in order to estimate the optimal date for IBD vaccination, due to disturbances in yolk sac resorption early after hatch. PMID- 27487520 TI - Serum malondialdehyde level and activity of total antioxidant status of dogs with age-related cataract. AB - STUDY OBJECTIVE: determination of malondialdehyde (MDA) level and total antioxidant status (TAS) in the serum of dogs with age-related cataract. MATERIAL AND METHODS: Forty dogs, 10-16 years of age, which were diagnosed with age related cataract were examined. The control group consisted of 12 dogs, 8-13 years of age, without cataract. MDA was determined using a Perkin-Elmer LS 30 luminescence spectrometer using the method with thiobarbituric acid (TBA). TAS was determined using the colorimetric method with a set of Randox Total Antioxidant Status reagents. RESULTS: The results show a higher level of MDA with statistically significant difference and lower activity of TAS in the serum of dogs with age-related cataract. CONCLUSIONS: The results obtained indicate higher systemic lipid peroxidation and weakening of the general defense system in dogs with age-related cataract. These results suggest that such conditions may have an effect on the development of age-related cataract and are consistent with the theory of free radical age-related cataract development. PMID- 27487521 TI - Cytodiagnostics of canine lymphomas - possibilities and limitations. AB - Malignant lymphomas are one of the most common malignant tumours occurring in dogs. The basic method of lymphoma diagnosis in human, as well as in canine oncology is histopathology supported by immunohistochemistry. It was suggested that in veterinary medicine excisional biopsy of lymph node and histopathology should be considered only where the cytologic diagnosis is equivocal or needs to be confirmed. There are at least three basic reasons for which cytological examination ought to be accepted as a sufficient and reliable diagnostic method for lymphoma in dogs. Firstly, most dog owners consider the fine-needle biopsy as an acceptable non-harmful method of sample collection. Secondly, an increasing number of studies recommend cytology as an accurate test for diagnosing and subtyping canine lymphoma. Finally, the vast majority of canine lymphoma subtypes belong to 4-5 categories characterized by a typical cytological picture. Immunocytochemical staining of cytological smears gives new diagnostic possibilities, such as detection of markers better characterizing given growth or a potential goal for target therapy in individual cases (for example inhibitors of platelet-derived growth factor). PMID- 27487522 TI - Secretory function of adipose tissue. AB - There are two kinds of adipose tissue in mammals: white adipose tissue - WAT and brown adipose tissue - BAT. The main function of WAT is accumulation of triacylglycerols whereas the function of BAT is heat generation. At present, WAT is also considered to be an endocrine gland that produces bioactive adipokines, which take part in glucose and lipid metabolism. Considering its endocrine function, the adipose tissue is not a homogeneous gland but a group of a few glands which act differently. Studies on the secretory function of WAT began in 1994 after discovery of leptin known as the satiation hormone, which regulates body energy homeostasis and maintainence of body mass. Apart from leptin, the following belong to adipokines: adiponectin, resistin, apelin, visfatin and cytokines: TNF and IL 6. Adiponectin is a polypeptide hormone of antidiabetic, anti-inflammatory and anti-atherogenic activity. It plays a key role in carbohydrate and fat metabolism. Resistin exerts a counter effect compared to adiponectin and its physiological role is to maintain fasting glycaemia. Visfatin stimulates insulin secretion and increases insulin sensitivity and glucose uptake by muscle cells and adipocytes. Apelin probably increases the insulin sensitivity of tissues. TNF evokes insulin resistance by blocking insulin receptors and inhibits insulin secretion. Approximately 30% of circulating IL 6 comes from adipose tissue. It causes insulin resistance by decreasing the expression of insulin receptors, decreases adipogenesis and adiponectin and visfatin secretion, and stimulates hepatic gluconeogenesis. In 2004, Bays introduced the notion of adiposopathy, defined as dysfunction of the adipose tissue, whose main feature is insulin and leptin resistance as well as the production of inflammatory cytokines: TNF and IL 6 and monocyte chemoattractant protein. This means that excess of adipose tissue, especially visceral adipose tissue, leads to the development of a chronic subclinical inflammatory condition, which favours the development of insulin resistance and Type 2 diabetes. Obesity is a systemic illness caused by energy transformation homeostasis disorder which results in an increase in the amount of body fat mass. It effects approximately 40% of dogs and 20% of cats. Illnesses which accompany obesity result, to a great extent, from the secretive role of adipose tissue, which is still little known, which should be included when planning treatment of an obese animal. PMID- 27487523 TI - A Unique Hybrid Quasi-Solid-State Electrolyte for Li-O2 Batteries with Improved Cycle Life and Safety. AB - In the context of the development of electric vehicle to solve the contemporary energy and environmental issues, the possibility of pushing future application of Li-O2 batteries as a power source for electric vehicles is particularly attractive. However, safety concerns, mainly derived from the use of flammable organic liquid electrolytes, become a major bottleneck for the strategically crucial applications of Li-O2 batteries. To overcome this issue, rechargeable solid-state Li-O2 batteries with enhanced safety is regarded as an appealing candidate. In this study, a hybrid quasi-solid-state electrolyte combing a polymer electrolyte with a ceramic electrolyte is first designed and explored for Li-O2 batteries. The proposed rechargeable solid-state Li-O2 battery delivers improved cycle life (>100 cycles) and safety. The feasibility study demonstrates that the hybrid quasi-solid-state electrolytes could be employed as a promising alternative strategy for the development of rechargeable Li-O2 batteries, hence encouraging more efforts devoted to explore other hybrid solid-state electrolytes for Li-O2 batteries upon future application. PMID- 27487524 TI - A performance evaluation of a new iron oxide-based porous ceramsite (IPC) in biological aerated filters. AB - A novel medium containing iron oxide-based porous ceramsite (IPC) and commercial ceramsite (CC) was used in two laboratory-scale upflow biological aerated filters (BAFs) to treat city wastewater to compare their efficacy in wastewater treatment. The IPC BAF and CC BAF were operated in water at 20-26 degrees C, an air/water (A/W) ratio of: 3:1 and hydraulic retention times (HRTs) of 7, 3.5, 1.75, and 0.5 h and the removal of ammonia nitrogen (NH3-N), total nitrogen (TN), total organic carbon (TOC), and phosphorus (P) were studied. Our results indicated that IPC BAF was superior to CC BAF in terms of TOC, TN, NH3-N, and P removal. IPC had higher total porosity and larger total surface area than CC. The interconnected porous structure of IPC was suitable to microbial growth, protozoan, and metazoan organisms were primarily found in the accumulated biofilm layer. Biomass, in the biofilm layer, was detected at three distinct distances (300, 900, and 1500 mm) from the bottom of the inlet filter, again indicating that the IPC was more suitable for biomass growth. The presence of biomass improves the simultaneous removal efficiency of nitrogen and phosphorus in the IPC BAF. Thus, our findings support IPC as a material for use in filter media in wastewater treatment BAFs. PMID- 27487525 TI - Effects of intensive neuropsychological rehabilitation for acquired brain injury. AB - The objective of the study was to examine the effects of a comprehensive neuropsychological rehabilitation programme (Intensive NeuroRehabilitation, INR) on the emotional and behavioural consequences of acquired brain injury (ABI). The participants were 75 adult patients suffering from ABI (33 traumatic brain injury, 14 stroke, 10 tumour, 6 hypoxia, 12 other), all of whom were admitted to the INR treatment programme. The main outcome measures were: general psychological well-being (Symptom-Checklist-90), depression and anxiety (Beck Depression Inventory-II, Hospital Anxiety and Depression Scale, State Trait Anxiety Inventory), and quality of life (Quality of Life in Brain Injury). The study was a non-blinded, waiting-list controlled trial. During the waiting-list period no or minimal care was provided. Multivariate analysis of the main outcome measures showed large effect sizes for psychological well-being (partial eta2 = .191, p < .001), depression (partial eta2 = .168, p < .001), and anxiety (partial eta2 = .182, p < .001), and a moderate effect size for quality of life (partial eta2 = .130, p = .001). Changes on neuropsychological tests did not differ between the groups. It was concluded that the INR programme improved general psychological well-being, depressive symptoms, anxiety, and quality of life. The programme does not affect cognitive functioning. PMID- 27487526 TI - Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass. AB - Romosozumab, a monoclonal antibody that binds sclerostin, has a dual effect on bone by increasing bone formation and reducing bone resorption, and thus has favorable effects in both aspects of bone volume regulation. In a phase 2 study, romosozumab increased areal BMD at the lumbar spine and total hip as measured by DXA compared with placebo, alendronate, and teriparatide in postmenopausal women with low bone mass. In additional analyses from this international, randomized study, we now describe the effect of romosozumab on lumbar spine and hip volumetric BMD (vBMD) and BMC at month 12 as assessed by QCT in the subset of participants receiving placebo, s.c. teriparatide (20 ug once daily), and s.c. romosozumab (210 mg once monthly). QCT measurements were performed at the lumbar spine (mean of L1 and L2 entire vertebral bodies, excluding posterior processes) and hip. One year of treatment with romosozumab significantly increased integral vBMD and BMC at the lumbar spine and total hip from baseline, and compared with placebo and teriparatide (all p < 0.05). Trabecular vertebral vBMD improved significantly and similarly from baseline (p < 0.05) with both romosozumab (18.3%) and teriparatide (20.1%), whereas cortical vertebral vBMD gains were larger with romosozumab compared with teriparatide (13.7% versus 5.7%, p < 0.0001). Trabecular hip vBMD gains were significantly larger with romosozumab than with teriparatide (10.8% versus 4.2%, p = 0.01), but were similar for cortical vBMD (1.1% versus -0.9%, p = 0.12). Cortical BMC gains were larger with romosozumab compared with teriparatide at both the spine (23.3% versus 10.9%, p < 0.0001) and hip (3.4% versus 0.0%, p = 0.03). These improvements are expected to result in strength gains and support the continued clinical investigation of romosozumab as a potential therapy to rapidly reduce fracture risk in ongoing phase 3 studies. (c) 2016 American Society for Bone and Mineral Research. PMID- 27487527 TI - Evaluation of the Biotoxicity of Tree Wood Ashes in Zebrafish Embryos. AB - Ashes derived from biomass combustion and used as soil fertilizers can generate negative environmental and human health risks, related to leaching of heavy metals and other putative toxic elements. Tree wood ash composition may vary depending on geographical location and surrounding industrial processes. In this study, we evaluated the biotoxicity of lixiviated tree wood ash samples from trees of the Ash (Fraxinus), Cherry (Pronus), Hazel (Corylus), and Black locust (Robinia) genus collected in an industrialized region in Northern Italy. Elemental chemical analysis of the samples was performed by total reflection X ray fluorescence technique and their biotoxicity was assessed in zebrafish (Danio rerio) embryos. Ashes from Ash, Cherry, and Hazel trees, but not Black locust trees, had a high concentration of heavy metals and other putative toxic elements. Accordingly, a dose-dependent increase in mortality rate and morphological and teratogenic defects was observed in zebrafish embryos treated with lixiviated Ash, Cherry, and Hazel tree wood samples, whereas the toxicity of Black locust tree wood ashes was negligible. In conclusion, lixiviated wood ashes from different plants show a different content of toxic elements that correlate with their biotoxic effects on zebrafish embryos. Tree wood ashes derived from biomass combustion may represent a potential risk for the environment and human health. PMID- 27487528 TI - [Two compartment model of body composition and abdominal fat area in postmenopausal women - pilot study]. AB - INTRODUCTION: Both menopausal period and aging have influence on body composition, increase of total body fat and visceral fat in particular. We should be aware that changes in body composition, mainly fat translocation to abdominal region, can occur without significant changes in body weight. Therefore quantitative abdominal fat assessment should be our aim. THE AIM: Body composition analysis based on two compartment model and abdominal fat area assessment in cross section. MATERIAL AND METHODS: Subjects in postmenopausal period (41 women) were recruited for this study and divided into 2 groups: group 1 - women aged 45-56 years and group 2 - women aged 57-79 years. Body composition analysis and abdominal fat area assessment were conducted by using bioelectrical impedance method with BioScan 920 (Maltron int.) accordingly with standardized procedure. RESULTS: Women in early postmenopausal stage (Group 1) had statistically significant lower total body fat percentage in comparison with women in late postmenopausal period (Group 2) (41.09 +/- 7.72% vs. 50.7 +/- 9.88%, p=0.0021). Also women in group 1 were characterized by significant lower visceral fat area (VAT) as well as subcutaneous fat area (SAT) in comparison with group 2 (respectively VAT 119.25 +/- 30.09 cm2 vs. 199.36 +/- 87.38 cm2, p=0.0011; SAT 175.19 +/-57.67 cm2 vs. 223.4+/-74.29 cm2, p=0.0336). According to VAT criteria (>120 cm2), 44% of women in group 1 and 80% in group 2 had excess of visceral fat. CONCLUSIONS: Both total body fat and intra-abdominal fat increased with age, independently of weight changes. PMID- 27487529 TI - [Life satisfaction and self-esteem among women in the menopausal time]. AB - INTRODUCTION: The period of menopause is usually a long-lasting, running process, with strong hormone changes which are manifested with somatic disorders and the lability of the emotional state. The degree of severity of the occurence of these symptoms can be variously bolstered. These changes can affect the quality of life and ones self-esteem. THE AIM: To assess the level of self-esteem of biopsychosocial functioning women in the menopausal time and the impact of menopause on women's quality of life. MATERIAL AND METHODS: A group of 90 women in perimenopausal aged 49-61 were enrolled in the study. Standardized psychological questionnaires (Kupperman Index, SES Rosenberg and WHOQoL-BREF) were used. Additional data was collected by using a questionnaire developed by the authors. In statistical analysis chi2, analysis of variance and Spearman's rank correlation models were used. RESULTS: A significant correlation relationship between level of education and the sphere of psychological evaluation (p <0.05); and between the place of residence, and the assessment of the quality of life in the social (p <0.1) and environmental (p <0.1) sphere. Among the respondents, 95.45% of women received the result of the scale SES > 25 indicating the correct (in the normal or higher range) self-esteem. CONCLUSIONS: In the studied group, women believe that they have the correct (in the normal or higher range) self-esteem. The surveyed women found as good their quality of life, the highest rated was social and psychological sphere, the lowest score received sphere of physical functioning (somatic). A statistically significant correlations were achieved between home and professional activity, and the assessment of the quality of life in the social and environmental sphere. The analysis showed a significant association correlation between level of education of women and the sphere of psychological evaluation. PMID- 27487530 TI - [Modern look at pharmacotherapy of osteoarthritis accomplished with cardiovascular disease]. AB - ABSTR ACTCT Introduction: At present, the main pathogenetic link in the development of OA as atherosclerosis is chronic inflammation, which is based on the activation of pro-inflammatory mediators and disorders of cholesterol metabolism. The aim of the research was to study the efficiency of the use of rosuvastatin in the treatment of patients with osteoarthritis in the combined arterial disease. MATERIAL AND METHODS: The study was conducted on the basis of the Poltava Regional Clinical Hospital. N.V. Sklifosovsky and Research Institute of Genetic and immunological bases of pathology and pharmacogenetics higher state educational institution of Ukraine "Ukrainian Medical Dental Academy" (HSEEU "UMUMCA"). Results of treatment of 30 patients with osteoarthritis and hypertension who received treatment with rosuvastatin. CONCLUSIONS: It was concluded that the use of rosuvastatin in these patients can reduce pain, improve joint function, reduce disease activity and improve quality of life for patients. Besides rosuvastatin does not affect the level of systolic and diastolic blood pressure and can be used with concomitant hypertension. PMID- 27487531 TI - [Harmful alcohol consumption: prevalence, trends, health burden, reduction strategy]. AB - INTRODUCTION: Harmful alcohol consumption constitutes a significant cause of the global burden of disease, causing more than 200 different diseases, 5.9% of all deaths worldwide, causing substantial medical and social costs, major economic loss, slowing progress towards the strategic goals of human development. THE AIM: to substantiate approaches to the formation of a national strategy to combat the harmful use of alcohol in Ukraine based on the analysis of the prevalence of alcohol consumption and related health and social problems and international experience and recommendations of WHO. MATERIAL AND METHODS: The study was based on analysis of the extent and patterns of alcohol consumption in Ukraine, levels, structure and dynamics of morbidity and mortality from diseases associated with alcohol abuse; investigation of preventive activities in primary healthcare, the existing problems and doctors' needs for prevention alcohol abuse, national and international experience on this problem.This work usesbibliosemantic, medical, statistical, sociological, epidemiological methods. The information base are: European Health for All Database (HFA-DB)for 2000-2012,Center of Medical Statistics, Ministry of Health of Ukraine for 2000-2015, questionnaire survey of physicians in primary care, strategic and policy documents of WHO, WHO Regional Office for Europe. RESULTS: In Ukraine, as in most countries in the WHO European Region prevalence of alcohol is high. In the ranking of the WHO European Region Ukraine ranks fifth in alcohol consumption per capita. The structure of consumption of alcoholic drinks is dominated by strong spirits (48%). There has been a negative trend for this indicator from 5.4 liters in 2002 to 15.6 liters in 2012.The dominant pattern of alcohol consumption is characterized by early onset of alcohol consumption, significant frequency, large doses, mostly strong alcohol beverages, with significant share of low-quality alcohol. This factor contributes to high levels of morbidity. A total of546.3 thousandpeople with mental and behavioral disorders due to use of psychoactive substances wereregistered in health care facilities in 2014. Standardized mortality rate from causes related to alcohol in Ukraine (185.4 per 100 thousand.) is one of the largest in Europe, with only Kazakhstan (308.4) and Belarus (187.9) being behind. Regular work aiming at prevention of alcohol abuse is carried out by 49.4% of primary care professionals; 21.3% of physiciansinsist on reducing alcohol use on occasion. CONCLUSION: Alcohol abuse is a major factor of morbidity, epidemic of noncommunicable diseases in Ukraine, causing significant medical and social costs and economic losts.Ukraine ranks fifth in alcohol consumption per capita among WHO European Region countries. High level and unhealthy patterns of alcohol consumption in the population causes high morbidity and mortality from noncommunicable diseases, accidents, exceeding pan-European indices and indicators in the European Union. Primary health care facility staff has insufficient knowledge, skills and gaps in professional training regarding the prevention of harmful use of alcohol.There is a high need for effective strategies to reduce the prevalence of this risk factor in Ukraine. In developing the National Action Plan to reduce the harmful use of alcohol, a national context and WHO recommendationsshould be considered, including improving the efficiency of health services, high-quality prevention and effective treatment of disorders caused by alcohol, countermeasures on driving drunk, limiting the sale and availability of alcohol, prevention the spread of manufacturing and marketing of alcoholbeverages produced illegally, including falsification, the revitalization of local communities, weakening the impact of marketing of alcohol beverages. PMID- 27487532 TI - Risk factors for development of hypertension in poltava region. AB - INTRODUCTION: Given the very dangerous situation in relation to cardiovascular morbidity, purpose of the study was to identify the main risk factors of hypertension among the population of Poltava region, to determine their role in the formation of this pathology. AIM: study the factors for development of hypertension in Poltava region Material and methods: The study was conducted by anonymous questionnaires of adults of Poltava region (1285 individuals in 2 groups: 563 individuals with hypertension, 722 people - healthy). The data, obtained in the study, were processed using special software - IBM SPSS Statistic Version 22.0. By logistic regression were identified risk factors that significantly affect the development of hypertension. RESULTS: According to the study identified major, statistically significant risk factors of hypertension among the population of Poltava region. Proved reliable impact these risk factors: age (over 40 years) - OR - 7.9, CI - 6,132-10,176, (p<0,001), gender (male) - OR - 1.899, CI - 1,512-2,386, (p<0,001), BMI (obesity) - OR - 3.9632, CI - 2,881-4,580, (p<0,001), smoking - OR - 1.918, CI - 1,263-2,913, (p=0,002), consumption of dairy products (occasionally) - OR - 1,553, CI - 1,215-1,985, (p<0,001), consumption of pork (often) - OR - 1,805, CI - 1,422-2,290, (p<0,001), consumption of beef (occasionally) - OR - 1,547, CI - 1,229-1,949, (p=0,006), consumption of smoked meat (often) - OR - 1,341, CI - 1,070-1,678, (p=0,006), consumption of sweets (often) - OR - 1,510, CI - 1,210-1,884, (p<0,001), night sleep (restless) - OR - 1,762, CI - 1,279-2,426, (p<0,001), duration of sleep (less than 6 hours) OR - 1,648, CI - 1,126-2,411, (p=0,01), physical activity (low) - OR - 2,734, CI - 2,102-3,555, (p<0,001), nature of the rest (passive) - OR - 2,476, CI - 1,970-3,112, (p<0,001), feeling stress (always) - OR - 1,537, CI - 1,227-1,926, (p<0,001), relations at home (tense) - OR - 3,072, CI - 1,517 6,221, (p=0,001), CVD in the family - OR - 1,397, CI - 1,110-1,758, (p=0,004), discomfort in the heart aria - OR - 3,090, CI - 2,453-3,893, (p<0,001), self treatment - OR - 1.942, CI - 1,553-2,428, (p<0,001). CONCLUSIONS: The study found regional differences in risk factors of hypertension among the population of Poltava region, emphasized the need to increase attention of health professionals of primary care for problems of cardiovascular disease, make a point of the need to intensify primary prevention, modernization of behavior on health among population, promotion of the principles of a healthy lifestyle. PMID- 27487533 TI - [Upgrading of complete removable prosthetic appliance of stomatological patients by the use of new base materials]. AB - INTRODUCTION: The effectiveness of orthopedic treatment of edentulous patients depends on the properties of the basic materials. The main group of materials for manufacturing of such structures are acrylic plastics of thermal polymerization. However, many years of experience in the use of plastics has revealed a number of shortcomings. One of the main is insufficient functional durability of prostheses, and as a consequence - the fragility of acrylic constructions. At present, more and more dentists use nonacrylic thermoplastics, which can improve the functional quality of full removable dentures, as well as, avoid the above disadvantages of acrylic basic plastic. AIM: The work is devoted to the study of comparative clinical effectiveness of dental prosthetic in edentulous patients using a variety of basic materials for the production of removable dentures. MATERIAL AND METHODS: In this work we used the following materials - "Ftorax" - acrylic plastic of hot polymerization and "Vertex Thermosense" - nonacrylic thermoplastic plastic. RESULTS: As a result of the performed work it can be concluded that the use of the basic thermoplastic materials, namely "Vertex Thermosense", allows to get more rapid adaptation of the patient to full removable dentures due to better fixation and stabilization. CONCLUSION: Based on the results of our comparative clinical study it can be recommended using of base material "Vertex Thermosense" in the clinic of prosthetic dentistry in treatment of edentulous patients. PMID- 27487534 TI - Quality of life in patients with nonalcoholic fatty liver disease in combination with essential hypertension considering taste sensitivity to sodium chloride. AB - INTRODUCTION: Nonalcoholic fatty liver disease and hypertensive disease - is the most common combination of abnormalities that occur in people suffering from metabolic syndrome. Their combination not only causes concurrent damage of the liver and the heart, caused by common pathogenic beginning, and also mutually complicate the disease course of each other. The leading role in the development of nonalcoholic fatty liver disease belongs to abdominal obesity and insulin resistance, and is seen as a manifestation of liver disease in metabolic syndrome. Genetic predisposition, lifestyle, improper nutrition, including excessive use of sodium chloride, lead to excessive formation of visceral adipose tissue with development of abdominal obesity, which is a likely criterion of insulin resistance. The long course of nonalcoholic fatty liver disease in combination with essential hypertension in excessive consumption of sodium chloride may negatively affect their quality of life. The aim of the study is to find out the features of quality of life in patients with nonalcoholic fatty liver disease in combination with hypertensive disease with different taste sensitivity to sodium chloride. MATERIAL AND METHODS: We have investigated the quality of life of 65 patients with nonalcoholic fatty liver disease in combination with hypertensive disease II stage with different taste sensitivity to sodium chloride. Salt taste sensitivity threshold to sodium chloride is determined by the method of R. Henkin. Assessment of quality of life was performed using the Ukrainian version of the questionnaire Medical Outcomes Study Short Form 36 (MO S SF-36). RESULTS: Was revealed that in patients with nonalcoholic fatty liver disease in combination with hypertensive disease II stage with high salt taste sensitivity threshold observed the decline in the quality of life that manifests as a decline in physical condition (especially of the physical functioning, physical role functioning and general health perceptions) and mental health (especially social functioning). Also the increased salt intake and salt appetite in patients with high salt taste sensitivity threshold were noted (p <0,05). CONCLUSIONS: Reducing the use of sodium chloride can be a preventive measure easier than a decrease in body weight, and one that will reduce the body weight, especially in people with nonalcoholic fatty liver disease in combination with hypertensive disease, can reduce the risk of complications and improve quality of life in patients. PMID- 27487535 TI - [Cytokine profile in young children with acute stenotic laryngotracheitis]. AB - INTRODUCTION: One of the most severe complications of acute respiratory infections in young children is acute stenotic laryngotracheitis (croup). The relationship between cytokine blood levels and symptoms of croup, croup severity, disease sequel, despite numerous studies is still unclear. AIM: Cytokine profile in young children with acute stenotic laryngotracheitis investigation. MATERIAL AND METHODS: 112 children aged 12 min. - 36 mon. with acute stenotic laryngotracheitis which were treated at the Lviv Regional Infectious Diseases Hospital were kept under observation. Croup symptoms, levels of interleukins (IL1, IL4, IL6, IL10, IL17) in serum, DNA and RNA viruses in respiratory nasal mucus were studied; Chan croup severity was used. RESULTS: In the pathogenesis of croup has an important role the imbalance between inflammatory (IL1, IL6) and anti-inflammatory (IL4, IL10, IL17) cytokines, which does not reduce the intensity of inflammatory reactions and its lead to local swelling, muscle spasm, excessive production of mucus in the place of viral replication. The levels of inflammatory and anti-inflammatory cytokines in the blood serum of children with croup were significantly higher than in patients with acute laryngitis. In patients with recurrent croup, unlike patients with the first case of croup does we don't see a significant correlation between the concentrations of inflammatory and anti-inflammatory cytokine levels Conclusions: The significantly higher levels of cytokines in children with croup compared with the group of patients with acute laryngitis were found, imbalance between anti-inflammatory (IL1, IL6) cytokine levels and inflammatory (IL4, IL10, IL17) cytokine levels in children who developed recurrent croup. PMID- 27487536 TI - [Evaluation of therapy efficiency in patients with combined course of copd and osteoarthritis]. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a disease that is characterized by chronic airflow limitation, a variety of pathological changes in the lungs, significant extrapulmonary manifestations, and severe comorbidities which may further aggravate the course of COPD [GOLD, 2013]. Intensity of systemic manifestations increases with the progression of obstruction, therefore the abovementioned symptoms are often overlooked and become apparent in the later stages of the disease. Systemic manifestations impair the quality of life, lead to early disability and significantly contribute to mortality in patients with COPD. Diseases of cardiovascular and musculoskeletal systems are the most serious and socially significant systemic manifestations of chronic obstructive pulmonary disease. Currently, there is no doubt that the activation of non-specific and specific immune responses in patients with COPD is associated with the influence of a number of universal mediators, among which a special place belongs to the cytokine network that controls implementation processes of the immune and inflammatory reactivity. The aim of our work was to increase the effectiveness of treatment in patients with chronic obstructive pulmonary disease in combination with osteoarthritis based on the study of clinical course, assessment of patient's life quality and substantiation of pharmacological correction. MATERIAL AND METHODS: The work was conducted on the basis of Poltava Regional Clinical Hospital named after N.V. Sklifosovskiy. The study was carried out at Research Institute for Genetics and Immunological Grounds of Pathology and Pharmacogenetics of Higher State Educational Establishment of Ukraine "Ukrainian Medical Stomatological Academy" (HSEEU "UMUMCA"). The study involved 40 patients with an average age of 54.4 +/- 3.1 years with acute exacerbation of COPD (clinical group B-C - GOLD II-III), in combination with OA. The duration of COPD was 16.2 +/- 2.1 years. Among patients there were 28 (70%) men and 12 (30%) women. All patients were smokers; the smoking period was 32.4 +/- 2.9 pack-years. OA in the phase of unstable remission was verified in all patients, large joints were involved - knee, shoulder, and ankle. Depending on the chosen option of treatment, patients were divided into two representative groups - I and II. Patients of group I received only standard treatment for COPD in accordance with existing protocols, and in group II fenspiride hydrochloride 80 mg 2 times a day was added to the basic therapy for 12 days. Full examination of patients was carried out at admission and after 3 months from the date of admission. RESULTS: According to the study, on addition of fenspiride to basic therapy in patients with constellation of COPD and OA, the regression of disease (reduction in cough) was observed by 2.9 +/- 0.4 days earlier, dyspnea by 2.3 +/- 0.33 than in the comparison group (p < 0.05), quality of life improved, and exercise tolerance increased. FEV1 in patients of group I after 3 months amounted to 62.6 +/- 4.2%, in group II - 68.1 +/- 4.9%, recurrence of airflow obstruction in both groups increased: in group I - by 4.2 +/- 1.1%, in group II - by 5.6 +/- 1.5%. Adding fenspiride hydrochloride to the treatment significantly improved the life quality of patients with COPD combined with OA at all scales of SF-36 questionnaire, reflecting the patient's physical condition, namely, physical activity, the role of physical problems in vital functions, the intensity of pain, overall health status, vitality. After 3 months of follow-up, in patients with comorbidity influenced by fenspiride hydrochloride against the background of traditional pathogenic therapy, the indicators of VAS significantly decreased by 1.9 times (3.18 +/- 0.24 cm versus 6.01 +/- 0.59 cm, p <0, 05), Lequesne index - by 2.0 times (9.42 +/- 1.81 points against 19.17 +/- 4.15 points, p <0.05) and WOM AC by 1.6 times (38.7 +/- 3.7 points against 63.8 +/- 8.3 points, p <0.05), respectively. In patients of group II, a more pronounced positive dynamics of reducing inflammatory activity, confirmed by the decrease in TNF-alpha content by 1.9 times (61.8 +/- 5.9 pg / ml versus 131.5 +/- 6.9 pg / ml, p <0.001) was observed. The hospitalization period of patients in group I was 14.3 +/- 0.4 days, in group II it was less and amounted to 12.9 +/- 0.5 days. CONCLUSIONS: Supplementary application of fenspiride hydrochloride in the treatment of COPD patients in combination with OA improves the outcomes of patients' treatment, quality of life and prolongation of remission, indicating a decrease in the severity of systemic inflammation. PMID- 27487537 TI - Specific features of cytological and colposcopical pattern in pregnant women with benign cervix uteri pathology in anamnesis. AB - INTRODUCTION: a tendency of increasing incidence of the cervix uteri precancer and cancer in women of reproductive age is noticed recently being related to the growth of number of the sexually-transmitted infections. The cervix uteri pathology incidence in women of fertile age is 20-25%. AIM: to study the specific features of the cytological and colposcopical pattern in pregnant patients with benign cervix uteri pathology in the anamnesis and the character of its change post partum. MATERIAL AND METHODS: we have examined 195 women during their pregnancy and 3-5 months post partum. All pregnant women, alongside with generally accepted clinical and laboratory examinations, were subjected to the simple and extended colposcopy, cytology of the targeted smears and, according to indications, the histological studies of bioptate. RESULTS: according to the results of the colcoscopical studies and the signs of the cervix uteri pathology found, the patients were divided into several groups. A control group included 49 pregnant women. The clinical and instrumental examination of 146 women with cervix uteri pathology has been carried out both during pregnancy and post partum. CONCLUSIONS: the structure of the clinical forms of benign and premalignant changes in the cervix uteri epithelium in pregnant patients has been found. Specific features of the cytological and colposcopical pattern in pregnant patients with benign cervix uteri pathology in anamnesis have been studied. The relationship between the parity of pregnancy, delivery, route of delivery and regress of both benign and premalignant changes in the cervix uteri epithelium 3 5 months post partum has been determined. PMID- 27487538 TI - Advanced endodontic developments in pulpectomy of primary teeth. AB - INTRODUCTION: To appraise studies about pulpectomy in primary teeth with nickel titanium rotary files and smear layer removal and to find out may these developments enhance pulpectomy outcomes in primary teeth. MATERIAL AND METHODS: A systematic search was implemented for PubMed, Google and Google Scholar between the years 1995-January 2016 to identify eligible studies. Studies design was established according to the CEBM recommendations. Evidence quality of studies was appraised by risk of bias. RESULTS: Six studies about pulpectomy met the inclusion criteria, of which five were randomized controlled trials. Only one research demonstrates the enhanced outcome of pulpectomy in primary teeth with smear layer removal. Chosen studies have low overall evidence quality. CONCLUSIONS: Given the paucity, high heterogeneity of high-quality articles and their level of bias, recommendation for the use of nickel-titanium rotary files and smear layer removal in pulpectomy in primary teeth can yet not be formulated. PMID- 27487539 TI - [Skin cancer of the nose - methods and results of surgical treatment]. AB - BACKGROUND: Non-melanoma skin cancer particularly basal cell carcinoma is the most common human malignancy in Caucasians. The majority of these tumours (80 90%) arise on the sun exposed parts of face. Lesions of the nose are the most challenging for the surgeon, because of the aesthetic feature. THE AIM: The aim of the study is to evaluate results of surgical treatment of nose skin cancer. MATERIALS AND METHOD: Authors analysed retrospectively 23 cases of skin cancer of the nose. Demographic data, aesthetic units, surgical methods and complications as well as aesthetic and functional results of treatment were noted. RESULTS: 23 people (9 male and 14 female) with 23 skin lesions were included to the study. The mean age was 72 +/- 13 years. Majority of tumours infiltrated more then 1 nose aesthetic subunit. The most common surgical method of reconstruction was bilobed flap. Most of patients presented good aesthetic and functional outcome. CONCLUSIONS: The most important stage of treatment is proper qualification to surgical treatment - selection of reconstruction method, what establish radicalness of resection and good aesthetic and functional results. PMID- 27487540 TI - [Reliability and validity of assessment of educational outcomes obtained by students of Medical Rescue at Medical University of Warsaw]. AB - INTRODUCTION: In the interest of preservation of high degree of objectivity of information about students' educational outcomes, a system of assessment needs to meet criteria of appropriate reliability and validity. THE AIM: Analysis of reliability and validity of the system of assessment of students' educational outcomes for courses followed by an examination and covered by a curriculum in Medical Rescue at Medical University of Warsaw (MU W). MATERIALS AND METHODS: A retrospective study enrolling a group of 421 students of eight subsequent full education cycles. Detailed data concerning grades for fourteen courses followed by an examination in the entire course of studies were collected. Reliability (Cronbach's alpha coefficient) and criteria validity (Spearman's rank correlation) were assessed. Internal consistency was estimated using a multiple regression model. RESULTS: The levels of assessment reliability for the general university, pre-clinical, and clinical scopes amounted to alpha: 0.42, 0.53, and 0.70, respectively. The strongest positive correlations between the results of pre-clinical and clinical trainings were found for the Anatomy course (r ~ 0.30). Only in the case of the Pharmacology course it was found that students' achievements in this field were significantly correlated with all other courses of clinical training. The influence of educational outcomes in particular areas of clinical training on the final grade for the entire course of studies was diverse (beta regression between 0.04 and 0.11). While the Pharmacology course had the strongest impact on final results, the Surgery course had the least influence on students' final grades (beta = 0.04). CONCLUSIONS: 1. Sufficient reliability of the system of assessment of educational outcomes in Medical Rescue showed good precision and repeatability of assessment. 2. A low level of validity was caused by a failure to keep the appropriateness of the assessment of educational outcomes in several clinical courses. 3. Prognostic and diagnostic validity of methods used for evaluation of competencies of Medical Rescue students at WMU needs to be assessed in the future. PMID- 27487541 TI - [Pathological changes in the microstructure of the sensomotor cortex of white rats with experimental subarachnoid hemorrhage and after experimental influences]. AB - INTRODUCTION: Many works are dedicated to research in the experiment of the cerebrovascular diseases and correction of pathological changes. Among these studies we have not found devoted czuciowo-ruchowej changes cortex of rats subarachnoid hemorrhage. MATERIAL AND METHODS: The study was conducted on 18 white rats weighing 220-310 g. The model of subarachnoid hemorrhage (SAH) was created on the base of methodology described by Dudhani RV et al. (2013). SAH develops immediately after injection of autologous arterial blood into the subarachnoid space. Five animals underwent everyday intraperitoneal injection of NO Donator (L-arginine aspartate) for 8 days from the beginning of the experiment. Sampling of the biological material carried on the ninth day after euthanasia of the test animals under anesthesia with diethyl ether. RESULTS: Swollen, rounded shape neurons were observed while watching the microscope slides of rat brain samples after autologous blood injection. Otherwise, others cells in the same sample looked atrophous, of reduced size, shrunken. There was observed increase in surface area to 623.1 +/- 36.0 MUm2 and volume of neurons to 949.8+/ 78.0 mkm3, significant compared to healthy animals. The severity of pathologic changes was lower in group of therapy by NO donator, namely, the bodies of neurons of the similar size, their shape is almost triangular, most neurons also as macroglial cells have close to normal structure and pericellular zone. CONCLUSIONS: SAH evokes a number of pathological changes in the rats' brain sensomotor cerebral cortex. Modeling of the SAH leads to significant (p<0,01) morphometric changes in the pyramidal neurons, namely, to increase of the surface of nerve cells in an average up 1.33 times and 1.5 times - of the volume. Therapy by NO donator of animals with model of SAH reduces the severity of cells' lesion, the majority of neurons and macroglial cells have the shape and pericellular spaces close to the normal. PMID- 27487542 TI - [The questions of improving the information-analytical component in the reform of the health care system in Ukraine]. AB - INTRODUCTION: A priority task of the development strategy of the Ukrainian health care system is the saving and improving of public health. With the development of new economic relations, health care restructuring, the introduction of new financing mechanisms to policy-makers have an important task of the organization of operational management on the basis of timely quality information. According to many authors, the ability to improve the quality of the received information is possible due to the intercalation of information technologies. The main aim of our study is to determine the main directions of modernization of information analytical component during the health care reform. MATERIAL AND METHODS: The medical institutions reporting forms (f.20, f.12, f.17, f.47) were analyzed to achieve the goal, were conducted a survey of primary care physicians. The survey was attended by 265 family doctors, 80 of whom are family doctors of family medicine clinic of the regional center, 185 - medical centers of primary health care district centers. RESULTS: The analysis of the sociological research indicates that the work of the family doctor is accompanied by filling a large number of records, so according to the survey, an average of doctors per day filled about 15.74 +2.2 registration forms, on average per month 333,7+ 30 a month. The necessity of reform of the information-analytical component of the health care system have noted by 94% 1.4. Do not have a automated workstation 34.5% + 5.3 physicians of the regional center and 68% + 3.4 countryside. Possession of the computer at user level observed by 92% + 1.6, which is a good basis for the introduction of information in healthcare system. CONCLUSIONS: The data of the sociological survey confirm the necession of structural-functional procuring of the system of information-analytical supporting of the healthcare system of Ukraine. Annual health statistics reports are still relevant, but they need to improve and adapt to the new conditions of functioning of healthcare system and should be subject to automated processing of data at all levels. PMID- 27487543 TI - [Analysis of orthodontic treatment efficiency in children with dental crowding]. AB - INTRODUCTION: Efficiency of dental treatment is necessary to provide optimal results with less outlay of clinical time and shorter duration of treatment and for stable and balanced occlusion. AIM: To compare duration of orthodontic treatment in children with dental crowding by authoring and traditional methods. MATERIAL AND METHODS: Orthodontic treatment of 37 patients with dental crowding of severe degree in period of mixed dentition was carried out. The first (1) (basic) group consisted of 27 patients (mean age 11,93+/-0,73 years) who were treated with removable orthodontic appliances of our own design and additional application of own theoretical and practical developments. Control group (2) consisted of 10 patients (mean age 12,6+/-1,28 years). They were treated by traditional removable appliances with screws. Student's t-test was applied to reveal significanse deference of the obtained results for different groups. Before treatment comparative analysis has not showed significant difference between groups depending on age, gender, sagittal, vertical and lateral malocclusion as well as localization and severity degree of dental crowding (P >0,05). RESULTS: It was found that treatment duration of malocclusion with dental crowding of the maxillary teeth for groups 1 and 2 was 11,95+/-0,85 and 18,75+/ 2,61 months respectively (P >0,05) . Duration of treatment for groups 1 and 2 of mandibular teeth crowding was 12,47+/-1,09 and 17,86+/-1,81 months respectively (P >0,05). CONCLUSIONS: It was proved that the application of own theoretical and practical developments which were introduced in orthodontic treatment of malocclusion complicated by dental crowding, makes it possible to reduce period of treatment on the average in 1,45 times in comparison with conventional. PMID- 27487544 TI - [Planning of volume and terms of orthodontic treatment of patients with transversal maloclusion]. AB - INTRODUCTION: In planning of orthodontic treatment, as well as the alleged end of the treatment of orthodontic patients with transversal malocclusion should first pay attention to the treatment of opportunistic diseases that can affect the outcome of treatment of orthodontic patients (for example, rehabilitation of the nasopharynx, the treatment of rickets, the treatment of scoliosis posture, scoliosis ). THE AIM: definition of related factors affecting the volume and timing of the treatment of patients with transversal malocclusion. MATERIAL AND METHODS: There were examined 32 patients with transversal malocclusion, and studied their medical history (Form 043). Patients were examined by standard algorithm survey. Two groups of patients by sex: Group 1: girls - 16 people and 2 th group: boys- 16 people. The material collected from 2010 to 2015. Patient age 12-17 years. RESULTS: Subjective attitude to the disease formed on the basis of a number of factors that can be grouped into the following categories: social and constitutional and individual psychological. Since incorrect posture and malocclusion are the cause and effect of each other, in such cases should be treated at the same time and bite and pathology of the musculoskeletal system (10, 11). It is clear that in the planning of orthodontic treatment should be part and treatment of posture and a close and fruitful collaboration with the doctor traumatologist orthopaedist. CONCLUSIONS: The sex of the patient, especially temperament, the doctor-patient relationship, as well as the presence of somatic diseases have a significant impact on the length and complexity of the orthodontic treatment. PMID- 27487545 TI - [The use of methotrexate in an inflammatory bowel diseases based on the review of the current literature]. AB - M ethotrexate (MTX) as an immunomodulatory drug has numerous applications in autoimmune diseases. Autoimmune patomechanism is one of the factors responsible for development of inflammatory bowel diseases (IBD). MTX is an alternative therapy in the treatment of IBD. Over the past several years clinical trials has confirmed the efficacy of MTX in the treatment of Crohn's disease (CD). Data concerning use of MTX in ulcerative colitis (UC) are not as numerous as in the CD. Currently, MTX is recommended for the induction treatment and maintenance therapy in CD patients, especially in steroid-dependent patients, disease refractory to corticosteroids, no improvement after treatment with azathioprine and 6-mercaptopurine, or in case of intolerance to these drugs. Preferred route of administration in the treatment of CD is parenteral supply. Contraception is indicated during MTX treatment since it's teratogenic. PMID- 27487546 TI - [Immobilize the person after injury - problems in the practice of the rescuer]. AB - The rescuer often has to deal with patients who have suffered trauma to the bone , including heads, spine, lower and upper limbs. Serious injuries or multiorgan grudges are a frequent result of communicative cases, and a fast but accurate examination is a condition of the success of a rescue operation, putting the preliminary diagnosis and implementing real rescue activities. Delays in a rescue operation or the lack appropriate the equipment is threatening the patient with the permanent disability or even a loss of life. It is important so that Teams of the Medical Rescue, the Aviation emergency ambulance service, individuals of the State Fire Service and Hospital accident wards have an equipment which will be compatible. With equipment which without no dilemmas will be used according to assigning him without anxiety that the use is equaling for loss of possessions or the exchange on worse or dirty. An next amendment to a bill about the National Medical rescue should obligatorily have regulations on the availability and compatibilities of equipment among others used in immobilizing traumatic and the National Health Fund should develop tough equipment principles in contracting services. All remarks and amendments to the provisions concerning the compatibility of equipment used in grudges they will have an intense influence on the quality of granted benefits in saving the health and the human life as well as will improve the comfort of the work of the paramedic. PMID- 27487547 TI - [Lactobacillus fermentum CECT5716 - probiotic from human milk with interesting properties]. AB - Probiotics are an intensively growing part of the pharmaceutical and nutrition industries. Along with the intensive development of sales volumes and product offers, more and more scientific publications on this subject are available (at the time of writing this article there are available almost 14 thousand publications in PubMed library). Scientists are trying to find new uses and new sources for this crucial group of nutrients or potential drugs. At the beginning of the XXI century it was discovered that the source of probiotics doesn't need to be only gastrointestinal tract (as previously thought), since they were obtained from breast milk which for many years were considered to be sterile. Probiotics from breast milk are an interesting group which could find application in mastitis, immunity support, infection prevention, infant colics and oral health. Main representative of this group is a strain of lactic acid bacteria Lactobacillus fermentum CECT5716. PMID- 27487549 TI - [Protection of medical personnel in contemporary armed conflicts]. AB - International humanitarian law provides special protection devices and medical personnel during armed conflicts. In today's wars it became more frequent lack of respect for the protective emblems of the red cross and red crescent and the lack of respect for medical activities. The paper presents selected issues of humanitarian law with a particular emphasis on the rules concerning the protection of medical services and victims of armed conflicts. All countries that have ratified the Geneva Conventions and Additional Protocols, are required to comply in time of war the principles contained in them and their dissemination in peacetime. Education societies in the field of international humanitarian law can help to eliminate attacks on medical facilities and personnel and significantly improve the fate of the victims of armed conflict and mitigate the cruelty of war. Knowledge of humanitarian law does not prevent further wars, but it can cause all parties to any armed conflict will abide by its rules during such activities. PMID- 27487548 TI - [Amaurosis fugax in inferior wall myocardial infarction with ST segment elevation]. AB - The patient, a fifty nine year old male, was admitted to the ward with symptoms of inferior wall myocardial infarction with ST segment elevation combined with intermittent right side sight loss. Despite typical resting stenocardial chest pain, ST segment elevation in ECG, transient symptoms of acute heart failure and slightly elevated myocardial necrosis biomarkers, coronarography did not reveal obvious source of myocardial ischemia. Moreover, echocardiography did not confirm decreased ejection fraction. However further research confirmed critical stenosis of the left internal carotid artery and chronic occlusion of the right internal carotid artery. Several questions were raised during diagnostic process including: the cause of cardiac ischemia and the cause of cerebral ischemia. Clinical data analysis and available literature allowed authors to exclude cerebral ischemia as a source of ECG ischemic changes and to establish transient myocardial ischemia causing circulatory decompensation amplified by carotid arteries atherosclerosis as the source of neurological symptoms. PMID- 27487550 TI - [Manual therapy in general practice]. AB - The article is devoted to manual therapy practice for diagnostics and treatment of vertebrogenic pain syndrome in general practice. Analytical roundup of sources proves medical advantage of implementation of manual therapy basic methods by general practice specialists. PMID- 27487551 TI - [Immunohistochemical description of proliferative activity and apoptosis of lung squamous cell carcinoma (literature review)]. AB - The analysis of the publications are describe immunohistochemical study of proliferative activity and apoptosis of lung squamous cell carcinoma. Established that the imbalance between proliferation and cell death is a key process in the development of tumors. However, the value of tumor markers in histogenesis and morfogenesis of tumors and forecast their occurrence is not studied enough. Despite the significant amount of scientific literature devoted to this issue, has not yet established a clear link expression of immunohistochemical markers of proliferation and apoptosis with the degree of differentiation of squamous cell lung cancer. Analysis of the literature shows that the morphology of this histogenetics type lung cancer at the cellular, subcellular structural and functional levels are controversial and require detailed investigation. PMID- 27487552 TI - A novel homozygous mutation causing hereditary tyrosinemia type I in yakut patient in russia: case report. AB - INTRODUCTION: Tyrosinemia type 1 (HT1) (OM IM 276700) is an inborn error of tyrosine catabolism caused be fumarylacetoacetate hedralase deficiency (FAH). In tyrosinemia type I, dietary therapy and nitisinone (Orfandin(r)), liver transplantation are effective . AIM: We present here the first report on identification of FAH mutation in HT1 Yakut patient from Russia with a novel one. MATERIAL AND METHODS: The material for the clinical study is based on the genetic data of the patient card with tyrosinemia type 1, which is observed in the medical-genetic consultations Republican Hospital No1-National Medical Center of the Republic of Sakha (Yakutia). For molecular genetic analysis has been used venous whole blood, taken with the written consent from the patient, his relatives and 200 healthy Yakuts. All regions of the FAH gene spanning exons were amplified by PCR and mutational analyses was carried out by direct sequencing. Results of sequencing were confirmed by restriction fragment length polymorphism (PCR-RELF) analyses. RESULTS: 1 one-year-old child was identified with a diagnosis hereditary tyrosinemia type Ia, acute form. In exon 13 of the FAH gene a novel mutation c.1090 G>C (GLu364GLn) in the homozygous state was found in patient, and in heterozygous state in both parents. The child is treated Nitisinone therapy. DNA diagnostics of c.1090 G>C mutation frequency in the FAH gene was conducted using PCR and RFLP analysis in 200 unrelated Yakuts. The frequency of heterozygous carrier was 1.0%. PMID- 27487553 TI - [Clinical and morphological observation of purulent iliopsoitis]. AB - The article describes the modern literary data on classification, etiology, pathogenesis and predisposing factors in the development of purulent iliopsoitis. Where are clinical and morphological analysis of five deaths cases of purulent ileopsoitis. On the basis of these studies found that purulent ileopsoitis that occur in middle and old age, are more common in women, can be either unilateral or bilateral localization. Purulent ileopsoitis arises by forming abscess in the iliopsoas muscle. Primary ileopsoitis arises in connection with injuries gluteal and lumbar region. Secondary ileopsoit developed as a complication of inflammatory and neoplastic processes, with an initial mechanism for the development of the pathological process were necrotic changes in the external iliac lymph nodes. In vivo it is difficult to diagnose, that's why is necessary to apply a comprehensive study, including clinical data, anamnesis, general clinical and laboratory parameters, instrumental methods. PMID- 27487554 TI - Aspects of public health within accreditation of public healthcare management specialists in ukraine and russia in the late 18th - early 19th century (dedicated to the 250th anniversary of a prominent professor Mukhin E.O.). AB - Public healthcare management and supply of qualified medical personnel attained state significance in the early 19th century, the issue to be regulated by special and general law regulations. Public health promotion was the duty of medical authorities, which required professional training in this branch. The article contains the requirements for the employers' knowledge and skills in the mentioned area of medicine. The author reveals the main questions which medical authorities were concerned with and the main requirements for academic examinations. PMID- 27487555 TI - [Shame of having a disabled child]. AB - This work is devoted to the problem of shame linked to disability in children. It has been inspired by patients - disabled infants and their parents. The shame evidently experienced during meetings with parents learning about their child's condition leads to many difficult questions. Shame is not a simple, isolated emotion. It is a complicated feeling, closely connected to various shame-related emotions and experiences. Shame leads to a sense of guilt and self-blame. Shame linked to a child's disability is a shame of 'lacking' and low self-esteem. Additionally it is feeling of nakedness, vulnerability and despoilment of intimacy; it makes parents feel forced to put their interior world on display and to show their weakness caused by their child's condition. Sometimes shame is an experience of humiliation, or hurt dignity caused by the looks of other people. It is also the shame of one's own difficult thoughts, desire to escape responsibility. It is being ashamed of experiencing shame. It is an emotion of ultimate suffering, often returning during whole life. One solution to the 'discomfort of birth' could be a lonely island. The issue is not that simple, however, and philosophy helps in this respect. A being is good and it has to be good. One cannot be someone, one is not. This is the difference between a being and a desire. There is love and acceptance, but there is also shame - even on a lonely island. PMID- 27487556 TI - Conformal BaTiO3 Films with High Piezoelectric Coupling through an Optimized Hydrothermal Synthesis. AB - Two-dimensional (2D) ferroelectric films have vast applications due to their dielectric, ferroelectric, and piezoelectric properties that meet the requirements of sensors, nonvolatile ferroelectric random access memory (NVFeRAM) devices, and micro-electromechanical systems (MEMS). However, the small surface area of these 2D ferroelectric films has limited their ability to achieve higher memory storage density in NVFeRAM devices and more sensitive sensors and transducer. Thus, conformally deposited ferroelectric films have been actively studied for these applications in order to create three-dimensional (3D) structures, which lead to a larger surface area. Most of the current methods developed for the conformal deposition of ferroelectric films, such as metal organic chemical vapor deposition (MOCVD) and plasma-enhanced vapor deposition (PECVD), are limited by high temperatures and unstable and toxic organic precursors. In this paper, an innovative fabrication method for barium titanate (BaTiO3) textured films with 3D architectures is introduced to alleviate these issues. This fabrication method is based on converting conformally grown rutile TiO2 nanowire arrays into BaTiO3 textured films using a simple two-step hydrothermal process which allows for thickness-controlled growth of conformal films on patterned silicon wafers coated with fluorine-doped tin oxide (FTO). Moreover, the processing parameters have been optimized to achieve a high piezoelectric coupling coefficient of 100 pm/V. This high piezoelectric response along with high relative dielectric constant (epsilonr = 1600) of the conformally grown textured BaTiO3 films demonstrates their potential application in sensors, NVFeRAM, and MEMS. PMID- 27487557 TI - Attacks Intended to Seriously Harm and Co-occurring Drug Use Among Youth in the United States. AB - BACKGROUND: While it is known that substance use and violence co-occur, less is understood in terms of how this relationship might vary based on the degree of youth involvement in violence. OBJECTIVES: This study sought to examine the prevalence and degree that substance use disorders (SUD) and related intrapersonal and contextual factors were associated with violent attacks. METHOD: Repeated cross-sectional data from a population-based study (National Survey on Drug Use and Health) of youth ages 12-17 (n = 216,852) in the United States between 2002 and 2013 were pooled to increase the analytic sample size. Survey multinomial regression was used to examine psychosocial and substance use differences between youth reporting episodic (1-2 times, n = 13,091; 5.84%) and repeated violent attacks (3+ times, n = 1,819; 0.83%) in contrast with youth reporting no attacks. Additional analyses examined the association of sociodemographic, intrapersonal, and contextual factors with SUD among youth reporting violent attacks. RESULTS: The prevalence of SUD among youth with no attacks was 6% compared to 22% among episodic and 36% among repeatedly violent youth. Violence-involved youth were substantially more likely to experience elevated sensation-seeking, easy drug access, and recent drug offers and less likely to benefit from religiosity and protective substance use beliefs. CONCLUSIONS/IMPORTANCE: Findings highlight the importance of distinguishing between the various gradations of violence among youth in understanding the relationship between substance use and violence, and shed light on the intrapersonal and contextual factors that can help identify violent youth at greatest risk for substance use problems. PMID- 27487558 TI - BRM polymorphisms, pancreatic cancer risk and survival. AB - Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM 1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex. BRM suppression can be reversed pharmacologically.(1) Our group and others have reported associations with lung, head and neck, hepatocellular cancer risk,(1-3) and with lung and esophageal cancer prognosis (ASCO 2013; abstract 11057 & 4077). Herein, we assessed risk and survival associations with pancreatic cancer. A provincial population-based case-control study was conducted with 623 histologically confirmed pancreatic adenocarcinoma cases and 1,192 age/gender distribution-matched controls.(4) Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Median age was 65 y; 52% were male; Stage I (8%), II (55%), III (14%), IV (23%); 53% after curative resection, 79% after chemotherapy; and 83% had died. In the risk analysis, adjusted odds ratios (aOR) were 1.01 (95% CI: 0.1-2.0) and 0.96 (95% CI: 0.7-1.3) for the homozygotes of BRM-741 and BRM-1321, respectively; aOR of double-homozygotes was 1.11 (95% CI: 0.80-1.53), compared to the double-wildtype. For the survival analysis, adjusted hazard ratios (aHR) were 2.19 (95% CI: 1.9-2.5) for BRM-741 and 1.94 (95% CI: 1.7-2.2) for BRM-1321, per unit increase in variant alleles. Compared with the double-wildtype, aHR for carrying no, one, and two double homozygotes were 2.14 (95% CI: 1.6-2.8), 4.17 (95% CI: 3.0-5.7), 8.03 (95% CI: 5.7-11.4), respectively. In conclusion, two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival. PMID- 27487559 TI - Evaluation of efficacy and biocompatibility of a new absorbable synthetic substitute as a dural onlay graft in a large animal model. AB - BACKGROUND: Numerous dura substitutes are commercially available, but no absorbable synthetic dura repair product has been used for both onlay and suture applications. OBJECTIVE: The safety and effectiveness of a new absorbable synthetic substitute composed of Poly-L-lactide microfibers as onlay dural graft were evaluated. METHODS: Physical properties and performance of the microfibrous synthetic dural substitute implanted as an onlay or suturable grafts were compared with these commercial products, including CODMAN ETHISORBTM Dura Patch and DuraGenTM Dural Graft Matrix, in a canine duraplasty model. The cerebrospinal fluid (CSF) leakage, macroscopic and microscopic observation at 30 and 90 days after implantation were investigated. RESULTS: The absorbable synthetic dural substitute exhibited good wettability and conformability. When implanted as an onlay graft, it can prevent CSF leakage and integrate with the surrounding tissue to repair dural defects, indicating its good efficacy and biocompatibility as an onlay graft. CONCLUSION: Based on the excellent physical properties and performances mentioned above, the new absorbable synthetic substitute can be applied as a dural graft for both onlay and suturable applications. PMID- 27487560 TI - Correction to Tetrahydroisoquinoline-Derived Urea and 2,5-Diketopiperazine Derivatives as Selective Antagonists of the Transient Receptor Potential Melastatin 8 (TRPM8) Channel Receptor and Antiprostate Cancer Agents. PMID- 27487561 TI - Spatial tuning and brain state account for dorsal hippocampal CA1 activity in a non-spatial learning task. AB - The hippocampus is a brain area crucial for episodic memory in humans. In contrast, studies in rodents have highlighted its role in spatial learning, supported by the discovery of place cells. Efforts to reconcile these views have found neurons in the rodent hippocampus that respond to non-spatial events but have not unequivocally dissociated the spatial and non-spatial influences on these cells. To disentangle these influences, we trained freely moving rats in trace eyeblink conditioning, a hippocampally dependent task in which the animal learns to blink in response to a tone. We show that dorsal CA1 pyramidal neurons are all place cells, and do not respond to the tone when the animal is moving. When the animal is inactive, the apparent tone-evoked responses reflect an arousal-mediated resumption of place-specific firing. These results suggest that one of the main output stages of the hippocampus transmits only spatial information, even in this non-spatial task. PMID- 27487562 TI - Phosphorus removal performance and population structure of phosphorus accumulating organisms in HA-A/A-MCO sludge reduction process. AB - We developed a new sludge reduction HA-A/A-MCO (Hydrolysis-Acidogenosis Anaerobic/Anoxic -Multistep Continuous Oxic tank) process, which has improved phosphate (P) and nitrogen (N) removal. Its biological treatment unit uses an A2/O P & N removal process with hydrolysis acidification, multistep continuous aeration, and continuous flow, coupled with sidestream P removal by draining out anaerobic P-bearing wastewater. The process has advanced synchronization of P and N removal and sludge reduction. The improved performance is closely associated with the population structure of P-accumulating organisms (PAOs). This study investigated the relationship between P removal performance and the population structure of PAOs. The results show that the average effluent P content of HA-A/A MCO process was only 0.44 mg/L, when the influent P concentration was 8~12 mg/L. The effluent met the A standard set by GB18918-2002. PAOs were able to effectively release 1 mg of P and absorb 2.8 mg of P. The system removed P by draining out anaerobic P-rich wastewater, as P had been reduced in the aerobic absorption process. This reduced the need for excess P uptake ability of the PAOs. The bacterial pure culture method was applied to isolate 5 PAOs with typical P absorption and removel features. 16SrDNA amplification and sequence analysis revealed that Acinetobacter sp. and Lampropedia sp played dominant roles in anaerobic P-releasing process. Moreover, Devosia sp. and Bdellovibrio sp were the primary strains in the aerobic tank, and, they were the major stains for P absorption. Uncultured Bacterium and other uncultured strains were detected in the anoxic tank. PMID- 27487563 TI - The miR-204-3p-targeted IGFBP2 pathway is involved in xanthohumol-induced glioma cell apoptotic death. AB - Xanthohumol (XN), a prenylated chalcone extracted from hop plant Humulus lupulus L. (Cannabaceae), has potential for cancer therapy, including gliomas. Micro (mi)RNAs are small noncoding RNAs that control gene expression. Several miRNAs have been identified to participate in regulating glioma development. However, no studies have demonstrated whether miRNA is involved in XN cytotoxicity resulting in glioma cell death. This study investigated the effects of XN-mediated miRNA expression in activating apoptotic pathways in glioblastoma U87 MG cells. First, we found that XN significantly reduced cell viability and induced apoptosis via pro-caspase-3/8 cleavage and poly(ADP ribose) polymerase (PARP) degradation. We also identified that pro-caspase-9 cleavage, Bcl2 family expression changes, mitochondrial dysfunction, and intracellular ROS generation also participated in XN-induced glioma cell death. With a microarray analysis, miR-204-3p was identified as the most upregulated miRNA induced by XN cytotoxicity. The extracellular signal-regulated kinase (ERK)/c-Fos pathway was validated to participate in XN-upregulated miR-204-3p expression. With a promoter assay and ChIP analysis, we found that c-Fos dose-dependently bound to the miR-204-3p gene promoter region. Furthermore, miR-204-3p levels decreased in several glioma cell lines compared to astrocytes. Overexpression of miR-204-3p enhanced glioma cell apoptosis. IGFBP2, an upregulated regulator of glioma proliferation, was validated by a TCGA analysis as a direct target gene of miR-204-3p. XN's inhibition of the IGFBP2/AKT/Bcl2 pathway via miR-204-3p targeting played a critical role in mediating glioma cell death. These results emphasized that the XN-mediated miR-204-3p network may provide novel therapeutic strategies for future glioblastoma therapy and drug development. PMID- 27487564 TI - Dihydromyricetin suppresses inflammatory responses in vitro and in vivo through inhibition of IKKbeta activity in macrophages. AB - Dihydromyricetin (DMY) a flavonoid derived from medicinal plant Ampelopsis grossedentata, possesses anti-oxidative and anti-inflammatory effects in vitro, however, the in vivo anti-inflammatory action of DMY remains unknown. In the current study, carrageenan-induced paw edema in rat, an acute inflammation model, and RAW264.7 macrophages activated by LPS were employed to evaluate the anti inflammatory potency of DMY in vivo and in vitro. Results showed that DMY significantly attenuated rat paw edema induced by carrageenan. Also, DMY markedly inhibited NO secretion, iNOS, and COX-2 protein expression, as well as p65 phosphorylation via suppression of IKKbeta activity and IKKalpha/beta phosphorylation in RAW264.7 cells. And using high resolution Atomic Force Microscope (AFM), we also proved that DMY prevented morphological change and membrane alterations of RAW 264.7 macrophages caused by LPS stimulation. As activation of macrophages is one of major factors in carrageenan-induced paw edema of rats, the anti-inflammatory action of DMY is suggested to be closely associated with suppression of macrophage activation. These findings indicate that DMY is valuable of being further investigated as a candidate new agent for treating inflammatory conditions, and suggest that AFM could be a powerful nanotool for anti-inflammatory investigations. SCANNING 38:901-912, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27487565 TI - Synthesis and pharmacological characterization of novel N-(trans-4-(2-(4 (benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)cyclohexyl)amides as potential multireceptor atypical antipsychotics. AB - A series of novel benzisothiazolylpiperazine derivatives combining potent dopamine D2 and D3, and serotonin 5-HT1A and 5-HT2A receptor properties were synthesized and evaluated for their potential antipsychotic properties. The most promising derivative was 9j. The unique pharmacological features of 9j were a high affinity for D2, D3, 5-HT1A, and 5-HT2A receptors, together with a 20-fold selectivity for the D3 versus D2 subtype, and a low affinity for muscarinic M1 (reducing the risk of anticholinergic side effects), and for hERG channels (reducing incidence of QT interval prolongation). In animal behavioral models, 9j inhibited the locomotor-stimulating effects of phencyclidine, blocked conditioned avoidance response, and improved the cognitive deficit in the novel object recognition tests in rats. 9j exhibited a low potential for catalepsy, consistent with results with risperidone. In addition, favorable brain penetration of 9j in rats was detected. These studies have demonstrated that 9j is a potential atypical antipsychotic candidate. PMID- 27487566 TI - alpha-N-heterocyclic thiosemicarbazone Fe(III) complex: Characterization of its antitumor activity and identification of anticancer mechanism. AB - We synthesized an alpha-N-heterocyclic thiosemicarbazone ligand (L) and its Fe complex (C1) and assessed their chemical and biological properties in order to understand their marked activity. Electrochemical studies and ascorbate oxidation studies demonstrated that C1 shows considerable redox activity, and Fe(III/II) redox potentials was within the range accessible to cellular oxidants and reductants. Absorption spectral, emission spectral and viscosity analysis reveal that L and C1 interacted with DNA through intercalation and C1 exhibited a higher DNA binding ability. Agarose gel electrophoresis experiments indicated that C1 exhibited the highest pBR322 DNA cleaving ability. In vitro, C1 showed significantly more anticancer activity than the ligand alone. Moreover, C1 induces production of reactive oxygen species (ROS) and DNA damage, resulting in activation of the p53 pathway, cell cycle arrest at the S phase, and mitochondria mediated apoptosis by regulating the expression of Bcl-2 family proteins. PMID- 27487567 TI - Inhibitory activity evaluation and mechanistic studies of tetracyclic oxindole derivatives as alpha-glucosidase inhibitors. AB - alpha-Glucosidase inhibitors are known to prevent the digestion of carbohydrates and reduce the impact of carbohydrates on blood glucose. Three series of tetracyclic oxindole derivatives were designed, synthesized and evaluated for alpha-glucosidase inhibitory activity in vitro. Compound 6t exhibited the most potent inhibitory activity with IC50 0.7 MUM and was about 170 times as active as acarbose (IC50 = 115.8 MUM). The kinetic analysis of compound 6t revealed it inhibited alpha-glucosidase in an irreversible and mixed manner. Fluorescence spectra indicated that 6t directly bound to alpha-glucosidase. Docking simulation showed the existence of potential H-bonding, van der Waals, Pi and Sigma-Pi interactions between 6t and alpha-glucosidase. PMID- 27487568 TI - Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of theophylline containing acetylenes and theophylline containing 1,2,3 triazoles with variant nucleoside derivatives. AB - A new series of theophylline containing acetylene derivatives (6a-6b and 7-13) and theophylline containing 1,2,3-triazoles with variant nucleoside derivatives (20-32) have been designed and synthesized. These compounds were screened for anticancer and antimicrobial activity. Further the computational docking and 2D QSAR were performed using MOE software to identify novel scaffolds. The results showed that compound 29 and 30 exhibit significant cytotoxic effect on all four cancer cells such as lung (A549), colon (HT-29), breast (MCF-7) and melanoma (A375) with IC50 values of 2.56, 2.19, 1.89, 4.89 MUM and 3.57, 2.90, 2.10, 5.81 MUM respectively. Whereas quite different results were observed for these compounds in antimicrobial studies. Compounds 11, 21 and 26 have exhibited significant minimum inhibitory concentrations (MIC) against Staphylococcus aureus, Bacillus cereus, Escherichia coli and Pseudomonas aeruginosa. The docking studies demonstrate that compound 27, 28, 29 and 30 have good dock score and binding affinities with various therapeutic targets in cancer cell proliferation. In addition these compounds have shown acceptable correlation with bioassay results in the regression plots generated in 2D QSAR models. This is the first report to demonstrate the theophylline containing acetylene derivatives and theophylline containing 1,2,3-triazole nucleoside hybrids as potential anticancer and antimicrobial agents with comprehensive in silico analysis. PMID- 27487569 TI - Design and synthesis of 1,2,3-triazole-containing N-acyl zanamivir analogs as potent neuraminidase inhibitors. AB - The design of potent metabolically stable neuraminidase (NA) inhibitors represents an attractive approach for treating influenza virus infection. In this study, we describe the exploitation of the 150-cavity in the active site of group 1 NA for the design, synthesis, and in vitro evaluation of new triazole containing N-acyl derivatives related to Zanamivir. Inhibition studies with influenza virus NAs of group 1 (H1N1) and group 2 (H3N2) revealed that several of them are good inhibitors, with IC50 values in the low nanomolar (2.3 nM-31 nM) range. Substituents that form stable van der Waals interaction with the 150 cavity residues play crucial roles in NA inhibition as demonstrated by the potency of 6a (H1N1 IC50 = 2.3 nM, and H3N2 IC50 = 2.9 nM). Docking studies indicated that the cyclohexane-substituted triazole ring extended toward the hydrophobic region in the active site of group 1 NA in open form. The high potency observed for inhibitor 6a may be attributable to the highly favorable hydrophobic interactions in this region. PMID- 27487570 TI - Chalcogen containing heterocyclic scaffolds: New hybrids with antitumoral activity. AB - In this work, 27 novel hybrid derivatives containing diverse substituents with chalcogen atoms (selenium or sulfur) and several active heterocyclic scaffolds have been synthesized. Compounds were tested against two human cancer cells lines (MCF7 and PC-3) and a normal human mammary epithelial cell line (184B5) in order to determine their activity and selectivity against malignant cells. Ten compounds showed GI50 values below 10 MUM in at least one of the cancer cell lines and six of them exhibited a selectivity index higher than 9. In general, selenium-containing compounds were more active than their corresponding sulfur analogs but we found some thiocyanate derivatives with comparable or higher activity and selectivity. Among the different substituents, the seleno- and thio cyanate groups showed the most promising results. On the basis of their potent activity and high selectivity index, compounds 7e and 8f (containing a thiocyanate and a selenocyanate group, respectively) were selected for further biological evaluation. Both the compounds induced caspase-dependent cell death and cell cycle arrest in G2/M phase. In addition, these compounds do not violate any of the Lipinski's Rule of Five and thus possess good potential to become drugs, compound 7e being particularly promising. PMID- 27487571 TI - Comparison of anti-OJ antibody detection assays between an immunoprecipitation assay and line blot assay. PMID- 27487572 TI - Clinical features and prognosis of patients with myelodysplastic syndromes who were exposed to atomic bomb radiation in Nagasaki. AB - There is evidence that radiation exposure is a causative factor of myelodysplastic syndromes (MDS). However, little is known about whether radiation exposure is also a prognostic factor of MDS. We investigated the impact of radiation exposure on the prognosis of MDS in Nagasaki atomic bomb survivors using the International Prognostic Scoring System (IPSS) and the revised version (IPSS-R). Subjects were 140 patients with primary MDS diagnosed between 1985 and 2011 and evaluable for IPSS, IPSS-R, and exposure distance. Of those, 31 were exposed at <1.5 km, 35 at 1.5-2.99 km, and 74 at >=3.0 km. By the end of March 2014, 47 patients (34%) progressed to overt leukemia and 106 (75.7%) died. By comparing with patients exposed at >=3.0 km, those exposed at <1.5 km had significantly higher frequencies of abnormal chromosome (P = 0.02), intermediate/poor IPSS, and intermediate/poor/very poor IPSS-R cytogenetic category (P = 0.0001, and P < 0.0001, respectively). As with de novo MDS, multivariate Cox regression analyses revealed that cytogenetic abnormalities, IPSS karyotype, and IPSS-R cytogenetics were significantly associated with poor survival, and cumulative incidence of leukemic transformation in MDS among atomic bomb survivors, but exposure distance was not associated with any poor outcomes. These suggest that exposure to the greater dose of atomic bomb radiation is associated with developing poor cytogenetic abnormalities in MDS, which might consequently lead to overt leukemia among atomic bomb survivors. PMID- 27487574 TI - Bacterial magnetic nanoparticles for photothermal therapy of cancer under the guidance of MRI. AB - The bacterial magnetic nanoparticles (BMPs) are biomineralized by the magnetotactic bacteria and naturally covered with a layer of biomembrane. Herein, BMPs were isolated and firstly used for the photothermal therapy (PTT) of cancer under the guidance of magnetic resonance imaging (MRI) in vitro and in vivo. The results showed that BMPs could rapidly convert the energy of 808 nm near-infrared (NIR) light into heat. After internalization by the HepG2 tumor cells, BMPs with good biocompatibility could induce an efficient killing effect after NIR light irradiation, along with a change of mitochondrial membrane potential (DeltaPsim) and level of intracellular reactive oxygen species (ROS). The in vivo therapy also confirms that PTT with BMPs could effectively and completely ablate the tumor in mice without inducing observable toxicity. T2-weighted MRI showed a clear tumor boundary and a 25% enhancement of negative contrast enhancement at the tumor site, suggesting that BMPs can act as an effective MRI contrast agent for guiding the PTT. Our results indicate that BMPs could be a potential theranostic agent for simultaneous MRI and PTT of cancer. PMID- 27487573 TI - Comparative Effectiveness of Cognitive Therapy and Dynamic Psychotherapy for Major Depressive Disorder in a Community Mental Health Setting: A Randomized Clinical Noninferiority Trial. AB - IMPORTANCE: Dynamic psychotherapy (DT) is widely practiced in the community, but few trials have established its effectiveness for specific mental health disorders relative to control conditions or other evidence-based psychotherapies. OBJECTIVE: To determine whether DT is not inferior to cognitive therapy (CT) in the treatment of major depressive disorder (MDD) in a community mental health setting. DESIGN, SETTING, AND PARTICIPANTS: From October 28, 2010, to July 2, 2014, outpatients with MDD were randomized to treatment delivered by trained therapists. Twenty therapists employed at a community mental health center in Pennsylvania were trained by experts in CT or DT. A total of 237 adult outpatients with MDD seeking services at this site were randomized to 16 sessions of DT or CT delivered across 5 months. Final assessment was completed on December 9, 2014, and data were analyzed from December 10, 2014, to January 14, 2016. INTERVENTIONS: Short-term DT or CT. MAIN OUTCOMES AND MEASURES: Expert blind evaluations with the 17-item Hamilton Rating Scale for Depression. RESULTS: Among the 237 patients (59 men [24.9%]; 178 women [75.1%]; mean [SD] age, 36.2 [12.1] years) treated by 20 therapists (19 women and 1 man; mean [SD] age, 40.0 [14.6] years), 118 were randomized to DT and 119 to CT. A mean (SD) difference between treatments was found in the change on the Hamilton Rating Scale for Depression of 0.86 (7.73) scale points (95% CI, -0.70 to 2.42; Cohen d, 0.11), indicating that DT was statistically not inferior to CT. A statistically significant main effect was found for time (F1,198 = 75.92; P = .001). No statistically significant differences were found between treatments on patient ratings of treatment credibility. Dynamic psychotherapy and CT were discriminated from each other on competence in supportive techniques (t120 = 2.48; P = .02), competence in expressive techniques (t120 = 4.78; P = .001), adherence to CT techniques (t115 = -7.07; P = .001), and competence in CT (t115 = -7.07; P = .001). CONCLUSIONS AND RELEVANCE: This study suggests that DT is not inferior to CT on change in depression for the treatment of MDD in a community mental health setting. The 95% CI suggests that the effects of DT are equivalent to those of CT. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01207271. PMID- 27487575 TI - Comparison of trout hepatocytes and liver S9 fractions as in vitro models for predicting hepatic clearance in fish. AB - Isolated hepatocytes and liver S9 fractions have been used to collect in vitro biotransformation data for fish as a means of improving modeled estimates of chemical bioaccumulation. To date, however, there have been few direct comparisons of these 2 methods. In the present study, cryopreserved trout hepatocytes were used to measure in vitro intrinsic clearance rates for 6 polycyclic aromatic hydrocarbons (PAHs). These rates were extrapolated to estimates of in vivo intrinsic clearance and used as inputs to a well stirred liver model to predict hepatic clearance. Predicted rates of hepatic clearance were then evaluated by comparison with measured rates determined previously using isolated perfused livers. Hepatic clearance rates predicted using hepatocytes were in good agreement with measured values (<2.1-fold difference for 5 of 6 compounds) under 2 competing binding assumptions. These findings, which may be attributed in part to high rates of PAH metabolism, are similar to those obtained previously using data from liver S9 fractions. For 1 compound (benzo[a]pyrene), the in vivo intrinsic clearance rate calculated using S9 data was 10-fold higher than that determined using hepatocytes, possibly due to a diffusion limitation on cellular uptake. Generally, however, there was good agreement between calculated in vivo intrinsic clearance rates obtained using either in vitro test system. These results suggest that both systems can be used to improve bioaccumulation assessments for fish, particularly when vitro rates of activity are relatively high, although additional work is needed to determine if the chemical domain of applicability for each system differs. Environ Toxicol Chem 2017;36:463-471. Published 2016 SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 27487576 TI - Data fusion of near-infrared and mid-infrared spectra for identification of rhubarb. AB - Rhubarb has different medicinal efficacy to official rhubarb and may affect the clinical medication safety. In order to guarantee the quality of rhubarb, we established a method to distinguish unofficial rhubarbs. 52 official and unofficial rhubarb samples were analyzed using near-infrared (NIR) spectroscopy and mid-infrared (MIR) spectroscopy for classification. The feature vectors, which were selected by wavelet compression (WC) and interval partial least squares (iPLS) from NIR, MIR spectra, were fused together for identifying rhubarb samples. Partial least squares-discriminant analysis (PLS-DA), soft independent modeling of class analogies (SIMCA), support vector machine (SVM) and artificial neural network (ANN) were compared for classifying rhubarb. The use of data fusion strategies improved the classification model and allowed correct classification of all the samples. PMID- 27487577 TI - Impact of Fe on structural modification and room temperature magnetic ordering in BaTiO3. AB - Ba1-xFexTiO3 (x=0, 0.005, 0.01) polycrystalline ceramics are prepared using solid state reaction method. Structural studies through XRD, Raman and XPS confirm single tetragonal phase for BaTiO3 whereas a structural disorder tends to intervene with the introduction of smaller Fe ions which reduces the tolerance factor and tetragonality ratio. Grain size of the samples is estimated using SEM micrographs with ImageJ software and chemical composition is confirmed using EDX spectra. Raman spectra measured in the temperature range of 303K to 573K showers light on the structural phase transition exploiting a significant disappearance of the 306cm-1 mode. Further, structural analyses suggest the entry of Fe into the B-site upon increasing its concentration in BaTiO3. The dopant sensitive modes lying at around 640cm-1 and 650cm-1 are assigned to lattice strain. A reduction in ferroelectric to paraelectric transition temperature is observed with a transformation from diffused type to normal ferroelectric upon the increased Fe content. The oxidation state of Fe in the BaTiO3 lattice has been decided using EPR Spectra precisely. Room temperature magnetic ordering is observed in Fe substituted BaTiO3 using PPMS. The coexistence of ferroelectric and magnetic ordering is established in the present study for optimized Fe substituted BaTiO3. PMID- 27487578 TI - Terbinafine inhibits gap junctional intercellular communication. AB - Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca(2+) concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. PMID- 27487579 TI - Extension of Expiration Dates for Four Body System Listings. Final rule. AB - We are extending the expiration dates of the following body systems in the Listing of Impairments (listings) in our regulations: Musculoskeletal System, Cardiovascular System, Digestive System, and Skin Disorders. We are making no other revisions to these body systems in this final rule. This extension ensures that we will continue to have the criteria we need to evaluate impairments in the affected body systems at step three of the sequential evaluation processes for initial claims and continuing disability reviews. PMID- 27487580 TI - Medicare, Medicaid, and Children's Health Insurance Programs: Announcement of the Provider Enrollment Moratoria Access Waiver Demonstration of Part B Non Emergency Ground Ambulance Suppliers and Home Health Agencies in Moratoria Designated Geographic Locations. Implementation of the waiver demonstration. AB - This notice announces the Provider Enrollment Moratoria Access Waiver Demonstration of Part B Non-Emergency Ground Ambulance Suppliers and Home Health Agencies in 6 states. The demonstration is being implemented in accordance with section 402 of the Social Security Amendments of 1967 and gives CMS the authority to grant waivers to the statewide enrollment moratoria on a case-by-case basis in response to access to care issues, and to subject providers and suppliers enrolling via such waivers to heightened screening, oversight, and investigations. PMID- 27487581 TI - Medicare, Medicaid, and Children's Health Insurance Programs: Announcement of the Implementation and Extension of Temporary Moratoria on Enrollment of Part B Non-Emergency Ground Ambulance Suppliers and Home Health Agencies in Designated Geographic Locations and Lifting of the Temporary Moratoria on Enrollment of Part B Emergency Ground Ambulance Suppliers in All Geographic Locations. Extension, implementation, and lifting of temporary moratoria. AB - This document announces the extension of temporary moratoria on the enrollment of new Medicare Part B non-emergency ground ambulance suppliers and Medicare home health agencies (HHAs), subunits, and branch locations in specific locations within designated metropolitan areas in Florida, Illinois, Michigan, Texas, Pennsylvania, and New Jersey to prevent and combat fraud, waste, and abuse. It also announces the implementation of temporary moratoria on the enrollment of new Medicare Part B non-emergency ground ambulance suppliers and Medicare HHAs, subunits, and branch locations in Florida, Illinois, Michigan, Texas, Pennsylvania, and New Jersey on a statewide basis. In addition, it announces the lifting of the moratoria on all Part B emergency ground ambulance suppliers. These moratoria, and the changes described in this document, also apply to the enrollment of HHAs and non-emergency ground ambulance suppliers in Medicaid and the Children's Health Insurance Program. PMID- 27487582 TI - Leadership Development in Dental Education: Report on the ADEA Leadership Institute, 2000-14. AB - The American Dental Education Association's Leadership Institute (ADEA LI) is the association's flagship development program for those aspiring to leadership in dental and higher education. As with previous studies of the ADEA LI, ADEA will use information from the survey described in this report to improve the ADEA LI curriculum and to guide other leadership development efforts. In 2014-15, ADEA distributed a 50-item online survey via email to all ADEA LI alumni from the classes of 2000 through 2014. The survey included selected-response questions, closed-ended questions, and open-response questions. The survey had an overall response rate of 47% (133/285); response rates to individual items varied. The mean age of the respondents when they participated in the Institute was 48.5 years. Men and women were almost equally represented among the respondents. Nearly half reported their ultimate career goal as department chair, associate dean, or assistant dean, while 20 (15.8%) indicated a goal of becoming dean and 15 (11.8%) aspired to administrative roles higher than dean. Areas the respondents recommended for improvement included more programming in budgeting and financial management, fundraising, and personnel management. Almost 100% of the respondents indicated they would recommend the ADEA LI to others. Overall, the survey respondents confirmed the value of the ADEA LI in their assessment of their fellowship and its subsequent application to their careers. Comparison of elements from this study to previous studies of ADEA LI alumni demonstrates the effectiveness of past changes made to the Institute and the creation of additional ADEA leadership initiatives. PMID- 27487583 TI - [Not Available]. PMID- 27487584 TI - [Commentary for Guest Editorial: Mario Maj: 21st century psychiatry: The need for a unified framework]. PMID- 27487585 TI - [90 years from the date of a birth]. PMID- 27487586 TI - [85 years from the date of a birth]. PMID- 27487587 TI - [70 years from the date of a birth]. PMID- 27487588 TI - [70 years from the date of a birth]. PMID- 27487589 TI - THE PREDICTIVE VALUE OF SERUM URIC ACID FOR THE OCCURRENCE, SEVERITY AND OUTCOMES OF PRE-ECLAMPSIA AMONG PARTURIENTS AT NNEWI, NIGERIA. AB - OBJECTIVE: To determine the predictive value of serum uric acid for preeclampsia, its severity and pregnancy outcome. METHODS: This is a cohort study that was performed on normal pregnant women attending antenatal clinic at Nnamdi Azikiwe University Teaching Hospital Nnewi Nigeria. Serum uric acid was determined in 200 women attending antenatal clinic between the gestational ages of 14 and 26 weeks. The women were followed up at 2 weekly intervals until 36 weeks and weekly thereafter until delivery. Women who developed pre-eclampsia or eclampsia were identified. Pregnancy outcomes were determined as well as fetal and placental weights. The data was analised with SPSS version 16.0. The chi square was used for test of significance. The positive and negative predictive values were determined. RESULTS: A total of 200 normal pregnant women were recruited for the study. Nine of them were lost to follow up. Subsequently, 10.5% of the women developed preeclampsia. The positive and negative predictive values of serum uric acid for preeclampsia were 78.9% and 97.1%, respectively. CONCLUSION: Serum uric acid was found to be a useful predictor of the occurrence of preeclampsia and its severity. PMID- 27487590 TI - SPUTUM SMEAR PATTERN AMONG PATIENTS DIAGNOSED WITH PULMONARY TUBERCULOSIS IN MAKURDI, NORTH CENTRAL NIGERIA. AB - BACKGROUND: Tuberculosis (TB) is endemic in Nigeria due mainly to the high burden of HIV/AIDS and especially in Benue state which has the highest prevalence of HIV in Nigeria. Sputum smear examination is of importance in the diagnosis of pulmonary TB and can be smear-positive or negative. In this study, we analyzed the sputum smear results of all patients diagnosed to have PTB during the time under review. METHODS: The study was a retrospective study done with records of patients diagnosed with PTB between July 2009 and July 2011. The sample size was 305. AIM: To determine the smear patterns in pulmonary tuberculosis and its relationship with HIV status. RESULTS: There was slight male preponderance among the study group. 37% were found to be smear positive, out of which 63.7% and 36.3% were males and females respectively. The highest frequency was between 21 40 years and in this age group there were more males than females.72.1% wereTB/HIV co-infected and 29.1% of the TB/HIV co-infected patients had smear positiveTuberculosis. CONCLUSION: There is a high burden of TB/HIV co-infection affecting predominantly the youths. Sputum smear results in TB/HIV co-infection are largely negative. There is the need for provision of other diagnostic tests to improve the diagnosis of TB in our environment and targeted intervention among the youth to reduce the burden of TB/HIV. PMID- 27487591 TI - DETERMINANTS OF SPECIALTY CHOICE OF RESIDENT DOCTORS; CASE STUDY--AMONG RESIDENT DOCTORS IN NIGERIA. AB - OBJECTIVE: This study examined medical specialty selection by Nigerian resident doctors using a marketing research approach to determine the selection criteria and the role of perceptions, expected remuneration, and job placement prospects of various specialties in the selection process. METHODS: Data were from the Community of residents from April 2014 to July 2014. The cohort included 200 residents, but only 171 had complete information. Data were obtained from a cross section of resident doctors in the Lagos State University Teaching Hospital and at the 2014 Ordinary General Meeting of the National Association of Resident Doctors(NARD) where representatives from over 50 Teaching hospitals in Nigeria attended. Using a client behaviour model as a framework, a tripartite questionnaire was designed and administered to residents to deduce information on their knowledge about and interests in various specialties, their opinions of sixteen specialties, and the criteria they used in specialty selection. RESULTS: A total of 171 (85.5%) questionnaires were returned. ln many instances, consistency between selection criteria and perceptions of a specialty were accompanied by interest in pursuing the specialty. Job security, job availability on completion of programme, duration of training and qualifying examinations were highly correlated with p value < 0.05. Results of the Principal Component Analysis show two components (with Eigen values greater than one) explaining 65.3% of the total variance. The first component had placement and training and practice related variables loaded on it while the second component was loaded with job security and financial remuneration related variables. CONCLUSIONS: Using marketing research concepts for medical specialty selection (Weissmanet al 2012) stipulates that choice of speciality is influenced by criteria and perception. This study shows that job security expected financial remuneration, and examination requirements for qualification are major determinants of the choice of speciality for residents. PMID- 27487592 TI - PREVALENCE OF HYPERTENSION AMONG FIREFIGHTERS IN RIVERS STATE, SOUTH-SOUTH, NIGERIA. AB - BACKGROUND: High blood pressure is a major cause of morbidity and mortality in Sub-Saharan Africa and firemen (firefighters) may be especially predisposed to it or even exacerbate pre-existing hypertension as a result of the nature of their job. This study was to determine the prevalence of hypertension among firemen in Rivers state, South-South Nigeria. METHODS: Following ethical clearance, 125 consenting firemen of the Rivers State Fire Service were recruited in this descriptive cross sectional study. They responded to a pre-tested, structured, closed-ended self-administered questionnaire which probed their socio demographics, knowledge, attitude and practice towards hypertension. Also, their blood pressures heights and weights were measured from where Body Mass Index (BMI) was calculated. A WalkThrough Survey for immediate work place situation and safety was carried out. Data collected were later analyzed using descriptive and analytical statistical tools. RESULTS: There was a 9.6% prevalence of hypertension among this group of workers in Rivers State. The workforce was essentially young with a modal age group of between 31-36 years. The attendant associated risk factors included altered sleep patterns, over weight and smoking which were all statistically significant P < 0.05. Whilst knowledge of hypertension was high (96%), the behaviour of respondents towards prevention and control of hypertension was poor. CONCLUSION: There is hypertension among firemen of the Rivers State Fire Service occasioned by modifiable risk factors despite adequate knowledge. It is recommended that intensive health education, early detection and treatment be instituted among this group of workers. PMID- 27487593 TI - DEPRESSION, ANXIETY, STRESS, AND THEIR ASSOCIATED FACTORS AMONG CORPS MEMBERS SERVING IN KEBBI STATE. AB - BACKGROUND: Depression, anxiety and stress, are not only health problems by themselves, but also associated with other negative health consequences. The national youth service is usually characterized by a number of new challenges and experiences which may require life style adjustments by the corps member. However, no previous study on psychological factors has been conducted among corps members. OBJECTIVE: This study was conducted to determine the prevalence of depression, anxiety and, stress and their associated factors among corps members serving in Kebbi state. METHODS: A cross-sectional study was conducted among 264 corps members from four local government areas of the state. Selection of the local government areas and the individual participants was by simple random sampling. Data was collected from May to June 2014 using a self-administered questionnaire. Data analysis used chi-square test to identify the relationship between categorical variables and multivariate logistic regression to identify the independent factors for depression, anxiety and stress each. RESULTS: The response rate was 97%. Most of the respondents were males (63.6%), single (85.5%), and above 20 years of age (71.6%). The overall prevalences of depression, anxiety and stress among the respondents were 36.4%, 54.5% and 18.2% respectively. The independent factors for depression were; being from the North central (OR = 5.99; 95% CI: 2.194-16.354) or South-south; and the perception of earning enough income (OR = 2.987; 95% CI: 1.062-8.400). For anxiety, male gender (OR = 0.411; 95% CI: 0.169-0.999); and being from the North central were significant risk factors (OR = 3.731; 95% CI: 1.450-9.599). Being above 26 years of age was an independent risk factor for stress (OR = 0.083; 95% CI: 0.018 0.381). Also, those who had ever schooled outside their towns of residence were less likely to be stressed compared to those who had never (OR = 0.30; 95% CI: 0.110-0.855). All other factors did not show any significant association with any of the outcome variables in multivariate analysis. CONCLUSION: In conclusion, the prevalences of depression, anxiety and stress are high among corps members serving in Kebbi state. There is need to expand the scope of this study to a national level so as to get a bigger picture of the problem. PMID- 27487594 TI - PREDICTORS OF INTESTINAL HELMINTHIC INFECTIONS AMONG SCHOOL CHILDREN IN GWAGWALADA, ABUJA, NIGERIA. AB - BACKGROUND: Prevalence and risk factors predisposing to intestinal helminthic infections vary widely. Risk factors to intestinal helminthic infections among children have not been documented in Gwagwalada, Nigeria which necessitated present study. OBJECTIVE: To determine risk factors to intestinal helminthiasis among children aged 1-15 years in Gwagwalada, Nigeria. METHODS: Cross-sectional study was carried out from June to November, 2011 in public schools using multi staged, random sampling. Risk factors and helminth species were determined. Multiple stool samples were analyzed using the Kato-Katz technique. Participants had a single anal swab to search for Enterobius ova. RESULTS: Of 220 subjects evaluated, prevalence rate of intestinal helminthic infections was 73.2%. Most common helminth identified was Ascaris lumbricoides (40.9%) and least was Trichostrongylus species (2.3%). Logistic regression analysis showed that significant, predictors of intestinal helminthiasis among subjects were female gender (P = 0.028), lack of hand washing after defecation (P < 0.01), multiple sources of drinking water (P = 0.011) and eating of unwashed fruits/vegetables (P = 0.012). CONCLUSION: The present study identified predictors of intestinal helminthiasis among children Gwagwalada. Efforts should be made to institute regular health education, provision of potable water, environmental sanitation and de-worming programmes for children, as ways of reducing burden of the infections. PMID- 27487595 TI - PRIMARY POSTPARTUM HAEMORRHAGE IN FEDERAL MEDICAL CENTRE, OWERRI, NIGERIA: A SIX YEAR REVIEW. AB - BACKGROUND: Primary postpartum hemorrhage is an obstetric emergency and is a leading cause of maternal morbidity and mortality in developing countries. It a condition that requires vigilance, prompt and appropriate management. OBJECTIVE: To determine the prevalence and determinants of primary post partum haemorrhage in Federal Medical Centre Owerri. METHODS: All cases of all cases of primary post partum haemorrhage managed at FMC Owerri. The case notes were retrieved from the hospital's Records Department and information on socio-demographic characteristics, nature of labour (spontaneous, induced or augmented) duration of labour and mode of delivery and birth weight, estimated blood loss and the need for blood transfusion were obtained. RESULTS: Out of a total of 4889 deliveries, 3725 (76.2%) women had vaginal delivery while 1,164 (23.8%) women had caesarean section. Out of these deliveries, 166 women had Primary Post Partum Hemorrhage (PPH), giving a prevalence of 3.4%. Multiparous women had higher prevalence compared to nulliparas: 88 (48.3%) versus 37 (22.2%) respectively. The commonest cause of primary PPH was uterine atony 72 (43.4%) and cervical laceration was the least cause constituting 13 (7.7%). Caesarean section was associated with higher prevalence of post partum haemorrhage, 94 (56.4%). Duration of second and third stages of labour lasting more than 30 minutes and 10 minutes respective were associated with higher risk of primary PPH:82 (49.5%) and 87 (52.3) respectively. CONCLUSION: Supervised antenatal care, active management of labour and emergency obstetric care, if employed religiously will drastically reduce post partum haemorrhage and thus its associated complications. PMID- 27487596 TI - PATIENT'S PERCEPTION ON THE QUALITY OF RADIOTHERAPY SERVICES IN TWO TEACHING HOSPITALS IN NIGERIA. AB - OBJECTIVE: Patient satisfaction is an important and commonly used indicator for measuring the quality in health care. Patient satisfaction affects clinical outcomes, patient retention, and medical malpractice claims. It affects the timely, efficient, and patient-centered delivery of quality health care. A review of quality of services from the patient's perspective could be a method of assessing in order to improve services and achieve total quality management. This study was designed to assess patients' perception on the quality of Radiotherapy services in Lagos University Teaching Hospital (LUTH) Lagos and University College Hospital (UCH) Ibadan. METHODOLOGY: This study is a cross-sectional study. This research lasted for a period of two months and all patients receiving radiotherapy within is period were included in this study. A total of 246 questionnaires were completed (152 and 94 in LUTH and UCH respectively) and the data collection was by semi-structured questionnaire. Data obtained were collected and analyzed using SPSS statistics [Social Sciences Statistical Package] 17.0 version. RESULTS: The findings of this research indicated that 68.4% in LUTH and 53.2% in UCH of the patients experienced good care. It also revealed that there is good interaction between the staff and the patient. Most of the patients spent more than 3 hours before receiving treatment and also the reason for such delay were not explained to them. The rate of preferential treatment was noted to be high. CONCLUSION: This study will contribute positively towards achieving effective and qualitative radiotherapy services by creating awareness for the need to minimize patient waiting time as well as the need to explain the reason for such delays. The department should adopt better ways of appointment system so that treatment will be on first come first serve basis. This study will contribute positively towards achieving effective and qualitative radiotherapy services by creating awareness for the need to minimize patient waiting time as well as the need to explain the reason for such delays. The department should adopt better ways of appointment system so that treatment will be on first come first serve basis. PMID- 27487597 TI - AWARENESS AND ATTITUDE OF DIABETIC PATIENTS ON DIABETIC EYE COMPLICATIONS IN PORT HARCOURT, NIGERIA. AB - BACKGROUND: Diabetes mellitus has significant ocular morbidities leading to visual impairment and blindness. Most patients are not aware that diabetes mellitus affect the eye with potential debilitating consequences. The study examines the awareness and attitude of diabetic patients attending the endocrinology clinic of the University of Port Harcourt Teaching Hospital, Port Harcourt, on diabetic eye complications in order to examine factors that may be contributingto poor visual outcome. AIM: To assess the awareness and attitude of diabetic patients on diabetic eye complications in Port Harcourt, Nigeria. METHODS: This hospital-based cross-sectional study carried out between 25th March and 28th June, 2011 had 225 adult diabetics attending the Endocrinology clinic of the University of Port Harcourt Teaching Hospital, Port Harcourt daily balloted for. From questionnaires and ocular examinations were recorded in the data sheets and analysed using the SPSS version 16 (2007). Simple statistics andcomparisons of associated variables were made using Chi-square. RESULTS: Of the 225 patients examined, 128 (56.9%) were aware that diabetes could affect the eye while 97 (43.1%) were not aware. Only a quarter (33, 25.8%) of them knew of specific eye complications of diabetes.There was no gender specific significant difference (p = 0.195). Age and educational status significantly affected their awareness (p < 0.005).The duration of diabetes did not have significant impact on the level of awareness of the patients (p = 0.066). Only 103 (45.8%) of those examined had ever had previous eye examination of which 26 (26.3%) did so prior to their diagnosis with diabetes mellitus. Less than a quarter (22.3%) was referred by doctors for the eye examination. Age, sex, educational status and level of awareness did not significantly influence the number of those who had the eye examination while the duration of diabetes significant affect the number of those who had eye examination (p < 0.005). CONCLUSION: The study underscores the need to improve patients' education on diabetic eye complications and encourage primary care physicians to refer diabetic patients for early ocular examination. PMID- 27487598 TI - HEMATOLOGICAL INDICES IN AUTOMOTIVE TECHNICIANS IN NNEWI, SOUTH-EAST NIGERIA. AB - BACKGROUND: Occupational exposure to petroleum products is known to be associated with a number of health risks as well as adverse effects on haematological indices. OBJECTIVE: To evaluate the effect of exposure to petroleum products on haematological parameters in automobile mechanics in Nnewi, south-east Nigeria. SUBJECTS AND METHODS: Fifty (50) automobile technicians and 50 healthy controls participated in the study. Full blood count was performed for each participant using the automated Sysmex haemocytometer (Model PCE 210) while data analysis was done using the SPSS (statistical package for social sciences) version 16 computer soft ware (Chicago, IL, Inc.). Results were expressed as frequencies, means and standard deviations; comparison of haematological parameters was made between subjects and controls and at different durations of exposure using the students' t-test and analysis of variance (ANOVA), respectively. The level of statistical significance was p < 0.05 (at 95% CI). Ethical approval was obtained from the Institutional review board and all participants gave informed consent. RESULTS: There red blood cell count (RBC) and haematocrit were significantly lower while the platelet count was significantly higher in test subjects compared with controls (p values; 0.04, 0.03 and 0.01, respectively). Correspondingly, the mean cell volume (MCV) and mean cell haemoglobin (MCH) were significantly lower in test subjects compared with controls (p = 0.62 and 0.03, respectively). The red cell count, MCV and platelet count significantly decreased with increasing duration of work exposure (p = 0.001, respectively). CONCLUSION: Occupational exposure to petroleum products adversely affects blood counts, with a significant decrease in RBC, MCV and platelet count as duration of exposure increases. PMID- 27487599 TI - EFFECTS OF ROOT CANAL IRRIGANTS ON THE PLANKTONIC FORM OF ENTEROCOCCUS FAECALIS: A REVIEW. AB - BACKGROUND: Bacteria play an essential role in the initiation and perpetuation of pulpal and periapical pathoses. Enterococcus faecalis is associated with both primary and persistent endodontic infections. However, the frequency of E. faecalis in persistent periradicular lesions has been shown to be very higher than primary infections. AIM: The purpose of this paper was to review the effect of various irrigation solutions such as sodium hypochlorite, chlorhexidine, MTAD and Tetraclean against E. faecalis. METHODS: Papers used in this review were found by searching the key words (Root canal irrigant, sodium hypochlorite, chlorhexidine, MTAD, Tetraclean, Enterococcus faecalis) in PubMed. RESULTS: It seems that, although some both sodium hypochlorite and chlorhexidine were very effective against E. faecalis. The other discussed irrigant and Tetraclean, MTAD, were effective against E. faecalis in both agar diffusion test and tooth model experiments. CONCLUSION: It can be concluded that all discussed irrigation solutions were effective against the planktonic form of Enterococcus faecalis. PMID- 27487600 TI - GIANT PSEUDOANEURYSM OF A SPLANCHNIC ARTERY; A Case Report. AB - A true aneurysm is defined as an enlargement of an artery resulting in a diameter more than 1.5 times the anatomic size. It can be fusiform when it covers the entire perimeter of the vessel, or saccular when it bulges on one side of the artery. The pseudoaneurysm is a pulsating encapsulated haematoma in communication with the lumen of the ruptured vessel,which affects the the intima and the media and which is stopped from developing by the adventitia and the surrounding connective tissue. Geographically, aneurysm can be broadly divided into intracranial and extracranial types.While the neurosurgeon manages the intracranial types, the vascular surgeon manages the extracranial types. Vascular surgeons also do divide the extracranial types into central (abdominal-aorto iliac, thoracic including ascending, transverse aortic arch and descending), peripheral (extremities) and visceral (splanchnic arteries). Splanchnic artery aneurysm includes the coeliac, superior mesenteric, inferior mesenteric arteries including their branches. Of all intra-abdominal aneurysms, only around 5% are due to the splanchnic arteries,which could be either true or pseudo. The prevalence has been estimated at 0.1-0.2%. PMID- 27487601 TI - TRANSMIGRATION OF INTRA-UTERINE DEVICE, EXPLORATORY LAPAROTOMY, RETRIEVAL AND REPAIR OF PERFORATED UTERUS. AB - BACKGROUND: Perforation of the uterus following transmigration of Intra-uterine devise (IUD) is an uncommon finding of insertion of IUD. There is associated increased risk of accidental pregnancy,morbidity and mortality. AIM: To report a rare clinical condition in which there was uterine perforation following migration of IUD and to increase awareness of this condition in our environment. CASE REPORT: A 37 year old para 6+0 woman (all alive) who presented with a ten day history of lower abdominal pains following IUD insertion. Examination revealed tenderness in the suprapubic region and non-visualization of IUD thread per vaginam. Pelvic USS showed an empty uterine cavity while an abdominopelvic x ray following tracer IUD insertion showed the IUD to be outside the uterine cavity. She had an exploratory laparotomy for retrieval of transmigrated IUD and repair of perforated uterus. CONCLUSION: Transmigrated IUD with uterine perforation is distressing uncommmon clinical condition, and it is reported with the hope of increasing the awareness and possibly prevent this avoidable uncommon complication. PMID- 27487602 TI - RECURRENT PLEOMORPHIC ADENOMA OF THE UPPER LIP: CASE REPORT AND REVIEW OF THE LITERATURE. AB - INTRODUCTION: Pleomorphic adenoma or mixed tumour is a benign salivary gland tumour, presenting usually in the parotid or submandibular glands. This tumour contains elements of both epithelial and mesenchymal origin. They are the most common tumours (50%), (60-65%) of the major and minor salivary glands. The palate is considered as the most common intraoral site (42.8-68.8%), followed by the upper lip (10.1%) and cheek (5.5%). CASE REPORT: A 37 year old female Nigerian house wife was seen with a four year history of painless slowly progressive upper lip swelling. Prior to her presentation, she had surgery for same swelling in a peripheral hospital. All other histories were not significant. CONCLUSION: PA remains the commonest benign minor salivary gland neoplasm and excision with safe margins the treatment of choice. PMID- 27487603 TI - REVIEW OF CONTROL OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION IN NIGERIA. AB - The global scourge of human immunodeficiency virus (HIV) infection is inundating, especially in sub-Saharan Africa and in particular Nigeria which is home to 10% of the world's HIV-infected persons. The target of the millennium development goal 6 is to halt and reverse the spread of HIV/AIDS by 2015. HIV control in Nigeria was initially shrouded in denial and apathy. Subsequently, a more pragmatic approach was launched during the tenure of President Olusegun Obasanjo. Several policies were formulated. The national prevalence of HIV witnessed some progressive decline and is currently 4.1%. There is now improvement in both HIV awareness and counselling and testing. Greater access to antiretroviral therapy and other support services have also been witnessed with over 300,000 persons currently on drugs. Notable achievements have been recorded in prevention of mother to child transmission (PMTC). However, with increased access to antiretroviral therapy, antiretroviral drug resistance has become inevitable. Acquired drug resistance is high-82% and transmitted drug resistance ranges between 0.7 and 4.5%. The achievements were largely facilitated by international partnerships which have become more streamlined in recent years. A sustained shift to indigenously sourced financial and manpower resource has become imperative. It is also important to integrate HIV facilities with other existing health care facilities for sustainability and cost-effectiveness. In an attempt to strengthen the national response, President Goodluck Ebele Jonathan launched the President's Comprehensive Response Plan for HIV/AIDS in Nigeria. It is hoped that this well-articulated policy would be well implemented to significantly reverse the epidemic. PMID- 27487604 TI - REFERENCE VALUES OF FETAL PEAK SYSTOLIC BLOOD FLOW VELOCITY IN THE MIDDLE CEREBRAL ARTERY AT 12-41 WEEKS OF GESTATION IN JOS, NORTH CENTRAL NIGERIA. AB - OBJECTIVES: The objectives of this prospective cross sectional study are (i) to establish new reference values of peak systolic blood flow velocity measurement in the fetal middle cerebral artery (MCA-PSV) following validated methodological guidelines (ii) to correlat peak systolic velocity with gestational age and (iii) to establish regression prediction model of MCA-PSV for our population. PATIENTS AND METHODS: Cross-sectional data were obtained from 480 low risk pregnant women and cross validated by 120 high risk pregnant women between 12 and 41 weeks' gestation. Reference ranges for MCA-PSV were constructed and for each measurement linear regression models were fitted separately to the mean and standard deviations (SD) as a function of gestational age. A comparison was made between the reference ranges produced in our study and those of Caucasians. RESULTS: Tables of mean values of peak systolic velocity and percentile with regression equations of MCA-PSV are resented, with suggested limits of 2.5th as lower borderline and 97.5th values representing the upper borderline of normal. Foetal middle cerebral artery peak systolic velocity demonstrated simple continues increase and strong positive correlation with gestational age. Calculated values of z were higher than critical values for PSV of subjects and Caucasian values; p < 0.05 CONCLUSIONS: We have constructed reference ranges for MCA-PSV of gestation 1,241 week period and because the methodological flaws of published study have been eliminated, cross validated by a control group including larger sample size drawn from our population we therefore consider this to be useful for clinical practice. PMID- 27487605 TI - MATERNAL MORTALITY AUDIT IN A TERTIARY HEALTH INSTITUTION IN NIGERIA: LESSONS FROM DIRECT CAUSES AND ITS DRIVERS. AB - INTRODUCTION: Nigeria has the second highest number of maternal deaths in the world.The study aimed at determining the causes of and non-obstetric contributors to maternal mortality at a tertiary referral hospital. MATERIALS AND METHODS: It was a prospective audit of all consecutive maternal deaths in the hospital over a three-year period. Immediately after the death, information wvas retrieved via a data collection form. Data were analysed with SPSS-20. RESULTS: Seventy deaths were examined over the study period. Maternal mortality ratio was 1,265/100,000 live births. The annual ratio decreased steadily over the study period. Most of the deaths were of multiparous women who had not received any antenatal care, and were mostly postpartum,within 24 hours of delivery. Most of them were critically ill on admission to the hospital. Major causes of death were haemorrhage (36%), sepsis (17%) and hypertensive disorders (16%).Delays were identified in 34.3% of cases; most (70.1%) were Phase III delays. DISCUSSION: Direct causes of maternal mortality are consistent with those found in literature. Steps which the centre has been taken to counter direct and non-obstetric causes are discussed. Possible strategies to improve health financing and referral system are proffered. PMID- 27487606 TI - STROKE: CRITICAL APPRAISSAL OF INTENSIVE CARE MANAGEMENT. AB - BACKGROUND: Stroke is a common medical condition in the medical units. Stroke patients are usually managed on the medical wards while some that needs organ support are admitted into the intensive care unit. However there is conflicting data on the benefits or otherwise of admitting stroke patients into the intensive care unit. This necessitated this study to know how much benefit is derived from admitting stroke patients into the intensive care unit. AIM AND OBJECTIVE: The study aims at the benefits of admitting stroke patients into the intensive care unit. The objective included studying the prognostic factors that determines the outcome of stroke patients admitted into the intensive care unit. METHODOLOGY: The case files of all patients admitted and managed in the intensive care unit of LAUTECH teaching hospital between 2002 and 2014 were retrieved and were analysed. The factors used in analyzing included the type of stroke, the age of the patients, the Glasgow Coma scale at admission, the need for intubation and mechanical ventilation as well as the percentage mortality in each subsets. RESULTS: A total of 48 patients were admitted over the study period of which 19 were males and 29 were females. The percentage mortality in females was 78.95 while mortality in males was 62.5%. The higher the age the worse the prognosis, the higher the GCS the better the prognosis. Patients that were intubated and ventilated had percentage mortality of 68.8% and better than non ventilated patients. The hemorrhagic strokes also carries worse prognosis. CONCLUSION: The admission of stroke patients to the intensive care unit should be individualized considering the above mentioned prognostic factors. However patients that are likely to benefit from intensive care unit should be admitted early for them to derive the maximum benefits. PMID- 27487607 TI - BODY MASS INDEX IS A POOR PREDICTOR OF MALNUTRITION IN HOSPITALIZED PATIENTS. AB - OBJECTIVE: Comparison between Subjective Global Assessment and Body Mass Index to determine the nutritional status in patients admitted in an Internal Medicine Service. METHODS: Prospective, longitudinal, observational study of a population of 152 patients, using the Subjective Global Assessment and Body Mass Index. Plasma levels of albumin, functional capacity weight and income conditions were determined. Statistics: methods of chi-square test for univariate analysis, non parametric tests and logistic regression were used. RESULTS: 152 patients, of which 48.70% had malnutrition, moderate malnutrition 34.2% (group B) and 14.5% severe malnutrition (group C) were included. No association between Subjective Global Assessment and Body Mass Index was shown to determine nutritional status. MalnutrItion was associated with age over 60 years, male sex, and diagnosis of oncologic andinfectious diseases, as well as the level of functional ability. CONCLUSIONS: Body Mass Index is not a suitable method to assess the impact of malnutrition in hospitalized patients compared with the Subjective Global Assessment. PMID- 27487608 TI - CHALLENGES IN THE MANAGEMENT OF GLAUCOMA IN A DEVELOPING COUNTRY; A QUALITATIVE STUDY OF PROVIDERS' PERSPECTIVES. AB - BACKGROUND: Glaucoma management is challenging to patients as well as to the eye care providers. The study is aimed at describing the challenges faced by providers using qualitative methods. METHODS: In-depth interviews were conducted with selected Ophthalmologists and resident doctors in ophthalmology at centres offering medical and surgical glaucoma services in Lagos state, Nigeria, according to established qualitative methods. This was done using semi structured, open ended questions to explore the providers' perspective on glaucoma burden, challenges in the management, surgery for glaucoma, acceptance of glaucoma surgery by patients, and recommendations for improving glaucoma services. The discussions were recorded with the aid of a micro-cassette recorder. Familiarisation was done to identify key ideas in the data, then, the main themes and sub-themes were identified. Quotes that reflect the themes and sub-themes were then identified in the data. RESULTS: In-depth interviews were conducted with a total of 11 ophthalmologists and resident doctors in training. Majority were of the opinion that glaucoma is a significant burden constituting about 35% of outpatient visits. Identified patient related challenges include; late presentation, lack of glaucoma awareness, delay in referral from optometrists, and poor compliance with medications. Shortages in needed equipment were also identified. Availability, affordability and counterfeiting of drugs were the major challenges related to medical treatment. Majority of the participants agreed that surgery should be offered to the patients as soon as the diagnosis of glaucoma is made. However, continuous monitoring of the patient on medical treatment is another line of option for them in early cases; if they are convinced the patients will be compliant. Some respondents considered the current number of glaucoma surgeries as adequate, while some think otherwise. Reasons put forward for reluctance to offer glaucoma surgery include; late presentation, lack of patient satisfaction, complications of surgery, and negative publicity. CONCLUSION: Even though the challenges in the management of glaucoma in developing countries are many, they are not insurmountable. There is need for concerted and integrated efforts involving all cadres of eye care practitioners, patients, institutions and governments to address this important eye disease. Improved awareness, provision of adequate equipment, availability and affordability of medications, need for training and retraining of eye care providers are all important measures that can lead to better management of the glaucoma patient. PMID- 27487609 TI - PREVALENCE OF METABOLIC SYNDROME AMONG APPARENTLY HEALTHY ADULTS IN A RURAL COMMUNITY, IN NORTH-WESTERN NIGERIA. AB - BACKGROUND: Metabolic syndrome (MetS) is a cluster of multiple metabolic abnormalities that increases the risk of cardiovascular morbidity and mortality, and a resultant severe economic implication. This study assessed the burden of MetS in a Nigerian rural community setting. METHOD: This was a cross-sectional, community based study on apparently healthy subjects. A multi stage cluster sampling technique was employed to recruit the study subjects. A standardized pre tested questionnaire was used to obtain data, and blood samples from subjects were analysed using standard laboratory techniques. MetS was defined using the NCEP-ATP3 criteria. Data were analysed using STATA version II, and a p value of < 0.05 was considered statistically significant. RESULTS: A total of 450 subjects completed the study, with 38% being males, and a mean age of 40.27 +/- 16.41 years. MetS was found in 116 (25.78%) of the subjects. Of these, systemic hypertension was found in 91(78.45%), while all (116) had elevated cholesterol and triglycerides. Abdominal adiposity was found in 45 (38.79%) subjects and 44 (37.93%) had Type 2 diabetes mellitus. CONCLUSION: The prevalence of MetS and its components in our studied population was high; hence the need for further large population based studies to determine its predictors in our environment. PMID- 27487610 TI - PREVALENCE, PATTERN AND RISK FACTORS FOR RETINAL VASCULAR OCCLUSIONS IN A TERTIARY HOSPITAL IN JOS, NIGERIA. AB - INTRODUCTION: Retinal vascular occlusions are the second most common retinal vascular diseases following diabetic retinopathy. They are associated with several systemic and ocular pathologies and are significant causes of visual loss. OBJECTIVE: This study aims to determine the prevalence, pattern and risk factors for retinal vascular occlusions in a tertiary hospital in Jos, Nigeria. METHODOLOGY: A retrospective review of all cases of retinal vascular occlusions seen in the eye clinic from January 2011 to December 2014 was carried out. The patients were identified from the clinic register and their case folders retrieved. The following data were then extracted from the files; patients' age, sex, presenting visual acuity, presence of any systemic disorders and type of retinal vascular occlusion. Data analysis was done using Epi Info 7. RESULTS: Three thousand eight hundred and twenty one new patients were seen during the study period and there were 52 (1.36%) cases of retinal vascular occlusions. Only the case files of 44 (84.6%) patients were available and were analysed. These were made up of 17 (39%) males and 27 (61%) females. These had a total of 46 retinal vascular occlusions made up of 37 (80.4%) retinal vein occlusions, 8 (17.4%) central retinal artery occlusions and a case (2.2%) of combined central retinal artery and vein occlusion. Hypertension and diabetes were the most common systemic risk factors while glaucoma was the most common ocular association. CONCLUSION: Retinal vascular occlusions are uncommon in our centre but lead to severe visual loss and are associated with significant systemic pathologies. PMID- 27487611 TI - CLINICOPATHOLOGICAL PRESENTATION AND MANAGEMENT OUTCOME OF APPENDICITIS IN GOMBE, NORTH-EAST NIGERIA: A 7-YEAR RETROSPECTIVE AUDIT. AB - BACKGROUND: Acute appendicitis is a common cause of acute abdomen and right iliac fossa pain in the study centre with attendant negative appendicectomies. AIM: To study the demographic pattern, aetiology, clinical presentation and management outcome of appendicitis. METHODS: This is a retrospective study carried out on patients, who had appendicectomies between January 2007 and December 2014. A total of two hundred and thirteen (213) cases were operated during the study period. Only one hundred and forty one (141) folders retrieved. Relevant clinical information were entered in to a proforma designed for the study. Statistical analysis was done using Epi info (version 3.5.1). Quantitative data were presented in frequencies and percentages,mean and standard deviations were calculated. RESULT: Out of the 141 patients, 55 (39.0%) were males while 86 (61.0%) were females giving a M:F = 1:1.6. Their ages range from 8 to 65 years. The peak age group was 21-30 years. Acute inflammation was seen in 69 (48.9%) patients, lymphoid hyperplasia in 39 (27.7%) patients while parasitic appendicitis was seen in one (0.7%) patient. Post-operative complications observed include surgical site infection in 7 (5.0%) patients, delayed wound healing in 11(7.8%) patients and enterocutaneous fistula in one (0.7%) patient. CONCLUSION: The diagnosis of appendicitis still rests on the pillars of thorough clinical evaluation. The judicious use of modern diagnostic equipment will reduce the rate of negative appendicectomies. PMID- 27487612 TI - CHALLENGES IN SETTING UP QUALITY CONTROL IN DIAGNOSTIC RADIOLOGY FACILITIES IN NIGERIA. AB - BACKGROUND: The Nigerian Nuclear Regulatory Authority (NNRA) was established to regulate and control the use of radioactive and radiation emitting sources in Nigeria. Quality control (QC) on diagnostic radiology equipment form part of the fundamental requirements for the authorization of diagnostic radiology facilities in the Country. METHOD: Some quality control tests (output, exposure linearity and reproducibility) were measured on the x-ray machines in the facilities that took part in the study. Questionnaire was developed to evaluate the frequencies at which QC tests were conducted in the facilities and the challenges in setting up QC. RESULTS: Results show great variation in the values of the QC parameters measured. Inadequate cooperation by facilities management, lack of QC equipment and insufficient staff form the major challenges in setting up QC in the facilities under study. The responses on the frequencies at which QC tests should be conducted did not correspond to the recommended standards; indicating that personnel were not familiar with QC implementation and may require further training on QC. PMID- 27487613 TI - PERCEPTION OF QUALITY CONTROL BY PERSONNEL IN DIAGNOSTIC RADIOLOGY FACILITIES IN AKWA IBOM STATE, NIGERIA. AB - BACKGROUND: The perception of quality control (QC) implementation by personnel in diagnostic radiology facilities can affect service delivery and deprive the facilities of the benefits associated with QC implementation. The responses by personnel working in diagnostic radiology facilities in Akwa Ibom State, Nigeria, concerning the implementation of quality control in diagnostic radiology has been assessed in order to ascertain their perception of QC implementation. METHOD: A total of thirty eight (38) radiology personnel from twenty radiology facilities took part in the study that was conducted using a twenty item questionnaire that was initially tested for reliability. RESULT: Responses from the surveyed personnel showed a positive perception for some QC items and a seeming lack of interest in some other items. This situation may be due to the perceived lack of interest and lack of cooperation from management of their facilities. The personnel also felt that they did not have sufficient training to implement QC and that QC results were difficult to analyse. PMID- 27487614 TI - TOBACCO ABUSE AND ITS HEALTH EFFECT. AB - Tobacco smoking is still one of the most important risk factor for Respiratory and cardiovascular diseases and an estimated 90% of causes of lung cancer are attributable toTobacco smocking and equally 90% of peripheral vascular disease in non-diabetic population is attributable to Tobacco smoking, despite the health effect there is disturbing figures of people who take up smoking habit daily and increase level of failed quit smoking attempts. Environment and genetics still plays major role, and various forms of tobacco is used worldwide and its health consequence has been highlighted. Monitoring tobacco use and prevention policies through effective tax laws is paramount to reduction of the tobacco health effects in our environments. PMID- 27487615 TI - CURRENT MANAGEMENT OF PERIPARTUM CARDIOMYOPATHY: A REVIEW. AB - BACKGROUND: Demarkis et al in 1971 described 27 patients who presented during pueperium with cardiomegaly, abnormal electrocardiographic findings, congestive heart failure and named the syndrome "peripartum cardiomyopathy". The aim of this review is to document the current concepts in the management of peripartum cardiomyopathy. MATERIALSAND METHODS: A search of the literature was done using PubMed, Goggle scholar and books from authors' collections. RESULTS: The cause of the disease might be environmental and genetic factors. Diagnostic echocardiographic criteria include left ventricular ejection fraction of less than 45% or a combination of M-mode fractional shortening of less than 30% and end diastolic dimension of greater than 2.7 cm/m2. Electrocardiogram, magnetic resonance imaging, endomyocardial biopsy and cardiac catheterization aid in the diagnosis and management of peripartum cardiomyopathy. Treatment includes both conventional pharcomological heart failure and peripartum cardiomyopathy targeted therapies.Therapeutic decisions are influenced by drug safety profiles during pregnancy and lactation. Mechanical support and transplantation might be necessary in severe cases. CONCLUSION: Peripartum cardiomyopathy is an uncommon but life threatening cardiac failure of unknown aetiology encountered in late pregnancy or postpartum period. Management aims at improving heart failure symptoms through conventional therapies and then at administering targeted therapies.The risk of recurrence in future pregnancies should always be considered. PMID- 27487616 TI - DISTAL ILEAL STENOSING SUBSEROSAL LIPOMA: A CASE REPORT. AB - Lipoma is the commonest soft tissue tumour and ubiquitous in distribution. The gastrointestinal tract is a rare site for this neoplasm. This 38 years old patient presented to the surgical emergency unit of the Jos University Teaching Hospital with features of intestinal obstruction which was confirmed by plain abdominal X-ray. Patient was resuscitated and had exploratory laparotomy. At surgery, a dilated, oedematous, and pale segment of ileum was seen measuring 56 cm in length and 10 cm short of the ileo-caecal junction, where an obstruction had occurred.The distal segment was collapsed. A limited right hemi-colectomy was done with ileocolic anastomosis. Specimen received atthe Histopathology Laboratory consisted of 45 cm of the ileum, the caecum, appendix, and proximal 25 cm of the colon in continuity. There was stenosis affecting the distal 30 cm of the ileum. The wall of the stenosed part of ileum had intramural fat at the sub serosal locale. Histology confirmed the presence of sheets of matured adipocytes between the muscularispropria and serosa. Patient condition improved and was discharged seven days after surgery. This case is reported five months after surgery. We recommend that lipoma be at all times considered in the differential diagnosis of intestinal obstruction. PMID- 27487617 TI - TMJ ANKYLOSIS: MANAGEMENT WITH RECONSTRUCTION AND INTERPOSITIONAL ARTHROPLASTY. AB - Temporomandibular joint (TMJ) ankylosis is a very desolating structural condition that involves fusion of the mandibular condyle to the base of the skull. It causes difficulty in mastication and breathing. Trauma and Infections are usually responsible. If trauma occurs in young age, it leads to disturbance in growth & facial asymmetry. Treatment of temporomandibular joint (TMJ) ankylosis usually requires adequate excision of the involved ankylotic block (arthroplasty) or interpositional arthroplasty using autogenous or alloplastic materials. Early mobilization, physiotherapy & strict follow up are essential to prevent postop adhesions. In our cases fascia lata was used as an interpositional grafting material. One case was treated by gap arthroplasty, second case by costochondral graft & third case was managed with titanium condylar prosthesis. PMID- 27487618 TI - FOREIGN BODY IN THE NASOPHARYNX; MASQUERADING AS PHARYNGOTONSILLITIS. AB - Foreign body (FB) in the aerodigestive tracts has been commonly reported but findings of impacted foreign bodies in the nasopharynx following inhalation/ingestion are very rare. Most of the FB gets lodged as a result of forceful vomiting, coughing,and digital manoeuvres for removal of FB in the oropharynx. Several objects have been identified lodged in the nasopharynx. No age group is spared although most victims are children under 10 years of age. Foreign bodies in the nasopharynx can be uneventful or potentially dangerous depending on type, size and location as it may cause sudden airway obstruction, or local pressure necrosis of alimentary or respiratory tract or both. Presentation in children is usually with a history of swallowed FB which may not be witnessed in children, choking, cough, bluish discolouration, breathlessness, drooling of saliva, halitosis, rhinorrhoea, snoring, stridor, dysphagia, vomiting and dysphonia. A foreign body in the nasopharynx is a challenge to patient, parents, the physician and the ENT surgeon, as it may be miss-diagnosed, in the index case, as Pharyngotonsilitis. The index patient, a 14 month child,was presented with a two days history of fever, drooling of saliva, mouth breathing, and digital manipulation. Lateral imaging of the post nasal space following initial treatment with antibiotics, aided the diagnosis of a periwinkle shell in the nasopharyngx that was removed during a nasopharyngoscopy under general anaesthesia without complication and subsequently discharged home. This emphasizes a high index of suspicion for FB in the nasopharynx in children with history of missing foreign body, digital manipulation, drooling of saliva and mouth breathing. Lateral X-ray of the postnasal space, neck, chest and abdomen should be the minimum investigation required. PMID- 27487619 TI - [Not Available]. PMID- 27487620 TI - [Curative treatment for esophageal cancer: results of a multidisciplinary consensus]. AB - The management of patients with resectable cancer of the esophagus or gastroesophageal junction is currently not standardized. A multi- disciplinary regional consensus has been developed and is presented in this article. The standard workup includes an upper endoscopy, ultrasonography and a CT-scan. For locally advanced tumors, surgery should be associated with either preoperative radiochemotherapy orperioperative chemotherapy after discussion in multidisciplinary tumor board. Before the operation, smoking and alcohol cessation is imperative and nutritional status should be optimized. Nowadays, surgery is well standardized and generally performed minimally invasive accesses. After surgery, clinical and oncological follow-up is necessary. PMID- 27487621 TI - [Giant hernias with loss of domain: what is the best way to prepare patients?]. AB - Giant hernias with loss of domain induce physiological modifications that impair quality of life and make more complex their surgical management. A good preparation of patients before surgery is the key to an eventless postoperative course. The progressive pre-operative pneumoperitoneum (PPP) is one of the described abdominal augmentation protocols which can help patients to tolerate hernia content reintegration and avoid components separation technique during hernia repair. This article describes the management of these complex patients. We also report the case of a patient who follows successfully a PPP protocol. PMID- 27487622 TI - [Cystic lesions of the pancreas from the general practitioner's point of view]. AB - The detection rate of cystic lesions of the pancreas has increased following the widespread use of high-resolution imaging technologies. CT-scan, MRI and echo endoscopy are diagnostic modalities. Pseudocyst is the most common lesion. It is benign and can be managed with endoscopic treatment. Mucinous cystic neoplasia and Intraductal Papillary Mucinous Neoplasia (IPMN) carry a risk for malignant transformation. The surgical treatment of these lesions has to be discussed by a multidisciplinary board. Serous cystic neoplasia and pseudopapillar and solid neoplasia are two rare types of lesion. The aim of this article is to present the diagnostic pathway and the management of these lesions from the general practitioner point of view. PMID- 27487623 TI - [Preoperative assessment for extended hepatic resection]. AB - The number of major hepatectomy performed for the treatment of primary or secondary liver cancer has increased over the past two decades. By definition, a major hepatectomy includes the resection of at least three liversegments. Advances in anesthesiology, surgical and radiological techniques and perioperative management allowed a broad patient selection with increased security. Every case must be discussed in multidisciplinary tumor board, and preoperative assessment should include biological, volumetric and functional hepatic parameters. In case of preoperative insufficient liver volume, portal vein embolization allows increasing the size of liver remnant. This paper aims describing preoperative work-up. PMID- 27487624 TI - [Multidisciplinary treatment of locally advanced rectal cancer]. AB - Treatment of patients with locally advanced rectal cancer remains challenging. Preoperative imaging with pelvic MRI allows to identify patients for multimodal treatment including induction chemothe- rapy or neoadjuvant radio-chemotherapy and an extended surgical resection. With multidisciplinary approach and an experienced team, excellent oncologic results may be achieved, as well as a good function and quality of life, even with preservation of the anus in the majority of patients. PMID- 27487625 TI - [Management of peritoneal carcinomatosis with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy]. AB - In 2016, peritoneal carcinomatosis can be considered as a chronic disease that can be treated and sometimes cured. Hyperthermic Intra PEritoneal Chemotherapy (HIPEC) is a procedure developed in the eighties. Combined with CytoReductive (CR) surgery, this protocol underwent a considerable expansion in Washington Cancer Institute. CR combined with HIPEC was demonstrated to be the only curative treatment for PseudoMyxoma Peritonei syndrome (PMP). It is actually approved in the management of peritoneal carcinomatosis of ovarian, colorectal, or peritoneal primitive (mesothelioma) origin but is still studied for gastric cancer. CR/HIPEC is associated with an important mortality and morbidity. This article takes stock of indications to CR/HIPEC. PMID- 27487626 TI - [Not Available]. PMID- 27487627 TI - [Not Available]. PMID- 27487628 TI - [Not Available]. PMID- 27487629 TI - [Not Available]. PMID- 27487630 TI - [Not Available]. PMID- 27487631 TI - [Not Available]. PMID- 27487632 TI - [Not Available]. PMID- 27487634 TI - [Not Available]. PMID- 27487633 TI - [Not Available]. PMID- 27487635 TI - NEOSTIGMINE VERSUS SUGAMMADEX FOR REVERSAL OF NEUROMUSCULAR BLOCK. PMID- 27487636 TI - REMIFENTANIL VS FENTANYL DURING DAY CASE DENTAL SURGERY IN PEOPLE WITH SPECIAL NEEDS: A COMPARATIVE, PILOT STUDY OF THEIR EFFECT ON STRESS RESPONSE AND POSTOPERATIVE PAIN. AB - BACKGROUND: People with special needs undergoing dental surgery frequently require general anesthesia. We investigated the effect of remifentanil vs fentanyl on stress response and postoperative pain in people with special needs undergoing day-case dental surgery. METHODS: Forty-six adult patients with cognitive impairment undergoing day-case dental surgery under general anesthesia were allocated to receive intraoperatively either fentanyl 50 MUg iv bolus (group F, n = 23) or continuous infusion of remifentanil 0.5-1 MUg/kg/min (group R, n = 23). Iintraoperative hemodynamic parameters were recorded and serum inflammatory mediators [tumor necrosis factor-alpha, substance-P], stress hormons (melatonin, cortisol) and beta-endorphin were measured. Postoperative pain was assessed during the first postoperative 12 hours with the Wong-Baker faces pain-rating scale. RESULTS: Demographics were similar in two groups. The two groups did not differ regarding their effects on inflammatory mediators, stress hormons and postoperative pain scores. However, the use of remifentanil prevented intraoperative increases of arterial blood pressure and heart rate. CONCLUSIONS: Remifentanil and fentanyl did not affect differently stress and inflammatory hormones during day-case dental surgery, although remifentanil may render intraoperative management of hemodynamic responses easier. Both opioids are equally efficient for postoperative pain management following dental surgery in people with special needs. PMID- 27487637 TI - COMPARISON OF THE BONFILS INTUBATION FIBRESCOPE VERSUS C-MAC VIDEOLARYNGOSCOPE. AB - BACKGROUND: This prospective, randomized, single blind, single operator study was conducted to compare hemodynamic responses when endotracheal intubation was performed using the Bonfils intubation fibrescope versus the C-MAC videolaryngoscope. METHOD: Forty-four ASA I patients aged between 18 and 60 years, scheduled for elective surgery requiring endotracheal intubation were recruited. They were randomized into the Bonfils group or C-MAC group. Hemodynamic changes, laryngeal view, duration of intubation and post intubation complications were evaluated. Mean arterial pressure, heart rate and oxygen saturation were monitored pre and post-induction, pre and post-intubation, and at 1 minute intervals thereafter for 10 minutes. RESULTS: Endotracheal intubation was successful at first attempt in 90.9% in both groups. Heart rate was significantly higher in the Bonfils group (p < 0.05) compared to the C-MAC group and values were sustained throughout the study. There was no difference in the mean arterial pressure (MAP) between the two groups. Mean time to intubation was significantly longer in the Bonfils group (28.8 vs. 24.7 seconds, p = 0.02). There were no significant differences in laryngeal view and post intubation complications between the groups. CONCLUSION: Intubation using the Bonfils intubation fibrescope took longer, and resulted in significantly higher heart rate when compared with the C-MAC videolaryngoscope. PMID- 27487638 TI - A COMPARATIVE STUDY OF THE ANALGESIC EFFECT OF INTRAVENOUS PETHIDINE VS. KETOROLAC AFTER INGUINAL HERNIA SURGERY IN CHILDREN UNDER GENERAL ANESTHESIA. AB - INTRODUCTION: Postoperative pain due to tissue damage caused during surgery not only causes discomfort for the patients, but can also result in prolonged hospitalization, increased morbidity and respiratory disorders, and readmission to the hospital. For postoperative pain control, numerous methods and medications have been suggested, such as non-steroidal anti-inflammatory drugs (NSAIDs) and narcotics. Pethidine, as a narcotic analgesic, and ketorolac, as an NSAID, are widely used for pain control. Thus, in this study, the effects of these two drugs were studied and compared in terms of pain control after inguinal hernia surgery in children of 1-12 years of age. MATERIALS AND METHODS: Sixty-six children undergoing inguinal herniorrhaphy were selected and randomly divided into 2 groups. The first group received 0.5 mg/kg ketorolac and the second group received 1 mg/kg pethidine during extubation. Postoperative pain (using Wong Baker pain scale) and complications were measured until 24 hours after surgery. RESULTS: Mean and standard deviations of postoperative pain 1 hour after surgery in the pethidin and ketorolac groups were 5.06 +/- 1.41 and 3.88 +/- 0.93, respectively. The scale was significantly lower in the ketorolac group (P < 0.001). Postoperative pain intensity 2 hours after surgery in these two groups was 4.48 +/- 1.52 and 3.55 +/- 1.15, respectively, and the difference between the two groups was significant (P = 0.006). The variation in postoperative pain intensity in the ketorolac group was statistically lower than the pethidin group (P = 0.020). CONCLUSION. PMID- 27487639 TI - SHORT-TERM POSTOPERATIVE COGNITIVE FUNCTION OF ELDERLY PATIENTS UNDERGOING FIRST VERSUS REPEATED EXPOSURE TO GENERAL ANESTHESIA. AB - BACKGROUND: General anesthesia (GA) may affect cognitive functions and result in postoperative cognitive dysfunction. The aim of our prospective pilot study was to compare the short-term postoperative cognitive function of unimpaired elderly patients undergoing first versus repeated exposure to GA. METHODS: After approval from the Hospital Ethics Committee and informed consent of all participants, 46 patients, 70.1 +/- 7.1 years of age, 20 men and 26 women were enrolled in the study. Twenty-five patients belonged to group A (never received GA before) and 21 patients belonged to group B (received at least once GA the last 5 years). Each patient was evaluated preoperatively and the 8th day postoperatively by a blinded examiner with a battery of neurocognitive tests. RESULTS: Group B patients performed preoperatively worse in Trail Making Test Part A, Stroop Color and Word Test and Three Words-Three Shapes Test. Postoperatively there were differences in almost every neurocognitive test, with group B patients again achieving the worse scores. This came along with increased Beck Depression Inventory Test score and increased incidence of delirium in Group B patients. CONCLUSION: Our pilot study suggests that prior exposure of elderly patients to GA might lead to prolonged cognitive impairment and repeated GA exposure seems to be a potential risk factor for greater short-term postoperative cognitive impairment. PMID- 27487640 TI - COMPARISON OF THE EFFECTS OF PREEMPTIVE INTRAVENOUS AND RECTAL ACETAMINOPHEN ON PAIN MANAGEMENT AFTER INGUINAL HERNIORRHAPHY IN CHILDREN: A PLACEBO-CONTROLLED STUDY. AB - BACKGROUND: Postoperative pain management is a critical concern in pediatric surgery. Acetaminophen is the safest and most widely used analgesic in children. The present study compared the analgesic efficacy of intravenous (IV) and rectal acetaminophen versus placebo in children undergoing inguinal herniorrhaphy. METHODS: A total of 120 children, who were candidate for elective surgical repair of unilateral inguinal hernia, were enrolled and randomly allocated to four groups of 30 patients each to receive IV acetaminophen, acetaminophen suppository, IV placebo, and placebo suppository during surgery. Postoperative pain scores, measured on the Face, Legs, Activity, Cry, and Consolability (FLACC) scale, were recorded and compared. RESULTS: The four groups had no significant differences in the mean age, weight, length of stay in the recovery room, and duration of operation. The frequency of postoperative vomiting was significantly lower in the IV and rectal acetaminophen groups compared to the two placebo groups (P = 0.04). The mean pain scores of the two acetaminophen groups were similar during the first two hours after surgery. These scores were significantly lower than the scores of the placebo groups. However, the four groups were not significantly different in terms of pain scores at the fourth, sixth, and 12th postoperative hours. During the first hour after surgery, IV acetaminophen had the largest analgesic effect. Moreover, among all four groups, the IV acetaminophen group had the highest sedation level in the recovery room. CONCLUSION: Both IV and rectal acetaminophen were more effective than placebo in pain relief after inguinal hernia repair in children. They were also associated with lower frequencies of postoperative vomiting. The greatest analgesic efficacy of both forms was observed during the first two hours after surgery. PMID- 27487641 TI - ANESTHETIC MANAGEMENT DURING COMBINED LIVER AND KIDNEY TRANSPLANTATION. AB - Combined liver and kidney transplantation is a highly demanding and challenging procedure for anesthesiologists due to the lengthy and complicated nature of the procedure, the critical patient condition and the need to balance the intravascular volume to maintain the venous outflow of the hepatic allograft and also the diuresis of the renal allograft. Intravascular volume management and coagulation control, seem to be the most important issues during combined liver and kidney transplantation. There is sparsity of data in the literature concerning the anesthetic and fluid management in CLKT. We present and discuss the anesthetic management in a case series in three patients, who underwent combined liver and kidney transplantation in our institution during the last two years. PMID- 27487642 TI - TORSADES DE POINTES ASSOCIATED WITH TAKOTSUBO CARDIOMYOPATHY IN AN ANOREXIA NERVOSA PATIENT DURING EMERGENCE FROM GENERAL ANESTHESIA. AB - Takotsubo cardiomyopathy, also known as stress-induced cardiomyopathy, is a disease in which the patient exhibits transient, reversible left ventricular dysfunction that is triggered by physical or emotional stress. Prolongation of QT interval, a risk factor for arrhythmia and sudden death, has been reported to be prevalent among patients with Takotsubo cardiomyopathy and is also observed in those with severe anorexia nervosa. In this report, we describe the rare case of a 30-year-old female patient with anorexia nervosa who developed Torsades de Pointes associated with Takotsubo cardiomyopathy during emergence from general anesthesia for emergency exploratory laparotomy. PMID- 27487643 TI - PERIOPERATIVE CARE OF A CHILD WITH CRISPONI SYNDROME. AB - Crisponi syndrome is an autosomal recessive disorder characterized by intermittent episodes of muscular contraction of the facial muscles with trismus and excessive salivation simulating a tetanic spasm. These episodes occur in response to tactile stimulation or during crying. Associated physical and constitutional findings include characteristic facial anomalies, camptodactyly, intermittent hyperthermia, and feeding difficulties. We present a 15-month-old girl who required anesthetic care during laparoscopic fundoplication and gastric tube insertion. The perioperative implications of the disorder are reviewed and suggestions for anesthetic management provided. PMID- 27487644 TI - LOEYS-DIETZ SYNDROME: PERIOPERATIVE ANESTHESIA CONSIDERATIONS. AB - Loeys-Dietz syndrome (LDS) is a rare autosomal dominant disease related to genetic mutations in receptors for the cytokine transforming growth factor receptor type 1 (TGFB-R1) or 2 gene (TGFB-R2) on the cell surface. LDS results in abnormal protein synthesis and dysfunctional connective tissue, which can result in unique cardiovascular anesthesia challenges related to perioperative management. Patients with LDS may manifest hypertelorism, bifid uvula or cleft palate, and arterial tortuosity. Virtually all LDS patients show some type of abnormal skin findings and bleeding tendency. These patients may show a rapid progression of aortic dilation, regurgitation, and a propensity towards rupture and/or dissection at a much earlier age and smaller aneurysm size. LDS patients who require surgical intervention require meticulous vigilance from the anesthesiologist. We describe a 26 year old patient with documented LDS type 1 who presented for repair of an ascending/root aneurysm in this case report. Recognition of LDS and intra-operative management of the cardiovascular manifestations of this disease is paramount in ensuring successful surgical outcome and to limit morbidity and mortality. PMID- 27487645 TI - ECG-ELECTRODE INDUCED HYPOPIGMENTATION. AB - Skin reactions following the application of electrocardiography (ECG) electrodes have been reported in adults and children, and are postulated to result from contact with the conductive gel or adhesive used on the electrodes. Although contact dermatitis is the usual cause of such reactions, contact depigmentation or hypopigmentation may also occur. We report a case of hypopigmentation in a healthy boy following continuous electrocardiography monitoring during general anesthesia for dental rehabilitation. PMID- 27487646 TI - PERIOPERATIVE CARE OF AN INFANT WITH GOMEZ-LOPEZ-HERNANDEZ SYNDROME. AB - Gomez-Lopez-Hernandez syndrome, also known as cerebello-trigeminal dermal dysplasia, is a rare neurocutaneous syndrome classically characterized by the triad of rhombencephalosynapsis, trigeminal anesthesia, and bilateral parietal alopecia. Associated clinical features include a characteristic facial appearance (mid-face hypoplasia, hypertelorism, and low-set, posteriorly rotated ears), brachycephaly, strabismus, ataxia, developmental delay, short stature, and corneal opacities. Given the associated congenital anomalies, anesthetic care may be required for various surgical interventions. We report a 7-month-old with Gomez-Lopez-Hernandez syndrome scheduled for laparoscopic gastrostomy with tube placement and frenulotomy under general anesthesia. The potential perioperative implications of such patients are reviewed and options for anesthetic care discussed. PMID- 27487648 TI - ARTERIAL CANNULATION: SIMPLE SWAYING MANEUVER MAY BE AN ANSWER TO COUNTER FAILURE/COMPLICATION RATES. PMID- 27487647 TI - ANESTHESIA FOR CHARCOT-MARIE-TOOTH DISEASE: CASE REPORT. AB - Charcot-Marie-Tooth disease comprises a group of disorders characterized by progressive muscle weakness and wasting. Reviewing the anaesthetic literature produced conflicting reports about the best anaesthetic options for patients with CMTD; as they are at increased risk of prolonged response to muscle relaxants, malignant hyperthermia and risks of regional anaesthesia. We present a case of the successful use of total intravenous anaesthesia with dexmedetomidine and propofol combined with caudal block using bupivacaine mixed with dexmedetomidine without any complications, for a 17 year old male patient with Charcot Marie Tooth disease who underwent a lower limb orthopedic surgery. PMID- 27487649 TI - PALPATE INTERCRISTAL LINE CORRECTLY: NOT TRANSGRESS TOO HIGH: CAN BE TOO CLOSE TO CONUS MEDULLARIS. PMID- 27487650 TI - Editorial. PMID- 27487651 TI - Treatment of Bignathic Malocclusions With Multistage Active Force Orthodontic Movements in a Cat. AB - Abstract Untreated malocclusions may lead to negative oral health sequelae including, but not limited to, pain, dental trauma, periodontal disease, and endodontic disease. Thus, orthodontic treatments of malocclusion in companion animals are often pursued for reasons other than cosmesis. Treatment may provide a pain-free, functional occlusion with the opportunity for the best possible long term oral health. This report describes the multistage orthodontic treatment of a bignathic malocclusion in a cat, highlighting the complexities and complications that may arise with orthodontic movement of multiple teeth. PMID- 27487652 TI - Bridging Plate Development for Treatment of Segmental Bone Defects of the Canine Mandible: Mechanical Tests and Finite Element Method. AB - With regard to the canine mandible, a mistaken concept of application is to assume that systemic plate-bone resistance is provided by the implant so that biomechanical position could be ignored. Because the alveolar border of the mandible is a tensile zone, the plate would ideally be positioned near this area while avoiding important structures. The aim of this study was to develop 2 bridging plates for the treatment of a segmental bone defect of the canine mandible using monocortical screws to avoid damage to the tooth roots and remaining neurovascular structures. Computed tomography images of the heads of 4 dogs (rottweiler, Doberman, boxer, and miniature poodle breeds) were used as models to develop the project. The images were reconstructed in 3-dimensional (3D) format. For each dog breed, 6 mandible prototypes were produced, each with a segmental bone defect in the right mandible. The mandibular reconstruction was performed with pure titanium bridging plate and locking screws. One plate model was developed for medium- and large-breed dogs and another for small-breed dogs. Mechanical testing showed the platemandible system resists the bite forces in all dog breeds. All safety factors were greater than I in the platemandible system for medium- and large-breed dogs and greater than 10 in the plate-mandible system for small-breed dogs. Thus, bridging plates designed with differentiated geometry and monocortical locking screws showed mechanical resistance to support simulated induced bone model defects and were able to support at least 5 times the value of bite force for each evaluated dog. PMID- 27487653 TI - Quantification of Canine Dental Plaque Using Quantitative Light-Induced Fluorescence. AB - The aim of this work was to evaluate Quantitative Light-induced Fluorescence (QLF) as an alternative to the established Logan and Boyce method for determining plaque coverage of dogs' teeth. In a series of studies in conscious and anesthetized dogs, QLF showed good intra-photographer repeatability (coefficient of variation [CV] of 7.5% for undisclosed teeth) and inter-photographer reproducibility (CV of 3.2% for undisclosed teeth and 8.5% for disclosed teeth). The QLF software accurately identifies areas of plaque as demonstrated by comparison to the variability of 5 human scorers, manually marking plaque on QLF acquired images (P = 0.1). There was good agreement with the modified Logan and Boyce method in the percentage reduction in plaque accumulation measured when dogs were fed an oral care chew versus no chew. To see a 15% difference in plaque accumulation, which is considered sufficient by the Veterinary Oral Health Council to differentiate between 2 treatments, a retrospective power analysis (90%) of the data established that only 7 dogs would be required, compared to 19 dogs for the modified Logan and Boyce method. QLF is a reliable method for measuring dental plaque in dogs with the added advantage that it is not subjective and requires fewer animals. PMID- 27487654 TI - Measuring Rabbit (Oryctolagus cuniculus) Tooth Growth and Eruption by Fluorescence Markers and Bur Marks. AB - Rabbits (Oryctolagus cuniculus) and rodents possess continuously growing teeth, and dental problems are a major health issue in these species. Knowledge of tooth growth characteristics is required to adequately treat dental problems and advise owners concerning diets. Most research was performed using bur marks and measuring eruption and wear manually. However, this method cannot be applied to teeth less rostral than the first premolar; therefore, for evaluation of molars, other methods are needed. We evaluated the use of fluorochromes xylenol orange and calcein green to measure growth rates of rabbit teeth and compared this method to results obtained by manually measuring the distance between a bur mark and the gingival margin of the same tooth (eruption) and by measuring the distance between the bur mark and the apex of the same tooth on computed tomography scans (growth). Apical fluorochrome measurements correlated well with eruption and growth rates obtained with bur marks, whereas measurements coronal to the pulp cavity did not. Growth rates were approximately 1.9 mm/wk for maxillary and 2.2 mm/wk for mandibular incisors. Growth rates of premolars were 2.14 +/- 0.28 mm/wk in rabbits on a grass/rice hulls/sand pelleted diet and 0.93 +/- 0.18 mm/wk in rabbits on a hay diet. Growth of molars could only be assessed using the measurement in dentin on the wall of the pulp cavity, which does not account for the real growth. However, being similar to this measurement in premolars, one could hypothesize similar growth in molars as in premolars. We conclude that the application of fluorochrome staining can be used to measure tooth growth in teeth that are not accessible for bur marks or in animals that are too small to assess tooth eruption or growth by bur marks. PMID- 27487655 TI - Modified Labial Button Technique for Maintaining Occlusion After Caudal Mandibular Fracture/Temporomandibular Joint Luxation in the Cat. AB - Maxillofacial trauma in cats often results in mandibular symphyseal separation in addition to injuries of the caudal mandible and/or temporomandibular joint (TMJ). Caudal mandibular and TMJ injuries are difficult to access and stabilize using direct fixation techniques, thus indirect fixation is commonly employed. The immediate goals of fixation include stabilization for return to normal occlusion and function with the long-term objective of bony union. Indirect fixation techniques commonly used for stabilization of caudal mandibular and temporomandibular joint fracture/luxation include maxillomandibular fixation (MMF) with acrylic composite, interarcade wiring, tape muzzles, and the bignathic encircling and retaining device (BEARD) technique. This article introduces a modification of the previously described "labial reverse suture through buttons" technique used by Koestlin et al and the "labial locking with buttons" technique by Rocha et al. In cases with minimally displaced subcondylar and pericondylar fractures without joint involvement, the labial button technique can provide sufficient stabilization for healing. Advantages of the modified labial button technique include ease of application, noninvasive nature, and use of readily available materials. The construct can remain in place for a variable of amount of time, depending on its intended purpose. It serves as an alternative to the tape muzzle, which is rarely tolerated by cats. This technique can be easily used in conjunction with other maxillomandibular repairs, such as cerclage wire fixation of mandibular symphyseal separation. The purpose of this article is to demonstrate a modified labial button technique for maintaining occlusion of feline caudal mandibular fractures/TMJ luxations in a step-by-step fashion. PMID- 27487656 TI - [CHARACTERISTICS OF OSTEOCYTE CELL LINES FROM BONES FORMED AS A RESULT OF MEMBRANOUS (SKULL BONES) AND CHONDRAL (LONG BONES) OSSIFICATION]. AB - The aim of this work was to analyze the literature data and the results of authors' own research, to answer the question--if the osteocytes of bone tissues resulting from membranous and chondral ossification, belong to one or to different cell lines. The differences between the cells of osteocyte lines derived from bones resulting from membranous and chondral ossification were established in: 1) the magnitude of the mechanical signal, initiating the development of the process of mechanotransduction; 2) the nature of the relationship between the magnitude of the mechanical signal that initiates the reorganization of the architecture of bone structures and the resource of their strength; in membranous bones significantly lower mechanical signal caused a substantially greater increment of bone strength resource; 3) the biological activity of bone structures, bone fragments formed from membranous tissue were more optimal for transplantation; 4) the characteristics of expression of functional markers of bone cells at different stages of their differentiation; 5) the nature of the reaction of bone cells to mechanical stress; 6) the sensitivity of bone cells to one of the factors controlling the process of mechanotransduction (PGI2); 7) the functioning of osteocytes during lactation. These differences reflect the functional requirements to the bones of the skeleton--the supporting function in the bones of the limbs and the shaping and protection in the bones of the cranial vault. These data suggest that the results of research conducted on the bones of the skull, should not be transferred to the entire skeleton as a whole. PMID- 27487657 TI - [THE DISTRIBUTION OF CORTICO-THALAMIC PROJECTIONS OF DIFFERENT OF DIFFERENT SOMATOTOPIC REPRESENTATIONS OF PRIMARY MOTOR AND SENSORY CORTEX]. AB - The peculiarities of localization and distribution of cortico-thalamic efferents of different somatotopical representations of primary motor (MI) and sensory (SI) cortex were studied in cat brain. MI efferent fibers (4y, 6ab areas) preferentially projected to ventral posterolateral and medial (VPL, VPM), ventrolateral (VL), and reticular (R) nuclei, localized in rostral part of the thalamus (T), as opposed to SI (areas 1, 2, 3a, 3b), which projected preferentially to caudal part of T, VPL, VPM and R nuclei. Latero-medial organization of cortico-thalamic connections was demonstrated, with predominant localization of cortical representation of hindlimbs in the lateral part of VPL, of forelimbs--in the medial part of VPL, of face and head--also in VM and VPM. Quantitative analysis of the distribution of corticothalamic efferents of different somatotopical representations of MI has demonstrated the most extensive, massive connections with T nuclei (VPL, VL, R) of the motor representation of forelimb, followed by the representation of hindlimb, trunk and, finally, the minimal projection of the representation of face and head. As opposed to motor representation of the forelimb and also of the face and head, with uniform distribution of fibers in VPL, VL and R, the number of efferents of motor representation of hindlimb, passing in VL, was almost 2.5 time lower than in VPL and R, whereas the representation of trunk had the predominant projection to VL. Dominant cortico-thalamic connection suggests greater involvement of T nuclei studied in the realization of functional specialization of certain somatotopical representations of MI. PMID- 27487658 TI - [REACTIVE CHANGES IN THE ASTROCYTES OF FOREBRAIN NUCLEUS ACCUMBENS AFTER RESTRICTION OF BLOOD FLOW IN THE BASIN OF BOTH COMMON CAROTID ARTERIES IN RATS]. AB - Reactive changes of astrocytes were studied in forebrain nucleus accumbens in rats (n = 12) after global cerebral ischemia induced by bilateral occlusion of both common carotid arteries, which is a frequently used model to assess the effectiveness of pharmacological agents that have anti-ischemic and neuroprotective properties. Under these conditions, the nucleus accumbens was in the area of partial ischemia. Morphometric study of nucleus accumbens was performed in three groups of rats (4 animals in each group) after ligation of both common carotid arteries, after a sham operation and in healthy animals. Astrocytes were demonstrated in serial sections using the reaction to glial fibrillary acidic protein counterstained with hematoxylin. 7 days after the surgery, in each animal the number of astrocytes was counted in the sections in 7 successiive squares of 0.01 mm2 each, the distance between their bodies and the capillary wall was measured within the circle of 20 MUm radius, the cell body area and the length of their main processes were determined. It is found that astrocytes in the nucleus accumbens in the model of bilateral occlusion of the common carotid arteries for 7 days experienced a partial state of ischemia. Their reactive changes were manifested by the signs of the cytotoxic edema, damaging intermediate filament proteins in their bodies, processes and in the perivascular glial membranes. The concentration of the astrocyte cell bodies near blood capillaries is the adaptation mechanism and is a condition for the survival of cells under the restriction of blood flow in the brain. PMID- 27487659 TI - [LOCALIZATION AND QUANTITATIVE ASSESSMENT OF OXYGEN-DEPENDENT HYPOXIA-INDUCIBLE FACTOR 1alpha IN THE BRAIN OF MITTEN CRAB ERIOCHEIR JAPONICA IN NORM AND IN ACUTE ANOXIA (AN IMMUNOHISTOCHEMICAL STUDY)]. AB - Using immunoblotting and immunocytochemistry, the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) was studied in the brain of the mitten crab Eriocheir japonica in norm and at 2, 4, 6 and 12 hours of anoxia on the model of water deprivation. In intact crabs, the number of immunopositive neurons was small, but it increased with anoxia duration. Particularly pronounced increase in the proportion of neurons with the HIF-1alpha expression was found in cell group 6. In group 9/11. the highest expression index was observed between 2-6 hours of anoxia. In group 17, significant changes in the proportion of immunopositive cells was observed only after 2 hours of anoxia. After 6 hours of anoxia, proportion of neurons with HIF-1alpha expression within all cell groups was reduced, but the reactions appeared in the blood cells. It is assumed that the increase in the proportion of immunopositive neurons and the appearance of the expression of HIF-1alpha in blood cells in the anoxic brain play an important role in providing compensatory and protective processes, enhancing adaptive capacity of mitten crab under the conditions of hypoxic stress. PMID- 27487660 TI - [CELL CONTACT PROTEIN BETA-CATENIN IN EPENDYMAL AND EPITHELIAL CELLS OF THE CHOROID PLEXUS OF THE CEREBRAL LATERAL VENTRICLES]. AB - The purpose of this study was to examine the distribution pattern of cellular contacts protein beta-catenin in the choroid plexus and ependyma of lateral ventricles of the brain. The study was conducted on frontal sections of the brain of Wistar rats (n = 10) using polyclonal antibodies against beta-catenin. The obtained preparations were analyzed by microscopy in transmitted light and using confocal laser microscopy. To study the distribution of beta-catenin in different projections, three-dimensional reconstruction was performed. The study demonstrated different distribution patterns of this protein in ependyma and choroid plexus. Unlike ependyma, in the cells of the choroid plexus beta-catenin was distributed in the same way as in simple epithelial tissues (on the basal and lateral borders of the cells). This may indicate different tissue attribution of the ependyma and the choroid plexus epithelium, despite their common origin. PMID- 27487661 TI - [EXPRESSION OF DOUBLECORTIN AND NeuN IN THE DEVELOPING CEREBELLAR NEURONS IN RAT]. AB - This work was performed on the offspring of 5 outbred female albino rats to give a comparative immunohistochemical evaluation of doublecortin (DCX) and NeuN expression in the neurons of the cerebellar cortex and nucleus interpositus in the early postnatal ontogenesis (postnatal days 2-15). DCX expression was detected in postmitotic neurons of the external granular layer and migrating neurons of the cerebellar cortex. At postnatal days 2 and 7 DCX expression in neocerebellum was higher than in paleocerebellum. NeuN expression was found to appear in migrating granule neurons, and reach the maximum in mature neurons of internal granular layer. DCX expression was not detected in Purkinje cells and in the nucleus interpositus of the cerebellum. In neurons of the nucleus interpositus the expression of NeuN progressively increased from postnatal days 2 to 15. Thus, a comparative immunohistochemical study of the dynamics of the expression of the pair of molecular markers studied proved to be an effective way of the assessment of the development of granular neurons of the cerebellum in early postnatal ontogenesis. PMID- 27487662 TI - [CHARACTERISTICS OF THE RETINA IN CHRONIC STRESS IN LABORATORY RATS OF DIFFERENT AGE GROUPS]. AB - The retina was studied in albino laboratory male rats of two age groups (12 and 24 months), 10 animals in each subjected to chronic combined stress. The stress was caused in animals by simultaneous exposure to pulsed light, loud sound, swinging and restriction of mobility for 7 days, 30 mm daily. The retina of intact rats of the corresponding age groups (n = 20) served as control. Enucleated eyes of stressed and control animals were processed with standard histological technique and stained with Nissl's method and hematoxylin-eosin. The retina of the stressed animals of both age groups showed the decrease in the number of cells and the disarrangement of its layers, most pronounced in the layers of photoreceptor neurons and ganglion cells. The comparative morphometric analysis demonstrated a reduction of the layer thickness and cell numerical density in the retina of stressed animals, both young (12 months) and old (24 months), as compared to that of control animals. PMID- 27487663 TI - [CHANGES OF THE CONTENT OF DLL4 AND Jag-1 ANGIOGENESIS REGULATORS IN HUMAN DERMIS IN ONTOGENESIS]. AB - The goal of this study was to examine the contents of D114 and Jag-1 angiogenesis regulators in human dermis at different age periods. D114 and Jag-1 were demonstrated by indirect immunohistochemistry in skin sections of fetuses of 20 40 gestational weeks and in persons aged from birth to 85 years. D114 was studied in 150 skin samples of 72 females and 78 males, while Jag-1 was examined in 120 samples of 58 females and 62 males. It is found that the immunoreactivity was mainly expressed by the endothelial cells. Vessels, which gave a positive reaction to D114 and Jag-1, were found throughout the entire thickness of the dermis, both in fetuses, and people of all age groups. Expression of D114 in the vessels of dermal microvasculature was shown to increase from 20 weeks of gestation to 20 years. With the further age increase, the intensity of the reaction of blood vessels for D114 was decreased. Expression of Jag-1 in dermal microvessels was enhanced from 20 weeks of gestation to 85 years. The results are discussed in connection with the role of D114 and Jag-1 in angiogenesis in human dermis during ontogeny. PMID- 27487664 TI - [CLINICAL SIGNIFICANCE OF ANATOMICAL VARIABILITY OF THE LEFT INFERIOR PHRENIC VEIN]. AB - The diaphragm was taken from the corpses of 80 humans of both sexes of adult age and was studied using the complex of preparation, injection, morphometric and of variational-statistical methods. A significant anatomical variation of the left inferior phrenic veins was found, that was characterized by different variants of their confluence, and variation of their diameters. Five variants of the confluence of the left inferior phrenic veins were defined. It was shown that the variant of confluence of the left inferior phrenic veins into a single trunk fusing with the inferior vena cava was suitable for catheterization. Suitable for catheterization left inferior phrenic veins may be divided into freely catheterizable (diameter of 5 mm and more).and conditionally catheterizable (diameter less Than 5 mm). When performing cardiac resynchronization therapy, the vein can be used as an alternative way (along with the coronary sinus of the heart) for transvenous delivery system of stimulation electrode. Variants of confluence of the left inferior phrenic vein in hepatic and adrenal veins were not suitable for catheterization. PMID- 27487665 TI - [MORPHO-FUNCTIONAL CHANGES OF THYMUS TISSUES IN CHILDREN WITH CONGENITAL HEART DISEASE]. AB - Biopsy specimens of the thymus were studied in children aged under 11 months (n = 77) with congenital heart defects and circulatory hypoxia of varying severity. Histological sections were stained with hematoxylin-eosin and Shubich's method (to demonstrate mast cells). The expression of Ki-67, CD3 and CD34 was assessed by immunohistochemistry. The ultrastructure of thymic tissues was also examined. It was found that the severity of hypoxia determined the morphological changes in the organ associated with a development of large complex of tissue reactions. A disruption of internal structure and a loss of integrity of epithelio-reticular cells and thymocytes were demonstrated in ultrathin sections. Thymocyte proliferation index (Ki-67) and thymocytopoiesis intensity (CD3+) were reduced in all the zones of the thymus. The degree of hypoxia affected the redistribution of CD3+ lymphocytes leading to their accumulation in the medulla. The processes of endogenous regeneration took place which involved the cells of fibroblastic line and progenitor cells (CD34+) together with active formation of new blood vessels. These findings suggest that the morphological changes identified in the tissues of the thymus are a manifestation of tissue adaptation to hypoxia of varying severity under conditions of endogenous regeneration, simultaneously reflecting the processes of substitution cytogenesis. PMID- 27487666 TI - [MORPHOMETRIC AND HISTOCHEMICAL CHARACTERISTICS OF THE THYROID GLAND AFTER ADMINISTRATION OF HYDRA PEPTIDE MORPHOGEN]. AB - The effect of Hydra peptide morphogen (HPM) on quantitative histochemical and morphometric parameters of the thyroid gland (TG) was studied. The experiments were conducted on 40 outbred albino male mice weighing 20-25 g, which were injected intraperitoneally with HPM at the dose of 100 MUg/kg of body weight per day for 5 days. Relative volumes occupied by the epithelium (E), including its follicular (E(f)), interfollicular (E(i)) components, and colloid (C) were determined using stereological method on TG transverse sections. E(f)/E(i) and E/C ratios were calculated as the indices of follicular organization and TG activity, respectively. Mitotic activity of thyrocytes was also evaluated. The enzymes, characterizing the metabolic activity of thyrocytes: NADH-diaphorase, succinate- and lactate dehydrogenases were demonstrated on cryostat sections of material, frozen in liquid nitrogen and their activity was assessed cytophotometrically. The results demonstrated that HPM administration lead to a significant increase in relative volume of thyroid epithelium with a concomitant reduction of the volume of the colloid. E(f)/E(i) ratio was not significantly different from that in the control. HPM also induced a significant increase of thyrocyte proliferation rate and of the activity of enzymes studied. Collectively, the quantitative histoenzymological and morphometric data obtained indicate the stimulating effect of HPM on TG functional activity and thyrocyte proliferation. PMID- 27487667 TI - [SUSTENTOCYTE NUMBERS IN THE NEONATAL PERIOD IN THE OFFSPRING OF FEMALE RATS WITH EXPERIMENTAL LIVER DAMAGE]. AB - On serial histological sections of the testes, stained with hematoxylin-eosin, using a morphometric device, the total numbers of spermatogenic cells and sustentocytes (Sertoli cells) were measured in the convoluted seminiferous tubules of neonatal rat pups. Experimental groups consisted of rats born from females with experimental liver damage of various origins--autoimmune (n = 33), toxic (n = 32), alcoholic (n = 12), and medicinal (n = 27). The control group included pups born from normal female rats (n = 14). In experimental rats both increase and decrease of the total number of sustentocytes was detected. In the animals of most of the experimental groups, sustentocyte cell index reflecting the ratio of the number of spermatogenic cells and sustentocytes, was decreased. PMID- 27487668 TI - [INTERRELATION BETWEEN THE PREOPERATIVE MORPHOLOGICAL CHARACTERISTICS OF PERIPHERAL BLOOD AND THE QUALITY OF ENGRAFTMENT OF VASCULARIZED ADIPO-FASCIO CUTANEOUS FLAPS IN RATS]. AB - The aim of this work was to determine the interrelation between the preoperative blood counts and the quality of vascularized adipo-fascio-cutaneous flap survival. In 10 adult male Wistar rats, a flap with the area of 18 cm2 was formed on the basis of superficial inferior epigastric artery; after a 90 min ischemic period it was replanted. 12 days after operation the quality of flap survival was assessed with computer-assisted planimetry. It was found that the combination of preoperative leukocyte, thrombocyte, neutrophil and eosinophil counts as well as reactive lymphocyte counts close to the maximal reference values increased the probability of epidermolysis. PMID- 27487669 TI - [MORPHOLOGICAL CHARACTERISTICS OF OSSEOINTEGRATION AFTERAPPLICATION OF TITANIUM IMPLANTS WITH BIOACTIVE COATING AND RECOMBINANT BONE MORPHOGENETIC PROTEIN]. AB - Experiments were carried out on 22 albino male Wistar rats to study the morphological peculiarities of osseointegration of titanium grafts with bioactive surface stimulated additionally with bone plastic material "Gamalant-paste-FORTE Plus" containing recombinant human bone morphogenetic protein-2 (rhBMP-2). In 9 rats the implants were placed into femoral bones after local treatment of bone canal with rhBMP-2-containing material. Another 9 animals were implanted but received no treatment, 4 rats formed the group of intact control. Zone of osseointegration was studied 4, 8 and 12 weeks after graft placement using histological and morphometric methods as well as immune histochemistry to demonstrate osteonectin, CD68, MMP-9, and TIMP-1. The study showed that preliminary treatment of bone canal with rhBMP-2-containing material preceding implant placement was accompanied by an additional osteoinductive effect. More intense and outrunning bone formation in the area of osseointegration was observed, together with remodeling and compaction of the contiguous cancellous bone, thus providing the necessary balance between MMP-9 and TIMP-1 with a high level of each factor expression. PMID- 27487670 TI - [CURRENT HISTOCHEMICAL METHODS OF TISSUE IRON DEMONSTRATION BASED ON PERLS' REACTION]. AB - The article presents the information on the modern modifications of Perls' reaction including diaminobenzidine enhancement according to R. Meguro (for various tissues). M.A. Smith (for nervous tissue), S.M. Levine (for detection of iron in oligodendrocytes and myelinated nervous fibers), and our own modification for visualization of the nucleolar iron. The analysis is performed of the advantages and disadvantages of these modifications of histochemical demonstration of iron. It is shown that the use of new methodological approaches significantly increases the sensitivity of Perls' reaction. Control procedures allow to to eliminate the possibility of artifacts. PMID- 27487671 TI - [The development of morphological research on the problem of gravitational overload effect in S. M. Kirov Military medical Academy]. PMID- 27487672 TI - [Modern clinical anatomy, problems of its teaching and development in Russia]. PMID- 27487673 TI - [Not Available]. PMID- 27487674 TI - [Prevention and remission of diabetes: is it feasible?]. AB - Prevention of type 2 diabetes is a major public health objective in view of the increasing prevalence of obesity in the population, the medical community and politicians to develop preventive strategies as well as effective interventions to induce remission of diabetes. Clinical studies indicate that intensive medical treatment through lifestyle adaptations and even more bariatric surgery can prevent or rather delay type 2 diabetes onset and factor remission but with a positive effect which progressively decreases with time. Duration of diabetes and weight loss are major prognostic factors. New strategies are necessary to improve both short- and long-term efficacy of diabetes prevention and remission. PMID- 27487675 TI - [Cardiovascular safety of antidiabetics]. AB - Type 2 diabetes is characterized by a high risk of micro- and macro-vascular complications. Cardiovascular diseases are the leading cause of death of diabetic patients. In this context, the search for molecules decreasing cardiovascular mortality makes sense. Until the EMPA-REG OUTCOME study published late 2015, showing a reduction of cardiovascular mortality of patients treated with empagliflozin, an SGLT2 inhibitor, there was no molecule known to decrease cardiovascular mortality. The purpose of this article is to review the various existing antidiabetic molecules and their impact (positive/neutral/negative) on cardiovascular mortality. PMID- 27487676 TI - [Gestational diabetes--what are the non-medical approaches?]. AB - Gestational diabetes is a multifactorial disease that increases the risk for complications for the mother and her child in the short and long term. The perinatal period represents an opportunity not only to assist the mother in improving her own health but also that of the future generation. This article focuses on lifestyle and psychological aspects that form the base for non-medical treatment approaches. Considering different risk factors separately is not sufficient for the improvement of the metabolic and mental health of women with gestational diabetes. With a multimodal interdisciplinary approach that includes physical activity, dietary advice and psychological support, an improvement of the health and well-being of both the mother and her child is expected. Future studies are necessary to confirm this proposed care approach. PMID- 27487677 TI - [Preventive measures of diabetic foot complications]. AB - Diabetic foot complications are a public health challenge and preventive measures although simple are often not enforced, as evidenced by the lack of decrease in the rate of ulcers and amputation in Switzerland. This article proposes a risk score to grade individual risk of the diabetic patient and an individualized prevention measures as this risk. We discuss the importance of collaboration of various specialists. Two areas are important, first the early involvement of specialists in revascularization because the diabetic population with feet at risk of ulceration risk nowadays primarily has neuro-ichemic ulcerations and also the close collaboration with podiatrists and orthopedic shoemakers who are full partners of the multidisciplinary team. PMID- 27487678 TI - [Insulin and oral antidiabetes drugs: how associate these treatments in ambulatory care?]. AB - Type 2 diabetes mellitus is a complex and progressive metabolic disease involving more than 400 millions of people worldwide. The treatments need to be constantly managed to maintain appropriate glycemic control and avoiding complications. There is a wide variety of therapeutic option including oral antidiabetes drugs or new insulin on the market. The initiation of insulin treatment seems a mandatory step for a large panel of patients. Therefore, it is important to know the indications to initiate insulin treatment and the best way to associate it with antidiabetes drugs. PMID- 27487679 TI - [Use of new antidiabetics in the elderly population]. AB - Over the last few years, we have noticed the arrival on the market of new antidiabetic treatments. These represent an potential advantage because of the increase in the prevalence of type 2 diabetes, particularly in the elderly population. Nevertheless, elderly patients have a number of frailties that should be considered in the treatment of this condition. There is a lack of literature in this population as elderly are frequently excluded from randomized controlled trials. Therefore, guidelines were developed based on the consensus of experts in geriatrics and diabetology for this specific population. We have to consider the potential benefits and adverse effects of the new antidiabetics in older patients. PMID- 27487680 TI - [Not Available]. PMID- 27487681 TI - [Not Available]. PMID- 27487682 TI - [Not Available]. PMID- 27487683 TI - [Not Available]. PMID- 27487684 TI - [Not Available]. PMID- 27487685 TI - [Not Available]. PMID- 27487686 TI - [Not Available]. PMID- 27487687 TI - [Not Available]. PMID- 27487688 TI - [Not Available]. PMID- 27487689 TI - [Not Available]. PMID- 27487690 TI - [Not Available]. PMID- 27487691 TI - [Complication rates after amniocentesis in twin pregnancies: a case control study and review of the literature]. AB - BACKGROUND: Twin pregnancies nave a nigner risk of fetal malformation than singleton pregnancies. The literature suggests a higher risk of fetal loss associated to amniocentesis in twin pregnancies compared to singleton ones. However, published studies are very heterogeneous, rarely controlled or are not taking into account many confounding factors. OBSERVATIONS: To assess all complications that can be associated with amniocentesis in twin pregnancies. MATERIALS AND METHODS: We collected retrospectively medical data concerning twin pregnancies that underwent an amniocentesis in Erasme and Edith Cavell (IMEC) hospitals in Brussels since February 2002. We compared all the complications to those of twin pregnancies that haven't undertaken amniocentesis and singleton pregnancies that underwent amniocentesis. The cases and control groups were matched for age, parity and gestational age at the time of amniocentesis. RESULTS: 94 cases of twin pregnancies that underwent amniocentesis (group I) were included and compared to 94 twin pregnancies that haven't undertaken amniocentesis and 94 singleton pregnancies that underwent amniocentesis. The rate of intra-uterine growth restriction and pregnancies obtained by assisted reproductive medicine was significantly higher in the group I for the latter, the rate of late miscarriage was 2.1%, the rate of overall foetal loss is 2.68%, the rate of overall preterm birth <= 37 SA was 59.3% (6.4% <= 28 SA and 29.8% <= 34 SA). These complications were not significantly higher than those of the control groups after multivariable logistic regression analysis. CONCLUSION: Our data showed no increased risk of foetal loss or preterm birth among twins that underwent amniocentesis compared to controls. PMID- 27487692 TI - [On the relationship between emotional dependency and abuse]. AB - Abuse is a complex psychosocial issue with multiple implications. This paper takes a look at the physical and psychological manifestations of domestic violence, i.e. between adult (romantic) partners as well as abuse of the elderly. Past studies have looked at the relationship between emotional dependency, the occurence and sustainability of abuse and the likehood that a victimized person will terminate a relationship. Indeed, individuals with Dependent Personality Disorder (DPD) or with dependent characteristics present a higher risk of becoming abusive (both physically and mentally) as well as becoming a victim of abuse. Regarding the elderly, the concept of "reverse violence"--where the current abuser was the victim of the senior who is being abused-, also entails dependent relationships. We identified three concepts that are necessary in the understanding of how dependent relationships underpin abuse: Rusbult's model of commitment in intimate relationships, the notion of dependency-possessiveness and Murphy et al's notion of escalating affective dependency. Thus, it is imperative that future studies in the field of domestic violence look at the dynamics of dyads rather than the individuals alone. PMID- 27487693 TI - [Management of Acute Gastroenteritis in Children]. AB - Acute gastroenteritis remains one of the most frequent disorders in infants and children. The cornerstone of the treatment is oral rehydration, although the latter does not reduce the duration of the diarrhea, which is about four days. As a consequence, this quite benign condition of acute gastroenteritis in our countries still does have an important socio-economic impact. Therefore, recent European guidelines and recommendations consider the use of different medications and agents that reduce the duration of diarrhea. PMID- 27487694 TI - [Maturity onset diabetes of the young: just think about it]. AB - Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes with onset in patients aged less than 25 years. It is a heterogeneous disorder due to heterozygous monogenic mutations with an autosomal dominant transmission. It could represent 2 to 5% of diabetes but is often under-diagnosed. We report three different cases of MODY, two without associated abnormalities and one with renal disorder. Mutations concern genes that are directly involved in the beta-cell function. In patients with non-syndromic diabetes, more than 99% of MODY result from mutations in hepatocyte nuclear factor-1-alpha (HNF-1-alpha ; formerly MODY 3), glucokinase (MODY 2), or HNF-4-alpha (MODY 1). The symptoms manifest slowly with the absence of obesity and ketosis in most cases. MODY is usually treated by diet, oral diabetes medications or insulin. Treatment and prognosis vary depending on the genetic mutation. Clinicians should keep in mind the possibility of MODY, especially in antibody-negative youth with familial diabetes. Making a diagnosis of MODY may have important implications for the guidance of appropriate treatment, prognosis and genetic counselling. PMID- 27487695 TI - [Transdural spinal cord herniation: A rare cause of Brown-Sequard syndrome]. AB - We report a rare case of thoracic spinal cord herniation due to a defect of the anterior dura mater causing a progressive myelopathy. This case, illustrated by magnetic resonance and surgical imageries, will make the reader aware of this entity and then prevent misdiagnosis. PMID- 27487696 TI - [A 38 years old female with inflammatory myofibroblastic tumor and lactic acidosis]. AB - Inflammatory myofibroblastic tumors (IMT) are rare tumors. They were originally described in the lung, but they have been now observed in many others locations, mainly abdominal and pelvic. These tumors are usually benign but their recurrent nature and the presence of an abnormality of chromosome band 2p23 in some of them, suggest that some lesions form a true tumor entity. Surgical excision as complete as possible is the gold standard treatment. We report the case of a 38 years old female, who presented a recurrent metastasizing inflammatory myofibroblastic tumor causing lactic acidosis and other biological abnormalities such as hypercalcemia, hypoalbuminemia, hypoglycemia, disseminated intravascular coagulation and inflammatory syndrome. PMID- 27487697 TI - [Bilateral adrenal hemorrhage (BAH): cannabis and vascular involvement]. AB - We report the case of a 39-year-old man with bilateral adrenal haemorrhage. The diagnosis is rarely primarily made with imaging alone. Our patient had a previous history of a stroke six years prior to this episode. We evoke the possibility that long-term daily cannabis use could be the underlying cause of the patient's vascular pathologies. After thorough review of existing literature, this link was found to be probable. Cannabis is the most consumed recreational drug in the world, and this tendency is ever-increasing. Serious complications other than psychiatric resulting from consumption are reported with increasing frequency. Neurological, cerebrovascular, cardiovascular and respiratory complications have been observed. It is thus important to remain vigilant when patients are hospitalised notably through the emergency department, in order to obtain a complete anamnesis, optimise screening, and to adapt the treatment of these patients. PMID- 27487698 TI - [Parietal seeding of HCC after percutaneous radiofrequency thermal ablation]. PMID- 27487699 TI - [History of pneumology in antiquity (part 2)]. AB - Nowadays, Hippocrate, "The Father of Medicine", still influences our medicine. He was famous because of the great medical corpus texts preserved in his name. Only recently, our universities have updated the famous Hippocratic Oath to avoid contradictions with our modern ethics. Hippocrate was a great clinician but a poor anatomist. Hippocratical humourism remained accurate until the age of the enlightenment (18th century). Furthermore, it is difficult to distinguish medicine from philosophy in Greek antiquity. So we have to contextualize Greek ancient medicine in this philosophical field. In the 3rd century before Christus (BC), the centre of gravity in medicine shifted to Alexandria. Indeed, a famous academic library was created in 288 BC. At the same time, dissection of human cadavers was authorized until the first century BC. This enabled the evolution of the knowledge in anatomy and physiology. Rome was still polytheistic population until the end of ancient times. Rome integrated Greek gods in his pantheon. Asclepios became Aesculapius. Rome despises physicians in the first ancient age of Rome. The family's father provided medical cares. A lot of Greek physicians settled then in Rome. Again, roman medicine grew in parallel with philosophical trends. These trends were called "sects" but in fact, they were rather medical schools. In this review, we will especially talk about three physicians of this period: Aurelius Cornelius Celsus, Aretee of Cappadocia and Galenus of Pergamon. Thereafter, medical knowledge did not really change significantly until Renaissance period. PMID- 27487700 TI - [Not Available]. PMID- 27487701 TI - Doing Harm: Physicians, Enemy Combatants, and Torture. PMID- 27487703 TI - Whom We Look Up To. PMID- 27487702 TI - What if Policy Makers Used Evidence When Legislating? A Case Study With Maryland's Unique Compounding Law. PMID- 27487704 TI - Introduction. PMID- 27487705 TI - Will Clinical Practice Guidelines Protect Against Malpractice Risk? PMID- 27487706 TI - Emergency Care in Maryland: The Expanding Role of Evidence Based Medicine and the Medicare Waiver. AB - The 2014 Maryland Medicare Waiver alters the reimbursement model by transitioning from fee-for-service to global payments for hospitals. This increases the need for hospital-based emergency departments to become more cost-conscious, particularly regarding high-cost imaging and admission decisions. Evidence based medicine offers a potential solution to achieve these aims. Development and use of validated clinical decision rules and care pathways can reduce unnecessary testing and reduce hospital admissions where a patient could be treated as an outpatient. Paired with functional systems incorporating alternative care pathways and health information technology, clinical decision rules can reduce cost without sacrificing patient safety or experience. PMID- 27487707 TI - The Emperor's New Boards: (Or How I Learned To Stop Worrying and Love That Test). PMID- 27487708 TI - What's the Evidence for Evidence Based Medicine? PMID- 27487709 TI - The Trial: A Medical Allegory. PMID- 27487710 TI - Physician Volunteerism: Making a Difference One Patient at a Time. PMID- 27487711 TI - Final Words. PMID- 27487712 TI - [MESSAGE FROM THE TRUSTEES]. PMID- 27487713 TI - [Ocular Manifestations Induced by Diversification of Anticancer Agents--Focus on Corneal Disorders]. PMID- 27487714 TI - [Guide for Clinical Use of Hydroxychloroquine]. PMID- 27487715 TI - [Intravitreal Triamcinolone Acetonide for Persistent Diabetic Macular Edema after Vitrectomy]. AB - PURPOSE: To determine whether intravitreal triamcinolone acetonide (IVTA) is effective in resolving edema in eyes with persistent diabetic macular edema (DME) after vitrectomy. PATIENTS AND METHODS: Sixteen eyes of 16 patients were given 4 mg IVTA after vitrectomy for DME. The best-corrected visual acuity (BCVA), central macular thickness (CMT), and average threshold (AT) of the central retina were determined during the 24 weeks follow-up period. Patients were divided into two groups; early treatment group and late treatment group. RESULTS: The BCVA was significantly improved at 12 weeks, the CMT was significantly improved at 24 weeks, and the AT was significantly improved at 4 weeks after IVTA (repeated ANOVA, p < 0.05). The BCVA was more significantly improved in the early treatment group than in the late treatment group at 4 and 12 weeks (unpaired t test, p < 0.05). CONCLUSION: Our results indicate that IVTA should be considered as treatment for patients with persistent DME after vitrectomy, especially with early treatment patients. PMID- 27487716 TI - [Efficacy and Safety of A0001 (Brilliant Blue G250) for Internal Limiting Membrane Staining and Peeling: Phase III Investigator-initiated Multicenter Clinical Trial]. AB - PURPOSE: To investigate the efficacy and safety of A0001 (brilliant blue G250) for visualization of the internal limiting membrane (ILM) during and after vitrectomy. METHODS: Patients (n = 31) requiring ILM peeling during vitrectomy were enrolled in this clinical trial. After injection of A0001 (range: 0.0625 to 0. 125 mg), the staining grade and the peeling ease of the ILM were evaluated in five steps (levels 0 to 4). The safety of A0001 was investigated for 7 days after surgery. RESULTS: From the evaluation of a primary endpoint by the Independent Data Monitoring Committee (IDMC) and a secondary endpoint by each surgeon, A0001 was effective in all cases at three or more levels ( >= level 2 was defined as effective) for evaluation of the grade of visualization and operating ease. Adverse events occurring in two or more cases included elevated intraocular pressure, eye pain, eye discharges, and retinal bleeding. One serious adverse event was a case of unclosed macular hole after vitrectomy, but the patient recovered after reoperation. CONCLUSIONS: A0001 was effective and safe for visualization of the ILM during vitrectomy, and there was an improvement in ease of operation. PMID- 27487718 TI - [Japan Cornea Conference 2016]. PMID- 27487717 TI - [A Case of a Corneal Disorder after Breast Cancer Treatment with Nab-paclitaxel]. AB - BACKGROUND: We report a case of a corneal disorder after breast cancer treatment with a microtubule inhibitor, nab-paclitaxel (Abraxane). CASE: A 55-year-old woman, who was referred to our clinic, presented with blurred vision. 2 weeks previously, she had been undergoing treatment with nab-paclitaxel, trastuzumab and pertuzumab. Visual acuity was 20/60 in right eye and 20/40 in left eye. Slit lamp examination showed an atypical epithelium invasion of the cornea in both eyes and small epithelial defect in left eye. After the nab-paclitaxel treatment was discontinued the corneal findings improved. 4 months later, visual acuity was 20/15 in right eye and 20/20 in left eye. CONCLUSIONS: Nab-paclitaxel can cause severe corneal disorders, but the possibility that trastuzumab and pertuzumab combination therapy is associated with these disorders cannot be denied. Clinicians should consider the possibility of the side effects caused by systemic administration in cases of corneal disorders of uncertain etiology. PMID- 27487719 TI - [PROGRESS REPORT FROM THE STRATEGIC PLANNING COMMITTEE]. PMID- 27487720 TI - [EDITOR'S NOTE]. PMID- 27487721 TI - Prospects and progress in cell therapy for acute respiratory distress syndrome. AB - INTRODUCTION: Despite progress in understanding the pathophysiology of the acute respiratory distress syndrome (ARDS), it remains a devastating clinical disorder associated with high mortality rates, and those who survive can experience significant long-term morbidity. Recent advances in the management of ARDS have mostly been achieved in supportive care, including the use of protective mechanical ventilation, neuromuscular blocking agents, prone positioning, and conservative fluid strategies. However, to date, no pharmacologic therapy has been able to act effectively on disease-specific pathways or to reduce mortality. In this context, current advances in understanding the potential roles of alternative approaches, such as cell therapy, offer new hope for ARDS. AREAS COVERED: This review discusses the use of mesenchymal stromal (stem) cells (MSCs) in pre-clinical experimental models of ARDS and in ongoing clinical trials. EXPERT OPINION: Through the secretion of soluble mediators and extracellular vesicles, MSCs have been shown to modulate inflammation, enhance bacterial clearance, and reduce organ injury and death, making them a potential novel treatment for ARDS. Initial clinical trials have demonstrated the safety of MSC administration in patients with ARDS but further investigations are required to further characterize the efficacy profile of these therapies. PMID- 27487722 TI - Bioassay Development for Ultrasensitive Detection of Influenza A Nucleoprotein Using Digital ELISA. AB - Flu is caused by the influenza virus that, due to mutations, keeps our body vulnerable for infections, making early diagnosis essential. Although immuno based diagnostic tests are available, they have low sensitivity and reproducibility. In this paper, the prospect of detecting influenza A virus using digital ELISA has been studied. To appropriately select bioreceptors for this bioassay, seven commercial antibodies against influenza A nucleoprotein were methodically tested for their reactivity and binding affinity. The study has been performed on two markedly different platforms, being an enzyme-linked immunosorbent assay and a surface plasmon resonance system. The selected antibodies displayed completely different behavior on the two platforms and in various assay configurations. Surprisingly, the antibodies that showed overall good reactivity on both platforms had the highest dissociation constant among the tested antibodies, suggesting that, although important, binding affinity is not the only parameter to be considered when selecting antibodies. Moreover, only one antibody had the capacity to capture the nucleoprotein directly in lysis buffer used for releasing this viral protein, which might pose a huge advantage when developing assays with a fast time-to-result. This antibody was implemented on an in-house developed digital ELISA platform for ultrasensitive detection of recombinant nucleoprotein, reaching a detection limit of 4 +/- 1 fM in buffer and 10 +/- 2 fM in 10-fold diluted nasopharyngeal swabs, which is comparable to currently available fast molecular detection techniques. These results point to a great potential for ultrasensitive immuno-based influenza detection. PMID- 27487724 TI - Single-Step Nanoporation of Water-Immersed Polystyrene Film by Gaseous Nanobubbles. AB - Nanoporation of planar polystyrene (PS) film by gaseous nanobubbles is described. Ambient gas (air) surface nanobubbles are used to create rounded nanopinholes in supported ultrathin PS films immersed in water. Nanoporation proceeds under biocompatible conditions-in deionized water at room temperature (20 degrees C) in the absence of any high-energy-demanding processes, in a single step triggered by short (5 s) moderate pressure drop (Deltap ~ -10 kPa) applied on an aqueous phase. Atomic force microscopy (AFM) analysis shows a relatively narrow dimensional distribution, with the prevailing nanopinhole radius of 10 nm and uniform spread with an appearance density of ~600/MUm2. The nanoporation mechanism is discussed. "Nanobubble/tip-assisted" nanoindentation phenomenon is observed based on the compounded interaction of the surface nanobubble with the AFM tip upon prolonged in situ nanobubble scanning. PMID- 27487723 TI - Systematic Early Intervention for Bereaved: Study Protocol of a Pilot Randomized Controlled Trial With Families Who Suddenly Lose a Partner and a Parent. AB - BACKGROUND: Grief has been associated with several long-term negative outcomes for both surviving parents and bereaved children, especially when it is preceded by unnatural and violent deaths. Nevertheless, it has been an underestimated public health problem with few, if any, empirically documented early preventive intervention programs. The best time to start them is also a major question that requires further evidence. OBJECTIVE: The overall aim of this study is to assess the feasibility of a future larger trial, informing sample size calculation, recruitment/randomization procedures, retention rates, data collection forms, and outcomes. This study will also explore: (1) the early effects of Systematic Early Intervention for Bereaved (SEIB) compared with the early effects of care as usual, and (2) the effects of the immediate SEIB version compared with the effects of the delayed SEIB version. METHODS: In a pilot randomized controlled trial (RCT) with a delayed intervention design, suddenly bereaved families will be assigned to: the immediate-SEIB intervention group, or the delayed-SEIB intervention group. Participants will fill in a set of self-report measures at baseline, and after 3, 6, and 9 months follow-up. Quantitative data on traumatic stress symptoms, complicated grief, psychological wellbeing, daily functioning, social support, parental capacity, parenting practices, and family functioning will be collected to inform power calculations and explore SEIB's preliminary effects. Data on the flow of participants throughout the trial will be analyzed in order to estimate recruitment and retention rates. Two brief questionnaires were developed to assess recruitment procedures, randomization, and data collection materials. RESULTS: Recruitment for this project started in August 2015, and follow-up data collection will be completed in June 2017. CONCLUSIONS: This study prepares the ground work for the design and implementation of a main trial and may add preliminary knowledge to the significance of early supportive practices that have been commonly used regardless of their sparse evidence. PMID- 27487725 TI - Chromatin remodelling and antisense-mediated up-regulation of the developmental switch gene eud-1 control predatory feeding plasticity. AB - Phenotypic plasticity has been suggested to act through developmental switches, but little is known about associated molecular mechanisms. In the nematode Pristionchus pacificus, the sulfatase eud-1 was identified as part of a developmental switch controlling mouth-form plasticity governing a predatory versus bacteriovorous mouth-form decision. Here we show that mutations in the conserved histone-acetyltransferase Ppa-lsy-12 and the methyl-binding-protein Ppa mbd-2 mimic the eud-1 phenotype, resulting in the absence of one mouth-form. Mutations in both genes cause histone modification defects and reduced eud-1 expression. Surprisingly, Ppa-lsy-12 mutants also result in the down-regulation of an antisense-eud-1 RNA. eud-1 and antisense-eud-1 are co-expressed and further experiments suggest that antisense-eud-1 acts through eud-1 itself. Indeed, overexpression of the antisense-eud-1 RNA increases the eud-1-sensitive mouth form and extends eud-1 expression. In contrast, this effect is absent in eud-1 mutants indicating that antisense-eud-1 positively regulates eud-1. Thus, chromatin remodelling and antisense-mediated up-regulation of eud-1 control feeding plasticity in Pristionchus. PMID- 27487726 TI - Postoperative Changes in Strabismus, Ductions, Exophthalmometry, and Eyelid Retraction After Orbital Decompression for Thyroid Orbitopathy. AB - INTRODUCTION: Surgical rehabilitation of thyroid orbitopathy involves reducing proptosis, treating strabismus, lengthening the eyelids, and managing aesthetic changes. Not all are necessary in each patient; however, they often are. The current investigation intends to describe postdecompression changes that may influence the staging of these procedures. METHODS: In this retrospective cohort study, records of 169 patients who underwent orbital decompression between 1983 and 2001 were reviewed. A single orbital specialist confirmed all measurements. Time to follow up was defined as the most recent follow up after decompression and prior to any secondary procedures. No strabismus or eyelid surgery was performed at the time of decompression. Strabismus was measured with alternating prism cover test. Ductions were estimated utilizing Hirschberg's method. Exophthalmometry was measured with Hertel. Eyelid positions were defined relative to the pupillary light reflex. Strabismus data were analyzed within eye pairs. Ductions, exophthalmometry and eyelid position were analyzed for each eye. T-test for paired data was utilized to compare means pre- and postoperatively. RESULTS: The study population was on average 45 years old and 73.4% women. Average length of follow up was 1.2 years. Esotropia was significantly increased after decompression by an average of 8.1 prism diopters (p < 0.01). Exotropia and vertical deviations were not significantly altered. Ductions decreased by >5 degrees in at least one meridian for 68.1% of the population. Upper eyelid retraction remained unchanged; however, lower eyelid retraction improved by 50% from 1.4 mm to 0.7 mm (p < 0.01). Exophthalmometry improved from 23.5 mm to 19.7 mm (p < 0.01), and this result was correlated with the number of walls removed (Pearson r = -0.302, p < 0.01). CONCLUSIONS: On average, esotropia and ductions tend to worsen with decompression surgery. This result supports the clinical dictum to avoid strabismus surgery until after decompression. The improvement in lower eyelid retraction suggests that at least lower eyelid-lengthening surgery should be reserved for after decompression, as there may be significant spontaneous improvement, while the same may not be true for upper eyelid retraction, which does not tend to change with decompression. PMID- 27487727 TI - A Conjunctival Melanoma Causing Bloody Tears. PMID- 27487728 TI - Globe Tenting Due to Displaced Lateral Orbital Wall Fragment. PMID- 27487729 TI - Bacterial Biofilms in Jones Tubes. AB - PURPOSE: To investigate the presence and microbiology of bacterial biofilms on Jones tubes (JTs) by direct visualization with scanning electron microscopy and polymerase chain reaction (PCR) of representative JTs, and to correlate these findings with inflammation and/or infection related to the JT. METHODS: In this study, prospective case series were performed. JTs were recovered from consecutive patients presenting to clinic for routine cleaning or recurrent irritation/infection. Four tubes were processed for scanning electron microscopy alone to visualize evidence of biofilms. Two tubes underwent PCR alone for bacterial quantification. One tube was divided in half and sent for scanning electron microscopy and PCR. Symptoms related to the JTs were recorded at the time of recovery. RESULTS: Seven tubes were obtained. Five underwent SEM, and 3 out of 5 showed evidence of biofilms (60%). Two of the 3 biofilms demonstrated cocci and the third revealed rods. Three tubes underwent PCR. The predominant bacteria identified were Pseudomonadales (39%), Pseudomonas (16%), and Staphylococcus (14%). Three of the 7 patients (43%) reported irritation and discharge at presentation. Two symptomatic patients, whose tubes were imaged only, revealed biofilms. The third symptomatic patient's tube underwent PCR only, showing predominantly Staphylococcus (56%) and Haemophilus (36%) species. Two of the 4 asymptomatic patients also showed biofilms. All symptomatic patients improved rapidly after tube exchange and steroid antibiotic drops. CONCLUSIONS: Bacterial biofilms were variably present on JTs, and did not always correlate with patients' symptoms. Nevertheless, routine JT cleaning is recommended to treat and possibly prevent inflammation caused by biofilms. PMID- 27487730 TI - Intracellular Elemental Patterns of Apoptosis Resistance in Transdifferentiated Androgen-Dependent Prostatic Carcinoma Cells. AB - The acquisition of neuroendocrine (NE) characteristics by prostate cancer (PC) cells relates to tumor progression and hormone resistance. PC cells may survive and function in androgen-deprived environments, where they could establish paracrine signaling networks, providing stimuli for the propagation of local carcinoma cells. We previously demonstrated, using electron probe X-ray microanalysis (EPXMA), in LNCaP, PC-3, and Du 145 cell lines that apoptosis is associated with intracellular elemental changes, and that the NE secretory products, bombesin and calcitonin, inhibit etoposide-induced apoptosis, as well as some of these elemental changes. In this study, LNCaP cells were induced in vitro to transdifferentiate under androgen deprivation, to mimic the role of NE cells in the apoptotic activity of transdifferentiated androgen-dependent PC cells. Changes in intracellular ion content associated with apoptosis, assessed by EPXMA, demonstrate that the transdifferentiated LNCaP cells are resistant to etoposide-induced apoptosis and also to the etoposide-induced elemental changes. The aggressive malignant potential of PC with neuroendocrine differentiation, associated with hormonal independence, is partly because of the ability that most NE tumor cells have to escape apoptosis, which can enhance the malignant properties of tumor cells and may have therapeutic implications as tumor cells are usually resistant to cytotoxic drugs as etoposide. PMID- 27487731 TI - Radiation-induced solidification of ionic liquid under extreme electric field. AB - An extreme electric field on the order of 10(10) V m(-1) was applied to the free surface of an ionic liquid to cause electric-field-induced evaporation of molecular ions from the liquid. The point of ion emission was observed in situ using a TEM. The resulting electrospray emission process was observed to create nanoscale high-aspect-ratio dendritic features that were aligned with the direction of the electric field. Upon removal of the stressing field the features were seen to remain, indicating that the ionic liquid residue was solidified or gelled. Similar electrospray experiments performed in a field-emission scanning electron microscope revealed that the features are created when the high-energy electron beam damages the molecular structure of the ionic liquid. While the electric field does not play a direct role in the fluid modification, the electric stress was critical in detecting the liquid property change. It is only because the electric stress mechanically elongated the fluid during the electrospray process and these obviously non-liquid structures persisted when the field was removed that the damage was evident. This evidence of ionic liquid radiation damage may have significant bearing on electrospray devices where it is possible to produce high-energy secondary electrons through surface impacts of emitted ions downstream of the emitter. Any such impacts that are in close proximity could see reflected secondary electrons impact the emitter causing gelling of the ionic liquid. PMID- 27487732 TI - Cerebrospinal Fluid Chemokine (C-C Motif) Ligand 2 Is an Early-Response Biomarker for Blast-Overpressure-Wave-Induced Neurotrauma in Rats. AB - Chemokines and their receptors are of great interest within the milieu of immune responses elicited in the central nervous system in response to trauma. Chemokine (C-C motif)) ligand 2 (CCL2), which is also known as monocyte chemotactic protein 1, has been implicated in the pathogenesis of traumatic brain injury (TBI), brain ischemia, Alzheimer's disease, and other neurodegenerative diseases. In this study, we investigated the time course of CCL2 accumulation in cerebrospinal fluid (CSF) after exposures to single and repeated blast overpressures of varied intensities along with the neuropathological changes and motor deficits resulting from these blast conditions. Significantly increased concentrations of CCL2 in CSF were evident by 1 h of blast exposure and persisted over 24 h with peak levels measured at 6 h post-injury. The increased levels of CCL2 in CSF corresponded with both the number and intensities of blast overpressure and were also commensurate with the extent of neuromotor impairment and neuropathological abnormalities resulting from these exposures. CCL2 levels in CSF and plasma were tightly correlated with levels of CCL2 messenger RNA in cerebellum, the brain region most consistently neuropathologically disrupted by blast. In view of the roles of CCL2 that have been implicated in multiple neurodegenerative disorders, it is likely that the sustained high levels of CCL2 and the increased expression of its main receptor, CCR2, in the brain after blast may similarly contribute to neurodegenerative processes after blast exposure. In addition, the markedly elevated concentration of CCL2 in CSF might be a candidate early-response biomarker for diagnosis and prognosis of blast-induced TBI. PMID- 27487733 TI - Protective effects of glycyrrhizic acid from edible botanical glycyrrhiza glabra against non-alcoholic steatohepatitis in mice. AB - Non-alcoholic steatohepatitis (NASH) is a syndrome with simultaneous severe hepatic steatosis, lobular inflammation and pericelluar fibrosis. The purpose of the present study is to investigate the protective effect of glycyrrhizic acid (GA), a natural triterpene glycoside from edible botanical glycyrrhiza glabra, on NASH induced by a methionine and choline-deficient (MCD) diet in mice, and further to elucidate the mechanisms of GA protection. Serum ALT and AST assay and H&E staining were used to identify the amelioration of the liver histopathological changes. Serum and hepatic lipid assay and Oil Red O staining were used to measure lipid accumulation. Hepatic inflammatory and fibrosis gene determination, as well as Mason Trichrome and Sirius Red staining were used to determine the reduction of hepatic inflammation and pericelluar fibrosis. Quantitative real-time PCR and Western blot assays were used to elucidate the mechanisms underlying GA protection. The results indicated that GA treatment reduced hepatic lipogenesis through a decrease in hepatic levels of SREBP-1c, FAS, ACC1 and SCD1, and increased lipid metabolism through an induction of PPARalpha, CPT1alpha, ACADS and LPL. GA also reduced hepatic inflammation via a decrease in the expression of the hepatic inflammatory genes MCP-1 and VCAM-1. In addition, GA reduced liver fibrosis through limiting HSC activation and collagen deposition. In conclusion, GA produces a markedly protective effect against NASH induced by a methionine and choline-deficient (MCD) diet in mice. PMID- 27487734 TI - Clonal Origin of Hepatocellular Carcinoma and Recurrence After Liver Transplantation. AB - BACKGROUND This study aimed to determine whether patterns of tumor clonal origin in pluri-nodular hepatocellular carcinoma (PNHC) could serve as an indicator of tumor recurrence following liver transplantation. MATERIAL AND METHODS Tumor tissue samples from 60 PNHC patients who underwent liver transplantation were examined. The diagnosis of patients conformed to the University of California San Francisco (UCSF) standards for pluri-nodular hepatocellular carcinoma. We performed loss of heterozygosity tests at multiple microsatellite sites to determine the clonal origins of the tumors. Clinical information, pathological data, preoperative serum alpha-feto protein (AFP) and postoperative follow-ups were obtained and correlations between the clonal origin of the tumor, tumor-free survival, pathological characteristics, and AFP levels in serum were studied. RESULTS A total of 165 tumor nodules were collected. Tumor clonal origins were identified as intrahepatic metastasis (IM; 41.67%), multicentric occurrence (MO; 55%) or unidentified (3.33%). Three-year tumor-free survival for the IM group was 48% compared to 75.76% in the MO group (p<0.05), while the occurrence of microscopic tumor thrombus was 100% and 3.03% (p<0.05) for these groups, respectively. The degree of tumor differentiation was 80% for the IM group and 18.18% for the MO group (p<0.05), while the mean AFP concentration for these groups was 226.80 MUg/L (2.78-3000 MUg/L) and 24.59 MUg/L (1.16-531. 30 MUg/L; p<0.05), respectively. CONCLUSIONS Clonal origin patterns can serve as important indicators to predict the recurrence of PNHC following liver transplantation. Taken together with pathological characteristics and preoperative serum AFP levels, the risk of recurrence can be established in advance. PMID- 27487735 TI - Bath-related thunderclap headache: Case report of a male patient. AB - Bath-related thunderclap headache (BRTH) is a rare entity, closed to reversible cerebral vasoconstriction syndrome. It is only described in middle-aged women and mainly Asiatic ethnic origins. Role of estrogen is consequently discussed. We report here a case of a 36-year-old man, admitted for five episodes of thunderclap headaches, triggered by hot shower. This is the first male case of BRTH, opposing only a hormonal hypothesis. Furthermore, this African patient consolidates the non-exclusivity of this affection to Asian ethnic origins. PMID- 27487736 TI - Osteochondral Autograft Transfer Versus Microfracture in the Knee: A Meta analysis of Prospective Comparative Studies at Midterm. AB - PURPOSE: To compare microfracture (MFX) and osteochondral autograft transfer (OAT) surgical techniques to determine (1) postoperative activity level, (2) subjective patient outcomes, (3) failure rates, and (4) assess if any lesion characteristics favored one technique over the other. METHODS: A comprehensive review of literature was performed of all studies comparing MFX and OAT. Studies included were all prospective studies that reported on activity-based outcome measures such as Tegner activity scores and subjective outcomes such as the International Knee Documentation Committee score. Failure rates, as determined by the publishing authors, were recorded for each study. Meta-analyses were conducted using a random-effects model. Paired standardized mean differences (Hedges's g to account for small sample bias) were used for continuous outcome measures, and risk ratios (Mantel-Haenszel method for small sample bias) for dichotomous outcome measures. RESULTS: Six prospective studies satisfied the eligibility criteria and included 249 patients (186 male, 120 female) with an average age of 26.4 years and follow-up of 67.2 months. Tegner scores were superior in patients treated with OAT compared with MFX (DeltaOAT-MFX for pre post scores = 0.94 Tegner points, standardized mean difference [SMD] = 0.469, P = .005). Failure rates of MFX were higher than OAT (OAT = 11%, MFX = 32%, risk ratio = 2.42, P < .036). OAT was superior to MFX at 3 years in relation to subjective outcome scores (SMD = 0.404, P = .008). When assessing OAT lesions larger than 3 cm2, OAT was superior to MFX with respect to activity level (SMD = 0.506, P = .001). CONCLUSIONS: OAT may achieve higher activity levels and lower risk of failure when compared with MFX for cartilage lesions greater than 3 cm2 in the knee, although there was no significant difference for lesions less than 3 cm2 at midterm. However, because of variability in patient-specific factors such as age, preinjury activity level, lesion location and size, the superiority of OAT over MFX cannot be generalized to all patient populations and therefore requires individualized patient care. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and II studies. PMID- 27487737 TI - The True Recurrence Rate and Factors Predicting Recurrent Instability After Nonsurgical Management of Traumatic Primary Anterior Shoulder Dislocation: A Systematic Review. AB - PURPOSE: To (1) define the cumulative recurrence rate after primary anterior shoulder dislocation in Level I and II comparative studies and (2) to pool risk ratios for common risk factors to provide a clinically practical hierarchy of modifiable and nonmodifiable risk factors for recurrence. METHODS: Level I and II prognostic studies were identified using the electronic databases CINAHL, Embase, and MEDLINE from inception to December 2014. Included studies (n = 15) had recurrent dislocation as the main outcome, and a minimum 2-year follow-up. The cumulative odds ratio of prognostic factors was calculated where appropriate. Bias was assessed in each study using the Quality in Prognosis Studies (QUIPS) tool. RESULTS: The reported rate of recurrence ranged from 19% to 88% (pooled overall = 21%; pooled Level I only = 47%). The pooled time to recurrence was 10.8 months (standard deviation 0.42). Male sex (n = 6 studies) conferred a 2.68 (1.66 4.31; P < .001) and patient age <20 years (n = 4 studies) conferred a 12.76 (5.77 28.2; P < .001; vs >20 years) increased odds of recurrence. An associated greater tuberosity fracture (n = 7 studies) decreased the odds of recurrence by 3.8 times (2.94-5.00; P < .001). The quality of evidence was moderate for age, low for sex, and very low for all other prognostic variables. CONCLUSIONS: The pooled rate of recurrence after primary anterior shoulder instability was found to be 21% among moderate- to high-quality prognostic studies. Male sex and younger age predicted a significantly higher risk of recurrent instability (approaching 80%), whereas concurrent fracture of the greater tuberosity significantly decreased the risk of subsequent recurrent dislocation. However, considering the quality of available evidence for these predictors, there remains a clear need for further high quality prospective studies. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II prognostic studies. PMID- 27487738 TI - Genetic Analysis of Mismatch Repair Genes Alterations in Extramammary Paget Disease. AB - Extramammary Paget disease (EMPD) is a rare cutaneous malignant neoplasm. The familial occurrence of EMPD and the high risk of concomitant secondary tumors in EMPD patients have gained much attention. These findings highlight the importance of genetic alterations in the tumorigenesis of this skin cancer. Genetic tests and functional analysis of mismatch repair (MMR) genes were performed in EMPD. The results showed that 8 of 20 cases with germline MMR genes mutations and 5 of them exhibited microsatellite instability (MSI). Immunohistochemical staining showed that the tumor tissues from 20 patients had the normal expression of MLH1 but 5 cases had the reduced expression of MSH2. There is a nearly significant correlation between MSI and germline mutations. In 172 cases, rates of germline and somatic mutations were 34.3% and 13.4%, respectively. The mutations of MLH1 V384D (15.7%), R217C (4.1%), and I219V (5.2%) were common in this cancer. In addition, the yeast 2-hybrid and immunoprecipitation assays exhibited reduced interaction between MLH1 and PMS2 in MLH1 V384D and R217C but not I219V. Moreover, MLH1 V384D and R217C had impaired MMR activity compared with the wild type and I219V mutation by an in vitro MMR assay. The germline mutations in MMR genes are involved in the pathogenesis of EMPD and partially explain the genetic abnormalities for this disease. PMID- 27487739 TI - Mesenteric Arteriovenous Dysplasia/Vasculopathy Is Distinct From Fibromuscular Dysplasia. AB - Fibromuscular dysplasia (FMD) is a noninflammatory, nonatherosclerotic vasculopathy that usually affects the carotid and renal arteries. We have observed FMD-like vascular changes in specimens resected for ischemia or Crohn's disease (CD). On the basis of a systematic clinicopathologic review of these 11 cases identified between 1982 and 2014, we describe a distinct mesenteric vasculopathy that involves both arteries and veins [mesenteric arteriovenous dysplasia/vasculopathy (MAVD/V)] and is characterized by (1) concentric/eccentric smooth muscle collarette around the tunica media of both the artery and the vein in >=2 foci, (2) varying degrees of intimal and medial hyperplasia and adventitial fibrosis, and (3) lack of inflammation or thrombi. MAVD/V cases were clinically diagnosed as CD (45%), mass/lesion (27%), ischemia (9%), obstruction (9%), or rectal prolapse (9%). Abdominal pain for >1 year was the most common symptom. Most patients were women (M:F=1:2.7; mean age, 63 y). Mucosal changes mimicking CD, such as architectural distortion (55%), multifocal ulcers (73%), and pyloric gland metaplasia (64%), were common; however, no granulomas or transmural lymphoid aggregates were identified. Ischemic pattern of injury was seen in 4 cases. Upon follow-up (mean, 31.2 mo), 8 patients were found to be asymptomatic, 2 had died of unrelated causes, and 1 was lost to follow-up. We propose the name MAVD/V for a distinct noninflammatory, nonatherosclerotic, localized form of mesenteric vasculopathy that involves both arteries and veins, distinct from FMD. Unlike FMD, surgical resection appears to be curative, with a favorable clinical outcome. Awareness of this vascular entity is important as patients may be potentially misdiagnosed as having CD and ischemic bowel disease. PMID- 27487740 TI - Interobserver Reproducibility of Percent Gleason Pattern 4 in Prostatic Adenocarcinoma on Prostate Biopsies. AB - In the WHO Classification of Tumours of the Urinary System and Male Genital Organs published in 2016, it was officially recommended that the percent of Gleason pattern 4 (GP4) be reported on pathology reports to better reflect the extent in Gleason score 7 tumors. In this study we assessed the reproducibility of reporting GP4 on prostate biopsies. We analyzed prospectively 422 cores containing GP4 from our consult cases over a period of 2.5 months. The percent pattern 4 was assigned to all the cases in 10% increments from 0% to 100% (with the addition of 5%) by 1 of 4 fellows in urological pathology and by the expert urological pathologist. Out of 422 cores, 32% were an exact match and 75% were within +/-10% (weighted kappa [kappaW] value 0.67). Cases were further stratified on the basis of (1) scattered versus clustered GP4 in the background of Gleason pattern 3, (2) continuous versus discontinuous tumor involvement, (3) cribriform/glomeruloid pattern only versus poorly formed/fused pattern versus mixed cribriform and poorly formed/fused pattern, and (4) total tumor involvement of the core (<=10% vs. >10% of the core). No significant differences were observed in the first 3 variables. However, in cases with <=10% involvement of the core, 61% were within +/-10% (kappaW=0.50) compared with cases with >10% involvement of the core, in which 78% were within +/-10% (kappaW=0.70). In summary, we showed that assessment of percent GP4 was relatively reproducible, with substantial agreement within +/-10% in cases. However, with <10% involvement of the core, it was more difficult to assess in smaller foci, with only moderate agreement. Given that in a small focus only a few glands of a given pattern can markedly affect the percent GP4, consideration should be given to not recording percent GP4 in small foci of Gleason score 7 tumors on needle biopsy. PMID- 27487741 TI - Low-grade Serous Carcinoma of the Ovary: Clinicopathologic Analysis of 52 Invasive Cases and Identification of a Possible Noninvasive Intermediate Lesion. AB - Low-grade serous carcinoma (LGSC) is an uncommon but distinct histologic subtype of ovarian carcinoma. Although the histologic features and natural history of LGSC have been described in the literature, there is no robust correlative study that has specifically addressed histologic features in correlation with clinical follow-up. To refine the criteria for invasion patterns of LGSC and determine additional clinically pertinent morphologic features of LGSC predisposing to a more aggressive clinical course, the clinicopathologic features of 52 LGSCs were evaluated and compared with those of a large series of serous borderline tumors (SBT), with and without invasive implants. To qualify for LGSC, the tumor needed to demonstrate destructive invasion, nuclear atypia that was mild to moderate at most (grade 1 or 2), and a mitotic index that did not exceed 12 mitoses per 10 high-power fields. On the basis of histologic evaluation, destructive invasion was classified into 7 primary architectural patterns: (1) micropapillary and/or complex papillary; (2) compact cell nests; (3) inverted macropapillae; (4) cribriform; (5) glandular and/or cystic; (6) solid sheets with slit-like spaces; and (7) single cells. Five-year overall survival and disease-free survival for LGSC were 82% (median, 72 mo) and 47% (median, 54 mo), respectively. All the patients with fatal outcome demonstrated tumors showing invasion with predominant patterns of cribriform glands, micropapillae and/or complex papillae, or compact cell nests. Notably, 2 of 9 patients with fatal outcome had only small foci of destructive invasion (2 and 3 mm, respectively) with compact cell nests and cribriform glands as the predominant patterns. There was no statistically significant association between pattern of invasion and disease-free survival. Classic stromal microinvasion, as defined by nondestructive stromal invasion <5 mm was identified in 52% of LGSC and was statistically more frequent in LGSC than in SBT (P<0.001). In 2 LGSCs, there were areas demonstrating an intraluminal solid proliferation of tumor cells with grade 1 or 2 nuclear atypia, which we hypothesize may represent a noninvasive form of LGSC, as similar non-invasive proliferations of morphologically low-grade serous carcinomatous cells were also identified in 8 SBTs, in either solid or compact glandular/papillary formations. One patient with this isolated noninvasive pattern in SBT developed LGSC 40 months after initial operation. LGSC was typically high stage (FIGO stages II to IV, 86%) and bilateral (68%), with multiple foci of invasion (82%). Bilaterality was significantly more common in high-stage disease (P=0.009). LGSC was associated with SBT in 84% of cases, most commonly usual type (27%), followed by cribriform (18%), micropapillary (11%), or mixed cribriform and micropapillary (7%) types; focal micropapillary and/or cribriform features were present in an additional 16%. The presence of intraluminal proliferations of cells resembling LGSC occurring in SBT should prompt additional tumor sampling and assiduous evaluation of implants (if present), as this appears to represent a form of intraepithelial carcinoma, which may be associated with invasion elsewhere. PMID- 27487742 TI - Correction: Tuning the Schottky contacts in the phosphorene and graphene heterostructure by applying strain. AB - Correction for 'Tuning the Schottky contacts in the phosphorene and graphene heterostructure by applying strain' by Biao Liu et al., Phys. Chem. Chem. Phys., 2016, 18, 19918-19925. PMID- 27487743 TI - High Prevalence of Acute Exacerbation of Interstitial Lung Disease in Japanese Patients with Systemic Sclerosis. AB - Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by extensive fibrosis and autoantibodies. Its clinical manifestations are diverse and include Raynaud's phenomenon, gastrointestinal dysmotility, interstitial lung disease (ILD), pulmonary hypertension, and renal crisis. Among these, ILD is the primary cause of SSc-related death. It has been considered that acute exacerbation of ILD (AE-ILD) is not common in patients with SSc; however, little is known about the prevalence of AE-ILD in Japanese patients with SSc. In this study, we aimed to clarify the prevalence, clinical characteristics, and prognosis of patients with SSc who developed AE-ILD and to identify predictive factors for AE-ILD in our Japanese cohorts. Clinical data of patients who visited our department from 1990 to 2014 and fulfilled the 2013 classification criteria for SSc were retrospectively reviewed. A total of 139 patients were enrolled. The mean age of onset was 49.1 years, and 113 (81.3%) patients were female; 116 (83.5%) had limited cutaneous involvement, and the overall 10-year survival rate was 92.0%. Among 66 (47.5%) patients with ILD, 13 (9.4%) developed AE-ILD. Patients with AE-ILD had a significantly higher incidence of overlap with polymyositis (PM) or dermatomyositis (DM) and lower prevalence of anticentromere antibodies with higher mortality rate compared with those without AE-ILD. Multivariate Cox regression analysis identified that an overlap with PM or DM was the most significant predictive factor for AE-ILD. Our study results suggest that Japanese patients with SSc, particularly patients overlapped with PM or DM, have a high risk of AE-ILD. PMID- 27487744 TI - Impact of clinical training on supra-aortic duplex and transcranial doppler examination concordance. AB - Sonographic tests are observer-dependent. With 1,527 consecutive patients, 22 trainees were assessed at baseline and after a hands-on 1:1 program, with a pre examination median of 76 studies/trainee. We evaluated the required number of supervised examinations to reach a 0.80 kappa index (ki). Statistics included linear and exponential generalized estimating equation models. In the exponential model, 76 studies for carotid-duplex and >102 for vertebral-duplex and transcranial Doppler were needed for a 0.80 ki. "Relevant-categories" after training ki was 0.80 in carotid-duplex and transcranial Doppler but 0.60 in vertebral-duplex. A fixed training does not guarantee a high ki. Measuring the acquired skills of every trainee would improve quality. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:571-579, 2016. PMID- 27487745 TI - Structural insights into cardiolipin transfer from the Inner membrane to the outer membrane by PbgA in Gram-negative bacteria. AB - The outer membrane (OM) of Gram-negative bacteria is a unique asymmetric lipid bilayer in which the outer leaflet is composed of lipopolysaccharide (LPS) and the inner leaflet is formed by glycerophospholipid (GPL). The OM plays a fundamental role in protecting Gram-negative bacteria from harsh environments and toxic compounds. The transport and assembly pathways for phospholipids of bacterial OM are unknown. Cardiolipin (CL) plays an important role in OM biogenesis and pathogenesis, and the inner membrane (IM) protein PbgA, containing five transmembrane domains and a globular domain in periplasm has been recently identified as a CL transporter from the IM to the OM with an unknown mechanism. Here we present the first two crystal structures of soluble periplasmic globular domain of PbgA from S. typhimurium and E. coli, which revealed that the globular domains of PbgA resemble the structures of the arylsulfatase protein family and contains a novel core hydrophobic pocket that may be responsible for binding and transporting CLs. Our structural and functional studies shed an important light on the mechanism of CL transport in Gram-negative bacteria from the IM to the OM, which offers great potential for the development of novel antibiotics against multi-drug resistant bacterial infections. PMID- 27487747 TI - Direct reprogramming to multipotent trophoblast stem cells, and is pluripotency needed for regenerative medicine either? PMID- 27487746 TI - Strength Training Prevents Hyperinsulinemia, Insulin Resistance, and Inflammation Independent of Weight Loss in Fructose-Fed Animals. AB - The aim of this study was to compare the effects of aerobic, strength, and combined training on metabolic disorders induced by a fructose-rich diet. Wistar rats (120 days old) were randomized into five groups (n = 8-14): C (control diet and sedentary), F (fed the fructose-rich diet and sedentary), FA (fed the fructose-rich diet and subject to aerobic exercise), FS (fed the fructose-rich diet and subject to strength exercise), and FAS (fed the fructose-rich diet and subject to combined aerobic and strength exercises). After the 8-week experiment, glucose homeostasis, blood biochemistry, tissue triglycerides, and inflammation were evaluated and analyzed. The strength protocol exerted greater effects on glucose homeostasis, insulin sensitivity, and liver lipid contents than other protocols (all P < 0.05). All three exercise protocols induced a remarkable reduction in inflammation, tissue triglyceride content, and inflammatory pathways, which was achieved through c-Jun NH2-terminal kinase (JNK) phosphorylation and factor nuclear kappa B (NFkB) activation in both the liver and the muscle. Our data suggest that strength training reduced the severity of most of the metabolic disorders induced by a fructose-rich diet and could be the most effective strategy to prevent or treat fructose-induced metabolic diseases. PMID- 27487749 TI - Attending a Professional Conference. PMID- 27487748 TI - Inherited dysfunctional platelet P2Y12 receptor mutations associated with bleeding disorders. AB - The platelet adenosine 5'-diphosphate (ADP) receptor P2Y12 (P2Y12R) plays a critical role in platelet aggregation. The present report illustrates an update of dysfunctional platelet P2Y12R mutations diagnosed with congenital lifelong bleeding problems. Described patients with heterozygous or homozygous substitution in the P2Y12R gene and qualitative abnormalities of the platelet P2Y12R are summarized. Recently, a further dysfunctional variant of P2Y12R has been identified in two brothers who presented with a lifelong severe bleeding disorder. During in vitro aggregation studies, the patient's platelets show a markedly reduced and rapid reversible ADP-promoted aggregation. A homozygous c.561T>A substitution that changes the codon for His187 to Gln (p.His187Gln) in the P2Y12R gene has been identified. This mutation causes no change in receptor expression but decreases the affinity of the ligand for the receptor, even at high concentrations. Structure modelling studies indicated that the p.His187Gln mutation, located in the fifth transmembrane spanning domain (TM5), impairs conformational changes of the receptor. Structural integrity of the TM5 region is necessary for agonist and antagonist binding and for correct receptor function. PMID- 27487750 TI - The Certified Clinical Nurse Leader in Critical Care. AB - Challenges of the current health system in the United States call for collaboration of health care professionals, careful utilization of resources, and greater efficiency of system processes. Innovations to the delivery of care include the introduction of the clinical nurse leader role to provide leadership at the point of care, where it is needed most. Clinical nurse leaders have demonstrated their ability to address needed changes and implement improvements in processes that impact the efficiency and quality of patient care across the continuum and in a variety of settings, including critical care. This article describes the role of the certified clinical nurse leader, their education and skill set, and outlines outcomes that have been realized by their efforts. Specific examples of how clinical nurse leaders impact critical care nursing are discussed. PMID- 27487751 TI - Cardiac Radiofrequency Ablation: A Clinical Update for Nurses. AB - The field of electrophysiology (EP) has rapidly evolved from a focus on diagnostic procedures to an emphasis on interventions. Many cardiac arrhythmias traditionally treated with antiarrhythmic agents, cardioversion, or cardiac surgery are now routinely cured with cardiac ablation. To optimally manage the care of cardiac ablation patients, it is essential that nurses have an understanding of the EP procedures and related nursing implications. There are extensive evidence-based resources available in the medical literature; however, there are limited publications geared toward nurses caring for cardiac ablation patients.This article provides an overview of EP diagnostic and cardiac radio frequency ablation procedures for select atrial and ventricular tachyarrhythmias. Evidence-based nursing practices related to postprocedure care will be addressed. The objective of this article is to increase nurses' knowledge of common cardiac ablation procedures and the nursing management of the patient postprocedure. PMID- 27487752 TI - Implementation of a Nurse-Led Family Meeting in a Neuroscience Intensive Care Unit. AB - PURPOSE/OBJECTIVES: The aims of this study were to develop, implement, and evaluate the impact of early intensive care unit (ICU) nurse-led family meetings on nurse-family communication, family decision making, and satisfaction of family members. BACKGROUND: Intensive care unit nurses are in an ideal position to meet family needs, and family members may cope better with the crisis of an ICU admission if consistent honest information is provided by nurses; however, there are no early ICU family meetings led by bedside nurses. METHODS: This quality improvement project was implemented in a 10-bed neuroscience ICU over a 3-month period. A convenience sample of 23 nurses participated in the project. Following development of a communication protocol to facilitate nurse-led meetings, the nurses received education and then implemented the protocol. Thirty-one family members participated in the project. Family members were surveyed before and after the meetings. RESULTS: Mean meeting time was 26 (SD, 14) minutes. Following implementation of the meetings, findings demonstrated that families felt that communication improved (P = .02 and P = .008), they had appropriate information for decision making allowing them to feel in control (P = .002), and there was an increase in family satisfaction (P = .001). CONCLUSION: Early ICU nurse-led family meetings were feasible, improved communication between ICU nurses and family members, facilitated decision making in ICU families, and increased satisfaction of family members. PMID- 27487753 TI - Evaluation of a Progressive Mobility Protocol in Postoperative Cardiothoracic Surgical Patients. AB - Cardiothoracic surgical patients are at high risk for complications related to immobility, such as increased intensive care and hospital length of stay, intensive care unit readmission, pressure ulcer development, and deep vein thrombosis/pulmonary embolus. A progressive mobility protocol was started in the thoracic cardiovascular intensive care unit in a rural academic medical center. The purpose of the progressive mobility protocol was to increase mobilization of postoperative patients and decrease complications related to immobility in this unique patient population. A matched-pairs design was used to compare a randomly selected sample of the preintervention group (n = 30) to a matched postintervention group (n = 30). The analysis compared outcomes including intensive care unit and hospital length of stay, intensive care unit readmission occurrence, pressure ulcer prevalence, and deep vein thrombosis/pulmonary embolism prevalence between the 2 groups. Although this comparison does not achieve statistical significance (P < .05) for any of the outcomes measured, it does show clinical significance in a reduction in hospital length of stay, intensive care unit days, in intensive care unit readmission rate, and a decline in pressure ulcer prevalence, which is the overall goal of progressive mobility. This study has implications for nursing, hospital administration, and therapy services with regard to staffing and cost savings related to fewer complications of immobility. Future studies with a larger sample size and other populations are warranted. PMID- 27487754 TI - An Association Between Pain and American Association of Respiratory Care 2010 Guidelines During Tracheal Suctioning. AB - INTRODUCTION: Tracheal suctioning is recalled by mechanically ventilated patients as the most painful procedure during their stay in the intensive care unit. AIM: The aim of this study was to evaluate whether the implementation of American Association of Respiratory Care suction guidelines positively affects the levels of patients' pain. MATERIALS AND METHODS: This is a prospective observational study on adult patients admitted to 2 general intensive care units. Pain levels in sedated mechanically ventilated patients were recorded before, during, and after tracheal suctioning, using the Critical Care Pain Observation Tool (CPOT). RESULTS: Forty-seven patients were enrolled, with a mean age of 61.72 (+/-18.46) years. Median CPOT value was 0 (quartile 1 [Q1] [25%], 0; quartile 3 [Q3] [75%], 0; min, 0; max, 2) during the procedure. The Critical Care Pain Observation Tool reached a median value of 3, while 5 minutes after suctioning. Postprocedural CPOT median score was 0 (Q1 [25%], 0; Q3 [75%], 0; min, 0; max, 2). The median number of passes during suctioning was 1 (Q1, 1; Q3, 2). The sizes of suction catheters used in the recorded procedures were as follows: 12F in 27 cases (57%), 14F in 18 cases (38%), and 10F in 2 cases (5%). The median size of the endotracheal tube was 7.5 mm (Q1, 7.5; Q3, 8). The correct ratio between endotracheal tube diameter and suction catheter was used in 24 procedures (51%). CONCLUSIONS: Despite the low number of patients, this study showed that the implementation of the American Association of Respiratory Care 2010 endotracheal suctioning guidelines into practice helps to reduce procedural-induced pain. Therefore, training and continuing education are important for clinical staff performing tracheal suctioning. PMID- 27487758 TI - A Closing Word. PMID- 27487756 TI - A Pilot Study Implementing a Protocol Using Dexmedetomidine as a Safe Alternative to Traditional Sedation to Decrease Ventilator Days for Patients Difficult to Extubate. AB - BACKGROUND: Traditional sedation for mechanically ventilated patients causes delirium, which increases the patients' length of stay while hospitalized. When extubation is attempted, these medications must be discontinued because of the side effect of respiratory depression, leaving patients anxious and agitated, delaying extubation and prolonging the need for mechanical ventilation. Dexmedetomidine is a safe alternative sedative that does not cause delirium or respiratory depression. During the weaning process, dexmedetomidine can be continued, allowing the patient to remain calm and successfully extubated. OBJECTIVES: The aim of this study is to decrease the length of stay for mechanically ventilated patients by implementing a dexmedetomidine protocol for difficult-to-extubate patients during the weaning process. METHODS: A preintervention/postintervention design pilot study was done comparing the patient mean of length of stay on mechanical ventilation. A Mann-Whitney U test was used because of the small sample size. RESULTS: Over the 3-month implementation period, 15 patients received dexmedetomidine. None of the patients experienced adverse reactions while on dexmedetomidine. There was a trend of decreasing mechanical ventilation length of stay but no significant difference was noted between the preimplementation and postimplementation groups. CONCLUSION: Dexmedetomidine was a safe alternative to traditional sedation for difficult-to-extubate patients when a bolus dose was not given. PMID- 27487759 TI - Do Not Forget the Clinical Nurse Leader. PMID- 27487760 TI - Response to Letter to Editor. PMID- 27487761 TI - Morbidity and medication consumption among users of home telecare services. AB - Telecare is a healthcare resource based on new technologies that, through the services offered, attempt to help elderly people to continue living in their homes. In this sense, first-generation telecare services have quickly developed in Europe. The aim of this work was to define the profile, pattern of medication consumption and disease frequencies of elderly users of a telecare service. The cross-sectional study involved 742 Spanish community-dwelling elders (85.3% of the total users aged 65 years and over who used a telecare service before the end of the data collection period). Data were collected between March and September 2012. Subjects' mean age was 83.3 (SD 6.6) years, and the majority lived alone (78.3%) and were female (85.8%). The mean Charlson comorbidity index score was 1.13 (SD 1.1), and the mean number of prescribed medications per day was 5.6 (SD 3.0). The most frequent diseases were hypertension (51.1%) and rheumatic disorders (44%); and the most consumed medications were those for the cardiovascular (75%) and nervous (65.2%) systems. For the total sample, the three main determinants of polymedication (five or more medications) were hypertension, anxiety-depressive symptoms and coronary heart disease. Regardless of the social elements contributing to the implementation of telecare services, specific health characteristics of potential users, such as morbidity and polypharmacy, should be carefully considered when implementing telecare services in the coming years. PMID- 27487762 TI - Cultural influences on suicide in Japan. AB - Following the economic crash of the late 1990s, the suicide rate in Japan increased to a rate of over 30 000 people per year and has been one of the highest in the world. Cultural factors have influenced this high suicide rate, such as a tradition of honorable suicide as well as permissive attitudes towards suicide that remain in modern times. Additionally, the economic downturn, particularly the trend of unemployment in middle-aged men, also played a significant role in the high suicide rate. The suicide rate has started to decrease in recent years perhaps in part due to suicide prevention measures undertaken by the government. PMID- 27487763 TI - Transcatheter aortic valve repair for management of aortic insufficiency in patients supported with left ventricular assist devices. AB - The development of new aortic insufficiency after a period of support with a left ventricular assist device can result in progressive heart failure symptoms. Transcatheter aortic valve repair can be an effective treatment in selected patients, but the lack of aortic valve calcification can result in unstable prostheses or paravalvular leak. We describe a technique of deploying a self expanding CoreValve (Medtronic, Minneapolis, MN, USA) into the aortic annulus, followed by a balloon-expandable SAPIEN-3 (Edwards, Irvine, CA, USA). PMID- 27487765 TI - New Volleyballenes: Y20C60 and La20C60. AB - Two new stable Volleyballenes, the Y20C60 and La20C60 molecular clusters, are proposed on the basis of first-principles density functional theory. In conjunction with recent findings for the scandium system, these findings establish Volleyballene M20C60 molecules as a general class of stable molecules within the fullerene family. Both Y20C60 and La20C60 molecules have Th point group symmetries and relatively large HOMO-LUMO gaps. PMID- 27487764 TI - Combined effects of cadmium and salinity on juvenile Takifugu obscurus: cadmium moderates salinity tolerance; salinity decreases the toxicity of cadmium. AB - Obscure puffer Takifugu obscurus, a species of anadromous fish, experiences several salinity changes in its lifetime. Cadmium (Cd) is a toxic heavy metal that can potentially induce oxidative stress in fish. The present study aimed to detect the combined effects of Cd (0, 5, 10, 20 and 50 mg L(-1)) and salinity (0, 15 and 30 ppt) on juvenile T. obscurus. Results showed the juveniles could survive well under different salinities; however, with Cd exposure, the survival rates significantly decreased at 0 and 30 ppt. At 15 ppt, tolerance to Cd increased. Cd exposure clearly induced oxidative stress, and the responses among different tissues were qualitatively similar. Salinity acted as a protective factor which could reduce the reactive oxygen species and malondialdehyde levels. In addition, salinity could enhance the antioxidant defense system, including superoxide dismutase, catalase and glutathione. Na(+)/K(+)-ATPase activity significantly decreased under Cd exposure in gill, kidney and intestine. These findings indicated that Cd could moderate the adaptability of juvenile T. obscurus to high salinity and low salinity played a protective role upon Cd exposure. Thus, the role of salinity should be considered when evaluating the effect of heavy metals on anadromous and estuarine fishes. PMID- 27487766 TI - Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia. AB - Vascular cognitive impairment is the second most common form of dementia. The pathogenic pathways leading to vascular cognitive impairment remain unclear but clinical and experimental data have shown that chronic reactive astrogliosis occurs within white matter lesions, indicating that a sustained pro-inflammatory environment affecting the white matter may contribute towards disease progression. To model vascular cognitive impairment, we induced prolonged mild cerebral hypoperfusion in mice by bilateral common carotid artery stenosis. This chronic hypoperfusion resulted in reactive gliosis of astrocytes and microglia within white matter tracts, demyelination and axonal degeneration, consecutive spatial memory deficits, and loss of white matter integrity, as measured by ultra high-field magnetic resonance diffusion tensor imaging. White matter astrogliosis was accompanied by activation of the pro-inflammatory transcription factor nuclear factor (NF)-kB in reactive astrocytes. Using mice expressing a dominant negative inhibitor of NF-kB under the control of the astrocyte-specific glial fibrillary acid protein (GFAP) promoter (GFAP-IkBalpha-dn), we found that transgenic inhibition of astroglial NF-kB signaling ameliorated gliosis and axonal loss, maintained white matter structural integrity, and preserved memory function. Collectively, our results imply that pro-inflammatory changes in white matter astrocytes may represent an important detrimental component in the pathogenesis of vascular cognitive impairment, and that targeting these pathways may lead to novel therapeutic strategies. PMID- 27487767 TI - The global threat of Zika virus to pregnancy: epidemiology, clinical perspectives, mechanisms, and impact. AB - Zika virus (ZIKV) is a mosquito-borne flavivirus that has newly emerged as a significant global threat, especially to pregnancy. Recent major outbreaks in the Pacific and in Central and South America have been associated with an increased incidence of microcephaly and other abnormalities of the central nervous system in neonates. The causal link between ZIKV infection during pregnancy and microcephaly is now strongly supported. Over 2 billion people live in regions conducive to ZIKV transmission, with ~4 million infections in the Americas predicted for 2016. Given the scale of the current pandemic and the serious and long-term consequences of infection during pregnancy, the impact of ZIKV on health services and affected communities could be enormous. This further highlights the need for a rapid global public health and research response to ZIKV to limit and prevent its impact through the development of therapeutics, vaccines, and improved diagnostics. Here we review the epidemiology of ZIKV; the threat to pregnancy; the clinical consequences and broader impact of ZIKV infections; and the virus biology underpinning new interventions, diagnostics, and insights into the mechanisms of disease. PMID- 27487768 TI - The occurrence of spoilage yeasts in cream-filled bakery products. AB - BACKGROUND: Filling creams can provide an adequate substrate for spoilage yeasts because some yeasts can tolerate the high osmotic stress in these products. To discover the source of spoilage of a cream-filled baked product, end products, raw materials, indoor air and work surfaces were subjected to microbiological and molecular analyses. The efficacy of disinfectants against spoilage yeasts was also assessed. RESULTS: The analyses on end products revealed the presence of the closest relatives to Zygosaccharomyces bailii with counts ranging from 1.40 to 4.72 log cfu g-1 . No spoilage yeasts were found in the indoor air and work surfaces. Polymerase chain reaction-denaturing gradient gel electrophoresis analysis, carried out directly on filling creams collected from unopened cans, showed the presence of bands ascribed to the closest relatives to Z. bailii sensu lato, although with counts < 1 log cfu g-1 . Susceptibility testing of yeast isolates to disinfectants showed a significantly lower effect of 10% alkyl dimethyl benzyl ammonium chloride. Different responses of isolates to the tested disinfectants were seen. CONCLUSION: To guarantee the quality of end products, reliable and sensitive methods must be used. Moreover, hygiene and the application of good manufacturing practices represent the most efficient way for the prevention and minimization of cross-contamination. (c) 2016 Society of Chemical Industry. PMID- 27487769 TI - Population genetic processes affecting the mode of selective sweeps and effective population size in influenza virus H3N2. AB - BACKGROUND: Human influenza virus A/H3N2 undergoes rapid adaptive evolution in response to host immunity. Positively selected amino acid substitutions have been detected mainly in the hemagglutinin (HA) segment. The genealogical tree of HA sequences sampled over several decades comprises a long trunk and short side branches, which indicates small effective population size. Various studies have reproduced this unique genealogical structure by modeling recurrent positive selection. However, it has not been clearly demonstrated whether recurrent selective sweeps alone can explain the limited level of genetic diversity observed in the HA of H3N2. In addition, the variation-reducing impacts of other evolutionary processes - background selection and complex demography - relative to that of positive selection have never been explicitly evaluated. RESULTS: In this paper, using computer simulation of a viral population evolving under recurrent selective sweeps we demonstrate that positive selection alone, if it occurs at a rate estimated by previous studies, cannot lead to such a small effective population size. Genetic hitchhiking fails to completely wipe out pre existing variation because soft, rather than hard, selective sweeps prevail under realistic parameters of mutation rate and population size. We find that antigenic cluster-transition substitutions in HA occur as hard sweeps. This indicates that the effective population size under which those mutations arise must be much smaller than the actual population size due to other evolutionary forces before selective sweeps further reduce it. We thus examine the effects of background selection and metapopulation dynamics in reducing the effective population size, using parameter values that reproduce other aspects of molecular evolution in H3N2. When either process is incorporated in recurrent selective sweep simulation, selective sweeps are mostly hard and the observed level of synonymous diversity is obtained with large census population size. CONCLUSIONS: Background selection and metapopulation dynamics have greater variation reducing power than recurrent positive selection under realistic parameters in H3N2. Therefore, these evolutionary processes are likely to play crucial roles in reducing the effective population size of H3N2 viruses and thus explaining the characteristic shape of H3N2 genealogy. PMID- 27487770 TI - Community-based pediatric palliative care for health related quality of life, hospital utilization and costs lessons learned from a pilot study. AB - BACKGROUND: Children with chronic complex-medical conditions comprise a small minority of children who require substantial healthcare with major implications for hospital utilization and costs in pediatrics. Community-Based Pediatric Palliative Care (CBPPC) provides a holistic approach to patient care that can improve their quality of life and lead to reduced costs of hospital care. This study's purpose was to analyze and report unpublished evaluation study results from 2007 that demonstrate the potential for CBPPC on Health Related Quality of Life (HRQoL) and hospital utilization and costs in light of the increasing national focus on the care of children with complex-medical conditions, including the Affordable Care Act's emphasis on patient-centered outcomes. METHODS: A multi method research design used primary data collected from caregivers to determine the Program's potential impact on HRQoL, and administrative data to assess the Program's potential impact on hospital utilization and costs. Caregivers (n=53) of children enrolled in the Northeast Florida CBPPC program (Community PedsCare) through the years 2002-2007 were recruited for the Health Related Quality of Life (HRQoL) study. Children (n=48) enrolled in the Program through years 2000-2006 were included in the utilization and cost study. RESULTS: HRQoL was generally high, and hospital charges per child declined by $1203 for total hospital services (p=.34) and $1047 for diagnostic charges per quarter (p=0.13). Hospital length of stay decreased from 2.92 days per quarter to 1.22 days per quarter (p<.05). CONCLUSION: The decrease in hospital utilization and costs and the high HRQoL results indicate that CBPPC has the potential to influence important outcomes for the quality of care available for children with complex-medical conditions and their caregivers. PMID- 27487771 TI - Immunoregulatory soluble CTLA-4 modifies effector T-cell responses in systemic lupus erythematosus. AB - BACKGROUND: The inhibitory CTLA-4 molecule is a crucial regulator of immune responses and a target for therapeutic intervention in both autoimmunity and cancer. In particular, CTLA-4 is important in controlling antigen-specific immunity, including responses to autoantigens associated with autoimmune disease. Here, we investigate cytokine responses to a range of lupus-associated autoantigens and assess whether the alternatively spliced isoform of CTLA-4, soluble CTLA-4 (sCTLA-4), contributes to immune regulation of autoantigen specific immunity in systemic lupus erythematosus (SLE). METHODS: The cell culture supernatant production of sCTLA-4 as well as the cytokines IL-10, IFN gamma, and IL-17 from peripheral blood mononuclear cells (PBMC) from lupus patients and age- and sex-matched healthy volunteer donors were measured in response to previously identified histone and small nuclear ribonucleoprotein (snRNP) autoantigen-derived peptides (H391-105, H471-93, and U170K131-151) by ELISA. We also examined the functional contribution of sCTLA-4 to immune regulation in the context of these autoantigenic peptides following blockade of sCTLA-4 with a selective anti-sCTLA-4 monoclonal antibody, JMW-3B3. RESULTS: We identified responses to autoantigenic peptides, which revealed qualitative differences in cytokine (IL-10, IL-17, and IFN-gamma) profiles between SLE patients and healthy donors. PBMC from healthy donors responded to each of the lupus peptides by secreting IFN-gamma and IL-17, but PBMC from SLE patients produced IL-10. Although we did not observe differences in the levels of serum or PBMC culture supernatant sCTLA-4 in either cohort, blockade of sCTLA-4 in PBMC cultures responding to antigen enhanced the cytokine profiles associated with each group. CONCLUSION: The results show that lupus autoantigen-derived peptides display varied immunogenicity in lupus versus healthy volunteer donors, while sCTLA-4 acts to regulate the T-cell activity independently of response profile. PMID- 27487774 TI - Dyella humi sp. nov., isolated from forest soil. AB - A Gram-stain-negative, aerobic, motile, rod-shaped, yellow-pigmented bacterium, designated as DHG40T, was isolated from a soil sample collected from the forest of Dinghushan Biosphere Reserve, Guangdong Province, China. Strain DHG40T grew at pH 4.0-8.0 and 10-37 degrees C (optimum at pH 6.0-7.0 and 25-28 degrees C). NaCl inhibited growth at concentrations above 2.5 % (w/v). Phylogenetic analysis based on 16S rRNA gene sequences revealed that the isolate fell within the cluster of the genus Dyella. Strain DHG40T was closely related to Dyella ginsengisoli Gsoil 3046T (97.6 % 16S rRNA gene sequence similarity), Dyella marensis CS5-B2T (97.5 %), Dyella koreensis BB4T (97.4 %) and Dyella jejuensis JP1T (97.4 %). The DNA-DNA relatedness values between strain DHG40T and its phylogenetically closest relatives were all below 40 %. The DNA G+C content was 60.3 mol%. In addition, iso-C15 : 0, iso-C16 : 0, iso-C17 : 0 and iso-C17 : 1omega9c were the major fatty acids (>10 %) and ubiquinone-8 was the respiratory quinone. The major polar lipids were phosphatidylethanolamine, phosphatidylmethylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, an unidentified aminolipid and an unidentified phospholipid. On the basis of phylogenetic, phenotypic, physiological and chemotaxonomic distinctiveness, strain DHG40T should be placed in the genus Dyella as a representative of a novel species, for which the name Dyella humi sp. nov. is proposed. The type strain is DHG40T (=KCTC 42629T=LMG 28842T). PMID- 27487773 TI - Pathogenesis of Korean SapelovirusA in piglets and chicks. AB - Sapelovirus A (SV-A), formerly known as porcine sapelovirus as a member of a new genus Sapelovirus, is known to cause enteritis, pneumonia, polioencephalomyelitis and reproductive disorders in pigs. We have recently identified alpha2,3-linked sialic acid on GD1a ganglioside as a functional SV-A receptor rich in the cells of pigs and chickens. However, the role of GD1a in viral pathogenesis remains elusive. Here, we demonstrated that a Korean SV-A strain could induce diarrhoea and intestinal pathology in piglets but not in chicks. Moreover, this Korean SV-A strain had mild extra-intestinal tropisms appearing as mild, non-suppurative myelitis, encephalitis and pneumonia in piglets, but not in chicks. By real-time reverse transcription (RT) PCR, higher viral RNA levels were detected in faecal samples than in sera or extra-intestinal organs from virus-inoculated piglets. Immunohistochemistry confirmed that high viral antigens were detected in the epithelial cells of intestines from virus-inoculated piglets but not from chicks. This Korean SV-A strain could bind the cultured cell lines originated from various species, but replication occurred only in cells of porcine origin. These data indicated that this Korean SV-A strain could replicate and induce pathology in piglets but not in chicks, suggesting that additional porcine-specific factors are required for virus entry and replication. In addition, this Korean SV-A strain is enteropathogenic, but could spread to the bloodstream from the gut and disseminate to extra-intestinal organs and tissues. These results will contribute to our understanding of SV-A pathogenesis so that efficient anti-sapelovirus drugs and vaccines could be developed in the future. PMID- 27487772 TI - IABP: history-evolution-pathophysiology-indications: what we need to know. AB - Treatment with the intraaortic balloon pump (IABP) is the most common form of mechanical support for the failing heart. Augmentation of diastolic pressure during balloon inflation contributes to the coronary circulation and the presystolic deflation of the balloon reduces the resistance to systolic output. Consequently, the myocardial work is reduced. The overall effect of the IABP therapy is an increase in the myocardial oxygen supply/demand ratio and thus in endocardial viability.This is an overall synopsis of what we need to know regarding IABP. Furthermore, this review article attempts to systematically delineate the pathophysiology linked with the hemodynamic consequences of IABP therapy. The authors also look at the future of the use of the balloon pump and conclude that the positive multi-systemic hemodynamic regulation during IABP treatment should further justify its use. PMID- 27487775 TI - Characteristics and outcomes of women initiating ART during pregnancy versus breastfeeding in Option B+ in Malawi. AB - BACKGROUND: Malawi adopted the PMTCT strategy 'Option B+' in 2011, providing life long ART for all HIV-infected pregnant and breastfeeding women. We explored differences in characteristics and outcomes of women initiating ART during pregnancy versus breastfeeding. METHODS: We conducted a retrospective cohort analysis of women in Zomba District, southern Malawi, from January 2012- September 2013. Data were extracted from the Zomba District Observational Cohort Study, a surveillance project collecting data from standardized Ministry of Health ART monitoring tools. RESULTS: 1986 (67.2 %) women initiated ART during pregnancy and 969 (32.8 %) during breastfeeding. Women initiating ART in breastfeeding were more likely to be > 30 years (aOR = 1.33, 95 % CI1.11-1.59, p = 0.003) and have WHO Stage 3/4 (aOR = 2.74, 95 % CI1.94-3.87, p < 0.001). Eighteen (0.6 %) deaths occurred and 942 (31.9 %) women defaulted ART. 'Early' death (< 30 days) occurred in 3 (0.1 %) women and 449 (16.4 %) women defaulted early. Death/default < 30 days was more likely among women initiating ART during pregnancy (aOR 1.62, 95 % CI1.28-2.05, p < 0.001) or < 30 years old (aOR 1.27, 95 % CI 1.02-1.57, p = 0.03) and was less likely among those with WHO Stage 3/4 (aOR 0.30, 95 % CI 0.15-0.60, p < 0.001). Using Kaplan-Meier estimators to investigate time to death/default, we showed a sharp drop in death/default-free survival probability at time zero, yet survival probability decreased in a nearly linear manner after this initial period of high default. Women under 30 years had increased rates of death/default over time (log rank test: p < 0.001), however no significant differences were observed in death/default over time associated with timing of ART initiation, documented clinical stage at initiation, health clinic size or adherence rates. CONCLUSIONS: Many women in Malawi started ART during breastfeeding within Option B+ and were older and had more advanced WHO Clinical Staging. This represents a missed PMTCT opportunity to initiate treatment early in pregnancy. Early defaulting is identified as a challenge within Option B+, and was more likely among younger women and those initiating ART in pregnancy. Targeted research to understand factors associated with uptake of ART during pregnancy and retention in care could improve the efficacy of Option B+ in Malawi. PMID- 27487777 TI - Hepatic hydatid disease complications: review of imaging findings and clinical implications. AB - Hydatid disease is a zoonotic parasitic disease. The liver is the most commonly affected organ, and hepatic hydatid disease complications are not uncommon. Hydatid cyst superinfection, intrabiliary rupture, and direct rupture into the thoracic or abdominal cavities are the frequently encountered complications. Other exceedingly rare complications include rupture of the cyst into hollow viscera, abdominal wall invasion, and hepatic vasculature-related complications such as portal vein thrombosis and Budd-Chiari syndrome. These complications have variable clinical presentations and imaging findings and require different medical and surgical managements. We aim to provide a spectrum of imaging findings of different common and uncommon complications of hepatic hydatid disease with emphasis on their clinical implications. PMID- 27487776 TI - Application of a simplified definition of diastolic function in severe sepsis and septic shock. AB - BACKGROUND: Left ventricular diastolic dysfunction is common in patients with severe sepsis or septic shock, but the best approach to categorization is unknown. We assessed the association of common measures of diastolic function with clinical outcomes and tested the utility of a simplified definition of diastolic dysfunction against the American Society of Echocardiography (ASE) 2009 definition. METHODS: In this prospective observational study, patients with severe sepsis or septic shock underwent transthoracic echocardiography within 24 h of onset of sepsis (median 4.3 h). We measured echocardiographic parameters of diastolic function and used random forest analysis to assess their association with clinical outcomes (28-day mortality and ICU-free days to day 28) and thereby suggest a simplified definition. We then compared patients categorized by the ASE 2009 definition and our simplified definition. RESULTS: We studied 167 patients. The ASE 2009 definition categorized only 35 % of patients. Random forest analysis demonstrated that the left atrial volume index and deceleration time, central to the ASE 2009 definition, were not associated with clinical outcomes. Our simplified definition used only e' and E/e', omitting the other measurements. The simplified definition categorized 87 % of patients. Patients categorized by either ASE 2009 or our novel definition had similar clinical outcomes. In both definitions, worsened diastolic function was associated with increased prevalence of ischemic heart disease, diabetes, and hypertension. CONCLUSIONS: A novel, simplified definition of diastolic dysfunction categorized more patients with sepsis than ASE 2009 definition. Patients categorized according to the simplified definition did not differ from patients categorized according to the ASE 2009 definition in respect to clinical outcome or comorbidities. PMID- 27487778 TI - Identification and characterization of novel anticoagulant peptide with thrombolytic effect and nutrient oligopeptides with high branched chain amino acid from Whitmania pigra protein. AB - Natural and nutrient substances for cardiovascular disease are promising and capture researchers' minds. Two kinds of novel bioactive peptides (high Fischer's ratio oligopeptides and anticoagulant peptides) were obtained from Whitmania pigra protein via enzymatic hydrolysis. An oligopeptide (MW<874.0 Da) named as HF2 was obtained via chromatography purification procedures with a high Fischer's ratio of 31.92 +/- 1.36 and low phenylalanine + tyrosine content of 0.98 +/- 0.04 %. Another peptide (WA3-1), prepared by alcalase AF 2.4 L-catalyzed hydrolysis and then purified by DEAE Sepharose FF, gel Sephadex G-15 chromatography, exhibited high anticoagulant activity with prolonging significantly plasma clotting time on activated partial thromboplastin time, prothrombin time, thrombin time (p < 0.01) and powerful thrombolytic activity. Amino acid composition and MALDI-TOF/TOF MS analysis showed that WA3-1 contained 11 amino acids (MW: 1422.0 Da) with the sequence as NH2-His-Asp-Phe-Leu-Asn-Asn-Lys-Leu Glu-Tyr-Glu-COOH. Abundant negatively charged amino acids in C-terminal, as well as the special residue Lys contribute to its anticoagulant capacity. This research provided a novel natural candidate for the manufacture of nutrient oligopeptides with high branched chain amino acid, and anticoagulant thrombolytic agent in pharmaceutical industry with helping prevent from thrombosis and related cardiovascular diseases. PMID- 27487779 TI - Primary pulmonary plasmacytoma: a case report introduction. AB - BACKGROUND: Extramedullary plasmacytoma is a rare plasma cell neoplasm within soft tissue and without bone marrow involvement or other systemic characteristics of multiple myeloma. Primary pulmonary plasmacytoma is a rare type of extramedullary plasmacytoma. CASE PRESENTATION: A 48-year-old male with a tumor in the right middle ear was referred to our hospital. A routine chest X-ray was arranged and showed enlargement of the left lung hilum. His bilateral breathing sounded clear. A chest CT scan revealed a well-circumscribed mass. Pathological biopsy yielded a diagnosis of isolated pulmonary plasmacytoma. CONCLUSIONS: This is the first presentation of primary pulmonary plasmacytoma with a solitary pulmonary nodule and no lymph node involvement. PMID- 27487780 TI - Outcomes from an orientation model to reduce attrition in paediatric weight management. AB - We aimed to reduce attrition of newly referred patients in a paediatric weight management programme by implementing an orientation to address families' expectations and screen for and support behavioural and mental health problems and psychosocial stressors at programme outset. Orientation impact was monitored with run charts with percentages of scheduled encounters completed. Long-term impact was assessed by comparing patients in the initial 6 months of the orientation to a baseline group of referred patients during the same 6-month time interval in the prior year (Pre-Orientation Group). The outcome measure was programme attrition within 15 months. Groups were compared using Kaplan-Meier survival analysis and Cox proportional hazards regression modelling. Patients in the Orientation Group had a 23% increased odds of attrition compared to patients in the Pre-Orientation group (adjusted Hazard ratio, aHR 1.23; 95% confidence interval, CI: 1.01, 1.51) and shorter median duration of follow-up (2.0 vs. 2.9 months, P = 0.004). An increase in body mass index z-score of 1 unit resulted in a nearly fivefold increased odds of attrition (aHR 5.24; 95% CI: 2.95, 9.3). An orientation for new patients did not reduce attrition within 15 months. We suggest that ongoing retention strategies should be embedded into the treatment phase of the programme. PMID- 27487781 TI - Focus on nutrition. PMID- 27487782 TI - Clinical Presentation and Outcomes Associated with Different Treatment Modalities for Pediatric Bark Scorpion Envenomation. AB - INTRODUCTION: Scorpion envenomation is potentially life-threatening and affects children in the Southwestern USA. An FDA-approved antivenom is available, but its high cost has led to use of off-label antivenom dosing or supportive care alone as alternatives to FDA-recommended dosing. This study sought to determine whether treatment approach influences outcomes in envenomated children. METHODS: A retrospective cohort study of children with grade III or IV scorpion envenomation evaluated in Phoenix Children's Hospital ED between September 1, 2011, and March 31, 2014. Patients were grouped based on treatment: group 1, supportive care only; group 2, FDA-recommended dosing (3-vial initial dose); group 3, "off label" dosing (1-2 vial initial dose). Primary outcomes were ED length of stay and hospital admission. Secondary outcomes were mechanical ventilation and aspiration pneumonia. RESULTS: One hundred fifty-six patients were included with 58 patients in group 1, 16 patients in group 2, and 82 patients in group 3. Group 1 was significantly older than the antivenom groups (p < 0.001), and group 2 was younger than group 3 (p = 0.024). Envenomation grade was also different, with group 1 having fewer grade IV then groups 2 and 3 (p < 0.001). Three percent of group 1, 56 % of group 2, and 28 % of group 3 had respiratory distress (p < 0.001). ED LOS was not significantly different between groups. Hospital admission occurred in 3.4 % group 1, no group 2, and 8.5 % group 3 patients. Two intubations and two aspirations occurred in group 3. CONCLUSIONS: In this study, clinical presentation appeared to influence treatment. Groups that received antivenom had a higher envenomation grade than the group that received supportive care. The FDA-recommended dosing group was younger and had more respiratory distress than those treated with initial doses of 1-2 vials. Outcomes were not significantly different between groups. Prospective studies may identify the ideal population for each treatment approach. PMID- 27487783 TI - A Cluster Randomised Controlled Trial of a Brief Child Health Nurse Intervention to Reduce Infant Secondhand Smoke Exposure. AB - Background Exposure to secondhand smoke (SHS) is a significant contributor to ill health in children. A study was undertaken to determine the effectiveness of two brief multi-strategic child health nurse delivered interventions in: decreasing the prevalence of infants exposed to SHS; decreasing the prevalence of smoking amongst parent/carers of infants and increasing the prevalence of household smoking bans. Methods This study was a 3 arm, cluster randomised controlled trial. Clusters were 39 community based well child health clinics in one local area health service. Clinics were stratified according to annual number of client appointments and then randomly assigned in a 1:1:1 ratio, (Intervention 1: Intervention 2: Control), with 13 clinics in each cluster. Parents/carers of infants in the intervention groups received a brief multi-strategic intervention from child health nurses during clinic consultations. Treatment condition 1 included computer delivered risk assessment and feedback and nurse brief advice. Treatment condition 2 included all elements of Treatment condition 1 with the addition of biochemical feedback of infant SHS exposure. Results When compared to the Control group at 12 months, no significant differences in the prevalence of infant exposure to SHS were detected from baseline to follow-up for Treatment condition 1 (OR 1.16, 95 % CI 0.73-1.85, p = 0.53) or Treatment condition 2 (OR 1.30, 95 % CI 0.88-1.92, p = 0.19) Similarly, no significant differences were detected in the proportion of parent/carers who reported that they were smokers (T1:OR 0.95, 95 % CI 0.78-1.15, p = 0.58 and T2:OR 0.97, 95 % CI 0.80-1.18, p = 0.77), or in the proportion of households reported to have a complete smoking ban (T1:OR 1.21, 95 % CI 0.89-1.64, p = 0.23 and T2:OR 1.06, 95 % CI 0.79-1.43, p = 0.68). Conclusions Further research is required to identify effective interventions that can be consistently provided by child health nurses if the potential of such settings to contribute to reductions in child SHS exposure is to be realised. PMID- 27487784 TI - Epidemiology of invasive pneumococcal infections: manifestations, incidence and case fatality rate correlated to age, gender and risk factors. AB - BACKGROUND: Incidence, manifestations and case-fatality rate (CFR) of invasive pneumococcal disease (IPD) vary with age and comorbidities. New vaccines, changing age distribution, prolonged survival among immunocompromised patients and improved sepsis management have created a need for an update of basic facts to inform vaccine recommendations. METHODS: Age, gender and comorbidities were related to manifestations and death for 2977 consecutive patients with IPD in a Swedish region with 1.5 million inhabitants during 13 years before introduction of pneumococcal conjugate vaccines (PCV) in the infant vaccination program. These data were related to population statistics and prevalence of several comorbidities, and compared with two previous studies giving a total follow-up of 45 years in the same area. RESULTS: The annual incidence was 15/100,000 for any IPD and 1.1/100,000 for meningitis; highest among elderly followed by children < 2 years. It was 2238/100,000 among myeloma patients, followed by chronic lymphatic leukemia, hemodialysis and lung cancer, but not elevated among asthma patients. CFR was 10 % among all patients, varying from 3 % below 18 years to 22 % >= 80 years. During 45 years, the IPD incidence increased threefold and CFR dropped from 20 to 10 %. Meningitis incidence remained stable (1.1/100,000/year) but CFR dropped from 33 to 13 %. IPD-specific mortality decreased among children <2 years from 3.1 to 0.46/100,000/year but tripled among those >=65 years. CONCLUSIONS: IPD incidence and CFR vary widely between age and risk groups and over time even without general infant vaccination. Knowledge about specific epidemiological characteristics is important for informing and evaluating vaccination policies. PMID- 27487786 TI - Therapeutic Effect of Chang'an I Recipe ( I ) on Irritable Bowel Syndrome with Diarrhea: A Multicenter Randomized Double-Blind Placebo-Controlled Clinical Trial. AB - OBJECTIVE: To evaluate the efficacy and safety of Chinese medicine (CM) decoction Chang'an I Recipe ( I ) in the treatment of irritable bowel syndrome with diarrhea (IBS-D). METHOD: A multicenter, randomized, double-blind, placebo controlled clinical trial was designed. Based on the order of inclusion, the IBS D patients were randomly assigned to the treatment group or the placebo control group, administrated with Chang'an I Recipe or placebo, 150 mL/bag, 3 times daily, for 8 weeks. The primary indices of efficacy included the effective rates of IBS symptom severity score (IBS-SSS) and the differences in adequate relief (AR) responder; the secondary indexes of efficacy included the changes in scores of the IBS Quality of Life (IBS-QOL) and Hospital Anxiety and Depression (HAD) scales. The safety indices included adverse events and related laboratory tests. RESULTS: A total of 216 patients were included, with 109 in the treatment group and 107 in the control group, and finally 206 were included in the full analysis set (FAS), 191 were included in the per protocol set (PPS). In FAS, the total effective rate was 67.6% and 40.2% for the treatment and control groups, respectively, with 95% confidence interval (CI) for difference in the effective rates between the two groups of 14.4%-40.2%; while in PPS, the total effective rate was 71.3% and 41.2% for the treatment and control groups, respectively (95% CI 16.6%-43.4%). The consistent conclusions of FAS and PPS showed a better efficacy in the treatment group. Both FAS and PPS showed higher AR responder in the treatment group (FAS: 59.6% vs. 35.5%; PPS: 62.8% vs. 38.1%). As for IBS-QOL, the total score and scores in various dimensions of IBS-QOL were not significantly different between the two groups (P>0.05). Both anxiety and depression scales of HAD were not significantly different between the two groups (P>0.05). No adverse events or laboratory abnormalities were found to be obviously related to the tested drugs or clinically significant. CONCLUSION: Chang'an I Recipe was more effective than placebo in the treatment of IBS-D, with no obvious adverse reactions. (No.ChiCTR-TRC-09000328). PMID- 27487785 TI - Neurons in the brain of the desert locust Schistocerca gregaria sensitive to polarized light at low stimulus elevations. AB - Desert locusts (Schistocerca gregaria) sense the plane of dorsally presented polarized light through specialized dorsal eye regions that are likely adapted to exploit the polarization pattern of the blue sky for spatial orientation. Receptive fields of these dorsal rim photoreceptors and polarization-sensitive interneurons are directed toward the upper sky but may extend to elevations below 30 degrees . Behavioral data, however, suggests that S. gregaria is even able to detect polarized light from ventral directions but physiological evidence for this is still lacking. In this study we characterized neurons in the locust brain showing polarization sensitivity at low elevations down to the horizon. In most neurons polarization sensitivity was absent or weak when stimulating from the zenith. All neurons, including projection and commissural neurons of the optic lobe and local interneurons of the central brain, are novel cell types, distinct from polarization-sensitive neurons studied so far. Painting dorsal rim areas in both eyes black to block visual input had no effect on the polarization sensitivity of these neurons, suggesting that they receive polarized light input from the main eye. A possible role of these neurons in flight stabilization or the perception of polarized light reflected from bodies of water or vegetation is discussed. PMID- 27487787 TI - Pharmacophore Based 3D-QSAR, Virtual Screening and Docking Studies on Novel Series of HDAC Inhibitors with Thiophen Linker as Anticancer Agents. AB - BACKGROUND: Histone deacetylase (HDAC) inhibitors can reactivate gene expression and inhibit the growth and survival of cancer cells. OBJECTIVE: To identify the important pharmacophoric features and correlate 3Dchemical structure with biological activity using 3D-QSAR and Pharmacophore modeling studies. METHOD: The pharmacophore hypotheses were developed using e-pharmacophore script and phase module. Pharmacophore hypothesis represents the 3D arrangement of molecular features necessary for activity. A series of 55 compounds with wellassigned HDAC inhibitory activity were used for 3D-QSAR model development. RESULTS: Best 3D QSAR model, which is a five partial least square (PLS) factor model with good statistics and predictive ability, acquired Q2 (0.7293), R2 (0.9811), cross validated coefficient rcv 2=0.9807 and R2 pred=0.7147 with low standard deviation (0.0952). Additionally, the selected pharmacophore model DDRRR.419 was used as a 3D query for virtual screening against the ZINC database. In the virtual screening workflow, docking studies (HTVS, SP and XP) were carried out by selecting multiple receptors (PDB ID: 1T69, 1T64, 4LXZ, 4LY1, 3MAX, 2VQQ, 3C10, 1W22). Finally, six compounds were obtained based on high scoring function (dock score -11.2278-10.2222 kcal/mol) and diverse structures. CONCLUSION: The structure activity correlation was established using virtual screening, docking, energetic based pharmacophore modelling, pharmacophore, atom based 3D QSAR models and their validation. The outcomes of these studies could be further employed for the design of novel HDAC inhibitors for anticancer activity. PMID- 27487788 TI - Identification of Novel Structurally Diverse Anaplastic Lymphoma Kinase Inhibitors Based on Pharmacophore Modeling, Virtual Screening and Molecular Docking. AB - AIM AND OBJECTIVE: Anaplastic lymphoma kinase, an insulin receptor protein tyrosine kinase, is a very attractive receptor protein target for anticancer therapy. This study was undertaken to identify novel structurally diverse anaplastic lymphoma kinase inhibitors. MATERIAL AND METHOD: Pharmacophore hypotheses modeling, virtual screening and molecular docking were used to detect potential inhibitors of anaplastic lymphoma kinase in this paper. RESULTS: After the generation of ten pharmacophore hypotheses, Hypo1 with the highest correlation value (0.981), lowest RMS (0.565), highest cost difference (83.850) along with four typical chemical features was regarded as the best hypothesis. Hypo1 contains a hydrogen bond acceptor, a hydrogen bong donor, a hydrophobic and a ring aromatic feature. And then, hypo1 was validated and used to screen three databases after screened by Lipinski's rule of five. 3015 hits screened by Hypo1 were submitted to molecular docking based on the crystal structure of anaplastic lymphoma kinase. CONCLUSION: all the seven molecules formed hydrogen bond interaction with Met1199 as well as formed several other hydrogen bond interactions with different residues. All of them formed Van Der Waals interaction with hydrophobic pocket which made up of residues of Ala1148, Leu1256, Leu1196, Leu1198 Val1130 and Val1180. Some of them also formed van der Waals interaction in somewhere else of protein pocket. PMID- 27487790 TI - [MIF in post-resuscitation syndrome : No marker of inflammation, but of tissue damage]. PMID- 27487789 TI - Fibrillin-1 (FBN-1) a new marker of germ cell neoplasia in situ. AB - BACKGROUND: Germ cell neoplasia in situ (GCNIS), is preinvasive stage of testicular germ cell tumours (TGCTs). Fibrillins, which are integral components of microfibrils are suggested to be involved in cancer pathogenesis and maintenance of embryonic stem cells pluripotency. The aim of this study was to examine fibrillin-1 (FBN-1) expression in TGCTs patients. METHODS: Surgical specimens from 203 patients with TGCTs were included into the translational study. FBN-1 expression was evaluated in the tumour tissue, in GCNIS and in adjacent non-neoplastic testicular tissue in all available cases. Tissue samples were processed by the tissue microarray method. FBN-1 was detected by immunohistochemistry using goat polyclonal antibody and the expression was evaluated by the multiplicative quickscore (QS). RESULTS: The highest FBN-1 positivity was detected in GCNIS (mean QS = 11.30), with overexpression of FBN-1 (QS >9) in the majority (77.1 %) of cases. Expression of FBN-1 in all subtypes of TGCTs was significantly lower in comparison to expression in GCNIS (all p <0.001). Seminoma had significantly higher expression compared to EC, ChC and TER (all p <0.05), but not to YST (p = 0.84). In non-neoplastic testicular tissue the FBN-1 positivity was very low (mean QS = 0.02). Sensitivity, specificity, positive and negative predictive value of FBN-1 expression for diagnosis of GCNIS were 97.1, 98.8, 98.6 and 97.7 %. CONCLUSIONS: FBN-1 is overexpressed in TGCTs and especially in GCNIS when compared to non-neoplastic testicular tissue in patients with germ cell tumors and could be involved in germ cell neoplasia in situ development. PMID- 27487791 TI - Aluminium salalens vs. salans: "Initiator Design" for the isoselective polymerisation of rac-lactide. AB - We report the rationalised design of aluminium initiators and their application for ROP of rac-lactide (rac-LA). A very minor change to the ligand backbone (imine reduction) to give secondary amines was found to have a dramatic effect on activity and selectivity with isotactic PLA being realised. PMID- 27487792 TI - Clinical interventions for venous leg ulcers: Proposals to improve the quality of clinical leg ulcer research. AB - The present status of clinical leg ulcer healing research was reviewed by 25 experts over 2 days on September 28 and 29, 2015. Multiple clinical effectiveness reviews were presented suggesting that published clinical wound healing research often does not meet present (2015) evidence based standards. Specific areas requiring remediation were highlighted and approaches to overcoming existing challenges were proposed. Participants using anonymous voting technology developed an action plan to resolve perceived deficiencies. Statements were accepted if 75% of participants agreed. Older patients with a high frequency of comorbid conditions posed particular difficulties in designing clinical research protocols and better diagnostic categorization is necessary A standardized model template for collecting information about diagnosis and evaluation of the effect of interventions on healing of all types of leg ulcers was considered a high priority. Such a model template could be modified depending on the specific etiology of the leg ulcers. Generally agreed on quantifiable standards to establish degree of morbidity was considered a high priority. There was universal agreement that sources of funding and conflicts of interest needed to be disclosed in presentations and all publications. All clinical research studies should be registered with appropriate authorities. There was substantial enthusiasm for a clinical research network with quality standards for membership and an advisory research core available to investigators. Such a network should be funded and actively managed to insure long-term viability. The governance of such an entity needs to be established by the wound care community. The present trend to integrate patients into the clinical research process was endorsed and there was enthusiasm to develop patient advocacy for wound healing research. PMID- 27487793 TI - Evolving Concepts in Phases I and II Drug Development for Crohn's Disease. AB - The highest attrition rates during drug development programmes occur at the proof of concept stage. Given the large number of molecules under development for Crohn's disease, a need exists to improve the efficiency of early drug development by fast-tracking promising agents and terminating ineffective ones. Multiple opportunities are available to achieve these goals, including the use of more responsive outcome measures, and the incorporation of sophisticated pharmacokinetic modelling and/or highly specific pharmacodynamic markers into exposure-based dosing regimens and novel trial designs. In this article we review these strategies and propose an integrated paradigm of early drug development in Crohn's disease. PMID- 27487794 TI - Early Splenic Flexure Intubation Competency Predicts Early Cecal Intubation Competency in Gastroenterology Fellows. AB - BACKGROUND: Trainees learn colonoscopy skills at varying speeds. We hypothesized that a fellow's ability to reliably reach the splenic flexure early in training could predict the number of procedures required to achieve competency in intubating the cecum. METHODS: This was a retrospective analysis of prospectively collected data. The most proximal site in the colon reached independently by GI fellows was recorded on consecutive colonoscopies. The number of procedures required to achieve splenic flexure intubation rate (SFIR) >= 90 % by cumulative summation learning curve and cecal intubation rate (CIR) >= 90 % by rolling average was calculated. Fellows were then dichotomized into "Early" versus "Late" learners based on the median number of procedures required to achieve SFIR >= 90 %. The number of procedures required to achieve CIR >= 90 % was then compared between the groups. RESULTS: Fellows achieved SFIR >= 90 % at a median of 37 colonoscopies. Fellows who achieved SFIR competency early achieved CIR >= 90 % at a mean of 208 procedures versus 352 procedures in the fellows who achieved SFIR competency late (p = 0.03). CONCLUSIONS: Data from a single academic medical center show that whether a trainee will learn endoscopy quickly compared to his/her peers can be predicted early in their endoscopy training by tracking SFIR. This knowledge could be used to customize endoscopy curriculum. PMID- 27487795 TI - Safety and Efficacy of a Same-Day Low-Volume 1 L PEG Bowel Preparation in Colonoscopy for the Elderly People and People with Renal Dysfunction. AB - INTRODUCTION: A same-day low-volume 1 L polyethylene glycol (PEG) for bowel preparation before colonoscopy was developed to improve patients' compliance. We aimed to evaluate the efficacy and safety of this regimen especially for the elderly and patients with renal dysfunction. METHODS: All consecutive patients who underwent colonoscopy in our center from November 2014 to September 2015 were included. Patients undertook a low-residue diet with 10 mL sodium picosulfate 1 day before colonoscopy. Subsequently, they had 1 L low-volume PEG (MoviPrep) and 0.5 L water 4 h before the examination. Clinical outcomes, including cleansing level using the Boston bowel preparation score (BBPS), in the elderly and special elderly (65-79 and >=80 years old) were analyzed and compared with the non elderly (18-64 years old). Additionally, patients with renal dysfunction were analyzed with respect to both complications and changes in blood parameters. RESULTS: A total of 5427 patients (mean age: 64.5 +/- 13.8) were analyzed. The rate of BBPS >= 6 in the elderly (2761 patients), special-elderly (565 patients), and non-elderly (2101 patients) was 94.1, 91.8, and 94.6 %, respectively. In the special-elderly, the rate of renal dysfunction was 14.8 %, and no severe complications were detected after colonoscopy. Additionally, there were no severe complications in 86 patients with renal dysfunction, though elevation of hematocrit was shown after intake of 1 L PEG (before, 36.7 +/- 6.1 vs. after, 39.0 +/- 5.7, P = 0.006). CONCLUSIONS: Our study shows the safety and efficacy of same-day low-volume 1 L PEG bowel preparation in colonoscopy for the elderly and patients with renal dysfunction. PMID- 27487796 TI - Fully Automated Evaluation of Total Glomerular Number and Capillary Tuft Size in Nephritic Kidneys Using Lightsheet Microscopy. AB - The total number of glomeruli is a fundamental parameter of kidney function but very difficult to determine using standard methodology. Here, we counted all individual glomeruli in murine kidneys and sized the capillary tufts by combining in vivo fluorescence labeling of endothelial cells, a novel tissue-clearing technique, lightsheet microscopy, and automated registration by image analysis. Total hands-on time per organ was <1 hour, and automated counting/sizing was finished in <3 hours. We also investigated the novel use of ethyl-3-phenylprop-2 enoate (ethyl cinnamate) as a nontoxic solvent-based clearing reagent that can be handled without specific safety measures. Ethyl cinnamate rapidly cleared all tested organs, including calcified bone, but the fluorescence of proteins and immunohistochemical labels was maintained over weeks. Using ethyl cinnamate cleared kidneys, we also quantified the average creatinine clearance rate per glomerulus. This parameter decreased in the first week of experimental nephrotoxic nephritis, whereas reduction in glomerular numbers occurred much later. Our approach delivers fundamental parameters of renal function, and because of its ease of use and speed, it is suitable for high-throughput analysis and could greatly facilitate studies of the effect of kidney diseases on whole organ physiology. PMID- 27487797 TI - Association between vitamin D deficiency and pre-existing resistance-associated hepatitis C virus NS5A variants. AB - AIM: Although interferon-free therapy with direct-acting antivirals has developed as a standard of care for chronic hepatitis C, the existence of resistance associated variants (RAVs) has a negative impact on treatment results. Recently, several studies indicated a relationship between chronic hepatitis C and serum vitamin D levels. However, the relationship between RAVs at the hepatitis C virus non-structure 5A (NS5A) region and serum vitamin D level has not yet been examined. METHODS: Among patients with genotype 1 chronic hepatitis C who were enrolled in a multicenter cooperative study, our subjects comprised 247 patients in whom it was possible to measure RAVs at the NS5A region. These RAVs were measured using a direct sequencing method. RESULTS: The median age of patients was 70 years (range, 24-87 years), and the number of female patients was 135 (54.7%). The median serum 25(OH) D3 level was 22 ng/mL (range, 6-64 ng/mL). L31 and Y93 RAVs at the NS5A region were detected in 3.7% (9/247) and 13.4% (33/247) of patients, respectively. Multivariate analysis identified vitamin D deficiency (serum 25(OH) D3 <= 20 ng/mL) (P = 5.91 * 10-5 , odds ratio = 5.015) and elderly age (>70 years) (P = 1.85 * 10-3 , odds ratio = 3.364) as contributing independent factors associated with the presence of the L31 and/or Y93 RAVs. The Y93H RAV was detected in 25.9% (29/112) of patients with a vitamin D deficiency, and in 8.9% (12/135) of those with a serum 25(OH) D3 level >20 ng/mL (P = 4.90 * 10-3 ). CONCLUSION: We showed that RAVs at the NS5A region are associated with vitamin D deficiency and elderly age, which may have a negative influence on innate/adaptive immune responses to hepatitis C virus infection. PMID- 27487798 TI - A 24-channel shim array for the human spinal cord: Design, evaluation, and application. AB - PURPOSE: A novel multichannel shim array is introduced to improve MRI and spectroscopic studies of the human spinal cord. METHODS: Twenty-four-channel shim and 8-channel transceiver arrays were designed to insert into the patient bed table to lie in close proximity to the subject's spine. The reference field patterns of each of the shim channels (Hz/A) were determined empirically via gradient echo field mapping and subsequently used to demonstrate shim performance at 3 Tesla using an ex vivo phantom, which incorporated a fixed human spine. The shim was further demonstrated on five healthy volunteers. RESULTS: Application of the shim to the ex vivo phantom reduced the standard deviation of the field over the spinal volume of interest (123.4 cm3 ) from an original 51.3 Hz down to 32.5 Hz, amounting to an improvement in field homogeneity of 36.6%. In vivo, the spine shim resulted in an average improvement in field homogeneity of 63.8 +/- 15.4%. CONCLUSION: The localized spine shim offers a promising new means of correcting magnetic field distortion in the spinal cord. Magn Reson Med 76:1604-1611, 2016. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27487799 TI - Efmoroctocog Alfa: A Review in Haemophilia A. AB - Efmoroctocog alfa (Elocta((r)), Eloctate((r)), EloctateTM), a first-in-class recombinant factor VIII-Fc fusion protein (rFVIIIFc), has an extended half-life compared with conventional factor VIII (FVIII) preparations, including recombinant FVIII (rFVIII) products. It is approved for the treatment and prophylaxis of bleeding in patients with haemophilia A in multiple countries worldwide. Data accumulated from pivotal phase III studies (A-LONG in adults and adolescents aged >=12 years; Kids A-LONG in children aged <12 years) and their ongoing extension study (ASPIRE) have demonstrated the long-term effectiveness of efmoroctocog alfa for the treatment of acute bleeding episodes, perioperative management and routine prophylaxis in previously treated males with severe haemophilia A. Among patients on individualized efmoroctocog alfa prophylaxis who had previously received FVIII prophylaxis, all but one of those aged >=12 years and three-quarters of those aged <12 years reduced their injection frequency compared with their pre-study regimen. FVIII replacement therapy with efmoroctocog alfa was generally well tolerated in previously treated patients, with no evidence of increased immunogenicity. The safety and efficacy of FVIII replacement therapy with efmoroctocog alfa in previously untreated males aged <6 years with severe haemophilia A are currently being evaluated. Although there are no direct, head-to-head studies, the available clinical trial evidence indicates that efmoroctocog alfa provides an effective alternative to conventional FVIII preparations (including rFVIIIs) for the management of haemophilia A. Moreover, by reducing the frequency of injections required, it has the potential to reduce treatment burden, and hence improve adherence to prophylaxis. PMID- 27487800 TI - A 1.35 Mb DNA fragment is inserted into the DHMN1 locus on chromosome 7q34-q36.2. AB - Distal hereditary motor neuropathies predominantly affect the motor neurons of the peripheral nervous system leading to chronic disability. Using whole genome sequencing (WGS) we have identified a novel structural variation (SV) within the distal hereditary motor neuropathy locus on chromosome 7q34-q36.2 (DHMN1). The SV involves the insertion of a 1.35 Mb DNA fragment into the DHMN1 disease locus. The source of the inserted sequence is 2.3 Mb distal to the disease locus at chromosome 7q36.3. The insertion involves the duplication of five genes (LOC389602, RNF32, LMBR1, NOM1, MNX1) and partial duplication of UBE3C. The genomic structure of genes within the DHMN1 locus are not disrupted by the insertion and no disease causing point mutations within the locus were identified. This suggests the novel SV is the most likely DNA mutation disrupting the DHMN1 locus. Due to the size and position of the DNA insertion, the gene(s) directly affected by the genomic re-arrangement remains elusive. Our finding represents a new genetic cause for hereditary motor neuropathies and highlights the growing importance of interrogating the non-coding genome for SV mutations in families which have been excluded for genome wide coding mutations. PMID- 27487801 TI - Genome-wide scans reveal variants at EDAR predominantly affecting hair straightness in Han Chinese and Uyghur populations. AB - Hair straightness/curliness is one of the most conspicuous features of human variation and is particularly diverse among populations. A recent genome-wide scan found common variants in the Trichohyalin (TCHH) gene that are associated with hair straightness in Europeans, but different genes might affect this phenotype in other populations. By sampling 2899 Han Chinese, we performed the first genome-wide scan of hair straightness in East Asians, and found EDAR (rs3827760) as the predominant gene (P = 4.67 * 10-16), accounting for 3.66 % of the total variance. The candidate gene approach did not find further significant associations, suggesting that hair straightness may be affected by a large number of genes with subtle effects. Notably, genetic variants associated with hair straightness in Europeans are generally low in frequency in Han Chinese, and vice versa. To evaluate the relative contribution of these variants, we performed a second genome-wide scan in 709 samples from the Uyghur, an admixed population with both eastern and western Eurasian ancestries. In Uyghurs, both EDAR (rs3827760: P = 1.92 * 10-12) and TCHH (rs11803731: P = 1.46 * 10-3) are associated with hair straightness, but EDAR (OR 0.415) has a greater effect than TCHH (OR 0.575). We found no significant interaction between EDAR and TCHH (P = 0.645), suggesting that these two genes affect hair straightness through different mechanisms. Furthermore, haplotype analysis indicates that TCHH is not subject to selection. While EDAR is under strong selection in East Asia, it does not appear to be subject to selection after the admixture in Uyghurs. These suggest that hair straightness is unlikely a trait under selection. PMID- 27487803 TI - Effects of temperature and diet on length-weight relationship and condition factor of the juvenile Malabar blood snapper (Lutjanus malabaricus Bloch & Schneider, 1801). AB - In this study we aimed to analyze the effects of water temperature and diet on the length-weight relationship and condition of juvenile Malabar blood snapper Lutjanus malabaricus over a 30-d experimental period. The experiment was conducted in the laboratory using a flow-through-sea-water system. The fish were subjected to four different temperatures (22, 26, 30, and 34 degrees C) and two diets (commercial pellet and natural shrimp). Fish were fed twice daily. L. malabaricus exhibited negative allometric growth (b<3) at the beginning of the experiment (Day 0) at all temperatures and both diets except for 22 degrees C fed with shrimp, which showed isometric growth (b=3). Conversely, at the end of the experiment (Day 30) fish showed isometric growth (b=3) at 30 degrees C fed with the pellet diet, indicating that the shape of the fish did not change with increasing weight and length, and a positive allometric growth (b>3) at 30 degrees C fed with shrimp diet, which indicated that fish weight increases faster than their length. The rest of the temperatures represented negative allometric growth (b<3) on both diet, meaning that fish became lighter with increasing size. The condition factors in the initial and final measurements were greater than 1, indicating the state of health of the fish, except for those fed on a pellet diet at 34 degrees C. However, the best condition was obtained at 30 degrees C on both diets. Nevertheless, diets did not have a significant effect on growth and condition of juvenile L. malabaricus. The data obtained from this study suggested culturing L. malabaricus at 30 degrees C and feeding on the pellet or shrimp diet, which will optimize the overall production and condition of this commercially important fish species. PMID- 27487802 TI - Comparative genomic analysis of Lactobacillus plantarum ZJ316 reveals its genetic adaptation and potential probiotic profiles. AB - OBJECTIVE: In previous studies, Lactobacillus plantarum ZJ316 showed probiotic properties, such as antimicrobial activity against various pathogens and the capacity to significantly improve pig growth and pork quality. The purpose of this study was to reveal the genes potentially related to its genetic adaptation and probiotic profiles based on comparative genomic analysis. METHODS: The genome sequence of L. plantarum ZJ316 was compared with those of eight L. plantarum strains deposited in GenBank. BLASTN, Mauve, and MUMmer programs were used for genome alignment and comparison. CRISPRFinder was applied for searching the clustered regularly interspaced short palindromic repeats (CRISPRs). RESULTS: We identified genes that encode proteins related to genetic adaptation and probiotic profiles, including carbohydrate transport and metabolism, proteolytic enzyme systems and amino acid biosynthesis, CRISPR adaptive immunity, stress responses, bile salt resistance, ability to adhere to the host intestinal wall, exopolysaccharide (EPS) biosynthesis, and bacteriocin biosynthesis. CONCLUSIONS: Comparative characterization of the L. plantarum ZJ316 genome provided the genetic basis for further elucidating the functional mechanisms of its probiotic properties. ZJ316 could be considered a potential probiotic candidate. PMID- 27487804 TI - Association of VIPR-1 gene polymorphisms and haplotypes with egg production in laying quails. AB - The laying quail is a worldwide breed which exhibits high economic value. In our current study, the vasoactive intestinal peptide receptor-1 (VIPR-1) was selected as the candidate gene for identifying traits of egg production. A single nucleotide polymorphism (SNP) detection was performed in 443 individual quails, including 196 quails from the H line, 202 quails from the L line, and 45 wild quails. The SNPs were genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Two mutations (G373T, A313G) were detected in all the tested quail populations. The associated analysis showed that the SNP genotypes of the VIPR-1 gene were significantly linked with the egg weight of G373T and A313G in 398 quails. The quails with the genotype GG always exhibited the largest egg weight for the two mutations in the H and L lines. Linkage disequilibrium (LD) analysis indicated that G373T and A313G loci showed the weakest LD. Seven main diplotypes from the four main reconstructed haplotypes were observed, indicating a significant association of diplotypes with egg weight. Quails with the h1h2 (GGGT) diplotype always exhibited the smallest egg weight and largest egg number at 20 weeks of age. The overall results suggest that the alterations in quails may be linked with potential major loci or genes affecting reproductive traits. PMID- 27487805 TI - Probiotic properties of lactic acid bacteria isolated from traditionally fermented Xinjiang cheese. AB - Six lactic acid bacterial (LAB) strains were isolated from traditionally fermented Xinjiang cheese and evaluated for functional and probiotic properties and potentials as starter cultures. The isolated six LAB strains comprised Lactobacillus rhamnosus (one strain), Lactobacillus helveticus (one strain), and Enterococcus hirae (four strains). All of the six strains were tolerant to acidic and bile salt conditions. Among which, the L. rhamnosus R4 strain showed more desirable antimicrobial, auto-aggregation, and hydrophobic activity. In addition, the strain L. rhamnosus R4 exhibited the highest level of free radical scavenging activity (53.78% of 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals and 45.79% of hydroxyl radicals). L. rhamnosus R4 also demonstrated cholesterol and triglyceride degradation by 50.97% and 28.92%, respectively. To further examine the health-promoting effects of these LAB strains on host lifespan, Caenorhabditis elegans was used as an in vivo model. Worms fed LAB as a food source had significant differences in lifespan compared to those fed Escherichia coli OP50 (as a negative control). Feeding of L. rhamnosus R4 extended the mean lifespan of C. elegans by up to 36.1% compared to that of the control. The results suggest that the strains isolated from Xinjiang fermented dairy products have high potential as starter cultures in the cheese industry. PMID- 27487806 TI - Chryseobacterium chengduensis sp. nov. isolated from the air of captive giant panda enclosures in Chengdu, China. AB - A Gram-negative, aerobic, non-motile, rod-shaped bacterial strain, designated 25 1(T), was isolated from the air inside giant panda enclosures at the Chengdu Research Base of Giant Panda Breeding, China. Strain 25-1(T) grew optimally at pH 7.0-8.0, at 28-30 degrees C and in the presence of NaCl concentrations from 0.0% to 0.5 %. 16S rRNA gene sequence analysis indicated that strain 25-1(T) belongs to the genus Chryseobacterium within the family Flavobacteriaceae and is related most closely to C. carnis G81(T) (96.4% similarity), C. lathyri RBA2-6(T) (95.8% similarity), and C. zeae JM1085(T) (95.8% similarity). Its genomic DNA G+C molar composition was 36.2%. The major cellular fatty acids were iso-C15:0 (44.0%), iso C17:0 3OH (19.8%) and C16:1 omega7c/16:1 omega6c (12.7%). The only isoprenoid quinone was menaquinone 6 (MK-6). The major polar lipids were phosphatidylethanolamine, two unidentified amino lipids and two unidentified lipids. The DNA-DNA relatedness between strain 25-1(T) and C. lathyri RBA2-6(T) was 38%. Phenotypic, genotypic, and phylogenetic characteristics indicated that strain 25-1(T) is a novel member of the genus Chryseobacterium, for which the name C. chengduensis sp. nov. is proposed. The type strain is 25-1(T) (CCTCC AB2015133(T)=DSM 100396(T)). PMID- 27487807 TI - Statistical culture-based strategies to enhance chlamydospore production by Trichoderma harzianum SH2303 in liquid fermentation. AB - Trichoderma-based formulations are applied as commercial biocontrol agents for soil-borne plant pathogens. Chlamydospores are active propagules in Trichoderma spp., but their production is currently limited due to a lack of optimal liquid fermentation technology. In this study, we explored response surface methodologies for optimizing fermentation technology in Trichoderma SH2303. Our initial studies, using the Plackett-Burman design, identified cornmeal, glycerol, and initial pH levels as the most significant factors (P<0.05) for enhancing the production of chlamydospores. Subsequently, we applied the Box-Behnken design to study the interactions between, and optimal levels of, a number of factors in chlamydospore production. These statistically predicted results indicated that the highest number of chlamydospores (3.6*10(8) spores/ml) would be obtained under the following condition: corn flour 62.86 g/L, glycerol 7.54 ml/L, pH 4.17, and 6-d incubation in liquid fermentation. We validated these predicted values via three repeated experiments using the optimal culture and achieved maximum chlamydospores of 4.5*10(8) spores/ml, which approximately a 8-fold increase in the number of chlamydospores produced by T. harzianum SH2303 compared with that before optimization. These optimized values could help make chlamydospore production cost-efficient in the future development of novel biocontrol agents. PMID- 27487808 TI - Emergy assessment of three home courtyard agriculture production systems in Tibet Autonomous Region, China. AB - Home courtyard agriculture is an important model of agricultural production on the Tibetan plateau. Because of the sensitive and fragile plateau environment, it needs to have optimal performance characteristics, including high sustainability, low environmental pressure, and high economic benefit. Emergy analysis is a promising tool for evaluation of the environmental-economic performance of these production systems. In this study, emergy analysis was used to evaluate three courtyard agricultural production models: Raising Geese in Corn Fields (RGICF), Conventional Corn Planting (CCP), and Pea-Wheat Rotation (PWR). The results showed that the RGICF model produced greater economic benefits, and had higher sustainability, lower environmental pressure, and higher product safety than the CCP and PWR models. The emergy yield ratio (EYR) and emergy self-support ratio (ESR) of RGICF were 0.66 and 0.11, respectively, lower than those of the CCP production model, and 0.99 and 0.08, respectively, lower than those of the PWR production model. The impact of RGICF (1.45) on the environment was lower than that of CCP (2.26) and PWR (2.46). The emergy sustainable indices (ESIs) of RGICF were 1.07 and 1.02 times higher than those of CCP and PWR, respectively. With regard to the emergy index of product safety (EIPS), RGICF had a higher safety index than those of CCP and PWR. Overall, our results suggest that the RGICF model is advantageous and provides higher environmental benefits than the CCP and PWR systems. PMID- 27487809 TI - Effect of Tai Chi exercise on blood lipid profiles: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: Studies have demonstrated that Tai Chi exercise improves blood lipid level with inconsistent results. A meta-analysis was conducted to quantify the effects of Tai Chi on blood lipid profiles in humans. METHODS: We screened the databases of PubMed, EMBASE, Cochrane Library (Central), Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang data, and Clinicaltrials.gov for randomized controlled trials with Physiotherapy Evidence Database (PEDro) score more than 3 points up to June 2015. Six studies involving 445 subjects were included. Most trials applied 12-week Tai Chi intervention courses. RESULTS: In comparison with the control group, blood triglyceride (TG) level difference between follow-up and baseline was statistically significantly lower in the Tai Chi practicing group (weighted mean difference (WMD) -16.81 mg/dl; 95% confidence intervals (CI) -31.27 to -2.35 mg/dl; P=0.02). A trend to improving total cholesterol (TC) reduction was found with Tai Chi (WMD -7.96 mg/dl; 95% CI -17.30 to 1.39 mg/dl; P=0.10). However, no difference was found in blood low-density lipoprotein cholesterol (LDL-C) or high-density lipoprotein cholesterol (HDL-C). CONCLUSIONS: Tai Chi exercise lowered blood TG level with a trend to decrease blood TC level. Our data suggest that Tai Chi has the potential to implement meaningful blood lipid modification and serve as an adjunctive exercise modality. The relationship between Tai Chi exercise regimen and lipid profile change might have a scientific priority for future investigation. PMID- 27487810 TI - Anticoagulation versus antiplatelet or no therapy in patients undergoing bioprosthetic valve implantation: a systematic review and meta-analysis. AB - OBJECTIVE: Use of vitamin K antagonist (VKA) versus antiplatelet (AP)/no therapy following bioprosthetic valve implantation remains controversial. The aims of the current study were to (a) systematically review the published literature comparing the use of VKA versus AP/no treatment in such patients and (b) perform a meta-analysis of the risks and benefits of using a VKA compared with AP/no therapy. METHODS: Five databases were searched including PubMed, Medline, Embase, Ovid and Cochrane for randomised clinical trials and observational studies comparing VKA (group I) versus AP/no therapy (group II). Outcome was after surgical intervention. Mantel-Haenszel odds ratio (OR) was calculated using random-effects meta-analysis for the outcome. Heterogeneity was assessed by I2 statistics. A total of 14 studies were included (two randomised trials, 12 observational studies and one conference abstract, 31 740 patients). RESULTS: Between groups I (VKA) and II (AP/no therapy), there were no differences in thromboembolic events (145 (1%) vs 262 (1.5%), OR 0.96 (95% CI 0.60 to 1.52)), all-cause mortality (351 (3.5%) vs 415 (2.9%), OR 1.48 (95% CI 0.87 to 2.50)) or need for redo surgery (47 (3.3%) vs 55 (3.2%); OR 0.81 (95% CI 0.42 to 1.58)). However, there were more bleeding events in group I versus group II (292 (2.6%) vs 189 (1.1%); OR 2.26 (95% CI 1.67 to 3.05)). CONCLUSIONS: In a meta-analysis of randomised and observational studies of VKA versus AP/no treatment in patients undergoing bioprosthetic valve implantation, there was no benefit of adding a VKA regarding thromboembolism or mortality. However, use of a VKA was associated with increased risk of major bleeding. PMID- 27487811 TI - Histone deacetylase inhibitors interfere with angiogenesis by decreasing endothelial VEGFR-2 protein half-life in part via a VE-cadherin-dependent mechanism. AB - Recent evidence suggests that histone deacetylase inhibitors (HDACi) may mediate part of their antitumor effects by interfering with tumor angiogenesis. As signalling via the vascular endothelial growth factor receptor-2 (VEGFR-2) pathway is critical for angiogenic responses during tumor progression, we explored whether established antitumor effects of HDACi are partly mediated through diminished endothelial VEGFR-2 expression. We therefore examined the potential impact of three different HDACi, trichostatin A (TSA), sodium butyrate (But) and valproic acid (VPA), on VEGFR-2 protein expression. TSA, VPA and But significantly inhibit VEGFR-2 protein expression in endothelial cells. Pertinent to these data, VEGFR-2 protein half-life is shown to be decreased in response to HDACi. Recently, it could be demonstrated that expression of VE-cadherin influences VEGFR-2 protein half-life. In our experiments, VEGFR-2 downregulation was accompanied by HDACi-induced VE-cadherin suppression. Interestingly, siRNA mediated knockdown of VE-cadherin led to a pronounced loss of VEGFR-2 expression on the protein as well as on the mRNA level, implicating that VE-cadherin not only influences VEGFR-2 protein half-life but also the transcriptional level. To further distinguish which of the eight different histone deacetylases are responsible for the regulation of VEGFR-2 expression, specific HDAC genes were silenced by transfecting respective siRNAs. These studies revealed that HDACs 1, 4, 5 and 6 are preferentially involved in VEGFR-2 expression. Therefore, these results provide an explanation for the anti-angiogenic action of HDAC inhibitors via a VE-cadherin, HDAC 1 and HDACs 4-6-mediated suppression of VEGFR-2 expression and might be of importance in the development of new anti-angiogenic drugs. PMID- 27487813 TI - Emotion: Exciting extinction. PMID- 27487812 TI - Thrombin Activable Fibrinolysis Inhibitor in Beta Thalassemia. AB - OBJECTIVES: To study plasma levels of Thrombin activable fibrinolysis inhibitor (TAFI) in children with beta-thalassemia major. METHODS: Fifty beta-thalassemia major patients, 1.4 to 17 y of age, with number of transfusions received varying from 21 to 162 were selected at random and complete blood count (CBC), coagulation parameters [Prothrombin time (PT), Activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, protein C, protein S, antithrombin, Tissue plasminogen activator (t-PA), Plasminogen activator inhibitor (PAI-1)] and TAFI were performed. RESULTS: PT and aPTT were prolonged in 18 % and 30 % of cases respectively. Reduced activity of Protein C (PC) was observed in 50 % of cases and Protein S (PS) was reduced in 54 % of cases. t-PA levels were significantly higher in cases. TAFI levels were 17.24 +/- 4.05 ng/ml which were significantly higher than the control group (15.01 +/- 3.28; p = 0.003) No significant correlation of TAFI was observed with Hb, platelet counts, liver enzymes, serum ferritin, PC, PS, D-dimer, t-PA or PAI-1. CONCLUSIONS: There is an ongoing subclinical activation of coagulation cascade and fibrinolytic system in thalassemia major (TM) patients. Higher levels of TAFI in the present study with no significant correlation with other parameters were noted, thus pointing out to its independent role in contribution to hypercoagulable state in thalassemia. TAFI serves as a link between two limbs of hemostasis, with its higher levels promoting inhibition of fibrinolytic system and thus promoting a hypercoagulable state. Performing TAFI levels in thalassemic patients could help to detect the early coagulopathy in these patients and hence these patients can be closely monitored for any evidence of thrombosis. PMID- 27487814 TI - Neuroimmunology: Social support from the immune system. PMID- 27487815 TI - Mechanistic insight on (E)-methyl 3-(2-aminophenyl)acrylate cyclization reaction by multicatalysis of solvent and substrate. AB - The reaction mechanism of (E)-methyl 3-(2-aminophenyl)acrylate (A) with phenylisothiocyanate (B) as well as the vital roles of substrate A and solvent water were investigated under unassisted, water-assisted, substrate A-assisted, and water-A-assisted conditions. The reaction proceeds with four processes via nucleophilic addition, deprotonation and protonation, intramolecular cyclization with hydrogen transfer, and keto-enol tautomerization. According to the different H-shift mode, two possible types of H-shift P1 and P2 are carefully investigated to identify the most preferred pathway, differing in the ?NH2 group deprotonation and ?CH group of A protonation processes. It is found that substrate A and water not only act as reactant and solvent, but also as catalyst, proton shuttle, and stabilizer in effectively lowering the energy barrier. Therefore, the results demonstrate that the strong donating and accepting ability of ?NH2 group on A and the presence of bulk water are the keys to the title reaction proceed. (c) 2016 Wiley Periodicals, Inc. PMID- 27487816 TI - Effect of Ginkgo Biloba Extract on the Pharmacokinetics and Metabolism of Clopidogrel in Rats. AB - Ginkgo biloba extract (GBE), a traditional herbal product used worldwide as both medicine and supplement, is often supplied with clopidogrel for the treatment of cerebrovascular diseases. The aim of the current study was to explore the effect of GBE on the metabolism and pharmacokinetics of clopidogrel. The in vitro study using rat liver microsomes revealed that GBE significantly induced the conversion of clopidogrel into its active metabolite. The effect of GBE on the pharmacokinetics of clopidogrel was also investigated in vivo. Compared to rats without GBE pretreatment, administration of 4 mg/kg, 20 mg/kg, and 100 mg/kg of GBE significantly decreased the Cmax and the AUC0-infinity of clopidogrel in a dose-dependent manner. As expected, pretreatment of high dose GBE significantly increased the Cmax and AUC0-infinity of the clopidogrel active metabolite. However, no marked change was observed following medium and low dose of GBE, suggesting that the biotransformation of clopidogrel was altered differently by high dose of GBE. Our study suggested that the awareness of the potential herb drug interactions between GBE and clopidogrel should be increased in clinical practice. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27487818 TI - Frequency-dependent selection: a diversifying force in microbial populations. PMID- 27487817 TI - Negative frequency-dependent interactions can underlie phenotypic heterogeneity in a clonal microbial population. AB - Genetically identical cells in microbial populations often exhibit a remarkable degree of phenotypic heterogeneity even in homogenous environments. Such heterogeneity is commonly thought to represent a bet-hedging strategy against environmental uncertainty. However, evolutionary game theory predicts that phenotypic heterogeneity may also be a response to negative frequency-dependent interactions that favor rare phenotypes over common ones. Here we provide experimental evidence for this alternative explanation in the context of the well studied yeast GAL network. In an environment containing the two sugars glucose and galactose, the yeast GAL network displays stochastic bimodal activation. We show that in this mixed sugar environment, GAL-ON and GAL-OFF phenotypes can each invade the opposite phenotype when rare and that there exists a resulting stable mix of phenotypes. Consistent with theoretical predictions, the resulting stable mix of phenotypes is not necessarily optimal for population growth. We find that the wild-type mixed strategist GAL network can invade populations of both pure strategists while remaining uninvasible by either. Lastly, using laboratory evolution we show that this mixed resource environment can directly drive the de novo evolution of clonal phenotypic heterogeneity from a pure strategist population. Taken together, our results provide experimental evidence that negative frequency-dependent interactions can underlie the phenotypic heterogeneity found in clonal microbial populations. PMID- 27487819 TI - Heel ulcers do heal in patients with diabetes. AB - A heel ulcer is considered to be a serious complication in patients with diabetes, and there is limited information regarding outcome. In most of the literature, a poor prognosis is described. The aim of this study was to investigate a large cohort of ulcers located in the heel in patients with diabetes. Seven hundred and sixty-eight patients [median age 73 (17-98)], presenting with a heel ulcer at a multidisciplinary diabetes foot clinic, fulfilled the inclusion criteria and were followed-up until final outcome. Fifty eight per cent of the patients healed primarily; 7% healed after major debridement; 9% healed after amputation and 25% died unhealed. Median healing time was 17 weeks. Ulcer progression was seen in 19% of patients. Thirty-one percent of patients had severe peripheral vascular disease. A creatinine level below 91 umol/l was related to a higher probability for healing without major debridement or amputation, whereas vascular surgery, nephropathy and oedema were related to a lower probability for healing without major debridement or amputation. Two thirds of heel ulcers do heal in patients with diabetes despite patients being elderly and with extensive comorbidity. The extent of peripheral vascular disease, nephropathy, oedema and decreased renal function are important factors influencing outcome. PMID- 27487820 TI - Surface expression of hippocampal NMDA GluN2B receptors regulated by fear conditioning determines its contribution to memory consolidation in adult rats. AB - The number and subtype composition of N-methyl-d-aspartate receptor (NMDAR) at synapses determines their functional properties and role in learning and memory. Genetically increased or decreased amount of GluN2B affects hippocampus-dependent memory in the adult brain. But in some experimental conditions (e.g., memory elicited by a single conditioning trial (1 CS-US)), GluN2B is not a necessary factor, which indicates that the precise role of GluN2B in memory formation requires further exploration. Here, we examined the role of GluN2B in the consolidation of fear memory using two training paradigms. We found that GluN2B was only required for the consolidation of memory elicited by five conditioning trials (5 CS-US), not by 1 CS-US. Strikingly, the expression of membrane GluN2B in CA1was training-strength-dependently increased after conditioning, and that the amount of membrane GluN2B determined its involvement in memory consolidation. Additionally, we demonstrated the increases in the activities of cAMP, ERK, and CREB in the CA1 after conditioning, as well as the enhanced intrinsic excitability and synaptic efficacy in CA1 neurons. Up-regulation of membrane GluN2B contributed to these enhancements. These studies uncover a novel mechanism for the involvement of GluN2B in memory consolidation by its accumulation at the cell surface in response to behavioral training. PMID- 27487821 TI - 2.4 A resolution crystal structure of human TRAP1NM, the Hsp90 paralog in the mitochondrial matrix. AB - TRAP1 is an organelle-specific Hsp90 paralog that is essential for neoplastic growth. As a member of the Hsp90 family, TRAP1 is presumed to be a general chaperone facilitating the late-stage folding of Hsp90 client proteins in the mitochondrial matrix. Interestingly, TRAP1 cannot replace cytosolic Hsp90 in protein folding, and none of the known Hsp90 co-chaperones are found in mitochondria. Thus, the three-dimensional structure of TRAP1 must feature regulatory elements that are essential to the ATPase activity and chaperone function of TRAP1. Here, the crystal structure of a human TRAP1NM dimer is presented, featuring an intact N-domain and M-domain structure, bound to adenosine 5'-beta,gamma-imidotriphosphate (ADPNP). The crystal structure together with epitope-mapping results shows that the TRAP1 M-domain loop 1 contacts the neighboring subunit and forms a previously unobserved third dimer interface that mediates the specific interaction with mitochondrial Hsp70. PMID- 27487822 TI - Structural basis for the binding of succinate to succinyl-CoA synthetase. AB - Succinyl-CoA synthetase catalyzes the only step in the citric acid cycle that provides substrate-level phosphorylation. Although the binding sites for the substrates CoA, phosphate, and the nucleotides ADP and ATP or GDP and GTP have been identified, the binding site for succinate has not. To determine this binding site, pig GTP-specific succinyl-CoA synthetase was crystallized in the presence of succinate, magnesium ions and CoA, and the structure of the complex was determined by X-ray crystallography to 2.2 A resolution. Succinate binds in the carboxy-terminal domain of the beta-subunit. The succinate-binding site is near both the active-site histidine residue that is phosphorylated in the reaction and the free thiol of CoA. The carboxy-terminal domain rearranges when succinate binds, burying this active site. However, succinate is not in position for transfer of the phosphoryl group from phosphohistidine. Here, it is proposed that when the active-site histidine residue has been phosphorylated by GTP, the phosphohistidine displaces phosphate and triggers the movement of the carboxylate of succinate into position to be phosphorylated. The structure shows why succinyl CoA synthetase is specific for succinate and does not react appreciably with citrate nor with the other C4-dicarboxylic acids of the citric acid cycle, fumarate and oxaloacetate, but shows some activity with L-malate. PMID- 27487823 TI - Crystal structure of the fluorescent protein from Dendronephthya sp. in both green and photoconverted red forms. AB - The fluorescent protein from Dendronephthya sp. (DendFP) is a member of the Kaede like group of photoconvertible fluorescent proteins with a His62-Tyr63-Gly64 chromophore-forming sequence. Upon irradiation with UV and blue light, the fluorescence of DendFP irreversibly changes from green (506 nm) to red (578 nm). The photoconversion is accompanied by cleavage of the peptide backbone at the C(alpha)-N bond of His62 and the formation of a terminal carboxamide group at the preceding Leu61. The resulting double C(alpha)=C(beta) bond in His62 extends the conjugation of the chromophore pi system to include imidazole, providing the red fluorescence. Here, the three-dimensional structures of native green and photoconverted red forms of DendFP determined at 1.81 and 2.14 A resolution, respectively, are reported. This is the first structure of photoconverted red DendFP to be reported to date. The structure-based mutagenesis of DendFP revealed an important role of positions 142 and 193: replacement of the original Ser142 and His193 caused a moderate red shift in the fluorescence and a considerable increase in the photoconversion rate. It was demonstrated that hydrogen bonding of the chromophore to the Gln116 and Ser105 cluster is crucial for variation of the photoconversion rate. The single replacement Gln116Asn disrupts the hydrogen bonding of Gln116 to the chromophore, resulting in a 30-fold decrease in the photoconversion rate, which was partially restored by a further Ser105Asn replacement. PMID- 27487824 TI - The 1.1 A resolution structure of a periplasmic phosphate-binding protein from Stenotrophomonas maltophilia: a crystallization contaminant identified by molecular replacement using the entire Protein Data Bank. AB - During efforts to crystallize the enzyme 2,4-dihydroxyacetophenone dioxygenase (DAD) from Alcaligenes sp. 4HAP, a small number of strongly diffracting protein crystals were obtained after two years of crystal growth in one condition. The crystals diffracted synchrotron radiation to almost 1.0 A resolution and were, until recently, assumed to be formed by the DAD protein. However, when another crystal form of this enzyme was eventually solved at lower resolution, molecular replacement using this new structure as the search model did not give a convincing solution with the original atomic resolution data set. Hence, it was considered that these crystals might have arisen from a protein impurity, although molecular replacement using the structures of common crystallization contaminants as search models again failed. A script to perform molecular replacement using MOLREP in which the first chain of every structure in the PDB was used as a search model was run on a multi-core cluster. This identified a number of prokaryotic phosphate-binding proteins as scoring highly in the MOLREP peak lists. Calculation of an electron-density map at 1.1 A resolution based on the solution obtained with PDB entry 2q9t allowed most of the amino acids to be identified visually and built into the model. A BLAST search then indicated that the molecule was most probably a phosphate-binding protein from Stenotrophomonas maltophilia (UniProt ID B4SL31; gene ID Smal_2208), and fitting of the corresponding sequence to the atomic resolution map fully corroborated this. Proteins in this family have been linked to the virulence of antibiotic-resistant strains of pathogenic bacteria and with biofilm formation. The structure of the S. maltophilia protein has been refined to an R factor of 10.15% and an Rfree of 12.46% at 1.1 A resolution. The molecule adopts the type II periplasmic binding protein (PBP) fold with a number of extensively elaborated loop regions. A fully dehydrated phosphate anion is bound tightly between the two domains of the protein and interacts with conserved residues and a number of helix dipoles. PMID- 27487825 TI - Fixed target combined with spectral mapping: approaching 100% hit rates for serial crystallography. AB - The advent of ultrafast highly brilliant coherent X-ray free-electron laser sources has driven the development of novel structure-determination approaches for proteins, and promises visualization of protein dynamics on sub-picosecond timescales with full atomic resolution. Significant efforts are being applied to the development of sample-delivery systems that allow these unique sources to be most efficiently exploited for high-throughput serial femtosecond crystallography. Here, the next iteration of a fixed-target crystallography chip designed for rapid and reliable delivery of up to 11 259 protein crystals with high spatial precision is presented. An experimental scheme for predetermining the positions of crystals in the chip by means of in situ spectroscopy using a fiducial system for rapid, precise alignment and registration of the crystal positions is presented. This delivers unprecedented performance in serial crystallography experiments at room temperature under atmospheric pressure, giving a raw hit rate approaching 100% with an effective indexing rate of approximately 50%, increasing the efficiency of beam usage and allowing the method to be applied to systems where the number of crystals is limited. PMID- 27487826 TI - TakeTwo: an indexing algorithm suited to still images with known crystal parameters. AB - The indexing methods currently used for serial femtosecond crystallography were originally developed for experiments in which crystals are rotated in the X-ray beam, providing significant three-dimensional information. On the other hand, shots from both X-ray free-electron lasers and serial synchrotron crystallography experiments are still images, in which the few three-dimensional data available arise only from the curvature of the Ewald sphere. Traditional synchrotron crystallography methods are thus less well suited to still image data processing. Here, a new indexing method is presented with the aim of maximizing information use from a still image given the known unit-cell dimensions and space group. Efficacy for cubic, hexagonal and orthorhombic space groups is shown, and for those showing some evidence of diffraction the indexing rate ranged from 90% (hexagonal space group) to 151% (cubic space group). Here, the indexing rate refers to the number of lattices indexed per image. PMID- 27487827 TI - RoboDiff: combining a sample changer and goniometer for highly automated macromolecular crystallography experiments. AB - Automation of the mounting of cryocooled samples is now a feature of the majority of beamlines dedicated to macromolecular crystallography (MX). Robotic sample changers have been developed over many years, with the latest designs increasing capacity, reliability and speed. Here, the development of a new sample changer deployed at the ESRF beamline MASSIF-1 (ID30A-1), based on an industrial six-axis robot, is described. The device, named RoboDiff, includes a high-capacity dewar, acts as both a sample changer and a high-accuracy goniometer, and has been designed for completely unattended sample mounting and diffraction data collection. This aim has been achieved using a high level of diagnostics at all steps of the process from mounting and characterization to data collection. The RoboDiff has been in service on the fully automated endstation MASSIF-1 at the ESRF since September 2014 and, at the time of writing, has processed more than 20 000 samples completely automatically. PMID- 27487828 TI - Structural basis for the extended substrate spectrum of AmpC BER and structure guided discovery of the inhibition activity of citrate against the class C beta lactamases AmpC BER and CMY-10. AB - AmpC BER is an extended substrate spectrum class C beta-lactamase with a two amino-acid insertion in the R2 loop compared with AmpC EC2. The crystal structures of AmpC BER (S64A mutant) and AmpC EC2 were determined. Structural comparison of the two proteins revealed that the insertion increases the conformational flexibility of the R2 loop. Two citrate molecules originating from the crystallization solution were observed in the active site of the S64A mutant. One citrate molecule makes extensive interactions with active-site residues that are highly conserved among class C beta-lactamases, whereas the other one is weakly bound. Based on this structural observation, it is demonstrated that citrate, a primary metabolite that is widely used as a food additive, is a competitive inhibitor of two class C beta-lactamases (AmpC BER and CMY-10). Consequently, the data indicate enhancement of the flexibility of the R2 loop as an operative strategy for molecular evolution of extended-spectrum class C beta lactamases, and also suggest that the citrate scaffold is recognized by the active sites of class C beta-lactamases. PMID- 27487829 TI - Progression of Metabolic Syndrome Severity During the Menopausal Transition. AB - BACKGROUND: After menopause, women exhibit a higher prevalence of the metabolic syndrome (MetS) and higher risk of cardiovascular disease. However, the timing of changes in MetS severity over the menopausal transition and whether these changes differ by racial/ethnic group remain unclear. METHODS AND RESULTS: We assessed data from 1470 women from the Atherosclerosis Risk in Communities cohort who experienced transition in menopausal status over 10 years (visits 1-4). We used linear mixed models to evaluate changes by menopausal status (premenopause, perimenopause, and postmenopause) in a MetS severity Z-score and in the individual MetS components. While there were gradual increases in MetS severity over time across menopause stages, black women in particular exhibited more rapid progression in MetS severity during the premenopausal and perimenopausal periods than during the postmenopausal period. In the postmenopausal period (compared with prior periods), white women exhibited unfavorable decreases in high-density lipoprotein, while black women exhibited favorable alterations in the rate of change for waist circumference, triglycerides, high-density lipoprotein, and glucose, contributing to the slowed progression of MetS severity. These changes were all observed after adjusting for hormone replacement treatment. CONCLUSIONS: During menopausal transition, women exhibited rapid increases in MetS severity during the premenopausal and perimenopausal periods, with black women having significant reductions in this increase in severity during the postmenopausal period. These data suggest that the higher prevalence of MetS in postmenopausal women may be caused more by changes during the menopausal transition than by postmenopause. These findings may thus have implications regarding the timing of cardiovascular risk relative to menopause. PMID- 27487830 TI - The morphology of the adrenal gland in the European bison (Bison bonasus). AB - BACKGROUND: The anatomy of the adrenal glands has been widely studied in many species of domestic and wild mammals. However, there are no available literature reports describing the morphology and morphometry of the adrenal glands of the European bison (Bison bonasus). RESULTS: The study was conducted on 97 European bison of both sexes. The growth of the adrenal glands corresponded to the growth of the whole body, with the largest increase in size occurring in the first 2 years of the animal's life, followed by a slower increase in size until the animal was 5-7 years old. There were no statistically significant differences between ipsilateral adrenal glands of males and females with respect to age. There was no statistically significant difference in weight between the left and the right adrenal gland. However, there was a difference in the length, width and thickness of the two glands. Reference intervals for adrenal gland size and weight were computed separately for two bison age groups (up to 2 years of age and older than two years). The adrenal gland consisted of a cortex and a medulla. The connective-tissue capsule contained two layers. It had a fibrous structure and abundant adipose tissue. The cortex was divided into three zones. The zona glomerulosa contained cells arranged in bundles and curves. Numerous apoptotic cells were observed among regular cells in the zona reticularis. There were vacuoles in the cells of both zona fasciculata and zona reticularis, which formed a foamy cytoplasm. The adrenal medulla was composed of large, dark cells with a highly basophilic cytoplasm in the superficial region and of smaller, lighter cells in deeper layers. Sinusoidal vessels were located in the central part of the medulla. CONCLUSIONS: The left adrenal gland was significantly longer, narrower and thinner than the right one. There were no significant differences in the structure of the adrenal medulla and cortex of the European bison compared to other species of domestic and wild mammals. There was a thick layer of adipose cells at numerous locations in the adrenal capsule of the bison. PMID- 27487831 TI - Human neuronal changes in brain edema and increased intracranial pressure. AB - Functional and molecular changes associated with pathophysiological conditions are relatively easily detected based on tissue samples collected from patients. Population specific cellular responses to disease might remain undiscovered in samples taken from organs formed by a multitude of cell types. This is particularly apparent in the human cerebral cortex composed of a yet undefined number of neuron types with a potentially different involvement in disease processes. We combined cellular electrophysiology, anatomy and single cell digital PCR in human neurons identified in situ for the first time to assess mRNA expression and corresponding functional changes in response to edema and increased intracranial pressure. In single pyramidal cells, mRNA copy numbers of AQP1, AQP3, HMOX1, KCNN4, SCN3B and SOD2 increased, while CACNA1B, CRH decreased in edema. In addition, single pyramidal cells increased the copy number of AQP1, HTR5A and KCNS1 mRNAs in response to increased intracranial pressure. In contrast to pyramidal cells, AQP1, HMOX1and KCNN4 remained unchanged in single cell digital PCR performed on fast spiking cells in edema. Corroborating single cell digital PCR results, pharmacological and immunohistochemical results also suggested the presence of KCNN4 encoding the alpha-subunit of KCa3.1 channels in edema on pyramidal cells, but not on interneurons. We measured the frequency of spontaneous EPSPs on pyramidal cells in both pathophysiological conditions and on fast spiking interneurons in edema and found a significant decrease in each case, which was accompanied by an increase in input resistances on both cell types and by a drop in dendritic spine density on pyramidal cells consistent with a loss of excitatory synapses. Our results identify anatomical and/or physiological changes in human pyramidal and fast spiking cells in edema and increased intracranial pressure revealing cell type specific quantitative changes in gene expression. Some of the edema/increased intracranial pressure modulated and single human pyramidal cell verified gene products identified here might be considered as novel pharmacological targets in cell type specific neuroprotection. PMID- 27487832 TI - Evaluation of a quantitative measurement of suprapatellar effusion by ultrasonography and its association with symptoms of radiographic knee osteoarthritis: a cross-sectional observational study. AB - BACKGROUND: Quantitative measurement of knee joint effusion by ultrasonography has not been well established; however, a categorical measurement (e.g., a >=4-mm deep suprapatellar pouch) is recommended. Therefore, the current study aimed to elucidate the association between symptoms of knee osteoarthritis (OA) and the quantitative measurement of suprapatellar effusion by ultrasonography. METHODS: One hundred twenty-seven volunteers participated (31 men and 96 women; mean age: 68.3 +/- 9.8 years; body mass index: 23.2 +/- 3.0 kg/m(2)). The Kellgren-Lawrence grades (KLGs) of both knees were assessed; all subjects had definitive osteoarthritic change (KLG >=2) in both knee joints. Joint effusion was evaluated using an ultrasound probe, which was placed longitudinally on the suprapatellar pouch, and we determined the area (mm(2)) of the echo-free space. Then we summed the effusion area of both knees. All subjects answered the knee injury and osteoarthritis outcome scale (KOOS) questionnaire. Multiple linear regression analysis was conducted to elucidate the association between the summed value of the knee effusion area and the KOOS subscales, which were adjusted by age, sex, body mass index, and KLG. RESULTS: Of 254 knees, 180 were KLG 2, 57 were KLG 3, and 17 were KLG 4. The multiple regression models showed that the quantitative knee effusion area significantly correlated with the following KOOS subscales: pain (B = -0.057; beta = -0.253; P = 0.002), symptom (B = -0.053; beta = -0.251; P = 0.002), sport and recreation (B = -0.069; beta = -0.205; P = 0.007), and quality of life (B = -0.083; beta = -0.276; P = 0.001). CONCLUSION: In this cross sectional study, the quantitative measurement of suprapatellar effusion by ultrasonography was associated with symptoms of radiographic knee OA. PMID- 27487833 TI - Towards human-controlled, real-time shape sensing based flexible needle steering for MRI-guided percutaneous therapies. AB - BACKGROUND: Accurate needle placement into soft tissue is essential to percutaneous prostate cancer diagnosis and treatment procedures. METHODS: This paper discusses the steering of a 20 gauge (G) FBG-integrated needle with three sets of Fiber Bragg Grating (FBG) sensors. A fourth-order polynomial shape reconstruction method is introduced and compared with previous approaches. To control the needle, a bicycle model based navigation method is developed to provide visual guidance lines for clinicians. A real-time model updating method is proposed for needle steering inside inhomogeneous tissue. A series of experiments were performed to evaluate the proposed needle shape reconstruction, visual guidance and real-time model updating methods. RESULTS: Targeting experiments were performed in soft plastic phantoms and in vitro tissues with insertion depths ranging between 90 and 120 mm. Average targeting errors calculated based upon the acquired camera images were 0.40 +/- 0.35 mm in homogeneous plastic phantoms, 0.61 +/- 0.45 mm in multilayer plastic phantoms and 0.69 +/- 0.25 mm in ex vivo tissue. CONCLUSIONS: Results endorse the feasibility and accuracy of the needle shape reconstruction and visual guidance methods developed in this work. The approach implemented for the multilayer phantom study could facilitate accurate needle placement efforts in real inhomogeneous tissues. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27487834 TI - The Changing Political Undercurrents in Health Services Delivery in Sub-Saharan Africa. AB - This article reviews the changing political undercurrent in health service delivery in Sub-Saharan Africa, chronicling the ideological shift in orientation toward neoliberalism in the health sector, an ideology crafted and introduced into Sub-Saharan Africa by the International Monetary Fund and the World Bank. The article examines the implication of this neoliberal reform on the efficiency in health care provision and on the quality and accessibility of health services by the poor and vulnerable. Drawing inference from countries like Nigeria, the authors argue that the ascendency of neoliberalism in the health systems of Sub Saharan Africa has engendered unethical practices and introduced elements of moral hazard in the health sector, reducing the incentive for governments to develop effective service delivery over the long term. The authors therefore advocate for a rejection of neoliberal ideology in favor of a universal coverage principle if an inclusive health system is to be developed. PMID- 27487835 TI - The History and Future of Neoliberal Health Reform: Obamacare and Its Predecessors. AB - The Colombian reform of 1994, through a strange historical sequence, became a model for health reform in Latin America, Europe, and the United States. Officially, the reform aimed to improve access for the uninsured and underinsured, in collaboration with the private, for-profit insurance industry. After several historical attempts at health reform adhering to the neoliberal pattern, favored by international financial institutions and multinational insurance corporations, the Affordable Care Act (ACA) similarly enhanced access by corporations to public-sector trust funds. An ideology favoring for-profit corporations in the marketplace justified these reforms through unproven claims about the efficiency of the private sector and enhanced quality of care under principles of competition and business management. The ACA maintains this historical continuity by dealing with health care as a commodity bought and sold in a marketplace, rather than a fundamental human right to be guaranteed according to principles of social solidarity. As the ACA heads toward probable failure, a space finally will open for a U.S. national health program that does not follow same historical patterns of the neoliberal model. PMID- 27487836 TI - Health Promotion and Education: A Study of the Effectiveness of Programs Focusing on the Aging Process. AB - Considering the population aging and the failure of biologistic and hospital based treatment model, health promotion programs based on scientific evidence are necessary. A comprehensive review of literature was performed, aiming to identify and analyze health promotion and education experiments focused on the aging process. Papers published in eight databases, together with the database of the Pan-American Health Organization, were selected based on review of titles and abstracts, followed by a full text review conducted by two independent reviewers. A total of 22 studies were included, the majority of which adopted a quantitative approach, with a sample larger than 100 elderly or pre-retirement individuals. The majority of studies reported positive results in terms of health promotion and education. One study obtained minimum improvement and one reported that no statistically significant improvement had occurred. The positive effects most indicated by authors were: general or self-perceived improvement in physical health, improvement in psychosocial aspects and in relation to the aging process, improvement in adherence to preventative actions and in healthy conduct and lifestyle, increase in level of physical activity, improvement in quality of life and/or physical well-being, and improvement in activities of daily living or reduction of the risk of developing disabilities. PMID- 27487837 TI - Minimally invasive approach for percutaneous CentriMag right ventricular assist device support using a single PROTEKDuo Cannula. AB - BACKGROUND: Right ventricular failure is a serious complication after left ventricular assist device placement. CASE PRESENTATION: A 70-year-old male in decompensated heart failure with right ventricular failure after the placement of a left ventricular assist device. A single dual-lumen PROTEKDuo cannula was inserted percutaneously via the internal jugular vein to draw blood from the right atrium and return into the pulmonary artery using the CentriMag system, by passing the failing ventricle. The patient was successfully weaned from right ventricular assist device. CONCLUSIONS: In comparison to two-cannula conventional procedures, this right ventrivular assist device system improves patient rehabilitation and minimizes blood loss and risk of infection, while shortening procedure time and improving clinical outcomes in right ventricular failure. PMID- 27487838 TI - Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy. AB - Doxorubicin (DOX) is an effective anti-cancer agent. However, DOX treatment increases patient susceptibility to dilated cardiomyopathy. DOX predisposes cardiomyocytes to insult by suppressing mitochondrial energy metabolism, altering calcium flux, and disrupting proteolysis and proteostasis. Prior studies have assessed the role of macroautophagy in DOX cardiotoxicity; however, limited studies have examined whether DOX mediates cardiac injury through dysfunctions in inter- and/or intra-lysosomal signaling events. Lysosomal signaling and function is governed by transcription factor EB (TFEB). In the present study, we hypothesized that DOX caused myocyte injury by impairing lysosomal function and signaling through negative regulation of TFEB. Indeed, we found that DOX repressed cellular TFEB expression, which was associated with impaired cathepsin proteolytic activity across in vivo, ex vivo, and in vitro models of DOX cardiotoxicity. Furthermore, we observed that loss of TFEB was associated with reduction in macroautophagy protein expression, inhibition of autophagic flux, impairments in lysosomal cathepsin B activity, and activation of cell death. Restoration and/or activation of TFEB in DOX-treated cardiomyocytes prevented DOX induced suppression of cathepsin B activity, reduced DOX-mediated reactive oxygen species (ROS) overproduction, attenuated activation of caspase-3, and improved cellular viability. Collectively, loss of TFEB inhibits lysosomal autophagy, rendering cardiomyocytes susceptible to DOX-induced proteotoxicity and injury. Our data reveal a novel mechanism wherein DOX primes cardiomyocytes for cell death by depleting cellular TFEB. PMID- 27487839 TI - Two independent evolutionary routes to Na+/H+ cotransport function in membrane pyrophosphatases. AB - Membrane-bound pyrophosphatases (mPPases) hydrolyze pyrophosphate (PPi) to transport H(+), Na(+) or both and help organisms to cope with stress conditions, such as high salinity or limiting nutrients. Recent elucidation of mPPase structure and identification of subfamilies that have fully or partially switched from Na(+) to H(+) pumping have established mPPases as versatile models for studying the principles governing the mechanism, specificity and evolution of cation transporters. In the present study, we constructed an accurate phylogenetic map of the interface of Na(+)-transporting PPases (Na(+)-PPases) and Na(+)- and H(+)-transporting PPases (Na(+),H(+)-PPases), which guided our experimental exploration of the variations in PPi hydrolysis and ion transport activities during evolution. Surprisingly, we identified two mPPase lineages that independently acquired physiologically significant Na(+) and H(+) cotransport function. Na(+),H(+)-PPases of the first lineage transport H(+) over an extended [Na(+)] range, but progressively lose H(+) transport efficiency at high [Na(+)]. In contrast, H(+)-transport by Na(+),H(+)-PPases of the second lineage is not inhibited by up to 100 mM Na(+) With the identification of Na(+),H(+)-PPase subtypes, the mPPases protein superfamily appears as a continuum, ranging from monospecific Na(+) transporters to transporters with tunable levels of Na(+) and H(+) cotransport and further to monospecific H(+) transporters. Our results lend credence to the concept that Na(+) and H(+) are transported by similar mechanisms, allowing the relative efficiencies of Na(+) and H(+) transport to be modulated by minor changes in protein structure during the course of adaptation to a changing environment. PMID- 27487840 TI - Phosphorylation of the dimeric cytoplasmic domain of the phytosulfokine receptor, PSKR1. AB - Phytosulfokines (PSKs) are plant peptide hormones that co-regulate plant growth, differentiation and defense responses. PSKs signal through a plasma membrane localized leucine-rich repeat receptor-like kinase (phytosulfokine receptor 1, PSKR1) that also contains a functional cytosolic guanylate cyclase with its cyclase catalytic center embedded within the kinase domain. To functionally characterize this novel type of overlapping dual catalytic function, we investigated the phosphorylation of PSKR1 in vitro Tandem mass spectrometry of the cytoplasmic domain of PSKR1 (PSKR1cd) revealed at least 11 phosphorylation sites (8 serines, 2 threonines and 1 tyrosine) within the PSKR1cd. Phosphomimetic mutations of three serine residues (Ser686, Ser696 and Ser698) in tandem at the juxta-membrane position resulted in enhanced kinase activity in the on-mutant that was suppressed in the off-mutant, but both mutations reduced guanylate cyclase activity. Both the on and off phosphomimetic mutations of the phosphotyrosine (Tyr888) residue in the activation loop suppressed kinase activity, while neither mutation affected guanylate cyclase activity. Size exclusion and analytical ultracentrifugation analysis of the PSKR1cd suggest that it is reversibly dimeric in solution, which was further confirmed by biflourescence complementation. Taken together, these data suggest that in this novel type of receptor domain architecture, specific phosphorylation and dimerization are possibly essential mechanisms for ligand-mediated catalysis and signaling. PMID- 27487842 TI - An extension of generalized pairwise comparisons for prioritized outcomes in the presence of censoring. AB - Generalized pairwise comparisons have been proposed to permit a comprehensive assessment of several prioritized outcomes between two groups of observations. This procedure estimates Delta, the net chance of a better outcome with treatment than with control by comparing the patients outcomes among all possible pairs taking one patient from the treatment group and one patient from the control group. For time to event outcomes, the standard procedure of generalized pairwise comparisons is analogous to the Gehan's modification of the Mann-Whitney test which is biased in presence of censored observation and less powerful than Efron's modification of this test. We adapt Efron's modification to generalized pairwise comparisons. We show how a pairwise contribution to Delta can be calculated from the estimates of the survival function in the presence of right censored data. We performed a simulation study to assess the bias, the type I error and the power of the new procedure. The estimate of Delta with the new procedure is only slightly biased even in presence of heavy censoring. We also show how this bias can be corrected when only one time-to-event outcome is analyzed. The new procedure has higher power in most cases compared to the standard procedure. PMID- 27487841 TI - Lactobacillus oligofermentans glucose, ribose and xylose transcriptomes show higher similarity between glucose and xylose catabolism-induced responses in the early exponential growth phase. AB - BACKGROUND: Lactobacillus oligofermentans has been mostly isolated from cold stored packaged meat products in connection with their spoilage, but its precise role in meat spoilage is unknown. It belongs to the L. vaccinostercus group of obligate heterofermentative lactobacilli that generally ferment pentoses (e.g. xylose and ribose) more efficiently than hexoses (e.g. glucose). However, more efficient hexose utilization can be induced. The regulation mechanisms of the carbohydrate catabolism in such bacteria have been scarcely studied. To address this question, we provided the complete genome sequence of L. oligofermentans LMG 22743(T) and generated time course transcriptomes during its growth on glucose, ribose and xylose. RESULTS: The genome was manually annotated and its main functional features were examined. L. oligofermentans was confirmed to be able to efficiently utilize several hexoses and maltose, which is, presumably, induced by its repeated cultivation with glucose in vitro. Unexpectedly, in the beginning of the exponential growth phase, glucose- and xylose-induced transcriptome responses were more similar, whereas toward the end of the growth phase xylose and ribose transcriptomes became more alike. The promoter regions of genes simultaneously upregulated both on glucose and xylose in comparison with ribose (particularly, hexose and xylose utilization genes) were found to be enriched in the CcpA- binding site. Transcriptionally, no glucose-induced carbon catabolite repression was detected. The catabolism of glucose, which requires initial oxidation, led to significant overexpression of the NAD(P)H re-oxidation genes, the upstream regions of which were found to contain a motif, which was highly similar to a Rex repressor binding site. CONCLUSIONS: This paper presents the second complete genome and the first study of carbohydrate catabolism-dependent transcriptome response for a member of the L. vaccinostercus group. The transcriptomic changes detected in L. oligofermentans for growth with different carbohydrates differ significantly from those of facultative heterofermentative lactobacilli. The mechanism of CcpA regulation, putatively contributing to the observed similarities between glucose- and xylose-induced transcriptome responses and the absence of stringent carbon catabolite control, requires further studies. Finally, the cell redox balance maintenance, in terms of the NAD(P)+/NAD(P)H ratio, was predicted to be regulated by the Rex transcriptional regulator, supporting the previously made inference of Rex-regulons for members of the Lactobacillaceae family. PMID- 27487843 TI - An overview of methods for network meta-analysis using individual participant data: when do benefits arise? AB - Network meta-analysis (NMA) is a common approach to summarizing relative treatment effects from randomized trials with different treatment comparisons. Most NMAs are based on published aggregate data (AD) and have limited possibilities for investigating the extent of network consistency and between study heterogeneity. Given that individual participant data (IPD) are considered the gold standard in evidence synthesis, we explored statistical methods for IPD NMA and investigated their potential advantages and limitations, compared with AD NMA. We discuss several one-stage random-effects NMA models that account for within-trial imbalances, treatment effect modifiers, missing response data and longitudinal responses. We illustrate all models in a case study of 18 antidepressant trials with a continuous endpoint (the Hamilton Depression Score). All trials suffered from drop-out; missingness of longitudinal responses ranged from 21 to 41% after 6 weeks follow-up. Our results indicate that NMA based on IPD may lead to increased precision of estimated treatment effects. Furthermore, it can help to improve network consistency and explain between-study heterogeneity by adjusting for participant-level effect modifiers and adopting more advanced models for dealing with missing response data. We conclude that implementation of IPD-NMA should be considered when trials are affected by substantial drop-out rate, and when treatment effects are potentially influenced by participant-level covariates. PMID- 27487844 TI - Meta-analysis for the comparison of two diagnostic tests to a common gold standard: A generalized linear mixed model approach. AB - Meta-analysis of diagnostic studies is still a rapidly developing area of biostatistical research. Especially, there is an increasing interest in methods to compare different diagnostic tests to a common gold standard. Restricting to the case of two diagnostic tests, in these meta-analyses the parameters of interest are the differences of sensitivities and specificities (with their corresponding confidence intervals) between the two diagnostic tests while accounting for the various associations across single studies and between the two tests. We propose statistical models with a quadrivariate response (where sensitivity of test 1, specificity of test 1, sensitivity of test 2, and specificity of test 2 are the four responses) as a sensible approach to this task. Using a quadrivariate generalized linear mixed model naturally generalizes the common standard bivariate model of meta-analysis for a single diagnostic test. If information on several thresholds of the tests is available, the quadrivariate model can be further generalized to yield a comparison of full receiver operating characteristic (ROC) curves. We illustrate our model by an example where two screening methods for the diagnosis of type 2 diabetes are compared. PMID- 27487845 TI - Hepatitis B infection awareness, vaccine perceptions and uptake, and serological profile of a group of health care workers in Yaounde, Cameroon. AB - BACKGROUND: Cameroon is one of the countries in Africa with the highest burden of Hepatitis B infection. Health care workers are known to be at risk of occupational exposure to blood and other infectious bodily fluids. The aim of this study was to assess the profile of serological markers of hepatitis B virus (HBV) infection, knowledge and perceptions regarding HBV infection among health care workers in a health area in Yaounde. METHODS: A cross-sectional study was conducted in the Mvog-Ada Health Area of the Djoungolo Health District from March 1 to November 31, 2014. All consenting health care workers were included in the study. Serological markers of HBV (HBs Ag, Hbe Ag, anti-HBs Ab, anti-HBe Ab, anti HBc Ab) were qualitatively tested using Biotech(r)(OneHBV-5 parameter rapid test website) in each participant and the anti-HBs antibodies were quantified by ELISA (Biorex) among those who were positive with the qualitative test. Chi square test or its equivalents were used to compare qualitative variables and a p-value less than or equal to 0.05 was considered significant. RESULT: A total of 100 participants were retained for the study out of 163 in the health area giving a response rate of 61.34 %; the mean age was 30.5 (SD 6.8) years and 71 % of participants were women. Forty seven percent (47 %) of workers had good level of knowledge of HBV infection. The men were 3.20 times (95 % CI: 1.02-9.19, p = 0.04) more likely to have a good level of knowledge than women. Participants with a university study level were more (95 % CI: 3.17-25, p < 0.0001) likely to have a good level of knowledge than those with a high school study level. Ninety-six percent of participants thought that they were at a greater risk of becoming infected with HBV than the general population, 93 % felt that the vaccine should be compulsory and all (100 %) were willing to recommend it to others. However, only 19 % had received at least one dose of the vaccine. The proportion of HBs Ag was 11 %. The different serological profiles with regard to HBV infection were naive subjects (62 %), chronic carriers (11 %), vaccinated (19 %) and subjects naturally immunized (8 %). Three out of the 19 participants who received at least one dose of the vaccine, only 9 (47.4 %) of whom had titers >=100 IU/l indicating a good response to vaccination. Among those who received three doses of the vaccine (n = 12, 63 %), 2 (16, 66 %) had poor response to vaccination (HBs Ab titers < 100 IU/l). CONCLUSION: The prevalence of HBs Ag among health care workers in the Mvog-Ada Health Area is high (11 %). These workers are at high risk of HBV infection because of very low vaccine uptake and poor post-exposure practices. Their knowledge of HBV infection is non-optimal. PMID- 27487846 TI - Nuclear internal transcribed spacer-1 as a sensitive genetic marker for environmental DNA studies in common carp Cyprinus carpio. AB - The recently developed environmental DNA (eDNA) analysis has been used to estimate the distribution of aquatic vertebrates by using mitochondrial DNA (mtDNA) as a genetic marker. However, mtDNA markers have certain drawbacks such as variable copy number and maternal inheritance. In this study, we investigated the potential of using nuclear DNA (ncDNA) as a more reliable genetic marker for eDNA analysis by using common carp (Cyprinus carpio). We measured the copy numbers of cytochrome b (CytB) gene region of mtDNA and internal transcribed spacer 1 (ITS1) region of ribosomal DNA of ncDNA in various carp tissues and then compared the detectability of these markers in eDNA samples. In the DNA extracted from the brain and gill tissues and intestinal contents, CytB was detected at 95.1 +/- 10.7 (mean +/- 1 standard error), 29.7 +/- 1.59 and 24.0 +/- 4.33 copies per cell, respectively, and ITS1 was detected at 1760 +/- 343, 2880 +/- 503 and 1910 +/- 352 copies per cell, respectively. In the eDNA samples from mesocosm, pond and lake water, the copy numbers of ITS1 were about 160, 300 and 150 times higher than those of CytB, respectively. The minimum volume of pond water required for quantification was 33 and 100 mL for ITS1 and CytB, respectively. These results suggested that ITS1 is a more sensitive genetic marker for eDNA studies of C. carpio. PMID- 27487847 TI - Left-sided pancreatic incidentalomas treated with laparoscopic approach: a report of 20 cases. AB - BACKGROUND: The diffusion of cross-sectional imaging has recently permitted the detection of an increasing number of incidentalomas localized in the distal pancreas. Currently, there are no studies in the literature exploring the laparoscopic approach as treatment for left-sided pancreatic incidentalomas. METHODS AND RESULTS: We report a series of 20 incidentalomas localized in the body and tail of the pancreas treated with laparoscopic surgery over the period 2010-2014. The incidental masses of our series included a great variety of histotypes and a relevant proportion of malignant lesions. In two cases, the laparoscopic procedures were converted to open surgery. No postoperative death was observed. The postoperative pancreatic fistula rate was 20 %, and the new onset diabetes rate was 25 %. CONCLUSIONS: Left-sided pancreatic incidentalomas in patients with minor comorbidities can be safely treated with laparoscopic approach. Only clinical trials will confirm whether laparoscopic surgery is an effective treatment for malignant lesions. PMID- 27487848 TI - Determination of knowledge levels, attitude and behaviors of female university students concerning cervical cancer, human papiloma virus and its vaccine. AB - BACKGROUND: The purpose of the study is to investigate knowledge, attitudes and behaviours concerning cervical cancer, HPV and HPV vaccine of female students studying at a university in a health related department and explore variables affecting taking the vaccine. METHODS: The research group consists of female students attending a health related department in Balikesir University. The data of this cross-sectional research was collected via surveys. RESULTS: The average total knowledge score of the students concerning risks, symptoms and screening methods of cervical cancer and HPV vaccines was 14.15 +/- 6.7. The HPV knowledge score of the students attending the faculty of medicine was higher compared to the students attending other departments and their HPV vaccine knowledge score was higher compared to the students attending nursing and paramedics students. The HPV vaccine knowledge score of the students attending the department of midwifery was significantly higher compared to other students. Only 0.9 % of the students took the vaccine. One third of the students who did not take the vaccine did not know that the vaccine was available in our country. In terms of the department that they attended, the students with a higher total knowledge score compared to the average (OR:1.5) and students with history of cancer in their families (OR:1.6) were more likely to consider taking the vaccine. CONCLUSIONS: Research group's knowledge on risk factors of cervical cancer, Pap smear test, symptoms and prevention ways of cancer, HPV and HPV vaccine was low. PMID- 27487849 TI - Nutritional assessment and post-procedural complications in older stroke patients after insertion of percutaneous endoscopic gastrostomy - a retrospective study. AB - BACKGROUND: Oropharyngeal dysphagia is one of the major complications of stroke and a risk factor for malnutrition and prolonged in-hospital stay. OBJECTIVE: The overall aim was to describe to what extent nutritional assessments (i.e. BMI kg/m(2), eating problem, and weight loss) were performed and documented in the records of older stroke patients treated with enteral nutrition by percutaneous endoscopic gastrostomy (PEG). A secondary aim was to identify documented post procedural complications after PEG insertion during hospital stay. DESIGN: The study is retrospective. Data were collected from records of 161 stroke patients >=65 years, who received PEG, admitted to three stroke units during a 4-year period. RESULTS: Mean age of the patients was 82.2 (+/-7) years, and 86% of the patients were >=75 years old. On admission, body weight was documented in 50% of the patients and at discharge in 38% of the patients. BMI data were not documented at all at discharge in one of the units. Almost 80% of the patients fulfilled the European Network criteria for multimorbidity. Morbidity and multimorbidity correlated to the length of stay (p<0.0005). Complications were reported in 111 (69%) of the patient records. In 53 patients (33%) more than one complication was reported. A total of 116 pressure ulcers were reported and 30 patients had more than one pressure ulcer. The number of complications was related to weight loss (p=0.046) and BMI change (p=0.018). CONCLUSIONS: Essential information of the patient's nutritional status was poorly recorded which could affect the patient's nutritional treatment during the hospital stay. This study indicates that implementation of guidelines in patients with stroke is needed. The high number of pressure ulcers was an unexpected finding. PMID- 27487850 TI - Low-molecular-weight fucoidan and high-stability fucoxanthin from brown seaweed exert prebiotics and anti-inflammatory activities in Caco-2 cells. AB - BACKGROUND: The aim of this study is to investigate the anti-inflammatory effects of low-molecular-weight fucoidan (LMF) and high-stability fucoxanthin (HS-Fucox) in a lipopolysaccharide-induced inflammatory Caco-2 cell line co-culture with B. lactis. METHODS: We used various methods such as transepithelial resistance (TER) assay, cytokine secretion assay, and tight junction protein mRNA expression assay to examine LMF and HS-Fucox anti-inflammatory properties. RESULTS: LMF and HS Fucox activated probiotic growth and reduced the inflammation of the intestinal epithelial cells. Moreover, the combination of LMFHS-Fucox dramatically enhanced the intestinal epithelial barrier and immune function against the lipopolysaccharide effect by inhibiting IL-1beta and TNF-alpha and promoting IL 10 and IFN-gamma. CONCLUSION: These findings suggested that LMF and HS-Fucox, alone or in combination, could be the potential natural compounds to enhance the immune system and have an anti-inflammatory effect on the intestinal cells. PMID- 27487851 TI - Human Fetuin-A Rs4918 Polymorphism and its Association with Obesity in Healthy Persons and in Patients with Myocardial Infarction in Two Hungarian Cohorts. AB - BACKGROUND Human fetuin A (AHSG) has been associated with the development of obesity, insulin resistance, type 2 diabetes mellitus, and atherosclerosis. Observations on the role of AHSG rs4918 single-nucleotide polymorphism are contradictory. We investigated the association between variants of rs4918 and parameters of obesity, lipid status, tumor necrosis factor-alpha (TNFalpha), adipokines (adiponectin, resistin, leptin), and insulin resistance in healthy persons and in patients with previous myocardial infarction. MATERIAL AND METHODS This was a cross-sectional study comprising cohort 1 (81 healthy individuals) and cohort 2 (157 patients with previous myocardial infarction). We used the allele specific KASP genotyping assay to detect rs4918 polymorphism. RESULTS In cohort 1, G-nucleotide carriers had significantly lower serum TNFalpha, adiponectin, and higher leptin concentrations than in non-G carriers. These differences, however, were not observed in cohort 2. In cohort 2, G-carriers had lower BMI and waist circumferences than in non-G carriers. The G allele was more frequent among lean than obese patients (RR=1.067, 95%CI=1.053-2.651, p=0.015). An association between BMI and rs4918 polymorphism was observed among patients without diabetes (CC/CG/GG genotypes: p=0.003, G vs. non-G allele: p=0.008) but not in diabetics. In addition, a strong linearity between BMI and the CC/CG/GG genotypes (association value: 4.416, p=0.036) and the frequency of the G allele (7.420, p=0.006) could be identified. In cohort 2, non-obese, non-diabetic G-carriers still had lower BMI and waist circumferences than in non-G carriers. CONCLUSIONS The rs4918 minor variant is associated with lower TNFalpha and adiponectin, higher leptin levels in healthy persons, and more favorable anthropomorphic parameters of obesity in cohort 2. PMID- 27487853 TI - Ocular complications in HIV positive patients on antiretroviral therapy in Ghana. AB - BACKGROUND: Patients infected with human immunodeficiency virus (HIV) usually develop some form of ocular complication in the different segments of the eye due to immune deficiency. In Ghana, data regarding ocular complications among HIV/AIDS patients is scarce. This study investigated the occurrence of ocular complications in HIV infected patients undergoing antiretroviral therapy at the Agogo Presbyterian Hospital in the Ashanti Region of Ghana. METHODS: Blood samples were taken from 100 confirmed HIV infected patients. The CD4 + T cell count and WHO clinical staging were determined. The patients were taken through thorough ophthalmic assessments to determine any ocular complications. RESULTS: Forty-eight patients (48 %) had at least one HIV-related ocular complication. These complications occurred more frequently among those with CD4 counts below 200 cells/MUL. Of the participants with HIV-related ocular complications, 11 (23 %) had retinal microvasculopathy, 10 (21 %) showed allergic conjunctivitis, 7 (15 %) had HIV retinopathy and 7 (15 %) had conjunctival carcinoma. All the participants in the study were on first-line antiretroviral therapy; 68 % were females and 72 % were in the Stage 3 of the WHO Clinical Staging of HIV infection. CONCLUSION: The prevalence of ocular complications in HIV positive persons under treatment in Ghana is high. Lower CD4 + T cell counts coupled with age were predisposing factors to HIV-related ocular complications. PMID- 27487852 TI - The use of digital PCR to improve the application of quantitative molecular diagnostic methods for tuberculosis. AB - BACKGROUND: Real-time PCR (qPCR) based methods, such as the Xpert MTB/RIF, are increasingly being used to diagnose tuberculosis (TB). While qualitative methods are adequate for diagnosis, the therapeutic monitoring of TB patients requires quantitative methods currently performed using smear microscopy. The potential use of quantitative molecular measurements for therapeutic monitoring has been investigated but findings have been variable and inconclusive. The lack of an adequate reference method and reference materials is a barrier to understanding the source of such disagreement. Digital PCR (dPCR) offers the potential for an accurate method for quantification of specific DNA sequences in reference materials which can be used to evaluate quantitative molecular methods for TB treatment monitoring. METHODS: To assess a novel approach for the development of quality assurance materials we used dPCR to quantify specific DNA sequences in a range of prototype reference materials and evaluated accuracy between different laboratories and instruments. The materials were then also used to evaluate the quantitative performance of qPCR and Xpert MTB/RIF in eight clinical testing laboratories. RESULTS: dPCR was found to provide results in good agreement with the other methods tested and to be highly reproducible between laboratories without calibration even when using different instruments. When the reference materials were analysed with qPCR and Xpert MTB/RIF by clinical laboratories, all laboratories were able to correctly rank the reference materials according to concentration, however there was a marked difference in the measured magnitude. CONCLUSIONS: TB is a disease where the quantification of the pathogen could lead to better patient management and qPCR methods offer the potential to rapidly perform such analysis. However, our findings suggest that when precisely characterised materials are used to evaluate qPCR methods, the measurement result variation is too high to determine whether molecular quantification of Mycobacterium tuberculosis would provide a clinically useful readout. The methods described in this study provide a means by which the technical performance of quantitative molecular methods can be evaluated independently of clinical variability to improve accuracy of measurement results. These will assist in ultimately increasing the likelihood that such approaches could be used to improve patient management of TB. PMID- 27487854 TI - Risk Factors for Stroke among Young-Old and Old-Old Community-Dwelling Adults in Japan: The Ohasama Study. AB - AIM: Few studies have addressed stroke risk factors in older populations, particularly among the old-old. We examined differences in traditional risk factors for stroke among the old-old compared with the young-old in community dwelling Japanese adults. METHODS: We followed 2,065 residents aged >= 60 years who had no history of stroke. Traditional risk factors for stroke were obtained from a self-administered questionnaire at baseline. We classified participants into two age categories, 60-74 years (n=1,502) and >= 75 years (n=563), and assessed whether traditional risk factors were differentially associated with stroke incidence according to age category. Hazard ratios were calculated by the Cox proportional hazards model, adjusting for confounding factors and competing risk of death. RESULTS: During a median follow-up of 12.8 and 7.9 years, 163 and 111 participants aged 60-74 and >= 75 years, respectively, developed a first stroke. Hypertension was consistently associated with increased risk of stroke, regardless of age category. Diabetes mellitus was associated with increased risk of stroke in those aged 60-74 years (hazard ratio, 1.50; 95% confidence interval, 1.00-2.25), but not in those aged >= 75 years (hazard ratio, 0.65; 95% confidence interval, 0.33-1.29), with significant interaction by age (P=0.035). No traditional risk factor other than hypertension was associated with stroke among those aged >= 75 years. CONCLUSION: Those with hypertension had significantly higher stroke risk among old people, while diabetes mellitus was differentially associated with stroke according to age category. Our findings indicate the importance of different prevention strategies for stroke incidence according to age category. PMID- 27487855 TI - Commentary: Stabilizing Constructs through Collaboration across Different Research Fields as a Way to Foster the Integrative Approach of the Research Domain Criteria (RDoC) Project. PMID- 27487856 TI - XPO1, therapeutic ... and prognostic target in sarcomas. PMID- 27487857 TI - Role of monocytes and endothelial cells in heparin-induced thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) is an autoimmune disorder characterised by thrombocytopenia and thrombosis. The mechanisms leading to platelet destruction are complex and the thrombotic complications of HIT appear to be due to multiple different intravascular targets. The dual binding of HIT antibodies to platelet surface PF4/GAG complexes and to FcgammaRIIA likely leads to both platelet clearance and to their direct activation. Monocytes and endothelial cells bind PF4 with higher avidity than platelets and are more resistant to competitive removal of surface-bound PF4 in the presence of heparin. Binding of HIT antibodies to PF4/glycosaminoglycan complexes on the surface on these cells leads to their activation and increased procoagulant activity. Binding of higher levels of PF4 released from activated platelets to the endothelium may lead to changes of the anticoagulant properties of the glycocalyx and target the endothelial cells for HIT antibodies. Pathogenic antibodies bound to endothelial cells further promote prothrombotic conditions by a mechanism that is independent of FcgammaR activation, yet not completely understood. A more detailed understanding of the role of monocytes and endothelium may identify new targets for intervention to mitigate the risk of thrombosis with less impact on systemic haemostasis than current approaches to treatment for this serious disorder. PMID- 27487858 TI - Biologic modulation in renal regeneration. AB - INTRODUCTION: Chronic kidney disease (CKD) is recognized as a health care problem of increasing importance. Following the discovery of renal progenitors, the investigation of new therapeutic approaches to promote the kidney regenerative capacity has received increasing research attention. AREAS COVERED: The authors discuss the current knowledge of glomerular regeneration by renal progenitors and the modulation of their behavior through chemical and biological agents. The regenerative capacity of renal progenitors after injury must be regulated in order to prevent an inefficient or excessive response that could lead to a failed attempt to replace lost podocytes. In addition, they discuss the most relevant pathways involved in tubular repair and how these could be modulated in order to obtain renal regeneration rather than progression of a fibrotic maladaptive response. EXPERT OPINION: Modulation of the endogenous renal regenerative capacity is a new approach in the treatment of kidney diseases. Research efforts that concentrate on the potential regenerative capacity of the kidney can be advantageous when the experimental results are translated into clinical practice and may open the way to new therapeutic strategies for CKD. PMID- 27487859 TI - Pharmacological and toxicological assessment of innovative self-assembled polymeric micelles as powders for insulin pulmonary delivery. AB - AIM: Explore the use of polymeric micelles in the development of powders intended for pulmonary delivery of biopharmaceuticals, using insulin as a model protein. MATERIALS & METHODS: Formulations were assessed in vitro for aerosolization properties and in vivo for efficacy and safety using a streptozotocin-induced diabetic rat model. RESULTS: Powders presented good aerosolization properties like fine particle fraction superior to 40% and a mass median aerodynamic diameter inferior of 6 MUm. Endotracheally instilled powders have shown a faster onset of action than subcutaneous administration of insulin at a dose of 10 IU/kg, with pharmacological availabilities up to 32.5% of those achieved by subcutaneous route. Additionally, micelles improved the hypoglycemic effect of insulin. Bronchoalveolar lavage screening for toxicity markers (e.g., lactate dehydrogenase, cytokines) revealed no signs of lung inflammation and cytotoxicity 14 days postadministration. CONCLUSION: Developed powders showed promising safety and efficacy characteristics for the systemic delivery of insulin by pulmonary administration. PMID- 27487860 TI - Psoriatic arthritis: lessons from imaging studies and implications for therapy. AB - INTRODUCTION: Modern imaging may aid in the diagnosis, prognosis and monitoring of therapeutic response in psoriatic arthritis (PsA). Detection of osteitis and technical advances like whole body magnetic resonance imaging (MRI) exemplify the value of this technology. Areas covered: Ultrasound (US) provides a clinic-based tool for evaluating both joint pathologies and extra-articular structures (especially enthesitis) including skin and nail disease. Recent studies have demonstrated subclinical disease in psoriasis without arthritis, as well as in PsA, with implications for diagnosis and treatment classification. Modern imaging can also facilitate decisions on tapering of expensive biologics, though real world clinical studies are still lacking. Expert commentary: The increase in novel PsA therapies should increase the utilization of modern imaging, providing both increased validation of imaging biomarkers as well as responsive outcome measures. PMID- 27487861 TI - A new template for referees and guidance on writing high quality papers. PMID- 27487862 TI - Photon radiotherapy has reached its limit in terms of catching up dosimetrically with proton therapy. PMID- 27487863 TI - Robert O. Gorson, M.S. PMID- 27487864 TI - Noninvasive microwave ablation zone radii estimation using x-ray CT image analysis. AB - PURPOSE: The aims of this study were to noninvasively and automatically estimate both the radius of the ablated liver tissue and the radius encircling the treated zone, which also defines where the tissue is definitely untreated during a microwave (MW) thermal ablation procedure. METHODS: Fourteen ex vivo bovine fresh liver specimens were ablated at 40 W using a 14 G microwave antenna, for durations of 3, 6, 8, and 10 min. The tissues were scanned every 5 s during the ablation using an x-ray CT scanner. In order to estimate the radius of the ablation zone, the acquired images were transformed into a polar presentation by displaying the Hounsfield units (HU) as a function of angle and radius. From this polar presentation, the average HU radial profile was analyzed at each time point and the ablation zone radius was estimated. In addition, textural analysis was applied to the original CT images. The proposed algorithm identified high entropy regions and estimated the treated zone radius per time. The estimated ablated zone radii as a function of treatment durations were compared, by means of correlation coefficient and root mean square error (RMSE) to gross pathology measurements taken immediately post-treatment from similarly ablated tissue. RESULTS: Both the estimated ablation radii and the treated zone radii demonstrated strong correlation with the measured gross pathology values (R(2) >= 0.89 and R(2) >= 0.86, respectively). The automated ablation radii estimation had an average discrepancy of less than 1 mm (RMSE = 0.65 mm) from the gross pathology measured values, while the treated zone radii showed a slight overestimation of approximately 1.5 mm (RMSE = 1.6 mm). CONCLUSIONS: Noninvasive monitoring of MW ablation using x-ray CT and image analysis is feasible. Automatic estimations of the ablation zone radius and the radius encompassing the treated zone that highly correlate with actual ablation measured values can be obtained. This technique can therefore potentially be used to obtain real time monitoring and improve the clinical outcome. PMID- 27487865 TI - Generic and robust method for automatic segmentation of PET images using an active contour model. AB - PURPOSE: Although positron emission tomography (PET) images have shown potential to improve the accuracy of targeting in radiation therapy planning and assessment of response to treatment, the boundaries of tumors are not easily distinguishable from surrounding normal tissue owing to the low spatial resolution and inherent noisy characteristics of PET images. The objective of this study is to develop a generic and robust method for automatic delineation of tumor volumes using an active contour model and to evaluate its performance using phantom and clinical studies. METHODS: MASAC, a method for automatic segmentation using an active contour model, incorporates the histogram fuzzy C-means clustering, and localized and textural information to constrain the active contour to detect boundaries in an accurate and robust manner. Moreover, the lattice Boltzmann method is used as an alternative approach for solving the level set equation to make it faster and suitable for parallel programming. Twenty simulated phantom studies and 16 clinical studies, including six cases of pharyngolaryngeal squamous cell carcinoma and ten cases of nonsmall cell lung cancer, were included to evaluate its performance. Besides, the proposed method was also compared with the contourlet-based active contour algorithm (CAC) and Schaefer's thresholding method (ST). The relative volume error (RE), Dice similarity coefficient (DSC), and classification error (CE) metrics were used to analyze the results quantitatively. RESULTS: For the simulated phantom studies (PSs), MASAC and CAC provide similar segmentations of the different lesions, while ST fails to achieve reliable results. For the clinical datasets (2 cases with connected high-uptake regions excluded) (CSs), CAC provides for the lowest mean RE (-8.38% +/- 27.49%), while MASAC achieves the best mean DSC (0.71 +/- 0.09) and mean CE (53.92% +/- 12.65%), respectively. MASAC could reliably quantify different types of lesions assessed in this work with good accuracy, resulting in a mean RE of -13.35% +/- 11.87% and -11.15% +/- 23.66%, a mean DSC of 0.89 +/- 0.05 and 0.71 +/- 0.09, and a mean CE of 19.19% +/- 7.89% and 53.92% +/- 12.65%, for PSs and CSs, respectively. CONCLUSIONS: The authors' results demonstrate that the developed novel PET segmentation algorithm is applicable to various types of lesions in the authors' study and is capable of producing accurate and consistent target volume delineations, potentially resulting in reduced intraobserver and interobserver variabilities observed when using manual delineation and improved accuracy in treatment planning and outcome evaluation. PMID- 27487866 TI - Impact of bowtie filter and object position on the two-dimensional noise power spectrum of a clinical MDCT system. AB - PURPOSE: Noise characteristics of clinical multidetector CT (MDCT) systems can be quantified by the noise power spectrum (NPS). Although the NPS of CT has been extensively studied in the past few decades, the joint impact of the bowtie filter and object position on the NPS has not been systematically investigated. This work studies the interplay of these two factors on the two dimensional (2D) local NPS of a clinical CT system that uses the filtered backprojection algorithm for image reconstruction. METHODS: A generalized NPS model was developed to account for the impact of the bowtie filter and image object location in the scan field-of-view (SFOV). For a given bowtie filter, image object, and its location in the SFOV, the shape and rotational symmetries of the 2D local NPS were directly computed from the NPS model without going through the image reconstruction process. The obtained NPS was then compared with the measured NPSs from the reconstructed noise-only CT images in both numerical phantom simulation studies and experimental phantom studies using a clinical MDCT scanner. The shape and the associated symmetry of the 2D NPS were classified by borrowing the well known atomic spectral symbols s, p, and d, which correspond to circular, dumbbell, and cloverleaf symmetries, respectively, of the wave function of electrons in an atom. Finally, simulated bar patterns were embedded into experimentally acquired noise backgrounds to demonstrate the impact of different NPS symmetries on the visual perception of the object. RESULTS: (1) For a central region in a centered cylindrical object, an s-wave symmetry was always present in the NPS, no matter whether the bowtie filter was present or not. In contrast, for a peripheral region in a centered object, the symmetry of its NPS was highly dependent on the bowtie filter, and both p-wave symmetry and d-wave symmetry were observed in the NPS. (2) For a centered region-ofinterest (ROI) in an off centered object, the symmetry of its NPS was found to be different from that of a peripheral ROI in the centered object, even when the physical positions of the two ROIs relative to the isocenter were the same. (3) The potential clinical impact of the highly anisotropic NPS, caused by the interplay of the bowtie filter and position of the image object, was highlighted in images of specific bar patterns oriented at different angles. The visual perception of the bar patterns was found to be strongly dependent on their orientation. CONCLUSIONS: The NPS of CT depends strongly on the bowtie filter and object position. Even if the location of the ROI with respect to the isocenter is fixed, there can be different symmetries in the NPS, which depend on the object position and the size of the bowtie filter. For an isolated off-centered object, the NPS of its CT images cannot be represented by the NPS measured from a centered object. PMID- 27487867 TI - Technical Note: On the impact of the incident electron beam energy on the primary dose component of flattening filter free photon beams. AB - PURPOSE: For commercially available linear accelerators (Linacs), the electron energies of flattening filter free (FFF) and flattened (FF) beams are either identical or the electron energy of the FFF beam is increased to match the percentage depth dose curve (PDD) of the FF beam (in reference geometry). This study focuses on the primary dose components of FFF beams for both kinds of settings, studied on the same Linac. METHODS: The measurements were conducted on a VersaHD Linac (Elekta, Crawley, UK) for both FF and FFF beams with nominal energies of 6 and 10 MV. In the clinical setting of the VersaHD, the energy of FFFM (Matched) beams is set to match the PDDs of the FF beams. In contrast the incident electron beam of the FFFU beam was set to the same energy as for the FF beam. Half value layers (HVLs) and a dual parameter beam quality specifier (DPBQS) were determined. RESULTS: For the 6 MV FFFM beam, HVL and DPBQS values were very similar compared to those of the 6 MV FF beam, while for the 10 MV FFFM and FF beams, only %dd(10)x and HVL values were comparable (differences below 1.5%). This shows that matching the PDD at one depth does not guarantee other beam quality dependent parameters to be matched. For FFFU beams, all investigated beam quality specifiers were significantly different compared to those for FF beams of the same nominal accelerator potential. The DPBQS of the 6 MV FF and FFFM beams was equal within the measurement uncertainty and was comparable to published data of a machine with similar TPR20,10 and %dd(10)x. In contrast to that, the DPBQS's two parameters of the 10 MV FFFM beam were substantially higher compared to those for the 10 MV FF beam. CONCLUSIONS: PDD-matched FF and FFF beams of both nominal accelerator potentials were observed to have similar HVL values, indicating similarity of their primary dose components. Using the DPBQS revealed that the mean attenuation coefficient was found to be the same within the uncertainty of 0.8% for 6 MV FF and 6 MV FFFM beams, while for 10 MV beams, they differed by 6.4%. This shows that the DPBQS can provide a differentiation of photon beam characteristics that would remain hidden by the use of a single beam quality specifier, such as %dd(10)x or HVL. PMID- 27487868 TI - Technical Note: Dosimetric effects of couch position variability on treatment plan quality with an MRI-guided Co-60 radiation therapy machine. AB - PURPOSE: Magnetic resonance imaging (MRI) guidance in radiation therapy brings real-time imaging and adaptive planning into the treatment vault where it can account for interfraction and intrafraction movement of soft tissue. The only commercially available MRI-guided radiation therapy device is a three-head (60)Co and MRI system with an integrated treatment planning system (TPS). Couch attenuation of the beam of up to 20% is well modeled in the TPS. Variations in the patient's day-to-day position introduce discrepancies in the actual couch attenuation as modeled in the treatment plan. For this reason, the authors' institution avoids plans with beams that pass through or near the couch edges. This study investigates the effects of differential beam attenuation by the couch due to couch shifts in order to determine whether couch edge avoidance restrictions can be lifted. Couch shifts were simulated using a Monte Carlo treatment planning system and ion chamber measurements performed for validation. METHODS: A total of 27 plans from 23 patients were investigated. Couch shifts of 1 and 2 cm were introduced in combinations of lateral and vertical directions to simulate patient position variations giving 16 shifted plans per reference plan. The 1 and 2 cm shifts were based on shifts recorded in 320 treatment fractions. RESULTS: Following TG176 recommendations for measurement methods, couch attenuation measurements agreed with TPS modeled attenuation to within 2.1%. Planning target volume D95 changed less than 1% for 1 and 2 cm couch shifts in only the x-direction and less than 3% for all directions. CONCLUSIONS: Dosimetry of all plans tested was robust to couch shifts up to +/-2 cm. In general, couch shifts resulted in clinically insignificant dosimetric deviations. It is conceivable that in certain cases with large systematic couch shifts and plans that are particularly sensitive to shifts, dosimetric changes might rise to a clinically significant level. PMID- 27487869 TI - Use of radiochromic film as a high-spatial resolution dosimeter by Raman spectroscopy. AB - PURPOSE: Due to increasing demand for high-spatial resolution dosimetry, radiochromic films have been investigated as potential candidates but are often limited by the scanning system, e.g., flatbed optical scanner. In this study, Raman spectroscopy in conjunction with a microscope was selected as an alternative method for high-spatial resolution dosimetry of radiochromic film. METHODS: Unlaminated GafchromicTM EBT3 films were irradiated with doses between 0 and 50 Gy using 6 MV x-rays of a clinical linear accelerator. Depth profiling from the surface of unlaminated film was performed to acquire the maximum Raman intensity peaks of C=C and C=C stretching bands of diacetylene polymer. The Raman mapping technique for a region of interest (200 * 200, 30 * 30 MUm(2)) was developed to reduce a large variation in a Raman spectrum produced with a sampling resolution of a few MUm. The preprocessing of Raman spectra was carried out to determine a dosimetric relationship with the amount of diacetylene polymerization. RESULTS: Due to partial diacetylene polymerization upon irradiation, two Raman peaks of C=C and C=C stretching bands were observed around 1447 and 2060 cm(-1), respectively. The maximum intensities of the two peaks were obtained by positioning a focused laser spot on the surface of unlaminated film. For the dose range of 0-50 Gy, the band heights of both C=C and C=C peaks increase asymptotically with increasing doses and can be fit with an exponential function of two components. The relative standard deviation in Raman mapping was found to be less than +/-5%. By using this technique, dose uniformity was found to be within +/-2%. CONCLUSIONS: The Raman intensity for C=C and C=C peaks increases with an increase in the amount of diacetylene polymerization due to an increase in dose. This study shows the potential of Raman spectroscopy as an alternative for absolute dosimetry verifications with a high-spatial resolution of a few MUm, but these findings need to be further validated for the purpose of microdosimetry. PMID- 27487870 TI - Library based x-ray scatter correction for dedicated cone beam breast CT. AB - PURPOSE: The image quality of dedicated cone beam breast CT (CBBCT) is limited by substantial scatter contamination, resulting in cupping artifacts and contrast loss in reconstructed images. Such effects obscure the visibility of soft-tissue lesions and calcifications, which hinders breast cancer detection and diagnosis. In this work, we propose a library-based software approach to suppress scatter on CBBCT images with high efficiency, accuracy, and reliability. METHODS: The authors precompute a scatter library on simplified breast models with different sizes using the geant4-based Monte Carlo (MC) toolkit. The breast is approximated as a semiellipsoid with homogeneous glandular/adipose tissue mixture. For scatter correction on real clinical data, the authors estimate the breast size from a first-pass breast CT reconstruction and then select the corresponding scatter distribution from the library. The selected scatter distribution from simplified breast models is spatially translated to match the projection data from the clinical scan and is subtracted from the measured projection for effective scatter correction. The method performance was evaluated using 15 sets of patient data, with a wide range of breast sizes representing about 95% of general population. Spatial nonuniformity (SNU) and contrast to signal deviation ratio (CDR) were used as metrics for evaluation. RESULTS: Since the time-consuming MC simulation for library generation is precomputed, the authors' method efficiently corrects for scatter with minimal processing time. Furthermore, the authors find that a scatter library on a simple breast model with only one input parameter, i.e., the breast diameter, sufficiently guarantees improvements in SNU and CDR. For the 15 clinical datasets, the authors' method reduces the average SNU from 7.14% to 2.47% in coronal views and from 10.14% to 3.02% in sagittal views. On average, the CDR is improved by a factor of 1.49 in coronal views and 2.12 in sagittal views. CONCLUSIONS: The library-based scatter correction does not require increase in radiation dose or hardware modifications, and it improves over the existing methods on implementation simplicity and computational efficiency. As demonstrated through patient studies, the authors' approach is effective and stable, and is therefore clinically attractive for CBBCT imaging. PMID- 27487871 TI - Robotic path-finding in inverse treatment planning for stereotactic radiosurgery with continuous dose delivery. AB - PURPOSE: Continuous dose delivery in radiation therapy treatments has been shown to decrease total treatment time while improving the dose conformity and distribution homogeneity over the conventional step-and-shoot approach. The authors develop an inverse treatment planning method for Gamma Knife(r) PerfexionTM that continuously delivers dose along a path in the target. METHODS: The authors' method is comprised of two steps: find a path within the target, then solve a mixed integer optimization model to find the optimal collimator configurations and durations along the selected path. Robotic path-finding techniques, specifically, simultaneous localization and mapping (SLAM) using an extended Kalman filter, are used to obtain a path that travels sufficiently close to selected isocentre locations. SLAM is novelly extended to explore a 3D, discrete environment, which is the target discretized into voxels. Further novel extensions are incorporated into the steering mechanism to account for target geometry. RESULTS: The SLAM method was tested on seven clinical cases and compared to clinical, Hamiltonian path continuous delivery, and inverse step-and shoot treatment plans. The SLAM approach improved dose metrics compared to the clinical plans and Hamiltonian path continuous delivery plans. Beam-on times improved over clinical plans, and had mixed performance compared to Hamiltonian path continuous plans. The SLAM method is also shown to be robust to path selection inaccuracies, isocentre selection, and dose distribution. CONCLUSIONS: The SLAM method for continuous delivery provides decreased total treatment time and increased treatment quality compared to both clinical and inverse step-and shoot plans, and outperforms existing path methods in treatment quality. It also accounts for uncertainty in treatment planning by accommodating inaccuracies. PMID- 27487872 TI - Interobserver variability in identification of breast tumors in MRI and its implications for prognostic biomarkers and radiogenomics. AB - PURPOSE: To assess the interobserver variability of readers when outlining breast tumors in MRI, study the reasons behind the variability, and quantify the effect of the variability on algorithmic imaging features extracted from breast MRI. METHODS: Four readers annotated breast tumors from the MRI examinations of 50 patients from one institution using a bounding box to indicate a tumor. All of the annotated tumors were biopsy proven cancers. The similarity of bounding boxes was analyzed using Dice coefficients. An automatic tumor segmentation algorithm was used to segment tumors from the readers' annotations. The segmented tumors were then compared between readers using Dice coefficients as the similarity metric. Cases showing high interobserver variability (average Dice coefficient <0.8) after segmentation were analyzed by a panel of radiologists to identify the reasons causing the low level of agreement. Furthermore, an imaging feature, quantifying tumor and breast tissue enhancement dynamics, was extracted from each segmented tumor for a patient. Pearson's correlation coefficients were computed between the features for each pair of readers to assess the effect of the annotation on the feature values. Finally, the authors quantified the extent of variation in feature values caused by each of the individual reasons for low agreement. RESULTS: The average agreement between readers in terms of the overlap (Dice coefficient) of the bounding box was 0.60. Automatic segmentation of tumor improved the average Dice coefficient for 92% of the cases to the average value of 0.77. The mean agreement between readers expressed by the correlation coefficient for the imaging feature was 0.96. CONCLUSIONS: There is a moderate variability between readers when identifying the rectangular outline of breast tumors on MRI. This variability is alleviated by the automatic segmentation of the tumors. Furthermore, the moderate interobserver variability in terms of the bounding box does not translate into a considerable variability in terms of assessment of enhancement dynamics. The authors propose some additional ways to further reduce the interobserver variability. PMID- 27487873 TI - Validation of a pretreatment delivery quality assurance method for the CyberKnife Synchrony system. AB - PURPOSE: To evaluate the geometric and dosimetric accuracies of the CyberKnife Synchrony respiratory tracking system (RTS) and to validate a method for pretreatment patient-specific delivery quality assurance (DQA). METHODS: An EasyCube phantom was mounted on the ExacTrac gating phantom, which can move along the superior-inferior (SI) axis of a patient to simulate a moving target. The authors compared dynamic and static measurements. For each case, a Gafchromic EBT3 film was positioned between two slabs of the EasyCube, while a PinPoint ionization chamber was placed in the appropriate space. There were three steps to their evaluation: (1) the field size, the penumbra, and the symmetry of six secondary collimators were measured along the two main orthogonal axes. Dynamic measurements with deliberately simulated errors were also taken. (2) The delivered dose distributions (from step 1) were compared with the planned ones, using the gamma analysis method. The local gamma passing rates were evaluated using three acceptance criteria: 3% local dose difference (LDD)/3 mm, 2%LDD/2 mm, and 3%LDD/1 mm. (3) The DQA plans for six clinical patients were irradiated in different dynamic conditions, to give a total of 19 cases. The measured and planned dose distributions were evaluated with the same gamma-index criteria used in step 2 and the measured chamber doses were compared with the planned mean doses in the sensitive volume of the chamber. RESULTS: (1) A very slight enlargement of the field size and of the penumbra was observed in the SI direction (on average <1 mm), in line with the overall average CyberKnife system error for tracking treatments. (2) Comparison between the planned and the correctly delivered dose distributions confirmed the dosimetric accuracy of the RTS for simple plans. The multicriteria gamma analysis was able to detect the simulated errors, proving the robustness of their method of analysis. (3) All of the DQA clinical plans passed the tests, both in static and dynamic conditions. No statistically significant differences were found between static and dynamic cases, confirming the high degree of accuracy of the Synchrony RTS. CONCLUSIONS: The presented methods and measurements verified the mechanical and dosimetric accuracy of the Synchrony RTS. Their method confirms the fact that the RTS, if used properly, is able to treat a moving target with great precision. By combining PinPoint ion chamber, EBT3 films, and gamma evaluation of dose distributions, their DQA method robustly validated the effectiveness of CyberKnife and Synchrony system. PMID- 27487874 TI - An online replanning method using warm start optimization and aperture morphing for flattening-filter-free beams. AB - PURPOSE: In a situation where a couch shift for patient positioning is not preferred or prohibited (e.g., MR-linac), segment aperture morphing (SAM) can address target dislocation and deformation. For IMRT/VMAT with flattening-filter free (FFF) beams, however, SAM method would lead to an adverse translational dose effect due to the beam unflattening. Here the authors propose a new two-step process to address both the translational effect of FFF beams and the target deformation. METHODS: The replanning method consists of an offline and an online step. The offline step is to create a series of preshifted-plans (PSPs) obtained by a so-called "warm start" optimization (starting optimization from the original plan, rather than from scratch) at a series of isocenter shifts. The PSPs all have the same number of segments with very similar shapes, since the warm start optimization only adjusts the MLC positions instead of regenerating them. In the online step, a new plan is obtained by picking the closest PSP or linearly interpolating the MLC positions and the monitor units of the closest PSPs for the shift determined from the image of the day. This two-step process is completely automated and almost instantaneous (no optimization or dose calculation needed). The previously developed SAM algorithm is then applied for daily deformation. The authors tested the method on sample prostate and pancreas cases. RESULTS: The two step interpolation method can account for the adverse dose effects from FFF beams, while SAM corrects for the target deformation. Plan interpolation method is effective in diminishing the unflat beam effect and may allow reducing the required number of PSPs. The whole process takes the same time as the previously reported SAM process (5-10 min). CONCLUSIONS: The new two-step method plus SAM can address both the translation effects of FFF beams and target deformation, and can be executed in full automation except the delineation of target contour required by the SAM process. PMID- 27487875 TI - Optical CT imaging of solid radiochromic dosimeters in mismatched refractive index solutions using a scanning laser and large area detector. AB - PURPOSE: The practical use of the PRESAGE(r) solid plastic dosimeter is limited by the inconvenience of immersing it in high-viscosity oils to achieve refractive index matching for optical computed tomography (CT) scanning. The oils are slow to mix and difficult to clean from surfaces, and the dosimeter rotation can generate dynamic Schlieren inhomogeneity patterns in the reference liquid, limiting the rotational and overall scan speed. Therefore, it would be beneficial if lower-viscosity, water-based solutions with slightly unmatched refractive index could be used instead. The purpose of this work is to demonstrate the feasibility of allowing mismatched conditions when using a scanning laser system with a large acceptance angle detector. A fiducial-based ray path measurement technique is combined with an iterative CT reconstruction algorithm to reconstruct images. METHODS: A water based surrounding liquid with a low viscosity was selected for imaging PRESAGE(r) solid dosimeters. Liquid selection was optimized to achieve as high a refractive index as possible while avoiding rotation-induced Schlieren effects. This led to a refractive index mismatch of 6% between liquid and dosimeters. Optical CT scans were performed with a fan-beam scanning-laser optical CT system with a large area detector to capture most of the refracted rays. A fiducial marker placed on the wall of a cylindrical sample occludes a given light ray twice. With knowledge of the rotation angle and the radius of the cylindrical object, the actual internal path of each ray through the dosimeter can be calculated. Scans were performed with 1024 projections of 512 data samples each, and rays were rebinned to form 512 parallel-beam projections. Reconstructions were performed on a 512 * 512 grid using 100 iterations of the SIRT iterative CT algorithm. Proof of concept was demonstrated with a uniformly attenuating solution phantom. PRESAGE(r) dosimeters (11 cm diameter) were irradiated with Cobalt-60 irradiator to achieve either a uniform dose or a 2-level "step-dose" pattern. RESULTS: With 6% refractive index mismatching, a circular field of view of 85% of the diameter of a cylindrical sample can be reconstructed accurately. Reconstructed images of the test solution phantom were uniform (within 3%) inside this radius. However, the dose responses of the PRESAGE(r) samples were not spatially uniform, with variations of at least 5% in sensitivity. The variation appears as a "cupping" artifact with less sensitivity in the middle than at the periphery of the PRESAGE(r) cylinder. Polarization effects were also detected for these samples. CONCLUSIONS: The fiducial-based ray path measurement scheme, coupled with an iterative reconstruction algorithm, enabled optical CT scanning of PRESAGE(r) dosimeters immersed in mismatched refractive index solutions. However, improvements to PRESAGE(r) dose response uniformity are required. PMID- 27487876 TI - Energy dependent response of plastic scintillation detectors to photon radiation of low to medium energy. AB - PURPOSE: Plastic scintillation detectors are promising candidates for the dosimetry of low- to medium-energy photons but quantitative knowledge of their energy response is a prerequisite for their correct use. The purpose of this study was to characterize the energy dependent response of small scintillation detectors (active volume <1 mm(3)) made from the commonly used plastic scintillator BC400. METHODS: Different detectors made from BC400 were calibrated at a number of radiation qualities ranging from 10 to 280 kV and at a (60)Co beam. All calibrations were performed at the Physikalisch-Technische Bundesanstalt, the National Metrology Institute of Germany. The energy response in terms of air kerma, dose to water, and dose to the scintillator was determined. Conversion factors from air kerma to dose to water and to dose to the scintillator were derived from Monte Carlo simulations. In order to quantitatively describe the energy dependence, a semiempirical model known as unimolecular quenching or Birks' formula was fitted to the data and from this the response to secondary electrons generated within the scintillator material BC400 was derived. RESULTS: The detector energy response in terms of air kerma differs for different scintillator sizes and different detector casings. It is therefore necessary to take attenuation within the scintillator and in the casing into account when deriving the response in terms of dose to water from a calibration in terms of air kerma. The measured energy response in terms of dose to water for BC400 cannot be reproduced by the ratio of mean mass energy-absorption coefficients for polyvinyl toluene to water but shows evidence of quenching. The quenching parameter kB in Birks' formula was determined to be kB = (12.3 +/- 0.9) mg MeV(-1) cm(-2). CONCLUSIONS: The energy response was quantified relative to the response to (60)Co which is the common radiation quality for the calibration of therapy dosemeters. The observed energy dependence could be well explained with the assumption of ionization quenching as described by Birks' formula. Plastic scintillation detectors should be calibrated at the same radiation quality that they will be used at and changes of the spectrum within the application need to be considered. The authors results can be used to evaluate the range of validity of a given calibration. PMID- 27487877 TI - Multisource inverse-geometry CT. Part I. System concept and development. AB - PURPOSE: This paper presents an overview of multisource inverse-geometry computed tomography (IGCT) as well as the development of a gantry-based research prototype system. The development of the distributed x-ray source is covered in a companion paper [V. B. Neculaes et al., "Multisource inverse-geometry CT. Part II. X-ray source design and prototype," Med. Phys. 43, 4617-4627 (2016)]. While progress updates of this development have been presented at conferences and in journal papers, this paper is the first comprehensive overview of the multisource inverse geometry CT concept and prototype. The authors also provide a review of all previous IGCT related publications. METHODS: The authors designed and implemented a gantry-based 32-source IGCT scanner with 22 cm field-of-view, 16 cm z-coverage, 1 s rotation time, 1.09 * 1.024 mm detector cell size, as low as 0.4 * 0.8 mm focal spot size and 80-140 kVp x-ray source voltage. The system is built using commercially available CT components and a custom made distributed x-ray source. The authors developed dedicated controls, calibrations, and reconstruction algorithms and evaluated the system performance using phantoms and small animals. RESULTS: The authors performed IGCT system experiments and demonstrated tube current up to 125 mA with up to 32 focal spots. The authors measured a spatial resolution of 13 lp/cm at 5% cutoff. The scatter-to-primary ratio is estimated 62% for a 32 cm water phantom at 140 kVp. The authors scanned several phantoms and small animals. The initial images have relatively high noise due to the low x ray flux levels but minimal artifacts. CONCLUSIONS: IGCT has unique benefits in terms of dose-efficiency and cone-beam artifacts, but comes with challenges in terms of scattered radiation and x-ray flux limits. To the authors' knowledge, their prototype is the first gantry-based IGCT scanner. The authors summarized the design and implementation of the scanner and the authors presented results with phantoms and small animals. PMID- 27487878 TI - Multisource inverse-geometry CT. Part II. X-ray source design and prototype. AB - PURPOSE: This paper summarizes the development of a high-power distributed x-ray source, or "multisource," designed for inverse-geometry computed tomography (CT) applications [see B. De Man et al., "Multisource inverse-geometry CT. Part I. System concept and development," Med. Phys. 43, 4607-4616 (2016)]. The paper presents the evolution of the source architecture, component design (anode, emitter, beam optics, control electronics, high voltage insulator), and experimental validation. METHODS: Dispenser cathode emitters were chosen as electron sources. A modular design was adopted, with eight electron emitters (two rows of four emitters) per module, wherein tungsten targets were brazed onto copper anode blocks-one anode block per module. A specialized ceramic connector provided high voltage standoff capability and cooling oil flow to the anode. A matrix topology and low-noise electronic controls provided switching of the emitters. RESULTS: Four modules (32 x-ray sources in two rows of 16) have been successfully integrated into a single vacuum vessel and operated on an inverse geometry computed tomography system. Dispenser cathodes provided high beam current (>1000 mA) in pulse mode, and the electrostatic lenses focused the current beam to a small optical focal spot size (0.5 * 1.4 mm). Controlled emitter grid voltage allowed the beam current to be varied for each source, providing the ability to modulate beam current across the fan of the x-ray beam, denoted as a virtual bowtie filter. The custom designed controls achieved x-ray source switching in <1 MUs. The cathode-grounded source was operated successfully up to 120 kV. CONCLUSIONS: A high-power, distributed x-ray source for inverse geometry CT applications was successfully designed, fabricated, and operated. Future embodiments may increase the number of spots and utilize fast read out detectors to increase the x-ray flux magnitude further, while still staying within the stationary target inherent thermal limitations. PMID- 27487879 TI - First evaluation of the feasibility of MLC tracking using ultrasound motion estimation. AB - PURPOSE: To quantify the performance of the Clarity ultrasound (US) imaging system (Elekta AB, Stockholm, Sweden) for real-time dynamic multileaf collimator (MLC) tracking. METHODS: The Clarity calibration and quality assurance phantom was mounted on a motion platform moving with a periodic sine wave trajectory. The detected position of a 30 mm hypoechogenic sphere within the phantom was continuously reported via Clarity's real-time streaming interface to an in-house tracking and delivery software and subsequently used to adapt the MLC aperture. A portal imager measured MV treatment field/MLC apertures and motion platform positions throughout each experiment to independently quantify system latency and geometric error. Based on the measured range of latency values, a prostate stereotactic body radiation therapy (SBRT) delivery was performed with three realistic motion trajectories. The dosimetric impact of system latency on MLC tracking was directly measured using a 3D dosimeter mounted on the motion platform. RESULTS: For 2D US imaging, the overall system latency, including all delay times from the imaging and delivery chain, ranged from 392 to 424 ms depending on the lateral sector size. For 3D US imaging, the latency ranged from 566 to 1031 ms depending on the elevational sweep. The latency-corrected geometric root-mean squared error was below 0.75 mm (2D US) and below 1.75 mm (3D US). For the prostate SBRT delivery, the impact of a range of system latencies (400-1000 ms) on the MLC tracking performance was minimal in terms of gamma failure rate. CONCLUSIONS: Real-time MLC tracking based on a noninvasive US input is technologically feasible. Current system latencies are higher than those for x ray imaging systems, but US can provide full volumetric image data and the impact of system latency was measured to be small for a prostate SBRT case when using a US-like motion input. PMID- 27487880 TI - Feasibility of MRI-only treatment planning for proton therapy in brain and prostate cancers: Dose calculation accuracy in substitute CT images. AB - PURPOSE: Magnetic resonance imaging (MRI) is increasingly used for radiotherapy target delineation, image guidance, and treatment response monitoring. Recent studies have shown that an entire external x-ray radiotherapy treatment planning (RTP) workflow for brain tumor or prostate cancer patients based only on MRI reference images is feasible. This study aims to show that a MRI-only based RTP workflow is also feasible for proton beam therapy plans generated in MRI-based substitute computed tomography (sCT) images of the head and the pelvis. METHODS: The sCTs were constructed for ten prostate cancer and ten brain tumor patients primarily by transforming the intensity values of in-phase MR images to Hounsfield units (HUs) with a dual model HU conversion technique to enable heterogeneous tissue representation. HU conversion models for the pelvis were adopted from previous studies, further extended in this study also for head MRI by generating anatomical site-specific conversion models (a new training data set of ten other brain patients). This study also evaluated two other types of simplified sCT: dual bulk density (for bone and water) and homogeneous (water only). For every clinical case, intensity modulated proton therapy (IMPT) plans robustly optimized in standard planning CTs were calculated in sCT for evaluation, and vice versa. Overall dose agreement was evaluated using dose volume histogram parameters and 3D gamma criteria. RESULTS: In heterogeneous sCTs, the mean absolute errors in HUs were 34 (soft tissues: 13, bones: 92) and 42 (soft tissues: 9, bones: 97) in the head and in the pelvis, respectively. The maximum absolute dose differences relative to CT in the brain tumor clinical target volume (CTV) were 1.4% for heterogeneous sCT, 1.8% for dual bulk sCT, and 8.9% for homogenous sCT. The corresponding maximum differences in the prostate CTV were 0.6%, 1.2%, and 3.6%, respectively. The percentages of dose points in the head and pelvis passing 1% and 1 mm gamma index criteria were over 91%, 85%, and 38% with heterogeneous, dual bulk, and homogeneous sCTs, respectively. There were no significant changes to gamma index pass rates for IMPT plans first optimized in CT and then calculated in heterogeneous sCT versus IMPT plans first optimized in heterogeneous sCT and then calculated on standard CT. CONCLUSIONS: This study demonstrates that proton therapy dose calculations on heterogeneous sCTs are in good agreement with plans generated with standard planning CT. An MRI only based RTP workflow is feasible in IMPT for brain tumors and prostate cancers. PMID- 27487881 TI - Reconstruction of implanted marker trajectories from cone-beam CT projection images using interdimensional correlation modeling. AB - PURPOSE: Cone-beam CT (CBCT) is a widely used imaging modality for image-guided radiotherapy. Most vendors provide CBCT systems that are mounted on a linac gantry. Thus, CBCT can be used to estimate the actual 3-dimensional (3D) position of moving respiratory targets in the thoracic/abdominal region using 2D projection images. The authors have developed a method for estimating the 3D trajectory of respiratory-induced target motion from CBCT projection images using interdimensional correlation modeling. METHODS: Because the superior-inferior (SI) motion of a target can be easily analyzed on projection images of a gantry mounted CBCT system, the authors investigated the interdimensional correlation of the SI motion with left-right and anterior-posterior (AP) movements while the gantry is rotating. A simple linear model and a state-augmented model were implemented and applied to the interdimensional correlation analysis, and their performance was compared. The parameters of the interdimensional correlation models were determined by least-square estimation of the 2D error between the actual and estimated projected target position. The method was validated using 160 3D tumor trajectories from 46 thoracic/abdominal cancer patients obtained during CyberKnife treatment. The authors' simulations assumed two application scenarios: (1) retrospective estimation for the purpose of moving tumor setup used just after volumetric matching with CBCT; and (2) on-the-fly estimation for the purpose of real-time target position estimation during gating or tracking delivery, either for full-rotation volumetric-modulated arc therapy (VMAT) in 60 s or a stationary six-field intensity-modulated radiation therapy (IMRT) with a beam delivery time of 20 s. RESULTS: For the retrospective CBCT simulations, the mean 3D root-mean-square error (RMSE) for all 4893 trajectory segments was 0.41 mm (simple linear model) and 0.35 mm (state-augmented model). In the on-the-fly simulations, prior projections over more than 60 degrees appear to be necessary for reliable estimations. The mean 3D RMSE during beam delivery after the simple linear model had established with a prior 90 degrees projection data was 0.42 mm for VMAT and 0.45 mm for IMRT. CONCLUSIONS: The proposed method does not require any internal/external correlation or statistical modeling to estimate the target trajectory and can be used for both retrospective image-guided radiotherapy with CBCT projection images and real-time target position monitoring for respiratory gating or tracking. PMID- 27487882 TI - A model of tungsten anode x-ray spectra. AB - PURPOSE: A semiempirical model for x-ray production in tungsten thick-targets was evaluated using a new characterization of electron fluence. METHODS: Electron fluence is modeled taking into account both the energy and angular distributions, each of them adjusted to Monte Carlo simulated data. Distances were scaled by the CSDA range to reduce the energy dependence. Bremsstrahlung production was found by integrating the cross section with the fluence in a 1D penetration model. Characteristic radiation was added using a semiempirical law whose validity was checked. The results were compared the experimental results of Bhat et al., with the SpekCalc numerical tool, and with mcnpx simulation results from the work of Hernandez and Boone. RESULTS: The model described shows better agreement with the experimental results than the SpekCalc predictions in the sense of area between the spectra. A general improvement of the predictions of half-value layers is also found. The results are also in good agreement with the simulation results in the 50-640 keV energy range. CONCLUSIONS: A complete model for x-ray production in thick bremsstrahlung targets has been developed, improving the results of previous works and extending the energy range covered to the 50-640 keV interval. PMID- 27487883 TI - Backscatter dose effects for high atomic number materials being irradiated in the presence of a magnetic field: A Monte Carlo study for the MRI linac. AB - PURPOSE: To quantify and explain the backscatter dose effects for clinically relevant high atomic number materials being irradiated in the presence of a 1.5 T transverse magnetic field. METHODS: Interface effects were investigated using Monte Carlo simulation techniques. We used gpumcd (v5.1) and geant4 (v10.1) for this purpose. gpumcd is a commercial software written for the Elekta AB, MRI linac. Dose was scored using gpumcd in cubic voxels of side 1 and 0.5 mm, in two different virtual phantoms of dimensions 20 * 20 * 20 cm and 5 * 5 * 13.3 cm, respectively. A photon beam was generated from a point 143.5 cm away from the isocenter with energy distribution sampled from a histogram representing the true Elekta, MRI linac photon spectrum. A slab of variable thickness and position containing either bone, aluminum, titanium, stainless steel, or one of the two different dental filling materials was inserted as an inhomogeneity in the 20 * 20 * 20 cm phantom. The 5 * 5 * 13.3 cm phantom was used as a clinical test case in order to explain the dose perturbation effects for a head and neck cancer patient. The back scatter dose factor (BSDF) was defined as the ratio of the doses at a given depth with and without the presence of the inhomogeneity. Backscattered electron fluence was calculated at the inhomogeneity interface using geant4. A 1.5 T magnetic field was applied perpendicular to the direction of the beam in both phantoms, identical to the geometry in the Elekta MRI linac. RESULTS: With the application of a 1.5 T magnetic field, all the BSDF's were reduced by 12%-47%, compared to the no magnetic field case. The corresponding backscattered electron fluence at the interface was also reduced by 45%-64%. The reduction in the BSDF at the interface, due to the application of the magnetic field, is manifested in a different manner for each material. In the case of bone, the dose drops at the interface contrary to the expected increase when no magnetic field is applied. In the case of aluminum, the dose at the interface is the same with and without the presence of the aluminum. For all of the other materials the dose increases at the interface. CONCLUSIONS: The reduction in dose at the interface, in the presence of the magnetic field, is directly related to the reduction in backscattered electron fluence. This reduction occurs due to two different reasons. First, the electron spectrum hitting the interface is changed when the magnetic field is turned on, which results in changes in the electron scattering probability. Second, some electrons that have curved trajectories due to the presence of the magnetic field are absorbed by the higher density side of the interface and no longer contribute to the backscattered electron fluence. PMID- 27487884 TI - Experimental feasibility of multistatic holography for breast microwave radar image reconstruction. AB - PURPOSE: The goal of this study was to assess the experimental feasibility of circular multistatic holography, a novel breast microwave radar reconstruction approach, using experimental datasets recorded using a preclinical experimental setup. The performance of this approach was quantitatively evaluated by calculating the signal to clutter ratio (SCR), contrast to clutter ratio (CCR), tumor to fibroglandular response ratio (TFRR), spatial accuracy, and reconstruction time. METHODS: Five datasets were recorded using synthetic phantoms with the dielectric properties of breast tissue in the 1-6 GHz range using a custom radar system developed by the authors. The datasets contained synthetic structures that mimic the dielectric properties of fibroglandular breast tissues. Four of these datasets the authors covered an 8 mm inclusion that emulated a tumor. A custom microwave radar system developed at the University of Manitoba was used to record the radar responses from the phantoms. The datasets were reconstructed using the proposed multistatic approach as well as with a monostatic holography approach that has been previously shown to yield the images with the highest contrast and focal quality. RESULTS: For all reconstructions, the location of the synthetic tumors in the experimental setup was consistent with the position in the both the monostatic and multistatic reconstructed images. The average spatial error was less than 4 mm, which is half the spatial resolution of the data acquisition system. The average SCR, CCR, and TFRR of the images reconstructed with the multistatic approach were 15.0, 9.4, and 10.0 dB, respectively. In comparison, monostatic images obtained using the datasets from the same experimental setups yielded average SCR, CCR, and TFRR values of 12.8, 4.9, and 5.9 dB. No artifacts, defined as responses generated by the reconstruction method of at least half the energy of the tumor signatures, were noted in the multistatic reconstructions. The average execution time of the images formed using the proposed approach was 4 s, which is one order of magnitude faster than the current state-of-the-art time-domain multistatic breast microwave radar reconstruction algorithms. CONCLUSIONS: The images generated by the proposed method show that multistatic holography is capable of forming spatially accurate images in real-time with signal to clutter levels and contrast values higher than other published monostatic and multistatic cylindrical radar reconstruction approaches. In comparison to the monostatic holographic approach, the images generated by the proposed multistatic approach had SCR values that were at least 50% higher. The multistatic images had CCR and TFRR values at least 200% greater than those formed using a monostatic approach. PMID- 27487885 TI - An experimental extrapolation technique using the Gafchromic EBT3 film for relative output factor measurements in small x-ray fields. AB - PURPOSE: An experimental extrapolation technique is presented, which can be used to determine the relative output factors for very small x-ray fields using the Gafchromic EBT3 film. METHODS: Relative output factors were measured for the Brainlab SRS cones ranging in diameters from 4 to 30 mm(2) on a Novalis Trilogy linear accelerator with 6 MV SRS x-rays. The relative output factor was determined from an experimental reducing circular region of interest (ROI) extrapolation technique developed to remove the effects of volume averaging. This was achieved by scanning the EBT3 film measurements with a high scanning resolution of 1200 dpi. From the high resolution scans, the size of the circular regions of interest was varied to produce a plot of relative output factors versus area of analysis. The plot was then extrapolated to zero to determine the relative output factor corresponding to zero volume. RESULTS: Results have shown that for a 4 mm field size, the extrapolated relative output factor was measured as a value of 0.651 +/- 0.018 as compared to 0.639 +/- 0.019 and 0.633 +/- 0.021 for 0.5 and 1.0 mm diameter of analysis values, respectively. This showed a change in the relative output factors of 1.8% and 2.8% at these comparative regions of interest sizes. In comparison, the 25 mm cone had negligible differences in the measured output factor between zero extrapolation, 0.5 and 1.0 mm diameter ROIs, respectively. CONCLUSIONS: This work shows that for very small fields such as 4.0 mm cone sizes, a measureable difference can be seen in the relative output factor based on the circular ROI and the size of the area of analysis using radiochromic film dosimetry. The authors recommend to scan the Gafchromic EBT3 film at a resolution of 1200 dpi for cone sizes less than 7.5 mm and to utilize an extrapolation technique for the output factor measurements of very small field dosimetry. PMID- 27487886 TI - Technical Note: A treatment plan comparison between dynamic collimation and a fixed aperture during spot scanning proton therapy for brain treatment. AB - PURPOSE: To quantitatively assess the advantages of energy-layer specific dynamic collimation system (DCS) versus a per-field fixed aperture for spot scanning proton therapy (SSPT). METHODS: Five brain cancer patients previously planned and treated with SSPT were replanned using an in-house treatment planning system capable of modeling collimated and uncollimated proton beamlets. The uncollimated plans, which served as a baseline for comparison, reproduced the target coverage and organ-at-risk sparing of the clinically delivered plans. The collimator opening for the fixed aperture-based plans was determined from the combined cross sections of the target in the beam's eye view over all energy layers which included an additional margin equivalent to the maximum beamlet displacement for the respective energy of that energy layer. The DCS-based plans were created by selecting appropriate collimator positions for each row of beam spots during a Raster-style scanning pattern which were optimized to maximize the dose contributions to the target and limited the dose delivered to adjacent normal tissue. RESULTS: The reduction of mean dose to normal tissue adjacent to the target, as defined by a 10 mm ring surrounding the target, averaged 13.65% (range: 11.8%-16.9%) and 5.18% (2.9%-7.1%) for the DCS and fixed aperture plans, respectively. The conformity index, as defined by the ratio of the volume of the 50% isodose line to the target volume, yielded an average improvement of 21.35% (19.4%-22.6%) and 8.38% (4.7%-12.0%) for the DCS and fixed aperture plans, respectively. CONCLUSIONS: The ability of the DCS to provide collimation to each energy layer yielded better conformity in comparison to fixed aperture plans. PMID- 27487887 TI - An integrated model-driven method for in-treatment upper airway motion tracking using cine MRI in head and neck radiation therapy. AB - PURPOSE: For the first time, MRI-guided radiation therapy systems can acquire cine images to dynamically monitor in-treatment internal organ motion. However, the complex head and neck (H&N) structures and low-contrast/resolution of on board cine MRI images make automatic motion tracking a very challenging task. In this study, the authors proposed an integrated model-driven method to automatically track the in-treatment motion of the H&N upper airway, a complex and highly deformable region wherein internal motion often occurs in an either voluntary or involuntary manner, from cine MRI images for the analysis of H&N motion patterns. METHODS: Considering the complex H&N structures and ensuring automatic and robust upper airway motion tracking, the authors firstly built a set of linked statistical shapes (including face, face-jaw, and face-jaw-palate) using principal component analysis from clinically approved contours delineated on a set of training data. The linked statistical shapes integrate explicit landmarks and implicit shape representation. Then, a hierarchical model-fitting algorithm was developed to align the linked shapes on the first image frame of a to-be-tracked cine sequence and to localize the upper airway region. Finally, a multifeature level set contour propagation scheme was performed to identify the upper airway shape change, frame-by-frame, on the entire image sequence. The multifeature fitting energy, including the information of intensity variations, edge saliency, curve geometry, and temporal shape continuity, was minimized to capture the details of moving airway boundaries. Sagittal cine MR image sequences acquired from three H&N cancer patients were utilized to demonstrate the performance of the proposed motion tracking method. RESULTS: The tracking accuracy was validated by comparing the results to the average of two manual delineations in 50 randomly selected cine image frames from each patient. The resulting average dice similarity coefficient (93.28% +/- 1.46%) and margin error (0.49 +/- 0.12 mm) showed good agreement between the automatic and manual results. The comparison with three other deformable model-based segmentation methods illustrated the superior shape tracking performance of the proposed method. Large interpatient variations of swallowing frequency, swallowing duration, and upper airway cross-sectional area were observed from the testing cine image sequences. CONCLUSIONS: The proposed motion tracking method can provide accurate upper airway motion tracking results, and enable automatic and quantitative identification and analysis of in-treatment H&N upper airway motion. By integrating explicit and implicit linked-shape representations within a hierarchical model-fitting process, the proposed tracking method can process complex H&N structures and low-contrast/resolution cine MRI images. Future research will focus on the improvement of method reliability, patient motion pattern analysis for providing more information on patient-specific prediction of structure displacements, and motion effects on dosimetry for better H&N motion management in radiation therapy. PMID- 27487888 TI - Technical Note: spektr 3.0-A computational tool for x-ray spectrum modeling and analysis. AB - PURPOSE: A computational toolkit (spektr 3.0) has been developed to calculate x ray spectra based on the tungsten anode spectral model using interpolating cubic splines (TASMICS) algorithm, updating previous work based on the tungsten anode spectral model using interpolating polynomials (TASMIP) spectral model. The toolkit includes a matlab (The Mathworks, Natick, MA) function library and improved user interface (UI) along with an optimization algorithm to match calculated beam quality with measurements. METHODS: The spektr code generates x ray spectra (photons/mm(2)/mAs at 100 cm from the source) using TASMICS as default (with TASMIP as an option) in 1 keV energy bins over beam energies 20-150 kV, extensible to 640 kV using the TASMICS spectra. An optimization tool was implemented to compute the added filtration (Al and W) that provides a best match between calculated and measured x-ray tube output (mGy/mAs or mR/mAs) for individual x-ray tubes that may differ from that assumed in TASMICS or TASMIP and to account for factors such as anode angle. RESULTS: The median percent difference in photon counts for a TASMICS and TASMIP spectrum was 4.15% for tube potentials in the range 30-140 kV with the largest percentage difference arising in the low and high energy bins due to measurement errors in the empirically based TASMIP model and inaccurate polynomial fitting. The optimization tool reported a close agreement between measured and calculated spectra with a Pearson coefficient of 0.98. CONCLUSIONS: The computational toolkit, spektr, has been updated to version 3.0, validated against measurements and existing models, and made available as open source code. Video tutorials for the spektr function library, UI, and optimization tool are available. PMID- 27487889 TI - Texture analyses of quantitative susceptibility maps to differentiate Alzheimer's disease from cognitive normal and mild cognitive impairment. AB - PURPOSE: Although a number of studies have focused on finding anatomical regions in which iron concentrations are high, no study has been conducted to examine the overall variations in susceptibility maps of Alzheimer's disease (AD). The objective of this study, therefore, was to differentiate AD from cognitive normal (CN) and mild cognitive impairment (MCI) using a texture analysis of quantitative susceptibility maps (QSMs). METHODS: The study was approved by the local institutional review board, and informed consent was obtained from all subjects. In each participant group-CN, MCI, and AD-18 elderly subjects were enrolled. A fully first-order flow-compensated 3D gradient-echo sequence was run to obtain axial magnitudes and phase images and to produce QSM data. Sagittal structural 3D T1-weighted (3DT1W) images were also obtained with the magnetization-prepared rapid acquisition of gradient-echo sequence to obtain brain tissue images. The first- and second-order texture parameters of the QSMs and 3DT1W images were obtained to evaluate group differences using a one-way analysis of covariance. RESULTS: For the first-order QSM analysis, mean, standard deviation, and covariance of signal intensity separated the subject groups (F = 5.191, p = 0.009). For the second-order analysis, angular second moment, contrast, and correlation separated the subject groups (F = 6.896, p = 0.002). Finally, a receiver operating characteristic curve analysis differentiated MCI from CN in white matter on the QSMs (z = 3.092, p = 0.0020). CONCLUSIONS: This was the first study to evaluate the textures of QSM in AD, which overcame the limitations of voxel-based analyses. The QSM texture analysis successfully distinguished both AD and MCI from CN and outperformed the voxel-based analysis using 3DT1-weighed images in separating MCI from CN. The first-order textures were more efficient in differentiating MCI from CN than did the second-order. PMID- 27487890 TI - Technical Note: Correction for intra-chamber dose gradients in reference dosimetry of flattening-filter-free MV photon beams. AB - PURPOSE: To estimate and correct for the volume averaging effect which results from the intra-chamber dose gradients when a Farmer ionization chamber (IC) is used for reference dosimetry in flattening-filter-free (FFF) MV photon beams. METHODS: An intra-chamber dose gradients correction factor (kicdg) to the charge reading of a Farmer IC is estimated by comparison to a small volume IC (~0.1 cm(3)), in the FFF beams of a TrueBeamTM (Varian, Inc.) linear accelerators. An independent estimate of the correction for the volume averaging effect (pvol) is deduced using the ratio of the active length (L) of the Farmer IC to the integral of a high-resolution FFF radial dose profile over this same length. RESULTS: Mean (sd) values for kicdg equal to 1.0025 (0.0025) for 6 MV-FFF, and equal to 1.0057 (0.0025) for 10 MV-FFF, were estimated based on four dosimetry sessions, performed in a time interval of six months. Similarly, pvol (Farmer) equal to 1.0030 (0.0003) for 6 MV-FFF, and equal to 1.0063 (0.0005) for 10 MV-FFF, were computed. CONCLUSIONS: The systematic bias which results from intra-chamber dose gradients when a Farmer IC is used for reference dosimetry in FFF MV photon beams is estimated to be -0.6% for 10 MV-FFF, and -0.3% for 6 MV-FFF, based on the obtained values of the factor kicdg. This bias can be corrected, within 0.1%, by the simple measure of pvol at the beginning of the dosimetry session. PMID- 27487891 TI - Introduction of a novel ultrahigh sensitivity collimator for brain SPECT imaging. AB - PURPOSE: Noise levels of brain SPECT images are highest in central regions, due to preferential attenuation of photons emitted from deep structures. To address this problem, the authors have designed a novel collimator for brain SPECT imaging that yields greatly increased sensitivity near the center of the brain without loss of resolution. This hybrid collimator consisted of ultrashort cone beam holes in the central regions and slant-holes in the periphery (USCB). We evaluated this collimator for quantitative brain imaging tasks. METHODS: Owing to the uniqueness of the USCB collimation, the hole pattern required substantial variations in collimator parameters. To utilize the lead-casting technique, the authors designed two supporting plates to position about 37 000 hexagonal, slightly tapered pins. The holes in the supporting plates were modeled to yield the desired focal length, hole length, and septal thickness. To determine the properties of the manufactured collimator and to compute the system matrix, the authors prepared an array of point sources that covered the entire detector area. Each point source contained 32 MUCi of Tc-99m at the first scan time. The array was imaged for 5 min at each of the 64 shifted locations to yield a 2-mm sampling distance, and hole parameters were calculated. The sensitivity was also measured using a point source placed along the central ray at several distances from the collimator face. High-count projection data from a five-compartment brain phantom were acquired with the three collimators on a dual-head SPECT/CT system. The authors calculated Cramer-Rao bounds on the precision of estimates of striatal and background activity concentration. In order to assess the new collimation system to detect changes in striatal activity, the authors evaluated the precision of measuring a 5% decrease in right putamen activity. The authors also reconstructed images of projection data obtained by summing data from the individual phantom compartments. RESULTS: The sensitivity of the novel cone-beam collimator varied with distance from the detector face; it was higher than that of the fan-beam collimator by factors ranging from 2.7 to 162. Examination of the projections of the point sources revealed that only a few holes were distorted or partially blocked, indicating that the intensive manual fabrication process was very successful. Better reconstructed phantom images were obtained from the USCB+FAN collimator pair than from either LEHR or FAN collimation. For the left caudate, located near the center of the brain, the detected counts were 9.8 (8.3) times higher for UCSB compared with LEHR (FAN), averaged over 60 views. The task specific SNR for detecting a 5% decrease in putamen uptake was 7.4 for USCB and 3.2 for LEHR. CONCLUSIONS: The authors have designed and manufactured a novel collimator for brain SPECT imaging. The sensitivity is much higher than that of a fan-beam collimator. Because of differences between the manufactured collimator and its design, reconstruction of the data requires a measured system matrix. The authors have demonstrated the potential of USCB collimation for improved precision in estimating striatal uptake. The novel collimator may be useful for early detection of Parkinson's disease, and for monitoring therapy response and disease progression. PMID- 27487892 TI - A patch-based pseudo-CT approach for MRI-only radiotherapy in the pelvis. AB - PURPOSE: In radiotherapy based only on magnetic resonance imaging (MRI), knowledge about tissue electron densities must be derived from the MRI. This can be achieved by converting the MRI scan to the so-called pseudo-computed tomography (pCT). An obstacle is that the voxel intensities in conventional MRI scans are not uniquely related to electron density. The authors previously demonstrated that a patch-based method could produce accurate pCTs of the brain using conventional T1-weighted MRI scans. The method was driven mainly by local patch similarities and relied on simple affine registrations between an atlas database of the co-registered MRI/CT scan pairs and the MRI scan to be converted. In this study, the authors investigate the applicability of the patch-based approach in the pelvis. This region is challenging for a method based on local similarities due to the greater inter-patient variation. The authors benchmark the method against a baseline pCT strategy where all voxels inside the body contour are assigned a water-equivalent bulk density. Furthermore, the authors implement a parallelized approximate patch search strategy to speed up the pCT generation time to a more clinically relevant level. METHODS: The data consisted of CT and T1-weighted MRI scans of 10 prostate patients. pCTs were generated using an approximate patch search algorithm in a leave-one-out fashion and compared with the CT using frequently described metrics such as the voxel-wise mean absolute error (MAEvox) and the deviation in water-equivalent path lengths. Furthermore, the dosimetric accuracy was tested for a volumetric modulated arc therapy plan using dose-volume histogram (DVH) point deviations and gamma-index analysis. RESULTS: The patch-based approach had an average MAEvox of 54 HU; median deviations of less than 0.4% in relevant DVH points and a gamma-index pass rate of 0.97 using a 1%/1 mm criterion. The patch-based approach showed a significantly better performance than the baseline water pCT in almost all metrics. The approximate patch search strategy was 70x faster than a brute-force search, with an average prediction time of 20.8 min. CONCLUSIONS: The authors showed that a patch-based method based on affine registrations and T1-weighted MRI could generate accurate pCTs of the pelvis. The main source of differences between pCT and CT was positional changes of air pockets and body outline. PMID- 27487893 TI - Optimization-based scatter estimation using primary modulation for computed tomography. AB - PURPOSE: Scatter reduces the image quality in computed tomography (CT), but scatter correction remains a challenge. A previously proposed primary modulation method simultaneously obtains the primary and scatter in a single scan. However, separating the scatter and primary in primary modulation is challenging because it is an underdetermined problem. In this study, an optimization-based scatter estimation (OSE) algorithm is proposed to estimate and correct scatter. METHODS: In the concept of primary modulation, the primary is modulated, but the scatter remains smooth by inserting a modulator between the x-ray source and the object. In the proposed algorithm, an objective function is designed for separating the scatter and primary. Prior knowledge is incorporated in the optimization-based framework to improve the accuracy of the estimation: (1) the primary is always positive; (2) the primary is locally smooth and the scatter is smooth; (3) the location of penumbra can be determined; and (4) the scatter-contaminated data provide knowledge about which part is smooth. RESULTS: The simulation study shows that the edge-preserving weighting in OSE improves the estimation accuracy near the object boundary. Simulation study also demonstrates that OSE outperforms the two existing primary modulation algorithms for most regions of interest in terms of the CT number accuracy and noise. The proposed method was tested on a clinical cone beam CT, demonstrating that OSE corrects the scatter even when the modulator is not accurately registered. CONCLUSIONS: The proposed OSE algorithm improves the robustness and accuracy in scatter estimation and correction. This method is promising for scatter correction of various kinds of x-ray imaging modalities, such as x-ray radiography, cone beam CT, and the fourth-generation CT. PMID- 27487894 TI - Optimization of yttrium-90 PET for simultaneous PET/MR imaging: A phantom study. AB - PURPOSE: Positron emission tomography (PET) imaging of yttrium-90 in the liver post radioembolization has been shown useful for personalized dosimetry calculations and evaluation of extrahepatic deposition. The purpose of this study was to quantify the benefits of several MR-based data correction approaches offered by using a combined PET/MR system to improve Y-90 PET imaging. In particular, the feasibility of motion and partial volume corrections were investigated in a controlled phantom study. METHODS: The ACR phantom was filled with an initial concentration of 8 GBq of Y-90 solution resulting in a contrast of 10:1 between the hot cylinders and the background. Y-90 PET motion correction through motion estimates from MR navigators was evaluated by using a custom-built motion stage that simulated realistic amplitudes of respiration-induced liver motion. Finally, the feasibility of an MR-based partial volume correction method was evaluated using a wavelet decomposition approach. RESULTS: Motion resulted in a large (~40%) loss of contrast recovery for the 8 mm cylinder in the phantom, but was corrected for after MR-based motion correction was applied. Partial volume correction improved contrast recovery by 13% for the 8 mm cylinder. CONCLUSIONS: MR-based data correction improves Y-90 PET imaging on simultaneous PET/MR systems. Assessment of these methods must be studied further in the clinical setting. PMID- 27487895 TI - Development of bimetallic (Zn@Au) nanoparticles as potential PET-imageable radiosensitizers. AB - PURPOSE: Gold nanoparticles (GNPs) are being investigated actively for various applications in cancer diagnosis and therapy. As an effort to improve the imaging of GNPs in vivo, the authors developed bimetallic hybrid Zn@Au NPs with zinc cores and gold shells, aiming to render them in vivo visibility through positron emission tomography (PET) after the proton activation of the zinc core as well as capability to induce radiosensitization through the secondary electrons produced from the gold shell when irradiated by various radiation sources. METHODS: Nearly spherical zinc NPs (~5-nm diameter) were synthesized and then coated with a ~4.25 nm gold layer to make Zn@Au NPs (~13.5-nm total diameter). 28.6 mg of these Zn@Au NPs was deposited (~100 MUm thick) on a thin cellulose target and placed in an aluminum target holder and subsequently irradiated with 14.15-MeV protons from a GE PETtrace cyclotron with 5-MUA current for 5 min. After irradiation, the cellulose matrix with the NPs was placed in a dose calibrator to assess the induced radioactivity. The same procedure was repeated with 8-MeV protons. Gamma ray spectroscopy using an high-purity germanium detector was conducted on a very small fraction (<1 mg) of the irradiated NPs for each proton energy. In addition to experimental measurements, Monte Carlo simulations were also performed with radioactive Zn@Au NPs and solid GNPs of the same size irradiated with 160-MeV protons and 250-kVp x-rays. RESULTS: The authors measured 168 MUCi of activity 32 min after the end of bombardment for the 14.15-MeV proton energy sample using the (66)Ga setting on a dose calibrator; activity decreased to 2 MUCi over a 24-h period. For the 8-MeV proton energy sample, PET imaging was additionally performed for 5 min after a 12-h delay. A 12-h gamma ray spectrum showed strong peaks at 511 keV (2.05 * 10(6) counts) with several other peaks of smaller magnitude for each proton energy sample. PET imaging showed strong PET signals from mostly decaying (66)Ga. The Monte Carlo results showed that radioactive Zn@Au NPs and solid GNPs provided similar characteristics in terms of their secondary electron spectra when irradiated. CONCLUSIONS: The Zn@Au NPs developed in this investigation have the potential to be used as PET-imageable radiosensitizers for radiotherapy applications as well as PET tracers for molecular imaging applications. PMID- 27487896 TI - Technical Report: Evaluation of peripheral dose for flattening filter free photon beams. AB - PURPOSE: To develop a comprehensive peripheral dose (PD) dataset for the two unflattened beams of nominal energy 6 and 10 MV for use in clinical care. METHODS: Measurements were made in a 40 * 120 * 20 cm(3) (width * length * depth) stack of solid water using an ionization chamber at varying depths (dmax, 5, and 10 cm), field sizes (3 * 3 to 30 * 30 cm(2)), and distances from the field edge (5-40 cm). The effects of the multileaf collimator (MLC) and collimator rotation were also evaluated for a 10 * 10 cm(2) field. Using the same phantom geometry, the accuracy of the analytic anisotropic algorithm (AAA) and Acuros dose calculation algorithm was assessed and compared to the measured values. RESULTS: The PDs for both the 6 flattening filter free (FFF) and 10 FFF photon beams were found to decrease with increasing distance from the radiation field edge and the decreasing field size. The measured PD was observed to be higher for the 6 FFF than for the 10 FFF for all field sizes and depths. The impact of collimator rotation was not found to be clinically significant when used in conjunction with MLCs. AAA and Acuros algorithms both underestimated the PD with average errors of -13.6% and -7.8%, respectively, for all field sizes and depths at distances of 5 and 10 cm from the field edge, but the average error was found to increase to nearly -69% at greater distances. CONCLUSIONS: Given the known inaccuracies of peripheral dose calculations, this comprehensive dataset can be used to estimate the out-of-field dose to regions of interest such as organs at risk, electronic implantable devices, and a fetus. While the impact of collimator rotation was not found to significantly decrease PD when used in conjunction with MLCs, results are expected to be machine model and beam energy dependent. It is not recommended to use a treatment planning system to estimate PD due to the underestimation of the out-of-field dose and the inability to calculate dose at extended distances due to the limits of the dose calculation matrix. PMID- 27487897 TI - Technical Note: Dose effects of 1.5 T transverse magnetic field on tissue interfaces in MRI-guided radiotherapy. AB - PURPOSE: The integration of MRI with a linear accelerator (MR-linac) offers great potential for high-precision delivery of radiation therapy (RT). However, the electron deflection resulting from the presence of a transverse magnetic field (TMF) can affect the dose distribution, particularly the electron return effect (ERE) at tissue interfaces. The purpose of the study is to investigate the dose effects of ERE at air-tissue and lung-tissue interfaces during intensity modulated radiation therapy (IMRT) planning. METHODS: IMRT and volumetric modulated arc therapy (VMAT) plans for representative pancreas, lung, breast, and head and neck (HN) cases were generated following commonly used clinical dose volume (DV) criteria. In each case, three types of plans were generated: (1) the original plan generated without a TMF; (2) the reconstructed plan generated by recalculating the original plan with the presence of a TMF of 1.5 T (no optimization); and (3) the optimized plan generated by a full optimization with TMF = 1.5 T. These plans were compared using a variety of DV parameters, including V100%, D95%, DHI [dose heterogeneity index: (D20%-D80%)/Dprescription], Dmax, and D1cc in OARs (organs at risk) and tissue interface. All the optimizations and calculations in this work were performed on static data. RESULTS: The dose recalculation under TMF showed the presence of the 1.5 T TMF can slightly reduce V100% and D95% for PTV, with the differences being less than 4% for all but one lung case studied. The TMF results in considerable increases in Dmax and D1cc on the skin in all cases, mostly between 10% and 35%. The changes in Dmax and D1cc on air cavity walls are dependent upon site, geometry, and size, with changes ranging up to 15%. The VMAT plans lead to much smaller dose effects from ERE compared to fixed-beam IMRT in pancreas case. When the TMF is considered in the plan optimization, the dose effects of the TMF at tissue interfaces (e.g., air-cavity wall, lung-tissue interfaces, skin) are significantly reduced in most cases. CONCLUSIONS: The doses on tissue interfaces can be significantly changed by the presence of a TMF during MR-guided RT when the magnetic field is not included in plan optimization. These changes can be substantially reduced or even eliminated during VMAT/IMRT optimization that specifically considers the TMF, without deteriorating overall plan quality. PMID- 27487898 TI - Technical Note: Robust measurement of the slice-sensitivity profile in breast tomosynthesis. AB - PURPOSE: The purpose of this work is to improve the repeatability of the measurement of the slice-sensitivity profile (SSP) in reconstructed breast tomosynthesis volumes. METHODS: A grid of aluminum ball-bearings (BBs) within a PMMA phantom was imaged on breast tomosynthesis systems from three different manufacturers. The full-width half-maximum (FWHM) values were measured for the SSPs of the BBs in the reconstructed volumes. The effect of transforming the volumes from a Cartesian coordinate system (CCS) to a cone-beam coordinate system (CBCS) on the variability in the FWHM values was assessed. RESULTS: Transforming the volumes from a CCS to a CBCS before measuring the SSPs reduced the coefficient of variation (COV) in the measurements of FWHM in repeated measurements by 56% and reduced the dependence of the FWHM values on the location of the BBs within the reconstructed volume by 76%. CONCLUSIONS: Measuring the SSP in the volumes in a CBCS improves the robustness of the measurement. PMID- 27487899 TI - Integrated PET/MR breast cancer imaging: Attenuation correction and implementation of a 16-channel RF coil. AB - PURPOSE: This study aims to develop, implement, and evaluate a 16-channel radiofrequency (RF) coil for integrated positron emission tomography/magnetic resonance (PET/MR) imaging of breast cancer. The RF coil is designed for optimized MR imaging performance and PET transparency and attenuation correction (AC) is applied for accurate PET quantification. METHODS: A 16-channel breast array RF coil was designed for integrated PET/MR hybrid imaging of breast cancer lesions. The RF coil features a lightweight rigid design and is positioned with a spacer at a defined position on the patient table of an integrated PET/MR system. Attenuation correction is performed by generating and applying a dedicated 3D CT based template attenuation map. Reposition accuracy of the RF coil on the system patient table while using the positioning frame was tested in repeated measurements using MR-visible markers. The MR, PET, and PET/MR imaging performances were systematically evaluated using modular breast phantoms. Attenuation correction of the RF coil was evaluated with difference measurements of the active breast phantoms filled with radiotracer in the PET detector with and without the RF coil in place, serving as a standard of reference measurement. The overall PET/MR imaging performance and PET quantification accuracy of the new 16-channel RF coil and its AC were then evaluated in first clinical examinations on ten patients with local breast cancer. RESULTS: The RF breast array coil provides excellent signal-to-noise ratio and signal homogeneity across the volume of the breast phantoms in MR imaging and visualizes small structures in the phantoms down to 0.4 mm in plane. Difference measurements with PET revealed a global loss and thus attenuation of counts by 13% (mean value across the whole phantom volume) when the RF coil is placed in the PET detector. Local attenuation ranging from 0% in the middle of the phantoms up to 24% was detected in the peripheral regions of the phantoms at positions closer to attenuating hardware structures of the RF coil. The position accuracy of the RF coil on the patient table when using the positioning frame was determined well below 1 mm for all three spatial dimensions. This ensures perfect position match between the RF coil and its three-dimensional attenuation template during the PET data reconstruction process. When applying the CT-based AC of the RF coil, the global attenuation bias was mostly compensated to +/-0.5% across the entire breast imaging volume. The patient study revealed high quality MR, PET, and combined PET/MR imaging of breast cancer. Quantitative activity measurements in all 11 breast cancer lesions of the ten patients resulted in increased mean difference values of SUVmax 11.8% (minimum 3.2%; maximum 23.2%) between nonAC images and images when AC of the RF breast coil was applied. This supports the quantitative results of the phantom study as well as successful attenuation correction of the RF coil. CONCLUSIONS: A 16-channel breast RF coil was designed for optimized MR imaging performance and PET transparency and was successfully integrated with its dedicated attenuation correction template into a whole-body PET/MR system. Systematic PET/MR imaging evaluation with phantoms and an initial study on patients with breast cancer provided excellent MR and PET image quality and accurate PET quantification. PMID- 27487900 TI - Technical Note: Evaluation of a 160-mm/256-row CT scanner for whole-heart quantitative myocardial perfusion imaging. AB - PURPOSE: The authors investigated the performance of a recently introduced 160 mm/256-row CT system for low dose quantitative myocardial perfusion (MP) imaging of the whole heart. This platform is equipped with a gantry capable of rotating at 280 ms per full cycle, a second generation of adaptive statistical iterative reconstruction (ASiR-V) to correct for image noise arising from low tube voltage potential/tube current dynamic scanning, and image reconstruction algorithms to tackle beam-hardening, cone-beam, and partial-scan effects. METHODS: Phantom studies were performed to investigate the effectiveness of image noise and artifact reduction with a GE Healthcare Revolution CT system for three acquisition protocols used in quantitative CT MP imaging: 100, 120, and 140 kVp/25 mAs. The heart chambers of an anthropomorphic chest phantom were filled with iodinated contrast solution at different concentrations (contrast levels) to simulate the circulation of contrast through the heart in quantitative CT MP imaging. To evaluate beam-hardening correction, the phantom was scanned at each contrast level to measure the changes in CT number (in Hounsfield unit or HU) in the water-filled region surrounding the heart chambers with respect to baseline. To evaluate cone-beam artifact correction, differences in mean water HU between the central and peripheral slices were compared. Partial-scan artifact correction was evaluated from the fluctuation of mean water HU in successive partial scans. To evaluate image noise reduction, a small hollow region adjacent to the heart chambers was filled with diluted contrast, and contrast-to-noise ratio in the region before and after noise correction with ASiR-V was compared. The quality of MP maps acquired with the CT system was also evaluated in porcine CT MP studies. Myocardial infarct was induced in a farm pig from a transient occlusion of the distal left anterior descending (LAD) artery with a catheter-based interventional procedure. MP maps were generated from the dynamic contrast-enhanced (DCE) heart images taken at baseline and three weeks after the ischemic insult. RESULTS: Their results showed that the phantom and animal images acquired with the CT platform were minimally affected by image noise and artifacts. For the beam hardening phantom study, changes in water HU in the wall surrounding the heart chambers greatly reduced from >+/-30 to <= +/- 5 HU at all kVp settings except one region at 100 kVp (7 HU). For the cone-beam phantom study, differences in mean water HU from the central slice were less than 5 HU at two peripheral slices with each 4 cm away from the central slice. These findings were reproducible in the pig DCE images at two peripheral slices that were 6 cm away from the central slice. For the partial-scan phantom study, standard deviations of the mean water HU in 10 successive partial scans were less than 5 HU at the central slice. Similar observations were made in the pig DCE images at two peripheral slices with each 6 cm away from the central slice. For the image noise phantom study, CNRs in the ASiR-V images were statistically higher (p < 0.05) than the non-ASiR V images at all kVp settings. MP maps generated from the porcine DCE images were in excellent quality, with the ischemia in the LAD territory clearly seen in the three orthogonal views. CONCLUSIONS: The study demonstrates that this CT system can provide accurate and reproducible CT numbers during cardiac gated acquisitions across a wide axial field of view. This CT number fidelity will enable this imaging tool to assess contrast enhancement, potentially providing valuable added information beyond anatomic evaluation of coronary stenoses. Furthermore, their results collectively suggested that the 100 kVp/25 mAs protocol run on this CT system provides sufficient image accuracy at a low radiation dose (<3 mSv) for whole-heart quantitative CT MP imaging. PMID- 27487901 TI - Patient positioning in radiotherapy based on surface imaging using time of flight cameras. AB - PURPOSE: To evaluate the patient positioning accuracy in radiotherapy using a stereo-time of flight (ToF)-camera system. METHODS: A system using two ToF cameras was used to scan the surface of the patients in order to position them daily on the treatment couch. The obtained point clouds were registered to (a) detect translations applied to the table (intrafraction motion) and (b) predict the displacement to be applied in order to place the patient in its reference position (interfraction motion). The measures provided by this system were compared to the effectively applied translations. The authors analyzed 150 fractions including lung, pelvis/prostate, and head and neck cancer patients. RESULTS: The authors obtained small absolute errors for displacement detection: 0.8 +/- 0.7, 0.8 +/- 0.7, and 0.7 +/- 0.6 mm along the vertical, longitudinal, and lateral axes, respectively, and 0.8 +/- 0.7 mm for the total norm displacement. Lung cancer patients presented the largest errors with a respective mean of 1.1 +/- 0.9, 0.9 +/- 0.9, and 0.8 +/- 0.7 mm. CONCLUSIONS: The proposed stereo-ToF system allows for sufficient accuracy and faster patient repositioning in radiotherapy. Its capability to track the complete patient surface in real time could allow, in the future, not only for an accurate positioning but also a real time tracking of any patient intrafraction motion (translation, involuntary, and breathing). PMID- 27487902 TI - Modification and validation of an analytical source model for external beam radiotherapy Monte Carlo dose calculations. AB - PURPOSE: A dose calculation tool, which combines the accuracy of the dose planning method (DPM) Monte Carlo code and the versatility of a practical analytical multisource model, which was previously reported has been improved and validated for the Varian 6 and 10 MV linear accelerators (linacs). The calculation tool can be used to calculate doses in advanced clinical application studies. One shortcoming of current clinical trials that report dose from patient plans is the lack of a standardized dose calculation methodology. Because commercial treatment planning systems (TPSs) have their own dose calculation algorithms and the clinical trial participant who uses these systems is responsible for commissioning the beam model, variation exists in the reported calculated dose distributions. Today's modern linac is manufactured to tight specifications so that variability within a linac model is quite low. The expectation is that a single dose calculation tool for a specific linac model can be used to accurately recalculate dose from patient plans that have been submitted to the clinical trial community from any institution. The calculation tool would provide for a more meaningful outcome analysis. METHODS: The analytical source model was described by a primary point source, a secondary extra-focal source, and a contaminant electron source. Off-axis energy softening and fluence effects were also included. The additions of hyperbolic functions have been incorporated into the model to correct for the changes in output and in electron contamination with field size. A multileaf collimator (MLC) model is included to facilitate phantom and patient dose calculations. An offset to the MLC leaf positions was used to correct for the rudimentary assumed primary point source. RESULTS: Dose calculations of the depth dose and profiles for field sizes 4 * 4 to 40 * 40 cm agree with measurement within 2% of the maximum dose or 2 mm distance to agreement (DTA) for 95% of the data points tested. The model was capable of predicting the depth of the maximum dose within 1 mm. Anthropomorphic phantom benchmark testing of modulated and patterned MLCs treatment plans showed agreement to measurement within 3% in target regions using thermoluminescent dosimeters (TLD). Using radiochromic film normalized to TLD, a gamma criteria of 3% of maximum dose and 2 mm DTA was applied with a pass rate of least 85% in the high dose, high gradient, and low dose regions. Finally, recalculations of patient plans using DPM showed good agreement relative to a commercial TPS when comparing dose volume histograms and 2D dose distributions. CONCLUSIONS: A unique analytical source model coupled to the dose planning method Monte Carlo dose calculation code has been modified and validated using basic beam data and anthropomorphic phantom measurement. While this tool can be applied in general use for a particular linac model, specifically it was developed to provide a singular methodology to independently assess treatment plan dose distributions from those clinical institutions participating in National Cancer Institute trials. PMID- 27487903 TI - Variability in CT lung-nodule quantification: Effects of dose reduction and reconstruction methods on density and texture based features. AB - PURPOSE: To investigate the effects of dose level and reconstruction method on density and texture based features computed from CT lung nodules. METHODS: This study had two major components. In the first component, a uniform water phantom was scanned at three dose levels and images were reconstructed using four conventional filtered backprojection (FBP) and four iterative reconstruction (IR) methods for a total of 24 different combinations of acquisition and reconstruction conditions. In the second component, raw projection (sinogram) data were obtained for 33 lung nodules from patients scanned as a part of their clinical practice, where low dose acquisitions were simulated by adding noise to sinograms acquired at clinical dose levels (a total of four dose levels) and reconstructed using one FBP kernel and two IR kernels for a total of 12 conditions. For the water phantom, spherical regions of interest (ROIs) were created at multiple locations within the water phantom on one reference image obtained at a reference condition. For the lung nodule cases, the ROI of each nodule was contoured semiautomatically (with manual editing) from images obtained at a reference condition. All ROIs were applied to their corresponding images reconstructed at different conditions. For 17 of the nodule cases, repeat contours were performed to assess repeatability. Histogram (eight features) and gray level co-occurrence matrix (GLCM) based texture features (34 features) were computed for all ROIs. For the lung nodule cases, the reference condition was selected to be 100% of clinical dose with FBP reconstruction using the B45f kernel; feature values calculated from other conditions were compared to this reference condition. A measure was introduced, which the authors refer to as Q, to assess the stability of features across different conditions, which is defined as the ratio of reproducibility (across conditions) to repeatability (across repeat contours) of each feature. RESULTS: The water phantom results demonstrated substantial variability among feature values calculated across conditions, with the exception of histogram mean. Features calculated from lung nodules demonstrated similar results with histogram mean as the most robust feature (Q <= 1), having a mean and standard deviation Q of 0.37 and 0.22, respectively. Surprisingly, histogram standard deviation and variance features were also quite robust. Some GLCM features were also quite robust across conditions, namely, diff. variance, sum variance, sum average, variance, and mean. Except for histogram mean, all features have a Q of larger than one in at least one of the 3% dose level conditions. CONCLUSIONS: As expected, the histogram mean is the most robust feature in their study. The effects of acquisition and reconstruction conditions on GLCM features vary widely, though trending toward features involving summation of product between intensities and probabilities being more robust, barring a few exceptions. Overall, care should be taken into account for variation in density and texture features if a variety of dose and reconstruction conditions are used for the quantification of lung nodules in CT, otherwise changes in quantification results may be more reflective of changes due to acquisition and reconstruction conditions than in the nodule itself. PMID- 27487904 TI - Resolution recovery for Compton camera using origin ensemble algorithm. AB - PURPOSE: Compton cameras (CCs) use electronic collimation to reconstruct the images of activity distribution. Although this approach can greatly improve imaging efficiency, due to complex geometry of the CC principle, image reconstruction with the standard iterative algorithms, such as ordered subset expectation maximization (OSEM), can be very time-consuming, even more so if resolution recovery (RR) is implemented. We have previously shown that the origin ensemble (OE) algorithm can be used for the reconstruction of the CC data. Here we propose a method of extending our OE algorithm to include RR. METHODS: To validate the proposed algorithm we used Monte Carlo simulations of a CC composed of multiple layers of pixelated CZT detectors and designed for imaging small animals. A series of CC acquisitions of small hot spheres and the Derenzo phantom placed in air were simulated. Images obtained from (a) the exact data, (b) blurred data but reconstructed without resolution recovery, and (c) blurred and reconstructed with resolution recovery were compared. Furthermore, the reconstructed contrast-to-background ratios were investigated using the phantom with nine spheres placed in a hot background. RESULTS: Our simulations demonstrate that the proposed method allows for the recovery of the resolution loss that is due to imperfect accuracy of event detection. Additionally, tests of camera sensitivity corresponding to different detector configurations demonstrate that the proposed CC design has sensitivity comparable to PET. When the same number of events were considered, the computation time per iteration increased only by a factor of 2 when OE reconstruction with the resolution recovery correction was performed relative to the original OE algorithm. We estimate that the addition of resolution recovery to the OSEM would increase reconstruction times by 2-3 orders of magnitude per iteration. CONCLUSIONS: The results of our tests demonstrate the improvement of image resolution provided by the OE reconstructions with resolution recovery. The quality of images and their contrast are similar to those obtained from the OE reconstructions from scans simulated with perfect energy and spatial resolutions. PMID- 27487905 TI - Image quality comparison between single energy and dual energy CT protocols for hepatic imaging. AB - PURPOSE: Multi-detector computed tomography (MDCT) enables volumetric scans in a single breath hold and is clinically useful for hepatic imaging. For simple tasks, conventional single energy (SE) computed tomography (CT) images acquired at the optimal tube potential are known to have better quality than dual energy (DE) blended images. However, liver imaging is complex and often requires imaging of both structures containing iodinated contrast media, where atomic number differences are the primary contrast mechanism, and other structures, where density differences are the primary contrast mechanism. Hence it is conceivable that the broad spectrum used in a dual energy acquisition may be an advantage. In this work we are interested in comparing these two imaging strategies at equal dose and more complex settings. METHODS: We developed numerical anthropomorphic phantoms to mimic realistic clinical CT scans for medium size and large size patients. MDCT images based on the defined phantoms were simulated using various SE and DE protocols at pre- and post-contrast stages. For SE CT, images from 60 kVp through 140 with 10 kVp steps were considered; for DE CT, both 80/140 and 100/140 kVp scans were simulated and linearly blended at the optimal weights. To make a fair comparison, the mAs of each scan was adjusted to match the reference radiation dose (120 kVp, 200 mAs for medium size patients and 140 kVp, 400 mAs for large size patients). Contrast-to-noise ratio (CNR) of liver against other soft tissues was used to evaluate and compare the SE and DE protocols, and multiple pre- and post-contrasted liver-tissue pairs were used to define a composite CNR. To help validate the simulation results, we conducted a small clinical study. Eighty-five 120 kVp images and 81 blended 80/140 kVp images were collected and compared through both quantitative image quality analysis and an observer study. RESULTS: In the simulation study, we found that the CNR of pre contrast SE image mostly increased with increasing kVp while for post-contrast imaging 90 kVp or lower yielded higher CNR images, depending on the differential iodine concentration of each tissue. Similar trends were seen in DE blended CNR and those from SE protocols. In the presence of differential iodine concentration (i.e., post-contrast), the CNR curves maximize at lower kVps (80-120), with the peak shifted rightward for larger patients. The combined pre- and post-contrast composite CNR study demonstrated that an optimal SE protocol has better performance than blended DE images, and the optimal tube potential for SE scan is around 90 kVp for a medium size patients and between 90 and 120 kVp for large size patients (although low kVp imaging requires high x-ray tube power to avoid photon starvation). Also, a tin filter added to the high kVp beam is not only beneficial for material decomposition but it improves the CNR of the DE blended images as well. The dose adjusted CNR of the clinical images also showed the same trend and radiologists favored the SE scans over blended DE images. CONCLUSIONS: Our simulation showed that an optimized SE protocol produces up to 5% higher CNR for a range of clinical tasks. The clinical study also suggested 120 kVp SE scans have better image quality than blended DE images. Hence, blended DE images do not have a fundamental CNR advantage over optimized SE images. PMID- 27487906 TI - Delivered dose uncertainty analysis at the tumor apex for ocular brachytherapy. AB - PURPOSE: To estimate the total dosimetric uncertainty at the tumor apex for ocular brachytherapy treatments delivered using 16 mm Collaborative Ocular Melanoma Study (COMS) and Super9 plaques loaded with (125)I seeds in order to determine the size of the apex margin that would be required to ensure adequate dosimetric coverage of the tumor. METHODS: The total dosimetric uncertainty was assessed for three reference tumor heights: 3, 5, and 10 mm, using the Guide to the expression of Uncertainty in Measurement/National Institute of Standards and Technology approach. Uncertainties pertaining to seed construction, source strength, plaque assembly, treatment planning calculations, tumor height measurement, plaque placement, and plaque tilt for a simple dome-shaped tumor were investigated and quantified to estimate the total dosimetric uncertainty at the tumor apex. Uncertainties in seed construction were determined using EBT3 Gafchromic film measurements around single seeds, plaque assembly uncertainties were determined using high resolution microCT scanning of loaded plaques to measure seed positions in the plaques, and all other uncertainties were determined from the previously published studies and recommended values. All dose calculations were performed using plaque simulator v5.7.6 ophthalmic treatment planning system with the inclusion of plaque heterogeneity corrections. RESULTS: The total dosimetric uncertainties at 3, 5, and 10 mm tumor heights for the 16 mm COMS plaque were 17.3%, 16.1%, and 14.2%, respectively, and for the Super9 plaque were 18.2%, 14.4%, and 13.1%, respectively (all values with coverage factor k = 2). The apex margins at 3, 5, and 10 mm tumor heights required to adequately account for these uncertainties were 1.3, 1.3, and 1.4 mm, respectively, for the 16 mm COMS plaque, and 1.8, 1.4, and 1.2 mm, respectively, for the Super9 plaque. These uncertainties and associated margins are dependent on the dose gradient at the given prescription depth, thus resulting in the changing uncertainties and margins with depth. CONCLUSIONS: The margins determined in this work can be used as a guide for determining an appropriate apex margin for a given treatment, which can be chosen based on the tumor height. The required margin may need to be increased for more complex scenarios (mushroom shaped tumors, tumors close to the optic nerve, oblique muscle related tilt, etc.) than the simple dome-shaped tumor examined and should be chosen on a case-by-case basis. The sources of uncertainty contributing most significantly to the total dosimetric uncertainty are seed placement within the plaques, treatment planning calculations, tumor height measurement, and plaque tilt. This work presents an uncertainty-based, rational approach to estimating an appropriate apex margin. PMID- 27487907 TI - CNR considerations for rapid real-time MRI tumor tracking in radiotherapy hybrid devices: Effects of B0 field strength. AB - PURPOSE: This work examines the subject of contrast-to-noise ratio (CNR), specifically between tumor and tissue background, and its dependence on the MRI field strength, B0. This examination is motivated by the recent interest and developments in MRI/radiotherapy hybrids where real-time imaging can be used to guide treatment beams. The ability to distinguish a tumor from background tissue is of primary importance in this field, and this work seeks to elucidate the complex relationship between the CNR and B0 that is too often assumed to be purely linear. METHODS: Experimentally based models of B0-dependant relaxation for various tumor and normal tissues from the literature were used in conjunction with signal equations for MR sequences suitable for rapid real-time imaging to develop field-dependent predictions for CNR. These CNR models were developed for liver, lung, breast, glioma, and kidney tumors for spoiled gradient-echo, balanced steady-state free precession (bSSFP), and single-shot half-Fourier fast spin echo sequences. RESULTS: Due to the pattern in which the relaxation properties of tissues are found to vary over B0 field (specifically the T1 time), there was always an improved CNR at lower fields compared to linear dependency. Further, in some tumor sites, the CNR at lower fields was found to be comparable to, or sometimes higher than those at higher fields (i.e., bSSFP CNR for glioma, kidney, and liver tumors). CONCLUSIONS: In terms of CNR, lower B0 fields have been shown to perform as well or better than higher fields for some tumor sites due to superior T1 contrast. In other sites this effect was less pronounced, reversing the CNR advantage. This complex relationship between CNR and B0 reveals both low and high magnetic fields as viable options for tumor tracking in MRI/radiotherapy hybrids. PMID- 27487908 TI - Reference dosimetry in magnetic fields: formalism and ionization chamber correction factors. AB - PURPOSE: Magnetic resonance imaging-guided radiotherapy (MRIgRT) provides superior soft-tissue contrast and real-time imaging compared with standard image guided RT, which uses x-ray based imaging. Several groups are developing integrated MRIgRT machines. Reference dosimetry with these new machines requires accounting for the effects of the magnetic field on the response of the ionization chambers used for dose calibration. Here, the authors propose a formalism for reference dosimetry with integrated MRIgRT devices. The authors also examined the suitability of the TPR10 (20) and %dd(10)x beam quality specifiers in the presence of magnetic fields and calculated detector correction factors to account for the effects of the magnetic field for a range of detectors. METHODS: The authors used full-head and point-source Monte Carlo models of an MR-linac along with detailed detector models of an Exradin A19, an NE2571, and several PTW Farmer chambers to calculate magnetic field correction factors for six commercial ionization chambers in three chamber configurations. Calculations of ionization chamber response (performed with geant4) were validated with specialized Fano cavity tests. %dd(10)x values, TPR10 (20) values, and Spencer-Attix water-to-air restricted stopping power ratios were also calculated. The results were further validated against measurements made with a preclinical functioning MR-linac. RESULTS: The TPR10 (20) was found to be insensitive to the presence of the magnetic field, whereas the relative change in %dd(10)x was 2.4% when a transverse 1.5 T field was applied. The parameters chosen for the ionization chamber calculations passed the Fano cavity test to within ~0.1%. Magnetic field correction factors varied in magnitude with detector orientation with the smallest corrections found when the chamber was parallel to the magnetic field. CONCLUSIONS: Reference dosimetry can be performed with integrated MRIgRT devices by using magnetic field correction factors, but care must be taken with the choice of beam quality specifier and chamber orientation. The uncertainties achievable under this formalism should be similar to those of conventional formalisms, although this must be further quantified. PMID- 27487909 TI - Transversus abdominis plane block after laparoscopic colonic resection in cancer patients: A randomised clinical trial. AB - BACKGROUND: A key point in pathways for optimal rehabilitation and enhanced recovery is an effective postoperative multimodal pain treatment regimen. OBJECTIVE: To investigate the analgesic effects of transversus abdominis plane (TAP) block in conjunction with paracetamol and ibuprofen in patients undergoing laparoscopic colonic resection. DESIGN: Randomised placebo-controlled double blind study. SETTING: Herlev University Hospital, Copenhagen, Denmark, from March 2010 to February 2013. PATIENTS: Eighty adult patients scheduled for elective laparoscopic colectomy. INTERVENTIONS: Bilateral TAP block with 20 ml of either ropivacaine or isotonic saline. MAIN OUTCOME MEASURES: Visual analogue scale (VAS) pain scores (0 to 100 mm) while coughing at 6 h after surgery (primary outcome). Secondary outcomes were area under the curve pain scores (2 to 24 h) at rest and while coughing, 24-h morphine consumption and incidence of nausea and vomiting. RESULTS: VAS pain scores at 6 h while coughing was not different between groups (median, interquartile range), TAP, 27 (11 to 45) mm vs. placebo, 33 (20 to 49) mm (P = 0.20). Total 24-h morphine consumption was reduced in the TAP block group vs. placebo group, 30 (15 to 41) mg vs. 43 (30 to 67) mg, respectively (P = 0.008). This difference was most pronounced in the first postoperative hours. The remaining outcomes did not differ between groups. CONCLUSION: TAP block used in combination with paracetamol and ibuprofen did not reduce pain after laparoscopic colonic surgery. However, we found a 30% reduction in opioid use, most marked in the early postoperative period. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01418144). PMID- 27487910 TI - Implementation of patient blood management remains extremely variable in Europe and Canada: the NATA benchmark project: An observational study. AB - BACKGROUND: Preoperative anaemia is associated with increased postoperative morbidity and mortality. Patient blood management (PBM) is advocated to improve patient outcomes. OBJECTIVES: NATA, the 'Network for the advancement of patient blood management, haemostasis and thrombosis', initiated a benchmark project with the aim of providing the basis for educational strategies to implement optimal PBM in participating centres. DESIGN: Prospective, observational study with online data collection in 11 secondary and tertiary care institutions interested in developing PBM. SETTING: Ten European centres (Austria, Spain, England, Denmark, Belgium, Netherlands, Romania, Greece, France, and Germany) and one Canadian centre participated between January 2010 and June 2011. PATIENTS: A total of 2470 patients undergoing total hip (THR) or knee replacement, or coronary artery bypass grafting (CABG), were registered in the study. Data from 2431 records were included in the final analysis. MAIN OUTCOME MEASURES: Primary outcome measures were the incidence and volume of red blood cells (RBC) transfused. Logistic regression analysis identified variables independently associated with RBC transfusions. RESULTS: The incidence of transfusion was significantly different between centres for THR (range 7 to 95%), total knee replacement (range 3 to 100%) and CABG (range 20 to 95%). The volume of RBC transfused was significantly different between centres for THR and CABG. The incidence of preoperative anaemia ranged between 3 and 40% and its treatment between 0 and 40%, the latter not being related to the former. Patient characteristics, evolution of haemoglobin concentrations and blood losses were also different between centres. Variables independently associated with RBC transfusion were preoperative haemoglobin concentration, lost volume of RBC and female sex. CONCLUSION: Implementation of PBM remains extremely variable across centres. The relative importance of factors explaining RBC transfusion differs across institutions, some being patient related whereas others are related to the healthcare process. The results reported confidentially to each centre will allow them to implement tailored measures to improve their PBM strategies. PMID- 27487911 TI - Suberanilohydroxamic acid (vorinostat) synergistically enhances the cytotoxicity of doxorubicin and cisplatin in osteosarcoma cell lines. AB - Osteosarcoma is the most common primary bone cancer in children and is a highly malignant disease, in which 25% of patients present with metastasis at diagnosis. Considerable advances in the treatment of localized disease have been achieved since the introduction of combined modality treatment, increasing the prognosis of overall survival to 70%. Yet, established therapies have only limited success in treating both metastatic disease and nonresponders to primary chemotherapy. Therefore, new therapeutic approaches are required, particularly for the control of osteosarcoma in these patient groups. Epigenetically modifying substances are a class of emerging drugs that have shown therapeutic potential in various hematological and solid cancers. We examined the cytotoxic effects of 5 azacitidine, 3-deazaneplanocin A, and suberanilohydroxamic acid (SAHA) on osteosarcoma cell lines HOS, MG-63, MNNG, and ZK-58. SAHA was the only chemical agent that exerted a strong, growth-limiting effect in all cell lines tested. The growth-limiting effect of SAHA was accompanied by features characteristic of apoptotic death. We found that cotreatment with SAHA and cisplatin showed strong synergism in all cell lines. The effect of cotreatment with SAHA and doxorubicin was cell line dependent. In the cell lines HOS, MG-63, and MNNG, the combined effect was synergistic, whereas in the cell line ZK-58, SAHA antagonized doxorubicin. The strong synergism of SAHA indicated that in combination with cisplatin, it might enable a promising add-on to current therapy regimens. However, considering the cell line-dependent effect that was found when SAHA was combined with doxorubicin, further experimentation is needed. PMID- 27487912 TI - A Simple and Robust Bedside Model for Mortality Risk in Pediatric Patients With Acute Respiratory Distress Syndrome. AB - OBJECTIVES: Despite declining mortality, acute respiratory distress syndrome is still involved in up to one third of pediatric intensive care deaths. The recently convened Pediatric Acute Lung Injury Consensus Conference has outlined research priorities for the field, which include the need for accurate bedside risk stratification of patients. We aimed to develop a simple yet robust model of mortality risk among pediatric patients with acute respiratory distress syndrome to facilitate the targeted application of high-risk investigational therapies and stratification for enrollment in clinical trials. DESIGN: Prospective, multicenter cohort. SETTING: Five academic PICUs. PATIENTS: Three hundred eight children greater than 1 month and less than or equal to 18 years old, admitted to the ICU, with bilateral infiltrates on chest radiograph and PaO2/FIO2 ratio less than 300 in the clinical absence of left atrial hypertension. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty clinical variables were recorded in the following six categories: demographics, medical history, oxygenation, ventilation, radiographic imaging, and multiple organ dysfunction. Data were measured 0-24 and 48-72 hours after acute respiratory distress syndrome onset (day 1 and 3) and examined for associations with hospital mortality. Among 308 enrolled patients, mortality was 17%. Children with a history of cancer and/or hematopoietic stem cell transplant had higher mortality (47% vs 11%; p < 0.001). Oxygenation index, the PaO2/FIO2 ratio, extrapulmonary organ dysfunction, Pediatric Risk of Mortality-3, and positive cumulative fluid balance were each associated with mortality. Using two statistical approaches, we found that a parsimonious model of mortality risk using only oxygenation index and cancer/hematopoietic stem cell transplant history performed as well as other more complex models that required additional variables. CONCLUSIONS: In the PICU, oxygenation index and cancer/hematopoietic stem cell transplant history can be used on acute respiratory distress syndrome day 1 or day 3 to predict hospital mortality without the need for more complex models. These findings may simplify risk assessment for clinical trials, counseling families, and high-risk interventions such as extracorporeal life support. PMID- 27487913 TI - Bedside Ultrasound for Tracheal Tube Verification in Pediatric Emergency Department and ICU Patients: A Systematic Review. AB - OBJECTIVES: Improper placement of the tracheal tube during intubation can lead to dangerous complications, and bedside ultrasound has been proposed as a method of quickly and accurately identifying tube placement. Recent studies in adults have found it to be accurate, but its applicability in pediatric patients is unclear. This systematic review aims to describe the current available data on the accuracy and feasibility of bedside ultrasound for tracheal tube placement in children. DATA SOURCES: OVID MEDLINE and EMBASE. STUDY SELECTION: Available articles on bedside neck or lung/diaphragm ultrasound for confirmation of tracheal tube placement in children through December 2015. DATA EXTRACTION: Two reviewers screened studies for eligibility and abstracted data independently. The quality of selected articles was evaluated using Quality Assessment of Diagnostic Accuracy Studies statement. DATA SYNTHESIS: A total of nine articles were identified: one study using neck ultrasound, two using lung/diaphragmatic ultrasound, one with both, and five studies looking at direct visualization of the tracheal tube tip met our inclusion criteria. There were 81 intubations evaluated using neck ultrasound, 214 intubations evaluated using diaphragmatic or pleural sliding, and 165 intubations evaluated for feasibility of bedside ultrasound in visualizing tracheal tube tip placement. The sensitivities of transtracheal ultrasound for intubation were overall high ranging from 0.92 to 1.00 with excellent specificities at 1.00. For lung ultrasound, the sensitivities for tracheal placement versus esophageal placement were high at 1.00, but only one study reported esophageal intubations and had a specificity of 1.00. When assessing the appropriate tracheal tube depth for tracheal intubations using lung ultrasound, the sensitivities ranged from 0.91 to 1.00 with specificities ranging from 0.5 to 1.0. Regarding feasibility of direct visualization of tracheal tube tip, visualization ranged from 83% to 100%. CONCLUSION: Bedside ultrasound has been described to be feasible in determining tracheal tube placement in several small single center studies and could be a useful adjunct tool in confirming tracheal tube placement in critically ill pediatric patients, but further studies are needed to assess its accuracy in a randomized multicenter setting. PMID- 27487914 TI - High-Volume Hemofiltration in Critically Ill Patients With Secondary Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome: A Prospective Study in the PICU. AB - OBJECTIVES: Hemophagocytic lymphohistiocytosis, which includes primary (familial) and secondary hemophagocytic lymphohistiocytosis, is a fatal disease in children. Macrophage activation syndrome was defined in patients who met secondary hemophagocytic lymphohistiocytosis criteria with an underlying autoimmune disease. High-volume hemofiltration has shown beneficial effects in severe sepsis and multiple organ dysfunction syndrome. Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome shares many pathophysiologic similarities with sepsis. The present study assessed the effects of high-volume hemofiltration in children with secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. DESIGN: A single-center nonrandomized concurrent control trial. SETTING: The PICU of Shanghai Children's Hospital, Shanghai Jiao Tong University. PATIENTS: Thirty-three critically ill secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome patients treated between January 2010 and December 2014. INTERVENTIONS: Thirty three patients were divided into two groups: high-volume hemofiltration + hemophagocytic lymphohistiocytosis-2004 group (17 cases) or hemophagocytic lymphohistiocytosis-2004 group (16 cases). High-volume hemofiltration was defined as an ultrafiltrate flow rate of 50-70 mL/kg/hr. Clinical and biological variables were assessed before initiation and after 48 and 72 hours of high volume hemofiltration therapy. MEASUREMENTS AND MAIN RESULTS: The total mortality rate was 42.4% (14/33), but mortality at 28 days was not significantly different between the two groups (high-volume hemofiltration + hemophagocytic lymphohistiocytosis-2004 group: five deaths, 29.4%; hemophagocytic lymphohistiocytosis-2004 group: nine deaths, 56.3%; chi-square, 2.431; p = 0.119). Children received high-volume hemofiltration for 60.2 +/- 42.0 hours. After 48 and 72 hours respectively, a significant decrease in serum ferritin (p < 0.001), aspartate aminotransferase (p = 0.037 and p < 0.001), total bilirubin (p = 0.041 and p = 0.037), and serum creatinine (p = 0.006 and p = 0.004) levels were observed. Furthermore, the natural killer-cell activity up-regulated (p = 0.047) after 72 hours. Furthermore, significantly decreased levels of serum tumor necrosis factor-alpha (from 91.5 +/- 44.7 ng/L at 48 hr to 36.7 +/- 24.9 ng/L at 72 hr; p = 0.007)) and interleukin-6 (from 46.9 +/- 21.1 ng/L at 48 hr to 27.7 +/ 14.5 ng/L at 72 hr; p < 0.0001) were observed. After 7 days, patients receiving high-volume hemofiltration had significantly lower bilirubin, creatinine, ferritin, procalcitonin, lactate dehydrogenase level, tumor necrosis factor alpha, and interleukin-6 levels, and needed less mechanical ventilation compared with hemophagocytic lymphohistiocytosis-2004 group patients. No serious adverse events were observed. CONCLUSIONS: High-volume hemofiltration may improve organ function by decreasing cytokine levels (tumor necrosis factor-alpha and interleukin-6). High-volume hemofiltration may be an effective adjunctive treatment in secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. PMID- 27487915 TI - Evolution of a G protein-coupled receptor response by mutations in regulatory network interactions. AB - All cellular functions depend on the concerted action of multiple proteins organized in complex networks. To understand how selection acts on protein networks, we used the yeast mating receptor Ste2, a pheromone-activated G protein coupled receptor, as a model system. In Saccharomyces cerevisiae, Ste2 is a hub in a network of interactions controlling both signal transduction and signal suppression. Through laboratory evolution, we obtained 21 mutant receptors sensitive to the pheromone of a related yeast species and investigated the molecular mechanisms behind this newfound sensitivity. While some mutants show enhanced binding affinity to the foreign pheromone, others only display weakened interactions with the network's negative regulators. Importantly, the latter changes have a limited impact on overall pathway regulation, despite their considerable effect on sensitivity. Our results demonstrate that a new receptor ligand pair can evolve through network-altering mutations independently of receptor-ligand binding, and suggest a potential role for such mutations in disease. PMID- 27487916 TI - A mixed grape and blueberry extract is safe for dogs to consume. AB - BACKGROUND: Grape and blueberry extracts are known to protect against age-related cognitive decline. However, beneficial effects achieved by mixing grape and blueberry extracts have yet to be evaluated in dogs, or their bioavailability assessed. Of concern to us were cases of acute renal failure in dogs, after their ingestion of grapes or raisins. The European Pet Food Industry Federation (2013) considers only the grape or raisin itself to be potentially dangerous; grape-seed extracts per-se, are not considered to be a threat. Our aim was therefore to evaluate the renal and hepatic safety, and measure plasma derivatives of a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium) in dogs. Polyphenol expression was analyzed by UHPLC-MS/MS over 8 hours, for dogs given PEGB at 4 mg/kg. Safety was evaluated using four groups of 6 dogs. These groups received capsules containing no PEGB (control), or PEGB at 4, 20, or 40 mg/kg BW/d, for 24 weeks. Blood and urine samples were taken the week prior to study commencement, then at the end of the 24-wk study period. Routine markers of renal and liver damage, including creatinine (Creat), blood urea nitrogen, albumin, minerals, alkaline phosphatase (ALP), and alanine transaminase (ALT) were measured. Biomarkers for early renal damage were also evaluated in plasma (cystatin C (CysC), and neutrophil gelatinase-associated lipocalin (NGAL)), and urine (CysC, clusterin (Clu), and NGAL). Ratios of urinary biomarkers to Creat were calculated, and compared with acceptable maximal values obtained for healthy dogs, as reported in the literature. RESULTS: While several PEGB-specific polyphenols and metabolites were detected in dog plasma, at the end of the PEGB consumption period, our biomarker analyses presented no evidence of either renal or liver damage (Creat, BUN, ionogram, albumin and ALT, ALP). Similarly, no indication of early renal damage could be detected. Plasma CysC, urinary CysC/Creat, Clu/Creat, and NGAL/Creat ratios were all beneath reported benchmarked maximums, with no evidence of PEGB toxicity. CONCLUSIONS: Long-term consumption of a pet specific blend of a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium), was not associated with renal or hepatic injury, and can therefore be considered safe. PMID- 27487917 TI - Thermal fluctuations affect the transcriptome through mechanisms independent of average temperature. AB - Terrestrial ectotherms are challenged by variation in both mean and variance of temperature. Phenotypic plasticity (thermal acclimation) might mitigate adverse effects, however, we lack a fundamental understanding of the molecular mechanisms of thermal acclimation and how they are affected by fluctuating temperature. Here we investigated the effect of thermal acclimation in Drosophila melanogaster on critical thermal maxima (CTmax) and associated global gene expression profiles as induced by two constant and two ecologically relevant (non-stressful) diurnally fluctuating temperature regimes. Both mean and fluctuation of temperature contributed to thermal acclimation and affected the transcriptome. The transcriptomic response to mean temperatures comprised modification of a major part of the transcriptome, while the response to fluctuations affected a much smaller set of genes, which was highly independent of both the response to a change in mean temperature and to the classic heat shock response. Although the independent transcriptional effects caused by fluctuations were relatively small, they are likely to contribute to our understanding of thermal adaptation. We provide evidence that environmental sensing, particularly phototransduction, is a central mechanism underlying the regulation of thermal acclimation to fluctuating temperatures. Thus, genes and pathways involved in phototransduction are likely of importance in fluctuating climates. PMID- 27487918 TI - Cu2O Photocathode for Low Bias Photoelectrochemical Water Splitting Enabled by NiFe-Layered Double Hydroxide Co-Catalyst. AB - Layered double hydroxides (LDHs) are bimetallic hydroxides that currently attract considerable attention as co-catalysts in photoelectrochemical (PEC) systems in view of water splitting under solar light. A wide spectrum of LDHs can be easily prepared on demand by tuning their chemical composition and structural morphology. We describe here the electrochemical growth of NiFe-LDH overlayers on Cu2O electrodes and study their PEC behavior. By using the modified Cu2O/NiFe-LDH electrodes we observe a remarkable seven-fold increase of the photocurrent intensity under an applied voltage as low as -0.2 V vs Ag/AgCl. The origin of such a pronounced effect is the improved electron transfer towards the electrolyte brought by the NiFe-LDH overlayer due to an appropriate energy level alignment. Long-term photostability tests reveal that Cu2O/NiFe-LDH photocathodes show no photocurrent loss after 40 hours of operation under light at -0.2 V vs Ag/AgCl low bias condition. These improved performances make Cu2O/NiFe-LDH a suitable photocathode material for low voltage H2 production. Indeed, after 8 hours of H2 production under -0.2 V vs Ag/AgCl the PEC cell delivers a 78% faradaic efficiency. This unprecedented use of Cu2O/NiFe-LDH as an efficient photocathode opens new perspectives in view of low biasd or self-biased PEC water splitting under sunlight illumination. PMID- 27487919 TI - Fanconi-Bickel syndrome in two Palestinian children: marked phenotypic variability with identical mutation. AB - BACKGROUND: Fanconi-Bickel syndrome (FBS, OMIM 227810) is a rare autosomal recessive disease caused by a deficiency of glucose transporter 2 (GLUT2), a member of the facilitative glucose transporter family (Santer et al. J Inherit Metab Dis 21:191-194, 1998). The typical clinical picture is characterized by hepatorenal glycogen accumulation resulting in hepato- and nephromegaly, impaired utilization of glucose and galactose, proximal renal tubular dysfunction, rickets and severe short stature. CASE PRESENTATION: We report 2 Palestinian patients from 2 families who were homozygous for the mutation p.R301X (C>T) in exon 7of GLUT2 gene. Patient 1 showed clinical and laboratory improvement with age characterized by normal growth and resolution of rickets. Patient 2 had severe phenotype characterized by progressive weight loss, persistent metabolic acidosis, marked polyuria and clinical and laboratory findings of rickets progressing to death at age 10 months. CONCLUSION: This report further expands the clinical spectrum of FBS even with identical mutations. Other yet unknown genetic, environmental or stochastic factors may be responsible for phenotypic variability. PMID- 27487920 TI - Crystal structure of the PAS domain of the hEAG potassium channel. AB - KCNH voltage-gated potassium channels play critical roles in regulating cellular functions. The channel is composed of four subunits, each of which contains six transmembrane helices forming the central pore. The cytoplasmic parts of the subunits present a Per-Arnt-Sim (PAS) domain at the N-terminus and a cyclic nucleotide-binding homology domain at the C-terminus. PAS domains are conserved from prokaryotes to eukaryotes and are involved in sensing signals and cellular responses. To better understand the functional roles of PAS domains in KCNH channels, the structure of this domain from the human ether-a-go-go channel (hEAG channel) was determined. By comparing it with the structures of the Homo sapiens EAG-related gene (hERG) channel and the Drosophila EAG-like K(+) (dELK) channel and analyzing the structural features of the hEAG channel, it was identified that a hydrophobic patch on the beta-sheet may mediate interaction between the PAS domain and other regions of the channel to regulate its functions. PMID- 27487921 TI - Envelope protein VP24 from White spot syndrome virus: expression, purification and crystallization. AB - White spot syndrome virus (WSSV) is a major shrimp pathogen known to infect penaeid shrimp and other crustaceans. VP24 is one of the major envelope proteins of WSSV. In order to facilitate purification, crystallization and structure determination, the predicted N-terminal transmembrane region of approximately 26 amino acids was truncated from VP24 and several mutants were prepared to increase the proportion of selenomethionine (SeMet) residues for subsequent structural determination using the SAD method. Truncated VP24, its mutants and the corresponding SeMet-labelled proteins were purified, and the native and SeMet proteins were crystallized by the hanging-drop vapour-diffusion method. Crystals of VP24 were obtained using a reservoir consisting of 0.1 M Tris-HCl pH 8.5, 2.75 M ammonium acetate with a drop volume ratio of two parts protein solution to one part reservoir solution. Notably, ATP was added as a critical additive to the drop with a final concentration of 10 mM. Crystals of SeMet-labelled VP24 mutant diffracted to 3.0 A resolution and those of the native diffracted to 2.4 A resolution; the crystals belonged to space group I213, with unit-cell parameters a = b = c = 140 A. PMID- 27487922 TI - Malonate in the nucleotide-binding site traps human AKAP18gamma/delta in a novel conformational state. AB - A-kinase anchoring proteins (AKAPs) are a family of proteins that provide spatiotemporal resolution of protein kinase A (PKA) phosphorylation. In the myocardium, PKA and AKAP18gamma/delta are found in complex with sarcoendoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) and phospholamban (PLB). This macromolecular complex provides a means by which anchored PKA can dynamically regulate cytoplasmic Ca(2+) release and re-uptake. For this reason, AKAP18gamma/delta presents an interesting drug target with therapeutic potential in cardiovascular disease. The crystal structure of the central domain of human AKAP18gamma has been determined at the atomic resolution of 1.25 A. This first structure of human AKAP18gamma is trapped in a novel conformation by a malonate molecule bridging the important R-loop with the 2H phosphoesterase motif. Although the physiological substrate of AKAP18gamma is currently unknown, a potential proton wire deep in the central binding crevice has been indentified, leading to bulk solvent below the R-loop. Malonate complexed with AKAP18gamma at atomic resolution provides an excellent starting point for structure-guided drug design. PMID- 27487923 TI - Structure of the human DNA-repair protein RAD52 containing surface mutations. AB - The Rad52 protein is a eukaryotic single-strand DNA-annealing protein that is involved in the homologous recombinational repair of DNA double-strand breaks. The isolated N-terminal half of the human RAD52 protein (RAD52(1-212)) forms an undecameric ring structure with a surface that is mostly positively charged. In the present study, it was found that RAD52(1-212) containing alanine mutations of the charged surface residues (Lys102, Lys133 and Glu202) is highly amenable to crystallization. The structure of the mutant RAD52(1-212) was solved at 2.4 A resolution. The structure revealed an association between the symmetry-related RAD52(1-212) rings, in which a partially unfolded, C-terminal region of RAD52 extended into the DNA-binding groove of the neighbouring ring in the crystal. The alanine mutations probably reduced the surface entropy of the RAD52(1-212) ring and stabilized the ring-ring association observed in the crystal. PMID- 27487924 TI - Crystallization and X-ray diffraction analysis of an L-arabinonate dehydratase from Rhizobium leguminosarum bv. trifolii and a D-xylonate dehydratase from Caulobacter crescentus. AB - L-Arabinonate dehydratase (EC 4.2.1.25) and D-xylonate dehydratase (EC 4.2.1.82) are two enzymes that are involved in a nonphosphorylative oxidation pathway of pentose sugars. L-Arabinonate dehydratase converts L-arabinonate into 2-dehydro-3 deoxy-L-arabinonate, and D-xylonate dehydratase catalyzes the dehydration of D xylonate to 2-dehydro-3-deoxy-D-xylonate. L-Arabinonate and D-xylonate dehydratases belong to the IlvD/EDD family, together with 6-phosphogluconate dehydratases and dihydroxyacid dehydratases. No crystal structure of any L arabinonate or D-xylonate dehydratase is available in the PDB. In this study, recombinant L-arabinonate dehydratase from Rhizobium leguminosarum bv. trifolii (RlArDHT) and D-xylonate dehydratase from Caulobacter crescentus (CcXyDHT) were heterologously expressed in Escherichia coli and purified by the use of affinity chromatography followed by gel-filtration chromatography. The purified proteins were crystallized using the hanging-drop vapour-diffusion method at 293 K. Crystals of RlArDHT that diffracted to 2.40 A resolution were obtained using sodium formate as a precipitating agent. They belonged to space group P21, with unit-cell parameters a = 106.07, b = 208.61, c = 147.09 A, beta = 90.43 degrees . Eight RlArDHT molecules (two tetramers) in the asymmetric unit give a VM value of 3.2 A(3) Da(-1) and a solvent content of 62%. Crystals of CcXyDHT that diffracted to 2.66 A resolution were obtained using sodium formate and polyethylene glycol 3350. They belonged to space group C2, with unit-cell parameters a = 270.42, b = 236.13, c = 65.17 A, beta = 97.38 degrees . Four CcXyDHT molecules (a tetramer) in the asymmetric unit give a VM value of 4.0 A(3) Da(-1) and a solvent content of 69%. PMID- 27487925 TI - Structure of the lutein-binding domain of human StARD3 at 1.74 A resolution and model of a complex with lutein. AB - A crystal structure of the lutein-binding domain of human StARD3 (StAR-related lipid-transfer protein 3; also known as MLN64) has been refined to 1.74 A resolution. A previous structure of the same protein determined to 2.2 A resolution highlighted homology with StARD1 and shared cholesterol-binding character. StARD3 has since been recognized as a carotenoid-binding protein in the primate retina, where its biochemical function of binding lutein with specificity appears to be well suited to recruit this photoprotective molecule. The current and previous structures correspond closely to each other (r.m.s.d. of 0.25 A), especially in terms of the helix-grip fold constructed around a solvent filled cavity. Regions of interest were defined with alternate conformations in the current higher-resolution structure, including Arg351 found within the cavity and Omega1, a loop of four residues found just outside the cavity entrance. Models of the complex with lutein generated by rigid-body docking indicate that one of the ionone rings must protrude outside the cavity, and this insight has implications for molecular interactions with transport proteins and enzymes that act on lutein. Interestingly, models with the E-ionone ring characteristic of lutein pointing towards the bottom of the cavity were associated with fewer steric clashes, suggesting that steric complementarity and ligand asymmetry may play a role in discriminating lutein from the other ocular carotenoids zeaxanthin and meso-zeaxanthin, which only have beta-ionone rings. PMID- 27487926 TI - Structural analysis of a function-associated loop mutant of the substrate recognition domain of Fbs1 ubiquitin ligase. AB - The SCF ubiquitin ligase comprises four components: Skp1, Cul1, Rbx1 and a variable-subunit F-box protein. The F-box protein Fbs1, which recognizes the N linked glycoproteins, is involved in the endoplasmic reticulum-associated degradation pathway. Although FBG3, another F-box protein, shares 51% sequence identity with Fbs1, FBG3 does not bind glycoproteins. To investigate the sequence structure relationship of the substrate-binding pocket, the crystal structure of a mutant substrate-binding domain of Fbs1 in which the six nonconserved regions (beta1, beta2-beta3, beta3-beta4, beta5-beta6, beta7-beta8 and beta9-beta10) of Fbs1 were substituted with those of FBG3 was determined. The substrate-binding pocket of this model exhibits structural features that differ from those of Fsb1. PMID- 27487927 TI - Crystal structures of a subunit of the formylglycinamide ribonucleotide amidotransferase, PurS, from Thermus thermophilus, Sulfolobus tokodaii and Methanocaldococcus jannaschii. AB - The crystal structures of a subunit of the formylglycinamide ribonucleotide amidotransferase, PurS, from Thermus thermophilus, Sulfolobus tokodaii and Methanocaldococcus jannaschii were determined and their structural characteristics were analyzed. For PurS from T. thermophilus, two structures were determined using two crystals that were grown in different conditions. The four structures in the dimeric form were almost identical to one another despite their relatively low sequence identities. This is also true for all PurS structures determined to date. A few residues were conserved among PurSs and these are located at the interaction site with PurL and PurQ, the other subunits of the formylglycinamide ribonucleotide amidotransferase. Molecular-dynamics simulations of the PurS dimer as well as a model of the complex of the PurS dimer, PurL and PurQ suggest that PurS plays some role in the catalysis of the enzyme by its bending motion. PMID- 27487928 TI - Crystal structure of the antigen-binding fragment of a monoclonal antibody specific for the multidrug-resistance-linked ABC transporter human P glycoprotein. AB - P-glycoprotein (P-gp) is a polyspecific ATP-dependent transporter linked to multidrug resistance in cancers that plays important roles in the pharmacokinetics of a large number of drugs. The drug-resistance phenotype of P gp can be modulated by the monoclonal antibody UIC2, which specifically recognizes human P-gp in a conformation-dependent manner. Here, the purification, sequence determination and high-resolution structure of the Fab fragment of UIC2 (UIC2/Fab) are reported. Purified UIC2/Fab binds human P-gp with a 1:1 stoichiometry. Crystals of UIC2/Fab are triclinic (space group P1), with unit cell parameters a = 40.67, b = 44.91, c = 58.09 A, alpha = 97.62, beta = 99.10, gamma = 94.09 degrees , and diffracted X-rays to 1.6 A resolution. The structure was determined by molecular replacement and refined to 1.65 A resolution. The asymmetric unit contains one molecule of UIC2/Fab, which exhibits a positively charged antigen-binding surface, suggesting that it might recognize an oppositely charged extracellular epitope of P-gp. PMID- 27487929 TI - Crystal structure of Rv3899c(184-410), a hypothetical protein from Mycobacterium tuberculosis. AB - Rv3899c is a hypothetical protein from Mycobacterium tuberculosis which is conserved across mycobacteria. It is predicted to be secreted and has been found in culture filtrates. It has been proposed as a potential vaccine candidate; however, its biological function is unknown. Here, the global structure of Rv3899c(184-410), a fragment of Rv3899c, is reported. The structure resembles the shell of a sea snail, and its N- and C-termini form two relatively independent compact domains: an alpha/beta/alpha sandwich folding domain and an alpha-helix bundle domain. There are no reported protein structures for any Rv3899c homologues; this structure provides the first structural glimpse of a new protein family consisting of Rv3899c and its homologues. PMID- 27487930 TI - Characterization of the NTPR and BD1 interacting domains of the human PICH-BEND3 complex. AB - Chromosome integrity depends on DNA structure-specific processing complexes that resolve DNA entanglement between sister chromatids. If left unresolved, these entanglements can generate either chromatin bridging or ultrafine DNA bridging in the anaphase of mitosis. These bridge structures are defined by the presence of the PICH protein, which interacts with the BEND3 protein in mitosis. To obtain structural insights into PICH-BEND3 complex formation at the atomic level, their respective NTPR and BD1 domains were cloned, overexpressed and crystallized using 1.56 M ammonium sulfate as a precipitant at pH 7.0. The protein complex readily formed large hexagonal crystals belonging to space group P6122, with unit-cell parameters a = b = 47.28, c = 431.58 A and with one heterodimer in the asymmetric unit. A complete multiwavelength anomalous dispersion (MAD) data set extending to 2.2 A resolution was collected from a selenomethionine-labelled crystal at the Swiss Light Source. PMID- 27487932 TI - Cross-sectional imaging in cancers of the head and neck: how we review and report. AB - Cancer of the head and neck is the sixth most frequent cancer worldwide and associated with significant morbidity. The head and neck area is complex and divided into various anatomical and functional subunits. Imaging is performed by cross-sectional modalities like computed tomography, magnetic resonance imaging, ultrasound and positron emission tomography-computed tomography, usually with fluorine-18-deoxy-D-glucose. Therefore, knowledge of the cross-sectional anatomy is very important. This article seeks to give an overview of the various cross sectional imaging modalities used in the evaluation of head and neck cancers. It briefly describes the anatomy of the extracranial head and neck and the role of imaging as well as the imaging appearance of tumours and their extension to lymph nodes, bone and surrounding tissue. The advantages and disadvantages as well as basic requirements of the various modalities are described along with ways of optimizing imaging quality. A general guideline for prescription of the various modalities is given. Pitfalls are many and varied and can be due to anatomical variation, due to pathology which can be misinterpreted and technical due to peculiarities of the various imaging modalities. Knowledge of these pitfalls can help to avoid misinterpretation. The important points to be mentioned while reporting are also enumerated. PMID- 27487933 TI - Protein patterning by a DNA origami framework. AB - A spatial arrangement of proteins provides structural and functional advantages in vast technological applications as well as fundamental research. Most protein patterning procedures employ complicated, time consuming and very costly nanofabrication techniques. As an alternative route, we developed a fully biomolecular self-assembly method using DNA Origami Frames (DOF) as a template for both small and large scale protein patterning. We employed a triangular DOF (tDOF) to arrange the Bovine Serum Albumin (BSA) protein. Our in situ protein patterning strategy provides a novel, fully organic platform using a fast and low cost surface approach with possible utilization in fundamental science and technological applications. PMID- 27487931 TI - Crystal structure of AibC, a reductase involved in alternative de novo isovaleryl coenzyme A biosynthesis in Myxococcus xanthus. AB - Isovaleryl coenzyme A (IV-CoA) performs a crucial role during development and fruiting-body formation in myxobacteria, which is reflected in the existence of a de novo biosynthetic pathway that is highly upregulated when leucine, the common precursor of IV-CoA, is limited. The final step in de novo IV-CoA biosynthesis is catalyzed by AibC, a medium-chain dehydrogenase/reductase. Here, the crystal structure of AibC from Myxococcus xanthus refined to 2.55 A resolution is presented. The protein adopts two different conformations in the crystal lattice, which is a consequence of partial interaction with the purification tag. Based on this structure, it is suggested that AibC most probably uses a Zn(2+)-supported catalytic mechanism in which NADPH is preferred over NADH. Taken together, this study reveals structural details of the alternative IV-CoA-producing pathway in myxobacteria, which may serve as a base for further biotechnological research and biofuel production. PMID- 27487934 TI - Adenomyoepithelioma of the breast with late pulmonary metastases - case report and review of the literature. AB - BACKGROUND: Adenomyoepithelioma (AME) of the breast is a rare tumour of unpredictable clinical behaviour. Most of the tumours are benign with some giving local recurrences or distant metastases. CASE PRESENTATION: We report a case of late lung metastases in a woman with a history of breast adenomyoepithelioma. Partial lobectomy was performed for lung lesions and initial diagnosis was epithelial-myoepithelial carcinoma. CONCLUSION: Careful slide's revision of both breast and pulmonary lesions showed identical microscopic appearance with lung tumour performing more malignant features. Tumour cells in both: breast and pulmonary lesions were positive for cytokeratin and EMA (epithelial cells) and also for SMA, S100 and vimentin (myoepithelial cells). Two years and 7 months follow-up showed no recurrent neoplastic disease in our patient. PMID- 27487936 TI - Peptide self-assembly: thermodynamics and kinetics. AB - Self-assembling systems play a significant role in physiological functions and have therefore attracted tremendous attention due to their great potential for applications in energy, biomedicine and nanotechnology. Peptides, consisting of amino acids, are among the most popular building blocks and programmable molecular motifs. Nanostructures and materials assembled using peptides exhibit important potential for green-life new technology and biomedical applications mostly because of their bio-friendliness and reversibility. The formation of these ordered nanostructures pertains to the synergistic effect of various intermolecular non-covalent interactions, including hydrogen-bonding, pi-pi stacking, electrostatic, hydrophobic, and van der Waals interactions. Therefore, the self-assembly process is mainly driven by thermodynamics; however, kinetics is also a critical factor in structural modulation and function integration. In this review, we focus on the influence of thermodynamic and kinetic factors on structural assembly and regulation based on different types of peptide building blocks, including aromatic dipeptides, amphiphilic peptides, polypeptides, and amyloid-relevant peptides. PMID- 27487935 TI - Aroma characterization based on aromatic series analysis in table grapes. AB - Aroma is an important part of quality in table grape, but the key aroma compounds and the aroma series of table grapes remains unknown. In this paper, we identified 67 aroma compounds in 20 table grape cultivars; 20 in pulp and 23 in skin were active compounds. C6 compounds were the basic background volatiles, but the aroma contents of pulp juice and skin depended mainly on the levels of esters and terpenes, respectively. Most obviously, 'Kyoho' grapevine series showed high contents of esters in pulp, while Muscat/floral cultivars showed abundant monoterpenes in skin. For the aroma series, table grapes were characterized mainly by herbaceous, floral, balsamic, sweet and fruity series. The simple and visualizable aroma profiles were established using aroma fingerprints based on the aromatic series. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) showed that the aroma profiles of pulp juice, skin and whole berries could be classified into 5, 3, and 5 groups, respectively. Combined with sensory evaluation, we could conclude that fatty and balsamic series were the preferred aromatic series, and the contents of their contributors (beta-ionone and octanal) may be useful as indicators for the improvement of breeding and cultivation measures for table grapes. PMID- 27487937 TI - Systemic lupus erythematosus: New role for CD95L in TH17 cell recruitment. PMID- 27487938 TI - Osteoarthritis: Joint resurfacing possibilities loom large. PMID- 27487940 TI - Hexagonal NiS nanobelts as advanced cathode materials for rechargeable Al-ion batteries. AB - Hexagonal NiS nanobelts served as novel cathode materials for rechargeable Al-ion batteries based on an AlCl3/[EMIm]Cl ionic liquid electrolyte system. The nano banded structure of the materials can facilitate the electrolyte immersion and enhance Al(3+) diffusion. The hexagonal NiS nanobelt based cathodes exhibit high storage capacity, good cyclability and low overpotential. PMID- 27487939 TI - Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes. AB - FasL-mediated cytotoxicity is one of the mechanisms that CTLs use to kill tumor cells. However, human colon carcinoma often deregulates the Fas signaling pathway to evade host cancer immune surveillance. We aimed at testing the hypothesis that novel ceramide analogs effectively modulate Fas function to sensitize colon carcinoma cells to FasL-induced apoptosis. We used rational design and synthesized twenty ceramide analogs as Fas function modulators. Five ceramide analogs, IG4, IG7, IG14, IG17, and IG19, exhibit low toxicity and potent activity in sensitization of human colon carcinoma cells to FasL-induced apoptosis. Functional deficiency of Fas limits both FasL and ceramide analogs in the induction of apoptosis. Ceramide enhances FasL-induced activation of the MAPK, NF kappaB, and caspase 8 despite induction of potent tumor cell death. Finally, a sublethal dose of several ceramide analogs significantly increased CTL-mediated and FasL-induced apoptosis of colon carcinoma cells. We have therefore developed five novel ceramide analogs that act at a sublethal dose to enhance the efficacy of tumor-specific CTLs, and these ceramide analogs hold great promise for further development as adjunct agents in CTL-based colon cancer immunotherapy. PMID- 27487941 TI - Magnetic domain wall gratings for magnetization reversal tuning and confined dynamic mode localization. AB - High density magnetic domain wall gratings are imprinted in ferromagnetic antiferromagnetic thin films by local ion irradiation by which alternating head to-tail-to-head-to-tail and head-to-head-to-tail-to-tail spatially overlapping domain wall networks are formed. Unique magnetic domain processes result from the interaction of anchored domain walls. Non-linear magnetization response is introduced by the laterally distributed magnetic anisotropy phases. The locally varying magnetic charge distribution gives rise to localized and guided magnetization spin-wave modes directly constrained by the narrow domain wall cores. The exchange coupled multiphase material structure leads to unprecedented static and locally modified dynamic magnetic material properties. PMID- 27487942 TI - Rapid screening of copper intermediates in Cu(i)-catalyzed azide-alkyne cycloaddition using a modified ICP-MS/MS platform. AB - Rapid screening of Cu(+)-intermediates by using (63)Cu(+) or (65)Cu(+) ions as catalysts with or without ligand protection in Cu(i)-catalyzed azide-alkyne cycloaddition was realized using an on-line modified ICP-MS/MS platform in this work, while the Cu(+)-intermediates without ligand protection are very active, which are extremely difficult to be observed using other existing techniques. This universal platform was suitable to study the mechanism of organic reactions catalyzed by unstable metal(i) ions as well as to discover new candidates for metal(i) catalysts. PMID- 27487943 TI - Street-level bureaucracy and policy implementation in community public health nursing: a qualitative study of the experiences of student and novice health visitors. AB - : Aim To explore the experiences of student and novice health visitors in implementing health visiting policy reform pre- and post-qualification. BACKGROUND: In England, public health nursing has been subject to major policy reform. The Health Visitor Implementation Plan (2011) set out a plan to recruit increasing numbers of nurses and midwives to the profession to deliver an expanded and refocussed health visiting service. Exploring this policy change from the viewpoint of those new to health visiting offers a unique perspective into how a specific policy vision is translated into nursing practice. METHODS: A descriptive qualitative study in which participants were enrolled on a one-year post-graduate health visiting course at a University in South West of England. Qualitative data were collected pre- and post-qualification. A total of 16 interviews and a focus group were conducted with nine participants between September 2012 and March 2013. Findings Descriptive data were interpreted using Lipsky's theoretical framework of street-level bureaucracy. Three themes emerged which relate to this 'bottom-up' perspective on policy implementation; readiness to operationalise policy, challenges in delivering the service vision; and using discretion in delivering the vision. Community public health nurses operate as street-level bureaucrats in negotiating the demands of policy and practice, and by this means, attempt to reconcile professional values with institutional constraints. Barriers to policy implementation at a local level mediate the effects of policy reform, ultimately impacting upon outcomes for children and families. PMID- 27487944 TI - The long terminal repeat negative control region is a critical element for insertional oncogenesis after gene transfer into hematopoietic progenitors with Moloney murine leukemia viral vectors. AB - Integrating vectors based on gamma-retroviruses and containing full-length long terminal repeats (LTRs) have been associated with activation of oncogene expression and leukemogenesis in human gene therapy trials. Identification of the specific molecular elements of the LTRs that have a role in insertional oncogenesis events is important as it can lead to the development of safer gene transfer vectors. The negative control region (NCR) of the LTR is a particularly well-conserved sequence among mammalian gamma-retroviruses with demonstrated regulatory activity of gene transcription in hematopoietic cells, which led us to hypothesize that this region may have a role in insertional oncogenesis after gamma-retroviral vector (GV)-mediated gene transfer into hematopoietic progenitors. We used an in vitro assay of murine bone marrow cell immortalization to compare the immortalization capabilities of a series of GVs carrying murine leukemia virus (MLV) LTR deletion mutants. Compared with GV carrying the full length MLV LTR, deletion of the complete LTR enhancer sequence showed significant reduction of immortalization rates. However, the use of a mutant LTR deleted of the enhancer sequence, with exception of the NCR, did not affect immortalization. Importantly, the inclusion of an LTR mutant devoid only of the NCR did show significant reduction of immortalization rates compared with the full LTR sequence. Therefore, our data point to the NCR as a key element for immortalization and justify additional studies to evaluate its specific role in MLV-mediated insertional oncogenesis. PMID- 27487945 TI - Relationship between body mass index and family functioning, family communication, family type and parenting style among African migrant parents and children in Victoria, Australia: a parent-child dyad study. AB - BACKGROUND: Although childhood obesity prevalence is stabilised in developed countries including Australia, it is continuing to rise among migrants and socially disadvantaged groups in these countries. African migrants and refugees in particular, are at high risk of obesity due to changes in their family dynamics. The aim of this study was to examine the difference between children and parental perception of family functioning, family communication, family type and parenting styles and their relationship with body mass index. METHODS: A cross-sectional parent-child dyad study was conducted among 284 African families from migrant and refugee backgrounds living in metropolitan Melbourne, Australia. Bilingual workers were trained to collect demographic, anthropometric and questionnaire data on family functioning, parenting, family type and family communication. RESULTS: Parents and children reported different levels of family dynamics. Children reported a higher prevalence of poor family functioning (61.5 %, 95 % CI: 55.6, 67.2 versus 56.8 %, 95 % CI: 49.7, 61.6) and protective family type (29 %, 95 % CI: 23.9, 34.5 vs. 13.4 %, 95 % CI: 9.9, 17.9), but a lower prevalence of authoritative parenting style (51.6 %, 95 % CI: 45.7, 57.5 vs. 63 %, 95 % CI: 57.5, 68.8) than parents. There was a positive relationship between poor family functioning and child BMI both before (beta = 1.28; 95 % CI: 0.14, 2.41; p < 0.05) and after (beta = 1.73; 95 % CI: 0.53, 2.94; p < 0.001) controlling for confounders, and an inverse relationship between consensual family type and child BMI after adjustment (beta = -1.92; 95 % CI: -3.59, -0.24; p < 0.05). There was no significant relationship between parental BMI and family functioning, communication, family type or parenting style. CONCLUSION: Children's perception of poor family functioning was associated with childhood obesity. Family interventions to reduce childhood obesity need to adopt an intergenerational approach to promote a clear understanding of family dynamics between children and parents. Unless these intergenerational challenges associated with family dynamics are clearly addressed in obesity interventions, current obesity prevention initiatives will continue to widen the childhood obesity gap in Australia. PMID- 27487946 TI - Evolutionary and functional analysis of mulberry type III polyketide synthases. AB - BACKGROUND: Type III polyketide synthases are important for the biosynthesis of flavonoids and various plant polyphenols. Mulberry plants have abundant polyphenols, but very little is known about the mulberry type III polyketide synthase genes. An analysis of these genes may provide new targets for genetic improvement to increase relevant secondary metabolites and enhance the plant tolerance to biotic and abiotic stresses. RESULTS: Eighteen genes encoding type III polyketide synthases were identified, including six chalcone synthases (CHS), ten stilbene synthases (STS), and two polyketide synthases (PKS). Functional characterization of four genes representing most of the MnCHS and MnSTS genes by coexpression with 4-Coumaroyl-CoA ligase in Escherichia coli indicated that their products were able to catalyze p-coumaroyl-CoA and malonyl-CoA to generate naringenin and resveratrol, respectively. Microsynteny analysis within mulberry indicated that segmental and tandem duplication events contributed to the expansion of the MnCHS family, while tandem duplications were mainly responsible for the generation of the MnSTS genes. Combining the evolution and expression analysis results of the mulberry type III PKS genes indicated that MnCHS and MnSTS genes evolved mainly under purifying selection to maintain their original functions, but transcriptional subfunctionalization occurred during long-term species evolution. Moreover, mulberry leaves can rapidly accumulated oxyresveratrol after UV-C irradiation, suggesting that resveratrol was converted to oxyresveratrol. CONCLUSIONS: Characterizing the functions and evolution of mulberry type III PKS genes is crucial for advancing our understanding of these genes and providing the basis for further studies on the biosynthesis of relevant secondary metabolites in mulberry plants. PMID- 27487947 TI - Enhanced Impact of Cholesterol Absorption Marker on New Atherosclerotic Lesion Progression After Coronary Intervention During Statin Therapy. AB - AIM: Clinical trials suggest that residual risks remain for coronary artery disease (CAD) during low-density lipoprotein cholesterol (LDL-C) lowering therapy. We aimed to investigate the role of exogenous lipids in the prognosis of CAD after percutaneous coronary intervention (PCI). METHODS: A total of 145 patients with CAD, who underwent elective PCI, and 82 non-CAD (control) patients were enrolled in this study. CAD patients underwent follow-up coronary angiography 6-9 months after PCI, and were classified into three groups: 1) patients who showed in-stent restenosis (ISR) in the original stented segment, 2) patients with other non-target coronary atherosclerotic lesions (de novo), and 3) patients with neither ISR nor a de novo lesion. Biochemical analyses were performed on fasting serum samples at the time of follow-up coronary angiography. RESULTS: Despite the controlled serum LDL-C levels, CAD patients with statin showed elevated cholesterol absorption marker campesterol/total cholesterol (TC), synthesis marker lathosterol/TC, campesterol/lathosterol ratio, and apolipoprotein B48 (apoB48) concentration compared with non-CAD patients. The high campesterol/TC, campesterol/lathosterol ratio, and apoB48 concentration were associated with de novo lesion progression after PCI. In stepwise multivariate logistic regression analysis, campesterol/TC and apoB48 concentrations were independent risk factors for de novo lesion progression in statin-treated CAD patients after PCI. CONCLUSION: The increase of cholesterol absorption marker and apoB48 concentration may lead to the progression of de novo lesions, and these markers may represent a residual risk during statin treatment after PCI. PMID- 27487948 TI - Comparative genomic analysis of retrogene repertoire in two green algae Volvox carteri and Chlamydomonas reinhardtii. AB - BACKGROUND: Retroposition, one of the processes of copying the genetic material, is an important RNA-mediated mechanism leading to the emergence of new genes. Because the transcription controlling segments are usually not copied to the new location in this mechanism, the duplicated gene copies (retrocopies) become pseudogenized. However, few can still survive, e.g. by recruiting novel regulatory elements from the region of insertion. Subsequently, these duplicated genes can contribute to the formation of lineage-specific traits and phenotypic diversity. Despite the numerous studies of the functional retrocopies (retrogenes) in animals and plants, very little is known about their presence in green algae, including morphologically diverse species. The current availability of the genomes of both uni- and multicellular algae provides a good opportunity to conduct a genome-wide investigation in order to fill the knowledge gap in retroposition phenomenon in this lineage. RESULTS: Here we present a comparative genomic analysis of uni- and multicellular algae, Chlamydomonas reinhardtii and Volvox carteri, respectively, to explore their retrogene complements. By adopting a computational approach, we identified 141 retrogene candidates in total in both genomes, with their fraction being significantly higher in the multicellular Volvox. Majority of the retrogene candidates showed signatures of functional constraints, thus indicating their functionality. Detailed analyses of the identified retrogene candidates, their parental genes, and homologs of both, revealed that most of the retrogene candidates were derived from ancient retroposition events in the common ancestor of the two algae and that the parental genes were subsequently lost from the respective lineages, making many retrogenes 'orphan'. CONCLUSION: We revealed that the genomes of the green algae have maintained many possibly functional retrogenes in spite of experiencing various molecular evolutionary events during a long evolutionary time after the retroposition events. Our first report about the retrogene set in the green algae provides a good foundation for any future investigation of the repertoire of retrogenes and facilitates the assessment of the evolutionary impact of retroposition on diverse morphological traits in this lineage. REVIEWERS: This article was reviewed by William Martin and Piotr Zielenkiewicz. PMID- 27487949 TI - Primary intraspinal dumbbell-shaped mesenchymal chondrosarcoma with massive calcifications: a case report and review of the literature. AB - BACKGROUND: Mesenchymal chondrosarcoma is a rare malignant tumor arising from bone or soft tissues. Instraspinal dumbbell-shaped mesenchymal chondrosarcoma is even rarer; however, it should not be neglected by clinicians. CASE PRESENTATION: A 26-year-old female was referred to our hospital with a 1.5-month history of sciatic pain and numbness in the left leg. Computed tomography and magnetic resonance imaging scans revealed an intraspinal dumbbell-shaped mass which had distinguishing features of neurogenic tumors, surprisingly, with massive calcifications, and no tumor metastasis was found. Then the patient underwent a total resection of the tumor, and during the operation, we found that the right nerve root of the fifth lumbar almost disappeared. The tumor was diagnosed as mesenchymal chondrosarcoma by histopathological examination after operation. Adjuvant therapies were not performed. However, recurrence of the tumor occurred 5 months later, and she underwent a total resection again combined with radiotherapy after second surgery. CONCLUSIONS: To the best of our knowledge, this case study presents the first report in literature about primary instraspinal dumbbell-shaped mesenchymal chondrosarcoma with massive calcifications, which may provide some evidence for clinical practice. As the clinical symptoms and radiographic findings of mesenchymal chondrosarcoma are usually not specific, clinicians should consider it as a possible case and diagnose it through careful histopathological examination. Sometimes, calcification could be seen in tumors, which may influence or reflect the growth of tumor and disease prognosis. Although prognosis in mesenchymal chondrosarcoma varies from person to person, generally, complete resection, adjuvant therapy, and regular examinations are recommended to perform for patients with mesenchymal chondrosarcoma. PMID- 27487950 TI - Carrageenan delays cell cycle progression in human cancer cells in vitro demonstrated by FUCCI imaging. AB - BACKGROUND: Carrageenan is a sulfated polysaccharide that exists in red seaweeds recently shown to have anticancer properties. Previous findings show various effects of carrageenan suppressing tumor cell growth. One of the hallmarks of cancer is uncontrolled proliferation, a consequence of loss of normal cell-cycle control, that underlies tumor growth. Recently there is an increasing interest in potential anticancer agents that affect cell cycle in cancer cells. Thus, in this study we investigated the effects of carrageenan on the tumor cell cycle. METHODS: Using human cervical carcinoma cells (HeLa) cells as and human umbilical vein endothelial cells (HUVEC), the cytotoxic effects of kappa carrageenan (k-CO) and lambda carrageenan (lambda-CO) at the concentrations of 250-2500 MUg/mL were observed. Cell viability was determined using the MTT assay while cell death rates were determined using staining with calcein-AM/propidium iodide. Cell-cycle profile and progression were demonstrated with HeLa cells expressing FUCCI (fluorescence ubiquitination-based cell-cycle indicator) probes (HeLa-FUCCI). RESULTS: Carrageenan had no significant effect on HUVEC (normal cells). In contrast both forms of carrageenan were cytotoxic towards HeLa cells (cancer cells). Furthermore, according to cell-cycle analysis with FUCCI cells, the cell cycle of HeLa cells was delayed in specific phases due to different carrageenan treatments. CONCLUSION: Considering these results, it could be suggested that carrageenan affects the cell-cycle of HeLa cells not only by arresting the cell cycle in specific phases but also by delaying the time needed for the cell to progress through the cell cycle. Additionally, different types of carrageenans have different effects on cell cycle progression. This effect of carrageenan towards cancer cells could possibly be developed into a tumor cell-specific anticancer agent. PMID- 27487951 TI - Benefits of Adding a Rapid PCR-Based Blood Culture Identification Panel to an Established Antimicrobial Stewardship Program. AB - Studies have demonstrated that the combination of antimicrobial stewardship programs (ASP) and rapid organism identification improves outcomes in bloodstream infections (BSI) but have not controlled for the incremental contribution of the individual components. Hospitalized adult patients with blood culture pathogens on a rapid, multiplex PCR-based blood culture identification panel (BCID) that included 19 bacterial species, 5 Candida spp., and 4 antimicrobial resistance genes were studied over sequential time periods in a pre-post quasiexperimental study in 3 groups in the following categories: conventional organism identification (controls), conventional organism identification with ASP (AS), and BCID with ASP (BCID). Clinical and economic outcomes were compared between groups. There were 783 patients with positive blood cultures; of those patients, 364 (115 control, 104 AS, and 145 BCID) met inclusion criteria. The time from blood culture collection to organism identification was shorter in the BCID group (17 h; P < 0.001) than in the control group (57 h) or the AS group (54 h). The BCID group had a shorter time to effective therapy (5 h; P < 0.001) than the control group (15 h) or AS group (13 h). The AS (57%) and BCID (52%) groups had higher rates of antimicrobial de-escalation than the control group (34%), with de escalation occurring sooner in the BCID group (48 h; P = 0.034) than in the AS group (61 h) or the control group (63 h). No difference between the control group, AS group, and BCID group was seen with respect to mortality, 30-day readmission, intensive care unit length of stay (LOS), postculture LOS, or costs. In patients with BSI, ASP alone improved antimicrobial utilization. Addition of BCID to an established ASP shortened the time to effective therapy and further improved antimicrobial use compared to ASP alone, even in a setting of low antimicrobial resistance rates. PMID- 27487952 TI - Norovirus Whole-Genome Sequencing by SureSelect Target Enrichment: a Robust and Sensitive Method. AB - Norovirus full-genome sequencing is challenging due to sequence heterogeneity among genomes. Previous methods have relied on PCR amplification, which is problematic due to primer design, and transcriptome sequencing (RNA-Seq), which nonspecifically sequences all RNA, including host and bacterial RNA, in stool specimens. Target enrichment uses a panel of custom-designed 120-mer RNA baits that are complementary to all publicly available norovirus sequences, with multiple baits targeting each position of the genome, which overcomes the challenge of primer design. Norovirus genomes are enriched from stool RNA extracts to minimize the sequencing of nontarget RNA. SureSelect target enrichment and Illumina sequencing were used to sequence full genomes from 507 norovirus-positive stool samples with reverse transcription-real-time PCR cycle threshold (CT) values of 10 to 43. Sequencing on an Illumina MiSeq system in batches of 48 generated, on average, 81% on-target reads per sample and 100% genome coverage with >12,000-fold read depth. Samples included genotypes GI.1, GI.2, GI.3, GI.6, GI.7, GII.1, GII.2, GII.3, GII.4, GII.5, GII.6, GII.7, GII.13, GII.14, and GII.17. When outliers were accounted for, we generated >80% genome coverage for all positive samples, regardless of CT values. A total of 164 samples were tested in parallel with conventional PCR genotyping of the capsid shell domain; 164/164 samples were successfully sequenced, compared to 158/164 samples that were amplified by PCR. Four of the samples that failed capsid PCR analysis had low titers, which suggests that target enrichment is more sensitive than gel-based PCR. Two samples failed PCR due to primer mismatches; target enrichment uses multiple baits targeting each position, thus accommodating sequence heterogeneity among norovirus genomes. PMID- 27487953 TI - Molecular Microbiological Profile of Chronic Suppurative Otitis Media. AB - Chronic suppurative otitis media (CSOM) presents with purulent otorrhea (ear discharge), is characterized by chronic inflammation of the middle ear and mastoid cavity, and contributes to a significant disease burden worldwide. Current antibiotic therapy is guided by swab culture results. In the absence of detailed molecular microbiology studies of CSOM patients, our current understanding of the microbiota of CSOM (and indeed of the healthy ear) remains incomplete. In this prospective study, 24 patients with CSOM were recruited, along with 22 healthy controls. Culture-based techniques and 16S rRNA gene amplicon sequencing were used to profile the bacterial community for each patient. Comparisons between patients with and without cholesteatoma in the middle ear and mastoid cavity were also made. A major finding was that the middle ear of many healthy controls was not sterile, which is contradictory to the results of previous studies. However, sequencing data showed that Staphylococcus aureus, along with a range of other Gram-positive and Gram-negative organisms, were present in all subgroups of CSOM and healthy controls. Large interpatient variability in the microbiota was observed within each subgroup of CSOM and controls, and there was no bacterial community "signature" which was characteristic of either health or disease. Comparisons of the culture results with the molecular data show that culture-based techniques underestimate the diversity of bacteria found within the ear. This study reports the first detailed examination of bacterial profiles of the ear in healthy controls and patients with CSOM. PMID- 27487954 TI - Molecular Diagnostic Testing for Aspergillus. AB - The direct detection of Aspergillus nucleic acid in clinical specimens has the potential to improve the diagnosis of aspergillosis by offering more rapid and sensitive identification of invasive infections than is possible with traditional techniques, such as culture or histopathology. Molecular tests for Aspergillus have been limited historically by lack of standardization and variable sensitivities and specificities. Recent efforts have been directed at addressing these limitations and optimizing assay performance using a variety of specimen types. This review provides a summary of standardization efforts and outlines the complexities of molecular testing for Aspergillus in clinical mycology. PMID- 27487955 TI - Spatiotemporal Expression Patterns and Antibody Reactivity of Taeniidae Endophilin B1. AB - Larval Taeniidae, such as metacestodes of Taenia solium, Echinococcus granulosus, and Echinococcus multilocularis, produce chronic and fatal helminthic diseases. Proper identification of these zoonotic cestodiases is often challenging and is hampered in some clinical settings. Endophilin B1 plays critical roles in the maintenance of membrane contours and endocytosis. We isolated proteins homologous to endophilin B1 from T. solium, Taenia saginata, and Taenia asiatica The three Taeniidae endophilin B1 proteins shared 92.9 to 96.6% sequence identity. They harbored a Bin1/amphiphysin/Rvs (BAR) domain and residues for a dimeric interface but lacked a SRC homology 3 (SH3) domain. Endophilin B1 showed a unique immunological profile and was abundantly expressed in the tegumental syncytium of Taeniidae metacestodes and adults. Bacterially expressed recombinant T. solium endophilin B1 (rTsMEndoB1) demonstrated a sensitivity of 79.7% (345/433 cases) for serodiagnosis of larval Taeniidae infections. The protein showed strong immune recognition patterns against sera from patients with chronic neurocysticercosis, cystic echinococcosis, or advanced-stage alveolar echinococcosis. Adult Taeniidae infections exhibited moderate degrees of positive antibody responses (65.7% [23/35 samples]). rTsMEndoB1 showed some cross reactivity with sera from patients infected with Diphyllobothriidae (23.6% [25/106 samples]) but not with sera from patients with other parasitic diseases or normal controls. The specificity was 91.7% (256/301 samples). The positive and negative predictive values were 93.6% and 73.4%, respectively. Our results demonstrate that Taeniidae endophilin B1 may be involved in the control of membrane dynamics, thus contributing to shaping and maintaining the tegumental curvature. rTsMEndoB1 may be useful for large-scale screening, as well as for individual diagnosis and follow-up surveillance of Taeniidae infections. PMID- 27487956 TI - Evaluation of Semiautomated IS6110-Based Restriction Fragment Length Polymorphism Typing for Mycobacterium tuberculosis in a High-Burden Setting. AB - The manual IS6110-based restriction fragment length polymorphism (RFLP) typing method is highly discriminatory; however, it is laborious and technically demanding, and data exchange remains a challenge. In an effort to improve IS6110 based RFLP to make it a faster format, DuPont Molecular Diagnostics recently introduced the IS6110-PvuII kit for semiautomated typing of Mycobacterium tuberculosis using the RiboPrinter microbial characterization system. This study aimed to evaluate the semiautomated RFLP typing against the standard manual method. A total of 112 isolates collected between 2013 and 2014 were included. All isolates were genotyped using manual and semiautomated RFLP typing methods. Clustering rates and discriminatory indexes were compared between methods. The overall performance of semiautomated RFLP compared to manual typing was excellent, with high discriminatory index (0.990 versus 0.995, respectively) and similar numbers of unique profiles (72 versus 74, respectively), numbers of clustered isolates (33 versus 31, respectively), cluster sizes (2 to 6 and 2 to 5 isolates, respectively), and clustering rates (21.9% and 17.1%, respectively). The semiautomated RFLP system is technically simple and significantly faster than the manual RFLP method (8 h versus 5 days). The analysis is fully automated and generates easily manageable databases of standardized fingerprints that can be easily exchanged between laboratories. Based on its high-throughput processing with minimal human effort, the semiautomated RFLP can be a very useful tool as a first-line method for routine typing of M. tuberculosis isolates, especially where Beijing strains are highly prevalent, followed by manual RFLP typing if resolution is not achieved, thereby saving time and labor. PMID- 27487957 TI - Characterization of Vibrio cholerae Strains Isolated from the Nigerian Cholera Outbreak in 2010. AB - We examined clinical samples from Nigerian patients with acute watery diarrhea for Vibrio cholerae during the 2010 cholera outbreak. A total of 109 suspected isolates were characterized, but only 57 V. cholerae strains could be confirmed using multiplex real-time PCR as well as rpoB sequencing and typed as V. cholerae O:1 Ogawa biotype El Tor. This finding highlighted the need for accurate diagnosis of cholera in epidemic countries to implement life-saving interventions. PMID- 27487958 TI - A Novel SimpleProbe PCR Assay for Detection of Mutations in the 23S rRNA Gene Associated with Macrolide Resistance in Mycoplasma genitalium in Clinical Samples. AB - Macrolide-resistant strains of Mycoplasma genitalium are an increasing problem throughout the world, and the implementation of a rapid and sensitive assay for mutation detection to guide treatment is needed. Macrolide-resistant strains have been shown to contain base substitutions in positions 2058 and 2059 (Escherichia coli numbering) in region V of the 23S rRNA gene. In this study, we present a SimpleProbe PCR followed by melting curve analysis to differentiate between macrolide-resistant mutants and wild types. The assay was performed on 159 Mycoplasma genitalium-positive samples, and the results were compared with DNA sequencing. We also looked at the prevalence of macrolide-resistant strains in a Norwegian population. Of 139 samples characterized successfully by sequencing, 54 (39%) were wild types and 85 (61%) were mutants, consisting of 59 (42%) A2059G, 24 (17%) A2058G, 1 (1%) A2058T, and 1 (1%) A2059C mutation. The melting curve analysis correctly differentiated between wild-type and mutant strains in all cases, but it could not identify the different mutant types. The SimpleProbe PCR proved to be a simple, rapid, and reliable method for the detection of macrolide resistant isolates of Mycoplasma genitalium in a clinical setting. PMID- 27487959 TI - Proton pump inhibitors are associated with increased risk of development of chronic kidney disease. AB - BACKGROUND: Acute interstitial nephritis secondary to proton pump inhibitors (PPIs) frequently goes undiagnosed due to its subacute clinical presentation, which may later present as chronic kidney disease (CKD). We investigated the association of PPI use with the development of CKD and death. METHODS: Two separate retrospective case-control study designs were employed with a prospective logistic regression analysis of data to evaluate the association of development of CKD and death with PPI use. The population included 99,269 patients who were seen in primary care VISN2 clinics from 4/2001 until 4/2008. For evaluation of the CKD outcome, 22,807 with preexisting CKD at the first observation in Veterans Affairs Health Care Upstate New York (VISN2) network data system were excluded. Data obtained included use of PPI (Yes/No), demographics, laboratory data, pre-PPI comorbidity variables. RESULTS: A total of 19,311/76,462 patients developed CKD. Of those who developed CKD 24.4 % were on PPI. Patients receiving PPI were less likely to have vascular disease, COPD, cancer and diabetes. Of the total of 99,269 patients analyzed for mortality outcome, 11,758 died. A prospective logistic analysis of case-control data showed higher odds for development of CKD (OR 1.10 95 % CI 1.05-1.16) and mortality (OR 1.76, 95 % CI 1.67-1.84) among patients taking PPIs versus those not on PPIs. CONCLUSIONS: Use of proton pump inhibitors is associated with increased risk of development of CKD and death. With the large number of patients being treated with proton pump inhibitors, healthcare providers need to be better educated about the potential side effects of these medications. PMID- 27487960 TI - Readability of patient education materials in ophthalmology: a single-institution study and systematic review. AB - BACKGROUND: Patient education materials should be written at a level that is understandable for patients with low health literacy. The aims of this study are (1) to review the literature on readability of ophthalmic patient education materials and (2) to evaluate and revise our institution's patient education materials about glaucoma using evidence-based guidelines on writing for patients with low health literacy. METHODS: A systematic search was conducted on the PubMed/MEDLINE database for studies that have evaluated readability level of ophthalmic patient education materials, and the reported readability scores were assessed. Additionally, we collected evidence-based guidelines for writing easy to-read patient education materials, and these recommendations were applied to revise 12 patient education handouts on various glaucoma topics at our institution. Readability measures, including Flesch-Kincaid Grade Level (FKGL), and word count were calculated for the original and revised documents. The original and revised versions of the handouts were then scored in random order by two glaucoma specialists using the Suitability Assessment of Materials (SAM) instrument, a grading scale used to evaluate suitability of health information materials for patients. Paired t test was used to analyze changes in readability measures, word count, and SAM score between original and revised handouts. Finally, five glaucoma patients were interviewed to discuss the revised materials, and patient feedback was analyzed qualitatively. RESULTS: Our literature search included 13 studies that evaluated a total of 950 educational materials. Among the mean FKGL readability scores reported in these studies, the median was 11 (representing an eleventh-grade reading level). At our institution, handouts' readability averaged a tenth-grade reading level (FKGL = 10.0 +/- 1.6), but revising the handouts improved their readability to a sixth-grade reading level (FKGL = 6.4 +/- 1.2) (p < 0.001). Additionally, the mean SAM score of our institution's handouts improved from 60 +/- 7 % (adequate) for the original versions to 88 +/- 4 % (superior) for the revised handouts (p < 0.001). CONCLUSIONS: Our systematic review of the literature reveals that ophthalmic patient education materials are consistently written at a level that is too high for many patients to understand. Our institution's experience suggests that applying guidelines on writing easy-to-understand material can improve the readability and suitability of educational materials for patients with low health literacy. PMID- 27487962 TI - Commentary: Chloride Regulation: A Dynamic Equilibrium Crucial for Synaptic Inhibition. PMID- 27487961 TI - Impact of reticulated platelets on antiplatelet response to thienopyridines is independent of platelet turnover. AB - Reticulated platelets are associated with impaired antiplatelet response to thienopyridines. It is uncertain whether this interaction is caused by a decreased drug exposure due to high platelet turnover reflected by elevated levels of reticulated platelets or by intrinsic properties of reticulated platelets. This study sought to investigate if the impact of reticulated platelets on early antiplatelet response to thienopyridines is mainly caused by platelet turnover as previously suggested. Elective patients undergoing coronary intervention were randomised to loading with clopidogrel 600 mg or prasugrel 60 mg (n=200). Adenosine diphosphate (ADP)-induced platelet reactivity was determined by impedance aggregometry before, at 30, 60, 90, and 120 minutes and at day 1 after loading. Immature platelet count was assessed as marker of reticulated platelets by flow cytometry. Platelet reactivity increased with rising levels of immature platelet count in both groups. This effect was more distinctive in patients on clopidogrel as compared to patients on prasugrel. Overall, immature platelet count correlated well with on-treatment platelet reactivity at all time-points (p < 0.001). These correlations did not change over time in the entire cohort as well as in patients treated with clopidogrel or prasugrel indicating an effect independent of platelet turnover (comparison of correlations 120 minutes/day 1: p = 0.64). In conclusion, the association of immature platelet count with impaired antiplatelet response to thienopyridines is similar early and late after loading. This finding suggests as main underlying mechanism another effect of reticulated platelets on thienopyridines than platelet turnover. PMID- 27487963 TI - Could peptide-decorated nanoparticles provide an improved approach for treating pregnancy complications? PMID- 27487964 TI - Molecular Dynamics Simulations of Hydration Effects on Solvation, Diffusivity, and Permeability in Chitosan/Chitin Films. AB - The effects of hydration on the solvation, diffusivity, solubility, and permeability of oxygen molecules in sustainable, biodegradable chitosan/chitin food packaging films were studied via molecular dynamics and confined random walk simulations. With increasing hydration, the membrane has a more homogeneous water distribution with the polymer chains being fully solvated. The diffusivity increased by a factor of 4 for oxygen molecules and by an order of magnitude for water with increasing the humidity. To calculate the Henry's constant and solubility of oxygen in the membranes with changing hydration, the excess chemical potential was calculated via free energy perturbation, thermodynamic integration and direct particle deletion methods. The simulations predicted a higher solubility and permeability for the lower humidity, in contradiction to experimental results. All three methods for calculating the solubility were in good agreement. It was found that the Coulombic interactions in the potential caused the oxygen to bind too strongly to the protonated amine group. Insight from this work will help guide molecular modeling of chitosan/chitin membranes, specifically permeability measurements for small solute molecules. Efforts to chemically tailor chitosan/chitin membranes to favor discrete as opposed to continuous aqueous domains could reduce oxygen permeability. PMID- 27487965 TI - NKG2D Acts as a Co-Receptor for Natural Killer Cell-Mediated Anti-HIV-1 Antibody Dependent Cellular Cytotoxicity. AB - The utility of antibody-dependent cellular cytotoxicity (ADCC) for eliminating HIV-1-infected cells is of much interest for the design of both prophylactic vaccines for HIV-1 prevention and therapeutics to eliminate latently infected cells following reactivation. Significant research has been conducted to understand the antibody specificities involved in anti-HIV-1 ADCC responses. Perhaps equally important as the identity of the antibodies mediating these responses are factors regulating the ability of ADCC effector cells, in particular, natural killer (NK) cells, to respond to antibody-coated target cells. Indeed, a plethora of activating and inhibitory receptors expressed on the surface of NK cells might act in conjunction with CD16 to influence ADCC. As the expression of NKG2D and its ligands has been linked to HIV-1 disease progression, we evaluated if signals through NKG2D were involved in anti-HIV-1 ADCC. Utilizing assays measuring cytolysis, we provide the first data implicating NKG2D in antibody-dependent NK cell responses against a target cell line either pulsed with gp120 or infected with HIV-1. These observations are highly significant for understanding antibody-dependent NK cell responses against HIV-1 and might be useful for optimizing prophylactics and therapeutics aiming to utilize antibodies and optimally functional NK cells to control HIV-1. PMID- 27487966 TI - Community nurse-led initiation of antiviral therapy for chronic hepatitis C in people who inject drugs does not increase uptake of or adherence to treatment. AB - BACKGROUND: Chronic hepatitis C is common in people who inject drugs (PWID) and this population serves as a reservoir for infection. Treatment levels are low among this group, ranging from 1 to 19%. We explored whether a nurse-initiated community treatment model increased uptake of and adherence to interferon-based therapies. METHODS: This was a cluster randomized trial of nurse-initiated versus physician-initiated antiviral therapy with pegylated interferon and ribavirin for hepatitis C virus in community clinics (trial registration: ISRCTN07774040). RESULTS: The proportion of participants initiating treatment during follow-up was 10% with nurse-initiated (6/62) and 9% with physician-initiated (6/76) therapy. Adherence was similar in both groups, with only one patient in each arm not adhering to therapy. There were no serious adverse events, but interferon-related side effects were common. Drug and alcohol use did not change during therapy. CONCLUSION: Despite easy access to antiviral therapy, uptake of treatment was poor, with no significant difference between the groups. Nurse-led initiation of interferon-based antiviral therapy in PWID did not lead to increased uptake of, response to or adherence with treatment. Further service improvement is unlikely to increase the proportion of PWID undergoing antiviral therapy for hepatitis C virus and early adoption of interferon-free regimens may increase the proportion initiating and completing treatment. PMID- 27487967 TI - Factors Affecting Burn Contracture Outcome in Developing Countries: A Review of 2506 Patients. AB - INTRODUCTION: Burn contractures hinder joint mobility, resulting in functional impairment and reduced quality of life. This is of greater significance in developing countries where there are fewer resources for assistance with such impairments. Contracture release reduces deformity, but multiple factors affect the extent of postsurgical improvements and outcomes. Elucidating these factors may enable surgeons to better care for burn patients. This study assesses factors that impact burn contracture resolution in developing nations. METHODS: A retrospective review of 2506 burn contractures was performed using information extracted from a large nongovernment organization (ReSurge International) database from Nepal, India, and Zambia. Data points included age, type of burn, time elapsed between injury and release, and extent of final release achieved based on preoperative and postoperative images of hand (n = 1960), elbow (n = 371), and knee (n = 176) contractures. Hand improvement was scored based on digit/wrist involvement (severity of dysfunction) and joint extension capability (functionality); elbow and knee improvement were calculated using preoperative and postoperative joint angles. Multivariate analysis was performed. RESULTS: Hands burned by hot liquid had greater functionality after surgery than open-fire burns (P < 0.01). Improvement in severity of dysfunction and functionality were inversely correlated to age (P < 0.01) and time until surgery (P < 0.01). Elbow improvement decreased as age increased (P < 0.01). Postoperative increase of knee extension decreased for each year elapsed between injury and surgery (P < 0.01). CONCLUSIONS: Burn type, age when burned, and timing of surgery were significant factors affecting hand outcomes, whereas age affected elbow outcomes, and time elapsed until surgery affected knee results. An algorithm was formulated to enable physicians in developing countries with limited resources to triage patients and optimize patient outcomes. PMID- 27487968 TI - The Simultaneous Use of Breast Reduction and Internal Mammary Artery Perforator Flap in Sternal Wound Reconstruction. AB - Internal mammary artery perforator (IMAP)-based fasciocutaneous flaps have recently gained popularity in sternal wound reconstruction due to their decreased donor site morbidity. However, patients with significant macromastia or who are obese present a challenge when using these flaps due to their anatomy and associated comorbid conditions. Despite the prevalence of this population, there is a relative paucity of data on the use of local fasciocutaneous flaps and techniques to close sternotomy wounds in the obese population with hypertrophic or ptotic breasts. The authors describe a novel technique using simultaneous unilateral breast reduction with a fifth intercostal IMAP-based flap for closure of a median sternotomy wound through a case presentation, an anatomical injection study, and review of the literature. Five fresh female cadavers were used to conduct 8 trials of injection of the IMAP arteries, isolation of the fifth IMAP branch, and elevation of a local flap. The literature was comprehensively reviewed with a total of 33 cases of IMAP flaps for sternal reconstruction being described. The most commonly used perforators with the second and sixth IMAPs. Overall complication rate was reported to be 9.1% (3/33), with 2 cases reporting dehiscence and 1 with flap tip necrosis. No cases reported use of the fifth IMAP or formal breast reduction procedures, which was successfully performed in a 40 year-old diabetic female patient history of multiple left-sided thoracic surgeries and radiation with a chronic sternal wound. PMID- 27487969 TI - Dilated right internal thoracic artery as a systemic pulmonary shunt. AB - We report the use of a dilated right internal thoracic artery as a systemic pulmonary shunt in a patient with a single ventricle who developed a systemic pulmonary shunt stenosis following a modified Norwood's procedure. The systemic to-pulmonary artery shunt was performed at 13 months of age, and the patient has stable oxygen saturations five years after the surgery. PMID- 27487970 TI - Corrigendum: Generation of stem cell-derived beta-cells from patients with type 1 diabetes. PMID- 27487971 TI - Early dumping syndrome is not a complication but a desirable feature of Roux-en-Y gastric bypass surgery. AB - Early dumping syndrome after gastric bypass surgery due to rapid delivery of hyperosmolar nutrients into the bowel causing intense symptoms is often described as a complication. Twelve patients, mean age 47 years, were interviewed approximately 9 years post-operation. The interviews were audiotaped and transcribed verbatim, followed by an inductive content analysis to reveal patients' experience of the dumping syndrome. The core category 'Dumping syndrome is a positive consequence of Roux-en-Y gastric bypass surgery and a tool to control food intake' was identified based on the following four sub-categories: (i) 'The multidimensional emergence and effects of dumping syndrome', (ii) 'Dumping syndrome as something positive although unpleasant', (iii) 'Developing coping mechanisms and ingenious strategies' and (iv) 'My own fault if I expose myself to dumping syndrome'. From the patients' perspective, dumping syndrome gives control over food intake; although the symptoms were unpleasant, patients considered dumping syndrome as a positive protection against over-consumption. Hence, healthcare professionals should not present dumping syndrome as a complication but rather as an aid to control eating behaviour and excessive food intake. PMID- 27487972 TI - Organisational strategies to implement hospital pressure ulcer prevention programmes: findings from a national survey. AB - AIM: To describe the presence and operationalisation of organisational strategies to support implementation of pressure ulcer prevention programmes across acute care hospitals in a large, integrated health-care system. BACKGROUND: Comprehensive pressure ulcer programmes include nursing interventions such as use of a risk assessment tool and organisational strategies such as policies and performance monitoring to embed these interventions into routine care. The current literature provides little detail about strategies used to implement pressure ulcer prevention programmes. METHODS: Data were collected by an e-mail survey to all chief nursing officers in Veterans Health Administration acute care hospitals. Descriptive and bivariate statistics were used to summarise survey responses and evaluate relationships between some variables. RESULTS: Organisational strategies that support implementation of a pressure ulcer prevention programme (policy, committee, staff education, wound care specialists, and use of performance data) were reported at high levels. Considerable variations were noted in how these strategies were operationalised within individual hospitals. CONCLUSION: Organisational strategies to support implementation of pressure ulcer preventive programmes are often not optimally operationalised to achieve consistent, sustainable performance. IMPLICATIONS FOR NURSING MANAGEMENT: The results of the present study highlight the role and influence of nurse leaders on pressure ulcer prevention program implementation. PMID- 27487973 TI - Self-management in temporomandibular disorders: a systematic review of behavioural components. AB - The aim of this qualitative systematic review was to identify the behaviour change techniques most frequently employed in published temporomandibular disorder (TMD) self-management (SM) programmes. The reviewers matched the components of SM programmes into the relevant behaviour change technique domains according to the definitions of the behaviour change taxonomy (version 1). Electronic databases were searched for randomised controlled trials assessing an SM programme for TMD. Manual searches were also conducted for potentially important journals. Eligibility criteria for the review included: the type of study, the participants, the intervention utilised and the comparators/control. Fifteen randomised controlled trials with 554 patients were included in this review. The review concludes a minority of the available behaviour change techniques are currently employed in SM programmes. Other behaviour change techniques should be examined to see whether there is a theoretical underpinning that might support their inclusion in self-management programmes in TMD. Further trials are required to conclude that SM programmes are more effective than no treatment at all and or placebo. With more structured SM programmes, greater therapeutic benefits might be achieved, and certainly if SM programmes published in the literature define their components through use of the behaviour change taxonomy, it would be easier for clinicians to replicate efficacious programmes. PMID- 27487974 TI - Pediatric Obesity: Is There Room for Active Video Games in Prevention or Management? AB - Children and adolescents spend a considerable amount of time engaged in sedentary behaviors that have been shown to favor weight gain and impaired physical fitness. Active video games have been proposed to increase physical activity levels. Although active video games may offer an interesting alternative to reducing sedentary time for children, the present commentary aimed to determine whether there is adequate evidence that compared active video gaming to real-life play and exercise. Given the dearth of data, it is not possible at present to support the use of active video games as substitutes for traditional forms of active play and health-enhancing physical activity. Further research should be encouraged and therapists should not consider active video games exclusively for intervention in children with obesity. PMID- 27487975 TI - Comparative study of the effects of bupropion and escitalopram on Internet gaming disorder. AB - AIM: We compared the efficacy of bupropion and escitalopram treatments in Internet gaming disorder (IGD) patients. METHODS: We recruited 119 adolescents and adults with IGD. We treated these participants for 6 weeks in three groups as follows: 44 participants were treated with bupropion SR (bupropion group), 42 participants were treated with escitalopram (escitalopram group), and 33 patients without any medication were observed in the community (observation group). At baseline and at the 6-week follow-up visit, all subjects were evaluated using the Clinical Global Impression-Severity Scale, the Young Internet Addiction Scale, the Beck Depression Inventory, the ADHD Rating Scale, and the Behavioral Inhibition and Activation Scales. RESULTS: Both the escitalopram group and the bupropion group showed improvement on all clinical symptom scales after 6 weeks of treatment compared to the observation group. Additionally, the bupropion group showed greater improvement on scores for the Clinical Global Impression-Severity Scale, the Young Internet Addiction Scale, the ADHD Rating Scale, and the Behavioral Inhibition Scale than the escitalopram group. CONCLUSION: Both bupropion and escitalopram were effective in treating and managing IGD symptoms. Moreover, bupropion appeared to be more effective than escitalopram in improving attention and impulsivity in IGD patients. In addition, attention and impulsivity seem to be important for the management of IGD. PMID- 27487976 TI - The moderating role of intrinsic value in the relation between psychological needs support and academic engagement in mathematics among Chinese adolescent students. AB - This study was to assess the moderating roles of intrinsic value in the relation of basic psychological needs support to academic engagement in mathematics. We recruited 246 middle school students by using the Basic Psychological Needs Support Scale, the Intrinsic Value Scale and the Academic Engagement Scale. This study found that both basic psychological needs support and intrinsic value had significant predictions on the three aspects of academic engagement. Moreover, the interaction item between basic psychological needs support and intrinsic value could significantly affect emotional and cognitive engagement, but not behavioural engagement. The findings indicated that except for behavioural engagement, the associations between basic psychological need support and emotional or cognitive engagement could be moderated by intrinsic value. This study provides a special perspective for educators and researchers to recognise the role of intrinsic value in promoting adolescents' higher levels of involvement in mathematics class. PMID- 27487977 TI - Growth and wetting of water droplet condensed between micron-sized particles and substrate. AB - We study heterogeneous condensation growth of water droplets on micron-sized particles resting on a level substrate. Through numerical simulations on equilibrium droplet profiles, we find multiple wetting states towards complete wetting of the particle. Specifically, a partially wetting droplet could undergo a spontaneous transition to complete wetting during condensation growth, for contact angles above a threshold minimum. In addition, we find a competitive wetting behavior between the particle and the substrate, and interestingly, a reversal of the wetting dependence on contact angles during late stages of droplet growth. Using quasi-steady assumption, we simulate a growing droplet under a constant condensation flux, and the results are in good agreement with our experimental observations. As a geometric approximation for particle clusters, we propose and validate a pancake model, and with it, show that a particle cluster has greater wetting tendency compared to a single particle. Together, our results indicate a strong interplay between contact angle, capillarity and geometry during condensation growth. PMID- 27487978 TI - Inkjet Printing Based Mono-layered Photonic Crystal Patterning for Anti counterfeiting Structural Colors. AB - Photonic crystal structures can be created to manipulate electromagnetic waves so that many studies have focused on designing photonic band-gaps for various applications including sensors, LEDs, lasers, and optical fibers. Here, we show that mono-layered, self-assembled photonic crystals (SAPCs) fabricated by using an inkjet printer exhibit extremely weak structural colors and multiple colorful holograms so that they can be utilized in anti-counterfeit measures. We demonstrate that SAPC patterns on a white background are covert under daylight, such that pattern detection can be avoided, but they become overt in a simple manner under strong illumination with smartphone flash light and/or on a black background, showing remarkable potential for anti-counterfeit techniques. Besides, we demonstrate that SAPCs yield different RGB histograms that depend on viewing angles and pattern densities, thus enhancing their cryptographic capabilities. Hence, the structural colorations designed by inkjet printers would not only produce optical holograms for the simple authentication of many items and products but also enable a high-secure anti-counterfeit technique. PMID- 27487979 TI - Short-term and long-term outcomes of laparoscopic hepatectomy, microwave ablation, and open hepatectomy for small hepatocellular carcinoma: a 5-year experience in a single center. AB - AIM: Laparoscopic hepatectomy (LH), microwave ablation (MWA), and open hepatectomy (OH) are three widely used methods to treat small hepatocellular carcinoma (HCC). However, few studies have compared the short- and long-term outcomes of these three treatments. The aim of this study was to investigate their effectiveness. METHODS: The data were reviewed from 280 patients with HCCs measuring <=3 cm (Barcelona Clinic Liver Cancer stage 0 or A) who received LH (n = 133), OH (n = 87), or MWA (n = 60) in our research center from 2005 to 2010. Short-term outcomes included intraoperative blood loss, operation time, and length of hospital stay. The disease-free survival and overall survival rates were analyzed as long-term outcomes. RESULTS: The patients in the MWA and LH groups showed better short-term outcomes compared with those in the OH group. There were no significant differences in overall survival rates among the three treatments. The LH group showed significantly lower recurrence rates than the MWA group (P = 0.0146). CONCLUSIONS: Laparoscopic hepatectomy may be a better option for patients with small HCC located on the liver surface and left lateral lobe. The short-term outcome of MWA is promising, although the high risk of local recurrence after the operation should be considered when planning treatment. PMID- 27487980 TI - Zn-biofortification enhanced nitrogen metabolism and photorespiration process in green leafy vegetable Lactuca sativa L. AB - BACKGROUND: Excessive rates of nitrogen (N) fertilizers may result in elevated concentrations of nitrate (NO3- ) in plants. Considering that many programs of biofortification with trace elements are being performed, it has become important to study how the application of these elements affects plant physiology and, particularly, N utilization in leaf crops. The main objective of the present study was to determine whether the NO3- accumulation and the nitrogen use efficiency was affected by the application of different doses of Zn in Lactuca sativa plants. RESULTS: Zn doses in the range 80-100 umol L-1 produced an increase in Zn concentration provoking a decrease of NO3- concentration and increase of the nitrate reductase, glutamine synthetase and aspartate aminotransferase activities, as well as the photorespiration processes. As result, we observed an increase in reduced N, total N concentration and N utilization efficiency. Consequently, at a dose of 80 umol L-1 of Zn, the amino acid concentration increased significantly. CONCLUSION: Adequate Zn fertilization is an important critical player in lettuce, especially at a dose of 80 umol L-1 of Zn, because it could result in an increase in the Zn concentration, a reduction of NO3- levels and an increase the concentration of essential amino acids, with all of them having beneficial properties for the human diet. (c) 2016 Society of Chemical Industry. PMID- 27487981 TI - Calcium oxalate crystal production and density at different phenological stages of soybean plants (Glycine max L.) from the southeast of the Pampean Plain, Argentina. AB - Glycine max L. (soybean) is one of the major crops of the world. Although the process of biomineralisation has been reported in some organs of soybean, we now report the description and quantification of calcium oxalate crystals in vegetative and reproductive organs of soybean during its life cycle, as they act as an important source of calcium to the soil, once the harvesting is finished. Through diaphanisation, cross-sectioning, optical and scanning electron microscopy analysis of the organs, morphology, size and location of the crystals were identified. In addition, crystal density (n degrees crystals.mm-2 ) and the input of crystals to soil (n degrees crystals.ha-1 ) were calculated. Soybean produced prismatic calcium oxalate crystals in vegetative and reproductive organs, generally associated with vascular bundles, resulting in a potencial transfer to the soil of 81.4 x 107 crystals.ha-1 throughout its life cycle. Pods were the organs with higher calcium oxalate crystal production (1112.7 +/- 384.6 crystals.mm-2 ), but with the smaller size (12.3 +/- 2.1 MUm long). However, cotyledons were the organs that produce the larger crystals (21.3 +/- 3.5 MUm long), but in lesser amounts (150.9 +/- 64.4 crystals.mm-2 ). In leaves, although crystal size did not differ from vegetative to reproductive stage (14.5 +/- 4.2 and 14.5 +/- 4 MUm in length, respectively), the crystal density increased (293.2 and 409 crystals.mm-2 , respectively). These results will contribute to knowledge of the amount of calcium oxalate crystals involved in the process of Ca recycling through cultivated vegetation in fields from humid plains at medium latitudes, which therefore have biological, botanical, biogeochemical and pedological relevance. PMID- 27487982 TI - The ginger component 6-shogaol prevents TNF-alpha-induced barrier loss via inhibition of PI3K/Akt and NF-kappaB signaling. AB - SCOPE: Anti-inflammatory properties of the ginger-derived pungent component 6 shogaol (6-SG) have been studied intensively in recent years. Purpose of this study was to characterize the influence of 6-SG on inflammation-related intestinal barrier dysfunction, especially its paracellular component. METHODS AND RESULTS: The effect of 6-SG was studied in the human intestinal cell models HT-29/B6 and Caco-2 either under control conditions or challenged by the pro inflammatory cytokine tumor necrosis factor alpha (TNF-alpha). Electrophysiological measurements, freeze-fracture electron microscopy, and protein analyses were performed. 6-SG partially prevented both, the TNF-alpha induced decrease in transepithelial resistance and the rise in fluorescein permeability. By inhibiting phosphatidylinositol-3-kinase/Akt signaling 6-SG prevented the TNF-alpha-induced increase in protein expression of claudin-2, a channel-forming tight junction protein. In addition, the TNF-alpha-induced disassembly of the sealing tight junction protein claudin-1 was attenuated, the latter of which was due to TNF-alpha-triggered phosphorylation of nuclear factor kappa light chain enhancer of activated B cells (NF-kappaB). CONCLUSION: 6-SG has barrier-protective effects by affecting TNF-alpha-induced claudin-2 upregulation and claudin-1 disassembly via inhibition of phoshatidylinositol-3-kinase/Akt and nuclear factor kappa light chain enhancer of activated B-cell signaling. Therefore, 6-SG-containing food might be beneficial for barrier preservation during intestinal inflammation. PMID- 27487984 TI - Therapeutic applications of conditioned medium from adipose tissue. AB - For the past number of decades, adipose tissue has attracted significant interest due to its complicated composition and versatile functions. Adipose tissue is no longer considered to be just an energy-storing fat pad, but is also a key ring player in interaction networks between various organs and tissues. A wide range of factors released by adipose tissue are responsible for regulation of adipose tissue and other distant target tissues and cells, such as kidneys, skeletal muscle, the cardiovascular system and the immune system, in an auto-/paracrine manner. A mixture of bioactive molecules makes up the conditioned medium of adipose tissue. The beneficial role played by these bioactive molecules in angiogenesis, wound healing, tissue regeneration and immunomodulation has been demonstrated by various studies. Study of this conditioned medium helps deepen our understanding of underlying mechanisms and broadens the potential for therapeutic applications. In this review, we have aimed to improve fundamental understanding of conditioned medium from adipose tissue and to summarize recent efforts to study its therapeutic applications. PMID- 27487983 TI - Subject-level reliability analysis of fast fMRI with application to epilepsy. AB - PURPOSE: Recent studies have applied the new magnetic resonance encephalography (MREG) sequence to the study of interictal epileptic discharges (IEDs) in the electroencephalogram (EEG) of epileptic patients. However, there are no criteria to quantitatively evaluate different processing methods, to properly use the new sequence. METHODS: We evaluated different processing steps of this new sequence under the common generalized linear model (GLM) framework by assessing the reliability of results. A bootstrap sampling technique was first used to generate multiple replicated data sets; a GLM with different processing steps was then applied to obtain activation maps, and the reliability of these maps was assessed. RESULTS: We applied our analysis in an event-related GLM related to IEDs. A higher reliability was achieved by using a GLM with head motion confound regressor with 24 components rather than the usual 6, with an autoregressive model of order 5 and with a canonical hemodynamic response function (HRF) rather than variable latency or patient-specific HRFs. Comparison of activation with IED field also favored the canonical HRF, consistent with the reliability analysis. CONCLUSION: The reliability analysis helps to optimize the processing methods for this fast fMRI sequence, in a context in which we do not know the ground truth of activation areas. Magn Reson Med 78:370-382, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27487985 TI - Bioimpedance Spectroscopy for Breast Cancer Related Lymphedema Assessment: Clinical Practice Guidelines. AB - With improved breast cancer survivorship, lymphedema of the arm is a growing concern for many patients following treatment. Diagnosis and management of breast cancer related lymphedema (BCRL) is often delayed due to low sensitivity diagnostic techniques and a failure to incorporate BCRL assessments into standard clinical practice. Bioimpedance spectroscopy (BIS) is an increasingly utilized diagnostic technique that allows for the subclinical detection of BCRL, prior to clinically evident disease. We provide a summary of the data supporting the early detection and treatment of BCRL, a comparison of BCRL diagnostic modalities and data supporting the utilization of BIS. Finally, clinical practice guidelines will be provided to allow for the incorporation of BIS into the standard management of breast cancer patients prior to and following locoregional and systemic therapy. These clinical practice guidelines offer clinicians a method to introduce bioimpedance into routine breast cancer care. With increasing focus on BCRL, such protocols will allow for prospective evaluation of patients and early diagnosis and treatment. PMID- 27487986 TI - The effect of healthy dietary consumption on executive cognitive functioning in children and adolescents: a systematic review. AB - A systematic review was conducted to evaluate whether healthier dietary consumption among children and adolescents impacts executive functioning. PubMed, Education Resources Information Center, PsychINFO and Thomson Reuters' Web of Science databases were searched, and studies of executive functioning among children or adolescents aged 6-18 years, which examined food quality, macronutrients and/or foods, were included. Study quality was also assessed. In all, twenty-one studies met inclusion criteria. Among the twelve studies examining food quality (n 9) or macronutrient intakes (n 4), studies examining longer-term diet (n 6) showed positive associations between healthier overall diet quality and executive functioning, whereas the studies examining the acute impact of diet (n 6) were inconsistent but suggestive of improvements in executive functioning with better food quality. Among the ten studies examining foods, overall, there was a positive association between healthier foods (e.g. whole grains, fish, fruits and/or vegetables) and executive function, whereas less-healthy snack foods, sugar-sweetened beverages and red/processed meats were inversely associated with executive functioning. Taken together, evidence suggests a positive association between healthy dietary consumption and executive functioning. Additional studies examining the effects of healthier food consumption, as well as macronutrients, on executive functioning are warranted. These studies should ideally be conducted in controlled environments and use validated cognitive tests. PMID- 27487987 TI - Characterization of lipopeptides produced by Bacillus licheniformis using liquid chromatography with accurate tandem mass spectrometry. AB - RATIONALE: The plant endophyte Bacillus licheniformis, isolated from leaves of Vitis vinifera, was studied to individuate and characterize the presence of bioactive lipopeptides having amino acidic structures. METHODS: Crude extracts of liquid cultures were analyzed by ultra-high-performance liquid chromatography (UHPLC) coupled to a quadrupole time-of-flight (QTOF) mass analyzer. Chromatographic conditions were optimized in order to obtain an efficient separation of the different isobaric lipopeptides, avoiding merged fragmentations of co-eluted isomeric compounds and reducing possible cross-talk phenomena. Composition of the amino acids was outlined through the interpretation of the fragmentation behavior in tandem high-resolution mass spectrometry (HRMS/MS) mode, which showed both common-class and peculiar fragment ions. Both [M + H](+) and [M + Na](+) precursor ions were fragmented in order to differentiate some isobaric amino acids, i.e. Leu/Ile. Neutral losses characteristic of the iso acyl chain were also evidenced. RESULTS: More than 90 compounds belonging to the classes of surfactins and lichenysins, known as biosurfactant molecules, were detected. Sequential LC/HRMS/MS analysis was used to identify linear and cyclic lipopeptides, and to single out the presence of a large number of isomers not previously reported. Some critical issues related to the simultaneous selection of different compounds by the quadrupole filter were highlighted and partially solved, leading to tentative assignments of several structures. Linear lichenysins are described here for the first time. CONCLUSIONS: The approach was proved to be useful for the characterization of non-target lipopeptides, and proposes a rationale MS experimental scheme aimed to investigate the difference in amino acid sequence and/or in the acyl chain of the various congeners, when standards are not available. Results expanded the knowledge about production of linear and cyclic bioactive compounds from Bacillus licheniformis, clarifying the structures of isomeric forms, and enabling the use of selected endophytes to produce fungicides for eco-friendly biocontrol. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27487988 TI - Defining the origins of electron transfer at screen-printed graphene-like and graphite electrodes: MoO2 nanowire fabrication on edge plane sites reveals electrochemical insights. AB - Molybdenum (di)oxide (MoO2) nanowires are fabricated onto graphene-like and graphite screen-printed electrodes (SPEs) for the first time, revealing crucial insights into the electrochemical properties of carbon/graphitic based materials. Distinctive patterns observed in the electrochemical process of nanowire decoration show that electron transfer occurs predominantly on edge plane sites when utilising SPEs fabricated/comprised of graphitic materials. Nanowire fabrication along the edge plane sites (and on edge plane like-sites/defects) of graphene/graphite is confirmed with Cyclic Voltammetry, Scanning Electron Microscopy (SEM) and Raman Spectroscopy. Comparison of the heterogeneous electron transfer (HET) rate constants (k degrees ) at unmodified and nanowire coated SPEs show a reduction in the electrochemical reactivity of SPEs when the edge plane sites are effectively blocked/coated with MoO2. Throughout the process, the basal plane sites of the graphene/graphite electrodes remain relatively uncovered; except when the available edge plane sites have been utilised, in which case MoO2 deposition grows from the edge sites covering the entire surface of the electrode. This work clearly illustrates the distinct electron transfer properties of edge and basal plane sites on graphitic materials, indicating favourable electrochemical reactivity at the edge planes in contrast to limited reactivity at the basal plane sites. In addition to providing fundamental insights into the electron transfer properties of graphite and graphene-like SPEs, the reported simple, scalable, and cost effective formation of unique and intriguing MoO2 nanowires realised herein is of significant interest for use in both academic and commercial applications. PMID- 27487989 TI - A large set of 26 new reference transcriptomes dedicated to comparative population genomics in crops and wild relatives. AB - We produced a unique large data set of reference transcriptomes to obtain new knowledge about the evolution of plant genomes and crop domestication. For this purpose, we validated a RNA-Seq data assembly protocol to perform comparative population genomics. For the validation, we assessed and compared the quality of de novo Illumina short-read assemblies using data from two crops for which an annotated reference genome was available, namely grapevine and sorghum. We used the same protocol for the release of 26 new transcriptomes of crop plants and wild relatives, including still understudied crops such as yam, pearl millet and fonio. The species list has a wide taxonomic representation with the inclusion of 15 monocots and 11 eudicots. All contigs were annotated using BLAST, prot4EST and Blast2GO. A strong originality of the data set is that each crop is associated with close relative species, which will permit whole-genome comparative evolutionary studies between crops and their wild-related species. This large resource will thus serve research communities working on both crops and model organisms. All the data are available at http://arcad bioinformatics.southgreen.fr/. PMID- 27487990 TI - Adding energy minimization strategy to peptide-design algorithm enables better search for RNA-binding peptides: Redesigned lambda N peptide binds boxB RNA. AB - Our previously developed peptide-design algorithm was improved by adding an energy minimization strategy which allows the amino acid sidechains to move in a broad configuration space during sequence evolution. In this work, the new algorithm was used to generate a library of 21-mer peptides which could substitute for lambda N peptide in binding to boxB RNA. Six potential peptides were obtained from the algorithm, all of which exhibited good binding capability with boxB RNA. Atomistic molecular dynamics simulations were then conducted to examine the ability of the lambda N peptide and three best evolved peptides, viz. Pept01, Pept26, and Pept28, to bind to boxB RNA. Simulation results demonstrated that our evolved peptides are better at binding to boxB RNA than the lambda N peptide. Sequence searches using the old (without energy minimization strategy) and new (with energy minimization strategy) algorithms confirm that the new algorithm is more effective at finding good RNA-binding peptides than the old algorithm. (c) 2016 Wiley Periodicals, Inc. PMID- 27487991 TI - Therapeutic Value of Adeno Associated Virus as a Gene Therapy Vector for Parkinson's Disease - A Focused Review. AB - Although adeno-associated viral vectors have been studied for a long time, its importance as a viable gene therapy strategy has been thrusted into the limelight only in the recent years. Due to the admirable characteristics of these vectors, their potential has been thoughtfully utilized in the treatment of several neurodegenerative diseases. This mini-review focuses at recapitulating the therapeutic advances of adeno-associated viral vectors in the treatment of Parkinson's disease by studying the various animal model experiments and clinical trials conducted since the advent of adeno-associated viral vector - based gene therapy. Additionally, the chronological analysis of the studies in the review makes it easier to understand the challenges and foretell the future prospects in this field of therapeutics. PMID- 27487992 TI - Patient intention and self-reported compliance in relation to emergency department attendance after using an after hours GP helpline. AB - OBJECTIVE: To determine ED attendance and compliance with GP advice following a call to an after hours telephone triage and advice service. METHODS: A descriptive study of users' of an after hours helpline self-reported ED attendance and compliance with GP recommendation, based on routinely collected service data and telephone survey results for 2783 callers in 2011-2012. The outcome measure was self-reported health service utilisation following advice from a GP on an after hours helpline. RESULTS: One-third of the sample - 934 callers - intended to visit the ED. Of these, 504 (54%, 95% CI 50.7%-57.2%) reported taking other less urgent options. The GP assessment confirmed the original intention for 224 callers (24%, 95% CI 21.2%-26.9%). However, 151 patients (16%, 95% CI 13.8%-18.6%) did attend the ED as they had originally intended despite the GP's recommendation to seek less serious care, whereas a further 55 patients (6%, 95% CI 4.4%-7.6%) assessed by the GP as requiring ED care chose a less serious option. Fifty-five per cent of all callers who attended ED did not intend to visit the ED prior to their call. The overall net result was a small reduction in ED attendance compared with original intentions. CONCLUSION: An after hours GP helpline may divert some callers intending to go to the ED to other care. However, patient non-compliance may limit the capacity of telephone triage and advice service to reduce demand for ED. Further research is needed to better understand the effect of the service. PMID- 27487994 TI - Why understanding the asthma chronic obstructive pulmonary disease overlap syndrome (ACOS) is important to the clinician. PMID- 27487993 TI - The causal relevance of body mass index in different histological types of lung cancer: A Mendelian randomization study. AB - Body mass index (BMI) is inversely associated with lung cancer risk in observational studies, even though it increases the risk of several other cancers, which could indicate confounding by tobacco smoking or reverse causality. We used the two-sample Mendelian randomization (MR) approach to circumvent these limitations of observational epidemiology by constructing a genetic instrument for BMI, based on results from the GIANT consortium, which was evaluated in relation to lung cancer risk using GWAS results on 16,572 lung cancer cases and 21,480 controls. Results were stratified by histological subtype, smoking status and sex. An increase of one standard deviation (SD) in BMI (4.65 Kg/m(2)) raised the risk for lung cancer overall (OR = 1.13; P = 0.10). This was driven by associations with squamous cell (SQ) carcinoma (OR = 1.45; P = 1.2 * 10(-3)) and small cell (SC) carcinoma (OR = 1.81; P = 0.01). An inverse trend was seen for adenocarcinoma (AD) (OR = 0.82; P = 0.06). In stratified analyses, a 1 SD increase in BMI was inversely associated with overall lung cancer in never smokers (OR = 0.50; P = 0.02). These results indicate that higher BMI may increase the risk of certain types of lung cancer, in particular SQ and SC carcinoma. PMID- 27487995 TI - Ascorbic acid co-administration with artemisinin based combination therapies in falciparum malaria. PMID- 27487996 TI - NAT2 gene polymorphism: covert drug interaction causing phenytoin toxicity. PMID- 27487997 TI - Why is the oral cholera vaccine not considered an option for prevention of cholera in India? Analysis of possible reasons. PMID- 27487998 TI - Zika virus: Indian perspectives. AB - The emergence of Zika virus (ZiV), a mosquito borne Flavivirus like dengue (DEN) and chikungunya (CHIK), in Brazil in 2014 and its spread to various countries have led to a global health emergency. Aedes aegypti is the major vector for ZiV. Fast dissemination of this virus in different geographical areas posses a major threat especially to regions where the population lacks herd immunity against the ZiV and there is abundance of Aedes mosquitoes. In this review, we focus on current global scenario, epidemiology, biology, diagnostic challenges and remedial measures for ZiVconsidering the Indian perspective. PMID- 27488000 TI - In vitro effects of co-incubation of blood with artemether/lumefantrine & vitamin C on the viscosity & elasticity of blood. AB - BACKGROUND & OBJECTIVES: The antimalarial combination drug artemether/lumefantrine has been shown to be effective against malaria parasite through its haemolytic action. This drug is sometimes co-administered with vitamin C in patients with malaria. Vitamin C is associated with antioxidant properties which would be expected to protect against haemolytic effects of this antimalarial drug. This study was designed to investigate in vitro effects of co incubation of artemether/lumefantrine with vitamin C on the viscosity and elasticity of blood. METHODS: Blood was collected from 12 healthy female volunteers with normal haemoglobin genotype (HbAA). A Bioprofiler was used to measure the viscosity and elasticity of untreated blood samples (control) and samples exposed to artemether/lumefantrine (0.06/0.36 mg/ml) alone and with low or high dose vitamin C (equivalent to adult doses of 100 or 500 mg). RESULTS: artemether/lumefantrine significantly (p<0.05) reduced viscosity of blood from 4.72 +/- 0.38 to 3.78 +/- 0.17 mPa.s. Addition of vitamin C (500 mg) further reduced blood viscosity to 2.67 +/- 0.05 mPa.s. The elasticity of blood was significantly (p<0.05) reduced from 0.33 +/- 0.04 mPa.s to 0.24 +/- 0.03 mPa.s by the antimalarial drug, and further reduced to 0.13 +/- 0.02 mPa.s in the presence of vitamin C (500 mg). INTERPRETATION & CONCLUSIONS: Co-incubation of blood with vitamin C and antimalarial combination drug potentiates the haemolytic effects of the latter on reducing blood viscosity and elasticity in vitro. This may possibly have implications in relation to haemolysis in patients receiving vitamin C supplementation with artemether/lumefantrine during malaria therapy. PMID- 27487999 TI - Shigellosis: Epidemiology in India. AB - Shigellosis is one of the major causes of diarrhoea in India. The accurate estimates of morbidity and mortality due to shigellosis are lacking, though it is endemic in the country and has been reported to cause many outbreaks. The limited information available indicates Shigella to be an important food- borne pathogen in India. S. flexneri is the most common species, S. sonnei and non-agglutinable Shigellae seem to be steadily surfacing, while S. dysenteriae has temporarily disappeared from the northern and eastern regions. Antibiotic-resistant strains of different Shigella species and serotypes have emerged all over the world. Especially important is the global emergence of multidrug resistant Shigellae, notably the increasing resistance to third generation cephalosporins and fluoroquinolones, and also azithromycin. This calls for a continuous and strong surveillance of antibiotic resistance across the country for periodic updation of the local antibiograms. The prevention of shigellosis is desirable as it will substantially reduce the morbidity associated with diarrhoea in the country. Public health measures like provision of safe water and adequate sanitation are of immense importance to reduce the burden of shigellosis, however, the provision of resources to develop such an infrastructure in India is a complex issue and will take time to resolve. Thus, the scientific thrust should be focused towards development of a safe and affordable multivalent vaccine. this review is focused upon the epidemiology, disease burden and the therapeutic challenges of shigellosis in Indian perspective. PMID- 27488001 TI - N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study. AB - BACKGROUND & OBJECTIVES: Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously. METHODS: Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR. RESULTS: The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group. INTERPRETATION & CONCLUSIONS: Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures. PMID- 27488002 TI - Interleukin-1beta (IL-1beta) & IL-4 gene polymorphisms in patients with systemic lupus erythematosus (SLE) & their association with susceptibility to SLE. AB - BACKGROUND & OBJECTIVES: Interleukin-1 (IL-1) is one of the pro-inflammatory cytokines that plays a main role in the regulation of immune and inflammatory responses. Interleukin 4 (IL-4) as an anti-inflammatory cytokine regulates balance between Th1 and Th2 immune responses. this study was undertaken to investigate the IL-1beta and IL-4 genes polymorphisms in patients with systemic lupus erythematosus (SLE) and also association between the polymorphisms and susceptibility to SLE. METHODS: One hundred and sixty three SLE patients and 180 healthy controls were genotyped for the IL-4 VNTR (variable number tandem repeat), IL-1beta C-511T and IL-1beta T-31C polymorphisms by polymerase chain reaction (PCR) or PCR-RFLP (restriction fragment length polymorphism) method. RESULTS: The frequencies of CC genotype and C allele of the IL-1beta T-31C polymorphism were significantly (P<0.01) lower in SLE patients than controls. Moreover, the frequencies of RP1/RP2 genotype and RP2 allele of IL-4 VNTR polymorphism were significantly (P<0.05) higher in the SLE patients. No association was observed between IL-1beta C-511T polymorphism and increased risk of SLE. We observed increased frequency of CT and TT genotypes of IL-1beta C-511T polymorphism in SLE patients with malar rash compared to SLE patients without this manifestation. INTERPRETATION & CONCLUSIONS: The present findings suggest that IL-1beta T-31C and IL-4 VNTR polymorphisms but not IL-1beta C-511T polymorphism may contribute in SLE pathogenesis. In addition, CT and TT genotypes of IL-1beta C-511T polymorphism were associated with SLE. PMID- 27488003 TI - Image guided versus palpation guided core needle biopsy of palpable breast masses: a prospective study. AB - BACKGROUND & OBJECTIVES: Biopsy of palpable breast masses can be performed manually by palpation guidance or under imaging guidance. Based on retrospective studies, image guided biopsy is considered more accurate than palpation guided breast biopsy; however, these techniques have not been compared prospectively. We conducted this prospective study to verify the superiority and determine the size of beneficial effect of image guided biopsy over palpation guided biopsy. METHODS: Over a period of 18 months, 36 patients each with palpable breast masses were randomized into palpation guided and image guided breast biopsy arms. Ultrasound was used for image guidance in 33 patients and mammographic (stereotactic) guidance in three patients. All biopsies were performed using 14 gauge automated core biopsy needles. Inconclusive, suspicious or imaging histologic discordant biopsies were repeated. RESULTS: Malignancy was found in 30 of 36 women in palpation guided biopsy arm and 27 of 36 women in image guided biopsy arm. Palpation guided biopsy had sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 46.7, 100, 100, 27.3 per cent, respectively, for diagnosing breast cancer. Nineteen of 36 women (52.8%) required repeat biopsy because of inadequate samples (7 of 19), suspicious findings (2 of 19) or imaging-histologic discordance (10 of 19). On repeat biopsy, malignancy was found in all cases of imaging-histologic discordance. Image guided biopsy had 96.3 per cent sensitivity and 100 per cent specificity. There was no case of inadequate sample or imaging-histologic discordance with image guided biopsy. INTERPRETATION & CONCLUSIONS: Our results showed that in palpable breast masses, image guided biopsy was superior to palpation guided biopsy in terms of sensitivity, false negative rate and repeat biopsy rates. PMID- 27488004 TI - A clinicopathological study of primary central nervous system lymphomas & their association with Epstein-Barr virus. AB - BACKGROUND & OBJECTIVES: Primary central nervous system lymphomas (PCNSLs) are relatively uncommon, accounting for 2-3 per cent of primary brain tumours. Majority of these are diffuse large B cell lymphomas (DLBCL) occurring both in immunocompromised and immunocompetent patients. We undertook this study to classify PCNSL into germinal centre (GC) and non-germinal centre (NGC) type based on Hans classification and to find the role of Epstein-Barr virus (EBV) in pathogenesis both by conventional immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). METHODS: The consecutive cases of PCNSL during a 10 years period were analysed by IHC for CD45, CD20, CD3, B-cell lymphoma 2 and 6 (Bcl-2 and Bcl-6), B-cell specific octamer binding protein-1 (BOB-1), multiple myeloma oncogene-1 (MUM-1), EBV latent-membrane protein 1 (LMP-1), cyclin-D1, CD10, CD5 and CD23, as well as by CISH for EBV. RESULTS: During a period of 10 years, 65 PCNSL were diagnosed which comprised 0.69 per cent (65/9476) of all intracranial tumours. The mean age of presentation was 49 yr with sex ratio (M:F) of 1.4:1. Most common location was supratentorial region with predominant involvement of frontal lobe. Single lesions were seen in 38 (58.4%) and multifocal lesions in 27 (41.5%) patients. None of the patients were immunocompromised. All cases were B cell immunophenotype and were DLBCL except one case of follicular lymphoma. According to Hans classification, majority of them were NGC (n=51, 79.6%) and 13 (20.3%) were GC type. Bcl-2 expression was noted in 34 (52.3%) tumours. EBV was positive in three (4.6%) cases; two were detected both by IHC and CISH and one case by CISH only. INTERPRETATION & CONCLUSIONS: In Indian population, PCNSL occurs mainly in immunocompetent patients, and a decade earlier than in western population. Immunophenotyping revealed that all cases were DLBCL with predominance of NGC type. No prognostic difference was seen between GC and NGC DLBCL. Association of EBV was rare and this virus was possibly not involved in the pathogenesis of PCNSL in immunocompetent individuals. CISH was an easy, economical and less cumbersome method for detection of EBV in PCNSL. PMID- 27488005 TI - Cystic fibrosis transmembrane conductance regulator (CFTR) gene abnormalities in Indian males with congenital bilateral absence of vas deferens & renal anomalies. AB - BACKGROUND & OBJECTIVES: The role of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in congenital bilateral absence of vas deferens and unilateral renal agenesis (CBAVD-URA) has been controversial. Here, we report the cases of five Indian males with CBAVD-URA. The objective was to evaluate the presence or absence of CFTR gene mutations and variants in CBAVD-URA. The female partners of these males were also screened for cystic fibrosis (CF) carrier status. METHODS: Direct DNA sequencing of CFTR gene was carried out in five Indian infertile males having CBAVD-URA. Female partners (n=5) and healthy controls (n=32) were also screened. RESULTS: Three potential regulatory CFTR gene variants (c.1540A>G, c.2694T>G and c.4521G>A) were detected along with IVS8-5T mutation in three infertile males with CBAVD-URA. Five novel CFTR gene variants (c.621+91A>G, c.2752+106A>T, c.2751+85_88delTA, c.3120+529InsC and c.4375-69C>T), four potential regulatory CFTR gene variants (M470V, T854T, P1290P, Q1463Q) and seven previously reported CFTR gene variants (c.196+12T>C, c.875+40A>G, c.3041 71G>C, c.3271+42A>T, c.3272-93T>C, c.3500-140A>C and c.3601-65C>A) were detected in infertile men having CBAVD and renal anomalies Interpretation & conclusions: Based on our findings, we speculate that CBAVD-URA may also be attributed to CFTR gene mutations and can be considered as CFTR-related disorder (CFTR-RD). The CFTR gene mutation screening may be offered to CBAVD-URA men and their female partners undergoing ICSI. Further studies need to be done in a large sample to confirm the findings. PMID- 27488006 TI - Dual hit lipopolysaccharide & oleic acid combination induced rat model of acute lung injury/acute respiratory distress syndrome. AB - BACKGROUND & OBJECTIVES: Despite advances in therapy and overall medical care, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) management remains a problem. Hence the objective of this study was to develop a rat model that mimics human ALI/ARDS. METHODS: Four groups of Wistar rats, 48 per group were treated with (i) intratracheal (IT) lipopolysaccharide (LPS) (5 mg/kg) dissolved in normal saline (NS), (ii) intravenous (iv) oleic acid (OA) (250 MUl/kg) suspension in bovine serum albumin (BSA), (iii) dual hit: IT LPS (2 mg/kg) dissolved in NS and iv OA (100 MUl/kg) and (iv) control group: IT NS and iv BSA. From each group at set periods of time various investigations like chest x-rays, respiratory rate (RR), tidal volume (TV), total cell count, differential cell count, total protein count and cytokine levels in bronchoalveolar lavage fluid (BALF), lung wet/dry weight ratio and histopathological examination were done. RESULTS: It was noted that the respiratory rate, and tumour necrosis factor alpha (TNF-alpha) levels were significantly higher at 4 h in the dual hit group as compared to LPS, OA and control groups. Interleukin-6 (IL-6) levels were significantly higher in the dual hit group as compared to LPS at 8 and 24 h, OA at 8 h and control (at all time intervals) group. IL-1beta levels were significantly higher in LPS and dual hit groups at all time intervals, but not in OA and control groups. The injury induced in dual hit group was earlier and more sustained as compared to LPS and OA alone. INTERPRETATION & CONCLUSIONS: The lung pathology and changes in respiration functions produced by the dual hit model were closer to the diagnostic criteria of ALI/ARDS in terms of clinical manifestations and pulmonary injury and the injury persisted longer as compared to LPS and OA single hit model. Therefore, the ARDS model produced by the dual hit method was closer to the diagnostic criteria of ARDS in terms of clinical manifestations and pulmonary injury. PMID- 27488007 TI - Frequency of Mi(a) antigen: A pilot study among blood donors. AB - The Miltenberger (Mi) classes represent a group of phenotypes for red cells that carry low frequency antigens associated with the MNSs blood group system. This pilot study was aimed at determining the Mia antigen positivity in the blood donor population in a tertiary care hospital in New Delhi, India. The study was performed between June to August 2014 on eligible blood donors willing to participate. Antigen typing was performed using monoclonal anti-Mia antiserum by tube technique. Only one of the 1000 blood donors (0.1%) tested was found to be Mia antigen positive. the Mia antigen can, therefore, be considered as being rare in the Indian blood donor population. PMID- 27488008 TI - Baseline characteristics of HIV & hepatitis B virus (HIV/HBV) co-infected patients from Kolkata, India. AB - BACKGROUND & OBJECTIVES: Hepatitis B virus (HBV) and HIV co-infection has variable prevalence worldwide. In comparison to HBV mono-infection, the course of chronic HBV infection is accelerated in HIV/HBV co-infected patients. the present study was carried out to analyse the baseline characteristics (clinical, biochemical, serological and virological) of treatment naive HIV/HBV co-infected and HIV mono-infected patients. METHODS: Between July 2011 and January 2013, a total number of 1331 HIV-seropositive treatment naive individuals, enrolled in the ART Centre of Calcutta School of Tropical Medicine, Kolkata, India, were screened for hepatitis B surface antigen (HBsAg). A total of 1253 HIV mono infected and 78 HIV/HBV co-infected patients were characterized. The co-infected patients were evaluated for HBeAg and anti-HBe antibody by ELISA. HIV RNA was quantified for all co-infected patients. HBV DNA was detected and quantified by real time-PCR amplification followed by HBV genotype determination. RESULTS: HIV/HBV co-infected patients had proportionately more advanced HIV disease (WHO clinical stage 3 and 4) than HIV mono-infected individuals (37.1 vs. 19.9%). The co-infected patients had significantly higher serum bilirubin, alanine aminotransferase (ALT), alkaline phosphatase and ALT/platelet ratio index (APRI). CD4 count was non-significantly lower in co-infected patients. Majority (61.5%) were HBeAg positive with higher HIV RNA (P<0.05), HBV DNA (p<0.001) and APRI (p<0.05) compared to those who were HBeAg negative. HBV/D was the predominant genotype (73.2%) and D2 (43.7%) was the commonest subgenotype. INTERPRETATION & CONCLUSIONS: HIV/HBV co-infected patients had significantly higher serum bilirubin, ALT, alkaline phosphatase and lower platelet count. HBeAg positive co infected patients had higher HIV RNA and HBV DNA compared to HBeAg negative co infected patients. Prior to initiation of antiretroviral treatment (ART) all patients should be screened for HBsAg to initiate appropriate ART regimen. PMID- 27488009 TI - Subinhibitory concentration of ciprofloxacin targets quorum sensing system of Pseudomonas aeruginosa causing inhibition of biofilm formation & reduction of virulence. AB - BACKGROUND & OBJECTIVES: Biofilms formed by pseudomonas aeruginosa lead to persistent infections. Use of antibiotics for the treatment of biofilm induced infection poses a threat towards development of resistance. Therefore, the research is directed towards exploring the property of antibiotics which may alter the virulence of an organism besides altering its growth. The aim of this study was to evaluate the role of subinhibitory concentration of ciprofloxacin (CIP) in inhibiting biofilm formation and virulence of P. aeruginosa. METHODS: Antibiofilm potential of subinhibitory concentration of CIP was evaluated in terms of log reduction, biofilm forming capacity and coverslip assay. P. aeruginosa isolates (grown in the presence and absence of sub-MIC of CIP) were also evaluated for inhibition in motility, virulence factor production and quorum sensing (QS) signal production. RESULTS: Sub-minimum inhibitory concentration (sub-MIC) of CIP significantly reduced the motility of P. aeruginosa stand and strain and clinical isolates and affected biofilm forming capacity. Production of protease, elastase, siderophore, alginate, and rhamnolipid was also significantly reduced by CIP. INTERPRETATION & CONCLUSIONS: Reduction in virulence factors and biofilm formation was due to inhibition of QS mechanism which was indicated by reduced production of QS signal molecules by P. aeruginosa in presence of subinhibitory concentration of CIP. PMID- 27488010 TI - Isolation & characterization of Brucella melitensis isolated from patients suspected for human brucellosis in India. AB - BACKGROUND & OBJECTIVES: Brucellosis is endemic in the southern part of India. A combination of biochemical, serological and molecular methods is required for identification and biotyping of Brucella. The present study describes the isolation and biochemical, molecular characterization of Brucella melitensis from patients suspected for human brucellosis. METHODS: The blood samples were collected from febrile patients suspected to have brucellosis. A total of 18 isolates were obtained from 102 blood samples subjected to culture. The characterization of these 18 isolates was done by growth on Brucella specific medium, biochemical reactions, CO2 requirement, H2S production, agglutination with A and M mono-specific antiserum, dye sensitivity to basic fuchsin and thionin. Further, molecular characterization of the isolates was done by amplification of B. melitensis species specific IS 711 repetitive DNA fragment and 16S (rRNA) sequence analysis. PCR-restriction fragment length polymorphism (RFLP) analysis of omp2 locus and IS711 gene was also done for molecular characterization. RESULTS: All 102 suspected samples were subjected to bacteria isolation and of these, 18 isolates could be recovered on blood culture. The biochemical, PCR and PCR-RFLP and 16s rRNA sequencing revealed that all isolates were of B. melitensis and matched exactly with reference strain B. melitensis 16M. INTERPRETATION & CONCLUSIONS: The present study showed an overall isolation rate of 17.64 per cent for B. melitensis. There is a need to establish facilities for isolation and characterization of Brucella species for effective clinical management of the disease among patients as well as surveillance and control of infection in domestic animals. Further studies are needed from different geographical areas of the country with different level of endemicity to plan and execute control strategies against human brucellosis. PMID- 27488011 TI - M types & toxin gene profile of group A streptococci isolated from children in Dibrugarh district of Assam, India. PMID- 27488012 TI - Hajdu-Cheney syndrome - a rare cause of micrognathia. PMID- 27488013 TI - Giant virilizing adrenocarcinoma: Rare presentation & management dilemma. PMID- 27488014 TI - Tuberous sclerosis with bilateral giant renal angiomyolipomas. PMID- 27488015 TI - M2L4 coordination capsules with tunable anticancer activity upon guest encapsulation. AB - Metallosupramolecular cages and capsules have gained increasing popularity as both molecular containers and anticancer agents. For successful combination of these properties a thorough analysis of the effect of guest encapsulation on the host's cytotoxic properties is highly required. Here we report on the cytotoxicity modulation of Pt(ii) and Pd(ii)-linked M2L4 coordination capsules upon encapsulation of guest molecules such as pyrene and caffeine. The anticancer activity of the capsules against various human cancer cells (HT-29, T-24, HL-60 and its resistant counterparts HL-60/Dox and HL-60/CDDP) significantly altered upon the guest encapsulation. The encapsulation of pyrene molecules causes a decrease in the cytotoxicity of the Pt(ii) capsule, which is stronger than that of the Pd(ii) capsule. The cytotoxicities of the caffeine containing capsules are lower than that of the empty capsules (except for HL-60), but still superior to cisplatin under the same conditions. The observed trends in the anticancer activity of the capsules and their host-guest complexes correlate with their different stabilities toward glutathione, estimated by NMR-based kinetic experiments. Mechanistic insights into the observed cytotoxicities are obtained by fluorescence microscopy imaging of tumor cells treated with the capsules and their pyrene complexes. The data suggest the glutathione-triggered disassembly of the capsular structures as a potential activation pathway for their cytotoxicities. PMID- 27488016 TI - Baseline correction of AFM force curves in the force-time representation. AB - This note reports on the proper correction of force data acquired with an atomic force microscope (AFM). The force-time representation is hereby used to obtain the correction factors for the overall offset and slope for a single force-time curve, as the initial force, F0 = F(t0 ), and the rate of change in the force per unit of time, dF/dt, respectively. The report shows that a complete set of force data, including the approach, delay and retraction regions, can be simultaneously corrected in the force-time representation by subtracting the line CLt = F0 + dF/dt.t to the experimental data. The method described here outperforms the one commonly employed in the correction of AFM force curves and highlights the convenience of using the force-time representation for force data processing wherein the artifactual behavior can be expressed as a single, differentiable function of time. PMID- 27488017 TI - Analysis of aflatoxins in traditional Chinese medicines: Classification of analytical method on the basis of matrix variations. AB - A classification system for analytical methods was developed for the first time to determine the presence of aflatoxins B1, B2, G1 and G2 in traditional Chinese medicines (TCMs) based on different matrix types using ultra-performance liquid chromatography-tandem mass spectrometry. A useful characteristic of the approach was that the TCMs could be systematically divided into four categories (i.e., volatile oils, proteins, polysaccharides and fatty oils) depending on the matrix types. The approach concluded that different types of TCMs required different optimal sample preparation procedures. Based on the optimized analytical conditions, the limits of detection and quantification, average recoveries and linearity of four aflatoxins were determined and conformed to research limits. Of 22 TCMs samples, 14 samples were contaminated with at least one type aflatoxin at concentrations ranging from 0.2 to 7.5 MUg/kg, and the average contents of aflatoxins were significantly different for the different matrix types. Moreover, we found a potential link between the contamination levels of aflatoxins and matrix types. TCMs containing fatty oils were the most susceptible to contamination by aflatoxins and followed by TCMs containing polysaccharides and proteins; TCMs containing abundant amounts of volatile oils were less prone to contamination. PMID- 27488019 TI - Induction of pulmonary antibodies against oxidized lipids in mice exposed to cigarette smoke. AB - BACKGROUND: Chronic cigarette smoke exposure is known to activate the adaptive immune system; however, the functional role of these processes is currently unknown. Given the role of oxidized lipids in driving innate inflammatory responses to cigarette smoke, we investigated whether an adaptive immune response against damaged lipids was induced following chronic cigarette smoke exposure. METHODS AND RESULTS: Using a well-established mouse model, we showed that cigarette smoke exposure led to a progressive increase in pulmonary antibodies against oxidized low-density lipoprotein (OxLDL). Functionally, we found that intranasal delivery of an antibody against oxidized phosphatidylcholine (anti OxPC; clone E06) increased lipid and particle uptake by pulmonary macrophages without exacerbating cigarette smoke-induced neutrophilia. We also found that anti-OxPC treatment increased particle uptake following smoking cessation. Finally, the frequency of pulmonary macrophages with internalized particles was increased after prolonged smoke exposure, at which time lung anti-OxPC responses were highest. CONCLUSIONS: Altogether, this is the first report to demonstrate a non-pathogenic, and possibly protective, function of a newly identified autoantibody induced by chronic cigarette smoke exposure. PMID- 27488020 TI - Treatment of breast cancer 2 (BRCA2)-mutant follicular dendritic cell sarcoma with a poly ADP-ribose polymerase (PARP) inhibitor: a case report. AB - BACKGROUND: Follicular dendritic cell sarcoma is a rare tumour with clinical behaviour covering a spectrum from indolent to aggressive disease. Treatment recommendations are currently based on case reports and small series describing combinations of surgery, chemotherapy and radiotherapy providing the best patient outcomes. Recent knowledge on molecular aberrations in this disease have not yet impacted on therapeutic decisions. CASE PRESENTATION: We describe a case of progressive follicular dendritic cell sarcoma of the lung and pleura, treated based on knowledge of the tumour's molecular aberrations. The patient was initially treated with surgery, chemotherapy and radiotherapy and developed disease progression. Mutation testing by Caris molecular intelligence demonstrated a breast cancer 2 gene mutation and further treatment with carboplatin and veliparib achieved disease stabilisation. CONCLUSION: Understanding of the molecular profile of rare tumours is key to improve therapeutic decision making and patient outcomes. PMID- 27488022 TI - Transgenerational transmission of pregestational and prenatal experience: maternal adversity, enrichment, and underlying epigenetic and environmental mechanisms. AB - Transgenerational transmission refers to positive and negative adaptations in brain function and behavior that affect following generations. In this paper, empirical findings regarding the transgenerational transmission of maternal adversity during three critical periods - childhood, pregestational adulthood and pregnancy - will be reviewed in terms of pregnancy outcomes, maternal care, offspring behavior and development, and physiological functioning. Research on the transgenerational transmission of enrichment and the implications for interventions to ameliorate the consequences of adversity will also be presented. In the final section, underlying epigenetic and environmental mechanisms that have been proposed to explain how experience is transferred across generations through transgenerational transmission will be reviewed. Directions for future research are suggested throughout. PMID- 27488021 TI - Assembly of Bak homodimers into higher order homooligomers in the mitochondrial apoptotic pore. AB - In mitochondrial apoptosis, Bak is activated by death signals to form pores of unknown structure on the mitochondrial outer membrane via homooligomerization. Cytochrome c and other apoptotic factors are released from the intermembrane space through these pores, initiating downstream apoptosis events. Using chemical crosslinking and double electron electron resonance (DEER)-derived distance measurements between specific structural elements in Bak, here we clarify how the Bak pore is assembled. We propose that previously described BH3-in-groove homodimers (BGH) are juxtaposed via the 'alpha3/alpha5' interface, in which the C termini of helices alpha3 and alpha5 are in close proximity between two neighboring Bak homodimers. This interface is observed concomitantly with the well-known 'alpha6:alpha6' interface. We also mapped the contacts between Bak homodimers and the lipid bilayer based on EPR spectroscopy topology studies. Our results suggest a model for the lipidic Bak pore, whereby the mitochondrial targeting C-terminal helix does not change topology to accommodate the lining of the pore lumen by BGH. PMID- 27488023 TI - Excision of HIV-1 DNA by gene editing: a proof-of-concept in vivo study. PMID- 27488024 TI - Revealing Hidden Schatzki Rings Using the Bolster Technique. PMID- 27488026 TI - Immature Oocytes from Unprimed Juvenile Mice Become a Valuable Source for Embryo Production When Using C-Type Natriuretic Peptide as Essential Component of Culture Medium. AB - C-type natriuretic peptide (CNP) and its receptor natriuretic peptide receptor 2 (NPR2) play a paramount role in the maintenance of oocyte meiotic arrest in antral follicles via the regulation of the intra-oocyte levels of cyclic guanosine monophosphate and cyclic adenosine monophosphate. We investigated the potential of CNP 1) to maintain oocyte meiotic arrest during a prolonged prematuration culture and 2) to sustain acquisition of developmental competence of immature cumulus-oocyte complexes (COCs). Compact COCs were collected from small antral follicles of prepubertal unprimed mice and placed in prematuration culture under different CNP-supplemented media conditions. A preliminary analysis showed a dose-dependent effect of CNP on the maintenance of meiotic arrest. A dose of 25 nM maintained oocytes under meiotic arrest for 24 h, and this period was extended to 48 h in the presence of estradiol. Analysis of transzonal projections of COCs cultured with CNP indicated that oocyte-cumulus connections were well preserved after the prolonged prematuration culture. Furthermore, CNP medium supplemented with FSH and GDF9 promoted oocyte growth and induced a shift in oocyte chromatin configuration from a predominantly dispersed to a condensed configuration. Following in vitro maturation, oocytes cultured under CNP were capable of extruding the first polar body at a high rate (around 80%). Blastocyst formation was significantly improved when oocytes were cultured under CNP supplemented medium containing FSH and GDF9. This study reports for the first time a prolonged prematuration culture system, with CNP as the pivotal factor, that can efficiently maintain oocytes retrieved from unprimed prepubertal mice under meiotic arrest while promoting their acquisition of developmental competence. PMID- 27488027 TI - Downregulation of miR-199a-5p Disrupts the Developmental Potential of In Vitro Fertilized Mouse Blastocysts. AB - Although in vitro fertilization (IVF), one of the most effective and successful assisted reproductive technologies, is widely used for treating infertility and in animal breeding, increasing evidence indicates that IVF offspring are linked to various short- or long-term consequences. Erroneous epigenetic modifications induced by IVF are suspected of contributing to these consequences. Among these epigenetic modifications, microRNAs may affect embryo implantation and early postimplantation development. Here, we performed comparative microRNA profiling between in vivo-fertilized (IVO group) and in vitro-fertilized (IVF group) mouse embryos at Embryonic Day 3.5 (E3.5) and E7.5. Our dynamic analyses showed that the dysregulated microRNAs were mainly associated with the regulation of genes involved in carcinogenesis, genetic information processing, glucose metabolism, cytoskeleton organization, and neurogenesis. Further analysis showed that miR 199a-5p was consistently downregulated in IVF embryos compared with their IVO counterparts. Through gain- and loss-of-function experiments, we demonstrated that IVF-induced downregulation of miR-199a-5p results in a higher glycolytic rate and lower developmental potential of IVF blastocysts, including cell lineage misallocation and lower fetal survival post implantation. Therefore, preventing downregulation of miR-199a-5p may become an effective strategy for improving the development of IVF peri-implantation embryos in the future. PMID- 27488025 TI - Daptomycin for the treatment of major gram-positive infections after cardiac surgery. AB - BACKGROUND: Infection is a main cause of morbidity and mortality after heart surgery, with multi-resistant pathogens increasingly representing a challenge. Daptomycin provides bactericidal activity against gram-positive organisms that are resistant to standard treatment including vancomycin. METHODS: A cohort of cardiac surgical patients, treated with daptomycin for major infection at two tertiary care centers, were retrospectively studied with a particular focus on the type of infection, causative pathogens and co-infections, daptomycin dosage, adverse events and outcome in order to provide evidence for the efficiency and safety of daptomycin in a distinct high-risk patient population. RESULTS: Sixty five patients (87.7 % males, 60.4 +/- 13.5 years) who had undergone aortic surgery (20.0 %), ventricular assist device (VAD) implantation (21.5 %), combined procedures (21.5 %), coronary artery bypass grafting (12.3 %), isolated valve surgery (15.4 %) and heart transplantation (7.7 %) were diagnosed with catheter related infection (26.1 %), valve endocarditis (18.8 %), sternal wound (13.0 %), VAD-associated (11.6 %), cardiac implantable electrophysiological device (CIED) associated (4.1 %), respiratory tract (4.3 %), bloodstream (4.3 %) and other infection (4.3 %). In 13.0 %, no focus of infection was identified though symptoms of severe infection were present. The most frequent pathogens were Staphylococcus epidermidis (30.4 %), Staphylococcus aureus (23.1 %) and Enterococcus species (10.1 %). Daptomycin doses ranging from 3 mg/kg every 48 h to 10 mg/kg every 24 h were administered for 15.4 +/- 11.8 days. 87.0 % of the cases were classified as success, 7.2 % as treatment failure and 5.8 as non evaluable. Adverse events were limited to one case of mild and one case of moderate neutropenia with recovery upon termination of treatment. CONCLUSION: Daptomycin proved safe and effective in major infection in high-risk cardiac surgical patients. PMID- 27488028 TI - Deficiency of SPATA46, a Novel Nuclear Membrane Protein, Causes Subfertility in Male Mice. AB - Teratozoospermia is generally associated with clinical infertility. Despite numerous studies, the molecular mechanisms underlying male infertility are still poorly understood. In the present study, we demonstrated that deletion of Spata46, a gene encoding a novel protein of unknown function found in mouse testis, was responsible for male subfertility, and the cause of subfertility was characterized as abnormal sperm head shape and a failure of sperm-egg fusion. We also demonstrated that SPATA46 was expressed predominantly in condensed spermatids, with a highly specific localization restricted to the subacrosomal area; the protein is located at the nuclear membrane due to a transmembrane region in the N-terminus of the protein. At the subcellular level, SPATA46 deficient condensed spermatids displayed structural defects consisting of a discontinuous nuclear envelope and a cavity in the nucleus associated with an abnormal nuclear shape. Additionally, in vitro, we determined that the absence of SPATA46 led to accumulation of sperm around the perivitelline space of eggs, and the same phenomenon was also observed for natural sperm incubated with an anti SPATA46 antibody, suggesting functional relevance of SPATA46 for sperm-egg fusion. Taken together, these results indicated that SPATA46 is a novel protein involved in reshaping of the sperm head and sperm-egg fusion. PMID- 27488029 TI - Characterizing the Spermatogonial Response to Retinoic Acid During the Onset of Spermatogenesis and Following Synchronization in the Neonatal Mouse Testis. AB - Retinoic acid (RA), the active metabolite of vitamin A, is known to be required for the differentiation of spermatogonia. The first round of spermatogenesis initiates in response to RA and occurs in patches along the length of the seminiferous tubule. However, very little is known about the individual differentiating spermatogonial populations and their progression through the cell cycle due to the heterogeneous nature of the onset of spermatogenesis. In this study, we utilized WIN 18,446 and RA as tools to generate testes enriched with different populations of spermatogonia to further investigate 1) the undifferentiated to differentiating spermatogonial transition, 2) the progression of the differentiating spermatogonia through the cell cycle, and 3) Sertoli cell number in response to altered RA levels. WIN 18,446/RA-treated neonatal mice were used to determine when synchronous S phases occurred in the differentiating spermatogonial population following treatment. Five differentiating spermatogonial S phase windows were identified between spermatogonial differentiation and formation of preleptotene spermatocytes. In addition, a slight increase in Sertoli cell number was observed following RA treatment, possibly implicating a role for RA in Sertoli cell cycle progression. This study has enhanced our understanding of the spermatogonial populations present in the neonatal testis during the onset of spermatogenesis by mapping the cell cycle kinetics of both the undifferentiated and the differentiating spermatogonial populations and identifying the precise timing of when specific individual differentiating spermatogonial populations are enriched within the testis following synchrony, thus providing an essential tool for further study of the differentiating spermatogonia. PMID- 27488031 TI - Retinoic Acid Regulates Calcium Signaling to Promote Mouse Ovarian Granulosa Cell Proliferation. AB - Normal development of ovarian follicles is critical for female reproduction and endocrine function. We have identified retinoic acid (RA) and the RA-degrading enzyme CYP26B1 as regulators of ovarian follicle development and showed that RA and a CYP26 inhibitor stimulated ovarian granulosa cell proliferation. The mechanism underpinning RA-dependent proliferation, however, is not known. The current study was designed to examine the role of intracellular calcium (Ca2+) signaling in mediating the effects of RA on primary mouse granulosa cell proliferation. In single-cell Ca2+ imaging experiments, treatment of cultured granulosa cells with RA increased the steady-state Ca2+ content of the endoplasmic reticulum (ER) stores. This correlated with increased store-operated Ca2+ entry (SOCE) and enhanced inositol 1,4,5-trisphosphate receptor (IP3R) dependent Ca2+ release. In proliferation assays, RA treatment or Cyp26b1 knockdown stimulated proliferation, whereas Cyp26b1 overexpression inhibited proliferation. When RA was given together with 2-aminoethoxydiphenylborane (2 APB), a blocker of IP3R-dependent ER Ca2+ release and SOCE, with xestospongin C, a selective IP3R- receptor antagonist, or with 3,5-bis (trifluoromethyl)pyrazole (BTP-2), a specific SOCE blocker, the stimulatory effect of RA on cell proliferation was abolished. Further investigation showed that treatment with 2 APB or BTP-2 inhibited RA induction of RA response element (RARE) activation in granulosa cells, confirming an important role for Ca2+ signaling in mediating RA actions. Overall, these data support a model in which RA regulates ovarian follicle development by stimulating granulosa cell proliferation and that this stimulatory effect is at least in part driven by the modulation of Ca2+ signaling. PMID- 27488030 TI - Reactive Oxygen Stimulation of Interleukin-6 Release in the Human Trophoblast Cell Line HTR-8/SVneo by the Trichlorethylene Metabolite S-(1,2-Dichloro)-l Cysteine. AB - Trichloroethylene (TCE) is a common environmental pollutant associated with adverse reproductive outcomes in humans. TCE intoxication occurs primarily through its biotransformation to bioactive metabolites, including S-(1,2 dichlorovinyl)-l-cysteine (DCVC). TCE induces oxidative stress and inflammation in the liver and kidney. Although the placenta is capable of xenobiotic metabolism and oxidative stress and inflammation in placenta have been associated with adverse pregnancy outcomes, TCE toxicity in the placenta remains poorly understood. We determined the effects of DCVC by using the human extravillous trophoblast cell line HTR-8/SVneo. Exposure to 10 and 20 MUM DCVC for 10 h increased reactive oxygen species (ROS) as measured by carboxydichlorofluorescein fluorescence. Moreover, 10 and 20 MUM DCVC increased mRNA expression and release of interleukin-6 (IL-6) after 24-h exposure, and these responses were inhibited by the cysteine conjugate beta-lyase inhibitor aminooxyacetic acid and by treatments with antioxidants (alpha-tocopherol and deferoxamine), suggesting that DCVC-stimulated IL-6 release in HTR-8/SVneo cells is dependent on beta-lyase metabolic activation and increased generation of ROS. HTR-8/SVneo cells exhibited decreased mitochondrial membrane potential at 5, 10, and 20 MUM DCVC at 5, 10, and 24 h, showing that DCVC induces mitochondrial dysfunction in HTR-8/Svneo cells. The present study demonstrates that DCVC stimulated ROS generation in the human placental cell line HTR-8/SVneo and provides new evidence of mechanistic linkage between DCVC-stimulated ROS and increase in proinflammatory cytokine IL 6. Because abnormal activation of cytokines can disrupt trophoblast functions necessary for placental development and successful pregnancy, follow-up investigations relating these findings to physiologic outcomes are warranted. PMID- 27488032 TI - The Effect of Coumestrol on Progesterone and Prostaglandin Production in the Mare: In Vitro and In Vivo Studies. AB - Coumestrol (Cou) is a plant-derived phytoestrogen that induces various pathologies in the female reproductive tract. Although effects of phytoestrogens on reproductive function in other species are well documented, their influence on progesterone (P4) and prostaglandin (PG) secretion in the mare is unknown. The aim of this study was to determine if Cou directly affects P4 and PG concentrations (in vivo) and endometrial PG secretion (in vitro) in the mare. In experiment 1, the mares (n = 4) were fed for 14 days on a diet containing increasing proportions of alfalfa pellets (250 g-1 kg/day). An additional 4 mares were fed a standard diet (control group). Sequential blood samples were obtained for 8 h after feeding on Days 13 and 14 (1 kg/day alfalfa pellets). Feeding the mares alfalfa pellets up-regulated PGE2 and 13,14-dihydro-15-ketoprostaglandin F2alpha (PGFM) and down-regulated P4 in the blood plasma compared to those in the control group (P < 0.05). In experiment 2, epithelial and stromal cells were exposed to E2 (10-9 M) or Cou (10-8 M) for 24 h. In the in vitro study, Cou increased PG secretion in epithelial and stromal cells (P < 0.05). In both types of endometrial cells, Cou up-regulated PTGS-2 protein expression (P < 0.05). Moreover, PGES and PGFS proteins were up-regulated by Cou in epithelial cells (P < 0.01). These results indicate that Cou can disturb reproductive function by affecting reproductive hormone secretion and altering the endometrial milieu through PG stimulation. Coumestrol therefore may impair physiologic regulation of the estrous cycle and early pregnancy. PMID- 27488033 TI - Sexually Dimorphic Gene Expression in Bovine Conceptuses at the Initiation of Implantation. AB - In cattle, maternal recognition of pregnancy occurs on Day 16 via secretion of interferon tau (IFNT) by the conceptus. The endometrium can distinguish between embryos with different developmental competencies. In eutherian mammals, X chromosome inactivation (XCI) is required to ensure an equal transcriptional level of most X-linked genes for both male and female embryos in adult tissues, but this process is markedly different in cattle than mice. We examined how sexual dimorphism affected conceptus transcript abundance and amino acid composition as well as the endometrial transcriptome during the peri-implantation period of pregnancy. Of the 5132 genes that were differentially expressed on Day 19 in male compared to female conceptuses, 2.7% were located on the X chromosome. Concentrations of specific amino acids were higher in the uterine luminal fluid of male compared to female conceptuses, while female conceptuses had higher transcript abundance of specific amino acid transporters (SLC6A19 and SLC1A35). Of note, the endometrial transcriptome was not different in cattle gestating a male or a female conceptus. These data support the hypothesis that, far from being a blastocyst-specific phenomenon, XCI is incomplete before and during implantation in cattle. Despite differences in transcript abundance and amino acid utilization in male versus female conceptuses, the sex of the conceptus itself does not elicit a different transcriptomic response in the endometrium. PMID- 27488035 TI - Hearing impairment and contributing factors among fertilizer factory workers. AB - INTRODUCTION: Hearing impairment remains the main occupational health problem in the manufacturing industry, and its contributing factors have not been well controlled. METHODS: Unmatched case control and comparative studies were carried out among fertilizer factory workers in Sarawak with the aim of determining contributing factors for hearing impairment. Respondents consisted of 49 cases that were diagnosed from 2005 to 2008 with 98 controls from the same work places. Chi-square test and Mann-Whitney test were used in a univariate analysis to determine the association between hearing impairment and the contributing risks being studied. RESULTS: The results of the univariate analysis showed that hearing impairment was significantly (p<0.05) associated with older age, lower education level, high smoking dose, high occupational daily noise dose, longer duration of service, infrequent used of hearing protection device (HPD), and low perception of sound on HPD usage. Multivariate logistic regression of hearing impairment after controlling for age found the following five variables: occupational daily noise dose >=50% (OR 3.48, 95% CI 1.36-8.89), >=15 years of services (OR 2.92, 95% CI 1.16-7.33), infrequent use of HPD (OR 2.79, 95% CI 1.15 6.77), low perception of sound on HPD (POR 2.77, 95% CI 1.09-6.97), and smoking more than 20 packs per year (OR 4.71, 95% CI 1.13-19.68). DISCUSSION: In conclusion, high occupational noise exposure level, longer duration of service, low perception of sound on HPD, infrequent used of HPD, and smoking more than 20 packs per year were the contributing factors to hearing impairment, and appropriate intervention measures should be proposed and taken into considerations. PMID- 27488034 TI - KLF10 Mediated Epigenetic Dysregulation of Epithelial CD40/CD154 Promotes Endometriosis. AB - Endometriosis is a highly prevalent, chronic, heterogeneous, fibro-inflammatory disease that remains recalcitrant to conventional therapy. We previously showed that loss of KLF11, a transcription factor implicated in uterine disease, results in progression of endometriosis. Despite extensive homology, co-expression, and human disease association, loss of the paralog Klf10 causes a unique inflammatory, cystic endometriosis phenotype in contrast to fibrotic progression seen with loss of Klf11. We identify here for the first time a novel role for KLF10 in endometriosis. In an animal endometriosis model, unlike wild-type controls, Klf10(-/-) animals developed cystic lesions with massive immune infiltrate and minimal peri-lesional fibrosis. The Klf10(-/-) disease progression phenotype also contrasted with prolific fibrosis and minimal immune cell infiltration seen in Klf11(-/-) animals. We further found that lesion genotype rather than that of the host determined each unique disease progression phenotype. Mechanistically, KLF10 regulated CD40/CD154-mediated immune pathways. Both inflammatory as well as fibrotic phenotypes are the commonest clinical manifestations in chronic fibro-inflammatory diseases such as endometriosis. The complementary, paralogous Klf10 and Klf11 models therefore offer novel insights into the mechanisms of inflammation and fibrosis in a disease-relevant context. Our data suggests that divergence in underlying gene dysregulation critically determines disease-phenotype predominance rather than the conventional paradigm of inflammation being precedent to fibrotic scarring. Heterogeneity in clinical progression and treatment response are thus likely from disparate gene regulation profiles. Characterization of disease phenotype-associated gene dysregulation offers novel approaches for developing targeted, individualized therapy for recurrent and recalcitrant chronic disease. PMID- 27488036 TI - Hazard of ultraviolet radiation emitted in gas metal arc welding of mild steel. AB - OBJECTIVES: Ultraviolet radiation (UVR) emitted during arc welding frequently causes keratoconjunctivitis and erythema in the workplace. The degree of hazard from UVR exposure depends on the welding method and conditions. Therefore, it is important to identify the UVR levels present under various conditions. METHODS: We experimentally evaluated the UVR levels emitted in gas metal arc welding (GMAW) of mild steel. We used both a pulsed welding current and a non-pulsed welding current. The shielding gases were 80% Ar + 20% CO2 and 100% CO2. The effective irradiance defined in the American Conference of Governmental Industrial Hygienists guidelines was used to quantify the UVR hazard. RESULTS: The effective irradiance measured in this study was in the range of 0.51-12.9 mW/cm2 at a distance of 500 mm from the arc. The maximum allowable exposure times at these levels are only 0.23-5.9 s/day. CONCLUSIONS: The following conclusions were made regarding the degree of hazard from UVR exposure during the GMAW of mild steel: (1) It is more hazardous at higher welding currents than at lower welding currents. (2) At higher welding currents, it is more hazardous when 80% Ar + 20% CO2 is used as a shielding gas than when 100% CO2 is used. (3) It is more hazardous for pulsed welding currents than for non-pulsed welding currents. (4) It appears to be very hazardous when metal transfer is the spray type. This study demonstrates that unprotected exposure to UVR emitted by the GMAW of mild steel is quite hazardous. PMID- 27488037 TI - Efficacy of exercise therapy in workers with rotator cuff tendinopathy: a systematic review. AB - OBJECTIVE: To perform a systematic review of randomized controlled trials (RCTs) on the efficacy of therapeutic exercises for workers suffering from rotator cuff (RC) tendinopathy. METHODS: A literature search in four bibliographical databases (Pubmed, CINAHL, EMBASE, and PEDro) was conducted from inception up to February 2015. RCTs were included if participants were workers suffering from RC tendinopathy, the outcome measures included work-related outcomes, and at least one of the interventions under study included exercises. The methodological quality of the studies was evaluated with the Cochrane Risk of Bias Assessment tool. RESULTS: The mean methodological score of the ten included studies was 54.4%+/-17.2%. Types of workers included were often not defined, and work-related outcome measures were heterogeneous and often not validated. Three RCTs of moderate methodological quality concluded that exercises were superior to a placebo or no intervention in terms of function and return-to-work outcomes. No significant difference was found between surgery and exercises based on the results of two studies of low to moderate methodological quality. One study of low methodological quality, comparing a workplace-based exercise program focusing on the participants' work demands to an exercise program delivered in a clinical setting, concluded that the work-based intervention was superior in terms of function and return-to-work outcomes. CONCLUSION: There is low to moderate-grade evidence that therapeutic exercises provided in a clinical setting are an effective modality to treat workers suffering from RC tendinopathy and to promote return-to-work. Further high quality studies comparing different rehabilitation programs including exercises in different settings with defined workers populations are needed to draw firm conclusions on the optimal program to treat workers. PMID- 27488038 TI - Influence of different safety shoes on gait and plantar pressure: a standardized examination of workers in the automotive industry. AB - OBJECTIVE: Working conditions, such as walking and standing on hard surfaces, can increase the development of musculoskeletal complaints. At the interface between flooring and musculoskeletal system, safety shoes may play an important role in the well-being of employees. The aim of this study was to evaluate the effects of different safety shoes on gait and plantar pressure distributions on industrial flooring. METHODS: Twenty automotive workers were individually fitted out with three different pairs of safety shoes ( "normal" shoes, cushioned shoes, and midfoot bearing shoes). They walked at a given speed of 1.5 m/s. The CUELA measuring system and shoe insoles were used for gait analysis and plantar pressure measurements, respectively. Statistical analysis was conducted by ANOVA analysis for repeated measures. RESULTS: Walking with cushioned safety shoes or a midfoot bearing safety shoe led to a significant decrease of the average trunk inclination (p<0.005). Furthermore, the average hip flexion angle decreased for cushioned shoes as well as midfoot bearing shoes (p<0.002). The range of motion of the knee joint increased for cushioned shoes. As expected, plantar pressure distributions varied significantly between cushioned or midfoot bearing shoes and shoes without ergonomic components. CONCLUSION: The overall function of safety shoes is the avoidance of injury in case of an industrial accident, but in addition, safety shoes could be a long-term preventive instrument for maintaining health of the employees' musculoskeletal system, as they are able to affect gait parameters. Further research needs to focus on safety shoes in working situations. PMID- 27488039 TI - Diagnosis accuracy of two vision screeners for visual health surveillance of workers who use video display terminals. AB - OBJECTIVE: To compare the diagnostic accuracy of two vision screeners by a visual examination performed by an optometrist (gold standard) and to evaluate the concordance between both screeners and between each screener and the gold standard. METHODS: This was a cross-sectional study that included computer workers who attended a routine yearly health examination. The study included administrative office workers (n=91) aged 50.2+/-7.9 years (mean+/-standard deviation), 69.2% of whom were women and 68.1% of whom used video display terminals (VDT) for >4 h/day. The routine visual examination included monocular and binocular distance visual acuity (VA), distance and near lateral phoria (LP), stereo acuity (SA), and color vision. Tests were repeated with Optec 6500 (by Stereo Optical) and Visiotest (by Essilor) screeners. Sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), and false positive and negative rates were calculated. Kappa coefficient (kappa) was used to measure the concordance of the screeners and the gold standard. RESULTS: The sensitivity and specificity for monocular VA were over 80% for both vision screeners; PPV was below 25%. Sensitivity and specificity were lower for SA (55% 70%), PPV was 50%, and NPV was 75% for both screeners. For distance LP, sensitivity and PPV were <10% in both cases. The screeners differed in their values for near LP: Optec 6500 had higher sensitivity (43.5%), PPV (37.0%), and NPV (79.7%); whereas the Visiotest had higher specificity (83.8%). For color vision, Visiotest showed low sensitivity, low PPV, and high specificity. Visiotest obtained false positive rates that were lower or similar to Optec 6500, and both screeners obtained false negative rates below 50%. Both screeners showed poor concordance (kappa<0.40). CONCLUSIONS: A high value for NPV would qualify both screeners as acceptable alternatives for visual health surveillance when used as a screening tool; patients with positive test results should be referred to a specialist. PMID- 27488041 TI - The moderating role of overcommitment in the relationship between psychological contract breach and employee mental health. AB - OBJECTIVES: This study investigated whether the association between perceived psychological contract breach (PCB) and employee mental health is moderated by the cognitive-motivational pattern of overcommitment (OC). Linking the psychological contract approach to the effort-reward imbalance model, this study examines PCB as an imbalance in employment relationships that acts as a psychosocial stressor in the work environment and is associated with stress reactions that in turn negatively affect mental health. METHODS: The analyses were based on a sample of 3,667 employees who participated in a longitudinal linked employer-employee survey representative of large organizations (with at least 500 employees who are subject so social security contributions) in Germany. Fixed-effects regression models, including PCB and OC, were estimated for employee mental health, and interaction effects between PCB and OC were assessed. RESULTS: The multivariate fixed-effects regression analyses showed a significant negative association between PCB and employee mental health. The results also confirmed that OC does indeed significantly increase the negative effect of PCB on mental health and that OC itself has a significant and negative effect on mental health. CONCLUSIONS: The results suggest that employees characterized by the cognitive-motivational pattern of OC are at an increased risk of developing poor mental health if they experience PCB compared with employees who are not overly committed to their work. The results of this study support the assumption that psychosocial work stressors play an important role in employee mental health. PMID- 27488040 TI - Nickel-smelting fumes increased the expression of HIF-1alpha through PI3K/ERK pathway in NIH/3T3 cells. AB - OBJECTIVE: The purpose of this study was to investigate the effects of Nickel (Ni) -smelting fumes on oncogenic proteins in vivo and in vitro. METHODS: Ni fallout beside a Ni smelting furnace in a factory was sampled to study its toxic effect. The effects of Ni-smelting fumes on the regulation of PI3K and ERK signaling pathways and the important downstream hypoxia inducible factor, HIF 1alpha, were studied both in NIH/3T3 cells and in the lung tissue of rats. NIH/3T3 cell transformation induced by Ni-smelting fumes was also observed. RESULTS: Ni-smelting fumes activated PI3K, p-AKT, p70S6K1, and ERK proteins and increased HIF-1alpha expression in a time- and dose-dependent manner. However, activation was suppressed when NIH/3T3 cells were pretreated with PI3K/AKT or ERK inhibitors. Ni-smelting fumes caused malignant transformation of NIH/3T3 cells. CONCLUSIONS: Ni-smelting fumes increased the expression of HIF-1alpha through the PI3K/ERK pathway in NIH/3T3 cells and induced malignant transformation in these cells indicating that Ni-smelting fumes may be a potential carcinogen in mammalian cells. PMID- 27488043 TI - An advanced case of indium lung disease with progressive emphysema. AB - OBJECTIVES: To report the occurrence of an advanced case of indium lung disease with severely progressive emphysema in an indium-exposed worker. CASE REPORT: A healthy 42-year-old male smoker was employed to primarily grind indium-tin oxide (ITO) target plates, exposing him to indium for 9 years (1998-2008). In 2004, an epidemiological study was conducted on indium-exposed workers at the factory in which he worked. The subject's serum indium concentration (In-S) was 99.7 MUg/l, while his serum Krebs von den Lungen-6 level was 2,350 U/ml. Pulmonary function tests showed forced vital capacity (FVC) of 4.17 l (91.5% of the JRS predicted value), forced expiratory volume in 1 s (FEV1) of 3.19 l (80.8% of predicted), and an FEV1-to-FVC ratio of 76.5%. A high-resolution chest computed tomography (HRCT) scan showed mild interlobular septal thickening and mild emphysematous changes. In 2008, he was transferred from the ITO grinding workplace to an inspection work section, where indium concentrations in total dusts had a range of 0.001-0.002 mg/m3. In 2009, the subject's In-S had increased to 132.1 MUg/l, and pulmonary function tests revealed obstructive changes. In addition, HRCT scan showed clear evidence of progressive lung destruction with accompanying severe centrilobular emphysema and interlobular septal thickening in both lung fields. The subject's condition gradually worsened, and in 2015, he was registered with the Japan Organ Transplant Network for lung transplantation (LTx). CONCLUSIONS: Heavy indium exposure is a risk factor for emphysema, which can lead to a severity level that requires LTx as the final therapeutic option. PMID- 27488042 TI - Dust-free bleaching powder may not prevent symptoms in hairdressers with bleaching-associated rhinitis. AB - OBJECTIVE: Hairdressers have an increased risk for airway symptoms especially when using hair-bleaching powder containing persulfate. To minimize exposure, dust-free bleaching powder (DFP) has been made available. We studied the effects of regular powder (RP) or DFP on the airway symptoms of hairdressers with hair bleaching associated rhinitis. METHODS: Twelve hairdressers each performed three hair-bleachings on a wig in an exposure chamber. Half of the subjects used RP and half used DFP. Exposure to persulfate and ammonia was measured. Before and after each bleaching, the participants stated their degree of airway symptoms on a visual analogue scale. Nasal lavage and blood were sampled before exposure, after the last bleaching, and in the morning after exposure to measure inflammatory markers. RESULTS: Exposure to persulfate was higher when using RP compared to DFP, 22 (11-55) vs. 12 (8-13) MUg/m3; median (min-max). Exposure to ammonia did not differ between the groups. Both groups reported an increase in asthma-like symptoms and this increase was significant. Neutrophils, lymphocytes, and monocytes increased after exposure in both groups; monocytes decreased the day after. In nasal lavage, IL-8 was increased the morning after for both types of powder, and the increase was significant in the total group. IL-6 increased immediately after exposure and the day after only in the group using RP. CONCLUSIONS: Although DFP powder emits lower levels of persulfate, effects are still elicited in symptomatic hairdressers. PMID- 27488044 TI - Investigation of rare chronic lipoid pneumonia associated with occupational exposure to paraffin aerosol. AB - OBJECTIVES: Occupational exposure to paraffin is an infrequent cause of lipoid pneumonia (LP) and related data are scare. We investigated the possible relationship between three rare cases of chronic LP and occupational exposure to paraffin aerosol in an iron foundry. METHODS: The three cases of LP and their workplaces were investigated using data from field investigations, air monitoring, pulmonary radiological examinations, cell staining, and lung biopsies. RESULTS: The patients had long-term occupational exposure to paraffin. X-ray diffraction testing revealed that the raw material from the workshop was paraffin crystal. The air concentrations of paraffin aerosol in workplaces were significantly higher than outdoor background levels. Small diffuse and miliary shadows with unclear edges were observed throughout the whole lungs via radiography. Computed tomography revealed diffuse punctate nodules and a high density of stripe-like shadows in both lungs (ground-glass opacity in a lower lobe, and a mass-like lesion and high translucent area near the bottom of the lung). Lipid-laden macrophages were found in the sputum and bronchial lavage. A broadened alveolar septum and local focal fibrosis were also discovered via lung biopsy. The inflammatory reaction in the lung tissues appeared to resolve over time. CONCLUSIONS: These three rare cases of chronic LP in workers during molding and repair processes were associated with occupational paraffin aerosol exposure. Therefore, primary prevention is essential for molding or repairing workers in the iron foundry, and a differential diagnosis of occupational chronic LP (vs. pneumoconiosis) should be considered when treating these workers. PMID- 27488045 TI - Buffering effect of workplace social capital on the association of job insecurity with psychological distress in Japanese employees: a cross-sectional study. AB - OBJECTIVES: The present study aimed to examine the buffering effect of workplace social capital (WSC) on the association of job insecurity with psychological distress in Japanese employees. METHODS: 2,971 employees from two factories of a manufacturing company in Japan completed a self-administered questionnaire including the scales on job insecurity, WSC, psychological distress, demographic and occupational characteristics, and quantitative workload. Using psychological distress (defined as a total score of the K6 scale >=5) as a dependent variable, multiple logistic regression analyses were conducted. In a series of analyses, interaction term of job insecurity*WSC was included in the model. RESULTS: After adjusting for demographic and occupational characteristics as well as for quantitative workload and interaction effect of quantitative workload*WSC, high job insecurity and low WSC were significantly associated with psychological distress. Furthermore, a significant interaction effect of job insecurity*WSC was observed. Specifically, the association of job insecurity with psychological distress was greater among those who perceived lower levels of WSC (prevalence odds ratio=3.79 [95% confidence interval=2.70-5.32] for high vs. low job insecurity subgroup) than among those who perceived higher levels of WSC (prevalence odds ratio=2.96 [95% confidence interval=2.19-4.01] for high vs. low job insecurity subgroup). These findings were replicated among permanent male employees in the gender-stratified analyses. CONCLUSIONS: The present study suggests that WSC has a buffering effect on the association of job insecurity with psychological distress at least among Japanese permanent male employees. PMID- 27488046 TI - Connexins in endothelial barrier function - novel therapeutic targets countering vascular hyperpermeability. AB - Prolonged vascular hyperpermeability is a common feature of many diseases. Vascular hyperpermeability is typically associated with changes in the expression patterns of adherens and tight junction proteins. Here, we focus on the less appreciated contribution of gap junction proteins (connexins) to basal vascular permeability and endothelial dysfunction. First, we assess the association of connexins with endothelial barrier integrity by introducing tools used in connexin biology and relating the findings to customary readouts in vascular biology. Second, we explore potential mechanistic ties between connexins and junction regulation. Third, we review the role of connexins in microvascular organisation and development, focusing on interactions of the endothelium with mural cells and tissue-specific perivascular cells. Last, we see how connexins contribute to the interactions between the endothelium and components of the immune system, by using neutrophils as an example. Mounting evidence of crosstalk between connexins and other junction proteins suggests that we rethink the way in which different junction components contribute to endothelial barrier function. Given the multiple points of connexin-mediated communication arising from the endothelium, there is great potential for synergism between connexin-targeted inhibitors and existing immune-targeted therapeutics. As more drugs targeting connexins progress through clinical trials, it is hoped that some might prove effective at countering vascular hyperpermeability. PMID- 27488047 TI - "It's my business, it's my body, it's my money": experiences of smokers who are not planning to quit in the next 30 days and their views about treatment options. AB - BACKGROUND: Current evidence-based smoking cessation treatments in the UK are only offered to smokers ready to quit within 30 days. This study reports the experiences of smokers who are not ready to quit and explores the types of intervention approaches that might engage them. METHODS: Five focus groups were conducted with smokers who had no plans to quit within 30 days (n = 32, 44 % female). Verbatim transcripts were analyzed thematically using Nvivo 10 software. RESULTS: Participants were ambivalent towards their own smoking, but the majority indicated they would like to quit someday. Smoking was seen both to hinder and facilitate social interactions, depending on the social norms of the participant's social circle. Participants reported that, when they perceive pressure to quit smoking, they respond defensively; concurrently, existing approaches to encouraging smoking cessation were seen as unappealing. In contrast, the importance of intrinsic motivation to quit was emphasized, and interventions that were tailored, increased intrinsic motivation and kept the smoker engaged in activities incompatible with smoking were preferred. CONCLUSIONS: Despite not planning to quit in the next 30 days, the majority of participants wanted to quit smoking at some point. Even if existing services were offered to smokers not planning to quit in the next 30 days, it is unlikely that these services would meet the needs of this population. Future research should explore novel approaches to appeal specifically to smokers not planning to quit in the next 30 days, such as encouraging engagement with activities incompatible with smoking and fostering non-smoking habits. PMID- 27488049 TI - Oral bioavailability enhancement through supersaturation: an update and meta analysis. AB - INTRODUCTION: With the increasing number of poorly water-soluble compounds in drug discovery pipelines, supersaturating drug delivery systems (SDDS) have attracted increased attention as an effective bioavailability enhancing approach. However, a systematic and quantitative synopsis of the knowledge about performance of SDDS is currently lacking. Such analysis of the recent achievements is to provide insights for formulation scientists dealing with poorly soluble compounds. Areas covered: A systematic search of two evidence based International databases, Medline and Embase, from 2010 to Dec 2015, has been performed. By conducting meta-analysis, box-plots, and correlation plots of the relevant data retrieved from literature, the current review addresses three quantitative questions: (1) how promising are SDDS for bioavailability enhancement? (2) which types of SDDS perform best? and (3) what are the most promising drug candidates? Four widely reported types of SDDS were compared: amorphous solid dispersions, nano-drug systems, supersaturable lipid-based formulations, and silica-based systems. Expert opinion: While SDDS formulations appear to be a promising candidate-enabling technique for drug development, the prediction of their in vivo performance by in vitro testing remains challenging. A transition from a trial-and-error development approach towards an approach guided by mechanistic insight, as well as the development of more efficient predictive tools for performance ranking is urgently needed. PMID- 27488048 TI - Exposure to various abscission-promoting treatments suggests substantial ERF subfamily transcription factors involvement in the regulation of cassava leaf abscission. AB - BACKGROUND: Cassava plants (Manihot esculenta Crantz) have obvious abscission zone (AZ) structures in their leaf pulvinus-petioles. Cassava leaf abscission can be triggered by either 17 days of water-deficit stress or 4 days of ethylene treatment. To date, little is known about cassava AP2/ERF factors, and less is known regarding their roles in regulating abscission zone development. RESULTS: Here, the cassava and Arabidopsis AP2/ERF genes were compared, finding that the cassava genome contains approximately 1.54-fold more ERF subfamily than the Arabidopsis genome. Microarray analysis was used to identify the AP2/ERF genes that are expressed in cassava leaf pulvinus-petiole abscission zones by comparing the AP2/ERF gene expression profiles of ethylene- and water-deficit stress induced leaf abscission. In total, 99 AP2/ERF genes were identified as expressed in AZs across six time points during both ethylene- and water-deficit stress induced leaf abscission. Comparative expression profile analysis of similar SOTA (Self Organizing Tree Algorithm) clusters at six time points during ethylene- and water-deficit stress-induced leaf abscission demonstrated that 20 ERF subfamily genes had similar expression patterns in response to both treatments. GO (Gene Ontology) annotation confirmed that all 20 ERF subfamily genes participate in ethylene-mediated signalling. Analysis of the putative ERF promoter regions shown that the genes contained primarily ethylene- and stress-related cis-elements. Further analysis of ACC oxidase activity in AZs across six time points during abscission shown increased ethylene production in response to both ethylene and water-deficit stress; however, the difference was more dramatic for water-deficit stress. Finally, the expression ratios of 20 ERF subfamily genes were analysed in two cassava cultivars, 'KU50' and 'SC5', that exhibit different levels of leaf abscission when challenged with the same water-deficit stress. The analysis indicated that most of the ERF genes were expressed at higher levels in the precocious abscission 'KU50' cultivar than in the delayed abscission 'SC5' cultivar. CONCLUSION: Ccomparative analysis of both ethylene- and water-deficit stress-induced leaf abscission shown that the ERF subfamily functions in the regulation of cassava abscission zone development. PMID- 27488052 TI - Application of proteomics in research on traditional Chinese medicine. AB - INTRODUCTION: Traditional Chinese medicine (TCM) is a widely used complementary alternative medicine approach. Although many aspects of its effectiveness have been approved clinically, rigorous scientific techniques are highly required to translate the promises from TCM into powerful modern therapies. In this respect, proteomics is useful because of its ability to unveil the underlying target proteins and/or protein biomarkers. AREAS COVERED: In this review, we summarize the recent interplay between proteomics and research on TCM, ranging from exploration of the medicinal materials to the biological basis of TCM concepts, and from pathological studies to pharmacological investigations. We show that proteomic analyses provide preliminary biological evidence of the promises in TCM, and the integration of proteomics with other omics and bioinformatics offers a comprehensive methodology to address the complications of TCM. Expert commentary: Currently, only limited information can be obtained regarding TCM issues and thus more work is required to resolve the ambiguity. As such, more collaborations between proteomics and other techniques (other omics, network pharmacology, etc.) are essential for deciphering the underlying biological basis in TCM topics. PMID- 27488051 TI - Treatment with L-citrulline and metformin in Duchenne muscular dystrophy: study protocol for a single-centre, randomised, placebo-controlled trial. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that affects 1 in 3500-6000 male births. Despite broad research aiming to improve muscle function as well as heart and brain function, sufficient therapeutic efficacy has not yet been achieved and current therapeutic management is still supportive. In a recent pilot trial, oral treatment with L-arginine and metformin showed consistent changes of muscular metabolism both in vitro and in vivo by raising NO levels and expression of mitochondrial proteins in the skeletal muscle tissue of patients with DMD. This randomised, double-blind, placebo-controlled trial aims to demonstrate the superiority of L-citrulline and metformin therapy over placebo in DMD patients with regard to the Motor Function Measure (MFM) D1 subscore (primary endpoint) as well as additional clinical and subclinical tests. METHODS/DESIGN: A total of 40-50 ambulant patients with DMD will be recruited at the outpatient department of the University of Basel Children's Hospital (Switzerland), as well as from the DMD patient registries of Switzerland, Germany and Austria. Patients will be randomly allocated to one of the two arms of the study and will receive either a combination of L-citrulline and metformin or placebo for 26 weeks. Co-medication with glucocorticoids is allowed. The primary endpoint is the change of the MFM D1 subscore from baseline to week 26 under L citrulline and metformin therapy. Secondary endpoints will include the motor function measure (MFM) and its items and subscores, the 6-minute walking test, timed function tests and quantitative muscle testing. Furthermore, quantitative muscle MRI assessment to evaluate the muscle fat fraction as well as safety and biomarker laboratory analyses from blood will be included. For comparison, muscle metabolism and mitochondrial function will be analysed in 10-20 healthy age matched male children. DISCUSSION: The aim of this study is to test if a 6-month treatment of a combination of L-citrulline and metformin is more effective than placebo in preventing loss of motor function and muscle degeneration in DMD. The MFM D1 subscore is used as a clinical outcome measure and a quantitative muscle MRI assessment as the surrogate outcome measure of fatty muscle degeneration. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01995032 . Registered on 20 November 2013. PMID- 27488053 TI - Elucidating diversity of exosomes: biophysical and molecular characterization methods. AB - Exosomes are cell-secreted nanovesicles present in biological fluids in normal and diseased conditions. Owing to their seminal role in cell-cell communication, emerging evidences suggest that exosomes are fundamental regulators of various diseases. Due to their potential usefulness in disease diagnosis, robust isolation and characterization of exosomes is critical in developing exosome based assays. In the last few years, different exosome characterization methods, both biophysical and molecular, have been developed to characterize these tiny vesicles. Here, in this review we summarize: first, biophysical techniques based on spectroscopy (e.g., Raman spectroscopy, dynamic light scattering) and other principles, for example, scanning electron microscopy, atomic force microscopy; second, antibody-based molecular techniques including flow cytometry, transmission electron microscopy and third, nanotechnology-dependent exosome characterization methodologies. PMID- 27488055 TI - Commentary: Rapid Phosphoproteomic Effects of Abscisic Acid (ABA) on Wild-Type and ABA Receptor-Deficient A. thaliana Mutants. PMID- 27488056 TI - Erratum to: Fertility rates among very young adolescent women: temporal and spatial trends in Brazil. PMID- 27488054 TI - Phytochemical, antioxidant and hepatoprotective effects of Alnus nitida bark in carbon tetrachloride challenged Sprague Dawley rats. AB - BACKGROUND: Alnus nitida (Spach) Endl. is traditionally used for inflammatory disorders. Diarylheptanoids constituents having diverse therapeutically importance including hepato-protective was reported in A. nitida. The aim of this study was to explore the antioxidant and hepato-protective profile of A. nitida stem bark's crude methanol extract (ANM). METHODS: Crude methanol extract of A. nitida stem bark and its derived fractions were assessed for phytochemical classes and in vitro antioxidant profiling by multidimensional assays. Hepato protective assessment of ANM was investigated on rats, which were made hepatotoxic using carbon tetrachloride (CCl4). Additionally HPLC-DAD analysis of ANM, and its derived ethyl acetate and aqueous fraction was carried out to determine the presence of active constituents. RESULTS: Qualitative analysis of crude extract-and its fractions depicted the presence of terpenoids, saponins, coumarins, phenols and flavonoids. Maximum quantity of total phenolic content (TPC) and total flavonoid content (TFC) was recorded in ANM and its derived fractions; n-hexane (ANH), chloroform (ANC), ethyl acetate (ANE) and the residual aqueous (ANA). ANM exhibited the best total antioxidant capacity, total reducing power, and scavenging of DPPH and OH radicals. ANE and ANA exhibited strong scavenging potential for iron chelation, nitric oxide and beta-carotene bleaching assay. ANM treatment converse the activities of serum-marker enzymes and lipid profile, altered by CCl4 treatment in rat. CCl4 induced hepatic-cirrhosis in rat resulted in decrease of antioxidant enzyme activities such as catalase, peroxidase, superoxide dismutase, glutathione peroxidase, glutathione-S transferase and glutathione reductase-which were restored towards the normal level with ANM. Similarly diminished level of reduced glutathione while enhanced level of lipid peroxides, hydrogen peroxide and nitrite in liver of cirrhotic rats was normalized by treatment of ANM. The histopathological studies of liver tissues also represented that ANM possessed the hepato-protective activity. HPLC DAD analysis against eight known standards confirmed the presence of gallic acid, catechin and rutin in ANM and in ANA while in ANE gallic acid was only detected. CONCLUSION: Based on the results of antioxidants, restoration of various antioxidant enzymes and histopathological studies, the recent study concludes that antioxidant potential of A. nitida bark might protect the liver damages. PMID- 27488057 TI - Developmental outcomes and physical activity behaviour in children post major surgery: an observational study. AB - BACKGROUND: Infants may be at neurodevelopmental risk from adverse events arising in the neonatal period. This study aimed to investigate the developmental outcomes and physical activity behaviours of term infants after neonatal major surgery, at age three years. METHODS: This prospective study enrolled infants who underwent major surgery in their first 90 days, between August 2006 and December 2008. Developmental status was assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Physical activity and sedentary behaviour (i.e. small screen recreation) (SSR) were assessed using the Preschool Age Physical Activity Questionnaire (Pre-PAQ). Activity (moving between slow to fast pace) and SSR were reported for a 3-day period. RESULTS: One hundred and thirty five children (68 major surgery, 67 control) were assessed, using both measures, at age three years. Both groups were within the average range across all domains of the BSID-III although the surgical group was significantly below the controls for cognition (t = -3.162, p = 0.002) receptive language (t = 3.790, p < 0.001) and fine motor skills (t = -2.153, p = 0.03). Mean activity time for the surgical group was 191 mins.day(-1), and 185 mins.day-1 for controls. Mean SSR time was 77 mins.day(-1), and 83 mins.day(-1) for the respective groups. There was no significant difference between groups for either physical activity (p = 0.71) or SSR time (p = 0.49). CONCLUSIONS: By age three, children who had major surgery in infancy are developmentally normal but have not quite caught up with their peer group in cognitive, receptive language and fine motor skill domains. Both groups met recommended 3 h of daily physical activity but exceeded 60-min SSR time recommended for preschool-age children. PMID- 27488059 TI - Carryover Effects in Sibling Comparison Designs. AB - A convenient way of dealing with confounding is the sibling comparison design, where the outcome in exposed individuals is compared with the outcome in their unexposed siblings. The standard analysis of sibling comparison designs assumes that the exposure and outcome of an individual do not affect the exposure and outcome of his/her siblings, sometimes referred to as an absence of sibling carryover or contagion effects. Unfortunately, there are many situations where carryover effects are likely to be present. In this article, we explore the consequences of carryover effects for sibling comparison designs. We show, using causal diagrams, when and why carryover effects lead to bias, and we investigate the sign and magnitude of this bias under various scenarios. PMID- 27488060 TI - Commentary: Integrating Complex Systems Thinking into Epidemiologic Research. PMID- 27488058 TI - Nox2-Mediated PI3K and Cofilin Activation Confers Alternate Redox Control of Macrophage Pinocytosis. AB - AIMS: Internalization of extracellular fluid and its solute by macropinocytosis requires dynamic reorganization of actin cytoskeleton, membrane ruffling, and formation of large endocytic vacuolar compartments, called macropinosomes, inside the cell. Although instigators of macropinocytosis, such as growth factors and phorbol esters, stimulate NADPH oxidase (Nox) activation and signal transduction mediators upstream of Nox assembly, including Rac1 and protein kinase C (PKC), are involved in macropinocytosis, the role of Nox enzymes in macropinocytosis has never been investigated. This study was designed to examine the role of Nox2 and the potential downstream redox signaling involved in macropinocytosis. RESULTS: Phorbol myristate acetate activation of human and murine macrophages stimulated membrane ruffling, macropinosome formation, and subsequent uptake of macromolecules by macropinocytosis. Mechanistically, we found that pharmacological blockade of PKC, transcriptional knockdown of Nox2, and scavenging of intracellular superoxide anion abolished phorbol ester-induced macropinocytosis. We observed that Nox2-derived reactive oxygen species via inhibition of phosphatase and tensin homolog and activation of the phosphoinositide-3-kinase (PI3K)/Akt pathway lead to activation of actin-binding protein cofilin, membrane ruffling, and macropinocytosis. Similarly, activation of macropinocytosis by macrophage colony-stimulating factor involves Nox2 mediated cofilin activation. Furthermore, peritoneal chimera experiments indicate that macropinocytotic uptake of lipids in hypercholesterolemic ApoE-/- mice was attenuated in Nox2y/- macrophages compared with wild-type controls. Innovation and Conclusion: In summary, these findings demonstrate a novel Nox2-mediated mechanism of solute uptake via macropinocytosis, with broad implications for both general cellular physiology and pathological processes. The redox mechanism described here may also identify new targets in atherosclerosis and other disease conditions involving macropinocytosis. Antioxid. Redox Signal. 26, 902-916. PMID- 27488061 TI - Giant sinus of Valsalva aneurysm. PMID- 27488062 TI - Molecular Genomics of Eye Diseases. PMID- 27488063 TI - Ocular Gene Therapy-The Future Is Now. PMID- 27488064 TI - Age-Related Macular Degeneration: Genetics and Biology. AB - Age-related macular degeneration (AMD), widely prevalent across the globe, is a major stakeholder among adult visual morbidity and blindness, not only in the Western world but also in Asia. Several risk factors have been identified, including critical genetic factors, which were never imagined 2 decades ago. The etiopathogenesis is emerging to demonstrate that immune and complement-related inflammation pathway members chronically exposed to environmental insults could justifiably influence disease morbidity and treatment outcomes. Approximately half a dozen physiological and biochemical cascades are disrupted in the AMD disease genesis, eventually leading to the distortion and disruption of the subretinal space, subretinal pigment epithelium, and Bruch membrane, thus setting off chaos and disorder for signs and symptoms to manifest. Approximately 3 dozen genetic factors have so far been identified, including the recent ones, through powerful genomic technologies and large robust sample sizes. The noteworthy genetic variants (common and rare) are complement factor H, complement factor H related genes 1 to 5, C3, C9, ARMS2/HTRA1, vascular endothelial growth factor A, vascular endothelial growth factor receptor 2/KDR, and rare variants (show causal link) such as TIMP3, fibrillin, COL4A3, MMP19, and MMP9. Despite the enormous amount of scientific information generated over the years, diagnostic genetic or biomarker tests are still not available for clinicians to understand the natural course of the disease and its management in a patient. However, further research in the field should reduce this gap not only by aiding the clinician but also through the possibilities of clinical intervention with complement pathway related inhibitors entering preclinical and clinical trials in the near future. PMID- 27488065 TI - Myopia Genetics-The Asia-Pacific Perspective. AB - Myopia is a major cause of visual impairment worldwide. In particular, high myopia is associated with serious blinding complications, including retinal detachment, chorioretinal degeneration, and choroidal neovascularization. Myopia is multifactorial in etiology, resulting from the interaction of environmental and genetic risk factors. During the past 2 decades, a large number of gene loci and variants have been identified for myopia. There are more than 20 myopia associated loci spanning all chromosomes. Earlier findings were obtained mainly from family linkage analyses and candidate gene studies, and more recent results are principally from genome-wide association studies and exome sequencing. Some genetic associations have been successfully validated and replicated in populations of different geographic localities and ethnicities, but some have not. Compared with Whites, Asian populations-in particular Japanese, Korean, and Chinese-have a much higher prevalence of myopia, especially high myopia. Both genetic and environmental factors contribute to such ethnic variations. This review attempts to summarize and compare the allelic frequencies of gene variants known to be associated with myopia in different ethnic groups, especially in the Asia-Pacific region. PMID- 27488066 TI - Gene-Based Therapies for Leber Hereditary Optic Neuropathy. Hype or Hope? AB - Leber hereditary optic neuropathy has now joined Leber congenital amaurosis in the list of genetic eye diseases undergoing gene therapy clinical trials. Although a dramatic response to treatment would be welcome, a minor improvement in vision is a major challenge in efficacy assessment, given this may occur spontaneously as part of the natural history of minor recovery in some patients. Thus, we must await the outcome of adequately powered clinical trials to know if the treatment is effective, particularly given the likely high cost of such therapeutic interventions in the future. We need global cooperation to ensure that the most suitable patients are enrolled in these trials and that support is provided for participants who need to travel from the Asia-Pacific region to Europe or North America if there are no local arms of these trials. PMID- 27488067 TI - Glaucoma Genetics: Recent Advances and Future Directions. AB - Once considered primarily a disease of aging caused by unknown environmental influences, the notion that heritable factors could significantly contribute to the pathogenesis of sporadic glaucoma has rapidly gained traction. In part, this is due to the rapid and definitive identification of genes with strong effects on familial, earlier onset forms of glaucoma. Although the endpoint of glaucoma is irreversible optic nerve damage accompanied by blindness, the initial inciting trigger could differ. To this end, well-powered genome-wide association studies have each been conducted for primary open-angle glaucoma, primary angle-closure glaucoma, along with exfoliation syndrome and glaucoma. Each of these studies has revealed sets of significantly associated genetic loci implicating biological pathways that do not overlap between the forms of glaucoma. Although substantial biological insight has been gained from their identification, much further work remains to definitively link the implicated genetic variants with glaucoma causation. It is also hoped that the genetic findings could point us to potential routes of therapy beyond that of intraocular pressure-lowering medications or surgery. PMID- 27488068 TI - Genetics of Retinoblastoma. AB - Retinoblastoma is a malignant retinal tumor that affects young children. Mutations in the RB1 gene cause retinoblastoma. Mutations in both RB1 alleles within the precursor retinal cell are essential, with one mutation that may be germline or somatic and the second one that is always somatic. Identification of the RB1 germline status of a patient allows differentiation between sporadic and heritable retinoblastoma variants. Application of this knowledge is crucial for assessing short-term (risk of additional tumors in the same eye and other eye) and long-term (risk of nonocular malignant tumors) prognosis and offering cost effective surveillance strategies. Genetic testing and genetic counseling are therefore essential components of care for all children diagnosed with retinoblastoma. The American Joint Committee on Cancer has acknowledged the importance of detecting this heritable trait and has introduced the letter "H" to denote a heritable trait of all cancers, starting with retinoblastoma (in publication). In this article, we discuss the clinically relevant aspects of genetic testing and genetic counseling for a child with retinoblastoma. PMID- 27488069 TI - Retinitis Pigmentosa: Progress and Perspective. AB - Retinitis pigmentosa is the most common form of hereditary retinal degeneration causing blindness. Great progress has been made in the identification of the causative genes. Gene diagnosis will soon become an affordable routine clinical test because of the wide application of next-generation sequencing. Gene-based therapy provides hope for curing the disease. Investigation into the molecular pathways from mutation to rod cell death may reveal targets for developing new treatment. Related progress with existing systematic review is briefly summarized so that readers may find the relevant references for in-depth reading. Future trends in the study of retinitis pigmentosa are also discussed. PMID- 27488070 TI - Strategies for Gene Mapping in Inherited Ophthalmic Diseases. AB - Gene mapping of inherited ophthalmic diseases such as congenital cataracts, retinal degeneration, glaucoma, age-related macular degeneration, myopia, optic atrophy, and eye malformations has shed more light on the disease pathology, identified targets for research on therapeutics, earlier detection, and treatment options for disease management and patient care. This article details the different approaches to gene identification for both Mendelian and complex eye disorders. PMID- 27488071 TI - Gene Therapy for Age-Related Macular Degeneration. AB - The purpose of this article was to evaluate safety and signals of efficacy of gene therapy with subretinal rAAV.sFlt-1 for wet age-related macular degeneration (wet AMD). A phase 1 dose-escalating single-center controlled unmasked human clinical trial was followed up by extension of the protocol to a phase 2A single center trial. rAAV.sFlt-1 vector was used to deliver a naturally occurring anti vascular endothelial growth factor agent, sFlt-1, into the subretinal space. In phase 1, step 1 randomized 3 subjects to low-dose rAAV.sFlt-1 (1 * 10 vector genomes) and 1 subject to the control arm; step 2 randomized an additional 3 subjects to treatment with high-dose rAAV.sFlt-1 (1 * 10 vector genomes) and 1 subject to the control arm. Follow-up studies demonstrated that rAAV.sFlt-1 was well tolerated with a favorable safety profile in these elderly subjects with wet AMD. Subretinal injection was highly reproducible, and no drug-related adverse events were reported. Procedure-related adverse events were mild and self resolving. Two phakic patients developed cataract and underwent cataract surgery. Four of the 6 patients responded better than the small control group in this study and historical controls in terms of maintaining vision and a relatively dry retina with zero ranibizumab retreatments per annum. Two patients required 1 ranibizumab injection over the 52-week follow-up period. rAAV.sFlt-1 gene therapy may prove to be a potential adjunct or alternative to conventional intravitreal injection for patients with wet AMD by providing extended delivery of a naturally occurring antiangiogenic protein. PMID- 27488072 TI - Clustered Regularly Interspaced Short Palindromic Repeats: Challenges in Treating Retinal Disease. AB - Ophthalmic researchers and clinicians arguably have led the way for safe, effective gene therapy, most notably with adeno-associated viral gene supplementation in the treatment for patients with Leber congenital amaurosis type 2 with mutations in the RPE65 gene. These successes notwithstanding, most other genetic retinal disease will be refractory to supplementation. The ideal gene therapy approach would correct gene mutations to restore normal function in the affected cells. Gene editing in which a mutant allele is inactivated or converted to sequence that restores normal function is hypothetically one such approach. Such editing involves site-specific digestion of mutant genomic DNA followed by repair. Previous experimental approaches were hampered by inaccurate and high rates of off-site lesioning and by overall low digestion rates. A new tool, clustered regularly interspaced short palindromic repeats coupled with the nuclease Cas9, may address both shortcomings. Some of the many challenges that must be addressed in moving clustered regularly interspaced short palindromic repeats coupled with the nuclease Cas9 therapies to the ophthalmic clinic are discussed here. PMID- 27488073 TI - Exercise as Gene Therapy: BDNF and DNA Damage Repair. AB - DNA damage is a common feature of neurodegenerative illnesses, and the ability to repair DNA strand breaks and lesions is crucial for neuronal survival, reported by Jeppesen et al (Prog Neurobiol. 2011;94:166-200) and Shiwaku et al (Curr Mol Med. 2015;15:119-128). Interventions aimed at repairing these lesions, therefore, could be useful for preventing or delaying the progression of disease. One potential strategy for promoting DNA damage repair (DDR) is exercise. Although the role of exercise in DDR is not understood, there is increasing evidence that simple physical activity may impact clinical outcomes for neurodegeneration. Here, we discuss what is currently known about the molecular mechanisms of brain derived neurotrophic factor and how these mechanisms might influence the DDR process. PMID- 27488074 TI - Gene Therapy and Gene Editing for the Corneal Dystrophies. AB - Despite ever-increasing understanding of the genetic underpinnings of many corneal dystrophies, gene therapy designed to ameliorate disease has not yet been reported in any human patient. In this review, we explore the likely reasons for this apparent failure of translation. We identify the requirements for success: the genetic defect involved must have been identified and mapped, vision in the affected patient must be significantly impaired or likely to be impaired, no better or equivalently effective treatment must be available, the treatment must be capable of modulating corneal pathology, and delivery of the construct to the appropriate cell must be practicable. We consider which of the corneal dystrophies might be amenable to treatment by genetic manipulations, summarize existing therapeutic options for treatment, and explore gene editing using clustered regularly interspaced short palindromic repeat/Cas and other similar transformative technologies as the way of the future. We then summarize recent laboratory-based advances in gene delivery and the development of in vitro and in vivo models of the corneal dystrophies. Finally, we review recent experimental work that has increased our knowledge of the pathobiology of these conditions. PMID- 27488075 TI - Enhanced hydrogenation activity and diastereomeric interactions of methyl pyruvate co-adsorbed with R-1-(1-naphthyl)ethylamine on Pd(111). AB - Unmodified racemic sites on heterogeneous chiral catalysts reduce their overall enantioselectivity, but this effect is mitigated in the Orito reaction (methyl pyruvate (MP) hydrogenation to methyl lactate) by an increased hydrogenation reactivity. Here, this effect is explored on a R-1-(1-naphthyl)ethylamine (NEA) modified Pd(111) model catalyst where temperature-programmed desorption experiments reveal that NEA accelerates the rates of both MP hydrogenation and H/D exchange. NEA+MP docking complexes are imaged using scanning tunnelling microscopy supplemented by density functional theory calculations to allow the most stable docking complexes to be identified. The results show that diastereomeric interactions between NEA and MP occur predominantly by binding of the C=C of the enol tautomer of MP to the surface, while simultaneously optimizing C=O....H2N hydrogen-bonding interactions. The combination of chiral NEA driven diastereomeric docking with a tautomeric preference enhances the hydrogenation activity since C=C bonds hydrogenate more easily than C=O bonds thus providing a rationale for the catalytic observations. PMID- 27488076 TI - Child and youth experiences and perspectives of cerebral palsy: a qualitative systematic review: letter to the editor. PMID- 27488077 TI - Response to Boyd letter. PMID- 27488079 TI - Time-dependent uptake and trafficking of vesicles capturing extracellular S100B in cultured rat astrocytes. AB - Astrocytes, the most heterogeneous glial cells in the central nervous system, contribute to brain homeostasis, by regulating a myriad of functions, including the clearance of extracellular debris. When cells are damaged, cytoplasmic proteins may exit into the extracellular space. One such protein is S100B, which may exert toxic effects on neighboring cells unless it is removed from the extracellular space, but the mechanisms of this clearance are poorly understood. By using time-lapse confocal microscopy and fluorescently labeled S100B (S100B Alexa488 ) and fluorescent dextran (Dextran546 ), a fluid phase uptake marker, we examined the uptake of fluorescently labeled S100B-Alexa488 from extracellular space and monitored trafficking of vesicles that internalized S100B-Alexa488 . Initially, S100B-Alexa488 and Dextran546 internalized with distinct rates into different endocytotic vesicles; S100B-Alexa488 internalized into smaller vesicles than Dextran546 . At a later stage, S100B-Alexa488 -positive vesicles substantially co-localized with Dextran546 -positive endolysosomes and with acidic LysoTracker-positive vesicles. Cell treatment with anti-receptor for advanced glycation end products (RAGE) antibody, which binds to RAGE, a 'scavenger receptor', partially inhibited uptake of S100B-Alexa488 , but not of Dextran546 . The dynamin inhibitor dynole 34-2 inhibited internalization of both fluorescent probes. Directional mobility of S100B-Alexa488 -positive vesicles increased over time and was inhibited by ATP stimulation, an agent that increases cytosolic free calcium concentration ([Ca2+ ]i ). We conclude that astrocytes exhibit RAGE- and dynamin-dependent vesicular mechanism to efficiently remove S100B from the extracellular space. If a similar process occurs in vivo, astroglia may mitigate the toxic effects of extracellular S100B by this process under pathophysiologic conditions. This study reveals the vesicular clearance mechanism of extracellular S100B in astrocytes. Initially, fluorescent S100B internalizes into smaller endocytotic vesicles than dextran molecules. At a later stage, both probes co-localize within endolysosomes. S100B internalization is both dynamin- and RAGE-dependent, whereas dextran internalization is dependent on dynamin. Vesicle internalization likely mitigates the toxic effects of extracellular S100B and other waste products. PMID- 27488080 TI - Validation of Random Sampling as an Estimation Procedure for Lyme Disease Surveillance in Massachusetts and Minnesota. AB - Many disease surveillance programs, including the Massachusetts Department of Public Health and the Minnesota Department of Health, are challenged by marked increases in Lyme disease (LD) reports. The purpose of this study was to retrospectively analyse LD reports from 2005 through 2012 to determine whether key epidemiologic characteristics were statistically indistinguishable when an estimation procedure based on sampling was utilized. Estimates of the number of LD cases were produced by taking random 20% and 50% samples of laboratory-only reports, multiplying by 5 or 2, respectively, and adding the number of provider reported confirmed cases. Estimated LD case counts were compared to observed, confirmed cases each year. In addition, the proportions of cases that were male, were <=12 years of age, had erythema migrans (EM), had any late manifestation of LD, had a specific late manifestation of LD (arthritis, cranial neuritis or carditis) or lived in a specific region were compared to the proportions of cases identified using standard surveillance to determine whether estimated proportions were representative of observed proportions. Results indicate that the estimated counts of confirmed LD cases were consistently similar to observed, confirmed LD cases and accurately conveyed temporal trends. Most of the key demographic and disease manifestation characteristics were not significantly different (P < 0.05), although estimates for the 20% random sample demonstrated greater deviation than the 50% random sample. Applying this estimation procedure in endemic states could conserve limited resources by reducing follow-up effort while maintaining the ability to track disease trends. PMID- 27488081 TI - Minocycline combination therapy with fluvoxamine in moderate-to-severe obsessive compulsive disorder: A placebo-controlled, double-blind, randomized trial. AB - AIM: Several lines of evidence implicate glutamatergic dysfunction in the pathophysiology of obsessive-compulsive disorder (OCD), presenting this neurotransmitter as a target for the development of novel pharmacotherapy. The objective of this study was to assess the efficacy of minocycline as an augmentative agent to fluvoxamine in the treatment of patients with OCD. METHODS: One hundred and two patients with the diagnosis of moderate-to-severe OCD were recruited to this study. A randomized double-blind trial was designed and patients received either L-carnosine or placebo as adjuvant to fluvoxamine for 10 weeks. The patients randomly received either minocycline 100 mg twice per day or placebo for 10 weeks. All patients received fluvoxamine (100 mg/day) for the first 4 weeks, followed by 200 mg/day for the rest of the trial, regardless of their treatment groups. Participants were evaluated using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). The main outcome measure was to assess the efficacy of minocycline in improving the OCD symptoms. RESULTS: General linear model repeated measures demonstrated significant effect for time * treatment interaction on the Y-BOCS total scores, F(1.49, 137.93) = 7.1, P = 0.003, and Y BOCS Obsession subscale score, F(1.54, 141.94) = 9.72, P = 0.001, and near significant effect for the Y-BOCS Compulsion subscale score, F(1.27, 117.47) = 2.92, P = 0.08. A significantly greater rate of partial and complete response was observed in the minocycline group (P < 0.001). The frequency of side-effects was not significantly different between the treatment arms. CONCLUSION: The results of this study suggest that minocycline could be a tolerable and effective adjuvant in the management of patients with OCD. PMID- 27488083 TI - The mediating role of relatedness need satisfaction in the relationship between charitable behavior and well-being: Empirical evidence from China. AB - Based on self-determination theory, the current research aimed to explore the potential mediating effect of relatedness need satisfaction on the relationship between charitable behavior and well-being in the Chinese context. Employing a cross-sectional design, participants reported data on the aforementioned variables in Study 1. The results indicated that relatedness need satisfaction mediated the positive relationship between charitable behavior and hedonic well being and that between charitable behavior and eudaimonic well-being. Subsequently, a field experiment was conducted in Study 2. Participants rated their levels of relatedness need satisfaction and well-being after charitable donation behaviors were primed. We again observed consistent results. Specifically, charitable behavior was positively associated with both hedonic and eudaimonic well-being, and these relationships were mediated by relatedness need satisfaction. The above findings help to clarify the association between charitable behavior and people's subjective feelings (i.e., well-being), and they deepen our understanding of the underlying mechanism from the perspective of psychological needs satisfaction. PMID- 27488082 TI - Copulatory plugs inhibit the reproductive success of rival males. AB - Ejaculated proteins play important roles in reproductive fitness. In many species, seminal fluid coagulates and forms what has been referred to as a copulatory plug in the female's reproductive tract. In mice, previous work demonstrated that knockout males missing a key seminal fluid protein were unable to form a plug and less successful at siring litters in noncompetitive matings (one female, one male), probably the result of reduced sperm transport or insufficient stimulation of the female. Here, we extend these previous studies to competitive matings (one female, two males) and make two key insights. First, when first males were unable to form a plug, they lost almost all paternity to second males to mate. Thus, the copulatory plugs of second males could not rescue the reduced fertility of first males. Second, we showed that the copulatory plug of first males effectively blocked fertilization by second males, even if first males were vasectomized. Taken together, our experiments demonstrated that first males lost almost all paternity if they never formed a plug. We discuss our results in the context of natural populations, where in spite of the strong effects seen here, pregnant female mice regularly carry litters fertilized by more than one male. PMID- 27488084 TI - Melanocortin-1 Receptor Polymorphisms and the Risk of Complicated Sepsis After Trauma: A Candidate Gene Association Study. AB - OBJECTIVE: The aim of the study was to determine if melanocortin-1 receptor (MC1R) single nucleotide polymorphisms (SNPs) are associated with complicated sepsis after trauma. BACKGROUND: Nosocomial infections are an important cause of morbidity and mortality after trauma. Several SNPs in inflammation-related genes have been associated with sepsis. MC1R is an anti-inflammatory mediator that may be involved in the immune response after trauma. PATIENTS AND METHODS: We genotyped eight common MC1R SNPs in genomic DNA from subjects enrolled in a previously reported prospective cohort study. Subjects were adult trauma patients admitted to the intensive care unit at a Level 1 trauma center (2003-2005). RESULTS: A total of 1,246 subjects were included in the analysis. The majority were male (70%), severely injured (81%), and injured by a blunt mechanism (89%). Forty percent developed sepsis, and 23% developed complicated sepsis, which was defined as sepsis with organ dysfunction. In logistic regression analysis, with adjustments for age, sex, body mass index, injury severity score, red blood cell transfusion requirement, and mechanism of injury, the MC1RR163Q variant (rs885479) was associated with a lower risk of developing complicated sepsis (adjusted odds ratio [ORadj] = 0.48, 95% confidence interval [CI]: 0.28-0.81, P = 0.006). In a subgroup of 511 subjects with genome-wide SNP data, the association between the MC1RR163Q variant and complicated sepsis remained significant after adjusting for genetic substructure (by principal components) and the above clinical factors (ORadj = 0.30, 95% CI: 0.13-0.70, P = 0.005). CONCLUSIONS: MC1RR163Q is associated with a lower risk of complicated sepsis after trauma. Therapeutic targeting of MC1R may be beneficial for trauma patients at risk for complicated sepsis. PMID- 27488086 TI - Is Selective Digestive Decontamination Useful for Critically Ill Patients? AB - In this study we review the rationale for using selective digestive decontamination (SDD) in critically ill patients, and its effects on clinical outcomes and rates of infection with antimicrobial-resistant microorganisms. SDD consists of the application of nonabsorbable antibiotics to the oropharynx and through a nasogastric or nasoenteral tube, in association with a 4-day course of an intravenous third-generation cephalosporin. The enteral component aims at preventing oral and rectal colonization with potentially pathogenic nosocomial aerobic gram-negative bacilli and yeasts while preserving normal protective anaerobic enteral flora. The short-course systemic component aims at eradicating oral endogenous gram-positive bacteria. SDD decreases the risk of nosocomial infections, and reduces by one-quarter the mortality of patients on mechanical ventilation in settings with low prevalence of antibiotic resistance. Evidence from randomized trials suggests that SDD does not increase rates of antimicrobial resistant microorganisms, and may reduce resistance rates to some antibiotics. However, several limitations decrease our confidence on these data, particularly for settings with high baseline rates of antimicrobial-resistant microorganisms. Although SDD has a clear potential to improve clinical outcomes of critically patients, its long-term ecologic effects on rates of antimicrobial resistant require appropriate assessment by large multinational cluster randomized trials. Before these results are available, the use of SDD cannot be recommended in most parts of the world, except in settings with very low baseline prevalence of antibiotic resistance. PMID- 27488085 TI - Retinoic Acid Improves Incidence and Severity of Necrotizing Enterocolitis by Lymphocyte Balance Restitution and Repopulation of LGR5+ Intestinal Stem Cells. AB - Necrotizing enterocolitis (NEC) is the most devastating gastrointestinal disease of the premature infant. We have recently shown that NEC development occurs after an increase in proinflammatory CD4Th17 (Th17) cells and reduced anti-inflammatory forkhead box P3 regulatory T cells (Tregs) to the premature small intestine of mice and humans, which can be experimentally reversed in mice by administration of all-trans retinoic acid (ATRA). We have also shown that NEC is characterized by apoptosis of Lgr5-positive intestinal stem cells (ISCs-Lgr5 cells) within the crypts of Lieberkuhn, which are subsequently essential for intestinal homeostasis. We now hypothesize that the normal lymphocyte balance within the lamina propria of the intestine can be achieved via administration of ATRA which restores mucosal integrity by preventing the loss of ISCs. Using both in vivo and in vitro strategies, we now demonstrate that Th17 recruitment and Treg depletion lead to increased apoptosis within ISC niches, significantly impairing proliferative capacity and mucosal healing. ATRA exerted its protective effects by preventing T cell imbalance, ultimately leading to the protection of the ISC pool preventing the development of NEC in mice. These findings raise the exciting possibility that dietary manipulations could prevent and treat NEC by modulating lymphocyte balance and the ISC pool within the newborn small intestine. PMID- 27488087 TI - Moderate Hypothermia Improves Cardiac and Vascular Function in a Pig Model of Ischemic Cardiogenic Shock Treated With Veno-Arterial ECMO. AB - Cardiogenic shock (CS) patients treated with extracorporeal membrane oxygenation (ECMO) have severe cardiac failure, associated with ischemia-reperfusion. The use of moderate hypothermia during ischemia-reperfusion syndrome is supported by experimental data. We therefore studied the effects of moderate hypothermia on cardiac and vascular function in pig ischemic CS treated with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). CS was induced in 12 anesthetized pigs by coronary ligation. After 1 h of CS, VA-ECMO was initiated and pigs were randomized to normothermia (38 degrees C) or moderate hypothermia (34 degrees C) during 8 h. Intrinsic cardiac function was measured using a left ventricular conductance catheter. At the end of the experiment, tissues were harvested for Western blotting. ECMO associated with norepinephrine infusion and volume resuscitation increased mean arterial pressure, mixed venous oxygen saturation as well as carotid, renal, and coronary blood flow without any differences between normothermia and hypothermia. Hypothermia was associated with less fluid and less norepinephrine infusion, lower lactate level, and higher urinary output. Vascular reactivity was superior in hypothermia comparatively to normothermia as expressed using norepinephrine dose-response curves. Pressure development during isovolumic contraction, left ventricular ejection fraction, and prerecruitable stroke work index were higher in the hypothermia group. There were no differences between normothermia and hypothermia with regard to carotid and mesenteric protein expression for iNOs, eNOS, and phospho AKt/AKt measured at the end of the experimentation. The incidence of surgical bleeding and coagulation disorders was the same in both groups. In conclusion, moderate and rapid hypothermia improves hemodynamics and cardiac and vascular function in a pig model of ischemic CS treated with ECMO. PMID- 27488089 TI - Augmented Passive Immunotherapy with P4 Peptide Improves Phagocyte Activity in Severe Sepsis. AB - INTRODUCTION: Antimicrobial resistance threatens to undermine treatment of severe infection; new therapeutic strategies are urgently needed. Preclinical work shows that augmented passive immunotherapy with P4 peptide increases phagocytic activity and shows promise as a novel therapeutic strategy. Our aim was to determine ex vivo P4 activity in a target population of patients admitted to critical care with severe infection. METHODS: We prospectively recruited UK critical care unit patients with severe sepsis and observed clinical course (>=3 months postdischarge). Blood samples were taken in early (<=48 h postdiagnosis, n = 54), latent (7 days postdiagnosis, n = 39), and convalescent (3-6 months postdiagnosis, n = 18) phases of disease. The primary outcome measure was killing of opsonized Streptococcus pneumoniae by neutrophils with and without P4 peptide stimulation. We also used a flow cytometric whole blood phagocytosis assay to determine phagocyte association and oxidation of intraphagosomal reporter beads. RESULTS: P4 peptide increased neutrophil killing of opsonized pneumococci by 8.6% (confidence interval 6.35-10.76, P < 0.001) in all phases of sepsis, independent of infection source and microbiological status. This represented a 54.9% increase in bacterial killing compared with unstimulated neutrophils (15.6%) in early phase samples. Similarly, P4 peptide treatment significantly increased neutrophil and monocyte intraphagosomal reporter bead association and oxidation, independent of infection source. CONCLUSIONS: We have extended preclinical work to demonstrate that P4 peptide significantly increases phagocytosis and bacterial killing in samples from a target patient population with severe sepsis. This study supports the rationale for augmented passive immunotherapy as a therapeutic strategy in severe sepsis. PMID- 27488090 TI - Aged Human Stored Red Blood Cell Supernatant Inhibits Macrophage Phagocytosis in an HMGB1 Dependent Manner After Trauma in a Murine Model. AB - Red blood cell transfusions in the setting of trauma are a double-edged sword, as it is a necessary component for life-sustaining treatment in massive hemorrhagic shock, but also associated with increased risk for nosocomial infections and immune suppression. The mechanisms surrounding this immune suppression are unclear. Using supernatant from human packed red blood cell (RBC), we demonstrate that clearance of Escherichia coli by macrophages is inhibited both in vitro and in vivo using a murine model of trauma and hemorrhagic shock. We further explore the mechanism of this inhibition by demonstrating that human-stored RBCs contain soluble high-mobility group box 1 protein (HMGB1) that increases throughout storage. HMGB1 derived from the supernatant of human-stored RBCs was shown to inhibit bacterial clearance, as neutralizing antibodies to HMGB1 restored the ability of macrophages to clear bacteria. These findings demonstrate that extracellular HMGB1 within stored RBCs could be one factor leading to immune suppression following transfusion in the trauma setting. PMID- 27488091 TI - Evidence of Netosis in Septic Shock-Induced Disseminated Intravascular Coagulation. AB - INTRODUCTION: Neutrophils extracellular traps (NETs) have recently emerged as a new potential link between inflammation, immunity, and thrombosis and could play a key role in septic shock-induced disseminated intravascular coagulation (DIC) pathogenesis. The objective of our study was to investigate a potential link between NETosis and septic shock-induced DIC. METHODS: Twenty patients with septic shock (10 without and 10 with DIC according to JAAM 2006 score) were prospectively included in our study. Vascular cell activation was assessed by microparticle (MP) measurement. NETosis was investigated at days 1, 3, and 7 using two different approaches: probing and measurement of neutrophil DNA decompaction by neutrophil-side fluorescence light (NEUT-SFL) as recorded by an automated blood cell cytometer and the assessment of nucleosomes and NETs (DNA bound myeloperoxidase, DNA-MPO). RESULTS: Endothelial-derived CD105-MPs, leucocyte-derived CD11a-MPs/leucocyte, and neutrophil-derived CD66b MPs/neutrophil count ratios significantly increased in DIC compared with non-DIC patients, indicating on-going cell activation (P <0.05). NEUT-SFL, indicating DNA decompaction, was significantly higher in DIC patients. Circulating nucleosomes and DNA-MPO were increased in DIC patients (P <0.05). There were significant correlations between: nucleosomes and NETs (r = 0.397, P = 0.004), NEUT-SFL and nucleosomes (r = 0.243, P = 0.032), NEUT-SFL and DNA-MPO (r = 0.266, P = 0.024). CONCLUSION: NEUT-SFL, NETs, and elevated nucleosome concentrations were all correlated to DIC (P <0.05). We have shown that NETosis is significantly correlated to septic shock-induced DIC. PMID- 27488092 TI - The Airway Microbiome at Birth. AB - Alterations of pulmonary microbiome have been recognized in multiple respiratory disorders. It is critically important to ascertain if an airway microbiome exists at birth and if so, whether it is associated with subsequent lung disease. We found an established diverse and similar airway microbiome at birth in both preterm and term infants, which was more diverse and different from that of older preterm infants with established chronic lung disease (bronchopulmonary dysplasia). Consistent temporal dysbiotic changes in the airway microbiome were seen from birth to the development of bronchopulmonary dysplasia in extremely preterm infants. Genus Lactobacillus was decreased at birth in infants with chorioamnionitis and in preterm infants who subsequently went on to develop lung disease. Our results, taken together with previous literature indicating a placental and amniotic fluid microbiome, suggest fetal acquisition of an airway microbiome. We speculate that the early airway microbiome may prime the developing pulmonary immune system, and dysbiosis in its development may set the stage for subsequent lung disease. PMID- 27488094 TI - Hepatocellular carcinoma developed in a living donor after left lobe donation: a case for caution. AB - Although it has been recognized that those who are positive for anti-hepatitis B core antibody (anti-HBcAb) and negative for hepatitis B surface antigen (HBsAg) with normal liver function could be donors for living donor liver transplantation under appropriate prophylaxis, the negative impact of positive HBcAb on such donors themselves has not been reported. We present a case of a living donor with positive HBcAb, who donated his left lobe for his sister with unresectable giant hepatic hemangioma, and the donor himself developed a de novo hepatocellular carcinoma (HCC) 10 years after donation. He had been lost from the follow-up program since 1 year after donation. Imaging studies showed a heterogeneously enhanced mass compatible with HCC, which was 9 cm in size with portal invasion into the anterior portal vein of the remnant liver. Re-laparotomy for hepatectomy with the removal of the tumor thrombus in the anterior portal vein of the remnant liver was carried out, and he is free from recurrence 6 months after surgery on prophylactic sorafenib. At our institute, 58 (9.6%) donors among the 603 living donors were anti-HBcAb positive and anti-HBsAg negative, and we started regular HCC surveillance using sonogram every 6 months for these patients. PMID- 27488093 TI - Predictive Immunohistochemical Markers Related to Drug Selection for Patients Treated with Sunitinib or Sorafenib for Metastatic Renal Cell Cancer. AB - Targeted drug decisions in metastatic renal cell carcinoma are exclusively made on the basis of clinical criteria. We investigated whether these biomarkers (HIF 1alpha, HIF-2alpha, CAIX, VEGF, VEGFR1, VEGFR2, VEGFR3, PDGFB, PDGFRA, PDGFRB, CD31, CD44, bcl-xL, KIT, p21, CXCR4, PTEN, (CSF)-1R, RET, and FLT-3) can predictive the different effects between sunitinib and sorafenib treatments and are available to guide targeted drug selection. We enrolled all patients who underwent nephrectomy with postoperative sunitinib- or sorafenib-treatment at our institution from 2007 to 2012. Immunohistochemical approach was applied to assess the potential differential effects of immunostainings between sunitinib- and sorafenib-treated groups. We found that patients with high HIF-2alpha, CD31 expression showed greater relative PFS and OS benefit and patients with high CAIX expression presented greater relative OS benefit from sunitinib than from sorafenib, patients with high VEGFR1 or PDGFRB expression levels exhibited worse relative PFS benefit from sunitinib than from sorafenib. Namely high HIF-2alpha, CD31, and CAIX expression levels along with low VEGFR1 and PDGFRB expression levels improved the benefit of sunitinib treatment compared with sorafenib treatment. These results can identify whether patients can benefit more from sunitinib or sorafenib for drug selection guidance, eventually with precision medicine. PMID- 27488095 TI - Papain-like cysteine proteases as hubs in plant immunity. AB - 902 I. 902 II. 903 III. 903 IV. 903 V. 905 VI. 905 VII. 905 906 References 906 SUMMARY: Plants deploy a sophisticated immune system to cope with different microbial pathogens and other invaders. Recent research provides an increasing body of evidence for papain-like cysteine proteases (PLCPs) being central hubs in plant immunity. PLCPs are required for full resistance of plants to various pathogens. At the same time, PLCPs are targeted by secreted pathogen effectors to suppress immune responses. Consequently, they are subject to a co-evolutionary host-pathogen arms race. When activated, PLCPs induce a broad spectrum of defense responses including plant cell death. While the important role of PLCPs in plant immunity has become more evident, it remains largely elusive how these enzymes are activated and which signaling pathways are triggered to orchestrate different downstream responses. PMID- 27488096 TI - Early silicification of leaves and roots of seedlings of a panicoid grass grown under different conditions: anatomical relations and structural role. AB - Grasses accumulate high amounts of silica deposits in tissues of all their organs, especially at mature stage. However, when and under which conditions do grass seedlings begin to produce these silica deposits and their relation with anatomy and development is little known. Here we investigated the silicification process in the first leaves and roots of seedlings of Bothriochloa laguroides grown in different substrate and Si treatments. The distribution and content of silica deposits in the organs of the seedlings grown under different conditions were analyzed through staining techniques and SEM-EDAX analyses. Leaf silica deposits were accumulated 3-4 days after the first leaf emergence, also under low silica solution (0.17-0.2 mM). Their location was mainly restricted to short costal cells from basal sectors, and scarcely in trichomes and xylem at tips. Silica content in leaves increased with the age of the seedlings. Roots presented dome-shaped silica aggregates, between 4-12 MUm of diameter, located in the inner tangential wall of endodermal cells and similar to those produced at maturity. Silicification begins early in the first photosynthetic leaf, and silica distribution is opposite to that found in mature plants, mainly restricted to basal sectors, probably acting as a reinforcing element. The fast incorporation of solid amorphous silica in leaves and roots, may be useful for farm applications in species that are Si-fertilized. PMID- 27488097 TI - Prioritizing individual genetic variants after kernel machine testing using variable selection. AB - Kernel machine learning methods, such as the SNP-set kernel association test (SKAT), have been widely used to test associations between traits and genetic polymorphisms. In contrast to traditional single-SNP analysis methods, these methods are designed to examine the joint effect of a set of related SNPs (such as a group of SNPs within a gene or a pathway) and are able to identify sets of SNPs that are associated with the trait of interest. However, as with many multi SNP testing approaches, kernel machine testing can draw conclusion only at the SNP-set level, and does not directly inform on which one(s) of the identified SNP set is actually driving the associations. A recently proposed procedure, KerNel Iterative Feature Extraction (KNIFE), provides a general framework for incorporating variable selection into kernel machine methods. In this article, we focus on quantitative traits and relatively common SNPs, and adapt the KNIFE procedure to genetic association studies and propose an approach to identify driver SNPs after the application of SKAT to gene set analysis. Our approach accommodates several kernels that are widely used in SNP analysis, such as the linear kernel and the Identity by State (IBS) kernel. The proposed approach provides practically useful utilities to prioritize SNPs, and fills the gap between SNP set analysis and biological functional studies. Both simulation studies and real data application are used to demonstrate the proposed approach. PMID- 27488099 TI - Is IGF-1 a key player in the pathogenesis of acromegaly-associated cutis verticis gyrata? PMID- 27488098 TI - Urinary excretion of Citrus flavanones and their major catabolites after consumption of fresh oranges and pasteurized orange juice: A randomized cross over study. AB - SCOPE: Orange juice contains flavanones including hesperidin and narirutin, albeit at lower concentrations as compared to orange fruit. Therefore, we compared bioavailability and colonic catabolism of flavanones from orange juice to a 2.4-fold higher dose from fresh oranges. METHODS AND RESULTS: Following a randomized two-way cross-over design, 12 healthy subjects consumed a test meal comprising either fresh oranges or pasteurized orange juice, delivering 1774 and 751 MUmol of total Citrus flavanones, respectively. Deglucuronidated and desulfated hesperetin, naringenin, and the flavanone catabolites 3-(3'-hydroxy-4' methoxyphenyl)propionic acid, 3-(3'-hydroxyphenyl)hydracrylic acid, 4 hydroxyhippuric acid, and hippuric acid were quantitated in 24-h urine by UHPLC MS/MS. Differences in urinary hesperetin excretion were found to be nonsignificant (p = 0.5209) both after consumption of orange fruit (21.6 +/- 8.0 MUmol) and juice (18.3 +/- 7.2 MUmol). By analogy, postprandial flavanone catabolite excretions were highly similar between treatments. Excretion of 3-(3' hydroxy-4'-methoxyphenyl)propionic acid was inversely related to that of hesperetin, illustrating the catabolite/precursor relationship. CONCLUSION: Despite 2.4-fold higher doses, excretion of flavanones from ingested fresh orange fruit did not differ from that following orange juice consumption, possibly due to a saturation of absorption or their entrapment in the fiber-rich matrix of the fruit. PMID- 27488100 TI - Knowledge and beliefs of young people about medicines in the UK. AB - OBJECTIVES: To investigate knowledge and beliefs regarding medicines among young people in the South-East of England. METHODS: A cross-sectional survey was conducted among young people aged 12-17 years in three state secondary schools which participated in the Pharmacy and Biomedical Sciences Outreach Program (POP) - scientific workshops in south-east England. KEY FINDINGS: One hundred questionnaires were successfully completed giving a response rate of 75%. The median knowledge score was 62.3% (+/-19.8). Increase in knowledge of medicines was positively associated with increase in age and with a positive belief about medicines. One of the questions answered that scored less than 50% was concerning the use of antibiotics. CONCLUSIONS: Knowledge of medicines appeared to be adequate among young people and was higher with a positive belief about medicines. However, there was variability in how well different questions were answered suggesting inclusion in the school curriculum would be beneficial in order to reduce the misinformation that was apparent, particularly regarding the potential non-adherence to antibiotics. PMID- 27488101 TI - Osteoarthritis is associated with symptoms of common mental disorders among former elite athletes. AB - PURPOSE: The primary aim was to establish the association between osteoarthritis (OA) and the occurrence and comorbidity of symptoms of common mental disorders (CMD: distress, anxiety/depression, sleep disturbance, adverse alcohol use) in a group of former elite athletes (rugby, football, ice hockey, Gaelic sports and cricket). A secondary aim was to explore this association in the subgroups of sports. METHODS: Cross-sectional analysis was performed on the baseline questionnaires from five prospective cohort studies conducted between April 2014 and January 2016 in former elite athletes of rugby, football, ice hockey, Gaelic sports and cricket. The presence of OA (diagnosed by a medical professional) was examined with a single question, and symptoms of CMD were evaluated through multiple validated questionnaires (4DSQ, GHQ-12, PROMIS, AUDIT-C). RESULTS: There was a significant association between OA and symptoms of distress (OR 1.7, 95 % CI 1.2-2.6), sleep disturbance (OR 1.6, 95 % CI 1.1-2.3), adverse alcohol use (OR 1.8, 95 % CI 1.2-2.6) and a comorbidity of symptoms of CMD (OR 1.5, 95 % CI 1.0 2.1) in former elite athletes. CONCLUSION: OA might be a risk factor for developing symptoms of CMD in former elite athletes. The clinical relevance of this study is that an interdisciplinary approach to the clinical care and support of former elite athletes after their careers is advocated as the interaction between the physical and mental health issues occurring on the long term is complex. Monitoring OA among former elite athletes should be empowered while strategies to prevent symptoms worsening should be developed and implemented. The self-awareness, prevention and care of mental health problems that might occur after a professional sports career should also be addressed. LEVEL OF EVIDENCE: Level III. PMID- 27488103 TI - Theoretical study of coupling p-aminothiophenol to hydroazo- and azo-adducts on Au(111). AB - Aminothiophenol/Au(111) has been adopted as an exemplary model in plasmonics research, including surface-enhanced Raman spectroscopy, due to its high plasmonic-induced spectral-signal enhancement. The present work was aimed at clarifying whether aminothiophenol on Au(111) is chemically stable in the absence of any photo- and plasmonic-induced effects. Briefly, first-principles calculations were employed to track the detailed mechanism of oxidative coupling of p-aminothiophenol (PATP) to its azo-adduct with an N = N bond, i.e., p,p' dimercaptoazobenzene (DMAB). Our results show the following: first, in the presence of adsorbed O2, PATP fractures its N-H bond and transfers the hydrogen to a nearby oxygen. This pathway is more favorable than the transfer of H to Au, but the activation barrier of 0.9 eV is still too high for the reaction to occur in the absence of thermal-, photo-, or plasmonic-activation. If this bar can be lifted, two such dehydrogenated PATP can couple themselves to form an adduct with a N-N bond, i.e., p,p'-dimercaptohydroazobenzene (DMHAB), and this reaction is exoergic with an energy barrier of 0.57 eV. Again, this step is slow in the absence of moderate thermal activation or photo-/plasmonic-activation. Finally, dehydrogenation of DMHAB gives the azo-adduct of DMAB, and this reaction is spontaneous, with no energy barrier. PMID- 27488102 TI - Molecular cloning and in silico characterization of knottin peptide, U2-SCRTX Lit2, from brown spider (Loxosceles intermedia) venom glands. AB - Inhibitor cystine knots (ICKs) are a family of structural peptides with a large number of cysteine residues that form intramolecular disulfide bonds, resulting in a knot. These peptides are involved in a variety of biological functions including predation and defense, and are found in various species, such as spiders, scorpions, sea anemones, and plants. The Loxosceles intermedia venom gland transcriptome identified five groups of ICK peptides that represent more than 50 % of toxin-coding transcripts. Here, we describe the molecular cloning of U2-Sicaritoxin-Lit2 (U2-SCRTX-Lit2), bioinformatic characterization, structure prediction, and molecular dynamic analysis. The sequence of U2-SCRTX-Lit2 obtained from the transcriptome is similar to that of MU-Hexatoxin-Mg2, a peptide that inhibits the insect Nav channel. Bioinformatic analysis of sequences classified as ICK family members also showed a conservation of cysteine residues among ICKs from different spiders, with the three dimensional molecular model of U2-SCRTX-Lit2 similar in structure to the hexatoxin from MU-hexatoxin-Mg2a. Molecular docking experiments showed the interaction of U2-SCRTX-Lit2 to its predictable target-the Spodoptera litura voltage-gated sodium channel (SlNaVSC). After 200 ns of molecular dynamic simulation, the final structure of the complex showed stability in agreement with the experimental data. The above analysis corroborates the existence of a peptide toxin with insecticidal activity from a novel ICK family in L. intermedia venom and demonstrates that this peptide targets Nav channels. PMID- 27488104 TI - Effect of electric charging on the velocity of water flow in CNT. AB - The role of electrical charge in controlling the velocity of water molecules in a finite single-walled carbon nanotube (CNT) was studied in detail using molecular dynamics simulation. Different test cases were examined to determine the parameters affecting the control of water-flow velocity in CNT upon electrically charging the surface of a CNT. The results showed that charge magnitude and volume, as well as the charging scenario, are the parameters having greatest effect. The implementation of electric charge on the surface of a CNT was demonstrated to decrease the resistance of CNT to incoming water flow at the entrance, but to increase friction-type resistance to flow along the CNT. Therefore, through controlling the magnitude of electric charge, water flow through the CNT may be accelerated, or decelerated. The results show that the velocity of molecular flow in the CNT increases to a maximum value, and then decreases with electric charge regardless of its sign. In the case studied here, this maximum velocity occurs at electric charging of +/-0.25e/atom. It was also shown that, to reach similar flow velocities in a CNT, it is not sufficient to merely implement equal volumes of electric charge, where the volume of electric charging is defined as charge magnitude * charging time. In fact , both magnitude of charging and volume of electric charging must be equal to each other. These findings, together with options to implement scenarios with alternative charging, provide the means to effectively adjust desired velocities in a CNT. PMID- 27488106 TI - 54th ISCEV Symposium. PMID- 27488105 TI - Changes in miR-221/222 Levels in Invasive and In Situ Carcinomas of the Breast: Differences in Association with Estrogen Receptor and TIMP3 Expression Levels. AB - BACKGROUND: Breast cancer (BC) is a heterogeneous group of diseases that still represents a major cause of death in the female population. MicroRNAs (miRNAs, miRs), such as miR-221 and miR-222, have been shown to be involved in BC pathology by acting via its target genes such as tissue inhibitor of metalloproteinase 3 (TIMP3). OBJECTIVES: The main goals of this study were to find differences in miR-221/222 levels of expression in BC groups based on invasiveness, and to investigate the association with estrogen receptor (ER), TIMP3 messenger RNA (mRNA) levels, and clinicopathological characteristics of patients and tumors. METHODS: In this study, we measured levels of miR-221/222 in 63 breast tissue samples by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) using TaqMan(r) technology and immunohistochemistry. RESULTS: miR-221/222 levels varied significantly across groups based on invasiveness (P < 0.001). In in situ tumors, miR-221 and miR-222 were negatively associated with ER (P = 0.001, r = -0.714, and P = 0.013, r = -0.585, respectively). In invasive breast carcinomas associated with non-invasive tumors, miR-222 was inversely associated with ER (P = 0.039, r = -0.620). Pure invasive BCs showed a positive correlation of miR-221 and miR-222 with TIMP3 mRNA levels (P = 0.008, r = 0.508, and P = 0.010, r = 0.497, respectively). CONCLUSION: An increase in miR-221/222 might be an important event for in situ carcinoma formation, and miR-221/222 may be important molecules that highlight potential differences between invasive breast carcinomas associated with non-invasive and pure invasive BCs. PMID- 27488107 TI - Roles of mitophagy in cellular physiology and development. AB - The autophagic degradation of mitochondria, or mitophagy, has been shown to occur in eukaryotic cells under various physiological conditions. Broadly, these fall into two categories: quality-control related mitophagy and developmentally induced mitophagy. Quality-control related mitophagy, which is the lysosomal/vacuolar degradation of malfunctioning or superfluous mitochondria, is an important housekeeping function in respiring eukaryotic cells. It plays an essential role in physiological homeostasis and its deregulation has been linked to the progression of late-onset diseases. On the other hand, developmental processes such as reticulocyte maturation have also been shown to involve mitophagy. Importantly, there are clear differences between these processes. Unlike our knowledge of the more general degradation of soluble cytosolic content during starvation-induced macroautophagy, the mechanisms involved in the selective autophagic degradation of mitochondria have only recently begun to receive significant attention. Here, we review the current literature on these topics and proceed to provide specific examples from yeast and mammalian systems. Finally, we cover experimental approaches, with a focus on proteomic methods dedicated to the study of mitophagy in different systems. PMID- 27488108 TI - [Ponseti method for treatment of idiopathic clubfoot]. AB - OBJECTIVE: Pain-free, plantigrade, functional foot through gentle manipulation without extended surgery and with decreased probability of relapse. INDICATIONS: Idiopathic clubfoot; neurogenic and secondary clubfeet. CONTRAINDICATIONS: None. SURGICAL TECHNIQUE: Simultaneous correction of all components of the clubfoot. Mainly conservative, with serial casts. Slight supination to address the cavus and increasing abduction to align the midfoot bones while putting counter pressure on the head of the talus. Surgery primarily only to correct the equinus, which can often not be accomplished through casting, and consists of a simple subcutaneous section. Due to tendency to relapse, further surgery might be necessary, followed by serial casting. Remaining deformity can be treated by percutaneous lengthening of the Achilles tendon, percutaneous release of the plantar fascia or a transfer of the tibialis anterior tendon to the third cuneiform. POSTOPERATIVE MANAGEMENT: Abduction orthosis for stabilization of the clinical result 24 h/day for 3 months, then only at night- and naptime through end of the third year of life. Follow-up every 3-4 months. PMID- 27488109 TI - DNA damage after chronic oxytocin administration in rats: a safety yellow light? AB - Adjuvant therapy is a common therapeutic strategy used for schizophrenia management. Oxytocin has shown promising results as antipsychotic adjuvant in patients with schizophrenia. Although short-term clinical studies have indicated tolerability and no major side-effect manifestation, long-term studies remain needed. In this study, we investigated whether oxytocin chronic administration in rats may lead to brain DNA damage by comet assay. Our results suggest that 21 and 56-day treatment with once daily intraperitoneal oxytocin (0.1, 1.0 and 10.0 mg/kg) may cause substantial DNA damage in hippocampus. We have not found differences on body weight gain. Our findings also point that further clinical and preclinical studies evaluating oxytocin safety after chronic exposure are necessary. PMID- 27488111 TI - Neuroprotective effect of Cucumis melo Var. flexuosus leaf extract on the brains of rats with streptozotocin-induced diabetes. AB - The central nervous system is one of the most vulnerable organs affected by the oxidative stress associated with diabetes mellitus. Healthy food provides an important source for antioxidants. Therefore, the protective effect of Cucumis melo var. flexuosus (C. melo var. flexuosus) leaf extract on the brains of diabetic rats was investigated. Adult male albino rats divided into 5 groups of 6 rats each were assigned into a normal control group and four diabetic groups. Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (STZ; 60 mg/kg bw). One of the four diabetic groups was left untreated and was considered as a diabetic control group while the three other groups were treated with C. melo var. flexuosus leaf extract at the doses of 30, 60 and 120 mg/kg bw for a period of 30 days. After completion of experimental duration plasma and brains were used for evaluating biochemical changes. The obtained data showed that C. melo var. flexuosus leaf extract treatment lowered blood glucose, glycated hemoglobin, brain tumor necrosis factor-alpha, interleukin levels, brain malondialdehyde content and caspase-3 activity. Furthermore, the treatment resulted in a marked increase in plasma dopamine, melatonin, brain vascular endothelial growth factor-A levels, brain catalase and superoxide dismutase activities. From the present study, it can be concluded that the C. melo var. flexuosus leaf extract exerts a neuroprotective effect against oxidative damage associated with diabetes. PMID- 27488110 TI - SB203580 reverses memory deficits and depression-like behavior induced by microinjection of Abeta1-42 into hippocampus of mice. AB - A high co-morbidity between Alzheimer's disease (AD) and depression suggests there might be similar mechanisms underlying the course of these diseases. Previous studies have shown that p38MAPK plays a critical role in the pathophysiology of AD and depression. However, little is known about whether SB203580, a selective inhibitor of p38MAPK, may protect against AD-associated cognitive impairments and depression-like behavior, simultaneously. Herein, we have shown, for the first time, that SB203580 may reverse memory impairments and depression-like behavior induced by hippocampal infusion of beta-amyloid 1-42 (Abeta1-42), as measured by novel object recognition, Morris water maze, tail suspension and forced-swimming tests. In addition, phorbol 12-myristate 13 acetate (PMA), a PKC activator which also activates p38MAPK, significantly abolished the effects of SB203580. Moreover, Abeta1-42 causes increased phosphorylation of p38MAPK and decreased phosphorylation of Ser9-glycogen synthase kinase 3beta (GSK3beta) and cAMP-response element binding protein (CREB) in the hippocampus of mice, which could be significantly reversed by SB203580. Our results suggest that SB203580 reversed Abeta1-42-induced cognitive impairments and depression-like behavior via inhibiting p38MAPK signaling pathway, which not only supports p38MAPK as a therapeutic target for AD associated cognitive dysfunction and depression-like behavior, but also provides experimental basis for the use of SB203580 in co-morbidity of AD and depression. PMID- 27488112 TI - A longitudinal study of patients with cirrhosis treated with L-ornithine L aspartate, examined with magnetization transfer, diffusion-weighted imaging and magnetic resonance spectroscopy. AB - The presence of overt hepatic encephalopathy (HE) is associated with structural, metabolic and functional changes in the brain discernible by use of a variety of magnetic resonance (MR) techniques. The changes in patients with minimal HE are less well documented. Twenty-two patients with well-compensated cirrhosis, seven of whom had minimal HE, were examined with cerebral 3 Tesla MR techniques, including T1- and T2-weighted, magnetization transfer and diffusion-weighted imaging and proton magnetic resonance spectroscopy sequences. Studies were repeated after a 4-week course of oral L-ornithine L-aspartate (LOLA). Results were compared with data obtained from 22 aged-matched healthy controls. There was no difference in mean total brain volume between patients and controls at baseline. Mean cerebral magnetization transfer ratios were significantly reduced in the globus pallidus and thalamus in the patients with cirrhosis irrespective of neuropsychiatric status; the mean ratio was significantly reduced in the frontal white matter in patients with minimal HE compared with healthy controls but not when compared with their unimpaired counterparts. There were no significant differences in either the median apparent diffusion coefficients or the mean fractional anisotropy, calculated from the diffusion-weighted imaging, or in the mean basal ganglia metabolite ratios between patients and controls. Psychometric performance improved in 50 % of patients with minimal HE following LOLA, but no significant changes were observed in brain volumes, cerebral magnetization transfer ratios, the diffusion weighted imaging variables or the cerebral metabolite ratios. MR variables, as applied in this study, do not identify patients with minimal HE, nor do they reflect changes in psychometric performance following LOLA. PMID- 27488113 TI - Postoperative Bleeding and Leakage after Sleeve Gastrectomy: a Single-Center Experience. PMID- 27488115 TI - Cytosolic Ku70 regulates Bax-mediated cell death. AB - The first known function of Ku70 is as a DNA repair factor in the nucleus. Using neuronal neuroblastoma cells as a model, we have established that cytosolic Ku70 binds to the pro-apoptotic protein Bax in the cytosol and blocks Bax's cell death activity. Ku70-Bax binding is regulated by Ku70 acetylation in that when Ku70 is acetylated Bax dissociates from Ku70, triggering cell death. We propose that Ku70 may act as a survival factor in these cells such that Ku70 depletion triggers Bax dependent cell death. Here, we addressed two fundamental questions about this model: (1) Does all Bax, which is a cytosolic protein, bind to all cytosolic Ku70? and (2) Is Ku70 a survival factor in cells types other than neuronal neuroblastoma cells? We show here that, in neuronal neuroblastoma cells, only a small fraction of Ku70 binds to a small fraction of Bax; most Bax is monomeric. Interestingly, there is no free or monomeric Ku70 in the cytosol; most cytosolic Ku70 is in complex with other factors forming several high molecular weight complexes. A fraction of cytosolic Ku70 also binds to cytosolic Ku80, Ku70's binding partner in the nucleus. Ku70 may not be a survival factor in some cell types (Ku70-depletion less sensitive) because Ku70 depletion does not affect survival of these cells. These results indicate that, in addition to Ku70 acetylation, other factors may be involved in regulating Ku70-Bax binding in the Ku70-depletion less sensitive cells because Ku70 acetylation in these cells is not sufficient to dissociate Bax from Ku70 or to activate Bax. PMID- 27488114 TI - Pregnancy Following Bariatric Surgery-Medical Complications and Management. AB - Bariatric surgery is most commonly carried out in women of childbearing age. Whilst fertility rates are improved, pregnancy following bariatric surgery poses several challenges. Whilst rates of many adverse maternal and foetal outcomes in obese women are reduced after bariatric surgery, pregnancy is best avoided for 12 24 months to reduce the potential risk of intrauterine growth retardation. Dumping syndromes are common after bariatric surgery and can present diagnostic and therapeutic challenges in pregnancy. Early dumping occurs due to osmotic fluid shifts resulting from rapid gastrointestinal food transit, whilst late dumping is characterized by a hyperinsulinemic response to rapid absorption of simple carbohydrates. Dietary measures are the mainstay of management of dumping syndromes but pharmacotherapy may sometimes become necessary. Acarbose is the least hazardous pharmacological option for the management of postprandial hypoglycemia in pregnancy. Nutrient deficiencies may vary depending on the type of surgery; it is important to optimize the nutritional status of women prior to and during pregnancy. Dietary management should include adequate protein and calorie intake and supplementation of vitamins and micronutrients. A high clinical index of suspicion is required for early diagnosis of surgical complications of prior weight loss procedures during pregnancy, including small bowel obstruction, internal hernias, gastric band erosion or migration and cholelithiasis. PMID- 27488116 TI - Proteomic analysis of differentially expressed proteins in vitreous humor of patients with retinoblastoma using iTRAQ-coupled ESI-MS/MS approach. AB - There is close proximity of vitreous humor with the tumor bulk in eyes with retinoblastoma. This renders vitreous humor a promising source to evaluate disease-specific protein targets in retinoblastoma. We studied the differential proteome of vitreous fluid in retinoblastoma tumors (n = 4) as compared to controls (n = 4). The vitreous humor was depleted off the high abundant fraction using MARS-6 affinity column. Subsequently, the tryptic peptides were derivatised with iTRAQ labels. The labelled peptides were pooled and subjected to fractionation using bRPLC. This was followed by protein identification and quantification using electrospray ionisation mass spectrometry (ESI-MS/MS) approach. The identified proteins were subjected to bioinformatics analysis utilizing PANTHER 7.0 and IPA software. Four hundred and thirty-one non-redundant (362 upregulated and 69 downregulated) proteins (>=2 unique peptides, +/- 1.5 folds, p < 0.05) were identified. The majority of the proteins were cytoplasmic (40 %), majorly involved in catalytic (32.7 %) and binding activities (26.3 %). Highly deregulated proteins included MMP2, TNC, CD44, SUZ12 and CRABP1. The protein expression of GFAP, CRABP1, MMP2 and TNC was validated by western blotting. Pathway and network analyses revealed p38MAPK and Akt signalling to be the most significantly regulated pathways in retinoblastoma. This is the first report of differential vitreous proteome of retinoblastoma and highlights novel protein targets, such as MMP2, TNC and CRABP1. Further investigations into unravelling the biological role of the proteins and their prospects of being utilised as potential candidates in therapeutics are warranted. PMID- 27488117 TI - IQGAP1 gene silencing induces apoptosis and decreases the invasive capacity of human hepatocellular carcinoma cells. AB - IQ motif-containing GTPase-activating proteins (IQGAPs) belong to a conserved family, and they are involved in various intracellular processes. IQGAP1 is expressed in all cells, while IQGAP2 and IQGAP3 are mainly expressed in hepatic cells. IQGAP1 has been suggested to be an oncogene, while IQGAP2 is considered a tumor-suppressor gene. However, the relationship between RAS family genes and IQGAP genes remains unclear. We recently demonstrated this interaction in a chemically induced mouse liver cancer. In this study, IQGAP1 expression was partially silenced in human hepatocellular carcinoma (HepG2) cells. We investigated the impact of IQGAP1 silencing on the interactions of IQGAP and RAS with several apoptotic proteins, including caspase-3 (CASP3), BCL2-associated X protein (BAX), and B-cell leukemia/lymphoma 2 (BCL2). Additionally, we investigated the effects of the interactions of these genes on cell viability, proliferation, apoptosis, and invasive capacity. IQGAP1 siRNA-treated HepG2 cells showed lower invasive capacity than the control cells, and this reduction was time- and vector concentration-dependent. In addition, IQGAP1 silencing resulted in significantly lower IQGAP1 level and subsequently higher IQGAP2 and IQGAP3 expression in HepG2 cells than in the control. Flow cytometry analyses indicated that the silencing of IQGAP1 can induce early and late apoptosis in HepG2 cells. Additionally, IQGAP2, IQGAP3, CASP3, and BAX were upregulated whereas IQGAP1 and BCL2 were downregulated in the siRNA-treated cells. Furthermore, we observed that the mRNA levels of HRAS, KRAS, NRAS, and MRAS decreased upon IQGAP1 silencing. These findings indicate that IQGAP1 potentially regulates the expression of IQGAP and RAS gene families and demonstrate its regulatory role in the apoptotic network. Taken together, our findings suggest that IQGAP1 silencing plays crucial roles in the apoptosis of HepG2 cells and lowers their proliferative and invasive capacities. PMID- 27488118 TI - Selvester QRS score and total perfusion deficit calculated by quantitative gated single-photon emission computed tomography in patients with prior anterior myocardial infarction in the coronary intervention era. AB - Selvester QRS scoring system has an advantage of being inexpensive and easily accessible for estimating myocardial infarct (MI) size. We assessed the correlation and agreement between QRS score and total perfusion deficit (TPD) calculated by quantitative gated single-photon emission computed tomography (QGS) in patients with prior anterior MI undergoing coronary intervention. Sixty-six patients with prior anterior MI and 66 age- and sex-matched control subjects were enrolled. QRS score was obtained using a 50-criteria and 31-point system. QRS score was significantly higher in patients with prior anterior MI than control subjects (12.8 +/- 8.9 vs 1.1 +/- 2.7 %, p < 0.001). In overall patients (n = 132), QRS score was correlated well with TPD (r = 0.81, p < 0.001). This good correlation was found even in patients with TPD <=40 % (n = 126) or in patients with TPD <=30 % (n = 117). In overall patients, MI size estimated by QRS score was 7.0 +/- 8.8 %, which was significantly smaller than TPD, 11.4 +/- 14.0 % (p < 0.001). Bland-Altman plot showed that there was an increasing difference between QRS score and TPD with increasing MI size. When Blant-Altman plots were applied to patients with TPD <=40 % and further in patients with TPD <=30 %, the difference between QRS score and TPD became smaller, and the agreement became better. In overall patients, QRS score was correlated well with QGS measurements, such as end-diastolic volume (r = 0.62, p < 0.001), end-systolic volume (r = 0.67, p < 0.001), or ejection fraction (r = -0.73, p < 0.001). Our results suggest that QRS score reflects TPD well in patients with prior anterior MI, whose TPD is less than approximately 30 % even in the coronary intervention era. PMID- 27488119 TI - Microparticles in patients undergoing transcatheter aortic valve implantation (TAVI). AB - Degenerative aortic stenosis (AS) is the most frequent form of acquired valvular heart disease. AS is known to entail endothelial dysfunction caused by increased mechanical shear stress leading to elevated circulatory levels of microparticles. Endothelial and platelet microparticles (EMP and PMP) are small vesicles that originate from activated cells and thrombocytes. We sought to evaluate whether transcatheter aortic valve implantation (TAVI) procedure would elicit effects on circulating EMP and PMP. 92 patients undergoing TAVI procedure for severe AS were included in this study. Samples were obtained at each visit before TAVI, 1 week post-procedure and at 1, 3 and after 6 months after TAVI and were evaluated using flow cytometry. A 12 month clinical follow-up was also performed. CD62E+ EMP concentration before TAVI was 21.11 % (+/-6.6 % SD) and declined to 20.99 % (+/ 6.8 % SD) after 1 week, to 16.63 % (+/-5.4 % SD, p < 0.0001) after 1 month, to 17.08 % (+/-4.6 % SD, p < 0.0001) after 3 months and to 15.94 % (+/-5.4 % SD, p < 0.0001) after 6 months. CD31+/CD42b-, CD31+/Annexin+/- EMP remained unchanged. CD31+/CD41b+ PMP evidenced a slight, but statistically significant increase after TAVI and remained elevated during the entire follow-up. Apart from a procedure related improvement in echocardiographic parameters, TAVI procedure led also to a decline in CD62E+ EMP. The reduction in pressure gradients with less hemodynamic shear stress seems also to have beneficially affected endothelial homeostasis. PMID- 27488120 TI - Acute and Chronic Complications in Patients with Ductal Carcinoma in Situ Treated with Intraoperative Radiation Therapy. AB - Intraoperative radiation therapy (IORT) delivers radiation therapy directly to the tumor bed at the time of surgery. Minimal data are available regarding IORT complications in patients diagnosed with ductal carcinoma in situ (DCIS) using the Xoft(r) Axxent eBx(r) System. 146 patients with pure DCIS received X-ray based IORT therapy using the Xoft(r) Axxent eBx(r) System at Hoag Memorial Hospital Presbyterian between June 2010 to April 2016 and were accrued to an IORT data registry study. The protocols were approved by the institutional review board and met the guidelines of their responsible governmental agency. Data were collected at 1 week, 1 month, 6 months, 1 year, and thereafter yearly. Acute complications were defined as those occurring within the first month. Chronic complications were those that persisted beyond 6 months. Acute complications were observed in 18% of patients and included hematomas that required drainage, an infection treated with antibiotics, and erythema. Chronic complications were observed in 12% of patients and included a seroma, fibrosis and hyperpigmentation. The majority of acute and chronic problems were mild (Grade I). If Grade I erythema, fibrosis, and hyperpigmentation are not included, only 11/146 patients (7.5%) had significant complications. The rate of acute and chronic complications from X-ray IORT in DCIS patients was low compared to historical toxicity rates observed in DCIS patients treated with whole breast irradiation. Our data indicate that X-ray IORT can be utilized safely in patients diagnosed with DCIS. PMID- 27488121 TI - Resveratrol primes the effects of physical activity in old mice. AB - Decrease in muscle mass and performance with ageing is one of the main factors of frailty in the elderly. Maintenance of muscle performance by involving in physical activities is essential to increase independence and quality of life among elderly. The use of natural compounds with ergogenic activity in old people would increase the effect of moderate exercises in the maintenance of physiological muscle capacity. Resveratrol (RSV), a polyphenol found in walnuts, berries and grapes, shows this ergogenic activity. By using young, mature and old mice as models, we have found that RSV improves muscle performance in mature and old animals but not in young animals. Without showing significant effect by itself, RSV primed the effect of exercise by increasing endurance, coordination and strength in old animals. This effect was accompanied by a higher protection against oxidative damage and an increase in mitochondrial mass. RSV increased catalase and superoxide dismutase protein levels in muscle and primed exercise to reverse the decrease in their activities during ageing. Furthermore, RSV increased the level of mitochondrial mass markers such as cytochrome C, mitochondrial transcription factor A and nuclear respiratory factor-1 in muscle in exercised animals. Our results indicate that RSV can be considered an ergogenic compound that helps maintain muscle performance during ageing and subsequently reduces frailty and increases muscle performance in old individuals practising moderate exercise. PMID- 27488122 TI - The circadian clock regulates inflammatory arthritis. AB - There is strong diurnal variation in the symptoms and severity of chronic inflammatory diseases, such as rheumatoid arthritis. In addition, disruption of the circadian clock is an aggravating factor associated with a range of human inflammatory diseases. To investigate mechanistic links between the biological clock and pathways underlying inflammatory arthritis, mice were administered collagen (or saline as a control) to induce arthritis. The treatment provoked an inflammatory response within the limbs, which showed robust daily variation in paw swelling and inflammatory cytokine expression. Inflammatory markers were significantly repressed during the dark phase. Further work demonstrated an active molecular clock within the inflamed limbs and highlighted the resident inflammatory cells, fibroblast-like synoviocytes (FLSs), as a potential source of the rhythmic inflammatory signal. Exposure of mice to constant light disrupted the clock in peripheral tissues, causing loss of the nighttime repression of local inflammation. Finally, the results show that the core clock proteins cryptochrome (CRY) 1 and 2 repressed inflammation within the FLSs, and provide novel evidence that a CRY activator has anti-inflammatory properties in human cells. We conclude that under chronic inflammatory conditions, the clock actively represses inflammatory pathways during the dark phase. This interaction has exciting potential as a therapeutic avenue for treatment of inflammatory disease. Hand, L. E., Hopwood, T. W., Dickson, S. H., Walker, A. L., Loudon, A. S. I., Ray, D. W., Bechtold, D. A., Gibbs, J. E. The circadian clock regulates inflammatory arthritis. PMID- 27488124 TI - Interventions to improve hospital patient satisfaction with healthcare providers and systems: a systematic review. AB - BACKGROUND: Many hospital systems seek to improve patient satisfaction as assessed by the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys. A systematic review of the current experimental evidence could inform these efforts and does not yet exist. METHODS: We conducted a systematic review of the literature by searching electronic databases, including MEDLINE and EMBASE, the six databases of the Cochrane Library and grey literature databases. We included studies involving hospital patients with interventions targeting at least 1 of the 11 HCAHPS domains, and that met our quality filter score on the 27 item Downs and Black coding scale. We calculated post hoc power when appropriate. RESULTS: A total of 59 studies met inclusion criteria, out of these 44 did not meet the quality filter of 50% (average quality rating 27.8%+/-10.9%). Of the 15 studies that met the quality filter (average quality rating 67.3%+/-10.7%), 8 targeted the Communication with Doctors HCAHPS domain, 6 targeted Overall Hospital Rating, 5 targeted Communication with Nurses, 5 targeted Pain Management, 5 targeted Communication about Medicines, 5 targeted Recommend the Hospital, 3 targeted Quietness of the Hospital Environment, 3 targeted Cleanliness of the Hospital Environment and 3 targeted Discharge Information. Significant HCAHPS improvements were reported by eight interventions, but their generalisability may be limited by narrowly focused patient populations, heterogeneity of approach and other methodological concerns. CONCLUSIONS: Although there are a few studies that show some improvement in HCAHPS score through various interventions, we conclude that more rigorous research is needed to identify effective and generalisable interventions to improve patient satisfaction. PMID- 27488123 TI - Motor neuron mitochondrial dysfunction in spinal muscular atrophy. AB - Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, predominantly affects high metabolic tissues including motor neurons, skeletal muscles and the heart. Although the genetic cause of SMA has been identified, mechanisms underlying tissue-specific vulnerability are not well understood. To study these mechanisms, we carried out a deep sequencing analysis of the transcriptome of spinal motor neurons in an SMA mouse model, in which we unexpectedly found changes in many genes associated with mitochondrial bioenergetics. Importantly, functional measurement of mitochondrial activities showed decreased basal and maximal mitochondrial respiration in motor neurons from SMA mice. Using a reduction-oxidation sensitive GFP and fluorescence sensors specifically targeted to mitochondria, we found increased oxidative stress level and impaired mitochondrial membrane potential in motor neurons affected by SMA. In addition, mitochondrial mobility was impaired in SMA disease conditions, with decreased retrograde transport but no effect on anterograde transport. We also found significantly increased fragmentation of the mitochondrial network in primary motor neurons from SMA mice, with no change in mitochondria density. Electron microscopy study of SMA mouse spinal cord revealed mitochondria fragmentation, edema and concentric lamellar inclusions in motor neurons affected by the disease. Intriguingly, these functional and structural deficiencies in the SMA mouse model occur during the presymptomatic stage of disease, suggesting a role in initiating SMA. Altogether, our findings reveal a critical role for mitochondrial defects in SMA pathogenesis and suggest a novel target for improving tissue health in the disease. PMID- 27488125 TI - Tavaborole, Efinaconazole, and Luliconazole: Three New Antimycotic Agents for the Treatment of Dermatophytic Fungi. AB - Fungal diseases of the nail bed (onychomycosis) and epidermis are recurrent illnesses in the elderly and immunocompromised patients, which have few efficacious treatment options. Current treatment options for onychomycosis are limited to topical agents, laser treatment, and oral antifungals. Previous generations of topical agents were not efficacious, owing to poor penetration of the nail bed. Oral antifungal drugs, such as itraconazole, terbinafine, and fluconazole, not only give better response rates but also inhibit a host of CYP450 enzymes. Oral antifungals can exacerbate drug-drug interactions for patients taking other medications concurrently. Newer topical agents might recognize improved efficacy and provide therapeutic alternatives when the use of oral antifungal agents is contraindicated. Recently, the Food and Drug Administration (FDA) approved efinaconazole and tavaborole for the treatment of onychomycosis. Additionally, the FDA approved luliconazole for the treatment of tinea pedis, tinea cruris, and tinea corporis. This review examines the mechanism of action, spectrum of activity, pharmacokinetics, and clinical trials data and considers the place in therapy for these 3 new antimycotic agents. PMID- 27488126 TI - Walking towards personalized medicine in pulmonary rehabilitation: Comorbidities and COPD. PMID- 27488127 TI - Aspects of skeletal muscles in chronic respiratory disease. PMID- 27488128 TI - MR Parametric Mapping as a Biomarker of Early Joint Degeneration. AB - CONTEXT: Osteoarthritis (OA) is a common, worldwide disorder. Magnetic resonance (MR) imaging can directly and noninvasively evaluate articular cartilage and has emerged as an essential tool in the study of OA. EVIDENCE ACQUISITION: A PubMed search was performed using the keywords quantitative MRI and cartilage. No limits were set on the range of years searched. Articles were reviewed for relevance with an emphasis on in vivo studies performed at 3 tesla. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: T2, T2*, T1 (particularly when measured after exogenous contrast administration, such as with the delayed gadolinium-enhanced MR imaging of cartilage [dGEMRIC] technique), and T1rho are among the most widely utilized quantitative MR imaging techniques to evaluate cartilage and have been implemented in various patient cohorts. Existing challenges include reproducibility of results, insufficient consensus regarding optimal sequences and parameters, and interpretation of values. CONCLUSION: Quantitative assessment of cartilage using MR imaging techniques likely represents the best opportunity to identify early cartilage degeneration and to follow patients after treatment. Despite existing challenges, ongoing work and unique approaches have shown exciting and promising results. PMID- 27488130 TI - Advances in the Physiology of GPR55 in the Central Nervous System. AB - BACKGROUND: The G protein-coupled receptor 55 (GPR55) is a mammalian orphan receptor that awaits a formal classification. There are an increasing number of reports directed to know the physiology and pathophysiology of this receptor. Lamentably, its functions in the central nervous system (CNS) have been scarcely elucidated. METHODS: A bibliographic search in PubMed database about GPR55 actions in the CNS was made. The information was grouped for brain structures to facilitate the interpretation. Finally, we constructed a schematic representation of the current knowledge about the potential participation of GPR55 in some physiological and pathophysiological events. RESULTS: Seventy nine papers were included in the review. Only few of them showed data about GPR55 (mRNA/protein) expression in multiple brain areas. The rest showed findings in different preparations both in vitro and in vivo conditions that allowed us to speculate a potential activity of GPR55 in the different brain areas. CONCLUSION: GPR55 mRNA is expressed in several brain areas as the hippocampus, hypothalamus, frontal cortex and cerebellum; but due to the lack of information, only some speculative information about its function in these regions has been suggested. Therefore, this review provide relevant information to motivate further research about GPR55 physiology/pathophysiology in the CNS. PMID- 27488131 TI - Penicillin binding protein 3 of Staphylococcus aureus NCTC 8325-4 binds and activates human plasminogen. AB - BACKGROUND: Staphylococcus aureus is a versatile pathogen expressing a number of virulence-associated adhesive molecules. In a previous study, we generated in a secretion-competent Escherichia coli strain a library of random FLAG-tag positive (FTP) polypeptides of S. aureus. To identify adhesive proteins and gain additional knowledge on putative virulence factors of S. aureus, we here screened the FTP library against human serum proteins. FINDINGS: Staphylococcus aureus NCTC 8325-4, origin of the FTP library, adhered to immobilized plasminogen in vitro. In an enzyme-linked immunoassay a C-terminal part of penicillin binding protein 3 (PBP3), included in the FTP library, bound to immobilized plasminogen. We expressed and purified full-length PBP3 and its C-terminal fragments as recombinant proteins. In a time-resolved fluorometry-based assay the PBP3 polypeptides bound to immobilized plasminogen. The polypeptides enhanced formation of plasmin from plasminogen as analyzed by cleavage of a chromogenic plasmin substrate. CONCLUSIONS: The present findings, although preliminary, demonstrate reliably that S. aureus NCTC 8325-4 adheres to immobilized plasminogen in vitro and that the adhesion may be mediated by a C-terminal fragment of the PBP3 protein. The full length PBP3 and the penicillin binding C terminal domain of PBP3 expressed as recombinant proteins bound plasminogen and activated plasminogen to plasmin. These phenomena were inhibited by the lysine analogue epsilon-aminocaproic acid suggesting that the binding is mediated by lysine residues. A detailed molecular description of surface molecules enhancing the virulence of S. aureus will aid in understanding of its pathogenicity and help in design of antibacterial drugs in the future. PMID- 27488132 TI - Correction: In vivo 808 nm image-guided photodynamic therapy based on an upconversion theranostic nanoplatform. AB - Correction for 'In vivo 808 nm image-guided photodynamic therapy based on an upconversion theranostic nanoplatform' by Xiaomin Liu, et al., Nanoscale, 2015, 7, 14914-14923. PMID- 27488135 TI - Second sphere coordination of hybrid metal-organic materials: solid state reactivity. AB - When compared to other hybrid metal organic materials such as metal-organic frameworks, hydrogen bonded materials self-assembled by metals and organic molecules using second sphere interactions have been poorly investigated. Consequently, their solid-sate properties are also scarce. In this perspective, earlier research mainly on host-guest chemistry and its evolution towards more extended structures by applying crystal engineering principles using second sphere coordination is described. Crystal-to-crystal guest exchange reactions, permanently porous hybrid metal organic materials, mechanochemical reactivity, thermally induced phase transformations as well as some examples of functional technological applications using second sphere adducts such as gas adsorption, separation and non-linear optical phenomena are also reported. Although some tutorial reviews on second sphere adducts have been conducted mainly in the solution state focusing on metal based anion receptors, to the best of our knowledge, an overview on relevant works that focus on the solid-state properties has not been carried out. The aim of this article is to highlight from some of the early fundamental work to the latest reports on hybrid metal-organic materials self-assembled via second sphere interactions with a focus on solid state chemistry. PMID- 27488134 TI - Australian human and parrot Chlamydia psittaci strains cluster within the highly virulent 6BC clade of this important zoonotic pathogen. AB - Chlamydia psittaci is an avian pathogen and zoonotic agent of atypical pneumonia. The most pathogenic C. psittaci strains cluster into the 6BC clade, predicted to have recently emerged globally. Exposure to infected parrots is a risk factor with limited evidence also of an indirect exposure risk. Genome sequencing was performed on six Australian human and a single avian C. psittaci strain isolated over a 9 year period. Only one of the five human patients had explicit psittacine contact. Genomics analyses revealed that the Australian C. psittaci strains are remarkably similar, clustering tightly within the C. psittaci 6BC clade suggested to have been disseminated by South America parrot importation. Molecular clock analysis using the newly sequenced C. psittaci genomes predicted the emergence of the 6BC clade occurring approximately 2,000 years ago. These findings reveal the potential for an Australian natural reservoir of C. psittaci 6BC strains. These strains can also be isolated from seriously ill patients without explicit psittacine contact. The apparent recent and global spread of C. psittaci 6BC strains raises important questions over how this happened. Further studies may reveal whether the dissemination of this important zoonotic pathogen is linked to Australian parrot importation rather than parrots from elsewhere. PMID- 27488133 TI - Skeletal complications in cancer patients with bone metastases. AB - As a result of significant improvements in current therapies, the life expectancy of cancer patients with bone metastases has dramatically improved. Unfortunately, these patients often experience skeletal complications that significantly impair their quality of life. The major skeletal complications associated with bone metastases include: cancer-induced bone pain, hypercalcemia, pathological bone fractures, metastatic epidural spinal cord compression and cancer cachexia. Once cancer cells invade the bone, they perturb the normal physiology of the marrow microenvironment, resulting in bone destruction, which is believed to be a direct cause of skeletal complications. However, full understanding of the mechanisms responsible for these complications remains unknown. In the present review, we discuss the complications associated with bone metastases along with matched conventional therapeutic strategies. A better understanding of this topic is crucial, as targeting skeletal complications can improve both the morbidity and mortality of patients suffering from bone metastases. PMID- 27488136 TI - Using thermal desorption electrospray ionization mass spectrometry to rapidly determine antimicrobial preservatives in cosmetics. AB - RATIONALE: Characterization and quantification of permitted preservatives are important inspections to prevent the overuse of preservatives in authentic formulations. However, the complexity of sample matrices makes preservative determination in cosmetics a tedious process. A rapid analytical strategy to identify preservatives would insure large numbers of products are in compliance with government regulations. METHODS: Thermal desorption electrospray ionization mass spectrometry (TD-ESI-MS) was used to directly detect preservative compounds in authentic formulations without sample pretreatment. The technique employs a metal probe, which was configured for sampling cosmetics in their original states and was inserted in a closed preheated oven to thermally desorb analytes. The desorbed analytes were then carried by a nitrogen gas stream into an ESI plume, where the formed ions were subsequently detected by the mass analyzer. RESULTS: The TD-ESI mass and tandem mass spectra of different classes of preservative standards were rapidly obtained, and the limits of detection were far below the legal limit of their respective concentrations. The preservatives were also directly detected in different types of authentic formulations in the absence of sample preparation, and within a few seconds per sample. Calibration curves for preservatives in four common formulations yielded good linearity in the regulation-allowed range. CONCLUSIONS: Due to its sensitivity, short analysis time, repeatability, and quantitative ability, TD-ESI-MS may serve as a suitable tool for large-scale screening of cosmetic preservatives to assure product safety. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27488137 TI - "Water-in-salt" electrolytes enable the use of cost-effective aluminum current collectors for aqueous high-voltage batteries. AB - The extended electrochemical stability window offered by highly concentrated electrolytes allows the operation of aqueous batteries at voltages significantly above the thermodynamic stability limit of water, at which the stability of the current collector potentially limits the cell voltage. Here we report the observation of suppressed anodic dissolution of aluminum in "water-in-salt" electrolytes enabling roll-to-roll electrode fabrication for high-voltage aqueous lithium-ion batteries on cost-effective light-weight aluminum current collectors using established lithium-ion battery technology. PMID- 27488138 TI - Draft genome of an iconic Red Sea reef fish, the blacktail butterflyfish (Chaetodon austriacus): current status and its characteristics. AB - Butterflyfish are among the most iconic of the coral reef fishes and represent a model system to study general questions of biogeography, evolution and population genetics. We assembled and annotated the genome sequence of the blacktail butterflyfish (Chaetodon austriacus), an Arabian region endemic species that is reliant on coral reefs for food and shelter. Using available bony fish (superclass Osteichthyes) genomes as a reference, a total of 28 926 high-quality protein-coding genes were predicted from 13 967 assembled scaffolds. The quality and completeness of the draft genome of C. austriacus suggest that it has the potential to serve as a resource for studies on the co-evolution of reef fish adaptations to the unique Red Sea environment, as well as a comparison of gene sequences between closely related congeneric species of butterflyfish distributed more broadly across the tropical Indo-Pacific. PMID- 27488140 TI - Following a potential epileptogenic insult, prolonged high rates of nonlinear dynamical regimes of intermittency type is the hallmark of epileptogenesis. AB - The lack of a marker of epileptogenesis is an unmet medical need, not only from the clinical perspective but also from the point of view of the pre-clinical research. Indeed, the lack of this kind of marker affects the investigations on the mechanisms of epileptogenesis as well as the development of novel therapeutic approaches aimed to prevent or to mitigate the severity of the incoming epilepsy in humans. In this work, we provide evidence that in an experimental model of epileptogenesis that mimics the alteration of the blood-brain barrier permeability, a key-mechanism that contributes to the development of epilepsy in humans and in animals, the prolonged occurrence in the electrocorticograms (ECoG) of high rates of a nonlinear dynamical regimes known as intermittency univocally characterizes the population of experimental animals which develop epilepsy, hence it can be considered as the first biophysical marker of epileptogenesis. PMID- 27488141 TI - Gaps in Research on Adverse Events to Transfusion in Pediatrics. AB - Adverse consequences of blood transfusion in children are not completely understood. Much remains to be learned about defining their mechanisms, learning how they can be avoided, and improving our understanding how to minimize the morbidity of their consequences. All types of transfusion reactions can occur in children. This article focuses on four adverse consequences that have particular relevance for pediatric populations: cytomegalovirus transmission, red blood cell alloimmunization, immune altering consequences of transfusion, and necrotizing enterocolitis. PMID- 27488142 TI - Combining web-based tools for transparent evaluation of data for risk assessment: developmental effects of bisphenol A on the mammary gland as a case study. AB - Different tools have been developed that facilitate systematic and transparent evaluation and handling of toxicity data in the risk assessment process. The present paper sets out to explore the combined use of two web-based tools for study evaluation and identification of reliable data relevant to health risk assessment. For this purpose, a case study was performed using in vivo toxicity studies investigating low-dose effects of bisphenol A on mammary gland development. The reliability of the mammary gland studies was evaluated using the Science in Risk Assessment and Policy (SciRAP) criteria for toxicity studies. The Health Assessment Workspace Collaborative (HAWC) was used for characterizing and visualizing the mammary gland data in terms of type of effects investigated and reported, and the distribution of these effects within the dose interval. It was then investigated whether there was any relationship between study reliability and the type of effects reported and/or their distribution in the dose interval. The combination of the SciRAP and HAWC tools allowed for transparent evaluation and visualization of the studies investigating developmental effects of BPA on the mammary gland. The use of these tools showed that there were no apparent differences in the type of effects and their distribution in the dose interval between the five studies assessed as most reliable and the whole data set. Combining the SciRAP and HAWC tools was found to be a useful approach for evaluating in vivo toxicity studies and identifying reliable and sensitive information relevant to regulatory risk assessment of chemicals. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27488143 TI - Prothrombin complex concentrates versus fresh frozen plasma for warfarin reversal. A systematic review and meta-analysis. AB - Urgent reversal of warfarin is required for patients who experience major bleeding or require urgent surgery. Treatment options include the combination of vitamin K and coagulation factor replacement with either prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP). However, the optimal reversal strategy is unclear based on clinically relevant outcomes. We searched in MEDLINE, EMBASE and Cochrane library to December 2015. Thirteen studies (5 randomised studies and 8 observational studies) were included. PCC use was associated with a significant reduction in all-cause mortality compared to FFP (OR= 0.56, 95 % CI; 0.37-0.84, p=0.006). A higher proportion of patients receiving PCC achieved haemostasis compared to those receiving FFP, but this was not statistically significant (OR 2.00, 95 % CI; 0.85-4.68). PCC use was more likely to achieve normalisation of international normalised ratio (INR) (OR 10.80, 95 % CI; 6.12-19.07) and resulted in a shorter time to INR correction (mean difference -6.50 hours, 95 %CI; -9.75 to -3.24). Red blood cell transfusion was not statistically different between the two groups (OR 0.88, 95 % CI: 0.53 1.43). Patients receiving PCC had a lower risk of post-transfusion volume overload compared to FFP (OR 0.27, 95 % CI; 0.13-0.58). There was no statistically significant difference in the risk of thromboembolism following administration of PCC or FFP (OR 0.91, 95 % CI; 0.44-1.89). In conclusion, as compared to FFP, the use of PCC for warfarin reversal was associated with a significant reduction in all-cause mortality, more rapid INR reduction, and less volume overload without an increased risk of thromboembolic events. PMID- 27488144 TI - Silacyclopropylideneplatinum(0) Complex as a Robust and Efficient Hydrosilylation Catalyst. AB - The base-stabilized silacyclopropylidene 1 behaves as a versatile strongly nucleophilic ligand toward transition metals. The strong silylene-metal binding related to both increased sigma-donating and pi-accepting character of silylene 1 compared to N-heterocyclic carbenes (NHCs) allowed the synthesis of robust and air-stable silylene complexes. Of particular interest, the corresponding platinum(0) complex 6 exhibits high stability and a high level of selectivity and catalytic activity in hydrosilylation reactions that is superior to that of the related NHC-Pt(0) complexes. PMID- 27488145 TI - Yellow Neointima Following Stent Implantation in the Superficial Femoral Artery on Angioscopy. PMID- 27488146 TI - Interaction Between Brain and Heart. PMID- 27488147 TI - Is ophthalmology becoming a pain in the neck? PMID- 27488148 TI - Biopsy techniques for intraocular tumors. AB - Biopsy involves the surgical removal of a tissue specimen for histopathologic evaluation. Most intraocular tumors are reliably diagnosed based on the clinical evaluation or with noninvasive diagnostic techniques. However, accurately diagnosing a small percentage of tumors can be challenging. A tissue biopsy is thus needed to establish a definitive diagnosis and plan the requisite treatment. From fine-needle aspiration biopsy (FNAB) to surgical excision, all tissue collection techniques have been studied in the literature. Each technique has its indications and limitations. FNAB has been reported to provide for 88-95% reliable and safe ophthalmic tumor diagnosis and has gained popularity for prognostic purposes and providing eye conserving treatment surgeries. The technique and instrumentation for biopsy vary depending upon the tissue involved (retina, choroid, subretinal space, vitreous, and aqueous), suspected diagnosis, size, location, associated retinal detachment, and clarity of the media. The cytopathologist confers a very important role in diagnosis and their assistance plays a key role in managing and planning the treatment for malignancies. PMID- 27488149 TI - Clinical profile of medicolegal cases presenting to the eye casualty in a tertiary care center in India. AB - PURPOSE: The purpose of this study was to analyze the clinical profile of medicolegal cases (MLCs) presenting to the eye casualty in a tertiary care hospital. MATERIALS AND METHODS: Retrospective review of records. The cases were grouped according to the Ocular Trauma Classification Group classification system. RESULTS: Out of 188 MLCs, 164 (87.2%) were male. Mean age (+/-standard deviation) was 31.6 (+/-12.7) years. Age ranged from 7 to 75 years. Twenty-six (13.8%) patients had bilateral involvement. The fist was the most common mode of injury, which was seen in 109 (58%) cases. A total of 27 (14.3%) patients had associated extraocular injury. No evidence of ocular or orbital trauma (malingering) could be found in 13 (7%) patients. Mechanical trauma was present in 169 (90%) patients with injury to globe in 129 (69%) patients and injury to lid or orbit without damage to the globe in 40 (21%) patients. Chemical injury was observed in 6 (3%) patients. Closed globe injury (CGI) was seen in 116 eyes and open globe injury (OGI) was noted in 29 eyes. The most common type of injury, zone, pupil, and grade of injury in CGI were Type A or contusion (79%), Zone I (72%), Pupil B (absence of relative afferent pupillary defect) in 95%, and Grade A [visual acuity (VA) >=20/40] in 68% of the eyes, respectively. The most common type of injury, zone, pupil, and grade of injury in OGI were Type B or penetrating (48%), Zone II (38%), Pupil B (59%), and Grade D (VA 4/200-light perception) (42%), respectively. CONCLUSIONS: The most common form and mode of ocular injury in MLC were closed globe injury and fist, respectively. The most common type of injury in CGI and OGI was contusion and penetrating injury, respectively. PMID- 27488150 TI - Change of retinal pigment epithelial atrophy after anti-vascular endothelial growth factor treatment in exudative age-related macular degeneration. AB - PURPOSE: The study aimed to investigate the quantitative changes of retinal pigment epithelial (RPE) atrophy during a 24-month follow-up period of anti vascular endothelial growth factor (VEGF) for exudative age-related macular degeneration (AMD). MATERIALS AND METHODS: This is a retrospective study. Sixty five eyes of 62 consecutive patients with naomicronve exudative AMD who had received treatment with anti-VEGF therapy and followed for more 24 months were enrolled. All patients received three initial monthly injections of anti-VEGF (ranibizumab or bevacizumab), followed by pro re nata or treat-and-extend protocol. Color fundus image, optical coherence tomography, and fundus autofluorescence were evaluated for RPE atrophy. Multiple regression analysis was performed to investigate the predictive factors found during univariate analysis to identify an association with increased RPE atrophic areas. RESULTS: The mean number of anti-VEGF treatments was 9.18. RPE atrophic area was 1.293 +/- 1.298 mm 2 at baseline and enlarged to 2.394 +/- 1.940 mm 2 after 24 months, which differed significantly (P = 0.001). Multiple regression analysis revealed that larger areas of RPE atrophy at month 4 and larger numbers of anti-VEGF treatments were associated with increased RPE atrophic areas. CONCLUSIONS: RPE atrophy progresses in eyes with exudative AMD during anti-VEGF treatment. Larger areas of RPE atrophy at month 4 and larger numbers of anti-VEGF injections were associated with an increased risk of progression of RPE atrophy the following treatment. These findings may be useful to clinicians using intravitreal anti-VEGF for the treatment of exudative AMD, both for selecting an appropriate treatment plan and for predicting the progression of RPE atrophy. PMID- 27488151 TI - Effect of thiamine pyrophosphate on retinopathy induced by hyperglycemia in rats: A biochemical and pathological evaluation. AB - PURPOSE: Information is lacking on the protective effects of thiamine pyrophosphate (TPP) against hyperglycemia-induced retinopathy in rats. This study investigated the biochemical and histopathological aspects of the effect of TPP on hyperglycemia-induced retinopathy induced by alloxan in rats. MATERIALS AND METHODS: The rats were separated into a diabetic TPP-administered group (DTPG), a diabetes control group (DCG) and a healthy group (HG). While the DTPG was given TPP, the DCG and HG were administered distilled water as a solvent at the same concentrations. This procedure was repeated daily for 3 months. At the end of this period, all of the rats were euthanized under thiopental sodium anesthesia, and biochemical and histopathological analyses of the ocular retinal tissues were performed. The results of the DTPG were compared with those of the DCG and HG. RESULTS: TPP prevented hyperglycemia by increasing the amount of malondialdehyde and decreasing endogen antioxidants, including total glutathione, glutathione reductase, glutathione S-transferase and superoxide dismutase. In addition, the amounts of the DNA oxidation product 8-hydroxyguanine were significantly lower in the retinas of the DTPG compared to the DCG. In the retinas of the DCG, there was a marked increase in vascular structures and congestion, in addition to edema. In contrast, little vascularization and edema were observed in the DTPG, and there was no congestion. The results suggest that TPP significantly reduced the degree of hyperglycemia-induced retinopathy. CONCLUSIONS: The results of this study indicate that TPP may be useful for prophylaxis against diabetic retinopathy. PMID- 27488152 TI - Failure to initiate early insulin therapy - A risk factor for diabetic retinopathy in insulin users with Type 2 diabetes mellitus: Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetics Study (SN-DREAMS, Report number 35). AB - CONTEXT: Insulin users have been reported to have a higher incidence of diabetic retinopathy (DR). AIM: The aim was to elucidate the factors associated with DR among insulin users, especially association between duration, prior to initiating insulin for Type 2 diabetes mellitus (DM) and developing DR. MATERIALS AND METHODS: Retrospective cross-sectional observational study included 1414 subjects having Type 2 DM. Insulin users were defined as subjects using insulin for glycemic control, and insulin nonusers as those either not using any antidiabetic treatment or using diet control or oral medications. The duration before initiating insulin after diagnosis was calculated by subtracting the duration of insulin usage from the duration of DM. DR was clinically graded using Klein's classification. SPSS (version 9.0) was used for statistical analysis. RESULTS: Insulin users had more incidence of DR (52.9% vs. 16.3%, P < 0.0001) and sight threatening DR (19.1% vs. 2.4%, P < 0.0001) in comparison to insulin nonusers. Among insulin users, longer duration of DM (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.00-1.25, P = 0.044) and abdominal obesity (OR 1.15, 95% CI 1.02 1.29, P = 0.021) was associated with DR. The presence of DR was significantly associated with longer duration (>=5 years) prior to initiating insulin therapy, overall (38.0% vs. 62.0%, P = 0.013), and in subjects with suboptimal glycemic control (32.5% vs. 67.5%, P = 0.022). CONCLUSIONS: The presence of DR is significantly associated with longer duration of diabetes (>5 years) and sub optimal glycemic control (glycosylated hemoglobin <7.0%). Among insulin users, abdominal obesity was found to be a significant predictor of DR; DR is associated with longer duration prior to initiating insulin therapy in Type 2 DM subjects with suboptimal glycemic control. PMID- 27488153 TI - Preferences of ophthalmic plastics patients and their caregivers toward the doctors' attire and initial communications: A tertiary eye care study. AB - PURPOSE: The aims of this study were to determine the acceptability levels of different styles of the doctors' dress and the expectations from the initial phases of physician-patient encounter. METHODS: The study design was a cross sectional descriptive type using the survey methodology. A survey based on a five point questionnaire was performed on all consecutive patients or their caregivers, aged >=15, visiting the ophthalmic plastics outpatient clinics at a tertiary eye care institute. The participants were shown three sets of photographs and were required to answer a questionnaire which consisted of five questions. Data collected include participant demographics and their preferences with regards to the physician's attire and initial communications. RESULTS: A total of 300 consecutive responses were analyzed. The mean age of the participants was 37.2 years. Among the participants, 87.6% (263/300) and 90.3% (271/300) preferred a white coat for the male and female physicians, respectively (P < 0.001). The most common second preference was scrubs for both the males and female physicians. 92.3% (277/300) preferred the attire to have an identification display. The overwhelming majority of respondents (95.6%, 287/300) preferred the physicians to address them by their name and 98.6% (296/300) liked if their physicians smiled while addressing them. CONCLUSIONS: White coat was the main preferred attire among respondents. Increased awareness of the patient's expectations plays a crucial role in enhancing their satisfaction. PMID- 27488154 TI - Correlation between retinal sensitivity and cystoid space characteristics in diabetic macular edema. AB - PURPOSE: To evaluate the correlation between retinal sensitivity and cystoid space characteristics in eyes with diabetic macular edema (DME). MATERIALS AND METHODS: Prospective cross-sectional study of 22 subjects with DME (32 treatment naive eyes). All study subjects underwent complete ophthalmic examination, including slit-lamp biomicroscopy and dilated fundus examination. All subjects underwent spectral domain optical coherence tomography (SD-OCT) and microperimetry (MP). Intraretinal cystoid space (ICS) volume was generated after manual delineation of cystoid space boundaries using the three-dimensional-OCT software. Various SD-OCT parameters, including retinal thickness, retinal volume, cystoid space volume, cystoid space intensity, and outer retinal structure integrity, were correlated with MP parameters and best-corrected visual acuity (BCVA). RESULTS: Subject's mean age was 57 +/- 9 years. The mean logarithm of minimum angle of resolution BCVA was 0.4 +/- 0.2. The intraclass correlation coefficient for inter- and intra-grader assessment of cystoid space volume by manual delineation was 0.99 and 0.99, respectively. Mean total ICS volume was 0.4 +/- 0.4 mm 3 and for the foveal center, subfield was 0.1 +/- 0.1 mm 3 . Mean retinal sensitivity was 12.89 +/- 10 dB; however, foveal retinal sensitivity was 12.3 +/- 11.1 dB. We found no significant correlation between BCVA and total cystoid space volume (r = 0.33, P = 0.06). Correlation between total retinal sensitivity and total ICS was negative and nonsignificant (r = -0.17, P = 0.36). Correlation between foveal retinal sensitivity and foveal cystoid space intensity was moderate and marginally significant (r = -0.43, P = 0.05). CONCLUSION: Total cystoid space volume was not significantly correlated with BCVA or total retinal sensitivity in subjects with DME. Foveal cystoid space optical intensity was negatively correlated with foveal retinal sensitivity. These findings suggest further investigation of cystoid space characteristics in the setting of DME may be of value. PMID- 27488155 TI - Prostaglandin-associated periorbitopathy. PMID- 27488156 TI - Intralesional and topical interferon therapy following incomplete primary excision of ocular surface squamous neoplasia. PMID- 27488157 TI - First case report of isolated aspergillus dacryoadenitis. AB - We report a case of isolated Aspergillus dacryoadenitis. A 23-year-old male presented with dull ache, diffuse swelling in superolateral quadrant of the right orbit and proptosis for 4 months. Ocular examination showed conjunctival congestion, discharge in the fornix and palpable lacrimal gland (LG) mass. Routine hematological investigations followed by computed tomography scan of orbits were done. He did not respond to a course of systemic and topical antibiotics. Lateral orbitotomy with extended lid crease incision was performed with excision biopsy of LG. Abundant blackish material was found in the LG intraoperatively. The specimen was sent for histopathological examination (HPE). HPE report showed Aspergillus. Thorough ENT and systemic evaluation ruled out any other site with the fungus. To the best of our knowledge, this is the first case report of Aspergillus infection in LG. PMID- 27488158 TI - Purtscher-like retinopathy: A rare complication of peribulbar anesthesia. AB - Purtscher and Purtscher-like retinopathy is a distinctive retinal syndrome characterized by ischemic retinal whitening in a peripapillary pattern. We report a case of Purtscher-like retinopathy in a healthy 64-year-old man after a routine peribulbar anesthetic injection for cataract surgery. Although peribulbar anesthesia is considered to be a safer alternative to retrobulbar anesthesia, it has been associated with unusual but grave complications including central retinal artery occlusion. PMID- 27488159 TI - Solid variant of orbital angioleiomyoma: An unusual tumor at an unusual site. AB - We describe the clinicopathological features of a solid variant of orbital angioleiomyoma. A review of clinical records, diagnostic, and radiographic studies combined with histopathological evaluation with standard histochemical staining and immunohistochemistry was conducted. A 22-year-old male patient presented with a mass in the region of the left lacrimal gland that was gradually increasing over the past 2 years. Radiological and clinical examinations showed no signs suspicious of a malignancy and fine needle aspiration cytology was inconclusive. Therefore, an excision biopsy was performed. On histopathological examination, the picture was consistent with a benign spindle cell tumor. Immunohistochemistry showed positivity for CD 34 and CD 31 (markers for vascular endothelium). The tumor also showed positivity for smooth muscle actin and Ki-67 proliferative index was low. Angioleiomyomas are rarely encountered in the orbit and has features seen in leiomyoma as well as some vascular tumor elements. In most cases, surgical excision is usually curative. PMID- 27488160 TI - Unilateral anterior persistent fetal vasculature in a child with blepharophimosis ptosis-epicanthus inversus syndrome: A surgical challenge. AB - Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant genetic disease. It is clinically characterized by four major features; blepharophimosis, ptosis, epicanthus inversus, and telecanthus. We report a case of a 1-year-old female with BPES with unilateral anterior persistent fetal vasculature (PFV). On examination, she was found to have all the clinical features of BPES, along with calcified and partially absorbed cataract with elongated ciliary processes in her left eye. B-scan of left eye showed attached retina with no evidence of posterior PFV. Systemic examination was normal. She underwent cataract surgery with primary posterior capsulotomy with intraocular lens implantation under general anesthesia. Literature search did not reveal any previous reports of unilateral anterior PFV and BPES. The clinical features, other associations, and the difficulties in the surgical management of this condition are discussed. PMID- 27488161 TI - One Chinese case with benign reactive lymphoid hyperplasia of the uvea. PMID- 27488162 TI - Response to: Bilateral lateral rectus myotoxicity after retrobulbar anesthesia. PMID- 27488163 TI - Response to: Choroidal thickness changes after dynamic exercise as measured by spectral-domain optical coherence tomography. PMID- 27488164 TI - Comment to: Effect of lanosterol on human nuclei. PMID- 27488165 TI - Authors' reply. PMID- 27488166 TI - Comment to: Dual effect hypothesis of insulin analogs on diabetic retinopathy. PMID- 27488167 TI - Author's reply. PMID- 27488168 TI - Comment to: Iris-claw intraocular lens implantation: Anterior chamber versus retropupillary implantation. PMID- 27488169 TI - Authors' reply. PMID- 27488170 TI - Effects of maltreatment and parental schizophrenia spectrum disorders on early childhood social-emotional functioning: a population record linkage study. AB - AIMS: Childhood maltreatment and a family history of a schizophrenia spectrum disorder (SSD) are each associated with social-emotional dysfunction in childhood. Both are also strong risk factors for adult SSDs, and social-emotional dysfunction in childhood may be an antecedent of these disorders. We used data from a large Australian population cohort to determine the independent and moderating effects of maltreatment and parental SSDs on early childhood social emotional functioning. METHODS: The New South Wales Child Development Study combines intergenerational multi-agency data using record linkage methods. Multiple measures of social-emotional functioning (social competency, prosocial/helping behaviour, anxious/fearful behaviour; aggressive behaviour, and hyperactivity/inattention) on 69 116 kindergarten children (age ~5 years) were linked with government records of child maltreatment and parental presentations to health services for SSD. Multivariable analyses investigated the association between maltreatment and social-emotional functioning, adjusting for demographic variables and parental SSD history, in the population sample and in sub-cohorts exposed and not exposed to parental SSD history. We also examined the association of parental SSD history and social-emotional functioning, adjusting for demographic variables and maltreatment. RESULTS: Medium-sized associations were identified between maltreatment and poor social competency, aggressive behaviour and hyperactivity/inattention; small associations were revealed between maltreatment and poor prosocial/helping and anxious/fearful behaviours. These associations did not differ greatly when adjusted for parental SSD, and were greater in magnitude among children with no history of parental SSD. Small associations between parental SSD and poor social-emotional functioning remained after adjusting for demographic variables and maltreatment. CONCLUSIONS: Childhood maltreatment and history of parental SSD are associated independently with poor early childhood social-emotional functioning, with the impact of exposure to maltreatment on social-emotional functioning in early childhood of greater magnitude than that observed for parental SSDs. The impact of maltreatment was reduced in the context of parental SSDs. The influence of parental SSDs on later outcomes of maltreated children may become more apparent during adolescence and young adulthood when overt symptoms of SSD are likely to emerge. Early intervention to strengthen childhood social-emotional functioning might mitigate the impact of maltreatment, and potentially also avert future psychopathology. PMID- 27488171 TI - Expression of a Grapevine NAC Transcription Factor Gene Is Induced in Response to Powdery Mildew Colonization in Salicylic Acid-Independent Manner. AB - Tissue colonization by grape powdery mildew (PM) pathogen Erysiphe necator (Schw.) Burr triggers a major remodeling of the transcriptome in the susceptible grapevine Vitis vinifera L. While changes in the expression of many genes bear the signature of salicylic acid (SA) mediated regulation, the breadth of PM induced changes suggests the involvement of additional regulatory networks. To explore PM-associated gene regulation mediated by other SA-independent systems, we designed a microarray experiment to distinguish between transcriptome changes induced by E. necator colonization and those triggered by elevated SA levels. We found that the majority of genes responded to both SA and PM, but certain genes were responsive to PM infection alone. Among them, we identified genes of stilbene synthases, PR-10 proteins, and several transcription factors. The microarray results demonstrated that the regulation of these genes is either independent of SA, or dependent, but SA alone is insufficient to bring about their regulation. We inserted the promoter-reporter fusion of a PM-responsive transcription factor gene into a wild-type and two SA-signaling deficient Arabidopsis lines and challenged the resulting transgenic plants with an Arabidopsis-adapted PM pathogen. Our results provide experimental evidence that this grape gene promoter is activated by the pathogen in a SA-independent manner. PMID- 27488172 TI - Vascular type Ehlers-Danlos syndrome is associated with platelet dysfunction and low vitamin D serum concentration. AB - BACKGROUND: The vascular type represents a very rare, yet the clinically most fatal entity of Ehlers-Danlos syndrome (EDS). Patients are often admitted due to arterial bleedings and the friable tissue and the altered coagulation contribute to the challenge in treatment strategies. Until now there is little information about clotting characteristics that might influence hemostasis decisively and eventually worsen emergency situations. RESULTS: 22 vascular type EDS patients were studied for hemoglobin, platelet volume and count, Quick and activated partial thromboplastin time, fibrinogen, factor XIII, von Willebrand disease, vitamin D and platelet aggregation by modern standard laboratory methods. Results show a high prevalence of over 50 % for platelet aggregation disorders in vascular type EDS patients, especially for collagen and epinephrine induced tests, whereas the plasmatic cascade did not show any alterations. Additionally, more than half of the tested subjects showed low vitamin D serum levels, which might additionally affect vascular wall integrity. CONCLUSION: The presented data underline the importance of detailed laboratory screening methods in vascular type EDS patients in order to allow for targeted application of platelet interacting substances that might be of decisive benefit in the emergency setting. PMID- 27488173 TI - Home blood pressure and cardiovascular risk in treated hypertensive patients: the prognostic value of the first and second measurements and the difference between them in the HONEST study. AB - Hypertension guidelines recommend using the average of two home blood pressure (HBP) measurements obtained on one occasion to monitor blood pressure. We studied the prognostic value of the first and second measurements or their average value during the follow-up period, as well as the relationships among the difference between the first and second HBP measurements and the prognosis using data from the HONEST (HBP measurement with Olmesartan-Naive patients to Establish Standard Target blood pressure) study. During the mean 2.02 years follow-up, 280 patients had cardiovascular events. Hazard ratios (HRs) for cardiovascular events for each 1 mm Hg increase in the first, second and averaged morning home systolic blood pressure (MHSBP) were similar. Hazards were significantly higher in patients with a large difference between the first and second MHSBP (DeltaMHSBP) of <-5 mm Hg (HR: 2.12) or ?5 mm Hg (HR: 1.44) compared with those with a small DeltaMHSBP of ?-5 to <5 mm Hg using the Cox proportional hazards model adjusted for the averaged MHSBP during the follow-up and other risk factors. Hazards in patients with an averaged MHSBP ?145 mmHg and a small DeltaMHSBP (HR: 3.11), those with an averaged MHSBP ?125 to <145 mm Hg and a large DeltaMHSBP (HR: 1.91) and those with an averaged MHSBP ?145 mm Hg and a large DeltaMHSBP (HR: 4.63) were higher compared with those with an averaged MHSBP <125 mm Hg and a small DeltaMHSBP. In conclusion, the first, second and averaged MHSBP measurements have similar prognostic values. Prognosis is worse for patients with a large DeltaMHSBP. In clinical practice, it would be prudent to measure the HBP two times and use the average HBP of two measurements obtained on one occasion with particular attention to patients with a large DeltaMHSBP. PMID- 27488174 TI - Bessel beams with spatial oscillating polarization. AB - Bessel beams are widely used in optical metrology mainly because of their large Rayleigh range (focal length). Radial/azimuthal polarization of such beams is of interest in the fields of material processing, plasma absorption or communication. In this paper an experimental set-up is presented, which generates a Bessel-type vector beam with a spatial polarization, oscillating along the optical axis, when propagating in free space. A first holographic axicon (HA) HA1 produces a normal, linearly polarized Bessel beam, which by a second HA2 is converted into the spatial oscillating polarized beam. The theory is briefly discussed, the set-up and the experimental results are presented in detail. PMID- 27488175 TI - Multilayered materials based on biopolymers as drug delivery systems. AB - INTRODUCTION: The design of efficient therapeutic delivery devices has become a tremendously active area of research with a strong contribution from the layer-by layer (LbL) technology. The application of this simple yet firmly established technique for the design of drug reservoirs originates a multitude of multilayered systems of tailored architecture and with a high level of control of drug administration. Areas covered: This review will focus on the most recent and original research on LbL assemblies based on biopolymers including polysaccharides, polypeptides and proteins, with potential use in drug delivery. Herein, drug reservoirs consisting of multilayered planar films and capsules will be examined with emphasis on the ones benefiting from the non-cytotoxic and biocompatible nature of biopolymers, which are suitable to load, protect and release a high payload of toxic and fragile drugs. Expert opinion: The combination of biopolymers with LbL technology has undergone extensive research, still, there is a multitude of R&D opportunities for the design of smart drug delivery systems with distinct multilayered morphologies, low immunological response, non-invasive drug release devices, as well as the design of theranostic systems combining diagnostics and therapeutic features. Further developments in terms of scaling towards mass production in the pharmaceutical industry are expected in the long-term. PMID- 27488176 TI - Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy. AB - AIMS: We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding. MATERIALS & METHODS: In total, 982 warfarin-treated patients from the RE-LY trial were studied. RESULTS: After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R(2) by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding. CONCLUSIONS: We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort. PMID- 27488177 TI - Pseudochaetosphaeronema ginkgonis sp. nov., an endophyte isolated from Ginkgo biloba. AB - An endophytic strain (designated as SYPF 7195T) was isolated from a branch of a ginkgo tree in Liaoning province of China. Strain SYPF 7195T was characterized by its grey to greyish-green aerial mycelium, velvety to floccose surface and swelling near the septa. Phylogenetic analyses, which were inferred from the internal transcribed spacer (ITS) and partial sequences of the LSU and SSU of the rDNA and translation elongation factor 1-alpha (TEF1), showed that strain SYPF 7195T belonged to the genus Pseudochaetosphaeronema, and was distinct from all other species with high bootstrap-supported values (92 %). Strain SYPF 7195T constitutes a separate evolutionary clade with Pseudochaetosphaeronema larense and Pseudochaetosphaeronema martinelli, with P. martinelli as its closest phylogenetic neighbour. The nucleotide differences between strain SYPF 7195T and P. martinelli were 71 substitutions in the ITS region. Strain SYPF 7195Tcould also be distinguished from P. martinelli by a number of physiological characteristics. Combined with morphology and molecular analyses, strain SYPF 7195T merits recognition as a representative of a novel species of the genus Pseudochaetosphaeronema, for which the name Pseudochaetosphaeronemaginkgonis sp. nov. is proposed. The type strain is CBS 140953T (=CGMCC 3.17865T=SYPF 7195T). The Mycobank number is MB 816567. PMID- 27488178 TI - How does HPV vaccination status relate to risk perceptions and intention to participate in cervical screening? a survey study. AB - BACKGROUND: Women in several countries will soon be covered by two preventive programmes targeting cervical cancer: HPV vaccination and cervical screening. The HPV vaccines are expected to prevent approximately 70 % of cervical cancers. It has been speculated, that HPV vaccinated women will not attend screening because they falsely think that the vaccine has eliminated their cervical cancer risk. The aim of this study was to investigate the association between HPV vaccination status and perceptions of cervical cancer risk; perceptions of vaccine effect; and intention to participate in cervical screening. Furthermore, to investigate associations between perceptions of cervical cancer risk and intention to participate in cervical screening. METHODS: A random sample of Danish women from the birth cohorts 1993-1995 was invited to complete a web-based questionnaire concerning risk perceptions and intentions to participate in cervical screening. Main outcomes were: perceived lifetime-risk of cervical cancer; perceived HPV vaccine effect; and intention to participate in cervical screening. RESULTS: HPV vaccinated women more often than unvaccinated women intended to participate in screening: adjusted odds ratio (OR) for being HPV vaccinated when intending to participate in screening of 3.89 (95 % CI: 2.50-6.06). HPV vaccinated women perceived cervical cancer risk to be higher than unvaccinated women did: adjusted OR of 0.11 (95 % CI: 0.03-0.39) and 0.51 (95 % CI: 0.33-0.78) for being HPV vaccinated while having the lowest perception of risk (in two different pre specified dichotomisations). HPV vaccinated women perceived the vaccine effect to be larger than unvaccinated women did: adjusted OR of 0.31 (95 % CI: 0.18-0.51) and 0.37 (95 % CI: 0.25-0.53) for being HPV vaccinated while having the lowest perception of vaccine effect (in two different pre-specified dichotomisations). There were no associations between perceived cervical cancer risk and intention to participate in screening. CONCLUSIONS: HPV vaccinated women more often than unvaccinated women intended to participate in screening and they perceived cervical cancer risk to be higher and the vaccine effect to be larger than unvaccinated women did. However, in our analyses, risk perceptions could not explain screening intentions neither among vaccinated nor among unvaccinated women. PMID- 27488179 TI - Morphometric characterisation of pterygium associated with corneal stromal scarring using high-resolution anterior segment optical coherence tomography. AB - AIMS: To investigate the role of high-resolution anterior segment optical coherence tomography (HR-ASOCT) in the assessment of pterygia. METHODS: Single centre cross-sectional study. Patients with primary pterygium and/or pingueculae were included. Clinical assessment included HR-ASOCT, colour photography, keratometry followed by histology. Associations were tested between HR-ASOCT features of the pterygium and the degree of corneal scarring and elastotic degeneration, astigmatism and best-corrected visual acuity. RESULTS: 29 eyes of 26 patients with pterygium and 6 patients with pinguecula were included. Apical anterior stromal scarring was found in 23 cases (79.3%) reaching a mean depth of 68.8+/-21.7 um (minimum: 33 um, maximum: 126 um). Increased stromal scarring and subepithelial elastotic degenerative tissue was significantly associated with HR ASOCT features of flat bridging of the corneoscleral transition zone (p<0.01) reduced thickness of the pterygium head (p=0.01), and a greater degree of corneal astigmatism (p=0.04). CONCLUSIONS: HR-ASOCT is a useful tool for the assessment and monitoring of pterygia in clinical practice. Features associated with increased stromal scarring and astigmatism are reduced thickness of the head of the pterygium and flat bridging of the corneoscleral transition zone. PMID- 27488180 TI - ABSSeq: a new RNA-Seq analysis method based on modelling absolute expression differences. AB - BACKGROUND: The recent advances in next generation sequencing technology have made the sequencing of RNA (i.e., RNA-Seq) an extemely popular approach for gene expression analysis. Identification of significant differential expression represents a crucial initial step in these analyses, on which most subsequent inferences of biological functions are built. Yet, for identification of these subsequently analysed genes, most studies use an additional minimal threshold of differential expression that is not captured by the applied statistical procedures. RESULTS: Here we introduce a new analysis approach, ABSSeq, which uses a negative binomal distribution to model absolute expression differences between conditions, taking into account variations across genes and samples as well as magnitude of differences. In comparison to alternative methods, ABSSeq shows higher performance on controling type I error rate and at least a similar ability to correctly identify differentially expressed genes. CONCLUSIONS: ABSSeq specifically considers the overall magnitude of expression differences, which enhances the power in detecting truly differentially expressed genes by reducing false positives at both very low and high expression level. In addition, ABSSeq offers to calculate shrinkage of fold change to facilitate gene ranking and effective outlier detection. PMID- 27488182 TI - Validation of a symphysis-fundal height chart developed for pregnancy complicated by diabetes and hyperglycemia: an observational study. AB - BACKGROUND: The present study validates a symphysis-fundal height chart (SFH chart) for pregnant women with type 2 diabetes mellitus (DM2), gestational diabetes mellitus (GDM) and mild gestational hyperglycemia (MGH) attending at the Diabetes and Pregnancy Reference Service of the Botucatu Medical School, UNESP, Brazil. METHODS: A cross-sectional study was carried out to evaluate the performance of the specific FHC in predicting small (SGA) and large (LGA) for gestational age newborns (NB). We evaluated 206 pregnant women with DM2, GDM or MGH and their NB. The last symphysis-fundal height measure, taken at birth, was used to determine the sensitivity index (Sens), specificity index (Spe), positive prediction value (PPV), negative prediction value (NPV) and accuracy in predicting SGA and LGA. The gold standard was the Lubchenco birth weight/gestational age ratio evaluated at birth. RESULTS: The mothers showed adequate glycemic control; 91.3 % of all pregnant women achieved HbA1c < 6,5 % in the third trimester. The SFH-chart tested achieved 100 % of Sens and NPV in predicting both SGA and LGA, with accuracy of 90.3 % (85.5; 93.6) and 91.8 % (87.2; 94.8), respectively, for predicting SGA and LGA newborns. CONCLUSIONS: The Basso SFH-chart showed high performance in predicting both SGA and LGA newborns of DM-2, GDM and MGH mothers, with better performance than the national reference SFH-chart. These findings support the internal validation of the Basso SFH-chart, which may be implemented in the prenatal care of the Diabetes and Pregnancy Reference Service-Botucatu Medical School/UNESP. PMID- 27488181 TI - European COMPARative Effectiveness research on blended Depression treatment versus treatment-as-usual (E-COMPARED): study protocol for a randomized controlled, non-inferiority trial in eight European countries. AB - BACKGROUND: Effective, accessible, and affordable depression treatment is of high importance considering the large personal and economic burden of depression. Internet-based treatment is considered a promising clinical and cost-effective alternative to current routine depression treatment strategies such as face-to face psychotherapy. However, it is not clear whether research findings translate to routine clinical practice such as primary or specialized mental health care. The E-COMPARED project aims to gain knowledge on the clinical and cost effectiveness of blended depression treatment compared to treatment-as-usual in routine care. METHODS/DESIGN: E-COMPARED will employ a pragmatic, multinational, randomized controlled, non-inferiority trial in eight European countries. Adults diagnosed with major depressive disorder (MDD) will be recruited in primary care (Germany, Poland, Spain, Sweden, and the United Kingdom) or specialized mental health care (France, The Netherlands, and Switzerland). Regular care for depression is compared to "blended" service delivery combining mobile and Internet technologies with face-to-face treatment in one treatment protocol. Participants will be followed up at 3, 6, and 12 months after baseline to determine clinical improvements in symptoms of depression (primary outcome: Patient Health Questionnaire-9), remission of depression, and cost-effectiveness. Main analyses will be conducted on the pooled data from the eight countries (n = 1200 in total, 150 participants in each country). DISCUSSION: The E-COMPARED project will provide mental health care stakeholders with evidence-based information and recommendations on the clinical and cost-effectiveness of blended depression treatment. TRIAL REGISTRATION: France: ClinicalTrials.gov NCT02542891 . Registered on 4 September 2015; Germany: German Clinical Trials Register DRKS00006866 . Registered on 2 December 2014; The Netherlands: Netherlands Trials Register NTR4962 . Registered on 5 January 2015; Poland: ClinicalTrials.Gov NCT02389660 . Registered on 18 February 2015; Spain: ClinicalTrials.gov NCT02361684 . Registered on 8 January 2015; Sweden: ClinicalTrials.gov NCT02449447 . Registered on 30 March 2015; Switzerland: ClinicalTrials.gov NCT02410616 . Registered on 2 April 2015; United Kingdom: ISRCTN registry, ISRCTN12388725 . Registered on 20 March 2015. PMID- 27488183 TI - Platelet inhibitory effects of juices from Pachyrhizus erosus L. root and Psidium guajava L. fruit: a randomized controlled trial in healthy volunteers. AB - BACKGROUND: The purpose of this study is to investigate cardiovascular benefits of juices obtained from two commonly consumed fruits in Thailand, Pachyrhizus erosus, L. (yam bean) and Psidium guajava, L. (guava), by examining their acute cardiovascular effects in healthy volunteers. Possible involvements of the dietary nitrate on their effects were investigated as well. METHOD: Thirty healthy volunteers were randomly divided into three groups of 10 subjects per group and each group was allocated to drink 500 ml of freshly prepared yam bean root juice, guava fruit juice, or water. Systemic nitrate and nitrite concentrations, heart rate, systolic and diastolic blood pressure, serum K(+) concentrations, ex vivo platelet aggregation, and plasma cGMP concentrations were monitored at the baseline and at various time points after the intake of juices or water. Data were compared by repeated measures ANOVA. RESULTS: Following the ingestion of both yam bean root juice and guava fruit juice, collagen-induced but not ADP-induced platelet aggregation was attenuated. Ingestion of yam bean root juice increased systemic nitrate and nitrite concentrations whereby elevated nitrite concentrations correlated with the extent of inhibiting collagen-induced platelet aggregation. In addition, positive correlation between systemic nitrite and plasma cGMP concentrations and negative correlation between plasma cGMP concentrations and the extent of collagen-induced platelet aggregation were revealed. Nevertheless, yam bean root juice reduced only diastolic blood pressure while guava fruit juice reduced heart rate, systolic and diastolic blood pressure. CONCLUSION: The present study has illustrated, for the first time, acute inhibitory effects of yam bean root juice and guava fruit juice on ex vivo collagen-induced platelet aggregation in healthy subjects. Dietary nitrate was shown to underlie the effect of yam bean root juice but not that of guava fruit juice. Following yam bean root juice ingestion, systemic nitrate apparently converts to nitrite and further to NO which may attenuate platelet responses to collagen stimulation. Cardiovascular benefits of juices from yam bean root and guava fruit are noteworthy in term of the cardiovascular health-promoting approach. TRIAL REGISTRATION: Randomized controlled trial TCTR20150228001 . PMID- 27488184 TI - Erratum to: Involvement of DNMT 3B promotes epithelial-mesenchymal transition and gene expression profile of invasive head and neck squamous cell carcinomas cell lines. PMID- 27488185 TI - Thickness-Dependent Binding Energy Shift in Few-Layer MoS2 Grown by Chemical Vapor Deposition. AB - The thickness-dependent surface states of MoS2 thin films grown by the chemical vapor deposition process on the SiO2-Si substrates are investigated by X-ray photoelectron spectroscopy. Raman and high-resolution transmission electron microscopy suggest the thicknesses of MoS2 films to be ranging from 3 to 10 layers. Both the core levels and valence band edges of MoS2 shift downward ~0.2 eV as the film thickness increases, which can be ascribed to the Fermi level variations resulting from the surface states and bulk defects. Grainy features observed from the atomic force microscopy topographies, and sulfur-vacancy induced defect states illustrated at the valence band spectra imply the generation of surface states that causes the downward band bending at the n-type MoS2 surface. Bulk defects in thick MoS2 may also influence the Fermi level oppositely compared to the surface states. When Au contacts with our MoS2 thin films, the Fermi level downshifts and the binding energy reduces due to the hole doping characteristics of Au and easy charge transfer from the surface defect sites of MoS2. The shift of the onset potentials in hydrogen evolution reaction and the evolution of charge-transfer resistances extracted from the impedance measurement also indicate the Fermi level varies with MoS2 film thickness. The tunable Fermi level and the high chemical stability make our MoS2 a potential catalyst. The observed thickness-dependent properties can also be applied to other transition-metal dichalcogenides (TMDs), and facilitates the development in the low-dimensional electronic devices and catalysts. PMID- 27488186 TI - Nonmedical use of prescription drugs in the European Union. AB - BACKGROUND: Nonmedical prescription drug use (NMPDU) refers to the self-treatment of a medical condition using medication without a prescriber's authorization as well as use to achieve euphoric states. This article reports data from a cross national investigation of NMPDU in five European Countries, with the aim to understand the prevalence and characteristics of those engaging in NMPDU across the EU. METHODS: A parallel series of self-administered, cross-sectional, general population surveys were conducted in 2014. Data were collected using multi-stage quota sampling and then weighted using General Exponential Model. A total of 22,070 non-institutionalized participants, aged 12 to 49 years, in 5 countries: Denmark, Germany, Great Britain, Spain, and Sweden. Lifetime and past-year nonmedical use of prescription medications such as stimulants, opioids, and sedatives were ascertained via a modified version of the World Health Organization's Composite International Diagnostic Interview. Information about how the medications were acquired for NMPDU were also collected from the respondent. RESULTS: Lifetime and past-year prevalence of nonmedical prescription drug use was estimated for opioids (13.5 and 5.0 %), sedatives (10.9 and 5.8 %), and stimulants (7.0 and 2.8 %). Germany exhibited the lowest levels of NMPDU, with Great Britain, Spain, and Sweden having the highest levels. Mental and sexual health risk factors were associated with an increased likelihood of past year nonmedical prescription drug use. Among past-year users, about 32, 28, and 52 % of opioid, sedative, and stimulant nonmedical users, respectively, also consumed illicit drugs. Social sources (sharing by friends/family) were the most commonly endorsed methods of acquisition, ranging from 44 % (opioids) to 62 % (sedatives). Of interest is that Internet pharmacies were a common source of medications for opioids (4.1 %), stimulants (7.6 %), and sedatives (2.7 %). CONCLUSIONS: Nonmedical prescription drug use was reported across the five EU countries we studied, with opioids and sedatives being the most prevalent classes of prescription psychotherapeutics. International collaborations are needed for continued monitoring and intervention efforts to target population subgroups at greatest risk for NMDU. PMID- 27488187 TI - Material hardship and children's social-emotional development: Testing mitigating effects of Child Development Accounts in a randomized experiment. AB - BACKGROUND: Research has established a negative association between household material hardship and children's mental health. This study examines whether Child Development Accounts (CDAs), an economic intervention that encourages families to accumulate assets for children's long-term development, mitigate the association between material hardship and children's social-emotional development. METHODS: Researchers conducted a randomized experiment of CDAs in Oklahoma, USA, with a probability sample (N = 7328) of all infants born in two 3-month periods in 2007. After agreeing to participate in the experiment, caregivers of 2704 infants completed a baseline survey and were assigned randomly to the treatment (n = 1358) or control group (n = 1346). The intervention exposed the treatment group to a CDA, which consisted of an Oklahoma 529 College Savings Plan account, financial incentives and financial information. RESULTS: Material hardship has a negative association with the social-emotional development of children around the age of 4 years. Estimates from regression analysis indicate that CDAs mitigate about 50% of the negative association between material hardship and children's social-emotional development. CONCLUSIONS: Although they do not provide direct support for consumption in households experiencing material hardship, CDAs may improve child development by influencing parenting practices and parents' expectations for their children. We discuss the implications of using asset building programmes to improve child development. PMID- 27488188 TI - Dissecting relative contributions of cis- and trans-determinants to nucleosome distribution by comparing Tetrahymena macronuclear and micronuclear chromatin. AB - The ciliate protozoan Tetrahymena thermophila contains two types of structurally and functionally differentiated nuclei: the transcriptionally active somatic macronucleus (MAC) and the transcriptionally silent germ-line micronucleus (MIC). Here, we demonstrate that MAC features well-positioned nucleosomes downstream of transcription start sites and flanking splice sites. Transcription-associated trans-determinants promote nucleosome positioning in MAC. By contrast, nucleosomes in MIC are dramatically delocalized. Nucleosome occupancy in MAC and MIC are nonetheless highly correlated with each other, as well as with in vitro reconstitution and predictions based upon DNA sequence features, revealing unexpectedly strong contributions from cis-determinants. In particular, well positioned nucleosomes are often matched with GC content oscillations. As many nucleosomes are coordinately accommodated by both cis- and trans-determinants, we propose that their distribution is shaped by the impact of these nucleosomes on the mutational and transcriptional landscape, and driven by evolutionary selection. PMID- 27488189 TI - Impact of donor-recipient phylogenetic distance on bacterial genome transplantation. AB - Genome transplantation (GT) allows the installation of purified chromosomes into recipient cells, causing the resulting organisms to adopt the genotype and the phenotype conferred by the donor cells. This key process remains a bottleneck in synthetic biology, especially for genome engineering strategies of intractable and economically important microbial species. So far, this process has only been reported using two closely related bacteria, Mycoplasma mycoides subsp. capri (Mmc) and Mycoplasma capricolum subsp. capricolum (Mcap), and the main factors driving the compatibility between a donor genome and a recipient cell are poorly understood. Here, we investigated the impact of the evolutionary distance between donor and recipient species on the efficiency of GT. Using Mcap as the recipient cell, we successfully transplanted the genome of six bacteria belonging to the Spiroplasma phylogenetic group but including species of two distinct genera. Our results demonstrate that GT efficiency is inversely correlated with the phylogenetic distance between donor and recipient bacteria but also suggest that other species-specific barriers to GT exist. This work constitutes an important step toward understanding the cellular factors governing the GT process in order to better define and eventually extend the existing genome compatibility limit. PMID- 27488190 TI - Force and twist dependence of RepC nicking activity on torsionally-constrained DNA molecules. AB - Many bacterial plasmids replicate by an asymmetric rolling-circle mechanism that requires sequence-specific recognition for initiation, nicking of one of the template DNA strands and unwinding of the duplex prior to subsequent leading strand DNA synthesis. Nicking is performed by a replication-initiation protein (Rep) that directly binds to the plasmid double-stranded origin and remains covalently bound to its substrate 5'-end via a phosphotyrosine linkage. It has been proposed that the inverted DNA sequences at the nick site form a cruciform structure that facilitates DNA cleavage. However, the role of Rep proteins in the formation of this cruciform and the implication for its nicking and religation functions is unclear. Here, we have used magnetic tweezers to directly measure the DNA nicking and religation activities of RepC, the replication initiator protein of plasmid pT181, in plasmid sized and torsionally-constrained linear DNA molecules. Nicking by RepC occurred only in negatively supercoiled DNA and was force- and twist-dependent. Comparison with a type IB topoisomerase in similar experiments highlighted a relatively inefficient religation activity of RepC. Based on the structural modeling of RepC and on our experimental evidence, we propose a model where RepC nicking activity is passive and dependent upon the supercoiling degree of the DNA substrate. PMID- 27488191 TI - BMP and WNT: the road to cardiomyocytes is paved with precise modulation. PMID- 27488192 TI - On-the-road driving performance after use of the antihistamines mequitazine and l mequitazine, alone and with alcohol. AB - OBJECTIVE: Previous studies demonstrated that mequitazine produces mild sedation after single doses. Its enantiomer, l-mequitazine, has a stronger potency for the H1 receptor. The aim of the current study was to assess the effects of l mequitazine and mequitazine, alone and with alcohol, on driving. METHODS: Twenty five healthy volunteers were treated with l-mequitazine 2.5, 5.0 and 10 mg, mequitazine 10 mg and placebo, alone and in combination with alcohol in a double blind crossover design. Driving performance was assessed using the standardized highway driving test in normal traffic. Its primary measure is the Standard Deviation of the Lateral Position (SDLP). Secondary measures consisted of an auditory word learning test during driving, and subjective measures of driving performance. RESULTS: L-mequitazine 2.5 and 5.0 mg showed no effect on SDLP in the highway driving test, while SDLP significantly increased after l-mequitazine 10 mg (alone +1.59 cm; with alcohol +1.41 cm) and mequitazine 10 mg (with alcohol +1.17 cm). Alcohol significantly impaired all performance measures (SDLP +2.63 cm) but did not interact with the effects of treatment. Subjective measures indicated that participants were aware of the impairing effects of alcohol, but not of l-mequitazine and mequitazine. CONCLUSION: L-mequitazine can be considered safe to drive in dosages of 2.5 and 5.0 mg. L-mequitazine 10 mg led to mild driving impairment. Alcohol impaired all performance measures and added to the effects of l-mequitazine and mequitazine. PMID- 27488194 TI - Cyto- and genotoxic potential of water samples from polluted areas in Kosovo. AB - Reports on the state of the environment in Kosovo have emphasized that river and ground water quality is affected by pollution from untreated urban water as well as the waste water from the industry. One of the main contributors to this pollution is located in Obiliq (coal power plants). Prishtina-the capital city of Kosovo-is heavily influenced too. Furthermore, the pollutants combined together with those from heavy traffic are dissolved in Prishtina runoff water, which is discharged into the creek entering the river Sitnica together with urban waste water. The available data show the complex pollution with excessive quantities of nitrites, suspended materials, organic compounds, detergents, heavy metals, polychlorinated biphenyls, etc. In this study, the cytotoxic and genotoxic potential of water samples taken at these sites was tested in primary rat hepatocytes. The results obtained indicate that water samples collected in Prishtina and Obiliq had a significant cytotoxic potential in primary rat hepatocyte cultures even when diluted to 1 %. The increased cytotoxicity, however, was not accompanied by an increased genotoxicity as measured by the percentage of micronucleated cells. Further investigations addressing the chemical composition of the samples and the identification of the toxicants responsible for the cytotoxic effects found will be carried out in a next step. PMID- 27488193 TI - Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression. AB - RATIONALE: The N-methyl-D-aspartate (NMDA) receptor antagonists, including R ketamine and rapastinel (formerly GLYX-13), show rapid antidepressant effects in animal models of depression. OBJECTIVE: We compared the rapid and sustained antidepressant effects of R-ketamine and rapastinel in the social defeat stress model. RESULTS: In the tail suspension and forced swimming tests, R-ketamine (10 mg/kg, intraperitoneal (i.p.)) or rapastinel (10 mg/kg, i.p.) significantly attenuated the increased immobility time in the susceptible mice, compared with the vehicle-treated group. In the sucrose preference test, both compounds significantly enhanced the reduced preference in susceptible mice 2, 4, or 7 days after a single injection. All mice were sacrificed 8 days after a single injection. Western blot analyses showed that R-ketamine, but not rapastinel, significantly attenuated the reduced brain-derived neurotrophic factor (BDNF) TrkB signaling, postsynaptic density protein 95 (PSD-95), and GluA1 (a subtype of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor) in the prefrontal cortex, dentate gyrus, and CA3 of the hippocampus in the susceptible mice. In contrast, both compounds had no effect against the increased BDNF-TrkB signaling, PSD-95, and GluA1 seen in the nucleus accumbens of susceptible mice. Moreover, sustained antidepressant effect of R-ketamine (3 mg/kg, intravenous (i.v.)), but not rapastinel (3 mg/kg, i.v.), was detected 7 days after a single dose. CONCLUSIONS: These results highlight R-ketamine as a longer lasting antidepressant compared with rapastinel in social defeat stress model. It is likely that synaptogenesis including BDNF-TrkB signaling in the prefrontal cortex (PFC) and hippocampus may be required for the mechanisms promoting this sustained antidepressant effect. PMID- 27488195 TI - Assessment of pollutant load emission from combined sewer overflows based on the online monitoring. AB - Cities equipped with combined sewer systems discharge during wet weather a lot of pollutants into receiving waters by combined storm overflows (CSOs). According to the Polish legislation, CSOs should be activated no more than ten times per year, but in Lodz, most of the 18 existing CSOs operate much more frequently. To assess the pollutant load emitted by one of the existing CSOs, the sensors for measuring the concentration of total suspended solids (SOLITAX sc) and dissolved chemical oxygen demand (UVAS plus) installed in the overflow chamber as well as two flowmeters placed in the outflow sewer were used. In order to check the data from sensors, laboratory tests of combined wastewater quality were conducted simultaneously. For the analysis of the total pollutant load emitted from the overflow, the raw data was denoised using the Savitzky-Golay method. Comparing the load calculated from the analytical results to online smoothed measurements, negligible differences were found, which confirms the usefulness of applying the sensors in the combined sewer system. Online monitoring of the quantity and quality of wastewater emitted by the combined sewer overflows to water receivers, provides a considerable amount of data very useful for combined sewerage upgrading based on computer modelling, and allows for a significant reduction of laboratory analysis. PMID- 27488196 TI - A system dynamics approach for hospital waste management in a city in a developing country: the case of Nablus, Palestine. AB - Hospitals and health centers provide a variety of healthcare services and normally generate hazardous waste as well as general waste. General waste has a similar nature to that of municipal solid waste and therefore could be disposed of in municipal landfills. However, hazardous waste poses risks to public health, unless it is properly managed. The hospital waste management system encompasses many factors, i.e., number of beds, number of employees, level of service, population, birth rate, fertility rate, and not in my back yard (NIMBY) syndrome. Therefore, this management system requires a comprehensive analysis to determine the role of each factor and its influence on the whole system. In this research, a hospital waste management simulation model is presented based on the system dynamics technique to determine the interaction among these factors in the system using a software package, ithink. This model is used to estimate waste segregation as this is important in the hospital waste management system to minimize risk to public health. Real data has been obtained from a case study of the city of Nablus, Palestine to validate the model. The model exhibits wastes generated from three types of hospitals (private, charitable, and government) by considering the number of both inpatients and outpatients depending on the population of the city under study. The model also offers the facility to compare the total waste generated among these different types of hospitals and anticipate and predict the future generated waste both infectious and non-infectious and the treatment cost incurred. PMID- 27488198 TI - Visible Light-Induced Carbonylation Reactions with Organic Dyes as the Photosensitizers. AB - Dyes can CO do it: Organic dyes and pigments are usually applied in textile dyeing, which can be dated back to the Neolithic period. Interestingly, the possibility to use organic dyes as photoredox catalysts has also been noticed by organic chemists and applied in organic synthesis. Carbonylation reactions as a powerful procedure in carbonyl-containing compound preparation have also been studied. In this manuscript, the recent achievements in using organic dyes as visible-light sensitizers in carbonylation chemistry are summarized and discussed. PMID- 27488197 TI - Determination of total arsenic and arsenic species in drinking water, surface water, wastewater, and snow from Wielkopolska, Kujawy-Pomerania, and Lower Silesia provinces, Poland. AB - Arsenic is a ubiquitous element which may be found in surface water, groundwater, and drinking water. In higher concentrations, this element is considered genotoxic and carcinogenic; thus, its level must be strictly controlled. We investigated the concentration of total arsenic and arsenic species: As(III), As(V), MMA, DMA, and AsB in drinking water, surface water, wastewater, and snow collected from the provinces of Wielkopolska, Kujawy-Pomerania, and Lower Silesia (Poland). The total arsenic was analyzed by inductively coupled plasma mass spectrometry (ICP-MS), and arsenic species were analyzed with use of high performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC/ICP-MS). Obtained results revealed that maximum total arsenic concentration determined in drinking water samples was equal to 1.01 MUg L(-1). The highest concentration of total arsenic in surface water, equal to 3778 MUg L(-1) was determined in Trujaca Stream situated in the area affected by geogenic arsenic contamination. Total arsenic concentration in wastewater samples was comparable to those determined in drinking water samples. However, significantly higher arsenic concentration, equal to 83.1 +/- 5.9 MUg L(-1), was found in a snow sample collected in Legnica. As(V) was present in all of the investigated samples, and in most of them, it was the sole species observed. However, in snow sample collected in Legnica, more than 97 % of the determined concentration, amounting to 81 +/- 11 MUg L(-1), was in the form of As(III), the most toxic arsenic species. PMID- 27488199 TI - Rearfoot Transcutaneous Oximetry is a Useful Tool to Highlight Ischemia of the Heel. AB - PURPOSE: To demonstrate the usefulness of rearfoot transcutaneous oximetry to assess the peripheral arterial disease in diabetic patients with heel ulcer. METHODS: From our database of 550 critical limb ischemia diabetic patients followed after a percutaneous transluminal angioplasty, we have selected patients with below the knee arterial disease. Patients were grouped according to the dorsal transcutaneous oximetry value (Group A < 30 mmHg; Group B >= 30 mmHg). Patients of Group B had a second oximetry performed at the rearfoot, close to the lesion localized in all cases at the heel. Finally, the analysis of the arterial pattern disease has been done. RESULTS: We selected 191 patients: Group A (151 patients), dorsal transcutaneous oximetry of 11.8 +/- 0.7 mmHg; Group B (40 patients), dorsal transcutaneous oximetry of 44.2 +/- 10.1 mmHg. In Group B, rearfoot oximetry was 20.5 +/- 5 mmHg, significantly lower than dorsal oximetry (p = 0.0179). The anterior tibial artery was involved in all patients of Group A. In Group B, the anterior tibial artery was involved in 15 subjects and never alone; the posterior tibial artery was involved in 20 subjects and in 11 cases alone. The peroneal artery was affected in 20 subjects and in 14 patients alone. CONCLUSION: When a heel lesion is present and the transcutaneous oximetry recorded on the dorsum of the foot does not confirm the presence of critical limb ischemia (not <=30 mmHg), a second oximetry recorded on the rearfoot is useful to point out ischemia of the peroneal artery and/or of the posterior tibial artery. PMID- 27488200 TI - Phytoplankton responses to temperature increases are constrained by abiotic conditions and community composition. AB - Effects of temperature changes on phytoplankton communities seem to be highly context-specific, but few studies have analyzed whether this context specificity depends on differences in the abiotic conditions or in species composition between studies. We present an experiment that allows disentangling the contribution of abiotic and biotic differences in shaping the response to two aspects of temperature change: permanent increase of mean temperature versus pulse disturbance in form of a heat wave. We used natural communities from six different sites of a floodplain system as well as artificially mixed communities from laboratory cultures and grew both, artificial and natural communities, in water from the six different floodplain lakes (sites). All 12 contexts (2 communities * 6 sites) were first exposed to three different temperature levels (12, 18, 24 degrees C, respectively) and afterward to temperature pulses (4 degrees C increase for 7 h day(-1)). Temperature-dependent changes in biomass and community composition depended on the initial composition of phytoplankton communities. Abiotic conditions had a major effect on biomass of phytoplankton communities exposed to different temperature conditions, however, the effect of biotic and abiotic conditions together was even more pronounced. Additionally, phytoplankton community responses to pulse temperature effects depended on the warming history. By disentangling abiotic and biotic effects, our study shows that temperature-dependent effects on phytoplankton communities depend on both, biotic and abiotic constraints. PMID- 27488201 TI - Combining Passive Sampling with Toxicological Characterization of Complex Mixtures of Pollutants from the Aquatic Environment. AB - The combination of polymer-based passive sampling to collect complex environmental mixtures of pollutants, the transfer of these mixtures into bioassays, and their related toxicological characterization is still in its infancy. However, this approach has considerable potential to improve environmental hazard and risk assessment for two reasons. First, the passive sampler collects a broad range of chemicals representing the fraction of compounds available for diffusion and (bio)uptake, excluding a large part of the matrix; thus, extensive sample cleanup which could discriminate certain compounds can be avoided. Second, the toxicological characterization of samples using bioassays is complementary to chemical (target) analysis within environmental monitoring because it captures all chemicals exerting the same mode of toxic action and acting jointly in mixtures, thus providing a comprehensive picture of their overall combined effects. The scientific literature describes a range of examples from the water phase where passive sampling is usually carried out in the kinetic uptake regime for most chemicals although some may already have reached equilibrium. The composition of the chemical mixture changes from the water phase to the passive sampling material because of kinetic effects and polymer/water partition coefficients which depend on the chemicals' hydrophobicity. In contrast, only a few applications in sediment and biota have been described, but amongst these some pioneering studies have demonstrated the feasibility and potential of this combined approach. This chapter gives an overview of what has been carried out in this research area, focusing on opportunities and challenges, and points out desirable future developments with a focus on the importance of choosing a suitable combination of sampling and dosing to transfer (or re-establish) the environmental mixture into the bioassay. PMID- 27488202 TI - Rapid reduction of antibodies and improvement of disease activity by immunoadsorption in Chinese patients with severe systemic lupus erythematosus. AB - This was an exploratory analysis comparing the safety and efficacy of immunoadsorption (IAS) combination therapy in severe systemic lupus erythematosus (SLE) receiving corticosteroid pulse and immunosuppressant treatment. Patients enrolled all had predominant organ involvement including proteinuria, thrombocytopenia, pericardial effusion, and cerebral involvement requiring corticosteroid pulse treatment. Fifty-two patients in study group received IAS plus corticosteroid and cyclophosphamide treatment. Fifty-two patients in non-IAS group received corticosteroid and cyclophosphamide treatment. Outcome measurement included C3, dsDNA, AnuA, and SLE disease activity index (SLEDAI) 2k score and in particular cases, proteinuria quantification and platelet count. Disease activity dropped significantly in both groups. Improvement of disease activity markers was more significant in study group than that in non-IAS group. The lower dosage of steroid in study group suggested the steroid-sparing effect of IAS. No severe adverse effect occurred during IAS. Our study suggested IAS as an additional therapy to steroid pulse and immunosuppressant in treating severe SLE. PMID- 27488203 TI - Endocannabinoids participate in placental apoptosis induced by hypoxia inducible factor-1. AB - During pregnancy, apoptosis is a physiological event critical in the remodeling and aging of the placenta. Increasing evidence has pointed towards the relevance of endocannabinoids (ECs) and hypoxia as modulators of trophoblast cell death. However, the relation between these factors is still unknown. In this report, we evaluated the participation of ECs in placental apoptosis induced by cobalt chloride (CoCl2), a hypoxia mimicking agent that stabilizes the expression of hypoxia inducible factor-1 alpha (HIF-1alpha). We found that HIF-1alpha stabilization decreased FAAH mRNA and protein levels, suggesting an increase in ECs tone. Additionally, CoCl2 incubation and Met-AEA treatment reduced cell viability and increased TUNEL-positive staining in syncytiotrophoblast layer. Immunohistochemical analysis demonstrated Bax and Bcl-2 protein expression in the cytoplasm of syncytiotrophoblast. Finally, HIF-1alpha stabilization produced an increase in Bax/Bcl-2 ratio, activation of caspase 3 and PARP cleavage. All these changes in apoptotic parameters were reversed with AM251, a CB1 antagonist. These results demonstrate that HIF-1alpha may induce apoptosis in human placenta via intrinsic pathway by a mechanism that involves activation of CB1 receptor suggesting a role of the ECs in this process. PMID- 27488204 TI - Alcohol and Opioid Use Disorder in Older Adults: Neglected and Treatable Illnesses. AB - The purpose of this article is to provide an overview of alcohol use disorder (AUD) and opioid use disorder (OUD) in older adults for general psychiatrists. The rapid growth of the geriatric population in the USA has wide-ranging implications as the baby boomer generation ages. Various types of substance use disorders (SUDs) are common in older adults, and they often take a greater toll on affected older adults than on younger adults. Due to multiple reasons, SUDs in older adults are often under-reported, under-detected, and under-treated. Older adults often use substances, which leads to various clinical problems. Space limitations prevents a comprehensive review; therefore, we primarily focus on alcohol use disorder and the problem of opioid use disorder, with more emphasis given to the latter, because the opioid use epidemic in the USA has gained much attention. We reviewed the literature on the topics, integrated across geriatric psychiatry, addiction psychiatry, research, and national trends. We discuss unique vulnerabilities of older adults to SUDs with regard to management of SUDs in older adults, medication-assisted treatment (MAT), and psychosocial treatments. We encourage general psychiatrists to raise their awareness of SUDs in older adults and to provide brief intervention or referral for further assessment. PMID- 27488205 TI - Pet Ownership and the Risk of Dying. PMID- 27488206 TI - An Algorithm and R Program for Fitting and Simulation of Pharmacokinetic and Pharmacodynamic Data. AB - BACKGROUND AND OBJECTIVES: Pharmacokinetic/pharmacodynamic link models are widely used in dose-finding studies. By applying such models, the results of initial pharmacokinetic/pharmacodynamic studies can be used to predict the potential therapeutic dose range. This knowledge can improve the design of later comparative large-scale clinical trials by reducing the number of participants and saving time and resources. However, the modeling process can be challenging, time consuming, and costly, even when using cutting-edge, powerful pharmacological software. Here, we provide a freely available R program for expediently analyzing pharmacokinetic/pharmacodynamic data, including data importation, parameter estimation, simulation, and model diagnostics. METHODS: First, we explain the theory related to the establishment of the pharmacokinetic/pharmacodynamic link model. Subsequently, we present the algorithms used for parameter estimation and potential therapeutic dose computation. The implementation of the R program is illustrated by a clinical example. The software package is then validated by comparing the model parameters and the goodness-of-fit statistics generated by our R package with those generated by the widely used pharmacological software WinNonlin. RESULTS: The pharmacokinetic and pharmacodynamic parameters as well as the potential recommended therapeutic dose can be acquired with the R package. The validation process shows that the parameters estimated using our package are satisfactory. CONCLUSIONS: The R program developed and presented here provides pharmacokinetic researchers with a simple and easy-to-access tool for pharmacokinetic/pharmacodynamic analysis on personal computers. PMID- 27488207 TI - The first Turkish illustrated surgical textbook 'Cerrahiyetu'l-Haniyye'. PMID- 27488208 TI - The Selection and Control of Starting Materials Should be Governed by Science and Risk-Based Approaches. PMID- 27488209 TI - Getting Burned by Lactic Acid. PMID- 27488210 TI - Circulating PCSK9 levels and CETP plasma activity are independently associated in patients with metabolic diseases. AB - BACKGROUND: PCSK9 inhibition is a new powerful cholesterol-lowering strategy. Recently, it was reported that CETP inhibitors influence PCSK9 levels as an off target effect. We explored the relationship between circulating PCSK9 levels and CETP activity in patients with metabolic disease who were not on lipid-lowering therapy. METHODS: Plasma CETP activity and PCSK9 levels were measured in 450 participants (median age, 58 years; 49 % women) who attended the metabolism unit because of metabolic syndrome (MetS) (78 %), atherogenic dyslipidemia (32 %), obesity (50 %), type 2 diabetes mellitus (72 %), and other risk factors (13 %). A 6 week lipid-lowering drug wash-out period was established in treated patients. RESULTS: Both PCSK9 levels and CETP activity were higher in patients with an increasing number of MetS components. PCSK9 levels were positively correlated with CETP activity in the entire cohort (r = 0.256, P < 0.0001) independent of age, gender, body mass index (BMI), systolic blood pressure (SBP), LDL cholesterol (LDL-C), triglycerides and glucose. Individuals with the loss-of function PCSK9 genetic variant rs11591147 (R46L) had lower levels of PCSK9 (36.5 %, P < 0.0001) and LDL-C (17.8 %, P = 0.010) as well as lower CETP activity (10.31 %, P = 0.009). This association remained significant in the multiple regression analysis even after adjusting for gender, age, BMI, LDL-C, triglycerides, glucose, lecithin-cholesterol acyltransferase, SBP and MetS (P = 0.003). CONCLUSIONS: Our data suggest a metabolic association between PCSK9 and CETP independent of lipid-lowering treatment. The clinical implications of this metabolic relationship could be relevant for explaining the effect of PCSK9 and CETP inhibition on overall lipid profiles. PMID- 27488213 TI - Use of PlasmaJet for Peritoneal Carcinomatosis in Ovarian Cancer. AB - OBJECTIVE: This study aimed to assess the role and complications of extensive cytoreduction with PlasmaJet (Plasma Surgical, Roswell, Ga) in ovarian cancer with peritoneal carcinomatosis. MATERIALS: All patients undergoing primary, secondary, or interval debulking surgery for ovarian cancer and treated with PlasmaJet between October 2013 and February 2015 were analyzed. RESULTS: Nineteen patients were enrolled. The median operative time was 270 minutes, median blood loss was 700 mL, and median length of stay was 9 days. In all patients, complete resection of all macroscopic disease was achieved.We used PlasmaJet to remove peritoneal carcinomatosis on the abdominal peritoneum, intestinal mesentery, bowel serosa, and diaphragmatic region. Overall, we treated 66 organs with PlasmaJet in our series. No bowel or urological fistulas were observed. According to the Clavien-Dindo classification, 13 adverse events were recorded at grade 2 or lesser. We observed only 1 grade 3 adverse event. No postoperative mortality was recorded. CONCLUSIONS: In our series, the PlasmaJet seems to be an efficient device for tumor ablation or dissection to obtain complete resection of all macroscopic disease in patients with peritoneal carcinomatosis. PMID- 27488212 TI - Randomized Trial of Computerized Cognitive Behavioral Therapy for Alcohol Use Disorders: Efficacy as a Virtual Stand-Alone and Treatment Add-On Compared with Standard Outpatient Treatment. AB - BACKGROUND: Cognitive behavioral therapy (CBT) is an evidence-based treatment for alcohol use disorders (AUDs), yet is rarely implemented with high fidelity in clinical practice. Computer-based delivery of CBT offers the potential to address dissemination challenges, but to date there have been no evaluations of a web based CBT program for alcohol use within a clinical sample. METHODS: This study randomized treatment-seeking individuals with a current AUD to 1 of 3 treatments at a community outpatient facility: (i) standard treatment as usual (TAU); (ii) TAU plus on-site access to a computerized CBT targeting alcohol use (TAU + CBT4CBT); or (iii) CBT4CBT plus brief weekly clinical monitoring (CBT4CBT + monitoring). Participant alcohol use was assessed weekly during an 8-week treatment period, as well as 1, 3, and 6 months after treatment. RESULTS: Sixty eight individuals (65% male; 54% African American) were randomized (TAU = 22; TAU + CBT4CBT = 22; CBT4CBT + monitoring = 24). There were significantly higher rates of treatment completion among participants assigned to 1 of the CBT4CBT conditions compared to TAU (Wald = 6.86, p < 0.01). Significant reductions in alcohol use were found across all conditions within treatment, with participants assigned to TAU + CBT4CBT demonstrating greater increases in percentage of days abstinent (PDA) compared to TAU, t(536.4) = 2.68, p < 0.01, d = 0.71, 95% CI (0.60, 3.91), for the full sample. Preliminary findings suggest the estimated costs of all self-reported AUD-related services utilized by participants were considerably lower for those assigned to CBT4CBT conditions compared to TAU, both within treatment and during follow-up. CONCLUSIONS: This trial demonstrated the safety, feasibility, and preliminary efficacy of web-based CBT4CBT targeting alcohol use. CBT4CBT was superior to TAU at increasing PDA when delivered as an add-on, and it was not significantly different from TAU or TAU + CBT4CBT when delivered with clinical monitoring only. PMID- 27488214 TI - Current South African clinical Practice in Debulking Surgery for Ovarian Cancer. AB - INTRODUCTION: The aim of this study was to assess practice patterns and rationale with regard to debulking surgery for advanced epithelial ovarian carcinoma among South African Gynaecological oncologists. METHODS: A survey was distributed to all practicing gynecological oncologists in South Africa. It was structured to assess definitions of optimal debulking, procedures used to achieve optimal debulking, and reasons for not performing specific procedures. Respondents were also asked to report on experience and additional surgical training to improve skill in performing ultra-radical debulking surgery. RESULTS: Eighty percent of gynecological oncologists completed the survey. Sixty percent of respondents reported that they view optimal debulking as no visible disease, and this was achieved in 63% of surgical cases. The most common barriers to optimal debulking were medical comorbidities (85%), followed by lack of expertise in ultra-radical debulking surgery (55%) and advanced patient age (40%). At operation, the most common disease findings precluding optimal debulking were large volume confluent peritoneal disease and confluent diaphragmatic disease. All of the surgeons perform excision of bulky pelvic and lower paraaortic nodes themselves. Bowel resections are often performed with the help of a colleague, but more than half of the respondents never perform diaphragmatic stripping, resection of liver metastases, distal pancreatic resection, or ablation of peritoneal metastases. Overall, most participants seem to regularly perform debulking procedures in the pelvis but are less comfortable with resection of upper abdominal or peritoneal disease. Most common reasons for not performing procedures were concerns about patient morbidity and concerns regarding benefit. Fifty percent of respondents also reported a lack of personal expertise in performing ultra-radical debulking procedures. CONCLUSIONS: The progression of South African Gynaecological Oncologist towards more aggressive debulking surgery is following international trends, but many of the surgeons report a lack of experience in ultra-radical debulking surgery, especially in the upper abdomen. PMID- 27488215 TI - Primary Placement of Incisional Negative Pressure Wound Therapy at Time of Laparotomy for Gynecologic Malignancies. AB - OBJECTIVE: Wound complications are an important cause of postoperative morbidity amongst patient with gynecologic malignancies. We evaluated whether the placement of prophylactic negative pressure wound therapy (NPWT) at the time of laparotomy for gynecologic cancer surgery reduces wound complication rates. METHODS: A retrospective analysis of patients undergoing laparotomy with primary wound closure performed by a gynecologic oncologist at a single academic institution over a 5-year study period was performed. Patients who had placement of prophylactic NPWT dressing were compared with patients with a standard closure. Postoperative outcomes were examined. RESULTS: A total of 230 patients were identified: 208 women received standard wound care, 22 received NPWT. Groups were similar in age, prevalence of diabetes, tobacco use, and number of previous abdominal procedures. Intraoperative factors including length of procedure and transfusion requirements were similar. Body mass index for patients receiving standard treatment was 30.67 compared with 41.29 for NPWT group (P < 0.001). Incidence of all wound complications was 19.7% for those receiving standard treatment versus 27.3% for NPWT group (P = 0.40). Length of hospital stay was similar between the 2 groups (5.25 vs 6.22 days, P = 0.20). There were 3 hospital readmissions for wound complications-none occurred in women with a prophylactic NPWT dressing. CONCLUSIONS: Despite significantly higher obesity rates, patients with prophylactic NPWT dressing placement had similar rates of wound complications. Our findings suggest a potential therapeutic benefit in the use of prophylactic NPWT for the reduction of wound complications in this high-risk gynecologic oncology patient population. PMID- 27488216 TI - Incidence and Characteristics of Unsuspected Neoplasia Discovered in High-Risk Women Undergoing Risk Reductive Bilateral Salpingooophorectomy. AB - OBJECTIVE: Risk reducing salpingooophorectomy is recommended to women with a BReast CAncer susceptibility gene (BRCA) 1 or 2 germline mutation to reduce the risk of ovarian cancer. The incidence of unsuspected neoplasia varies in the literature. The purpose of this study was to identify the rate of unsuspected neoplasia in a high-risk Australian population, discuss their management, and assess the clinical outcome. METHOD: This is a retrospective review of all women undergoing risk reductive salpingooophorectomy between January 2006 and December 2014. The medical, operative, and pathology results were reviewed. The specimens were assessed using the Sectioning and Extensively Examining the Fimbriated End protocol to the fallopian tube, and the ovary was also examined using 2 to 3 mm sectioning. RESULTS: During the study period, 138 patients underwent risk reducing salpingooophorectomy for a known BRCA 1 or 2 germline mutation or a high risk personal or family history of ovarian cancer. Five patients with neoplasia were identified, 2 with invasive tubal carcinoma and 3 with serous tubal intraepithelial carcinoma (STIC), giving an overall incidence of 3.62%. Invasive tubal carcinoma occurred in 1 woman with a BRCA 1 mutation and 1 woman with a BRCA 2 mutation. The incidence of carcinoma in women with either a BRCA 1 or 2 germline mutation was subsequently 2.78%. STIC occurred in 2 women with a BRCA 1 germline mutation and 1 woman carrying a BRCA 2 germline mutation. The incidence of STIC in women with either a BRCA 1 or 2 germline mutation was subsequently 4.17%. Of the patients with STIC, all 3 remain disease free at an average follow up period of 79.33 months. CONCLUSIONS: In this retrospective review, we found the incidence of neoplasia within a high-risk Australian population undergoing risk-reducing bilateral salpingo-oophorectomy to be 3.62%. The incidence of STIC was 2.17%. During our follow-up period, all patients with STIC remained disease free. PMID- 27488217 TI - Physical Activity Correlates, Barriers, and Preferences for Women With Gynecological Cancer. AB - OBJECTIVE: Physical activity is associated with improved health outcomes for people with cancer. We aimed to identify physical activity correlates, barriers, and preferences among women with gynecological cancer. METHODS AND MATERIALS: A self-administered questionnaire was completed by 101 women diagnosed with gynecological cancer (mostly ovarian cancer [59%] and endometrial cancer [23%]) within the previous 2 years, at 2 major hospitals in Sydney, Australia. Physical activity was measured for the past 7 days. Thirteen potential barriers were scored on a 5-point scale. Associations with physical activity were assessed using Spearman correlations (rs) and multivariate logistic regression. RESULTS: Factors associated with being sufficiently active (>=150 min/wk physical activity) were being in the follow-up phase of the cancer trajectory (odds ratio [OR], 7.0; 95% confidence interval [CI], 1.5 to 33.4 compared with other phases) and prediagnosis physical activity (OR, 4.6; 95% CI, 1.1 to 18.5 for the highest vs lowest tertile). The most common barriers were "too tired" and "not well enough," and both were associated with lower physical activity (rs, -0.20 and 0.22, respectively). The odds of having disease-specific barriers was higher for women with ovarian cancer (OR, 4.6; P = 0.04) and women receiving chemotherapy or radiation therapy (OR, 8.3; P = 0.008). "Lack of interest" (rs, -0.26) and "never been active" (rs, -0.23) were also inversely correlated with physical activity, although less common. Forty-three percent of women indicated that they were extremely or very interested to have a one-to-one session with an exercise physiologist. Participants' preferred time of starting a physical activity program was 3 to 6 months after treatment (26%) or during treatment (23%). Walking was the preferred type of physical activity. CONCLUSIONS: Strategies to increase physical activity among women with gynecological cancer should include a focus on reducing disease-specific barriers and target women who have done little physical activity in the past or who are in the treatment phases of care. PMID- 27488211 TI - Erythropoietin and mTOR: A "One-Two Punch" for Aging-Related Disorders Accompanied by Enhanced Life Expectancy. AB - Life expectancy continues to increase throughout the world, but is accompanied by a rise in the incidence of non-communicable diseases. As a result, the benefits of an increased lifespan can be limited by aging-related disorders that necessitate new directives for the development of effective and safe treatment modalities. With this objective, the mechanistic target of rapamycin (mTOR), a 289-kDa serine/threonine protein, and its related pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), proline rich Akt substrate 40 kDa (PRAS40), AMP activated protein kinase (AMPK), Wnt signaling, and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), have generated significant excitement for furthering novel therapies applicable to multiple systems of the body. Yet, the biological and clinical outcome of these pathways can be complex especially with oversight of cell death mechanisms that involve apoptosis and autophagy. Growth factors, and in particular erythropoietin (EPO), are one avenue under consideration to implement control over cell death pathways since EPO can offer potential treatment for multiple disease entities and is intimately dependent upon mTOR signaling. In experimental and clinical studies, EPO appears to have significant efficacy in treating several disorders including those involving the developing brain. However, in mature populations that are affected by aging-related disorders, the direction for the use of EPO to treat clinical disease is less clear that may be dependent upon a number of factors including the understanding of mTOR signaling. Continued focus upon the regulatory elements that control EPO and mTOR signaling could generate critical insights for targeting a broad range of clinical maladies. PMID- 27488218 TI - Predictive Capacity of 3 Comorbidity Indices in Estimating Survival Endpoints in Women With Early-Stage Endometrial Carcinoma. AB - OBJECTIVE: The negative impact of comorbidity on survival in women with endometrial carcinoma (EC) is well-known. Few validated comorbidity indices are available for clinical use, such as the Charlson Comorbidity Index (CCI), the Age Adjusted CCI (AACCI), and the Adult Comorbidity Evaluation-27 (ACE-27). The aim of the study is to determine which index best correlates with survival endpoints in women with EC. MATERIALS AND METHODS: We identified 1132 women with early stage EC treated at an academic center. Three scores were calculated for each patient using CCI, AACCI, and ACE-27 at the time of hysterectomy. Univariate and multivariable modeling was used to determine predictors of survival. RESULTS: For each of the studied comorbidity indices, the highest scores were significantly correlated with poorer overall survival. The hazard ratio of death from any cause was 3.92 for AACCI, 2.25 for CCI, and 1.57 for ACE-27. All 3 indices were independent predictors of overall survival with a P value of less than 0.001 on multivariate analysis. In addition, lymphovascular space invasion, lower uterine segment involvement, and tumor grade were predictors of overall survival. Lymphovascular space invasion, grade (P < 0.001), and high AACCI score were the only significant predictors of recurrence-free survival (RFS). Lymphovascular space invasion and tumor grade were the only 2 predictors of disease-specific survival. CONCLUSIONS: Although all 3 studied comorbidity indices were significant predictors of overall survival in women with early-stage EC, AACCI showed a stronger association. It should be considered for evaluating comorbidity in women with early-stage EC. PMID- 27488219 TI - Altered Mental Status in ICU Patients: Diagnostic Yield of Noncontrast Head CT for Abnormal and Communicable Findings. AB - OBJECTIVE: To evaluate the diagnostic yield of noncontrast head CT for acute communicable findings in ICU patients specifically scanned for altered mental status. DESIGN: Retrospective observational cohort study. SETTING: University Hospital Neuroscience, Medical, and Surgical ICUs. PATIENTS: ICU patients with new-onset altered mental status. INTERVENTION: Noncontrast head CT. MEASUREMENTS AND MAIN RESULTS: Reports on head CTs from two university hospitals performed for the sole indication of altered mental status in ICU patients between July 2011 and June 2013 were reviewed for 1) acute (new or worsening) hemorrhage, 2) mass effect/herniation, 3) infarction, and 4) hydrocephalus. Subgroup analyses of positive findings were performed by 1) ICU group type, 2) age, and 3) race. A total of 2,486 head CTs were performed in 1,357 patients whose age ranged from 14 to 116 years (median, 59; mean, 57.6 +/- 16). Acute communicable findings in at least one of four categories were present in 22.8% (566/2,486) of examinations, with hydrocephalus being most common (11.5% [286/2,486]). The frequency of any acute communicable findings in neuroscience, medical, and surgical ICUs was 28.6% (471/1,648), 9.8% (43/440), and 13.1% (52/398), respectively. Neuroscience ICU head CTs had significantly higher rates of acute communicable findings in all categories, except for acute infarction, compared with the other two ICUs (p < 0.001). Acute hydrocephalus (13.6% vs 7.4%; p < 0.001) and mass effect (6.7% vs 4.3%; p = 0.01) were more common in patients less than 65 years. For other acute categories, no significant difference was noted by age. There was no significant difference in the likelihood of a positive examination by race. CONCLUSIONS: Almost one in four head CTs in a university ICU patient population performed for primary indication of altered mental status yields abnormal communicable findings. In this patient population, utilization management barriers to examination ordering should be minimized. PMID- 27488220 TI - Functional Status Score for the ICU: An International Clinimetric Analysis of Validity, Responsiveness, and Minimal Important Difference. AB - OBJECTIVES: To evaluate the internal consistency, validity, responsiveness, and minimal important difference of the Functional Status Score for the ICU, a physical function measure designed for the ICU. DESIGN: Clinimetric analysis. SETTINGS: Five international datasets from the United States, Australia, and Brazil. PATIENTS: Eight hundred nineteen ICU patients. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Clinimetric analyses were initially conducted separately for each data source and time point to examine generalizability of findings, with pooled analyses performed thereafter to increase power of analyses. The Functional Status Score for the ICU demonstrated good to excellent internal consistency. There was good convergent and discriminant validity, with significant and positive correlations (r = 0.30-0.95) between Functional Status Score for the ICU and other physical function measures, and generally weaker correlations with nonphysical measures (|r| = 0.01-0.70). Known group validity was demonstrated by significantly higher Functional Status Score for the ICU scores among patients without ICU-acquired weakness (Medical Research Council sum score, >= 48 vs < 48) and with hospital discharge to home (vs healthcare facility). Functional Status Score for the ICU at ICU discharge predicted post ICU hospital length of stay and discharge location. Responsiveness was supported via increased Functional Status Score for the ICU scores with improvements in muscle strength. Distribution-based methods indicated a minimal important difference of 2.0-5.0. CONCLUSIONS: The Functional Status Score for the ICU has good internal consistency and is a valid and responsive measure of physical function for ICU patients. The estimated minimal important difference can be used in sample size calculations and in interpreting studies comparing the physical function of groups of ICU patients. PMID- 27488221 TI - Administration of Pure Ergothioneine to Healthy Human Subjects: Uptake, Metabolism, and Effects on Biomarkers of Oxidative Damage and Inflammation. AB - AIM: We investigated the uptake and pharmacokinetics of l-ergothioneine (ET), a dietary thione with free radical scavenging and cytoprotective capabilities, after oral administration to humans, and its effect on biomarkers of oxidative damage and inflammation. RESULTS: After oral administration, ET is avidly absorbed and retained by the body with significant elevations in plasma and whole blood concentrations, and relatively low urinary excretion (<4% of administered ET). ET levels in whole blood were highly correlated to levels of hercynine and S methyl-ergothioneine, suggesting that they may be metabolites. After ET administration, some decreasing trends were seen in biomarkers of oxidative damage and inflammation, including allantoin (urate oxidation), 8-hydroxy-2' deoxyguanosine (DNA damage), 8-iso-PGF2alpha (lipid peroxidation), protein carbonylation, and C-reactive protein. However, most of the changes were non significant. INNOVATION: This is the first study investigating the administration of pure ET to healthy human volunteers and monitoring its uptake and pharmacokinetics. This compound is rapidly gaining attention due to its unique properties, and this study lays the foundation for future human studies. CONCLUSION: The uptake and retention of ET by the body suggests an important physiological function. The decreasing trend of oxidative damage biomarkers is consistent with animal studies suggesting that ET may function as a major antioxidant but perhaps only under conditions of oxidative stress. Antioxid. Redox Signal. 26, 193-206. PMID- 27488222 TI - Exposure to bacterial endotoxin generates a distinct strain of alpha-synuclein fibril. AB - A single amyloidogenic protein is implicated in multiple neurological diseases and capable of generating a number of aggregate "strains" with distinct structures. Among the amyloidogenic proteins, alpha-synuclein generates multiple patterns of proteinopathies in a group of diseases, such as Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). However, the link between specific conformations and distinct pathologies, the key concept of the strain hypothesis, remains elusive. Here we show that in the presence of bacterial endotoxin, lipopolysaccharide (LPS), alpha-synuclein generated a self-renewable, structurally distinct fibril strain that consistently induced specific patterns of synucleinopathies in mice. These results suggest that amyloid fibrils with self-renewable structures cause distinct types of proteinopathies despite the identical primary structure and that exposure to exogenous pathogens may contribute to the diversity of synucleinopathies. PMID- 27488223 TI - Recruitment methods in a clinical trial of provoked vulvodynia: Predictors of enrollment. AB - BACKGROUND: Successful recruitment in clinical trials for chronic pain conditions is challenging, especially in women with provoked vulvodynia due to reluctance in discussing pain associated with sexual intercourse. The most successful recruitment methods and the characteristics of women reached with these methods are unknown. OBJECTIVE: To compare the effectiveness and efficiency of four recruitment methods and to determine socioeconomic predictors for successful enrollment in a National Institutes of Health-sponsored multicenter clinical trial evaluating a gabapentin intervention in women with provoked vulvodynia. METHODS: Recruitment methods utilized mass mailing, media, clinician referrals and community outreach. Effectiveness (number of participants enrolled) and efficiency (proportion screened who enrolled) were determined. Socioeconomic variables including race, educational level, annual household income, relationship status, age, menopausal status and employment status were also evaluated regarding which recruitment strategies were best at targeting specific cohorts. RESULTS: Of 868 potential study participants, 219 were enrolled. The most effective recruitment method in enrolling participants was mass mailing ( p < 0.001). There were no statistically significant differences in efficiency between recruitment methods ( p = 0.11). Relative to clinician referral, black women were 13 times as likely to be enrolled through mass mailing (adjusted odds ratio 12.5, 95% confidence interval, 3.6-43.1) as white women. There were no differences in enrollment according to educational level, annual income, relationship status, age, menopausal status, or employment status and recruitment method. CONCLUSION: In this clinical trial, mass mailing was the most effective recruitment method. Race of participants enrolled in a provoked vulvodynia trial was related to the recruitment method. PMID- 27488224 TI - Assessment of the effectiveness of three different cephalosporin/clavulanate combinations for the phenotypic confirmation of extended-spectrum beta-lactamase producing bacteria isolated from urine samples at National Public Health Laboratory, Kathmandu, Nepal AB - BACKGROUND: The extended-spectrum beta-lactamase (ESBL) producing bacteria are present as the serious public health problems due to their resistance to large number of antibiotics. The main aims of this study were to determine the prevalence and antibiotic resistance patterns of bacteria producing extended spectrum beta-lactamases (ESBLs) and to find the suitable cephalosporin/clavulanate combination for phenotypic confirmation of ESBL production. METHODS: During the study period from April 2013 to November 2013, a total of 1003 urine samples from the patients visiting National Public Health Laboratory, Kathmandu, Nepal were collected and processed. The isolates were identified with the help of colony characteristics, gram stain and conventional biochemical tests. Antimicrobial susceptibility testing was performed by Kirby Bauer disc diffusion method. ESBL production screening was done by using ceftriaxone, while ESBL production confirmation was done by using three different 3rd generation cephalosporin/clavulanate combinations. RESULTS: Of the 138 isolates, Escherichia coli was the most predominant with 88 (63.8 %) isolates. Among the antibiotics tested for gram negative bacteria, highest susceptibility was seen toward imipenem followed by amikacin. Of the total isolates, 68 (49.3 %) were suspected as ESBL producers. Of these, 44 (64.7 %) were phenotypically confirmed to be ESBL producers. The majority of ESBL producers were E. coli with 34 (72.3 %) isolates. Of the three different 3rd generation cephalosporin/clavulanate combinations used, ceftazidime/clavulanate combination was found to be most effective for phenotypic confirmation of ESBL producers and was statistically highly significant (P < 0.01). CONCLUSION: Based on the findings of our study, we recommend to use ceftazidime/clavulanate combination for phenotypic confirmation of ESBL producers. Routine ESBL testing for uropathogens along with conventional antibiogram would be useful for proper early management of all the cases of urinary tract infections. PMID- 27488225 TI - Shifting blame: Buprenorphine prescribers, addiction treatment, and prescription monitoring in middle-class America. AB - Growing nonmedical prescription opioid analgesic use among suburban and rural Whites has changed the public's perception of the nature of opioid addiction, and of appropriate interventions. Opioid addiction has been recast as a biological disorder in which patients are victims of their neurotransmitters and opioid prescribers are irresponsible purveyors of dangerous substances requiring controls. This framing has led to a different set of policy responses than the "War on Drugs" that has focused on heroin trade in poor urban communities; in response to prescription opioid addiction, prescription drug monitoring programs and tamper-resistant opioid formulations have arisen as primary interventions in place of law enforcement. Through the analysis of preliminary findings from interviews with physicians who are certified to manage opioid addiction with the opioid pharmaceutical buprenorphine, we argue that an increase in prescriber monitoring has shifted the focus from addicted people to prescribers as a threat, paradoxically driving users to illicit markets and constricting their access to pharmaceutical treatment for opioid addiction. Prescriber monitoring is also altering clinical cultures of care, as general physicians respond to heightened surveillance and the psychosocial complexities of treating addiction with either rejection of opioid dependent patients, or with resourceful attempts to create support systems for their treatment where none exists. PMID- 27488228 TI - Boron isotope fractionation in magma via crustal carbonate dissolution. AB - Carbon dioxide released by arc volcanoes is widely considered to originate from the mantle and from subducted sediments. Fluids released from upper arc carbonates, however, have recently been proposed to help modulate arc CO2 fluxes. Here we use boron as a tracer, which substitutes for carbon in limestone, to further investigate crustal carbonate degassing in volcanic arcs. We performed laboratory experiments replicating limestone assimilation into magma at crustal pressure-temperature conditions and analysed boron isotope ratios in the resulting experimental glasses. Limestone dissolution and assimilation generates CaO-enriched glass near the reaction site and a CO2-dominated vapour phase. The CaO-rich glasses have extremely low delta(11)B values down to -41.50/00, reflecting preferential partitioning of (10)B into the assimilating melt. Loss of (11)B from the reaction site occurs via the CO2 vapour phase generated during carbonate dissolution, which transports (11)B away from the reaction site as a boron-rich fluid phase. Our results demonstrate the efficacy of boron isotope fractionation during crustal carbonate assimilation and suggest that low delta(11)B melt values in arc magmas could flag shallow-level additions to the subduction cycle. PMID- 27488226 TI - Brachial artery flow-mediated dilatation and carotid intima-media thickness in young ED patients with insulin resistance. AB - The evidence of a close relationship between cardiovascular disease and erectile dysfunction (ED) is well documented. The aim of this study is to investigate whether there is an early asymptomatic impairment of the peripheral vasculature in young ED patients without obvious cardiovascular disease. We studied a total of 261 ED patients (19-40 years old) and 40 age-matched healthy controls. All participants received questionnaires of cardiovascular risk factors and erectile function assessment, were subjected to lab tests of fasting blood sample, and underwent the ultrasonographic examination of brachial artery flow-mediated dilation (FMD) and carotid intima-media thickness (c-IMT). Insulin resistance (IR) was measured by the homeostasis model assessment of insulin resistance (HOMA IR). Compared with normal human controls, FMD was significantly lower, whereas the average c-IMT was significantly greater in ED patients. An inverse correlation was found between FMD and mean c-IMT. The ED patients had significantly higher levels of fasting glucose, fasting insulin and HOMA-IR index, but showed relatively lower total testosterone and prolactin levels than the controls. Both FMD and c-IMT showed a significant correlation with International Index of Erectile Function-5 questionnaire (IIEF-5) score, age and HOMA-IR. Multivariate stepwise regression analysis demonstrated that age, HOMA-IR and IIEF-5 score were the risk factors associated with FMD and c-IMT. In conclusion, young ED patients in association with IR display diminished FMD and increased c-IMT. Furthermore, ED, HOMA-IR and age are independent predictors of the two subclinical atherosclerotic markers. PMID- 27488227 TI - Emotion dynamics and tinnitus: Daily life data from the "TrackYourTinnitus" application. AB - It is well established that emotions influence tinnitus, but the role of emotion dynamics remains unclear. The present study investigated emotion dynamics in N = 306 users of the "TrackYourTinnitus" application who completed the Mini-Tinnitus Questionnaire (Mini-TQ) at one assessment point and provided complete data on at least five assessment points for the following state variables: tinnitus loudness, tinnitus distress, arousal, valence. The repeated arousal and valence ratings were used for two operationalizations of emotion dynamics: intra individual variability of affect intensity (pulse) as well as intra-individual variability of affect quality (spin). Pearson correlation coefficients showed that the Mini-TQ was positively correlated with pulse (r = 0.19; p < 0.05) as well as with spin (r = 0.12; p < 0.05). Multilevel models revealed the following results: increases in tinnitus loudness were more strongly associated with increases in tinnitus distress at higher levels of pulse as well as at higher levels of spin (both p < 0.05), whereby increases in tinnitus loudness correlated even stronger with increases in tinnitus distress when both pulse as well as spin were high (p < 0.05). Moreover, increases in spin were associated with a less favorable time course of tinnitus loudness (p < 0.05). To conclude, equilibrating emotion dynamics might be a potential target in the prevention and treatment of tinnitus. PMID- 27488229 TI - First report of the isolation of Lactococcus garvieae from a platelet concentrate in Japan. AB - BACKGROUND: Bacterial contamination of platelet concentrates (PCs) remains a serious problem in transfusion. We have been conducting sterility tests on all PCs rejected by blood centers or hospitals due to abnormal appearances. We recently experienced a case in which discrepant results were obtained between the methods used to identify a bacterial species isolated from a PC, requiring further analyses. STUDY DESIGN AND METHODS: Bacteria were isolated from a PC using the BacT/ALERT system and plate culture. The species was identified using biochemical tests and molecular analysis. Phylogenetic trees were constructed using sequences of the 16S ribosomal RNA (rRNA) and superoxide dismutase (sodA) genes from the bacterial isolate and related species. In addition, the isolate was cultured at temperatures of 10 degrees C and below to determine its growth activity at low temperatures. RESULTS: Biochemical tests determined that the isolate was Streptococcus alactolyticus, whereas molecular analysis determined that it was Lactococcus garvieae. These two species belonged to different clusters on the phylogenetic tree. Similar to L. garvieae, the isolate could grow at 10 degrees C. CONCLUSIONS: We conclude that the isolate was L. garvieae according to molecular identification and its growth characteristic at 10 degrees C. Molecular analysis enabled the identification of this species, which was difficult to classify by biochemical tests. Blood facilities need to be prepared with multiple techniques, including genetic analysis techniques, for identifying contaminating bacterial species. L. garvieae can grow at 10 degrees C and can contaminate both red blood cell concentrates and PCs; thus, this species should be listed as a cryophilic bacterium that could threaten blood safety. PMID- 27488230 TI - Sulla carnosa modulates root invertase activity in response to the inhibition of long-distance sucrose transport under magnesium deficiency. AB - Being the principal product of photosynthesis, sucrose is involved in many metabolic processes in plants. As magnesium (Mg) is phloem mobile, an inverse relationship between Mg shortage and sugar accumulation in leaves is often observed. Mg deficiency effects on carbohydrate contents and invertase activities were determined in Sulla carnosa Desf. Plants were grown hydroponically at different Mg concentrations (0.00, 0.01, 0.05 and 1.50 mM Mg) for one month. Mineral analysis showed that Mg contents were drastically diminished in shoots and roots mainly at 0.01 and 0.00 mM Mg. This decline was adversely associated with a significant increase of sucrose, fructose and mainly glucose in shoots of plants exposed to severe deficiency. By contrast, sugar contents were severely reduced in roots of these plants indicating an alteration of carbohydrate partitioning between shoots and roots of Mg-deficient plants. Cell wall invertase activity was highly enhanced in roots of Mg-deficient plants, while the vacuolar invertase activity was reduced at 0.00 mM Mg. This decrease of vacuolar invertase activity may indicate the sensibility of roots to Mg starvation resulting from sucrose transport inhibition. 14 CO2 labeling experiments were in accordance with these findings showing an inhibition of sucrose transport from source leaves to sink tissues (roots) under Mg depletion. The obtained results confirm previous findings about Mg involvement in photosynthate loading into phloem and add new insights into mechanisms evolved by S. carnosa to cope with Mg shortage in particular the increase of the activity of cell wall invertase. PMID- 27488231 TI - The safety and efficacy of nivolumab in advanced (metastatic) non-small cell lung cancer. AB - INTRODUCTION: Advanced non-small cell lung cancer (NSCLC) is a challenging oncological problem. Following standard initial therapy, disease progression will typically develop. Patients with relapsed or refractory disease are left with limited treatment options. The advent of nivolumab, a monoclonal antibody against Program Death-1 (PD-1), has substantially changed the outlook for such patients. AREA COVERED: Nivolumab is the first checkpoint immunotherapeutic agent to gain regulatory approval for NSCLC. By enabling host immune-mediated cytotoxic activity against tumor cells, nivolumab induces a partial or complete tumor response in 15-20% of patients, regardless of number of previous lines of anti cancer therapy. Nivolumab-related adverse effects are generally milder and less frequent than those observed with conventional cytotoxic chemotherapy. Although immune-related adverse events such as fatal pneumonitis have been reported with nivolumab therapy, most adverse events are reversible with a prompt immunosuppression. Studies investigating nivolumab in combination with other agents are ongoing. Expert commentary: Nivolumab represents a significant breakthrough in the treatment of advanced NSCLC. Its therapeutic role for NSCLC may soon expand to include consolidation or maintenance setting. Furthermore, several clinical trials investigating the combination of nivolumab with other immunologic or non-immunologic treatments are ongoing and these will likely result in additional roles of nivolumab in NSCLC. PMID- 27488232 TI - Managing reversal of direct oral anticoagulants in emergency situations. Anticoagulation Education Task Force White Paper. AB - Anticoagulation is the cornerstone of prevention and treatment of venous thromboembolism (VTE) and stroke prevention in patients with atrial fibrillation (AF). However, the mechanisms by which anticoagulants confer therapeutic benefit also increase the risk of bleeding. As such, reversal strategies are critical. Until recently, the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban lacked a specific reversal agent. This report is based on findings from the Anticoagulation Education Task Force, which brought together patient groups and professionals representing different medical specialties with an interest in patient safety and expertise in AF, VTE, stroke, anticoagulation, and reversal agents, to discuss the current status of anticoagulation reversal and fundamental changes in management of bleeding associated with DOACs occasioned by the approval of idarucizumab, a specific reversal agent for dabigatran, as well as recent clinical data on specific reversal agents for factor Xa inhibitors. Recommendations are given for when there is a definite need for a reversal agent (e.g. in cases of life-threatening bleeding, bleeding into a closed space or organ, persistent bleeding despite local haemostatic measures, and need for urgent interventions and/or interventions that carry a high risk for bleeding), when reversal agents may be helpful, and when a reversal agent is generally not needed. Key stakeholders who require 24-7/around-the-clock access to these agents vary among hospitals; however, from a practical perspective the emergency department is recommended as an appropriate location for these agents. Clearly, the advent of new agents requires standardised protocols for treating bleeding on an institutional level. PMID- 27488233 TI - Trends in racial/ethnic and income disparities in foods and beverages consumed and purchased from stores among US households with children, 2000-2013. AB - BACKGROUND: It is unclear whether racial/ethnic and income differences in foods and beverages obtained from stores contribute to disparities in caloric intake over time. OBJECTIVE: We sought to determine whether there are disparities in calories obtained from store-bought consumer packaged goods (CPGs), whether brands (name brands compared with private labels) matter, and if disparities have changed over time. DESIGN: We used NHANES individual dietary intake data among households with children along with the Nielsen Homescan data on CPG purchases among households with children. With NHANES, we compared survey-weighted energy intakes for 2003-2006 and 2009-2012 from store and nonstore sources by race/ethnicity [non-Hispanic whites (NHWs), non-Hispanic blacks (NHBs), and Hispanic Mexican-Americans) and income [<=185% federal poverty line (FPL), 186 400% FPL, and >400% FPL]. With the Nielsen data, we compared 2000-2013 trends in calories purchased from CPGs (obtained from stores) across brands by race/ethnicity (NHW, NHB, and Hispanic) and income. We conducted random-effect models to derive adjusted trends and differences in calories purchased (708,175 observations from 64,709 unique households) and tested whether trends were heterogeneous by race/ethnicity or income. RESULTS: Store-bought foods and beverages represented the largest component of dietary intake, with greater decreases in energy intakes in nonstore sources for foods and in store sources for beverages. Beverages from stores consistently decreased in all subpopulations. However, in adjusted models, reductions in CPG calories purchased in 2009-2012 were slower for NHB and low-income households than for NHW and high income households, respectively. The decline in calories from name-brand food purchases was slower among NHB, Hispanic, and lowest-income households. NHW and high-income households had the highest absolute calories purchased in 2000. CONCLUSIONS: Across 2 large data sources, we found decreases in intake and purchases of beverages from stores across racial/ethnic and income groups. However, potentially beneficial reductions in calories purchased were more pronounced in some subgroups over others. PMID- 27488234 TI - Higher concentrations of serum iron and transferrin saturation but not serum ferritin are associated with cancer outcomes. AB - BACKGROUND: Although the carcinogenic potential of iron has been shown, evidence from observational studies that have linked serum iron variables and cancer outcomes has been inconsistent. OBJECTIVE: We investigated whether higher iron concentrations increased risk of cancer outcomes. DESIGN: A prospective examination of iron biomarkers as independent risk factors for cancer was assessed in 1597 men and 1795 women aged 25-79 y who participated in the 1994/1995 Busselton Health Survey and had relevant data, no history of cancer before the survey, and serum ferritin concentrations >=20 MUg/L. Follow-up for incident cancers and death from cancer was available to 2010. Proportional hazards regression modeling was performed to investigate if iron status predicted cancer incidence and mortality. RESULTS: After adjustments for age, smoking, drinking, anthropometric and biochemical variables, or menopausal status (breast cancer), higher serum iron concentrations and transferrin saturation were associated with increased risks of incident nonskin cancer [HR for iron: 1.83 (95% CI: 1.21, 2.76; P < 0.01); HR for transferrin saturation: 1.68 (95% CI: 1.18, 2.38; P < 0.01)] including breast cancer [HR for iron: 2.45 (95% CI:1.12, 5.34; P < 0.05); HR for transferrin saturation: 1.90 (95% CI:1.02, 3.56; P < 0.05)] in women. Transferrin saturation was also associated with a greater risk of cancer death (HR: 2.48; 95% CI: 1.28, 4.82; P < 0.01). In men, higher iron concentrations were associated with reduced risks of incident nonskin cancer (HR: 0.65; 95% CI: 0.42, 0.99; P < 0.05) including colorectal cancer (HR: 0.34; 95% CI: 0.12, 0.95; P < 0.05). There was no association between serum iron and colorectal cancer risk in women. Serum ferritin was not associated with cancer risk or cancer death. CONCLUSIONS: Higher transferrin saturation or serum iron concentrations were associated with increased nonskin cancer risk and increased risk of cancer death. Conversely, in men, higher serum iron concentrations were associated with decreased risk of nonskin cancer. The molecular basis for the observed differences in the association between serum iron and nonskin cancer risk is unclear. PMID- 27488235 TI - Biomarkers of browning of white adipose tissue and their regulation during exercise- and diet-induced weight loss. AB - BACKGROUND: A hypothesis exists whereby an exercise- or dietary-induced negative energy balance reduces human subcutaneous white adipose tissue (scWAT) mass through the formation of brown-like adipocyte (brite) cells. However, the validity of biomarkers of brite formation has not been robustly evaluated in humans, and clinical data that link brite formation and weight loss are sparse. OBJECTIVES: We used rosiglitazone and primary adipocytes to stringently evaluate a set of biomarkers for brite formation and determined whether the expression of biomarker genes in scWAT could explain the change in body composition in response to exercise training combined with calorie restriction in obese and overweight women (n = 79). DESIGN: Gene expression was derived from exon DNA microarrays and preadipocytes from obesity-resistant and -sensitive mice treated with rosiglitazone to generate candidate brite biomarkers from a microarray. These biomarkers were evaluated against data derived from scWAT RNA from obese and overweight women before and after supervised exercise 5 d/wk for 16 wk combined with modest calorie restriction (~0.84 MJ/d). RESULTS: Forty percent of commonly used brite gene biomarkers exhibited an exon or strain-specific regulation. No biomarkers were positively related to weight loss in human scWAT. Greater weight loss was significantly associated with less uncoupling protein 1 expression (P = 0.006, R(2) = 0.09). In a follow-up global analysis, there were 161 genes that covaried with weight loss that were linked to greater CCAAT/enhancer binding protein alpha activity (z = 2.0, P = 6.6 * 10(-7)), liver X receptor alpha/beta agonism (z = 2.1, P = 2.8 * 10(-7)), and inhibition of leptin-like signaling (z = -2.6, P = 3.9 * 10(-5)). CONCLUSION: We identify a subset of robust RNA biomarkers for brite formation and show that calorie-restriction-mediated weight loss in women dynamically remodels scWAT to take on a more-white rather than a more-brown adipocyte phenotype. PMID- 27488236 TI - Vitamin D-enhanced eggs are protective of wintertime serum 25-hydroxyvitamin D in a randomized controlled trial of adults. AB - BACKGROUND: Despite numerous animal studies that have illustrated the impact of additional vitamin D in the diet of hens on the resulting egg vitamin D content, the effect of the consumption of such eggs on vitamin D status of healthy individuals has not, to our knowledge, been tested. OBJECTIVE: We performed a randomized controlled trial (RCT) to investigate the effect of the consumption of vitamin D-enhanced eggs (produced by feeding hens at the maximum concentration of vitamin D3 or serum 25-hydroxyvitamin D [25(OH)D3] lawfully allowed in feed) on winter serum 25(OH)D in healthy adults. DESIGN: We conducted an 8-wk winter RCT in adults aged 45-70 y (n = 55) who were stratified into 3 groups and were requested to consume <=2 eggs/wk (control group, in which status was expected to decline), 7 vitamin D3-enhanced eggs/wk, or seven 25(OH)D3-enhanced eggs/wk. Serum 25(OH)D was the primary outcome. RESULTS: Although there was no significant difference (P > 0.1; ANOVA) in the mean preintervention serum 25(OH)D in the 3 groups, it was ~7-8 nmol/L lower in the control group than in the 2 groups who consumed vitamin D-enhanced eggs. With the use of an ANCOVA, in which baseline 25(OH)D was accounted for, vitamin D3-egg and 25(OH)D3-egg groups were shown to have had significantly higher (P <= 0.005) postintervention serum 25(OH)D than in the control group. With the use of a within-group analysis, it was shown that, although serum 25(OH)D in the control group significantly decreased over winter (mean +/- SD: -6.4 +/- 6.7 nmol/L; P = 0.001), there was no change in the 2 groups who consumed vitamin D-enhanced eggs (P > 0.1 for both). CONCLUSION: Weekly consumption of 7 vitamin D-enhanced eggs has an important impact on winter vitamin D status in adults. This trial was registered at clinicaltrials.gov as NCT02678364. PMID- 27488237 TI - Habitual intake of anthocyanins and flavanones and risk of cardiovascular disease in men. AB - BACKGROUND: Although increased fruit intake reduces cardiovascular disease (CVD) risk, which fruits are most beneficial and what key constituents are responsible are unclear. Habitual intakes of flavonoids, specifically anthocyanins and flavanones, in which >90% of habitual intake is derived from fruit, are associated with decreased CVD risk in women, but associations in men are largely unknown. OBJECTIVE: We examined the relation between habitual anthocyanin and flavanone intake and coronary artery disease and stroke in the Health Professionals Follow-Up Study. DESIGN: We followed 43,880 healthy men who had no prior diagnosed CVD or cancer. Flavonoid intake was calculated with the use of validated food-frequency questionnaires. RESULTS: During 24 y of follow-up, 4046 myocardial infarction (MI) and 1572 stroke cases were confirmed by medical records. Although higher anthocyanin intake was not associated with total or fatal MI risk, after multivariate adjustment an inverse association with nonfatal MI was observed (HR: 0.87; 95% CI: 0.75, 1.00; P = 0.04; P-trend = 0.098); this association was stronger in normotensive participants (HR: 0.81; 95% CI: 0.69, 0.96; P-interaction = 0.03). Anthocyanin intake was not associated with stroke risk. Although flavanone intake was not associated with MI or total stroke risk, higher intake was associated with a lower risk of ischemic stroke (HR: 0.78; 95% CI: 0.62, 0.97; P = 0.03, P-trend = 0.059), with the greatest magnitude in participants aged >=65 y (P-interaction = 0.04). CONCLUSIONS: Higher intakes of fruit-based flavonoids were associated with a lower risk of nonfatal MI and ischemic stroke in men. Mechanistic studies and clinical trials are needed to unravel the differential benefits of anthocyanin- and flavanone-rich foods on cardiovascular health. PMID- 27488239 TI - Adherence to the cancer prevention recommendations of the World Cancer Research Fund/American Institute for Cancer Research and mortality: a census-linked cohort. AB - BACKGROUND: Modifiable lifestyle factors linked to cancer offer great potential for prevention. Previous studies suggest an association between adherence to recommendations on healthy lifestyle and cancer mortality. OBJECTIVES: The aim of this study was to examine whether adherence to the cancer prevention recommendations of the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) is associated with reduced all-cause, total cancer, and specific cancer type mortality. DESIGN: We built a lifestyle score that included 3 categories, based on the recommendations of the WCRF/AICR. Applying Cox regression models, we investigated the association with all-cause, total cancer, and specific cancer type mortality; in addition, we included cardiovascular disease (CVD) mortality. We used census- and death registry-linked survey data allowing a mortality follow-up for <=32 y. Our analysis included 16,722 participants. Information on lifestyle score components and confounders was collected at baseline. RESULTS: Over a mean follow-up of 21.7 y, 3730 deaths were observed (1332 cancer deaths). Comparing best with poorest category of the lifestyle score showed an inverse association with all-cause (HR: 0.82; 95% CI: 0.75, 0.89) and total cancer (men only, HR: 0.69; 95% CI: 0.57, 0.84) mortality. We estimated that ~13% of premature cancer deaths in men would have been preventable if lifestyle score levels had been high. Inverse associations were observed for lung, upper aerodigestive tract, stomach, and prostate cancer mortality [men and women combined, HR: 0.72; 95% CI: 0.51, 0.99; HR: 0.49; 95% CI: 0.26, 0.92; HR: 0.34; 95% CI: 0.14, 0.83; HR: 0.48; 95% CI: 0.28, 0.82 (men only), respectively]. CVD mortality was not associated with the lifestyle score (men and women combined, HR: 0.96; 95% CI: 0.82, 1.13). CONCLUSIONS: Our results support the importance of adhering to recommendations for a healthy lifestyle with regard to all-cause and cancer mortality. To reduce the burden of cancer in the population, preventive measures should stress the potential of low-risk health behavior patterns rather than of specific risk factors only. PMID- 27488238 TI - Mediterranean diet score and left ventricular structure and function: the Multi Ethnic Study of Atherosclerosis. AB - BACKGROUND: Data are limited on the relation between dietary patterns and left ventricular (LV) structure and function. OBJECTIVE: We examined cross-sectional associations of a diet-score assessment of a Mediterranean dietary pattern with LV mass, volume, mass-to-volume ratio, stroke volume, and ejection fraction. DESIGN: We measured LV variables with the use of cardiac MRI in 4497 participants in the Multi-Ethnic Study of Atherosclerosis study who were aged 45-84 y and without clinical cardiovascular disease. We calculated a Mediterranean diet score from intakes of fruit, vegetables, nuts, legumes, whole grains, fish, red meat, the monounsaturated fat:saturated fat ratio, and alcohol that were self-reported with the use of a food-frequency questionnaire. We used linear regression with adjustment for body size, physical activity, and cardiovascular disease risk factors to model associations and assess the shape of these associations (linear or quadratic). RESULTS: The Mediterranean diet score had a slight U-shaped association with LV mass (adjusted means: 146, 145, 146, and 147 g across quartiles of diet score, respectively; P-quadratic trend = 0.04). The score was linearly associated with LV volume, stroke volume, and ejection fraction: for each +1-U difference in score, LV volume was 0.4 mL higher (95% CI: 0.0, 0.8 mL higher), the stroke volume was 0.5 mL higher (95% CI: 0.2, 0.8 mL higher), and the ejection fraction was 0.2 percentage points higher (95% CI: 0.1, 0.3 percentage points higher). The score was not associated with the mass-to-volume ratio. CONCLUSIONS: A higher Mediterranean diet score is cross-sectionally associated with a higher LV mass, which is balanced by a higher LV volume as well as a higher ejection fraction and stroke volume. Participants in this healthy, multiethnic sample whose dietary patterns most closely conformed to a Mediterranean-type pattern had a modestly better LV structure and function than did participants with less-Mediterranean-like dietary patterns. This trial was registered at clinicaltrials.gov as NCT00005487. PMID- 27488241 TI - Exploring the mechanism of DNA polymerases by analyzing the effect of mutations of active site acidic groups in Polymerase beta. AB - Elucidating the catalytic mechanism of DNA polymerase is crucial for a progress in the understanding of the control of replication fidelity. This work tries to advance the mechanistic understanding by analyzing the observed effect of mutations of the acidic groups in the active site of Polymerase beta as well as the pH effect on the rate constant. The analysis involves both empirical valence bond (EVB) free energy calculations and considerations of the observed pH dependence of the reaction. The combined analysis indicates that the proton transfer (PT) from the nucleophilic O3' has two possible pathways, one to D256 and the second to the bulk. We concluded based on calculations and the experimental pH profile that the most likely path for the wild-type (WT) and the D256E and D256A mutants is a PT to the bulk, although the WT may also use a PT to Asp 256. Our analysis highlights the need for very extensive sampling in the calculations of the activation barrier and also clearly shows that ab initio QM/MM calculations that do not involve extensive sampling are unlikely to give a clear quantitative picture of the reaction mechanism. Proteins 2016; 84:1644 1657. (c) 2016 Wiley Periodicals, Inc. PMID- 27488240 TI - Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts. AB - BACKGROUND: Genome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer's disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported. However, disparate descriptions of BIN1 expression and localization in the brain previously reported in the literature and the lack of clarity on brain BIN1 isoforms present formidable challenges to our understanding of how genetic variants in BIN1 increase the risk for AD. METHODS: In this study, we analyzed BIN1 mRNA and protein levels in human brain samples from individuals with or without AD. In addition, we characterized the BIN1 expression and isoform diversity in human and rodent tissue by immunohistochemistry and immunoblotting using a panel of BIN1 antibodies. RESULTS: Here, we report on BIN1 isoform diversity in the human brain and document alterations in the levels of select BIN1 isoforms in individuals with AD. In addition, we report striking BIN1 localization to white matter tracts in rodent and the human brain, and document that the large majority of BIN1 is expressed in mature oligodendrocytes whereas neuronal BIN1 represents a minor fraction. This predominant non-neuronal BIN1 localization contrasts with the strict neuronal expression and presynaptic localization of the BIN1 paralog, Amphiphysin 1. We also observe upregulation of BIN1 at the onset of postnatal myelination in the brain and during differentiation of cultured oligodendrocytes. Finally, we document that the loss of BIN1 significantly correlates with the extent of demyelination in multiple sclerosis lesions. CONCLUSION: Our study provides new insights into the brain distribution and cellular expression of an important risk factor associated with late-onset AD. We propose that efforts to define how genetic variants in BIN1 elevate the risk for AD would behoove to consider BIN1 function in the context of its main expression in mature oligodendrocytes and the potential for a role of BIN1 in the membrane remodeling that accompanies the process of myelination. PMID- 27488242 TI - First genetic linkage map of Taraxacum koksaghyz Rodin based on AFLP, SSR, COS and EST-SSR markers. AB - Taraxacum koksaghyz Rodin (TKS) has been studied in many occasions as a possible alternative source for natural rubber production of good quality and for inulin production. Some tire companies are already testing TKS tire prototypes. There are also many investigations on the production of bio-fuels from inulin and inulin applications for health improvement and in the food industry. A limited amount of genomic resources exist for TKS and particularly no genetic linkage map is available in this species. We have constructed the first TKS genetic linkage map based on AFLP, COS, SSR and EST-SSR markers. The integrated linkage map with eight linkage groups (LG), representing the eight chromosomes of Russian dandelion, has 185 individual AFLP markers from parent 1, 188 individual AFLP markers from parent 2, 75 common AFLP markers and 6 COS, 1 SSR and 63 EST-SSR loci. Blasting the EST-SSR sequences against known sequences from lettuce allowed a partial alignment of our TKS map with a lettuce map. Blast searches against plant gene databases revealed some homologies with useful genes for downstream applications in the future. PMID- 27488243 TI - Suspicion in the workplace: Organizational conspiracy theories and work-related outcomes. AB - Belief in conspiracy theories about societal events is widespread and has important consequences for political, health, and environmental behaviour. Little is known, however, about how conspiracy theorizing affects people's everyday working lives. In the present research, we predicted that belief in conspiracy theories about the workplace would be associated with increased turnover intentions. We further hypothesized that belief in these organizational conspiracy theories would predict decreased organizational commitment and job satisfaction. Finally, we hypothesized that these factors would mediate the relationship between organizational conspiracy theories and turnover intentions. In three studies (one correlational and two experiments, Ns = 209, 119, 202), we found support for these hypotheses. The current studies therefore demonstrate the potentially adverse consequences of conspiracy theorizing for the workplace. We argue that managers and employees should be careful not to dismiss conspiracy theorizing as harmless rumour or gossip. PMID- 27488245 TI - Protistan predation interferes with bacterial long-term adaptation to substrate restriction by selecting for defence morphotypes. AB - Bacteria that are introduced into aquatic habitats face a low substrate environment interspersed with rare productive 'hotspots', as well as high protistan grazing. Whereas the former condition should select for growth performance, the latter should favour traits that reduce predation mortality, such as the formation of large cell aggregates. However, protected morphotypes often convey a growth disadvantage, and bacteria thus face a trade-off between investing in growth or defence traits. We set up an evolutionary experiment with the freshwater isolate Sphingobium sp. strain Z007 that conditionally increases aggregate formation in supernatants from a predator-prey coculture. We hypothesized that low substrate levels would favour growth performance and reduce the aggregated subpopulation, but that the concomitant presence of a flagellate predator might conserve the defence trait. After 26 (1-week) growth cycles either with (P+) or without (P-) predators, bacteria had evolved into strikingly different phenotypes. Strains from P- had low numbers of aggregates and increased growth yield, both at the original rich growth conditions and on various single carbon sources. By contrast, isolates from the P+ treatment formed elevated proportions of defence morphotypes, but exhibited lower growth yield and metabolic versatility. Moreover, the evolved strains from both treatments had lost phenotypic plasticity of aggregate formation. In summary, the (transient) residence of bacteria at oligotrophic conditions may promote a facultative oligotrophic life style, which is advantageous for survival in aquatic habitats. However, the investment in defence against predation mortality may constrain microbial adaptation to the abiotic environment. PMID- 27488244 TI - Activation of sigma1 and sigma2 receptors by afobazole increases glial cell survival and prevents glial cell activation and nitrosative stress after ischemic stroke. AB - Activation of sigma receptors at delayed time points has been shown to decrease injury following ischemic stroke. The mixed sigma1/sigma2 receptor agonist, 5 ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole (afobazole), provides superior long-term outcomes compared to other sigma ligands in the rat middle cerebral artery occlusion (MCAO) stroke model. Experiments using the MCAO model were carried out to determine the molecular mechanism involved in the beneficial effects of afobazole. Administration of afobazole (3 mg/kg) at delayed time points post-stroke significantly increased the number of microglia and astrocytes detected in the ipsilateral hemisphere at 96 h post-surgery. Morphological analysis of the microglia indicated that a greater number of these cells were found in the ramified resting state in MCAO animals treated with afobazole relative to MCAO vehicle controls. Similarly, fewer reactive astrocytes were detected in the injured hemisphere of afobazole-treated animals. Both the enhanced survival and reduced activation of glial cells were abolished by co application of either a sigma1 (BD-1063) or a sigma2 (SM-21) receptor antagonist with afobazole. To gain further insight into the mechanisms by which afobazole lessens stroke injury, we probed the brain sections for markers of neuroinflammation (tumor necrosis factor alpha) and nitrosative stress (S nitrosocysteine). Data show that afobazole significantly reduces S nitrosocysteine levels, but does not alter tumor necrosis factor alpha expression 96 h after an ischemic stroke. Taken together our data indicate that afobazole acting via both sigma1 and sigma2 receptors decreases stroke injury by enhancing glial cell survival, blocking ischemia-induced glial cell activation, and decreasing nitrosative stress. PMID- 27488247 TI - Unique molecular geometries of reduced 4- and 5-coordinate zinc complexes stabilised by diiminopyridine ligand. AB - Stepwise reduction of the diiminopyridine (dimpyr) complex, dimpyrZnCl2, by KC8 leads to molecular zinc compounds dimpyrZnCl (2) and dimpyrZnCl(DMAP) (3, DMAP = 4-dimethylaminopyridine), which were characterized by X-ray diffraction and EPR spectroscopy. Compound 2 shows an unusual nearly square planar geometry of the zinc atom equally ligated by two imine groups. X-ray crystallographic and EPR data suggest significant delocalization of the zinc 4p electron onto the non innocent dimpyr ligand. The chloride in 2 can also be substituted by a methyl group upon addition of methyl lithium to generate compound 4, dimpyrZnMe. The novel alkylzinc compound displayed approximate square planar geometry around the zinc centre and significant delocalization of electron density onto the dimpyr ligand, as revealed by X-ray crystallographic studies and EPR spectroscopy, akin to 2. Further reduction of 3 leads to compound 5, dimpyrZn(DMAP)2. X-ray diffraction study of 5 revealed an unprecedented see-saw geometry around the four coordinate zinc center with significant electron density transfer to the dimpyr ligand, supported by DFT calculations. PMID- 27488246 TI - The combination of dulaglutide and biguanide reduced bodyweight in Japanese patients with type 2 diabetes. AB - The efficacy and safety of once-weekly dulaglutide 0.75 mg (dulaglutide) in Japanese patients with type 2 diabetes (T2D) were evaluated according to subgroups defined by concomitant oral hypoglycaemic agents. This exploratory analysis included data from a randomized, open-label, phase III study that compared dulaglutide with insulin glargine (glargine) (n = 361). The three subgroups were dulaglutide or glargine in combination with sulphonylurea (SU) alone, biguanide (BG) alone or SU and BG combined. There were no clinically relevant differences in glycated haemoglobin (HbA1c) changes among the three subgroups in the dulaglutide group; in the glargine group, a numerically greater reduction was observed in combination with BG alone compared to the other two groups (SU alone and SU + BG). Weight loss was observed with dulaglutide in combination with BG alone or with SU + BG. The incidence of adverse events among subgroups was significantly different in the glargine group but not in the dulaglutide group. Incidence of hypoglycaemia was highest in combination with SU for both treatments. For patients with T2D, dulaglutide added to concomitant BG may be more likely to result in weight loss than dulaglutide added to concomitant SU. PMID- 27488248 TI - A comparative assessment of SNP and microsatellite markers for assigning parentage in a socially monogamous bird. AB - Single-nucleotide polymorphisms (SNPs) are preferred over microsatellite markers in many evolutionary studies, but have only recently been applied to studies of parentage. Evaluations of SNPs and microsatellites for assigning parentage have mostly focused on special cases that require a relatively large number of heterozygous loci, such as species with low genetic diversity or with complex social structures. We developed 120 SNP markers from a transcriptome assembled using RNA-sequencing of a songbird with the most common avian mating system social monogamy. We compared the effectiveness of 97 novel SNPs and six previously described microsatellites for assigning paternity in the black throated blue warbler, Setophaga caerulescens. We show that the full panel of 97 SNPs (mean Ho = 0.19) was as powerful for assigning paternity as the panel of multiallelic microsatellites (mean Ho = 0.86). Paternity assignments using the two marker types were in agreement for 92% of the offspring. Filtering individual samples by a 50% call rate and SNPs by a 75% call rate maximized the number of offspring assigned with 95% confidence using SNPs. We also found that the 40 most heterozygous SNPs (mean Ho = 0.37) had similar power to assign paternity as the full panel of 97 SNPs. These findings demonstrate that a relatively small number of variable SNPs can be effective for parentage analyses in a socially monogamous species. We suggest that the development of SNP markers is advantageous for studies that require high-throughput genotyping or that plan to address a range of ecological and evolutionary questions. PMID- 27488249 TI - Evaluating empirical contact networks as potential transmission pathways for infectious diseases. AB - Networks are often used to incorporate heterogeneity in contact patterns in mathematical models of pathogen spread. However, few tools exist to evaluate whether potential transmission pathways in a population are adequately represented by an observed contact network. Here, we describe a novel permutation based approach, the network k-test, to determine whether the pattern of cases within the observed contact network are likely to have resulted from transmission processes in the network, indicating that the network represents potential transmission pathways between nodes. Using simulated data of pathogen spread, we compare the power of this approach to other commonly used analytical methods. We test the robustness of this technique across common sampling constraints, including undetected cases, unobserved individuals and missing interaction data. We also demonstrate the application of this technique in two case studies of livestock and wildlife networks. We show that the power of the k-test to correctly identify the epidemiologic relevance of contact networks is substantially greater than other methods, even when 50% of contact or case data are missing. We further demonstrate that the impact of missing data on network analysis depends on the structure of the network and the type of missing data. PMID- 27488250 TI - Elasto-capillarity in insect fibrillar adhesion. AB - The manipulation of microscopic objects is challenging because of high adhesion forces, which render macroscopic gripping strategies unsuitable. Adhesive footpads of climbing insects could reveal principles relevant for micro-grippers, as they are able to attach and detach rapidly during locomotion. However, the underlying mechanisms are still not fully understood. In this work, we characterize the geometry and contact formation of the adhesive setae of dock beetles (Gastrophysa viridula) by interference reflection microscopy. We compare our experimental results to the model of an elastic beam loaded with capillary forces. Fitting the model to experimental data yielded not only estimates for seta adhesion and compliance in agreement with previous direct measurements, but also previously unknown parameters such as the volume of the fluid meniscus and the bending stiffness of the tip. In addition to confirming the primary role of surface tension for insect adhesion, our investigation reveals marked differences in geometry and compliance between the three main kinds of seta tips in leaf beetles. PMID- 27488252 TI - Somatic mosaicism in B cells of a patient with autosomal dominant hyper IgE syndrome. AB - Hyper IgE syndrome (HIES) is characterized by recurrent skin abscesses, eczema, pneumonia, and high levels of serum IgE. Nonimmunologic manifestations of HIES include a characteristic face, pathologic dentition, scoliosis, bone alterations, hyperextensible joints, and vascular abnormalities. Somatic mosaicism is defined by the presence of two or more populations of cells with different genotypes in one individual. In this report, we describe one patient with classical HIES and another patient with a mild phenotype, both harboring the same genetic mutation. The patient with a mild phenotype did not present the characteristic face, had normal production of IL-17A by T CD4+ cells, but had low phosphorylation of STAT 3 in B cells. Interestingly, the mutation found in B cells was absent in other cell types analyzed, in agreement with the presence of a somatic mosaic genotype. The clinical and functional differences observed between these patients justify the use of complementary tools for a better definition of the cases. These approaches allow for a better understanding of complex phenotypes associated with somatic mosaicisms, and present the possibility to analyze the role of B lymphocytes in the pathophysiology of this disease. This knowledge has an impact on not only the treatment but also the provision of appropriate genetic counseling. PMID- 27488253 TI - Penicillium pedernalense sp. nov., isolated from whiteleg shrimp heads waste compost. AB - Novel Penicillium-like strains were isolated during the characterization of the mycobiota community dynamics associated with shrimp waste composting. Phylogenetic analysis of the partial beta-tubulin (BenA) gene and the ribosomal DNA internal transcribed spacer region (ITS1-5.8S-ITS2) sequences revealed that the novel strains were members of section Lanata-Divaricata and were closely related to Penicillium infrabuccalum DAOMC 250537T. On the basis of morphological and physiological characterization, and phylogenetic analysis, a novel Penicillium species, Penicillium pedernalense sp. nov., is proposed. The type strain is F01-11T (=CBS 140770T=CECT 20949T), which was isolated from whiteleg shrimp (Litopenaeus vannamei) heads waste compost in the Pedernales region (Manabi province, Ecuador). PMID- 27488254 TI - Effects of ankyrin 3 gene risk variants on brain structures in patients with bipolar disorder and healthy subjects. AB - AIM: The intronic single-nucleotide polymorphism rs10994336 of the ankyrin 3 gene (ANK3 ) is one of the genome-wide supported risk variants for bipolar disorder (BD), and the T-allele of rs10761482 is also reported to have relevance to BD. We investigated the effect of ANK3 rs10761482 genetic variation on brain structure. METHODS: Subjects were 43 BD patients and 229 healthy volunteers. We evaluated the effects of ANK3 rs10761482 genetic variation on diagnosis, and of the genotype-by-diagnosis interaction on the brain structure and the degree of age related brain atrophy on magnetic resonance imaging data evaluated by voxel-based morphometry. RESULTS: BD patients showed significantly lower fractional anisotropy value in the bilateral parietal regions, left fronto-occipital fasciculus, and corpus callosum, compared to healthy subjects. Further, we found considerable decreases of fractional anisotropy in the forceps minor in non-T allele BD patients compared with the T-carrier patient group. We also found significant lessening of age-related brain atrophy in the T-allele carrier groups compared with the non-T-allele carrier groups in the area around the cerebrospinal space, cingulate cortices, and cerebellum. CONCLUSION: Our results suggest the influence of the ANK3 on age-related brain atrophy. The ankyrin 3 genotype may be associated with pathogenesis of age-related neurodegeneration, and, in part, of BD. PMID- 27488255 TI - Exploring the relationship between physical activity, life goals and health related quality of life among high school students: a cross-sectional study. AB - BACKGROUND: Two models were developed to increase high school students' participation in physical education (PE): "motion enjoyment" and "sport enjoyment". The first model focuses on increasing knowledge about the health benefits of a physically active lifestyle and thereby promoting a positive attitude towards physical activity, whereas the second model focuses on techniques and practices for enhancing athletic performance. The aims of the present study are to investigate and understand the similarities and differences between students selecting "motion enjoyment" vs. "sport enjoyment" and to examine the extent to which life goals and reported physical activity are associated with health-related quality of life (HRQOL). METHOD: A total of 156 high school students (mean age, 16 years [standard deviation = 0.8], 123 girls and 33 boys) were included in this cross-sectional study. HRQOL and life goals were measured using KIDSCREEN-10 and the Adolescent Life Goal Profile Scale, respectively. Physical activity was measured using a self-reporting questionnaire intended to describe the students' leisure-time activity. Independent sample t tests, chi-square, one-way analyses of variance and multiple regression analysis were applied. RESULTS: Self-reported physical activity level and HRQOL were higher among students in the "sport enjoyment" program, while the perceived importance of life goals was the same regardless of the preferred PE model. Multiple regression analyses revealed that the perceived importance of relations oriented life goals (B = -5.61; 95 % confidence interval CI = -10.53 to -0.70; p = .026), perceived importance of generativity-oriented life goals (B = 4.14.; 95 % CI = 0.85 to 7.422; p = .014), perceived attainability of relations-oriented life goals (B = 7.28; 95 % CI = 2.49 to 12.07; p = .003), age (B = -7.29; 95 % CI = -11.38 to -3.20; p = .001) and gender, with boys as the reference group (B = 12.10; 95 % CI = -19.09 to -5.11; p = .001), were independently associated with increased HRQOL. In exploring the relationships of self-reported physical activity during leisure time, stage of change (B = 3.53; 95 % CI = 1.49 to 5.51; p = .001), gender, with boys as the reference group (B = -8.90; 95 % CI = -15.80 to -2.00; p = .012), and age (B = -6.62; 95 % CI = -10.57 to -2.66; p = .001) were independently associated with increased HRQOL. CONCLUSION: Self-reported physical activity habits and life goals were associated with HRQOL to a limited extent. However, the perceived importance of life goals appears to reflect other aspects of individual well-being than HRQOL. PMID- 27488256 TI - Automated statistical experimental design approach for rapid separation of coenzyme Q10 and identification of its biotechnological process related impurities using UHPLC and UHPLC-APCI-MS. AB - A novel ultra high performance liquid chromatography method development strategy was ameliorated by applying quality by design approach. The developed systematic approach was divided into five steps (i) Analytical Target Profile, (ii) Critical Quality Attributes, (iii) Risk Assessments of Critical parameters using design of experiments (screening and optimization phases), (iv) Generation of design space, and (v) Process Capability Analysis (Cp) for robustness study using Monte Carlo simulation. The complete quality-by-design-based method development was made automated and expedited by employing sub-2 MUm particles column with an ultra high performance liquid chromatography system. Successful chromatographic separation of the Coenzyme Q10 from its biotechnological process related impurities was achieved on a Waters Acquity phenyl hexyl (100 mm * 2.1 mm, 1.7 MUm) column with gradient elution of 10 mM ammonium acetate buffer (pH 4.0) and a mixture of acetonitrile/2-propanol (1:1) as the mobile phase. Through this study, fast and organized method development workflow was developed and robustness of the method was also demonstrated. The method was validated for specificity, linearity, accuracy, precision, and robustness in compliance to the International Conference on Harmonization, Q2 (R1) guidelines. The impurities were identified by atmospheric pressure chemical ionization-mass spectrometry technique. Further, the in silico toxicity of impurities was analyzed using TOPKAT and DEREK software. PMID- 27488258 TI - A literature review of the training offered to qualified prescribers to use electronic prescribing systems: why is it so important? AB - OBJECTIVES: A key element of the implementation and ongoing use of an electronic prescribing (ePrescribing) system is ensuring that users are, and remain, sufficiently trained to use the system. Studies have suggested that insufficient training is associated with suboptimal use. However, it is not clear from these studies how clinicians are trained to use ePrescribing systems or the effectiveness of different approaches. We sought to describe the various approaches used to train qualified prescribers on ePrescribing systems and to identify whether users were educated about the pitfalls and challenges of using these systems. METHODS: We performed a literature review, using a systematic approach across three large databases: Cumulative Index Nursing and Allied Health Literature, Embase and Medline were searched for relevant English language articles. Articles that explored the training of qualified prescribers on ePrescribing systems in a hospital setting were included. KEY FINDINGS: Our search of 'all training' approaches returned 1155 publications, of which seven were included. A separate search of 'online' training found three relevant publications. Training methods in the 'all training' category included clinical scenarios, demonstrations and assessments. Regarding 'online' training approaches; a team at the University of Victoria in Canada developed a portal containing simulated versions of electronic health records, where individuals could prescribe for fictitious patients. Educating prescribers about the challenges and pitfalls of electronic systems was rarely discussed. CONCLUSIONS: A number of methods are used to train prescribers; however, the lack of papers retrieved suggests a need for additional studies to inform training methods. PMID- 27488259 TI - Near-peer medical student simulation training. AB - BACKGROUND: There is growing concern that medical students are inadequately prepared for life as a junior doctor. A lack of confidence managing acutely unwell patients is often cited as a barrier to good clinical care. With medical schools investing heavily in simulation equipment, we set out to explore if near peer simulation training is an effective teaching format. METHODS: Medical students in their third year of study and above were invited to attend a 90 minute simulation teaching session. The sessions were designed and delivered by final-year medical students using clinical scenarios mapped to the Sheffield MBChB curriculum. Candidates were required to assess, investigate and manage an acutely unwell simulated patient. Pre- and post-simulation training Likert scale questionnaires were completed relating to self-reported confidence levels. There is growing concern that medical students are inadequately prepared for life as a junior doctor RESULTS: Questionnaires were completed by 25 students (100% response rate); 52 per cent of students had no prior simulation experience. There were statistically significant improvements in self-reported confidence levels in each of the six areas assessed (p < 0.005). Thematic analysis of free-text comments indicated that candidates enjoyed the practical format of the sessions and found the experience useful. DISCUSSION: Our results suggest that near-peer medical student simulation training benefits both teacher and learner and that this simplistic model could easily be replicated at other medical schools. As the most junior members of the team, medical students are often confined to observer status. Simulation empowers students to practise independently in a safe and protected environment. Furthermore, it may help to alleviate anxiety about starting work as a junior doctor and improve future patient care. PMID- 27488257 TI - Genome comparisons provide insights into the role of secondary metabolites in the pathogenic phase of the Photorhabdus life cycle. AB - BACKGROUND: Bacteria within the genus Photorhabdus maintain mutualistic symbioses with nematodes in complicated lifecycles that also involves insect pathogenic phases. Intriguingly, these bacteria are rich in biosynthetic gene clusters that produce compounds with diverse biological activities. As a basis to better understand the life cycles of Photorhabdus we sequenced the genomes of two recently discovered representative species and performed detailed genomic comparisons with five publically available genomes. RESULTS: Here we report the genomic details of two new reference Photorhabdus species. By then conducting genomic comparisons across the genus, we show that there are several highly conserved biosynthetic gene clusters. These clusters produce a range of bioactive small molecules that support the pathogenic phase of the integral relationship that Photorhabdus maintain with nematodes. CONCLUSIONS: Photorhabdus contain several genetic loci that allow them to become specialist insect pathogens by efficiently evading insect immune responses and killing the insect host. PMID- 27488260 TI - Dietary choline and betaine intake, choline-metabolising genetic polymorphisms and breast cancer risk: a case-control study in China. AB - Choline and betaine are essential nutrients involved in one-carbon metabolism and have been hypothesised to affect breast cancer risk. Functional polymorphisms in genes encoding choline-related one-carbon metabolism enzymes, including phosphatidylethanolamine N-methyltransferase (PEMT), choline dehydrogenase (CHDH) and betaine-homocysteine methyltransferase (BHMT), have important roles in choline metabolism and may thus interact with dietary choline and betaine intake to modify breast cancer risk. This study aimed to investigate the interactive effect of polymorphisms in PEMT, BHMT and CHDH genes with choline/betaine intake on breast cancer risk among Chinese women. This hospital-based case-control study consecutively recruited 570 cases with histologically confirmed breast cancer and 576 age-matched (5-year interval) controls. Choline and betaine intakes were assessed by a validated FFQ, and genotyping was conducted for PEMT rs7946, CHDH rs9001 and BHMT rs3733890. OR and 95 % CI were estimated using unconditional logistic regression. Compared with the highest quartile of choline intake, the lowest intake quartile showed a significant increased risk of breast cancer. The SNP PEMT rs7946, CHDH rs9001 and BHMT rs3733890 had no overall association with breast cancer, but a significant risk reduction was observed among postmenopausal women with AA genotype of BHMT rs3733890 (OR 0.49; 95 % CI 0.25, 0.98). Significant interactions were observed between choline intake and SNP PEMT rs7946 (P interaction=0.029) and BHMT rs3733890 (P interaction=0.006) in relation to breast cancer risk. Our results suggest that SNP PEMT rs7946 and BHMT rs3733890 may interact with choline intake on breast cancer risk. PMID- 27488262 TI - The impact of multiple chronic diseases on hospitalizations for ambulatory care sensitive conditions. AB - BACKGROUND: The high financial burden of avoidable hospitalizations has led to an increase of the study of hospitalizations for ambulatory care sensitive conditions (ACSC). There is limited information on the impact of secondary diagnoses on these hospitalizations, although patients' social and demographic characteristics, as well as the coexistence of multiple diseases are often identified in the literature as risk factors for avoidable hospitalizations. This study explores the impact of chronic conditions on the likelihood of hospitalizations for ACSC. METHODS: Data were extracted from the Portuguese hospital discharge database. Avoidable hospitalizations were identified according to the Canadian Institute for Healthcare Information, and chronic conditions were identified according to criteria set by the Agency for Healthcare Research and Quality. A retrospective study analysing all patients hospitalized for an ACSC and all patients hospitalized for non-ACSC was made, using multiple logistic regression models to identify the impact of chronic conditions on the risk of admission. RESULTS: The risk of an avoidable hospitalization increases by a factor of 1.35 (95 % CI [1.34;1.35]) for each additional chronic condition, and 1.55 (95 % CI [1.55;1.56]) for each additional body system affected. The respiratory and circulatory systems have the most impact on the risk of ACSC, increasing the risk by 8.72 (95 % CI [8.58;8.86]) and 3.01 (95 % CI [2.95;3.06]), respectively. CONCLUSIONS: The number of chronic conditions and the body systems affected increase the risk of hospital admissions for ACSC. PMID- 27488261 TI - Relaxin serum levels in acute heart failure are associated with pulmonary hypertension and right heart overload. AB - AIMS: Despite the promising results of serelaxin as a new potential acute heart failure (HF) therapy, its clinical use preceded the understanding of the endogenous relaxin system in HF. We aimed to evaluate relaxin circulating levels in a population of acute HF and their association with clinical and echocardiographic parameters. METHODS AND RESULTS: We included 117 patients from a registry of acute HF. Admission serum relaxin was measured using an enzyme linked immunosorbent assay (ELISA) kit. Clinical, analytical, and echocardiographic parameters were compared between patients with relaxin levels above and below the median. Median age was 82 years [interquartile range (IQR) 72 87], 41% of the patients were male, and 63% had systolic dysfunction. Median serum relaxin was 31.4 pg/mL (IQR 0.6-89.8). Patients with relaxin levels above the median had more peripheral oedema (89.8% vs. 68.4%, P = 0.004) and a significantly higher sodium retention score (mean 4.8 +/- 1.5 vs. 3.6 +/- 2.0, P < 0.001). These patients also had significantly higher systolic pulmonary arterial pressure [median 47.0 (IQR 36.0-61.0) vs. 34.5 (IQR 25.0-51.0) mmHg, P = 0.002], higher prevalence of right ventricular (RV) systolic dysfunction (28.1% vs. 10.3%, P = 0.02), RV dilation (31.0% vs. 5.3%, P < 0.001), and right atrial dilation (66.1% vs. 36.5%, P = 0.002), and less inferior vena cava diameter variability (40% vs. 60%, P = 0.009). No differences were noted regarding admission blood pressure, left chamber dimensions, or LV function. CONCLUSION: In our population of acute HF patients, admission relaxin serum levels were associated with clinical and echocardiographic markers of pulmonary hypertension, RV dysfunction, and overload, suggesting a role for circulating relaxin as a biomarker in this setting. PMID- 27488263 TI - Comparison of optomagnetic and AC susceptibility readouts in a magnetic nanoparticle agglutination assay for detection of C-reactive protein. AB - There is an increasing need to develop biosensor methods that are highly sensitive and that can be combined with low-cost consumables. The use of magnetic nanoparticles (MNPs) is attractive because their detection is compatible with low cost disposables and because application of a magnetic field can be used to accelerate assay kinetics. We present the first study and comparison of the performance of magnetic susceptibility measurements and a newly proposed optomagnetic method. For the comparison we use the C-reactive protein (CRP) induced agglutination of identical samples of 100nm MNPs conjugated with CRP antibodies. Both methods detect agglutination as a shift to lower frequencies in measurements of the dynamics in response to an applied oscillating magnetic field. The magnetic susceptibility method probes the magnetic response whereas the optomagnetic technique probes the modulation of laser light transmitted through the sample. The two techniques provided highly correlated results upon agglutination when they measure the decrease of the signal from the individual MNPs (turn-off detection strategy), whereas the techniques provided different results, strongly depending on the read-out frequency, when detecting the signal due to MNP agglomerates (turn-on detection strategy). These observations are considered to be caused by differences in the volume-dependence of the magnetic and optical signals from agglomerates. The highest signal from agglomerates was found in the optomagnetic signal at low frequencies. PMID- 27488264 TI - An O2-sensing stressosome from a Gram-negative bacterium. AB - Bacteria have evolved numerous pathways to sense and respond to changing environmental conditions, including, within Gram-positive bacteria, the stressosome complex that regulates transcription of general stress response genes. However, the signalling molecules recognized by Gram-positive stressosomes have yet to be identified, hindering our understanding of the signal transduction mechanism within the complex. Furthermore, an analogous pathway has yet to be described in Gram-negative bacteria. Here we characterize a putative stressosome from the Gram-negative bacterium Vibrio brasiliensis. The sensor protein RsbR binds haem and exhibits ligand-dependent control of the stressosome complex activity. Oxygen binding to the haem decreases activity, while ferrous RsbR results in increased activity, suggesting that the V. brasiliensis stressosome may be activated when the bacterium enters anaerobic growth conditions. The findings provide a model system for investigating ligand-dependent signalling within stressosome complexes, as well as insights into potential pathways controlled by oxygen-dependent signalling within Vibrio species. PMID- 27488265 TI - Molecular Engineering of Potent Sensitizers for Very Efficient Light Harvesting in Thin-Film Solid-State Dye-Sensitized Solar Cells. AB - Dye-sensitized solar cells (DSSCs) have shown significant potential for indoor and building-integrated photovoltaic applications. Herein we present three new D A-pi-A organic sensitizers, XY1, XY2, and XY3, that exhibit high molar extinction coefficients and a broad absorption range. Molecular modifications of these dyes, featuring a benzothiadiazole (BTZ) auxiliary acceptor, were achieved by introducing a thiophene heterocycle as well as by shifting the position of BTZ on the conjugated bridge. The ensuing high molar absorption coefficients enabled the fabrication of highly efficient thin-film solid-state DSSCs with only 1.3 MUm mesoporous TiO2 layer. XY2 with a molar extinction coefficient of 6.66 * 10(4) M( 1) cm(-1) at 578 nm led to the best photovoltaic performance of 7.51%. PMID- 27488267 TI - Bilateral Myeloid Sarcoma of Breast in a Young Male Occurring after 11 Years of Chronic Myeloid Leukemia Diagnosis: A Unique Pattern of Relapse. PMID- 27488266 TI - Indicated school-based intervention to improve depressive symptoms among at risk Chilean adolescents: a randomized controlled trial. AB - BACKGROUND: Depression is a disabling condition affecting people of all ages, but generally starting during adolescence. Schools seem to be an excellent setting where preventive interventions may be delivered. This study aimed to test the effectiveness of an indicated school-based intervention to reduce depressive symptoms among at-risk adolescents from low-income families. METHODS: A two-arm, parallel, randomized controlled trial was conducted in 11 secondary schools in vulnerable socioeconomic areas in Santiago, Chile. High-risk students in year 10 (2 degrees Medio) were invited to a baseline assessment (n = 1048). Those who scored >=10 (boys) and >=15 (girls) in the BDI-II were invited to the trial (n = 376). A total of 342 students consented and were randomly allocated into an intervention or a control arm in a ratio of 2:1. The intervention consisted of 8 group sessions of 45 min each, based on cognitive-behavioural models and delivered by two trained psychologists in the schools. Primary (BDI-II) and secondary outcomes (measures of anxiety, automatic thoughts and problem-solving skills) were administered before and at 3 months post intervention. The primary outcome was the recovery rate, defined as the proportion of participants who scored in the BDI-II <10 (among boys) and <15 (among girls) at 3 months after completing the intervention. RESULTS: There were 229 participants in the intervention group and 113 in the control group. At 3-month follow-up 81.4 % in the intervention and 81.7 % in the control group provided outcome data. The recovery rate was 10 % higher in the intervention (50.3 %) than in the control (40.2 %) group; with an adjusted OR = 1.62 (95 % CI: 0.95 to 2.77) (p = 0.08). No difference between groups was found in any of the secondary outcomes. Secondary analyses revealed an interaction between group and baseline BDI-II score. CONCLUSIONS: We found no clear evidence of the effectiveness of a brief, indicated school-based intervention based on cognitive-behavioural models on reducing depressive symptoms among Chilean adolescents from low-income families. More research is needed in order to find better solutions to prevent depression among adolescents. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33871591 . Retrospectively registered 29 June 2011. PMID- 27488268 TI - One-Step Synthesis of Microporous Carbon Monoliths Derived from Biomass with High Nitrogen Doping Content for Highly Selective CO2 Capture. AB - The one-step synthesis method of nitrogen doped microporous carbon monoliths derived from biomass with high-efficiency is developed using a novel ammonia (NH3)-assisted activation process, where NH3 serves as both activating agent and nitrogen source. Both pore forming and nitrogen doping simultaneously proceed during the process, obviously superior to conventional chemical activation. The as-prepared nitrogen-doped active carbons exhibit rich micropores with high surface area and high nitrogen content. Synergetic effects of its high surface area, microporous structure and high nitrogen content, especially rich nitrogen containing groups for effective CO2 capture (i.e., phenyl amine and pyridine nitrogen) lead to superior CO2/N2 selectivity up to 82, which is the highest among known nanoporous carbons. In addition, the resulting nitrogen-doped active carbons can be easily regenerated under mild conditions. Considering the outstanding CO2 capture performance, low production cost, simple synthesis procedure and easy scalability, the resulting nitrogen-doped microporous carbon monoliths are promising candidates for selective capture of CO2 in industrial applications. PMID- 27488269 TI - The bile acid chenodeoxycholic acid directly modulates metabolic pathways in white adipose tissue in vitro: insight into how bile acids decrease obesity. AB - Obesity is a worldwide epidemic, and associated pathologies, including type 2 diabetes and cardiovascular alterations, are increasingly escalating morbidity and mortality. Despite intensive study, no effective simple treatment for these conditions exists. As such, the need for go-to drugs is serious. Bile acids (BAs) present the possibility of reversing these problems, as various in vivo studies and clinical trials have shown significant effects with regard to weight and obesity reduction, insulin sensitivity restoration and cardiovascular improvements. However, the mechanism of action of BA-induced metabolic improvement has yet to be fully established. The currently most accepted model involves non-shivering thermogenesis for energy waste, but this is disputed. As such, we propose to determine whether the BA chenodeoxycholic acid (CDCA) can exert anti-obesogenic effects in vitro, independent of thermogenic brown adipose tissue activation. By exposing differentiated 3 T3-L1 adipocytes to high glucose and CDCA, we demonstrate that this BA has anti-obesity effects in vitro. Nuclear magnetic resonance spectroscopic analysis of metabolic pathways clearly indicates an improvement in metabolic status, as these cells become more oxidative rather than glycolytic, which may be associated with an increase in fatty acid oxidation. Our work demonstrates that CDCA-induced metabolic alterations occur in white and brown adipocytes and are not totally dependent on endocrine/nervous system signaling, as thought until now. Furthermore, future exploration of the mechanisms behind these effects will undoubtedly reveal interesting targets for clinical modulation. PMID- 27488270 TI - Proportional estimation of finger movements from high-density surface electromyography. AB - BACKGROUND: The importance to restore the hand function following an injury/disease of the nervous system led to the development of novel rehabilitation interventions. Surface electromyography can be used to create a user-driven control of a rehabilitation robot, in which the subject needs to engage actively, by using spared voluntary activation to trigger the assistance of the robot. METHODS: The study investigated methods for the selective estimation of individual finger movements from high-density surface electromyographic signals (HD-sEMG) with minimal interference between movements of other fingers. Regression was evaluated in online and offline control tests with nine healthy subjects (per test) using a linear discriminant analysis classifier (LDA), a common spatial patterns proportional estimator (CSP-PE), and a thresholding (THR) algorithm. In all tests, the subjects performed an isometric force tracking task guided by a moving visual marker indicating the contraction type (flexion/extension), desired activation level and the finger that should be moved. The outcome measures were mean square error (nMSE) between the reference and generated trajectories normalized to the peak-to-peak value of the reference, the classification accuracy (CA), the mean amplitude of the false activations (MAFA) and, in the offline tests only, the Pearson correlation coefficient (PCORR). RESULTS: The offline tests demonstrated that, for the reduced number of electrodes (<=24), the CSP-PE outperformed the LDA with higher precision of proportional estimation and less crosstalk between the movement classes (e.g., 8 electrodes, median MAFA ~ 0.6 vs. 1.1 %, median nMSE ~ 4.3 vs. 5.5 %). The LDA and the CSP-PE performed similarly in the online tests (median nMSE < 3.6 %, median MAFA < 0.7 %), but the CSP-PE provided a more stable performance across the tested conditions (less improvement between different sessions). Furthermore, THR, exploiting topographical information about the single finger activity from HD-sEMG, provided in many cases a regression accuracy similar to that of the pattern recognition techniques, but the performance was not consistent across subjects and fingers. CONCLUSIONS: The CSP-PE is a method of choice for selective individual finger control with the limited number of electrodes (<24), whereas for the higher resolution of the recording, either method (CPS-PA or LDA) can be used with a similar performance. Despite the abundance of detection points, the simple THR showed to be significantly worse compared to both pattern recognition/regression methods. Nevertheless, THR is a simple method to apply (no training), and it could still give satisfactory performance in some subjects and/or simpler scenarios (e.g., control of selected fingers). These conclusions are important for guiding future developments towards the clinical application of the methods for individual finger control in rehabilitation robotics. PMID- 27488271 TI - Kinetic and computational analysis of the reversible inhibition of porcine pancreatic elastase: a structural and mechanistic approach. AB - Structural and mechanistic insights were revealed for the reversible inhibition of Porcine Pancreatic Elastase (PPE); the kinetics of uninhibited and inhibited hydrolysis of substrate Suc-AAA-pNA was analyzed thoroughly. Additionally, the interactions between PPE and its inhibitor were studied by computational techniques. The uninhibited hydrolysis of Suc-AAA-pNA by PPE proceeds through a virtual transition state, involving an inferior physical and another dominating chemical step, where two stabilized reactant states precede the predominant acyl enzyme. Different kinds of bonding with the PPE-backbone residues, including those of the catalytic triad, were found during the MD simulation of 5 ns, as key interactions favoring a higher stabilization of the best ranked complex PPE CF3C(O)-KA-NHPh-p-CF3. The proton inventories of the inhibited hydrolysis of Suc AAA-pNA by PPE, were ruled out the existence of any virtual transition state and thus they argue for a different mode of catalysis involving a structurally disturbed PPE molecule. Thereafter, a novel inhibition mechanism was suggested. PMID- 27488272 TI - A process evaluation of a cluster randomised trial to reduce potentially inappropriate prescribing in older people in primary care (OPTI-SCRIPT study). AB - BACKGROUND: The OPTI-SCRIPT cluster randomised controlled trial (RCT) found that a three-phase multifaceted intervention including academic detailing with a pharmacist, GP-led medicines reviews, supported by web-based pharmaceutical treatment algorithms, and tailored patient information leaflets, was effective in reducing potentially inappropriate prescribing (PIP) in Irish primary care. We report a process evaluation exploring the implementation of the intervention, the experiences of those participating in the study and lessons for future implementation. METHODS: The OPTI-SCRIPT trial included 21 GP practices and 196 patients. The process evaluation used mixed methods. Quantitative data were collected from all GP practices and semi-structured interviews were conducted with GPs from intervention and control groups, and a purposive sample of patients from the intervention group. All interviews were transcribed verbatim and analysed using a thematic analysis. RESULTS: Despite receiving a standardised academic detailing session, intervention delivery varied among GP practices. Just over 70 % of practices completed medicines review as recommended with the patient present. Only single-handed practices conducted reviews without patients present, highlighting the influence of practice characteristics and resources on variation. Medications were more likely to be completely stopped or switched to another more appropriate medication when reviews were conducted with patients present. The patient information leaflets were not used by any of the intervention practices. Both GP (32 %) and patient (40 %) recruitment rates were modest. For those who did participate, overall, the experience was positively viewed, with GPs and patients referring to the value of medication reviews to improve prescribing and reduce unnecessary medications. Lack of time in busy GP practices and remuneration were identified as organisational barriers to future implementation. CONCLUSIONS: The OPTI-SCRIPT intervention was positively viewed by both GPs and patients, both of whom valued the study's objectives. Patient information leaflets were not a successful component of the intervention. Academic detailing and medication reviews are important components in changing PIP, and having patients present during the review process seems to be a more effective approach for decreasing PIP. TRIAL REGISTRATION: Current controlled trials ISRCTN41694007 . Registered on 21 March 2012. PMID- 27488274 TI - Prevention of microalbuminuria using early intervention with renin-angiotensin system inhibitors in patients with type 2 diabetes: A systematic review. AB - HYPOTHESIS/OBJECTIVES: Early prevention of diabetic nephropathy by way of blocking the renin-angiotensin system (RAS) in patients with normoalbuminuria seems rational, but trials have so far shown conflicting results. The present meta-analysis was undertaken to investigate if such treatment can prevent development of microalbuminuria. MATERIALS AND METHODS: We searched MEDLINE, EMBASE and the Cochrane Library (2 June 2014) for randomised controlled trials, with a population of patients with type 2 diabetes and normoalbuminuria, comparing angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs) to placebo. Studies had to have at least 50 participants in each arm and one year of follow-up. Random and fixed effect models were performed as well as trial sequential analysis. RESULTS: Six trials were included in the analysis (n=16,921). Overall risk of bias was variable. In a fixed model analysis ACE or ARB treatment was superior to placebo in relation to prevention of development of microalbuminuria, risk ratio 0.84 (95% confidence interval (CI) 0.79-0.88) p<0.001, I(2)=23%, similar to random model results. Treatment also showed a trend towards a reduction in all-cause mortality(p=0.07). CONCLUSIONS: We conclude that in patients with type 2 diabetes and normoalbuminuria, early intervention with ACEis or ARBs reduces the risk for development of microalbuminuria. PMID- 27488273 TI - Exposure to mercury in susceptible population groups living in the former mercury mining town of Idrija, Slovenia. AB - 500 years of mercury (Hg) mining in the town of Idrija has caused severe pollution in Idrija and its surroundings. Following the closure of the mine in 1995, the environment remains contaminated with Hg. Sources of elemental-, inorganic- and methyl Hg exposure were identified, potential environmental level of exposure to Hg was evaluated and actual internal exposure to Hg was assessed in selected susceptible population groups comprising school-age children and pregnant women living in Idrija and in control groups from rural and urban environments. The study of pregnant women (n=31) was conducted between 2003 and 2008, and the study of school-age children (n=176) in 2008. Potential interaction of Hg with selenium (Se) in plasma was assessed in both study populations, while in pregnant women antioxidative enzyme activity (glutathione peroxidase, superoxide dismutase and catalase) in erythrocytes of maternal and cord blood was also assessed. Actual exposure to Hg as indicated by levels of Hg in children's blood (geometric mean (GM) 0.92ug/L), mother's blood (GM 1.86ug/L), children's urine (GM 1.08ug/g crea.), mother's urine (GM 2.51ug/L), children's hair (GM 241ng/g) and mother's hair (GM 251ng/g) was higher in the two study groups from Idrija than in the control groups from rural areas, but was still at the level of a "normal" population and reflects mainly exposure to elemental Hg (Hg degrees ) from dental amalgam and, to a certain extent atmospheric Hg degrees . Furthermore, the internal doses of Hg received during pregnancy did not decrease the bioavailability of Se. Based on observation in children, the increase in Se protein expression is suggested to be a consequence of moderately elevated exposure to Hg degrees . The observed changes in activity of antioxidative enzymes, as biomarkers of oxidative stress, appear to be mainly associated with pregnancy per se and not with an increased exposure to Hg. In view of the continuing increased potential for Hg exposure and the low number of pregnant women studied, the results warrant a further longitudinal study of a larger group of pregnant women residing in the area of the former mercury mine. PMID- 27488275 TI - Angiotensin II Type 1 receptor (AGTR1) gene polymorphisms are associated with vascular manifestations in patients with systemic sclerosis (SSc). AB - INTRODUCTION: Systemic sclerosis (SSc) shows variable clinical expression in different ethnic groups; vascular abnormalities are a prominent feature of this disease and its clinical expression may be influenced by genetic factors. PATIENTS AND METHODS: Herein, we describe 15 polymorphisms of the renin angiotensin-aldosterone pathway in 170 Mexican admixed SSc patients (defined as patients with Mexican ancestry for at least 3 generations) and 199 healthy controls. We determined the presence of angiotensin II Type 1 receptor (AGTR1), angiotensin converting enzyme (ACE) and Endothelin 1 single nucleotide polymorphisms (SNPs) using 5' exonuclease TaqMan genotyping assays on a 7900HT real-time fast polymerase chain reaction (PCR) system. RESULTS: These polymorphisms had a similar distribution between SSc patients and controls, but we found that the AGTR1 G-680T (rs275652) (p = 0.02; OR 3.5; 95%CI 1.2-10.4) and AGTR1 A-119G (rs275653) (p = 0.008; OR 4.2; 95% CI 1.5-12.1) polymorphisms were associated with severe vascular involvement in our SSc patients. CONCLUSIONS: This is the first report of the association of these polymorphisms with vasculopathy in Mexican admixed SSc patients. Our findings suggested that the angiotensin II Type 1 receptor genotype may influence the clinical expression of vasculopathy in these patients. Functional analyses should follow. PMID- 27488276 TI - Serum activity of angiotensin converting enzyme 2 is decreased in patients with acute ischemic stroke. AB - Levels of angiotensin converting enzyme 2 (ACE2), a cardio and neuro-protective carboxypeptidase, are dynamically altered after stroke in preclinical models. We sought to characterize the previously unexplored changes in serum ACE2 activity of stroke patients and the mechanism of these changes. Serum samples were obtained from patients during acute ischemic stroke (n=39), conditions mimicking stroke (stroke-alert, n=23), or from control participants (n=20). Enzyme activity levels were analyzed by fluorometric assay and correlated with clinical variables by regression analyses. Serum ACE2 activity was significantly lower in acute ischemic stroke as compared to both control and stroke-alert patients, followed by an increase to control levels at three days. Serum ACE2 activity significantly correlated with the presence of ischemic stroke after controlling for other factors (P=0.01). Additional associations with ACE2 activity included a positive correlation with systolic blood pressure at presentation in stroke-alert (R(2)=0.24, P=0.03), while stroke levels showed no correlation (R(2)=0.01, P=0.50). ACE2 sheddase activity was unchanged between groups. These dynamic changes in serum ACE2 activity in stroke, which concur with preclinical studies, are not likely to be driven primarily by acute changes in blood pressure or sheddase activity. These findings provide new insight for developing therapies targeting this protective system in ischemic stroke. PMID- 27488277 TI - Behavior of chemiluminescent assays to measure serum testosterone during androgen deprivation therapy. PMID- 27488278 TI - Weight loss among women and men in the ASPIRE-VA behavioral weight loss intervention trial. AB - OBJECTIVE: Weight loss was examined among women and men veterans in a clinical trial comparing Aspiring for Lifelong Health (ASPIRE), a "small changes" weight loss program using either mixed-sex group-visit or telephone-based coaching, to MOVE!((r)) , the usual mixed-sex group-based program. METHODS: Linear mixed effects models were used to calculate adjusted percent weight change at 12 months by sex and compare outcomes across arms within sex. RESULTS: Analyses included 72 women (ASPIRE-Phone = 26; ASPIRE-Group = 26; MOVE! = 20) and 409 men (ASPIRE Phone = 136; ASPIRE-Group = 134; MOVE! = 139). At 12 months, women displayed significant weight loss from baseline in ASPIRE-Group (-2.6%) and MOVE! (-2.7%), but not ASPIRE-Phone (+0.2%). Between-arm differences in weight change among women were: ASPIRE-Group versus ASPIRE-Phone, -2.8% (P = 0.15); MOVE! versus ASPIRE-Phone, -2.8% (P = 0.20); and ASPIRE-Group versus MOVE!, 0.0% (P = 1.0). At 12 months, men lost significant weight from baseline across arms (ASPIRE-Phone, 1.5%; ASPIRE-Group, -2.5%; MOVE!, -1.0%). Between-arm differences in weight change among men were: ASPIRE-Group versus ASPIRE-Phone, -0.9% (P = 0.23); MOVE! versus ASPIRE-Phone, +0.5% (P = 0.76); ASPIRE-Group versus MOVE!, -1.5% (P = 0.03). CONCLUSIONS: Mixed-sex, group-based programs can result in weight loss for both women and men veterans. PMID- 27488280 TI - Oxytetracycline recovery from aqueous media using computationally designed molecularly imprinted polymers. AB - Polymers for recovery/removal of the antimicrobial agent oxytetracycline (OTC) from aqueous media were developed with use of computational design and molecular imprinting. 2-Hydroxyethyl methacrylate, 2-acrylamide-2-methylpropane sulfonic acid (AMPS), and mixtures of the two were chosen according to their predicted affinity for OTC and evaluated as functional monomers in molecularly imprinted polymers and nonimprinted polymers. Two levels of AMPS were tested. After bulk polymerization, the polymers were crushed into particles (200-1000 MUm). Pressurized liquid extraction was implemented for template removal with a low amount of methanol (less than 20 mL in each extraction) and a few extractions (12 18 for each polymer) in a short period (20 min per extraction). Particle size distribution, microporous structure, and capacity to rebind OTC from aqueous media were evaluated. Adsorption isotherms obtained from OTC solutions (30-110 mg L(-1)) revealed that the polymers prepared with AMPS had the highest affinity for OTC. The uptake capacity depended on the ionic strength as follows: purified water > saline solution (0.9 % NaCl) > seawater (3.5 % NaCl). Polymer particles containing AMPS as a functional monomer showed a remarkable ability to clean water contaminated with OTC. The usefulness of the stationary phase developed for molecularly imprinted solid-phase extraction was also demonstrated. Graphical Abstract Selection of functional monomers by molecular modeling renders polymer networks suitable for removal of pollutants from contaminated aqueous environments, under either dynamic or static conditions. PMID- 27488282 TI - New Stethoscope With Extensible Diaphragm. AB - BACKGROUND: This study compared the diagnostic efficacy of the common suspended diaphragm stethoscope (SDS) with a new extensible diaphragm stethoscope (EDS) for low-frequency heart sounds. METHODS AND RESULTS: The EDS was developed by using an ethylene propylene diene monomer diaphragm. The results showed that the EDS enhanced both the volume and quality of low-frequency heart sounds, and improved the ability of examiners to auscultate such heart sounds. CONCLUSIONS: Based on the results of the sound analysis, the EDS is more efficient than the SDS. (Circ J 2016; 80: 2047-2049). PMID- 27488281 TI - Redefining the role of peripheral LPS as a neuroinflammatory agent and evaluating the role of hydrogen sulphide through metformin intervention. AB - OBJECTIVE: The present study was aimed to enumerate the role of metformin associated H2S release against lipopolysaccharide (LPS) induced neuroinflammation. MATERIALS AND METHODS: Five groups of animals were subjected to treatment as control (normal saline), toxic control (LPS, 125 ug/kg, i.p.), and three separate groups treated with 6.25, 12.5, and 25 mg/kg of metformin along with LPS for a period of 28 days. LPS was administered on 1st, 2nd, 3rd, 4th, 23rd, 24th, 25th and 26th day. The animals were evaluated for behavioral (elevated plus maze, rotarod and actophotometer); biochemical (plasma and tissue H2S, COX, LOX and NO), antioxidant (TBARS, SOD, catalase, protein carbonyl and GSH) and liver toxicity (SGOT and SGPT) markers. The brain tissues were further evaluated histopathologically, free fatty acid profile and NF-kappaB expression. RESULT: The LPS could not hasten any significant behavioral, biochemical, antioxidant and histopathological changes in the brain tissue. LPS also failed to modify the free fatty acid profile and NF-kappaB expression in the brain tissue. The LPS demarcated a well-defined peripheral inflammation as perceived through the plasma H2S, NO, SGOT and SGPT. Metformin administration demonstrated a marked effect on the peripheral inflammation induced by LPS. CONCLUSION: The LPS (i.p.) administration is devoid of any neuroinflammatory effects; however, precipitates peripheral inflammatory reactions and the same can could be attributed to the fact that LPS is devoid of/confined by very minimal permeability across the blood brain barrier. Metformin demonstrated a significant effect on peripheral inflammatory reactions precipitated through LPS. PMID- 27488283 TI - Right Heart Hemodynamics in Pulmonary Hypertension - An Echocardiography and Catheterization Study. AB - BACKGROUND: Echocardiography (ECHO) plays a key role in both the diagnosis and prognosis of pulmonary hypertension (PH). Many equations have been published to assess right heart hemodynamics using ECHO. The objective of this study was to test the accuracy and precision of different echocardiographic equations in comparison with the right heart catheterization. METHODS AND RESULTS: Complete right heart hemodynamic assessments were prospectively obtained from 115 individuals (mean age 66+/-1 years; 57 males) who had known or suspected PH. Several equations were tested for the estimation of right atrial pressure, mean and systolic pulmonary artery pressure (MPAP), cardiac output, pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance (PVR). The accuracy of ECHO was good, with a mean difference <2 mmHg for all of the pressure calculations and +/-0.6 L/min for cardiac output. However, the PVR estimation was weak using any one of the formulae. For all the parameters, the precision of ECHO was moderate. The MPAP calculation detected PH with a sensibility of 97% and specificity of 83%. However, ECHO underdiagnosed post-capillary PH. CONCLUSIONS: ECHO is a good method for the diagnosis of PH, with an adequate calculation of right pressures, but cannot accurately calculate PCWP and PVR. (Circ J 2016; 80: 2019-2025). PMID- 27488284 TI - Angioscopic Assessment of Stent Stability and Neointimal Coverage After Implantation of 2nd-Generation Drug-Eluting Stents - Comparison With Bare-Mental Stents and 1st-Generation Drug-Eluting Stents. PMID- 27488285 TI - Dawn of a New Era - The Far Lower, the Far Better Low-Density Lipoprotein Cholesterol Story in Japan. PMID- 27488286 TI - Old landfill leachate treatment through multistage process: membrane adsorption bioreactor and nanofitration. AB - A bench-scale integrated process based on submerged aerobic powdered activated carbon-membrane bioreactor (PAC-MBR) has been utilized and established for the treatment of landfill leachate. The results showed that the submerged PAC-MBR system effectively removed biodegradable trace organic compounds by the average removal rate about 71 % at optimum food to microorganism (F/M) ratio of 0.4 gCOD/g day under a HRT of 24 h. Adding nanofiltration (NF) process increased the treatment efficiency up to 99 %. Further, adding powdered activated carbon to activated sludge (AS) resulted in a higher adsorption capacity in comparison with AS. Adsorption isotherms were investigated and fitted by the Langmuir and Freundlich isotherm models in which the Langmuir model performed better. The specific oxygen uptake rate (SOUR) showed that adding PAC reduces the effects of COD on microorganism activities. NH3-N, TKN and Heavy metals removal efficiency amounted to 97 +/- 2, 96 +/- 2, and 99 +/- 2 %, respectively. PMID- 27488287 TI - Functional acute liver failure after treatment with pegylated asparaginase in a patient with acute lymphoblastic leukemia: potential impact of plasmapheresis. PMID- 27488288 TI - Synthesis of esters via sp(3) C-H functionalisation. AB - Oxidative C-O bond formation via sp(3) C-H functionalisation represents an attractive approach for the synthesis of esters. This review focuses on the recent advances of sp(3) C-H bond functionalisation strategies for ester synthesis from unconventional precursors using transition metal/metal free catalysts in combination with various oxidants. Various classes of esters and the mechanisms of their formation are discussed with numerous examples. PMID- 27488289 TI - Clinical and Radiological Study Focused on Relief of Low Back Pain After Decompression Surgery in Selected Patients With Lumbar Spinal Stenosis Associated With Grade I Degenerative Spondylolisthesis. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of the present study was to identify the clinical and radiological features of low back pain (LBP) that was relieved after decompression alone of lumbar spinal stenosis (LSS) associated with grade I lumbar degenerative spondylolisthesis (LDS). SUMMARY OF BACKGROUND DATA: Although decompression and fusion are generally the recommended surgical treatments of LDS, several authors have reported that some patients with LDS could obtain good clinical results including relief from LBP by decompression alone. The pathogenesis of relief from LBP after decompression is, however, not known. METHODS: Forty patients with LSS associated with grade I LDS, who underwent a minimally invasive surgical-decompression were enrolled in the present study. All patients complained preoperatively of predominantly leg related symptoms and LBP (>= 4 points on Numeric Rating Scale). Clinical and radiological assessments were performed 1 year after surgery (a relief of LBP: Numeric Rating Scale reduction >=3 points and valuation <=3 points) and at the last follow-up. We conducted a comparative study between patient groups with and without the relief from LBP (groups R and N, respectively). RESULTS: Twenty-nine patients were distributed to group R and the remaining 11 patients to group N. Preoperatively, there was a significant difference between the two groups for age and radiographic flexibility for lumbar extension. Postoperatively, there was a positive correlation between improvement in both LBP and leg symptoms. The clinical outcomes of group R were significantly better than those of group N throughout follow-up period (mean 37 mo). In group R, sagittal lumbopelvic radiographic parameters improved significantly after surgery. CONCLUSION: Although the causes of LBP are varied in each patients, our results show that concomitant LSS itself might cause LBP in some patients with grade I LDS, because it involves impingement of the neural tissue and discordant sagittal lumbopelvic alignment. LEVEL OF EVIDENCE: 3. PMID- 27488290 TI - Direct Repair of Lumbar Pars Interarticularis Defects by Utilizing Intraoperative O-Arm-Based Navigation and Microendoscopic Techniques. AB - STUDY DESIGN: A retrospective analysis of the clinical outcomes of eight patients with the lumbar pars interarticulars defects treated by direct repair with the aid of intraoperative O-arm based navigation and microendoscopic techniques. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of direct screw repair by using minimally invasive surgery for the lumbar pars interarticulars defects in a pilot study. SUMMARY OF BACKGROUND DATA: Direct repair of pars interarticulars defects has been used to treat young adult patients. Reports concerning direct repair by minimally invasive techniques for pars interarticulars defects are quite rare. METHODS: Review of medical records identified eight consecutive patients treated with intraoperative O-arm based navigation and microendoscopic techniques. Debridement and autograft of pars interarticularis defects was performed under microendoscopic procedure. Then, percutaneous bilateral intralaminar screws were inserted by utilizing intraoperative navigation. The clinical and radiological data were collected and analyzed retrospectively. RESULTS: Eight patients had a mean age of 28.4 years, and five were 30 years or younger at the time of treatment. Symptoms included axial back pain in 100% of patients without concomitant radiculopathy. Autograft was used in all cases. The average follow-up duration was 27.4 months with a range of 20 to 33 months. Symptoms resolved completely or partially in all patients. Low back pain visual analog scores decrease from preoperative 6.8 to postoperative 1.4 of eight cases. Of 16 pars defects, healing was observed in 13 (81.3%) at last radiological follow-up. One patient with bilateral fusion failure refused revision surgery because of mild complaint. No complications such as dural tear, nerve root injury, and infection occurred. CONCLUSION: Minimally invasive direct repair of the pars interarticularis defects with intralaminar screws by using microendoscopic system and navigation procedure can provide safe and effective treatment of spondylolysis with satisfactory clinical and radiological outcomes, which need some special tools with steep learning curve. LEVEL OF EVIDENCE: 4. PMID- 27488291 TI - Increased Segmental Range of Motion Is Correlated With Spondylolisthesis in the Cervical Spine After Laminoplasty. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: The aim of this study was to determine the incidence of increased segmental range of motion (ROM) after laminoplasty and to clarify whether increased ROM is associated with spondylolisthesis. Finally, we explored the effect of increased segmental ROM on clinical results. SUMMARY OF BACKGROUND DATA: Cervical laminoplasty for cervical spondylotic myelopathy causes reduced ROM, possibly due to the unintended contracture of the facet joint or a bony union. Although it is rarely studied, ROM may also increase following laminoplasty. Thus far, there are no reports describing the correlation between increased segmental ROM and segmental spondylolisthesis after laminoplasty. METHODS: We evaluated 187 segments from 39 cervical spondylotic myelopathy patients who underwent bilateral open door laminoplasty from C2 to C7. The segmental ROM and spondylolisthesis were measured using dynamic radiographs that were obtained preoperatively and 2 years postoperatively. The Japanese Orthopedic Association (JOA) score was used for clinical evaluation. To compare the clinical results, we compared the cases with increased ROM in at least one segment with the remaining cases. RESULTS: Increased segmental ROM (i.e., >=5 degrees increase) was observed in 25 of 187 segments (13.4%) from 14 cases. There was a strong correlation between increased ROM and spondylolisthesis. A high preoperative disc height was associated with increased segmental ROM 2 years postoperation. Regardless of the correlation with spondylolisthesis, there was no statistically significant correlation between increased segmental ROM and JOA score. CONCLUSION: The decrease in segmental ROM after laminoplasty was not uniform. Approximately 13.4% of all segments showed increased ROM. The preoperative disc height might influence the risk for increased segmental ROM. Furthermore, increased ROM was correlated with spondylolisthesis in the segment, though it was not correlated with clinical results. LEVEL OF EVIDENCE: 4. PMID- 27488292 TI - Impact of Insulin Dependence on Perioperative Outcomes Following Anterior Cervical Discectomy and Fusion. AB - STUDY DESIGN: A retrospective analysis of prospectively collected data. OBJECTIVE: Our objective was to analyze insulin-dependent and noninsulin dependent diabetes mellitus (IDDM and NIDDM) as potential risk factors for complications, reoperations, and readmissions within 30 days following anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: ACDF is a common surgical procedure with growing utilization and good long-term outcomes. Readmissions and reoperations are associated with increased morbidity and inferior long-term outcomes. IDDM and NIDDM are often associated with increased complication rates. METHODS: This was a retrospective analysis of prospectively collected data from the ACS NSQIP database. Patients >=18 years old undergoing ACDF from 2005 to 2012 were included. Readmission, perioperative events, and reoperation within 30 days following ACDF were measured. Patient demographics, perioperative data, preoperative labs, and postoperative events were assessed. Patients with NIDDM or IDDM were compared with nondiabetic patients using multivariate logistic regression analysis with significance defined as P < 0.05. Odds ratio (OR) was calculated with a 95% confidence interval (CI). RESULTS: Three thousand seven hundred twenty-six patients were included of whom 270 were NIDDM and 171 IDDM. Readmissions and reoperation data were available only from 2011 to 2012, including 1423 nondiabetes mellitus (non-DM), 193 NIDDM, and 87 IDDM cases. NIDDM was associated with higher rates of urinary tract infection (UTI) (P < 0.007), and return to operating room (P = 0.012) than nondiabetic patients. IDDM was associated with higher rates of reoperations (P = 0.04), readmissions (P < 0.0001), and total length of stay (LOS) >5 days (P < 0.0001). Following adjusted multivariate analysis, only IDDM status remained an independent predictor for 30-day readmission (OR 4.8, 95% CI 2.3-10.1). CONCLUSION: Patients with NIDDM and IDDM were at an increased risk for several postoperative complications following ACDF. IDDM was independently associated with increased 30-day readmission rates. Diabetic patients should be counseled appropriately, and the importance of close perioperative care is highlighted in this study. LEVEL OF EVIDENCE: 3. PMID- 27488293 TI - Evidence-Based Review and Survey of Expert Opinion of Reconstruction of Metastatic Spine Tumors. AB - STUDY DESIGN: Systematic review and consensus expert opinion. OBJECTIVE: To provide surgeons and other health care professionals with guidelines for surgical reconstruction of metastatic spine disease based on evidence and expert opinion. SUMMARY OF BACKGROUND DATA: The surgical treatment of spinal metastases is controversial. Specifically two aspects of surgical reconstruction are addressed in this study: (i) choice of bone graft used during surgery for metastatic spine tumors and (ii) the design of reconstruction or construct to stabilize. METHODS: A systematic review of the available medical literature from 1980 to 2015 was conducted, and combined with consensus expert opinion from a recent survey of spine surgeons who treat metastatic spine tumors. RESULTS: There is very little evidence in the literature to provide guidance on the use of bone graft in metastatic tumor reconstruction. There is little evidence in the literature to support the preferential use of one graft type over the other. Approximately, 41% of respondents said they used bone graft or bone graft substitutes to accomplish fusion. There were 17 studies that described the use of a prefabricated prosthetic, 10 studies describing the use of polymethyl methacrylate (PMMA) bone cement, and only three studies describing the use of bone graft for anterior column reconstruction. The use of structural allograft was most popular among the experts for anterior reconstruction, followed by cage reconstruction, and PMMA bone cement. CONCLUSION: Achieving bony union may be of importance for the maintenance of spinal stability in the long term after reconstruction. Whether bony union is required for patients with shorter life expectancies is debatable. The literature supports the use of anterior reconstruction with either a prefabricated prosthetic or PMMA bone cement. It also supports the use of an anterior construct reinforced with bilateral posterior instrumentation when performing a three-column reconstruction. LEVEL OF EVIDENCE: N/A. PMID- 27488294 TI - Stereotactic Body Radiotherapy for Spinal Metastases: What are the Risks and How Do We Minimize Them? AB - STUDY DESIGN: Systematic literature review. OBJECTIVES: To summarize the risks of 3 key complications of stereotactic body radiotherapy (SBRT) for spinal metastases, that is, radiation myelopathy (RM), vertebral compression fracture (VCF), and epidural disease progression, and to discuss strategies for minimizing them. SUMMARY OF BACKGROUND DATA: RM, VCF and epidural disease progression are now recognized as important risks following SBRT for spine metastases. It is unclear at this stage exactly how large these risks are and what strategies can be employed to minimize these risks. METHODS: A systematic review of the literature using MEDLINE and a review of the bibliographies of reviewed articles on SBRT for spinal metastases were conducted. RESULTS: The initial literature search revealed a total of 376 articles, of which 38 were pertinent to the study objectives. The risk of RM following SBRT was found to be dependent on the maximum dose to the spinal cord and estimated to be <=5% if the recommended published thecal sac dose constraints are adhered to. The crude risk of VCF was 13.7% (range: 0.7%-40.5%), and, on average, 45% were surgically salvaged. It has been shown that the risk of VCF is dependent on several anatomic and tumor related factors including the SBRT dose per fraction. The crude risk of local failure at 1 year was 21.4% (range: 12%-27%) of which 67% (range: 38%-96%) occurred within the epidural space. The grade of epidural disease has been shown to be associated with the risk of local failure. CONCLUSION: The risk of RM after spinal SBRT is low in particular if recommended dose metrics are adhered to. There is a significant risk of both VCF and epidural disease progression after spinal SBRT. These risks can potentially be minimized by identifying the risk factors for these complications, and performing careful radiotherapy and surgical planning. LEVEL OF EVIDENCE: 2. PMID- 27488295 TI - Benign Tumors of the Spine: Has New Chemotherapy and Interventional Radiology Changed the Treatment Paradigm? AB - STUDY DESIGN: Clinically based systematic review. OBJECTIVE: To determine the role of (A) medical treatment and (B) interventional radiology as either adjuvant or stand-alone treatment in primary benign bone tumors of the spine. METHODS: A multidisciplinary panel of spine surgeons, radiation oncologists, and medical oncologists elaborated specific focused questions regarding aneurysmal bone cyst, giant cell tumor, and osteoid osteoma. Denosumab, bisphosphonate, interferon, bone marrow aspirate, doxycycline, thermal ablation, and selective arterial embolization were identified as areas of interest for the article. A systematic review was performed through MEDLINE and EMBASE. Recommendations based on the literature review and clinical expertise were issued using the GRADE system. RESULTS: The overall quality of the literature is very low with few multicenter prospective studies. For giant cell tumor, combination with Denosumab identified 14 pertinent articles with four multicenter prospective studies. Nine studies were found on bisphosphonates and six for selective arterial embolization. The search on aneurysmal bone cyst and selective arterial embolization revealed 12 articles. Combination with Denosumab, Doxycycline, and bone marrow aspirate identified four, two, and three relevant articles respectively. Eleven focused articles were selected on the role of thermal ablation in osteoid osteoma. CONCLUSION: Alternative and adjuvant therapy for primary benign bone tumors have emerged. Their ability to complement or replace surgery is now being scrutinized and they may impact significantly the algorithm of treatment of these tumors. Most of the data are still emerging and further research is desirable. Close collaboration between the different specialists managing these pathologies is crucial. LEVEL OF EVIDENCE: N/A. PMID- 27488296 TI - A Systematic Review With Consensus Expert Opinion of Best Reconstructive Techniques After Osseous En Bloc Spinal Column Tumor Resection. AB - STUDY DESIGN: Systematic literature review and consensus expert opinion. OBJECTIVE: To provide recommendations on reconstructive constructs for large tumor resections of the spinal column. Four questions were studied: (1) What are the best reconstructive options for single versus multilevel resections? (2) Should short segment fixation be considered in primary tumor reconstruction? (3) How should reconstructive techniques differ at various regions of the spine? (4) Does planned postoperative radiation change the fusion strategy? SUMMARY OF BACKGROUND DATA: Primary spinal tumors requiring en bloc resection are rare. Most studies focus on disease-free survival and local recurrence rates. Few studies focus on reconstructive options and outcomes with respect to fusion rates and need for revision. METHODS: A literature search was performed from January 1990 to December 2013. Data were combined and construct survivorship summarized. A survey was administered to international spine tumor surgeons, evaluating reconstructive preferences. RESULTS: The search yielded 381 articles, 12 included in the final analysis. Revision rates for anterior reconstruction were similar for autogenous strut grafts (10%), cages (7.7%), and allograft strut grafts (8.3%). There were two reports of revision from short to long segment constructs and three reports of broken pedicle screws, one requiring revision. Expert survey results revealed that most surgeons preferred cages packed with morcelized allograft and autograft (75%) for anterior reconstruction of single-level vertebrectomies, and strut bone grafting at the cervicothoracic junction (65%) and when more than one vertebrae was resected in the mid-thoracic spine (75%). Surgeons may alter their fusion technique if postoperative radiation is planned. CONCLUSION: Posterior reconstruction with at least two vertebral levels above and below is recommended. Cages should be used for single-level defects and structural bone graft alone, or in combination with a cage, should be used when spanning a defect greater than two vertebral bodies. Planned postoperative radiation may affect fusion strategy. LEVEL OF EVIDENCE: N/A. PMID- 27488297 TI - The Spinal Instability Neoplastic Score: Impact on Oncologic Decision-Making. AB - STUDY DESIGN: Systematic literature review. OBJECTIVE: To address the following questions in a systematic literature review: 1. How is spinal neoplastic instability defined or classified in the literature before and after the introduction of the Spinal Instability Neoplastic Score (SINS)? 2. How has SINS affected daily clinical practice? 3. Can SINS be used as a prognostic tool? SUMMARY OF BACKGROUND DATA: Spinal neoplastic-related instability was defined in 2010 and simultaneously SINS was introduced as a novel tool with criteria agreed upon by expert consensus to assess the degree of spinal stability. METHODS: PubMed, Embase, and clinical trial databases were searched with the key words "spinal neoplasm," "spinal instability," "spinal instability neoplastic score," and synonyms. Studies describing spinal neoplastic-related instability were eligible for inclusion. Primary outcomes included studies describing and/or defining neoplastic-related instability, SINS, and studies using SINS as a prognostic factor. RESULTS: The search identified 1414 articles, of which 51 met the inclusion criteria. No precise definition or validated assessment tool was used specific to spinal neoplastic-related instability prior to the introduction of SINS. Since the publication of SINS in 2010, the vast majority of the literature regarding spinal instability has used SINS to assess or describe instability. Twelve studies specifically investigated the prognostic value of SINS in patients who underwent radiotherapy or surgery. CONCLUSION: No consensus could be determined regarding the definition, assessment, or reporting of neoplastic-related instability before introduction of SINS. Defining spinal neoplastic-related instability and the introduction of SINS have led to improved uniform reporting within the spinal neoplastic literature. Currently, the prognostic value of SINS is controversial. LEVEL OF EVIDENCE: N/A. PMID- 27488298 TI - Clinical Decision Making: Integrating Advances in the Molecular Understanding of Spine Tumors. AB - STUDY DESIGN: Literature review. OBJECTIVE: To describe advancements in molecular techniques, biomarkers, technology, and targeted therapeutics and the potential these modalities hold to predict treatment paradigms, clinical outcomes, and/or survival in patients diagnosed with primary spinal column tumors. SUMMARY OF BACKGROUND DATA: Advances in molecular technologies and techniques have influenced the prevention, diagnosis, and overall management of patients diagnosed with cancer. Assessment of genomic, proteomic alterations, epigenetic, and posttranslational modifications as well as developments in diagnostic modalities and targeted therapeutics, although the best studied in nonspinal metastatic disease, have led to increased understanding of spine oncology that is expected to improve patient outcomes. In this manuscript, the technological advancements that are expected to change the landscape of spinal oncology are discussed with a focus on how these technologies will aid in clinical decision making for patients diagnosed with primary spinal tumors. METHODS: A review of the literature was performed focusing on studies that integrated next-generation sequencing, circulating tumor cells/circulating tumor DNA, advances in imaging modalities and/or radiotherapy in the diagnosis and treatment of cancer. RESULTS: We discuss genetic and epigenetic drivers, aberrations in receptor tyrosine kinase signaling, and emerging therapeutic strategies that include receptor tyrosine kinase inhibitors, immunotherapy strategies, and vaccine-based cancer prevention strategies. CONCLUSION: The wide range of approaches currently in use and the emerging technologies yet to be fully realized will allow for better development of rationale therapeutics to improve patient outcomes. LEVEL OF EVIDENCE: N/A. PMID- 27488299 TI - Molecular Markers and Targeted Therapeutics in Metastatic Tumors of the Spine: Changing the Treatment Paradigms. AB - STUDY TYPE: A review of the literature. OBJECTIVE: The aim of this study was to discuss the evolution of molecular signatures and the history and development of targeted therapeutics in metastatic tumor types affecting the spinal column. SUMMARY OF BACKGROUND DATA: Molecular characterization of metastatic spine tumors is expected to usher in a revolution in diagnostic and treatment paradigms. Molecular characterization will provide critical information that can be used for initial diagnosis, prognosticating the ideal treatment strategy, assessment of treatment efficacy, surveillance and monitoring recurrence, and predicting complications, clinical outcome, and overall survival in patients diagnosed with metastatic cancers to the spinal column. METHODS: A review of the literature was performed focusing on illustrative examples of the role that molecular-based therapeutics have played in clinical outcomes for patients diagnosed with metastatic tumor types affecting the spinal column. RESULTS: The impact of molecular therapeutics including receptor tyrosine kinases and immune checkpoint inhibitors and the ability of molecular signatures to provide prognostic information are discussed in metastatic breast cancer, lung cancer, prostate cancer, melanoma, and renal cell cancer affecting the spinal column. CONCLUSION: For the providers who will ultimately counsel patients diagnosed with metastases to the spinal column, molecular advancements will radically alter the management/surgical paradigms utilized. Ultimately, the translation of these molecular advancements into routine clinical care will greatly improve the quality and quantity of life for patients diagnosed with spinal malignancies and provide better overall outcomes and counseling for treating physicians. LEVEL OF EVIDENCE: N/A. PMID- 27488300 TI - Predicting Neurologic Recovery after Surgery in Patients with Deficits Secondary to MESCC: Systematic Review. AB - STUDY DESIGN: Systematic literature review and expert survey OBJECTIVE.: The aim of this study was to determine factors associated with neurologic improvement in patients with neurologic deficits secondary to metastatic epidural spinal cord compression (MESCC). Clear understanding of these factors will guide surgical decision-making by helping to elucidate which patients are more likely to benefit from surgery and how surgeons can increase the probability of neurologic and functional restoration. SUMMARY OF BACKGROUND DATA: Surgical spinal cord decompression has been shown to improve neurologic function in patients with symptomatic MESCC. However, prognostication of neurologic improvement after surgery remains challenging, owing to sparse data and complexity of these patients. METHODS: PubMed and Embase databases were searched for relevant publications. PRISMA Statement guided publication selection and data reporting. GRADE guidelines were used for evidence quality evaluation and recommendation formulation. RESULTS: Low-quality evidence supports the use of the duration and severity of neurologic deficit as predictors of neurological recovery in patients with MESCC. Low-quality evidence supports the use of thoracic level of compression and previous irradiation as adverse predictors of neurological recovery. Nearly all of the AOSpine Knowledge Forum Tumor members who responded to the survey agreed that ambulation with assistance represented a successful surgical result and that duration of ambulation loss and the severity of weakness should be considered when trying to predict whether surgery would result in restoration of ambulation. CONCLUSIONS: Review of literature and expert opinion support the importance of duration of ambulation loss and the severity of neurologic deficit (muscle strength, bladder function) in prediction of neurologic recovery among patients with symptomatic MESCC. Efforts to reduce the duration of ambulation loss and to prevent progression of neurologic deficits should be made to improve the probability of neurologic recovery. LEVEL OF EVIDENCE: 2. PMID- 27488301 TI - Impact of Age on 30-day Complications After Adult Deformity Surgery. AB - STUDY DESIGN: A retrospective analysis. OBJECTIVE: The aim of this study was to identify whether age is a risk factor for postoperative complications after adult deformity surgery (ADS). SUMMARY OF BACKGROUND DATA: Spinal deformity is a prevalent cause of morbidity in the elderly population, occurring in as many as 68% of patients older than 60 years. Given the increasing prevalence of adult spinal deformities and an aging population, understanding the safety of ADS in elderly patients is becoming increasingly important. METHODS: A retrospective cohort analysis was performed on the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database from 2010 to 2014. Patients (>=18 years of age) from the NSQIP database undergoing ADS were separated into age-based cohorts (<=52, 53-61, 62-69, and >=70 years of age). Age groups were determined by interquartile analysis. Chi-squared, t tests, and multivariate logistic regression models were used to identify independent risk factors. RESULTS: A total of 5805 patients met the inclusion criteria. Age groups 1, 2, 3, and 4 contained 1518 (26.1%), 1478 (25.4%), 1451 (25.0%), and 1358 (23.4%) patients, respectively. Multivariate logistic regression analysis revealed increasing age (relative to age group 1) to be an independent risk factor for prolonged length of stay [odds ratio (OR) 1.39, confidence interval (CI) 1.12-1.69], all complications (OR 1.64, CI 1.35-2.00), renal complications (OR 3.45, CI 1.43-8.33), urinary tract infection (OR 2.70, CI 1.49-4.76), postoperative transfusion (OR 1.47, CI 1.20-1.82), and unplanned readmission (OR 1.64, CI 1.18-2.23). Gradations in ORs existed between the different cohorts, such that the deleterious effect of age was less pronounced in cohort 3 compared with cohort 4, and even more less so between cohort 2 and cohort 4. CONCLUSION: Age has been shown to be an independent risk factor for increased length of stay, all complications, renal complications, urinary tract infection, transfusion, and unplanned readmission. LEVEL OF EVIDENCE: 3. PMID- 27488302 TI - Risk factors in multiple sclerosis: a population-based case-control study in Sicily. Background and methods. AB - Incidence of multiple sclerosis (MS) has steeply increased over time during the last 30 years in the city of Catania. We carried out a population-based case control study to evaluate the possible role of both environmental and genetic factors. From 1975 to 2004 in Catania, 367 MS patients diagnosed according to the Poser's criteria had the onset of disease. A sample of MS patients was randomly selected from this incident cohort. Three controls matched by age and sex were randomly selected from the rosters of 14 GPs. Controls were proportionally selected according to the distribution by municipality of the target population using a multistage sampling methods. All cases and controls underwent a face-to face interview to record information concerning environmental factors and a blood sample was taken for serological and genetic analysis. 164 MS patients (64 % women; mean age of 46.4 +/- 10.7) and 481 controls (69 % women; mean age of 47.7 +/- 14.8) were enrolled in the study. The distribution of the whole population and the selected controls by municipalities was similar. A blood sample was taken from 150 MS cases and from 337 controls. At the end of the enrolment, we obtained a representative sample of the MS cases and population controls avoiding possible selection bias. Participation rate was very high also concerning the collection of biological specimens. PMID- 27488303 TI - Asymptomatic central pontine myelinolysis without hyponatriemia in diffuse large B cell lymphoma. PMID- 27488304 TI - Inhibition of P-TEFb disrupts global transcription, oocyte maturation, and embryo development in the mouse. AB - Positive transcription elongation factor b (P-TEFb) is an RNA polymerase II kinase that phosphorylates Ser2 of the carboxyl-terminal domain and promotes the elongation phase of transcription. Despite the fact that P-TEFb has role in many cellular processes, the role of this kinase complex remains to be understood in early developmental events. In this study, using immunocytochemical analyses, we find that the P-TEFb components, Cyclin T1, CDK9, and its T-loop phosphorylated form, are localized to nuclear speckles, as well as in nucleoli in mouse germinal vesicle oocytes. Moreover, using fluorescence in situ hybridization, we show that in absence of CDK9 activity, nucleolar integration, as well as production of 28S rRNA is impaired in oocytes and embryos. We also present evidence indicating that P-TEFb kinase activity is essential for completion of mouse oocyte maturation and embryo development. Treatment with CDK9 inhibitor, flavopiridol resulted in metaphase I arrest in maturing oocytes. Inhibition of CDK9 kinase activity did not interfere with in vitro fertilization and pronuclear formation. However, when zygotes or 2-cell embryos were treated with flavopiridol only in their G2 phase of the cell cycle, development to the blastocyst stage was impaired. Inhibition of the CDK9 activity after embryonic genome activation resulted in failure to form normal blastocysts and aberrant phosphorylation of RNA polymerase II CTD. In all stages analyzed, treatment with flavopiridol abrogated global transcriptional activity. Collectively, our data suggest that P-TEFb kinase activity is crucial for oocyte maturation, embryo development, and regulation of global RNA transcription in mouse early development. PMID- 27488305 TI - Patch testing of food allergens promotes Th17 and Th2 responses with increased IL 33: a pilot study. PMID- 27488306 TI - The Sadomasochism Checklist: A Tool for the Assessment of Sadomasochistic Behavior. AB - Various scientific disciplines devoted to the study of sexual behavior are concerned with the understanding of sadomasochistic (SM) practices. However, only a fragmented body of theories, opinions, and studies is available, which limits the systematic study of this field. Empirical studies and tools for the assessment of SM tendencies are particularly sparse. Our aim was to develop a comprehensive tool for the assessment of an individual's engagement in SM practices. A comprehensive 24-item checklist of different types of SM play was generated with the assistance of members of the German SM community, covering both a dominance scale and a submission scale. The sadomasochism checklist was administered in an online study to a sample of 652 adults (345 female, 307 male), with 527 participants being active members in the SM community. Both the frequency of SM behavior and the attraction to the types of SM practices were assessed. Results revealed a one-factor structure for the dominance as well as the submission scale. The distinction between different types of practices (soft play, domination/submission, beating, toys, breath and bodily fluids) was confirmed using principal component analysis. Cronbach's alpha was appropriate. The total scores for the dominance and the submission scale distinguish between participants with different preferences for dominant and submissive practices. The newly developed scale is a reliable and valid tool for the assessment of the frequency of and attraction to SM behavior. It aims to provide the basis for future systematic studies on sadomasochism. PMID- 27488307 TI - Variation in Sexual Identification Among Behaviorally Bisexual Women in the Midwestern United States: Challenging the Established Methods for Collecting Data on Sexual Identity and Orientation. AB - Collecting information on sexual identity is critical to ensuring the visibility of minority populations who face stigmatization and discrimination related to sexual identities. However, it is challenging to capture the nuances of sexual identity with traditional survey research methods. Using a mixed-methods approach, we gathered data on the sexual identities of 80 behaviorally bisexual women in the Midwestern United States through an online survey. When provided different types of measures (e.g., open ended and fixed response) and different contexts in which to identify (e.g., private and public), participants varied in how they reported their sexual identities. Qualitative analysis of participant narratives around identity change finds partitioning and ranking of attraction is a key component in understanding behaviorally bisexual women's identities. We further identify a division regarding the desired outcomes of identity development processes. Given the multiple ways in which participants identified depending upon the type of measure and the context specified, and the variation in identification over time, results support reconsidering the capability of typical measures and methods used in survey research to capture sexual identity information. Additionally, findings highlight the utility of including multiple, context-specific measures of sexual identities in future research. PMID- 27488308 TI - [Tinea in the genital area : A diagnostic and therapeutic challenge]. AB - Pubogenital tinea or tinea genitalis represents a rare type of dermatophytosis which, however, is increasingly being diagnosed. The mons pubis is affected, but also the outer regions to the penis shaft and the labia together with the groins. Pubogenital tinea is a more superficial erythrosquamous type, but strong inflammatory dermatomycoses of the genital area as tinea genitalis profunda ranging to kerion celsi are observed. A total of 30 patients (14-63 years of age, 11 men and 19 women) with pubogenital tinea are described. Most patients originated from Graz, Austria, while 2 patients were from Germany (Saxony and Isle of Sylt). Causative agents were mainly zoophilic dermatophytes: Microsporum (M.) canis (11), Trichophyton (T.) interdigitale (9), T. anamorph of Arthroderma benhamiae (2), and T. verrucosum (1). Anthropophilic fungi were T. rubrum (6) and T. tonsurans (1). Anamnestic questions should include contact with pets, physical activities, and travel. Genital shaving and concurrent tinea pedis and onychomycosis are disposing factors. Treatment consisted of oral antifungals except in the three women who were pregnant. Preferably, itraconazole or terbinafine was used, while in a single case, fluconazole was administered. Griseofulvin was not used, because this classic systemic antifungal agent is not allowed any more in Austria. In one patient, oral antifungal therapy was changed from itraconazole to terbinafine due to inefficacy. PMID- 27488309 TI - A prospective study investigating the causes of warfarin under-utilization in Chinese patients. AB - Background Warfarin is efficacious for ischemic stroke prevention in intermediate to high-risk patients with atrial fibrillation; thus, warfarin is the recommended treatment according to evidence-based guidelines. Objective This prospective study evaluated the reasons for under-utilization of warfarin in Chinese patients with non-valvular atrial fibrillation (NVAF). Setting The People's Hospital of Henan Province of Zhengzhou City, which is a 3900-bed tertiary-care teaching institution. Methods We extracted data from an existing patient database. Patients at risk for thromboembolism were categorized based on CHA2DS2-VASc [congestive heart failure, hypertension, age >=75 (doubled), diabetes, prior stroke (doubled), vascular disease, age 65-74 years, and sex category (female)] scores. Main outcome measure The percent of warfarin utilization was estimated in recruited patients. Any demographic and clinical factors associated with warfarin under-utilization were identified using a logistic regression model. Results Among the patient sample (n = 612), 569 patients had a CHA2DS2-VASc score of >=1. At presentation, warfarin under utilization was estimated to be 27.1 %. Only 120 patients (25.1 %) considered to be at the highest risk were prescribed warfarin. Binary logistic regression analysis indicated that previous stroke, age >=75 years, and anti-platelet therapy were associated with warfarin under-utilization. Conclusion Patients with CHA2DS2-VASc scores >=1 who were admitted with NVAF were under prescribed warfarin, and 138 patients were not treated with either warfarin or other antithrombotic therapies. In conclusion, a more aggressive approach for stroke prevention in NVAF patients is required. PMID- 27488310 TI - Polycomb complex PRC1 as gatekeeper of intestinal stem cell identity. AB - Intestinal stem cells (ISCs) are adult multipotent cells essential for the maintenance of intestinal epithelial homeostasis. Wnt signaling activity ensures that the pool of ISCs at the basis of the intestinal crypts is preserved. Dysregulation of the Wnt pathway is often observed in cancer and supports malignant progression. Chiacchiera and colleagues recently demonstrated the implication of the polycomb complex PRC1 in the regulation of the Wnt pathway in adult ISCs. The authors show that PRC1 maintains intestinal homeostasis by repressing the expression of ZICs, a family of transcription factors inactivating the beta-catenin/TCF complex. Importantly, interfering with PRC1 activity completely inhibits the formation of Wnt-dependent tumors. These findings reveal a new layer of epigenetic regulation of the Wnt pathway and open novel opportunities for cancer stem cell targeted therapy. PMID- 27488311 TI - Correction of penile ventral curvature in patients with minor or no hypospadias: a single surgeon's experience of 43 cases. AB - PURPOSE: To report our experience of correcting penile ventral curvature associated with minor or no hypospadias. METHODS: We reviewed 43 penile ventral curvature patients treated by a single surgeon from 1997 to 2015. Of these, 23 had minor hypospadias. Curvature was corrected using degloving, chordectomy, dorsal plication (DP), tunica albuginea incision (TAI), or a combination of these. Outcome was confirmed by induced artificial erection and post-operative appearance. RESULTS: Mean age at curvature correction was 3.2 +/- 2.6 years. 17/43 had degloving and chordectomy (DC), 16/43 had DP after DC, and 10/43 had TAI after DC, because of ventral shortening and severe curvature caused by a short hypoplastic urethra. Other procedures required were primary meatoplasty (n = 4) and urethroplasty (UP; n = 1) at the time of curvature correction, and UP after correction of curvature (n = 11). Complications included recurrence of curvature after DP (n = 3/16; 18.8 %) and urethral stenosis after UP with tubed peritoneum (n = 1/10; 10 %). There were no recurrences of curvature in TAI cases. Parents reported penile cosmesis as good (n = 38; 88.4 %), acceptable (n = 4; 9.3 %), or poor (n = 1; 2.3 %). CONCLUSION: We recommend TAI followed by UP for correcting penile ventral curvature with short hypoplastic urethra. Tubed peritoneum is not recommended for UP. PMID- 27488313 TI - Current Treatment Strategies for Heart Failure: Role of Device Therapy and LV Reconstruction. AB - OPINION STATEMENT: Medical care of heart failure (HF) begins with the determination of the cause of the heart failure and diagnosing potential reversible causes (i.e., coronary heart disease, hyperthyroidism, etc.). Medical therapy includes pharmacological and nonpharmacological strategies that limit and/or reverse the signs and symptoms of HF. Initial behavior modification includes dietary sodium and fluid restriction to avoid weight gain; and encouraging physical activity when appropriate. Optimization of medical therapy is the first line of treatment that includes the use of diuretics, vasodilators (i.e., ACE inhibitors or ARBs), beta blockers, and potentially inotropic agents and anticoagulation depending on the patient's severity of heart failure and LV dysfunction. As heart failure advances despite optimized medical management, cardiac resynchronization therapy (CRT), and implantable cardioverter defibrillators (ICDs) are appropriate device therapies. The development of progressive end-stage HF, despite maximal medical therapy, necessitates the consideration of mechanical circulatory devices such as ventricular assist devices (VADs) either as a bridge to heart transplantation or as destination therapy. Despite the advances in the treatment of heart failure, there is still a large morbidity and mortality associated with HF, thus the need to develop newer strategies for the treatment of HF. PMID- 27488312 TI - Generalized recovery algorithm for 3D super-resolution microscopy using rotating point spread functions. AB - Super-resolution microscopy with phase masks is a promising technique for 3D imaging and tracking. Due to the complexity of the resultant point spread functions, generalized recovery algorithms are still missing. We introduce a 3D super-resolution recovery algorithm that works for a variety of phase masks generating 3D point spread functions. A fast deconvolution process generates initial guesses, which are further refined by least squares fitting. Overfitting is suppressed using a machine learning determined threshold. Preliminary results on experimental data show that our algorithm can be used to super-localize 3D adsorption events within a porous polymer film and is useful for evaluating potential phase masks. Finally, we demonstrate that parallel computation on graphics processing units can reduce the processing time required for 3D recovery. Simulations reveal that, through desktop parallelization, the ultimate limit of real-time processing is possible. Our program is the first open source recovery program for generalized 3D recovery using rotating point spread functions. PMID- 27488314 TI - A hepatoid carcinoma of the pancreatic head. AB - Hepatoid carcinoma (HC) is an extremely rare form of neoplasm. Its cellular structure resembles that of a hepatocellular carcinoma (HCC). To date, only 26 cases of hepatoid carcinoma of the pancreas have been reported in the literature. We report the diagnosis of a hepatoid carcinoma of the pancreatic head in a 78 year-old male patient. The tumor was detected incidentally during routine abdominal ultrasound scanning. Laboratory tests did not show any abnormalities except for a monoclonal gammopathy of undetermined significance. After CT, MRI, and laparoscopic biopsy that failed to obtain the diagnosis, the patient underwent a Whipple procedure. The final pathology report described a hepatoid carcinoma of the pancreatic head (pathological T3, N0 (0/10), L0, V0, R0, M0). After the patient recovered, no further therapy was recommended by the tumor board and he was discharged. Regular follow-up was suggested; however, the patient suddenly died of acute coronary artery disease 2 months after surgery. PMID- 27488315 TI - Mass Spectrometry Based Mechanistic Insights into Formation of Tris Conjugates: Implications on Protein Biopharmaceutics. AB - We present here extensive mass spectrometric studies on the formation of a Tris conjugate with a therapeutic monoclonal antibody. The results not only demonstrate the reactive nature of the Tris molecule but also the sequence and reaction conditions that trigger this reactivity. The results corroborate the fact that proteins are, in general, prone to conjugation and/or adduct formation reactions and any modification due to this essentially leads to formation of impurities in a protein sample. Further, the results demonstrate that the conjugation reaction happens via a succinimide intermediate and has sequence specificity. Additionally, the data presented in this study also shows that the Tris formation is produced in-solution and is not an in-source phenomenon. We believe that the facts given here will open further avenues on exploration of Tris as a conjugating agent as well as ensure that the use of Tris or any ionic buffer in the process of producing a biopharmaceutical drug is monitored closely for the presence of such conjugate formation. Graphical Abstract ?. PMID- 27488316 TI - The Development of Novel Nanodiamond Based MALDI Matrices for the Analysis of Small Organic Pharmaceuticals. AB - The utility of novel functionalized nanodiamonds (NDs) as matrices for matrix assisted laser desorption ionization-mass spectrometry (MALDI-MS) is described herein. MALDI-MS analysis of small organic compounds (<1000 Da) is typically complex because of interferences from numerous cluster ions formed when using conventional matrices. To expand the use of MALDI for the analysis of small molecules, novel matrices were designed by covalently linking conventional matrices (or a lysine moiety) to detonated NDs. Four new functionalized NDs were evaluated for their ionization capabilities using five pharmaceuticals with varying molecular structures. Two ND matrices were able to ionize all tested pharmaceuticals in the negative ion mode, producing the deprotonated ions [M - H](-). Ion intensity for target analytes was generally strong with enhanced signal-to-noise ratios compared with conventional matrices. The negative ion mode is of great importance for biological samples as interference from endogenous compounds is inherently minimized in the negative ion mode. Since the molecular structures of the tested pharmaceuticals did not suggest that negative ion mode would be preferable, this result magnifies the importance of these findings. On the other hand, conventional matrices primarily facilitated the ionization as expected in the positive ion mode, producing either the protonated molecules [M + H](+) or cationic adducts (typically producing complex spectra with numerous adduct peaks). The data presented in this study suggests that these matrices may offer advantages for the analysis of low molecular weight pharmaceuticals/metabolites. Graphical Abstract ?. PMID- 27488317 TI - Ion Mobility-Mass Spectrometry as a Tool for the Structural Characterization of Peptides Bearing Intramolecular Disulfide Bond(s). AB - Disulfide bonds are post-translationnal modifications that can be crucial for the stability and the biological activities of natural peptides. Considering the importance of these disulfide bond-containing peptides, the development of new techniques in order to characterize these modifications is of great interest. For this purpose, collision cross cections (CCS) of a large data set of 118 peptides (displaying various sequences) bearing zero, one, two, or three disulfide bond(s) have been measured in this study at different charge states using ion mobility mass spectrometry. From an experimental point of view, CCS differences (DeltaCCS) between peptides bearing various numbers of disulfide bonds and peptides having no disulfide bonds have been calculated. The DeltaCCS calculations have also been applied to peptides bearing two disulfide bonds but different cysteine connectivities (Cys1-Cys2/Cys3-Cys4; Cys1-Cys3/Cys2-Cys4; Cys1-Cys4/Cys2-Cys3). The effect of the replacement of a proton by a potassium adduct on a peptidic structure has also been investigated. Graphical Abstract ?. PMID- 27488318 TI - Hepatitis c eradication: It's now or never...let's get to work. PMID- 27488319 TI - Is endoscopic papillary large balloon dilation safe for treating large CBD stones? AB - In recent years, endoscopic papillary large balloon dilation (EPLBD) with endoscopic sphincterotomy (EST) has been shown to be an effective technique for the removal of large or difficult common bile duct (CBD) stones, as an alternative to EST. Reviewing the literature published since 2003, it is understood that EPLBD has fewer associated overall complications than EST. Bleeding occurred less frequently with EPLBD than with EST. There was no significant difference in postendoscopic retrograde cholangiopancreatography pancreatitis or perforation. Recent accumulated results of EPLBD with or even without EST suggest that it is a safe and effective procedure for the removal of large or difficult bile duct stones without any additional risk of severe adverse events, when performed under appropriate guidelines. Since use of a larger balloon can tear the sphincter as well as the bile duct, possibly resulting in bleeding and perforation, a balloon size that is equal to or smaller in diameter than the diameter of the native distal bile duct is recommended. The maximum transverse diameter of the stone and the balloon-stone diameter ratio have a tendency to affect the success or failure of complete removal of stones by large balloon dilation to prevent adverse effects such as perforation and bleeding. One should take into account the size of the native bile duct, the size and burden of stones, the presence of stricture of distal bile duct, and the presence of the papilla in or adjacent to a diverticulum. Even though the results of EPLBD indicate that it is a relatively safe procedure in patients with common duct stones with a dilated CBD, the recommended guidelines should be followed strictly for the prevention of major adverse events such as bleeding and perforation. PMID- 27488320 TI - Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: A new approach. AB - Gastrointestinal (GI) cancer is the term for a group of cancers affecting the digestive system. After binding to the neurokinin-1 (NK-1) receptor, the undecapeptide substance P (SP) regulates GI cancer cell proliferation and migration for invasion and metastasis, and controls endothelial cell proliferation for angiogenesis. SP also exerts an antiapoptotic effect. Both SP and the NK-1 receptor are located in GI tumor cells, the NK-1 receptor being overexpressed. By contrast, after binding to the NK-1 receptor, NK-1 receptor antagonists elicit the inhibition (epidermal growth factor receptor inhibition) of the proliferation of GI cancer cells in a concentration-dependent manner, induce the death of GI cancer cells by apoptosis, counteract the Warburg effect, inhibit cancer cell migration (counteracting invasion and metastasis), and inhibit angiogenesis (vascular endothelial growth factor inhibition). NK-1 receptor antagonists are safe and well tolerated. Thus, the NK-1 receptor could be considered as a new target in GI cancer and NK-1 receptor antagonists (eg, aprepitant) could be a new promising approach for the treatment of GI cancer. PMID- 27488321 TI - Epidemiology, disease burden, and treatment strategies of chronic hepatitis C virus infections in Saudi Arabia in the new treatment paradigm shift. AB - BACKGROUND/AIMS: Around 101,000 individuals are estimated to be viremic for chronic hepatitis C virus (HCV) in the Kingdom of Saudi Arabia (KSA) in 2014; however, only about 20% have been diagnosed. We aim to assess baseline epidemiology, disease burden, and evaluate strategies to eliminate HCV in KSA. MATERIALS AND METHODS: The infected population and disease progression were modeled using age- and gender-defined cohorts to track HCV incidence, prevalence, hepatic complications, and mortality. Baseline assumptions and transition probabilities were extracted from the literature. The impacts of two scenarios on HCV-related disease burden were considered through increases in treatment efficacy alone or treatment and diagnosis. RESULTS: In 2030, it is estimated by the base scenario that viremic prevalence will increase to 103,000 cases, hepatocellular carcinoma (HCC) to 470, decompensated and compensated cirrhosis cases to 1,300 and 15,400, respectively, and liver-related mortality to 670 deaths. Using high efficacy treatment alone resulted in 2030 projection of 80,700 viremic cases, 350 HCC cases, 480 liver-related deaths, and 850 and 11,500 decompensated and compensated cirrhosis cases, respectively. With an aggressive treatment strategy, in 2030 there will be about 1,700 viremic cases, 1 HCC case, about 20 liver-related deaths, and 5 and 130 cases of decompensated and compensated cirrhosis, respectively. Delaying this strategy by one year would result in 360 additional deaths by 2030. CONCLUSIONS: HCV in KSA remains constant, and cases of advanced liver disease and mortality continue to rise. Considered increases in treatment efficacy and number treated would have a significantly greater impact than increased treatment efficacy alone. The projected impact will facilitate disease forecasting, resource planning, and strategies for HCV management. Increased screening and diagnosis would likely be required as part of a national strategy. PMID- 27488322 TI - A quick screening model for symptomatic bacterascites in cirrhosis. AB - BACKGROUND: Diagnosis of spontaneous bacterial peritonitis in cirrhosis can be made when a patient has an ascites polymorphonuclear leukocyte count >=250/mm3. However, symptomatic bacterascites, which is a variant of spontaneous bacterial peritonitis with signs of infection but an ascites polymorphonuclear leukocyte count <250/mm3, cannot be confirmed until the time-consuming ascites culture becomes positive. Currently, early indicators for symptomatic bacterascites remain undetermined. AIMS: To develop a quick screening model for early detection of symptomatic bacterascites in cirrhosis. MATERIALS AND METHODS: Data on patients with cirrhotic ascites from two hospitals (from 2010 to 2014) were collected retrospectively. Patients with symptomatic bacterascites were enrolled in the case group and compared with patients without any infection in the control group. Logistic regression analysis was used to build a model for screening symptomatic bacterascites, and a receiver operating characteristics curve was used to assess the model. RESULTS: In total, 103 patients were enrolled in the case group and 204 patients were enrolled in the control group. A screening model was constructed based on body temperature, abdominal tenderness, blood neutrophil percentage, blood total bilirubin, prothrombin time, and ascites nucleated leukocyte count. The area under the receiver operating characteristic curve was 0.939; a screening score of 0.328 was the best cutoff value. CONCLUSION: Patients with suspected symptomatic bacterascites can be quickly screened according to the developed model, and a screening score >=0.328 indicates symptomatic bacterascites. PMID- 27488323 TI - Significance of BMI1 and FSCN1 expression in colorectal cancer. AB - BACKGROUND/AIMS: Colorectal cancer (CRC) is the third most common type of cancer in terms of incidence and the fourth in cause of death world-wide, underscoring the need to identify novel biomarkers for early diagnosis, as well as improved disease stratification and treatment choices. PATIENTS AND METHODS: The Gene Expression Omnibus (GSE21510) and the Cancer Genome Atlas (TCGA) CRC datasets were utilized in the current study. GeneSpring 13.0 was used for normalization and analysis. The log-rank test was used to compare the outcome between expression groups. RESULT: Significant upregulation of BMI1 (2.3 FC, P = 3.7 * 10 18) and FSCN1 (1.3 FC,P = 4.7 * 10-3) was observed in CRC. High BMI1 expression was associated with reduced overall survival (OS) [Hazard ratio (HR), 1.87; 95% CI. 1.17-3.03; P= 0.009] and reduced disease-free survival (DFS) [HR, 162; 95% CI 1.01-2.63;P = 0.045]. Similarly, high expression of FSCN1 was associated with reduced OS (HR, 2.0; 95% CI, 1.24-3.2; P= 0.0044) and reduced DFS (HR, 1.60; 95% CI, 0.99-2.57;P = 0.055). Importantly, BMI1high/FSCN1high patients experienced the worst OS (HR, 3.17; 95% CI, 1.77-6.15; P= 0.0002) and DFS (HR, 2.34; 95% CI, 1.27-4.67,P = 0.0078). Using pathway analyses, tumors overexpressing BMI1 were enriched in zinc finger proteins and genes involved in DNA binding and regulation of transcription, whereas tumors expressing FSCN1 were enriched in genes involved in cell migration. CONCLUSION: Our data revealed poor OS and DFS in CRC patients overexpressing BMI1 or FSCN1 and suggest that these two markers in combination may represent superior prognostic marker to either one. Targeting BMI1 and FSCN1 may also provide potential therapeutic opportunity in CRC. PMID- 27488325 TI - Catheter-related blood stream infection in patients receiving long-term home parenteral nutrition: Tertiary care hospital experience in Saudi Arabia. AB - BACKGROUND/AIM: Parenteral nutrition (PN) is a lifesaving therapy for patients with many severe conditions, including intestinal failure. Some patients require long-term PN therapy, which makes home parenteral nutrition (HPN) an attractive option to improve the quality of life. Among the most common and serious complications observed in these patients are catheter-related blood stream infections (CRBSIs). The aim of our study is to determine the frequency of CRBSI among patients receiving long-term HPN. PATIENTS AND METHODS: A retrospective chart review was conducted for patients enrolled in the HPN program between 2006 and 2012. Data on the demographic characteristics, indications and duration of PN therapy, catheter type, number of admissions because of CRBSI, and blood culture results were recorded. RESULTS: Eight pediatric patients were included (mean age of 3.5 years at the start of HPN). Microvillus inclusive disease was noted in 50% of these patients, and 75% of them received HPN under parents' care. CRBSI resulted in 60 admissions with a median of 182 days of hospital stay and 74 changes of central venous catheters. The rate of CRBSI was 2.9 per 1000 catheter days. Staphylococcus species were the most prevalent pathogens (32%), followed by Klebsiella pneumoniae (5%). CONCLUSION: In this small group of HPN patients, the BSI rate was 2.9 infections per 1000 catheter days, and most common causative organisms were Staphylococcus species. We believe that a well-established training program for caregivers can reduce the rate of infectious complications associated with long-term PN support. PMID- 27488324 TI - Transient elastography in clinical detection of liver cirrhosis: A systematic review and meta-analysis. AB - BACKGROUND/AIMS: Transient elastography is a noninvasive method for measuring liver fibrosis. This meta-analysis assesses the diagnostic performance of transient elastography of detecting liver cirrhosis in patients with liver disease. PATIENTS AND METHODS: We searched MEDLINE, Cochrane, EMBASE databases until Jan 31, 2015, using the following search terms: elastography and liver cirrhosis. Included studies assessed patients with a diagnosis of liver cirrhosis, with an index test of transient elastography, and with the reference standard being a histopathological exam by liver biopsy. Sensitivity analysis and assessment of risk of bias and publication bias were performed. RESULTS: Fifty seven studies were included in the meta-analysis with a total of 10,504 patients. The pooled estimate for the sensitivity of transient elastography for detecting liver fibrosis was 81% and the specificity was 88%. The imputed diagnostic odds ratio (DOR) was 26.08 and the area under the receiver-operating characteristic (AUROC) curve was 0.931. CONCLUSION: Our findings indicate that transient elastography shows good sensitivity, specificity and a high accuracy for detecting liver cirrhosis. Transient elastography can be used as an additional method for the clinical diagnosis of liver fibrosis and cirrhosis. PMID- 27488326 TI - Sequential versus concomitant therapy for eradication of Helicobacter Pylori in patients with perforated duodenal ulcer: A randomized trial. AB - OBJECTIVES: Comparison of Helicobacter pylori eradication rates, side effects, compliance, cost, and ulcer recurrence of sequential therapy (ST) with that of concomitant therapy (CT) in patients with perforated duodenal ulcer following simple omental patch closure. METHODS: Sixty-eight patients with perforated duodenal ulcer treated with simple closure and found to be H. pylori positive on three months follow-up were randomized to receive either ST or CT for H. pylori eradication. Urease test and Giemsa stain were used to assess for H. pylori eradication status. Follow-up endoscopies were done after 3 months, 6 months, and 1 year to evaluate the ulcer recurrence. RESULTS: H. pylori eradication rates were similar in ST and CT groups on intention-to-treat (ITT) analysis (71.43% vs 81.80%,P = 0.40). Similar eradication rates were also found in per-protocol (PP) analysis (86.20% vs 90%,P = 0.71). Ulcer recurrence rate in ST groups and CT groups at 3 months (17.14% vs 6.06%,P = 0.26), 6 months (22.86% vs 9.09%,P = 0.19), and at 1 year (25.71% vs 15.15%,P = 0.37) of follow-up was also similar by ITT analysis. Compliance and side effects to therapies were comparable between the groups. The most common side effects were diarrhoea and metallic taste in ST and CT groups, respectively. A complete course of ST costs Indian Rupees (INR) 570.00, whereas CT costs INR 1080.00. CONCLUSION: H. pylori eradication rates, side effects, compliance, cost, and ulcer recurrences were similar between the two groups. The ST was more economical compared with CT. PMID- 27488327 TI - A randomized controlled trial on the effect of vitamin D3 on inflammation and cathelicidin gene expression in ulcerative colitis patients. AB - BACKGROUND: Inflammatory bowel disease (IBD) is an intestinal chronic inflammatory condition and includes Crohn's disease (CD) and ulcerative colitis (UC). It has been proposed that Vitamin D supplementation may have a beneficial role in IBD. AIM: To characterize the effects of Vitamin D on cathelicidin (hCAP/LL37) gene expression, ESR, and serum hs-CRP levels. MATERIALS AND METHODS: Ninety UC patients on remission were randomized to receive 300,000 IU intramuscular Vitamin D or 1 mL normal saline as placebo, respectively. Before and 90 days after intervention, serum levels of 25 (OH)-Vitamin D3, PTH, Calcium, ESR, and hs-CRP were measured. Cathelicidin gene expression was also quantified using qRT-PCR. RESULTS: Baseline serum 25-OH-Vitamin D3 levels were not different between the two groups and after intervention, increased only in Vitamin D group (P < 0.001). Hs-CRP levels were lower in Vitamin D group after intervention (Before: 3.43 +/- 3.47 vs 3.86 +/- 3.55 mg/L, P = 0.56; after: 2.31 +/- 2.25 vs 3.90 +/- 3.97 mg/L, P= 0.023). ESR decreased significantly in Vitamin D group (Before: 12.4 +/- 6.1 vs 12.1 +/- 5.3 mm/h, P= 0.77; after: 6.7 +/- 4.5 vs 11.4 +/- 5.5 mm/h, P< 0.001). The mean fold change in hCAP18 gene expression in Vitamin D group was significantly higher than placebo group. (Mean +/- SD: 3.13 +/- 2.56 vs 1.09 +/- 0.56; median +/- interquartile range: 2.17 +/- 3.81 vs 0.87 +/- 0.53, P< 0.001). CONCLUSION: Decreases in ESR and hs-CRP levels and increase in LL37 gene expression support the hypothesis that Vitamin D supplementation may have a beneficial role in UC patients. PMID- 27488329 TI - The LMS and Z scale growth reference for Saudi school-age children and adolescents. AB - BACKGROUND/AIM: To establish L, M, and S parameters and z score reference for the assessment of nutrition and growth of Saudi school-age children and adolescents. SUBJECTS AND METHODS: Data from the original cross-sectional study were reanalyzed. The L, M, and S parameters and z scores were calculated for weight, height and body mass index for school-age children and adolescents. RESULTS: A total of 19,299 subjects from 5 to 18 years of age were included. All were Saudi nationals and 9,827 (50.9%) were boys. The L M S parameters and z scores for weight for age, height for age, and BMI for age for boys and girls are presented in detailed tables across the age of commonly used z scores (+3, +2, +1, 0, -1, 2, -3). Graphs corresponding to the same parameters (weight, height, and BMI) showing the main z scores across all ages from 5 to 18 years are illustrated. CONCLUSION: This report provides the first reference for nutritional status and growth of Saudi school-age children and adolescents. This tool is essential for more accurate assessment of growth and nutrition in various clinical conditions and research. PMID- 27488328 TI - New combined parameter of liver and splenic stiffness as determined by elastography in healthy volunteers. AB - BACKGROUND: The diagnosis of chronic liver disease (CLD) leading to fibrosis, cirrhosis, and portal hypertension had witnessed dramatic changes after the introduction of noninvasive figure accessible tools over the past few years. Imaging techniques that are based on evaluation of the liver stiffness was particularly useful in this respect. Acoustic radiation force impulse (ARFI) emerged as an interesting figure tool with reliable repute and high precision. AIMS: To evaluate liver stiffness measurement (LSM) and splenic stiffness measurement (SSM) in healthy volunteers as concluded by the ARFI technique and to out a numeric calculated ratio that may reflect their correlation in the otherwise healthy liver. PATIENTS AND METHODS: A ratio (splenic stiffness/liver stiffness in kPa) was determined in 207 consenting healthy subjects and was investigated with respect to age, gender, ethnic origin, body mass index (BMI), liver and spleen sizes healthy volunteers, alanine aminotransferase (ALT), aspartate aminotransferase (AST), platelet count (PLT), APRI, and FIB-4 scores. RESULTS: Data from this work led to computing an index of 4.72 (3.42-7.33) in healthy persons on an average. Females had a higher index than males 6.37 vs 4.92, P=0.002. There was not any significant difference of the ratio in different age groups; ethnic origins; any correlation between SSM/LSM ratio and BMI; liver and spleen sizes; or ALT, AST, PLT, APRI, and FIB-4 scores. CONCLUSIONS: A quantifiable numeric relationship between splenic and liver stiffness in the healthy subjects could be computed to a parameter expressed as SSM/LSM ratio. We believe that this ratio can be a useful reference tool for further researches in CLD. PMID- 27488330 TI - Endoscopic ultrasound-guided antegrade stenting in an occluded biliary self expandable metal stent. AB - Endoscopic ultrasound-guided biliary drainage (EUS-BD) is an attractive option for patients who cannot undergo conventional endoscopic retrograde cholangiopancreatography (ERCP) and do not want surgery or percutaneous drainage procedures. We present the use of EUS-antegrade (EUS-AG) insertion of a self expandable metal stent (SEMS) in a patient with a common hepatic duct cholangiocarcinoma, as well as a huge gastric lipoma, after recurrent biliary obstruction of a prior SEMS inserted via ERCP in the same session as a duodenal stent insertion for gastric outlet obstruction. PMID- 27488331 TI - Impact of pediatric inflammatory bowel disease on linear growth: Data from a national cohort study in Saudi Arabia. PMID- 27488332 TI - From legacy to novel: vidian neurectomy and eustachian tube balloon dilatation in modern ENT practice. PMID- 27488333 TI - Balloon dilation for eustachian tube dysfunction: systematic review. AB - BACKGROUND: Eustachian tube dysfunction is a disorder for which there are limited medical and surgical treatments. Recently, eustachian tube balloon dilation has been proposed as a potential solution. METHOD: A systematic literature review was performed. Abstracts were selected for relevance, and pooled data analysis and qualitative analysis was conducted. RESULTS: Nine prospective studies, describing 713 eustachian tube balloon dilations in 474 patients (aged 18-86 years), were identified. Follow-up duration ranged from 1.5 to 18 months. Ability to perform a Valsalva manoeuvre improved from 20 to 177 out of 245 ears following eustachian tube balloon dilation and, where data were reported in terms of patient numbers, from 15 to 189 out of 210 patients. Tympanograms were classified as type A in 7 out of 141 ears pre-operatively and in 86 out of 141 ears post-operatively. CONCLUSION: Prospective case series can confirm the safety of eustachian tube balloon dilation. As a potential solution for chronic eustachian tube dysfunction, further investigations are warranted to establish a higher level of evidence of efficacy. PMID- 27488334 TI - Open and endovascular repair of aneurysms affecting the distal extracranial internal carotid artery: case series. AB - OBJECTIVE: Three cases of internal carotid artery aneurysm affecting the distal cervical segment were retrospectively reviewed. METHODS: Two patients underwent open surgical repair requiring petrous segment exposure for bypass of the affected segment using a Fisch type A lateral skull base approach. The third patient underwent endovascular stenting. RESULTS: There were no cerebrovascular complications post-operatively. Both open repair patients experienced temporary lower cranial nerve palsies. One required facial nerve grafting. All patients had patent grafts at follow up. The stent graft patient had a small endoleak at six months. CONCLUSION: Endovascular and open approaches both have advantages and disadvantages. Treatment needs to be tailored to the lesion and the patient. An open surgical approach is difficult but well established. Endovascular treatment of these lesions is a relatively recent technique, and new cases need to be continually reported with a view to attaining long-term data. PMID- 27488335 TI - The role of subtotal petrosectomy in cochlear implantation. AB - BACKGROUND: Subtotal petrosectomy combined with cochlear implantation is a procedure required in specific situations. METHODS: A retrospective review of all cases of subtotal petrosectomy in cochlear implant surgery over a five-year period was performed. The indications, complications and outcomes for this procedure are outlined. RESULTS: Sixteen patients underwent cochlear implantation in combination with subtotal petrosectomy and blind sac closure of the external auditory meatus from 2008 to 2013. Seventy-five per cent of these were completed as a two-stage procedure and 25 per cent as a single-stage procedure. The most common indications for the procedure were chronic otitis media, previous radical cavity, and for surgical access in challenging anatomy or in drill-out procedures. Mastoids were obliterated with fat or musculoperiosteal flaps. The complication rate relating to blind sac closure was 6 per cent. Cochlear implants were successfully placed in all cases and there was no incidence of device failure. CONCLUSION: For patients with chronic suppurative otitis media or existing mastoid cavities, subtotal petrosectomy with blind sac closure of the external auditory canal, closure of the eustachian tube, and cavity obliteration is an effective technique to facilitate safe cochlear implantation. PMID- 27488336 TI - Wide anterior neck dissection for management of recurrent thyroglossal duct cysts in adults. AB - OBJECTIVE: Thyroglossal duct cyst recurrence following resection is attributed to anatomical variability and residual thyroglossal ducts. In adults, thyroglossal duct cyst recurrence is extremely rare and a surgical solution is yet to be well explored. This paper describes our approach to the management of recurrent thyroglossal duct cysts and sinuses in adults using a wide anterior neck dissection. METHOD: A retrospective review was performed to identify adults who underwent a wide anterior neck dissection for recurrent thyroglossal duct cyst management between 1 January 2009 and 1 January 2015. RESULTS: Six males and one female were included in the series (mean age, 26.4 +/- 10.9 years). Recurrence occurred at a mean of 18 +/- 9.8 months following primary surgical management (3 patients underwent cystectomy and 4 had a Sistrunk procedure). All patients subsequently underwent wide anterior neck dissection; there was no further recurrence over the 12-month average follow-up period. CONCLUSION: This paper describes a wide anterior neck dissection technique for the management of recurrent thyroglossal duct cysts or sinuses in adults; this approach addresses the variable anatomy of the thyroglossal duct and is associated with minimal morbidity. PMID- 27488337 TI - Synchronous or metachronous lymphoma and metastatic cutaneous squamous cell carcinoma in the head and neck region: a diagnostic and management dilemma. AB - OBJECTIVE: To review our experience of managing patients with a dual diagnosis of metastatic cutaneous squamous cell carcinoma in the head and neck region and low grade non-Hodgkin lymphoma. The secondary aim was to evaluate the utility of 18F fluorodeoxyglucose positron emission tomography during diagnosis. METHODS: Patients diagnosed with metastatic cutaneous squamous cell carcinoma of the head and neck and low-grade non-Hodgkin lymphoma, in a five-year period, were identified. Patient, tumour and treatment characteristics were identified. 18F fluorodeoxyglucose positron emission tomography imaging was reviewed and correlated with histopathology findings. RESULTS: Eight patients were identified. There was a delay in diagnosis of metastatic squamous cell carcinoma in two patients. 18F-fluorodeoxyglucose positron emission tomography differentiated metastatic squamous cell carcinoma from low-grade non-Hodgkin lymphoma with a sensitivity of 88.2 per cent and a specificity of 94.7 per cent. In 38 per cent of patients, compromises in management had to be made. CONCLUSION: The management of metastatic squamous cell carcinoma can be challenging in patients with low grade non-Hodgkin lymphoma. 18F-fluorodeoxyglucose positron emission tomography can be useful in the diagnosis of metastatic squamous cell carcinoma in patients with low-grade non-Hodgkin lymphoma. PMID- 27488338 TI - Elevated serum thyroglobulin levels at the time of ablative radioactive iodine therapy indicate a worse prognosis in thyroid cancer: an Australian retrospective cohort study. AB - BACKGROUND: Serum thyroglobulin is used as a surrogate marker for well differentiated thyroid carcinoma recurrence. This study investigates whether thyroglobulin measured at the time of ablative radioactive iodine therapy predicts disease-free survival. METHODS: A retrospective review was conducted of patients with well-differentiated thyroid carcinoma presenting from 1989 to 2010 at the Royal Prince Alfred Hospital, New South Wales, Australia. Disease-free survival of patients with a significantly elevated stimulated thyroglobulin level (27.5 ug/l or higher) at the time of ablative radioactive iodine therapy was compared to that of patients without a significantly elevated thyroglobulin level using univariate analysis. RESULTS: Patients with a thyroglobulin level of 27.5 ug/l or higher had an increased relative risk of disease recurrence of 4.50 (95 per cent confidence interval = 1.35-15.04). If lateral neck dissection was required at the time of surgery, patients also had an increased relative risk of macroscopic disease recurrence of 4.94 (95 per cent confidence interval = 1.47 16.55). CONCLUSION: An elevated thyroglobulin level of 27.5 ug/l or higher at the time of ablative radioactive iodine therapy is a prognostic indicator for macroscopic disease recurrence in well-differentiated thyroid carcinoma. PMID- 27488339 TI - Role of neck dissection in metastatic squamous cell carcinoma to the parotid gland. AB - OBJECTIVE: To investigate the rate of occult neck disease in patients with metastatic squamous cell carcinoma to the parotid gland following parotidectomy and neck dissection. METHODS: A consecutive series of patients treated between 2000 and 2014 for metastatic squamous cell carcinoma to the parotid were analysed. Patients were included if they had no clinical or radiological evidence of neck disease. Pathology of parotidectomy and neck dissection specimens was reviewed. Other variables analysed included patient immune status, surgery type, complications, use of positron emission tomography scanning and treatment with radiotherapy. RESULTS: Sixty-five patients had no clinical or radiological evidence of neck disease initially. Forty-six patients (70.8 per cent) underwent neck dissection. Occult neck disease was only found in 8 of the 46 patients (17.3 per cent). Occult neck disease was found more often in those with immunocompromise (5.7 vs 38.5 per cent, p = 0.003). Patients who were immunocompromised had a significantly worse disease-specific survival rate at five years (0 vs 92 per cent, p = 0.0001). CONCLUSION: Occult neck disease was seen in 17.3 per cent of patients and immunosuppression was a significant predictor for this. PMID- 27488340 TI - Melioidosis in a patient with chronic rhinosinusitis. AB - BACKGROUND: Melioidosis is a serious infection caused by soil-dwelling Gram negative bacillus Burkholderia pseudomallei. It is most commonly reported in Northern Australia, Southeast and Southern Asia, China, and Taiwan. METHODS: A case report and short review of the literature are presented. Presentation, diagnosis including genomic sequencing, and acute and long-term management are discussed. RESULTS: A 58-year-old female presented with chronic rhinosinusitis secondary to melioidosis. This is the third reported incidence of sinusitis secondary to melioidosis, which occurred in an otherwise well female with no risk factors and no apparent cause of exposure. Treatment involved an acute phase in which meropenem was administered parenterally for two weeks, followed by a prolonged oral course of trimethoprim-sulfamethoxazole for three months, as per recommended guidelines. CONCLUSION: In patients presenting with refractory chronic rhinosinusitis, ENT surgeons should consider the presence of unusual causative pathogens such as B pseudomallei, particularly in those with recent travel history to Northern Queensland and/or Southeast Asia. PMID- 27488341 TI - A systematic review of the evidence base for vidian neurectomy in managing rhinitis. AB - BACKGROUND: Vidian neurectomy has been proposed as a surgical option for rhinitis refractory to medical treatment. However, the evidence base for its benefit remains controversial. METHODS: A systematic review was performed. Studies reporting original data on patients with rhinitis treated by vidian neurectomy were included. Patient-reported outcome measures were the primary outcome investigated; specific peri-operative morbidities were the secondary outcome. RESULTS: A total of 1012 articles fulfilled the search criteria, 32 of which were included in the study. Patient-reported outcome measures were compared before and after surgery in eight studies. There were 529 patients represented in these trials. Significant improvement in rhinorrhoea was reported in all eight studies. Temporary dry eyes was reported in 24.63 per cent of cases (272 out of 1104 cases). There was no report of cranial nerve deficit or eye movement disturbance. CONCLUSION: Endoscopic vidian neurectomy does have a role in the surgical management of refractory rhinitis, particularly in patients with non-allergic rhinitis, but a well-designed cohort trial would be advantageous to clarify long term outcomes. PMID- 27488342 TI - Fluidized Bed Hot Melt Granulation with Hydrophilic Materials Improves Enalapril Maleate Stability. AB - This work aimed at developing enalapril maleate granules in order to improve its stability in solid dosage form. Granules were prepared by hot melt granulation using a fluidized bed apparatus. Gelucire 50/13(r), polyethylene glycol 6000 e Poloxamer 407(r) were studied and compared as binders in 2 * 2 factorial designs where the proportions of enalapril maleate, binders and spray dried lactose were varied. The granulation process resulted in high yields and granule sizes that indicated the prevalence of particles coating. Furthermore, the granules obtained showed adequate flowability and a fast dissolution rate of enalapril maleate with almost 100% of the drug released in 10 min. The stability of enalapril maleate in hard gelatin capsules showed that the drug stability was greatly increased in granules, since for raw drug, the remaining content of enalapril maleate after 91 days was 68.4% and, for granules, the content was always above 93%. This result was confirmed by the quantification of the degradation products, enalaprilat and diketopiperazine, which were found in very low content in granules samples. The results demonstrate that fluidized bed hot melt granulation with hydrophilic binders is a suitable alternative for improving the chemical stability of enalapril maleate. PMID- 27488343 TI - Integrated paediatric fever management and antibiotic over-treatment in Malawi health facilities: data mining a national facility census. AB - BACKGROUND: There are growing concerns about irrational antibiotic prescription practices in the era of test-based malaria case management. This study assessed integrated paediatric fever management using malaria rapid diagnostic tests (RDT) and Integrated Management of Childhood Illness (IMCI) guidelines, including the relationship between RDT-negative results and antibiotic over-treatment in Malawi health facilities in 2013-2014. METHODS: A Malawi national facility census included 1981 observed sick children aged 2-59 months with fever complaints. Weighted frequencies were tabulated for other complaints, assessments and prescriptions for RDT-confirmed malaria, IMCI-classified non-severe pneumonia, and clinical diarrhoea. Classification trees using model-based recursive partitioning estimated the association between RDT results and antibiotic over treatment and learned the influence of 38 other input variables at patient-, provider- and facility-levels. RESULTS: Among 1981 clients, 72 % were tested or referred for malaria diagnosis and 85 % with RDT-confirmed malaria were prescribed first-line anti-malarials. Twenty-eight percent with IMCI-pneumonia were not prescribed antibiotics (under-treatment) and 59 % 'without antibiotic need' were prescribed antibiotics (over-treatment). Few clients had respiratory rates counted to identify antibiotic need for IMCI-pneumonia (18 %). RDT-negative children had 16.8 (95 % CI 8.6-32.7) times higher antibiotic over-treatment odds compared to RDT-positive cases conditioned by cough or difficult breathing complaints. CONCLUSIONS: Integrated paediatric fever management was sub-optimal for completed assessments and antibiotic targeting despite common compliance to malaria treatment guidelines. RDT-negative results were strongly associated with antibiotic over-treatment conditioned by cough or difficult breathing complaints. A shift from malaria-focused 'test and treat' strategies toward 'IMCI with testing' is needed to improve quality fever care and rational use of both anti malarials and antibiotics in line with recent global commitments to combat resistance. PMID- 27488344 TI - Global transcriptional start site mapping in Geobacter sulfurreducens during growth with two different electron acceptors. AB - Geobacter sulfurreducens is an anaerobic soil bacterium that is involved in biogeochemical cycles of elements such as Fe and Mn. Although significant progress has been made in the understanding of the electron transfer processes in G. sulfurreducens, little is known about the regulatory mechanisms involved in their control. To expand the study of gene regulation in G. sulfurreducens, we carried out a genome-wide identification of transcription start sites (TSS) by 5'RACE and by deep RNA sequencing of primary mRNAs in two growth conditions. TSSs were identified along G. sulfurreducens genome and over 50% of them were located in the upstream region of the associated gene, and in some cases we detected genes with more than one TSS. Our global mapping of TSSs contributes with valuable information, which is needed for the study of transcript structure and transcription regulation signals and can ultimately contribute to the understanding of transcription initiation phenomena in G. sulfurreducens. PMID- 27488345 TI - Alpha-7 Nicotinic Receptors in Nervous System Disorders: From Function to Therapeutic Perspectives. AB - BACKGROUND: The alpha7 nicotinic receptor consists of identical subunits and is one of the most abundant acetylcholine receptors in the mammalian central nervous system. However its expression is also found in the peripheral nervous system as well as in the immune system and various peripheral tissues. Nicotinic Receptors: They are involved in the regulation of several activities ranging from excitatory neurotransmission, the modulation of the release of several neurotransmitters, regulation of neurite outgrowth, and even neuronal survival/death. Its expression is found in brain areas that underlie learning and memory, suggesting their involvement in regulating cognitive functions. The alpha7-nicotinic receptor has a strategic role during development in regulating molecular pathways activated during neurogenesis. Because of its pleiotropic effects, receptor dysfunction or dysregulated expression is found in pathophysiological conditions of the nervous system including neurodegenerative diseases and neurodevelopmental disorders. CONCLUSION: Here we review the physiological and pathological roles of alpha-7 nicotinic receptor in different nervous system disorders and the current therapeutic strategies developed to target selectively this receptor for potentiating or reducing its functions. PMID- 27488346 TI - A case of acute onset postoperative gas gangrene caused by Clostridium perfringens. AB - BACKGROUND: Gas gangrene is a necrotic infection of soft tissue associated with high mortality rates. We report a case of postoperative gas gangrene with very acute onset and rapid progression of symptoms. To our knowledge, this case is the most acute onset of postoperative gas gangrene ever reported. CASE PRESENTATION: A 65-year-old Japanese female patient developed a shock state 16 h after radical cystectomy with ileal conduit reconstruction. Two days after the operation, she was transferred to the intensive care unit because of deterioration in her respiratory and circulatory condition. Soon after moving her to the ICU, a subcutaneous hemorrhage-like skin rash appeared and extended rapidly over her left side. Blood tests performed on admission to the ICU indicated severe metabolic acidosis, liver and renal dysfunction, and signs of disseminated intravascular coagulation. Suspecting necrotizing fasciitis or gas gangrene, we performed emergency fasciotomy. Subsequently, multidisciplinary treatment, including empirical therapy using multiple antibiotics, mechanical ventilation, hyperbaric oxygen therapy, polymyxin B-immobilized fiber column direct hemoperfusion, and continuous hemodiafiltration, was commenced. Culture of the debris from a wound abscess removed by emergency fasciotomy detected the presence of Clostridium perfringens. We hypothesized that the source of infection in this case may have been the ileum used for bladder reconstruction. Although the initial treatment prevented further clinical deterioration, she developed secondary infection from the 3rd week onward, due to infection with multiple pathogenic bacteria. Despite prompt diagnosis and intensive therapy, the patient died 38 days after the operation. CONCLUSION: Although the patient did not have any specific risk factors for postsurgical infection, she developed a shock state only 16 h after surgery due to gas gangrene. Our experience highlights the fact that physicians should be aware that any patient could possibly develop gas gangrene postoperatively. PMID- 27488347 TI - A Neuroscience-Based Nomenclature (NbN) for Psychotropic Agents. PMID- 27488348 TI - Virtual Breast Quasi-static Elastography (VBQE). AB - Viscoelasticity Imaging (VEI) has been proposed to measure relaxation time constants for characterization of in vivo breast lesions. In this technique, an external compression force on the tissue being imaged is maintained for a fixed period of time to induce strain creep. A sequence of ultrasound echo signals is then utilized to generate time-resolved strain measurements. Relaxation time constants can be obtained by fitting local time-resolved strain measurements to a viscoelastic tissue model (e.g., a modified Kevin-Voigt model). In this study, our primary objective is to quantitatively evaluate the contrast transfer efficiency (CTE) of VEI, which contains useful information regarding image interpretations. Using an open-source simulator for virtual breast quasi-static elastography (VBQE), we conducted a case study of contrast transfer efficiency of VEI. In multiple three-dimensional (3D) numerical breast phantoms containing various degrees of heterogeneity, finite element (FE) simulations in conjunction with quasi-linear viscoelastic constitutive tissue models were performed to mimic data acquisition of VEI under freehand scanning. Our results suggested that there were losses in CTE, and the losses could be as high as -18 dB. FE results also qualitatively corroborated clinical observations, for example, artifacts around tissue interfaces. PMID- 27488349 TI - A recurring mutation in the respiratory complex 1 protein NDUFB11 is responsible for a novel form of X-linked sideroblastic anemia. AB - The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited blood disorders characterized by pathological mitochondrial iron deposition in erythroid precursors. Each known cause has been attributed to a mutation in a protein associated with heme biosynthesis, iron-sulfur cluster biogenesis, mitochondrial translation, or a component of the mitochondrial respiratory chain. Here, we describe a recurring mutation, c.276_278del, p.F93del, in NDUFB11, a mitochondrial respiratory complex I-associated protein encoded on the X chromosome, in 5 males with a variably syndromic, normocytic CSA. The p.F93del mutation results in respiratory insufficiency and loss of complex I stability and activity in patient-derived fibroblasts. Targeted introduction of this allele into K562 erythroleukemia cells results in a proliferation defect with minimal effect on erythroid differentiation potential, suggesting the mechanism of anemia in this disorder. PMID- 27488350 TI - Blockade of interleukin-27 signaling reduces GVHD in mice by augmenting Treg reconstitution and stabilizing Foxp3 expression. AB - Reestablishment of competent regulatory pathways has emerged as a strategy to reduce the severity of graft-versus-host disease (GVHD), and recalibrate the effector and regulatory arms of the immune system. However, clinically feasible, cost-effective strategies that do not require extensive ex vivo cellular manipulation have remained elusive. In the current study, we demonstrate that inhibition of the interleukin-27p28 (IL-27p28) signaling pathway through antibody blockade or genetic ablation prevented lethal GVHD in multiple murine transplant models. Moreover, protection from GVHD was attributable to augmented global reconstitution of CD4+ natural regulatory T cells (nTregs), CD4+ induced Tregs (iTregs), and CD8+ iTregs, and was more potent than temporally concordant blockade of IL-6 signaling. Inhibition of IL-27p28 also enhanced the suppressive capacity of adoptively transferred CD4+ nTregs by increasing the stability of Foxp3 expression. Notably, blockade of IL-27p28 signaling reduced T-cell-derived IL-10 production in conventional T cells; however, there was no corresponding effect in CD4+ or CD8+ Tregs, indicating that IL-27 inhibition had differential effects on IL-10 production and preserved a mechanistic pathway by which Tregs are known to suppress GVHD. Targeting of IL-27 therefore represents a novel strategy for the in vivo expansion of Tregs and subsequent prevention of GVHD without the requirement for ex vivo cellular manipulation, and provides additional support for the critical proinflammatory role that members of the IL-6 and IL-12 cytokine families play in GVHD biology. PMID- 27488352 TI - Carbon-Coated Co(3+)-Rich Cobalt Selenide Derived from ZIF-67 for Efficient Electrochemical Water Oxidation. AB - Oxygen evolution reaction (OER) electrocatalysts are confronted with challenges such as sluggish kinetics, low conductivity, and instability, restricting the development of water splitting. In this study, we report an efficient Co(3+)-rich cobalt selenide (Co0.85Se) nanoparticles coated with carbon shell as OER electrocatalyst, which are derived from zeolitic imidazolate framework (ZIF-67) precursor. It is proposed that the organic ligands in the ZIF-67 can effectively enrich and stabilize the Co(3+) ions in the inorganic-organic frameworks and subsequent carbon-coated nanoparticles. In alkaline media, the catalyst exhibits excellent OER performances, which are attributed to its abundant active sites, high conductivity, and superior kinetics. PMID- 27488351 TI - Sex-dependent adaptive changes in serotonin-1A autoreceptor function and anxiety in Deaf1-deficient mice. AB - The C (-1019) G rs6295 promoter polymorphism of the serotonin-1A (5-HT1A) receptor gene is associated with major depression in several but not all studies, suggesting that compensatory mechanisms mediate resilience. The rs6295 risk allele prevents binding of the repressor Deaf1 increasing 5-HT1A receptor gene transcription, and the Deaf1-/- mouse model shows an increase in 5-HT1A autoreceptor expression. In this study, Deaf1-/- mice bred on a mixed C57BL6 BALB/c background were compared to wild-type littermates for 5-HT1A autoreceptor function and behavior in males and females. Despite a sustained increase in 5 HT1A autoreceptor binding levels, the amplitude of the 5-HT1A autoreceptor mediated current in 5-HT neurons was unaltered in Deaf1-/- mice, suggesting compensatory changes in receptor function. Consistent with increased 5-HT1A autoreceptor function in vivo, hypothermia induced by the 5-HT1A agonist DPAT was augmented in early generation male but not female Deaf1-/- mice, but was reduced with succeeding generations. Loss of Deaf1 resulted in a mild anxiety phenotype that was sex-and test-dependent, with no change in depression-like behavior. Male Deaf1 knockout mice displayed anxiety-like behavior in the open field and light dark tests, while female Deaf1-/- mice showed increased anxiety only in the elevated plus maze. These data show that altered 5-HT1A autoreceptor regulation in male Deaf1-/- mice can be compensated for by generational adaptation of receptor response that may help to normalize behavior. The sex dependence of Deaf1 function in mice is consistent with a greater role for 5-HT1A autoreceptors in sensitivity to depression in men. PMID- 27488353 TI - Moderator's view: Salt, cardiovascular risk, observational research and recommendations for clinical practice. AB - In observational studies, blood pressure (BP), cholesterol and nutritional status biomarkers, including sodium intake, coherently show a J- or U-shaped relationship with health outcomes. Yet these data may reflect a stable sodium intake or a reduced intake due to comorbidities or intercurrent disease, or an intentional decrease in salt intake. Adjusting for comorbidities and risk factors may fail to eliminate confounding. For cholesterol and BP, we base our recommendations for prevention and treatment on interventional (experimental) studies. For sodium, we lack the perfect large-scale trial we would need, but substantial circumstantial information derived from interventional studies cannot be ignored. The objection that modelling the risk of salt excess for cardiovascular disease events based on the effect of salt intake on BP is unjustified fails to consider a recent meta-analysis showing that, independently of the intervention applied, intensive BP-lowering treatment (average BP 133/76 mmHg), compared with the less intensive treatment (140/81 mmHg), is associated with a 14% risk reduction for major cardiovascular events. In this knowledge context, inertia, i.e. awaiting the 'mother trial', is not justified. While recognizing that this trial may still be needed and that actual data, rather than modelled data, are the ideal solution, for now, the World Health Organization recommendation of reducing salt intake to <2 g/day of sodium (5 g/day of salt) in adults stands. PMID- 27488354 TI - Con: Reducing salt intake at the population level: is it really a public health priority? AB - Scientific evidence to support the recommended salt intake of < 5.8 g/day is virtually non-existingent. There are no randomized controlled trials (RCTs) to investigate the effect of salt reduction (SR) below 5.8 g on health outcomes. The effect of SR on blood pressure (BP) reaches maximal efficacy at 1 week. RCTs in healthy individuals lasting at least 1 week show that the effect of SR on BP is <1 mmHg, but that SR has significant side effects, including increases in renin, aldosterone, noradrenalin, adrenalin, cholesterol and triglyceride. Still, disregarding confounders and side effects, health authorities use BP effects obtained in studies of pre-hypertensive and hypertensive patients to recommend SR in the healthy population and use these biased BP effects in statistical models indirectly to project millions of saved lives. These fantasy projections are in contrast to real data from prospective observational population studies directly associating salt intake with mortality, which show that salt intake <5.8 g/day is associated with an increased mortality of ~15%. The population studies also show that a very high salt intake >12.2 g is associated with increased mortality. However, since <5% of populations consume such high amounts of salt, SR at the population level should not be a public health priority. Consequently, this policy should be abolished, not because any attempt to implement it has failed, and not because it costs taxpayers and food consumers unnecessary billions of dollars, but because-if implemented-it might kill people instead of saving them. PMID- 27488355 TI - Pro: Reducing salt intake at population level: is it really a public health priority? AB - A reduction in salt intake reduces blood pressure, stroke and other cardiovascular events, including chronic kidney disease, by as much as 23% (i.e. 1.25 million deaths worldwide). It is effective in both genders, any age, ethnic group, and in high-, medium- and low-income countries. Population salt reduction programmes are both feasible and effective (preventive imperative). Salt reduction programmes are cost-saving in all settings (high-, middle- and low income countries) (economic imperative). Public health policies are powerful, rapid, equitable and cost-saving (political imperative). The important shift in public health has not occurred without obstinate opposition from organizations concerned primarily with the profits deriving from population high salt intake and less with public health benefits. A key component of the denial strategy is misinformation (with 'pseudo' controversies). In general, poor science has been used to create uncertainty and to support inaction. This paper summarizes the evidence in favour of a global salt reduction strategy and analyses the peddling of well-worn myths behind the false controversies. PMID- 27488356 TI - Priority of the genus name Clostridium Prazmowski 1880 (Approved Lists 1980) vs Sarcina Goodsir 1842 (Approved Lists 1980) and the creation of the illegitimate combinations Clostridium maximum (Lindner 1888) Lawson and Rainey 2016 and Clostridium ventriculi (Goodsir 1842) Lawson and Rainey 2016 that may not be used. AB - In a recent publication that attempts to deal with the growing problem of taxa being added to the genus Clostridium that are outside of Clostridium (16S rRNA) group I, a solution is proposed that seeks to limit the genus Clostridium Prazmowski 1880 (Approved Lists 1980) to a small number of species 'related' to the type species, Clostridium butyricum Prazmowski 1880 (Approved Lists 1980). It has been proposed that this genus should also include members of the genus Sarcina Goodsir 1842 (Approved Lists 1980), Sarcinamaxima Lindner 1888 (Approved Lists 1980) and Sarcinaventriculi Goodsir 1842 (Approved Lists 1980), the latter being the nomenclatural type of the genus Sarcina Goodsir 1842 (Approved Lists 1980). In making proposals to treat the genus name Sarcina Goodsir 1842 (Approved Lists 1980) as a synonym of ClostridiumPrazmowski 1880 (Approved Lists 1980), reference is made to the wording of the International Code of Nomenclature of Bacteria. However, while that wording is factually correct, other parts of the Code are relevant to this issue and clearly indicate that the proposed course of action is not sanctioned by texts that have not been directly made reference to. Rather than avoiding confusion it has been contributed to, and it is necessary to document where the problems lie. PMID- 27488357 TI - Use of electronic cigarettes among secondary and high school students from a socially disadvantaged rural area in Poland. AB - BACKGROUND: The use of e-cigarettes has been growing and has become a significant public health concern. Prevention of the youth access to, initiation and continuous use of e-cigarettes with special attention to vulnerable groups is a subject of a health debate. However, still little is known about characteristics of the underage e-cigarette users from different geographic and socio-economic backgrounds as well as other potential factors associated with the use of e cigarettes, including simultaneous use with tobacco products or alcohol. The aim of the study was to investigate the prevalence and factors associated with ever and continued e-cigarette use among the secondary and high school students from a socially disadvantaged rural area in Poland. METHODS: The study sample consisted of 3552 students aged 13-19 years from Piotrkowski district. The anonymous, self administered questionnaire adapted from the Global Youth Tobacco Survey was implemented to collect relevant information. The uni- and multivariate logistic regression analyses were applied to identify factors associated with ever, current (in the previous 30 days) and continued e-cigarette use. RESULTS: Almost 22 % of the sample reported ever e-cigarettes use and 27 % of the respondents indicated e-cigarettes use in the past month. Boys, in comparison with girls, were more likely to report current e-cigarette use (OR = 1.7; p < 0.001). Current e-cigarette use was strongly associated with alcohol consumption (OR = 4.3; p < 0.001), current (OR = 32.5; p < 0.001) and ever tobacco smoking (OR = 7.5; p < 0.001) as well as smoking parents (OR = 1.4; p < 0.05) and friends (OR = 4.5; p < 0.05). The use of e-cigarettes was also significantly associated with harm perception (p < 0.001). A similar pattern was observed among ever e-cigarette users. Male gender (OR = 1.4; p < 0.05), current tobacco smoking (OR = 3.0; p < 0.01) and lack of knowledge about a ban on smoking in the school (OR = 1.4; p < 0.05) were predictors of the continued e-cigarette use. Higher paternal education (OR = 0.5; p < 0.001) and perception of e-cigarettes as more harmful comparing to tobacco (OR = 0.2; p < 0.001) protected from the continued e-cigarette use. CONCLUSIONS: E-cigarette use is widespread in the investigated population, especially among boys, those with other risky behaviors and with smoking parents or friends. There is a need for further research and preventive policies to protect the youth from that exposure. PMID- 27488358 TI - Genome-wide association mapping of soybean chlorophyll traits based on canopy spectral reflectance and leaf extracts. AB - BACKGROUND: Chlorophyll is a major component of chloroplasts and a better understanding of the genetic basis of chlorophyll in soybean [Glycine max (L.) Merr.] might contribute to improving photosynthetic capacity and yield in regions with adverse environmental conditions. A collection of 332 diverse soybean genotypes were grown in 2 years (2009 and 2010) and chlorophyll a (eChl_A), chlorophyll b (eChl_B), and total chlorophyll (eChl_T) content as well as chlorophyll a/b ratio (eChl_R) in leaf tissues were determined by extraction and spectrometric determination. Total chlorophyll was also derived from canopy spectral reflectance measurements using a model of wavelet transformed spectra (tChl_T) as well as with a spectral reflectance index (iChl_T). RESULTS: A genome wide associating mapping approach was employed using 31,253 single nucleotide polymorphisms (SNPs) to identify loci associated with the extract based eChl_A, eChl_B, eChl_R and eChl_T measurements and the two canopy spectral reflectance based methods (tChl_T and iChl_T). A total of 23 (14 loci), 15 (7 loci) and 14 SNPs (10 loci) showed significant association with eChl_A, eChl_B and eChl_R respectively. A total of 52 unique SNPs were significantly associated with total chlorophyll content based on at least one of the three approaches (eChl_T, tChl_T and iChl_T) and likely tagged 27 putative loci for total chlorophyll content, four of which were indicated by all three approaches. CONCLUSIONS: Results presented here show that markers for chlorophyll traits can be identified in soybean using both extract-based and canopy spectral reflectance-based phenotypes, and confirm that high-throughput phenotyping-amenable canopy spectral reflectance measurements can be used for association mapping. PMID- 27488359 TI - Effect of gamma-carboxylase inhibition on serum osteocalcin may be partially protective against developing diabetic cardiomyopathy in type 2 diabetic rats. AB - AIMS: To investigate the possible protective effect of elevated undercarboxylated osteocalcin on diabetic cardiomyopathy mechanisms and risk factors. METHODS: In all, 32 male rats were divided into four groups: control, diabetic, diabetic warfarin and normal warfarin-treated groups. Isolated heart functions were assessed; fasting serum insulin, glucose and glycosylated haemoglobin, homeostasis model assessment insulin resistance and lipid profile were investigated. Serum undercarboxylated osteocalcin and adiponectin were also measured. In cardiac tissue, malondialdehyde content, acyl-CoA dehydrogenase gene expression, Bax/Bcl2 ratio, sarcoendoplasmic reticulum calcium ATPase and osteocalcin receptor (G protein-coupled receptor family C group 6 member A) genes expression were investigated. RESULTS: Prophylactic elevation of undercarboxylated osteocalcin was accompanied by improved insulin sensitivity and lipid profile, increased serum adiponectin, upregulated myocardial osteocalcin receptor with preserved left ventricular function, decreased cardiac malondialdehyde content, acyl-CoA dehydrogenase and Bax/Bcl2 ratio. CONCLUSION: Undercarboxylated osteocalcin was suggested to have protective effects against diabetic cardiomyopathy, possibly through direct action on upregulated G protein coupled receptor family C group 6 member A and indirectly via adiponectin. These effects may be mediated through antagonizing oxidative stress and apoptosis. PMID- 27488360 TI - Fasting glucose levels, incident diabetes, subclinical atherosclerosis and cardiovascular events in apparently healthy adults: A 12-year longitudinal study. AB - We aimed to study the association between fasting plasma glucose, diabetes incidence and cardiovascular burden after 10-12 years. We evaluated diabetes and cardiovascular events incidences, carotid intima-media thickness and coronary artery calcium scores in ELSA-Brasil (the Brazilian Longitudinal Study of Adult Health) baseline (2008-2010) of 1536 adults without diabetes in 1998. We used regression models to estimate association with carotid intima-media thickness (in mm), coronary artery calcium scores (in Agatston points) and cardiovascular events according to fasting plasma glucose in 1998. Adjusted diabetes incidence rate was 9.8/1000 person-years (95% confidence interval: 7.7-13.6/1000 person years). Incident diabetes was positively associated with higher fasting plasma glucose. Fasting plasma glucose levels 110-125 mg/dL were associated with higher carotid intima-media thickness (beta = 0.028; 95% confidence interval: 0.003 0.053). Excluding those with incident diabetes, there was a borderline association between higher carotid intima-media thickness and fasting plasma glucose 110-125 mg/dL (beta = 0.030; 95% confidence interval: -0.005 to 0.065). Incident diabetes was associated with higher carotid intima-media thickness (beta = 0.034; 95% confidence interval: 0.015-0.053), coronary artery calcium scores ?400 (odds ratio = 2.84; 95% confidence interval: 1.17-6.91) and the combined outcome of a coronary artery calcium scores ?400 or incident cardiovascular event (odds ratio = 3.50; 95% confidence interval: 1.60-7.65). In conclusion, fasting plasma glucose in 1998 and incident diabetes were associated with higher cardiovascular burden. PMID- 27488362 TI - Impact of timing from blood sampling to pharmacodynamic assessment on measures of platelet reactivity in patients treated with P2Y12 receptor inhibitors. AB - Several platelet function tests (PFT) are available to assess the pharmacodynamic (PD) effects of P2Y12 inhibitors. However, there are technical variances between PFT, and P2Y12 inhibitors differ in pharmacological properties. Manufactures of PFT recommend a time-frame within which assessments needs to be executed. However, if the timing from blood sampling to processing affects PD results is unknown. We conducted a prospective study assessing the impact of timing from blood sampling to processing on PD measures using three different PFT. We studied 60 aspirin-treated patients with coronary artery disease (CAD) on maintenance P2Y12 inhibiting therapy [clopidogrel 75 mg/day (n=20), prasugrel 10 mg/day (n=20) and ticagrelor 90 mg bid (n=20)]. PD assessments (trough levels) were performed by VerifyNow P2Y12 (VN), light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein (VASP) at 30 minutes, 2 and 4 hours post sampling; VASP was also performed at 24 hours. P2Y12 reaction units (PRU) by VN significantly decreased over time with all P2Y12 inhibitors (clopidogrel p<0.001; prasugrel p=0.016; ticagrelor p<0.001). PRU at 30 minutes and 2 hours were similar, but decreased at 4 hours. LTA showed consistent findings with VN. Conversely, PD measures as assessed by VASP were stable over time (p>0.1 for all P2Y12 inhibitors). In conclusion, in CAD patients on maintenance therapy with P2Y12 inhibitors, timing from blood sampling to processing significantly influences PD measures as assessed by VN and LTA, but not by VASP. PMID- 27488361 TI - Learning from doing: the case for combining normalisation process theory and participatory learning and action research methodology for primary healthcare implementation research. AB - BACKGROUND: The implementation of research findings is not a straightforward matter. There are substantive and recognised gaps in the process of translating research findings into practice and policy. In order to overcome some of these translational difficulties, a number of strategies have been proposed for researchers. These include greater use of theoretical approaches in research focused on implementation, and use of a wider range of research methods appropriate to policy questions and the wider social context in which they are placed. However, questions remain about how to combine theory and method in implementation research. In this paper, we respond to these proposals. DISCUSSION: Focussing on a contemporary social theory, Normalisation Process Theory, and a participatory research methodology, Participatory Learning and Action, we discuss the potential of their combined use for implementation research. We note ways in which Normalisation Process Theory and Participatory Learning and Action are congruent and may therefore be used as heuristic devices to explore, better understand and support implementation. We also provide examples of their use in our own research programme about community involvement in primary healthcare. CONCLUSIONS: Normalisation Process Theory alone has, to date, offered useful explanations for the success or otherwise of implementation projects post-implementation. We argue that Normalisation Process Theory can also be used to prospectively support implementation journeys. Furthermore, Normalisation Process Theory and Participatory Learning and Action can be used together so that interventions to support implementation work are devised and enacted with the expertise of key stakeholders. We propose that the specific combination of this theory and methodology possesses the potential, because of their combined heuristic force, to offer a more effective means of supporting implementation projects than either one might do on its own, and of providing deeper understandings of implementation contexts, rather than merely describing change. PMID- 27488364 TI - Erratum to: Classical swine fever virus NS5A protein changed inflammatory cytokine secretion in porcine alveolar macrophages by inhibiting the NF-kappaB signaling pathway. PMID- 27488363 TI - Intestinal development of bovine foetuses during gestation is affected by foetal sex and maternal nutrition. AB - We aimed to evaluate the effects of maternal nutrition (MN) and foetal sex on the intestinal development of bovine foetuses throughout different days of gestation (DG). Forty-four multiparous, dry Holstein * Gyr cows with average initial body weight of 480 +/- 10 kg were fed the same diet of either restricted feeding at 1.15% of body weight (CO, n = 24) or fed ad libitum (overnourished, ON, n = 20). Six cows from CO group and five cows from ON group were slaughtered at 139, 199, 241 and 268 DG, and foetuses were necropsied to evaluate the intestinal development. The mass, length and density of foetal intestines were not affected by MN (p >= 0.260). An interaction between MN and DG was observed for the villi length of jejunum (p = 0.006) and ileum (p < 0.001). Villi length of jejunum and ileum was higher (p < 0.10) in foetuses from ON-fed cows than in foetuses from CO fed cows at 139 DG. However, at 199 DG, the villi length of jejunum and ileum of foetuses from CO-fed cows was higher than in foetuses from ON-fed cows. Despite these differences, MN did not affect the villi length of jejunum and ileum at 268 DG (p > 0.10). Female foetuses had greater small intestine mass (p = 0.093), large intestine mass (p = 0.022), small intestine mass in proportion to body mass (p = 0.017) and large intestine mass in proportion to body mass (p < 0.001) than male foetuses. Female foetuses had also longer small intestine (p = 0.077) and greater small intestine density (p = 0.021) and villi length of jejunum (p = 0.001) and ileum (p = 0.010) than males. We conclude that MN affects the pathway for the development of foetal villi length throughout the gestation in bovine foetuses without changing the final villi length. Female foetuses had higher intestinal mass, density and villi length than males during the foetal phase in bovines. PMID- 27488365 TI - Effect of medication timing on anticoagulation stability in users of warfarin (the INRange RCT): study protocol for a randomized controlled trial. AB - BACKGROUND: Warfarin is an oral anticoagulant medication that disrupts the liver's production of clotting factors. While this medication is highly effective for the prevention of thromboembolic events, it also has a narrow therapeutic range and a vulnerability to interactions with other drugs and vitamin K containing foods. Warfarin is commonly ingested at dinnertime, the same time of day that dietary vitamin K consumption (found largely in green leafy vegetables) is most variable. While the long half-life of warfarin might make this irrelevant, the ultra short half-life of vitamin K and the possibility of a hepatic first-pass effect for warfarin make it worth evaluating whether morning ingestion of warfarin, when vitamin K levels are consistently low, leads to greater stability of its anticoagulant effect. An examination of the timing of administration on the effectiveness of warfarin has never before been conducted. METHODS/DESIGN: This is a 7-month Prospective Randomized Open Blinded End-point (PROBE) study in which established evening warfarin users (primary care managed Canadian outpatients in the provinces of British Columbia and Alberta) will be randomized to either switch to morning ingestion of warfarin (the intervention) or to continue with evening use (the control). The primary outcome is the percent change in the proportion of time spent outside the therapeutic range of the international normalized ratio (INR) blood test. Secondary outcomes include change in proportion of time spent within the therapeutic INR range (TTR), percentage of patients with TTR >75 %, percentage of patients with TTR <60 %, and major warfarin-related cardiovascular events (including all-cause mortality, hospitalization for stroke, hospitalization for GI bleeding, and deep venous thrombosis/pulmonary embolism). We will also compare whether day-to-day variability in the consumption of high vitamin K-containing foods at baseline affects the baseline TTR in this cohort of evening warfarin users. DISCUSSION: This study addresses whether the timing of warfarin ingestion influences the stability of its anticoagulant effect. Should morning ingestion prove superior, the safety and effectiveness of this medication, and hence the prevention of stroke, pulmonary embolus, and major hemorrhage, could potentially be improved with no added cost or inconvenience to the patient. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02376803 . Registered on 25 February 2015. PMID- 27488366 TI - Allogeneic anorectal transplantation in rats: technical considerations and preliminary results. AB - Fecal incontinence is a challenging condition with numerous available treatment modalities. Success rates vary across these modalities, and permanent colostomy is often indicated when they fail. For these cases, a novel potential therapeutic strategy is anorectal transplantation (ATx). We performed four isogeneic (Lewis to-Lewis) and seven allogeneic (Wistar-to-Lewis) ATx procedures. The anorectum was retrieved with a vascular pedicle containing the aorta in continuity with the inferior mesenteric artery and portal vein in continuity with the inferior mesenteric vein. In the recipient, the native anorectal segment was removed and the graft was transplanted by end-to-side aorta-aorta and porto-cava anastomoses and end-to-end colorectal anastomosis. Recipients were sacrificed at the experimental endpoint on postoperative day 30. Surviving animals resumed normal body weight gain and clinical performance within 5 days of surgery. Isografts and 42.9% of allografts achieved normal clinical evolution up to the experimental endpoint. In 57.1% of allografts, signs of immunological rejection (abdominal distention, diarrhea, and anal mucosa inflammation) were observed three weeks after transplantation. Histology revealed moderate to severe rejection in allografts and no signs of rejection in isografts. We describe a feasible model of ATx in rats, which may allow further physiological and immunologic studies. PMID- 27488367 TI - ERPs in an oddball task under vection-inducing visual stimulation. AB - The neural mechanisms underlying the vection illusion are not fully understood. A few studies have analyzed visually evoked potentials or event-related potentials (ERPs) when participants were exposed to vection-inducing stimulation. However, none of them tested how such stimulation influences the brain activity during performance of the simultaneous visual task. In the present study, ERPs were recorded while subjects (N = 19) performed a discrimination oddball task. Two stimuli (O or X) were presented on the background of central and peripheral visual fields consisting of altered black and white vertical stripes that were stationary or moving horizontally. Three different combinations of these fields were created: (1) both center and periphery stationary (control condition), (2) both center and periphery moving, (3) center stationary and periphery moving. Mean reaction times to targets were shortest in the control condition. The amplitudes of P1 and N2 at occipital locations, and the amplitude of P3 at frontal, central, and parietal locations, were attenuated, and the P3 exhibited longer peak latency when both central and peripheral visual fields were moving. These potentials reflect initial sensory processing and the degree of attention required for processing visual stimuli and performing the task. Our findings suggest that the integration of central and peripheral moving visual fields enhances the vection illusion and slows down reaction times to targets in the oddball task and disrupts the magnitude of electrophysiological responses to targets. PMID- 27488368 TI - Behavioral and Nondirective Guided Self-Help for Parents of Children with Externalizing Behavior: Mediating Mechanisms in a Head-To-Head Comparison. AB - Parent training (PT) delivered as a guided self-help intervention may be a cost- and time-effective intervention in the treatment of children with externalizing disorders. In face-to-face PT, parenting strategies have repeatedly been identified as mediating mechanisms for the decrease of children's problem behavior. Few studies have examined possible mediating effects in guided self help interventions for parents. The present study aimed to investigate possible mediating variables of a behaviorally oriented guided self-help program for parents of children with externalizing problems compared to a nondirective intervention in a clinical sample. A sample of 110 parents of children with externalizing disorders (80 % boys) were randomized to either a behaviorally oriented or a nondirective guided self-help program. Four putative mediating variables were examined simultaneously in a multiple mediation model using structural equation modelling. The outcomes were child symptoms of ADHD and ODD as well as child externalizing problems, assessed at posttreatment. Analyses showed a significant indirect effect for dysfunctional parental attributions in favor of the group receiving the behavioral program, and significant effects of the behavioral program on positive and negative parenting and parental self efficacy, compared to the nondirective intervention. Our results indicate that a decrease of dysfunctional parental attributions leads to a decrease of child externalizing problems when parents take part in a behaviorally oriented guided self-help program. However, none of the putative mediating variables could explain the decrease in child externalizing behavior problems in the nondirective group. A change in dysfunctional parental attributions should be considered as a possible mediator in the context of PT. PMID- 27488370 TI - Treatment Effects for Dysphagia in Adults with Multiple Sclerosis: A Systematic Review. AB - Dysphagia or swallowing difficulties have been reported to be a concern in adults with multiple sclerosis (MS). This problem can result in several complications including aspiration pneumonia, reduced quality of life and an increase in mortality rate. No previous systematic reviews on treatment effects for dysphagia in MS have been published. The main objective of this study is to summarise and qualitatively analyse published studies on treatment effects for dysphagia in MS. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were applied to conduct a systematic search of seven databases, using relevant key words, and subsequent analysis of the identified studies. The studies were required to meet all three inclusion criteria of including a statement on intention to treat, or measure the effects of treatment for dysphagia in adults with MS and data on treatment outcomes for at least one adult diagnosed with MS. Retained studies were evaluated by two independent reviewers using a critical appraisal tool. This study has not been registered. A total of 563 studies were identified from the database searches. After screening and assessment of full articles for eligibility, five studies were included in the review. Three examined electrical stimulation and two examined the use of botulinum toxin. One study testing electrical stimulation was a randomised controlled trial, two were well-designed case series and two were case series lacking experimental control. All studies reported some positive effects on dysphagia; however, treatments that involved the use of electrical stimulation showed larger effect sizes. There is a paucity of evidence to guide treatment of dysphagia in MS, with only electrical stimulation and botulinum toxin treatment represented in the literature search conducted here. While both treatments show initial promise for reducing the swallowing impairment, they require further research using well-controlled experimental designs to determine their clinical applicability and long-term treatment effects for dysphagia across different types and severity of MS. PMID- 27488369 TI - Born in Bradford's Better Start: an experimental birth cohort study to evaluate the impact of early life interventions. AB - BACKGROUND: Early interventions are recognised as key to improving life chances for children and reducing inequalities in health and well-being, however there is a paucity of high quality research into the effectiveness of interventions to address childhood health and development outcomes. Planning and implementing standalone RCTs for multiple, individual interventions would be slow, cumbersome and expensive. This paper describes the protocol for an innovative experimental birth cohort: Born in Bradford's Better Start (BiBBS) that will simultaneously evaluate the impact of multiple early life interventions using efficient study designs. Better Start Bradford (BSB) has been allocated L49 million from the Big Lottery Fund to implement 22 interventions to improve outcomes for children aged 0-3 in three key areas: social and emotional development; communication and language development; and nutrition and obesity. The interventions will be implemented in three deprived and ethnically diverse inner city areas of Bradford. METHOD: The BiBBS study aims to recruit 5000 babies, their mothers and their mothers' partners over 5 years from January 2016-December 2020. Demographic and socioeconomic information, physical and mental health, lifestyle factors and biological samples will be collected during pregnancy. Parents and children will be linked to their routine health and local authority (including education) data throughout the children's lives. Their participation in BSB interventions will also be tracked. BiBBS will test interventions using the Trials within Cohorts (TwiCs) approach and other quasi-experimental designs where TwiCs are neither feasible nor ethical, to evaluate these early life interventions. The effects of single interventions, and the cumulative effects of stacked (multiple) interventions on health and social outcomes during the critical early years will be measured. DISCUSSION: The focus of the BiBBS cohort is on intervention impact rather than observation. As far as we are aware BiBBS is the world's first such experimental birth cohort study. While some risk factors for adverse health and social outcomes are increasingly well described, the solutions to tackling them remain elusive. The novel design of BiBBS can contribute much needed evidence to inform policy makers and practitioners about effective approaches to improve health and well-being for future generations. PMID- 27488371 TI - Comparison of detection methods and follow-up study on the tyrosine kinase inhibitors therapy in non-small cell lung cancer patients with ROS1 fusion rearrangement. AB - BACKGROUND: The screening of ROS proto-oncogene 1, receptor tyrosine kinase(ROS1) fusion rearrangement might be potentially beneficial for an effective therapy against non-small cell lung cancer (NSCLC). However, the three main ROS1 rearrangement detection methods have limitations, and no routine protocol for the detection of ROS1 rearrangement in NSCLC is available. In this study, our aims were to compare immunohistochemistry (IHC), fluorescent in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (qRT-PCR) in their ability to detect ROS1 rearrangement in NSCLC, and discuss the clinical characteristics and histopathology of the patients with ROS1 rearrangement. Moreover, the effects of tyrosine kinase inhibitors (TKIs) therapy on the patients with ROS1 rearrangement and advanced stage disease (III b-IV) were investigated. METHODS: Patients with a previously diagnosed NSCLC were recruited in this study from November 2013 to October 2015. IHC was performed using the D4D6 monoclonal antibody (mAb) in an automatic IHC instrument, while FISH and qRT PCR were carried out to confirm the IHC results. FISH and qRT-PCR positive cases underwent direct sequencing. After detection, patients with advanced ROS1 rearranged NSCLC had received TKI therapy. RESULTS: Two hundred and thirty-eight patients were included in this study. ROS1 rearrangement was detected in 10 patients. The concordant rate of FISH and qRT-PCR results was 100 %, while in the FISH and IHC results high congruence was present when IHC showed a diffusely (>=60 % tumor cells) 2-3+ cytoplasmic reactivity pattern. Patients harboring ROS1 rearrangement were mostly young (8/10), females (7/10) and non-smokers (7/10) with adenocarcinoma (10/10) and acinar pattern. Most of their tumor were in intermediate grade (6/8). Among these 10 patients, three of them in stage IV with ROS1 rearrangement gained benefits from ROS1 TKI therapy. CONCLUSIONS: IHC, FISH and qRT-PCR can reliably detect ROS1 rearrangement in NSCLC, while IHC can be used as a preliminary screening tool. These results supported the efficacy of ROS1 TKI therapy in treating advanced NSCLC patients with ROS1 rearrangement. PMID- 27488372 TI - LPS-matured CD11c+ bone marrow-derived dendritic cells can initiate autoimmune pathology with minimal injection site inflammation. AB - The pathogenesis of human autoimmune disorders is incompletely understood. This has led to the development of numerous murine models in which the pathogenesis of autoimmunity can be probed and the efficacy of novel therapies can be tested. One of the most widely-used murine models of autoimmunity is experimental autoimmune encephalomyelitis (EAE). To induce autoimmune pathology, mice are often immunized with an autoantigen alongside an adjuvant, typically complete Freund's adjuvant (CFA). Unfortunately, CFA causes significant inflammation at the site of administration. Despite the well-recognized complication of injection site inflammation, CFA with autoantigen immunization is widely used to induce central nervous system autoimmunity. We performed a literature review which allowed us to estimate that over 10,000 mice were immunized with CFA in published EAE studies in 2013. In this study, we demonstrated that subcutaneously administered myelin basic protein (MBP)-pulsed CD11c+ bone marrow-derived dendritic cells (BMDC) were as effective at inducing EAE as subcutaneously administered MBP plus CFA. Importantly, we also discovered that the CD11c+ BMDC caused significantly less injection site inflammation than MBP plus CFA immunization. This study demonstrated that the use of CD11c+ BMDC can enable the development of autopathogenic T-cells to be studied in vivo without the unwanted side-effects of long-lasting injection site inflammation. This model represents a significant refinement to existing EAE models and may lead to the improvement of the welfare of experimental mice used to study the development of autoimmunity in vivo. PMID- 27488373 TI - Hyperthermia phased arrays pre-treatment evaluation. AB - PURPOSE: In the hyperthermia treatment of deep-seated tumours by a phased array of radiofrequency (RF) antennas, heatability will be investigated in terms of power-to-tumour and other figures-of-merit of hyperthermia treatments to be optimised. The assumption is that each source is individually constrained to not exceed a maximal nominal power. The nominal power may differ from a source to another as a physical limit or an operative modality. METHOD: Under such constraint, new procedures for the maximisation of (i) power-to-tumour, (ii) heating efficiency and, in general, (iii) power ratios as tumour-heating selectivity are proposed. (iv) The problem whether a tumour is equally heatable after turning off some antennas is addressed as array thinning. CASE STUDY: An array of eight dipoles arranged on two lines around a head/neck is introduced to perform a numerical analysis. The achievable power-to-tumour according to the new optimizations and other performance indices adopted from the literature is tested against values of power that can be found to be sufficient for heating tumours to clinical temperatures. New solutions to data rendering in hyperthermia heating are proposed. PMID- 27488374 TI - Nodal signalling in Xenopus: the role of Xnr5 in left/right asymmetry and heart development. AB - Nodal class TGF-beta signalling molecules play essential roles in establishing the vertebrate body plan. In all vertebrates, nodal family members have specific waves of expression required for tissue specification and axis formation. In Xenopus laevis, six nodal genes are expressed before gastrulation, raising the question of whether they have specific roles or act redundantly with each other. Here, we examine the role of Xnr5. We find it acts at the late blastula stage as a mesoderm inducer and repressor of ectodermal gene expression, a role it shares with Vg1. However, unlike Vg1, Xnr5 depletion reduces the expression of the nodal family member xnr1 at the gastrula stage. It is also required for left/right laterality by controlling the expression of the laterality genes xnr1, antivin (lefty) and pitx2 at the tailbud stage. In Xnr5-depleted embryos, the heart field is established normally, but symmetrical reduction in Xnr5 levels causes a severely stunted midline heart, first evidenced by a reduction in cardiac troponin mRNA levels, while left-sided reduction leads to randomization of the left/right axis. This work identifies Xnr5 as the earliest step in the signalling pathway establishing normal heart laterality in Xenopus. PMID- 27488375 TI - An invertebrate-specific miRNA targeted the ancient cholinergic neuroendocrine system of oyster. AB - Acetylcholine (ACh) is the main neurotransmitter in the cholinergic neuroendocrine system and plays an indispensable role in modulating diverse immune responses. As important transporters in choline uptake, choline transporter-like proteins (CTLs) can control ACh synthesis and release indirectly in multiple organisms. In this study, cgi-miR-2d, an invertebrate-specific miRNA in oyster Crassostrea gigas, is proved to repress the synthesis/release of ACh by targeting CgCTL1 and choline uptake in haemocytes during the early stage of pathogen infection. In short, an opposite expression pattern between CgCTL1 and cgi-miR-2d is observed during Vibrio splendidus infection, accompanied by changes in haemolymph ACh. In addition, the expression level of CgCTL1 is found to be significantly repressed after cgi-miR-2d overexpression in vivo, while both haemocyte choline and haemolymph ACh are also decreased simultaneously, similar to the finding in CgCTL1 knock-down assay. As a result, the expression of two tumour necrosis factor-like proteins and the bacteriostatic activity of oyster haemocytes are found to be altered significantly by either gain-of-function cgi miR-2d or knock-down of CgCTL1. To our knowledge, this is the first miRNA identified in invertebrates that can target the ancient cholinergic system and augment immune response during infection. PMID- 27488377 TI - Elevated extension of longevity by cyclically heat stressing a set of recombinant inbred lines of Drosophila melanogaster throughout their adult life. AB - An extremely high (about 100 %) increase in longevity is reported for a subset of recombinant inbred lines (RILs) of Drosophila melanogaster subjected to a cyclic heat stress throughout the adult life. Previous work showed that both longevity and heat sensitivity highly differed among RILs. The novel heat stress treatment used in this study consisted of 5 min at 38 degrees C applicated approximately every 125 min throughout the adult life starting at the age of 2 days. In spite of the exceptionally high increase in longevity in a set of RILs, the same heat stress treatment reduced rather than increased longevity in other RILs, suggesting that heat-induced hormesis is dependent on the genotype and/or the genetic background. Further, one quantitative trait locus (QTL) was identified for heat-induced hormesis on chromosome 2 (bands 28A1-34D2) in one RIL panel (RIL D48) but it was not significant in its reciprocal panel (RIL-SH2). The level of heat-induced hormesis showed a sexual dimorphism, with a higher number of lines exhibiting higher hormesis effects in males than in females. The new heat stress treatment in this study suggests that longevity can be further extended than previously suggested by applying a cyclic and mild stress throughout the life, depending on the genotype. PMID- 27488376 TI - Nitric oxide signals are interlinked with calcium signals in normal pancreatic stellate cells upon oxidative stress and inflammation. AB - The mammalian diffuse stellate cell system comprises retinoid-storing cells capable of remarkable transformations from a quiescent to an activated myofibroblast-like phenotype. Activated pancreatic stellate cells (PSCs) attract attention owing to the pivotal role they play in development of tissue fibrosis in chronic pancreatitis and pancreatic cancer. However, little is known about the actual role of PSCs in the normal pancreas. These enigmatic cells have recently been shown to respond to physiological stimuli in a manner that is markedly different from their neighbouring pancreatic acinar cells (PACs). Here, we demonstrate the capacity of PSCs to generate nitric oxide (NO), a free radical messenger mediating, for example, inflammation and vasodilatation. We show that production of cytosolic NO in PSCs is unambiguously related to cytosolic Ca(2+) signals. Only stimuli that evoke Ca(2+) signals in the PSCs elicit consequent NO generation. We provide fresh evidence for the striking difference between signalling pathways in PSCs and adjacent PACs, because PSCs, in contrast to PACs, generate substantial Ca(2+)-mediated and NOS-dependent NO signals. We also show that inhibition of NO generation protects both PSCs and PACs from necrosis. Our results highlight the interplay between Ca(2+) and NO signalling pathways in cell cell communication, and also identify a potential therapeutic target for anti inflammatory therapies. PMID- 27488378 TI - What is the Intraarticular Concentration of Tobramycin Using Low-dose Tobramycin Bone Cement in TKA: An In Vivo Analysis? AB - BACKGROUND: Antibiotic-impregnated bone cement has increased in popularity as an effort to reduce the risk of infection in high-risk TKAs. However, limited data has been reported regarding antibiotic levels achieved when using tobramycin impregnated bone cement after implanting total knee components. QUESTIONS/PURPOSES: We asked: (1) What is the tobramycin serum and knee intraarticular levels in patients undergoing primary TKA using tobramycin cement? (2) What is the intraarticular tobramycin level for patients receiving only intravenous tobramycin? METHODS: All patients undergoing primary TKA by one of the two study surgeons (GV, JP) during a 6-month period were evaluated for inclusion and invited to participate. The study enrolled 15 patients undergoing primary TKA by one of two surgeons (GV, JP) who met inclusion criteria; treatment allocation was assigned randomly through blinded envelope. The study group consisted of 10 patients whose components were implanted using a commercially prepared low-dose tobramycin bone cement mixture (1 g/40 g). The control group consisted of five patients who received standard weight-based dose intravenous tobramycin. Samples of serum and Hemovac(r) drain-collected intraarticular hematoma were analyzed at 6, 24, and 48 hours postoperatively. Tobramycin levels were measured using an immunoassay technique with a low-end sensitivity of 0.28 MUg/mL. Mann-Whitney U tests were performed to compare the serum and intraarticular tobramycin concentrations at each time in the independent variable of group (Control and Study). RESULTS: The median (interquartile range [IQR]) intraarticular tobramycin concentrations for the study group, with tobramycin impregnated bone cement, was 31.8 (29.0) MUg/mL at 6 hours, 17.1 (13.1) MUg/mL at 24 hours, and 6.8 (6.8) MUg/mL at 48 hours. The intraarticular tobramycin concentrations of this study group were larger than those for the control group at 6 hours (median = 1.3; IQR = 0.7; p = 0.002), 24 hours (median = 1.3, IQR = 1.0; p = 0.002), and 48 hours (median = 1.4; IQR = 1.0; p = 0.02). The serum concentrations for the tobramycin-impregnated bone cement group were 0.3 MUg/mL or less for all samples whereas serum concentrations and median (IQR) for the control group were 1.2 (2.6) MUg/mL, 1.6 (4.4) MUg/mL, and 2.0 (3.3) MUg/mL at 6, 24, and 48 hours respectively. The serum levels for the tobramycin-impregnated cement group were less than those for the control group at 6 hours (p = 0.001), 24 (p = 0.001), and 48 hours (p < 0.001). CONCLUSIONS: Tobramycin-impregnated bone cement provides a way to deliver antibiotics in patients undergoing TKA. This supratherapeutic short-term prophylactic perioperative antibiotic local delivery can be achieved with limited systemic absorption, whereas joint tobramycin levels were less than therapeutic levels when given intravenously alone. In the control group, with only intravenous tobramycin, a subtherapeutic (< 2.0 MUg/mL) level of tobramycin was found in all the intraarticular samples at 6, 24, and 48 hours. Based on the evidence obtained in this study, commercially prepared low-dose tobramycin bone cement can be used to obtain short-term supratherapeutic local concentrations in the knee while maintaining serum tobramycin levels at a minimum. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 27488379 TI - Periprosthetic UHMWPE Wear Debris Induces Inflammation, Vascularization, and Innervation After Total Disc Replacement in the Lumbar Spine. AB - BACKGROUND: The pathophysiology and mechanisms driving the generation of unintended pain after total disc replacement (TDR) remain unexplored. Ultrahigh molecular-weight polyethylene (UHMWPE) wear debris from TDRs is known to induce inflammation, which may result in pain. QUESTIONS/PURPOSES: The purpose of this study was to determine whether (1) periprosthetic UHMWPE wear debris induces immune responses that lead to the production of tumor necrosis factor-alpha (TNFalpha) and interleukin (IL)-1beta, the vascularization factors, vascular endothelial growth factor (VEGF) and platelet-derived growth factor-bb (PDGFbb), and the innervation/pain factors, nerve growth factor (NGF) and substance P; (2) the number of macrophages is associated with the production of the aforementioned factors; (3) the wear debris-induced inflammatory pathogenesis involves an increase in vascularization and associated innervation. METHODS: Periprosthetic tissues from our collection of 11 patients with contemporary TDRs were evaluated using polarized light microscopy to quantify UHMWPE wear particles. The major reason for revision (mean implantation time of 3 years [range, 1-6 years]) was pain. For control subjects, biopsy samples from four patients with degenerative disc disease with severe pain and autopsy samples from three normal patients with no history of back pain were also investigated. Immunohistochemistry and histology were used to identify secretory factors, macrophages, and blood vessels. Immunostained serial sections were imaged at *200 magnification and using MATLAB and NIH ImageJ, a threshold was determined for each factor and used to quantify positive staining normalized to tissue sectional area. The Mann Whitney U test was used to compare results from different patient groups, whereas the Spearman Rho test was used to determine correlations. Significance was based on p < 0.05. RESULTS: The mean percent area of all six inflammatory, vascularization, and innervation factors was higher in TDR tissues when compared with normal disc tissues. Based on nonparametric data analysis, those factors showing the most significant increase included TNFalpha (5.17 +/- 1.76 versus 0.05 +/- 0.03, p = 0.02), VEGF (3.02 +/- 1.01 versus 0.02 +/- 0.002, p = 0.02), and substance P (4.15 +/- 1.01 versus 0.08 +/- 0.04, p = 0.02). The mean percent area for IL-1beta (2.41 +/- 0.66 versus 0.13 +/- 0.13, p = 0.01), VEGF (3.02 +/- 1.01 versus 0.34 +/- 0.29, p = 0.04), and substance P (4.15 +/- 1.01 versus 1.05 +/- 0.46, p = 0.01) was also higher in TDR tissues when compared with disc tissues from patients with painful degenerative disc disease. Five of the factors, TNFalpha, IL-1beta, VEGF, NGF, and substance P, strongly correlated with the number of wear particles, macrophages, and blood vessels. The most notable correlations included TNFalpha with wear particles (p < 0.001, rho = 0.63), VEGF with macrophages (p = 0.001, rho = 0.71), and NGF with blood vessels (p < 0.001, rho = 0.70). Of particular significance, the expression of PDGFbb, NGF, and substance P was predominantly localized to blood vessels/nerve fibers. CONCLUSIONS: These findings indicate wear debris-induced inflammatory reactions can be linked to enhanced vascularization and associated innervation/pain factor production at periprosthetic sites around TDRs. Elucidating the pathogenesis of inflammatory particle disease will provide information needed to identify potential therapeutic targets and treatment strategies to mitigate pain and potentially avoid revision surgery. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 27488380 TI - Thromboprophylaxis using combined intermittent pneumatic compression and pharmacologic prophylaxis versus pharmacologic prophylaxis alone in critically ill patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Venous thromboembolism (VTE) remains a common problem in critically ill patients. Pharmacologic prophylaxis is currently the standard of care based on high-level evidence from randomized controlled trials. However, limited evidence exists regarding the effectiveness of intermittent pneumatic compression (IPC) devices. The Pneumatic compREssion for preventing VENous Thromboembolism (PREVENT trial) aims to determine whether the adjunct use of IPC with pharmacologic prophylaxis compared to pharmacologic prophylaxis alone in critically ill patients reduces the risk of VTE. METHODS/DESIGN: The PREVENT trial is a multicenter randomized controlled trial, which will recruit 2000 critically ill patients from over 20 hospitals in three countries. The primary outcome is the incidence of proximal lower extremity deep vein thrombosis (DVT) within 28 days after randomization. Radiologists interpreting the scans are blinded to intervention allocation, whereas the patients and caregivers are unblinded. The trial has 80 % power to detect a 3 % absolute risk reduction in proximal DVT from 7 to 4 %. DISCUSSION: The first patient was enrolled in July 2014. As of May 2015, a total of 650 patients have been enrolled from 13 centers in Saudi Arabia, Canada and Australia. The first interim analysis is anticipated in July 2016. We expect to complete recruitment by 2018. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02040103 (registered on 3 November 2013). Current controlled trials: ISRCTN44653506 (registered on 30 October 2013). PMID- 27488381 TI - Factors associated with late stage at diagnosis among Puerto Rico's government health plan colorectal cancer patients: a cross-sectional study. AB - BACKGROUND: Late stage at diagnosis of cancer is considered a key predictor factor for a lower survival rate. Knowing and understanding the barriers to an early diagnosis of colorectal cancer is critical in the fight to reduce the social and economic burden caused by cancer in Puerto Rico. This study evaluates factors associated to colorectal cancer stage at diagnosis among Puerto Rico's Government Health Plan (GHP) patients. METHODS: We conducted a cross-sectional study based on a secondary data analysis using information from the Puerto Rico Central Cancer Registry (PRCCR) and the Puerto Rico Health Insurance Administration (PRHIA). Logistic regression models were used to estimate the unadjusted odds ratio (ORs) and adjusted odds ratio (AORs), and their 95 % confidence intervals (CIs). Colorectal cancer cases diagnosed between January 1, 2012 and December 31, 2012, among persons 50 to 64 years of age, participants of the GHP and with a cancer diagnosis reported to the PRCCR were included in the study. RESULTS: There were 68 (35.79 %) colorectal cancer patients diagnosed at early stage while 122 (64.21 %) where diagnosed at late stage. In the multivariate analysis having a diagnostic delay of more than 59 days (AOR 2.94, 95 % CI: 1.32 to 6.52) and having the first visit through the emergency room (AOR 3.48, 95 % CI: 1.60 to 7.60) were strong predictors of being diagnosed with colorectal cancer at a late stage. CONCLUSIONS: These results are relevant to understand the factors that influence the outcomes of colorectal cancer patients in the GHP. Therefore, it is important to continue developing studies to understand the Government Health Plan patient's pathways to a cancer diagnosis, in order to promote assertive decisions to improve patient outcomes. PMID- 27488382 TI - Anti-erythrocyte antibodies may contribute to anaemia in Plasmodium vivax malaria by decreasing red blood cell deformability and increasing erythrophagocytosis. AB - BACKGROUND: Plasmodium vivax accounts for the majority of human malaria infections outside Africa and is being increasingly associated in fatal outcomes with anaemia as one of the major complications. One of the causes of malarial anaemia is the augmented removal of circulating non-infected red blood cells (nRBCs), an issue not yet fully understood. High levels of auto-antibodies against RBCs have been associated with severe anaemia and reduced survival of nRBCs in patients with falciparum malaria. Since there are no substantial data about the role of those antibodies in vivax malaria, this study was designed to determine whether or not auto-antibodies against erythrocytes are involved in nRBC clearance. Moreover, the possible immune mechanisms elicited by them that may be associated to induce anaemia in P. vivax infection was investigated. METHODS: Concentrations of total IgG were determined by sandwich ELISA in sera from clinically well-defined groups of P. vivax-infected patients with or without anaemia and in healthy controls never exposed to malaria, whereas the levels of specific IgG to nRBCs were determined by cell-ELISA. Erythrophagocytosis assay was used to investigate the ability of IgGs purified from each studied pooled sera in enhancing nRBC in vitro clearance by THP-1 macrophages. Defocusing microscopy was employed to measure the biomechanical modifications of individual nRBCs opsonized by IgGs purified from each group. RESULTS: Anaemic patients had higher levels of total and specific anti-RBC antibodies in comparison to the non anaemic ones. Opsonization with purified IgG from anaemic patients significantly enhanced RBCs in vitro phagocytosis by THP-1 macrophages. Auto-antibodies purified from anaemic patients decreased the nRBC dynamic membrane fluctuations suggesting a possible participation of such antibodies in the perturbation of erythrocyte flexibility and morphology integrity maintenance. CONCLUSIONS: These findings revealed that vivax-infected patients with anaemia have increased levels of IgG auto-antibodies against nRBCs and that their deposition on the surface of non-infected erythrocytes decreases their deformability, which, in turn, may enhance nRBC clearance by phagocytes, contributing to the anaemic outcome. These data provide insights into the immune mechanisms associated with vivax malaria anaemia and may be important to the development of new therapy and vaccine strategies. PMID- 27488383 TI - The role of positron emission tomography in the evaluation of myocardial ischemia in women. AB - Cardiovascular disease continues to be the number one cause of death in women, yet most women are unaware of their risk. Over the last decade, radionuclide myocardial perfusion imaging with positron emission tomography (PET) has become a powerful tool for the diagnosis and risk stratification of patients with known or suspected coronary artery disease (CAD). This editorial viewpoint will review the maturing role of PET imaging in women, particularly as applied to the evaluation of ischemic heart disease. Specifically, we focus on distinct advantages offered by PET imaging in the evaluation of myocardial ischemia in women: (1) improved diagnostic accuracy, including in the presence of breast or adipose tissue and small left ventricular cavity size, (2) decreased radiation exposure through the use of short-lived radiopharmaceuticals, and (3) the ability to quantify myocardial blood flow and coronary flow reserve to diagnose ischemia, even in the absence of obstructive CAD. As such, cardiac PET perfusion imaging stands to play a unique role in defining the diagnosis and prognosis of women with ischemic heart disease, while also guiding new treatment strategies for their more prevalent cardiovascular disease phenotypes. PMID- 27488384 TI - How do we manage blood product support in the massively hemorrhaging obstetric patient? AB - Obstetric hemorrhage remains a leading cause of maternal mortality with more than 140,000 deaths annually worldwide. Abnormal placentation has increased to become the most common diagnosis requiring massive blood transfusion in obstetrics, with uterine atony a close second. At our institution, as well as nationwide, there has been a steady increase in pregnancies complicated by abnormal placentation, including accreta, increta, and percreta. Providers at our facility created the New England Center for Placental Disorders in May 2015 to address these complex patients. The incidence of accreta has actually increased 10-fold over the past 50 years, becoming the most common reason for cesarean hysterectomy in highly industrialized countries. The most common risk factor for accreta is repeat cesarean sections, particularly those with associated placenta previa. Contemporary cesarean section rates have risen, with more than 1.2 million women having had a cesarean section in the United States in 2014. We present a case vignette of a multiparous woman presenting with heavy vaginal bleeding at 30 weeks' gestation with imaging concerning for placenta accreta and possible percreta. We describe our approach to the management of these complicated patients. PMID- 27488385 TI - Effect of eliminating open defecation on diarrhoeal morbidity: an ecological study of Nyando and Nambale sub-counties, Kenya. AB - BACKGROUND: Defecating in the open predisposes people to soil transmitted helminthes and diarrhoeal diseases. An estimated 5.6 million Kenyans defecate in the open. Kenya launched a program to eradicate open defecation by 2013 in the rural areas. By end of 2013, only two sub-counties had eliminated open defecation. These are Nambale and Nyando. The study looked at the impact of eradicating open defecation on diarrhea prevalence among children in these two sub-counties. METHODS: Data on diarrhoea morbidity among children under 5 years was extracted from the Kenya Health Information System for all the sub-counties in Busia and Kisumu counties for 2012, 2013 and 2014 respectively. Prevalence was calculated for each sub-county in Kisumu for comparison with Nyando's. Prevalence was also calculated for each sub-county in Busia County and compared to that of Nambale sub-county. A Mann-Whitney U Test was done to test the null hypothesis that diarrhoea prevalence was similar in both open defecation and open defecation free sub-counties. RESULTS: A Mann-Whitney U Test revealed significant difference in diarrhoeal prevalence of open defecation sub-counties (Md = 18.4, n = 34) and open defecation free sub-counties (Md = 9.8, n = 5), U = 9, z = -3.2, p = .001. Among the two Counties, Nambale had the lowest prevalence. It recorded a decline from 9.8 to 5.7 % across the three years. Prevalence for diarrhoea cases in Nyando declined from 19.1 to 15.2 % across the three years. Nyando initially had the second highest prevalence in Kisumu County and by 2014 it had the lowest prevalence. CONCLUSIONS: The two sub-counties with open defecation free status had lower prevalence of diarrhoea cases compared to sub-counties which were yet to attain open defecation free status. This suggests that elimination of open defecation may reduce the number of diarrhoea cases. PMID- 27488386 TI - A comparison of different functions for predicted protein model quality assessment. AB - In protein structure prediction, a considerable number of models are usually produced by either the Template-Based Method (TBM) or the ab initio prediction. The purpose of this study is to find the critical parameter in assessing the quality of the predicted models. A non-redundant template library was developed and 138 target sequences were modeled. The target sequences were all distant from the proteins in the template library and were aligned with template library proteins on the basis of the transformation matrix. The quality of each model was first assessed with QMEAN and its six parameters, which are C_beta interaction energy (C_beta), all-atom pairwise energy (PE), solvation energy (SE), torsion angle energy (TAE), secondary structure agreement (SSA), and solvent accessibility agreement (SAE). Finally, the alignment score (score) was also used to assess the quality of model. Hence, a total of eight parameters (i.e., QMEAN, C_beta, PE, SE, TAE, SSA, SAE, score) were independently used to assess the quality of each model. The results indicate that SSA is the best parameter to estimate the quality of the model. PMID- 27488387 TI - Catalytic asymmetric bromochlorination of aromatic allylic alcohols promoted by multifunctional Schiff base ligands. AB - It was found that the tridentate O,N,O-type Schiff base ligand bearing suitable substituents was a highly effective promoter in the catalytic asymmetric bromochlorination reaction, in which the corresponding aromatic bromochloroalcohols with vicinal halogen-bearing stereocenters were formed with perfect regioselectivity, with moderate to excellent enantioselectivities (up to 93% ee), and with good yields and chemoselectivities. PMID- 27488388 TI - Adherence to antidepressants among women and men described with trajectory models: a Swedish longitudinal study. AB - PURPOSE: The purpose of this study are to analyse adherence to antidepressant treatment over 2 years in Sweden among women and men who initiated treatment with citalopram and to identify groups at risk of non-adherence using trajectory models. METHODS: The study population, including individuals 18-85 years who initiated citalopram use between 1 July 2006 and 30 June 2007, was identified in the Swedish Prescribed Drug Register and followed for 2 years. Adherence was estimated with continuous measure of medication acquisition (CMA) and group-based trajectory modelling, a method which describes adherence patterns over time by estimating trajectories of adherence and the individual's probability of belonging to a specific trajectory. RESULTS: The study population included 54,248 individuals, 64 % women. Mean CMA was 52 % among women and 50 % among men (p < 0.001). Five different adherence patterns (Trajectories) were identified. Similar proportion of women and men belonged to each Trajectory. Around 29 % of the women and 27 % of the men belonged to the Trajectory which showed full adherence throughout the 2-year study period. The other four Trajectories showed adherence that declined to different degrees and at different stages in time. Having low socioeconomic status was more common among individuals in Trajectories showing declining adherence than in the adherent Trajectory. CONCLUSIONS: Using trajectory modelling, five Trajectories describing different patterns of adherence to citalopram treatment over time were identified. A large proportion discontinued treatment early and having low socioeconomic status increased the risk of being non-adherent. PMID- 27488389 TI - Influence of genetic polymorphisms in cytochrome P450 oxidoreductase on the variability in stable warfarin maintenance dose in Han Chinese. AB - PURPOSE: The aim of this study was to investigate whether any of the single nucleotide polymorphisms (SNPs) in the POR gene were significantly associated with CYP activity and expression, and could contribute to the total variability in stable warfarin maintenance doses in Han Chinese. METHODS: A total of 408 patients treated at the First Affiliated Hospital of Sun Yat-Sen University were eligible for the study and had attained a stable warfarin maintenance dose at the start of the investigation. Demographics, warfarin maintenance doses, and concomitant medications were documented. Genomic DNA was extracted from peripheral blood samples and genotyped for ten SNPs (CYP 2C9*2 and *3, CYP4F2 rs2108622, VKORC1 -1639C>T, and potential POR genes of rs10239977, rs3815455, rs41301394, rs56256515, rs1057868, and rs2286823) using the Sequenom MassARRAY genotyping system. RESULTS: A predictive model of warfarin maintenance dose was established and indicated that age, gender, body surface area, aspirin use, CYP2C9*3, CYP4F2 rs2108622, VKORC1 -1639C>T, and POR*37 831-35C>T accounted for 42.4 % of dose variance in patients undergoing anticoagulant treatment. The contribution of POR*37 831-35C>T to warfarin dose variation was only 3.9 %. CONCLUSIONS: For the first time, the SNP POR*37 831-35C>T was confirmed as a minor but statistically significant factor associated with interindividual variation in warfarin maintenance dose in Han Chinese. The POR*37 gene polymorphism should be considered in future algorithms for faster and more reliable achievement of stable warfarin maintenance doses. PMID- 27488390 TI - The GOOD life: Study protocol for a social norms intervention to reduce alcohol and other drug use among Danish adolescents. AB - BACKGROUND: It is currently unknown if school-based social norms interventions are effective in preventing harmful alcohol consumption and other drug use among adolescents in Denmark. This paper describes the social norms-based programme The GOOD life and the design of a cluster-randomized controlled trial to test its effectiveness. METHODS/DESIGN: The intervention The GOOD life is composed of three social norms components representing three different communication channels, namely face-to-face communication (normative feedback session), print communication (posters) and interactive media (web application). The intervention period of 8 weeks is preceded and followed by data collection, with the follow-up taking place 3 months after baseline. Public schools in the Region of Southern Denmark with grades 8 and 9 are invited to participate in the study and participating schools are randomly allocated to either intervention or control schools. The aim is to recruit a total of 39 schools and a sample of 1.400 pupils for the trial. An online questionnaire is conducted to examine the use of alcohol, tobacco and marijuana as well as the perceived frequency of use among peers of their own grade, which is measured before and after the intervention. Baseline data is used to develop social norms messages which are included in the three intervention components. Primary outcomes are binge drinking (more than 5 units at one occasion) and perceived frequency of binge drinking among peers, while smoking, marijuana use and alcohol-related harm will be assessed as secondary outcomes. DISCUSSION: The GOOD life study will provide necessary insights on descriptive and injunctive norms regarding alcohol and other drug use among Danish adolescents. In addition, it will provide new knowledge and insight on the feasibility, implementation context and effectiveness of a newly developed social norms intervention in the Danish school context. TRIAL REGISTRATION: Date of registration: 17 February 2016 (retrospectively registered) at Current Controlled Trials with study ID ISRCTN27491960. PMID- 27488391 TI - Multi-organ benign and malignant tumors: recognizing Cowden syndrome: a case report and review of the literature. AB - BACKGROUND: Cowden syndrome is an autosomal dominant disorder with a predisposition to multiple benign and malignant tumors. In our patient, in addition to breast and endometrial malignancies as well as facial trichilemmomas, she was noted to have multiple meningiomas, pancreatic lipomas and lung cysts. These latter lesions have been noted in previous Cowden syndrome case reports, but are not included in the diagnostic criteria at this time. To our knowledge, this is the first case of multiple meningiomas in this syndrome. Further studies are therefore warranted to assess the significance of these findings in Cowden syndrome. CASE PRESENTATION: A middle-aged Afro-Caribbean known endometrial carcinoma patient (post surgery and adjuvant radiotherapy), presented with a locally advanced breast carcinoma. She received neoadjuvant chemotherapy followed by a modified radical mastectomy and axillary lymph node clearance. Her past medical history included a sphenoid wing meningioma for which she received definitive external beam radiotherapy. She was also known to have a multinodular goiter, anal polyp and longstanding mucocutaneous lesions. Further workup revealed additional smaller meningiomas, a parotid arteriovenous malformation, a lung cyst and pancreatic lipomas. Overall, consortium criteria were met for the diagnosis of Cowden syndrome. Furthermore, genetic testing identified a pathogenic mutation in the PTEN gene. She will be closely followed with annual clinical examination, dermatologic assessment and screening colonoscopies. She will perform interval whole body contrast enhanced CT for continued surveillance for metastatic disease. CONCLUSION: Cowden syndrome is likely to be an under diagnosed condition, but critically important to identify due to its cancer predisposition. When encountering multi-organ tumors, diagnostic criteria for Cowden syndrome should be sought in order to increase the diagnostic rates. Cancer surveillance for carcinoma detection in the early and curative stages remains the most critical aspect of management. PMID- 27488392 TI - Cognitive Bias Modification Training During Inpatient Alcohol Detoxification Reduces Early Relapse: A Randomized Controlled Trial. AB - BACKGROUND: Relapse is common in alcohol-dependent individuals and can be triggered by alcohol-related cues in the environment. It has been suggested that these individuals develop cognitive biases, in which cues automatically capture attention and elicit an approach action tendency that promotes alcohol seeking. The study aim was to examine whether cognitive bias modification (CBM) training targeting approach bias could be delivered during residential alcohol detoxification and improve treatment outcomes. METHODS: Using a 2-group parallel block (ratio 1:1) randomized controlled trial with allocation concealed to the outcome assessor, 83 alcohol-dependent inpatients received either 4 sessions of CBM training where participants were implicitly trained to make avoidance movements in response to pictures of alcoholic beverages and approach movements in response to pictures of nonalcoholic beverages, or 4 sessions of sham training (controls) delivered over 4 consecutive days during the 7-day detoxification program. The primary outcome measure was continuous abstinence at 2 weeks postdischarge. Secondary outcomes included time to relapse, frequency and quantity of alcohol consumption, and craving. Outcomes were assessed in a telephonic follow-up interview. RESULTS: Seventy-one (85%) participants were successfully followed up, of whom 61 completed all 4 training sessions. With an intention-to-treat approach, there was a trend for higher abstinence rates in the CBM group relative to controls (69 vs. 47%, p = 0.07); however, a per-protocol analysis revealed significantly higher abstinence rates among participants completing 4 sessions of CBM relative to controls (75 vs. 45%, p = 0.02). Craving score, time to relapse, mean drinking days, and mean standard drinks per drinking day did not differ significantly between the groups. CONCLUSIONS: This is the first trial demonstrating the feasibility of CBM delivered during alcohol detoxification and supports earlier research suggesting it may be a useful, low cost adjunctive treatment to improve treatment outcomes for alcohol-dependent patients. PMID- 27488393 TI - Solution NMR structures of the C-domain of Tetrahymena cytoskeletal protein Tcb2 reveal distinct calcium-induced structural rearrangements. AB - Tcb2 is a calcium-binding protein that localizes to the membrane-associated skeleton of the ciliated protozoan Tetrahymena thermophila with hypothesized roles in ciliary movement, cell cortex signaling, and pronuclear exchange. Tcb2 has also been implicated in a unique calcium-triggered, ATP-independent type of contractility exhibited by filamentous networks isolated from the Tetrahymena cytoskeleton. To gain insight into Tcb2's structure-function relationship and contractile properties, we determined solution NMR structures of its C-terminal domain in the calcium-free and calcium-bound states. The overall architecture is similar to other calcium-binding proteins, with paired EF-hand calcium-binding motifs. Comparison of the two structures reveals that Tcb2-C's calcium-induced conformational transition differs from the prototypical calcium sensor calmodulin, suggesting that the two proteins play distinct functional roles in Tetrahymena and likely have different mechanisms of target recognition. Future studies of the full-length protein and the identification of Tcb2 cellular targets will help establish the molecular basis of Tcb2 function and its unique contractile properties. Proteins 2016; 84:1748-1756. (c) 2016 Wiley Periodicals, Inc. PMID- 27488394 TI - Effect of ramosetron on QTc interval: a randomised controlled trial in patients undergoing off-pump coronary artery bypass surgery. AB - BACKGROUND: Ramosetron is a relatively new 5-hydroxytryptamine three receptor antagonist with higher binding affinity and more prolonged duration of action compared to ondansetron. The present study was performed to evaluate the effects of ramosetron on QTc interval and possible cardiovascular adverse effects in patients undergoing cardiac surgery. METHOD: A total of 114 patients who underwent off-pump coronary artery bypass surgery were enrolled in this randomised placebo-controlled trial. Patients were allocated into two groups that received intravenous injection of 0.3 mg ramosetron or normal saline during induction of anaesthesia. QTc intervals were measured before the operation, intraoperatively (0, 1, 2, 3, 5, 10, 15, 30, 45, 60, 90, 120, and 240 min after injection of ramosetron or normal saline), at the end of the operation, and on postoperative day 1. RESULTS: There were no differences in mean QTc interval between groups at every time point. However, maximal change in QTc interval during surgery was higher in the ramosetron group than the placebo group (25.1 +/ 22.0 vs. 17.5 +/- 14.5 ms, 95 % CI 0.34-14.78, P = 0.040). Also, there were more patients with a QTc interval increase of > 60 ms in the ramosetron group (5 vs. 0, 95 % CI 1.6-18.0, P = 0.021). There were no significant differences in cardiovascular complications. CONCLUSIONS: Ramosetron administered during induction of anaesthesia may affect maximal change in QTc interval during off pump coronary artery bypass surgery. Ramosetron should be used with caution in high risk patients for developing Torsades de Pointes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02139241. Registered November 12, 2013. PMID- 27488395 TI - DEF6 expression in ovarian carcinoma correlates with poor patient survival. AB - BACKGROUND: Increased expression of DEF6 is correlated with the malignant behavior of various cancers. Both DEF6 and p16 contribute to the regulation of cell cycle progression, and p53 plays important role in the cell cycle checkpoints. This study was designed to elucidate the prognostic significance of DEF6, p53 and p16 immunoexpressions in different histology subtypes of ovarian carcinoma. METHODS: Immunohistochemistry results of DEF6, p53 and p16 on ovarian carcinoma were compared with histology subtypes, clinical data, overall survival (OS) and disease-free survival (DFS) by Cox regression and Kaplan-Meier analysis. RESULTS: We studied 180 cases of ovarian carcinomas (75 high-grade serous, 41 clear cell, 36 mucinous and 28 endometrioid), including 109 FIGO stage I-II cases and 71 FIGO stage III-IV cases. Ovarian carcinomas positive for both DEF6 and p16 expression were associated with the worst OS (P = 0.027) and DFS (P = 0.023), whereas those negative for both DEF6 and p16 had the best OS and DFS. Aberrant p53 expression combined with positive DEF6 was associated with worst OS (P = 0.031) and DFS (P = 0.028). Kaplan-Meier analysis showed that significantly shorter survival rates were seen in patients with high expressions of DEF6 (P = 0.008) and p16 (P = 0.022). Patients with aberrant p53 expression in high-grade serous carcinoma (P = 0.012) and patients with high DEF6 expression in clear cell carcinoma (P = 0.001) were also associated with shorter overall survival. In univariate analysis, FIGO stage, DEF6 and p16 were associated with poor prognosis. DEF6 expression was the only independent prognostic factor correlated with shorted OS (HR 2.115; P = 0.025) and DFS (HR 2.248; P = 0.016) upon multivariate analysis. CONCLUSIONS: DEF6 expression may serve as an independent prognostic factor, and interacted positively with p16 toward high tumor stage and shorter survival. PMID- 27488396 TI - The potential of chondrogenic pre-differentiation of adipose-derived mesenchymal stem cells for regeneration in harsh nucleus pulposus microenvironment. AB - Recent studies indicated that cell-based therapy could be a promising approach to treat intervertebral disc degeneration. Though the harsh microenvironment in disc is still challenging to implanted cells, it could be overcome by pre-conditioning graft cells before transplantation, suggested by previous literatures. Therefore, we designed this study to identify the potential effect of chondrogenic pre differentiation on adipose-derived mesenchymal stem cells in intervertebral disc like microenvironment, characterized by limited nutrition, acidic, and high osmosis in vitro. Adipose-derived mesenchymal stem cells of rat were divided into five groups, embedded in type II collagen scaffold, and cultured in chondrogenic differentiation medium for 0, 3, 7, 10, and 14 days. Then, the adipose-derived mesenchymal stem cells were implanted and cultured in intervertebral disc-like condition. The proliferation and differentiation of adipose-derived mesenchymal stem cells were evaluated by cell counting kit-8 test, real-time quantitative polymerase chain reaction, and Western blotting and immunofluorescence analysis. Analyzed by the first week in intervertebral disc-like condition, the results showed relatively greater proliferative capability and extracellular matrix synthesis ability of the adipose-derived mesenchymal stem cells pre differentiated for 7 and 10 days than the control. We concluded that pre differentiation of rat adipose-derived mesenchymal stem cells in chondrogenic culture medium for 7 to 10 days could promote the regeneration effect of adipose derived mesenchymal stem cells in intervertebral disc-like condition, and the pre differentiated cells could be a promising cell source for disc regeneration medicine. PMID- 27488397 TI - GSK and Google form partnership to develop bioelectronic medicines. PMID- 27488398 TI - Investigation of cobalt(iii)-triazole systems as prototypes for hypoxia-activated drug delivery. AB - Three novel cobalt(iii)-triazole complexes with structural and redox properties suitable for hypoxia-activated drug delivery were obtained. A major influence of the ancillary ligands (TPA, py2en, py2enMe2) on the electronic properties and reactivity of their complexes was observed. An [O2]-dependent reduction to cobalt(ii) by ascorbic acid provided evidence of hypoxic selectivity. PMID- 27488399 TI - Monocytes and Macrophages: A Fresh Look at Functional and Phenotypic Diversity. AB - This Forum addresses the functional and phenotypical diversity of monocytes and macrophages and explores new mechanisms that contribute to the plasticity of these cells. The contributors provide in-depth and comprehensive overviews on selected key mechanisms underlying macrophage plasticity and diversity and how they related to human disease and aging. What emerges from these contributions is the importance of the interactions of macrophages with their dynamic microenvironment and the need for a better mechanistic understanding of how these cells sense environmental cues, integrate and respond to these signals, and thereby themselves help shape their microenvironment. Antioxid. Redox Signal. 25, 756-757. PMID- 27488400 TI - Where do you come from and what are you going to become, reactive astrocyte? PMID- 27488401 TI - Genotype Frequencies of CYP2C19, P2Y12 and GPIIIa Polymorphisms in Coronary Heart Disease Patients of Han Ethnicity, and Their Impact on Clopidogrel Responsiveness. AB - To investigate the genotype frequencies of cytochrome P450, family2, subfamily C, polypeptide19 (CYP2C19); P2Y12 receptor; and glycoprotein IIIa polymorphisms in patients with coronary heart disease and their impact on clopidogrel responsiveness and major adverse cardiac events (MACEs).A total of 146 coronary heart disease patients of Han ethnicity, on a clopidogrel regimen, were enrolled. Polymerase chain reaction and DNA sequencing were used to detect the genotype and allelic frequencies of CYP2C19 ((*)2,(*)3,(*)17), P2Y12 (C34T, G52T, T744C) and GPIIIa (T1565C) polymorphisms. Clinical and laboratory data were compared between the high on-treatment platelet reactivity (HTPR) versus normal groups.HTPR was identified in 35 (24%) patients. CYP2C19(*)2 (G681A) polymorphism was found to be significantly associated with HTPR (P < 0.05). A allele frequencies were significantly higher in the HTPR group versus the normal group (P < 0.05). On logistic regression analysis, CYP2C19(*)2 (G681A) polymorphism was found to be an independent risk factor associated with HTPR. No link could be established between genetic polymorphisms and recurrence of MACEs, or between HTPR and recurrence of MACEs.The genetic polymorphisms in CYP2C19(*)2 were closely associated with HTPR. The frequency of the A allele of CYP2C19(*)2 was significantly associated with HTPR, with A allele carriers being more likely to develop HTPR. PMID- 27488404 TI - Health Concept and Knowledge Management: Twenty-five Years of Evolution. AB - OBJECTIVES: The fields of health terminology, classification, ontology, and related information models have evolved dramatically over the past 25 years. Our objective was to review notable trends, described emerging or enabling technologies, and highlight major terminology systems during the interval. METHODS: We review the progression in health terminology systems informed by our own experiences as part of the community involved in this work, reinforced with literature review and citation. RESULTS: The transformation in size, scope, complexity, and adoption of health terminological systems and information models has been tremendous, on the scale of orders of magnitude. CONCLUSION: The present "big science" era of inference and discovery in biomedicine would not have been possible or scalable absent the growth and maturation of health terminology systems and information models over the past 25 years. PMID- 27488403 TI - Progress in Biomedical Knowledge Discovery: A 25-year Retrospective. AB - OBJECTIVES: We sought to explore, via a systematic review of the literature, the state of the art of knowledge discovery in biomedical databases as it existed in 1992, and then now, 25 years later, mainly focused on supervised learning. METHODS: We performed a rigorous systematic search of PubMed and latent Dirichlet allocation to identify themes in the literature and trends in the science of knowledge discovery in and between time periods and compare these trends. We restricted the result set using a bracket of five years previous, such that the 1992 result set was restricted to articles published between 1987 and 1992, and the 2015 set between 2011 and 2015. This was to reflect the current literature available at the time to researchers and others at the target dates of 1992 and 2015. The search term was framed as: Knowledge Discovery OR Data Mining OR Pattern Discovery OR Pattern Recognition, Automated. RESULTS: A total 538 and 18,172 documents were retrieved for 1992 and 2015, respectively. The number and type of data sources increased dramatically over the observation period, primarily due to the advent of electronic clinical systems. The period 1992- 2015 saw the emergence of new areas of research in knowledge discovery, and the refinement and application of machine learning approaches that were nascent or unknown in 1992. CONCLUSIONS: Over the 25 years of the observation period, we identified numerous developments that impacted the science of knowledge discovery, including the availability of new forms of data, new machine learning algorithms, and new application domains. Through a bibliometric analysis we examine the striking changes in the availability of highly heterogeneous data resources, the evolution of new algorithmic approaches to knowledge discovery, and we consider from legal, social, and political perspectives possible explanations of the growth of the field. Finally, we reflect on the achievements of the past 25 years to consider what the next 25 years will bring with regard to the availability of even more complex data and to the methods that could be, and are being now developed for the discovery of new knowledge in biomedical data. PMID- 27488406 TI - Number of negative lymph nodes as a prognostic factor in esophageal squamous cell carcinoma. AB - INTRODUCTION: The aim of this study is to investigate the number of negative lymph nodes (NLNs) as a prognostic factor for survival in patients with resected esophageal squamous cell carcinoma. METHODS: A total of 381 esophageal squamous cell carcinoma patients who had underwent surgical resection as the primary treatment was enrolled into this retrospective study. The impact of number of NLNs on patient's overall survival was assessed and compared with the factors among the current tumor-nodes-metastasis (TNM) staging system. RESULTS: The number of NLNs was closely related to the overall survival, and the 5-year survival rate was 45.4% for number of NLNs of >20 (142 cases) and 26.4% for NLNs <= 20 (239 cases) (P = 0.001). In multivariate survival analysis, the number of NLNs remained an independent prognostic factor (P = 0.002) as did the other current TNM factors. For subgroup analysis, the predictive value of number of NLNs was significant in patients with T3 or T4 disease (P = 0.001) and patients with N1 and N2-3 disease (P = 0.025, 0.043), but not in patients with T1 or T2 disease or patients with N0 disease. CONCLUSIONS: The number of NLNs, which represents the extent of lymphadenectomy for esophageal squamous cell carcinoma, could impact the overall survival of patients with resected esophageal squamous cell carcinoma, especially among those with nodal-positive disease and advanced T stage tumor. PMID- 27488402 TI - Clinical Decision Support: a 25 Year Retrospective and a 25 Year Vision. AB - OBJECTIVE: The objective of this review is to summarize the state of the art of clinical decision support (CDS) circa 1990, review progress in the 25 year interval from that time, and provide a vision of what CDS might look like 25 years hence, or circa 2040. METHOD: Informal review of the medical literature with iterative review and discussion among the authors to arrive at six axes (data, knowledge, inference, architecture and technology, implementation and integration, and users) to frame the review and discussion of selected barriers and facilitators to the effective use of CDS. RESULT: In each of the six axes, significant progress has been made. Key advances in structuring and encoding standardized data with an increased availability of data, development of knowledge bases for CDS, and improvement of capabilities to share knowledge artifacts, explosion of methods analyzing and inferring from clinical data, evolution of information technologies and architectures to facilitate the broad application of CDS, improvement of methods to implement CDS and integrate CDS into the clinical workflow, and increasing sophistication of the end-user, all have played a role in improving the effective use of CDS in healthcare delivery. CONCLUSION: CDS has evolved dramatically over the past 25 years and will likely evolve just as dramatically or more so over the next 25 years. Increasingly, the clinical encounter between a clinician and a patient will be supported by a wide variety of cognitive aides to support diagnosis, treatment, care-coordination, surveillance and prevention, and health maintenance or wellness. PMID- 27488405 TI - Biomedical and Health Informatics Education - the IMIA Years. AB - OBJECTIVE: This paper presents the development of medical informatics education during the years from the establishment of the International Medical Informatics Association (IMIA) until today. METHOD: A search in the literature was performed using search engines and appropriate keywords as well as a manual selection of papers. The search covered English language papers and was limited to search on papers title and abstract only. RESULTS: The aggregated papers were analyzed on the basis of the subject area, origin, time span, and curriculum development, and conclusions were drawn. CONCLUSIONS: From the results, it is evident that IMIA has played a major role in comparing and integrating the Biomedical and Health Informatics educational efforts across the different levels of education and the regional distribution of educators and institutions. A large selection of references is presented facilitating future work on the field of education in biomedical and health informatics. PMID- 27488408 TI - Disruption of YLR162W in Saccharomyces cerevisiae results in increased tolerance to organic solvents. AB - OBJECTIVE: To identify a novel gene responsible for organic solvent-tolerance by screening a transposon-mediated deletion mutant library based on Saccharomyces cerevisiae L3262. RESULTS: One strain tolerant of up to 0.5 % (v/v) n-hexane and cyclohexane was isolated. The determination of transposon insertion site identified one gene, YLR162W, and revealed disruption of the ORF of this gene, indicating that organic solvent tolerance can be conferred. Such a tolerant phenotype reverted to the sensitive phenotype on the autologous or overexpression of this gene. This transposon mutant grew faster than the control strain when cultured at 30 degrees C in YPD medium containing 0.5 % (v/v) n-hexane and cyclohexane respectively. CONCLUSION: Disruption of YLR162W in S. cerevisiae results in increased tolerance to organic solvents. PMID- 27488409 TI - Erratum to: In Vitro Methods for Studying the Mechanisms of Resistance to DNA Damaging Therapeutic Drugs. PMID- 27488410 TI - Case report: small cell transformation and metastasis to the breast in a patient with lung adenocarcinoma following maintenance treatment with epidermal growth factor receptor tyrosine kinase inhibitors. AB - BACKGROUND: Breast metastasis from lung cancer has been reported, but not from SCLC that is transformed from lung adenocarcinoma during maintenance treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Transformation to small cell lung cancer(SCLC), although uncommonly seen, has been associated with resistance to EGFR-TKI therapy in lung adenocarcinomas. CASE PRESENTATION: We describe a case of a 49-year-old man with lung adenocarcinoma harboring L858R point mutation at the exon 21 of the epidermal growth factor receptor (EGFR). During the maintenance treatment with EGFR-TKI, the patient presented with a right breast mass, which was accompanied by elevated serum neuron specific enolase (NSE) level. The histological examination of biopsies from the breast mass and enlarging lung mass revealed SCLC that was less sensitive to standard SCLC treatment. The breast tumor was positive for thyroid transcription factor-1 (TTF-1), consistent with a lung primary cancer. CONCLUSION: This is the first case report of small cell transformation and metastatic to the breast in a patient with lung adenocarcinoma following EGFR-TKI treatment. Repeat biopsy is important for evaluation of evolving genetic and histologic changes and selection of appropriate treatment. and serum NSE measurement may be useful for detection of small cell transformation in cases with resistance to EGFR-TKI therapy. PMID- 27488411 TI - Cool Runnings - an app-based intervention for reducing hot drink scalds: study protocol for a randomised controlled trial. AB - BACKGROUND: Globally, burns are the fifth leading cause of non-fatal children's injuries, and the leading cause of childhood burns is hot beverage scalds. Although there have been a number of programmes aimed at preventing scalds in children, very few have specifically addressed hot beverage scalds, and fewer have reported a reduction in injury rates. In Australia, hot beverage scalds account for 18 % of all childhood burns - a figure that has remained constant for the past decade. Innovative new technologies, such as Smartphone applications (apps), present a novel way for delivering individual-level injury prevention messages. The low cost, scalability and broad reach make this technology an ideal channel for health interventions. One of the latest methods being used in health related apps aimed at behaviour change is gamification. Gamification uses the gaming principles of rewards, competition and personalisation to engage participants and motivate them towards preferred behaviours. This intervention will use a Smartphone app-based platform that combines gamification and behaviour change strategies to increase knowledge and awareness of hot beverage scald risks and burn first aid among mothers of young children. METHODS/DESIGN: This is a two group, parallel, single-blinded randomised control trial (RCT) to evaluate the efficacy of a Smartphone app-based injury prevention intervention. The primary outcome measure is change in knowledge. Change in knowledge is measured in three components: knowledge of correct burns first aid; knowledge of the main cause of burns/scalds in children aged 0-15yrs; knowledge of the main age group at risk for burns/scalds. The secondary outcome measures relate to the gamification methods, measuring participants frequency of engagement with the Cool Runnings app. Queensland-based mothers aged 18+ years who own a Smartphone and have at least one child aged 5-12 months are eligible to participate. DISCUSSION: To our knowledge, this is the first study to evaluate an app-based delivery of injury prevention messages, and the first study to test the efficacy of gamification techniques in an injury prevention intervention. If this intervention is found to be effective, this RCT will provide a platform for targeting other childhood injury prevention campaigns. TRIAL REGISTRATION: This trial was registered on 14 January 2016 with the Australian New Zealand Clinical Trials Registry ( ACTRN12616000019404 ). PMID- 27488412 TI - Implementation challenges in delivering team-based care ('TEAMcare') for patients with chronic obstructive pulmonary disease in a public hospital setting: a mixed methods approach. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is considered a multisystem disease, in which comorbidities feature prominently. COPD guidelines recommend holistic assessment and management of relevant comorbid diseases but there is limited information as to how this is best achieved. This pilot study aimed to explore the views of stakeholders, including patients and the healthcare team, on the feasibility, acceptability and barriers to a collaborative, multidisciplinary team-based care intervention ('TEAMcare') to improve health outcomes in COPD patients, within the context of a local hospital outpatient clinic. METHODS: A mixed methods study design was used. A COPD care algorithm was developed based on the Australasian guidelines, COPDX. COPD participants were consecutively recruited from an outer metropolitan hospital's respiratory clinic. Participants attended for follow up visits at 5 and 10 months to ascertain clinical status, algorithm compliance and to review and revise management recommendations. The intervention was conducted using existing resources, involving collaboration with general practice and the publicly-funded local chronic disease management programme (Medicare Local). Stakeholders provided qualitative feedback about the intervention in terms of feasibility, acceptability and barriers via structured and semi-structured interviews. All interviews were recorded, transcribed verbatim and analysed using qualitative thematic analysis to identify key concepts and themes. RESULTS: The study protocol was abandoned prematurely due to clear lack of feasibility. Of 12 participants, 4 withdrew and none completed pulmonary rehabilitation (PR). The main reasons for non-participation or study withdrawal related to reluctance to attend PR (6 of 16) and the burden of increased appointments (4 of 16). PR conflicted with employment hours, which presented problems for some participants. Similarly, themes that emerged from qualitative data indicate healthcare provider perception of deficiencies in funding (for infrastructure and staffing). Health literacy, motivation, organisation and functional impairment were issues for patients. CONCLUSIONS: Available data from this small pilot provided valuable insights to inform future design and implementation strategies. Delivering structured team-based care to COPD patients presents challenges. In addition to enhancing health resources for engaging COPD patients, a focus on health literacy and improving health service access, including colocalisation and access outside business hours, may be required. TRIAL REGISTRATION: ACTRN12616000342415 ; 16/03/2016. PMID- 27488413 TI - Isoforms of the Erythropoietin receptor in dopaminergic neurons of the Substantia Nigra. AB - Erythropoietin receptor (EpoR) regulates erythrocytes differentiation in blood. In the brain, EpoR has been shown to protect several neuronal cell types from cell death, including the A9 dopaminergic neurons (DA) of the Substantia Nigra (SN). These cells form the nigrostriatal pathway and are devoted to the control of postural reflexes and voluntary movements. Selective degeneration of A9 DA neurons leads to Parkinson's disease. By the use of nanoCAGE, a technology that allows the identification of Transcription Start Sites (TSSs) at a genome-wide level, we have described the promoter-level expression atlas of mouse A9 DA neurons purified with Laser Capture Microdissection (LCM). Here, we identify mRNA variants of the Erythropoietin Receptor (DA-EpoR) transcribed from alternative TSSs. Experimental validation and full-length cDNA cloning is integrated with gene expression analysis in the FANTOM5 database. In DA neurons, the EpoR gene encodes for a N-terminal truncated receptor. Based on STAT5 phosphorylation assays, we show that the new variant of N-terminally truncated EpoR acts as decoy when co-expressed with the full-length form. A similar isoform is also found in human. This work highlights new complexities in the regulation of Erythropoietin (EPO) signaling in the brain. PMID- 27488414 TI - The masculinity paradox: facial masculinity and beardedness interact to determine women's ratings of men's facial attractiveness. AB - In many species, male secondary sexual traits have evolved via female choice as they confer indirect (i.e. genetic) benefits or direct benefits such as enhanced fertility or survival. In humans, the role of men's characteristically masculine androgen-dependent facial traits in determining men's attractiveness has presented an enduring paradox in studies of human mate preferences. Male-typical facial features such as a pronounced brow ridge and a more robust jawline may signal underlying health, whereas beards may signal men's age and masculine social dominance. However, masculine faces are judged as more attractive for short-term relationships over less masculine faces, whereas beards are judged as more attractive than clean-shaven faces for long-term relationships. Why such divergent effects occur between preferences for two sexually dimorphic traits remains unresolved. In this study, we used computer graphic manipulation to morph male faces varying in facial hair from clean-shaven, light stubble, heavy stubble and full beards to appear more (+25% and +50%) or less (-25% and -50%) masculine. Women (N = 8520) were assigned to treatments wherein they rated these stimuli for physical attractiveness in general, for a short-term liaison or a long-term relationship. Results showed a significant interaction between beardedness and masculinity on attractiveness ratings. Masculinized and, to an even greater extent, feminized faces were less attractive than unmanipulated faces when all were clean-shaven, and stubble and beards dampened the polarizing effects of extreme masculinity and femininity. Relationship context also had effects on ratings, with facial hair enhancing long-term, and not short-term, attractiveness. Effects of facial masculinization appear to have been due to small differences in the relative attractiveness of each masculinity level under the three treatment conditions and not to any change in the order of their attractiveness. Our findings suggest that beardedness may be attractive when judging long-term relationships as a signal of intrasexual formidability and the potential to provide direct benefits to females. More generally, our results hint at a divergence of signalling function, which may result in a subtle trade-off in women's preferences, for two highly sexually dimorphic androgen-dependent facial traits. PMID- 27488415 TI - Smoking, physical inactivity and obesity as predictors of healthy and disease free life expectancy between ages 50 and 75: a multicohort study. AB - BACKGROUND: Smoking, physical inactivity and obesity are modifiable risk factors for morbidity and mortality. The aim of this study was to examine the extent to which the co-occurrence of these behaviour-related risk factors predict healthy life expectancy and chronic disease-free life expectancy in four European cohort studies. METHODS: Data were drawn from repeated waves of four cohort studies in England, Finland, France and Sweden. Smoking status, physical inactivity and obesity (body mass index >=30 kg/m2) were examined separately and in combination. Health expectancy was estimated by using two health indicators: suboptimal self rated health and having a chronic disease (cardiovascular disease, cancer, respiratory disease and diabetes). Multistate life table models were used to estimate sex-specific healthy life expectancy and chronic disease-free life expectancy from ages 50 to 75 years. RESULTS: Compared with men and women with at least two behaviour-related risk factors, those with no behaviour-related risk factors could expect to live on average8 years longer in good health and 6 years longer free of chronic diseases between ages 50 and 75. Having any single risk factor was also associated with reduction in healthy years. No consistent differences between cohorts were observed. CONCLUSIONS: Data from four European countries show that persons with individual and co-occurring behaviour-related risk factors have shorter healthy life expectancy and shorter chronic disease free life expectancy. Population level reductions in smoking, physical inactivity and obesity could increase life-years lived in good health. PMID- 27488416 TI - Using Gini coefficient to determining optimal cluster reporting sizes for spatial scan statistics. AB - BACKGROUND: Spatial and space-time scan statistics are widely used in disease surveillance to identify geographical areas of elevated disease risk and for the early detection of disease outbreaks. With a scan statistic, a scanning window of variable location and size moves across the map to evaluate thousands of overlapping windows as potential clusters, adjusting for the multiple testing. Almost always, the method will find many very similar overlapping clusters, and it is not useful to report all of them. This paper proposes to use the Gini coefficient to help select which of the many overlapping clusters to report. METHODS: The Gini coefficient provides a quick and intuitive way to evaluate the degree of the heterogeneity of the collection of clusters, which is useful to explain how well the cluster collection reveal the underlying true cluster patterns. Using simulation studies and real cancer mortality data, it is compared with the traditional approach for reporting non-overlapping clusters. RESULTS: The Gini coefficient can identify a more refined collection of non-overlapping clusters to report. For example, it is able to determine when it makes more sense to report a collection of smaller non-overlapping clusters versus a single large cluster containing all of them. It also fulfils a set of desirable theoretical properties, such as being invariant under a uniform multiplication of the population numbers by the same constant. CONCLUSIONS: The Gini coefficient can be used to determine which set of non-overlapping clusters to report. It has been implemented in the free SaTScanTM software version 9.3 ( www.satscan.org ). PMID- 27488417 TI - Headache-Specific Locus of Control and Migraine-Related Quality of Life: Understanding the Role of Anxiety. AB - PURPOSE: This cross-sectional study examined the relationship between headache specific locus of control (HSLC) and migraine-related quality of life, and anxiety as a mediator of this relationship. METHOD: Two hundred and thirty-two people with migraine participated in the treatment of severe migraine trial. At baseline, participants completed self-report questionnaires of headache-specific locus of control (HSLC; subscales = internal, chance, and medical professionals), anxiety, and migraine-related quality of life. Correlations examined relationships between HSLC, anxiety, and migraine-related quality of life; ordinary least squares regression evaluated anxiety as a mediator of the relationship between HSLC and migraine-related quality of life. RESULTS: Higher internal HSLC was related to higher overall migraine-related quality of life (ps < .05) and emotion function impairments (p = .012). Anxiety mediated the relationship between internal HSLC and all measures of migraine-specific quality of life (ps < .05). Higher external (medical professionals and chance) HSLC was related to higher migraine-related quality of life impairments (all ps < .001). CONCLUSION: All HSLC beliefs are associated with higher migraine-related quality of life impairments. Anxiety mediates the relationship between internal HSLC and migraine-related quality of life. PMID- 27488418 TI - Interhospital Transfer of Ruptured AAA's for EVAR: Preposterous or Prudent? PMID- 27488419 TI - Every Cloud Has a Silver Lining: Proneurogenic Effects of Abeta Oligomers and HMGB-1 via Activation of the RAGE-NF-kappaB Axis. AB - BACKGROUND & OBJECTIVE: Since its initial discovery, current understanding on the functional role of the Receptor for Advanced Glycation End-products (RAGE) in physiology and in pathology has impressively grown, especially in consideration of its large ligand repertoire (AGEs, HMGB-1, beta amyloid, S100B/S100A12) and its potential involvement in the pathophysiology of several chronic human disorders. Downstream RAGE engagement by its ligands, NF-kappaB signaling activation has been demonstrated in several cell phenotypes, including neurons and glia. Based on the observation that in Alzheimer's Disease (AD) brain expression of RAGE and its ligands is upregulated and that RAGE/NF-kappaB axis activation can trigger an autoregulatory loop which further amplifies neuroinflammation and neurodegeneration, this signaling pathway has been hypothesized to greatly contribute to AD pathophysiology. Herein we review the vast array of information supporting a detrimental role of RAGE/NF-kappaB axis activation in AD brain and discuss those data in the context of recent findings obtained in our laboratory pointing to an unexpected effect elicited by this signaling pathway which may rather contribute to reparative mechanisms in AD, namely positive modulation of adult neurogenesis. Interestingly, the proneurogenic effect resulting from RAGE/NF-kappaB axis activation could be induced by molecules which are commonly considered as mediators of toxicity, like Abeta oligomers and HMGB-1. CONCLUSION: Altogether, despite a large set of data suggesting that RAGE may represent an interesting target for the pharmacological treatment of AD, the complex functional roles of the receptor would require the use of molecules able to counteract RAGE negative effects without altering the positive ones such as the promotion of adult neurogenesis. PMID- 27488420 TI - Comparable Neuroprotective Effects of Pergolide and Pramipexole on Ferrous Sulfate-Induced Dopaminergic Cell Death in Cell Culture. AB - BACKGROUND: Dopamine agonists are utilized clinically as an initial treatment in younger Parkinson's disease patients to delay the side effects associated with commencement of levodopa medication. These agonists also serveas adjunctive therapeutics with levodopa to lower the incidence of adverse motor symptoms in advanced stages of the disease. OBJECTIVES: To compare the neuroprotective effects of the dopamine agonists pergolide and pramipexole on ferrous sulfate induced neurotoxicity in dopaminergic neurons from primary mesencephalic cell culture. METHODS: Pergolide (0.001-1 MUM) and pramipexole (0.01-200 MUM) were administered to 8 day primary murine mesencephalic cultures for 24 h. in the presence or absence of desferal, sulpiride or cycloheximide. Ferrous sulfate (450 MUM) was then added for 24 hrs. Lactate dehydrogenase was assayed in the supernatant, glutathione concentrations measured in cell lysates and fixed cells were stained for tyrosine hydroxylase. RESULTS: Ferrous sulphate induced neurotoxity in cultures (p<0.0001) was abolished in the presence of the iron chelator desferal (p<0.008). Both pergolide (p<0.0001) and pramipexole (p<0.0001) significantly protected dopaminergic neurons against ferrous sulfate induced neurotoxicity and pramipexole helped preserve neurite morphology. Pramipexole treatment significantly reduced lactate dehydrogenase release (p<0.0001) as a measure of cellular injury. The dopamine receptor antagonist sulpiride (p<0.0001) and the protein synthesis inhibitor cycloheximide (p<0.0001) reduced the neuroprotective effects of pergolide indicating the involvement receptor stimulation and de novo protein synthesis in pergolide-mediated neuroprotection. Pramipexole also significantly reversed the decrease in cellular glutathione concentrations induced by ferrous sulfate (p<0.001). CONCLUSION: Both pergolide and pramipexole protect dopaminergic neurons against the neurotoxicity of ferrous sulfate. Pergolide specifically protects dopaminergic neurons through activation of dopamine receptors and de novo protein synthesis whereas pramipexole shows an overall effect through an antioxidant mechanism. PMID- 27488421 TI - Nanomaterials for Neurology: State-of-the-Art. AB - Despite the numerous challenges associated with the application of nanotechnology in neuroscience, it promises to have a significant impact on our understanding of how the nervous system works, how it fails in disease, and the development of earlier and less-invasive diagnostic procedures so we can intervene in the pre clinical stage of neurological disease before extensive neurological damage has taken place. Ultimately, both the challenges and opportunities that nanotechnology presents stem from the fact that this technology provides a way to interact with neural cells at the molecular level. In this review we provide a neurobiological overview of key neurological disorders, describe the different types of nanomaterials in use and discuss their current and potential uses in neuroscience. We also discuss the issue of toxicity in these nanomaterials. This review presents many of the different applications that advances in nanotechnology are having in the field of neurological sciences, especially the high impact they are having in the development of new treatment modalities for neurological disorders that will induce the expected physiological response while minimizing undesirable secondary effects. In conclusion, we weigh in on what the promises and challenges are for future development in this groundbreaking field. PMID- 27488422 TI - Lithium Restores Age-related Olfactory Impairment in the Ts65Dn Mouse Model of Down Syndrome. AB - BACKGROUND & OBJECTIVE: Down syndrome, a genetic condition caused by triplication of chromosome 21, is characterized by widespread neurogenesis reduction and cognitive impairment. Unlike other brain functions, smell is not impaired at early life stages and olfactory deterioration begins to appear in adulthood. Similarly to individuals with Down syndrome, in the Ts65Dn mouse model of Down syndrome smell function is normal at early life stages. Smell impairment only appears in adulthood associated with a reduction in the number of new granule neurons migrated to the olfactory bulb from the subventricular zone. Based on evidence that lithium positively impacts neurogenesis, the goal of current study was to establish whether treatment with lithium restores olfactory bulb neurogenesis and olfactory performance in middle-aged Ts65Dn mice. METHOD: Euploid and Ts65Dn mice aged 13 months were treated with lithium chow or control chow for one month. Before the end of treatment, mice were injected with BrdU, in order to label proliferating cells. Results showed that in Ts65Dn mice lithium treatment restored the number of neural precursor cells in the subventricular zone of the lateral ventricle, rostral migratory stream and olfactory bulb. This effect was accompanied by restoration of olfactory performance. Unlike in olfactory neurogenic regions, treatment had no neurogenesis-enhancing effect on the subgranular zone of the hippocampal dentate gyrus, indicating that lithium has no generalized positive effect on the brain. CONCLUSION: Results suggest that lithium may have a positive impact in brain disorders that, similarly to Down syndrome, are characterized by olfactory decline and neurogenesis impairment in the subventricular zone. PMID- 27488424 TI - Abstracts from the International Surgical Congress of the Association of Surgeons of Great Britain and Ireland, Belfast, 2016. PMID- 27488423 TI - Metabotropic Glutamate Receptor 7 (mGluR7) as a Target for Modulating Pain-evoked Activities of Neurons in the Hippocampal CA3 Region of Rats. AB - BACKGROUND: Metabotropic glutamate could contribute to the development of neuropathic pain-related behaviors. Previously, we have confirmed that the glutamic acid and dizocilpine maleate in the hippocampal CA3 region are involved in the modulation of noxious stimulation. However, whether the metabotropic glutamate receptor 7 (mGluR7) can modulate the pain-evoked electrical activities of pain-excited neurons and pain-inhibited neurons in the hippocampal CA3 region is not clear. OBJECTIVE: The study aimed to examine the effects of mGluR7 allosteric agonist N,N'-dibenzhydrylethane- 1,2-diamine dihydrochloride (AMN082) and antagonist 6-(4-methoxyphenyl)-5-methyl-3- pyridin-4-ylisoxazolo[4,5 c]pyridin-4(5H)-one (MMPIP) on the pain-evoked electrical activities of pain excited neurons and pain-inhibited neurons in the CA3 region of rats. METHOD: A train of electric impulses applied to the sciatic nerve were used for noxious stimulation. The bio-electrical activities of pain-excited neuron or pain inhibited neuron in the CA3 region were recorded by a glass microelectrode. RESULTS: Our results exhibited that intra-CA3 region administration of the glutamic acid or AMN082 increased the pain-evoked discharged frequency and shortened the latency of pain-excited neuron, while decreased the pain-evoked discharged frequency and prolonged the inhibitory duration of paininhibited neuron in the CA3 region. The intra-CA3 region microinjection of MMPIP produced the opposite response. CONCLUSION: These findings demonstrated that the glutamic acid and mGluR7 in hippocampal CA3 region are involved in the modulation of nociceptive information transmission by regulating pain-evoked electric activities of pain-excited neurons and pain-inhibited neurons. PMID- 27488426 TI - Asymmetry-induced resistive switching in Ag-Ag2S-Ag memristors enabling a simplified atomic-scale memory design. AB - Prevailing models of resistive switching arising from electrochemical formation of conducting filaments across solid state ionic conductors commonly attribute the observed polarity of the voltage-biased switching to the sequence of the active and inert electrodes confining the resistive switching memory cell. Here we demonstrate stable switching behaviour in metallic Ag-Ag2S-Ag nanojunctions at room temperature exhibiting similar characteristics. Our experimental results and numerical simulations reveal that the polarity of the switchings is solely determined by the geometrical asymmetry of the electrode surfaces. By the lithographical design of a proof of principle device we demonstrate the merits of simplified fabrication of atomic-scale, robust planar Ag2S memory cells. PMID- 27488425 TI - Mood, anxiety, and alcohol use disorders and later cause-specific sick leave in young adult employees. AB - BACKGROUND: Mental disorders strongly influence work capability in young adults, but it is not clear which disorders that are most strongly associated with sick leave, and which diagnoses that are stated on the sick leave certificates. Better knowledge of the impairments associated with different mental disorders is needed for optimal planning of interventions and prioritization of health services. In the current study, we investigate the prospective associations between eight mood, anxiety, and alcohol use disorders, and later sick leave granted for mental, somatic, or any disorder. METHODS: Lifetime mental disorders were assessed by structured diagnostic interviews in 2,178 young adults followed for eight years with registry data on sick leave. Relative risk ratios were estimated for the associations between each mental disorder and the different forms of sick leave. RESULTS: All included diagnoses were associated with later sick leave. In adjusted analyses, major depressive disorder and generalized anxiety disorder were the strongest predictors of sick leave granted for mental disorders, whereas social anxiety disorder and specific phobia were the strongest predictors of sick leave granted for somatic disorders. Specific phobia and major depressive disorder had the highest attributable fractions for all-cause sick leave. CONCLUSIONS: Mood and anxiety disorders constituted independent risk factors for all cause sick leave, whereas alcohol use disorders seemed to be of less importance in young adulthood. Disorders characterised by distress were most strongly associated with sick leave granted for mental disorders, whereas disorders characterised by fear primarily predicted sick leave granted for somatic conditions. A large part of all sick leave is related to specific phobia, due to the high prevalence of this disorder. The impairment associated with this common disorder may be under-acknowledged, and it could decrease work capacity among individuals with somatic disorders. This disorder has good treatment response and may be overlooked as a target for interventions aimed at prevention of sick leave. PMID- 27488427 TI - 68Ga-PSMA PET/MR Showing Intense PSMA Uptake in Nodular Fasciitis Mimicking Prostate Cancer Metastasis. AB - The recently introduced PSMA PET has developed as a powerful imaging tool for staging of prostate cancer. This case showed an intense uptake of Ga-PSMA in a soft-tissue mass of the rectus femoris muscle. Histopathology revealed the diagnosis of fasciitis nodularis. Therefore, it advises caution particularly in patients with solitary and atypical located lesions as they might not be indicative for metastatic prostate cancer, but eventually be caused by different conditions. PMID- 27488429 TI - Reverse Mismatch Pattern in Cardiac 18F-FDG Viability PET/CT Is Not Associated With Poor Outcome of Revascularization: A Retrospective Outcome Study of 91 Patients With Heart Failure. AB - PURPOSE: Revascularization strategies in patients with ischemic heart failure (HF) should be based on evidence of reversible perfusion defects and myocardial viability. Myocardial viability assessment is preferably based on dual isotope PET using perfusion and metabolism tracers. However, in a nonnegligible subset of HF patients, reverse mismatch (RM) pattern (reduced glucose uptake relative to perfusion) of unknown origin is observed. We aimed to investigate determinants of RM and the impact of RM on the subsequent improvement in left ventricular function by revascularization. PATIENTS AND METHODS: Ninety-one patients (12 women, 25 with diabetes) with HF undergoing Rb perfusion PET and hyperinsulinemic euglycemic clamp F-FDG viability PET were retrospectively reviewed. RESULTS: Follow-up time was 12 to 33 months. In 30 of 91 patients, hypometabolic myocardium exceeded the percentage of hypoperfused myocardium; however, only in 12 of 91 patients was the RM considered significant (percentage RM in the left ventricle, 42.5 +/- 12.9 [reverse patients] vs 14.1 +/- 8.6 [scar and hibernation patients]; P < 0.001). Diabetes status per se did not predict RM, but a significant inverse correlation between insulin sensitivity and RM was observed. The frequency of hospitalization, cardiac death, and myocardial infarctions were not significantly higher in RM patients. Reverse mismatch patients benefited from revascularization to the same extent as patient with normal metabolic patterns. CONCLUSIONS: Reverse mismatch is common among HF patients (~15%) and is inversely correlated to insulin sensitivity. It is not, however, associated with increased cardiac morbidity and mortality and does not predict a worse outcome after revascularization. PMID- 27488430 TI - Pitfalls in the Performance and Interpretation of Scintigraphic Imaging for Pleuroperitoneal Shunt. AB - Ascites can cause pleural effusions when the peritoneal fluid crosses the diaphragm through a pleuroperitoneal shunt in the setting of hepatic cirrhosis (hepatic hydrothorax) or malignant ascites. Scintigraphic imaging for pleuroperitoneal shunt requires intraperitoneal injection of Tc-SC or Tc macroaggregated albumin followed by planar imaging of the chest and abdomen. Pleuroperitoneal shunt is confirmed by identifying radiotracer crossing the diaphragm from the peritoneal to pleural space. An atlas of pleuroperitoneal shunt imaging pitfalls is presented to facilitate optimal performance and interpretation of nuclear pleuroperitoneal shunt examinations. Examples include cases of nondiagnostic radiotracer injections, processing errors, and nontarget uptake. PMID- 27488431 TI - 123I-FP-CIT-SPECT in Encephalitis Involving Substantia Nigra. AB - I-FP-CIT-SPECT is currently used to detect functional impairment of striatal structures. We report herein a case where I-FP-CIT abnormalities are seemingly related to an encephalitis involving substantia nigra. A few months after a documented encephalitis, a 19-year-old woman experienced a Parkinsonism with a right dominance. There was a reduction in the striatal binding of I-FP-CIT, especially on the left side, in accordance with the right dominance of the Parkinsonism. PMID- 27488432 TI - Intense 99mTc-MDP and 18F-NaF Activity in Long-standing Subcutaneous Implants. AB - A 64-year-old woman with a newly diagnosed left breast cancer underwent a presurgical Tc-MDP whole-body imaging, which showed 1 intense activity in the midline upper abdomen and another overlapping the upper thoracic spine. An F-NaF PET/CT scan performed a day later also revealed the elevated activity in the same regions. The activity corresponded to calcified subcutaneous implants, which were placed there more than 30 years ago. PMID- 27488434 TI - Investigating the risk factors of vestibular dysfunction and the relationship with presbyacusis in Singapore. AB - OBJECTIVES: This study aimed to determine the prevalence of vestibular dysfunction in the Singaporean elderly and its association with presbyacusis, age and other associated risk factors. METHODS: A cross-sectional study was undertaken in a tertiary otorhinolaryngology department and the community. Healthy adults aged 40 years and above who participated in the institution's community presbyacusis screening programme were invited to participate. The main outcome measures including pure tone audiometry and vestibular assessment were obtained using a modified Clinical Test of Sensory Interaction on Balance. RESULTS: The prevalence of vestibular dysfunction and presbyacusis in the study population of 216 participants was 30.1 per cent (95 per cent confidence interval, 24.0 to 36.2 per cent) and 55.6 per cent (95 per cent confidence interval, 49.0 to 62.2 per cent), respectively. The median age was 60 years (range, 40-86 years). The adjusted odds ratio for vestibular dysfunction increased by 6.2 per cent with every year of life (p 0.05). CONCLUSION: Vestibular dysfunction is independently associated with ageing and presbyacusis. Further research into the benefits of additional screening for vestibular dysfunction in elderly presbyacusis patients is warranted. PMID- 27488433 TI - Interaction between synaptic inhibition and glial-potassium dynamics leads to diverse seizure transition modes in biophysical models of human focal seizures. AB - How focal seizures initiate and evolve in human neocortex remains a fundamental problem in neuroscience. Here, we use biophysical neuronal network models of neocortical patches to study how the interaction between inhibition and extracellular potassium ([K (+)] o ) dynamics may contribute to different types of focal seizures. Three main types of propagated focal seizures observed in recent intracortical microelectrode recordings in humans were modelled: seizures characterized by sustained (~30-60 Hz) gamma local field potential (LFP) oscillations; seizures where the onset in the propagated site consisted of LFP spikes that later evolved into rhythmic (~2-3 Hz) spike-wave complexes (SWCs); and seizures where a brief stage of low-amplitude fast-oscillation (~10-20 Hz) LFPs preceded the SWC activity. Our findings are fourfold: (1) The interaction between elevated [K (+)] o (due to abnormal potassium buffering by glial cells) and the strength of synaptic inhibition plays a predominant role in shaping these three types of seizures. (2) Strengthening of inhibition leads to the onset of sustained narrowband gamma seizures. (3) Transition into SWC seizures is obtained either by the weakening of inhibitory synapses, or by a transient strengthening followed by an inhibitory breakdown (e.g. GABA depletion). This reduction or breakdown of inhibition among fast-spiking (FS) inhibitory interneurons increases their spiking activity and leads them eventually into depolarization block. Ictal spike-wave discharges in the model are then sustained solely by pyramidal neurons. (4) FS cell dynamics are also critical for seizures where the evolution into SWC activity is preceded by low-amplitude fast oscillations. Different levels of elevated [K (+)] o were important for transitions into and maintenance of sustained gamma oscillations and SWC discharges. Overall, our modelling study predicts that the interaction between inhibitory interneurons and [K (+)] o glial buffering under abnormal conditions may explain different types of ictal transitions and dynamics during propagated seizures in human focal epilepsy. PMID- 27488435 TI - Vaccine hesitancy among general practitioners: evaluation and comparison of their immunisation practice for themselves, their patients and their children. AB - To gain knowledge about vaccine hesitancy among general practitioners (GPs), we conducted a survey to compare their vaccination attitudes for themselves, their children and their patients. A questionnaire survey was sent to GPs working in private practice in the Rhone-Alpes region, France, between October 2013 and January 2014. GPs' immunisation practices for diphtheria-tetanus-poliomyelitis (DTP), measles-mumps-rubella (MMR), pneumococcal, pertussis, hepatitis B (hepB), human papillomavirus (HPV), seasonal and H1N1 influenza and meningococcal C (menC) vaccines were considered. Divergence was defined by the presence of at least one different immunisation practice between their patients and their children. A total of 693 GPs answered the questionnaire. When considering all investigated vaccines, 45.7 % of divergence was found. Individually, divergence was highest for the newest and more controversial, i.e. HPV (11.8 %), hepB (13.1 %), menC (23.7 %) and pneumococcal (19.8 %) vaccines. Only 73.9 % of GPs declared that they recommended HPV vaccine for their daughters. After multivariate analysis, older age was associated with higher risk of divergence. According to the French 2012 recommendations, GPs were insufficiently immunised, with 88 % for DTP and 72 % for pertussis. GPs declared to recommend vaccination against DTP, pertussis and MMR for their patients and their children in more than 95 % of cases. The declared rates of recommendation were lower than 90 % for other vaccines. These results bring new insight about vaccine hesitancy. GPs have divergent immunisation attitudes toward their relatives and their patients, especially when considering the newest and most controversial vaccines, with HPV vaccine being the main focus of controversies. PMID- 27488436 TI - Change of annexin binding of monocytes as an expression of cellular response to Candida albicans: down-regulation in severe sepsis. AB - To study the differences of monocyte activation by albicans and non-albicans species of Candida and its change in sepsis, peripheral blood mononuclear cells were isolated from 17 healthy volunteers and 26 patients with severe sepsis/shock, and incubated in the absence/presence of heat-killed (HK) isolates of four different Candida species and purified beta-D-glucan from C.albicans. Experiments were repeated in the presence and absence of inhibitors of intracellular activation pathways. Expression of annexin V on cells membranes of monocytes and lymphocytes, cytoplasmic activity of caspase-3, and DNA fragmentation of monocytes were studied. Membrane expression of annexin V on viable monocytes of healthy volunteers decreased significantly after incubation with C.albicans but not with non-albicans species. The decrease was dose dependent from the Candida inoculum and by the concentration of beta-D-glucan. A relationship with inhibition of apoptosis was found as the activity of caspase-3 activity, and the level of DNA fragmentation were also decreased. Incubation in the absence/presence of inhibitors showed that the decrease by annexin V expression resulted by activation of the dectin-1 pathway and Raf-1 by beta-D glucan. The decrease of annexin V(+)/PI(-) expression was not shown on monocytes of patients with severe sepsis/shock, where no effect of inhibitors was found. Decrease of annexin V binding on monocytes can be viewed as a selective response to C.albicans partly effected through activation of dectin-1. This response is down-regulated after a septic insult. PMID- 27488437 TI - Success of benznidazole chemotherapy in chronic Trypanosoma cruzi-infected patients with a sustained negative PCR result. AB - Cure assessment in chronic Trypanosoma cruzi infection is controversial, mainly because of the lack of reliable tests to ensure parasite elimination. Here, we assess the impact of benznidazole therapy on the conventional serology and parasitaemia in chronic Chagas disease. A total of 455 patients with long-term Trypanosoma cruzi infection underwent specific chemotherapy with benznidazole. Their parasitological status was assessed by polymerase chain reaction (PCR) detection of T. cruzi DNA. Drops in the titres of antibody levels were serially measured by indirect immunofluorescence assay (IFI) and chemiluminescent microparticle immunoassay (CMIA). Patients were monitored during the treatment period and for a further 90, 150 and 240 days. Controls were repeated yearly during the 7-year follow-up. The PCR result was negative in all patients between 60-day (n = 22) and 90-day (n = 294) controls. Treatment failure was detected in 45 patients and was significantly more frequent in those who did not complete the therapy [12 out of 13 (92 %) vs. 33 out of 442 (7 %)] (p = 0.0001). A significant drop in serum titres was detected after the first follow-up year in patients with sustained negative PCR results: 2nd year (p = 0.029 by IFI; p = 0.002 by CMIA), 5th year (p = 0.036 by IFI; p = 0.039 by CMIA) and 6th year (p = 0.028 by IFI; p = 0.019 by CMIA). The results point to a beneficial effect of benznidazole and may be the cure of chronic patients who had a consistently negative PCR result throughout the follow-up period. PMID- 27488438 TI - Klebsiella pneumoniae bloodstream infection, antimicrobial resistance and consumption trends in Ireland: 2008 to 2013. AB - This study aimed to describe the epidemiology and antimicrobial resistance trends of Klebsiella pneumoniae bloodstream infection (BSI) in Ireland, in conjunction with national antimicrobial consumption data, during the period 2008 to 2013. A retrospective cohort study of K. pneumoniae BSI cases was conducted, based on notifications from Irish microbiology laboratories to the Health Protection Surveillance Centre (HPSC). In total, 1942 K. pneumoniae BSI cases were identified over 6 years, with 310 reported in 2008 and 326 reported in 2013. From 2008 to 2013, the proportion of isolates resistant to co-amoxiclav (24 % versus 29 %), piperacillin-tazobactam (11 % versus 27 %), third generation cephalosporins (3GC) (11 % versus 21 %), fluoroquinolones (13 % versus 21 %) and gentamicin (11 % versus 17 %) increased overall, concurrent with increasing national rates of antimicrobial consumption in Ireland (acute hospitals: 35.87 versus 39.77 defined daily doses (DDD) per 100 bed days used (BDU); and community: 6.38 versus 7.85 DDD per 1000 inhabitants per day (DID)). Enhanced data on the patient's admission route was available for 735 (38 %) cases. Overall, 51 % (n = 378) were categorised as 'acquired in the reporting hospital'. The all-cause mortality was 20 %, with 115 deaths, 101 (88 %) of whom died within 30 days of blood culture sampling date. K. pneumoniae is the second most common cause of Gram-negative BSI in Ireland, with most cases healthcare-associated and an all-cause mortality of 20 % reported in this study. Annual increases in resistance to different antimicrobial classes and in a multi-drug resistant phenotype have been observed, concurrent with increasing national broad spectrum antimicrobial consumption. These trends portend a risk to patient outcomes and highlight the urgency for individual prescribers to evaluate their antimicrobial prescribing habits in hospitals, long-term care and community settings. PMID- 27488439 TI - Co-stimulatory CD28 and transcription factor NFKB1 gene variants affect idiopathic recurrent miscarriages. AB - Co-stimulatory CD28 and transcription factor NFKB1 genes are considered as a crucial player in the determination of inflammatory responses; genetic variability in these may modulate the risk for idiopathic recurrent miscarriages (IRM). We investigated the association of functional variants of CD28 (rs3116496 T/C) and NFKB1 (rs28362491 ins/del and rs696 A/G) with IRM cases. We recruited 200 IRM women with a history of at least three consecutive pregnancy losses before 20th week of pregnancy and 300 fertile control women. Determination of CD28 (rs3116496 T/C) and NFKB1 (rs28362491 ins/del and rs696 A/G) gene variants were based on the polymerase chain reaction pursued by restriction fragment length polymorphism analysis and validated with Sanger sequencing. Single marker analysis and multifactor dimensionality reduction (MDR) model used to predict the IRM risk. We observed nearly three- to twofold increased risk in single marker analysis for minor homozygous genotypes of rs3116496 T/C, rs28362491 ins/del and rs696 A/G tag-SNPs in IRM cases, suggesting the risk association. In MDR analysis, we observed 10.5-fold augmented risk among IRM women in three-SNP model (rs3116496 T/C, rs28362491 ins/del and rs696 A/G). The eQTL mapping analyses was performed to strengthen the results of our study. The eQTL mapping analysis revealed that the variations in CD28 and NFKB1 gene content might affect the abundance of transcripts of CD28 and Family with sequence similarity 177 member A1 (FAM177A1) genes, respectively. These results suggest that CD28 and NFKB1 gene variants may be associated with increased risks to IRM. PMID- 27488440 TI - Regulation of LOXL2 and SERPINH1 by antitumor microRNA-29a in lung cancer with idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that is refractory to treatment and carries a high mortality rate. IPF is frequently associated with lung cancer. Identification of molecular targets involved in both diseases may elucidate novel molecular mechanisms contributing to their pathology. Recent studies of microRNA (miRNA) expression signatures showed that microRNA-29a (miR-29a) was downregulated in IPF and lung cancer. The aim of this study was to investigate the functional significance of miR-29a in lung cancer cells (A549 and EBC-1) and lung fibroblasts (MRC-5) and to identify molecular targets modulated by miR-29a in these cells. We confirmed the downregulation of miR-29a in clinical specimens of IPF and lung cancer. Restoration of miR-29a suppressed cancer cell aggressiveness and fibroblast migration. A combination of gene expression data and in silico analysis showed that a total of 24 genes were putative targets of miR-29a. Among them, lysyl oxidase-like 2 (LOXL2) and serpin peptidase inhibitor clade H, member 1 (SERPINH1) were direct targets of miR-29a by luciferase reporter assays. The functions of LOXL2 and SERPINH1 contribute significantly to collagen biosynthesis. Overexpression of LOXL2 and SERPINH1 was observed in clinical specimens of lung cancer and fibrotic lesions. Downregulation of miR-29a caused overexpression of LOXL2 and SERPINH1 in lung cancer and IPF, suggesting that these genes are involved in the pathogenesis of these two diseases. PMID- 27488443 TI - Whole-gene CFTR sequencing combined with digital RT-PCR improves genetic diagnosis of cystic fibrosis. AB - Despite extensive screening, 1-5% of cystic fibrosis (CF) patients lack a definite molecular diagnosis. Next-generation sequencing (NGS) is making affordable genetic testing based on the identification of variants in extended genomic regions. In this frame, we analyzed 23 CF patients and one carrier by whole-gene CFTR resequencing: 4 were previously characterized and served as controls; 17 were cases lacking a complete diagnosis after a full conventional CFTR screening; 3 were consecutive subjects referring to our centers, not previously submitted to any screening. We also included in the custom NGS design the coding portions of the SCNN1A, SCNN1B and SCNN1G genes, encoding the subunits of the sodium channel ENaC, which were found to be mutated in CF-like patients. Besides 2 novel SCNN1B missense mutations, we identified 22 previously-known CFTR mutations, including 2 large deletions (whose breakpoints were precisely mapped), and novel deep-intronic variants, whose role on splicing was excluded by ex-vivo analyses. Finally, for 2 patients, compound heterozygotes for a CFTR mutation and the intron-9c.1210-34TG[11-12]T5 allele-known to be associated with decreased CFTR mRNA levels-the molecular diagnosis was implemented by measuring the residual level of wild-type transcript by digital reverse transcription polymerase chain reaction performed on RNA extracted from nasal brushing. PMID- 27488444 TI - Obesity and urolithiasis: evidence of regional influences. AB - There is evidence that obese patients have an increased risk of renal stone formation, although this relationship could be less evident in some populations. The aim of this study was to evaluate the impact of overweight and obesity on the risk of renal stone formation in a population consuming a Mediterranean diet and to better elucidate the mechanisms underlying the increased risk of urolithiasis observed in obese subjects. We performed a retrospective review of 1698 stone forming patients (mean age 45.9 +/- 14.6 years; 984/714 M/F), attending outpatient stone clinics in Milan and Florence, seen between January 1986 and June 2014. Records were reviewed and data collected pertaining to age, gender, weight, height, stone composition, association with diabetes type 2 or gout and metabolic profile of 24-h urine to perform a descriptive study. We estimated prevalence ratios for body mass index (BMI) categories (underweight: BMI <18.5, normal: BMI 18.5-24.9, overweight: BMI 25-29.9 and obese >=30). Overweight and obesity were present in 40.7 and 8 % of the men and in 19.9 and 8.7 % of the women in the study population. The mean BMI of patients with urolithiasis was found to be 24.5 +/- 7.5 kg/m2. BMI values were positively correlated with age (p = 0.000) and mean BMI was higher in males than in females (25.5 +/- 8.9 vs 23.2 +/- 4.4 kg/m2). In males, rates of overweight and obesity in renal stone formers were higher than the rates reported in the Italian general population in 2004 only for the age group 25-44 years, whereas males in all the other age groups and in females the rates of overweight and obesity in renal stone formers were similar to rates reported in the Italian general population. The rates of overweight and obesity were significantly different in patients with different chemical stone composition. In particular, patients with uric acid stones have rates of overweight and obesity higher than patients with calcium stones or other types of calculi. Also the rates of type 2 diabetes and gout were greater in patients with overweight and obesity. In overweight and obese patients, the urinary excretion of risk factors for stone formation, such as calcium, oxalate and urate, and also of inhibitory substances, such as citrate, were significantly higher than in patients with normal weight or underweight. The prevalence of overweight and obesity in patients with urinary calculi from a country consuming a Mediterranean diet is not higher than in the general population. It should be taken into account that not all the dietary patterns that are associated with obesity may involve a parallel increase in the risk of forming kidney stones and that epidemiological findings from one country could not be confirmed in other countries with different climatic, socioeconomic and cultural features. PMID- 27488445 TI - [Kurt Seidel (1914-1990) : Between medicine and politics]. AB - Prof. Dr. med. Kurt Seidel played an outstanding role in the post-war history of rheumatology in eastern Germany. This is documented by the textbook articles and review articles written by him, by the foundation and leadership over many years of the working and research group of rheumatology in Jena, by his role in the formation of the divided society of the German Democratic Republic (GDR) and by the preparation of its chronical in 1984. An appreciation of his achievements against the background of the scientific political circumstances prevailing at that time is documented through a dissertation. PMID- 27488442 TI - Functional RNAs control T follicular helper cells. AB - T follicular helper cells (Tfh cells), which are a prototypic subset of effector CD4+ T cells, regulate the production of high-affinity antibodies by controlling B cells at initial and recall phases. Since the discovery of Tfh cells in human tonsils, many notable studies focusing on Tfh cells have clarified mechanisms underlying Tfh-cell-related physiological and pathological settings. Results of these studies revealed a chief regulatory function of BCL6 in Tfh cells and the involvement of Tfh cells in the pathogenesis of various disorders including autoimmune diseases, allergies and cancers. Further, accumulating evidence has revealed microRNAs (miRNAs) of functional noncoding RNAs (ncRNAs) to be cardinal regulators of Tfh cells during the processes of development, differentiation and plasticity. In this review article, we summarize and discuss the results of recent studies about miRNAs operating Tfh-cell function and their relationships in diseases. Through the window of such functional ncRNAs, the functional significance of Tfh cells in CD4+ T-cell biology is becoming apparent. Studies to determine the complex background of the genetic program of Tfh cells operated by functional RNAs should lead to an understanding of the manifestations of Tfh cells with unidentified pathophysiological relevance. PMID- 27488441 TI - MicroRNAs in non-small cell lung cancer and idiopathic pulmonary fibrosis. AB - In spite of advances in the diagnosis and current molecular target therapies of lung cancer, this disease remains the most common cause of cancer-related death worldwide. Approximately 80% of lung cancers is non-small cell lung cancer (NSCLC), and 5-year survival rate of the disease is ~20%. On the other hand, idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. IPF is refractory to treatment and has a very low survival rate. Moreover, IPF is frequently associated with lung cancer. However, the common mechanisms shared by these two diseases remain poorly understood. In the post-genome sequence era, the discovery of noncoding RNAs, particularly microRNAs (miRNAs), has had a major impact on most biomedical fields, and these small molecules have been shown to contribute to the pathogenesis of NSCLC and IPF. Investigation of novel RNA networks mediated by miRNAs has improved our understanding of the molecular mechanisms of these diseases. This review summarizes our current knowledge on aberrantly expressed miRNAs regulating NSCLC and IPF based on miRNA expression signatures. PMID- 27488446 TI - [Diagnostics and treatment of polymyalgia rheumatica]. AB - Polymyalgia rheumatica (PMR) is the most common autoimmune inflammatory disease in older persons with an average age of onset of 73 years. Typical symptoms include acute or subacute bilateral shoulder pain with severe stiffness and often neck and bilateral hip pain. Giant cell arteritis (GCA) occurs in approximately 20 % of cases and up to two thirds of patients with GCA have symptoms of PMR. There are many disease which mimic PMR, elderly onset rheumatoid arthritis is frequently misdiagnosed as PMR. Although there are no specific laboratory tests, C-reactive protein and erythrocyte sedimentation rates are elevated in over 90 % of patients. The diagnosis may be aided by imaging, especially ultrasonography and magnetic resonance imaging (MRI). Treatment currently consists of glucocorticoids at an initial dose of 12.5-25 mg prednisone equivalent daily. Treatment duration is typically 2-3 years but may be longer. Under certain conditions low-dose methotrexate can be used as adjuvant therapy. PMID- 27488447 TI - [Treat-to-target (T2T) recommendation for patients with spondyloarthritis - translation into German]. AB - The management of patients with spondyloarthritis (SpA) has experienced a paradigm shift in recent years. This is true for the treatment of axial as well as peripheral manifestations. International treat to target (T2T) recommendations for SpA based on the T2T strategy have now also been published, which contain 5 higher level principles (A-E) in addition to the 15 recommendations. In order to make the recommendations known and to promote national distribution, German experts have now issued a translation of the T2T recommendations for SpA into German. PMID- 27488448 TI - Repeated eye reduction events reveal multiple pathways to degeneration in a family of marine snails. AB - Eye reduction occurs in many troglobitic, fossorial, and deep-sea animals but there is no clear consensus on its evolutionary mechanism. Given the highly conserved and pleiotropic nature of many genes instrumental to eye development, degeneration might be expected to follow consistent evolutionary trajectories in closely related animals. We tested this in a comparative study of ocular anatomy in solariellid snails from deep and shallow marine habitats using morphological, histological, and tomographic techniques, contextualized phylogenetically. Of 67 species studied, 15 lack retinal pigmentation and at least seven have eyes enveloped by surrounding epithelium. Independent instances of reduction follow numerous different morphological trajectories. We estimate eye loss has evolved at least seven times within Solariellidae, in at least three different ways: characters such as pigmentation loss, obstruction of eye aperture, and "lens" degeneration can occur in any order. In one instance, two morphologically distinct reduction pathways appear within a single genus, Bathymophila. Even amongst closely related animals living at similar depths and presumably with similar selective pressures, the processes leading to eye loss have more evolutionary plasticity than previously realized. Although there is selective pressure driving eye reduction, it is clearly not morphologically or developmentally constrained as has been suggested by previous studies. PMID- 27488449 TI - A decision analytic model to investigate the cost-effectiveness of poisoning prevention practices in households with young children. AB - BACKGROUND: Systematic reviews and a network meta-analysis show home safety education with or without the provision of safety equipment is effective in promoting poison prevention behaviours in households with children. This paper compares the cost-effectiveness of home safety interventions to promote poison prevention practices. METHODS: A probabilistic decision-analytic model simulates healthcare costs and benefits for a hypothetical cohort of under 5 year olds. The model compares the cost-effectiveness of home safety education, home safety inspections, provision of free or low cost safety equipment and fitting of equipment. Analyses are conducted from a UK National Health Service and Personal Social Services perspective and expressed in 2012 prices. RESULTS: Education without safety inspection, provision or fitting of equipment was the most cost effective strategy for promoting safe storage of medicines with an incremental cost-effectiveness ratio of L2888 (95 % credible interval (CrI) L1990-L5774) per poison case avoided or L41,330 (95%CrI L20,007-L91,534) per QALY gained compared with usual care. Compared to usual care, home safety interventions were not cost effective in promoting safe storage of other household products. CONCLUSION: Education offers better value for money than more intensive but expensive strategies for preventing medicinal poisonings, but is only likely to be cost effective at L30,000 per QALY gained for families in disadvantaged areas and for those with more than one child. There was considerable uncertainty in cost effectiveness estimates due to paucity of evidence on model parameters. Policy makers should consider both costs and effectiveness of competing interventions to ensure efficient use of resources. PMID- 27488450 TI - MAD2B promotes tubular epithelial-to-mesenchymal transition and renal tubulointerstitial fibrosis via Skp2. AB - : The mitotic arrest deficient protein MAD2B is a well-defined anaphase-promoting complex/cyclosome (APC/C) inhibitor and a small subunit of DNA polymerase zeta. It is critical for mitotic control and DNA repair. However, the pathological role of MAD2B in kidney diseases has not been fully elucidated. In the present study, we aim to explore the role of MAD2B in the pathogenesis of renal tubulointerstitial fibrosis (TIF) and the underlying mechanism. By immunofluorescence and immunohistochemistry, we found an obvious MAD2B enhancement in tubular area of TIF patients and unilateral ureteral obstruction (UUO) mice. In vitro, transforming growth factor-beta1 (TGF-beta1) induced a time dependent MAD2B accumulation prior to tubular epithelial-to-mesenchymal transition (EMT) in a rat proximal tubular epithelial cell line, NRK-52E. Knocking down MAD2B using siRNA dramatically inhibited TGF-beta1-induced tubular EMT process and subsequent extracellular matrix (ECM) production. We also found that Skp2, a confirmed APC/C-CDH1 substrate and E-cadherin destroyer, was increased in TGF-beta1-treated proximal tubular epithelial cells, which could be blocked by MAD2B depletion. In addition, Skp2 expression was also found to be increased in the renal tubular area of UUO mice. Locally knocking down MAD2B expression in the renal cortex using lentiviral transfection inhibited Skp2 expression, tubular EMT, and subsequent ECM accumulation. Taken together, our data suggests a pro-fibrotic role of MAD2B in the pathogenesis of tubular EMT and TIF by inducing Skp2 expression. MAD2B might be a potential target of promising interventions for renal TIF. KEY MESSAGES: Renal fibrosis activates MAD2B expression in renal tubules of human and mouse. TGF-beta1 contributes to MAD2B enhancement in rat tubular epithelial cells. MAD2B depletion alleviates renal tubulointerstitial fibrosis in vivo and in vitro. MAD2B promotes EMT transition in rat tubular epithelial cells by inducing Skp2. PMID- 27488451 TI - Mitochondrial aldehyde dehydrogenase 2 deficiency aggravates energy metabolism disturbance and diastolic dysfunction in diabetic mice. AB - : Diabetes causes energy metabolism disturbance and may lead to cardiac dysfunction. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects cardiac function from myocardial damage. Therefore, understanding of its roles in diabetic heart is critical for developing new therapeutics targeting ALDH2 and mitochondrial function for diabetic hearts. This study investigated the impact of ALDH2 deficiency on diastolic function and energy metabolism in diabetic mice. Diabetes was induced in ALDH2 knockout and wild-type mice by streptozotocin. Cardiac function was determined by echocardiography. Glucose uptake, energy status, and metabolic profiles were used to evaluate cardiac energy metabolism. The association between ALDH2 polymorphism and diabetes was also analyzed in patients. Echocardiography revealed preserved systolic function and impaired diastolic function in diabetic ALDH2-deficient mice. Energy reserves (phosphocreatine/adenosine triphosphate ratio) were reduced in the diabetic mutants and were associated with diastolic dysfunction. Western blot analysis showed that diabetes induces accumulated lipid peroxidation products and escalated AMP-activated protein kinase-LKB1 pathway. Further, ALDH2 deficiency exacerbated the diabetes-induced deficient myocardial glucose uptake and other perturbations of metabolic profiles. Finally, ALDH2 mutations were associated with worse diastolic dysfunction in diabetic patients. Together, our results demonstrate that ALDH2 deficiency and resulting energy metabolism disturbance is a part of pathology of diastolic dysfunction of diabetic hearts, and suggest that patients with ALDH2 mutations are vulnerable to diabetic damage. KEY MESSAGE: ALDH2 deficiency exacerbates diastolic dysfunction in early diabetic hearts. ALDH2 deficiency triggers decompensation of metabolic reserves and energy metabolism disturbances in early diabetic hearts. ALDH2 deficiency potentiates oxidative stress and AMPK phosphorylation induced by diabetes via post translational regulation of LKB1. Diabetic patients with ALDH2 mutations are predisposed to worse diastolic dysfunction. PMID- 27488453 TI - Breast Hypertrophy Induced by Ombitasvir/Paritaprevir/Ritonavir and Ribavirina. PMID- 27488454 TI - Orbital Inflammation Secondary to Zoledronic Acid, a Rare Presentation. PMID- 27488452 TI - Resveratrol inhibits renal interstitial fibrosis in diabetic nephropathy by regulating AMPK/NOX4/ROS pathway. AB - : Renal interstitial fibrosis is a major pathologic feature of diabetic nephropathy, while the pathogenesis and therapeutic interventions of diabetic renal interstitial fibrosis are not well established. In this study, we first demonstrated that high glucose could induce renal fibroblast (NRK-49F) cell proliferation and activation to myofibroblasts, accompanied by a significant increase in the intracellular levels of reactive oxygen species (ROS) derived from nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). ROS-mediated ERK1/2 activation was found to play a crucial role in high glucose-induced fibroblast proliferation and activation. Resveratrol, like the NOX4-targeting small interfering RNA (siRNA), markedly inhibited high glucose-induced fibroblast proliferation and activation by reducing NOX4-derived ROS production. It was then revealed that the increase in the expression of NOX4 induced by high glucose was due to the inactivation of AMP-activated protein kinase (AMPK), which could be reversed by resveratrol. Further in vivo investigation demonstrated that resveratrol treatment significantly attenuated renal fibrosis in db/db mice, accompanied by an evident increase in phospho-AMPK and decrease in NOX4. In summary, our results suggest that high glucose can directly promote renal fibroblasts proliferation and activation in a ROS-dependent manner, and resveratrol is a potential therapeutic agent against diabetic renal fibrosis via regulation of AMPK/NOX4/ROS signaling. KEY MESSAGE: Resveratrol inhibits high glucose-induced NRK cell activation by decreasing NOX4-derived ROS. Resveratrol inhibits high glucose-induced NOX4 expression in NRK cells via activation of AMPK. ROS-activated ERK1/2 signaling is involved in high glucose-induced NRK cell activation. Resveratrol attenuated renal fibrosis in db/db mice via regulation of AMPK/NOX4/ROS signaling. PMID- 27488455 TI - Pontibacter virosus sp. nov., isolated from a hexachlorocyclohexane-contaminated dumpsite. AB - A Gram-staining-negative, red-pigmented, motile, rod-shaped bacterial strain, designated as W14T, was isolated from a hexachlorocyclohexane-contaminated dumpsite located in the northern part of India at Ummari Village, Lucknow. Phylogenetic analysis based on 16S rRNA gene sequence showed that the strain belongs to the genus Pontibacter with highest sequence similarity to Pontibacter lucknowensis DM9T (98.1 %). The 16S rRNA gene sequence similarity between strain W14T and members of other species of the genus Pontibacter ranged from 98.1 to 94.2 %. The DNA-DNA relatedness between strain W14T and P. lucknowensis DM9T was 33.7 % and with other closely related strains was found to be less than 20 %, confirming it to represent a novel species. The DNA G+C content of strain W14T was 51.3 mol%. Strain W14T was oxidase- and catalase-positive. The predominant cellular fatty acids were summed feature 4 (C17 : 1 iso I/anteiso B and C17 : 1 anteiso B/iso I), iso-C15 : 0 and iso-C17 : 0 3-OH. The polar lipid profile of strain W14T consisted of phosphatidylethanolamine, diphosphatidylglycerol, aminolipid and glycolipid. On the basis of the results obtained from DNA-DNA hybridization, biochemical and physiological tests in this study, strain W14T represents a novel species of the genus Pontibacter, for which the name Pontibacter virosus sp. nov. is proposed. The type strain is W14T (=MCC 2932T=DSM 100231T=KCTC 42941T). PMID- 27488456 TI - Conceptualizing and Measuring Weekend versus Weekday Alcohol Use: Item Response Theory and Confirmatory Factor Analysis. AB - Culturally, people tend to abstain from alcohol intake during the weekdays and wait to consume in greater frequency and quantity during the weekends. The current research sought to empirically justify the days representing weekday versus weekend alcohol consumption. In study 1 (N = 419), item response theory was applied to a two-parameter (difficulty and discrimination) model that evaluated the days of drinking (frequency) during the typical 7-day week. Item characteristic curves were most similar for Monday, Tuesday, and Wednesday (prototypical weekday) and for Friday and Saturday (prototypical weekend). Thursday and Sunday, however, exhibited item characteristics that bordered the properties of weekday and weekend consumption. In study 2 (N = 403), confirmatory factor analysis was applied to test six hypothesized measurement structures representing drinks per day (quantity) during the typical week. The measurement model producing the strongest fit indices was a correlated two-factor structure involving separate weekday and weekend factors that permitted Thursday and Sunday to double load on both dimensions. The proper conceptualization and accurate measurement of the days demarcating the normative boundaries of "dry" weekdays and "wet" weekends are imperative to inform research and prevention efforts targeting temporal alcohol intake patterns. PMID- 27488457 TI - KiVa Anti-Bullying Program in Italy: Evidence of Effectiveness in a Randomized Control Trial. AB - The present study aims to evaluate the effectiveness of the KiVa anti-bullying program in Italy through a randomized control trial of students in grades 4 and 6. The sample involved 2042 students (51 % female; grade 4, mean age = 8.85; ds = 0.43; grade 6, mean age = 10.93; ds = 0.50); 13 comprehensive schools were randomly assigned into intervention (KiVa) or control (usual school provision) conditions. Different outcomes (bullying, victimization, pro-bullying attitudes, pro-victim attitudes, empathy toward victims), analyses (longitudinal mixed model with multiple-item scales; longitudinal prevalence of bullies and victims using Olweus' single question), and estimates of effectiveness (Cohen's d; odds ratios) were considered in order to compare the Italian results with those from other countries. Multilevel models showed that KiVa reduced bullying and victimization and increased pro-victim attitudes and empathy toward the victim in grade 4, with effect sizes from 0.24 to 0.40. In grade 6, KiVa reduced bullying, victimization, and pro-bullying attitudes; the effects were smaller as compared to grade 4, yet significant (d >= 0.20). Finally, using Olweus dichotomous definition of bullies and victims, results showed that the odds of being a victim were 1.93 times higher for a control student than for a KiVa student in grade 4. Overall, the findings provide evidence of the effectiveness of the program in Italy; the discussion will focus on factors that influenced successfully the transportability of the KiVa program in Italy. PMID- 27488459 TI - Confirmation of association between Lewis blood group antigens and secretor status in pemphigus vulgaris. PMID- 27488458 TI - Epidermal growth factor receptor is expressed and active in a subset of acute myeloid leukemia. AB - The epidermal growth factor receptor (EGFR) inhibitor erlotinib has been shown to induce complete remission of acute myeloid leukemia (AML) in two patients with concurrent lung cancer and raised attention for a role of EGFR in AML whereas a recent phase II clinical study with gefitinib in AML demonstrated a negative result on the outcome. However, from several studies, EGFR expression in AML is poorly defined and the role of EGFR in AML remains unclear. Herein, we report the results of EGFR expression in AML of large cohorts of adult and pediatric AML patients with the data of total protein and phosphorylation levels of EGFR. Our data conclude that there is the expression of EGFR at the protein level in a subset of AML, which was identified to be functionally active in ~15 % of AML patients. This suggests that future studies need to be conducted with a subset of AML patients characterized by high EGFR expression. PMID- 27488460 TI - SM-1, a novel PAC-1 derivative, activates procaspase-3 and causes cancer cell apoptosis. AB - PURPOSE: To develop more potent procaspase-3 activator, 7 novel derivatives of PAC-1 were synthesized and evaluated. Among them, SM-1 stood out for its promising activity and good pharmacokinetics properties. The purpose of this study is to elucidate the pharmacological mechanism of SM-1 and evaluate its efficacy and toxicity in-depth. METHODS: To reveal the effects of SM-1 on caspase 3 activity, both in vitro activation assay and in cells fluorometric assay were tested. The protein levels and distributions of procaspase-3 and cleaved caspase 3 were also measured by western blot and immunostaining. MTT assay, apoptosis assay and mouse xenograft model were applied to evaluate the efficacy of SM-1. Preliminary safety assessments also tested the acute toxicity and tissue distribution of SM-1. RESULTS: Compared to PAC-1, SM-1 showed higher cytotoxicity in cancer cells. Further investigation demonstrated that SM-1 relieved zinc mediated inhibition of procaspase-3 and activated the caspase-3 activity both in tube test and in cells. Efficacy evaluation showed SM-1-induced cell apoptosis mainly via activation of caspase-3 and reduced tumor size in mouse xenograft model. Its apoptosis induction efficacy was higher than PAC-1. The preliminary safety assessment demonstrated that the overall LD50 of SM-1 lied between 500 and 1000 mg/kg and the distribution of SM-1 in brain was low. CONCLUSIONS: We identified SM-1 as a promising antitumor candidate, which displayed enhanced procaspase-3 activating activity and potent cytotoxicity for cancer cells but low toxicity for normal cells. PMID- 27488461 TI - Erratum to: Management of patients with T1b esophageal adenocarcinoma: a retrospective cohort study on patient management and risk of metastatic disease. PMID- 27488462 TI - Leptin deficiency in mice counteracts imiquimod (IMQ)-induced psoriasis-like skin inflammation while leptin stimulation induces inflammation in human keratinocytes. AB - Leptin is an adipocyte-derived cytokine secreted mostly by adipose tissue. Serum leptin levels are elevated in obese individuals and correlate positively with body mass index (BMI). Interestingly, serum leptin levels are also elevated in patients with psoriasis and correlate positively with disease severity. Psoriasis is associated with obesity; patients with psoriasis have a higher incidence of obesity, and obese individuals have a higher risk of developing psoriasis. Additionally, obese patients with psoriasis experience a more severe degree of psoriasis. In this study, we hypothesised that leptin may link psoriasis and obesity and plays an aggravating role in psoriasis. To investigate leptin's role in psoriasis, we applied the widely accepted imiquimod (IMQ)-induced psoriasis like skin inflammation mouse model on leptin-deficient (ob/ob) mice and evaluated psoriasis severity. Moreover, we stimulated human keratinocytes with leptin and investigated the effect on proliferation and expression of pro-inflammatory proteins. In ob/ob mice, clinical signs of erythema, infiltration and scales in dorsal skin and inflammation in ear skin, as measured by ear thickness, were attenuated and compared with wt mice. Moreover, IL-17A and IL-22 mRNA expression levels, as well as increased epidermal thickness, were significantly less induced. In vitro, the effect of leptin stimulation on human keratinocytes demonstrated increased proliferation and induced secretion of several pro inflammatory proteins; two hallmarks of psoriasis. In conclusion, leptin deficiency attenuated IMQ-induced psoriasis-like skin inflammation in a mouse model, and leptin stimulation induced a pro-inflammatory phenotype in human keratinocytes, thus, supporting an aggravating role of leptin in psoriasis. PMID- 27488463 TI - Intracluster Correlation Coefficients of Household Economic and Agricultural Outcomes in Mozambique. AB - BACKGROUND: This article offers important statistics to evaluators planning future evaluations in southeast Africa. There are little to no published statistics describing the variance of southeast African agricultural and household indicators. OBJECTIVE: We seek to publish the standard deviations, intracluster correlation coefficients (ICCs), and R 2s from outcomes and covariates used in a 2014 quasi-experimental evaluation of the Millennium Challenge Corporation's Mozambique Farmer Income Support Project (FISP) and thus guide researchers in their calculation of design effects relevant to future evaluations in the region. METHOD: We summarize data from a roughly 168-item farmer survey conducted in 1,227 households during June-July 2014 in coconut farming regions of the Zambezia province in Mozambique. We report descriptive statistics, estimates of ICC, and R 2s obtained from linear regression models with cluster random effects. We consider three different cluster definitions. RESULTS: We report ICCs for a range of different specifications. For the FISP evaluation, the average design effect for education outcomes is 1.16. Average design effects for wealth measures based on consumption are 1.23. For agricultural-related outcomes, 1.05 is the average design effects for income measures, 1.47 for knowledge, and 1.64 for sales of specific crops. CONCLUSION: We offer a detailed picture of the variance structure of agricultural and other outcomes in Mozambique. Our results indicate that the design effect associated with these outcomes is less than the rule-of-thumb design effect (2.0) used in nutrition studies which are commonly cited in the studies of this region. PMID- 27488464 TI - One in 10 young people experiences a distressing sexual problem. PMID- 27488465 TI - Wrinkled silica/titania nanoparticles with tunable interwrinkle distances for efficient utilization of photons in dye-sensitized solar cells. AB - Efficient light harvesting is essential for the realization of high energy conversion efficiency in dye-sensitized solar cells (DSCs). State-of-the-art mesoporous TiO2 photoanodes fall short for collection of long-wavelength visible light photons, and thus there have been efforts on introduction of scattering nanoparticles. Herein, we report the synthesis of wrinkled silica/titania nanoparticles with tunable interwrinkle distances as scattering materials for enhanced light harvesting in DSCs. These particles with more than 20 times larger specific surface area (>400 m(2)/g) compared to the spherical scattering particles (<20 m(2)/g) of the similar sizes gave rise to the dye-loading amounts, causing significant improvements in photocurrent density and efficiency. Moreover, dependence of spectral scattering properties of wrinkled particles on interwrinkle distances, which was originated from difference in overall refractive indices, was observed. PMID- 27488466 TI - Basilar artery hypoplasia associated with changes of brainstem potential, transcranial Doppler and perfusion-weighted imaging. AB - OBJECTIVE: The aim of this study was to observe brainstem hemodynamic alterations associated with basilar artery hypoplasia (BAH). METHODS: Nine hundred and fifty two consecutive patients received emergency multimodal computed tomography; magnetic resonance imaging and magnetic resonance angiogram during the period of January 2011 to December 2014 were included. The vascular risk factors, brainstem auditory evoked potential (BAEP), blink reflex (BR), transcranial Doppler (TCD) and dynamic susceptibility contrast-enhanced perfusion-weighted imaging were completed. RESULTS: There was significant difference in the abnormal rates of TCD and BAEP between BAH and non-BAH patients. A positive correlation between basilar artery diameter and systolic velocity among BAH patients was suggested. V-wave value was used to predict posterior circulation infarction (PCI) with the sensitivity of 0.933 and specificity of 0.50 with the cutoff value of 5.97 s. Abnormal BR rate was also significantly different in BAH and non-BAH patients. The latency of R2 was used to predict PCI with the sensitivity of 0.933 and specificity of 0.50 with the cutoff value of 46.4 ms. The incidence of hypoperfusion was higher in BAH than non-BAH group and it was significant difference. CONCLUSION: BAH is closely associated with hemodynamic alterations within the pons, which might contribute to vascular vertigo due to regional hypoperfusion. PMID- 27488467 TI - The development and initial validation of a new tool to measure self-awareness of driving ability after brain injury. AB - AIM: The aim of this study was to develop and provide initial validation data for a self-awareness of on-road driving ability measure for individuals with brain injury. METHOD: Thirty-nine individuals with Traumatic Brain Injury completed an on-road driving assessment, the Self-Regulation Skills Interview (SRSI) and the newly developed Brain Injury Driving Self-Awareness Measure (BIDSAM). RESULTS: BIDSAM self, clinician and discrepancy scales demonstrated high levels of internal consistency (alpha = 0.83-0.92). Criterion-related validity was established by demonstrating significantly higher correlations between clinician ratings and on-road performances, rs = 0.82, P < 0.01, compared to self-ratings, rs = 0.45, P < 0.05. Discrepancy scores were significantly correlated with the SRSI emergent, rs = 0.52, P < 0.01, and anticipatory awareness scores, rs = 0.37, P < 0.05, indicative of convergent validity. CONCLUSIONS: These results provide initial support for the BIDSAM as a reliable and valid measure of self awareness of on-road driving ability following TBI. PMID- 27488468 TI - Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel alpha1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel alpha1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA 223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co injection of a CACNA1C-specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease. PMID- 27488470 TI - Successful implementation of an Enhanced Recovery After Surgery program shortens length of stay and improves postoperative pain, and bowel and bladder function after colorectal surgery. AB - BACKGROUND: Despite international data indicating that Enhanced Recovery After Surgery (ERAS) programs, which combine evidence-based perioperative strategies, expedite recovery after surgery, few centers have successfully adopted this approach within the U.S. We describe the implementation and efficacy of an ERAS program for colorectal abdominal surgery in a tertiary teaching center in the U.S. METHODS: We used a multi-modal and continuously evolving approach to implement an ERAS program among all patients undergoing colorectal abdominal surgery at a single hospital at the University of California, San Francisco. 279 patients who participated in the Enhanced Recovery after Surgery program were compared to 245 previous patients who underwent surgery prior to implementation of the program. Primary end points were length of stay and readmission rates. Secondary end points included postoperative pain scores, opioid consumption, postoperative nausea and vomiting, length of urinary catheterization, and time to first solid meal. RESULTS: ERAS decreased both median total hospital length of stay (6.4 to 4.4 days) and post-procedure length of stay (6.0 to 4.1 days). 30 day all-cause readmission rates decreased from 21 to 9.4 %. Pain scores improved on postoperative day 0 (3.2 to 2.1) and day 1 (3.2 to 2.6) despite decreased opioid. Median time to first solid meal decreased from 4.7 to 2.7 days and duration of urinary catheterization decreased from 74 to 46 h. Similar improvements were observed in all other secondary end points. CONCLUSIONS: These results confirm that a multidisciplinary, iterative, team-based approach is associated with a reduction in hospital stay and an acceleration in recovery without increasing readmission rates. PMID- 27488469 TI - Suppression of amyloid fibrils using the GroEL apical domain. AB - In E. coli cells, rescue of non-native proteins and promotion of native state structure is assisted by the chaperonin GroEL. An important key to this activity lies in the structure of the apical domain of GroEL (GroEL-AD) (residue 191-376), which recognizes and binds non-native protein molecules through hydrophobic interactions. In this study, we investigated the effects of GroEL-AD on the aggregation of various client proteins (alpha-Synuclein, Abeta42, and GroES) that lead to the formation of distinct protein fibrils in vitro. We found that GroEL AD effectively inhibited the fibril formation of these three proteins when added at concentrations above a critical threshold; the specific ratio differed for each client protein, reflecting the relative affinities. The effect of GroEL-AD in all three cases was to decrease the concentration of aggregate-forming unfolded client protein or its early intermediates in solution, thereby preventing aggregation and fibrillation. Binding affinity assays revealed some differences in the binding mechanisms of GroEL-AD toward each client. Our findings suggest a possible applicability of this minimal functioning derivative of the chaperonins (the "minichaperones") as protein fibrillation modulators and detectors. PMID- 27488471 TI - Diminished IL-17A levels may protect filarial-infected individuals from development of rheumatoid arthritis and systemic lupus erythematosus. AB - Nematode infections have been observed to inversely correlate with autoimmune disorders. Recently, we have shown the absence of filarial infection in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) who live in filarial-endemic areas. The mechanism(s) by which filarial-infected individuals are protected against the development of RA or SLE are unknown. In mice CIA, an experimental model for RA, ES-62, an execratory product of rodent filarial nematode , has been shown to improve arthritis through suppression of the IL-17 pathway. A total of 160 individuals, 40 each of endemic normal, filarial-infected cases, SLE and RA patients, from filarial-endemic areas, were enrolled in the study. Plasma levels of IL17-A, IFN-alpha and TNF-alpha were quantified by enzyme linked immunosorbent assay (ELISA). RA and SLE patients displayed significantly higher plasma IL-17A, IFN-alpha and TNF-alpha levels compared to endemic normal and infected individuals. Furthermore, IL-17A levels were significantly low in participants with filarial infection compared to endemic controls ( p < 0.05). Interestingly, plasma IL-17A levels correlated inversely with circulating filarial antigen (CFA) ( p = 0.004, Spearman r = -0.51). Filarial infection was associated with low plasma IL-17A levels, a mechanism by which it possibly protects individuals in filarial-endemic areas from the development of autoimmune disorders like RA and SLE. PMID- 27488472 TI - Impact of concomitant medication use on belimumab efficacy and safety in patients with systemic lupus erythematosus. AB - Practicing physicians have requested efficacy and safety data for belimumab, when used with specific systemic lupus erythematosus (SLE) medications. This was a post hoc analysis of pooled efficacy and safety data from patients who received belimumab 10 mg/kg plus standard of care (SoC) or placebo (SoC) in two Phase III, randomized trials, BLISS-52 and BLISS-76. Patients were categorized into four groups based on baseline concomitant medication usage: steroids only; antimalarials (AM) only; steroids + AM; or steroids + AM + immunosuppressants (IS). The primary endpoint was the SLE Responder Index (SRI) at Week 52. SRI over time and individual SRI components were secondary endpoints. Time to first flare and changes in concomitant medications were exploratory endpoints. Safety was assessed using adverse event (AE) reporting. Across 834 patients, steroids + AM was the largest group (n = 346, 41.5%) and AM only was the smallest (n = 77, 9.2%). Disease duration was shortest in the steroids + AM group (5.7 years vs 6.4 7.1 years); SELENA-SLEDAI scores were similar across groups. At Week 52, the percentage of SRI responders was greatest in the steroids + AM group for belimumab 10 mg/kg (59%) compared with placebo (44%); treatment response and SRI component improvements were also observed across other groups. The probability of experiencing an SLE flare was reduced in the steroids-only group for patients who received belimumab 10 mg/kg compared with placebo (64.3% vs 78.1%; hazard ratio 0.64; 95% confidence interval: 0.42-0.96). There was little or no change in daily AM or IS dose in any group. For all groups, there was a general decrease in steroid dose over time; a quarter to a third of patients experienced decreased steroid doses at Week 52. The overall safety profile was similar across treatment arms and concomitant medication groups, with the exception of serious AEs in the steroids + AM group (belimumab 10 mg/kg 16%, placebo 8%). The efficacy and safety of belimumab in combination with SoC was demonstrated for various groupings of steroids, AM and IS. These findings may improve the understanding of the safety and efficacy of adding belimumab to different treatments. PMID- 27488473 TI - Severe disease presentation and poor outcomes among pediatric systemic lupus erythematosus patients in South Africa. AB - Background Systemic lupus erythematosus (SLE) is a life-threatening multisystem autoimmune disease that is more severe in patients of African ancestry and children, yet pediatric SLE on the African continent has been understudied. This study describes a cohort of pediatric SLE (PULSE) patients in South Africa. Methods Patients with a diagnosis of SLE (1997 American College of Rheumatology criteria) diagnosed prior to age 19 years in Cape Town, South Africa, were enrolled in this cross-sectional study from September 2013 to December 2014. Information on clinical and serological characteristics was extracted from medical records. Results were compared to a well-described North American pediatric SLE cohort. Results Seventy-two South African patients were enrolled in the study; mean age 11.5 years; 82% were girls. The racial distribution was 68% Coloured, 24% Black, 5% White and 3% Asian/Indian. Most patients presented with severe lupus nephritis documented by renal biopsy (61%). Of patients with lupus nephritis, 63% presented with International Society of Nephrology/Renal Pathology Society class III or IV. Patients in the PULSE cohort were more likely to be treated with cyclophosphamide, methotrexate and azathioprine. The PULSE cohort had high disease activity at diagnosis (mean Systemic Lupus Erythematosus Disease Activity Index-2K (SLEDAI-2K) 20.6). The SLEDAI-2K at enrolment in the PULSE cohort (5.0) did not differ from the North American pediatric SLE cohort (4.8). Sixty-three per cent of the PULSE cohort had end organ damage with Systemic Lupus International Collaborating Clinics Damage Index (SLICC-DI) score >0 (mean SLICC DI 1.9), compared to 23% in a previously reported US cohort. Within the PULSE cohort, nine (13%) developed end-stage renal disease with six (8%) requiring transplant, strikingly higher than North American peers (transplant rate <1%). Conclusions The PULSE cohort had highly active multiorgan disease at diagnosis and significant disease damage at enrolment in the South African registry. South African patients have severe lupus nephritis and poor renal outcomes compared to North American peers. Our study revealed a severe disease phenotype in the PULSE cohort resulting in poor outcomes in this high-risk population. PMID- 27488475 TI - Fluoromicrometry: A Method for Measuring Muscle Length Dynamics with Biplanar Videofluoroscopy. AB - Accurate measurements of muscle length changes are essential for understanding the biomechanics of musculoskeletal systems, and can provide insights into muscular work, force, and power. Muscle length has typically been measured in vivo using sonomicrometry, a method that measures distances by sending and receiving sound pulses between piezoelectric crystals. Here, we evaluate an alternative method, fluoromicrometry, which measures muscle length changes over time by tracking the three-dimensional positions of implanted, radio-opaque markers via biplanar videofluoroscopy. To determine the accuracy and precision of fluoromicrometry, we simultaneously measured length changes of an isolated muscle, the frog sartorius, in an in vitro setup using both fluoromicrometry and a servomotor. For fluoromicrometry to perfectly match the results of the servomotor, the relationship between the two measurements should be linear, with a slope of 1. Measurements of muscle shortening from fluoromicrometry and the motor were compared across 11 isotonic contractions. The precision of fluoromicrometry was +/-0.09 mm, measured as the root mean square error of the regression of fluoromicrometry versus servomotor muscle lengths. Fluoromicrometry was also accurate: the mean slope of the fluoromicrometry-servomotor regressions did not differ significantly from the ideal line once off-axis motion was removed. Thus, fluoromicrometry provides a useful alternative for measuring muscle length, especially in studies of live animals, as it permits long-term marker implantation, wireless data collection, and increased spatial sampling. Fluoromicrometry can also be used with X-Ray Reconstruction of Moving Morphology to simultaneously measure muscle shortening and skeletal kinematics, providing a potent new tool for biomechanics research. PMID- 27488474 TI - Improving children's health and development in British Columbia through nurse home visiting: a randomized controlled trial protocol. AB - BACKGROUND: Nurse-Family Partnership is a nurse home visitation program that aims to improve the lives of young mothers and their children. The program focuses on women who are parenting for the first time and experiencing socioeconomic disadvantage. Nurse visits start as early in pregnancy as possible and continue until the child reaches age two years. The program has proven effective in the United States - improving children's mental health and development and maternal wellbeing, and showing long-term cost-effectiveness. But it is not known whether the same benefits will be obtained in Canada, where public services differ. The British Columbia Healthy Connections Project therefore involves a randomized controlled trial evaluating Nurse-Family Partnership's effectiveness compared with existing (usual) services in improving children's mental health and early development and mother's life circumstances. The trial's main aims are to: reduce childhood injuries by age two years (primary outcome indicator); reduce prenatal nicotine and alcohol use; improve child cognitive and language development and behaviour at age two years; and reduce subsequent pregnancies by 24 months postpartum. Potential explanatory factors such as maternal mental health (including self-efficacy) are also being assessed, as is the program's impact on exposure to intimate-partner violence. To inform future economic evaluation, data are also being collected on health and social service access and use. METHODS/DESIGN: Eligible and consenting participants (N = 1040) are being recruited prior to 28 weeks gestation then individually randomized to receive existing services (comparison group) or Nurse-Family Partnership plus existing services (intervention group). Nurse-Family Partnership is being delivered following fidelity guidelines. Data are being collected during in person and telephone interviews at: baseline; 34-36 weeks gestation; and two, 10, 18 and 24 months postpartum. Additional data will be obtained via linkages from provincial datasets. Recruitment commenced in October 2013 and will continue for approximately three years. DISCUSSION: This trial will provide important information about the generalizability of Nurse-Family Partnership to the Canadian context. Findings will be published in peer-reviewed journals and shared with policymakers and practitioners through extensive public health collaborations already underway. TRIAL REGISTRATION: Registered July 18, 2013 with ClinicalTrials.gov Identifier: NCT01672060 . PMID- 27488476 TI - A needs assessment of community pharmacists for pharmacist specialization in Canada. AB - OBJECTIVES: Pharmacists are increasingly providing specialized services. However, no process exists for specialist certification in Canada. The aim of this study was to determine the extent to which Canadian community pharmacists support the development of a certification system for specialization. METHODS: This study utilized a cross-sectional online survey of licensed Canadian pharmacists identified through the member databases of national and regional pharmacy associations. A questionnaire was developed (in French and English) and distributed via email, on behalf of the researchers, by multiple pharmacy organizations in January 2015. Multivariate logistic regressions were conducted to identify which sub-groups of respondents supported the creation of a certification system and which supported mandatory certification. KEY FINDINGS: A total of 770 responses were received. Many respondents were practising specialists (30.0%, 205/683) and the most commonly reported specialty areas were diabetes, smoking cessation and geriatrics. Almost 85% (n = 653/770) supported creation of a Canadian certification process and 68.5% (n = 447/653) felt certification should be mandatory. Respondents believed that the primary benefit of a certification system was greater public confidence in pharmacist specialist skills. They also felt that the most important factor in the development of the system is to create national definitions for specialty practice. The main barrier was the lack of reimbursement for specialty services in Canada. CONCLUSIONS: The majority of Canadian community pharmacist respondents support the creation of a certification process for pharmacist specialization. Future study is required to confirm this finding in a larger sample and to determine the optimal model and the financial feasibility of a national system in Canada. PMID- 27488477 TI - Measuring pediatric quality of care in rural clinics-a multi-country assessment Cambodia, Guatemala, Zambia and Kenya. AB - OBJECTIVE: To assess the quality of care provided in rural pediatric facilities in Cambodia, Guatemala, Kenya and Zambia DESIGN: All public health facilities in four districts in each country were included in the assessment. Based on utilization patterns, five children under five were selected randomly from each facility to perform the Integrated Management of Childhood Illness (IMCI) assessments followed by exit interviews with their caretakers. SETTING: Seventy rural ambulatory pediatric care facilities. PARTICIPANTS: Three hundred and forty pediatric case management observations and exit interviews with child caretakers. MAIN OUTCOME MEASURE: IMCI index of observed quality of care for patient assessment and counseling RESULTS: Screening for danger signs, diarrhea and fever showed significant differences between countries (P < 0.001), with facilities in Cambodia and Guatemala performing better. More than 90% of the children were screened for fever in all three countries, but <75% were screened in Cambodia. The assessment of nutritional status, checking weight against growth chart and palmar pallor for anemia, was suboptimal in all countries. Mean consultation time ranged from 8.2 minutes in Zambia and 12.6 minutes in Guatemala. Child age, consultation time, health provider cadre and presenting symptoms were significantly associated with higher quality of assessment and counseling care as measured by the IMCI index. CONCLUSIONS: Achieving the goals of universal health coverage in these contexts must be complimented with accelerated efforts for capacity investments at the primary care level to ensure optimal quality of healthcare and favorable health outcomes for children, who still experience a high disease burden for these common IMCI conditions. PMID- 27488478 TI - Apocynin Suppresses Lipopolysaccharide-Induced Inflammatory Responses Through the Inhibition of MAP Kinase Signaling Pathway in RAW264.7 Cells. AB - Apocynin, an inhibitor of NADPH oxidase, exhibits anti-inflammatory properties in ulcerative colitis. However, the underlying mechanism by which apocynin exerts this effect has not been clearly demonstrated. The objective of this study was to elucidate the anti-inflammatory mechanism of apocynin in lipopolysaccharide (LPS) challenged RAW264.7 macrophage cells. Apocynin inhibited LPS-induced extracellular secretion of the pro-inflammatory mediators, nitric oxide (NO) and PGE2 and the expression of inducible nitric oxide synthase and cyclooxygenase-2. Apocynin also suppressed LPS-induced secretion of the pro-inflammatory cytokine, tumor necrosis factor-alpha and LPS-induced degradation of IkappaB, which retains NF-kappaB in the cytoplasm, consequently inhibiting the transcription of pro inflammatory genes by NF-kappaB in the nucleus. To elucidate the underlying anti inflammatory mechanism of apocynin, the involvement of the mitogen-activated protein (MAP) kinases, c-jun N-terminal kinase, extracellular signal-regulated kinases, and p38 was examined. Apocynin attenuated LPS-induced activation of all three MAP kinases in a concentration-dependent manner. The present study demonstrates apocynin exerts anti-inflammatory activity via the suppression of MAP kinase signaling pathways in LPS-challenged RAW264.7 macrophage cells. Drug Dev Res, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27488479 TI - Oncological outcomes and complication rates after laparoscopic-assisted cryoablation: a European Registry for Renal Cryoablation (EuRECA) multi institutional study. AB - OBJECTIVE: To assess complication rates and intermediate oncological outcomes of laparoscopic-assisted cryoablation (LCA) in patients with small renal masses (SRMs). PATIENTS AND METHODS: A retrospective review of 808 patients treated with LCA for T1a SRMs from 2005 to 2015 at eight European institutions. Complications were analysed according to the Clavien-Dindo classification. Kaplan-Meier analyses were used to estimate 5- and 10-year disease-free survival (DFS) and overall survival (OS). RESULTS: The median [interquartile (IQR)] age was 67 (58 74) years. The median (IQR) tumour size was 25 (19-30) mm. The transperitoneal approach was used in 77.7% of the patients. The median postoperative hospital stay was 2 days. In all, 514 patients with a biopsy-confirmed renal cell carcinoma (RCC) were available for survival analyses. The median (IQR) follow-up for the RCC-cohort was 36 (14-56) months. A total of 32 patients (6.2%) were diagnosed with treatment failure. The 5-/10-year DFS was 90.4%/80.0% and 5-/10 year OS was 83.2%/64.4%, respectively. A total of 134 postoperative complications (16.6%) were reported, with severe complications (grade >=III) in 26 patients (3.2%). An American Society of Anesthesiologists score of 3 was associated with an increased risk of overall complications (odds ratio 2.85, 95% confidence interval 1.32-6.20; P = 0.005). CONCLUSIONS: This large series of LCA demonstrates satisfactory long-term oncological outcomes for SRMs. However, although LCA is considered a minimally invasive procedure, risk of complications should be considered when counselling patients. PMID- 27488480 TI - Factors associated with suicide among adolescents and young adults not in mental health treatment at time of death. AB - BACKGROUND: Suicide is the third-leading cause of death among Illinois residents aged 15 to 24 years. The Illinois Violent Death Reporting System (IVDRS) was developed to help prevent these deaths by providing timely, complete data. Understanding the circumstances surrounding suicide for those aged 15 to 24 years who are not receiving mental health treatment can help others: (1) recognize signs of potential crisis and (2) connect them to mental health treatment. METHODS: The IVDRS data were collected from five Illinois counties-Cook, DuPage, Kane, McHenry, and Peoria-from 2005 to 2010. All cases with the manner suicide, aged 15 to 24 years, were extracted for analysis. Data were described using frequencies and percentages, and statistical differences between groups were determined using chi analysis. RESULTS: There were a total of 386 suicides in those aged 15 to 24 years in IVDRS from 2005 to 2010. Most 15- to 19-year-olds (67%) and 20- to 24-year-olds (78%) were not receiving mental health treatment at the time of death. Among those not receiving mental health treatment, 22% and 13% of those aged 15 to 19 and 20 to 24 years, respectively, had disclosed their intent to commit suicide to another. One third were identified as being depressed or in a depressed mood (not necessarily a clinical diagnosis) in both age groups. One quarter in both age groups experienced a crisis (current, acute precipitating, or forthcoming event) within 2 weeks of their suicides. CONCLUSIONS: The majority of adolescents and young adults were not in mental health treatment at the time death. Among those not in mental health treatment at the time of death, the 15- to 19-year-olds were more likely to share their suicidal intentions than the 20- to 24-year-olds. LEVEL OF EVIDENCE: Epidemiological study, level IV. PMID- 27488481 TI - The effect of gun control laws on hospital admissions for children in the United States. AB - BACKGROUND: Gun control laws vary greatly between states within the United States. We hypothesized that states with strict gun laws have lower mortality and resource utilization rates from pediatric firearms-related injury admissions. METHODS: Kids' Inpatient Database (1997-2012) was searched for accidental (E922), self-inflicted (E955), assault (E965), legal intervention-related (E970), or undetermined circumstance (E985) firearm injuries. Patients were younger than 20 years and admitted for their injuries. Case incidence trends were examined for the study period. Propensity score-matched analyses were performed using 38 covariates to compare outcomes between states with strict or lenient gun control laws. RESULTS: Overall, 38,424 cases were identified, with an overall mortality of 7%. Firearm injuries were most commonly assault (64%), followed by accidental (25%), undetermined circumstance (7%), or self-inflicted (3%). A small minority involved military-grade weapons (0.2%). Most cases occurred in lenient gun control states (48%), followed by strict (47%) and neutral (6%).On 1:1 propensity score-matched analysis, in-hospital mortality by case was higher in lenient (7.5%) versus strict (6.5%) states, p = 0.013. Lenient states had a proportionally higher rate of accidental (31%) and self-inflicted injury (4%) versus strict states (17% and 1.6%, respectively), p < 0.001. Assault-related injuries were proportionally lower in lenient (54%) versus strict (75%) states, p < 0.001. Military-grade weapons were more common in lenient (0.4%) versus strict (0.1%) states, p = 0.001. CONCLUSIONS: These findings highlight the importance of legislative measures and their role in injury prevention, as firearm injuries are entirely avoidable mechanisms of injury. Lenient gun control contributes not only to worse outcomes per case, but also to a more significant and detrimental impact on public health. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 27488482 TI - An effective way to utilize daycare organizations to distribute home safety equipment. AB - BACKGROUND: Safety equipment installed in the home can reduce pediatric injuries. The purpose of this study was to compare the proper use of home safety equipment installed by an injury prevention specialist to equipment installed by a family after distribution at a daycare. METHODS: A prospective study involving two daycare organizations from a high-risk community was performed. Both groups consisted of families with children 4 to 24 months old who received a packet containing: cabinet and drawer latches, carbon monoxide (CO) detector, magnetic phone list, and five other items. After consent was obtained, both groups completed a prescreen survey to determine current equipment use. The self installation group (SI) from one daycare received home safety equipment and education for self-installation of the equipment. The professional installation group (PI) from a comparable daycare received the same equipment and education; however, equipment was installed for them. Assessments of equipment usage and maintenance were performed at follow-up home visits 6 to 9 months after equipment disbursement. Frequencies and chi analysis were used for comparisons. RESULTS: Seventy-nine SI families and 81 PI families were enrolled. There was no difference in home equipment use between the groups prior to interventions with CO detectors (11.4% vs. 12.3%), cabinet locks (2.5% vs. 11.1%), drawer locks (0% vs. 2.5%), or posted emergency numbers (24.1% vs. 19.8%). Follow-up home visits occurred in 71 SI families (87.7%) and 75 PI families (92.6%). In both groups, there was a significantly increased use of CO detectors (73.2% vs. 89.3%, p = 0.02), cabinet locks (38.0% vs. 78.7%, p < 0.001), and drawer locks (22.5% vs. 62.7%, p < 0.001); posted emergency number increased in both groups, but the difference was not significant (78.9% vs. 89.3%, p = 0.11). CONCLUSION: When provided with home safety equipment, it is used much of the time; however, equipment installed by a professional resulted in higher use than if self installed. For some equipment, distribution of products in daycare settings may be just as effective as if professionally installed. PMID- 27488483 TI - Rear-seat seatbelt laws and restraint use in rear-seated teen passengers traveling in passenger vehicles involved in a fatal collision on a US roadway. AB - BACKGROUND: There is widespread belief that after childhood rear-seated motor vehicle occupants do not need to wear-seat seatbelts to travel safely. This belief is reflected in the fact that, in many states, teen passengers can ride legally unbelted in the rear seat of a passenger vehicle. METHODS: The Fatality Analysis Reporting System for 2010-2011 was used to examine factors associated with teen use of rear-seat seatbelts (n = 3,655) and with injury outcomes of belted and unbelted rear-seated teen passengers traveling in a passenger vehicle on a US roadway. Multilevel models controlled for nonindependence of cases using SAS Glimmix. Odds ratio (OR) is reported with 95% confidence interval (CI). RESULTS: Slightly more than half (50.8%) of rear-seated teens were restrained, but this declined linearly with age from 65.8% of 13- to 14-year-olds to 43.3% of 18- to 19-year-olds. Overall, 77.0% of rear-seat mortality occurred in unbelted teens. Passengers of belted drivers were more frequently belted (64.1% vs. 19.0%, chi = 586.2, p < 0.0001). Nearly one-fifth (18.5%) of rear-seated teens were ejected, with 95.8% of ejections in unrestrained teens. Presence of a rear-seat seatbelt law was associated with higher restraint use (55.9% vs. 40.0%, chi = 89.0, p < 0.0001). However, in adjusted multilevel, multivariable models, belt status varied by whether the seatbelt law was primary (OR, 1.60; 95% CI, 1.29 1.99) or secondary enforcement (OR, 1.33; 95% CI, 0.98-1.78). CONCLUSION: Presence of a primary enforced rear-seat seatbelt law was associated with significantly higher belt use. Ejection was associated with higher mortality and being unrestrained. More than three quarters of rear-seated teens who died were unrestrained. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 27488484 TI - Severe unintentional injuries sustained by Ohio children: Is there urban/rural variation? AB - BACKGROUND: Determining at risk populations is essential to developing interventions that prevent injuries. This study examined the rates of severe unintentional injuries among urban versus rural Ohio children. METHODS: Demographic and injury data for children 0 to 14 years old who had unintentional injuries from January 1, 2003, to December 31, 2012, were extracted retrospectively from the Ohio Trauma Acute Care Registry. Cases with no designated county were excluded. Injury rates per 100,000 children 14 years or younger were calculated annually using county of residence and US census data. Each county was assigned an urbanization level based on population density (A = most urban, D = most rural). RESULTS: There were 40,625 patients from 88 Ohio counties who met the inclusion criteria; the overall annual injury rate was 231.9. The mean age was 6.7 (SD, 4.5) years; 26,035 (64.1%) were male, and 31,468 (77.5%) were white. There were 593 deaths (1.5%). Injury rates by urbanization level were as follows: A: 120.4, B: 196.8, C: 249.1, and D: 247.4 (p = 0.04). Nearly 50% of all deaths occurred in the most urban counties. Those in the most urban areas were more likely to suffer injury from burns, drownings, and suffocations and less likely to be injured by animal bites or motorized vehicle collisions (p < 0.001). Length of stay and injury severity score were highest in the most urban children (p < 0.001). CONCLUSION: While rural counties experienced higher injury rates, urban areas suffered more severe injuries. Specific mechanisms of injury differed by demographics and urbanization in Ohio, suggesting areas for targeted injury prevention. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 27488485 TI - Rates of firearm homicide by Chicago region, age, sex, and race/ethnicity, 2005 2010. AB - BACKGROUND: The United States reports the highest levels of firearm homicide incidences compared to other high income countries, and the focus and causes of these incidences within the US differ by demographic characteristics and location such as urban versus rural environment. Despite these findings, few studies have published on rates varied by region within a city. OBJECTIVE: This study aims to provide descriptive analysis of the rates of firearm homicide by age, sex, and race/ethnicity in each of the seven City of Chicago regions, and to determine if the rates of firearm homicide differ by demographics among the seven City of Chicago regions. METHODS: The Illinois Violent Death Reporting System conducts routine surveillance of violent deaths. Decedents were selected according to the following criteria: manner of death was homicide, weapon type was firearm, and location of injury that led to death was the City of Chicago. Location of injury was broken down by regions: North, Northwest, Center, West, South, Southwest, and Far South. Multiyear rates per 100,000 and corresponding 95% confidence intervals were calculated. RESULTS: There were 2,254 victims of homicide by firearm in the City of Chicago. The overall rate across Chicago for all demographics was 12.9 (12.1-13.5 per 100,000) with an average age of 27.4. The highest age group (20 24) for firearm homicide rates was 43.2 (39.7-46.7) per 100,000. For the youngest age group (10-14), only the Southwest (3.3-10.4) region reported any firearm incidence. The 20 to 24 age group reported the highest rates of all age groups within the South (107.9-151.7), West (80.3-108.2), and Far South (69.6-105.3) regions, whereas the North and Northwest reported the lowest rates for all regions by age. Black firearm homicide rates were 33.5 (31.9-35.1) per 100,000 versus Hispanic and non-Hispanic white firearm homicide rates of 8.5 (7.7-9.3) and 1.2 (1-1.5) per 100,000, respectively. Lastly, the West reported the highest firearm rates at 29.1 (657). CONCLUSION: In conclusion, Chicago is a large city that has high variation in firearm homicide rates among its constituent regions; therefore, an overall firearm homicide rate for the city of Chicago as a whole is not an accurate representation of the true nature of firearm homicides. Policy implementation may be made more effective by providing more regional analysis and targeted interventions via multipronged initiatives to help reduce future firearm rates, and funding for issues that address systemic poverty and adequate access to care and medical facilities. LEVEL OF EVIDENCE: Epidemiologic study, level IV. PMID- 27488486 TI - Evaluating distracted driving behaviors in parents of children in suburban and rural areas of Alabama. AB - BACKGROUND: Distracting driving is considered a dangerous epidemic in teenage drivers and adult drivers nationwide. Cell phone use, such as talking and texting is one of the most common driving distractions among adult and teenage drivers. Using the model of a previously published study from New Haven, Connecticut, we sought to investigate the driving behaviors of parents while transporting their children in Alabama. METHODS: A comparison study was conducted of 150 participants from suburban (n = 86) and rural (n = 64) clinics in Alabama. Participants were recruited to complete a survey regarding their cell phone usage while driving with children. The inclusion criteria were having children younger than 18 years, a valid driver's license, and cell phone and English speaking. The survey consisted of 10 questions focusing on parental driving behaviors. Following the survey, an educational intervention was provided. A Z test proportions was used to compare the responses. RESULTS: Ninety percent of the suburban parents reported cell phone use while driving their children as compared with 86% of the rural parents. A significant difference was found between suburban parents and rural parents for cell phone use in speaker mode (Z = 3.35; p < 0.001; 95% confidence interval, 13-45), reading and sending texts while driving (Z = 4.1; p < 0.001; 95% CI, 19-51), and surfing the Internet (Z = 4.9; p < 0.001; 95% CI, 25-57). There was no statistical significance noted for the following: use of Bluetooth device, talking on the cell phone when parked/at red light, and texting while parked/at red light. CONCLUSIONS: Cell phone use among parents while transporting children is common in the state of Alabama. Parents living in suburban areas use cell phones in the speaker mode, read and send text messages, and surf the Web more often when compared with parents in rural areas. Further research on how to best implement injury prevention interventions should be done to target high-risk areas with distracted driving behaviors. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 27488487 TI - Evaluating the reliability of an injury prevention screening tool: Test-retest study. AB - BACKGROUND: A standardized injury prevention (IP) screening tool can identify family risks and allow pediatricians to address behaviors. To assess behavior changes on later screens, the tool must be reliable for an individual and ideally between household members. Little research has examined the reliability of safety screening tool questions. This study utilized test-retest reliability of parent responses on an existing IP questionnaire and also compared responses between household parents. METHODS: Investigators recruited parents of children 0 to 1 year of age during admission to a tertiary care children's hospital. When both parents were present, one was chosen as the "primary" respondent. Primary respondents completed the 30-question IP screening tool after consent, and they were re-screened approximately 4 hours later to test individual reliability. The "second" parent, when present, only completed the tool once. All participants received a 10-dollar gift card. Cohen's Kappa was used to estimate test-retest reliability and inter-rater agreement. Standard test-retest criteria consider Kappa values: 0.0 to 0.40 poor to fair, 0.41 to 0.60 moderate, 0.61 to 0.80 substantial, and 0.81 to 1.00 as almost perfect reliability. RESULTS: One hundred five families participated, with five lost to follow-up. Thirty-two (30.5%) parent dyads completed the tool. Primary respondents were generally mothers (88%) and Caucasian (72%). Test-retest of the primary respondents showed their responses to be almost perfect; average 0.82 (SD = 0.13, range 0.49-1.00). Seventeen questions had almost perfect test-retest reliability and 11 had substantial reliability. However, inter-rater agreement between household members for 12 objective questions showed little agreement between responses; inter-rater agreement averaged 0.35 (SD = 0.34, range -0.19-1.00). One question had almost perfect inter-rater agreement and two had substantial inter-rater agreement. CONCLUSIONS: The IP screening tool used by a single individual had excellent test retest reliability for nearly all questions. However, when a reporter changes from pre- to postintervention, differences may reflect poor reliability or different subjective experiences rather than true change. PMID- 27488488 TI - Twenty years of Injury Free Coalition for Kids: Precision focus on relentless problems. PMID- 27488489 TI - Teaching leadership in trauma resuscitation: Immediate feedback from a real-time, competency-based evaluation tool shows long-term improvement in resident performance. AB - BACKGROUND: Limited data exist on how to develop resident leadership and communication skills during actual trauma resuscitations. METHODS: An evaluation tool was developed to grade senior resident performance as the team leader during full-trauma-team activations. Thirty actions that demonstrated the Accreditation Council for Graduate Medical Education core competencies were graded on a Likert scale of 1 (poor) to 5 (exceptional). These actions were grouped by their respective core competencies on 5 * 7-inch index cards. In Phase 1, baseline performance scores were obtained. In Phase 2, trauma-focused communication in services were conducted early in the academic year, and immediate, personalized feedback sessions were performed after resuscitations based on the evaluation tool. In Phase 3, residents received only evaluation-based feedback following resuscitations. RESULTS: In Phase 1 (October 2009 to April 2010), 27 evaluations were performed on 10 residents. In Phase 2 (April 2010 to October 2010), 28 evaluations were performed on nine residents. In Phase 3 (October 2010 to January 2012), 44 evaluations were performed on 13 residents. Total scores improved significantly between Phases 1 and 2 (p = 0.003) and remained elevated throughout Phase 3. When analyzing performance by competency, significant improvement between Phases 1 and 2 (p < 0.05) was seen in all competencies (patient care, knowledge, system-based practice, practice-based learning) with the exception of "communication and professionalism" (p = 0.56). Statistically similar scores were observed between Phases 2 and 3 in all competencies with the exception of "medical knowledge," which showed ongoing significant improvement (p = 0.003). CONCLUSIONS: Directed resident feedback sessions utilizing data from a real-time, competency-based evaluation tool have allowed us to improve our residents' abilities to lead trauma resuscitations over a 30-month period. Given pressures to maximize clinical educational opportunities among work-hour constraints, such a model may help decrease the need for costly simulation-based training. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 27488490 TI - Anti-Xa-guided enoxaparin thromboprophylaxis reduces rate of deep venous thromboembolism in high-risk trauma patients. AB - BACKGROUND: Appropriate prophylaxis against venous thromboembolism (VTE) remains undefined. This study evaluated an anti-Xa-guided enoxaparin thromboprophylaxis (TPX) protocol on the incidence of VTE in high-risk trauma patients based on Greenfield's Risk Assessment Profile (RAP) score. METHODS: This is a retrospective observational study of patients admitted to a trauma intensive care unit over a 12-month period. Patients were included if they received anti-Xa guided enoxaparin TPX. Dosage was adjusted to a prophylactic peak anti-Xa level of 0.2 to 0.4 IU/mL. Subgroup analysis was performed on high-risk patients (RAP score >=10) who received lower-extremity duplex ultrasound surveillance for deep vein thrombosis (DVT). Data are expressed as mean +/- SD. Significance was assessed at p < 0.05. RESULTS: One hundred thirty-one patients received anti-Xa guided enoxaparin TPX. Four patients were excluded for age or acute VTE on admission. Fifty-six patients with RAP score of >=10 and surveillance duplex evaluations were included in the subgroup analysis with mean age 43 +/- 20 years, Injury Severity Score of 25 +/- 10, and RAP score of 16 +/- 4. Prophylactic anti Xa levels were initially achieved in 34.6% of patients. An additional 25.2% required 40 to 60 mg twice daily to reach prophylactic levels; 39.4% never reached prophylactic levels. Weight, body mass index, ISS, and RAP score were significantly higher with subprophylactic anti-Xa levels. One patient developed bleeding complications (0.8%). No patient developed intracerebral bleeding or heparin-induced thrombocytopenia.Nine VTE events occurred in the high-risk subgroup, including four DVT (7.1%), all asymptomatic, and five pulmonary emboli (8.9%). The historical rate of DVT in similar patients (ISS 31 +/- 12 and RAP score 16 +/- 5) was 20.5%, a significant decrease (p = 0.031). Mean chest Abbreviated Injury Scale scores were significantly higher for patients developing pulmonary emboli than DVT, 3.0 +/- 1.1 vs. 0.0 (p < 0.001). CONCLUSIONS: Mean chest Abbreviated Injury Scale score was higher in patients developing pulmonary embolism. Increased weight, body mass index, ISS, and RAP score are associated with subprophylactic anti-Xa levels. Anti-Xa-guided enoxaparin dosing reduced the rate of DVT from 20.5% to 7.1% in high-risk trauma patients. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 27488491 TI - Effect of time to operation on mortality for hypotensive patients with gunshot wounds to the torso: The golden 10 minutes. AB - INTRODUCTION: Timely hemorrhage control is paramount in trauma; however, a critical time interval from emergency department arrival to operation for hypotensive gunshot wound (GSW) victims is not established. We hypothesize that delaying surgery for more than 10 minutes from arrival increases all-cause mortality in hypotensive patients with GSW. METHODS: Data of adults (n = 309) with hypotension and GSW to the torso requiring immediate operation from January 2004 to September 2013 were retrospectively reviewed. Patients with resuscitative thoracotomies, traumatic brain injury, transfer from outside institutions, and operations occurring more than 1 hour after arrival were excluded. Survival analysis using multivariate Cox regression models was used for comparison. Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported. Statistical significance was considered at p <= 0.05. RESULTS: The study population was aged 32 +/- 12 years, 92% were male, Injury Severity Score was 24 +/- 15, systolic blood pressure was 81 +/- 29 mm Hg, Glasgow Coma Scale score was 13 +/- 4. Overall mortality was 27%. Mean time to operation was 19 +/- 13 minutes. After controlling for organ injury, patients who arrived to the operating room after 10 minutes had a higher likelihood of mortality compared with those who arrived in 10 minutes or less (HR, 1.89; 95% CI, 1.10-3.26; p = 0.02); this was also true in the severely hypotensive patients with systolic blood pressure of 70 mm Hg or less (HR, 2.67; 95% CI, 0.97-7.34; p = 0.05). The time associated with a 50% cumulative mortality was 16 minutes. CONCLUSIONS: Delay to the operating room of more than 10 minutes increases the risk of mortality by almost threefold in hypotensive patients with GSW. Protocols should be designed to shorten time in the emergency department. Further prospective observational studies are required to validate these findings. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 27488492 TI - A novel methodology to characterize interfacility transfer strategies in a trauma transfer network. AB - BACKGROUND: More than half of severely injured patients are initially transported from the scene of injury to nontrauma centers (NTCs), with many requiring subsequent transfer to trauma center (TC) care. Definitive care in the setting of severe injury is time sensitive. However, transferring severely injured patients from an NTC is a complex process often fraught with delays. Selection of the receiving TC and the mode of interfacility transport both strongly influence total transfer time and are highly amenable to quality improvement initiatives. METHODS: We analyzed transfer strategies, defined as the pairing of a destination and mode of transport (land vs. rotary wing vs. fixed wing), for severely injured adult patients. Existing transfer strategies at each NTC were derived from trauma registry data. Geographic Information Systems network analysis was used to identify the strategy that minimized transfer times the most as well as alternate strategies (+15 or +30 minutes) for each NTC. Transfer network efficiency was characterized based on optimality and stability. RESULTS: We identified 7,702 severely injured adult patients transferred from 146 NTCs to 9 TCs. Nontrauma centers transferred severely injured patients to a median of 3 (interquartile range, 1-4) different TCs and utilized a median of 4 (interquartile range, 2-6) different transfer strategies. After allowing for the use of alternate transfer strategies, 73.1% of severely injured patients were transported using optimal/alternate strategies, and only 40.4% of NTCs transferred more than 90% of patients using an optimal/alternate transfer strategy. Three quarters (75.5%) of transfers occurred between NTCs and their most common receiving TC. CONCLUSION: More than a quarter of patients with severe traumatic injuries undergoing interfacility transport to a TC in Ontario are consistently transported using a nonoptimal combination of destination and mode of transport. Our novel analytic approach can be easily adapted to different system configurations and provides actionable data that can be provided to NTCs and other stakeholders. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 27488493 TI - Activation of the protein C pathway and endothelial glycocalyx shedding is associated with coagulopathy in an ovine model of trauma and hemorrhage. AB - INTRODUCTION: Acute traumatic coagulopathy (ATC) is an endogenous coagulopathy that develops following tissue injury and shock. The pathogenesis of ATC remains poorly understood, with platelet dysfunction, activation of the protein C pathway, and endothelial glycocalyx shedding all hypothesized to contribute to onset. The primary aim of this study was to develop an ovine model of traumatic coagulopathy, with a secondary aim of assessing proposed pathophysiological mechanisms within this model. METHODS: Twelve adult Samm-Border Leicester cross ewes were anesthetized, instrumented, and divided into three groups. The moderate trauma group (n = 4) underwent 20% blood volume hemorrhage, bilateral tibial fractures, and pulmonary contusions. The severe trauma group (n = 4) underwent the same injuries, an additional hamstring crush injury, and 30% blood volume hemorrhage. The remaining animals (n = 4) were uninjured controls. Blood samples were collected at baseline and regularly after injury for evaluation of routine hematology, arterial blood gases, coagulation and platelet function, and factor V, factor VIII, plasminogen activator inhibitor 1, syndecan 1, and hyaluranon levels. RESULTS: At 4 hours after injury, a mean increase in international normalized ratio of 20.50% +/- 12.16% was evident in the severe trauma group and 22.50% +/- 1.00% in the moderate trauma group. An increase in activated partial thromboplastin time was evident in both groups, with a mean of 34.25 +/- 1.71 seconds evident at 2 hours in the severe trauma animals and 34.75 +/- 2.50 seconds evident at 4 hours in the moderate trauma animals. This was accompanied by a reduction in ROTEM EXTEM A10 in the severe trauma group to 40.75 +/- 8.42 mm at 3 hours after injury. Arterial lactate and indices of coagulation function were significantly correlated (R = -0.86, p < 0.0001). Coagulopathy was also correlated with activation of the protein C pathway and endothelial glycocalyx shedding. While a significant reduction in platelet count was evident in the severe trauma group at 30 minutes after injury (p = 0.018), there was no evidence of altered platelet function on induced aggregation testing. Significant fibrinolysis was not evident. CONCLUSIONS: Animals in the severe trauma group developed coagulation changes consistent with current definitions of ATC. The degree of coagulopathy was correlated with the degree of shock, quantified by arterial lactate. Activation of the protein C pathway and endothelial glycocalyx shedding were correlated with the development of coagulopathy; however, altered platelet function was not evident in this model. PMID- 27488494 TI - Inter-relation between brain-derived neurotrophic factor and antioxidant enzymes in bipolar disorder. AB - OBJECTIVES: Accumulating evidence indicates that oxidative stress and neurotrophins have a bidirectional relationship. In this post hoc, exploratory analysis, we investigated the association between plasma brain-derived neurotrophic factor (BDNF) levels and activities of the antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) in individuals with bipolar disorder (BD) and healthy controls. METHODS: We measured plasma levels of BDNF and activities of GPx and SOD in individuals with BD (n=59) and healthy controls (n=26). Information related to current and past psychiatric/medical history, as well as to metabolic comorbidities, was also reported. RESULTS: There were negative correlations between BDNF, GPx (r=-.449, P<=.001) and GPx/SOD ratio (r=-.503, P<.001), and a positive correlation between BDNF and SOD (r=.254, P=.020). There was a moderating effect of body mass index (BMI) on the association between BDNF and GPx/SOD rate ratio [(RR)=1.002, P=.034]; interactions between impaired glucose metabolism (IGM), GPx (RR=1.016, P=.033), and GPx/SOD ratio (RR=1.026, P=.002) were also observed. These results were significant in models that included age, gender, alcohol, tobacco and medication use. CONCLUSIONS: There was a robust and independent correlation between peripheral BDNF and antioxidant enzyme activities in individuals with BD, which was moderated by metabolic comorbidities. These results reinforce the concept that these systems are associated and further extend knowledge of the putative effect of metabolic comorbidities in the pathophysiological substrates of BD. PMID- 27488495 TI - Adiposity influences airway wall thickness and the asthma phenotype of HIV associated obstructive lung disease: a cross-sectional study. AB - BACKGROUND: Airflow obstruction, which encompasses several phenotypes, is common among HIV-infected individuals. Obesity and adipose-related inflammation are associated with both COPD (fixed airflow obstruction) and asthma (reversible airflow obstruction) in HIV-uninfected persons, but the relationship to airway inflammation and airflow obstruction in HIV-infected persons is unknown. The objective of this study was to determine if adiposity and adipose-associated inflammation are associated with airway obstruction phenotypes in HIV-infected persons. METHODS: We performed a cross-sectional analysis of 121 HIV-infected individuals assessed with pulmonary function testing, chest CT scans for measures of airway wall thickness (wall area percent [WA%]) and adipose tissue volumes (mediastinal and subcutaneous), as well as HIV- and adipose-related inflammatory markers. Participants were defined as COPD phenotype (post-bronchodilator FEV1/FVC < lower limit of normal) or asthma phenotype (doctor-diagnosed asthma or bronchodilator response). Pearson correlation coefficients were calculated between adipose measurements, WA%, and pulmonary function. Multivariable logistic and linear regression models were used to determine associations of airflow obstruction and airway remodeling (WA%) with adipose measurements and participant characteristics. RESULTS: Twenty-three (19 %) participants were classified as the COPD phenotype and 33 (27 %) were classified as the asthma phenotype. Body mass index (BMI) was similar between those with and without COPD, but higher in those with asthma compared to those without (mean [SD] 30.7 kg/m(2) [8.1] vs. 26.5 kg/m(2) [5.3], p = 0.008). WA% correlated with greater BMI (r = 0.55, p < 0.001) and volume of adipose tissue (subcutaneous, r = 0.40; p < 0.001; mediastinal, r = 0.25; p = 0.005). Multivariable regression found the COPD phenotype associated with greater age and pack-years smoking; the asthma phenotype with younger age, female gender, smoking history, and lower adiponectin levels; and greater WA% with greater BMI, younger age, higher soluble CD163, and higher CD4 counts. CONCLUSIONS: Adiposity and adipose-related inflammation are associated with an asthma phenotype, but not a COPD phenotype, of obstructive lung disease in HIV infected persons. Airway wall thickness is associated with adiposity and inflammation. Adipose-related inflammation may play a role in HIV-associated asthma. PMID- 27488496 TI - Pulmonary melanoma and "crazy paving" patterns in chest images: a case report and literature review. AB - BACKGROUND: In the lung, melanoma is mostly arranged as patterns of multiple nodules, solitary nodules, or miliary invasions. Very rarely, it also displays a "crazy paving" pattern (also described as a "paving stone," "flagstone," or "slabstone" pattern), which is rarer still in discrete bilateral nodules. This pattern is considered to be caused by pulmonary alveolar proteinosis, but its association with various diseases is unclear. CASE PRESENTATION: A 60-year-old man was diagnosed with pulmonary melanoma. Computed tomography revealed discrete bilateral nodules surrounded by a "paving" pattern. A literature review found more than 40 types of diseases that have presented with "paving" patterns in the lung-predominantly pulmonary alveolar proteinosis, viral pneumonia, exogenous lipoid pneumonia, bacterial pneumonia, pulmonary alveolar microlithiasis, interstitial pneumonia, ARDS, squalene aspiration pneumonia, radiation pneumonitis, drug-induced pneumonitis, pulmonary leptospirosis, pulmonary hemorrhage, and pulmonary nocardiosis. CONCLUSIONS: We describe the first case of pulmonary melanoma in the form of discrete bilateral nodules accompanied with a computed tomography paving pattern. Although pulmonary paving patterns are rare, more than 40 diseases reportedly display them; clinicians should consider melanoma of the lung in differential diagnoses for patients who show such a pattern. PMID- 27488497 TI - Deep-water parasite diversity in Lake Tanganyika: description of two new monogenean species from benthopelagic cichlid fishes. AB - BACKGROUND: Lake Tanganyika is the world's second deepest lake. Its diverse cichlid assemblage offers a unique opportunity for studying a deep-water host parasite model in freshwater. Low host specificity and a broad host range including representatives of the Bathybatini tribe in the only monogenean parasite described from this habitat, Cichlidogyrus casuarinus Pariselle, Muterezi Bukinga & Vanhove, 2015 suggest a link between lower specificity and lower host density. Conversely, high host specificity and species richness are reported for monogeneans of the lake's littoral cichlids. We further investigated whether the deep-water environment in Lake Tanganyika is really monogenean species-depauperate by investigating the monogenean fauna of Trematocara unimaculatum (a representative of the tribe Trematocarini, the sister lineage of the Bathybatini) and Benthochromis horii, a member of the tribe Benthochromini, found in the same deep-water habitat as the already known hosts of C. casuarinus. METHODS: Sclerotised structures of the collected monogenean individuals were characterised morphologically using light microscopy and morphometrics. RESULTS: Both examined cichlid species are infected by a single monogenean species each, which are new to science. They are described as Cichlidogyrus brunnensis n. sp., infecting T. unimaculatum, and Cichlidogyrus attenboroughi n. sp., parasitising on B. horii. Diagnostic characteristics include the distal bifurcation of the accessory piece in C. brunnensis n. sp. and the combination of long auricles and no heel in C. attenboroughi n. sp. In addition C. brunnensis n. sp. does not resemble C. casuarinus, the only species of Cichlidogyrus thus far reported from the Bathybatini. Also Cichlidogyrus attenboroughi n. sp. does not resemble any of the monogenean species documented from the pelagic zone of the lake and is among the few described species of Cichlidogyrus without heel. CONCLUSIONS: As two new and non-resembling Cichlidogyrus species are described from T. unimaculatum and B. horii, colonisation of the deep-water habitat by more than one morphotype of Cichlidogyrus is evident. Based on morphological comparisons with previously described monogenean species, parasite transfers with the littoral zone are possible. Therefore, parasites of pelagic cichlids in the lake do not seem to only mirror host phylogeny and the evolutionary history of this host-parasite system merits further attention. PMID- 27488498 TI - The Status of Methicillin Resistance Among Egyptian Staphylococcus aureus Isolates: An Overview. AB - Methicillin resistant Staphylococcus aureus (MRSA) is responsible for a large number of antibiotic resistant infections worldwide. Understanding the epidemiology and identifying the molecular characteristics of MRSA is elemental in designing infection control plans to minimize the risks associated with these infections. The prevalence of MRSA varies between the different geographic regions. In Egypt, such knowledge is sparse, with a limited number of isolated studies reporting the infection rate of MRSA in select parts of the country. This work summarizes the few published reports that described MRSA prevalence and types in Egypt. PMID- 27488499 TI - Identification of Novel SCIRR69-Interacting Proteins During ER Stress Using SILAC Immunoprecipitation Quantitative Proteomics Approach. AB - Spinal cord injury and regeneration-related protein #69 (SCIRR69),also known as cAMP-responsive element-binding protein 3-like 2, belongs to the CREB/ATF family, some members of which play significant roles in ER stress. However, it is still not fully elucidated whether SCIRR69 involves in ER stress and its biochemical and functional roles during ER stress. In this study, we firstly treated fetal rat spinal cord neuron cells (SCN) and PC12 cells with ER stress activator thapsigargin (TG) or tunicamycin (TM) and then detected the expression pattern of SCIRR69 in response to ER stress at mRNA and protein levels using real-time PCR assay and immunoblotting. Results showed that the expression pattern of SCIRR69 was largely consistent with those of ER stress marker (ATF6, BIP and CHOP) at either mRNA level or protein level, implying that SCIRR69 may play important roles in ER stress. Subsequently, we used stable isotope labeling by amino acids in cell culture (SILAC)-immunoprecipitation quantitative proteomics to identify interaction partners of SCIRR69 during TG-induced ER stress in PC12 cells and found that transitional endoplasmic reticulum ATPase (TERA) and sideroflexin-1 (SFXN1) were potential SCIRR69-interacting proteins. The interaction between SCIRR69 and TERA or SFXN1 was validated using co-immunoprecipitation. Those results provide some clues for novel signaling nexuses that made by interactions between SCIRR69 and TERA or SFXN1. Our findings may facilitate a better understanding of the fundamental functions of SCIRR69 during ER stress. PMID- 27488500 TI - Biological evaluation of dimethylpyridine-platinum complexes with potent antiproliferative activity. AB - This study investigates the effect of three new platinum complexes: Pt2(2,4 dimethylpyridine)4(berenil)2 (Pt14), Pt2(3,4-dimethylpyridine)4(berenil)2 (Pt15) and Pt2(3,5-dimethylpyridine)4(berenil)2 (Pt16) on growth and viability of breast cancer cells and their putative mechanism(s) of cytotoxicity. Cytotoxicity was measured with MTT assay and inhibition of [3H]thymidine incorporation into DNA in both breast cancer cells. Results revealed that Pt14-Pt16 exhibit substantially greater cytotoxicity than cisplatin against MCF-7 and MDA-MB-231 breast cancer cells. In the case of human skin fibroblast cell, cytotoxicity assays demonstrated that these compounds are less toxic to normal cells than cisplatin. In addition, the effects of Pt14-Pt16 are investigated using the flow cytometry assessment of annexin V binding, analysis of mitochondrial potential, markers of apoptosis such as caspase-3, caspase-8, caspase-9, caspase-10 and defragmentation of DNA by TUNEL assay. These results indicate that Pt14-Pt16 induce apoptosis by the mitochondrial and external pathway. PMID- 27488501 TI - wisepair: a computer program for individual matching in genetic tracking studies. AB - Individual-based data sets tracking organisms over space and time are fundamental to answering broad questions in ecology and evolution. A 'permanent' genetic tag circumvents a need to invasively mark or tag animals, especially if there are little phenotypic differences among individuals. However, genetic tracking of individuals does not come without its limits; correctly matching genotypes and error rates associated with laboratory work can make it difficult to parse out matched individuals. In addition, defining a sampling design that effectively matches individuals in the wild can be a challenge for researchers. Here, we combine the two objectives of defining sampling design and reducing genotyping error through an efficient Python-based computer-modelling program, wisepair. We describe the methods used to develop the computer program and assess its effectiveness through three empirical data sets, with and without reference genotypes. Our results show that wisepair outperformed similar genotype matching programs using previously published from reference genotype data of diurnal poison frogs (Allobates femoralis) and without-reference (faecal) genotype sample data sets of harbour seals (Phoca vitulina) and Eurasian otters (Lutra lutra). In addition, due to limited sampling effort in the harbour seal data, we present optimal sampling designs for future projects. wisepair allows for minimal sacrifice in the available methods as it incorporates sample rerun error data, allelic pairwise comparisons and probabilistic simulations to determine matching thresholds. Our program is the lone tool available to researchers to define parameters a priori for genetic tracking studies. PMID- 27488502 TI - Controlled Synthesis of Carbon-Supported Gold Clusters for Rational Catalyst Design. AB - The development of novel catalysts based on metal clusters requires a rational design principle as well as atomically precise synthetic methods. Toward this goal, we have developed a method to precisely and independently control the size, composition, and surface modification of heterogeneous gold clusters by calcination of the ligand-protected Au clusters on carbon supports. We studied the effects of these structural parameters using benzyl alcohol oxidation as a test reaction. Unexpectedly, Au144 and Au~330 on hierarchically porous carbon exhibited significantly higher turnover frequency than Au25 and Au38 . This size dependence is ascribed to the difference in the geometric structures of the Au clusters; Au144 and Au~330 have an icosahedral-based structure whereas Au25 and Au38 have a face-centered cubic structure. Doping of a single Pd atom into Au25 supported on carbon nanotubes remarkably enhanced the catalytic activity. The doping effect is explained in terms of the accelerated formation of the carbocation intermediate due to electron transfer from Pd to Au, since the doped Pd is buried within the Au clusters and is located at the interface between the supports. Residual thiolates on Au25 affected both the activity and selectivity; selective oxidation to benzaldehyde was achieved at optimized coverage. Non formation of benzoic acid is due to the suppression of oxidation activity by electron withdrawal by thiolates and non-formation of benzyl benzoate is due to the site-isolation effect by thiolates. These results will provide useful information for the rational design of gold-cluster-based catalysts with desired performance. PMID- 27488503 TI - Resilience of the Asian atmospheric circulation shown by Paleogene dust provenance. AB - The onset of modern central Asian atmospheric circulation is traditionally linked to the interplay of surface uplift of the Mongolian and Tibetan-Himalayan orogens, retreat of the Paratethys sea from central Asia and Cenozoic global cooling. Although the role of these players has not yet been unravelled, the vast dust deposits of central China support the presence of arid conditions and modern atmospheric pathways for the last 25 million years (Myr). Here, we present provenance data from older (42-33 Myr) dust deposits, at a time when the Tibetan Plateau was less developed, the Paratethys sea still present in central Asia and atmospheric pCO2 much higher. Our results show that dust sources and near-surface atmospheric circulation have changed little since at least 42 Myr. Our findings indicate that the locus of central Asian high pressures and concurrent aridity is a resilient feature only modulated by mountain building, global cooling and sea retreat. PMID- 27488504 TI - Resting state brain dynamics and its transients: a combined TMS-EEG study. AB - The brain at rest exhibits a spatio-temporally rich dynamics which adheres to systematic behaviours that persist in task paradigms but appear altered in disease. Despite this hypothesis, many rest state paradigms do not act directly upon the rest state and therefore cannot confirm hypotheses about its mechanisms. To address this challenge, we combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to study brain's relaxation toward rest following a transient perturbation. Specifically, TMS targeted either the medial prefrontal cortex (MPFC), i.e. part of the Default Mode Network (DMN) or the superior parietal lobule (SPL), involved in the Dorsal Attention Network. TMS was triggered by a given brain state, namely an increase in occipital alpha rhythm power. Following the initial TMS-Evoked Potential, TMS at MPFC enhances the induced occipital alpha rhythm, called Event Related Synchronisation, with a longer transient lifetime than TMS at SPL, and a higher amplitude. Our findings show a strong coupling between MPFC and the occipital alpha power. Although the rest state is organized around a core of resting state networks, the DMN functionally takes a special role among these resting state networks. PMID- 27488505 TI - Variants and pitfalls on radioiodine scans in pediatric patients with differentiated thyroid carcinoma. AB - BACKGROUND: Potentially false-positive findings on radioiodine scans in children with differentiated thyroid carcinoma can mimic functioning thyroid tissue and functioning thyroid carcinomatous tissue. Such false-positive findings comprise variants and pitfalls that can vary slightly in children as compared with adults. OBJECTIVE: To determine the patterns and frequency of these potential false positive findings on radioiodine scans in children with differentiated thyroid carcinoma. MATERIALS AND METHODS: We reviewed a total of 223 radioiodine scans from 53 pediatric patients (mean age 13.3 years, 37 girls) with differentiated thyroid carcinoma. Focal or regional activity that likely did not represent functioning thyroid tissue or functioning thyroid carcinomatous tissue were categorized as variants or pitfalls. The final diagnosis was confirmed by reviewing the concurrent and follow-up clinical data, correlative ultrasonography, CT scanning, serum thyroglobulin and antithyroglobulin antibody levels. We calculated the frequency of these variants and pitfalls from diagnostic and post-therapy radioiodine scans. RESULTS: The most common variant on the radioiodine scans was the thymic activity (24/223, 10.8%) followed by the cardiac activity (8/223, 3.6%). Salivary contamination and star artifact, caused by prominent thyroid remnant, were the most important observed pitfalls. CONCLUSION: Variants and pitfalls that mimic functioning thyroid tissue or functioning thyroid carcinomatous tissue on radioiodine scan in children with differentiated thyroid carcinoma are not infrequent, but they decrease in frequency on successive radioiodine scans. Potential false-positive findings can be minimized with proper knowledge of the common variants and pitfalls in children and correlation with clinical, laboratory and imaging data. PMID- 27488506 TI - Virtual radiology rounds: adding value in the digital era. AB - BACKGROUND: To preserve radiology rounds in the changing health care environment, we have introduced virtual radiology rounds, an initiative enabling clinicians to remotely review imaging studies with the radiologist. OBJECTIVE: We describe our initial experience with virtual radiology rounds and referring provider impressions. MATERIALS AND METHODS: Virtual radiology rounds, a web-based conference, use remote sharing of radiology workstations. Participants discuss imaging studies by speakerphone. Virtual radiology rounds were piloted with the Neonatal Intensive Care Unit (NICU) and the Congenital Cardiovascular Care Unit (CCVCU). Providers completed a survey assessing the perceived impact and overall value of virtual radiology rounds on patient care using a 10-point scale. Pediatric radiologists participating in virtual radiology rounds completed a survey assessing technical, educational and clinical aspects of this methodology. RESULTS: Sixteen providers responded to the survey; 9 NICU and 7 CCVCU staff (physicians, nurse practitioners and fellows). Virtual radiology rounds occurred 4-5 sessions/week with an average of 6.4 studies. Clinicians rated confidence in their own image interpretation with a 7.4 average rating for NICU and 7.5 average rating for CCVCU. Clinicians unanimously rated virtual radiology rounds as adding value. NICU staff preferred virtual radiology rounds to traditional rounds and CCVCU staff supported their new participation in virtual radiology rounds. Four of the five pediatric radiologists participating in virtual radiology rounds responded to the survey reporting virtual radiology rounds to be easy to facilitate (average rating: 9.3), to moderately impact interpretation of imaging studies (average rating: 6), and to provide substantial educational value for radiologists (average rating: 8.3). All pediatric radiologists felt strongly that virtual radiology rounds enable increased integration of the radiologist into the clinical care team (average rating: 8.8). CONCLUSION: Virtual radiology rounds are a viable alternative to radiology rounds enabling improved patient care and education of providers. PMID- 27488507 TI - Image quality and dose differences caused by vendor-specific image processing of neonatal radiographs. AB - BACKGROUND: Image processing plays an important role in optimizing image quality and radiation dose in projection radiography. Unfortunately commercial algorithms are black boxes that are often left at or near vendor default settings rather than being optimized. OBJECTIVE: We hypothesize that different commercial image processing systems, when left at or near default settings, create significant differences in image quality. We further hypothesize that image-quality differences can be exploited to produce images of equivalent quality but lower radiation dose. MATERIALS AND METHODS: We used a portable radiography system to acquire images on a neonatal chest phantom and recorded the entrance surface air kerma (ESAK). We applied two image-processing systems (Optima XR220amx, by GE Healthcare, Waukesha, WI; and MUSICA(2) by Agfa HealthCare, Mortsel, Belgium) to the images. Seven observers (attending pediatric radiologists and radiology residents) independently assessed image quality using two methods: rating and matching. Image-quality ratings were independently assessed by each observer on a 10-point scale. Matching consisted of each observer matching GE-processed images and Agfa-processed images with equivalent image quality. A total of 210 rating tasks and 42 matching tasks were performed and effective dose was estimated. RESULTS: Median Agfa-processed image-quality ratings were higher than GE processed ratings. Non-diagnostic ratings were seen over a wider range of doses for GE-processed images than for Agfa-processed images. During matching tasks, observers matched image quality between GE-processed images and Agfa-processed images acquired at a lower effective dose (11 +/- 9 MUSv; P < 0.0001). CONCLUSION: Image-processing methods significantly impact perceived image quality. These image-quality differences can be exploited to alter protocols and produce images of equivalent image quality but lower doses. Those purchasing projection radiography systems or third-party image-processing software should be aware that image processing can significantly impact image quality when settings are left near default values. PMID- 27488508 TI - Evaluation of motion and its effect on brain magnetic resonance image quality in children. AB - BACKGROUND: Motion artifacts pose significant problems for the acquisition of MR images in pediatric populations. OBJECTIVE: To evaluate temporal motion metrics in MRI scanners and their effect on image quality in pediatric populations in neuroimaging studies. MATERIALS AND METHODS: We report results from a large pediatric brain imaging study that shows the effect of motion on MRI quality. We measured motion metrics in 82 pediatric patients, mean age 13.4 years, in a T1 weighted brain MRI scan. As a result of technical difficulties, 5 scans were not included in the subsequent analyses. A radiologist graded the images using a 4 point scale ranging from clinically non-diagnostic because of motion artifacts to no motion artifacts. We used these grades to correlate motion parameters such as maximum motion, mean displacement from a reference point, and motion-free time with image quality. RESULTS: Our results show that both motion-free time (as a ratio of total scan time) and average displacement from a position at a fixed time (when the center of k-space was acquired) were highly correlated with image quality, whereas maximum displacement was not as good a predictor. Among the 77 patients whose motion was measured successfully, 17 had average displacements of greater than 0.5 mm, and 11 of those (14.3%) resulted in non-diagnostic images. Similarly, 14 patients (18.2%) had less than 90% motion-free time, which also resulted in non-diagnostic images. CONCLUSION: We report results from a large pediatric study to show how children and young adults move in the MRI scanner and the effect that this motion has on image quality. The results will help the motion-correction community in better understanding motion patterns in pediatric populations and how these patterns affect MR image quality. PMID- 27488509 TI - Patient's age rather than severity of the arrhythmia influences the cost of medical treatment of atrioventricular nodal or atrioventricular reciprocating tachycardia. AB - PURPOSE: Radiofrequency ablation (RFA) is considered the treatment of choice in cases of atrioventricular nodal reciprocating tachycardia (AVNRT) and atrioventricular reciprocating tachycardia (AVRT). Published studies suggest a considerable time gap between the onset of the arrhythmia, correct diagnosis, and RFA which may reach 10-15 years. The cost of medical treatment during that period may be substantial. The aim of the study was to calculate the annual direct medical cost of medical treatment of patients with AVNRT and AVRT and identify potential factors influencing this cost. METHODS: Based on the consumption of particular resources and the unit costs of services in 2013, we calculated the annual direct medical cost of care for patients with AVNRT and AVRT in Poland. We adopted the public payer's and societal perspectives. Data on health resources was collected with a structured questionnaire and medical records of patients scheduled for RFA. Additional analyses were performed to identify factors influencing this cost. RESULTS: We enrolled 82 patients: mean age 43.9 +/- 14.1 years old and mean symptom duration before the RFA 13.0 +/- 11.3 years. The median annual cost of medical treatment was 546 USD [312-957], 411 ? [278-786], and 616 USD [369-1044], 464 ? [235-721], for the public payer and the common perspective, respectively, with hospitalizations being the main cost component. In multivariate analysis, only the age of the patient significantly influenced this cost. CONCLUSIONS: The annual cost of medical treatment of AVNRT or AVRT is substantial and dependent on the age of the patient rather than the severity of the arrhythmia (NCT01594814). PMID- 27488511 TI - Occupational exposures among nurses caring for chemotherapy patients Quantitative analysis of cyclophosphamide and alpha-fluoro-beta-alanine in urine. AB - OBJECTIVES: The aim of this study was to measure the antineoplastic drug content in urine and verify the situation of occupational exposure of the antineoplastic drug among nurses who care for patients undergoing chemotherapy. METHODS: Ten female nurses who were caring for patients receiving chemotherapy were the subjects of this study. Urine samples were collected over 24-hour periods, and each sample was analyzed. The excretion of cyclophosphamide (CP) and alpha-fluoro beta-alanine (FBAL) were measured in the urine of the 10 nurses. CP and FBAL were detected separately using gas chromatography tandem mass spectrometry (GC-MSMS) methods (Exposure Control, the Netherlands). RESULT: CP was detected in 24 urine samples of 9 nurses. The total amount of CP excreted ranged from 5.4 to 44.2 ng/24-hours. The mean amount of CP excreted per nurse was 16.8 ng/24-hours. No significant difference was observed between the hospital I and II. FBAL was not detected in any of the urine samples. CP was detected in the urine of the nurses prior to their work shift. Moreover, CP was detected in the urine of the nurses who were not caring for patients in the intravenous drip of CP. There was most what answered that there was hair loss in health condition. CONCLUSION: The results reveal that almost all nurses were exposed to cyclophosphamide. Even when the patient in the intravenous drip of CP was not being cared for, it became clear that exposure by CP existed. As the route of the exposure to CP, the inhalation or dermal absorption can be considered. To ensure minimum exposed to antineoplastic drugs, suitable personal protective equipment needs to be equipped also of various scenes of caring for chemotherapy patients. Moreover, it is important to keep an eye on the monitoring of the antineoplastic drug in the environment and a nurse's health condition periodically going forward. PMID- 27488510 TI - Low-light-level therapy as a treatment for minimal hepatic encephalopathy: behavioural and brain assessment. AB - Minimal hepatic encephalopathy (MHE) has been shown to affect daily functioning, quality of life, driving and overall mortality. However, little is known about treating or diagnosing early impairments involved in MHE. We studied one of its precipitating factors, portal hypertension. The purpose was to evaluate an enhancement in neuronal metabolism through low-light-level therapy (LLLT) and whether this therapy has effects on behavioural task acquisition. Rats were trained to perform a stimulus-response task using the Morris water maze. Three groups of animals were used: a SHAM (sham-operated) group (n = 7), a portal hypertension (PH) group (n = 7) and a PH + LLLT group (n = 7). The triple portal vein ligation method was used to create an animal model of the early developmental phase of HE, and then the animals were exposed to 670 + 10 nm LED light at a dose of 9 J/cm2 once a day for 7 days. The metabolic activity of the brains was studied with cytochrome c oxidase histochemistry. There were differences in behavioural performance, with an improvement in the PH + LLLT group. Energetic brain metabolism revealed significant differences between the groups in all the brain structures analysed, except the anterodorsal thalamus. At the same time, in different brain networks, the PH group showed a more complicated relationship among the structures, while the SHAM and PH + LLLT groups had similar patterns. In this study, we provide the first preliminary insights into the validity of LLLT as a possible intervention to improve memory under minimal hepatic encephalopathy conditions. PMID- 27488512 TI - Impact of drinking and smoking habits on cerebrovascular disease risk among male employees. AB - OBJECTIVE: We aimed to analyze the impact of drinking and smoking behavior on the risk of developing cerebrovascular diseases among male employees aged 20-46 years. Twenty years of follow-up data of male employees enrolled in the DENSO Health Insurance Program were used for analyses. SUBJECTS AND METHODS: Of 29,048 male employees aged 20-46 years who were enrolled in the insurance program in 1994, 25,084 (86.4%) employees underwent annual health check-ups until 2003 without missing an appointment. Of these 25,084 employees, the data of 11,784 (40.6%) employees who self-reported drinking and smoking habits were used for analyses. The hazard ratio and 95% confidence intervals (CIs) for developing cerebrovascular disease in 2004-2013 were calculated in four risk groups categorized as per drinking and smoking behavior in the young group who were in their 20s and the middle-aged group who were in their 30s-40s in 1994. Based on their drinking behavior, participants were categorized into two groups: "not drinking or drinking sometimes" and "drinking every day." Based on their smoking behavior, participants were also categorized into two groups: "not smoking for 10 years" and "smoking for 10 years." RESULTS: A Cox's proportional hazard model revealed that after controlling for body mass index, systolic blood pressure, triglycerides, total cholesterol, fasting plasma glucose, and age, the hazard ratios for "smoking and drinking every day" were 3.82 (95% CI: 1.40-10.41) in the young group and 2.31 (95% CI: 1.27-4.17) in the middle-aged group. DISCUSSION: Male employees who had been drinking and smoking for 10 years had a higher risk of developing cerebrovascular diseases. To prevent cerebrovascular diseases among male employees, it may be effective to offer behavior change interventions for both drinking and smoking habits, regardless of the age group. PMID- 27488513 TI - Anaerobic bacterial contamination after use and assessment of countermeasures a dust mask facepiece. PMID- 27488514 TI - Variability in concentrations of zinc in serum and feed when using zinc oxide as a supplement for the prevention of facial eczema. AB - AIMS: To determine the variability of concentrations of Zn in feed, when used as a supplement to prevent facial eczema, and to determine the variability in concentrations of Zn in serum between cows and herds that are being supplemented with ZnO in feed, using in-shed feeders or on a feed pad. METHODS: Sixteen commercial dairy farms in the Waikato region of New Zealand were enrolled, that were supplementing cows with ZnO in the feed using either an automatic in-shed feeder (ASF) or a feed pad (FP) using a feed-out or mixer wagon. On each farm 10 cows were selected by the farmer, that were assumed to be representative of the age and liveweight of the herd. Four hours after supplement feeding, each cow was weighed and a blood sample collected for measurement of concentrations of Zn in serum. Three samples of feed were collected from each farm for Zn analysis, from the beginning, middle and end of the feed being distributed. Levene's test for homoscedasticity was used to analyse whether there were differences in variation of individual concentrations of Zn in serum, and in the feed, between the two feeding systems. Multivariable linear regression was used to examine associations between age, feeding method or liveweight and concentrations of Zn in serum, after accounting for the variability between farms. RESULTS: Of the 163 cows sampled, concentrations of Zn in serum were between 20-35 umol/L in 75/163 (46 (95% CI=38-54)%) cows; were <20 umol/L in 71/163 (44 (95% CI=36-52)%) cows, and >35 umol/L in 17/163 (10 (95% CI=6-16)%) cows. The variation in concentrations of Zn in serum in individual cows differed between farms (p<0.001), and the variability was greater for cows fed using a FP than ASF (p<0.001). There was no difference in the variation of concentrations of Zn in feed between the two feeding methods (p=0.54), but concentrations of Zn in serum were associated with the amount of Zn offered in feed (p=0.008). CONCLUSIONS AND CLINICIAL RELEVENCE: There was significant variability between farms in the concentrations of Zn in the serum of cows being supplemented with ZnO in feed. Only 46% of cows sampled had concentrations of Zn between 20-35 umol/L. Effective management of facial eczema should include monitoring Zn in the feed and in serum to ensure cows are receiving the correct dose they require. PMID- 27488515 TI - Ultrafast Surface-Enhanced Raman Probing of the Role of Hot Electrons in Plasmon Driven Chemistry. AB - Hot electrons generated through plasmonic excitations in metal nanostructures show great promise for efficiently driving chemical reactions with light. However, the lifetime, yield, and mechanism of action of plasmon-generated hot electrons involved in a given photocatalytic process are not well understood. Here, we develop ultrafast surface-enhanced Raman scattering (SERS) as a direct probe of plasmon-molecule interactions in the plasmon-catalyzed dimerization of 4 nitrobenzenethiol to p,p'-dimercaptoazobenzene. Ultrafast SERS probing of these molecular reporters in plasmonic hot spots reveals transient Fano resonances, which we attribute to near-field coupling of Stokes-shifted photons to hot electron-driven metal photoluminescence. Surprisingly, we find that hot spots that yield more photoluminescence are much more likely to drive the reaction, which indirectly proves that plasmon-generated hot electrons induce the photochemistry. These ultrafast SERS results provide insight into the relative reactivity of different plasmonic hot spot environments and quantify the ultrafast lifetime of hot electrons involved in plasmon-driven chemistry. PMID- 27488516 TI - Factors influencing disclosure among women experiencing intimate partner violence during pregnancy in Moshi Municipality, Tanzania. AB - BACKGROUND: Intimate Partner Violence (IPV) has serious negative health effects to millions of women around the globe. While disclosing IPV could open doors for support and eventually prevent partner abuse, the factors associated with IPV disclosure during pregnancy are not well known. The aim of this study was to examine factors influencing IPV disclosure to any person of interest or organization supporting women during pregnancy in Moshi Municipality, Tanzania. METHODS: Data were from a prospective cohort study of 1123 pregnant women followed-up by the project aiming to assess the impact of violence in the reproductive health conducted in Moshi Municipality, Tanzania from March 2014 to May 2015. Inclusion criteria to the current analysis were all 339 pregnant women who reported to have experienced physical, sexual and/or emotional violence during the index pregnancy. Data analysis used SPSS Version 20. Odds ratio with 95 % Confidence Interval (CI) for factors associated with IPV disclosure was estimated using multivariate logistic regression models while controlling for age, education and parity. A p-value of less than 0.05 was considered for a statistically significant difference. RESULTS: IPV disclosure was found to be 23.3 % (n = 79). Disclosure of IPV was less likely among unemployed (OR = 0.5, 95 % CI 0.30-0.90) and women whose index pregnancy was unplanned (OR = 0.53, 95 % CI 0.29-0.98). Women who regularly participated in women's or community groups, religious groups or political associations at least once a month had 2 times higher odds of IPV disclosure compared to those who did not attend regularly (OR = 2.12, 95 % CI 1.13-3.95). Most of the abused women during pregnancy who disclosed their experience of IPV (69 %) disclosed to a member of the family of birth followed by friends (14 %) and a member of family of the partner (11 %). CONCLUSIONS: Most of the women who experienced IPV during pregnancy kept suffering in silence while less than a quarter of all the abused (23.3 %) disclosed their experience to someone. Identification of the women experiencing IPV during pregnancy should be done as a starting point for supporting victim of IPV. Women empowerment in economical and reproductive health will reduce their vulnerability and facilitate disclosure of IPV for support. Key individuals who informally support victims of IPV should be targeted in interventions. PMID- 27488517 TI - Quality of life among working and non-working adolescents. AB - PURPOSE: This study investigated the association between work, work intensity, and quality of life (QOL) among adolescents in Washington State. METHODS: Data from the 2010 Washington Healthy Youth Survey of public school students in 8, 10, and 12th grades were analyzed. Students were categorized as working or not working. Work intensity was classified by self-reported number of hours worked per week. Respondent QOL was measured using the Youth Quality of Life Instrument Healthy Youth Survey Version (YQOL-HYS). Linear regression models evaluated the association between employment variables and scores on the YQOL-HYS. RESULTS: In total, 27, 26, and 47 % of students in grades 8, 10, and 12 reported currently working, respectively. For 8th and 10th graders, working was significantly associated with lower QOL scores compared to non-working students. Across all grades, increased work intensity was associated with significantly lower QOL. Participation in after-school activities demonstrated a protective effect. CONCLUSIONS: While work is often a positive experience for adolescents, among younger teens and those who work many hours, employment during the school year may have a deleterious impact on QOL. Further research is necessary to better understand whether employment, particularly in early adolescence, may have negative ramifications on QOL among young workers. PMID- 27488518 TI - The impact of HLA-matching on reduced intensity conditioning regimen unrelated donor allogeneic stem cell transplantation for acute myeloid leukemia in patients above 50 years-a report from the EBMT acute leukemia working party. AB - BACKGROUND: Data comparing fully matched and mismatched-unrelated-donor (M- and mM-URD) allogeneic hematopoietic stem cell transplant (allo-SCT) following reduced intensity conditioning regimens for acute myeloid leukemia are limited. METHODS: We retrospectively compared the outcome of 3398 patients above the age of 50 years who underwent 10/10 M-URD (n = 2567), 9/10 (n = 723), or 8/10 (n = 108) mM-URD allo-SCT for acute myeloid leukemia after reduced intensity conditioning regimen between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. RESULTS: HLA matching had no impact on engraftment (p = 0.31). In univariate analysis, in comparison to 10/10 M-URD, mM-URD was associated with higher incidence of grade II-IV acute graft-versus-host disease (GVHD) (p = 0.0002), similar rates of chronic GVHD (p = 0.138) but increased incidence of its extensive form (p = 0.047). Compared to 10/10 M-URD, patients transplanted in the first complete remission (CR1) with a 9 or an 8/10 mM-URD had decreased 2-year leukemia free (LFS) (p = 0.005) and overall survivals (OS) (56.7, 46.1, and 50.2 %, respectively, p = 0.005), while outcomes were comparable between all groups for patients transplanted beyond CR1. In multivariate analysis, 9/10 versus 10/10 URD was associated with higher non-relapse mortality (HR 1.34, p = 0.001), similar risk of relapse and chronic GVHD and inferior LFS (HR 1.25, p = 0.0001), and OS (HR 1.27, p = 0.0001). There was no difference in adjusted transplant outcomes between 9/10 and 8/10 mM-URD. CONCLUSIONS: Reduced intensity conditioned allo-SCT with a 10/10 M-URD remains the preferable option for AML patients above the age of 50 years. The use of a 9/10 or an 8/10 mM-URD in patients not having a fully matched donor represents an alternative therapeutic option that should be compared to other alternative donor transplant strategies. PMID- 27488519 TI - How randomised trials have improved the care of children with kidney disease. AB - Randomised controlled trials (RCTs) provide the most reliable way to evaluate the benefits and harms of interventions. Participants are divided into groups using methods that balance the characteristics (both known and unknown) of the participants between treatment groups; thus, differences in outcomes are due to the interventions administered. From Cochrane Kidney and Transplant's Specialised Register, a comprehensive registry of trials in kidney disease, we identified 482 trials involving children. The vast majority concerned urinary tract infection (UTI; 134) and nephrotic syndrome (136). Most were small, with a median enrolment of 46 children, with only 26 trials enrolling 200 or more participants, and of these, 18 involved children with UTI. We discuss a number of important advances in the care of children with UTI with or without vesico-ureteric reflux, nephrotic syndrome, chronic kidney disease (CKD) and kidney transplantation that have been driven largely by trials in these conditions. PMID- 27488520 TI - Acidosis Acts through HSP90 in a PHD/VHL-Independent Manner to Promote HIF Function and Stem Cell Maintenance in Glioma. AB - Hypoxia is a common feature of solid tumors, which controls multiple aspects of cancer progression. One important function of hypoxia and the hypoxia-inducible factors (HIF) is the maintenance of cancer stem-like cells (CSC), a population of tumor cells that possess stem cell-like properties and drives tumor growth. Among the changes promoted by hypoxia is a metabolic shift resulting in acidification of the tumor microenvironment. Here, we show that glioma hypoxia and acidosis functionally cooperate in inducing HIF transcription factors and CSC maintenance. We found that these effects did not involve the classical PHD/VHL pathway for HIF upregulation, but instead involved the stress-induced chaperone protein HSP90. Genetic or pharmacologic inactivation of HSP90 inhibited the increase in HIF levels and abolished the self-renewal and tumorigenic properties of CSCs induced by acidosis. In clinical specimens of glioma, HSP90 was upregulated in the hypoxic niche and was correlated with a CSC phenotype. Our findings highlight the role of tumor acidification within the hypoxic niche in the regulation of HIF and CSC function through HSP90, with implications for therapeutic strategies to target CSC in gliomas and other hypoxic tumors. Cancer Res; 76(19); 5845-56. (c)2016 AACR. PMID- 27488521 TI - Inducing Differentiation of Premalignant Hepatic Cells as a Novel Therapeutic Strategy in Hepatocarcinoma. AB - Hepatocellular carcinoma (HCC) represents the second leading cause of cancer related deaths and is reported to be resistant to chemotherapy caused by tumor initiating cells. These tumor-initiating cells express stem cell markers. An accumulation of tumor-initiating cells can be found in 2% to 50% of all HCC and is correlated with a poor prognosis. Mechanisms that mediate chemoresistance include drug export, increased metabolism, and quiescence. Importantly, the mechanisms that regulate quiescence in tumor-initiating cells have not been analyzed in detail so far. In this research we have developed a single cell tracking method to follow up the fate of tumor-initiating cells during chemotherapy. Thereby, we were able to demonstrate that mCXCL1 exerts cellular state-specific effects regulating the resistance to chemotherapeutics. mCXCL1 is the mouse homolog of the human IL8, a chemokine that correlates with poor prognosis in HCC patients. We found that mCXCL1 blocks differentiation of premalignant cells and activates quiescence in tumor-initiating cells. This process depends on the activation of the mTORC1 kinase. Blocking of the mTORC1 kinase induces differentiation of tumor-initiating cells and allows their subsequent depletion using the chemotherapeutic drug doxorubicin. Our work deciphers the mCXCL1-mTORC1 pathway as crucial in liver cancer stem cell maintenance and highlights it as a novel target in combination with conventional chemotherapy. Cancer Res; 76(18); 5550-61. (c)2016 AACR. PMID- 27488522 TI - Structural Basis for Induction of Peripheral Neuropathy by Microtubule-Targeting Cancer Drugs. AB - Peripheral neuropathy is a serious, dose-limiting side effect of cancer treatment with microtubule-targeting drugs. Symptoms present in a "stocking-glove" distribution, with longest nerves affected most acutely, suggesting a length dependent component to the toxicity. Axonal transport of ATP-producing mitochondria along neuronal microtubules from cell body to synapse is crucial to neuronal function. We compared the effects of the drugs paclitaxel and ixabepilone that bind along the lengths of microtubules and the drugs eribulin and vincristine that bind at microtubule ends, on mitochondrial trafficking in cultured human neuronal SK-N-SH cells and on axonal transport in mouse sciatic nerves. Antiproliferative concentrations of paclitaxel and ixabepilone significantly inhibited the anterograde transport velocity of mitochondria in neuronal cells, whereas eribulin and vincristine inhibited transport only at significantly higher concentrations. Confirming these observations, anterogradely transported amyloid precursor protein accumulated in ligated sciatic nerves of control and eribulin-treated mice, but not in paclitaxel-treated mice, indicating that paclitaxel inhibited anterograde axonal transport, whereas eribulin did not. Electron microscopy of sciatic nerves of paclitaxel-treated mice showed reduced organelle accumulation proximal to the ligation consistent with inhibition of anterograde (kinesin based) transport by paclitaxel. In contrast, none of the drugs significantly affected retrograde (dynein based) transport in neuronal cells or mouse nerves. Collectively, these results suggest that paclitaxel and ixabepilone, which bind along the lengths and stabilize microtubules, inhibit kinesin-based axonal transport, but not dynein-based transport, whereas the microtubule-destabilizing drugs, eribulin and vincristine, which bind preferentially to microtubule ends, have significantly less effect on all microtubule-based axonal transport. Cancer Res; 76(17); 5115-23. (c)2016 AACR. PMID- 27488523 TI - Exercise and Prognosis on the Basis of Clinicopathologic and Molecular Features in Early-Stage Breast Cancer: The LACE and Pathways Studies. AB - To investigate whether the impact of postdiagnosis exercise on breast cancer outcomes in women diagnosed with early-stage breast cancer differs on the basis of tumor clinicopathologic and molecular features. Using a prospective design, 6,211 patients with early-stage breast cancer from two large population-based cohort studies were studied. Age-adjusted and multivariable Cox regression models were performed to determine the relationship between exercise exposure (total MET hours/week) and recurrence and breast cancer-related death for: (i) all patients ("unselected" cohort), and on the basis of (ii) classic clinicopathologic features, (iii) clinical subtypes, (iv) PAM50-based molecular intrinsic subtypes, and (v) individual PAM50 target genes. After a median follow-up of 7.2 years, in the unselected cohort (n = 6,211) increasing exercise exposure was not associated with a reduction in the risk of recurrence (adjusted Ptrend = 0.60) or breast cancer-related death (adjusted Ptrend = 0.39). On the basis of clinicopathologic features, an exercise-associated reduction in breast cancer-related death was apparent for tumors <2 cm [HR, 0.50; 95% confidence interval (CI), 0.34-0.72], well/moderately differentiated tumors (HR, 0.63; 95% CI, 0.43-0.91), and ER positive tumors (HR, 0.72; 95% CI, 0.53-0.97). Stratification by clinical subtype indicated that the ER(+)/PR(+)/HER2(-)/low-grade clinical subtype was preferentially responsive to exercise (recurrence: adjusted HR, 0.63; 95% CI, 0.45-0.88; breast cancer-related death: adjusted HR, 0.57; 95% CI, 0.37-0.86). The impact of exercise on cancer outcomes appears to differ as a function of pathologic and molecular features in early-stage breast cancer. Cancer Res; 76(18); 5415-22. (c)2016 AACR. PMID- 27488524 TI - In Vivo FRET Imaging of Tumor Endothelial Cells Highlights a Role of Low PKA Activity in Vascular Hyperpermeability. AB - Vascular hyperpermeability is a pathological hallmark of cancer. Previous in vitro studies have elucidated roles of various signaling molecules in vascular hyperpermeability; however, the activities of such signaling molecules have not been examined in live tumor tissues for technical reasons. Here, by in vivo two photon excitation microscopy with transgenic mice expressing biosensors based on Forster resonance energy transfer, we examined the activity of protein kinase A (PKA), which maintains endothelial barrier function. The level of PKA activity was significantly lower in the intratumoral endothelial cells than the subcutaneous endothelial cells. PKA activation with a cAMP analogue alleviated the tumor vascular hyperpermeability, suggesting that the low PKA activity in the endothelial cells may be responsible for the tumor-tissue hyperpermeability. Because the vascular endothelial growth factor (VEGF) receptor is a canonical inducer of vascular hyperpermeability and a molecular target of anticancer drugs, we examined the causality between VEGF receptor activity and the PKA activity. Motesanib, a kinase inhibitor for VEGF receptor, activated tumor endothelial PKA and reduced the vascular permeability in the tumor. Conversely, subcutaneous injection of VEGF decreased endothelial PKA activity and induced hyperpermeability of subcutaneous blood vessels. Notably, in cultured human umbilical vascular endothelial cells, VEGF activated PKA rather than decreasing its activity, highlighting the remarkable difference between its actions in vitro and in vivo These data suggested that the VEGF receptor signaling pathway increases vascular permeability, at least in part, by reducing endothelial PKA activity in the live tumor tissue. Cancer Res; 76(18); 5266-76. (c)2016 AACR. PMID- 27488525 TI - Multivalent Peptoid Conjugates Which Overcome Enzalutamide Resistance in Prostate Cancer Cells. AB - Development of resistance to antiandrogens for treating advanced prostate cancer is a growing concern and extends to recently developed therapeutics, including enzalutamide. Therefore, new strategies to block androgen receptor (AR) function in prostate cancer are required. Here, we report the characterization of a multivalent conjugate presenting two bioactive ethisterone ligands arrayed as spatially defined pendant groups on a peptoid oligomer. The conjugate, named Multivalent Peptoid Conjugate 6 (MPC6), suppressed the proliferation of multiple AR-expressing prostate cancer cell lines including those that failed to respond to enzalutamide and ARN509. The structure-activity relationships of MPC6 variants were evaluated, revealing that increased spacing between ethisterone moieties and changes in peptoid topology eliminated its antiproliferative effect, suggesting that both ethisterone ligand presentation and scaffold characteristics contribute to MPC6 activity. Mechanistically, MPC6 blocked AR coactivator-peptide interaction and prevented AR intermolecular interactions. Protease sensitivity assays suggested that the MPC6-bound AR induced a receptor conformation distinct from that of dihydrotestosterone- or enzalutamide-bound AR. Pharmacologic studies revealed that MPC6 was metabolically stable and displayed a low plasma clearance rate. Notably, MPC6 treatment reduced tumor growth and decreased Ki67 and AR expression in mouse xenograft models of enzalutamide-resistant LNCaP-abl cells. Thus, MPC6 represents a new class of compounds with the potential to combat treatment-resistant prostate cancer. Cancer Res; 76(17); 5124-32. (c)2016 AACR. PMID- 27488526 TI - Paired Exome Analysis Reveals Clonal Evolution and Potential Therapeutic Targets in Urothelial Carcinoma. AB - Greater knowledge concerning tumor heterogeneity and clonality is needed to determine the impact of targeted treatment in the setting of bladder cancer. In this study, we performed whole-exome, transcriptome, and deep-focused sequencing of metachronous tumors from 29 patients initially diagnosed with early-stage bladder tumors (14 with nonprogressive disease and 15 with progressive disease). Tumors from patients with progressive disease showed a higher variance of the intrapatient mutational spectrum and a higher frequency of APOBEC-related mutations. Allele-specific expression was also higher in these patients, particularly in tumor suppressor genes. Phylogenetic analysis revealed a common origin of the metachronous tumors, with a higher proportion of clonal mutations in the ancestral branch; however, 19 potential therapeutic targets were identified as both ancestral and tumor-specific alterations. Few subclones were present based on PyClone analysis. Our results illuminate tumor evolution and identify candidate therapeutic targets in bladder cancer. Cancer Res; 76(19); 5894-906. (c)2016 AACR. PMID- 27488527 TI - Monocyte Induction of E-Selectin-Mediated Endothelial Activation Releases VE Cadherin Junctions to Promote Tumor Cell Extravasation in the Metastasis Cascade. AB - Tumor cells interact with blood constituents and these interactions promote metastasis. Selectins are vascular receptors facilitating interactions of tumor cells with platelets, leukocytes, and endothelium, but the role of endothelial E selectin remains unclear. Here we show that E-selectin is a major receptor for monocyte recruitment to tumor cell-activated endothelium. Experimental and spontaneous lung metastasis using murine tumor cells, without E-selectin ligands, were attenuated in E-selectin-deficient mice. Tumor cell-derived CCL2 promoted endothelial activation, resulting in enhanced endothelial E-selectin expression. The recruitment of inflammatory monocytes to metastasizing tumor cells was dependent on the local endothelial activation and the presence of E-selectin. Monocytes promoted transendothelial migration of tumor cells through the induction of E-selectin-dependent endothelial retractions and a subsequent modulation of tight junctions through dephosphorylation of VE-cadherin. Thus, endothelial E-selectin shapes the tumor microenvironment through the recruitment, adhesion, and activation of monocytes that facilitate tumor cell extravasation and thereby metastasis. These findings provide evidence that endothelial E selectin is a novel factor contributing to endothelial retraction required for efficient lung metastasis. Cancer Res; 76(18); 5302-12. (c)2016 AACR. PMID- 27488528 TI - Splenic Marginal Zone Granulocytes Acquire an Accentuated Neutrophil B-Cell Helper Phenotype in Chronic Lymphocytic Leukemia. AB - Recruitment of tumor-associated macrophages and neutrophils (TAM and TAN) to solid tumors contributes to immunosuppression in the tumor microenvironment; however, their contributions to lymphoid neoplasms are less clear. In human chronic lymphocytic leukemia (CLL), tumor B cells lodge in lymph nodes where interactions with the microenvironment occur. Tumor cell homing stimulates proliferation, such that engagement of the B-cell receptor is important for malignant progression. In the EMU-Tcl1 murine model of CLL, we identified gene expression signatures indicative of a skewed polarization in the phenotype of monocytes and neutrophils. Selective ablation of either of these cell populations in mice delayed leukemia growth. Despite tumor infiltration of these immune cells, a systemic inflammation was not detected. Notably, in progressive CLL, splenic neutrophils were observed to differentiate toward a B-cell helper phenotype, a process promoted by the induction of leukemia-associated IL10 and TGFbeta. Our results suggest that targeting aberrant neutrophil differentiation and restoring myeloid cell homeostasis could limit the formation of survival niches for CLL cells. Cancer Res; 76(18); 5253-65. (c)2016 AACR. PMID- 27488529 TI - TG2 and NF-kappaB Signaling Coordinates the Survival of Mantle Cell Lymphoma Cells via IL6-Mediated Autophagy. AB - Expression of the transglutaminase TG2 has been linked to constitutive activation of NF-kappaB and chemotherapy resistance in mantle cell lymphoma (MCL) cells. TG2 forms complexes with NF-kappaB components, but mechanistic insights that could be used to leverage therapeutic responses has been lacking. In the current study, we address this issue with the discovery of an unexpected role for TG2 in triggering autophagy in drug-resistant MCL cells through induction of IL6. CRISPR-mediated silencing of TG2 delayed apoptosis while overexpressing TG2 enhanced tumor progression. Under stress, TG2 and IL6 mediate enhanced autophagy formation to promote MCL cell survival. Interestingly, the autophagy product ATG5 involved in autophagosome elongation positively regulated TG2/NF-kappaB/IL6 signaling, suggesting a positive feedback loop. Our results uncover an interconnected network of TG2/NF-kappaB and IL6/STAT3 signaling with autophagy regulation in MCL cells, the disruption of which may offer a promising therapeutic strategy. Cancer Res; 76(21); 6410-23. (c)2016 AACR. PMID- 27488531 TI - An In Vivo Reporter to Quantitatively and Temporally Analyze the Effects of CDK4/6 Inhibitor-Based Therapies in Melanoma. AB - Aberrant cell-cycle progression is a hallmark feature of cancer cells. Cyclin dependent kinases 4 and 6 (CDK4/6) drive progression through the G1 stage of the cell cycle, at least in part, by inactivating the tumor suppressor, retinoblastoma. CDK4/6 are targetable and the selective CDK4/6 inhibitor, palbociclib, was recently FDA approved for the treatment of estrogen receptor positive, HER2-negative advanced breast cancer. In cutaneous melanoma, driver mutations in NRAS and BRAF promote CDK4/6 activation, suggesting that inhibitors such as palbociclib are likely to provide therapeutic benefit in combination with BRAF inhibitors and/or MEK inhibitors that are FDA-approved. However, the determinants of the response to CDK4/6 inhibitors alone and in combination with other targeted inhibitors are poorly defined. Furthermore, in vivo systems to quantitatively and temporally measure the efficacy of CDK4/6 inhibitors and determine the extent that CDK activity is reactivated during acquired resistance are lacking. Here, we describe the heterogeneous effects of CDK4/6 inhibitors, the expression of antiapoptotic proteins that associate with response to CDK4/6 and MEK inhibitors, and the development of a luciferase-based reporter system to determine the effects of CDK4/6 inhibitors alone and in combination with MEK inhibitors in melanoma xenografts. These findings are likely to inform on-going and future clinical trials utilizing CDK4/6 inhibitors in cutaneous melanoma. Cancer Res; 76(18); 5455-66. (c)2016 AACR. PMID- 27488530 TI - JARID1B Enables Transit between Distinct States of the Stem-like Cell Population in Oral Cancers. AB - The degree of heterogeneity among cancer stem cells (CSC) remains ill-defined and may hinder effective anti-CSC therapy. Evaluation of oral cancers for such heterogeneity identified two compartments within the CSC pool. One compartment was detected using a reporter for expression of the H3K4me3 demethylase JARID1B to isolate a JARID1B(high) fraction of cells with stem cell-like function. JARID1B(high) cells expressed oral CSC markers including CD44 and ALDH1 and showed increased PI3K pathway activation. They were distinguished from a fraction in a G0-like cell-cycle state characterized by low reactive oxygen species and suppressed PI3K/AKT signaling. G0-like cells lacked conventional CSC markers but were primed to acquire stem cell-like function by upregulating JARID1B, which directly mediated transition to a state expressing known oral CSC markers. The transition was regulated by PI3K signals acting upstream of JARID1B expression, resulting in PI3K inhibition depleting JARID1B(high) cells but expanding the G0 like subset. These findings define a novel developmental relationship between two cell phenotypes that may jointly contribute to CSC maintenance. Expansion of the G0-like subset during targeted depletion of JARID1B(high) cells implicates it as a candidate therapeutic target within the oral CSC pool. Cancer Res; 76(18); 5538 49. (c)2016 AACR. PMID- 27488532 TI - The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma. AB - Despite advances in diagnostics, less than 5% of patients with periampullary tumors experience an overall survival of five years or more. Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater, an enlargement of liver and pancreas ducts where they join and enter the small intestine. In this study, we analyzed copy number aberrations using Affymetrix SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo University Hospital to identify genome-wide copy number aberrations, putative driver genes, deregulated pathways, and potential prognostic markers. Results were validated in a separate cohort derived from The Cancer Genome Atlas Consortium (n = 127). In contrast to many other solid tumors, periampullary adenocarcinomas exhibited more frequent genomic deletions than gains. Genes in the frequently codeleted region 17p13 and 18q21/22 were associated with cell cycle, apoptosis, and p53 and Wnt signaling. By integrating genomics and transcriptomics data from the same patients, we identified CCNE1 and ERBB2 as candidate driver genes. Morphologic subtypes of periampullary adenocarcinomas (i.e., pancreatobiliary or intestinal) harbor many common genomic aberrations. However, gain of 13q and 3q, and deletions of 5q were found specific to the intestinal subtype. Our study also implicated the use of the PAM50 classifier in identifying a subgroup of patients with a high proliferation rate, which had impaired survival. Furthermore, gain of 18p11 (18p11.21-23, 18p11.31-32) and 19q13 (19q13.2, 19q13.31-32) and subsequent overexpression of the genes in these loci were associated with impaired survival. Our work identifies potential prognostic markers for periampullary tumors, the genetic characterization of which has lagged. Cancer Res; 76(17); 5092-102. (c)2016 AACR. PMID- 27488533 TI - Stimulation of Natural Killer Cell-Mediated Tumor Immunity by an IL15/TGFbeta Neutralizing Fusion Protein. AB - The clinical efficacy of immune cytokines used for cancer therapy is hampered by elements of the immunosuppressive tumor microenvironment such as TGFbeta. Here we demonstrate that FIST15, a recombinant chimeric protein composed of the T-cell stimulatory cytokine IL15, the sushi domain of IL15Ralpha and a TGFbeta ligand trap, can overcome immunosuppressive TGFbeta to effectively stimulate the proliferation and activation of natural killer (NK) and CD8+ T cells with potent antitumor properties. FIST15-treated NK and CD8+ T cells produced more IFNgamma and TNFalpha compared with treatment with IL15 and a commercially available TGFbeta receptor-Fc fusion protein (sTbetaRII) in the presence of TGFbeta. Murine B16 melanoma cells, which overproduce TGFbeta, were lysed by FIST15-treated NK cells in vitro at doses approximately 10-fold lower than NK cells treated with IL15 and sTbetaRII. Melanoma cells transduced to express FIST15 failed to establish tumors in vivo in immunocompetent murine hosts and could only form tumors in beige mice lacking NK cells. Mice injected with the same cells were also protected from subsequent challenge by unmodified B16 melanoma cells. Finally, mice with pre-established B16 melanoma tumors responded to FIST15 treatment more strongly compared with tumors treated with control cytokines. Taken together, our results offer a preclinical proof of concept for the use of FIST15 as a new class of biological therapeutics that can coordinately neutralize the effects of immunosuppressive TGFbeta in the tumor microenvironment while empowering tumor immunity. Cancer Res; 76(19); 5683-95. (c)2016 AACR. PMID- 27488536 TI - Exceptional Single-Molecule Transport Properties of Ladder-Type Heteroacene Molecular Wires. AB - A series of ladder-type fused heteroacenes consisting of thiophenes and benzothiophenes were synthesized and functionalized with thiol groups for single molecule electrical measurements via a scanning tunneling microscopy break junction method. It was found that this molecular wire system possesses exceptional charge transport properties with weak length dependence. The tunneling decay constant beta was estimated to be 0.088 and 0.047 A(-1) under 0.1 and 0.5 bias, respectively, which is one of the lowest beta values among other non-metal-containing molecular wires, indicating that a planar ladder structure favors charge transport. Transition voltage spectroscopy showed that the energy barrier decreases as the length of the molecule increases. The general trend of the energy offsets derived from the transition voltage via the Newns-Anderson model agrees well with that of the Fermi/HOMO energy level difference. Nonequilibrium Green's function/density functional theory was used to further investigate the transport process in these molecular wires. PMID- 27488534 TI - Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk. AB - Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3'-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 * 10-8). CYP2A6 activity was correlated (r = 0.32; P < 0.0001) with total nicotine equivalents (a measure of nicotine uptake). When we examined the effect of these variants on lung cancer risk in the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium GWAS dataset (13,479 cases and 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. Two hundred and twenty-six of the 248 variants associated with CYP2A6 activity in the MEC were available in TRICL. Of them, 81% had directionally consistent risk estimates, and six were globally significantly associated with lung cancer. When conditioning on nine known functional variants and two deletions, the top two SNPs (rs56113850 in MEC and rs35755165 in TRICL) remained significantly associated with CYP2A6 activity in MEC and lung cancer in TRICL. The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer. Although the variants identified in these studies may be used as risk prediction markers, the exact causal variants remain to be identified. Cancer Res; 76(19); 5768-76. (c)2016 AACR. PMID- 27488537 TI - Diffusion-Induced Hydrophilic Conversion of Polydimethylsiloxane/Block-Type Phospholipid Polymer Hybrid Substrate for Temporal Cell-Adhesive Surface. AB - In this study, diffusion-induced hydrophobic-hydrophilic conversion of the surface of the cross-linked polydimethylsiloxane (PDMS) substrate was realized by employing a simple swelling-deswelling process of PDMS substrate in a block-type polymer solution with the aim of development of a temporal cell-adhesive substrate. The ABA block-type polymer composed of poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) segment and PDMS segment with over 70% of dimethylsiloxane unit composition could be successfully incorporated in the PDMS substrate during the swelling-deswelling process to prepare the PDMS/phospholipid block copolymer hybrid substrates. During the aging process of the PDMS substrate for 4 days in aqueous medium, its surface property changed gradually from hydrophobic to hydrophilic. X-ray photoelectron spectroscopy and atomic force microscopy data provided strong evidence that the time-dependent hydrophilic conversion of the PDMS/block-type phospholipid polymer hybrid substrate was induced by the diffusion of the hydrophilic PMPC segment in the block-type polymer to be tethered on the substrate. During the hydrophilic conversion process, surface-adsorbed fibronectin was gradually desorbed from the substrate surface, and this resulted in successful detachment of two-dimensional connected cell crowds. PMID- 27488535 TI - Heme Oxygenase-1 Controls an HDAC4-miR-206 Pathway of Oxidative Stress in Rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is an aggressive soft tissue cancer characterized by disturbed myogenic differentiation. Here we report a role for the oxidative stress response factor HO-1 in progression of RMS. We found that HO-1 was elevated and its effector target miR-206 decreased in RMS cell lines and clinical primary tumors of the more aggressive alveolar phenotype (aRMS). In embryonal RMS (eRMS), HO-1 expression was induced by Pax3/7-FoxO1, an aRMS hallmark oncogene, followed by a drop in miR-206 levels. Inhibition of HO-1 by tin protoporphyrin (SnPP) or siRNA downregulated Pax3/7-FoxO1 target genes and induced a myogenic program in RMS. These effects were not mediated by altered myoD expression; instead, cells with elevated HO-1 produced less reactive oxygen species, resulting in nuclear localization of HDAC4 and miR-206 repression. HO-1 inhibition by SnPP reduced growth and vascularization of RMS tumors in vivo accompanied by induction of miR-206. Effects of SnPP on miR-206 expression and RMS tumor growth were mimicked by pharmacologic inhibition of HDAC. Thus, HO-1 inhibition activates an miR-206-dependent myogenic program in RMS, offering a novel therapeutic strategy for treatment of this malignancy. Cancer Res; 76(19); 5707-18. (c)2016 AACR. PMID- 27488538 TI - Sensory neuropathy in progressive motor neuronopathy (pmn) mice is associated with defects in microtubule polymerization and axonal transport. AB - Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) are now recognized as multi-system disorders also involving various non-motor neuronal cell types. The precise extent and mechanistic basis of non-motor neuron damage in human ALS and ALS animal models remain however unclear. To address this, we here studied progressive motor neuronopathy (pmn) mice carrying a missense loss of-function mutation in tubulin binding cofactor E (TBCE). These mice manifest a particularly aggressive form of motor axon dying back and display a microtubule loss, similar to that induced by human ALS-linked TUBA4A mutations. Using whole nerve confocal imaging of pmn * thy1.2-YFP16 fluorescent reporter mice and electron microscopy, we demonstrate axonal discontinuities, bead-like spheroids and ovoids in pmn suralis nerves indicating prominent sensory neuropathy. The axonal alterations qualitatively resemble those in phrenic motor nerves but do not culminate in the loss of myelinated fibers. We further show that the pmn mutation decreases the level of TBCE, impedes microtubule polymerization in dorsal root ganglion (DRG) neurons and causes progressive loss of microtubules in large and small caliber suralis axons. Live imaging of axonal transport using GFP tagged tetanus toxin C-fragment (GFP-TTC) demonstrates defects in microtubule based transport in pmn DRG neurons, providing a potential explanation for the axonal alterations in sensory nerves. This study unravels sensory neuropathy as a pathological feature of mouse pmn, and discusses the potential contribution of cytoskeletal defects to sensory neuropathy in human motor neuron disease. PMID- 27488539 TI - Silence of MACC1 decreases cell migration and invasion in human malignant melanoma through inhibiting the EMT. AB - Metastasis-associated colon cancer 1 (MACC1) has been demonstrated to promote metastasis of several cancers via regulating epithelial-mesenchymal transition (EMT). However, its biological behavior in human malignant melanoma remains unclear. In this study, MACC1 downregulation was established in two melanoma cell lines (A375 and G361 cells) using RNA interference, as confirmed by quantitative real time PCR (qRT-PCR) and Western blot analysis. Subsequently, we investigated the effects of MACC1 silencing on cell mobility, migration and invasion using scratch wound and Transwell assays. Our results indicated that knockdown of MACC1 significantly suppressed cell migration and invasion ability of both melanoma cell lines. Moreover, downregulation of MACC1 upregulated E-cadherin, N-cadherin and Vimentin, as confirmed by qRT-PCR, Western blot and immunofluorescent Staining analysis. These findings suggest MACC1 might serve as a new molecular target for the treatment of melanoma by a novel mechanism underlying the metastasis of melanoma cells. PMID- 27488540 TI - Effects of iron and carbon monoxide on Lachesis muta muta venom-mediated degradation of plasmatic coagulation. AB - Hypofibrinogenemia is an important clinical consequence following envenomation by Lachesis muta muta, usually attenuated or prevented by administration of antivenom. The venom of L. m. muta contains both a metalloproteinase fibrinogenase and a serine protease thrombin-like enzyme, and exposure of fibrinogen to iron (Fe) and carbon monoxide (CO) has been demonstrated to decrease its catalysis by such enzymes. Using thrombelastographic analytical techniques, it was determined that this venom displayed weak procoagulant effects combined with fibrinogenolytic effects, and pretreatment of plasma with Fe and CO markedly attenuated venom-mediated effects. Additional experiments involving heparin exposure and varying calcium concentrations demonstrated that modification of fibrinogen with Fe and CO in human plasma rendered fibrinogen not recognizable to the fibrinogenolytic metalloproteinase but did not prevent polymerization by the thrombin-like serine protease. Lastly, when venom was exposed to CO in isolation and then placed in plasma, the fibrinogenase was inhibited but the thrombin-like enzyme was not inhibited. In sum, utilizing relatively facile modifications, we demonstrated with thrombelastography that Fe and/or CO addition can protect human plasmatic coagulation from fibrinogenase activity but not the effects of the thrombin-like activity of L. m. muta venom. PMID- 27488542 TI - NEET: India's single exam for admission to medical school promises transparency and quality. PMID- 27488541 TI - [Complex regional pain syndrome following distal fractures of the radius : Epidemiology, pathophysiological models, diagnostics and therapy]. AB - The complex regional pain syndrome (CRPS) still represents an incompletely etiologically understood complication following fractures of the distal radius. The incidence of CRPS following fractures of the distal radius varies between 1 % and 37 %. Pathophysiologically, a complex interaction of inflammatory, somatosensory, motor and autonomic changes is suspected, leading to a persistent maladaptive response and sensitization of the central and peripheral nervous systems with development of the corresponding symptoms. Decisive for the diagnostics are a detailed patient medical history and a clinical hand surgical, neurological and pain-related examination with confirmation of the Budapest criteria. Among the types of apparatus used for diagnostics, 3-phase bone scintigraphy and temperature measurement have a certain importance. A multimodal therapy started as early as possible is the most promising approach for successful treatment. As part of a multimodal rehabilitation the main focus of therapy lies on pain relief and functional aspects. PMID- 27488543 TI - Rufibacter ruber sp. nov., isolated from fragmentary rock. AB - A red-pigmented, Gram-stain-negative, rod-shaped, aerobic bacterium, designated strain CCM 8646T, was isolated from stone fragments in James Ross Island, Antarctica. Strain CCM 8646T was able to grow from 10 to 40 degrees C, in the presence of up to 1 % (w/v) NaCl and at pH 7.0-11.0. Analysis of the 16S rRNA gene sequence placed strain CCM 8646T in the genus Rufibacter with the closest relative being Rufibacter roseus H359T (97.07 % 16S rRNA gene sequence similarity). The digital DNA-DNA hybridization values between strain CCM 8646T and R. roseus H359T were low (21.30+/-2.34 %). The major quinone was menaquinone MK-7. The polar lipids comprised phosphatidylethanolamine, an unknown aminoglycolipid and six unknown polar lipids. The G+C content of strain CCM 8646T was 51.54 mol%. On the basis of phenotypic, chemotaxonomic and genotyping results, strain CCM 8646T is considered to represent a novel species within the genus Rufibacter, for which the name Rufibacter ruber sp. nov. is proposed. The type strain is CCM 8646T (=LMG 29438T). PMID- 27488545 TI - Age-related differences in trunk muscle reflexive behaviors. AB - Reports of larger passive and similar intrinsic trunk stiffness in older vs. younger populations suggest a diminishing demand for reflexive contributions of trunk muscles to spinal stability with aging. It remains unclear, though, whether such diminishing demands result in deterioration of trunk muscle reflexive behaviors. A cross-sectional study was completed to assess age-related differences in the latency and likelihood of trunk muscle reflexive responses to sudden perturbations. Sixty healthy individuals, aged 20-70 years, were recruited to form five equal-sized and gender-balanced age groups. Using a displacement control, sudden perturbation paradigm, the latency and likelihood of trunk muscle reflexive responses to sudden perturbations were estimated, and the influences of age, gender, and level of effort (20% versus 30% of maximum voluntary exertion MVE) were evaluated. There were no consistent age-related differences found in any of the measures of trunk muscle reflexive behavior. However, the latency of muscle response to perturbation was generally higher among older individuals, and this difference was significant in the condition involving 30% MVE effort. With an increase in level of effort (from 20% to 30% of MVE), there was a ~7% increase in the latency of trunk muscle responses to anteriorly-directed perturbations as well as ~ 15% (21%) decrease (increase) in response likelihood during anteriorly (posteriorly) directed perturbations. Furthermore, the reflexive response likelihood of trunk muscles was 28% (58%) larger (smaller) in female vs. male participants during anteriorly (posteriorly) directed perturbations. Our results did not, in general, support the hypothesis of an age-related decay in reflexive trunk muscle behaviors. Larger reflexive responses were associated with lower trunk intrinsic stiffness among females and during a lower level of effort, suggesting a secondary role for reflexive responses in spinal stability. Such secondary compensatory responses appear, however, to be consistent over a wide age range. PMID- 27488546 TI - Consensus documents and challenges in hypertension research. PMID- 27488544 TI - Significant improvement of direct reprogramming efficacy of fibroblasts into progenitor endothelial cells by ETV2 and hypoxia. AB - BACKGROUND: Endothelial progenitor cell (EPC) transplantation is a promising therapy for ischemic diseases such as ischemic myocardial infarction and hindlimb ischemia. However, limitation of EPC sources remains a major obstacle. Direct reprogramming has become a powerful tool to produce EPCs from fibroblasts. Some recent efforts successfully directly reprogrammed human fibroblasts into functional EPCs; however, the procedure efficacy was low. This study therefore aimed to improve the efficacy of direct reprogramming of human fibroblasts to functional EPCs. METHODS: Human fibroblasts isolated from foreskin were directly reprogrammed into EPCs by viral ETV2 transduction. Reprogramming efficacy was improved by culturing transduced fibroblasts in hypoxia conditions (5 % oxygen). Phenotype analyses confirmed that single-factor ETV2 transduction successfully reprogrammed dermal fibroblasts into functional EPCs. RESULTS: Hypoxia treatment during the reprogramming procedure increased the efficacy of reprogramming from 1.21 +/- 0.61 % in normoxia conditions to 7.52 +/- 2.31 % in hypoxia conditions. Induced EPCs in hypoxia conditions exhibited functional EPC phenotypes similar to those in normoxia conditions, such as expression of CD31 and VEGFR2, and expressed endothelial gene profiles similar to human umbilical vascular endothelial cells. These cells also formed capillary-like networks in vitro. CONCLUSION: Our study demonstrates a new simple method to increase the reprogramming efficacy of human fibroblasts to EPCs using ETV2 and hypoxia. PMID- 27488547 TI - Joint statement of the European Association for the Study of Obesity and the European Society of Hypertension: obesity and heart failure. AB - Obese individuals are more likely to develop heart failure. Yet, once heart failure is established, the impact of overweight and obesity on prognosis and survival is unclear. The purpose of this joint scientific statement of the European Association for the Study of Obesity and the European Society of Hypertension is to provide an overview on the current scientific literature on obesity and heart failure in terms of prognosis, mechanisms, and clinical management implications. Moreover, the document identifies open questions that ought to be addressed. The need for more tailored weight management recommendations in heart failure will be emphasized and, in line with the emerging evidence, aims to distinguish between primary disease and secondary outcome prevention. In the primary prevention of heart failure, it appears prudent advising obese individuals to lose or achieve a healthy body weight, especially in those with risk factors such as hypertension or type 2 diabetes. However, there is no evidence from clinical trials to guide weight management in overweight or obese patients with established heart failure. Prospective clinical trials are strongly encouraged. PMID- 27488548 TI - ECG left atrial abnormality: a marker of stroke prediction in hypertension. PMID- 27488549 TI - Spironolactone versus renal nerve denervation for treatment of uncontrolled resistant hypertension. PMID- 27488550 TI - Impact of volunteer-related and methodology-related factors on the reproducibility of brachial artery flow-mediated vasodilation: analysis of 672 individual repeated measurements. AB - OBJECTIVES: Brachial artery flow-mediated dilation (FMD) is a popular technique to examine endothelial function in humans. Identifying volunteer and methodological factors related to variation in FMD is important to improve measurement accuracy and applicability. METHODS: Volunteer-related and methodology-related parameters were collected in 672 volunteers from eight affiliated centres worldwide who underwent repeated measures of FMD. All centres adopted contemporary expert-consensus guidelines for FMD assessment. After calculating the coefficient of variation (%) of the FMD for each individual, we constructed quartiles (n = 168 per quartile). Based on two regression models (volunteer-related factors and methodology-related factors), statistically significant components of these two models were added to a final regression model (calculated as beta-coefficient and R). This allowed us to identify factors that independently contributed to the variation in FMD%. RESULTS: Median coefficient of variation was 17.5%, with healthy volunteers demonstrating a coefficient of variation 9.3%. Regression models revealed age (beta = 0.248, P < 0.001), hypertension (beta = 0.104, P < 0.001), dyslipidemia (beta = 0.331, P < 0.001), time between measurements (beta = 0.318, P < 0.001), lab experience (beta = 0.133, P < 0.001) and baseline FMD% (beta = 0.082, P < 0.05) as contributors to the coefficient of variation. After including all significant factors in the final model, we found that time between measurements, hypertension, baseline FMD% and lab experience with FMD independently predicted brachial artery variability (total R = 0.202). CONCLUSION: Although FMD% showed good reproducibility, larger variation was observed in conditions with longer time between measurements, hypertension, less experience and lower baseline FMD%. Accounting for these factors may improve FMD% variability. PMID- 27488551 TI - Cortisol/cortisone ratio and matrix metalloproteinase-9 activity are associated with pediatric primary hypertension. AB - OBJECTIVE: To identify novel biomarkers associated with pediatric primary hypertension. METHODS: We recruited 350 participants (4-16 years). Anthropometric parameters and aldosterone, plasma renin activity, cortisol, cortisone, Homeostasis Model Assessment Insulin Resistance (HOMA-IR), high-sensitivity C reactive protein, adiponectin, IL-6, plasminogen activator inhibitor type 1 levels and matrix metalloproteinase-9 and matrix metalloproteinase-2 (MMP-9 and MMP-2) activities were measured. Genomic DNA was isolated. Patients with altered glucose metabolism, severe obesity [BMI-SD score (BMI-SDS) > 2.5], renovascular disease, primary aldosteronism and apparent mineralocorticoid excess syndrome were excluded. RESULTS: In selected participants (n = 320), SBP was positively correlated with BMI-SDS (r = 0.382, P < 0.001), HOMA-IR (r = 0.211, P < 0.001), MMP-9 activity (r = 0.215, P < 0.001) and the cortisol/cortisone ratio (r = 0.231, P < 0.001). DBP showed similar correlations with these variables. No correlation was observed with aldosterone or plasma renin activity. Participants were categorized as hypertensive (n = 59) or nonhypertensive (n = 261). In the univariate analysis, hypertensive patients had higher BMI-SDS (P < 0.001), HOMA IR (P < 0.001), high-sensitivity C-reactive protein (P < 0.001), MMP-9 activity (P < 0.001), plasminogen activator inhibitor type 1 (P < 0.001) and cortisol/cortisone ratio (P < 0.001) than nonhypertensive patients. Multiple regression analysis showed that the variables that remained associated with hypertension were higher BMI-SDS [odds ratio (OR) = 3.74; 95% confidence interval (CI) = 1.84-7.58], a higher cortisol/cortisone ratio (OR = 3.92; 95% CI = 1.98 7.71) and increased MMP-9 activity (OR = 4.23; 95% CI = 2.15-8.32). CONCLUSION: We report that MMP-9 activity and the cortisol/cortisone ratio were higher in pediatric primary hypertensive patients, and these associations were independent of the effect of obesity. The potential role of these novel biomarkers in predicting hypertension risk and blood pressure regulation warrants further investigation. PMID- 27488552 TI - Control of blood pressure and risk attenuation: a public health intervention in rural Bangladesh, Pakistan, and Sri Lanka: feasibility trial results. AB - BACKGROUND: High blood pressure (BP) is the leading attributable risk for cardiovascular disease globally. There is little information on effective and sustainable public health system strategies for managing hypertension in South Asian countries. We conducted a feasibility study to gather preliminary data to optimize BP-lowering strategies for a public health intervention in rural communities in Bangladesh, Pakistan, and Sri Lanka. METHODS: A mixed method feasibility study comprised a 3-month pre and postevaluation of a multicomponent intervention (MCI), including BP screening and home health education by trained government community health worker (CHW); providers trained in hypertension management, and compensation of CHW for additional services. Checklists were used to document care. Stakeholder interviews were also conducted. Individuals aged 40 years and above with high BP (systolic >=140 mmHg or diastolic >=90 mmHg based on two readings from 2 separate days, or receiving antihypertensive medications) were enrolled from rural communities in Bangladesh, Pakistan, and Sri Lanka. BP was measured at baseline and 3 months postintervention. RESULTS: A total of 412 (90%) of the 454 eligible individuals were recruited. Of those recruited, 90% received home health education session by trained CHWs, 80% were referred to trained providers, of whom 83% completed the management checklist. A follow-up rate of 95.6% was achieved. The mean SBP declined significantly by 4.5 mmHg 95% confidence interval (2.3, 6.7) mmHg (P < 0.001) in the overall pooled analysis in three countries; however, it varied among countries. BP decline was 10.5 mmHg (8.1, 13.0 mmHg) (P < 0.001) in the pooled analysis of individuals with uncontrolled hypertension at baseline, and was also significant each of the three countries. All 98 stakeholders strongly supported upscaling the proposed MCI strategies. CONCLUSION: The proposed MCI is feasible for implementation and requires long-term, large-scale evaluation in the rural public health infrastructure in South Asian countries to determine sustainability of health system changes and BP control. If these long-term effects are confirmed, MCI may be a long-term strategy for tackling rising rates of cardiovascular disease in low-resourced countries.Clintrial.gov NCT02341651. PMID- 27488553 TI - Applications might be subject to medical device regulation. PMID- 27488554 TI - Reply. PMID- 27488555 TI - Number-space associations without language: Evidence from preverbal human infants and non-human animal species. AB - It is well known that humans describe and think of numbers as being represented in a spatial configuration, known as the 'mental number line'. The orientation of this representation appears to depend on the direction of writing and reading habits present in a given culture (e.g., left-to-right oriented in Western cultures), which makes this factor an ideal candidate to account for the origins of the spatial representation of numbers. However, a growing number of studies have demonstrated that non-verbal subjects (preverbal infants and non-human animals) spontaneously associate numbers and space. In this review, we discuss evidence showing that pre-verbal infants and non-human animals associate small numerical magnitudes with short spatial extents and left-sided space, and large numerical magnitudes with long spatial extents and right-sided space. Together this evidence supports the idea that a more biologically oriented view can account for the origins of the 'mental number line'. In this paper, we discuss this alternative view and elaborate on how culture can shape a core, fundamental, number-space association. PMID- 27488556 TI - Evolution of speech and evolution of language. AB - Speech is the physical signal used to convey spoken language. Because of its physical nature, speech is both easier to compare with other species' behaviors and easier to study in the fossil record than other aspects of language. Here I argue that convergent fossil evidence indicates adaptations for complex vocalizations at least as early as the common ancestor of Neanderthals and modern humans. Furthermore, I argue that it is unlikely that language evolved separately from speech, but rather that gesture, speech, and song coevolved to provide both a multimodal communication system and a musical system. Moreover, coevolution must also have played a role by allowing both cognitive and anatomical adaptations to language and speech to evolve in parallel. Although such a coevolutionary scenario is complex, it is entirely plausible from a biological point of view. PMID- 27488557 TI - Why do animals differ in their susceptibility to geometrical illusions? AB - In humans, geometrical illusions are thought to reflect mechanisms that are usually helpful for seeing the world in a predictable manner. These mechanisms deceive us given the right set of circumstances, correcting visual input where a correction is not necessary. Investigations of non-human animals' susceptibility to geometrical illusions have yielded contradictory results, suggesting that the underlying mechanisms with which animals see the world may differ across species. In this review, we first collate studies showing that different species are susceptible to specific illusions in the same or reverse direction as humans. Based on a careful assessment of these findings, we then propose several ecological and anatomical factors that may affect how a species perceives illusory stimuli. We also consider the usefulness of this information for determining whether sight in different species might be more similar to human sight, being influenced by contextual information, or to how machines process and transmit information as programmed. Future testing in animals could provide new theoretical insights by focusing on establishing dissociations between stimuli that may or may not alter perception in a particular species. This information could improve our understanding of the mechanisms behind illusions, but also provide insight into how sight is subjectively experienced by different animals, and the degree to which vision is innate versus acquired, which is difficult to examine in humans. PMID- 27488559 TI - Exploring electronic effects on the partitioning of actinides(iii) from lanthanides(iii) using functionalised bis-triazinyl phenanthroline ligands. AB - The first examples of 4,7-disubstituted 2,9-bis(5,5,8,8-tetramethyl-5,6,7,8 tetrahydro-1,2,4-benzo-triazin-3-yl)-1,10-phenanthroline (CyMe4-BTPhen) ligands are reported herein. Evaluating the kinetics, selectivity and stoichiometry of actinide(iii) and lanthanide(iii) radiotracer extractions has provided a mechanistic insight into the extraction process. For the first time, it has been demonstrated that metal ion extraction kinetics can be modulated by backbone functionalisation and a promising new CHON compliant candidate ligand with enhanced metal ion extraction kinetics has been identified. The effects of 4,7 functionalisation on the equilibrium metal ion distribution ratios are far more pronounced than those of 5,6-functionalisation. The complexation of Cm(iii) with two of the functionalised ligands was investigated by TRLFS and, at equilibrium, species of 1 : 2 [M : L] stoichiometry were observed exclusively. A direct correlation between the ELUMO-EHOMO energy gap and metal ion extraction potential is reported, with DFT studies reaffirming experimental findings. PMID- 27488558 TI - The composite face illusion. AB - Few findings in cognitive science have proved as influential as the composite face effect. When the top half of one face is aligned with the bottom half of another, and presented upright, the resulting composite arrangement induces a compelling percept of a novel facial configuration. Findings obtained using composite face procedures have contributed significantly to our understanding of holistic face processing, the detrimental effects of face inversion, the development of face perception, and aberrant face perception in clinical populations. Composite paradigms continue to advance our knowledge of face perception, as exemplified by their recent use for investigating the perceptual mechanisms underlying dynamic face processing. However, the paradigm has been the subject of intense scrutiny, particularly over the last decade, and there is a growing sense that the composite face illusion, whilst easy to illustrate, is deceptively difficult to measure and interpret. In this review, we provide a focussed overview of the existing composite face literature, and identify six priorities for future research. Addressing these gaps in our knowledge will aid the evaluation and refinement of theoretical accounts of the illusion. PMID- 27488560 TI - Expanding the phenotype of hawkinsinuria: new insights from response to N-acetyl L-cysteine. AB - Hawkinsinuria is a rare disorder of tyrosine metabolism that can manifest with metabolic acidosis and growth arrest around the time of weaning off breast milk, typically followed by spontaneous resolution of symptoms around 1 year of age. The urinary metabolites hawkinsin, quinolacetic acid, and pyroglutamic acid can aid in identifying this condition, although their relationship to the clinical manifestations is not known. Herein we describe clinical and laboratory findings in two fraternal twins with hawkinsinuria who presented with failure to thrive and metabolic acidosis. Close clinical follow-up and laboratory testing revealed previously unrecognized hypoglycemia, hypophosphatemia, combined hyperlipidemia, and anemia, along with the characteristic urinary metabolites, including massive pyroglutamic aciduria. Treatment with N-acetyl-L-cysteine (NAC) restored normal growth and normalized or improved most biochemical parameters. The dramatic response to NAC therapy supports the idea that glutathione depletion plays a key role in the pathogenesis of hawkinsinuria. PMID- 27488561 TI - Diagnostic and prognostic value of in vivo proton MR spectroscopy for Zellweger syndrome spectrum patients. AB - Defects in the biogenesis of peroxisomes cause a clinically and genetically heterogeneous group of neurometabolic disorders, the Zellweger syndrome spectrum (ZSS). Diagnosis predominantly is based on characteristic clinical symptoms, a typical biochemical profile, as well as on identification of the molecular defect in any of the 12 known human PEX genes. The diagnostic workup can be hindered if the typical clinical symptoms are missing and predicting the clinical course of a given patient is almost unfeasible. As a safe and noninvasive method to analyze specific chemical compounds in localized brain regions, in vivo proton magnetic resonance spectroscopy (MRS) can provide an indication in this diagnostic process and may help predict the clinical course. However, to date, there are very few reports on this topic. In this study, we performed localized in vivo proton MRS without confounding contributions from T1- and T2-relaxation effects at 2 Tesla in a comparably large group of seven ZSS patients. Patients' absolute metabolite concentrations in cortical gray matter, white matter, and basal ganglia were assessed and compared with age-matched control values. Our results confirm and extend knowledge about in vivo MRS findings in ZSS patients. Besides affirmation of nonspecific reduction of N-acetylaspartate + N-acetylaspartylglutamate (tNAA) in combination with lipid accumulation as a diagnostic hint for this disease group, the amount of tNAA loss seems to reflect disease burden and may prove to be of prognostic value regarding the clinical course of an already diagnosed patient. PMID- 27488562 TI - Comparison of 10 single and stepped methods to identify frail older persons in primary care: diagnostic and prognostic accuracy. AB - BACKGROUND: Many instruments have been developed to identify frail older adults in primary care. A direct comparison of the accuracy and prevalence of identification methods is rare and most studies ignore the stepped selection typically employed in routine care practice. Also it is unclear whether the various methods select persons with different characteristics. We aimed to estimate the accuracy of 10 single and stepped methods to identify frailty in older adults and to predict adverse health outcomes. In addition, the methods were compared on their prevalence of the identified frail persons and on the characteristics of persons identified. METHODS: The Groningen Frailty Indicator (GFI), the PRISMA-7, polypharmacy, the clinical judgment of the general practitioner (GP), the self-rated health of the older adult, the Edmonton Frail Scale (EFS), the Identification Seniors At Risk Primary Care (ISAR PC), the Frailty Index (FI), the InterRAI screener and gait speed were compared to three measures: two reference standards (the clinical judgment of a multidisciplinary expert panel and Fried's frailty criteria) and 6-years mortality or long term care admission. Data were used from the Dutch Identification of Frail Elderly Study, consisting of 102 people aged 65 and over from a primary care practice in Amsterdam. Frail older adults were oversampled. The accuracy of each instrument and several stepped strategies was estimated by calculating the area under the ROC-curve. RESULTS: Prevalence rates of frailty ranged from 14.8 to 52.9 %. The accuracy for recommended cut off values ranged from poor (AUC = 0.556 ISAR-PC) to good (AUC = 0.865 gait speed). PRISMA-7 performed best over two reference standards, GP predicted adversities best. Stepped strategies resulted in lower prevalence rates and accuracy. Persons selected by the different instruments varied greatly in age, IADL dependency, receiving homecare and mood. CONCLUSION: We found huge differences between methods to identify frail persons in prevalence, accuracy and in characteristics of persons they select. A necessary next step is to find out which frail persons can benefit from intervention before case finding programs are implemented. Further evidence is needed to guide this emerging clinical field. PMID- 27488563 TI - Is rehabilitation post critical illness a new anti-inflammatory agent? PMID- 27488564 TI - Stimulating therapy for obstructive sleep apnoea. PMID- 27488565 TI - Sevelamer crystals in the bronchus: a case report. PMID- 27488566 TI - A mixed methods protocol to evaluate the effect and cost-effectiveness of an Integrated electronic Diagnosis Approach (IeDA) for the management of childhood illnesses at primary health facilities in Burkina Faso. AB - BACKGROUND: Burkina Faso introduced the Integrated Management of Childhood Illnesses (IMCI) strategy in 2003. However, an evaluation conducted in 2013 found that only 28 % of children were assessed for three danger signs as recommended by IMCI, and only 15 % of children were correctly classified. About 30 % of children were correctly prescribed with an antibiotic for suspected pneumonia or oral rehydration salts (ORS) for diarrhoea, and 40 % were correctly referred. Recent advances in information and communication technologies (ICT) and use of electronic clinical protocols hold the potential to transform healthcare delivery in low-income countries. However, no evidence is available on the effect of ICT on adherence to IMCI. This paper describes the research protocol of a mixed methods study that aims to measure the effect of the Integrated electronic Diagnosis Approach innovation (an electronic IMCI protocol provided to nurses) in two regions of Burkina Faso. METHODS/DESIGN: The study combines a stepped-wedge trial, a realistic evaluation and an economic study in order to capture the effect of the innovation after its introduction on the level of adherence, cost and acceptability. DISCUSSION: The main challenge is to interconnect the three substudies. In integrating outcome, process and cost data, we focus on three key questions: (i) How does the effectiveness and the cost of the intervention vary by type of health worker and type of health centre? (ii) What is the impact of changes in the content, coverage and quality of the IeDA intervention on adherence and cost-effectiveness? (iii) What mechanisms of change (including costs) might explain the relationship between the IeDA intervention and adherence? TRIAL REGISTRATION: Clinicaltrials.gov, NCT02341469 . PMID- 27488568 TI - The Influence of Averageness on Adults' Perceptions of Attractiveness: The Effect of Early Visual Deprivation. AB - Adults who missed early visual input because of congenital cataracts later have deficits in many aspects of face processing. Here we investigated whether they make normal judgments of facial attractiveness. In particular, we studied whether their perceptions are affected normally by a face's proximity to the population mean, as is true of typically developing adults, who find average faces to be more attractive than most other faces. We compared the judgments of facial attractiveness of 12 cataract-reversal patients to norms established from 36 adults with normal vision. Participants viewed pairs of adult male and adult female faces that had been transformed 50% toward and 50% away from their respective group averages, and selected which face was more attractive. Averageness influenced patients' judgments of attractiveness, but to a lesser extent than controls. The results suggest that cataract-reversal patients are able to develop a system for representing faces with a privileged position for an average face, consistent with evidence from identity aftereffects. However, early visual experience is necessary to set up the neural architecture necessary for averageness to influence perceptions of attractiveness with its normal potency. PMID- 27488567 TI - Evidence of non-response bias in the Press-Ganey patient satisfaction survey. AB - BACKGROUND: Measures of patient satisfaction have gained prominence in recent years as changes to the American health care system have led to the incorporation of such metrics into reimbursement models. The response rate for widely-used outpatient satisfaction metrics and variables influencing the probability of survey nonresponse remain largely unknown. METHODS: We reviewed all unique adult patients (16,779) who completed an outpatient encounter in the Department of Orthopaedic surgery at our academic institution from 1/1/13 to 10/24/13. Survey data was linked to each clinic visit, and patient factors including age, sex, insurance type, zip code, and orthopaedic subspecialty visited were recorded. The overall survey response rate was calculated. Logistic regression was performed, and unadjusted and adjusted odds ratios of patients' probability of responding to the Press-Ganey survey were calculated. RESULTS: Two thousand seven hundred sixty two (16.5 %) of individuals completed a Press-Ganey patient satisfaction survey and 14017 patients did not respond. For those patients considered responders, 906 patients (32.8 %) did not complete all the survey items. Among these 906 patients, the mean number of missing items was 2.24 (Standard Deviation SD: 2.19). Age, sex, insurance type, and orthopaedic subspecialty were all found to be associated with the odds of responding to our patient satisfaction survey. Advancing age increased the odds of responding to the survey (Adjusted Odds Ratio (OR) = 3.396 for >=65 vs. 18-29, p < 0.001). Several variables were associated with a decreased odds of survey response, and included male sex (Adjusted OR = 0.782 for Males vs. Females, p < 0.001), insurance type (Adjusted OR = 0.311 for Medicaid/Self-Pay vs. Private), and subspecialty type (Adjusted OR = 0.623 for Trauma vs. Adult Reconstruction). CONCLUSIONS: The response rate to the Press Ganey Medical Practice Survey of outpatient satisfaction is low in an orthopaedic outpatient population, and furthermore, is impacted by patient characteristics such as age, sex, insurance type, and type of orthopaedic subspecialist encountered. The findings of the present study should inform future non-response weighting procedures in this area. More research is needed to assess non-response bias-including follow-up studies of non-respondents-in order to more accurately measure of patient satisfaction. PMID- 27488569 TI - In-hospital measurement of left ventricular ejection fraction and one-year outcomes in acute coronary syndromes: results from the IMMEDIATE Trial. AB - BACKGROUND: In patients with acute coronary syndrome (ACS), reduced left ventricular ejection fraction (LVEF) is a known marker for increased mortality. However, the relationship between LVEF measured during index ACS hospitalization and mortality and heart failure (HF) within 1 year are less well-defined. METHODS: We performed a retrospective analysis of 445 participants in the IMMEDIATE Trial who had LVEF measured by left ventriculography or echocardiogram during hospitalization. RESULTS: Adjusting for age and coronary artery disease (CAD) history, lower LVEF was significantly associated with 1-year mortality or hospitalization for HF. For every 5 % LVEF reduction, the hazard ratio [HR] was 1.26 (95 % CI 1.15, 1.38, P < 0.001). Participants with LVEF < 40 % had higher hazard of 1-year mortality or HF hospitalization than those with LVEF > 40 (HR 3.59; 95 % CI 2.05, 6.27, P < 0.001). The HRs for the association of LVEF with the study outcomes were similar whether measured by left ventriculography or by echocardiography, (respectively, HR 1.32; 95 % CI 1.15, 1.51 and 1.21; 95 % CI 1.106, 1.35, interaction P = 0.32) and whether done within 24 h or not within 24 h (respectively, HR 1.28; 95 % CI 1.10, 1.50 and 1.23; 95 % CI 1.10, 1.38, interaction P = 0.67). CONCLUSIONS: Among patients with ACS, lower in-hospital LVEF is associated with increased 1-year mortality or hospitalization for HF, regardless of the method or timing of the LVEF assessment. This has prognostic implications for clinical practice and suggests the possibility of using various methods of LVEF determination in clinical research. PMID- 27488570 TI - An intravoxel oriented flow model for diffusion-weighted imaging of the kidney. AB - By combining intravoxel incoherent motion (IVIM) and diffusion tensor imaging (DTI) we introduce a new diffusion model called intravoxel oriented flow (IVOF) that accounts for anisotropy of diffusion and the flow-related signal. An IVOF model using a simplified apparent flow fraction tensor (IVOFf ) is applied to diffusion-weighted imaging of human kidneys. The kidneys of 13 healthy volunteers were examined on a 3 T scanner. Diffusion-weighted images were acquired with six b values between 0 and 800 s/mm(2) and 30 diffusion directions. Diffusivity and flow fraction were calculated for different diffusion models. The Akaike information criterion was used to compare the model fit of the proposed IVOFf model to IVIM and DTI. In the majority of voxels the proposed IVOFf model with a simplified apparent flow fraction tensor performs better than IVIM and DTI. Mean diffusivity is significantly higher in DTI compared with models that account for the flow-related signal. The fractional anisotropy of diffusion is significantly reduced when flow fraction is considered to be anisotropic. Anisotropy of the apparent flow fraction tensor is significantly higher in the renal medulla than in the cortex region. The IVOFf model describes diffusion-weighted data in the human kidney more accurately than IVIM or DTI. The apparent flow fraction in the kidney proved to be anisotropic. PMID- 27488572 TI - The SICAM-trial: evaluating the effect of spouses' involvement through case management in older patients' fast-track programmes during and after total hip replacement. AB - AIM: The aim of this study was to evaluate the effect of spouses' involvement in older patients' care trajectories, using case management as intervention in total hip replacement through fast-track programmes. BACKGROUND: Patients need their spouses to be involved in their fast-track programmes and this involvement is often associated with improvements in patient outcomes. However, the effect of spouses' involvement in older patients' fast-track programmes has not yet been investigated. DESIGN: A two-group quasi-experimental design with pre-test and repeated post-test measures was conducted in an orthopaedic ward of a Danish Regional Hospital from February 2014-June 2015. Spouse-patient dyads were initially recruited for the control group (n = 14), receiving usual care; dyads for the intervention group (n = 15) were recruited afterwards, receiving case management intervention elements before, during and after admission. METHODS: Face-to-face interviews on questionnaires were conducted with spouses and patients at baseline, 2 weeks and 3 months after discharge, measuring spouses' caregiver satisfaction, difficulties and level of anxiety and patients' functional and nutritional status, pain and level of depression. RESULTS: The results showed that there were no differences between the groups with regard to any of the outcome measures. However, statistically significant improvements were found in the patient groups on functional status, pain and depression and in the groups of spouses on caregiver satisfaction. CONCLUSION: The case management intervention seemed to have an effect in patient and spousal groups; however, this improvement could also have been caused by the effect of fast-track treatment. PMID- 27488573 TI - Living-donor parathyroid allotransplantation for therapy-refractory postsurgical persistent hypoparathyroidism in a nontransplant recipient - three year results: a case report. AB - BACKGROUND: Therapy-refractory persistent hypoparathyroidism after extensive neck surgery is a rare but severe complication. Parathyroid allotransplantation may represent a definitive treatment option. CASE PRESENTATION: A 32-year old female was referred to our hospital with intractable persistent hypocalcemia after neck surgery for papillary thyroid cancer. Despite optimal medical treatment including calcium and vitamin D supplementation and even hormonal replacement therapy hypocalcemic symptoms failed to improve. The quality of life was considered very low. In light of the unsuccessful medical therapy and the young age of the patient parathyroid allotransplantation seemed an attractive treatment option to restore normal calcium homeostasis despite of the need for immunosuppressive therapy after the procedure. Therefore, we performed living-donor allotransplantation of two healthy parathyroid glands to the recipient's left forearm. The surgical intervention was successful. Neither the donor nor the recipient showed any complications. In the postoperative course clinical symptoms of hypocalcemia significantly improved whereas serum calcium and parathyroid hormone (PTH) levels progressively increased into the normal range. Former intense replacement therapy could be discontinued completely in a stepwise fashion. To date, nearly three years after transplantation, the patient remains asymptomatic with normal serum levels of calcium and PTH. CONCLUSION: Successful living-donor parathyroid allotransplantation for postsurgical hypoparathyroidism represents an innovative therapeutic strategy that could provide the definitive treatment in those patients in which the disease is therapy-refractory. The procedure can be justified even in nontransplant recipients. Retrieval of parathyroid glands from healthy donors is feasible and safe. PMID- 27488574 TI - A randomized crossover study to assess the pharmacokinetics of a novel amphetamine extended-release orally disintegrating tablet in healthy adults. AB - OBJECTIVES: In this pharmacokinetic (PK) study in healthy adults, we sought to: (1) compare the PK properties of a novel amphetamine extended-release orally disintegrating tablet formulation (Adzenys XR-ODTTM [AMP XR-ODT]) to a reference extended-release mixed amphetamine salts (MAS ER) formulation and (2) assess the effect of food on AMP XR-ODT. METHODS: Forty-two adults were enrolled in a single dose, open-label, 3-period, 3-treatment, randomized crossover study and received an 18.8-mg dose of AMP XR-ODT (fasted or fed) or equivalent dose (30 mg) of MAS ER (fasted). Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), elimination half-life (T1/2), area under the concentration-time curve from time zero to last quantifiable concentration (AUClast), from time zero to infinity (AUCinf), relevant partial AUCs, and weight-normalized clearance (CL/F/kg) were assessed. The PK parameters were compared across treatments using an ANOVA. Safety was also assessed. RESULTS: A total of 39 adults completed this study. The geometric mean ratios (90% confidence interval [CI]) for AMP XR-ODT/MAS ER Cmax, AUC5-last, AUClast, and AUCinf were within 80%-125% for both d-and l-amphetamine. The 90% CIs for AUC0-5 were slightly below the 80%-125% range. When AMP XR-ODT was administered with food, there was a slight decrease in the d-and l-amphetamine Cmax and approximately a 2-hour delay in Tmax. The most common adverse events reported (>5% of participants) were dry mouth, palpitations, nausea, dizziness, headache, anxiety, and nasal congestion. CONCLUSIONS: AMP XR-ODT displayed a PK profile similar to MAS ER, and no clinically relevant food effect was observed. PMID- 27488575 TI - High-Intensity Drinking Among Young Adults in the United States: Prevalence, Frequency, and Developmental Change. AB - BACKGROUND: This study is the first to examine the developmental course of high intensity drinking (i.e., consuming 10+ drinks in a row) across late adolescence and the transition to adulthood. METHODS: National longitudinal data (N = 3,718) from Monitoring the Future were used to examine trajectories of 10+ high intensity drinking from age 18 through 25/26 overall and across sociodemographic subgroups; results were compared with similar analysis of 5+ binge drinking trajectories. RESULTS: Results document that 10+ drinkers consume not just a greater quantity of alcohol on a given drinking occasion, but also engage in 5+ drinking more frequently than drinkers who do not report having 10 or more drinks. Developmental patterns for 10+ and 5+ drinking were similar, with peak frequencies reported at age 21/22. Greater peaks in both 10+ and 5+ drinking were documented among men and among college attenders, compared with women and nonattenders, respectively. However, there was a steeper decline in 10+ drinking after age 21/22, indicating that risk for consumption of 10 or more drinks in a row is more clearly focused on the early 20s. Patterns of developmental change in both behaviors were driven largely by college students: No significant age related change in 10+ drinking was observed among men and women who did not go to college, and no significant age-related change in 5+ drinking was observed among female nonattenders. CONCLUSIONS: Findings underscore the importance of recognizing high-intensity drinkers as a unique high-risk group, and that college attendance is associated with particularly strong peaks in the developmental course of high-intensity drinking. PMID- 27488577 TI - L1CAM as a prognostic marker in stage I endometrial cancer: a validation study. AB - BACKGROUND: L1 cell adhesion molecule (L1CAM) overexpression has been reported to be strongly associated with poor prognosis in early stage endometrial cancer (EC). We aimed at the validation of L1CAM as a marker of poor prognosis in an independent study population. METHODS: Patients with endometrioid EC FIGO stage I, were treated at Oslo University Hospital between 2005 and 2012. L1CAM expression was detected by immunohistochemistry with >10 % L1CAM staining defined as positive. Risks of relapse and death were estimated as hazard ratios (HRs) with 95 % confidence intervals (95 % CI). RESULTS: Of 450 patients, 388 (86 %) were evaluable for L1CAM expression and 35 (9 %) were L1CAM positive. After follow-up for a median time of 4.8 years (0.1-8.8), 33 (8 %) patients had recurred. 6/35 (17 %) L1CAM positive patients relapsed compared to 27/353 (8 %) L1CAM-negative patients. There were 7 (20 %) deaths in the L1CAM positive group, and 34 (10 %) in the negative group. In multivariate analysis, controlled for age and FIGO stage, L1CAM positivity was not significantly associated with the risk of relapse (HR 2.08, 95 % CI: 0.85-5.10, p = 0.11) or death of all-cause (HR 1.81, 95 % CI: 0.79-4.11, p = 0.16). In patients who were not treated with chemotherapy, L1CAM was significantly associated with risk of relapse (HR 2.9; 95 % CI: 1.08-7.56; p = 0.04). CONCLUSION: Our report confirms that L1CAM is associated with a more aggressive tumortype and more distant relapses. The overall recurrence rate in this population was low as were the absolute differences between L1CAM positive and negative patients. In this independent study sample, L1CAM failed to be a clinically relevant marker of poor prognosis in stage I endometrioid endometrial carcinoma. PMID- 27488578 TI - Transcriptomic analysis of mouse liver reveals a potential hepato-enteric pathogenic mechanism in acute Toxoplasma gondii infection. AB - BACKGROUND: Toxoplasma gondii is a worldwide spread pathogen which can infect all tissues of its host. The transcriptomic responses of infected brain and spleen have been reported. However, our knowledge of the global transcriptomic change in infected liver is limited. Additionally, T. gondii infection represents a highly dynamic process involving complex biological responses of the host at many levels. Herein, we describe such processes at a global level by discovering gene expression changes in mouse livers after acute infection with T. gondii ToxoDB#9 strain. RESULTS: Global transcriptomic analysis identified 2,758 differentially expressed transcripts in infected liver, of which 1,356 were significantly downregulated and 1,402 upregulated. GO and KEGG database analyses showed that host immune responses were upregulated, while the metabolic-related processes/pathways were downregulated, especially xenobiotic metabolism, fatty acid metabolism, energy metabolism, and bile biosynthesis and secretion. The metabolism of more than 800 chemical compounds including anti-Toxoplasma prescribed medicines were predicted to be modulated during acute T. gondii infection due to the downregulation of enzymes involved in xenobiotic metabolism. CONCLUSIONS: To the best of our knowledge, this is the first global transcriptomic analysis of mouse liver infected by T. gondii. The present data indicate that during the early stage of liver infection, T. gondii can induce changes in liver xenobiotic metabolism, upregulating inflammatory response and downregulating hepatocellular PPAR signaling pathway, altering host bile biosynthesis and secretion pathway; these changes could enhance host intestinal dysbacteriosis and thus contribute to the pathological changes of both liver and intestine of infected mice. These findings describe the biological changes in infected liver, providing a potential mechanistic pathway that links hepatic and intestinal pathologies to T. gondii infection. PMID- 27488579 TI - A simple biomarker scoring matrix for early gastric cancer detection. AB - Gastric cancer (GC) is a major cause of death in many parts of the world. While 90% of early GC is curable by resection, only about 5% of patients diagnosed in the late stages survive beyond five years. This provides strong impetus to push for early GC detection through the use of non-invasive biomarkers, before metastatic complications arise. It is also of strong medical interest to identify patients of the diffuse subtype at the earliest time possible, since the disease variant progresses very rapidly and is associated with much higher mortality rate. In this study, we compared quantitatively the gastric fluid proteome of 70 GC patients to 17 individuals with benign gastritis in search of potential biomarkers that aid in GC diagnosis, prognosis and subtype stratification. We report that as much as half of the gastric fluid proteome is subject to regulation in diseased states, and propose a simple biomarker panel scoring matrix for early GC detection with diagnostic sensitivity of 95.7%. We also demonstrate as proof-of-concept that a digitised record generated with SWATH-MS based on 380 protein abundance signatures from the gastric fluid could segregate patients with diffuse-type GC. PMID- 27488580 TI - Testosterone differentially regulates targets of lipid and glucose metabolism in liver, muscle and adipose tissues of the testicular feminised mouse. AB - Testosterone deficiency is commonly associated with obesity, metabolic syndrome, type 2 diabetes and their clinical consequences-hepatic steatosis and atherosclerosis. The testicular feminised mouse (non-functional androgen receptor and low testosterone) develops fatty liver and aortic lipid streaks on a high-fat diet, whereas androgen-replete XY littermate controls do not. Testosterone treatment ameliorates these effects, although the underlying mechanisms remain unknown. We compared the influence of testosterone on the expression of regulatory targets of glucose, cholesterol and lipid metabolism in muscle, liver, abdominal subcutaneous and visceral adipose tissue. Testicular feminised mice displayed significantly reduced GLUT4 in muscle and glycolytic enzymes in muscle, liver and abdominal subcutaneous but not visceral adipose tissue. Lipoprotein lipase required for fatty acid uptake was only reduced in subcutaneous adipose tissue; enzymes of fatty acid synthesis were increased in liver and subcutaneous tissue. Stearoyl-CoA desaturase-1 that catalyses oleic acid synthesis and is associated with insulin resistance was increased in visceral adipose tissue and cholesterol efflux components (ABCA1, apoE) were decreased in subcutaneous and liver tissue. Master regulator nuclear receptors involved in metabolism-Liver X receptor expression was suppressed in all tissues except visceral adipose tissue, whereas PPARgamma was lower in abdominal subcutaneous and visceral adipose tissue and PPARalpha only in abdominal subcutaneous. Testosterone treatment improved the expression (androgen receptor independent) of some targets but not all. These exploratory data suggest that androgen deficiency may reduce the buffering capability for glucose uptake and utilisation in abdominal subcutaneous and muscle and fatty acids in abdominal subcutaneous. This would lead to an overspill and uptake of excess glucose and triglycerides into visceral adipose tissue, liver and arterial walls. PMID- 27488581 TI - FOXD3 controls pluripotency through modulating enhancer activity. PMID- 27488582 TI - Liposomal Encapsulation Enzymes: From Medical Applications to Kinetic Characteristics. AB - Liposomes and nanoliposomes as small vesicles composed of phospholipid bilayer (entrapping one or more hydrophilic or lipophilic components) have recently found several potential applications in medicine and food industry. These vesicles may protect the core materials from moisture, heat and other extreme conditions. They may also provide controlled release of various bioactive agents, including food ingredients at the right place and time. Potential applications of enzyme-loaded liposomes are in the medical or biomedical field, particularly for the enzymereplacement therapy, as well as cheese industry for production of functional foods with improved health beneficial impacts on the consumer. Encapsulation process has a recondite impact on enzymes. In fact, liposome preparation techniques may alter the pH and temperature optima, affinity of the enzyme to substrate (Km), and maximum rate of reaction (Vmax). In addition, in this paper, the impact of process variables on the kinetic characteristics of enzymes encapsulated in liposomes was investigated. Also, the effects of enzyme entrapment in liposomes, prepared by different methods, on the catalytic efficiency of enzyme, as well as its kinetic properties and stability compared to native (free) enzymes has been reviewed. PMID- 27488583 TI - Vaccine Ingredients: Components that Influence Vaccine Efficacy. AB - Vaccination is defined as the administration of an antigenic material in order to stimulate the immune system, leading to the development of adaptive immunity to a pathogen. Vaccines can prevent or reduce morbidity from a vast number of infections. This manuscript presents an analysis of vaccine types and vaccine substances, concentrating on individual components including the active ingredient, adjuvants, preservatives, stabilizers, inactivators, antibiotics, diluents and other substances. While many papers have been published on individual vaccine components, this review provides detail on a wide range of the most commonly-used vaccine ingredients and components that have been tested in clinical trials. PMID- 27488584 TI - A Global View on Narcolepsy - A Review Study. AB - Narcolepsy is an incurable neurological disorder when the brain is not able to regulate a sleep and wakefulness cycle correctly. The affected person suddenly falls asleep during the day or he/she suffers from excessive day sleepiness. In addition, people may also suffer from cataplexy, hypnagogic hallucinations, sleep paralysis, and disturbed nighttime sleep. The purpose of this review study is to provide the latest information on both clinical and socioeconomic issues in the field of narcolepsy treatment and emphasize its benefits and limitations. The methodological approaches include a method of literature review of available sources exploring the issue of narcolepsy, both from a global and specific perspective point of view. On the basis of evaluation of these literature sources, the researched issue is examined. The main benefits (e.g., new drugs are being tested or non-invasive cognitive behavioral therapies are being applied) and limitations (e.g., late diagnosis of the disease or lifelong and costly treatment) of the treatment of narcolepsy are highlighted. The findings call for more research in the field of the development of novel drugs reflecting understanding of the neurological basis of narcolepsy and early diagnosis in order to eliminate the symptoms of narcolepsy and prevent the development of this disease. PMID- 27488585 TI - A Review on Pharmacological Properties of Coumarins. AB - The coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in many natural products, displays diverse pharmacological properties. It has attracted the attention of chemists and medicinal chemists for decades. Many molecules based on the coumarin ring system have been described utilizing innovative synthetic methods. These synthetic routes have led to interesting analogues of coumarins which possess pharmacological activities like anti-HIV, antimicrobial, antiinflammatory, anticancer, anti-TB, anticonvulsant and MAO inhibitory properties. Details of these studies, correlating structure with biological activity are described in this review. PMID- 27488586 TI - Research Progress of Mechanisms of Ceftriaxone Associated Nephrolithiasis. AB - BACKGROUND: Urinary calculi can be caused by a variety of reasons, such as metabolic abnormalities, urinary tract infection and obstruction. Certain medications can induce urinary stone disease. Ceftriaxone, a third generation cephalosporin with broad spectrum antibiotic activity, primarily eliminated by the kidneys, has now been widely used for treatment of infection. It has been long considered safe, especially in children. However, more and more cases about ceftriaxone induced nephrolithiasis as a rare side effect have been reported. CONCLUSION: This complication generally resolves spontaneously with cessation of the drug. Severe nephrolithiasis can cause post renal acute renal failure (PARF). There is limited information about how this complication develops, though high doses and extended treatment periods are generally considered to be responsible. Understanding the mechanisms would help the doctors to be aware of this rare complication and respond with proper treatment. The primary goal of this review is to discuss the possible mechanisms based on the most recent literatures. PMID- 27488587 TI - Treatment interruption during radiation therapy: Experience at a single institution in the Republic of Korea. AB - AIM: Our study analyzed the frequency and causes of treatment interruption among patients undergoing radiation therapy (RT). METHODS: A total of 1637 RT courses in 1500 patients were reviewed from September 2009 to October 2013. A continuous break over 7 days or a discontinuous break over 14 days was regarded as a temporary break and RT under 80% of planned treatment was regarded as incomplete. RESULTS: Two-hundred and twenty courses (13.4%) with treatment interruption were identified. Half of the patients received RT with a definitive aim, and the other half for palliative care. Completion after temporary break, near completion and incompletion were noticed in 12.3%, 21.3%, and 66.4% of cases, respectively. Among patients with a definite aim, thorax (19.2%) and abdomen (16.3%) had a higher interruption rate. For brain and bone with a palliative aim, the frequency of interruption was about 16%. Old age and worse performance negatively affected interruption. The most common cause of treatment interruption was cancer progression including death (30%) and the next was treatment-related side effects (23.1%). CONCLUSION: About 13% of RT cases were interrupted. Two third of patients received less than 80% of the planned RT. To improve RT completion rate, multidirectional efforts are needed. PMID- 27488588 TI - Comment on: "5-year outcomes of 1-stage gastric band removal and sleeve gastrectomy". PMID- 27488589 TI - Modified Arrow Flap Technique for Nipple Reconstruction. PMID- 27488590 TI - Morphological Characterization of Acinar Cluster in Mouse Lung Using a Multiscale based Segmentation Algorithm on Synchrotron Micro-CT Images. AB - Understanding the three-dimensional morphology of pulmonary acini is essential when exploring the biomechanics of respiratory function. In this study, we characterized the morphology of individual acini and a cluster of acini stemming from the same terminal conducting airway using a quantitative approach based on the semi-automatic segmentation of synchrotron micro-CT images of mouse lung. The volume and surface area of five clusters of mouse acini including 50 individual acini were estimated based on the voxel and surface mesh of segmented acini at FRC. The pathway length and width were estimated for one cluster including 15 acini based on the skeleton of segmented acini. The acinar volume was 0.09 +/- 0.07 mm(3) (mean +/- SD), and the surface area was 6.82 +/- 4.49 mm(2) , in agreement with previous studies. The volume of the acinar clusters was 0.89 +/- 0.34 mm(3) , and the surface area was 68.18 +/- 17.66 mm(2) . The largest volume acinus per cluster was found in the distal region of the terminal conducting airway, and apparent respiratory bronchioles were observed only in large-volume acini. The generation number of pathways per acinus was 8 +/- 2 (range: 6-12). The pathway length at lower generations (generations 2-6) increased with the generation number in a single cluster, while did not significantly change at lower generations in some acinar groups. The pathway width increased with increasing generation numbers. Our approach characterized the quantitative morphology of pulmonary acinar clusters in mouse lung, and the results can be used in further biomechanical simulation studies. Anat Rec, 299:1424-1434, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27488591 TI - Investigation of injection dose and camera integration time on quantifying pharmacokinetics of a Cy5.5-GX1 probe with dynamic fluorescence imaging in vivo. AB - The aim of this article is to investigate the influence of a tracer injection dose (ID) and camera integration time (IT) on quantifying pharmacokinetics of Cy5.5-GX1 in gastric cancer BGC-823 cell xenografted mice. Based on three factors, including whether or not to inject free GX1, the ID of Cy5.5-GX1, and the camera IT, 32 mice were randomly divided into eight groups and received 60 min dynamic fluorescence imaging. Gurfinkel exponential model (GEXPM) and Lammertsma simplified reference tissue model (SRTM) combined with a singular value decomposition analysis were used to quantitatively analyze the acquired dynamic fluorescent images. The binding potential (Bp) and the sum of the pharmacokinetic rate constants (SKRC) of Cy5.5-GX1 were determined by the SRTM and EXPM, respectively. In the tumor region, the SKRC value exhibited an obvious trend with change in the tracer ID, but the Bp value was not sensitive to it. Both the Bp and SKRC values were independent of the camera IT. In addition, the ratio of the tumor-to-muscle region was correlated with the camera IT but was independent of the tracer ID. Dynamic fluorescence imaging in conjunction with a kinetic analysis may provide more quantitative information than static fluorescence imaging, especially for a priori information on the optimal ID of targeted probes for individual therapy. PMID- 27488592 TI - Factors influencing the perceived quality of clinical supervision of occupational therapists in a large Australian state. AB - BACKGROUND/AIM: Clinical supervision is important for effective health service delivery, professional development and practice. Despite its importance there is a lack of evidence regarding the factors that improve its quality. This study aimed to investigate the factors that influence the quality of clinical supervision of occupational therapists employed in a large public sector health service covering mental health, paediatrics, adult physical and other practice areas. METHODS: A mixed method, sequential explanatory study design was used consisting of two phases. This article reports the quantitative phase (Phase One) which involved administration of the Manchester Clinical Supervision Scale (MCSS 26) to 207 occupational therapists. RESULTS: Frequency of supervision sessions, choice of supervisor and the type of supervision were found to be the predictor variables with a positive and significant influence on the quality of clinical supervision. Factors such as age, length of supervision and the area of practice were found to be the predictor variables with a negative and significant influence on the quality of clinical supervision. CONCLUSION: Factors that influence the perceived quality of clinical supervision among occupational therapists have been identified. High quality clinical supervision is an important component of clinical governance and has been shown to be beneficial to practitioners, patients and the organisation. Information on factors that make clinical supervision effective identified in this study can be added to existing supervision training and practices to improve the quality of clinical supervision. PMID- 27488593 TI - Meta-analysis of colorectal cancer follow-up after potentially curative resection. AB - BACKGROUND: After potentially curative resection of primary colorectal cancer, patients may be monitored by measurement of carcinoembryonic antigen and/or CT to detect asymptomatic metastatic disease earlier. METHODS: A systematic review and meta-analysis was conducted to find evidence for the clinical effectiveness of monitoring in advancing the diagnosis of recurrence and its effect on survival. MEDLINE (Ovid), Embase, the Cochrane Library, Web of Science and other databases were searched for randomized comparisons of increased intensity monitoring compared with a contemporary standard policy after resection of primary colorectal cancer. RESULTS: There were 16 randomized comparisons, 11 with published survival data. More intensive monitoring advanced the diagnosis of recurrence by a median of 10 (i.q.r. 5-24) months. In ten of 11 studies the authors reported no demonstrable difference in overall survival. Seven RCTs, published from 1995 to 2016, randomly assigned 3325 patients to a monitoring protocol made more intensive by introducing new methods or increasing the frequency of existing follow-up protocols versus less invasive monitoring. No detectable difference in overall survival was associated with more intensive monitoring protocols (hazard ratio 0.98, 95 per cent c.i. 0.87 to 1.11). CONCLUSION: Based on pooled data from randomized trials published from 1995 to 2016, the anticipated survival benefit from surgical treatment resulting from earlier detection of metastases has not been achieved. PMID- 27488594 TI - Listeria monocytogenes Inhibits Serotonin Transporter in Human Intestinal Caco-2 Cells. AB - Listeria monocytogenes is a Gram-positive bacterium that can cause a serious infection. Intestinal microorganisms have been demonstrated to contribute to intestinal physiology not only through immunological responses but also by modulating the intestinal serotonergic system. Serotonin (5-HT) is a neuromodulator that is synthesized in the intestinal epithelium and regulates the whole intestinal physiology. The serotonin transporter (SERT), located in enterocytes, controls intestinal 5-HT availability and therefore serotonin's effects. Infections caused by L. monocytogenes are well described as being due to the invasion of intestinal epithelial cells; however, the effect of L. monocytogenes on the intestinal epithelium remains unknown. The main aim of this work, therefore, was to study the effect of L. monocytogenes on SERT. Caco2/TC7 cell line was used as an enterocyte-like in vitro model, and SERT functional and molecular expression assays were performed. Our results demonstrate that living L. monocytogenes inhibits serotonin uptake by reducing SERT expression at the brush border membrane. However, neither inactivated L. monocytogenes nor soluble metabolites were able to affect SERT. The results also demonstrate that L. monocytogenes yields TLR2 and TLR10 transcriptional changes in intestinal epithelial cells and suggest that TLR10 is potentially involved in the inhibitory effect observed on SERT. Therefore, L. monocytogenes, through TLR10-mediated SERT inhibition, may induce increased intestinal serotonin availability and potentially contributing to intestinal physiological changes and the initiation of the inflammatory response. PMID- 27488596 TI - TDP-43 pathology and cognition in ALS: A prospective clinicopathologic correlation study. AB - OBJECTIVE: Although a systematic spread of pathologic TDP-43 expression throughout the CNS in amyotrophic lateral sclerosis (ALS) has been proposed, the relationship between cognition and the extent and neuroanatomic distribution of TDP-43 pathology has not received considerable attention. METHODS: We investigated the association between cognitive functioning and the extent of TDP 43 pathology in postmortem CNS tissue from 18 patients with ALS stratified into 3 groups based on detailed prospective neuropsychological testing (cognitively not impaired, n = 6; cognitively impaired, n = 6; ALS- frontotemporal dementia [FTD], n = 6) and analyzed these cases for clinicopathologic correlations. RESULTS: Our findings demonstrate a close relationship between cognition and the extent of TDP 43 pathology in non-primary motor areas with a striking difference between ALS FTD and the 2 other cognitive groups. The specificity of our results was underscored by 2 key findings: first, the absence of an Alzheimer pathology effect, a common confounder in older patients; second, the lack of correlations between the primary motor regions with the highest TDP-43 intensity and cognitive status. CONCLUSIONS: Our data suggest a distinct dynamic of TDP-43 progression and distribution in ALS-FTD in contrast to ALS without FTD. PMID- 27488595 TI - Expression of p53, p16, cyclin D1, epidermal growth factor receptor and Notch1 in patients with temporal bone squamous cell carcinoma. AB - BACKGROUND: The aim of this study was to investigate the expression of p53, p16, cyclin D1, epidermal growth factor receptor (EGFR) and Notch1 in temporal bone squamous cell carcinoma (TBSCC) tissue samples by immunohistochemistry (IHC), and to evaluate the association between these biomarkers and clinicopathological features. METHODS: We performed a retrospective, single-institution review of 30 TBSCC patients treated with curative intent between April 2006 and March 2015. All tissue samples were obtained from pretreatment biopsy specimens or surgical specimens and using IHC staining. RESULTS: Ten patients were categorized as T1, seven as T2, five as T3 and eight as T4. Nine patients had clinically positive lymph node metastasis. The positive expression of p53 and EGFR was significantly associated with T classification (P = 0.042 and P = 0.0039). EGFR expression was significantly more frequent in patients with positive lymph node metastasis compared with patients without node involvement (P = 0.017). In the analysis of the association between protein expression by IHC staining and prognosis, the positive expression of EGFR and Notch1 was significantly correlated with poor survival outcomes in TBSCC (P = 0.015 and P = 0.025) CONCLUSION: Overexpression of p53 and EGFR may be valuable biomarkers for identifying individuals at high risk of developing tumors in TBSCC. Furthermore, the positive expression of EGFR was significantly associated with poor survival outcome. Anti-EGFR therapy has potential for use as the treatment modality of choice for advanced-stage TBSCC as well as other head and neck squamous cell carcinomas. PMID- 27488597 TI - Incident parkinsonism in older adults without Parkinson disease. AB - OBJECTIVE: To determine the incidence of parkinsonism in community-dwelling older adults without Parkinson disease. METHODS: Four parkinsonian signs were assessed with a modified motor portion of the Unified Parkinson's Disease Rating Scale in 2,001 older adults without parkinsonism. We used Cox proportional hazards models to determine the associations of age and sex with incident parkinsonism (2 or more signs). We calculated the number of events per 1,000 person-years of observation in 3 age strata. Next, we investigated several potential risk factors for incident parkinsonism. Then, we examined longitudinal progression of parkinsonism using discrete-time multistate Markov models. RESULTS: Average age at baseline was 76.8 years (SD 7.62 years). During an average of 5 years of follow-up, 964/2,001 (48.2%) developed parkinsonism. Age (hazard ratio [HR] 1.09, 95% confidence interval [CI] 1.08-1.10) but not male sex (HR 1.06, 95% CI 0.91 1.23) was associated with incident parkinsonism. The incidence of parkinsonism per 1,000 person-years of follow-up was 36.0 for adults <75 years of age, 94.8 for those 75-84, and 160.5 for those 85 years or older. Depressive symptoms, neuroticism, urinary incontinence, sleep complaints, and chronic health conditions were associated with incident parkinsonism. Secondary analyses suggest that risk factors are linked with incident parkinsonism via early motor signs of parkinsonism and cognitive function. Transition modeling suggests that while parkinsonism may fluctuate, it is progressive in most older adults and its risk factors increase the odds of its progression. CONCLUSIONS: Parkinsonism is common in older adults and increases with age. Identifying modifiable risk factors may decrease the magnitude of this growing public health problem. PMID- 27488598 TI - Lower microstructural integrity of brain white matter is related to higher mortality. AB - OBJECTIVE: To investigate the association of cerebral white matter microstructural integrity with mortality. METHODS: We included 4,294 individuals, free from stroke and dementia (mean age 63.6 years, 44% male) from the population based Rotterdam Study (2006-2011). Diffusion-MRI was used to assess the microstructural integrity of the white matter, both globally and for specific white matter tracts. Fractional anisotropy and mean diffusivity were the measures used to quantify white matter integrity. All-cause mortality and cause-specific mortality was recorded with a median follow-up time of 5.4 and 4.6 years, respectively. Cox regression models, adjusted for age, sex, APOE epsilon4 allele carriership, cardiovascular risk factors, and macrostructural MRI changes, were used to estimate hazard ratios. RESULTS: During the follow-up time, 216 participants (5.0%) died of all causes, 31 (0.7%) of cardiovascular causes, and 102 individuals (2.4%) died of noncardiovascular causes. Each SD decrease in fractional anisotropy and each SD increase in mean diffusivity was associated with a 1.37-fold (95% confidence interval: 1.20-1.57) and a 1.49-fold (95% confidence interval: 1.28-1.75) higher hazard of all-cause mortality, respectively. The associations were more prominent with cardiovascular mortality than with noncardiovascular mortality. In tract-specific analyses, we observed that association tracts were more prominently related to mortality. CONCLUSIONS: Our findings suggest that impairments in cerebral white matter, even at early stages, are not limited to adverse brain outcomes and they are related to mortality, especially from cardiovascular causes. PMID- 27488599 TI - A marked contrast between serotonergic and dopaminergic changes in dopa responsive dystonia. PMID- 27488600 TI - Lumpers or splitters: Evaluation and management of embolic stroke of undetermined source. PMID- 27488601 TI - Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population. AB - OBJECTIVE: We investigated whether the C9orf72 expansion mutation in patients with amyotrophic lateral sclerosis (ALS) is associated with unique demographic and clinical features. METHODS: Between 2001 and 2015, approximately half of all patients attending the Emory ALS Clinic agreed to donate DNA for research. This research cohort of 781 patients was screened for the C9orf72 expansion, and demographic and clinical data were compared between those with and without the C9orf72 mutation. For mutation carriers without a family history of ALS, we sought further family history of dementia and other non-ALS neurodegenerative diseases in first-degree relatives. RESULTS: The C9orf72 expansion was identified in 61 patients (7.8%). Compared to those without the expansion mutation, these patients did not differ in race, age, or site of onset. As expected, C9orf72 patients were more likely to have a family history of ALS (59% vs 7.9%) and to present with comorbid frontotemporal dementia (FTD) (14.8% vs 1.7%). Survival was shorter in patients with the expansion (log-rank chi(2)[1] = 45.323, p < 0.001). Further investigation in 28 patients initially categorized as having no known family history of ALS identified a family history of dementia in 16 cases; 6 of these had characteristics suggestive of FTD. CONCLUSIONS: Comparing the C9orf72 ALS population to the general ALS population, there were no differences in race, age at onset, or proportion of patients with bulbar onset disease. Differences identified in patients with the C9orf72 mutation included shortened survival and an equal proportion of men and women. In addition, we found that assessing family history for dementia may identify other family members likely to be carrying the C9orf72 expansion, reduce the number of sporadic cases, and thus increase our understanding of disease penetrance. PMID- 27488602 TI - The value of transesophageal echocardiography for embolic strokes of undetermined source. AB - OBJECTIVE: Our aim was to evaluate the diagnostic yield of transesophageal echocardiography (TEE) in consecutive patients with ischemic stroke (IS) fulfilling the diagnostic criteria of embolic strokes of undetermined source (ESUS). METHODS: We prospectively evaluated consecutive patients with acute IS satisfying ESUS criteria who underwent in-hospital TEE examination in 3 tertiary care stroke centers during a 12-month period. We also performed a systematic review and meta-analysis estimating the cumulative effect of TEE findings on therapeutic management for secondary stroke prevention among different IS subgroups. RESULTS: We identified 61 patients with ESUS who underwent investigation with TEE (mean age 44 +/- 12 years, 49% men, median NIH Stroke Scale score = 5 points [interquartile range: 3-8]). TEE revealed additional findings in 52% (95% confidence interval [CI]: 40%-65%) of the study population. TEE findings changed management (initiation of anticoagulation therapy, administration of IV antibiotic therapy, and patent foramen ovale closure) in 10 (16% [95% CI: 9%-28%]) patients. The pooled rate of reported anticoagulation therapy attributed to abnormal TEE findings among 3,562 acute IS patients included in the meta-analysis (12 studies) was 8.7% (95% CI: 7.3%-10.4%). In subgroup analysis, the rates of initiation of anticoagulation therapy on the basis of TEE investigation did not differ (p = 0.315) among patients with cryptogenic stroke (6.9% [95% CI: 4.9%-9.6%]), ESUS (8.1% [95% CI: 3.4%-18.1%]), and IS (9.4% [95% CI: 7.5%-11.8%]). CONCLUSIONS: Abnormal TEE findings may decisively affect the selection of appropriate therapeutic strategy in approximately 1 of 7 patients with ESUS. PMID- 27488603 TI - Role of sleep-disordered breathing and sleep-wake disturbances for stroke and stroke recovery. AB - BACKGROUND: Sleep-disordered breathing (SDB) and sleep-wake disturbances (SWD) are highly prevalent in stroke patients. Recent studies suggest that they represent both a risk factor and a consequence of stroke and affect stroke recovery, outcome, and recurrence. METHODS: Review of literature. RESULTS: Several studies have proven SDB to represent an independent risk factor for stroke. Sleep studies in TIA and stroke patients are recommended in view of the very high prevalence (>50%) of SDB (Class IIb, level of evidence B). Treatment of obstructive SDB with continuous positive airway pressure is recommended given the strength of the increasing evidence in support of a positive effect on outcome (Class IIb, level of evidence B). Oxygen, biphasic positive airway pressure, and adaptive servoventilation may be considered in patients with central SDB. Recently, both reduced and increased sleep duration, as well as hypersomnia, insomnia, and restless legs syndrome (RLS), were also suggested to increase stroke risk. Mainly experimental studies found that SWD may in addition impair neuroplasticity processes and functional stroke recovery. Treatment of SWD with hypnotics and sedative antidepressants (insomnia), activating antidepressants or stimulants (hypersomnia), dopaminergic drugs (RLS), and clonazepam (parasomnias) are based on single case observations and should be used with caution. CONCLUSIONS: SDB and SWD increase the risk of stroke in the general population and affect short- and long-term stroke recovery and outcome. Current knowledge supports the systematic implementation of clinical procedures for the diagnosis and treatment of poststroke SDB and SWD on stroke units. PMID- 27488604 TI - The MEssaging for Diabetes (MED) intervention improves short-term medication adherence among low-income adults with type 2 diabetes. AB - Adults with type 2 diabetes (T2DM) and low socioeconomic status (SES) have high rates of medication nonadherence, and, in turn, suboptimal glycemic control (hemoglobin A1c [HbA1c]). We tested the initial efficacy of a short message service (SMS) text messaging and interactive voice response (IVR) intervention to promote adherence among this high-risk group. Eighty low SES, diverse adults with T2DM used the MEssaging for Diabetes (MED) SMS/IVR intervention for 3 months. We used a pre-post single group design to explore adherence changes over 3 months, and a quasi-experimental design to test the impact of MED on HbA1c among the intervention group relative to a matched, archival control group. Compared to baseline, adherence improved at one (AOR 3.88, 95 % CI 1.79, 10.86) and at 2 months (AOR 3.76, 95 % CI 1.75, 17.44), but not at 3 months. HbA1c remained stable, with no differences at 3 months between the intervention group and the control group. MED had a positive, short-term impact on adherence, which did not translate to improvements in HbA1c. Future research should explore the longer term impact of SMS/IVR interventions on the medication adherence of high risk adults with T2DM. PMID- 27488605 TI - A Direct Approach to In-Plane Stress Separation using Photoelastic Ptychography. AB - The elastic properties of materials, either under external load or in a relaxed state, influence their mechanical behaviour. Conventional optical approaches based on techniques such as photoelasticity or thermoelasticity can be used for full-field analysis of the stress distribution within a specimen. The circular polariscope in combination with holographic photoelasticity allows the sum and difference of principal stress components to be determined by exploiting the temporary birefringent properties of materials under load. Phase stepping and interferometric techniques have been proposed as a method for separating the in plane stress components in two-dimensional photoelasticity experiments. In this paper we describe and demonstrate an alternative approach based on photoelastic ptychography which is able to obtain quantitative stress information from far fewer measurements than is required for interferometric based approaches. The complex light intensity equations based on Jones calculus for this setup are derived. We then apply this approach to the problem of a disc under diametrical compression. The experimental results are validated against the analytical solution derived by Hertz for the theoretical displacement fields for an elastic disc subject to point loading. PMID- 27488606 TI - Multiple imputation of completely missing repeated measures data within person from a complex sample: application to accelerometer data in the National Health and Nutrition Examination Survey. AB - The Physical Activity Monitor component was introduced into the 2003-2004 National Health and Nutrition Examination Survey (NHANES) to collect objective information on physical activity including both movement intensity counts and ambulatory steps. Because of an error in the accelerometer device initialization process, the steps data were missing for all participants in several primary sampling units, typically a single county or group of contiguous counties, who had intensity count data from their accelerometers. To avoid potential bias and loss in efficiency in estimation and inference involving the steps data, we considered methods to accurately impute the missing values for steps collected in the 2003-2004 NHANES. The objective was to come up with an efficient imputation method that minimized model-based assumptions. We adopted a multiple imputation approach based on additive regression, bootstrapping and predictive mean matching methods. This method fits alternative conditional expectation (ace) models, which use an automated procedure to estimate optimal transformations for both the predictor and response variables. This paper describes the approaches used in this imputation and evaluates the methods by comparing the distributions of the original and the imputed data. A simulation study using the observed data is also conducted as part of the model diagnostics. Finally, some real data analyses are performed to compare the before and after imputation results. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 27488607 TI - Statins worsen glycemic control of T2DM in target LDL-c level and LDL-c reduction dependent manners: a meta-analysis. AB - OBJECTIVE: Recent studies demonstrated that a low target low-density lipoprotein cholesterol (LDL-c) level, high LDL-c reduction and high dose of statin therapy increased incident diabetes. This study aimed to explore how statin therapy influences glycemic control in type 2 diabetes mellitus (T2DM). METHODS: Medline, Embase, and Cochrane Central were searched for randomized control trials inT2DM. Trials with target LDL-c levels of <=2.6 mmol/L or LDL-c reduction of >=30% were analyzed. Then, we calculated mean differences in glycosylated hemoglobin (HbA1c) and fasting blood glucose via stratified LDL-c level, relative LDL-c reduction and statin dose. RESULTS: In total, trials involving 6,875 participants (3,619 statins, 3,256 controls) were included. Meta-analysis showed that detrimental effect of intensive LDL-c lowering statin therapy on HbA1c (SMD 0.10%; 95% CI 0.05, 0.15; p = 0.000) was more severe than all statin trials analyzed together (SMD 0.07%; 95% CI 0.02, 0.12; p = 0.005). Stratified analyses revealed that the effects on HbA1c became increasingly significant as target LDL-c level decreased and LDL-c reduction increased. Low baseline LDL-c and endpoint LDL-c levels were risk factors involved in increasing HbA1c level during statin therapy. CONCLUSIONS: Statin therapy worsens the glycemic control of T2DM in target LDL-c level and LDL-c reduction dependent manners. PMID- 27488608 TI - The association of the neighbourhood built environment with objectively measured physical activity in older adults with and without lower limb osteoarthritis. AB - BACKGROUND: This study examined the associations of objectively measured neighbourhood built environment characteristics with objectively measured physical activity (PA) in older people with and without lower limb osteoarthritis (LLOA), and assessed whether these relationships differ between both groups. METHODS: Data from the Dutch component of the European Project on OSteoArthritis were used. American College of Rheumatology classification criteria were used to diagnose LLOA (knee and/or hip osteoarthritis). Daily average time spent on total PA and separate PA intensity categories, including light PA, low-light PA, high light PA, and moderate to vigorous PA, were measured using Actigraph GT3X accelerometers. Geographic Information Systems were used to measure street connectivity (number of street connections per km(2)) and distances (in km) to resources (health care resources, retail resources, meeting places, and public transport) within neighbourhoods. Multiple Linear Regression Analyses were used to examine the associations between measures of the neighbourhood built environment and PA, adjusted for several confounders. RESULTS: Of all 247 participants (66-85 years), 41 (16.6 %) had LLOA. The time spent on any PA did not differ significantly between participants with and without LLOA (LLOA: Mean = 268.3, SD = 83.3 versus non-LLOA: Mean = 275.8, SD = 81.2; p = 0.59). In the full sample, no measures of the neighbourhood built environment were statistically significantly associated with total PA. Larger distances to specific health care resources (general practice and physiotherapist) and retail resources (supermarket) were associated with more time spent on PA in older people with LLOA than in those without LLOA. In particular, the associations of light and high-light PA with distances to these specific resources were stronger in participants with LLOA compared to their counterparts without LLOA. CONCLUSIONS: Specific attributes of the neighbourhood built environment are more strongly associated with PA in older people with LLOA than in those without LLOA. Knowledge on the relationship between objectively measured neighbourhood characteristics and PA in older people with and without LLOA could be used to inform policymakers and city planners about adaptation of neighbourhoods and their infrastructures to appropriately facilitate PA in healthy and functionally impaired older adults. PMID- 27488609 TI - Lutein attenuates oxidative stress markers and ameliorates glucose homeostasis through polyol pathway in heart and kidney of STZ-induced hyperglycemic rat model. AB - PURPOSE: Lutein's role on chronic hyperglycemia-induced oxidative stress and associated glucose homeostasis in heart and kidney is limited. Purpose of the study is to investigate the effect of lutein on cardiac and renal polyol pathway enzymes and oxidative stress markers under hyperglycemia-induced oxidative stress condition using streptozotocin (STZ)-injected rat model. METHODS: STZ-induced hyperglycemic (fasting blood glucose >=11 mM) male Wistar rats were divided into two groups (n = 11/group). Group 1 received micellar lutein (39 nmol/day/rat) and group 2 (negative control) received micelle without lutein for 8 weeks. A separate group (no STZ injected) served as a positive control (n = 11/group). Oral glucose tolerance test (OGTT), biweekly urine glucose and activities of aldose reductase (AR) and sorbitol dehydrogenase (SDH) enzymes were assessed. Activities of antioxidant enzymes and antioxidant level were also evaluated. RESULTS: Lutein-administered hyperglycemic rats showed better glucose tolerance as evidenced with OGTT and biweekly urine glucose when compared to negative control. Activities of AR and SDH were decreased in heart and kidney of lutein fed hyperglycemic rats. Also, they had significantly (p < 0.05) decreased malondialdehyde levels (66, 34, and 33 %) and increased reduced glutathione level (81, 18 and 92 %) in serum, heart and kidney, respectively. Altered antioxidant enzyme activities such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione transferase were also affected in serum, heart and kidney of lutein-fed diabetic group. CONCLUSION: Lutein prevented cardiac and renal injury in STZ-induced hyperglycemic rats due to potential amelioration of altered activities in polyol pathway and oxidative stress markers. PMID- 27488610 TI - The in vivo antineoplastic and therapeutic efficacy of troxerutin on rat preneoplastic liver: biochemical, histological and cellular aspects. AB - PURPOSE: Troxerutin (TXER), a trihydroxyethylated derivative of the natural bioflavonoid rutin, abundantly found in tea, various fruits and vegetables, is known to exhibit ample pharmacological properties. In the present investigation, we examined the antineoplastic, therapeutic efficacy and furthermore the possible mechanisms of action of TXER against NAFLD/NASH progression to hepatocarcinogenesis. METHODS: The effect of TXER (12.5, 25 or 50 mg/kg b.w/day) was evaluated on the nitrosodiethylamine (NDEA) model of hepatocarcinogenesis in rats, after 16 weeks of oral treatment, with special focus on liver specific enzymes, xenobiotic metabolizing enzymes, antioxidant status, lipid peroxidation profile, DNA damage, fibrosis, cell proliferation and inflammatory status. RESULTS: Administration of TXER to hepatocellular carcinoma-bearing rats restored the enzyme activities and the hepatic architecture. Furthermore, TXER significantly curtailed NDEA-induced DNA damage, cell proliferation, inflammation, fibrosis and hepatic hyperplasia. CONCLUSION: This study provides the evidence that troxerutin exerts a significant therapeutic effect against liver cancer by modulating liver function enzymes, xenobiotic enzymes, oxidative damage, inhibiting cell proliferation, suppressing inflammatory response and induction of apoptosis. PMID- 27488611 TI - Correlation between visit-to-visit and short-term blood pressure variability calculated using different methods and glomerular filtration rate. AB - The aim of this study was to explore the correlation between visit-to-visit and short-term blood pressure variability (BPV), including systolic BPV (SBPV) and diastolic BPV (DBPV), calculated using different methods, and the glomerular filtration rate (GFR) in a late, middle-aged population. Using cluster sampling, we randomly selected retired employees of the Kailuan Group who were ?60 years and participated in a third health examination for 24-h ambulatory blood pressure monitoring and inspection. Among the 3064 randomly selected observation subjects, 2464 were included based on the criteria. BPV was calculated using s.d., coefficient of variation (CV, s.d./Mean), variability independent of mean (VIM, s.d./Meanx) and BPV ratio (BPVR, s.d. (SBPV)/s.d. (DBPV)). Multivariate linear regression was used to analyse the correlation between estimated GFR (eGFR) and BPV calculated using different methods. The mean age of 2464 subjects was 67.4+/ 6.1 years, with 1667 male subjects (67.7%). A total of 2104 cases were included in the visit-to-visit BPV group, and 1382 in the short-term BPV group. SBPV calculated using different methods showed statistically significant increasing trends for the SBP versus all s.d. and short-term BPVR. There was a significant, positive correlation between the visit-to-visit and short-term BPV calculated using different methods, which were all negatively correlated with eGFR (P<0.05). Multivariate linear regression analysis showed that, with correction for possible confounding factors, SBPV (24-h s.d., CV and VIM, and daytime CV and night time CV) and all DBPV demonstrated negative linear relationships with eGFR (P<0.05). PMID- 27488612 TI - The new Asian modified CKD-EPI equation leads to more accurate GFR estimation in Chinese patients with CKD. AB - OBJECTIVE: To verify whether the new Asian modified CKD-EPI equation improved the performance of original one in determining GFR in Chinese patients with CKD. METHOD: A well-designed paired cohort was set up. Measured GFR (mGFR) was the result of 99mTc-diethylene triamine pentaacetic acid (99mTc-DTPA) dual plasma sample clearance method. The estimated GFR (eGFR) was the result of the CKD-EPI equation (eGFR1) and the new Asian modified CKD-EPI equation (eGFR2). The comparisons were performed to evaluate the superiority of the eGFR2 in bias, accuracy, precision, concordance correlation coefficient and the slope of regression equation and measure agreement. RESULTS: A total of 195 patients were enrolled and analyzed. The new Asian modified CKD-EPI equation improved the performance of the original one in bias and accuracy. However, nearly identical performance was observed in the respect of precision, concordance correlation coefficient, slope of eGFR against mGFR and 95 % limit of agreement. In the subgroup of GFR < 60 mL min-1/1.73 m2, the bias of eGFR1 was less than eGFR2 but they have comparable precision and accuracy. In the subgroup of GFR > 60 mL min 1/1.73 m2, eGFR2 performed better than eGFR1 in terms of bias and accuracy. CONCLUSION: The new Asian modified CKD-EPI equation can lead to more accurate GFR estimation in Chinese patients with CKD in general practice, especially in the higher GFR group. PMID- 27488613 TI - Genetic analyses of herding traits in the Border Collie using sheepdog trial data. AB - The aim of this study was to evaluate the quality of the data provided from sheepdog trials in Norway, estimate heritabilities, repeatabilities and genetic correlations for the traits included in the trial and make recommendations on how sheepdog trials best can be utilized in the breeding of Border Collies in Norway. The analyses were based on test results from sheepdog trials carried out in Norway from 1993 to 2012. A total of 45 732 records from 3841 Border Collies were available, but after quality assurance only a third was left. The results demonstrated little information in the data. Heritabilities varied between 0.010 and 0.056 with standard errors ranging from 0.010 to 0.023, while repeatabilities ranged from 0.041 to 0.286. There is a need to assure the quality of data to improve the information in the test results. We recommend adding new traits based on the Herding Trait Characterization scheme evaluated in Sweden, and on traits from the predatory motor pattern, regarded as common for all dogs. These new traits may be scored across the elements that make up the current trial system, which should be kept in place to stimulate participation in the genetic evaluation scheme. PMID- 27488614 TI - An ovarian bioreactor for in vitro culture of the whole bovine ovary: a preliminary report. AB - BACKGROUND: Improved cancer therapeutics and enhanced cancer survivorship have emphasized the severe long-term side effects of chemotherapy. Specifically, studies have linked many chemotherapy agents with primary ovarian insufficiency, although an exact insult model has not yet been determined. To investigate and ultimately solve this problem, a novel device for extended study of mammalian ovaries in vitro was developed. METHODS: A bioreactor was fabricated for bovine ovarian culture that provides intravascular delivery of media to the ovary through isolation and cannulation of a main ovarian artery branch. Whole ovaries were cultured in vitro using three methods: (1) continuously supplied fresh culture media, (2) recirculated culture media, or (3) continuously supplied fresh culture media supplemented with 500 nM doxorubicin for 24 or 48 h. TUNEL assay was used to assess apoptotic cell percentages in the three groups as compared to uncultured baseline ovaries. RESULTS: The ovary culture method was shown to maintain cell viability by effectively delivering nutrient-enriched pH-balanced media at a constant flow rate. Lower apoptosis observed in ovaries cultured in continuously supplied fresh culture media illustrates that this culture device and method are the first to sustain whole bovine ovary viability for 48 h. Meanwhile, the increase in the percentage of cell apoptosis with doxorubicin treatment indicates that the device can provide an alternative model for testing chemotherapy and chemoprotection treatments to prevent primary ovarian insufficiency in cancer patients. CONCLUSIONS: An ovarian bioreactor with consistent culture media flow through an ovarian vasculature-assisted approach maintains short-term whole bovine ovary viability. PMID- 27488615 TI - The crystal structure of Clostridium perfringens SleM, a muramidase involved in cortical hydrolysis during spore germination. AB - Clostridium perfringens spores employ two peptidoglycan lysins to degrade the spore cortex during germination. SleC initiates cortex hydrolysis to generate cortical fragments that are degraded further by the muramidase SleM. Here, we present the crystal structure of the C. perfringens S40 SleM protein at 1.8 A. SleM comprises an N-terminal catalytic domain that adopts an irregular alpha/beta barrel fold that is common to GH25 family lysozymes, plus a C-terminal fibronectin type III domain. The latter is involved in forming the SleM dimer that is evident in both the crystal structure and in solution. A truncated form of SleM that lacks the FnIII domain shows reduced activity against spore sacculi indicating that this domain may have a role in facilitating the position of substrate with respect to the enzyme's active site. Proteins 2016; 84:1681-1689. (c) 2016 Wiley Periodicals, Inc. PMID- 27488616 TI - [Mesenchymal tumors of the mediastinum]. AB - Mesenchymal neoplasms of the thymus and mediastinum account for only 2 % of neoplasms of the mediastinum and are therefore very rare. With very few exceptions the histology, immunohistochemistry and (based on current knowledge) molecular biology of mediastinal soft tissue tumors are not different from their counterparts in other organs. Characteristic features are more concerned with clinical epidemiological and therapeutic aspects as well as the multitude of possible differential diagnoses. With the exception of organ-specific tumors, such as gastrointestinal stromal tumors (GIST), virtually all entities encountered in peripheral soft tissues can also arise in the mediastinum. Primary mediastinal soft tissue sarcomas (STS) must be distinguished from secondary radiation-induced STS after irradiation, e. g. for breast cancer and Hodgkin's lymphoma and from STS arising as somatic type malignancies in mediastinal germ cell tumors. PMID- 27488618 TI - Molecular diagnosis of African tick bite fever using eschar swabs in a traveller returning from Tanzania. AB - African tick bite fever is an emerging infectious disease among travellers caused by the pathogen Rickettsia africae. Most travel-associated cases have been reported from countries in southern Africa. So far it has rarely been reported among travellers to eastern Africa and our patient is one of the first described cases imported from Tanzania. A woman presented with fever, chills, headache, myalgia and a rickettsial eschar on her ankle after returning from Tanzania. The diagnosis of African tick bite fever is often based on clinical grounds due to a lack of reliable diagnostic tests at commencement of symptoms. In this patient direct molecular detection of R. africae was performed by PCR from a sample obtained non-invasively with a swab from the rickettsial eschar. A positive PCR result was achieved although the patient had already started antibiotic treatment with doxycycline. In conclusion, this non-invasive method enables early diagnosis of African tick bite fever by direct molecular detection of R. africae and might improve the management of undifferentiated fever in travellers from Africa. PMID- 27488617 TI - The environmental carcinogen benzo[a]pyrene induces a Warburg-like metabolic reprogramming dependent on NHE1 and associated with cell survival. AB - Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na(+)/H(+) exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration). PMID- 27488619 TI - Commemorating John F. MacDonald and the Art of Being a Mentor. AB - John F. MacDonald was a close friend and mentor whose life was ended far too soon on April 22, 2014. To those who knew him, John was an endearing blend of fiery Scotsman, compassionate socialist, dedicated family man, and tireless investigator. Those close to him valued his loyalty and friendship, relished his biting wit, and puzzled at his self-deprecating manner. His career spanned a remarkable period of discovery from the early identification of excitatory amino acid, to the molecular cloning and characterization of glutamate receptors and the elucidation of mechanisms responsible for regulating their function. A true pioneer in each of these areas, John's research has had a lasting impact on our understanding of excitatory synaptic transmission and its plasticity. Our intent in commemorating John's work is to focus on some notable discoveries that highlight the impact and innovative aspects of John's work. In doing so, we also wish to highlight just how greatly our understanding of the glutamate transmitter systems has advanced since the late 1970s, when John first launched his independent neuroscience career. PMID- 27488620 TI - [Trauma of the lumbar spine and the thoracolumbar junction]. AB - CLINICAL/METHODICAL ISSUE: Patients who have experienced high energy trauma have a particularly high risk of suffering from fractures of the thoracic and lumbar spine. The detection of spinal injuries and the correct classification of fractures before surgery are not only absolute requirements for the implementation of appropriate surgical treatment but they are also decisive for the choice of surgical procedure. STANDARD RADIOLOGICAL METHODS: By the application of spiral computed tomography (CT) crucial additional information on the morphology of the fracture can be gained in order to estimate the fracture type and possibly the indications for specific surgical treatment options. Magnetic resonance imaging (MRI) is ideally suited to provide valuable additional information regarding injuries to the discoligamentous structures of the spine. PERFORMANCE: Magerl et al. developed a comprehensive classification especially for injuries of the thoracic and lumbar spine, which was adopted by the working group for osteosynthesis (AO). This is based on a 2-pillar model of the spinal column. The classification is based on the pathomorphological characteristics of fractures recognizable by imaging. The injury pattern is of particular importance. ACHIEVEMENTS: In spinal trauma a distinction is made between stable and unstable fractures. The treatment of spinal injuries depends on the severity of the overall injury pattern. PRACTICAL RECOMMENDATIONS: Besides adequate initial treatment at the scene, a trauma CT should be immediately carried out in order that no injuries are overlooked and to ensure a rapid decision on the treatment procedure. PMID- 27488621 TI - Increasing strength and conductivity of Cu alloy through abnormal plastic deformation of an intermetallic compound. AB - The precipitation strengthening of Cu alloys inevitably accompanies lowering of their electric conductivity and ductility. We produced bulk Cu alloys arrayed with nanofibers of stiff intermetallic compound through a precipitation mechanism using conventional casting and heat treatment processes. We then successfully elongated these arrays of nanofibers in the bulk Cu alloys to 400% of original length without breakage at room temperature using conventional rolling process. By inducing such an one-directional array of nanofibers of intermetallic compound from the uniform distribution of fine precipitates in the bulk Cu alloys, the trade-off between strength and conductivity and between strength and ductility could be significantly reduced. We observed a simultaneous increase in electrical conductivity by 1.3 times and also tensile strength by 1.3 times in this Cu alloy bulk compared to the conventional Cu alloys. PMID- 27488622 TI - Cryptic Caribbean species of Scorpaena (Actinopterygii: Scorpaeniformes) suggested by cytogenetic and molecular data. AB - Cytogenetic and molecular analyses enabled identification of two cytotypes among individuals of the spotted scorpion fish Scorpaena plumieri from Margarita Island, Venezuela. Cytotype 1 was characterized by 48 subtelo-acrocentric chromosomes and fundamental number (number of chromosome arms; FN) equalled 48, while cytotype 2 was characterized by two metacentric and 46 subtelo-acrocentric chromosomes and FN was 50. These cytotypes also differed in the location of the ribosomal gene clusters and in the distribution of the constitutive heterochromatin. Moreover, fish from the cytotypes 1 and 2 were found to belong to distinct mitochondrial lineages. The presence of two S. plumieri cytotypes from two lineages separated by high genetic distance suggests that they correspond to sympatric cryptic species. PMID- 27488623 TI - Dual Perspectives. PMID- 27488624 TI - Functional Heterogeneity in the Bed Nucleus of the Stria Terminalis. AB - Early work stressed the differing involvement of the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) in the genesis of fear versus anxiety, respectively. In 2009, Walker, Miles, and Davis proposed a model of amygdala-BNST interactions to explain these functional differences. This model became extremely influential and now guides a new wave of studies on the role of BNST in humans. Here, we consider evidence for and against this model, in the process highlighting central principles of BNST organization. This analysis leads us to conclude that BNST's influence is not limited to the generation of anxiety-like responses to diffuse threats, but that it also shapes the impact of discrete threatening stimuli. It is likely that BNST-CeA interactions are involved in modulating responses to such threats. In addition, whereas current views emphasize the contributions of the anterolateral BNST region in anxiety, accumulating data indicate that the anteromedial and anteroventral regions also play a critical role. The presence of multiple functional subregions within the small volume of BNST raises significant technical obstacles for functional imaging studies in humans. PMID- 27488626 TI - Orientation Selectivity in the Retina: ON Cell Types and Mechanisms. PMID- 27488627 TI - Presynaptic Deficits at Neuromuscular Junctions: A Specific Cause and Potential Target of Axonal Neuropathy in Type 2 Charcot-Marie-Tooth Disease. PMID- 27488625 TI - Contributions of the Central Extended Amygdala to Fear and Anxiety. AB - It is widely thought that phasic and sustained responses to threat reflect dissociable circuits centered on the central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST), the two major subdivisions of the central extended amygdala. Early versions of this hypothesis remain highly influential and have been incorporated into the National Institute of Mental Health Research Research Domain Criteria framework. However, new observations encourage a different perspective. Anatomical studies show that the Ce and BST form a tightly interconnected unit, where different kinds of threat-relevant information can be integrated and used to assemble states of fear and anxiety. Imaging studies in humans and monkeys show that the Ce and BST exhibit similar functional profiles. Both regions are sensitive to a range of aversive challenges, including uncertain or temporally remote threat; both covary with concurrent signs and symptoms of fear and anxiety; both show phasic responses to short-lived threat; and both show heightened activity during sustained exposure to diffusely threatening contexts. Mechanistic studies demonstrate that both regions can control the expression of fear and anxiety during sustained exposure to diffuse threat. These observations compel a reconsideration of the central extended amygdala's contributions to fear and anxiety and its role in neuropsychiatric disease. PMID- 27488628 TI - Zinc Selectively Blocks Neurosteroid-Sensitive Extrasynaptic deltaGABAA Receptors in the Hippocampus. AB - Zinc (Zn(2+)) is an essential cofactor in mammalian cells and neurons. Zn(2+) is released from synaptic vesicles of certain nerve terminals in the hippocampus during neuronal activity. Zn(2+) has been shown to inhibit synaptic GABAA receptors and alter the hippocampal network excitability. However, the ability of Zn(2+) to block extrasynaptic receptors remains unclear. Endogenous neurosteroids, such as allopregnanolone (AP), regulate neuronal excitability by allosteric activation of synaptic and extrasynaptic GABAA receptors. Neurosteroids activate extrasynaptic deltaGABAA receptor-mediated tonic inhibition in dentate gyrus granule cells (DGGCs), thereby contributing to the regulation of downstream circuit excitability. Here we report a novel inhibitory role of Zn(2+) at neurosteroid-sensitive, extrasynaptic deltaGABAA receptors by electrophysiological recordings in DGGCs from adult mice. Zn(2+) displayed a concentration-dependent, reversible noncompetitive blockade of AP-sensitive tonic current in DGGCs (IC50, 16 MUm). Tonic current was fully blocked by Zn(2+), akin to the GABAA receptor antagonist gabazine. Zn(2+) inhibition of tonic current was lacking in DGGCs from delta-subunit knock-out mice. Moreover, AP-activated synaptic receptor-mediated phasic currents were not affected by Zn(2+) Finally, intrahippocampal infusion of Zn(2+) elicited rapid epileptiform activity and significantly blocked the antiseizure activity of AP in the kindling model of epilepsy. Thus, Zn(2+) inhibition of neurosteroid-sensitive, extrasynaptic GABAA receptors in the hippocampus has direct implications in many brain hyperexcitability conditions, such as seizures, epileptogenesis, and epilepsy. Zn(2+) interactions may aid to further understand the physiology of extrasynaptic GABAA receptors. SIGNIFICANCE STATEMENT: Zn(2+) is most abundant in the synaptic vesicles of hippocampal mossy fibers. Zn(2+) release occurs with neuronal excitation, including seizure events, and exerts powerful excitability effects in the hippocampus circuits. Zn(2+) inhibits synaptic GABAA receptors, but its interaction is less well appreciated at the extrasynaptic receptors, which respond sensitively to endogenous neurosteroids. Here, we describe selective functional blockade by Zn(2+) of neurosteroid-sensitive, extrasynaptic GABAA receptors in the mouse hippocampus dentate gyrus, a key region associated with epilepsy and memory disorders. By demonstrating that extracellular Zn(2+) prevents neurosteroid augmentation of tonic current and protection against limbic seizures, our findings provide novel implications of this potential antagonistic interaction in a variety of neurological conditions. PMID- 27488629 TI - Direction Selectivity in Drosophila Emerges from Preferred-Direction Enhancement and Null-Direction Suppression. AB - Across animal phyla, motion vision relies on neurons that respond preferentially to stimuli moving in one, preferred direction over the opposite, null direction. In the elementary motion detector of Drosophila, direction selectivity emerges in two neuron types, T4 and T5, but the computational algorithm underlying this selectivity remains unknown. We find that the receptive fields of both T4 and T5 exhibit spatiotemporally offset light-preferring and dark-preferring subfields, each obliquely oriented in spacetime. In a linear-nonlinear modeling framework, the spatiotemporal organization of the T5 receptive field predicts the activity of T5 in response to motion stimuli. These findings demonstrate that direction selectivity emerges from the enhancement of responses to motion in the preferred direction, as well as the suppression of responses to motion in the null direction. Thus, remarkably, T5 incorporates the essential algorithmic strategies used by the Hassenstein-Reichardt correlator and the Barlow-Levick detector. Our model for T5 also provides an algorithmic explanation for the selectivity of T5 for moving dark edges: our model captures all two- and three-point spacetime correlations relevant to motion in this stimulus class. More broadly, our findings reveal the contribution of input pathway visual processing, specifically center-surround, temporally biphasic receptive fields, to the generation of direction selectivity in T5. As the spatiotemporal receptive field of T5 in Drosophila is common to the simple cell in vertebrate visual cortex, our stimulus response model of T5 will inform efforts in an experimentally tractable context to identify more detailed, mechanistic models of a prevalent computation. SIGNIFICANCE STATEMENT: Feature selective neurons respond preferentially to astonishingly specific stimuli, providing the neurobiological basis for perception. Direction selectivity serves as a paradigmatic model of feature selectivity that has been examined in many species. While insect elementary motion detectors have served as premiere experimental models of direction selectivity for 60 years, the central question of their underlying algorithm remains unanswered. Using in vivo two-photon imaging of intracellular calcium signals, we measure the receptive fields of the first direction-selective cells in the Drosophila visual system, and define the algorithm used to compute the direction of motion. Computational modeling of these receptive fields predicts responses to motion and reveals how this circuit efficiently captures many useful correlations intrinsic to moving dark edges. PMID- 27488630 TI - A Neural Model of MST and MT Explains Perceived Object Motion during Self-Motion. AB - When a moving object cuts in front of a moving observer at a 90 degrees angle, the observer correctly perceives that the object is traveling along a perpendicular path just as if viewing the moving object from a stationary vantage point. Although the observer's own (self-)motion affects the object's pattern of motion on the retina, the visual system is able to factor out the influence of self-motion and recover the world-relative motion of the object (Matsumiya and Ando, 2009). This is achieved by using information in global optic flow (Rushton and Warren, 2005; Warren and Rushton, 2009; Fajen and Matthis, 2013) and other sensory arrays (Dupin and Wexler, 2013; Fajen et al., 2013; Dokka et al., 2015) to estimate and deduct the component of the object's local retinal motion that is due to self-motion. However, this account (known as "flow parsing") is qualitative and does not shed light on mechanisms in the visual system that recover object motion during self-motion. We present a simple computational account that makes explicit possible mechanisms in visual cortex by which self motion signals in the medial superior temporal area interact with object motion signals in the middle temporal area to transform object motion into a world relative reference frame. The model (1) relies on two mechanisms (MST-MT feedback and disinhibition of opponent motion signals in MT) to explain existing data, (2) clarifies how pathways for self-motion and object-motion perception interact, and (3) unifies the existing flow parsing hypothesis with established neurophysiological mechanisms. SIGNIFICANCE STATEMENT: To intercept targets, we must perceive the motion of objects that move independently from us as we move through the environment. Although our self-motion substantially alters the motion of objects on the retina, compelling evidence indicates that the visual system at least partially compensates for self-motion such that object motion relative to the stationary environment can be more accurately perceived. We have developed a model that sheds light on plausible mechanisms within the visual system that transform retinal motion into a world-relative reference frame. Our model reveals how local motion signals (generated through interactions within the middle temporal area) and global motion signals (feedback from the dorsal medial superior temporal area) contribute and offers a new hypothesis about the connection between pathways for heading and object motion perception. PMID- 27488631 TI - Knowledge Acquisition during Exam Preparation Improves Memory and Modulates Memory Formation. AB - According to the schema-relatedness hypothesis, new experiences that make contact with existing schematic knowledge are more easily encoded and remembered than new experiences that do not. Here we investigate how real-life gains in schematic knowledge affect the neural correlates of episodic encoding, assessing medical students 3 months before and immediately after their final exams. Human participants were scanned with functional magnetic resonance imaging while encoding associative information that varied in relatedness to medical knowledge (face-diagnosis vs face-name pairs). As predicted, improvements in memory performance over time were greater for face-diagnosis pairs (high knowledge relevance) than for face-name pairs (low knowledge-relevance). Improved memory for face-diagnosis pairs was associated with smaller subsequent memory effects in the anterior hippocampus, along with increased functional connectivity between the anterior hippocampus and left middle temporal gyrus, a region important for the retrieval of stored conceptual knowledge. The decrease in the anterior hippocampus subsequent memory effect correlated with knowledge accumulation, as independently assessed by a web-based learning platform with which participants studied for their final exam. These findings suggest that knowledge accumulation sculpts the neural networks associated with successful memory formation, and highlight close links between knowledge acquired during studying and basic neurocognitive processes that establish durable memories. SIGNIFICANCE STATEMENT: In a sample of medical students, we tracked knowledge accumulation via a web based learning platform and investigated its effects on memory formation before and after participants' final medical exam. Knowledge accumulation led to significant gains in memory for knowledge-related events and predicted a selective decrease in hippocampal activation for successful memory formation. Furthermore, enhanced functional connectivity was found between hippocampus and semantic processing regions. These findings (1) demonstrate that knowledge facilitates binding in the hippocampus by enhancing its communication with the association cortices, (2) highlight close links between knowledge induced in the real world and basic neurocognitive processes that establish durable memories, and (3) exemplify the utility of combining laboratory-based cognitive neuroscience research with real-world educational technology for the study of memory. PMID- 27488632 TI - Voluntary Running Exercise-Mediated Enhanced Neurogenesis Does Not Obliterate Retrograde Spatial Memory. AB - Running exercise (RE) improves cognition, formation of anterograde memories, and mood, alongside enhancing hippocampal neurogenesis. A previous investigation in a mouse model showed that RE-induced increased neurogenesis erases retrograde memory (Akers et al., 2014). However, it is unknown whether RE-induced forgetting is common to all species. We ascertained whether voluntary RE-induced enhanced neurogenesis interferes with the recall of spatial memory in rats. Young rats assigned to either sedentary (SED) or running exercise (RE) groups were first subjected to eight learning sessions in a water maze. A probe test (PT) conducted 24 h after the final training session confirmed that animals in either group had a similar ability for the recall of short-term memory. Following this, rats in the RE group were housed in larger cages fitted with running wheels, whereas rats in the SED group remained in standard cages. Animals in the RE group ran an average of 78 km in 4 weeks. A second PT performed 4 weeks after the first PT revealed comparable ability for memory recall between animals in the RE and SED groups, which was evidenced through multiple measures of memory retrieval function. The RE group displayed a 1.5- to 2.1-fold higher hippocampal neurogenesis than SED rats. Additionally, both moderate and brisk RE did not interfere with the recall of memory, although increasing amounts of RE proportionally enhanced neurogenesis. In conclusion, RE does not impair memory recall ability in a rat model despite substantially increasing neurogenesis. SIGNIFICANCE STATEMENT: Running exercise (RE) improves new memory formation along with an increased neurogenesis in the hippocampus. In view of a recent study showing that RE-mediated increased hippocampal neurogenesis promotes forgetfulness in a mouse model, we ascertained whether a similar adverse phenomenon exists in a rat model. Memory recall ability examined 4 weeks after learning confirmed that animals that had run a mean of 78 km and displayed a 1.5- to 2.1-fold increase in hippocampal neurogenesis demonstrated similar proficiency for memory recall as animals that had remained sedentary. Furthermore, both moderate and brisk RE did not interfere with memory recall, although increasing amounts of RE proportionally enhanced neurogenesis, implying that RE has no adverse effects on memory recall. PMID- 27488633 TI - Noninvasive Evaluation of Cellular Proliferative Activity in Brain Neurogenic Regions in Rats under Depression and Treatment by Enhanced [18F]FLT-PET Imaging. AB - Neural stem cells in two neurogenic regions, the subventricular zone and the subgranular zone (SGZ) of the hippocampal dentate gyrus, can divide and produce new neurons throughout life. Hippocampal neurogenesis is related to emotions, including depression/anxiety, and the therapeutic effects of antidepressants, as well as learning and memory. The establishment of in vivo imaging for proliferative activity of neural stem cells in the SGZ might be used to diagnose depression and to monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging with 3'-deoxy-3'-[(18)F]fluoro-l-thymidine ([(18)F]FLT) has been studied to allow visualization of proliferative activity in two neurogenic regions of adult mammals; however, the PET imaging has not been widely used because of lower accumulation of [(18)F]FLT, which does not allow quantitative assessment of the decline in cellular proliferative activity in the SGZ under the condition of depression. We report the establishment of an enhanced PET imaging method with [(18)F]FLT combined with probenecid, an inhibitor of drug transporters at the blood-brain barrier, which can allow the quantitative visualization of neurogenic activity in rats. Enhanced PET imaging allowed us to evaluate reduced cell proliferation in the SGZ of rats with corticosterone induced depression, and further the recovery of proliferative activity in rats under treatment with antidepressants. This enhanced [(18)F]FLT-PET imaging technique with probenecid can be used to assess the dynamic alteration of neurogenic activity in the adult mammalian brain and may also provide a means for objective diagnosis of depression and monitoring of the therapeutic effect of antidepressant treatment. SIGNIFICANCE STATEMENT: Adult hippocampal neurogenesis may play a role in major depression and antidepressant therapy. Establishment of in vivo imaging for hippocampal neurogenic activity may be useful to diagnose depression and monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging has been studied to allow visualization of neurogenic activity; however, PET imaging has not been widely used due to the lower accumulation of the PET tracer in the neurogenic regions. Here, we succeeded in establishing highly quantitative PET imaging for neurogenic activity in adult brain with an inhibitor for drug transporter. This enhanced PET imaging allowed evaluation of the decline of neurogenic activity in the hippocampus of rats with depression and the recovery of neurogenic activity by antidepressant treatment. PMID- 27488634 TI - Interaction of ARC and Daxx: A Novel Endogenous Target to Preserve Motor Function and Cell Loss after Focal Brain Ischemia in Mice. AB - The aim of this study was to explore the signaling and neuroprotective effect of transactivator of transcription (TAT) protein transduction of the apoptosis repressor with CARD (ARC) in in vitro and in vivo models of cerebral ischemia in mice. In mice, transient focal cerebral ischemia reduced endogenous ARC protein in neurons in the ischemic striatum at early reperfusion time points, and in primary neuronal cultures, RNA interference resulted in greater neuronal susceptibility to oxygen glucose deprivation (OGD). TAT.ARC protein delivery led to a dose-dependent better survival after OGD. Infarct sizes 72 h after 60 min middle cerebral artery occlusion (MCAo) were on average 30 +/- 8% (mean +/- SD; p = 0.005; T2-weighted MRI) smaller in TAT.ARC-treated mice (1 MUg intraventricularly during MCAo) compared with controls. TAT.ARC-treated mice showed better performance in the pole test compared with TAT.beta-Gal-treated controls. Importantly, post-stroke treatment (3 h after MCAo) was still effective in affording reduced lesion volume by 20 +/- 7% (mean +/- SD; p < 0.05) and better functional outcome compared with controls. Delayed treatment in mice subjected to 30 min MCAo led to sustained neuroprotection and functional behavior benefits for at least 28 d. Functionally, TAT.ARC treatment inhibited DAXX-ASK1 JNK signaling in the ischemic brain. ARC interacts with DAXX in a CARD-dependent manner to block DAXX trafficking and ASK1-JNK activation. Our work identifies for the first time ARC-DAXX binding to block ASK1-JNK activation as an ARC-specific endogenous mechanism that interferes with neuronal cell death and ischemic brain injury. Delayed delivery of TAT.ARC may present a promising target for stroke therapy. SIGNIFICANCE STATEMENT: Up to now, the only successful pharmacological target of human ischemic stroke is thrombolysis. Neuroprotective pharmacological strategies are needed to accompany therapies aiming to achieve reperfusion. We describe that apoptosis repressor with CARD (ARC) interacts and inhibits DAXX and proximal signals of cell death. In a murine stroke model mimicking human malignant infarction in the territory of the middle cerebral artery, TAT.ARC salvages brain tissue when given during occlusion or 3 h delayed with sustained functional benefits (28 d). This is a promising novel therapeutic approach because it appears to be effective in a model producing severe injury by interfering with an array of proximal signals and effectors of the ischemic cascade, upstream of JNK, caspases, and BIM and BAX activation. PMID- 27488635 TI - Systemic Delivery of a Brain-Penetrant TrkB Antagonist Reduces Cocaine Self Administration and Normalizes TrkB Signaling in the Nucleus Accumbens and Prefrontal Cortex. AB - Cocaine exposure alters brain-derived neurotrophic factor (BDNF) expression in the brain. BDNF signaling through TrkB receptors differentially modulates cocaine self-administration, depending on the brain regions involved. In the present study, we determined how brain-wide inhibition of TrkB signaling affects cocaine intake, the motivation for the drug, and reinstatement of drug taking after extinction. To overcome the inability of TrkB ligands to cross the blood-brain barrier, the TrkB antagonist cyclotraxin-B was fused to the nontoxic transduction domain of the tat protein from human immunodeficiency virus type 1 (tat cyclotraxin-B). Intravenous injection of tat-cyclotraxin-B dose-dependently reduced cocaine intake, motivation for cocaine (as measured under a progressive ratio schedule of reinforcement), and reinstatement of cocaine taking in rats allowed either short or long access to cocaine self-administration. In contrast, the treatment did not affect operant responding for a highly palatable sweet solution, demonstrating that the effects of tat-cyclotraxin-B are specific for cocaine reinforcement. Cocaine self-administration increased TrkB signaling and activated the downstream Akt pathway in the nucleus accumbens, and had opposite effects in the prefrontal cortex. Pretreatment with tat-cyclotraxin-B normalized protein levels in these two dopamine-innervated brain regions. Cocaine self administration also increased TrkB signaling in the ventral tegmental area, where the dopaminergic projections originate, but pretreatment with tat-cyclotraxin-B did not alter this effect. Altogether, our data show that systemic administration of a brain-penetrant TrkB antagonist leads to brain region-specific effects and may be a potential pharmacological strategy for the treatment of cocaine addiction. SIGNIFICANCE STATEMENT: Brain-derived neurotrophic factor (BDNF) signaling through TrkB receptors plays a well established role in cocaine reinforcement. However, local manipulation of BDNF signaling yields divergent effects, depending on the brain region, thereby questioning the viability of systemic TrkB targeting for the treatment of cocaine use disorders. Our study provides first-time evidence that systemic administration of a brain-penetrant TrkB antagonist (tat-cyclotraxin-B) reduces several behavioral measures of cocaine dependence, without altering motor performance or reinforcement by a sweet palatable solution. In addition, although cocaine self-administration produced opposite effects on TrkB signaling in the nucleus accumbens and prefrontal cortex, tat-cyclotraxin-B administration normalized these cocaine induced changes in both brain regions. PMID- 27488636 TI - Two-Dimensional Cochlear Micromechanics Measured In Vivo Demonstrate Radial Tuning within the Mouse Organ of Corti. AB - The exquisite sensitivity and frequency discrimination of mammalian hearing underlie the ability to understand complex speech in noise. This requires force generation by cochlear outer hair cells (OHCs) to amplify the basilar membrane traveling wave; however, it is unclear how amplification is achieved with sharp frequency tuning. Here we investigated the origin of tuning by measuring sound induced 2-D vibrations within the mouse organ of Corti in vivo Our goal was to determine the transfer function relating the radial shear between the structures that deflect the OHC bundle, the tectorial membrane and reticular lamina, to the transverse motion of the basilar membrane. We found that, after normalizing their responses to the vibration of the basilar membrane, the radial vibrations of the tectorial membrane and reticular lamina were tuned. The radial tuning peaked at a higher frequency than transverse basilar membrane tuning in the passive, postmortem condition. The radial tuning was similar in dead mice, indicating that this reflected passive, not active, mechanics. These findings were exaggerated in Tecta(C1509G/C1509G) mice, where the tectorial membrane is detached from OHC stereocilia, arguing that the tuning of radial vibrations within the hair cell epithelium is distinct from tectorial membrane tuning. Together, these results reveal a passive, frequency-dependent contribution to cochlear filtering that is independent of basilar membrane filtering. These data argue that passive mechanics within the organ of Corti sharpen frequency selectivity by defining which OHCs enhance the vibration of the basilar membrane, thereby tuning the gain of cochlear amplification. SIGNIFICANCE STATEMENT: Outer hair cells amplify the traveling wave within the mammalian cochlea. The resultant gain and frequency sharpening are necessary for speech discrimination, particularly in the presence of background noise. Here we measured the 2-D motion of the organ of Corti in mice and found that the structures that stimulate the outer hair cell stereocilia, the tectorial membrane and reticular lamina, were sharply tuned in the radial direction. Radial tuning was similar in dead mice and in mice lacking a tectorial membrane. This suggests that radial tuning comes from passive mechanics within the hair cell epithelium, and that these mechanics, at least in part, may tune the gain of cochlear amplification. PMID- 27488637 TI - Nalcn Is a "Leak" Sodium Channel That Regulates Excitability of Brainstem Chemosensory Neurons and Breathing. AB - The activity of background potassium and sodium channels determines neuronal excitability, but physiological roles for "leak" Na(+) channels in specific mammalian neurons have not been established. Here, we show that a leak Na(+) channel, Nalcn, is expressed in the CO2/H(+)-sensitive neurons of the mouse retrotrapezoid nucleus (RTN) that regulate breathing. In RTN neurons, Nalcn expression correlated with higher action potential discharge over a more alkalized range of activity; shRNA-mediated depletion of Nalcn hyperpolarized RTN neurons, and reduced leak Na(+) current and firing rate. Nalcn depletion also decreased RTN neuron activation by the neuropeptide, substance P, without affecting pH-sensitive background K(+) currents or activation by a cotransmitter, serotonin. In vivo, RTN-specific knockdown of Nalcn reduced CO2-evoked neuronal activation and breathing; hypoxic hyperventilation was unchanged. Thus, Nalcn regulates RTN neuronal excitability and stimulation by CO2, independent of direct pH sensing, potentially contributing to respiratory effects of Nalcn mutations; transmitter modulation of Nalcn may underlie state-dependent changes in breathing and respiratory chemosensitivity. SIGNIFICANCE STATEMENT: Breathing is an essential, enduring rhythmic motor activity orchestrated by dedicated brainstem circuits that require tonic excitatory drive for their persistent function. A major source of drive is from a group of CO2/H(+)-sensitive neurons in the retrotrapezoid nucleus (RTN), whose ongoing activity is critical for breathing. The ionic mechanisms that support spontaneous activity of RTN neurons are unknown. We show here that Nalcn, a unique channel that generates "leak" sodium currents, regulates excitability and neuromodulation of RTN neurons and CO2 stimulated breathing. Thus, this work defines a specific function for this enigmatic channel in an important physiological context. PMID- 27488638 TI - Feature-Selective Attentional Modulations in Human Frontoparietal Cortex. AB - Control over visual selection has long been framed in terms of a dichotomy between "source" and "site," where top-down feedback signals originating in frontoparietal cortical areas modulate or bias sensory processing in posterior visual areas. This distinction is motivated in part by observations that frontoparietal cortical areas encode task-level variables (e.g., what stimulus is currently relevant or what motor outputs are appropriate), while posterior sensory areas encode continuous or analog feature representations. Here, we present evidence that challenges this distinction. We used fMRI, a roving searchlight analysis, and an inverted encoding model to examine representations of an elementary feature property (orientation) across the entire human cortical sheet while participants attended either the orientation or luminance of a peripheral grating. Orientation-selective representations were present in a multitude of visual, parietal, and prefrontal cortical areas, including portions of the medial occipital cortex, the lateral parietal cortex, and the superior precentral sulcus (thought to contain the human homolog of the macaque frontal eye fields). Additionally, representations in many-but not all-of these regions were stronger when participants were instructed to attend orientation relative to luminance. Collectively, these findings challenge models that posit a strict segregation between sources and sites of attentional control on the basis of representational properties by demonstrating that simple feature values are encoded by cortical regions throughout the visual processing hierarchy, and that representations in many of these areas are modulated by attention. SIGNIFICANCE STATEMENT: Influential models of visual attention posit a distinction between top down control and bottom-up sensory processing networks. These models are motivated in part by demonstrations showing that frontoparietal cortical areas associated with top-down control represent abstract or categorical stimulus information, while visual areas encode parametric feature information. Here, we show that multivariate activity in human visual, parietal, and frontal cortical areas encode representations of a simple feature property (orientation). Moreover, representations in several (though not all) of these areas were modulated by feature-based attention in a similar fashion. These results provide an important challenge to models that posit dissociable top-down control and sensory processing networks on the basis of representational properties. PMID- 27488639 TI - Hepatocyte Growth Factor-c-MET Signaling Mediates the Development of Nonsensory Structures of the Mammalian Cochlea and Hearing. AB - The stria vascularis is a nonsensory structure that is essential for auditory hair cell function by maintaining potassium concentration of the scala media. During mouse embryonic development, a subpopulation of neural crest cell-derived melanocytes migrates and incorporates into a subregion of the cochlear epithelium, forming the intermediate cell layer of the stria vascularis. The relation of this developmental process to stria vascularis function is currently unknown. In characterizing the molecular differentiation of developing peripheral auditory structures, we discovered that hepatocyte growth factor (Hgf) is expressed in the future stria vascularis of the cochlear epithelium. Its receptor tyrosine kinase, c-Met, is expressed in the cochlear epithelium and melanocyte derived intermediate cells in the stria vascularis. Genetic dissection of HGF signaling via c-MET reveals that the incorporation of the melanocytes into the future stria vascularis of the cochlear duct requires c-MET signaling. In addition, inactivation of either the ligand or receptor developmentally resulted in a profound hearing loss at young adult stages. These results suggest a novel connection between HGF signaling and deafness via melanocyte deficiencies. SIGNIFICANCE STATEMENT: We found the roles of hepatocyte growth factor (HGF) signaling in stria vascularis development for the first time and that lack of HGF signaling in the inner ear leads to profound hearing loss in the mouse. Our findings reveal a novel mechanism that may underlie human deafness DFNB39 and DFNB97. Our findings reveal an additional example of context-dependent c-MET signaling diversity, required here for proper cellular invasion developmentally that is essential for specific aspects of auditory-related organogenesis. PMID- 27488640 TI - A Subtype of Olfactory Bulb Interneurons Is Required for Odor Detection and Discrimination Behaviors. AB - Neural circuits that undergo reorganization by newborn interneurons in the olfactory bulb (OB) are necessary for odor detection and discrimination, olfactory memory, and innate olfactory responses, including predator avoidance and sexual behaviors. The OB possesses many interneurons, including various types of granule cells (GCs); however, the contribution that each type of interneuron makes to olfactory behavioral control remains unknown. Here, we investigated the in vivo functional role of oncofetal trophoblast glycoprotein 5T4, a regulator for dendritic arborization of 5T4-expressing GCs (5T4 GCs), the level of which is reduced in the OB of 5T4 knock-out (KO) mice. Electrophysiological recordings with acute OB slices indicated that external tufted cells (ETCs) can be divided into two types, bursting and nonbursting. Optogenetic stimulation of 5T4 GCs revealed their connection to both bursting and nonbursting ETCs, as well as to mitral cells (MCs). Interestingly, nonbursting ETCs received fewer inhibitory inputs from GCs in 5T4 KO mice than from those in wild-type (WT) mice, whereas bursting ETCs and MCs received similar inputs in both mice. Furthermore, 5T4 GCs received significantly fewer excitatory inputs in 5T4 KO mice. Remarkably, in olfactory behavior tests, 5T4 KO mice had higher odor detection thresholds than the WT, as well as defects in odor discrimination learning. Therefore, the loss of 5T4 attenuates inhibitory inputs from 5T4 GCs to nonbursting ETCs and excitatory inputs to 5T4 GCs, contributing to disturbances in olfactory behavior. Our novel findings suggest that, among the various types of OB interneurons, the 5T4 GC subtype is required for odor detection and discrimination behaviors. SIGNIFICANCE STATEMENT: Neuronal circuits in the brain include glutamatergic principal neurons and GABAergic interneurons. Although the latter is a minority cell type, they are vital for normal brain function because they regulate the activity of principal neurons. If interneuron function is impaired, brain function may be damaged, leading to behavior disorder. The olfactory bulb (OB) possesses various types of interneurons, including granule cells (GCs); however, the contribution that each type of interneuron makes to the control of olfactory behavior remains unknown. Here, we analyzed electrophysiologically and behaviorally the function of oncofetal trophoblast glycoprotein 5T4, a regulator for dendritic branching in OB GCs. We found that, among the various types of OB interneuron, the 5T4 GC subtype is required for odor detection and odor discrimination behaviors. PMID- 27488641 TI - Reciprocal Control of Drinking Behavior by Median Preoptic Neurons in Mice. AB - Stimulation of glutamatergic neurons in the subfornical organ drives drinking behavior, but the brain targets that mediate this response are not known. The densest target of subfornical axons is the anterior tip of the third ventricle, containing the median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT), a region that has also been implicated in fluid and electrolyte management. The neurochemical composition of this region is complex, containing both GABAergic and glutamatergic neurons, but the possible roles of these neurons in drinking responses have not been addressed. In mice, we show that optogenetic stimulation of glutamatergic neurons in MnPO/OVLT drives voracious water consumption, and that optogenetic stimulation of GABAergic neurons in the same region selectively reduces water consumption. Both populations of neurons have extensive projections to overlapping regions of the thalamus, hypothalamus, and hindbrain that are much more extensive than those from the subfornical organ, suggesting that the MnPO/OVLT serves as a key link in regulating drinking responses. SIGNIFICANCE STATEMENT: Neurons in the median preoptic nucleus (MnPO) and organum vasculosum of the lamina terminalis (OVLT) are known to regulate fluid/electrolyte homeostasis, but few studies have examined this issue with an appreciation for the neurochemical heterogeneity of these nuclei. Using Cre-Lox genetic targeting of Channelrhodospin-2 in transgenic mice, we demonstrate that glutamate and GABA neurons in the MnPO/OVLT reciprocally regulate water consumption. Stimulating glutamatergic MnPO/OVLT neurons induced water consumption, whereas stimulating GABAergic MnPO neurons caused a sustained and specific reduction in water consumption in dehydrated mice, the latter highlighting a heretofore unappreciated role of GABAergic MnPO neurons in thirst regulation. These observations represent an important advance in our understanding of the neural circuits involved in the regulation of fluid/electrolyte homeostasis. PMID- 27488642 TI - An EEG Investigation of Sleep Homeostasis in Healthy and CLN5 Batten Disease Affected Sheep. AB - Sheep have large brains with human-like anatomy, making them a useful species for studying brain function. Sleep homeostasis has not been studied in sheep. Here, we establish correlates of sleep homeostasis in sheep through a sleep deprivation experiment. We then use these correlates to elucidate the nature of sleep deficits in a naturally occurring ovine model of neuronal ceroid lipofuscinosis (NCL, Batten disease) caused by a mutation in CLN5 In humans, mutations in this gene lead to cortical atrophy and blindness, as well as sleep abnormalities. We recorded electroencephalograms (EEGs) from unaffected and early stage CLN5(-/-) (homozygous, affected) sheep over 3 consecutive days, the second day being the sleep deprivation day. In unaffected sheep, sleep deprivation led to increased EEG delta (0.5-4 Hz) power during non-rapid eye movement (NREM) sleep, increased time spent in the NREM sleep state, and increased NREM sleep bout length. CLN5(-/ ) sheep showed comparable increases in time spent in NREM sleep and NREM sleep bout duration, verifying the presence of increased sleep pressure in both groups. Importantly, CLN5(-/-) sheep did not show the increase in NREM sleep delta power seen in unaffected sheep. This divergent delta power response is consistent with the known cortical degeneration in CLN5(-/-) sheep. We conclude that, whereas sleep homeostasis is present in CLN5(-/-) sheep, underlying CLN5(-/-) disease processes prevent its full expression, even at early stages. Such deficits may contribute to early abnormalities seen in sheep and patients and warrant further study. SIGNIFICANCE STATEMENT: Sleep abnormalities pervade most neurological diseases, including the neuronal ceroid lipofuscinoses (NCLs). Here, we show that, in an ovine model of a variant late-infantile NCL, there is abnormal expression of sleep homeostasis. Whereas some sleep pressure correlates respond to sleep deprivation, the strongest electroencephalogram (EEG) correlate of sleep pressure, non-REM delta power, failed to increase. This highlights the relevance of sleep deficits in this disease, in which the drive for sleep exists but the underlying disease prevents its full expression. Sleep abnormalities could contribute to early disease symptoms such as behavioral disorder and cognitive decline. Our study also shows sleep homeostatic EEG correlates in sheep, opening up new opportunities for studying sleep in a large social mammal with complex human-like brain neuroanatomy. PMID- 27488643 TI - Role of Binaural Temporal Fine Structure and Envelope Cues in Cocktail-Party Listening. AB - While conversing in a crowded social setting, a listener is often required to follow a target speech signal amid multiple competing speech signals (the so called "cocktail party" problem). In such situations, separation of the target speech signal in azimuth from the interfering masker signals can lead to an improvement in target intelligibility, an effect known as spatial release from masking (SRM). This study assessed the contributions of two stimulus properties that vary with separation of sound sources, binaural envelope (ENV) and temporal fine structure (TFS), to SRM in normal-hearing (NH) human listeners. Target speech was presented from the front and speech maskers were either colocated with or symmetrically separated from the target in azimuth. The target and maskers were presented either as natural speech or as "noise-vocoded" speech in which the intelligibility was conveyed only by the speech ENVs from several frequency bands; the speech TFS within each band was replaced with noise carriers. The experiments were designed to preserve the spatial cues in the speech ENVs while retaining/eliminating them from the TFS. This was achieved by using the same/different noise carriers in the two ears. A phenomenological auditory-nerve model was used to verify that the interaural correlations in TFS differed across conditions, whereas the ENVs retained a high degree of correlation, as intended. Overall, the results from this study revealed that binaural TFS cues, especially for frequency regions below 1500 Hz, are critical for achieving SRM in NH listeners. Potential implications for studying SRM in hearing-impaired listeners are discussed. SIGNIFICANCE STATEMENT: Acoustic signals received by the auditory system pass first through an array of physiologically based band-pass filters. Conceptually, at the output of each filter, there are two principal forms of temporal information: slowly varying fluctuations in the envelope (ENV) and rapidly varying fluctuations in the temporal fine structure (TFS). The importance of these two types of information in everyday listening (e.g., conversing in a noisy social situation; the "cocktail-party" problem) has not been established. This study assessed the contributions of binaural ENV and TFS cues for understanding speech in multiple-talker situations. Results suggest that, whereas the ENV cues are important for speech intelligibility, binaural TFS cues are critical for perceptually segregating the different talkers and thus for solving the cocktail party problem. PMID- 27488644 TI - A Quantitative Analysis of Context-Dependent Remapping of Medial Frontal Cortex Neurons and Ensembles. AB - The frontal cortex has been implicated in a number of cognitive and motivational processes, but understanding how individual neurons contribute to these processes is particularly challenging as they respond to a broad array of events (multiplexing) in a manner that can be dynamically modulated by the task context, i.e., adaptive coding (Duncan, 2001). Fundamental questions remain, such as how the flexibility gained through these mechanisms is balanced by the need for consistency and how the ensembles of neurons are coherently shaped by task demands. In the present study, ensembles of medial frontal cortex neurons were recorded from rats trained to perform three different operant actions either in two different sequences or two different physical environments. Single neurons exhibited diverse mixtures of responsivity to each of the three actions and these mixtures were abruptly altered by context/sequence switches. Remarkably, the overall responsivity of the population remained highly consistent both within and between context/sequences because the gains versus losses were tightly balanced across neurons and across the three actions. These data are consistent with a reallocation mixture model in which individual neurons express unique mixtures of selectivity for different actions that become reallocated as task conditions change. However, because the allocations and reallocations are so well balanced across neurons, the population maintains a low but highly consistent response to all actions. The frontal cortex may therefore balance consistency with flexibility by having ensembles respond in a fixed way to task-relevant actions while abruptly reconfiguring single neurons to encode "actions in context." SIGNIFICANCE STATEMENT: Flexible modes of behavior involve performance of similar actions in contextually relevant ways. The present study quantified the changes in how rat medial frontal cortex neurons respond to the same actions when performed in different task contexts (sequences or environments). Most neurons altered the mixture of actions they were responsive to in different contexts or sequences. Nevertheless, the responsivity profile of the ensemble remained fixed as did the ability of the ensemble to differentiate between the three actions. These mechanisms may help to contextualize the manner in which common events are represented across different situations. PMID- 27488645 TI - A Trial-by-Trial Window into Sensorimotor Transformations in the Human Motor Periphery. AB - The appearance of a novel visual stimulus generates a rapid stimulus-locked response (SLR) in the motor periphery within 100 ms of stimulus onset. Here, we recorded SLRs from an upper limb muscle while humans reached toward (pro-reach) or away (anti-reach) from a visual stimulus. The SLR on anti-reaches encoded the location of the visual stimulus rather than the movement goal. Further, SLR magnitude was attenuated when subjects reached away from rather than toward the visual stimulus. Remarkably, SLR magnitudes also correlated with reaction times on both pro-reaches and anti-reaches, but did so in opposite ways: larger SLRs preceded shorter latency pro-reaches but longer latency anti-reaches. Although converging evidence suggests that the SLR is relayed via a tectoreticulospinal pathway, our results show that task-related signals modulate visual signals feeding into this pathway. The SLR therefore provides a trial-by-trial window into how visual information is integrated with cognitive control in humans. SIGNIFICANCE STATEMENT: The presentation of a visual stimulus elicits a trial-by trial stimulus-locked response (SLR) on the human limb within 100 ms. Here, we show that the SLR continues to reflect stimulus location even when subjects move in the opposite direction (an anti-reach). Remarkably, the attenuation of SLR magnitude reflected the cognitive control required to generate a correct anti reach, with greater degrees of attenuation preceding shorter-latency anti-reaches and no attenuation preceding error trials. Our results are strikingly similar to neurophysiological recordings in the superior colliculus of nonhuman primates generating anti-saccades, implicating the tectoreticulospinal pathway. Measuring SLR magnitude therefore provides an unprecedented trial-by-trial opportunity to assess the influence of cognitive control on the initial processing of a visual stimulus in humans. PMID- 27488646 TI - Thomas Boulton. PMID- 27488647 TI - Laetoli footprints reveal bipedal gait biomechanics different from those of modern humans and chimpanzees. AB - Bipedalism is a key adaptation that shaped human evolution, yet the timing and nature of its evolution remain unclear. Here we use new experimentally based approaches to investigate the locomotor mechanics preserved by the famous Pliocene hominin footprints from Laetoli, Tanzania. We conducted footprint formation experiments with habitually barefoot humans and with chimpanzees to quantitatively compare their footprints to those preserved at Laetoli. Our results show that the Laetoli footprints are morphologically distinct from those of both chimpanzees and habitually barefoot modern humans. By analysing biomechanical data that were collected during the human experiments we, for the first time, directly link differences between the Laetoli and modern human footprints to specific biomechanical variables. We find that the Laetoli hominin probably used a more flexed limb posture at foot strike than modern humans when walking bipedally. The Laetoli footprints provide a clear snapshot of an early hominin bipedal gait that probably involved a limb posture that was slightly but significantly different from our own, and these data support the hypothesis that important evolutionary changes to hominin bipedalism occurred within the past 3.66 Myr. PMID- 27488648 TI - The evolution of eggshell cuticle in relation to nesting ecology. AB - Avian eggs are at risk of microbial infection prior to and during incubation. A large number of defence mechanisms have evolved in response to the severe costs imposed by these infections. The eggshell's cuticle is an important component of antimicrobial defence, and its role in preventing contamination by microorganisms in domestic chickens is well known. Nanometer-scale cuticular spheres that reduce microbial attachment and penetration have recently been identified on eggs of several wild avian species. However, whether these spheres have evolved specifically for antimicrobial defence is unknown. Here, we use comparative data on eggshell cuticular structure and nesting ecology to test the hypothesis that birds nesting in habitats with higher risk of infection (e.g. wetter and warmer) are more likely to evolve cuticular nanospheres on their eggshells than those nesting in less risky habitats. We found that nanostructuring, present in 54 of 296 analysed species, is the ancestral condition of avian eggshells and has been retained more often in taxa that nest in humid infection-prone environments, suggesting that they serve critical roles in antimicrobial egg defence. PMID- 27488649 TI - Dispersal propensity, but not flight performance, explains variation in dispersal ability. AB - Enhanced dispersal ability may lead to accelerated range expansion and increased rates of population establishment, thereby affecting population genetic structure and evolutionary potential. Morphological, behavioural and physiological traits that characterize dispersive individuals from residents are poorly understood for many invertebrate systems, especially in non-polymorphic pterygote species. Here we examined phenotypic differences between dispersal-prone and philopatric individuals from repeated mark-release-recapture (MRR) experiments using an invasive agricultural pest, Ceratitis capitata Comprehensive morphometric assessment and subsequent minimal adequate modelling using an information theoretic approach identified thorax mass : body mass ratio as a key predictor of disperser flies under semi-natural conditions. Performance differences in flight ability were then examined under controlled laboratory conditions to assess whether greater thorax mass : body mass ratio was associated with enhanced flight ability. The larger thorax : body mass ratio was associated with measurable differences in mean flight duration, most predominantly in males, and also by their willingness to disperse, scored as the number and duration of voluntary flights. No other measures of whole-animal flight performance (e.g. mean and peak vertical force, total or maximum flight duration) differed. Variation in voluntary behaviour may result in significant alterations of movement behaviour and realized dispersal in nature. This phenomenon may help explain intraspecific variation in the dispersal ability of insects. PMID- 27488650 TI - Pigmented anatomy in Carboniferous cyclostomes and the evolution of the vertebrate eye. AB - The success of vertebrates is linked to the evolution of a camera-style eye and sophisticated visual system. In the absence of useful data from fossils, scenarios for evolutionary assembly of the vertebrate eye have been based necessarily on evidence from development, molecular genetics and comparative anatomy in living vertebrates. Unfortunately, steps in the transition from a light-sensitive 'eye spot' in invertebrate chordates to an image-forming camera style eye in jawed vertebrates are constrained only by hagfish and lampreys (cyclostomes), which are interpreted to reflect either an intermediate or degenerate condition. Here, we report-based on evidence of size, shape, preservation mode and localized occurrence-the presence of melanosomes (pigment bearing organelles) in fossil cyclostome eyes. Time of flight secondary ion mass spectrometry analyses reveal secondary ions with a relative intensity characteristic of melanin as revealed through principal components analyses. Our data support the hypotheses that extant hagfish eyes are degenerate, not rudimentary, that cyclostomes are monophyletic, and that the ancestral vertebrate had a functional visual system. We also demonstrate integument pigmentation in fossil lampreys, opening up the exciting possibility of investigating colour patterning in Palaeozoic vertebrates. The examples we report add to the record of melanosome preservation in Carboniferous fossils and attest to surprising durability of melanosomes and biomolecular melanin. PMID- 27488651 TI - Parallel telomere shortening in multiple body tissues owing to malaria infection. AB - Several studies have shown associations between shorter telomere length in blood and weakened immune function, susceptibility to infections, and increased risk of morbidity and mortality. Recently, we have shown that malaria accelerates telomere attrition in blood cells and shortens lifespan in birds. However, the impact of infections on telomere attrition in different body tissues within an individual is unknown. Here, we tested whether malarial infection leads to parallel telomere shortening in blood and tissue samples from different organs. We experimentally infected siskins (Spinus spinus) with the avian malaria parasite Plasmodium ashfordi, and used real-time quantitative polymerase chain reaction (PCR) to measure telomere length in control and experimentally infected siskins. We found that experimentally infected birds showed faster telomere attrition in blood over the course of infection compared with control individuals (repeatedly measured over 105 days post-infection (DPI)). Shorter telomeres were also found in the tissue of all six major organs investigated (liver, lungs, spleen, heart, kidney, and brain) in infected birds compared with controls at 105 DPI. To the best of our knowledge, this is the first study showing that an infectious disease results in synchronous telomere shortening in the blood and tissue cells of internal organs within individuals, implying that the infection induces systemic stress. Our results have far-reaching implications for understanding how the short-term effects of an infection can translate into long term costs, such as organ dysfunction, degenerative diseases, and ageing. PMID- 27488652 TI - Seeing red to being red: conserved genetic mechanism for red cone oil droplets and co-option for red coloration in birds and turtles. AB - Avian ketocarotenoid pigments occur in both the red retinal oil droplets that contribute to colour vision and bright red coloration used in signalling. Turtles are the only other tetrapods with red retinal oil droplets, and some also display red carotenoid-based coloration. Recently, the CYP2J19 gene was strongly implicated in ketocarotenoid synthesis in birds. Here, we investigate CYP2J19 evolution in relation to colour vision and red coloration in reptiles using genomic and expression data. We show that turtles, but not crocodiles or lepidosaurs, possess a CYP2J19 orthologue, which arose via gene duplication before turtles and archosaurs split, and which is strongly and specifically expressed in the ketocarotenoid-containing retina and red integument. We infer that CYP2J19 initially functioned in colour vision in archelosaurs and conclude that red ketocarotenoid-based coloration evolved independently in birds and turtles via gene regulatory changes of CYP2J19 Our results suggest that red oil droplets contributed to colour vision in dinosaurs and pterosaurs. PMID- 27488653 TI - Lifespan, growth rate, and body size across latitude in marine Bivalvia, with implications for Phanerozoic evolution. AB - Mean body size in marine animals has increased more than 100-fold since the Cambrian, a discovery that brings to attention the key life-history parameters of lifespan and growth rate that ultimately determine size. Variation in these parameters is not well understood on the planet today, much less in deep time. Here, we present a new global database of maximum reported lifespan and shell growth coupled with body size data for 1 148 populations of marine bivalves and show that (i) lifespan increases, and growth rate decreases, with latitude, both across the group as a whole and within well-sampled species, (ii) growth rate, and hence metabolic rate, correlates inversely with lifespan, and (iii) opposing trends in lifespan and growth combined with high variance obviate any demonstrable pattern in body size with latitude. Our observations suggest that the proposed increase in metabolic activity and demonstrated increase in body size of organisms over the Phanerozoic should be accompanied by a concomitant shift towards faster growth and/or shorter lifespan in marine bivalves. This prediction, testable from the fossil record, may help to explain one of the more fundamental patterns in the evolutionary and ecological history of animal life on this planet. PMID- 27488654 TI - Loss of MPZL3 function causes seborrhoeic dermatitis-like phenotype in mice. PMID- 27488655 TI - Development and optimization of a competitive binding assay for the galactophilic low affinity lectin LecA from Pseudomonas aeruginosa. AB - Infections with the Gram-negative bacterium Pseudomonas aeruginosa result in a high mortality among immunocompromised patients and those with cystic fibrosis. The pathogen can switch from planktonic life to biofilms, and thereby shields itself against antibiotic treatment and host immune defense to establish chronic infections. The bacterial protein LecA, a C-type lectin, is a virulence factor and an integral component for biofilm formation. Inhibition of LecA with its carbohydrate ligands results in reduced biofilm mass, a potential Achilles heel for treatment. Here, we report the development and optimization of a fluorescence polarization-based competitive binding assay with LecA for application in screening of potential inhibitors. As a consequence of the low affinity of d galactose for LecA, the fluorescent ligand was optimized to reduce protein consumption in the assay. The assay was validated using a set of known inhibitors of LecA and IC50 values in good agreement with the known Kd values were obtained. Finally, we employed the optimized assay to screen sets of synthetic thio galactosides and natural blood group antigens and report their structure-activity relationship. In addition, we evaluated a multivalent fluorescent assay probe for LecA and report its applicability in an inhibition assay. PMID- 27488656 TI - Effects of Newtonian gravitational self-interaction in harmonically trapped quantum systems. AB - The Schrodinger-Newton equation has gained attention in the recent past as a nonlinear modification of the Schrodinger equation due to a gravitational self interaction. Such a modification is expected from a fundamentally semi-classical theory of gravity and can, therefore, be considered a test case for the necessity of the quantisation of the gravitational field. Here we provide a thorough study of the effects of the Schrodinger-Newton equation for a micron-sized sphere trapped in a harmonic oscillator potential. We discuss both the effect on the energy eigenstates and the dynamical behaviour of squeezed states, covering the experimentally relevant parameter regimes. PMID- 27488657 TI - Psychometric properties of the Postpartum Depression Predictors Inventory-Revised for pregnant women in Mexico. AB - This study assessed the reliability and concurrent validity of the prenatal section of the Postpartum Depression Predictors Inventory-Revised for 250 pregnant women receiving prenatal care in Mexico. The Postpartum Depression Predictors Inventory-Revised has shown adequate psychometric properties for English-speaking perinatal women, but no similar data have been reported for Spanish-speaking samples. The results show that the Postpartum Depression Predictors Inventory-Revised is highly reliable and exhibits adequate concurrent validity compared to the Edinburgh Postnatal Depression Scale. These findings suggest that the Postpartum Depression Predictors Inventory-Revised can be a reliable instrument in prenatal care services for detecting risk factors for perinatal depression in Mexican women and potentially in other Spanish-speaking populations. PMID- 27488658 TI - Routine primary care screening for intimate partner violence and other adverse psychosocial exposures: what's the evidence? AB - BACKGROUND: Family physicians and other primary care practitioners are encouraged or expected to screen for an expanding array of concerns and problems including intimate partner violence (IPV). While there is no debate about the deleterious impact of violence and other adverse psychosocial exposures on health status, the key question raised here is about the value of routine screening in primary care for such exposures. DISCUSSION: Several characteristics of IPV have led to consideration for routine IPV screening in primary care and during other healthcare encounters (e.g., emergency room visits) including: its high prevalence, concern that it may not be raised spontaneously if not prompted, and the burden of suffering associated with this exposure. Despite these factors, there are now three randomized controlled trials showing that screening does not reduce IPV or improve health outcomes. Yet, recommendations to routinely screen for IPV persist. Similarly, adverse childhood experiences (ACEs) have several characteristics (e.g., high frequency, predictive power of such experiences for subsequent health problems, and concerns that they might not be identified without screening) suggesting they too should be considered for routine primary care screening. However, demonstration of strong associations with health outcomes, and even causality, do not necessarily translate into the benefits of routine screening for such experiences. To date, there have been no controlled trials examining the impact and outcomes - either beneficial or harmful - of routine ACEs screening. Even so, there is an expansion of calls for routine screening for ACEs. While we must prioritize how best to support and intervene with patients who have experienced IPV and other adverse psychosocial exposures, we should not be lulled into a false sense of security that our routine use of "screeners" results in better health outcomes or less violence without evidence for such. Decisions about implementation of routine screening for psychosocial concerns need similar rigorous debate and scrutiny of empirical evidence as that recommended for proposed physical health screening (e.g., for prostate and breast cancer). PMID- 27488659 TI - Detection and identification of the heterogeneous novel subgroup 16SrXIII-(A/I)I phytoplasma associated with strawberry green petal disease and Mexican periwinkle virescence. AB - Phytoplasmas (species of the genus 'CandidatusPhytoplasma') are insect-vectored phytopathogenic bacteria associated with economically and ecologically important crop diseases. Strawberry production represents an important part of agricultural activity in Mexico and elsewhere, and infection of plants with phytoplasma renders the fruit inedible by altering plant development, resulting in virescence and phyllody. In this study we examined samples taken from four strawberry plants showing symptoms associated with strawberry green petal disease and from two periwinkle plants showing virescence, sampled in different areas of Mexico. Analysis of the 16S rRNA-encoding sequences showed that the plants were infected with a phytoplasma previously identified as Mexican periwinkle virescence (MPV; 16SrXIII). Examination of bacterial sequences from these samples revealed that two distinct 16S rRNA gene sequences were present in each sample along with a single chaperonin-60 (cpn60) sequence and a single rpoB sequence, suggesting that this strain displays 16S rRNA gene sequence heterogeneity. Two distinct rrn operons, identified with subgroup 16SrXIII-A and the newly described subgroup 16SrXIII-I, were identified from the six samples analyzed, delineating the novel subgroup 16SrXIII-(A/I)I, following the nomenclature proposed for heterogeneous subgroups. PMID- 27488660 TI - Increased hypertrophic response with increased mechanical load in skeletal muscles receiving identical activity patterns. AB - It is often assumed that mechanical factors are important for effects of exercise on muscle, but during voluntary training and most experimental conditions the effects could solely be attributed to differences in electrical activity, and direct evidence for a mechanosensory pathway has been scarce. We here show that, in rat muscles stimulated in vivo under deep anesthesia with identical electrical activity patterns, isometric contractions induced twofold more hypertrophy than contractions with 50-60% of the isometric force. The number of myonuclei and the RNA levels of myogenin and myogenic regulatory factor 4 were increased with high load, suggesting that activation of satellite cells is mechano dependent. On the other hand, training induced a major shift in fiber type distribution from type 2b to 2x that was load independent, indicating that the electrical signaling rather than mechanosignaling controls fiber type. RAC-alpha serine/threonine protein kinase (Akt) and ribosomal protein S6 kinase beta-1 (S6K1) were not significantly differentially activated by load, suggesting that the differences in mechanical factors were not important for activating the Akt/mammalian target of rapamycin/S6K1 pathway. The transmembrane molecule syndecan-4 implied in overload hypertrophy in cardiac muscle was not load dependent, suggesting that mechanosignaling in skeletal muscle is different. PMID- 27488661 TI - Tensional homeostasis in endothelial cells is a multicellular phenomenon. AB - Mammalian cells of various types exhibit the remarkable ability to adapt to externally applied mechanical stresses and strains. Because of this adaptation, cells can maintain their endogenous mechanical tension at a preferred (homeostatic) level, which is essential for normal physiological functions of cells and tissues and provides protection against various diseases, including atherosclerosis and cancer. Conventional wisdom is that the cell possesses the ability to maintain tensional homeostasis on its own. Recent findings showed, however, that isolated cells cannot maintain tensional homeostasis. Here we studied the effect of multicellular interactions on tensional homeostasis by measuring traction forces in isolated bovine aortic endothelial cells and in confluent and nonconfluent cell clusters of different sizes. We found that, in isolated cells, the traction field exhibited a highly dynamic and erratic behavior. However, in cell clusters, dynamic fluctuations of the traction field became attenuated with increasing cluster size, at a rate that was faster in nonconfluent than confluent clusters. The driving mechanism of attenuation of traction field fluctuations was statistical averaging of the noise, and the impeding mechanism was nonuniform stress distribution in the clusters, which resulted from intercellular force transmission, known as a "global tug-of-war." These results show that isolated cells could not maintain tensional homeostasis, which confirms previous findings, and that tensional homeostasis is a multicellular phenomenon, which is a novel finding. PMID- 27488662 TI - Ketoisocaproic acid, a metabolite of leucine, suppresses insulin-stimulated glucose transport in skeletal muscle cells in a BCAT2-dependent manner. AB - Although leucine has many positive effects on metabolism in multiple tissues, elevated levels of this amino acid and the other branched-chain amino acids (BCAAs) and their metabolites are implicated in obesity and insulin resistance. While some controversies exist about the direct effect of leucine on insulin action in skeletal muscle, little is known about the direct effect of BCAA metabolites. Here, we first showed that the inhibitory effect of leucine on insulin-stimulated glucose transport in L6 myotubes was dampened when other amino acids were present, due in part to a 140% stimulation of basal glucose transport (P < 0.05). Importantly, we also showed that alpha-ketoisocaproic acid (KIC), an obligatory metabolite of leucine, stimulated mTORC1 signaling but suppressed insulin-stimulated glucose transport (-34%, P < 0.05) in an mTORC1-dependent manner. The effect of KIC on insulin-stimulated glucose transport was abrogated in cells depleted of branched-chain aminotransferase 2 (BCAT2), the enzyme that catalyzes the reversible transamination of KIC to leucine. We conclude that although KIC can modulate muscle glucose metabolism, this effect is likely a result of its transamination back to leucine. Therefore, limiting the availability of leucine, rather than those of its metabolites, to skeletal muscle may be more critical in the management of insulin resistance and its sequelae. PMID- 27488663 TI - Toll-like receptor 4 mutation suppresses hyperhomocysteinemia-induced hypertension. AB - Hyperhomocysteinemia (HHcy) has been observed to promote hypertension, but the mechanisms are unclear. Toll-like receptor 4 (TLR-4) is a cellular membrane protein that is ubiquitously expressed in all cell types of the vasculature. TLR 4 activation has been known to promote inflammation that has been associated with the pathogenesis of hypertension. In this study we hypothesize that HHcy induces hypertension by TLR-4 activation, which promotes inflammatory cytokine (IL-1beta, IL-6, and TNF-alpha) upregulation and initiation of mitochondria-dependent apoptosis, leading to cell death and chronic vascular inflammation. To test this hypothesis, we used C57BL/6J (WT) mice, cystathionine beta-synthase (CBS) deficient (CBS+/-) mice with genetic mild HHcy, C3H/HeJ (C3H) mice with TLR-4 mutation, and mice with combined genetic HHcy and TLR-4 mutation (CBS+/-/C3H). Ultrasonography of the superior mesenteric artery (SMA) detected an increase in wall-to-lumen ratio, resistive index (RI), and pulsatility index (PI). Tail cuff blood pressure (BP) measurement revealed elevated BP in CBS+/- mice. RI, PI, and wall-to-lumen ratio of the SMA in CBS+/-/C3H mice were similar to the control group, and BP was significantly alleviated. TLR-4, IL-1beta, IL-6, and TNF-alpha expression were upregulated in the SMA of CBS+/- mice and reduced in the SMA of CBS+/-/C3H mice. Molecules involved in the mitochondria-mediated cell death pathway (BAX, caspase-9, and caspase-3) were upregulated in CBS+/- mice and attenuated in CBS+/-/C3H mice. We conclude that HHcy promotes TLR-4-driven chronic vascular inflammation and mitochondria-mediated cell death, inducing hypertension. TLR-4 mutation attenuates vascular inflammation and cell death, which suppress hypertension. PMID- 27488664 TI - Activation of Nrf2 contributes to the protective effect of Exendin-4 against angiotensin II-induced vascular smooth muscle cell senescence. AB - Oxidative stress and impaired antioxidant defense are believed to be contributors to the cardiovascular aging process. The transcription factor nuclear factor-E2 related factor 2 (Nrf2) plays a key role in orchestrating cellular antioxidant defenses and maintaining redox homeostasis. Our previous study showed that Exendin-4, a glucagon-like peptide-1 analog, alleviates angiotensin II (ANG II) induced vascular smooth muscle cell (VSMC) senescence by inhibiting Rac1 activation via cAMP/PKA (Zhao L, Li AQ, Zhou TF, Zhang MQ, Qin XM. Am J Physiol Cell Physiol 307: C1130-C1141, 2014). The objective of this study is to investigate if Nrf2 mediates the antisenescent effect of Exendin-4 in ANG II induced VSMCs. Here we report that Exendin-4 triggered Nrf2 nuclear translocation, a downstream target of cAMP-responsive element-binding protein (CREB) and expressions of antioxidant genes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO-1) in a dose- and time-dependent manner. In addition, knock-down of Nrf2 attenuated the inhibitory effects of Exendin-4 on ANG II-induced superoxidant generation and VSMC senescence. PKA/CREB pathway participated in the upregulations of HO-1 and NQO-1 induced by Exendin-4. Notably, our study revealed that Exendin-4 dose-dependently increased the acetylation of Nrf2 and the recruitment of transcriptional coactivator CREB binding protein (CBP) to Nrf2. The Exendin-4-induced Nrf2 transactivation was diminished in the presence of CBP small interfering RNA. Microscope imaging of Nrf2, as well as immunoblotting for Nrf2, showed that the Exendin-4-evoked Nrf2 acetylation favored its nuclear retention. Importantly, CBP silencing attenuated the suppressing effects of Exendin-4 on ANG II-induced VSMC senescence and superoxidant production. In conclusion, these results provide a mechanistic insight into how Nrf2 signaling mediates the antisenescent and antioxidative effects induced by Exendin-4 in VSMCs. PMID- 27488666 TI - PIP2 in pancreatic beta-cells regulates voltage-gated calcium channels by a voltage-independent pathway. AB - Phosphatidylinositol-4,5-bisphosphate (PIP2) is a membrane phosphoinositide that regulates the activity of many ion channels. Influx of calcium primarily through voltage-gated calcium (CaV) channels promotes insulin secretion in pancreatic beta-cells. However, whether CaV channels are regulated by PIP2, as is the case for some non-insulin-secreting cells, is unknown. The purpose of this study was to investigate whether CaV channels are regulated by PIP2 depletion in pancreatic beta-cells through activation of a muscarinic pathway induced by oxotremorine methiodide (Oxo-M). CaV channel currents were recorded by the patch-clamp technique. The CaV current amplitude was reduced by activation of the muscarinic receptor 1 (M1R) in the absence of kinetic changes. The Oxo-M-induced inhibition exhibited the hallmarks of voltage-independent regulation and did not involve PKC activation. A small fraction of the Oxo-M-induced CaV inhibition was diminished by a high concentration of Ca2+ chelator, whereas >=50% of this inhibition was prevented by diC8-PIP2 dialysis. Localization of PIP2 in the plasma membrane was examined by transfecting INS-1 cells with PH-PLCdelta1, which revealed a close temporal association between PIP2 hydrolysis and CaV channel inhibition. Furthermore, the depletion of PIP2 by a voltage-sensitive phosphatase reduced CaV currents in a way similar to that observed following M1R activation. These results indicate that activation of the M1R pathway inhibits the CaV channel via PIP2 depletion by a Ca2+-dependent mechanism in pancreatic beta- and INS-1 cells and thereby support the hypothesis that membrane phospholipids regulate ion channel activity by interacting with ion channels. PMID- 27488665 TI - Insulin and SGK1 reduce the function of Na+/monocarboxylate transporter 1 (SMCT1/SLC5A8). AB - SMCTs move several important fuel molecules that are involved in lipid, carbohydrate, and amino acid metabolism, but their regulation has been poorly studied. Insulin controls the translocation of several solutes that are involved in energetic cellular metabolism, including glucose. We studied the effect of insulin on the function of human SMCT1 expressed in Xenopus oocytes. The addition of insulin reduced alpha-keto-isocaproate (KIC)-dependent 22Na+ uptake by 29%. Consistent with this result, the coinjection of SMCT1 with SGK1 cRNA decreased the KIC-dependent 22Na+ uptake by 34%. The reduction of SMCT1 activity by SGK1 depends on its kinase activity, and it was observed that the coinjection of SMCT1 with S442D-SGK1 (a constitutively active mutant) decreased the KIC-dependent 22Na+ uptake by 50%. In contrast, an SMCT1 coinjection with K127M-SGK1 (an inactive mutant) had no effect on the KIC-dependent Na+ uptake. The decreasing SMCT1 function by insulin or SGK1 was corroborated by measuring [1-14C]acetate uptake and the electric currents of SMCT1-injected oocytes. Previously, we found that SMCT2/Slc5a12-mRNA, but not SMCT1/Slc5a8-mRNA, is present in zebrafish pancreas (by in situ hybridization); however, SLC5a8 gene silencing was associated with the development of human pancreatic cancer. We confirmed that the mRNA and protein of both transporters were present in rat pancreas using RT-PCR with specific primers, Western blot analysis, and immunohistochemistry. Additionally, significant propionate-dependent 22Na+ uptake occurred in pancreatic islets and was reduced by insulin treatment. Our data indicate that human SMCT1 is regulated by insulin and SGK1 and that both SMCTs are present in the mammalian pancreas. PMID- 27488667 TI - KATP channel deficiency in mouse FDB causes an impairment of energy metabolism during fatigue. AB - The skeletal muscle ATP-sensitive K+ (KATP) channel is crucial in preventing fiber damage and contractile dysfunction, possibly by preventing damaging ATP depletion. The objective of this study was to investigate changes in energy metabolism during fatigue in wild-type and inwardly rectifying K+ channel (Kir6.2)-deficient (Kir6.2-/-) flexor digitorum brevis (FDB), a muscle that lacks functional KATP channels. Fatigue was elicited with one tetanic contraction every second. Decreases in ATP and total adenylate levels were significantly greater in wild-type than Kir6.2-/- FDB during the last 2 min of the fatigue period. Glycogen depletion was greater in Kir6.2-/- FDB for the first 60 s, but not by the end of the fatigue period, while there was no difference in glucose uptake. The total amount of glucosyl units entering glycolysis was the same in wild-type and Kir6.2-/- FDB. During the first 60 s, Kir6.2-/- FDB generated less lactate and more CO2; in the last 120 s, Kir6.2-/- FDB stopped generating CO2 and produced more lactate. The ATP generated during fatigue from phosphocreatine, glycolysis (lactate), and oxidative phosphorylation (CO2) was 3.3-fold greater in Kir6.2-/- than wild-type FDB. Because ATP and total adenylate were significantly less in Kir6.2-/- FDB, it is suggested that Kir6.2-/- FDB has a greater energy deficit, despite a greater ATP production, which is further supported by greater glucose uptake and lactate and CO2 production in Kir6.2-/- FDB during the recovery period. It is thus concluded that a lack of functional KATP channels results in an impairment of energy metabolism. PMID- 27488668 TI - Activation of MEK/ERK signaling contributes to the PACAP-induced increase in guinea pig cardiac neuron excitability. AB - Pituitary adenylate cyclase (PAC)-activating polypeptide (PACAP) peptides (Adcyap1) signaling at the selective PAC1 receptor (Adcyap1r1) participate in multiple homeostatic and stress-related responses, yet the cellular mechanisms underlying PACAP actions remain to be completely elucidated. PACAP/PAC1 receptor signaling increases excitability of neurons within the guinea pig cardiac ganglia, and as these neurons are readily accessible, this neuronal system is particularly amenable to study of PACAP modulation of ionic conductances. The present study investigated how PACAP activation of MEK/ERK signaling contributed to the peptide-induced increase in cardiac neuron excitability. Treatment with the MEK inhibitor PD 98059 blocked PACAP-stimulated phosphorylated ERK and, in parallel, suppressed the increase in cardiac neuron excitability. However, PD 98059 did not blunt the ability of PACAP to enhance two inward ionic currents, one flowing through hyperpolarization-activated nonselective cationic channels (Ih) and another flowing through low-voltage-activated calcium channels (IT), which support the peptide-induced increase in excitability. Thus a PACAP- and MEK/ERK-sensitive, voltage-dependent conductance(s), in addition to Ih and IT, modulates neuronal excitability. Despite prior work implicating PACAP downregulation of the KV4.2 potassium channel in modulation of excitability in other cells, treatment with the KV4.2 current blocker 4-aminopyridine did not replicate the PACAP-induced increase in excitability in cardiac neurons. However, cardiac neurons express the ERK target, the NaV1.7 sodium channel, and treatment with the selective NaV1.7 channel inhibitor PF-04856264 decreased the PACAP modulation of excitability. From these results, PACAP/PAC1 activation of MEK/ERK signaling may phosphorylate the NaV1.7 channel, enhancing sodium currents near the threshold, an action contributing to repetitive firing of the cardiac neurons exposed to PACAP. PMID- 27488669 TI - Nuclear V-type ATPase. Focus on "Vacuolar H+-ATPase in the nuclear membranes regulates nucleo-cytosolic proton gradients". PMID- 27488670 TI - New pieces in the complex puzzle of aberrant vacuolation. Focus on "Active vacuolar H+ ATPase and functional cycle of Rab5 are required for the vacuolation defect triggered by PtdIns(3,5)P2 loss under PIKfyve or Vps34 deficiency". PMID- 27488672 TI - The potassium channels TASK2 and TREK1 regulate functional differentiation of murine skeletal muscle cells. AB - Two-pore domain potassium (K2P) channels influence basic cellular parameters such as resting membrane potential, cellular excitability, or intracellular Ca2+ concentration [Ca2+]i While the physiological importance of K2P channels in different organ systems (e.g., heart, central nervous system, or immune system) has become increasingly clear over the last decade, their expression profile and functional role in skeletal muscle cells (SkMC) remain largely unknown. The mouse SkMC cell line C2C12, wild-type mouse muscle tissue, and primary mouse muscle cells (PMMs) were analyzed using quantitative PCR, Western blotting, and immunohistochemical stainings as well as functional analysis including patch clamp measurements and Ca2+ imaging. Mouse SkMC express TWIK-related acid sensitive K+ channel (TASK) 2, TWIK-related K+ channel (TREK) 1, TREK2, and TWIK related arachidonic acid stimulated K+ channel (TRAAK). Except TASK2 all mentioned channels were upregulated in vitro during differentiation from myoblasts to myotubes. TASK2 and TREK1 were also functionally expressed and upregulated in PMMs isolated from mouse muscle tissue. Inhibition of TASK2 and TREK1 during differentiation revealed a morphological impairment of myoblast fusion accompanied by a downregulation of maturation markers. TASK2 and TREK1 blockade led to a decreased K+ outward current and a decrease of ACh-dependent Ca2+ influx in C2C12 cells as potential underlying mechanisms. K2P-channel expression was also detected in human muscle tissue by immunohistochemistry pointing towards possible relevance for human muscle cell maturation and function. In conclusion, our findings for the first time demonstrate the functional expression of TASK2 and TREK1 in muscle cells with implications for differentiation processes warranting further investigations in physiologic and pathophysiologic scenarios. PMID- 27488673 TI - Our self-tracking movement and health literacy: are we really making every moment count? AB - There is a growing movement related to self-tracking in the quest for better health. Why do so many people like to use 'intelligent tools' like shiny sensors or mobile apps to keep an eye on every move? Do they really help us drive sustained healthy behavioral changes? Despite technological advances and product promises, we must remember that technology alone does not facilitate change to optimize health benefits. The purpose of the commentary is to pose the question: How 'health literate' do we have to be to reap the actionable health benefits of self-tracking? Research has revealed the prevalence of limited health literacy across the globe. Health literacy involves a complex set of inter-connected skills, including acting upon health information. This commentary puts attention on health literacy as an essential human tool to better equip people to overcome barriers and use devices to leverage their full potential. PMID- 27488671 TI - Deletion of calponin 2 in macrophages attenuates the severity of inflammatory arthritis in mice. AB - Calponin is an actin cytoskeleton-associated protein that regulates motility based cellular functions. Three isoforms of calponin are present in vertebrates, among which calponin 2 encoded by the Cnn2 gene is expressed in multiple types of cells, including blood cells from the myeloid lineage. Our previous studies demonstrated that macrophages from Cnn2 knockout (KO) mice exhibit increased migration and phagocytosis. Intrigued by an observation that monocytes and macrophages from patients with rheumatoid arthritis had increased calponin 2, we investigated anti-glucose-6-phosphate isomerase serum-induced arthritis in Cnn2 KO mice for the effect of calponin 2 deletion on the pathogenesis and pathology of inflammatory arthritis. The results showed that the development of arthritis was attenuated in systemic Cnn2-KO mice with significantly reduced inflammation and bone erosion than that in age- and stain background-matched C57BL/6 wild-type mice. In vitro differentiation of calponin 2-null mouse bone marrow cells produced fewer osteoclasts with decreased bone resorption. The attenuation of inflammatory arthritis was confirmed in conditional myeloid cell-specific Cnn2-KO mice. The increased phagocytotic activity of calponin 2-null macrophages may facilitate the clearance of autoimmune complexes and the resolution of inflammation, whereas the decreased substrate adhesion may reduce osteoclastogenesis and bone resorption. The data suggest that calponin 2 regulation of cytoskeleton function plays a novel role in the pathogenesis of inflammatory arthritis, implicating a potentially therapeutic target. PMID- 27488674 TI - Why is malaria associated with poverty? Findings from a cohort study in rural Uganda. AB - BACKGROUND: Malaria control and sustainable development are linked, but implementation of 'multisectoral' intervention is restricted by a limited understanding of the causal pathways between poverty and malaria. We investigated the relationships between socioeconomic position (SEP), potential determinants of SEP, and malaria in Nagongera, rural Uganda. METHODS: Socioeconomic information was collected for 318 children aged six months to 10 years living in 100 households, who were followed for up to 36 months. Mosquito density was recorded using monthly light trap collections. Parasite prevalence was measured routinely every three months and malaria incidence determined by passive case detection. First, we evaluated the association between success in smallholder agriculture (the primary livelihood source) and SEP. Second, we explored socioeconomic risk factors for human biting rate (HBR), parasite prevalence and incidence of clinical malaria, and spatial clustering of socioeconomic variables. Third, we investigated the role of selected factors in mediating the association between SEP and malaria. RESULTS: Relative agricultural success was associated with higher SEP. In turn, high SEP was associated with lower HBR (highest versus lowest wealth index tertile: Incidence Rate Ratio 0.71, 95 % confidence intervals (CI) 0.54-0.93, P = 0.01) and lower odds of malaria infection in children (highest versus lowest wealth index tertile: adjusted Odds Ratio 0.52, 95 % CI 0.35-0.78, P = 0.001), but SEP was not associated with clinical malaria incidence. Mediation analysis suggested that part of the total effect of SEP on malaria infection risk was explained by house type (24.9 %, 95 % CI 15.8-58.6 %) and food security (18.6 %, 95 % CI 11.6-48.3 %); however, the assumptions of the mediation analysis may not have been fully met. CONCLUSION: Housing improvements and agricultural development interventions to reduce poverty merit further investigation as multisectoral interventions against malaria. Further interdisplinary research is needed to understand fully the complex pathways between poverty and malaria and to develop strategies for sustainable malaria control. PMID- 27488675 TI - Cost-effectiveness analysis of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (VR-CAP) in patients with previously untreated mantle cell lymphoma. AB - BACKGROUND: Mantle cell lymphoma (MCL) is a rare and aggressive form of non Hodgkin's lymphoma. Bortezomib is the first product to be approved for the treatment of patients with previously untreated MCL, for whom haematopoietic stem cell transplantation is unsuitable, and is used in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (VR-CAP). The National Institute of Health and Care Excellence recently recommended the use of VR-CAP in the UK following a technology appraisal. We present the cost effectiveness analysis performed as part of that assessment: VR-CAP versus the current standard of care regimen of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in a UK setting. METHODS: A lifetime economic model was developed with health states based upon line of treatment and progression status. Baseline patient characteristics, dosing, safety and efficacy were based on the LYM-3002 trial. As overall survival data were immature, survival was modelled by progression status, and post-progression survival was assumed equal across arms. Utilities were derived from LYM-3002 and literature, and standard UK cost sources were used. RESULTS: Treatment with VR-CAP compared to R-CHOP gave an incremental quality-adjusted life year (QALY) gain of 0.81 at an additional cost of L16,212, resulting in a base case incremental cost-effectiveness ratio of L20,043. Deterministic and probabilistic sensitivity analyses showed that treatment with VR-CAP was cost effective at conventional willingness-to-pay thresholds (L20,000 L30,000 per QALY). CONCLUSIONS: VR-CAP is a cost-effective option for previously untreated patients with MCL in the UK. PMID- 27488676 TI - Erratum to: B-cell repertoire dynamics after sequential hepatitis B vaccination and evidence for cross-reactive B-cell activation. PMID- 27488677 TI - Corrigendum: Cidea improves the metabolic profile through expansion of adipose tissue. PMID- 27488678 TI - Iron Telluride-Decorated Reduced Graphene Oxide Hybrid Microspheres as Anode Materials with Improved Na-Ion Storage Properties. AB - Transition-metal telluride materials are studied as the anode materials for Na ion batteries (NIBs). The FeTe2-reduced graphene oxide (rGO) hybrid powders (first target material) are prepared via spray pyrolysis and subsequent tellurization. The H2Te gas treatment transforms the Fe3O4-rGO powders to FeTe2 rGO hybrid powders with FeTe2 nanocrystals (various sizes <100 nm) embedded within the rGO. The FeTe2-rGO hybrid powders contain 5 wt % rGO. The Na-ion storage mechanism for FeTe2 in NIBs is described by FeTe2 + 4Na(+) + 4e(-)<->Fe + 2Na2Te. The FeTe2-rGO hybrid discharge process forms metallic Fe nanocrystals and Na2Te by a conversion reaction of FeTe2 with Na ions. The discharge capacities of the FeTe2-rGO hybrid powders for the first and 80th cycles are 493 and 293 mA h g(-1), respectively. The discharge capacities of the bare FeTe2 powders for the first and 80th cycles are 462 and 83 mA h g(-1), respectively. The FeTe2-rGO hybrid powders have superior Na-ion storage properties compared to bare FeTe2 powders owing to their high structural stability and electrical conductivity. PMID- 27488679 TI - Nanodiamonds: a critical component of anodes for high performance lithium-ion batteries. AB - Detonation nanodiamonds (DNDs) have been introduced into a carbonaceous anode for improving the performance of lithium ion batteries (LIBs). The lithium storage capacity, cycling performance and stability of the LIBs are increased and this is related to the DNDs' unique characteristics of chemical inertness, a larger surface area, low expansion, and high lithium adsorption capacity. PMID- 27488680 TI - Advances in drug delivery to high grade gliomas. AB - If cancer is hard to be treated, brain cancer is even more, caused by the inability of many effective drugs given systemically to cross the blood brain and blood tumor barriers and reach adequate concentrations at the tumor sites. Effective delivery of drugs to brain cancer tissues is thus a necessary, albeit not sufficient, condition to effectively target the disease. In order to analyze the current status of research on drug delivery to high grade gliomas (HGG-WHO grades III and IV), the most frequent and aggressive brain cancers, a literature search was conducted in PubMed using the terms: "drug delivery and brain tumor" over the publication year 2015. Currently explored drug delivery techniques for HGG include the convection and permeabilization-enhanced deliveries, drug releasing depots and Ommaya reservoirs. The efficacy/safety ratio widely varies among these techniques and the success of current efforts to increase this ratio widely varies as well. PMID- 27488682 TI - Another example of enzymatic promiscuity: the polyphosphate kinase of Streptomyces lividans is endowed with phospholipase D activity. AB - Polyphosphate kinases (PPK) from different bacteria, including that of Streptomyces lividans, were shown to contain the typical HKD motif present in phospholipase D (PLD) and showed structural similarities to the latter. This observation prompted us to investigate the PLD activity of PPK of S. lividans, in vitro. The ability of PPK to catalyze the hydrolysis of phosphatidylcholine (PC), the PLD substrate, was assessed by the quantification of [3H]phosphatidic acid (PA) released from [3H]PC-labeled ELT3 cell membranes. Basal cell membrane PLD activity as well as GTPgammaS-activated PLD activity was higher in the presence than in absence of PPK. After abolition of the basal PLD activity of the membranes by heat or tryptic treatment, the addition of PPK to cell membranes was still accompanied by an increased production of PA demonstrating that PPK also bears a PLD activity. PLD activity of PPK was also assessed by the production of choline from hydrolysis of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) in the presence of the Amplex Red reagent and compared to two commercial PLD enzymes. These data demonstrated that PPK is endowed with a weak but clearly detectable PLD activity. The question of the biological signification, if any, of this enzymatic promiscuity is discussed. PMID- 27488681 TI - Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease: a nested case-control study. AB - Lesser degrees of terminal duct-lobular unit (TDLU) involution predict higher breast cancer risk; however, standardized measures to quantitate levels of TDLU involution have only recently been developed. We assessed whether three standardized measures of TDLU involution, with high intra/inter pathologist reproducibility in normal breast tissue, predict subsequent breast cancer risk among women in the Mayo benign breast disease (BBD) cohort. We performed a masked evaluation of biopsies from 99 women with BBD who subsequently developed breast cancer (cases) after a median of 16.9 years and 145 age-matched controls. We assessed three metrics inversely related to TDLU involution: TDLU count/mm(2), median TDLU span (microns, which approximates acini content), and median category of acini counts/TDLU (0-10; 11-20; 21-30; 31-50; >50). Associations with subsequent breast cancer risk for quartiles (or categories of acini counts) of each of these measures were assessed with multivariable conditional logistic regression to estimate odds ratios (ORs) and 95 % confidence intervals (CI). In multivariable models, women in the highest quartile compared to the lowest quartiles of TDLU counts and TDLU span measures were significantly associated with subsequent breast cancer diagnoses; TDLU counts quartile4 versus quartile1, OR = 2.44, 95 %CI 0.96-6.19, p-trend = 0.02; and TDLU spans, quartile4 versus quartile1, OR = 2.83, 95 %CI = 1.13-7.06, p-trend = 0.03. Significant associations with categorical measures of acini counts/TDLU were also observed: compared to women with median category of <10 acini/TDLU, women with >25 acini counts/TDLU were at significantly higher risk, OR = 3.40, 95 %CI 1.03-11.17, p trend = 0.032. Women with TDLU spans and TDLU count measures above the median were at further increased risk, OR = 3.75 (95 %CI 1.40-10.00, p-trend = 0.008), compared with women below the median for both of these metrics. Similar results were observed for combinatorial metrics of TDLU acini counts/TDLU, and TDLU count. Standardized quantitative measures of TDLU counts and acini counts approximated by TDLU span measures or visually assessed in categories are independently associated with breast cancer risk. Visual assessment of TDLU numbers and acini content, which are highly reproducible between pathologists, could help identify women at high risk for subsequent breast cancer among the million women diagnosed annually with BBD in the US. PMID- 27488683 TI - Tutorial in biostatistics: data-driven subgroup identification and analysis in clinical trials. AB - It is well known that both the direction and magnitude of the treatment effect in clinical trials are often affected by baseline patient characteristics (generally referred to as biomarkers). Characterization of treatment effect heterogeneity plays a central role in the field of personalized medicine and facilitates the development of tailored therapies. This tutorial focuses on a general class of problems arising in data-driven subgroup analysis, namely, identification of biomarkers with strong predictive properties and patient subgroups with desirable characteristics such as improved benefit and/or safety. Limitations of ad-hoc approaches to biomarker exploration and subgroup identification in clinical trials are discussed, and the ad-hoc approaches are contrasted with principled approaches to exploratory subgroup analysis based on recent advances in machine learning and data mining. A general framework for evaluating predictive biomarkers and identification of associated subgroups is introduced. The tutorial provides a review of a broad class of statistical methods used in subgroup discovery, including global outcome modeling methods, global treatment effect modeling methods, optimal treatment regimes, and local modeling methods. Commonly used subgroup identification methods are illustrated using two case studies based on clinical trials with binary and survival endpoints. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27488684 TI - Targeting deficient DNA damage repair in gastric cancer. AB - INTRODUCTION: Over recent years our understanding of DNA damage repair has evolved leading to an expansion of therapies attempting to exploit DNA damage repair deficiencies across multiple solid tumours. Gastric cancer has been identified as a tumour where a subgroup of patients demonstrates deficiencies in the homologous recombination pathway providing a potential novel treatment approach for this poor prognosis disease. AREA COVERED: This review provides an overview of DNA damage repair and how this has been targeted to date in other tumour types exploiting the concept of synthetic lethality. This is followed by a discussion of how deficiencies in homologous recombination may be identified across tumour types and on recent progress in targeting DNA repair deficiencies in gastric cancer. EXPERT OPINION: Gastric cancer remains a difficult malignancy to treat and the possibility of targeting deficient DNA repair in a subgroup of patients is an exciting prospect. Future combinations with immunotherapy and radiotherapy are appealing and appear to have a sound biological rationale. However, much work remains to be done to understand the significance of the genetic and epigenetic alterations involved, to elucidate the optimum predictive signatures or biomarkers and to consider means of overcoming treatment resistance. PMID- 27488685 TI - Modulation of nociceptive threshold by combined hormonal contraceptives in women with oestrogen-withdrawal migraine attacks: a pilot study. AB - BACKGROUND: Menstrually-related headache and headaches associated with oestrogen withdrawal are common conditions, whose pathophysiology has not been completely elucidated. In this study we evaluated the influence of combined hormonal contraceptives (CHC) on pain threshold in women presenting migraine attacks during hormone-free interval. FINDINGS: Eleven women with migraine attacks recurring exclusively during the oestrogen-withdrawal period were studied with the nociceptive flexion reflex, a neurophysiological assessment of the pain control systems, during the third week of active treatment and during the hormone free interval. During the hormone-free interval, nociceptive withdrawal reflex threshold was significantly lower (12.8 +/- 8.0 mA) as compared to the third week of hormonal treatment (15.6 +/- 6.6 mA) (p = 0.02). No change was observed in the pain perceived and in the temporal summation. CONCLUSIONS: Oestrogen withdrawal may mediate an increased sensitivity to somatosensory stimuli in women with migraine attacks recurring during the hormone-free interval. PMID- 27488686 TI - Synthesis of Dipyridyl Ketone Isonicotinoyl Hydrazone Copper(II) Complex: Structure, Anticancer Activity and Anticancer Mechanism. AB - In an effort to better understand the biological efficacy of the tridentate aroyl hydrazone Cu(II) complexes, the Cu(II) complex of di-2-pyridyl ketone isonicotinoyl hydrazone ligand (HL), {[Cu(L)(H2O)].H2O.NO3}n (C1) was synthesized and characterized. Single crystal X-ray study reveals that complex C1 forms 1D zigzag chains in solid state. In water, the hydrolysis of the 1D zigzag chains was observed, and finally formation of monomeric species. In vitro studies revealed that complex C1 showed significantly more anticancer activity than the ligand alone. Investigation of the anticancer mechanisms of C1, confirmed that the Cu(II) complex exhibit a strong capacity to promote productions of reactive oxygen species (ROS), leading to caspase-dependent apoptotic cell death. PMID- 27488687 TI - A Highly Selective and Sensitive Fluorescent Chemosensor for Aluminum Ions Based on Schiff Base. AB - An efficient "off-on" type fluorescent chemosensor, (E)-N'-(4-(diethylamino)-2 hydroxybenzylidene)-2-hydroxybenzohydrazide (H 2 L), based on Schiff base for the determination of Al3+ has been designed, synthesized, and evaluated. Upon treated with Al3+, the fluorescence of H 2 L was enhanced 45-fold due to the chelation enhanced fluorescence (CHEF) effect based on the formation of a 1:1 complex between the chemosensor and Al3+. Other metal ions, such as Na+, K+, Mg2+, Ca2+, Cu2+, Ga3+, Zn2+, Cr3+, Cd2+, Ag+, Fe3+, In3+, Mn2+, Pb2+, Co2+, and Ni2+ had little effect on the fluorescence. The results demonstrate that the chemosensor H 2 L has stronger affinity with Al3+ than other metal ions. The detection limit of H 2 L for sensing Al3+ is 3.60 * 10-6 M in EtOH-H2O (3:7, v/v) solution. And the recognizing behavior has been investigated both experimentally and computationally. PMID- 27488688 TI - The role of community pharmacists in supporting self-management in patients with psoriasis. AB - BACKGROUND: The majority of patients with psoriasis have mild to moderate disease which can be managed in primary care with topical therapies. The supportive role of pharmacists for patients with long-term dermatological conditions is largely unknown. OBJECTIVE: To assess the impact of an educational intervention delivered by community pharmacists to improve self-management for people with psoriasis. METHOD: The study involved a pre- and post-intervention design. Seven community pharmacies were selected based on their location (urban, rural etc.) and the pharmacists recruited via local comprehensive research networks. Patients with mild to moderate psoriasis were recruited either opportunistically or via a letter of invite by pharmacists who undertook a face-to-face consultation with one follow-up visit after 6 weeks. The primary outcome was the change in person centred dermatology self-care index (PEDESI) score and secondary outcomes were the self-assessed psoriasis and severity index (SAPASI), measuring disease severity and the dermatology quality of life index (DLQI). KEY FINDINGS: A total of 47 patients were recruited. At 6 weeks, 42/47 (89.3%) patients completed the follow-up consultation. There was a significant increase in mean PEDESI scores (25.15 versus 17.78, P < 0.001) at 6 weeks compared to baseline. Similarly, SAPASI (11.60 versus 7.74, P < 0.001) and DLQI (7.21 versus 4.14, P < 0.001) scores improved significantly. CONCLUSION: Pharmacist-assisted support for patients with psoriasis improved knowledge, reduced disease severity and the impact on quality of life. These results suggest that community pharmacists might have an important role to play in facilitating self-management for patients with psoriasis. PMID- 27488689 TI - ERRATUM. PMID- 27488691 TI - Financial Insecurity: Putting our Money where our Mouth is. PMID- 27488693 TI - Population genetic inferences using immune gene SNPs mirror patterns inferred by microsatellites. AB - Single nucleotide polymorphisms (SNPs) are replacing microsatellites for population genetic analyses, but it is not apparent how many SNPs are needed or how well SNPs correlate with microsatellites. We used data from the gopher tortoise, Gopherus polyphemus-a species with small populations, to compare SNPs and microsatellites to estimate population genetic parameters. Specifically, we compared one SNP data set (16 tortoises from four populations sequenced at 17 901 SNPs) to two microsatellite data sets, a full data set of 101 tortoises and a partial data set of 16 tortoises previously genotyped at 10 microsatellites. For the full microsatellite data set, observed heterozygosity, expected heterozygosity and FST were correlated between SNPs and microsatellites; however, allelic richness was not. The same was true for the partial microsatellite data set, except that allelic richness, but not observed heterozygosity, was correlated. The number of clusters estimated by structure differed for each data set (SNPs = 2; partial microsatellite = 3; full microsatellite = 4). Principle component analyses (PCA) showed four clusters for all data sets. More than 800 SNPs were needed to correlate with allelic richness, observed heterozygosity and expected heterozygosity, but only 100 were needed for FST . The number of SNPs typically obtained from next-generation sequencing (NGS) far exceeds the number needed to correlate with microsatellite parameter estimates. Our study illustrates that diversity, FST and PCA results from microsatellites can mirror those obtained with SNPs. These results may be generally applicable to small populations, a defining feature of endangered and threatened species, because theory predicts that genetic drift will tend to outweigh selection in small populations. PMID- 27488692 TI - Effectiveness of educational outreach in infectious diseases management: a cluster randomized trial in Uganda. AB - BACKGROUND: Integrated Infectious Diseases Capacity Building Evaluation (IDCAP) teams designed and implemented two health worker in-service training approaches: 1) an off-site classroom-based integrated management of infectious diseases (IMID) course with distance learning aspects, and 2) on-site support (OSS), an educational outreach intervention. We tested the effects of OSS on workload and 12 facility performance indicators for emergency triage assessment and treatment, HIV testing, and malaria and pneumonia case management among outpatients by two subgroups: 1) mid-level practitioners (MLP) who attended IMID training (IMID-MLP) and 2) health workers who did not (No-IMID). METHODS: Thirty-six health facilities participated in the IDCAP trial, with 18 randomly assigned to Arm A and 18 to Arm B. Two MLP in both arms received IMID. All providers at Arm A facilities received nine monthly OSS visits from April to December 2010 while Arm B did not. From November 2009 to December 2010, 777,667 outpatient visits occurred. We analyzed 669,580 (86.1 %) outpatient visits, where provider cadre was reported. Treatment was provided by 64 IMID-MLP and 1,515 No-IMID providers. The effect of OSS was measured by the difference in pre/post changes across arms after controlling for covariates (adjusted ratio of relative risks = a RRR). RESULTS: The effect of OSS on patients-per-provider-per-day (workload) among IMID MLP (aRRR = 1.21; p = 0.48) and No-IMID (aRRR = 0.90; p = 0.44) was not statistically significant. Among IMID-MLP, OSS was effective for three indicators: malaria cases receiving an appropriate antimalarial (aRRR = 1.26, 99 % CI = 1.02-1.56), patients with negative malaria test result prescribed an antimalarial (aRRR = 0.49, 99 % CI = 0.26-0.92), and patients with acid-fast bacilli smear negative result receiving empiric treatment for acute respiratory infection (aRRR = 2.04, 99 % CI = 1.06-3.94). Among No-IMID, OSS was effective for two indicators: emergency and priority patients admitted, detained or referred (aRRR = 2.12, 99 % CI = 1.05-4.28) and emergency patients receiving at least one appropriate treatment (aRRR = 1.98, 99 % CI = 1.21-3.24). CONCLUSION: Effects of OSS on workload were not statistically significant. Significant OSS effects on facility performance across subgroups were heterogeneous. OSS supported MLP who diagnosed and treated patients to apply IMID knowledge. For other providers, OSS supported team work to manage emergency patients. This evidence on OSS effectiveness could inform interventions to improve health workers' capacity to deliver better quality infectious diseases care. PMID- 27488694 TI - Zinc supplementation during in vitro maturation increases the production efficiency of cloned pigs. AB - Zinc supplementation (0.8 ug/ml) in in vitro maturation (IVM) medium significantly enhances oocyte quality. In this study, we compared the development of somatic cell nuclear transfer (SCNT) embryos produced from conventional IVM (control) and zinc-supplemented IVM oocytes. A total of 1206 and 890 SCNT embryos were produced using control and zinc-supplemented oocytes, respectively, and then were transferred to 11 and 8 recipients, respectively. Five control recipients and three zinc-supplemented recipients became pregnant. Two live piglets and eight mummies were born from two control recipients, and ten live piglets and six stillborn piglets were born from three zinc-supplemented recipients. The production efficiency significantly increased in the zinc-supplemented group (0.33% vs. 3.02%). This report suggests that zinc supplementation in IVM medium improved the production efficiency of cloned pigs. PMID- 27488695 TI - Association between time to progression and subsequent survival inceritinib treated patients with advanced ALK-positive non-small-cell lung cancer. AB - OBJECTIVE: Time to progression (TTP) is a surrogate marker of overall survival (OS). However, OS is also dependent on post-progression survival (PPS). This study evaluated the association between TTP and the duration of PPS among adult patients who received ceritinib (Zykadia 1 ) for the treatment of advanced anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC). RESEARCH DESIGN AND METHODS: A pooled analysis was performed on 181 ASCEND-1 (phase I) and ASCEND-2 (phase II) patients who experienced disease progression while on ceritinib. TTP was assessed on its association with PPS in a Kaplan Meier analysis and in Cox proportional hazard models, adjusted for clinical covariates. MAIN OUTCOME MEASURES: Main outcomes measured include TTP, PPS, and OS. RESULTS: Patients with TTP >=6 months experienced significantly longer PPS compared to those with TTP <6 months (median: 9.8 vs. 6.5 months, log-rank p value < .01). When TTP was assessed as a continuous variable, every 3 months of longer TTP was associated with a 21% lower hazard of death following progression (hazard ratio [HR]: 0.79, 95% confidence interval [CI]: 0.63-1.00; adjusted HR: 0.79, 95% CI: 0.64-0.99). This positive association translated into an OS benefit: each 3 months of longer TTP was associated with a lower hazard of death (adjusted HR: 0.46, 95% CI: 0.37-0.58). Median OS was 20.0 months for patients with TTP >=6 months and was 10.9 months for patients with TTP <6 months. CONCLUSIONS: A longer duration of TTP after treatment with ceritinib was significantly associated with a longer duration of both PPS and OS. PMID- 27488697 TI - Caesarean section and its impact on fertility and time to a subsequent pregnancy in Germany: a database analysis in gynecological practices. AB - PURPOSE: To analyze the impact of caesarean section (CS) on fertility and time to pregnancy in German gynecological practices. METHODS: Women initially diagnosed for the first time with a vaginal delivery (VD) or CS between 2000 and 2013 were identified by 227 gynecologists in the IMS Disease Analyzer database. They were included if they were aged between 16 and 40 years, and were not previously diagnosed with female sterility. The two main outcomes were the first-time diagnosis of female sterility and the time between the first delivery and the next pregnancy within 10 years. A multivariate Cox regression model was used to predict these outcomes on the basis of patient characteristics. RESULTS: 6483 patients were included in the CS group and 6483 in the VD group. Mean age was 30.6 years and the proportion of individuals with private health insurance amounted to 9.0 %. Within 10 years of the index date, 19.5 % of women who delivered by CS and 18.3 % of women who delivered vaginally were diagnosed with sterility (p value = 0.0148). CS and polycystic ovary syndrome significantly increased the risk of sterility. Within 10 years of the index date, 57.9 % of women who underwent a CS and 64.0 % of women who delivered vaginally were pregnant for the second time (p value <0.001). CS, polycystic ovary syndrome, and the deterioration of menstrual cycle significantly decreased the chance of becoming pregnant a second time. CONCLUSIONS: CS is associated with an increased risk of sterility and a decreased number of subsequent pregnancies in Germany. PMID- 27488698 TI - Growth hormone co-treatment within a GnRH agonist long protocol improves implantation and pregnancy rates in patients undergoing IVF-ET. AB - OBJECTIVE: The efficacy of growth hormone (GH) co-treatment within a GnRH agonist long regimen, in women with a normal ovarian response to controlled ovarian hyperstimulation (COH), for IVF was assessed. METHODS: This retrospective clinical trial was performed in a private-assisted reproduction centre. The study involved 1114 patients who responded normally to high-dose gonadotropin treatment. The study group of 556 patients was given in a daily subcutaneous injection of 4.5 IU of GH co-treatment, starting from the initial day of gonadotropin treatment and lasting for 5 days. The control group of 558 patients received the same treatment protocol without the GH co-treatment. The participants were further divided into two subgroups: age >=35 years and age <35 years. The primary endpoint of the study was IVF-ET outcomes. RESULTS: The demographic characteristics did not significantly differ between the groups. The implantation rate (36.7 vs. 20.4 %, P < 0.05) and clinical pregnancy rate (57.3 vs. 30.1 %, P < 0.05) were significantly higher in the study group than in the control group. An analysis using a multivariate logistic regression model showed that GH was a significant factor for predicting pregnancy outcomes (OR 3.125, 95 % CI 2.441-4.000). Furthermore, for the >=35-year-old group, the endometrial thickness was significantly greater (11.99 +/- 2.21 vs. 11.62 +/- 2.45, P < 0.05) in the study group than in the control group; in contrast, for the <35-year-old group, the high-quality embryo rate was significantly higher (71.7 vs. 68.3 %, P < 0.05) in the study group than in the control group. CONCLUSION: Our study showed that co-treatment with GH in a GnRH agonist long protocol in patients who responded normally while undergoing IVF-ET could increase the implantation and pregnancy rates. PMID- 27488696 TI - Systematic review and meta-analysis of nasal potential difference in hypoxia induced lung injury. AB - Nasal potential difference (NPD), a well-established in vivo clinical test for cystic fibrosis, reflects transepithelial cation and anion transport in the respiratory epithelium. To analyze whether NPD can be applied to diagnose hypoxic lung injury, we searched PubMed, EMBASE, Scopus, Web of Science, Ovid MEDLINE, and Google Scholar, and analyzed data retrieved from eleven unbiased studies for high altitude pulmonary edema (HAPE) and respiratory distress syndrome (RDS) using the software RevMan and R. There was a significant reduction in overall basal (WMD -5.27 mV, 95% CI: -6.03 to -4.52, P < 0.00001, I(2) = 42%), amiloride sensitive (ENaC) (-2.87 mV, 95% CI: -4.02 to -1.72, P < 0.00001, I(2) = 51%), and -resistant fractions (-3.91 mV, 95% CI: -7.64 to -0.18, P = 0.04, I(2) = 95%) in lung injury patients. Further analysis of HAPE and RDS separately corroborated these observations. Moreover, SpO2 correlated with ENaC-associated NPD positively in patients only, but apparently related to CFTR-contributed NPD level inversely. These correlations were confirmed by the opposite associations between NPD values and altitude, which had a negative regression with SpO2 level. Basal NPD was significantly associated with amiloride-resistant but not ENaC fraction. Our analyses demonstrate that acute lung injury associated with systemic hypoxia is characterized by dysfunctional NPD. PMID- 27488699 TI - The association of DENND1A gene polymorphisms and polycystic ovary syndrome risk: a systematic review and meta-analysis. AB - PURPOSE: Polycystic ovary syndrome is heterogeneity disease, and the association with DEEND1A gene has been discussed incompatibly for a long time. We conducted a meta-analysis to evaluate the rs10818854, rs2479106, and rs10986105 polymorphism in DENND1A gene with PCOS susceptibility. METHODS: Meta-analysis was performed for common allele versus rare allele using random effect model on published papers from January 1, 1980 to October 1, 2015. Subgroup analysis, sensitivity analysis and publication bias were also carried out ultimately. The combined odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated to estimate the strength of the association. RESULTS: The results showed that rs10818854 (OR = 1.36, 95 % CI 1.12-1.61) and rs10986105 (OR = 1.39, 95 % CI 1.20-1.58) polymorphism increased the risk of PCOS probably. A significant association was also found between rs2479106 mutation and Asian PCOS patients but not Europeans (OR = 1.32, 95 % CI 1.25-1.39; OR = 1.01, 95 % CI 0.97-1.05, respectively). CONCLUSIONS: In conclusion, the DENND1A gene variant is likely to have influence on PCOS risk. Further studies are warranted to assess these associations in greater detail, especially in different populations and different subtype of PCOS patients. PMID- 27488700 TI - Determinants of cumulative ART live-birth rates in a single-center study: age, fertilization modality, and first-cycle outcome. AB - PURPOSE: To analyze cumulative and single-cycle success rates of IVF and intracytoplasmic sperm injection (ICSI) separately in relation to female age, fertilization modality, and first-cycle outcome. METHODS: The study involved 2997 patients and couples, respectively, who underwent 5339 fresh and 3006 cryo cycles using pronuclear-stage oocytes. Fertilization was achieved by the conventional IVF or ICSI. Because of legal restrictions in Germany, no embryo selection was performed. All cycles were documented prospectively. Kaplan-Meier survival rates were calculated for all treatment cycles and transferred embryos. RESULTS: Essentially, the success of assisted reproductive technology (ART) depends on a woman's age and on skilful counselling. Cumulative pregnancy and live-birth rates are the best indicators of successful ART. Probably for the first time, we determined these cumulative rates separately for IVF and ICSI, and found them to be almost identical. Live-birth rates reached 70-95 %, except for women aged over 40 years, whose chances of life birth are limited to about 25 %. Live-birth rate per retrieval was 25.61 % for IVF and 26.3 % for ICSI. Time to pregnancy was shorter for women who underwent a successful treatment in their first cycle. CONCLUSIONS: The primary intention for the choice of fertilization modality between IVF and ICSI is the prevention of a relative or total fertilization failure. Such treatment failure is best prevented through ICSI, which results in slightly higher clinical pregnancy rates per started cycle. After embryo transfer, there are no differences in the success rates of IVF and ICSI. The supposed cumulative live-birth rates are useful as a basis for counselling subfertile couples to help reduce the high discontinuation rate, which is still the main reason for inefficacy in ART. Following an unsuccessful first treatment cycle, the prognosis remains positive, but until success is achieved, more treatment cycles are necessary. PMID- 27488701 TI - A comparison among different methods of letrozole combined with gonadotropin in an antagonist protocol and high-dose gonadotropin ovarian stimulation antagonist protocol in poor ovarian responders undergoing in vitro fertilization. AB - PURPOSE: This study aimed at comparing the effects of different methods of letrozole combined with gonadotropin (Gn) and high-dose Gn ovarian stimulation in antagonist protocol. METHODS: Retrospectively reviewed 220 poor responders from August 2012 to July 2014 at Peking University Third Hospital Reproductive Medical Center. Patients were divided into Group 1 (LZ 5 mg for 5 days sequentially overlapping with Gn cycles; n = 60), group 2 (LZ 7.5 mg for 3 days sequentially with Gn cycles; n = 60), and group 3 (high-dose Gn cycles; n = 100). We compared the basic status of patients and clinical outcomes of the three groups. RESULTS: Basic characteristics of patients were comparable among groups. Group 1 had significantly higher LH levels on day 7 and hCG than Group 2 and 3 (P < 0.05). Group 1 had significantly higher early LH elevation rate (>20 IU/L) on the hCG day than Groups 2 and 3 (11.7 vs. 6.7 and 2.0 %; P < 0.05). The amount of Gn used in LZ groups was significantly lower than Group 3 (P < 0.01). However, the clinical pregnancy rate and live birth rate were comparable among groups. CONCLUSION: In conclusion, the LZ/antagonist protocol is a cost-effective and patient friendly protocol, LZ 5 mg for 5 days sequentially overlapping with Gn protocol has comparable pregnancy outcomes, and LZ 7.5 mg for 3 days sequentially with the Gn protocol even has better clinical outcomes when compared with the standard GnRH antagonist protocol in poor responders. LZ 7.5 mg for 3 days sequentially with the Gn protocol appeared to have resulted in fewer improper LH surges and better outcomes than LZ 5 mg for 5 days sequentially overlapping with Gn in antagonist protocol. PMID- 27488702 TI - Validation of the distress and impact thermometer and the changes of mood during the first 6 months of treatment in gynecological cancer patients: a Kansai Clinical Oncology Group (KCOG)-G1103 prospective study. AB - PURPOSE: To verify distress and impact thermometer (DIT) for screening emotional distress in gynecological cancer patients by Hospital Anxiety and Depression Scale total (HADS-T) as gold standard and to assess emotional changes by DIT and HADS-T. METHODS: A prospective study was conducted in newly diagnosed gynecological cancer patients during the peri-treatment period after the cancer diagnosis followed by 6-month. We defined a HADS-T score of >=11 as being indicative of emotional distress. RESULTS: 117 patients were enrolled between May 1, 2011 and March 31, 2012, and 95 were eligible. The median age was 54 years (range 31-77). (1) From the baseline to 3-month, distress (DIT-D) >=4 with Impact (DIT-I) >=2 exhibited sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) of 0.776 [95 % confidential interval (CI) 0.688, 0.850], 0.889 (95 % CI 0.824, 0.954), 0.868 (95 % CI 0.792, 0.949), and 0.808 (95 % CI 0.731, 0.886), respectively. (2) At 6-month, DIT-D >=2 with DIT-I >=1 exhibited sensitivity, specificity, PPV and NPV of 0.893 (95 % CI 0.778, 1), 0.825 (95 % CI 0.707, 0.942), 0.781 (95 % CI 0.638, 0.928), and 0.917 (95 % CI 0.826, 1). (3) At 6-month, the HADS-T, DIT-D, and DIT-I scores in individual patients were significantly reduced by a mean of 4.57 (p < 0.0001), 2.34 (p < 0.0001), and 1.10 (p = 0.0031), respectively, compared with those scores of baseline (Student's paired t test), but still remained high. CONCLUSIONS: (1) On acute phase within 3-month setting, DIT; DIT-D >=4 with DIT-I >=2, is a reliable cut-off to screen emotional distress among gynecological cancer patients. (2) The patients' moods had improved, but not completely recovered at 6-month after the diagnosis. PMID- 27488703 TI - Self-expanding plastic stent for esophageal leaks and fistulae. AB - BACKGROUND: Self-expanding plastic stents (SEPS) have emerged as a good alternative to surgery in esophageal leaks and fistulae. There is scarce published literature regarding its efficacy in these conditions. We present our experience with SEPS in treatment of esophageal leaks and fistulae. METHODS: Consecutive patients admitted in a tertiary referral center who underwent SEPS placement for esophageal leak or fistula between February 2012 and February 2015 were retrospectively evaluated. Patients underwent prior assessment with upper gastrointestinal endoscopic and thoracic contrast-enhanced computed tomography assessment. SEPS (25-mm flares, 21-mm diameter) were placed under fluoroscopic guidance. A silk thread tied to upper end was routed through nostril and fixed to prevent stent migration. Nasojejunal tube was inserted in all patients. Intercostal drain was inserted in the case of hydro/pyopneumothorax. RESULTS: Twelve patients [eight male, median age 45.3 years (19 to 65 years)] were included. Etiologies were spontaneous leaks due to Boerhaave syndrome (n = 2), corrosive fistulae (n = 2), tubercular fistulae (n = 4), invasive Candida esophagitis-induced fistula (n = 1), iatrogenic leaks (n = 2; one achalasia dilatation, one obesity surgery), and pancreaticoesophageal fistula due to ruptured pancreatic pseudocyst (n = 1). Stent placement was successful in all patients with no immediate postprocedure complications. Successful healing was seen in nine patients (75 %). Stents were removed after a median time of 83.5 days (13-190 days). Stent migration was seen in four patients (33.3 %), and in two of them, it was retrieved and redeployed; none had early migration (<72 h). Reasons for SEPS failure in our cohort were failure of effective sepsis control in two patients and poor wound healing seen in one patient having multiple tubercular fistulae. CONCLUSION: SEPS is a safe, well-tolerated treatment with good success rate (75 %) in treatment of esophageal leaks and fistulae. PMID- 27488704 TI - Removal of multi-dye wastewater by the novel integrated adsorption and Fenton oxidation process in a fluidized bed reactor. AB - Traditionally, a few processes have to be employed in sequence for multi-dye removal, due to the different physical and chemical characteristics of the dyes. In this study, we innovatively developed an integrated adsorption and Fenton oxidation fluidized bed reactor (FBR) based on the hydraulic classification theory, which could efficiently remove dispersed red, acid yellow, and reactive brilliant dyes. The fluidized solids such as ceramsite and activated carbon could be separately fluidized at the bottom and the top part of the FBR, respectively. As a result, Fenton oxidization of dyes was promoted by the fluidization of ceramsite and activated carbon. Besides, adsorption of activated carbon could synergistically act on the dyes. The results showed that the removal efficiencies of acid yellow 2G, disperse red 60, and reactive brilliant blue X-BR could reach 100, 79.8, and 84.9 % in 10 min, respectively. Lots of intermediates with unsaturated bonds were generated during Fenton reaction, which was further removed by adsorption of activated carbon. Consequently, a high COD removal of 93 % was obtained. Interestingly, some of Fe3+ produced during Fenton reaction was further precipitated and crystallized as FeO(OH) or Fe(OH)3 on the surface of activated carbon and ceramsite, which could be potentially recycled for further utilization as a heterogeneous catalyst. Meanwhile, the other Fe3+ might be removed in the form of ferro-organic complexes by adsorption onto the activated carbon. Thus, only a little iron hydroxide sludge was generated in the FBR. This novel FBR gave us an effective clue to realize multi-reactions for textile wastewater treatment by employing hydraulic classification fluidization. PMID- 27488705 TI - Biodegradable packaging materials conception based on starch and polylactic acid (PLA) reinforced with cellulose. AB - The plastic materials used for packaging are increasing leading to a considerable amount of undegradable solid wastes. This work deals with the reduction of conventional plastics waste and the natural resources preservation by using cellulosic polymers from renewable resources (alfa and luffa). Plasticized starch films syntheses were achieved at a laboratory scale. These natural films showed some very attractive mechanical properties at relatively low plasticizers levels (12 to 17 % by weight). Furthermore, mixtures including polylactic acid polymer (PLA) and cellulose fibers extracted from alfa and luffa were investigated by melt extrusion technique. When used at a rate of 10 %, these fibers improved the mixture mechanical properties. Both developed materials were biodegradable, but the plasticized starch exhibited a faster biodegradation kinetic compared to the PLA/cellulose fibers. These new materials would contribute to a sustainable development and a waste reduction. PMID- 27488706 TI - Stoichiometry evaluation of biohydrogen production from various carbohydrates. AB - In this paper, biochemical hydrogen potential (BHP) tests were conducted to investigate H2 production from different substrate with acid-treated anaerobic digested sludge at the mesophilic range. The sludge was collected from an anaerobic digester and was subjected to sulfuric acid pretreatments at pH 3 for 24 h. The effects of substrate type (glucose, fructose, and sucrose as carbon source) were investigated in batch experiments. Results showed that substrate degradation rate for all of the substrates was up 95 % and the electron equivalent balance showed good closure for glucose and sucrose. Batch experiments showed that the maximum molar hydrogen yield with glucose, fructose, and sucrose was 3.27, 3.16, and 6.46 mol H2/mol of substrate. The maximum cumulative biohydrogen production was 1552, 1487, and 1366 mL and maximum hydrogen production rate was 308, 279, and 275 mL/h for glucose, sucrose, and fructose, respectively. The experimental results suggest that the formation of hydrogen associates with the main aqueous products, i.e., acetate butyrate. PMID- 27488707 TI - Efficient decomposition of perchlorate to chloride ions in subcritical water by use of steel slag. AB - Decomposition of perchlorate (ClO4-) in subcritical water in the presence of steel slag, a by-product of the steel industry, was investigated. Reactivity of ClO4- was low in pure subcritical water state up to 300 degrees C, whereas adding steel slag efficiently accelerated the decomposition of ClO4- to Cl-, with no leaching of heavy metals such as chromium and other environmentally undesirable elements (boron and fluorine). When the reaction was performed in subcritical water at a relatively low temperature (250 degrees C) for 6 h, virtually all ClO4- ions were removed from the reaction solution. The concentration of Cl- after the reaction was well accounted for by the sum of the amount of Cl- ascribed to the decomposition of ClO4- and the amount of Cl- leached from the slag. This method was successfully applied to decompose ClO4- in water samples collected from a man-made reflection pond following a fireworks display, even though these samples contained much higher concentrations of Cl- and SO42- than ClO4-. PMID- 27488708 TI - The assessment of health impacts and external costs of natural gas-fired power plant of Qom. AB - The external health damage costs of the combined cycle natural gas-fired power plant of Qom were investigated via the simplified impact pathway approach. Emitted particulate matter (PM10) and gaseous pollutants (NO x , CO, and SO2) from the power plant stack were measured The health effects and related costs were estimated by QUERI model from AirPacts according to the emissions, source and stack parameters, pollutant depletion velocities, exposure-response functions, local and regional population density, and detailed meteorological data. The results showed that the main health effect was assigned to the nitrate as restricted activity days (RAD) with 25,240 days/year. For all pollutants, the maximum health damage costs were related to the long-term mortality (49 %), restricted activity days (27 %), and chronic bronchitis (21 %). The annual health damage costs were approximately 4.76 million US$, with the cost being 0.096 US per kWh of generating electricity. Although the health damage costs of gas-fired power plant were lower than those of other heavy fuels, it seems essential to consider the health and environmental damages and focus on the emission control strategies, particularly in site selection for the new power plants and expanding the current ones. PMID- 27488709 TI - Drugs of environmental concern modify Solea senegalensis physiology and biochemistry in a temperature-dependent manner. AB - The alerted presence in recent decades of pharmaceuticals has become an issue of environmental concern, and most of the mechanisms of biotransformation and biochemical and physiological responses to them in fish are still unknown, as well as the influence of water temperature in their ability to cope with them. This study aims to detect the main effects of two of the most widespread drugs on a set of physiological and biochemical markers in Solea senegalensis. Sole juveniles acclimatized at 15 and 20 degrees C were administered an intraperitoneal injection of the non-steroidal anti-inflammatory drug ibuprofen (IB; 10 mg/kg) and the anti-convulsant drug carbamazepine (CBZ; 1 mg/kg). Two days after the injection, liver, muscle and plasma were sampled. Liver enzymatic activities of 15 degrees C acclimated fish were more responsive to pharmaceuticals than those acclimated at 20 degrees C, especially for CYP450 related activities (7-ethoxyresorufin (EROD), 7-methoxyresorufin (MROD), 3-cyano 7-ethoxycoumarin (CECOD) and 7-benzyloxy-4-[trifluoromethyl]-coumarin-O debenzyloxylase (BFCOD)) and uridine diphosphate glucuronosyltransferase (UDPGT). Cytosolic anti-oxidant enzyme activities and glutathione S-transferase (GST) did not show a clear effect of temperature. Glucose and transferase activities in plasma were not affected by the treatments, while ammonium, osmolality and lactate were affected by both pharmaceuticals. Plasma triglycerides were affected in a temperature-dependent manner, and creatinine was only responsive to CBZ injection. HSP70 levels in muscle were only affected by CBZ injection. Some of the physiological identified responses to IB and CBZ are proposed as endpoints in further chronic studies. PMID- 27488710 TI - Oxidative stress in two tropical species after exposure to diesel oil. AB - Recent offshore petroleum exploration has increased the risks of oil spills worldwide. We investigated biomarker responses to diesel oil exposure in two tropical and subtropical species, the clam Anomalocardia flexuosa and the polychaete Laeonereis culveri. Animals were exposed to oil-spiked sediment at two different concentrations (0.5 L and 1.0 L m-2). Activities of antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx); glutathione transferase (GST); and lipid peroxides (LPO) were assessed in bivalve digestive glands and polychaete whole-body homogenates at 36 and 60 h of exposure. Significant variation in enzymatic antioxidant activity depended on the sampling time after exposure. No similar response patterns, either increases or decreases, were detected for the two target species, and biomarker responses were species-specific. L. culveri showed clearer patterns in its antioxidant response and should be prioritized over other species in biomonitoring studies involving oil exposure. Understanding the temporal variability of these biomarkers is a necessary action before implementing them as indicators measures in oil contamination biomonitoring programs. Our results provide a better understanding of biomarker responses in subtropical species, evidencing their potential use as sentinels of oil contamination. PMID- 27488711 TI - Moringa oleifera-mediated coagulation of textile wastewater and its biodegradation using novel consortium-BBA grown on agricultural waste substratum. AB - Generation of secondary sludge is a major concern of textile dye removal by coagulation process. Combinatorial coagulation-biodegradation treatment system has been found efficient in degradation of coagulated textile dye sludge. Moringa oleifera seed powder (700 mg L-1) was able to coagulate textile dyestuff from real textile wastewater with 98 % color removal. Novel consortium-BBA was found to decolorize coagulated dye sludge. Parameters that significantly affect coagulation process were optimized using response surface methodology. The bench scale stirred tank reactor (50-L capacity) designed with optimized parameters for coagulation process could efficiently remove 98, 89, 78, and 67 % of American Dye Manufacturer's Institute (ADMI) in four repetitive cycles, respectively. Solid state fermentation composting reactor designed to treat coagulated dye sludge showed 96 % removal of dye within 10 days. Coagulation of dyes from textile wastewater and degradation of coagulated dye sludge were confirmed by Fourier transform infrared spectroscopy (FTIR) analysis. Cell morphology assay, comet assay, and phytotoxicity confirmed the formation of less toxic products after coagulation and degradation mechanism. PMID- 27488712 TI - Organic acid compounds in root exudation of Moso Bamboo (Phyllostachys pubescens) and its bioactivity as affected by heavy metals. AB - Moso bamboo (Phyllostachys pubescens) has great potential as phytoremediation material in soil contaminated by heavy metals. A hydroponics experiment was conducted to determine organic acid compounds of root exudates of lead- (Pb), zinc- (Zn), copper- (Cu), and cadmium (Cd)-tolerant of Moso bamboo. Plants were grown in nutrients solution which included Pb, Zn, Cu, and Cd applied as Pb(NO3)2 (200 MUM), ZnSO4.7H2O (100 MUM), CuSO4.5H2O (25 MUM), and CdCl2 (10 MUM), respectively. Oxalic acid and malic acid were detected in all treatments. Lactic acid was observed in Cu, Cd, and control treatments. The oxalic was the main organic acid exudated by Moso bamboo. In the sand culture experiment, the Moso bamboo significantly activated carbonate heavy metals under activation of roots. The concentration of water-soluble metals (except Pb) in sand were significantly increased as compared with control. Organic acids (1 mM mixed) were used due to its effect on the soil adsorption of heavy metals. After adding mixed organic acids, the Cu and Zn sorption capacity in soils was decreased markedly compared with enhanced Pb and Cd sorption capacity in soils. The sorption was analyzed using Langmuir and Freundlich equations with R 2 values that ranged from 0.956 to 0.999 and 0.919 to 0.997, respectively. PMID- 27488713 TI - Exploring the potential of fungi isolated from PAH-polluted soil as a source of xenobiotics-degrading fungi. AB - The aim of this study was to find polycyclic aromatic hydrocarbon (PAH)-degrading fungi adapted to polluted environments for further application in bioremediation processes. In this study, a total of 23 fungal species were isolated from a historically pyrogenic PAH-polluted soil in Spain and taxonomically identified. The dominant groups in these samples were the ones associated with fungi belonging to the Ascomycota phylum and two isolates belonging to the Mucoromycotina subphylum and Basiodiomycota phylum. We tested their ability to convert the three-ring PAH anthracene in a 42-day time course and analysed their ability to secrete extracellular oxidoreductase enzymes. Among the 23 fungal species screened, 12 were able to oxidize anthracene, leading to the formation of 9,10-anthraquinone as the main metabolite, a less toxic one than the parent compound. The complete removal of anthracene was achieved by three fungal species. In the case of Scopulariopsis brevicaulis, extracellular enzyme independent degradation of the initial 100 MUM anthracene occurred, whilst in the case of the ligninolytic fungus Fomes (Basidiomycota), the same result was obtained with extracellular enzyme-dependent transformation. The yield of accumulated 9,10-anthraquinone was 80 and 91 %, respectively, and Fomes sp. could slowly deplete it from the growth medium when offered alone. These results are indicative for the effectiveness of these fungi for pollutant removal. Graphical abstract ?. PMID- 27488714 TI - Bioremediation of domestic and industrial wastewaters integrated with enhanced biodiesel production using novel oleaginous microalgae. AB - The study illustrates the synergistic potential of novel microalgal, Chlamydomonas debaryana IITRIND3, for phycoremediation of domestic, sewage, paper mill and dairy wastewaters and then subsequent utilisation of its biomass for biodiesel production. Among these wastewaters, maximum lipid productivity (87.5 +/- 2.3 mg L-1 day-1) was obtained in dairy wastewater with removal efficiency of total nitrogen, total phosphorous, chemical oxygen demand and total organic carbon to be 87.56, 82.17, 78.57 and 85.97 %, respectively. Metal ions such as sodium, calcium, potassium and magnesium were also removed efficiently from the wastewaters tested. Pigment analysis revealed loss of chlorophyll a while increase in carotenoid content in algal cells cultivated in different wastewaters. Biochemical data of microalgae grown in different wastewaters showed reduction in protein content with an increase in carbohydrate and lipid contents. The major fatty acids in algal cells grown in dairy wastewater were C14:0, C16:0, C16:1, C18:0, C18:2 and C18:3. The physical properties of biodiesel derived from microalgae grown in dairy wastewater were in compliance with the ASTM D6751 and EN 14214 fuel standards and were comparable to plant oil methyl esters. PMID- 27488715 TI - Critical nutrient thresholds needed to control eutrophication and synergistic interactions between phosphorus and different nitrogen sources. AB - Eutrophication is one of the greatest threats to global freshwater ecosystems. The phytoplankton responses to nutrient inputs vary in different water bodies, so it is particularly important to determine the nutrient thresholds and synergistic interactions between nutrients in different freshwater ecosystems. Field sampling and bioassay experiments were conducted to determine the thresholds of soluble reactive phosphorus (SRP), nitrate-nitrogen (NO3-N), and ammonium-nitrogen (NH4 N) in Miyun Reservoir. A separate nutrient addition bioassay was designed to assess the synergistic interactions between these nutrients. Chlorophyll a (Chl a) concentrations were used to estimate phytoplankton biomass. The results showed the following: (1) nutrient threshold bioassay indicated that eutrophication thresholds of SRP, NO3-N, and NH4-N should be targeted at below 0.04 mg P L-1, 0.5 mg N L-1, and 0.3 mg N L-1, respectively, to limit the growth of phytoplankton. (2) The stimulatory effect of "NH4-N plus P" on phytoplankton biomass was greater than "NO3-N plus P" at the same N concentration, and "NH4-N plus NO3-N" did not show such associated stimulatory effect as "NH4-N plus P" or "NO3-N plus P". (3) The average concentrations of total phosphorus (TP), NO3-N, and NH4-N in Miyun Reservior were 0.017 mg P L-1, 0.620 mg N L-1, and 0.143 mg N L-1, respectively. The reservoir-wide average Chl a is below 20 MUg L-1 on an annual basis. (4) Ammonium was an important factor for the growth of phytoplankton and inputs of both NH4-N and NO3-N should be reduced to control bloom formation. Our findings imply that although P load reduction is important, appropriate reductions of all forms of N in watershed is recommended in the nutrient management strategy for Miyun Reservoir. PMID- 27488716 TI - Interactions and accumulation differences of metal(loid)s in three sea cucumber species collected from the Northern Mediterranean Sea. AB - This study was conducted on Holothuria polii, Holothuria tubulosa, and Holothuria mammata collected from five stations with different depths in the Northern Mediterranean Sea. The body walls and guts of these holothurians were examined in terms of interactions of 10 metals (iron (Fe), copper (Cu), manganese (Mn), zinc (Zn), chromium (Cr), cobalt (Co), vanadium (V), nickel (Ni), cadmium (Cd), and lead (Pb)) and one metalloid (arsenic (As)) using a multivariate analysis, and interspecies differences were determined. The multivariate analysis of variance (MANOVA) revealed significant differences between the species in terms of metal(loid) accumulations. The principal component analysis (PCA) showed a more association between H. tubulosa and H. polii with regard to the accumulation. The cluster analysis (CA) located Pb concentrations of the guts to the farthest place from all elements regardless of the species. A correlation analysis displayed that the element concentrations of the guts were more closely related to each other compared with those of the walls. The most inconsistent element in terms of correlations was the gut Fe contents. Accordingly, while Fe concentrations of H. mammata and H. tubulosa were correlated with all elements (except Pb) in divalent metal transporter 1 (DMT1) (divalent cation transporter 1 (DCT1) or natural resistance-associated macrophage protein 2 (NRAMP2)) belonging to the NRAM protein family, this was not the case in H. polii. Consequently, significant relationships between accumulated metal(loid)s that changed by tissues and sea cucumber species were observed. PMID- 27488717 TI - Analytical tools employed to determine pharmaceutical compounds in wastewaters after application of advanced oxidation processes. AB - Today, the presence of contaminants in the environment is a topic of interest for society in general and for the scientific community in particular. A very large amount of different chemical substances reaches the environment after passing through wastewater treatment plants without being eliminated. This is due to the inefficiency of conventional removal processes and the lack of government regulations. The list of compounds entering treatment plants is gradually becoming longer and more varied because most of these compounds come from pharmaceuticals, hormones or personal care products, which are increasingly used by modern society. As a result of this increase in compound variety, to address these emerging pollutants, the development of new and more efficient removal technologies is needed. Different advanced oxidation processes (AOPs), especially photochemical AOPs, have been proposed as supplements to traditional treatments for the elimination of pollutants, showing significant advantages over the use of conventional methods alone. This work aims to review the analytical methodologies employed for the analysis of pharmaceutical compounds from wastewater in studies in which advanced oxidation processes are applied. Due to the low concentrations of these substances in wastewater, mass spectrometry detectors are usually chosen to meet the low detection limits and identification power required. Specifically, time-of-flight detectors are required to analyse the by-products. PMID- 27488718 TI - Integrated expanded granular sludge bed and sequential batch reactor treating beet sugar industrial wastewater and recovering bioenergy. AB - The exponential rise in energy demand vis-a-vis depletion of mineral oil resources has accelerated recovery of bioenergy from organic waste. In this study, a laboratory-scale anaerobic (An)/aerobic (Ar) system comprising of expanded granular sludge bed (EGSB) reactor coupled to an aerobic sequential batch reactor (SBR) was constructed to treat beet sugar industrial wastewater (BSIW) of chemical oxygen demand (COD) 1665 mg L-1 while harnessing methane gas. The EGSB reactor generated methane at the rate of 235 mL/g COD added, with considerably higher than previously reported methane content of 86 %. Meanwhile, contaminants were successfully reduced in the combined An/Ar system, realizing a removal rate of more than 71.4, 97.3, 97.7, and 99.3 % of organic matter as total phosphorus, total nitrogen, biological oxygen demand (BOD), and soluble COD, respectively. Microbial community analysis showed that the bacterial genus Clostridium sp. and archaeal genus Methanosaeta sp. dominated the EGSB reactor, while Rhodobacter sp. dominance was observed in the SBR. The obtained experimental results indicate that the integration of expanded granular sludge bed and sequential batch reactor in treating BSIW obtained competitively outstanding performance. PMID- 27488719 TI - Is CO2 emission a side effect of financial development? An empirical analysis for China. AB - Based on panel data for 29 Chinese provinces from 1995 to 2012, this paper explores the relationship between financial development and environmental quality in China. A comprehensive framework is utilized to estimate both the direct and indirect effects of financial development on CO2 emissions in China using a carefully designed two-stage regression model. The first-difference and orthogonal-deviation Generalized Method of Moments (GMM) methods are used to control for potential endogeneity and introduce dynamics. To ensure the robustness of the estimations, two indicators measuring financial development financial depth and financial efficiency-are used. The empirical results indicate that the direct effects of financial depth and financial efficiency on environmental quality are positive and negative, respectively. The indirect effects of both indicators are U shaped and dominate the shape of the total effects. These findings suggest that the influences of the financial development on environment depend on the level of economic development. At the early stage of economic growth, financial development is environmentally friendly. When the economy is highly developed, a higher level of financial development is harmful to the environmental quality. PMID- 27488720 TI - Improving sensitivity for microchip electrophoresis interfaced with inductively coupled plasma mass spectrometry using parallel multichannel separation. AB - We reported sensitivity enhancement using multichannel parallel separation for microchip electrophoresis hyphenated with inductively coupled plasma mass spectrometry (MCE-ICP-MS) in this study. By using 2-20 array lanes for parallel separation, the sensitivity of the MCE-ICP-MS system was proportionally improved by 2-20 folds. No significantly adverse effect of parallel separation on column efficiency and resolution was observed. Rapid separation of Hg(2+) and methylmercuric (MeHg) ion within 36s under an electric field of 800Vcm(-1) was achieved in the 2-cm twenty-channels with a background electrolyte of 5mmolL(-1) borate buffer (pH 9.2). Detection limits of Hg(2+) and MeHg by the proposed system were decreased to 6.8-7.1ngL(-1). Good agreement between determined values and certified values of a certified reference fish was obtained with recoveries ranged between 94-98%. All results prove its advantages including high sensitivity, high efficiency and low operation cost, which are beneficial to routine analysis of metal speciation in environmental, biological and food fields. PMID- 27488721 TI - Characterization of sulfur and nitrogen compounds in Brazilian petroleum derivatives using ionic liquid capillary columns in comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometric detection. AB - Diesel and naphtha samples were analyzed using ionic liquid (IL) columns to evaluate the best column set for the investigation of organic sulfur compounds (OSC) and nitrogen(N)-containing compounds analyses with comprehensive two dimensional gas chromatography coupled to time-of-flight mass spectrometry detector (GC*GC/TOFMS). Employing a series of stationary phase sets, namely DB 5MS/DB-17, DB-17/DB-5MS, DB-5MS/IL-59, and IL-59/DB-5MS, the following parameters were systematically evaluated: number of tentatively identified OSC, 2D chromatographic space occupation, number of polyaromatic hydrocarbons (PAH) and OSC co-elutions, and percentage of asymmetric peaks. DB-5MS/IL-59 was chosen for OSC analysis, while IL59/DB-5MS was chosen for nitrogen compounds, as each stationary phase set provided the best chromatographic efficiency for these two classes of compounds, respectively. Most compounds were tentatively identified by Lee and Van den Dool and Kratz retention indexes, and spectra-matching to library. Whenever available, compounds were also positively identified via injection of authentic standards. PMID- 27488722 TI - Validation of the PECARN clinical decision rule for children with minor head trauma: a French multicenter prospective study. AB - BACKGROUND: To date, the Pediatric Emergency Care Applied Research Network (PECARN) rule for identifying children who are at very low risk of clinically important traumatic brain injuries after minor head trauma has not been validated prospectively in an independent population. Our goal was to evaluate the diagnostic performance of the PECARN clinical decision rule in a French pediatric population in multiple clinical settings. METHODS: We conducted a multicenter, prospective, non-interventional cohort study of patients with minor head trauma who presented to three emergency departments in France. We enrolled patients younger than 16 years of age seeking a consultation within 24 h of head trauma with Glasgow Coma Scale scores of 14-15. RESULTS: During the study period, we included 1499 children of which 421 (28 %) were under 2 years of age, and 955 (64 %) were male. A cranial computed tomography (CT) scan was performed on 76 patients (5.1 %). Of the 1499 included patients, 9 children (0.6 %) had a clinically-important traumatic brain injury, and none were classified as very low risk by the PECARN rule. In our study, the sensitivity of this clinical decision rule was 100 % (95 % CI 66.4 to 100 %), the specificity was 69.9 % (95 % CI 67.5 to 72.2 %) and the negative predictive value was 100 % (95 % CI 99.7 to 100 %). DISCUSSION: Our study confirmed the good predictive performances of the PECARN clinical decision rule for minor head trauma in children. The PECARN rule performed similarly to our study and to its internal validation study. CONCLUSIONS: We conducted an external validation study of the PECARN clinical decision rule for the detection of clinically-important traumatic brain injuries in children with minor head trauma, according to the methodological standards. The PECARN rule successfully identified all patients with clinically-important traumatic brain injuries, with a limited use of CT scans. Conducting a broad validation study with a large cohort is a prerequisite to provide sufficient statistical power before authorizing its implementation and generalization. TRIAL REGISTRATION: This study has been registered in ClinicalTrials.gov with identifier number: NCT02752711 on April 27, 2016. PMID- 27488723 TI - Internal and External Validation of a Computer-Assisted Surveillance System for Hospital-Acquired Infections in a 754-Bed General Hospital in the Netherlands. AB - OBJECTIVE To evaluate a computer-assisted point-prevalence survey (CAPPS) for hospital-acquired infections (HAIs). DESIGN Validation cohort. SETTING A 754-bed teaching hospital in the Netherlands. METHODS For the internal validation of a CAPPS for HAIs, 2,526 patients were included. All patient records were retrospectively reviewed in depth by 2 infection control practitioners (ICPs) to determine which patients had suffered an HAI. Preventie van Ziekenhuisinfecties door Surveillance (PREZIES) criteria were used. Following this internal validation, 13 consecutive CAPPS were performed in a prospective study from January to March 2013 to determine weekly, monthly, and quarterly HAI point prevalence. Finally, a CAPPS was externally validated by PREZIES (Rijksinstituut voor Volksgezondheid en Milieu [RIVM], Bilthoven, Netherlands). In all evaluations, discrepancies were resolved by consensus. RESULTS In our series of CAPPS, 83% of the patients were automatically excluded from detailed review by the ICP. The sensitivity of the method was 91%. The time spent per hospital-wide CAPPS was ~3 hours. External validation showed a negative predictive value of 99.1% for CAPPS. CONCLUSIONS CAPPS proved to be a sensitive, accurate, and efficient method to determine serial weekly point-prevalence HAI rates in our hospital. Infect Control Hosp Epidemiol 2016;1-6. PMID- 27488724 TI - An In Vitro Model That Predicts the Therapeutic Efficacy of Immunomodulatory Antibodies. AB - Immunomodulatory monoclonal antibodies (mAbs) have efficacy in patients with advanced cancer and are the focus of intensive research. However, cures are infrequent and responses vary among tumor types and among subjects with the same tumor. An in vitro test would be valuable to determine the most effective mAb combination for a given case and to evaluate novel agents. Toward this goal, we investigated the ability of various mAb combinations to generate a tumor destructive immune response in vitro in the presence of lymphoid cells from mice with established TC1 lung carcinoma, B16 melanoma, or SW1 melanoma. The data strongly correlate (r=0.9, 0.89, and 0.91, respectively) with the therapeutic efficacy of the respective mAb combinations. Both in vivo and in vitro, tumor destruction was associated with a shift from a Th2 to a Th1 response and included a dramatic increase of long-term memory cells. A combination of mAbs to CD137/PD 1/CTLA4/CD19 was most efficacious. PMID- 27488725 TI - Engineering Hematopoietic Cells for Cancer Immunotherapy: Strategies to Address Safety and Toxicity Concerns. AB - Advances in cancer immunotherapies utilizing engineered hematopoietic cells have recently generated significant clinical successes. Of great promise are immunotherapies based on chimeric antigen receptor-engineered T (CAR-T) cells that are targeted toward malignant cells expressing defined tumor-associated antigens. CAR-T cells harness the effector function of the adaptive arm of the immune system and redirect it against cancer cells, overcoming the major challenges of immunotherapy, such as breaking tolerance to self-antigens and beating cancer immune system-evasion mechanisms. In early clinical trials, CAR-T cell-based therapies achieved complete and durable responses in a significant proportion of patients. Despite clinical successes and given the side effect profiles of immunotherapies based on engineered cells, potential concerns with the safety and toxicity of various therapeutic modalities remain. We discuss the concerns associated with the safety and stability of the gene delivery vehicles for cell engineering and with toxicities due to off-target and on-target, off tumor effector functions of the engineered cells. We then overview the various strategies aimed at improving the safety of and resolving toxicities associated with cell-based immunotherapies. Integrating failsafe switches based on different suicide gene therapy systems into engineered cells engenders promising strategies toward ensuring the safety of cancer immunotherapies in the clinic. PMID- 27488726 TI - Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials. AB - AIMS: EMPAREG OUTCOME study showed a reduction in cardiovascular events in patients treated with the sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin, as compared to placebo. Other drugs of the same class are currently been investigated for cardiovascular outcomes. In the meanwhile, a re analysis of data collected in available studies can add relevant insight. METHODS: A MEDLINE search for SGLT-2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, luseogliflozin) was performed, collecting all randomized trials up to November 16, 2015. All trials with a duration of treatment >=12 weeks, enrolling patients with type 2 diabetes, comparing a SGLT2i with placebo or other comparators were included. The principal outcome was the effect of SGLT2i on all-cause and cardiovascular mortality. Secondary endpoints were myocardial infarction and stroke. Mantel-Haenszel odds ratio with 95 % confidence interval (MH-OR) was calculated. RESULTS: A total of 71 trials were included (31,199 and 16,088 patients in SGLT2i and comparator groups). Treatment with SGLT2i was associated with a significant reduction in all cause mortality (MH-OR 0.70 [0.59-0.83], p < 0.001), cardiovascular mortality (MH OR 0.43 [0.36-0.53], p < 0.001), and myocardial infarction (MH-OR 0.77 [0.63 0.94], p < 0.01), but not stroke (MH-OR 1.09 [0.86-1.38], p = 0.50), with no apparent difference across molecules (after excluding cardiovascular outcome trials). CONCLUSIONS: Available data suggest that the beneficial action observed with empagliflozin on all-cause and cardiovascular mortality in EMPAREG OUTCOME study is a class effect. The present meta-analysis showed a significantly reduction in myocardial infarction, with no increased risk of stroke. PMID- 27488727 TI - Replication of genome-wide association signals in Asian Indians with early-onset type 2 diabetes. AB - AIMS: To evaluate the association of 87 genetic variants previously associated with type 2 diabetes mellitus (T2DM) in genome-wide association studies of populations of European ancestry in an Asian Indian population with early-onset type 2 diabetes mellitus (EOT2DM). METHODS: The study groups comprised of 877 type 2 diabetes individuals, 436 individuals with EOT2DM (age at diagnosis below 35 years), 441 individuals with older T2DM (diagnosis at 35 years or greater) and controls with normal glucose tolerance (NGT) (n = 400 younger than 35 years; n = 438 older than 35 years). The participants were genotyped for 87 SNPs from 44 genes and 27 intergenic loci. Associations were tested using logistic regression. RESULTS: All the variants in TCF7L2 and CDKN2A/2B showed study-wide significance (p < 1.4 * 10-4) with T2DM, but only rs7903146, rs12243326, rs12255372 of TCF7L2 and rs7020996 of CDKN2A/2B showed study-wide significance (p < 1.4 * 10-4) with EOT2DM in this population. In addition, an intergenic SNP on chromosome 1 (rs10493685) was also shown to be study-wide significant (p = 7.1 * 10-6). Several additional SNPs previously associated with T2DM reached borderline significance in this study, but may have been limited by relatively low sample numbers. Various other SNPs of T2DM were not associated with EOT2DM. CONCLUSIONS: Some of the variants in TCF7L2 and CDKN2A/2B associated with T2DM are associated with EOT2DM as well. An intergenic SNP on chromosome 1p31 showed association only with early-onset T2DM in this Asian Indian population. The lack of association with many other SNPs of T2DM may be a reflection of the lack of power of the study, sample size, differences in the frequencies of genetic polymorphisms in different ethnic groups, effect sizes, as well as ancestral differences in pattern of LD between the genetic variants involved in early- and late-onset T2DM. PMID- 27488728 TI - Mechanistic insights into the role of PC- and PCP-type palladium catalysts in asymmetric hydrophosphination of activated alkenes incorporating potential coordinating heteroatoms. AB - The impact of the structural attributes of chiral PC- and PCP-palladium catalysts was investigated in the asymmetric hydrophosphination of various heterocycle functionalized enone substrates. Due to the architecture of the catalysts, they are confronted with potential catalyst deactivation arising from the coordination of the electron-rich heteroatoms (P, O, N and S) to the metal center. A systematic variation of the location and identity of the heteroatoms demonstrated the impact of structural modifications on the substrates, which have a significant influence on both yields (16-99%) and enantioselectivities (0-99%). A detailed discussion on the distinct catalytic mechanisms (intra- vs. inter molecular addition) provides important information to explain the results obtained. PMID- 27488729 TI - The Pharmacological Costs of Complete Liver Resections in Unselected Advanced Colorectal Cancer Patients: Focus on Targeted Agents. A Review of Randomized Clinical Trials. AB - BACKGROUND: The aim of this study was to evaluate the pharmacological costs of conversion chemotherapy with targeted biological agents in an unselected population of advanced colorectal cancer (CRC) patients in order to achieve an R0 liver resection. METHODS: Full reports and updates of randomized clinical trials (RCTs) that compared at least two front-line therapy regimens with targeted biological agents for advanced CRC patients were selected. The present evaluation was restricted to randomized phase II and III trials. The costs of drugs are at the Pharmacy Hospital and are expressed in euros (?). RESULTS: Our study began with the evaluation of 683 abstracts. Forty-eight trials were considered appropriate for further analysis. A more in-depth evaluation looking for the trials reporting the liver resection rates following conversion chemotherapy brought to the exclusion of other 37 trials, leaving 11 randomized trials (three phase II trials, including 522 patients and eight phase III trials, including 7191 patients). The pharmacological costs of conversion therapy increased with the substitution of prolonged infusion 5-Fluorouracil by capecitabine and, to a much higher extent, with the introduction of biologicals. CONCLUSIONS: Two key issues are presented in this review. First, the pharmacological costs of commonly used front line regimens based on the targeted biological agents for the treatment of advanced CRC are highly variable. Second, the performance of the published schemes, in terms of resection rates, depends on patient's selection, tumor characteristics, and on the type of the scheme. PMID- 27488730 TI - Feasibility work to inform the design of a randomized clinical trial of wound dressings in elective and unplanned abdominal surgery. AB - BACKGROUND: Designing RCTs in surgery requires consideration of existing evidence, stakeholders' views and emerging interventions, to ensure that research questions are relevant to patients, surgeons and the health service. When there is uncertainty about RCT design, feasibility work is recommended. This study aimed to assess how feasibility work could inform the design of a future pilot study and RCT (Bluebelle, HTA - 12/200/04). METHODS: This was a prospective survey of dressings used to cover abdominal wounds. Surgical trainees from 25 hospitals were invited to participate. Information on patient risk factors, operation type and type of wound dressings used was recorded for elective and unplanned abdominal procedures over a 2-week interval. The types of dressing used were summarized, and associations with operation type and patient risk factors explored. RESULTS: Twenty hospitals participated, providing data from 727 patients (1794 wounds). Wounds were predominantly covered with basic dressings (1203 of 1769, 68.0 per cent) and tissue adhesive was used in 27.4 per cent (485 of 1769); dressing type was missing for 25 wounds. Just 3.6 per cent of wounds (63 of 1769) did not have a dressing applied at the end of the procedure. There was no evidence of an association between type of dressing used and patient risk factors, type of operation, or elective and unscheduled surgery. CONCLUSION: Based on the findings from this large study of current practice, the pilot study design has evolved. The inclusion criteria have expanded to encompass patients undergoing unscheduled surgery, and tissue adhesive as a dressing will be evaluated as an additional intervention group. Collaborative methods are recommended to inform the design of RCTs in surgery, helping to ensure they are relevant to current practice. PMID- 27488733 TI - Supercritical Fluid Synthesis and Tribological Applications of Silver Nanoparticle-decorated Graphene in Engine Oil Nanofluid. AB - Silver nanoparticle-decorated graphene nanocomposites were synthesized by a facile chemical reduction approach with the assistance of supercritical CO2 (ScCO2). The silver nanoparticles with diameters of 2-16 nm are uniformly distributed and firmly anchored on graphene nanosheets. The tribological properties of the as-synthesized nanocomposites as lubricant additives in engine oil were investigated by a four-ball tribometer. The engine oil with 0.06~0.10 wt.% Sc-Ag/GN nanocomposites displays remarkable lubricating performance, superior than the pure engine oil, the engine oil containing zinc dialkyl dithiophosphate (ZDDP), as well as the oil dispersed with the single nanomaterial of graphene oxides (GOs) and nano-Ag particles alone. The remarkable lubricating behaviors of Sc-Ag/GN probably derive from the synergistic interactions of nano Ag and graphene in the nanocomposite and the action of the formed protective film on the contact balls. The anchored nano-Ag particles on graphene expand the interlamination spaces of graphene nanosheets and can prevent them from restacking during the rubbing process, resulting in the full play of lubricating activity of graphene. The formed protective film on the friction pairs significantly reduces the surface roughness of the sliding balls and hence preventing them from direct interaction during the sliding process. PMID- 27488732 TI - Ergonomic design and evaluation of a diagnostic ultrasound transducer holder. AB - BACKGROUND: Work-related musculoskeletal disorders (WMSDs) are injuries and disorders that affect the body's movement and musculoskeletal system. Awkward postures represent one of the major ergonomic risk factors that cause WMSDs among sonographers while working with an ultrasound transducer. This study aimed to design and evaluate a new holder for the ultrasound transducer. MATERIALS AND METHODS: In the first phase a new holder was designed for the transducer, considering design principles. Evaluation of the new holder was then carried out by electrogoniometry and a locally perceived discomfort (LPD) scale. RESULTS: The application of design principles to the new holder resulted in an improvement of wrist posture and comfort. Wrist angles in extension, flexion, radial deviation and ulnar deviation were lower with utilization of the new holder. The severity of discomfort based on the LPD method in the two modes of work with and without the new holder was reported with values of 1.3 and 1.8, respectively (p < 0.05). CONCLUSION: Overall, this study indicated that applying ergonomics design principles was effective in minimizing wrist deviation and increasing comfort while working with the new holder. PMID- 27488731 TI - Sound tuning of amygdala plasticity in auditory fear conditioning. AB - Various auditory tones have been used as conditioned stimuli (CS) for fear conditioning, but researchers have largely neglected the effect that different types of auditory tones may have on fear memory processing. Here, we report that at lateral amygdala (LA) synapses (a storage site for fear memory), conditioning with different types of auditory CSs (2.8 kHz tone, white noise, FM tone) recruits distinct forms of long-term potentiation (LTP) and inserts calcium permeable AMPA receptor (CP-AMPAR) for variable periods. White noise or FM tone conditioning produced brief insertion (<6 hr after conditioning) of CP-AMPARs, whereas 2.8 kHz tone conditioning induced more persistent insertion (>=6 hr). Consistently, conditioned fear to 2.8 kHz tone but not to white noise or FM tones was erased by reconsolidation-update (which depends on the insertion of CP-AMPARs at LA synapses) when it was performed 6 hr after conditioning. Our data suggest that conditioning with different auditory CSs recruits distinct forms of LA synaptic plasticity, resulting in more malleable fear memory to some tones than to others. PMID- 27488734 TI - Effects of life-history requirements on the distribution of a threatened reptile. AB - Survival and reproduction are the two primary life-history traits essential for species' persistence; however, the environmental conditions that support each of these traits may not be the same. Despite this, reproductive requirements are seldom considered when estimating species' potential distributions. We sought to examine potentially limiting environmental factors influencing the distribution of an oviparous reptile of conservation concern with respect to the species' survival and reproduction and to assess the implications of the species' predicted climatic constraints on current conservation practices. We used ecological niche modeling to predict the probability of environmental suitability for the alligator snapping turtle (Macrochelys temminckii). We built an annual climate model to examine survival and a nesting climate model to examine reproduction. We combined incubation temperature requirements, products of modeled soil temperature data, and our estimated distributions to determine whether embryonic development constrained the northern distribution of the species. Low annual precipitation constrained the western distribution of alligator snapping turtles, whereas the northern distribution was constrained by thermal requirements during embryonic development. Only a portion of the geographic range predicted to have a high probability of suitability for alligator snapping turtle survival was estimated to be capable of supporting successful embryonic development. Historic occurrence records suggest adult alligator snapping turtles can survive in regions with colder climes than those associated with consistent and successful production of offspring. Estimated egg incubation requirements indicated that current reintroductions at the northern edge of the species' range are within reproductively viable environmental conditions. Our results highlight the importance of considering survival and reproduction when estimating species' ecological niches, implicating conservation plans, and benefits of incorporating physiological data when evaluating species' distributions. PMID- 27488736 TI - A descriptive analysis of medical health services utilization of Veterans living in Ontario: a retrospective cohort study using administrative healthcare data. AB - BACKGROUND: Health services utilization by Veterans following release may be different than the general population as the result of occupational conditions, requirements and injuries. This study provides the first longitudinal overview of Canadian Veteran healthcare utilization in the Ontario public health system. METHODS: This is a retrospective cohort study designed to use Ontario's provincial healthcare data to study the demographics and healthcare utilization of Canadian Armed Forces (CAF) & RCMP Veterans living in Ontario. Veterans were eligible for the study if they released between January 1, 1990 and March 31, 2013. Databases at the Institute for Clinical Evaluative Sciences were linked by a unique identifier to study non-mental health related hospitalizations, emergency department visits, and physician visits. Overall and age-stratified descriptive statistics were calculated in five-year intervals following the date of release. RESULTS: The cohort is comprised of 23, 818 CAF or RCMP Veterans. Following entry into the provincial healthcare system, 82.6 % (95 % CI 82.1-83.1) of Veterans saw their family physician at least once over the first five years following release, 60.7 % (95 % CI 60.0-61.3) saw a non-mental health specialist, 40.8 % (95 % CI 40.2-41.5) went to the emergency department in that same time period and 9.9 % (9.5-10.3) were hospitalized for non-mental health related complaints. Patterns of non-mental health services utilization appeared to be time and service dependant. Stratifying health services utilization by age of the Veteran at entry into the provincial healthcare system revealed significant differences in service use and intensity. CONCLUSION: This study provides the first description of health services utilization by Veterans, following release from the CAF or RCMP. This work will inform the planning and delivery of support to Veterans in Ontario. PMID- 27488737 TI - Sleep Quality: A Pilot Study Comparing Patients With and Without Injection Related Venous Ulcers. AB - PURPOSE: The purposes of this study were to (a) compare sleep quality of persons with and without injection-related venous ulcers (VU) and (b) examine associations between global sleep quality with age, sex, comorbidities, pain, nutrition, physical health rating, fatigue, emotional problems, health-related quality of life, attitude toward physical activity, and number of ulcers. DESIGN: This study used a cross-sectional design. SUBJECTS AND SETTING: The participants included 31 patients with VU and 30 without VU (men [n = 35] and women; mean age = 54 years) who were attending an indigent clinic for wound care or general health. METHODS: Participants were recruited from an urban clinic when they came for primary care or wound care. Questionnaires were administered at that time and included the Pittsburgh Sleep Quality Index (PSQI), Mini Nutrition Assessment, Patient Reported Outcomes Measurement Information System (PROMIS) questions about general physical health, fatigue, emotional problems, and quality of life, Brief Pain Inventory worst pain rating, Positive Attitude and Motivation for Physical Activity Scale, wound assessment, and demographic factors. RESULTS: The 2 groups did not differ on the PSQI in terms of time going to bed, minutes to fall asleep, time awakening, hours slept, and time in bed. Those with VU compared to without VU took more medications to help sleep (P<= .03). There were no significant differences in PSQI correlations across groups. All study variables except age, gender, and quality of life were significantly related to Global sleep disturbance score. A higher number of comorbid conditions, worse pain, poorer nutrition, poor physical health rating, greater fatigue, more emotional problems, and poor attitude toward physical activity were related to greater sleep disturbances for all participants. Both groups had mean Global PSQI scores greater than 5 (with VU = 7.83 and without VU = 8.2), indicating sleep problems. CONCLUSIONS: Study findings suggest that sleep disturbances may be a concern in persons with VU and are related to many variables. Assessing sleep along with other aspects of wound care may provide a more comprehensive assessment of factors affecting a person with a VU. PMID- 27488735 TI - The impact of leadership hubs on the uptake of evidence-informed nursing practices and workplace policies for HIV care: a quasi-experimental study in Jamaica, Kenya, Uganda and South Africa. AB - BACKGROUND: The enormous impact of HIV on communities and health services in Sub Saharan Africa and the Caribbean has especially affected nurses, who comprise the largest proportion of the health workforce in low- and middle-income countries (LMICs). Strengthening action-based leadership for and by nurses is a means to improve the uptake of evidence-informed practices for HIV care. METHODS: A prospective quasi-experimental study in Jamaica, Kenya, Uganda and South Africa examined the impact of establishing multi-stakeholder leadership hubs on evidence informed HIV care practices. Hub members were engaged through a participatory action research (PAR) approach. Three intervention districts were purposefully selected in each country, and three control districts were chosen in Jamaica, Kenya and Uganda. WHO level 3, 4 and 5 health care institutions and their employed nurses were randomly sampled. Self-administered, validated instruments measured clinical practices (reports of self and peers), quality assurance, work place policies and stigma at baseline and follow-up. Standardised average scores ranging from 0 to 1 were computed for clinical practices, quality assurance and work place policies. Stigma scores were summarised as 0 (no reports) versus 1 (one or more reports). Pre-post differences in outcomes between intervention and control groups were compared using the Mantel Haenszel chi-square for dichotomised stigma scores, and independent t tests for other measures. For South Africa, which had no control group, pre-post differences were compared using a Pearson chi-square and independent t test. Multivariate analysis was completed for Jamaica and Kenya. Hub members in all countries self-assessed changes in their capacity at follow-up; these were examined using a paired t test. RESULTS: Response rates among health care institutions were 90.2 and 80.4 % at baseline and follow-up, respectively. Results were mixed. There were small but statistically significant pre-post, intervention versus control district improvements in workplace policies and quality assurance in Jamaica, but these were primarily due to a decline in scores in the control group. There were modest improvements in clinical practices, workplace policies and quality assurance in South Africa (pre-post) (clinical practices of self-pre 0.67 (95 % CI, 0.62, 0.72) versus post 0.78 (95 % CI, 0.73-0.82), p = 0.002; workplace policies-pre 0.82 (95 % CI, 0.70, 0.85) versus post 0.87 (95 % CI, 0.84, 0.90), p = 0.001; quality assurance-pre 0.72 (95 % CI, 0.67, 0.77) versus post 0.84 (95 % CI, 0.80, 0.88)). There were statistically significant improvements in scores for nurses stigmatising patients (Jamaica reports of not stigmatising-pre-post intervention 33.9 versus 62.4 %, pre-post control 54.7 versus 64.4 %, p = 0.002-and Kenya pre post intervention 35 versus 51.6 %, pre-post control 34.2 versus 47.8 %, p = 0.006) and for nurses being stigmatised (Kenya reports of no stigmatisation-pre post intervention 23 versus 37.3 %, pre-post control 15.4 versus 27 %, p = 0.004). Multivariate results for Kenya and Jamaica were non-significant. Twelve hubs were established; 11 were active at follow-up. Hub members (n = 34) reported significant improvements in their capacity to address care gaps. CONCLUSIONS: Leadership hubs, comprising nurses and other stakeholders committed to change and provided with capacity building can collectively identify issues and act on strategies that may improve practice and policy. Overall, hubs did not provide the necessary force to improve the uptake of evidence-informed HIV care in their districts. If hubs are to succeed, they must be integrated within district health authorities and become part of formal, legal organisations that can regularise and sustain them. PMID- 27488738 TI - Adolescent Perspectives Following Ostomy Surgery: A Grounded Theory Study. AB - PURPOSE: This purpose of this study was to provide a theoretical account of how adolescents aged 13 to 18 years process the experience of having an ostomy. DESIGN: Qualitative study using grounded theory design. SUBJECTS AND SETTING: The sample comprised of 12 English-speaking adolescents aged 13-18 years: 10 with an ostomy and 2 with medical management of their disease. METHODS: Respondents completed audio-recorded interviews that were transcribed verbatim. Data were analyzed using the constant comparative method until data saturation occurred. Dedoose, a Web-based qualitative methods management tool, was used to capture major themes arising from the data. RESULTS: Study results indicate that for adolescents between 13 and 18 years of age, processing the experience of having an ostomy includes concepts of the "physical self" and "social self" with the goal of "normalizing." Subcategories of physical self include (a) changing reality, (b) learning, and (c) adapting. Subcategories of social self include (a) reentering and (b) disclosing. CONCLUSIONS: This study sheds light on how adolescents process the experience of having an ostomy and how health care providers can assist adolescents to move through the process to get back to their desired "normal" state. Health care providers can facilitate the adolescent through the ostomy experience by being proactive in conversations not only about care issues but also about school and family concerns and spirituality. Further research is needed in understanding how parents process their adolescents' ostomy surgery experience and how spirituality assists adolescents in coping and adjustment with body-altering events. PMID- 27488739 TI - Incontinence-Associated Dermatitis (IAD). PMID- 27488740 TI - Feasibility of a Web-Based Self-management Intervention for Intermittent Urinary Catheter Users With Spinal Cord Injury. AB - PURPOSE: The purpose of this study was to evaluate the feasibility of a new Web based intermittent catheter self-management intervention. DESIGN: We tested the acceptability and usability of intervention components, which included multiple Web-based materials (an online urinary diary adapted for mobile phone use and an educational booklet), 3 phone calls with a nurse, and a peer-led discussion forum. SUBJECTS AND SETTING: Thirty adults with spinal cord injury using intermittent catheterization for bladder drainage were enrolled; 26 participants received the nurses' phone-based consultations. METHODS: Preliminary effectiveness of new self-efficacy and self-management scales were evaluated using baseline and 3-month online surveys. Participants' perceived value of the intervention components, self-management changes, and suggestions were assessed with data from the 3-month surveys, followed by brief tape-recorded interviews. RESULTS: Several catheter practices improved somewhat over 3 months. The frequency of catheterizations every 4 to 6 hours increased from 71% to 77%. Self management of neurogenic bladder dysfunction increased significantly (P = .032); participant comments indicated that fluid intake was the biggest change. Catheter related self-efficacy and quality-of-life scores increased but not significantly. The frequency of urinary tract infection and pain did not change significantly. For feasibility, intervention components, with the exception of the forum, were rated highly by the majority of participants for usefulness, satisfaction (desired information), and Web-based usability. CONCLUSION: Further testing of this intervention is recommended in a multisite randomized clinical trial. PMID- 27488741 TI - [German national second-opinion network for testicular cancer and penile carcinoma : Two sources for evidence-based information]. AB - BACKGROUND: The second-opinion network for testicular cancer is an internet-based platform addressing physicians treating testicular cancer patients. They are offered a second-opinion before determining further therapy after orchiectomy and completion of staging. THEME: The high rate of discrepancies between the first and second opinion in more than 30 % supports the assumption of a deficit in the implementation of treatment guidelines. In 2015, approximately 22 % of the newly diagnosed cases with testicular cancer in Germany were covered by this system. According to the present interim analysis, the second-opinion platform helps to avoid overtreatment of testicular cancer patients. The high acceptance of the project and the encouraging results of this interim analysis gave rise to considerations to apply the second-opinion model to penile carcinoma. Data from the UK and the Netherlands show that the second-opinion network for penile cancer could help to improve treatment standards and results in Germany. Current data and the intended further development of the system are discussed. PMID- 27488742 TI - Physiology in Perspective: The Body's Tubes Sustain Life but Underlie Disease. PMID- 27488744 TI - Surgical quality of minimally invasive adrenalectomy for adrenocortical carcinoma: a contemporary analysis using the National Cancer Database. AB - OBJECTIVES: To compare quality outcomes between open (OA) and minimally invasive (MIA) adrenalectomy for adrenocortical carcinoma (ACC). PATIENTS AND METHODS: In the National Cancer Database, we identified 481 patients with non-metastatic ACC who underwent adrenalectomy from 2010 to 2013. OA and MIA were compared on positive surgical margin (PSM) and lymph node dissection (LND) rates (primary outcomes), and lymph node yield, length of stay (LOS), readmission, and overall survival (secondary outcomes). Using the intention-to-treat principle, minimally invasive-converted-to-open cases were considered MIA. Logistic regression analysis was used to identify predictors of PSMs and LND. Associations between approach and the outcomes were further assessed by stage and tumour size. RESULTS: Overall, 161 patients (33.5%) underwent MIA. MIA was used more commonly in older, comorbid patients; for smaller, localised tumours; and at lower-volume centres. In the intention-to-treat analysis, MIA independently predicted PSMs [odds ratio (OR) 2.0, 95% confidence interval (CI) 1.1-3.6; P = 0.03) and no LND (OR 0.1, 95% CI 0.03-0.6; P = 0.01). On subgroup analysis, the association between MIA and PSMs only held true for pT3 disease (48.7% vs 26.7%, P = 0.01). A higher PSM rate was seen for tumours of >=10 cm managed with MIA vs OA, but this difference was not significant (28.2% vs 18.5%, P = 0.16). Likewise, the association between MIA and no LND was only observed for male patients, tumours >=10 cm, and cN0 disease. After excluding minimally-invasive-converted-to-open cases, the difference in PSM was less pronounced and non-significant (OR 1.8, 95% CI 0.9-3.4; P = 0.08). MIA was associated with significantly shorter median LOS (3 vs 6 days, P < 0.01) and non-significantly decreased readmissions (4.4% vs 8.8%, P = 0.08) compared to OA without any difference in lymph node yield or overall survival. CONCLUSION: For organ-confined disease, MIA offers comparable surgical quality to OA, while expediting inpatient recovery. OA is associated with superior outcomes for locally advanced disease. PMID- 27488745 TI - Structure activity relationship study on the peptide hormone preptin, a novel bone-anabolic agent for the treatment of osteoporosis. AB - Preptin is a 34-residue pancreatic hormone shown to be anabolic to bone in vitro and in vivo. The bone activity of preptin resides within the (1-16) N-terminal fragment. Due to its peptidic nature, the truncated fragment of preptin is enzymatically unstable; however it provides an attractive framework for the creation of stable analogues using various peptidomimetic techniques. An alanine scan of preptin (1-16) was undertaken which showed that substitution of Ser at position 3 or Pro at position 14 did not inhibit the proliferative activity of preptin in primary rat osteoblasts (bone-forming cells). Importantly, Ser-3 to Ala substitution also showed a significant activity on osteoblast differentiation in vitro and increased the formation of mineralised bone matrix. Additional modifications with non-proteinogenic amino acids at position 3 improved the stability in liver microsomes, but diminished the osteoblast proliferative activity. In addition, to provide greater structural diversity, a series of macrocyclic preptin (1-16) analogues was synthesised using head-to-tail and head to-side chain macrolactamisation as well as ring-closing metathesis. However, a detrimental effect on osteoblast activity was observed upon macrocyclisation. PMID- 27488743 TI - Regulation of Gastrointestinal Smooth Muscle Function by Interstitial Cells. AB - Interstitial cells of mesenchymal origin form gap junctions with smooth muscle cells in visceral smooth muscles and provide important regulatory functions. In gastrointestinal (GI) muscles, there are two distinct classes of interstitial cells, c-Kit(+) interstitial cells of Cajal and PDGFRalpha(+) cells, that regulate motility patterns. Loss of these cells may contribute to symptoms in GI motility disorders. PMID- 27488746 TI - Relationship between calculated total antioxidant status and atherosclerotic coronary artery disease. AB - OBJECTIVE: Antioxidants play a major role in the cellular protection cascade against oxidative damage. Oxidative stress has been linked to the pathogenesis of coronary atherosclerosis. Our aim was to evaluate the association between calculated serum total antioxidant status (cTAS) and the presence and severity of coronary artery disease (CAD). METHODS: One hundred and seventy-four patients with angiographically documented significant (>=50%) luminal stenosis (n=123) or with minimal (<50%) luminal stenosis (n=51) in at least one coronary artery or major branch segment in the epicardial coronary tree were categorized as CAD+ group; 88 patients with no luminal stenosis were considered as the control group. The level of cTAS (mmol/L) was evaluated using the following equation: (0.63*albumin concentration)+(1.02*uric acid concentration)+(1.53*bilirubin concentration). RESULTS: In univariate analyses, mean levels of cTAS, uric acid, and creatinine were significantly higher in CAD+ group than in controls. However, adjusted cTAS level was not found to be a CAD predictor in the total population [odds ratio (OR)=1.20; 95% confidence interval (CI): 0.81-1.76; p=0.364] or in men (OR=1.25; 95% CI: 0.73-2.12; p=0.420) and women (OR=1.20; 95% CI: 0.66-2.19; p=0.553). A weak but statistically significant correlation was found between cTAS and Gensini score (Spearman's rho=0.16, p=0.015). CONCLUSION: In patients with suspicious CAD, the level of cTAS was not found to be an independent predictor for the presence of CAD. Further studies with larger sample size are required to confirm the results. PMID- 27488747 TI - SYNTAX score predicts postoperative atrial fibrillation in patients undergoing on pump isolated coronary artery bypass grafting surgery. AB - OBJECTIVE: Atrial fibrillation (AF) is the most common arrhythmia following coronary artery by-pass graft surgery (CABG). The value of SYNTAX score to predict postoperative atrial fibrillation (PoAF) has not been clearly addressed. We aimed to evaluate this relationship in patients undergoing isolated CABG. METHODS: This study was designed as a single-center, non-randomized, observational, prospective study. Ninety-four patients undergoing isolated on pump CABG, who had sinus rhythm and were older than 18 years, were enrolled. Demographic characteristics of the patients were recorded; SYNTAX score was calculated preoperatively for each patient. The univariate and multivariate logistic regression analysis were used to determine for predictors of PoAF. RESULTS: The median SYNTAX score of the enrolled patients was 21, (56-5). PoAF was observed in 31 (33.3%) patients. Univariate logistic regression showed that age, chronic obstructive pulmonary disease (COPD), red blood cell distribution width (RDW), urea, initial troponin I, peak postoperative troponin I, interventricular septum, left atrial diameter, and SYNTAX score were significantly associated with the frequency of PoAF following CABG. An independent association was identified with age [beta: 0.088, p:0.023, OR: 1.092, 95% CI (1.012-1.179)], COPD [(beta: 2.222, p:0.003, OR: 9.228, 95% CI (2.150 39.602)], and SYNTAX score [(beta: 0.130, p:0.002, OR: 1.139, 95% CI (1.050 1.235)]. CONCLUSION: This study showed that a higher SYNTAX score was related to more frequent PoAF in patients undergoing isolated on-pump CABG. PMID- 27488748 TI - Relationship between the presence of left atrial thrombus in patients with mitral stenosis and platelet-to-lymphocyte ratio. AB - OBJECTIVE: Rheumatic carditis-induced mitral valve disease is associated with a chronic inflammatory process. The close relationship between inflammation and prothrombotic processes is known. Our goal was to examine the relationship between the presence of left atrial (LA) thrombus in patients with rheumatic mitral valve stenosis (RMVS) and platelet-to-lymphocyte ratio (PLR), which is an inflammatory marker. METHODS: This cross-sectional study included 351 consecutive patients diagnosed with RMVS upon presentation to the cardiology polyclinic. All patients were evaluated using transthoracic and transesophageal echocardiography and were divided into 2 groups: those with and without LA thrombus. In addition to echocardiographic and biochemical parameters, PLR was compared between the groups. Student's t-test, Mann-Whitney U test, logistic regression analysis, and receiver operating characteristic (ROC) curve analysis were used for statistical analysis. RESULTS: No significant differences in terms of age, gender, body mass index, and comorbidities were found between the groups with and without LA thrombus. In the group with LA thrombus, higher red cell distribution width, mean platelet volume, and platelet count and lower lymphocyte count were detected. In addition, C-reactive protein levels were significantly higher in the LA thrombus group (4.7 vs. 2.7 mg/L, p<0.001). PLR was significantly higher in patients with thrombus than in those without (133+/-38 vs. 119+/-31, p=0.001). Higher PLR was identified as independently associated with the presence of LA thrombus (odds ratio: 1.03, 95% confidence interval: 1-1.06, p=0.016). CONCLUSION: Higher PLR was detected in the LA thrombus group of patients with RMVS. PMID- 27488749 TI - Evaluation of heart rate recovery index in heavy smokers. AB - OBJECTIVE: Cigarette smoking increases the risk of cardiovascular events. The heart rate recovery index (HRRI) is an indicator of autonomous nervous system function and is an independent prognostic risk factor for cardiovascular diseases. In this study, we aimed to evaluate HRRI in heavy smokers. METHODS: A total of 179 apparently healthy subjects (67 non-smokers as the control group and 112 heavy smokers) were enrolled into this prospective cross-sectional study. The presence of hypertension, diabetes mellitus, and known cardiac or non-cardiac diseases was specified as the exclusion criteria. Heavy cigarette smoking was defined as the consumption of more than one packet of cigarette per day. All subjects underwent the maximal Bruce treadmill test. HRRIs of the heavy cigarette smoker group at 1, 2, 3, and 5 min after maximal exercise were calculated and compared to those of the control group. Student t-test, chi-square test, and analysis of covariance were used for statistical analysis. RESULTS: The baseline characteristics of the two groups were similar, except for body mass index and high-density lipoprotein level. HRRIs at 1, 2, 3, and 5 min after maximal exercise were found to be significantly lower in the heavy smoker group (HRRI1: 26.78+/-8.81 vs. 32.82+/-10.34, p<0.001; HRRI2: 44.37+/-12.11 vs. 51.72+/-12.87, p<0.001; HRRI3: 52.73+/-11.54 vs. 57.22+/-13.51, p=0.018; and HRRI5: 58.31+/ 10.90 vs. 62.33+/-13.02, p=0.029). CONCLUSIONS: In the present study, we found that HRRI was impaired in heavy smokers. Our results suggest that beside previously known untoward effects on vascular biology, heavy smoking also has deleterious effects on the neuro-cardiovascular system. PMID- 27488750 TI - Feasibility and clinical benefit of cognitive-behavioral intervention for preparing patients for transesophageal echocardiography. AB - OBJECTIVE: Despite premedication, anxiety in patients undergoing transesophageal echocardiography (TEE) is prevalent, often causing adverse physiological and psychological effects and contributing to decreased patient compliance. We aimed to evaluate the feasibility of cognitive-behavioral intervention (CBI) in patients undergoing TEE and to assess its impact on the severity of anxiety, patient's and physician's comfort, and administered dose of sedatives. METHODS: Our study was designed as a prospective, single-center, single-blinded, case controlled pilot study. The study group comprised 49 patients (26 men, 66+/-8 years old) referred for TEE. Before the examination, 26 randomly selected patients underwent CBI. Sedatives were administered, if necessary. After the examination, patient anxiety and patient's and physician's comfort were evaluated using dedicated questionnaires and scores. Intergroup comparison was performed using Student's t-test for independent variables and Mann-Whitney U test and Pearson's chi-square test or Fisher's exact test for categorical variables. RESULTS: The mean level of pre-TEE distress and anxiety were significantly lower in patients receiving CBI than in those without intervention (p=0.022). Furthermore, the application of CBI significantly reduced patient's discomfort (p<0.001) and resulted in increased comfort of physician (p<0.001) during TEE. The need of sedative administration (31% vs. 91%, p<0.001) and its mean dose was significantly lower in patients receiving CBI (1.6+/-0.5 mg vs. 2.7+/-1.6 mg midazolam, p=0.009). CONCLUSIONS: CBI is feasible in patients undergoing TEE. It decreases patient's anxiety and discomfort and increases physician's comfort. It also results in reduced use of sedatives during the examination. PMID- 27488751 TI - Late deterioration of left ventricular function after right ventricular pacemaker implantation. AB - OBJECTIVES: Right ventricular (RV) pacing induces a left bundle branch block pattern on ECG and may promote heart failure. Patients with dual chamber pacemakers (DCPs) who present with progressive reduction in left ventricular ejection fraction (LVEF) secondary to RV pacing are candidates for cardiac resynchronization therapy (CRT). This study analyzes whether upgrading DCP to CRT with the additional implantation of a left ventricular (LV) lead improves LV function in patients with reduced LVEF following DCP implantation. METHODS: Twenty-two patients (13 males) implanted with DCPs and a high RV pacing percentage (>90%) were evaluated in term of new-onset heart failure symptoms. The patients were enrolled in this retrospective single-center study after obvious causes for a reduced LVEF were excluded with echocardiography and coronary angiography. In all patients, DCPs were then upgraded to biventricular devices. LVEF was analyzed with a two-sided t-test. QRS duration and brain natriuretic peptide (BNP) levels were analyzed with the unpaired t-test. RESULTS: LVEF declined after DCP implantation from 54+/-10% to 31+/-7%, and the mean QRS duration was 161+/-20 ms during RV pacing. NT-pro BNP levels were elevated (3365+/-11436 pmol/L). After upgrading to a biventricular device, a biventricular pacing percentage of 98.1+/-2% was achieved. QRS duration decreased to 108+/-16 ms and 106+/-20 ms after 1 and 6 months, respectively. There was a significant increase in LVEF to 38+/-8% and 41+/-11% and a decrease in NT-pro BNP levels to 3088+/-2326 pmol/L and 1860+/-1838 pmol/L at 1 and 6 months, respectively. CONCLUSION: Upgrading to CRT may be beneficial in patients with DCPs and heart failure induced by a high RV pacing percentage. PMID- 27488752 TI - The rs6817105 polymorphism on chromosome 4q25 is associated with the risk of atrial fibrillation in the Chinese Han population. AB - OBJECTIVE: Previous genome-wide association studies (GWASs) have identified rs6817105-a single nucleotide polymorphism (SNP) on chromosome 4q25-to be associated with the risk of atrial fibrillation (AF) in a European-descent population. We recently demonstrated this association in a large cohort of Japanese ancestry. Our present study was designed to determine this association in the Chinese Han population. METHODS: This case-control study included 597 AF cases and 996 AF-free controls, and rs6817105 SNPs were genotyped using the TaqMan allelic discrimination assay. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated in logistic regression models. RESULTS: The genotype distribution of rs6817105-CC was significantly more frequent in the AF patients than in the controls (p=3.24*10-32). In our study, logistic regression analysis showed a strong association between rs6817105 and the risk of AF (additive model: OR=2.22, 95%CI=1.89-2.61, p=2.33*10-22; dominant model: OR=2.96, 95%CI: 2.16-4.07, p=2.03*10-11; recessive model: OR=2.83, 95%CI=2.27-3.54, p=4.00*10-20). Stratification analyses showed a borderline statistical difference between subgroups of age for the association of rs6817105 with AF risk (p=0.049). However, further interactive analysis indicated no significant interaction between genotype of rs6817105 and age (p=0.178). CONCLUSION: Our finding suggested that SNP rs6817105 may be associated with a high significant risk of AF in the Chinese Han population, although more replicative studies of larger sample size are needed to confirm this finding. PMID- 27488753 TI - AB0 blood types: impact on development of prosthetic mechanical valve thrombosis. AB - OBJECTIVE: The non-O alleles of the ABO genotype have been associated with an increased risk of thrombosis. We aimed to assess the association between blood group status and prosthetic valve thrombosis. METHODS: The association between AB0 blood group status and prosthetic valve thrombosis was assessed in this retrospective study. Transesophageal echocardiography was performed in 149 patients with a diagnosis of prosthetic valve thrombosis and in 192 control subjects. RESULTS: Non-0 blood group type (p<0.001), presence of NYHA class III IV status (p<0.001), and central nervous system (p<0.001) and non-central nervous system (p<0.001) emboli were significantly more prevalent in prosthetic valve thrombosis patients than in the control subjects. The incidence of ineffective anticoagulation was higher in patients with prosthetic valve thrombosis than in controls (p<0.001), as was the presence of moderate to severe left atrial spontaneous echo contrast (p<0.001). The non-0 blood prosthetic valve thrombosis subgroup had a higher incidence of obstructive thrombi and central nervous system thrombotic events than having 0 blood prosthetic valve thrombosis subgroup. Non-0 blood group, ineffective anticoagulation, left atrial spontaneous echo contrast, and a poor NYHA functional capacity were identified to be the predictors of prosthetic valve thrombosis. CONCLUSION: Our data demonstrate that patients with non-0 compared with 0 blood groups have higher incidence of prosthetic valve thrombosis and central nervous system embolism and similar rates of non-central nervous system embolism at presentation compared with 0 blood group type. Thus, non-O blood group may be a risk factor that may be prone to the development of prosthetic valve thrombosis in patients with prosthetic heart valves. PMID- 27488755 TI - Relation between serum sodium levels and clinical outcomes in Turkish patients hospitalized for heart failure: a multi-center retrospective observational study. AB - OBJECTIVE: The purpose of the study was to analyze the prevalence of hyponatremia and related 1-year outcomes of patients hospitalized for decompensated heart failure with reduced ejection fraction (HFrEF) in Turkish patients. METHODS: A total of 500 hospitalized patients with HFrEF were consecutively included in a retrospective study at 19 participating hospitals. Patients were categorized according to their serum sodium levels (sNa) on admission day as normonatremic (135-145 mEq/L) and hyponatremic (<135 mEq/L). One-year all-cause mortality, re hospitalization rates, and the impact of the changes in sNa at the time of discharge to clinical outcomes were examined. RESULTS: Hyponatremia was observed in 29% of patients. Patients with hyponatremia had lower blood pressures, creatinine clearance, and left ventricular ejection fraction and higher serum creatinine and BUN levels on admission compared with those with normonatremia. Hyponatremia was associated with higher 1-year all-cause mortality (14% vs. 2.6%, p<0.001) and re-hospitalization rates (46.9% vs. 33.7%, p=0.005). After adjustment for covariates, hyponatremia was independently associated with 1-year all-cause mortality (adjusted HR, 4.762; 95% CI, 1.941-11.764; p=0.001). At discharge, only 50.8% of hyponatremic patients were corrected to normonatremia (>=135 mEq/L). Those with persistent hyponatremia had the highest all-cause mortality (p<0.001). CONCLUSION: In this study, it is demonstrated that hyponatremia is relatively common and is associated with increased 1-year all cause mortality and re-hospitalization rates among Turkish patients hospitalized with HFrEF. Approximately 50% of the patients with initial low sNa had persistent hyponatremia at discharge, and these patients had the worst clinical outcomes. PMID- 27488754 TI - Post-discharge heart failure monitoring program in Turkey: Hit-PoinT. AB - OBJECTIVE: The aim of this study was to assess the efficacy and feasibility of an enhanced heart failure (HF) education with a 6-month telephone follow- up program in post-discharge ambulatory HF patients. METHODS: The Hit-Point trial was a multicenter, randomized, controlled trial of enhanced HF education with a 6-month telephone follow-up program (EHFP) vs routine care (RC) in patients with HF and reduced ejection fraction. A total of 248 patients from 10 centers in various geographical areas were randomized: 125 to EHFP and 123 to RC. Education included information on adherence to treatment, symptom recognition, diet and fluid intake, weight monitoring, activity and exercise training. Patients were contacted by telephone after 1, 3, and 6 months. The primary study endpoint was cardiovascular death. RESULTS: Although all-cause mortality didn't differ between the EHFP and RC groups (p=NS), the percentage of cardiovascular deaths in the EHFP group was significantly lower than in the RC group at the 6-month follow up (5.6% vs. 8.9%, p=0.04). The median number of emergency room visits was one and the median number of all cause hospitalizations and heart failure hospitalizations were zero. Twenty-tree percent of the EHFP group and 35% of the RC group had more than a median number of emergency room visits (p=0.05). There was no significant difference regarding the median number of all-cause or heart failure hospitalizations. At baseline, 60% of patients in EHFP and 61% in RC were in NYHA Class III or IV, while at the 6-month follow up only 12% in EHFP and 32% in RC were in NYHA Class III or IV (p=0.001). CONCLUSION: These results demonstrate the potential clinical benefits of an enhanced HF education and follow up program led by a cardiologist in reducing cardiovascular deaths and number of emergency room visits with an improvement in functional capacity at 6 months in post-discharge ambulatory HF patients. PMID- 27488756 TI - Investigation of the arterial stiffness and associated factors in patients with familial Mediterranean fever. AB - OBJECTIVE: Because of the ongoing and recurring inflammatory state in familial Mediterranean fever (FMF), patients may experience a high risk of cardiovascular events. Our aim was to investigate the arterial stiffness and associated factors in patients with FMF. METHODS: Sixty-nine consecutive FMF patients (including 11 females) and 35 controls (including 5 females) were enrolled in the study. The demographical, clinical, and laboratory data and genetic mutations of the patients were recorded. In the study, FMF patients according to the Tel-Hashomer criteria were included, whereas patients with other known inflammatory rheumatologic disease, atherosclerotic cardiovascular disease, hypertension, diabetes, those under the age of 18 years, or those refusing to participate in the study were excluded. Arterial stiffness measurements were performed using the TensioMed device (TensoMed Ltd, Budapest, Hungary). RESULTS: The patient and control groups were similar in terms of the mean ages, BMIs, gender, systolic blood pressures, and smoking. FMF patients had a higher pulse wave velocity (PWV) (7.73+/-1.3 and 7.18+/-1.1 m/s; p=0.03) and lower brachial and aortic augmentation indexes (-64.6+/-14.6% and -54.6+/-25.9%, p=0.041 and 4.9+/-7.4% and 14.0+/-11.5%, p=0.025, respectively) compared with the controls. Thirty-one (45%) patients were in the "during-attack" state and had higher PWV (8.17+/-1.6 and 7.38+/-0.9 m/s; p=0.027) compared with the asymptomatic patients. PWV was correlated to serum CRP, WBC, ESR, fibrinogen, and neutrophil/lymphocyte ratios (r=0.666, 0.429, 0.441, 0.388, and 0.460, respectively). The genetic mutation and predominant attack type had no effect on arterial stiffness. CONCLUSION: FMF patients have increased arterial stiffness during attacks compared with asymptomatic patients and controls. The impaired arterial stiffness is correlated to the severity of the inflammatory state rather than to the attack type or genetic mutations. PMID- 27488757 TI - High blood pressure: An obscuring misnomer? AB - High blood pressure (BP) has been identified as a major risk factor for cardiovascular complications. Although two-way association between BP and hypertensive complications makes hypertension a near-ideal biomarker, BP as "the cause" for the complications of HT per se still needs more evidence. Another entirely possible hemodynamic candidate for causing hypertensive cardiovascular adverse events can be flow or its iterations, which might have escaped the attention because of its perfect correlation with pressure and harder technical measurement. In this article, we analyze the evidence in hand to compare flow- and pressure-related phenomena to delineate which of the two is the dominant mediator of complications related to hypertension and should be the target for therapy. A "flow-" rather than a "pressure-" based factor, as the causative or major driving mediator of common hypertensive complications, may change our understanding of hypertension pathophysiology. PMID- 27488758 TI - A hypertrophic and dilated cardiomyopathic sudden cardiac death case; de novo mutations in TTN and SGCD genes. PMID- 27488760 TI - Vascular risk in familial Mediterranean fever. PMID- 27488759 TI - Long-term prognostic significance of pentraxin-3 in patients with acute myocardial infarction: 5-year prospective cohort study. AB - OBJECTIVE: A predictive role of serum Pentraxin 3 (PTX3) for short-term adverse cardiovascular events including mortality in acute myocardial infarction (AMI) was reported in recent studies. The aim of the study was to investigate long-term prognostic significance of serum PTX3 in an AMI with 5-year follow-up period in this study. METHODS: In this prospective study, 140 patients, who were admitted to the emergency department between January 2011 and December 2011 with acute chest pain and/or dyspnea and diagnosed with AMI and 60 healthy controls were included. PTX3 levels were measured at admission by using an ELISA method. The study group was divided into tertiles on the basis of admission PTX3 values: the high-PTX3 group (>=4.27 ng/mL), the middle-PTX3 groups (4.27-1.63 ng/mL), and the low-PTX3 group (<=1.63 ng/mL). RESULTS: PTX3 level was significantly more greatly increased in the AMI group than in the controls (2.27+/-0.81 vs. 0.86+/-0.50 ng/mL, p<0.001). PTX3 level was found to be significantly positively correlated with TIMI score (r=0.368, p=0.037), high sensitive C-reactive protein (hsCRP) (r=0.452, p=0.024), pro-BNP (r=0.386, p=0.029), troponin I (r=0.417, p=<0.001), and GRACE score (r=0.355, p=0.045), and negatively correlated with HDL cholesterol (r=-0.203, p=0.016) and LVEF (r=-0.345, p=0.028). In multivariate analysis, PTX3 (OR=1.12, 95% CI 1.04-1.20; p=0.001) was a significant independent predictor of long-term cardiovascular mortality, after adjusting for other risk factors. CONCLUSION: PTX3 is a novel biomarker that may help to identify high risk individuals with AMI, who are potentially at risk of early major adverse cardiovascular events including mortality in the long-term period. PMID- 27488761 TI - Modified transesophageal echocardiography of the dissected thoracic aorta; a novel diagnostic approach. AB - BACKGROUND: Transesophageal echocardiography (TEE) is a key diagnostic modality in patients with acute aortic dissection, yet its sensitivity is limited by a "blind-spot" caused by air in the trachea. After placement of a fluid-filled balloon in the trachea visualization of the thoracic aorta becomes possible. This method, modified TEE, has been shown to be an accurate test for the diagnosis of upper aortic atherosclerosis. In this study we discuss how we use modified TEE for the diagnosis and management of patients with (suspected) acute aortic dissection. NOVEL DIAGNOSTIC APPROACH OF THE DISSECTED AORTA: Modified TEE provides the possibility to obtain a complete echocardiographic overview of the thoracic aorta and its branching vessels with anatomical and functional information. It is a bedside test, and can thus be applied in hemodynamic instable patients who cannot undergo computed tomography. Visualization of the aortic arch allows differentiation between Stanford type A and B dissections and visualization of the proximal cerebral vessels enables a timely identification of impaired cerebral perfusion. During surgery modified TEE can be applied to identify the true lumen for cannulation, and to assure that the true lumen is perfused. Also, the innominate- and carotid arteries can be assessed for structural integrity and adequate perfusion during multiple phases of the surgical repair. CONCLUSIONS: Modified TEE can reveal the "blind-spot" of conventional TEE. In patients with (suspected) aortic dissection it is thus possible to obtain a complete echocardiographic overview of the thoracic aorta and its branches. This is of specific merit in hemodynamically unstable patients who cannot undergo CT. Modified TEE can guide also guide the surgical management and monitor perfusion of the cerebral arteries. PMID- 27488762 TI - Role of dihydrofolate reductase in tetrahydrobiopterin biosynthesis and lipid metabolism in the oleaginous fungus Mortierella alpina. AB - Mortierella alpina is a well-known polyunsaturated fatty acid-producing oleaginous fungus. Analysis of the Mort. alpina genome suggests that there is a putative dihydrofolate reductase (DHFR) gene playing a role in the salvage pathway of tetrahydrobiopterin (BH4), which has never been explored in fungi before. DHFR is the sole source of tetrahydrofolate and plays a key role in maintaining BH4 levels. Transcriptome data analysis revealed that DHFR was up regulated by nitrogen exhaustion, when Mort. alpina starts to accumulate lipids. Significant changes were found in the fatty acid profile in Mort. alpina grown on medium containing DHFR inhibitors compared to Mort. alpina grown on medium without inhibitors. To explore the role of DHFR in folate/BH4 metabolism and its relationship to lipid biosynthesis, we expressed heterologously the gene encoding DHFR from Mort. alpina in Escherichia coli and we purified the recombinant enzyme to homogeneity. The enzymatic activity was investigated by liquid chromatography and MS and VIS-UV spectroscopy. The kinetic parameters and the effects of temperature, pH, metal ions and inhibitors on the activity of DHFR were also investigated. The transcript level of cytosolic NADPH-producing gene involved in folate metabolism is down-regulated by DHFR inhibitors, which highlights the functional significance of DHFR in lipid biosynthesis. The relationship between DHFR and lipid metabolism is thus of major importance, and folate metabolism may be an alternative NADPH source in fatty acid synthesis. To our knowledge, this study is the first to report the comprehensive characterization of a BH4salvage pathway in a fungus. PMID- 27488765 TI - Step aside, Olympics: here's the Cybathlon. PMID- 27488764 TI - Nitrates for the prevention of cardiac morbidity and mortality in patients undergoing non-cardiac surgery. AB - BACKGROUND: Cardiac complications are not uncommon in patients undergoing non cardiac surgery, especially in patients with coronary artery disease (CAD) or at high risk of CAD. Perioperative cardiac complications can lead to mortality and morbidity, as well as higher costs for patient care. Nitrates, which are among the most commonly used cardiovascular drugs, perform the function of decreasing cardiac preload while improving cardiac blood perfusion. Sometimes, nitrates are administered to patients undergoing non-cardiac surgery to reduce the incidence of cardiac complications, especially for patients with CAD. However, their effects on patients' relevant outcomes remain controversial. OBJECTIVES: * To assess effects of nitrates as compared with other interventions or placebo in reducing cardiac risk (such as death caused by cardiac factors, angina pectoris, acute myocardial infarction, acute heart failure and cardiac arrhythmia) in patients undergoing non-cardiac surgery.* To identify the influence of different routes and dosages of nitrates on patient outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Chinese BioMedical Database until June 2014. We also searched relevant conference abstracts of important anaesthesiology or cardiology scientific meetings, the database of ongoing trials and Google Scholar.We reran the search in January 2016. We added three potential new studies of interest to the list of 'Studies awaiting classification' and will incorporate them into our formal review findings for the review update. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing nitrates versus no treatment, placebo or other pharmacological interventions in participants (15 years of age and older) undergoing non-cardiac surgery under any type of anaesthesia. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. Two review authors selected trials, extracted data from included studies and assessed risk of bias. We resolved differences by discussion and, when necessary, sought help and suggestions from a third review author. We used a random-effects model for data analysis. MAIN RESULTS: We included 27 randomized controlled trials (RCTs) (8244 participants analysed). Investigators reported 12 different comparisons of three different nitrates (nitroglycerin, isosorbide dinitrate and nicorandil) versus no treatment, placebo or other pharmacological interventions. All participants were older than 15 years of age. More than half of the trials used general anaesthesia. Surgical procedures in most trials were at low to moderate risk for perioperative cardiac complications. Only two comparisons including three studies reported the primary outcome - all-cause mortality up to 30 days post operation. Researchers reported other morbidity outcomes and adverse events in a variable and heterogeneous way, resulting in limited available data for inclusion in the meta-analysis. We determined that the overall methodological quality of included studies was fair to low, in accordance with risk of bias in most domains.In summary, we found no difference in the primary outcome - all cause mortality up to 30 days post operation - when nitroglycerin was compared with no treatment (one study, 60 participants, 0/30 vs 1/30; (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.01 to 7.87, very low-quality evidence based on GRADE criteria) or with placebo (two studies, 89 participants, 1/45 vs 0/44; RR 2.81, 95% CI 0.12 to 63.83, very low-quality evidence). Regarding our secondary outcomes, we noted no statistically significant differences in angina pectoris, acute myocardial infarction, acute heart failure, cardiac arrhythmia or cardiac arrest in any comparisons. In comparisons versus nitroglycerin, although more events of cardiac ischaemia were observed in participants receiving no treatment or placebo, we found no statistically significant differences in any comparisons, except the comparison of nicorandil versus placebo. One study revealed a potential dose-dependent protective effect of nicorandil for cardiac ischaemia.Adverse events were reported in a heterogeneous way among the comparisons. In general, more participants treated with nitrates had hypotension, tachycardia and headache, but investigators reported no statistically significant differences between groups in any comparisons. AUTHORS' CONCLUSIONS: This systematic review suggests that nitroglycerin or isosorbide dinitrate is not associated with improvement in mortality and cardiac complications among patients undergoing non-cardiac surgery. Limited evidence suggests that nicorandil may reduce the risk of cardiac ischaemia in participants undergoing non-cardiac surgery. Additional studies are needed to consolidate the evidence.However, the data included in many of the analyses in this review are sparse - that is, adequate data are few - resulting in very low power to detect differences between nitrates and comparators. Thus, a more objective conclusion would state that available evidence is insufficient to show whether nitrates are associated with improvement in mortality and cardiac complications among patients undergoing non cardiac surgery.Over the past decade, no high-quality studies have focused on association of cardiac mortality and morbidity with use of nitrates during non cardiac surgery. This review underlines the need for well-designed trials in this field. PMID- 27488763 TI - Emergency Department Visits for Adverse Drug Reactions Involving Alcohol: United States, 2005 to 2011. AB - BACKGROUND: Alcohol consumption may interfere with absorption, distribution, metabolism, and excretion of medications and increase risk of adverse drug reactions (ADR). Studies report increasing prescription medication use over time, with many U.S. drinkers using alcohol-interactive medication. This study identified trends in incidence of U.S. emergency department (ED) visits for ADR with alcohol involvement (ADR-A), compared characteristics and disposition between ADR-A visits and ADR visits without alcohol involvement (ADR-NA), and examined frequency of implicated medications in such visits for 2005 to 2011. METHODS: ADR visits were identified through the Drug Abuse Warning Network, a national surveillance system monitoring drug-related ED visits. Analysis accounted for sampling design effects and sampling weights. Estimates are presented for totals (ages 12+), age group, and/or sex. Trends were assessed by joinpoint log-linear regression. Differences between ADR-A and ADR-NA visits were compared using two-tailed Rao-Scott chi-square tests. RESULTS: From 2005 to 2011, incidence of ADR-A visits increased for males and females ages 21 to 34 and females ages 55+. An average of 25,303 ADR-A visits ages 12+ occurred annually. Compared with ADR-NA visits, ADR-A visits were more likely to involve males, patients ages 21 to 54, and 2+ implicated drugs. Alcohol involvement increased odds of more serious outcomes from ADR visits. Central nervous system (CNS) agents were the most common medications in ADR-A visits (59.1%), with nearly half being analgesics (mainly opioid). About 13.8% of ADR-A visits involved psychotherapeutic agents, including antidepressants. Besides CNS and psychotherapeutic agents, ADR-A visits involved a higher percentage of genitourinary-tract agents (mainly for impotence) than ADR-NA visits. Sex and age variations were observed with certain implicated medications. CONCLUSIONS: ED visits for alcohol-drug interactions can be prevented by avoiding alcohol when taking alcohol-interactive medications. Our results underscore the need for healthcare professionals to routinely ask patients about alcohol consumption and warn of ADR risks before prescribing and dispensing alcohol-interactive medications. PMID- 27488766 TI - UK research assessment should boost support for principal investigators. PMID- 27488778 TI - Troubled Japanese space agency seeks fresh start. PMID- 27488767 TI - Donald Trump's appeal should be a call to arms. PMID- 27488779 TI - Monumental proof to torment mathematicians for years to come. PMID- 27488780 TI - Scientists seek influence on 'Brexit ministry'. PMID- 27488782 TI - Corrections. PMID- 27488781 TI - Legal confusion threatens to slow data science. PMID- 27488783 TI - Scholarly Olympics: How the games have shaped research. PMID- 27488784 TI - Welcome to the Cyborg Olympics. PMID- 27488785 TI - Take responsibility for electronic-waste disposal. PMID- 27488789 TI - Endocrine disruptors: Refereed science to guide action on EDCs. PMID- 27488790 TI - China: Standardize R&D costing. PMID- 27488791 TI - Health research: Mentoring female scientists in Africa. PMID- 27488792 TI - China: Change tack to boost basic research. PMID- 27488793 TI - Correction. PMID- 27488794 TI - Atomic physics: A milestone in quantum computing. PMID- 27488795 TI - Biomedical science: Protection for anaesthetized mice. PMID- 27488796 TI - Quantum physics: Destruction of discrete charge. PMID- 27488797 TI - Controlling charge quantization with quantum fluctuations. AB - In 1909, Millikan showed that the charge of electrically isolated systems is quantized in units of the elementary electron charge e. Today, the persistence of charge quantization in small, weakly connected conductors allows for circuits in which single electrons are manipulated, with applications in, for example, metrology, detectors and thermometry. However, as the connection strength is increased, the discreteness of charge is progressively reduced by quantum fluctuations. Here we report the full quantum control and characterization of charge quantization. By using semiconductor-based tunable elemental conduction channels to connect a micrometre-scale metallic island to a circuit, we explore the complete evolution of charge quantization while scanning the entire range of connection strengths, from a very weak (tunnel) to a perfect (ballistic) contact. We observe, when approaching the ballistic limit, that charge quantization is destroyed by quantum fluctuations, and scales as the square root of the residual probability for an electron to be reflected across the quantum channel; this scaling also applies beyond the different regimes of connection strength currently accessible to theory. At increased temperatures, the thermal fluctuations result in an exponential suppression of charge quantization and in a universal square-root scaling, valid for all connection strengths, in agreement with expectations. Besides being pertinent for the improvement of single-electron circuits and their applications, and for the metal-semiconductor hybrids relevant to topological quantum computing, knowledge of the quantum laws of electricity will be essential for the quantum engineering of future nanoelectronic devices. PMID- 27488798 TI - Demonstration of a small programmable quantum computer with atomic qubits. AB - Quantum computers can solve certain problems more efficiently than any possible conventional computer. Small quantum algorithms have been demonstrated on multiple quantum computing platforms, many specifically tailored in hardware to implement a particular algorithm or execute a limited number of computational paths. Here we demonstrate a five-qubit trapped-ion quantum computer that can be programmed in software to implement arbitrary quantum algorithms by executing any sequence of universal quantum logic gates. We compile algorithms into a fully connected set of gate operations that are native to the hardware and have a mean fidelity of 98 per cent. Reconfiguring these gate sequences provides the flexibility to implement a variety of algorithms without altering the hardware. As examples, we implement the Deutsch-Jozsa and Bernstein-Vazirani algorithms with average success rates of 95 and 90 per cent, respectively. We also perform a coherent quantum Fourier transform on five trapped-ion qubits for phase estimation and period finding with average fidelities of 62 and 84 per cent, respectively. This small quantum computer can be scaled to larger numbers of qubits within a single register, and can be further expanded by connecting several such modules through ion shuttling or photonic quantum channels. PMID- 27488799 TI - Carbon-based tribofilms from lubricating oils. AB - Moving mechanical interfaces are commonly lubricated and separated by a combination of fluid films and solid 'tribofilms', which together ensure easy slippage and long wear life. The efficacy of the fluid film is governed by the viscosity of the base oil in the lubricant; the efficacy of the solid tribofilm, which is produced as a result of sliding contact between moving parts, relies upon the effectiveness of the lubricant's anti-wear additive (typically zinc dialkyldithiophosphate). Minimizing friction and wear continues to be a challenge, and recent efforts have focused on enhancing the anti-friction and anti-wear properties of lubricants by incorporating inorganic nanoparticles and ionic liquids. Here, we describe the in operando formation of carbon-based tribofilms via dissociative extraction from base-oil molecules on catalytically active, sliding nanometre-scale crystalline surfaces, enabling base oils to provide not only the fluid but also the solid tribofilm. We study nanocrystalline catalytic coatings composed of nitrides of either molybdenum or vanadium, containing either copper or nickel catalysts, respectively. Structurally, the resulting tribofilms are similar to diamond-like carbon. Ball-on-disk tests at contact pressures of 1.3 gigapascals reveal that these tribofilms nearly eliminate wear, and provide lower friction than tribofilms formed with zinc dialkyldithiophosphate. Reactive and ab initio molecular-dynamics simulations show that the catalytic action of the coatings facilitates dehydrogenation of linear olefins in the lubricating oil and random scission of their carbon-carbon backbones; the products recombine to nucleate and grow a compact, amorphous lubricating tribofilm. PMID- 27488800 TI - 'Kudos' promises to help scientists promote their papers to new audiences. PMID- 27488802 TI - Do children, adolescents, and young adults with type 1 diabetes have increased prevalence of sleep disorders? AB - BACKGROUND: Sleep has been shown to impact glucose regulation, and may be altered in persons with type 1 diabetes (T1D). OBJECTIVE: To assess sleep characteristics in T1D patients and the possible association between sleep disturbances and diabetes-related variables. SUBJECTS AND METHODS: In a cross-sectional study in 154 young patients with T1D and 154 age-range-matched nondiabetic controls subjective sleep characteristics were assessed using validated questionnaires: Sleep Disturbance Scale for Children (SDSC), Adolescent Sleep-Wake Scale (ASWS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS). Clinical and disease-related variables were obtained from medical charts. RESULTS: Sleep disorders were frequent in all age groups, with no significant difference in prevalence or total scores of the SDSC, ASWS, PSQI, or ESS between the patients and the controls. In T1D children, SDSC score was significantly higher in those using continuous glucose monitoring (CGM) vs glucose meters (P = .042). The score of disorders related to "initiating and maintaining sleep" was significantly higher in those treated with pumps vs patients treated with injections (P = .014), in those using CGM vs glucose meters (P = .02), and in those with nocturnal hypoglycemia vs those without (P = .023). The percentage of children with excessive daytime sleepiness was significantly lower in patients vs controls (P = .035). No significant differences were found in the other two age groups. CONCLUSIONS/INTERPRETATION: The prevalence of sleep disorders among most of the young T1D patients was no higher than in the nondiabetic population. Studies using objective sleep measures are warranted to further assess sleep quality in T1D patients. PMID- 27488803 TI - A role for the spindle assembly checkpoint in the DNA damage response. AB - Spontaneous DNA damage poses a continuous threat to genomic integrity. If unchecked, genotoxic insults result in genomic instability, a hallmark of cancer cells. In eukaryotic cells a DNA Damage Response (DDR) detects and responds to genotoxic stress, acting as an anti-cancer barrier in humans. Among other actions, the DDR blocks the segregation of incompletely replicated or damaged chromosomes, thus preventing aneuploidy. In a work aimed at better understanding such S-M control, we recently showed that cells block anaphase through different control pathways. The S phase checkpoint kinase Mec1/ATR inhibits mitotic Cyclin Dependent Kinase activity through effector kinases Swe1/Wee1 and Rad53/Chk2. Cells also stabilize the levels of Pds1/securin to block sister chromatid segregation in response to DNA damage. We show here that Pds1/securin abundance is still secured when the S phase checkpoint response is fully abrogated in mec1/ATR tel1/ATM double null mutants. When such cells are exposed to genotoxic stress, Pds1/securin is stabilized in a spindle assembly checkpoint (SAC) dependent manner. Disruption of the SAC and the S phase checkpoint together, allows chromosome segregation in the presence of DNA damage or replication stress. Our results place the SAC as a part of the DDR, which appears to count on different, independent control layers to preserve genomic integrity when chromosome replication is challenged. PMID- 27488805 TI - First record of predation between Dasyatis species. PMID- 27488804 TI - Plastid phylogenomic study of species within the genus Zea: rates and patterns of three classes of microstructural changes. AB - This project examines the relationships within the genus Zea using complete plastid genomes (plastomes). While Zea mays has been well studied, congeneric species have yet to be as thoroughly examined. For this study four complete plastomes and a fifth nearly complete plastome were sequenced in the five species (Zea diploperennis, Zea perennis, Zea luxurians, Zea nicaraguensis, and Zea mays subsp. huehuetenangensis) by Sanger or next-generation methods. An analysis of the microstructural changes, such as inversions, insertion or deletion mutations (indels) and determination of their frequencies were performed for the complete plastomes. It was determined that 193 indels and 15 inversions occurred across the examined plastomes of Zea. Tandem repeat indels were the most common type of microstructural change observed. Divergence times were estimated using a noncorrelated relaxed clock method. Divergence dates for specific nodes relative to Zea were calculated to fall between 38,000 years before present (YBP) for the subspecies included in this study and 23,000 YBP for section Luxuriantes included in this study. The stem lineage of all Zea species was calculated to have diverged at 176,000 YBP. The calculated mutation rates for the genus fell within the range of 1.7E-8 to 3.5E-8 microstructural changes per site per year. These rates of change are not uniform, despite the close relationships of taxa in this study. Phylogenomic analyses using full plastome alignments were also conducted to compare tree topologies from different types of mutations. In most cases, the previous work examining Zea mitochondrial and nuclear data was confirmed. PMID- 27488806 TI - Ultrasensitive sandwich-type electrochemical immunosensor based on trimetallic nanocomposite signal amplification strategy for the ultrasensitive detection of CEA. AB - A novel and ultrasensitive sandwich-type electrochemical immunosensor was designed for the quantitative detection of carcino-embryonic antigen (CEA). This immunosensor was developed by using the trimetallic NiAuPt nanoparticles on graphene nanosheets (NGs) nanosheets (NiAuPt-NGs) as excellent labels and beta cyclodextrin functionalized reduced graphene oxide nanosheets (CD-NGs) as the platform. The CD-NGs with high specific surface area good biocompatibility and the ideal dispersibility was used to capture the primary antibodies (Ab1) efficiently. The trimetallic NiAuPt-NGs nanocomposites were used as the labels for signal amplification, showing better electrocatalytic activity towards the reduction of hydrogen peroxide (H2O2), which is much better than that the monometallic Pt-NGs, bimetallic NiPt-NGs and AuPt-NGs due to the synergetic effect presented in NiAuPt-NGs. The NiAuPt-NGs nanocomposites consist of tightly coupled nanostructures of Au, Ni and Pt, which have neither an alloy nor a core shell structure. Under the optimal conditions, a linear range from 0.001-100 ng/mL and a low detection limit of 0.27 pg/mL were obtained for CEA. The proposed electrochemical sandwich-type immunosensor may have a promising application in bioassay and it enriches the electrochemical immunoassays. PMID- 27488807 TI - A comparison of immunohistochemical and molecular methods used for analyzing the BRAF V600E gene mutation in malignant melanoma in Taiwan. AB - AIMS: The BRAF V600 mutation has been shown to be clinically meaningful in terms of both the prognosis and sensitivity of BRAF inhibitors in patients with metastatic melanoma. Recently, a BRAF V600E mutation-specific antibody, VE1, was generated for the detection of tumors bearing BRAF V600E mutations. To determine the clinical value of immunohistochemical testing, we compared the prevalence of mutant BRAF detected by VE1 with direct sequencing results. METHODS: Paraffin embedded, formalin-fixed melanoma biopsies were analyzed for the BRAF mutation status by immunohistochemistry with the VE1 antibody. Sanger sequencing was applied to verify the immunohistochemical results. RESULTS: A total of 73 melanoma cases with tumor samples from primary lymph nodes and metastatic sites were selected for this study. Direct sequencing demonstrated that 18 of 73 cases (24.6%) harbored the BRAF V600 mutation: 17 with V600E and one with V600K. All 18 tumors shown to harbor the BRAF V600E/K mutations were VE1-positive. One additional case was false-positive for VE1. The sensitivity and specificity of VE1 was 100% (18/18) and 98% (54/55), respectively. The overall concordance between the immunohistochemical method and direct sequencing was excellent (98.6%). CONCLUSIONS: Our findings demonstrate that immunohistochemical analysis using VE1 constitutes a highly sensitive test for the detection of BRAF mutations and suggest that this cost-effective method is suitable as a rapid diagnostic approach complementary to molecular testing. PMID- 27488809 TI - Human rights in occupational therapy education: A step towards a more occupationally just global society. AB - BACKGROUND/AIM: Education on human rights will place occupational therapists in a strong position to address societal inequities that limit occupational engagement for many client groups. The imminent changes to the Minimum Standard for the Education of Occupational Therapists engender efforts towards social change and will require university-level human rights education. This education might enhance the profession's influence on disadvantaging social structures in order to effect social change. To contribute to the evidence base for social change education in occupational therapy, this research aims to understand the knowledge, skills, confidence and learning experiences of occupational therapy students who completed a human rights course. METHODS: Final year occupational therapy students responded to questionnaires which included listing human rights, a human rights scale measuring knowledge and confidence for working towards human rights, and open questions. Numbers of rights listed, knowledge scores and confidence scores were calculated. Responses to the open questions were thematically analysed. RESULTS: After completing a human rights course, students had good knowledge and moderate confidence to work with human rights. Three themes were identified including 'learning about human rights', 'learning about structural, societal and global perspectives on occupational engagement' and 'learning how occupational therapists can work with groups, communities and populations: becoming articulate and empowered'. CONCLUSIONS: Human rights education fosters the development of occupational therapists who are skilled, knowledgeable, confident and empowered to address occupational injustices, according to these research findings. To develop a more occupationally just global society, education that considers iniquitous social structures and human rights is necessary. PMID- 27488808 TI - Hypoxic Preconditioning Inhibits Hypoxia-induced Apoptosis of Cardiac Progenitor Cells via the PI3K/Akt-DNMT1-p53 Pathway. AB - Research has demonstrated that hypoxic preconditioning (HP) can enhance the survival and proliferation of cardiac progenitor cells (CPCs); however, the underlying mechanisms are not fully understood. Here, we report that HP of c-kit (+) CPCs inhibits p53 via the PI3K/Akt-DNMT1 pathway. First, CPCs were isolated from the hearts of C57BL/6 mice and further purified by magnetic-activated cell sorting. Next, these cells were cultured under either normoxia (H0) or HP for 6 hours (H6) followed by oxygen-serum deprivation for 24 hours (24h). Flow cytometric analysis and MTT assays revealed that hypoxia-preconditioned CPCs exhibited an increased survival rate. Western blot and quantitative real-time PCR assays showed that p53 was obviously inhibited, while DNMT1 and DNMT3beta were both significantly up-regulated by HP. Bisulphite sequencing analysis indicated that DNMT1 and DNMT3beta did not cause p53 promoter hypermethylation. A reporter gene assay and chromatin immunoprecipitation analysis further demonstrated that DNMT1 bound to the promoter locus of p53 in hypoxia-preconditioned CPCs. Together, these observations suggest that HP of CPCs could lead to p53 inhibition by up-regulating DNMT1 and DNMT3beta, which does not result in p53 promoter hypermethylation, and that DNMT1 might directly repress p53, at least in part, by binding to the p53 promoter locus. PMID- 27488810 TI - A case series and a review of the literature on foreign modelling agent reaction: an emerging problem. AB - Foreign modelling agent reactions (FMAR) are the result of the injection of unapproved high-viscosity fluids with the purpose of cosmetic body modelling. Its consequences lead to ulceration, disfigurement and even death, and it has reached epidemic proportions in several regions of the world. We describe a series of patients treated for FMARs in a specialised wound care centre and a thorough review of the literature. A retrospective chart review was performed from January 1999 to September 2015 of patients who had been injected with non-medical foreign agents and who developed cutaneous ulceration needing treatment at the dermatology wound care centre. This study involved 23 patients whose ages ranged from 22 to 67 years with higher proportion of women and homosexual men. The most commonly injected sites were the buttocks (38.5%), legs (18%), thighs (15.4%) and breasts (11.8%). Mineral oil (39%) and other unknown substances (30.4%) were the most commonly injected. The latency period ranged from 1 week to 17 years. Complications included several skin changes such as sclerosis and ulceration as well as systemic complications. FMAR is a severe syndrome that may lead to deadly complications, and is still very common in Latin America. PMID- 27488811 TI - An epitope-imprinted piezoelectric diagnostic tool for Neisseria meningitidis detection. AB - Neisseria meningitidis, a human-specific bacterial pathogen causes bacterial meningitis by invading the meninges (outer lining) of central nervous system. It is the polysaccharide present on the bacterial capsid that distinguishes various serogroups of N. meningitidis and can be utilized as antigens to elicit immune response. A computational approach identified candidate T-cell epitopes from outer membrane proteins Por B of N. meningitidis (MC58): (273 KGLVDDADI282 in loop VII and 170 GRHNSESYH179 in loop IV) present on the exposed surface of immunogenic loops of class 3 outer membrane proteins allele of N. meningitidis. One of them, KGLVDDADI is used here for designing a diagnostic tool via molecularly imprinted piezoelectric sensor (molecularly imprinted polymer-quartz crystal microbalance) for N. meningitidis strain MC58. Methacrylic acid, ethylene glycol dimethacrylate and azoisobutyronitrile were used as functional monomer, cross-linker and initiator, respectively. The epitope can be simultaneously bound to methacrylic acid and fitted into the shape-selective cavities. On extraction of epitope sequence from thus grafted polymeric film, shape-selective and sensitive sites were generated on electrochemical quartz crystal microbalance crystal, ie, known as epitope imprinted polymers. Imprinting was characterized by atomic force microscopy images. The epitope-imprinted sensor was able to selectively bind N. meningitidis proteins present in blood serum of patients suffering from brain fever. Thus, fabricated sensor can be used as a diagnostic tool for meningitis disease. PMID- 27488812 TI - Skin protective effect of guava leaves against UV-induced melanogenesis via inhibition of ORAI1 channel and tyrosinase activity. AB - Ultraviolet (UV) irradiation is a major environmental factor affecting photoageing, which is characterized by skin wrinkle formation and hyperpigmentation. Although many factors are involved in the photoageing process, UV irradiation is thought to play a major role in melanogenesis. Tyrosinase is the key enzyme in melanin synthesis; therefore, many whitening agents target tyrosinase through various mechanisms, such as direct interference of tyrosinase catalytic activity or inhibition of tyrosinase mRNA expression. Furthermore, the highly selective calcium channel ORAI1 has been shown to be associated with UV induced melanogenesis. Thus, ORAI1 antagonists may have applications in the prevention of melanogenesis. Here, we aimed to identify the antimelanogenesis agents from methanolic extract of guava leaves (Psidium guajava) that can inhibit tyrosinase and ORAI1 channel. The n-butanol (47.47%+/-7.503% inhibition at 10 MUg/mL) and hexane (57.88%+/-7.09% inhibition at 10 MUg/mL) fractions were found to inhibit ORAI1 channel activity. In addition, both fractions showed effective tyrosinase inhibitory activity (68.3%+/-0.50% and 56.9%+/-1.53% inhibition, respectively). We also confirmed that the hexane fraction decreased the melanin content induced by UVB irradiation and the ET-1-induced melanogenesis in murine B16F10 melanoma cells. These results suggest that the leaves of P. guajava can be used to protect against direct and indirect UV-induced melanogenesis. PMID- 27488813 TI - Cadaver-Based Simulation Increases Resident Confidence, Initial Exposure to Fundamental Techniques, and May Augment Operative Autonomy. AB - OBJECTIVE: Surgical simulation is an important adjunct in surgical education. The majority of operative procedures can be simplified to core components. This study aimed to quantify a cadaver-based simulation course utility in improving exposure to fundamental maneuvers, resident and attending confidence in trainee capability, and if this led to earlier operative independence. DESIGN: A list of fundamental surgical procedures was established by a faculty panel. Residents were assigned to a group led by a chief resident. Residents performed skills on cadavers appropriate for PGY level. A video-recorded examination where they narrated and demonstrated a task independently was then graded by attendings using standardized rubrics. Participants completed surveys regarding improvements in knowledge and confidence. SETTING: The course was conducted at the Emory University School of Medicine and the T3 Laboratories in Atlanta, GA. PARTICIPANTS: A total of 133 residents and 41 attendings participated in the course. 133 (100%) participating residents and 32 (78%) attendings completed surveys. RESULTS: Resident confidence in completing the assigned skill independently increased from 3 (2-3) to 4 (3-4), p < 0.01. Residents stated that a median of 40% (interquartile range: 20%-60%) of procedures were performed for the first time in the course, and the same number had been performed only in the course. The percentage of skills attendings believed residents could perform independently increased from 40% (40%-60%) to 60% (60%->80%), p < 0.04. Attendings were more likely to grant autonomy in the operating room after this exercise (4 [3-5]). CONCLUSIONS: A cadaveric skills course focused on fundamental maneuvers with objective confirmation of success is a viable adjunct to clinical operative experience. Residents were formally exposed to fundamental surgical maneuvers earlier as a result of this course. This activity improved both resident and attending confidence in trainee operative skill, resulting in increased attending willingness to grant a higher level of autonomy in the operating room. PMID- 27488814 TI - Diffusion of Robotic Technology Into Urologic Practice has Led to Improved Resident Physician Robotic Skills. AB - OBJECTIVE: To investigate whether propagation of robotic technology into urologic practice and training programs has improved baseline urology resident trainee robotic skills. DESIGN: Questionnaires were completed by each urology resident trainee participating in a training course and asked about access to robotic simulation, robot experience, and console time. Baseline resident trainee scores on the Mimic Robotic Simulator (Mimic Technologies, Inc., Seattle, WA) from 27 participants of 2012 course were compared with the 2015 scores of 34 trainees on 4 standard Mimic exercises using Wilcoxon rank-sum tests. p = 0.05 or less were considered statistically significant. PARTICIPANTS AND SETTING: Totally, 34 resident trainees from 17 programs in the Southeast Section of the American Urological Association participated in an annual 2-day robotic training course. RESULTS: Overall score, economy of motion score, and time to complete exercise were all significantly better in the 2015 trainee group compared with the 2012 trainee group (p < 0.001) for the Peg Board 1, Camera Targeting 2, and Energy Dissection exercises. Overall scores for needle targeting improved between 2012 and 2015 (p = 0.04). Trainee access to a simulator was not associated with overall score on any of the 4 exercises in the 2015 group. In the 2015 group, actual robotic console time was associated with better overall scores in Camera Targeting 2 (p = 0.02) and Peg Board 1 (p = 0.04). CONCLUSIONS: Baseline resident trainee performance on basic robotic simulator exercises has improved over the past 3 years irrespective of robotic simulator access or console time. PMID- 27488815 TI - Editorial introduction. PMID- 27488816 TI - Heterochromatin compaction is regulated by Suv4-20h1 to maintains skeletal muscle stem cells quiescence. AB - In this report, Boonsanay and colleagues describe a novel mechanism of maintenance of skeletal muscle stem cells [also known as satellite cells (SCs)] quiescence via the di-methyltransferase Suv4-20h1, regulator of heterochromatin formation. Conditional ablation of Suv4-20h1 in SCs leads notably to the loss of the histone modification H4K20me2 on the distal regulatory element of Myod combined with a relocation of the Myod locus toward a central position in the nucleus. This switch in nuclear compartment is correlated with decreased facultative H3K27me3 associated heterochromatin, and an increase in spontaneously activated MYOD-expressing SCs in homeostatic muscles. Consequently, Suv4-20h1 knock-out SCs demonstrate compromised stem cell potential, as they fail to efficiently self-renew and replenish the SC pool upon muscle injury. Strikingly, restoring MYOD expression alone rescues the levels of facultative chromatin and reverses the loss-of-quiescence phenotype. PMID- 27488817 TI - Extensive Lobular Carcinoma In Situ with Pagetoid Spread into Multiple Papillomas of the Breast. PMID- 27488818 TI - Transcriptome landscape of Synechococcus elongatus PCC 7942 for nitrogen starvation responses using RNA-seq. AB - The development of high-throughput technology using RNA-seq has allowed understanding of cellular mechanisms and regulations of bacterial transcription. In addition, transcriptome analysis with RNA-seq has been used to accelerate strain improvement through systems metabolic engineering. Synechococcus elongatus PCC 7942, a photosynthetic bacterium, has remarkable potential for biochemical and biofuel production due to photoautotrophic cell growth and direct CO2 conversion. Here, we performed a transcriptome analysis of S. elongatus PCC 7942 using RNA-seq to understand the changes of cellular metabolism and regulation for nitrogen starvation responses. As a result, differentially expressed genes (DEGs) were identified and functionally categorized. With mapping onto metabolic pathways, we probed transcriptional perturbation and regulation of carbon and nitrogen metabolisms relating to nitrogen starvation responses. Experimental evidence such as chlorophyll a and phycobilisome content and the measurement of CO2 uptake rate validated the transcriptome analysis. The analysis suggests that S. elongatus PCC 7942 reacts to nitrogen starvation by not only rearranging the cellular transport capacity involved in carbon and nitrogen assimilation pathways but also by reducing protein synthesis and photosynthesis activities. PMID- 27488819 TI - Septic arthritis of the knee due to Raoultella ornithinolytica. PMID- 27488820 TI - Pleural fluid adenosine deaminase/serum C-reactive protein ratio for the differentiation of tuberculous and parapneumonic effusions with neutrophilic predominance and high adenosine deaminase levels. AB - PURPOSE: Tuberculous pleural effusion (TPE) and parapneumonic effusion (PPE) are usually distinguished by cellular predominance and pleural fluid adenosine deaminase (ADA) levels. However, both diseases may occasionally show similar neutrophilic predominance and high ADA levels. In such cases, the differential diagnosis between TPE and PPE is challenging and has been rarely investigated. METHODS: A retrospective study was conducted on TPE and PPE patients with neutrophilic exudate and pleural fluid ADA levels >=40 U/L. Individual and combined parameters of routine blood and pleural fluid tests were compared between the two groups, and receiver operating characteristic (ROC) curves were constructed for identifying TPE. RESULTS: Thirty-six TPE and 41 PPE patients were included. White blood cell counts, serum C-reactive protein (S-CRP), and pleural fluid pH, lactate dehydrogenase, and ADA levels showed significant difference between the two groups (p < 0.001). Among multiple parameters, pleural fluid ADA/S-CRP ratio, which best reflected different local and systemic characteristics between TPE and PPE, provided the highest diagnostic accuracy with an area under the ROC curve of 0.93. At a cutoff value of 5.62, ADA/S-CRP ratio had a sensitivity of 89 %, specificity of 88 %, positive likelihood ratio of 7.29, and negative likelihood ratio of 0.13 for identifying TPE. Additionally, more than half of TPE patients had a ratio above 15.82, while none of PPE patients showed such findings. CONCLUSIONS: Pleural fluid ADA/S-CRP ratio, as a simple method using routine laboratory tests, may be helpful in discriminating between TPE and PPE patients with neutrophilic predominance and ADA >=40 U/L. PMID- 27488821 TI - Effects of Physical Exercise on the Intestinal Mucosa of Rats Submitted to a Hypothalamic Obesity Condition. AB - The small intestine plays a role in obesity as well as in satiation. However, the effect of physical exercise on the morphology and function of the small intestine during obesity has not been reported to date. This study aimed to evaluate the effects of physical exercise on morphological aspects of the rat small intestine during hypothalamic monosodium glutamate (MSG)-induced obesity. The rats were divided into four groups: Sedentary (S), Monosodium Glutamate (MSG), Exercised (E), and Exercised Monosodium Glutamate (EMSG). The MSG and EMSG groups received a daily injection of monosodium glutamate (4 g/kg) during the 5 first days after birth. The S and E groups were considered as control groups and received injections of saline. At weaning, at 21 days after birth, the EMSG and E groups were submitted to swimming practice 3 times a week until the 90th day, when all groups were sacrificed and the parameters studied recorded. Exercise significantly reduced fat deposits and the Lee Index in MSG-treated animals, and also reduced the thickness of the intestinal wall, the number of goblet cells and intestinal alkaline phosphatase activity. However, physical activity alone increased the thickness and height of villi, and the depth of the crypts. In conclusion, regular physical exercise may alter the morphology or/and functions of the small intestine, reducing the prejudicial effects of hypothalamic obesity. Anat Rec, 299:1389-1396, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27488822 TI - Self-Healing Hydrogels. AB - Over the past few years, there has been a great deal of interest in the development of hydrogel materials with tunable structural, mechanical, and rheological properties, which exhibit rapid and autonomous self-healing and self recovery for utilization in a broad range of applications, from soft robotics to tissue engineering. However, self-healing hydrogels generally either possess mechanically robust or rapid self-healing properties but not both. Hence, the development of a mechanically robust hydrogel material with autonomous self healing on the time scale of seconds is yet to be fully realized. Here, the current advances in the development of autonomous self-healing hydrogels are reviewed. Specifically, methods to test self-healing efficiencies and recoveries, mechanisms of autonomous self-healing, and mechanically robust hydrogels are presented. The trends indicate that hydrogels that self-heal better also achieve self-healing faster, as compared to gels that only partially self-heal. Recommendations to guide future development of self-healing hydrogels are offered and the potential relevance of self-healing hydrogels to the exciting research areas of 3D/4D printing, soft robotics, and assisted health technologies is highlighted. PMID- 27488823 TI - Does screening for and intervening with multiple health compromising behaviours and mental health disorders amongst young people attending primary care improve health outcomes? A systematic review. AB - BACKGROUND: Adolescence and young adulthood are important developmental periods. Screening for health compromising behaviours and mental health disorders during routine primary care visits has the potential to assist clinicians to identify areas of concern and provide appropriate interventions. The objective of this systematic review is to investigate whether screening and subsequent interventions for multiple health compromising behaviours and mental health disorders in primary care settings improves the health outcomes of young people. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines, literature searches were conducted in Medline, PsycINFO, Scopus and Cochrane Library databases (Prospero registration number CRD42013005828) using search terms representing four thematic concepts: primary care, young people, screening, and mental health and health compromising behaviour. To be eligible for inclusion, studies had to: include a measure of health outcome; include at least 75 % of participants aged under 25 years; use a screening tool that assessed more than one health domain; and be conducted within a primary care setting. Risk of bias was assessed using the Quality Rating Scale. RESULTS: From 5051 articles identified, nine studies fulfilled the inclusion criteria and were reviewed: two randomised controlled trials (RCTs), one pilot RCT, two clustered RCTs, one randomised study with multiple intervention groups and no control group, one cluster RCT with two active arms, one longitudinal study and one pre-post study. Seven studies, including two RCTs and one clustered RCT, found positive changes in substance use, diet, sexual health or risky sexual behaviour, alcohol-related risky behaviour, social stress, stress management, helmet use, sleep and exercise. Of only two studies reporting on harms, one reported a negative health outcome of increased alcohol use. CONCLUSIONS: There is some evidence that the use of screening and intervention with young people for mental health disorder or health compromising behaviours in clinical settings improves health outcomes. Along with other evidence that young people value discussions of health risks with their providers, these discussions should be part of the routine primary care of young people. Further quality studies are needed to strengthen this evidence. PMID- 27488824 TI - Dulaglutide in the treatment of adult type 2 diabetes: a perspective for primary care providers. AB - Approximately 90% of T2D patients in the US are diagnosed and treated in the primary care setting, and the majority of the burden of disease management falls to primary care providers. Here, we discuss the clinical data for once weekly dulaglutide, e.g. the results of seven completed Phase 3 trials, patient preference studies, patient reported outcomes (PRO), and clinical data surrounding the dulaglutide administration device. Dulaglutide 1.5 mg once weekly demonstrated superiority to placebo, metformin, sitagliptin, exenatide BID, and insulin glargine (in 2 trials), and non-inferiority to liraglutide in reduction of HbA1c from baseline, with an acceptable safety profile. Dulaglutide-treated patients achieved the composite endpoint of an HbA1c <7.0% with no hypoglycemia, no severe hypoglycemia, and no weight gain significantly more than metformin, sitagliptin, exenatide BID or insulin glargine treated patients. Dulaglutide consistently showed an early onset of glycemic control, lasting up to 104 weeks. Additionally, PRO and patient preference data support the benefit of once weekly dulaglutide for the treatment of T2D. PMID- 27488825 TI - US officials issue travel alert for Miami area as Zika cases rise to 15. PMID- 27488826 TI - Safety Assessment of Hydroxypropyl Bis(N-Hydroxyethyl-p-Phenylenediamine) HCl as Used in Cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (CIR Panel) reviewed the safety of hydroxypropyl bis(N-Hydroxyethyl-p-Phenylenediamine) HCl, which functions as an oxidative hair dye ingredient. The Panel considered relevant animal and human data provided in this safety assessment and concluded that hydroxypropyl bis(N hydroxyethyl-p-phenylenediamine) HCl is safe for use in oxidative hair dye formulations as described in this safety assessment. PMID- 27488827 TI - The natural history of cutaneous propionibacteria, and reclassification of selected species within the genus Propionibacterium to the proposed novel genera Acidipropionibacterium gen. nov., Cutibacterium gen. nov. and Pseudopropionibacterium gen. nov. AB - The genus Propionibacterium in the family Propionibacteriaceaeconsists of species of various habitats, including mature cheese, cattle rumen and human skin. Traditionally, these species have been grouped as either classical or cutaneous propionibacteria based on characteristic phenotypes and source of isolation. To re-evaluate the taxonomy of the family and to elucidate the interspecies relatedness we compared 162 public whole-genome sequences of strains representing species of the family Propionibacteriaceae. We found substantial discrepancies between the phylogenetic signals of 16S rRNA gene sequence analysis and our high resolution core-genome analysis. To accommodate these discrepancies, and to address the long-standing issue of the taxonomically problematic Propionibacterium propionicum, we propose three novel genera, Acidipropionibacterium gen. nov., Cutibacterium gen. nov. and Pseudopropionibacterium gen. nov., and an amended description of the genus Propionibacterium. Furthermore, our genome-based analyses support the amounting evidence that the subdivision of Propionibacterium freudenreichii into subspecies is not warranted. Our proposals are supported by phylogenetic analyses, DNA G+C content, peptidoglycan composition and patterns of the gene losses and acquisitions in the cutaneous propionibacteria during their adaptation to the human host. PMID- 27488830 TI - Indirect Calorimetry in Mechanically Ventilated Patients: A Prospective, Randomized, Clinical Validation of 2 Devices Against a Gold Standard. AB - BACKGROUND AND AIMS: The 2 currently available indirect calorimeters, CCM Express Indirect Calorimeter (MedGraphics, St Paul, MN) and Quark RMR ICU Indirect Calorimeter (COSMED, Rome, Italy), have not been validated against a gold standard in mechanically ventilated patients. Our aim was to do so using a gold standard, modified Tissot bell-spirometer method in mechanically ventilated patients who were hemodynamically, respiratory, and metabolically stable. METHODS: We studied 30 patients undergoing general anesthesia and major gynecological surgery. We measured oxygen consumption ([Formula: see text]O2) and resting energy expenditure (REE) in a randomized, sequential, crossover design with double determination of each device. RESULTS: Compared with the modified Tissot bell-spirometer, the CCM Express Indirect Calorimeter demonstrated a mean Delta-REE of +361 kcal/d, corresponding to a 31% overestimation of energy requirements. Bland-Altman analysis for REE showed a mean (SD) bias of 384 (124) with limits of agreement 142-627 kcal/d. QUARK RMR ICU demonstrated a mean Delta REE of 81 kcal/d, corresponding to a 7% overestimation of energy requirements. Bland-Altman plot analysis showed a mean (SD) bias of 77 (167) with limits of agreement -249 to 404 kcal/d. CONCLUSIONS: The QUARK RMR ICU Indirect Calorimeter compared better with the gold standard for values of [Formula: see text]O2 and REE than did the CCM Express Indirect Calorimeter in mechanically ventilated patients who were circulatory and respiratory stable. Both indirect calorimeters had low precision. PMID- 27488829 TI - Development and Validation of a Method for Alcohol Analysis in Brain Tissue by Headspace Gas Chromatography with Flame Ionization Detector. AB - Ethanol is the most widely used and abused drug. While blood is the preferred specimen for analysis, tissue specimens such as brain serve as alternative specimens for alcohol analysis in post-mortem cases where blood is unavailable or contaminated. A method was developed using headspace gas chromatography with flame ionization detection (HS-GC-FID) for the detection and quantification of ethanol, acetone, isopropanol, methanol and n-propanol in brain tissue specimens. Unfixed volatile-free brain tissue specimens were obtained from the Department of Pathology at Virginia Commonwealth University. Calibrators and controls were prepared from 4-fold diluted homogenates of these brain tissue specimens, and were analyzed using t-butanol as the internal standard. The chromatographic separation was performed with a Restek BAC2 column. A linear calibration was generated for all analytes (mean r2 > 0.9992) with the limits of detection and quantification of 100-110 mg/kg. Matrix effect from the brain tissue was determined by comparing the slopes of matrix prepared calibration curves with those of aqueous calibration curves; no significant differences were observed for ethanol, acetone, isopropanol, methanol and n-propanol. The bias and the CVs for all volatile controls were <=10%. The method was also evaluated for carryover, selectivity, interferences, bench-top stability and freeze-thaw stability. The HS GC-FID method was determined to be reliable and robust for the analysis of ethanol, acetone, isopropanol, methanol and n-propanol concentrations in brain tissue, effectively expanding the specimen options for post-mortem alcohol analysis. PMID- 27488828 TI - Marked changes in dendritic structure and spine density precede significant neuronal death in vulnerable cortical pyramidal neuron populations in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is characterised by the death of upper (corticospinal) and lower motor neurons (MNs) with progressive muscle weakness. This incurable disease is clinically heterogeneous and its aetiology remains unknown. Increased excitability of corticospinal MNs has been observed prior to symptoms in human and rodent studies. Increased excitability has been correlated with structural changes in neuronal dendritic arbors and spines for decades. Here, using a modified Golgi-Cox staining method, we have made the first longitudinal study examining the dendrites of pyramidal neurons from the motor cortex, medial pre-frontal cortex, somatosensory cortex and entorhinal cortex of hSOD1(G93A) (SOD1) mice compared to wild-type (WT) littermate controls at postnatal (P) days 8-15, 28-35, 65-75 and 120. Progressive decreases in dendritic length and spine density commencing at pre-symptomatic ages (P8-15 or P28-35) were observed in layer V pyramidal neurons within the motor cortex and medial pre frontal cortex of SOD1 mice compared to WT mice. Spine loss without concurrent dendritic pathology was present in the pyramidal neurons of the somatosensory cortex from disease-onset (P65-75). Our results from the SOD1 model suggest that dendritic and dendritic spine changes foreshadow and underpin the neuromotor phenotypes present in ALS and may contribute to the varied cognitive, executive function and extra-motor symptoms commonly seen in ALS patients. Determining if these phenomena are compensatory or maladaptive may help explain differential susceptibility of neurons to degeneration in ALS. PMID- 27488831 TI - Mass production of shaped particles through vortex ring freezing. AB - A vortex ring is a torus-shaped fluidic vortex. During its formation, the fluid experiences a rich variety of intriguing geometrical intermediates from spherical to toroidal. Here we show that these constantly changing intermediates can be 'frozen' at controlled time points into particles with various unusual and unprecedented shapes. These novel vortex ring-derived particles, are mass produced by employing a simple and inexpensive electrospraying technique, with their sizes well controlled from hundreds of microns to millimetres. Guided further by theoretical analyses and a laminar multiphase fluid flow simulation, we show that this freezing approach is applicable to a broad range of materials from organic polysaccharides to inorganic nanoparticles. We demonstrate the unique advantages of these vortex ring-derived particles in several applications including cell encapsulation, three-dimensional cell culture, and cell-free protein production. Moreover, compartmentalization and ordered-structures composed of these novel particles are all achieved, creating opportunities to engineer more sophisticated hierarchical materials. PMID- 27488832 TI - Ultrasound-guided percutaneous lavage of calcific bursitis of the medial collateral ligament of the knee: a case report and review of the literature. AB - OBJECTIVES: Calcification of the medial collateral ligament (MCL) of the knee is rare. The literature reports no positive outcomes when conservative treatment has been followed. This paper reports a case of such calcification and its treatment using ultrasound-guided percutaneous lavage (UGPL). METHODS: A 66-year-old patient presented with medial knee pain. X-ray, ultrasound, and magnetic resonance (MR) examinations revealed calcific bursitis of the MCL, which was treated by UGPL. RESULTS: One month after treatment the patient was asymptomatic. X-ray, ultrasound, and MR examinations confirmed the almost complete disappearance of the calcification; only very tiny fragments remained. CONCLUSIONS: Calcific bursitis of the MCL of the knee is very uncommon, but should be taken into account in differential diagnoses for medial knee pain. UGPL is proposed as a treatment for this condition. PMID- 27488833 TI - Comparison of MRI and PET-CT in detecting the loco-regional recurrence of soft tissue sarcomas during surveillance. AB - OBJECTIVE: To investigate the diagnostic performance of MRI and PET-CT for the detection of loco-regional recurrences after soft tissue sarcoma (STS) excision. MATERIALS AND METHODS: From Dec 2003 to Aug 2014, 394 patients with STSs, who were included in the electronic patient registry for initial or repeated surgery at our hospital, were retrospectively reviewed. We identified 152 patients who underwent regular postoperative follow-ups with both MRI and PET-CT, obtained within a 3 month period of each other. We analyzed differences in the performance of MRI and PET-CT for the diagnosis of loco-regional recurrences using McNemar's test. The receiver-operating characteristic curves and calculations of the area under the curve were used. RESULTS: Twenty patients were found to have a loco regional recurrence after tumor excision. For MRI and PET-CT, the sensitivities were 90.0 and 95.0 %, and the specificities 97.7 and 95.5 %, respectively, with positive predictive values of 85.7 and 76.0 % and negative predictive values of 98.5 and 99.2 %, respectively. No significant difference was detected between the sensitivities of MRI and PET-CT (p = 0.125). The area under the receiver operating characteristic curve for PET-CT (0.952) was not significantly greater than that for MRI (0.939; p = 0.6). CONCLUSION: MRI of the area of interest is recommended for evaluation of tumor recurrence after surgical excision of STS. PET-CT was shown to be effective for detection of STS recurrence, and comparable to MRI. However, if PET-CT or MRI findings are inconclusive, the other modality may be helpful in differentiating tumor recurrence from post-therapeutic tissue change. PMID- 27488834 TI - Casein kinase 1alpha has a non-redundant and dominant role within the CK1 family in melanoma progression. AB - BACKGROUND: We previously identified CK1alpha as a novel tumor suppressor in melanoma and reported that the loss of CK1alpha leads to increased proliferation and invasive growth of melanoma cells by strong activation of the Wnt/beta catenin signaling pathway. METHODS: In this study we analyzed expression and the functional effects of the dominantly expressed CK1- isoforms alpha, delta and epsilon in melanoma cells by quantitative real-time PCR, western blot and immunohistochemistry. We down-regulated CK1 kinase activity with isoform specific siRNAs and small molecule inhibitors. Vice versa we overexpressed the CK1 isoforms alpha, delta and epsilon using viral vectors and tested the biological effects on melanoma cell proliferation, migration and invasion. RESULTS: We show that protein expression of all three CK1-isoforms is downregulated in metastatic melanoma cells compared to benign melanocytic cells. Furthermore, the CK1delta and epsilon isoforms are able to negatively regulate expression of each other, whereas CK1alpha expression is independently regulated in melanoma cells. Inhibition of the expression and activity of CK1delta or CK1epsilon by specific inhibitors or siRNAs had no significant effect on the growth and survival of metastatic melanoma cells. Moreover, the over-expression of CK1delta or CK1epsilon in melanoma cells failed to induce cell death and cell cycle arrest although p53 signaling was activated. This is in contrast to the effects of CK1alpha where up-regulated expression induces cell death and apoptosis in metastatic melanoma cells. CONCLUSION: These data indicate that CK1alpha has a dominant and non-redundant function in melanoma cells and that the CK1delta and epsilon isoforms are not substantially involved in melanoma progression. PMID- 27488835 TI - Family Qualities, Self-Deprecation, and Depressive Symptoms of Zoroastrian Young Adults in Immigrant Families. AB - The aim of this study was to examine family qualities and self-deprecation in relation to depressive symptoms of young adult Zoroastrians from immigrant families in North America. Using snowball sampling and online surveys, self report data were collected from 171 Zoroastrian young adults (i.e., 18-30 years old) about their perception of cohesion in their families, conflict with their parents, and the extent that they met parental general expectations (e.g., not embarrassing the family). The findings from a path analysis showed that parent child conflict and meeting parental expectations were indirectly related to depressive symptoms through self-deprecation. Also, higher family cohesion predicted lower levels of depressive symptoms among Zoroastrian young adults. These results are similar to findings in studies with non Zoroastrians. The results suggested prevention and interventions to decrease depressive symptoms could target self-deprecating thoughts as well as perceived family dynamics. PMID- 27488836 TI - Blood fatty acid patterns are associated with prostate cancer risk in a prospective nested case-control study. AB - BACKGROUND: Circulating fatty acids are highly correlated with each other, and analyzing fatty acid patterns could better capture their interactions and their relation to prostate cancer. We aimed to assess the associations between data derived blood fatty acid patterns and prostate cancer risk. METHODS: We conducted a nested case-control study in the Physicians' Health Study. Fatty acids levels were measured in whole blood samples of 476 cases and their matched controls by age and smoking status. Fatty acid patterns were identified using principal component analysis. Conditional logistic regression was used to estimate odds ratio (OR) and 95 % confidence interval (CI). RESULTS: Two patterns explaining 40.9 % of total variation in blood fatty acid levels were identified. Pattern 1, which mainly reflects polyunsaturated fatty acid metabolism, was suggestively positively related to prostate cancer risk (ORquintile 5 vs. quintile 1 = 1.37, 95 % CI = 0.91-2.05, P trend = 0.07). Pattern 2, which largely reflects de novo lipogenesis, was significantly associated with higher prostate cancer risk (ORquintile5 vs. quintile1 = 1.63, 95 % CI = 1.04-2.55, P trend = 0.02). This association was similar across tumor stage, grade, clinical aggressiveness categories and follow-up time. CONCLUSION: The two patterns of fatty acids we identified were consistent with known interactions between fatty acid intake and metabolism. A pattern suggestive of higher activity in the de novo lipogenesis pathway was related to higher risk of prostate cancer. PMID- 27488837 TI - A safe-repositioning maneuver for the management of benign paroxysmal positional vertigo: Gans vs. Epley maneuver; a randomized comparative clinical trial. AB - Benign paroxysmal positional vertigo (BPPV) is the most common cause of peripheral vertigo. Some repositioning maneuvers have been described for its management. The aim of this study was comparing the therapeutic effect of Epley and Gans maneuvers in BPPV. This randomized clinical trial was performed from September to December 2015. 73 patients with true vertigo diagnosed as BPPV enrolled the study. They randomly assigned in quadripartite blocks to modified Epley maneuver group (E) or Gans maneuver group (G). 1 day and 1 week after intervention, the objective and subjective responses to treatment were assessed. Statistical analysis was performed using the Chi-square test and regression model in the SPSS software version 21. Thirty patients enrolled each group with a mean age of 46.9 +/- 13.4 (E group) and 46.7 +/- 7.5 year (G group). 23.3 % of E group and 26.7 % of G group were men (p = 0.766). In E and G groups in the first day, subjective outcomes revealed 86.7 and 60 % rate of success (p = 0.02); and 86.7 and 56.7 % of patients exhibited objective improvement, respectively (p = 0.01). After 1 week, the subjective and objective outcomes revealed improvement among 70 % of E group and 46.7 % of G group (p = 0.067). The only complication with significant difference was cervical pain with a higher rate in E group (23.3 vs. 0.0 %, p = 0.005). These results revealed the similar long-term efficacy of Epley and Gans maneuver for the treatment of BPPV. Cervical pain was most frequent complication of Epley maneuver. PMID- 27488838 TI - Effects of aging on the relationship between cognitive demand and step variability during dual-task walking. AB - A U-shaped relationship between cognitive demand and gait control may exist in dual-task situations, reflecting opposing effects of external focus of attention and attentional resource competition. The purpose of the study was twofold: to examine whether gait control, as evaluated from step-to-step variability, is related to cognitive task difficulty in a U-shaped manner and to determine whether age modifies this relationship. Young and older adults walked on a treadmill without attentional requirement and while performing a dichotic listening task under three attention conditions: non-forced (NF), forced-right (FR), and forced-left (FL). The conditions increased in their attentional demand and requirement for inhibitory control. Gait control was evaluated by the variability of step parameters related to balance control (step width) and rhythmic stepping pattern (step length and step time). A U-shaped relationship was found for step width variability in both young and older adults and for step time variability in older adults only. Cognitive performance during dual tasking was maintained in both young and older adults. The U-shaped relationship, which presumably results from a trade-off between an external focus of attention and competition for attentional resources, implies that higher-level cognitive processes are involved in walking in young and older adults. Specifically, while these processes are initially involved only in the control of (lateral) balance during gait, they become necessary for the control of (fore-aft) rhythmic stepping pattern in older adults, suggesting that attentional resources turn out to be needed in all facets of walking with aging. Finally, despite the cognitive resources required by walking, both young and older adults spontaneously adopted a "posture second" strategy, prioritizing the cognitive task over the gait task. PMID- 27488839 TI - The predictive value of early acute kidney injury for long-term survival and quality of life of critically ill patients. AB - BACKGROUND: Prognostic factors for the combination of long-term survival and health-related quality of life (HRQoL) after intensive care unit (ICU) stay have not yet been studied. Our aim was to assess whether early acute kidney injury (eAKI), AKI occurring on the first day of ICU admission, is an independent predictor of this combined one-year outcome. METHODS: We included all patients admitted to the mixed ICU of the University Medical Centre Utrecht between July 2009 and April 2013, excluding patients with chronic dialysis, cardiac surgery, and length of stay shorter than 24 hours. eAKI was defined using the risk, injury, failure, loss, end-stage renal failure (RIFLE) classification, using a newly developed algorithm to classify AKI based on routinely collected patient data. In one-year survivors, HRQoL was measured using the EuroQoL 5D-3LTM (EQ-5D) questionnaire. The primary outcome measure was "poor outcome", defined as an EQ 5D index score <0.4 or death after one year follow up. A multivariable Poisson regression model was performed to adjust for age, comorbidities, admission type and severity of disease factors. RESULTS: We enrolled 2,420 patients, of whom 871 (36.0 %) died within one year. An additional 286 of 1549 one-year survivors (11.8 %) experienced low HRQoL. The respective incidence of the RIFLE classes, risk, injury and failure, were 456 (18.8 %), 253 (10.5 %) and 123 (5.1 %). After adjustment for other covariates, the RIFLE classes, injury and failure, were independently associated with poor outcome (adjusted relative risk 1.14, 95 % CI 1.01, 1.29; p = 0.03, and 1.25, 95 % CI 1.01, 1.55; p = 0.04), when compared to no eAKI patients . The constituents of this composite outcome were also analysed separately. In a Cox regression model the RIFLE classes, injury and failure, were significantly associated with mortality (adjusted hazard ratio 1.35, 95 % CI 1.11, 1.65; p <0.01, and 1.78, 95 % CI 1.38, 2.30; p <0.01). In one-year survivors specifically, none of the RIFLE classes were significantly associated with low HRQoL. CONCLUSIONS: ICU patients with moderate or severe AKI during the first 24 hours have a higher probability of mortality or low HRQoL (combined poor outcome), one year after ICU admission. Together with other available early prognostic factors, information on early acute kidney injury could improve informed decision-making on the continuation or withdrawal of treatment in ICU patients. PMID- 27488840 TI - Engaging diverse populations in biospecimen donation: results from the Hoy y Manana study. AB - The disproportionately lower number of certain subpopulations participating in clinical and prevention research has a significant impact on the representativeness of scientific outcomes. The Hoy y Manana program (Today and Tomorrow) was developed as a culturally and linguistically appropriate education program to engage diverse medically underserved populations without a cancer diagnosis in biospecimen donation for cancer genomic research. Participants were recruited to in-depth community-based educational programs (~45-60-min duration) or during open events in the community based on a convenience sampling. Programs were offered in English and Spanish. An on-site mobile lab along with phlebotomy services was provided at all programs and events to collect participant biospecimen (blood) samples to be stored at the cancer center's Data Bank and BioRepository (DBBR). The distributions for education, race/ethnicity, and gender were similar across the event types. Most of the participants were women. The analysis sample had a total of 311 participants, including 231 from the education programs and 80 participants from open events. Those with a higher education (college or more) were more likely to donate than those with a lower level of education (high school or less) (45 vs 28 %, p = 0.007). Actual donation status was not associated with age or race. Willingness to donate a biospecimen and biospecimen donation rates followed the same pattern with respect to participants with higher levels of education being more willing to donate and giving a blood donation. Prior to outreach efforts, less than 6 % of specimens donated to DBBR from healthy/non-cancer patients were from minority participants. PMID- 27488841 TI - Total knee arthroplasty in patients with Ranawat type-II valgus arthritic knee with a marked coronal femoral bowing deformity: comparison between computer assisted surgery and intra-articular resection. AB - BACKGROUND: Proper limb and component alignments as well as soft tissue balance are vital for the longevity and optimal long-term outcomes of total knee arthroplasty (TKA). This procedure is technically demanding in patients with Ranawat type-II valgus arthritic knees with marked coronal femoral bowing. Computer-assisted surgery (CAS) and intra-articular bone resection with TKA are the treatments of choice for patients with ipsilateral extra-articular deformity. In theory, both CAS and intra-articular bone resection are beneficial in Ranawat type-II valgus arthritic knees with marked coronal femoral bowing deformity, but the literature on this topic is sparse. We compared the benefits of using these two techniques for TKA under this circumstance. METHODS: Patients who had Ranawat type-II valgus arthritic knees and marked coronal femoral bowing deformity and had undergone TKA at our hospital between 2005 and 2013 were enrolled in this retrospective study. Patients treated with CAS were assigned to the CAS-TKA group; patients treated with intra-articular bone resection were assigned to the Bone-Resect-TKA group. Radiographic parameters and clinical outcomes (International Knee Society (IKS) scores and patellar scores) in both groups were compared. RESULTS: Forty-seven patients (50 knees) met the inclusion criteria: 22 knees in the CAS-TKA group and 28 knees in the Bone-Resect-TKA group. Lateral retinaculum release was significantly (P = 0.008) higher in the Bone-Resect-TKA group. The joint-line was significantly properly restored in the CAS-TKA group (P = 0.011). The reconstructed mechanical axis was significantly (P = 0.012) closer to normal in the CAS-TKA group than in the Bone-Resect-TKA group. For component alignment, the femoral valgus and femoral flexion angles were significantly better in the CAS-TKA group (P = 0.002 and P = 0.006, respectively), but not the tibial valgus, tibial flexion, or patellar tilting angles. IKS scores and patellar scores were not significantly different between groups at a mean follow up of 60.2 months. CONCLUSIONS: CAS-TKA was effective for obtaining proper alignment and joint-line restoration in patients with Ranawat type-II valgus arthritic knees and marked coronal femoral bowing deformity, but not for yielding better clinical outcomes. Additional large-scale prospective randomized cohort studies with long-term follow-ups are necessary to make evidence-based recommendations. PMID- 27488842 TI - Pre- and postoperative correlation of patient-reported outcome measures with standardized Timed Up and Go (TUG) test results in lumbar degenerative disc disease. AB - BACKGROUND: The Timed Up and Go (TUG) test is a reliable tool for evaluating objective functional impairment (OFI) in patients with degenerative disc disease before a surgical intervention. The aim of this study is to assess the validity of the TUG test to measure change in function postoperatively. METHODS: In a prospective two-center study, OFI was assessed by the TUG test in patients scheduled for lumbar spine surgery, as well as 3 days (D3) and 6 weeks (W6) postoperatively. At each time point, the TUG test results were correlated with established subjective measures of pain intensity (visual analogue scale (VAS) for back and leg pain), functional impairment (Oswestry Disability Index (ODI)) and health-related quality of life (HRQoL; Short Form-12 (SF12)). RESULTS: The patient cohort comprised 136 patients with a mean age of 57.7 years; 76 were males, 54 had a microdiscectomy for lumbar disc herniation, 58 a decompression for a lumbar spinal stenosis, 24 had a surgical fusion procedure. The mean OFI t score was 125.1 before surgery, and as patients improved on the subjective measures in the postoperative interval, the OFI t-score likewise decreased to 118.8 (D3) and 103.4 (W6). The Pearson correlation coefficient (PCC) between the OFI t-score and VAS leg pain was 0.187 preoperatively (p = 0.029) and 0.252 at W6 (p = 0.003). The PCC between OFI t-score and the ODI was 0.324 preoperatively (p < 0.001) and 0.413 at W6 (p < 0.001). The PCC between OFI t-score and physical HRQoL (SF12) was -0.091 preoperatively (p = 0.293) and -0.330 at W6 (p < 0.001). CONCLUSIONS: The TUG test is sensitive to change, and reflects the postoperative functional outcome even more exact than preoperatively, as indicated by better correlation coefficients of the OFI t-score with subjective measures of pain intensity, functional impairment and HRQoL. PMID- 27488843 TI - Effects of aging and freezing/thawing sequence on quality attributes of bovine Mm. gluteus medius and biceps femoris. AB - OBJECTIVE: The effects of aging and freezing/thawing sequence on color, physicochemical, and enzymatic characteristics of two beef muscles (Mm. gluteus medius, GM and biceps femoris, BF) were evaluated. METHODS: Beef muscles at 3 d postmortem were assigned to four different combinations of aging and freezing/thawing sequence as follows; aging at 2 degrees C for 3 wk (A3, never frozen control), freezing at -28 degrees C for 2 wk then thawing (F2, frozen/thawed-only), aging at 2 degrees C for 3 wk, freezing at -28 degrees C for 2 wk then thawing (A3F2), and freezing at -28 degrees C for 2 wk, thawing then further aging at 2 degrees C for 3 wk (F2A3). RESULTS: No significant interactions between different aging/freezing/thawing treatments and muscle type on all measurements were found. Postmortem aging, regardless of aging/freezing/thawing sequence, had no impact on color stability of frozen/thawed beef muscles (p<0.05). F2A3 resulted in higher purge loss than F2 and A3F2 treatments (p<0.05). A3F2 and F2A3 treatments resulted in lower shear force of beef muscles compared to F2 (p<0.05). Although there was no significant difference in glutathione peroxidase (GSH-Px) activity, F2A3 had the highest beta N-acetyl glucominidase (BNAG) activity in purge, but the lowest BNAG activity in muscle (p<0.05). GM muscle exhibited higher total color changes and purge loss, and lower GSH-Px activity than BF muscle. CONCLUSION: The results from this present study indicate that different combinations of aging/freezing/thawing sequence would result in considerable impacts on meat quality attributes, particularly thaw/purge loss and tenderness. Developing a novel freezing strategy combined with postmortem aging will be beneficial for the food/meat industry to maximize its positive impacts on tenderness, while minimizing thaw/purge loss of frozen/thawed meat. PMID- 27488844 TI - Effects of beta-Glucan on the Release of Nitric Oxide by Macrophages Stimulated with Lipopolysaccharide. AB - This research analyzed the effect of beta-glucan that is expected to alleviate the production of the inflammatory mediator in macrophagocytes, which are processed by the lipopolysaccharide (LPS) of Escherichia. The incubated layer was used for a nitric oxide (NO) analysis. The DNA-binding activation of the small unit of nuclear factor-kappaB was measured using the enzyme-linked immunosorbent assay-based kit. In the RAW264.7 cells that were vitalized by Escherichia coli (E. coli) LPS, the beta-glucan inhibited both the combatant and rendering phases of the inducible NO synthase (iNOS)-derived NO. beta-Glucan increased the expression of the heme oxygenase-1 (HO-1) in the cells that were stimulated by E. coli LPS, and the HO-1 activation was inhibited by the tin protoporphyrin IX (SnPP). This shows that the NO production induced by LPS is related to the inhibition effect of beta-glucan. The phosphorylation of c-Jun N-terminal kinases (JNK) and the p38 induced by the LPS were not influenced by the beta-glucan, and the inhibitory kappaB-alpha (IkappaB-alpha) decomposition was not influenced either. Instead, beta-glucan remarkably inhibited the phosphorylation of the signal transducer and activator of transcription-1 (STAT1) that was induced by the E. coli LPS. Overall, the beta-glucan inhibited the production of NO in macrophagocytes that was vitalized by the E .coli LPS through the HO-1 induction and the STAT1 pathways inhibition in this research. As the host immune response control by beta-glucan weakens the progress of the inflammatory disease, beta glucan can be used as an effective immunomodulator. PMID- 27488845 TI - Effects of Physically Effective Neutral Detergent Fiber Content on Intake, Digestibility, and Chewing Activity in Fattening Heifer Fed Total Mixed Ration. AB - The objective of this study was to determine the effects of physically effective neutral detergent fiber (peNDF) content in total mixed ration (TMR) on dry matter intake, digestibility, and chewing activity in fattening Hanwoo (Bos taurus coreanae) heifers. The experiment was designed as a replicated 3*3 Latin square using 12 heifers. Fattening heifers were offered one of three diets [high (T1), medium (T2), and low (T3) peNDF] obtained by different mixing times (3, 10, and 25 min) for the same TMR feed. The peNDF content of TMR was determined by multiplying the proportion of dry matter retained by a 1.18 mm-screen in a Penn State Particle Separator by the dietary NDF content. The peNDF1.18 content was 30.36%, 29.20%, and 27.50% for the T1, T2, and T3 diets, respectively (p<0.05). Dry matter intake was not affected by peNDF content in TMR. Total weight gain in T1 group was significantly higher (p<0.05) than in T2 and T3 groups. However, weight gain did not differ between T2 and T3 groups. The feed conversion ratio decreased with an increase in the peNDF content (T1: 12.18, T2: 14.17, and T3: 14.01 g/g). An increase in the peNDF content of TMR was associated with a linear increase in the digestibility of dry matter, crude protein, crude fiber, neutral detergent fiber, and acid detergent fiber (p<0.05). Also, an increase in peNDF content of the TMR resulted in a linear increase in the number of chews in eating and ruminating (p<0.05), and consequently in the number of total chews (p<0.05). These results indicate that peNDF content affects digestibility and chewing activity. Consequently, the peNDF content of TMR should be considered for improving feed efficiency, digestibility, body weight gain, and performance in fattening heifers. PMID- 27488847 TI - Distinct transcriptional regulation of the two Escherichia coli transhydrogenases PntAB and UdhA. AB - Transhydrogenases catalyse interconversion of the redox cofactors NADH and NADPH, thereby conveying metabolic flexibility to balance catabolic NADPH formation with anabolic or stress-based consumption of NADPH. Escherichia coli is one of the very few microbes that possesses two isoforms: the membrane-bound, proton translocating transhydrogenase PntAB and the cytosolic, energy-independent transhydrogenase UdhA. Despite their physiological relevance, we have only fragmented information on their regulation and the signals coordinating their counteracting activities. Here we investigated PntAB and UdhA regulation by studying transcriptional responses to environmental and genetic perturbations. By testing pntAB and udhA GFP reporter constructs in the background of WT E. coli and 62 transcription factor mutants during growth on different carbon sources, we show distinct transcriptional regulation of the two transhydrogenase promoters. Surprisingly, transhydrogenase regulation was independent of the actual catabolic overproduction or underproduction of NADPH but responded to nutrient levels and growth rate in a fashion that matches the cellular need for the redox cofactors NADPH and/or NADH. Specifically, the identified transcription factors Lrp, ArgP and Crp link transhydrogenase expression to particular amino acids and intracellular concentrations of cAMP. The overall identified set of regulators establishes a primarily biosynthetic role for PntAB and link UdhA to respiration. PMID- 27488848 TI - Out of the corner of the driver's eye: Peripheral processing of hazards in static traffic scenes. AB - Effective gaze control in traffic, based on peripheral visual information, is important to avoid hazards. Whereas previous hazard perception research mainly focused on skill-component development (e.g., orientation and hazard processing), little is known about the role and dynamics of peripheral vision in hazard perception. We analyzed eye movement data from a study in which participants scanned static traffic scenes including medium-level versus dangerous hazards and focused on characteristics of fixations prior to entering the hazard region. We found that initial saccade amplitudes into the hazard region were substantially longer for dangerous (vs. medium-level) hazards, irrespective of participants' driving expertise. An analysis of the temporal dynamics of this hazard-level dependent saccade targeting distance effect revealed that peripheral hazard-level processing occurred around 200-400 ms during the course of the fixation prior to entering the hazard region. An additional psychophysical hazard detection experiment, in which hazard eccentricity was manipulated, revealed better detection for dangerous (vs. medium-level) hazards in both central and peripheral vision. Furthermore, we observed a significant perceptual decline from center to periphery for medium (but not for highly) dangerous hazards. Overall, the results suggest that hazard processing is remarkably effective in peripheral vision and utilized to guide the eyes toward potential hazards. PMID- 27488850 TI - Magnetic resonance imaging of pelvic floor dysfunction - joint recommendations of the ESUR and ESGAR Pelvic Floor Working Group. AB - OBJECTIVE: To develop recommendations that can be used as guidance for standardized approach regarding indications, patient preparation, sequences acquisition, interpretation and reporting of magnetic resonance imaging (MRI) for diagnosis and grading of pelvic floor dysfunction (PFD). METHODS: The technique included critical literature between 1993 and 2013 and expert consensus about MRI protocols by the pelvic floor-imaging working group of the European Society of Urogenital Radiology (ESUR) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) from one Egyptian and seven European institutions. Data collection and analysis were achieved in 5 consecutive steps. Eighty-two items were scored to be eligible for further analysis and scaling. Agreement of at least 80 % was defined as consensus finding. RESULTS: Consensus was reached for 88 % of 82 items. Recommended reporting template should include two main sections for measurements and grading. The pubococcygeal line (PCL) is recommended as the reference line to measure pelvic organ prolapse. The recommended grading scheme is the "Rule of three" for Pelvic Organ Prolapse (POP), while a rectocele and ARJ descent each has its specific grading system. CONCLUSION: This literature review and expert consensus recommendations can be used as guidance for MR imaging and reporting of PFD. KEY POINTS: * These recommendations highlight the most important prerequisites to obtain a diagnostic PFD-MRI. * Static, dynamic and evacuation sequences should be generally performed for PFD evaluation. * The recommendations were constructed through consensus among 13 radiologists from 8 institutions. PMID- 27488851 TI - Dynamic contrast enhanced MR imaging for evaluation of angiogenesis of hepatocellular nodules in liver cirrhosis in N-nitrosodiethylamine induced rat model. AB - PURPOSE: To investigate whether dynamic contrast -enhanced MRI (DCE-MRI) can distinguish the type of liver nodules in a rat model with N-nitrosodiethylamine- induced cirrhosis. METHODS: Liver nodules in cirrhosis were induced in 60 male Wistar rats via 0.01 % N-nitrosodiethylamine in the drinking water for 35-100 days. The nodules were divided into three groups: regenerative nodule (RN), dysplastic nodule (DN), and hepatocellular carcinoma (HCC). DCE-MRI was performed, and parameters including transfer constant (Ktrans), rate constant (Kep), extravascular extracellular space volume fraction (Ve), and initial area under the contrast concentration versus time curve (iAUC) were measured and compared. RESULTS: The highest Ktrans and iAUC values were seen in HCC, followed by DN and RN (all P < 0.05). The area under the receiver operating characteristic curve (AUROC) for DN and HCC were 0.738 and 0.728 for Ktrans and iAUC, respectively. The AUROC for HCC were 0.850 and 0.840 for Ktrans and iAUC, respectively. Ordinal logistic regression analysis showed that Ktrans had a high goodness of fit (0.970, 95 % confidence interval, 13.751-24.958). CONCLUSION: DCE MRI is a promising method to differentiate of liver nodules. Elevated Ktrans suggested that the nodules may be transformed into HCC. KEY POINTS: * DCE-MRI is promising for differentiating among RN, DN, and HCC * K trans and iAUC positively correlated with malignancy degree of liver nodules * Elevated K trans suggests that the nodules may be transformed into HCC. PMID- 27488852 TI - An evaluation of the current patterns and practices of educational supervision in postgraduate medical education in the UK. AB - INTRODUCTION: Globally, clinical supervision has been widely adopted and studied. But in the UK, another variant of supervision has developed in the form of educational supervision. The quality of supervision remains highly variable and inadequate time, investment and guidance hinders its ability to actually benefit trainees. Therefore, undertaking a detailed study of the patterns and practices in educational supervision to inform developments in supervisory practice would be extremely beneficial. METHODS: In this mixed methods study, educational supervisors and trainees working within a large London Trust were surveyed online about their experiences of educational supervision. In addition, observations of supervision sessions with a small group of supervisor and trainee pairs followed up by semi-structured interviews were conducted. The quantitative data were analyzed using statistical software via descriptive statistics. The qualitative data underwent thematic framework analysis. RESULTS: Both the qualitative and quantitative data revealed that whilst most junior doctors and supervisors value the ideal of educational supervision as a process for engaging in mentoring dialogues, it can become a tick box exercise, devaluing its usefulness and purpose. Trainees highlighted the need for more frequent formal meeting along with better preparation by supervisors. Supervisors would appreciate more support from trusts to help them enhance supervision for trainees. CONCLUSION: The effectiveness of educational supervision can be improved with trainees and supervisors engaging in meaningful preparation and proactive communication before meetings. During these formal meetings, improving the quality of feedback and ensuring that regular mentoring dialogues occurred would be highly valuable. PMID- 27488853 TI - Supercapacitors Based on Reduced Graphene Oxide Nanofibers Supported Ni(OH)2 Nanoplates with Enhanced Electrochemical Performance. AB - Pseudocapacitive materials are critical to the development of supercapacitors but usually suffer from poor conductivity and bad cycling property. Here, we describe the production of novel graphene oxide nanofibers (GONFs) via a partial oxidization and exfoliation method and concurrently report that highly crystallized Ni(OH)2 nanoplates uniformly grow on reduced GONFs' outer graphene nanosheets through the hydrothermal method. Because of their unique structure with high electric conductivity, the rGONF/Ni(OH)2 composite exhibits superior specific capacitance (SC), favorable rate capability and enhanced cycling stability relative to other composites or hybrids, e.g., 1433 F g(-1) at 5 mV s( 1) scan rate, 986 F g(-1) at 40 mV s(-1), and 90.5% capacitance retention after 2000 cycles, and as-fabricated rGONF/Ni(OH)2//active carbon asymmetric supercapacitor (ASC) exhibits a remarkable energy density and a 85.3% high retention (44.1 Wh kg(-1) at 467 W kg(-1) and 37.6 Wh kg(-1) at 3185 W kg(-1)) with a wide potential window of 0-1.7 V. Therefore, this study shows that rGONFs offers an exciting opportunity as substrate materials for supercapacior applications and opens up a new pathway for design and manufacture of novel supercapacitor electrode materials. PMID- 27488854 TI - Grueneberg Glomeruli in the Olfactory Bulb are Activated by Odorants and Cool Temperature. AB - Neurons of the Grueneberg ganglion respond to cool temperatures as well as to distinct odorants and extend axonal processes to the olfactory bulb of the brain. Analyses of transgenic mice, in which Grueneberg ganglion neurons and their axons are labeled, revealed that these axons innervated nine distinct glomeruli distributed in a characteristic topographical pattern in dorsal, lateral, ventral, and medial regions of rather posterior areas in the bulb. To assess activation of these glomeruli (hereinafter designated as Grueneberg glomeruli) upon stimulation of Grueneberg ganglion neurons, mice were exposed to the odorant 2,3-dimethylpyrazine (2,3-DMP) and the expression of the activity-dependent marker c-Fos in juxtaglomerular cells of the relevant glomeruli was monitored. It was found that all of these glomeruli were activated, irrespective of their localization in the bulb. To verify that the activation of juxtaglomerular cells in Grueneberg glomeruli was indeed based on stimulation of Grueneberg ganglion neurons, the 2,3-DMP-induced responses in these glomeruli were investigated in mice lacking the cyclic nucleotide-gated channel CNGA3 which is critical for chemo- and thermosensory signal transduction in Grueneberg ganglion neurons. This approach revealed that elimination of CNGA3 led to a reduction of the odorant induced activity in Grueneberg glomeruli, indicating that the activation of these glomeruli is based on a preceding stimulation of the Grueneberg ganglion. Analyzing whether Grueneberg glomeruli in the bulb might also process thermosensory information, it was found that upon exposure to coolness, Grueneberg glomeruli were activated. Investigating mice lacking CNGA3, the activation of these glomeruli by cool temperatures was attenuated. PMID- 27488856 TI - A H(+)-triggered bubble-generating nanosystem for killing cancer cells. AB - We constructed a H(+)-triggered bubble-generating nanosystem (BGNS), which generated CO2 bubbles in the acidic environment of lysosomes after being internalized by cancer cells. The quickly generated bubbles caused enhanced lysosomal membrane permeabilization. As expected, H(+)-triggered BGNS possessed remarkable cytotoxicity against MCF-7 breast cancer cells, and successfully overcame the multidrug resistance of MCF-7/ADR cells. PMID- 27488855 TI - Atorvastatin Attenuates Ischemia/Reperfusion-Induced Hippocampal Neurons Injury Via Akt-nNOS-JNK Signaling Pathway. AB - Ischemia-induced brain damage leads to apoptosis like delayed neuronal death in selectively vulnerable regions, which could further result in irreversible damages. Previous studies have demonstrated that neurons in the CA1 area of hippocampus are particularly sensitive to ischemic damage. Atorvastatin (ATV) has been reported to attenuate cognitive deficits after stroke, but precise mechanism for neuroprotection remains unknown. Therefore, the aims of this study were to investigate the neuroprotective mechanisms of ATV against ischemic brain injury induced by cerebral ischemia reperfusion. In this study, four-vessel occlusion model was established in rats with cerebral ischemia. Rats were divided into five groups: sham group, I/R group, I/R+ATV group, I/R+ATV+LY, and I/R+SP600125 group. Cresyl violet staining was carried out to examine the neuronal death of hippocampal CA1 region. Immunoblotting was used to detect the expression of the related proteins. Results showed that ATV significantly protected hippocampal CA1 pyramidal neurons against cerebral I/R. ATV could increase the phosphorylation of protein kinase B (Akt1) and nNOS, diminished the phosphorylation of JNK3 and c Jun, and further inhibited the activation of caspase-3. Whereas, all of the aforementioned effects of ATV were reversed by LY294002 (an inhibitor of Akt1). Furthermore, pretreatment with SP600125 (an inhibitor of JNK) diminished the phosphorylation of JNK3 and c-Jun, and further inhibited the activation of caspase-3 after cerebral I/R. Taken together, our results implied that Akt mediated phosphorylation of nNOS is involved in the neuroprotection of ATV against ischemic brain injury via suppressing JNK3 signaling pathway that provide a new experimental foundation for stroke therapy. PMID- 27488858 TI - HIV encephalitis with subcortical tau deposition: imaging pathology in vivo using F-18 THK 5117. PMID- 27488857 TI - Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer's disease. AB - PURPOSE: The cannabinoid type 2 receptor (CB2R) is expressed by immune cells such as monocytes and macrophages. In the brain, CB2R is primarily found on microglia. CB2R upregulation has been reported in animal models of Alzheimer's disease, with a preferential localization near amyloid beta (Abeta) plaques, and in patients post mortem. We performed in vivo brain imaging and kinetic modelling of the CB2R tracer [11C]NE40 in healthy controls (HC) and in patients with Alzheimer's disease (AD) to investigate whether higher CB2R availability regionally colocalized to Abeta deposits is present in vivo. METHODS: Dynamic 90-min [11C]NE40 PET scans were performed in eight HC and nine AD patients with full kinetic modelling using arterial sampling and metabolite correction and partial volume correction. All AD patients received a static [11C]PIB scan 40 min after injection. In four HC, a retest scan with [11C]NE40 PET was performed within 9 weeks to investigate test-retest characteristics. RESULTS: [11C]NE40 was metabolized quickly leading to 50 % of intact tracer 20 min after injection and 20 % at 90 min. A two-tissue kinetic model fitted most of the time-activity curves best; both binding potential (BPND) and distribution volume (V T) parameters could be used. Brain uptake was generally low with an average K 1 value of 0.07 ml/min/ml tissue. V T and BPND were in the range of 0.7 - 1.8 and 0.6 - 1.6, respectively. Test values in HC were about 30 % for V T and BPND. AD patients showed overall significantly lower CB2R binding. No relationship was found between regional or global amyloid load and CB2R availability. CONCLUSION: Kinetic modelling of [11C]NE40 is possible with a two-tissue reversible model. In contrast to preclinical and post-mortem data, [11C]NE40 PET shows lower CB2R availability in vivo in AD patients, with no relationship to Abeta plaques. A possible explanation for these findings is that [11C]NE40 binds to CB2R with lower affinity and/or selectivity than to CB1R. PMID- 27488859 TI - Changes in P2Y12 reaction units after switching treatments from prasugrel to clopidogrel in Japanese patients with acute coronary syndrome followed by elective coronary stenting. AB - Patients with ischemic heart disease are administered a dual antiplatelet therapy after percutaneous coronary intervention. This consists of aspirin and thienopyridine, which can be switched from prasugrel to clopidogrel. However, the impact of switching is unknown. This study aimed to determine the efficacy and safety of switching from prasugrel to clopidogrel in Japanese patients. One hundred and thirty-six patients with acute coronary syndrome scheduled to undergo percutaneous coronary intervention and patients with coronary artery disease requiring elective coronary stenting were enrolled. Patients were randomly assigned into the following groups: prasugrel for 6 weeks at loading/maintenance doses of 20/3.75 mg (Continued Group; n = 68) or prasugrel at 20/3.75 mg for 2 weeks followed by clopidogrel at 75 mg for 4 weeks (Switched Group; n = 68). Aspirin (loading dose/maintenance dose 324/81-100 mg/day) was coadministered in both groups. The primary endpoint was the mean P2Y12 reaction unit (PRU) at week 6 and the secondary endpoint was the PRU in groups subdivided based on the presence of CYP2C19 gene polymorphisms. At week 6, the PRU was significantly lower in the Continued Group relative to the Switched Group (140.7 and 183.0, respectively; P < 0.001), which was also evident after correction with the baseline values (144.1 vs. 176.6, respectively; P = 0.005). Extensive and poor metabolizers in the Switched Group, based on CYP2C19 gene polymorphisms, had significantly higher PRU values than those in the Continued Group. Thus, switching treatments from prasugrel to clopidogrel significantly increased the PRU in patients receiving antiplatelet therapy subsequent to percutaneous coronary intervention. Clinical Trial Registration UMIN ID, UMIN000015122. PMID- 27488860 TI - Comments regarding: The benefits of using a vacuum-assisted socket system to improve balance and gait in elderly transtibial amputees by Samitier et al. PMID- 27488861 TI - Reply to: Comments regarding: The benefits of using a vacuum-assisted socket system to improve balance and gait in elderly transtibial amputees by Samitier et al. PMID- 27488862 TI - Intraspinal cavernous bleeding during early pregnancy. PMID- 27488864 TI - Salmonella in Wild Birds Utilizing Protected and Human Impacted Habitats, Uganda. AB - As human populations in Africa expand, humans encroach and modify wildlife habitats for farming, fishing, tourism, or settlement. Anthropogenic activities in shared environments may promote transmission of zoonotic pathogens between humans, domestic animals, and wildlife. Between July 2012 and February 2014, we evaluated Salmonella prevalence, serovars, genotypes, and antibiotic resistant phenotypes in resident and migratory birds utilizing human-impacted habitats in northwestern Lake Victoria and protected habitats in Queen Elisabeth National Park. Salmonella occurrence in the urban environment was assessed by sampling storm-water and wastewater from a channel that drains Kampala City into Lake Victoria. Salmonella was detected in 4.3% pooled bird fecal samples, and 57.1% of environmental samples. While birds in impacted and protected areas shared serovars, the genotypes were distinct. We found distinct strains in birds and the environment suggesting some strains in birds are host adapted, and strains circulating in the environment may not necessarily disseminate to birds. Conversely, birds in both impacted and protected areas shared strains with the urban environment, suggesting Salmonella disseminates between impacted environments and birds across sites. Overall, more strains were observed in the urban environment compared to birds, and poses risk of Salmonella reemergence in birds and transmission across species and space. PMID- 27488863 TI - Long-term treatment with thiamine as possible medical therapy for Friedreich ataxia. AB - Thiamine (vitamin B1) is a cofactor of fundamental enzymes of cell energetic metabolism; its deficiency causes disorders affecting both the peripheral and central nervous system. Previous studies reported low thiamine levels in cerebrospinal fluid and pyruvate dehydrogenase dysfunction in Friedreich ataxia (FRDA). We investigated the effect of long-term treatment with thiamine in FRDA, evaluating changes in neurological symptoms, echocardiographic parameters, and plasma FXN mRNA levels. Thirty-four consecutive FRDA patients have been continuously treated with intramuscular thiamine 100 mg twice a week and have been assessed with the Scale for the Assessment and Rating of Ataxia (SARA) at baseline, after 1 month, and then every 3 months during treatment. Thiamine administration ranged from 80 to 930 days and was effective in improving total SARA scores from 26.6 +/- 7.7 to 21.5 +/- 6.2 (p < 0.02). Moreover, deep tendon reflexes reappeared in 57 % of patients with areflexia at baseline, and swallowing improved in 63 % of dysphagic patients. Clinical improvement was stable in all patients, who did not show worsening even after 2 years of treatment. In a subgroup of 13 patients who performed echocardiogram before and during treatment, interventricular septum thickness reduced significantly (p < 0.02). Frataxin mRNA blood levels were modestly increased in one-half of treated patients. We suppose that a focal thiamine deficiency may contribute to a selective neuronal damage in the areas involved in FRDA. Further studies are mandatory to evaluate thiamine role on FXN regulation, to exclude placebo effect, to verify our clinical results, and to confirm restorative and neuroprotective action of thiamine in FRDA. PMID- 27488865 TI - Green tea cultivar 'Benifuuki' potentiates split vaccine-induced immunoglobulin A production. AB - Influenza is a widespread disease caused by infection with the influenza virus. Vaccination is considered to be the main countermeasure against influenza. A split vaccine is widely used to avoid severe adverse events, and it induces strong humoral immunity. However, the split vaccine alone cannot elicit mucosal immunity, including IgA production, and its preventative effects are limited. Here, we show that the green tea cultivar 'Benifuuki' extract enhanced the effect of a split vaccine on mucosal immunity. The frequency of IgA+ cells was increased in lung and Peyer's patch that received Benifuuki diet. Secretion of hemagglutinin-specific mucosal IgA, which is closely linked to the prevention of viral infection, was significantly increased in the bronchoalveolar lavage fluid of split vaccine-immunized BALB/c mice that were administered green tea Benifuuki extract. Our findings suggest that Benifuuki intake enhanced the effects of the split vaccine on mucosal immunity. PMID- 27488866 TI - Optimal control therapy and vaccination for special HIV-1 model with delay. AB - In this paper, we consider a four dimensional model of the human immunodeficiency virus-1 (HIV-1) with delay, which is an extension of some three dimensional models. We approach the treatment problem by adding two controllers to the system for inhibiting viral production. The optimal controller [Formula: see text] is considered for vaccine and [Formula: see text] for the drug. The Pontryagin maximum principle with delay is used to characterize these optimal controls. At the end, numerical results are presented to illustrate the optimal solutions. The validity of the model was confirmed by proper semi-quantitative simulation of some clinical data. The model was used to predict the possible beneficial effects of vaccine and anti-retroviral drug administration in HIV-1 disease. PMID- 27488867 TI - The undesirable retroactive changes to Rule 8 of the International Code of Nomenclature of Prokaryotes. AB - Changes have been made to Rule 8 of the International Code of Nomenclature of Prokaryotes that caters for the names and nomenclatural types of classes and subclasses. The changes are retroactive because they are not specifically restricted in time. Consequently, that influences names of classes and subclasses and their nomenclatural types that have previously appeared in print. PMID- 27488869 TI - Erdheim-Chester Disease with Emperipolesis: A Unique Case Involving the Heart. AB - Histiocytosis is an uncommon disease characterized by excessive accumulation of histiocytes. Here, we report a rare case of non-Langerhans-cell histiocytosis in a 51-year-old woman who presented with severe symptoms of pericardial effusion. Radiologic investigation also detected multiple bone (lower limbs, vertebrae, ribs, and ilium) lesions. Resected pericardium showed abundant mono- or multi nucleated non-foamy histiocytes (CD68+/CD163+/S-100+/CD1alpha-/langerin-) in a fibroinflammatory background. The histiocytes demonstrated emperipolesis of lymphocytes, a hallmark feature of Rosai-Dorfman disease (RDD). However, molecular analysis revealed a BRAF V600E mutation of the proliferating histiocytes, highlighting the neoplastic features frequently observed in another non-Langerhans-cell histiocytosis known as Erdheim-Chester Disease (ECD). We consider this case to be a unique presentation of ECD harboring some RDD-like cells with emperipolesis, but not a case of RDD with a BRAF mutation concerning its clinical manifestation (involvement of the heart and bones) and neoplastic features. PMID- 27488870 TI - The Prevalence of Founder Mutations among Individuals from Families with Familial Pancreatic Cancer Syndrome. AB - PURPOSE: Familial pancreatic cancer describes families with at least two first degree relatives with pancreatic cancer that do not fulfil the criteria of other inherited tumor syndromes with increased risks of pancreatic cancer. Although much has been learned regarding the aggregation of pancreatic cancer in some families, the genetic basis for this familial aggregation is poorly understood. This study evaluated the prevalence of 10 Polish founder mutations in four genes among individuals from families with diagnosed familial pancreatic cancer syndrome and assessed their possible association with the familial pancreatic cancer (FPC) risk in Poland. MATERIALS AND METHODS: In this study, 400 FPC individuals and 4,000 control subjects were genotyped for founder mutations in BRCA1 (5382insC, 4153delA, C61G), CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), NBS1 (657del5), and PALB2 (509_510delGA, 172_175delTTGT) genes. RESULTS: A statistically significant association was observed between the 172_175delTTGT mutation of the PALB2 gene and an increased risk of FPC syndrome (odds ratio [OR], 10.05; p=0.048). In addition, an increased risk of cancer was observed in the FPC family members with a BRCA1 mutation (OR, 6.72; p=0.006). Novel associations were found between the FPC family members with cancer and CHEK2 mutations (OR, 2.26; p=0.008) with a noticeable contribution of the missense variant, I157T of CHEK2 (OR, 2.17; p=0.026). CONCLUSION: The founder mutations in the genes, BRCA1, PALB2, and CHEK2, cause a small percentage of familial pancreatic cancer syndrome in the Polish population. Following confirmation in larger studies, these mutations can be added to the panel of genes to be tested in families with a diagnosis of FPC syndrome. PMID- 27488871 TI - Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy. AB - PURPOSE: When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser. MATERIALS AND METHODS: This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA. RESULTS: PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss. CONCLUSION: The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen. PMID- 27488872 TI - Inhibition of SKP2 Sensitizes Bromocriptine-Induced Apoptosis in Human Prolactinoma Cells. AB - PURPOSE: Prolactinoma (prolactin-secreting pituitary adenoma) is one of the most common estrogen-related functional pituitary tumors. As an agonist of the dopamine D2 receptor, bromocriptine is used widely to inhibit prolactinoma progression. On the other hand, it is not always effective in clinical application. Although a dopamine D2 receptor deficiency contributes to the impaired efficiency of bromocriptine therapy to some extent, it is unknown whether there some other underlying mechanisms leading to bromocriptine resistance in prolactinoma treatment. That is the main point addressed in this project. MATERIALS AND METHODS: Human prolactinoma samples were used to analyze the S-phase kinase associated protein 2 (SKP2) expression level. Nutlin 3/adriamycin/cisplatin-treated GH3 and MMQ cells were used to analyze apoptosis in SKP2 overexpression or knockdown cells. SKP2 expression and the interaction partners of SKP2 were also detected after a bromocriptine treatment in 293T. Apoptosis was analyzed in C25 and bromocriptine-treated GH3 cells. RESULTS: Compared to normal pituitary samples, most prolactinoma samples exhibit higher levels of SKP2 expression, which could inhibit apoptosis in a p53-dependent manner. In addition, the bromocriptine treatment prolonged the half-life of SKP2 and resulted in SKP2 overexpression to a greater extent, which in turn compromised its pro-apoptotic effect. As a result, the bromocriptine treatment combined with C25 (a SKP2 inhibitor) led to the maximal apoptosis of human prolactinoma cells. CONCLUSION: These findings indicated that SKP2 inhibition sensitized the prolactinoma cells to bromocriptine and helped promote apoptosis. Moreover, a combined treatment of bromocriptine and C25 may contribute to the maximal apoptosis of human prolactinoma cells. PMID- 27488873 TI - Phase II Study of Irinotecan and Cisplatin Combination Chemotherapy in Metastatic, Unresectable Esophageal Cancer. AB - PURPOSE: The objective of this multicenter phase II study was to evaluate the efficacy and safety of irinotecan and cisplatin combination chemotherapy in metastatic, unresectable esophageal cancer. MATERIALS AND METHODS: Patients were treated with irinotecan 65 mg/m2 and cisplatin 30 mg/m2 on days 1 and 8 of each 21-day treatment cycle. The primary endpoint was response rate, and secondary endpoints were survival, duration of response, initial metabolic response rate, and toxicity. RESULTS: A total of 27 patients with squamous cell histology were enrolled in the study. The median age of the patients was 61 years. The objective response rate of the 20 patients in the perprotocol group was 30.0% (90% confidence interval [CI], 13.2 to 46.9). The median follow-up duration was 10.0 months, and the median progression-free survival and overall survival were 4.5 months (95% CI, 1.6 to 6.2) and 8.8 months (95% CI, 4.7 to 10.5), respectively. Four of 13 patients (30.8%) evaluated showed initial metabolic response. The median duration of response for partial responders was 5.0 months (range, 3.4 to 8.0 months). The following grade 3/4 treatment-related hematologic toxicities were reported: neutropenia (40.7%), anaemia (22.2%), and thrombocytopenia (7.4%). Two patients experienced febrile neutropenia. The most common grade 3/4 non hematologic toxicities were asthenia (14.8%) and diarrhoea (11.1%). CONCLUSION: Irinotecan and cisplatin combination chemotherapy showed modest anti-tumour activity and manageable toxicity for patients with metastatic, unresectable esophageal cancer. PMID- 27488874 TI - Comparison of Clinical Outcomes of BRCA1/2 Pathologic Mutation, Variants of Unknown Significance, or Wild Type Epithelial Ovarian Cancer Patients. AB - PURPOSE: The purpose of this study was to investigate the clinical features of epithelial ovarian cancer (EOC) patients according to BRCA1/2 mutation status (mutation, variant of uncertain significance [VUS], or wild type). MATERIALS AND METHODS: We analyzed 116 patients whose BRCA1/2 genetic test results were available for mutation type and clinical features, including progression-free survival (PFS), overall survival (OS), and response rate. These characteristics were compared according to BRCA1/2 mutation status. RESULTS: Thirty-seven (37/116, 31.9%) BRCA1/2mutations were identified (BRCA1, 30; BRCA2, 7). Mutation of c.3627_3628insA (p.Leu1209_Glu1210?fs) in BRCA1 was observed in five patients (5/37, 13.5%). Twenty-five patients had BRCA1/2 VUSs (25/116, 21.6%). Personal histories of breast cancer were observed in 48.6% of patients with BRCA1/2 mutation (18/37), 16.0% of patients with BRCA1/2 VUS (4/25), and 7.4% of patients with BRCA wild type (4/54) (p < 0.001). Patients with BRCA1/2 mutation showed longer OS than those with BRCA1/2 wild type (p=0.005). No significant differences were detected in PFS, OS, or response rates between patients with BRCA1/2 VUS and BRCA1/2 mutation (p=0.772, p=0.459, and p=0.898, respectively). CONCLUSION: Patientswith BRCA1/2 mutation had longer OS than thosewith BRCA1/2wild type. Patients with BRCA1/2 mutation and BRCA1/2 VUS displayed similar prognoses. PMID- 27488875 TI - Predictive Value of Tertiary Lymphoid Structures Assessed by High Endothelial Venule Counts in the Neoadjuvant Setting of Triple-Negative Breast Cancer. AB - PURPOSE: The tertiary lymphoid structure (TLS) is an important source of tumor infiltrating lymphocytes (TILs), which have a strong prognostic and predictive value in triple-negative breast cancer (TNBC). A previous study reported that the levels of CXCL13 mRNA expression were associated with TLSs, but measuring the gene expression is challenging in routine practice. Therefore, this study evaluated the MECA79-positive high endothelial venule (HEV) densities and their association with the histopathologically assessed TLSs in biopsy samples. In addition, the relationship of TLSs with the CXCL13 transcript levels and clinical outcomes were examined. MATERIALS AND METHODS: A total of 108 TNBC patients treated with neoadjuvant chemotherapy (NAC) were studied. The amounts of TILs and TLSs were measured histopathologically using hematoxylin and eosin-stained slides. The HEV densities and TIL subpopulations were measured by immunohistochemistry for MECA79, CD3, CD8, and CD20. CXCL13mRNA expression levels using a NanoString assay (NanoString Technologies). RESULTS: The mean number of HEVs in pre-NAC biopsies was 12 (range, 0 to 72). The amounts of TILs and TLSs, HEV density, and CXCL13 expression showed robust correlations with each other. A lower pre-NAC clinical T stage, higher TIL and TLS levels, a higher HEV density, CD20-positive cell density, and CXCL13 expression were significant predictors of a pathologic complete response (pCR). Higher CD8-positive cell density and levels of CXCL13 expression were significantly associated with a better disease-free survival rate. CONCLUSION: MECA79-positive HEV density in pre-NAC biopsies is an objective and quantitative surrogate marker of TLS and might be a valuable tool for predicting pCR of TNBC in routine pathology practice. PMID- 27488877 TI - Factors associated with increasing campylobacteriosis incidence in Michigan, 2004 2013. AB - This study was conducted to examine the incidence trend of campylobacteriosis in Michigan over a 10-year period and to investigate risk factors and clinical outcomes associated with infection. Campylobacter case data from 2004 to 2013 was obtained from the Michigan Disease Surveillance System. We conducted statistical and spatial analyses to examine trends and identify factors linked to campylobacteriosis as well as ecological associations using animal density data from the National Agricultural Statistics Service. An increasing trend of Campylobacter incidence and hospitalization was observed, which was linked to specific age groups and rural residence. Cases reporting ruminant contact and well water as the primary drinking source had a higher risk of campylobacteriosis, while higher cattle density was associated with an increased risk at the county level. Additional studies are needed to identify age-specific risk factors and examine prevalence and transmission dynamics in ruminants and the environment to aid in the development of more effective preventive strategies. PMID- 27488876 TI - Feasibility and Efficacy of Eribulin Mesilate in Korean Patients with Metastatic Breast Cancer: Korean Multi-center Phase IV Clinical Study Results. AB - PURPOSE: Eribulin mesilate was approved for the treatment of patients with locally advanced or metastatic breast cancer (MBC), who had received at least two chemotherapeutic regimens, including anthracycline and taxane. On the other hand, the efficacy and safety information of eribulin in Korean patients is limited by the lack of clinical trials. MATERIALS AND METHODS: In this multicenter, open label, single-arm, phase IV study, locally advanced or MBC patients were enrolled between June 2013 and April 2014 from 14 centers in Korea. One point four mg/m2 dose of eribulin was administered on days 1 and 8 of every 21 days. The primary endpoint was the frequency and intensity of the treatment emergent adverse event. The secondary endpoint was the disease control rate, which included the rate of complete responses, partial responses, and stable disease. RESULTS: A total of 101 patients received at least one dose of eribulin and were included in the safety set. The patients received a total of 543 treatment cycles, with a median of three cycles (range, 1 to 31 cycles). The most common adverse event was neutropenia (91.1% of patients, 48.3% of cycles). The frequent non-hematological adverse events included alopecia, decrease in appetite, fatigue/asthenia, and myalgia/arthralgia. The peripheral neuropathy of any grade occurred in 27 patients (26.7%), including grade 3 in two patients. Disease control rate was 52.7% and 51.3% of patients in the full analysis set and per-protocol set, respectively. CONCLUSION: This study demonstrated the feasible safety profile and activity of eribulin in Korean patients with MBC. PMID- 27488879 TI - Erratum to: Complete genome sequence of Colocasia bobone disease-associated virus, a putative cytorhabdovirus infecting taro. PMID- 27488878 TI - "Cytoplasmic domain effects on exposure of co-receptor-binding sites of HIV-1 Env". AB - We defined the effects of the cytoplasmic domain (CT) of the Env glycoprotein on co-receptor usage of HIV-1 by reciprocal exchanges of regions containing V3-V5 loops between CD4-dependent and CD4-independent isolates. Primary HIV-1 isolate Env clones CD8 CXCR4-tropic 92UG046 CT84 with an 84-aa truncated CT domain, CD4 CXCR4-tropic 92UG046, and CD4 CCR5-tropic SF162 with full-length (FL) CT domains were used for comparison. The parental 92UG046 Env with CT84 was not fusogenic, but a chimeric SF162 V3-V5-CT84 with an 84-aa truncated CT domain, which demonstrated a switched co-receptor specificity, exhibited syncytium-formation activity with 3T3T4X4 cells. The wild-type (WT) SF162 Env with CT84 or full length CT was fusogenic in 3T3T4R5 cells. By exchange of V3-V5 loops, we were able to alter WT SF162 to switch its co-receptor preference, which was not dependent on CT domain length. These results provide evidence that CT domains can induce conformational changes in functional regions of gp120 and determine receptor tropism but do not modulate HIV-1 co-receptor specificity. PMID- 27488880 TI - Ontario plans to stop funding high dose opioids. PMID- 27488881 TI - Isolation of Treponema DNA from Necrophagous Flies in a Natural Ecosystem. AB - BACKGROUND: Recently, the World Health Organization launched a campaign to eradicate the tropical disease yaws, caused by the bacterium Treponema pallidum subsp. pertenue; however, for decades researchers have questioned whether flies act as a vector for the pathogen that could facilitate transmission. METHODS: A total of 207 fly specimens were trapped in areas of Africa in which T. pallidum induced skin ulcerations are common in wild baboons; 88 flies from Tarangire National Park and 119 from Lake Manyara National Park in Tanzania were analyzed by PCR for the presence of T. pallidum DNA. FINDINGS: We report that in the two study areas, T. pallidum DNA was found in 17-24% of wild-caught flies of the order Diptera. Treponemal DNA sequences obtained from many of the flies match sequences derived from nearby baboon T. pallidum strains, and one of the fly species with an especially high prevalence of T. pallidum DNA, Musca sorbens, has previously been shown to transmit yaws in an experimental setting. INTERPRETATION: Our results raise the possibility that flies play a role in yaws transmission; further research is warranted, given how important understanding transmission is for the eradication of this disfiguring disease. PMID- 27488882 TI - Cell cycle arrest and mechanism of apoptosis induction in H400 oral cancer cells in response to Damnacanthal and Nordamnacanthal isolated from Morinda citrifolia. AB - Oral cancer is the eleventh most prevalent cancer worldwide. The most prevalent oral cancer is oral squamous cell carcinoma (OSCC). Damnacanthal (DAM) and nordamnacanthal (NDAM), the anthraquinone compounds, are isolated from the root of Morinda citrifolia L. (Noni), which has been used for the treatment of several chronic diseases including cancer. The objectives of this study were to evaluate the cytotoxicity, cell death mode, cell cycle, and the molecular mechanism of apoptosis induced by DAM and NDAM on OSCC. The cytotoxic effects of these compounds against OSCC cell lines were determined by MTT assay. The cell death mode was analysed by DNA laddering and FITC-annexin V/PI flow cytometric assays. In addition, the mechanism of apoptosis induced by DAM and NDAM was detected using mitochondrial membrane potential, Cytochrome c, and caspases assays. Finally, the effect of DAM and NDAM on cell cycle phase distribution of OSCC cells was detected by flow cytometry. In the present study, DAM and NDAM showed cytotoxicity towards OSCC cell lines and the maximum growth inhibition for both compounds was observed in H400 cells with IC50 value of 1.9 and 6.8 MUg/ml, respectively, after 72 h treatment. The results also demonstrated the inhibition of H400 OSCC cells proliferation, internucleosomal cleavage of DNA, activation of intrinsic apoptosis pathway, and cell cycle arrest caused by DAM and NDAM. Therefore, these findings suggest that DAM and NDAM can be potentially used as antitumor agents for oral cancer therapy. PMID- 27488884 TI - Saturation dynamics and working limits of saturated absorption cavity ringdown spectroscopy. AB - Cavity ringdown spectroscopy (CRDS) in the linear absorption regime is a well established method for sensitive trace gas detection, but only a few studies have addressed quantitative measurements in the presence of a saturated sample. In fact, saturation is usually avoided in order to escape from the required complex modeling of the saturation process that depends on the characteristics of the absorbing species, its interaction with the surrounding gas as well as on the temporal and spectral characteristics of the cavity excitation. Conversely, the novel saturated-absorption cavity ringdown spectroscopy approach (SCAR/Sat-CRDS) takes advantage of sample saturation in order to allow one to extract both the gas absorption and the empty cavity loss rates from a single ringdown event. Using a new continuous-wave infrared CRD spectrometer equipped with a tunable narrow-bandwidth high-power OPO laser system and a 18 bit digitizer, the transient dynamics of absorption saturation and the working limits of the Sat CRDS approach in terms of its ability to extract reliable trace gas concentrations have been experimentally studied in this work. Using a strong methane transition as a test case, the excitation power P0 and saturation power PS have been systematically varied to explore a wide range of saturation regimes. At pressures 5 MUbar < p < 2 mbar, the saturation intensity revealed a nearly linear pressure dependence showing that non-collisional processes contribute to the overall relaxation. A ratio of P0/PS ~ 15 turned out to be optimal with working limits of 5 < P0/PS < 300. Moreover, the ratio of the absorption and empty cavity loss rates, gammag/gammac, has been varied to test the dynamic range of the method. At gammag > gammac, a pronounced coupling between the two parameters has been observed. Finally, a standard error analysis was performed revealing that the Sat-CRDS approach holds its advantages over conventional CRDS implementations in particular when the attainable ultimate detection sensitivity is limited by uncertainties in the empty cavity ringdown constant. PMID- 27488883 TI - A high-throughput AO/PI-based cell concentration and viability detection method using the Celigo image cytometry. AB - To ensure cell-based assays are performed properly, both cell concentration and viability have to be determined so that the data can be normalized to generate meaningful and comparable results. Cell-based assays performed in immuno oncology, toxicology, or bioprocessing research often require measuring of multiple samples and conditions, thus the current automated cell counter that uses single disposable counting slides is not practical for high-throughput screening assays. In the recent years, a plate-based image cytometry system has been developed for high-throughput biomolecular screening assays. In this work, we demonstrate a high-throughput AO/PI-based cell concentration and viability method using the Celigo image cytometer. First, we validate the method by comparing directly to Cellometer automated cell counter. Next, cell concentration dynamic range, viability dynamic range, and consistency are determined. The high throughput AO/PI method described here allows for 96-well to 384-well plate samples to be analyzed in less than 7 min, which greatly reduces the time required for the single sample-based automated cell counter. In addition, this method can improve the efficiency for high-throughput screening assays, where multiple cell counts and viability measurements are needed prior to performing assays such as flow cytometry, ELISA, or simply plating cells for cell culture. PMID- 27488885 TI - Two years into the Sunshine Act: synopsis of opportunities, challenges, learnings, and potential implications. AB - Responsible transparency helps to promote integrity between industry and researchers and has the potential to increase public trust. As part of its inevitable evolution, the Open Payments database is likely to have opportunities to increase and improve the context around the data that it reports, thus leading to a decrease in the currently encountered confusion and misinterpretation of the data. A major challenge faced by the Centers for Medicare and Medicaid Services is to make the data more informative and educational, to allow the Sunshine Act to meet its transparency goals while improving healthcare innovation. PMID- 27488886 TI - Carotid baroreflex control of heart rate is enhanced, while control of mean arterial pressure is preserved during whole body heat stress in young healthy men. AB - Whole body heat stress (WBH) results in numerous cardiovascular alterations that ultimately reduce orthostatic tolerance. While impaired carotid baroreflex (CBR) function during WBH has been reported as a potential reason for this decrement, study design considerations may limit interpretation of previous findings. We sought to test the hypothesis that CBR function is unaltered during WBH. CBR function was assessed in 10 healthy male subjects (age: 26 +/- 3; height: 185 +/- 7 cm; weight: 82 +/- 10 kg; BMI: 24 +/- 3 kg/m2; means +/- SD) using 5-s trials of neck pressure (+45, +30, and +15 Torr) and neck suction (-20, -40, -60, and 80 Torr) during normothermia (NT) and passive WBH (Delta core temp ~1 degrees C). Analyses of stimulus response curves (four-parameter logistic model) for CBR control of heart rate (CBR-HR) and mean arterial pressure (CBR-MAP), as well as separate two-way ANOVA of the hypotensive and hypertensive stimuli (factor 1: thermal condition, factor 2: chamber pressure), were performed. For CBR-HR, maximal gain was increased during WBH (-0.73 +/- 0.11) compared with NT (-0.39 +/ 0.04, mean +/- SE, P = 0.03). In addition, the CBR-HR responding range was increased during WBH (33 +/- 5) compared with NT (19 +/- 2 bpm, P = 0.03). Separate analysis of hypertensive stimulation revealed enhanced HR responses during WBH at -40, -60, and -80 Torr (condition * chamber pressure interaction, P = 0.049) compared with NT. For CBR-MAP, both logistic analysis and separate two way ANOVA revealed no differences during WBH. Therefore, in response to passive WBH, CBR control of heart rate (enhanced) and arterial pressure (no change) is well preserved. PMID- 27488887 TI - Testosterone therapy in men with testosterone deficiency: are the benefits and cardiovascular risks real or imagined? AB - In the adult male, testosterone (T) deficiency (TD) also known as male hypogonadism, is a well-established medical condition, which has been recognized for more than a century. T therapy in men with TD was introduced as early as 1940s and was reported to improve overall health with no concomitant serious adverse effects. A wealth of recent studies demonstrated that T therapy in men with TD is associated with increased lean body mass, reduced fat mass and waist circumference, improvement in glycemic control, and reduced obesity. T therapy is also associated with improvements in lipid profiles, amelioration of metabolic syndrome (Met S) components, reduced inflammatory biomarkers, reduced systolic and diastolic blood pressure, and improvements in sexual function. More importantly, T therapy is associated with amelioration of diabetes and reduced mortality. However, few studies, marred with serious methodological and analytical flaws reported between 2010 and 2014, suggested that T therapy is associated with increased cardiovascular (CV) risk. As summarized in this review, a thorough and critical analysis of these studies showed that the risks purported are unsubstantiated and such studies lacked credible scientific and clinical evidence. Moreover, recent observational, registry studies, clinical trials, and meta-analyses, all revealed no increase in CV risks in men receiving T therapy. In this review, the benefits of T therapy in adult men with TD and the lack of credible evidence suggesting that T therapy is linked to increased CV risks are discussed. It should be noted that the literature is replete with studies demonstrating beneficial effects of T therapy on CV and overall health. PMID- 27488888 TI - Sex differences in the cardiovascular consequences of the inspiratory muscle metaboreflex. AB - It is currently unknown whether sex differences exist in the cardiovascular consequences of the inspiratory muscle metaboreflex. We hypothesized that the activation of the inspiratory muscle metaboreflex will lead to less of an increase in mean arterial pressure (MAP) and limb vascular resistance (LVR) and less of a decrease in limb blood flow (QL) in women compared with men. Twenty healthy men (n = 10, 23 +/- 2 yr) and women (n = 10, 22 +/- 3 yr) were recruited for this study. Subjects performed inspiratory resistive breathing tasks (IRBTs) at 2% or 65% of their maximal inspiratory mouth pressure (PIMAX). During the IRBTs, the breathing frequency was 20 breaths/min with a 50% duty cycle. At rest and during the IRBTs, MAP was measured via automated oscillometry, QL was measured via Doppler ultrasound, and LVR was calculated. EMG was recorded on the leg to ensure no muscle contraction occurred. The 65% IRBT led to attenuated increases (P < 0.01) from baseline in women compared with men for MAP (W: 7.3 +/- 2.0 mmHg; M: 11.1 +/- 5.0 mmHg) and LVR (W: 17.7% +/- 14.0%; M: 47.9 +/- 21.0%), as well as less of a decrease (P < 0.01) in QL (W: -7.5 +/- 9.9%; M: -23.3 +/- 10.2%). These sex differences in MAP, QL, and LVR were still present in a subset of subjects matched for PIMAX The 2% IRBT resulted in no significant changes in MAP, QL, or LVR across time or between men and women. These data indicate premenopausal women exhibit an attenuated inspiratory muscle metaboreflex compared with age-matched men. PMID- 27488889 TI - Dietary thylakoids reduce visceral fat mass and increase expression of genes involved in intestinal fatty acid oxidation in high-fat fed rats. AB - Thylakoids reduce body weight gain and body fat accumulation in rodents. This study investigated whether an enhanced oxidation of dietary fat-derived fatty acids in the intestine contributes to the thylakoid effects. Male Sprague-Dawley rats were fed a high-fat diet with (n = 8) or without thylakoids (n = 8) for 2 wk. Body weight, food intake, and body fat were measured, and intestinal mucosa was collected and analyzed. Quantitative real-time PCR was used to measure gene expression levels of key enzymes involved in fatty acid transport, fatty acid oxidation, and ketogenesis. Another set of thylakoid-treated (n = 10) and control rats (n = 10) went through indirect calorimetry. In the first experiment, thylakoid-treated rats (n = 8) accumulated 25% less visceral fat than controls. Furthermore, fatty acid translocase (Fat/Cd36), carnitine palmitoyltransferase 1a (Cpt1a), and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) genes were upregulated in the jejunum of the thylakoid-treated group. In the second experiment, thylakoid-treated rats (n = 10) gained 17.5% less weight compared with controls and their respiratory quotient was lower, 0.86 compared with 0.91. Thylakoid-intake resulted in decreased food intake and did not cause steatorrhea. These results suggest that thylakoids stimulated intestinal fatty acid oxidation and ketogenesis, resulting in an increased ability of the intestine to handle dietary fat. The increased fatty acid oxidation and the resulting reduction in food intake may contribute to the reduced fat accumulation in thylakoid-treated animals. PMID- 27488890 TI - Deletion of soluble epoxide hydrolase enhances coronary reactive hyperemia in isolated mouse heart: role of oxylipins and PPARgamma. AB - The relationship between soluble epoxide hydrolase (sEH) and coronary reactive hyperemia (CRH) response to a brief ischemic insult is not known. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia/reperfusion injury. sEH converts EETs into dihydroxyeicosatrienoic-acids (DHETs). Therefore, we hypothesized that knocking out sEH enhances CRH through modulation of oxylipin profiles, including an increase in EET/DHET ratio. Compared with sEH+/+, sEH-/- mice showed enhanced CRH, including greater repayment volume (RV; 28% higher, P < 0.001) and repayment/debt ratio (32% higher, P < 0.001). Oxylipins from the heart perfusates were analyzed by LC MS/MS. The 14,15-EET/14,15-DHET ratio was 3.7-fold higher at baseline (P < 0.001) and 5.6-fold higher post-ischemia (P < 0.001) in sEH-/- compared with sEH+/+ mice. Likewise, the baseline 9,10- and 12,13-EpOME/DiHOME ratios were 3.2-fold (P < 0.01) and 3.7-fold (P < 0.001) higher, respectively in sEH-/- compared with sEH+/+ mice. 13-HODE was also significantly increased at baseline by 71% (P < 0.01) in sEH-/- vs. sEH+/+ mice. Levels of 5-, 11-, 12-, and 15 hydroxyeicosatetraenoic acids were not significantly different between the two strains (P > 0.05), but were decreased postischemia in both groups (P = 0.02, P = 0.04, P = 0.05, P = 0.03, respectively). Modulation of CRH by peroxisome proliferator-activated receptor gamma (PPARgamma) was demonstrated using a PPARgamma-antagonist (T0070907), which reduced repayment volume by 25% in sEH+/+ (P < 0.001) and 33% in sEH-/- mice (P < 0.01), and a PPARgamma-agonist (rosiglitazone), which increased repayment volume by 37% in both sEH+/+ (P = 0.04) and sEH-/- mice (P = 0.04). l-NAME attenuated CRH in both sEH-/- and sEH+/+ These data demonstrate that genetic deletion of sEH resulted in an altered oxylipin profile, which may have led to an enhanced CRH response. PMID- 27488891 TI - Diffusive shunting of gases and other molecules in the renal vasculature: physiological and evolutionary significance. AB - Countercurrent systems have evolved in a variety of biological systems that allow transfer of heat, gases, and solutes. For example, in the renal medulla, the countercurrent arrangement of vascular and tubular elements facilitates the trapping of urea and other solutes in the inner medulla, which in turn enables the formation of concentrated urine. Arteries and veins in the cortex are also arranged in a countercurrent fashion, as are descending and ascending vasa recta in the medulla. For countercurrent diffusion to occur, barriers to diffusion must be small. This appears to be characteristic of larger vessels in the renal cortex. There must also be gradients in the concentration of molecules between afferent and efferent vessels, with the transport of molecules possible in either direction. Such gradients exist for oxygen in both the cortex and medulla, but there is little evidence that large gradients exist for other molecules such as carbon dioxide, nitric oxide, superoxide, hydrogen sulfide, and ammonia. There is some experimental evidence for arterial-to-venous (AV) oxygen shunting. Mathematical models also provide evidence for oxygen shunting in both the cortex and medulla. However, the quantitative significance of AV oxygen shunting remains a matter of controversy. Thus, whereas the countercurrent arrangement of vasa recta in the medulla appears to have evolved as a consequence of the evolution of Henle's loop, the evolutionary significance of the intimate countercurrent arrangement of blood vessels in the renal cortex remains an enigma. PMID- 27488892 TI - Hydrogen sulfide as a regulator of respiratory epithelial sodium transport: the role of sodium-potassium ATPase. Focus on "Hydrogen sulfide contributes to hypoxic inhibition of airway transepithelial sodium absorption". PMID- 27488893 TI - Moving the needle: Optimizing classification for glioma. AB - Genomic markers provide unbiased information that is increasingly being used to enhance traditional histopathology approaches for classification of cancer samples. PMID- 27488894 TI - Comment on "Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice". AB - In Apc(Min) mice (an animal model of colorectal carcinogenesis) fed a high-fat diet, low doses of resveratrol suppress intestinal adenoma development more potently than high doses do; however, these findings appear affected by multiple confounding factors, as resveratrol alone added to a standard diet has opposite outcomes. PMID- 27488895 TI - Response to comment on "Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice". AB - Low-dose resveratrol did not have the opposite effect on intestinal adenoma development when given in a standard diet instead of a high-fat diet, although we agree on the need for more information on the interaction of diet-derived compounds such as resveratrol and other lifestyle, metabolic and hormonal factors. PMID- 27488896 TI - Relationship between vaginal microbial dysbiosis, inflammation, and pregnancy outcomes in cervical cerclage. AB - Preterm birth, the leading cause of death in children under 5 years, may be caused by inflammation triggered by ascending vaginal infection. About 2 million cervical cerclages are performed annually to prevent preterm birth. The procedure is thought to provide structural support and maintain the endocervical mucus plug as a barrier to ascending infection. Two types of suture material are used for cerclage: monofilament or multifilament braided. Braided sutures are most frequently used, although no evidence exists to favor them over monofilament sutures. We assessed birth outcomes in a retrospective cohort of 678 women receiving cervical cerclage in five UK university hospitals and showed that braided cerclage was associated with increased intrauterine death (15% versus 5%; P = 0.0001) and preterm birth (28% versus 17%; P = 0.0006) compared to monofilament suture. To understand the potential underlying mechanism, we performed a prospective, longitudinal study of the vaginal microbiome in women at risk of preterm birth because of short cervical length (<=25 mm) who received braided (n = 25) or monofilament (n = 24) cerclage under comparable circumstances. Braided suture induced a persistent shift toward vaginal microbiome dysbiosis characterized by reduced Lactobacillus spp. and enrichment of pathobionts. Vaginal dysbiosis was associated with inflammatory cytokine and interstitial collagenase excretion into cervicovaginal fluid and premature cervical remodeling. Monofilament suture had comparatively minimal impact upon the vaginal microbiome and its interactions with the host. These data provide in vivo evidence that a dynamic shift of the human vaginal microbiome toward dysbiosis correlates with preterm birth. PMID- 27488897 TI - The chaperone co-inducer BGP-15 alleviates ventilation-induced diaphragm dysfunction. AB - Ventilation-induced diaphragm dysfunction (VIDD) is a marked decline in diaphragm function in response to mechanical ventilation, which has negative consequences for individual patients' quality of life and for the health care system, but specific treatment strategies are still lacking. We used an experimental intensive care unit (ICU) model, allowing time-resolved studies of diaphragm structure and function in response to long-term mechanical ventilation and the effects of a pharmacological intervention (the chaperone co-inducer BGP-15). The marked loss of diaphragm muscle fiber function in response to mechanical ventilation was caused by posttranslational modifications (PTMs) of myosin. In a rat model, 10 days of BGP-15 treatment greatly improved diaphragm muscle fiber function (by about 100%), although it did not reverse diaphragm atrophy. The treatment also provided protection from myosin PTMs associated with HSP72 induction and PARP-1 inhibition, resulting in improvement of mitochondrial function and content. Thus, BGP-15 may offer an intervention strategy for reducing VIDD in mechanically ventilated ICU patients. PMID- 27488898 TI - Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPalpha expression. AB - Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPalpha (CCAAT/enhancer binding protein alpha) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBPalpha suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBPalpha expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBPalpha expression and positive expression of the oncogenic protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) have prognostic value. We also generated a lung-specific mouse model of C/EBPalpha deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBPalpha-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBPalpha is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBPalpha loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBPalpha and high BMI1. PMID- 27488899 TI - Phosphatidylserine Converts Immunogenic Recombinant Human Acid Alpha-Glucosidase to a Tolerogenic Form in a Mouse Model of Pompe Disease. AB - Development of unwanted immune responses against therapeutic proteins is a major clinical complication. Recently, we have shown that exposure of Factor VIII in the presence of phosphatidylserine (PS) induces antigen-specific hyporesponsiveness to Factor VIII rechallenge, suggesting that PS is not immune suppressive, but rather immune regulatory in that PS converts an immunogen to a tolerogen. Since PS is exposed in the outer leaflet during apoptosis, we hypothesize that PS imparts tolerogenic activity to this natural process. Thus, immunization with PS containing liposomes would mimic this natural process. Here, we investigate the immune regulatory effects of PS in inducing tolerance toward recombinant human acid alpha-glucosidase (rhGAA). rhGAA was found to complex with PS liposomes through hydrophobic interactions, and incubation PS-rhGAA with dendritic cells resulted in the increased secretion of transforming growth factor beta. Immunization with PS-rhGAA or O-phospho-L-serine-rhGAA led to a reduction in anti-rhGAA antibody response which persisted despite rechallenge with free rhGAA. Importantly, the titer levels in a majority of these animals remained unchanged after rechallenge and can be considered nonresponders. These data provide evidence that PS liposomes can be used to induce tolerance toward therapeutic proteins, in general. PMID- 27488900 TI - Cholesterol-Targeted Anticancer and Apoptotic Effects of Anionic and Polycationic Amphiphilic Cyclodextrin Nanoparticles. AB - Amphiphilic cyclodextrins (CDs) are biocompatible derivatives of natural CDs and are able to form nanoparticles or polyplexes spontaneously. In this study, nanoparticles prepared from nonionic (6OCaprobetaCD) or cationic amphiphilic CD (PC betaCDC6) were used comparatively to develop nanoparticles intended for breast cancer therapy. The characterization of these nanoparticles was performed both by in vitro and cell culture studies. Furthermore, the apoptotic and cytotoxic effects of blank amphiphilic CDs were demonstrated by various mechanistic methods including Caspase-8 activity, lipid peroxidation assay, TUNEL assay, Tali((r))-based image analysis, cholesterol assay, and gene expression studies. Blank nanoparticles exerted cytotoxicity against a variety of cancer cells (MCF-7, HeLa, HepG2, and MB49) but none to healthy cells (L929, G/G). Interestingly, blank 6OCaprobetaCD and blank PC betaCDC6 derivatives were found to be intrinsically effective on cell number and membrane integrity of MCF-7 cells in apoptosis studies. Further in-depth studies were performed to elucidate the selective mechanism of anticancer action in MCF-7 cells caused by these amphiphilic CDs. In conclusion, blank amphiphilic CD nanoparticles induced apoptosis through mitochondrial pathway targeted to cholesterol microdomains in cancer cell membrane. PMID- 27488901 TI - Particle Formation and Aggregation of a Therapeutic Protein in Nanobubble Suspensions. AB - The generation of nanobubbles following reconstitution of lyophilized trehalose formulations has recently been reported. Here, we characterize particle formation and aggregation of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in reconstituted formulations of lyophilized trehalose. Particle characterization methods including resonant mass measurement and nanoparticle tracking analysis were used to count and size particles generated upon reconstitution of lyophilized trehalose formulations. In addition, accelerated degradation studies were conducted to monitor rhIL-1ra aggregation in solutions containing various concentrations of suspended nanobubbles. Reconstitution of lyophilized trehalose formulations with solutions containing rhIL-1ra reduced nanobubble concentrations and generated negatively buoyant particles attributed to aggregated rhIL-1ra. Furthermore, levels of rhIL-1ra aggregation following incubation in aqueous solution correlated with concentrations of suspended nanobubbles. The results of this study suggest that nanobubbles may be a contributor to protein aggregation and particle formation in reconstituted, lyophilized therapeutic protein formulations. PMID- 27488902 TI - Studying the Propensity of Compounds to Supersaturate: A Practical and Broadly Applicable Approach. AB - Supersaturating drug delivery systems can enhance the oral bioavailability of poorly soluble drug compounds. Supersaturation of such compounds has been studied in many different ways; however, a more standardized method is required. The rationale of choosing suitable concentrations of supersaturation to study has previously been very inconsistent. This makes comparisons between studies and compounds difficult, as the propensity of compounds to supersaturate varies greatly. This study presents a standardized method to study the supersaturation of drug compounds. The method allows, both, for a ranking of compounds according to their supersaturation propensity and the effectiveness of precipitation inhibitors. The time-concentration profile of supersaturation and precipitation was studied in situ for 4 different concentrations for 6 model compounds (albendazole, aprepitant, danazol, felodipine, fenofibrate, and tadalafil) in the MUDISS ProfilerTM in fasted-state simulated intestinal fluid. A relation between the induction time of nucleation and the initial supersaturated concentration could be established based on classical nucleation theory. The model compounds had different propensities to upersaturate. The data show that a single degree of supersaturation or concentration would not have described the different systems adequately. The method could be used in early preformulation for characterization of supersaturation propensity of novel compounds or precipitation inhibitor effects. PMID- 27488903 TI - Magneto-Optical Activity in High Index Dielectric Nanoantennas. AB - The magneto-optical activity, namely the polarization conversion capabilities of high-index, non-absorbing, core-shell dielectric nanospheres is theoretically analyzed. We show that, in analogy with their plasmonic counterparts, the polarization conversion in resonant dielectric particles is linked to the amount of electromagnetic field probing the magneto-optical material in the system. However, in strong contrast with plasmon nanoparticles, due to the peculiar distribution of the internal fields in resonant dielectric spheres, the magneto optical response is fully governed by the magnetic (dipolar and quadrupolar) resonances with little effect of the electric ones. PMID- 27488904 TI - PACSIN1 regulates the dynamics of AMPA receptor trafficking. AB - Dynamic trafficking of AMPA receptors (AMPARs) into and out of synapses plays an important role in synaptic plasticity. We previously reported that the protein kinase C and casein kinase II substrate in neurons (PACSIN) forms a complex with AMPARs through its interaction with the protein interacting with C-kinase 1 (PICK1) to regulate NMDA receptor (NMDAR)-induced AMPAR endocytosis and cerebellar long-term depression. However, the molecular mechanism by which PACSIN regulates the dynamics of AMPAR trafficking remains unclear. Using a pH-sensitive green fluorescent protein, pHluorin, tagged to the extracellular domain of the GluA2 subunit of AMPARs, we demonstrate dual roles for PACSIN1 in controlling the internalization and recycling of GluA2 after NMDAR activation. Structure and function analysis reveals a requirement for the PACSIN1 F-BAR and SH3 domains in controlling these NMDAR-dependent processes. Interestingly, the variable region, which binds to PICK1, is not essential for NMDAR-dependent GluA2 internalization and is required only for the correct recycling of AMPARs. These results indicate that PACSIN is a versatile membrane deformation protein that links the endocytic and recycling machineries essential for dynamic AMPAR trafficking in neurons. PMID- 27488906 TI - Rule 27 of the International Code of Nomenclature of prokaryotes: the basonym is not enough. AB - Proposals to make changes to the wording of Rule 27 of the International Code of Nomenclature of Prokaryotes have been made that include the requirement to make reference to the basonym of a new combination. While this is a step in the right direction, it does not solve problems where new combinations are associated with multiple heterotypic synonyms and the new combination is based on the selection of the genus name or species epithet that is contrary to the Rules. PMID- 27488905 TI - Advanced breast cancer clinical nursing curriculum: review and recommendations. AB - PURPOSE: The needs and concerns of patients with advanced breast cancer are changing at every phase of the care intervention. Management and coordination of hospital resources and services are also steadily evolving. The objective of the present expert report is to define a new oncology nursing role specialising in advanced breast cancer, to help guide patients throughout the whole healthcare itinerary. METHODS: A group of eight experts in oncology nursing and medical oncology defined the content index of the curriculum document. A systematic review of bibliography was carried out, and the relevant contents were extracted. Based on these contents and the participants' experience, recommendations were formulated and validated through a Delphi questionnaire and a participative meeting. RESULTS: The advanced breast cancer clinical nurse (ABCCN) should develop a clinical, psychosocial role focused on coordinating patients in the healthcare network. The nurse would be in charge of evaluating and supervising the care administered and the healthcare resources used. The ABCCN should be aware and participate in the protocols and available resources, be able to solve conflicts, deal with burn-out signs and have clinical, coaching and team-working abilities. The proposed curriculum provides a specific process for the care of patients, as well as an implementation process. CONCLUSIONS: The ABCCN's role is crucial to assume the best care and the optimisation of available resources. This review and consensus document provides the required tools for the implementation in hospitals. PMID- 27488907 TI - Detection of kobuvirus RNA in Japanese domestic dogs. AB - To investigate whether kokuvirus is present in Japanese dogs, we examined the fecal samples obtained from 94 diarrheal household dogs and 50 clinically healthy kenneled dogs by RT-PCR. The gene was detected in 37.2% and 48.0% in the former and the latter, respectively, suggesting that canine kobuvirus (CaKoV) is circulating among Japanese dogs. From the result of the latter, however, CaKoV may not be a primary pathogen. Furthermore, all gene-positive dogs were purebreds aged four months or younger. This finding suggests that CaKoV endemic is confined in multi-dog environments, and the dogs have a strong age-dependent resistance to CaKoV. PMID- 27488908 TI - Intracranial stenosis in cognitive impairment and dementia. AB - Intracranial stenosis is a common vascular lesion observed in Asian and other non Caucasian stroke populations. However, its role in cognitive impairment and dementia has been under-studied. We, therefore, examined the association of intracranial stenosis with cognitive impairment, dementia and their subtypes in a memory clinic case-control study, where all subjects underwent detailed neuropsychological assessment and 3 T neuroimaging including three-dimensional time-of-flight magnetic resonance angiography. Intracranial stenosis was defined as >=50% narrowing in any of the intracranial arteries. A total of 424 subjects were recruited of whom 97 were classified as no cognitive impairment, 107 as cognitive impairment no dementia, 70 vascular cognitive impairment no dementia, 121 Alzheimer's Disease, and 30 vascular dementia. Intracranial stenosis was associated with dementia (age/gender/education - adjusted odds ratios (OR): 4.73, 95% confidence interval (CI): 1.93-11.60) and vascular cognitive impairment no dementia (OR: 3.98, 95% CI: 1.59-9.93). These associations were independent of cardiovascular risk factors and MRI markers. However, the association with Alzheimer's Disease and vascular dementia became attenuated in the presence of white matter hyperintensities. Intracranial stenosis is associated with vascular cognitive impairment no dementia independent of MRI markers. In Alzheimer's Disease and vascular dementia, this association is mediated by cerebrovascular disease. Future studies focusing on perfusion and functional markers are needed to determine the pathophysiological mechanism(s) linking intracranial stenosis and cognition so as to identify treatment strategies. PMID- 27488909 TI - Insulin resistance is associated with lower arterial blood flow and reduced cortical perfusion in cognitively asymptomatic middle-aged adults. AB - Insulin resistance (IR) is associated with poor cerebrovascular health and increased risk for dementia. Little is known about the unique effect of IR on both micro- and macrovascular flow particularly in midlife when interventions against dementia may be most effective. We examined the effect of IR as indexed by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) on cerebral blood flow in macro- and microvessels utilizing magnetic resonance imaging (MRI) among cognitively asymptomatic middle-aged individuals. We hypothesized that higher HOMA-IR would be associated with reduced flow in macrovessels and lower cortical perfusion. One hundred and twenty cognitively asymptomatic middle-aged adults (57 +/- 5 yrs) underwent fasting blood draw, phase contrast-vastly undersampled isotropic projection reconstruction (PC VIPR) MRI, and arterial spin labeling (ASL) perfusion. Higher HOMA-IR was associated with lower arterial blood flow, particularly within the internal carotid arteries (ICAs), and lower cerebral perfusion in several brain regions including frontal and temporal lobe regions. Higher blood flow in bilateral ICAs predicted greater cortical perfusion in individuals with lower HOMA-IR, a relationship not observed among those with higher HOMA-IR. Findings provide novel evidence for an uncoupling of macrovascular blood flow and microvascular perfusion among individuals with higher IR in midlife. PMID- 27488910 TI - Diphenhydramine as a selective probe to study H+-antiporter function at the blood brain barrier: Application to [11C]diphenhydramine positron emission tomography imaging. AB - Diphenhydramine, a sedative histamine H1-receptor (H1R) antagonist, was evaluated as a probe to measure drug/H+-antiporter function at the blood-brain barrier. In situ brain perfusion experiments in mice and rats showed that diphenhydramine transport at the blood-brain barrier was saturable, following Michaelis-Menten kinetics with a Km = 2.99 mM and Vmax = 179.5 nmol s-1 g-1. In the pharmacological plasma concentration range the carrier-mediated component accounted for 77% of diphenhydramine influx while passive diffusion accounted for only 23%. [14C]Diphenhydramine blood-brain barrier transport was proton and clonidine sensitive but was influenced by neither tetraethylammonium, a MATE1 (SLC47A1), and OCT/OCTN (SLC22A1-5) modulator, nor P-gp/Bcrp (ABCB1a/1b/ABCG2) deficiency. Brain and plasma kinetics of [11C]diphenhydramine were measured by positron emission tomography imaging in rats. [11C]Diphenhydramine kinetics in different brain regions were not influenced by displacement with 1 mg kg-1 unlabeled diphenhydramine, indicating the specificity of the brain positron emission tomography signal for blood-brain barrier transport activity over binding to any central nervous system target in vivo. [11C]Diphenhydramine radiometabolites were not detected in the brain 15 min after injection, allowing for the reliable calculation of [11C]diphenhydramine brain uptake clearance (Clup = 0.99 +/- 0.18 mL min-1 cm-3). Diphenhydramine is a selective and specific H+ antiporter substrate. [11C]Diphenhydramine positron emission tomography imaging offers a reliable and noninvasive method to evaluate H+-antiporter function at the blood-brain barrier. PMID- 27488911 TI - An automated method measures variability in P-glycoprotein and ABCG2 densities across brain regions and brain matter. AB - Changes in P-glycoprotein and ABCG2 densities may play a role in amyloid-beta accumulation in Alzheimer's disease. However, previous studies report conflicting results from different brain regions, without correcting for changes in vessel density. We developed an automated method to measure transporter density exclusively within the vascular space, thereby correcting for vessel density. We then examined variability in transporter density across brain regions, matter, and disease using two cohorts of post-mortem brains from Alzheimer's disease patients and age-matched controls. Changes in transporter density were also investigated in capillaries near plaques and on the mRNA level. P-glycoprotein density varied with brain region and matter, whereas ABCG2 density varied with brain matter. In temporal cortex, P-glycoprotein density was 53% lower in Alzheimer's disease samples than in controls, and was reduced by 35% in capillaries near plaque deposits within Alzheimer's disease samples. ABCG2 density was unaffected in Alzheimer's disease. No differences were detected at the transcript level. Our study indicates that region-specific changes in transporter densities can occur globally and locally near amyloid-beta deposits in Alzheimer's disease, providing an explanation for conflicting results in the literature. When differences in region and matter are accounted for, changes in density can be reproducibly measured using our automated method. PMID- 27488912 TI - Four years of corneal keratoplasty in Italian paediatric patients: indications and clinical outcomes. AB - PURPOSE: The purpose was to evaluate indications and clinical outcomes in paediatric corneal keratoplasty. METHODS: Fifty-four eyes of 43 patients who underwent corneal keratoplasty from the 1st of January 2010 through the 31st of December 2013 at the Bambino Gesu Children's Hospital in Rome, Italy, were retrospectively evaluated. To assess the effect of age on graft failure rate, the recipient age was considered as a dichotomous variable (<=5 or >5 years) and a 2X2 table was developed, using the chi-square test for testing the statistical significance. Furthermore, two separate subgroup analyses were conducted on patients of <=5 years and those of >5 years, to evaluate the effect of penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty (DALK) on the graft failure rate. The level of statistical significance was set at p < 0.05 RESULTS: Mean recipient age was 8.9 +/- 5.7 [SD] years. Mean follow-up time was 22.8 months. Main preoperative diagnoses were keratoconus (37 %) and congenital glaucoma (20 %). Patients <=5 years showed a higher percentage of graft failure (p = 0.0008). PK and DALK did not show statistically significant differences regarding the graft failure in both subgroups (p = 0.15 for <=5 years group and p = 0.27 for >5 years group, respectively). However, across groups DALK provided a lower rate of graft failure. CONCLUSIONS: Our findings suggest that children older than 5 years show a significantly better graft outcome and that DALK seems to offer greatest benefits in terms of failure risk in paediatric patients. PMID- 27488914 TI - Relationship Between Intrinsic Motivation and Undergraduate Students' Depression and Stress: The Moderating Effect of Interpersonal Conflict. AB - This study examined the effect of intrinsic academic motivation and interpersonal conflict on the perceived depression and stress. Participants were 537 Chinese undergraduate students (191 males and 346 females; M age = 20.4 years, SD age = 1.3). They completed four scales measuring intrinsic academic motivation, interpersonal conflict, stress, and depression. Linear regressions were conducted with intrinsic academic motivation, interpersonal conflict, and their interaction as independent variables to predict depression and stress. Results showed that intrinsic academic motivation was negatively, while interpersonal conflict was positively, associated with depression and stress. Moreover, the interaction was significant: negative association of "intrinsic academic motivation and depression" and that of "intrinsic academic motivation and stress" was weaker among participants who reported higher (vs. lower) levels of interpersonal conflict. PMID- 27488913 TI - Severity of clinical presentation in youth with type 1 diabetes is associated with differences in brain structure. AB - OBJECTIVE: Differences in cognition and brain structure have been found in youth with type 1 diabetes compared with controls, even after relatively short disease duration. To determine whether severity of clinical presentation contributes to these differences, we obtained structural magnetic resonance imaging (MRI) scans in youth ages 7-17 who were either newly diagnosed with type 1 diabetes (<3.5 months from diagnosis, n = 46) or a sibling without diabetes (n = 28). RESEARCH DESIGN AND METHODS: Severity of presentation was measured by the presence of diabetic ketoacidosis (DKA) and degree of hyperglycemia exposure [hemoglobin A1c (HbA1c)] at diagnosis. MRI were obtained using T1-weighted, T2-weighted, and diffusion-weighted sequences. RESULTS: Within the group with type 1 diabetes, 12 subjects presented in DKA and 34 did not. After controlling for age, sex, and multiple comparisons, the type 1 diabetes group had lower volume in the left temporal-parietal-occipital cortex compared with controls. Within the type 1 diabetes group, DKA at presentation was associated with lower radial, axial, and mean diffusivity (MD) throughout major white matter tracts and higher HbA1c was associated with lower hippocampal, thalamic, and cerebellar white matter volumes, lower right posterior parietal cortical thickness, and greater right occipital cortical thickness. CONCLUSION: These data suggest that severity of clinical presentation is an important factor in predicting brain structural differences in youth with type 1 diabetes approximately 3 months after diagnosis. PMID- 27488915 TI - Characterisation of atopic dermatitis (AD) endotypes and novel treatment targets: towards a molecular classification. PMID- 27488916 TI - Saving antibiotics for when they are really needed: the Dutch example. PMID- 27488917 TI - Epidemiology and economic burden of measles, mumps, pertussis, and varicella in Germany: a systematic review. AB - OBJECTIVES: Despite the availability of vaccines and the existence of public vaccination recommendations, outbreaks of vaccine-preventable childhood diseases still cause public health debate. The objective of this systematic review was to provide an overview of the current epidemiology and economic burden of measles, mumps, pertussis, and varicella in Germany. METHODS: We systematically reviewed studies published since 2000. The literature search was conducted using PubMed and EMBASE. Also, we used German notification data to give an up-to-date overview of the epidemiology of the four diseases under consideration. RESULTS: Thirty-six studies were included in our review. Results suggest that there is still considerable morbidity due to childhood diseases in Germany. Studies providing cost estimates are scarce. Comparative analyses of different data sources (notification data vs. claims data) revealed a potential underestimation of incidence estimates when using notification data. Furthermore, several studies showed regional differences in incidence of some of the diseases under consideration. CONCLUSIONS: Our findings underline the need for improved vaccination and communication strategies targeting all susceptible age and risk groups on a national and local level. PMID- 27488918 TI - Molecular Properties of Drugs Interacting with SLC22 Transporters OAT1, OAT3, OCT1, and OCT2: A Machine-Learning Approach. AB - Statistical analysis was performed on physicochemical descriptors of ~250 drugs known to interact with one or more SLC22 "drug" transporters (i.e., SLC22A6 or OAT1, SLC22A8 or OAT3, SLC22A1 or OCT1, and SLC22A2 or OCT2), followed by application of machine-learning methods and wet laboratory testing of novel predictions. In addition to molecular charge, organic anion transporters (OATs) were found to prefer interacting with planar structures, whereas organic cation transporters (OCTs) interact with more three-dimensional structures (i.e., greater SP3 character). Moreover, compared with OAT1 ligands, OAT3 ligands possess more acyclic tetravalent bonds and have a more zwitterionic/cationic character. In contrast, OCT1 and OCT2 ligands were not clearly distinquishable form one another by the methods employed. Multiple pharmacophore models were generated on the basis of the drugs and, consistent with the machine-learning analyses, one unique pharmacophore created from ligands of OAT3 possessed cationic properties similar to OCT ligands; this was confirmed by quantitative atomic property field analysis. Virtual screening with this pharmacophore, followed by transport assays, identified several cationic drugs that selectively interact with OAT3 but not OAT1. Although the present analysis may be somewhat limited by the need to rely largely on inhibition data for modeling, wet laboratory/in vitro transport studies, as well as analysis of drug/metabolite handling in Oat and Oct knockout animals, support the general validity of the approach-which can also be applied to other SLC and ATP binding cassette drug transporters. This may make it possible to predict the molecular properties of a drug or metabolite necessary for interaction with the transporter(s), thereby enabling better prediction of drug-drug interactions and drug-metabolite interactions. Furthermore, understanding the overlapping specificities of OATs and OCTs in the context of dynamic transporter tissue expression patterns should help predict net flux in a particular tissue of anionic, cationic, and zwitterionic molecules in normal and pathophysiological states. PMID- 27488920 TI - Parametric recursive system identification and self-adaptive modeling of the human energy metabolism for adaptive control of fat weight. AB - A mathematical model has been developed to facilitate indirect measurements of difficult to measure variables of the human energy metabolism on a daily basis. The model performs recursive system identification of the parameters of the metabolic model of the human energy metabolism using the law of conservation of energy and principle of indirect calorimetry. Self-adaptive models of the utilized energy intake prediction, macronutrient oxidation rates, and daily body composition changes were created utilizing Kalman filter and the nominal trajectory methods. The accuracy of the models was tested in a simulation study utilizing data from the Minnesota starvation and overfeeding study. With biweekly macronutrient intake measurements, the average prediction error of the utilized carbohydrate intake was -23.2 +/- 53.8 kcal/day, fat intake was 11.0 +/- 72.3 kcal/day, and protein was 3.7 +/- 16.3 kcal/day. The fat and fat-free mass changes were estimated with an error of 0.44 +/- 1.16 g/day for fat and -2.6 +/- 64.98 g/day for fat-free mass. The daily metabolized macronutrient energy intake and/or daily macronutrient oxidation rate and the daily body composition change from directly measured serial data are optimally predicted with a self-adaptive model with Kalman filter that uses recursive system identification. PMID- 27488919 TI - Development of Poly Unsaturated Fatty Acid Derivatives of Aspirin for Inhibition of Platelet Function. AB - The inhibition of platelet aggregation is key to preventing conditions such as myocardial infarction and ischemic stroke. Aspirin is the most widely used drug to inhibit platelet aggregation. Aspirin absorption can be improved further to increase its permeability across biologic membranes via esterification or converting the carboxylic acid to an anhydride. There are several reports indicating that omega-3 and omega-6 fatty acids such as linoleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) separately inhibit platelet aggregation. Herein, we synthesize anhydride conjugates of aspirin with linoleic acid, EPA, and DHA to form aspirin anhydrides that are expected to have higher permeability across cellular membranes. These aspirin-fatty acid anhydrides inhibited platelet aggregation in washed human platelets and platelet rich plasma in a dose-dependent manner. In particular, the aspirin-DHA anhydride displayed similar effectiveness to aspirin. Platelet aggregation studies conducted in the presence of various platelet agonists indicated that the aspirin lipid conjugates act through inhibition of the cyclooxygenase (COX)-thromboxane synthase (TXAS) pathway. Hence, we performed detailed biochemical studies using purified COX-1 as well as TXAS stabilized in nanoscale lipid bilayers of nanodiscs to confirm results from the platelet aggregation studies. We show that although all of the aspirin conjugates act through the COX-TXAS pathway by inhibiting COX-1, the parent fatty acids do not act via this pathway. Finally, we studied the hydrolysis of these compounds in buffer and human plasma, and we demonstrate that all of the aspirin-fatty acid conjugates hydrolyze to the parent molecules aspirin and fatty acid in a controlled manner. PMID- 27488921 TI - The humidifier disinfectant case and the legislative challenges of the 20th Congress. AB - A number of absurdities surrounding the humidifier disinfectant (HD) incident may have occurred because 1) a judicial system operates on the underlying false assumption that the involved parties are equals in knowledge, information and resource mobilization capabilities, regardless of respective real status as company or individual; 2) there is a lack of a system that mandates a company to prevent and actively manage possible catastrophes; 3) the regulatory scheme makes companies believe that as long as they are complying with the existing regulations, they have satisfied all of their responsibilities. I believe that this issue is an opportunity to bring about changes in the judicial redress system, the system of internal management of manufacturers, and the regulatory system of the government. The following regulation amendments are needed to move towards the changes stated above. First, legislation relating to victim relief that is applicable to the HD incident must be established. Second, a risk management system must be formed within the manufacturing company and to this end an institutional environment for the system must be established within regulatory framework. Furthermore, legislation must be passed that could punish companies themselves that have caused severe damage to individuals because they had failed to take necessary actions to avoid foreseeable harm. Finally, the framework of regulation must be changed so that the company, who has the necessary information regarding the product and the component chemicals used in the product, must self directed experiment and assessment of the safety of their own products. PMID- 27488925 TI - Expression analysis and promoter methylation under osmotic and salinity stress of TaGAPC1 in wheat (Triticum aestivum L). AB - Cytosolic glyceraldehyde-3-phosphate dehydrogenase (GAPC) catalyzes a key reaction in glycolysis and encoded by a multi-gene family which showed instability expression under abiotic stress. DNA methylation is an epigenetic modification that plays an important role in gene regulation in response to abiotic stress. The comprehension of DNA methylation at promoter region of TaGAPC1 can provide insights into the transcription regulation mechanisms of plant genes under abiotic stress. In this study, we cloned TaGAPC1 genes and its promoters from two wheat genomes, then investigated the expression patterns of TaGAPC1 under osmotic and salinity stress, and analyzed the promoter sequences. Moreover, the methylation patterns of promoters under stress were confirmed. Expression analysis indicated that TaGAPC1 was induced inordinately by stresses in two wheat genotypes with contrasting drought tolerance. Several stress-related cis-acting elements (MBS, DRE, GT1 and LTR et al.) were located in its promoters. Furthermore, the osmotic and salinity stress induced the demethylation of CG and CHG nucleotide in the promoter region of Changwu134. The methylation level of CHG and CHH in promoter of Zhengyin1 was always increased under stresses, and the CG contexts remained unchanged. The cytosine loci of stress-related cis-acting elements also showed different methylation changes in this process. These results provide insights into the relationship between promoter methylation and gene expression, promoting the function investigation of GAPC. PMID- 27488926 TI - Folding recombinant spider-silk in H2 O: Effect of osmolytes on the solution conformation of a 15-repeat spider-silk mimetic. AB - The folding of a recombinant spider silk protein-polymer in the presence of the tri-methylamine osmolytes TMANO and Betaine in 80% H2 O is reported. Circular dichroism measurements (CD) reveal an increase in alpha-helical secondary structure with increasing osmolyte concentrations, as determined by an increase in ellipticity at 222 nm. Consistent with this observation, the signal for random coil sampling, observed at 205 nm, is greatly reduced with increasing trimethylamine. Fluorescence spectra of a single tyrosine positioned within the conserved 33-amino acid repeat primary sequence (of the spider-silk mimetic) complements the conformational changes observed by CD. Importantly, there is a correlation between the number of Alkyl-groups (CH3 -) on the amine of the osmolyte and enhanced helicity of the 15-repeat silk-mimetic for the osmolytes tested, ie TMANO, Betaine, Sarcosine and Glycine. These preliminary results are applicable to storing and processing recombinant silk sequences in H2 O, an important mile-stone for widespread use of recombinant silk polymers. PMID- 27488928 TI - Residual risk and waste in donated blood with pooled nucleic acid testing. AB - An accurate estimation of the residual risk of transfusion-transmittable infections (TTIs), which includes the human immunodeficiency virus (HIV), hepatitis B and C viruses (HBV, HCV), among others, is essential, as it provides the basis for blood screening assay selection. While the highly sensitive nucleic acid testing (NAT) technology has recently become available, it is highly costly. As a result, in most countries, including the United States, the current practice for human immunodeficiency virus, hepatitis B virus, hepatitis C virus screening in donated blood is to use pooled NAT. Pooling substantially reduces the number of tests required, especially for TTIs with low prevalence rates. However, pooling also reduces the test's sensitivity, because the viral load of an infected sample might be diluted by the other samples in the pool to the point that it is not detectable by NAT, leading to potential TTIs. Infection-free blood may also be falsely discarded, resulting in wasted blood. We derive expressions for the residual risk, expected number of tests, and expected amount of blood wasted for various two-stage pooled testing schemes, including Dorfman-type and array-based testing, considering infection progression, infectivity of the blood unit, and imperfect tests under the dilution effect and measurement errors. We then calibrate our model using published data and perform a case study. Our study offers key insights on how pooled NAT, used within different testing schemes, contributes to the safety and cost of blood. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27488927 TI - Inhibition of the 3-hydroxy-3-methyl-glutaryl-CoA reductase induces orofacial defects in zebrafish. AB - BACKGROUND: Orofacial clefts (OFCs) are common birth defects, which include a range of disorders with a complex etiology affecting formation of craniofacial structures. Some forms of syndromic OFCs are produced by defects in the cholesterol pathway. The principal enzyme of the cholesterol pathway is the 3 hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Our aim is to study whether defects of HMGCR function would produce orofacial malformation similar to those found in disorders of cholesterol synthesis. METHODS: We used zebrafish hmgcrb mutants and HMGCR inhibition assay using atorvastatin during early and late stages of orofacial morphogenesis in zebrafish. To describe craniofacial phenotypes, we stained cartilage and bone and performed in situ hybridization using known craniofacial markers. Also, we visualized neural crest cell migration in a transgenic fish. RESULTS: Our results showed that mutants displayed loss of cartilage and diminished orofacial outgrowth, and in some cases palatal cleft. Late treatments with statin show a similar phenotype. Affected-siblings displayed a moderate phenotype, whereas early-treated embryos had a minor cleft. We found reduced expression of the downstream component of Sonic Hedgehog-signaling gli1 in ventral brain, oral ectoderm, and pharyngeal endoderm in mutants and in late atorvastatin-treated embryos. CONCLUSION: Our results suggest that HMGCR loss-of function primarily affects postmigratory cranial neural crest cells through abnormal Sonic Hedgehog signaling, probably induced by reduction in metabolites of the cholesterol pathway. Malformation severity correlates with the grade of HMGCR inhibition, developmental stage of its disruption, and probably with availability of maternal lipids. Together, our results might help to understand the spectrum of orofacial phenotypes found in cholesterol synthesis disorders. Birth Defects Research (Part A) 106:814-830, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27488929 TI - Intratubular large cell hyalinizing Sertoli cell tumor of the testis presenting with prepubertal gynecomastia: a case report. AB - Intratubular large cell hyalinizing Sertoli cell neoplasia (ITLCHSCN) resulting from Sertoli cells of the testis are mainly reported in young adults and these are rarely seen in childhood. The most common presenting symptoms of the patients diagnosed with ITLCHSCN are gynecomastia, enlargement in the testicles, increase in growth velocity, and advanced bone age. Symptoms are basically resulting from increased aromatase enzyme activity in Sertoli cells. In this case report, an eight-and-a-half-year-old case presenting with complaint of bilateral gynecomastia since two years, showing no endocrine abnormality in laboratory during two years of follow-up, determined to have progression in bilateral gynecomastia, increase in testicular volumes, advanced bone age, increase in growth velocity in the clinical follow-up, and diagnosed with ITLCHSCN after testis biopsy was presented. PMID- 27488930 TI - Persistence of rubella and mumps antibodies, following changes in the recommended age for the second dose of MMR vaccine in Portugal. AB - In Portugal, the recommended age for the second dose of MMR (MMR2) was changed from 10-13 years to 5-6 years for those born in 1994 and afterwards. This study aimed to assess if MMR schedule and time elapsed from the last dose are associated with the concentration of rubella and mumps IgG antibodies. Three Portuguese birth cohorts (convenience samples) were selected for this study (66, 59 and 41 participants born respectively in 1990-1993, 1994-1995 and 2001-2003). Geometric mean concentrations (GMC) for mumps IgG were respectively 36, 30 and 38 RU/ml (P = 0.236) and for rubella IgG were 18, 20 and 17 IU/ml (P = 0.641). For both specific antibodies, no differences were observed with time since MMR2. Receiving MMR2 at 5-6 or 10-13 years was not associated with concentration of both antibodies. The GMC of rubella IgG was lower in males (P = 0.029). Taking into account previous evidence and the logistics needed to change vaccination schedules, it seems reasonable that sustaining very high coverage with two doses of MMR is currently the most pragmatic way to control mumps and rubella rather than any changes to the schedule. PMID- 27488931 TI - The influence of prostate-specific antigen density on positive and negative predictive values of multiparametric magnetic resonance imaging to detect Gleason score 7-10 prostate cancer in a repeat biopsy setting. AB - OBJECTIVES: To evaluate the influence of prostate-specific antigen density (PSAD) on positive (PPV) and negative (NPV) predictive values of multiparametric magnetic resonance imaging (mpMRI) to detect Gleason score >=7 cancer in a repeat biopsy setting. PATIENTS AND METHODS: Retrospective study of 514 men with previous prostate biopsy showing no or Gleason score 6 cancer. All had mpMRI, graded 1-5 on a Likert scale for cancer suspicion, and subsequent targeted and 24 core systematic image-fusion guided transperineal biopsy in 2013-2015. The NPVs and PPVs of mpMRIs for detecting Gleason score >=7 cancer were calculated (+/-95% confidence intervals) for PSAD <=0.1, 0.1-0.2, <=0.2 and >0.2 ng/mL/mL, and compared by chi-square test for linear trend. RESULTS: Gleason score >=7 cancer was detected in 31% of the men. The NPV of Likert 1-2 mpMRI was 0.91 (+/-0.04) with a PSAD of <=0.2 ng/mL/mL and 0.71 (+/-0.16) with a PSAD of >0.2 ng/mL/mL (P = 0.003). For Likert 3 mpMRI, PPV was 0.09 (+/-0.06) with a PSAD of <=0.2 ng/mL/mL and 0.44 (+/-0.19) with a PSAD of >0.2 ng/mL/mL (P = 0.002). PSAD also significantly affected the PPV of Likert 4-5 mpMRI lesions: the PPV was 0.47 (+/ 0.08) with a PSAD of <=0.2 ng/mL/mL and 0.66 (+/-0.10) with a PSAD of >0.2 ng/mL/mL (P < 0.001). CONCLUSION: In a repeat biopsy setting, a PSAD of <=0.2 ng/mL/mL is associated with low detection of Gleason score >=7 prostate cancer, not only in men with negative mpMRI, but also in men with equivocal imaging. Surveillance, rather than repeat biopsy, may be appropriate for these men. Conversely, biopsies are indicated in men with a high PSAD, even if an mpMRI shows no suspicious lesion, and in men with an mpMRI suspicious for cancer, even if the PSAD is low. PMID- 27488932 TI - Pathological Features of Fatal Crocodile Attacks in Northern Australia, 2005 2014. AB - Eleven deaths from crocodile attacks in the Northern Territory, Australia were reviewed. The male:female ratio was 8:3; age range-10-62 years, average 29.4 years. Four children were included (one boy and three girls, aged 10, 11, and two at 12 years), and there were seven aboriginal victims (64%). The attacks were witnessed in eight cases with the victims swimming in freshwater N = 5, standing on a river bank N = 1, fishing in fresh water N = 1, or diving in the sea N = 1. At autopsy, several distinct patterns of injury were observed ranging from complete traumatic disruption of the body with only incomplete remains for examination (N = 5), to crushing of the head with fractures of the skull (N = 4), crushing of the chest with fractures of the ribs and sternum (N = 2), and avulsion of limbs (N = 4). In one case, there was decapitation. Autopsy evaluations were complicated by decomposition and loss of body parts. PMID- 27488933 TI - Effect of the allelic variants of ABCB1, CYP2D6 and HTR3B on response of ramosetron to prevent chemotherapy-induced nausea and vomiting in Korean cancer patients. AB - AIM: Despite appropriate use of antiemetics including 5-hydroxytryptamine type 3 (5-HT3 ) receptor antagonists, chemotherapy-induced nausea and vomiting (CINV) is still an unsolved problem in patients with anticancer drugs. We examined whether the variants of ABCB1, CYP2D6 and HTR3B affect efficacy of ramosetron, a selective 5-HT3 receptor antagonist in a dose escalation clinical trial. METHODS: We conducted a clinical trial on patients who underwent FOLFOX combination chemotherapy. The participants were randomized into three groups of ramosetron: 0.3 mg (standard dose), 0.45 mg and 0.6 mg. Rhodes index of nausea, vomiting and retching were measured at 1, 6 h, day 1, day 2 and day 7 after the administration of ramosetron as a clinical parameter of CINV and polymorphism was analyzed from genomic DNA. RESULTS: There was a dose-dependent decrease in the nausea and vomiting scores at day 1 and day 2, not statistically significant. The Rhodes index of nausea, vomiting and retching score at day 1 in participants with HTR3B 100_-102delAAG deletion variants was significantly higher than wild type participants, regardless of dosages. However, the polymorphisms including ABCB1, CYP2D6 and other HTR3B genes did not affect response to ramosetron after chemotherapy. CONCLUSION: These results suggest that the -AAG deletion variant of the 5-HT3B receptor gene may contribute to variability in response to antiemetic therapy for CINV regardless of dose escalation. These results suggest that carrying a -100_-102delAAG variant of 5-HT3 gene should be supported by alternate or additive antiemetics in addition to 5-HT3 antagonists to control acute emesis. PMID- 27488934 TI - The CelluTome epidermal graft-harvesting system: a patient-reported outcome measure and cost evaluation study. AB - Conventional split skin grafts (SSG) require anaesthesia, specialist equipment and can have high donor site (DS) morbidity. The CelluTome epidermal graft harvesting device is a novel alternative, providing pain-free epidermal skin grafts (ESG) in the outpatient setting, with projected minimal DS trauma and improved patient satisfaction. This study aimed to compare ESG with SSG by evaluating patient-related outcome measures (PROMs) and the cost implications of both. Twenty patients answered a graft satisfaction questionnaire that evaluated: donor/graft site noticeability, aesthetic concerns, adverse problems and patient satisfaction. Cost/patient was calculated based on total operative expenses and five clinic follow-ups. In 100% of the ESG cases, there were no DS noticeability or adverse problems compared to 25% in the SSG group. Complete satisfaction with DS appearance was observed in 100% of the ESG cases (50% SSG). Noticeability, adverse problems and overall satisfaction were significantly better in ESG cases (P < 0.05). Graft site parameters were comparable with similar healing outcomes. The cost per patient for ESG was L431 and L1489 for SSG, with an annual saving of L126 960 based on 10 grafts/month. For the right patient, CelluTome provides comparable wound healing, with reduced DS morbidity and higher patient satisfaction. PMID- 27488935 TI - Assumption-versus data-based approaches to summarizing species' ranges. AB - For conservation decision making, species' geographic distributions are mapped using various approaches. Some such efforts have downscaled versions of coarse resolution extent-of-occurrence maps to fine resolutions for conservation planning. We examined the quality of the extent-of-occurrence maps as range summaries and the utility of refining those maps into fine-resolution distributional hypotheses. Extent-of-occurrence maps tend to be overly simple, omit many known and well-documented populations, and likely frequently include many areas not holding populations. Refinement steps involve typological assumptions about habitat preferences and elevational ranges of species, which can introduce substantial error in estimates of species' true areas of distribution. However, no model-evaluation steps are taken to assess the predictive ability of these models, so model inaccuracies are not noticed. Whereas range summaries derived by these methods may be useful in coarse-grained, global-extent studies, their continued use in on-the-ground conservation applications at fine spatial resolutions is not advisable in light of reliance on assumptions, lack of real spatial resolution, and lack of testing. In contrast, data-driven techniques that integrate primary data on biodiversity occurrence with remotely sensed data that summarize environmental dimensions (i.e., ecological niche modeling or species distribution modeling) offer data-driven solutions based on a minimum of assumptions that can be evaluated and validated quantitatively to offer a well-founded, widely accepted method for summarizing species' distributional patterns for conservation applications. PMID- 27488937 TI - An in situ FTIR spectroscopic and thermogravimetric analysis study of the dehydration and dihydroxylation of SnO2: the contribution of the (100), (110) and (111) facets. AB - Nanoparticulate SnO2 produced by a hydrothermal method was characterised by BET, XRD, TGA-MS and in situ variable temperature diffuse reflectance infra red spectroscopy (DRIFTS) to determine the surface behaviour of water. For the (100) facets, hydrogen bonding does not occur, and water adsorption is less strong than for the (111) and (110) facets where hydrogen bonding does occur. Reversible uptake of oxygen was observed. These findings have implications for other surface gas reactions in which Ni and Sb co-doped SnO2 (NATO) anodes are used for ozone generation. BET showed the relatively high surface area and nanometer scale of the SnO2 particles, whilst XRD confirmed the nano dimension of the crystallites and showed only the cassiterite phase. TGA analysis indicated four temperature regions over which mass loss was observed. These and the in situ DRIFTS studies revealed the existence of various forms of water associated with specific crystal facets of the SnO2, as well as the existence of isolated O-H groups and adsorbed oxygen species. Electronic absorptions were also observed and the data rationalised in terms of the existence of both free electron absorptions, and absorptions from oxygen vacancy states. The role of adsorbed molecular oxygen in electrochemical ozone generation at Ni and Sb co-doped SnO2 (NATO) anodes was strongly suggested by this work. PMID- 27488938 TI - Synthetic receptor molecules for selective fluorescence detection of 8-oxo-dGTP in aqueous media. AB - A series of 9-hydroxy-1,3-diazaphenoxazine-2-one derivatives were synthesized as fluorescent receptor molecules for 8-oxo-dGTP, which attach the cyclen-zinc complex at the 3-N position as the binding site for the triphosphate and the (2 aryloxycarbonylamino)ethyl group at the 9-O position as the hydrogen bonding site for 8-oxoguanine. Among these molecules, the receptor molecule 5a-Zn constructed of the ethyl linker at 3-N and the (2-benzyloxycarbonyl amino)ethyl group at 9-O displayed the best recognition ability for 8-oxoguanosine triphosphate (8-oxo dGTP) in aqueous media. The receptor 5a-Zn was also shown to selectively detect 8 oxo-dGTP in a cell lysate solution. PMID- 27488936 TI - Large-scale analysis reveals populational contributions of cortical spike rate and synchrony to behavioural functions. AB - KEY POINTS: There have been few systematic population-wide analyses of relationships between spike synchrony within a period of several milliseconds and behavioural functions. In this study, we obtained a large amount of spike data from > 23,000 neuron pairs by multiple single-unit recording from deep layer neurons in motor cortical areas in rats performing a forelimb movement task. The temporal changes of spike synchrony in the whole neuron pairs were statistically independent of behavioural changes during the task performance, although some neuron pairs exhibited correlated changes in spike synchrony. Mutual information analyses revealed that spike synchrony made a smaller contribution than spike rate to behavioural functions. The strength of spike synchrony between two neurons was statistically independent of the spike rate-based preferences of the pair for behavioural functions. ABSTRACT: Spike synchrony within a period of several milliseconds in presynaptic neurons enables effective integration of functional information in the postsynaptic neuron. However, few studies have systematically analysed the population-wide relationships between spike synchrony and behavioural functions. Here we obtained a sufficiently large amount of spike data among regular-spiking (putatively excitatory) and fast-spiking (putatively inhibitory) neuron subtypes (> 23,000 pairs) by multiple single-unit recording from deep layers in motor cortical areas (caudal forelimb area, rostral forelimb area) in rats performing a forelimb movement task. After holding a lever, rats pulled the lever either in response to a cue tone (external-trigger trials) or spontaneously without any cue (internal-trigger trials). Many neurons exhibited functional spike activity in association with forelimb movements, and the preference of regular-spiking neurons in the rostral forelimb area was more biased toward externally triggered movement than that in the caudal forelimb area. We found that a population of neuron pairs with spike synchrony does exist, and that some neuron pairs exhibit a dependence on movement phase during task performance. However, the population-wide analysis revealed that spike synchrony was statistically independent of the movement phase and the spike rate-based preferences of the pair for behavioural functions, whereas spike rates were clearly dependent on the movement phase. In fact, mutual information analyses revealed that the contribution of spike synchrony to the behavioural functions was small relative to the contribution of spike rate. Our large-scale analysis revealed that cortical spike rate, rather than spike synchrony, contributes to population coding for movement. PMID- 27488939 TI - Evolutionary dynamics of selfish DNA explains the abundance distribution of genomic subsequences. AB - Since the sequencing of large genomes, many statistical features of their sequences have been found. One intriguing feature is that certain subsequences are much more abundant than others. In fact, abundances of subsequences of a given length are distributed with a scale-free power-law tail, resembling properties of human texts, such as Zipf's law. Despite recent efforts, the understanding of this phenomenon is still lacking. Here we find that selfish DNA elements, such as those belonging to the Alu family of repeats, dominate the power-law tail. Interestingly, for the Alu elements the power-law exponent increases with the length of the considered subsequences. Motivated by these observations, we develop a model of selfish DNA expansion. The predictions of this model qualitatively and quantitatively agree with the empirical observations. This allows us to estimate parameters for the process of selfish DNA spreading in a genome during its evolution. The obtained results shed light on how evolution of selfish DNA elements shapes non-trivial statistical properties of genomes. PMID- 27488940 TI - Containment of Ebola and Polio in Low-Resource Settings Using Principles and Practices of Emergency Operations Centers in Public Health. AB - Emergency Operations Centers (EOCs) have been credited with driving the recent successes achieved in the Nigeria polio eradication program. EOC concept was also applied to the Ebola virus disease outbreak and is applicable to a range of other public health emergencies. This article outlines the structure and functionality of a typical EOC in addressing public health emergencies in low-resource settings. It ascribes the successful polio and Ebola responses in Nigeria to several factors including political commitment, population willingness to engage, accountability, and operational and strategic changes made by the effective use of an EOC and Incident Management System. In countries such as Nigeria where the central or federal government does not directly hold states accountable, the EOC provides a means to improve performance and use data to hold health workers accountable by using innovative technologies such as geographic position systems, dashboards, and scorecards. PMID- 27488941 TI - Impact of preoperative antithrombotic therapy on blood management after implantation of primary total knee arthroplasty. AB - Red blood cell concentrates (RCC) substitution after total knee arthroplasty (TKA) is correlated with multifold of complications and an independent predictor for higher postoperative mortality. TKA is mainly performed in elderly patients with pre-existing polymorbidity, often requiring permanent preoperative antithrombotic therapy (PAT). The aim of this retrospective analysis was to investigate the impact of demand for PAT on inpatient blood management in patients undergoing TKA. In this study 200 patients were retrospectively evaluated after TKA for differences between PAT and non-PAT regarding demographic parameters, preoperative ASA score > 2, duration of operation, pre-, and intraoperative hemoglobin level, and postoperative parameters including amount of wound drainage, RCC requirement, and inpatient time. In a multivariate logistic regression analysis the independent influences of PAT, demographic parameters, ASA score > 2, and duration of the operation on RCC demand following TKA were analyzed. Patients with PAT were significantly older, more often had an ASA > 2 at surgery, needed a higher number of RCCs units and more frequently and had lower perioperative hemoglobin levels. Multivariate logistic regression revealed PAT was an independent predictor for RCC requirement. PAT patients are more likely to require RCC following TKA and should be accurately monitored with respect to postoperative blood loss. PMID- 27488942 TI - Artemisinin-A Gift from Traditional Chinese Medicine to the World (Nobel Lecture). AB - Malaria has long been a devastating and life-threatening global epidemic disease in human history. Artemisinin, the active substance against malaria, was first isolated and tested in the 1970s in China. The important role played by traditional Chinese medicine in the discovery of artemisinin is described by Y. Tu in her Nobel Lecture. PMID- 27488943 TI - New hope for chronic myelogenous leukemia patients: dasatinib offers better efficacy with shorter treatment. AB - Although the discovery of tyrosine kinase inhibitors (TKIs) has dramatically improved the prognoses of chronic myelogenous leukemia (CML) patients, a cure has remained elusive. Unanswered questions include how long must a patient continue on TKI therapy, and how does a patient know when he/she can safely stop or finish this therapy? Imagawa et al. have carefully addressed these questions of safety and efficacy using a stop study of the second-generation TKI dasatinib. The results of a multicenter phase II trial termed the "dasatinib discontinuation" (DADI) trial indicated that 48% (30/63) of CML patients who had maintained a deep molecular response (DMR) to second-line or subsequent dasatinib therapy for at least for 1 year did not show any signs of disease relapse. Thus, even after it is stopped, dasatinib treatment may decrease the chance of disease relapse and provide a curative benefit to CML patients. This work by Imagawa et al. strongly supports the clinical utility of the second-generation TKI dasatinib for CML treatment. PMID- 27488944 TI - An evaluation of the effect of an angiotensin-converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: a randomised placebo-controlled trial (AARDVARK). AB - BACKGROUND: Although data are inconsistent, angiotensin-converting enzyme inhibitors (ACE-Is) have been associated with a reduced incidence of abdominal aortic aneurysm (AAA) rupture in analysis of administrative databases. OBJECTIVES: (1) To investigate whether or not the ACE-I perindopril (Coversyl arginine, Servier) reduces small AAA growth rate and (2) to evaluate blood pressure (BP)-independent effects of perindopril on small AAA growth and to compare the repeatability of measurement of internal and external aneurysm diameters. DESIGN: A three-arm, multicentre, single-blind, randomised placebo controlled trial. SETTING: Fourteen hospitals in England. PARTICIPANTS: Men or women aged >= 55 years with an AAA of 3.0-5.4 cm in diameter by internal or external measurement according to ultrasonography and who met the trial eligibility criteria. INTERVENTIONS: Patients were randomised to receive 10 mg of perindopril arginine daily, 5 mg of the calcium channel blocker amlodipine daily or placebo daily. MAIN OUTCOME MEASURES: The primary outcome was AAA diameter growth using external measurements in the longitudinal plane, which in-trial studies suggested was the preferred measure. Secondary outcome measures included AAA rupture, AAA repair, modelling of the time taken for the AAA to reach the threshold for intervention (5.5 cm) or referral for surgery, tolerance of study medication (measured by compliance, adverse events and quality of life) and a comparison of the repeatability of measures of internal and external AAA diameter. Patients were followed up every 3-6 months over 2 years. RESULTS: In total, 227 patients were recruited and randomised into the three groups, which were generally well matched at baseline. Multilevel modelling was used to determine the maximum likelihood estimates for AAA diameter growth. No significant differences in the estimates of annual growth were apparent [1.68 (standard error 0.02) mm, 1.77 (0.02) mm and 1.81 (0.02) mm in the placebo, perindopril and amlodipine groups, respectively]. Similarly, no significant differences in the slopes of modelled growth over time were apparent between perindopril and placebo (p = 0.78) or between perindopril and amlodipine (p = 0.89). The results were essentially unaffected by adjustment for potential confounders. Compliance, measured by pill counts, was good throughout (> 80% at all visit time points). There were no significant in-trial safety concerns. Six patients withdrew because of adverse events attributed to the study medications (n = 2 perindopril, n = 4 amlodipine). No patients ruptured their AAA and 27 underwent elective surgery during the trial (n = 9 placebo, n = 10 perindopril, n = 8 amlodipine). CONCLUSIONS: We were unable to demonstrate a significant impact of perindopril compared with placebo or amlodipine on small AAA growth over a 2 year period. Furthermore, there were no differences in the times to reach a diameter of 5.5 cm or undergo surgery among the three groups. Perindopril and amlodipine were well tolerated by this population. External AAA measurements were found to be more repeatable than internal measurements. The observed AAA growth measurement variability was greater than that expected pre trial. This, combined with slower than expected mean growth rates, resulted in our having limited power to detect small differences between growth rates and hence this adds uncertainty to the interpretation of the results. Several further analyses are planned including a multivariate analysis of determinants of AAA growth, an evaluation of the possible differential effect of perindopril on fast AAA growth and an investigation into the roles of central BP and BP variability on AAA growth. TRIAL REGISTRATION: Current Controlled Trials ISRCTN51383267. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 59. See the NIHR Journals Library website for further project information. The NIHR Biomedical Research Centre based at Imperial College NHS Trust supported the trial. Servier provided perindopril at no charge. PMID- 27488946 TI - Phylogeographic Patterns in Africa and High Resolution Delineation of Genetic Clades in the Lion (Panthera leo). AB - Comparative phylogeography of African savannah mammals shows a congruent pattern in which populations in West/Central Africa are distinct from populations in East/Southern Africa. However, for the lion, all African populations are currently classified as a single subspecies (Panthera leo leo), while the only remaining population in Asia is considered to be distinct (Panthera leo persica). This distinction is disputed both by morphological and genetic data. In this study we introduce the lion as a model for African phylogeography. Analyses of mtDNA sequences reveal six supported clades and a strongly supported ancestral dichotomy with northern populations (West Africa, Central Africa, North Africa/Asia) on one branch, and southern populations (North East Africa, East/Southern Africa and South West Africa) on the other. We review taxonomies and phylogenies of other large savannah mammals, illustrating that similar clades are found in other species. The described phylogeographic pattern is considered in relation to large scale environmental changes in Africa over the past 300,000 years, attributable to climate. Refugial areas, predicted by climate envelope models, further confirm the observed pattern. We support the revision of current lion taxonomy, as recognition of a northern and a southern subspecies is more parsimonious with the evolutionary history of the lion. PMID- 27488947 TI - Metformin Enhances the Therapy Effects of Anti-IGF-1R mAb Figitumumab to NSCLC. AB - The insulin-like growth factor (IGF) signaling system plays a critical role in tumorigenesis, highlighting the potential of targeting IGF-1R as an anti-cancer therapy. Although multiple anti-IGF-1R monoclonal antibody (mAb) drugs have been developed, challenges remain in the validation of the therapeutic effects and understanding the molecular mechanism of these mAbs. Herein, we conducted a study to validate the effect of Figitumumab (CP), an anti-IGF-1R mAb, in a panel of non small cell lung cancer (NSCLC) cell lines. We found all tested cell lines were sensitive to CP, and CP could block IGF-1R and the downstream PI3K/AKT pathway activation. Unexpectedly, we found CP could activate ERK signaling pathway in IGF 1R kinase independent manner, which we further verified was mainly mediated by beta-arrestin2. We also investigated the anti-tumor effect of metformin alone as well as its combination with CP to target NSCLC. Metformin could target IGF-1R signaling pathway by attenuating PI3K/AKT and MEK/ERK signaling pathways and down regulating IGF-1R. Finally, we found that combining metformin with CP could further induce IGF-1R down-regulation and was more effective to target NSCLC cells. Our data suggests the combining of metformin with CP has additive therapeutic value against NSCLC. PMID- 27488948 TI - Novel reovirus associated with epidemic mortality in wild largemouth bass (Micropterus salmoides). AB - Reoviruses (family Reoviridae) infect vertebrate and invertebrate hosts with clinical effects ranging from inapparent to lethal. Here, we describe the discovery and characterization of Largemouth bass reovirus (LMBRV), found during investigation of a mortality event in wild largemouth bass (Micropterus salmoides) in 2015 in WI, USA. LMBRV has spherical virions of approximately 80 nm diameter containing 10 segments of linear dsRNA, aligning it with members of the genus Orthoreovirus, which infect mammals and birds, rather than members of the genus Aquareovirus, which contain 11 segments and infect teleost fishes. LMBRV is only between 24 % and 68 % similar at the amino acid level to its closest relative, Piscine reovirus (PRV), the putative cause of heart and skeletal muscle inflammation of farmed salmon. LMBRV expands the known diversity and host range of its lineage, which suggests that an undiscovered diversity of related pathogenic reoviruses may exist in wild fishes. PMID- 27488949 TI - More tolerance for dendritic cells in psoriasis. PMID- 27488950 TI - Photoactive platinum(ii) beta-diketonates as dual action anticancer agents. AB - Platinum(ii) complexes, viz. [Pt(L)(cur)] (1), [Pt(L)(py-acac)] (2) and [Pt(L)(an acac)] (3), where HL is 4,4'-bis-dimethoxyazobenzene, Hcur is curcumin, Hpy-acac and Han-acac are pyrenyl and anthracenyl appended acetylacetone, were prepared, characterized and their anticancer activities were studied. Complex [Pt(L)(acac)] (4) was used as a control. Complex 1 showed an absorption band at 430 nm (epsilon = 8.8 * 10(4) M(-1) cm(-1)). The anthracenyl and pyrenyl complexes displayed bands near 390 nm (epsilon = 3.7 * 10(4) for 3 and 4.4 * 10(4) M(-1) cm(-1) for 2). Complex 1 showed an emission band at 525 nm (Phi = 0.017) in 10% DMSO-DPBS (pH, 7.2), while 2 and 3 were blue emissive (lambdaem = 440 and 435, Phi = 0.058 and 0.045). There was an enhancement in emission intensity on glutathione (GSH) addition indicating diketonate release. The platinum(ii) species thus formed acted as a transcription inhibitor. The released beta-diketonate base showed photo-chemotherapeutic activity. The complexes photocleaved plasmid DNA under blue light of 457 nm forming ~75% nicked circular (NC) DNA with hydroxyl radicals and singlet oxygen as the ROS. Complexes 1-3 were photocytotoxic in skin keratinocyte HaCaT cells giving IC50 of 8-14 MUM under visible light (400-700 nm, 10 J cm(-2)), while being non-toxic in the dark (IC50: ~60 MUM). Complex 4 was inactive. Complexes 1-3 generating cellular ROS caused apoptotic cell death under visible light as evidenced from DCFDA and annexin-V/FITC-PI assays. This work presents a novel way to deliver an active platinum(ii) species and a phototoxic beta-diketone species to the cancer cells. PMID- 27488951 TI - Intraperitoneal injection (IP), Intravenous injection (IV) or anal injection (AI)? Best way for mesenchymal stem cells transplantation for colitis. AB - Stem cell transplantation showed promising results in IBD management. However, the therapeutic impacts of cell delivery route that is critical for clinical translation are currently poorly understood. Here, three different MSCs delivery routes: intraperitoneal (IP), intravenous (IV), and anal injection (AI) were compared on DSS-induced colitic mice model. The overall therapeutic factors, MSCs migration and targeting as well as local immunomodulatory cytokines and FoxP3(+) cells infiltration were analyzed. Colitis showed varying degrees of alleviation after three ways of MSCs transplantation, and the IP injection showed the highest survival rate of 87.5% and displayed the less weight loss and quick weight gain. The fecal occult blood test on the day 3 also showed nearly complete absence of occult blood in IP group. The fluorescence imaging disclosed higher intensity of engrafted cells in inflamed colon and the corresponding mesentery lymph nodes (MLNs) in IP and AI groups than the IV group. Real time-PCR and ELISA also demonstrate lower TNF-alpha and higher IL-10, TSG-6 levels in IP group. The immunohistochemistry indicated higher repair proliferation (Ki-67) and more FoxP3(+) cells accumulation of IP group. IP showed better colitis recovery and might be the optimum MSCs delivery route for the treatment of DSS-induced colitis. PMID- 27488952 TI - Postoperative ileus: in search of an international consensus on definition, diagnosis, and treatment. AB - PURPOSE: Postoperative ileus (POI) is a frequent complication after abdominal surgery; nonetheless, it remains poorly defined. Our aim was to achieve an international consensus among leading colorectal surgeons on definition, prevention, and treatment of POI. METHODS: Thirty-five experts from five continents participated in a three-round Delphi process. Round 1 contained open ended questions on POI and postoperative nausea and vomiting (PONV). Round 2 included closed-ended questions. Round 3 measured agreement on a 5-point Likert scale. Consensus was defined when items were rated as agree or strongly agree by at least 70 % of the experts. RESULTS: Experts reached following consensus: POI is a temporary inhibition (86 %) of gastrointestinal motility after surgical intervention due to non-mechanical causes (89 %) and prevents sufficient oral intake (96 %). Abdominal distension/tenderness are the most relevant clinical signs (71 %). Nasogastric tube placement is not mandatory (78 %) but can be removed without previous clamping (81 %)/gastrointestinal contrast study (100 %). Preventive measures are recommended to decrease the risk of POI (96 %): narcotic sparing analgesia (89 %) and fluid optimization (74 %). Treatment of POI should include stimulation of ambulation (96 %) and stop of opioids (74 %). Total parenteral nutrition is recommended from the 7th day without sufficient oral intake (81 %). There was no consensus on the ranking of POI's symptoms, on the imaging modality of choice for the diagnosis of POI, neither on the difference between POI and PONV. CONCLUSIONS: This Delphi study achieved consensus on the definition, relevant clinical signs, prevention, treatment, and supportive care of POI. Areas of non-consensus were identified (necessity and modality of radiologic imaging to establish the diagnosis, difference between POI and PONV), giving opportunity for further research. PMID- 27488953 TI - Gastric cancer from operating theatre to bench in Korea. PMID- 27488954 TI - Ionic imbalance induced self-propulsion of liquid metals. AB - Components with self-propelling abilities are important building blocks of small autonomous systems and the characteristics of liquid metals are capable of fulfilling self-propulsion criteria. To date, there has been no exploration regarding the effect of electrolyte ionic content surrounding a liquid metal for symmetry breaking that generates motion. Here we show the controlled actuation of liquid metal droplets using only the ionic properties of the aqueous electrolyte. We demonstrate that pH or ionic concentration gradients across a liquid metal droplet induce both deformation and surface Marangoni flow. We show that the Lippmann dominated deformation results in maximum velocity for the self propulsion of liquid metal droplets and illustrate several key applications, which take advantage of such electrolyte-induced motion. With this finding, it is possible to conceive the propulsion of small entities that are constructed and controlled entirely with fluids, progressing towards more advanced soft systems. PMID- 27488956 TI - Biosequestration of copper by bacteria isolated from an abandoned mine by using microbially induced calcite precipitation. AB - Abandoned mine sites are frequently polluted with high concentrations of heavy metals. In this study, 25 calcite-forming bacteria were newly isolated from the soil of an abandoned metal mine in Korea. Based on their urease activity, calcite production, and resistance to copper toxicity, four isolates were selected and further identified by 16S rRNA gene sequencing. Among the isolates, Sporosarcina soli B-22 was selected for subsequent copper biosequestration studies, using the sand impermeability test by production of calcite and extracellular polymeric substance. High removal rates (61.8%) of copper were obtained when the sand samples were analyzed using an inductively coupled plasma-optical emission spectrometer following 72 h of incubation. Scanning electron microscopy showed that the copper carbonate precipitates had a diameter of approximately 5-10 MUm. X-ray diffraction further confirmed the presence of copper carbonate and calcium carbonate crystals. PMID- 27488955 TI - Propofol Is Mitochondrion-Toxic and May Unmask a Mitochondrial Disorder. AB - There are indications that preexisting mitochondrial disorders or beta-oxidation defects predispose for propofol infusion syndrome. This review aimed at investigating if propofol infusion syndrome occurs exclusively in patients with mitochondrial disorder and if propofol can unmask a mitochondrial disorder. Propofol infusion syndrome has been reported in genetically confirmed mitochondrial disorder patients. In addition, muscle biopsy of patients with propofol infusion syndrome revealed complex IV or complex II deficiency. In animal studies propofol disrupted the electron flow along the respiratory chain and decreased complex I, complex II, and complex III of the respiratory chain. In addition, propofol disrupted the permeability transition pore and reduced the mitochondrial membrane potential. In conclusion, propofol is mitochondrion-toxic and mitochondrial disorder patients should not receive propofol in high dosages over a prolonged period of time. Short-term application of propofol should be safe even in mitochondrial disorder patients. Not only does propofol infusion syndrome occur in mitochondrial disorder patients, but mitochondrial disorder patients are likely at higher risk to develop propofol infusion syndrome. Patients who develop propofol infusion syndrome should be screened for mitochondrial disorder. Propofol infusion syndrome is preventable if risk factors are thoroughly assessed, and if long-term propofol is avoided in patients at risk for propofol infusion syndrome. PMID- 27488957 TI - Rhodococcus jostii RHA1 TadA-homolog deletion mutants accumulate less polyhydroxyalkanoates (PHAs) than the parental strain. PMID- 27488958 TI - Corticosteroids: the knee jerk response. PMID- 27488959 TI - When Terminal Illness Is Worse Than Death: A Multicenter Study of Health-Care Providers' Resuscitation Desires. AB - PURPOSE: To investigate how a terminal illness may affect the health-care providers' resuscitation preferences. METHODS: We conducted a cross-sectional survey in 9 health-care institutions located in 4 geographical regions in North and Central America, investigating attitudes toward end-of-life practices in health-care providers. Statistical analysis included descriptive statistics and chi2 test for the presence of associations ( P < 0.05 being significant) and Cramer V for the strength of the association. The main outcome measured the correlation between the respondents' present code status and their preference for cardiopulmonary resuscitation (CPR) in case of terminal illness. RESULTS: A total of 852 surveys were completed. Among the respondents, 21% (n = 180) were physicians, 36.9% (n = 317) were nurses, 10.5% (n = 90) were medical students, and 265 participants were other staff members of the institutions. Most respondents (58.3%; n = 500) desired "definitely full code" (physicians 73.2%; n = 131), only 13.8% of the respondents (physicians 8.33%; n = 15) desired "definitely no code" or "partial support," and 20.9% of the respondents (n = 179; among physicians 18.4%; n = 33) had never considered their code status. There was an association between current code status and resuscitation preference in case of terminal illness ( P < .001), but this association was overall quite weak (Cramer V = 0.180). Subgroup analysis revealed no association between current code status and terminal illness code preference among physicians ( P = .290) and nurses ( P = .316), whereupon other hospital workers were more consistent ( P < .01, Cramer V = .291). CONCLUSION: Doctors and nurses have different end-of-life preferences than other hospital workers. Their desire to undergo CPR may change when facing a terminal illness. PMID- 27488960 TI - Macondo oil in deep-sea sediments: Part 1 - sub-sea weathering of oil deposited on the seafloor. AB - Chemical analysis of sediment cores collected up to 8km from the Macondo well in 2010/2011 demonstrates the extent of weathering of the Macondo oil deposited in deep-sea sediments following the Deepwater Horizon disaster. On average, dissolution and biodegradation of the oil on the seafloor increased with distance from the well indicating that weathering occurred rapidly and overwhelmingly during the oil's transport as dispersed oil droplets within the deep-sea plume. Beyond about 5km from the well, the oil deposited on the seafloor had lost most mass below C25, was relatively enriched in n-C25+ n-alkanes and C3- and C4 alkylated benz[a]anthracenes/chrysenes, the latter owing to 95% depletion of total PAHs. Biodegradation of C28 and C29 tricyclic terpanes, C34 and C35 17alpha(H),21beta(H)-homohopanes, C27 13beta(H),17alpha(H)-dia and C27 14beta(H),17beta(H)-steranes and dissolution of C26 to C28 triaromatic steroids occurred. The results provide a means to distinguish Macondo oil in deep-sea sediments from naturally-occurring seep oils and pervasive ambient background hydrocarbons. PMID- 27488961 TI - Curvature of iris profile in spectral domain optical coherence tomography and dependency to refraction, age and pupil size - the MIPH Eye&Health Study. AB - PURPOSE: Optical coherence tomography (OCT) of the anterior segment allows quantitative analysis of the geometry of the iris. We performed spectral domain OCT examinations in healthy emmetropic, hyperopic and myopic subjects to investigate iris curvature and its associations. METHODS: In a cross-sectional study, out of 4617 eyes (2309 subjects) those with refractive errors of <-4 or >+3 dioptres were identified by objective refraction. The iris was examined using the anterior segment mode of a spectral domain 3D OCT-2000 (Topcon Inc., Japan) in the temporal meridian, and OCT scans were investigated with respect to presence and amount of convex and concave iris configuration. Ninety-three eyes of 50 subjects served as emmetropic group (-0.5 <= x <=+0.5 dioptres). Previous ocular surgery was exclusion criterion. RESULTS: Six hundred and sixty-eight eyes of 398 persons [292 male (76%); age range; 18-66 years] were included in the study. In the myopic group, 105 eyes had a concave iris configuration (26%), while in the hyperopic group, no eye had this configuration (0%) and in the emmetropic group five eyes (5%). Convex iris configuration was found in 96% of hyperopic, in 85% of the emmetropic and in 67% of the myopic eyes. There was an association between concave iris configuration and myopia, younger age and male gender, and with anterior chamber angle width. CONCLUSION: Spectral domain OCT images can be used for analysis of the iris structure and geometry. Our results are limited to the properties of the study population having an age range from 18 to 66 years and consisting mainly of men. PMID- 27488963 TI - Primary Noncutaneous Malignant Melanoma of the Breast. AB - Primary noncutaneous breast melanoma without an apparent skin primary lesion is uncommon. Its pathogenesis is debated with some authors believing that it is a metastatic disease from an undiscovered primary or a primary that has since completely regressed but it may be a true primary tumor arising from ectopic melanocytes. We present a case of a V600E BRAF mutation-positive primary noncutaneous breast melanoma diagnosed at an early stage in a screening mammogram as a solitary breast lesion without nodal involvement. Considerations of treatment of this rare disease are discussed. PMID- 27488962 TI - Normal stroma suppresses cancer cell proliferation via mechanosensitive regulation of JMJD1a-mediated transcription. AB - Tissue homeostasis is dependent on the controlled localization of specific cell types and the correct composition of the extracellular stroma. While the role of the cancer stroma in tumour progression has been well characterized, the specific contribution of the matrix itself is unknown. Furthermore, the mechanisms enabling normal-not cancer-stroma to provide tumour-suppressive signals and act as an antitumorigenic barrier are poorly understood. Here we show that extracellular matrix (ECM) generated by normal fibroblasts (NFs) is softer than the CAF matrix, and its physical and structural features regulate cancer cell proliferation. We find that normal ECM triggers downregulation and nuclear exit of the histone demethylase JMJD1a resulting in the epigenetic growth restriction of carcinoma cells. Interestingly, JMJD1a positively regulates transcription of many target genes, including YAP/TAZ (WWTR1), and therefore gene expression in a stiffness-dependent manner. Thus, normal stromal restricts cancer cell proliferation through JMJD1a-dependent modulation of gene expression. PMID- 27488964 TI - Ultrasound elastographic evaluation of the median nerve in hemodialysis with carpal tunnel syndrome. AB - PURPOSE: The aim of this study was to compare the elasticity of the median nerve (MN) between hemodialysis (HD) patients without carpal tunnel syndrome (CTS) and with CTS, and to evaluate the diagnostic usefulness of the elasticity of the MN in HD-CTS. MATERIALS AND METHODS: The MN in 22 HD patients without CTS and 49 HD CTS patients was studied. The cross-sectional area (CSA) and the elasticity of the MN, which was measured as the subcutaneous fat/median nerve (SF/MN) strain ratio, were evaluated. RESULTS: The mean SF/MN strain ratio in the groups that had received hemodialysis for 0-5, >5-10, and >10-15 years was 1.4 +/- 0.28, 1.7 +/- 0.18, and 2.0 +/- 0.67, respectively. The mean CSA of the MN in the three groups was 9.9 +/- 1.30, 11.6 +/- 1.61, and 13.4 +/- 2.14 mm2, respectively. The presence of CTS was predicted by means of SF/MN strain ratio and CSA cutoff values of 1.8 and 11 mm2, respectively. Both the SF/MN strain ratio and the CSA in the patients with CTS were higher than those in the patients without CTS (P < 0.05). The sensitivity and specificity of the SF/MN strain ratio and CSA of the MN were 75 and 92 % and 79.2 and 84 %, respectively. CONCLUSION: Sonoelastography helps to improve the diagnostic accuracy of the ultrasonographic assessment of CTS. PMID- 27488965 TI - Short cervix detection in pregnant women by transabdominal sonography with post void technique. AB - PURPOSE: This study aimed to evaluate the diagnostic properties of transabdominal sonography with the post-void technique for cervical length measurement. METHODS: This study was a prospective cohort study. The inclusion criteria were pregnant women aged 18-40 years with gestational age of 18-23 completed weeks. Transabdominal sonography with vertical bladder depth of less than 5 cm and transvaginal cervical length measurements were carried out by a single experienced sonographer. RESULTS: There were 307 eligible pregnant women. The mean age of all subjects was 29.0 years. The mean cervical length obtained through transabdominal and transvaginal measurement was 3.33 and 3.47 cm, respectively. Ten patients (3.3 %) were identified as having a short cervix using transvaginal sonography, and 12 patients (3.9 %) were identified using transabdominal sonography. CONCLUSION: Transabdominal sonography with vertical bladder depth of less than 5 cm performed better compared with transvaginal sonography. It may not be necessary to perform transvaginal sonography if transabdominal sonography reveals the cervical length to be more than 2.5 cm. PMID- 27488966 TI - Narrow QRS Tachycardia with RR Alternans: What Is the Mechanism? PMID- 27488967 TI - For Hospital Readmissions, Hindsight is Not 20/20. PMID- 27488968 TI - Approaching End-of-Life with Aplomb and Plombage. PMID- 27488969 TI - Using Adherence Information to Improve Care: From Clinic Visits to Populations. PMID- 27488971 TI - Capsule Commentary on Goodwin et al., Receipt of Cancer Screening is a Predictor of Life Expectancy. PMID- 27488972 TI - The Electrocardiogram Following Dynamic Cardiomyoplasty. PMID- 27488970 TI - Why Aren't More Primary Care Residents Going into Primary Care? A Qualitative Study. AB - BACKGROUND: Workforce projections indicate a potential shortage of up to 31,000 adult primary care providers by the year 2025. Approximately 80 % of internal medicine residents and nearly two-thirds of primary care internal medicine residents do not plan to have a career in primary care or general internal medicine. OBJECTIVE: We aimed to explore contextual and programmatic factors within primary care residency training environments that may influence career choices. DESIGN: This was a qualitative study based on semi-structured, in-person interviews. PARTICIPANTS: Three primary care internal medicine residency programs were purposefully selected to represent a diversity of training environments. Second and third year residents were interviewed. APPROACH: We used a survey guide developed from pilot interviews and existing literature. Three members of the research team independently coded the transcripts and developed the code structure based on the constant comparative method. The research team identified emerging themes and refined codes. ATLAS.ti was used for the analysis. KEY RESULTS: We completed 24 interviews (12 second-year residents, and 12 third-year residents). The age range was 27-39 years. Four recurrent themes characterized contextual and programmatic factors contributing to residents' decision-making: resident expectations of a career in primary care, navigation of the boundary between social needs and medical needs, mentorship and perceptions of primary care, and structural features of the training program. CONCLUSIONS: Addressing aspects of training that may discourage residents from careers in primary care such as lack of diversity in outpatient experiences and resident frustration with their inability to address social needs of patients, and strengthening aspects of training that may encourage interests in careers in primary care such as mentorship and protected time away from inpatient responsibilities during primary care rotations, may increase the proportion of residents enrolled in primary care training programs who pursue a career in primary care. PMID- 27488973 TI - HLA-DRB1*16:39, a novel HLA-DRB1*16 variant, discovered in a Taiwanese bone marrow hematopoietic stem cell donor. AB - One nucleotide substitution at residue 112 of the HLA-DRB1*16:02:01:01 results in a novel allele, HLA-DRB1*16:39. PMID- 27488974 TI - Complex High-Aspect-Ratio Metal Nanostructures by Secondary Sputtering Combined with Block Copolymer Self-Assembly. AB - High-resolution (10 nm), high-areal density, high-aspect ratio (>5), and morphologically complex nanopatterns are fabricated from a single conventional block copolymer (BCP) structure with a 70 nm scale resolution and an aspect ratio of 1, through the secondary-sputtering phenomenon during the Ar-ion-bombardment process. This approach provides a foundation for the design of new routes to BCP lithography. PMID- 27488975 TI - Overall and Gender-specific Associations between C-reactive Protein and Stroke Occurrence: A Cross-sectional Study in US. PMID- 27488976 TI - Multiple Embolic Infarction Due to a Primary Aortic Intimal Sarcoma. PMID- 27488977 TI - Imaging Predictors for Atherosclerosis-Related Intracranial Large Artery Occlusions in Acute Anterior Circulation Stroke. PMID- 27488978 TI - Extended Use of Hypothermia in Elderly Patients with Malignant Cerebral Edema as an Alternative to Hemicraniectomy. AB - BACKGROUND AND PURPOSE: The use of decompressive hemicraniectomy (DHC) for the treatment of malignant cerebral edema can decrease mortality rates. However, this benefit is not sufficient to justify its use in elderly patients. We investigated the effects of therapeutic hypothermia (TH) on safety, feasibility, and functional outcomes in elderly patients with malignant middle cerebral artery (MCA) infarcts. METHODS: Elderly patients 60 years of age and older with infarcts affecting more than two-thirds of the MCA territory were included. Patients who could not receive DHC were treated with TH. Hypothermia was started within 72 hours of symptom onset and was maintained for a minimum of 72 hours with a target temperature of 33 degrees C. Modified Rankin Scale (mRS) scores at 3 months following treatment and complications of TH were used as functional outcomes. RESULTS: Eleven patients with a median age of 76 years and a median National Institutes of Health Stroke Scale score of 18 were treated with TH. The median time from symptom onset to initiation of TH was 30.3+/-23.0 hours and TH was maintained for a median of 76.7+/-57.1 hours. Shivering (100%) and electrolyte imbalance (82%) were frequent complications. Two patients died (18%). The mean mRS score 3 months following treatment was 4.9+/-0.8. CONCLUSIONS: Our results suggest that extended use of hypothermia is safe and feasible for elderly patients with large hemispheric infarctions. Hypothermia may be considered as a therapeutic alternative to DHC in elderly individuals. Further studies are required to validate our findings. PMID- 27488979 TI - Neural Stem Cells and Ischemic Brain. AB - Stroke activates neural stem cells in the ventricular-subventricular zone (V/SVZ) of the lateral ventricle, which increases neuroblasts and oligodendrocyte progenitor cells (OPCs). Within the ischemic brain, neural stem cells, neuroblasts and OPCs appear to actively communicate with cerebral endothelial cells and other brain parenchymal cells to mediate ischemic brain repair; however, stroke-induced neurogenesis unlikely plays any significant roles in neuronal replacement. In this mini-review, we will discuss recent findings how intercellular communications between stroke-induced neurogenesis and oligodendrogenesis and brain parenchymal cells could potentially facilitate brain repair processes. PMID- 27488981 TI - Prevalence and Characteristics of Unruptured Cerebral Aneurysms in Ischemic Stroke Patients. AB - BACKGROUND AND PURPOSE: The prevalence of unruptured cerebral aneurysms (UCAs) in ischemic stroke patients is not clearly defined. This study aimed to measure the prevalence and characteristics of UCAs in patients with acute ischemic stroke (AIS) and to compare our findings with those of the general population. In addition, we investigated the factors associated with cerebral aneurysms in AIS patients. METHODS: We retrospectively reviewed the brain magnetic resonance angiography images of 955 patients with AIS and 2,118 controls who had received a brain magnetic resonance angiography as part of a health check-up. We investigated the prevalence, size, location, and risk factors of the subjects in the context of UCAs. RESULTS: UCAs were found in 74 patients with AIS (7.7%) and in 79 who received a health check-up (3.7%). The prevalence of UCAs was significantly higher in the AIS group than in the health check-up group (odds ratio 2.17, 95% confidence interval 1.56-3.01). The mean aneurysm diameter was larger in the AIS group than in the health check-up group (3.75 mm vs. 3.02 mm, P=0.009). UCAs were primarily located in the internal carotid artery in both groups, and aneurysms in the middle cerebral artery were particularly common in the AIS group. According to multivariate analysis, hypertension alone was associated with an increased prevalence of UCAs in stroke patients. CONCLUSIONS: This study identified a higher prevalence and larger size of UCAs in AIS patients than in the general population. Hypertension was an independent risk factor of UCA in AIS. PMID- 27488980 TI - Association between Aortic Atheroma and Cerebral Small Vessel Disease in Patients with Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Cerebral small vessel disease (SVDs) are related with large artery atherosclerosis. However, the association between aortic atheroma (AA) and cerebral small vessel disease has rarely been reported. This study evaluated the relationship between presence and burden of AAs and those of SVDs in patients with acute ischemic stroke. METHODS: We included 737 consecutive patients who underwent transesophageal echocardiography (TEE) and brain magnetic resonance imaging (MRI) for evaluation of acute stroke. AA subtypes were classified as complex aortic plaque (CAP) and simple aortic plaque (SAP). Presence and burden of SVDs including cerebral microbleeds (CMBs), white matter hyperintensities (WMHs), perivascular spaces (PVSs), asymptomatic lacunar infarctions (ALIs), and total SVD score, were investigated. RESULTS: AA was found by TEE in 360 (48.8%) patients including 11.6% with CAP and 37.2% with SAP. One or more types of SVDs was found in 269 (36.4%) patients. In multivariable analysis, presence of CMBs (odds ratio [OR] 4.68), high-grade WMHs (OR 3.13), high-grade PVSs (OR 3.35), and ALIs (OR 4.24) were frequent in patients with AA than those without AA. Each 1-point increase in total SVD score increased the odds of presence of CAP (OR 1.94, 95% confidence interval (CI) 1.44-1.85) and SAP (OR 1.54, 95% CI 1.35-1.75). CONCLUSIONS: In this study, patients with AA frequently had cerebral SVDs. Larger burden of AA was associated with advanced cerebral SVDs. Our findings give an additional information for positive relationship with systemic atherosclerosis and coexisting cerebral SVDs in acute ischemic stroke patients. PMID- 27488982 TI - Effects of Acute Exposure to Sublethal Waterborne Cadmium on Energy Homeostasis in Silver Carp (Hypophthalmichthys molitrix). AB - Effects of acute exposure to sublethal waterborne cadmium (Cd) on energy homeostasis in filter-feeding fishes have rarely been studied. The response patterns of energy substances were investigated in juvenile silver carp (Hypophthalmichthys molitrix) exposed to sublethal waterborne Cd for 96 h. The results showed the 96hLC50 of Cd on juvenile silver carp was 1.723 mg/L. Sublethal acute exposure of Cd significantly affected the energy homeostasis of juvenile silver carp, including increase in plasma glucose and lactate, and decrease in plasma triglyceride, muscle glycogen and triglyceride and liver glycogen. The results indicated that glycogen and triglyceride prior to protein were mobilized to meet the increased demands for detoxication and repair mechanism to sublethal waterborne Cd exposure, and glycogen level depleted faster and restored slower in the liver than in the white muscle in juvenile silver carp. PMID- 27488983 TI - Simplifying and enhancing the use of PyMOL with horizontal scripts. AB - Scripts are used in PyMOL to exert precise control over the appearance of the output and to ease remaking similar images at a later time. We developed horizontal scripts to ease script development. A horizontal script makes a complete scene in PyMOL like a traditional vertical script. The commands in a horizontal script are separated by semicolons. These scripts are edited interactively on the command line with no need for an external text editor. This simpler workflow accelerates script development. In using PyMOL, the illustration of a molecular scene requires an 18-element matrix of view port settings. The default format spans several lines and is laborious to manually reformat for one line. This default format prevents the fast assembly of horizontal scripts that can reproduce a molecular scene. We solved this problem by writing a function that displays the settings on one line in a compact format suitable for horizontal scripts. We also demonstrate the mapping of aliases to horizontal scripts. Many aliases can be defined in a single script file, which can be useful for applying costume molecular representations to any structure. We also redefined horizontal scripts as Python functions to enable the use of the help function to print documentation about an alias to the command history window. We discuss how these methods of using horizontal scripts both simplify and enhance the use of PyMOL in research and education. PMID- 27488985 TI - Antioxidant efficacy of Kalanchoe daigremontiana bufadienolide-rich fraction in blood plasma in vitro. AB - CONTEXT: The main source of bufadienolides is toad venom; however, plants such as members of Kalanchoe Adans. (Crassulaceae) genus may also synthesize these bioactive substances. OBJECTIVE: This is the first study on antioxidant effects and cytotoxicity of bufadienolide-rich fraction isolated from Kalanchoe daigremontiana Raym.-Hamet & H. Perrier. MATERIALS AND METHODS: The methanolic fraction was extracted from the plant roots and contained 0.48 mg bufadienolides/mg of dry mass (11alpha,19-dihydroksytelocinobufagin, bersaldegenin-1-acetate, bersaldegenin-1,3,5-orthoacetate, 19-(acetyloxy) 3beta,5beta,11alpha,14-tetrahydroxyl-12-oxo-bufa-20,22-dienolide and 19 (acetyloxy)-1beta,3beta,5beta,14-tetrahydroxyl-bufa-20,22-dienolide, mainly). The cytotoxicity of K. daigremontiana fraction was evaluated in an in vitro experimental model of blood platelets. The viability of blood platelets was determined on the basis of a release of lactate dehydrogenase. RESULTS: The fraction scavenged DPPH* radicals, with EC50 of 21.80 MUg/mL. Studies on an experimental model of blood plasma under peroxynitrite-induced oxidative stress revealed that the plant preparation had moderate antioxidant properties. Levels of 3-nitrotyrosine and thiol groups indicated that the protective effect of K. daigremontiana was significant mainly for its concentration of 50 MUg/mL. No effect was found in prevention of oxidation of low-molecular plasma thiols (glutathione, cysteine and cysteinylglycine). Simultaneously, measurements of lipid hydroperoxides and thiobarbituric acid-reactive substances (TBARS) indicated that the examined fraction might be effective antioxidant at broader concentration range, that is 1-5 and 25-50 MUg/mL for hydroperoxides and TBARS generation, respectively. No cytotoxicity was observed at the concentration range of 1-50 MUg/mL. CONCLUSIONS: Based on the obtained results, we suggest that antioxidant activity may additionally contribute to beneficial properties of K. daigremontiana-derived extracts. PMID- 27488984 TI - Second-line treatment for metastatic clear cell renal cell cancer: experts' consensus algorithms. AB - BACKGROUND: Second-line systemic treatment options for metastatic clear cell renal cell cancer (mccRCC) are diverse and treatment strategies are variable among experts. Our aim was to investigate the approach for the second-line treatment after first-line therapy with a tyrosine kinase inhibitor (TKI). Recently two phase III trials have demonstrated a potential role for nivolumab (NIV) and cabozantinib (CAB) in this setting. We aimed to estimate the impact of these trials on clinical decision making. MATERIALS AND METHODS: Eleven international experts were asked to provide their treatment strategies for second line systemic therapy for mccRCC in the current setting and once NIV and CAB will be approved and available. The treatment strategies were analyzed with the objective consensus approach. RESULTS: The analysis of the decision trees revealed everolimus (EVE), axitinib (AXI), NIV and TKI switch (sTKI) as therapeutic options after first-line TKI therapy in the current situation and mostly NIV and CAB in the future setting. The most commonly used criteria for treatment decisions were duration of response, TKI tolerance and zugzwang a composite of several related criteria. CONCLUSION: In contrast to the first-line setting, recommendations for second-line systemic treatment of mccRCC among experts were not as heterogeneous. The agents mostly used after disease progression on a first-line TKI included: EVE, AXI, NIV and sTKI. In the future setting of NIV and CAB availability, NIV was the most commonly chosen drug, whereas several experts identified situations where CAB would be preferred. PMID- 27488986 TI - MEMORIAL. PMID- 27488987 TI - Brazilian scale of hearing and language development in children (EDAL-1) with cochlear implant and less than two years of hearing AGE. AB - OBJECTIVE: To present the protocol called the Brazilian Scale of Hearing and Language Development. MATERIALS AND METHODS: This is a protocol developed in order to assess and record the development of hearing and language skills in young children who have undergone cochlear implantation during the first two years of hearing age. It was applied to the parents of 41 children over a period of 12 months at the cochlear implant clinic in the Pequeno Principe Hospital in Curitiba, Brazil. Registered were: the time taken to implement the protocol; ease of understanding the questions; numerical results obtained by the children evaluated. RESULTS: In general, the questions were considered easy to understand. The minimum time taken for application of the protocol was two minutes and the maximum was 11 minutes. At the end of the evaluation, it was possible to quantify the development in 100% of the cases. CONCLUSIONS: EDAL proved an agile, quick and easy, instrument to be used in the first two years of hearing age. PMID- 27488988 TI - Preliminary longitudinal results of neuropsychological education as first and sole intervention for new tinnitus patients. AB - INTRODUCTION: Tinnitus is a potentially aggravating symptom without curative treatment. Cognitive Behavioral Therapy has been proved effective. It aims to learn to cope with tinnitus by reducing fearfull appraisal of tinnitus. Education is an important part of that therapy. Neuropsychological education alone in an early stage of the symptom might reduce the need for extensive therapy. OBJECTIVE: To evaluate change of tinnitus related handicaps after neuropsychological education. MATERIALS AND METHODS: One hundred and six new tinnitus patients without otological ilnesses were educated in a neurophysiological model of tinnitus after otological inspection and audiometry. This was organized as a monthly standard session. Primary outcome was the Tinnitus Handicap Inventory (THI) score and subscores before intervention and 6 weeks after with follow up after 12 months. Seventy four participants were included for analysis. RESULTS: Six weeks post intervention a trend was seen in reduction of catastrophic reactions. After 12 months a significant decrease in THI scores was observed (all p values <= 0.01). The majority received no other treatment after the education. There were no significant differences between participants evaluating the workshop positively or negatively with respect to THI scores or tinnitus severity. CONCLUSION: Neuropsychological education may be a sufficient intervention for new tinnitus sufferers. PMID- 27488989 TI - Tinnitus and temporomandibular disorders: the knowledge of professionals for primary health care in the city of Curitiba. AB - INTRODUCTION: The high prevalence of temporomandibular disorders and tinnitus along with the negative effects on the quality of life of affected individuals makes this association a matter of public health. OBJECTIVE: To assess the knowledge of primary health care professionals about the interrelationship between temporomandibular disorders and tinnitus. MATERIALS AND METHODS: This was a quantitative cross-sectional study, using a structured, self-administered questionnaire for a group of 54 dental surgeons. The statistical analysis used involved descriptive analyses through absolute and relative frequency distributions. RESULTS: The results showed that the professionals do not, as a routine, examine the temporomandibular joints and masticatory muscles during physical examination. In addition, there was a low percentage of correct answers on questions that assess knowledge. CONCLUSIONS: There is a need to inform dentists about the interrelationship between temporomandibular disorders and tinnitus. Furthermore, there is a need to encourage managers to establish teaching and learning tools that support and strengthen the role of dentists in primary health care. In this way, routine visits might minimize these disorders, and thus contribute to the quality of life of the population. PMID- 27488990 TI - The impact of tinnitus on the quality of life in patients with temporomandibular dysfunction. AB - INTRODUCTION: The most common otological symptoms in patients with temporomandibular disorders (TMD) are ear fullness, tinnitus and ear pain. OBJECTIVE: To evaluate the impact of tinnitus on the quality of life for patients with TMD. METHOD: This is a quantitative, cross-sectional retrospective study. The sample consisted of 19 individuals with TMD, 17 (89.47%) females and 2 (10.53%) male, mean age 53.5 years. Data collection consisted of: anamnesis, pure tone audiometry, acuphenometry and application of the Portuguese version of the Tinnitus Handicap Inventory (Brazilian THI). RESULTS: 63.12% had had tinnitus for less than five years, and 15.79% had tinnitus that sounded like whistling, rain and/or a cricket. There was a predominance of laterality in the right ear (42.11%). 52.63% of the subjects reported that their tinnitus is continuous, while 31.58% stated that it lasts for days, and 47.37% report that it is common. The audiometry revealed mean audiometric thresholds above 25 dB HL in the high frequencies (3000, 4000, 6000 and 8000 Hz) bilaterally. In acuphenometry, the average loudness of the tinnitus was 21 dB SL the right ear and 17.85 dB SL in the left ear, and the average tinnitus pitch was 3775 Hz in the right ear and 3750 Hz in the left ear. The total THI score was 37.8 points. It appears that there is significant correlation between the THI scale, time of tinnitus duration and its occurrence. CONCLUSION: Tinnitus reported in patients with TMD caused moderate impact on quality of life and can be seen in the presence of background noise although daily activities can still be performed. PMID- 27488992 TI - Description of tinnitus and its relation to discomfort level in a group of elderly hearing aid wearers. AB - INTRODUCTION: Evaluating quality of life for tinnitus patients has been an interest of several specialties that have seen the negative impact that the disorder has on people. OBJECTIVE: To assess and qualify tinnitus in a group of elderly hearing aid wearers. MATERIALS AND METHODS: A descriptive cross-sectional study involving 53 elderly patients with tinnitus without remission after wearing hearing aids. All subjects were submitted to: a medical evaluation, an audiological evaluation, acuphenometry, an investigation of tinnitus annoyance level and quality of life. RESULTS: There were 20 men and 33 women. The mean age was 72.5 years. The sample was mostly characterized by having sensorineural hearing loss (84%), moderate to moderately severe (86%) and downward sloping (82%). With respect to the description of the tinnitus sound, the most common were a hissing sound (93%) of average pitch (84%). Regarding the subjects' perception of tinnitus, it was found that subjects had varying levels of annoyance: mild (25%), moderate (33%), severe (22%), most severe (20%). Men are more bothered by tinnitus than women. Most of the sample reported being satisfied or very satisfied with their quality of life. CONCLUSION: It was possible to evaluate and qualify tinnitus in the sample. Although tinnitus is a frequent audiological symptom that interferes in the life of the elderly, in the sample it did not weigh heavily in terms of quality of life. PMID- 27488991 TI - Speech language pathology findings in a Treacher Collins syndrome patient. AB - BACKGROUND: Treacher Collins syndrome (TCS) is a rare disorder with different levels of severity due to congenital head and face abnormalities which affect language, orofacial musculature, voice and breadth, suction, chewing and swallowing functions. AIMS: This paper objectifies to report a Treacher Collins syndrome patient, describing phonoaudiological changes that can be found in individuals suffering from this syndrome. METHODS & PROCEDURES: The study was carried out with a male child at a teaching Speech Language Pathology clinic in Southern Brazil. The patient underwent audiological assessment, as well as orofacial motricity, swallowing, voice and speech assessments. OUTCOMES & RESULTS: By means of the assessments, it was possible to perceive that the patient presents moderate hearing loss, inadequacy of phonoarticulatory organs, base of the tongue going backwards and epiglottis collapse over the larynx. In spite of evidencing significant difficulty in producing speech sounds, due to musculoskeletal changes, he effectively interacts in communicative situations, besides understanding sentences and narrated stories. CONCLUSIONS & IMPLICATIONS: The screened case report evidences that an interdisciplinary follow-up is indispensable for this patient suffering from Treacher Collins syndrome, which implies not only speech language therapeutic follow-up, but also in ear, nose and throat and orthodontics areas. PMID- 27488993 TI - Amplified music with headphones and its implications on hearing health in teens. AB - OBJECTIVE: To analyze the habits and behavior of adolescents exposed to amplified music with headphones and its implications on their hearing health. METHODS: One hundred thirty-one high school students, aged 15 to 18 years were given a questionnaire containing closed questions regarding their habits and behavior related to personal stereos use. It is a descriptive cross-sectional study and used the Chi-square test. RESULTS: It was shown that 79% of young people make use of portable music devices, 61.83% have a habit of using them often, 34.35% have long periods of exposure, and 37.40% use them at high volume. In terms of symptoms, present were: difficulty concentrating 63.36%; the need to ask people to repeat what was said 64.12%; the need to increase the TV volume 43.51%; tinnitus 38.93%, excitability 38.93%; and 36.64% of teens say they are somewhat worried about losing their hearing through the use of personal stereos. For the preventive aspects, 90.84% believe that noise is part of society, 80.92% find it important to reduce noise pollution, 51.91% would like to know the influence of the noise/pollution, but 74.81% would not like to participate in projects with questions about hearing health. CONCLUSION: The youths in this study are making indiscriminate use of personal stereos with headphones, within a population at risk for hearing loss considering its habits. Hearing Health Promotion Programs are recommended for this population. PMID- 27488994 TI - Occurrence of tinnitus and other auditory symptoms among musicians playing different instruments. AB - INTRODUCTION: Tinnitus is one of the most reported auditory symptoms among musicians and can negatively influence their ability to work, sometimes even more severely than hearing loss. OBJECTIVES: To analyze the occurrence of tinnitus and other auditory symptoms in musicians who play different instruments. METHODS: One hundred musicians participated by answering a questionnaire on instrument played, practice time with the instrument, occurrence of tinnitus, hearing difficulties, and intolerance to loud sounds. The symptoms were analyzed in relation to gender, musical instrument, and time of experience using statistical tests such as the Chi-squared test and Difference in Proportions test at a significance level of 0.05 as well as finding the Prevalence Ratio. RESULTS: Tinnitus was the most frequent symptom among musicians, especially among those who play amplified instruments. There was an association between tinnitus and hearing difficulty, and between instrument experience time and intolerance to loud sounds. The proportion of musicians with occasional tinnitus was high among those with less than 15 years of musical practice, and 4.53 times more prevalent in those with more than 15 years of experience. CONCLUSION: The presence of auditory symptoms, especially tinnitus, among musicians reinforces the need for implementation of hearing conservation programs for this profession. PMID- 27488995 TI - The efficacy of hearing aids for emotional and auditory tinnitus issues. AB - INTRODUCTION: The use of hearing aids has been one of the strategies to reduce tinnitus perception and improve sufferers' quality of life when this symptom is associated to hearing impairment. OBJECTIVE: To assess the remission of emotional and auditory tinnitus impacts on users of hearing aids. METHODS: It is an experimental, descriptive study carried out with 17 users of unilateral or bilateral hearing aids, reporting tinnitus, submitted to otorhinolaryngological screening, tonal audiometry, logoaudiometry and acoustic imittance testing, who also answered the Iowa Tinnitus Activities Questionnaire, as well as the Iowa Tinnitus Handicap Questionnaire. RESULTS: There was significant difference in tinnitus data scoring before the use of hearing aids and after fitting the hearing aids. CONCLUSION: Analysis of the results evidences that the use of hearing aids improves tinnitus patients' quality of life, mainly regarding their emotional and auditory aspects. PMID- 27488996 TI - Manifestations of a low-frequency sound of unknown origin perceived worldwide, also known as "the Hum" or the "Taos Hum". AB - INTRODUCTION: "The Hum" and "Taos Hum" are the common terms used for an annoying low-frequency sound of unknown and seemingly mysterious external causes. The Hum is a phenomenon occurring worldwide that affects approximately 2% of the population, called hearers or hummers. OBJECTIVE: This study investigates the different manifestations of the Hum based on questionnaires tailor-made for hearers, with the aim to demystify this phenomenon. MATERIALS AND METHODS: Questionnaires completed by 162 hearers were evaluated, with a focus on three often-reported features: whether their Hum forms beats with external sounds, whether head rotations remove their Hum, and if air travel produces a time lag until the Hum reappears. RESULTS AND CONCLUSIONS: The presence of at least one of the three features is typical of the Hum for 73% hearers. The three features are statistically significant dependent on each other. Hum-oscillations are typically influenced by head rotation and by sounds and are most likely located in the semicircular canals and the cochlea. Therefore, for the majority of hearers, the Hum may represent a rare form of tinnitus that has nothing to do with external sounds. The remaining group doesn't experience any feature of a typical hearer. PMID- 27488998 TI - Acute kidney injury induces hallmarks of polycystic kidney disease. AB - Acute kidney injury (AKI) and autosomal dominant polycystic kidney disease (ADPKD) are considered separate entities that both frequently cause renal failure. Since ADPKD appears to depend on a polycystin-1 (Pc1) or Pc2 dosage mechanism, we investigated whether slow progression of cystogenesis in two Pkd1 transgenic mouse models can be accelerated with moderate ischemia-reperfusion injury (IRI). Transient unilateral left ischemic kidneys in both nontransgenic and transgenic mice reproducibly develop tubular dilatations, cysts, and typical PKD cellular defects within 3 mo post-IRI. Similar onset and severity of IRI induced-cystogenesis independently of genotype revealed that IRI is sufficient to promote renal cyst formation; however, this response was not further amplified by the transgene in Pkd1 mouse models. The IRI nontransgenic and transgenic kidneys showed from 16 days post-IRI strikingly increased and sustained Pkd1/Pc1 (>3 fold) and Pc2 (>8-fold) expression that can individually be cystogenic in mice. In parallel, long-term and important stimulation of hypoxia-inducible factor 1alpha expression was induced as in polycystic kidney disease. While mammalian target of rapamycin signaling is activated, stimulation of the Wnt pathway, with markedly increased active beta-catenin and c-Myc expression in IRI renal epithelium, uncovered a similar regulatory cystogenic response shared by IRI and ADPKD. Our study demonstrates that long-term AKI induces cystogenesis and cross talk with ADPKD Pc1/Pc2 pathogenic signaling. PMID- 27488997 TI - Phosphatase inhibition increases AQP2 accumulation in the rat IMCD apical plasma membrane. AB - Vasopressin triggers the phosphorylation and apical plasma membrane accumulation of aquaporin 2 (AQP2), and it plays an essential role in urine concentration. Vasopressin, acting through protein kinase A, phosphorylates AQP2. However, the phosphorylation state of AQP2 could also be affected by the action of protein phosphatases (PPs). Rat inner medullas (IM) were incubated with calyculin (PP1 and PP2A inhibitor, 50 nM) or tacrolimus (PP2B inhibitor, 100 nM). Calyculin did not affect total AQP2 protein abundance (by Western blot) but did significantly increase the abundances of pS256-AQP2 and pS264-AQP2. It did not change pS261 AQP2 or pS269-AQP2. Calyculin significantly enhanced the membrane accumulation (by biotinylation) of total AQP2, pS256-AQP2, and pS264-AQP2. Likewise, immunohistochemistry showed an increase in the apical plasma membrane association of pS256-AQP2 and pS264-AQP2 in calyculin-treated rat IM. Tacrolimus also did not change total AQP2 abundance but significantly increased the abundances of pS261 AQP2 and pS264-AQP2. In contrast to calyculin, tacrolimus did not change the amount of total AQP2 in the plasma membrane (by biotinylation and immunohistochemistry). Tacrolimus did increase the expression of pS264-AQP2 in the apical plasma membrane (by immunohistochemistry). In conclusion, PP1/PP2A regulates the phosphorylation and apical plasma membrane accumulation of AQP2 differently than PP2B. Serine-264 of AQP2 is a phosphorylation site that is regulated by both PP1/PP2A and PP2B. This dual regulatory pathway may suggest a previously unappreciated role for multiple phosphatases in the regulation of urine concentration. PMID- 27488999 TI - Renal phenotype in Bardet-Biedl syndrome: a combined defect of urinary concentration and dilution is associated with defective urinary AQP2 and UMOD excretion. AB - The renal phenotype in Bardet-Biedl syndrome (BBS) is highly variable. The present study describes renal findings in 41 BBS patients and analyzes the pathogenesis of hyposthenuria, the most common renal dysfunction. Five of 41 patients (12%) showed an estimated glomerular filtration rate < 60 ml.min-1.1.73 m-2 Urine protein and urine albumin-to-creatinine ratio were over 200 and 30 mg/g in 9/24 and 7/23 patients, respectively. Four of 41 patients showed no renal anomalies on ultrasound. Twenty of 34 patients had hyposthenuria in the absence of renal insufficiency. In all 8 of the hyposthenuric patients studied, dDAVP failed to elevate urine osmolality (Uosm), suggesting a nephrogenic origin. Interestingly, water loading (WL) did not result in a significant reduction of Uosm, indicating combined concentrating and diluting defects. dDAVP infusion induced a significant increase of plasma Factor VIII and von Willebrand Factor levels, supporting normal function of the type 2 vasopressin receptor at least in endothelial cells. While urinary aquaporin 2 (u-AQP2) abundance was not different between patients and controls at baseline, the dDAVP-induced increased u-AQP2 and the WL-induced reduction of u-AQP2 were blunted in patients with a combined concentrating and diluting defect, suggesting a potential role of AQP2 in the defective regulation of water absorption. Urine Uromodulin excretion was reduced in all hyposthenuric patients, suggesting a thick ascending limb defect. Interestingly, renal Na, Cl, Ca, but not K handling was impaired after acute WL but not at basal. In summary, BBS patients show combined urinary concentration and dilution defects; a thick ascending limb and collecting duct tubulopathy may underlie impaired water handling. PMID- 27489000 TI - Restructuring of Holocentric Centromeres During Meiosis in the Plant Rhynchospora pubera. AB - Centromeres are responsible for the correct segregation of chromosomes during mitosis and meiosis. Holocentric chromosomes, characterized by multiple centromere units along each chromatid, have particular adaptations to ensure regular disjunction during meiosis. Here we show by detecting CENH3, CENP-C, tubulin, and centromeric repeats that holocentromeres may be organized differently in mitosis and meiosis of Rhynchospora pubera Contrasting to the mitotic linear holocentromere organization, meiotic centromeres show several clusters of centromere units (cluster-holocentromeres) during meiosis I. They accumulate along the poleward surface of bivalents where spindle fibers perpendicularly attach. During meiosis II, the cluster-holocentromeres are mostly present in the midregion of each chromatid. A linear holocentromere organization is restored after meiosis during pollen mitosis. Thus, a not yet described case of a cluster-holocentromere organization, showing a clear centromere restructuration between mitosis and meiosis, was identified in a holocentric organism. PMID- 27489001 TI - Histone Deacetylases with Antagonistic Roles in Saccharomyces cerevisiae Heterochromatin Formation. AB - As the only catalytic member of the Sir-protein gene-silencing complex, Sir2's catalytic activity is necessary for silencing. The only known role for Sir2's catalytic activity in Saccharomyces cerevisiae silencing is to deacetylate N terminal tails of histones H3 and H4, creating high-affinity binding sites for the Sir-protein complex, resulting in association of Sir proteins across the silenced domain. This histone deacetylation model makes the simple prediction that preemptively removing Sir2's H3 and H4 acetyl substrates, by mutating these lysines to unacetylatable arginines, or removing the acetyl transferase responsible for their acetylation, should restore silencing in the Sir2 catalytic mutant. However, this was not the case. We conducted a genetic screen to explore what aspect of Sir2's catalytic activity has not been accounted for in silencing. Mutation of a nonsirtuin histone deacetylase, Rpd3, restored Sir-protein-based silencing in the absence of Sir2's catalytic activity. Moreover, this antagonism could be mediated by either the large or the small Rpd3-containing complex. Interestingly, this restoration of silencing appeared independent of any known histone H3 or H4 substrates of Rpd3 Investigation of Sir-protein association in the Rpd3 mutant revealed that the restoration of silencing was correlated with an increased association of Sir proteins at the silencers, suggesting that Rpd3 was an antagonist of Sir2's function in nucleation of Sir proteins to the silencer. Additionally, restoration of silencing by Rpd3 was dependent on another sirtuin family member, Hst3, indicating multiple antagonistic roles for deacetylases in S. cerevisiae silencing. PMID- 27489002 TI - Gene and Network Analysis of Common Variants Reveals Novel Associations in Multiple Complex Diseases. AB - Genome-wide association (GWA) studies typically lack power to detect genotypes significantly associated with complex diseases, where different causal mutations of small effect may be present across cases. A common, tractable approach for identifying genomic elements associated with complex traits is to evaluate combinations of variants in known pathways or gene sets with shared biological function. Such gene-set analyses require the computation of gene-level P-values or gene scores; these gene scores are also useful when generating hypotheses for experimental validation. However, commonly used methods for generating GWA gene scores are computationally inefficient, biased by gene length, imprecise, or have low true positive rate (TPR) at low false positive rates (FPR), leading to erroneous hypotheses for functional validation. Here we introduce a new method, PEGASUS, for analytically calculating gene scores. PEGASUS produces gene scores with as much as 10 orders of magnitude higher numerical precision than competing methods. In simulation, PEGASUS outperforms existing methods, achieving up to 30% higher TPR when the FPR is fixed at 1%. We use gene scores from PEGASUS as input to HotNet2 to identify networks of interacting genes associated with multiple complex diseases and traits; this is the first application of HotNet2 to common variation. In ulcerative colitis and waist-hip ratio, we discover networks that include genes previously associated with these phenotypes, as well as novel candidate genes. In contrast, existing methods fail to identify these networks. We also identify networks for attention-deficit/hyperactivity disorder, in which GWA studies have yet to identify any significant SNPs. PMID- 27489003 TI - Extracting patterns of morphometry distinguishing HIV associated neurodegeneration from mild cognitive impairment via group cardinality constrained classification. AB - HIV-Associated Neurocognitive Disorder (HAND) is the most common constellation of cognitive dysfunctions in chronic HIV infected patients age 60 or older in the U.S. Only few published methods assist in distinguishing HAND from other forms of age-associated cognitive decline, such as Mild Cognitive Impairment (MCI). In this report, a data-driven, nonparameteric model to identify morphometric patterns separating HAND from MCI due to non-HIV conditions in this older age group was proposed. This model enhanced the potential for group separation by combining a smaller, longitudinal data set containing HAND samples with a larger, public data set including MCI cases. Using cross-validation, a linear model on healthy controls to harmonize the volumetric scores extracted from MRIs for demographic and acquisition differences between the two independent, disease specific data sets was trained. Next, patterns distinguishing HAND from MCI via a group sparsity constrained logistic classifier were identified. Unlike existing approaches, our classifier directly solved the underlying minimization problem by decoupling the minimization of the logistic regression function from enforcing the group sparsity constraint. The extracted patterns consisted of eight regions that distinguished HAND from MCI on a significant level while being indifferent to differences in demographics and acquisition between the two sets. Individually selecting regions through conventional morphometric group analysis resulted in a larger number of regions that were less accurate. In conclusion, simultaneously analyzing all brain regions and time points for disease specific patterns contributed to distinguishing with high accuracy HAND-related impairment from cognitive impairment found in the HIV uninfected, MCI cohort. Hum Brain Mapp 37:4523-4538, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27489005 TI - Consumption of Walnuts in Combination with Other Whole Foods Produces Physiologic, Metabolic, and Gene Expression Changes in Obese C57BL/6J High-Fat Fed Male Mice. AB - BACKGROUND: Although a reductionist approach has sought to understand the roles of individual nutrients and biochemicals in foods, it has become apparent that there can be differences when studying food components in isolation or within the natural matrix of a whole food. OBJECTIVE: The objective of this study was to determine the ability of whole-food intake to modulate the development of obesity and other metabolic dysfunction in mice fed a high-fat (HF), Western-style obesogenic diet. To test the hypothesis that an n-3 (omega-3) polyunsaturated fatty acid-rich food could synergize with other, largely polyphenol-rich foods by producing greater reductions in metabolic disease conditions, the intake of English walnuts was evaluated in combination with 9 other whole foods. METHODS: Eight-week-old male C57Bl/6J mice were fed low-fat (LF; 10% fat) and HF control diets, along with an HF diet with 8.6% (wt:wt) added walnuts for 9 wk. The HF control diet contained 46% fat with added sucrose (10.9%, wt:wt) and cholesterol (1%, wt:wt); the added sucrose and cholesterol were not present in the LF diet. Other groups were provided the walnut diet with a second whole food-raspberries, apples, cranberries, tart cherries, broccoli sprouts, olive oil, soy protein, or green tea. All of the energy-containing whole foods were added at an energy level equivalent to 1.5 servings/d. Body weights, food intake, and glucose tolerance were determined. Postmortem, serum lipids and inflammatory markers, hepatic fat, gene expression, and the relative concentrations of 594 biochemicals were measured. RESULTS: The addition of walnuts with either raspberries, apples, or green tea reduced glucose area under the curve compared with the HF diet alone ( 93%, -64%, and -54%, respectively, P < 0.05). Compared with HF-fed mice, mice fed walnuts with either broccoli sprouts or green tea (-49% and -61%, respectively, P < 0.05) had reduced hepatic fat concentrations. There were differences in global gene expression patterns related to whole-food content, with many examples of differences in LF- and HF-fed mice, HF- and walnut-fed mice, and mice fed walnuts and walnuts plus other foods. The mean +/- SEM increase in relative hepatic concentrations of the n-3 fatty acids alpha-linolenic acid, eicosapentanoic acid, and docosapentanoic acid in all walnut-fed groups was 124% +/- 13%, 159% +/- 11%, and 114% +/- 10%, respectively (P < 0.0001), compared with LF- and HF-fed mice not consuming walnuts. CONCLUSIONS: In obese male mice, walnut consumption with an HF Western-style diet caused changes in hepatic fat concentrations, gene expression patterns, and fatty acid concentrations. The addition of a second whole food in combination with walnuts produced other changes in metabolite concentrations and gene expression patterns and other physiologic markers. Importantly, these substantial changes occurred in mice fed typical amounts of intake, representing only 1.5 servings each food/d. PMID- 27489004 TI - Psychological Distress Mediates the Association between Food Insecurity and Suboptimal Sleep Quality in Latinos with Type 2 Diabetes Mellitus. AB - BACKGROUND: Evidence increasingly indicates that poor sleep quality is a major public health concern. Household food insecurity (HFI) disproportionately affects Latinos and is a novel risk factor for poor sleep quality. Psychological distress may be a potential mechanism through which HFI affects sleep quality. Sleep, food insecurity, and distress are linked to type 2 diabetes mellitus. OBJECTIVES: We examined the relations between HFI, psychological distress, and sleep quality and tested whether psychological distress mediates the relation between HFI and sleep in people with diabetes mellitus. METHODS: Latinos with type 2 diabetes mellitus (n = 121) who completed baseline assessments for the CALMS-D (Community Health Workers Assisting Latinos Manage Stress and Diabetes) stress management intervention trial completed the US Household Food Security Survey, and measures of depressive symptoms [Personal Health Questionnaire Depression Scale (PHQ-8)], anxiety symptoms [Patient-Reported Outcomes Measurement Information System (PROMIS)-short], diabetes distress [Problem Areas in Diabetes Questionnaire (PAID 5)], and sleep quality [Pittsburgh Sleep Quality Index (PSQI)]. Psychological distress was operationalized with the PHQ-8, PROMIS-short, and PAID-5 scales. We used unadjusted and adjusted indirect effect tests with bias-corrected bootstrapped 95% CIs on 10,000 samples to test both relations between variables and potential mediation. RESULTS: Mean age was 61 y, 74% were women, and 67% were food insecure. Experiencing HFI was associated with both greater psychological distress and worse sleep quality (P < 0.05). Depressive symptoms (adjusted R2: 2.22, 95% CI: 1.27, 3.42), anxiety symptoms (adjusted R2: 1.70, 95% CI: 0.87, 2.85), and diabetes mellitus distress (adjusted R2: 0.60, 95% CI: 0.11, 1.32) each mediated the relation between HFI and worse sleep quality with and without adjustment for age, education, income, marital status, and employment status. CONCLUSIONS: Household food insecurity is a common and potent household stressor that is associated with suboptimal sleep quality through psychological distress. Efforts to improve food security and decrease psychological distress may yield improved sleep in this high-risk population. The CALMS-D stress management trial was registered at clinicaltrials.gov as NCT01578096. PMID- 27489006 TI - Hedonic Hunger Is Related to Increased Neural and Perceptual Responses to Cues of Palatable Food and Motivation to Consume: Evidence from 3 Independent Investigations. AB - BACKGROUND: The Power of Food Scale (PFS) seeks to identify individuals who experience high appetitive drive in response to food cues, which is a construct termed "hedonic hunger." OBJECTIVE: The purpose of this study was to assess cross sectional correlates and predictive power of PFS scores to probe the construct of hedonic hunger. METHODS: Separate data from 3 studies (study 1, n = 44; study 2, n = 398; study 3, n = 100) were used to evaluate the construct of hedonic hunger. We examined the correlations between the PFS and neural responsivity during intake and anticipated intake of palatable foods, behavioral food reinforcement, perceptual hedonic ratings of food images, and change in body mass index (BMI) and binge eating over time. RESULTS: Hedonic hunger was strongly related to bilateral brain response in regions implicated in oral somatosensory processing during cue-elicited anticipation of food intake (study 1; right postcentral gyrus: r = 0.67, P < 0.001; left postcentral gyrus: r = 0.64, P < 0.001), and was correlated with behavioral food reinforcement (study 2; r = 0.31, P = 0.03) and perceptual hedonic ratings (study 3; r = 0.24, P = 0.02). Hedonic hunger was not associated with baseline BMI (studies 1-3: P = 0.14, 0.21, and 0.37, respectively) or change in BMI over the 2-y follow-up (studies 1 and 2: P = 0.14 and 0.37, respectively) but was significantly correlated with baseline binge eating in 2 samples (study 1: r = 0.58, P = 0.001; study 2: r = 0.31, P = 0.02; and study 3: P = 0.02). CONCLUSIONS: Hedonic hunger was not predictive of weight regulation. However, individuals who report high hedonic hunger are likely to show increased neural and perceptual responses to cues of palatable foods, increased motivation to consume such foods, and a greater likelihood of current binge eating. PMID- 27489007 TI - Intake of Caffeinated Soft Drinks before and during Pregnancy, but Not Total Caffeine Intake, Is Associated with Increased Cerebral Palsy Risk in the Norwegian Mother and Child Cohort Study. AB - BACKGROUND: Postnatal administration of caffeine may reduce the risk of cerebral palsy (CP) in vulnerable low-birth-weight neonates. The effect of antenatal caffeine exposure remains unknown. OBJECTIVE: We investigated the association of intake of caffeine by pregnant women and risk of CP in their children. METHODS: The study was based on The Norwegian Mother and Child Cohort Study, comprising >100,000 live-born children, of whom 222 were subsequently diagnosed with CP. Mothers reported their caffeine consumption in questionnaires completed around pregnancy week 17 (102,986 mother-child pairs), week 22 (87,987 mother-child pairs), and week 30 (94,372 mother-child pairs). At week 17, participants were asked about present and prepregnancy consumption. We used Cox regression models to estimate associations between exposure [daily servings (1 serving = 125 mL) of caffeinated coffee, tea, and soft drinks and total caffeine consumption] and CP in children, with nonconsumers as the reference group. Models included adjustment for maternal age and education, medically assisted reproduction, and smoking, and for each source of caffeine, adjustments were made for the other sources. RESULTS: Total daily caffeine intake before and during pregnancy was not associated with CP risk. High consumption (>=6 servings/d) of caffeinated soft drinks before pregnancy was associated with an increased CP risk (HR: 1.9; 95% CI: 1.2, 3.1), and children of women consuming 3-5 daily servings of caffeinated soft drinks during pregnancy weeks 13-30 also had an increased CP risk (HR: 1.7; 95% CI: 1.1, 2.8). A mean daily consumption of 51-100 mg caffeine from soft drinks during the first half of pregnancy was associated with a 1.9-fold increased risk of CP in children (HR: 1.9; 95% CI: 1.1, 3.6). CONCLUSIONS: Maternal total daily caffeine consumption before and during pregnancy was not associated with CP risk in children. The observed increased risk with caffeinated soft drinks warrants further investigation. PMID- 27489008 TI - Coffee Drinking Is Widespread in the United States, but Usual Intake Varies by Key Demographic and Lifestyle Factors. AB - BACKGROUND: Despite widespread popularity and possible health effects, the prevalence and distribution of coffee consumption in US adults are poorly characterized. OBJECTIVE: We sought to estimate usual daily coffee intakes from all coffee-containing beverages, including decaffeinated and regular coffee, among US adults according to demographic, socioeconomic, and health-related factors. METHODS: Dietary intake data from <=2 nonconsecutive 24-h dietary recalls and a food-frequency questionnaire administered during the NHANES 2003 2006 were used to estimate the person-specific probability of consuming coffee on a particular day and the usual amount consumed on consumption days. Trends in population mean coffee consumption over time were evaluated by using multiple linear regression and 1-d 24-h recall data from NHANES 2003-2012. Analyses were weighted to be representative of the US adult population aged >=20 y. RESULTS: An estimated 154 million adults, or 75% of the US population, aged >=20 y reported drinking coffee; 49% reported drinking coffee daily. Prevalence did not vary by sex, education, income, or self-reported general health (all P >= 0.05) but did vary by age, race/ethnicity, smoking status, and alcohol drinking (all P < 0.05). Among coffee drinkers, the mean +/- SE usual intake was 14.1 +/- 0.5 fluid ounces/d (417 +/- 15 mL/d). Mean usual intakes were higher in men than women, in older age groups than in those aged 20 to <30 y, in non-Hispanic whites than in non-Hispanic blacks or Hispanic/other races, in smokers than in never smokers, and in daily alcohol consumers than in nonconsumers (all P < 0.05). Population mean coffee consumption was stable from 2003 to 2012 (P-trend = 0.09). CONCLUSIONS: Coffee is widely consumed in the United States, with usual intakes varying by lifestyle and demographic factors, most notably by age. Longitudinal studies are needed to determine whether observed differences by age reflect birth cohort effects or changes in drinking patterns over the lifetime. PMID- 27489010 TI - Prolonged Exclusive Breastfeeding Duration Is Positively Associated with Risk of Anemia in Infants Aged 12 Months. AB - BACKGROUND: The association between exclusive breastfeeding duration and infant anemia is not clear. OBJECTIVE: This study aimed to assess the association of exclusive breastfeeding duration with risk of anemia in infants at 12 mo of age and in children aged 48-71 mo in mainland China. METHODS: Detailed breastfeeding information and anthropometric data were obtained for 65,256 children enrolled in the Jiaxing Birth Cohort at 1, 3, and 6 mo of age. Hemoglobin was measured in 25,549 children at 12 mo and in 32,770 children between the ages of 48 and 71 mo. Anemia was defined as hemoglobin concentrations <110 g/L in children aged <60 mo and <115 g/L in children aged >=60 mo. The associations between exclusive breastfeeding duration and risk of anemia were assessed as adjusted ORs by using multiple logistic regression. RESULTS: Overall anemia prevalences at 12 and 48-71 mo were 24.9% and 9.9%, respectively. Exclusive breastfeeding for >=6 mo, but not for 3-5 mo, was significantly associated with a higher risk of anemia in infants at age 12 mo (OR: 1.15; 95% CI: 1.02, 1.29; P = 0.02) compared with exclusive breastfeeding for <3 mo. For young children aged 48-71 mo, this finding was only marginally significant (OR: 1.13; 95% CI: 0.99, 1.29; P = 0.08). Prolonged duration of exclusive breastfeeding was also significantly associated with decreased hemoglobin concentrations of -0.56 g/L (95% CI: -1.10, -0.03; P = 0.04) in infants and -0.99 g/L (95% CI: -1.44, -0.55; P < 0.001) in young children. CONCLUSIONS: Exclusive breastfeeding for >=6 mo was associated with an increased risk of anemia in infants aged 12 mo and with lower hemoglobin concentrations in both infants aged 12 mo and young children aged 48-71 mo. Parents should provide infants with an adequate source of iron after 6 mo of exclusive breastfeeding. PMID- 27489009 TI - Serum Immune System Biomarkers Neopterin and Interleukin-10 Are Strongly Related to Tryptophan Metabolism in Healthy Young Adults. AB - BACKGROUND: Changes in tryptophan metabolism through the vitamin B-6-dependent kynurenine pathway have been linked to activation of the immune system. OBJECTIVE: We hypothesized that blood concentrations of tryptophan and its catabolites were associated with biomarkers relevant to inflammatory processes in healthy noninflamed subjects. METHODS: Healthy young adults (n = 737) aged 18-28 y without any known diseases or clinical evidence of inflammation provided blood samples for analysis of serum tryptophan/kynurenine metabolites, neopterin, C reactive protein (CRP), and plasma pyridoxal 5'-phosphate (PLP) with LC-tandem mass spectrometry methodologies. A panel of cytokines was measured in serum by using high-sensitivity ELISA assays. Anthropometric and lifestyle data were collected by questionnaire. Multiple linear regression analysis to determine the effect of measured serum cytokine concentrations as predictors of tryptophan metabolites was performed on inverse normal-rank transformations of the data, adjusted for sex, body mass index, smoking, alcohol intake, and contraceptive use in women. RESULTS: Median serum CRP and neopterin concentrations were well below established clinical cutoffs for inflammation. We observed significant positive associations between serum interleukin-10 (IL-10) and serum kynurenine (P = 0.0002), the kynurenine-to-tryptophan ratio (KTR) (P = 0.003), 3 hydroxykynurenine (P = 0.01), and 3-hydroxyanthranilic acid (P = 0.04). Serum neopterin was positively associated with kynurenine, the KTR (both P < 0.0001), and anthranilic acid (P = 0.004), and was negatively associated with serum tryptophan (P = 0.01) and PLP (P < 0.0001). Serum tumor necrosis factor alpha was also negatively associated with tryptophan (P < 0.001). CONCLUSIONS: In healthy young adults with no apparent inflammatory conditions, serum tryptophan metabolites are significantly associated with key immune system biomarkers. The observed association between IL-10 and kynurenine is unexpected and suggests that kynurenine-linked mechanisms promoting negative regulation of inflammatory responses are associated with normal immune homeostasis. PMID- 27489011 TI - Comparison of Preventive and Therapeutic Zinc Supplementation in Young Children in Burkina Faso: A Cluster-Randomized, Community-Based Trial. AB - BACKGROUND: The WHO and UNICEF recommend therapeutic zinc supplementation (TZS) for the treatment of diarrhea. In zinc-deficient populations, preventive zinc supplementation might provide greater benefits for reducing diarrhea and malaria incidence and increasing growth and plasma zinc (pZn) concentration. If effective, intermittent preventive zinc supplementation (IPZS) would cost less than daily preventive zinc supplementation (DPZS). OBJECTIVE: We assessed the effects of IPZS, DPZS, and TZS in children on the primary outcomes of diarrhea incidence, malaria incidence, growth, and pZn concentration compared with nonsupplemented control groups. METHODS: Rural Burkinabe children (n = 7641; 6-30 mo old) in 36 clusters were randomly assigned to 1 of 5 treatment groups for 16, 32, or 48 wk: 1) IPZS (10 mg Zn/d for 10 d every 16 wk); 2) DPZS (7 mg Zn/d); 3) TZS (20 mg Zn/d for 10 d for diarrhea); 4) morbidity surveillance control (MSC); or 5) nonintervention control (NIC). Supplemented groups remained masked until completion of primary analyses with mixed models. RESULTS: At baseline, stunting (28.6%) and low pZn concentration (<65 MUg/dL; 43.5%) were common. After 48 wk, mean +/- SE pZn increased more (P = 0.008) in the DPZS group (3.9 +/- 1.3 MUg/dL) than in the TZS (-0.5 +/- 1.2 MUg/dL) and NIC (-1.2 +/- 0.9 MUg/dL) groups. All supplemented groups had a moderately lower incidence of reported diarrhea (0.48 0.49 compared with 0.57 episodes/100 d, P = 0.001) and reported fever (1.1-1.2 compared with 1.5 episodes/100d, P < 0.001) and gained slightly less length (3.15 3.20 compared with 3.36 cm/16 wk, P < 0.001) than the MSC group, but did not differ from each other. Prevalence of diarrhea and incidences of confirmed fever and malaria were not different across study groups. CONCLUSIONS: The preventive and TZS groups had reduced diarrhea incidence, but it is uncertain whether this resulted from a functional response to zinc or reporting bias. The comparison should be re-examined in populations known to respond to zinc supplementation. This trial was registered at www.clinicaltrials.gov as NCT00944359. PMID- 27489012 TI - Erratum to: A novel procedure on next generation sequencing data analysis using text mining algorithm. PMID- 27489013 TI - Renal fossa recurrence after nephrectomy for renal cell carcinoma: prognostic features and oncological outcomes. AB - OBJECTIVES: To describe the clinicopathological features associated with increased risk of renal fossa recurrence (RFR) after radical nephrectomy (RN) and to describe the prognostic features associated with cancer-specific survival (CSS) among patients with RFR treated with primary locally directed therapy, systemically directed therapy or expectant management. PATIENTS AND METHODS: The records of 2 502 patients treated with RN for unilateral, sporadic, localized renal cell carcinoma (RCC) between 1970 and 2006 were reviewed. CSS after RFR was estimated using the Kaplan-Meier method. Associations with the development of RFR and CSS after RFR were evaluated using Cox proportional hazards regression models. RESULTS: A total of 33 (1.3%) patients developed isolated RFR (iRFR) and 30 (1.2%) patients developed RFR in the setting of synchronous metastases after RN (study cohort, N = 63). The median follow-up for the series was 9.0 years after RN and 6.0 years after RFR diagnosis. On multivariable analysis, advanced pathological stage (pT2: hazard ratio [HR] 4.36, P = 0.004; pT3/4: HR 4.39, P = 0.003) and coagulative necrosis (HR 2.71, P = 0.006) were independently associated with increased risk of iRFR. The median time to recurrence was 1.5 years after RN among the 33 patients with iRFR, and 1.4 years among all patients. Overall, the median CSS was 2.5 years after diagnosis of iRFR, 1.3 years after RFR in the setting of synchronous metastases, and 2.2 years overall. After primary locally directed therapy (surgery, ablation or radiation), systemic therapy or expectant management, the 3-year CSS rates among patients with iRFR were 63%, 50% and 13% (P = 0.001) and were 64%, 50% and 28% (P = 0.006) among all patients, respectively. On multivariable analysis, when compared with observation, locally directed therapies were associated with a significantly decreased risk of death from RCC (HR 0.26, P < 0.001). CONCLUSIONS: Renal fossa recurrence is a rare event after RN for RCC and portends a poor prognosis, even in the absence of synchronous metastases. Development of iRFR is associated with advanced stage and aggressive tumour biology. Patients who underwent primary locally directed therapy had superior CSS compared with those treated with expectant management, supporting the use of aggressive local treatment in carefully selected patients with RFR. Future research is needed to determine the optimum role and sequencing of combined therapy in patients with this rare entity. PMID- 27489014 TI - Genomic validation of the differential preservation of population history in modern human cranial anatomy. AB - OBJECTIVES: In modern humans, the significant correlation between neutral genetic loci and cranial anatomy suggests that the cranium preserves a population history signature. However, there is disagreement on whether certain parts of the cranium preserve this signature to a greater degree than other parts. It is also unclear how different quantitative measures of phenotype affect the association of genetic variation and anatomy. Here, we revisit these matters by testing the correlation of genetic distances and various phenotypic distances for ten modern human populations. MATERIALS AND METHODS: Geometric morphometric shape data from the crania of adult individuals (n = 224) are used to calculate phenotypic PST , Procrustes, and Mahalanobis distances. We calculate their correlation to neutral genetic distances, FST , derived from single nucleotide polymorphisms (SNPs). We subset the cranial data into landmark configurations that include the neurocranium, the face, and the temporal bone in order to evaluate whether these cranial regions are differentially correlated to neutral genetic variation. RESULTS: Our results show that PST , Mahalanobis, and Procrustes distances are correlated with FST distances to varying degrees. They indicate that overall cranial shape is significantly correlated with neutral genetic variation. Of the component parts examined, PST distances for both the temporal bone and the face have a stronger association with FST distances than the neurocranium. When controlling for population divergence time, only the whole cranium and the temporal bone have a statistically significant association with FST distances. DISCUSSION: Our results confirm that the cranium, as a whole, and the temporal bone can be used to reconstruct modern human population history. PMID- 27489015 TI - Trans-oral fine needle aspiration cytology in cervical (C1 and C2) vertebral lesions: a novel diagnostic approach. AB - OBJECTIVE: Fine needle aspiration (FNA) cytology is a relatively non-invasive method for diagnosing both superficial and deep-seated neoplastic and non neoplastic lesions. In this study, we evaluated the diagnostic utility of trans oral FNA in cervical (C1 and C2) vertebral and paravertebral lesions. MATERIAL AND METHODS: Eighteen FNA cases of cervical vertebral and paravertebral lesions performed by a trans-oral route without any image-guidance between 1995 and 2014 were retrieved from the archives of the cytology department at PGIMER, Chandigarh and reviewed. RESULTS: Out of 18 cases, a definite diagnosis was given in 15 cases (83.3%). The commonest diagnosis seen was granulomatous inflammation consistent with tuberculosis (33.3%). CONCLUSION: Trans-oral FNA is a quick, inexpensive and relatively safe outpatient procedure for sampling C1 and C2 vertebral and paravertebral lesions, which are clinically and radiologically difficult to approach. It helps in the early diagnosis and management of these patients. PMID- 27489016 TI - Connecting Education to Quality: Engaging Medical Students in the Development of Evidence-Based Clinical Decision Support Tools. AB - PROBLEM: Evidence-based practice (EBP) skills are crucial for delivering high quality patient care. It is essential that medical students learn EBP concepts through a practical, in-depth research project. To date, literature on preparing students in this manner is limited. APPROACH: In academic year 2014-2015, the Medical University of South Carolina's (MUSC's) Center for Evidence-Based Practice (now known as the Value Institute) partnered with College of Medicine faculty to revitalize the undergraduate medical student EBP curriculum. Without adding to the number of the lecture hours, the curriculum was restructured to be more process driven, project based, and clinically relevant. The resulting yearlong EBP course partnered small teams of medical students with interprofessional clinical teams to engage the students in developing evidence based clinical decision support tools. OUTCOMES: The content developed during the EBP projects is currently being used to develop evidence-based clinical practice guidelines and accompanying order sets. NEXT STEPS: It is likely that this model will serve as a new framework for guideline development and will greatly expand the breadth of evidence-based content currently produced and available for clinicians at the MUSC. It would be feasible to offer a similar course within the MUSC to other disciplines and colleges, or at other institutions, if there were support from administration, interest on the part of clinicians and medical faculty, and individuals with the required expertise available to develop the curriculum and facilitate the course. It is worth considering how to improve the course and evaluating opportunities to implement it within other settings. PMID- 27489017 TI - Choosing Wisely for Medical Education: Six Things Medical Students and Trainees Should Question. AB - PROBLEM: Physician behaviors that promote overuse of health care resources develop early in training, and the medical education environment helps foster such behaviors. The authors describe the development of a Choosing Wisely list for medical students aimed at helping to curb overuse. APPROACH: The list was developed in 2015 by Choosing Wisely Canada (CWC) in partnership with the Canadian Federation of Medical Students and the Federation medicale etudiante du Quebec, which together represent all medical students in Canada. CWC convened a student-led taskforce to develop recommendations targeting medical student behaviors with respect to resource stewardship practices. Students at all 17 Canadian medical schools were consulted via an online questionnaire to solicit feedback on a list of 10 candidate recommendations. The taskforce used this student feedback in finalizing the list. OUTCOMES: The final list of "Six Things That Medical Students and Trainees Should Question" highlights both behaviors students should avoid (e.g., "Don't suggest ordering the most invasive test before considering other less invasive options") and behaviors related to aspects of medical training that may promote overuse, such as the hierarchical nature of clinical supervision (e.g., "Don't hesitate to ask for clarification on tests, treatments, or procedures that you believe may be ordered inappropriately"). Based on student requests for illustrative examples, clinical vignettes were developed. NEXT STEPS: This list highlights medical student behaviors and aspects of the academic environment that drive overuse. It is also relevant to faculty, whose behaviors and supervision practices influence trainees. PMID- 27489018 TI - The Impact of Project ECHO on Participant and Patient Outcomes: A Systematic Review. AB - PURPOSE: Project Extension for Community Healthcare Outcomes (ECHO) uses tele education to bridge knowledge gaps between specialists at academic health centers and primary care providers from remote areas. It has been implemented to address multiple medical conditions. The authors examined evidence of the impact of all Project ECHO programs on participant and patient outcomes. METHOD: The authors searched PubMed, MEDLINE, EMBASE, PsycINFO, and ProQuest from January 2000 to August 2015 and the reference lists of identified reviews. Included studies were limited to those published in English, peer-reviewed articles or indexed abstracts, and those that primarily focused on Project ECHO. Editorials, commentaries, gray literature, and non-peer-reviewed articles were excluded. The authors used Moore's evaluation framework to organize study outcomes for quality assessment. RESULTS: The authors identified 39 studies describing Project ECHO's involvement in addressing 17 medical conditions. Evaluations of Project ECHO programs generally were limited to outcomes from Levels 1 (number of participants) to 4 (providers' competence) of Moore's framework (n = 22 studies, with some containing data from multiple levels). Studies also suggested that Project ECHO changed provider behavior (n = 1), changed patient outcomes (n = 6), and can be cost-effective (n = 2). CONCLUSIONS: Project ECHO is an effective and potentially cost-saving model that increases participant knowledge and patient access to health care in remote locations, but further research examining its efficacy is needed. Identifying and addressing potential barriers to Project ECHO's implementation will support the dissemination of this model as an education and practice improvement initiative. PMID- 27489019 TI - Predictors of community-associated Staphylococcus aureus, methicillin-resistant and methicillin-susceptible Staphylococcus aureus skin and soft tissue infections in primary-care settings. AB - Skin and soft tissue infections (SSTIs) due to Staphylococcus aureus have become increasingly common in the outpatient setting; however, risk factors for differentiating methicillin-resistant S. aureus (MRSA) and methicillin susceptible S. aureus (MSSA) SSTIs are needed to better inform antibiotic treatment decisions. We performed a case-case-control study within 14 primary care clinics in South Texas from 2007 to 2015. Overall, 325 patients [S. aureus SSTI cases (case group 1, n = 175); MRSA SSTI cases (case group 2, n = 115); MSSA SSTI cases (case group 3, n = 60); uninfected control group (control, n = 150)] were evaluated. Each case group was compared to the control group, and then qualitatively contrasted to identify unique risk factors associated with S. aureus, MRSA, and MSSA SSTIs. Overall, prior SSTIs [adjusted odds ratio (aOR) 7.60, 95% confidence interval (CI) 3.31-17.45], male gender (aOR 1.74, 95% CI 1.06-2.85), and absence of healthcare occupation status (aOR 0.14, 95% CI 0.03 0.68) were independently associated with S. aureus SSTIs. The only unique risk factor for community-associated (CA)-MRSA SSTIs was a high body weight (?110 kg) (aOR 2.03, 95% CI 1.01-4.09). PMID- 27489020 TI - Outcomes in Diabetic Patients Undergoing Orbital Atherectomy System. AB - OBJECTIVES: We evaluated the angiographic and clinical outcomes of orbital atherectomy to treat severely calcified coronary lesions in diabetic and non diabetic patients. BACKGROUND: Diabetics have increased risk for death, myocardial infarction, and target vessel revascularization after percutaneous coronary intervention. Severely calcified coronary lesions are associated with increased cardiac events. Orbital atherectomy facilitates stent delivery and optimizes stent expansion by modifying severely calcified plaque. Outcomes in diabetic patients who undergo orbital atherectomy have not been reported. METHODS: Our retrospective multicenter registry included 458 consecutive real world patients with severely calcified coronary arteries who underwent orbital atherectomy. The primary safety endpoint was the rate of major adverse cardiac and cerebrovascular events at 30 days. RESULTS: Diabetics represented 42.1% (193/458) of the entire cohort. The primary endpoint was similar in diabetics and non-diabetics (1.0% vs. 3.0%%, P = 0.20), as were 30-day rates of death (0.5% vs. 1.9%, P = 0.41), myocardial infarction (0.5% vs. 1.5%, P = 0.40), target vessel revascularization (0% vs. 0%, P = 1), and stroke (0% vs. 0.4%, P > 0.9). Angiographic complications and stent thrombosis rate were low and did not differ between the 2 groups. CONCLUSION: Diabetics represented a sizeable portion of patients who underwent orbital atherectomy. Diabetics who had severely calcified coronary arteries and underwent orbital atherectomy had low event rates that were similar to non-diabetics. Orbital atherectomy appears to be a viable treatment strategy for diabetic patients. Randomized trials with longer-term follow-up are needed to determine the ideal treatment strategy for diabetics. PMID- 27489021 TI - Service quality and patient experiences of ambulatory care in a specialized clinic vs. a general hospital. AB - OBJECTIVES: Health care organizations are constantly looking for ways to establish a differential advantage to attract customers. To this end, service quality has become an important differentiator in the strategy of health care organizations. In this study, we compared the service quality and patient experience in an ambulatory care setting of a physician-owned specialized facility with that of a general hospital. METHOD: A comparative case study with a mixed method design was employed. Data were gathered through a survey on health service quality and patient experience, completed with observations, walkthroughs, and photographic material. RESULTS: Service quality and patient experiences are high in both the investigated health care facilities. A significant distinction can be made between the two facilities in terms of interpersonal quality (p = 0.001) and environmental quality (P <= 0.001), in favor of the medical center. The difference in environmental quality is also indicated by the scores given by participants who had been in both facilities. Qualitative analysis showed higher administrative quality in the medical center. Environmental quality and patient experience can predict the interpersonal quality; for environmental quality, interpersonal quality and age are significant predictors. CONCLUSIONS: Service quality and patient experiences are high in both facilities. The medical center has higher service quality for interpersonal and environmental service quality and is more process-centered. PMID- 27489022 TI - Premedication with Clarithromycin Is Effective against Secondary Bacterial Pneumonia during Influenza Virus Infection in a Pulmonary Emphysema Mouse Model. AB - Secondary bacterial pneumonia (SBP) during influenza increases the severity of chronic obstructive pulmonary disease (COPD) and its associated mortality. Macrolide antibiotics, including clarithromycin (CAM), are potential treatments for a variety of chronic respiratory diseases owing to their pharmacological activities, in addition to antimicrobial action. We examined the efficacy of CAM for the treatment of SBP after influenza infection in COPD. Specifically, we evaluated the effect of CAM in elastase-induced emphysema mice that were inoculated with influenza virus (strain A/PR8/34) and subsequently infected with macrolide-resistant Streptococcus pneumoniae CAM was administered to the emphysema mice 4 days prior to influenza virus inoculation. Premedication with CAM improved pathologic responses and bacterial load 2 days after S. pneumoniae inoculation. Survival rates were higher in emphysema mice than control mice. While CAM premedication did not affect viral titers or exert antibacterial activity against S. pneumoniae in the lungs, it enhanced host defense and reduced inflammation, as evidenced by the significant reductions in total cell and neutrophil counts and interferon (IFN)-gamma levels in bronchoalveolar lavage fluid and lung homogenates. These results suggest that CAM protects against SBP during influenza in elastase-induced emphysema mice by reducing IFN-gamma production, thus enhancing immunity to SBP, and by decreasing neutrophil infiltration into the lung to prevent injury. Accordingly, CAM may be an effective strategy to prevent secondary bacterial pneumonia in COPD patients in areas in which vaccines are inaccessible or limited. PMID- 27489023 TI - CIB1 and CIB2 are HIV-1 helper factors involved in viral entry. AB - HIV-1 relies on the host-cell machinery to accomplish its replication cycle, and characterization of these helper factors contributes to a better understanding of HIV-host interactions and can identify potential novel antiviral targets. Here we explored the contribution of CIB2, previously identified by RNAi screening as a potential helper factor, and its homolog, CIB1. Knockdown of either CIB1 or CIB2 strongly impaired viral replication in Jurkat cells and in primary CD4+ T lymphocytes, identifying these proteins as non-redundant helper factors. Knockdown of CIB1 and CIB2 impaired envelope-mediated viral entry for both for X4 and R5-tropic HIV-1, and both cell-free and cell-associated entry pathways were affected. In contrast, the level of CIB1 and CIB2 expression did not influence cell viability, cell proliferation, receptor-independent viral binding to the cell surface, or later steps in the viral replication cycle. CIB1 and CIB2 knockdown was found to reduce the expression of surface molecules implicated in HIV-1 infection, including CXCR4, CCR5 and integrin alpha4beta7, suggesting at least one mechanism through which these proteins promote viral infection. Thus, this study identifies CIB1 and CIB2 as host helper factors for HIV-1 replication that are required for optimal receptor-mediated viral entry. PMID- 27489025 TI - Erratum to: Opening Skinner's Box: an Introduction. AB - [This corrects the article DOI: 10.1007/s40614-014-0016-z.]. PMID- 27489026 TI - A N-heterocyclic tetracarbene Pd(ii) moiety containing a Pd(ii)-Pb(ii) bimetallic MOF for three-component cyclotrimerization via benzyne. AB - A novel Pd(ii)-Pb(ii) bimetallic metal-organic framework Pd(ii)-Pb(ii)-MOF (B) which contains an N-heterocyclic tetracarbene Pd(ii) moiety was synthesized based on a chelating N-heterocyclic dicarbene Pd(ii)-NHDC ligand (A) under solvothermal conditions. It can be a highly active heterogeneous catalyst for three-component cyclotrimerization via benzyne species. PMID- 27489024 TI - Ethanol modulates facial stimulation-evoked outward currents in cerebellar Purkinje cells in vivo in mice. AB - Acute ethanol overdose can induce dysfunction of cerebellar motor regulation and cerebellar ataxia. In this study, we investigated the effect of ethanol on facial stimulation-evoked inhibitory synaptic responses in cerebellar Purkinje cells (PCs) in urethane-anesthetized mice, using in vivo patch-clamp recordings. Under voltage-clamp conditions, ethanol (300 mM) decreased the amplitude, half-width, rise time and decay time of facial stimulation-evoked outward currents in PCs. The ethanol-induced inhibition of facial stimulation-evoked outward currents was dose-dependent, with an IC50 of 148.5 mM. Notably, the ethanol-induced inhibition of facial stimulation-evoked outward currents were significantly abrogated by cannabinoid receptor 1 (CB1) antagonists, AM251 and O-2050, as well as by the CB1 agonist WIN55212-2. Moreover, the ethanol-induced inhibition of facial stimulation-evoked outward currents was prevented by cerebellar surface perfusion of the PKA inhibitors H-89 and Rp-cAMP, but not by intracellular administration of the PKA inhibitor PKI. Our present results indicate that ethanol inhibits the facial stimulation-evoked outward currents by activating presynaptic CB1 receptors via the PKA signaling pathway. These findings suggest that ethanol overdose impairs sensory information processing, at least in part, by inhibiting GABA release from molecular layer interneurons onto PCs. PMID- 27489027 TI - Ultraperformance Liquid Chromatography-Tandem Mass Spectrometry Method for Profiling Ketolic and Phenolic Sex Steroids Using an Automated Injection Program Combined with Diverter Valve Switch and Step Analysis. AB - Sex steroids are involved in many physiological and pathological processes. The determination of sex steroids is essential to understand the mechanisms of human health and diseases. Derivatization techniques could specifically enhance the sensitivities for sex steroids with a given functional group. However, no derivatization reagents are available for profiling multifunctional sex steroids, including phenolic estrogens, ketolic androgens, and ketolic progestogens, in a single analytical run. In the present study, a novel method involving ultraperformance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-MS/MS) was developed for profiling both ketolic and phenolic sex steroids in human serum using an automated injection program combined with diverter valve switch and step analysis (AIDSA). The human serum, prepared through liquid-liquid extraction and subsequently derivatized using Girard P offline, was automatically injected twice under the automated injection program. For the first injection, Girard P-derivatized ketolic sex steroids were loaded onto the column, and subsequently, the second injection and online derivatization of the same sample using dansyl chloride were performed in the injector needle for 15 min. The dansyl-labeled phenolic sex steroids were then loaded onto the column. The diverter valve worked in coordination with the injection program to import the derivatized sex steroids and remove excess derivatization reagents. The two types of derivatives were individually analyzed in a step-by-step manner. In addition, online dansyl derivatization and Girard P derivative analyses were simultaneously implemented to shorten the total analysis time. This method was well validated and applied to determine the sex steroid levels in human serum. PMID- 27489028 TI - Real-World Data: Policy Issues Regarding their Access and Use. AB - As real-world data (RWD) in health care begin to cross over to the Big Data realms, a panel of health economists was gathered to establish how well the current US policy environment further the goals of RWD and, if not, what can be done to improve matters. This report summarizes these discussions spanning the current US landscape of RWD availability and usefulness, private versus public development of RWD assets, the current inherent bias in terms of access to RWD, and guiding principles in providing quality assessments of new RWD studies. Three main conclusions emerge: (1) a business case is often required to incentivize investments in RWD assets. However, access restrictions for public data assets have failed to generate a proper market for these data and hence may have led to an underinvestment of public RWDs; (2) Very weak empirical evidence exist on for profit entities misusing public RWD data entities to further their own agendas, which is the basis for supporting access restrictions of public RWD data; and (3) perhaps developing standardized metrics that could flag misuse of RWDs in an efficient way could help quell some of the fear of sharing public RWD assets with for-profit entities. It is hoped that these discussions and conclusions would pave the way for more rigorous and timely debates on the greater availability and accessibility of RWD assets. PMID- 27489029 TI - Nucleation of Amyloid Oligomers by RepA-WH1-Prionoid-Functionalized Gold Nanorods. AB - Understanding protein amyloidogenesis is an important topic in protein science, fueled by the role of amyloid aggregates, especially oligomers, in the etiology of a number of devastating human degenerative diseases. However, the mechanisms that determine the formation of amyloid oligomers remain elusive due to the high complexity of the amyloidogenesis process. For instance, gold nanoparticles promote or inhibit amyloid fibrillation. We have functionalized gold nanorods with a metal-chelating group to selectively immobilize soluble RepA-WH1, a model synthetic bacterial prionoid, using a hexa-histidine tag (H6). H6-RepA-WH1 undergoes stable amyloid oligomerization in the presence of catalytic concentrations of anisotropic nanoparticles. Then, in a physically separated event, such oligomers promote the growth of amyloid fibers of untagged RepA-WH1. SERS spectral changes of H6-RepA-WH1 on spherical citrate-AuNP substrates provide evidence for structural modifications in the protein, which are compatible with a gradual increase in beta-sheet structure, as expected in amyloid oligomerization. PMID- 27489031 TI - Small molecule based N-phenyl carbazole substituted diketopyrrolopyrroles as donors for solution-processed bulk heterojunction organic solar cells. AB - We report two acetylene-bridged small molecules DPP5 and DPP6 with low HOMO-LUMO gaps as donors along with PC71BM as an acceptor for the fabrication of solution processed bulk heterojunction solar cells. After the optimization, i.e. weight ratio of donor to acceptor and surface treatment of the active layer, we achieved overall power conversion efficiencies up to 4.65% (Jsc = 8.19 mA cm(-2), Voc = 0.98 V and FF = 0.58) and 5.73% (Jsc = 9.58 mA cm(-2), Voc = 0.98 V and FF = 0.61), for DPP5:PC71BM and DPP6:PC71BM respectively, which are superior to those for the devices based on as-cast active layers. The significant change in the power conversion efficiency is attributed to the improvement in nanoscale morphology, balanced charge transport and charge collection efficiency, induced through the surface treatment. PMID- 27489030 TI - Isothiourea-catalysed enantioselective pyrrolizine synthesis: synthetic and computational studies. AB - The catalytic enantioselective synthesis of a range of cis-pyrrolizine carboxylate derivatives with outstanding stereocontrol (14 examples, >95 : 5 dr, >98 : 2 er) through an isothiourea-catalyzed intramolecular Michael addition lactonisation and ring-opening approach from the corresponding enone acid is reported. An optimised and straightforward three-step synthetic route to the enone acid starting materials from readily available pyrrole-2-carboxaldehydes is delineated, with benzotetramisole (5 mol%) proving the optimal catalyst for the enantioselective process. Ring-opening of the pyrrolizine dihydropyranone products with either MeOH or a range of amines leads to the desired products in excellent yield and enantioselectivity. Computation has been used to probe the factors leading to high stereocontrol, with the formation of the observed cis steroisomer predicted to be kinetically and thermodynamically favoured. PMID- 27489032 TI - Facial Soft Tissue Depth Measurement: Validation of the 75-Shormax. AB - The shorth and 75-shormax were recently posited as an improved alternative to the arithmetic mean for describing facial soft tissue thicknesses in craniofacial identification. The shorth better estimates the data peak, while the 75-shormax provides improved provisions for a long right tail. When first proposed, the 75 shormax was subjectively gauged. Herein, shormax errors are calculated at every whole percentile to quantitatively determine zones of error minimization in two large samples: (a) CT data of French adults, n-range = 211-469 individuals; and (b) all C-Table data, n-range = 60-1065 individuals [including part but not all of sample (a)]. The smallest residuals were found at the 79th percentile (mean of raw residuals) and the 74th percentile (mean of absolute residuals). The 75 shormax is subsequently verified as good error minimizer since the absolute differences carry the greatest weight and the 74th percentile closely approximates the 75th percentile. PMID- 27489033 TI - The association of three promoter polymorphisms in interleukin-10 gene with the risk for colorectal cancer and hepatocellular carcinoma: A meta-analysis. AB - Mounting evidence supports a potent inhibitory role of interleukin-10 (IL-10) in tumor carcinogenesis, angiogenesis and metastasis. This meta-analysis was designed to examine the association of three promoter polymorphisms (-592C > A, 819C > T and -1082G > A) in IL-10 gene with the risk for colorectal cancer and hepatocellular carcinoma. Qualification assessment and data collection were completed by two authors independently. The random-effects model using the DerSimonian and Laird method was fitted by the STATA software. Twenty-five articles involving 5933 cases and 9724 controls were meta-analyzed. Overall comparisons of the mutant alleles (-592A, -819T and -1082A) of three promoter polymorphisms with alternative wild alleles failed to reveal any statistical significance for both colorectal cancer and hepatocellular carcinoma (P > 0.05), and the likelihood of heterogeneity was low (I(2) < 50%). For -592C > A polymorphism, a significant risk for colorectal cancer was identified when analysis was restricted to East Asians (odds ratio or OR = 1.41, 95% confidence interval or CI: 1.18-1.68, P < 0.001) and retrospective studies (OR = 1.23, 95% CI: 1.09-1.39, P = 0.001). As weighed by the Egger's test and the fill-and-trim method, there was a low probability of publication bias for all studied polymorphisms. Our findings collectively suggest that the -592C > A polymorphism in IL-10 gene might be a susceptibility locus for colorectal cancer in East Asians. PMID- 27489035 TI - Correction to Drag Reduction using Lubricant-Impregnated Surfaces in Viscous Laminar Flow. PMID- 27489034 TI - The impact of lower limb chronic oedema on patients' quality of life. AB - This study aimed to explore patients' perceptions regarding the impact that lower limb chronic oedema has on their quality of life (QoL). A quantitative descriptive design was used to collect data from patients with lower limb chronic oedema. A condition-specific validated questionnaire was distributed to a purposive sample (n = 122) through manual lymphatic drainage/vascular/health clinics in Ireland. Results indicated that patients with lower limb chronic oedema experience a wide range of physical problems such as limb heaviness (74%, n = 66), weakness (44%, n = 40) and pain (38%, n = 34). Additionally, difficulties with walking (53%, n = 48), standing (51%, n = 46) and bending (45%, n = 40) were reported. Concerns regarding poor body image were strongly evident (76%, n = 68). Difficulties finding clothing/footwear to fit oedematous limb(s) were reported (59%, n = 53), in addition to finding clothes that participants would like to wear (64%, n = 58). Emotional symptoms of irritability (42%, n = 38), anxiety (41%, n = 37) and tension (40%, n = 36) were reported. Over half of the participants (55%, n = 49) stated that their chronic swelling affected their social functioning and their ability to engage in leisure activities. This study has identified that lower limb chronic oedema has significant psychological, social and physical implications for persons' QoL. PMID- 27489036 TI - Medication use and adherence among multi-ethnic community-dwelling older adults in Malaysia. AB - AIM: The present study assessed adherence, barriers, belief and awareness towards the use of medications among multi-ethnic community-dwelling older adults in Malaysia. Medication accessibility, expenditure and perceptions towards medicine labeling among older adults were also evaluated. METHODS: A cross-sectional study was carried out in the central region of Malaysia from January to August 2015. The older adults enrolled in an ongoing prospective community-based geriatric cohort study and prescribed with medicines were interviewed using a 50-item validated questionnaire. RESULTS: Of the 79 older adults interviewed, 39.2% had >=4 prescribed medications. Most obtained their medications free-of-charge from government hospitals (66, 83.5%). Nearly half (35, 44.3%) had trouble reading labels for medicines that they had received. Chinese older adults (P = 0.001) and those with lower monthly household income (P < 0.001) expressed difficulty in reading medication labels. Most (59, 75.0%) were unable to differentiate between generic and brand names of the medications, and 49.4% of the older adults did not know that all medicines had to be registered with the Ministry of Health, Malaysia. Most older adults had positive beliefs about the necessity of their medications, and 50.6% (n = 40) reported high medication adherence. The medication adherence score was negatively correlated with the concerns score (r = -0.5, P < 0.001). CONCLUSIONS: The findings from the present study provide a unique insight into the diversity of medication use among multiethnic community dwelling older adults. Although high adherence to medications and positive beliefs about the necessity of medications were reported by the older adults, their knowledge about medications remained insufficient and they had difficulty in reading medication labels. Geriatr Gerontol Int 2017; 17: 1214-1220. PMID- 27489037 TI - Evidence of proteinuria, but no other characteristics of pre-eclampsia, in relaxin-deficient mice. AB - Pre-eclampsia (PE) is a leading cause of maternal and fetal death, characterised by an imbalance of placental growth factors and hypertension at >20 weeks gestation. Impaired maternal systemic vascular adaptations and fetal growth restriction are features of both PE and pregnant relaxin-deficient (Rln-/-) mice. The aim of the present study was to investigate whether these phenotypes in Rln-/ mice are associated with abnormal placental growth factor expression, increased soluble fms-like tyrosine kinase-1 (sFlt-1), proteinuria and/or hypertension during pregnancy. In addition, we examined relaxin and relaxin receptor (relaxin/insulin like family peptide receptor 1 (RXFP1)) mRNA expression in placentas of women with PE. There was no significant difference in placental vascular endothelial growth factor A (VegfA) and placenta growth factor (Plgf) gene expression between Rln-/- and wild-type mice. Circulating plasma sFlt-1 concentrations in pregnant mice of both genotypes and ages were increased compared with non-pregnant mice but were lower in younger pregnant Rln-/- mice compared with aged-matched Rln+/+ mice. Aged pregnant Rln-/- mice had higher urinary albumin:creatinine ratios compared with age-matched Rln+/+ mice, indicative of proteinuria. Systolic and diastolic blood pressures did not differ between genotypes. In addition, PE in women was not associated with altered placental mRNA expression of RLN2 or RXFP1 at term. Overall, the data demonstrate that pregnant Rln-/- mice do not have the typical characteristics of PE. However, these mice show evidence of proteinuria, but we suggest that this results from systemic renal vascular dysfunction before pregnancy. PMID- 27489039 TI - An all-atom, active site exploration of antiviral drugs that target Flaviviridae polymerases. AB - Natural 2'-modified nucleosides are the most widely used antiviral therapy. In their triphosphorylated form, also known as nucleotide analogues, they target the active site of viral polymerases. Viral polymerases have an overall right-handed structure that includes the palm, fingers and thumb domains. These domains are further subdivided into structurally conserved motifs A-G, common to all viral polymerases. The structural motifs encapsulate the allosteric/initiation (N1) and orthosteric/catalytic (N2) nucleotide-binding sites. The current study investigated how nucleotide analogues explore the N2 site of viral polymerases from three genera of the family Flaviviridae using a stochastic, biophysical, Metropolis Monte Carlo-based software. The biophysical simulations showed a statistical distinction in nucleotide-binding energy and exploration between phylogenetically related viral polymerases. This distinction is clearly demonstrated by the respective analogue contacts made with conserved viral polymerase residues, the heterogeneous dynamics of structural motifs, and the orientation of the nucleotide analogues within the N2 site. Being able to simulate what occurs within viral-polymerase-binding sites can prove useful in rational drug designs against viruses. PMID- 27489040 TI - Chromatin silencing maintains the identity of intestinal stem cells. PMID- 27489041 TI - One step engineering of the small-subunit ribosomal RNA using CRISPR/Cas9. AB - Bacteria are indispensable for the study of fundamental molecular biology processes due to their relatively simple gene and genome architecture. The ability to engineer bacterial chromosomes is quintessential for understanding gene functions. Here we demonstrate the engineering of the small-ribosomal subunit (16S) RNA of Mycoplasma mycoides, by combining the CRISPR/Cas9 system and the yeast recombination machinery. We cloned the entire genome of M. mycoides in yeast and used constitutively expressed Cas9 together with in vitro transcribed guide-RNAs to introduce engineered 16S rRNA genes. By testing the function of the engineered 16S rRNA genes through genome transplantation, we observed surprising resilience of this gene to addition of genetic elements or helix substitutions with phylogenetically-distant bacteria. While this system could be further used to study the function of the 16S rRNA, one could envision the "simple" M. mycoides genome being used in this setting to study other genetic structures and functions to answer fundamental questions of life. PMID- 27489042 TI - Shh... Sweat gland in progress! PMID- 27489043 TI - On the potential for BECCS efficiency improvement through heat recovery from both post-combustion and oxy-combustion facilities. AB - In order to mitigate climate change to no more than 2 degrees C, it is well understood that it will be necessary to directly remove significant quantities of CO2, with bioenergy CCS (BECCS) regarded as a promising technology. However, BECCS will likely be more costly and less efficient at power generation than conventional CCS. Thus, approaches to improve BECCS performance and reduce costs are of importance to facilitate the deployment of this key technology. In this study, the impact of biomass co-firing rate and biomass moisture content on BECCS efficiency with both post- and oxy-combustion CO2 capture technologies was evaluated. It was found that post-combustion capture BECCS (PCC-BECCS) facilities will be appreciably less efficient than oxy-combustion capture BECCS (OCC-BECCS) facilities. Consequently, PCC-BECCS have the potential to be more carbon negative than OCC-BECCS per unit electricity generated. It was further observed that the biomass moisture content plays an important role in determining the BECCS facilities' efficiency. This will in turn affect the enthalpic content of the BECCS plant exhaust and implies that exhaust gas heat recovery may be an attractive option at higher rates of co-firing. It was found that there is the potential for the recovery of approximately 2.5 GJheat per tCO2 at a temperature of 100 degrees C from both PCC-BECCS and OCC-BECCS. On- and off-site applications for this recovered heat are discussed, considering boiler feedwater pre-heating, solvent regeneration and district heating cases. PMID- 27489044 TI - Polarization-dependent fluorescence correlation spectroscopy for studying structural properties of proteins in living cell. AB - Rotational diffusion measurement is predicted as an important method in cell biology because the rotational properties directly reflect molecular interactions and environment in the cell. To prove this concept, polarization-dependent fluorescence correlation spectroscopy (pol-FCS) measurements of purified fluorescent proteins were conducted in viscous solution. With the comparison between the translational and rotational diffusion coefficients obtained from pol FCS measurements, the hydrodynamic radius of an enhanced green fluorescent protein (EGFP) was estimated as a control measurement. The orientation of oligomer EGFP in living cells was also estimated by pol-FCS and compared with Monte Carlo simulations. The results of this pol-FCS experiment indicate that this method allows an estimation of the molecular orientation using the characteristics of rotational diffusion. Further, it can be applied to analyze the degree of molecular orientation and multimerization or detection of tiny aggregation of aggregate-prone proteins. PMID- 27489045 TI - Cytotoxic Oxygenated Steroids from the Soft Coral Nephthea erecta. AB - A new 10-demethylated steroid, nephtheasteroid A (1), a new 19-oxygenated steroid, nephtheasteroid B (2) as well as five known steroids 3-7 were isolated from the organic extract of a Taiwanese soft coral Nephthea erecta. The structure was determined by means of IR, MS, and NMR techniques. Among these metabolites, 1 is rarely found in steroids possessing a 19-norergostane skeleton. In vitro cytotoxicity study using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that compounds 3 and 4 exhibited cytotoxicity against human chronic myelogenous leukemia (K562), human acute lymphoblastic leukemia (Molt-4), human T lymphoblastoid (Sup-T1), and human leukemic monocyte lymphoma (U937), with IC50 of 6.5-14.0 uM. PMID- 27489046 TI - Practical Synthesis of Axially Chiral Dicarboxylates via Pd-Catalyzed External-CO Free Carbonylation. AB - We have developed a safe and practical synthetic method for preparing axially chiral diphenyl dicarboxylates using Pd-catalyzed external-CO-free carbonylation with phenyl formate as a CO surrogate. Optimized conditions consisted of axially chiral [1,1'-binaphthalene]-2,2'-diyl ditriflate and its congeners, each easily prepared from commercially available enantiomerically pure diols, Pd(OAc)2, 1,3 bis(diphenylphosphino)propane, ethyldiisopropylamine, and no solvent. To demonstrate the potential utility of these products, this method was conducted on gram-scale and the phenyl ester products were converted to other useful compounds, and both processes were carried out without difficulty. PMID- 27489047 TI - Papilloedema secondary to oligodendroglioma. AB - Oligodendrogliomas are rare slow-growing asymptomatic glial tumours that usually present in patients in their fourth to sixth decades of life. Neurological symptoms that may present include nausea, headache, vomiting, diplopia, confusion, focal weakness, numbness and seizures. The treatment of oligodendroglioma tumours is based on functional status classification, lumbar puncture, imaging of the head, tumour biopsy and genetic testing. Grades II and IV oligodendroglial tumours, which have co-deletion of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) and mutations in isocitrate dehydrogenase, have the most favourable prognosis, as they respond well to neurosurgery and chemotherapy. This report will discuss a general case of papilloedema in a young patient with oligodendroglioma and the role of the optometrist in its post-neurosurgical and chemotherapeutic care. PMID- 27489049 TI - Efficacy and safety of doublet versus single agent as salvage treatment for metastatic breast cancer pretreated with anthracyclines and taxanes: a systematic review and meta-analysis. AB - AIM: To perform a systematic review and meta-analysis of randomized controlled trials to compare the efficacy and safety of doublet versus single agent as salvage treatment for pretreated metastatic breast cancer. METHODS: A comprehensive literature search was performed to identify relevant randomized controlled trials (RCTs). All clinical studies were independently identified by two authors for inclusion. Demographic data, treatment regimens, objective response rate (ORR), and progression-free survival (PFS) and overall survival (OS) were extracted and analyzed using Comprehensive MetaAnalysis software (Version 2.0). RESULTS: Thirteen RCTs involving 4878 pretreated metastatic breast cancer patients were ultimately identified. The pooled results demonstrated that doublet combination therapy significantly improved ORR (RR 1.13, 95% CI: 1.01 1.27, p < .001) and PFS (hazard ration [HR] 0.83, 95% CI: 0.73-0.96, p = .011), but not OS (HR 0.93, 95% CI: 0.86-1.01, p = .065). Similar results were observed in sub-group analysis according to treatment regimens. Additionally, more incidences of grade 3 or 4 myelosuppression toxicities nausea and fatigue were observed in doublet combination therapy. CONCLUSIONS: In comparison with a single agent alone, doublet combination therapy as salvage treatment for pretreated metastatic breast cancer patients significantly improves ORR and PFS, but not OS. Further studies are recommended to identify patients who will most likely benefit from the appropriate doublet combination therapy. PMID- 27489050 TI - Eccentric Atrial Activation During a Narrow QRS Tachycardia: What Is the Mechanism? PMID- 27489048 TI - DNA hydroxymethylation controls cardiomyocyte gene expression in development and hypertrophy. AB - Methylation at 5-cytosine (5-mC) is a fundamental epigenetic DNA modification associated recently with cardiac disease. In contrast, the role of 5 hydroxymethylcytosine (5-hmC)-5-mC's oxidation product-in cardiac biology and disease is unknown. Here we assess the hydroxymethylome in embryonic, neonatal, adult and hypertrophic mouse cardiomyocytes, showing that dynamic modulation of hydroxymethylated DNA is associated with specific transcriptional networks during heart development and failure. DNA hydroxymethylation marks the body of highly expressed genes as well as distal regulatory regions with enhanced activity. Moreover, pathological hypertrophy is characterized by a shift towards a neonatal 5-hmC distribution pattern. We also show that the ten-eleven translocation 2 (TET2) enzyme regulates the expression of key cardiac genes, such as Myh7, through 5-hmC deposition on the gene body and at enhancers. Thus, we provide a genome-wide analysis of 5-hmC in the cardiomyocyte and suggest a role for this epigenetic modification in heart development and disease. PMID- 27489051 TI - Myocarditis in Clinical Practice. AB - Myocarditis is a polymorphic disease characterized by great variability in clinical presentation and evolution. Patients presenting with severe left ventricular dysfunction and life-threatening arrhythmias represent a demanding challenge for the clinician. Modern techniques of cardiovascular imaging and the exhaustive molecular evaluation of the myocardium with endomyocardial biopsy have provided valuable insight into the pathophysiology of this disease, and several clinical registries have unraveled the disease's long-term evolution and prognosis. However, uncertainties persist in crucial practical issues in the management of patients. This article critically reviews current information for evidence-based management, offering a rational and practical approach to patients with myocarditis. For this review, we searched the PubMed and MEDLINE databases for articles published from January 1, 1980, through December 31, 2015, using the following terms: myocarditis, inflammatory cardiomyopathy, and endomyocardial biopsy. Articles were selected for inclusion if they represented primary data or were review articles published in high-impact journals. In particular, a risk oriented approach is proposed. The different patterns of presentation of myocarditis are classified as low-, intermediate-, and high-risk syndromes according to the most recent evidence on prognosis, clinical findings, and both invasive and noninvasive testing, and appropriate management strategies are proposed for each risk class. PMID- 27489052 TI - Postoperative Pyoderma Gangrenosum: A Clinical Review of Published Cases. AB - Postoperative pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterized by PG at surgical incisions. It is often misdiagnosed as wound infection, and pathergy may complicate wound debridement. From September 1, 2013, through November 30, 2013, a literature search was conducted of articles published from January 1, 1978, through December 31, 2012. We referenced PubMed, MEDLINE, and Mayo Clinic Libraries using the keywords pyoderma gangrenosum, postoperative pyoderma gangrenosum, postsurgical pyoderma gangrenosum, superficial granulomatous pyoderma, pathergic pyoderma, and pyoderma gangrenosum associated with surgery, incision, breast, and wound dehiscence. In addition, all titles from PubMed with the words pyoderma gangrenosum were reviewed manually for postoperative cases. Of 136 patients, 90 (66%) did not have associated systemic diseases. If a comorbidity was present, hematologic disorders were most common. In addition, 29% (28) of women had predisposing disease vs 53% (19) of men. Women had more frequent breast involvement (P<.001); chest involvement was more common in men (P=.005). Girls and women aged 13 to 64 years had more frequent breast involvement (P=.01). Sites were distributed equally for men regardless of age (P=.40). Antibiotic drug therapy was begun and debridement occurred in 90% (110 of 122 treated patients) and 73% (90 of 123 available patients), respectively. Postoperative PG has less association with systemic disease than its nonpostoperative counterpart. Antibiotic drug therapy is routinely initiated. Affected sites are often debrided, causing additional wound breakdown. Early diagnosis may prevent complications. PMID- 27489053 TI - Secondary preventive medication use in a prevalent population-based cohort of acute coronary syndrome survivors. AB - AIM: Describe the dispensing patterns for guideline-recommended medications during 2008 in people with acute coronary syndrome (ACS) and how dispensing varies by gender and time since last ACS hospitalization. METHOD: A descriptive cohort spanning 20 years of people alive post-ACS in 2008. We extracted all ACS hospitalizations and deaths in Western Australia (1989-2008), and all person linked Pharmaceutical Benefits Scheme claims nationally for 2008. Participants were 23 642 men and women (36.8%), alive and aged 65-89 years in mid-2008 who were hospitalized for ACS between 1989 and 2008. Main outcome was the proportion of the study cohort (in 2008) dispensed guideline-recommended cardiovascular medications in that year. Adjusted odds ratios estimating the association between type (and number) of guideline-recommended medications and time since last ACS hospitalization. RESULTS: Medications most commonly dispensed in 2008 were statins (79.6% of study cohort) and then angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEi/ARBs) (71.1%), aspirin or clopidogrel (59.4%), and beta-blockers (54.6%). Only 51.8% of the cohort was dispensed three or more of these drug types in 2008. Women with ACS were 18% less likely to be dispensed statins (adjusted odds ratio (OR)=0.82; 95% CI 0.76-0.88). Overall, for each incremental year since last ACS admission, there was an 8% increased odds (adjusted OR=1.08; 95% CI 1.07-1.08) of being dispensed fewer of the recommended drug regimen in 2008. CONCLUSION: Longer time since last ACS admission was associated with dispensing fewer medications types and combinations in 2008. Interventions are warranted to improve dispensing long term and any apparent gender inequality in the drug class filled. PMID- 27489055 TI - Metabolomic study of wild and cultivated caper (Capparis spinosa L.) from different areas of Sardinia and their comparative evaluation. AB - Capparis spinosa L. (Capparidaceae), also known as caper, is widely known for its very aromatic flower buds (capers),that are largely employed as a flavouring in cooking. Capparis species are regarded as a potential source of important bioactive compounds, in fact, due to their botanical relationship with Brassica species; they contain glucosinolates, secondary plant metabolites, that have been studied for their potential anticarcinogenic properties. In addition, the presence of other numerous beneficial compounds such as polyphenols, alkaloids, lipids, vitamins and minerals have been reported. The aim of this study was to individuate and determinate the principal bioactive compounds occurring in different part (leaves, buds and flowers) of wild and cultivated C. spinosa collected from different area of Sardinia (Italy). Ultra-high performance liquid chromatography-triple quadrupole/linear ion trap tandem mass spectrometry methods were used for identification and simultaneous determination of 27 bioactive molecules. Analysis of different samples revealed qualitative and quantitative differences in the content of flavonoids, glucosinolates, anthocyanins and phenolic acids. In particular, glucocapparin resulted the most abundant with values ranging from 112 to 364 mg/100 g Fresh Weight (FW); followed by rutin with highest value of 126 mg/100 g FW, 4-hydroxyglucobrassicin with highest value of 42 mg/100 g FW and isorhamnetin 3-O-rutinoside with highest value of 24 mg/100 g FW. Based on this metabolomic targeted approach, quantitative results were treated by principal component analysis to explore and visualise correlation and discrimination among collections of C. spinosa samples. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27489054 TI - Load-induced enhancement of Dynein force production by LIS1-NudE in vivo and in vitro. AB - Most sub-cellular cargos are transported along microtubules by kinesin and dynein molecular motors, but how transport is regulated is not well understood. It is unknown whether local control is possible, for example, by changes in specific cargo-associated motor behaviour to react to impediments. Here we discover that microtubule-associated lipid droplets (LDs) in COS1 cells respond to an optical trap with a remarkable enhancement in sustained force production. This effect is observed only for microtubule minus-end-moving LDs. It is specifically blocked by RNAi for the cytoplasmic dynein regulators LIS1 and NudE/L (Nde1/Ndel1), but not for the dynactin p150(Glued) subunit. It can be completely replicated using cell free preparations of purified LDs, where duration of LD force production is more than doubled. These results identify a novel, intrinsic, cargo-associated mechanism for dynein-mediated force adaptation, which should markedly improve the ability of motor-driven cargoes to overcome subcellular obstacles. PMID- 27489056 TI - Preoperative Paravertebral Block Improves Postoperative Pain Control and Reduces Hospital Length of Stay in Patients Undergoing Autologous Breast Reconstruction after Mastectomy for Breast Cancer. AB - BACKGROUND: Postoperative pain is a major challenge for patients undergoing breast reconstruction after surgical treatment of breast cancer, resulting in prolonged hospitalizations and additional resource utilization. Evidence on the efficacy of techniques to minimize postoperative pain in autologous breast reconstruction is lacking. We sought to determine whether preoperative paravertebral block (PVB), a regional anesthetic technique, affects postoperative pain control and hospital length of stay (LOS) in patients undergoing autologous breast reconstruction. METHODS: Consecutive patients undergoing postmastectomy autologous breast reconstruction between 2012 and 2015 were identified from a prospectively collected database to compare those who received PVB to those who did not. Primary outcomes included self-reported pain score, time to oral-only narcotic usage (TTON), and LOS. Sample differences were compared using Wilcoxon rank-sum and Chi square tests for continuous and categorical variables. Kaplan Meier analysis was used to evaluate TTON and LOS, with Mantel-Cox test used to compare groups. RESULTS: Of 78 patients, 39 received PVB and 39 did not. Study groups did not differ regarding age, body mass index, American Society of Anesthesiologists class, mastectomy type, flap type, or cancer stage (p > 0.05). Patients in the PVB group reported significantly lower postoperative pain at 2 (p < 0.01) and 24 h (p < 0.01) and shorter median TTON (66 vs. 76 h, p < 0.01). Importantly, median LOS was reduced for patients receiving a PVB in both hours (95 vs. 116, p < 0.01) and hospital nights (4 vs. 5, p = 0.05). CONCLUSIONS: Preoperative PVB is associated with improved postoperative pain control and shorter hospitalizations for patients with breast cancer undergoing postmastectomy autologous reconstruction. PMID- 27489057 TI - Short- and Long-Term Outcomes After Gastrectomy in Elderly Gastric Cancer Patients. AB - BACKGROUND: The number of elderly patients undergoing gastric cancer surgery has recently increased. We therefore evaluated the short- and long-term outcomes of elderly patients after curative gastrectomy. METHODS: Overall, 824 patients were included in this retrospective study, which comprised of a non-elderly group (60 64 years; n = 558), an early-elderly group (75-79 years; n = 198), and a late elderly group (>=80 years; n = 68) who underwent curative gastrectomy for gastric cancer between 2005 and 2009. Postoperative complications, according to the Clavien-Dindo classification, and survival of both elderly groups were compared with the non-elderly group. Postoperative life expectancy of the late-elderly group was compared with the corresponding aged general population. RESULTS: Overall and severe (grade III or higher) complications in the early-elderly group were comparable with the non-elderly group; however, those in the late-elderly group were significantly more common than in the non-elderly group (p = 0.013 and p = 0.043, respectively). Multivariable analysis revealed that age >=80 years was an independent risk factor for severe complications (hazard ratio 3.02, 95 % confidence interval 1.12-8.17; p = 0.029), and the disease-specific survivals of both elderly groups were comparable with the non-elderly group in all TNM stages. Postoperative life expectancy of late-elderly patients eliminating death from recurrence was comparable with the corresponding aged general population eliminating death from gastric cancer. CONCLUSIONS: Gastric cancer surgery in elderly patients aged >=80 years achieves reasonable long-term survival despite the increased risk of severe complications. PMID- 27489058 TI - Minimally Invasive Gastric Surgery. AB - The incidence of gastric cancer is increasing in the United States, particularly for various subtypes as well as presenting in earlier states. Such changes have allowed various centers to increasingly offer less invasive approaches to the treatment of gastric cancer, namely laparoscopic and robotic techniques. Minimally invasive gastrectomy has been suggested to have similar oncology outcomes compared to open procedures. In the last two decades, large retrospective and a series of randomized trials evaluated the role of minimally invasive gastrectomy for early gastric cancer, distal gastrectomy, total gastrectomy and advanced gastric cancer. As the experience with emerging technologies such as robotic assisted gastrectomies increases, the indications for minimally invasive surgery will likely expand. PMID- 27489060 TI - Narrow QRS Tachycardia with Long RP Interval: What Is the Mechanism? PMID- 27489059 TI - Long-Term Outcome of Rectal Cancer With Clinically (EUS/MRI) Metastatic Mesorectal Lymph Nodes Treated by Neoadjuvant Chemoradiation: Role of Organ Preservation Strategies in Relation to Pathologic Response. AB - BACKGROUND: Organ preservation strategies are under investigation for patients with locally advanced rectal cancer (LARC) who achieve a complete pathologic response in the primary tumor (ypT0) after neoadjuvant chemoradiation therapy (CRT). This study explored the value of this approach for cN+ patients. METHODS: Data were retrieved from our institutional prospective rectal cancer database. Tumors with mesorectal lymph nodes larger than 5 mm shown on endorectal ultrasonography, pelvic magnetic resonance imaging, or both were staged as cN+. RESULTS: The study population comprised 226 patients (142 men and 84 women; median age, 64 years) with LARC who underwent CRT followed by surgery including total mesorectal excision (TME) (n = 179) and full-thickness local excision (LE) (n = 47) between 1996 and 2013. At staging, 123 patients (54.4 %) were cN+. In 65 cases (28.7 %), ypCR was observed. Metastatic mesorectal lymph nodes (ypN+) were detected in 41.6 % of the cN+ patients and in 2.8 % of the cN0 patients (P < 0.01). Among the cN+ patients, 16 % of the ypT0 cases were ypN+ compared with 51.8 % of the no-ypT0 cases (P < 0.01). Among the cN+ patients who underwent TME, the 5-year disease-specific survival (DSS) and disease-free survival (DFS) rates were respectively 100 and 91.6 % for the ypT0 patients compared with 71.2 and 58.0 % for the no-ypT0 patients (P = 0.01). Among the ypN+ patients, the 5-year DSS and DFS rates were both 100 % for the ypT0 cases compared with 59.1 and 43.3 % for the no-ypT0 patients. Among the cN+ and ypT0 patients, the 5-year DSS and DFS were respectively 100 and 85.7 % for the TME patients compared with 100 and 91.6 % for the LE patients. In the multivariate analysis, ypT0 was the only independent prognostic factor. CONCLUSIONS: Protocols aimed at organ preservation in LARC that achieve ypT0 after CRT can be offered also to cN+ patients. PMID- 27489061 TI - Posterior reversible encephalopathy syndrome (PRES) as a complication of Guillain Barre' syndrome (GBS). AB - A 17-year-old Pakistani female patient presented with acute onset flaccid quadriparesis with nerve conduction studies showing demyelinating polyneuropathy consistent with Guillain-Barre' syndrome. She was treated with 4 plasmapheresis sessions. She developed raised blood pressure, headache, visual loss and generalised seizures on the 13th day of admission. MRI of the brain on contrast showed findings of altered signals low on T1-weighted image, high on T2-weighted image and fluid-attenuated inversion recovery in the white matter of bilateral occipital, parietal and right frontal lobe consistent with posterior reversible encephalopathy syndrome. The patient was administered antiepileptic and antihypertensive drugs to control seizures and blood pressure. She was discharged in a stable state. On follow-up her visual loss had recovered completely and she had regained full motor strength in all four extremities after 6 weeks. Fresh MRI of the brain revealed complete resolution of lesions. Antihypertensive and antiepileptic medication was discontinued. She is independent in all her daily activities. PMID- 27489062 TI - Tamoxifen precipitation of familial hypertriglyceridaemia: a rare cause of acute pancreatitis. AB - Drug-induced pancreatitis is uncommon, and is estimated to account for between 0.1% and 5% of cases. Tamoxifen is commonly used in the management of oestrogen receptor-positive breast cancer. We present a rare case of tamoxifen-related hyperlipidaemia resulting in repeated episodes of pancreatitis, which, to the best of our knowledge, has only been documented a few times in the literature. A 36-year-old woman with familial hypertriglyceridaemia presented with recurrent episodes of abdominal pain, modest increases in serum amylase levels and normal liver function tests. The patient had recently been diagnosed with breast carcinoma and was managed with wide local excision (WLE), adjuvant radiotherapy and tamoxifen. On each admission, the patient's symptoms were confirmed either biochemically and/or radiologically. Analysis of the case led to a diagnosis of precipitation of familial hypertriglyceridaemia from tamoxifen use resulting in pancreatitis. Management was altered with tamoxifen cessation and initiation of second-line hormonal therapy. Tamoxifen use needs consideration, especially in those with familial hyperlipidaemia. PMID- 27489063 TI - Non-lethal Clostridium sordellii bacteraemia in an immunocompromised patient with pleomorphic sarcoma. AB - Clostridium sordellii is a spore-forming anaerobic Gram-positive rod that has rarely been reported to cause disease in humans. Resultant mortality from infection is estimated at nearly 70% and is most often correlated with gynaecological procedures, intravenous drug abuse or trauma. C. sordellii infection often presents similarly to toxic shock syndrome (TSS); notable features of infection include refractory hypotension, haemoconcentration and marked leucocytosis. Although clinically similar to TSS, a notable difference is C. sordellii infections rarely involve fever. The organism's major toxins include haemorrhagic (TcsH) and lethal factor (TcsL), which function to disrupt cytoskeletal integrity. Current literature suggests treating C. sordelli infection with a broad-spectrum penicillin, metronidazole and clindamycin. We present a case of C. sordellii bacteraemia and septic shock in an immunocompromised patient who was recently diagnosed with pleomorphic gluteal sarcoma. Despite presenting in critical condition, the patient improved after aggressive hemodynamic resuscitation, source control and intravenous antibiotic therapy. PMID- 27489064 TI - Silent myocardial infarction secondary to cardiac autonomic neuropathy in a patient with rheumatoid arthritis. AB - An 83-year-old female patient with rheumatoid arthritis and hypertension presented to the emergency department with fever and chills of 1 day duration. On examination, temperature was 100.9 F, heart rate 111/min and she had orthostatic hypotension. Laboratory tests showed elevated blood urea nitrogen and white cell count. The patient underwent treatment for symptomatic urinary tract infection and while her fever and leucocytosis resolved, tachycardia persisted. An EKG done showed T inversions in leads II, III, arteriovenous fistula, V2 and V3. Troponin I was elevated. Nuclear stress test revealed apical wall motion abnormality confirming myocardial infarction. Ewing's tests were carried out at bedside and these diagnosed severe autonomic neuropathy. Rheumatoid arthritis can cause cardiac autonomic neuropathy from chronic inflammation. This case entails the importance of assessing and detecting cardiac autonomic neuropathy in chronic inflammatory conditions, and the need to be cautious of acute coronary events in these patients, even for minimal or no symptoms. PMID- 27489065 TI - Urgent decisions and a tight spot: embolic infarction of a herniated cerebellar tonsil. AB - A previously well 30-year-old woman presented at 17:30 with a sudden onset of dizziness, ataxia and headache. She was initially investigated with a CT scan of the brain and lumbar puncture, which yielded no diagnosis. Subsequent MR scan revealed multiple posterior circulation infarcts, along with a previously undiagnosed Arnold-Chiari 2 malformation with an associated syrinx of her cervical and thoracic spine. The infarct involved one of the herniated cerebellar tonsils. Oedema of an infarct in the herniated tonsils caused compression of the medulla at the foramen magnum, with associated neurological symptoms including Lhermitte's phenomenon and headache on valsalva manoeuvre. Owing to these symptoms a surgical decompression was performed. The most likely aetiology of her stroke was determined to be a paradoxical embolus via patent foramen ovale. PMID- 27489066 TI - Multidrug-resistant Fusarium keratitis: diagnosis and treatment considerations. AB - Mycotic keratitis is an ocular infective process derived from any fungal species capable of corneal invasion. Despite its rarity in developed countries, its challenging and elusive diagnosis may result in keratoplasty or enucleation following failed medical management. Filamentous fungi such as Fusarium are often implicated in mycotic keratitis. Bearing greater morbidity than its bacterial counterpart, mycotic keratitis requires early clinical suspicion and initiation of antifungal therapy to prevent devastating consequences. We describe a case of multidrug-resistant mycotic keratitis in a 46-year-old man who continued to decline despite maximal therapy and therapeutic keratoplasty. Finally, enucleation was performed as a means of source control preventing dissemination of a likely untreatable fungal infection into the orbit. Multidrug-resistant Fusarium is rare, and may progress to endophthalmitis. We discuss potential management options which may enhance diagnosis and outcome in this condition. PMID- 27489067 TI - Single case of purple urine bag syndrome in an elderly woman with stroke. AB - Purple urine bag syndrome is an unusual condition that heralds an underlying urinary tract infection, in which certain bacteria produce a purple discolouration within the catheter bag of affected cases. It is most often seen in elderly women with constipation. While alarming, it can be resolved by treating the infection causing it. This report presents an elderly patient who developed the condition while an inpatient, and discusses the pathogenesis behind the condition. PMID- 27489068 TI - Lipoma of mandibular buccal vestibule: a case with histopathological literature review. AB - Lipoma is a tumour of soft tissue with rare occurrence in oral cavity accounting for only 1-4% of benign oral tumours. Most common sites of involvement are the buccal mucosa, tongue and floor of the mouth with typical presentation of an asymptomatic, soft, smooth-surfaced, nodular and yellowish mass. Histopathologically, a classical lipoma resembles normal adipose tissue and it has multiple variants which are less commonly seen except fibrolipoma. The article presents a case report of a relatively large oral classical lipoma in a 60-year-old man on a rare site, mandibular buccal vestibule, along with a review of the literature and special emphasis on its various histopathological variants. PMID- 27489069 TI - Renal amyloidosis in leprosy, an infrequent cause of nephrotic syndrome in Europe. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae The main clinical manifestations involve the skin and the peripheral nervous system. Several types of nephropathy have been described in leprosy. One frequent form of renal involvement is amyloidosis, especially in patients with lepromatous leprosy. In these patients, end-stage renal disease is an important contributor to morbidity and mortality. Here, we present the case of a patient with nephrotic syndrome caused by secondary amyloidosis, chronic peripheral neuropathy and a history of leprosy. The patient was correctly treated in her youth, which is the best way to avoid renal pathology, but she developed a nephrotic syndrome years later. PMID- 27489070 TI - New use for an old drug: oral ketamine for treatment-resistant depression. AB - Treatment-resistant depression (TRD) is a disabling disorder that can interfere with a patient's capacity to understand and participate in medical care and thus negatively impact individual morbidity and mortality. Hospitalised patients with TRD may require rapid alleviation of severe symptomatology, particularly when suicidal or if unable to participate in care decisions. Ketamine is well known for its anaesthetic effects and its use as a 'street' drug; however, its action as an N-methyl-D-aspartate receptor antagonist makes ketamine a potential therapy for TRD. The majority of studies investigating ketamine for TRD have used intravenous drug delivery, demonstrating benefit for rapid alleviation and sustained response of depression symptoms. Oral ketamine for urgent alleviation of TRD symptoms is less reported. We describe rapid alleviation of severe TRD with oral ketamine in a severely ill postoperative hospitalised patient, and review the current literature on 'off-label' use of ketamine for treatment of refractory depression. PMID- 27489071 TI - A curious cause of appendicitis. AB - A previously healthy 10-year-old boy presented to the emergency department with central abdominal pain, loose stool and vomiting. He was diagnosed with gastroenteritis, but was well enough to be discharged. The next day he reattended with ongoing diarrhoea and vomiting, with the pain now localised to the right iliac fossa (RIF). Acute appendicitis was suspected, and he was taken for laparoscopic appendicectomy. At surgery, a gangrenous appendix was found, with pus extending from the pelvis up to the liver. The appendix was excised and thorough peritoneal washout performed. Postoperatively, he received 48 hours of intravenous antibiotics and was discharged home. Unfortunately the boy presented again 11 days later with right lower quadrant pain and fever. Ultrasound revealed a collection in the RIF, and he returned to theatre for washout. His recovery was slow until the peritoneal pus sent for bacterial culture grew Salmonella enteritidis, identification of which facilitated appropriate antibiotic treatment. PMID- 27489072 TI - Rare cause of aortic regurgitation. PMID- 27489073 TI - Morning glory anomaly with peripapillary staphyloma. PMID- 27489074 TI - Controlled Coalescence of AlGaN Nanowire Arrays: An Architecture for Nearly Dislocation-Free Planar Ultraviolet Photonic Device Applications. AB - Nearly dislocation-free semipolar AlGaN templates are achieved on c-plane sapphire substrate through controlled nanowire coalescence by selective-area epitaxy. The coalesced Mg-doped AlGaN layers exhibit superior charge-carrier transport properties. Semipolar-AlGaN ultraviolet light-emitting diodes demonstrate excellent performance. This work establishes the use of engineered nanowire structures as a viable architecture to achieve large-area, dislocation free planar photonic and electronic devices. PMID- 27489075 TI - Mortality in people with intellectual disabilities in England. AB - BACKGROUND: People with intellectual disabilities (IDs) die at younger ages than the general population, but nationally representative and internationally comparable mortality data about people with ID, quantifying the extent and pattern of the excess, have not previously been reported for England. METHOD: We used data from the Clinical Practice Research Datalink database for April 2010 to March 2014 (CPRD GOLD September 2015). This source covered several hundred participating general practices comprising roughly 5% of the population of England in the period studied. General practitioner (GP) records identified people diagnosed by their GP as having ID. Linked national death certification data allowed us to derive corresponding mortality data for people with and without ID, overall and by cause. RESULTS: Mortality rates for people with ID were significantly higher than for those without. Their all-cause standardised mortality ratio was 3.18. Their life expectancy at birth was 19.7 years lower than for people without ID. Circulatory and respiratory diseases and neoplasms were the three most common causes of death for them. Cerebrovascular disease, thrombophlebitis and pulmonary embolism all had standardised mortality ratios greater than 3 in people with ID. This has not been described before. Other potentially avoidable causes included epilepsy (3.9% of deaths), aspiration pneumonitis (3.6%) and colorectal cancer (2.4%). Avoidable mortality analysis showed a higher proportion of deaths from causes classified as amenable to good medical care but a lower proportion from preventable causes compared with people without ID. International comparison to areas for which data have been published in sufficient detail for calculation of directly standardised rates suggest England may have higher death rates for people with ID than areas in Canada and Finland, and lower death rates than Ireland or the State of Massachusetts in the USA. CONCLUSIONS: National data about mortality in people with ID provides a basis for public health interventions. Linked data using GP records to identify people with ID could provide comprehensive population-based monitoring in England, unbiased by the circumstances of illnesses or death; to date information governance constraints have prevented this. However, GPs in England currently identify only around 0.5% of the population as having ID, suggesting that individuals with mild, non-syndromic ID are largely missed. Notably common causes of death suggest control of cardiovascular risk factors, epilepsy and dysphagia, management of thrombotic risks and colorectal screening are important areas for health promotion initiatives. PMID- 27489076 TI - Pharmacokinetics and metabolism of [14C]-tozadenant (SYN-115), a novel A2a receptor antagonist ligand, in healthy volunteers. AB - 1. This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of 14C-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease. 2. Six healthy male subjects received a single oral dose of tozadenant (240 mg containing 81.47 KBq of [14C]-tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC MS/MS and HPLC-AMS with fraction collection. 3. At 4 h, the Cmax of tozadenant was 1.74 MUg/mL and AUC(0-t) 35.0 h MUg/mL, t1/2 15 h, Vz/F 1.82 L/kg and CL/F 1.40 mL/min/kg. For total [14C] radioactivity, the Cmax was 2.29 MUg eq/mL at 5 h post-dose and AUC(0-t) 43.9 h MUg eq/mL. Unchanged tozadenant amounted to 93% of the radiocarbon AUC(0-48h). At 312 h post-dose, cumulative urinary and fecal excretion of radiocarbon reached 30.5% and 55.1% of the dose, respectively. Unchanged tozadenant reached 11% in urine and 12% of the dose in feces. Tozadenant was excreted as metabolites, including di-and mono-hydroxylated metabolites, N/O dealkylated metabolites, hydrated metabolites. 4. The only identified species circulating in plasma was unchanged tozadenant. Tozadenant was primarily excreted in urine and feces in the form of metabolites. PMID- 27489078 TI - A proactive task set influences how response inhibition is implemented in the basal ganglia. AB - Increasing a participant's ability to prepare for response inhibition is known to result in longer Go response times and is thought to engage a "top-down fronto striatal inhibitory task set." This premise is supported by the observation of anterior striatum activation in functional magnetic resonance imaging (fMRI) analyses that focus on uncertain versus certain Go trials. It is assumed that setting up a proactive inhibitory task set also influences how participants subsequently implement stopping. To assess this assumption, we aimed to manipulate the degree of proactive inhibition in a modified stop-signal task to see how this manipulation influences activation when reacting to the Stop cue. Specifically, we tested whether there is differential activity of basal ganglia nuclei, namely the subthalamic nucleus (STN) and anterior striatum, on Stop trials when stop-signal probability was relatively low (20%) or high (40%). Successful stopping was associated with increased STN activity when Stop trials were infrequent and increased caudate head activation when Stop trials were more likely, suggesting a different implementation of reactive response inhibition by the basal ganglia for differing degrees of proactive response control. Hum Brain Mapp 37:4706-4717, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27489077 TI - The Effect of Guided Web-Based Cognitive Behavioral Therapy on Patients With Depressive Symptoms and Heart Failure: A Pilot Randomized Controlled Trial. AB - BACKGROUND: Depressive symptoms, and the associated coexistence of symptoms of anxiety and decreased quality of life (QoL), are common in patients with heart failure (HF). However, treatment strategies for depressive symptoms in patients with HF still remain to be established. Internet-based cognitive behavioral therapy (ICBT), as guided self-help CBT programs, has shown good effects in the treatment of depression. Until now, ICBT has not been evaluated in patients with HF with depressive symptoms. OBJECTIVE: The aims of this study were to (1) evaluate the effect of a 9-week guided ICBT program on depressive symptoms in patients with HF; (2) investigate the effect of the ICBT program on cardiac anxiety and QoL; and (3) assess factors associated with the change in depressive symptoms. METHODS: Fifty participants were randomized into 2 treatment arms: ICBT or a Web-based moderated discussion forum (DF). The Patient Health Questionnaire 9 was used to measure depressive symptoms, the Cardiac Anxiety Questionnaire (CAQ) was used to measure cardiac-related anxiety, and the Minnesota Living with Heart Failure questionnaire was used to measure QoL. Data were collected at baseline and at follow-up at the end of the 9-week intervention. Intention-to treat analysis was used, and missing data were imputed by the Expectation Maximization method. Between-group differences were determined by analysis of covariance with control for baseline score and regression to the mean. RESULTS: No significant difference in depressive symptoms between the ICBT and the DF group at the follow-up was found, [F(1,47)=1.63, P=.21] and Cohen's d=0.26. Secondary within-group analysis of depressive symptoms showed that such symptoms decreased significantly in the ICBT group from baseline to the follow-up (baseline M=10.8, standard deviation [SD]=5.7 vs follow-up M=8.6, SD=4.6, t(24)=2.6, P=.02, Cohen's d=0.43), whereas in the DF group, there was no significant change (baseline M=10.6, SD=5.0, vs follow-up M=9.8, SD=4.3, t(24)=0.93, P=.36. Cohen's d=0.18). With regard to CAQ and QoL no significant differences were found between the groups (CAQ [d(1,47)=0.5, P=.48] and QoL [F(1,47)=2.87, P=.09]). In the ICBT group in the CAQ subscale of fear, a significant within-group decrease was shown (baseline M=1.55 vs follow-up M=1.35, P=.04). In the ICBT group, the number of logins to the Web portal correlated significantly with improvement in depressive symptoms (P=.02), whereas higher age (P=.01) and male sex (P=.048) were associated with less change in depressive symptoms. This study is underpowered because of difficulties in the recruitment of patients. CONCLUSIONS: Guided ICBT adapted for persons with HF and depressive symptoms was not statistically superior to participation in a Web-based DF. However, within the ICBT group, a statically significant improvement of depressive symptoms was detected. CLINICALTRIAL: Clinicaltrials.gov NCT01681771; https://clinicaltrials.gov/ct2/show/NCT01681771 (Archived by WebCite at http://www.webcitation.org/6ikzbcuLN). PMID- 27489079 TI - Oxidative stress status in Chinese women with different clinical phenotypes of polycystic ovary syndrome. AB - OBJECTIVE: To determine oxidative stress status and its association with clinical and metabolic parameters in Chinese women with different clinical phenotypes of polycystic ovary syndrome (PCOS). DESIGN: A cross-sectional study. PATIENTS: A total of 544 patients with PCOS and 468 control women were included. MEASUREMENTS: The total oxidant status (TOS) was determined using a microplate colorimetric method. Total antioxidant capacity (T-AOC), oxidative stress index (OSI, the ratios of TOS to T-AOC) and clinical, hormonal and metabolic parameters were also analysed. RESULTS: TOS and OSI were significantly higher in each of the four PCOS phenotypes based on the Rotterdam criteria than in the control women and higher in patients with hyperandrogenism (HA) than in those without HA (P < 0.05). TOS, T-AOC and OSI were higher in lean patients than in lean controls (P < 0.05). These values, except OSI, were also higher in overweight/obese patients than in lean patients, and lean or overweight/obese controls (P < 0.05). Multivariate regression analysis demonstrated that apolipoprotein (apo)A1, the Ferriman-Gallwey score, triglyceride (TG), oestradiol (E2 ), high-density lipoprotein cholesterol (HDL-C) and 2-h glucose levels were the main predictors of TOS; the Ferriman-Gallwey score, E2 , apoA1, TG and HDL-C levels were the main predictors of OSI. CONCLUSIONS: Patients with PCOS with HA have higher oxidative stress levels compared with those without HA. The increased oxidative stress in PCOS is related to HA status, increased plasma glucose, TG, HDL-C and E2 levels, decreased apoA1 concentrations and a relative shortage of antioxidant capacity. PMID- 27489080 TI - Why metal-oxos react with dihydroanthracene and cyclohexadiene at comparable rates, despite having different C-H bond strengths. A computational study. AB - 1,4-Cyclohexadiene (CHD) and 9,10-dihydroanthracene (DHA) are two substrates used to probe the steric requirements of metal-oxo oxidants in H-atom-transfer (HAT) reactions, based on the assumption that they have comparable C-H bond dissociation enthalpies (BDEs). We use computations to demonstrate that the BDE of DHA is ~3.5 kcal mol(-1) larger than that of CHD and that their often comparable reactivity is based on a competing interplay of bond strengths and favorable van der Waals interactions. PMID- 27489082 TI - Actual lowering effect of metabolic syndrome on serum prostate-specific antigen levels is partly concealed by enlarged prostate: results from a large-scale population-based study. AB - OBJECTIVES: To clarify the lowering effect of metabolic syndrome (MetS) on serum prostate-specific antigen (PSA) levels in a Chinese screened population. SUBJECTS AND METHODS: A total of 45 540 ostensibly healthy men aged 55-69 years who underwent routine health check-ups at Beijing Shijitan Hospital between 2008 and 2015 were included in the study. All the men underwent detailed clinical evaluations. PSA mass density was calculated (serum PSA level * plasma volume / prostate volume) for simultaneously adjusting plasma volume and prostate volume. According to the modified National Cholesterol Education Programme-Adult Treatment Panel (NCEP-ATP) III criteria, patients were dichotomized by the presence of MetS, and differences in PSA density and PSA mass density were compared between groups. Linear regression analysis was used to evaluate the effect of MetS on serum PSA levels. RESULTS: When larger prostate volume in men with MetS was adjusted for, both PSA density and PSA mass density in men with MetS were significantly lower than in men without MetS, and the estimated difference in mean serum PSA level between men with and without MetS was greater than that before adjusting for prostate volume. In the multivariate regression model, the presence of MetS was independently associated with an 11.3% decline in serum PSA levels compared with the absence of MetS. In addition, increasing number of positive MetS components was significantly and linearly associated with decline in serum PSA levels. CONCLUSION: The actual lowering effect of MetS on serum PSA levels was partly concealed by the enlarged prostate in men with MetS, and the presence of MetS was independently associated with lower serum PSA levels. Urologists need to be aware of the effect of MetS on serum PSA levels and should discuss this subject with their patients. PMID- 27489081 TI - Activation of liver X receptor attenuates lysophosphatidylcholine-induced IL-8 expression in endothelial cells via the NF-kappaB pathway and SUMOylation. AB - The liver X receptor (LXR) is a cholesterol-sensing nuclear receptor that has an established function in lipid metabolism; however, its role in inflammation is elusive. In this study, we showed that the LXR agonist GW3965 exhibited potent anti-inflammatory activity by suppressing the firm adhesion of monocytes to endothelial cells. To further address the mechanisms underlying the inhibition of inflammatory cell infiltration, we evaluated the effects of LXR agonist on interleukin-8 (IL-8) secretion and nuclear factor-kappa B (NF-kappaB) activation in human umbilical vein endothelial cells (HUVECs). The LXR agonist significantly inhibited lysophosphatidylcholine (LPC)-induced IL-8 production in a dose dependent manner without appreciable cytotoxicity. Western blotting and the NF kappaB transcription activity assay showed that the LXR agonist inhibited p65 binding to the IL-8 promoter in LPC-stimulated HUVECs. Interestingly, knockdown of the indispensable small ubiquitin-like modifier (SUMO) ligases Ubc9 and Histone deacetylase 4 (HDAC4) reversed the increase in IL-8 induced by LPC. Furthermore, the LPC-induced degradation of inhibitory kappaBalpha was delayed under the conditions of deficient SUMOylation or the treatment of LXR agonist. After enhancing SUMOylation by knockdown SUMO-specific protease Sentrin-specific protease 1 (SENP1), the inhibition of GW3965 was rescued on LPC-mediated IL-8 expression. These findings indicate that LXR-mediated inflammatory gene repression correlates to the suppression of NF-kappaB pathway and SUMOylation. Our results suggest that LXR agonist exerts the anti-atherosclerotic role by attenuation of the NF-kappaB pathway in endothelial cells. PMID- 27489083 TI - Fate of Enlarged Iliac Arteries After Endovascular or Open Abdominal Aortic Aneurysm Repair. AB - PURPOSE: To examine the fate of untreated ectatic and aneurysmal common iliac arteries (CIAs) after open treatment and endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA). METHODS: Databases of scientific literature were searched between January 1980 and February 2016 to identify publications on the follow-up of ectatic and aneurysmal CIAs after open or endovascular AAA repair. The primary outcome measure was the increase of iliac artery diameter during follow-up. The secondary outcome was the subsequent reintervention rate during follow-up. RESULTS: Only 3 open AAA and 3 EVAR studies containing 1239 patients met the inclusion criteria for analysis. In the open AAA group, ectatic iliac arteries (defined as 12-18 mm) had a diameter progression of 1.7 to 1.8 mm during a follow-up period of 51.6 to 85.2 months. The aneurysmal iliac arteries (>18 mm) in the open repair group showed a faster growth (2.3-3.0 mm) in a follow-up period of 50.4 to 85.2 months. The pooled assessment of arteries >=18 mm had a mean growth of 2.56 mm at 60 months of follow-up. In the entire open AAA cohort, the reintervention rate for CIA transformation was <1%. In the EVAR studies, arbitrary cutoff sizes of 16 to 20 mm for ectatic arteries and >20 mm for aneurysmal arteries were used. During a follow-up of 39.2 to 60 months, the diameter progression was 1.5 mm for the 16-mm iliac arteries and 2.7 mm for the 20-mm iliac arteries. The need for endovascular reinterventions was similar in patients with previously normal or enlarged CIAs. CONCLUSION: After open AAA repair, the overall size of CIA aneurysms grows slowly, but enlarged CIAs >20 mm in EVAR patients show faster growth during follow-up. However, the need for secondary interventions was similar in patients with normal or enlarged CIAs post EVAR. PMID- 27489084 TI - Commentary: Challenging Anatomy and Mortality After Endovascular Treatment of Ruptured Aortic Aneurysm: Proceed With Caution When Treating the Hostile Neck. PMID- 27489085 TI - Autoimmune progesterone dermatitis: Case report of an unexpected treatment reaction. AB - Autoimmune progesterone dermatitis (APD) is a rare skin condition with a varying morphology, which appears on a monthly basis during the luteal phase of the menstrual cycle and resolves spontaneously with the endogenous decrease in progesterone during menses. We present the case of 39-year-old multiparous Caucasian woman with generalised, self-limited urticaria in her perimenstrual period. APD was diagnosed in light of the cyclical nature of the symptoms. An intradermal test with the administration of 0.5 mg/mL of medroxyprogesterone acetate showed a positive result. She started using vaginal hormonal contraceptive that paradoxically exacerbate the symptoms, which ceased after the removal of the device. An oral combined contraceptive was initiated instead, with complete resolution of the symptoms. We share the case because of the rarity of the situation, emphasising the importance of a multidisciplinary team for differential diagnosis and patient follow up. PMID- 27489086 TI - Pleomorphic lobular carcinoma of the breast: a comparison of cytopathological features with other lobular carcinoma variants. AB - OBJECTIVE: Pleomorphic lobular carcinoma (PLC) is a subtype of breast cancer with unique morphological features, but it remains controversial whether PLC should be considered an independent disease entity. The aim of this study was to illustrate cytopathological characteristics of PLC in comparison with other lobular carcinoma variants. METHODS: We investigated clinicopathological features of PLC (n = 11) compared with those of other variants of invasive lobular carcinoma (ILC, non-PLC) (n = 32). Histological variants of the non-PLC group consisted of classic (n = 25), solid (n = 2), alveolar (n = 1) and a tubulolobular type (n = 4). A review of cytological reports and fine needle aspiration (FNA) smear samples was performed for the PLC (n = 9) and non-PLC (n = 27) groups. RESULTS: Patients with PLC were older, and had a higher nuclear grade and a higher incidence of axillary lymph node metastasis and triple negative phenotype than non-PLC patients (P = 0.007, P < 0.001, P = 0.02 and P < 0.001, respectively). Cytological findings in PLC included medium- to large-sized nuclei, prominent nucleoli, a moderate-to-severe degree of pleomorphism, apocrine change and background necrosis, none of which were evident in the smears of the non-PLC group (P < 0.001, P = 0.002, P < 0.001, P < 0.001, and P = 0.03, respectively). Despite these differences, patients with PLC and non-PLC showed similar clinical outcomes in our follow-up period. CONCLUSIONS: Based on our results, a cytological diagnosis of PLC should be proposed if there are moderate- to large sized nuclei, prominent nucleoli, a moderate-to severe degree of nuclear pleomorphism, apocrine change and necrosis in the background in FNA biopsy samples. PMID- 27489087 TI - Assessing the Quality of Economic Evaluations of FDA Novel Drug Approvals: A Systematic Review. AB - OBJECTIVE: To systematically review and assess the quality of the novel drugs' economic evaluation literature in print during the drugs' early commercial availability following US regulatory approval. DATA SOURCES: MEDLINE and the United Kingdom National Health Service Economic Evaluation Database were searched from 1946 through December 2011 for economic evaluations of the 50 novel drugs approved by the FDA in 2008 and 2009. STUDY SELECTION AND DATA EXTRACTION: The inclusion criteria were English-language, peer-reviewed, original economic evaluations (cost-utility, cost-effectiveness, cost-minimization, and cost benefit analyses). We extracted and analyzed data from 36 articles considering 19 of the 50 drugs. Two reviewers assessed each publication's quality using the Quality of Health Economic Studies (QHES) instrument and summarized study quality on a 100-point scale. DATA SYNTHESIS: Study quality had a mean of 70.0 +/- 16.2 QHES points. The only study characteristics associated with QHES score (with P < 0.05) were having used modeling or advanced statistics, 75.1 versus 61.9 without; using quality-adjusted life years as an outcome, 75.9 versus 64.7 without; and cost-utility versus cost-minimization analysis, 75.9 versus 58.7. Studies most often satisfied quality aspects about stating study design choices and least often satisfied aspects about justifying design choices. CONCLUSION: The reviewed literature considered a minority of the 2008-2009 novel drugs and had mixed study quality. Cost-effectiveness stakeholders might benefit from efforts to improve the quality and quantity of literature examining novel drugs. Editors and reviewers may support quality improvement by stringently imposing economic evaluation guidelines about justifying study design choices. PMID- 27489088 TI - Cannabinoid Hyperemesis Syndrome: A Paradoxical Case. PMID- 27489090 TI - On understanding the self of the schizophrenics. AB - Identified as a mental disorder by Emil Kraepelin and Eugen Bleuler (1858-1939), schizophrenia has been subject to various criticisms, on both political and scientific grounds. Still, until the latest edition of the Diagnostic and Statistical Manual of Mental Disorders, DSM-5, as the'Spectrum of Schizophrenia and Other Psychotic Disorders'. In this article, we will assume a neutral conception of 'mental disorder' and describe schizophrenia broadly as a kind of altered state of consciousness. The alteration is so radical that some authors argue schizophrenia resists any attempt at being comprehended and that the only possible explanation for its occurrence is causal-mechanical. This idea that schizophrenia does not allow for any degree of understanding goes back to Jaspers, the founder of Psychopathology. The aim of this article is to show that, although emerging from the same line of thought of Jaspers, the more recent phenomenologists who revisit classical Phenomenology, overcome the barrier between explaining and understanding. The argument here is that schizophrenia can be at least partially understood if we maintain an open mind towards people who do not share part of our world. PMID- 27489089 TI - Mediation Analysis for Health Disparities Research. AB - Social epidemiologists often seek to determine the mechanisms that underlie health disparities. This work is typically based on mediation procedures that may not be justified with exposures of common interest in social epidemiology. In this analysis, we explored the consequences of using standard approaches, referred to as the difference and generalized product methods, when mediator outcome confounders are associated with the exposure. We compared these with inverse probability-weighted marginal structural models, the structural transformation method, doubly robust g-estimation of a structural nested model, and doubly robust targeted minimum loss-based estimation. We used data on 900,726 births from 2003 to 2007 in the Penn Moms study, conducted in Pennsylvania, to assess the extent to which breastfeeding prior to hospital discharge explained the racial disparity in infant mortality. Overall, for every 1,000 births, 3.36 more infant deaths occurred among non-Hispanic black women relative to all other women (95% confidence interval: 2.78, 3.93). Using the difference and generalized product methods to assess the disparity that would remain if everyone breastfed prior to discharge suggested a complete elimination of the disparity (risk difference = -0.87 per 1,000 births; 95% confidence interval: -1.39, -0.35). In contrast, doubly robust methods suggested a reduction in the disparity to 2.45 (95% confidence interval: 2.20, 2.71) more infant deaths per 1,000 births among non-Hispanic black women. Standard approaches for mediation analysis in health disparities research can yield misleading results. PMID- 27489091 TI - A Fatal Case of a Ruptured Cerebral Aneurysm Detected by Postmortem Computed Tomography Angiography Using a New Contrast-Medium Solution. AB - Forensic autopsy is still the criterion standard in legal investigations. Currently, notable transformation is occurring because postmortem imaging is being increasingly endorsed. This article highlights the effectiveness of postmortem computed tomography angiography by using a new contrast medium mixture as a solitary tool to define the cause and manner of death in a ruptured cerebral aneurysm case. Based on the imaging results, autopsy was not mandated and the case was closed. PMID- 27489092 TI - Negative Aging Attitudes Predict Greater Reactivity to Daily Stressors in Older Adults. AB - Objectives: In order to understand conflicting findings regarding the emotional reactions of older adults to daily stressors, we examined the possibility that negative aging attitudes could function as an important individual differences factor related to stressor reactivity. Method: Using a daily dairy design, we examined the aging attitudes of 43 older adults reporting on 380 total days. Participants reported their aging attitudes on Day 1, followed by their stressor exposure and negative affect on Days 2-9. Covariates included age, gender, education, and personality. Results: Using multilevel modeling, our results suggest that individuals with more positive aging attitudes report consistent levels of affect across study days regardless of stressors, whereas those with more negative aging attitudes reported increased emotional reactivity to daily stressors. Discussion: Positive aging attitudes may serve as a resource that helps buffer reactions to daily stressors. PMID- 27489093 TI - Abstracts Presented at the Joint Summer Meeting of the British Association of Clinical Anatomists, the European Association for Clinical Anatomy and the Sociedad Anatomica Espanola on 24th-27th June 2015 at the Medicine and Pharmacy Faculty, Rouen, France. PMID- 27489094 TI - Prosopagnosia as unusual presentation of semantic dementia: a case study. AB - OBJECT: Semantic dementia is one of the main clinical variants of frontotemporal dementia and it is characterized by severe loss of conceptual knowledge with relative preservation of other cortical abilities. METHODS: We described a case of a patient affected by right temporal variant of frontotemporal lobar degeneration, characterized by prosopagnosia as an unusual disease onset. RESULTS: The neuropsychological evaluation showed a progressive deficit in face recognition and a slow decline in language in the absence of behavioral alterations. Magnetic resonance imaging showed diffuse vascular ischemic lesions, cortical atrophy in bilateral temporal lobes, and a marked bilateral decrease hippocampal volume, mainly involving the right side. CONCLUSIONS: Our findings suggest that prosopagnosia could be a predictive marker of atypical semantic dementia onset. PMID- 27489095 TI - Epidemiological and Evolutionary Inference of the Transmission Network of the 2014 Highly Pathogenic Avian Influenza H5N2 Outbreak in British Columbia, Canada. AB - The first North American outbreak of highly pathogenic avian influenza (HPAI) involving a virus of Eurasian A/goose/Guangdong/1/1996 (H5N1) lineage began in the Fraser Valley of British Columbia, Canada in late November 2014. A total of 11 commercial and 1 non-commercial (backyard) operations were infected before the outbreak was terminated. Control measures included movement restrictions that were placed on a total of 404 individual premises, 150 of which were located within a 3 km radius of an infected premise(s) (IP). A complete epidemiological investigation revealed that the source of this HPAI H5N2 virus for 4 of the commercial IPs and the single non-commercial IP likely involved indirect contact with wild birds. Three IPs were associated with the movement of birds or service providers and localized/environmental spread was suspected as the source of infection for the remaining 4 IPs. Viral phylogenies, as determined by Bayesian Inference and Maximum Likelihood methods, were used to validate the epidemiologically inferred transmission network. The phylogenetic clustering of concatenated viral genomes and the median-joining phylogenetic network of the viruses supported, for the most part, the transmission network that was inferred by the epidemiologic analysis. PMID- 27489096 TI - Macrophage polarization in experimental and clinical choroidal neovascularization. AB - Macrophages play an important role in the development of age-related macular degeneration (AMD). In this study, the spatial and temporal changes and the polarization of macrophages in murine laser-induced choroidal neovascularization (CNV) were investigated, and the polarized M1 and M2 biomarkers in the aqueous humors of neovascular AMD (nAMD) patients were studied. Macrophages, the main infiltrating inflammatory cells in CNV lesions, were evidenced by a significant increase in F4/80 mRNA expression and by the infiltration of F4/80+ cells in the lesions and the vicinity of laser-induced CNV. The mRNA expressions of M1-related markers were dramatically upregulated in the early stage, while the M2-related markers were slightly upregulated in the middle stage and sustained until the late stage. The results of immunostaining showed a similar early-but-transient M1 pattern and a delayed-but-sustained M2 pattern in laser-induced CNV. In addition, a higher M2/M1 ratio was found in both the murine models (Arg-1/iNOS and CCL22/CXCL10) and the aqueous humors of nAMD patients (CCL22/CXCL10) than in the controls. Our results suggested that the dynamic patterns of M1 and M2 were different in both the experimental and clinical CNV. The M2 macrophages were predominant and may play a more important role in the development of CNV. PMID- 27489098 TI - Three-Dimensional Ni2P Nanoarray: An Efficient Catalyst Electrode for Sensitive and Selective Nonenzymatic Glucose Sensing with High Specificity. AB - It is highly attractive to construct a natural enzyme-free electrode for sensitive and selective detection of glucose. In this Letter, we report that a Ni2P nanoarray on conductive carbon cloth (Ni2P NA/CC) behaves as an efficient three-dimensional catalyst electrode for glucose electrooxidation under alkaline conditions. Electrochemical measurements demonstrate that the Ni2P NA/CC, when used as a nonenzymatic glucose sensor, offers superior analytical performances with a short response time of 5 s, a wide detection range of 1 MUM to 3 mM, a low detection limit of 0.18 MUM (S/N = 3), a response sensitivity of 7792 MUA mM(-1) cm(-2), and satisfactory selectivity, specificity, and reproducibility. Moreover, it can also be used for glucose detection in human blood serum, promising its application toward determination of glucose in real samples. PMID- 27489097 TI - Xenomicrobiology: a roadmap for genetic code engineering. AB - Biology is an analytical and informational science that is becoming increasingly dependent on chemical synthesis. One example is the high-throughput and low-cost synthesis of DNA, which is a foundation for the research field of synthetic biology (SB). The aim of SB is to provide biotechnological solutions to health, energy and environmental issues as well as unsustainable manufacturing processes in the frame of naturally existing chemical building blocks. Xenobiology (XB) goes a step further by implementing non-natural building blocks in living cells. In this context, genetic code engineering respectively enables the re-design of genes/genomes and proteins/proteomes with non-canonical nucleic (XNAs) and amino (ncAAs) acids. Besides studying information flow and evolutionary innovation in living systems, XB allows the development of new-to-nature therapeutic proteins/peptides, new biocatalysts for potential applications in synthetic organic chemistry and biocontainment strategies for enhanced biosafety. In this perspective, we provide a brief history and evolution of the genetic code in the context of XB. We then discuss the latest efforts and challenges ahead for engineering the genetic code with focus on substitutions and additions of ncAAs as well as standard amino acid reductions. Finally, we present a roadmap for the directed evolution of artificial microbes for emancipating rare sense codons that could be used to introduce novel building blocks. The development of such xenomicroorganisms endowed with a 'genetic firewall' will also allow to study and understand the relation between code evolution and horizontal gene transfer. PMID- 27489099 TI - Time-frequency distribution properties of event-related potentials in mental fatigue induced by visual memory tasks. AB - Prolonged periods of demanding cognitive tasks lead to an exhausted feeling known as mental fatigue. The neural underpinnings of mental fatigue are still under exploration. In the present study, we aimed to identify neurophysiological indicators of mental fatigue by studying the time-frequency distribution of the event-related potentials (ERPs) measured in N=26 adults in nonfatigued versus fatigued states. We were interested in the frontal theta and occipital alpha variations, which have shown consistent relationships with mental fatigue in previous studies. Furthermore, we expected differential changes in left and right electrodes, in line with previously detected lateralization effects in cognitive tasks. Mental fatigue was induced by a sustained two-back verbal visual memory task for 125 min and assessed using the Chalder Fatigue Scale. We applied a high resolution time-frequency analysis method called smoothed pseudo Wigner Ville distribution and used regional integrals as indicators for changing trends of signal energy. Results showed an increase in ERP frontal theta energy (P=0.03) and a decrease in occipital alpha energy (P=0.028) when participants became mentally fatigued. The change in frontal theta was more pronounced in left electrode sites (P=0.032), hinting toward a differential fatigue effect in the two hemispheres. The results were discussed on the basis of previous lateralization studies with memory tasks and interpreted as an indicator of a causal relationship between the sustained task execution and the physiological changes. Our findings also suggest that the ERP signal energy variations in frontal theta and occipital alpha might be used as neural biomarkers to assess mental fatigue. PMID- 27489100 TI - Can color changes alter the neural correlates of recognition memory? Manipulation of processing affects an electrophysiological indicator of conceptual implicit memory. AB - It has been widely shown that recognition memory includes two distinct retrieval processes: familiarity and recollection. Many studies have shown that recognition memory can be facilitated when there is a perceptual match between the studied and the tested items. Most event-related potential studies have explored the perceptual match effect on familiarity on the basis of the hypothesis that the specific event-related potential component associated with familiarity is the FN400 (300-500 ms mid-frontal effect). However, it is currently unclear whether the FN400 indexes familiarity or conceptual implicit memory. In addition, on the basis of the findings of a previous study, the so-called perceptual manipulations in previous studies may also involve some conceptual alterations. Therefore, we sought to determine the influence of perceptual manipulation by color changes on recognition memory when the perceptual or the conceptual processes were emphasized. Specifically, different instructions (perceptually or conceptually oriented) were provided to the participants. The results showed that color changes may significantly affect overall recognition memory behaviorally and that congruent items were recognized with a higher accuracy rate than incongruent items in both tasks, but no corresponding neural changes were found. Despite the evident familiarity shown in the two tasks (the behavioral performance of recognition memory was much higher than at the chance level), the FN400 effect was found in conceptually oriented tasks, but not perceptually oriented tasks. It is thus highly interesting that the FN400 effect was not induced, although color manipulation of recognition memory was behaviorally shown, as seen in previous studies. Our findings of the FN400 effect for the conceptual but not perceptual condition support the explanation that the FN400 effect indexes conceptual implicit memory. PMID- 27489101 TI - Highly Conformal Deposition of an Ultrathin FeOOH Layer on a Hematite Nanostructure for Efficient Solar Water Splitting. AB - An ultrathin (ca. 2 nm) amorphous FeOOH overlayer was deposited conformally on a hematite nanostructure by a simple solution-based precipitation method, to generate an oxygen evolution cocatalyst for efficient solar water splitting. This uniform and highly conformal coating of the ultrathin metal oxyhydroxide is rare and is distinguished from the layers prepared by other conventional methods. With the FeOOH overlayer as the cocatalyst, the water oxidation photocurrent of hematite increased by a factor of approximately two and the onset potential shifted in the cathodic direction by 0.12 V under 1 sun illumination. The enhanced performance was attributed to the improved water oxidation kinetics and the passivation of the surface states of the hematite. PMID- 27489102 TI - Activation of the Human Epithelial Sodium Channel (ENaC) by Bile Acids Involves the Degenerin Site. AB - The epithelial sodium channel (ENaC) is a member of the ENaC/degenerin ion channel family, which also includes the bile acid-sensitive ion channel (BASIC). So far little is known about the effects of bile acids on ENaC function. ENaC is probably a heterotrimer consisting of three well characterized subunits (alphabetagamma). In humans, but not in mice and rats, an additional delta subunit exists. The aim of this study was to investigate the effects of chenodeoxycholic, cholic, and deoxycholic acid in unconjugated (CDCA, CA, and DCA) and tauro-conjugated (t-CDCA, t-CA, t-DCA) form on human ENaC in its alphabetagamma- and deltabetagamma-configuration. We demonstrated that tauro conjugated bile acids significantly stimulate ENaC in the alphabetagamma- and in the deltabetagamma-configuration. In contrast, non-conjugated bile acids have a robust stimulatory effect only on deltabetagammaENaC. Bile acids stimulate ENaC mediated currents by increasing the open probability of active channels without recruiting additional near-silent channels known to be activated by proteases. Stimulation of ENaC activity by bile acids is accompanied by a significant reduction of the single-channel current amplitude, indicating an interaction of bile acids with a region close to the channel pore. Analysis of the known ASIC1 (acid-sensing ion channel) crystal structure suggested that bile acids may bind to the pore region at the degenerin site of ENaC. Substitution of a single amino acid residue within the degenerin region of betaENaC (N521C or N521A) significantly reduced the stimulatory effect of bile acids on ENaC, suggesting that this site is critical for the functional interaction of bile acids with the channel. PMID- 27489103 TI - The CaVbeta Subunit Protects the I-II Loop of the Voltage-gated Calcium Channel CaV2.2 from Proteasomal Degradation but Not Oligoubiquitination. AB - CaVbeta subunits interact with the voltage-gated calcium channel CaV2.2 on a site in the intracellular loop between domains I and II (the I-II loop). This interaction influences the biophysical properties of the channel and leads to an increase in its trafficking to the plasma membrane. We have shown previously that a mutant CaV2.2 channel that is unable to bind CaVbeta subunits (CaV2.2 W391A) was rapidly degraded (Waithe, D., Ferron, L., Page, K. M., Chaggar, K., and Dolphin, A. C. (2011) J. Biol. Chem. 286, 9598-9611). Here we show that, in the absence of CaVbeta subunits, a construct consisting of the I-II loop of CaV2.2 was directly ubiquitinated and degraded by the proteasome system. Ubiquitination could be prevented by mutation of all 12 lysine residues in the I-II loop to arginines. Including a palmitoylation motif at the N terminus of CaV2.2 I-II loop was insufficient to target it to the plasma membrane in the absence of CaVbeta subunits even when proteasomal degradation was inhibited with MG132 or ubiquitination was prevented by the lysine-to-arginine mutations. In the presence of CaVbeta subunit, the palmitoylated CaV2.2 I-II loop was protected from degradation, although oligoubiquitination could still occur, and was efficiently trafficked to the plasma membrane. We propose that targeting to the plasma membrane requires a conformational change in the I-II loop that is induced by binding of the CaVbeta subunit. PMID- 27489104 TI - The Nuclear Protein IkappaBzeta Forms a Transcriptionally Active Complex with Nuclear Factor-kappaB (NF-kappaB) p50 and the Lcn2 Promoter via the N- and C terminal Ankyrin Repeat Motifs. AB - The nuclear protein IkappaBzeta, comprising the N-terminal trans-activation domain and the C-terminal ankyrin repeat (ANK) domain composed of seven ANK motifs, activates transcription of a subset of nuclear factor-kappaB (NF-kappaB) dependent innate immune genes such as Lcn2 encoding the antibacterial protein lipocalin-2. Lcn2 activation requires formation of a complex containing IkappaBzeta and NF-kappaB p50, a transcription factor that harbors the DNA binding Rel homology region but lacks a trans-activation domain, on the promoter with the canonical NF-kappaB-binding site (kappaB site) and its downstream cytosine-rich element. Here we show that IkappaBzeta productively interacts with p50 via Asp-451 in the N terminus of ANK1, a residue that is evolutionarily conserved among IkappaBzeta and the related nuclear IkappaB proteins Bcl-3 and IkappaBNS Threonine substitution for Asp-451 abrogates direct association with the kappaB-site-binding protein p50, complex formation with the Lcn2 promoter DNA, and activation of Lcn2 transcription. The basic residues Lys-717 and Lys-719 in the C-terminal region of ANK7 contribute to IkappaBzeta binding to the Lcn2 promoter, probably via interaction with the cytosine-rich element required for Lcn2 activation; glutamate substitution for both lysines results in a loss of transcriptionally active complex formation without affecting direct contact of IkappaBzeta with p50. Both termini of the ANK domain in Bcl-3 and IkappaBNS function in a manner similar to that of IkappaBzeta to interact with promoter DNA, indicating a common mechanism in which the nuclear IkappaBs form a regulatory complex with NF-kappaB and promoter DNA via the invariant aspartate in ANK1 and the conserved basic residues in ANK7. PMID- 27489105 TI - NADPH Oxidases Are Essential for Macrophage Differentiation. AB - NADPH oxidases (NOXs) are involved in inflammation, angiogenesis, tumor growth, and osteoclast differentiation. However, the role of NOX1 and NOX2 in macrophage differentiation and tumor progression is still elusive. Here we report that NOX1 and NOX2 are critical for the differentiation of monocytes to macrophages, the polarization of M2-type but not M1-type macrophages, and the occurrence of tumor associated macrophages (TAMs). We found that deletion of both NOX1 and NOX2 led to a dramatic decrease in ROS production in macrophages and resulted in impaired efficiency in monocyte-to-macrophage differentiation and M2-type macrophage polarization. We further showed that NOX1 and NOX2 were critical for the activation of the MAPKs JNK and ERK during macrophage differentiation and that the deficiency of JNK and ERK activation was responsible for the failure of monocyte-to-macrophage differentiation, in turn affecting M2 macrophage polarization. Furthermore, we demonstrated that the decrease in M2 macrophages and TAMs, concomitant with the reduction of cytokine and chemokine secretion, contributed to the delay in wound healing and the inhibition of tumor growth and metastasis in NOX1/2 double knockout mice compared with WT mice. Collectively, these data provide direct evidence that NOX1 and NOX2 deficiency impairs macrophage differentiation and the occurrence of M2-type TAMs during tumor development. PMID- 27489106 TI - KHARON Is an Essential Cytoskeletal Protein Involved in the Trafficking of Flagellar Membrane Proteins and Cell Division in African Trypanosomes. AB - African trypanosomes and related kinetoplastid parasites selectively traffic specific membrane proteins to the flagellar membrane, but the mechanisms for this trafficking are poorly understood. We show here that KHARON, a protein originally identified in Leishmania parasites, interacts with a putative trypanosome calcium channel and is required for its targeting to the flagellar membrane. KHARON is located at the base of the flagellar axoneme, where it likely mediates targeting of flagellar membrane proteins, but is also on the subpellicular microtubules and the mitotic spindle. Hence, KHARON is probably a multifunctional protein that associates with several components of the trypanosome cytoskeleton. RNA interference-mediated knockdown of KHARON mRNA results in failure of the calcium channel to enter the flagellar membrane, detachment of the flagellum from the cell body, and disruption of mitotic spindles. Furthermore, knockdown of KHARON mRNA induces a lethal failure of cytokinesis in both bloodstream (mammalian host) and procyclic (insect vector) life cycle stages, and KHARON is thus critical for parasite viability. PMID- 27489107 TI - Regulation of Ubiquitin-like with Plant Homeodomain and RING Finger Domain 1 (UHRF1) Protein Stability by Heat Shock Protein 90 Chaperone Machinery. AB - As a protein critical for DNA maintenance methylation and cell proliferation, UHRF1 is frequently highly expressed in various human cancers and is considered as a drug target for cancer therapy. In a high throughput screening for small molecules that induce UHRF1 protein degradation, we have identified the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). We present evidence that UHRF1 interacts with HSP90 chaperone complex and is a novel HSP90 client protein. Pharmacological inhibition of HSP90 with 17-AAG or 17 dimethylaminoethylamino-17-demethoxygeldanamycin results in UHRF1 ubiquitination and proteasome-dependent degradation. Interestingly, this HSP90 inhibitor-induced UHRF1 degradation is independent of CHIP and CUL5, two previously identified ubiquitin E3 ligases for HSP90 client proteins. In addition, this degradation is dependent neither on the intrinsic E3 ligase of UHRF1 nor on the E3 ligase SCF(beta-TRCP) that has been implicated in regulation of UHRF1 stability. We also provide evidence that HSP90 inhibitors may suppress cancer cell proliferation in part through its induced UHRF1 degradation. Taken together, our results identify UHRF1 as a novel HSP90 client protein and shed light on the regulation of UHRF1 stability and function. PMID- 27489108 TI - The Receptor Site and Mechanism of Action of Sodium Channel Blocker Insecticides. AB - Sodium channels are excellent targets of both natural and synthetic insecticides with high insect selectivity. Indoxacarb, its active metabolite DCJW, and metaflumizone (MFZ) belong to a relatively new class of sodium channel blocker insecticides (SCBIs) with a mode of action distinct from all other sodium channel targeting insecticides, including pyrethroids. Electroneutral SCBIs preferably bind to and trap sodium channels in the inactivated state, a mechanism similar to that of cationic local anesthetics. Previous studies identified several SCBI sensing residues that face the inner pore of sodium channels. However, the receptor site of SCBIs, their atomic mechanisms, and the cause of selective toxicity of MFZ remain elusive. Here, we have built a homology model of the open state cockroach sodium channel BgNav1-1a. Our computations predicted that SCBIs bind in the inner pore, interact with a sodium ion at the focus of P1 helices, and extend their aromatic moiety into the III/IV domain interface (fenestration). Using model-driven mutagenesis and electrophysiology, we identified five new SCBI sensing residues, including insect-specific residues. Our study proposes the first three-dimensional models of channel-bound SCBIs, sheds light on the molecular basis of MFZ selective toxicity, and suggests that a sodium ion located in the inner pore contributes to the receptor site for electroneutral SCBIs. PMID- 27489109 TI - Chaperonin-containing T-complex Protein 1 Subunit zeta Serves as an Autoantigen Recognized by Human Vdelta2 gammadelta T Cells in Autoimmune Diseases. AB - Human gammadelta T cells recognize conserved endogenous and stress-induced antigens typically associated with autoimmune diseases. However, the role of gammadelta T cells in autoimmune diseases is not clear. Few autoimmune disease related antigens recognized by T cell receptor (TCR) gammadelta have been defined. In this study, we compared Vdelta2 TCR complementarity-determining region 3 (CDR3) between systemic lupus erythematosus (SLE) patients and healthy donors. Results show that CDR3 length distribution differed significantly and displayed oligoclonal characteristics in SLE patients when compared with healthy donors. We found no difference in the frequency of Jdelta gene fragment usage between these two groups. According to the dominant CDR3delta sequences in SLE patients, synthesized SL2 peptides specifically bound to human renal proximal tubular epithelial cell line HK-2; SL2-Vm, a mutant V sequence of SL2, did not bind. We identified the putative protein ligand chaperonin-containing T-complex protein 1 subunit zeta (CCT6A) using SL2 as a probe in HK-2 cell protein extracts by affinity chromatography and liquid chromatography-electrospray ionization tandem mass spectrometry analysis. We found CCT6A expression on the surface of HK 2 cells. Cytotoxicity of only Vdelta2 gammadelta T cells to HK-2 cells was blocked by anti-CCT6A antibody. Finally, we note that CCT6A concentration was significantly increased in plasma of SLE and rheumatoid arthritis patients. These data suggest that CCT6A is a novel autoantigen recognized by Vdelta2 gammadelta T cells, which deepens our understanding of mechanisms in autoimmune diseases. PMID- 27489111 TI - Characterization of the diffusive dynamics of particles with time-dependent asymmetric microscopy intensity profiles. AB - We put forth an algorithm to track isolated micron-size solid and liquid particles that produce time-dependent asymmetric intensity patterns. This method quantifies the displacement of a particle in the image plane from the peak of a spatial cross-correlation function with a reference image. The peak sharpness results in subpixel resolution. We demonstrate the utility of the method for tracking liquid droplets with changing shapes and micron-size particles producing images with exaggerated asymmetry. We compare the accuracy of diffusivity determination with particles of known size by this method to that by common tracking techniques and demonstrate that our algorithm is superior. We address several open questions on the characterization of diffusive behaviors. We show that for particles, diffusing with a root-mean-square displacement of 0.6 pixel widths in the time between two successive recorded frames, more accurate diffusivity determinations result from mean squared displacement (MSD) for lag times up to 5 time intervals and that MSDs determined from non-overlapping displacements do not yield more accurate diffusivities. We discuss the optimal length of image sequences and demonstrate that lower frame rates do not affect the accuracy of the estimated diffusivity. PMID- 27489112 TI - Computational insight into the catalytic implication of head/tail-first orientation of arachidonic acid in human 5-lipoxygenase: consequences for the positional specificity of oxygenation. AB - In the present work we have combined homology modeling, protein-ligand dockings, quantum mechanics/molecular mechanics calculations and molecular dynamics simulations to generate human 5-lipoxygenase (5-LOX):arachidonic acid (AA) complexes consistent with the 5-lipoxygenating activity (which implies hydrogen abstraction at the C7 position). Our results suggest that both the holo and the apo forms of human Stable 5-LOX could accommodate AA in a productive form for 5 lipoxygenation. The former, in a tail-first orientation, with the AA carboxylate end interacting with Lys409, gives the desired structures with C7 close to the Fe OH(-) cofactor and suitable barrier heights for H7 abstraction. Only when using the apo form structure, a head-first orientation with the AA carboxylate close to His600 (a residue recently proposed as essential for AA positioning) is obtained in the docking calculations. However, the calculated barrier heights for this head-first orientation are in principle consistent with 5-LOX specificity, but also with 12/8 regioselectivity. Finally, long MD simulations give support to the recent hypothesis that the Phe177 + Tyr181 pair needs to close the active site access during the chemical reaction, and suggest that in the case of a head-first orientation Phe177 may be the residue interacting with the AA carboxylate. PMID- 27489110 TI - Identification of NEK3 Kinase Threonine 165 as a Novel Regulatory Phosphorylation Site That Modulates Focal Adhesion Remodeling Necessary for Breast Cancer Cell Migration. AB - Accumulating evidence supports a role for prolactin (PRL) in the development and progression of human breast cancer. Although PRL is an established chemoattractant for breast cancer cells, the precise molecular mechanisms of how PRL regulates breast cancer cell motility and invasion are not fully understood. PRL activates the serine/threonine kinase NEK3, which was reported to enhance breast cancer cell migration, invasion, and the actin cytoskeletal reorganization necessary for these processes. However, the specific mechanisms of NEK3 activation in response to PRL signaling have not been defined. In this report, a novel PRL-inducible regulatory phosphorylation site within the activation segment of NEK3, threonine 165 (Thr-165), was identified. Phosphorylation at NEK3 Thr-165 was found to be dependent on activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway using both pharmacological inhibition and siRNA-mediated knockdown approaches. Strikingly, inhibition of phosphorylation at NEK3 Thr-165 by expression of a phospho-deficient mutant (NEK3-T165V) resulted in increased focal adhesion size, formation of zyxin-positive focal adhesions, and reorganization of the actin cytoskeleton into stress fibers. Concordantly, NEK3 T165V cells exhibited migratory defects. Together, these data support a modulatory role for phosphorylation at NEK3 Thr-165 in focal adhesion maturation and/or turnover to promote breast cancer cell migration. PMID- 27489113 TI - Variable Presentations of Lethal Colloid Cysts. AB - Four cases of colloid cysts that led to death are reported to demonstrate their nonspecific and protean presentations at autopsy: a 27-year-old man with severe occipital headache, blurred vision, drowsiness and vomiting; a 44-year-old man with recent memory disturbance; a 54-year-old man with head and neck pains, tiredness, urinary incontinence, confusion, and drowsiness; and a 66-year-old man with severe frontal headache, gait disturbance, vomiting, and syncope with a previous episode of confusion and disorientation. Each death was due to an occult colloid cyst obstructing the foramen of Monro causing acute hydrocephalus. Nonspecific manifestations may mean that the diagnosis of colloid cyst is only made at the time of autopsy. The possibility of rare cases being familial may necessitate medical review of family members. Forensic evaluation should identify how a colloid cyst was related to the mechanism of death and whether there are any features that were associated with precipitate decline. PMID- 27489114 TI - Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus. AB - TOR signaling pathway regulator-like (TIPRL) is a regulatory protein which inhibits the catalytic subunits of Type 2A phosphatases. Several cellular contexts have been proposed for TIPRL, such as regulation of mTOR signaling, inhibition of apoptosis and biogenesis and recycling of PP2A, however, the underlying molecular mechanism is still poorly understood. We have solved the crystal structure of human TIPRL at 2.15 A resolution. The structure is a novel fold organized around a central core of antiparallel beta-sheet, showing an N terminal alpha/beta region at one of its surfaces and a conserved cleft at the opposite surface. Inside this cleft, we found a peptide derived from TEV-mediated cleavage of the affinity tag. We show by mutagenesis, pulldown and hydrogen/deuterium exchange mass spectrometry that this peptide is a mimic for the conserved C-terminal tail of PP2A, an important region of the phosphatase which regulates holoenzyme assembly, and TIPRL preferentially binds the unmodified version of the PP2A-tail mimetic peptide DYFL compared to its tyrosine phosphorylated version. A docking model of the TIPRL-PP2Ac complex suggests that TIPRL blocks the phosphatase's active site, providing a structural framework for the function of TIPRL in PP2A inhibition. PMID- 27489115 TI - A prospective, multicentre, open-label, single-arm clinical trial for treatment of chronic complex diabetic foot wounds with exposed tendon and/or bone: positive clinical outcomes of viable cryopreserved human placental membrane. AB - Complex diabetic foot ulcers (DFUs) with exposed tendon or bone remain a challenge. They are more susceptible to complications such as infection and amputation and require treatments that promote rapid development of granulation tissue and, ultimately, reepithelialisation. The clinical effectiveness of viable cryopreserved human placental membrane (vCHPM) for DFUs has been established in a level 1 trial. However, complex wounds with exposed deeper structures are typically excluded from randomised controlled clinical trials despite being common in clinical practice. We report the results of a prospective, multicentre, open-label, single-arm clinical trial to establish clinical outcomes when vCHPM is applied weekly to complex DFUs with exposed deep structures. Patients with type 1 or type 2 diabetes and a complex DFU extending through the dermis with evidence of exposed muscle, tendon, fascia, bone and/or joint capsule were eligible for inclusion. Of the 31 patients enrolled, 27 completed the study. The mean wound area was 14.6 cm2 , and mean duration was 7.5 months. For patients completing the protocol, the primary endpoint, 100% wound granulation by week 16, was met by 96.3% of patients in a mean of 6.8 weeks. Complete wound closure occurred in 59.3% (mean 9.1 weeks). The 4-week percent area reduction was 54.3%. There were no product-related adverse events. Four patients (13%) withdrew, two (6.5%) for non-compliance and two (6.5%) for surgical intervention. PMID- 27489116 TI - Is there an obesity paradox in the Japanese elderly population? A community-based cohort study of 13 280 men and women. AB - AIM: Despite increased interest in an obesity paradox (i.e. a survival advantage of being obese), evidence remains sparse in Japanese populations. We aimed to verify this phenomenon among community-dwelling older adults in Japan. METHODS: Older adults aged 65-84 years randomly chosen from all 74 municipalities in Shizuoka Prefecture completed questionnaires including body mass index information. Participants were followed from 1999 to 2009. Following World Health Organization guidelines, participants were classified using an appropriate body mass index for Asian populations as follows: <18.5 kg/m2 (underweight), 18.5-23.0 kg/m2 (normal weight), 23.0-27.5 kg/m2 (overweight) and >=27.5 kg/m2 (obesity). We estimated hazard ratios and their 95% confidence intervals for all-cause mortality, controlling for sex, age, smoking status, alcohol consumption, physical activity, hypertension and diabetes mellitus. RESULTS: Compared with normal-weight participants, overweight/obese participants tended to have lower hazard ratios; the multivariate hazard ratios (95% confidence interval) were 0.86 (0.62-1.19) for obesity, 0.83 (0.73-0.94) for overweight and 1.60 (1.40-1.82) for underweight. In subgroup analyses by sex and age, the hazard ratios tended to be lower among obese men, albeit not significantly; hazard ratios (95% confidence interval) were 0.56 (0.25-1.27) in men aged 65-74 years, and 0.78 (0.41-1.45) in men aged 75-84 years. CONCLUSIONS: The present study provides evidence of a conservative obesity paradox among older Japanese people, using the appropriate body mass index cut-off points for Asian populations. In particular, obese older men tend to have a lower risk of all-cause mortality. Geriatr Gerontol Int 2017; 17: 1257-1264. PMID- 27489117 TI - Cohesin complex is a major player on the stage of leukemogenesis. PMID- 27489118 TI - Diagnostic accuracy of procalcitonin and presepsin for infectious disease in patients with acute kidney injury. AB - Procalcitonin (PCT) and presepsin (PSEP) are sepsis markers, but their diagnostic accuracy may be compromised in acute kidney injury (AKI). We evaluated their diagnostic accuracy in patients with/without AKI. This retrospective study comprised 91 patients with at least one criterion of systematic inflammatory response syndrome. AKI markers plasma neutrophil gelatinase-associated lipocalin (NGAL), plasma cystatin C (CysC), and estimated glomerular filtration rate (eGFR) were measured upon hospital admission and on days 1, 3, 5, and 7. Patients were divided into non-AKI and AKI groups. APACHE II severity scores were determined. PCT and PSEP levels were increased significantly in non-AKI and AKI patients with infection. NGAL, CysC, and eGFR in patients with infection were associated with PCT, PSEP, and APACHE II score, and levels of PCT and PSEP were correlated significantly with disease severity. PCT and PSEP are useful markers of bacterial infections in AKI but different thresholds should be applied. PMID- 27489119 TI - Recovery of Neisseria gonorrhoeae from 4 commercially available transport systems. AB - Four commercial transport systems for the recovery of Neisseria gonorrhoeae were evaluated in support of the need to obtain culture isolates for the detection of antimicrobial resistance. Bacterial recovery from the InTray GC system was superior with minimal loss of viability in contrast to non-nutritive transport systems. PMID- 27489120 TI - Oxidative Stress Is Involved in the Renal Dysfunction Induced by Sinoaortic Denervation in Rats. AB - The hypothesis that oxidative stress contributes to renal dysfunction in sinoaortically denervated (SAD) rats was investigated. Rats were sinoaortically denervated and received treatment with tempol (0.5 mmol/L in drinking water) for 8 weeks. Although the tempol treatment of the SAD rats had no significant effect on blood pressure or blood pressure viability, it significantly ameliorated the renal dysfunction as indicated by increases in renal blood flow (RBF) and the glomerular filtration rate (GFR) and reductions in plasma creatinine, blood urea nitrogen (BUN), the urine albumin excretion rate (UAE), and the glomerular sclerosis score (GSS). The SAD rats treated with tempol exhibited decreased plasma and renal malondialdehyde (MDA) levels and reduced renal formation of reactive oxygen species (ROS), superoxide (O2-), peroxynitrite (OONO-) and 3 nitrotyrosine. Treatment with tempol suppressed the nuclear concentration of nuclear factor-kappaB (NF-kappaB) and reduced the renal levels of macrophage chemoattractant protein 1 (MCP-1) and interleukin-6 (IL-6). The tempol-treated SAD rats exhibited decreased renal advanced glycation end product (AGE) levels and decreased receptor for advanced glycation end products (RAGE) protein expression. The tempol treatment of the SAD rats restored mitochondrial adenosine triphosphate (ATP) formation, DNA content, membrane integrity and the renal oxygen consumption rate. Additionally, the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S epoxide transferase (GST), and catalase were decreased, and the activities of xanthin oxidase (XO) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were enhanced in the kidneys of the SAD rats. In conclusion, our work firstly provided direct evidence that oxidative stress played an important role in the renal dysfunction of SAD rats. PMID- 27489121 TI - Visual-cognitive tools used to determine fitness-to-drive may reflect normal aging. AB - BACKGROUND: Scores on many visual-cognitive tools are proposed as indicators of fitness-to-drive. A purported feature of some tools and one believed to be important is that they are 'age-independent'. Specifically, scores are not correlated with age and poor scores represent a pathological process rather than normal aging. Yet, we know that several cognitive abilities are associated with age. One potential reason for the apparent age-independence of some tools is that focusing on older drivers leads to 'range restriction', a statistical issue that reduces the magnitude of correlations when values for one variable are restricted to a smaller range than naturally occurs. Hence, the purpose of this study was to investigate whether age is correlated with scores on visual-cognitive tests when we examine the full age range. METHODS: We recruited 114 drivers aged 18 to 89 years (mean: 42.30 +/- 26.50 years). Participants completed several visual cognitive tools often used to examine fitness-to-drive (Trail Making Tests A and B, Attention Network Test and 'useful field of view'). RESULTS: Correlations between age and test scores for drivers 65 years and older only ranged from 0.03 to 0.48. With the whole age range, correlations ranged from 0.56 to 0.84. We also compared ordinary Pearson correlations among visual-cognitive tests scores to the corresponding partial correlations after removing the effect of age. Whereas ordinary Pearson correlations ranged from 0.40 to 0.69, partial correlations ranged from 0.01 to 0.30. CONCLUSION: Test scores may reflect age-associated normal biological changes. These results have implications for predicting fitness to-drive among older drivers and suggest caution in using these scores. PMID- 27489123 TI - Lead Angle Matters: Side Effects of Deep Brain Stimulation Improved With Adjustment of Lead Angle. AB - BACKGROUND: Targeting the subthalamic nucleus (STN) for deep brain stimulation (DBS) using standard stereotactic coordinates in conjunction with high-resolution magnetic resonance imaging (MRI) generally results in effective symptomatic relief for the cardinal motor features of Parkinson's disease (PD). The angle of approach, however, influences the resultant field of stimulation and can lead to undesired side effects. METHODS: We review a case where symptomatic improvement was accompanied by significant side effects despite reasonable STN stereotactic base coordinates. Revision of the lead using similar base coordinates but a significantly different angle of approach greatly improved the outcome. RESULTS: Stimulation ventromedial to the STN improved tremors but brought about dysarthria and dystonia. Computer-based stimulation field modeling helped understand the regions associated with the side effects and illustrate the difference between pre- and post-revision stimulation fields. CONCLUSION: Lead angle can impact DBS outcome and should be taken into consideration. PMID- 27489122 TI - Downregulation of the long noncoding RNA GAS5-AS1 contributes to tumor metastasis in non-small cell lung cancer. AB - Long noncoding RNA (lncRNA) plays pivotal roles in cancer development. To date, only a small number of lncRNAs have been characterized at functional level. Here, we discovered a novel lncRNA termed GAS5-AS1 as a tumor suppressor in non-small cell lung cancer (NSCLC). The expression of GAS5-AS1 in NSCLC tumors was much lower than that in the adjacent normal lung tissues. The reduced GAS5-AS1 was significantly correlated with larger tumors, higher TNM stages, and lymph node metastasis in NSCLC patients. While ectopic expression or specific knockdown of GAS5-AS1 had no effect on proliferation, cell cycle progression, and apoptosis, it dramatically decreased or increased, respectively, NSCLC cell migration and invasion. Overexpression of GAS5-AS1 in NSCLC cells reduced a cohort of molecules (ZEB1, N-cadherin, Vimentin, and/or Snail1) critical for epithelial-mesenchymal transition (EMT). Furthermore, the DNA demethylating agent 5-aza-2-deoxycytidine failed to upregulate GAS5-AS1 in NSCLC cells, whereas the pan-HDAC inhibitors panobinostat and SAHA significantly induced GAS5-AS1 in a dose-dependent manner. In addition, GAS5-AS1 can be upregulated by specific knockdown of HDAC1 or HDAC3. Collectively, our data suggest that histone modifications play a major role leading to epigenetic silencing of GAS5-AS1 in NSCLC and subsequently promote tumor metastasis via upregulation of several key EMT markers. PMID- 27489124 TI - Goodbye BRONJ... Hello MRONJ. PMID- 27489125 TI - Discriminating in favour of or against men with increased risk of finasteride related side effects? PMID- 27489126 TI - Blood film findings in anaplasmosis. PMID- 27489127 TI - Insight into In Situ Amphiphilic Functionalization of Few-Layered Transition Metal Dichalcogenide Nanosheets. AB - A facile route toward functionalized amphiphilic layered transition-metal dichalcogenide nanosheets through in situ polymerization of polystyrene polyacrylamide copolymers is established. The attachment of copolymers greatly affects their dispersibility in different kinds of solvents. Surface-tension components, polarity, and coordination effects of the copolymer are found to be the main factors affecting the dispersibility. PMID- 27489128 TI - Experimental Identification of Electric Field Excitation Mechanisms in a Structural Transition of Tokamak Plasmas. AB - Self-regulation between structure and turbulence, which is a fundamental process in the complex system, has been widely regarded as one of the central issues in modern physics. A typical example of that in magnetically confined plasmas is the Low confinement mode to High confinement mode (L-H) transition, which is intensely studied for more than thirty years since it provides a confinement improvement necessary for the realization of the fusion reactor. An essential issue in the L-H transition physics is the mechanism of the abrupt "radial" electric field generation in toroidal plasmas. To date, several models for the L H transition have been proposed but the systematic experimental validation is still challenging. Here we report the systematic and quantitative model validations of the radial electric field excitation mechanism for the first time, using a data set of the turbulence and the radial electric field having a high spatiotemporal resolution. Examining time derivative of Poisson's equation, the sum of the loss-cone loss current and the neoclassical bulk viscosity current is found to behave as the experimentally observed radial current that excites the radial electric field within a few factors of magnitude. PMID- 27489129 TI - Synthesis and characterization of insulin/zirconium phosphate@TiO2 hybrid composites for enhanced oral insulin delivery applications. AB - In this work, a series of composites of insulin (Ins)/zirconium phosphate (ZrP) were synthesized by intercalation method, then, these composites were coated with TiO2 by sol-gel method to prepare Ins/ZrP@TiO2 hybrid composites and the drug release of the composites was investigated by using UV-Vis spectroscopy. Ins/ZrP (10, 30, 60 wt%) composites were prepared by intercalation of insulin into the ZrP layers in water. Then Ins/ZrP composites were coated with different amounts of TiO2 (30, 50, 100 wt %) by using titanium tetra n-butoxide, as precursor. Formation of intercalated Ins/ZrP and Ins/ZrP@TiO2 hybrid composites was characterized by FT-IR, FE-SEM, BET and XRD analysis. Zeta potential of the optimized Ins/ZrP@TiO2 hybrid composite was determined -27.2 mV. Cytotoxic effects of the optimized Ins/ZrP@TiO2 hybrid composite against HeLa and Hek293T cell lines were evaluated using MTT assay and the results showed that designed drug delivery system was not toxic in biological environment. Compared to the Ins/ZrP composites, incorporation of TiO2 coating enhanced the drug entrapment considerably, and reduced the drug release. The Ins/ZrP composites without TiO2 coating released the whole drug after 30 min in pH 7.4 (phosphate buffer solution) while the TiO2-coated composites released the entrapped drug after 20 h. In addition to increasing the shelf life of hormone, this nanoencapsulation and nanocoating method can convert the insulin utilization from injection to oral and present a painless and more comfortable treatment for diabetics. PMID- 27489130 TI - Corrigendum: Observation of a topological crystalline insulator phase and topological phase transition in Pb1-xSnxTe. PMID- 27489131 TI - Maltaricin CPN, a new class IIa bacteriocin produced by Carnobacterium maltaromaticum CPN isolated from mould-ripened cheese. AB - AIMS: The purpose of this study was to isolate, characterize and determine the structure and the antibacterial activities of a bacteriocin produced by Carnobacterium maltaromaticum CPN, a strain isolated from unpasteurized milk Camembert cheese. METHODS AND RESULTS: This bacteriocin, termed maltaricin CPN, was produced at higher amounts in MRS broth at temperatures between 15 degrees C and 25 degrees C. It was purified to homogeneity from culture supernatant by using a simple method consisting of cation-exchange and reversed-phase chromatographies. Mass spectrometry showed that maltaricin was a 4427.29 Da bacteriocin. Its amino acid sequence was determined by Edman degradation which showed that it had close similarity with bacteriocins of the class IIa. Maltaricin CPN consisted in fact of 44 unmodified amino acids including two cysteine residues at positions 9 and 14 linked by a disulphide bond. The antimicrobial activity of maltaricin CPN covered a range of bacteria, with strong activity against many species of Gram-positive bacteria, especially the food borne pathogen Listeria monocytogenes, but no activity against Gram-negative ones. CONCLUSIONS: In the studied conditions, C. maltaromaticum CPN produced a new class IIa bacteriocin with strong anti-Listeria activity. SIGNIFICANCE AND IMPACT OF THE STUDY: The study covers the purification and the structural characterization of a new bacteriocin produced by strain C. maltaromaticum CPN isolated from Camembert cheese. Its activity against strains of L. monocytogenes and higher production rates at relatively low temperatures show potential technological applications to improve the safety of refrigerated food. PMID- 27489132 TI - Organocatalyzed Novel Synthetic Methodology for Highly Functionalized Piperidines as Potent alpha-Glucosidase Inhibitors. AB - An efficient atom-economic one-pot synthesis of highly functionalized piperidines was achieved by catalytic multicomponent reaction. A wide range of heterogeneous and homogenous catalysts were explored; however, promising results were achieved when a beta-keto-ester was reacted with selected aromatic aldehydes and anilines by using N-acetyl glycine (NAG) as catalyst. The implication of this methodology is straightforward since the products were precipitated out from the reaction solution, eliminating the need of column chromatography purifications. The synthesized piperidines were screened against alpha-glucosidase inhibition, which revealed that these compounds were very active inhibitors, and some of the compounds showed even better inhibition than the reference compound, at low micromolar concentrations. In silico molecular modeling was also performed to investigate the binding modes of the compounds into the active sites of the target protein. PMID- 27489133 TI - The protective effect of resveratrol against cytotoxicity induced by mycotoxin, zearalenone. AB - Zearalenone (ZEA), a non-steroidal estrogenic mycotoxin, is widely present in cereals and agricultural products. The literature reports suggest that oxidative damage seems to be a key determinant of ZEA-induced toxicity, and the protective effect of resveratrol (RSV), an antioxidant phenolic compound, on ZEA-induced cytotoxicity to HEK293 cells was investigated. The experimental results showed that ZEA decreased cell viability in a dose dependent manner with an IC50 value of 80 MUM, and induced an increase in intracellular reactive oxygen species (ROS) in HEK293 cells. A remarkable elevation of MDA and decreased activity of manganese superoxide dismutase (MnSOD) were also observed. A decrease in mitochondrial membrane potential (MMP), cell cycle arrest at the G0/G1 phase, and increased cell apoptosis indicate a mitochondria-mediated apoptosis. RSV (2 MUM) pretreatment not only recovered the activity of MnSOD, but also improved ZEA induced cytotoxicity evidenced by increased MMP and cell viability, and decreased ROS. Furthermore, RSV pretreatment substantially upregulated the expression of the SIRT1 gene by 6.8 fold, reduced the acetylation level of the forkhead transcription factor FOXO3a, and decreased the expression ratio of Bax/Bcl-2. All these results demonstrated that RSV exhibited significant protective effects on ZEA-induced cell damage, and this effect may be attributed to the upregulation of SIRT1 and activation of FOXO3a-mediated pathways to enhance the resistance of cells to oxidative stress induced by ZEA exposure. PMID- 27489134 TI - Long-Term Results After Single and Multiple Procedures of Ablation of Ventricular Tachycardia. AB - INTRODUCTION: The aim of this study was to assess long-term results after single and multiple procedures of catheter ablation of ventricular tachycardia (VT). While it is generally accepted that multiple procedures are sometimes necessary in order to achieve long-term clinical success, the literature on this issue displays wide variability. METHODS: We assessed the outcome of 160 consecutive patients who underwent 214 ablation procedures in the period 2008 to May 2015: 93 had overt structural heart disease (SHD) (previous myocardial infarction in 74 cases) and 67 had no SHD. RESULTS: After the first procedure, the 1-year actuarial recurrence rates were 25% in patients with SHD and 5% in those without. However, recurrences increased progressively after the first year, reaching 46% and 35%, respectively, at 5 years. Overall, VT recurred in 35/93 (38%) patients with SHD and 22/67 (33%) patients without. Redo (1 to 4) procedures were performed in 28 (20%) patients with SHD and 18 (27%) patients without. After the last procedure, the 1-year actuarial recurrence rates were 5% in patients with SHD and 7% in those without, and the corresponding rates at 5 years were 23% and 7%. During follow-up, 21 patients died (all in the SHD group): no death was related to VT recurrence. CONCLUSIONS: During long-term follow-up, VT frequently recurs after the first procedure, both in patients with SHD and in those without; multiple procedures are needed in order to increase the success rate. PMID- 27489135 TI - Characterization and Evaluation of a Salmonella enterica Serotype Senftenberg Mutant Created by Deletion of Virulence-Related Genes for Use as a Live Attenuated Vaccine. AB - Natural infections of chickens with Salmonella enterica subsp. enterica serovar Senftenberg (S. Senftenberg) are characterized by low-level intestinal invasiveness and insignificant production of antibodies. In this study, we investigated the potential effects of lon and cpxR gene deletions on the invasiveness of S Senftenberg into the intestinal epithelium of chickens and its ability to induce an immune response, conferring protection against S Senftenberg infection. With the allelic exchange method, we developed JOL1596 (Deltalon), JOL1571 (DeltacpxR), and JOL1587 (Deltalon DeltacpxR) deletion mutants from wild type S Senftenberg. Deletion of the lon gene from S Senftenberg produced increased frequency of elongated cells, with significantly greater amounts of exopolysaccharide (EPS) than in the cpxR-deleted strain and the wild-type strain. The in vivo intestinal loop invasion assay showed a significant increase in epithelial invasiveness for JOL1596 (Deltalon) and JOL1587 (Deltalon DeltacpxR), compared to JOL1571 (DeltacpxR) and the wild-type strain. Furthermore, the S Senftenberg wild-type and mutant strains were internalized at high levels inside activated abdominal macrophages from chicken. The in vivo inoculation of JOL1587 (Deltalon DeltacpxR) into chickens led to colonization of the liver, spleen, and cecum for a short time. Chickens inoculated with JOL1587 (Deltalon DeltacpxR) showed significant increases in humoral, mucosal, and cellular immune responses specific to S Senftenberg antigens. Postchallenge, compared to the control group, the JOL1587 (Deltalon DeltacpxR)-inoculated chickens showed not only lower persistence but also faster clearance of wild-type S Senftenberg from the cecum. We conclude that the increased intestinal invasiveness and colonization of internal organs exhibited by JOL1587 (Deltalon DeltacpxR) led to the establishment of immunogenicity and conferred protective efficacy against S Senftenberg infections in chickens. PMID- 27489137 TI - Angular default mode network connectivity across working memory load. AB - Initially identified during no-task, baseline conditions, it has now been suggested that the default mode network (DMN) engages during a variety of working memory paradigms through its flexible interactions with other large-scale brain networks. Nevertheless, its contribution to whole-brain connectivity dynamics across increasing working memory load has not been explicitly assessed. The aim of our study was to determine which DMN hubs relate to working memory task performance during an fMRI-based n-back paradigm with parametric increases in difficulty. Using a voxel-wise metric, termed the intrinsic connectivity contrast (ICC), we found that the bilateral angular gyri (core DMN hubs) displayed the greatest change in global connectivity across three levels of n-back task load. Subsequent seed-based functional connectivity analysis revealed that the angular DMN regions robustly interact with other large-scale brain networks, suggesting a potential involvement in the global integration of information. Further support for this hypothesis comes from the significant correlations we found between angular gyri connectivity and reaction times to correct responses. The implication from our study is that the DMN is actively involved during the n-back task and thus plays an important role related to working memory, with its core angular regions contributing to the changes in global brain connectivity in response to increasing environmental demands. Hum Brain Mapp 38:41-52, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27489136 TI - Multifunctional T Cell Response to DosR and Rpf Antigens Is Associated with Protection in Long-Term Mycobacterium tuberculosis-Infected Individuals in Colombia. AB - Multifunctional T cells have been shown to be protective in chronic viral infections. In mycobacterial infections, however, evidence for a protective role of multifunctional T cells remains inconclusive. Short-term cultures of peripheral blood mononuclear cells stimulated with the Mycobacterium tuberculosis RD1 antigens 6-kDa early secretory antigenic target (ESAT6) and 10-kDa culture filtrate antigen (CFP10), which are induced in the early infection phase, have been mainly used to assess T cell multifunctionality, although long-term culture assays have been proposed to be more sensitive than short-term assays for assessment of memory T cells, which are essential for long-term immunity. Here we used a long-term culture assay system to study the T cell immune responses to the M. tuberculosis latency-associated DosR antigens and reactivation-associated Rpf antigens, compared to ESAT6 and CFP10, in patients with pulmonary tuberculosis (PTB) and household contacts of PTB patients with long-term latent tuberculosis infection (ltLTBI), in a community in which M. tuberculosis is endemic. Our results showed that the DosR antigens Rv1737c (narK2) and Rv2029c (pfkB) and the Rv2389c (rpfD) antigen of M. tuberculosis induced higher frequencies of CD4+ or CD8+ mono- or bifunctional (but not multifunctional) T cells producing interferon gamma (IFN-gamma) and/or tumor necrosis alpha (TNF-alpha) in ltLTBI, compared to PTB. Moreover, the frequencies of CD4+ and/or CD8+ T cells with a CD45RO+ CD27+ phenotype were higher in ltLTBI than in PTB. Thus, the immune responses to selected DosR and Rpf antigens may be associated with long-term latency, correlating with protection from M. tuberculosis reactivation in ltLTBI. Further study of the functional and memory phenotypes may contribute to further discrimination between the different states of M. tuberculosis infections. PMID- 27489138 TI - Highly stable tandem solar cell monolithically integrating dye-sensitized and CIGS solar cells. AB - A highly stable monolithic tandem solar cell was developed by combining the heterogeneous photovoltaic technologies of dye-sensitized solar cell (DSSC) and solution-processed CuInxGa1-xSeyS1-y (CIGS) thin film solar cells. The durability of the tandem cell was dramatically enhanced by replacing the redox couple from to [Co(bpy)3](2+) /[Co(bpy)3](3+)), accompanied by a well-matched counter electrode ( PEDOT: PSS) and sensitizer (Y123). A 1000 h durability test of the DSSC/CIGS tandem solar cell in ambient conditions resulted in only a 5% decrease in solar cell efficiency. Based on electrochemical impedance spectroscopy and photoelectrochemical cell measurement, the enhanced stability of the tandem cell is attributed to minimal corrosion by the cobalt-based polypyridine complex redox couple. PMID- 27489139 TI - Distinctive microRNA expression in early stage nasopharyngeal carcinoma patients. AB - The goal of this study was to investigate microRNAs (miRs) expression at different stages of nasopharyngeal carcinoma (NPC). MiR expression profiling at various stages of NPC was performed by miR array and further verified using quantitative real-time RT-PCR. Pathway enrichment analysis was carried out to identify the functional pathways regulated by the miRs. The expression of a selected group of identified miRs was verified in stage I NPC by in situ hybridization (ISH). A total of 449 miRs were identified with significantly different expressions between NPC tissues and normal pharyngeal tissues. Eighty four miRs were dysregulated only in stage I NPC, among which 45 miRs were up regulated and the other 39 were down-regulated. Pathway enrichment assay revleaed that three significantly down-regulated and three significantly up-regulated miRs involved in 12 pathways associating with tumour formation and progression. Quantitative RT-PCR confirmed the miR array result. In addition, the low expression levels of hsa-miR-4324, hsa-miR-203a and hsa-miR-199b-5p were further validated in stage I NPC by ISH. This present study identifed the miR signature in stage I NPC, providing the basis for early detection and treatment of NPC. PMID- 27489140 TI - Prostate cancer outcomes for men who present with symptoms at diagnosis. AB - OBJECTIVE: To compare clinical features, treatments and outcomes in men with non metastatic prostate cancer (PCa) according to whether they were referred for symptoms or elevated prostate-specific antigen (PSA) level. PATIENTS AND METHODS: This study used data from the South Australia Prostate Cancer Clinical Outcomes Collaborative database; a multi-institutional clinical registry covering both the public and private sectors. We included all non-metastatic cases from 1998 to 2013 referred for urinary/prostatic symptoms or elevated PSA level. Multivariate Poisson regression was used to identify characteristics associated with symptomatic presentation and compare treatments according to reason for referral. Outcomes (i.e. overall survival, PCa-specific survival, metastasis-free survival and disease-free survival) were compared using multivariate Cox proportional hazards and competing risk regression. RESULTS: Our analytical cohort consisted of 4 841 men with localized PCa. Symptomatic men had lower-risk disease (incidence ratio [IR] 0.70, 95% confidence interval [CI] 0.61-0.81 for high vs low risk), fewer radical prostatectomies (IR 0.64, CI: 0.56-0.75) and less radiotherapy (IR 0.86, CI: 0.77-0.96) than men presenting with elevated PSA level. All-cause mortality (hazard ratio [HR] 1.31, CI: 1.16-1.47), disease specific mortality (HR 1.42, CI: 1.13-1.77) and risk of metastases (HR 1.36, CI: 1.13-1.64) were higher for men presenting with symptoms, after adjustment for other clinical characteristics; however, risk of disease progression did not differ (HR 0.90, CI: 0.74-1.07) amongst those treated curatively. Subgroup analyses indicated poorer PCa survival for symptomatic referral among men undergoing radical prostatectomy (HR 3.4, CI: 1.3-8.8), those aged >70 years (HR 1.4, CI: 1.0-1.8), men receiving private treatment (HR 2.1, CI: 1.3-3.3), those diagnosed via biopsy (HR 1.3, CI: 1.0-1.7) and those diagnosed before 2006 (HR 1.6, CI: 1.2-2.7). CONCLUSION: Our results suggest that symptomatic presentation may be an independent negative prognostic indicator for PCa survival. More complete assessment of disease grade and extent, more definitive treatment and increased post-treatment monitoring among symptomatic cases may improve outcomes. Further research to determine any pathophysiological basis for poor outcomes in symptomatic men is warranted. PMID- 27489141 TI - Aqueous fruit extract of Mimusops elengi causes reversible suppression of spermatogenesis and fertility in male mice. AB - Antifertility efficacy of oral administration of aqueous fruit extract of Mimusops elengi (200, 400 and 600 mg kg(-1) body weight/day for 35 days) was evaluated in Parkes strain male mice. Various reproductive end points such as histopathology, sperm parameters, testosterone level, haematology, serum biochemistry and fertility indices were assessed; activities of 3beta- and 17beta hydroxysteroid dehydrogenases, and immunoblot expressions of StAR and P450scc in the testis were also assessed. Histologically, testes in Mimusops-treated mice showed nonuniform and diverse degenerative changes in the seminiferous tubules; both affected and normal tubules were observed in the same sections of testis. The treatment had adverse effects on testicular hydroxysteroid dehydrogenases and StAR and P450scc, serum level of testosterone and on motility, viability and number of spermatozoa in cauda epididymis. However, serum levels of alanine aminotransferase, aspartate aminotransferase and creatinine, and haematological parameters were not affected by the treatment. Also, libido was not affected in treated males, but their fertility was markedly suppressed. By 56 days of treatment withdrawal, the alterations caused in the above parameters recovered to control levels, suggesting that Mimusops treatment causes reversible suppression of spermatogenesis and fertility in Parkes mice. Further, there were no detectable signs of toxicity in treated males. PMID- 27489142 TI - Assessment of 3 Bowel Preparation Protocols for Computed Tomography Pneumocolonography in Normal Dogs. AB - OBJECTIVE: To investigate the effects of 3 different bowel preparation protocols on interpretation of computed tomography (CT) pneumocolonography images. STUDY DESIGN: Experimental crossover design. ANIMALS: Intact male, hound-cross, research colony dogs (n=4). METHODS: All dogs received the 3 different bowel preparation protocols for CT pneumocolonography in the same order, with a minimum of 2 weeks between protocols. For each segment of large bowel, the subjective adequacy of bowel cleansing was assessed, residual fecal and bowel volumes were calculated, and the density of fecal material in the bowel lumen was measured. Linear mixed effect models that included a random dog effect were used to evaluate mean differences in outcome measures across protocols. RESULTS: No dogs experienced any clinical problems associated with the protocols or CT pneumocolonography. Bowel cleansing was considered adequate for CT pneumocolonography interpretation for all 3 protocols. There was a significant effect of protocol on residual fecal volumes and the fecal:bowel volume ratio, with the 2 protocols that included an extended fast producing the lowest total residual fecal volumes. There was a significant effect of protocol on maximum measured density of residual fecal material with the 2 protocols including iodinated contrast having the highest density. CONCLUSIONS: All protocols were sufficient for CT pneumocolonography interpretation and contrast-tagging of residual fecal material was successful with oral iopamidol administration. An at home bowel cleansing protocol may provide adequate bowel cleansing for CT pneumocolonography image interpretation. PMID- 27489143 TI - Integrating Evidence From Systematic Reviews, Qualitative Research, and Expert Knowledge Using Co-Design Techniques to Develop a Web-Based Intervention for People in the Retirement Transition. AB - BACKGROUND: Integrating stakeholder involvement in complex health intervention design maximizes acceptability and potential effectiveness. However, there is little methodological guidance about how to integrate evidence systematically from various sources in this process. Scientific evidence derived from different approaches can be difficult to integrate and the problem is compounded when attempting to include diverse, subjective input from stakeholders. OBJECTIVE: The intent of the study was to describe and appraise a systematic, sequential approach to integrate scientific evidence, expert knowledge and experience, and stakeholder involvement in the co-design and development of a complex health intervention. The development of a Web-based lifestyle intervention for people in retirement is used as an example. METHODS: Evidence from three systematic reviews, qualitative research findings, and expert knowledge was compiled to produce evidence statements (stage 1). Face validity of these statements was assessed by key stakeholders in a co-design workshop resulting in a set of intervention principles (stage 2). These principles were assessed for face validity in a second workshop, resulting in core intervention concepts and hand drawn prototypes (stage 3). The outputs from stages 1-3 were translated into a design brief and specification (stage 4), which guided the building of a functioning prototype, Web-based intervention (stage 5). This prototype was de risked resulting in an optimized functioning prototype (stage 6), which was subject to iterative testing and optimization (stage 7), prior to formal pilot evaluation. RESULTS: The evidence statements (stage 1) highlighted the effectiveness of physical activity, dietary and social role interventions in retirement; the idiosyncratic nature of retirement and well-being; the value of using specific behavior change techniques including those derived from the Health Action Process Approach; and the need for signposting to local resources. The intervention principles (stage 2) included the need to facilitate self-reflection on available resources, personalization, and promotion of links between key lifestyle behaviors. The core concepts and hand-drawn prototypes (stage 3) had embedded in them the importance of time use and work exit planning, personalized goal setting, and acceptance of a Web-based intervention. The design brief detailed the features and modules required (stage 4), guiding the development of wireframes, module content and functionality, virtual mentors, and intervention branding (stage 5). Following an iterative process of intervention testing and optimization (stage 6), the final Web-based intervention prototype of LEAP (Living, Eating, Activity, and Planning in retirement) was produced (stage 7). The approach was resource intensive and required a multidisciplinary team. The design expert made an invaluable contribution throughout the process. CONCLUSIONS: Our sequential approach fills an important methodological gap in the literature, describing the stages and techniques useful in developing an evidence based complex health intervention. The systematic and rigorous integration of scientific evidence, expert knowledge and experience, and stakeholder input has resulted in an intervention likely to be acceptable and feasible. PMID- 27489145 TI - Massive central nervous system infiltration by CD56-positive plasma cells in multiple myeloma. PMID- 27489144 TI - Intrinsic limits to gene regulation by global crosstalk. AB - Gene regulation relies on the specificity of transcription factor (TF)-DNA interactions. Limited specificity may lead to crosstalk: a regulatory state in which a gene is either incorrectly activated due to noncognate TF-DNA interactions or remains erroneously inactive. As each TF can have numerous interactions with noncognate cis-regulatory elements, crosstalk is inherently a global problem, yet has previously not been studied as such. We construct a theoretical framework to analyse the effects of global crosstalk on gene regulation. We find that crosstalk presents a significant challenge for organisms with low-specificity TFs, such as metazoans. Crosstalk is not easily mitigated by known regulatory schemes acting at equilibrium, including variants of cooperativity and combinatorial regulation. Our results suggest that crosstalk imposes a previously unexplored global constraint on the functioning and evolution of regulatory networks, which is qualitatively distinct from the known constraints that act at the level of individual gene regulatory elements. PMID- 27489146 TI - Bioremediation at a global scale: from the test tube to planet Earth. AB - Planet Earth's biosphere has evolved over billions of years as a balanced bio geological system ultimately sustained by sunpower and the large-scale cycling of elements largely run by the global environmental microbiome. Humans have been part of this picture for much of their existence. But the industrial revolution started in the XIX century and the subsequent advances in medicine, chemistry, agriculture and communications have impacted such balances to an unprecedented degree - and the problem has nothing but exacerbated in the last 20 years. Human overpopulation, industrial growth along with unsustainable use of natural resources have driven many sites and perhaps the planetary ecosystem as a whole, beyond recovery by spontaneous natural means, even if the immediate causes could be stopped. The most conspicuous indications of such a state of affairs include the massive change in land use, the accelerated increase in the levels of greenhouse gases, the frequent natural disasters associated to climate change and the growing non-recyclable waste (e.g. plastics and recalcitrant chemicals) that we release to the Environment. While the whole planet is afflicted at a global scale by chemical pollution and anthropogenic emissions, the ongoing development of systems and synthetic biology, metagenomics, modern chemistry and some key concepts from ecological theory allow us to tackle this phenomenal challenge and propose large-scale interventions aimed at reversing and even improving the situation. This involves (i) identification of key reactions or processes that need to be re-established (or altogether created) for ecosystem reinstallation, (ii) implementation of such reactions in natural or designer hosts able to self replicate and deliver the corresponding activities when/where needed in a fashion guided by sound ecological modelling, (iii) dispersal of niche-creating agents at a global scale and (iv) containment, monitoring and risk assessment of the whole process. PMID- 27489147 TI - Testosterone Deficiency and Bone Metabolism Damage in Testicular Cancer Survivors. AB - The aim of the study was to investigate the influence of therapeutic modalities and sexual hormone levels on changes in bone mineral density (BMD) in testicular cancer (TC) survivors. In a cross-sectional descriptive, long-term follow-up study, a total of 1,249 long-term TC survivors were evaluated according to treatment modality: orchiectomy (OE) only, OE + chemotherapy (CT), or OE + radiotherapy (RT). Luteinizing hormone (LH), total testosterone (TST), marker of bone resorption (beta-carboxyl-terminal cross-linking telopeptide of type I collagen-CTx), and BMD were evaluated. Standard statistical techniques were used to test the differences between groups of patients. TST decrease was observed in 46/313 TC survivors after OE alone, in 103/665 after OE + CT, and in 66/271 after OE + RT. LH increase was observed in 23/313 TC survivors after OE alone, in 154/665 after OE + CT, and in 43/271 after OE + RT. CTx increase was observed in 116/313 TC survivors after OE alone, in 324/665 after OE + CT, and in 82/271 after OE + RT. Osteopenia/osteoporosis occurred in 136/313 TC survivors after OE alone, in 298/665 after OE + CT, and in 139/271 after OE + RT. TC survivors after RT have statistically significant decreased TST levels, increased LH and nonsignificant worse BMD (osteopenia/osteoporosis) in comparison with TC survivors after OE alone or CT. TST decrease and LH increase were statistically significant, more frequently observed in patients with osteopenia/osteoporosis. Examination of TST is an important part of follow-up in TC survivors with bilateral as well as unilateral disease. The important part of standard examination algorithm should be also the osteological examination of TC survivors mainly in patients with androgen deficiency. PMID- 27489148 TI - Pulmonary Function of Young Muslim Males During the Month of Ramadan: Some Points to Highlight. PMID- 27489149 TI - Correction: Decision analytic cost-effectiveness model to compare prostate cryotherapy to androgen deprivation therapy for treatment of radiation recurrent prostate cancer. PMID- 27489150 TI - Correction: Effect modification of FADS2 polymorphisms on the association between breastfeeding and intelligence: protocol for a collaborative meta-analysis. PMID- 27489151 TI - Cross-sectional study exploring barriers to adverse drug reactions reporting in community pharmacy settings in Dhaka, Bangladesh. AB - OBJECTIVES: To assess community pharmacists'/pharmacy technicians' knowledge and perceptions about adverse drug reactions (ADRs) and barriers towards the reporting of such reactions in Dhaka, Bangladesh. METHOD: A cross-sectional study was planned to approach potential respondents for the study. A self-administered questionnaire was delivered to community pharmacists/pharmacy technicians (N=292) practising in Dhaka, Bangladesh. RESULTS: The overall response to the survey was 69.5% (n=203). The majority of the sample was comprised of pharmacy technicians (152, 74.9%) who possessed a diploma in pharmacy, followed by pharmacists (37, 18.2%) and others (12, 5.9%). Overall, 72 (35.5%) of the respondents disclosed that they had experienced an ADR at their pharmacy, yet more than half (105, 51.7%) were not familiar with the existence of an ADR reporting body in Bangladesh. Exploring the barriers to the reporting of ADRs, it was revealed that the top four barriers to ADR reporting were 'I do not know how to report (Relative Importance Index (RII)=0.998)', 'reporting forms are not available (0.996)', 'I am not motivated to report (0.997)' and 'Unavailability of professional environment to discuss about ADR (RII=0.939)'. In addition to these, a majority (141, 69.46%) were not confident about the classification of ADRs (RII=0.889) and were afraid of legal liabilities associated with reporting ADRs (RII=0.806). Moreover, a lack of knowledge about pharmacotherapy and the detection of ADRs was another major factor hindering their reporting (RII=0.731). CONCLUSIONS: The Directorate of Drug Administration in Bangladesh needs to consider the results of this study to help it improve and simplify ADR reporting in Bangladeshi community pharmacy settings. PMID- 27489152 TI - Interleukin-1beta and tumour necrosis factor-alpha levels in conjunctiva of diabetic patients with symptomatic moderate dry eye: case-control study. AB - OBJECTIVES: To compare expression of interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha in the conjunctiva of diabetic and non-diabetic patients with symptomatic moderate dry eye. SETTING AND PARTICIPANTS: Nineteen diabetic patients with dry eye, 15 non-diabetic patients with dry eye and 14 diabetic patients without dry eye were recruited. The relative expression of IL-1beta and TNF-alpha in conjunctival impression cytology (CIC) specimens was evaluated using immunofluorescent staining and in conjunctival biopsy specimens using immunohistochemical staining. RESULTS: The diabetic dry eye group showed significantly higher grades of metaplasia than the non-diabetic dry eye and diabetic without dry eye groups (both p<0.05). There was no significant difference in the concentration of IL-1beta and TNF-alpha in CIC specimens between the three groups (p=0.504 and p=0.310, respectively). The mean levels of IL-1beta and TNF-alpha in conjunctival biopsy specimens from the diabetic dry eye group was significantly increased compared with the non-diabetic dry eye and diabetic without dry eye groups (p=0.002, p<0.001; p=0.001, p<0.001, respectively). Interestingly, IL-1beta- and TNF-alpha-positive cells were mainly located in the basal layer of the conjunctival epithelium, and rarely seen in the apical conjunctival epithelium in the three groups. The levels of both IL-1beta and TNF-alpha did not correlate with conjunctival squamous metaplasia grades. CONCLUSIONS: Levels of IL-1beta and TNF-alpha in conjunctival biopsy specimens were increased in diabetic patients with dry eye, while levels of IL-1beta and TNF-alpha in apical conjunctival epithelium were similar in the CIC specimens. These findings suggest that the inflammatory response is not limited to the surface of conjunctival epithelial cells, and is more serious in the basal layer of the epithelium, which may play an important role in the pathogenesis of dry eye in diabetic patients. PMID- 27489153 TI - Effectiveness of one-to-one volunteer support for patients with psychosis: protocol of a randomised controlled trial. AB - INTRODUCTION: Social isolation is common in patients with psychosis and associated with a number of negative outcomes. Programmes in which volunteers provide one-to-one support-often referred to as befriending-have been reputed to achieve favourable outcomes. However, trial-based evidence for their effectiveness is limited. METHODS AND ANALYSIS: This is a randomised controlled trial comparing the effects of one-to-one volunteer support with an active control condition for patients with psychosis over a 1-year period. Patients in the intervention group will receive the support of a volunteer for 1 year, who will meet them weekly and engage them in social and recreational activities. Patients in the control group will not receive support from a volunteer. In both groups, patients will be given a booklet detailing locally available social activities and otherwise receive treatment as usual. Patients, volunteers, clinicians and researchers involved in the delivery of the intervention will not be blinded to group assignment, while researchers carrying out data collection will be blinded. Data collection will be conducted at baseline, at 6 and 12 months. The primary outcome is the amount of time spent engaging in social activities per day. Secondary outcomes include symptoms, quality of life, self esteem and costs of care. Attitudes of volunteers towards mentally ill people will be assessed. Finally, in-depth interviews will be conducted with patients and volunteers. ETHICS AND DISSEMINATION: The study has been approved by the National Research Ethics Service (NRES) Committee London-Camden & Kings Cross (reference 15/LO/0674). The findings of the trial will be published in open access peer-reviewed journals and in the National Institute for Health Research (NIHR) journals library, and presented at scientific conferences. In addition, findings will be summarised for a lay audience and circulated to all relevant National Health Service (NHS) and voluntary organisations. TRIAL REGISTRATION NUMBER: ISRCTN14021839; Pre-results. PMID- 27489154 TI - Bibliometric analysis of scientific publications in transplantation journals from Mainland China, Japan, South Korea and Taiwan between 2006 and 2015. AB - OBJECTIVES: The aim of this study is to compare the quantity and quality of scientific publications in transplantation fields that were written by researchers from Mainland China, Japan, South Korea and Taiwan in the East Asia region. SETTINGS: East Asia. PARTICIPANTS AND OUTCOME MEASURES: Articles except editorials, conference abstracts, letters, news and corrections published in 25 transplantation journals from 2006 to 2015 were screened with the Web of Science database. The number of total and annual articles, article types (study design and transplantation site), impact factor, citations and articles in the high impact journals was determined to assess the quantity and quality of transplantation research from East Asia. The correlation of socioeconomic factors and annual publications was also analysed. RESULTS: From 2006 to 2015, there were 47 141 articles published in transplantation journals, of which researchers from Japan published 3694 articles, followed by Mainland China, South Korea and Taiwan with 2778, 1643 and 951 articles, respectively. Similar trends were observed in accumulated impact factor, accumulated citations, articles in the high-impact journals and articles on transplantation site. Publications from Japan had the highest average impact factor and citation, while those from Mainland China had the lowest. Additionally, in terms of study design, authors from Mainland China contributed to most clinical trials and randomised controlled trials, but authors from Japan contributed to most case reports. The annual numbers of articles from Mainland China and South Korea increased linearly (p<0.05), but those from Japan and Taiwan remained stable for the period studied. The annual numbers of articles from Mainland China and South Korea were positively correlated with gross domestic product (p<0.05). CONCLUSIONS: Transplantation research productivity in East Asia is highly skewed, with gross domestic product having a significant positive correlation. Mainland China still lags far behind Japan in most bibliometric indicators; thus, there is vast room for improvement. PMID- 27489155 TI - Long-term changes in the heat-mortality relationship according to heterogeneous regional climate: a time-series study in South Korea. AB - OBJECTIVES: Several studies identified a heterogeneous impact of heat on mortality in hot and cool regions during a fixed period, whereas less evidence is available for changes in risk over time due to climate change in these regions. We compared changes in risk during periods without (1996-2000) and with (2008 2012) heatwave warning forecasts in regions of South Korea with different climates. METHODS: Study areas were categorised into 3 clusters based on the spatial clustering of cooling degree days in the period 1993-2012: hottest cluster (cluster H), moderate cluster (cluster M) and cool cluster (cluster C). The risk was estimated according to increases in the daily all-cause, cardiovascular and respiratory mortality per 1 degrees C change in daily temperature above the threshold, using a generalised additive model. RESULTS: The risk of all types of mortality increased in cluster H in 2008-2012, compared with 1996-2000, whereas the risks in all-combined regions and cooler clusters decreased. Temporal increases in mortality risk were larger for some vulnerable subgroups, including younger adults (<75 years), those with a lower education and blue-collar workers, in cluster H as well as all-combined regions. Different patterns of risk change among clusters might be attributable to large increases in heatwave frequency or duration during study periods and the degree of urbanisation in cluster H. CONCLUSIONS: People living in hotter regions or with a lower socioeconomic status are at higher risk following an increasing trend of heat-related mortality risks. Continuous efforts are needed to understand factors which affect changes in heat-related mortality risks. PMID- 27489156 TI - Does a mandibular overdenture improve nutrient intake and markers of nutritional status better than conventional complete denture? A systematic review and meta analysis. AB - OBJECTIVES: The need for denture treatment in public health will increase as the population ages. However, the impact of dentures on nutrition, particularly overdenture treatment, remains unclear although the physical and psychological effects are known. We investigated whether treatment with a mandibular implant supported overdenture improves nutrient intake and markers of nutritional status better than a conventional complete denture in edentulous patients. DESIGN: Systematic review and meta-analysis. METHODS: Medline, EMBASE and the Cochrane Central Register of Controlled Trials were searched for eligible studies published up to April 2016. We included studies which compared the treatment effect of an overdenture to conventional denture on nutrition, in which primary outcomes included changes in intake of macronutrients and/or micronutrients and/or indicators of nutritional status. Two reviewers independently evaluated eligible studies and assessed the risk of bias. We used a fixed effects model to estimate the weighted mean difference (WMD) and 95% CI for change in body mass index (BMI), albumin and serum vitamin B12 between overdenture and conventional denture 6 months after treatment. RESULTS: Of 108 eligible studies, 8 studies involving 901 participants were included in the narrative appraisal. Four studies reported changes in markers of nutritional status and nutrient intake after treatment with a prosthetic, regardless of type. In a meta-analysis of 322 participants aged 65 years or older from three studies, pooled analysis suggested no significant difference in change in BMI between an overdenture and conventional denture 6 months after treatment (WMD=-0.18 kg/m(2) (95% CI -0.52 to 0.16)), and no significant difference in change in albumin or vitamin B12 between the two treatments. CONCLUSIONS: The modifying effect of overdenture treatment on nutritional status might be limited. Further studies are needed to evaluate the effectiveness and efficacy of denture treatments. PMID- 27489157 TI - Live cumulative network meta-analysis: protocol for second-line treatments in advanced non-small-cell lung cancer with wild-type or unknown status for epidermal growth factor receptor. AB - INTRODUCTION: Many second-line treatments for advanced non-small-cell lung cancer (NSCLC) have been assessed in randomised controlled trials, but which treatments work the best remains unclear. Novel treatments are being rapidly developed. We need a comprehensive up-to-date evidence synthesis of all these treatments. We present the protocol for a live cumulative network meta-analysis (NMA) to address this need. METHODS AND ANALYSIS: We will consider trials of second-line treatments in patients with advanced NSCLC with wild-type or unknown epidermal growth factor receptor status. We will consider any single agent of cytotoxic chemotherapy, targeted therapy, combination of cytotoxic chemotherapy and targeted therapy and any combination of targeted therapies. The primary outcomes will be overall survival and progression-free survival. The live cumulative NMA will be initiated with a NMA and then iterations will be repeated at regular intervals to keep the NMA up-to-date over time. We have defined the update frequency as 4 months, based on an assessment of the pace of evidence production on this topic. Each iteration will consist of six methodological steps: adaptive search for treatments and trials, screening of reports and selection of trials, data extraction, assessment of risk of bias, update of the network of trials and synthesis, and dissemination. We will set up a research community in lung cancer, with different groups of contributors of different skills. We will distribute tasks through online crowdsourcing. This proof-of-concept study in second-line treatments of advanced NSCLC will allow one for assessing the feasibility of live cumulative NMA and opening the path for this new form of synthesis. ETHICS AND DISSEMINATION: Ethical approval is not required because our study will not include confidential participant data and interventions. The description of all the steps and the results of this live cumulative NMA will be available online. TRIAL REGISTRATION NUMBER: CRD42015017592. PMID- 27489158 TI - Venous thromboembolism in medical patients during hospitalisation and 3 months after hospitalisation: a prospective observational study. AB - OBJECTIVES: This study was conducted to assess the incidence and risk factors for venous thromboembolism (VTE) in a cohort of medical patients both during the period of hospitalisation and following discharge. DESIGN: This was a prospective observational study to document the risk profile and incidence of VTE posthospitalisation among all medical patients admitted to our institution during the trial period. SETTINGS: Primary healthcare. Single tertiary referral centre, Tasmania, Australia. PARTICIPANTS: A total of 986 patients admitted to the medical ward between January 2012 and September 2012 were included in the study with male to female ratio of 497:489. The mean age of patients was 68 years (range 17-112, SD 16). RESULTS: Overall, 54/986 patients (5.5%) had a VTE during the study period. Of these, 40/54 (74.1%) occurred during hospitalisation and 14/54 (25.9%) occurred following discharge. VTE risk factors revealed in multivariate analysis to be associated with a previous diagnosis of VTE (p<0.001, OR=6.63, 95% CI 3.3 to 13.36), the occurrence of surgery within the past 30 days (p<0.001, OR=2.52, 95% CI 1.33 to 4.79) and an admission diagnosis of pulmonary disease (p<0.01, OR 3.61, 95% CI 1.49 to 8.76). Mobility within 24 hours of admission was not associated with an increased risk. There was risk of VTE when the length of stay prolonged (p=0.046, OR=1.01, 95% CI 1.00 to 1.03), however it was not sustained with multivariate modelling. VTE-specific prophylaxis was used in 53% of the studied patients. Anticoagulation including antiplatelet agents were administered in 63% of patients who developed VTE. CONCLUSIONS: This prospective observational study found that 5.5% of the studied patients developed VTE. Among those, 25.9% (14/54) of patients had a detected VTE posthospitalisation with this risk being increased if there was a history of VTE, recent surgery and pulmonary conditions. Thromboprophylaxis may be worth considering in these cohorts. Further study to confirm these findings are warranted. TRIAL REGISTRATION NUMBER: ACTRN12611001255976. PMID- 27489159 TI - Protocol of the PLeural Effusion And Symptom Evaluation (PLEASE) study on the pathophysiology of breathlessness in patients with symptomatic pleural effusions. AB - INTRODUCTION: Pleural effusion is a common clinical problem that can complicate many medical conditions. Breathlessness is the most common symptom of pleural effusion of any cause and the most common reason for pleural drainage. However, improvement in breathlessness following drainage of an effusion is variable; some patients experience either no benefit or a worsening of their breathlessness. The physiological mechanisms underlying breathlessness in patients with a pleural effusion are unclear and likely to be multifactorial with patient-related and effusion-related factors contributing. A comprehensive study of the physiological and symptom responses to drainage of pleural effusions may provide a clearer understanding of these mechanisms, and may identify predictors of benefit from drainage. The ability to identify those patients whose breathlessness will (or will not) improve after pleural fluid drainage can help avoid unnecessary pleural drainage procedures, their associated morbidities and costs. The PLeural Effusion And Symptom Evaluation (PLEASE) study is a prospective study to comprehensively evaluate factors contributing to pleural effusion-related breathlessness. METHODS AND ANALYSIS: The PLEASE study is a single-centre prospective study of 150 patients with symptomatic pleural effusions that require therapeutic drainage. The study aims to identify key factors that underlie breathlessness in patients with pleural effusions and develop predictors of improvement in breathlessness following effusion drainage. Participants will undergo evaluation pre-effusion and post-effusion drainage to assess their level of breathlessness at rest and during exercise, respiratory and other physiological responses as well as respiratory muscle mechanics. Pre-drainage and post-drainage parameters will be collected and compared to identify the key factors and mechanisms that correlate with improvement in breathlessness. ETHICS AND DISSEMINATION: Approved by the Sir Charles Gairdner Group Human Research Ethics Committee (HREC number 2014-079). Registered with the Australian New Zealand Clinical Trials Registry (ACTRN12616000820404). Results will be published in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: ACTRN12616000820404; Pre-results. PMID- 27489160 TI - Are inter- and intraspecific variations of sapling crown traits consistent with a strategy promoting light capture in tropical moist forest? AB - BACKGROUND AND AIMS: Morphological variation in light-foraging strategies potentially plays important roles in efficient light utilization and carbon assimilation in spatially and temporally heterogeneous environments such as tropical moist forest understorey. By considering a suite of morphological traits at various hierarchical scales, we examined the functional significance of crown shape diversity and plasticity in response to canopy openness. METHODS: We conducted a field comparative study in French Guiana among tree saplings of 14 co occurring species differing in light-niche optimum and breadth. Each leaf, axis or crown functional trait was characterized by a median value and a degree of plasticity expressed under contrasting light regimes. KEY RESULTS: We found divergent patterns between shade-tolerant and heliophilic species on the one hand and between shade and sun plants on the other. Across species, multiple regression analysis showed that relative crown depth was positively correlated with leaf lifespan and not correlated with crown vertical growth rate. Within species displaying a reduction in crown depth in the shade, we observed that crown depth was limited by reduced crown vertical growth rate and not by accelerated leaf or branch shedding. In addition, the study provides contrasting examples of morphological multilevel plastic responses, which allow the maintenance of efficient foliage and enable effective whole-plant light capture in shaded conditions under a moderate vertical light gradient. CONCLUSIONS: This result suggests that plastic adjustment of relative crown depth does not reflect a strategy maximizing light capture efficiency. Integrating and scaling-up leaf level dynamics to shoot- and crown-level helps to interpret in functional and adaptive terms inter- and intraspecific patterns of crown traits and to better understand the mechanism of shade tolerance. PMID- 27489161 TI - The moss Funaria hygrometrica has cuticular wax similar to vascular plants, with distinct composition on leafy gametophyte, calyptra and sporophyte capsule surfaces. AB - BACKGROUND AND AIMS: Aerial surfaces of land plants are covered with a waxy cuticle to protect against water loss. The amount and composition of cuticular waxes on moss surfaces had rarely been investigated. Accordingly, the degree of similarity between moss and vascular plant waxes, and between maternal and offspring moss structure waxes is unknown. To resolve these issues, this study aimed at providing a comprehensive analysis of the waxes on the leafy gametophyte, gametophyte calyptra and sporophyte capsule of the moss Funaria hygrometrica METHODS: Waxes were extracted from the surfaces of leafy gametophytes, gametophyte calyptrae and sporophyte capsules, separated by gas chromatography, identified qualitatively with mass spectrometry, and quantified with flame ionization detection. Diagnostic mass spectral peaks were used to determine the isomer composition of wax esters. KEY RESULTS: The surfaces of the leafy gametophyte, calyptra and sporophyte capsule of F. hygrometrica were covered with 0.94, 2.0 and 0.44 MUg cm(-2) wax, respectively. While each wax mixture was composed of mainly fatty acid alkyl esters, the waxes from maternal and offspring structures had unique compositional markers. beta-Hydroxy fatty acid alkyl esters were limited to the leafy gametophyte and calyptra, while alkanes, aldehydes and diol esters were restricted to the sporophyte capsule. Ubiquitous fatty acids, alcohols, fatty acid alkyl esters, aldehydes and alkanes were all found on at least one surface. CONCLUSIONS: This is the first study to determine wax coverage (MUg cm(-2)) on a moss surface, enabling direct comparisons with vascular plants, which were shown to have an equal amount or more wax than F. hygrometrica Wax ester biosynthesis is of particular importance in this species, and the ester-forming enzyme(s) in different parts of the moss may have different substrate preferences. Furthermore, the alkane-forming wax biosynthesis pathway, found widely in vascular plants, is active in the sporophyte capsule, but not in the leafy gametophyte or calyptra. Overall, wax composition and coverage on F. hygrometrica were similar to those reported for some vascular plant species, suggesting that the underlying biosynthetic processes in plants of both lineages were inherited from a common ancestor. PMID- 27489162 TI - Small-Molecule Compounds Exhibiting Target-Mediated Drug Disposition (TMDD): A Minireview. AB - Nonlinearities are commonplace in pharmacokinetics, and 1 special source is the saturable binding of the drug to a high-affinity, low-capacity target, a phenomenon known as target-mediated drug disposition (TMDD). Compared with large molecule compounds undergoing TMDD, which has been well recognized due to its high prevalence, TMDD in small-molecule compounds is more counterintuitive and has not been well appreciated. With more and more potent small-molecule drugs acting on highly specific targets being developed as well as increasingly sensitive analytical techniques becoming available, many small-molecule compounds have recently been reported to have nonlinear pharmacokinetics imparted by TMDD. To expand our current knowledge of TMDD in small-molecule compounds and increase the awareness of this clinically important phenomenon, this minireview provides an overview of the small-molecule compounds that demonstrate nonlinear pharmacokinetics imparted by TMDD. The present review also summarizes the general features of TMDD in small-molecule compounds and highlights the differences between TMDD in small-molecule compounds and large-molecule compounds. PMID- 27489163 TI - Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up regulation of miR-30b and miR-378. AB - Emerging evidence suggests that n-3 polyunsaturated fatty acids (PUFA) promote brown adipose tissue thermogenesis. However, the underlying mechanisms remain elusive. Here, we hypothesize that n-3 PUFA promotes brown adipogenesis by modulating miRNAs. To test this hypothesis, murine brown preadipocytes were induced to differentiate the fatty acids of palmitic, oleate, or eicosapentaenoic acid (EPA). The increases of brown-specific signature genes and oxygen consumption rate by EPA were concurrent with up-regulation of miR-30b and 378 but not by oleate or palmitic acid. Next, we hypothesize that free fatty acid receptor 4 (Ffar4), a functional receptor for n-3 PUFA, modulates miR-30b and 378. Treatment of Ffar4 agonist (GW9508) recapitulated the thermogenic activation of EPA by increasing oxygen consumption rate, brown-specific marker genes, and miR-30b and 378, which were abrogated in Ffar4-silenced cells. Intriguingly, addition of the miR-30b mimic was unable to restore EPA-induced Ucp1 expression in Ffar4-depleted cells, implicating that Ffar4 signaling activity is required for up-regulating the brown adipogenic program. Moreover, blockage of miR-30b or 378 by locked nucleic acid inhibitors significantly attenuated Ffar4 as well as brown-specific signature gene expression, suggesting the signaling interplay between Ffar4 and miR-30b/378. The association between miR-30b/378 and brown thermogenesis was also confirmed in fish oil-fed C57/BL6 mice. Interestingly, the Ffar4 agonism-mediated signaling axis of Ffar4-miR-30b/378-Ucp1 was linked with an elevation of cAMP in brown adipocytes, similar to cold-exposed or fish oil-fed brown fat. Taken together, our work identifies a novel function of Ffar4 in modulating brown adipogenesis partly through a mechanism involving cAMP activation and up-regulation of miR-30b and miR-378. PMID- 27489164 TI - Soluble egg antigens of Schistosoma japonicum induce senescence in activated hepatic stellate cells by activation of the STAT3/p53/p21 pathway. AB - Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs). Recent findings suggest that senescence of activated HSCs might limit the development of liver fibrosis. Based on previously observed anti-fibrotic effects of soluble egg antigens from Schistosoma japonicum in vitro, we hypothesized that SEA might play a crucial role in alleviating liver fibrosis through promoting senescence of activated HSCs. We show here that SEA inhibited expression of alpha SMA and pro-collagen I and promoted senescence of activated HSCs in vitro. In addition, SEA induced an increased expression of P-p53 and p21. Knockdown of p53 inhibited the expression of p21 and failed to induce senescence of activated HSCs. Phosphorylated STAT3 was elevated upon SEA stimulation, while loss of STAT3 decreased the level of p53 and senescence of HSCs. Results from immunoprecipitation analysis demonstrated that SOCS3 might be involved in the SEA induced senescence in HSCs through its interaction with p53. This study demonstrates the potential capacity of SEA in restricting liver fibrosis through promoting senescence in HSCs. Furthermore, a novel STAT3-p53-p21 pathway might participate in the observed SEA-mediated senescence of HSCs. Our results suggest that SEA might carry potential therapeutic effects of restraining liver fibrosis through promoting senescence. PMID- 27489165 TI - Pipeline Embolization Device for Small Intracranial Aneurysms: Evaluation of Safety and Efficacy in a Multicenter Cohort. AB - BACKGROUND: To date, the use of the flow-diverting Pipeline Embolization Device (PED) for small intracranial aneurysms (<= 7 mm) has been reported only in single center series. OBJECTIVE: To evaluate the safety and efficacy of the PED in a multicenter cohort. METHODS: Five major academic institutions in the United States provided data on patient demographics, aneurysm features, and treatment characteristics of consecutive patients with aneurysms <= 7 mm treated with a PED between 2009 and 2015. Radiographic outcome was assessed with digital subtraction angiography. Clinical outcome was measured with the modified Rankin Scale. RESULTS: The cumulative number of aneurysms <= 7 mm treated with PED at the 5 institutions was 149 in 117 patients (age, 54 years [range, 29-87 years]; male to female, 1-5.9). Aneurysms were most commonly located in the paraophthalmic segment (67.1%) of the internal carotid artery. Radiographic outcome at last follow-up was available for 123 aneurysms (82.6%), with a complete occlusion rate of 87%. Thromboembolic and symptomatic procedural complications occurred in 8.7% and 6% of the aneurysms treated, respectively. There was 1 mortality (0.9%) unrelated to the PED procedure. Multivariable logistic regression identified size < 4 mm, balloon angioplasty to open the device, and simultaneous treatment of multiple aneurysms as predictors of procedural complications. Good clinical outcome was achieved in 96% of electively treated patients. CONCLUSION: In the largest series on PED for small aneurysms to date, data suggest that treatment with the flow-diverting PED is safe and efficacious, with complication rates comparable to those for traditional endovascular techniques. PMID- 27489166 TI - Syndrome of the Trephined: A Systematic Review. AB - BACKGROUND: Syndrome of the trephined (SoT) is a rare, important complication of a craniectomy characterized by neurological dysfunction that improves with cranioplasty. Its varied symptoms include motor, cognitive, and language deficits. Its exact characterization appears suboptimal, with differing approaches of evaluation. Accordingly, this topic is in great need of further investigation. OBJECTIVE: To accurately describe SoT and explore methods of an objective diagnosis/evaluation. METHODS: Electronic searches of PubMed, MEDLINE, Web of Knowledge, and PsycINFO databases used the key words "syndrome of the trephined" and "sinking skin flap." Non-English-language and duplicate articles were eliminated. Title and abstract reviews were selected for relevance. Full text reviews were selected for articles providing individual characteristics of SoT patients. RESULTS: This review identified that SoT most often occurs in male patients (60%) at 5.1 +/- 10.8 months after craniectomy for neurotrauma (38%). The average reported craniectomy is 88.3 +/- 34.4 cm and usually exists with a "sunken skin flap" (93%). Symptoms most commonly include motor, cognitive, and language deficits (57%, 41%, 28%, respectively), with improvement after cranioplasty within 3.8 +/- 3.9 days. Functional independence with activities of daily living is achieved by 54.9% of patients after 2.9 +/- 3.4 months of rehabilitation. However, evaluation of SoT is inconsistent, with only 53% of reports documenting objective studies. DISCUSSION: SoT is a variable phenomenon associated with a prolonged time to cranioplasty. Due to current weaknesses in objectivity, we hypothesize that SoT is often underdiagnosed and recommend a multifaceted approach for consistent evaluation. CONCLUSION: SoT is a serious complication that lacks exact characterization and deserves future investigation. Improved understanding and recognition have important implications for early intervention and patient outcomes. ABBREVIATIONS: ADLs, activities of daily livingCBF, cerebral blood flowSoT, syndrome of the trephinedVP, ventriculoperitoneal. PMID- 27489167 TI - Identification and Cost of Potentially Avoidable Transfers to a Tertiary Care Neurosurgery Service: A Pilot Study. AB - BACKGROUND: Thousands of neurosurgical emergencies are transferred yearly to tertiary care facilities to assume a higher level of care. Several studies have examined how neurosurgical transfers influence patient outcomes, but characteristics of potentially avoidable transfers have yet to be investigated. OBJECTIVE: To identify whether potentially avoidable transfers represent a significant portion of transfers to a tertiary neurosurgical facility. METHODS: In this cohort study, we evaluated 916 neurosurgical patients transferred to a tertiary care facility over a 2-year period. Transfers were classified as potentially avoidable when no neurosurgical diagnostic test, intervention, or intensive monitoring was deemed necessary (n = 180). The remaining transfers were classified as justifiable (n = 736). The main outcomes and measures were age, sex, diagnosis, insurance status, intervention, distance of transfer, length of hospital and intensive care unit stay, mortality, discharge disposition, and cost. RESULTS: Nearly 20% of transfers were identified as being potentially avoidable. Although some of these patients had suffered devastating, irrecoverable neurological insults, many had innocuous conditions that did not require transfer to a higher level of care. Justifiable transfers tend to involve patients with nontraumatic intracranial hemorrhage and cranial neoplasm. Both groups were admitted to the intensive care unit at the same rate (approximately 70% of patients). Finally, the direct transportation cost of potentially avoidable transfers was $1.46 million over 2 years. CONCLUSION: This study identified the frequency and expense of potentially avoidable transfers. There is a need for closer examination of the clinical and financial implications of potentially avoidable transfers. ABBREVIATIONS: CI, confidence intervalIQR, interquartile rangeJT, justifiable transferOR, odds ratioPAT, potentially avoidable transferUAB, University of Alabama at Birmingham. PMID- 27489168 TI - Inappropriate behaviors and hypersexuality in individuals with dementia: An overview of a neglected issue. AB - Behavioral and psychological symptoms of dementia are very common in patients affected by dementia, and are associated with high rates of institutionalization. Behavioral and psychological symptoms of dementia consist of aggressive behavior, delusions, hallucinations, depression, apathy, wandering, stereotyped and inappropriate sexual behavior. Interestingly, the latter has been reported to be relatively uncommon, but causing immense distress to patients and their caregivers. The genesis of inappropriate behavior is considered a combination of neurological, psychological and social factors. Although assessment is mainly carried out by clinical observation and interviews with caregivers, the most appropriate management of behavioral and psychological symptoms of dementia, including hypersexuality, is a combination of pharmacological and non pharmacological interventions, according to specific symptoms, degree of cognitive dysfunction and subtype of dementia. The present narrative review will mainly focus on aggressiveness, disinhibition, aberrant motor, and sexually inappropriate behavior diagnostic work-up and treatment, in an attempt to provide both the patients and their caregivers with useful information to better manage these symptoms and improve their quality of life. Space is particularly dedicated to inappropriate sexual behavior, which is still considered a neglected issue. Geriatr Gerontol Int 2017; 17: 865-874. PMID- 27489169 TI - Testosterone for Poor Ovarian Responders: Lessons From Ovarian Physiology. AB - Testosterone, an androgen that directly binds to the androgen receptor, has been shown in previous small randomized controlled trials to increase the reproductive outcomes of poor ovarian responders. In most of these studies, transdermal testosterone in relatively high doses was administered before ovarian stimulation with a duration varying from 5 to 21 days. Nevertheless, the key question to be asked is whether, based on ovarian physiology and testosterone pharmacokinetics, a short course of testosterone administration of more than 10 mg could be expected to have any beneficial effect on reproductive outcome. The rationale for asking this question lies in the existing scientific evidence derived from basic research and animal studies regarding the action of androgens during folliculogenesis, showing that their main effect in follicular development is defined during the earlier developmental stages. In addition, extreme testosterone excess is not only likely to induce adverse events but has also the potential to be ineffective and even detrimental. Thus, evidence from clinical studies is not enough to either "reopen" or "close" the "androgen chapter" in poor responders, mainly because the short administration and the high dose of testosterone is not in line with the ovarian actions of androgens and the presence of androgen receptors during follicular development. PMID- 27489170 TI - Using the placebo effect: how expectations and learned immune function can optimize dermatological treatments. AB - The role of placebo and nocebo effects-that is positive or negative treatment effects that are entirely a consequence of the patient's expectations and beliefs about a treatment outcome in terms of efficacy, safety, usability or side effects has been shown for almost all types of diseases and physiological response systems. Evidence for the relevance of placebo and nocebo effects in dermatology is also increasing, particularly for symptoms of itch and learned (conditioned) immune function. In addition, increasing knowledge is available about the neurobiological mechanisms of action, such as the role of the dopaminergic system. Studies on this topic offer innovative perspectives to unravel the multifactorial pathways of treatment effects and to use research designs for experimental research that provide full insight into the role of placebo and nocebo effects. Moreover, intervention strategies can be developed for dermatology practice that optimize regular treatments with innovative non pharmacological treatment strategies (e.g. optimized doctor-patient communication and treatment adherence, or prevention of nocebo reactions with regard to adverse side effects). In addition, evidence on learned immune function offers new pathways to optimize pharmacological treatments (e.g. dosage adjustments and conditioning of physiological responses), the ultimate goal being to prevent individual treatment failures and maximize regular treatment effects. PMID- 27489171 TI - 'I didn't see that coming': simulated visual fields and driving hazard perception test performance. AB - BACKGROUND: Evidence is limited regarding specific types of visual field loss associated with unsafe driving. We use novel gaze-contingent software to examine the effect of simulated visual field loss on computer-based driving hazard detection with the specific aim of testing the impact of scotomata located to the right and left of fixation. METHODS: The 'hazard perception test' is a component of the UK driving licence examination, which measures speed of detecting 15 different hazards in a series of real-life driving films. We have developed a novel eye-tracking and computer set up capable of generating a realistic gaze contingent scotoma simulation (GazeSS) overlaid on film content. Thirty drivers with healthy vision completed three versions of the hazard perception test in a repeated measures experiment. In two versions, GazeSS simulated a scotoma in the binocular field of view to the left or right of fixation. A third version was unmodified to establish baseline performance. RESULTS: Participants' mean baseline hazard perception test score was 51 +/- 7 (out of 75). This reduced to 46 +/- 9 and 46 +/- 11 when completing the task with a binocular visual field defect located to the left and right of fixation, respectively. While the main effect of simulated visual field loss on performance was statistically significant (p = 0.007), there were no average differences in the experimental conditions where a scotoma was located in the binocular visual field to the right or left of fixation. CONCLUSION: Simulated visual field loss impairs driving hazard detection on a computer-based test. There was no statistically significant difference in average performance when the simulated scotoma was located to the right or left of fixation of the binocular visual field, but certain types of hazard caused more difficulties than others. PMID- 27489172 TI - On the positional and orientational order of water and methanol around indole: a study on the microscopic origin of solubility. AB - Although they are both highly polar liquids, there are a number of compounds, such as many pharmaceuticals, which show vastly different solubilities in methanol compared with water. From theories of the hydrophobic effect, it might be predicted that this enhanced solubility is due to association between drugs and the less polar -CH3 groups on methanol. In this work, detailed analysis on the atomic structural interactions between water, methanol and the small molecule indole - which is a precursor to many drugs and is sparingly soluble in water yet highly soluble in methanol - reveal that indole preferentially interacts with both water and methanol via electrostatic interactions rather than with direction interactions to the -CH3 groups. The presence of methanol hydrogen bonds with pi electrons of the benzene ring of indole can explain the increase in solubility of indole in methanol relative to water. In addition, the excess entropy calculations performed here suggest that this solvation is enthalpically rather than entropically driven. PMID- 27489173 TI - A Non-Exploding Alkali Metal Drop on Water: From Blue Solvated Electrons to Bursting Molten Hydroxide. AB - Alkali metals in water are always at the brink of explosion. Herein, we show that this vigorous reaction can be kept in a non-exploding regime, revealing a fascinating richness of hitherto unexplored chemical processes. A combination of high-speed camera imaging and visible/near-infrared/infrared spectroscopy allowed us to catch and characterize the system at each stage of the reaction. After gently placing a drop of a sodium/potassium alloy on water under an inert atmosphere, the production of solvated electrons became so strong that their characteristic blue color could be observed with the naked eye. The exoergic reaction leading to the formation of hydrogen and hydroxide eventually heated the alkali metal drop such that it became glowing red, and part of the metal evaporated. As a result of the reaction, a perfectly transparent drop consisting of molten hydroxide was temporarily stabilized on water through the Leidenfrost effect, bursting spectacularly after it had cooled sufficiently. PMID- 27489174 TI - HDL subfractions and very early CAD: novel findings from untreated patients in a Chinese cohort. AB - Coronary artery disease (CAD) in very young individuals is a rare disease associated with poor prognosis. However, the role of specific lipoprotein subfractions in very young CAD patients (<=45 years) is not established yet. A total of 734 consecutive CAD subjects were enrolled and were classified as very early (n = 81, <=45), early (n = 304, male: 45-55; female: 45-65), and late (n = 349, male: >55; female: >65) groups. Meanwhile, a group of non-CAD subjects were also enrolled as controls (n = 56, <=45). The lipoprotein separation was performed using Lipoprint System. As a result, the very early CAD patients have lower large high-density lipoprotein (HDL) subfraction and higher small low density lipoprotein (LDL) subfraction (p < 0.05). Although body mass index was inversely related to large HDL subfraction, overweight did not influence its association with very early CAD. In the logistic regression analysis, large HDL was inversely [OR 95% CI: 0.872 (0.825-0.922)] while small LDL was positively [1.038 (1.008-1.069)] related to very early CAD. However, after adjusting potential confounders, the association was only significant for large HDL [0.899 (0.848-0.954)]. This study firstly demonstrated that large HDL subfraction was negatively related to very early CAD suggestive of its important role in very early CAD incidence. PMID- 27489175 TI - The MEEK technique: 10-year experience at a tertiary burn centre. AB - Extensive full-thickness burns pose a great challenge to the burn surgeon. Lack of autograft donor sites is an important limiting factor to achieving wound closure. To overcome this problem, various methods of treatment have been suggested in the past, including the MEEK technique. This study was carried out at the Bogenhausen Hospital Burn Unit, Munich, Germany from 2006 to 2015. There were a total of 148 skin grafting operations. The modified MEEK technique was performed on 67 patients. Patients included 34 males and 33 females, with an average age of 39.6 years. The mean percentage body surface burned was 65%, and full-thickness injury occurred in 52%. The mean area graft per procedure was 20%. The viability of the graft as assessed between the 7th and 10th day was generally in the range of 60-90%. The average number of operations required was 2.21. The mean length of stay was 27 days. Infection was documented in five patients, and seven deaths occurred. The mean follow-up was 3.2 years. When faced with large surface area burns and limited donor sites, the MEEK technique is a satisfactory method for coverage. PMID- 27489176 TI - Crucial Role Reported for TSPO in Viability and Steroidogenesis is a Misconception. Commentary: Conditional Steroidogenic Cell-Targeted Deletion of TSPO Unveils a Crucial Role in Viability and Hormone-Dependent Steroid Formation. PMID- 27489177 TI - Both monovalent cations and plectin are potent modulators of mechanical properties of keratin K8/K18 networks. AB - Intermediate filament (IF) networks are a major contributor to cell rigidity and thus serve as vital elements to preserve the integrity of entire cell layers. Keratin K8 and K18 IFs are the basic constituents of the cytoskeleton of epithelial cells. The mechanical properties of K8/K18 networks depend on the structural arrangements of individual filaments within the network. This paper investigates the architecture of these networks in vitro under the influence of the monovalent cation potassium and that of the cytolinker protein plectin. Whereas increasing amounts of potassium ions lead to filament bundling, plectin interlinks filaments at filament intersection points but does not lead to bundle formation. The mechanics of the resulting networks are investigated by microrheology with assembled K8/K18 networks. It is shown that bundling induced by potassium ions significantly stiffens the network. Furthermore, our measurements reveal an increase in plectin-mediated keratin network rigidity as soon as an amount corresponding to more than 20% of the plectin present in cells is added to the keratin IF networks. In parallel, we investigated the influence of plectin on cell rigidity in detergent-extracted epithelial vulva carcinoma derived A431 cells in situ. These cytoskeletons, containing mostly IFs, actin filaments and associated proteins, exhibit a significantly decreased stiffness, when plectin is downregulated to ~10% of the normal value. Therefore, we assume that plectin, via the formation of IF-IF connections and crosslinking of IFs to actin filaments, is an important contributor to cell stiffness. PMID- 27489178 TI - Acute migraine medication adherence, migraine disability and patient satisfaction: A naturalistic daily diary study. AB - Objective To examine the influence of acute migraine medication adherence on migraine disability and acute medication satisfaction. Methods Adults with migraine completed three months of daily electronic diaries assessing headache symptoms, acute medication taken, acute medication satisfaction, and daily migraine disability. Repeated measures mixed-effects models examined the effect of initial medication type [migraine-specific medication (MSM) vs. over-the counter analgesic (OTC) vs. an opiate/barbiturate], the severity of pain at dosing, and their interaction with daily migraine disability and satisfaction with acute medication. Results Participants (N = 337; 92.5% female; 91.1% Caucasian, non-Hispanic; 84.0% with episodic migraine) recorded 29,722 diary days. Participants took acute medication on 96.5% of 8090 migraine days. MSM was most frequently taken first (58%), followed by OTC (29.9%) and an opiate/barbiturate (12.1%). Acute medication was most frequently taken when pain was mild (41.2%), followed by moderate (37.7%) and severe pain (11.4%). Initially dosing with MSM while pain was mild was associated with the lowest daily disability [medication * pain at dosing F (4, 6336.12) = 58.73, p < .001] and highest acute medication satisfaction [medication * pain at dosing F (4, 3867.36) = 24.00, p < .001]. Conclusion Using an MSM (triptan or ergot) first was associated with the lowest migraine disability and highest acute medication satisfaction. PMID- 27489179 TI - A boy with bilateral SUNA: A case report. AB - Background Short-lasting unilateral neuralgiform headache attacks (SUNA) is a primary headache characterized by frequent attacks of severe headaches in association with ipsilateral cranial autonomic features. SUNA is defined as a strictly unilateral pain and bilateral cases are very unusual, so secondary causes should be searched for vigorously if there are bilateral symptoms. Despite a number of therapeutic trials, effective management for the majority of SUNA patients is not available at present. Management of SUNA is often difficult. Case We report the case of a young boy with bilateral SUNA attacks, with no detected underlying cause, who is responsive to indomethacin. Conclusion Rarely, primary SUNA can present with bilateral symptoms. According to our experience in this case, indomethacin should always be offered to patients with suspected SUNA. PMID- 27489180 TI - Oliver Sacks and migraine. AB - Background Oliver Sacks (1933-2015) published a large number of books on a variety of neurological topics. Of these, numerous copies have been sold and they probably serve as the only or main source of information on neurological diseases for many persons without a medical background. His first book was on migraine and in his subsequent books many descriptions of migraine can be found, mainly those of auras. Methods We explored the descriptions of migraine in Sacks' work in order to evaluate the image of migraine offered to the readers. Conclusion Oliver Sacks gave wonderful descriptions of migraine auras, but hardly any of migraine headache. Furthermore, he described rare auras such as 'amusia' and olfactory auras. Overall, this makes his descriptions of migraine not very useful to serve as medical information for laypersons. Oliver Sacks, however, wrote great literature. PMID- 27489181 TI - Hyperargininemia and renal oxidative stress: Prevention by antioxidants and NG nitro-l-arginine methyl ester. AB - We investigated the in vitro and in vivo effects of arginine (Arg) on thiobarbituric acid-reactive substances (TBA-RS) and on the activities of catalase (CAT), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) in renal tissues of rats. We also studied the influence of antioxidants (alpha tocopherol plus ascorbic acid) and nitric oxide synthase inhibitor NG -nitro-l arginine methyl ester (l-NAME) on the effects elicited by Arg. Results showed that Arg in vitro (1.5 mM) decreased SOD activity and increased the levels of TBA RS in the renal medulla. Acute administration of Arg [0.8 g/kg, intraperitoneal injection] decreased CAT activity, increased SOD activity and TBA-RS levels in the renal medulla, and decreased CAT activity in the renal cortex of rats. Most results were prevented by antioxidants and/or l-NAME. Data indicate that Arg causes an oxidative imbalance in the renal tissues studied; however, in the presence of antioxidants and l-NAME, some of these alterations in oxidative stress were prevented. PMID- 27489182 TI - What can we learn about breathlessness from population-based and administrative health data? AB - PURPOSE OF REVIEW: To review the findings and methodological strengths and limitations of studies of breathlessness using population-based or routinely collected data, including the novel methodology of the registry-based randomized controlled trial (R-RCT). RECENT FINDINGS: Breathlessness severe enough to restrict activity is common and increases in the last months of life both among elderly in the community and among patients in specialized palliative care. During the last week of life, risk factors for more severe breathlessness have been identified. Patients with advanced chronic obstructive or interstitial lung disease experience more breathlessness than patients dying from lung cancer. Breathlessness often remains unrelieved or only partially relieved at the end of life. SUMMARY: Data from population-based or health-administrative databases can inform on the epidemiology, associated factors and the potential impact of breathlessness. Potential strengths of these data are high precision and generalizability because of large, nonselective study populations with high completeness of follow-up of outcomes such as survival. Potential limitations include residual confounding and insufficient data quality which is unaffected by increasing the sample size. The R-RCT methodology combines strengths of randomization with those of large representative databases to evaluate effectiveness in clinical care. PMID- 27489183 TI - The evolving role of chemotherapy in prostate cancer. PMID- 27489185 TI - The DnaA inhibitor SirA acts in the same pathway as Soj (ParA) to facilitate oriC segregation during Bacillus subtilis sporulation. AB - DNA replication and chromosome segregation must be carefully regulated to ensure reproductive success. During Bacillus subtilis sporulation, chromosome copy number is reduced to two, and cells divide asymmetrically to produce the future spore (forespore) compartment. For successful sporulation, oriC must be captured in the forespore. New rounds of DNA replication are prevented in part by SirA, a protein that utilizes residues in its N-terminus to directly target Domain I of the bacterial initiator, DnaA. Using a quantitative forespore chromosome organization assay, we show that SirA also acts in the same pathway as another DnaA regulator, Soj, to promote oriC capture in the forespore. By analyzing loss of-function variants of both SirA and DnaA, we observe that SirA's ability to inhibit DNA replication can be genetically separated from its role in oriC capture. In addition, we identify substitutions near the C-terminus of SirA and in DnaA Domain III that enhance interaction between the two proteins. One such variant, SirAP141T , remained functional in regard to inhibiting replication, but was unable to support oriC capture. Collectively, our results support a model in which SirA targets DnaA Domain I to inhibit DNA replication, and DnaA Domain III to facilitate Soj-dependent oriC capture in the forespore. PMID- 27489186 TI - The influence of computerized interpretation of an electrocardiogram reading. PMID- 27489187 TI - Cardiomyopathies: In vitro genetic correction of familial dilated cardiomyopathy. PMID- 27489188 TI - Imaging: Cost-effectiveness of FFRCT-guided care. PMID- 27489189 TI - Atherosclerosis: Treating atherosclerosis with antitumour antibodies. PMID- 27489192 TI - Inflammation: Targeting the NLRP3 inflammasome after MI. PMID- 27489191 TI - Antithrombotic therapy for secondary prevention of atherothrombotic events in cerebrovascular disease. AB - Atherothrombosis is the common underlying process for numerous progressive manifestations of cardiovascular disease, including coronary artery disease (CAD) and cerebrovascular disease (CVD). Antiplatelet therapy is the cornerstone of pharmacological management in patients with atherothrombosis. Over the past 20 years, major advances in antiplatelet pharmacotherapy have been made, particularly for the treatment of patients with CAD. The treatment of patients with concomitant CAD and CVD is complex, owing to their increased risk of both ischaemia and bleeding. When CVD arises from large artery atherosclerosis, antithrombotic therapies are essential to prevent stroke or transient ischaemic attack (TIA). However, the use of antithrombotic medications in patients with CVD can put them at high risk of intracranial haemorrhage. As such, the risk-benefit profile of various combinations of antiplatelet agents in patients with both CAD and CVD is uncertain. This Review provides a state-of-the-art account of the available evidence on antithrombotic therapies for the secondary prevention of atherothrombotic events in patients with concomitant CAD and CVD, particularly those with a history of noncardioembolic stroke or TIA. PMID- 27489190 TI - Electrophysiological and molecular mechanisms of paroxysmal atrial fibrillation. AB - Atrial fibrillation (AF) is an extremely prevalent arrhythmia that presents a wide range of therapeutic challenges. AF usually begins in a self-terminating paroxysmal form (pAF). With time, the AF pattern often evolves to become persistent (nonterminating within 7 days). Important differences exist between pAF and persistent AF in terms of clinical features, in particular the responsiveness to antiarrhythmic drugs and ablation therapy. AF mechanisms have been extensively reviewed, but few or no Reviews focus specifically on the pathophysiology of pAF. Accordingly, in this Review, we examine the available data on the electrophysiological basis for pAF occurrence and maintenance, as well as the molecular mechanisms forming the underlying substrate. We first consider the mechanistic insights that have been obtained from clinical studies in the electrophysiology laboratory, noninvasive observations, and genetic studies. We then discuss the information about underlying molecular mechanisms that has been obtained from experimental studies on animal models and patient samples. Finally, we discuss the data available from animal models with spontaneous AF presentation, their relationship to clinical findings, and their relevance to understanding the mechanisms underlying pAF. Our analysis then turns to potential factors governing cases of progression from pAF to persistent AF and the clinical implications of the basic mechanisms we review. We conclude by identifying and discussing questions that we consider particularly important to address through future research in this area. PMID- 27489194 TI - Elevated nitric oxide levels associated with hepatic cell apoptosis during liver injury. AB - Hepatic injury is a major event in liver surgery such as liver transplantation and it always leads to hepatic cell apoptosis. Nitric oxide (NO) is a key signaling regulation molecule. Many researchers have shown that increased NO level can influence liver cell apoptosis by promoting or inhibiting the relative signaling pathways that are involved in the caspase family, Bax/Bcl-2, mitochondria, oxidative stress, death receptors, and mitogen-activated protein kinases. Elucidating the relationships between NO and hepatic cell apoptosis is necessary for ameliorating prognosis of liver surgery. This article reviews the newest research progress in the relationships between higher NO levels and hepatic cell apoptosis in liver injury. PMID- 27489193 TI - Parity-time-symmetry enhanced optomechanically-induced-transparency. AB - We propose and analyze a scheme to enhance optomechanically-induced-transparency (OMIT) based on parity-time-symmetric optomechanical system. Our results predict that an OMIT window which does not exist originally can appear in weak optomechanical coupling and driving system via coupling an auxiliary active cavity with optical gain. This phenomenon is quite different from these reported in previous works in which the gain is considered just to damage OMIT phenomenon even leads to electromagnetically induced absorption or inverted-OMIT. Such enhanced OMIT effects are ascribed to the additional gain which can increase photon number in cavity without reducing effective decay. We also discuss the scheme feasibility by analyzing recent experiment parameters. Our work provide a promising platform for the coherent manipulation and slow light operation, which has potential applications for quantum information processing and quantum optical device. PMID- 27489195 TI - Potentiation of luteolin cytotoxicity by flavonols fisetin and quercetin in human chronic lymphocytic leukemia cell lines. AB - Despite numerous studies chronic lymphocytic leukemia (CLL) still remains an incurable disease. Therefore, all new compounds and novel strategies which are able to eradicate CLL cells should be considered as valuable clues for a potential future remedy against this malignancy. In the present study, the cytotoxic profiles of natural flavonoids were described in two human CLL cell lines, HG-3 and EHEB, indicating the flavone luteolin as the most potent flavonoid with half-maximal inhibitory constants (IC50) of 37 MUM and 26 MUM, respectively. Luteolin significantly increased the apoptotic cell population in both cell lines by increasing the activities of caspases-3 and -9 and triggering the intrinsic apoptotic pathway. Two flavonols, fisetin and quercetin, were somewhat less efficient in suppressing cellular viability, whereas baicalein, chrysin, (+)-catechin and hesperetin exerted only a small or no response at doses as high as 100 MUM. Both fisetin and quercetin were able to augment the cytotoxic activity of luteolin in both cell lines by reducing the IC50 values up to four fold. As a result of this, luteolin displayed cytotoxicity activity already at low micromolar concentrations that could potentially be physiologically achievable through oral ingestion. No other tested flavonoids were capable of sensitizing CLL cells to luteolin pointing to a specific binding of fisetin and quercetin to the cellular targets which interfere with the signaling pathways induced by luteolin. Although further molecular studies to unravel this potentiating mechanism are certainly needed, this phenomenon could contribute to future remedies for prevention and treatment of chronic lymphocytic leukemia. PMID- 27489196 TI - Current-induced alternating reversed dual-echo-steady-state for joint estimation of tissue relaxation and electrical properties. AB - PURPOSE: To develop a current-induced, alternating reversed dual-echo-steady state-based magnetic resonance electrical impedance tomography for joint estimation of tissue relaxation and electrical properties. METHODS: The proposed method reverses the readout gradient configuration of conventional, in which steady-state-free-precession (SSFP)-ECHO is produced earlier than SSFP-free induction-decay (FID) while alternating current pulses are applied in between the two SSFPs to secure high sensitivity of SSFP-FID to injection current. Additionally, alternating reversed dual-echo-steady-state signals are modulated by employing variable flip angles over two orthogonal injections of current pulses. Ratiometric signal models are analytically constructed, from which T1 , T2 , and current-induced Bz are jointly estimated by solving a nonlinear inverse problem for conductivity reconstruction. Numerical simulations and experimental studies are performed to investigate the feasibility of the proposed method in estimating relaxation parameters and conductivity. RESULTS: The proposed method, if compared with conventional magnetic resonance electrical impedance tomography, enables rapid data acquisition and simultaneous estimation of T1 , T2 , and current-induced Bz , yielding a comparable level of signal-to-noise ratio in the parameter estimates while retaining a relative conductivity contrast. CONCLUSION: We successfully demonstrated the feasibility of the proposed method in jointly estimating tissue relaxation parameters as well as conductivity distributions. It can be a promising, rapid imaging strategy for quantitative conductivity estimation. Magn Reson Med 78:107-120, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27489197 TI - Letter to the Editor: On the Growth of Hematopoietic Stem Cells and Childhood Leukemias. PMID- 27489198 TI - Interplay between aggression, brain monoamines and fur color mutation in the American mink. AB - Domestication of wild animals alters the aggression towards humans, brain monoamines and coat pigmentation. Our aim is the interplay between aggression, brain monoamines and depigmentation. The Hedlund white mutation in the American mink is an extreme case of depigmentation observed in domesticated animals. The aggressive (-2.06 +/- 0.03) and tame (+3.5 +/- 0.1) populations of wild-type dark brown color (standard) minks were bred during 17 successive generations for aggressive or tame reaction towards humans, respectively. The Hedlund mutation was transferred to the aggressive and tame backgrounds to generate aggressive ( 1.2 +/- 0.1) and tame (+3.0 +/- 0.2) Hedlund minks. Four groups of 10 males with equal expression of aggressive (-2) or tame (+5) behavior, standard or with the Hedlund mutation, were selected to study biogenic amines in the brain. Decreased levels of noradrenaline in the hypothalamus, but increased concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid and dopamine metabolite, homovanillic acid, in the striatum were measured in the tame compared with the aggressive standard minks. The Hedlund mutation increased noradrenaline level in the hypothalamus and substantia nigra, serotonin level in the substantia nigra and striatum and decreased dopamine concentration in the hypothalamus and striatum. Significant interaction effects were found between the Hedlund mutation and aggressive behavior on serotonin metabolism in the substantia nigra (P < 0.001), dopamine level in the midbrain (P < 0.01) and its metabolism in the striatum (P < 0.05). These results provide the first experimental evidence of the interplay between aggression, brain monoamines and the Hedlund mutation in the American minks. PMID- 27489199 TI - Is There a Free Lunch in Inference? AB - The field of psychology, including cognitive science, is vexed by a crisis of confidence. Although the causes and solutions are varied, we focus here on a common logical problem in inference. The default mode of inference is significance testing, which has a free lunch property where researchers need not make detailed assumptions about the alternative to test the null hypothesis. We present the argument that there is no free lunch; that is, valid testing requires that researchers test the null against a well-specified alternative. We show how this requirement follows from the basic tenets of conventional and Bayesian probability. Moreover, we show in both the conventional and Bayesian framework that not specifying the alternative may lead to rejections of the null hypothesis with scant evidence. We review both frequentist and Bayesian approaches to specifying alternatives, and we show how such specifications improve inference. The field of cognitive science will benefit because consideration of reasonable alternatives will undoubtedly sharpen the intellectual underpinnings of research. PMID- 27489200 TI - Exploring Human Cognition Using Large Image Databases. AB - Most cognitive psychology experiments evaluate models of human cognition using a relatively small, well-controlled set of stimuli. This approach stands in contrast to current work in neuroscience, perception, and computer vision, which have begun to focus on using large databases of natural images. We argue that natural images provide a powerful tool for characterizing the statistical environment in which people operate, for better evaluating psychological theories, and for bringing the insights of cognitive science closer to real applications. We discuss how some of the challenges of using natural images as stimuli in experiments can be addressed through increased sample sizes, using representations from computer vision, and developing new experimental methods. Finally, we illustrate these points by summarizing recent work using large image databases to explore questions about human cognition in four different domains: modeling subjective randomness, defining a quantitative measure of representativeness, identifying prior knowledge used in word learning, and determining the structure of natural categories. PMID- 27489201 TI - Corrigendum for: The Ethics of Belief, Cognition, and Climate Change Pseudoskepticism: Implications for Public Discourse, by Lawrence Torcello in TopiCS in Cognitive Science, 8(1). PMID- 27489202 TI - Five-day study to judge the short-term effect of a benzoyl peroxide 3% gel on acne lesions. AB - INTRODUCTION: Acne is a common, chronic skin disease that has both physical and psychological consequences. Over-the-counter products are a treatment option frequently chosen by dermatologists and acne sufferers for reasons of cost or convenience. There are reports that such products can effect rapid resolution in certain lesion parameters. AIMS: To evaluate the short-term effect of a benzoyl peroxide 3% gel on acne lesions. METHODS: A 5-day, double-blind, randomized clinical trial was conducted among subjects with mild-to-moderate acne. Subjects applied the benzoyl peroxide 3% gel, a salicylic acid 2% gel, or a vehicle gel under supervision once daily for 4 days. Target lesion parameters of swelling, diameter, and erythema were evaluated at various times after the first and subsequent applications. RESULTS: Although target lesion parameters showed overall improvement from baseline, the effects of the active treatment gels were not significantly different from those of the vehicle gel at any evaluation. The assessed parameters showed marked variability in target lesion behavior at the subject level over the course of the study. CONCLUSIONS: The results of this study illustrate the unpredictability of individual acne lesion's responses to therapy and the challenge associated with using these responses to judge short term treatment efficacy. While rapid acne resolution is desired by patients and consumers, setting realistic expectations for treatment response is critical to encourage compliance and avoid disappointment. PMID- 27489203 TI - Combined use of ionic liquid and sulfobutylether-beta-cyclodextrin as electrolyte additives for separation and determination of camptothecin alkaloids by CZE. AB - This work reported that ionic liquid (IL) ([Bmim] [PF6 ]) and sulfobutylether beta-CD (SBE-beta-CD) were used as electrolyte additives for the separation and determination of camptothecin (CPT) alkaloids by CZE. Separation parameters such as the buffer type, pH, and concentration of the running buffer, the concentration of SBE-beta-CD and IL, temperature, and separation voltage were all investigated in order to achieve the maximum possible resolution. The four analytes were baseline separated within 10 min in capillary at the separation voltage of 15 kV with a running buffer consisting of 20 mM borate buffer, 20 mM IL, and 100 mM SBE-beta-CD at pH 9.0. Under such conditions, good linearity about two orders of magnitudes of peak areas was achieved for the investigated CPT alkaloids with the correlation coefficients ranging from 0.9946 to 0.9985. For all analytes, detection limits (S/N = 3) and quantitation limits (S/N = 10) range from 0.05 to 0.92 MUg/mL and 0.17 to 3.06 MUg/mL, respectively. The proposed method has not only been successfully applied to the separation and determination of CPT alkaloids but also showed that IL seemed to be a promising additive in CZE separation. PMID- 27489204 TI - Home-Based Psychiatric Outpatient Care Through Videoconferencing for Depression: A Randomized Controlled Follow-Up Trial. AB - BACKGROUND: There is a tremendous opportunity for innovative mental health care solutions such as psychiatric care through videoconferencing to increase the number of people who have access to quality care. However, studies are needed to generate empirical evidence on the use of psychiatric outpatient care via videoconferencing, particularly in low- and middle-income countries and clinically unsupervised settings. OBJECTIVE: The objective of this study was to evaluate the effectiveness and feasibility of home-based treatment for mild depression through psychiatric consultations via videoconferencing. METHODS: A randomized controlled trial with a 6- and 12-month follow-up including adults with mild depression treated in an ambulatory setting was conducted. In total, 107 participants were randomly allocated to the videoconferencing intervention group (n=53) or the face-to-face group (F2F; n=54). The groups did not differ with respect to demographic characteristics at baseline. The F2F group completed monthly follow-up consultations in person. The videoconferencing group received monthly follow-up consultations with a psychiatrist through videoconferencing at home. At baseline and after 6 and 12 months, in-person assessments were conducted with all participants. Clinical outcomes (severity of depression, mental health status, medication course, and relapses), satisfaction with treatment, therapeutic relationship, treatment adherence (appointment compliance and dropouts), and medication adherence were assessed. RESULTS: The severity of depression decreased significantly over the 12-month follow-up in both the groups. There was a significant difference between groups regarding treatment outcomes throughout the follow-up period, with better results in the videoconferencing group. There were 4 relapses in the F2F group and only 1 in the videoconferencing group. No significant differences between groups regarding mental health status, satisfaction with treatment, therapeutic relationship, treatment adherence, or medication compliance were found. However, after 6 months, the rate of dropouts was significantly higher in the F2F group (18.5% vs 5.7% in the videoconferencing group, P<.05). CONCLUSIONS: Psychiatric treatment through videoconferencing in clinically unsupervised settings can be considered feasible and as effective as standard care (in-person treatment) for depressed outpatients with respect to clinical outcomes, patient satisfaction, therapeutic relationship, treatment adherence, and medication compliance. These results indicate the potential of telepsychiatry to extend access to psychiatric care to remote and underserved populations. CLINICALTRIAL: Clinicaltrials.gov NCT01901315; https://clinicaltrials.gov/ct2/show/NCT01901315 (Archived by WebCite at http://www.webcitation.org/6jBTrIVwg). PMID- 27489205 TI - ART is an alternative for restoring occlusoproximal cavities in primary teeth - evidence from an updated systematic review and meta-analysis. AB - BACKGROUND: A previous systematic review showed that atraumatic restorative treatment (ART) can be an option to restore the occlusoproximal cavities in primary teeth; however, few studies fulfilled the criteria of inclusion to generate a high level of evidence. AIM: To update the existing systematic review and address questions regarding survival rate of ART restorations compared to the conventional approach in occlusoproximal cavities in primary molars. DESIGN: The search was extended beyond the original search through the PubMed/MEDLINE database up to February 2016. Furthermore, Web of Science and EMBASE were searched. The inclusion criteria were subjects related to the scope of the systematic review. After selection by title and abstract, potentially eligible articles were read in full and included in accordance with exclusion criteria. Meta-analysis was carried out with the outcome being the survival rate of restorations. RESULTS: The search strategy identified 560 potentially relevant studies, in addition to 127 from the original systematic review. A total of four articles were included in the qualitative and quantitative analyses. Meta analysis showed no statistically significant difference between ART and conventional approaches in survival rate of occlusoproximal cavities (OR = 0.887, 95% CI: 0.574-1.371). CONCLUSION: ART restorations have similar survival rate compared to conventional treatment and can be considered an option to restore occlusoproximal cavities in primary molars. PMID- 27489206 TI - Mapping the patent landscape of synthetic biology for fine chemical production pathways. AB - A goal of synthetic biology bio-foundries is to innovate through an iterative design/build/test/learn pipeline. In assessing the value of new chemical production routes, the intellectual property (IP) novelty of the pathway is important. Exploratory studies can be carried using knowledge of the patent/IP landscape for synthetic biology and metabolic engineering. In this paper, we perform an assessment of pathways as potential targets for chemical production across the full catalogue of reachable chemicals in the extended metabolic space of chassis organisms, as computed by the retrosynthesis-based algorithm RetroPath. Our database for reactions processed by sequences in heterologous pathways was screened against the PatSeq database, a comprehensive collection of more than 150M sequences present in patent grants and applications. We also examine related patent families using Derwent Innovations. This large-scale computational study provides useful insights into the IP landscape of synthetic biology for fine and specialty chemicals production. PMID- 27489207 TI - Genome-Wide Analysis of Polyadenylation Events in Schmidtea mediterranea. AB - In eukaryotes, 3' untranslated regions (UTRs) play important roles in regulating posttranscriptional gene expression. The 3'UTR is defined by regulated cleavage/polyadenylation of the pre-mRNA. The advent of next-generation sequencing technology has now enabled us to identify these events on a genome wide scale. In this study, we used poly(A)-position profiling by sequencing (3P Seq) to capture all poly(A) sites across the genome of the freshwater planarian, Schmidtea mediterranea, an ideal model system for exploring the process of regeneration and stem cell function. We identified the 3'UTRs for ~14,000 transcripts and thus improved the existing gene annotations. We found 97 transcripts, which are polyadenylated within an internal exon, resulting in the shrinking of the ORF and loss of a predicted protein domain. Around 40% of the transcripts in planaria were alternatively polyadenylated (ApA), resulting either in an altered 3'UTR or a change in coding sequence. We identified specific ApA transcript isoforms that were subjected to miRNA mediated gene regulation using degradome sequencing. In this study, we also confirmed a tissue-specific expression pattern for alternate polyadenylated transcripts. The insights from this study highlight the potential role of ApA in regulating the gene expression essential for planarian regeneration. PMID- 27489208 TI - Interallelic Transcriptional Enhancement as an in Vivo Measure of Transvection in Drosophila melanogaster. AB - Transvection-pairing-dependent interallelic regulation resulting from enhancer action in trans-occurs throughout the Drosophila melanogaster genome, likely as a result of the extensive somatic homolog pairing seen in Dipteran species. Recent studies of transvection in Drosophila have demonstrated important qualitative differences between enhancer action in cis vs. in trans, as well as a modest synergistic effect of cis- and trans-acting enhancers on total tissue transcript levels at a given locus. In the present study, we identify a system in which cis- and trans-acting GAL4-UAS enhancer synergism has an unexpectedly large quantitative influence on gene expression, boosting total tissue transcript levels at least fourfold relative to those seen in the absence of transvection. We exploit this strong quantitative effect by using publicly available UAS-shRNA constructs from the TRiP library to assay candidate genes for transvection activity in vivo The results of the present study, which demonstrate that in trans activation by simple UAS enhancers can have large quantitative effects on gene expression in Drosophila, have important new implications for experimental design utilizing the GAL4-UAS system. PMID- 27489209 TI - Cross-Validation Without Doing Cross-Validation in Genome-Enabled Prediction. AB - Cross-validation of methods is an essential component of genome-enabled prediction of complex traits. We develop formulae for computing the predictions that would be obtained when one or several cases are removed in the training process, to become members of testing sets, but by running the model using all observations only once. Prediction methods to which the developments apply include least squares, best linear unbiased prediction (BLUP) of markers, or genomic BLUP, reproducing kernels Hilbert spaces regression with single or multiple kernel matrices, and any member of a suite of linear regression methods known as "Bayesian alphabet." The approach used for Bayesian models is based on importance sampling of posterior draws. Proof of concept is provided by applying the formulae to a wheat data set representing 599 inbred lines genotyped for 1279 markers, and the target trait was grain yield. The data set was used to evaluate predictive mean-squared error, impact of alternative layouts on maximum likelihood estimates of regularization parameters, model complexity, and residual degrees of freedom stemming from various strengths of regularization, as well as two forms of importance sampling. Our results will facilitate carrying out extensive cross-validation without model retraining for most machines employed in genome-assisted prediction of quantitative traits. PMID- 27489210 TI - Genome Evolution in Three Species of Cactophilic Drosophila. AB - We report genomes of two species of cactophilic Drosophila: Drosophila arizonae and D. navojoa These two are the closest relatives of D. mojavensis, forming the D. mojavensis cluster. D. mojavensis and D. arizonae diverged from D. navojoa ~5.8 Mya, while the split between D. arizonae and D. mojavensis is more recent, at 1.5 Mya. Together the three genomes provide opportunities to examine genomic changes associated with speciation and host shifts in this ecologically defined group of flies. The three species are also separated by fixed inversion differences in three of their six chromosomes. While the levels of nucleotide divergence in the colinear chromosomes are significantly lower than in the inverted chromosomes, consistent with a past role of the inversions in preventing gene flow, the patterns differ among the inverted chromosomes when the locations of nucleotides inside or outside of the inversions are considered. For Muller element E, there is greater divergence external to the inversion breakpoints. For Muller A, the divergence is slightly higher inside the inversions, while for Muller B, the breakpoints and hence the difference in substitutions in relation to the inversions could not be determined. The differences among the inverted chromosomes, especially once the breakpoints are clearly established, could aid in dating the origins of the inversions. PMID- 27489212 TI - Preferential intracellular pH regulation: hypotheses and perspectives. AB - The regulation of vertebrate acid-base balance during acute episodes of elevated internal PCO2 is typically characterized by extracellular pH (pHe) regulation. Changes in pHe are associated with qualitatively similar changes in intracellular tissue pH (pHi) as the two are typically coupled, referred to as 'coupled pH regulation'. However, not all vertebrates rely on coupled pH regulation; instead, some preferentially regulate pHi against severe and maintained reductions in pHe Preferential pHi regulation has been identified in several adult fish species and an aquatic amphibian, but never in adult amniotes. Recently, common snapping turtles were observed to preferentially regulate pHi during development; the pattern of acid-base regulation in these species shifts from preferential pHi regulation in embryos to coupled pH regulation in adults. In this Commentary, we discuss the hypothesis that preferential pHi regulation may be a general strategy employed by vertebrate embryos in order to maintain acid-base homeostasis during severe acute acid-base disturbances. In adult vertebrates, the retention or loss of preferential pHi regulation may depend on selection pressures associated with the environment inhabited and/or the severity of acid-base regulatory challenges to which they are exposed. We also consider the idea that the retention of preferential pHi regulation into adulthood may have been a key event in vertebrate evolution, with implications for the invasion of freshwater habitats, the evolution of air breathing and the transition of vertebrates from water to land. PMID- 27489211 TI - Assessment of the Pharmacokinetics, Pharmacodynamics, and Safety of Single Doses of TV-1106, a Long-Acting Growth Hormone, in Healthy Japanese and Caucasian Subjects. AB - TV-1106 is a human serum albumin genetically fused to recombinant human growth hormone, designed to provide a long-acting alternative to daily growth hormone (GH) injections in patients with GH deficiency. This study investigated the pharmacokinetics, pharmacodynamics, and safety of single subcutaneous doses of TV 1106 (7.5, 15, 50, and 100 mg) in Japanese (n = 44) and caucasian (n = 44) healthy subjects. TV-1106 pharmacokinetics and pharmacodynamics were comparable in Japanese and caucasian populations. TV-1106 demonstrated relatively slow absorption (median tmax , 10-30 hours) and a mean elimination half-life of 26-36 hours. Apparent clearance and volume of distribution decreased with increasing TV 1106 doses in both populations and appeared to increase more than dose proportionality across the tested doses. Insulin-like growth factor-1 (IGF-1) and IGF binding protein-3 (IGFBP-3) increased in a dose-related manner, with maximum responses observed at 33-96 and 42-109 hours, respectively. IGF-1 and IGFBP-3 returned to baseline values at 168 hours following 7.5 and 15 mg of TV-1106, and 336 hours following 50 and 100 mg of TV-1106. TV-1106 appeared safe in both populations. There was no evidence of differences in pharmacokinetics, pharmacodynamics, or safety of TV-1106 between Japanese and caucasian populations. The data also demonstrate long-acting growth hormone properties of TV-1106 and support its potential for once-weekly dosing. PMID- 27489213 TI - Amphibious fishes: evolution and phenotypic plasticity. AB - Amphibious fishes spend part of their life in terrestrial habitats. The ability to tolerate life on land has evolved independently many times, with more than 200 extant species of amphibious fishes spanning 17 orders now reported. Many adaptations for life out of water have been described in the literature, and adaptive phenotypic plasticity may play an equally important role in promoting favourable matches between the terrestrial habitat and behavioural, physiological, biochemical and morphological characteristics. Amphibious fishes living at the interface of two very different environments must respond to issues relating to buoyancy/gravity, hydration/desiccation, low/high O2 availability, low/high CO2 accumulation and high/low NH3 solubility each time they traverse the air-water interface. Here, we review the literature for examples of plastic traits associated with the response to each of these challenges. Because there is evidence that phenotypic plasticity can facilitate the evolution of fixed traits in general, we summarize the types of investigations needed to more fully determine whether plasticity in extant amphibious fishes can provide indications of the strategies used during the evolution of terrestriality in tetrapods. PMID- 27489214 TI - The high cost of reproduction in sea otters necessitates unique physiological adaptations. AB - Superimposed on inherently high basal metabolic demands, the additional energetic requirements of reproduction can push female sea otters beyond physiological limits. Indeed, the resulting energy imbalance contributes to disproportionately high rates of mortality at the end of lactation in this species. To examine and quantify metabolic changes associated with reproduction, we measured the resting metabolic rate (RMR) of a female sea otter across gestation, lactation and non reproductive periods. Concurrently, measurements were made on a non-breeding control female. Our results suggest that RMR declines during gestation. Conversely, RMR increases during lactation, reaches a peak at 3-4 months postpartum, and remains elevated until weaning. Combining these direct measurements with published data, we found the cost of pup rearing to be significantly higher than previously estimated. High baseline energy demands and limited energy reserves, combined with significant lactation and pup rearing costs, appear to necessitate metabolic and thermal lability during key reproductive stages. PMID- 27489215 TI - Repair of traumatized mammalian hair cells via sea anemone repair proteins. AB - Mammalian hair cells possess only a limited ability to repair damage after trauma. In contrast, sea anemones show a marked capability to repair damaged hair bundles by means of secreted repair proteins (RPs). Previously, it was found that recovery of traumatized hair cells in blind cavefish was enhanced by anemone derived RPs; therefore, the ability of anemone RPs to assist recovery of damaged hair cells in mammals was tested here. After a 1 h incubation in RP-enriched culture media, uptake of FM1-43 by experimentally traumatized murine cochlear hair cells was restored to levels comparable to those exhibited by healthy controls. In addition, RP-treated explants had significantly more normally structured hair bundles than time-matched traumatized control explants. Collectively, these results indicate that anemone-derived RPs assist in restoring normal function and structure of experimentally traumatized hair cells of the mouse cochlea. PMID- 27489216 TI - Ammonia excretion in mytilid mussels is facilitated by ciliary beating. AB - The excretion of nitrogenous waste products in the form of ammonia (NH3) and ammonium (NH4 (+)) is a fundamental process in aquatic organisms. For mytilid bivalves, little is known about the mechanisms and sites of excretion. This study investigated the localization and the mechanisms of ammonia excretion in mytilid mussels. An Rh protein was found to be abundantly expressed in the apical cell membrane of the plicate organ, which was previously described as a solely respiratory organ. The Rh protein was also expressed in the gill, although at significantly lower concentrations, but was not detectable in mussel kidney. Furthermore, NH3/NH4 (+) was not enriched in the urine, suggesting that kidneys are not involved in active NH3/NH4 (+) excretion. Exposure to elevated seawater pH of 8.5 transiently reduced NH3/NH4 (+) excretion rates, but they returned to control values following 24 h acclimation. These mussels had increased abundance of V-type H(+)-ATPase in the apical membranes of plicate organ cells; however, NH3/NH4 (+) excretion rates were not affected by the V-type H(+)-ATPase specific inhibitor concanamycin A (100 nmol l(-1)). In contrast, inhibition of ciliary beating with dopamine and increased seawater viscosity significantly reduced NH3 excretion rates under control pH (8.0). These results suggest that NH3/NH4 (+) excretion in mytilid mussels takes place by passive NH3 diffusion across respiratory epithelia via the Rh protein, facilitated by the water current produced for filter feeding, which prevents accumulation of NH3 in the boundary layer. This mechanism would be energy efficient for sessile organisms, as they already generate water currents for filter feeding. PMID- 27489217 TI - Intermuscular pressure between synergistic muscles correlates with muscle force. AB - The purpose of the study was to examine the relationship between muscle force generated during isometric contractions (i.e. at a constant muscle-tendon unit length) and the intermuscular (between adjacent muscles) pressure in synergistic muscles. Therefore, the pressure at the contact area of the gastrocnemius and plantaris muscle was measured synchronously to the force of the whole calf musculature in the rabbit species Oryctolagus cuniculus Similar results were obtained when using a conductive pressure sensor, or a fibre-optic pressure transducer connected to a water-filled balloon. Both methods revealed a strong linear relationship between force and pressure in the ascending limb of the force length relationship. The shape of the measured force-time and pressure-time traces was almost identical for each contraction (r=0.97). Intermuscular pressure ranged between 100 and 700 mbar (70,000 Pa) for forces up to 287 N. These pressures are similar to previous (intramuscular) recordings within skeletal muscles of different vertebrate species. Furthermore, our results suggest that the rise in intermuscular pressure during contraction may reduce the force production in muscle packages (compartments). PMID- 27489218 TI - Arginine and proline applied as food additives stimulate high freeze tolerance in larvae of Drosophila melanogaster. AB - The fruit fly Drosophila melanogaster is an insect of tropical origin. Its larval stage is evolutionarily adapted for rapid growth and development under warm conditions and shows high sensitivity to cold. In this study, we further developed an optimal acclimation and freezing protocol that significantly improves larval freeze tolerance (an ability to survive at -5 degrees C when most of the freezable fraction of water is converted to ice). Using the optimal protocol, freeze survival to adult stage increased from 0.7% to 12.6% in the larvae fed standard diet (agar, sugar, yeast, cornmeal). Next, we fed the larvae diets augmented with 31 different amino compounds, administered in different concentrations, and observed their effects on larval metabolomic composition, viability, rate of development and freeze tolerance. While some diet additives were toxic, others showed positive effects on freeze tolerance. Statistical correlation revealed tight association between high freeze tolerance and high levels of amino compounds involved in arginine and proline metabolism. Proline- and arginine-augmented diets showed the highest potential, improving freeze survival to 42.1% and 50.6%, respectively. Two plausible mechanisms by which high concentrations of proline and arginine might stimulate high freeze tolerance are discussed: (i) proline, probably in combination with trehalose, could reduce partial unfolding of proteins and prevent membrane fusions in the larvae exposed to thermal stress (prior to freezing) or during freeze dehydration; (ii) both arginine and proline are exceptional among amino compounds in their ability to form supramolecular aggregates which probably bind partially unfolded proteins and inhibit their aggregation under increasing freeze dehydration. PMID- 27489219 TI - P450 aromatase: a key enzyme in the spermatogenesis of the Italian wall lizard, Podarcis sicula. AB - P450 aromatase is a key enzyme in steroidogenesis involved in the conversion of testosterone into 17beta-estradiol. We investigated the localization and the expression of P450 aromatase in Podarcis sicula testes during the different phases of the reproductive cycle: summer stasis (July-August), early autumnal resumption (September), middle autumnal resumption (October-November), winter stasis (December-February), spring resumption (March-April) and the reproductive period (May-June). Using immunohistochemistry, we demonstrated that the P450 aromatase is always present in somatic and germ cells of P. sicula testis, particularly in spermatids and spermatozoa, except in early autumnal resumption, when P450 aromatase is evident only within Leydig cells. Using real-time PCR and semi-quantitative blot investigations, we also demonstrated that both mRNA and protein were expressed in all phases, with two peaks of expression occurring in summer and in winter stasis. These highest levels of P450 aromatase are in line with the increase of 17beta-estradiol, responsible for the spermatogenesis block typical of this species. Differently, in autumnal resumption, the level of P450 aromatase dramatically decreased, along with 17beta-estradiol levels, and testosterone titres increased, responsible for the subsequent renewal of spermatogenesis not followed by spermiation. In spring resumption and in the reproductive period we found intermediate P450 aromatase amounts, low levels of 17beta-estradiol and the highest testosterone levels determining the resumption of spermatogenesis needed for reproduction. Our results, the first collected in a non-mammalian vertebrate, indicate a role of P450 aromatase in the control of steroidogenesis and spermatogenesis, particularly in spermiogenesis. PMID- 27489220 TI - Avian thermoregulation in the heat: evaporative cooling capacity in an archetypal desert specialist, Burchell's sandgrouse (Pterocles burchelli). PMID- 27489221 TI - Geriatric problems correlated with cognitive decline using a screening test named "Dr. SUPERMAN" for comprehensive geriatric assessment in elderly inpatients. AB - AIM: We have recently developed and validated a screening test for comprehensive geriatric assessment (CGA). We investigated the prevalence of geriatric problems in elderly inpatients using CGA, and determined the relationship between geriatric problems and cognitive decline. METHODS: We enrolled consecutive elderly inpatients aged >65 years who were admitted to all of the hospital departments at Tokyo Medical University Hospital, Tokyo, Japan, between July and December 2013. We investigated the prevalence of specific geriatric problems or situations in elderly inpatients using a screening test for CGA named "Dr. SUPERMAN." We examined 3969 elderly inpatients (2211 men and 1758 women; mean age 75.5 +/- 6.7 years) using CGA. Inpatients were divided into three groups by age, namely, 65-74 years, 75-84 years and >=85 years. Inpatients were divided into the two groups of "internal medicine" and "other departments." RESULTS: Geriatric problems were more frequently found in patients who were aged >=85 years and admitted to "internal medicine" departments. Furthermore, multiple regression analysis found cognitive decline significantly correlated with ADL decline, age, poor medication adherence, upper and lower extremity function disorder, visual/auditory disorder, and urinary disorder. In particular, cognitive decline strongly correlated with a decline in activities of daily living. CONCLUSIONS: CGA should be considered for the treatment of elderly inpatients, particularly those with cognitive decline and admitted to "internal medicine" departments. Geriatr Gerontol Int 2017; 17: 1252-1256. PMID- 27489222 TI - Normalising and planning for death in residential care: findings from a qualitative focus group study of a specialist palliative care intervention. AB - BACKGROUND: Improving access to palliative care for older adults living in residential care is recognised internationally as a pressing clinical need. The integration of specialist palliative care in residential care for older adults is not yet standard practice. OBJECTIVE: This study aimed to understand the experience and impact of integrating a specialist palliative care model on residents, relatives and staff. METHODS: Focus groups were held with staff (n=40) and relatives (n=17). Thematic analysis was applied to the data. RESULTS: Three major themes were identified. The intervention led to (1) normalising death and dying in these settings, (2) timely access to a palliative care specialist who was able to prescribe anticipatory medications aiding symptom management and unnecessary hospitalisations and (3) better decision-making and planned care for residents, which meant that staff and relatives were better informed about, and prepared for, the resident's likely trajectory. CONCLUSIONS: The intervention normalised death and dying and also underlined the important role that specialists play in providing staff education, timely access to medicines and advance care planning. The findings from our study, and the growing wealth of evidence integrating specialist palliative care in residential care for older adults, indicate a number of priorities for care providers, academics and policymakers. Further work on determining the role of primary and specialist palliative care services in residential care settings is needed to inform service delivery models. PMID- 27489223 TI - Ghrelin O-acyltransferase (GOAT), a specific enzyme that modifies ghrelin with a medium-chain fatty acid. AB - In the gastric peptide hormone ghrelin, serine 3 (threonine 3 in frogs) is modified, primarily by n-octanoic acid; this modification is essential for ghrelin's activity. The enzyme that transfers n-octanoic acid to Ser3 of ghrelin is ghrelin O-acyltransferase (GOAT). GOAT, the only enzyme known to catalyze acyl modification of ghrelin, specifically modifies serine (or threonine) at the third position and does not modify other serine residues in ghrelin peptides. GOAT prefers n-hexanoyl-CoA over n-octanoyl-CoA as the acyl donor, although in the stomach the n-octanoyl form is the predominant form of acyl-modified ghrelin. GOAT is a promising target for drug development to treat metabolic diseases and eating disorders. PMID- 27489224 TI - Simulating the slow to fast switch in cytochrome c oxidase catalysis by introducing a loop flip near the enzyme's cytochrome c (substrate) binding site. AB - The mitochondrial enzyme cytochrome c oxidase catalyzes the reduction of molecular oxygen in the critical step of oxidative phosphorylation that links the oxidation of food consumed to ATP production in cells. The enzyme catalyzes the reduction of oxygen at two vastly different rates that are thought to be linked to two different conformations but the conformation of the "fast enzyme" remains obscure. In this study, we demonstrated how oxygen binding at haem a3 could trigger long-distance conformational changes and then simulated a conformational change in an eight-residue loop near the enzyme's substrate (cytochrome c) binding site. We then used this modified cytochrome c oxidase (COX) to simulate a stable COX-cytochrome c enzyme-substrate (ES) complex. Compared to ES complexes formed in the absence of the conformation change, the distance between the redox centers of the two proteins was reduced by half and instead of nine, only four COX amino acid residues were found along the axis linking the electron entry point and the CuA redox center of COX: We proposed that intramolecular electron transfer in COX occurs via a charge/hydrogen relay system involving these four residues. We suggest that the conformational change and resulting shortened electron pathway are features of fast-acting COX. PMID- 27489225 TI - The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration. AB - OBJECTIVES: The circadian clocks are internal timing mechanisms that drive ~24 hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional circadian clocks and if so, how their dysregulation is implicated in IVD degeneration. METHODS: Clock gene dynamics in ex vivo IVD explants (from PER2:: luciferase (LUC) reporter mice) and human disc cells (transduced with lentivirus containing Per2::luc reporters) were monitored in real time by bioluminescence photon counting and imaging. Temporal gene expression changes were studied by RNAseq and quantitative reverse transcription (qRT)-PCR. IVD pathology was evaluated by histology in a mouse model with tissue specific deletion of the core clock gene Bmal1. RESULTS: Here we show the existence of the circadian rhythm in mouse IVD tissue and human disc cells. This rhythm is dampened with ageing in mice and can be abolished by treatment with interleukin-1beta but not tumour necrosis factor alpha. Time-series RNAseq revealed 607 genes with 24-hour patterns of expression representing several essential pathways in IVD physiology. Mice with conditional knockout of Bmal1 in their disc cells demonstrated age-related degeneration of IVDs. CONCLUSIONS: We have established autonomous circadian clocks in mouse and human IVD cells which respond to age and cytokines, and control key pathways involved in the homeostasis of IVDs. Genetic disruption to the mouse IVD molecular clock predisposes to IVD degeneration. These results support the concept that disruptions to circadian rhythms may be a risk factor for degenerative IVD disease and low back pain. PMID- 27489227 TI - Cultivating Resilience in Families Who Foster: Understanding How Families Cope and Adapt Over Time. AB - Families who foster offer essential care for children and youth when their own parents are unable to provide for their safety and well-being. Foster caregivers face many challenges including increased workload, emotional distress, and the difficulties associated with health and mental health problems that are more common in children in foster care. Despite these stressors, many families are able to sustain fostering while maintaining or enhancing functioning of their unit. This qualitative study applied an adaptational process model of family resilience that emerged in previous studies to examine narratives of persistent, long-term, and multiple fostering experiences. Data corroborated previous research in two ways. Family resilience was again described as a transactional process of coping and adaptation that evolves over time. This process was cultivated through the activation of 10 family strengths that are important in different ways, during varied phases. PMID- 27489226 TI - Response to: 'The role of infrapatellar fat pad resection in total knee arthroplasty' by White et al. PMID- 27489228 TI - A cost-effectiveness analysis of optimal care for diabetic foot ulcers in Australia. AB - In addition to affecting quality of life, diabetic foot ulcers (DFUs) impose an economic burden on both patients and the health system. This study developed a Markov model to analyse the cost-effectiveness of implementing optimal care in comparison with the continuation of usual care for diabetic patients at high risk of DFUs in the Australian setting. The model results demonstrated overall 5-year cost savings (AUD 9100.11 for those aged 35-54, $9391.60 for those aged 55-74 and $12 394.97 for those aged 75 or older) and improved health benefits measured in quality-adjusted life years (QALYs) (0.13 QALYs, 0.13 QALYs and 0.16 QALYs, respectively) for high-risk patients receiving optimal care for DFUs compared with usual care. Total cost savings for Australia were estimated at AUD 2.7 billion over 5 years. Probabilistic sensitivity analysis showed that optimal care always had a higher probability of costing less and generating more health benefits. This study provides important evidence to inform Australian policy decisions on the efficient use of health resources and supports the implementation of evidence-based optimal care in Australia. Furthermore, this information is of great importance for comparable developed countries that could reap similar benefits from investing in these well-known evidence-based strategies. PMID- 27489229 TI - Response: Commentary: Enhanced Monitoring of the Preterm Infant during Stabilization in the Delivery Room. PMID- 27489230 TI - Development of a neurofeedback protocol targeting the frontal pole using near infrared spectroscopy. AB - AIM: Neurofeedback has been studied with the aim of controlling cerebral activity. Near-infrared spectroscopy is a non-invasive neuroimaging technique used for measuring hemoglobin concentration changes in cortical surface areas with high temporal resolution. Thus, near-infrared spectroscopy may be useful for neurofeedback, which requires real-time feedback of repeated brain activation measurements. However, no study has specifically targeted neurofeedback, using near-infrared spectroscopy, in the frontal pole cortex. METHODS: We developed an original near-infrared spectroscopy neurofeedback system targeting the frontal pole cortex. Over a single day of testing, each healthy participant (n = 24) received either correct or incorrect (Sham) feedback from near-infrared spectroscopy signals, based on a crossover design. RESULTS: Under correct feedback conditions, significant activation was observed in the frontal pole cortex (P = 0.000073). Additionally, self-evaluation of control and metacognitive beliefs were associated with near-infrared spectroscopy signals (P = 0.006). CONCLUSION: The neurofeedback system developed in this study might be useful for developing control of frontal pole cortex activation. PMID- 27489231 TI - Obovatol Induces Apoptosis in Non-small Cell Lung Cancer Cells via C/EBP Homologous Protein Activation. AB - Although obovatol, a phenolic compound from the bark of Magnolia obovata, was known to have antioxidant, neuroprotective, antiinflammatory, antithrombotic and antitumour effects, its underlying antitumour mechanism is poorly understood so far. Thus, in the present study, the antitumour molecular mechanism of obovatol was investigated in non-small cell lung cancer cells (NSCLCs). Obovatol exerted cytotoxicity in A549 and H460 NSCLCs, but not in BEAS-2B cells. Also, obovatol increased sub-G1 accumulation and early and late apoptotic portion in A549 and H460 NSCLCs. Consistently, obovatol cleaved PARP, activated caspase 9/3 and Bax and attenuated the expression of cyclin D1 in A549 and H460 NSCLCs. Interestingly, obovatol upregulated the expression of endoplasmic reticulum stress proteins such as C/EBP homologous protein (CHOP), IRE1alpha, ATF4 and p elF2 in A549 and H460 NSCLCs. Conversely, depletion of CHOP blocked the apoptotic activity of obovatol to increase sub-G1 accumulation in A549 and H460 NSCLCs. Overall, our findings support scientific evidences that obovatol induces apoptosis via CHOP activation in A549 and H460 NSCLCs. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27489232 TI - Exercise From the Perspective of Iranian Traditional Medicine. AB - Exercise, in Iranian traditional medicine, is 1 of the 6 principles recommended for maintaining good health. There are some considerations that must be taken into account before, during, and after exercise. Exercise has different terms in different individuals, seasons, and ages. According to these principles, the interval between exercise and eating food is very important. Exercise after eating is inappropriate, and it is recommended that the best time for exercise is after food has been completely digested and before the next meal. According to the opinion of traditional medicine philosophers, exercise should be done after the complete digestion of food. Exercise may be more effective if it is done according to traditional medicine view at appropriate times and conditions with sufficient intensity and duration. PMID- 27489233 TI - Mindfulness-Based Stress Reduction as a Stress Management Intervention for Cancer Care: A Systematic Review. AB - Cancer is acknowledged as a source of stress for many individuals, often leading to suffering, which can be long-lasting. Mindfulness-based stress reduction offers an effective way of reducing stress among cancer patients by combining mindfulness meditation and yoga in an 8-week training program. The purpose of this study was to inspect studies from October 2009 to November 2015 and examine whether mindfulness-based stress reduction can be utilized as a viable method for managing stress among cancer patients. A systematic search from Medline, CINAHL, and Alt HealthWatch databases was conducted for quantitative articles involving mindfulness-based stress reduction interventions targeting cancer patients. A total of 13 articles met the inclusion criteria. Of these 13 studies, 9 demonstrated positive changes in either psychological or physiological outcomes related to anxiety and/or stress, with 4 describing mixed results. Despite the limitations, mindfulness-based stress reduction appears to be promising for stress management among cancer patients. PMID- 27489234 TI - Legionella saoudiensis sp. nov., isolated from a sewage water sample. AB - A Gram-stain-negative, bacilli-shaped bacterial strain, LS-1T, was isolated from a sewage water sample collected in Jeddah, Saudi Arabia. The taxonomic position of strain LS-1T was investigated using a polyphasic taxonomic approach. Phylogenetic analysis based on 16S rRNA gene sequences and those of four other genes indicated that strain LS-1T belongs to the genus Legionella in the family Legionellaceae. Regarding the 16S rRNA gene, the most closely related species are Legionella rowbothamii LLAP-6T (98.6 %) and Legionella lytica L2T (98.5 %). The mip gene sequence of strain LS-1T showed 94 % sequence similarity with that of L. lytica L2T and 93 % similarity with that of L. rowbothamii LLAP-6T. Strain LS-1T grew optimally at a temperature of 32 degrees C on a buffered charcoal yeast extract (BCYE) agar plate in a 5 % CO2 atmosphere and had a flagellum. The combined phylogenetic, phenotypic and genomic sequence data suggest that strain LS-1T represents a novel species of the genus Legionella, for which the name Legionella saoudiensis sp. nov. is proposed. The type strain is LS-1T (=DSM 101682T=CSUR P2101T). PMID- 27489235 TI - Grain production versus resource and environmental costs: towards increasing sustainability of nutrient use in China. AB - Over the past five decades, Chinese grain production has increased 4-fold, from 110 Mt in 1961 to 557 Mt in 2014, with less than 9% of the world's arable land feeding 22% of the world's population, indicating a substantial contribution to global food security. However, compared with developed economies, such as the USA and the European Union, more than half of the increased crop production in China can be attributed to a rapid increase in the consumption of chemicals, particularly fertilizers. Excessive fertilization has caused low nutrient use efficiency and high environmental costs in grain production. We analysed the key requirements underpinning increased sustainability of crop production in China, as follows: (i) enhance nutrient use efficiency and reduce nutrient losses by fertilizing roots not soil to maximize root/rhizosphere efficiency with innovative root zone nutrient management; (ii) improve crop productivity and resource use efficiency by matching the best agronomic management practices with crop improvement; and (iii) promote technology transfer of the root zone nutrient management to achieve the target of high yields and high efficiency with low environmental risks on a broad scale. Coordinating grain production and environmental protection by increasing the sustainability of nutrient use will be a key step in achieving sustainable crop production in Chinese agriculture. PMID- 27489237 TI - Response to the Editor: On the Growth of Hematopoietic Stem Cells and Childhood Leukemias. PMID- 27489236 TI - Identification and characterization of wheat drought-responsive MYB transcription factors involved in the regulation of cuticle biosynthesis. AB - A plant cuticle forms a hydrophobic layer covering plant organs, and plays an important role in plant development and protection from environmental stresses. We examined epicuticular structure, composition, and a MYB-based regulatory network in two Australian wheat cultivars, RAC875 and Kukri, with contrasting cuticle appearance (glaucousness) and drought tolerance. Metabolomics and microscopic analyses of epicuticular waxes revealed that the content of beta diketones was the major compositional and structural difference between RAC875 and Kukri. The content of beta-diketones remained the same while those of alkanes and primary alcohols were increased by drought in both cultivars, suggesting that the interplay of all components rather than a single one defines the difference in drought tolerance between cultivars. Six wheat genes encoding MYB transcription factors (TFs) were cloned; four of them were regulated in flag leaves of both cultivars by rapid dehydration and/or slowly developing cyclic drought. The involvement of selected MYB TFs in the regulation of cuticle biosynthesis was confirmed by a transient expression assay in wheat cell culture, using the promoters of wheat genes encoding cuticle biosynthesis-related enzymes and the SHINE1 (SHN1) TF. Two functional MYB-responsive elements, specifically recognized by TaMYB74 but not by other MYB TFs, were localized in the TdSHN1 promoter. Protein structural determinants underlying the binding specificity of TaMYB74 for functional DNA cis-elements were defined, using 3D protein molecular modelling. A scheme, linking drought-induced expression of the investigated TFs with downstream genes that participate in the synthesis of cuticle components, is proposed. PMID- 27489238 TI - Feasibility of screening for atrial fibrillation in primary care: Just a heartbeat away? PMID- 27489239 TI - Dyspepsia and the microbiome: time to focus on the small intestine. PMID- 27489241 TI - Anti-NKG2D monoclonal antibody (NNC0142-0002) in active Crohn's disease: a randomised controlled trial. AB - OBJECTIVE: Anti-NKG2D (NNC0142-0002) is an antagonising human immunoglobulin G4 monoclonal antibody that binds to natural killer group 2 member D (NKG2D) receptors, which are expressed by T cells and innate lymphoid cells, and may be linked to mucosal damage in Crohn's disease (CD). DESIGN: Seventy-eight patients (aged >=18 and <=75 years) with CD for >=3 months, Crohn's Disease Activity Index (CDAI) >=220 and <=450 and either C-reactive protein >=10 mg/L or endoscopic evidence of inflammation, were randomised 1:1 to a single subcutaneous (SC) dose of 2 mg/kg anti-NKG2D or placebo. Primary endpoint was change in CDAI (DeltaCDAI) from baseline to week 4. Prespecified significance level was 10% for CDAI endpoints. A futility analysis was instituted due to slow recruitment. RESULTS: Primary endpoint was not significantly different between anti-NKG2D and placebo (week 4 DeltaCDAI=-16); however, there was a significant difference by week 12 (DeltaCDAI=-55; p<=0.10). Significant improvements were noted in the non-failure to biologics subgroup (treated with anti-NKG2D (n=28)) from week 1 onward. Greater effects of anti-NKG2D were also observed in patients with baseline CDAI >=330. Frequencies of adverse events (AEs) were comparable between anti-NKG2D and placebo. Most AEs were mild (49%) or moderate (43%). No antidrug antibodies were observed. CONCLUSIONS: A single SC dose of 2 mg/kg anti-NKG2D did not reduce disease activity at week 4 versus placebo, but the difference was significant at week 12, and effects were evident in key subgroups. These data support further development of anti-NKG2D in IBD. TRIAL REGISTRATION NUMBER: NCT01203631. PMID- 27489242 TI - Locked Away: Percutaneous Closure of a Malignant Left Atrial Appendage to Constrain an Unresolvable Thrombus. PMID- 27489244 TI - The Impact of Diabetes and Comorbidities on the Outcome of Heart Failure Patients Treated With Cardiac Resynchronization Therapy: Implications for Patient Management. PMID- 27489243 TI - Diabetes Mellitus and Outcomes of Cardiac Resynchronization With Implantable Cardioverter-Defibrillator Therapy in Older Patients With Heart Failure. AB - BACKGROUND: Large-scale data on outcomes with cardiac resynchronization therapy with defibrillator in patients with diabetes mellitus are limited. We compared outcomes after cardiac resynchronization therapy with defibrillator implantation among patients with heart failure who have diabetes mellitus versus those without diabetes mellitus. METHODS AND RESULTS: Survival curves and covariate adjusted hazard ratio (HR) or odds ratio were used to assess the risks for death, readmission, and device-related complications by diabetes mellitus status among 18 428 patients at least 65 years old receiving cardiac resynchronization therapy with defibrillator from the National Cardiovascular Data Registry, implantable cardioverter-defibrillator registry between 2006 and 2009, with up to 3 years of follow-up. Accounting for differences between groups, compared with those without diabetes mellitus (n=11 345), patients with diabetes mellitus (n=7083) had a higher risk of death both at 1 year (HR, 1.16 [95% confidence interval (CI), 1.05 1.29]; P=0.0037) and 3 years (HR, 1.21 [1.14-1.29]; P<0.001) after device implantation and higher risks of all-cause readmission (sub-HR, 1.16 [1.11-1.21] at 1 year; P<0.0001; sub-HR, 1.15 [1.11-1.19] at 3 years; P<0.0001) and heart failure-related readmission (sub-HR, 1.18 [1.09-1.28] at 1 year; P<0.0001; and sub-HR, 1.22 [1.15-1.30] at 3 years; P<0.0001). Device-related complications within 90 days did not differ between those with and without diabetes mellitus (odds ratio: 0.90 [0.77-1.06]; P=0.37). Interactions of age, sex, ischemic cardiomyopathy, renal failure, or QRS duration were not significant. CONCLUSIONS: In older patients with heart failure receiving cardiac resynchronization therapy with defibrillator, diabetes mellitus was independently associated with greater risks of death and rehospitalization, but similar risks of procedural complications. PMID- 27489245 TI - Increased Benefit With Vorapaxar Use in Patients With a History of Myocardial Infarction and Diabetes Mellitus: What the Data Show Us. AB - Type 2 diabetes mellitus (T2DM) is a progressive and multifactorial metabolic disease mainly characterized by hyperglycemia and insulin resistance. Abnormal platelet reactivity associated with an increased risk of cardiovascular disease (CVD) is also a feature characteristic of patients with T2DM. Dual antiplatelet therapy consisting of aspirin and an adenosine diphosphate platelet P2Y12 receptor antagonist, such as clopidogrel, represents the standard antithrombotic regimen for the secondary prevention of CVD risk in T2DM. However, a high proportion of patients with T2DM exhibit high on-treatment platelet reactivity to aspirin and/or clopidogrel, associated with a greater risk of adverse cardiovascular events compared with nondiabetic patients. Consequently, novel antiplatelet therapeutic approaches may be required in order to avoid such events. Vorapaxar is a novel antiplatelet agent that targets the platelet protease-activated receptor 1 and inhibits thrombin-induced platelet activation. Vorapaxar has been studied in 2 phase III clinical trials and has been approved for use in the secondary prevention of atherothrombotic events in patients with a previous myocardial infarction (MI) or peripheral arterial disease. New data from the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial MI cohort demonstrate that the subgroup of patients with T2DM exhibits increased benefit from vorapaxar use compared with non-T2DM patients. The aim of the present work is to critically review the current knowledge concerning vorapaxar use in patients with T2DM as well as to discuss the possible mechanism(s) underlying vorapaxar's beneficial effect in T2DM. PMID- 27489247 TI - Evaluating an Adaptive and Interactive mHealth Smoking Cessation and Medication Adherence Program: A Randomized Pilot Feasibility Study. AB - BACKGROUND: Mobile health (mHealth) interventions hold great promise for helping smokers quit since these programs can have wide reach and facilitate access to comprehensive, interactive, and adaptive treatment content. However, the feasibility, acceptability, and effectiveness of these programs remain largely untested. OBJECTIVE: To assess feasibility and acceptability of the My Mobile Advice Program (MyMAP) smoking cessation program and estimate its effects on smoking cessation and medication adherence to inform future research planning. METHODS: Sixty-six smokers ready to quit were recruited from a large regional health care system and randomized to one of two mHealth programs: (1) standard self-help including psychoeducational materials and guidance how to quit smoking or (2) an adaptive and interactive program consisting of the same standard mHealth self-help content as controls received plus a) real-time, adaptively tailored advice for managing nicotine withdrawal symptoms and medication side effects and b) asynchronous secure messaging with a cessation counselor. Participants in both arms were also prescribed a 12-week course of varenicline. Follow-up assessments were conducted at 2 weeks post-target quit date (TQD), 3 months post-TQD, and 5 months post-TQD. Indices of program feasibility and acceptability included acceptability ratings, utilization metrics including use of each MyMAP program component (self-help content, secure messaging, and adaptively tailored advice), and open-ended feedback from participants. Smoking abstinence and medication adherence were also assessed to estimate effects on these treatment outcomes. RESULTS: Utilization data indicated the MyMAP program was actively used, with higher mean program log-ins by experimental than control participants (10.6 vs 2.7, P<.001). The majority of experimental respondents thought the MyMAP program could help other people quit smoking (22/24, 92%) and consistently take their stop-smoking medication (17/22, 97%) and would recommend the program to others (20/23, 87%). They also rated the program as convenient, responsive to their needs, and easy to use. Abstinence rates at 5-month follow-up were 36% in the experimental arm versus 24% among controls (odds ratio 1.79 [0.61 5.19], P=.42). Experimental participants used their varenicline an average of 46 days versus 39 among controls (P=.49). More than two-thirds (22/33, 67%) of experimental participants and three-quarters (25/33, 76%) of controls prematurely discontinued their varenicline use (P=.29). CONCLUSIONS: The MyMAP intervention was found to be feasible and acceptable. Since the study was not powered for statistical significance, no conclusions can be drawn about the program's effects on smoking abstinence or medication adherence, but the overall study results suggest further evaluation in a larger randomized trial is warranted. CLINICALTRIAL: ClinicalTrials.gov NCT02136498; https://clinicaltrials.gov/ct2/show/NCT02136498 (Archived by WebCite at http://www.webcitation.org/6jT3UMFLj). PMID- 27489246 TI - Functional conservation of MBD proteins: MeCP2 and Drosophila MBD proteins alter sleep. AB - Proteins containing a methyl-CpG-binding domain (MBD) bind 5mC and convert the methylation pattern information into appropriate functional cellular states. The correct readout of epigenetic marks is of particular importance in the nervous system where abnormal expression or compromised MBD protein function, can lead to disease and developmental disorders. Recent evidence indicates that the genome of Drosophila melanogaster is methylated and two MBD proteins, dMBD2/3 and dMBD-R2, are present. Are Drosophila MBD proteins required for neuronal function, and as MBD-containing proteins have diverged and evolved, does the MBD domain retain the molecular properties required for conserved cellular function across species? To address these questions, we expressed the human MBD-containing protein, hMeCP2, in distinct amine neurons and quantified functional changes in sleep circuitry output using a high throughput assay in Drosophila. hMeCP2 expression resulted in phase-specific sleep loss and sleep fragmentation with the hMeCP2-mediated sleep deficits requiring an intact MBD domain. Reducing endogenous dMBD2/3 and dMBD-R2 levels also generated sleep fragmentation, with an increase in sleep occurring upon dMBD-R2 reduction. To examine if hMeCP2 and dMBD-R2 are targeting common neuronal functions, we reduced dMBD-R2 levels in combination with hMeCP2 expression and observed a complete rescue of sleep deficits. Furthermore, chromosomal binding experiments indicate MBD-R2 and MeCP2 associate on shared genomic loci. Our results provide the first demonstration that Drosophila MBD containing family members are required for neuronal function and suggest that the MBD domain retains considerable functional conservation at the whole organism level across species. PMID- 27489240 TI - Ulcerative proctitis is a frequent location of paediatric-onset UC and not a minor disease: a population-based study. AB - OBJECTIVE: Natural history of paediatric-onset ulcerative proctitis (UP) is poorly described. Our aim was to describe the phenotype and disease course of incident UP in a population-based study of paediatric-onset UC. PATIENTS AND METHODS: All patients with UC diagnosed <17 years from 1988 to 2004, and followed during >2 years have been extracted from a population-based registry. UC location was defined according to the Paris classification. Cumulative risks for use of immunosuppressants (IS), anti-tumour necrosis factor alpha (TNF-alpha) therapy, colonic extension and colectomy were described using Kaplan-Meier method. Risk factors for colonic extension were assessed using Cox proportional hazards models. RESULTS: 158 patients with paediatric-onset UC (91 females) with a median age at diagnosis of 14.5 years (Q1: 11.4-Q3: 16.1) have been identified and followed during a median of 11.4 years (8.2-15.8). Among them, 25% had UP (E1) at diagnosis and 49% of them presented a colonic extension at maximal follow-up. In these children, the cumulative risk for colonic extension was 10% at 1 year, 45% at 5 years and 52% at 10 years. No parameter at diagnosis was associated with colonic extension in the UP (E1 group). IS use was significantly lower in patients with UP than in those with E2, E3 or E4 location (p=0.049). For the UP cohort, the cumulative risk for colectomy was 3% at 1 year, 10% at 5 years, 13% at 10 years and 13% at 15 years. Risks for colonic extension, treatment with anti TNF-alpha and colectomy did not differ between the E1 group and the E2-E3-E4 group. CONCLUSIONS: UP is frequent in paediatric-onset UC and should not be considered as a minor disease. Compared with more extensive UC locations, risks for colonic extension, anti-TNF-alpha therapy and colectomy were similar in UP, whereas the risk for use of IM was lower. PMID- 27489248 TI - Roles of long noncoding RNAs in chromosome domains. AB - The cell nucleus is highly organized and functionally compartmentalized. Double stranded naked DNA is complexed with core histones and assembled into nucleosomes and chromatin, which are surrounded by nuclear domains composed of RNAs and proteins. Recently, three-dimensional views of chromosome organization beyond the level of the nucleosome have been established and are composed of several layers of chromosome domains. Only a small portion of the human genome encodes proteins; the majority is pervasively transcribed into noncoding RNAs whose functions are under intensive investigation. Importantly, the questions of how nuclear retained noncoding RNAs play roles in orchestrating the chromatin structure that have been addressed. We discuss the novel noncoding RNA clusters, Eleanors, which are derived from a large chromatin domain. They accumulate at the site of their own transcription to form RNA clouds in the nucleus, and they activate gene expression in the chromatin domain. Noncoding RNAs have emerging roles in genome regulation that are integrated into the spatial organization of chromatin and the nucleus. WIREs RNA 2017, 8:e1384. doi: 10.1002/wrna.1384 For further resources related to this article, please visit the WIREs website. PMID- 27489249 TI - First Reported Case of MitraClip Placement Due to Mitral Valve Flail in the Setting of Cardiac Amyloidosis. PMID- 27489251 TI - Diabetes-related stigma affects the quality of life of people living with diabetes mellitus in Switzerland: implications for healthcare providers. AB - There is a growing body of scientific evidence that stigma represents a reality for many people living with diabetes (PWD). However, little is known about the impact of experienced stigma. Against this background, the present study aimed to establish, by means of an in-depth consideration of the situation in Switzerland, whether and how experienced and perceived stigma impact the quality of life of those PWD affected. In this cross-sectional study, an anonymous paper-and-pencil self-administered questionnaire (SAQ) was used for data collection. The SAQ drew on a qualitative elicitation study and was distributed in 2013 to the readers of a Swiss journal destined to people living with diabetes. Data were analysed using descriptive statistics and structural equation modelling. The sample included 3347 people (response rate of 16%) with type 1 and 2 diabetes, aged 16-96. Respondents who reported higher levels of perceived stigma reported higher levels of psychological distress (beta = 0.37), more pronounced depressive symptoms (beta = 0.33) and less social support (beta = -0.22). Higher psychological distress (beta = -0.29) and more pronounced depressive symptoms (beta = -0.28), in turn, predicted lower quality of life. Findings suggest that stigma should be considered as an additional predictor of quality of life in PWD. Therefore, healthcare providers should support PWD's fight against stigma. Especially, social workers are called to engage in advocacy to reduce discrimination against PWD and claim equal chances for them. They are also called to develop and implement interventions to correct stereotypes about PWD. PMID- 27489250 TI - An assessment of a massively parallel sequencing approach for the identification of individuals from mass graves of the Spanish Civil War (1936-1939). AB - Next-generation sequencing technologies have opened new opportunities in forensic genetics. Here, we assess the applicability and performance of the MiSeq FGxTM & ForenSeqTM DNA Signature Prep Kit (Illumina) for the identification of individuals from the mass graves of the Spanish Civil War (1936-1939). The main limitations for individual identification are the low number of possible first degree living relatives and the high levels of DNA degradation reported in previous studies. Massively parallel sequencing technologies enabling the analysis of hundreds of regions and prioritizing short length amplicons constitute a promising tool for this kind of approaches. In this study, we first explore the power of this new technology to detect first- and second-degree kinship given different scenarios of DNA degradation. Second, we specifically assess its performance in a set of low DNA input samples previously analyzed with CE technologies. We conclude that this methodology will allow identification of up to second-degree relatives, even in situations with low sequencing performance and important levels of allele drop-out; it is thus a technology that resolves previous drawbacks and that will allow a successful approximation to the identification of remains. PMID- 27489253 TI - Novel Concordance Between Geographic, Environmental, and Genetic Structure in the Ecological Generalist Prickly Sculpin (Cottus asper) in California. AB - Ecological generalists may contain a wealth of information concerning diversity, ecology, and geographic connectivity throughout their range. We explored these ideas in prickly sculpin (Cottus asper), a small generalist freshwater fish species where coastal forms have potentially undergone radiations into inland lacustrine and riverine environments. Using a 962bp cytochrome b mtDNA marker and 11 microsatellites, we estimated diversity, divergence times, gene flow, and structure among populations at 43 locations throughout California. We then incorporated genetic and GIS data into ecological niche models to assess ecological conditions within identified groups. Though not reciprocally monophyletic, unique mtDNA haplotypes, microsatellite clustering, and measures of isolation by distance (Coastal: r = 0.960, P < 0.001; Inland: r = 0.277, P = 0.148) suggest 2 novel taxonomic groups, Coastal and Inland (constrained to Great Central Valley). Divergence estimates of 41-191 kya combined with the regional biogeographic history suggest geographic barriers are absent between groups since divergence, but ecological niche modeling revealed significant environmental differences (t = 10.84, P < 0.001). Introgressed individuals were also discovered between groups in an ecologically and geographically intermediate region. Population structure was limited, predominately found in tributaries of the San Joaquin basin in the Inland group. Overall, C. asper exhibited substantial genetic diversity, despite its ecological generality, reflecting California's historically unique and complex hydrology. More broadly, this study illustrates variable environments within the range of a generalist species may mask genetic divergences and should not be overlooked in biodiversity assessments. PMID- 27489252 TI - Heritability of Recurrent Exertional Rhabdomyolysis in Standardbred and Thoroughbred Racehorses Derived From SNP Genotyping Data. AB - Recurrent exertional rhabdomyolysis (RER) in Thoroughbred and Standardbred racehorses is characterized by episodes of muscle rigidity and cell damage that often recur upon strenuous exercise. The objective was to evaluate the importance of genetic factors in RER by obtaining an unbiased estimate of heritability in cohorts of unrelated Thoroughbred and Standardbred racehorses. Four hundred ninety-one Thoroughbred and 196 Standardbred racehorses were genotyped with the 54K or 74K SNP genotyping arrays. Heritability was calculated from genome-wide SNP data with a mixed linear and Bayesian model, utilizing the standard genetic relationship matrix (GRM). Both the mixed linear and Bayesian models estimated heritability of RER in Thoroughbreds to be approximately 0.34 and in Standardbred racehorses to be approximately 0.45 after adjusting for disease prevalence and sex. To account for potential differences in the genetic architecture of the underlying causal variants, heritability estimates were adjusted based on linkage disequilibrium weighted kinship matrix, minor allele frequency and variant effect size, yielding heritability estimates that ranged between 0.41-0.46 (Thoroughbreds) and 0.39-0.49 (Standardbreds). In conclusion, between 34-46% and 39-49% of the variance in RER susceptibility in Thoroughbred and Standardbred racehorses, respectively, can be explained by the SNPs present on these 2 genotyping arrays, indicating that RER is moderately heritable. These data provide further rationale for the investigation of genetic mutations associated with RER susceptibility. PMID- 27489255 TI - Comparison of second-line immunosuppressants for childhood refractory nephrotic syndrome: a systematic review and network meta-analysis. AB - Although, most patients respond initially to therapy for nephrotic syndrome, about 70% of patients have a relapse. Currently, there is no consensus about the most appropriate second-line agent in children who continue to suffer a relapse. This network meta-analysis was designed to compare the efficacy and safety of the commonly used immunosuppressive agents in second-line therapeutic agents (ie, cyclophosphamide, cyclosporine, tacrolimus and mycophenolate mofetil) for refractory childhood nephrotic syndrome. MEDLINE, Cochrane, EMBASE and Google Scholar databases were searched until October 17, 2015 using the following search terms: cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil and childhood nephrotic syndrome. Randomized controlled trials, prospective 2-arm studies and cohort studies were included. 7 studies with 391 patients were included. Bayesian network meta-analysis found that treatment with mycophenolate mofetil had the greatest odds of relapse compared with tacrolimus (pooled OR=49.72, 95% credibility interval (CrI) 1.65 to 2483.32), cyclophosphamide (pooled OR=72.05, 95% CrI 1.44 to 13633.33) and cyclosporine (pooled OR=11.42, 95% CrI 1.03 to 131.60). Rank probability analysis found cyclophosphamide was the best treatment with the lowest relapse rate as compared with other treatments (rank probability=0.58), and tacrolimus was ranked as the second best (rank probability=0.38). Our findings support the use of cyclophosphamide and tacrolimus in treating children with relapsing nephrotic syndrome. PMID- 27489254 TI - Normalization of NAD+ Redox Balance as a Therapy for Heart Failure. AB - BACKGROUND: Impairments of mitochondrial function in the heart are linked intricately to the development of heart failure, but there is no therapy for mitochondrial dysfunction. METHODS: We assessed the reduced/oxidized ratio of nicotinamide adenine dinucleotide (NADH/NAD(+) ratio) and protein acetylation in the failing heart. Proteome and acetylome analyses were followed by docking calculation, mutagenesis, and mitochondrial calcium uptake assays to determine the functional role of specific acetylation sites. The therapeutic effects of normalizing mitochondrial protein acetylation by expanding the NAD(+) pool also were tested. RESULTS: Increased NADH/NAD(+) and protein hyperacetylation, previously observed in genetic models of defective mitochondrial function, also are present in human failing hearts as well as in mouse hearts with pathologic hypertrophy. Elevation of NAD(+) levels by stimulating the NAD(+) salvage pathway suppressed mitochondrial protein hyperacetylation and cardiac hypertrophy, and improved cardiac function in responses to stresses. Acetylome analysis identified a subpopulation of mitochondrial proteins that was sensitive to changes in the NADH/NAD(+) ratio. Hyperacetylation of mitochondrial malate-aspartate shuttle proteins impaired the transport and oxidation of cytosolic NADH in the mitochondria, resulting in altered cytosolic redox state and energy deficiency. Furthermore, acetylation of oligomycin-sensitive conferring protein at lysine-70 in adenosine triphosphate synthase complex promoted its interaction with cyclophilin D, and sensitized the opening of mitochondrial permeability transition pore. Both could be alleviated by normalizing the NAD(+) redox balance either genetically or pharmacologically. CONCLUSIONS: We show that mitochondrial protein hyperacetylation due to NAD(+) redox imbalance contributes to the pathologic remodeling of the heart via 2 distinct mechanisms. Our preclinical data demonstrate a clear benefit of normalizing NADH/NAD(+) imbalance in the failing hearts. These findings have a high translational potential as the pharmacologic strategy of increasing NAD(+) precursors are feasible in humans. PMID- 27489256 TI - P values: from suggestion to superstition. AB - A threshold probability value of 'p<=0.05' is commonly used in clinical investigations to indicate statistical significance. To allow clinicians to better understand evidence generated by research studies, this review defines the p value, summarizes the historical origins of the p value approach to hypothesis testing, describes various applications of p<=0.05 in the context of clinical research and discusses the emergence of p<=5*10(-8) and other values as thresholds for genomic statistical analyses. Corresponding issues include a conceptual approach of evaluating whether data do not conform to a null hypothesis (ie, no exposure-outcome association). Importantly, and in the historical context of when p<=0.05 was first proposed, the 1-in-20 chance of a false-positive inference (ie, falsely concluding the existence of an exposure outcome association) was offered only as a suggestion. In current usage, however, p<=0.05 is often misunderstood as a rigid threshold, sometimes with a misguided 'win' (p<=0.05) or 'lose' (p>0.05) approach. Also, in contemporary genomic studies, a threshold of p<=10(-8) has been endorsed as a boundary for statistical significance when analyzing numerous genetic comparisons for each participant. A value of p<=0.05, or other thresholds, should not be employed reflexively to determine whether a clinical research investigation is trustworthy from a scientific perspective. Rather, and in parallel with conceptual issues of validity and generalizability, quantitative results should be interpreted using a combined assessment of strength of association, p values, CIs, and sample size. PMID- 27489258 TI - Older workers-workplace health evidence-based practice? PMID- 27489259 TI - Jean-Charles Develly, Impression sur etoffes. Teinture (Printing fabrics. Dyeing) c.1830. PMID- 27489260 TI - More hot air. PMID- 27489262 TI - Comment on: 'Systematic review of the cardiovascular effects of occupational noise' by Skogstad et al. PMID- 27489263 TI - Response to letter from Dr Dzhambow. PMID- 27489264 TI - Systematic review of the cardiovascular effects of occupational noise. PMID- 27489265 TI - Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan. AB - The envelope glycoprotein (Env) is the major target for HIV-1 broadly neutralizing antibodies (bNAbs). One of the mechanisms that HIV has evolved to escape the host's immune response is to mask conserved epitopes on Env with dense glycosylation. Previous studies have shown that the removal of a particular conserved glycan at N197 increases the neutralization sensitivity of the virus to antibodies targeting the CD4 binding site (CD4bs), making it a site of significant interest from the perspective of vaccine design. At present, the structural consequences that result from the removal of the N197 glycan have not been characterized. Using native-like SOSIP trimers, we examine the effects on antigenicity and local structural dynamics resulting from the removal of this glycan. A large increase in the binding of CD4bs and V3-targeting antibodies is observed for the N197Q mutant in trimeric Env, while no changes are observed with monomeric gp120. While the overall structure and thermostability are not altered, a subtle increase in the flexibility of the variable loops at the trimeric interface of adjacent protomers is evident in the N197Q mutant by hydrogen deuterium exchange mass spectrometry. Structural modeling of the glycan chains suggests that the spatial occupancy of the N197 glycan leads to steric clashes with CD4bs antibodies in the Env trimer but not monomeric gp120. Our results indicate that the removal of the N197 glycan enhances the exposure of relevant bNAb epitopes on Env with a minimal impact on the overall trimeric structure. These findings present a simple modification for enhancing trimeric Env immunogens in vaccines. IMPORTANCE: The HIV-1 Env glycoprotein presents a dense patchwork of host cell-derived N-linked glycans. This so-called glycan shield is considered to be a major protective mechanism against immune recognition. While the positions of many N-linked glycans are isolate specific, some are highly conserved and are believed to play key functional roles. In this study, we examine the conserved, CD4 binding site-proximal N197 glycan and demonstrate that its removal both facilitates neutralizing antibody access to the CD4 binding site and modestly impacts the structural dynamics at the trimer crown without drastically altering global Env trimer stability. This indicates that surgical glycosylation site modification may be an effective way of sculpting epitope presentation in Env-based vaccines. PMID- 27489266 TI - Mutations That Determine Resistance Breaking in a Plant RNA Virus Have Pleiotropic Effects on Its Fitness That Depend on the Host Environment and on the Type, Single or Mixed, of Infection. AB - Overcoming host resistance in gene-for-gene host-virus interactions is an important instance of host range expansion, which can be hindered by across-host fitness trade-offs. Trade-offs are generated by negative effects of host range mutations on the virus fitness in the original host, i.e., by antagonistic pleiotropy. It has been reported that different mutations in Pepper mild mottle virus (PMMoV) coat protein result in overcoming L-gene resistance in pepper. To analyze if resistance-breaking mutations in PMMoV result in antagonistic pleiotropy, all reported mutations determining the overcoming of L(3) and L(4) alleles were introduced in biologically active cDNA clones. Then, the parental and mutant virus genotypes were assayed in susceptible pepper genotypes with an L(+), L(1), or L(2) allele, in single and in mixed infections. Resistance breaking mutations had pleiotropic effects on the virus fitness that, according to the specific mutation, the host genotype, and the type of infection, single or mixed with other virus genotypes, were antagonistic or positive. Thus, resistance breaking mutations can generate fitness trade-offs both across hosts and across types of infection, and the frequency of host range mutants will depend on the genetic structure of the host population and on the frequency of mixed infections by different virus genotypes. Also, resistance-breaking mutations variously affected virulence, which may further influence the evolution of host range expansion. IMPORTANCE: A major cause of virus emergence is host range expansion, which may be hindered by across-host fitness trade-offs caused by negative pleiotropy of host range mutations. An important instance of host range expansion is overcoming host resistance in gene-for-gene plant-virus interactions. We analyze here if mutations in the coat protein of Pepper mild mottle virus determining L-gene resistance-breaking in pepper have associated fitness penalties in susceptible host genotypes. Results show that pleiotropic effects of resistance-breaking mutations on virus fitness depend on the specific mutation, the susceptible host genotype, and the type of infection, single or mixed, with other virus genotypes. Accordingly, resistance-breaking mutations can have negative, positive, or no pleiotropic effects on virus fitness. These results underscore the complexity of host range expansion evolution and, specifically, the difficulty of predicting the overcoming of resistance factors in crops. PMID- 27489267 TI - Acute Liver Damage Associated with Innate Immune Activation in a Small Nonhuman Primate Model of Hepacivirus Infection. AB - Despite its importance in shaping adaptive immune responses, viral clearance, and immune-based inflammation, tissue-specific innate immunity remains poorly characterized for hepatitis C virus (HCV) infection due to the lack of access to acutely infected tissues. In this study, we evaluated the impact of natural killer (NK) cells and myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells on control of virus replication and virus-induced pathology caused by another, more rapidly resolving hepacivirus, GB virus B (GBV-B), in infections of common marmosets. High plasma and liver viral loads and robust hepatitis characterized acute GBV-B infection, and while viremia was generally cleared by 2 to 3 months postinfection, hepatitis and liver fibrosis persisted after clearance. Coinciding with peak viral loads and liver pathology, the levels of NK cells, mDCs, and pDCs in the liver increased up to 3-fold. Although no obvious numerical changes in peripheral innate cells occurred, circulating NK cells exhibited increased perforin and Ki67 expression levels and increased surface expression of CXCR3. These data suggested that increased NK cell arming and proliferation as well as tissue trafficking may be associated with influx into the liver during acute infection. Indeed, NK cell frequencies in the liver positively correlated with plasma (R = 0.698; P = 0.015) and liver (R = 0.567; P = 0.057) viral loads. Finally, soluble factors associated with NK cells and DCs, including gamma interferon (IFN-gamma) and RANTES, were increased in acute infection and also were associated with viral loads and hepatitis. Collectively, the findings showed that mobilization of local and circulating innate immune responses was linked to acute virus-induced hepatitis, and potentially to resolution of GBV-B infection, and our results may provide insight into similar mechanisms in HCV infection. IMPORTANCE: Hepatitis C virus (HCV) infection has created a global health crisis, and despite new effective antivirals, it is still a leading cause of liver disease and death worldwide. Recent evidence suggests that innate immunity may be a potential therapeutic target for HCV, but it may also be a correlate of increased disease. Due to a lack of access to human tissues with acute HCV infection, in this study we evaluated the role of innate immunity in resolving infection with a hepacivirus, GBV-B, in common marmosets. Collectively, our data suggest that NK cell and DC mobilization in acute hepacivirus infection can dampen virus replication but also regulate acute and chronic liver damage. How these two opposing effects on the host may be modulated in future therapeutic and vaccine approaches warrants further study. PMID- 27489268 TI - Infectious Progression of Canine Distemper Virus from Circulating Cerebrospinal Fluid into the Central Nervous System. AB - In the current study, we generated recombinant chimeric canine distemper viruses (CDVs) by replacing the hemagglutinin (H) and/or phosphoprotein (P) gene in an avirulent strain expressing enhanced green fluorescent protein (EGFP) with those of a mouse-adapted neurovirulent strain. An in vitro experimental infection indicated that the chimeric CDVs possessing the H gene derived from the mouse adapted CDV acquired infectivity for neural cells. These cells lack the CDV receptors that have been identified to date (SLAM and nectin-4), indicating that the H protein defines infectivity in various cell lines. The recombinant viruses were administered intracerebrally to 1-week-old mice. Fatal neurological signs of disease were observed only with a recombinant CDV that possessed both the H and P genes of the mouse-adapted strain, similar to the parental mouse-adapted strain, suggesting that both genes are important to drive virulence of CDV in mice. Using this recombinant CDV, we traced the intracerebral propagation of CDV by detecting EGFP. Widespread infection was observed in the cerebral hemispheres and brainstems of the infected mice. In addition, EGFP fluorescence in the brain slices demonstrated a sequential infectious progression in the central nervous system: CDV primarily infected the neuroependymal cells lining the ventricular wall and the neurons of the hippocampus and cortex adjacent to the ventricle, and it then progressed to an extensive infection of the brain surface, followed by the parenchyma and cortex. In the hippocampal formation, CDV spread in a unidirectional retrograde pattern along neuronal processes in the hippocampal formation from the CA1 region to the CA3 region and the dentate gyrus. Our mouse model demonstrated that the main target cells of CDV are neurons in the acute phase and that the virus spreads via neuronal transmission pathways in the hippocampal formation. IMPORTANCE: CDV is the etiological agent of distemper in dogs and other carnivores, and in many respects, the pathogenesis of CDV infection in animals resembles that of measles virus infection in humans. We successfully generated a recombinant CDV containing the H and P genes from a mouse-adapted neurovirulent strain and expressing EGFP. The recombinant CDV exhibited severe neurovirulence with high mortality, comparable to the parental mouse-adapted strain. The mouse-infectious model could become a useful tool for analyzing CDV infection of the central nervous system subsequent to passing through the blood-cerebrospinal fluid barrier and infectious progression in the target cells in acute disease. PMID- 27489269 TI - Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease. AB - Bundibugyo virus (BDBV) is the etiological agent of a severe hemorrhagic fever in humans with a case-fatality rate ranging from 25 to 36%. Despite having been known to the scientific and medical communities for almost 1 decade, there is a dearth of studies on this pathogen due to the lack of a small animal model. Domestic ferrets are commonly used to study other RNA viruses, including members of the order Mononegavirales To investigate whether ferrets were susceptible to filovirus infections, ferrets were challenged with a clinical isolate of BDBV. Animals became viremic within 4 days and succumbed to infection between 8 and 9 days, and a petechial rash was observed with moribund ferrets. Furthermore, several hallmarks of human filoviral disease were recapitulated in the ferret model, including substantial decreases in lymphocyte and platelet counts and dysregulation of key biochemical markers related to hepatic/renal function, as well as coagulation abnormalities. Virological, histopathological, and immunohistochemical analyses confirmed uncontrolled BDBV replication in the major organs. Ferrets were also infected with Ebola virus (EBOV) to confirm their susceptibility to another filovirus species and to potentially establish a virus transmission model. Similar to what was seen with BDBV, important hallmarks of human filoviral disease were observed in EBOV-infected ferrets. This study demonstrates the potential of this small animal model for studying BDBV and EBOV using wild-type isolates and will accelerate efforts to understand filovirus pathogenesis and transmission as well as the development of specific vaccines and antivirals. IMPORTANCE: The 2013-2016 outbreak of Ebola virus in West Africa has highlighted the threat posed by filoviruses to global public health. Bundibugyo virus (BDBV) is a member of the genus Ebolavirus and has caused outbreaks in the past but is relatively understudied, likely due to the lack of a suitable small animal model. Such a model for BDBV is crucial to evaluating vaccines and therapies and potentially understanding transmission. To address this, we demonstrated that ferrets are susceptible models to BDBV infection as well as to Ebola virus infection and that no virus adaptation is required. Moreover, these animals develop a disease that is similar to that seen in humans and nonhuman primates. We believe that this will improve the ability to study BDBV and provide a platform to test vaccines and therapeutics. PMID- 27489270 TI - Inhibition of Human Metapneumovirus Binding to Heparan Sulfate Blocks Infection in Human Lung Cells and Airway Tissues. AB - Human metapneumovirus (HMPV), a recently discovered paramyxovirus, infects nearly 100% of the world population and causes severe respiratory disease in infants, the elderly, and immunocompromised patients. We previously showed that HMPV binds heparan sulfate proteoglycans (HSPGs) and that HMPV binding requires only the viral fusion (F) protein. To characterize the features of this interaction critical for HMPV binding and the role of this interaction in infection in relevant models, we utilized sulfated polysaccharides, heparan sulfate mimetics, and occluding compounds. Iota-carrageenan demonstrated potent anti-HMPV activity by inhibiting binding to lung cells mediated by the F protein. Furthermore, analysis of a minilibrary of variably sulfated derivatives of Escherichia coli K5 polysaccharide mimicking the HS structure revealed that the highly O-sulfated K5 polysaccharides inhibited HMPV infection, identifying a potential feature of HS critical for HMPV binding. The peptide dendrimer SB105-A10, which binds HS, reduced binding and infection in an F-dependent manner, suggesting that occlusion of HS at the target cell surface is sufficient to prevent infection. HMPV infection was also inhibited by these compounds during apical infection of polarized airway tissues, suggesting that these interactions take place during HMPV infection in a physiologically relevant model. These results reveal key features of the interaction between HMPV and HS, supporting the hypothesis that apical HS in the airway serves as a binding factor during infection, and HS modulating compounds may serve as a platform for potential antiviral development. IMPORTANCE: Human metapneumovirus (HMPV) is a paramyxovirus that causes respiratory disease worldwide. It has been previously shown that HMPV requires binding to heparan sulfate on the surfaces of target cells for attachment and infection. In this study, we characterize the key features of this binding interaction using heparan sulfate mimetics, identify an important sulfate modification, and demonstrate that these interactions occur at the apical surface of polarized airway tissues. These findings provide insights into the initial binding step of HMPV infection that has potential for antiviral development. PMID- 27489271 TI - Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements. AB - Human papillomavirus 18 (HPV18) is the second most common oncogenic HPV type associated with cervical, anogenital, and oropharyngeal cancers. Like other oncogenic HPVs, HPV18 encodes two major (one early and one late) polycistronic pre-mRNAs that are regulated by alternative RNA splicing to produce a repertoire of viral transcripts for the expression of individual viral genes. However, RNA cis-regulatory elements and trans-acting factors contributing to HPV18 alternative RNA splicing remain unknown. In this study, an exonic splicing enhancer (ESE) in the nucleotide (nt) 3520 to 3550 region in the HPV18 genome was identified and characterized for promotion of HPV18 929^3434 splicing and E1^E4 production through interaction with SRSF3, a host oncogenic splicing factor differentially expressed in epithelial cells and keratinocytes. Introduction of point mutations in the SRSF3-binding site or knockdown of SRSF3 expression in cells reduces 929^3434 splicing and E1^E4 production but activates other, minor 929^3465 and 929^3506 splicing. Knockdown of SRSF3 expression also enhances the expression of E2 and L1 mRNAs. An exonic splicing silencer (ESS) in the HPV18 nt 612 to 639 region was identified as being inhibitory to the 233^416 splicing of HPV18 E6E7 pre-mRNAs via binding to hnRNP A1, a well-characterized, abundantly and ubiquitously expressed RNA-binding protein. Introduction of point mutations into the hnRNP A1-binding site or knockdown of hnRNP A1 expression promoted 233^416 splicing and reduced E6 expression. These data provide the first evidence that the alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host trans-acting splicing factors. IMPORTANCE: Expression of HPV18 genes is regulated by alternative RNA splicing of viral polycistronic pre-mRNAs to produce a repertoire of viral early and late transcripts. RNA cis elements and trans-acting factors contributing to HPV18 alternative RNA splicing have been discovered in this study for the first time. The identified ESS at the E7 open reading frame (ORF) prevents HPV18 233^416 splicing in the E6 ORF through interaction with a host splicing factor, hnRNP A1, and regulates E6 and E7 expression of the early E6E7 polycistronic pre-mRNA. The identified ESE at the E1^E4 ORF promotes HPV18 929^3434 splicing of both viral early and late pre-mRNAs and E1^E4 production through interaction with SRSF3. This study provides important observations on how alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host splicing factors and offers potential therapeutic targets to overcome HPV-related cancer. PMID- 27489272 TI - ITCH E3 Ubiquitin Ligase Interacts with Ebola Virus VP40 To Regulate Budding. AB - Ebola virus (EBOV) and Marburg virus (MARV) belong to the Filoviridae family and can cause outbreaks of severe hemorrhagic fever, with high mortality rates in humans. The EBOV VP40 (eVP40) and MARV VP40 (mVP40) matrix proteins play a central role in virion assembly and egress, such that independent expression of VP40 leads to the production and egress of virus-like particles (VLPs) that accurately mimic the budding of infectious virus. Late (L) budding domains of eVP40 recruit host proteins (e.g., Tsg101, Nedd4, and Alix) that are important for efficient virus egress and spread. For example, the PPxY-type L domain of eVP40 and mVP40 recruits the host Nedd4 E3 ubiquitin ligase via its WW domains to facilitate budding. Here we sought to identify additional WW domain host interactors and demonstrate that the PPxY L domain motif of eVP40 interacts specifically with the WW domain of the host E3 ubiquitin ligase ITCH. ITCH, like Nedd4, is a member of the HECT class of E3 ubiquitin ligases, and the resultant physical and functional interaction with eVP40 facilitates VLP and virus budding. Identification of this novel eVP40 interactor highlights the functional interplay between cellular E3 ligases, ubiquitination, and regulation of VP40-mediated egress. IMPORTANCE: The unprecedented magnitude and scope of the recent 2014-2015 EBOV outbreak in West Africa and its emergence here in the United States and other countries underscore the critical need for a better understanding of the biology and pathogenesis of this emerging pathogen. We have identified a novel and functional EBOV VP40 interactor, ITCH, that regulates VP40-mediated egress. This virus-host interaction may represent a new target for our previously identified small-molecule inhibitors of virus egress. PMID- 27489274 TI - Global Transcriptional Analysis of Virus-Host Interactions between Phage phi29 and Bacillus subtilis. AB - The study of phage-host relationships is essential to understanding the dynamic of microbial systems. Here, we analyze genome-wide interactions of Bacillus subtilis and its lytic phage phi29 during the early stage of infection. Simultaneous high-resolution analysis of virus and host transcriptomes by deep RNA sequencing allowed us to identify differentially expressed bacterial genes. Phage phi29 induces significant transcriptional changes in about 0.9% (38/4,242) and 1.8% (76/4,242) of the host protein-coding genes after 8 and 16 min of infection, respectively. Gene ontology enrichment analysis clustered upregulated genes into several functional categories, such as nucleic acid metabolism (including DNA replication) and protein metabolism (including translation). Surprisingly, most of the transcriptional repressed genes were involved in the utilization of specific carbon sources such as ribose and inositol, and many contained promoter binding-sites for the catabolite control protein A (CcpA). Another interesting finding is the presence of previously uncharacterized antisense transcripts complementary to the well-known phage phi29 messenger RNAs that adds an additional layer to the viral transcriptome complexity. IMPORTANCE: The specific virus-host interactions that allow phages to redirect cellular machineries and energy resources to support the viral progeny production are poorly understood. This study provides, for the first time, an insight into the genome-wide transcriptional response of the Gram-positive model Bacillus subtilis to phage phi29 infection. PMID- 27489273 TI - Role of the B Allele of Influenza A Virus Segment 8 in Setting Mammalian Host Range and Pathogenicity. AB - Two alleles of segment 8 (NS) circulate in nonchiropteran influenza A viruses. The A allele is found in avian and mammalian viruses, but the B allele is viewed as being almost exclusively found in avian viruses. This might reflect the fact that one or both of its encoded proteins (NS1 and NEP) are maladapted for replication in mammalian hosts. To test this, a number of clade A and B avian virus-derived NS segments were introduced into human H1N1 and H3N2 viruses. In no case was the peak virus titer substantially reduced following infection of various mammalian cell types. Exemplar reassortant viruses also replicated to similar titers in mice, although mice infected with viruses with the avian virus derived segment 8s had reduced weight loss compared to that achieved in mice infected with the A/Puerto Rico/8/1934 (H1N1) parent. In vitro, the viruses coped similarly with type I interferons. Temporal proteomics analysis of cellular responses to infection showed that the avian virus-derived NS segments provoked lower levels of expression of interferon-stimulated genes in cells than wild type derived NS segments. Thus, neither the A nor the B allele of avian virus-derived NS segments necessarily attenuates virus replication in a mammalian host, although the alleles can attenuate disease. Phylogenetic analyses identified 32 independent incursions of an avian virus-derived A allele into mammals, whereas 6 introductions of a B allele were identified. However, A-allele isolates from birds outnumbered B-allele isolates, and the relative rates of Aves-to-Mammalia transmission were not significantly different. We conclude that while the introduction of an avian virus segment 8 into mammals is a relatively rare event, the dogma of the B allele being especially restricted is misleading, with implications in the assessment of the pandemic potential of avian influenza viruses. IMPORTANCE: Influenza A virus (IAV) can adapt to poultry and mammalian species, inflicting a great socioeconomic burden on farming and health care sectors. Host adaptation likely involves multiple viral factors. Here, we investigated the role of IAV segment 8. Segment 8 has evolved into two distinct clades: the A and B alleles. The B-allele genes have previously been suggested to be restricted to avian virus species. We introduced a selection of avian virus A- and B-allele segment 8s into human H1N1 and H3N2 virus backgrounds and found that these reassortant viruses were fully competent in mammalian host systems. We also analyzed the currently available public data on the segment 8 gene distribution and found surprisingly little evidence for specific avian host restriction of the B-clade segment. We conclude that B-allele segment 8 genes are, in fact, capable of supporting infection in mammals and that they should be considered during the assessment of the pandemic risk of zoonotic influenza A viruses. PMID- 27489275 TI - Protective Effects of Glutamine Antagonist 6-Diazo-5-Oxo-l-Norleucine in Mice with Alphavirus Encephalomyelitis. AB - Inflammation is a necessary part of the response to infection but can also cause neuronal injury in both infectious and autoimmune diseases of the central nervous system (CNS). A neurovirulent strain of Sindbis virus (NSV) causes fatal paralysis in adult C57BL/6 mice during clearance of infectious virus from the CNS, and the virus-specific immune response is implicated as a mediator of neuronal damage. Previous studies have shown that survival is improved in T-cell deficient mice and in mice with pharmacological inhibition of the inflammatory response and glutamate excitotoxicity. Because glutamine metabolism is important in the CNS for the generation of glutamate and in the immune system for lymphocyte proliferation, we tested the effect of the glutamine antagonist DON (6 diazo-5-oxo-l-norleucine) on the outcome of NSV infection in mice. DON treatment for 7 days from the time of infection delayed the onset of paralysis and death. Protection was associated with reduced lymphocyte proliferation in the draining cervical lymph nodes, decreased leukocyte infiltration into the CNS, lower levels of inflammatory cytokines, and delayed viral clearance. In vitro studies showed that DON inhibited stimulus-induced proliferation of lymphocytes. When in vivo treatment with DON was stopped, paralytic disease developed along with the inflammatory response and viral clearance. These studies show that fatal NSV induced encephalomyelitis is immune mediated and that antagonists of glutamine metabolism can modulate the immune response and protect against virus-induced neuroinflammatory disease. IMPORTANCE: Encephalomyelitis due to infection with mosquito-borne alphaviruses is an important cause of death and of long-term neurological disability in those who survive infection. This study demonstrates the role of the virus-induced immune response in the generation of neurological disease. DON, a glutamine antagonist, inhibited the proliferation of lymphocytes in response to infection, prevented the development of brain inflammation, and protected mice from paralysis and death during treatment. However, because DON inhibited the immune response to infection, clearance of the virus from the brain was also prevented. When treatment was stopped, the immune response was generated, brain inflammation occurred, virus was cleared, and mice developed paralysis and died. Therefore, more definitive treatment for alphaviral encephalomyelitis should inhibit virus replication as well as neuroinflammatory damage. PMID- 27489276 TI - Flexibility of the Head-Stalk Linker Domain of Paramyxovirus HN Glycoprotein Is Essential for Triggering Virus Fusion. AB - The Paramyxoviridae comprise a large family of enveloped, negative-sense, single stranded RNA viruses with significant economic and public health implications. For nearly all paramyxoviruses, infection is initiated by fusion of the viral and host cell plasma membranes in a pH-independent fashion. Fusion is orchestrated by the receptor binding protein hemagglutinin-neuraminidase (HN; also called H or G depending on the virus type) protein and a fusion (F) protein, the latter undergoing a major refolding process to merge the two membranes. Mechanistic details regarding the coupling of receptor binding to F activation are not fully understood. Here, we have identified the flexible loop region connecting the bulky enzymatically active head and the four-helix bundle stalk to be essential for fusion promotion. Proline substitution in this region of HN of parainfluenza virus 5 (PIV5) and Newcastle disease virus HN abolishes cell-cell fusion, whereas HN retains receptor binding and neuraminidase activity. By using reverse genetics, we engineered recombinant PIV5-EGFP viruses with mutations in the head stalk linker region of HN. Mutations in this region abolished virus recovery and infectivity. In sum, our data suggest that the loop region acts as a "hinge" around which the bulky head of HN swings to-and-fro to facilitate timely HN mediate F-triggering, a notion consistent with the stalk-mediated activation model of paramyxovirus fusion. IMPORTANCE: Paramyxovirus fusion with the host cell plasma membrane is essential for virus infection. Membrane fusion is orchestrated via interaction of the receptor binding protein (HN, H, or G) with the viral fusion glycoprotein (F). Two distinct models have been suggested to describe the mechanism of fusion: these include "the clamp" and the "provocateur" model of activation. By using biochemical and reverse genetics tools, we have obtained strong evidence in favor of the HN stalk-mediated activation of paramyxovirus fusion. Specifically, our data strongly support the notion that the short linker between the head and stalk plays a role in "conformational switching" of the head group to facilitate F-HN interaction and triggering. PMID- 27489277 TI - Mouse Hepatitis Virus Infection Induces a Toll-Like Receptor 2-Dependent Activation of Inflammatory Functions in Liver Sinusoidal Endothelial Cells during Acute Hepatitis. AB - Under physiological conditions, the liver sinusoidal endothelial cells (LSECs) mediate hepatic immune tolerance toward self or foreign antigens through constitutive expression of anti-inflammatory mediators. However, upon viral infection or Toll-like receptor 2 (TLR2) activation, LSECs can achieve proinflammatory functions, but their role in hepatic inflammation during acute viral hepatitis is unknown. Using the highly virulent mouse hepatitis virus type 3 (MHV3) and the attenuated variants 51.6-MHV3 and YAC-MHV3, exhibiting lower tropism for LSECs, we investigated in vivo and in vitro the consequence of LSEC infection on their proinflammatory profiles and the aggravation of acute hepatitis process. In vivo infection with virulent MHV3, in comparison to attenuated strains, resulted in fulminant hepatitis associated with higher hepatic viral load, tissue necrosis, and levels of inflammatory mediators and earlier recruitment of inflammatory cells. Such hepatic inflammatory disorders correlated with disturbed production of interleukin-10 (IL-10) and vascular factors by LSECs. We next showed in vitro that infection of LSECs by the virulent MHV3 strain altered their production of anti-inflammatory cytokines and promoted higher release of proinflammatory and procoagulant factors and earlier cell damage than infection by attenuated strains. This higher replication and proinflammatory activation in LSECs by the virulent MHV3 strain was associated with a specific activation of TLR2 signaling by the virus. We provide evidence that TLR2 activation of LSCEs by MHV3 is an aggravating factor of hepatic inflammation and correlates with the severity of hepatitis. Taken together, these results indicate that preservation of the immunotolerant properties of LSECs during acute viral hepatitis is imperative in order to limit hepatic inflammation and damage. IMPORTANCE: Viral hepatitis B and C infections are serious health problems affecting over 350 million and 170 million people worldwide, respectively. It has been suggested that a balance between protection and liver damage mediated by the host's immune response during the acute phase of infection would be determinant in hepatitis outcome. Thus, it appears crucial to identify the factors that predispose in exacerbating liver inflammation to limit hepatocyte injury. Liver sinusoidal endothelial cells (LSECs) can express both anti- and proinflammatory functions, but their role in acute viral hepatitis has never been investigated. Using mouse hepatitis virus (MHV) infections as animal models of viral hepatitis, we report for the first time that in vitro and in vivo infection of LSECs by the pathogenic MHV3 serotype leads to a reversion of their intrinsic anti-inflammatory phenotype toward a proinflammatory profile as well to as disorders in vascular factors, correlating with the severity of hepatitis. These results highlight a new virus-promoted mechanism of exacerbation of liver inflammatory response during acute hepatitis. PMID- 27489278 TI - Entry of Classical Swine Fever Virus into PK-15 Cells via a pH-, Dynamin-, and Cholesterol-Dependent, Clathrin-Mediated Endocytic Pathway That Requires Rab5 and Rab7. AB - Classical swine fever virus (CSFV), a member of the genus Pestivirus within the family Flaviviridae, is a small, enveloped, positive-strand RNA virus. Due to its economic importance to the pig industry, the biology and pathogenesis of CSFV have been investigated extensively. However, the mechanisms of CSFV entry into cells are not well characterized. In this study, we used systematic approaches to dissect CSFV cell entry. We first observed that CSFV infection was inhibited by chloroquine and NH4Cl, suggesting that viral entry required a low-pH environment. By using the specific inhibitor dynasore, or by expressing the dominant negative (DN) K44A mutant, we verified that dynamin is required for CSFV entry. CSFV particles were observed to colocalize with clathrin at 5 min postinternalization, and CSFV infection was significantly reduced by chlorpromazine treatment, overexpression of a dominant negative form of the EPS15 protein, or knockdown of the clathrin heavy chain by RNA interference. These results suggested that CSFV entry depends on clathrin. Additionally, we found that endocytosis of CSFV was dependent on membrane cholesterol, while neither the overexpression of a dominant negative caveolin mutant nor the knockdown of caveolin had an effect. These results further suggested that CSFV entry required cholesterol and not caveolae. Importantly, the effect of DN mutants of three Rab proteins that regulate endosomal traffic on CSFV infection was examined. Expression of DN Rab5 and Rab7 mutants, but not the DN Rab11 mutant, significantly inhibited CSFV replication. These results were confirmed by silencing of Rab5 and Rab7. Confocal microscopy showed that virus particles colocalized with Rab5 or Rab7 during the early phase of infection within 45 min after virus entry. These results indicated that after internalization, CSFV moved to early and late endosomes before releasing its RNA. Taken together, our findings demonstrate for the first time that CSFV enters cells through the endocytic pathway, providing new insights into the life cycle of pestiviruses. IMPORTANCE: Bovine viral diarrhea virus (BVDV), a single stranded, positive-sense pestivirus within the family Flaviviridae, is internalized by clathrin-dependent receptor-mediated endocytosis. However, the detailed mechanism of cell entry is unknown for other pestiviruses, such as classical swine fever (CSF) virus (CSFV). CSFV is the etiological agent of CSF, a highly contagious disease of swine that causes numerous deaths in pigs and enormous economic losses in China. Understanding the entry pathway of CSFV will not only advance our knowledge of CSFV infection and pathogenesis but also provide novel drug targets for antiviral intervention. Based on this objective, we used systematic approaches to dissect the pathway of entry of CSFV into PK-15 cells. This is the first report to show that the entry of CSFV into PK-15 cells requires a low-pH environment and involves dynamin- and cholesterol-dependent, clathrin-mediated endocytosis that requires Rab5 and Rab7. PMID- 27489279 TI - Neuroinvasion of alpha-Synuclein Prionoids after Intraperitoneal and Intraglossal Inoculation. AB - alpha-Synuclein is a soluble, cellular protein that in a number of neurodegenerative diseases, including Parkinson's disease and multiple system atrophy, forms pathological deposits of protein aggregates. Because misfolded alpha-synuclein has some characteristics that resemble those of prions, we investigated its potential to induce disease after intraperitoneal or intraglossal challenge injection into bigenic Tg(M83(+/-):Gfap-luc(+/-)) mice, which express the A53T mutant of human alpha-synuclein and firefly luciferase. After a single intraperitoneal injection with alpha-synuclein fibrils, four of five mice developed paralysis and alpha-synuclein pathology in the central nervous system, with a median incubation time of 229 +/- 17 days. Diseased mice accumulated aggregates of Sarkosyl-insoluble and phosphorylated alpha-synuclein in the brain and spinal cord, which colocalized with ubiquitin and p62 and were accompanied by gliosis. In contrast, only one of five mice developed alpha synuclein pathology in the central nervous system after intraglossal injection with alpha-synuclein fibrils, after 285 days. These findings are novel and important because they show that, similar to prions, alpha-synuclein prionoids can neuroinvade the central nervous system after intraperitoneal or intraglossal injection and can cause neuropathology and disease. IMPORTANCE: Synucleinopathies are neurodegenerative diseases that are characterized by the pathological presence of aggregated alpha-synuclein in cells of the nervous system. Previous studies have shown that alpha-synuclein aggregates made of recombinant protein or derived from brains of patients can spread in the central nervous system in a spatiotemporal manner when inoculated into the brains of animals and can induce pathology and neurologic disease, suggesting that misfolded alpha-synuclein can behave similarly to prions. Here we show that alpha-synuclein inoculation into the peritoneal cavity or the tongue in mice overexpressing alpha-synuclein causes neurodegeneration after neuroinvasion from the periphery, which further corroborates the prionoid character of misfolded alpha-synuclein. PMID- 27489280 TI - Fungus-Derived Neoechinulin B as a Novel Antagonist of Liver X Receptor, Identified by Chemical Genetics Using a Hepatitis C Virus Cell Culture System. AB - Cell culture systems reproducing virus replication can serve as unique models for the discovery of novel bioactive molecules. Here, using a hepatitis C virus (HCV) cell culture system, we identified neoechinulin B (NeoB), a fungus-derived compound, as an inhibitor of the liver X receptor (LXR). NeoB was initially identified by chemical screening as a compound that impeded the production of infectious HCV. Genome-wide transcriptome analysis and reporter assays revealed that NeoB specifically inhibits LXR-mediated transcription. NeoB was also shown to interact directly with LXRs. Analysis of structural analogs suggested that the molecular interaction of NeoB with LXR correlated with the capacity to inactivate LXR-mediated transcription and to modulate lipid metabolism in hepatocytes. Our data strongly suggested that NeoB is a novel LXR antagonist. Analysis using NeoB as a bioprobe revealed that LXRs support HCV replication: LXR inactivation resulted in dispersion of double-membrane vesicles, putative viral replication sites. Indeed, cells treated with NeoB showed decreased replicative permissiveness for poliovirus, which also replicates in double-membrane vesicles, but not for dengue virus, which replicates via a distinct membrane compartment. Together, our data suggest that LXR-mediated transcription regulates the formation of virus-associated membrane compartments. Significantly, inhibition of LXRs by NeoB enhanced the activity of all known classes of anti-HCV agents, and NeoB showed especially strong synergy when combined with interferon or an HCV NS5A inhibitor. Thus, our chemical genetics analysis demonstrates the utility of the HCV cell culture system for identifying novel bioactive molecules and characterizing the virus-host interaction machinery. IMPORTANCE: Hepatitis C virus (HCV) is highly dependent on host factors for efficient replication. In the present study, we used an HCV cell culture system to screen an uncharacterized chemical library. Our results identified neoechinulin B (NeoB) as a novel inhibitor of the liver X receptor (LXR). NeoB inhibited the induction of LXR regulated genes and altered lipid metabolism. Intriguingly, our results indicated that LXRs are critical to the process of HCV replication: LXR inactivation by NeoB disrupted double-membrane vesicles, putative sites of viral replication. Moreover, NeoB augmented the antiviral activity of all known classes of currently approved anti-HCV agents without increasing cytotoxicity. Thus, our strategy directly links the identification of novel bioactive compounds to basic virology and the development of new antiviral agents. PMID- 27489281 TI - Human Choline Kinase-alpha Promotes Hepatitis C Virus RNA Replication through Modulation of Membranous Viral Replication Complex Formation. AB - Hepatitis C virus (HCV) infection reorganizes cellular membranes to create an active viral replication site named the membranous web (MW). The role that human choline kinase-alpha (hCKalpha) plays in HCV replication remains elusive. Here, we first showed that hCKalpha activity, not the CDP-choline pathway, promoted viral RNA replication. Confocal microscopy and subcellular fractionation of HCV infected cells revealed that a small fraction of hCKalpha colocalized with the viral replication complex (RC) on the endoplasmic reticulum (ER) and that HCV infection increased hCKalpha localization to the ER. In the pTM-NS3-NS5B model, NS3-NS5B expression increased the localization of the wild-type, not the inactive D288A mutant, hCKalpha on the ER, and hCKalpha activity was required for effective trafficking of hCKalpha and NS5A to the ER. Coimmunoprecipitation showed that hCKalpha was recruited onto the viral RC presumably through its binding to NS5A domain 1 (D1). hCKalpha silencing or treatment with CK37, an hCKalpha activity inhibitor, abolished HCV-induced MW formation. In addition, hCKalpha depletion hindered NS5A localization on the ER, interfered with NS5A and NS5B colocalization, and mitigated NS5A-NS5B interactions but had no apparent effect on NS5A-NS4B and NS4B-NS5B interactions. Nevertheless, hCKalpha activity was not essential for the binding of NS5A to hCKalpha or NS5B. These findings demonstrate that hCKalpha forms a complex with NS5A and that hCKalpha activity enhances the targeting of the complex to the ER, where hCKalpha protein, not activity, mediates NS5A binding to NS5B, thereby promoting functional membranous viral RC assembly and viral RNA replication. IMPORTANCE: HCV infection reorganizes the cellular membrane to create an active viral replication site named the membranous web (MW). Here, we report that human choline kinase-alpha (hCKalpha) acts as an essential host factor for HCV RNA replication. A fraction of hCKalpha colocalizes with the viral replication complex (RC) on the endoplasmic reticulum (ER) in HCV-infected cells. NS3-NS5B expression increases ER localization of wild-type, but not D288A mutant, hCKalpha, and hCKalpha activity facilitates the transport of itself and NS5A to the ER. Silencing or inactivation of hCKalpha abrogates MW formation. Moreover, hCKalpha is recruited by NS5A independent of hCKalpha activity, presumably through binding to NS5A D1. hCKalpha activity then mediates the ER targeting of the hCKalpha-NS5A complex. On the ER membrane, hCKalpha protein, per se, induces NS5A binding to NS5B, thereby promoting membranous RC formation and viral RNA replication. Our study may benefit the development of hCKalpha-targeted anti-HCV therapeutics. PMID- 27489282 TI - Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 Is an Important Surface Attachment Factor That Facilitates Entry of Middle East Respiratory Syndrome Coronavirus. AB - The spike proteins of coronaviruses are capable of binding to a wide range of cellular targets, which contributes to the broad species tropism of coronaviruses. Previous reports have demonstrated that Middle East respiratory syndrome coronavirus (MERS-CoV) predominantly utilizes dipeptidyl peptidase 4 (DPP4) for cell entry. However, additional cellular binding targets of the MERS CoV spike protein that may augment MERS-CoV infection have not been further explored. In the current study, using the virus overlay protein binding assay (VOPBA), we identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a novel cell surface binding target of MERS-CoV. CEACAM5 coimmunoprecipitated with the spike protein of MERS-CoV in both overexpressed and endogenous settings. Disrupting the interaction between CEACAM5 and MERS-CoV spike with anti-CEACAM5 antibody, recombinant CEACAM5 protein, or small interfering RNA (siRNA) knockdown of CEACAM5 significantly inhibited the entry of MERS-CoV. Recombinant expression of CEACAM5 did not render nonpermissive baby hamster kidney (BHK21) cells susceptible to MERS-CoV infection. Instead, CEACAM5 overexpression significantly enhanced the attachment of MERS-CoV to the BHK21 cells. More importantly, the entry of MERS-CoV was increased when CEACAM5 was overexpressed in permissive cells, which suggested that CEACAM5 could facilitate MERS-CoV entry in conjunction with DPP4 despite not being able to support MERS CoV entry independently. Taken together, the results of our study identified CEACAM5 as a novel cell surface binding target of MERS-CoV that facilitates MERS CoV infection by augmenting the attachment of the virus to the host cell surface. IMPORTANCE: Infection with the Middle East respiratory syndrome coronavirus (MERS CoV) is associated with the highest mortality rate among all known human pathogenic coronaviruses. Currently, there are no approved vaccines or therapeutics against MERS-CoV infection. The identification of carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a novel cell surface binding target of MERS-CoV advanced our knowledge on the cell binding biology of MERS-CoV. Importantly, CEACAM5 could potentiate the entry of MERS-CoV by functioning as an attachment factor. In this regard, CEACAM5 could serve as a novel target, in addition to dipeptidyl peptidase-4 (DPP4), in the development of antiviral strategies for MERS-CoV. PMID- 27489284 TI - Leukotriene B4 Receptor 2 Is Critical for the Synthesis of Vascular Endothelial Growth Factor in Allergen-Stimulated Mast Cells. AB - Mast cells are among the principal effector cells in the pathogenesis of allergic asthma. In allergic reactions, allergen (Ag)-induced cross-linking of IgE bound to FcepsilonRI on mast cells results in the production of vascular endothelial growth factor (VEGF), which is essential for the initiation and development of the allergic response. Despite the central role of VEGF in allergic asthma, the signaling events responsible for the production of VEGF remain unclear, particularly in Ag-stimulated mast cells. In the present study, we observed that blocking leukotriene B4 receptor 2 (BLT2) completely abrogated the production of VEGF in Ag-stimulated bone marrow-derived mast cells (BMMCs). The synthesis of BLT2 ligands (leukotriene B4 and 12(S)-hydroxyeicosatetraenoic acid) was also required for VEGF production, suggesting a mediating role of an autocrine BLT2 ligands-BLT2 axis in the production of VEGF in mast cells. The NADPH oxidase 1 reactive oxygen species-NF-kappaB cascade is downstream of BLT2 during Ag signaling to VEGF synthesis in mast cells. Furthermore, the level of VEGF synthesis in genetically mast cell-deficient Kit(W/Wv) mice was significantly lower than that in wild-type mice in the OVA-induced asthma model, suggesting that mast cells play a critical role in the synthesis of VEGF in OVA-induced allergic asthma. Importantly, VEGF production was restored to the levels observed in wild-type mice after adoptive transfer of normal BMMCs into Kit(W/Wv) mice but was not restored in BLT2(-/-) BMMC-reconstituted Kit(W/Wv) mice in the OVA induced asthma model. Taken together, our results suggest that BLT2 expression in mast cells is essential for the production of VEGF in OVA-induced allergic asthma. PMID- 27489283 TI - Rpl22 Loss Selectively Impairs alphabeta T Cell Development by Dysregulating Endoplasmic Reticulum Stress Signaling. AB - Although ribosomal proteins (RP) are thought to primarily facilitate biogenesis of the ribosome and its ability to synthesize protein, emerging evidence suggests that individual RP can perform critical regulatory functions that control developmental processes. We showed previously that despite the ubiquitous expression of the RP ribosomal protein L22 (Rpl22), germline ablation of Rpl22 in mice causes a selective, p53-dependent block in the development of alphabeta, but not gammadelta, T cell progenitors. Nevertheless, the basis by which Rpl22 loss selectively induces p53 in alphabeta T cell progenitors remained unclear. We show in this study that Rpl22 regulates the development of alphabeta T cells by restraining endoplasmic reticulum (ER) stress responses. In the absence of Rpl22, ER stress is exacerbated in alphabeta, but not gammadelta, T cell progenitors. The exacerbated ER stress in Rpl22-deficient alphabeta T lineage progenitors is responsible for selective induction of p53 and their arrest, as pharmacological induction of stress is sufficient to induce p53 and replicate the selective block of alphabeta T cells, and attenuation of ER stress signaling by knockdown of protein kinase R-like ER kinase, an ER stress sensor, blunts p53 induction and rescues development of Rpl22-deficient alphabeta T cell progenitors. Rpl22 deficiency appears to exacerbate ER stress by interfering with the ability of ER stress signals to block new protein synthesis. Our finding that Rpl22 deficiency exacerbates ER stress responses and induces p53 in alphabeta T cell progenitors provides insight into how a ubiquitously expressed RP can perform regulatory functions that are selectively required by some cell lineages but not others. PMID- 27489285 TI - MAGE-C2-Specific TCRs Combined with Epigenetic Drug-Enhanced Antigenicity Yield Robust and Tumor-Selective T Cell Responses. AB - Adoptive T cell therapy has shown significant clinical success for patients with advanced melanoma and other tumors. Further development of T cell therapy requires improved strategies to select effective, yet nonself-reactive, TCRs. In this study, we isolated 10 TCR sequences against four MAGE-C2 (MC2) epitopes from melanoma patients who showed clinical responses following vaccination that were accompanied by significant frequencies of anti-MC2 CD8 T cells in blood and tumor without apparent side effects. We introduced these TCRs into T cells, pretreated tumor cells of different histological origins with the epigenetic drugs azacytidine and valproate, and tested tumor and self-reactivities of these TCRs. Pretreatment of tumor cells upregulated MC2 gene expression and enhanced recognition by T cells. In contrast, a panel of normal cell types did not express MC2 mRNA, and similar pretreatment did not result in recognition by MC2-directed T cells. Interestingly, the expression levels of MC2, but not those of CD80, CD86, or programmed death-ligand 1 or 2, correlated with T cell responsiveness. One of the tested TCRs consistently recognized pretreated MC2(+) cell lines from melanoma, head and neck, bladder, and triple-negative breast cancers but showed no response to MHC-eluted peptides or peptides highly similar to MC2. We conclude that targeting MC2 Ag, combined with epigenetic drug-enhanced antigenicity, allows for significant and tumor-selective T cell responses. PMID- 27489286 TI - ADAM17 is a Tumor Promoter and Therapeutic Target in Western Diet-associated Colon Cancer. AB - PURPOSE: Epidermal growth factor receptors (EGFR) are required for tumor promotion by Western diet. The metalloprotease, ADAM17 activates EGFR by releasing pro-EGFR ligands. ADAM17 is regulated by G-protein-coupled receptors, including CXCR4. Here we investigated CXCR4-ADAM17 crosstalk and examined the role of ADAM17 in tumorigenesis. EXPERIMENTAL DESIGN: We used CXCR4 inhibitor, AMD3100 and ADAM17 inhibitor, BMS566394 to assess CXCR4-ADAM17 crosstalk in colon cancer cells. We compared the expression of CXCR4 ligand, CXCL2, and ADAM17 in mice fed Western diet versus standard diet. Separately, mice were treated with marimastat, a broad-spectrum ADAM17 inhibitor, or AMD3100 to assess EGFR activation by ADAM17 and CXCR4. Using Apc-mutant Min mice, we investigated the effects of ADAM17/10 inhibitor INCB3619 on tumorigenesis. To assess the effects of colonocyte ADAM17, mice with ADAM17 conditional deletion were treated with azoxymethane (AOM). ADAM17 expression was also compared in colonocytes from primary human colon cancers and adjacent mucosa. RESULTS: CXCL12 treatment activated colon cancer cell EGFR signals, and CXCR4 or ADAM17 blockade reduced this activation. In vivo, Western diet increased CXCL12 in stromal cells and TGFalpha in colonocytes. Marimastat or AMD3100 caused >50% reduction in EGFR signals (P < 0.05). In Min mice, INCB3619 reduced EGFR signals in adenomas and inhibited intestinal tumor multiplicity (P < 0.05). In the AOM model, colonocyte ADAM17 deletion reduced EGFR signals and colonic tumor development (P < 0.05). Finally, ADAM17 was upregulated >2.5-fold in human malignant colonocytes. CONCLUSIONS: ADAM17 is a Western diet-inducible enzyme activated by CXCL12-CXCR4 signaling, suggesting the pathway: Western diet->CXCL12->CXCR4->ADAM17->TGFalpha >EGFR. ADAM17 might serve as a druggable target in chemoprevention strategies. Clin Cancer Res; 23(2); 549-61. (c)2016 AACR. PMID- 27489288 TI - Antihypoxic Potentiation of Standard Therapy for Experimental Colorectal Liver Metastasis through Myo-Inositol Trispyrophosphate. AB - PURPOSE: Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard of-care treatment. EXPERIMENTAL DESIGN: We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential. RESULTS: ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure. CONCLUSIONS: Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887-97. (c)2016 AACR. PMID- 27489287 TI - Skeletal Muscle Measures as Predictors of Toxicity, Hospitalization, and Survival in Patients with Metastatic Breast Cancer Receiving Taxane-Based Chemotherapy. AB - PURPOSE: Severe skeletal muscle (SM) loss (sarcopenia) is associated with poor cancer outcomes, including reduced survival and increased toxicity. This study investigates SM measures in metastatic breast cancer (MBC) patients receiving first-line taxane-based chemotherapy and evaluates associations with treatment toxicity and other outcomes. EXPERIMENTAL DESIGN: Using computerized tomography (CT) images taken for the evaluation of disease burden, skeletal muscle area (SMA), and density (SMD) were measured at the third lumbar vertebrae. Sarcopenia was defined as skeletal muscle index (SMI = SMA/height2) <= 41. Skeletal muscle gauge (SMG) was created by multiplying SMI * SMD. Fisher exact tests, t tests, the Kaplan-Meier method, and Cox regression modeling were used. RESULTS: MBC patients (N = 40), median age 55 (range, 34-80), 58% sarcopenic, median SMG 1296 AU (SD, 522). Grade 3-4 toxicity was found in 57% of sarcopenic versus 18% of non sarcopenic patients (P = 0.02). Toxicity-related hospitalizations were also higher in sarcopenic patients (39% vs. 0%, P = 0.005) as were any adverse events defined as any grade 3-4 toxicities, hospitalizations, dose reductions, or dose delay-(74% vs. 35%, P = 0.02). Low SMG was associated with grade 3-4 toxicity (P = 0.04), hospitalization (P = 0.01), and time to treatment failure (for progression or toxicity; P = 0.03). Low SMG had a borderline significant association with any adverse event (P = 0.06) and overall survival (P = 0.07). CONCLUSIONS: SM measures are associated with toxicity outcomes and survival in MBC patients receiving first-line taxane-based chemotherapy. Further studies are needed to explore how routinely obtained CT scans can be used to individualize dosing and improve treatment planning. Clin Cancer Res; 23(3); 658-65. (c)2016 AACR. PMID- 27489289 TI - Individualized Molecular Analyses Guide Efforts (IMAGE): A Prospective Study of Molecular Profiling of Tissue and Blood in Metastatic Triple-Negative Breast Cancer. AB - PURPOSE: The clinical utility of next-generation sequencing (NGS) in breast cancer has not been demonstrated. We hypothesized that we could perform NGS of a new biopsy from patients with metastatic triple-negative breast cancer (TNBC) in a clinically actionable timeframe. EXPERIMENTAL DESIGN: We planned to enroll 40 patients onto a prospective study, Individualized Molecular Analyses Guide Efforts (IMAGE), to evaluate the feasibility of obtaining a new biopsy of a metastatic site, perform NGS (FoundationOne), and convene a molecular tumor board to formulate treatment recommendations within 28 days. We collected blood at baseline and at time of restaging to assess cell-free circulating plasma tumor DNA (ptDNA). RESULTS: We enrolled 26 women with metastatic TNBC who had received >=1 line of prior chemotherapy, and 20 (77%) underwent NGS of a metastatic site biopsy. Twelve (60%) evaluable patients received treatment recommendations within 28 days of consent. The study closed after 20 patients underwent NGS, based on protocol-specified interim futility analysis. Three patients went on to receive genomically directed therapies. Twenty-four of 26 patients had genetic alterations successfully detected in ptDNA. Among 5 patients, 4 mutations found in tumor tissues were not identified in blood, and 4 mutations found in blood were not found in corresponding tumors. In 9 patients, NGS of follow-up blood samples showed 100% concordance with baseline blood samples. CONCLUSIONS: This study demonstrates challenges of performing NGS on prospective tissue biopsies in patients with metastatic TNBC within 28 days, while also highlighting the potential use of blood as a more time-efficient and less invasive method of mutational assessment. Clin Cancer Res; 23(2); 379-86. (c)2016 AACR. PMID- 27489292 TI - Systemic lupus erythematosus: not just a rash. PMID- 27489291 TI - Cell-free Determination of Binary Complexes That Comprise Extended Protein Protein Interaction Networks of Yersinia pestis. AB - Binary protein interactions form the basic building blocks of molecular networks and dynamic assemblies that control all cellular functions of bacteria. Although these protein interactions are a potential source of targets for the development of new antibiotics, few high-confidence data sets are available for the large proteomes of most pathogenic bacteria. We used a library of recombinant proteins from the plague bacterium Yersinia pestis to probe planar microarrays of immobilized proteins that represented ~85% (3552 proteins) of the bacterial proteome, resulting in >77,000 experimentally determined binary interactions. Moderate (KD ~MUm) to high-affinity (KD ~nm) interactions were characterized for >1600 binary complexes by surface plasmon resonance imaging of microarrayed proteins. Core binary interactions that were in common with other gram-negative bacteria were identified from the results of both microarray methods. Clustering of proteins within the interaction network by function revealed statistically enriched complexes and pathways involved in replication, biosynthesis, virulence, metabolism, and other diverse biological processes. The interaction pathways included many proteins with no previously known function. Further, a large assembly of proteins linked to transcription and translation were contained within highly interconnected subregions of the network. The two-tiered microarray approach used here is an innovative method for detecting binary interactions, and the resulting data will serve as a critical resource for the analysis of protein interaction networks that function within an important human pathogen. PMID- 27489290 TI - Association of AR-V7 and Prostate-Specific Antigen RNA Levels in Blood with Efficacy of Abiraterone Acetate and Enzalutamide Treatment in Men with Prostate Cancer. AB - PURPOSE: We evaluated the association of PSA and androgen receptor splice variant 7 (AR-V7) transcript levels in patients' blood with time to treatment failure (TTF) and overall survival (OS) with abiraterone acetate and/or enzalutamide treatment in castration-resistant prostate cancer (CRPC) patients. EXPERIMENTAL DESIGN: RNA levels of AR-V7 and PSA in peripheral blood collected before treatment were quantified using droplet digital-PCR in retrospective cohorts treated with abiraterone acetate (N = 81) or enzalutamide (N = 51) for CRPC. Multivariable Cox regression adjusted for known prognostic factors was used for analyses. RESULTS: PSA transcripts were detected in 57% of abiraterone acetate treated patients and in 63% of enzalutamide-treated patients. PSA-positive patients had a shorter TTF than PSA-negative patients [adjusted HR = 2.27 (95% confidence interval (CI) 1.26-4.10) and 2.60 (95% CI, 1.19-5.69); P = 0.006 and 0.017 in abiraterone acetate and enzalutamide cohorts, respectively]. Patients with a higher-AR-V7 transcript level had a shorter TTF with abiraterone acetate and enzalutamide in univariate analysis (median 8.0 months vs. 15.6 months, P = 0.046 in abiraterone acetate-cohort and 3.6 months vs. 5.6 months; P = 0.050 in enzalutamide cohort). In multivariable models, the association with TTF remained significant in the enzalutamide cohort (adjusted HR = 2.02; 95% CI, 1.01-4.05; P = 0.048), but statistically insignificant in the abiraterone acetate cohort. In both cohorts, we observed potential prognostic value of both PSA and AR-V7 RNA expression on OS; patients with detectable PSA transcripts and high AR-V7 predicted the poorest OS. CONCLUSIONS: PSA and AR-V7 transcripts in blood potentially serve as biomarkers predicting TTF and OS with abiraterone acetate or enzalutamide treatment. If validated prospectively, their detection could be facilitated without isolation of circulating tumor cells. Clin Cancer Res; 23(3); 726-34. (c)2016 AACR. PMID- 27489293 TI - Non-accidental salt poisoning. PMID- 27489294 TI - Communities need to be equal partners in determining whether research is acceptable. PMID- 27489295 TI - Health Care Maintenance for the Pediatric Patient With Inflammatory Bowel Disease. AB - Nearly one-quarter of patients with inflammatory bowel disease (IBD) are younger than 20 years of age at diagnosis. Furthermore, the incidence of IBD in children continues to increase. Nevertheless, variation in management exists within the care of patients with IBD with regards to disease screening and preventive care. A multidisciplinary approach that involves the general practitioner and pediatric gastroenterologist is needed to routinely monitor growth, bone health, vitamin and mineral deficiencies, vaccination status, and endoscopic surveillance. It is also important to monitor for extraintestinal manifestations of IBD that may affect the liver, joints, skin, and eyes. The purpose of this article is to provide an updated overview of comprehensive care for pediatric patients with IBD. PMID- 27489296 TI - Communication Challenges in Neonatal Encephalopathy. AB - BACKGROUND: Families must process complex information related to neonatal encephalopathy and therapeutic hypothermia. METHODS: In this mixed methods study, semi-structured interviews were performed with parents whose infants were enrolled in an existing longitudinal cohort study of therapeutic hypothermia between 2011 and 2014. RESULTS: Thematic saturation was achieved after 20 interviews. Parental experience of communicating with clinicians was characterized by 3 principle themes. Theme 1 highlighted that a fragmented communication process mirrored the chaotic maternal and neonatal course. Parents often received key information about neonatal encephalopathy and therapeutic hypothermia from maternal clinicians. Infant medical information was often given to 1 family member (60%), who felt burdened by the responsibility to relay that information to others. Families universally valued the role of the bedside nurse, who was perceived as the primary source of communication for most (75%) families. Theme 2 encompassed the challenges of discussing the complex therapy of therapeutic hypothermia: families appreciated clinicians who used lay language and provided written material, and they often felt overwhelmed by technical information that made it hard to understand the "big picture" of their infant's medical course. Theme 3 involved the uncertain prognosis after neonatal encephalopathy. Parents appreciated specific expectations about their infant's long-term development, and experienced long-term distress about prognostic uncertainty. CONCLUSIONS: Communicating complex and large volumes of information in the midst of perinatal crisis presents inherent challenges for both clinicians and families. We identified an actionable set of communication challenges that can be addressed with targeted interventions. PMID- 27489297 TI - Stronger and More Vulnerable: A Balanced View of the Impacts of the NICU Experience on Parents. AB - For parents, the experience of having an infant in the NICU is often psychologically traumatic. No parent can be fully prepared for the extreme stress and range of emotions of caring for a critically ill newborn. As health care providers familiar with the NICU, we thought that we understood the impact of the NICU on parents. But we were not prepared to see the children in our own families as NICU patients. Here are some of the lessons our NICU experience has taught us. We offer these lessons in the hope of helping health professionals consider a balanced view of the NICU's impact on families. PMID- 27489298 TI - Sequential Acquisition of Anal Human Papillomavirus (HPV) Infection Following Genital Infection Among Men Who Have Sex With Women: The HPV Infection in Men (HIM) Study. AB - BACKGROUND: The purpose of this study was to assess the risk of sequential acquisition of anal human papillomavirus (HPV) infection following a type specific genital HPV infection for the 9-valent vaccine HPV types and investigate factors associated with sequential infection among men who have sex with women (MSW). METHODS: Genital and anal specimens were available for 1348 MSW participants, and HPV genotypes were detected using the Roche Linear Array assay. Sequential risk of anal HPV infection was assessed using hazard ratios (HRs) among men with prior genital infection, compared with men with no prior genital infection, in individual HPV type and grouped HPV analyses. RESULTS: In individual analyses, men with prior HPV 16 genital infections had a significantly higher risk of subsequent anal HPV 16 infections (HR, 4.63; 95% confidence interval [CI], 1.41-15.23). In grouped analyses, a significantly higher risk of sequential type-specific anal HPV infections was observed for any of the 9 types (adjusted HR, 2.80; 95% CI, 1.32-5.99), high-risk types (adjusted HR, 2.65; 95% CI, 1.26, 5.55), and low-risk types (adjusted HR, 5.89; 95% CI, 1.29, 27.01). CONCLUSIONS: MSW with prior genital HPV infections had a higher risk of a subsequent type-specific anal infection. The higher risk was not explained by sexual intercourse with female partners. Autoinoculation is a possible mechanism for the observed association. PMID- 27489299 TI - Human Papillomavirus Prevalence Among 88 Male Virgins Residing in Brazil, Mexico, and the United States. AB - This study determined the prevalence and risk factors for genital human papillomavirus (HPV) detection among men who deny ever engaging in penetrative sex. A questionnaire was administered to 4123 men from a cohort study of HPV natural history. Genital exfoliated cells were collected and genotyped for 36 HPV types. Eighty-eight men were classified as virgins. Log-binomial regression models identified factors associated with genital HPV detection. The prevalence of any and high-risk HPV types among 88 male virgins was 25.0% and 18.2%, respectively. Age and smoking status were associated with HPV detection. Further studies are needed to better understand the risk for HPV infection among male virgins. PMID- 27489300 TI - What Is the Correct Approach for Comparing GFR by Different Methods across Levels of GFR? PMID- 27489301 TI - Measurement Error as Alternative Explanation for the Observation that CrCl/GFR Ratio is Higher at Lower GFR. AB - BACKGROUND AND OBJECTIVES: Overestimation of GFR by urinary creatinine clearance (CrCl) at lower levels of GFR has long been attributed to enhanced creatinine secretion. However, this does not take into consideration the contribution of errors in measured GFR (and CrCl) due to short-term biologic variability or test imprecision. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed cross sectional data among 1342 participants from the Chronic Renal Insufficiency Cohort study with baseline measurement of GFR by iothalamate clearance (iGFR) and CrCl by 24-hour urine collection. We examined the CrCl/iGFR ratio classified by categories of iGFR and also by categories of CrCl. RESULTS: Overall, mean CrCl/iGFR ratio was 1.13. CrCl/iGFR ratio was higher at lower iGFR categories. In contrast, this ratio was lower at lower CrCl levels. We hypothesize these relationships could be due to measurement error, which is bolstered by replicating these trends in a simulation and modeling exercise in which there was no variation in the ratio of CrCl/iGFR with true kidney function but taking into account the effect of measurement error in both CrCl and iGFR (of magnitudes previously described in the literature). In our simulated data, the observed CrCl/iGFR ratio was higher at lower observed iGFR levels when patients were classified by categories of observed iGFR. When the same patients were classified by categories of observed CrCl, the observed CrCl/iGFR ratio was lower at lower observed CrCl levels. CONCLUSIONS: The combined empirical and modeling results suggest that measurement errors (in both CrCl and iGFR) should be considered as an alternative explanation for the longstanding observation that the ratio of CrCl to iGFR gets larger as iGFR decreases. PMID- 27489302 TI - A misleading false-negative result of Pneumocystis real-time PCR assay due to a rare punctual mutation: A French multicenter study. AB - This article describes a previously unreported mutation at position 210 (C210T) of the mitochondrial large subunit ribosomal RNA (mtLSUrRNA) gene of Pneumocystis jirovecii, which led to a false-negative result of a real-time polymerase chain reaction (PCR) assay. Since the aforementioned real-time PCR assay is widely used in France, a French multicenter study was conducted to estimate the mutation frequency and its potential impact on the routine diagnosis of Pneumocystis pneumonia (PCP). Through analysis of data obtained from eight centers, the mutation frequency was estimated at 0.28%. This low frequency should not call into question the routine use of this PCR assay. Nonetheless, the occurrence of the false-negative PCR result provides arguments for maintaining microscopic techniques combined to PCR assays to achieve PCP diagnosis. PMID- 27489303 TI - An in vitro model of granuloma-like cell aggregates substantiates early host immune responses against Mycobacterium massiliense infection. AB - Mycobacterium massiliense (M. mass), belonging to the M. abscessus complex, is a rapidly growing mycobacterium that is known to cause tuberculous-like lesions in humans. To better understand the interaction between host cells and M. mass, we used a recently developed in vitro model of early granuloma-like cell aggregates composed of human peripheral blood mononuclear cells (PBMCs). PBMCs formed granuloma-like, small and rounded cell aggregates when infected by live M. mass Microscopic examination showed monocytes and macrophages surrounded by lymphocytes, which resembled cell aggregation induced by M. tuberculosis (M. tb). M. mass-infected PBMCs exhibited higher expression levels of HLA-DR, CD86 and CD80 on macrophages, and a significant decrease in the populations of CD4+ and CD8+ T cells. Interestingly, low doses of M. mass were sufficient to infect PBMCs, while active host cell death was gradually induced with highly increased bacterial loads, reflecting host destruction and dissemination of virulent rapid growing mycobacteria (RGM). Collectively, this in vitro model of M. mass infection improves our understanding of the interplay of host immune cells with mycobacteria, and may be useful for developing therapeutics to control bacterial pathogenesis. PMID- 27489305 TI - Progresses in developmental biology. PMID- 27489306 TI - Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans. AB - Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders. PMID- 27489304 TI - Zebrafish P54 RNA helicases are cytoplasmic granule residents that are required for development and stress resilience. AB - Stress granules are cytoplasmic foci that directly respond to the protein synthesis status of the cell. Various environmental insults, such as oxidative stress or extreme heat, block protein synthesis; consequently, mRNA will stall in translation, and stress granules will immediately form and become enriched with mRNAs. P54 DEAD box RNA helicases are components of RNA granules such as P-bodies and stress granules. We studied the expression, in cytoplasmic foci, of both zebrafish P54 RNA helicases (P54a and P54b) during development and found that they are expressed in cytoplasmic granules under both normal conditions and stress conditions. In zebrafish embryos exposed to heat shock, some proportion of P54a and P54b helicases move to larger granules that exhibit the properties of genuine stress granules. Knockdown of P54a and/or P54b in zebrafish embryos produces developmental abnormalities restricted to the posterior trunk; further, these embryos do not form stress granules, and their survival upon exposure to heat-shock conditions is compromised. Our observations fit the model that cells lacking stress granules have no resilience or ability to recover once the stress has ended, indicating that stress granules play an essential role in the way organisms adapt to a changing environment. PMID- 27489307 TI - Platelets in Pulmonary Immune Responses and Inflammatory Lung Diseases. AB - Platelets are essential for physiological hemostasis and are central in pathological thrombosis. These are their traditional and best known activities in health and disease. In addition, however, platelets have specializations that broaden their functional repertoire considerably. These functional capabilities, some of which are recently discovered, include the ability to sense and respond to infectious and immune signals and to act as inflammatory effector cells. Human platelets and platelets from mice and other experimental animals can link the innate and adaptive limbs of the immune system and act across the immune continuum, often also linking immune and hemostatic functions. Traditional and newly recognized facets of the biology of platelets are relevant to defensive, physiological immune responses of the lungs and to inflammatory lung diseases. The emerging view of platelets as blood cells that are much more diverse and versatile than previously thought further predicts that additional features of the biology of platelets and of megakaryocytes, the precursors of platelets, will be discovered and that some of these will also influence pulmonary immune defenses and inflammatory injury. PMID- 27489308 TI - Copy-number variations are enriched for neurodevelopmental genes in children with developmental coordination disorder. AB - BACKGROUND: Developmental coordination disorder is a common neurodevelopment disorder that frequently co-occurs with other neurodevelopmental disorders including attention-deficit hyperactivity disorder (ADHD). Copy-number variations (CNVs) have been implicated in a number of neurodevelopmental and psychiatric disorders; however, the proportion of heritability in developmental coordination disorder (DCD) attributed to CNVs has not been explored. OBJECTIVE: This study aims to investigate how CNVs may contribute to the genetic architecture of DCD. METHODS: CNV analysis was performed on 82 extensively phenotyped Canadian children with DCD, with or without co-occurring ADHD and/or reading disorder, and 2988 healthy European controls using identical genome-wide SNP microarrays and CNV calling algorithms. RESULTS: An increased rate of large and rare genic CNVs (p=0.009) was detected, and there was an enrichment of duplications spanning brain-expressed genes (p=0.039) and genes previously implicated in other neurodevelopmental disorders (p=0.043). Genes and loci of particular interest in this group included: GAP43, RBFOX1, PTPRN2, SHANK3, 16p11.2 and distal 22q11.2. Although no recurrent CNVs were identified, 26% of DCD cases, where sample availability permitted segregation analysis, were found to have a de novo rare CNV. Of the inherited CNVs, 64% were from a parent who also had a neurodevelopmental disorder. CONCLUSIONS: These findings suggest that there may be shared susceptibility genes for DCD and other neurodevelopmental disorders and highlight the need for thorough phenotyping when investigating the genetics of neurodevelopmental disorders. Furthermore, these data provide compelling evidence supporting a genetic basis for DCD, and further implicate rare CNVs in the aetiology of neurodevelopmental disorders. PMID- 27489309 TI - SERCA2 Deficiency Impairs Pancreatic beta-Cell Function in Response to Diet Induced Obesity. AB - The sarcoendoplasmic reticulum (ER) Ca(2+) ATPase 2 (SERCA2) pump is a P-type ATPase tasked with the maintenance of ER Ca(2+) stores. Whereas beta-cell SERCA2 expression is reduced in diabetes, the role of SERCA2 in the regulation of whole body glucose homeostasis has remained uncharacterized. To this end, SERCA2 heterozygous mice (S2HET) were challenged with a high-fat diet (HFD) containing 45% of kilocalories from fat. After 16 weeks of the HFD, S2HET mice were hyperglycemic and glucose intolerant, but adiposity and insulin sensitivity were not different between HFD-fed S2HET mice and HFD-fed wild-type controls. Consistent with a defect in beta-cell function, insulin secretion, glucose induced cytosolic Ca(2+) mobilization, and the onset of steady-state glucose induced Ca(2+) oscillations were impaired in HFD-fed S2HET islets. Moreover, HFD fed S2HET mice exhibited reduced beta-cell mass and proliferation, altered insulin production and proinsulin processing, and increased islet ER stress and death. In contrast, SERCA2 activation with a small molecule allosteric activator increased ER Ca(2+) storage and rescued tunicamycin-induced beta-cell death. In aggregate, these data suggest a critical role for SERCA2 and the regulation of ER Ca(2+) homeostasis in the beta-cell compensatory response to diet-induced obesity. PMID- 27489310 TI - Partial Disruption of Lipolysis Increases Postexercise Insulin Sensitivity in Skeletal Muscle Despite Accumulation of DAG. AB - Type 2 diabetes and skeletal muscle insulin resistance have been linked to accumulation of the intramyocellular lipid-intermediate diacylglycerol (DAG). However, recent animal and human studies have questioned such an association. Given that DAG appears in different stereoisomers and has different reactivity in vitro, we investigated whether the described function of DAGs as mediators of lipid-induced insulin resistance was dependent on the different DAG isomers. We measured insulin-stimulated glucose uptake in hormone-sensitive lipase (HSL) knockout (KO) mice after treadmill exercise to stimulate the accumulation of DAGs in skeletal muscle. We found that, despite an increased DAG content in muscle after exercise in HSL KO mice, the HSL KO mice showed a higher insulin-stimulated glucose uptake postexercise compared with wild-type mice. Further analysis of the chemical structure and cellular localization of DAG in skeletal muscle revealed that HSL KO mice accumulated sn-1,3 DAG and not sn-1,2 DAG. Accordingly, these results highlight the importance of taking the chemical structure and cellular localization of DAG into account when evaluating the role of DAG in lipid-induced insulin resistance in skeletal muscle and that the accumulation of sn-1,3 DAG originating from lipolysis does not inhibit insulin-stimulated glucose uptake. PMID- 27489311 TI - Micromachining and validation of the scanning acoustic microscope spatial resolution and sensitivity calibration block for 20-230 MHz frequency range. AB - Scanning acoustic microscopy (SAM) is used as a routine non-destructive test tool for different diagnostic examinations: detection of defects such as microcracks, delamination, disbonding, inclusions, subsurface features in materials such as pores and cracks. SAM can be operated in a wide frequency range from Megahertz to Gigahertz. SAM measurement spatial resolution is diffraction limited by the wavelength of the acoustic wave in particular medium and also depends on individual transducers geometry. Actual SAM spatial resolution can be determined by measuring calibrated lithographically formed microstructures in high acoustic impedance materials. Numerical acoustic signal simulation method, based on the diffraction approach, was employed for the selection of the calibration block pattern geometry and linear dimensions of the elements. Universal calibration block for SAM operating in a 20-230 MHz frequency range was micromachined in high acoustic impedance ceramic substrates. Differently spaced (from 18 to 185 um) lines of the same width and different widths (from 17 to 113 um) but similar spacing lines were imposed in alumina ceramics employing one step lithography process, i.e. femtosecond laser ablation. Proposed SAM calibration pattern linear dimensions were characterized employing optical and scanning electron microscopy. Finally the samples were measured with SAM employing different frequency transducers and results were compared with the numerical simulations. It was obtained that resolution of SAM operating with 230 MHz transducer is not worse than 40 um. PMID- 27489313 TI - Persistence of Racial and Ethnic Differences in Utilization and Adverse Outcomes of Total Joint Replacement. PMID- 27489312 TI - Transcriptome Profiling of the Green Alga Spirogyra pratensis (Charophyta) Suggests an Ancestral Role for Ethylene in Cell Wall Metabolism, Photosynthesis, and Abiotic Stress Responses. AB - It is well known that ethylene regulates a diverse set of developmental and stress-related processes in angiosperms, yet its roles in early-diverging embryophytes and algae are poorly understood. Recently, it was shown that ethylene functions as a hormone in the charophyte green alga Spirogyra pratensis Since land plants evolved from charophytes, this implies conservation of ethylene as a hormone in green plants for at least 450 million years. However, the physiological role of ethylene in charophyte algae has remained unknown. To gain insight into ethylene responses in Spirogyra, we used mRNA sequencing to measure changes in gene expression over time in Spirogyra filaments in response to an ethylene treatment. Our analyses show that at the transcriptional level, ethylene predominantly regulates three processes in Spirogyra: (1) modification of the cell wall matrix by expansins and xyloglucan endotransglucosylases/hydrolases, (2) down-regulation of chlorophyll biosynthesis and photosynthesis, and (3) activation of abiotic stress responses. We confirmed that the photosynthetic capacity and chlorophyll content were reduced by an ethylene treatment and that several abiotic stress conditions could stimulate cell elongation in an ethylene dependent manner. We also found that the Spirogyra transcriptome harbors only 10 ethylene-responsive transcription factor (ERF) homologs, several of which are regulated by ethylene. These results provide an initial understanding of the hormonal responses induced by ethylene in Spirogyra and help to reconstruct the role of ethylene in ancestral charophytes prior to the origin of land plants. PMID- 27489314 TI - Racial and Ethnic Disparities in Utilization Rate, Hospital Volume, and Perioperative Outcomes After Total Knee Arthroplasty. AB - BACKGROUND: Previous studies of racial disparities in total joint replacement, particularly total knee arthroplasty, in the U.S. have predominantly focused on disparities between blacks and whites and were limited to Medicare patients or veterans, populations that are not representative of the entire U.S. POPULATION: We sought to study racial disparities in the utilization of total knee arthroplasty, the use of high-volume hospitals, and total knee arthroplasty outcomes, including mortality and complications, using all-payer databases. METHODS: We analyzed data from 8 years and 8 racially diverse states in the State Inpatient Databases (SID). Patient race was categorized according to the SID as white, black, Hispanic, Asian, Native American, and mixed race. Both crude and adjusted racial and/or ethnic disparities were evaluated. RESULTS: In comparison with whites (4.65 per 1000 population per year), black (3.90), Hispanic (3.71), Asian (3.89), Native American (4.40), and mixed-race (3.69) populations had lower rates of total knee arthroplasty utilization (p < 0.0001). After risk adjustment, the rate of total knee arthroplasty utilization was significantly lower for blacks (odds ratio [OR] = 0.87 [95% confidence interval (CI), 0.85 to 0.89]; p < 0.0001), Hispanics (OR = 0.76 [95% CI, 0.68 to 0.83]; p < 0.0001), Asians (OR = 0.83 [95% CI, 0.78 to 0.89]; p < 0.0001), Native Americans (OR = 0.87 [95% CI, 0.81 to 0.93]; p < 0.0001), and mixed race (OR = 0.84 [95% CI, 0.79 to 0.90]; p < 0.0001) compared with the rate for whites. Lower rates of total knee arthroplasty utilization for blacks, Hispanics, and mixed-race groups became worse over the years. Patients from minority groups were less likely to undergo total knee arthroplasty in high-volume hospitals than were whites. Moreover, the rates of mortality were significantly higher for blacks (OR = 1.52 [95% CI, 1.17 to 1.97]; p = 0.0017), Native Americans (OR = 6.52 [95% CI, 4.63 to 9.17]; p < 0.0001), and mixed-race patients (OR = 4.35 [95% CI, 3.24 to 5.84]; p < 0.0001). Blacks (OR = 1.08 [95% CI, 1.01 to 1.15]; p = 0.01) and mixed-race patients (OR = 1.17 [95% CI, 1.001 to 1.36]; p = 0.04) had higher rates of complications than whites. CONCLUSIONS: Minorities had lower rates of total knee arthroplasty utilization but higher rates of adverse health outcomes associated with the procedure, even after adjusting for patient-related and health-care system-related characteristics. Utilization rates were based on overall population as the proportion of the population with osteoarthritis requiring arthroplasty is unknown. Future studies that consider specific patient-level information with psychosocial and behavioral factors are needed. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27489315 TI - The Effect of the Risser Stage on Bracing Outcome in Adolescent Idiopathic Scoliosis. AB - BACKGROUND: To determine the influence of the Risser sign on the need for surgery in children wearing orthoses for the treatment of adolescent idiopathic scoliosis (AIS), data on compliance with brace wear were collected and analyzed. METHODS: One hundred and sixty-eight patients were prospectively enrolled at the time that brace wear had been prescribed and were followed until the cessation of bracing or the need for surgery. Inclusion criteria were a curve magnitude between 25 degrees and 45 degrees ; a Risser stage of 0, 1, or 2; and, if female, <1 year post menarche at the time of brace prescription. Compliance was measured using thermal monitors. RESULTS: The prevalence of surgery, or progression to a curve magnitude of >=50 degrees , was 44.2% for patients at Risser stage 0 (n = 120), 6.9% for patients at Risser stage 1 (n = 29), and 0% for patients at Risser stage 2 (n = 19). Brace wear averaged 11.3, 13.4, and 14.2 hours per day for the Risser stage-0, 1, and 2 groups, respectively. While the groups had no difference in initial curve magnitude (p = 0.11), more patients at Risser stage 0 had progression to surgery than did patients at Risser stage 1 or stage 2 despite bracing (p < 0.0001). Twenty-six (41.9%) of 62 Risser stage-0 patients who wore braces >=12.9 hours per day had progression to surgery. Ten patients at Risser stage 0 with closed triradiate cartilage wore braces >=18 hours per day, and none underwent surgery. In comparison, 7 of 10 patients at Risser stage 0 with open triradiate cartilage and similar daily brace wear underwent surgery. Of 9 patients at Risser stage 0 with open triradiate cartilage who wore braces >=12.9 hours daily for curves measuring <30 degrees , 7 had a nonsurgical outcome. CONCLUSIONS: Patients at Risser stage 0 are at risk for surgery despite brace wear. In these patients, 12.9 hours of daily wear-the number of hours linked with a successful outcome in the BRAIST (Bracing in Adolescent Idiopathic Scoliosis Trial)-did not prevent surgery. Patients with open triradiate cartilage were at highest risk, especially those with curves of >=30 degrees . Risser stage-0 patients should be prescribed a minimum of 18 hours of brace wear. Bracing should be initiated for curves of <30 degrees in patients at Risser stage 0, especially those with open triradiate cartilage. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 27489316 TI - The Importance of Sufficient Graft Material in Achieving Foot or Ankle Fusion. AB - BACKGROUND: Nonunion, an important complication following foot and ankle arthrodesis, causes substantial morbidity and disability. In patients undergoing hindfoot and ankle arthrodesis, autogenous bone graft (autograft) or a suitable alternative is often used to promote osseous fusion across the joint. This study assessed the importance of adequate graft material in the fusion space to achieve joint fusion during ankle and hindfoot arthrodesis. METHODS: This study used data from a previously published clinical trial of grafting material (recombinant human platelet-derived growth factor-BB with beta-tricalcium phosphate [rhPDGF BB/beta-TCP] or autograft) for healing in hindfoot and ankle arthrodesis to correlate the amount of graft fill at 9 weeks with ultimate healing. Patients who received supplemental graft material for ankle or hindfoot arthrodesis for end stage ankle or hindfoot arthritis were stratified according to nonunion risk factors and surgical fusion site. Patients underwent arthrodesis using standard rigid internal fixation. Graft fill was defined as "adequate" if the material occupied >=50% of the cross-sectional area of the fusion space on a computed tomography (CT) scan made at 9 weeks. Fusion was defined as osseous bridging of >=50% of each articulation on a CT scan made at 24 weeks. Three hundred and seventy-nine patients with 573 joints (383 managed with rhPDGF-BB/beta-TCP and 190 managed with autograft) that underwent arthrodesis had complete follow-up with 9-week and 24-week CT scans available. RESULTS: Overall, 472 (82%) of 573 joints had adequate graft fill; of those, 383 (81%) were successfully fused at 24 weeks compared with 21 (21%) of 101 joints without adequate graft fill (p < 0.0001). Absolute fusion rate differences (joints with adequate fill minus those without adequate fill) were consistent across joints (61% to 63%) and for graft materials. The overall odds ratio (OR) of successful fusion in joints with adequate graft fill compared with those without adequate graft fill was 16.4 (95% confidence interval, 9.6 to 27.9). CONCLUSIONS: This study demonstrates an association between the amount of graft material and successful hindfoot and ankle arthrodesis. Graft material filling of >=50% of the fusion space at 9 weeks, regardless of type or origin, was associated with significantly higher fusion rates at 24 weeks. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 27489317 TI - Arthroscopic Lateral Collateral Ligament Repair. AB - BACKGROUND: Lateral ulnar collateral ligament injury following unstable elbow dislocation can induce posterolateral rotatory instability that requires surgery. The aim of this study was to determine the effectiveness of arthroscopic repair of the lateral collateral ligament (LCL) complex in an unstable elbow joint. METHODS: The study group consisted of 13 patients who experienced posterolateral rotatory instability after an unstable elbow dislocation with an injury to the lateral ulnar collateral ligament. The diagnosis was confirmed with computed tomography (CT), magnetic resonance imaging (MRI), and physical examination. The patients underwent arthroscopically assisted surgery between May 2011 and January 2013 and were followed for a minimum of 18 months postoperatively. Coronoid and/or radial head fractures combined with the ligament injury were treated through an arthroscopic technique. Range of motion, pain, outcomes according to the Mayo Elbow Performance Score (MEPS) and Nestor grading system, and surgical complications were evaluated. CT and MRI were performed at 3 months postoperatively, and isometric muscle strength was measured at the time of final follow-up. RESULTS: At the time of final follow-up, at a minimum of 18 months, all 13 patients reported complete resolution of the instability and average (and standard deviation) extension of 3 degrees +/- 1 degrees , flexion of 138 degrees +/- 6 degrees , supination of 88 degrees +/- 5 degrees , and pronation of 87 degrees +/- 6. The mean MEPS was 92 points and, according to this validated outcome score, the results were rated as excellent in 12 patients and good in 1 patient. According to the Nestor grading system, the results were rated as excellent in 11 patients and good in 2. Complete healing was seen on the 3 month follow-up MRI in 12 patients; however, 1 patient had mild widening of the radiocapitellar joint space with incomplete healing but no instability symptoms. All patients demonstrated normal strength on elbow flexion, extension, pronation, and supination at the final follow-up visit. CONCLUSIONS: Arthroscopic repair of the LCL complex in patients with posterolateral rotatory instability after an unstable elbow dislocation, with or without an intra-articular fracture, is an alternative treatment option for restoring elbow stability and achieving satisfactory clinical and radiographic results. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27489318 TI - The Long-Term Outcome After Varus Derotational Osteotomy for Legg-Calve-Perthes Disease: A Mean Follow-up of 42 Years. AB - BACKGROUND: Varus derotational osteotomy (VDRO) is one of the most common surgical treatments for Legg-Calve-Perthes disease, yet its long-term results have not been fully assessed. We aimed to determine the long-term clinical and radiographic outcomes following VDRO. METHODS: Forty patients (43 hips) who underwent VDRO for Legg-Calve-Perthes disease at our institution from 1959 to 1983, and participated in a follow-up study completed 10 years earlier, were approached for the present study. Clinical examination and radiographs were evaluated. Hip status and well-being were assessed with the Harris hip score and the Short Form-36 (SF-36). RESULTS: Thirty-five patients (37 hips) participated in the study. Information regarding the need for an arthroplasty was gathered on 4 additional hips from the previous study. The mean follow-up was 42.5 years (range, 32.4 to 56.5 years), with a mean patient age of 50.2 years (range, 35.9 to 67.8 years). In total, 7 patients (7 hips; 17% of 41 hips for which information was available, including 1 hip from the original cohort of 40 patients [43 hips]), underwent a total hip arthroplasty for hip pain. Excluding patients who had undergone an arthroplasty, the mean Harris hip and SF-36 scores were 79.8 points (range, 23.1 to 100 points) and 74.8 (range, 15.1 to 100), respectively. Twenty (64.5%) of the 31 hips that had not been replaced achieved a good or excellent Harris hip score (>=80 points). Sixteen (57.1%) of 28 hips with follow-up radiographs had no, or minimal, signs of osteoarthritis. The Stulberg classification was associated with the Harris hip score, the SF-36 score, hip pain, a Trendelenburg sign, coxa magna, and the Tonnis grade. In a multivariate analysis, the Stulberg classification was the only factor associated with fair or poor outcomes (a Harris hip score of <80 points). Patients with a Stulberg class III or IV hip had significant deterioration with respect to the Harris hip score and Tonnis grade during the 10-year period since the last follow-up. CONCLUSIONS: A long-term follow-up of patients who were operatively treated for Legg-Calve Perthes disease revealed that a low proportion underwent total hip arthroplasty and a relatively high proportion maintained good clinical and radiographic outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27489319 TI - Midterm Results of Porous Tantalum Femoral Cones in Revision Total Knee Arthroplasty. AB - BACKGROUND: Severe bone loss during a revision total knee arthroplasty (TKA) remains a challenging problem. The purpose of this study was to determine the midterm clinical outcomes, fixation as evaluated radiographically, and survivorship of tantalum femoral cones used during revision TKAs in patients with severe femoral bone loss. METHODS: From 2003 to 2011, 159 tantalum metaphyseal femoral cones were implanted in 157 patients at a single institution. Knee Society scores, radiographic results, and implant survivorship were analyzed. Two patients were lost to follow-up. Nineteen died of causes unrelated to the surgery but had been followed for >2 years and thus were included in the study. The mean age at the time of the index surgery was 64 years, and 82 patients were male. The mean duration of follow-up was 5 years (range, 2 to 10 years). RESULTS: The mean Knee Society score increased from 47 preoperatively to 65 at the most recent follow-up evaluation (p = 0.1). Radiographically, all 134 unrevised femoral cones were seen to be well fixed without any evidence of loosening. At 5 years, 23 cones had been revised: 14 because of infection, 6 because of aseptic loosening of the cone (all in hinged TKAs in patients with a Type-3 defect), and 3 because of ligamentous instability. The 5-year survivorship was 96% when the end point was revision of the cone due to aseptic loosening, 84% when it was revision of the cone for any reason, and 70% when it was any reoperation. CONCLUSIONS: In what we believe to be the largest series of such implants, femoral cones provided a durable and reliable option for metaphyseal fixation during revision TKA with severe femoral bone loss. Aseptic failure of the femoral cone was associated with use of a hinged TKA in a patient with a Type-3 bone defect. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27489320 TI - Risk Factors for Deep Infection Following Plate Fixation of Proximal Tibial Fractures. AB - BACKGROUND: The risk factors are unclear for deep surgical site infection after plate fixation of proximal tibial fractures. The objective of this study was to identify the patient and surgical procedure-related risk factors for infection using established criteria for deep surgical site infection. METHODS: A total of 655 proximal tibial fractures were treated with open reduction and plate fixation at our center between 2004 and 2013. We identified 34 patients with deep surgical site infection. A control group of 136 patients was randomly selected from the non-infected cohort. Potential risk factors for deep surgical site infection were identified by reviewing surgical, medical, and radiographic records. Independent risk factors for infection were identified from multivariable logistic regression analysis using a stepwise procedure. RESULTS: The prevalence of deep surgical site infection was 5.2%, the mean age of affected patients was 55 years (range, 16 to 84 years), and 35% of patients were female. Twenty-eight of 34 deep infections were diagnosed within 2 months (acute onset), and only 6 infections were diagnosed >6 months after the index surgical procedure. Nine of the 28 acute onset infections were treated with antibiotic therapy and debridement. Seventeen patients (50%) required muscle flap coverage, and 5 patients (15%) eventually required above-the-knee amputation. In the multivariable logistic regression analysis with odds ratios (ORs) and 95% confidence intervals (95% CIs), independent predictors of infection were patient age of >=50 years (OR, 3.6 [95% CI, 1.3 to 10.1]); obesity, defined as a body mass index of >=30 kg/m(2) (OR, 6.5 [95% CI, 2.2 to 18.9]); alcohol abuse (OR, 6.7 [95% CI, 2.4 to 19.2]); OTA/AO type-C fracture (OR, 2.8 [95% CI, 1.1 to 7.5]); use of a temporary spanning external fixator (OR, 3.9 [95% CI, 1.4 to 11.1]); and a 4-compartment fasciotomy (OR, 4.5 [95% CI, 1.3 to 15.7]). CONCLUSIONS: There is high morbidity associated with deep surgical site infection in plated proximal tibial fractures. Patients who are >=50 years of age, obese patients, those with a history of alcohol abuse, or those with an OTA/AO-type-C fracture are at high risk for infection. Performing a fasciotomy also increases the risk of deep infection and should be implemented with meticulous technique when deemed necessary. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27489321 TI - The Rotterdam Foot Classification: A Classification System for Medial Polydactyly of the Foot. AB - BACKGROUND: Polydactyly at the medial side of the foot ("medial polydactyly" of the foot) is a rare and diverse congenital anomaly. In order to plan and evaluate surgical treatment, the classification of medial polydactyly is useful. The aim of our study was to develop a reliable and valid classification system for medial polydactyly of the foot that is more useful than previous systems for preoperative evaluation and surgical planning. METHODS: A review of the literature and the clinical experience of a single experienced surgeon were used to determine classification categories. We identified all patients with medial polydactyly who had preoperative radiographs and clinical photographs and were treated at our hospital between 1993 and 2014. All affected feet were assessed according to our proposed classification system, the Rotterdam foot classification. The intrarater and interrater reliability among 5 observers who evaluated 30 feet were assessed with use of the Cohen kappa (kappa) statistic. RESULTS: We developed a classification system that describes duplication type, syndactyly, the presence of a hypoplastic ray, and deviation of the hallux. Seventy-three feet were classified according to the system. Seven duplication types were distinguished. Complete metatarsal duplication was most frequently seen (in 29%). Twelve feet showed a broad hallux without external expression of duplication. Syndactyly between medial and lateral (duplicate) halluces was present in 30 feet; between the lateral hallux and second toe, in 13 feet; and between both duplicated halluces and the lateral hallux and second toe, in 21 feet. A hypoplastic ray was seen in 75% of the feet. Intrarater agreement for duplication, hypoplastic rays, syndactyly, and deviation were, respectively, kappa = 0.79, 0.75, 0.59, and 0.78. Interrater agreement for duplication, hypoplastic rays, syndactyly, and deviation were, respectively, kappa = 0.72, 0.54, 0.48, and 0.64. CONCLUSIONS: The proposed classification system contains 4 categories of anatomic features of the foot. Classification of all categories shows moderate to good reliability. Use of the Rotterdam classification in evaluating medial polydactyly improves type-specific description, which may, in the future, enhance the evaluation of surgical treatment. CLINICAL RELEVANCE: The Rotterdam foot classification system is a reliable and easy-to-use system that we believe will improve communication between clinicians and researchers and facilitate the evaluation of treatment results in medial polydactyly of the foot. PMID- 27489322 TI - Morphology and Prevalence Study of Lumbar Scoliosis in 7,075 Multiracial Asian Adults. AB - BACKGROUND: Lumbar scoliosis affects patients' quality of life and will increasingly burden the health-care system as the population ages, yet there have been few reports of its prevalence in Asians. The aim of this study was to identify the prevalence of scoliosis, curve characteristics, and risk factors for development of scoliosis in an Asian population. METHODS: A retrospective cross sectional study was conducted using spinal images obtained from dual x-ray absorptiometry (DXA) scans of individuals >=40 years of age. Scoliosis was defined as a curvature of >10 degrees . A multivariate analysis for risk factors for development of lumbar scoliosis was performed. RESULTS: Of 7,075 patients studied, 645 (9.1%) were identified as having scoliosis. The average age of the patients with scoliosis was 61 years (range, 40 to 98 years). The mean curve prevalence was 9.4% in women and 6.5% in men. The average Cobb angle was 16.5 degrees (range, 10 degrees to 66 degrees ). Multivariate analysis showed an increased risk of scoliosis in women (relative risk [RR] = 2.4, 95% CI =1.4 to 4.3), Chinese patients (RR = 2.4, 95% CI = 1.4 to 4.3), Malay patients (RR = 2.5, 95% CI = 1.3 to 4.9), and patients with spinal fracture (RR = 5.1, 95% CI = 3.0 to 8.8). The risk of scoliosis was found to increase as patients progressed through each decade of life after the age of 40 years (6th decade: RR = 1.6, 95% CI = 1.1 to 2.4, p = 0.026; 7th decade: RR = 2.7, 95% CI = 1.8 to 4.1, p < 0.001; 8th decade: RR = 5.0, 95% CI = 3.2 to 7.9, p < 0.001; and 9th decade: RR = 8.8, 95% CI = 4.3 to 17.9, p < 0.001). CONCLUSIONS: The prevalence of lumbar scoliosis in Asian adults was found to be 9.1%. A nearly exponential increase in scoliosis prevalence from the 5th decade of life (4%) to the >=9th decade (25%) and a majority of left-sided scoliotic curves, measuring between 10 degrees and 19 degrees with an L2 apex, was found. Older age, female sex, Chinese or Malay race, and vertebral fracture increased the risk of scoliosis developing. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27489323 TI - Positive Culture During Reimplantation Increases the Risk of Subsequent Failure in Two-Stage Exchange Arthroplasty. AB - BACKGROUND: It is strongly recommended that tissue and synovial fluid culture samples be obtained during reimplantation performed as part of a 2-stage exchange arthroplasty. The rate of positive cultures during reimplantation and the influence of positive cultures on subsequent outcomes, to our knowledge, are unknown. This study was designed to determine the rate of positive cultures during reimplantation and to investigate the association between positive cultures at reimplantation and subsequent outcomes. METHODS: We retrospectively reviewed the data of 259 patients who met the Musculoskeletal Infection Society criteria for periprosthetic joint infection (PJI) and who underwent both stages of 2-stage exchange arthroplasty at our institution from 1999 to 2013. Among these patients were 267 PJIs (186 knees and 81 hips); 33 (12.4%) had >=1 positive culture result at reimplantation. Treatment failure was assessed according to the Delphi-based consensus definition. Logistic regression analysis was performed to assess the predictors of positive culture and risk factors for failure of 2-stage exchange arthroplasty. RESULTS: Of the 33 cases with PJI, 15 (45.5%) had a subsequent failure of the 2-stage exchange arthroplasty compared with 49 (20.9%) of the cases that were culture-negative at reimplantation. When controlling for other variables using multivariate analyses, the risk of treatment failure was higher (odds ratio = 2.53; 95% confidence interval [CI] = 1.13 to 5.64) and reinfection occurred earlier (hazard ratio = 2.00; 95% CI = 1.05 to 3.82) for the cases with a positive culture during reimplantation. The treatment failure rate did not differ (p = 0.73) between cases with >=2 positive cultures (36.4%) and 1 positive culture (50%). CONCLUSIONS: Positive intraoperative culture at the time of reimplantation, regardless of the number of positive samples, was independently associated with >2 times the risk of subsequent treatment failure and earlier reinfection. Surgeons should be aware that a positive culture at the time of reimplantation independently increases the risk of subsequent failure. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 27489324 TI - Advances in 3D-Printed Pediatric Prostheses for Upper Extremity Differences. AB - ?The prohibitive cost of cutting-edge prostheses prevents many children with a limb difference from obtaining them; however, new developments in 3-dimensional (3D) printing have the potential to increase the accessibility, customization, and procurement of such devices.?Children with upper limb differences are ideal candidates for currently available 3D-printed devices because they quickly damage and outgrow prostheses, and the low cost of 3D printing makes repairs and upgrades substantially more affordable.?Physicians and medical practitioners should become familiar with the possibilities of 3D-printed devices in order to determine the benefits and utility for their patients. PMID- 27489325 TI - Cartilage-Repair Innovation at a Standstill: Methodologic and Regulatory Pathways to Breaking Free. AB - Articular cartilage defects strongly predispose patients to developing early joint degeneration and osteoarthritis, but for more than 15 years, no new cartilage-repair technologies that we know of have been approved by the U.S. Food and Drug Administration. Many studies examining novel approaches to cartilage repair, including cell, tissue, or matrix-based techniques, have shown great promise, but completing randomized controlled trials (RCTs) to establish safety and efficacy has been challenging, providing a major barrier to bringing these innovations into clinical use. In this article, we review reasons that surgical innovations are not well-suited for testing through RCTs. We also discuss how analytical methods for reducing bias, such as propensity scoring, make prospective observational studies a potentially viable alternative for testing the safety and efficacy of cartilage-repair and other novel therapies, offering the real possibility of therapeutic innovation. PMID- 27489326 TI - A 5-Year Update on the Uneven Distribution of Women in Orthopaedic Surgery Residency Training Programs in the United States. AB - BACKGROUND: This study was undertaken to update our report from academic years 2004-2005 through 2008-2009, to include 5 additional years of the Association of American Medical Colleges GME Track data. This study will test the hypothesis that, when compared with the data from 2004-2005 through 2008-2009, there were no substantial changes from 2009-2010 through 2013-2014 in the distribution of orthopaedic surgery residency programs that train female residents and have been accredited by the Accreditation Council for Graduate Medical Education (ACGME). METHODS: Data for all ACGME-accredited orthopaedic surgery residency training programs in the United States were analyzed for 2009-2010 through 2013-2014, in the same manner as our previous report analyzed data for 2004-2005 through 2008 2009. Programs were classified as having 0, 1, 2, or >2 women in training (i.e., for postgraduate year [PGY]-1 through PGY-5) for each of the 5 academic years. Programs were also analyzed for the percentage of female residents in training and were classified as being above the national average (>20%), similar to the national average (between 10% and 20%), or below the national average (<10%) for each of the 5 academic years. RESULTS: During the time period of 2004 to 2009, the mean percentage of female trainees in U.S. orthopaedic surgery residency programs was 11.6%, and during the time period of 2009 to 2014, this mean percentage increased to 12.6%. Residency programs in the United States do not train women at an equal rate. In the 5 years examined (2009 to 2014), 30 programs had no female trainees and 49 programs had >20% women enrolled in at least 1 of the 5 years, 8 programs had no female trainees enrolled in any of the 5 years, and 9 programs had >20% women enrolled in each of the 5 years. CONCLUSIONS: Female medical students continue to pursue orthopaedic surgery as a career at rates lagging behind all other surgical specialties. Not all residency programs train women at equal rates. The period of 2009-2010 through 2013-2014 showed a greater percentage of programs (68%) training >=2 women than the period of 2004 2005 through 2008-2009 (61%). Obstacles to attracting women to orthopaedic surgery should continue to be identified and to be addressed. PMID- 27489327 TI - Adolescent Idiopathic Scoliosis: Immaturity Predicts Progression, but Is More Brace Wear Time Beneficial? Commentary on an article by Lori A. Karol, MD, et al.: "The Effect of the Risser Stage on Bracing Outcome in Adolescent Idiopathic Scoliosis". PMID- 27489328 TI - Please Teach Us More! Commentary on an article by G. David Potter III, MD, et al.: "Midterm Results of Porous Tantalum Femoral Cones in Revision Total Knee Arthroplasty". PMID- 27489329 TI - Cutaneous Disease as the First Manifestation of Cystic Echinococcosis. PMID- 27489332 TI - Questioning the Effectiveness of Oral Cholera Vaccine in Port-au-Prince Slums. PMID- 27489333 TI - In Response. PMID- 27489334 TI - hs-CRP Predicts Improvement in Depression in Patients With Type 1 Diabetes and Major Depression Undergoing Depression Treatment: Results From the Diabetes and Depression (DAD) Study. PMID- 27489335 TI - Longitudinal Associations of Exposure to Perfluoroalkylated Substances in Childhood and Adolescence and Indicators of Adiposity and Glucose Metabolism 6 and 12 Years Later: The European Youth Heart Study. AB - OBJECTIVE: To investigate the long-term association of exposure to perfluoroalkylated substances, including perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), during childhood (9 years) and adolescence (15 years) on indicators of adiposity and glucose metabolism in adolescence (15 years) and young adulthood (21 years). Secondarily, we aim to clarify the degree of tracking of exposure from childhood into young adulthood. RESEARCH DESIGN AND METHODS: Data derived from a large multicenter prospective cohort study, in which the same participants have been observed from childhood (N = 590), during adolescence (N = 444), and into young adulthood (N = 369). Stored plasma samples were analyzed for PFOS and PFOA. Indicators of adiposity comprising body height, body weight, sum of four skinfolds, and waist circumference, as well as indicators of glucose metabolism, comprising fasting blood glucose, triglyceride, and insulin levels, beta-cell function, and insulin resistance, have been collected at all study waves. Multiple linear regression was applied in order to model earlier exposure on later outcome while controlling for baseline outcome levels, sex, age, and socioeconomic factors. RESULTS: Childhood exposure to PFOS was associated with indicators of adiposity at 15 years of age that are displayed in elevated BMI, skinfold thickness, and waist circumference, as well as increased skinfold thickness and waist circumference at 21 years of age. PFOA exposure in childhood was associated with decreased beta-cell function at 15 years of age. We did not observe associations between exposure during adolescence and indicators of adiposity and glucose metabolism in young adulthood. CONCLUSIONS: This study found evidence for childhood exposure to PFOS and PFOA predicting adiposity at 15 and 21 years of age and impaired beta-cell function at 15 years of age, respectively. PMID- 27489336 TI - Discordance Between Central (Brain) and Pancreatic Action of Exenatide in Lean and Obese Subjects. AB - OBJECTIVE: This study examined the effect of exenatide on brain activity measured by functional (f)MRI and on insulin secretion in lean and obese normal-glucose tolerant individuals. RESEARCH DESIGN AND METHODS: The brain fMRI signal in response to high-calorie-content food pictures was measured with and without intravenous exenatide infusion in 10 lean and 10 obese healthy volunteers. Insulin secretion was measured with a two-step (+100 and +200 mg/dL) hyperglycemic clamp with exenatide and with saline infusion. RESULTS: The brain fMRI signal in response to food pictures in amygdala, insula, hippocampus, and frontal cortex was significantly greater in obese versus lean individuals. Intravenous exenatide significantly inhibited the fMRI signal in response to food pictures in obese individuals but did not affect the brain fMRI signal in lean subjects. Conversely, exenatide infusion caused an 18.5-fold increase in insulin secretion in lean individuals compared with an 8.8-fold increase in obese subjects. No significant correlation was observed between inhibition of the brain fMRI signal and increase in insulin secretion during exenatide infusion. CONCLUSIONS: Exenatide causes greater augmentation in insulin secretion in lean compared with obese individuals but inhibits the brain response to food pictures only in obese individuals. PMID- 27489337 TI - Subjects With Extreme-Duration Type 1 Diabetes Exhibit No Structural or Functional Abnormality on Cardiac MRI. PMID- 27489338 TI - Transient endoreplication down-regulates the kinesin-14 HSET and contributes to genomic instability. AB - Polyploid cancer cells exhibit chromosomal instability (CIN), which is associated with tumorigenesis and therapy resistance. The mechanisms that induce polyploidy and how these mechanisms contribute to CIN are not fully understood. Here we evaluate CIN in human cells that become polyploid through an experimentally induced endoreplication cycle. When these induced endoreplicating cells (iECs) returned to mitosis, it resulted in aneuploidy in daughter cells. This aneuploidy resulted from multipolar divisions, chromosome missegregation, and failure in cytokinesis. The iECs went through several rounds of division, ultimately spawning proliferative cells of reduced ploidy. iECs have reduced levels of the kinesin-14 HSET, which likely accounts for the multipolar divisions, and overexpression of HSET reduced spindle multipolarity. However, HSET overexpression had only mild effects on CIN, suggesting that additional defects must contribute to genomic instability in dividing iECs. Overall our results suggest that transient endoreplication cycles generate a diverse population of proliferative aneuploid cells that have the potential to contribute to tumor heterogeneity. PMID- 27489339 TI - The sequential activation of the mitotic microtubule assembly pathways favors bipolar spindle formation. AB - Centrosome maturation is the process by which the duplicated centrosomes recruit pericentriolar components and increase their microtubule nucleation activity before mitosis. The role of this process in cells entering mitosis has been mostly related to the separation of the duplicated centrosomes and thereby to the assembly of a bipolar spindle. However, spindles can form without centrosomes. In fact, all cells, whether they have centrosomes or not, rely on chromatin-driven microtubule assembly to form a spindle. To test whether the sequential activation of these microtubule assembly pathways, defined by centrosome maturation and nuclear envelope breakdown, plays any role in spindle assembly, we combined experiments in tissue culture cells and Xenopus laevis egg extracts with a mathematical model. We found that interfering with the sequential activation of the microtubule assembly pathways compromises bipolar spindle assembly in tissue culture cells but not in X. laevis egg extracts. Our data suggest a novel function for centrosome maturation that determines the contribution of the chromosomal microtubule assembly pathway and favors bipolar spindle formation in most animal cells in which tubulin is in limiting amounts. PMID- 27489340 TI - Loss of Galpha12/13 exacerbates apical area dependence of actomyosin contractility. AB - During development, coordinated cell shape changes alter tissue shape. In the Drosophila ventral furrow and other epithelia, apical constriction of hundreds of epithelial cells folds the tissue. Genes in the Galpha12/13 pathway coordinate collective apical constriction, but the mechanism of coordination is poorly understood. Coupling live-cell imaging with a computational approach to identify contractile events, we discovered that differences in constriction behavior are biased by initial cell shape. Disrupting Galpha12/13 exacerbates this relationship. Larger apical area is associated with delayed initiation of contractile pulses, lower apical E-cadherin and F-actin levels, and aberrantly mobile Rho-kinase structures. Our results suggest that loss of Galpha12/13 disrupts apical actin cortex organization and pulse initiation in a size dependent manner. We propose that Galpha12/13 robustly organizes the apical cortex despite variation in apical area to ensure the timely initiation of contractile pulses in a tissue with heterogeneity in starting cell shape. PMID- 27489341 TI - Subnuclear positioning and interchromosomal clustering of the GAL1-10 locus are controlled by separable, interdependent mechanisms. AB - On activation, the GAL genes in yeast are targeted to the nuclear periphery through interaction with the nuclear pore complex. Here we identify two cis acting "DNA zip codes" from the GAL1-10 promoter that are necessary and sufficient to induce repositioning to the nuclear periphery. One of these zip codes, GRS4, is also necessary and sufficient to promote clustering of GAL1-10 alleles. GRS4, and to a lesser extent GRS5, contribute to stronger expression of GAL1 and GAL10 by increasing the fraction of cells that respond to the inducer. The molecular mechanism controlling targeting to the NPC is distinct from the molecular mechanism controlling interchromosomal clustering. Targeting to the nuclear periphery and interaction with the nuclear pore complex are prerequisites for gene clustering. However, once formed, clustering can be maintained in the nucleoplasm, requires distinct nuclear pore proteins, and is regulated differently through the cell cycle. In addition, whereas targeting of genes to the NPC is independent of transcription, interchromosomal clustering requires transcription. These results argue that zip code-dependent gene positioning at the nuclear periphery and interchromosomal clustering represent interdependent phenomena with distinct molecular mechanisms. PMID- 27489342 TI - Microtubule aging probed by microfluidics-assisted tubulin washout. AB - Microtubules switch stochastically between phases of growth and shrinkage. The molecular mechanism responsible for the end of a growth phase, an event called catastrophe, is still not understood. The probability for a catastrophe to occur increases with microtubule age, putting constraints on the possible molecular mechanism of catastrophe induction. Here we used microfluidics-assisted fast tubulin washout experiments to induce microtubule depolymerization in a controlled manner at different times after the start of growth. We found that aging can also be observed in this assay, providing valuable new constraints against which theoretical models of catastrophe induction can be tested. We found that the data can be quantitatively well explained by a simple kinetic threshold model that assumes an age-dependent broadening of the protective cap at the microtubule end as a result of an evolving tapered end structure; this leads to a decrease of the cap density and its stability. This analysis suggests an intuitive picture of the role of morphological changes of the protective cap for the age dependence of microtubule stability. PMID- 27489343 TI - RIC-3 phosphorylation enables dual regulation of excitation and inhibition of Caenorhabditis elegans muscle. AB - Brain function depends on a delicate balance between excitation and inhibition. Similarly, Caenorhabditis elegans motor system function depends on a precise balance between excitation and inhibition, as C. elegans muscles receive both inhibitory, GABAergic and excitatory, cholinergic inputs from motor neurons. Here we show that phosphorylation of the ER-resident chaperone of nicotinic acetylcholine receptors, RIC-3, leads to increased muscle excitability. RIC-3 phosphorylation at Ser-164 depends on opposing functions of the phosphatase calcineurin (TAX-6), and of the casein kinase II homologue KIN-10. Effects of calcineurin down-regulation and of phosphorylated RIC-3 on muscle excitability are mediated by GABAA receptor inhibition. Thus RIC-3 phosphorylation enables effects of this chaperone on GABAA receptors in addition to nAChRs. This dual effect provides coordinated regulation of excitation and inhibition and enables fine-tuning of the excitation-inhibition balance. Moreover, regulation of inhibitory GABAA signaling by calcineurin, a calcium- and calmodulin-dependent phosphatase, enables homeostatic balancing of excitation and inhibition. PMID- 27489344 TI - Transcriptomics and Biochemical Profiling: Current Dynamics in Elucidating the Potential Attributes of Olive. AB - Various transcriptome studies have remained useful in unraveling the complexity of molecular pathways regulating the oil biochemical contents and fruit characteristics of agronomic value in olive. Genes networks associated with plant architect and abiotic stress tolerance have been constructed due to robust genomic data generated by the tools of genomics. This, familiarity will accelerate the breeding programmes in making the selection of high yielding olive genotypes promptly and efficiently. Moreover, comparative transcriptome studies for endogeneous enzymes at different expression sites explicate the contribution of various pathways in phenol and lipid oxidation in olive. Recently, non targeted metabolomics and metabolic profiling techniques have not only made the understanding of metabolic changes easy but also elucidate biomarkers in fruits related to agronomic parameters and abiotic stresses. However, the alteration in the architectural build up of phenotypes auth-enticates the conservation of their potential genetic links that will invoke interest for future olive breeding. PMID- 27489345 TI - Structural basis of HIV inhibition by translocation-defective RT inhibitor 4' ethynyl-2-fluoro-2'-deoxyadenosine (EFdA). AB - 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is the most potent nucleoside analog inhibitor of HIV reverse transcriptase (RT). It retains a 3'-OH yet acts as a chain-terminating agent by diminishing translocation from the pretranslocation nucleotide-binding site (N site) to the posttranslocation primer-binding site (P site). Also, facile misincorporation of EFdA-monophosphate (MP) results in difficult-to-extend mismatched primers. To understand the high potency and unusual inhibition mechanism of EFdA, we solved RT crystal structures (resolutions from 2.4 to 2.9 A) that include inhibition intermediates (i) before inhibitor incorporation (catalytic complex, RT/DNA/EFdA-triphosphate), (ii) after incorporation of EFdA-MP followed by dT-MP (RT/DNAEFdA-MP(P)* dT-MP(N) ), or (iii) after incorporation of two EFdA-MPs (RT/DNAEFdA-MP(P)* EFdA-MP(N) ); (iv) the latter was also solved with EFdA-MP mismatched at the N site (RT/DNAEFdA MP(P)* EFdA-MP(*N) ). We report that the inhibition mechanism and potency of EFdA stem from interactions of its 4'-ethynyl at a previously unexploited conserved hydrophobic pocket in the polymerase active site. The high resolution of the catalytic complex structure revealed a network of ordered water molecules at the polymerase active site that stabilize enzyme interactions with nucleotide and DNA substrates. Finally, decreased translocation results from favorable interactions of primer-terminating EFdA-MP at the pretranslocation site and unfavorable posttranslocation interactions that lead to observed localized primer distortions. PMID- 27489346 TI - Pacemaker-neuron-dependent disturbance of the molecular clockwork by a Drosophila CLOCK mutant homologous to the mouse Clock mutation. AB - Circadian clocks are composed of transcriptional/translational feedback loops (TTFLs) at the cellular level. In Drosophila TTFLs, the transcription factor dCLOCK (dCLK)/CYCLE (CYC) activates clock target gene expression, which is repressed by the physical interaction with PERIOD (PER). Here, we show that amino acids (AA) 657-707 of dCLK, a region that is homologous to the mouse Clock exon 19-encoded region, is crucial for PER binding and E-box-dependent transactivation in S2 cells. Consistently, in transgenic flies expressing dCLK with an AA657-707 deletion in the Clock (Clk(out)) genetic background (p{dClk-Delta};Clk(out)), oscillation of core clock genes' mRNAs displayed diminished amplitude compared with control flies, and the highly abundant dCLKDelta657-707 showed significantly decreased binding to PER. Behaviorally, the p{dClk-Delta};Clk(out) flies exhibited arrhythmic locomotor behavior in the photic entrainment condition but showed anticipatory activities of temperature transition and improved free running rhythms in the temperature entrainment condition. Surprisingly, p{dClk Delta};Clk(out) flies showed pacemaker-neuron-dependent alterations in molecular rhythms; the abundance of dCLK target clock proteins was reduced in ventral lateral neurons (LNvs) but not in dorsal neurons (DNs) in both entrainment conditions. In p{dClk-Delta};Clk(out) flies, however, strong but delayed molecular oscillations in temperature cycle-sensitive pacemaker neurons, such as DN1s and DN2s, were correlated with delayed anticipatory activities of temperature transition. Taken together, our study reveals that the LNv molecular clockwork is more sensitive than the clockwork of DNs to dysregulation of dCLK by AA657-707 deletion. Therefore, we propose that the dCLK/CYC-controlled TTFL operates differently in subsets of pacemaker neurons, which may contribute to their specific functions. PMID- 27489347 TI - microRNA-309 targets the Homeobox gene SIX4 and controls ovarian development in the mosquito Aedes aegypti. AB - Obligatory blood-triggered reproductive strategy is an evolutionary adaptation of mosquitoes for rapid egg development. It contributes to the vectorial capacity of these insects. Therefore, understanding the molecular mechanisms underlying reproductive processes is of particular importance. Here, we report that microRNA 309 (miR-309) plays a critical role in mosquito reproduction. A spatiotemporal expression profile of miR-309 displayed its blood feeding-dependent onset and ovary-specific manifestation in female Aedes aegypti mosquitoes. Antagomir silencing of miR-309 impaired ovarian development and resulted in nonsynchronized follicle growth. Furthermore, the genetic disruption of miR-309 by CRISPR/Cas9 system led to the developmental failure of primary follicle formation. Examination of genomic responses to miR-309 depletion revealed that several pathways associated with ovarian development are down-regulated. Comparative analysis of genes obtained from the high-throughput RNA sequencing of ovarian tissue from the miR-309 antagomir-silenced mosquitoes with those from the in silico computation target prediction identified that the gene-encoding SIX homeobox 4 protein (SIX4) is a putative target of miR-309. Reporter assay and RNA immunoprecipitation confirmed that SIX4 is a direct target of miR-309. RNA interference of SIX4 was able to rescue phenotypic manifestations caused by miR 309 depletion. Thus, miR-309 plays a critical role in mosquito reproduction by targeting SIX4 in the ovary and serves as a regulatory switch permitting a stage specific degradation of the ovarian SIX4 mRNA. In turn, this microRNA (miRNA) targeted degradation is required for appropriate initiation of a blood feeding triggered phase of ovarian development, highlighting involvement of this miRNA in mosquito reproduction. PMID- 27489349 TI - Hypoxia-NOTCH1-SOX2 signaling is important for maintaining cancer stem cells in ovarian cancer. AB - Hypoxia and NOTCH signaling have been reported to be associated with the self renewal and drug resistance of cancer stem cells (CSCs). However, the molecular mechanisms by which hypoxia and NOTCH signaling stimulate the self-renewal and drug resistance of ovarian CSCs are poorly understood. In the present study, we identified SOX2 as a key transcription factor for CSC-like characteristics in the downstream of hypoxia-induced NOTCH signaling in epithelial ovarian cancer cells. Hypoxic treatment or overexpression of intracellular domain of NOTCH1 (NICD1) in ovarian cancer cells increased sphere formation, drug resistance, and expression of CSC-associated genes such as SOX2, ALDH, and ABC transporters. Hypoxic treatment increased the expression of NICD1, and hypoxic treatment or NICD1 overexpression increased SOX2 promoter activity, which was inhibited by deletion of HIF-1 or CSL binding sites. Furthermore, DAPT treatment decreased the effect of hypoxic treatment, and SOX2 knockdown decreased the effect of hypoxic treatment and NICD overexpression on sphere formation and drug resistance in established ovarian cancer cell lines and primary ovarian cancer cells. These results suggest that hypoxia-NOTCH1-SOX2 signaling axis is important for activation of ovarian CSCs, which may provide a novel opportunity for developing therapeutics to eradicate CSCs in ovarian cancer patients. PMID- 27489348 TI - Structure of fully protonated proteins by proton-detected magic-angle spinning NMR. AB - Protein structure determination by proton-detected magic-angle spinning (MAS) NMR has focused on highly deuterated samples, in which only a small number of protons are introduced and observation of signals from side chains is extremely limited. Here, we show in two fully protonated proteins that, at 100-kHz MAS and above, spectral resolution is high enough to detect resolved correlations from amide and side-chain protons of all residue types, and to reliably measure a dense network of (1)H-(1)H proximities that define a protein structure. The high data quality allowed the correct identification of internuclear distance restraints encoded in 3D spectra with automated data analysis, resulting in accurate, unbiased, and fast structure determination. Additionally, we find that narrower proton resonance lines, longer coherence lifetimes, and improved magnetization transfer offset the reduced sample size at 100-kHz spinning and above. Less than 2 weeks of experiment time and a single 0.5-mg sample was sufficient for the acquisition of all data necessary for backbone and side-chain resonance assignment and unsupervised structure determination. We expect the technique to pave the way for atomic-resolution structure analysis applicable to a wide range of proteins. PMID- 27489350 TI - Phosphatidyl inositol-3 kinase (PIK3CA) E545K mutation confers cisplatin resistance and a migratory phenotype in cervical cancer cells. AB - The phosphatidylinositol-3 kinase (PI3K)/Akt/mTOR signaling pathway is activated in many human cancers. Previously, we reported that patients with early stage cervical cancer whose tumours harbour PIK3CA exon 9 or 20 mutations have worse overall survival in response to treatment with radiation and cisplatin than patients with wild-type PIK3CA. The purpose of this study was to determine whether PIK3CA-E545K mutation renders cervical cancer cells more resistant to cisplatin and/or radiation, and whether PI3K inhibition reverses the phenotype. We found that CaSki cells that are heterozygous for the PIK3CA-E545K mutation are more resistant to cisplatin or cisplatin plus radiation than either HeLa or SiHa cells that express only wild-type PIK3CA. Similarly, HeLa cells engineered to stably express PIK3CA-E545K were more resistant to cisplatin or cisplatin plus radiation than cells expressing only wild-type PIK3CA or with PIK3CA depleted. Cells expressing the PIK3CA-E545K mutation also had constitutive PI3K pathway activation and increased cellular migration and each of these phenotypes was reversed by treatment with the PI3K inhibitor GDC-0941/Pictilisib. Our results suggests that cervical cancer patients whose tumours are positive for the PIK3CA E545K mutation may benefit from PI3K inhibitor therapy in concert with standard cisplatin and radiation therapy. PMID- 27489351 TI - Constitutive gp130 activation rapidly accelerates the transformation of human hepatocytes via an impaired oxidative stress response. AB - Pro-inflammatory signaling pathways, especially interleukin 6 (IL-6), and reactive oxygen species (ROS) promote carcinogenesis in the liver. In order to elucidate the underlying oncogenic mechanism, we activated the IL-6 signal transducer glycoprotein 130 (gp130) via stable expression of a constitutively active gp130 construct (L-gp130) in untransformed telomerase-immortalized human fetal hepatocytes (FH-hTERT). As known from hepatocellular adenomas, forced gp130 activation alone was not sufficient to induce malignant transformation. However, additional challenge of FH-hTERT L-gp130 clones with oxidative stress resulted in 2- to 3-fold higher ROS levels and up to 6-fold more DNA-double strand breaks (DSB). Despite increased DNA damage, ROS-challenged FH-hTERT L-gp130 clones displayed an enhanced proliferation and rapidly developed colony growth capabilities in soft agar. As driving gp130-mediated oncogenic mechanism, we detected a decreased expression of antioxidant genes, in particular glutathione peroxidase 3 and apolipoprotein E, and an absence of P21 upregulation following ROS-conferred induction of DSB. In summary, an impaired oxidative stress response in hepatocytes with gp130 gain-of-function mutations, as detected in dysplastic intrahepatic nodules and hepatocellular adenomas, is one of the central oncogenic mechanisms in chronic liver inflammation. PMID- 27489352 TI - S18 family of mitochondrial ribosomal proteins: evolutionary history and Gly132 polymorphism in colon carcinoma. AB - S18 family of mitochondrial ribosomal proteins (MRPS18, S18) consists of three members, S18-1 to -3. Earlier, we found that overexpression of S18-2 protein resulted in immortalization and eventual transformation of primary rat fibroblasts. The S18-1 and -3 have not exhibited such abilities. To understand the differences in protein properties, the evolutionary history of S18 family was analyzed. The S18-3, followed by S18-1 and S18-2 emerged as a result of ancient gene duplication in the root of eukaryotic species tree, followed by two metazoan specific gene duplications. However, the most conserved metazoan S18 homolog is the S18-1; it shares the most sequence similarity with S18 proteins of bacteria and of other eukaryotic clades. Evolutionarily conserved residues of S18 proteins were analyzed in various cancers. S18-2 is mutated at a higher rate, compared with S18-1 and -3 proteins. Moreover, the evolutionarily conserved residue, Gly132 of S18-2, shows genetic polymorphism in colon adenocarcinomas that was confirmed by direct DNA sequencing.Concluding, S18 family represents the yet unexplored important mitochondrial ribosomal proteins. PMID- 27489353 TI - HPV16 E6-E7 induces cancer stem-like cells phenotypes in esophageal squamous cell carcinoma through the activation of PI3K/Akt signaling pathway in vitro and in vivo. AB - High-risk human papillomavirus (HPV), especially HPV16, correlates with cancerogenesis of human esophageal squamous cell carcinoma (ESCC) and we have reported that HPV16 related with a poor prognosis of ESCC patients in China. We aim to investigate the potential role and mechanism of HPV16 in ESCC development and progress. Our following researches demonstrated that ESCC cells which were stably transfected by HPV16 E6-E7 lentiviral vector showed a remarkable cancer stem-like cells (CSCs) phenotype, such as: migration, invasion, spherogenesis, high expression of CSCs marker in ESCC---p75NTR, chemoresistance, radioresistance, anti-apoptosis ability in vitro and cancerogenesis in vivo. HPV16 E6-E7 induced PI3K/Akt signaling pathway activation and this affect could be effectively inhibited by LY294002, a specific PI3K inhibitor. It was also indicated that the inhibition of PI3K/Akt signaling pathway by PI3K and Akt siRNA reverse the effect which induced by HPV16 E6-E7 in ESCC cells. Taken together, the present study demonstrates that HPV16 E6-E7 promotes CSCs phenotype in ESCC cells through the activation of PI3K/Akt signaling pathway. Targeting the PI3K/Akt signaling pathway in HPV16 positive tissues is an available therapeutic for ESCC patients. PMID- 27489354 TI - Association of the GLB1 rs4678680 genetic variant with risk of HBV-related hepatocellular carcinoma. AB - Accumulated evidences demonstrated that GLB1 is involved in cell senescence and cancer development. The GLB1 rs4678680 single nucleotide polymorphism (SNP) has been identified as a hepatocellular carcinoma (HCC) susceptibility polymorphism by a genome-wide association study in Korean population previously. However, little or nothing was known about its involvement and functional significance in hepatitis B viruses (HBV)-related HCC in Chinese. Therefore, we investigated the association between the GLB1 rs4678680 SNP and HBV-related HCC risk as well as its biological function in vivo. Genotypes were determined in two independent case-control sets from two medical centers of China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The potential regulation role the rs4678680 genetic variant on GLB1 expression was examined with HCC and normal liver tissues. We found that The rs4678680 G allele was showed to be risk allele; individuals with the TG genotype had an OR of 1.51 (95% CI = 1.10-2.07, P = 0.010, Shandong set) or 1.49 (95% CI = 1.11-1.99, P = 0.008, Jiangsu set) for developing HBV-related HCC, respectively, compared with individuals with the TT genotype. This association was more pronounced in males, individuals aged older than 57 years and drinkers (all P < 0.05). In the genotype phenotype correlation analyses of fifty-six human liver tissue samples, rs4678680 TG or GG was associated with a statistically significant increase of GLB1 mRNA expression (P < 0.05). Our data indicated that the GLB1 rs4678680 SNP contributes to susceptibility to develop HBV-related HCC, highlighting the involvement of GLB1 and cell senescence in etiology of HCC. PMID- 27489355 TI - The prognostic value of CSCs biomarker CD133 in NSCLC: a meta-analysis. AB - The prognostic value of cancer stem cells (CSCs) marker CD133 in non-small-cell lung cancer (NSCLC) remains controversial. We performed this meta-analysis of 32 eligible studies to clarify the prognostic value of CD133 and provide evidence for CSCs hypothesis. We calculated pooled hazard ratio (HR) for survival outcomes and pooled odds ratio (OR) for clinical parameters associated with CD133 in total 3595 NSCLC patients by STATA. Our results showed that NSCLC patients with higher CD133 expression had shorter overall survival time only in Asian patients (HR = 3.80, 95% CI: 3.12-4.04, p < 0.001; I2 = 32%) but not in Caucasian patients (HR = 1.15, 95% CI: 0.88-1.52, p = 0.307; I2 = 0%), suggesting that differential prognostic value of CD133 in distinct ethnic group. We speculated that the intrinsic EGFR gene status of CSCs might be responsible for this racial difference. Additionally, we found that higher expression of CD133 was associated with poor differentiation (OR = 2.03, 95% CI: 1.32-3.14, p = 0.001) and lymph node metastasis (OR = 2.39, 95% CI: 1.62-3.52, p < 0.001) but there was no significant difference of CD133 expression between adenocarcinoma and squamous carcinoma (OR = 1.13, 95% CI: 0.93-1.38, p = 0.3) in NSCLC patients. These results may provide a new therapeutic perspective on the treatment of NSCLC patients according to the expression of CD133 in distinct ethnic group. PMID- 27489356 TI - A scoring system basing pathological parameters to predict regional lymph node metastasis after preoperative chemoradiotherapy for locally advanced rectal cancer: implication for local excision. AB - Local excision is an alternative to radical surgery that is indicated in patients with locally advanced rectal cancer (LARC) who have a good response to chemoradiotherapy (CRT). Regional lymph node status is a major uncertainty during local excision of LARC following CRT. We retrospectively reviewed clinicopathologic variables for 244 patients with LARC who were treated at our institute between December 2000 and December 2013 in order to identify independent predictors of regional lymph node metastasis. Multivariate analysis of the training sample demonstrated that histopathologic type, tumor size, and the presence of lymphovascular invasion were significant predictors of regional nodal metastasis. These variables were then incorporated into a scoring system in which the total scores were calculated based on the points assigned for each parameter. The area under the curve in the receiver operating characteristic analysis was 0.750, and the cutoff value for the total score to predict regional nodal metastasis was 7.5. The sensitivity of our system was 73.2% and the specificity was 69.4%. The sensitivity was 77.8% and the specificity was 51.2% when the scoring system was applied to the testing sample. Using this system, we could accurately predict regional nodal metastases in LARC patients following CRT, which may be useful for stratifying patients in clinical trials and selecting potential candidates for organ-sparing surgery following CRT for LARC. PMID- 27489357 TI - Increased frequency of circulating Th22 cells in patients with B-cell non Hodgkin's lymphoma. AB - T helper (Th) 22 cells play important roles in the pathogenesis of autoimmune and inflammatory diseases, and their function in tumors remains uncertain. In the current study, we investigated the alternations and clinical significance of circulating Th22 cells in patients with B-cell non-Hodgkin's lymphoma (B-NHL). We found that the frequency of Th22 cells was significantly elevated in peripheral blood of newly-diagnosed B-NHL patients, and returned to normal level after chemotherapy. In consistent with increased Th22 frequency, plasma IL-22 and IL-6 levels in B-NHL patients were remarkably increased. Moreover, the increased Th22 frequency was associated with the older age (> 60 yr) and a poorer response to therapy in B-NHL patients. In addition, there existed a statistically positive correlation between circulating Th22 and Th17 frequencies in B-NHL patients. Our data demonstrated that circulating Th22 frequency was associated with the clinical outcome and prognosis of B-NHL patients, indicating that Th22 immune response might play an important role in the development and progression of B NHL. PMID- 27489358 TI - Notch1 directly induced CD133 expression in human diffuse type gastric cancers. AB - CD133 is considered as a stem-like cell marker in some cancers including gastric cancers, and Notch1 signaling is known to play an important role in the maintenance and differentiation of stem-like cells. We aimed to investigate whether Notch1 signaling contributes to the carcinogenesis of gastric cancers and CD133 induction. CD133 expression was detected in 51.4% of diffuse type gastric cancers while it was not detected in intestinal type gastric cancers. Similarly, only poorly-differentiated gastric cancer cell lines expressed CD133 and activated-Notch1. Inhibiting Notch1 signaling resulted in decreased CD133 expression, side population cells, cell proliferation and anchorage independent cell growth. Chromatin immunoprecipitation suggested that this Notch1 dependent regulation of CD133 was caused by direct binding of activated-Notch1 to the RBP Jkappa binding site in the 5' promoter region of CD133 gene. In addition, knocking down RBP-Jkappa reduced CD133 induction in activated-Notch1 transfected cells. These findings suggested that Notch1 signaling plays an important role in the maintenance of the cancer stem-like phenotype in diffuse type gastric cancer through an RBP-Jkappa dependent pathway and that inhibiting Notch1 signaling could be an effective therapy against CD133 positive diffuse type gastric cancers. PMID- 27489359 TI - Urban-rural disparity of overweight/obesity distribution and its potential trend with breast cancer among Chinese women. AB - OBJECTIVE: To evaluate the urban-rural disparity of overweight/obesity and explore its potential trend with breast cancer among Chinese women. RESULTS: The prevalence of overweight/obesity for Chinese rural women (35.2%, 29.2% for overweight and 6.0% for obesity) was significantly higher than that for Chinese urban women (33.4%, 27.7% for overweight and 5.7% for obesity) (P < 0.001). For either rural or urban women, the prevalence of overweight/obesity was highest in north region, followed by east region for rural women and north-east region for urban women. For rural women, higher prevalence of overweight/obesity was significantly positively associated with elder age, Han nationality, low level of education, no occupation, high family income, less number of family residents, insurance, and elder age at marriage. Similar positive associations were also found for urban women, except negative associations for high family income, less number of family residents, and elder age at marriage. A non-significant positive trend between overweight/obesity and breast cancer was found for rural women [odds ratio (OR): 1.06; 95% confidence interval (CI): 0.87-1.29], but a significant positive trend for urban women (OR: 1.55; 95% CI: 1.19-2.02). MATERIALS AND METHODS: A total of 1 210 762 participants were recruited from the Chinese National Breast Cancer Screening Program. Overweight and obesity were defined as body mass index (BMI) ranged 24.0-27.9 kg/m2 and BMI >= 28.0kg/m2, respectively. CONCLUSIONS: There was an obvious urban-rural disparity of overweight/obesity distribution among Chinese women, which could also lead to an obvious disparity of breast cancer distribution. PMID- 27489360 TI - Amplification of TLK2 Induces Genomic Instability via Impairing the G2-M Checkpoint. AB - : Managing aggressive breast cancers with enhanced chromosomal instability (CIN) is a significant challenge in clinics. Previously, we described that a cell cycle associated kinase called Tousled-like kinase 2 (TLK2) is frequently deregulated by genomic amplifications in aggressive estrogen receptor-positive (ER+) breast cancers. In this study, it was discovered that TLK2 amplification and overexpression mechanistically impair Chk1/2-induced DNA damage checkpoint signaling, leading to a G2-M checkpoint defect, delayed DNA repair process, and increased CIN. In addition, TLK2 overexpression modestly sensitizes breast cancer cells to DNA-damaging agents, such as irradiation or doxorubicin. To our knowledge, this is the first report linking TLK2 function to CIN, in contrast to the function of its paralog TLK1 as a guardian of genome stability. This finding yields new insight into the deregulated DNA damage pathway and increased genomic instability in aggressive ER+ breast cancers. IMPLICATIONS: Targeting TLK2 presents an attractive therapeutic strategy for the TLK2-amplified breast cancers that possess enhanced genomic instability and aggressiveness. Mol Cancer Res; 14(10); 920-7. (c)2016 AACR. PMID- 27489361 TI - Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow. AB - : Matrix metalloproteinase 9 (MMP-9/Gelatinase B) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and plays a central role in tumor cell invasion and metastasis. Here we complemented mechanistic insights in the cancer biology of MMP-9 and investigated the effects of specific long-term loss-of-function, by genetic ablation, of MMP-9 on PDAC initiation and progression in the well established KPC mouse model of spontaneous PDAC. Tumor growth and progression were analyzed by histopathology and IHC. Invasive growth of PDAC cells was analyzed by both in vitro (proliferation, survival, migration, invasion assays) and in vivo (experimental metastasis assays) methods. Retroviral shRNAi was used to knockdown target genes (MMP-9, IL6R). Gene expression was analyzed by qRT-PCR, immunoblot, ELISA, in situ hybridization, and zymography. PDAC tumors from MMP-9 deficient mice were dramatically larger, more invasive, and contained more stroma. Yet, ablation of MMP-9 in PDAC cells did not directly promote invasive growth. Interestingly, systemic ablation of MMP-9 led to increased IL6 levels resulting from abrogation of MMP-9-dependent SCF signaling in the bone marrow. IL6 levels in MMP-9-/- mice were sufficient to induce invasive growth and STAT3 activation in PDAC cells via IL6 receptor (IL6R). Interference with IL6R blocked the increased invasion and metastasis of PDAC cells in MMP-9-deficient hosts. In conclusion, ablation of systemic MMP-9 initiated fatal communication between maintenance of physiological functions of MMP-9 in the bone marrow and invasive growth of PDAC via the IL6/IL6R/STAT3 axis. IMPLICATIONS: Thus, the beneficial effects of host MMP-9 on PDAC are an important caveat for the use of systemic MMP 9 inhibitors in cancer. Mol Cancer Res; 14(11); 1147-58. (c)2016 AACR. PMID- 27489362 TI - Mechanical effort predicts the selection of ankle over hip strategies in nonstepping postural responses. AB - Experimental studies have shown that a continuum of ankle and hip strategies is used to restore posture following an external perturbation. Postural responses can be modeled by feedback control with feedback gains that optimize a specific objective. On the one hand, feedback gains that minimize effort have been used to predict muscle activity during perturbed standing. On the other hand, hip and ankle strategies have been predicted by minimizing postural instability and deviation from upright posture. It remains unclear, however, whether and how effort minimization influences the selection of a specific postural response. We hypothesize that the relative importance of minimizing mechanical work vs. postural instability influences the strategy used to restore upright posture. This hypothesis was investigated based on experiments and predictive simulations of the postural response following a backward support surface translation. Peak hip flexion angle was significantly correlated with three experimentally determined measures of effort, i.e., mechanical work, mean muscle activity and metabolic energy. Furthermore, a continuum of ankle and hip strategies was predicted in simulation when changing the relative importance of minimizing mechanical work and postural instability, with increased weighting of mechanical work resulting in an ankle strategy. In conclusion, the combination of experimental measurements and predictive simulations of the postural response to a backward support surface translation showed that the trade-off between effort and postural instability minimization can explain the selection of a specific postural response in the continuum of potential ankle and hip strategies. PMID- 27489363 TI - Sour taste increases swallowing and prolongs hemodynamic responses in the cortical swallowing network. AB - Sour stimuli have been shown to upregulate swallowing in patients and in healthy volunteers. However, such changes may be dependent on taste-induced increases in salivary flow. Other mechanisms include genetic taster status (Bartoshuk LM, Duffy VB, Green BG, Hoffman HJ, Ko CW, Lucchina LA, Weiffenbach JM. Physiol Behav 82: 109-114, 2004) and differences between sour and other tastes. We investigated the effects of taste on swallowing frequency and cortical activation in the swallowing network and whether taster status affected responses. Three-milliliter boluses of sour, sour with slow infusion, sweet, water, and water with infusion were compared on swallowing frequency and hemodynamic responses. The sour conditions increased swallowing frequency, whereas sweet and water did not. Changes in cortical oxygenated hemoglobin (hemodynamic responses) measured by functional near-infrared spectroscopy were averaged over 30 trials for each condition per participant in the right and left motor cortex, S1 and supplementary motor area for 30 s following bolus onset. Motion artifact in the hemodynamic response occurred 0-2 s after bolus onset, when the majority of swallows occurred. The peak hemodynamic response 2-7 s after bolus onset did not differ by taste, hemisphere, or cortical location. The mean hemodynamic response 17-22 s after bolus onset was highest in the motor regions of both hemispheres, and greater in the sour and infusion condition than in the water condition. Genetic taster status did not alter changes in swallowing frequency or hemodynamic response. As sour taste significantly increased swallowing and cortical activation equally with and without slow infusion, increases in the cortical swallowing were due to sour taste. PMID- 27489364 TI - Responses of non-eye-movement central vestibular neurons to sinusoidal yaw rotation in compensated macaques after unilateral semicircular canal plugging. AB - After vestibular labyrinth injury, behavioral measures of vestibular performance recover to variable degrees (vestibular compensation). Central neuronal responses after unilateral labyrinthectomy (UL), which eliminates both afferent resting activity and sensitivity to movement, have been well-studied. However, unilateral semicircular canal plugging (UCP), which attenuates angular-velocity detection while leaving afferent resting activity intact, has not been extensively studied. The current study reports response properties of yaw-sensitive non-eye-movement rhesus macaque vestibular neurons after compensation from UCP. The responses at a series of frequencies (0.1-2 Hz) and peak velocities (15-210 degrees /s) were compared between neurons recorded before and at least 6 wk after UCP. The gain (sp/s/ degrees /s) of central type I neurons (responding to ipsilateral yaw rotation) on the side of UCP was reduced relative to normal controls at 0.5 Hz, +/-60 degrees /s [0.48 +/- 0.30 (SD) normal, 0.32 +/- 0.15 ipsilesion; 0.44 +/- 0.2 contralesion]. Type II neurons (responding to contralateral yaw rotation) after UCP have reduced gain (0.40 +/- 0.27 normal, 0.35 +/- 0.25 ipsilesion; 0.25 +/- 0.18 contralesion). The difference between responses after UCP and after UL is primarily the distribution of type I and type II neurons in the vestibular nuclei (type I neurons comprise 66% in vestibular nuclei normally; 51% ipsilesion UCP; 59% contralesion UCP; 38% ipsilesion UL; 65% contralesion UL) and the magnitude of the responses of type II neurons ipsilateral to the lesion. These differences suggest that the need to compensate for unilateral loss of resting vestibular nerve activity after UL necessitates a different strategy for recovery of dynamic vestibular responses compared to after UCP. PMID- 27489365 TI - Motor outcomes of feedback delays and implicit/explicit strategy use: experimental considerations and clinical implications. AB - Sensorimotor adaptation requires integration of internal models of motor control with feedback from the external environment. As highlighted by Brudner, Kethidi, Graeupner, Ivry, and Taylor (J Neurophysiol 115: 1499-1511, 2016), feedback characteristics, error or outcome based, as well as temporal constraints can impact motor learning and adaptation strategies. These findings provide novel insight into the underlying components of motor control, which can be applied to future clinical and experimental research on motor processes. PMID- 27489366 TI - Losing touch: age-related changes in plantar skin sensitivity, lower limb cutaneous reflex strength, and postural stability in older adults. AB - Age-related changes in the density, morphology, and physiology of plantar cutaneous receptors negatively impact the quality and quantity of balance relevant information arising from the foot soles. Plantar perceptual sensitivity declines with age and may predict postural instability; however, alteration in lower limb cutaneous reflex strength may also explain greater instability in older adults and has yet to be investigated. We replicated the age-related decline in sensitivity by assessing monofilament and vibrotactile (30 and 250 Hz) detection thresholds near the first metatarsal head bilaterally in healthy young and older adults. We additionally applied continuous 30- and 250-Hz vibration to drive mechanically evoked reflex responses in the tibialis anterior muscle, measured via surface electromyography. To investigate potential relationships between plantar sensitivity, cutaneous reflex strength, and postural stability, we performed posturography in subjects during quiet standing without vision. Anteroposterior and mediolateral postural stability decreased with age, and increases in postural sway amplitude and frequency were significantly correlated with increases in plantar detection thresholds. With 30-Hz vibration, cutaneous reflexes were observed in 95% of young adults but in only 53% of older adults, and reflex gain, coherence, and cumulant density at 30 Hz were lower in older adults. Reflexes were not observed with 250-Hz vibration, suggesting this high frequency cutaneous input is filtered out by motoneurons innervating tibialis anterior. Our findings have important implications for assessing the risk of balance impairment in older adults. PMID- 27489367 TI - Postsynaptic nicotinic acetylcholine receptors facilitate excitation of developing CA1 pyramidal neurons. AB - The hippocampus plays a key role in learning and memory. The normal development and mature function of hippocampal networks supporting these cognitive functions depends on afferent cholinergic neurotransmission mediated by nicotinic acetylcholine receptors. Whereas it is well-established that nicotinic receptors are present on GABAergic interneurons and on glutamatergic presynaptic terminals within the hippocampus, the ability of these receptors to mediate postsynaptic signaling in pyramidal neurons is not well understood. We use whole cell electrophysiology to show that heteromeric nicotinic receptors mediate direct inward currents, depolarization from rest and enhanced excitability in hippocampus CA1 pyramidal neurons of male mice. Measurements made throughout postnatal development provide a thorough developmental profile for these heteromeric nicotinic responses, which are greatest during the first 2 wk of postnatal life and decrease to low adult levels shortly thereafter. Pharmacological experiments show that responses are blocked by a competitive antagonist of alpha4beta2* nicotinic receptors and augmented by a positive allosteric modulator of alpha5 subunit-containing receptors, which is consistent with expression studies suggesting the presence of alpha4beta2 and alpha4beta2alpha5 nicotinic receptors within the developing CA1 pyramidal cell layer. These findings demonstrate that functional heteromeric nicotinic receptors are present on CA1 pyramidal neurons during a period of major hippocampal development, placing these receptors in a prime position to play an important role in the establishment of hippocampal cognitive networks. PMID- 27489368 TI - Cerebellar tDCS dissociates the timing of perceptual decisions from perceptual change in speech. AB - Neuroimaging studies suggest that the cerebellum might play a role in both speech perception and speech perceptual learning. However, it remains unclear what this role is: does the cerebellum help shape the perceptual decision, or does it contribute to the timing of perceptual decisions? To test this, we used transcranial direct current stimulation (tDCS) in combination with a speech perception task. Participants experienced a series of speech perceptual tests designed to measure and then manipulate (via training) their perception of a phonetic contrast. One group received cerebellar tDCS during speech perceptual learning, and a different group received sham tDCS during the same task. Both groups showed similar learning-related changes in speech perception that transferred to a different phonetic contrast. For both trained and untrained speech perceptual decisions, cerebellar tDCS significantly increased the time it took participants to indicate their decisions with a keyboard press. By analyzing perceptual responses made by both hands, we present evidence that cerebellar tDCS disrupted the timing of perceptual decisions, while leaving the eventual decision unaltered. In support of this conclusion, we use the drift diffusion model to decompose the data into processes that determine the outcome of perceptual decision-making and those that do not. The modeling suggests that cerebellar tDCS disrupted processes unrelated to decision-making. Taken together, the empirical data and modeling demonstrate that right cerebellar tDCS dissociates the timing of perceptual decisions from perceptual change. The results provide initial evidence in healthy humans that the cerebellum critically contributes to speech timing in the perceptual domain. PMID- 27489369 TI - Spatial spread of local field potential is band-pass in the primary visual cortex. AB - Local field potential (LFP) is a valuable tool in understanding brain function and in brain machine-interfacing applications. However, there is no consensus on the spatial extent of the cortex that contributes to the LFP (its "spatial spread"), with different studies reporting values between a few hundred micrometers and several millimeters. Furthermore, the dependency of the spatial spread on frequency, which could reflect properties of the network architecture and extracellular medium, is not well studied, with theory and models predicting either "all-pass" (frequency-independent) or "low-pass" behavior. Surprisingly, we found the LFP spread to be "band-pass" in the primate primary visual cortex, with the greatest spread in the high-gamma range (60-150 Hz). This was accompanied by an increase in phase coherency across neighboring sites in the same frequency range, consistent with the findings of a recent model that reconciles previous studies by suggesting that spatial spread depends on neuronal correlations. PMID- 27489370 TI - High-fidelity optical excitation of cortico-cortical projections at physiological frequencies. AB - Optogenetic activation of axons is a powerful approach for determining the synaptic properties and impact of long-range projections both in vivo and in vitro. However, because of the difficulty of measuring activity in axons, our knowledge of the reliability of optogenetic axonal stimulation has relied on data from somatic recordings. Yet, there are many reasons why activation of axons may not be comparable to cell bodies. Thus we have developed an approach to more directly assess the fidelity of optogenetic activation of axonal projections. We expressed opsins (ChR2, Chronos, or oChIEF) in the mouse primary visual cortex (V1) and recorded extracellular, pharmacologically isolated presynaptic action potentials in response to axonal activation in the higher visual areas. Repetitive stimulation of axons with ChR2 resulted in a 70% reduction in the fiber volley amplitude and a 60% increase in the latency at all frequencies tested (10-40 Hz). Thus ChR2 cannot reliably recruit axons during repetitive stimulation, even at frequencies that are reliable for somatic stimulation, likely due to pronounced channel inactivation at the high light powers required to evoke action potentials. By comparison, oChIEF and Chronos evoked photocurrents that inactivated minimally and could produce reliable axon stimulation at frequencies up to 60 Hz. Our approach provides a more direct and accurate evaluation of the efficacy of new optogenetic tools and has identified Chronos and oChIEF as viable tools to interrogate the synaptic and circuit function of long-range projections. PMID- 27489371 TI - Effect of phenytoin on sodium conductances in rat hippocampal CA1 pyramidal neurons. AB - The antiepileptic drug phenytoin (PHT) is thought to reduce the excitability of neural tissue by stabilizing sodium channels (NaV) in inactivated states. It has been suggested the fast-inactivated state (IF) is the main target, although slow inactivation (IS) has also been implicated. Other studies on local anesthetics with similar effects on sodium channels have implicated the NaV voltage sensor interactions. In this study, we reexamined the effect of PHT in both equilibrium and dynamic transitions between fast and slower forms of inactivation in rat hippocampal CA1 pyramidal neurons. The effects of PHT were observed on fast and slow inactivation processes, as well as on another identified "intermediate" inactivation process. The effect of enzymatic removal of IF was also studied, as well as effects on the residual persistent sodium current (INaP). A computational model based on a gating charge interaction was derived that reproduced a range of PHT effects on NaV equilibrium and state transitions. No effect of PHT on IF was observed; rather, PHT appeared to facilitate the occupancy of other closed states, either through enhancement of slow inactivation or through formation of analogous drug-bound states. The overall significance of these observations is that our data are inconsistent with the commonly held view that the archetypal NaV channel inhibitor PHT stabilizes fast inactivation states, and we demonstrate that conventional slow activation "IS" and the more recently identified intermediate-duration inactivation process "II" are the primary functional targets of PHT. In addition, we show that the traditional explanatory frameworks based on the "modulated receptor hypothesis" can be substituted by simple, physiologically plausible interactions with voltage sensors. Additionally, INaP was not preferentially inhibited compared with peak INa at short latencies (50 ms) by PHT. PMID- 27489373 TI - Get the Diagnosis: an evidence-based medicine collaborative Wiki for diagnostic test accuracy. AB - BACKGROUND: Despite widespread calls for its use, there are challenges to the implementation of evidence-based medicine (EBM) in clinical practice. METHODS: In response to the challenges of finding timely, pertinent information on diagnostic test accuracy, we developed an online, crowd-sourced Wiki on diagnostic test accuracy called Get the Diagnosis (GTD, http://www.getthediagnosis.org). RESULTS: Since its launch in November 2008 till October 2015, GTD has accumulated information on 300 diagnoses, with 1617 total diagnostic entries. There are a total of 1097 unique diagnostic tests with a mean of 5.4 tests (range 0-38) per diagnosis. 73% of entries (1182 of 1617) have an associated sensitivity and specificity and 89% of entries (1432 of 1617) have associated peer-reviewed literature citations. Altogether, GTD contains 474 unique literature citations. For a sample of three diagnoses, the search precision (percentage of relevant results in the first 30 entries) in GTD was 100% as compared with a range of 13.3%-63.3% for PubMed and between 6.7% and 76.7% for Google Scholar. CONCLUSION: GTD offers a fast, precise and efficient way to look up diagnostic test accuracy. On three selected examples, GTD had a greater precision rate compared with PubMed and Google Scholar in identifying diagnostic test information. GTD is a free resource that complements other currently available resources. PMID- 27489372 TI - Timeliness of referral of children with new onset type 1 diabetes. AB - INTRODUCTION: Type 1 diabetes (T1D) is characterised by autoimmune destruction of pancreatic beta cells leading to insulin deficiency. Prompt referral to a specialist paediatric diabetes team (PDT) for insulin initiation and further management is important to prevent diabetic ketoacidosis (DKA), which remains the most common cause of death in this condition. OBJECTIVE: The aim was to study the timeliness of referrals from general practitioners (GPs) to PDT, of children suspected of having TID. METHOD: We carried out a survey of the practice of GPs when they suspect TID in a young person, to investigate whether they recognised the need for urgent referral to PDT. In addition, we carried out retrospective case notes review of children diagnosed with diabetes mellitus between January 2005 and December 2014. RESULTS: 111/300 (37%) of GPs replied to survey. Of these, 73/111 (65.8%) would have referred promptly to the PDT in accordance with National Guidelines. However, 34.2% would have taken an action that would have led to delay in referral to PDT. 96 children were diagnosed with TID during the audit period. There was a delay in referral in 35 (36.5%) children. 19/35 (54.3%) of these children presented with DKA. Mean duration of delay in presentation to the PDT was 1.8 days. In both survey and audit, the most common reason for delayed referral was GP attempting to confirm the diagnosis by undertaking further diagnostic tests. CONCLUSIONS: Our study has identified a modifiable reason for delayed referrals of children with TID. PMID- 27489374 TI - Occlusive retinal vasculitis secondary to Behcet's disease. PMID- 27489375 TI - Clinicopathological and prognostic significance of survivin expression in renal cancer patients: a meta-analysis. AB - BACKGROUND: Survivin has been reported to play a role in the diagnosis and prognosis of renal cell carcinoma (RCC); however, published data on this subject are conflicting. AIM: To conduct a meta-analysis to evaluate the impact of survivin as a prognostic marker and its association with clinicopathological variables in patients with RCC. METHOD: Comprehensive searches of electronic databases (PubMed, ISI Web of Knowledge Embase, Google Scholar Web and the Cochrane Library) were updated to June 2016 to retrieve eligible studies. The association strength was measured with relative risks (RRs) and pooled HRs with 95% CIs, which were extracted and pooled to determine the association between survivin expression and patient survival and clinicopathological features. RESULTS: Ten studies with 1063 cases of RCC were included. Positive survivin expression in RCC was associated with the TNM stage (pooled RR 1.49; 95% CI 1.07 to 2.07) or Fuhrman grade (pooled RR 1.63; 95% CI 1.15 to 2.32) in patients. The correlation between survivin expression and gender was not significant (pooled RR 0.97; 95% CI 0.83 to 1.15). In addition, a considerable association was found between survivin expression and overall survival for patients with RCC (pooled HR 1.94; 95% CI 1.24 to 3.05 (multivariate model) and 5.41; 95% CI 4.08 to 7.17 (univariate model)). CONCLUSIONS: Our results indicate that survivin is of prognostic significance in patients with RCC. PMID- 27489376 TI - Fecal Microbiota Transplantation and Its Usage in Neuropsychiatric Disorders. AB - Fecal microbiota transplantation has a 1700-year history. This forgotten treatment method has been put into use again during the last 50 years. The interest in microbiota-gut-brain axis and fecal microbiota transplantation is rapidly increasing. New evidence is obtained in the etiopathogenesis of neuropsychiatric disorders. There is a large number of experimental and clinical researches in the field of gut-brain axis. There is limited information on fecal microbiota transplantation. Despite this, initial results are promising. It is commonly used in the treatment of gastrointestinal diseases such as Clostridium difficile infection, Crohn's disease, ulcerative colitis. It is also experimentally used in the treatment of metabolic and autoimmune diseases. There are case reports that it is effective in the treatment of autism, Parkinson's disease, multiple sclerosis, chronic fatigue syndrome and irritable bowel syndrome. Its implementation is easy, and it is a cheap and reliable treatment method. However, the long-term risks are unknown. Additionally, standard application protocols have not yet been established. There are a lot of questions to be answered. A university in Turkey has got official permission this year, and started to apply fecal microbiota transplantation. In this review, neuropsychiatric areas of use of fecal microbiota transplantation have been discussed in the light of the current information. PMID- 27489378 TI - Association of Polymorphisms within the Serotonin Receptor Genes 5-HTR1A, 5 HTR1B, 5-HTR2A and 5-HTR2C and Migraine Susceptibility in a Turkish Population. AB - OBJECTIVE: Migraine, a highly prevelant headache disorder, is regarded as a polygenic multifactorial disease. Serotonin (5-HT) and their respective receptors have been implicated in the patogenesis. METHODS: We investigated the 5-HT1A, 5 HT1B, 5-HT2A, and 5-HT2C receptor gene polymorphisms and their association with migraine in Turkish patients. The rs6295, rs1300060, rs1228814, rs6311, rs6313, rs6314, rs6318, rs3813929 (-759C/T) and rs518147 polymorphisms were analyzed in 135 patients with migraine and 139 healthy subjects, using a BioMark 96.96 dynamic array system. RESULTS: We found no difference in the frequency of the analyzed eight out of nine polymorpisms between migraine and control groups. However, a significant association was found between the rs3813929 polymorphism in the promoter region of 5-HTR2C gene and migraine. Also, the allele of rs3813929 was more common in the migraine group. CONCLUSION: This result suggests that the 5-HTR2C rs3813929 polymorphism can be a genetic risk factor for migraine in a Turkish population. PMID- 27489377 TI - Effects of Antipsychotics on Bone Mineral Density in Patients with Schizophrenia: Gender Differences. AB - Low bone mineral density (BMD) and osteoporosis are common in patients with schizophrenia and detrimental to illness prognosis and life quality. Although the pathogenesis is not fully clear, series of studies have revealed factors related to low BMD such as life style, psychotic symptoms, medication use and the activity of bone absorption markers. It has been known that antipsychotic-induced hyperprolactinemia plays a critical role on decreased BMD. However, it remains uncertain whether the risk factors differ between men and women. According to the effect on prolactin, antipsychotics can be classified into two groups: prolactin sparing (PS) and prolactin-raising (PR). Our previous study has demonstrated that clozapine which is among the PS antipsychotics is beneficial for BMD when compared with PR antipsychotics in women with chronic schizophrenia. We have also found that risks factors associated with low BMD are different between men and women, suggesting that gender-specific risk factors should be considered for intervention of bone loss in patients with schizophrenia. This article reviews the effects of antipsychotics use on BMD with particular discussion for the differences on gender and age, which implicate the alterations of sex and other related hormones. In addition, currently reported protective and risk factors, as well as the effects of medication use on BMD including the combination of antipsychotics and other psychotropic agents and other potential medications are also reviewed. PMID- 27489379 TI - Investigation of Dysregulation of Several MicroRNAs in Peripheral Blood of Schizophrenia Patients. AB - OBJECTIVE: The prevalence of schizophrenia is 1%, and it is a debilitating disorder that often results in a shortened lifespan. Peripheral blood samples are good candidates to investigate because they can be easily drawn, and they are widely studied in psychiatric disorders. MicroRNAs are small non-coding RNA transcripts. They regulate the expression of genes by binding to the 3' untranslated region (UTR) of mRNAs and pointing them to degrade. In this study, we aimed to investigate the expression of miR-9-5p, miR-29a-3p, miR-106-5p, miR 106b-5p, miR-107, miR-125a-3p, and miR-125b-3p in schizophrenia patients and healthy controls. METHODS: We collected blood samples from 16 patients with schizophrenia and 16 healthy controls. MicroRNAs were measured with reverse transcriptase polymerase chain reaction. RESULTS: Schizophrenia patients showed statistically significant upregulation of five microRNAs: miR9-5p (p=0.002), miR29a-3p (p<0.001), miR106b-5p (p=0.002), miR125a-3p (p<0.001), and miR125b-3p (p=0.018). CONCLUSION: Our results increased the value of the miR106 and miR29 families as potentially and consistently dysregulated in psychiatric disorders. Our results should be considered preliminary, and they need confirmation in future studies with larger sample sizes. PMID- 27489380 TI - Efficacy and Tolerability of Paliperidone Extended-release in the Treatment of First-episode Psychosis: An Eight-week, Open-label, Multicenter Trial. AB - OBJECTIVE: We investigated the efficacy and tolerability of paliperidone extended release (ER) tablets in patients with first-episode psychosis (n=75). METHODS: This was an 8-week, open-label, multicenter trial. The primary outcome variable was scores on the Positive and Negative Syndrome Scale (PANSS); secondary measures included the Scale for the Assessment of Negative Symptoms (SANS), the Cognitive Assessment Interview (CAI), and the Global Assessment of Functioning (GAF). To assess safety, we measured drug-related adverse events, weight, lipid related variables, and prolactin and administered the Simpson-Angus Rating Scale (SARS), the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Scale (BAS), the Arizona Sexual Experiences Scale (ASEX), and the Udvalg for Kliniske Undersogelser side effect rating scale (UKU). RESULTS: The administration of paliperidone ER resulted in significant improvement in the PANSS, SANS, CAI, and GAF scores (p<0.001) over time. This improvement was evident as early as 1 week. The most frequent adverse events were akathisia, somnolence, anxiety, and sedation, which were well tolerated. Modest increases in weight and lipid profiles were also noted. Prolactin levels were substantially increased at the endpoint in both male and female patients. CONCLUSION: These results indicate that paliperidone ER is effective and is characterized by good tolerability in the treatment of positive and negative symptoms and cognitive functioning in first-episode psychosis. PMID- 27489381 TI - Gender-specific Associations of the Brain-derived Neurotrophic Factor Val66Met Polymorphism with Neurocognitive and Clinical Features in Schizophrenia. AB - OBJECTIVE: To explore associations of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with cognitive functioning and psychopathology in patients with schizophrenia. METHODS: We included 133 subjects meeting the DSM-IV criteria for schizophrenia who were in the post-acute stage of the disease. BDNF Val66Met genotypes were identified via polymerase chain reaction. The computerized neurocognitive function battery, Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Social and Occupational Functioning Scale (SOFAS), and the Subjective Well-being under Neuroleptic Treatment (SWN-K) were administered. Gender-stratified sub-analysis was also conducted to identify gender-specific patterns in the findings. RESULTS: In male patients, no significant difference in any measure by BDNF genotype was evident. In female patients, scores on the CDSS and total PANSS and all subscales were significantly higher in valine (Val) carriers. In addition, scores on the SOFAS and SWN-K were significantly lower in Val carriers. In terms of neurocognitive measures, female patients with the Val allele had significantly poorer reaction times and fewer correct responses on the Continuous Performance Test (CPT) and the Trail Making Test (Parts A and B). After adjustment of PANSS total scores and log-transformed CDSS scores, CPT outcomes were significantly poorer in female patients with than in those without the Val allele. CONCLUSION: Gender-specific associations of the Val allele with poor neurocognitive function and more severe psychopathology were evident. Further studies are required to explore the mechanisms of these differences and the potential utility of the BDNF genotype as a predictor of outcome in patients with schizophrenia. PMID- 27489382 TI - Differential Effects of Olanzapine and Haloperidol on MK-801-induced Memory Impairment in Mice. AB - OBJECTIVE: We investigated the differential effects of the antipsychotic drugs olanzapine and haloperidol on MK-801-induced memory impairment and neurogenesis in mice. METHODS: MK-801 (0.1 mg/kg) was administered 20 minutes prior to behavioral testing over 9 days. Beginning on the sixth day of MK-801 treatment, either olanzapine (0.05 mg/kg) or haloperidol (0.05 mg/kg) was administered 40 minutes prior to MK-801 for the final 4 days. Spatial memory performance was measured using a Morris water maze (MWM) test for 9 days (four trials/day). Immunohistochemistry with bromodeoxyuridine (BrdU) was used to identify newborn cells labeled in tissue sections from the dentate gyrus of the hippocampus. RESULTS: MK-801 administration over 9 days significantly impaired memory performance in the MWM test compared to untreated controls (p<0.05) and these deficits were blocked by treatment with olanzapine (p<0.05) but not haloperidol. The administration of MK-801 also resulted in a decrease in the number of BrdU labeled cells in the dentate gyrus (28.6%; p<0.01), which was prevented by treatment with olanzapine (p<0.05) but not haloperidol. CONCLUSION: These results suggest that olanzapine has a protective effect against cognitive impairments induced by MK-801 in mice via the stimulating effects of neurogenesis. PMID- 27489383 TI - A Questionnaire-based Study of the Views of Schizophrenia Patients and Psychiatric Healthcare Professionals in Japan about the Side Effects of Clozapine. AB - OBJECTIVE: It is well documented that clozapine treatment causes agranulocytosis, but it can also induce drowsiness, constipation, and hypersalivation; however, these symptoms are usually less severe. It has been reported that clozapine treated patients with schizophrenia and psychiatric healthcare professionals consider different side effects to be important. The aim of this study was to assess current practice related to the side effects of clozapine in clozapine treated patients with schizophrenia and psychiatric healthcare professionals in Japan. METHODS: Data were collected from January 2014 to August 2015 in Okehazama Hospital, Kakamigahara Hospital, and Numazu Chuo Hospital. Clozapine-treated patients with schizophrenia and psychiatric healthcare professionals (psychiatrists and pharmacists) were enrolled in this study. RESULTS: Of the 106 patients and 120 psychiatric healthcare professionals screened, 100 patients and 104 healthcare professionals were included in this study. We asked the patients what side effects caused them trouble and we asked psychiatric healthcare professionals what side effects caused them concern. The patients and psychiatrists held similarly positive views regarding the efficacy of clozapine. The healthcare professionals were concerned about agranulocytosis (92.4%), blood routines (61.3%). On the other hand, the patients experienced hypersalivation (76.0%), sleepiness (51.0%). A positive correlation (R=0.696) was found between patient satisfaction and DAI-10 score. CONCLUSION: Patients experienced more problems than healthcare professionals expected. However, usage experience of clozapine healthcare professionals tended to have similar results to patients. It is necessary that all healthcare professionals fully understand the efficacy and potential side effects of clozapine. This is very important for promoting clozapine treatment in Japan. PMID- 27489385 TI - Zolpidem Induced Sleep-related Eating and Complex Behaviors in a Patient with Obstructive Sleep Apnea and Restless Legs Syndrome. AB - Zolpidem-induced sleep-related complex behaviors (SRCB) with anterograde amnesia have been reported. We describe herein a case in which the development of zolpidem-induced sleep-related eating disorder (SRED) and SRCB was strongly suspected. A 71-year-old Korean male was admitted to the Department of Psychiatry due to his repetitive SRED and SRCB with anterograde amnesia, which he reported as having occurred since taking zolpidem. The patient also had restless legs syndrome (RLS) and obstructive sleep apnea (OSA). His baseline serum iron level was low at admission. Zolpidem discontinuation resulted in the immediate disappearance of his SRED, but did not affect his RLS symptoms. These symptoms rapidly improved after adding a single i.v. iron injection once daily, and so he was discharged to day-clinic treatment. These findings indicate that zolpidem can induce SRCB. Although the pathophysiology of zolpidem-induced SRED and other SRCB remains unclear, clinicians should carefully monitor for the potential induction of complex behaviors associated with zolpidem in patients with comorbid RLS or OSA. PMID- 27489384 TI - Opioid Analgesics and Depressive Symptoms in Burn Patients: What Is the Real Relationship? AB - OBJECTIVE: Major burn injuries are strongly associated with both psychological trauma and severe pain, and opioids are the mainstay analgesics for the treatment of severe burn pain. The objectives of this study are to find the complex relationship between opioid dose, depression, and post-traumatic stress disorder (PTSD) symptoms during the acute management of pain in burn patients. METHODS: The symptoms of depression and PTSD were assessed in 43 burn patients immediately following wound stabilization and 2 weeks after the initial evaluation. RESULTS: Total opioid doses and Hamilton Depression Scale (HAMD) scores obtained during the second evaluation were positively but weakly correlated after controlling for age and total burn surface area (R=0.33, p=0.03). Moreover, pain management with opioids was significantly more common in burn patients with low Clinician Administered PTSD Scale scores (evaluation 1) and high HAMD scores (evaluation 2) (F=6.66, p=0.001). CONCLUSION: High opioid dose following acute burn trauma might have correlation with depressive symptoms. Monitoring of depressive symptoms may be important following acute burn trauma and consequent opioids pain management, particularly when PTSD symptoms appear minimal during the early stabilization of patients. PMID- 27489386 TI - Psychosis, Treatment Emergent Extrapyramidal Events, and Subsequent Onset of Huntington's Disease: A Case Report and Review of the Literature. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by a triad of progressive motor dysfunction, cognitive decline and psychiatric disturbances. The hallmark of HD is the distinctive choreiform movement disorder that typically has a subtle, insidious onset in the fourth to fifth decade of life and gradually worsens over 10 to 20 years until death. Notably, two-thirds of HD patients present with chorea and one third with mental changes. The prevalence of psychiatric symptoms is significantly higher than in the general population, and is estimated to be around 66-73%. Here, we report a unique case of subsequent onset of HD in a patient previously treated for schizophrenia and complicated by the extrapyramidal side effects to antipsychotics. PMID- 27489387 TI - Clinical Usefulness of Aripiprazole and Lamotrigine in Schizoaffective Presentation of Tuberous Sclerosis. AB - Tuberous sclerosis is not as rare as once thought and has high psychiatric comorbidities. However, bipolar or psychotic features associated with tuberous sclerosis have been rarely reported. This report first presents a tuberous sclerosis patient, resembling a schizoaffective disorder of bipolar type. A patient with known tuberous sclerosis displayed mood fluctuation and psychotic features. Her symptoms did not remit along with several psychiatric medications. After hospitalization, the patient responded well with lamotrigine and aripiprazole without exacerbation. As demonstrated in this case, tuberous sclerosis may also encompass bipolar affective or psychotic features. We would like to point out the necessity to consider bipolarity in evaluating and treating tuberous sclerosis. PMID- 27489388 TI - Dermatitis Artefacta Mimicking Borderline Personality Disorder: Sometimes, Skin Could Be Misleading. AB - Dermatitis artefacta lies in a gray zone, between the specialities of psychiatry and dermatology. The condition could mimic a number of other lesions and therefore is a source of much confusion in clinical practice. Here, we describe a case of dermatitis artefacta in an 11-years old girl, which resembled self harming behavior in Borderline personality disorder. We then discuss how the two could be differentiated and why this becomes imperative while dealing with such cases. PMID- 27489389 TI - Manic Symptoms Due to Methylphenidate Use in an Adolescent with Traumatic Brain Injury. AB - Almost one-fifth of children who sustain a traumatic brain injury (TBI) are under the risk of attention problems after injury. The efficacy and tolerability of methylphenidate (MPH) in children with a history of TBI have not been completely identified. In this case report, MPH-induced manic symptoms in an adolescent with TBI will be summarized. A male patient aged 17 years was admitted with the complaints of attention difficulties on schoolwork and forgetfullness which became evident after TBI. Long-acting MPH was administered with the dose of 18 mg/day for attention problems. After one week, patient presented with the complaints of talking to himself, delusional thoughts, irritability and sleeplessness. This case highlights the fact that therapeutic dose of MPH may cause mania-like symptoms in children with TBI. Close monitarization and slow dose titration are crucial when considering MPH in children with TBI. PMID- 27489390 TI - Lithium Toxicity Following Vertical Sleeve Gastrectomy: A Case Report. AB - We are presenting the first documented case of lithium toxicity after vertical sleeve gastrectomy surgery in an 18 year-old female with psychiatric history of bipolar disorder who was treated with lithium. This case illustrates the need for closer monitoring of lithium levels following bariatric surgery. Both psychiatrists and surgeons should be aware of the potential risk of lithium toxicity following bariatric surgery, as well as the need to judiciously monitor lithium level and possibly adjust the dose of some medications. PMID- 27489391 TI - Impact of High Dose Lorazepam on Seizure Threshold in Catatonia: Experience from a Case Study. PMID- 27489392 TI - A Case of May-Thurner Syndrome. AB - May-Thurner syndrome is the condition of the left common iliac vein being compressed between the right common iliac artery and the associated vertebral body. This condition has been linked to spontaneous episodes of deep vein thrombosis (DVT), especially in women aged 20-50, and it may contribute to the slightly higher tendency to develop left-sided (~56%) versus right-sided DVTs. A 50-year-old morbidly obese (BMI 42.7 kg/m2) female presented to the emergency room with acute left leg pain. Past medical history included asthma. Patient is employed as a helper in home health services; no recent history of travel and no history suggestive of hereditary thrombophilia. Prior tobacco use was noted. Patient was admitted to the medical floors and investigated for DVT. Ultrasound Doppler imaging of both legs demonstrated left-sided occlusive DVT in the popliteal, superficial femoral, common femoral veins with extension into the external iliac vein. Imaging in the right leg was unremarkable. Patient was treated with enoxaparin (Lovenox). A hypercoagulation panel was unremarkable. A left lower extremity venogram showed a thrombus at the level of the common femoral vein extending into the iliac vein with stasis of contrast within the right external iliac vein. Following that, she had venoplasty and thrombolytic therapy. The next day, she underwent left iliofemoral mechanical thrombectomy, venoplasty, and left common iliac vein stenting. After an uneventful recovery, the patient was discharged on rivaroxaban for 3 months. In summary, while this patient was initially thought to have unprovoked DVT, absence of any hypercoagulable disorders and the findings in venogram favored the diagnosis of May-Thurner syndrome. For women in this age group with this type of presentation, this is an important diagnosis to keep in mind. PMID- 27489393 TI - Urban family reconstitution-a worked example. AB - Family reconstitutions have been undertaken only rarely in urban settings due to the high mobility of historical urban populations, in both life and death. Recently Gill Newton has outlined a methodology for the reconstitution of urban populations and we applied a modified version of this method to the large Westminster parish of St. Martin in the Fields between 1752 and 1812, a period that posed particular difficulties for family reconstitution because of the rapid lengthening of the interval between birth and baptism.1 The extraordinary richness of the records for St. Martin in the Fields made it possible to investigate burial and baptismal practices in great detail, and the extent and impact of residential mobility. We found that short-range, inter-parochial movement was so frequent that it was necessary to confine the reconstitution sample to windows in which families registered events at a single street address. Using birth interval analysis and the frequencies of twin births it was possible to demonstrate that the registration of birth events was fairly complete, but that many infant and child burials were missed. These missing burials probably resulted from the unreported export of corpses for burial in other parishes, a phenomenon for which we had considerable evidence. The limitations of family reconstitution in this highly mobile and heterogeneous urban population is discussed and we demonstrate some checks and corrections that can be used to improve the quality of such reconstitutions. PMID- 27489394 TI - Understanding variability in crop response to fertilizer and amendments in sub Saharan Africa. AB - Improved understanding of soil fertility factors limiting crop productivity is important to develop appropriate soil and nutrient management recommendations in sub-Saharan Africa. Diagnostic trials were implemented in Kenya, Malawi, Mali, Nigeria and Tanzania, as part of the African Soils Information Service (AfSIS) project, to identify soil fertility constraints to crop production across various cropping systems and soil fertility conditions. In each country, one to three sites of 10 km * 10 km were included with each site having 12-31 field trials. The treatments tested included a control, an NPK treatment, three treatments in which the N, P and K nutrients were omitted one at a time from the NPK treatment, and three treatments in which secondary and micronutrients (Ca, Mg, S, Zn and B) simply referred here as multi-nutrients, manure and lime were added to the NPK. The field trials were conducted for 1-2 seasons; the test crop was maize except in Mali where sorghum was used. Nitrogen was limiting in all sites and generally the most limiting nutrient except in Sidindi (Kenya) and Kontela (Mali) where P was the most limiting. The general pattern in Kiberashi (Tanzania) shows none of the nutrients were limiting. K is mainly limiting in only one site (Mbinga) although incidences of K limitation were seen in almost all sites. Addition of multi-nutrients and manure further improved the yields of NPK in most sites. Cluster analyses revealed that maize crop in 11% of fields were highly responsive to nitrogen application, 25% (i.e., 21% poor and 4% fertile) 'non-responsive' to any nutrient or soil amendment, 28% being 'low responsive' and 36% of 'intermediate response'. This study indicates that constraints to crop production vary considerably even within a site, and that addressing limitations in secondary and micronutrients, and increasing soil carbon can improve response to fertilizers. For sustainable crop production intensification in smallholder farming systems in SSA, there is need to develop management strategies to improve efficiency of fertilizer use and of other inputs, recognizing the site-specific nutrient response patterns at various spatial scales. PMID- 27489395 TI - Response of bean cultures' water use efficiency against climate warming in semiarid regions of China. AB - Farm crop growing and high efficiency water resource utilizing are directly influenced by global warming, and a new challenge will be given to food and water resource security. A simulation experiment by farm warming with infrared ray radiator was carried out, and the result showed photosynthesis of broad bean was significantly faster than transpiration during the seedling stage, ramifying stage, budding stage, blooming stage and podding stage when the temperate was increased by 0.5-1.5 degrees C. But broad bean transpiration was faster than photosynthesis during the budding stage, blooming stage and podding stage when the temperature was increased by 1.5 degrees C above. The number of grain per hill and hundred-grain weight were significantly increased when the temperature was increased by 0.5-1.0 degrees C. But they significantly dropped and finally the yield decreased when the temperature was increased by 1.0 degrees C above. The broad bean yield decreased by 39.2-88.4% when the temperature was increased by 1.5-2.0 degrees C. The broad bean water use efficiency increased and then decreased with temperature rising. The water use efficiency increased when the temperature was increased by 1.0 degrees C below, and it quickly decreased when the temperature was increased by 1.0 degrees C above. In all, global warming in the future will significantly influence the growth, yield and water use efficiency of bean cultures in China's semiarid regions. PMID- 27489396 TI - International Classification of Functioning, Disability and Health in Audiological Practices. PMID- 27489397 TI - What Is the International Classification of Functioning, Disability and Health and Why Is It Relevant to Audiology? AB - The World Health Organization's International Classification of Functioning, Disability and Health (ICF) is widely used in disability and health sectors as a framework to describe the far-reaching effects of a range of health conditions on individuals. This biopsychosocial framework can be used to describe the experience of an individual in the components of body functions, body structures, and activities and participation, and it considers the influence of contextual factors (environmental and personal) on these components. Application of the ICF in audiology allows the use of a common language between health care professionals in both clinical and research settings. Furthermore, the ICF is promoted as a means of facilitating patient-centered care. In this article, the relevance and application of the ICF to audiology is described, along with clinical examples of its application in the assessment and management of children and adults with hearing loss. Importantly, the skills necessary for clinicians to apply the ICF effectively are discussed. PMID- 27489398 TI - The International Classification of Functioning, Disability and Health as a Framework for Providing Patient- and Family-Centered Audiological Care for Older Adults and Their Significant Others. AB - Hearing impairment is highly prevalent in the older population, and it impacts communication and quality of life for both the people with the hearing difficulties and their significant others. In this article, typical audiological assessment and management of an older adult is contrasted with a best practice approach wherein the World Health Organization's International Classification of Functioning, Disability and Health (ICF) framework is applied. The aim of the comparison is to demonstrate how the ICF expands our focus: rather than merely focusing on impairment, we also consider the activities, participation, and contextual factors for both the person with the hearing impairment and his or her family. A case example of an older patient and her spouse is provided, and their shared experience of the patient's hearing impairment is mapped onto the ICF framework. Family-centered hearing care is recommended for individualizing care and improving outcomes for older patients and their families. PMID- 27489399 TI - Hearing and Cognitive Impairment and the Role of the International Classification of Functioning, Disability and Health as a Rehabilitation Framework. AB - The International Classification of Functioning, Disability and Health (ICF) has been applied widely in the literature to describe and differentiate the broad implications of hearing impairment (HI) and cognitive impairment (CI) on communication. As CI and HI are largely age-related conditions, the likelihood of comorbidity of these conditions is high. In the context of an aging population, the prevalence of comorbidity is likely to rise, yet much of the clinical assessment and intervention in HI and CI occur separately. The benefit of addressing the dual impact of these conditions is of increasing clinical importance for all clinicians working with older adults and for audiologists and speech pathologists in particular. In this article, the ICF model will be applied to explore the everyday implications of HI and CI. Furthermore, the clinical implications of the ICF model are explored with particular respect to communication assessment and intervention options. The potential benefit of combining activity- and participation-focused interventions currently offered for HI and CI independently is examined. PMID- 27489401 TI - Aphasia and Auditory Processing after Stroke through an International Classification of Functioning, Disability and Health Lens. AB - Aphasia is an acquired language impairment affecting speaking, listening, reading, and writing. Aphasia occurs in about a third of patients who have ischemic stroke and significantly affects functional recovery and return to work. Stroke is more common in older individuals but also occurs in young adults and children. Because people experiencing a stroke are typically aged between 65 and 84 years, hearing loss is common and can potentially interfere with rehabilitation. There is some evidence for increased risk and greater severity of sensorineural hearing loss in the stroke population and hence it has been recommended that all people surviving a stroke should have a hearing test. Auditory processing difficulties have also been reported poststroke. The International Classification of Functioning, Disability and Health (ICF) can be used as a basis for describing the effect of aphasia, hearing loss, and auditory processing difficulties on activities and participation. Effects include reduced participation in activities outside the home such as work and recreation and difficulty engaging in social interaction and communicating needs. A case example of a young man (M) in his 30s who experienced a left-hemisphere ischemic stroke is presented. M has normal hearing sensitivity but has aphasia and auditory processing difficulties based on behavioral and cortical evoked potential measures. His principal goal is to return to work. Although auditory processing difficulties (and hearing loss) are acknowledged in the literature, clinical protocols typically do not specify routine assessment. The literature and the case example presented here suggest a need for further research in this area and a possible change in practice toward more routine assessment of auditory function post-stroke. PMID- 27489400 TI - The Application of the International Classification of Functioning, Disability and Health to Functional Auditory Consequences of Mild Traumatic Brain Injury. AB - This article reviews the auditory consequences of mild traumatic brain injury (mTBI) within the context of the International Classification of Functioning, Disability and Health (ICF). Because of growing awareness of mTBI as a public health concern and the diverse and heterogeneous nature of the individual consequences, it is important to provide audiologists and other health care providers with a better understanding of potential implications in the assessment of levels of function and disability for individual interdisciplinary remediation planning. In consideration of body structures and function, the mechanisms of injury that may result in peripheral or central auditory dysfunction in mTBI are reviewed, along with a broader scope of effects of injury to the brain. The activity limitations and participation restrictions that may affect assessment and management in the context of an individual's personal factors and their environment are considered. Finally, a review of management strategies for mTBI from an audiological perspective as part of a multidisciplinary team is included. PMID- 27489402 TI - Adolescents with Hearing Loss and the International Classification of Functioning, Health, and Disability: Children & Youth Version. AB - In 2007, the World Health Organization published a set of International Classification of Functioning, Disability and Health (ICF) codes designed for children and youth (ICF-CY version). The ICF-CY considers typical developmental changes associated with childhood while describing health status and the effects of intervention. In this article we will describe how a specific intervention (transition planning for adolescents) can be documented with the ICF-CY. Transition planning in health care prepares adolescents and their families for the transfer from pediatric to adult health services and has been demonstrated to be an effective practice for adolescents with many types of chronic health conditions (e.g., cystic fibrosis, epilepsy, diabetes). Audiology has not yet addressed transition planning for adolescents with hearing loss; therefore, we propose using the ICF-CY to design a pathway of care. The ICF-CY can standardize transition planning to the benefit of both teen patients and audiologists: teens and their families would gradually acquire necessary knowledge and skills, and audiologists would develop a meaningful data set to help further inform our pediatric practices, as well as give more structure, depth, and accountability to our role in rehabilitation. PMID- 27489403 TI - Relevance of the International Classification of Functioning, Health and Disability: Children & Youth Version in Early Hearing Detection and Intervention Programs. AB - Early hearing detection and intervention (EHDI) programs have been guided by principles from the Joint Committee on Infant Hearing and an international consensus of best practice principles for family-centered early intervention. Both resources provide a solid foundation from which to design, implement, and sustain a high-quality, family-centered EHDI program. As a result, infants born with permanent hearing loss and their families will have the support they need to develop communication skills. These families also will benefit from programs that align with the framework offered by the World Health Organization's International Classification of Functioning, Disability and Health: Children & Youth Version (ICF-CY). Within this framework, health and functioning is defined and measured by describing the consequences of the health condition (i.e., hearing loss) in terms of body function, structures, activity, and participation as well as social aspects of the child. This article describes the relevance of the ICF-CY for EHDI programs and offers a modified approach by including aspects of quality of life and human development across time. PMID- 27489404 TI - The Role of the World Health Organization's International Classification of Functioning, Health and Disability in Models of Infant Cochlear Implant Management. AB - Newborn hearing screening has led to the early diagnosis of hearing loss in neonates and early device fitting is common, based primarily on electrophysiologic and radiologic information, with some supplementary behavioral measures. Such early fitting of hearing devices, in particular cochlear implants (CIs), has been beneficial to the majority of children implanted under the age of 12 months who meet the cochlear implant candidacy criteria. Comorbidities are common in children with hearing loss, although they may not be evident in neonates and may not emerge until later in infants. Evidence suggests that the child's outcomes are strongly influenced by a range of environmental factors including emotional and social support from the immediate and extended family. Consequently, such factors are important in service planning and service delivery for babies and children receiving CIs. The World Health Organization's International Classification of Functioning, Health and Disability (ICF) can provide a framework to facilitate the holistic management of pediatric cochlear implant recipients. The ICF also can be used to map the progress of recipients over time to highlight emerging issues that require intervention. This article will discuss our preliminary use of the ICF to establish clinical practice; develop advocacy skills among clients and their families; identify eligibility for services such as support in educational settings; enable access to modes of service delivery such as telepractice; provide a conceptual framework for policy and program development for pediatric cochlear implant recipients (i.e., in both disability and health services); and, most importantly, establish a clear pathway for the longitudinal management of the cochlear implant in a child's future. It is anticipated that this model will be applied to other populations receiving cochlear implants through our program. PMID- 27489405 TI - Proton Dipolar Spin-Lattice Relaxation in Nano-channels of Natrolite. AB - The 1H nuclear magnetic resonance (NMR) spectra and the dipolar spin-lattice relaxation time T1D for 1H in the natural natrolite (Na2Al2Si3O10.2H2O) have been measured in the temperature range of 190-390 K. From the temperature transformations of 1H NMR spectra, it follows that at T > 300 K, the diffusion of water molecules along the nano-channels is observed. From experimental T1D data, it follows that the 180 degrees flip motion of the water molecules takes place in natrolite. At low temperature (T < 250 K), the dipolar interaction with paramagnetic impurities as a relaxation mechanism of 1H nuclei becomes significant. PMID- 27489406 TI - The journey of articular cartilage repair. PMID- 27489407 TI - Concepts in regenerative medicine: Past, present, and future in articular cartilage treatment. AB - Regenerative medicine is emerging with great interest and hope from patients, industry, academia, and medical professionals. Cartilage regeneration, restoration, or repair is one of the prime targets that remains largely unsolved, and many believe that regenerative medicine can possibly deliver solutions that can be widely used to address the current gap(s) in treatment. In the United States, Europe, Australia, and India the regulation of regenerative based treatments has become a big debate. Although the rules and regulations remain unclear, clinicians that are interested should carry-on with the best available guidelines to ensure safety and compliance during delivery in clinical practice to avoid regulatory infraction. Many have made significant investment of time, resources, and facilities in recent years to provide new regenerative treatment options and advance medical care for patients. Instead of reinventing the wheel, it would be more efficient to adopt currently accepted standards and nomenclature borrowed from transplantation science, and cord blood storage industries. The purposes of this article are to provide some historical background to the field of regenerative medicine as it applies to cartilage, and how this field has developed. This will be followed by a separate discussion on regulatory oversight and input and how it has influenced access to care. Furthermore, we discuss current clinical techniques and progress, and ways to deliver these treatments to patients safely, effectively, and in a cost sensitive manner, concluding with an overview of some of the promising regenerative techniques specific to cartilage. PMID- 27489408 TI - Microfracture for the treatment of cartilage defects in the knee joint - A golden standard? AB - The evidence for the effectiveness of the microfracture procedure is largely derived from case series and few randomized trials. Clinical outcomes improve with microfracture for the most part, but in some studies these effects are not sustained. The quality of cartilage repair following microfracture is variable and inconsistent due to unknown reasons. Younger patients have better clinical outcomes and quality of cartilage repair than older patients. When lesion location was shown to affect microfracture outcome, patients with lesions of the femoral condyle have the best clinical improvements and quality of cartilage repair compared with patients who had lesions in other areas. Patients with smaller lesions have better clinical improvement than patients with larger lesions. The necessity of long postoperative CPM and restricted weight bearing is widely accepted but not completely supported by solid data. Maybe new developments like the scaffold augmented microfracture(6) will show even more consistent clinical and biological results as well as faster rehabilitation for the treatment of small to medium sized cartilage defects in younger individuals. All in all there is limited evidence that micro fracture should be accepted as gold standard for the treatment of cartilage lesions in the knee joint. There is no study available which compares empty controls or non-surgical treatment/physiotherapy with microfracture. According to the literature there is even evidence for self regeneration of cartilage lesions. The natural history of damaged cartilage seems to be written e.g. by inflammatory processes, genetic predisposition and other factors. Possibly that explains the large variety of the clinical outcome after micro fracture and possibly the standard tools for evaluation of new technologies (randomized controlled trials, case series, etc.) are not sufficient (anymore). Future technologies will be evaluated by big data from international registries for earlier detection of safety issues, for detection of subtle but crucial co-factors for failure and osteoarthritis as well as for lower financial burdens affecting industry and healthcare systems likewise. PMID- 27489409 TI - Autologous bone-marrow mesenchymal cell induced chondrogenesis (MCIC). AB - Degenerative and traumatic articular cartilage defects are common, difficult to treat, and progressive lesions that cause significant morbidity in the general population. There have been multiple approaches to treat such lesions, including arthroscopic debridement, microfracture, multiple drilling, osteochondral transplantation and autologous chondrocyte implantation (ACI) that are currently being used in clinical practice. Autologous bone-marrow mesenchymal cell induced chondrogenesis (MCIC) is a single-staged arthroscopic procedure. This method combines a modified microfracture technique with the application of a bone marrow aspirate concentrate (BMAC), hyaluronic acid and fibrin gel to treat articular cartilage defects. We reviewed the current literatures and surgical techniques for mesenchymal cell induced chondrogenesis. PMID- 27489410 TI - Scaffold-free, stem cell-based cartilage repair. AB - Various approaches to treat articular cartilage have been widely investigated due to its poor intrinsic healing capacity. Stem cell-based therapy could be a promising approach as an alternative to chondrocyte-based therapy and some of these therapies have been already applied in clinical condition. This review discusses the current development of stem cell-based therapies in cartilage repair, specifically focusing on scaffold-free approaches. PMID- 27489411 TI - Autologous collagen induced chondrogenesis (ACIC: Shetty-Kim technique) - A matrix based acellular single stage arthroscopic cartilage repair technique. AB - The defects of articular cartilage in the knee joint are a common degenerative disease and currently there are several established techniques to treat this problem, each with their own advantages and shortcomings. Autologous chondrocyte implantation is the current gold standard but the technique is expensive, time consuming and most versions require two stage procedures and an arthrotomy. Autologous collagen induced chondrogenesis (ACIC) is a single-stage arthroscopic procedure and we developed. This method uses microfracture technique with atelocollagen mixed with fibrin gel to treat articular cartilage defects. We introduce this ACIC techniques and its scientific background. PMID- 27489412 TI - Non-operative management of osteoarthritis of the knee joint. AB - Osteoarthritis is a chronic disorder of synovial joints in which there is progressive softening and disintegration of articular cartilage accompanied by the growth of osteophytes. Treatment designed for osteoarthritis should aim at reducing pain, improve joint mobility, and limit functional impairment. It can be achieved by pharmacological and non-pharmacological means. Non-operative treatment of OA is useful for patients with KL grade 1-3, which are early stages of OA. However, in an advanced stage of OA (KL grade 4), surgical treatment is needed as definitive treatment. PMID- 27489413 TI - Mesenchymal stem cell therapy for osteoarthritis. AB - The versatility of mesenchymal stem cells (MSCs) as a treatment modality has landed it another repair target: osteoarthritis, a crippling cartilage disease that frequently afflicts the aged population. Through many studies, this newly discovered method has been shown to significantly alleviate the pain experienced by osteoarthritic patients. Notwithstanding the effectiveness of MSCs in this regard, varying degrees of success rates have also been reported, which is probably attributable to the different approaches adopted in harnessing MSCs' therapeutic value. Accordingly, it is pertinent to understand the contributory factors like MSC type, dosage, size of osteoarthritic lesion, MSC carrier, and mode of infusion, which would be briefly discussed in this review. PMID- 27489414 TI - 2016 barriers to cartilage restoration. AB - Cartilage restoration has flourished since the 1990s. The early pioneering work included cell therapy by Peterson, marrow stimulation by Johnson, osteochondral autograft treatments by Hangody, and osteochondral allografts by Gross. Since those early days, many scientists and clinicians have created "variations on a theme", markedly expanding the potential options for treating patients with symptomatic chondral lesions. Nevertheless, a variety of barriers exist between these new cartilage products and their clinical applications. These barriers may be categorized as cost, regulatory, insurance, and logistical issues. While absolute solutions will remain elusive, the current goal is to define these barriers as the first step toward solving these problems. PMID- 27489415 TI - Acute anterior cruciate ligament injuries in multisport elite players: Demography, association, and pattern in different sports. AB - BACKGROUND: Anterior cruciate ligament (ACL) tear rates are known to vary from sport to sport. To the best of our knowledge, the relationship of ACL injury with different sports is not reported earlier. The objective of the present study is to investigate the association of ACL injury with different sports and to document various associated ligamentous, meniscal, and chondral lesions of the knee. MATERIALS AND METHODS: Descriptive epidemiological study was carried out in a tertiary care center over a 10-year period. Data were collected of the 638 ACL injured elite sportspersons operated by us. Percentage of ACL injuries and other associated injuries of the knee in different games was calculated. Chi-square test was applied to analyze the relationship between injuries of the specific structures of knee and sports played. p values less than 0.05 were considered to be statistically significant with a confidence interval of 95%. RESULTS: Kabaddi and football constituted the highest percentage (61%) of ACL injuries. Associated injuries were 10 posterior cruciate ligament tears, 11 posterolateral corner injuries, three medial collateral ligament tears, 390 meniscal tears (206 medial, 184 lateral), 201 femoral/tibial condylar lesions (128 medial, 40 lateral femoral condyle and 17 medial, 16 lateral tibial condyle), and two common peroneal nerve injuries. Lateral meniscal tears in kabaddi and medial femoral condylar lesions in badminton were significantly higher. CONCLUSIONS: Kabaddi resulted in higher number of ACL injuries and other associated injuries to the knee. Further investigation is required to ascertain high-risk factors for such injuries. PMID- 27489416 TI - Current practice variations in the management of anterior cruciate ligament injuries in Delhi. AB - BACKGROUND: The aim of this study was to determine the current practices and preferences of the arthroscopic surgeons of Delhi in the diagnosis, treatment and rehabilitation of patients with anterior cruciate ligament (ACL) injury. METHODS: It was a cross-sectional descriptive study conducted among arthroscopic surgeons of Delhi. A survey was conducted using a questionnaire that was sent either by e mail or by direct contact to all sixty arthroscopic surgeons of Delhi. RESULTS: Forty-eight (80%) surgeons responded to our questionnaire. Maximum participants (83.3%) used semitendinosus/gracilis tendon autograft for ACL reconstruction (ACLR) and only 2.1% were using bone-patellar-tendon-bone (BPTB) autograft. Most preferred method of graft fixation was an 'interference screw' on the tibial side and an 'endobutton' on the femoral side, which was preferred by 95.83% and 93.75% surgeons, respectively. Almost all respondents (97%) used a bio-absorbable interference screw for tibial side graft fixation. Postoperative bracing was advised for <3 weeks by 47.9% surgeons and for 3-6 weeks by 31.3%. The results were analysed using statistical analysis. CONCLUSION: Surgeon preferences in ACLR differ considerably among the arthroscopic surgeons of Delhi. There is majority consensus for using Hamstring autograft (single bundle) with a suspensory fixation on the femoral side and an aperture fixation on the tibial side. Transportal technique of making the femoral tunnel and preservation of amputation stump were the preferred methods. However, differences exist over the timing of surgery, rehab after surgery, pain management, etc. PMID- 27489418 TI - Epidemiological profile of sports-related knee injuries in northern India: An observational study at a tertiary care centre. AB - BACKGROUND: Sports-related knee injuries occur commonly in athletes. However, there is no published epidemiological study from India till date. OBJECTIVES: The purpose of this study was to identify common injuries sustained by Indian athletes participating in different sports and to study various associated demographic features. A secondary objective was to investigate different factors, which may affect return to sport by the athlete. STUDY DESIGN: Cross-sectional study (observational study). STUDY CENTRE: Sports injury clinic, PGIMER, Chandigarh. METHODS: Out of 465 athletes who presented to us with sports-related knee injuries over a 5-year period, 363 athletes (from 24 different sports) with complete records were identified. Data were analysed for demographic features, type of sport, mechanism of injury, injury scenario, athlete's level of play, injury duration at presentation, injury patterns and type of management. Telephonic interviews were conducted with each athlete to enquire about return to sport and time lost in sport due to the knee injury. Factors associated with return to sport were investigated using statistical tests of association. RESULTS: Soccer was found to be the most common sport associated with knee injuries accounting for 30.6% of the injuries followed by kabaddi (20.9%). The most common mechanism was non-contact injury (64.4%). Competitive injuries were found to be significantly more than practice/training injuries (p < 0.0001). The most common injuries noted were ACL tears (n = 314) followed by meniscus injuries (n = 284) and the most common combination of injuries were an ACL tear with medial meniscus tear (n = 163). Only 39.8% of the athletes returned to sport. Mean duration of time lost in sport among those who returned to sport was 8.84 months. Return to sport was significantly associated with body mass index, level of competitiveness of the athlete and type of management (p = 0.017, 0.045 and <0.0001, respectively). CONCLUSION: Knee injuries take a huge toll on an athlete's career as observed in this study. Prevention of knee injuries is of paramount importance and more focussed epidemiological studies are needed for formulating policies to prevent sports injuries in both professional and amateur athletes. LEVEL OF EVIDENCE: IV. PMID- 27489417 TI - Comparative analysis of arthroscopic debridement in osseous versus soft tissue anterior ankle impingement. AB - BACKGROUND: Arthroscopic debridement has been a gold standard procedure for anterior ankle impingement, both in cases of osseous and soft tissue impingement. There is sparse literature on comparative outcome with respect to functional results between the two types of impingement post-arthroscopic debridement. METHODS: Our study included 14 patients diagnosed as cases of anterior ankle impingement on the basis of clinical and radiological examination. They were segregated into two groups (on the basis of cause of impingement (osseous versus soft tissue)). Both groups were treated by arthroscopic debridement. Primary outcome was patient satisfaction, which was assessed by Likert scale and clinical outcomes were measured using AOFAS ankle-hind foot scale, VAS score, range of motion and time to return to pre-injury activity level in both groups. RESULTS: Mean follow-up was of 15 months where eleven patients reported an excellent recovery, two patients had good recovery while one patient reported poor outcome. Mean AOFAS ankle hind foot scale improved from 50.5 preoperatively to 85.71 postoperatively (statistically significant; p value - 0.0001). Mean Likert scale value post-operative was 4.21. VAS score showed significant improvement in patients of both the groups. Range of motion was slightly better in soft tissue impingement type with a relatively shorter time to return to sports or preinjury activity level as compared to osseous impingement group. CONCLUSIONS: The patients in both the groups had comparable outcomes with no statistically significant difference with regard to patient satisfaction and clinical outcome. PMID- 27489419 TI - Loose body as an obstacle for posterolateral arthroscopic portal formation in the knee joint. AB - In this report, we present a case with difficult arthroscopic posterolateral portal formation due to loose body located in posterior compartment. These loose bodies are responsible for pain, decreased range of motion and cartilage damage in the knee joint. By making the posterior trans-septal portal prior, posterolateral portal could be made without difficulty completing the planned arthroscopic procedure. PMID- 27489420 TI - Finger trapped in door latch removed using an electric saw. A new technique and review of other techniques. AB - Trapping of fingers in metallic bands is a commonly encountered situation. The children, elderly people, and psychiatric patients are the usual victims. The constricting object in the digit causes obstruction to lymphatic and venous drainage leading to oedema distal to the constriction, which leads to further neurovascular compromise and presents as a surgical emergency. A 7-year-old boy presented to us with his right middle finger being stuck in a steel door latch. Multiple attempts were made to remove the trapped finger with conventional methods, and subsequently, it was removed by electric-driven metal cutting saw, which was not previously described in medical literature to the best of our knowledge. PMID- 27489421 TI - Clinical Characteristics of Odontogenic Cutaneous Fistulas. AB - BACKGROUND: Odontogenic cutaneous fistula appears as dimpling or a nodule with purulent discharge, usually in the chin or jaw. Affected patients usually seek help from dermatologists or surgeons rather than from dentists. However, clinical symptoms of facial skin fistula without dental problems can lead to misdiagnosis. OBJECTIVE: The purpose of this study was to investigate the clinical characteristics of patients with odontogenic cutaneous fistulas. METHODS: This retrospective observational study was performed at Chungbuk National University Hospital by analyzing patients who visited from April 1994 to September 2014. Following clinical and radiographic examinations, the paths and origins of sinus fistulas were determined. Investigated factors were gender, age, morphology, location, originating tooth, time to evolution, recurrence, and treatment method. RESULTS: Thirty-three patients (22 males, 11 females; average age 49.2 years) were examined during the investigation period. Thirty-four fistulas were diagnosed as odontogenic cutaneous fistulas. The most common morphology was dimpling (n=14, 41.2%). The various locations observed were related to the originating tooth. The most common site was the mandibular body related to mandibular molars. The referral clinical diagnosis was of odontogenic origin in 6 cases (18.2%). The majority of patients had experienced recurrence after treatment in previous clinics that had failed to diagnose odontogenic cutaneous fistula. Surgical fistulectomy and/or tooth treatment were performed in all cases. All patients were followed-up for 1 year. None showed signs of recurrence. CONCLUSION: Extraoral and dental examinations are required to make a diagnosis of odontogenic cutaneous fistula. Thus, cooperation between dermatologists and dentists is essential. PMID- 27489422 TI - Relation between the Peripherofacial Psoriasis and Scalp Psoriasis. AB - BACKGROUND: Facial involvement of psoriasis is known to be one of the clinical manifestations that indicate the severity of the psoriasis and thought to be more closely associated with certain distribution. Centrofacial (CF) psoriasis has been suggested to be related with severity of systemic disease while peripherofacial (PF) psoriasis has been thought to have connection with scalp psoriasis. OBJECTIVE: To analyze the epidemiologic characteristics, clinical features and subjective feelings of patients with facial psoriasis and to find out relationship between scalp psoriasis and facial involvement according to the facial types. METHODS: One hundred nineteen facial psoriasis patients were categorized into 3 types according to the distribution: PF type, CF type and mixed facial (MF) type. Onset and duration of facial and scalp psoriasis, and their relationship were questioned. Severity and extent of psoriasis on whole body, face, and scalp were rated by clinicians. RESULTS: There was no significant difference of whole body psoriasis area and severity index (PASI) and body surface area (BSA) score but scalp PASI and BSA was much higher in PF psoriasis compared to CF psoriasis (scalp PASI, 17.9 vs. 10.1; p=0.005) (scalp BSA, 40.9 vs. 22.2; p=0.002). According to the questionnaire, patient's objective feeling about the spreading of scalp lesion to facial area was markedly more prominent in the patients with peripheral involvement (PF+MF, 90.1%; CF, 54.2%; p<0.0001). CONCLUSION: Among subtypes of facial psoriasis, PF psoriasis is closely associated with spreading of scalp lesion into the face rather than reflecting the disease severity. PMID- 27489423 TI - Histopathological Differential Diagnosis of Psoriasis and Seborrheic Dermatitis of the Scalp. AB - BACKGROUND: The differential diagnosis of psoriasis and seborrheic dermatitis can be difficult when both conditions are localized to the scalp without the involvement of other skin sites. OBJECTIVE: We aimed to evaluate the histopathological differences between psoriasis and seborrheic dermatitis on the scalp and identify favorable criteria for their differential diagnosis. METHODS: We evaluated 15 cases of psoriasis and 20 cases of seborrheic dermatitis of the scalp that had been clinicopathologically diagnosed. Skin biopsy sections stained with H&E were examined. Additional immunohistochemistry was performed, including Ki-67, keratin 10, caspase-5, and GLUT-1. RESULTS: On histopathological examination, mounds of parakeratosis with neutrophils, spongiform micropustules of Kogoj, and clubbed and evenly elongated rete ridges were significantly more frequently observed in psoriasis. Follicular plugging, shoulder parakeratosis and prominent lymphocytic exocytosis were significantly more common in seborrheic dermatitis. Moreover, significantly higher mitotic figures were observed in psoriatic lesions than in seborrheic dermatitis. Immunohistochemistry did not show any difference between psoriasis and seborrheic dermatitis. CONCLUSION: Histopathological features favoring psoriasis include mounds of parakeratosis with neutrophils, spongiform micropustules of Kogoj, clubbed and evenly elongated rete ridges, and increased mitotic figures (>=6/high-powered field). Features indicating seborrheic dermatitis are follicular plugging, shoulder parakeratosis and prominent lymphocytic exocytosis. Immunohistochemistry was not helpful in differentiating psoriasis from seborrheic dermatitis. PMID- 27489424 TI - Single Low-Dose Radiation Induced Regulation of Keratinocyte Differentiation in Calcium-Induced HaCaT Cells. AB - BACKGROUND: We are continually exposed to low-dose radiation (LDR) in the range 0.1 Gy from natural sources, medical devices, nuclear energy plants, and other industrial sources of ionizing radiation. There are three models for the biological mechanism of LDR: the linear no-threshold model, the hormetic model, and the threshold model. OBJECTIVE: We used keratinocytes as a model system to investigate the molecular genetic effects of LDR on epidermal cell differentiation. METHODS: To identify keratinocyte differentiation, we performed western blots using a specific antibody for involucrin, which is a precursor protein of the keratinocyte cornified envelope and a marker for keratinocyte terminal differentiation. We also performed quantitative polymerase chain reaction. We examined whether LDR induces changes in involucrin messenger RNA (mRNA) and protein levels in calcium-induced keratinocyte differentiation. RESULTS: Exposure of HaCaT cells to LDR (0.1 Gy) induced p21 expression. p21 is a key regulator that induces growth arrest and represses stemness, which accelerates keratinocyte differentiation. We correlated involucrin expression with keratinocyte differentiation, and examined the effects of LDR on involucrin levels and keratinocyte development. LDR significantly increased involucrin mRNA and protein levels during calcium-induced keratinocyte differentiation. CONCLUSION: These studies provide new evidence for the biological role of LDR, and identify the potential to utilize LDR to regulate or induce keratinocyte differentiation. PMID- 27489425 TI - Efficacy of a Complex of 5-Aminolevulinic Acid and Glycyl-Histidyl-Lysine Peptide on Hair Growth. AB - BACKGROUND: Pattern hair loss is a very common problem. Although effective therapeutics for the treatment of pattern hair loss have been used, novel therapeutic modalities are still required to enhance hair growth. OBJECTIVE: We investigated the efficacy and safety of a complex (ALAVAX) of 5-aminolevulinic acid (5-ALA) and glycyl-histidyl-lysine (GHK) peptide for the treatment of pattern hair loss. METHODS: Forty-five patients with male pattern hair loss were treated with ALAVAX 100 mg/ml (group A), ALAVAX 50 mg/ml (group B) or placebo (group C) once a day for 6 months. Total hair count, hair length, hair thickness, patient's assessment and adverse events were evaluated at month 1, 3, and 6. RESULTS: An increase in hair count for 6 months was 52.6 (p<0.05) in group A, 71.5 (p<0.05) in group B, and 9.6 in group C. The ratio of changes in hair count between group B (2.38) and group C (1.21) at 6 months showed a statistically significant difference (p<0.05). The proportion above good satisfaction was higher in group A (26.7%) than in the other groups (group B: 14.3%, group C: 7.1%). There was no statistically significant difference in hair length and hair thickness among 3 groups at 6 months. There was no adverse event in 3 groups. CONCLUSION: Our study showed that a complex of 5-ALA and GHK peptide may be considered as one of the complementary agents for the treatment of male pattern hair loss. PMID- 27489426 TI - Safety and Tolerability of the Dual 5-Alpha Reductase Inhibitor Dutasteride in the Treatment of Androgenetic Alopecia. AB - BACKGROUND: After the approval of dutastride for androgenic alopecia (AGA) in 2009, Korean authority required a post-marketing surveillance to obtain further data on its safety profile. OBJECTIVE: The objective was to monitor adverse events (AEs) of dutasteride 0.5 mg in Korean AGA male patients in a clinical practice environment. METHODS: Open label, multi-center, non-interventional observational study was done from July 2009 to July 2013. AGA subjects (18~41 years of age) with no experience of dutasteride were enrolled. Dosage regimen was recommended according to the prescribing information. The incidences of any AEs, serious adverse events (SAEs), and adverse drug reactions (ADRs) were evaluated. Multiple logistic regression method was used to identify risk factors related to ADRs. Effectiveness was generally evaluated by physicians. RESULTS: During study period, 712 subjects were enrolled. The subjects of 29.3+/-6.0 years old exposed to dutasteride for 204.7+/-161.5 days. One hundred and ten (15.4%) of subjects reported 138 AEs. Four subjects (0.6%) reported 5 SAEs (right radius fracture, 2 events of chronic follicular tonsillitis, influenza infection, and acute appendicitis). Sixty-six subjects (9.3%) reported 80 ADRs. Most frequent ADRs were libido decreased (9 subjects, 1.3%), dyspepsia (8 subjects, 1.1%), impotence (7 subjects, 1.0%), and fatigue (5 subjects, 0.7%). Other interested ADRs were sexual function abnormality (4 subjects, 0.6%), gynecomastia (2 subjects, 0.3%), and ejaculation disorder (1 subject, 0.1%). Most subjects (78.6%) showed overall improvement after treatment of dutasteride in the effectiveness. CONCLUSION: Dutasteride 0.5 mg is to be well-tolerated in 18 to 41 years old AGA patients in a clinical practice environment. PMID- 27489427 TI - Immunohistochemical Comparison of IL-36 and the IL-23/Th17 Axis of Generalized Pustular Psoriasis and Acute Generalized Exanthematous Pustulosis. AB - BACKGROUND: Cutaneous pustular disorders include generalized pustular psoriasis (GPP) and acute generalized exanthematous pustulosis (AGEP). OBJECTIVE: To identify differences between GPP and AGEP, here we immunohistochemically evaluated interleukin (IL)-36 and the IL-23/Th17 axis. METHODS: This retrospective comparative immunohistochemical study was completed using 11 biopsies of 11 cases of GPP and 11 biopsies of 11 cases of AGEP. Through staining with the anti-IL-36-alpha (IL-36alpha), anti-IL-36 receptor antagonist (IL-36Ra), anti-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), anti-IL-23, anti-IL-17, and anti-IL-8 antibodies, main expression location and intensity were visualized in the epidermis and dermis. RESULTS: In both diseases, diffuse IL-36alpha expression was observed in the epidermis. IL-36Ra expression was observed in the dermal perivascular area as well as in the epidermis. NF kappaB expression was observed in the epidermis and perivascular dermal area. Diffuse IL-23 and IL-17 expression was seen in the whole epidermis and the perivascular dermal area. IL-8 was expressed in the subcorneal pustules and parakeratotic area. Contrary to other cytokines, IL-23 expression in the epidermis of patients with GPP was more intense than only that in patients with AGEP. CONCLUSION: Common pathomechanisms might exist in the development of GPP and AGEP based on these immunohistochemical results, but further studies are needed. PMID- 27489428 TI - Expression of Epidermal c-Kit+ of Vitiligo Lesions Is Related to Responses to Excimer Laser. AB - BACKGROUND: The survival and growth of melanocytes are controlled by the binding of stem cell factor to its cell surface receptor c-kit+ (CD117). We have observed that c-kit+ melanocytes existed in some lesions of vitiligo, while Melan A+ cells were absent. OBJECTIVE: To verify possible relation between c-kit+ expression and treatment response in non-segmental vitiligo lesions. METHODS: Skin biopsies were done from the center of the 47 lesions from the 47 patients with non-segmental vitiligo. Expression of c-kit+ and Melan A, and amounts of melanin in the epidermis were assessed in each lesion, and treatment responses to excimer laser were evaluated. RESULTS: Thirty-five of the 47 lesions (74.5%) had c-kit+ phenotypes. There was significant difference of c-kit staining value between good responders in 3 months of excimer laser treatment (average of 24 sessions) and the others. CONCLUSION: c-Kit expression in vitiliginous epidermis may be related to better treatment responses to excimer laser. PMID- 27489429 TI - Stressful Events and Serum Concentration of Substance P in Acne Patients. AB - BACKGROUND: Psychological stress is an important factor of acne pathogenesis. Stress related production of hormones, cytokines and neuropeptides may result in the chronic course and exacerbations of the disease. OBJECTIVE: The aim of the study was to evaluate the relationship between acne severity, intensity of emotional stress and serum concentration of substance P (scSP), to compare the intensity of adversities, psychological stress and scSP in acne patients with healthy controls and to compare coping techniques for stress. METHODS: The study consisted of 80 patients. Emotional stress was analyzed with the use of social readjustment rating scale, whereas the methods of coping with stress were assessed with the coping inventory for stressful situation questionnaire. The blood concentration of substance P was analyzed by enzyme-linked immunosorbent assay method in a group of 40 patients with acne vulgaris and in control subjects. RESULTS: There was no statistically significant difference between the severity of acne and the intensity of stress. Acne patients presented a higher average scSP than the controls. No statistically significant correlation was observed between the severity of acne and scSP; however, the intensity of stress correlated with scSP in the control group. The evaluation of methods of coping with stress showed significantly higher rate for the avoidance-oriented coping among acne patients. CONCLUSION: The number of stressful events is not a factor that determines the severity of acne. The course of the disease may depend on tolerance to stress and methods of coping with stress. PMID- 27489431 TI - Immunohistochemistry and Polymerase Chain Reaction for Detection Human Papilloma Virus in Warts: A Comparative Study. AB - BACKGROUND: Immunohistochemistry and polymerase chain reaction (PCR) are the most widely used methods for the detection of viruses. PCR is known to be a more sensitive and specific method than the immunohistochemical method at this time, but PCR has the disadvantages of high cost and skilled work to use widely. With the progress of technology, the immunohistochemical methods used in these days has come to be highly sensitive and actively used in the diagnostic fields. OBJECTIVE: To evaluate and compare the usefulness of immunohistochemistry and PCR for detection human papilloma virus (HPV) in wart lesions. METHODS: Nine biopsy samples of verruca vulgaris and 10 of condyloma accuminatum were examined. Immunohistochemical staining using monoclonal antibody to HPV L1 capsid protein and PCR were done for the samples. DNA sequencing of the PCR products and HPV genotyping were also done. RESULTS: HPV detection rate was 78.9% (88.9% in verruca vulgaris, 70.0% in condyloma accuminatum) on immunohistochemistry and 100.0% for PCR. HPV-6 genotype showed a lower positivity rate on immunohistochemistry (50.0%) as compared to that of the other HPV genotypes. CONCLUSION: Immunohistochemistry for HPV L1 capsid protein showed comparable sensitivity for detection HPV. Considering the high cost and great effort needed for the PCR methods, we can use immunohistochemistry for HPV L1 capsid protein with the advantage of lower cost and simple methods for HPV detection. PMID- 27489430 TI - Change in Antimicrobial Susceptibility of Skin-Colonizing Staphylococcus aureus in Korean Patients with Atopic Dermatitis during Ten-Year Period. AB - BACKGROUND: A small subset of adolescents atopic dermatitis (AD) tends to persist. This also leads to get more antibiotics exposure with advancing years. Antibiotic resistance has been regarded as a serious problem during Staphylococcus aureus treatment, especially methicillin-resistant S. aureus (MRSA). OBJECTIVE: It was investigated the S. aureus colonization frequency in the skin lesions and anterior nares of adolescent AD patients and evaluated the changes in S. aureus antimicrobial susceptibility for years. METHODS: Patients who visited our clinic from September 2003 to August 2005 were classified into group A, and patients who visited from August 2010 to March 2012 were classified into group B. To investigate the differences with regard to patients' age and disease duration, the patients were subdivided into groups according to age. Lesional and nasal specimens were examined. RESULTS: Among the 295 AD patients, the total S. aureus colonization rate in skin lesions was 66.9% (95/142) for group A and 78.4% (120/153) for group B. No significant changes in the systemic antimicrobial susceptibilities of S. aureus strains isolated from adolescent AD patients were observed during about 10-year period. The increased trend of MRSA isolation in recent adolescent AD outpatients suggest that the community including school could be the source of S. aureus antibiotic resistance and higher fusidic acid resistance rates provides evidence of imprudent topical use. CONCLUSION: Relatively high MRSA isolation and fusidic acid resistance rates in recent AD patients suggest that the community harbors antibiotic-resistant S. aureus. PMID- 27489432 TI - Increased Infiltration of CD8(+) T Cells by Dacarbazine in a Patient with Mucosal Penile Melanoma Refractory to Nivolumab. AB - Primary penile melanomas are rare tumors that represent less than 0.1% of all melanomas. We report a case of a 60-year-old Japanese male with a mucosal penile melanoma and describe an increased CD8(+) T cell infiltration in brain after dacarbazine (DTIC) administration. After partial penectomy and left inguinal lymphadenectomy, he developed multiple lung, bone, spleen, brain and skin metastases. He was treated with interferon-beta, DTIC and nivolumab. However, the metastases were not reduced in size. Immunohistochemistry showed an increase of CD8(+) T cell infiltration and programmed death-ligand 1 (PD-L1) expression after the administration of DTIC, but the expression of programmed cell death protein 1 (PD-1) was negative. We speculate that DTIC exerted immunostimulatory effects, but nivolumab was ineffective due to the negative expression of PD-1 and/or an insufficient infiltration of CD8(+) T cells. Although this is only one case, this case report could be the first step to discuss the development of effective therapies against melanoma to take advantage of the increased CD8(+) T cell infiltration elicited by chemotherapeutic agents. It would be beneficial to pay more attention to the relationship between DTIC and immune checkpoint modulators. PMID- 27489433 TI - Synchronous Occurrence of Primary Cutaneous Anaplastic Large Cell Lymphoma and Squamous Cell Carcinoma. AB - CD30+ lymphoproliferative disorders (LPD) represent a spectrum of T-cell lymphoma including lymphomatoid papulosis and anaplastic large cell lymphoma (ALCL). Epidermis overlying cutaneous CD30+ LPD often shows epidermal hyperplasia, hyperkeratosis, crusting, and ulceration and it is difficult to distinguish from carcinoma such as keratoacanthoma (KA) or squamous cell carcinoma (SCC). Several cases of pseudocarcinomatous hyperplasia mimicking KA or SCC in CD30+ LPD have been reported. The relationship between CD30+ LPD and epithelial proliferations has not yet well understood. It was reported that a variety of mediators, including epidermal growth factor (EGF), transforming growth factor-alpha and EGFR from CD30+ LPD could attribute to epidermal hyperplasia. However, separate and distinct SCC occurring in CD30+ LPD has rarely been reported. Herein, we present a rare case of coexistence of SCC and cutaneous ALCL located on the same region. PMID- 27489434 TI - Fibro-Osseous Pseudotumor of the Digit: A Diagnostic Pitfall of Extraskeletal Osteosarcoma. PMID- 27489435 TI - Extramammary Paget's Disease Combined with Squamous Cell Carcinoma In Situ of the Vulva: A Case Report and Differential Diagnosis. PMID- 27489436 TI - A Unique Cutaneous Presentation of Breast Cancer: A Red Apple Stuck in the Breast. PMID- 27489437 TI - Transepidermal Elimination of Gold Metals after Face-Lifting Acupuncture. PMID- 27489438 TI - Homozygous Deletion Mutation of the FERMT1 Gene in a Chinese Patient with Kindler Syndrome. PMID- 27489439 TI - A Case of Facial Sarcoptes scabiei in a Female Child. PMID- 27489440 TI - Cutaneous Sporotrichosis Presenting as Clinical Feature of Facial Cellulitis in an Adult. PMID- 27489441 TI - Scar Sarcoidosis Induced by Pulsed Dye Laser Treatment. PMID- 27489442 TI - A Case of Late Stage Sebaceous Trichofolliculoma Showing Overlapping Features with Folliculosebaceous Cystic Hamartoma. PMID- 27489443 TI - Multiple Acquired Periungual Fibrokeratoma. PMID- 27489444 TI - Donut Ablation Method as an Alternative to Surgical Excision or Total Ablational Laser Treatment. PMID- 27489445 TI - Acral Persistent Papular Mucinosis with Partial Response to Tacrolimus Ointment. PMID- 27489446 TI - Cutaneous Metastasis of Rhabdomyosarcoma Originated from Maxillary Sinus in a Young Adult Female. PMID- 27489447 TI - Palmoplantar Pustulosis Induced by both Adalimumab and Golimumab for Treatment of Ankylosing Spondylitis. PMID- 27489448 TI - The Epidemiology of Dermatophyte Infection in Southeastern Korea (1979~2013). PMID- 27489449 TI - Periungual Abscess Caused by Citrobacter braakii in a Patient with Chronic Paronychia. PMID- 27489450 TI - A Rare Cutaneous Adverse Reaction after Intra-Articular Injection of Hyaluronic Acid. PMID- 27489451 TI - Digital applications: the future in psychiatry? AB - Digital applications and new mobile technologies can change the nature of the psychiatrist-patient relationship and future clinical practice in terms of diagnosis, follow-up, and treatment, but need to be further studied. This issue explores these new approaches in psychiatry. PMID- 27489452 TI - The emerging story of emerging technologies in neuropsychiatry. AB - The growth of new technologies in health care is exponential, and the impact of such rapid technological innovation on health care delivery is substantial. This review describes two emerging technologies-mobile applications and wearable technologies-and uses a virtual case report to illustrate the impact of currently available technologies on the health care experience of a patient with neuropsychiatric illness. PMID- 27489453 TI - Issues and developments related to assessing function in serious mental illness. AB - Serious mental illness (SMI) results in functional disability that imposes a significant burden on individuals, caregivers, and society. Development of novel treatments is under way in an effort to improve the illness domains of cognitive impairment and negative symptoms and subsequently to improve functional outcomes. The assessment of functional outcomes in SMI faces a number of challenges, including the proliferation of assessment instruments and the differential prioritization of functional goals among stakeholder groups. Functional assessments relying on self- and informant report present a number of limitations. Identifying alternative strategies to assess functioning that are reliable, valid, and sensitive to change is necessary for use in clinical trials. Measures of functional capacity have been proposed for clinical trials investigating compounds to treat cognitive impairment in schizophrenia. Alternative approaches employing effort-based decision making or daily activity recording using instruments such as the Daily Activity Report may be more appropriate for studies focused on improving negative symptoms. PMID- 27489454 TI - Functional assessment in mental health: lessons from occupational therapy. AB - Occupational therapists have been conducting functional assessments since World War I, and this accumulated experience has taught us several critical lessons. First, a comprehensive profile of a patient's functioning requires multiple assessment methods. Second, assessment content and measurement constructs must change with the times. Third, technology can enhance and extend functional assessment. Fourth, performance-based assessments of everyday activities can also be used to measure body functions/impairments. However, while deconstructing activities into body functions/impairments is possible, the results do not reflect patients' abilities to integrate the cognitive, motor, sensory and affective functions necessary to complete a complex activity. Finally, the differential complexity of everyday activities that a patient can master or successfully complete can also provide a ruler with which to measure progress. PMID- 27489455 TI - Neurotechnological assessment of consciousness disorders: five ethical imperatives. AB - Disorders of consciousness (DOCs) cause great human suffering and material costs for society. Understanding of these disorders has advanced remarkably in recent years, but uncertainty remains with respect to the diagnostic criteria and standards of care. One of the most serious problems concerns misdiagnoses, their impact on medical decision-making, and on patients' well-being. Recent studies use neurotechnology to assess residual consciousness in DOC patients that traditional behavioral diagnostic criteria are unable to detect. The results show an urgent need to strengthen the development of new diagnostic tools and more refined diagnostic criteria. If residual consciousness may be inferred from robust and reproducible results from neurotechnological communication with DOC patients, this also raises ethical challenges. With reference to the moral notions of beneficence and fundamental rights, five ethical imperatives are here suggested in terms of diagnosis, communication, interpretation of subjective states, adaptation of living conditions, and care. PMID- 27489456 TI - Mobile technology for mental health assessment. AB - Assessment and outcome monitoring are critical for the effective detection and treatment of mental illness. Traditional methods of capturing social, functional, and behavioral data are limited to the information that patients report back to their health care provider at selected points in time. As a result, these data are not accurate accounts of day-to-day functioning, as they are often influenced by biases in self-report. Mobile technology (mobile applications on smartphones, activity bracelets) has the potential to overcome such problems with traditional assessment and provide information about patient symptoms, behavior, and functioning in real time. Although the use of sensors and apps are widespread, several questions remain in the field regarding the reliability of off-the-shelf apps and sensors, use of these tools by consumers, and provider use of these data in clinical decision-making. PMID- 27489458 TI - Prevention of suicidal behavior. AB - More than 800 000 people die every year from suicide, and about 20 times more attempt suicide. In most countries, suicide risk is highest in older males, and risk of attempted suicide is highest in younger females. The higher lethal level of suicidal acts in males is explained by the preference for more lethal methods, as well as other factors. In the vast majority of cases, suicidal behavior occurs in the context of psychiatric disorders, depression being the most important one. Improving the treatment of depression, restricting access to lethal means, and avoiding the Werther effect (imitation suicide) are central aspects of suicide prevention programs. In several European regions, the four-level intervention concept of the European Alliance Against Depression (www.EAAD.net), simultaneously targeting depression and suicidal behavior, has been found to have preventive effects on suicidal behavior. It has already been implemented in more than 100 regions in Europe. PMID- 27489457 TI - Technology to assess and support self-management in serious mental illness. AB - The functional impairment associated with serious mental illness (SMI) places an immense burden on individuals and society, and disability often persists even after efficacious treatment of psychopathologic symptoms. Traditional methods of measuring functioning have limitations, and numerous obstacles reduce the reach and impact of evidence-based interventions developed to improve functioning in SMI. This review describes the potential of technological innovations for overcoming the challenges involved in both functional assessment and intervention in people with SMI. Ecological momentary assessment (EMA), which involves the repeated sampling of naturalistic behaviors and experiences while individuals carry out their daily lives, has provided a new window through which the determinants of day-to-day function in SMI can be observed. EMA has several advantages over traditional assessment methods and has in recent years evolved to use mobile-based platforms, such as text messaging and smartphone applications, for both assessment and promotion of self-management in people with SMI. We will review promising data regarding the acceptability, adherence, and efficacy of EMA based mobile technologies; explore ways in which these technologies can extend the reach and impact of evidence-based psychosocial rehabilitative interventions in SMI; and outline future directions for research in this important area. PMID- 27489459 TI - A review of behavioral tailoring strategies for improving medication adherence in serious mental illness. AB - Nonadherence to psychopharmacological treatments poses a significant challenge to treatment success in individuals with serious mental illness, with upwards of 60% of people not taking their psychiatric medications as prescribed. Nonadherence is associated with adverse outcomes, including exacerbation of psychiatric symptoms, impaired functioning, increased hospitalizations and emergency room use, and increased health care costs. Whereas interventions using psychoeducation or cognitive approaches, such as motivational interviewing, have largely proven ineffective in improving adherence, approaches employing behavioral tailoring that incorporate medication taking into the daily routine and/or use environmental supports have shown promise. Recently, adherence-enhancing behavioral tailoring interventions that utilize novel technologies, such as electronic monitors and mobile phones, have been developed. Although interventions utilizing these platforms have the potential for widespread dissemination to a broad range of individuals, most require further empirical testing. This paper reviews selected behavioral tailoring strategies that aim to improve medication adherence and other functional outcomes among individuals with serious mental illness. PMID- 27489460 TI - Internet interventions for depression: new developments. AB - A wide range of Internet interventions, mostly grounded in methods of cognitive behavioral therapy, have been developed and tested for several mental disorders. The evidence to date shows that these interventions are effective in reducing symptoms of depression. Metaanalyses report small-to-medium effect sizes when Internet interventions are delivered as stand-alone self-help interventions (d=0.25-0.36), and medium-to-large effect sizes when delivered as therapist guided interventions (d=0.58-0.78), both compared with usual care. Only a minority of people suffering from depression receive adequate treatment, and Internet interventions might help bridge the large treatment gap. This review summarizes the current body of evidence and highlights pros and cons of Internet interventions. It also outlines how they could be implemented in mental health care systems and points out unresolved questions, as well as future directions, in this research field. PMID- 27489461 TI - Contributions of mobile technologies to addiction research. AB - Mobile technologies are revolutionizing the field of mental health, and particular progress has been made in their application to addiction research and treatment. The use of smartphones and other mobile devices has been shown to be feasible with individuals addicted to any of a wide range of substances, with few biases being observed concerning the repeated monitoring of daily life experiences, craving, or substance use. From a methodological point of view, the use of mobile technologies overcomes longstanding limitations of traditional clinical research protocols, including the more accurate assessment of temporal relationships among variables, as well as the reduction in both contextual constraints and discipline-specific methodological isolation. The present article presents a conceptual review of these advances while using illustrations of research applications that are capable of overcoming specific methodological barriers. Finally, a brief review of both the benefits and risks of mobile technology use for the treatment of patients will be addressed. PMID- 27489462 TI - Influenza and the use of oseltamivir in children. AB - Influenza is an infectious disease which causes significant morbidity and mortality. In the USA, approximately 200 000 hospital admissions and 36 000 deaths occur annualy due to severe influenza infections. Although influenza often causes a simple respiratory infection, it sometimes causes disorders affecting several organs including the lung, heart, brain, liver and muscles or serious life-threatening primary viral or secondary bacterial pneumonia. Currently, oseltamivir is the most important and effective drug for severe influenza infections. Severe influenza infections can be controlled and related deaths may be prevented with initiation of this drug especially within first 2 days. Oseltamivir is usually well tolerated and its most commonly reported side effect is related with the gastrointestinal system. In conclusion, the course of influenza changes in a positive direction and the rates of complications and mortality significantly reduce in patients in whom oseltamivir treatment is initiated as soon as possible. PMID- 27489463 TI - The protective effect of pomegranate juice in paracetamol-induced acute hepatotoxicity in rats. AB - AIM: Being the most commonly used antipyretic and analgesic, paracetamol is one of the most common causes of childhood poisoning in the world and maintains its importance also in our country. Paracetamol poisoning is one of the most common causes of liver failure. This study aimed to investigate if pomegranate juice had protective effect in acute liver toxicity related with paracetamol. MATERIAL AND METHODS: A total of 36 Wistar-Albino rats were divided into four groups as the paracetamol group (3 000 mg/kg paracetamol), the pomegranate juice + paracetamol group (1.5 mL pomegranate juice plus 3 000 mg/kg paracetamol), the pomegranate juice group (1.5 mL pomegranate juice) and the control group (1.5 mL distilled water). Pomegranate juice and distilled water were administered for eight days. Paracetamol was administered on day 8. The level of thiobarbituric acid reactive substances, as an oxidative marker, was measured in the blood and liver tissue on day 9. In addition, liver tissues were evaluated histologically (in terms of increased connective tissue, granular degeneration, mononuclear cell infiltration, necrotic cells and vascular congestion). RESULTS: The liver tissue and blood thiobarbituric acid reactive substances levels were found to be significantly lower in the pomegranate juice + paracetamol group compared to the paracetamol group (p<0.05). Histologically, structural changes related with damage were observed in both the paracetamol group and pomegranate juice + paracetamol group. The extent of damage was statistically significantly lower in the pomegranate juice + paracetamol group (p<0.001). CONCLUSIONS: Our results related with oxidative and histologic evaluation showed that pomegranate juice might have a preventive effect in paracetamol-induced acute liver damage. PMID- 27489464 TI - Febrile neutropenia in children with acute lymphoblastic leukemia: single center experience. AB - AIM: An important life-threatening complication of intensive chemotherapy administered in children with leukemia is febrile neutropenia. The objective of this study was to evaluate the clinical features and consequences of febrile neutropenia attacks in children who were treated for acute lymphoblastic leukemia. MATERIAL AND METHODS: Nighty-six children who received chemotherapy for acute lymphoblastic leukemia in our center between January 1995 and December 2010 were included in the study. The data related to demographic characteristics, treatment features, relapse and febrile neutropenia incidences, risk factors, culture results and prognosis were retrospectively evaluated from the patients' files. RESULTS: A total of two hundred-ninety nine febrile neutropenia attacks observed in the patients during initial treatment and relapse treatment were evaluated. When the incidence of febrile neutropenia was evaluated by years, it was observed that the patients treated after year 2000 had statistically significantly more febrile neutopenia attacks compared to the patients treated before year 2000. When the incidences of febrile neutropenia during initial treatment and during relapse treatment were compared, it was observed that more febrile neutropenia attacks occured during relapse treatment. Fifty-nine percent of all febrile neutropenia attacks were fever of unknown origin. Eighty microorganisms grew in cultures during febrile neutropenia throughout treatment in 75 patients; 86% were bacterial infections (50% gram positive and 50% gram negative), 8% were viral infections and 6% were fungal infections. Coagulase negative staphylococcus (n=17) was the most frequent gram positive pathogen; E. Coli (n=17) was the most commonly grown gram negative pathogen. CONCLUSIONS: In this study, it was found that an increase in the incidence of febrile neutropenia occured in years. Increments in treatment intensities increase the incidence of febrile neutropenia while improving survival. Evaluation of febrile neutropenia results by hematology-oncology units in years will be directive in early and successful treatment. PMID- 27489465 TI - Evaluation of cases with cerebral thrombosis in children. AB - AIM: We aimed to evaluate the patients who were followed up in our clinic with a diagnosis of cerebral sinovenous thrombosis in terms of age, sex, clinical findings, etiology, thrombophilic factors, imaging findings, treatment and prognosis. MATERIAL AND METHODS: The files of 11 patients who were followed up in our pediatric neurology clinic with a diagnosis of cerebral thrombosis between 1 December 2010 and 31 December 2014 were retrospectively analyzed. RESULTS: Seven of 11 patients were male (63.6%). The median age was 14 years (2-17 years). Six (54%) of the patients presented with a complaint of headache. Other complaints at presentation included diplopia (n:3), weakness and difficulty in speaking (n:1) and seizure (n:1). A diagnosis of pseudotumor cerebri was made in eight of the patients (72.7%). In the etiology, mastoiditis was found in three patients, mastoiditis and meningitis were found in combination in one patient, Behcet's disease was found in three patients and head trauma was found in one patient. In 3 patients, only prothrombotic genetic risk factors were present; one patient had deficiency of protein C and S, one patient had deficiency of antithrombin III and one patient had hyperhomosisteinemia in association with vitamin B12 deficiency. 1A homozygous MTFHR A1298C mutation was detected in the patient who had mastoiditis and meningitis and protein S deficiency and lupus anticoagulant were found in another patient who had mastoiditis. All patients received anticoagulant treatment and all patients recovered without neurological sequelae except one. CONCLUSIONS: Cerebral sinovenous thrombosis should be considered in patients who present with headache and focal neurological deficits. Appropriate utilization of imaging studies is necessary for the diagnosis. Detailed ear, nose and throat examination should be performed to detect mastoiditis. It is recommended that genetic risk factors should be investigated, because hereditary thrombophilis factors may have a role in children. Behcet's disease which is relatively common in our country should be considered in differential diagnosis. PMID- 27489466 TI - The effect of vitamin D on lower respiratory tract infections in children. AB - AIM: Lower respiratory tract infections including mainly pneumonia represent an important public health problem leading to high mortality and mobidity rates in children aged below five years in developing countries including our country. Vitamin D deficiency has been associated with increased risk of rickets/osteomalacia, various cancers, autoimmune diseases, hyperproliferative skin diseases, cardiovascular system diseases and infectious diseases. Vitamin D has an important role in cellular and humoral immunity and pulmonary functions. Vitamin D deficiency and lower respiratory tract infection are common health problems in children in our country and no clinical study investigating the relationship between these problems has been conducted so far. In this case control study, we aimed to assess the association between vitamin D level and lower respiratory tract infection in children. MATERIAL AND METHODS: Sixty-three children aged between six months and five years with lower respiratory infections and 59 age-matched children who had no history of respiratory symptoms in the last month and no accompanying chronic disease were compared in terms of vitamin D levels. The children in the patient group were also evaluated by the clinical picture. RESULTS: No significant correlation was found between vitamin D levels and lower respiratory tract infection in terms of disease and its severity. However, it was found that vitamin D deficiency/ insufficiency was observed with a high rate in all children included in the study. CONCLUSIONS: Although no correlation was found between vitamin D level and lower respiratory tract infection, it is recommended that vitamin D level should be measured in children with lower respiratory tract infection and vitamin D supplementation should be given to all children especially in winter months based on the fact that the level of vitamin D was lower than normal in approximately half of the children included in the study and considering the effects of vitamin D on infections, pulmonary functions and immunity. PMID- 27489467 TI - Celiac disease in children and adolescents with Hashimoto Thyroiditis. AB - AIM: The aim of this study was to evaluate clinical and laboratory findings and determine the prevalence of celiac disease (CD) in children with Hashimoto thyroiditis (HT). MATERIAL AND METHODS: The data of a total of 80 patients with positive anti-thyroid antibodies who were aged between 6 and 17.9 years were retrospectively studied. Age, gender, complaints at the time of presentation, family history of thyroid disorders, clinical and laboratory findings were recorded. The levels of thyrotropin, free thyroxin, thyroid autoantibodies (thyroid peroxidase and thyroglobulin antibodies), immunoglobulin A (IgA), anti tissue transglutaminase antibodies (IgA-tTG), and thyroid ultrasonography findings were enrolled. RESULTS: Eighty patients (65 females (81.2%) and 15 males (18,8%)) were included in the study. Family history of thyroid disease was present in 38 (47.5%) patients. The most common complaints at the time of presentation were goiter (%30) and weight gain (%25). Forty three (53.8%), 23 (28.7%), and 14 (17.5%) patients presented with euthyroidism, subclinical hypothyroidism and obvious hypothyroidism. Thirty seven (46.2%) patients had goiter. IgA-tTG was found to be positive after a diagnosis of HT was made in only one patient (1.25%) and the diagnosis of CD was confirmed when intestinal biopsy of this patient revealed villus atrophy, crypt hyperplasia and increase in the intraepithelial lymphocyte count. CONCLUSIONS: In our study, it was found that the most common complaints at presentation in patients with a diagnosis of hashimoto thyroiditis included goiter, weakness and weight gain and the prevalence of celiac diseases was found to be 1.25% (1/80). This study shows that the prevalence of CD in patients with a diagnosis of HT is higher compared to the prevalence in the healthy pediatric population. PMID- 27489468 TI - A rare sex chromosome aneuploidy: 48,XXYY syndrome. AB - 48,XXYY syndrome is a rare sex chromosome abnormality. Although some physical features are similar to Klinefelter syndrome(47,XXY), 48,XXYY is typically associated with different neuropsyhciatric symptoms and phenotypic findings. Approximately 100 cases with 48,XXYY have been reported to date. In this report, a patient who was diagnosed with 48,XXYY syndrome with clincal evaluation and cytogenetic analysis is presented. A 6-year old male patient was hospitalized due to recurrent respiratory tract infections, recurrent abdominal distention and dyspepsia. He was the first and only child of nonconsanguineous parents. He had a history of mild developmental retardation. In his history, it was learned that he received treatment for gastroesophageal reflux and his symptoms improved with treatment. On physical examination, his weight was found to be 31 kg (>97 centile) and his height was found to be 123 cm (90 centile). He had upslanted palpebral fissures, depressed nasal bridge, long philtrum, incomplete cleft lip and micrognathia. Clinodactilia was found in the fifth fingers in both hands and large big toes and adduction in the second and third toes were found in both feet. Karyotype analysis showed a chromosomal composition of 48,XXYY. The patient presented here is the second Turkish case of 48,XXYY syndrome. PMID- 27489469 TI - Sadfly fever: two case reports. AB - Sandfly fever, also known as 'three-day fever' or 'pappataci fever' or 'Phlebotomus fever' is a viral infection that causes self-limited influenza-like symptoms and characterized by a rapid onset. The disease occurs commonly in endemic areas in summer months and especially in August during which sandflies are active. In this article, two siblings who presented with high fever, redness in the eyes, headache, weakness, malaise and inability to walk, who were found to have increased liver function tests and creatine kinase levels and who were diagnosed with sadfly fever with positive sadfly IgM and IgG antibodies are reported because of the rarity of this disease. PMID- 27489470 TI - Withdrawal syndrome and hypomagnesaemia and in a newborn exposed to valproic acid and carbamazepine during pregnancy. AB - The usage of drugs during pregnancy affect the fetus and the newborn. In this report, we present findings from a newborn baby, whose mother was epileptic, and was under the treatment of valproic acid and carbamazepine during pregnancy. We have found symptoms of withdrawal syndrome, hyponatremia and feeding problem, which was most probably related to exposure to the mentioned drugs. We have also diagnosed hypomagnesaemia and atrial septal defect 4 milimeters in diameter. There are already many reports about the side effects of valproic acid and carbamazepine usage during pregnancy. To the best of our knowledge, hypomagnesaemia has not yet been reported as a side effect. We think that hypomagnesaemia is also related to the usage of antiepileptics. PMID- 27489471 TI - Five-year-old girl with tongue bleeding. PMID- 27489472 TI - Difficulties in the treatment of an Infant with Hemophilia B. PMID- 27489473 TI - A new species of Dianthus (Caryophyllaceae) from Antalya, South Anatolia, Turkey. AB - Dianthus multiflorus from Gazipasa (Antalya), south Anatolia (Turkey), is described as a new annual species with verrucose calyx. The morphological differences from the species within the same group with Dianthus multiflorus, which are Dianthus aydogdui, Dianthus cyri and Dianthus tripunctatus, are discussed. The International Union for Conservation of Nature (IUCN) threat category and observations on the ecology of the populations are noted. The karyology and seed micromorphology of Dianthus multiflorus and Dianthus tripunctatus were examined by light microscopy and scanning electron microscopy. PMID- 27489474 TI - Typification of names of South American taxa related to Woodsia montevidensis (Woodsiaceae). AB - A revision of the nomenclature of six South American taxa related to Woodsia is presented, as a part of a taxonomic revision of the genus in South America. Lectotypes are selected for Cheilanthes crenata, Woodsia crenata var. pallidipes, Woodsia incisa, Woodsia montevidensis var. fuscipes and the second step lectotypification for Dicksonia montevidensis and Woodsia peruviana, based on the analysis of their protologues and original herbarium material. All names are currently synonyms of Woodsia montevidensis. Physematium incisum (Gillies ex Hook. & Grev.) Kunze constitutes an illegitimate name and Physematium cumingianum is considered as nomen inquirendum. PMID- 27489475 TI - New functionally dioecious bush tomato from northwestern Australia, Solanum ossicruentum, may utilize "trample burr" dispersal. AB - A new Australian species of functionally dioecious bush tomato of Solanum subgenus Leptostemonum is described. Solanum ossicruentum Martine & J.Cantley, sp. nov., is thought to be allied with members of the problematic "Dioicum Complex" lineage, but differs in its short silvery indumentum, long calyx lobes, larger stature, and an unusual fruit morphology that may represent "trample burr" seed dispersal. The species occurs in a range extending from the eastern Kimberley in Western Australia to far northwestern Northern Territory and has been recognized for decades as a variant of Solanum dioicum W.Fitzg. Specimens of this species were previously referred to by D.E. Symon and others as Solanum dioicum 'Tanami.' Ex situ crossing studies and SEM images of inaperturate pollen grains produced in morphologically hermaphrodite flowers indicate that this taxon is functionally dioecious. The scientific name was chosen with the help of 150 seventh grade life science students from Pennsylvania, USA. PMID- 27489476 TI - Miconia papillosperma (Melastomataceae, Miconieae): a new species from Amazonas, Brazil. AB - Miconia papillosperma, a new species of Melastomataceae shrubs from Northern Brazil is described and illustrated. This new species is characterized by elliptic lanceolate leaves with the only pair of secondary veins running close to the margin. It is also unique in having seeds with a papillose testa, a character until now unknown in the Miconieae. The description of this new species from a relatively well collected area near a major road north of Manaus, Amazonas, Brazil, is further evidence of our lack of knowledge on plants in many Neotropical areas. PMID- 27489477 TI - Spiradiclis pengshuiensis (Ophiorrhizeae, Rubioideae), a new species from Chongqing, China. AB - Spiradiclis pengshuiensis Bo Pan & R. J. Wang (Rubiaceae) is described as a new species from Chongqing in SW China. It is morphologically compared with Spiradiclis pauciflora L. Wu & Q. R. Liu because of their similarities in habit, pubescent surface, small leaf laminas and subglobose capsules. Its conservation status is evaluated as "VU" according to the IUCN categories and criteria. PMID- 27489479 TI - A new species in the tree genus Polyceratocarpus (Annonaceae) from the Udzungwa Mountains of Tanzania. AB - Polyceratocarpus askhambryan-iringae, an endemic tree species of Annonaceae from the Udzungwa Mountains of Tanzania, is described and illustrated. The new species is identified as a member of the genus Polyceratocarpus by the combination of staminate and bisexual flowers, axillary inflorescences, subequal outer and inner petals, and multi-seeded monocarps with pitted seeds. From Polyceratocarpus scheffleri, with which it has previously been confused, it differs in the longer pedicels, smaller and thinner petals, shorter bracts, and by generally smaller, less curved monocarps that have a clear stipe and usually have fewer seeds. Because Polyceratocarpus askhambryan-iringae has a restricted extent of occurrence, area of occupancy, and ongoing degradation of its forest habitat, we recommend classification of it as Endangered (EN) on the IUCN Red List. PMID- 27489478 TI - Molecular and morphological evidence for Penstemon luculentus (Plantaginaceae): a replacement name for Penstemon fremontii var. glabrescens. AB - Penstemon luculentus R.L.Johnson & M.R.Stevens, nom. nov. replaces Penstemon fremontii var. glabrescens Dorn & Lichvar. The varietal name glabrescens was not elevated because it was already occupied by Penstemon glabrescens Pennell, a different species. This new arrangement is supported by molecular and morphological evidence. An analysis of genetic diversity in populations of both varieties of Penstemon fremontii Torr. & A. Gray (glabrescens and fremontii) from the Piceance Basin, Colorado, using SSR (simple sequences repeats) or microsatellites markers, revealed significant genetic differentiation between the two. Penstemon fremontii var. glabrescens was also genetically different from Penstemon gibbensii Dorn and Penstemon scariosus var. garrettii (Pennell) N.H. Holmgren. The combination of hirtellous stems, glabrous leaves, non-glandular inflorescence, and long anther hairs distinguish Penstemon luculentus from other morphologically similar species. PMID- 27489480 TI - New combinations in Odontostemma (Caryophyllaceae). AB - Sixty-three new combinations in Odontostemma (Alsineae, Caryophyllaceae) are made to accommodate placement of all currently recognized taxa of Arenaria subg. Odontostemma within the genus Odontostemma. PMID- 27489481 TI - A new species of Clinanthus from northern Peru (Asparagales, Amaryllidaceae, Amarylloideae, Clinantheae). AB - Clinanthus milagroanthus S. Leiva & Meerow, sp. nov. is described from the Department of La Libertad in Peru. The new species is most closely related to Clinanthus mirabilis (Ravenna) Meerow, with further affinities to Clinanthus viridiflorus (R. & P.) Meerow. It can be distinguished from Clinanthus mirabilis by its wider leaves, the much more brightly colored and wide spreading limb, and the much lighter colored perigone tube (yellowish green vs. dark green in Clinanthus mirabilis). A conspicuous bulge just proximal to the midpoint of the tube is a unique character of the new species. PMID- 27489482 TI - A revision of Poa subsection Aphanelytrum (Poaceae, Pooideae, Poaeae, Poinae); and a new species, Poa auriculata. AB - In this study the peculiar Andean grass genus Aphanelytrum, with two species, is reduced to Poa subsect. Aphanelytrum comb. & stat. nov. A third species, Festuca reclinata, is assigned to the subsection, which shows states transitional between a more typical Poa and Aphanelytrum. Poa subgen. Poa supersect. Homalopoa sect. Dioicopoa subsect. Aphanelytrum comb. & stat. nov. is characterized in having stooling perennials with decumbent to spreading culm bases that continuously branch and often root at low to mid-culm nodes, glabrous spikelets with long rachillas 1.2-4.2 mm long, short glumes less than 1/2 the length of the florets, and lemmas with bifid apexes that are mucronate to short-awned. We provide for the three species taxonomic discussions, morphological and anatomical descriptions, keys, illustrations, and a list of specimens. Also, we provide two new names, Poa hitchcockiana nom. nov. and Poa sanchez-vegae nom. nov., and one new combination, Poa reclinata comb. nov. A new species, Poa auriculata sp. nov. from Peru, not thought to be a member of Poa subsect. Aphanelytrum, is presented. It is the first in the genus with prominent auricles. In addition, we place Poa apiculata in Poa subgen. Poa supersect. Homalopoa sect. Dioicopoa subsect. Tovarochloa comb. & stat. nov. PMID- 27489483 TI - The Andean Paepalanthus pilosus complex (Eriocaulaceae): a revision with three new taxa. AB - A herbarium-based revision is provided for Paepalanthus pilosus and allies, five commonly confused species of cushion plants native to Andean paramo. These are placed in the recircumscribed Paepalanthus subsect. Cryptanthella Suess. The group includes Paepalanthus pilosus, Paepalanthus dendroides, and Paepalanthus lodiculoides. An additional two species and one variety are newly described: Paepalanthus caryonauta, Paepalanthus huancabambensis, and Paepalanthus pilosus var. leoniae. The latter two are Peruvian endemics, while Paepalanthus caryonauta is known from four countries, and has long been confused with other species. An additional, possibly undescribed taxon is noted from the Serrania de Perija, Colombia. Five new synonyms and three lectotypes are proposed, and the common misapplication of some names is noted. Within the Paepalanthus pilosus complex, species differences were found in timing of peduncle elongation, sex ratio, and leaf, perianth, diaspore and nectary morphology. Ecological differences are suggested by specimen data and a review of ecological literature. Descriptions, photographs and maps are provided for all species, as is a key to the groups of eriocaulaceous cushion plants from Andean South America. PMID- 27489484 TI - A brief botanical survey into Kumbira forest, an isolated patch of Guineo Congolian biome. AB - Kumbira forest is a discrete patch of moist forest of Guineo-Congolian biome in Western Angola central scarp and runs through Cuanza Norte and Cuanza Sul province. The project aimed to document the floristic diversity of the Angolan escarpment, a combination of general walk-over survey, plant specimen collection and sight observation was used to aid the characterization of the vegetation. Over 100 plant specimens in flower or fruit were collected within four identified vegetation types. The list of species includes two new records of Guineo Congolian species in Angola, one new record for the country and one potential new species. PMID- 27489485 TI - A new species of Amphitecna (Bignoniaceae) endemic to Chiapas, Mexico. AB - Amphitecna loreae Ortiz-Rodr. & Burelo, sp. nov. (Bignoniaceae), a new species endemic to the karst rainforest in southern Mexico, is described and illustrated. The new species differs from the other species of Amphitecna by the combination of cauliflorous inflorescences, larger flowers, buds rounded at apex, and globose ellipsoid rather than acuminate fruits. A key to the Mexican species of Amphitecna is presented. PMID- 27489486 TI - Cephalaria anamurensis (Caprifoliaceae), a new species from south Anatolia, Turkey. AB - A new species, Cephalaria anamurensis (Caprifoliaceae) is described and illustrated from south Anatolia, Turkey. The species grows on steppe and stony places in Anamur (C4 Mersin province) in south Anatolia. Diagnostic morphological characters from closely similar taxa are discussed. The geographical distribution of the new species and two closely related species in Turkey are mapped. PMID- 27489487 TI - Flora of Bokor National Park V: Two new species of Machilus (Lauraceae), M. bokorensis and M. brevipaniculata. AB - Two new species, Machilus bokorensis Yahara & Tagane and Machilus brevipaniculata Yahara & Tagane (Lauraceae) are described from Bokor National Park, Cambodia with their illustrations and DNA barcodes of the two plastid regions of rbcL and matK and the nuclear region of ITS. PMID- 27489488 TI - A new species of Eustigma (Hamamelidaceae) from Hon Ba Nature Reserve, Vietnam. AB - A new species of Hamamelidaceae, Eustigma honbaense H.Toyama, Tagane & V.S.Dang, sp. nov., is described from Hon Ba Nature Reserve, Vietnam. This species is similar to Eustigma oblongifolium Gardner & Champ., but differs from it in having entire leaves, longer infructescences, capsules with a longer apical part and seeds with a larger hilum. A description, preliminary conservation assessment, illustration and photographs of the new species are provided, as well as an updated key to the genus Eustigma. PMID- 27489489 TI - An updated checklist and key to the open-panicled species of Poa L. (Poaceae) in Peru including three new species, Poa ramoniana, Poa tayacajaensis, and Poa urubambensis. AB - We provide an updated checklist and key to the 30 Poa species with open panicles from Peru which includes previously circumscribed Dissanthelium and Aphanelytrum species, new taxon records, and three undescribed species. Poa compressa, Poa grisebachii, and Poa leioclada are recorded from Peru for the first time. A number of species are placed in synonymy: Poa carazensis, Poa ferreyrae and Poa tovarii are synonymized under the name Poa fibrifera; Poa adusta (tentatively) and Poa pilgeri are synonymized under Poa candamoana; Poa superata is synonymized under Poa grisebachii; and Poa paramoensis is synonymized under Poa huancavelicae. Included within this treatment are three new species, Poa ramoniana, Poa tayacajaensis and Poa urubambensis, which are described and illustrated. Poa ramoniana, found growing near lakes in high elevation Puna grasslands of Junin, is similar to a small form of Poa glaberrima, but differs in having rhizomes and growing to only 5 cm tall. Poa tayacajaensis, found from shrublands on Andean slopes of Huancavelica and Huanuco, bears similarities to Poa aequatoriensis but differs in having shorter lemmas which are pubescent between the veins, densely scabrous sheaths with smooth, glabrous throats, and shorter ligules. Poa urubambensis, a common element of the undisturbed Polylepis forest understory of the Cordillera Urubamba, Cusco, is distinct from all other members of open-panicled Poa's by having glabrous lemmas with a smooth and glabrous callus, and notably small anthers. The type material for the name Poa adusta is discussed and a lectotype is selected. PMID- 27489490 TI - Typifications and synonymy in Polystichum (Dryopteridaceae) from Chile and Argentina. AB - Polystichum Roth is one of the largest and most taxonomically challenging fern genera. South American species have a rich and complex nomenclatural history; many of the early names are inadequately typified. Based on extensive examination of original type material, we designate eleven lectotypes (including Aspidium mohrioides, Aspidium montevidense f. imbricata, Aspidium montevidense f. squamulosa, Aspidium plicatum, Aspidium pycnolepis, Dicksonia andina, Polystichum elegans, Polystichum mohrioides f. latifolia, Polystichum multifidum var. autranii, Polystichum platyphyllum var. kurtziana, and Polypodium polystichoides), and one neotype (Polystichum brongniartianum) for Polystichum taxa. Furthermore, three new synonyms are proposed. PMID- 27489491 TI - Bulbophyllum pingnanense (Orchidaceae, Epidendroideae, Dendrobiinae), a new species from Fujian, China. AB - A new orchid species, Bulbophyllum pingnanense, is described and illustrated from Fujian, China. It is similar to Bulbophyllum brevipedunculatum and Bulbophyllum albociliatum in vegetative and floral morphology, but it can be distinguished from Bulbophyllum brevipedunculatum by having a longer dorsal sepal with longer white ciliate on margin, longer and lanceolate lateral sepals, and a glabrous lip. It can be distinguished from Bulbophyllum albociliatum by having a shorter inflorescence, and a longer dorsal sepal. PMID- 27489492 TI - Telipogon diabolicus (Orchidaceae, Oncidiinae), a new species from southern Colombia. AB - A new species of the orchid genus Telipogon, Telipogon diabolicus, is described and illustrated. The information about its habitat is provided. The novelty resembles Telipogon tabanensis and Telipogon guacamayensis and it is characterized by the translucent flowers, the glabrous, distinctly clawed petals, the transversely elliptic lip, and the gynostemium ornamented with long setose hairs on both sides and shorter hairs at the apex. PMID- 27489493 TI - Popowia bachmaensis (Annonaceae), a new species from Bach Ma National Park, Central Vietnam. AB - A new species, Popowia bachmaensis Ngoc, Tagane & Yahara, sp. nov. is described from Bach Ma National Park in Thua Thien Hue Province, Central Vietnam. This species is morphologically similar to Popowia pisocarpa (Blume) Endl. ex Walp., but can be readily distinguished from it by its lower stems, smaller leaves, shorter flowering pedicels, shorter carpels, longer sepals and inner petals. A detailed description, comprising illustrations, and supplemented with DNA barcodes of the two regions of rbcL and matK, are provided. PMID- 27489494 TI - A revision of the "African Non-Spiny" Clade of Solanum L. (Solanum sections Afrosolanum Bitter, Benderianum Bitter, Lemurisolanum Bitter, Lyciosolanum Bitter, Macronesiotes Bitter, and Quadrangulare Bitter: Solanaceae). AB - The African Non-Spiny (ANS) clade contains 14 species of mostly large canopy lianas or scandent shrubs confined to Madagascar (10) and continental Africa (4, with with one species reaching the southern Arabian peninsula). Members of the clade were previously classified in sections Afrosolanum Bitter, Benderianum Bitter, Lemurisolanum Bitter, Macronesiotes Bitter and Quadrangulare Bitter, and were throught to be related to a variety of New World groups. The group is an early-branching lineage of non-spiny solanums and characters shared with other vining New World solanums are homoplastic. The 14 species of the group occupy a wide range of habitats, from wet forests in western Africa to savanna and dry forests of southern Madagascar and dune habitats in South Africa. Many members of the group are highly variable morphologically, and habit can vary between shrub and canopy vine in a single locality. We here review the taxonomic history, morphology, potential relationships and ecology of these species; we provide keys for their identification, descriptions, full synonymy (including designations of lectotypes and neotypes) and nomenclatural notes. Illustrations, distribution maps and preliminary conservation assessments are provided for all species. PMID- 27489495 TI - Generation of a Mouse Full-length Balancer with Versatile Cassette-shuttling Selection Strategy. AB - Balancer chromosomes are important tools for a variety of genetic manipulations in lower model organisms, owing to their ability to suppress recombination. In mouse, however, such effort has not been accomplished, mostly due to the size of the chromosomes and the complexity of multiple step chromosomal engineering. We developed an effective and versatile cassette-shuttling selection (CASS) strategy involving only two selection markers to achieve the sequential production of multiple large inversions along the chromosome. Using this strategy, we successfully generated the first full-length balancer in mice and showed that Balancer 17M-GFP can efficiently suppress recombination. Our study has not only generated a useful genetic resource, but also provided a strategy for constructing mammalian balancer chromosomes. PMID- 27489496 TI - Yorkie Facilitates Organ Growth and Metamorphosis in Bombyx. AB - The Hippo pathway, which was identified from genetic screens in the fruit fly, Drosophila melanogaster, has a major size-control function in animals. All key components of the Hippo pathway, including the transcriptional coactivator Yorkie that is the most critical substrate and downstream effector of the Hippo kinase cassette, are found in the silkworm, Bombyx mori. As revealed by microarray and quantitative real-time PCR, expression of Hippo pathway genes is particularly enriched in several mitotic tissues, including the ovary, testis, and wing disc. Developmental profiles of Hippo pathway genes are generally similar (with the exception of Yorkie) within each organ, but vary greatly in different tissues showing nearly opposing expression patterns in the wing disc and the posterior silk gland (PSG) on day 2 of the prepupal stage. Importantly, the reduction of Yorkie expression by RNAi downregulated Yorkie target genes in the ovary, decreased egg number, and delayed larval-pupal-adult metamorphosis. In contrast, baculovirus-mediated Yorkie(CA) overexpression upregulated Yorkie target genes in the PSG, increased PSG size, and accelerated larval-pupal metamorphosis. Together the results show that Yorkie potentially facilitates organ growth and metamorphosis, and suggest that the evolutionarily conserved Hippo pathway is critical for size control, particularly for PSG growth, in the silkworm. PMID- 27489497 TI - The Protein Elicitor PevD1 Enhances Resistance to Pathogens and Promotes Growth in Arabidopsis. AB - The protein elicitor PevD1, isolated from Verticillium dahlia, could enhance resistance to TMV in tobacco and Verticillium wilt in cotton. Here, the pevd1 gene was over-expressed in wild type (WT) Arabidopsis, and its biological functions were investigated. Our results showed that the transgenic lines were more resistant to Botrytis cinerea and Pseudomonas syringae pv. tomato DC3000 than the WT line was. In transgenic plants, both the germination time and bolting time required were significantly shorter and fresh weights and plant heights were significantly higher than those in the WT line. A transcriptomics study using digital gene expression profiling (DGE) was performed in transgenic and WT Arabidopsis. One hundred and thirty-six differentially expressed genes were identified. In transgenic Arabidopsis, three critical regulators of JA biosynthesis were up-regulated and JA levels were slightly increased. Three important repressors of the ABA-responsive pathway were up-regulated, indicating that ABA signal transduction may be suppressed. One CML and two WRKY TFs involved in Ca(2+)-responsive pathways were up-regulated, indicating that this pathway may have been triggered. In conclusion, we show that PevD1 is involved in regulating several plant endogenous signal transduction pathways and regulatory networks to enhance resistance and promote growth and development in Arabidopsis. PMID- 27489498 TI - Protective Effect of Thymoquinone against Cyclophosphamide-Induced Hemorrhagic Cystitis through Inhibiting DNA Damage and Upregulation of Nrf2 Expression. AB - Cyclophosphamide (CYP) induced hemorrhagic cystitis is a dose-limiting side effect involving increased oxidative stress, inflammatory cytokines and suppressed activity of nuclear factor related erythroid 2-related factor (Nrf2). Thymoquinone (TQ), an active constituent of Nigella sativa seeds, is reported to increase the expression of Nrf2, exert antioxidant action, and anti-inflammatory effects in the experimental animals. The present study was designed to explore the effects of TQ on CYP-induced hemorrhagic cystitis in Balb/c mice. Cystitis was induced by a single intraperitoneal injection of CYP (200 mg/kg). TQ was administered intraperitoneally at 5, 10 and 20 mg/kg doses twice a day, for three days before and three days after the CYP administration. The efficacy of TQ was determined in terms of the protection against the CYP-induced histological perturbations in the bladder tissue, reduction in the oxidative stress, and inhibition of the DNA fragmentation. Immunohistochemistry was performed to examine the expression of Nrf2. TQ protected against CYP-induced oxidative stress was evident from significant reduction in the lipid peroxidation, restoration of the levels of reduced glutathione, catalase and superoxide dismutase activities. TQ treatment significantly reduced the DNA damage evident as reduced DNA fragmentation. A significant decrease in the cellular infiltration, edema, epithelial denudation and hemorrhage were observed in the histological observations. There was restoration and rise in the Nrf2 expression in the bladder tissues of mice treated with TQ. These results confirm that, TQ ameliorates the CYP-induced hemorrhagic cystitis in mice through reduction in the oxidative stress, inhibition of the DNA damage and through increased expression of Nrf2 in the bladder tissues. PMID- 27489499 TI - The Involving Roles of Intrahepatic and Extrahepatic Stem/Progenitor Cells (SPCs) to Liver Regeneration. AB - Liver regeneration is usually attributed to mature hepatocytes, which possess a remarkable potential to proliferate under mild to moderate injury. However, when the liver is severely damaged or hepatocyte proliferation is greatly inhibited, liver stem/progenitor cells (LSPCs) will contribute to the liver regeneration process. LSPCs in the developing liver have been extensively characterized, however, their contributing role to liver regeneration has not been completely understood. In addition to the restoration of the liver parenchymal tissue by hepatocytes or/and LSPCs, or in some cases bone marrow (BM) derived cells, such as hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), the wound healing after injury in terms of angiopoiesis by liver sinusoidal endothelial cells (LSECs) or/and sinusoidal endothelial progenitor cells (SEPCs) is another important aspect taking place during regeneration. To conclude, liver regeneration can be mainly divided into three distinct restoring levels according to the cause and severity of injury: hepatocyte dominant regeneration, LSPCs mediated regeneration, extrahepatic stem cells participative regeneration. In this review, we focus on the recent findings of liver regeneration, especially on those related to stem/progenitor cells (SPCs)-mediated regeneration and their potential clinical applications and challenges. PMID- 27489500 TI - Selecting Cells for Bioartificial Liver Devices and the Importance of a 3D Culture Environment: A Functional Comparison between the HepaRG and C3A Cell Lines. AB - Recently, the first clinical trials on Bioartificial Livers (BALs) loaded with a proliferative human hepatocyte cell source have started. There are two cell lines that are currently in an advanced state of BAL development; HepaRG and HepG2/C3A. In this study we aimed to compare both cell lines on applicability in BALs and to identify possible strategies for further improvement. We tested both cell lines in monolayer- and BAL cultures on growth characteristics, hepatic differentiation, nitrogen-, carbohydrate-, amino acid- and xenobiotic metabolism. Interestingly, both cell lines adapted the hepatocyte phenotype more closely when cultured in BALs; e.g. monolayer cultures produced lactate, while BAL cultures showed diminished lactate production (C3A) or conversion to elimination (HepaRG), and urea cycle activity increased upon BAL culturing in both cell lines. HepaRG BALs outperformed C3A-BALs on xenobiotic metabolism, ammonia elimination and lactate elimination, while protein synthesis was comparable. In BAL cultures of both cell lines ammonia elimination correlated positively with glutamine production and glutamate consumption, suggesting ammonia elimination was mainly driven by the balance between glutaminase and glutamine synthetase activity. Both cell lines lacked significant urea cycle activity and both required multiple culture weeks before reaching optimal differentiation in BALs. In conclusion, culturing in BALs enhanced hepatic functionality of both cell lines and from these, the HepaRG cells are the most promising proliferative cell source for BAL application. PMID- 27489501 TI - BDNF-mediates Down-regulation of MicroRNA-195 Inhibits Ischemic Cardiac Apoptosis in Rats. AB - BACKGROUND: Our previous studies suggested that brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) axis inhibited cardiomyocyte apoptosis in myocardial infarction (MI). However, the relationship between BDNF and microRNA (miRNA) in cardiomyocytes are unclear. The present study was performed to investigate the role of miR-195 and the interplay between BDNF and miR-195 in ischemic cardiomyocyte apoptosis. METHODS: Male Wistar rats were subjected to coronary artery ligation, and primary neonatal rat ventricular myocytes were treated with hypoxia or hydrogen peroxide (H2O2). BDNF level in rat ventricles was measured by enzyme linked immunosorbent assay (ELISA). miR-195 mimic, inhibitor or negative control was transfected into the cardiomyocytes. Cell viability and apoptosis were detected by MTT assay and TdT-mediated dUTP nick end labeling (TUNEL) staining, respectively. Cardiac function and apoptosis were detected in MI rats intravenously injected with antagomiR-195. Luciferase assay, Western blot and Real-time RT-PCR were employed to clarify the interplay between miR-195 and BDNF. RESULTS: miR-195 level was dynamically regulated in response to MI and significantly increased in ischemic regions 24 h post-MI as well as in hypoxic or H2O2-treated cardiomyocytes. Meanwhile, BDNF protein level was rapidly increased in MI rats and H2O2-treated cardiomyocytes. Apoptosis in both hypoxic and H2O2-treated cardiomyocytes were markedly reduced and cell viability was increased by miR-195 inhibitor. Moreover, inhibition of miR-195 significantly improved cardiac function of MI rats. Bcl-2 but not BDNF was validated as the direct target of miR-195. Furthermore, BDNF abolished the pro-apoptotic role of miR-195, which was reversed by its scavenger TrkB-Fc. CONCLUSION: Up-regulation of miR-195 in ischemic cardiomyocytes promotes ischemic apoptosis by targeting Bcl-2. BDNF mitigated the pro-apoptotic effect of miR-195 in rat cardiomyocytes. These findings may provide better understanding of the pro-apoptotic role of miR 195 in MI and suggest that BDNF/miR-195/Bcl-2 axis may be beneficial for limiting myocardial ischemic injury. PMID- 27489502 TI - Fibroblast Growth Factor Receptor 3 Deficiency Does Not Impair the Osteoanabolic Action of Parathyroid Hormone on Mice. AB - PTH stimulates bone formation in Fgfr3 knockout mice through promotion of proliferation and differentiation in osteoblasts. INTRODUCTION: Previous studies showed that endogenous fibroblast growth factor 2 (FGF-2) is required for parathyroid hormone (PTH)-stimulated bone anabolic effects, however, the exact mechanisms by which PTH stimulate bone formation and the function of FGF receptors in mediating these actions are not fully defined. FGF receptor 3 (FGFR3) has been characterized as an important regulator of bone metabolism and is confirmed to cross-talk with PTH/PTHrP signal in cartilage and bone development. METHODS: Fgfr3 knockout and wild-type mice at 2-month-old and 4 month-old were intraperitoneally injected with PTH intermittently for 4 weeks and then the skeletal responses to PTH were assessed by dual energy X-ray absorptiometry (DEXA), micro-computed tomography (MUCT) and bone histomorphometry. RESULTS: Intermittent PTH treatment improved bone mineral density (BMD) and femoral mechanical properties in both Fgfr3 (-/-) and wild-type mice. Histomorphometric analysis showed that bone formation and bone resorption were increased in both genotypes following PTH treatment. PTH treatment increased trabecular bone volume (BV/TV) in WT and Fgfr3-deficient mice. The anabolic response in Fgfr3-deficient and wild-type bone is characterized by an increase of both bone formation and resorption-related genes following PTH treatment. In addition, we found that Fgfr3 null osteoblasts (compared to wild-type controls) maintained normal abilities to response to PTH-stimulated increase of proliferation, differentiation, expression of osteoblastic marker genes (Cbfa1, Osteopontin and Osteocalcin), and phosphorylation of Erk1/2. CONCLUSIONS: Bone anabolic effects of PTH were not impaired by the absence of FGFR3, suggesting that the FGFR3 signaling may not be required for osteoanabolic effects of PTH activities. PMID- 27489503 TI - Carbon Monoxide Improves Neurologic Outcomes by Mitochondrial Biogenesis after Global Cerebral Ischemia Induced by Cardiac Arrest in Rats. AB - Mitochondrial dysfunction contributes to brain injury following global cerebral ischemia after cardiac arrest. Carbon monoxide treatment has shown potent cytoprotective effects in ischemia/reperfusion injury. This study aimed to investigate the effects of carbon monoxide-releasing molecules on brain mitochondrial dysfunction and brain injury following resuscitation after cardiac arrest in rats. A rat model of cardiac arrest was established by asphyxia. The animals were randomly divided into the following 3 groups: cardiac arrest and resuscitation group, cardiac arrest and resuscitation plus carbon monoxide intervention group, and sham control group (no cardiac arrest). After the return of spontaneous circulation, neurologic deficit scores (NDS) and S-100B levels were significantly decreased at 24, 48, and 72 h, but carbon monoxide treatment improved the NDS and S-100B levels at 24 h and the 3-day survival rates of the rats. This treatment also decreased the number of damaged neurons in the hippocampus CA1 area and increased the brain mitochondrial activity. In addition, it increased mitochondrial biogenesis by increasing the expression of biogenesis factors including peroxisome proliferator-activated receptor-gamma coactivator 1alpha, nuclear respiratory factor-1, nuclear respiratory factor-2 and mitochondrial transcription factor A. Thus, this study showed that carbon monoxide treatment alleviated brain injury after cardiac arrest in rats by increased brain mitochondrial biogenesis. PMID- 27489504 TI - Cis-Natural Antisense Transcripts Are Mainly Co-expressed with Their Sense Transcripts and Primarily Related to Energy Metabolic Pathways during Muscle Development. AB - Cis-natural antisense transcripts (cis-NATs) are a new class of RNAs identified in various species. However, the biological functions of cis-NATs are largely unknown. In this study, we investigated the transcriptional characteristics and functions of cis-NATs in the muscle tissue of lean Landrace and indigenous fatty Lantang pigs. In total, 3,306 cis-NATs of 2,469 annotated genes were identified in the muscle tissue of pigs. More than 1,300 cis-NATs correlated with their sense genes at the transcriptional level, and approximately 80% of them were co expressed in the two breeds. Furthermore, over 1,200 differentially expressed cis NATs were identified during muscle development. Function annotation showed that the cis-NATs participated in muscle development mainly by co-expressing with genes involved in energy metabolic pathways, including citrate cycle (TCA cycle), glycolysis or gluconeogenesis, mitochondrial activation and so on. Moreover, these cis-NATs and their sense genes abruptly increased at the transition from the late fetal stages to the early postnatal stages and then decreased along with muscle development. In conclusion, the cis-NATs in the muscle tissue of pigs were identified and determined to be mainly co-expressed with their sense genes. The co-expressed cis-NATs and their sense gene were primarily related to energy metabolic pathways during muscle development in pigs. Our results offered novel evidence on the roles of cis-NATs during the muscle development of pigs. PMID- 27489505 TI - A Review of Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer. AB - Neoadjuvant chemoradiotherapy has become the standard treatment for locally advanced rectal cancer. Neoadjuvant chemoradiotherapy not only can reduce tumor size and recurrence, but also increase the tumor resection rate and anus retention rate with very slight side effect. Comparing with preoperative chemotherapy, preoperative chemoradiotherapy can further reduce the local recurrence rate and downstage. Middle and low rectal cancers can benefit more from neoadjuvant chemradiotherapy than high rectal cancer. It needs to refine the selection of appropriate patients and irradiation modes for neoadjuvant chemoradiotherapy. Different therapeutic reactions to neoadjuvant chemoradiotherapy affect the type of surgical techniques, hence calling for the need of much attention. Furthermore, many problems such as accurate staging before surgery, selection of suitable neoadjuvant chemoradiotherapy method, and sensitivity prediction to preoperative radiotherapy need to be well settled. PMID- 27489506 TI - Rapamycin Reduced Ischemic Brain Damage in Diabetic Animals Is Associated with Suppressions of mTOR and ERK1/2 Signaling. AB - The objectives of the present study are to investigate the activation of mTOR and ERK1/2 signaling after cerebral ischemia in diabetic rats and to examine the neuroprotective effects of rapamycin. Ten minutes transient global cerebral ischemia was induced in straptozotocin-induced diabetic hyperglycemic rats and non-diabetic, euglycemic rats. Brain samples were harvested after 16 h of reperfusion. Rapamycin or vehicle was injected 1 month prior to the induction of ischemia. The results showed that diabetes increased ischemic neuronal cell death and associated with elevations of p-P70S6K and Ras/ERK1/2 and suppression of p AMPKalpha. Rapamycin ameliorated diabetes-enhanced ischemic brain damage and suppressed phosphorylation of P70S6K and ERK1/2. It is concluded that diabetes activates mTOR and ERK1/2 signaling pathways in rats subjected to transient cerebral ischemia and inhibition of mTOR by rapamycin reduces ischemic brain damage and suppresses the mTOR and ERK1/2 signaling in diabetic settings. PMID- 27489507 TI - Rationing of nursing care interventions and its association with nurse-reported outcomes in the neonatal intensive care unit: a cross-sectional survey. AB - BACKGROUND: Evidence internationally suggests that staffing constraints and non supportive work environments result in the rationing of nursing interventions (that is, limiting or omitting interventions for particular patients), which in turn may influence patient outcomes. In the neonatal intensive care unit (NICU), preliminary studies have found that discharge preparation and infant comfort care are among the most frequently rationed nursing interventions. However, it is unknown if the rationing of discharge preparation is related to lower perceptions of parent and infant readiness for NICU discharge, and if reports of increased rationing of infant comfort care are related to lower levels of perceived neonatal pain control. The purpose of this study was to assess these relationships. METHODS: In late 2014, a cross-sectional survey was mailed to 285 Registered Nurses (RNs) working in one of 7 NICUs in the province of Quebec (Canada). The survey contained validated measures of care rationing, parent and infant readiness for discharge, and pain control, as well as items measuring RNs' characteristics. Multivariate regression was used to examine the association between care rationing, readiness for discharge and pain control, while adjusting for RNs' characteristics and clustering within NICUs. RESULTS: Overall, 125 RNs completed the survey; a 44.0 % response rate. Among the respondents, 28.0 and 40.0 % reported rationing discharge preparation and infant comfort care "often" or "very often", respectively. Additionally, 15.2 % of respondents felt parents and infants were underprepared for NICU discharge, and 54.4 % felt that pain was not well managed on their unit. In multivariate analyses, the rationing of discharge preparation was negatively related to RNs' perceptions of parent and infant readiness for discharge, while reports of rationing of parental support and teaching and infant comfort care were associated with less favourable perceptions of neonatal pain control. CONCLUSIONS: The rationing of nursing interventions appears to influence parent and infant readiness for discharge, as well as pain control in NICUs. Future investigations, in neonatal nursing care as well as in other nursing specialties, should address objectively measured patient outcomes (such as objective pain assessments and post-discharge outcomes assessed through administrative data). PMID- 27489508 TI - A case report of asymptomatic aortic thrombosis incidentally detected by computed tomography in apparently healthy subject with a history of cancer surgery. AB - BACKGROUND: Aortic thrombosis is a rare disease and only a few cases of the disease, especially associated with chemotherapy for malignant diseases and/or blood diseases, have been previously reported. Although Virchow's triad for thrombogenesis, namely hypercoagulability, blood flow stasis, and vessel wall injury, is the major factor promoting the formation of thrombosis, the detailed mechanism of the disease has not been well established. CASE PRESENTATION: We report a case of aortic thrombosis incidentally detected by computed tomography and then regressed by pharmacotherapy using warfarin. This case is an apparently healthy man in a postoperative state after lung cancer surgery with decreased protein-C activity. CONCLUSIONS: A case of aortic thrombosis without an obvious abnormality of the aorta was incidentally identified. A few cases of aortic thrombosis in healthy aortas have been reported to be associated with chemotherapy or blood diseases, however our present case did not had such a background. Although the detailed mechanism remains to be elucidated, this case suggests that aortic thrombosis can develop in apparently healthy subjects with a history of cancer surgery. PMID- 27489509 TI - Rapid assessment of disability in the Philippines: understanding prevalence, well being, and access to the community for people with disabilities to inform the W DARE project. AB - BACKGROUND: International recognition that people with disabilities were excluded from the Millennium Development Goals has led to better inclusion of people with disabilities in the recently agreed Global Goals for Sustainable Development (SDGs) 2015-2030. Given the current global agenda for disability inclusion, it is crucial to increase the understanding of the situation of people with disabilities in the Philippines. The aim of this study was to estimate the prevalence of disability and compare the well-being and access to the community between people with and without disabilities. METHODS: A population-based survey was undertaken in District 2 of Quezon City and in Ligao City. 60 clusters of 50 people aged 18 years and older were selected with probability proportion to size sampling from both locations. The Rapid Assessment of Disability (RAD) survey was used to identify people with disabilities based on their responses to activity limitations. The levels of well-being and access to the community for people with disabilities were compared with controls matched by age, gender, and cluster. Information on barriers to accessing the community was also collected. RESULTS: The prevalence of disability was 6.8 (95 % CI: 5.9, 7.9) and 13.6 % (95 % CI: 11.4, 16.2) in Quezon City and Ligao City respectively. Psychological distress was the most commonly reported condition in both locations, although it was often reported with a co-morbid condition related to sensory, physical, cognitive, and communication difficulties. The prevalence of disability was associated with age and no schooling, but not associated with poverty. People with disabilities had significantly lower well-being scores and reduced access to health services, work, rehabilitation, education, government social welfare, and disaster management than people without disability. Having a disability and negative family attitudes were reported as barriers for people with disabilities participating in work, community meetings, religious activities, and social activities. CONCLUSIONS: The prevalence of disability among adults in District 2 of Quezon City and in Ligao City is higher than the estimated national prevalence of disability derived from the 2010 Philippines census. Disability is also associated with lower well-being and reduced participation across a number of domains of community life. PMID- 27489510 TI - Socioeconomic status and self-rated health of Japanese people, based on age, cohort, and period. AB - BACKGROUND: Differences in health resulting from differences in socioeconomic status (SES) have been identified around the world. Age, period, and cohort (A-P C) differences in health are vital factors which are associated with disparities in SES. However, few studies have examined these differences simultaneously. Moreover, although self-rated health (SRH) has been frequently used as an indicator of health, biases in reporting SRH that depend on the socioeconomic characteristics of respondents have been scarcely adjusted in the previous studies. To overcome these limitations, we investigated the associations between disparities in SES and adjusted SRH based on A-P-C, by using a repeated, cross sectional survey of a nationally representative sample of Japanese people. In addition, we further investigated how exogenous (macroeconomic) conditions unique to a period or cohort would explain trends across successive periods and cohorts. METHODS: Data were obtained from a sample of 653,132 Japanese people that responded to the Comprehensive Survey of Living Conditions (CSLC), which is a cross-sectional survey that had been conducted every three years from 1986 to 2013, on over 10 occasions. In the CSLC, SES has been assessed by household income. We simultaneously controlled for each A-P-C dimension by using the model for cross-classification of random effects, and adjusting SRH data for reporting biases caused by differences in income and A-P-C. RESULTS: Differences in adjusted SRH associated with income differences decreased with age and reversed after 76 years of age. Period differences indicated that income differences peaked in 1992 and 2007. Moreover, differences in adjusted SRH associated with income differences decreased in periods with high unemployment across all periods. Furthermore, there were no cohort differences in adjusted SRH that were associated with income differences. CONCLUSION: In Japan, there are age and period variations associated with adjusted differences in SRH as assessed by income. Moreover, exogenous conditions in each period could help explain periodic trends across successive periods. PMID- 27489511 TI - Tumour volumes: Predictors of early treatment response in locally advanced head and neck cancers treated with definitive chemoradiation. AB - AIM: To analyse and predict early response 3 months post definitive chemoradiation (CCRT) utilising tumour volume (TV) measurement in locally advanced head and neck cancers (LAHNC). BACKGROUND: LAHNC are 3-dimentional lesions. The largest diameter of these tumours measured for T-classification may not necessarily reflect the true tumour dimensions. TV accurately reflects the tumour burden because it is a measurement of tumour burden in all three dimensions. MATERIALS AND METHODS: It is a single institutional prospective study including 101 patients with LAHNC treated with definitive CCRT. TV data noted were primary tumour volume (PTV), total nodal volume (TNV) and total tumour volume (TTV). Response evaluation was done at 3 months after the completion of definitive CCRT and patients were categorised either having achieved complete response (CR) or residual disease. RESULTS: Patients who had not achieved CR were found to have larger TV compared with those who had achieved CR. There were significant inverse correlations between PTV and response (median 16.37 cm(3) vs. 45.2 cm(3); p = 0.001), and between TTV and response (median 36.14 cm(3) vs. 66.06 cm(3); p < 0.001). Receiver operating characteristic (ROC) analysis identified an "optimal cut-off" value of 41 cm(3) for PTV and 42 cm(3) for TTV above and below which the magnitude of difference in response was the greatest. CONCLUSIONS: If response evaluation 3 months post CCRT is to be predicted it is simply not enough to measure the largest single dimension of the tumour. TV seems to be a better and more accurate reflection of the true total tumour burden or extent of the disease. PMID- 27489512 TI - Superior sulcus non-small cell lung carcinoma: A comparison of IMRT and 3D-RT dosimetry. AB - AIM: A dosimetric study comparing intensity modulated radiotherapy (IMRT) by TomoTherapy to conformational 3D radiotherapy (3D-RT) in patients with superior sulcus non-small cell lung cancer (NSCLC). BACKGROUND: IMRT became the main technique in modern radiotherapy. However it was not currently used for lung cancers. Because of the need to increase the dose to control lung cancers but because of the critical organs surrounding the tumors, the gains obtainable with IMRT is not still demonstrated. MATERIAL AND METHODS: A dosimetric comparison of the planned target and organs at risk parameters between IMRT and 3D-RT in eight patients who received preoperative or curative intent irradiation. RESULTS: In the patients who received at least 66 Gy, the mean V95% was significantly better with IMRT than 3D-RT (p = 0.043). IMRT delivered a lower D2% compared to 3D-RT (p = 0.043). The IH was significantly better with IMRT (p = 0.043). The lung V 5 Gy and V 13 Gy were significantly higher in IMRT than 3D-RT (p = 0.043), while the maximal dose (D max) to the spinal cord was significantly lower in IMRT (p = 0.043). The brachial plexus D max was significantly lower in IMRT than 3D-RT (p = 0.048). For patients treated with 46 Gy, no significant differences were found. CONCLUSION: Our study showed that IMRT is relevant for SS-NSCLC. In patients treated with a curative dose, it led to a reduction of the exposure of critical organs, allowing a better dose distribution in the tumor. For the patients treated with a preoperative schedule, our results provide a basis for future controlled trials to improve the histological complete response by increasing the radiation dose. PMID- 27489513 TI - Volumetric Modulated Arc Therapy (VMAT) make a difference in retro-orbital irradiation treatment of patients with bilateral Graves' ophthalmopathy. Comparative analysis of dosimetric parameters from different radiation techniques. AB - BACKGROUND: Graves' ophthalmopathy is the commonest extrathyroidal manifestation of Graves' disease. Treatment options include steroid therapy, corrective/decompressive surgery, radiation therapy or combination of these approaches. AIM: Our purpose was to investigate if retro-orbital irradiation with Volumetric Modulated Arc Therapy (VMAT) yielded better target coverage and dose sparing to adjacent normal structures compared to 3-Dimensional Conformal Radiotherapy (3DCRT) and Lateral Opposing Conformed Fields (LOCF). METHODS: Fourteen consecutive patients diagnosed with bilateral Graves' ophthalmopathy were prospectively recruited into this study from August 2012 until August 2014. An individual VMAT, 3DCRT and LOF plan was created for each patient. Conformity Index (CI), Homogeneity Index (HI) and other dosimetric parameters of the targets and organs-at-risk (OAR) were analyzed in all 28 orbits compared between the different techniques. RESULTS: CI generated by VMAT was superior to that produced by 3DCRT(p < .001) and LOF (p < .001). As expected, 3DCRT was also superior to LOF (p = .007). Regarding the OARs sparing dose (lens, globes, retina and lacrimal glands), VMAT showed a significant benefit when compared with 3DCRT and LOCF, with no differences between the two latter techniques. CONCLUSIONS: VMAT should be preferred over 3DCRT and LOF for bilateral Graves' ophthalmopathy treatment. PMID- 27489514 TI - Influence of the contrast agents on treatment planning dose calculations of prostate and rectal cancers. AB - AIM: The aim of the present study is to quantify differences in dose calculations caused by using CA and determine if the resulting differences are clinically significant. BACKGROUND: The influence of contrast agents (CA) on radiation dose calculations must be taken into account in treatment planning. MATERIALS AND METHODS: Eleven patients with pelvic cancers were included in this study and two sets of CTs were taken for each patient (without and with CA) in the same position and coordinates. Both sets of images were transferred to the DosiSoft ISOgray treatment planning system for contouring and calculating the dose distribution and monitor units (MUs) with Collapsed Cone and Superposition algorithms, respectively. All plans were generated on pre-contrast CT and subsequently copied to the post-contrast CT. Radiation dose calculations from the two sets of CTs were compared using a paired sample t-test. RESULTS: The results showed a statistically insignificant difference between pre- and post-contrast CT treatment plans for target volume and OARs (p > 0.05), except bladder organ in the prostate region (p < 0.05) but the relative mean dose and MU differences were less than 2% in any patient for 18 MV photon beam. CONCLUSIONS: Treatment planning on contrasted images generally showed a lower radiation dose to both target volume and OARs than plans on non-contrasted images. The results of this research showed that the small radiation dose differences between the plans for the CT scans with and without CA seem to be clinically insignificant; therefore, contrast-enhanced CT can be used for both target delineation and treatment planning of prostate and rectal cancers. PMID- 27489515 TI - Comparison of set-up errors by breast size on wing board by portal imaging. AB - AIM: To quantify and compare setup errors between small and large breast patients undergoing intact breast radiotherapy. METHODS: 20 patients were inducted. 10 small/moderate size breast in arm I and 10 large breast in arm II. Two orthogonal and one lateral tangent portal images (PIs) were obtained and analyzed for systematic (Sigma) and random (sigma) errors. Effect of no action level (NAL) was also evaluated retrospectively. RESULTS: 142 PIs were analyzed. Sigma(mm) was 3.2 versus 6.7 (p = 0.41) in the mediolateral (ML) direction, 2.1 versus 2.9 (p = 0.06) in the craniocaudal (CC) and 2.2 versus 3.6 (p = 0.08) in the anteroposterior (AP) direction in small and large breast, respectively. sigma(mm) was 3.0, 3.3 and 3.3 for small breast and 4.1, 3.7 and 3.2 for large breast in the ML, CC and AP direction (p = 0.07, 0.86, 0.37), respectively. 3 D Sigma(mm) was 2.7 versus 4.2 (p = 0.01) and sigma(mm) was 2.5 versus 3.2 (p = 0.14) in arm I and II, respectively. The standard deviation (SD) of variations (mm) in breast contour depicted by central lung distance (CLD) was 5.9 versus 7.4 (p < 0.001), central flash distance (CFD) 6.6 versus 10.5 (p = 0.002), inferior central margin (ICM) 4 versus 4.9 (p < 0.001) in arm I and II, respectively. NAL showed a significant reduction of systematic error in large breast in the mediolateral direction only. CONCLUSION: Wing board can be used in a busy radiotherapy department for setting up breast patients with a margin of 1.1 cm, 0.76 cm and 0.71 cm for small breasts and 1.96 cm, 1.12 cm and 0.98 cm for large breast in the ML, AP and CC directions, respectively. The large PTV margin in the mediolateral direction in large breast can be reduced using NAL. Further research is needed to optimize positioning of large breasted women. PMID- 27489516 TI - Study of the dosimetric differences between (192)Ir and (60)Co sources of high dose rate brachytherapy for breast interstitial implant. AB - AIM: The study intends to compare (192)Ir source against the (60)Co source for interstitial breast metal implant in high dose rate brachytherapy. BACKGROUND: Few studies have been reported to compare (60)Co and (192)Ir on HDR brachytherapy in gynaecology and prostate cancer and very few with reference to breast cancer. MATERIALS AND METHODS: Twenty patients who had undergone interstitial template guided breast implant were treated in HDR (192)Ir brachytherapy unit. Plans were generated substituting (60)Co source without changing the dwell positions and optimization. Cumulative dose volume histograms were compared. RESULTS: The reference isodose line enclosing CTV (CTVref) and the 2.34% difference seen in the volume enclosed by the reference isodose line (V ref) between the two isotopes show small but statistically significant difference (p < 0.05). In DHI, no difference was observed in the relative dose between the two sources (p = 0.823). The over dose volume index showed 11% difference. The conformity index showed 2.32% difference compared to (192)Ir (p < 0.05). D mean (%) and D max (%) for the heart, ipsilateral lung, ipsilateral ribs, skin presented very small difference. V 5% and V 10% of the heart shows 25% and 32% difference in dose. D 2cc (%) and D 0.1cc (%) for the contralateral breast, contralateral lung and D 2cc (%) of the skin displayed significant difference (p < 0.05). However, D 0.1cc (%) of the skin indicated no noteworthy difference with p = 0.343. CONCLUSION: Based on the 3D dosimetric analysis of patient plans considered in this study, most of the DVH parameters showed statistically significant differences which can be reduced by treatment planning optimization techniques. (60)Co isotope can be used as a viable alternative because of its long half-life, logistic advantages in procurement, infrequent need of source replacement and disposal of used source. PMID- 27489517 TI - Impact of reduction of flux overlap region on kilovoltage cone-beam computed tomography image quality and patients' exposure dose. AB - AIM: In high-precision radiation therapy, kilovoltage cone-beam computed tomography plays an important role in verifying the position of patient and localization of the target. However, the exposure dose is a problem with kilovoltage cone-beam computed tomography. Flux overlap region increases the patient dose around the center when the scan is performed in a full-scan mode. We assessed the influence of flux overlap region in a full-scan mode to understand the relationship between dose and image quality and investigated methods to achieve a dose reduction. METHOD: A Catphan phantom was scanned using various flux overlap region patterns in the pelvis on a full-scan mode. We used an intensity-modulated radiation therapy phantom for measuring the central dose. DoseLab was used to perform image analysis and to evaluate the linearity of the computed tomography values, uniformity, high-contrast resolution, and contrast-to noise ratio. RESULTS: The Hounsfield unit value varied by +/-40 Hounsfield unit of the acceptance value for the X1 field size of 3.5 cm. However, there were no differences in high-contrast resolution and contrast-to-noise ratio among different scan patterns. The absorbed dose decreased by 7% at maximum for the case within the tolerance value. CONCLUSION: Dose reduction is possible by reducing the overlap region after calibration and by performing computed tomography in the appropriate overlap region. PMID- 27489518 TI - Outcome of radiotherapy for pituitary adenomas. AB - AIM: The aim of this study was to analyze the outcome and toxicities and its correlation to patient related and treatment related factors. BACKGROUND: Pituitary adenomas are treated by radiation therapy (RT) as one of the modalities along with surgery and medical therapy. RT to pituitary adenomas is a challenge due to adjacent dose limiting structures such as optic apparatus and hypothalamus. MATERIALS AND METHODS: Between January 2004 and December 2010, 94 patients treated for pituitary adenoma with RT who had hospital records of a minimum follow-up of 1 year were included in the analysis. Tests of correlation were done with regards to treatment factors. RESULTS: Male preponderance was noted in our patient population. Nonfunctioning and functioning tumors were equal in number in this series. Hypopituitarism was associated in 58.5% of patients prior to RT. Radiological tumor progression was seen in one patient (1/94) who had a nonfunctioning tumor. Among functioning tumors, biochemical remission was seen in 93.6% of patients at a median follow-up of 6 years. CONCLUSIONS: Visual complication was seen in 5.3% of patients and worsening or new onset hypopituitarism was seen in 6.4%. Conventional 3-field technique was associated with significantly more visual complication compared to Stereotactic Radiation Therapy (SRT) technique. Doses <=50.4 Gy showed a trend of reduced rate of visual and endocrine complications with no compromise in efficacy. PMID- 27489519 TI - Dose distribution verification for GYN brachytherapy using EBT Gafchromic film and TG-43 calculation. AB - AIM: Verification of dose distributions for gynecological (GYN) brachytherapy implants using EBT Gafchromic film. BACKGROUND: One major challenge in brachytherapy is to verify the accuracy of dose distributions calculated by a treatment planning system. MATERIALS AND METHODS: A new phantom was designed and fabricated using 90 slabs of 18 cm * 16 cm * 0.2 cm Perspex to accommodate a tandem and Ovoid assembly, which is normally used for GYN brachytherapy treatment. This phantom design allows the use of EBT Gafchromic films for dosimetric verification of GYN implants with a cobalt-60 HDR system or a LDR Cs 137 system. Gafchromic films were exposed using a plan that was designed to deliver 1.5 Gy of dose to 0.5 cm distance from the lateral surface of ovoids from a pair of ovoid assembly that was used for treatment vaginal cuff. For a quantitative analysis of the results for both LDR and HDR systems, the measured dose values at several points of interests were compared with the calculated data from a commercially available treatment planning system. This planning system was utilizing the TG-43 formalism and parameters for calculation of dose distributions around a brachytherapy implant. RESULTS: The results of these investigations indicated that the differences between the calculated and measured data at different points were ranging from 2.4% to 3.8% for the LDR Cs-137 and HDR Co-60 systems, respectively. CONCLUSION: The EBT Gafchromic films combined with the newly designed phantom could be utilized for verification of the dose distributions around different GYN implants treated with either LDR or HDR brachytherapy procedures. PMID- 27489520 TI - Accuracy in automatic image registration between MV cone beam computed tomography and planning kV computed tomography in image guided radiotherapy. AB - AIM: To verify the accuracy of automatic image registration (IR) between the planning kilo voltage computed tomography (kV CT) and megavoltage cone beam computed tomography (MV CBCT) datasets using phantom and patient images. BACKGROUND: The automatic IR between MV CBCT and planning kV CT is a fast solution for performing online image guided radiotherapy (IGRT). The IR accuracy has to be verified periodically as it directly affects patient setup accuracy. MATERIALS AND METHODS: The automatic IR accuracy was evaluated using image quality phantom acquired with different kV CT slice thickness, different MV CBCT acquisition MUs and reconstruction slice size and thickness. The IR accuracy was also evaluated on patient images on different anatomical sites such as brain, head & neck, thorax and pelvis. The uncertainty in the automatic registration was assessed by introducing known offset to kV CT dataset and compared with the registration results. RESULTS: The result with the phantom images was within 2 mm in all three translational directions. The accuracy in automatic IR using patient images was within 2 mm in most of the cases. 3 mm planning kV CT slice thickness was sufficient to perform automatic IR successfully within 2 mm accuracy. The MV CBCT reconstruction parameters such as slice thickness and slice size had no effect on the registration accuracy. CONCLUSION: This study shows that the automatic IR is accurate within 2 mm and provides confidence in performing them between planning kV CT and MV CBCT image datasets for online image guided radiotherapy. PMID- 27489523 TI - New and Emerging Therapies. PMID- 27489524 TI - A Review of New Surgical and Endoscopic Therapies for Gastroesophageal Reflux Disease. AB - Treatment of gastroesophageal reflux disease in the United States today is binary, with the majority of patients with gastroesophageal reflux disease being treated with antisecre-tory medications and a minority of patients, typically those with volume regurgitation, undergoing Nissen fundoplication. However, there has been increasing dissatisfaction with proton pump inhibitor therapy among a significant number of patients with gastroesophageal reflux disease owing to cost, side effects, and refractory symptoms, and there has been a general reluctance to undergo surgical fundoplication due to its attendant side-effect profile. As a result, a therapy gap exists for many patients with gastroesophageal reflux disease. Alternative techniques are available for these gap patients, including 2 endoscopic fundoplication techniques, an endoscopic radiofrequency energy delivery technique, and 2 minimally invasive surgical procedures. These alternative techniques have been extensively evaluated; however, there are limitations to published studies, including arbitrary definitions of success, variable efficacy measurements, deficient reporting tools, inconsistent study designs, inconsistent lengths of follow-up postintervention, and lack of comparison data across techniques. Although all of the techniques appear to be safe, the endoscopic techniques lack demonstrable reflux control and show variable symptom improvement and variable decreases in proton pump inhibitor use. The surgical techniques are more robust, with evidence for adequate reflux control, symptom improvement, and decreased proton pump inhibitor use; however, these techniques are more difficult to perform and are more intrusive. Additionally, these alternative techniques have only been studied in patients with relatively normal anatomy. The field of gastroesophageal reflux disease treatment is in need of consistent definitions of efficacy, standardized study design and outcome measurements, and improved reporting tools before the role of these techniques can be fully ascertained. PMID- 27489522 TI - The NAD(+) precursor nicotinamide riboside decreases exercise performance in rats. AB - BACKGROUND: Nicotinamide adenine dinucleotide (NAD(+)) and its phosphorylated form (NADP(+)) are key molecules in ubiquitous bioenergetic and cellular signaling pathways, regulating cellular metabolism and homeostasis. Thus, supplementation with NAD(+) and NADP(+) precursors emerged as a promising strategy to gain many and multifaceted health benefits. In this proof-of-concept study, we sought to investigate whether chronic nicotinamide riboside administration (an NAD(+) precursor) affects exercise performance. METHODS: Eighteen Wistar rats were equally divided in two groups that received either saline vehicle or nicotinamide riboside at a dose of 300 mg/kg body weight/day for 21 days via gavage. At the end of the 21-day administration protocol, both groups performed an incremental swimming performance test. RESULTS: The nicotinamide riboside group showed a tendency towards worse physical performance by 35 % compared to the control group at the final 10 % load (94 +/- 53 s for the nicotinamide riboside group and 145 +/- 59 s for the control group; P = 0.071). CONCLUSION: Our results do not confirm the previously reported ergogenic effect of nicotinamide riboside. The potentially negative effect of nicotinamide riboside administration on physical performance may be attributed to the pleiotropic metabolic and redox properties of NAD(+) and NADP(+). PMID- 27489521 TI - Biotrophy at Its Best: Novel Findings and Unsolved Mysteries of the Arabidopsis Powdery Mildew Pathosystem. AB - It is generally accepted in plant-microbe interactions research that disease is the exception rather than a common outcome of pathogen attack. However, in nature, plants with symptoms that signify colonization by obligate biotrophic powdery mildew fungi are omnipresent. The pervasiveness of the disease and the fact that many economically important plants are prone to infection by powdery mildew fungi drives research on this interaction. The competence of powdery mildew fungi to establish and maintain true biotrophic relationships renders the interaction a paramount example of a pathogenic plant-microbe biotrophy. However, molecular details underlying the interaction are in many respects still a mystery. Since its introduction in 1990, the Arabidopsis-powdery mildew pathosystem has become a popular model to study molecular processes governing powdery mildew infection. Due to the many advantages that the host Arabidopsis offers in terms of molecular and genetic tools this pathosystem has great capacity to answer some of the questions of how biotrophic pathogens overcome plant defense and establish a persistent interaction that nourishes the invader while in parallel maintaining viability of the plant host. PMID- 27489526 TI - The Present and Future of Inflammatory Bowel Disease Treatment. PMID- 27489525 TI - An Overview of the Evolution of Direct Cholangioscopy Techniques for Diagnosis and Therapy. AB - Direct examination of the biliary tree with endoscopes has been a challenge since endoscopists began performing endoscopic retrograde cholangiopancreatography (ERCP) in the late 1960s. Previously, surgeons had used rigid instruments intraoperatively, which made examination difficult. The first direct cholangioscopy performed by an endoscopist was likely unintentionally done in a patient with postsurgical anatomy. Indirect imaging, ERCP, and percutaneous transhepatic cholangiography are helpful modalities for examining the biliary tree, but they are limited procedures, particularly with regard to the evaluation and treatment of strictures and bile duct stones. This article reviews the history and evolution of direct cholangioscopy since the advent of flexible endoscopes. Additionally, the article describes a new single-operator cholan gioscopy technique for direct visualization of the biliary tree for diagnosis and intervention. There remains opportunity for innovation as endoscopists strive for safe and less-invasive methods for the identification and treatment of biliary pathology. PMID- 27489527 TI - Update on Irritable Bowel Syndrome Diagnostics and Therapeutics. PMID- 27489528 TI - Current and Emerging Treatments for Alpha-1 Antitrypsin Deficiency. PMID- 27489529 TI - Updated Guidelines for Diagnosing and Managing Barrett Esophagus. PMID- 27489530 TI - Primary Pancreatic Lymphoma Presenting as Acute Pancreatitis. PMID- 27489531 TI - Metabolomics connects aberrant bioenergetic, transmethylation, and gut microbiota in sarcoidosis. AB - Sarcoidosis is a systemic granulomatous disease of unknown etiology. Granulomatous inflammation in sarcoidosis may affect multiple organs, including the lungs, skin, CNS, and the eyes, leading to severe morbidity and mortality. The underlying mechanisms for sustained inflammation in sarcoidosis are unknown. We hypothesized that metabolic changes play a critical role in perpetuation of inflammation in sarcoidosis. 1H nuclear magnetic resonance (NMR)-based untargeted metabolomic analysis was used to identify circulating molecules in serum to discriminate sarcoidosis patients from healthy controls. Principal component analyses (PCA) were performed to identify different metabolic markers and explore the changes of associated biochemical pathways. Using Chenomx 7.6 NMR Suite software, we identified and quantified metabolites responsible for such separation in the PCA models. Quantitative analysis showed that the levels of metabolites, such as 3-hydroxybutyrate, acetoacetate, carnitine, cystine, homocysteine, pyruvate, and trimethylamine N-oxide were significantly increased in sarcoidosis patients. Interestingly, succinate, a major intermediate metabolite involved in the tricyclic acid cycle was significantly decreased in sarcoidosis patients. Application of integrative pathway analyses identified deregulation of butanoate, ketone bodies, citric cycle metabolisms, and transmethylation. This may be used for development of new drugs or nutritional modification. PMID- 27489532 TI - Preclinical models for interrogating drug action in human cancers using Stable Isotope Resolved Metabolomics (SIRM). AB - AIMS: In this review we compare the advantages and disadvantages of different model biological systems for determining the metabolic functions of cells in complex environments, how they may change in different disease states, and respond to therapeutic interventions. BACKGROUND: All preclinical drug-testing models have advantages and drawbacks. We compare and contrast established cell, organoid and animal models with ex vivo organ or tissue culture and in vivo human experiments in the context of metabolic readout of drug efficacy. As metabolism reports directly on the biochemical state of cells and tissues, it can be very sensitive to drugs and/or other environmental changes. This is especially so when metabolic activities are probed by stable isotope tracing methods, which can also provide detailed mechanistic information on drug action. We have developed and been applying Stable Isotope-Resolved Metabolomics (SIRM) to examine metabolic reprogramming of human lung cancer cells in monoculture, in mouse xenograft/explant models, and in lung cancer patients in situ (Lane et al. 2011; T. W. Fan et al. 2011; T. W-M. Fan et al. 2012; T. W. Fan et al. 2012; Xie et al. 2014b; Ren et al. 2014a; Sellers et al. 2015b). We are able to determine the influence of the tumor microenvironment using these models. We have now extended the range of models to fresh human tissue slices, similar to those originally described by O. Warburg (Warburg 1923), which retain the native tissue architecture and heterogeneity with a paired benign versus cancer design under defined cell culture conditions. This platform offers an unprecedented human tissue model for preclinical studies on metabolic reprogramming of human cancer cells in their tissue context, and response to drug treatment (Xie et al. 2014a). As the microenvironment of the target human tissue is retained and individual patient's response to drugs is obtained, this platform promises to transcend current limitations of drug selection for clinical trials or treatments. CONCLUSIONS AND FUTURE WORK: Development of ex vivo human tissue and animal models with humanized organs including bone marrow and liver show considerable promise for analyzing drug responses that are more relevant to humans. Similarly using stable isotope tracer methods with these improved models in advanced stages of the drug development pipeline, in conjunction with tissue biopsy is expected significantly to reduce the high failure rate of experimental drugs in Phase II and III clinical trials. PMID- 27489533 TI - Partial Conservation between Mice and Humans in Olfactory Bulb Interneuron Transcription Factor Codes. AB - The mammalian main olfactory bulb (OB) has a large population of GABAergic inhibitory interneurons that contains several subtypes defined by the co expression other neurotransmitters and calcium binding proteins. The three most commonly studied OB interneuron subtypes co-express either Calretinin, Calbindin, or Tyrosine hydroxylase (Th). Combinations of transcription factors used to specify the phenotype of progenitors are referred to as transcription factor codes, and the current understanding of transcription factor codes that specify OB inhibitory neuron phenotypes are largely based on studies in mice. The conservation of these transcription factor codes in the human OB, however, has not been investigated. The aim of this study was to establish whether transcription factor codes in OB interneurons are conserved between mice and humans. This study compared the co-expression of Foxp2, Meis2, Pax6, and Sp8 transcription factors with Calretinin, Calbindin, or Th in human and mouse OB interneurons. This analysis found strong conservation of Calretinin co-expression with Sp8 and Meis2 as well as Th co-expression with Pax6 and Meis2. This analysis also showed that selective Foxp2 co-expression with Calbindin was conserved between mice and humans, which suggests Foxp2 is a novel determinant of the OB Calbindin interneuron phenotype. Together, the findings in this study provide insight into the conservation of transcription codes for OB interneuron phenotypes between humans and mice, as well as reveal some important differences between the species. This advance in our understanding of transcription factor codes in OB interneurons provides an important complement to the codes that have been established for other regions within the mammalian central nervous system, such as the cortex and spinal cord. PMID- 27489534 TI - Salivary Stress-Related Responses in Tinnitus: A Preliminary Study in Young Male Subjects with Tinnitus. AB - OBJECTIVE: This preliminary study examined if baseline measures of stress-related biomarkers as measured by salivary secretions of specific autonomic [measured by salivary alpha-amylase (sAA)], endocrine (measured by salivary cortisol), and immune (measured by salivary neopterin) responses are greater in male subjects with tinnitus in response to an induced-stress task. METHOD: Twenty male subjects with no significant hearing loss, 10 with tinnitus, and 10 without tinnitus were enrolled in this study.Salivary secretions were collected before and after the induced stress task at four different time intervals. RESULTS: sAA levels were lower in the tinnitus group in comparison to subjects without tinnitus, suggesting impaired sympathetic activity in the subjects with tinnitus although these levels remained stable throughout the stress experiment.While no significant effects could be obtained for salivary cortisol or neopterin, salivary neopterin levels were trending toward significance over all measurements. Behavioral measures of stress were found to correlate negatively with measures of sAA and salivary neopterin. CONCLUSION: The results of this study suggest impaired stress-related sAA mechanisms in male subjects with tinnitus, as evidenced by the different stress reactions induced in the endocrine system (as measured by salivary cortisol) and the immune system (as measured by salivary neopterin). PMID- 27489535 TI - Learning and Memory Deficits in Male Adult Mice Treated with a Benzodiazepine Sleep-Inducing Drug during the Juvenile Period. AB - Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, is also known to be important for brain development. Therefore, disturbances of GABA receptor (GABA-R) mediated signaling (GABA-R signal) during brain development may influence normal brain maturation and cause late-onset brain malfunctions. In this study, we examined whether the stimulation of the GABA-R signal during brain development induces late-onset adverse effects on the brain in adult male mice. To stimulate the GABA-R signal, we used either the benzodiazepine sleep-inducing drug triazolam (TZ) or the non benzodiazepine drug zolpidem (ZP). We detected learning and memory deficits in mice treated with TZ during the juvenile period, as seen in the fear conditioning test. On the other hand, ZP administration during the juvenile period had little effect. In addition, decreased protein expression of GluR1 and GluR4, which are excitatory neurotransmitter receptors, was detected in the hippocampi of mice treated with TZ during the juvenile period. We measured mRNA expression of the immediate early genes (IEGs), which are neuronal activity markers, in the hippocampus shortly after the administration of TZ or ZP to juvenile mice. Decreased IEG expression was detected in mice with juvenile TZ administration, but not in mice with juvenile ZP administration. Our findings demonstrate that TZ administration during the juvenile period can induce irreversible learning and memory deficits in adult mice. It may need to take an extra care for the prescription of benzodiazepine sleep-inducing drugs to juveniles because it might cause learning and memory deficits. PMID- 27489536 TI - Neural Activation during Anticipation of Near Pain-Threshold Stimulation among the Pain-Fearful. AB - Fear of pain (FOP) can increase risk for chronic pain and disability but little is known about corresponding neural responses in anticipation of potential pain. In this study, more (10 women, 6 men) and less (7 women, 6 men) pain-fearful groups underwent whole-brain functional magnetic resonance imaging (fMRI) during anticipation of near pain-threshold stimulation. Groups did not differ in the proportion of stimuli judged to be painful but pain-fearful participants reported significantly more state fear prior to stimulus exposure. Within the entire sample, stronger activation was found in several pain perception regions (e.g., bilateral insula, midcingulate cortex (MCC), thalamus, superior frontal gyrus) and visual areas linked to decoding stimulus valences (inferior orbital cortex) during anticipation of "painful" stimuli. Between groups and correlation analyses indicated pain-fearful participants experienced comparatively more activity in regions implicated in evaluating potential threats and processing negative emotions during anticipation (i.e., MCC, mid occipital cortex, superior temporal pole), though group differences were not apparent in most so-called "pain matrix" regions. In sum, trait- and task-based FOP is associated with enhanced responsiveness in regions involved in threat processing and negative affect during anticipation of potentially painful stimulation. PMID- 27489537 TI - What Does Cytochrome Oxidase Histochemistry Represent in the Visual Cortex? PMID- 27489538 TI - Knockout of Cyclophilin-D Provides Partial Amelioration of Intrinsic and Synaptic Properties Altered by Mild Traumatic Brain Injury. AB - Mitochondria are central to cell survival and Ca(2+) homeostasis due to their intracellular buffering capabilities. Mitochondrial dysfunction resulting in mitochondrial permeability transition pore (mPTP) opening has been reported after mild traumatic brain injury (mTBI). Cyclosporine A provides protection against the mPTP opening through its interaction with cyclophilin-D (CypD). A recent study has found that the extent of axonal injury after mTBI was diminished in neocortex in cyclophilin-D knockout (CypDKO) mice. Here we tested whether this CypDKO could also provide protection from the increased intrinsic and synaptic neuronal excitability previously described after mTBI in a mild central fluid percussion injury mice model. CypDKO mice were crossed with mice expressing yellow fluorescent protein (YFP) in layer V pyramidal neurons in neocortex to create CypDKO/YFP-H mice. Whole cell patch clamp recordings from axotomized (AX) and intact (IN) YFP+ layer V pyramidal neurons were made 1 and 2 days after sham or mTBI in slices from CypDKO/YFP-H mice. Both excitatory post synaptic currents (EPSCs) recorded in voltage clamp and intrinsic cellular properties, including action potential (AP), afterhyperpolarization (AHP), and depolarizing after potential (DAP) characteristics recorded in current clamp were evaluated. There was no significant difference between sham and mTBI for either spontaneous or miniature EPSC frequency, suggesting that CypDKO ameliorates excitatory synaptic abnormalities. There was a partial amelioration of intrinsic properties altered by mTBI. Alleviated were the increased slope of the AP frequency vs. injected current plot, the increased AP, AHP and DAP amplitudes. Other properties that saw a reversal that became significant in the opposite direction include the current rheobase and AP overshoot. The AP threshold remained depolarized and the input resistance remained increased in mTBI compared to sham. Additional altered properties suggest that the CypDKO likely has a direct effect on membrane properties, rather than producing a selective reduction of the effects of mTBI. These results suggest that inhibiting CypD after TBI is an effective strategy to reduce synaptic hyperexcitation, making it a continued target for potential treatment of network abnormalities. PMID- 27489539 TI - Role of Astroglial Hemichannels and Pannexons in Memory and Neurodegenerative Diseases. AB - Under physiological conditions, astroglial hemichannels and pannexons allow the release of gliotransmitters from astrocytes. These gliotransmitters are critical in modulating synaptic transmission, plasticity and memory. However, recent evidence suggests that under pathological conditions, they may be central in the development of various neurodegenerative diseases. Here we review current literature on the role of astroglial hemichannels and pannexons in memory, stress and the development of neurodegenerative diseases, and propose that they are not only crucial for normal brain function, including memory, but also a potential target for the treatment of neurodegenerative diseases. PMID- 27489540 TI - Adolescent Social Defeat Induced Alterations in Social Behavior and Cognitive Flexibility in Adult Mice: Effects of Developmental Stage and Social Condition. AB - Negative social experiences during adolescence increase the risk of psychiatric disorders in adulthood. Using "resident-intruder" stress, the present study aimed to investigate the effects of adolescent social defeat on emotional and cognitive symptoms associated with psychiatric disorders during adulthood and the effects of the developmental stage and social condition on this process. In Experiment 1, animals were exposed to social defeat or manipulation for 10 days during early adolescence (EA, postnatal days [PND] 28-37), late adolescence (LA, PND 38-47), and adulthood (ADULT, PND 70-79) and then singly housed until the behavioral tests. Behaviors, including social avoidance of the defeat context and cortically mediated cognitive flexibility in an attentional set-shifting task (AST), were assessed during the week following stress or after 6 weeks during adulthood. We determined that social defeat induced significant and continuous social avoidance across age groups at both time points. The mice that experienced social defeat during adulthood exhibited short-term impairments in reversal learning (RL) on the AST that dissipated after 6 weeks. In contrast, social defeat during EA but not LA induced a delayed deficit in extra-dimensional set-shifting (EDS) in adulthood but not during adolescence. In Experiment 2, we further examined the effects of social condition (isolation or social housing after stress) on the alterations induced by social defeat during EA in adult mice. The adult mice that had experienced stress during EA exhibited social avoidance similar to the avoidance identified in Experiment 1 regardless of the isolation or social housing after the stress. However, social housing after the stress ameliorated the cognitive flexibility deficits induced by early adolescent social defeat in the adult mice, and the social condition had no effect on cognitive function. These findings suggest that the effects of social defeat on emotion and cognitive function are differentially affected by the developmental stage and social condition. EA may comprise a particularly sensitive developmental period in which social defeat may produce a delayed impairment in cognitive flexibility during adulthood, and the social condition following stress appears to play an important intermediary role in the development of these cognitive deficits. PMID- 27489541 TI - Emotion Discrimination Using Spatially Compact Regions of Interest Extracted from Imaging EEG Activity. AB - Lately, research on computational models of emotion had been getting much attention due to their potential for understanding the mechanisms of emotions and their promising broad range of applications that potentially bridge the gap between human and machine interactions. We propose a new method for emotion classification that relies on features extracted from those active brain areas that are most likely related to emotions. To this end, we carry out the selection of spatially compact regions of interest that are computed using the brain neural activity reconstructed from Electroencephalography data. Throughout this study, we consider three representative feature extraction methods widely applied to emotion detection tasks, including Power spectral density, Wavelet, and Hjorth parameters. Further feature selection is carried out using principal component analysis. For validation purpose, these features are used to feed a support vector machine classifier that is trained under the leave-one-out cross validation strategy. Obtained results on real affective data show that incorporation of the proposed training method in combination with the enhanced spatial resolution provided by the source estimation allows improving the performed accuracy of discrimination in most of the considered emotions, namely: dominance, valence, and liking. PMID- 27489542 TI - Successful Multidisciplinary Treatment with Secondary Metastatic Liver Resection after Downsizing by Palliative Second-Line Treatment of Colorectal Cancer: A Curative Option. AB - INTRODUCTION: The prognostic outcome following progression after palliative first line treatment for patients suffering from metastatic colorectal adenocarcinoma is generally poor. Long-term relapse-free survival with palliative second-line treatment may be achieved in only a limited number of individual cases. CASE REPORT: A 37-year-old patient presented with bilobar liver metastases of colon cancer confirmed by histology with wild-type K-RAS (exon 2). Due to progressive disease after eight cycles of first-line therapy with FOLFIRI plus cetuximab, second-line chemotherapy with modified FOLFOX4 (mFOLFOX4) plus bevacizumab was initiated. During four cycles of mFOLFOX4 plus bevacizumab (2 months), no higher grade toxicity occurred. Liver MRI with contrast medium revealed downsizing of the segment II/III metastases, as well as regressive, small, faint, hardly definable lesions in segments VI and IVb. The interdisciplinary tumor board of the University of Erlangen thus decided to perform resection of the liver metastases. Segments II and III were resected, and the liver metastases in segments IVa and VI were excised (R0). Histopathology confirmed three of the R0 resected metastases to be completely necrotic, with residual scarring. As perioperative therapy, four additional cycles of mFOLFOX4 plus bevacizumab were administered postoperatively. No higher-grade toxicity was observed. Three years after the initial diagnosis, the patient is relapse free, professionally fully reintegrated, and has an excellent performance status. CONCLUSION: Patients suffering from metastatic colorectal cancer may benefit from multidisciplinary treatment with secondary metastatic liver resection after downsizing by palliative second-line treatment. In individual cases, patients may even have a curative treatment option, provided that close interdisciplinary collaboration exists. PMID- 27489544 TI - Prescription Factors Associated with Medication Non-adherence in Japan Assessed from Leftover Drugs in the SETSUYAKU-BAG Campaign: Focus on Oral Antidiabetic Drugs. AB - BACKGROUND: Medication adherence has an important influence on health outcomes in patients with chronic diseases. However, few studies have been performed in Japan to determine factors related to medication non-adherence. OBJECTIVE: The aim of this study was to identify prescription factors related to medication non adherence by investigating patient characteristics, all prescriptions, and prescriptions for oral antidiabetic drugs (OADs). METHODS: A retrospective cross sectional survey of prescription data about implementation of dosing regimen was performed at community pharmacies engaged in appropriate use of leftover drugs. We evaluated the amount of drugs originally prescribed and the reduced amount after use of leftover drugs, and then calculated prescription reduction ratio (PRR). We analyzed prescription factors contributing to non-adherence based on the PRR. RESULTS: Prescription information for 1207 patients was reviewed, revealing that patients were non-adherent to 58% of prescriptions. Lack of a drug copayment, fewer concurrent drugs, and drugs not in single-dose packaging were associated with non-adherence. Among the 1207 patients, 234 prescriptions for diabetes and 452 OAD formulations were included. Forty-seven percent of prescriptions and 29% of the formulations were non-adherent. A higher dosing frequency and preprandial administration were associated with non-adherence. Among the OADs, adherence was lower for alpha-glucosidase inhibitors and biguanides than for sulfonylureas. CONCLUSIONS: Several factors related to patient characteristics, general drug prescriptions, and OAD prescriptions were associated with non-adherence. Further consideration will be needed to improve adherence to medication in Japan. Health care providers should perform more careful monitoring of adherence in patients with the factors identified by this study. PMID- 27489543 TI - False Recognition in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease-Disinhibition or Amnesia? AB - Episodic memory recall processes in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) can be similarly impaired, whereas recognition performance is more variable. A potential reason for this variability could be false-positive errors made on recognition trials and whether these errors are due to amnesia per se or a general over-endorsement of recognition items regardless of memory. The current study addressed this issue by analysing recognition performance on the Rey Auditory Verbal Learning Test (RAVLT) in 39 bvFTD, 77 AD and 61 control participants from two centers (India, Australia), as well as disinhibition assessed using the Hayling test. Whereas both AD and bvFTD patients were comparably impaired on delayed recall, bvFTD patients showed intact recognition performance in terms of the number of correct hits. However, both patient groups endorsed significantly more false-positives than controls, and bvFTD and AD patients scored equally poorly on a sensitivity index (correct hits false-positives). Furthermore, measures of disinhibition were significantly associated with false positives in both groups, with a stronger relationship with false-positives in bvFTD. Voxel-based morphometry analyses revealed similar neural correlates of false positive endorsement across bvFTD and AD, with both patient groups showing involvement of prefrontal and Papez circuitry regions, such as medial temporal and thalamic regions, and a DTI analysis detected an emerging but non-significant trend between false positives and decreased fornix integrity in bvFTD only. These findings suggest that false-positive errors on recognition tests relate to similar mechanisms in bvFTD and AD, reflecting deficits in episodic memory processes and disinhibition. These findings highlight that current memory tests are not sufficient to accurately distinguish between bvFTD and AD patients. PMID- 27489546 TI - Corrigendum: Transient Hepatic Overexpression of Insulin-Like Growth Factor 2 Induces Free Cholesterol and Lipid Droplet Formation. AB - [This corrects the article on p. 147 in vol. 7, PMID: 27199763.]. PMID- 27489545 TI - Asthma and Rhinitis Induced by Selective Immediate Reactions to Paracetamol and Non-steroidal Anti-inflammatory Drugs in Aspirin Tolerant Subjects. AB - In subjects with non-steroidal anti-inflammatory drugs (NSAIDs)- exacerbated respiratory disease (NERD) symptoms are triggered by acetyl salicylic acid (ASA) and other strong COX-1 inhibitors, and in some cases by weak COX-1 or by selective COX-2 inhibitors. The mechanism involved is related to prostaglandin pathway inhibition and leukotriene release. Subjects who react to a single NSAID and tolerate others are considered selective responders, and often present urticaria and/or angioedema and anaphylaxis (SNIUAA). An immunological mechanism is implicated in these reactions. However, anecdotal evidence suggests that selective responders who present respiratory airway symptoms may also exist. Our objective was to determine if subjects might develop selective responses to NSAIDs/paracetamol that manifest as upper/lower airways respiratory symptoms. For this purpose, we studied patients reporting asthma and/or rhinitis induced by paracetamol or a single NSAID that tolerated ASA. An allergological evaluation plus controlled challenge with ASA was carried out. If ASA tolerance was found, we proceeded with an oral challenge with the culprit drug. The appearance of symptoms was monitored by a clinical questionnaire and by measuring FEV1 and/or nasal airways volume changes pre and post challenge. From a total of 21 initial cases, we confirmed the appearance of nasal and/or bronchial manifestations in ten, characterized by a significant decrease in FEV1% and/or a decrease in nasal volume cavity after drug administration. All cases tolerated ASA. This shows that ASA tolerant subjects with asthma and/or rhinitis induced by paracetamol or a single NSAID without skin/systemic manifestations exist. Whether these patients represent a new clinical phenotype to be included within the current classification of hypersensitivity reactions to NSAIDs requires further investigation. PMID- 27489548 TI - Corrigendum: Detecting Deception within Small Groups: A Literature Review. AB - [This corrects the article on p. 1012 in vol. 7, PMID: 27445957.]. PMID- 27489547 TI - Mirror Neurons System Engagement in Late Adolescents and Adults While Viewing Emotional Gestures. AB - Observing others' actions enhances muscle-specific cortico-spinal excitability, reflecting putative mirror neurons activity. The exposure to emotional stimuli also modulates cortico-spinal excitability. We investigated how those two phenomena might interact when they are combined, i.e., while observing a gesture performed with an emotion, and whether they change during the transition between adolescence and adulthood, a period of social and brain maturation. We delivered single-pulse transcranial magnetic stimulation (TMS) over the hand area of the left primary motor cortex of 27 healthy adults and adolescents and recorded their right first dorsal interossus (FDI) muscle activity (i.e., motor evoked potential - MEP), while they viewed either videos of neutral or angry hand actions and facial expressions, or neutral objects as a control condition. We reproduced the motor resonance and the emotion effects - hand-actions and emotional stimuli induced greater cortico-spinal excitability than the faces/control condition and neutral videos, respectively. Moreover, the influence of emotion was present for faces but not for hand actions, indicating that the motor resonance and the emotion effects might be non-additive. While motor resonance was observed in both groups, the emotion effect was present only in adults and not in adolescents. We discuss the possible neural bases of these findings. PMID- 27489549 TI - Role of ACTH in the Interactive/Paracrine Regulation of Adrenal Steroid Secretion in Physiological and Pathophysiological Conditions. AB - In the normal human adrenal gland, steroid secretion is regulated by a complex network of autocrine/paracrine interactions involving bioactive signals released by endothelial cells, nerve terminals, chromaffin cells, immunocompetent cells, and adrenocortical cells themselves. ACTH can be locally produced by medullary chromaffin cells and is, therefore, a major mediator of the corticomedullary functional interplay. Plasma ACTH also triggers the release of angiogenic and vasoactive agents from adrenocortical cells and adrenal mast cells and, thus, indirectly regulates steroid production through modulation of the adrenal blood flow. Adrenocortical neoplasms associated with steroid hypersecretion exhibit molecular and cellular defects that tend to reinforce the influence of paracrine regulatory loops on corticosteroidogenesis. Especially, ACTH has been found to be abnormally synthesized in bilateral macronodular adrenal hyperplasia responsible for hypercortisolism. In these tissues, ACTH is detected in a subpopulation of adrenocortical cells that express gonadal markers. This observation suggests that ectopic production of ACTH may result from impaired embryogenesis leading to abnormal maturation of the adrenogonadal primordium. Globally, the current literature indicates that ACTH is a major player in the autocrine/paracrine processes occurring in the adrenal gland in both physiological and pathological conditions. PMID- 27489550 TI - Genetic Dissection of the Regulatory Network Associated with High c-di-GMP Levels in Pseudomonas putida KT2440. AB - Most bacteria grow in nature forming multicellular structures named biofilms. The bacterial second messenger cyclic diguanosine monophosphate (c-di-GMP) is a key player in the regulation of the transition from planktonic to sessile lifestyles and this regulation is crucial in the development of biofilms. In Pseudomonas putida KT2440, Rup4959, a multidomain response regulator with diguanylate cyclase activity, when overexpressed causes an increment in the intracellular levels of c di-GMP that gives rise to a pleiotropic phenotype consisting of increased biofilm formation and crinkly colony morphology. In a broad genomic screen we have isolated mutant derivatives that lose the crinkly morphology, designed as cfc (crinkle free colony). A total of 19 different genes have been identified as being related with the emergence of the cfc phenotype either because the expression or functionality of Rup4959 is compromised, or due to a lack of transduction of the c-di-GMP signal to downstream elements involved in the acquisition of the phenotype. Discernment between these possibilities was investigated by using a c-di-GMP biosensor and by HPLC-MS quantification of the second messenger. Interestingly five of the identified genes encode proteins with AAA+ ATPase domain. Among the bacterial determinants found in this screen are the global transcriptional regulators GacA, AlgU and FleQ and two enzymes involved in the arginine biosynthesis pathway. We present evidences that this pathway seems to be an important element to both the availability of the free pool of the second messenger c-di-GMP and to its further transduction as a signal for biosynthesis of biopolimers. In addition we have identified an uncharacterized hybrid sensor histidine kinase whose phosphoaceptor conserved histidine residue has been shown in this work to be required for in vivo activation of the orphan response regulator Rup4959, which suggests these two elements constitute a two component phosphorelay system. PMID- 27489551 TI - Environmental Conditions Outweigh Geographical Contiguity in Determining the Similarity of nifH-Harboring Microbial Communities in Sediments of Two Disconnected Marginal Seas. AB - Ecological evidence suggests that heterotrophic diazotrophs fueled by organic carbon respiration in sediments play an important role in marine nitrogen fixation. However, fundamental knowledge about the identities, abundance, diversity, biogeography, and controlling environmental factors of nitrogen-fixing communities in open ocean sediments is still elusive. Surprisingly, little is known also about nitrogen-fixing communities in sediments of the more research accessible marginal seas. Here we report on an investigation of the environmental geochemistry and putative diazotrophic microbiota in the sediments of Bohai Sea, an eutrophic marginal sea of the western Pacific Ocean. Diverse and abundant nifH gene sequences were identified and sulfate-reducing bacteria (SRB) were found to be the dominant putative nitrogen-fixing microbes. Community statistical analyses suggested bottom water temperature, bottom water chlorophyll a content (or the covarying turbidity) and sediment porewater Eh (or the covarying pH) as the most significant environmental factors controlling the structure and spatial distribution of the putative diazotrophic communities, while sediment Hg content, sulfide content, and porewater [Formula: see text]-Si content were identified as the key environmental factors correlated positively with the nifH gene abundance in Bohai Sea sediments. Comparative analyses between the Bohai Sea and the northern South China Sea (nSCS) identified a significant composition difference of the putative diazotrophic communities in sediments between the shallow-water (estuarine and nearshore) and deep-water (offshore and deep-sea) environments, and sediment porewater dissolved oxygen content, water depth and in situ temperature as the key environmental factors tentatively controlling the species composition, community structure, and spatial distribution of the marginal sea sediment nifH-harboring microbiota. This confirms the ecophysiological specialization and niche differentiation between the shallow-water and deep-water sediment diazotrophic communities and suggests that the in situ physical and geochemical conditions play a more important role than geographical contiguity in determining the community similarity of the diazotrophic microbiota in marginal sea sediments. PMID- 27489552 TI - Cytochrome c as a Potentially Clinical Useful Marker of Mitochondrial and Cellular Damage. AB - Mitochondria are evolutionary endosymbionts derived from bacteria. Thus, they bear molecules, such as mitochondrial DNA (mtDNA) that contains CpG DNA repeats and N-formyl peptides (FPs), found in bacteria. Upon cell necrosis or apoptosis, these molecules are released into the interstitial space and the circulation and recognized by the immune cells through the same receptors that recognize pathogen associated molecular patterns, leading to inflammation. Other mitochondrial molecules are not of bacterial origin, but they may serve as danger-associated molecular patterns (DAMPs) when due to cell injury are translocated into inappropriate compartments. There they are recognized by pattern recognition receptors of the immune cells. Cytochrome c is such a molecule. In this review, experimental and clinical data are presented that confirms cytochrome c release into the extracellular space in pathological conditions characterized by cell death. This indicates that serum cytochrome c, which can be easily measured, may be a clinically useful marker for diagnosing and assessing the severity of such pathological entities. Reasonably, detection of high cytochrome c level into the circulation means release of various other molecules that serves as DAMPs when found extracellularly, the mtDNA and FPs included. Finally, because the release of this universally found compound into the extracellular space makes cytochrome c an ideal molecule to play the role of a DAMP per se, the available experimental and clinical data that support such a role are provided. PMID- 27489553 TI - Increased Needle Nitrogen Contents Did Not Improve Shoot Photosynthetic Performance of Mature Nitrogen-Poor Scots Pine Trees. AB - Numerous studies have shown that temperate and boreal forests are limited by nitrogen (N) availability. However, few studies have provided a detailed account of how carbon (C) acquisition of such forests reacts to increasing N supply. We combined measurements of needle-scale biochemical photosynthetic capacities and continuous observations of shoot-scale photosynthetic performance from several canopy positions with simple mechanistic modeling to evaluate the photosynthetic responses of mature N-poor boreal Pinus sylvestris to N fertilization. The measurements were carried out in August 2013 on 90-year-old pine trees growing at Rosinedalsheden research site in northern Sweden. In spite of a nearly doubling of needle N content in response to the fertilization, no effect on the long-term shoot-scale C uptake was recorded. This lack of N-effect was due to strong light limitation of photosynthesis in all investigated canopy positions. The effect of greater N availability on needle photosynthetic capacities was also constrained by development of foliar phosphorus (P) deficiency following N addition. Thus, P deficiency and accumulation of N in arginine appeared to contribute toward lower shoot-scale nitrogen-use efficiency in the fertilized trees, thereby additionally constraining tree-scale responses to increasing N availability. On the whole our study suggests that the C uptake response of the studied N-poor boreal P. sylvestris stand to enhanced N availability is constrained by the efficiency with which the additional N is utilized. This efficiency, in turn, depends on the ability of the trees to use the greater N availability for additional light capture. For stands that have not reached canopy closure, increase in leaf area following N fertilization would be the most effective way for improving light capture and C uptake while for mature stands an increased leaf area may have a rather limited effect on light capture owing to increased self-shading. This raises the question if N limitation in boreal forests acts primarily by constraining growth of young stands while the commonly recorded increase in stem growth of mature stands following N addition is primarily the result of altered allocation and only to a limited extent the result of increased stand C-capture. PMID- 27489554 TI - Nutritional and Sensory Evaluation of Injera Prepared from tef and Eragrostis curvula (Schrad.) Nees. Flours with Sorghum Blends. AB - Injera is a fermented, sour bread consumed as a staple food in Eritrea and Ethiopia. The bread can be prepared from various cereals but tef [Eragrostis tef (Zucc.) Trotter] is the most preferred ingredient. This study assessed the acceptability of injera prepared using grains of a closely related but underutilized grass, Eragrostis curvula (Schrad.) Nees. The nutritive value of the grains was compared and the sensory attributes of injera made from flours of tef (control) and E. curvula, each combined with 0, 5, and 10% of sorghum flour, were assessed using a tasting panel. Nutrient analysis showed that E. curvula contains more than double the amount of crude protein found in tef. E. curvula also contains higher fat, dietary fiber and mineral nutrients than tef. Injera made of E. tef and E. curvula flours showed non-significant differences in taste, texture, appearance and overall acceptability. This suggest that E. curvula has the potential to serve as a novel source of gluten-free flour for human consumption. Agronomically viewed, growing E. curvula could be more advantageous for smallholder farmers on marginal lands because the species is a perennial that can produce a seed harvest twice a year, unlike tef, which is annual crop. It also tolerates acidic soils better than tef. PMID- 27489555 TI - Mutation of Gly195 of the ChlH Subunit of Mg-chelatase Reduces Chlorophyll and Further Disrupts PS II Assembly in a Ycf48-Deficient Strain of Synechocystis sp. PCC 6803. AB - Biogenesis of the photosystems in oxygenic phototrophs requires co-translational insertion of chlorophyll a. The first committed step of chlorophyll a biosynthesis is the insertion of a Mg(2+) ion into the tetrapyrrole intermediate protoporphyrin IX, catalyzed by Mg-chelatase. We have identified a Synechocystis sp. PCC 6803 strain with a spontaneous mutation in chlH that results in a Gly195 to Glu substitution in a conserved region of the catalytic subunit of Mg chelatase. Mutant strains containing the ChlH Gly195 to Glu mutation were generated using a two-step protocol that introduced the chlH gene into a putative neutral site in the chromosome prior to deletion of the native gene. The Gly195 to Glu mutation resulted in strains with decreased chlorophyll a. Deletion of the PS II assembly factor Ycf48 in a strain carrying the ChlH Gly195 to Glu mutation did not grow photoautotrophically. In addition, the ChlH-G195E:DeltaYcf48 strain showed impaired PS II activity and decreased assembly of PS II centers in comparison to a DeltaYcf48 strain. We suggest decreased chlorophyll in the ChlH G195E mutant provides a background to screen for the role of assembly factors that are not essential under optimal growth conditions. PMID- 27489556 TI - Alternative Growth and Defensive Strategies Reveal Potential and Gender Specific Trade-Offs in Dioecious Plants Salix paraplesia to Nutrient Availability. AB - Population sex ratios of many dioecious plants in nature are biased. This may be attributed to sexually different resource demands and adaptive capacity. In male biasedPopulus, males often display stronger physiological adaptation than females. Interestingly, Populus and Salix, belonging to Salicaceae, display an opposite biased sex ratio, especially in nutrient-poor environmental conditions. Do female willows have a greater tolerance to nutrient deficiency than males? In this study, we investigated the growth and defensive strategies of Salix paraplesia cuttings, which were grown with high and low soil fertility for about 140 days over one growing season. Results suggest that different strategies for biomass allocation may result in sexually different defense capacities and trade offs between growth and defense. Females are likely to adopt radical strategies, overdrawing on available resources to satisfy both growth and defense, which seems to be more like a gamble compared with males. It is also suggested that females may have an extra mechanism to compensate for the investment in growth under nutrient-poor conditions. In summary, the results may help focus restoration efforts on sex selection such that a moderate increase in female willow quantity could increase the resistance and resilience of willow populations to early sporadic desertification. PMID- 27489557 TI - Altered Superficial White Matter on Tractography MRI in Alzheimer's Disease. AB - BACKGROUND/AIMS: Superficial white matter provides extensive cortico-cortical connections. This tractography study aimed to assess the diffusion characteristics of superficial white matter tracts in Alzheimer's disease. METHODS: Diffusion tensor 3T magnetic resonance imaging scans were acquired in 24 controls and 16 participants with Alzheimer's disease. Neuropsychological test scores were available in some participants. Tractography was performed by the Fiber Assignment by Continuous Tracking (FACT) method. The superficial white matter was manually segmented and divided into frontal, parietal, temporal and occipital lobes. The mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AxD) and fractional anisotropy (FA) of these tracts were compared between controls and participants with Alzheimer's disease and correlated with available cognitive tests while adjusting for age and white matter hyperintensity volume. RESULTS: Alzheimer's disease was associated with increased MD (p = 0.0011), increased RD (p = 0.0019) and increased AxD (p = 0.0017) in temporal superficial white matter. In controls, superficial white matter was associated with the performance on the Montreal Cognitive Assessment, Stroop and Trail Making Test B tests, whereas in Alzheimer's disease patients, it was not associated with the performance on cognitive tests. CONCLUSION: Temporal lobe superficial white matter appears to be disrupted in Alzheimer's disease. PMID- 27489558 TI - Does MRI Increase the Diagnostic Confidence of Physicians in an Outpatient Memory Clinic. AB - BACKGROUND AND AIM: Data showing the usefulness of MRI to improve the accuracy of the diagnostic process in cognitive disorders were derived from studies in tertiary referral centers. MRI is widely used as a diagnostic tool in everyday practice, but it is unknown what the actual added value of MRI is. We studied the usefulness of MRI in the diagnostic process by measuring the change of confidence of the physician. METHODS: Physicians indicated confidence in their diagnosis before and after presentation of MR images using a visual analogue scale from 0 100%. RESULTS: Use of MRI increased the level of confidence by 3% in experienced clinicians and by 9% in inexperienced physicians. In 2/125 cases, MRI showed an unexpected finding. CONCLUSION: MRI is a useful diagnostic tool in everyday practice of diagnosing cognitive disorders. PMID- 27489559 TI - Compensatory Postural Adjustments in an Oculus Virtual Reality Environment and the Risk of Falling in Alzheimer's Disease. AB - BACKGROUND/AIMS: Alzheimer's disease (AD) patients have an impaired ability to quickly reweight central sensory dependence in response to unexpected body perturbations. Herein, we aim to study provoked compensatory postural adjustments (CPAs) in a conflicting sensory paradigm with unpredictable visual displacements using virtual reality goggles. METHODS: We used kinematic time-frequency analyses of two frequency bands: a low-frequency band (LB; 0.3-1.5 Hz; mechanical strategy) and a high-frequency band (HB; 1.5-3.5 Hz; cognitive strategy). We enrolled 19 healthy subjects (controls) and 21 AD patients, divided according to their previous history of falls. RESULTS: The AD faller group presented higher power LB CPAs, reflecting their worse inherent postural stability. The AD patients had a time lag in their HB CPA reaction. CONCLUSION: The slower reaction by CPA in AD may be a reflection of different cognitive resources including body schema self-perception, visual motion, depth perception, or a different state of fear and/or anxiety. PMID- 27489560 TI - Creative Music Therapy in an Acute Care Setting for Older Patients with Delirium and Dementia. AB - BACKGROUND/AIMS: The acute hospital ward can be unfamiliar and stressful for older patients with impaired cognition, rendering them prone to agitation and resistive to care. Extant literature shows that music therapy can enhance engagement and mood, thereby ameliorating agitated behaviours. This pilot study evaluates the impact of a creative music therapy (CMT) programme on mood and engagement in older patients with delirium and/or dementia (PtDD) in an acute care setting. We hypothesize that CMT improves engagement and pleasure in these patients. METHODS: Twenty-five PtDD (age 86.5 +/- 5.7 years, MMSE 6/30 +/- 5.4) were observed for 90 min (30 min before, 30 min during, and 30 min after music therapy) on 3 consecutive days: day 1 (control condition without music) and days 2 and 3 (with CMT). Music interventions included music improvisation such as spontaneous music making and playing familiar songs of patient's choice. The main outcome measures were mood and engagement assessed with the Menorah Park Engagement Scale (MPES) and Observed Emotion Rating Scale (OERS). RESULTS: Wilcoxon signed-rank test showed a statistically significant positive change in constructive and passive engagement (Z = 3.383, p = 0.01) in MPES and pleasure and general alertness (Z = 3.188,p = 0.01) in OERS during CMT. The average pleasure ratings of days 2 and 3 were higher than those of day 1 (Z = 2.466, p = 0.014). Negative engagement (Z = 2.582, p = 0.01) and affect (Z = 2.004, p = 0.045) were both lower during CMT compared to no music. CONCLUSION: These results suggest that CMT holds much promise to improve mood and engagement of PtDD in an acute hospital setting. CMT can also be scheduled into the patients' daily routines or incorporated into other areas of care to increase patient compliance and cooperation. PMID- 27489561 TI - Determinants of exclusive breastfeeding practices among mothers in azezo district, northwest Ethiopia. AB - BACKGROUND: Exclusive breastfeeding (EBF) is a very important, long lasting and cost effective intervention to help reduce the morbidity and mortality of infants. However, a large proportion of infants are not exclusively breastfed as recommended by the World Health Organization. The study aim was to assess the exclusive breastfeeding practices and identify determinants among mothers in Azezo District, Ethiopia. METHODS: A community based cross-sectional study was conducted among 346 mothers with infants aged between 0-6 months. Data were collected using a pretested, interviewer administered questionnaire. Descriptive statistics and logistic regression analysis were used to describe the study objectives and identify the determinants of EBF in the previous 24 h. Associations between the study and outcome variables were described using odds ratios and 95 % confidence intervals (CI). RESULTS: Any breastfeeding and exclusive breastfeeding in the previous 24 h were 99 and 79 %, respectively. The mean number of exclusive breastfeeds in the 24 h period was 6.5. Exclusive breastfeeding rates were highest among mothers aged >= 30 years (Adjusted odds ratio [AOR] 1.75; 95 % CI 1.14, 3.42). Infants whose mothers were unemployed were more likely to be exclusively breastfed than infants whose mothers were employed (AOR 1.62; 95 % CI 1.03, 2.95). Mothers earning <= 1000 birr (US $47.62) monthly were 77 % less likely to practice EBF (AOR 0.23; 95 % CI 0.13, 0.44). Mothers who delivered at the healthcare facility practised more exclusive breastfeeding than those who delivered at home (AOR 2.18; 95 % CI 1.22, 4.35). Mothers who received antenatal and postnatal care had better rates of EBF (AOR 2.24; 95 % CI 1.18, 5.76 and AOR 1.62; 95 % CI 1.09, 3.21) and mothers not practicing prelacteal feeding were more likely to exclusively breastfeed compared with mothers practicing prelacteal feeding (AOR 2.16; 95 % CI 1.16, 4.06). CONCLUSIONS: Any breastfeeding and exclusive breastfeeding rates in the previous 24 h are relatively high in the study area compared with previous studies. Maternal factors (age, education, income, employment, antenatal care, prelacteal feeding), infants' age, delivery place and information access were independent predictors to EBF in previous 24 h. Improving the mother's knowledge, income, information access, nutritional counselling, quality of antenatal and postnatal care service, place of delivery and avoiding prelacteal feeding practices are important to improving the exclusive breastfeeding rate in the previous 24 h. PMID- 27489562 TI - First Report of Familial Juvenile Hyperuricemic Nephropathy (FJHN) in Iran Caused By a Novel De Novo Mutation (E197X) in UMOD. AB - Uromodulin (UMOD) gene mutation causes autosomal dominant Uromodulin-Associated Kidney Disease (UAKD), which in turn leads to end-stage renal disease. This is the first case report of a family with UAKD caused by a novel de novo mutation (E197X) in the UMOD gene. This case is a 28-year-old man with severely reduced kidney function [1]. No similar case was reported in his family history. This report highlights and reminds the importance of genetic screening in young patients involving kidney dysfunction, as the UAKD and some other kidney genetic diseases may be late-onset. PMID- 27489564 TI - Cancer of the vulva in Burkina Faso: a hospital-based case series. AB - BACKGROUND: Vulvar cancer is a rare gynaecological cancer. In Burkina Faso, the diagnosis of vulvar cancers is delayed and the prognosis is poor. However, no specific study on vulvar cancers has been conducted at the moment. This work aimed to study the characteristics of these cancers. METHODS: This is a prospective study on histologically confirmed primary cancers of the vulva diagnosed between 1st January 2013 and 30th June 2015. The demographic and clinical aspects were studied at the Yalgado Ouedraogo University Hospital of Ouagadougou (CHU-YO). RESULTS: We noticed 21 cases of vulvar cancers within 30 months, ranking it as the 4th most common gynaecological cancer. The average age of the patients was 55 years (standard deviation +/- 6.3) and the median age was 57 years. Scars resulting from female circumcision, menopause (n = 20) and HIV infection were noticed in 19 cases and 6 cases respectively. The average time from first symptoms to first consultation was 29 months. Pain and ulceration were the main reasons for consultation. The clinical picture was chiefly an ulcero granulating tumour. There was squamous cell carcinoma in 20 cases and basal carcinoma in 1 case. Fifteen patients were at stage III or IV, where of three patients had metastatic disease. We noticed vitiligo in 9 vulvar cancer cases. CONCLUSION: The cancer of the vulva is rare. Women are of menopausal age, are mostly circumcised and HIV-infection is common. A majority of patients sought consultation at advanced stage of disease, and diagnosis was belatedly made. Pain and ulceration were the main reasons for consultation. The sensitization of the population, education for self- examination would allow earlier diagnosis. PMID- 27489563 TI - An ABCD1 Mutation (c.253dupC) Caused Diverse Phenotypes of Adrenoleukodystrophy in an Iranian Consanguineous Pedigree. AB - OBJECTIVES: Current study was the first to report a consanguineous Iranian pedigree with ABCD1 mutation. METHODS: Targeted molecular analysis was initially performed in three affected individuals in one family suspected to have X-ALD due to chronic progressive spasticity. Upon confirmation of genetic diagnosis, further neurologic and genetic evaluation of all family members was done. RESULTS: A mutation in ABCD1 was identified in 35 affected individuals (out 96 pedigree members). The c. 253dup, in exon 1, leads to a frame shift and a premature stop codon at amino acid position 194 (p.Arg85Profs*110). Surprisingly, affected individuals in our cohort show some variability in phenotype, including childhood cerebral ALD, adrenomyeloneuropathy, and addison-only disease phenotypes, expanding the phenotype of X-ALD with p.Arg85Profs*110. CONCLUSION: This report characterizes the clinical spectrum of an expanded Iranian pedigree with X-ALD due to an ABCD1 mutation. Given a high frequency of carriers in this region, we expect the prevalence of X-ALD to be higher, underscoring the importance of genetic counseling through reliable identification of heterozygous as well as homozygote females in consanguineous communities. PMID- 27489565 TI - Mental health problems among conflict-affected adults in Grozny, Chechnya: a qualitative study. AB - BACKGROUND: A decade of conflict in Chechnya destroyed infrastructure and resulted in widespread exposure to violence. Amidst substantial reconstruction, periodic violence has contributed to an ongoing atmosphere of insecurity. We conducted a qualitative study to understand the mental health and psychosocial problems affecting adult Chechens in this context to inform development of assessment tools for an evaluation study related to individual counseling. METHODS: Data were collected in July 2014. A convenience sample of 59 Chechen adults was asked to Free List all problems affecting people in the area. Four problems were explored further in 19 Key Interviewee (KI) interviews, with respondents identified using snowball sampling. Data analysis was conducted in Russian by the Chechen interviewers. RESULTS: Multiple mental health and psychosocial problems emerged, including 'bad psychological health', 'depression', 'stress and nervous people', and 'problems in the family'. Aggression, 'emotional blowing', and 'not adequate' behavior were frequently reported indicators of these problems, with negative effects on the whole family. Chechens reported seeking help through informal social networks, psychiatric and psychological services, and Islamic Centers. CONCLUSION: Chechens reported mental health and psychosocial problems similar to those experienced in other post conflict settings. The description of 'emotional blowing' mirrored prior findings in Chechen asylum seekers and fits within a cluster of cultural concepts of distress featuring anger that has been identified in other conflict-affected populations. Further exploration of the nature and prevalence of this construct, as well as evaluations of interventions aimed at reducing these symptoms, is warranted. PMID- 27489566 TI - Sustainable bioenergy production with little carbon debt in the Loess Plateau of China. AB - BACKGROUND: As a key strategy for mitigating global climate change, bioenergy production by reducing CO2 emissions plays an important role in ensuring sustainable development. However, land-use change by converting natural ecosystems into energy crop field could create a carbon debt at the beginning. Thus, the potential carbon debt calculation is necessary for determining a promising bioenergy crop production, especially in the region rich of marginal land. RESULTS: Here, we used high-resolution historical land-use data to identify the marginal land available and to evaluate the carbon debt of planting Miscanthus in the Loess Plateau, China. We found that there were 27.6 Mha for energy production and 9.7 Mha for ecological restoration, with total annual production of 0.41 billion tons of biomass. We also found that soil carbon sequestration and total CO2 mitigation were 9.3 Mt C year(-1) and 542 Mt year( 1), respectively. More importantly, the result showed that planting Miscanthus on marginal land in the Loess Plateau only took 0.97 years on average to repay the carbon debt. CONCLUSIONS: Our study demonstrated that Miscanthus production in suitable marginal land in the Loess Plateau can offer considerable renewable energy and mitigate climate change with little carbon debt. These results suggested that bioenergy production in the similar arid and semiarid region worldwide would contribute to carbon sequestration in the context of rapid climate change. PMID- 27489567 TI - Multiple syntrophic interactions drive biohythane production from waste sludge in microbial electrolysis cells. AB - BACKGROUND: Biohythane is a new and high-value transportation fuel present as a mixture of biomethane and biohydrogen. It has been produced from different organic matters using anaerobic digestion. Bioenergy can be recovered from waste activated sludge through methane production during anaerobic digestion, but energy yield is often insufficient to sludge disposal. Microbial electrolysis cell (MEC) is also a promising approach for bioenergy recovery and waste sludge disposal as higher energy efficiency and biogas production. The systematic understanding of microbial interactions and biohythane production in MEC is still limited. Here, we report biohythane production from waste sludge in biocathode microbial electrolysis cells and reveal syntrophic interactions in microbial communities based on high-throughput sequencing and quantitative PCR targeting 16S rRNA gene. RESULTS: The alkali-pretreated sludge fed MECs (AS-MEC) showed the highest biohythane production rate of 0.148 L.L(-1)-reactor.day(-1), which is 40 and 80 % higher than raw sludge fed MECs (RS-MEC) and anaerobic digestion (open circuit MEC, RS-OCMEC). Current density, metabolite profiles, and hydrogen methane ratio results all confirm that alkali-pretreatment and microbial electrolysis greatly enhanced sludge hydrolysis and biohythane production. Illumina Miseq sequencing of 16S rRNA gene amplicons indicates that anode biofilm was dominated by exoelectrogenic Geobacter, fermentative bacteria and hydrogen producing bacteria in the AS-MEC. The cathode biofilm was dominated by fermentative Clostridium. The dominant archaeal populations on the cathodes of AS MEC and RS-MEC were affiliated with hydrogenotrophic Methanobacterium (98 %, relative abundance) and Methanocorpusculum (77 %), respectively. Multiple pathways of gas production were observed in the same MEC reactor, including fermentative and electrolytic H2 production, as well as hydrogenotrophic methanogenesis and electromethanogenesis. Real-time quantitative PCR analyses showed that higher amount of methanogens were enriched in AS-MEC than that in RS MEC and RS-OCMEC, suggesting that alkali-pretreated sludge and MEC facilitated hydrogenotrophic methanogen enrichment. CONCLUSION: This study proves for the first time that biohythane could be produced directly in biocathode MECs using waste sludge. MEC and alkali-pretreatment accelerated enrichment of hydrogenotrophic methanogen and hydrolysis of waste sludge. The results indicate syntrophic interactions among fermentative bacteria, exoelectrogenic bacteria and methanogenic archaea in MECs are critical for highly efficient conversion of complex organics into biohythane, demonstrating that MECs can be more competitive than conventional anaerobic digestion for biohythane production using carbohydrate-deficient substrates. Biohythane production from waste sludge by MEC provides a promising new way for practical application of microbial electrochemical technology. PMID- 27489568 TI - The ancestral chromosomes of Dromiciops gliroides (Microbiotheridae), and its bearings on the karyotypic evolution of American marsupials. AB - BACKGROUND: The low-numbered 14-chromosome karyotype of marsupials has falsified the fusion hypothesis claiming ancestrality from a 22-chromosome karyotype. Since the 14-chromosome condition of the relict Dromiciops gliroides is reminecent of ancestrality, its interstitial traces of past putative fusions and heterochromatin banding patterns were studied and added to available marsupials' cytogenetic data. Fluorescent in situ hybridization (FISH) and self-genomic in situ hybridization (self-GISH) were used to detect telomeric and repetitive sequences, respectively. These were complemented with C-, fluorescent banding, and centromere immunodetection over mitotic spreads. The presence of interstitial telomeric sequences (ITS) and diploid numbers were reconstructed and mapped onto the marsupial phylogenetic tree. RESULTS: No interstitial, fluorescent signals, but clearly stained telomeric regions were detected by FISH and self-GISH. Heterochromatin distribution was sparse in the telomeric/subtelomeric regions of large submetacentric chromosomes. Large AT-rich blocks were detected in the long arm of four submetacentrics and CG-rich block in the telomeric regions of all chromosomes. The ancestral reconstructions both ITS presence and diploid numbers suggested that ITS are unrelated to fusion events. CONCLUSION: Although the lack of interstitial signals in D. gliroides' karyotype does not prove absence of past fusions, our data suggests its non-rearranged plesiomorphic condition. PMID- 27489569 TI - Mango: combining and analyzing heterogeneous biological networks. AB - BACKGROUND: Heterogeneous biological data such as sequence matches, gene expression correlations, protein-protein interactions, and biochemical pathways can be merged and analyzed via graphs, or networks. Existing software for network analysis has limited scalability to large data sets or is only accessible to software developers as libraries. In addition, the polymorphic nature of the data sets requires a more standardized method for integration and exploration. RESULTS: Mango facilitates large network analyses with its Graph Exploration Language, automatic graph attribute handling, and real-time 3-dimensional visualization. On a personal computer Mango can load, merge, and analyze networks with millions of links and can connect to online databases to fetch and merge biological pathways. CONCLUSIONS: Mango is written in C++ and runs on Mac OS, Windows, and Linux. The stand-alone distributions, including the Graph Exploration Language integrated development environment, are freely available for download from http://www.complex.iastate.edu/download/Mango. The Mango User Guide listing all features can be found at http://www.gitbook.com/book/j23414/mango user-guide. PMID- 27489570 TI - Pinpointing the vesper bat transposon revolution using the Miniopterus natalensis genome. AB - BACKGROUND: Around 40 million years ago DNA transposons began accumulating in an ancestor of bats in the family Vespertilionidae. Since that time, Class II transposons have been continuously reinvading and accumulating in vespertilionid genomes at a rate that is unprecedented in mammals. Miniopterus (Miniopteridae), a genus of long-fingered bats that was recently elevated from Vespertilionidae, is the sister taxon to the vespertilionids and is often used as an outgroup when studying transposable elements in vesper bats. Previous wet-lab techniques failed to identify Helitrons, TcMariners, or hAT transposons in Miniopterus. Limitations of those methods and ambiguous results regarding the distribution of piggyBac transposons left some questions as to the distribution of Class II elements in this group. The recent release of the Miniopterus natalensis genome allows for transposable element discovery with a higher degree of precision. RESULTS: Here we analyze the transposable element content of M. natalensis to pinpoint with greater accuracy the taxonomic distribution of Class II transposable elements in bats. These efforts demonstrate that, compared to the vespertilionids, Class II TEs are highly mutated and comprise only a small portion of the M. natalensis genome. Despite the limited Class II content, M. natalensis possesses a limited number of lineage-specific, low copy number piggyBacs and shares several TcMariner families with vespertilionid bats. Multiple efforts to identify Helitrons, one of the major TE components of vesper bat genomes, using de novo repeat identification and structural based searches failed. CONCLUSIONS: These observations combined with previous results inform our understanding of the events leading to the unique Class II element acquisition that characterizes vespertilionids. While it appears that a small number of TcMariner and piggyBac elements were deposited in the ancestral Miniopterus + vespertilionid genome, these elements are not present in M. natalensis genome at high copy number. Instead, this work indicates that the vesper bats alone experienced the expansion of TEs ranging from Helitrons to piggyBacs to hATs. PMID- 27489571 TI - Hip dysplasia screening - epidemiological data from Valcea County. AB - RATIONALE: :In its most severe form, developmental dysplasia of the hip (DDH) is one of the most common congenital malformations. Uncorrected developmental dysplasia of the hip is associated with long-term morbidity such as gait abnormalities, chronic pain, and degenerative arthritis. AIMS: (1) to identify the risks and predisposing factors involved in DDH (2) to define the incidence of the disease locally; (3) to emphasize the importance of ultrasonography in early diagnosis of DDH. METHODS AND RESULTS: 1021 newborns in the Neonatal Department of Valcea County Emergency Hospital were analyzed. The information contained in the observation sheets was collected and upon this, the ultrasound was performed accordingly to Graf's classification. The following parameters were analyzed: sex, area of origin, gestational age, birthweight, type of delivery, parturition. Out of 1021 newborns, 27 had an abnormal ultrasound examination. 20 infants were diagnosed with DDH. Regarding the risk factors: cephalic delivery was associated with a lower risk/ the lowest of DDH (with p=0.045 for the right hip and p=0.001 for the left hip). Increased gestational age and increased birthweight were incriminating factors in the occurrence of DDH. DISCUSSION: Ultrasound imaging has become an accepted tool for accurately diagnosing DDH. PMID- 27489572 TI - Psychometric Validation of the Revised Family Affluence Scale: a Latent Variable Approach. AB - The aim was to develop and test a brief revised version of the family affluence scale. A total of 7120 students from Denmark, Greenland, Italy, Norway, Poland, Romania, Scotland and Slovakia reported on a list of 16 potential indicators of affluence. Responses were subject to item screening and test of dimensionality. Bifactor analysis revealed a strong general factor of affluence in all countries, but with additional specific factors in all countries. The specific factors mainly reflected overlapping item content. Item screening was conducted to eliminate items with low discrimination and local dependence, reducing the number of items from sixteen to six: Number of computers, number of cars, own bedroom, holidays abroad, dishwasher, and bathroom. The six-item version was estimated with Samejima's graded response model, and tested for differential item functioning by country. Three of the six items were invariant across countries, thus anchoring the scale to a common metric across countries. The six-item scale correlated with parental reported income groups in six out of eight countries. Findings support a revision to six items in the family affluence scale. PMID- 27489573 TI - Trends in Child Poverty in Sweden: Parental and Child Reports. AB - We use several family-based indicators of household poverty as well as child reported economic resources and problems to unravel child poverty trends in Sweden. Our results show that absolute (bread-line) household income poverty, as well as economic deprivation, increased with the recession 1991-96, then reduced and has remained largely unchanged since 2006. Relative income poverty has however increased since the mid-1990s. When we measure child poverty by young people's own reports, we find few trends between 2000 and 2011. The material conditions appear to have improved and relative poverty has changed very little if at all, contrasting the development of household relative poverty. This contradictory pattern may be a consequence of poor parents distributing relatively more of the household income to their children in times of economic duress, but future studies should scrutinze potentially delayed negative consequences as poor children are lagging behind their non-poor peers. Our methodological conclusion is that although parental and child reports are partly substitutable, they are also complementary, and the simultaneous reporting of different measures is crucial to get a full understanding of trends in child poverty. PMID- 27489575 TI - The initiation of post-synaptic protrusions. AB - The post-synaptic spines of neuronal dendrites are highly elaborate membrane protrusions. Their anatomy, stability and density are intimately linked to cognitive performance. The morphological transitions of spines are powered by coordinated polymerization of actin filaments against the plasma membrane, but how the membrane-associated polymerization is spatially and temporally regulated has remained ill defined. Here, we discuss our recent findings showing that dendritic spines can be initiated by direct membrane bending by the I-BAR protein MIM/Mtss1. This lipid phosphatidylinositol (PI(4,5)P2) signaling-activated membrane bending coordinated spatial actin assembly and promoted spine formation. From recent advances, we formulate a general model to discuss how spatially concentrated protein-lipid microdomains formed by multivalent interactions between lipids and actin/membrane regulatory proteins might launch cell protrusions. PMID- 27489574 TI - Do studies reporting 'U'-shaped serum 25-hydroxyvitamin D-health outcome relationships reflect adverse effects? AB - Several reports describe U-shaped 25-hydroxyvitamin D [25(OH)D] concentration health outcomes, including musculo-skeletal disorders such as falls and fractures, several cancers, cardiovascular disease (CVD), cognitive function, all cause mortality rates, birth outcomes, allergic reactions, frailty, and some other disorders. This paper reviews reports of U-shaped outcome associations with vitamin D status for evidence of underlying pathophysiological processes, or of confounding, finding that some U-shaped associations appear to be biologically meaningful, but that many could well reflect confounding by factors such as lifestyle, or hypovitaminosis D-related disease onset being masked by self supplementation that was begun too late to correct developing health problems but before baseline vitamin D status assessment. However, the various U-shaped associations for allergic reactions may be due to vitamin D modulation of the phenotype of the immune response, shifting the Th1-Th2 balance toward Th2 formation. For prostate cancer, there seems to be little effect of 25(OH)D concentration on incidence; however, there is an inverse correlation between 25(OH)D concentration and mortality rates. Future observational studies, and randomized controlled trial data analyses, should include adjustment for data collected on prior long-term vitamin D supplementation and solar UVB exposure, as well as other potential confounders. PMID- 27489576 TI - Fundamental awareness: A framework for integrating science, philosophy and metaphysics. AB - The ontologic framework of Fundamental Awareness proposed here assumes that non dual Awareness is foundational to the universe, not arising from the interactions or structures of higher level phenomena. The framework allows comparison and integration of views from the three investigative domains concerned with understanding the nature of consciousness: science, philosophy, and metaphysics. In this framework, Awareness is the underlying reality, not reducible to anything else. Awareness and existence are the same. As such, the universe is non material, self-organizing throughout, a holarchy of complementary, process driven, recursive interactions. The universe is both its own first observer and subject. Considering the world to be non-material and comprised, a priori, of Awareness is to privilege information over materiality, action over agency and to understand that qualia are not a "hard problem," but the foundational elements of all existence. These views fully reflect main stream Western philosophical traditions, insights from culturally diverse contemplative and mystical traditions, and are in keeping with current scientific thinking, expressible mathematically. PMID- 27489578 TI - An exploration of how to define and measure the evolution of behavior, learning, memory and mind across the full phylogenetic tree of life. AB - There are probably few terms in evolutionary studies regarding neuroscience issues that are used more frequently than 'behavior', 'learning', 'memory', and 'mind'. Yet there are probably as many different meanings of these terms as there are users of them. Further, investigators in such studies, while recognizing the full phylogenetic spectrum of life and the evolution of these phenomena, rarely go beyond mammals and other vertebrates in their investigations; invertebrates are sometimes included. What is rarely taken into consideration, though, is that to fully understand the evolution and significance for survival of these phenomena across phylogeny, it is essential that they be measured and compared in the same units of measurement across the full phylogenetic spectrum from aneural bacteria and protozoa to humans. This paper explores how these terms are generally used as well as how they might be operationally defined and measured to facilitate uniform examination and comparisons across the full phylogenetic spectrum of life. This paper has 2 goals: (1) to provide models for measuring the evolution of 'behavior' and its changes across the full phylogenetic spectrum, and (2) to explain why 'mind phenomena' cannot be measured scientifically at the present time. PMID- 27489577 TI - Inter-organelle ER-endolysosomal contact sites in metabolism and disease across evolution. AB - Since their initial observation, contact sites formed between different organelles have transitioned from ignored curiosities to recognized centers for the exchange of metabolites and lipids. Contact formed between the ER and endomembrane system (eg. the plasma membrane, endosomes, and lysosomes) is of particular biomedical interest, as it governs aspects of lipid metabolism, organelle identity, and cell signaling. Here, we review the field of ER endolysosomal communication from the perspective of three model systems: budding yeast, the fruit fly D. melanogaster, and mammals. From this broad perspective, inter-organelle communication displays a consistent role in metabolic regulation that was differentially tuned during the development of complex metazoan life. We also examine the current state of understanding of lipid exchange between organelles, and discuss molecular mechanisms by which this occurs. PMID- 27489579 TI - Life and evolution as physics. AB - What is evolution and why does it exist in the biological, geophysical and technological realms - in short, everywhere? Why is there a time direction - a time arrow - in the changes we know are happening every moment and everywhere? Why is the present different than the past? These are questions of physics, about everything, not just biology. The answer is that nothing lives, flows and moves unless it is driven by power. Physics sheds light on the natural engines that produce the power destroyed by the flows, and on the free morphing that leads to flow architectures naturally and universally. There is a unifying tendency across all domains to evolve into flow configurations that provide greater access for movement. This tendency is expressed as the constructal law of evolutionary flow organization everywhere. Here I illustrate how this law of physics accounts for and unites the life and evolution phenomena throughout nature, animate and inanimate. PMID- 27489581 TI - Anxiety and ritualization: Can attention discriminate compulsion from routine? AB - Despite the wide occurrence of ritual behavior in humans and animals, much of its causal underpinnings, as well as evolutionary functions, remain unknown. A prominent line of research focuses on ritualization as a response to anxiogenic stimuli. By manipulating anxiety levels, and subsequently assessing their motor behavior dynamics, our recent study investigated this causal link in a controlled way. As an extension to our original argument, we here discuss 2 theoretical explanations of rituals-ritualized behavior and automated behavior-and their link to anxiety. We propose that investigating participant's locus of attention can discriminate between these 2 models. PMID- 27489580 TI - Deciphering the roles of phosphoinositide lipids in phagolysosome biogenesis. AB - Professional phagocytes engulf microbial invaders into plasma membrane-derived phagosomes. These mature into microbicidal phagolysosomes, leading to killing of the ingested microbe. Phagosome maturation involves sequential fusion of the phagosome with early endosomes, late endosomes, and the main degradative compartments in cells, lysosomes. Some bacterial pathogens manipulate the phosphoinositide (PIP) composition of phagosome membranes and are not delivered to phagolysosomes, pointing at a role of PIPs in phagosome maturation. This hypothesis is supported by comprehensive microscopic studies. Recently, cell-free reconstitution of fusion between phagosomes and endo(lyso)somes identified phosphatidylinositol 4-phosphate [PI(4)P] and phosphatidylinositol 3-phosphate [PI(3)P] as key regulators of phagolysosome biogenesis. Here, we describe the emerging roles of PIPs in phagosome maturation and we present tools to study PIP involvement in phagosome trafficking using intact cells or purified compartments. PMID- 27489582 TI - Similar requirement for clathrin in EGF- and HGF- stimulated Akt phosphorylation. AB - Receptor tyrosine kinases, such as the epidermal growth factor (EGF) receptor (EGFR) and Met lead to activation of intracellular signals including Akt, a critical regulator of cell survival, metabolism and proliferation. Upon binding their respective ligands, each of these receptors is recruited into clathrin coated pits (CCPs) eventually leading to endocytosis. We have recently shown that phosphorylation of Gab1 and Akt following EGFR activation requires clathrin, but does not require receptor endocytosis. We examined whether clathrin regulates Akt signaling downstream of Met, as it does for EGFR signaling. Stimulation with the Met ligand Hepatocyte Growth Factor (HGF) leads to enrichment of phosphorylated Gab1 (pGab1) within CCPs in ARPE-19 cells. Perturbation of clathrin using the inhibitor pitstop2 decreases HGF-stimulated Akt phosphorylation. These results indicate that clathrin may regulate Met signaling leading to Akt phosphorylation similarly as it does for EGFR signaling. PMID- 27489583 TI - Glycosylation of arabinogalactan-proteins essential for development in Arabidopsis. AB - Arabinogalactan-proteins (AGPs) are ubiquitous cell wall components present throughout the plant kingdom. They are extensively post translationally modified by conversion of proline to hydroxyproline (Hyp) and by addition of arabinogalactan (AG) polysaccharides to Hyp residues. Two small gene subfamilies within the CAZy GT31 family, referred to as Hyp-galactosyltransferases (Hyp-GALTs and HPGTs), encode enzymes that specifically add galactose to AGP protein backbones as revealed by heterologous expression of the genes coupled with an in vitro enzyme assay and by biochemical characterization of the genetic knock-out mutants. Biochemical analysis of galt2galt5 double and hpgt1hpgt2hpgt3 triple knockout mutants revealed significant reductions in both AGP-specific Hyp-GALT activity and beta-Gal-Yariv precipitable AGPs. Further analysis of these mutants demonstrated both overlapping and distinct pleiotropic growth and development phenotypes, indicating the important contributions of the carbohydrate moieties toward AGP function. Current research indicates that all 8 Hyp-GALT/HPGT genes encode enzymes that catalyze the initial step for AGP glycosylation and that AGP glycans play essential roles in plant growth and development. PMID- 27489584 TI - Mechanical defenses of plant extrafloral nectaries against herbivory. AB - Extrafloral nectaries play an important role in plant defense against herbivores by providing nectar rewards that attract ants and other carnivorous insects. However, extrafloral nectaries can themselves be targets of herbivory, in addition to being exploited by nectar-robbing insects that do not provide defensive services. We recently found that the extrafloral nectaries of Vicia faba plants, as well as immediately adjacent tissues, exhibit high concentrations of chemical toxins, apparently as a defense against herbivory. Here we report that the nectary tissues of this plant also exhibit high levels of structural stiffness compared to surrounding tissues, likely due to cell wall lignification and the concentration of calcium oxalate crystals in nectary tissues, which may provide an additional deterrent to herbivore feeding on nectary tissues. PMID- 27489585 TI - Demonstrating the value of medicines: evolution of value equation and stakeholder perception of uncertainties. AB - It is important to evaluate how the value of medicine is assessed, as it may have important implications for health technology and reimbursement assessments. The value equation could comprise 'incremental benefit/outcome' (relative results of care in terms of patient health, comparing the innovation to best available alternative(s)) in the numerator and 'cost' (relative costs involved in the full cycle of care (or a defined period) for the patient's medical condition, incorporating the relevant cost-offsets due to displacement of best available alternative(s)) in the denominator. This 'relative value' combined with the overall net budget impact (of including the drug in the formulary or reimbursed drug list) at the concerned population level in the given institution/region/country may better inform the usefulness of the new therapeutic option to the healthcare system. As product value messages are created, anticipating external stakeholder questions and information needs, including addressing three main categories of 'uncertainties', namely the scientific uncertainties, usage uncertainties, and financial uncertainties, could facilitate demonstration of optimal product value and help informed decision making to benefit all stakeholders involved in the process. PMID- 27489586 TI - Challenges in striving to simultaneously achieve multiple resource allocation goals: the pan-Canadian Oncology Drug Review (pCODR) example. AB - The pan-Canadian Oncology Drug Review (pCODR) makes recommendations to Canada's provinces and territories (except Quebec) to guide their cancer drug funding decisions. The objective of this paper is to explore, using an economic perspective and the pCODR as an example, the challenges associated with striving to simultaneously achieve the goals of maximizing health benefits with available resources and improving access to a more consistent standard of care across Canada. The first challenge concerns how to interpret the goals in order to determine how resources should be allocated to achieve each goal. The second challenge relates to whether, if pursued simultaneously, both goals can be achieved to the same extent that each goal could have been achieved alone with the same available resources. Regarding the first challenge, we illustrate that, due to a lack of definitional clarity, it is difficult to determine exactly how resources should be allocated in order to achieve the goal of improving access to a more consistent standard of care across Canada. Regarding the second challenge, we illustrate that choosing to strive for both of the pCODR goals simultaneously will likely be associated with tradeoffs in the extent to which one or both goals can be achieved (relative to what could have been achieved for each goal alone with the same available resources). We suggest that, if the pCODR and the provincial drug plan decision-makers it supports want to strive for both goals simultaneously, they must prioritize the goals and explicitly identify the tradeoffs associated with the prioritization. This will ensure that the consequences of striving to simultaneously achieve both goals are explicit, transparent, and predictable for provincial drug plan decision-makers, physicians, patients, caregivers, and society as a whole. PMID- 27489587 TI - Curcumin Veto the Effects of Osteopontin (OPN) Specific Inhibitor on Leukemic Stem Cell Colony Forming Potential via Promotion of OPN Overexpression. AB - BACKGROUND: Acute myeloid leukemia (AML) is an immunophenotypically heterogeneous malignant disease, in which CD34 positivity is associated with poor prognosis. Osteopontin (OPN) plays different roles in physiologic and pathologic conditions like: survival, metastasis and cell protection from cytotoxic and apoptotic stimuli. Due to anti-apoptotic effect of OPN in normal and malignant cells, silencing of OPN leads to elevation of sensitivity towards chemotherapeutic agents and attenuates cancer cells migration and invasion. Therefore, the aim of this study was to evaluate OPN roles in modulating curcumin-mediated growth inhibitory on leukemic stem cells (LSCs) colony forming potential and survival in AML cell lines and primary CD34+/CD38- bone marrow-derived AML cells. MATERIALS AND METHODS: Primary human CD34+/CD38- cells were isolated from bone marrow mononuclear cells of 10 AML patients at initial state of diagnosis, using a CD34 Multi sort kit. The growth inhibitory effects of curcumin (CUR) were evaluated by MTT and colony-formation assays. Apoptosis was analyzed by 7AAD assay in CD34+ KG 1, U937 cell lines and primary isolated cells. Short interfering RNA (siRNA) against OPN was used for OPN silencing in both cell lines and primary AML cells. Then, transfected cells were incubated with/without curcumin. The change in OPN gene expression was examined by Real-time PCR. RESULTS: CUR inhibited proliferation and induced apoptosis in both KG-1 and U937 cells and also primary isolated AML cells. OPN silencing by siRNA increased the susceptibility of KG-1, U937 and primary CD34+/CD38- AML cells to apoptosis. Moreover, soft agar colony assays revealed that silencing of OPN with siRNA significantly decreased colony numbers in LSCs compared with the non-targeting group. Furthermore, CD34+/CD38- populations as a main LSCs compartment through OPN overexpression towards CUR treatment might be nullified the inhibitory effects of OPN siRNA on their survival and colony forming potential. CONCLUSION: Taken together, our results suggested that knockdown of OPN using OPN specific siRNA significantly decreased colony numbers in LSCs and this effect might be vetoed by LSCs via induction of OPN overexpressionin combination of CUR and siRNA. PMID- 27489588 TI - Association between Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms and Susceptibility to Childhood Acute Lymphoblastic Leukemia in an Iranian Population. AB - BACKGROUND: The present study was aimed to examine the possible association between methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms and childhood acute lymphoblastic leukemia (ALL) in a sample of Iranian population. SUBJECTS AND METHODS: A total of 220 subjects including 100 children diagnosed with ALL and 120 healthy children participated in the case-control study. The single nucleotide polymorphisms (SNPs) of MTHFR were determined by ARMS-PCR or PCR-RFLP method. RESULTS: Our investigation revealed that rs13306561 both TC and TC + CC genotypes decreased the risk of ALL compared to TT genotype (OR=0.32, 95%CI=0.15-0.68, p=0.002 and OR=0.35, 95%CI=0.17-0.70, p=0.003, respectively). In addition, the rs13306561 C allele decreased the risk of ALL in comparison with T allele (OR=0.42, 95% CI=0.22-0.78, P=0.005). MTHFR rs1801131 (A1298C) polymorphism showed that the AC heterozygous genotype decreased the risk of ALL in comparison with AA homozygous genotype (OR=0.43, 95%CI=0.21-0.90, p=0.037). Neither the overall Chi-square comparison of cases and control subjects (??2=5.54, p=0.063) nor the logistic regression analysis showed significant association between C677T polymorphism and ALL (OR=1.25, 95% CI=0.69-2.23, p=0.552; CT vs. CC). CONCLUSION: The current investigation findings showed that MTHFR rs1801131 and rs13306561 polymorphisms decreased the risk of ALL in the population which has been studied. Further studies with larger sample sizes and different ethnicities are required to validate our findings. PMID- 27489589 TI - Diagnosis and Classification of Acute Leukemia in Bone Marrow Trephine Biopsies, Utility of a Selected Panel of Minimal Immunohistochemical Markers. AB - BACKGROUND: Acute leukemias are characterized by neoplastic proliferation of hematopoietic stem cells and accumulation of blasts and immature cells in bone marrow. We applied a selective panel of immunohistochemical markers on bone marrow trephine tissue sections and observed their utility in diagnosis and typing of acute leukemia. MATERIALS AND METHODS: The study was done at PSG Institute of Medical Sciences and Research from 1st January, 2008 to 30th June, 2012. Immunohistochemistry was done to detect the expression of Myeloperoxidase (MPO), Terminal deoxynucleotidyl transferase (TdT), Cluster of Differentiation 3 (CD3) and Cluster of Differentiation 20 (CD20). RESULTS: On an average, 76 new cases of leukemia are diagnosed each year in our hospital. Of these 28.7% are acute leukemias, which had a bimodal peak age of occurrence with almost equal sex distribution. Only 9 cases could be typed as Acute Myeloid Leukemia (AML) or Acute Lymphoid Leukemia (ALL) purely by morphology. Another 10 cases were typed using cytochemistry. Immunohistochemical panel helped to type 90% of cases. We also identified 1 case of AML of ambiguous lineage. The data were analysed statistically using SPSS version 21 and found out that the immunohistochemistry was found to be extremely significant (p<001) by Chi-Square test. CONCLUSIONS: Based on our results, we suggest the use of this limited panel of markers for routine evaluation of all acute leukemias. It is easier to type using immunohistochemistry rather than flow cytometry, given the disadvantage of the costs involved with the latter. PMID- 27489590 TI - Evaluation of Minimal Residual Disease in Acute Myeloid Leukemia with NPM1 Marker. AB - BACKGROUND: Minimal residual disease (MRD) tests provide early identification of hematologic relapse and timely management of acute myeloid leukemia (AML) patients. Approximately, 50% of AML patients do not have clonal chromosomal aberrations and categorize as a cytogenetically normal acute myeloid leukemia (CN AML). About 60% of adult CN-AML has a mutation in exon 12 of NPM1 gene. This mutation is specific for malignant clone and potentially is a good marker of MRD. In this retrospective study, we set up a quantitative test for quantifying NPM1 type A mutation and AML patients carrying this mutation at the time of diagnosis, were followed-up. Materials and Methods : We prepared plasmids containing a cDNA fragment of NPM1 and ABL genes by PCR cloning. The plasmids were used to construct standard curves. Eleven patients were analyzed using established method. Serial PB and/or BM samples (n=71) were taken in 1-3 months intervals (mean 1.5-month intervals) and median follow-up duration after chemotherapy was 11 months (5-28.5 months). RESULTS: In this study, we developed RNA-based RQ-PCR to quantitation of NPM1 mutation A with sensitivities of 10((-5)). The percent of NPMmut/ABL level showed a range between 132 and 757 with median of 383.5 in samples at diagnosis. The median NPMmut transcript level log reduction was 3 logs. Relapse occurred in 54.5% of patients (n=6), all cases at diagnosis demonstrated the same mutation at relapse. In patients who experienced relapse, log reduction levels of NPM1 mRNA transcript after therapy were 4 (n=2), 3 (n=2) and 1 log (n=2). Totally, NPMmut level showed less than 5 log reduction in all of them, whereas this reduction was 5-6 logs in other patients. CONCLUSION: Despite the limitations of this study in terms of sample size and duration of follow-up, it showed the accuracy of set up for detection of mutation and this marker has worth for following-up at different stages of disease. Because of high frequency, stability, specificity to abnormal clone and high sensitivity, NPM1 is a suitable marker for monitoring of NPMc+ AML patients. PMID- 27489591 TI - Evaluation of Bone Mineral Density in Children with Acute Lymphoblastic Leukemia (ALL) and Non-Hodgkin's Lymphoma (NHL): Chemotherapy with/without Radiotherapy. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) are the most common malignancies in children and adolescents. Therapies such as corticosteroids, cytotoxic and radiotherapy will have harmful effect on bone mineral density (BMD) which can lead to increased possibility of osteoporosis and pathological fractures. SUBJECTS AND METHODS: This 3-year cross-sectional study was performed in 50 children with ALL (n=25) and NHL (n=25) at Dr. Sheikh Children's Hospital in Mashhad. Half the patients received chemotherapy alone (n=25), while the other half received chemotherapy plus radiotherapy (n=25). We assessed them in the remission phase by DEXA bone mineral densitometry at the lumbar spine and femoral neck (hip). The survey results were adjusted in accordance with age, height, sex and Body Mass Index. Results : The mean age was 3.93+/- 8.28 years. There was no significant difference in bone biomarkers (Ca, P, ALP, PTH) among ALL, NHL and also the two treatment groups. Children with ALL had lower density at the hip and lumbar spine (p-value<0.001 and p-value=0.018, respectively). Among the total of 50 patients, 3 patients had normal results for detected hip BMD (6%), while 14 (28%) had osteopenia and 33 had osteoporosis (66%). Only one patient had normal BMD among all the patients who received chemotherapy plus radiotherapy, whereas 2 patients had normal BMD with just chemotherapy treatment. Conclusion : Given that 94% of our patients had abnormal bone density, it seems to be crucial to pay more attention to the metabolic status and BMD in children with cancer. PMID- 27489592 TI - Human Platelet Lysate as a Xeno Free Alternative of Fetal Bovine Serum for the In Vitro Expansion of Human Mesenchymal Stromal Cells. AB - BACKGROUND: Mesenchymal stromal cells (MSCs) are employed in various different clinical settings in order to modulate immune response. Human autologous and allogeneic supplements including platelet derivatives such as platelet lysate (PL), platelet-released factors (PRF) and serum are assessed in clinical studies to replace fetal bovine serum (FBS). The immunosuppressive activity and multi potential characteristic of MSCs appear to be maintained when the cells are expanded in platelet derivatives. MATERIALS AND METHODS: Platelet-rich plasma was collected from umbrical cord blood (UCB). Platelet-derived growth factors obtained by freeze and thaw methods. CD62P expression was determined by flow cytometry. The concentration of PDGF-BB and PDGF-AB was detemined by ELISA. We tested the ability of a different concentration of PL-supplemented medium to support the ex vivo expansion of Wharton's jelly derived MSCs. We also investigated the biological/functional properties of expanded MSCs in presence of different concentration of PL. The conventional karyotyping was performed in order to study the chromosomal stability. The gene expression of Collagen I and II aggrecan and SOX-9 in the presence of different concentrations of PL was evaluated by Real-time PCR. RESULTS: We observed 5% and 10% PL, causing greater effects on proliferation of MSCs .These cells exhibited typical morphology, immunophenotype and differentiation capacity. The genetic stability of these derivative cells from Wharton's jelly was demonstrated by a normal karyotype. Furthermore, the results of Real-time PCR analysis showed that the expression of chondrocyte specific genes was higher in MSCs in the presence of 5% and 10% PL, compared with FBS supplement. CONCLUSIONS: We demonstrated that PL could be used as an alternative safe source of growth factors for expansion of MSCs and also maintained similar growing potential and phenotype without any effect on chromosomal stability. PMID- 27489594 TI - Difficult Diagnosis of Colon Adenocarcinoma Metastasis to Retina: A Case Report and Literature Review. AB - Intraocular metastatic tumors have been increasingly reported in the recent past. Unlike choroidal metastasis, metastasis to retina is very rare and so far has been reported in very few case reports only. A 56 year-old male who presented with a history of adenocarcinoma of the cecum and underwent lap colectomy for the primary cecal tumor, received adjuvant chemotherapy for a year after surgery and decided to stop. He was also diagnosed with metastasis to liver and lung at this time. He presented with left eye pain, pressure and decreased vision suspicious for retinal metastasis from cecal primary lesion, 2 years after initial diagnosis. A mass of 5 x 10 mm was found on ophthalmoscopic examination and on ultrasound of the eye, in spite of normal results of MRI of the orbit. Palliative radiation therapy of the left eye resulted in decreased eye pressure and improved vision. As retinal metastasis carries a poorer prognosis due to higher risk of spread to central nervous system, the diagnosis of retinal metastasis in case of gastrointestinal cancers patients who present with vision changes should be made urgently. These patients should be thoroughly investigated with a synergistic approach of opthalmoscopic examination, ultrasound of the eye along with other imaging modalities like MRI of the orbit and just not MRI of orbit. Immediate action in the form of surgical or radiation treatments of the metastatic tumors of the eye should be instituted early on for a better prognosis. PMID- 27489595 TI - Clavicular Chondrosarcoma: A Case Report and Brief Review of the Literature. AB - Clavicular bone tumors occur in less than 0.5 percent of bone tumors. Primary chondrosarcoma is very rare even among clavicle tumors. The main symptom is a touchable mass in 69 % of patients. Dedicated centers using FNA and cytology can reach a correct diagnosis in 94% of cases. Treatment planning is done using simple X-ray, CT-scan, shoulder MRI, chest CT-scan and whole body technetium scan. Treatment of choice for primary chondrosarcoma of clavicle is surgical resection. PMID- 27489593 TI - The Role of MicroRNAs in Myeloproliferative Neoplasia. AB - MiRs are 17-25 nucleotide non-coding RNAs. These RNAs target approximately 80% of protein coding mRNAs. MiRs control gene expression and altered expression of them affects the development of cancer. MiRs can function as tumor suppressor via down regulation of proto-oncogenes and may function as oncogenes by suppressing tumor suppressors. Myeloproliferative neoplasias (formerly known as chronic myeloproliferative disorders) form a class of hematologic malignancies demonstrating the expansion of stem cells in one or more hematopoietic cell lines. CML results from an acquired translocation known as BCR-ABL (Philadelphia chromosome). JAK2V617F mutation is present in over 95% of PV, 55% of ET and 65% of PMF cases. Aberrant expression of miR is associated with myeloproliferative neoplasias, pathogenesis, disease progress and response to treatment. MiRs can also be potential therapeutic targets. CML is mainly treated by tyrosine kinase inhibitors such as Imatinib. In addition, altered function of miRs may be used as a prognostic factor in treatment. Resistance to Imatinib is currently a major clinical problem. The role of a number of miRs has been demonstrated in this resistance. Changing expression pattern of miRs can be effective in response to treatment and inhibition of drug resistance. In this paper, we set out to evaluate the effect of miRs in pathogenesis and treatment of MPN. PMID- 27489596 TI - Periprocedural considerations of transcatheter aortic valve implantation for anesthesiologists. AB - Transcatheter aortic valve replacement (TAVR) is rapidly gaining popularity as a viable option in the management of patients with symptomatic aortic stenosis (AS) and high risk for open surgical intervention. TAVR soon expanding its indications from "high-risk" group of patients to those with "intermediate-risk". As an anesthesiologist; understanding the procedure and the challenges inherent to it is of utmost importance, in order to implement optimal care for this generally frail population undergoing a rather novel procedure. Cardiac anesthesiologists generally play a pivotal role in the perioperative care of the patients, and therefore they should be fully familiar with the circumstances occurring surrounding the procedure. Along with increasing experience and technical developments for TAVR, the procedure time becomes shorter. Due to this improvement in the procedure time, more and more anesthesiologists feel comfortable in using monitored anesthesia care with moderate sedation for patients undergoing TAVR. A number of complications could arise during the procedure needing rapid diagnoses and occasionally conversion to general anesthesia. This review focuses on the periprocedural anesthetic considerations for TAVR. PMID- 27489597 TI - Association of serum uric acid level with mortality and morbidity of patients with acute ST-elevation myocardial infarction. AB - INTRODUCTION: Investigating the clinical impact of serum uric acid (UA) and its lowering agents on the complications and mortality of acute ST-elevation myocardial infarction (STEMI) can open a new era in STEMI treatment. The aim of this study was to evaluate the effect of on admission serum UA level on the mortality and morbidity of patients admitted with STEMI. METHODS: A number of 608 patients with STEMI were enrolled in this study from December 21, 2012 until February 19, 2014. Patients were followed for 20 months. Male to female ratio was 2.53, and the mean age of patients was 62.6+/-13.4. The relationship between the level of UA and patients' mortality and morbidity, left ventricular ejection fraction (LVEF), atrial and ventricular arrhythmia was analyzed. RESULTS: Patients with high serum UA level had higher Killip class after STEMI (P=0.001). Mean LVEF was measured to be 39.5+/-9.6 in normal UA group and 34.6+/-11.6 in high UA group (P=0.001). In comparison with normal UA group, high UA group had significantly higher cTnI (2.68+/-0.09 vs 4.09+/-0.42, respectively, P=0.001), increased blood pressure (P=0.009), and higher atrial fibrillation (AF) occurrence (P=0.03), but no association was seen between ventricular tachycardia and serum UA level. Short term and midterm mortality were not different in two groups (P=0.44 and 0.31, respectively). CONCLUSION: In the current study, high serum UA level in patients with acute myocardial infarction (MI) was not associated with higher in-hospital or midterm mortality, but it was associated with lower LVEF, higher Killip class, elevated cTnI, creatinine, triglyceride, and higher AF. PMID- 27489598 TI - Serum cortisol level and adrenal reserve as a predictor of patients' outcome after successful cardiopulmonary resuscitation. AB - INTRODUCTION: It is thought that pituitary-adrenal axis has a fundamental role in outcome of cardiopulmonary arrest (CPA). This study designed to evaluate the correlation between adrenal reserve and post-resuscitation outcome. METHODS: In this clinical trial study, 52 consecutive patients with CPA were enrolled in two emergency departments (EDs) over a 3-month period. Plasma cortisol level was measured at the beginning of CPR. Intravenous adrenocorticotropic hormone (ACTH) stimulation test was carried out after successful CPR, and blood samples were taken at 30 and 60 minutes, and 24 hours thereafter. Patients were divided into two groups: in-hospital death or hospital discharge. RESULTS: In patients who died, baseline and post-ACTH serum cortisol after 30 and 60 minutes and 24 hours were higher than patients who discharged from the hospital, but it was not statistically significant except to that of minute 60 (P=0.49). A model of multivariate logistic regression analysis showed that age and need for vasopressor infusion correlated with mortality. CONCLUSION: Current study could not show the statistically significant difference in initial and post-ACTH serum cortisol levels between survivor and non-survivor patients with cardiac arrest who had initial successful CPR, except to that of minute 60. PMID- 27489599 TI - Effect of ischemic postconditioning on myocardial protection in patients undergoing coronary artery bypass grafting surgery with cardiopulmonary bypass. AB - INTRODUCTION: Reperfusion injury is a well-known phenomenon following restoration of the coronary circulation after coronary artery bypass grafting (CABG) that impairs myocardial function. In order to control the severity of this injury, we aimed to investigate the effect of a new conditioning strategy namely ischemic postconditioning (IPOC) along with controlled aortic root reperfusion (CARR) on myocardial protection in CABG surgery with cardiopulmonary bypass. METHODS: In a doubled blind clinical trial study, 51 patients undergoing first-time elective CABG were randomly divided in three groups: CARR, IPOC, and combination of IPOC and CARR. At the end of procedure and just before aortic cross-clamp removal, reperfusion was started as following: In CARR-receiving groups, the reperfusion was started with low perfusion pressures for 10 minutes, and in IPOC-receiving groups, three cycles of 1 minute episodes of ischemia separated by 1 minute episodes of reperfusion was applied as postconditioning protocol. Left ventricular ejection fraction (EF) (by echocardiography), inotrope requirement index, and myocardial arrhythmias were measured up to 72 hours after operation. RESULTS: Echocardiography revealed that the recovery of EF after operation in IPOC group was significantly higher than those of two other groups (P < 0.05). Inotropic support requirement was significantly lower in IPOC groups. In addition, the incidence of atrial and ventricular arrhythmias after opening of aortic clamp and in intensive care unit (ICU) as well as recovery time of cardiac rhythm upon reperfusion were lowered by administration of IPOC, as compared with CARR group. CONCLUSION: The study suggests that IPOC may provide clinical benefits against reperfusion injury in patients undergoing CABG surgery and maintain the post ischemic left ventricular performance. PMID- 27489600 TI - Comparison of current practices of cardiopulmonary perfusion technology in Iran with American Society of Extracorporeal Technology's standards. AB - INTRODUCTION: Standards have a significant role in showing the minimum level of optimal optimum and the expected performance. Since the perfusion technology staffs play an the leading role in providing the quality services to the patients undergoing open heart surgery with cardiopulmonary bypass machine, this study aimed to assess the standards on how Iranian perfusion technology staffs evaluate and manage the patients during the cardiopulmonary bypass process and compare their practice with the recommended standards by American Society of Extracorporeal Technology. METHODS: In this descriptive study, data was collected from 48 Iranian public hospitals and educational health centers through a researcher-created questionnaire. The data collection questionnaire assessed the standards which are recommended by American Society of Extracorporeal Technology. RESULTS: Findings showed that appropriate measurements were carried out by the perfusion technology staffs to prevent the hemodilution and avoid the blood transfusion and unnecessary blood products, determine the initial dose of heparin based on one of the proposed methods, monitor the anticoagulants based on ACT measurement, and determine the additional doses of heparin during the cardiopulmonary bypass based on ACT or protamine titration. It was done only in 4.2% of hospitals and health centers. CONCLUSION: Current practices of cardiopulmonary perfusion technology in Iran are inappropriate based on the standards of American Society of Cardiovascular Perfusion. This represents the necessity of authorities' attention to the validation programs and development of the caring standards on one hand and continuous assessment of using these standards on the other hand. PMID- 27489601 TI - Comparison of the patient radiation exposure during coronary angiography and angioplasty procedures using trans-radial and trans-femoral access. AB - INTRODUCTION: Cardiac catheterization procedure through the trans-radial access (TRA) have shown many clinical advantages over the trans-femoral (TFA), but despite its advantages, there are serious concerns regarding higher possible radiation dose for the patients and operators in TRA. This study was planned to compare the patients' radiation dose associated with TRA and TFA during coronary angiography (CA) and percutaneous transluminal coronary angioplasty (PTCA). METHODS: Of 700 candidates for angiography, 326 patients were entered the study. All the procedures were carried out by one interventional cardiologist employing the same angiography unit in Aalinasab hospital and the patients' dose area product (DAP), air kerma (AK), fluoroscopy time (FT) and cine film time (CFT) were then determined in both access groups (TRA,TFA) in CA, PTCA and CA+PTCA procedures. RESULTS: The mean FT, CFT and AK values in both TRA & TFA groups were the same in all procedures (P>0.05). The mean DAP in CA+PTCA procedures was 6704.01+/-3243.23 uGym(2) in femoral access compare with 5647.46+/-2797.74 uGym(2) in radial access, which were significantly less than that in TFA with P= 0.02. CONCLUSION: On the basis of the results obtained in this study, no differences were found in patients' radiation dose in both access groups, therefore with regard to comparatively more clinical advantages associated with the Trans-radial access technique it might be a good substitute for Trans-femoral access. PMID- 27489602 TI - Effect of Ventolin on QTc in children with respiratory distress. AB - INTRODUCTION: beta2-agonists are first election drugs for the treatment of respiratory disease that may alter cardiac autonomic modulation. The aim of this study was to evaluate the effects of nebulized Ventolin on electrocardiogram, particularly QTc interval to assess the potential arrhythmogenic risks. METHODS: A total of 192 patients between 2 months and 15 years which received nebulized Ventolin were enrolled in this study. Patients were divided into two groups. Electrocardiograms of patients before and after nebulized Ventolin were taken. Differences between two groups were assessed using a paired student's t test. RESULTS: There was statistically significant differences in QTc before and after Ventolin in each groups (P<0.005).Ventolin effect on QTc interval in both groups did not differ. In first group, there was statistically significant differences between heart rate before and after Ventolin taken (P=0.009) but in second group there was not statistically significant differences between heart rate (P=0.345). CONCLUSION: Although Ventolin can cause changes in QTc, Ventolin with 0.15 mg/kg/dose in comparison with 0.1 mg/kg/dose does not cause significant changes in QTc. PMID- 27489603 TI - Simultaneous thrombosis of multiple coronary arteries in a patient with rheumatoid arthritis. AB - We present a case of simultaneous coronary thrombosis of the left main, the left anterior descending artery and the right coronary artery in a patient, recently diagnosed with rheumatoid arthritis. PMID- 27489604 TI - Multiple coronary thrombosis. PMID- 27489605 TI - Prevention and Treatment of White Spot Lesions During and After Treatment with Fixed Orthodontic Appliances: a Systematic Literature Review. AB - OBJECTIVES: The aim of the systematic literature review is to update the evidence for the prevention of white spot lesions, using materials containing fluoride and/or casein phosphopeptide-amorphous calcium phosphate during and after treatment with fixed orthodontic appliances. MATERIAL AND METHODS: Information search for controlled studies on humans published between January 2008 and February 2016 was performed in PubMed, ScienceDirect, Embase, The Cochrane Library. Inclusion criteria were: the English language, study on humans, patients undergoing orthodontic treatment with fixed appliances, randomized or quasi randomized controlled clinical studies fluoride-containing product or casein derivates used throughout the appliance therapy or straightaway after debonding. RESULTS: 326 articles were reviewed (Embase 141, PubMed 129, ScienceDirect 41, Cochrane 15). Twelve clinical studies fulfilled all inclusion criteria. Use of fluoridated toothpaste had a remineralizing effect on white spot lesions (WSLs) (P < 0.05); fluoride varnish and casein supplements were effective in prevention and early treatment of WSLs (P < 0.05). CONCLUSIONS: Early detection of white spot lesions during orthodontic treatment would allow implementing preventive measures to control the demineralization process before lesions progress. The systemic review has showed that the usage of fluoride and casein supplements in ameliorating white spot lesions during and after fixed orthodontic treatment is significantly effective. However the use of casein phosphopeptide-amorphous calcium phosphate can be more beneficial than fluoride rinse in the reduction of demineralization spots. PMID- 27489606 TI - Inflammatory Cytokines Interleukin-1beta and Tumour Necrosis Factor-alpha - Novel Biomarkers for the Detection of Periodontal Diseases: a Literature Review. AB - OBJECTIVES: The article aims to discuss the IL-1beta and TNF-alpha potential use as salivary biomarkers of periodontal diseases pathogenesis and progression. MATERIAL AND METHODS: This literature review has been registered in PROSPERO database with following number: CRD42016035729. Data investigation was performed on PubMed database as the main source of studies. The following search terms were used: "salivary biomarkers", "periodontal diseases", "TNF-alpha", "Interleukin-1 beta". Clinical trials and animal experimental models of periodontal disease were included in the discussion. In regards to inclusive dates, published studies from January 2006 to December 2015 were considered in this review along with the mentioned inclusion criteria. RESULTS: IL-1beta and TNF-alpha salivary levels increased in diseased groups, they were associated with onset and disease severity, and their levels reduced in response to periodontal therapy. IL-1beta and TNF-alpha could be promising biomarkers in the detection of periodontal diseases. CONCLUSIONS: The use of a salivary cytokine-based diagnosis appears to be a screening method capable of diagnosing periodontal diseases in an early fashion, establishing an era of individualized clinical decisions. PMID- 27489607 TI - Designing for Safety: Implications of a Fifteen Year Review of Swallowed and Aspirated Dentures. AB - OBJECTIVES: Dentures are worn by around 20% of the population, yet if they become displaced they may enter the gastrointestinal or respiratory system, sometimes with grave consequences. The aim of this study was to review recent published literature in order to identify the epidemiology of patients and characteristics of swallowed and aspirated dental prostheses, and propose strategies to minimise these risks. MATERIAL AND METHODS: A fifteen year retrospective of published case series and case reports was carried out. Photographs, radiographs and descriptions of the dental prostheses were gathered, as well as the patient's presenting complaint, the anatomical site where the denture was caught and the procedure required to remove the denture. RESULTS: Ninety one separate events of swallowed or aspirated dentures were identified from 83 case reports and series from 28 countries. Average age was 55 years, and these were 74% male. Photographs were retrieved for 49 of these dentures. Clasps were present in 25 of the dentures. There was no significant difference between clasped and unclasped dentures for perforation rates, need for open surgery and spontaneously passed dentures. CONCLUSIONS: We discuss the implications of this study regarding denture designs, specifically the importance of using a radiopaque acrylic, using clasps when required even if there is a risk of aspiration, advising patients to return if a denture is loose or damaged, and finally that all patients who wear a denture are at risk of aspiration and swallowing events, and associated morbidity and mortality. PMID- 27489608 TI - Micro-CT Analysis of Bone Healing in Rabbit Calvarial Critical-Sized Defects with Solid Bioactive Glass, Tricalcium Phosphate Granules or Autogenous Bone. AB - OBJECTIVES: The purpose of the present study was to evaluate bone healing in rabbit critical-sized calvarial defects using two different synthetic scaffold materials, solid biodegradable bioactive glass and tricalcium phosphate granules alongside solid and particulated autogenous bone grafts. MATERIAL AND METHODS: Bilateral full thickness critical-sized calvarial defects were created in 15 New Zealand white adult male rabbits. Ten defects were filled with solid scaffolds made of bioactive glass or with porous tricalcium phosphate granules. The healing of the biomaterial-filled defects was compared at the 6 week time point to the healing of autologous bone grafted defects filled with a solid cranial bone block in 5 defects and with particulated bone combined with fibrin glue in 10 defects. In 5 animals one defect was left unfilled as a negative control. Micro-computed tomography (micro-CT) was used to analyze healing of the defects. RESULTS: Micro CT analysis revealed that defects filled with tricalcium phosphate granules showed new bone formation in the order of 3.89 (SD 1.17)% whereas defects treated with solid bioactive glass scaffolds showed 0.21 (SD 0.16)%, new bone formation. In the empty negative control defects there was an average new bone formation of 21.8 (SD 23.7)%. CONCLUSIONS: According to findings in this study, tricalcium phosphate granules have osteogenic potential superior to bioactive glass, though both particulated bone with fibrin glue and solid bone block were superior defect filling materials. PMID- 27489609 TI - Skeletal Stability after Large Mandibular Advancement (> 10 mm) with Bilateral Sagittal Split Osteotomy and Skeletal Elastic Intermaxillary Fixation. AB - OBJECTIVES: The aim of the present study was to assess the skeletal stability after large mandibular advancement (> 10 mm) with bilateral sagittal split osteotomy and skeletal elastic intermaxillary fixation and to correlate the skeletal stability with the vertical facial type. MATERIAL AND METHODS: A total of 33 consecutive patients underwent bimaxillary surgery to correct skeletal Class II malocclusion with a mandibular advancement (> 10 mm) measured at B-point and postoperative skeletal elastic intermaxillary fixation for 16 weeks. Skeletal stability was evaluated using lateral cephalometric radiographs obtained preoperative (T1), 8 weeks postoperatively (T2), and 18 month postoperatively (T3). B-point and pogonion (Pog) was used to measure the skeletal relapse and the mandibular plane angle (MP-angle) was used to determine the vertical facial type. RESULTS: The mean advancement from T1 to T2 were 11.6 mm and 13.5 mm at B-point and Pog, respectively. The mean skeletal relapse from T2 to T3 was -1.3 mm at B point and -1.6 mm at Pog. The nineteen patients characterized as long facial types, showed the highest amount of skeletal relapse (-1.5 mm at B-point and -1.9 mm at Pog). CONCLUSIONS: The present study showed a limited amount of skeletal relapse in large mandibular advancement (> 10 mm) with bilateral sagittal split osteotomy and skeletal elastic intermaxillary fixation. Bilateral sagittal split osteotomy in combination with skeletal intermaxillary fixation can therefore be an alternative to distraction osteogenesis in large mandibular advancements. PMID- 27489610 TI - Vertical Craniofacial Morphology and its Relation to Temporomandibular Disorders. AB - OBJECTIVES: This study investigated the association between craniofacial morphology and temporomandibular disorders in adults. The influence of different craniofacial morphologies on painful temporomandibular disorders was also evaluated. MATERIAL AND METHODS: A total of 200 subjects were selected, including 100 with temporomandibular disorders (TMD) and 100 without TMD (control), diagnosed by research diagnostic criteria for temporomandibular disorders. All subjects were submitted to lateral cephalometric radiographs, and classified as brachyfacial, mesofacial, or dolichofacial by Ricketts' analysis. Data were analysed by Tukey-Kramer and Chi-square tests. RESULTS: No association between craniofacial morphology and TMD was found (P = 0.6622). However, brachyfacial morphology influences the presence of painful TMD (P = 0.0077). CONCLUSIONS: Craniofacial morphology is not related to temporomandibular disorders in general. PMID- 27489611 TI - The phenotypic plasticity of developmental modules. AB - BACKGROUND: Organisms develop and evolve in a modular fashion, but how individual modules interact with the environment remains poorly understood. Phenotypically plastic traits are often under selection, and studies are needed to address how traits respond to the environment in a modular fashion. In this study, tissue specific plasticity of melanic spots was examined in the large milkweed bug, Oncopeltus fasciatus. RESULTS: Although the size of the abdominal melanic bands varied according to rearing temperatures, wing melanic bands were more robust. To explore the regulation of abdominal pigmentation plasticity, candidate genes involved in abdominal melanic spot patterning and biosynthesis of melanin were analyzed. While the knockdown of dopa decarboxylase (Ddc) led to lighter pigmentation in both the wings and the abdomen, the shape of the melanic elements remained unaffected. Although the knockdown of Abdominal-B (Abd-B) partially phenocopied the low-temperature phenotype, the abdominal bands were still sensitive to temperature shifts. These observations suggest that regulators downstream of Abd-B but upstream of DDC are responsible for the temperature response of the abdomen. Ablation of wings led to the regeneration of a smaller wing with reduced melanic bands that were shifted proximally. In addition, the knockdown of the Wnt signaling nuclear effector genes, armadillo 1 and armadillo 2, altered both the melanic bands and the wing shape. Thus, the pleiotropic effects of Wnt signaling may constrain the amount of plasticity in wing melanic bands. CONCLUSIONS: We propose that when traits are regulated by distinct pre patterning mechanisms, they can respond to the environment in a modular fashion, whereas when the environment impacts developmental regulators that are shared between different modules, phenotypic plasticity can manifest as a developmentally integrated system. PMID- 27489612 TI - The developmental and genetic bases of apetaly in Bocconia frutescens (Chelidonieae: Papaveraceae). AB - BACKGROUND: Bocconia and Macleaya are the only genera of the poppy family (Papaveraceae) lacking petals; however, the developmental and genetic processes underlying such evolutionary shift have not yet been studied. RESULTS: We studied floral development in two species of petal-less poppies Bocconia frutescens and Macleaya cordata as well as in the closely related petal-bearing Stylophorum diphyllum. We generated a floral transcriptome of B. frutescens to identify MADS box ABCE floral organ identity genes expressed during early floral development. We performed phylogenetic analyses of these genes across Ranunculales as well as RT-PCR and qRT-PCR to assess loci-specific expression patterns. We found that petal-to-stamen homeosis in petal-less poppies occurs through distinct developmental pathways. Transcriptomic analyses of B. frutescens floral buds showed that homologs of all MADS-box genes are expressed except for the APETALA3 3 ortholog. Species-specific duplications of other ABCE genes in B. frutescens have resulted in functional copies with expanded expression patterns than those predicted by the model. CONCLUSIONS: Petal loss in B. frutescens is likely associated with the lack of expression of AP3-3 and an expanded expression of AGAMOUS. The genetic basis of petal identity is conserved in Ranunculaceae and Papaveraceae although they have different number of AP3 paralogs and exhibit dissimilar floral groundplans. PMID- 27489614 TI - EphA5 and EphA6: regulation of neuronal and spine morphology. AB - BACKGROUND: The Eph family of receptor tyrosine kinases plays important roles in neural development. Previous studies have implicated Eph receptors and their ligands, the ephrins, in neuronal migration, axon bundling and guidance to specific targets, dendritic spine formation and neural plasticity. However, specific contributions of EphA5 and EphA6 receptors to the regulation of neuronal cell morphology have not been well studied. RESULTS: Here we show that deletion of EphA5 and EphA6 results in abnormal Golgi staining patterns of cells in the brain, and abnormal spine morphology. CONCLUSION: These observations suggest novel functions of these Eph receptors in the regulation of neuronal and spine structure in brain development and function. PMID- 27489613 TI - Developmental expression of "germline"- and "sex determination"-related genes in the ctenophore Mnemiopsis leidyi. AB - BACKGROUND: An essential developmental pathway in sexually reproducing animals is the specification of germ cells and the differentiation of mature gametes, sperm and oocytes. The "germline" genes vasa, nanos and piwi are commonly identified in primordial germ cells, suggesting a molecular signature for the germline throughout animals. However, these genes are also expressed in a diverse set of somatic stem cells throughout the animal kingdom leaving open significant questions for whether they are required for germline specification. Similarly, members of the Dmrt gene family are essential components regulating sex determination and differentiation in bilaterian animals, but the functions of these transcription factors, including potential roles in sex determination, in early diverging animals remain unknown. The phylogenetic position of ctenophores and the genome sequence of the lobate Mnemiopsis leidyi motivated us to determine the compliment of these gene families in this species and determine expression patterns during development. RESULTS: Our phylogenetic analyses of the vasa, piwi and nanos gene families show that Mnemiopsis has multiple genes in each family with multiple lineage-specific paralogs. Expression domains of Mnemiopsis nanos, vasa and piwi, during embryogenesis from fertilization to the cydippid stage, were diverse, with little overlapping expression and no or little expression in what we think are the germ cells or gametogenic regions. piwi paralogs in Mnemiopsis had distinct expression domains in the ectoderm during development. We observed overlapping expression domains in the apical organ and tentacle apparatus of the cydippid for a subset of "germline genes," which are areas of high cell proliferation, suggesting that these genes are involved with "stem cell" specification and maintenance. Similarly, the five Dmrt genes show diverse non-overlapping expression domains, with no clear evidence for expression in future gametogenic regions of the adult. We also report on splice variants for two Mnemiopsis Dmrt genes that impact the presence and composition of the DM DNA binding domain for these transcription factors. CONCLUSION: Our results are consistent with a potential role for vasa, piwi and nanos genes in the specification or maintenance of somatic stem cell populations during development in Mnemiopsis. These results are similar to previous results in the tentaculate ctenophore Pleurobrachia, with the exception that these genes were also expressed in gonads and developing gametes of adult Pleurobrachia. These differences suggest that the Mnemiopsis germline is either specified later in development than hypothesized, the germline undergoes extensive migration, or the germline does not express these classic molecular markers. Our results highlight the utility of comparing expression of orthologous genes across multiple species. We provide the first description of Dmrt expression in a ctenophore, which indicates that Dmrt genes are expressed in distinct structures and regions during development but not in future gametogenic regions, the only sex-specific structure for this hermaphroditic species. PMID- 27489615 TI - Exercise in space: the European Space Agency approach to in-flight exercise countermeasures for long-duration missions on ISS. AB - BACKGROUND: To counteract microgravity (uG)-induced adaptation, European Space Agency (ESA) astronauts on long-duration missions (LDMs) to the International Space Station (ISS) perform a daily physical exercise countermeasure program. Since the first ESA crewmember completed an LDM in 2006, the ESA countermeasure program has strived to provide efficient protection against decreases in body mass, muscle strength, bone mass, and aerobic capacity within the operational constraints of the ISS environment and the changing availability of on-board exercise devices. The purpose of this paper is to provide a description of ESA's individualised approach to in-flight exercise countermeasures and an up-to-date picture of how exercise is used to counteract physiological changes resulting from uG-induced adaptation. Changes in the absolute workload for resistive exercise, treadmill running and cycle ergometry throughout ESA's eight LDMs are also presented, and aspects of pre-flight physical preparation and post-flight reconditioning outlined. RESULTS: With the introduction of the advanced resistive exercise device (ARED) in 2009, the relative contribution of resistance exercise to total in-flight exercise increased (33-46 %), whilst treadmill running (42-33 %) and cycle ergometry (26-20 %) decreased. All eight ESA crewmembers increased their in-flight absolute workload during their LDMs for resistance exercise and treadmill running (running speed and vertical loading through the harness), while cycle ergometer workload was unchanged across missions. CONCLUSION: Increased or unchanged absolute exercise workloads in-flight would appear contradictory to typical post-flight reductions in muscle mass and strength, and cardiovascular capacity following LDMs. However, increased absolute in-flight workloads are not directly linked to changes in exercise capacity as they likely also reflect the planned, conservative loading early in the mission to allow adaption to uG exercise, including personal comfort issues with novel exercise hardware (e.g. the treadmill harness). Inconsistency in hardware and individualised support concepts across time limit the comparability of results from different crewmembers, and questions regarding the difference between cycling and running in uG versus identical exercise here on Earth, and other factors that might influence in-flight exercise performance, still require further investigation. PMID- 27489617 TI - 3D haptic modelling for preoperative planning of hepatic resection: A systematic review. AB - INTRODUCTION AND BACKGROUND: Three dimensional (3D) printing has gained popularity in the medical field because of increased research in the field of haptic 3D modeling. We review the role of 3D printing with specific reference to liver directed applications. METHODS: A literature search was performed using the scientific databases Medline and PubMed. We performed this in-line with the PRISMA [20] statement. We only included articles in English, available in full text, published about adults, about liver surgery and published between 2005 and 2015. The 3D model of a patient's liver venous vasculature and metastasis was prepared from a CT scan using Osirix software (Pixmeo, Gineva, Switzerland) and printed using our 3D printer (MakerBot Replicator Z18, US). To validate the model, measurements from the inferior vena cava (IVC) were compared between the CT scan and the 3D printed model. RESULTS: A total of six studies were retrieved on 3D printing directly related to a liver application. While stereolithography (STL) remains the gold standard in medical additive manufacturing, Fused Filament Fabrication (FFF), is cheaper and may be more applicable. We found our liver 3D model made by FFF had a 0.1 +/- 0.06 mm margin of error (mean +/- standard deviation) compared with the CT scans. CONCLUSION: 3D printing in general surgery is yet to be thoroughly exploited. The most relevant feature of interest with regard to liver surgery is the ability to view the 3D dimensional relationship of the various hepatic and portal veins with respect to tumor deposits when planning hepatic resection. Systematic review registration number: researchregistry1348. PMID- 27489618 TI - On the endoscopic methods used in pediatrics with questionable indications. AB - *Partial isolation from international scientific community can result in application of invasive methods without sufficient indications.*Performing invasive procedures, the risk-to-benefit ratio should be kept as low as possible.*Practical recommendations must be based on reliable and reproducible research. PMID- 27489619 TI - Surgical versus percutaneous techniques for peritoneal dialysis catheter placement: A meta-analysis of the outcomes. AB - BACKGROUND: Peritoneal dialysis (PD) is an effective method of renal replacement therapy for end-stage renal disease patients. The PD catheter could be inserted by surgical (open surgery/laparoscopic-assisted) or percutaneous techniques. However, the efficacy of the techniques, including catheter survival and catheter related complications, is still controversial. METHOD: The dataset was defined by searching PubMed, EMBASE, Google Scholar and the Cochrane database that had been published until July 2014. The meta-analysis was performed using Review Manager Software version 5.2.6. RESULT: The final analysis was conducted on 10 studies (2 randomized controlled studies (RCTs) and 8 retrospective studies), including 1626 patients. The pooled data demonstrate no significant difference in 1-year catheter survival (OR = 1.04, 95% CI = 0.52-2.10, P = 0.90) between surgical and percutaneous groups. However, the sensitivity analysis of the RCTs demonstrated that the incidence of overall infectious (OR = 0.26, 95% CI = 0.11-0.64, P = 0.003) and overall mechanical complications (OR = 0.32, 95% CI = 0.15-0.68, P = 0.003) were significantly lower in the percutaneous groups than the surgical groups. Furthermore, the subgroup analyses revealed no significant difference in the rates of peritonitis, tunnel and exit site infection, leakage, inflow-outflow obstruction, bleeding and hernia by comparing the methods. CONCLUSION: The results showed that the placement modality did not affect 1-year catheter survival. Percutaneous catheter placement is as safe and effective as surgical technique. PMID- 27489620 TI - The art of self-knowledge and deduction in clinical practice. AB - Clinical reasoning involves interviewing the patient, taking a history, and carefully scrutinising objects in the environment, via a physical examination, and the interpretation of medical results. Developments in medicine are trending towards the routine use of sophisticated diagnostic tools. While important, these trends may be leading clinicians to rely on expensive tests, while not using or improving the art of clinical deduction. The ideal clinician knows themselves and their environment, truly observes, imagines the possibilities, deduces from what they observe, and continually learns. This allows the clinician to use all of their senses, while not primarily relying on a diagnostic test. PMID- 27489622 TI - Perioperative use of steroids in neonatal heart surgery: Evidence based practice or tradition? AB - A best evidence topic was written according to a structured protocol. The question addressed was: Is the use of prophylactic, perioperative steroids associated with better clinical outcomes following heart surgery in neonates? Altogether, 194 papers were found using the reported search, of which 8 represented the best evidence to answer the clinical question. One study found improved hospital survival in the group without steroids. Steroids increased infection in one large retrospective study. Incidence of hyperglycaemia was increased in the steroid group in 2 out of 5 studies. Use of steroids was associated with a shorter duration of ventilation and better oxygenation in one study. Postoperative steroid infusion was associated with reduced low cardiac output syndrome, inotrope requirement and less fluid retention in two controlled trials in which all patients received preoperative steroid. High dose steroid was associated with renal dysfunction in one study, comparing single versus double dose steroid prophylaxis. Steroid non-recipients had a shorter intensive care length of stay in 2 out of 7 studies. We conclude that use of steroids perioperatively does not unequivocally improve clinical outcome in neonatal heart surgery. A large, multicentre prospective randomized controlled trial is needed to clarify the role of steroids in paediatric heart surgery. PMID- 27489621 TI - High-performance detection and early prediction of septic shock for alcohol-use disorder patients. AB - BACKGROUND: The presence of Alcohol Use Disorder (AUD) complicates the medical conditions of patients and increases the difficulty of detecting and predicting the onset of septic shock for patients in the ICU. METHODS: We have developed a high-performance sepsis prediction algorithm, InSight, which outperforms existing methods for AUD patient populations. InSight analyses a combination of singlets, doublets, and triplets of clinical measurements over time to generate a septic shock risk score. AUD patients obtained from the MIMIC III database were used in this retrospective study to train InSight and compare performance with the Modified Early Warning Score (MEWS), the Simplified Acute Physiology Score (SAPS II), and the Systemic Inflammatory Response Syndrome (SIRS) for septic shock prediction and detection. RESULTS: From 4-fold cross validation, InSight performs particularly well on diagnostic odds ratio and demonstrates a relatively high Area Under the Receiver Operating Characteristic (AUROC) metric. Four hours prior to onset, InSight had an average AUROC of 0.815, and at the time of onset, InSight had an average AUROC value of 0.965. When applied to patient populations where AUD may complicate prediction methods of sepsis, InSight outperforms existing diagnostic tools. CONCLUSIONS: Analysis of the higher order correlations and trends between relevant clinical measurements using the InSight algorithm leads to more accurate detection and prediction of septic shock, even in cases where diagnosis may be confounded by AUD. PMID- 27489623 TI - Laparoscopic colorectal resections with and without routine mechanical bowel preparation: A comparative study. AB - BACKGROUND: The benefit of mechanical bowel preparation (MBP) in patients undergoing laparoscopic colorectal resections remains a question. This study aimed to evaluate the effect of omitting MBP on patients undergoing laparoscopic bowel resections. METHODS: The outcomes of patients who underwent elective colorectal resections for cancer of colon and upper rectum without MBP were compared to a retrospective cohort who had MBP. RESULTS: There were 97 patients in the No-MBP group and 159 patients in the MBP group. Their mean age, operative risk, tumor size and stage of disease were similar. There were no significant differences in operative time and estimated blood loss. The anastomotic leakage rate was 1.0% in the No-MBP group and 0.6% in the MBP group, (p = 1.00). Wound infection rate were 4.1% and 3.8% in the No-MBP group and the MBP group respectively (p = 1.00). Overall surgical morbidity rate was 11.3% in the No-MBP group and 8.2% in the MBP group (p = 0.40). Conversion rates were 5.2% in the No MBP group and 6.9% in the MBP group, (p = 0.57). CONCLUSION: The omission of mechanical bowel preparation does not increase surgical morbidities in patients undergoing laparoscopic bowel resections. It also has no effect on operating time and conversion rate. PMID- 27489624 TI - Digital rectal examination for initial assessment of the multi-injured patient: Can we depend on it? AB - BACKGROUND: Digital rectal examination (DRE) is part of the assessment of trauma patients as recommended by ATLS((r)). The theory behind is to aid early diagnosis of potential lower intestinal, urethral and spinal cord injuries. Previous studies suggest that test characteristics of DRE are far from reliable. This study examines the correlation between DRE findings and diagnosis and whether DRE findings affect subsequent management. MATERIALS AND METHODS: Patients with ICD 10 codes for spinal cord, urethral and lower intestinal injuries were identified from the trauma registry at an urban university hospital between 2007 and 2011. A retrospective review of electronic medical records was carried out to analyse DRE findings and subsequent management. RESULTS: 253 patients met the inclusion criteria with a mean age of 44 +/- 20 years and mean ISS of 26 +/- 16. 160 patients had detailed DRE documentation with abnormal findings in 48%. Sensitivity rate was 0.47. Correlational analysis between examination findings and diagnosis gave a kappa of 0.12. Subsequent management was not altered in any case due to DRE findings. CONCLUSION: DRE in trauma settings has low sensitivity and does not change subsequent management. Excluding or postponing this examination should therefore be considered. PMID- 27489625 TI - Increased serum IgG4 levels and intimal IgG4-positive cell infiltration in rapidly growing aortic aneurysm. AB - A 67-year-old Japanese man had been complaining of discomfort in the chest and back and feeling febrile for 2 weeks. Chest computed tomography indicated a thoracic aortic aneurysm. He occasionally showed a high fever (up to 38.0 degrees C), even after hospital admission, irrespective of antibiotic therapy. The patient was found to have elevated serum IgG4 levels (366 mg/dL). The aneurysm demonstrated rapid growth; therefore, rifampicin-soaked woven Dacron synthetic graft replacement was performed 22 days after admission. Immunohistostatining of the resected aorta segment showed an IgG4-positive plasma cell infiltrate within the intimal layer neighboring the cholesterol-rich atheromatous plaque. After surgery, the patient's serum IgG4 level dropped acutely; however, it did not reach the normal range. The possible role of IgG4 in the development or suppression of aortic remodeling, as well as in atherogenesis, among patients with rapidly growing aortic aneurysm requires further investigation. PMID- 27489626 TI - Presumed hydrochlorothiazide-associated immunologic-hypersensitivity-induced pericardial effusion. AB - A 50-year-old Caucasian female presented for a second opinion regarding a newly diagnosed pericardial effusion. Seven months previously, hydrochlorothiazide was introduced into her pharmacologic regimen to aid in the management of her hypertension. A routine echocardiogram indicated a large pericardial effusion with signs of early cardiac tamponade. The patient subsequently underwent successful pericardiocentesis with complete drainage of the pericardial effusion. The effusion was empirically attributed to a viral etiology. Repeat echocardiograms showed recurrence of the pericardial effusion. Prior to undergoing a second pericardiocentesis with pericardial biopsy, as her physicians recommended, the patient sought a second opinion. While obtaining the patient's history, an allergy to sulfa was elicited. The possibility that the pericardial effusion may be secondary to an immunologic-hypersensitivity reaction was considered. It was recommended the patient discontinue the use of hydrochlorothiazide. Nine days following discontinuation of hydrochlorothiazide and without any other intervention, an echocardiogram was reported to show the size of the pericardial effusion had subsided substantially. Nine weeks following discontinuation, almost complete resolution of the pericardial effusion was reported. It is hypothesized that when treated with hydrochlorothiazide, the patient had an immune response leading to the pericardial effusion. PMID- 27489627 TI - Squamous cell carcinoma arising from congenital lymphedema. AB - Congenital lymphedema is a rare type of primary lymphedema occurring at birth or developing shortly later. Primary lymphedema can be classified according to whether it is familial or sporadic. The primary congenital familial lymphedema is also known as Milroy's disease. Majority of primary cases are sporadic type. Chronic lymphedema can be secondary to infections, surgery with lymph node excision, trauma, lymphadenectomy, radiotherapy, filarial infection, and so on. It is recognized that a variety of malignant tumors can arise in chronic congenital or acquired lymphedema; the most documented associations are lymphangiosarcoma, basal cell carcinoma, lymphoma, malignant melanoma, and Kaposi's sarcoma. A total of 13 cases of squamous cell carcinoma arising from chronic (primary or acquired) lymphedema have been reported, and only 3 cases of congenital lymphedema presented with squamous cell carcinoma as reported. A 32 year-old young male presented with chronic unilateral left lower limb lymphedema of 28 years duration. In addition, he had a 3-month history of a fungating cutaneous lesion on the lateral side measuring 2 cm * 1 cm in size. Fine-needle aspiration cytology was performed on the later mass, and a diagnosis of angiosarcoma was made. At histopathology, the appearances did not confirm angiosarcoma. However, an impression of carcinoma was made as squamous cells were observed in sheets. Immunohistochemistry was performed using markers for CD31, factor VIII (FVIII), and MiB. The epithelial marker cytokeratin was positive for squamoid cells and MiB index of 75%. The vascular markers FVIII and CD31 were negative, thus ruling out angiosarcoma. The final diagnosis was given as infiltrating squamous cell carcinoma in chronic lymphedema. PMID- 27489628 TI - A patient with profound weight loss after gastric bypass surgery: A case report. AB - INTRODUCTION: A case of profound weight loss after gastric bypass surgery with multiple negative evaluations. CASE PRESENTATION: A 41-year-old African-American female presented with greater-than-expected weight loss after gastric bypass and increasing abdominal pain over a 2-year period. An extensive workup was pursued for the patient with blood analysis, tumor markers, imaging studies both computed tomography and magnetic resonance imaging, arterial studies, and endoscopy from above and below, all of which demonstrated normal results. The patient was followed up without improvement, and repeated studies were also normal. The patient was labeled with a nonorganic etiology for her symptoms, which led to a psychiatry referral which was refused. CONCLUSION: The patient's surgeon, who already had removed a normal appendix and gallbladder, repeated a laparoscopic exam. The exam was normal except for a small focus of pancreatic cancer in the celiac plexus. The patient died from perioperative sepsis from peritonitis 2 days after surgery. The case is discussed and findings reviewed. PMID- 27489629 TI - A case of mistaken identity: When lupus masquerades as primary myelofibrosis. AB - INTRODUCTION: Autoimmune myelofibrosis is an uncommon hematologic disease characterized by anemia, bone marrow myelofibrosis, and an autoimmune feature. Myelofibrosis is often associated with other conditions, including infections, nutritional/endocrine dysfunction, toxin/drug exposure, and connective tissue diseases, including scleroderma and systemic lupus erythematosus. Absence of clonal markers (JAK2) and heterogeneity of the symptoms often complicate the diagnosis. CASE PRESENTATION: Here, we present two cases of systemic lupus erythematosus-induced autoimmune myelofibrosis. The first case is of a 36-year old African American female with diagnosis of systemic lupus erythematosus at the age of 12 years. The second patient is a 44-year-old African American male with family history of systemic lupus erythematosus who developed anemia and constitutional symptoms later on. Both patients showed hypercellularity and fibrotic changes of the bone marrow. Moreover, mutational analysis showed that both patients were wild type for JAK2 (V617F and exon 12) and MPL (exon 10). CONCLUSIONS: These two cases illustrate that anemic patients with fibrotic changes in the bone marrow without other clinicopathologic features associated with primary myelofibrosis in the presence of clinical manifestations and history of an autoimmune disease should suggest an autoimmune myelofibrosis. These cases demonstrate that a good clinical history combined with molecular technologies and pathomorphologic criteria are helpful in distinguishing between primary myelofibrosis and a nonclonal myelofibrosis from an associated condition. PMID- 27489630 TI - Palliative care consults in oncology: what are we waiting for? A case report. AB - Palliative care focuses on symptom management and decreased suffering in all aspects of health. Although it has been shown that palliative care improves emotional and clinical outcomes for patients and families, it remains an underutilized specialty particularly in the field of oncology. Involving cancer patients in palliative care can sometimes be confused with the idea of giving up, or losing hope. This is especially true when patients are young. The following case report provides an example of a patient who may have benefited from palliative specialists' involvement early in his disease, potentially sparing him and his family prolonged, physical, and emotional suffering. PMID- 27489631 TI - Isolated infrarenal abdominal aorta aneurysm in a 42-year-old patient with Marfan's syndrome: Case report. AB - Marfan's syndrome is an autosomal dominant disorder of connective tissue characterized by a large number of possible mutations and by heterogeneity of clinical presentation primarily in skeletal, ocular and cardiovascular organ systems. Cardiovascular complications of the disease are responsible for high mortality. The case of a 42-year-old patient with a progressive advanced abdominal aorta dilatation visualized on computed tomography images is presented. Pathogenesis, diagnosis and management of patients with Marfan's syndrome are also discussed. PMID- 27489632 TI - Elevated liver enzymes associated with dronedarone for atrial fibrillation. AB - A 51-year-old male with documented atrial fibrillation who was taking dronedarone 400 mg twice daily for approximately 3 months returned to the cardiologist for an ablation procedure. Baseline liver enzymes were within normal range prior to starting the medication and increased after the 3 months of therapy. Aspartate aminotransferase increased from 31 IU/L to 98 IU/L, and alanine aminotransferase increased from 21 IU/L to 101 IU/L. Two and a half months after discontinuation of the medication, liver enzymes normalized (aspartate aminotransferase: 30 IU/L and alanine aminotransferase: 25 IU/L). The Food and Drug Administration has now alerted health-care professionals of the potential for liver injury based upon post-marketing surveillance. The chronological course of elevated liver enzymes noted in our patient is suggestive of a dronedarone-induced problem. Clinicians should have a heightened awareness of the potential for liver enzyme elevation and injury with dronedarone and should monitor enzymes periodically, especially within the first 6 months of use. PMID- 27489633 TI - Hand replantation: A rare case report. AB - We report a case of a hand replantation. A 43-year-old male presented with an amputated right hand. After clinical and radiological examination of the amputated hand and the forearm stump, the patient was consented for hand replantation procedure. Both bones of the forearm were fixed using K-wires. Careful dissection, trimming and repair of the tendons, vessels (two arteries and one vein) and nerves was achieved. The patient tolerated the procedure well and 2 months later showed a progressive improvement in motor and sensory functions. We suggest that a single-vein repair is sufficient for a successful hand replantation. PMID- 27489634 TI - Elevated international normalized ratio with the consumption of grapefruit and use of warfarin. AB - A 65-year-old male with documented atrial flutter who was taking warfarin chronically returned to the anticoagulation clinic for follow-up, after having been on 10 mg daily for approximately 2 weeks. He had a previous sub-therapeutic international normalized ratio of 1.7 on a dose of 65 mg/week. The international normalized ratio at this visit was now 4.77 via venipuncture, after just an 8% increase in weekly dosing. He self-reported adherence to the new warfarin dosing but had begun eating grapefruit since last visit. The patient had no active bleeding and was told to decrease his dose to 8 mg daily. He also stopped eating the grapefruit. One week later, he returned to the clinic and the international normalized ratio was 2.1. He is currently back on warfarin 65 mg/week, and his international normalized ratio has been within therapeutic range for the past 4 months. Clinicians should have a heightened awareness of the potential for elevated international normalized ratio when grapefruit juice is consumed in a patient who is taking warfarin. PMID- 27489635 TI - Repetitive complications after prosthetic graft for inflammatory aortic aneurysm. AB - The presence of retroperitoneal fibrosis after an aortic graft replacement is a marker of poor prognosis following aortic graft replacement. Herein we report the case of a 39-year-old man with retroperitoneal fibrosis that had been causing ureteral obstruction. The man had undergone repeated aortic graft replacement due to bacteremia and aortic graft-small intestinal fistula that occurred 4 years after initial aortic grafting for an inflammatory aortic aneurysm. The patient was discharged after 4 weeks of intravenous antibiotic therapy following the latest aortic graft replacement. PMID- 27489636 TI - Tocilizumab improved clinical symptoms of a patient with systemic tophaceous gout who had symmetric polyarthritis and fever: An alternative treatment by blockade of interleukin-6 signaling. AB - Chronic tophaceous gout is the end stage of gout. We employed a blockade of interleukin-6 signaling therapy by tocilizumab instead of anakinra, an interleukin-1 receptor antagonist, for a 61-year-old Japanese woman diagnosed with tophaceous gout. Laboratory data showed that serum interleukin-6 concentration was elevated. Serum interleukin-1beta concentration was under the detectable level, although serum uric acid was elevated due to renal dysfunction. The secretion patterns of interleukin-1beta, tumor-necrosis factor-alpha, interleukin-6, and interleukin-8 from peripheral mononuclear cells isolated from the patient exhibited no remarkable differences compared with those of healthy volunteers. After treatment with the interleukin-6 receptor antagonist tocilizumab, serum interleukin-6 concentration decreased followed by improved clinical symptoms, such as reduced size of the subcutaneous nodules, no fever, and no acute gouty attacks during the treatment. Our case suggests that tocilizumab markedly improves clinical and laboratory manifestations in tophaceous gout with arthritis and fever as well as interleukin-1 blockade therapy. PMID- 27489637 TI - A case report of anxiety disorder preceding frontotemporal dementia with asymmetric right temporal lobe atrophy. AB - Behavioral variant frontotemporal dementia presents with progressive loss of social skills and cognition and is usually associated with asymmetric frontal or temporal lobe involvement. This article reports about a patient with a long history of anxiety disorder who later proceeded to develop behavioral variant frontotemporal dementia. Further discussion about selective specific network vulnerability and a possible link between these two conditions is provided. PMID- 27489638 TI - A noninvasive biomechanical treatment as an additional tool in the rehabilitation of an acute anterior cruciate ligament tear: A case report. AB - OBJECTIVES: Conservative treatments for anterior cruciate ligament (ACL) tears may have just as good an outcome as invasive treatments. These include muscle strengthening and neuromuscular proprioceptive exercises to improve joint stability and restore motion to the knee. The Purpose of the current work presents was to examine the feasibility of a novel non-invasive biomechanical treatment to improve the rehabilitation process following an ACL tear. This is a single case report that presents the effect of this therapy in a patient with a complete ACL rupture who chose not to undergo reconstructive surgery. METHODS: A 29-year old female athlete with an acute indirect injury to the knee who chose not to undergo surgery was monitored. Two days after injury the patient began AposTherapy. A unique biomechanical device was specially calibrated to the patient's feet. The therapy program was initiated, which included carrying out her daily routine while wearing the device. The subject underwent a gait analysis at baseline and follow-up gait analyses at weeks 1, 2, 4, 8, 12 and 26. RESULTS: A severe abnormal gait was seen immediately after injury, including a substantial decrease in gait velocity, step length and single limb support. In addition, limb symmetry was substantially compromised following the injury. After 4 weeks of treatment, patient had returned to normal gait values and limbs asymmetry reached the normal range. CONCLUSIONS: The results of this case report suggest that this conservative biomechanical therapy may have helped this patient in her rehabilitation process. Further research is needed in order to determine the effect of this therapy for patients post ACL injuries. PMID- 27489639 TI - Clinical impact of laboratory error on therapeutic drug monitoring of once-daily tobramycin in cystic fibrosis: Case series. AB - Once-daily dosing intravenous tobramycin is commonly used to treat cystic fibrosis pulmonary exacerbations. Clinicians often utilize historical therapeutic drug monitoring data to individualize the dose among patients who have been treated with tobramycin previously. This case series involves three patients with cystic fibrosis who had supra-therapeutic tobramycin levels despite use of a once daily dosing that produced therapeutic drug levels during a previous hospital admission, raising questions about the validity of these levels. Investigation into several potential sources of error led to the discovery of an analyzer error in the laboratory. Once the laboratory's tobramycin analyzer was recalibrated, the reported levels were comparable to historical levels. This case series emphasizes the clinical importance of critically analyzing reported levels, and specifically, the importance of utilizing past therapeutic drug monitoring data, if available, for all patients treated with intravenous tobramycin. If a patient was therapeutic on a similar dose of tobramycin during a previous admission, a dose adjustment may not be necessary, and clinicians should consider repeating levels while pursuing alternative explanations for the discrepant serum levels. PMID- 27489640 TI - Left-sided thoracoscopy in the prone position for surgery of distal esophageal benign pathologies. AB - Exposure of the distal esophagus can be achieved by a wide variety of surgical approaches. The standard procedure is mostly by laparoscopy. In cases where laparoscopy is relatively contraindicated, thoracoscopy is preferred. In this case, exposure of the distal esophagus from the aorta, heart and lung is technically challenging using thoracoscopy in the right lateral decubitus position. Surgery in the prone position for esophageal cancer has been successfully described in previous literature. We present our experience with left-sided thoracoscopy in the prone position in three patients with benign distal esophageal pathologies. This approach provided a much better exposure of the distal esophagus and enabled a successful surgery to be done in all patients with less manipulation of the lung. PMID- 27489641 TI - A six-time Ultraman winner and a normal heart: A case report. AB - Number of subjects currently participating in high-endurance aerobic exercise training regimens and competitions has substantially increased in recent years. While there is no doubt that regular exercise practice is fundamental for the maintenance of a good health, there have been reports of cardiac structural changes of subjects exposed to strenuous endurance physical exercise. This article reports a case of a 47-year-old male very successful sportsman-including being a six-time Ultraman winner-who has accumulated more than 50,000 h of training and competition in his 35-year career, averaging 25-30 h/week. Despite this huge amount of aerobic exercise, about 25 times larger than typically recommended dose for health purposes (i.e. 75 min of vigorous exercise per week), no major abnormalities were detected in electrocardiograms (rest and maximal exercise), transthoracic echocardiogram, and magnetic resonance imaging. In fact, after this complete evaluation, his heart was found to be quite normal. PMID- 27489642 TI - Improved myocardial perfusion after transmyocardial laser revascularization in a patient with microvascular coronary artery disease. AB - We report the case of a 59-year-old woman who presented with symptoms of angina that was refractory to medical management. Although her cardiac catheterization revealed microvascular coronary artery disease, her symptoms were refractory to optimal medical management that included ranolazine. After undergoing transmyocardial revascularization, her myocardial ischemia completely resolved and her symptoms dramatically improved. This case suggests that combination of ranolazine and transmyocardial revascularization can be applied to patients with microvascular coronary artery disease. PMID- 27489643 TI - Rheumatic heart disease in Tennessee: An overlooked diagnosis. AB - Rheumatic heart disease, already a major burden in low- and middle-income countries, is becoming an emerging problem in high-income countries. Although acute rheumatic fever and rheumatic heart disease have almost been eradicated in areas with established economies, the emergence of this problem may be attributable to the migration from low-income to high-income settings. Between 2010 and 2012, we diagnosed a cluster of rheumatic heart disease cases in children from the Middle Tennessee area. The goal of this report is to increase awareness among clinicians as the incidence and prevalence of acute rheumatic fever remain relatively significant in large US metropolitan areas. Although acute rheumatic fever is seasonal, a high suspicion index may lead to the early diagnosis and prevention of its cardiac complications. Furthermore, screening procedures may be recommended for populations at risk for rheumatic heart disease in endemic areas, and active surveillance with echocardiography-based screening might become very important. PMID- 27489644 TI - Cerebral contrast retention after difficult cardiac catheterization: Case report. AB - BACKGROUND: We report a diagnostic dilemma in a rare case of cerebral contrast retention after difficult cardiac catheterization in an elderly patient loaded with prasugrel. SUMMARY: Our case report describes a 77-year-old female with history of hypertension, diabetes, and dyslipidemia who presented to emergency department complaining of chest pain. Patient was found to have an inferior wall ST elevation myocardial infarction. The patient was loaded with aspirin and prasugrel and taken for emergent cardiac catheterization. Cardiac catheterization revealed two-vessel coronary artery disease with unsuccessful attempt of percutaneous intervention. Immediately after procedure, patient developed an episode of seizure. Emergent computed tomography scan of the brain revealed hyperdensity in the right frontoparietal region consistent with intracerebral bleed. Repeat computed tomography (24 h later) revealed substantial interval improvement of hyperdensity. Follow-up magnetic resonance imaging of the head was normal. Given the lack of magnetic resonance imaging changes, the rate of resolution on computed tomography without expected subacute changes, and the lack of neurologic findings, the initial hyperdensity seen on computed tomography of the brain was believed to be secondary to contrast leakage during cardiac catheterization as opposed to intracranial hemorrhage. PMID- 27489645 TI - Swelling of bilateral parotid glands: An unusual symptom of multisystem Langerhans cell histiocytosis. AB - OBJECTIVE: Langerhans cell histiocytosis is an unusual disorder of unknown etiology with heterogeneous clinical behaviors and variable outcomes. It can involve one or more organs or systems, but to our best knowledge, parotid glands involvement in Langerhans cell histiocytosis is extremely rare in English literature. METHOD: We report a 13-month-old girl who presented with bilateral parotid swelling as presenting symptom. She was misdiagnosed for 4 months, but final diagnosis was multisystem Langerhans cell histiocytosis. RESULT: After being treated for 18 months, the patient acquired complete remission and attained similar growth status to other healthy children. CONCLUSION: Langerhans cell histiocytosis may involve any organ; in patients with parotid enlargement, Langerhans cell histiocytosis should be kept in mind in the differential diagnoses. We emphasize the importance of biopsy for histologic evaluation as soon as possible and even repeatedly if initial results are negative for Langerhans cell histiocytosis. PMID- 27489646 TI - Fatal case of cephalexin-induced toxic epidermal necrolysis. AB - PURPOSE: To describe a case of toxic epidermal necrolysis likely caused by cephalexin with a review of the literature. CASE: An 80-year-old male with a known allergy to cephalosporins, residing at a long-term acute care hospital, received cephalexin for a urinary tract infection. And 1 day after starting therapy, the patient developed an extensive erythematous rash accompanied by skin sloughing; 4 days after receiving cephalexin, the patient was directly admitted to the burn intensive care unit and was diagnosed with toxic epidermal necrolysis involving 56% of the total body surface area. Progressive deterioration to multisystem organ failure ensued, and the patient died 5 days following his admission to the burn intensive care unit. At the time of death, ulcerations were noted over approximately 80% of his body. SUMMARY: The temporal association of the patient's ingestion of cephalexin for a urinary tract infection to his onset of toxic epidermal necrolysis suggests that this 80-year-old man developed toxic epidermal necrolysis following the administration of cephalexin for a urinary tract infection. PMID- 27489647 TI - Heparin-induced thrombocytopenia among patients of a comprehensive cancer center. AB - Most clinical studies of heparin-induced thrombocytopenia have not included cancer patients who have high risk of thromboembolism, frequent exposure to heparin, and many potential causes of thrombocytopenia other than heparin-induced thrombocytopenia. To estimate the incidence and prevalence of heparin-induced thrombocytopenia in cancer patients, we identified cases based on diagnostic codes, anti-heparin antibody testing, and clinical characteristics (4T score) at a comprehensive cancer center between 1 October 2008 and 31 December 2011. We estimated that the prevalence of heparin-induced thrombocytopenia to be 0.02% among all cancer patients and 0.24% among cancer patients exposed to heparin. The annual incidence of heparin-induced thrombocytopenia was 0.57 cases per 1000 cancer patients exposed to heparin. Of the 40 cancer patients with the International Classification of Diseases (Ninth Revision; ICD-9) code for heparin induced thrombocytopenia, positive anti-heparin antibody, and 4T score >=4, 5 (12.5%) died of related thromboembolic or hemorrhagic complications. In a multivariate logistic regression model, male gender was a significant (p = 0.035) factor, and non-hematological malignancy was a significant (p = 0.017) factor associated with anti-heparin antibody positivity. Future studies may further examine the risk factors associated with heparin-induced thrombocytopenia in larger cohorts. PMID- 27489648 TI - Groin pain after metal-on-metal hip resurfacing prosthesis. AB - Total hip replacement continues to be a widely successful operation, but persistent groin pain following a metal-on-metal hip resurfacing remains a problem for some patients. The concern regarding the safety and efficacy of metal on-metal total hip replacements has been rising. We present the case of a 47-year old man with groin pain after metal-on-metal hip resurfacing. We observed high metal ion levels detected in blood analytical studies and a pseudotumor in magnetic resonance imaging. Our patient was treated with a revision surgery. The progressive elevation of blood and urine metal levels in the presence of periarticular cysts and/or groin pain is a complication of metal-on-metal hip arthroplasty and needs revision surgery. PMID- 27489649 TI - Late-onset ornithine transcarbamylase deficiency: An under recognized cause of metabolic encephalopathy. AB - INTRODUCTION: Ornithine transcarbamylase deficiency is the most common inherited disorder of the urea cycle, has a variable phenotype, and is caused by mutations in the OTC gene. We report three cases of ornithine transcarbamylase deficiency to illustrate the late-onset presentation of this disorder and provide strategies for diagnosis and treatment. The patients were maternal first cousins, presenting with hyperammonemia and obtundation. Urea cycle disorder was not initially suspected in the first patient, delaying diagnosis. RESULTS: Sequencing of the OTC gene showed a novel missense mutation, c.563G > C (p.G188A). Numerous family members were found to carry this mutation, which shows a trend toward later onset. Each urea cycle disorder has its own unique pattern of biochemical abnormalities, which differ from non-metabolic causes of critical illness. CONCLUSION: Regardless of age, clinical suspicion of a urea cycle disorder is important in encephalopathic patients to ensure quick diagnosis and definitive treatment of the underlying inborn error of metabolism. PMID- 27489650 TI - Leukocytoclastic vasculitis in an adolescent with ulcerative colitis: Report of a case and review of the literature. AB - An adolescent female with long-standing, difficult-to-control ulcerative colitis developed leukocytoclastic vasculitis, a rare cutaneous extra-intestinal manifestation of the inflammatory bowel disease. The authors provide a literature review on leukocytoclastic vasculitis complicating ulcerative colitis. Furthermore, the clinical features of leukocytoclastic vasculitis are compared and contrasted with the more common cutaneous extra-intestinal manifestations of inflammatory bowel disease, erythema nodosum, and pyoderma gangrenosum. PMID- 27489651 TI - Successful cases of difficult inferior vena cava filter retrieval with the use of biopsy forceps: Biopsy forceps technique. AB - OBJECTIVES: For treatment and prevention of deep vein thrombosis(DVT) and pulmonary embolism(PE), retrievable inferior vena cava(IVC) filters have commonly been used as an effective bridge to anticoagulation. However, we experienced unexpected difficulty in endovascular retrieval of some IVC filters. Most problems were due to endovascular treatment devices issues, filter intimal migration, filter disintegration, filter-associated thrombosis, and right atrium/ventricle migration. METHODS: Disposable biopsy forceps was used to engage the filter hook and reform the shape of the filter struts. Endovascular retrieval assisted by use of the biopsy forceps via a similar vein was effective and provided a less-invasive, low cost method for removal of problematic IVC filters. RESULTS: We described easily performed methods that uses disposable biopsy forceps for the retrieval of IVC filters that are difficult to remove because of filter hook migration into the caval wall. CONCLUSION: We developed an easily performed method that uses intestine biopsy forceps for the retrieval of IVC filter that are difficult to remove. PMID- 27489652 TI - Endovascular treatment of arterio-ureteral fistulae with covered stents: Case series and review of the literature. AB - Arterio-ureteral fistulae are abnormal connections between an artery and the ureter and carry a high mortality. We present two cases of arterio-ureteral fistulae that presented with life-threatening hematuria. Both patients were treated with endovascular covered stent placement. PMID- 27489653 TI - Surgical repair of anomalous connection of the left coronary artery. AB - An asymptomatic 10-year-old girl with anomalous connection of the left coronary artery to the pulmonary artery underwent successful surgical repair to create a two-artery coronary system with a coronary elongation technique using an autologous pulmonary arterial wall flap. This technique facilitates direct and tension-free coronary artery re-implantation. PMID- 27489654 TI - "Cat Scratch Colon" and Cecal Barotrauma perforation during colonoscopy using CO2 insufflation. AB - Cecal perforation due to barotrauma is an increasingly recognized complication of colonoscopy when using room air for insufflation. CO2 is increasingly being utilized for insufflation due to more rapid absorption compared to ambient air and results in reduced post-procedural pain and flatulence. Use of CO2 is thought to protect against barotrauma injury, and use of CO2 during endoscopy has not previously been reported to cause barotrauma perforation during colonoscopy. We present a case of cecal perforation secondary to barotrauma during routine screening colonoscopy with CO2. PMID- 27489655 TI - Surgical repair of large aortocaval fistula with limited shunt: Case report. AB - A 67-year-old man was admitted with severe back pain and bilateral lower limb swelling. Enhanced computed tomography showed an infrarenal abdominal aortic aneurysm (92 * 75 mm(2)) and a short aortocaval fistula (7 mm). Immediately afterward, circulatory collapse occurred, and the patient was rushed to the operating theater. A much larger aortocaval fistula (22 * 35 mm(2)) than that demonstrated by preoperative computed tomography was found and was repaired with a Dacron patch while using two balloon-tipped catheters to control bleeding. Then, the abdominal aortic aneurysm was replaced with a bifurcated graft. The patient's postoperative course was uneventful. In this case, enhanced computed tomography detected the aortocaval fistula, but could not assess its size accurately. Successful surgical repair of an aortocaval fistula depends on early accurate delineation of the fistula and prompt control of bleeding. PMID- 27489656 TI - A novel mutation in the succinate dehydrogenase subunit D gene in siblings with the hereditary paraganglioma-pheochromocytoma syndrome. AB - Germline mutations in the succinate dehydrogenase complex subunit D gene are now known to be associated with hereditary paraganglioma-pheochromocytoma syndromes. Since the initial succinate dehydrogenase complex subunit D gene mutation was identified about a decade ago, more than 131 unique variants have been reported. We report the case of two siblings presenting with multiple paragangliomas and pheochromocytomas; they were both found to carry a mutation in the succinate dehydrogenase complex subunit D gene involving a substitution of thymine to guanine at nucleotide 236 in exon 3. This particular mutation of the succinate dehydrogenase complex subunit D gene has only been reported in one previous patient in Japan; this is, therefore, the first report of this pathogenic mutation in siblings and the first report of this mutation in North America. With continued screening of more individuals, we will be able to create a robust mutation database that can help us understand disease patterns associated with particular variants and may be a starting point in the development of new therapies for familial paraganglioma syndromes. PMID- 27489657 TI - Effect of correction of hindfoot valgus deformity on ankle joint pain relief in rheumatoid arthritis cases: A report of two cases. AB - We often see painful ankle joint destruction with painful hindfoot valgus deformity in rheumatoid arthritis. Our policy in such cases has been to first correct the hindfoot deformity in the subtalar joint with fusion, but then ankle joint pain has been observed. Two women with rheumatoid arthritis underwent correction and fusion surgery for hindfoot valgus deformity. They had been using wheelchairs because of severe pain in the ankle joint and hindfoot despite extensive medical treatment. After surgery, both patients complained of no pain in the hindfoot. Furthermore, dramatic pain reduction in the ankle joint was also observed especially in a case without ankle joint instability. Consequently, the patients could walk without any support. Correction of valgus hindfoot deformity contributes to centralizing the weight-bearing line in the ankle joint, leading to ankle joint pain relief. It appears possible to preserve the ankle joint without additional ankle surgery even in rheumatoid arthritis cases, if ankle is stable. PMID- 27489658 TI - All that wheezes: A young infant with a mediastinal mass. AB - Wheezing infants are frequently encountered in the emergency department. Bronchiolitis is the most commonly seen cause. Radiographs are not recommended in the routine management of bronchiolitis. We present the case of a young wheezing infant with a mildly abnormal chest x-ray whose cystic hygroma caused life threatening respiratory distress soon after he was admitted to the hospital. PMID- 27489659 TI - Conservative management of broken guidewire: Case reports. AB - Fractures of coronary guidewires during percutaneous coronary intervention within a coronary vessel lumen are a rare but serious complication. There have been several cases reported in the literature, some managed with surgical intervention, others with medical therapy. We present two prospective cases from our center. Both cases were managed successfully with medical therapy. PMID- 27489660 TI - Bronchoscopic interventions with surfactant and recombinant human deoxyribonuclease for acute respiratory distress syndrome-type respiratory syncytial virus-pneumonia in moderately preterm infants: Case series. AB - Atelectases, over-inflation of ventilated regions of the lung, and consecutive pneumothoraces are life-threatening conditions in mechanically ventilated infants with acute respiratory distress syndrome-type respiratory syncytial virus pneumonia. The accumulation of viscous secretions secondary to impaired mucociliary clearance in the more proximal parts of the bronchial tree is the prerequisite for atelectases and also prevents the delivery of inhaled medications to the more distal parts of the lung. Herein, we describe four moderately premature infants with respiratory failure on mechanical ventilation, displaying a total of 20 radiologically verified new atelectases that were treated by bronchoscopic interventions with consecutive suctioning of secretions, restoration of the surfactant film within the airways, and deposition of recombinant human deoxyribonuclease at the first segment level of the bronchial tree. On 13 occasions (65%), resolution of atelectases was proven by chest X-ray and resulted in improved lung function. We conclude that these bronchoscopic interventions may contribute to the restoration of the gas exchange area in moderately premature infants with acute respiratory distress syndrome-type respiratory syncytial virus-pneumonia. PMID- 27489661 TI - Delayed pneumothorax after laparoscopic sigmoid colectomy in a patient without underlying lung disease. AB - We present an unusual case of a delayed pneumothorax occurring approximately 72 h post-operatively in a patient without any underlying lung disease who had undergone laparoscopic sigmoid colon resection. The patient was in her mid-40s with a body mass index of 28.0 and had no history of smoking. Her spontaneous pneumothorax manifested without any precipitating events or complications during recovery. There was no evidence of any infectious process. There were no central line attempts and all ports were placed intra-peritoneally, and there was no evidence of any subcutaneous emphysema. One possible mechanism of injury that we propose is barotrauma from an extended period of time in Trendelenburg position. Notably, the only abnormal finding throughout the entire post-operative period preceding the delayed pneumothorax was a PO2 desaturation the day before. This case highlights the necessity to examine and investigate any desaturation post operatively and deliberate its possible significance. Furthermore, it demonstrates that, even during a normal recovery period for a patient without any underlying lung disease or risk factors, spontaneous pneumothorax could still develop in a delayed fashion multiple days post-operatively from a laparoscopic procedure. PMID- 27489662 TI - Hybrid endovascular and surgical approach for mycotic pseudoaneurysms of the extracranial internal carotid artery. AB - OBJECTIVES: Mycotic pseudoaneurysms of the extracranial internal carotid artery are rare, and their management often represents a challenge, but treatment is necessary due to the high risk of rupture and distal brain embolization. Systemic antibiotics associated with open surgical excision of the infected tissues and carotid reconstruction using autologous grafts are the treatment of choice. The use of endovascular techniques still remains controversial in infective fields; however, it can be an attractive alternative in high-risk patients or more often as a "temporary" solution to achieve immediate bleeding control for a safe surgical reconstruction. METHODS: We discuss the unusual case of an extracranial right internal carotid artery mycotic pseudoaneurysm following methicillin resistant Staphylococcus aureus infection, in a patient with poor general conditions. RESULTS AND CONCLUSION: The lesion was successfully treated using a hybrid endovascular and surgical procedure. PMID- 27489663 TI - A case of non-paraneoplastic anti-N-methyl d-aspartate receptor encephalitis presenting as a neuropsychiatric disorder. AB - N-methyl d-aspartate receptor antibody encephalitis can often be a paraneoplastic manifestation of occult malignancy such as ovarian teratoma and rarely teratoma of mediastinum or testis and small cell lung carcinoma. We report a case of non paraneoplastic anti-N-methyl d-aspartate receptor antibody-positive autoimmune encephalitis in a young patient who presented with neuropsychiatric features and made a very good recovery following treatment with intravenous immunoglobulin and steroids. The case highlights the need for increased vigilance for the condition in young females with or without a previous psychiatric history and emphasises the need for a multidisciplinary approach in the management of this challenging disorder with a good prognosis. PMID- 27489664 TI - Four-month-old infant with intussusception presenting as altered mental status. AB - OBJECTIVE: To remind pediatric care providers that an altered mental status can be the only presenting symptom for intussusception, a life-threatening diagnosis. METHOD: A case report that presents a unique presentation of intussusception: a 4 month old boy with neurological findings after a reported head injury. CONCLUSION: Diagnosis of intussusception in the pediatric population is highly dependent on its classical presenting signs and symptoms: sudden severe colicky abdominal pain, vomiting, and an abdominal mass in children between 3 months and 6 years of age. Consider that an altered mental status can be the only presenting symptom. PMID- 27489665 TI - Submandibular approach and use of Ligasure((r)) system in a complex carotid paraganglioma. AB - Carotid paragangliomas are rare tumors of slow growth, progressive, and highly vascularized; surgery is the chosen treatment, and most surgeons perform an approach with a longitudinal cervicotomy. OBJECTIVE: We present a case of carotid paraganglioma Shamblin III with skull base extension. METHODS: Submandibular approach and vascular sealing device of the Ligasure((r)) system were used in the surgery. RESULTS: We achieved complete resection using these adjunctive techniques. CONCLUSIONS: The use of these adjunctive techniques can be useful to manage large carotid body tumors. PMID- 27489666 TI - An illustrative case of primary angiitis of the central nervous system. AB - Primary angiitis of the central nervous system is a rare idiopathic vasculitis affecting small- and medium-sized vessels, isolated to the brain, leptomeninges and spinal cord. We report a case of biopsy-proven primary angiitis of the central nervous system, displaying some atypical features. This case highlights several key diagnostic and management issues of the disorder as well as its potential heterogeneity. PMID- 27489667 TI - Vitamin D and depression: A case series. AB - INTRODUCTION: Over two-thirds of Canadians are deficient in vitamin D. Clinical overlap can compound diagnosis of depression in vitamin D deficient individuals. Citing high costs, the Ministry of Health has restricted routine vitamin D screening and hence is not feasible. OBJECTIVES: The current case series is an attempt to recognise the clinical overlap between depression and vitamin D deficiency in order to avoid unnecessary antidepressant prescriptions and to demonstrate the role of collaborative care in such patients. METHOD: After appropriate ethics approval 62 patients from an outpatient clinic were screened for the diagnosis of treatment resistant depression. Those who had predominant somatic complaints were further screened for organic factors and those with inadequate vitamin D levels were referred to family physicians for supplementation with vitamin D. RESULTS: More than 50% were detected deficient in vitamin D after our evaluation. They showed subjective improvement with vitamin D supplements. No modification of antidepressants was needed. CONCLUSION: Vitamin D deficiency should be suspected in depressed patients with prominent somatic symptoms and their treatment resistance should be reconsidered to avoid unnecessary exposure to mood stabilisers. Collaborating with primary care is advocated. LIMITATION: Co-prescription of an antidepressant is a confounder in our case series, and we propose more organised studies with objective rating scales. PMID- 27489668 TI - Venlafaxine augmentation with agomelatine in a patient with obsessive-compulsive disorder and suicidal behaviors. AB - Obsessive-compulsive disorder is a chronic and disabling condition that often proves to be treatment resistant. Of the patients suffering from obsessive compulsive disorder, 10%-27% may attempt suicide at least once in their life. We report the case of a patient who presented severe obsessive-compulsive disorder symptoms and attempted suicide ingesting 25 tablets of fluoxetine (20 mg). The patient was treated with venlafaxine and agomelatine and showed improvement of obsessive symptoms and suicidal ideation. Future studies are needed to investigate this treatment regime in large cohorts of obsessive-compulsive disorder patients with suicidal ideation. PMID- 27489669 TI - Use of infrared thermography in children with shock: A case series. AB - Shock is a complex clinical syndrome caused by an acute failure of circulatory function resulting in inadequate tissue and organ perfusion. Digital infrared thermal imaging is a non-invasive technique that can detect changes in blood perfusion by detecting small changes in the temperature of the skin. In this preliminary study, eight pediatric patients (five boys, three girls), ages ranging from 6 to 14 years (average: 9.8 years), were admitted to the Intensive Care Unit at "Dr. Ignacio Morones Prieto" Central Hospital; here, the patients were examined using digital infrared thermal imaging. Patients in shock showed a significant decrease in distal temperature (at least 7 degrees ), compared to critically ill patients without shock. The latter group presented a skin temperature pattern very similar to the one previously reported for healthy children. The results show that infrared thermography can be used as a non invasive method for monitoring the temperature in pediatric patients in intensive care units in order to detect shock in its early stages. PMID- 27489670 TI - Sudden post-traumatic sensorineural hearing loss reverted to normal by sneezing. AB - An 11-year-old child with sudden post-traumatic sensorineural hearing loss regained his hearing functions after sneezing. This case report is a first in medical literature in describing recovery from hearing loss by sneezing. The therapeutic implications of this rare case deserve further investigation. PMID- 27489671 TI - Qigong program on insomnia and stress in cancer patients: A case series report. AB - BACKGROUND: In recent years, the interest in Qigong as an alternative therapy has grown following reports of its ability to regulate psychological factors in cancer patients. This is a case series to evaluate the outcome measures of Qigong when used as an adjunct to standard medical care to treat insomnia and stress in cancer patients. PATIENTS AND METHODS: The Qigong program was applied to four cancer patients with insomnia, stress, and anxiety. The program consisted of 30 min sessions involving exercise, patting of the 12 meridians, and spontaneous breathing exercises three times a week for a period of 4 weeks. The Pittsburgh Sleep Quality Index was measured as the primary outcome, while the Stress Scale, the State-Trait Anxiety Inventory, and the Functional Assessment Cancer Therapy General determined the secondary outcomes. Insomnia, stress, and anxiety levels were examined weekly, while quality of life was examined on the first visit and the last visit. RESULTS: The Pittsburgh Sleep Quality Index and Stress Scale scores were reduced after conduct of the Qigong program. CONCLUSION: This study could provide a better understanding of Qigong's influence on insomnia and stress in cancer patients. However, a larger controlled trial should be conducted to confirm these findings. PMID- 27489672 TI - Disseminated cryptococcosis in a patient with HIV/AIDS at a teaching hospital in Ghana. AB - OBJECTIVE: To raise awareness of the existence of cryptococcal infections in HIV/AIDS patients in Ghana. METHOD: Detailed postmortem gross and histopathological analysis of an HIV/AIDS patient suspected to have cryptococcal meningitis was carried out and histopathological findings correlated with clinical findings. RESULTS: showed disseminated Cryptococcosis in an HIV/AIDS patient which was confirmed with special stains. CONCLUSION: cryptococcal infection occurs in HIV /AIDS patients in Ghanaian and when clinically suspected the diagnosis should be pursued vigorously. PMID- 27489673 TI - Aneurysm growth after late conversion of thoracic endovascular aortic repair. AB - A 69-year-old man underwent thoracic endovascular aortic repair of a descending aortic aneurysm. Three years later, he developed impending rupture due to aneurysmal expansion that included the proximal landing zone. Urgent open surgery was performed via lateral thoracotomy, and a Dacron graft was sewn to the previous stent graft distally with Teflon felt reinforcement. Postoperatively, four sequential computed tomography scans demonstrated that the aneurysm was additionally increasing in size probably due to continuous hematoma production, suggesting a possibility of endoleaks. This case demonstrates the importance of careful radiologic surveillance after endovascular repair, and also after partial open conversion. PMID- 27489674 TI - A unique case of isolated, spontaneous, symptomatic celiac trunk dissection. AB - Cases of isolated spontaneous celiac trunk dissections have been appearing in the literature more recently with the increased availability of high-resolution computerized tomography angiograms. We report a unique case of this entity. A 48 year-old woman presented with acute abdominal pain that radiated to the back and worsened with breathing. This was diagnosed as a celiac trunk dissection by computerized tomography angiogram. She was treated conservatively with antihypertensive medications, anticoagulants, and opioid medication for pain control. PMID- 27489675 TI - Femorofemoral bypass allowed limb preservation after late diagnosis of left common iliac artery thrombosis due to blunt trauma: A case report. AB - OBJECTIVE: Acute common iliac artery occlusion which results from blunt abdominal trauma is rare and potentially leads to a late diagnosis. METHODS: We report a case of a 58-year-old patient who suffered a late diagnosed acute left common iliac artery occlusion secondary to abdominal trauma. An emergency exploratory laparotomy was performed to stop intra-abdominal bleeding, while his left limb ischemia was not noticed until 32 h later and femorofemoral bypass was then successfully performed for revascularization. Compartment syndrome was observed postoperatively, and fasciotomy was performed promptly. The wound was temporarily covered with Vaccum Sealing Drainage due to high skin tension. Patient underwent skin-grafting after leg swelling subsided. RESULTS: The follow-up turned out that these managements were valid in the preservation of the limb viability. CONCLUSIONS: This case highlights the prudent recognition of the acute lower extremity ischemia in the abdominal trauma and immediate remedy for acute iliac artery occlusion after a late diagnosis. PMID- 27489676 TI - Isolated fibrous dysplasia of the ethmoid sinus. AB - Fibrous dysplasia is a benign fibro-osseous lesion progressing with one or more bone involvements in the skeleton. Even though it is a benign tumor, it may potentially transform into a malignant one. While the most frequently involved zones in the head-neck zone include the maxilla, mandible, parietal, occipital, and temporal zones, the involvement of the ethmoid bone is rather rare. This article presents the case of a female patient who was diagnosed with fibrous dysplasia in the right ethmoid sinus based on the paranasal computerized tomography scan that was taken due to the symptoms of pain around the right eye, pressure, and a feeling of being pushed. PMID- 27489677 TI - Liver dysfunction and anti-thyroid therapy. AB - Thioamides have been used in the management of hyperthyroidism for over 50 years. Liver dysfunction is a rare but important side effect associated with their use. Recently, cases of liver failure associated with propylthiouracil have prompted the Federal Drug Administration to issue a Boxed Warning to the label of propylthiouracil regarding its risk of potentially fatal liver injury and acute liver failure in adults and children. Herein, we present a case to underline the importance of recognising the similar potential for severe hepatic dysfunction with the use of other thioamides. PMID- 27489678 TI - Spontaneous development of neoplasms in severe combined immunodeficient mice. AB - Severe combined immunodeficient (SCID) mice lack functional T and B cells. This renders them useful for implantation of human cells. The absence of immune cells, however, makes severe combined immunodeficient mice highly susceptible to infections and spontaneous development of malignancies; 2 of 114 CB17/Icr Prkdc(scid) /IcrIcoCrl severe combined immunodeficient mice aged 9 and 10 months developed spontaneous acute leukaemia and thymic lymphoma. The differential diagnosis of such an atypical lymphoid infiltrate includes 'leaky' severe combined immunodeficient mice, thymic lymphoma and acute leukaemia. Until this time, the link between the development of neoplasms in severe combined immunodeficient mice and the mutation remains unclear. PMID- 27489679 TI - Transumbilical glove port: A cost-effective method for single-incision laparoscopic hepatectomy. AB - OBJECTIVES: Emerging concepts of "reduced port surgery" have gained considerable attention from laparoscopic surgeons, including the field of liver resection. To date, 86 cases of single-incision laparoscopic hepatectomy (SILH) have been reported, with commercially available access devices being used in most of these cases. We report herein a use of homemade transumbilical glove port for SILH. METHODS: A 39-year-old woman represented giant hepatic hemangioma (9-cm in size) located at the left lateral segment (S2/3). Partial hepatectomy was performed by the glove method via single port access with conventional laparoscopic bipolar forceps, grasper and scissors without the need of any single-port specific devices. RESULTS: The operative time was 77 minutes, and intraoperative blood loss was 50 mL. The postoperative course was uneventful. CONCLUSIONS: Glove method not only has significant advantages in terms of cost, but also is superior in its versatility, allowing wider range of movements compared to conventional access devices. Taking in consideration its cost effectiveness and versatility, glove method may be a good option for SILH. PMID- 27489680 TI - Angiojet thrombolysis and vena cava filter insertion in a case of a duplicated inferior vena cava. AB - OBJECTIVES: Duplication of the inferior vena cava (IVC) complicates interventional procedures. This case report aims to shed light on this unusual anomaly and the preoperative considerations necessary when treatment of venous thromboembolism is undertaken. METHODS: An IRB approved case report of a 58 year old woman presented emergently with right lower extremity phlegmasia due to extensive thrombosis of her right iliofemoral and infrarenal portion of her duplicated IVC. RESULTS: The patient underwent IVC filter placement and rheolytic thrombectomy with thrombolysis using the Angiojet device followed by venoplasty and stenting of the iliofemoral system and right IVC. Complete symptomatic and radiographic resolution on duplex imaging was achieved at 1 year follow up. CONCLUSIONS: With adequate preoperative awareness of IVC anomalies and treatment options available satisfactory results can be achieved and complications minimized for this unique patient population. PMID- 27489681 TI - Endovascular repair of symptomatic carotid artery aneurysm with covered stent: A case report and literature review. AB - OBJECTIVES: Extracranial carotid artery true aneurysm is extremely uncommon, and definite treatment has traditionally involved open surgical repair. Although successful management of the internal carotid artery aneurysms using endovascular stenting and embolization has recently been reported, only a limited number of cases have been reported. METHODS: We present a case of symptomatic carotid true aneurysm repaired with covered stent and coil embolization of the external carotid artery. We also review the English literature and discuss the epidemiology, causes, diagnosis, and management options of internal carotid artery aneurysms. RESULTS: The patient did not have any complications, and was discharged home on the postoperative day 1 in stable condition. CONCLUSION: Our report suggests that endovascular procedure is feasible in the treatment of extracranial carotid artery aneurysms. PMID- 27489682 TI - Management of primary iliopsoas abscess in an immunocompetent patient followed by streptococcal toxic shock syndrome: A case report. AB - OBJECTIVES: Clinical diagnosis of iliopsoas abscess can be challenging, as this pathology often presents without obvious focal findings. Iliopsoas abscess should thus be a differential diagnosis for patients presenting with fever of unknown origin. PATIENT AND METHODS: A 62-year-old healthy Japanese man showed primary iliopsoas abscess of Klebsiella pneumoniae complicated by shock after a complete course of treatment for streptococcal toxic shock syndrome. Successful treatment was achieved with culture-driven antibiotic selection and delayed drainage. RESULTS: This case demonstrates the importance of identifying the causative microorganisms in iliopsoas abscess to guide therapy. The standard treatments for iliopsoas abscess are antibiotics and drainage of the abscess. Management of this case included successful antibiotic use along with delayed drainage. CONCLUSION: This case report advances the knowledge on the etiology of iliopsoas abscess and sheds light on the need for scientific development of a treatment strategy. PMID- 27489683 TI - Unrestricted access to medical case reports. PMID- 27489684 TI - A case of transient hypothermia after trans-lamina terminalis and third ventricle clipping of an extremely high-position basilar tip aneurysm. AB - Reports on the trans-lamina terminalis and trans-third ventricular approach are rare. The risk associated with this approach is unknown. After an unsuccessful endovascular surgery, we performed direct surgical clipping via the third ventricle on a 78-year-old woman presenting with an extremely high-positioned, ruptured basilar tip aneurysm. She experienced transient hypothermia for 5 days, and it was considered that this was due to hypothalamic dysfunction. It is necessary to recognize that there is the potential for hypothermia after surgery via the lamina terminalis and third ventricle, even though the mechanisms of hypothalamic thermoregulation are still unclear. PMID- 27489685 TI - Subclavian artery stenosis caused by a prominent first rib. AB - Thoracic outlet syndrome is a mechanical space problem in which the brachial plexus and/or subclavian vessels are compressed. Arterial compression is least common and almost always associated with a bony anomaly. We present a case of a 49-year-old woman with a prominent first rib which caused a subclavian artery stenosis. There are many options for subclavian artery repair through open surgery. In high-risk patients, minimal invasive techniques are favorable. To date, few case reports exist on an endovascular artery repair combined with open first rib resection. While long-term follow-up will be necessary, our preliminary results seem promising. PMID- 27489686 TI - Therapeutic hypothermia after cardiac arrest in Long QT syndrome: Could it be an adjunctive treatment to prevent dysrhythmias? AB - Therapeutic hypothermia has been used for neuroprotection following cardiac arrest presenting with ventricular tachycardia or ventricular fibrillation regardless of underlying cause. Long QT syndrome is a cause for polymorphic ventricular tachycardia, and we know that therapeutic hypothermia increases the QT interval. We managed a 27-year-old woman, who was 10 weeks post-partum, who collapsed secondary to ventricular fibrillation at home. Bystander cardiopulmonary resuscitation was started with successful resuscitation after a rescue shock from paramedics. On hospital admission, her computerised tomography head, computerised tomography pulmonary angiogram and echocardiography did not show any abnormality. Her baseline electrocardiogram showed prolonged QTc interval of 504 ms without ischaemic changes. After intubation and ventilation, she was treated with therapeutic hypothermia for 48 h. She had a further episode of polymorphic ventricular tachycardia requiring rescue shock just prior to starting therapeutic hypothermia in hospital. No dysrhythmias occurred during therapeutic hypothermia, although the QTc further increased. After stopping the therapeutic hypothermia, she had two further ventricular tachycardia episodes. After commencement of beta blockers, she remained free of arrhythmias, and an implantable cardioverter defibrillator was implanted, she has recovered without any neurological deficit. Ventricular dysrhythmias caused by prolongation of the QT interval during or after therapeutic hypothermia are not well understood. There has been a report of a patient also having ventricular dysrhythmia 2 h after re-warming post therapeutic hypothermia and also a report of arrhythmia free period during therapeutic hypothermia in a long QT syndrome patient; both these features are present in our patient. Re-warming is not usually known to cause any arrhythmias; however, it could be a problem in those with long QT syndrome. Whether therapeutic hypothermia has a place in helping to control ventricular dysrhythmias needs further study. PMID- 27489687 TI - Theophylline toxicity leading to suicidal ideation in a patient with no prior psychiatric illness. AB - Suicidal behavior is a common psychiatric emergency and is associated with psychiatric illness and history of prior suicide attempts. Neuropsychiatric manifestations related to theophylline toxicity are well described in literature. We report a case of theophylline toxicity manifesting as suicidal ideation in a patient with no prior psychiatric illness. PMID- 27489688 TI - Pre-operative endostent placement to allow the complete and safe resection of a recurrent tumor that had tightly adhered to the subclavian artery: A case report. AB - Radiation and tumor infiltration confer a high risk of bleeding on surgical removal of tumor. We report on the case of a 42-year-old woman with a recurrent occult subclavian tumor in her right breast. Computed tomography revealed enhanced tumor adhesion to the subclavian artery at the infraclavicular lymph node. No other metastases were detected. We pre-operatively performed stenting of the right subclavian artery, and the tumor was resected completely and safely. PMID- 27489689 TI - Communication failures during clinical handovers lead to a poor patient outcome: Lessons from a case report. AB - In the emergency department, communication failures occur in clinical handover due to the urgent, changing and unpredictable nature of care provision. We present a case report of a female patient who was assaulted, and identify how various factors interacted to produce communication failures at multiple clinical handovers, leading to a poor patient outcome. Several handovers created many communication failures at diverse time points. The bedside medical handover produced misunderstandings during verbal exchange of information between emergency department consultants and junior doctors, and there was miscommunication involving plastic registrars. There was a failure in adequately informing the general practitioner and the patient relating to follow-up care after discharge. Deficiencies of communication occurred with conveying changes in an investigative report. Communication could be improved by dividing the conduct of handover in a quiet room and at the bedside, ensuring multiple sources of information are used and encouraging role-modelling behaviours for junior clinicians. PMID- 27489690 TI - Use of a topical anhydrous silicone base containing fatty acids from pracaxi oil in a patient with a diabetic ulcer. AB - OBJECTIVES: The treatment of diabetic ulceration of the lower extremities is a complicated task due to the nature of the ulcer and potential underlying comorbidities. This report describes the case of a 61-year-old male patient with Type 2 Diabetes who presented with an ulcerative leg wound. The objective of this study was to evaluate the outcome of a topical compounded treatment. METHODS: The patient applied a compounded medicine containing 2% mupirocin in a topical anhydrous silicone base containing fatty acids from pracaxi oil directly to the ulcer for 63 days, 3 times daily. This regimen was supplemented with exercise and an additional compounded medicine applied to the wound margins in order to increase circulation. RESULTS: By the end of the application period, the patient's ulcer was fully closed. CONCLUSION: A topical anhydrous silicone compounding base containing fatty acids from pracaxi oil may be useful in the treatment of patients with diabetic ulcers. PMID- 27489691 TI - Fatal persistent methicillin-resistant Staphylococcus aureus bacteremia and vascular graft infections complicated with the formation of multiple abscesses despite aggressive medical therapy. AB - A 40-year-old man underwent ascending aorta replacement for an acute type A aortic dissection. After the operations, methicillin-resistant Staphylococcus aureus was identified in sputum and blood cultures. Although anti-methicillin resistant Staphylococcus aureus drugs were administered, most of the intermittent blood cultures remained positive. The focus of methicillin-resistant Staphylococcus aureus infection was not evident in the early stages, and no specific symptoms such as abscess or endocarditis were observed. However, abscesses in the brain, mediastinum and spleen were found 3 years after the operation. The minimum inhibitory concentration of vancomycin gradually increased from 1 to 4 ug/mL during the course of treatment. This case provides evidence for a potential role of combination therapy. PMID- 27489692 TI - Acute embolic occlusion of the right common iliac artery after revision total hip arthroplasty treated with catheter-directed thrombolysis and balloon angioplasty: A case report. AB - METHODS: A 63-year-old woman with atrial fibrillation presented clinical symptoms and signs of acute ischemia in the right lower extremity on the 17th postoperative day after revision total hip arthroplasty of the left hip for aseptic loosening of femoral component. Aspirin was discontinued 7 days before surgery. Both computed tomography angiography and digital subtraction angiography demonstrated complete occlusion of the right common iliac artery. An emergency catheter-directed thrombolysis with urokinase combined with balloon angioplasty was performed to obtain complete patency of the right common iliac artery. RESULTS: The patient received anticoagulation and antiplatelet therapy postoperatively and was fine at the 2-year follow-up. CONCLUSIONS: This case demonstrated that catheter-directed thrombolysis combined with balloon angioplasty could be an efficacious, minimally invasive approach for the treatment of acute embolic occlusion of the common iliac artery. Preoperative anticoagulation for patients undergoing total hip arthroplasty with long-term use of aspirin for atrial fibrillation needs further investigation. PMID- 27489693 TI - Inferior vena cava filter misplacement in the right atrium and migration to the right ventricle followed by successful removal using the endovascular technique: A case report and review of the literature. AB - Inferior vena cava filters are effective for preventing the passage of thrombi into the pulmonary arteries in patients with pulmonary embolism and deep vein thrombosis. These filters are indicated in patients with contraindications to anticoagulant therapy or in patients with recurrent acute pulmonary embolism despite the administration of anticoagulant therapy. However, the occurrence of filter-related complications, such as filter migration to the heart, has been increasing. Herein, we report a case of OptEase inferior vena cava filter misplacement in the right atrium. Although the filter migrated to the right ventricle, it was successfully removed and repositioned in the inferior vena cava using endovascular techniques. Unfortunately, moderate tricuspid regurgitation developed, due to the damage to the tricuspid valve that was caused by the procedure. We have also reviewed the relevant literature and discussed the possible strategies for managing cases of filter migration to the heart and preventing filter misplacement. PMID- 27489694 TI - First human case of avian influenza A (H5N6) in Yunnan province, China. AB - OBJECTIVE: To report clinical, virological, and epidemiological features of the first death caused by a H5N6 avian influenza virus in Yunnan Province, China. METHOD: The case was described in clinical expression, chest radiography, blood test and treatment. Real-time RT-PCR was used to detect H5N6 virus RNA in clinical and environment samples. Epidemiological investigation was performed including case exposure history determinant, close contacts follow up, and environment sample collection. RESULTS: The patient initially developed sore throat and coughs on 27 January 2015. The disease progressed to severe pneumonia, multiple organ dysfunction syndrome, and acute respiratory distress syndrome. And the patient died on 6 February. A highly pathogenic avian influenza A H5N6 virus was isolated from the tracheal aspirate specimen of the patient. The viral genome analyses revealed that the H5 hemmagglutinin gene belongs to 2.3.4.4 clade. Epidemiological investigation showed that the patient had exposure to wild bird. All close contacts of the patient did not present the same disease in seven consecutive days. A high H5 positive rate was detected in environmental samples from local live poultry markets. CONCLUSION: The findings suggest that studies on the source of the virus, transmission models, serologic investigations, vaccines, and enhancing surveillance in both humans and birds are necessary. PMID- 27489695 TI - Phlegmonous gastritis secondary to superior mesenteric artery syndrome. AB - We herein report a case of phlegmonous gastritis secondary to superior mesenteric artery syndrome. An 80-year-old woman visited the hospital emergency department with the chief complaints of epigastric pain and vomiting. She was hospitalized urgently following the diagnosis of superior mesenteric artery syndrome based on abdominal computed tomography findings. Conservative therapy was not effective, and phlegmonous gastritis was diagnosed based on the findings of upper gastrointestinal endoscopy and biopsy performed on the 12th day of the disease. Undernutrition and reduced physical activity were observed on hospital admission, and proactive nutritional therapy with enteral nutrition was started. An upper gastrointestinal series, performed approximately 1 month later, confirmed the persistence of strictures and impaired gastric emptying. Because conservative therapy was unlikely to improve oral food intake, open total gastrectomy was performed on the 94th day of the disease. Examination of surgically resected specimens revealed marked inflammation and fibrosis, especially in the body of the stomach. Following a good postoperative recovery, the patient was able to commence oral intake and left our hospital on foot approximately 1 month after surgery. PMID- 27489696 TI - Warning leak of intracranial aneurysm masquerading as sinus node dysfunction: A case report. AB - We describe the successful endovascular repair of an intracranial aneurysm causing subarachnoid hemorrhage in a 62-year-old man, who was initially diagnosed and treated as a case of symptomatic sinus bradycardia. The aim of this report and following discussion is to discuss the subtle warning signs of intracranial aneurysm that may masquerade as sinus node dysfunction. PMID- 27489697 TI - Total laparoscopic retrieval of inferior vena cava filter. AB - While there is some local variability in the use of inferior vena cava filters and there has been some evolution in the indications for filter placement over time, inferior vena cava filters remain a standard option for pulmonary embolism prophylaxis. Indications are clear in certain subpopulations of patients, particularly those with deep venous thrombosis and absolute contraindications to anticoagulation. There are, however, a variety of reported inferior vena cava filter complications in the short and long term, making retrieval of the filter desirable in most cases. Here, we present the case of a morbidly obese patient complaining of chronic abdominal pain after inferior vena cava filter placement and malposition of the filter with extensive protrusion outside the inferior vena cava. She underwent successful laparoscopic retrieval of her malpositioned inferior vena cava filters after failure of a conventional endovascular approach. PMID- 27489698 TI - Henoch-Schonlein purpura antecedent to Crohn's disease. AB - We report a 13-year-old youth who initially presented with the typical rash of Henoch-Schonlein purpura followed a month later by a nephrotic syndrome and hematuria. Renal biopsy revealed crescentic IgA nephropathy. The patient was aggressively treated with steroids leading to a remission of his nephrotic syndrome. Three years after his initial presentation, he developed bloody diarrhea and Crohn's disease was diagnosed. PMID- 27489699 TI - Use of the Wallstent for infrapopliteal arterial disease and varying vessel diameters. AB - There is little description of the Wallstent to treat infrapopliteal arterial disease. This may be a viable option due to its high conformability and ability to elongate in vessels of varying diameters. This case report highlights its use in this clinical situation. PMID- 27489700 TI - Steam-deformed Judkins-left guiding catheter with use of the GuideLiner((r)) catheter to deliver stents for anomalous right coronary artery. AB - OBJECTIVE: Percutaneous coronary intervention for anomalous right coronary artery (RCA) originating from the left coronary cusp is challenging because of our current inability to coaxially engage the guiding catheter. METHODS: We report a case of an 88-year-old woman with non-ST segment elevation myocardial infarction, with an anomalous RCA origin. Using either the Judkins-Left catheter or Amplatz Left catheter was difficult because of RCA ostium tortuosity. Thus, we used steam to deform the Judkins-Left catheter, but back-up support was insufficient to deliver the stent. RESULTS: We used GuideLiner(r), a novel pediatric catheter with rapid exchange/monorail systems, to enhance back-up support. CONCLUSIONS: We were able to successfully stent with both the deformed Judkins-Left guiding catheter and GuideLiner(r) for an anomalous RCA origin. PMID- 27489701 TI - Multiple endovascular aortic aneurysm repair graft failures and re-interventions over 15 years. AB - Re-intervention on abdominal aortic aneurysm treated by endovascular aortic aneurysm repair for complications such as endoleak, graft migration, and graft failure is relatively common. However, re-do endovascular aortic aneurysm repair can be complex, as the failed graft still resides within the vessel. In addition, some re-do endovascular aortic aneurysm repairs call for an advanced custom graft, which can further increase the complexity and technical skill required. We describe a case of a 15-year-old endovascular aortic aneurysm repair originally implanted in a 71-year-old man, followed by three separate complications requiring intervention. We describe important procedural decisions taken into consideration when presented with failure of an older graft. PMID- 27489702 TI - Successful embolization and long-term follow-up of a rare neonatal diaphragmatic hemangioma. AB - BACKGROUND: Congenital hemangioma of the diaphragm is an extremely rare disease in childhood. METHODS: We report a newborn presenting with progressive respiratory distress and massive right hydrothorax due to congenital diaphragmatic hemangioma, requiring sustained ventilation support and chest drainage. The angiography revealed that the giant diaphragmatic hemangioma was supplied by the right internal thoracic, inferior diaphragmatic, and intercostal arteries. The selective embolization of the main feeding vessels was successfully achieved using the Embosphere particulates. RESULTS: The clinical long-term follow-up demonstrated the resolution of the symptoms, pleural effusion, and nearly complete regression of the hemangioma at 18 months of age. CONCLUSION: Transcatheter embolization can provide an efficient therapy for symptomatic diaphramatic hemangioma. PMID- 27489703 TI - Variceal bleeding caused by oesophageal varices: A manifestation of hepatocellular carcinoma in a 17-year-old girl. AB - The authors present the rare case of a 17-year-old girl referred to the medical assessment unit following a large upper gastrointestinal haemorrhage. On further evaluation, she was found to have a primary hepatocellular carcinoma with extensive metastases. In our patient, the tumour was deemed incurable by resection, liver transplantation or percutaneous treatment. She underwent palliative chemotherapy and passed away 11 months following presentation. PMID- 27489704 TI - Endovascular management of early-onset post-nephrectomy renal arteriovenous fistula: A report of two cases. AB - PURPOSE: Here, we report two cases of early-onset post-nephrectomy renal arteriovenous fistula who were successfully managed by implantation of patent ductus arteriosus occluders. CASE REPORT: Both patients were female, aged 38 and 36 years. They received left renal nephrectomy 9 and 6 months, respectively, with a complaint of chest congestion and dyspnea before admitting to our center. Computed tomographic angiography revealed a huge arteriovenous fistula of the left renal pedicle with a renal venous aneurysm in both patients. The fistulas were isolated by implanting patent ductus arteriosus occluders in the renal artery stumps. Clinical symptoms disappeared after intervention. Computed tomographic angiography confirmed the effectiveness of the occluders during follow-up time. The venous aneurysms shrank to normal size. CONCLUSION: Our experience indicates that post-nephrectomy renal arteriovenous fistula can present as an early complication which can be efficiently managed by endovascular occlusion of the arterial stump by patent ductus arteriosus occluder. PMID- 27489705 TI - Ornidazole-induced ataxia in an Indian woman: A case report. AB - The nitroimidazole group of antibiotics like metronidazole have been reported to cause cerebellar ataxia as a rare side effect. Ornidazole, the newest derivative of this class, has a long half life and is very rarely known to cause cerebellar ataxia. Here, we report a 61-year-old patient who developed ataxia due to ornidazole to highlight an unusual adverse event that improved rapidly after discontinuation of the offending drug. PMID- 27489706 TI - High-grade primary myxoid lung sarcoma presenting as recurrent hemorrhagic pleural effusions in a young woman. AB - Primary lung sarcomas are rare but aggressive tumors accounting for less than 0.5% of all lung tumors. The diagnosis of primary lung sarcoma should only be considered after exclusion of other sites. A 32-year-old female presented with recurrent hemorrhagic pleural effusions, shortness of breath and persistent cough. Pleural effusion was drained twice, and each time its analysis was normal. Patient developed atelectasis of left lung with hemothorax for which she underwent video-assisted thoracoscopic surgery. A large mass was found compressing the entire lower lobe of left lung with extension into mediastinum, the biopsy of which showed myxoid sarcoma. The tumor was inoperable and options of chemotherapy or radiotherapy were discussed with the patient. Primary lung sarcoma can rarely present with recurrent hemorrhagic pleural effusion. A high degree of suspicion is required for early diagnosis as large hemothorax on computed tomography or chest X-ray may obscure lung mass and make its diagnosis difficult. PMID- 27489707 TI - Penetrating retro-orbital foreign body - large glass shards: A maxillofacial surgery case report. AB - OBJECTIVES: This case report looks at a 53-year-old patient who had suffered a penetrating foreign body injury to the retro-orbital space and the surgical approach taken to remove the large glass fragments found and to correct the damage caused. Having fallen while holding a drinking glass, this patient suffered multiple laceration injuries to the maxillofacial region upon the glass shattering in contact with the face. However, unbeknownst to the patient, several glass fragments became embedded in the retro-orbital space, and this was only detected on presentation 2 days post-injury with unusual symptoms of sharp, sudden pain elicited on extreme gaze as well as ocular motility restriction. METHODS: This embedded foreign body required a creative surgical approach to remove it involving gaining access to the retro-orbital space via a superior approach and cautiously following the path the glass shards took upon entry, all the way to the posterior aspect of superior rectus. Intra-operative radiographic guidance was required due to the restriction of operating within this space and particularly when removing glass fragments distal to superior rectus. RESULTS AND CONCLUSION: The patient recovered well and experienced an immediate improvement in ocular motility with a return to relative normality over the next few months. PMID- 27489708 TI - Duodenal neuroendocrine tumor and the onset of severe diabetes mellitus in a US veteran. AB - OBJECTIVE: Neuroendocrine tumors are neoplasms derived from endocrine cells, most commonly occurring in the gastrointestinal tract. Duodenal neuroendocrine tumors are rare tumors averaging 1.2-1.5 cm, and most are asymptomatic. Common presentation is abdominal pain, upper gastrointestinal bleed, constipation, anemia, and jaundice. METHODS: An adult, Black, male patient with newly diagnosed diabetes mellitus presented to the emergency department with elevated liver function test and fatigue. RESULTS: Magnetic resonance cholangiopancreatography demonstrated a large obstructing mass (3.6 cm * 4.4 cm * 3 cm) within the second and third portions of the duodenum at the ampulla. Esophagogastroduodenoscopy demonstrated an ulcerated duodenal mass that was biopsied. Immunohistochemical stains were positive for synaptophysin, chromogranin B, and CK7. Chromogranin A was in normal range. Post-Whipple procedure demonstrated a 5.5 cm * 4.1 cm * 2.9 cm duodenal mass with invasion of the subserosal tissue of the small intestine, a mitotic rate of 2 per high-power field, and antigen Ki-67 of 2%-5%. CONCLUSION: This case raises the question as to if the patient developed diabetes mellitus due to the tumor size and location or if the new onset of diabetes was coincidental. This case also demonstrates the importance of a proficient history and physical. PMID- 27489709 TI - Myeloid sarcoma of submandibular salivary gland. AB - OBJECTIVE: To report a rare case of a myeloid sarcoma of submandibular salivary gland. METHODS: A 65-year-old woman with a history of successfully treated myelodysplastic syndrome, presenting with periodic painful swelling of her right submandibular area. RESULTS: Physical evaluation, ultrasound and CT scan revealed the presence of a 3-cm mass contiguous to the submandibular salivary gland. A core needle biopsy confirmed the diagnosis of myeloid sarcoma. Bone marrow biopsy was still showing complete remission and the submandibular gland was the only extramedullary site involved. The patient was submitted to chemotherapy. CONCLUSION: Myeloid sarcoma is a rare extramedullary neoplasm. It can virtually involve any anatomic site, but it usually involves lymph nodes, paranasal sinuses, skin, soft tissue and periostium. Myeloid sarcomas of salivary glands are very rare and ENTs should be aware of this disease in order to include it in the differential diagnosis of a solitary neck mass. PMID- 27489710 TI - A case of anomalous coronary artery origin: The role of computerised tomography. AB - OBJECTIVE: To illustrate the utility of CT coronary angiography in the assessment of patients with anomalous coronary arteries. METHODS: A 65-year-old woman who presented with a clinical history of unstable angina was investigated with both computerised tomography and invasive coronary angiography. RESULTS: Coronary angiography demonstrated aberrant coronary arteries all arising from separate ostia from the right coronary cusp. Computerised tomography coronary angiography was required to confirm the course of the aberrant coronary arteries in relation to other cardiovascular structures. CONCLUSIONS: This case illustrates the important role of computerised tomography coronary angiography and that early use might avoid the need for invasive coronary angiography. PMID- 27489711 TI - Rhinogenic intracranial complication with postoperative frontal sinus pyocele and inverted papilloma in the nasal cavity: A case report and literature review. AB - We report a patient who had rhinogenic intracranial complication with postoperative frontal sinus pyocele and inverted papilloma in the nasal cavity. A 72-year-old woman had undergone surgery for frontal sinusitis via external incision at another hospital 13 years previously. Left-sided hemiparesis appeared in the patient and gradually worsened. Five days later, she exhibited disorientation, abnormal behavior, poor articulation, and difficulty in standing. Therefore, she was taken to the neurosurgery department by ambulance. An extensive frontal sinus pyocele was suspected, and a cerebral abscess and edema of the frontal lobe were observed on magnetic resonance imaging. After antibiotics, steroid and glycerol were administered for a few weeks; disorientation and left hemiparesis improved. Next, craniotomy for complete removal of the brain abscess by neurosurgeons and endoscopic endonasal surgery by otolaryngologists were carried out at the same surgery. From the analysis of the pathological mucosa sample taken from the right ethomoidal sinus during surgery, an inverted papilloma was diagnosed. The patient completely recovered and is currently receiving follow-up examination. Regarding rhinogenic intracranial complications, ascertaining clinical condition in order to determine the need for either immediate radical surgery, or for curative surgery after waiting for improvement of the overall body condition by conservative management, is still needed. PMID- 27489712 TI - Acute myocardial infarction in a young athlete: Optical coherence tomographic features of the culprit lesion. AB - OBJECTIVES: We report on a young male athlete who suffered from acute myocardial infarction immediately after a vigorous training. METHODS: A comprehensive optical coherence tomographic investigation of the culprit coronary artery was performed after the combined mechanical and pharmacological thrombus removal. RESULTS AND CONCLUSION: The imaging discovered a tear at the junction of the non obstructive, largely fibrotic plaque with the normal arterial wall. This exertion related vessel damage resulted in a dynamic thrombosis that almost completely occluded the culprit artery. As the vessel obstruction was not considered flow limiting, the stent implantation was not required and the patient was discharged on the double antiplatelet therapy and statin. PMID- 27489713 TI - Mediastinal mass diagnosed by endobronchial ultrasound as recurrent hepatocellular carcinoma in a post-liver transplantation patient. AB - OBJECTIVE: We presented a rare case of recurrent hepatocellular carcinoma after liver transplant manifested as an isolated mediastinal mass. METHODS: A 62-year old man was referred for evaluation of atypical chest pain and abnormal finding of a computed tomography of the chest. He had history of chronic hepatitis C liver cirrhosis and hepatocellular carcinoma underwent orthotopic liver transplant as a curative treatment three years earlier. RESULTS: The computed tomography of the chest demonstrated paratracheal mediastinal lymphadenopathy. He subsequently underwent endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA). The right paratracheal lymph node station 4R was sampled. Rapid on-site cytology evaluation demonstrated recurrent metastatic hepatocellular carcinoma. CONCLUSION: Pulmonologist should be cognizant of diagnostic utility of EBUS-TBNA in this clinical setting as more transplant patients on immunosuppressive medications with enlarged mediastinal lymphadenopathy of unknown origin will be referred for further evaluation. PMID- 27489714 TI - Zotarolimus-eluting stent fracture at initial implantation diagnosed with StentBoost. AB - Stent fracture is a rare complication of drug-eluting stent implantation with a reported rate of 0.84%-3.2% in various clinical studies with first-generation drug-eluting stents and 29% in autopsy studies. Sirolimus-eluting stents with their closed cell design were reported to be more prone to fracture compared to paclitaxel-eluting stents. Other risk factors for stent fracture are multiple stenting, longer stent length, chronic renal failure, right coronary artery intervention, and a higher maximal inflation pressure. The role of angiography in diagnosing stent fracture is limited, a fact also questioning the reliability of angiographic data. Image enhancement techniques like StentBoost are widely available in new-generation angiography systems and are used to assess stent expansion, overlap size, or to localize the postdilation balloon. Here, we report a case of zotarolimus-eluting stent fracture at initial implantation diagnosed with StentBoost. PMID- 27489715 TI - Incidental finding of a huge ovarian serous cystadenoma in an adolescent female with menorrhagia. AB - Pelvic tumors in adolescent females are very uncommon. While the most common presentation is pelvic discomfort, we report the case of a 14-year-old female presenting with menorrhagia which is an unusual initial complaint for a large pelvic tumor. Adolescent females who present with heavy menstrual bleeding initially undergo assessment to rule out a bleeding disorder. In this case, careful history and physical examination helped in making a quick diagnosis and management. Ultrasound of abdomen showed a huge cystic mass due to serous cystadenoma of the ovary. PMID- 27489716 TI - Post-biliary sphincterotomy bleeding despite covered metallic stent deployment. AB - OBJECTIVES: Several endoscopic techniques have been proposed for the management of post-sphincterotomy bleeding. Lately, self-expandable metal stents deployment has gained popularity especially as a rescue therapy when other endoscopic techniques fail. METHODS-RESULTS: We report the case report of a massive post sphincterotomy bleeding in a patient with a self-expandable metal stent in the biliary tree. Despite the presence of a correctly positioned self-expandable metal stent, a new endoscopic session was required to control the bleeding. CONCLUSIONS: Self-expandable metal stent may be useful to manage post-endoscopic sphincterotomy bleeding. However, up to now there is no specifically designed self-expandable metal stent for such complication. Large new designed self expandable metal stent may be a useful tool for biliary endoscopist. PMID- 27489717 TI - Endovascular stent-graft repair of spontaneous aorto-caval fistula secondary to a ruptured abdominal aortic aneurysm: An emergency management of hostile anatomy. AB - OBJECTIVES: Although endovascular aneurysm repair of aorto-caval fistula offers a safe and efficient approach compared to traditional open repair, endovascular techniques for the treatment of aorto-caval fistula with ruptured abdominal aortic aneurysms in emergency circumstance are not well established. This study aims to evaluate the effect of endovascular repair of aorto-caval fistula of a patient with ruptured abdominal aortic aneurysm and hostile anatomy. METHODS: we report a case of an aorto-caval fistula endovascular repaired in a 78-year-old male using a hybrid stent-graft technique. RESULTS: The patient had an uneventful recovery and CTA follow up showed no sign of ACF or any endoleak. CONCLUSION: This case highlights ACF might be managed by composite endograft implantation with careful and solid sealing of anchoring zones on the two sides. PMID- 27489719 TI - Ambiguous presentations of pulmonary epithelioid hemangioendothelioma: Two case reports of a rare pulmonary malignancy. AB - Pulmonary epithelioid hemangioendothelioma is an uncommon lung malignancy of endothelial origin. Besides demonstrating unpredictable presentation features and prognosis, the paucity of established treatment guidelines remains a challenge in managing these patients. We present two patients. The first patient presented with chronic productive cough over 1-year duration. He was initially diagnosed and showed partial response to treatment for cardiac failure. A persistent right upper zone consolidation on chest radiograph prompted further investigations which revealed the diagnosis of pulmonary epithelioid hemangioendothelioma. The second patient presented with right-sided hemiparesis for 1-month duration. Initial computer tomography scan of the brain showed findings of distant metastatic foci. Subsequent investigations revealed pulmonary epithelioid hemangioendothelioma as the primary lesion. Both patients succumbed without any treatment due to rapid progression of the disease. We believe that pulmonary epithelioid hemangioendothelioma is undoubtedly rarely reported in south-east Asia region. In these two case reports, the patients were diagnosed in west and east Malaysia, respectively, in the same year (2015). Both cases highlight the increasing prevalence of pulmonary epithelioid hemangioendothelioma. We postulate that this could possibly be secondary to the advancement in diagnostic capabilities and improved healthcare facilities available in this region. Late presentation of pulmonary epithelioid hemangioendothelioma generally results in grave prognosis. Further investigations are required to elucidate the nature of progression and therapeutic options for patients with pulmonary epithelioid hemangioendothelioma. PMID- 27489718 TI - Delayed presentation of a carotid pseudoaneurysm following penetrating neck trauma. AB - OBJECTIVE: Penetrating carotid trauma in a hemodynamically stable patient invariably presents with a pseudoaneurysm on initial imaging. Although extremely rare, delayed pseudoaneurysm formation has been reported. The purpose of this paper is to define this rare entity and propose a diagnostic and treatment plan. METHODS: We present a case of delayed presentation of carotid pseudoaneurysm following penetrating neck trauma. A systematic review of the literature was performed. RESULTS: A 21-year-old male presents to the trauma center after sustaining a gunshot wound to the left upper back resulting in a zone 2 hematoma and pneumothorax. Bullet fragment artifact interfered with computed tomography. Carotid angiogram was normal. The patient was discharged after 3 days. He returned to the Emergency Department 3 months later with a painful pulsatile hematoma. Computed tomography angiogram revealed a 6-cm pseudoaneurysm arising from the proximal left internal carotid artery (ICA). A left common carotid artery (CCA) to ICA bypass with reversed great saphenous vein was performed. The patient's post-operative course was uneventful, neurologic deficits improved, and he was discharged. CONCLUSION: Delayed presentation of traumatic pseudoaneurysms has been reported, although usually these cases are iatrogenic access complications in extremities. While endovascular therapies are first line for zone 1 and 3 vascular injuries, management of zone 2 injuries is still controversial. This patient was treated with a bypass due to the need to evacuate the hematoma that was exerting a mass effect in the neck. PMID- 27489720 TI - Use of remote blood releasing system for red cell transfusion in hospice care center. AB - OBJECTIVES: It is quite common to have advanced cancer or end-stage renal disease patients for regular or even frequent blood transfusion in palliative care. However, due to geographical reason in some hospice centers, blood transfusion is sometimes difficult if blood bank is closed during non-office hour or not available. METHODS: Here, we reported a new blood releasing system, that is, remote blood releasing system, that could be used safely by nursing staff alone when the blood bank was closed during the night time and holiday. RESULTS: On call nursing staff could collect red cells successful in these two cases. CONCLUSION: The new blood releasing system seems useful. However, larger sample sizes and longer period of study are required to estimate its efficacy and safety. The provision of antibody-positive red cells and platelet remained a limitation of this system. PMID- 27489721 TI - A corny cause of cerebrospinal fluid ascites: A case report and review of literature. AB - OBJECTIVE: To report a rare cause of cerebrospinal fluid ascites. METHODS: A 37 year-old female with history of intracranial hypertension and a ventriculo peritoneal shunt was referred to liver clinic for evaluation of newly developed ascites. RESULTS: Initially, the cause of ascites was thought to be secondary to a liver etiology. However, this was excluded after a comprehensive evaluation including portal pressure measurements. We determined the ascites to be infected cerebrospinal fluid secondary to a rare commensal organism, Corynebacterium non Jeikeium, which resolved after removing ventriculo-peritoneal shunt, appropriate antibiotics and conversion to a ventriculo-atrial shunt. CONCLUSION: Cerebrospinal fluid ascites is a rare complication of VP shunts and since 1976 only 8 cases of Corynebacterium non jk VP shunt infections have been reported in the literature but none associated with ascites. Also this report highlights the beneficial role of transjugular portal pressure measurements in the evaluation of ascites. PMID- 27489722 TI - Real-time quantitative PCR assay with Taqman((r)) probe for rapid detection of MCR-1 plasmid-mediated colistin resistance. AB - Here we report the development of two rapid real-time quantitative PCR assays with TaqMan((r)) probes to detect the MCR-1 plasmid-mediated colistin resistance gene from bacterial isolates and faecal samples from chickens. Specificity and sensitivity of the assay were 100% on bacterial isolates including 18 colistin resistant isolates carrying the mcr-1 gene (six Klebsiella pneumoniae and 12 Escherichia coli) with a calibration curve that was linear from 10(1) to 10(8) DNA copies. Five out of 833 faecal samples from chickens from Algeria were positive, from which three E. coli strains were isolated and confirmed to harbour the mcr-1 gene by standard PCR and sequencing. PMID- 27489723 TI - Dietary beet pulp decreases taurine status in dogs fed low protein diet. AB - BACKGROUND: It is known that large dogs who are fed lamb and rice diets are at increased risk to develop taurine-deficiency-induced dilated cardiomyopathy. Since dogs obligatorily conjugate bile acids (BA) with taurine, we determined whether rice bran (RB) or other fibers (cellulose; CL, beet pulp; BP) would affect BA excretion and/or the taurine status of dogs. RESULTS: Eighteen medium/large mixed-breed dogs were given purified diets containing CL, BP, or RB for 12 weeks. Taurine concentrations in plasma and whole blood were significantly decreased at week 12. The BP group, compared to the CL or RB groups, showed significantly lower taurine concentrations in plasma (6.5 +/- 0.5 vs 20.4 +/- 3.9 and 13.1 +/- 2.0 MUmol/L, respectively, P < 0.01, mean +/- SEM) and in whole blood (79 +/- 10 vs 143 +/- 14 and 127 +/- 14 MUmol/L, respectively, P < 0.01), lower apparent protein digestibility (81.9 +/- 0.6 vs 88.8 +/- 0.6 and 88.1 +/- 1.2 %, respectively, P < 0.01), and higher BA excretions (5.6 +/- 0.1 vs 3.4 +/- 0.5 and 3.4 +/- 0.4 MUmol/g feces, respectively, P < 0.05) at week 12. CONCLUSIONS: These results do not support the hypothesis that RB is likely to be a primary cause of lamb meal and rice diets, increasing the risk of taurine deficiency in large dogs. However these indicate that BP may contribute to a decrease taurine status in dogs by increasing excretion of fecal BA and decreasing protein digestibility, thus decreasing the bioavailability of sulfur amino acids, the precursors of taurine. PMID- 27489724 TI - Study on chemotaxis and chemokinesis of bone marrow-derived mesenchymal stem cells in hydrogel-based 3D microfluidic devices. AB - BACKGROUND: Controlling the fate of mesenchymal stems cells (MSCs) including proliferation, migration and differentiation has recently been studied by many researchers in the tissue engineering field. Especially, recruitment of stem cells to injury sites is the first and crucial step in tissue regeneration. Although significant progress has been made in the chemotactic migration of MSCs, MSC migration in three dimensional environments remains largely unknown. We developed a 3D hydrogel-based microfluidic-device to study the migration behavior of human MSCs in the presence of stromal-cell derived factor-1alpha (SDF-1alpha), interleukin 8 (IL-8) and Substance P (SP) which have been utilized as chemoattractant candidates of human mesenchymal stem cells (hMSCs). RESULTS: We systematically investigated the chemotactic migration behaviors of hMSCs and their responses to SDF-1alpha, IL-8, and SP. SDF-1alpha was shown to be the most fascinating chemoattractant candidate among those factors at a certain time point. We also found that each chemokine showed different chemoattractant abilities according to their concentration. In the case of SP, this factor showed chemokinesis not chemotaxis. Especially at a 7-8 * 10(-8) M concentration range, the chemokinesis ability driven by SP was further increased. The data suggest that some factors at the optimal concentration exhibit chemokinesis or chemotaxis in a 3D hydrogel-based microfluidic device. CONCLUSION: In this study on chemotaxis and chemokinesis of hMSCs, the system parameters such as chemokine concentration, system stability, and 2D or 3D microenvironment are critically important to obtain meaningful results. PMID- 27489725 TI - Direct photo-patterning on anthracene containing polymer for guiding stem cell adhesion. AB - BACKGROUND: Various micropatterned surfaces capable of guiding the selective adhesion of biomolecules such as proteins and cells are of great interests in biosensor, diagnostics, drug screening, and tissue engineering. In this study, we described a simple photo-patterning method to prepare micro-patterned films for stem cell patterning using anthracene containing polymers (PMAn). This micro patterned polymer film was prepared by the facile photo-reaction of anthracene units in polymer backbone structure. RESULTS: The UV irradiation of PMAn through a photomask resulted in the quenching of fluorescent intensity as well as the changes in surface wettability from hydrophobic to hydrophilic surface. As a result, UV exposed regions of PMAn film show lower fluorescent intensity as well as higher proliferation rate of mesenchymal stem cells (MSCs) than unexposed region of PMAn film. Furthermore, the selective MSC attachment was clearly observed in the UV exposed regions of PMAn film. CONCLUSION: We developed a simple cell patterning method with a fluorescent, biocompatible, and patternable polymer film containing anthracene units. This method provides a facile stem cell patterning method and could be extended to various patterning of biomaterials without labor-intensive preparation and no pre-treatment for complex interactions of cell-microenvironment. PMID- 27489727 TI - Development of rheumatoid arthritis during treatment of multiple sclerosis with interferon beta 1-a. Coincidence of two conditions or a complication of treatment: A case report. AB - Coexistence of multiple sclerosis (MS) with other autoimmune diseases has been attributed to common background genetic or environmental factors. This study presents development of rheumatoid arthritis (RA) during treatment of MS. The MS was confirmed by the Mc Donald criteria and the diagnosis of RA was confirmed by the ACR/EULAR criteria. A 35 years old women with 9 years of MS who was receiving interferon beta 1-a (INF) for 7 years and who did not respond to conventional therapy of RA over 8 months developed clinical manifestations of RA. But a rapid response was observed after discontinuation of INF. These findings suggest a possible contribution of INF in the development of RA. PMID- 27489726 TI - Flexible selection of diversified Na(+)/K(+)-ATPase alpha-subunit isoforms for osmoregulation in teleosts. AB - BACKGROUND AND METHODS: Multiple Na+/K+-ATPase (NKA) alpha-subunit isoforms express differentially in response to salinity transfer in teleosts but we observed that the isoform nomenclature is inconsistent with the phylogenetic relationship of NKA alpha-genes. We cloned the catalytic NKA alpha-subunit isoforms in eels and medaka, analyzed the time course of their expressions in osmoregulatory tissues after transfer from freshwater (FW) to seawater (SW), and performed phylogenetic analyses to deduce an evolutionary scenario that illustrates how various duplication events have led to the current genomic arrangement of NKA alpha-genes in teleosts. RESULTS AND DISCUSSION: Five and six alpha-subunits were cloned in eels and medaka respectively. In eels, the commonly reported alpha1a and alpha1b isoforms were absent while the alpha1c isoform was diversified instead (alpha1c-1, alpha1c-2, alpha1c-3, alpha2, and alpha3 in eels). Phylogenetic estimation indicated that the alpha1a and alpha1b isoforms from salmon, tilapia, and medaka were generated by independent duplication events and thus they are paralogous isoforms. Re-examination of expression changes of known isoforms after salinity challenge revealed that the isoforms selected as predominant SW-types varied among teleost lineages. Diversification of alpha1 isoforms occurred by various types of gene duplication, or by alternative transcription among tandem genes to form chimeric transcripts, but there is no trend for more alpha1 copies in euryhaline species. Our data suggest that the isoform switching between FW (alpha1a predominates) and SW (alpha1b predominates) that occurs in salmonids is not universal in teleosts. Instead, in eels, alpha1c 1 was the major alpha-subunit upregulated gill, intestine, and kidney in SW. Localization of both NKA mRNA and protein showed consistent upregulation in gill and intestine in SW eels, but not in renal distal and collecting tubules, where low transcript expression levels were accompanied by high protein levels, suggesting a tissue-specific translational regulation that determines and fine tunes the NKA expression. In medaka, alpha1b was upregulated in SW in anterior intestine while most other alpha-subunit isoforms were less responsive to salinity changes. CONCLUSION: By integrating gene expression and phylogenetic results, we propose that the major NKA alpha-subunits for SW acclimation were not ancestrally selected, but rather were flexibly determined in lineage-specific fashion in teleosts. PMID- 27489728 TI - Deeper insight into maternal genetic assessments and demographic history for Egyptian indigenous chicken populations using mtDNA analysis. AB - This study principally sought to reveal the demographic expansion of Egyptian indigenous chickens (EIC) using representative breeds: Sinai (North), Fayoumi (Middle) and Dandarawi (South) of Egypt as well as to deeply clarify their genetic diversity, possible matrilineal origin and dispersal routes. A total of 33 partial mitochondrial DNA sequences were generated from EIC and compared with a worldwide reference dataset of 1290 wild and domestic chicken sequences. Study populations had 12 polymorphic variable sites and 7 haplotypes. A lack of maternal substructure between EIC was detected (F ST = 0.003). The unimodal mismatch distribution and negative values of Tajima's D (-0.659) and Fu's Fs ( 0.157) indicated demographic expansion among EIC and pointed to Fayoumi as the oldest EIC population. Egyptian haplotypes were clustered phylogenetically into two divergent clades. Their phylogeography revealed an ancient single maternal lineage of Egyptian chickens likely derived from Indian-Subcontinent. Moreover, a recent maternal commercial heritage possibly originated in Yunnan-Province and/or surrounding areas was admixed restrictedly into Sinai. It is implied that Egypt was an entry point for Indian chicken into Africa and its further dispersal route to Europe. This study provides a clue supporting the previous assumption that urged utilizing consistent founder populations having closely related progenitors for synthetizing a stabilized homogenous crossbreed as a sustainable discipline in breeding program. PMID- 27489729 TI - Optimal PMU placement using topology transformation method in power systems. AB - Optimal phasor measurement units (PMUs) placement involves the process of minimizing the number of PMUs needed while ensuring the entire power system completely observable. A power system is identified observable when the voltages of all buses in the power system are known. This paper proposes selection rules for topology transformation method that involves a merging process of zero injection bus with one of its neighbors. The result from the merging process is influenced by the selection of bus selected to merge with the zero-injection bus. The proposed method will determine the best candidate bus to merge with zero injection bus according to the three rules created in order to determine the minimum number of PMUs required for full observability of the power system. In addition, this paper also considered the case of power flow measurements. The problem is formulated as integer linear programming (ILP). The simulation for the proposed method is tested by using MATLAB for different IEEE bus systems. The explanation of the proposed method is demonstrated by using IEEE 14-bus system. The results obtained in this paper proved the effectiveness of the proposed method since the number of PMUs obtained is comparable with other available techniques. PMID- 27489730 TI - Dynamic light scattering of xanthan gum biopolymer in colloidal dispersion. AB - The dynamical properties of nanogels of xanthan gum (XG) with hydrodynamic radius controlled in a size range from 5 nm to 35 nm, were studied at the different XG concentrations in water/sodium bis-2-ethylhexyl-sulfosuccinate (AOT)/decane reverse micelles (RMs) vs. mass fraction of nano-droplet (MFD) at W = 40, using dynamic light scattering (DLS). The diffusion study of nanometer-sized droplets by DLS technique indicated that enhancing concentration of the XG polysaccharide resulted in exchanging the attractive interaction between nano-gels to repulsive interaction, as the mass fraction of nano-droplets increased. The reorientation time (taur ) of water nanodroplets decreased with MFD for water-in-oil AOT micro emulsion comprising high concentration (0.0000625) of XG. On the other hand, decreasing concentration of biopolymer led to increasing the rotational correlation time of water nanodroplets with MFD. In conclusion, a single relaxation curve was observed for AOT inverse microemulsions containing different XG concentrations. Furthermore, the interaction between nanogels was changed from attractive to repulsive versus concentration of XG in the AOT RMs. PMID- 27489732 TI - Parametric and working fluid analysis of a combined organic Rankine-vapor compression refrigeration system activated by low-grade thermal energy. AB - The potential use of many common hydrofluorocarbons and hydrocarbons as well as new hydrofluoroolefins, i.e. R1234yf and R1234ze(E) working fluids for a combined organic Rankine cycle and vapor compression refrigeration (ORC-VCR) system activated by low-grade thermal energy is evaluated. The basic ORC operates between 80 and 40 degrees C typical for low-grade thermal energy power plants while the basic VCR cycle operates between 5 and 40 degrees C. The system performance is characterized by the overall system coefficient of performance (COPS) and the total mass flow rate of the working fluid for each kW cooling capacity ([Formula: see text]). The effects of different working parameters such as the evaporator, condenser, and boiler temperatures on the system performance are examined. The results illustrate that the maximum COPS values are attained using the highest boiling candidates with overhanging T-s diagram, i.e. R245fa and R600, while R600 has the lowest [Formula: see text] under the considered operating conditions. Among the proposed candidates, R600 is the best candidate for the ORC-VCR system from the perspectives of environmental issues and system performance. Nevertheless, its flammability should attract enough attention. The maximum COPS using R600 is found to reach up to 0.718 at a condenser temperature of 30 degrees C and the basic values for the remaining parameters. PMID- 27489731 TI - Temporary amygdala inhibition reduces stress effects in female mice. AB - The current study investigated the effect of temporary inhibition of amygdala in response to metabolic changes caused by stress in female mice. Unilateral and bilateral amygdala cannulation was carried out, and after a week of recovery, 2% lidocaine hydrochloride was injected into the mice amygdalae five minutes before the induction of stress. A communication box was employed to induce stress for four consecutive days and plasma corticosterone, food and water intake, weight changes, and anorexia were measured as stress-induced metabolic changes. Results demonstrated that stress, increases stress, increased plasma corticosterone concentrations, weight, food, and water intake. Temporary inhibition of the amygdala slightly decreased plasma corticosterone concentrations, but did not fully reduce the effect of stress. The bilateral injection of lidocaine hydrochloride to the amygdala reduced the effect of stress and reduced water intake and weight. Unilateral injection of lidocaine hydrochloride into the left and right amygdala reduced food intake. In conclusion, the present study demonstrated that the left side and right side of amygdala nuclei play a different role in metabolic responses in stress. PMID- 27489733 TI - Cystoscopy and intravesical bacille Calmette-Guerin therapy in antibiotic-naive patients with bladder cancer with asymptomatic bacteriuria: An update. AB - Urologists often insist on sterile urine before invasive outpatient urological procedures, and urine culture and antibiotics are usually given before cystoscopy or instillation of bacille Calmette-Guerin (BCG) therapy, especially in patients who have positive urine cultures. Our experience suggests that cystoscopy and induction BCG therapy can be performed safely, even in patients with asymptomatic bacteriuria, without pretreatment or prophylactic antibiotics. The rate of subsequent febrile urinary tract infection is <4% in both infected and uninfected patients. Pretreatment antibacterial therapy does not appear to be necessary before these two outpatient urological procedures in patients with bladder cancer. Such strategy facilitates timely interventions and reduces the possibility of antibiotic resistance. PMID- 27489734 TI - Bulbar urethral stricture: How to optimise the use of buccal mucosal grafts. AB - The use of buccal mucosa graft urethroplasty (BMGU) for bulbar urethral strictures has gained widespread popularity since the first report in 1996. Over the last two decades, there have been many modifications in the surgical technique. This, along with better understanding of urethral anatomy, has allowed the BMG to become the 'gold standard' in urethral substitution. The present article reviews the evolution and techniques of BMGU in order to answer the question - how do we optimise the use of BMGs? PMID- 27489735 TI - Phosphodiesterase type 5 inhibitors: Irrational use in Saudi Arabia. AB - OBJECTIVE: To identify the criteria of phosphodiesterase type 5 inhibitor (PDE5i) users and to analyse the knowledge, attitude, and practices of PDE5i use amongst Saudi men. SUBJECTS AND METHODS: A web-based, cross-sectional survey was conducted in Saudi Arabia between January and April 2015. Sexually active adult men were interviewed using a website questionnaire designed by the authors. Descriptive statistics were used to analyse the data. RESULTS: In all, 1008 men participated in the survey with 378 (37.5%) reporting use of PDE5i. Of those using PDE5i, 144 (38.1%) reported erectile dysfunction and 234 (61.9%) reported normal erection (recreational users). We found several demographic features, including high education level, health field occupation, high income, smoking, and increased frequency of sexual intercourse amongst the PDE5i users. Most of the PDE5i users (92.3%) had knowledge about PDE5i and 84.1% of them bought it without medical prescription. The most commonly used PDE5i was tadalafil (46.1%) and most of the users (79.9%) reported improvement in their sexual activity after PDE5i usage. Amongst the recreational users, the main reasons for PDE5i usage were curiosity (38.5%) and improving self-confidence (25.6%). Of them, 69.2% reported benefits from PDE5i usage, mainly in the form of enhancement of erection (36.7%) and increasing erection duration (31.2%). CONCLUSION: PDE5i use appears to be frequent in Saudi Arabia. Most of the users had knowledge about PDE5i and claimed to get benefits from it, even if used as a recreational drug. PMID- 27489736 TI - What is better in percutaneous nephrolithotomy - Prone or supine? A systematic review. AB - OBJECTIVE: To review the literature reporting the technique of percutaneous nephrolithotomy (PCNL) and outcomes for prone and supine PCNL, as PCNL is an established treatment for renal calculi and both prone and supine PCNL have been described, but there has been much debate as to the optimal position for renal access in PCNL. METHODS: A review of the medical literature was conducted using the PubMed database to identify relevant studies reporting on prone and supine PCNL published up until July 2015. Only publications in English were considered. Search terms included 'supine', 'prone', 'percutaneous nephrolithotomy', 'PCNL' and 'randomised controlled trial'. Articles relevant to the particular aspect of PCNL discussed were selected. RESULTS: In all, 30 articles were included in the literature review. Nine of these articles were of Level 1 Evidence as graded by the Oxford System of Evidence-based Medicine. CONCLUSION: The present systematic review highlights the benefits and disadvantages of supine and prone PCNL. The published data on supine and prone PCNL have shown no significant superiority of either approach. Whether prone or supine PCNL is optimal, remains a debatable topic. PMID- 27489737 TI - Does lithotripsy increase stone recurrence? A comparative study between extracorporeal shockwave lithotripsy and non-fragmenting percutaneous nephrolithotomy. AB - OBJECTIVES: To investigate the effect of stone fragmentation on late stone recurrence by comparing the outcome of extracorporeal shockwave lithotripsy (ESWL) and non-fragmenting percutaneous nephrolithotomy (PCNL), and to investigate factors contributing to recurrent calculi. PATIENTS AND METHODS: We evaluated stone recurrence in 647 patients who initially achieved a stone-free status after ESWL and compared the outcomes to 137 stone-free patients treated with PCNL without stone fragmentation. Patients were evaluated every 3 months during the first year and every 6 months thereafter to censorship or time of first new stone formation. Stone recurrence rates were calculated using the Kaplan-Meier method. The effects of demographics, stone characteristics, and intervention on the recurrence rate were studied using the log-rank test and the Cox-regression analysis. RESULTS: For ESWL the recurrence rates were 0.8%, 35.8% and 60.1% after 1, 5 and 10 years, which were comparable to the 1.5%, 35.5% and 74.9%, respectively found in the PCNL group (P = 0.57). Stone burden (>8 mm) and a previous history of stone disease were significantly associated with higher recurrence rates regardless of the method of stone intervention (P = 0.02 and P = 0.01, respectively). In the ESWL group, a stone length of >8 mm showed a higher recurrence rate (P = 0.007). In both the ESWL and PCNL groups, there was a significant shift from baseline stone location, with an increased tendency for most new stones to recur in the calyces as opposed to the pelvis. CONCLUSIONS: In comparison with PCNL, ESWL does not increase long-term stone recurrence in patients who become stone-free. The stone burden appears to be the primary factor in predicting stone recurrence after ESWL. PMID- 27489738 TI - Efficacy and safety of tamsulosin oral-controlled absorption system, solifenacin, and combined therapy for the management of ureteric stent-related symptoms. AB - OBJECTIVES: To evaluate the efficacy of solifenacin, tamsulosin oral-controlled absorption system (OCAS), and the combination of both drugs on JJ stent-related symptoms using the validated Arabic version of the ureteric stent symptom questionnaire (USSQ). PATIENTS AND METHODS: In all, 260 patients who had undergone JJ stenting of the ureter for different endoscopic urological procedures were postoperatively randomly assigned into four equal groups. Patients in Group I received no treatment and served as the control group, Group II patients received tamsulosin OCAS 0.4 mg daily, Group III patients received solifenacin 5 mg daily, and Group IV patients received a combination of both drugs. Before stent removal, all patients completed the Arabic version of the USSQ. RESULTS: In all, 234 patients completed the study, comprised of 56 in Group I, 59 in Group II, 58 in Group III, and 61 in Group IV. Baseline characteristics and indications for JJ stenting were comparable in the four groups. There were highly significant differences in all items of the USSQ between the treatment groups and the controls, while Group II and III were comparable. The USSQ score was significantly lower in Group IV vs Groups II and III. Crossing of the distal curl of the stent to the midline had a significant positive correlation with the severity of the urinary symptoms, body pain, general health, and work performance in the medicated groups. CONCLUSIONS: Combined therapy with tamsulosin OCAS 0.4 mg daily and solifenacin 5 mg daily is a safe and well-tolerated management for stent-related symptoms. However, stent position remains a significant factor affecting response to medical therapy and patients' health-related quality of life. PMID- 27489739 TI - Fluoroscopy free flexible ureteroscopy with holmium: Yttrium-aluminium-garnet laser lithotripsy for removal of renal calculi. AB - OBJECTIVE: To evaluate the feasibility of access sheath insertion and ureteric stent placement without image guidance in flexible ureteroscopic lithotripsy with holmium:yttrium-aluminium-garnet laser for renal stones. PATIENTS AND METHODS: Between March 2014 and October 2015, 80 patients with renal stones treated with flexible ureteroscopic laser lithotripsy were evaluated. Indications for surgery were renal obstruction, failed shockwave lithotripsy (SWL), stones in polycystic kidneys, and mal-rotated kidneys. A 6.5-F Cobra flexible ureteroscope was used in all cases with an access sheath of 12 F, 35/45 cm in length. Fluoroscopy was not intended for use in all cases and postoperative JJ stenting was optional. The perioperative complications were listed and the collected data were analysed. RESULTS: The study included 80 patients (66 male, 14 female), with a mean (SD; range) age of 48.2 (8; 28-54) years and a stone burden of 13 (3.5; range 6-23) mm. In all, 26 patients had a stone burden of >15 mm and 48 patients had lower calyceal stones. The mean (SD; range) operative time was 71.5 (20; 25-130) min. Overall, 76 (95%) access sheath insertions were performed successfully without the use of fluoroscopy. JJ stenting was used in 22 patients (27.5%). The mean (SD; range) hospital stay was 10 (8.5; 10-36) h. After one session, a stone-free rate (SFR) of 87.5% was achieved (93.3% for stones of <15 mm). A single session was successful in 87.9% of cases with lower calyceal stones, with a SFR of 91.7% for post-SWL failure cases. The perioperative complication rate was 15%. CONCLUSION: Access sheath insertion without fluoroscopic guidance is feasible. This technique reduces radiation exposure in patients requiring flexible ureteroscopy. PMID- 27489740 TI - Single versus multiple instillation of povidone iodine and urographin in the treatment of chyluria: A prospective randomised study. AB - OBJECTIVE: To compare the safety, efficacy and complications of single vs multiple instillations of povidone iodine (PI) and urographin as a sclerosing agent in the treatment of chyluria. PATIENTS AND METHODS: The study included 58 patients diagnosed with chyluria between March 2006 and January 2013. The inclusion criteria were either severe attacks of chyluria or patients with mild to-moderate chyluria who had failed conservative treatment. The patients were randomly allocated to one of two groups: those in Group A had a single instillation of a combination of PI 0.2% plus the contrast-agent urographin 76%, while those in Group B had multiple instillations of the same combination twice daily for 3 successive days. RESULTS: The mean (SD) age of the patients in Groups A and B was 38.22 (10.67) and 37.9 (10.86) years, respectively. Chyluria was severe in eight patients (14.8%), moderate in 25 (46.3%) and mild in 21 (38.9%). The success rate in Group A (single instillation) was 85.2% and in Group B (multiple instillation) was 88.9%. The recurrence rate in Group A was 14.8% with a disease-free duration (DFD) of 4-15 weeks, while in group B it was 11.1% with a DFD of 6-18 weeks. CONCLUSION: There was no significant difference between a single instillation of a combination of PI 0.2% and urographin 76% as a sclerosing agent in the treatment of chyluria and multiple instillations. However, the single instillation protocol is more cost effective with a shorter hospital stay. PMID- 27489741 TI - Feasibility and safety of laparoscopic adrenalectomy for large tumours. AB - OBJECTIVE: To verify the feasibility and safety of laparoscopic adrenalectomy for large tumours, as since it was described, the laparoscopic approach for adrenalectomy has become the 'gold standard' for small tumours and for large and non-malignant adrenal tumours many studies have reported acceptable results. PATIENTS AND METHODS: This is a retrospective study from a general surgery department from January 2006 to December 2013 including 45 patients (56 laparoscopic adrenalectomies). We divided patients into two groups according to tumour size: <5 or ?5 cm, we compared demographic data and peri- and postoperative outcomes. RESULTS: There was no statistical difference between the two groups for conversion rate (3.7% vs 11.7% P = 0.32), postoperative complications (14% vs 12%, P = 0.4), postoperative length of hospital stay (5 vs 6 days P = 0.43) or mortality (3.5% vs 0% P = 0.99). The only statistical difference was the operating time, at a mean (SD) 155 (60) vs 247 (71) min (P < 0.001). CONCLUSION: Laparoscopic adrenalectomy for large tumours needs more time but appears to be safe and feasible when performed by experienced surgeons. PMID- 27489743 TI - Prostate tissue retrieval after holmium laser enucleation of the prostate; assessment of non-morcellation approaches. PMID- 27489742 TI - Prostate tissue retrieval after holmium laser enucleation of the prostate; assessment of non-morcellation approaches. AB - OBJECTIVES: To review non-morcellation approaches for tissue retrieval after holmium laser enucleation of the prostate (HoLEP) and whether these approaches demolish the advantages of the HoLEP procedure. PATIENTS AND METHODS: We reviewed our prospectively maintained laser prostate database for HoLEP procedures where non-morcellation approaches were used for retrieval of the enucleated adenoma. Non-morcellation approaches were adopted in cases of morcellator malfunction or whenever concomitant pathology indicated laparotomy. Patients were stratified into the laparotomy group (Group I) or the transurethral resection (TUR) group (Group II). Safety and efficacy of each approach were assessed and compared. RESULTS: Between August 2012 and July 2015, of 392 HoLEP procedures non morcellation approaches were used for tissue retrieval in 37 (9.4%). In 19 procedures a laparotomy approach was adopted (17 mini-laparotomies and two conventional laparotomies for concomitant diverticulectomy). TUR of the enucleated adenoma was adopted in 18 patients. Baseline demographic data and indications for surgery were comparable between the groups. However, significantly larger prostates were treated in Group I. There were no significant differences between the groups for tissue retrieval time, histopathological findings of retrieved tissue, and peri-procedure biochemical changes. However, significantly more tissue was retrieved (median tissue weight 115 vs 38 g) and at a faster rate (4.6 vs 1.09 g/min) in Group I. The median hospital stay was similar in both groups, but the median time to catheter removal was longer in Group I (5 vs 2 days). Minimal and similar peri-procedure complications were reported in both groups and in both groups there was a significant and comparable improvement in all urinary outcome measures. CONCLUSION: In the absence or malfunction of a tissue morcellator, or whenever concomitant pathology indicates laparotomy, non-morcellation tissue retrieval approaches are feasible options for endourologists practicing transurethral enucleation of prostate adenoma. These approaches are valid alternatives retaining most of the advantages of the transurethral prostate enucleation procedure. PMID- 27489744 TI - Benign prostatic hyperplasia, metabolic syndrome and androgenic alopecia: Is there a possible relationship? AB - OBJECTIVE: To evaluate the incidence of benign prostatic hyperplasia (BPH) and metabolic syndrome in patients with androgenetic alopecia (AGA) in comparison with those with no AGA, as several previous studies have reported inconsistent results of an association between metabolic syndrome and BPH with AGA. PATIENTS SUBJECTS AND METHODS: This cross-sectional study included 400 participants, divided into 300 patients diagnosed with AGA, with different grades according to Norwood-Hamilton classification, and 100 control subjects with no AGA. Criteria for diagnosis of metabolic syndrome according to Adult Treatment Panel-III criteria (waist circumference, blood pressure, fasting blood sugar, high-density lipoprotein and triglycerides), as well as criteria for diagnosis of BPH (prostatic volume, urine flow, and prostate-specific antigen) were assessed in all patients and compared with the control subjects. RESULTS: There were significant differences between the AGA and no-AGA groups for the following variables: waist circumference, body mass index, fibrinogen level, fasting blood sugar, cholesterol, C-reactive protein, erythrocyte sedimentation rate, and glycosylated haemoglobin. There was a significant difference in number of patients with AGA manifesting criteria of metabolic syndrome (51% vs 28%), as well as BPH diagnostic criteria (36% vs 6.8%) compared with the control subjects. Both BPH and metabolic syndrome were shown to be significant independent variables associated with AGA. CONCLUSIONS: Dermatologists, urologists, and primary care physicians should monitor patients with early onset AGA for the development of urinary symptoms, to permit an earlier diagnosis of BPH; and for metabolic syndrome symptoms, to permit early diagnosis of cardiovascular risk factors. PMID- 27489745 TI - Tubularised incised-plate versus tubularisation of an intact and laterally augmented plate for hypospadias repair: A prospective randomised study. AB - OBJECTIVES: To compare the outcome of hypospadias repair using tubularised incised-plate (TIP) urethroplasty and tubularisation of an intact and laterally augmented urethral plate. PATIENTS AND METHODS: This prospective randomised study included 370 patients with primary distal hypospadias. All had urethral plate widths of 8-10 mm and a glans of ?15 mm. Exclusion criteria were previous repair, circumcision, a wide urethral plate of >10 mm or a narrow plate of <8 mm in diameter, a small glans of <15 mm in diameter, chordee of >30 degrees , and hormonal stimulation. Patients were randomised into two groups: Group 1 (185 patients) underwent TIP urethroplasty and Group 2 (185 patients) underwent tubularisation of the intact plate with lateral augmentation of the urethral plate using penile skin. The follow-up period was 12-28 months. RESULTS: There were 172 evaluable patients in Group 1 and 177 in Group 2. The urethroplasty was successful in 83.2% and 94.4% in Groups 1 and 2, respectively. Complications occurred in 16.8% in Group 1 and 5.6% in Group 2 (P = 0.001). Meatal stenosis occurred in 7% and 3.4% in Groups 1 and 2, respectively (P = 0.130). There were statistically significant differences in the wound dehiscence, fistula, and re operation rates of Group 1 versus Group 2, at 6% versus 0%, 9.8% versus 2.8%, and 13.4% versus 5.6%, respectively. The presence of mild chordee did not affect the complication rate (P = 0.242). The mean (SD) operative time was 56.7 (8.9) min in Group 1 and 93.7 (8.3) min in Group 2 (P < 0.001). CONCLUSION: The outcome of tubularised intact and laterally augmented plate is better than classical TIP urethroplasty of hypospadias. Further trials are mandatory to extend the indications of the technique. PMID- 27489746 TI - Parameter Estimation Using Divide-and-Conquer Methods for Differential Equation Models. PMID- 27489747 TI - Towards Self-regenerating Antimicrobial Polymer Surfaces. AB - Regeneration of functional polymer surfaces after damage or contamination is an unresolved scientific challenge, and also of practical importance. In this proof of-concept study, we present a method to regenerate a functional surface property using a polymer multi-layer architecture. This is exemplified using antimicrobially active surfaces. The idea is to shed the top layer of the polymer layer stack, like a reptile shedding its skin. The proof-of-concept stack consists of two antimicrobial layers and a degradable interlayer. Shedding of the top layer is enabled by degrading that interlayer. The shedding process was analyzed by quantitative fluorescence microscopy, ellipsometry, and FTIR spectroscopy. Antimicrobial assays revealed that the functionality of the emerging antimicrobial layer was fully retained after shedding. PMID- 27489748 TI - Novel Transabdominal Motor Action Potential (TaMAP) Neuromonitoring System for Spinal Surgery. AB - INTRODUCTION: Minimally invasive lateral lumbar interbody fusion (LLIF) approaches to the lumbar spine reduce patient morbidity compared to anterior or posterior alternatives. This approach, however, decreases direct anatomical visualization, creating the need for highly sensitive and specific neurophysiological monitoring. We seek to determine feasibility in 'transabdominal motor action potential (TaMAP)' monitoring as an assessment for the integrity of the neural elements during lateral-approach surgeries to the lumbar spine. METHODS: Cathode and anode leads were placed on the posterior and anterior surfaces of two porcine subjects. Currents of varying degrees were transmitted across, from front to back. Motor responses were monitored and recorded by needle electrodes in specific distal muscle groups of the lower extremity. Lastly, the cathode and anode were placed anterior and posterior to the chest wall and stimulated to the maximum of 1500 mA to determine any effect on cardiac rhythm. RESULTS: Responses were seen by measuring vertical height differences between peaks of corresponding evoked potentials. Recruitment began at 200 mA in the lower extremities. Stimulation at 450 mA recruited a reliable and distinguishable electrographic response from most muscle groups. Responses were recorded and reliably measured and increased in proportion to the graduation of transabdominal stimulation current; no responses were seen in the arms or face. 1500 mA across the chest wall failed to stimulate or induce cardiac arrhythmia on repeated stimulation, indicating safety of stimulation. CONCLUSION: TaMAPs seen in the animal model provide a potential alternative to standard transcranial motor evoked potentials done in the lateral approach of LLIFs. TaMAP recordings in most muscle groups were recordable and reliable, though some muscle groups failed to stimulate. Safety of transabdominal motor evoked potentials was confirmed in this porcine study. Future studies should examine TaMAPs reliability in detecting compressive lesions of nerve roots and peripheral nerves. PMID- 27489749 TI - Implementing an Innovative Prehospital Care Provider Training Course in Nine Cambodian Provinces. AB - Despite significant improvements in health outcomes nationally, many Cambodians continue to experience morbidity and mortality due to inadequate access to quality emergency medical services. Over recent decades, the Cambodian healthcare system and civil infrastructure have advanced markedly and now possess many of the components required to establish a well functioning emergency medical system. These components include enhanced access to emergency transportation through large scale road development efforts, widspread availability of emergency communication channels via the spread of cellphone and internet technology, and increased access to health services for poor patients through the implementation of health financing schemes. However, the system still lacks a number of key elements, one of which is trained prehospital care providers. Working in partnership with local providers, our team created an innovative, Cambodia specific prehospital care provider training course to help fill this gap. Participants received training on prehospital care skills and knowledge most applicable to the Cambodian healthcare system, which was divided into four modules: Basic Prehospital Care Skills and Adult Medical Emergencies, Traumatic Emergencies, Obstetric Emergencies, and Neonatal/Pediatric Emergencies. The course was implemented in nine of Cambodia's most populous provinces, concurrent with a number of overarching emergency medical service system improvement efforts. Overall, the course was administered to 1,083 Cambodian providers during a 27-month period, with 947 attending the entire course and passing the course completion exam. PMID- 27489750 TI - Conservative Treatment for Bilateral Displaced Proximal Humerus Head Fracture. AB - Proximal humerus fracture represents five to eight percent of all fractures and is twice as common in women than in men. Most cases of displaced fracture of the proximal humerus are treated surgically; it is probable that more cases are preferred to be treated surgically greater than required. The optimal treatment for these fractures remains controversial, but physicians have a tendency to treat via open reduction and fixation with angular locking plates or glenohumeral arthroplasty. We present a case of a 71-year-old woman with bilateral displaced proximal humeral fracture. Conservative treatment was initiated with two hanging casts, achieving radiological reduction on week one. After two additional weeks of casting, treatment continued with radiologic control and home physical therapy, ultimately an excellent functional outcome and adequate radiological reduction was obtained. Even in bilaterally displaced proximal humerus fractures, conservative treatment can be an efficient option, reducing complications, reaching adequate functional results and acceptable radiographic reduction.. PMID- 27489751 TI - Treatment of Aggressive Prolactin-Secreting Pituitary Adenomas with Adjuvant Temozolomide Chemotherapy: A Review. AB - Most prolactin-secreting pituitary adenomas demonstrate slow growth and are effectively managed with medical/surgical therapy. Rarely, these tumors can behave aggressively with rapid growth and invasion of local tissues, and are refractory to medical, surgical, or radio-surgical therapies. We report a case of a prolactin-secreting adenoma in a young woman, which became progressively aggressive and refractory to usual treatment modalities, but responded to treatment with the chemotherapeutic agent temozolomide. In addition, we review the literature for treatment of refractory adenomas with temozolomide. The clinical and pathologic characteristics of aggressive prolactin-secreting adenomas are reviewed, as well as their response to dopamine agonists, surgery, radiotherapy, and chemotherapy. PMID- 27489752 TI - NPH Log: Validation of a New Assessment Tool Leading to Earlier Diagnosis of Normal Pressure Hydrocephalus. AB - INTRODUCTION: Early treatment of normal pressure hydrocephalus (NPH) yields better postoperative outcomes. Our current tests often fail to detect significant changes at early stages. We developed a new scoring system (LP log score) to determine if this tool is more sensitive in detecting clinical differences than current tests. MATERIAL AND METHODS: Sixty-two consecutive new patients with suspected idiopathic NPH were studied. Secondary, previously treated and obstructive cases were not included. We collected age, pre- and post-lumbar puncture (LP) Tinetti, Timed Up and Go (TUG) Test, European NPH scale, and LP log scores. The LP log score is recorded at baseline and for seven consecutive days after removing 40 cc of cerebrospinal fluid (CSF) via LP. We studied the diagnostic accuracy of the tests for surgical indication. RESULTS: The post-LP log showed improvement in 90% of people with good baseline gait tests and in 93% of people who did not show any pre-LP and post-LP change in gait tests. Sensitivity, specificity, and accuracy to detect intention to treat when positive post-LP improvements were 4%, 100%, and 24%, respectively, for TUG, 21%, 86%, and 34%, respectively, for the Tinetti Mobility Test, 66%, 29%, and 58%, respectively, for Medical College of Virginia (MCV) grade, and 98%, 33%, and 85%, respectively, for LP log score. Pre-LP and post-LP TUG improvement and pre-LP and post-LP Tinetti improvement were not associated with a surgical indication (p > 0.05). LP log improvement was associated with surgical indication odds ratio (OR): 24.5 95% CI (2.4-248.12) (p = 0.007). CONCLUSIONS: LP log showed better sensitivity, diagnostic accuracy, and association with surgical indication than the current diagnostic approach. An LP log may be useful detecting NPH patients at earlier stages and, therefore, yield better surgical outcomes. PMID- 27489753 TI - Perforation of the Colon During Imatinib Mesylate (Gleevec) Treatment in a Patient with Chronic Myeloid Leukemia (CML). AB - Imatinib (Gleevec; STI-571) is a tyrosine-kinase inhibitor (TKI) used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) as well as gastrointestinal stromal tumor (GIST). The most common adverse effects with imatinib include superficial edema, muscle cramps, musculoskeletal pain, rash, fatigue, headache, and gastrointestinal side effects. Less frequent side effects include pancytopenia, febrile neutropenia, flushing, and liver function test abnormalities. Very rare side effects include secondary malignancies, Sweet's syndrome, angioedema, or cardiac arrest. We report the first case report of gastrointestinal perforation complicating imatinib treatment for CML. Unlike other antiangiogenic TKIs such as sunitinib or sorafenib that target vascular endothelial growth factor (VEGF) and known to cause gastrointestinal perforation, imatininib is a TKI with no known anti-VEGF activity, and so it remains unclear how imatinib would be associated with developing this life threatening complication. However, physicians caring for patients of imatinib should be aware of this potential toxicity. We suggest that careful attention and an appropriate clinical evaluation are required for patients presenting with gastrointestinal symptoms during imatinib treatment. PMID- 27489755 TI - Arthroscopic Bullet Removal From the Central and Peripheral Compartments of the Hip Joint. AB - Recent advances in hip arthroscopy offer an approach for treating an uncommon but highly disabling injury from intra-articular missile injury to the hip. Hip arthroscopy affords the patient the benefit of minimally invasive surgery while allowing for the diagnosis and treatment of concomitant pathology, which may be either acute, from the trauma of the missile, or chronic. We present a technique for the removal of projectiles from the central and peripheral compartments of the hip joint. Through a surgical series of a variety of gunshot wounds, we detail the unique aspects of retrieval for the various missile endpoints. We describe this technique for bullets or pieces of bullets lodged within the hip joint space, bone of the acetabulum, or femoral head. Furthermore, we provide an example in which hip arthroscopy is not a suitable option for treatment because of the resulting fracture pattern, which necessitates open reduction along with internal fixation. PMID- 27489756 TI - Basic Hip Arthroscopy: Anatomic Establishment of Arthroscopic Portals Without Fluoroscopic Guidance. AB - Hip arthroscopy has gained popularity in recent years for diagnostic and therapeutic hip preservation management. This article details the establishment of arthroscopic portals of the hip, specifically the anterolateral and modified anterior portals without fluoroscopic guidance. The anterolateral portal is established anatomically, and the modified anterior portal is then established under arthroscopic guidance. A through understanding of the hip anatomy allows for these portals to be made both safely and reliably for hip arthroscopies in the modified supine positioned patient. The reduced use of fluoroscopy with this technique lowers the risk of ionizing radiation exposure to the patient and surgeon. PMID- 27489754 TI - Non-Pharmacological Treatments for ADHD in Youth. AB - BACKGROUND: Complementary and alternative medicine (CAM) in psychiatry or integrative psychiatry covers a wide range of biological, psychological and mind body treatments that enhance standard medical practices and patient outcomes. While CAM approaches are popular amongst patients in their practice as well as in self-report because of their ease of use, health professionals have received limited education in these interventions and often are unaware of their patients' use of CAM treatments. METHOD: This overview highlights evidence-based CAM treatments for attention deficit hyperactivity disorder (ADHD) including dietary interventions, phytomedicines, mind-body practices and neurofeedback. RESULTS: While conventional treatments are the mainstays for ADHD, there are a large number of available treatments that can be used to enhance treatment response. CONCLUSION: With improved education and further scientific and clinical research, validated integrative treatments will provide more effective, lower risk and lower cost care for patients with ADHD. PMID- 27489757 TI - Superficial Medial Collateral Ligament of the Knee: Anatomic Augmentation With Semitendinosus and Gracilis Tendon Autografts. AB - The superficial medial collateral ligament (sMCL) and associated knee structures are the most commonly injured structures of the knee. Most isolated sMCL tears are treated nonoperatively. Several studies have described different algorithms for treatment of sMCL lesions, as well as different types of techniques, both in the acute and in chronic settings. The purpose of this article was to detail our anatomic sMCL augmentation technique using semitendinosus and gracilis tendon autografts. PMID- 27489758 TI - Recurrent hydropneumothorax: An unusual presentation for malignant pleural mesothelioma. AB - Mesothelioma is a rare pulmonary malignancy commonly associated with asbestos exposure. Its presentation is insidious and non-specific, with complaints of chest pain, dyspnea and cough. Chest X-ray may demonstrate unilateral pleural effusion. CT and PET scans may highlight nodular pleural plaques. Diagnosis often times is difficult with negative imaging and negative pleural fluid studies. In rare cases, hydropneumothoraces may be seen. We report a case of malignant pleural mesothelioma presenting as recurrent hydropneumothorax with negative CT scan of the chest for pleural abnormalities and negative pleural fluid studies. PMID- 27489759 TI - Fractured metallic tracheostomy tube: A rare complication of tracheostomy. AB - Although tracheostomy is a well-accepted procedure for airway management, some early and late complications may occur. Fracture of the tracheostomy tube (TT) is a rare complication, particularly in a patient with long-term use. Herein we report a case of fractured metallic TT migrating into the tracheobronchial tree. Rigid bronchoscopy was performed through the tracheostomy stoma and the fractured tube was successfully removed by a balloon catheter. Appropriate cleaning, routine careful examination, and scheduled replacement of the TT may help prevent this complication. PMID- 27489760 TI - A case of pulmonary Mycobacterium avium infection in an immunocompetent patient who showed a huge consolidation with a high FDG uptake on PET/CT. AB - We encountered a middle-aged afebrile immunocompetent woman with a slight cough. Positron emission tomography (PET)/computed tomography (CT) revealed a broad left upper-lobe consolidation without cavity lesions, small nodules, or bronchiectasis showing a positive fluorodeoxyglucose (FDG) uptake with a maximum standardized uptake value (SUVmax) of 26.9. Percutaneous needle lung biopsy specimens showed caseous granulomas without atypical cells and Mycobacterium avium was cultured from left pleural effusion, which developed after the biopsy. The consolidation significantly decreased following combination chemotherapy for approximately 2 years. Clinicians should remember that pulmonary M. avium infection could result in a large consolidation without other typical radiological findings. PMID- 27489761 TI - About the effect of pulmonary rehabilitation on lung function in patients with chronic obstructive pulmonary disease. AB - Detecting an improvement of lung function in a patient with chronic obstructive pulmonary disease (COPD) following pulmonary rehabilitation (PR) may appear unexpected, but actually recent studies showed that is not so rare. In fact, in a prospective study comparing a group of 190 COPD patients undergoing PR to a group of 67 patients treated only with drugs a mean improvement of FEV1 from 1240 mL to 1252.4 mL was found in the former, while the values changed from 1367 mL to 1150 mL in the latter (p < 0.001). Such improvement was detected also in a study in patients with very severe COPD, as assessed by a FEV1 increasing from 970 mL at baseline to 1080 mL after a 3-week PR inpatient program (p < 0.001). These observations suggest that improvement of lung function in COPD patients undergoing PR should be included among the expected outcomes and routinely assessed as an index of clinical success during the treatment. PMID- 27489762 TI - A favorable clinical effect of an expectorant in allergic bronchopulmonary mycosis caused by Schizophyllum commune. AB - An 80-year-old Japanese woman with wet cough and dyspnea was diagnosed with pneumonia at a clinic. Antibiotics did not improve her symptoms; therefore, she was referred to our hospital one month after symptom onset. Chest radiograph findings revealed complete collapse of the left lung. Bronchoscopy showed white mucus plug in the left main bronchus, which could not be removed. She was initially treated with bromhexine. Subsequently, culture results of the mucus plug specimen obtained during bronchoscopy yielded Schizophyllum commune. After three weeks, improvement of the collapsed lung was observed on chest radiograph. PMID- 27489763 TI - Nodular glomerulosclerosis in a patient with cystic fibrosis, but not diabetes mellitus: A paediatric case. AB - BACKGROUND: Nodular glomerulosclerosis is seen in insulin dependent diabetic patients with nephropathy. Kimmelstiel-Wilson nodules on biopsy are considered pathognomonic. Diabetic nephropathy is a spectrum of glomerular and tubular disease which correlates with the duration of the diabetes and the extent of glycaemic control. CASE REPORT: An eleven year old girl with cystic fibrosis was referred with persistent heavy proteinuria. She underwent a renal biopsy which revealed nodular glomerulosclerosis with Kimmelstiel-Wilson-like nodules. Her investigations for diabetes were negative and she was treated with enalapril. CONCLUSION: Nodular glomerulosclerosis in the absence of diabetes and poor glycaemic control have not previously been reported in a paediatric patient. In adult patients without diabetes, smoking, hypertension, hypercholestrolaemia and extrarenal vascular disease have been implicated. The proteinuria decreased after commencement of treatment with enalapril. A recurrence of proteinuria responded to a dose increase. PMID- 27489764 TI - Changing of IKZF1 genotype during Philadelphia-negative precursor-B acute lymphoblastic leukemia progression: a short clinical report. AB - *The case demonstrated a rare event of clonal heterogeneity by IKZF1 gene status in BCRABL1- ALL.*IKZF1 deletions are secondary events in ALL caused by clonal evolution during the treatment.*It's prognostic significance could be more crucial in BCR-ABL- rather than in BCR-ABL + ALL.*IKZF1 gene alterations may be determined and proved at the genome, expression and protein level.*IKZF1 deletions are suitable for MRD detection but not stable compared to Ig/TCR rearrangement. PMID- 27489765 TI - A remarkable hematological and molecular response pattern in a patient with polycythemia vera during combination therapy with simvastatin and alendronate. AB - We report a 57-year old man with polycythemia vera, who had a remarkable hematological and molecular response during treatment with simvastatin and alendronate. The patient was treated with this combination for 56 months, and during this period the patient has been in complete hematological remission. The JAK2-V617F allele burden has dropped from 64% to sustained values below 20%, and follow-up bone marrow biopsies have revealed no change in PV features, without any regular cytoreductive treatment. PMID- 27489766 TI - Enhanced international prognostic index in Japanese patients with diffuse large B cell lymphoma. AB - To evaluate the National Comprehensive Cancer Network (NCCN) International Prognostic Index (IPI), we analyzed 284 patients treated with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in our institution in Japan. Their 5-year overall survival (OS) by risk level was 80.7%, 74.8%, 55.4% and 67.5% (P=0.005); and their 5-year progression-free survival (PFS) was 76.8%, 78.6%, 63.7% and 58.3% (P=0.0722). The NCCN-IPI is a simple scale that uses conventional clinical factors, but did not reflect survival in our cohort. The NCCN-IPI may require further evaluation for different regions and ethnicities before adopting it for routine clinical use. PMID- 27489768 TI - Giant early components of somatosensory evoked potentials to tibial nerve stimulation in cortical myoclonus. AB - Enlarged cortical components of somatosensory evoked potentials (giant SEPs) recorded by electroencephalography (EEG) and abnormal somatosensory evoked magnetic fields (SEFs) recorded by magnetoencephalography (MEG) are observed in the majority of patients with cortical myoclonus (CM). Studies on simultaneous recordings of SEPs and SEFs showed that generator mechanism of giant SEPs involves both primary sensory and motor cortices. However the generator sources of giant SEPs have not been fully understood as only one report describes clearly giant SEPs following lower limb stimulation. In our study we performed a combined EEG-MEG recording on responses elicited by electric median and tibial nerve stimulation in a patient who developed consequently to methyl bromide intoxication CM with giant SEPs to median and tibial nerve stimuli. SEPs wave shapes were identified on the basis of polarity-latency components (e.g. P15-N20 P25) as defined by earlier studies and guidelines. At EEG recording, the SEP giant component did not appear in the latency range of the first cortical component for median nerve SEP (N20), but appeared instead in the range of the P37 tibial nerve SEP, which is currently identified as the first cortical component elicited by tibial nerve stimuli. Our MEG and EEG SEPs recordings also showed that components in the latency range of P37 were preceded by other cortical components. These findings suggest that lower limb P37 does not correspond to upper limb N20. MEG results confirmed that giant SEFs are the second component from both tibial (N43m-P43m) and median (N27m-P27m) nerve stimulation. MEG dipolar sources of these giant components were located in the primary sensory and motor area. PMID- 27489767 TI - Automated subfield volumetric analysis of hippocampus in temporal lobe epilepsy using high-resolution T2-weighed MR imaging. AB - BACKGROUND AND PURPOSE: Automated subfield volumetry of hippocampus is desirable for use in temporal lobe epilepsy (TLE), but its utility has not been established. Automatic segmentation of hippocampal subfields (ASHS) and the new version of FreeSurfer software (ver.6.0) using high-resolution T2-weighted MR imaging are candidates for this volumetry. The aim of this study was to evaluate hippocampal subfields in TLE patients using ASHS as well as the old and new versions of FreeSurfer. MATERIALS AND METHODS: We recruited 50 consecutive unilateral TLE patients including 25 with hippocampal sclerosis (TLE-HS) and 25 without obvious etiology (TLE-nonHS). All patients and 45 healthy controls underwent high-resolution T2-weighted and 3D-volume T1-weighted MRI scanning. We analyzed all of their MR images by FreeSurfer ver.5.3, ver.6.0 and ASHS. For each subfield, normalized z-scores were calculated and compared among groups. RESULTS: In TLE-HS groups, ASHS and FreeSurfer ver.6.0 revealed maximal z-scores in ipsilateral cornu ammonis (CA) 1, CA4 and dentate gyrus (DG), whereas in FreeSurfer ver.5.3 ipsilateral subiculum showed maximal z-scores. In TLE-nonHS group, there was no significant volume reduction by either ASHS or FreeSurfer. CONCLUSIONS: ASHS and the new version of FreeSurfer may have an advantage in compatibility with existing histopathological knowledge in TLE patients with HS compared to the old version of FreeSurfer (ver.5.3), although further investigations with pathological findings and/or surgical outcomes are desirable. PMID- 27489769 TI - Diffusivity in multiple sclerosis lesions: At the cutting edge? AB - BACKGROUND: Radial Diffusivity (RD) has been suggested as a promising biomarker associated with the level of myelination in MS lesions. However, the level of RD within the lesion is affected not only by loss of myelin sheaths, but also by the degree of tissue destruction. This may lead to exaggeration of diffusivity measures, potentially masking the effect of remyelination. OBJECTIVE: To test the hypothesis that the T2 hyperintense lesion edge that extends beyond the T1 hypointense lesion core is less affected by tissue loss, and therefore a more appropriate target for imaging biomarker development targeting de- and re myelination. METHOD: Pre- and post-gadolinium (Gd) enhanced T1, T2 and DTI images were acquired from 75 consecutive RRMS patients. The optic radiation (OR) was identified in individual patients using a template-based method. T2 lesions were segmented into T1-hypointense and T1-isointense areas and lesion masks intersected with the OR. Average Radial, Axial and Mean diffusivity (RD, AD and MD) and fractional anisotropy (FA) were calculated for lesions of the entire brain and the OR. In addition, Gd enhancing lesions were excluded from the analysis. RESULTS: 86% of chronic T2 lesions demonstrated hypointense areas on T1 weighted images, which typically occupied the central part of each T2 lesion, taking about 40% of lesional volume. The T1-isointense component of the T2 lesion was most commonly seen as a peripheral ring of relatively constant thickness ("T2 rim"). While changes of diffusivity between adjacent normal appearing white matter and the "T2-rim" demonstrated a disproportionally high elevation of RD compare to AD, the increase of water diffusion was largely isointense between the "T2-rim" and T1-hypointense parts of the lesion. CONCLUSION: Distinct patterns of diffusivity within the central and peripheral components of MS lesions suggest that axonal loss dominates in the T1 hypointense core. The effects of de/remyelination may be more readily detected in the "T2-rim", where there is relative preservation of structural integrity. Identifying and separating those patterns has an important implication for clinical trials of both neuroprotective and, in particular, remyelinating agents. PMID- 27489770 TI - Quantifying patterns of brain activity: Distinguishing unaffected siblings from participants with ADHD and healthy individuals. AB - Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent and heritable psychiatric disorders. While previous studies have focussed on mapping focal or connectivity differences at the group level, the present study employed pattern recognition to quantify group separation between unaffected siblings, participants with ADHD, and healthy controls on the basis of spatially distributed brain activations. This was achieved using an fMRI-adapted version of the Stop-Signal Task in a sample of 103 unaffected siblings, 184 participants with ADHD, and 128 healthy controls. We used activation maps derived from three task regressors as features in our analyses employing a Gaussian process classifier. We showed that unaffected siblings could be distinguished from participants with ADHD (area under the receiver operating characteristic curve (AUC) = 0.65, p = 0.002, 95% Modified Wald CI: 0.59-0.71 AUC) and healthy controls (AUC = 0.59, p = 0.030, 95% Modified Wald CI: 0.52-0.66 AUC), although the latter did not survive correction for multiple comparisons. Further, participants with ADHD could be distinguished from healthy controls (AUC = 0.64, p = 0.001, 95% Modified Wald CI: 0.58-0.70 AUC). Altogether the present results characterise a pattern of frontolateral, superior temporal and inferior parietal expansion that is associated with risk for ADHD. Unaffected siblings show differences primarily in frontolateral regions. This provides evidence for a neural profile shared between participants with ADHD and their healthy siblings. PMID- 27489771 TI - Discriminating among degenerative parkinsonisms using advanced (123)I-ioflupane SPECT analyses. AB - (123)I-ioflupane single photon emission computed tomography (SPECT) is a sensitive and well established imaging tool in Parkinson's disease (PD) and atypical parkinsonian syndromes (APS), yet a discrimination between PD and APS has been considered inconsistent at least based on visual inspection or simple region of interest analyses. We here reappraise this issue by applying advanced image analysis techniques to separate PD from the various APS. This study included 392 consecutive patients with degenerative parkinsonism undergoing (123)I-ioflupane SPECT at our institution over the last decade: 306 PD, 24 multiple system atrophy (MSA), 32 progressive supranuclear palsy (PSP) and 30 corticobasal degeneration (CBD) patients. Data analysis included voxel-wise univariate statistical parametric mapping and multivariate pattern recognition using linear discriminant classifiers. MSA and PSP showed less ioflupane uptake in the head of caudate nucleus relative to PD and CBD, yet there was no difference between MSA and PSP. CBD had higher uptake in both putamen relative to PD, MSA and PSP. Classification was significant for PD versus APS (AUC 0.69, p < 0.05) and between APS subtypes (MSA vs CBD AUC 0.80, p < 0.05; MSA vs PSP AUC 0.69 p < 0.05; CBD vs PSP AUC 0.69 p < 0.05). Both striatal and extra-striatal regions contain classification information, yet the combination of both regions does not significantly improve classification accuracy. PD, MSA, PSP and CBD have distinct patterns of dopaminergic depletion on (123)I-ioflupane SPECT. The high specificity of 84-90% for PD versus APS indicates that the classifier is particularly useful for confirming APS cases. PMID- 27489774 TI - LGI1-negative faciobrachial dystonic-like seizures originating from the insula. AB - We expand the differential diagnosis of LGI1-positive faciobrachial dystonic seizures (FBDS) by presenting a 67-year-old woman affected by seizures of similar semiology who was found to have insular epilepsy. We report the distinct characteristics of insular faciobrachial dystonic-like seizures that would help clinicians to differentiate them from typical LGI1-positive FBDS, thus, guiding therapy while awaiting antibody results. LGI1-negative faciobrachial dystonic like seizures should be considered when the seizure semiology includes unilateral and prolonged dystonia without loss of awareness, there is an ictal EEG correlate, MRI is suggestive of insular lesion, and when there is neither clearly associated memory impairment nor hyponatremia. PMID- 27489772 TI - Automated detection of cerebral microbleeds in patients with Traumatic Brain Injury. AB - In this paper a Computer Aided Detection (CAD) system is presented to automatically detect Cerebral Microbleeds (CMBs) in patients with Traumatic Brain Injury (TBI). It is believed that the presence of CMBs has clinical prognostic value in TBI patients. To study the contribution of CMBs in patient outcome, accurate detection of CMBs is required. Manual detection of CMBs in TBI patients is a time consuming task that is prone to errors, because CMBs are easily overlooked and are difficult to distinguish from blood vessels. This study included 33 TBI patients. Because of the laborious nature of manually annotating CMBs, only one trained expert manually annotated the CMBs in all 33 patients. A subset of ten TBI patients was annotated by six experts. Our CAD system makes use of both Susceptibility Weighted Imaging (SWI) and T1 weighted magnetic resonance images to detect CMBs. After pre-processing these images, a two-step approach was used for automated detection of CMBs. In the first step, each voxel was characterized by twelve features based on the dark and spherical nature of CMBs and a random forest classifier was used to identify CMB candidate locations. In the second step, segmentations were made from each identified candidate location. Subsequently an object-based classifier was used to remove false positive detections of the voxel classifier, by considering seven object-based features that discriminate between spherical objects (CMBs) and elongated objects (blood vessels). A guided user interface was designed for fast evaluation of the CAD system result. During this process, an expert checked each CMB detected by the CAD system. A Fleiss' kappa value of only 0.24 showed that the inter-observer variability for the TBI patients in this study was very large. An expert using the guided user interface reached an average sensitivity of 93%, which was significantly higher (p = 0.03) than the average sensitivity of 77% (sd 12.4%) that the six experts manually detected. Furthermore, with the use of this CAD system the reading time was substantially reduced from one hour to 13 minutes per patient, because the CAD system only detects on average 25.9 false positives per TBI patient, resulting in 0.29 false positives per definite CMB finding. PMID- 27489773 TI - The effective connectivity of the seizure onset zone and ictal perfusion changes in amygdala kindled rhesus monkeys. AB - Epileptic seizures are network-level phenomena. Hence, epilepsy may be regarded as a circuit-level disorder that cannot be understood outside this context. Better insight into the effective connectivity of the seizure onset zone and the manner in which seizure activity spreads could lead to specifically-tailored therapies for epilepsy. We applied the electrical amygdala kindling model in two rhesus monkeys until these animals displayed consistent stage IV seizures. At this stage, we investigated the effective connectivity of the amygdala by means of electrical microstimulation during fMRI (EM-fMRI). In addition, we imaged changes in perfusion during a seizure using ictal SPECT perfusion imaging. The spatial overlap between the connectivity network and the ictal perfusion network was assessed both at the regional level, by calculating Dice coefficients using anatomically defined regions of interest, and at the voxel level. The kindled amygdala was extensively connected to bilateral cortical and subcortical structures, which in many cases were connected multisynaptically to the amygdala. At the regional level, the spatial extents of many of these fMRI activations and deactivations corresponded to the respective increases and decreases in perfusion imaged during a stage IV seizure. At the voxel level, however, some regions showed residual seizure-specific activity (not overlapping with the EM-fMRI activations) or fMRI-specific activation (not overlapping with the ictal SPECT activations), indicating that frequently, only a part of a region anatomically connected to the seizure onset zone participated in seizure propagation. Thus, EM fMRI in the amygdala of electrically-kindled monkeys reveals widespread areas that are often connected multisynaptically to the seizure focus. Seizure activity appears to spread, to a large extent, via these connected areas. PMID- 27489775 TI - Forced normalization's converse as nature's model for use of ECT in the management of psychosis: An observational case series. PMID- 27489776 TI - A cross strain Plasmodium falciparum microarray optimized for the transcriptome analysis of Plasmodium falciparum patient derived isolates. AB - Malarial parasite P. falciparum, an apicomplexan protozoan has a 23.3 MB nuclear genome and encodes ~ 5600 transcripts. The genetic diversity of the parasite within and across geographical zones is a challenge to gene expression studies which are essential for understanding of disease process, outcome and developing markers for diagnostics and prognostics. Here, we describe the strategy involved in designing a custom P. falciparum 15K array using the Agilent platform and Genotypic's Right Design methodology to study the transcriptome of Indian field isolates for which genome sequence information is limited. The array contains probes representing genome sequences of two distinct geographical isolates (i.e. 3D7 and HB3) and sub-telomeric var gene sequences of a third isolate (IT4) known to adhere in culture condition. Probes in the array have been selected based on their efficiency to detect transcripts through a 244K array experimentation. Array performance for the 15K array, was evaluated and validated using RNA materials from P. falciparum clinical isolates. A large percentage (91%) of the represented transcripts was detected from Indian P. falciparum patient isolates. Replicated probes and multiple probes representing the same gene showed perfect correlation between them suggesting good probe performance. Additional transcripts could be detected due to inclusion of unique probes representing HB3 strain transcripts. Variant surface antigen (VSA) transcripts were detected by optimized probes representing the VSA genes of three geographically distinct strains. The 15K cross strain P. falciparum array has shown good efficiency in detecting transcripts from P. falciparum parasite samples isolated from patients. The low parasite loads and presence of host RNA makes arrays a preferred platform for gene expression studies over RNA-Seq. PMID- 27489777 TI - Clinical experience with N-carbamylglutamate in a single-centre cohort of patients with propionic and methylmalonic aciduria. AB - BACKGROUND: The effect of long-term N-carbamylglutamate (NCG) treatment on the rate and severity of decompensations due to propionic aciduria (PA) and methylmalonic aciduria (MMA) is unknown. This paper presents clinical experience from a single-centre cohort of patients with PA and MMA who received continuous long-term treatment with NCG. METHODS: The effect of oral NCG treatment (initial dose: 50 mg/kg/day) was investigated in patients with PA or MMA who were experiencing frequent progressive episodes of metabolic decompensation, who had pathological levels of ammonia, and who were referred to the Division of Metabolic Diseases, University Hospital of Padova between August 2014 and December 2015. Clinical and biochemical data, including the number of metabolic decompensations, lactic acid, uric acid and plasma ammonia levels, protein intake and body weight, were collected before and after the initiation of NCG treatment. RESULTS: Eight patients with PA (n = 4) and MMA (n = 4) aged 2-20 years were treated with NCG (50 mg/kg/day) for 7-16 months. Metabolic decompensation episodes decreased in number and severity, with three of the patients having no episodes (pre-treatment: 24 episodes; post-treatment: 9 episodes). After NCG treatment, all episodes were treated at home and none required hospitalisation, lactic acid values were 1.3-2.1 mmol/L and uric acid values were 0.21-0.36 mmol/L. Significant reductions in blood ammonia levels after NCG initiation were observed in five patients, whereas levels were reduced or maintained in the normal range in the remainder. Over the treatment period, patients had an increase in natural protein intake of 20-50% and gained 0-6.5 kg in bodyweight. CONCLUSION: These observations suggest that, in addition to short-term benefits for the acute treatment of hyperammonaemia, NCG may be effective and well tolerated as a long-term treatment in patients with severe PA and MMA, and that further prospective studies are warranted. PMID- 27489778 TI - The influence of a polymorphism in the gene encoding angiotensin converting enzyme (ACE) on treatment outcomes in late-onset Pompe patients receiving alglucosidase alfa. AB - Correlations between angiotensin-converting enzyme (ACE) genotype (I/I, I/D, D/D), disease severity at baseline and response to enzyme replacement therapy (ERT) were assessed in the Pompe disease Late-Onset Treatment Study (LOTS). No correlations were observed between ACE genotype and disease severity at baseline. However, D/D patients appeared to have a reduced response to alglucosidase alfa treatment than I/I or I/D patients, suggesting that ACE polymorphisms may influence the response to alglucosidase alfa treatment and warrants further investigation. PMID- 27489779 TI - Gross Findings of Widespread Visceral Metastasis of Prostatic Adenocarcinoma With Neuroendocrine Features: A Case Report. AB - Although prostate cancer is common in the western world and is associated with favorable overall survival, neuroendocrine prostate cancer is difficult to detect and is known to aggressively metastasize throughout the body. This subset of disease thus has a poor prognosis, and early detection and treatment of neuroendocrine prostate cancer may increase overall survival. We present a case of a now deceased 63 year old male with extensive epicardial, respiratory, hepato bilary, adrenal, genitourinary, and osseous tissue metastasis. PMID- 27489780 TI - A landscape-based cluster analysis using recursive search instead of a threshold parameter. AB - Cluster-based analysis methods in neuroimaging provide control of whole-brain false positive rates without the need to conservatively correct for the number of voxels and the associated false negative results. The current method defines clusters based purely on shapes in the landscape of activation, instead of requiring the choice of a statistical threshold that may strongly affect results. Statistical significance is determined using permutation testing, combining both size and height of activation. A method is proposed for dealing with relatively small local peaks. Simulations confirm the method controls the false positive rate and correctly identifies regions of activation. The method is also illustrated using real data. *A landscape-based method to define clusters in neuroimaging data avoids the need to pre-specify a threshold to define clusters.*The implementation of the method works as expected, based on simulated and real data.*The recursive method used for defining clusters, the method used for combining clusters, and the definition of the "value" of a cluster may be of interest for future variations. PMID- 27489781 TI - A genetically encoded bioluminescent indicator for illuminating proinflammatory cytokines. AB - We introduce a method to evaluate the activities of cytokines based on the nuclear transport of NF-kappaB. A pair of bioluminescent indicators was made for conferring cytokine sensitivity to cervical carcinoma-derived HeLa cells. The principle is based on reconstitution of split fragments of Renilla reniformis luciferase (RLuc) by protein splicing with a DnaE intein from Synechocystis sp. PCC6803. The bioluminescence intensity of thus reconstituted RLuc in the HeLa cells was used as a measure of the activities for cytokines. With the present method, we evaluated the activities of various cytokines based on the nuclear transport of NF-kappaB in human cervical carcinoma-derived HeLa cells carrying the indicators. The present approach to evaluating the activities of cytokines may provide a potential clinical value in monitoring drug activity and directing treatment for various diseases related with NF-kappaB. The method highlights the experimental procedure from our original publications, Anal. Biochem. 2006, 359, 147-149 and Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 11542. The summary of the method is: *Cytokine activities are determined within 2 h after stimulation.*Temporarily inactivated split-luciferase fragments are reconstituted by protein splicing.*Nucleartrafficking of NF-kappaB was illuminated for gauging the ligand-driven activity. PMID- 27489783 TI - Qatar Medical Journal at the forefront of medical publishing. PMID- 27489782 TI - Exercise reduces depressive symptoms in adults with arthritis: Evidential value. AB - AIM: To determine whether evidential value exists that exercise reduces depression in adults with arthritis and other rheumatic conditions. METHODS: Utilizing data derived from a prior meta-analysis of 29 randomized controlled trials comprising 2449 participants (1470 exercise, 979 control) with fibromyalgia, osteoarthritis, rheumatoid arthritis or systemic lupus erythematosus, a new method, P-curve, was utilized to assess for evidentiary worth as well as dismiss the possibility of discriminating reporting of statistically significant results regarding exercise and depression in adults with arthritis and other rheumatic conditions. Using the method of Stouffer, Z scores were calculated to examine selective-reporting bias. An alpha (P) value < 0.05 was deemed statistically significant. In addition, average power of the tests included in P-curve, adjusted for publication bias, was calculated. RESULTS: Fifteen of 29 studies (51.7%) with exercise and depression results were statistically significant (P < 0.05) while none of the results were statistically significant with respect to exercise increasing depression in adults with arthritis and other rheumatic conditions. Right-skew to dismiss selective reporting was identified (Z = -5.28, P < 0.0001). In addition, the included studies did not lack evidential value (Z = 2.39, P = 0.99), nor did they lack evidential value and were P-hacked (Z = 5.28, P > 0.99). The relative frequencies of P-values were 66.7% at 0.01, 6.7% each at 0.02 and 0.03, 13.3% at 0.04 and 6.7% at 0.05. The average power of the tests included in P-curve, corrected for publication bias, was 69%. Diagnostic plot results revealed that the observed power estimate was a better fit than the alternatives. CONCLUSION: Evidential value results provide additional support that exercise reduces depression in adults with arthritis and other rheumatic conditions. PMID- 27489784 TI - Advances in technology are changing the future of medicine. PMID- 27489785 TI - Allergen-specific immunotherapy in pediatric allergic asthma. AB - Allergen-specific immunotherapy (AIT) is the only curative way that can change the immunologic response to allergens and thus can modify the natural progression of allergic diseases. There are some important criteria which contributes significantly on efficacy of AIT, such as the allergen extract used for treatment, the dose and protocol, patient selection in addition to the severity and control of asthma. The initiation of AIT in allergic asthma should be considered in intermittent, mild and moderate cases which coexisting with other allergic diseases such as allergic rhinitis, and in case of unacceptable adverse effects of medications. Two important impact of AIT; steroid sparing effect and preventing from progression to asthma should be taken into account in pediatric asthma when making a decision on starting of AIT. Uncontrolled asthma remains a significant risk factor for adverse events and asthma should be controlled both before and during administration of AIT. The evidence concerning the efficacy of subcutaneous (SCIT) and sublingual immunotherapy (SLIT) for treatment of pediatric asthma suggested that SCIT decreases asthma symptoms and medication scores, whereas SLIT can ameliorate asthma symptoms. Although the effectiveness of SCIT has been shown for both seasonal and perennial allergens, the data for SLIT is less convincing for perennial allergies in pediatric asthma. PMID- 27489786 TI - Supporting the validation of the new allergic and hypersensitivity conditions section of the World Health Organization International Classification of Diseases 11. AB - BACKGROUND: The new International Classification of Diseases (ICD)-11 "Allergic and hypersensitivity conditions" section has been constructed as a result of a detailed and careful action plan based on scientific evidences for the necessity of changes and collaboration with the World Health Organization (WHO) ICD-11 revision governance. All the efforts are being acknowledged by the Joint Allergy Academies. OBJECTIVE: Considering the new classification model addressed to the allergic and hypersensitivity conditions and following the ICD WHO agenda, we believe it is the appropriate time to start supporting the validation process in collaboration with the WHO ICD governance. METHODS: We conducted a mapping of ICD 10 allergic and hypersensitivity conditions in the ICD-11 beta phase structure and categorized the conditions as fitting by "precoordination," "postcoordination," "indexed to the ICD-11 Foundation," "no code fit properly" or "no correspondence" in the ICD-11. RESULTS: From overall 125 ICD-10 entities spread in 6 chapters, 57.6% were able to be precoordinated, 4% postcoordinated, 12% indexed to the Foundation, 9.6% had no code fitting properly and 18.6% had no correspondence in the ICD-11 framework. CONCLUSION: We have been able to demonstrate that 83.2% of the ICD-10 allergic and hypersensitivity conditions could be captured by the current ICD-11 beta draft framework. We strongly believe that our findings constitute a key step forward for a softer transition of the ICD-10 allergic and hypersensitivity conditions to the ICD-11, supporting the WHO in this process as well as strengthening the visibility of the Allergy specialty and ensuring quality management of allergic patients. PMID- 27489788 TI - The efficacy of single premedication with antihistamines for radiocontrast media hypersensitivity. AB - BACKGROUND: Single premedication with antihistamines for radiocontrast media (RCM) hypersensitivity is frequently used in real world at the emergent situation although its efficacy is not proven. OBJECTIVE: To evaluate the effect of intravenous antihistamines as a premedication in general population who had experience of mild adverse reactions to iodinated RCM. METHODS: A retrospective observational study on 14,785 subjects who had RCM-enhanced computed tomography scans between January 2014 and December 2015 in Seoul National University Hospital Gangnam Healthcare Center, Seoul, South Korea. RESULTS: Among 453 subjects who had a history of mild RCM-induced hypersensitivity reactions, 273 subjects had a single premedication of intravenous antihistamine. When comparing antihistamine-premedication group and nonpremedication group, there is no protective effect of antihistamines on the incidence rate and severity of hypersensitivity (10.6% vs. 11.7%, p = 0.729). CONCLUSION: The clinical efficacy of a single premedication of antihistamines for mild RCM-induced hypersensitivity was not confirmed. PMID- 27489787 TI - Relationship between all fevers or fever after vaccination, and atopy and atopic disorders at 18 and 36 months. AB - BACKGROUND: Studies have reported that early febrile episodes and febrile episodes with infections are associated with a decreased risk of developing atopy. OBJECTIVE: To examine further the association between presence of and number of febrile episodes are with atopy and atopic diseases and if there was a difference between all fevers and fever after vaccination. METHODS: We studied 448 infants in a Singapore mother-offspring cohort study (Growing Up in Singapore Towards Healthy Outcomes) which had complete data for the exposures and outcomes of interest. Fever was defined as more than 38.0C and was self-reported. The presence of and number of febrile episodes were examined for association with outcome measures, namely parental reports of doctor-diagnosed asthma and eczema, and rhinitis, which was evaluated by doctors involved in the study at 18 and 36 months. These outcomes were considered atopic if there were 1 or more positive skin prick tests. RESULTS: The presence of all fevers from 0-6 months of age was associated with reduced odds of having atopy at 36 months of age (unadjusted odds ratio [OR], 0.628; 95% confidence interval [CI], 0.396-0.995). The presence of fever after vaccination from 0-24 months of age was associated with reduced odds of having atopy at 36 months of age (OR, 0.566; 95% CI, 0.350-0.915). The presence of all fevers from 0-6 months of age was associated with reduced odds of having atopic eczema at 36 months (OR, 0.430; 95% CI, 0.191-0.970). Fever was associated with increased odds of having doctor-diagnosed asthma and rhinitis. CONCLUSION: There was an inverse relationship between the presence of all fevers from 0-6 months of age and the development of atopy and eczema at 36 months of age. Fever after vaccination might be considered a subclinical infection that did not show the same effect in early life. PMID- 27489789 TI - Effect on quality of life of the mixed house dust mite/weed pollen extract immunotherapy. AB - BACKGROUND: Although many patients with allergic rhinitis have symptoms due to sensitization to more than one kind of allergens, and mixed allergen extracts are widely used for immunotherapy, there are few published trials. OBJECTIVE: Our study aimed to evaluate the effect of multiple-allergen immunotherapy on improving the symptoms and quality of life of allergic rhinitis patients. METHODS: We performed a 1-year single-center observation study of subcutaneous immunotherapy using house dust mite extract (n = 12), weed pollen extract (n = 21), or mixed house dust mite/weed pollen extract (n = 11) in 44 allergic rhinitis patients. All the allergens responsible for the symptom of each patient were included in his immunotherapy. Symptom score, medication score, and quality of life of the patients were evaluated before and after 1-year immunotherapy. Quality of life was evaluated with the Rhinoconjunctivitis Quality of Life Questionnaire. RESULTS: In all 3 groups receiving subcutaneous immunotherapy, significant improvement of symptom score, medication score, and quality of life was found vs. baseline at 1 year, irrespective of the allergen used. In the weed pollen season, the changes of quality of life questionnaire score after 1-year treatment were not significantly different between the weed pollen group (1.55 +/ 1.24) and the mixed house dust mite/weed pollen group (1.14 +/- 1.01). The same happened in the nonpollen seasons, during which dust mite immunotherapy (1.23 +/- 1.63) and mixed immunotherapy (0.60 +/- 0.47) did not show significantly different effect on the quality of life. CONCLUSION: The multiple-allergen immunotherapy might be effective in polysensitized allergic rhinitis patients, and could improve their quality of life. Our result did not show significant difference between the effects of multiple-allergen immunotherapy and mono allergen immunotherapy. PMID- 27489790 TI - Feasibility of a smartphone application based action plan and monitoring in asthma. AB - BACKGROUND: Asthma patients may experience acute episodic exacerbation. The guidelines recommend that written action plan should be given to asthma patients. However, no one can predict when and where acute exacerbation will happen. As people carry smart phone almost anytime and anywhere, smartphone application could be a useful tool in asthma care. We evaluated the feasibility of the ubiquitous healthcare system of asthma care using a smartphone application (snuCare) based on the self-management guideline or action plan. METHODS: Forty four patients including fragile asthmatics were enrolled from Seoul National University Bundang Hospital between December 2011 and February 2012. They were randomly assigned into application user (n = 22) or application nonuser group (n = 22). We evaluated user-satisfaction, and clinical parameters such as asthma control, Quality of Life Questionnaire for Adult Korean Asthmatics, and the adherence of patients. RESULTS: The characteristics were similar at baseline between the 2 groups except those who treated with short-term systemic steroid or increased dose of systemic steroid during previous 8 weeks (user vs. nonuser: 31.8% vs. 4.5%, p = 0.020). Total of 2,226 signals was generated during 8 weeks including 5 risky states. After eight weeks, the users answered that it was very easy to use the application, which was shown in highest scores in terms of satisfaction (mean +/- standard deviation, 4.3 +/- 0.56). Seventy-three percent of patients answered that the application was very useful for asthma care. User group showed improved the adherence scores (p = 0.017). One patient in application user group could avoid Emergency Department visit owing to the application while a patient in nonuser group visited Emergency Department. CONCLUSION: The ubiquitous healthcare system using a smartphone application (snuCare) based on the self-management guideline or action plan could be helpful in the monitoring and the management of asthma. PMID- 27489791 TI - Role of eosinophilic inflammation and atopy in elderly asthmatic patients. AB - BACKGROUND: Asthma in the elderly is severe and associated with poor treatment outcome. Although atopy has an important role in pathogenesis, its role in the elderly is unclear, partly due to immune senescence. OBJECTIVE: We aimed to examine the associations of Th2-mediated inflammation with asthma severity in the elderly. METHODS: Consecutive asthmatics older than 60 years without severe exacerbation within 8 weeks were enrolled. Atopic status was determined by positive serum specific IgE or skin prick test to common aeroallergens. Serum total IgE was measured simultaneously to exhaled fractional concentration of nitric oxide (FeNO). Asthma control level was assessed by using Thai Asthma Control Test (ACT) score. RESULTS: Total of 44 elderly asthmatic patients were enrolled. The mean age was 68.9 years and mean age of asthma diagnosis was 46.6 years. Seventy-seven percent of patients were female. Atopic status was found in 45.5% of patients. Uncontrolled asthma classified as ACT score < 20 was noted in 25% of elderly asthma, but its association with either high serum total IgE (>=120 IU/mL), high FeNO (>=50 ppb) or atopic status was not detected. CONCLUSION: One-fourth of elderly asthmatics were clinically uncontrolled, while atopy was confirmed in 45.5%. Neither high total IgE, high FeNO nor atopic status was associated with uncontrolled asthma in the elderly. Other factors might play role in asthma severity in the elderly, and has to be further investigated. PMID- 27489792 TI - Delayed diagnosis of allergic bronchopulmonary aspergillosis due to absence of asthmatic symptoms. AB - Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disease with small prevalence. Exposure to aspergillus mold causes immunologic hypersensitivity and may cause ranges of symptoms from minimal to detrimental outcomes. Diagnosing and treating the disease before the development of bronchiectasis may save the patient from poor outcomes. This report presents a case of recurrent ABPA without any symptom of asthma, which impeded the correct diagnosis even after numerous hospitalizations. PMID- 27489793 TI - Marking nut anaphylaxis. AB - Marking nut Semecarpus anacardium, so-called because it contains a pigment that has been used in the past to mark fabrics, is a known cause of contact hypersensitivity. It may be ingested as an ingredient of some traditional Hindi foods. We describe the first reported case of anaphylaxis to marking nut. PMID- 27489794 TI - Proctitis 1 Week after Stereotactic Body Radiation Therapy for Prostate Cancer: Implications for Clinical Trial Design. AB - BACKGROUND: Proctitis following prostate cancer radiation therapy is a primary determinant of quality of life (QOL). While previous studies have assessed acute rectal morbidity at 1 month after stereotactic body radiotherapy (SBRT), little data exist on the prevalence and severity of rectal morbidity within the first week following treatment. This study reports the acute bowel morbidity 1 week following prostate SBRT. MATERIALS AND METHODS: Between May 2013 and August 2014, 103 patients with clinically localized prostate cancer were treated with 35-36.25 Gy in five fractions using robotic SBRT delivered on a prospective clinical trial. Bowel toxicity was graded using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv.4). Bowel QOL was assessed using the EPIC-26 questionnaire bowel domain at baseline, 1 week, 1 month, and 3 months. Time dependent changes in bowel symptoms were statistically compared using the Wilcoxon signed-rank test. Clinically significant change was assessed by the minimally important difference (MID) in EPIC score. This was defined as a change of 1/2 standard deviation (SD) from the baseline score. RESULTS: One-hundred and three patients with a minimum of 3 months of follow-up were analyzed. The cumulative incidence of acute grade 2 gastrointestinal (GI) toxicity was 23%. There were no acute >= grade 3 bowel toxicities. EPIC bowel summary scores maximally declined at 1 week after SBRT (-13.9, p < 0.0001) before returning to baseline at 3 months after SBRT (+0.03, p = 0.94). Prior to treatment, 4.9% of men reported that their bowel bother was a moderate to big problem. This increased to 28.4% (p < 0.0001) 1 week after SBRT and returned to baseline at 3 months after SBRT (0.0%, p = 0.66). Only the bowel summary and bowel bother score declines at 1 week met the MID threshold for clinically significant change. CONCLUSION: The rate and severity of acute proctitis following prostate SBRT peaked at 1 week after treatment and returned to baseline by 3 months. Toxicity assessment at 1 week can therefore minimize recall bias and should aid in the design of future clinical trials focused on accurately capturing and minimizing acute morbidity following SBRT. PMID- 27489795 TI - Bone Marrow Immunity and Myelodysplasia. AB - Myelodysplastic syndrome (MDS) is characterized by an ineffective hematopoiesis with production of aberrant clones and a high cell apoptosis rate in bone marrow (BM). Macrophages are in charge of phagocytosis. Innate Immune cells and specific T cells are in charge of immunosurveillance. Little is known on BM cell recruitment and activity as BM aspirate is frequently contaminated with peripheral blood. But evidences suggest an active role of immune cells in protection against MDS and secondary leukemia. BM CD8(+) CD28(-) CD57(+) T cells are directly cytotoxic and have a distinct cytokine signature in MDS, producing TNF-alpha, IL-6, CCL3, CCL4, IL-1RA, TNFalpha, FAS-L, TRAIL, and so on. These tools promote apoptosis of aberrant cells. On the other hand, they also increase MDS-related cytopenia and myelofibrosis together with TGFbeta. IL-32 produced by stromal cells amplifies NK cytotoxicity but also the vicious circle of TNFalpha production. Myeloid-derived suppressing cells (MDSC) are increased in MDS and have ambiguous role in protection/progression of the diseases. CD33 is expressed on hematopoietic stem cells on MDS and might be a potential target for biotherapy. MDS also has impact on immunity and can favor chronic inflammation and emergence of autoimmune disorders. BM is the site of hematopoiesis and thus contains a complex population of cells at different stages of differentiation from stem cells and early engaged precursors up to almost mature cells of each lineage including erythrocytes, megakaryocytes, myelo-monocytic cells (monocyte/macrophage and granulocytes), NK cells, and B cells. Monocytes and B cell finalize their maturation in peripheral tissues or lymph nodes after migration through the blood. On the other hand, T cells develop in thymus and are present in BM only as mature cells, just like other well vascularized tissues. BM precursors have a strong proliferative capacity, which is usually associated with a high risk for genetic errors, cell dysfunction, and consequent cell death. Abnormal cells are prone to destruction through spontaneous apoptosis or because of the immunosurveillance that needs to stay highly vigilant. High rates of proliferation or differentiation failures lead to a high rate of cell death and massive release of debris to be captured and destroyed (1). Numerous macrophages reside in BM in charge of home-keeping. They have a high capacity of phagocytosis required for clearing all these debris. PMID- 27489797 TI - Emergence of Plasmid-Borne dfrA14 Trimethoprim Resistance Gene in Shigella sonnei. AB - The most common mechanism of trimethoprim (TMP)-resistance is the acquisition of dihydrofolate reductase enzyme resistant to this drug. Previous molecular characterization of TMP-genes resistance in Chilean isolates of Shigella sonnei searching for dfrA1 and dfrA8, showed solely the presence of dfrA8 (formerly dhfrIIIc). However, these genetic markers were absent in S. sonnei strains further isolated during an outbreak in 2009. To identify the TMP-resistance gene in these strains, a genomic DNA library from a TMP-resistant (TMP(R)) S. sonnei representative strain for the outbreak was used to clone, select and identify a TMP-resistance marker. The TMP(R) clone was sequenced by primer walking, identifying the presence of the dfrA14 gene in the sul2-strA'-dfrA14-'strA-strB gene arrangement, harbored in a native 6779-bp plasmid. The same plasmid was isolated by transforming with a ~4.2 MDa plasmid extracted from several TMP(R) S. sonnei strains into Escherichia coli. This plasmid, named pABC-3, was present only in dfrA14-positive strains and was homologous to a previously described pCERC-1, but different due to the absence of an 11-bp repetitive unit. The distribution of dfrA1, dfrA8, and dfrA14 TMP-resistance genes was determined in 126 TMP(R) S. sonnei isolates. Most of the strains (96%) carried only one of the three TMP-resistance genes assessed. Thus, all strains obtained during the 2009 outbreak harbored only dfrA14, whereas, dfrA8 was the most abundant gene marker before outbreak and, after the outbreak dfrA1 seems have appeared in circulating strains. According to PFGE, dfrA14-positive strains were clustered in a genetically related group including some dfrA1- and dfrA8-positive strains; meanwhile other genetic group included most of the dfrA8-positive strains. This distribution also correlated with the isolation period, showing a dynamics of trimethoprim genetic markers prevalent in Chilean S. sonnei strains. To our knowledge, dfrA14 gene associated to a small non-conjugative plasmid was detected for the first time in Shigella. Apparently, the strain causing the outbreak must have been introduced, changing drastically the genetic distribution of trimethoprim resistance in Chilean S. sonnei strains. PMID- 27489798 TI - Prospects for dengue vaccines for travelers. AB - Travel-acquired dengue cases have been increasing as the overall global dengue burden has expanded. In Korea, imported dengue cases have been reported since 2000 when it first became a notifiable disease. During the first four months of 2016, three times more dengue cases were reported in Korea than during the same period the previous year. A safe and efficacious vaccine for travelers would be beneficial to prevent dengue disease in individual travelers and potentially decrease the risk of virus spread to non-endemic areas. Here, we summarize the characteristics of dengue vaccines for travelers and review dengue vaccines currently licensed or in clinical development. PMID- 27489796 TI - Modification of Bacterial Effector Proteins Inside Eukaryotic Host Cells. AB - Pathogenic bacteria manipulate their hosts by delivering a number of virulence proteins -called effectors- directly into the plant or animal cells. Recent findings have shown that such effectors can suffer covalent modifications inside the eukaryotic cells. Here, we summarize the recent reports where effector modifications by the eukaryotic machinery have been described. We restrict our focus on proteins secreted by the type III or type IV systems, excluding other bacterial toxins. We describe the known examples of effectors whose enzymatic activity is triggered by interaction with plant and animal cell factors, including GTPases, E2-Ubiquitin conjugates, cyclophilin and thioredoxins. We focus on the structural interactions with these factors and their influence on effector function. We also review the described examples of host-mediated post translational effector modifications which are required for proper subcellular location and function. These host-specific covalent modifications include phosphorylation, ubiquitination, SUMOylation, and lipidations such as prenylation, fatty acylation and phospholipid binding. PMID- 27489799 TI - Accelerating the development of a group A Streptococcus vaccine: an urgent public health need. AB - Group A Streptococcus (GAS) infections cause substantial worldwide morbidity and mortality, mostly associated with suppurative complications such as pharyngitis, impetigo, and non-suppurative immune syndromes such as acute rheumatic fever, rheumatic heart disease, and acute post-streptococcal glomerulonephritis. Deaths occur mostly in children, adolescents, and young adults in particular pregnant women in low- and middle-income countries. GAS strains are highly variable, and a GAS vaccine would need to overcome the issue of multiple strains. Several approaches have been used multivalent vaccines using N-terminal polypeptides of different M protein; conserved M protein vaccines with antigens from the conserved C-repeat portion of the M protein; incorporation selected T- and B-cell epitopes from the C-repeat region in a synthetic polypeptide or shorter single minimal B-cell epitopes from this same region; and non-M protein approaches utilizing highly conserved motives of streptococcal C5a peptidase, GAS carbohydrate and streptococcal fibronectin-binding proteins. A GAS vaccine represents urgent need for this neglected disease and should therefore deserve the greatest attention of international organizations, donors, and vaccine manufacturers. PMID- 27489800 TI - Development of vaccines to Mycobacterium avium subsp. paratuberculosis infection. AB - Johne's disease or paratuberculosis is a chronic debilitating disease in ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). The disease causes significant economic losses in livestock industries worldwide. There are no effective control measures to eradicate the disease because there are no appropriate diagnostic methods to detect subclinically infected animals. Therefore, it is very difficult to control the disease using only test and cull strategies. Vaccination against paratuberculosis has been considered as an alternative strategy to control the disease when combined with management interventions. Understanding host-pathogen interactions is extremely important to development of vaccines. It has long been known that Th1-mediated cellular immune responses are play a crucial role in protection against MAP infection. However, recent studies suggested that innate immune responses are more closely related to protective effects than adaptive immunity. Based on this understanding, several attempts have been made to develop vaccines against paratuberculosis. A variety of ideas for designing novel vaccines have emerged, and the tests of the efficacy of these vaccines are conducted constantly. However, no effective vaccines are commercially available. In this study, studies of the development of vaccines for MAP were reviewed and summarized. PMID- 27489801 TI - Influenza virus vaccine for neglected hosts: horses and dogs. AB - This study provides information regarding vaccine research and the epidemiology of influenza virus in neglected hosts (horses and dogs). Equine influenza virus (EIV) causes a highly contagious disease in horses and other equids, and outbreaks have occurred worldwide. EIV has resulted in costly damage to the horse industry and has the ability of cross the host species barrier from horses to dogs. Canine influenza is a virus of equine or avian origin and infects companion animals that live in close contact with humans; this results in possible exposure to the seasonal epizootic influenza virus. There have been case reports of genetic reassortment between human and canine influenza viruses, which results in high virulence and the ability of transmission to ferrets. This emphasizes the need for vaccine research on neglected hosts to update knowledge on current strains and to advance technology for controlling influenza outbreaks for public health. PMID- 27489802 TI - Vaccination strategies in patients with solid organ transplant: evidences and future perspectives. AB - Solid organ transplant recipients need emphases on immunization that result in certainly decrease the risk of vaccine preventable diseases. Organ transplant candidate should complete the recommended full vaccination schedule as early as possible during the courses of underlying disease because the patients with end stage liver or renal disease have reduced immune response to vaccine. Furthermore, live attenuated vaccines are generally contraindicated after transplantation. This review summarizes current information and the evidences regarding the efficacy and safety of immunization in adult solid organ transplant candidates and recipients. PMID- 27489803 TI - An oral Aujeszky's disease vaccine (YS-400) induces neutralizing antibody in pigs. AB - PURPOSE: Aujeszky's disease (AD) is an economically important disease affecting both wild and domestic pigs of the species Sus scrofa. A previous study yielded serological evidence of AD in Korean wild boars, which could spread AD to other animals. A new Aujeszky's disease virus (ADV) bait vaccine is required to prevent AD outbreaks in swine. In the present study, we investigated the safety and immunogenicity of a gE-deleted marker vaccine, strain YS-400, in young domestic pigs. MATERIALS AND METHODS: The YS-400 strain was propagated in Vero cells, and the trial ADV bait vaccine (a vaccine blister in a matrix including an attractant) was prepared. Pigs were orally immunized with the vaccine (2 mL, 10(7.5) TCID50/mL) delivered using a syringe or in the bait vaccine. The animals were observed for 9 weeks after vaccination, and immunogenicity was assessed using a virus neutralization (VN) test and enzyme linked immunosorbent assay. RESULTS: The YS-400 strain was non-pathogenic to pigs when given orally and induced high VN titers (1:32-1:128) 6 weeks post-administration. Of the pigs given the ADV bait vaccine twice or three times, 40% were seropositive by 2 weeks, and 100% were seropositive by 7 weeks after the first dose. Pigs that consumed the AD bait vaccine three times developed VN titers that were slightly higher than those of pigs given the vaccine twice. CONCLUSION: Domestic pigs given the trial ADV bait vaccine exhibited no adverse effects and developed high VN titers against ADV, indicating that the YS-400 strain is safe and can prevent ADV infection in domestic pigs. PMID- 27489804 TI - QS-21 enhances the early antibody response to oil adjuvant foot-and-mouth disease vaccine in cattle. AB - PURPOSE: One of the most important tools against foot-and-mouth disease, a highly contagious and variable viral disease of cloven-hoofed animals, is vaccination. However, the effectiveness of foot-and-mouth disease vaccines on slowing the spread of the disease is questionable. In contrast, high potency vaccines providing early protection may solve issues with the spread of the disease, escaping mutants, and persistency. To increase the potency of the vaccine, additives such as saponin and aluminium hydroxide are used. However, the use of saponin with an oil adjuvant is not common and is sometimes linked to toxicity. QS-21, which is less toxic than Quil A, has been presented as an alternative for use with saponin. In this study, the addition of QS-21 to a commercially available foot-and-mouth disease water-in-oil-in-water emulsion vaccine was evaluated in cattle. MATERIALS AND METHODS: After vaccination, serum samples were collected periodically over 3 months. Sera of the QS-21 and normal oil vaccine groups were compared via serum virus neutralization antibody titre and liquid phase blocking enzyme-linked immunosorbent assay antibody titre. RESULTS: The results showed that there was a significant early antibody increase in the QS-21 group. CONCLUSION: Strong early virus neutralizing antibody response will be useful for emergency or ring vaccinations against foot-and-mouth disease in target animals. PMID- 27489805 TI - Protective efficacy and immune responses by homologous prime-booster immunizations of a novel inactivated Salmonella Gallinarum vaccine candidate. AB - PURPOSE: Salmonella enterica serovar Gallinarum (SG) ghost vaccine candidate was recently constructed. In this study, we evaluated various prime-boost vaccination strategies using the candidate strain to optimize immunity and protection efficacy against fowl typhoid. MATERIALS AND METHODS: The chickens were divided into five groups designated as group A (non-immunized control), group B (orally primed and boosted), group C (primed orally and boosted intramuscularly), group D (primed and boosted intramuscularly), and group E (primed intramuscularly and boosted orally). The chickens were primed with the SG ghost at 7 days of age and were subsequently boosted at the fifth week of age. Post-immunization, the plasma IgG and intestinal secretory IgA (sIgA) levels, and the SG antigen-specific lymphocyte stimulation were monitored at weekly interval and the birds were subsequently challenged with a virulent SG strain at the third week post-second immunization. RESULTS: Chickens in group D showed an optimized protection with significantly increased plasma IgG, sIgA, and lymphocyte stimulation response compared to all groups. The presence of CD4(+) and CD8(+) T cells and monocyte/macrophage (M/M) in the spleen, and splenic expression of cytokines such as interferon gamma (IFN-gamma) and interleukin 6 (IL-6) in the immunized chickens were investigated. The prime immunization induced significantly higher splenic M/M population and mRNA levels of IFN-gamma whereas the booster showed increases of splenic CD4(+) and CD8(+) T-cell population and IL-6 cytokine in mRNA levels. CONCLUSION: Our results indicate that the prime immunization with the SG ghost vaccine induced Th1 type immune response and the booster elicited both Th1- and Th2-related immune responses. PMID- 27489806 TI - Safety and immunogenicity of recombinant rabies virus (ERAGS) in mice and raccoon dogs. AB - PURPOSE: The development of a genetically modified live rabies vaccine applicable to wild raccoon dogs is necessary for the eradication of rabies in Korea. Thus, we constructed a recombinant rabies virus (RABV) called the ERAGS strain, using a reverse genetic system and evaluated its safety and efficacy in mice and its safety and immunogenicity in raccoon dogs. MATERIALS AND METHODS: ERAGS, which has Asn194Ser and Arg333Glu substitutions in the glycoprotein, was constructed using site-directed mutagenesis. Mice were inoculated with the ERAGS strain (either 10(5.0) or 10(7.0) FAID50/mL) via intramuscular (IM) or intracranial injections and then challenged with a virulent RABV. Raccoon dogs were administered the ERAGS strain (10(8.0) FAID50/mL) either orally or via the IM route and the immunogenicity of the strain was evaluated using fluorescent antibody virus neutralization tests. RESULTS: The ERAGS strain inoculated into murine neuroblastoma cells reached 10(7.8) FAID50/mL at 96-hour post-inoculation. The virus was not pathogenic and induced complete protection from virulent RABV in immunized 4- and 6-week-old mice. Korean raccoon dogs immunized with the ERAGS strain via IM or oral route were also safe from the virus and developed high titer levels (26.4-32.8 IU/mL) of virus-neutralizing antibody (VNA) at 4 weeks post-inoculation. CONCLUSION: The ERAGS RABV strain was effectively protective against rabies in mice and produced a high VNA titer in raccoon dogs. PMID- 27489807 TI - A recombinant rabies virus (ERAGS) for use in a bait vaccine for swine. AB - PURPOSE: Rabies viruses (RABV) circulating worldwide in various carnivores occasionally cause fatal encephalitis in swine. In this study, the safety and immunogenicity of a recombinant rabies virus, the ERAGS strain constructed with a reverse genetics system, was evaluated in domestic pigs. MATERIALS AND METHODS: Growing pigs were administered 1 mL (10(8.0) FAID50/mL) of the ERAGS strain via intramuscular (IM) or oral routes and were observed for 4 weeks' post inoculation. Three sows were also inoculated with 1 mL of the ERAGS strain via the IM route. The safety and immunogenicity in swine were evaluated using daily observation and a virus-neutralizing assay (VNA). Fluorescent antibody tests (FAT) for the RABV antigen and reverse transcriptase-polymerase chain reaction (RT-PCR) assays for the detection of the nucleocapsid (N) gene of RABV were conducted with brain tissues from the sows after necropsy. RESULTS: The growing pigs and sows administered the ERAGS strain did not exhibit any clinical sign of rabies during the test period test and did develop VNA titers. The growing pigs inoculated with the ERAGS strain via the IM route showed higher VNA titers than did those receiving oral administration. FAT and RT-PCR assays were unable to detect RABV in several tissues, including brain samples from the sows. CONCLUSION: Our results suggest that the ERAGS strain was safe in growing pigs and sows and induced moderate VNA titers in pigs. PMID- 27489808 TI - A Bordetella pertussis proteoliposome induces protection in mice without affecting the immunogenicity of diphtheria and tetanus toxoids in a trivalent formulation. AB - In this study, a formulation of Bordetella pertussis proteoliposome (PLBp), diphtheria, and tetanus toxoids and alum (DT-PLBp) was evaluated as a trivalent vaccine candidate in BALB/c mice. Vaccine-induced protection was estimated using the intranasal challenge for pertussis and enzyme-linked immunosorbent assay fvto assess serological responses for diphtheria or tetanus. Both, diphtheria-tetanus whole cell pertussis (DTP) and diphtheria-tetanus vaccines (DT) were used as controls. Animals immunized with DT-PLBp, PLBp alone, and DTP showed total reduction of CFU in lungs 7 days after intranasal challenge. Likewise, formulations DT-PLBp, DTP, and DT elicited antibody levels >=2 IU/mL against tetanus and diphtheria, considered protective when neutralization tests are used. Overall, results showed that combination of PLBp with tetanus and diphtheria toxoids did not affect the immunogenicity of each antigen alone. PMID- 27489809 TI - Bone Healing in Ovariectomized-rabbit Calvarial Defect with Tricalcium Phosphate Coated with Recombinant Human Bone Morphogenetic Protein-2 Genetically Engineered in Escherichia coli. AB - PURPOSE: This study compares the bone formation ability of tricalcium phosphate (TCP) with and without recombinant human bone morphogenetic protein-2 (rhBMP-2) and assesses TCP as a carrier of rhBMP-2. METHODS: Bilateral round defects (diameter: 8.0 mm) were formed in the cranium of eight New Zealand white rabbits. The defects were grafted with TCP only (control group) or with rhBMP-2-coated TCP (experimental group). The animals were sacrificed at 1st week, 2nd week, 4th week, and 8th week postoperatively; two rabbits sacrificed each time. The skulls were harvested and subjected to radiographic and histological examination. RESULTS: Radiologic evaluation showed faster bone remodeling in the experimental group than in the control group. Histologic evaluation (H&E, Masson's trichrome stain) showed rapid bone formation, remodeling and calcification in the 1st and 2nd week in the experimental group. Immunohistochemical evaluation showed higher expression rate of osteoprotegerin, receptor activator of nuclear factor kappaB ligand, and receptor activator of nuclear factor kappaB in the experimental group at the 1st and 2nd week than in the control group. CONCLUSION: rhBMP-2 coated TCP resulted in rapid bone formation, remodeling, and calcification due to rhBMP-2's osteogenic effect. TCP performed properly as a carrier for rhBMP-2. Thus, the use of an rhBMP-2 coating on TCP had a synergic effect on bone healing and, especially, bone remodeling and maturation. PMID- 27489810 TI - Bone Induction by Demineralized Dentin Matrix in Nude Mouse Muscles. AB - PURPOSE: This study examined the osteoinductive activity of demineralized human dentin matrix for nude mice. METHODS: Twenty healthy nude mice weighing about 15 to 20 g were used for study. Demineralized human dentin matrix was prepared and implanted into the dorsal portion of nude mice (subcutaneous), which were sacrificed at two, four, and eight weeks after demineralized dentin matrix grafting and evaluated histologically by H&E and Masson trichrome staining. The specimens were also evaluated histomorphometrically. RESULTS: The demineralized dentin matrix induced bone and cartilage formation independently in soft tissues. Histological examination showed bone-forming cells such as osteoblasts and fibroblasts at two, four, and eight weeks. CONCLUSION: These results suggest that demineralized human dentin matrix has osteoinductive ability, and is a good alternative to autogenous bone graft materials. PMID- 27489811 TI - Reconstruction of Defect after Treatment of Bisphosphonate-related Osteonecrois of the Jaw with Staged Iliac Bone Graft. AB - Bisphosphonate is used widely for osteoporosis treatment, but a rising concern is the risk of osteonecrosis after long-term bisphosphonate use. Such cases are increasing, suggesting a need for research to prevent and treat bisphosphonate related osteonecrosis of jaws. A 63-year-old female took bisphosphonate (Fosamax((r))) for four years for treatment of osteoporosis and stopped medication two months ago because of unhealed wound. She was treated with marginal mandibulectomy maintaining the inferior border, and a metal plate was placed to prevent mandible fracture. Four months after the mandibulectomy, mandible reconstruction surgery using iliac bone and allograft was done. Six months after reconstruction, implant placement and treatment with an overdenture was done without complications. This study presents a case with a successful result. PMID- 27489812 TI - Osteoradionecrosis of Jaw in Head and Neck Cancer Patient Treated with Free Iliac Bone and Umbilical Fat Pad Graft. AB - Osteoradionecrosis is one of the most serious complications of patients receiving radiation therapy. It is characterized by hypovascularity, hypocellularity, and hypoxia-inducing necrosis of bone and soft tissue following delayed healing. In this case, a 72-year-old man was referred to the Department of Oral and Maxillofacial Surgery complaining of trismus following extraction three months before first visit. He had a history of right tonsillectomy, radical neck dissection and radiotherapy performed due to right tonsillar cancer seven years prior. After the diagnosis of osteoradionecrosis on right mandibular body and angle, conservative antibiotic therapy was used first, but an orocutaneous fistula gradually formed, and extensive bony destruction and sequestrum were observed. Sequestrectomy, free particulated iliac bone and umbilical fat pad graft were performed via a submandibular approach under general anesthesia. Preoperative regular exams and delicate wound care led to secondary healing of the wound without vascularized free flap reconstruction. PMID- 27489813 TI - Cervical Necrotizing Fasciitis Caused by Dental Infection. AB - Necrotizing fasciitis (NF) is defined as rapidly progressive necrosis of subcutaneous fat and fascia. Although NF of the face is rare, its mortality rate is nearly 30%. It usually originates from dental infection and can lead to involvement of the neck, mediastinum, and chest wall. Complications resulting from pre-existing systemic diseases can increase the mortality rate. Known complication factors for NF include diabetes, malnutrition, advanced age, peripheral vascular disease, renal failure, and obesity. Here, we report a case of NF originating from dental infection in an 88-year-old woman already diagnosed with hypertension, thoracic aortic aneurysm, and renal diseases. Such conditions limited adequate surgical and antibiotic treatment. However, interdisciplinary treatment involving multiple departments was implemented with good results. PMID- 27489814 TI - Deep Neck Space Infection Caused by Keratocystic Odontogenic Tumor. AB - Keratocystic odontogenic tumor (KCOT) is a benign cystic intraosseous tumor of odontogenic origin. An infection of a KCOT is not common because KCOT is a benign developmental neoplasm. Moreover, a severe deep neck space infection with compromised airway caused by infected KCOT is rare. This report presents a 60 year-old male patient with a severe deep neck space infection related to an infected KCOT due to cortical bone perforation and rupture of the exudate. Treatment of the deep neck space infection and KCOT are reported. PMID- 27489815 TI - Treatment of Temporomandibular Joint Reankylosis by Submandibular Anchorage Technique with Temporalis Myofascial Flap. AB - Management of temporomandibular joint (TMJ) ankylosis is challenging for the oral and maxillofacial surgeon because it involves the mouth opening, dentofacial deformity, diet problem, and quality of life. Although surgical techniques to treat TMJ ankylosis have improved, reankylosis is a persistent problem. The temporalis myofascial flap provides good material for interpositional arthroplasty, because of its good vascular supply, anatomic proximity, and adequate thickness. This case report examines the efficacy of submandibular anchorage to prevent reankylosis by inhibiting flap dislocation. PMID- 27489816 TI - Corrigendum: Osteomyelitis Treated with Antibiotic Impregnated Polymethyl Methacrylate. AB - [This corrects the article on p. 396 in vol. 35.]. PMID- 27489817 TI - Metastasis via Peritumoral Lymphatic Dilation in Oral Squamous Cell Carcinoma. AB - PURPOSE: Nodal metastasis is the main prognostic factor in the patients with oral squamous cell carcinoma (OSCC). We investigated the association between tumor associated lymphatics and OSCC characteristics. METHODS: Thirty-four specimens were used for the immunohistochemical staining with the antibody for vascular endothelial growth factor (VEGF)-C, VEGF-D, VEGF receptor (VEGFR)-3, phosphorylated VEGFR-3, D2-40, and matrix metallproteinases (MMPs). We observed the distribution of the lymphangiogenic factors and quantified the degree of expression. We determined lymphatic vessel density (LVD) and lymphatic vessel dilatation with D2-40 immunostaining. We assessed the association of LVD or lymphatic vessel dilatation with tumor progression or tumor differentiation. RESULTS: OSCC cells expressed lymphangiogenic ligands. Lymphangiogenic receptor, VEGFR-3, was expressed and activated in some tumor cells as well as in tumor associated endothelial cells. LVD was not associated with tumor size or nodal status, but lymphatic vessel dilatation was higher in tumors with nodal metastasis, and also higher in poorly differentiated tumors. In stromal area of OSCC, MMP-1 and MMP-10 were up-regulated and the basement membrane of tumor associated endothelial cells was destroyed by these collagenases. CONCLUSION: In the primary tumors with nodal metastasis, especially in poorly differentiated OSCC, tumor cells invaded the dilated lymphatic vessels via ruptured sites. MMP-1 and MMP-10 are important in the lysis of the glycocalyx inside the tumor associated lymphatic endothelial cells. PMID- 27489818 TI - Bone Healing Properties of Autoclaved Autogenous Bone Grafts Incorporating Recombinant Human Bone Morphogenetic Protein-2 and Comparison of Two Delivery Systems in a Segmental Rabbit Radius Defect. AB - PURPOSE: This study aims to validate the effect of autoclaved autogenous bone (AAB), incorporating Escherichia coli-derived recombinant human bone morphogenetic protein-2 (ErhBMP-2), on critical-sized, segmental radius defects in rabbits. Delivery systems using absorbable collagen sponge (ACS) and fibrin glue (FG) were also evaluated. METHODS: Radius defects were made in 12 New Zealand white rabbits. After autoclaving, the resected bone was reinserted and fixed. The animals were classified into three groups: only AAB reinserted (group 1, control), and AAB and ErhBMP-2 inserted using an ACS (group 2) or FG (group 3) as a carrier. Animals were sacrificed six or 12 weeks after surgery. Specimens were evaluated using radiology and histology. RESULTS: Micro-computed tomography images showed the best bony union in group 2 at six and 12 weeks after operation. Quantitative analysis showed all indices except trabecular thickness were the highest in group 2 and the lowest in group 1 at twelve weeks. Histologic results showed the greatest bony union between AAB and radial bone at twelve weeks, indicating the highest degree of engraftment. CONCLUSION: ErhBMP-2 increases bony healing when applied on AAB graft sites. In addition, the ACS was reconfirmed as a useful delivery system for ErhBMP-2. PMID- 27489819 TI - Scanning Electron Microscopy and Energy Dispersive X-ray Spectroscopy Studies on Processed Tooth Graft Material by Vacuum-ultrasonic Acceleration. AB - PURPOSE: The current gold standard for clinical jawbone formation involves autogenous bone as a graft material. In addition, demineralized dentin can be an effective graft material. Although demineralized dentin readily induces heterotopic bone formation, conventional decalcification takes three to five days, so, immediate bone grafting after extraction is impossible. This study evaluated the effect of vacuum ultrasonic power on the demineralization and processing of autogenous tooth material and documented the clinical results of rapidly processed autogenous demineralized dentin (ADD) in an alveolar defects patient. METHODS: The method involves the demineralization of extracted teeth with detached soft tissues and pulp in 0.6 N HCl for 90 minutes using a heat controlled vacuum-ultrasonic accelerator. The characteristics of processed teeth were evaluated by scanning electron microscopy (SEM), and energy dispersive X-ray spectroscopy (EDS). Bone grafting using ADD was performed for narrow ridges augmentation in the mandibular area. RESULTS: The new processing method was completed within two hours regardless of form (powder or block). EDS and SEM uniformly demineralized autotooth biomaterial. After six months, bone remodeling was observed in augmented sites and histological examination showed that ADD particles were well united with new bone. No unusual complications were encountered. CONCLUSION: This study demonstrates the possibility of preparing autogenous tooth graft materials within two hours, allowing immediate one-day grafting after extraction. PMID- 27489820 TI - Powdered Wound Dressing Materials Made from wild Silkworm Antheraea pernyi Silk Fibroin on Full-skin Thickness Burn Wounds on Rats. AB - PURPOSE: This study evaluated powdered burn wound dressing materials from wild silkworm fibroin in an animal model. METHODS: Fifteen rats were used in this experiment. Full-thickness 2*2 cm burn wounds were created on the back of rats under anesthesia. In the two experimental groups, the wounds were treated with two different dressing materials made from silkworm fibroin. In the Control Group, natural healing without any dressing material was set as control. The wound surface area was measured at five days, seven days and 14 days. Wound healing was evaluated by histologic analysis. RESULTS: By gross observation, there were no infections or severe inflammations through 14 days post-injury. The differences among groups were statistically significant at seven days and 14 days, postoperatively (P <0.037 and 0.001, respectively). By post hoc test, the defect size was significantly smaller in experimental Group 1 compared with the Control Group and experimental Group 2 at seven days postoperatively (P =0.022 and 0.029, respectively). The difference between Group 1 and Group 2 was statistically significant at 14 days postoperatively (P <0.001). Group 1 and control also differed significantly (P =0.002). Group 1 showed a smaller residual scar than the Control Group and Group 2 at 14 days post-injury. Histologic analysis showed more re-epithelization in Groups 1 and 2 than in the Control Groups. CONCLUSION: Burn wound healing was accelerated with silk fibroin spun by wild silkworm Antheraea pernyi. There was no atypical inflammation with silk dressing materials. In conclusion, silk dressing materials can be used for treatment of burn wound. PMID- 27489821 TI - Risk Factors for Wound Dehiscence after Guided Bone Regeneration in Dental Implant Surgery. AB - PURPOSE: The purpose of this study was to evaluate risks for wound dehiscence after guided bone regeneration (GBR) in dental implant surgery. METHODS: Patients who received dental implant therapy with GBR procedure at Seoul National University Bundang Hospital (Seongnam, Korea) from June 2004 to May 2007 were included. The clinical outcome of interest was complications related to dental implant surgery. The factors influencing wound dehiscence, classified into patient-related factors, surgery-related factors and material-related factors, were evaluated. RESULTS: One hundred and fifteen cases (202 implants) were included in this study. Wound dehiscence (19.1%) was considered a major complication. The risk of wound dehiscence was higher in males than in females (odds ratio=4.279, P =0.014). In the main graft, the allogenic group had the lowest risk of wound dehiscence (odds ratio=0.106, P =0.006). Though the external connection group had a higher risk of wound dehiscence than the internal connection group (odds ratio=2.381), the difference was not significant (P =0.100). CONCLUSION: In this study, male gender and main graft have the highest risk of wound dehiscence. To reduce wound dehiscence after GBR, instructions on postoperative care with supplementary procedure for the protection of the wound dehiscence is recommended, especially to male patients. A main graft with a gel base can reduce the risk of wound dehiscence. PMID- 27489822 TI - Horizontal Ridge Augmentation with Piezoelectric Hinge-Assisted Ridge Split Technique in the Atrophic Posterior Mandible. AB - Onlay bone grafting, guided bone regeneration, and alveolar ridge split technique are considered reliable bone augmentation methods on the horizontally atrophic alveolar ridge. Among these techniques, alveolar ridge split procedures are technique-sensitive and difficult to perform in the posterior mandible. This case report describes successful implant placement with the use of piezoelectric hinge assisted ridge split technique in an atrophic posterior mandible. PMID- 27489823 TI - Partial Necrosis of the Mandibular Proximal Segment Following Transoral Vertical Ramus Osteotomy. AB - Transoral vertical ramus osteotomy (TOVRO) procedure can result in a variety of complications. Complications commonly reported include extensive bleeding due to major blood vessel injury, unpredictable fracture, postoperative infection, neurosensory deficit related Inferior alveolar nerve, insufficient osteosynthesis, and temporomandibular joint problem. The authors describe a case of partial necrosis of the mandibular proximal segment following TOVRO, a rarely reported complication. A 37-year-old otherwise healthy woman underwent Lefort l osteotomy and TOVRO to correct mandibular prognathism. Postoperatively, she developed pain and swelling in the right submandibular region and was found to have a partial necrosis of proximal segment. PMID- 27489824 TI - Comparison of Costochondral Graft and Customized Total Joint Reconstruction for Treatments of Temporomandibular Joint Replacement. AB - PURPOSE: We review published research on temporomandibular joint (TMJ) total replacement that compares costochondral graft and customized total joint reconstruction (especially TMJ concepts), focusing on effectiveness. METHODS: We searched PubMed databases, including prospective, retrospective, case-control or longitudinal studies and significant statistical analysis. In data analysis, we divided outcomes into 'Acceptable' or 'Non-acceptable'. RESULTS: There were seven articles found dealing with costochondral graft and 180 patients. The majority of patients had satisfactory treatment outcomes (n=109, 61%). There were six articles including 275 patients using the alloplastic material TMJ concepts. Almost all patients had satisfactory treatment outcomes (n=261, 95%). CONCLUSION: Comparing customized total joint reconstruction with costochondral graft, use of TMJ concepts resulted in increased quality of life and fewer complications. In conclusion, we judged that alloplastic material such as TMJ concepts is more effective device in total joint replacement than costochondral graft. PMID- 27489825 TI - Facial Bone Fracture Patients Visiting Pusan National University Hospital in Busan and Yangsan: Trends and Risks. AB - PURPOSE: This study examined patients with facial bone fracture visiting Pusan National University Dental Hospital to understand the trends, and to enhance appropriate care and treatment for patients with facial bone fracture. METHODS: We investigated 531 patients presenting with facial bone fracture in Yangsan and 802 patients in Busan from January 2010 to December 2013. We divided the patients by year, month, gender, age, site, and cause to compare with historic data and other studies. RESULTS: The gender ratio was 3.58:1 in Yangsan and 4.31:1 in Busan. Patients aged in their 20s had the highest number of facial bone fractures in both Yangsan and Busan. The most frequent fracture site was the mandible, and the most frequent cause was slip down in both Yangsan and Busan. CONCLUSION: The investigation and comparison of patients with facial bone fracture who visited Pusan National University Hospital located at Yangsan and Busan from 2010 to 2013 found a difference in the total number of patients at each hospital, but the trends were not significantly different. PMID- 27489826 TI - The Efficacy of the Graft Materials after Sinus Elevation: Retrospective Comparative Study Using Panoramic Radiography. AB - PURPOSE: This study compares and evaluates the efficacy of graft materials after maxillary sinus bone grafts with autogenous tooth bone graft material (AutoBT), demineralized freeze-dried bone allograft (DFDBA) and deproteinized bovine bone mineral (DBBM). METHODS: The study involved 30 sinuses in 26 patients who visited the Division of Oral and Maxillofacial Surgery, Department of Dentistry in Ajou University Hospital and received either AutoBT, DFDBA or DBBM with sinus elevation using the lateral window technique. Sinus graft height was measured before, immediately after, and six months after bone graft with panoramic radiography and the height changes of the sinus floor was compared according to the graft materials. RESULTS: After six months, the decrease ratio of graft heights were 13.57% for AutoBT group, 14.30% for DFDBA group, and 11.92% for DBBM group. There was no statistically significant difference. CONCLUSION: The new maxillary sinus floor formed by the upper border of bone graft material, can repneumatize after the maxillary sinus elevation. Thus, long-term stability of sinus graft height represents an important factor for implant success. We found that the three graft materials for sinus elevation do not differ significantly and all three graft materials showed excellent resistance to maxillary sinus repneumatization. However, due to the special circumstances of the maxillary sinus and small sample, the actual difference between the three graft materials may not have been detectable. Therefore further study needs to be conducted for more reliable study results. PMID- 27489827 TI - Anchor Plate Efficiency in Postoperative Orthodontic Treatment Following Orthognathic Surgery via Minimal Presurgical Orthodontic Treatment. AB - PURPOSE: The efficiency of an anchor plate placed during orthognathic surgery via minimal presurgical orthodontic treatment was evaluated by analyzing the mandibular relapse rate and dental changes. METHODS: The subjects included nine patients with Class III malocclusion who had bilateral sagittal split osteotomy at the Division of Oral and Maxillofacial Surgery, Department of Dentistry in Ajou University Hospital, after minimal presurgical orthodontic treatment. During orthognathic surgery, anchor plates were placed at both maxillary buttresses. The anchor plates were used to move maxillary teeth backward and for maximum anchorage of Class III elastics to minimize mandibular relapse during the postoperative orthodontic treatment. The lateral cephalometric X-ray was taken preoperatively (T0), postoperatively (T1), and one year after the surgery (T2). Seven measurements (distance from Pogonion to line Nasion-Nasion perpendicular [Pog-N Per.], angle of line B point-Nasion and Nasion-Sella [SNB], angle of line maxilla 1 root-maxilla 1 crown and Nasion-Sella [U1 to SN], distance from maxilla 1 crown to line A point-Nasion [U1 to NA], overbite, overjet, and interincisal angle) were taken. Measurements at T0 to T1 and T1 to T2 were compared and differences tested by standard statistical methods. RESULTS: The mean skeletal change was posterior movement by 13.87+/-4.95 mm based on pogonion from T0 to T1, and anterior movement by 1.54+/-2.18 mm from T1 to T2, showing relapse of about 10.2%. There were significant changes from T0 to T1 for both Pog-N Per. and SNB (P <0.05). However, there were no statistically significant changes from T1 to T2 for both Pog-N Per. and SNB. U1 to NA that represents the anterior-posterior changes of maxillary incisor did not differ from T0 to T1, yet there was a significant change from T1 to T2 (P <0.05). CONCLUSION: This study found that the anchor plate minimizes mandibular relapse and moves the maxillary teeth backward during the postoperative orthodontic treatment. Thus, we conclude that the anchor plate is clinically very useful. PMID- 27489828 TI - Considerations and Protocols in Virtual Surgical Planning of Reconstructive Surgery for More Accurate and Esthetic Neomandible with Deep Circumflex Iliac Artery Free Flap. AB - PURPOSE: The reconstruction of mandibular defects poses many difficulties due to the unique, complex shape of the mandible and the temporomandibular joints. With development of microvascular anastomosis, free tissue transplantation techniques, such as deep circumflex iliac artery (DCIA) flap and fibular free flap (FFF), were developed. The DCIA offers good quality and quantity of bone tissue for mandibular segmental defect and implant for dental rehabilitation. Virtual surgical planning (VSP) and stereolithography-guided osteotomy are currently successfully applied in three-dimensional mandibular reconstruction, but most use FFF. There are only a few articles on reconstruction with the DCIA that assess the postoperative results. METHODS: Three patients admitted during a five month period (April of 2013 to August of 2013) underwent resection of mandible and DCIA musculo-osseous reconstruction using a VSP and stereolithographic modeling and assessment of outcomes included technical accuracy, esthetic contour, and functional outcomes. RESULTS: This technique yielded iliac bone segment with excellent apposition and duplication of the preoperative plan. Flap survival was 100 percent and all patients maintained preoperative occlusion and contour. CONCLUSION: Based on our experience, we offer considerations and logically consistent protocols by classification of mandibular defects, and demonstrate the benefits in VSP and stereolithographic modeling of mandibular reconstructive surgery with DCIA flap. PMID- 27489829 TI - Trismus Due to Bilateral Coronoid Hyperplasia. AB - Bilateral coronoid hyperplasia causes painless progressive trismus, resulting from coronoid process impingement on the posterior aspect of the zygomatic bone. The etiology of coronoid hyperplasia is unclear, with various theories proposed. An endocrine stimulus, increased temporalis activity, trauma, genetic inheritance and familial occurrence have all been proposed, but no substantive evidence exists to support any of these hypotheses. Multiplanar reformatting of axial scans and 3-dimensional reconstruction permit precise reproduction of the shape and size of the coronoid and malar structures, and relationships of all structures of the temporal and infratemporal fossae. This case shows remarkably increased mouth opening by coronoidectomy in a patient who complained of trismus due to hyperplasia of coronoid process. PMID- 27489830 TI - Extensive Adenomatoid Odontogenic Tumor of the Maxilla: A Case Report of Conservative Surgical Excision and Orthodontic Alignment of Impacted Canine. AB - The present report describe the surgical therapy, clinical course, orthodontic treatment and morphological characteristics of an adenomatoid odontogenic tumor in the maxilla of an 11-year-old patient. The cystic tumor filled the maxillary sinus and involved a tooth. Marsupialization was accompanied by partial enucleation and applied traction to the affected tooth by a fixed orthodontic appliance. Healing was uneventful and no local recurrence was observed during a 1 year period of follow-up control. PMID- 27489831 TI - Correction of Lip Canting Using Bioabsorbables during Orthognathic Surgery. AB - Lip canting is associated with facial asymmetry, and is one of the most challenging problems in surgical correction of facial deformities. The author corrected lip canting using bioabsorbable devices during orthognathic surgery. Soft tissue suspension procedures were performed on four patients with facial asymmetry. Lip lines improved for all patients. Over an observation period of five years, no complications were noted, nor did any late relapse develop. Furthermore, as time past, the effect of the Endotine suspension procedure increased probably due to induction of fibrosis on surrounding soft tissues. PMID- 27489832 TI - Changes of the Airway Space and the Position of Hyoid Bone after Mandibular Set Back Surgery Using Bilateral Sagittal Split Ramus Osteotomy Technique. AB - PURPOSE: Although there have been several studies of reduced airway space after mandibular setback surgery using the sagittal split ramus osteotomy technique, research on the risk factors for changes of the airway space is lacking. Therefore, this study was performed to examine airway changes and the position of the hyoid bone after orthognathic surgery, and to assess possible risk factors. METHODS: In this retrospective study, 50 patients who underwent posterior displacement of the mandible by the bilateral sagittal split ramus osteotomy technique were included. Changes of the position of the hyoid bone and the airway space were analyzed over various follow-up periods, using cephalometric radiography taken preoperatively, immediately after surgery, eight weeks after surgery, six months after surgery, and one year after surgery. To identify risk factors, multiple regression analysis of age, gender, body mass index (BMI), posterior mandibular movement, and the presence of genioplasty was performed. RESULTS: Inferor and posterior movement of the hyoid bone was observed postoperatively, but subsequent observations showed regression towards the anterosuperior aspect. The airway space also significantly decreased after surgery (P <0.05), and increased slightly up until six months after surgery. The airway space significantly decreased (beta=0.47, P <0.01) as the amount of mandibular setback increased. However, age, sex, BMI, and presence of genioplasty were not associated with airway reduction. CONCLUSION: The amount of mandibular set back was significantly associated with postoperative reduction of airway space. It is necessary to establish a treatment plan considering this factor. PMID- 27489834 TI - A Clinical Study of Mandibular Angle Fracture. AB - PURPOSE: To establish management protocol for mandibular angle fracture, we describe pertinent factors including cause, impacted third molar and recent treatment tendency. METHODS: We examined the records of 62 patients who had unilateral mandibular angle fracture. Sixty patients who had open reduction surgery were examined at postoperative weeks 1, 4, 8, 12, and 28. RESULTS: Left mandibular angle fracture is frequent in younger males. Presence of the mandibular third molar can increase fracture risk. Because of attached muscle, favorable fractures occurred primarily in the mandibular angle area. CONCLUSION: Extracting the mandibular third molar can prevent angle fractures, and open reduction with only one plate adaptation is generally the proper treatment method for mandibular angle fracture. PMID- 27489833 TI - Soft Tissue Augmentation with Silk Composite Graft. AB - PURPOSE: The objective of this study was to evaluate the interaction between 4 hexylresorcinol (4HR) and antibody as that affects the performance of a silk-4HR combination graft for soft tissue augmentation in an animal model. METHODS: The silk graft materials consisted of four types: silk+10% tricalcium phosphate (TCP) (ST0), silk+10% TCP+1% 4HR (ST1), silk+10% TCP+3% 4HR (ST3), and silk+10% TCP+6% 4-HR (ST6). The antibody binding assay tested the 4HR effect and scanning electron microscopic (SEM) exam was done for silk grafts. The animal experiment used a subcutaneous pocket mouse model. The graft - SH0 or SH1 or SH3 or SH6 - was placed in a subcutaneous pocket. The animals were killed at one, two, and four weeks, postoperatively. The specimens were subjected to histological analysis and lysozyme assay. RESULTS: Groups with 4HR applied showed lower antibody binding affinity to antigen compared to groups without 4HR. In the SEM examination, there was no significant difference among groups. Histological examinations revealed many foreign body giant cells in ST0 and ST1 group at four weeks postoperatively. Both ST3 and ST6 groups developed significantly lower levels of giant cell values compared to ST0 and ST1 groups (P <0.001) at four weeks postoperatively. In the lysozyme assay, the ST1 and ST3 groups showed denser signals than the other groups. CONCLUSION: 4HR combined silk implants resulted in high levels of vascular and connective tissue regeneration. PMID- 27489835 TI - Surgical Management of Edentulous Atrophic Mandible Fractures in the Elderly. AB - Fractures of the mandible occur with a greater frequency in the elderly. This study reports three cases of edentulous atrophic mandible fracture in elderly patients treated with open reduction technique. Three patients who presented with edentulous atrophic mandible fractures underwent surgical management using open reduction and internal fixation. After treatment, clinical evaluations and postoperative complications were examined with postoperative x-ray. Patients were followed with clinical and radiographic examinations. In the postoperative clinical evaluation, two male patients healed well, but one female patient complained of pain and swelling. In radiographic examinations, no union delay or lack of fusion was observed in the edentulous area. Open reduction technique is a viable treatment option for the edentulous atrophic mandible fractures in geriatric patients. PMID- 27489836 TI - Simultaneous Glossectomy with Orthognathic Surgery for Mandibular Prognathism. AB - Macroglossia can create dental and skeletal instability after orthodontic treatment or orthognathic surgery for mandibular prognathism. In relevant literature, partial glossectomy is suggested for a good post-treatment prognosis. Most of the published partial glossectomy cases are two-staged surgery, because of concern about postoperative airway obstruction. As orthognathic surgical techniques and fixation method develop, however, concerns about postoperative airway obstruction have lessened. In this case, mandibular setback surgery and partial glossectomy were performed simultaneously, leading to stable recovery without any postoperative respiratory problems. After surgical technique to preserve the tongue tip, we achieved good outcomes without postoperative side effects of lingual hypoesthesia, pronunciation disorder and dyskinesia. We report this case with a literature review. PMID- 27489837 TI - Successful Localization of Intraoral Foreign Body with C-arm Fluoroscopy. AB - During surgical procedures, unexpected material, including surgical instruments and tissue segments, may get lost in the surgical field. Most of these should be immediately removed to prevent further complications, such as vital organ irritation, infection, and inflammatory pseudo-tumor formation. However, it is not always easy to define the exact location of the foreign body, especially if the item is very small and/or it is embedded in the soft tissue of the head and neck region. Intraoperative real-time radiological imaging with C-arm fluoroscopy can be useful to trace the three-dimensional location of small and embedded foreign bodies in the oral and maxillofacial area. We describe an unusual case of an embedded micro-screw in the intrinsic tongue muscle that had been dropped into the sublingual space during a lower alveolar bone graft procedure. The lost foreign body was accurately identified with C-arm fluoroscopy and safely removed without any further complications. PMID- 27489838 TI - Vertical Augmentation of Maxillary Posterior Alveolar Ridge Using Allogenic Block Bone Graft and Simultaneous Maxillary Sinus Graft. AB - The maxillary posterior area is the most challenging site for the dental implant. Although the sinus graft is a predictable and successful technique for rehabilitation of atrophic and pneumatized posterior maxilla, when there is severe destruction of alveolar bone, a very long crown length remains challenging after successful dental implants installation with sinus graft. We performed vertical augmentation of the maxillary posterior alveolar ridge using the allogenic block bone graft with a simultaneous sinus graft using allogenic and heterogenic bone chips. After about six months, we installed the dental implant. After this procedure, we achieved a more favorable crown-implant fixture ratio and better results clinically and biomechanically. This is a preliminary report of vertical augmentation of maxillary posterior alveolar ridge using allogenic block bone graft and simultaneous maxillary sinus graft. Further research requires longer observation and more patients. PMID- 27489839 TI - Corrective Rhinoplasty with Combined Use of Autogenous Auricular Cartilage and Porcine Dermal Collagen in Cleft Lip Nose Deformity. AB - Esthetic reconstruction of cleft lip nose deformity is a challenging task in surgical management of patients with orofacial cleft. The author reconstructed cleft lip nose deformity effectively using autogenous auricular cartilage and a relatively new graft material of porcine dermal collagen, PermacolTM. After correction of the deformed lower third of the nose with patient's auricular cartilage, we applied PermacolTM to augment the entire nasal dorsum. Three patients were treated and followed for up to five years. All patients improved in nose aesthetics without any inflammatory or immunogenic reaction. The author suggests that the use of PermacolTM for nasal profile augmentation in the treatment of cleft lip nose deformity is an alternative surgical strategy with minimal surgical invasiveness. The author report long-term experience with combined use of auricular cartilage and PermacolTM in nasal reconstruction for cleft lip nose deformity. PMID- 27489840 TI - Correction: Trismus Due to Bilateral Coronoid Hyperplasia. AB - [This corrects the article on p. 168 in vol. 36.]. PMID- 27489841 TI - Membranes for the Guided Bone Regeneration. AB - Many kinds of membrane have been used for the guided bone regeneration (GBR) technique. However, most membranes do not fulfill all requirements for the ideal membrane for the GBR technique. Among them, collagen membrane has been most widely used. However, its high price and weak tensile strength in wet condition are limitations for wide clinical application. Synthetic polymers have also been used for the GBR technique. Recently, silk based membrane has been considered as a membrane for the GBR technique. Despite many promising preclinical data for use of a silk membrane, clinical data regarding the silk membrane has been limited. However, silk based material has been used clinically as vessel-tie material and an electrospun silk membrane was applied successfully to patients. No adverse effect related to the silk suture has been reported. Considering that silk membrane can be provided to patients at a cheap price, its clinical application should be encouraged. PMID- 27489842 TI - Comparative Study of the Early Loading of Resorbable Blasting Media and Sandblasting with Large-grit and Acid-etching Surface Implants: A Retrospective Cohort Study. AB - PURPOSE: This study compares the prognosis (the survival rate and marginal bone loss) of resorbable blasting media (RBM) surface implants and sandblasting with large-grit and acid-etching (SLA) surface implants in the early loading. METHODS: This study targeted 123 patients treated by implants installation from January 2008 to March 2010. The loading was initiated in the maxilla within three to four months and in the mandible within one to two months. The types of restoration were single crown and fixed partial prosthesis. Those functioned over one year. The implants were classified by the surface of implants as Group 1: RBM surface (GS III; OSSTEM, Busan, Korea) and, Group 2: SLA surface (Superline; Dentium, Seoul, Korea). The groups were categorized by maxilla and mandible and compared by survival rate, marginal bone loss through clinical records evaluation, and radiographic measurements. RESULTS: The marginal bone loss in the maxilla was 0.14+/-0.34 mm (Group 1) and 0.30+/-0.37 mm (Group 2), a statistically significant difference (P <0.05). In the mandible those were 0.28+/-0.54 mm (Group 1) and 0.20+/-0.33 mm (Group 2), not significant (P >0.05). There was no significant difference of marginal bone loss between maxilla and mandible by groups. During observation there was no implant failure, a survival rate of 100%. CONCLUSION: Both surfaces showed an excellent survival rate, and the marginal bone loss was not substantial. PMID- 27489843 TI - Maxillofacial Trauma Trends at a Tertiary Care Hospital: A Retrospective Study. AB - PURPOSE: Maxillofacial fractures are rapidly increasing from car accidents, industrial accidents, teenaged criminal activity, and sports injuries. Accurate assessment, appropriate diagnosis, and preparing individual treatment plans are necessary to reduce surgical complications. We investigated recent trends of facial bone fracture by period, cause, and type, with the objective of reducing surgical complications. METHODS: To investigate time trends of maxillofacial fractures, we reviewed medical records from 2,196 patients with maxillofacial fractures in 1981~1987 (Group A), 1995~1999 (Group B), and 2008~2012 (Group C). We analyzed each group, comparing the number of patients, sex ratio, age, fracture site, and etiology. RESULTS: The number of patients in each period was 418, 516, and 1,262 in Groups A to C. Of note is the increase in the number of patients from Group A to C. The sex ratios were 5.6:1, 3.5:1, and 3.8:1 in Groups A, B, and C. The most affected age group for fracture is 20~29 in all three groups. Traffic accidents are the most common cause in Groups A and B, while there were somewhat different causes of fracture in Group C. Sports-induced facial trauma was twice as high in Group C compared with Group A and B. Mandible fracture accounts for a large portion of facial bone fractures overall. CONCLUSION: We observed an increase in facial bone fracture patients at Kyungpook National University Dental Hospital over the years. Although facial injury caused by traffic accidents was still a major cause of facial bone fracture in all periods, the percentage decreased. In recent years, isolated mandible fracture increased but mandible and mid-facial complex fracture decreased, possibly because of a reduction in traffic accidents. PMID- 27489844 TI - Anatomical and Functional Recovery of Intracapsular Fractures of the Mandibular Condyle: Analysis of 124 Cases after Closed Treatment. AB - PURPOSE: The purpose of this study is to evaluate the influence of intracapsular fracture lines of the mandibular condyle on the anatomical and functional recovery after non-surgical closed treatment. METHODS: Clinical and radiological follow-up of 124 patients with intracapsular fractures of the mandibular condyle was performed after closed treatment between 2005 and 2012. The intracapsular fractures were classified into three categories: type A (medial condylar pole fracture), type B (lateral condylar pole fracture with loss of vertical height) and type M (multiple fragments or comminuted fracture). RESULTS: By radiological finding, fracture types B and M lost up to 24% vertical height of the mandibular condyle compared to the height on the opposite side. In Type M, moderate to severe dysfunction was observed in 33% of the cases. Bilateral fractures were significantly associated with the risk of temporomandibular joint (TMJ) dysfunction in fracture types A and B. Bilateral fracture and TMJ dysfunction were not statistically significantly associated in type M fractures. CONCLUSION: Most of the mandibular intracapsular condylar fractures recovered acceptably after conservative non-surgical treatment with functional rehabilitation, even with some anatomical shortening of the condylar height. The poor functional recovery encountered in type M fractures, especially in cases with additional fracture sites and bilateral fractures, points up the limitation of closed treatment in such cases. PMID- 27489845 TI - The Retrospective Study of Closed Reduction of Nasal Bone Fracture. AB - PURPOSE: This study was conducted in order to investigate the therapeutic effect of closed reduction according to a classification in patients with nasal bone fracture. METHODS: The study was conducted retrospectively on 186 patients with a mean age of 38 years (range: 7 to 80 years). All patients were diagnosed by clinical and radiologic examination, and then classified according to Hwang's classification by computed tomography. The patients were further classified by their age, gender, causes of fracture, operation timing after fracture, concurrent facial bone fracture, and complications. All patients underwent the same reduction and treatment protocol and were then followed up regularly for at least three months. RESULTS: The cause of the fracture was slip down, and the highest prevalence was shown in the 20s. The mean operation timing after fracture was 4.1 days (range: 1 to 14 days), and it tended to be longer in the case of defected septal bone or more severe fracture. The most common concurrent facial bone fracture was orbital blow-out fracture, and zygomaticomaxillary complex and maxillary fracture occured frequently. The largest number of complications occurred in class III and IIBs patients, and the main complication was postoperative pain. CONCLUSION: Results of nasal bone closed reduction on the 186 patients showed that serious complications rarely occurred. Closed reduction is generally an effective treatment for nasal bone fracture. However, in the case of severe concurrent septal bone fracture or comminuted fracture with depression, open reduction should be considered. Further study with a larger number of patients and further classification is required. PMID- 27489846 TI - Effectiveness of Computed Tomography for Blow-out Fracture. AB - PURPOSE: This study assessed the association between eye symptoms (enophthalmos or diplopia) and site of damage, volume, deviated inferior rectus muscle (IRM) and type of fracture with computed tomography (CT). The intent is to anticipate the prognosis of orbital trauma at initial diagnosis. METHODS: Forty-five patients were diagnosed with fractures of the inferior wall of one orbit. Fracture area, volume of displaced tissue, deviated IRM, and type of fracture were evaluated from coronal CT by one investigator. The association of those variables with the occurrence of eye symptoms (diplopia and enophthalmos) was assessed. RESULTS: Of 45 patients, 27 were symptom-free (Group A) and 18 had symptoms (Group B) of enophthalmos and/or diplopia. In Group B, 12 had diplopia, one was enophthalmos, and five had both. By CT measurement, group A mean area was 192.6 mm(2) and the mean volume was 673.2 mm(3). Group B area was 316.2 mm(2) and volume was 1,710.6 mm(3). The volume was more influential on symptom occurrence. Each patient was categorized into four grades depending on the location of IRM. Symptom occurrence and higher grade were associated. Twenty-six patients had trap door fracture (one side, attached to the fracture), and 19 had punched-out fracture (both sides detached). The punched-out fracture was more strongly associated with symptoms and had statistically significantly higher area and volume. CONCLUSION: In orbital trauma, measurement of fracture area and volume, evaluation of the deviated IRM and classification of the fracture type by coronal CT can effectively predict prognosis and surgical indication. PMID- 27489847 TI - Effectiveness of Woven Silk Dressing Materials on Full-skin Thickness Burn Wounds in Rat Model. AB - PURPOSE: This study evaluated woven silk textile for burn wound dressing materials in an animal model. METHODS: Ten rats were used in this experiment. Full-thickness 2*2 cm burn wounds were created on the back of the rats under anesthesia. In the experimental group, the wounds were treated with three different dressing materials from woven silk textile. In the control group, natural healing without any dressing material was set as control. The wound surface area was measured at five days, seven days, and 14 days. Wound healing was evaluated by histologic analysis. RESULTS: There were no statistically significant differences among groups at five days post injury. The mean defect size at seven days was largest in Group 3 (462.87 mm(2)), and smallest in Group 1 (410.89 mm(2)), not a significant difference (P =0.341). The mean defect size at 14 days was smallest at the Group 3 (308.28 mm(2)) and largest in the control group (388.18 mm(2)), not a significant difference (P =0.190). The denuded area was smaller in Group 1 (84.57 mm(2)) and Group 2 (82.50 mm(2)) compared with the control group (195.93 mm(2)), not statistically significant differences (P =0.066, 0.062). The difference between Group 3 and control was also not statistically significant (P =0.136). In histologic analysis, the experimental groups re-epithelialized more than control groups. No evidence was found of severe inflammation. CONCLUSION: The healing of burn wounds was faster with silk weave textile more than the control group. There was no atypical inflammation with silk dressing materials. In conclusion, silk dressing materials could be used to treat burn wounds. PMID- 27489848 TI - Osteomyelitis in an Osteopathia Striata with Cranial Sclerosis Patient. AB - Osteopathia striata with cranial sclerosis (OS-CS) is characterized by linear bone dysplasia at the long bone radiographically and sclerotic change at the cranium. The purpose of this case report is to study the symptoms and treatments of osteomyelitis in a patient with OS-CS. A 41-year-old patient had pus discharge from a fistula at the mental region and increase in radiolucencies with sequestra in panoramic radiograph images. Computed tomography (CT) as well as radiograph images for the whole skeleton were taken. The patient was diagnosed with OS-CS. Sequestrectomy and fistulectomy were performed. The patient recovered and no relapse occurred within six months after surgery. For diagnosis of OS-CS, CT and additional radiograph images for the whole skeleton are required. Because of the increased bone density, this patient is prone to relapse after sequestrectomy. Therefore, the surgeon must minimize trauma with the least incision and exfoliation, and preoperative antibiotics. PMID- 27489849 TI - Nevoid Basal Cell Carcinoma Syndrome: A Case Report and Review of Korean Cases. AB - Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal genetic disease caused by a PTCH mutation. The disease is characterized by multiple basal cell carcinomas of the skin, multiple keratocystic odontogenic tumors (KCOTs) in the jaw, palmar and/or plantar pits, bifid ribs, ectopic calcification of the falx cerebri, and skeletal abnormalities. Early diagnosis is difficult in many cases because there may be a number of systemic symptoms. The purpose of this study is to report the case of a 12-year-old girl who was hospitalized with multiple KCOTs that occurred in the upper and lower jaws. Through characteristic clinical symptoms and radiologic findings, she was finally diagnosed as having NBCCS. This study also aims to organize the symptoms often observed in Korea using previously published case reports to provide useful information for the early diagnosis of NBCCS. PMID- 27489850 TI - Defatting Vestibuloplasty for Functional and Esthetic Reconstruction of Tongue. AB - The radial forearm free flap (RFFF) is a thin and pliable tissue with many advantages for tongue reconstruction. However, tongues reconstructed with RFFF occasionally need revision surgery because inadequate defect measurement at primary surgery can lead to bulkiness and limited movement of reconstructed tongue. In this case, the patient underwent partial glossectomy and RFFF reconstruction for treatment of tongue cancer five years prior. We could not make a lower denture for the patient, because the alveolo-lingual sulcus of tongue was almost lost. So we performed vestibuloplasty with a modified Kazanjian method on the lingual vestibule of the mandibular right posterior area, and defatting surgery to debulk the flap. After surgery, we observed that the color and texture of the revised tongue changed to become similar with adjacent tissue. The patient obtained a more functional and esthetic outcome. Accordingly, we present a case report with a review of relevant literature. PMID- 27489851 TI - Undifferentiated Pleomorphic Sarcoma in Mandible. AB - Undifferentiated pleomorphic sarcoma (UPS), previously known as malignant fibrous histiocytoma, occurs commonly in the soft tissues in adult, but is rare in the maxillofacial region. It consists of undifferentiated mesenchymal tumor cells resembling histiocytes and fibroblasts. The purpose of this article is to report a case of UPS in the mandible. A 44-year-old patient presented with a painful growing mass in the mandible of two months' duration. Computed tomography and positron emission tomography-computed tomography revealed an ill-defined heterogenous, hypermetabolic mass about 4 cm in size in the left mandible invading adjacent soft tissues. A left mandiblulectomy and reconstruction with a fibular free flap were performed. Immunohistochemical study gave a diagnosis of UPS. The patient was referred for adjuvant chemotherapy after surgical removal of the tumor. PMID- 27489852 TI - Decompression Device Using a Stainless Steel Tube and Wire for Treatment of Odontogenic Cystic Lesions: A Technical Report. AB - Decompression is considered an effective treatment for odontogenic cystic lesions in the jaw. A variety of decompression devices are successfully used for the treatment of keratocystic odontogenic tumors, radicular cysts, dentigerous cysts, and ameloblastoma. The purpose of these devices is to keep an opening between the cystic lesion and the oral environment during treatment. The aim of this report is to describe an effective decompression tube using a stainless steel tube and wire for treatment of jaw cystic lesions. PMID- 27489853 TI - Psychosocial Outcomes of Sharing a Diagnosis of Cancer with a Pediatric Patient. AB - PURPOSE: This innovative pilot study was designed to provide research-based evidence on the variables to consider informing a child of his/her cancer diagnosis, so as to minimize the negative psychosocial effects of the cancer experience on survivors. The hypotheses of the study were that "good information" about cancer, will allow the child a better understanding way to cope with treatment and improve sociopsychological outcomes at adulthood. METHODS: Ninety one adult childhood cancer (CC) survivors got the questionnaires while waiting to their routine checkup at a grate CC medical center in center Israel. RESULTS: To our surprise and not according to the hypothesis, there was a difference between children diagnosed up to 12 years of age and those diagnosed during adolescence. (Participants were divided into two groups according to their age at diagnosis: from birth to 12 years old and from age 12-18). In the group diagnosed at a younger age, those who had received "good information" were found to have better quality of life, lower mental pain, and higher mental pain tolerance than did those in the same group (diagnosed at a younger age) who received "not good information." By contrast, in the group diagnosed during adolescence, those who had received "not good information" scored higher on these measures than did their counterparts who had received "good information." CONCLUSION: Given that information conveyed to children diagnosed with cancer can have a significant impact on survivors' quality of life, further research is needed to determine the precise information to be divulged to children at the time of diagnosis. In the meantime, extreme caution, sensitivity, and careful judgment are required. CLINICAL RELEVANCE: Findings of the current study and of future studies can be used to formulate clear guidelines for assessing a child's readiness and the information to be divulged, so as to improve the quality of life of CC survivors. PMID- 27489854 TI - Nanochemistry of Protein-Based Delivery Agents. AB - The past decade has seen an increased interest in the conversion of food proteins into functional biomaterials, including their use for loading and delivery of physiologically active compounds such as nutraceuticals and pharmaceuticals. Proteins possess a competitive advantage over other platforms for the development of nanodelivery systems since they are biocompatible, amphipathic, and widely available. Proteins also have unique molecular structures and diverse functional groups that can be selectively modified to alter encapsulation and release properties. A number of physical and chemical methods have been used for preparing protein nanoformulations, each based on different underlying protein chemistry. This review focuses on the chemistry of the reorganization and/or modification of proteins into functional nanostructures for delivery, from the perspective of their preparation, functionality, stability and physiological behavior. PMID- 27489855 TI - Role of Cysteine Residues in the Carboxyl-Terminus of the Follicle-Stimulating Hormone Receptor in Intracellular Traffic and Postendocytic Processing. AB - Posttranslational modifications occurring during the biosynthesis of G protein coupled receptors include glycosylation and palmitoylation at conserved cysteine residues located in the carboxyl-terminus of the receptor. In a number of these receptors, these modifications play an important role in receptor function and particularly, in intracellular trafficking. In the present study, the three cysteine residues present in the carboxyl-terminus of the human FSHR were replaced with glycine by site-directed mutagenesis. Wild-type and mutant (Cys627/629/655Gly) FSHRs were then transiently expressed in HEK-293 cells and analyzed for cell-surface plasma membrane expression, agonist-stimulated signaling and internalization, and postendocytic processing in the absence and presence of lysosome and/or proteasome inhibitors. Compared with the wild-type FSHR, the triple mutant FSHR exhibited ~70% reduction in plasma membrane expression as well as a profound attenuation in agonist-stimulated cAMP production and ERK1/2 phosphorylation. Incubation of HEK-293 cells expressing the wild-type FSHR with 2-bromopalmitate (palmitoylation inhibitor) for 6 h, decreased plasma membrane expression of the receptor by ~30%. The internalization kinetics and beta-arrestin 1 and 2 recruitment were similar between the wild-type and triple mutant FSHR as disclosed by assays performed in non-equilibrium binding conditions and by confocal microscopy. Cells expressing the mutant FSHR recycled the internalized FSHR back to the plasma membrane less efficiently than those expressing the wild-type FSHR, an effect that was counteracted by proteasome but not by lysosome inhibition. These results indicate that replacement of the cysteine residues present in the carboxyl-terminus of the FSHR, impairs receptor trafficking from the endoplasmic reticulum/Golgi apparatus to the plasma membrane and its recycling from endosomes back to the cell surface following agonist-induced internalization. Since in the FSHR these cysteine residues are S-palmitoylated, the data presented emphasize on this posttranslational modification as an important factor for both upward and downward trafficking of this receptor. PMID- 27489856 TI - The Verrucomicrobia LexA-Binding Motif: Insights into the Evolutionary Dynamics of the SOS Response. AB - The SOS response is the primary bacterial mechanism to address DNA damage, coordinating multiple cellular processes that include DNA repair, cell division, and translesion synthesis. In contrast to other regulatory systems, the composition of the SOS genetic network and the binding motif of its transcriptional repressor, LexA, have been shown to vary greatly across bacterial clades, making it an ideal system to study the co-evolution of transcription factors and their regulons. Leveraging comparative genomics approaches and prior knowledge on the core SOS regulon, here we define the binding motif of the Verrucomicrobia, a recently described phylum of emerging interest due to its association with eukaryotic hosts. Site directed mutagenesis of the Verrucomicrobium spinosum recA promoter confirms that LexA binds a 14 bp palindromic motif with consensus sequence TGTTC-N4-GAACA. Computational analyses suggest that recognition of this novel motif is determined primarily by changes in base-contacting residues of the third alpha helix of the LexA helix-turn-helix DNA binding motif. In conjunction with comparative genomics analysis of the LexA regulon in the Verrucomicrobia phylum, electrophoretic shift assays reveal that LexA binds to operators in the promoter region of DNA repair genes and a mutagenesis cassette in this organism, and identify previously unreported components of the SOS response. The identification of tandem LexA-binding sites generating instances of other LexA-binding motifs in the lexA gene promoter of Verrucomicrobia species leads us to postulate a novel mechanism for LexA-binding motif evolution. This model, based on gene duplication, successfully addresses outstanding questions in the intricate co-evolution of the LexA protein, its binding motif and the regulatory network it controls. PMID- 27489857 TI - Elevated Linoleic Acid (A Pro-Inflammatory PUFA) and Liver Injury in a Treatment Naive HIV-HCV Co-Infected Alcohol Dependent Patient. AB - HIV and HCV co-infection is a unique disease condition, and medical management of such condition is difficult due to severity and systemic complications. Added with heavy alcohol drinking, risk of liver injury increases due to several pro inflammatory responses that subsequently get involved with alcohol metabolism. Elevated levels of fatty acids have been reported both in viral infections as well as alcoholic liver disease though such investigations have not addressed the adverse events with dual viral infection of HIV and HCV along with heavy drinking. This case report is of a patient with excessive alcohol drinking and first time diagnosis of HIV and HCV dual infection, elaborating concurrent alteration in Linoleic Acid (LA) levels and pro-inflammatory shift in omega 6/omega-3 ratio along with the elevations in liver injury markers. Elevated LA has been recently studied extensively for its role in alcoholic liver disease; and in the present case, we also found it to be clinically relevant to liver injury. PMID- 27489859 TI - The role of BRCA1-IRIS in ovarian cancer formation, drug resistance and progression. PMID- 27489860 TI - Ibrutinib repurposing: from B-cell malignancies to solid tumors. PMID- 27489858 TI - Persistent infections, immune-senescence and Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. Classical hallmarks of AD such as amyloid deposition and neurofibrillary tangles do not completely explain AD pathogenesis. Recent investigations proposed Abeta peptide as an anti-microbial factor. Our previous works suggested that the concomitant presence of single nucleotide polymorphisms (SNPs) from AD genetic studies might impair antiviral defenses and increase the individual susceptibility to herpes virus infection. Viruses of herpes family by inducing frequent cycles of reactivation and latency constantly challenge the immune response and drive the accumulation of memory T cells. However, the immune system is not able to completely eradicate these viruses. The continuous antigen stimulation activates chronic inflammatory responses that may progressively induce neurodegenerative mechanisms in genetically susceptible elderly. The aim of this paper is to suggest new perspectives in clinical pathogenesis of AD with potential prevention and new medical treatment of the age associated cognitive decline. PMID- 27489861 TI - Hidden association of Cowden syndrome, PTEN mutation and meningioma frequency. AB - Cowden syndrome (CS) is clinically presented by multiple hamartomas, often with mucocutaneous lesions, goiter, breast cancer and gastrointestinal polyps. CS is a genetic disorder of autosomal dominant inheritance and is one distinct syndrome of the phosphatase and tensin homolog on chromosome 10 (PTEN) hamartoma tumor spectrum. Noteworthy, PTEN germline mutations are related to a wide range of brain tumors. We performed a systematic analysis and review of the medical literature for Cowden syndrome and meningioma and additionally present the case of a 29-year- old CS patient diagnosed with multiple meningiomas. We found strong evidence for high incidence of brain tumors in CS patients. In particular meningiomas and gangliocytomas/Lhermitte-Duclos disease were often associated with 8% and 9% respectively in CS patients. Since aberrations in chromosome 10q are associated with meningiomas, it is likely that the underlying mutations in CS drive to a certain extent neoplastic meningioma growth. We propose to include meningiomas and brain tumors in the major criteria spectrum of CS-related disorders. This could warrant early diagnosis of brain lesions and close therapy, as well as better monitoring of patients with CS. PMID- 27489863 TI - Presence of both alterations in FGFR/FGF and PI3K/AKT/mTOR confer improved outcomes for patients with metastatic breast cancer treated with PI3K/AKT/mTOR inhibitors. AB - There is limited data on co-expression of FGFR/FGR amplifications and PI3K/ AKT/mTOR alterations in breast cancer. Tumors from patients with metastatic breast cancer referred to our Phase I Program were analyzed by next generation sequencing (NGS). Genomic libraries were selected for all exons of 236 (or 182) cancer-related genes sequenced to average depth of >500* in a CLIA laboratory (Foundation Medicine, Cambridge, MA, USA) and analyzed for all classes of genomic alterations. We report genomic profiles of 112 patients with metastatic breast cancer, median age 55 years (range, 27-78). Twenty-four patients (21%) had at least one amplified FGFR or FGF. Fifteen of the 24 patients (63%) also had an alteration in the PI3K/ AKT/mTOR pathway. There was no association between alterations in FGFR/FGF and PI3K/AKT/mTOR (P=0.49). Patients with simultaneous amplification in FGFR/FGF signaling and the PI3K/AKT/mTOR pathway had a higher rate of SD>=6 months/PR/ CR when treated with therapies targeting the PI3K/AKT/mTOR pathway than patients with only alterations in the PI3K/AKT/mTOR pathway (73% vs. 34%; P=0.0376) and remained on treatment longer (6.8 vs. 3.7 months; P=0.053). Higher response rates were seen in patients with simultaneous amplification in FGFR/FGF signaling and alterations in the PI3K/AKT/mTOR pathway who were treated with inhibitors of that pathway. PMID- 27489862 TI - Durable response of glioblastoma to adjuvant therapy consisting of temozolomide and a weekly dose of AMD3100 (plerixafor), a CXCR4 inhibitor, together with lapatinib, metformin and niacinamide. AB - Glioblastoma multiforme (GBM) is a CNS (central nervous system) malignancy with a low cure rate. Median time to progression after standard treatment is 7 months and median overall survival is 15 months [1]. Post-treatment vasculogenesis promoted by recruitment of bone marrow derived cells (BMDCs, CD11b+ myelomonocytes) is one of main mechanisms of GBM resistance to initial chemoradiotherapy treatment [2]. Local secretion of SDF-1, cognate ligand of BMDCs CXCR4 receptors attracts BMDCs to the post-radiation tumor site.[3]. This SDF-1 hypoxia-dependent effect can be blocked by AMD3100 (plerixafor) [4]. We report a GBM case treated after chemo- radiotherapy with plerixafor and a combination of an mTOR, a Sirt1 and an EGFRvIII inhibitor. After one year temozolomide and the EGFRvIII inhibitor were stopped. Plerixafor, and the MTOR and Sirt-1 inhibitors were continued. He is in clinical and radiologic remission 30 months from the initiation of his adjuvant treatment. To our knowledge, this is the first report of a patient treated for over two years with a CXCR4 inhibitor (plerixafor), as part of his adjuvant treatment. We believe there is sufficient experimental evidence to consider AMD3100 (plerixafor) part of the adjuvant treatment of GBM. SIGNIFICANCE: The adjuvant inhibition of GBM vasculogenesis(a process different from local angiogenesis) by specifically blocking the migration of BMDCs to the primary tumor site with inhibitors of the CXCR4/SDF-1 axis represents a potential novel therapeutic approach to GBM. There is significant pre-clinical evidence and validation for its use as demonstrated in a patient derived tumor xenograft model of GBM. Together with other specific anti-tumoral therapies, the active inhibition of vasculogenesis in the adjuvant treatment of GBM is deserving of further exploration. PMID- 27489864 TI - Familial adenomatous patients with desmoid tumours show increased expression of miR-34a in serum and high levels in tumours. AB - Familial adenomatous polyposis (FAP) is rare affecting 1 in 10,000 people and a subset (10%) are at risk of myofibroblastic desmoid tumours (DTs) after colectomy to prevent cancer. DTs are a major cause of morbidity and mortality. The absence of markers to monitor progression and a lack of treatment options are significant limitations to clinical management. We investigated microRNAs (miRNA) levels in DTs and serum using expression array analysis on two independent cohorts of FAP patients (total, n=24). Each comprised equal numbers of patients who had formed DTs (cases) and those who had not (controls). All controls had absence of DTs confirmed by clinical and radiological assessment over at least three years post- colectomy. Technical qPCR validation was performed using an expanded cohort (29 FAP patients; 16 cases and 13 controls). The most significant elevated serum miRNA marker of DTs was miR-34a-5p and in-situ hybridisation (ISH) showed most DTs analysed (5/6) expressed miRNA-34a-5p. Exome sequencing of tumour and matched germline DNA did not detect mutations within the miR-34a-5p transcript sites or 3'-UTR of target genes that would alter functional miRNA activity. In conclusion, miR-34a-5p is a potential circulatory marker and therapy target. A large prospective world-wide multi-centre study is now warranted. PMID- 27489865 TI - MRI phase changes in multiple sclerosis vs neuromyelitis optica lesions at 7T. AB - OBJECTIVE: To characterize paramagnetic MRI phase signal abnormalities in neuromyelitis optica spectrum disorder (NMOSD) vs multiple sclerosis (MS) lesions in a cross-sectional study. METHODS: Ten patients with NMOSD and 10 patients with relapsing-remitting MS underwent 7-tesla brain MRI including supratentorial T2* weighted imaging and supratentorial susceptibility weighted imaging. Next, we analyzed intra- and perilesional paramagnetic phase changes on susceptibility weighted imaging filtered magnetic resonance phase images. RESULTS: We frequently observed paramagnetic rim-like (75 of 232 lesions, 32%) or nodular (32 of 232 lesions, 14%) phase changes in MS lesions, but only rarely in NMOSD lesions (rim like phase changes: 2 of 112 lesions, 2%, p < 0.001; nodular phase changes: 2 of 112 lesions, 2%, p < 0.001). CONCLUSIONS: Rim-like or nodular paramagnetic MRI phase changes are characteristic for MS lesions and not frequently detectable in NMOSD. Future prospective studies should ask whether these imaging findings can be used as a biomarker to distinguish between NMOSD- and MS-related brain lesions. PMID- 27489866 TI - Lack of KIR4.1 autoantibodies in Japanese patients with MS and NMO. AB - OBJECTIVES: To examine anti-KIR4.1 antibodies by 2 different assays in Japanese patients with multiple sclerosis (MS) or neuromyelitis optica (NMO). METHODS: One hundred sixty serum samples from 57 patients with MS, 40 patients with NMO/NMO spectrum disorder (NMOSD), and 50 healthy controls (all were Japanese) were tested with ELISA using a synthetic peptide of the first extracellular portion of human KIR4.1. In addition, we attempted to detect anti-KIR4.1 immunoglobulin G in the serum by the luciferase immunoprecipitation systems (LIPS) with the full length of human KIR4.1 produced in a human cell line, which is highly sensitive to single or multiple epitopes. RESULTS: We failed to detect antibodies to the peptide fragment KIR4.1(83-120) in any case of MS and NMO/NMOSD using ELISA. Antibodies to the recombinant full length of KIR4.1 protein were detected in only 2 patients with MS and none in the patients with NMO/NMOSD by the LIPS assay. CONCLUSIONS: We developed 2 different methods (ELISA and LIPS) to measure autoantibodies to KIR4.1 in serum. We detected anti-KIR4.1 immunoglobulin G at a very low frequency in Japanese patients with MS or NMO/NMOSD. Serologic testing for human KIR4.1-specific antibodies is unlikely to improve the diagnosis of MS or NMO/NMOSD in Japanese patients. PMID- 27489867 TI - Diffusion-weighted MR imaging of non-complicated hepatic cysts: Value of 3T computed diffusion-weighted imaging. AB - PURPOSE: To investigate the utility of computed 3T diffusion-weighted imaging (c DWI) for the diagnosis of non-complicated hepatic cysts with a focus on the T2 shine-through effect. MATERIALS AND METHODS: In 50 patients with non-complicated hepatic cysts we acquired one set of DWIs (b-value 0 and 1000 s/mm(2)) at 1.5T, and two sets at 3T (b-value 0 and 1000 s/mm(2), TE 70 ms; b-value 0 and 600 s/mm(2), TE 60 ms). We defined the original DWIs acquired with b = 1000 s/mm(2) at 1.5T and 3T as "o-1.5T-1000" and "o-3T-1000". c-DWIs were calculated with 3T DWI at b-values of 0 and 600 s/mm(2). c-DWI with b = 1000 and 1500 s/mm(2) were defined as "c-1000" and "c-1500". Radiologists evaluated the signal intensity (SI) of the cysts using a 3-point score where 1 = not visible, 2 = discernible, and 3 = clearly visible. They calculated the contrast ratio (CR) between the cysts and the surrounding liver parenchyma on each DWIs and recorded the apparent diffusion coefficient (ADC) with a b-value = 0 and 1000 s/mm(2) on 1.5T- and 3T DWIs. RESULTS: Compared with o-1.5T-1000 DWI, the visual scores of all but the c 1500 DWIs were higher (p = 0.07 for c-1500- and p < 0.01 for the other DWIs). The CR at b = 1000 s/mm(2) was higher on o-3T-1000- than on o-1.5T-1000- (p < 0.01) but not higher than on c-1500 DWIs (p = 0.96). The CR at b = 0 s/mm(2) on 3T images with TE 70 ms was higher than on 1.5T images (p < 0.01). The ADC value was higher for 3T- than 1.5T images (p < 0.01). CONCLUSIONS: Non-complicated hepatic cysts showed higher SI on o-3T-1000- than o-1.5T-1000 DWIs due to the T2-shine through effect. This high SI was suppressed on c-1500 DWIs. PMID- 27489868 TI - Locally advanced rectal cancer: Qualitative and quantitative evaluation of diffusion-weighted MR imaging in the response assessment after neoadjuvant chemo radiotherapy. AB - PURPOSE: to investigate the added value of qualitative and quantitative evaluation of diffusion weighted (DW) magnetic resonance (MR) imaging in response assessment after neoadjuvant chemo-radiotherapy (CRT) in patients with locally advanced rectal cancer (LARC). METHODS: 31 patients with LARC (stage >= T3) were enrolled in the study. All patients underwent conventional MRI and DWI before starting therapy and after neoadjuvant CRT. All patients underwent surgery; pathologic staging represented the reference standard. For qualitative analysis, two radiologists retrospectively reviewed conventional MR images and the combined set of conventional and DW MR images and recorded their confidence level with respect to complete response (ypCR). For quantitative analysis, tumor's apparent diffusion coefficient (ADC) values were measured at each examination. ADC pre CRT, ADC post-CRT and Delta ADC post-ADC pre of the three groups of response (ypCR, partial response ypPR, stable disease ypSD) were compared. Receiver operating characteristics (ROC) curve analysis was employed to investigate the discriminatory capability for ypCR, responders (ypCR, ypPR) and ypSD of each measure. RESULTS: addition of DWI to conventional T2-weighted sequences improved diagnostic performance of MRI in the evaluation of ypCR. A low tumor ADC value in the pre-CRT examination, a high ADC value in the post-CRT examination, a high Delta ADC post-ADC pre [>0.3 (*10(-3) mm(2)/s)] were predictive of ypCR. CONCLUSIONS: DW sequences improve MR capability to evaluate tumor response to CRT. Nevertheless, no functional MR technique alone seems accurate enough to safely select patients with ypCR. PMID- 27489869 TI - Fiber tracking: A qualitative and quantitative comparison between four different software tools on the reconstruction of major white matter tracts. AB - PURPOSE: Diffusion tensor imaging (DTI) enables in vivo reconstruction of white matter (WM) pathways. Considering the emergence of numerous models and fiber tracking techniques, we herein aimed to compare, both quantitatively and qualitatively, the fiber tracking results of four DTI software (Brainance, Philips FiberTrak, DSI Studio, NordicICE) on the reconstruction of representative WM tracts. MATERIALS AND METHODS: Ten healthy participants underwent 30 directional diffusion tensor imaging on a 3T-Philips Achieva TX MR-scanner. All data were analyzed by two independent sites of experienced raters with the aforementioned software and the following WM tracts were reconstructed: corticospinal tract (CST); forceps major (Fmajor); forceps minor (Fminor); cingulum bundle (CB); superior longitudinal fasciculus (SLF); inferior fronto occipital fasciculus (IFOF). Visual inspection of the resulted tracts and statistical analysis (inter-rater and betweensoftware agreement; paired t-test) on fractional anisotropy (FA), axial and radial diffusivity (Daxial, Dradial) were applied for qualitative and quantitative evaluation of DTI software results. RESULTS: Qualitative evaluation of the extracted tracts confirmed anatomical landmarks at least for the core part of each tract, even though differences in the number of fibers extracted and the whole tract were evident, especially for the CST, Fmajor, Fminor and SLF. Descriptive values did not deviate from the expected range of values for healthy adult population. Substantial inter-rater agreement (intraclass correlation coefficient [ICC], Bland-Altman analysis) was found for all tracts (ICC; FA: 0.839-0.989, Daxial: 0.704-0.991, Dradial: 0.972 0.993). Low agreement for FA, Daxial and Dradial (ICC; Bland-Altman analysis) and significant paired t-test differences (p < 0.05) were detected regarding between software agreement. CONCLUSIONS: Qualitative comparison of four different DTI software in addition to substantial inter-rater but poor between-software agreement highlight the differences on existing fiber tracking methodologies and several particularities of each WM tract, further supporting the need for further study in both clinical and research settings. PMID- 27489870 TI - Data resulting from the CFD analysis of ten window frames according to the UNI EN ISO 10077-2. AB - Data are related to the numerical simulation performed in the study entitled "CFD modeling to evaluate the thermal performances of window frames in accordance with the ISO 10077" (Malvoni et al., 2016) [1]. The paper focuses on the results from a two-dimensional numerical analysis for ten frame sections suggested by the ISO 10077-2 and performed using GAMBIT 2.2 and ANSYS FLUENT 14.5 CFD code. The dataset specifically includes information about the CFD setup and boundary conditions considered as the input values of the simulations. The trend of the isotherms points out the different impacts on the thermal behaviour of all sections with air solid material or ideal gas into the cavities. PMID- 27489871 TI - Primary leiomyosarcoma of the omentum presenting as an ovarian carcinoma, case report and review of the literature. AB - Primary omental leiomyosarcoma is a rare tumor. We report a case of successfully resected omental leiomyosarcoma whose presentation mimicked ovarian carcinoma. Symptoms of abdominal distension and discomfort that lasted 8 months followed by pain lead to a diagnosis of a large mass in the abdomen. Physical examination revealed a large, over 20 cm tumor, suspected to be of ovarian origin. A small amount of ascites was found on Computerized Tomography (CT) and ultrasound (US) scans. Total abdominal hysterectomy with bilateral salpingo-oophorectomy, omentectomy and tumor debulking procedure was planned. Laparotomy revealed normal uterus ovaries and tubes with a leiomyosarcoma of the omentum which was completely resected successfully. Only 26 cases of primary leiomyosarcoma of the omentum were previously described in the literature. A review of the literature is also presented. PMID- 27489872 TI - An individual with human immunodeficiency virus, dementia, and central nervous system amyloid deposition. AB - Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) is found in 30%-50% of individuals with HIV infection. To date, no HIV+ individual has been reported to have a positive amyloid PET scan. We report a 71-year-old HIV+ individual with HAND. Clinical and neuropsychologic evaluations confirmed a progressive mild dementia. A routine brain MRI was normal for age. [18F]Fluorodeoxyglucose-PET revealed mild hypermetabolism in bilateral basal ganglia and hypometabolism of bilateral parietal cortex including the posterior cingulate/precuneus. Resting state functional MRI revealed altered connectivity as found with individuals with mild AD. CSF examination revealed a low Abeta42/tau index but a low phospho-tau. An amyloid PET/CT with [18F]florbetaben revealed pronounced cortical radiotracer deposition. This case report suggests that progressive dementia in older HIV+ individuals may be due to HAND, AD, or both. HIV infection does not preclude CNS Abeta/amyloid deposition. Amyloid PET imaging may be of value in distinguishing HAND from AD pathologies. PMID- 27489873 TI - Expanding the phenotypic associations of globular glial tau subtypes. AB - INTRODUCTION: Clinicopathologic correlation in non-Alzheimer's tauopathies is variable, despite refinement of pathologic diagnostic criteria. In the present study, the clinical and neuroimaging characteristics of globular glial tauopathy (GGT) were examined to determine whether subtyping according to consensus guidelines improves clinicopathologic correlation. METHODS: Confirmed GGT cases (n = 11) were identified from 181 frontotemporal tauopathy cases. Clinical and neuroimaging details were collected, and cases sub-typed according to the consensus criteria for GGT diagnosis. Relationships between clinical syndrome and GGT subtype were investigated. RESULTS: In total, 11 patients (seven males, four females, mean age = 67.3 +/- 10.6 years) with GGT were included. Most, but not all, presented with behavioral variant frontotemporal dementia, but none had amyotrophic lateral sclerosis. Subtyping of GGT proved to be difficult and did not improve clinicopathologic correlation. DISCUSSION: Sub-classification of GGT pathology may be difficult and did not improve clinicopathologic correlation. Better biomarkers of tau pathology are needed. PMID- 27489874 TI - Meeting physical activity recommendations may be protective against temporal lobe atrophy in older adults at risk for Alzheimer's disease. AB - INTRODUCTION: Physical activity (PA) is associated with brain health in older adults. However, it is unknown whether the current physical activity recommendations (PAR) impart substantive benefit. The objective of this study was to compare temporal lobe volumes between older adults who met PAR and those who did not. METHODS: Ninety-one enrollees from the Wisconsin Registry for Alzheimer's Prevention wore an accelerometer for seven consecutive days to quantify their PA behaviors and underwent a T-1 anatomic magnetic resonance imaging scan. Participants were categorized as either having met PAR or not based on the US Department of Health and Human Services recommendations of 150 minutes of moderate-to-vigorous physical activity per week. RESULTS: Participants who met PAR possessed significantly greater inferior (eta(2) P = .050) and anterior (eta(2) P = .055) temporal lobe volumes compared with those who did not (P < .05). DISCUSSION: Individuals at-risk for AD experience accelerated rates of brain atrophy. These results suggest that regular engagement in PA at or above PAR could attenuate this decline. PMID- 27489876 TI - Progression and predictors of mild cognitive impairment in Chinese elderly: A prospective follow-up in the Shanghai Aging Study. AB - INTRODUCTION: The Shanghai Aging Study is a community-based study aiming to investigate the incidence and progression of cognitive decline in Chinese elderly, with the operational procedures and diagnostic criteria similar to cohort studies in developed countries. METHODS: We prospectively evaluated 362 individuals with mild cognitive impairment (MCI) diagnosed at baseline through a clinical and neuropsychological interview. Diagnoses of dementia and MCI were made using standard criteria via consensus diagnosis. RESULTS: The conversion rate to dementia was 6.0 per 100 person-years, while the reversion rate to cognitive normal was 7.8 per 100 person-years. Amnestic MCI multiple domains was the most risky type for dementia (conversion rate: 14.2 per 100 person-years). Older age (hazard ratio [HR] = 1.09), apolipoprotein E (APOE epsilon4) (HR = 2.15), and low MMSE score (HR = 1.18) were predictors for dementia. DISCUSSION: Approximately 6% of elderly with MCI progress to dementia annually. Prospective studies are needed to further examine risk and protective predictors and to seek proper interventions for cognitive decline. PMID- 27489875 TI - White matter hyperintensities are more highly associated with preclinical Alzheimer's disease than imaging and cognitive markers of neurodegeneration. AB - INTRODUCTION: Cognitive tests and nonamyloid imaging biomarkers do not consistently identify preclinical AD. The objective of this study was to evaluate whether white matter hyperintensity (WMH) volume, a cerebrovascular disease marker, is more associated with preclinical AD than conventional AD biomarkers and cognitive tests. METHODS: Elderly controls enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 158) underwent florbetapir-PET scans, psychometric testing, neuroimaging with MRI and PET, and APOE genetic testing. Elderly controls the Parkinson's progression markers initiative (PPMI, n = 58) had WMH volume, cerebrospinal fluid (CSF) Abeta1-42, and APOE status measured. RESULTS: In the ADNI cohort, only WMH volume and APOE epsilon4 status were associated with cerebral Abeta (standardized beta = 0.44 and 1.25, P = .03 and .002). The association between WMH volume and APOE epsilon4 status with cerebral Abeta (standardized beta = 1.12 and 0.26, P = .048 and .045) was confirmed in the PPMI cohort. DISCUSSION: WMH volume is more highly associated with preclinical AD than other AD biomarkers. PMID- 27489877 TI - A missed detection of prodromal dementia may be the worst enemy of a timely diagnosis. PMID- 27489879 TI - Relationship between the Activities of Daily Living Questionnaire and the Montreal Cognitive Assessment. AB - INTRODUCTION: The Activities of Daily Living Questionnaire (ADL-Q) is an informant report questionnaire assessing functional impairment in daily living skills. Previous research has demonstrated correlations between ADL-Q and cognitive screening measures among patients with dementia. This study examined the relationship between ADL-Q and the Montreal Cognitive Assessment (MoCA), a brief cognitive screening. METHODS: Records of 448 individuals from an outpatient neurology clinic were reviewed. Pearson correlations were calculated between ADL Q scores and MoCA scores. Linear regression models were fit using demographic information to predict ADL-Q scores. MoCA scores were then added to the models to determine the increase in predictive value of the MoCA. RESULTS: Lower MoCA scores were associated with higher levels of functional impairment. For each model, adding the MoCA significantly improved model fit. DISCUSSION: Low scores on the MoCA, among patient's presenting for memory complaints, should raise concerns about functional decline and prompt for further assessment of functional ability. PMID- 27489878 TI - Untangling tau imaging. AB - In vivo imaging of tau deposits is providing a better understanding of the temporal and spatial tau deposition in the brain, allowing a more comprehensive insight into the causes, diagnoses, and potentially treatment of tauopathies such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, and some variants of frontotemporal lobar degeneration. The assessment of tau deposition in the brain over time will allow a deeper understanding of the relationship between tau and other variables such as cognition, genotype, and neurodegeneration, as well as assessing the role tau plays in ageing. Preliminary human studies suggest that tau imaging could also be used as a diagnostic, prognostic, and theranostic biomarker, as well as a surrogate marker for target engagement, patient recruitment, and efficacy monitoring for disease-specific therapeutic trials. PMID- 27489880 TI - Cognitive variability-A marker for incident MCI and AD: An analysis for the Alzheimer's Disease Neuroimaging Initiative. AB - INTRODUCTION: The potential of intra-individual cognitive variability (IICV) to predict incident mild cognitive impairment (MCI) or Alzheimer's disease (AD) was examined and compared to well-established neuroimaging and genetic predictors. METHODS: IICV was estimated using four neuropsychological measures for n = 1324 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who were cognitively healthy or diagnosed with MCI at baseline. IICV was used to predict time to incident MCI or AD, and compared to hippocampal volume loss and APOE epsilon4 status via survival analysis. RESULTS: In survival analyses, controlling for age, education, baseline diagonosis, and APOE epsilon4 status, likelihood ratio tests indicate that IICV is associated with time to cognitive status change in the full sample (P < .0001), and when the sample was restricted to individuals with MCI at baseline (P < .0001). DISCUSSION: These findings suggest IICV may be a low-cost, noninvasive alternative to traditional AD biomarkers. PMID- 27489881 TI - The association between pulse pressure change and cognition in late life: Age and where you start matters. AB - INTRODUCTION: Variations across studies in the association between blood pressure (BP) and cognition might be explained partly by duration of exposure to hypertension and partly by nonrandom attrition over time. Pulse pressure (PP) reflects arterial stiffness which may better reflect chronicity of hypertension. METHODS: Over six annual cycles, 1954 individuals aged 65+ years from a prospective population-based cohort underwent BP measurements and cognitive evaluations. We examined the relationship of change in five cognitive domains to longitudinal PP patterns across the late-life age spectrum, before and after stratifying by baseline systolic blood pressure (SBP) and adjusting for attrition. RESULTS: There were four longitudinal PP patterns: stable normal, stable high, increasing, and decreasing. Those with lower baseline SBP and an increasing or stable high PP had less decline in cognition, an effect that was attenuated with aging. Among those with higher baseline SBP, there were no differences across PP groups, but increasing age was consistently associated with greater cognitive decline. DISCUSSION: The effect of PP on cognitive decline depends on age, baseline SBP, and the trajectory of PP change. Cardiovascular mechanisms underlying cognitive aging should be recognized as nuanced and dynamic processes when exploring prevention and treatment targets in the elderly, so that the optimal timing and type of intervention can be identified. PMID- 27489883 TI - A systematic pipeline for the objective comparison of whole-brain spectroscopic MRI with histology in biopsy specimens from grade III glioma. AB - The diagnosis, prognosis, and management of patients with gliomas are largely dictated by the pathological analysis of tissue biopsied from a selected region within the lesion. However, due to the heterogeneous and infiltrative nature of gliomas, identifying the optimal region for biopsy with conventional magnetic resonance imaging (MRI) can be quite difficult. This is especially true for low grade gliomas, which often are non-enhancing tumors. To improve the management of patients with these tumors, the field of neuro-oncology requires an imaging modality that can specifically identify a tumor's most anaplastic/aggressive region(s) for biopsy targeting. The addition of metabolic mapping using spectroscopic MRI (sMRI) to supplement conventional MRI could improve biopsy targeting and, ultimately, diagnostic accuracy. Here, we describe a pipeline for the integration of state-of-the-art, high-resolution whole-brain 3D sMRI maps into a stereotactic neuronavigation system for guiding biopsies in gliomas with nonenhancing components. We also outline a machine-learning method for automated histology analysis that generates normalized, quantitative metrics describing tumor infiltration in immunohistochemically-stained tissue specimens. As a proof of concept, we describe the combination of these two techniques in a small cohort of grade III glioma patients. In this work, we aim to set forth a systematic pipeline to stimulate histopathology-image validation of advanced MRI techniques, such as sMRI. PMID- 27489882 TI - Developing and Conducting a Dissertation Study through the Community-Based Participatory Research Approach. AB - The community-based participatory research (CBPR) approach has been shown to be innovative and effective in conducting research with communities experiencing health disparities. Doctoral nursing students, and other doctoral students in the health sciences, who are interested in this approach can benefit through structured CBPR training experiences in learning how to engage with communities, build community capacity, share resources, implement CBPR study plans, and disseminate results of CBPR-focused studies. The objectives of this case-study are to demonstrate ways in which one doctoral student aligned with academic mentors and a funded CBPR project to build a relationship with the Sikh Asian Indian (AI) community of New York City to develop and implement a CBPR-focused doctoral dissertation study. The purpose of the research was to examine the relationship between the experience of perceived discrimination and health outcomes in this community. CBPR methods utilized in developing the study entailed the author partaking in formal and informal CBPR learning experiences, building relationships with community and academic partners early on through volunteering, developing a research plan in collaboration with members of the community and academic partners, identifying an appropriate setting and methods for recruitment and data collection, increasing capacity and resources for all partners (the author, community, and academic), and presenting dissertation study findings to the community. In conclusion, CBPR-focused doctoral experiences are novel pedagogical and professional approaches for nursing and health science students which can lead to mutual benefits for all involved, and ultimately successful and effective community-based health research. PMID- 27489884 TI - Soluble ADAM33 initiates airway remodeling to promote susceptibility for allergic asthma in early life. AB - Asthma is a chronic inflammatory airways disease that usually begins in early life and involves gene-environment interactions. Although most asthma exhibits allergic inflammation, many allergic individuals do not have asthma. Here, we report how the asthma gene a disintegrin and metalloprotease 33 (ADAM33) acts as local tissue susceptibility gene that promotes allergic asthma. We show that enzymatically active soluble ADAM33 (sADAM33) is increased in asthmatic airways and plays a role in airway remodeling, independent of inflammation. Furthermore, remodeling and inflammation are both suppressed in Adam33-null mice after allergen challenge. When induced in utero or added ex vivo, sADAM33 causes structural remodeling of the airways, which enhances postnatal airway eosinophilia and bronchial hyperresponsiveness following subthreshold challenge with an aeroallergen. This substantial gene-environment interaction helps to explain the end-organ expression of allergic asthma in genetically susceptible individuals. Finally, we show that sADAM33-induced airway remodeling is reversible, highlighting the therapeutic potential of targeting ADAM33 in asthma. PMID- 27489885 TI - Protective and detrimental effects of neuroectodermal cell-derived tissue factor in mouse models of stroke. AB - Within the CNS, a dysregulated hemostatic response contributes to both hemorrhagic and ischemic strokes. Tissue factor (TF), the primary initiator of the extrinsic coagulation cascade, plays an essential role in hemostasis and also contributes to thrombosis. Using both genetic and pharmacologic approaches, we characterized the contribution of neuroectodermal (NE) cell TF to the pathophysiology of stroke. We used mice with various levels of TF expression and found that astrocyte TF activity reduced to ~5% of WT levels was still sufficient to maintain hemostasis after hemorrhagic stroke but was also low enough to attenuate inflammation, reduce damage to the blood-brain barrier, and improve outcomes following ischemic stroke. Pharmacologic inhibition of TF during the reperfusion phase of ischemic stroke attenuated neuronal damage, improved behavioral deficit, and prevented mortality of mice. Our data demonstrate that NE cell TF limits bleeding complications associated with the transition from ischemic to hemorrhagic stroke and also contributes to the reperfusion injury after ischemic stroke. The high level of TF expression in the CNS is likely the result of selective pressure to limit intracerebral hemorrhage (ICH) after traumatic brain injury but, in the modern era, poses the additional risk of increased ischemia-reperfusion injury after ischemic stroke. PMID- 27489886 TI - A Conceptual Framework for the Progression of Balance Exercises in Persons with Balance and Vestibular Disorders. AB - There is little information in peer-reviewed literature to specifically guide the choice of exercise for persons with balance and vestibular disorders. The purpose of this study is to provide a rationale for the establishment of a progression framework and propose a logical sequence in progressing balance exercises for persons with vestibular disorders. Our preliminary conceptual framework was developed by a multidisciplinary team of physical therapists and engineers with extensive experience with people with vestibular disorders. Balance exercises are grouped into six different categories: static standing, compliant surface, weight shifting, modified center of gravity, gait, and vestibulo-ocular reflex (VOR). Through a systematized literature review, interviews and focus group discussions with physical therapists and postural control experts, and pilot studies involving repeated trials of each exercise, exercise progressions for each category were developed and ranked in order of degree of difficulty. Clinical expertise and experience guided decision making for the exercise progressions. Hundreds of exercise combinations were discussed and research is ongoing to validate the hypothesized rankings. The six exercise categories can be incorporated into a balance training program and the framework for exercise progression can be used to guide less experienced practitioners in the development of a balance program. It may also assist clinicians and researchers to design, develop, and progress interventions within a treatment plan of care, or within clinical trials. A structured exercise framework has the potential to maximize postural control, decrease symptoms of dizziness/visual vertigo, and provide "rules" for exercise progression for persons with vestibular disorders. The conceptual framework may also be applicable to persons with other balance related issues. PMID- 27489887 TI - Innervation of Gill Lateral Cells in the Bivalve Mollusc Crassostrea virginica Affects Cellular Membrane Potential and Cilia Activity. AB - Gill lateral cells of Crassostrea virginica are innervated by the branchial nerve, which contains serotonergic and dopaminergic fibers that regulate cilia beating rate. Terminal release of serotonin or dopamine results in an increase or decrease, respectively, of cilia beating rate in lateral gill cells. In this study we used the voltage sensitive fluorescent probe DiBAC4(3) to quantify changes in gill lateral cell membrane potential in response to electrical stimulation of the branchial nerve or to applications of serotonin and dopamine, and correlate these changes to cilia beating rates. Application of serotonin to gill lateral cells caused prolonged membrane depolarization, similar to plateau potentials, while increasing cilia beating rate. Application of dopamine hyperpolarized the resting membrane while decreasing cilia beating rate. Low frequency (5 Hz) electrical stimulations of the branchial nerve, which cause terminal release of endogenous serotonin, or high frequency (20 Hz) stimulations, which cause terminal release of endogenous dopamine, had the same effects on gill lateral cell membrane potentials and cilia beating rate as the respective applications of serotonin or dopamine. The study shows that innervation of gill lateral cells by the branchial nerve affects membrane potential as well as cilia beating rate, and demonstrates a strong correlation between changes in membrane potential and regulation of cilia beating rate. The study furthers the understanding of serotonin and dopamine signaling in the innervation and regulation of gill cilia in bivalves. The study also shows that voltage sensitive fluorescent probes like DiBAC 4(3) can be successfully used as an alternative to microelectrodes to measure changes in membrane potential of ciliated gill cells and other small cells with fast moving cilia. PMID- 27489888 TI - Methods to Reduce Medication Errors in a Clinical Trial of an Investigational Parenteral Medication. AB - There are few evidence-based guidelines to inform optimal design of complex clinical trials, such as those assessing the safety and efficacy of intravenous drugs administered daily with infusion times over many hours per day and treatment durations that may span years. This study is a retrospective review of inpatient administration deviation reports for an investigational drug that is administered daily with infusion times of 8-24 hours, and variable treatment durations for each patient. We report study design modifications made in 2007 2008 aimed at minimizing deviations from an investigational drug infusion protocol approved by an institutional review board and the United States Food and Drug Administration. Modifications were specifically aimed at minimizing errors of infusion rate, incorrect dose, incorrect patient, or wrong drug administered. We found that the rate of these types of administration errors of the study drug was significantly decreased following adoption of the specific study design changes. This report provides guidance in the design of clinical trials testing the safety and efficacy of study drugs administered via intravenous infusion in an inpatient setting so as to minimize drug administration protocol deviations and optimize patient safety. PMID- 27489889 TI - Fabrication of an "ion-imprinting" dual-emission quantum dot nanohybrid for selective fluorescence turn-on and ratiometric detection of cadmium ions. AB - In this work, we have fabricated a new dual-emission quantum dot (QD) nanohybrid for fluorescence ratiometric determination of cadmium ions (Cd2+) in water samples, where the "turn-on" model and "ion-imprinting" technique were incorporated simultaneously. The nanohybrid probe was composed of green-emitting CdSe QDs covalently linked onto the surface of silica nanoparticles embedded with red-emitting CdTe QDs. The chemical etching of ethylene diamine tetraacetic acid (EDTA) at the surface produced specific Cd2+ recognition sites and quenched the green fluorescence of outer CdSe QDs. Upon exposure to different amounts of Cd2+, the green fluorescence was gradually restored, whereas the inner red fluorescence remained constant. As a consequence, an obviously distinguishable fluorescence color variation (from red to green) of the probe solution was observed. Under the optimized conditions, the developed ratiometric sensor displayed a linear response range from 0.1 to 9 MUM with a detection limit of 25 nM (S/N = 3) for Cd2+, which could offer an alternative sensing approach for the highly sensitive and selective detection of heavy metal ions. PMID- 27489890 TI - Functional group migrations between boron and metal centres within transition metal-borane and -boryl complexes and cleavage of H-H, E-H and E-E' bonds. AB - This feature article examines some of the recent advances in the chemistry of Z type transition metal-borane and X-type transition metal-boryl complexes. It focuses on the employment of these boron-based functionalities acting as stores and transfer agents for functional groups such as hydrides, alkyl groups and aryl groups which can either be abstracted or delivered to the metal centre. The review also explores the rather novel reactivity involving the cleavage of H-H, E H and E-E' bonds (where E and E' are a range of groups) across the transition metal-boron bond in such complexes. It explores the early examples of the addition of H-H across transition metal-borane bonds and describes the new transformation in the context of other known modes of hydrogen activation including classic oxidative addition and heterolytic cleavage at transition metal centres as well as Frustrated Lewis Pair chemistry. Similar reactivity involving transition metal-boryl complexes are also described particularly those which undergo both boryl-to-borane and borane-to-borohydride transformations. The delivery of hydride to the metal centre in combination with the potential to regenerate the borohydride functional group via a recharging process is explored in the context of providing a new strategy for catalysis. Finally, a light hearted look at the analogy of the 'stinging processes' involving Trofimenko type ligands is taken one step further to determine whether it is indeed in the nature of scorpionate ligands to repeatedly 'sting' just as the real life scorpions do. PMID- 27489892 TI - CardioPulse. The Korean Society of Cardiology. PMID- 27489891 TI - CardioPulse. Francesco Cosentino MD PhD FESC, from Rome to the Karolinska Institute in Stockholm via the Mayo Clinic. PMID- 27489893 TI - Update on preoperative assessment for geriatric patients prior to elective surgery. PMID- 27489894 TI - HHS Lays Out Multifaceted Plan to Combat Opioid Abuse. PMID- 27489895 TI - Time Running Out for Physicians to Review Open Payments Data. PMID- 27489897 TI - HHS Says Basic Standards of Transparency Would Simplify Process for Sharing Patient Data. PMID- 27489896 TI - MedPAC Tackles Complex Issue of Low-Value Medical Services. PMID- 27489898 TI - Move to Protect Hospital-Employed Family Physicians Seen as Patient Advocacy. PMID- 27489899 TI - [Diabetes mellitus and chronic kidney disease: Possibilities of prediction, early diagnosis, and nephroprotection in the 21st century]. AB - The. review gives data on the prognostic value of genetic markers when analyzing the risk of chronic kidney disease in diabetes mellitus, those on new possibilities of early diagnosis of diabetic nephropathy using urinary biomarkers (nephrinuria, podocinuria) and proteomic urinalysis at the stage of normoalbuminuria. The interpretation of the index mrcroalbuminuria in type 2 diabetesis critically analyzed. The nephroprotective properties of novel classes of glucose-lowering drugs, such as incretins and gliflozins, are considered. PMID- 27489900 TI - Students Trained at Public Medical Schools Are More Likely to Practice in Primary Care. PMID- 27489901 TI - [Idiopathic membranous nephropathy: Evolution in understanding the problem]. AB - The review highlights the evolution of ideas on the. mechanisms responsible for the 'development of membranous nephropathy(MN), glomerulopathy that is the most common cause of nephrotic syndrome in adults. Primary emphasis is placed on the primary form of MN. The important step to understanding the nature of this clinical and morphological form of glomerulonephritis is to create its animal model (Heymann nephritis), then to decipher the mechanisms of immune complex damage (complement activation,a role of cellular immunity), and to identify autoantigens responsible for the development of idiopathic MN in man (podocyteneutral endopeptidase, transmembrane M-type phospholipase A2 receptor, thrombospondin type-1 domain-containing 7A. The findings constituted the basis for developing current methods for the diagnosis and treatment of MN, including the pathogenetically sound inhibition of autoantibody production, as well as a molecular orientation effect on podocyte dysfunction. PMID- 27489902 TI - [Difficulties in correcting hyperphosphatemia in patients with chronic renal failure. A place of noncalcium-containing phosphate-binding drugs]. AB - The review considers the current views of the mechanisms of hyperphosphatemia in patients with chronic renal failure. It shows indications for the use of different classes of phosphate-binding drugs to correct hyperphosphatemia. PMID- 27489903 TI - [The efficiency of antiviral therapy in patients with chronic -hepatitis C infected with hepatitis C virus recombinants]. AB - The review gives the data available in the literature in the efficiency of treatment in patients with chronic hepatitis C infected with hepatitis C virus.(HCV) recombinants, by applying various antiviral therapy regimens. The low efficiency of treatment with- pegylated interferons (PEG IFN) + ribavirin (RIB) and sofosburin (SOF) +RIB in this patient group (a sustained virologic response was achieved in 22 and 30.7%, respectively) compared with the efficiency of treatment (87-97 and 83-97%, respectively) inpatients infected with HCV genotype 2 does not allow the 2015 EASL HCV genotype 2 treatment regimens to be used in. such patients. In this connection, subtyping genotype 2 isolates by NS5B sequencing should be introduced into clinical laboratory practice to successfully detect recombinant HCVs and to enhance the efficiency of antiviral therapy. PMID- 27489905 TI - Groups advise house committee against changes to ACIP processes. PMID- 27489906 TI - Free CME available for using HHS' new opioid training tool. PMID- 27489904 TI - [Chronic kidney disease and atrial fibrillation as components of the cardiorenal continuum]. AB - The paper discusses the present-day idea on a relationship between atrial fibrillation and chronic kidney dis~ase, the specific features of therapeutic policy, and the place of antithrombotic therapy in particular."Based on the results of population-based studies,the authors set forth the specific features of cardiac arrhythmias concurrent with kidney injury, as well as promising directions to optimize management schemes for this category of patients. PMID- 27489907 TI - New resource helps physicians encourage Tdap vaccination for pregnant patients. PMID- 27489908 TI - Sudden onset bilateral lower limb weakness in a female patient with no significant past medical history. PMID- 27489909 TI - Groups Prod HHS to Recognize Advance Care Planning CPT Codes. PMID- 27489911 TI - GAO Levels Sharp Criticism Against Physician Fee Committee. PMID- 27489910 TI - FDA Denies Request to Weaken Smokeless Tobacco Warning. PMID- 27489912 TI - AAFP Warns FTC About Consequences of Insurance Mergers. PMID- 27489913 TI - Suicide. PMID- 27489916 TI - Practices Make Progress on Alternative Payment Models, but Struggles Remain. PMID- 27489915 TI - CMS Clarifies Use of CCM Code in Medicare Advantage Plans. PMID- 27489914 TI - Evert Joost Dorhout Mees. PMID- 27489917 TI - Register Now for Midwest's First Direct Primary Care Summit. PMID- 27489918 TI - Health Coaches Help Family Physicians Improve Chronic Disease Management. PMID- 27489919 TI - Two doctors who put Worcester on the medical heritage map. PMID- 27489920 TI - Additional comment to "Survey of prenatal testing for genetic disorders in Japan: Recent report". PMID- 27489921 TI - In Memoriam: A Tribute to Alan Magill. PMID- 27489922 TI - Interview with Rose Leke: Urging Female Scientists to Shoot for the Moon. PMID- 27489943 TI - Functional Modulation of a G Protein-Coupled Receptor Conformational Landscape in a Lipid Bilayer. AB - Mapping the conformational landscape of G protein-coupled receptors (GPCRs), and in particular how this landscape is modulated by the membrane environment, is required to gain a clear picture of how signaling proceeds. To this end, we have developed an original strategy based on solution-state nuclear magnetic resonance combined with an efficient isotope labeling scheme. This strategy was applied to a typical GPCR, the leukotriene B4 receptor BLT2, reconstituted in a lipid bilayer. Because of this, we are able to provide direct evidence that BLT2 explores a complex landscape that includes four different conformational states for the unliganded receptor. The relative distribution of the different states is modulated by ligands and the sterol content of the membrane, in parallel with the changes in the ability of the receptor to activate its cognate G protein. This demonstrates a conformational coupling between the agonist and the membrane environment that is likely to be fundamental for GPCR signaling. PMID- 27489944 TI - Transmission or Within-Host Dynamics Driving Pulses of Zoonotic Viruses in Reservoir-Host Populations. AB - Progress in combatting zoonoses that emerge from wildlife is often constrained by limited knowledge of the biology of pathogens within reservoir hosts. We focus on the host-pathogen dynamics of four emerging viruses associated with bats: Hendra, Nipah, Ebola, and Marburg viruses. Spillover of bat infections to humans and domestic animals often coincides with pulses of viral excretion within bat populations, but the mechanisms driving such pulses are unclear. Three hypotheses dominate current research on these emerging bat infections. First, pulses of viral excretion could reflect seasonal epidemic cycles driven by natural variations in population densities and contact rates among hosts. If lifelong immunity follows recovery, viruses may disappear locally but persist globally through migration; in either case, new outbreaks occur once births replenish the susceptible pool. Second, epidemic cycles could be the result of waning immunity within bats, allowing local circulation of viruses through oscillating herd immunity. Third, pulses could be generated by episodic shedding from persistently infected bats through a combination of physiological and ecological factors. The three scenarios can yield similar patterns in epidemiological surveys, but strategies to predict or manage spillover risk resulting from each scenario will be different. We outline an agenda for research on viruses emerging from bats that would allow for differentiation among the scenarios and inform development of evidence-based interventions to limit threats to human and animal health. These concepts and methods are applicable to a wide range of pathogens that affect humans, domestic animals, and wildlife. PMID- 27489945 TI - Socioeconomic Disadvantage Moderates the Association between Peripheral Biomarkers and Childhood Psychopathology. AB - BACKGROUND: Socioeconomic disadvantage (SED) has been consistently associated with early life mental health problems. SED has been shown to impact multiple biological systems, including the regulation of neurotrophic proteins, immune inflammatory and oxidative stress markers, which, conversely, have been reported to be relevant to physiological and pathological neurodevelopment This study investigated the relationship between SED, different domains of psychopathology, serum levels of interleukin-6 (IL6), thiobarbituric acid-reactive substance (TBARS) and brain-derived neurotrophic factor (BDNF). We hypothesized that a composite of socioeconomic risk would be associated with psychopathology and altered levels of peripheral biomarkers. In addition, we hypothesized that SED would moderate the associations between mental health problems, IL6, TBARS and BDNF. METHODS AND FINDINGS: Using a cross-sectional design, we measured the serum levels of IL6, TBARS and BDNF in 495 children aged 6 to 12. We also investigated socio-demographic characteristics and mental health problems using the Child Behaviour Checklist (CBCL) DSM-oriented scales. SED was evaluated using a cumulative risk model. Generalized linear models were used to assess associations between SED, biomarkers levels and psychopathology. SED was significantly associated with serum levels of IL6 (RR = 1.026, 95% CI 1.004; 1.049, p = 0.020) and TBARS (RR = 1.077, 95% CI 1.028; 1.127, p = 0.002). The association between SED and BDNF was not statistically significant (RR = 1.031, 95% CI 0.997; 1.066, p = 0.077). SED was also significantly associated with all CBCL DSM-oriented scales (all p < 0.05), whereas serum biomarkers (i.e. IL6, TBARS, BDNF) were associated with specific subscales. Moreover, the associations between serum biomarkers and domains of psychopathology were moderated by SED, with stronger correlations between mental health problems, IL6, TBARS, and BDNF being observed in children with high SED. CONCLUSIONS: In children, SED is highly associated with mental health problems. Our findings suggest that this association may be moderated via effects on multiple interacting neurobiological systems. PMID- 27489946 TI - Domain Architectures and Grain Boundaries in Chemical Vapor Deposited Highly Anisotropic ReS2 Monolayer Films. AB - Recent studies have shown that vapor phase synthesis of structurally isotropic two-dimensional (2D) MoS2 and WS2 produces well-defined domains with clean grain boundaries (GBs). This is anticipated to be vastly different for 2D anisotropic materials like ReS2 mainly due to large anisotropy in interfacial energy imposed by its distorted 1T crystal structure and formation of signature Re-chains along [010] b-axis direction. Here, we provide first insight on domain architecture on chemical vapor deposited (CVD) ReS2 domains using high-resolution scanning transmission electron microscopy, angle-resolved nano-Raman spectroscopy, reflectivity, and atomic force microscopy measurements. Results provide ways to achieve crystalline anisotropy in CVD ReS2, establish domain architecture of high symmetry ReS2 flakes, and determine Re-chain orientation within subdomains. Results also provide a first atomic resolution look at ReS2 GBs, and surprisingly we find that cluster and vacancy defects, formed by collusion of Re-chains at the GBs, dramatically impact the crystal structure by changing the Re-chain direction and rotating Re-chains 180 degrees along their b-axis. Overall results not only shed first light on domain architecture and structure of anisotropic 2D systems but also allow one to attain much desired crystalline anisotropy in CVD grown ReS2 for the first time for tangible applications in photonics and optoelectronics where direction-dependent dichroic and linearly polarized material properties are required. PMID- 27489948 TI - When the Minority Thinks "Essentially" Like the Majority: Blacks Distinguish Bio Somatic from Bio-Behavioral Essentialism in Their Conceptions of Whites, and Only the Latter Predicts Prejudice. AB - Essentialist beliefs about social groups can contribute to prejudice and intergroup distancing. To date, little data have been gathered regarding minority group members' essentialistic thinking about the White majority in the U.S. Do essentialist beliefs show a similar structure when minority group members are thinking about the majority as when the majority group is thinking about the minority group? Do minority group essentialist beliefs predict affective prejudice and diminished desire for intergroup contact as they do among White respondents? We sought answers to these questions in a study that included 248 African American participants. We found clear evidence that the structure of Blacks' essentialist thinking about Whites matches the structure of Whites' essentialist thinking about Blacks. Specifically, Black respondents made a distinction between bio-somatic and bio-behavioral essentialism, and reported stronger endorsement of the former as compared to the latter. Also replicating prior studies of Whites' essentialist thinking, only bio-behavioral essentialist beliefs were predictive of negative attitudes. This suggests that essentialism can be linked to prejudice even in contexts that do not involve a dominant group rationalizing its social advantages. Discussion centers on implications of this work for prejudice reduction. PMID- 27489949 TI - Recurrent Inhibition to the Medial Nucleus of the Trapezoid Body in the Mongolian Gerbil (Meriones Unguiculatus). AB - Principal neurons in the medial nucleus of the trapezoid body (MNTB) receive strong and temporally precise excitatory input from globular bushy cells in the cochlear nucleus through the calyx of Held. The extremely large synaptic currents produced by the calyx have sometimes led to the view of the MNTB as a simple relay synapse which converts incoming excitation to outgoing inhibition. However, electrophysiological and anatomical studies have shown the additional presence of inhibitory glycinergic currents that are large enough to suppress action potentials in MNTB neurons at least in some cases. The source(s) of glycinergic inhibition to MNTB are not fully understood. One major extrinsic source of glycinergic inhibitory input to MNTB is the ventral nucleus of the trapezoid body. However, it has been suggested that MNTB neurons receive additional inhibitory inputs via intrinsic connections (collaterals of glycinergic projections of MNTB neurons). While several authors have postulated their presence, these collaterals have never been examined in detail. Here we test the hypothesis that collaterals of MNTB principal cells provide glycinergic inhibition to the MNTB. We injected dye into single principal neurons in the MNTB, traced their projections, and immunohistochemically identified their synapses. We found that collaterals terminate within the MNTB and provide an additional source of inhibition to other principal cells, creating an inhibitory microcircuit within the MNTB. Only about a quarter to a third of MNTB neurons receive such collateral inputs. This microcircuit could produce side band inhibition and enhance frequency tuning of MNTB neurons, consistent with physiological observations. PMID- 27489947 TI - The Estrogen Receptor alpha-Cistrome Beyond Breast Cancer. AB - Although many tissues express estrogen receptor (ER)alpha, most studies focus on breast cancer where ERalpha occupies just a small fraction of its total repertoire of potential DNA-binding sites, based on sequence. This raises the question: Can ERalpha occupy these other potential binding sites in a different context? Ligands, splice variants, posttranslational modifications, and acquired mutations of ERalpha affect its conformation, which may alter chromatin interactions. To date, literature describes the DNA-binding sites of ERalpha (the ERalpha cistrome) in breast, endometrium, liver, and bone, in which the receptor mainly binds to enhancers. Chromosomal boundaries provide distinct areas for dynamic gene regulation between tissues, where the usage of enhancers deviates. Interactions of ERalpha with enhancers and its transcriptional complex depend on the proteome, which differs per cell type. This review discusses the biological variables that influence ERalpha cistromics, using reports from human specimens, cell lines, and mouse tissues, to assess whether ERalpha genomics in breast cancer can be translated to other tissue types. PMID- 27489952 TI - Correlation of 3D FLAIR and Dopamine Transporter Imaging in Patients With Parkinsonism. AB - OBJECTIVE: The purpose of this study is to evaluate direct in vivo visualization of nigrosome-1 in substantia nigra (SN) with 3D FLAIR imaging and its diagnostic value in predicting the intactness of presynaptic dopaminergic function of the nigrostriatal pathway. MATERIALS AND METHODS: Forty-five patients showing parkinsonism who underwent both 3D FLAIR and dopamine transporter (DAT) imaging were recruited. In total, 90 SNs were reviewed on axial 3D FLAIR images. We regarded oval or linear hyperintensities on the posterolateral side of SN as intact nigrosome-1. Two neuroradiologists independently evaluated the appearance of nigrosome-1, and disagreements were settled by consensus. Kappa values for interrater agreement were calculated. Diagnostic performances of the appearance of nigrosome-1 for predicting presynaptic dopaminergic function on DAT imaging and Parkinson disease (PD) were calculated. RESULTS: The diagnostic performances of a loss of nigrosome-1 on 3D FLAIR images were sensitivity of 85.7%, specificity of 85.4%, positive predictive value (PPV) of 83.7%, and negative predictive value (NPV) of 87.2% for predicting impaired presynaptic dopaminergic function on DAT imaging, and sensitivity of 94.7%, specificity of 76.9%, PPV of 85.7%, and NPV of 90.9% for predicting PD. When only oval hyperintensity was considered as intact nigrosome-1, its sensitivity and NPV were increased up to 95.2% and 91.7%, respectively, for predicting impaired presynaptic dopaminergic function on DAT imaging, and both increased to 100% for predicting PD. Interobserver agreement for the appearance of nigrosome-1 on 3D FLAIR images was substantial (kappa = 0.625). CONCLUSION: Nigrosome-1 could be visualized on 3D FLAIR images, and its loss can be used to predict presynaptic dopaminergic function and to diagnose PD with high accuracy. PMID- 27489950 TI - Antibiotic-Induced Gut Microbiota Disruption Decreases TNF-alpha Release by Mononuclear Cells in Healthy Adults. AB - OBJECTIVES: Broad-spectrum antibiotics disrupt the intestinal microbiota. The microbiota is essential for physiological processes, such as the development of the gut immune system. Recent murine data suggest that the intestinal microbiota also modulates systemic innate immune responses; however, evidence in humans is lacking. METHODS: Twelve healthy young men were given oral broad-spectrum antibiotics (ciprofloxacin 500 mg bid, vancomycin 500 mg tid and metronidazole 500 mg tid) for 7 days. At baseline, 1 day, and 6 weeks after antibiotics, blood and feces were sampled. Whole blood and isolated mononuclear cells were stimulated with selected Toll-like receptor agonists and heat-killed bacteria. Microbiota diversity and composition was determined using bacterial 16S rDNA sequencing. RESULTS: One day after the antibiotic course, microbial diversity was significantly lower compared with baseline. After antibiotic therapy, systemic mononuclear cells produced lower levels of tumor necrosis factor (TNF)-alpha after ex vivo stimulation with lipopolysaccharide (LPS). This diminished capacity to produce TNF-alpha was restored 6 weeks after cessation of antibiotic therapy. In whole blood, a reduced capacity to release interleukin (IL)-1beta and IL-6 was observed after LPS stimulation. Antibiotic treatment did not impact on differential leukocyte counts, phagocytosis, and cell surface markers of neutrophils and monocytes. CONCLUSIONS: In this proof-of-principle study of healthy subjects, microbiota disruption by broad-spectrum antibiotics is reversibly associated with decreased systemic cellular responsiveness towards LPS. The implications of these findings in a clinical setting remain to be determined. PMID- 27489951 TI - Fructose 1,6-Bisphosphate Aldolase, a Novel Immunogenic Surface Protein on Listeria Species. AB - Listeria monocytogenes is a ubiquitous food-borne pathogen, and its presence in food or production facilities highlights the importance of surveillance. Increased understanding of the surface exposed antigens on Listeria would provide potential diagnostic and therapeutic targets. In the present work, using mass spectrometry and genetic cloning, we show that fructose-1,6-bisphosphate aldolase (FBA) class II in Listeria species is the antigen target of the previously described mAb-3F8. Western and dot blot assays confirmed that the mAb-3F8 could distinguish all tested Listeria species from close-related bacteria. Localization studies indicated that FBA is present in every fraction of Listeria cells, including supernatant and the cell wall, setting Listeria spp. as one of the few bacteria described to have this protein on their cell surface. Epitope mapping using ORFeome display and a peptide membrane revealed a 14-amino acid peptide as the potential mAb-3F8 epitope. The target epitope in FBA allowed distinguishing Listeria spp. from closely-related bacteria, and was identified as part of the active site in the dimeric enzyme. However, its function in cell surface seems not to be host cell adhesion-related. Western and dot blot assays further demonstrated that mAb-3F8 together with anti-InlA mAb-2D12 could differentiate pathogenic from non-pathogenic Listeria isolated from artificially contaminated cheese. In summary, we report FBA as a novel immunogenic surface target useful for the detection of Listeria genus. PMID- 27489953 TI - Supervised Learning for Detection of Duplicates in Genomic Sequence Databases. AB - MOTIVATION: First identified as an issue in 1996, duplication in biological databases introduces redundancy and even leads to inconsistency when contradictory information appears. The amount of data makes purely manual de duplication impractical, and existing automatic systems cannot detect duplicates as precisely as can experts. Supervised learning has the potential to address such problems by building automatic systems that learn from expert curation to detect duplicates precisely and efficiently. While machine learning is a mature approach in other duplicate detection contexts, it has seen only preliminary application in genomic sequence databases. RESULTS: We developed and evaluated a supervised duplicate detection method based on an expert curated dataset of duplicates, containing over one million pairs across five organisms derived from genomic sequence databases. We selected 22 features to represent distinct attributes of the database records, and developed a binary model and a multi class model. Both models achieve promising performance; under cross-validation, the binary model had over 90% accuracy in each of the five organisms, while the multi-class model maintains high accuracy and is more robust in generalisation. We performed an ablation study to quantify the impact of different sequence record features, finding that features derived from meta-data, sequence identity, and alignment quality impact performance most strongly. The study demonstrates machine learning can be an effective additional tool for de-duplication of genomic sequence databases. All Data are available as described in the supplementary material. PMID- 27489954 TI - Dialect Interference in Lexical Processing: Effects of Familiarity and Social Stereotypes. AB - BACKGROUND/AIMS: The current study explored the roles of dialect familiarityand social stereotypes in dialect interference effects in a speeded lexical classification task. METHODS: Listeners classified the words bad and bed or had and head produced by local Midland and non-local Northern talkers and the words sod and side or rod and ride produced by non-local, non-stereotyped Northern and nonlocal, stereotyped Southern talkers in single- and mixed-talker blocks. RESULTS: Lexical classification was better for the local dialect than for the non local dialects, and for the stereotyped non-local dialect than for the non stereotyped non-local dialect. Dialect interference effects were observed for all three dialects, although the patterns of interference differed. For the local dialect, dialect interference was observed for response times, whereas for the non-local dialects, dialect interference was observed primarily for accuracy. CONCLUSION: These findings reveal complex interactions between indexical and lexical information in speech processing. PMID- 27489955 TI - SNVSniffer: an integrated caller for germline and somatic single-nucleotide and indel mutations. AB - BACKGROUND: Various approaches to calling single-nucleotide variants (SNVs) or insertion-or-deletion (indel) mutations have been developed based on next generation sequencing (NGS). However, most of them are dedicated to a particular type of mutation, e.g. germline SNVs in normal cells, somatic SNVs in cancer/tumor cells, or indels only. In the literature, efficient and integrated callers for both germline and somatic SNVs/indels have not yet been extensively investigated. RESULTS: We present SNVSniffer, an efficient and integrated caller identifying both germline and somatic SNVs/indels from NGS data. In this algorithm, we propose the use of Bayesian probabilistic models to identify SNVs and investigate a multiple ungapped alignment approach to call indels. For germline variant calling, we model allele counts per site to follow a multinomial conditional distribution. For somatic variant calling, we rely on paired tumor normal pairs from identical individuals and introduce a hybrid subtraction and joint sample analysis approach by modeling tumor-normal allele counts per site to follow a joint multinomial conditional distribution. A comprehensive performance evaluation has been conducted using a diversity of variant calling benchmarks. For germline variant calling, SNVSniffer demonstrates highly competitive accuracy with superior speed in comparison with the state-of-the-art FaSD, GATK and SAMtools. For somatic variant calling, our algorithm achieves comparable or even better accuracy, at fast speed, than the leading VarScan2, SomaticSniper, JointSNVMix2 and MuTect. CONCLUSIONS: SNVSniffers demonstrates the feasibility to develop integrated solutions to fast and efficient identification of germline and somatic variants. Nonetheless, accurate discovery of genetic variations is critical yet challenging, and still requires substantially more research efforts being devoted. SNVSniffer and synthetic samples are publicly available at http://snvsniffer.sourceforge.net . PMID- 27489957 TI - Thoracoamniotic Shunts in Macrocystic Lung Lesions: Case Series and Review of the Literature. AB - OBJECTIVE: To evaluate the efficiency of thoracoamniotic shunts for drainage of macrocystic-type congenital cystic adenomatoid malformation (CCAM). SUBJECTS AND METHODS: This was a retrospective study of 12 fetuses with a large thoracic cyst treated with thoracoamniotic shunting between 2004 and 2014 in a tertiary fetal therapy center. Medline was searched to identify cases of CCAM treated with thoracoamniotic shunting. RESULTS: In all cases the thoracic cyst was associated with major mediastinal shift, the CCAM volume ratio (CVR) was >1.6, and in eight cases there was associated hydrops. Shunt insertion was successfully carried out in all cases at a median gestational age of 24 weeks (range 18-34). In 10 cases there was live birth at a median age of 38 weeks (range 35-41), but in two hydropic fetuses there was intrauterine death. A literature search identified a total of 98 fetuses with CCAM treated with thoracoamniotic shunting between 1987 and 2016. In the combined data from the previous and the current study, the survival rate was 77% (53 of 69) for hydropic and 90% (37 of 41) for nonhydropic fetuses. CONCLUSIONS: The role of thoracoamniotic shunting in macrocystic lung lesions associated with hydrops is well accepted. Intrauterine intervention is also likely to be beneficial in the subgroup of nonhydropic fetuses with a CVR >1.6. PMID- 27489956 TI - Comparison of Brachyspira hyodysenteriae Isolates Recovered from Pigs in Apparently Healthy Multiplier Herds with Isolates from Herds with Swine Dysentery. AB - Swine dysentery (SD) is a mucohaemorrhagic colitis of grower/finisher pigs classically resulting from infection by the anaerobic intestinal spirochaete Brachyspira hyodysenteriae. This study aimed to determine whether B. hyodysenteriae isolates from pigs in three healthy German multiplier herds supplying gilts to other farms differed from isolates from nine German production herds with SD. Isolates were subjected to whole genomic sequencing, and in silico multilocus sequence typing showed that those from the three multiplier herds were of previously undescribed sequence types (ST132, ST133 and ST134), with all isolates from the same herd having the same ST. All isolates were examined for the presence of 332 genes encoding predicted virulence or virulence lifestyle associated factors, and these were well conserved. Isolates from one multiplier herd were atypical in being weakly haemolytic: they had 10 amino acid substitutions in the haemolysin III protein and five in the haemolysin activation protein compared to reference strain WA1, and had a disruption in the promoter site of the hlyA gene. These changes likely contribute to the weakly haemolytic phenotype and putative lack of virulence. These same isolates also had nine base pair insertions in the iron metabolism genes bitB and bitC and lacked five of six plasmid genes that previously have been associated with colonisation. Other overall differences between isolates from the different herds were in genes from three of five outer membrane proteins, which were not found in all the isolates, and in members of a block of six plasmid genes. Isolates from three herds with SD had all six plasmid genes, while isolates lacking some of these genes were found in the three healthy herds-but also in isolates from six herds with SD. Other differences in genes of unknown function or in gene expression may contribute to variation in virulence; alternatively, superior husbandry and better general health may have made pigs in the two multiplier herds colonised by "typical" strongly haemolytic isolates less susceptible to disease expression. PMID- 27489959 TI - Scale and Sampling Effects on Floristic Quality. AB - Floristic Quality Assessment (FQA) is increasingly influential for making land management decisions, for directing conservation policy, and for research. But, the basic ecological properties and limitations of its metrics are ill defined and not well understood-especially those related to sample methods and scale. Nested plot data from a remnant tallgrass prairie sampled annually over a 12-year period, were used to investigate FQA properties associated with species detection rates, species misidentification rates, sample year, and sample grain/area. Plot size had no apparent effect on Mean C (an area's average Floristic Quality level), nor did species detection levels above 65% detection. Simulated species misidentifications only affected Mean C values at greater than 10% in large plots, when the replaced species were randomly drawn from the broader county-wide species pool. Finally, FQA values were stable over the 12-year study, meaning that there was no evidence that the metrics exhibit year effects. The FQA metric Mean C is demonstrated to be robust to varied sample methodologies related to sample intensity (plot size, species detection rate), as well as sample year. These results will make FQA measures even more appealing for informing land-use decisions, policy, and research for two reasons: 1) The sampling effort needed to generate accurate and consistent site assessments with FQA measures is shown to be far lower than what has previously been assumed, and 2) the stable properties and consistent performance of metrics with respect to sample methods will allow for a remarkable level of comparability of FQA values from different sites and datasets compared to other commonly used ecological metrics. PMID- 27489960 TI - Correction: Metastases and Colon Cancer Tumor Growth Display Divergent Responses to Modulation of Canonical WNT Signaling. AB - [This corrects the article DOI: 10.1371/journal.pone.0150697.]. PMID- 27489961 TI - Ambient Engineering for High-Performance Organic-Inorganic Perovskite Hybrid Solar Cells. AB - Considering the evaporation of solvents during fabrication of perovskite films, the organic ambience will present a significant influence on the morphologies and properties of perovskite films. To clarify this issue, various ambiences of N,N dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and chlorobenzene (CBZ) are introduced during fabrication of perovskite films by two-step sequential deposition method. The results reveal that an ambient CBZ atmosphere is favorable to control the nucleation and growth of CH3NH3PbI3 grains while the others present a negative effect. The statistical results show that the average efficiencies of perovskite solar cells processed in an ambient CBZ atmosphere can be significantly improved by a relatively average value of 35%, compared with those processed under air. The efficiency of the best perovskite solar cells can be improved from 10.65% to 14.55% by introducing this ambience engineering technology. The CH3NH3PbI3 film with large-size grains produced in an ambient CBZ atmosphere can effectively reduce the density of grain boundaries, and then the recombination centers for photoinduced carriers. Therefore, a higher short circuit current density is achieved, which makes main contribution to the improvement in efficiency. These results provide vital progress toward understanding the role of ambience in the realization of highly efficient perovskite solar cells. PMID- 27489958 TI - Fzd4 Haploinsufficiency Delays Retinal Revascularization in the Mouse Model of Oxygen Induced Retinopathy. AB - Mutations in genes that code for components of the Norrin-FZD4 ligand-receptor complex cause the inherited childhood blinding disorder familial exudative vitreoretinopathy (FEVR). Statistical evidence from studies of patients at risk for the acquired disease retinopathy of prematurity (ROP) suggest that rare polymorphisms in these same genes increase the risk of developing severe ROP, implying that decreased Norrin-FZD4 activity predisposes patients to more severe ROP. To test this hypothesis, we measured the development and recovery of retinopathy in wild type and Fzd4 heterozygous mice in the absence or presence of ocular ischemic retinopathy (OIR) treatment. Avascular and total retinal vascular areas and patterning were determined, and vessel number and caliber were quantified. In room air, there was a small delay in retinal vascularization in Fzd4 heterozygous mice that resolved as mice reached maturity suggestive of a slight defect in retinal vascular development. Subsequent to OIR treatment there was no difference between wild type and Fzd4 heterozygous mice in the vaso obliterated area following exposure to high oxygen. Importantly, after return of Fzd4 heterozygous mice to room air subsequent to OIR treatment, there was a substantial delay in retinal revascularization of the avascular area surrounding the optic nerve, as well as delayed vascularization toward the periphery of the retina. Our study demonstrates that a small decrease in Norrin-Fzd4 dependent retinal vascular development lengthens the period during which complications from OIR could occur. PMID- 27489964 TI - The Applicability of Plantar Padding in Reducing Peak Plantar Pressure in the Forefeet of Healthy AdultsImplications for the Foot at Risk. AB - BACKGROUND: We investigated the effectiveness and durability of two types of plantar padding, the plantar metatarsal pad and the single wing plantar cover, which are commonly used for reducing forefoot plantar pressures. METHODS: Mean peak plantar pressure and impulse at the hallux and at the first, second, third, and fourth metatarsophalangeal joints across both feet were recorded using the two-step method in 18 individuals with normal asymptomatic feet. Plantar paddings were retained for 5 days, and their durability and effectiveness were assessed by repeating the foot plantar measurement at baseline and after 3 and 5 days. RESULTS: The single wing plantar cover devised from 5-mm felt adhesive padding was effective and durable in reducing peak plantar pressure and impulse at the first metatarsophalangeal joint (P = .001 and P = .015, respectively); however, it was not found to be effective in reducing peak plantar pressure and impulse at the hallux (P = .782 and P = .845, respectively). The plantar metatarsal pad was not effective in reducing plantar forefoot pressure and impulse at the second, third, and fourth metatarsophalangeal joints (P = .310 and P = .174, respectively). CONCLUSIONS: These results imply limited applicability of the single wing plantar cover and the plantar metatarsal pad in reducing hallux pressure and second through fourth metatarsophalangeal joint pressure, respectively. However, the single wing plantar cover remained durable for the 5 days of the trial and was effective in reducing the peak plantar pressure and impulse underneath the first metatarsophalangeal joint. PMID- 27489966 TI - Effect of Asymmetrical Load Carrying on Joint Kinetics of the Lower Extremity During Walking in High-Heeled Shoes in Young Women. AB - BACKGROUND: Carrying a load asymmetrically and walking in high-heeled shoes are common in women. Knowledge of the effects of the two combined conditions on lower limb kinetics is lacking. We sought to examine the effects of walking in high heeled shoes and carrying an asymmetrical load on the joint kinetics of the lower extremity in young women. METHODS: Fifteen participants were asked to walk in flat-heeled and 9-cm high-heeled shoes and to asymmetrically carry loads of 0% body weight (BW), 5% BW, and 10% BW. The three-dimensional joint moments of the hip, knee, and ankle in each of the walking conditions were studied through ground reaction force measurements and motion analysis. RESULTS: Walking in high heeled shoes and asymmetrically carrying a load of 5% or 10% BW resulted in significant differences in ankle joint moments of the loaded and unloaded lower limbs. Compared with walking in flat-heeled shoes, walking in high-heeled shoes and carrying a load asymmetrically significantly increased hip extension, hip abduction, knee extension, and knee adduction moments and decreased ankle plantar moment of the loaded leg. Walking in high-heeled shoes carrying a load of 10% BW resulted in greater significant changes in hip abduction, knee extension, and ankle dorsiflexion moments in the loaded leg than did carrying a load of 5% BW. CONCLUSIONS: These findings indicate that walking in high-heeled shoes and asymmetrical load carrying create significant differences in joint loading between the two limbs and alter lower-extremity kinetics. PMID- 27489962 TI - An Optimized Small Tissue Handling System for Immunohistochemistry and In Situ Hybridization. AB - Recent development in 3D printing technology has opened an exciting possibility for manufacturing 3D devices on one's desktop. We used 3D modeling programs to design 3D models of a tissue-handling system and these models were "printed" in a stereolithography (SLA) 3D printer to create precision histology devices that are particularly useful to handle multiple samples with small dimensions in parallel. Our system has been successfully tested for in situ hybridization of zebrafish embryos. Some of the notable features include: (1) A conveniently transferrable chamber with 6 mesh-bottomed wells, each of which can hold dozens of zebrafish embryos. This design allows up to 6 different samples to be treated per chamber. (2) Each chamber sits in a well of a standard 6-well tissue culture plate. Thus, up to 36 different samples can be processed in tandem using a single 6 well plate. (3) Precisely fitting lids prevent solution evaporation and condensation, even at high temperatures for an extended period of time: i.e., overnight riboprobe hybridization. (4) Flat bottom mesh maximizes the consistent treatment of individual tissue samples. (5) A magnet-based lifter was created to handle up to 6 chambers (= 36 samples) in unison. (6) The largely transparent resin aids in convenient visual inspection both with eyes and using a stereomicroscope. (7) Surface engraved labeling enables an accurate tracking of different samples. (8) The dimension of wells and chambers minimizes the required amount of precious reagents. (9) Flexible parametric modeling enables an easy redesign of the 3D models to handle larger or more numerous samples. Precise dimensions of 3D models and demonstration of how we use our devices in whole mount in situ hybridization are presented. We also provide detailed information on the modeling software, 3D printing tips, as well as 3D files that can be used with any 3D printer. PMID- 27489965 TI - Treatment of Ingrown Toenail with a Shape Memory Alloy Device. AB - BACKGROUND: We sought to report the clinical results of a new conservative treatment modality that uses a shape memory alloy device in patients with ingrown toenail. METHODS: A retrospective review was performed on 41 patients with ingrown toenail treated with the K-D device (S&C Biotech, Seoul, South Korea) between April 2013 and July 2014. Recurrence rate, cosmetic results, pain during the treatment period, and patient satisfaction were the major outcome measures. RESULTS: Patients were followed for at least 6 months (mean +/- SD, 8.6 +/- 2.1 months; range, 6-12 months). Recurrence was seen in eight patients (19.5%). Mean time to recurrence was 6.2 months (range, 3-10 months). Thirty-one patients (75.6%) were satisfied with the treatment. Thirty-five patients (85.4%) rated the application and treatment period as painless, and the remaining six (14.6%) noted pain particularly during shoe wearing. Thirty-one patients (75.6%) rated the cosmetic results as "excellent," four (9.8%) as "acceptable," and six (14.6%) as "poor." Satisfaction with the treatment, the cosmetic results, and pain were significantly worse in patients with recurrence (P = .0001 for all). All of the patients returned to their work immediately after application of the device. No complications occurred. CONCLUSIONS: The K-D device is a safe and effective treatment method for ingrown toenail. Although the recurrence rate is higher than for surgical treatment methods, the K-D device is a practical and painless method that provides immediate return to work and daily activities and excellent or acceptable cosmesis in most patients. PMID- 27489963 TI - Meltwater export of prokaryotic cells from the Greenland ice sheet. AB - Microorganisms are flushed from the Greenland Ice Sheet (GrIS) where they may contribute towards the nutrient cycling and community compositions of downstream ecosystems. We investigate meltwater microbial assemblages as they exit the GrIS from a large outlet glacier, and as they enter a downstream river delta during the record melt year of 2012. Prokaryotic abundance, flux and community composition was studied, and factors affecting community structures were statistically considered. The mean concentration of cells exiting the ice sheet was 8.30 * 104 cells mL-1 and we estimate that ~1.02 * 1021 cells were transported to the downstream fjord in 2012, equivalent to 30.95 Mg of carbon. Prokaryotic microbial assemblages were dominated by Proteobacteria, Bacteroidetes, and Actinobacteria. Cell concentrations and community compositions were stable throughout the sample period, and were statistically similar at both sample sites. Based on our observations, we argue that the subglacial environment is the primary source of the river-transported microbiota, and that cell export from the GrIS is dependent on discharge. We hypothesise that the release of subglacial microbiota to downstream ecosystems will increase as freshwater flux from the GrIS rises in a warming world. PMID- 27489967 TI - Normal Values of Pressures and Foot Areas Measured in the Static Condition. AB - BACKGROUND: Podiatric physicians are increasingly using pedobarographs to measure plantar pressure. However, normal values of static pedobarographic variables for healthy men and women are lacking, which makes it difficult to evaluate abnormal foot positioning in standing patients with low- or high-arched feet or painful feet. METHODS: During upright standing, a computerized pedobarograph measured the maximal (Pmax) and mean (Pmean) plantar pressures, total foot area, and forefoot and rearfoot areas in 84 healthy women and 84 healthy men, aged 18 to 83 years. After calibration of the pedobarograph, a correction factor was applied to area measurements, and data repeatability was assessed. RESULTS: The Pmax and Pmean values were not correlated with age but with weight, body mass index, and shoe size. Total foot area was significantly higher in male participants and correlated with body weight, body mass index, and shoe size but not with age. In both sexes, forefoot area was significantly lower than rearfoot area. Significant positive correlations were observed between forefoot and rearfoot areas and weight and shoe size. The forefoot-rearfoot area ratio did not vary with sex, weight, shoe size, and age. CONCLUSIONS: These data provide relationships between Pmax, Pmean, and foot areas and weight and shoe size and clearly indicate no age dependence of pedobarographic data. They also provide stable values of the forefoot-rearfoot area ratio. These data should help clinicians evaluate abnormal foot placement in standing patients. PMID- 27489969 TI - Surgical Reconstruction of the Forefoot with Hallux Valgus Associated with Metatarsus Adductus. AB - Metatarsus adductus is a structural deformity that may be associated with hallux valgus and that may lead to metatarsal pain and functional abnormality of the foot. Correcting hallux valgus is complicated in these cases because of the deviation in adduction of the lesser metatarsals, especially the second metatarsal that occupies the first intermetatarsal space. We report the case of a 49-year-old man who underwent a scarf osteotomy in the first metatarsal, shortening and abductor oblique distal osteotomies of the lesser metatarsals, and arthrodesis of the central toes with Z-lengthening of the capsule and long extensor tendons of the toes. PMID- 27489968 TI - Synovial Sarcoma in the Foot of a 5-Year-Old ChildA Case Report. AB - The purpose of this case report is to present a rare finding of synovial sarcoma in a 5-year-old child. Most soft-tissue masses of the foot are too often presumed to be small and benign; therefore, compared with soft-tissue sarcomas, they are difficult to clinically differentiate and treat. A 5-year-old girl presented with a painful lesion that was diagnosed as synovial sarcoma after an excisional biopsy was performed. This was an unexpected finding of synovial sarcoma involving the tibialis posterior tendon of her right foot. The patient presented with an 8-month history of tenderness and an antalgic gait. We would like to encourage that all soft-tissue tumors of the foot be preoperatively evaluated with the aid of diagnostic imaging so that a well-planned biopsy assessment can be performed, with adequate margins excised. PMID- 27489971 TI - Erratum. PMID- 27489970 TI - Charcot's Neuroarthropathy After Simultaneous Pancreas-Kidney TransplantA Case Report. AB - Simultaneous pancreas-kidney transplant (SPKT) is an accepted approach and the treatment of choice in patients with type 1 diabetes with accompanying end-stage renal disease. Charcot's neuroarthropathy of the foot (CN) is a fairly common and devastating complication found in patients with long-standing, mostly uncontrolled, diabetes. However, CN has also been identified as a posttransplant consequence of SPKT. Traditional postoperative immunosuppressive therapy, particularly the use of corticosteroids, is acknowledged as an additional risk factor for the development of de novo CN after SPKT. This article describes an unusual case of a patient who presented with full-blown CN deformity after SPKT. PMID- 27489972 TI - A Novel Method of Quantifying Gait Deviations Using Plantar Pressure Patterns. AB - BACKGROUND: Comparing the dynamic pedobarographic patterns of individuals is common practice in basic and applied research. However, this process is often time-consuming and complex, and commercially available software often lacks powerful visualization and interpretation tools. METHODS: We propose a simple method for displaying pixel-level pedobarographic deviations over time relative to a so-called reference pedobarographic pattern. This novel method contains four distinct automated preprocessing stages: 1) normalization of pedobarographic fields (for foot length and width), 2) temporal normalization, 3) a pixel-level z score-based calculation, and 4) color coding of the normalized pedobarographic fields. Group and patient-level comparisons were illustrated using an experimental data set including diabetic and nondiabetic patients. RESULTS: The automated procedure was found to be robust and quantified distinct temporal deviations in pedobarographic fields. CONCLUSIONS: The advantages of the novel method cover several domains, including visualization, interpretation, and education. PMID- 27489973 TI - "Pilot Hole" Technique for Interphalangeal Joint Fusion of Toes. AB - Fusion of an interphalangeal joint of a lesser toe is a commonly used procedure for addressing interphalangeal joint deformities such as a hammer or a claw toe. Fusion can be achieved by insertion of an intramedullary Kirschner wire in a retrograde manner. Deviation of the Kirschner wire from the intramedullary canal into the surrounding soft tissues is common. This can render the fusion unstable and can cause painful soft-tissue irritation and early Kirschner wire loosening, resulting in an unstable nonunion with recurrence of deformity. We describe a simple and reproducible technique to assist with optimal intramedullary placement of the Kirschner wire, thereby reducing the risk of complications after interphalangeal joint fusion of a toe. PMID- 27489974 TI - Building Effective Partnerships Between Vascular Surgeons and Podiatric Physicians in the Effective Management of Diabetic Foot Ulcers. AB - Both vascular surgeons and podiatric physicians care for patients with diabetic foot ulcerations (DFUs), one of today's most challenging health-care populations in the United States. The prevalence of DFUs has steadily increased, along with the rising costs associated with care. Because of the numerous comorbidities affecting these patients, it is necessary to take a multidisciplinary approach in the management of these patients. Such efforts, primarily led by podiatric physicians and vascular surgeons, have been shown to effectively decrease major limb loss. Establishing an interprofessional partnership between vascular surgery and podiatric medicine can lead to an improvement in the delivery of care and outcomes of this vulnerable patient population. PMID- 27489975 TI - Working Our Plan. PMID- 27489980 TI - In Situ Investigations of Laser-Generated Ligand-Free Platinum Nanoparticles by X ray Absorption Spectroscopy: How Does the Immediate Environment Influence the Particle Surface? AB - Pulsed laser ablation in liquid (PLAL) has proven its usefulness as a nanoparticle (NP) synthesis method alternative to traditional chemical reduction methods, where the absence of any molecular ligands or residual reactants makes laser-generated nanoparticles ideal reference materials for charge-transfer experiments. We synthesized additive-free platinum nanoparticles by PLAL and in situ characterized their interaction with H2O, sodium phosphate buffer, and sodium citrate as well as a TiO2 support by X-ray absorption fine structure (XAFS), i.e., X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS). Differences in the white-line intensity among the colloidal particles in the three liquids indicate that the respective NP solvent interaction varies in strength. The ions added ex situ diffuse through the particles' electric double layer and interact electrostatically with the Stern plane. Consequently, these ions weaken the interaction of the functional OH groups that are bound to the partially oxidized platinum surfaces and cause their partial reduction. Comparing XAFS spectra of laser-generated Pt NPs in citrate with wet-chemically synthesized ones (both ligand-covered) indicates different types of Pt-O bonds: a Pt(IV)O2 type in the case of wet-chemical NPs and a Pt(II)O type in the case of laser-generated NPs. A comparison of unsupported laser-generated platinum NPs in H2O with TiO2-supported ones shows no white-line intensity differences and also an identical number of Pt-O bonds in both cases. This suggests that in the deposition process at least part of the double-layer coating stays intact and that the ligand-free Pt particle properties are preserved in the TiO2-supported Pt particles, relevant for heterogeneous catalysis. PMID- 27489981 TI - Beat-to-beat T-wave alternans detection using the Ensemble Empirical Mode Decomposition method. AB - BACKGROUND: T-wave alternans (TWA) is defined as a consistent variation in the repolarization morphology that repeats on every other beat. This study aimed to evaluate beat-to-beat TWA detection using the Ensemble EMD (EEMD) method. METHOD: A total of 108 recordings of standard 12-lead ECGs of 69 healthy subjects (17 females, 42+/-18 years; 52 males, 40+/-13 years) and 39 cardiac-condition patients (ischemic cardiomyopathy; ICM and dilated cardiomyopathy; DCM) with left ventricular ejection fractions (LVEF) <=40% were studied. We first determined the QT interval of ECG via a template matching algorithm. Then, beat-to-beat T-waves were extracted to quantify beat-to-beat TWA. The EEMD method was applied to the T wave time series to decompose them into a set of intrinsic mode functions (IMFs). The instantaneous frequency was measured by performing the Hilbert transform on the selected IMF for extracting the features. Four different classifiers were applied to the extracted features to assess and classify the existence of TWA in the ECG signal. RESULTS: In the simulation study, the global classifier worked better than the subject-based classifier for detecting alternans in the T-waves. In addition, the average accuracy and sensitivity for detecting TWA were greater than 80%. In the real Holter ECG data obtained from Toronto General Hospital, the Ensemble classifier had higher classification accuracy, 74%, than other classifiers and a positive predictive value of 100%. CONCLUSION: In conclusion, the proposed Ensemble EMD method with Ensemble classifier can be utilized for detecting beat-to-beat TWA in the ECG signal. PMID- 27489982 TI - Venous thromboembolism in patients with hematologic malignancy and thrombocytopenia. AB - The optimal management of hematologic malignancy-associated venous thromboembolism (VTE) in patients with moderate-to-severe thrombocytopenia is unclear. This is a retrospective study of 128 adult patients with hematologic malignancies who were diagnosed with VTE. The outcome of patients with significant thrombocytopenia (<=50,000/uL) was compared with those without. Forty seven patients (36.7%) had a platelet count <=50,000/uL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 10,000/uL (range 2,000 45,000/uL) versus 165,000/uL (50,000-429,000/uL) in those without (P < 0.001). The median duration of significant thrombocytopenia in the first group was 10 days (1-35 days). Therapy during the period of significant thrombocytopenia included prophylactic-dose low-molecular-weight heparin (LMWH) (47%), therapeutic dose LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%), and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At a median follow-up of more than 2 years, the risk of clinically significant bleeding (11% vs 6%, P = 0.22) including major bleeding (6% vs 2%) and clot progression or recurrence (21% vs 22%, P = 1.00) were similar in patients with or without significant thrombocytopenia. In a multivariate analysis, the risk of recurrence/progression (hazard ratio, HR 0.59, 95% CI 0.21 1.66, P = 0.31) and hemorrhage rate (HR 0.29, 95% CI 0.05-1.56, P = 0.15) did not differ based on the presence of significant thrombocytopenia. Within the limits of this retrospective study, cautious use of prophylactic-dose LMWH may be safe in thrombocytopenic patients with hematologic malignancy-associated VTE. Am. J. Hematol. 91:E468-E472, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27489983 TI - Elevated FGF 21 in myotonic dystrophy type 1 and mitochondrial diseases. AB - INTRODUCTION: Human fibroblast growth factor 21 (FGF21) is a regulator of lipid and glucose metabolism. It is expressed in skeletal muscle and may be a sensitive and specific marker for mitochondrial diseases and other neuromuscular disorders. METHODS: Serum FGF21 levels were determined in 71 human samples. Thirty patients with mitochondrial disease, 16 patients with myotonic dystrophy type 1 (DM1), 5 patients with facioscapulohumeral dystrophy, and 20 healthy controls were enrolled. Results Serum FGF21 levels were significantly elevated in patients with progressive external ophthalmoplegia and DM1 compared with patients with facioscapulohumeral dystrophy, other types of mitochondrial diseases, and controls. In the mitochondrial disorder group, serum FGF21 levels were related to the number of ragged blue fibers. Significant insulin resistance was found in DM1 that might be responsible for FGF21 elevation. Conclusions FGF21 elevation may be associated with certain types of mitochondrial disease, and it is influenced by insulin resistance. Muscle Nerve 55: 564-569, 2017. PMID- 27489985 TI - Creative method of removing a giant fibrovascular polyp under endoscopic guidance. PMID- 27489984 TI - Endoscopic esophageal perforation extending upwards along the carotid arteries. PMID- 27489987 TI - Bilateral adrenal tuberculosis diagnosed by endoscopic ultrasound-guided fine needle aspiration cytology. PMID- 27489988 TI - Augmented endoscopic resection for fibrotic or recurrent colonic polyps using an ablation and cold avulsion technique. PMID- 27489989 TI - A novel endoscopic technique for closure of a large esophageal perforation using the clip-and-snare method with the prelooping technique. PMID- 27489986 TI - Endoscopic septotomy of a magnet-induced neoseptum in a large mid-esophageal diverticulum. PMID- 27489991 TI - A large delayed esophageal perforation due to chicken bone impaction treated by over-the-scope clipping. PMID- 27489990 TI - Novel technique to relax the lower esophageal sphincter during challenging peroral endoscopic myotomy (POEM). PMID- 27489992 TI - Single-step endoscopic ultrasound-guided fluoroless gallbladder drainage using the Axios lumen-apposing metal stent. PMID- 27489993 TI - Submucosal tunneling endoscopic resection for leiomyomas located on opposite esophageal walls: the role of a tortuous submucosal tunnel. PMID- 27489994 TI - Closure of an intestinal perforation with an autologous fat plug in a man with Crohn's disease. PMID- 27489995 TI - A novel clip-assisted method for endoscopic removal of an impacted toothpick from the colon. PMID- 27489996 TI - Esophageal post-inflammatory polyposis in extensive and severe Crohn's disease treated with anti-tumor necrosis factor alpha. PMID- 27489997 TI - Quantitative assessment of a spatial multicriteria model for highly pathogenic avian influenza H5N1 in Thailand, and application in Cambodia. AB - The Highly Pathogenic Avian Influenza H5N1 (HPAI) virus is now considered endemic in several Asian countries. In Cambodia, the virus has been circulating in the poultry population since 2004, with a dramatic effect on farmers' livelihoods and public health. In Thailand, surveillance and control are still important to prevent any new H5N1 incursion. Risk mapping can contribute effectively to disease surveillance and control systems, but is a very challenging task in the absence of reliable disease data. In this work, we used spatial multicriteria decision analysis (MCDA) to produce risk maps for HPAI H5N1 in poultry. We aimed to i) evaluate the performance of the MCDA approach to predict areas suitable for H5N1 based on a dataset from Thailand, comparing the predictive capacities of two sources of a priori knowledge (literature and experts), and ii) apply the best method to produce a risk map for H5N1 in poultry in Cambodia. Our results showed that the expert-based model had a very high predictive capacity in Thailand (AUC = 0.97). Applied in Cambodia, MCDA mapping made it possible to identify hotspots suitable for HPAI H5N1 in the Tonle Sap watershed, around the cities of Battambang and Kampong Cham, and along the Vietnamese border. PMID- 27489999 TI - Arhgef1 negatively regulates neurite outgrowth through activation of RhoA signaling pathways. AB - Neurite outgrowth is essential for the establishment of functional neuronal connections during brain development. This study identifies that Arhgef1 is predominantly expressed in early neuronal developmental stages and negatively regulates neurite outgrowth. Knockdown of Arhgef1 in either Neuro-2a cells or primary cortical neurons leads to excess growth of neurites, whereas overexpression of Arhgef1 prominently restricts neurite formation. Arhgef1 strongly activates RhoA activity while concomitantly inhibits Rac1 and Cdc42 activities. Pharmacological blockade of RhoA activity restores normal neurite outgrowth in Arhgef1-overexpressed neurons. Importantly, Arhgef1 promotes F-actin polymerization in neurons, probably through inhibiting the activity of the actin depolymerizing factor cofilin. Collectively, these findings reveal that Arhgef1 functions as a negative regulator of neurite outgrowth through regulating RhoA cofilin pathway and actin dynamics. PMID- 27489998 TI - Oryzamides A-E, Cyclodepsipeptides from the Sponge-Derived Fungus Nigrospora oryzae PF18. AB - Three new cyclohexadepsipeptides, oryzamides A-C (1-3), two isolation artifacts, oryzamides D (4) and E (5), and the known congener scopularide A (6), all possessing a rare 3-hydroxy-4-methyldecanoic acid (HMDA) substructure, were isolated from the mycelial extract of the sponge-derived fungus Nigrospora oryzae PF18. Their planar structures were elucidated by spectroscopic analysis and comparison with the literature data. The absolute configurations were determined using the advanced Marfey's method and single-crystal X-ray diffraction analysis. Among them, oryzamides D (4) and E (5) were a pair of diastereomers at the sulfur atom of the l-methionine sulfoxide residue, which showcased the possible separation of a pair of methionine sulfoxide diastereomers. The X-ray crystal structure of scopularide A (6) was obtained for the first time, thereby establishing its relative and absolute configuration at C-4 of the HMDA residue. Oryzamides A-C (1-3) did not display cytotoxic, antibacterial, antiparasitic, and NF-kappaB inhibitory activities. PMID- 27490002 TI - Motion of tympanic membrane in guinea pig otitis media model measured by scanning laser Doppler vibrometry. AB - Otitis media (OM) is an inflammatory or infectious disease of the middle ear. Acute otitis media (AOM) and otitis media with effusion (OME) are the two major types of OM. However, the tympanic membrane (TM) motion differences induced by AOM and OME have not been quantified in animal models in the literature. In this study, the guinea pig AOM and OME models were created by transbullar injection of Streptococcus pneumoniae type 3 and lipopolysaccharide, respectively. To explore the effects of OM on the entire TM vibration, the measurements of full-field TM motions were performed in the AOM, OME and untreated control ears by using scanning laser Doppler vibrometry (SLDV). The results showed that both AOM and OME generally reduced the displacement peak and produced the traveling-wave-like motions at relatively low frequencies. Compared with the normal ear, OME resulted in a significant change of the TM displacement mainly in the inferior portion of the TM, and AOM significantly affected the surface motion across four quadrants. The SLDV measurements provide more insight into sound-induced TM vibration in diseased ears. PMID- 27490004 TI - Disaster Management Response Guidelines for Departments of Orthopaedic Surgery. AB - Complacency and lack of preparation are major barriers to an effective disaster response. Leadership assignments and departmental organization for a response should be outlined in advance. Response rehearsal and after-action reviews allow for thoughtful change to a response plan. Hospital disaster alert notification systems should be standardized and should be understood. Communication systems used in a disaster should have redundancy. A department's response plan must be integrated into the overall hospital plan. Large casualty volumes require appropriate triage and resource allocation. Response provider emotional and health support is an important consideration. PMID- 27490003 TI - Drug-eluting balloon angioplasty versus uncoated balloon angioplasty for peripheral arterial disease of the lower limbs. AB - BACKGROUND: Atherosclerotic peripheral arterial disease (PAD) can lead to disabling ischemia and limb loss. Treatment modalities have included risk factor optimization through life-style modifications and medications, or operative approaches using both open and minimally invasive techniques, such as balloon angioplasty. Drug-eluting balloon (DEB) angioplasty has emerged as a promising alternative to uncoated balloon angioplasty for the treatment of this difficult disease process. By ballooning and coating the inside of atherosclerotic vessels with cytotoxic agents, such as paclitaxel, cellular mechanisms responsible for atherosclerosis and neointimal hyperplasia are inhibited and its devastating complications are prevented or postponed. DEBs are considerably more expensive than uncoated balloons, and their efficacy in improving patient outcomes is unclear. OBJECTIVES: To assess the efficacy of drug-eluting balloons (DEBs) compared with uncoated, nonstenting balloon angioplasty in people with symptomatic lower-limb peripheral arterial disease (PAD). SEARCH METHODS: The Cochrane Vascular Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched December 2015) and Cochrane Register of Studies (CRS) (2015, Issue 11). The TSC searched trial databases for details of ongoing and unpublished studies. SELECTION CRITERIA: We included all randomized controlled trials that compared DEBs with uncoated, nonstenting balloon angioplasty for intermittent claudication (IC) or critical limb ischemia (CLI). DATA COLLECTION AND ANALYSIS: Two review authors (AK, TA) independently selected the appropriate trials and performed data extraction, assessment of trial quality, and data analysis. The senior review author (DKR) adjudicated any disagreements. MAIN RESULTS: Eleven trials that randomized 1838 participants met the study inclusion criteria. Seven of the trials included femoropopliteal arterial lesions, three included tibial arterial lesions, and one included both. The trials were carried out in Europe and in the USA and all used the taxane drug paclitaxel in the DEB arm. Nine of the 11 trials were industry-sponsored. Four companies manufactured the DEB devices (Bard, Bavaria Medizin, Biotronik, and Medtronic). The trials examined both anatomic and clinical endpoints. There was heterogeneity in the frequency of stent deployment and the type and duration of antiplatelet therapy between trials. Using GRADE assessment criteria, the quality of the evidence presented was moderate for the outcomes of target lesion revascularization and change in Rutherford category, and high for amputation, primary vessel patency, binary restenosis, death, and change in ankle-brachial index (ABI). Most participants were followed up for 12 months, but one trial reported outcomes at five years.There were better outcomes for DEBs for up to two years in primary vessel patency (odds ratio (OR) 1.47, 95% confidence interval (CI) 0.22 to 9.57 at six months; OR 1.92, 95% CI 1.45 to 2.56 at 12 months; OR 3.51, 95% CI 2.26 to 5.46 at two years) and at six months and two years for late lumen loss (mean difference (MD) -0.64 mm, 95% CI -1.00 to -0.28 at six months; MD -0.80 mm, 95% CI -1.44 to -0.16 at two years). DEB were also superior to uncoated balloon angioplasty for up to five years in target lesion revascularization (OR 0.28, 95% CI 0.17 to 0.47 at six months; OR 0.40, 95% CI 0.31 to 0.51 at 12 months; OR 0.28, 95% CI 0.18 to 0.44 at two years; OR 0.21, 95% CI 0.09 to 0.51 at five years) and binary restenosis rate (OR 0.44, 95% CI 0.29 to 0.67 at six months; OR 0.38, 95% CI 0.15 to 0.98 at 12 months; OR 0.26, 95% CI 0.10 to 0.66 at two years; OR 0.12, 95% CI 0.05 to 0.30 at five years). There was no significant difference between DEB and uncoated angioplasty in amputation, death, change in ABI, change in Rutherford category and quality of life (QoL) scores, or functional walking ability, although none of the trials were powered to detect a significant difference in these clinical endpoints. We carried out two subgroup analyses to examine outcomes in femoropopliteal and tibial interventions as well as in people with CLI (4 or greater Rutherford class), and showed no advantage for DEBs in tibial vessels at six and 12 months compared with uncoated balloon angioplasty. There was also no advantage for DEBs in CLI compared with uncoated balloon angioplasty at 12 months. AUTHORS' CONCLUSIONS: Based on a meta-analysis of 11 trials with 1838 participants, there is evidence of an advantage for DEBs compared with uncoated balloon angioplasty in several anatomic endpoints such as primary vessel patency (high-quality evidence), binary restenosis rate (moderate quality evidence), and target lesion revascularization (low-quality evidence) for up to 12 months. Conversely, there is no evidence of an advantage for DEBs in clinical endpoints such as amputation, death, or change in ABI, or change in Rutherford category during 12 months' follow-up. Well-designed randomized trials with long-term follow-up are needed to compare DEBs with uncoated balloon angioplasties adequately for both anatomic and clinical study endpoints before the widespread use of this expensive technology can be justified. PMID- 27490005 TI - Treatment of Proximal Humeral Fractures: A Critical Analysis Review. AB - There is substantial variability in the treatment of proximal humeral fractures because of classification systems with poor interobserver reliability, rapid advances in technology (e.g., anatomically designed locking plates and reverse shoulder arthroplasty), and limited Level-I and II evidence for best treatments based on fracture patterns and physiological age. Almost three-quarters of proximal humeral fractures can be treated nonoperatively with good functional results as nearly 50% are nondisplaced or Neer one-part fractures. Another quarter occur in infirm patients or are characterized by fracture patterns that reliably heal well with minimal complications. Displaced fractures in physiologically young patients should preferentially be treated with open reduction and internal fixation (ORIF) as functional outcomes are generally good and anatomical restoration can improve the results of subsequent arthroplasty, if needed. Improved results with fixation have been reported in association with the use of bone substitutes, fibular strut allografts, and inferior head-supporting calcar screws to prevent humeral head displacement and screw perforation. A number of recent trials have brought into question the advantage of both ORIF and hemiarthroplasty over nonoperative treatment for patients over the age of sixty years who have three and four-part fractures without dislocations. Reverse shoulder arthroplasty initially showed varied results for the treatment of irreparable fractures in healthy older patients, but recent Level-I and II studies have shown an advantage over hemiarthroplasty. Medium and long-term data are still needed. PMID- 27490006 TI - Wrong-Site Surgery in Orthopaedics: Prevalence, Risk Factors, and Strategies for Prevention. AB - The incidence of wrong-site surgery in orthopaedics is unknown. This is due to a lack of data regarding the exact numbers of surgical procedures performed and a lack of a uniform mandatory error reporting infrastructure. Twenty-one percent of hand surgeons, 50% of spinal surgeons, and 8.3% of knee surgeons surveyed have reported performing at least one wrong-site surgery during their career. Every orthopaedic surgeon, no matter his or her orthopaedic subspecialty, is at risk for completing a wrong-site surgery during his or her career. Prevention of wrong site surgery should remain a priority for the orthopaedic community. Surgeon leadership, commitment, and vigilance are critical to improve patient safety by ensuring that validated safety processes are used in all orthopaedic settings including effective surgical team communication, checklists, and routine collection and analysis of quality and safety data. PMID- 27490008 TI - Biological Risk Factors for Nonunion of Bone Fracture. AB - Many risk factors for fracture nonunion are well supported in the orthopaedic literature, including location of the fracture site, surgical treatment, bone displacement, type of fixation, treatment delay, comminution, inadequate treatment, and wound infection. However, evidence from a systematic review suggests that patient-related or biological causes of nonunion may not be as well understood. Understanding the biological causes of nonunion is important for several reasons. Risk factors might identify patients prone to nonunion who could benefit from more aggressive intervention, and a clear idea of nonunion risk could be important when choosing between competing therapeutic options. Risk factors also can inform the design of clinical trials and clarify patient inclusion and exclusion criteria, so that small studies can yield more definitive answers. Finally, an understanding of patient risk profiles may enable clinicians to counsel patients more effectively and to set appropriate expectations for success. Patient age appears to be a strong risk factor for nonunion in some bones, a weak risk factor for nonunion in other bones, and perhaps not a significant risk factor for nonunion in certain bones. This observation suggests that there can be substantial bone-to-bone variation in nonunion risk. Age also may be a surrogate for the prevalence of risk factors that potentially increase with age, such as smoking, diabetes, obesity, or nonsteroidal anti-inflammatory drug (NSAID) use. Smoking has been replicated as a risk factor for nonunion only in retrospective studies involving the humerus and tibia. Smoking appears to have an important effect on nonunion, yet the incremental risk may be rather small, except in context with additional risk factors. Diabetes has been confirmed as a risk factor for nonunion only in retrospective studies involving the foot and ankle. Nonunion risk from diabetes alone may be small and the context of additional risk factors crucial; this could account for why it has been so difficult to predict nonunion in the individual patient. Prediction of fracture nonunion in the individual patient is a difficult problem. Fracture nonunion may be influenced by complex interactions between biological and surgical risk factors, and the nonunion rate varies from bone to bone. A randomized clinical trial may not appropriately control for all potential correlates and confounders and may require impractical sample sizes. A large claims-based study of real world fracture-healing outcomes is needed to provide guidance for randomized clinical trials that can test risk factors more rigorously. PMID- 27490007 TI - Rehabilitation Following Anterior Cruciate Ligament Tears in Children: A Systematic Review. AB - BACKGROUND: Anterior cruciate ligament (ACL) tears are increasingly prevalent in the pediatric population. ACL rehabilitation is an essential component of recovery following injury and reconstruction, yet there are few explicit descriptions of pediatric-specific ACL rehabilitation protocols in the literature, especially in the context of varying treatment interventions. Our aim was to systematically review the literature on rehabilitation following ACL tears in children in order to describe common principles among different treatment options and areas of future research. METHODS: Using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we performed a systematic review of the PubMed, EMBASE, and Cochrane databases (for the past five years) to identify detailed rehabilitation protocols described in the pediatric population following ACL rupture. When available, the following aspects of rehabilitation were extracted: "prehabilitation" (exercises prior to surgery), bracing, weight-bearing status, range of motion, strength, modalities (ice, heat, electrical stimulation, etc.), plyometrics/proprioceptive exercises, return-to sport criteria, and suggested ACL injury-prevention programs. RESULTS: Two hundred and two unique articles were identified. Twenty-seven articles meeting inclusion criteria with extractible rehabilitation data were included. A table, categorized by differing orthopaedic intervention, was designed to detail the components and duration of the different aspects of rehabilitation. While there are substantial differences across protocols, several trends emerged, particularly regarding weight-bearing, bracing, range of motion, and strength training. Interestingly, we found that many current protocols are based on time frame alone rather than on functional milestones; of the fourteen unique articles that addressed return-to-sport criteria by specific orthopaedic intervention, seven were based on temporal progression whereas seven also involved achievement of physical milestones. In addition, only three of the eight articles that mentioned a future ACL injury-prevention plan described a formal prevention program. CONCLUSION: We systematically identified, and subsequently outlined and compared, the current trends of the various components of pediatric-specific ACL rehabilitation protocols, categorized by orthopaedic intervention. Several protocols are based on time frames rather than milestones achieved, with newer protocols involving milestone-based progression. Newer protocols are also incorporating formal prevention programs. Just as skeletally immature patients require unique methods of operative fixation, so too do they require catered rehabilitation protocols. To effectively prevent re-rupture or contralateral injury, future research should focus on prospectively evaluating each component of the rehabilitation protocols described and return-to-sport criteria for young patients. PMID- 27490001 TI - Evidence of activity-dependent plasticity in the dorsal cochlear nucleus, in vivo, induced by brief sound exposure. AB - The purpose of the present study was to investigate the immediate effects of acute exposure to intense sound on spontaneous and stimulus-driven activity in the dorsal cochlear nucleus (DCN). We examined the levels of multi- and single unit spontaneous activity before and immediately following brief exposure (2 min) to tones at levels of either 109 or 85 dB SPL. Exposure frequency was selected to either correspond to the units' best frequency (BF) or fall within the borders of its inhibitory side band. The results demonstrate that these exposure conditions caused significant alterations in spontaneous activity and responses to BF tones. The induced changes have a fast onset (minutes) and are persistent for durations of at least 20 min. The directions of the change were found to depend on the frequency of exposure relative to BF. Transient decreases followed by more sustained increases in spontaneous activity were induced when the exposure frequency was at or near the units' BF, while sustained decreases of activity resulted when the exposure frequency fell inside the inhibitory side band. Follow up studies at the single unit level revealed that the observed activity changes were found on unit types having properties which have previously been found to represent fusiform cells. The changes in spontaneous activity occurred despite only minor changes in response thresholds. Noteworthy changes also occurred in the strength of responses to BF tones, although these changes tended to be in the direction opposite those of the spontaneous rate changes. We discuss the possible role of activity-dependent plasticity as a mechanism underlying the rapid emergence of increased spontaneous activity after tone exposure and suggest that these changes may represent a neural correlate of acute noise-induced tinnitus. PMID- 27490010 TI - Stereodivergent Synthesis of Chromanones and Flavanones via Intramolecular Benzoin Reaction. AB - The strategy of stereodivergent reactions on racemic mixtures (stereodivergent RRM) was employed for the first time in intramolecular benzoin reactions and led to the rapid access of chromanones/flavanones with two consecutive stereocenters. The easily separable stereoisomers of the products were obtained with moderate to excellent enantioselectivities in a single step. Catechol type additives proved crucial in achieving the desired diastereo- and enantioselectivities. PMID- 27490015 TI - Treatment of Foot Deformities in Arthrogryposis Multiplex Congenita. PMID- 27490014 TI - Assessment and Treatment of Extensor Carpi Ulnaris Tendon Pathology: A Critical Analysis Review. PMID- 27490016 TI - Antifibrinolytic Therapy for Perioperative Blood Conservation in Lower-Extremity Primary Total Joint Arthroplasty. PMID- 27490009 TI - Morphological and dynamic contrast enhanced MR imaging features for the differentiation of chordoma and giant cell tumors in the Axial Skeleton. AB - PURPOSE: To characterize the morphological and dynamic-contrast-enhanced (DCE) MRI features of chordoma and giant cell tumor (GCT) of bone occurring in the axial skeleton. MATERIALS AND METHODS: A total of 13 patients with chordoma and 26 patients with GCT who received conventional T1, T2, and DCE-MRI on 3 Tesla MR scanners were retrospectively identified and analyzed. Two radiologists evaluated morphological features independently, including the lesion location, expansile bone changes, vertebral compression, presence of paraspinal soft tissue mass, fibrous septa, and the signal intensity on T1WI and T2WI. The inter-observer agreement was evaluated by kappa test. The DCE kinetics was measured to obtain the initial area under curve (IAUC) and the wash-out slope; also the two compartmental pharmacokinetic model was applied to obtain Ktrans and kep . The diagnostic accuracy was evaluated by CHAID decision tree and ROC analysis. RESULTS: Chordomas were more likely to show soft tissue mass than GCTs (13/13 = 100% versus 15/26 = 58%; P = 0.007), as well as fibrous septa (9/13 = 69% versus 0; P < 0.001). In decision tree analysis, presence of fibrous septa and lesion location yield 31/39 = 79% accuracy. The DCE-MRI pharmacokinetic parameters Ktrans and kep of GCTs were significantly higher than those of chordomas, 0.13 +/ 0.65 versus 0.06 +/- 0.04 (1/min) for Ktrans , 0.62 +/- 0.22 versus 0.17 +/- 0.12 (1/min) for kep , P < 0.001 for both. If using kep = 0.43/min as the cut-off value, it achieved 100% sensitivity and 92% specificity to differentiate chordoma from GCT, with an overall accuracy of 37/39 = 95%. The IAUC was highly correlated with Ktrans (r = 0.94), and the slope was highly correlated with kep (r = 0.95). CONCLUSION: Several morphological features were significantly different between chordoma and GCT, but their diagnostic performance was inferior to that of DCE MRI. LEVEL OF EVIDENCE: 4 J. Magn. Reson. Imaging 2017;45:1068-1075. PMID- 27490017 TI - Classification of Advanced Human Cancers Based on Tumor Immunity in the MicroEnvironment (TIME) for Cancer Immunotherapy. PMID- 27490013 TI - Effects of Antibiotic Prophylaxis in Patients with Open Fracture of the Extremities: A Systematic Review of Randomized Controlled Trials. AB - BACKGROUND: The purpose of the present study was to perform a systematic review and meta-analysis of the use of alternative antibiotic regimens-including (A) antibiotic prophylaxis versus no prophylaxis, (B) longer versus shorter duration of antibiotic prophylaxis, and (C) alternative drugs-for patients with open fracture of the extremities. METHODS: Data sources included CINAHL, EMBASE, MEDLINE, the Cochrane Central Registry of Controlled Trials (CENTRAL), and the Cochrane database of systematic reviews from 1965 to December 2013. All randomized controlled trials comparing the effectiveness of antibiotic prophylaxis in patients with open fracture of the extremities were eligible. RESULTS: We identified 329 potentially eligible articles, of which seventeen proved to be eligible. In four randomized controlled trials involving 472 patients, we found a significantly lower infection rate in patients receiving antibiotic prophylaxis compared with those not receiving antibiotic prophylaxis (risk ratio = 0.37 [95% confidence interval, 0.21 to 0.66]; absolute risk reduction = 9.6% [95% confidence interval, 5.2% to 12.1%]). In three studies involving 1104 patients, we found no difference in the infection rate when a longer duration of antibiotics (three to five days) was compared with a shorter duration (one day) (risk ratio = 0.97; 95% confidence interval, 0.69 to 1.37). Confidence in the estimates for both questions was low to moderate. Individual comparisons of alternative drugs yielded estimates warranting only low to very low confidence. CONCLUSIONS: Results of randomized controlled trials performed to date provide evidence that antibiotic prophylaxis reduces subsequent infection and that courses as short as one day are as effective as courses of three to five days, although the evidence warrants only low to moderate confidence. Given current practice, a large, multicenter, low risk of bias, randomized controlled trial enrolling representative populations and addressing the duration of antibiotics may be the next optimum step in investigation. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 27490011 TI - Comparative Study of Charge-Assisted Hydrogen- and Halogen-Bonding Capabilities in Solution of Two-Armed Imidazolium Receptors toward Oxoanions. AB - Two-armed imidazolium-based anion receptors have been prepared. The central 2,7 disubstituted naphthalene ring features two photoactive anthracene end-capped side arms with central 2-bromoimidazolium or hydrogen-bonding imidazolium receptors. Combined emission and (1)H and (31)P NMR studies carried out in the presence of a wide variety of anions reveal that only HP2O7(3-), H2PO4(-), SO4(2 ), and F(-) anions promoted noticeable changes. The halogen receptor 6(2+).2PF6( ) acts as a selective fluorescent molecular sensor for H2PO4(-) anions, since only this anion promotes the appearance of the anthracene excimer emission band, whereas it remains unchanged in the presence of the other tested anions. In addition this halogen receptor behaves as a chemodosimeter toward HP2O7(3-) anion, through its transformation into the corresponding bis-imidazolone after debromination by the action of the basic anion. The association constant values of the halogen-bonding complexes in a competitive solvent CD3CN/MeOD (8/2) mixture with H2PO4(-) and SO4(2-) anions are higher than those found for the hydrogen-bonding counterpart. In contrast, in the less competitive CH3CN solvent higher binding affinity for anions corresponds to the hydrogen-bonding receptor 7(2+).2PF6(-). In addition, the receptor 6(2+).2PF6(-) represents a useful alternative as an imaging agent in living cells in a wide range of emission wavelengths. PMID- 27490020 TI - Clinical outcomes and safety of distal biceps repair using a modified entry point. AB - BACKGROUND: The purpose of this study is to determine the safety of a one incision technique for distal biceps repair with modified repair entry point in regards to the distance from the posterior interosseous nerve (PIN). Secondly, we present the clinical results of patients having undergone this procedure. METHODS: Ten cadaveric specimens were dissected to reveal the radial tuberosity. Two 1.6-mm guidewires were inserted into the radial tuberosity, one centrally, and one 5-mm more proximal. Both guidewires penetrated the dorsal cortex, and posterior dissection revealed their exit points. The distance from the PIN and each wire was determined using a vernier calliper. The functional outcomes of 10 patients' post repair were reviewed. Performance was determined using strength and range of motion (ROM) measurements. Functional impairment was assessed using the disability of the arm, shoulder and hand outcome measure (DASH score). The uninjured side was used as a control. RESULTS: The mean distance from the centre of the radial tuberosity to the PIN was 7.33 mm with a centrally placed wire, compared with 10.92 mm when measuring from the proximal guidewire (P < 0.05). Supination and flexion strengths were 83 and 90% of the uninjured side, respectively. There was a mean of 1.5 degrees loss of flexion and 0 degrees loss of extension. Loss of pronation and supination ROM were 0.5 degrees and 4.5 degrees on average, respectively. Average DASH score was 6.3. CONCLUSION: We recommend a 5-mm more proximal entry point for insertion of the guidewire during distal biceps repair. This poses less risk to the PIN without significant functional impairment. Our outcomes are comparable with those reported in the literature. PMID- 27490012 TI - Hamstring Injuries in Athletes: Diagnosis and Treatment. PMID- 27490023 TI - Design, synthesis and structure-activity relationships of novel 4 phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors. AB - A series of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety were synthesized and evaluated for their in vitro cytotoxic activity against four cancer cell lines (HT-29, H460, A549 and MKN-45). Most of the compounds exhibited moderate-to-significant cytotoxicity. Compounds 33, 37, 39, 44, 46, 47, 53, 55, 61, 64 and 66 were further examined for their inhibitory activity against c-Met kinase. The most promising compound 47 (with c-Met IC50 value of 1.57 nM) showed remarkable cytotoxicity against HT-29, H460, A549 and MKN-45 cell lines with IC50 values of 0.08 MUM, 0.14 MUM, 0.11 MUM and 0.031 MUM, respectively, and thus it was 1.1- to 2.3- fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity. PMID- 27490024 TI - Synthesis and antiproliferative mechanism of action of pyrrolo[3',2':6,7] cyclohepta[1,2-d]pyrimidin-2-amines as singlet oxygen photosensitizers. AB - A new series of pyrrolo[3',2':6,7]cyclohepta[1,2-d]pyrimidin-2-amines, was conveniently prepared using a versatile and high yielding multistep sequence. A good number of derivatives was obtained and the cellular photocytotoxicity was evaluated in vitro against three different human tumor cell lines with EC50 (0.08 4.96 MUM) values reaching the nanomolar level. Selected compounds were investigated by laser flash photolysis. The most photocytotoxic derivative, exhibiting a fairly long-lived triplet state (tau ~ 7 MUs) and absorbance in the UV-Vis, was tested in the photo-oxidations of 9,10-anthracenedipropionic acid (ADPA) by singlet oxygen. The photosentizing properties are responsible for the compounds' ability to photoinduce massive cell death with involvement of mitochondria. PMID- 27490025 TI - Pyrrolidinone and pyrrolidine derivatives: Evaluation as inhibitors of InhA and Mycobacterium tuberculosis. AB - A series of GEQ analogues bearing pyrrolidinone or pyrrolidine cores were synthesized and evaluated against InhA, essential target for Mycobacterium tuberculosis (M.tb) survival. The compounds were also evaluated against M.tb H37Rv growth. Interestingly, some of the compounds, not efficient as InhA inhibitors, are active against M.tb with MICs up to 1.4 MUM. In particular, compound 4b was screened with different M.tb mutated strains in order to identify the cellular target, but without success, suggesting a new possible mode of action. PMID- 27490022 TI - Design, synthesis and biological evaluation of novel cholesteryl ester transfer protein inhibitors bearing a cycloalkene scaffold. AB - Cholesteryl ester transfer protein (CETP) is a potential target for cardiovascular disease therapy as inhibition of CETP leads to increased HDL-C in humans. Based on the structure of Merck's biphenyl CETP inhibitor, we designed novel N,N-substituted-cycloalkenyl-methylamine scaffold derivatives by utilizing core replacement and conformational restriction strategies. Consequently, twenty eight compounds were synthesized and evaluated for their inhibitory activity against CETP. Their preliminary structure-activity relationships (SARs) studies indicate that polar substituents were tolerated in moiety A and hydrophobic alkyl groups at the 5-position of cyclohexene were critical for potency. Among them, compound 17a, bearing an N-(5-pyrazolyl-pyrimidin-2-yl)-cycloalkenyl- methylamine scaffold, exhibited excellent CETP inhibitory activity (IC50 = 0.07 MUM) in vitro. Furthermore, it showed an acceptable pharmacokinetic profile in S-D rats and efficient HDL-C increase in high-fat fed hamsters. PMID- 27490019 TI - Rationally Designed CeNP@MnMoS4 Core-Shell Nanoparticles for Modulating Multiple Facets of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a complicated multifactorial syndrome. Lessons have been learned through failed clinical trials that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here, we construct core-shell nanoparticles (CeNP@MnMoS4 ) targeting multiple key pathways of the AD pathogenesis, including elimination of toxic metal ions, decrease of oxidative stress, and promotion of neurite outgrowth. The SOD activity and copper removal capacity of CeNP@MnMoS4 -n (n represents the number of layers of MnMoS4 , n=1-5) was investigated in vitro. We found that CeNP@MnMoS4 -3 made an excellent balance between SOD activity and copper removal capacity. The effect of CeNP@MnMoS4 -3 on Cu(2+) -induced Abeta aggregation was studied by gel electrophoresis, transmission electron microscope (TEM), and atomic force microscopy (AFM). Compared with MnMoS4 or CeNP alone, a synergistic effect was observed. Moreover, CeNP@MnMoS4 -3 promoted neurite outgrowth in a dose-dependent manner. Taken together, the results reported in this work show the potential of new multifunctional core-shell nanoparticles as AD therapeutics. PMID- 27490030 TI - Analysis of the Resistance of Hepatitis C Virus NS5B Polymerase Inhibitors via Docking and Molecular Dynamics Simulation. AB - In this work, we examined how known single point mutations (P495S, P495L, P495A, P496A, P496S and V499A) in Hepatitis C virus NS5B polymerase influence the binding of benzimidazole-5-carboxamide derivatives which are potent NS5B inhibitors. Docking and molecular dynamics simulations were performed to analyze the binding of the inhibitors to the wild-type and mutant enzymes. Binding free energy calculations (MM-GB/SA method) and analyzing the decomposed binding free energy of individual residues were able to explain the differences in the inhibitory potency of the compounds at wild-type and mutant enzymes and hence account for the appearance of resistance of mutant enzymes to the studied inhibitors. The obtained results were found to be in agreement with the known experimental data. PMID- 27490027 TI - Patient independent representation of the detailed cardiac ventricular anatomy. AB - Reparameterization of surfaces is a widely used tool in computer graphics known mostly from the remeshing algorithms. Recently, the surface reparameterization techniques started to gain popularity in the field of medical imaging, but mostly for convenient 2D visualization of the information initially represented on 3D surfaces (e.g. continuous bulls-eye plot). However, by consistently mapping the 3D information to the same 2D domain, surface reparameterization techniques allow us to put into correspondence anatomical shapes of inherently different geometry. In this paper, we propose a method for anatomical parameterization of cardiac ventricular anatomies that include myocardium, trabeculations, tendons and papillary muscles. The proposed method utilizes a quasi-conformal flattening of the myocardial surfaces of the left and right cardiac ventricles and extending it to cover the interior of the cavities using the local coordinates given by the solution of the Laplace's equation. Subsequently, we define a geometry independent representation for the detailed cardiac left and right ventricular anatomies that can be used for convenient visualization and statistical analysis of the trabeculations in a population. Lastly we show how it can be used for mapping the detailed cardiac anatomy between different hearts, which is of considerable interest for detailed cardiac computational models or shape atlases. PMID- 27490029 TI - Importance of arterial stiffness in predicting cardiovascular events. AB - INTRODUCTION: Cardiovascular events represent an important cause of morbidity and mortality in the entire population. Arterial stiffness is currently considered one of the most important risk factors for the development of cardiovascular events. The gold-standard for evaluating arterial stiffness is pulse wave velocity (PWV). Recent studies have demonstrated that PWV is an independent risk factor regarding the development of cardiovascular events, especially in certain categories of patients. MATERIAL AND METHODS: The development of cardiovascular events was assessed in 174 patients admitted in the Center of Internal Medicine, Fundeni Clinical Institute, between January 2011 - May 2012. Arterial stiffness was evaluated by measuring PWV using the Sphygmocor system (AtCor, Australia), which is based on the principle of applanation tonometry. The patients were monitored for the development of cardiovascular events (ischemic heart disease, heart failure, stroke, acute myocardial infarction) and for death of cardiovascular cause, over a median period of 51.5 months (43-60 months). RESULTS: Of the 174 patients, 81 (46.6%) were women and 93 (53.4%) were men. Mean age was 55.96 years. 93 of the 174 patients had chronic kidney failure in different stages (47.3% in stage V). Regarding PWV in the patient group, we obtained a mean score of 9.382. We observed a significant difference regarding the PWV level only for acute myocardial infarction and death between patients who developed these events and those who did not. CONCLUSIONS: Our study demonstrates that PWV increase can be positively associated with the occurrence of cardiovascular events, particularly in certain groups of patients. PMID- 27490034 TI - Improving AutoDock Vina Using Random Forest: The Growing Accuracy of Binding Affinity Prediction by the Effective Exploitation of Larger Data Sets. AB - There is a growing body of evidence showing that machine learning regression results in more accurate structure-based prediction of protein-ligand binding affinity. Docking methods that aim at optimizing the affinity of ligands for a target rely on how accurate their predicted ranking is. However, despite their proven advantages, machine-learning scoring functions are still not widely applied. This seems to be due to insufficient understanding of their properties and the lack of user-friendly software implementing them. Here we present a study where the accuracy of AutoDock Vina, arguably the most commonly-used docking software, is strongly improved by following a machine learning approach. We also analyse the factors that are responsible for this improvement and their generality. Most importantly, with the help of a proposed benchmark, we demonstrate that this improvement will be larger as more data becomes available for training Random Forest models, as regression models implying additive functional forms do not improve with more training data. We discuss how the latter opens the door to new opportunities in scoring function development. In order to facilitate the translation of this advance to enhance structure-based molecular design, we provide software to directly re-score Vina-generated poses and thus strongly improve their predicted binding affinity. The software is available at http://istar.cse.cuhk.edu.hk/rf-score-3.tgz and http://crcm. marseille.inserm.fr/fileadmin/rf-score-3.tgz. PMID- 27490032 TI - Quality Assessment of Predicted Protein Models Using Energies Calculated by the Fragment Molecular Orbital Method. AB - Protein structure prediction directly from sequences is a very challenging problem in computational biology. One of the most successful approaches employs stochastic conformational sampling to search an empirically derived energy function landscape for the global energy minimum state. Due to the errors in the empirically derived energy function, the lowest energy conformation may not be the best model. We have evaluated the use of energy calculated by the fragment molecular orbital method (FMO energy) to assess the quality of predicted models and its ability to identify the best model among an ensemble of predicted models. The fragment molecular orbital method implemented in GAMESS was used to calculate the FMO energy of predicted models. When tested on eight protein targets, we found that the model ranking based on FMO energies is better than that based on empirically derived energies when there is sufficient diversity among these models. This model diversity can be estimated prior to the FMO energy calculations. Our result demonstrates that the FMO energy calculated by the fragment molecular orbital method is a practical and promising measure for the assessment of protein model quality and the selection of the best protein model among many generated. PMID- 27490031 TI - Molecular Determinants for the Binding Mode of Alkylphosphocholines in the C2 Domain of PKCalpha. AB - Alkylphosphocholines (APCs) and alkyl-lysophosphocholines (ALPs) are antineoplastic agents that interfere with cellular membranes and signaling proteins. Protein kinase Calpha (PKCalpha) is a signaling protein composed by catalytic (C3, C4) and regulatory domains (C1, C2). The C2 needs calcium (Ca(2+) ) and phosphatidylserine (PS) for activation. Miltefosine inhibits PKCalpha competitively with regard to PS and non-competitively with regard to Ca(2+) , however, the mechanism of action is unknown. We employed molecular docking, molecular dynamics and chemometric methods to verify how 7 APCs and ALPs derivatives and PS interact with the C2 domain. All ligands except PS were grouped in 2 clusters according to their interactions inside the enzyme. The findings showed that PS's phosphoryl oxygens interact with Ca(2+) , the serine moiety interacts with Asn189, and the carbonyl oxygen of the alkylic chain interacts with Arg249 and Thr251. On the other hand, ligands' phosphoryl oxygens interact with Asn189, Arg249, Thr250, and one water molecule instead of Ca(2+) . Because of the different binding mode, we hypothesize that the ligands cause conformational changes in the calcium binding region. Moreover, the packing mismatch between bilayer-forming lipids and ALP/APC chain impedes the C2 domain from docking to the internal leaflet of cellular membranes, interrupting PKCalpha activation. PMID- 27490026 TI - Surface Passivation for Reliable Measurement of Bulk Electronic Properties of Heterojunction Devices. AB - Quantum efficiency measurements of state of the art Cu(In,Ga)Se2 (CIGS) thin film solar cells reveal current losses in the near infrared spectral region. These losses can be ascribed to inadequate optical absorption or poor collection of photogenerated charge carriers. Insight on the limiting mechanism is crucial for the development of more efficient devices. The electron beam induced current measurement technique applied on device cross-sections promises an experimental access to depth resolved information about the charge carrier collection probability. Here, this technique is used to show that charge carrier collection in CIGS deposited by multistage co-evaporation at low temperature is efficient over the optically active region and collection losses are minor as compared to the optical ones. Implications on the favorable absorber design are discussed. Furthermore, it is observed that the measurement is strongly affected by cross section surface recombination and an accurate determination of the collection efficiency is not possible. Therefore it is proposed and shown that the use of an Al2 O3 layer deposited onto the cleaved cross-section significantly improves the accuracy of the measurement by reducing the surface recombination. A model for the passivation mechanism is presented and the passivation concept is extended to other solar cell technologies such as CdTe and Cu2 (Zn,Sn)(S,Se)4 . PMID- 27490033 TI - Computational Investigation and Experimental Validation of Crizotinib Resistance Conferred by C1156Y Mutant Anaplastic Lymphoma Kinase. AB - Crizotinib is an anticancer drug approved by FDA for the treatment of non-small cell lung cancer (NSCLC). The main target for crizotinib was anaplastic lymphoma kinase (ALK). However, evidences available indicate that C1156Y mutation in ALK confers resistance to crizotinib. Unfortunately, how mutation actually confers drug resistance is not well understood. Hence, in the present study computational approaches have been employed alongside KINOMEscan profiling technique to reveal the mechanism behind crizotinib resistance in ALK at a molecular level. The results of our analysis indicate that C1156Y mutation alters the conformation of the ALK binding pocket residues which results in a marked decrease in hydrogen bond interactions between crizotinib and ALK. This indicates that hydrogen bonding was a crucial effector of decreased binding affinity. Interestingly, the docking study also indicates that C1156Y mutation increases the affinity for ATP. Finally, our analysis theoretically suggests that M-1199 is a key residue responsible for the ALK drug selectivity. We certainly believe that these results may be immense importance for the molecular level understanding of crizotinib resistance pattern and also for designing a potential drug molecule for the treatment of lung cancer in the near future. PMID- 27490035 TI - Determination of Meta-Parameters for Support Vector Machine Linear Combinations. AB - Support vector machines (SVMs) are among the most popular machine learning methods for compound classification and other chemoinformatics tasks such as, for example, the prediction of ligand-target pairs or compound activity profiles. Depending on the specific applications, different SVM strategies can be used. For example, in the context of potency-directed virtual screening, linear combinations of multiple SVM models have been shown to enrich database selection sets with potent compounds compared to individual models. An open question concerning the use of SVM linear combinations (SVM-LCs) is how to best weight the models on a relative scale. Typically, linear weights are subjectively set. Herein, preferred weighting factors for SVM-LC were systematically determined. Therefore, weights were treated as meta-parameters and optimized by machine learning to enrich data set rankings with highly active compounds. The meta parameter approach has been applied to 10 screening data sets and found to further improve SVM performance over other SVM-LCs and support vector regression (SVR) models. The results show that optimal weights depend on data set characteristics and chosen molecular representations. In addition, individual models often do not contribute to the performance of SVM-LCs. Taken together, these findings emphasize the need for systematic meta-parameter estimation. PMID- 27490037 TI - Design of Novel Mycobacterium tuberculosis Pantothenate Synthetase Inhibitors: Virtual Screening, Synthesis and In Vitro Biological Activities. AB - Pantothenate synthetase (PS) enzyme involved in the pantothenate biosynthetic pathway is essential for the virulence and persistent growth of Mycobacterium tuberculosis (MTB). It is encoded by the panC gene, and has become an appropriate target for developing new therapeutics for tuberculosis. Here we report new inhibitors active against MTB PS developed using energy based pharmacophore modelling of the available protein?inhibitor complex (3IVX) and virtual screening of a large commercial library. The e-pharmacophore model consisted of a ring aromatic (R), negative ionizable (N) and acceptor (A) sites. Compounds 5 and 10 emerged as promising hits with IC50 s 2.18 uM and 6.63 uM respectively. Further structural optimization was attempted to optimize lead 10 using medicinal chemistry approach and six compounds were found to exhibit better enzyme inhibition compared to parent compound lead 10 (<6 uM). PMID- 27490036 TI - Hit Expansion from Screening Data Based upon Conditional Probabilities of Activity Derived from SAR Matrices. AB - A new methodology for activity prediction of compounds from SAR matrices is introduced that is based upon conditional probabilities of activity. The approach has low computational complexity, is primarily designed for hit expansion from biological screening data, and accurately predicts both active and inactive compounds. Its performance is comparable to state-of-the-art machine learning methods such as support vector machines or Bayesian classification. Matrix-based activity prediction of virtual compounds further extends the spectrum of computational methods for compound design. PMID- 27490028 TI - Amalgamated Reference Data for Size-Adjusted Bone Densitometry Measurements in 3598 Children and Young Adults-the ALPHABET Study. AB - The increasing use of dual-energy X-ray absorptiometry (DXA) in children has led to the need for robust reference data for interpretation of scans in daily clinical practice. Such data need to be representative of the population being studied and be "future-proofed" to software and hardware upgrades. The aim was to combine all available pediatric DXA reference data from seven UK centers to create reference curves adjusted for age, sex, ethnicity, and body size to enable clinical application, using in vivo cross-calibration and making data back and forward compatible. Seven UK sites collected data on GE Lunar or Hologic Scanners between 1996 and 2012. Males and females aged 4 to 20 years were recruited (n = 3598). The split by ethnic group was white 2887; South Asian 385; black Afro Caribbean 286; and mixed heritage 40. Scans of the total body and lumbar spine (L1 to L4 ) were obtained. The European Spine Phantom was used to cross-calibrate the 7 centers and 11 scanners. Reference curves were produced for L1 to L4 bone mineral apparent density (BMAD) and total body less head (TBLH) and L1 to L4 areal bone mineral density (aBMD) for GE Lunar Prodigy and iDXA (sex- and ethnic specific) and for Hologic (sex-specific). Regression equations for TBLH BMC were produced using stepwise linear regression. Scans of 100 children were randomly selected to test backward and forward compatibility of software versions, up to version 15.0 for GE Lunar and Apex 4.1 for Hologic. For the first time, sex- and ethnic-specific reference curves for lumbar spine BMAD, aBMD, and TBLH aBMD are provided for both GE Lunar and Hologic scanners. These curves will facilitate interpretation of DXA data in children using methods recommended in ISCD guidelines. The databases have been created to allow future updates and analysis when more definitive evidence for the best method of fracture prediction in children is agreed. (c) 2016 American Society for Bone and Mineral Research. PMID- 27490038 TI - Drug Side Effect Profiles as Molecular Descriptors for Predictive Modeling of Target Bioactivity. AB - We have explored the potential of using side effect profiles of drugs to predict their bioactivities at the receptor level. Serotonin 5-HT6 binding and dopamine antagonism were investigated in separate studies. A set of 5-HT6 binders and non binders was retrieved from the PDSP Ki database, whereas dopamine antagonists were retrieved from the MeSH Pharmaceutical Action file. The side effect data was extracted from ChemoText, a data repository containing MeSH annotations pulled from MEDLINE records. These side effects profiles were treated as molecular descriptors enabling a QSAR-like approach to build models that could reliably discriminate different classes of molecules, e.g., binders versus non-binders, and dopamine antagonists versus non-antagonists. Selected models with the best external prediction performances were applied to a library of ca. 1000 chemicals with known side effects profiles in order to predict their potential 5-HT6 binding and/or dopamine antagonism. In each case the virtual screening process was able to identify putatively active compounds that through subsequent literature-based validation were found to be likely or known 5-HT6 binders or dopamine antagonists. These results demonstrate that side effect profiles can be utilized to predict a drug's unknown molecular activity, thus representing a valuable opportunity in repositioning the drug for a new indications. PMID- 27490039 TI - Screening Chemicals for Receptor-Mediated Toxicological and Pharmacological Endpoints: Using Public Data to Build Screening Tools within a KNIME Workflow. AB - Assessing compounds for their pharmacological and toxicological properties is of great importance for industry and regulatory agencies. In this study an approach using open source software and open access databases to build screening tools for receptor-mediated effects is presented. The retinoic acid receptor (RAR), as a pharmacologically and toxicologically relevant target, was chosen for this study. RAR agonists are used in the treatment of a number of dermal conditions and specific types of cancer, such as acute promyelocytic leukemia. However, when administered chronically, there is strong evidence that RAR agonists cause hepatosteatosis and liver injury. After compiling information on ligand-protein interactions, common substructures and physico-chemical properties of ligands were identified manually and coded into SMARTS strings. Based on these SMARTS strings and calculated physico-chemical features, a rule-based screening workflow was built within the KNIME platform. The workflow was evaluated on two datasets: one with RAR agonists exclusively and another large, chemically diverse dataset containing only a few RAR agonists. Possible modifications and applications of screening workflows, dependent on their purpose, are presented. PMID- 27490018 TI - METACOHORTS for the study of vascular disease and its contribution to cognitive decline and neurodegeneration: An initiative of the Joint Programme for Neurodegenerative Disease Research. AB - Dementia is a global problem and major target for health care providers. Although up to 45% of cases are primarily or partly due to cerebrovascular disease, little is known of these mechanisms or treatments because most dementia research still focuses on pure Alzheimer's disease. An improved understanding of the vascular contributions to neurodegeneration and dementia, particularly by small vessel disease, is hampered by imprecise data, including the incidence and prevalence of symptomatic and clinically "silent" cerebrovascular disease, long-term outcomes (cognitive, stroke, or functional), and risk factors. New large collaborative studies with long follow-up are expensive and time consuming, yet substantial data to advance the field are available. In an initiative funded by the Joint Programme for Neurodegenerative Disease Research, 55 international experts surveyed and assessed available data, starting with European cohorts, to promote data sharing to advance understanding of how vascular disease affects brain structure and function, optimize methods for cerebrovascular disease in neurodegeneration research, and focus future research on gaps in knowledge. Here, we summarize the results and recommendations from this initiative. We identified data from over 90 studies, including over 660,000 participants, many being additional to neurodegeneration data initiatives. The enthusiastic response means that cohorts from North America, Australasia, and the Asia Pacific Region are included, creating a truly global, collaborative, data sharing platform, linked to major national dementia initiatives. Furthermore, the revised World Health Organization International Classification of Diseases version 11 should facilitate recognition of vascular-related brain damage by creating one category for all cerebrovascular disease presentations and thus accelerate identification of targets for dementia prevention. PMID- 27490040 TI - Destructive Otologic Foreign Body: Dangers of the Expanding Bead. PMID- 27490041 TI - Functional and structural changes of the urinary bladder following spinal cord injury; treatment with alpha lipoic acid. AB - BACKGROUND & AIM: Alpha lipoic acid (LA) was shown to exert neuroprotection in trauma-induced spinal cord injury (SCI), which is frequently associated with urinary bladder complaints in patients with SCI. Accordingly, the protective effects of LA on biochemical and histological changes in bladder as well as functional studies were assessed. METHODS: Wistar albino rats were divided as control, SCI, and LA (50 mg/kg/day, ip) treated SCI groups (SCI+LA). The standard weight-drop (100 g/cm force at T10) method was used to induce a moderately severe SCI. One week after the injury, neurological examination was performed and the rats were decapitated. Bladder samples were taken for histological examination, functional (isolated tissue bath) studies, and for the measurement of biochemical parameters (malondialdehyde, MDA; gluthathione, GSH; nerve growth factor, NGF; caspase-3, luminol and lucigenin chemiluminescences). RESULTS: SCI caused a significant (P < 0.001) increase in the detrusor muscle thickness. It increased the contractility responses to carbachol and relaxation responses to papaverine (P < 0.05-0.001). There were also significant alterations in MDA, caspase-3, luminol, and lucigenin chemiluminescences with concomitant decreases in NGF and GSH (P < 0.05). LA treatment reversed histological and functional (contraction and relaxation responses) changes induced by SCI (P < 0.05-0.001), but no significant recovery was observed in the impaired neurological functions. CONCLUSION: These results indicate that LA have a beneficial effect in improving the bladder tonus via its antioxidant and anti-inflammatory actions following SCI. PMID- 27490042 TI - Lentiviral HSV-Tk.007-mediated suicide gene therapy is not toxic for normal brain cells. AB - BACKGROUND: Gene therapeutic strategies with suicide genes are currently investigated in clinical trials for brain tumors. Previously, we have shown that lentiviral vectors delivering the suicide gene HSV-Tk to experimental brain tumors promote a highly significant treatment effect and thus are promising vectors for clinical translation. METHODS: In the present study, we tested lentiviral vectors delivering the suicide gene HSV-Tk.007, a highly active mutant of HSV-Tk, to rat brains as a preclinical toxicity study. We injected 10(6) vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped functional lentiviral particles harboring the suicide gene HSV-Tk.007 into the brain of healthy, immunocompetent rats. During prodrug treatment with ganciclovir (GCV), we measured weight and assessed the behavior of the rats in an open field test. After 14 days of GCV treatment, we analyzed HSV-Tk.007 expression in different brain cell populations, as well as inflammatory responses and apoptosis. RESULTS: During prodrug treatment with GCV, behavior experiments did not reveal differences between the treated rats and the control groups. Analysis of HSV-Tk expression in different brain cell populations showed that transduced normal brain cells survived GCV treatment. There were no statistically significant differences in the number of transduced cells between treatment and control groups. Furthermore, inflammatory responses and apoptosis of brain cells were not observed. CONCLUSIONS: We show that HSV-Tk.007-mediated suicide gene therapy is not toxic to normal brain cells. This observation is of high relevance for the translation of lentivirus-mediated suicide gene therapies into the clinic for the treatment of brain tumor patients. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27490043 TI - How does closed system vitrification of human oocytes affect the clinical outcome? A prospective, observational, cohort, noninferiority trial in an oocyte donation program. AB - OBJECTIVE: To evaluate whether is possible to vitrify oocytes in an aseptic (hermetically closed) fashion and maintain clinical results comparable with those of fresh oocytes. DESIGN: Prospective, observational, cohort, noninferiority trial. SETTING: Private in vitro fertilization center. PATIENT(S): One hundred eighty-four recipients of donated vitrified oocytes. INTERVENTION(S): Closed system vitrification. MAIN OUTCOME MEASURE(S): Pregnancy rate per cycle and clinical pregnancy rate per cycle. RESULT(S): No statistically significant differences were observed between two groups regarding the pregnancy rate per cycle (63.1% vs. 60.9%) or the clinical pregnancy rate per cycle (55.4% vs. 58.7%). Biochemical pregnancy rate was statistically significantly higher in the fresh group (7.6% vs. 2.2%). The mean number of embryos transferred was similar (2.0 +/- 0.0 vs. 1.97 +/- 0.3). Concerning embryologic data, there were no statistically significant differences regarding the fertilization, cleavage, top quality day-3 embryo, or blastocyst rates, whereas the top quality blastocyst rate on day 5 was statistically significantly higher in the fresh oocyte group (31.7% vs. 26.1%). CONCLUSION(S): Aseptically (in a closed system) vitrified oocytes show similar clinical efficiency compared with their sibling fresh oocytes. PMID- 27490045 TI - Human spermatogonial stem cells display limited proliferation in vitro under mouse spermatogonial stem cell culture conditions. AB - OBJECTIVE: To study the ability of human spermatogonial stem cells (hSSCs) to proliferate in vitro under mouse spermatogonial stem cell (mSSC) culture conditions. DESIGN: Experimental basic science study. SETTING: Reproductive biology laboratory. PATIENT(S): Cryopreserved testicular tissue with normal spermatogenesis obtained from three donors subjected to orchiectomy due to a prostate cancer treatment. INTERVENTION(S): Testicular cells used to create in vitro cell cultures corresponding to the following groups: [1] unsorted human testicular cells, [2] differentially plated human testicular cells, and [3] cells enriched with major histocompatibility complex class 1 (HLA-)/epithelial cell surface antigen (EPCAM+) in coculture with inactivated testicular feeders from the same patient. MAIN OUTCOME MEASURE(S): Analyses and characterization including immunocytochemistry and quantitative reverse-transcription polymerase chain reaction for somatic and germ cell markers, testosterone and inhibin B quantification, and TUNEL assay. RESULT(S): Putative hSSCs appeared in singlets, doublets, or small groups of up to four cells in vitro only when testicular cells were cultured in StemPro-34 medium supplemented with glial cell line-derived neurotrophic factor (GDNF), leukemia inhibitory factor (LIF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF). Fluorescence-activated cell sorting with HLA-/EPCAM+ resulted in an enrichment of 27% VASA+/UTF1+ hSSCs, compared to 13% in unsorted controls. Coculture of sorted cells with inactivated testicular feeders gave rise to an average density of 112 hSSCs/cm2 after 2 weeks in vitro compared with unsorted cells (61 hSSCs/cm2) and differentially plated cells (49 hSSCS/cm2). However, putative hSSCs rarely stained positive for the proliferation marker Ki67, and their presence was reduced to the point of almost disappearing after 4 weeks in vitro. CONCLUSION(S): We found that hSSCs show limited proliferation in vitro under mSSC culture conditions. Coculture of HLA /EPCAM+ sorted cells with testicular feeders improved the germ cell/somatic cell ratio. PMID- 27490044 TI - Pregnancy intentions-a complex construct and call for new measures. AB - OBJECTIVE: To estimate the prevalence of unintended pregnancies under relaxed assumptions regarding birth control use compared with a traditional constructed measure. DESIGN: Cross-sectional survey. SETTING: Not applicable. PATIENT(S): Nationally representative sample of U.S. women aged 15-44 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Prevalence of intended and unintended pregnancies as estimated by [1] a traditional constructed measure from the National Survey of Family Growth (NSFG), and [2] a constructed measure relaxing assumptions regarding birth control use, reasons for nonuse, and pregnancy timing. RESULT(S): The prevalence of unintended pregnancies was 6% higher using the traditional constructed measure as compared with the approach with relaxed assumptions (NSFG: 44%, 95% confidence interval [CI] 41, 46; new construct 38%, 95% CI, 36, 41). Using the NSFG approach, only 92% of women who stopped birth control to become pregnant and 0 women who were not using contraceptives at the time of the pregnancy and reported that they did not mind getting pregnant were classified as having intended pregnancies, compared with 100% using the new construct. CONCLUSION(S): Current measures of pregnancy intention may overestimate rates of unintended pregnancy, with over 340,000 pregnancies in the United States misclassified as unintended using the current approach, corresponding to an estimated savings of $678 million in public health-care expenditures. Current constructs make assumptions that may not reflect contemporary reproductive practices, so improved measures are needed. PMID- 27490046 TI - Dual trigger for final oocyte maturation improves the oocyte retrieval rate of suboptimal responders to gonadotropin-releasing hormone agonist. AB - OBJECTIVE: To identify the risk factors for suboptimal response to GnRH agonist (GnRH-a) trigger and evaluate the effect of hCG on the outcome of patients with suboptimal response to GnRH-a. DESIGN: A retrospective data analysis. SETTING: A tertiary-care academic medical center. PATIENT(S): A total of 8,092 women undergoing 8,970 IVF/intracytoplasmic sperm injection (ICSI) treatment cycles. INTERVENTION(S): All women underwent hMG + medroxyprogesterone acetate (MPA)/P treatment cycles during IVF/ICSI, which were triggered using a GnRH-a alone or in combination with hCG (1,000, 2,000, or 5,000 IU). Viable embryos were cryopreserved for later transfer. MAIN OUTCOME MEASURE(S): The rates of oocyte retrieval, mature oocytes, fertilization, and the number of oocytes retrieved, mature oocytes, and embryos frozen. RESULT(S): In total, 2.71% (243/8,970) of patients exhibited a suboptimal response to GnRH-a. The suboptimal responders (LH <=15 mIU/mL) had a significantly lower oocyte retrieval rate (48.16% vs. 68.26%), fewer mature oocytes (4.10 vs. 8.29), and fewer frozen embryos (2.32 vs. 3.54) than the appropriate responders. Basal LH levels served as the single most valuable marker for differentiating suboptimal responders with the areas under the receiver operating curve of 0.805. Administering dual trigger (GnRH-a and hCG 1,000, 2,000, 5,000 IU) significantly increased oocyte retrieval rates (60.04% vs. 48.16%; 68.13% vs. 48.16%; and 65.76% vs. 48.16%, respectively) in patients with a suboptimal response. CONCLUSION(S): Basal LH level was useful predictor of the suboptimal response to GnRH-a trigger. Administrating dual trigger including 1,000 IU hCG for final oocyte maturation could improve the oocytes retrieval rate of GnRH-a suboptimal responder. PMID- 27490047 TI - Morphometric Analyses by a New Slit-Lamp Endothelial Biomicroscope. AB - PURPOSE: A method called EndoKer was recently devised for the morphometric analysis of the cell mosaic of the corneal endothelium. Fully automatic cell recognition is performed on images acquired by a slit-lamp biomicroscope. The aim of this study was to evaluate the accuracy of the EndoKer results. METHODS: Analyses were performed on a polystyrene bead layer stratified on a contact lens and in vivo on 30 adults. Accuracy was evaluated by comparing the results of EndoKer with the true values obtained by manual counting of the cells in the same images. EndoKer results were also compared with those obtained with the Tomey EM3000 microscope. RESULTS: The accuracy of the results compared with the manual counting on the same images showed a difference of a few percent for the cell density and for hexagonality. This high accuracy derives from (1) the resolution of the slit-lamp images and (2) the improved cell recognition of the fully automatic method. A good agreement was also found between EndoKer and the Tomey EM3000 microscope results. CONCLUSIONS: Based on the investigated 30 cases, the slit-lamp biomicroscope may be a viable alternative to dedicated endothelial instruments, providing the additional advantages of a larger investigated area and the possibility to take images of different portions of the cornea. The calibration was performed during the development of the method by using polystyrene beads. The user is not required to perform this calibration. However, such a calibrated sample is suggested for those interested. PMID- 27490048 TI - Intrastromal Corneal Ring Segment Implantation in 409 Paracentral Keratoconic Eyes. AB - PURPOSE: To assess the efficacy outcomes of implanting intrastromal corneal ring segments (ICRS) to correct paracentral keratoconus. METHODS: Four hundred nine eyes with paracentral keratoconus, in which the differences between the axes of refractive cylinder and the corneal flattest meridian and the comatic aberration map were less than 30 degrees, were evaluated before and after the implantation of Ferrara-type ICRS. Snellen uncorrected and best-corrected distance visual acuity, residual refractive errors analyzed with vector analysis, and the root mean square for corneal coma-like aberration for a pupil size of 4.5 mm were recorded before and 6 months after ICRS implantation. RESULTS: The mean uncorrected distance visual acuity (Snellen decimal scale) rose from 0.19 +/- 0.19 before ICRS implantation to 0.42 +/- 0.30 after implantation (P < 0.0001). The mean preoperative best-corrected distance visual acuity was 0.69 +/- 0.24 and the postoperative value was 0.77 +/- 0.23 (P < 0.0001). The safety index was 1.13. The spherical equivalent declined steeply after ICRS implantation (P < 0.0001). Cylinder power decreased by more than 50% in 71% of the eyes. The root mean square for corneal coma-like aberration for a 4.5-mm pupil changed from 1.32 +/- 1.01 MUm before surgery to 1.06 +/- 0.85 MUm after surgery (P <= 0.001). CONCLUSIONS: The Ferrara-type ICRS implantation is a safe and effective procedure for treating patients with keratoconus that meets the morphological characteristics of the sample under study. PMID- 27490050 TI - Toxicity of Intracameral Injection of Fourth-Generation Fluoroquinolones on the Corneal Endothelium. AB - PURPOSE: The aim of this study was to compare the cellular susceptibility patterns and morphologic changes in the corneal endothelium associated with the use of fourth-generation fluoroquinolones. METHOD: Endothelial susceptibility was assessed through intracameral injection of besifloxacin, gatifloxacin, and moxifloxacin. Human umbilical vein endothelial cells (HUVECs) were used as the standard cellular lineage to assess the quantitative toxicity of each antibiotic solution. Qualitative changes in the morphologic character of the corneal structure and the endothelial layer were generated using a combination of ex vivo and in vivo assays. Experimental assays were conducted in triplicate, and the results were statistically analyzed. RESULTS: At 1 hour of exposure, all HUVECs exposed to antibiotics showed viability above 85%, after 3 hours of exposure to besifloxacin, gatifloxacin, and moxifloxacin, the percentages of viable cells were 68.3 +/- 4.0 (P < 0.001), 90.7 +/- 4.2 (P < 0.05), and 93.3 +/- 1.5 (P > 0.05), respectively. All fluoroquinolones tested showed toxicity to HUVECs, resulting in significant (P < 0.001) loss of cellular viability after 24 hours of drug exposure. Giant endothelial cells were observed in animals treated with the 3 fluoroquinolones in contrast to the absence of these abnormal cells in the untreated group. Early cellular detachment was seen in the endothelial layer after exposure to gatifloxacin and moxifloxacin. CONCLUSIONS: We concluded that injection of fourth-generation fluoroquinolones in the aqueous humor did not adversely affect the corneal endothelium. However, these results suggested that prophylactic intracameral injection of besifloxacin, gatifloxacin, or moxifloxacin, if needed, should be administered as a last therapeutic resource in clinical practice, with careful and constant monitoring of corneal endothelium. PMID- 27490049 TI - MicroRNA-29b Overexpression Decreases Extracellular Matrix mRNA and Protein Production in Human Corneal Endothelial Cells. AB - PURPOSE: MicroRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. We reported that levels of microRNA (miR)-29 family are decreased in corneas of patients with Fuchs endothelial corneal dystrophy (FECD). The miR-29 family regulates the production of extracellular matrix (ECM) proteins. Accumulation of ECM proteins in Descemet membrane is an important pathologic change in FECD. In this study, we transfected miR-29b into human corneal endothelial cells and tissues and evaluated ECM protein expression levels. METHODS: An immortalized Fuchs human corneal endothelial cell line (iFECD) was established by infection of corneal endothelial cells from patients with FECD with hTERT lentivirus. MiR-29b was transfected into iFECD, and the expression levels of ECMs collagen type 1 alpha 1 (COL1A1), collagen type 4 alpha 1 (COL4A1), and laminin gamma 1 (LAMC1) were evaluated with quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blot. Expression level of LAMC1 protein in miR-29b-transfected donor corneal endothelium was also evaluated by Western blot. RESULTS: Compared with control, miR-29b expression level after transfection of iFECD was increased to 335.6% (+/-91.0%), and ECM expression levels were significantly decreased. Compared with control, qRT-PCR demonstrated reduction of ECM to the following levels: COL1A1: 1.9% (+/-0.4%); COL4A1: 7.1% (+/-1.7%); and LAMC1: 21.5% (+/-2.7%). Western blot showed reduced protein expression: COL1A1: 4.8% (+/-3.2%); COL4A1: 42.5% (+/-25.0%); and LAMC1: 44.8% (+/-3.1%). In miR-29b-transfected corneal tissue, LAMC1 protein expression level was decreased to 14.4% (+/-20.5%). CONCLUSIONS: Overexpression of miR-29b decreased ECM protein production in human corneal endothelial cells. Thus, miR-29 replacement therapy might be a new treatment strategy for FECD aimed at reducing pathologic production of ECM proteins in Descemet membrane. PMID- 27490051 TI - Association Between Corneal Endothelial Cell Density and Topical Glaucoma Medication Use in an Eye Bank Donor Population. AB - PURPOSE: To evaluate the association between corneal endothelial cell density (ECD) and donor topical glaucoma medication use in an eye bank database. METHODS: Raw eye bank data included 19,159 donors over the period July 2007 to May 2015. Free-text, donor medication lists were retrospectively searched for glaucoma medication. Exclusion criteria were age less than 40 years, history of eye surgery, endothelial trauma, guttae, and cell densities <1000 or >3300/mm. Analysis of covariance was used to test differences in cell density between groups while adjusting for age. Linear regression was used to test the correlation of independent interval variables while adjusting for age. RESULTS: Twelve thousand one hundred fifty-seven donors were included in the final analysis; 134 were on topical glaucoma medication. The mean ECD for donors not on glaucoma medication and pooled donors on glaucoma medication was 2561 +/- 348 and 2516 +/- 320 cells/mm, respectively (P = 0.42). Subgroup analysis by medication class resulted in nonstatistically significant differences between ECDs of nonmedicated donors and donors on alpha agonists (P = 0.76), beta blockers (P = 0.90), carbonic anhydrase inhibitors (P = 0.13), cholinergics (P = 0.37), and prostaglandin analogs (P = 0.62). The number of glaucoma medication classes used by donors was not a statistically significant predictor of endothelial density (P = 0.298). CONCLUSIONS: Donors on topical glaucoma medication do not have ECDs statistically significantly lower than donors not on medication. PMID- 27490052 TI - Interface Fluid Syndrome After Laser In Situ Keratomileusis (LASIK) Because of Fuchs Endothelial Dystrophy Reversed by Descemet Membrane Endothelial Keratoplasty (DMEK). AB - PURPOSE: To describe a case that developed "interface fluid syndrome" after previous laser in situ keratomileusis (LASIK) because of Fuchs endothelial dystrophy (FED), which was reversed by Descemet membrane endothelial keratoplasty (DMEK). METHODS: A 58-year-old male patient presented with bilateral visual impairment owing to FED and visually significant cataract. Cataract surgery was carried out in both eyes followed by DMEK in his left eye. RESULTS: After cataract surgery, visual acuity did not improve sufficiently because corneal thickness increased and a fine cleft with interface fluid developed between the LASIK-flap and the residual stromal bed. After uneventful DMEK in his left eye, the fluid resolved within a week and visual acuity improved rapidly. CONCLUSIONS: This case demonstrates that "interface fluid syndrome" after LASIK caused by concomitant endothelial dysfunction may be reversed by DMEK allowing fast visual recovery. PMID- 27490053 TI - Bilateral Urrets-Zavalia Syndrome After Descemet Stripping Automated Endothelial Keratoplasty. AB - PURPOSE: To report a case of bilateral Urrets-Zavalia syndrome (UZS) after Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: Case report. RESULTS: A 61-year-old patient with Fuchs endothelial dystrophy initially developed UZS in the left eye after DSAEK. Thirteen months later, she underwent combined cataract surgery and DSAEK in the right eye, and postoperatively she was noted to have elevated intraocular pressure and a fixed and dilated pupil on the first postoperative day. Both pupils showed partial improvement in reactivity over the course of weeks to months. This is the first case of bilateral UZS after DSAEK surgery and in a patient with Fuchs dystrophy. CONCLUSIONS: UZS may occur bilaterally after DSAEK. Because elevated intraocular pressure has been shown to be a risk factor for this condition, this should be monitored closely during the postoperative period. PMID- 27490054 TI - Increased Straylight in Patients With Keratoconjunctivitis Sicca. PMID- 27490055 TI - Reply. PMID- 27490057 TI - Open Access and Online Journals in Orthopaedics: What Does the Future Hold? PMID- 27490056 TI - Three-dimensional synaptic analyses of mitral cell and external tufted cell dendrites in rat olfactory bulb glomeruli. AB - Recent studies have suggested that the two excitatory cell classes of the mammalian olfactory bulb, the mitral cells (MCs) and tufted cells (TCs), differ markedly in physiological responses. For example, TCs are more sensitive and broadly tuned to odors than MCs and also are much more sensitive to stimulation of olfactory sensory neurons (OSNs) in bulb slices. To examine the morphological bases for these differences, we performed quantitative ultrastructural analyses of glomeruli in rat olfactory bulb under conditions in which specific cells were labeled with biocytin and 3,3'-diaminobenzidine. Comparisons were made between MCs and external TCs (eTCs), which are a TC subtype in the glomerular layer with large, direct OSN signals and capable of mediating feedforward excitation of MCs. Three-dimensional analysis of labeled apical dendrites under an electron microscope revealed that MCs and eTCs in fact have similar densities of several chemical synapse types, including OSN inputs. OSN synapses also were distributed similarly, favoring a distal localization on both cells. Analysis of unlabeled putative MC dendrites further revealed gap junctions distributed uniformly along the apical dendrite and, on average, proximally with respect to OSN synapses. Our results suggest that the greater sensitivity of eTCs vs. MCs is due not to OSN synapse number or absolute location but rather to a conductance in the MC dendrite that is well positioned to attenuate excitatory signals passing to the cell soma. Functionally, such a mechanism could allow rapid and dynamic control of OSN-driven action potential firing in MCs through changes in gap junction properties. J. Comp. Neurol. 525:592-609, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27490058 TI - Acute Distal Radioulnar Joint Instability in Adults: A Critical Analysis Review. PMID- 27490059 TI - Defining Value in Hip and Knee Arthroplasty in the United States. PMID- 27490060 TI - Complex Regional Pain Syndrome. PMID- 27490061 TI - Understanding Multiple Sclerosis: Essentials for the Orthopaedic Surgeon. PMID- 27490062 TI - Evaluation and Treatment of Scaphoid Nonunions: A Critical Analysis Review. PMID- 27490063 TI - Arthroscopic Single-Row Versus Double-Row Repair for Full-Thickness Posterosuperior Rotator Cuff Tears: A Critical Analysis Review. PMID- 27490064 TI - Heat equation inversion framework for average SAR calculation from magnetic resonance thermal imaging. AB - Deposition of radiofrequency (RF) energy can be quantified via electric field or temperature change measurements. Magnetic resonance imaging has been used as a tool to measure three dimensional small temperature changes associated with RF radiation exposure. When duration of RF exposure is long, conversion from temperature change to specific absorption rate (SAR) is nontrivial due to prominent heat-diffusion and conduction effects. In this work, we demonstrated a method for calculation of SAR via an inversion of the heat equation including heat-diffusion and conduction effects. This method utilizes high-resolution three dimensional magnetic resonance temperature images and measured thermal properties of the phantom to achieve accurate calculation of SAR. Accuracy of the proposed method was analyzed with respect to operating frequency of a dipole antenna and parameters used in heat equation inversion. Bioelectromagnetics. 37:493-503, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27490065 TI - Unusual Photophobia in a Child. PMID- 27490067 TI - Care of Patients at the End of Life: Foreword. PMID- 27490066 TI - Ventilation, indoor air quality, and health in homes undergoing weatherization. AB - Ventilation standards, health, and indoor air quality have not been adequately examined for residential weatherization. This randomized trial showed how ASHRAE 62-1989 (n=39 houses) and ASHRAE 62.2-2010 (n=42 houses) influenced ventilation rates, moisture balance, indoor air quality, and self-reported physical and mental health outcomes. Average total airflow was nearly twice as high for ASHRAE 62.2-2010 (79 vs. 39 cfm). Volatile organic compounds, formaldehyde and carbon dioxide were all significantly reduced for the newer standard and first-floor radon was marginally lower, but for the older standard, only formaldehyde significantly decreased. Humidity in the ASHRAE 62.2-2010 group was only about half that of the ASHRAE 62-1989 group using the moisture balance metric. Radon was higher in the basement but lower on the first floor for ASHRAE 62.2-2010. Children in each group had fewer headaches, eczema, and skin allergies after weatherization and adults had improvements in psychological distress. Indoor air quality and health improve when weatherization is accompanied by an ASHRAE residential ventilation standard, and the 2010 ASHRAE standard has greater improvements in certain outcomes compared to the 1989 standard. Weatherization, home repair, and energy conservation projects should use the newer ASHRAE standard to improve indoor air quality and health. PMID- 27490068 TI - Care of Patients at the End of Life: Pharmacotherapeutic Management of Pain. AB - End-of-life care often involves management of pain. A patient's pain should be assessed using the Visual Analogue Scale, which uses a 0 to 10 score, with 0 indicating no pain and 10 the worst pain imaginable. Mild pain typically is managed with nonopioids (eg, acetaminophen, nonsteroidal anti-inflammatory drugs). More severe pain is managed with opioids. Opioid therapy should start with an immediate-release opioid to determine the dose needed to achieve pain control. This can be used to create a regimen with an extended-release formulation for daily pain management plus an immediate-release formulation for breakthrough pain. The breakthrough dose should be 10% to 15% of the total daily dosage administered every 2 to 3 hours. If there is a need to change opioids or convert from oral to parenteral opioids, a conversion table should be used to estimate the new dosage. Patients taking opioids often experience constipation, so also prescribing a laxative (eg, senna, sorbitol) is advised. Other adverse effects of opioids mainly occur when starting or increasing the dosage. These effects include nausea, sedation, neurotoxicity, and itching, and typically resolve in several days. Adjuvant drugs (eg, antidepressants, anticonvulsants) often are added to the opioid regimen, particularly for management of neuropathic pain. PMID- 27490069 TI - Care of Patients at the End of Life: Management of Nonpain Symptoms. AB - Management of nonpain symptoms can improve quality of life for patients at the end of life and their family members. Constipation is the most common nonpain symptom. It can be related to opioid therapy and/or medical conditions. After abdominal examination to detect masses or evidence of bowel obstruction and rectal examination to exclude fecal impaction, constipation should be managed with a stimulant laxative (eg, senna) or an osmotic laxative (eg, sorbitol). Dyspnea also is common, and often improves with use of a fan to blow air into the face, as well with breathing and relaxation exercises. However, many patients require titrated doses of opioids to address respiratory depression, and anxiolytics such as haloperidol may be needed to manage dyspnea-related anxiety. Oxygen typically is not effective in dyspnea management in nonhypoxemic patients at the end of life. Cough is managed with antitussives. Nausea and vomiting occur in 70% of patients in palliative care units. If no reversible etiology can be identified, dopamine antagonists and motility-enhancing drugs can be used. There are no clearly effective treatments to manage noisy respiratory secretions, but position change, decrease in fluid intake, and drugs such as scopolamine or glycopyrrolate may be effective. PMID- 27490070 TI - Care of Patients at the End of Life: Advance Care Planning. AB - Advance directives are legal documents that give instructions about how to provide care when patients develop life-threatening illnesses and can no longer communicate their wishes. Two types of documents are widely used-a living will and a durable power of attorney for health care. Most states also authorize physician orders for life-sustaining treatment. Physicians should encourage patients, particularly those with severe chronic or terminal conditions, to prepare advance directives. Medicare now reimburses billing codes for advance care consultations. Directions regarding cardiopulmonary resuscitation and artificial ventilation often are included in advance care plans, and use of artificial nutrition and hydration (ANH) also should be addressed, particularly for patients with advanced dementia. Evidence shows that in such patients, ANH does not prolong survival, increase comfort, or improve quality of life. Given the lack of benefit, physicians should recommend against use of ANH for patients with dementia. Finally, physicians should encourage use of hospice services by patients whose life expectancy is 6 months or less. Although Medicare and most other health care insurers cover hospice care, and despite evidence that patient and family satisfaction increase when hospice services are used, many patients do not use these services. PMID- 27490071 TI - Care of Patients at the End of Life: Surrogate Decision Making for Incapacitated Patients. AB - Competence is determined by a court of law, whereas physicians determine medical decision-making capacity (DMC). When patients lack DMC, a surrogate should be identified to make decisions. Ideally, patients will have created a durable power of attorney for health care. If a patient did not do this, state statutes specify which individuals can serve as surrogates; a current spouse typically is the first choice. Ideally, surrogates should use substituted judgment in making decisions. If this is not possible because the patient never shared end-of-life wishes with the surrogate, the surrogate can make decisions that, in the surrogate's opinion, are in the patient's best interests or that a reasonable individual would make. When no surrogate can be identified and a patient has no written advance directive, hospital ethics committees can assist with decisions, or, for some patients, a court will need to appoint a guardian. When there is a surrogate, difficulties can arise when family members disagree with the surrogate's decisions or when surrogates request treatments that, in the physician's opinion, would be futile or nonbeneficial. Hospital ethics committees may be able to assist in these situations, but appropriately conducted family meetings often resolve such difficulties. PMID- 27490072 TI - Orthopaedic Quality Reporting: A Comprehensive Review of the Current Landscape and a Roadmap for Progress. PMID- 27490073 TI - The Evaluation and Treatment of Pediatric Tarsal Coalitions: A Critical Analysis Review. PMID- 27490074 TI - Emerging Technologies for the Diagnosis of Periprosthetic Infection. PMID- 27490075 TI - The Treatment of Periprosthetic Femoral Fractures After Total Hip Arthroplasty: A Critical Analysis Review. PMID- 27490076 TI - Spinopelvic Balance. PMID- 27490077 TI - The Mucosal Innate Immune Response in Primary Human Papillomavirus Infection: A Pilot Study. AB - OBJECTIVES: The purpose of the study was to evaluate the mucosal immune response in women affected by primary human papillomavirus (HPV) infection, in comparison with HPV-negative women with no previous history of HPV. METHODS: A case-control study comparing the activity of myeloperoxidase (MPO) and lactoferrin (LF) between 19 HPV-positive and 19 HPV-negative women matched for age. Plasmatic and cervicovaginal levels of polymorphonuclear neutrophils (PMN) exhibiting MPO and LF receptors were measured using cytofluorimetric analysis and expressed as mean of percentages. RESULTS: Cervicovaginal levels of MPO-/LF- PMN were lower among HPV-negative women, with a mean rate of 18.81% (SD, 21.38), as opposed to a mean rate of 35.56% (SD, 21.02) (P = 0.020) in HPV-positive women. A similar significant difference was not proven in plasma. The mean rates of plasmatic levels of MPO-/LF- PMN were 36.21% (SD, 16.87) and 36.93% (SD, 10.54) (P = 0.875) in cases and controls, respectively. All patients were evaluated 1 year later, and only 6 cases became negative. CONCLUSIONS: The presence of MPO-/LF- PMN has been considered as a marker of lower rate of apoptosis of HPV-infected cells. This could explain why HPV-positive women are less capable to deal with a primary infection. PMID- 27490078 TI - Human Papillomavirus Types Involved in External Genital Warts in a Group of Argentinian Women in Buenos Aires. AB - OBJECTIVES: The aim of the study was to understand which human papillomavirus (HPV) types are involved in external genital warts (GWs) in a group of Argentinian women in Buenos Aires. METHODS: One hundred sixty consecutive women 15 to 45 years old with GWs were enrolled. All patients underwent confirmatory biopsy. In 150 of 160 patients, the diagnosis of GWs was confirmed by histology, DNA-HPV was investigated using polymerase chain reaction, and sequence analysis with generic primers MY09/11 was performed. RESULTS: HPV 6 and/or 11 was detected in 93.3% patients (140/150). HPV 6 was by far the most common type (80%), followed by HPV 11 (12.7%). Coinfection with these 2 types occurred in 0.7%. HPV 16 was found in 2% and HPV 73 in 0.7%. CONCLUSION: HPV 6 and/or 11 are present in 93.3% (95% confidence interval, 0.9-1.0) of external genital warts in a group of Argentinian women in Buenos Aires and, therefore, could be prevented with HPV vaccine (NCT 015998779). PMID- 27490080 TI - Spotlights on our sister journals: ChemPhysChem 15/2016. PMID- 27490079 TI - Human Papillomavirus-Induced Squamous Intraepithelial Lesions in Vulvar Lichen Planus. AB - OBJECTIVES: Approximately 50% of vulvar cancers arise after transforming infections with human papilloma virus (HPV) via the precursor squamous intraepithelial lesion (SIL). Lichen planus (LP)-associated vulvar cancers are typically HPV negative and arise via the precursor differentiated vulvar intraepithelial neoplasia (d-VIN). METHODS: An index case of vulvar high-grade squamous intraepithelial lesion (H-SIL) in an LP patient prompted this 12-year retrospective analysis about frequency of HPV-induced SIL in 785 biopsies of 584 patients with vulvar LP. All SIL were analyzed for p53 and p16 overexpression and for presence of DNA of 32 HPV subtypes. RESULTS: Nine (1.6%) of 584 women with papular (3) and mucosal "erosive" LP (6) presented with H-SIL (7) and low-grade SIL (2). All SILs harbored HPV16-DNA and showed p16-overexpression. Concomitant immune suppression included T-suppressor lymphocyte deficit (1), systemic (1), and topical (2) cortisone therapy. H-SILs regressed spontaneously (1) or after imiquimod therapy (3). Three women with erosive LP discontinued imiquimod because of side effects and had laser destruction (1), skinning vulvectomy (1), and surgery (1) for definitive treatment. Two women have recurrent vulvar SILs, and 1 woman progressed to invasive SCC. In the same patient population, 16 of 584 women had a d-VIN, and 9 of 16 with progression to SCC. CONCLUSIONS: H-SILs in vulvar LP are rare and may occur in the setting of risk factors. If clinical suspicion arises, biopsy and histological examination assist in correct etiologic classification of a precancerous lesion and subsequent therapy decisions. The minimal risk for H-SIL development in vulvar LP patients should not preclude therapy of LP. PMID- 27490081 TI - Environmental Isolation of Circulating Vaccine-Derived Poliovirus After Interruption of Wild Poliovirus Transmission - Nigeria, 2016. AB - In September 2015, more than 1 year after reporting its last wild poliovirus (WPV) case in July 2014 (1), Nigeria was removed from the list of countries with endemic poliovirus transmission,* leaving Afghanistan and Pakistan as the only remaining countries with endemic WPV. However, on April 29, 2016, a laboratory confirmed, circulating vaccine-derived poliovirus type 2 (cVDPV2) isolate was reported from an environmental sample collected in March from a sewage effluent site in Maiduguri Municipal Council, Borno State, a security-compromised area in northeastern Nigeria. VDPVs are genetic variants of the vaccine viruses with the potential to cause paralysis and can circulate in areas with low population immunity. The Nigeria National Polio Emergency Operations Center initiated emergency response activities, including administration of at least 2 doses of oral poliovirus vaccine (OPV) to all children aged <5 years through mass campaigns; retroactive searches for missed cases of acute flaccid paralysis (AFP), and enhanced environmental surveillance. Approximately 1 million children were vaccinated in the first OPV round. Thirteen previously unreported AFP cases were identified. Enhanced environmental surveillance has not resulted in detection of additional VDPV isolates. The detection of persistent circulation of VDPV2 in Borno State highlights the low population immunity, surveillance limitations, and risk for international spread of cVDPVs associated with insurgency-related insecurity. Increasing vaccination coverage with additional targeted supplemental immunization activities and reestablishment of effective routine immunization activities in newly secured and difficult-to-reach areas in Borno is urgently needed. PMID- 27490083 TI - My Time as Editor-in-Chief: What a Long Strange Trip It's Been. PMID- 27490084 TI - Simulation in Healthcare: Growin' up. PMID- 27490082 TI - Interactions between 4-aminoquinoline and heme: Promising mechanism against Trypanosoma cruzi. AB - Chagas disease is a neglected tropical disease caused by the flagellated protozoan Trypanosoma cruzi. The current drugs used to treat this disease have limited efficacy and produce severe side effects. Quinolines, nitrogen heterocycle compounds that form complexes with heme, have a broad spectrum of antiprotozoal activity and are a promising class of new compounds for Chagas disease chemotherapy. In this study, we evaluated the activity of a series of 4 arylaminoquinoline-3-carbonitrile derivatives against all forms of Trypanosoma cruzi in vitro. Compound 1g showed promising activity against epimastigote forms when combined with hemin (IC50<1 MUM), with better performance than benznidazole, the reference drug. This compound also inhibited the viability of trypomastigotes and intracellular amastigotes. The potency of 1g in combination with heme was enhanced against epimastigotes and trypomastigotes, suggesting a similar mechanism of action that occurs in Plasmodium spp. The addition of hemin to the culture medium increased trypanocidal activity of analog 1g without changing the cytotoxicity of the host cell, reaching an IC50 of 11.7 MUM for trypomastigotes. The mechanism of action was demonstrated by the interaction of compound 1g with hemin in solution and prevention of heme peroxidation. Compound 1g and heme treatment induced alterations of the mitochondrion-kinetoplast complex in epimastigotes and trypomastigotes and also, accumulation of electron-dense deposits in amastigotes as visualized by transmission electron microscopy. The trypanocidal activity of 4-aminoquinolines and the elucidation of the mechanism involving interaction with heme is a neglected field of research, given the parasite's lack of heme biosynthetic pathway and the importance of this cofactor for parasite survival and growth. The results of this study can improve and guide rational drug development and combination treatment strategies. PMID- 27490085 TI - Reporting Guidelines for Health Care Simulation Research: Where Is the learning? AB - STATEMENT: This is a commentary on the reporting guidelines article and offers some food for thought on the need to include learning and instructional feature variables in the reporting process. PMID- 27490086 TI - Efficacy of a multifactorial strategy for bowel preparation in diabetic patients undergoing colonoscopy: a randomized trial. AB - : Background and study aims: Previous studies have reported that diabetes mellitus is an independent risk factor for inadequate bowel preparation. Current guidelines do not recommend a specific preparation for this patient population. The aims of this study were to assess the efficacy, safety, and tolerability of an adapted preparation protocol for colon cleansing in patients with type 2 diabetes mellitus. Patients and methods: This randomized, single-blind, parallel group, superiority trial compared a conventional bowel preparation protocol (CBP) with a diabetes-specific preparation protocol (DSP). The CBP included a low-fiber diet for 3 days followed by a clear liquid diet for 24 hours before colonoscopy. The DSP included a multifactorial strategy combining an educational intervention, a low-fiber diet, and adjustment of blood glucose-lowering agents. All patients received 4 L of a polyethylene glycol solution in a split-dose regimen. The endoscopists were blinded to the preparation protocol. The primary outcome measure was inadequate bowel preparation according to the Boston Bowel Preparation Scale. Secondary outcome measures included hypoglycemic events, tolerability, and acceptability. Results: A total of 150 patients were included in the study (74 CBP and 76 DSP). Both groups were comparable in terms of baseline characteristics. Inadequate bowel cleansing was more frequent following CBP than DSP (20 % vs. 7 %, P = 0.014; risk ratio 3.1, 95 % confidence interval 1.2 - 8). Only CBP and performance status were independently associated with inadequate bowel preparation. Both preparations were equally tolerated and accepted by patients, and side-effects were similar between the groups. Conclusions: A multifactorial strategy for bowel preparation in patients with diabetes undergoing colonoscopy showed a threefold reduction in the rate of inadequate bowel preparation, with no differences in safety and tolerability compared with conventional preparation. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02300779). PMID- 27490087 TI - Update: Ongoing Zika Virus Transmission - Puerto Rico, November 1, 2015-July 7, 2016. AB - Zika virus is a flavivirus transmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes, and infection can be asymptomatic or result in an acute febrile illness with rash (1). Zika virus infection during pregnancy is a cause of microcephaly and other severe birth defects (2). Infection has also been associated with Guillain-Barre syndrome (GBS) (3) and severe thrombocytopenia (4,5). In December 2015, the Puerto Rico Department of Health (PRDH) reported the first locally acquired case of Zika virus infection. This report provides an update to the epidemiology of and public health response to ongoing Zika virus transmission in Puerto Rico (6,7). A confirmed case of Zika virus infection is defined as a positive result for Zika virus testing by reverse transcription polymerase chain reaction (RT-PCR) for Zika virus in a blood or urine specimen. A presumptive case is defined as a positive result by Zika virus immunoglobulin M (IgM) enzyme-linked immunosorbent assay (MAC-ELISA)* and a negative result by dengue virus IgM ELISA, or a positive test result by Zika IgM MAC-ELISA in a pregnant woman. An unspecified flavivirus case is defined as positive or equivocal results for both Zika and dengue virus by IgM ELISA. During November 1, 2015-July 7, 2016, a total of 23,487 persons were evaluated by PRDH and CDC Dengue Branch for Zika virus infection, including asymptomatic pregnant women and persons with signs or symptoms consistent with Zika virus disease or suspected GBS; 5,582 (24%) confirmed and presumptive Zika virus cases were identified. Persons with Zika virus infection were residents of 77 (99%) of Puerto Rico's 78 municipalities. During 2016, the percentage of positive Zika virus infection cases among symptomatic males and nonpregnant females who were tested increased from 14% in February to 64% in June. Among 9,343 pregnant women tested, 672 had confirmed or presumptive Zika virus infection, including 441 (66%) symptomatic women and 231 (34%) asymptomatic women. One patient died after developing severe thrombocytopenia (4). Evidence of Zika virus infection or recent unspecified flavivirus infection was detected in 21 patients with confirmed GBS. The widespread outbreak and accelerating increase in the number of cases in Puerto Rico warrants intensified vector control and personal protective behaviors to prevent new infections, particularly among pregnant women. PMID- 27490088 TI - Self-Assembled Redox Dual-Responsive Prodrug-Nanosystem Formed by Single Thioether-Bridged Paclitaxel-Fatty Acid Conjugate for Cancer Chemotherapy. AB - Chemotherapeutic efficacy can be greatly improved by developing nanoparticulate drug delivery systems (nano-DDS) with high drug loading capacity and smart stimulus-triggered drug release in tumor cells. Herein, we report a novel redox dual-responsive prodrug-nanosystem self-assembled by hydrophobic small-molecule conjugates of paclitaxel (PTX) and oleic acid (OA). Thioether linked conjugates (PTX-S-OA) and dithioether inserted conjugates (PTX-2S-OA) are designed to respond to the redox-heterogeneity in tumor. Dithioether has been reported to show redox dual-responsiveness, but we find that PTX-S-OA exhibits superior redox sensitivity over PTX-2S-OA, achieving more rapid and selective release of free PTX from the prodrug nanoassemblies triggered by redox stimuli. PEGylated PTX-S OA nanoassemblies, with impressively high drug loading (57.4%), exhibit potent antitumor activity in a human epidermoid carcinoma xenograft. This novel prodrug nanosystem addresses concerns related to the low drug loading and inefficient drug release from hydrophobic prodrugs of PTX, and provides possibilities for the development of redox dual-sensitive conjugates or polymers for efficient anticancer drug delivery. PMID- 27490089 TI - Targeted Mutagenesis and Combinatorial Library Screening Enables Control of Protein Orientation on Surfaces and Increased Activity of Adsorbed Proteins. AB - While nonspecific adsorption is widely used for immobilizing proteins on solid surfaces, the random nature of protein adsorption may reduce the activity of immobilized proteins due to occlusion of the active site. We hypothesized that the orientation a protein assumes on a given surface can be controlled by systematically introducing mutations into a region distant from its active site, thereby retaining activity of the immobilized protein. To test this hypothesis, we generated a combinatorial protein library by randomizing six targeted residues in a binding protein derived from highly stable, nonimmunoglobulin Sso7d scaffold; mutations were targeted in a region that is distant from the binding site. This library was screened to isolate binders that retain binding to its cognate target (chicken immunoglobulin Y, cIgY) as well as exhibit adsorption on unmodified silica at pH 7.4 and high ionic strength conditions. A single mutant, Sso7d-2B5, was selected for further characterization. Sso7d-2B5 retained binding to cIgY with an apparent dissociation constant similar to that of the parent protein; both mutant and parent proteins saturated the surface of silica with similar densities. Strikingly, however, silica beads coated with Sso7d-2B5 could achieve up to 7-fold higher capture of cIgY than beads coated with the parent protein. These results strongly suggest that mutations introduced in Sso7d-2B5 alter its orientation relative to the parent protein, when adsorbed on silica surfaces. Our approach also provides a generalizable strategy for introducing mutations in proteins so as to improve their activity upon immobilization, and has direct relevance to development of protein-based biosensors and biocatalysts. PMID- 27490090 TI - Probing the Interior Crystal Quality in the Development of More Efficient and Smaller Upconversion Nanoparticles. AB - Optical biomedical imaging using luminescent nanoparticles as contrast agents prefers small size, as they can be used at high dosages and efficiently cleared from body. Reducing nanoparticle size is critical for the stability and specificity for the fluorescence nanoparticles probes for in vitro diagnostics and subcellular imaging. The development of smaller and brighter upconversion nanoparticles (UCNPs) is accordingly a goal for complex imaging in bioenvironments. At present, however, small UCNPs are reported to exhibit less emission intensity due to increased surface deactivation and decreased number of dopants. Here we show that smaller and more efficient UCNPs can be made by improving the interior crystal quality via controlling heating rate during synthesis. We further developed a unique quantitative method for optical characterizations on the single UCNPs with varied sizes and the corresponding shell passivated UCNPs, confirming that the internal crystal quality dominates the relative emission efficiency of the UCNPs. PMID- 27490091 TI - Cerasoidine, a Bis-aporphine Alkaloid Isolated from Polyalthia cerasoides during Screening for Wnt Signal Inhibitors. AB - A new bis-aporphine alkaloid, cerasoidine (1), was isolated from the root extract of Polyalthia cerasoides together with the known bis-aporphine bidebiline E (2) during screening for compounds with Wnt signal inhibitory activities. The structure of cerasoidine (1) was established by X-ray analysis and shown by chiral HPLC analyses and electronic circular dichroism to be a 57:43 mixture of R(-)- and S(+)-atropisomers. Bidebiline E (2) exhibited inhibition of transcriptional activity of TCF/beta-catenin with an IC50 value of 20.2 MUM and was also found to inhibit Wnt signaling by decreasing nuclear beta-catenin. PMID- 27490092 TI - Catalytic Asymmetric Synthesis of Ketene Heterodimer beta-Lactones: Scope and Limitations. AB - In this article we describe extensive studies of the catalytic asymmetric heterodimerization of ketenes to give ketene heterodimer beta-lactones. The optimal catalytic system was determined to be a cinchona alkaloid derivative (TMS quinine or Me-quinidine). The desired ketene heterodimer beta-lactones were obtained in good to excellent yields (up to 90%), with excellent levels of enantioselectivity (>=90% ee for 33 Z and E isomer examples), good to excellent (Z)-olefin isomer selectivity (>=90:10 for 20 examples), and excellent regioselectivity (only one regioisomer formed). Full details of catalyst development studies, catalyst loading investigations, substrate scope exploration, protocol innovations (including double in situ ketene generation for 7 examples), and an application to a cinnabaramide A intermediate are described. The addition of lithium perchlorate (1-2 equiv) as an additive to the alkaloid catalyst system was found to favor formation of the E isomer of the ketene heterodimer. Ten examples were formed with moderate to excellent (E)-olefin isomer selectivity (74:25 to 97:3) and with excellent enantioselectivity (84-98% ee). PMID- 27490093 TI - Context-specific functional module based drug efficacy prediction. AB - BACKGROUND: It is necessary to evaluate the efficacy of individual drugs on patients to realize personalized medicine. Testing drugs on patients in clinical trial is the only way to evaluate the efficacy of drugs. The approach is labour intensive and requires overwhelming costs and a number of experiments. Therefore, preclinical model system has been intensively investigated for predicting the efficacy of drugs. Current computational drug sensitivity prediction approaches use general biological network modules as their prediction features. Therefore, they miss indirect effectors or the effects from tissue-specific interactions. RESULTS: We developed cell line specific functional modules. Enriched scores of functional modules are utilized as cell line specific features to predict the efficacy of drugs. Cell line specific functional modules are clusters of genes, which have similar biological functions in cell line specific networks. We used linear regression for drug efficacy prediction. We assessed the prediction performance in leave-one-out cross-validation (LOOCV). Our method was compared with elastic net model, which is a popular model for drug efficacy prediction. In addition, we analysed drug sensitivity-associated functions of five drugs - lapatinib, erlotinib, raloxifene, tamoxifen and gefitinib- by our model. CONCLUSIONS: Our model can provide cell line specific drug efficacy prediction and also provide functions which are associated with drug sensitivity. Therefore, we could utilize drug sensitivity associated functions for drug repositioning or for suggesting secondary drugs for overcoming drug resistance. PMID- 27490095 TI - Characterization of Portal Vein Thrombosis (Neoplastic Versus Bland) on CT Images Using Software-Based Texture Analysis and Thrombus Density (Hounsfield Units). AB - OBJECTIVE: The purpose of this study was to investigate the role of CT texture analysis and thrombus density (measured in Hounsfield units) in distinguishing between neoplastic and bland portal vein thrombosis (PVT) on portal venous phase CT. MATERIALS AND METHODS: In this retrospective study, 117 contrast-enhanced CT studies of 109 patients were included for characterization of PVT. Assessment of PVT was performed by estimation of CT textural features using CT texture analysis software and measurement of attenuation values. For CT texture analysis, filtered and unfiltered images were assessed to quantify heterogeneity using a set of predefined histogram-based texture parameters. The Mann-Whitney U test and binary logistic regression were applied for statistical significance. ROC curves were used to identify accuracy and optimal cutoff values. RESULTS: Of the 117 CT studies, 63 neoplastic thrombi and 54 bland thrombi were identified on the images. The two most discriminative CT texture analysis parameters to differentiate neoplastic from bland thrombus were mean value of positive pixels (without filtration, p < 0.001) and entropy (with fine filtration, p < 0.001). Mean thrombus density values could also reliably distinguish neoplastic (81.39 HU) and bland (32.88 HU) thrombi (p < 0.001). The AUCs were 0.97 for mean value of positive pixels (p < 0.001), 0.93 for entropy (p < 0.001), 0.99 for the model combining mean value of positive pixels and entropy (p < 0.001), 0.91 for thrombus density (p < 0.001), and 0.61 for the radiologist's subjective evaluation (p = 0.037). The optimal cutoffs values were 56.9 for mean value of positive pixels, 4.50 for entropy, and 54.0 HU for thrombus density. CONCLUSION: CT texture analysis and CT attenuation values allow reliable differentiation between neoplastic and bland thrombi on a single portal venous phase CT examination. PMID- 27490096 TI - Influence of Gas Adsorption and Gold Nanoparticles on the Electrical Properties of CVD-Grown MoS2 Thin Films. AB - Molybdenum disulfide (MoS2) has increasingly attracted attention from researchers and is now one of the most intensively explored atomic-layered two-dimensional semiconductors. Control of the carrier concentration and doping type of MoS2 is crucial for its application in electronic and optoelectronic devices. Because the MoS2 layers are atomically thin, their transport characteristics may be very sensitive to ambient gas adsorption and the resulting charge transfer. We investigated the influence of the ambient gas (N2, H2/N2, and O2) choice on the resistance (R) and surface work function (WF) of trilayer MoS2 thin films grown via chemical vapor deposition. We also studied the electrical properties of gold (Au)-nanoparticle (NP)-coated MoS2 thin films; their R value was found to be 2 orders of magnitude smaller than that for bare samples. While the WF largely varied for each gas, R was almost invariant for both the bare and Au-NP-coated samples regardless of which gas was used. Temperature-dependent transport suggests that variable range hopping is the dominant mechanism for electrical conduction for bare and Au-NP-coated MoS2 thin films. The charges transferred from the gas adsorbates might be insufficient to induce measurable R change and/or be trapped in the defect states. The smaller WF and larger localization length of the Au-NP-coated sample, compared with the bare sample, suggest that more carriers and less defects enhanced conduction in MoS2. PMID- 27490094 TI - Translesion Synthesis of the N(2)-2'-Deoxyguanosine Adduct of the Dietary Mutagen IQ in Human Cells: Error-Free Replication by DNA Polymerase kappa and Mutagenic Bypass by DNA Polymerases eta, zeta, and Rev1. AB - Translesion synthesis (TLS) of the N(2)-2'-deoxyguanosine (dG-N(2)-IQ) adduct of the carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) was investigated in human embryonic kidney 293T cells by replicating plasmid constructs in which the adduct was individually placed at each guanine (G1, G2, or G3) of the NarI sequence (5'-CG1G2CG3CC-3'). TLS efficiency was 38%, 29%, and 25% for the dG-N(2) IQ located at G1, G2, and G3, respectively, which suggests that dG-N(2)-IQ is bypassed more efficiently by one or more DNA polymerases at G1 than at either G2 or G3. TLS efficiency was decreased 8-35% in cells with knockdown of pol eta, pol kappa, pol iota, pol zeta, or Rev1. Up to 75% reduction in TLS occurred when pol eta, pol zeta, and Rev1 were simultaneously knocked down, suggesting that these three polymerases play important roles in dG-N(2)-IQ bypass. Mutation frequencies (MFs) of dG-N(2)-IQ at G1, G2, and G3 were 23%, 17%, and 11%, respectively, exhibiting a completely reverse trend of the previously reported MF of the C8-dG adduct of IQ (dG-C8-IQ), which is most mutagenic at G3 ( ( 2015 ) Nucleic Acids Res. 43 , 8340 - 8351 ). The major type of mutation induced by dG-N(2)-IQ was targeted G -> T, as was reported for dG-C8-IQ. In each site, knockdown of pol kappa resulted in an increase in MF, whereas MF was reduced when pol eta, pol iota, pol zeta, or Rev1 was knocked down. The reduction in MF was most pronounced when pol eta, pol zeta, and Rev1 were simultaneously knocked down and especially when the adduct was located at G3, where MF was reduced by 90%. We conclude that pol kappa predominantly performs error-free TLS of the dG-N(2)-IQ adduct, whereas pols eta, pol zeta, and Rev1 cooperatively carry out the error-prone TLS. However, in vitro experiments using yeast pol zeta and kappa showed that the former was inefficient in full-length primer extension on dG-N(2)-IQ templates, whereas the latter was efficient in both error-free and error-prone extensions. We believe that the observed differences between the in vitro experiments using purified DNA polymerases, and the cellular results may arise from several factors including the crucial roles played by the accessory proteins in TLS. PMID- 27490097 TI - Combinatorial Solid-Phase Synthesis and Biological Evaluation of Cyclodepsipeptide Destruxin B as a Negative Regulator for Osteoclast Morphology. AB - Combinatorial synthesis and biological evaluation of cyclodepsipeptide destruxin B have been achieved. The cyclization precursors were prepared by solid-phase peptide synthesis via a split and pool method utilizing SynPhase lanterns with colored tags and cogs, followed by cleavage from the polymer-support. Macrolactonization utilizing MNBA-DMAPO in solution-phase was successfully performed in parallel to afford the desired 64-member destruxin analogues in moderate to good yields. Biological evaluation of the synthesized analogues indicated that a MeAla residue for the building block A is required to induce the desired morphological changes in osteoclast-like multinuclear cells (OCLs), and introduction of the substituent at the R(4) position of a proline moiety is tolerated by the morphology and may enable the preparation of a molecular probe for the target identification in the osteoclasts. PMID- 27490098 TI - A Systematic Review of Randomized Controlled Trials on Oral Chinese Herbal Medicine for Prostate Cancer. AB - BACKGROUND: Prostate cancer is the most common malignant tumor associated with male reproductive system. OBJECTIVE: The existing eligible randomized controlled trials (RCTs) were critically appraised for the safety and effectiveness of CHM for prostate cancer. METHODS: A literature search was conducted by using PubMed, CENTRAL, CNKI, CBM, VIP and Wanfang databases until August 2015. RCTs of CHM or CHM plus conventional medicine for prostate cancer patients were included. The primary outcomes appraised were survival time, time to progression and quality of life. The risk of bias assessment according to the Cochrane Handbook was used to evaluate the methodological quality of the included trials. Revman 5.3 software was used for data analyses. Risk ratio and mean difference (MD) with a 95% confidence interval (CI) were used as effect measures. Meta-analysis was to be used if sufficient trials without obvious clinical or statistical heterogeneity were available. RESULTS: A total of 17 RCTs involving 1224 participants were analyzed. One trial was about CHM comparing to no treatment. The remaining 16 trials used CHMs as adjunctive treatment for endocrine therapy. Due to the poor quality of methodologies of most trials, only limited evidence showed that a combination of CHM and endocrine therapy might be more effective in restraining the development of the disease (MD 10.37 months, 95%CI 9.10 to 11.63 months), increasing patients' survival time (7-15 months) or improving patients' performance status, when compared to endocrine therapy alone (Karnofsky performance scale average changed 15 scores between groups). No severe adverse event was reported related to CHM. CONCLUSION: Due to the insufficient quality of trials that were analyzed, it is not appropriate to recommend any kind of CHMs in treating prostate cancer at the present time. Well-designed trials with high methodological quality are needed to validate the effect of CHMs for patients with prostate cancer. PMID- 27490099 TI - Identification of Novel Smoothened Ligands Using Structure-Based Docking. AB - The seven transmembrane protein Smoothened is required for Hedgehog signaling during embryonic development and adult tissue homeostasis. Inappropriate activation of the Hedgehog signalling pathway leads to cancers such as basal cell carcinoma and medulloblastoma, and Smoothened inhibitors are now available clinically to treat these diseases. However, resistance to these inhibitors rapidly develops thereby limiting their efficacy. The determination of Smoothened crystal structures enables structure-based discovery of new ligands with new chemotypes that will be critical to combat resistance. In this study, we docked 3.2 million available, lead-like molecules against Smoothened, looking for those with high physical complementarity to its structure; this represents the first such campaign against the class Frizzled G-protein coupled receptor family. Twenty-one high-ranking compounds were selected for experimental testing, and four, representing three different chemotypes, were identified to antagonize Smoothened with IC50 values better than 50 MUM. A screen for analogs revealed another six molecules, with IC50 values in the low micromolar range. Importantly, one of the most active of the new antagonists continued to be efficacious at the D473H mutant of Smoothened, which confers clinical resistance to the antagonist vismodegib in cancer treatment. PMID- 27490101 TI - Subcutaneous Immunoglobulin Therapy in the Chronic Management of Myasthenia Gravis: A Retrospective Cohort Study. AB - BACKGROUND: Immunoglobulin therapy has become a major treatment option in several autoimmune neuromuscular disorders. For patients with Myasthenia Gravis (MG), intravenous immunoglobulin (IVIg) has been used for both crisis and chronic management. Subcutaneous Immunoglobulins (SCIg), which offer the advantage of home administration, may be a practical and effective option in chronic management of MG. We analyzed clinical outcomes and patient satisfaction in nine cases of chronic disabling MG who were either transitioned to, or started de novo on SCIg. METHODS AND FINDINGS: This was a retrospective cohort study for the period of 2015-2016, with a mean follow-up period of 6.8 months after initiation of SCIg. All patients with MG treated with SCIg at the Ottawa Hospital, a large Canadian tertiary hospital with subspecialty expertise in neuromuscular disorders were included, regardless of MG severity, clinical subtype and antibody status. The primary outcome was MG disease activity after SCIg initiation. This outcome was measured by 1) the Myasthenia Gravis Foundation of America (MGFA) clinical classification, and 2) subjective scales of disease activity including the Myasthenia Gravis activities of daily living profile (MG-ADL), Myasthenia Gravis Quality-of-life (MG-QOL 15), Visual Analog (VA) satisfaction scale. We also assessed any requirement for emergency department visits or hospitalizations. Safety outcomes included any SCIg related complication. All patients were stable or improved for MGFA class after SCIg initiation. Statistically significant improvements were documented in the MG-ADL, MG-QOL and VAS scales. There were no exacerbations after switching therapy and no severe SCIg related complications. CONCLUSIONS: SCIg may be a beneficial therapy in the chronic management of MG, with favorable clinical outcome and patient satisfaction results. PMID- 27490100 TI - Early Fungicidal Activity as a Candidate Surrogate Endpoint for All-Cause Mortality in Cryptococcal Meningitis: A Systematic Review of the Evidence. AB - BACKGROUND: Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality. In clinical trials evaluating treatments for CM, biomarkers of early fungicidal activity (EFA) in cerebrospinal fluid (CSF) have been proposed as candidate surrogate endpoints for all- cause mortality (ACM). However, there has been no systematic evaluation of the group-level or trial-level evidence for EFA as a candidate surrogate endpoint for ACM. METHODS: We conducted a systematic review of randomized trials in treatment of CM to evaluate available evidence for EFA measured as culture negativity at 2 weeks/10 weeks and slope of EFA as candidate surrogate endpoints for ACM. We performed sensitivity analysis on superiority trials and high quality trials as determined by Cochrane measures of trial bias. RESULTS: Twenty-seven trials including 2854 patients met inclusion criteria. Mean ACM was 15.8% at 2 weeks and 27.0% at 10 weeks with no overall significant difference between test and control groups. There was a statistically significant group-level correlation between average EFA and ACM at 10 weeks but not at 2 weeks. There was also no statistically significant group-level correlation between CFU culture negativity at 2weeks/10weeks or average EFA slope at 10 weeks. A statistically significant trial-level correlation was identified between EFA slope and ACM at 2 weeks, but is likely misleading, as there was no treatment effect on ACM. CONCLUSIONS: Mortality remains high in short time periods in CM clinical trials. Using published data and Institute of Medicine criteria, evidence for use of EFA as a surrogate endpoint for ACM is insufficient and could provide misleading results from clinical trials. ACM should be used as a primary endpoint evaluating treatments for cryptococcal meningitis. PMID- 27490102 TI - Salicylic Acid and Sodium Salicylate Alleviate Cadmium Toxicity to Different Extents in Maize (Zea mays L.). AB - The role of salicylic acid in Cd tolerance has attracted more attention recently but no information is available on the efficiency of different forms of salicylic acid. The aim was thus to investigate whether both the acid and salt forms of salicylic acid provide protection against Cd stress and to compare their mode of action. Young maize plants were grown under controlled environmental conditions. One group of 10-day-old seedlings were treated with 0.5 mM SA or NaSA for 1 day then half of the pants were treated with 0.5 mM Cd for 1 day. Another group of seedlings was treated with 0.5 mM CdSO4 for 1 day without pre-treatment with SA or NaSA, while a third group was treated simultaneously with Cd and either SA or NaSA. Both salicylic acid forms reduced the Cd accumulation in the roots. Treatment with the acidic form meliorated the Cd accumulation in the leaves, while Na-salicylate increased the phytochelatin level in the roots and the amount of salicylic acid in the leaves. Furthermore, increased antioxidant enzyme activity was mainly induced by the acid form, while glutathione-related redox changes were influenced mostly by the salt form. The acidic and salt forms of salicylic acid affected the two antioxidant systems in different ways, and the influence of these two forms on the distribution and detoxification of Cd also differed. The present results also draw attention to the fact that generalisations about the stress protective mechanisms induced by salicylic acid are misleading since different forms of SA may exert different effects on the plants via separate mechanisms. PMID- 27490104 TI - Selective Data Analysis in Brown et al.'s Continued Critical Reanalysis. PMID- 27490103 TI - Co-Administration of Soy Isoflavones and Vitamin D in Management of Irritable Bowel Disease. AB - BACKGROUND AND AIMS: The substantial characteristics of Irritable Bowel Syndrome (IBS) are associated with estrogens in women. Both soy isoflavones and vitamin D can modulate estrogen receptors in the colonic smooth muscles. The aim of this study was to investigate the effects of soy isoflavones, vitamin D and their probable interactions in women with IBS. METHODS: In a factorial blinded randomized clinical trial, 100 women with IBS (age:18-75yr, were randomly assigned in 4 arms to receive either placebo of vitamin D and placebo of soy isoflavones (P+P), or placebo of vitamin D and soy isoflavones (P+S), or vitamin D and placebo of soy isoflavones (D+P), or vitamin D and soy isoflavones (D+S) for 6 weeks. Dosage of soy isoflavone was 2 capsules of 20 mg soy isoflavones per day, and dosage of vitamin D was one pearl of 50'000 IU biweekly. The clinical outcomes were IBS symptoms severity scores (IBS-SSS), disease- specific quality of life (IBS-QOL) and total score (IBS-TS) that evaluated at weeks 0, 6, and 10, and compared to each other. RESULTS: IBS-TS improved significantly in both S+P and D+P groups (p- value = 0.004, 0.015). The interaction effect of soy isoflavones and vitamin D on IBS-TS was significant (p<0.05). The interaction effect of soy isoflavones with vitamin D and the main effect of vitamin D on IBS SSS were not statistically significant, whereas IBS-SSS decreased significantly in S+P and D+P groups (p-value = 0.001, 0.047 respectively). CONCLUSION: Our results indicate that co-administration of soy isoflavones with vitamin D did not improve the IBS- SSS and IBS- QOL; however, it improved the IBS-TS. TRIAL REGISTRATION: Clinical Trials.gov NCT02026518. PMID- 27490105 TI - CONGENITAL CYSTIC LUNG LESIONS: EVOLUTION FROM IN-UTERO TO PATHOLOGY DIAGNOSIS - A MULTIDISCIPLINARY APPROACH. AB - Congenital cystic lung lesions (CCLL) are a group of rare pathologies that are usually diagnosed in the pre-natal period. The majority of these lesions are diagnosed at pathology examination as congenital pulmonary airway malformations (CPAM) and bronchopulmonary sequestration (BPS). These lesions are typically managed by surgical intervention within the first year of life and have an excellent prognosis. We examined the evolution of imaging appearances from prenatal diagnosis to postnatal work-up of these lesions and correlate imaging and pathological findings. An 8-year retrospective review of the perinatal and pathology database of a single tertiary care center identified 42 cases of CCLL of which 36 had known prenatal ultrasound and prenatal course available. Final pathologic diagnoses were: 15 CPAM (41%), 7 BPS (19%) and 9 hybrid BPS and CPAM lesions (25%). Five cases with bronchial atresia were also identified (either in isolation or associated with CPAM or BPS). The overall characteristics of these lesions by prenatal ultrasound, postnatal imaging, and ultimate histopathologic diagnosis are described. PMID- 27490106 TI - Identifying the topology of signaling networks from partial RNAi data. AB - BACKGROUND: Methods for inferring signaling networks using single gene knockdown RNAi experiments and reference networks have been proposed in recent years. These methods assume that RNAi information is available for all the genes in the signal transduction pathway, i.e., complete. This assumption does not always hold up since RNAi experiments are often incomplete and information for some genes is missing. RESULTS: In this article, we develop two methods to construct signaling networks from incomplete RNAi data with the help of a reference network. These methods infer the RNAi constraints for the missing genes such that the inferred network is closest to the reference network. We perform extensive experiments with both real and synthetic networks and demonstrate that these methods produce accurate results efficiently. CONCLUSIONS: Application of our methods to Wnt signal transduction pathway has shown that our methods can be used to construct highly accurate signaling networks from experimental data in less than 100 ms. The two methods that produce accurate results efficiently show great promise of constructing real signaling networks. PMID- 27490107 TI - Rh-Catalyzed [3 + 2] Cycloaddition of 1-Sulfonyl-1,2,3-triazoles: Access to the Framework of Aspidosperma and Kopsia Indole Alkaloids. AB - A Rh(II)-catalyzed dearomative intramolecular [3 + 2] dipolar cycloaddition involving the indolic C2-C3 carbon-carbon double bond has been developed. The reaction was launched from the triazole moiety within the substrate and proceeded efficiently under mild conditions. A wide range of functional groups could be tolerated. These features render the current reaction a highly useful tool for the synthesis of polycyclic indole alkaloids, as showcased by a rapid assembly of the core structure of Aspidosperma and the related alkaloids. PMID- 27490108 TI - The Virtuous Cycle of a Data Ecosystem. PMID- 27490110 TI - Metagenomic Analysis of Fungal Diversity on Strawberry Plants and the Effect of Management Practices on the Fungal Community Structure of Aerial Organs. AB - An amplicon metagenomic approach based on the ITS2 region of fungal rDNA was used to identify the composition of fungal communities associated with different strawberry organs (leaves, flowers, immature and mature fruits), grown on a farm using management practices that entailed the routine use of various chemical pesticides. ITS2 sequences clustered into 316 OTUs and Ascomycota was the dominant phyla (95.6%) followed by Basidiomycota (3.9%). Strawberry plants supported a high diversity of microbial organisms, but two genera, Botrytis and Cladosporium, were the most abundant, representing 70-99% of the relative abundance (RA) of all detected sequences. According to alpha and beta diversity analyses, strawberry organs displayed significantly different fungal communities with leaves having the most diverse fungal community, followed by flowers, and fruit. The interruption of chemical treatments for one month resulted in a significant modification in the structure of the fungal community of leaves and flowers while immature and mature fruit were not significantly affected. Several plant pathogens of other plant species, that would not be intuitively expected to be present on strawberry plants such as Erysiphe, were detected, while some common strawberry pathogens, such as Rhizoctonia, were less evident or absent. PMID- 27490109 TI - A Proteomic Investigation of Hepatic Resistance to Ascaris in a Murine Model. AB - The helminth Ascaris causes ascariasis in both humans and pigs. Humans, especially children, experience significant morbidity including respiratory complications, growth deficits and intestinal obstruction. Given that 800 million people worldwide are infected by Ascaris, this represents a significant global public health concern. The severity of the symptoms and associated morbidity are related to the parasite burden and not all hosts are infected equally. While the pathology of the disease has been extensively examined, our understanding of the molecular mechanisms underlying resistance and susceptibility to this nematode infection is poor. In order to investigate host differences associated with heavy and light parasite burden, an experimental murine model was developed utilising Ascaris-susceptible and -resistant mice strains, C57BL/6J and CBA/Ca, respectively, which experience differential burdens of migratory Ascaris larvae in the host lungs. Previous studies identified the liver as the site where this difference in susceptibility occurs. Using a label free quantitative proteomic approach, we analysed the hepatic proteomes of day four post infection C57BL/6J and CBA/Ca mice with and without Ascaris infection to identify proteins changes potentially linked to both resistance and susceptibility amongst the two strains, respectively. Over 3000 proteins were identified in total and clear intrinsic differences were elucidated between the two strains. These included a higher abundance of mitochondrial proteins, particularly those associated with the oxidative phosphorylation pathway and reactive oxygen species (ROS) production in the relatively resistant CBA/Ca mice. We hypothesise that the increased ROS levels associated with higher levels of mitochondrial activity results in a highly oxidative cellular environment that has a dramatic effect on the nematode's ability to successfully sustain a parasitic association with its resistant host. Under infection, both strains had increased abundances in proteins associated with the oxidative phosphorylation pathway, as well as the tricarboxylic acid cycle, with respect to their controls, indicating a general stress response to Ascaris infection. Despite the early stage of infection, some immune-associated proteins were identified to be differentially abundant, providing a novel insight into the host response to Ascaris. In general, the susceptible C57BL/6J mice displayed higher abundances in immune-associated proteins, most likely signifying a more active nematode cohort with respect to their CBA/Ca counterparts. The complement component C8a and S100 proteins, S100a8 and S100a9, were highly differentially abundant in both infected strains, signifying a potential innate immune response and the importance of the complement pathway in defence against macroparasite infection. In addition, the signatures of an early adaptive immune response were observed through the presence of proteins, such as plastin-2 and dipeptidyl peptidase 1. A marked decrease in proteins associated with translation was also observed in both C57BL/6J and CBA/Ca mice under infection, indicative of either a general response to Ascaris or a modulatory effect by the nematode itself. Our research provides novel insights into the in vivo host-Ascaris relationship on the molecular level and provides new research perspectives in the development of Ascaris control and treatment strategies. PMID- 27490111 TI - Adrenal Hormone and Metabolic Biomarker Responses to 30 min of Intermittent Cycling Exercise in Breast Cancer Survivors. AB - The aim of this study was to explore the effect of one bout of aerobic exercise on epinephrine, norepinephrine, cortisol, glucose, lactate, and free fatty acid (FFA) responses in breast cancer survivors and healthy controls. 9 female breast cancer survivors and 9 women without a history of cancer completed 30 min of cycle ergometry exercise at 60% of VO2peak. Blood samples were taken pre exercise, immediately post-exercise, and 2 h post-exercise from which plasma concentrations of study variables were measured. Immediately and 2 h post exercise, increases were observed in epinephrine (control group only) norepinephrine (both groups), lactate (both groups), and FFA (both groups immediately post-exercise; breast cancer survivor group only at 2 h post exercise) (p<0.05). Cortisol decreased immediately and 2 h post-exercise in the control group while glucose decreased immediately post-exercise in the breast cancer survivor group (p<0.05). In conclusion, breast cancer survivors appeared to display attenuated epinephrine, cortisol, and lactate responses while displaying larger magnitude changes in glucose and FFA responses compared to controls. These preliminary findings may have implications for the regulation of metabolism during exercise in breast cancer survivors. PMID- 27490112 TI - The Role of Body Habitus in Predicting Cardiorespiratory Fitness: The FRIEND Registry. AB - This study aimed to validate and cross-validate a non-exercise prediction model from a large and apparently healthy US cohort of individuals who underwent an analysis of body habitus (waist circumference (WC) and body mass index (BMI)) with measured CRF. The large cohort (5 030 individuals) was split into validation (4 030) and cross-validation (1 000) groups, whereby waist circumference and maximal aerobic capacity (VO2max) were assessed by rigorously approved laboratories. VO2max was estimated in 2 multiple regression equations using age, sex and either WC (r=0.77; standard error of the estimate (SEE) 6.70 mLO2?kg( 1)?min(-1)) or BMI (r=0.76; SEE 6.89 mLO2?kg(-1)?min(-1)).Cross-validation yielded similar results. However, as VO2max increased, there was increased bias, suggesting VO2max may be underestimated at higher values. Both WC and BMI prediction models yielded similar findings, with WC having a slightly smaller SEE. These measures of body habitus appear to be adequate in predicting CRF using non-exercise parameters, even without a measure of physical activity. Caution should be taken when using these equations in more fit individuals. PMID- 27490113 TI - Modeling the prevention of colorectal cancer from the combined impact of host and behavioral risk factors. AB - PURPOSE: This study investigated the utility of modeling modifiable lifestyle risk factors in addition to genetic variation in colorectal cancer (CRC) screening/prevention. METHODS: We derived a polygenic risk score for CRC susceptibility variants in combination with the established nongenetic risk factors of inflammatory bowel disease (IBD), adiposity, alcohol, red meat, fruit, vegetables, smoking, physical activity, and aspirin. We used the 37 known risk variants and 50 and 100% of all risk variants as calculated from a heritability estimate. We derived absolute risk from UK population age structure, incidence, and mortality rate data. RESULTS: Taking into account all risk factors (known variants), 42.2% of 55- to 59-year-old men with CRC have a risk at least as high as that of an average 60-year-old, the minimum eligible age for the UK NHS National Bowel Cancer Screening Program. If the male population is stratified by known variants and IBD status, then risk-difference estimates imply that for 10,000 50-year-old men in the 99th percentile, 760 cases could be prevented over a 25-year period through the modifiable risk factors, but in the lowest percentile, only 90 could be prevented. CONCLUSION: CRC screening and prevention centered on modifiable risk factors could be optimized if targeted at individuals at higher polygenic risk.Genet Med 19 3, 314-321. PMID- 27490114 TI - Is "incidental finding" the best term?: a study of patients' preferences. AB - PURPOSE: There is debate within the genetics community about the optimal term to describe genetic variants unrelated to the test indication but potentially important for health. Given the lack of consensus and the importance of adopting terminology that promotes effective clinical communication, we sought the opinion of clinical genetics patients. METHODS: Surveys and focus groups with two patient populations were conducted. Eighty-eight survey participants were asked to rank four terms according to how well each describes results unrelated to the test indication: incidental findings, secondary findings, additional findings, and ancillary findings. Participants in six focus groups were guided through a free thought exercise to describe the desired attributes of such a term and then asked to formulate the best term to represent this concept. RESULTS: The term additional findings had the most first-choice rankings by survey participants, followed by secondary findings, incidental findings, and ancillary findings. Most focus group participants preferred the term additional findings; they also gave reasons why other terms were not optimal. CONCLUSION: Additional findings was preferred because it was more neutral and accessible than other terms currently in use. Patient perceptions and comprehension will be framed by the terminology used by healthcare providers. Thus, patient opinions should be considered by medical genetics professionals.Genet Med 19 2, 176-181. PMID- 27490116 TI - Distributive justice, diversity, and inclusion in precision medicine: what will success look like? PMID- 27490115 TI - NR5A1 is a novel disease gene for 46,XX testicular and ovotesticular disorders of sex development. AB - PURPOSE: We aimed to identify the genetic cause in a cohort of 11 unrelated cases and two sisters with 46,XX SRY-negative (ovo)testicular disorders of sex development (DSD). METHODS: Whole-exome sequencing (n = 9), targeted resequencing (n = 4), and haplotyping were performed. Immunohistochemistry of sex-specific markers was performed on patients' gonads. The consequences of mutation were investigated using luciferase assays, localization studies, and RNA-seq. RESULTS: We identified a novel heterozygous NR5A1 mutation, c.274C>T p.(Arg92Trp), in three unrelated patients. The Arg92 residue is highly conserved and located in the Ftz-F1 region, probably involved in DNA-binding specificity and stability. There were no consistent changes in transcriptional activation or subcellular localization. Transcriptomics in patient-derived lymphocytes showed upregulation of MAMLD1, a direct NR5A1 target previously associated with 46,XY DSD. In gonads of affected individuals, ovarian FOXL2 and testicular SRY-independent SOX9 expression observed. CONCLUSIONS: We propose NR5A1, previously associated with 46,XY DSD and 46,XX primary ovarian insufficiency, as a novel gene for 46,XX (ovo)testicular DSD. We hypothesize that p.(Arg92Trp) results in decreased inhibition of the male developmental pathway through downregulation of female antitestis genes, thereby tipping the balance toward testicular differentiation in 46,XX individuals. In conclusion, our study supports a role for NR5A1 in testis differentiation in the XX gonad.Genet Med 19 4, 367-376. PMID- 27490117 TI - Contraceptive Use Among Nonpregnant and Postpartum Women at Risk for Unintended Pregnancy, and Female High School Students, in the Context of Zika Preparedness - United States, 2011-2013 and 2015. AB - Zika virus infection during pregnancy can cause congenital microcephaly and brain abnormalities (1,2). Since 2015, Zika virus has been spreading through much of the World Health Organization's Region of the Americas, including U.S. territories. Zika virus is spread through the bite of Aedes aegypti or Aedes albopictus mosquitoes, by sex with an infected partner, or from a pregnant woman to her fetus during pregnancy.* CDC estimates that 41 states are in the potential range of Aedes aegypti or Aedes albopictus mosquitoes (3), and on July 29, 2016, the Florida Department of Health identified an area in one neighborhood of Miami where Zika virus infections in multiple persons are being spread by bites of local mosquitoes. These are the first known cases of local mosquito-borne Zika virus transmission in the continental United States.(?) CDC prevention efforts include mosquito surveillance and control, targeted education about Zika virus and condom use to prevent sexual transmission, and guidance for providers on contraceptive counseling to reduce unintended pregnancy. To estimate the prevalence of contraceptive use among nonpregnant and postpartum women at risk for unintended pregnancy and sexually active female high school students living in the 41 states where mosquito-borne transmission might be possible, CDC used 2011-2013 and 2015 survey data from four state-based surveillance systems: the Behavioral Risk Factor Surveillance System (BRFSS, 2011-2013), which surveys adult women; the Pregnancy Risk Assessment Monitoring System (PRAMS, 2013) and the Maternal and Infant Health Assessment (MIHA, 2013), which surveys women with a recent live birth; and the Youth Risk Behavior Survey (YRBS, 2015), which surveys students in grades 9-12. CDC defines an unintended pregnancy as one that is either unwanted (i.e., the pregnancy occurred when no children, or no more children, were desired) or mistimed (i.e., the pregnancy occurred earlier than desired). The proportion of women at risk for unintended pregnancy who used a highly effective reversible method, known as long-acting reversible contraception (LARC), ranged from 5.5% to 18.9% for BRFSS-surveyed women and 6.9% to 30.5% for PRAMS/MIHA-surveyed women. The proportion of women not using any contraception ranged from 12.3% to 34.3% (BRFSS) and from 3.5% to 15.3% (PRAMS/MIHA). YRBS data indicated that among sexually active female high school students, use of LARC at last intercourse ranged from 1.7% to 8.4%, and use of no contraception ranged from 7.3% to 22.8%. In the context of Zika preparedness, the full range of contraceptive methods approved by the Food and Drug Administration (FDA), including LARC, should be readily available and accessible for women who want to avoid or delay pregnancy. Given low rates of LARC use, states can implement strategies to remove barriers to the access and availability of LARC including high device costs, limited provider reimbursement, lack of training for providers serving women and adolescents on insertion and removal of LARC, provider lack of knowledge and misperceptions about LARC, limited availability of youth-friendly services that address adolescent confidentiality concerns, inadequate client centered counseling, and low consumer awareness of the range of contraceptive methods available. PMID- 27490119 TI - Expanding Host Range and Cross-Species Infection of Hepatitis E Virus. PMID- 27490118 TI - HIF-2alpha Expression Regulates Sprout Formation into 3D Fibrin Matrices in Prolonged Hypoxia in Human Microvascular Endothelial Cells. AB - BACKGROUND: During short-term hypoxia, Hypoxia Inducible Factors (particular their subunits HIF-1alpha and HIF-2alpha) regulate the expression of many genes including the potent angiogenesis stimulator VEGF. However, in some pathological conditions chronic hypoxia occurs and is accompanied by reduced angiogenesis. OBJECTIVES: We investigated the effect of prolonged hypoxia on the proliferation and sprouting ability of human microvascular endothelial cells and the involvement of the HIFs and Dll4/Notch signaling. METHODS AND RESULTS: Human microvascular endothelial cells (hMVECs), cultured at 20% oxygen for 14 days and seeded on top of 3D fibrin matrices, formed sprouts when stimulated with VEGF A/TNFalpha. In contrast, hMVECs precultured at 1% oxygen for 14 days were viable and proliferative, but did not form sprouts into fibrin upon VEGF-A/TNFalpha stimulation at 1% oxygen. Silencing of HIF-2alpha with si-RNA partially restored the inhibition of endothelial sprouting, whereas HIF-1alpha or HIF-3alpha by si RNA had no effect. No involvement of Dll4/Notch pathway in the inhibitory effect on endothelial sprouting by prolonged hypoxia was found. In addition, hypoxia decreased the production of urokinase-type plasminogen activator (uPA), needed for migration and invasion, without a significant effect on its inhibitor PAI-1. This was independent of HIF-2alpha, as si-HIF-2alpha did not counteract uPA reduction. CONCLUSION: Prolonged culturing of hMVECs at 1% oxygen inhibited endothelial sprouting into fibrin. Two independent mechanisms contribute. Silencing of HIF-2alpha with si-RNA partially restored the inhibition of endothelial sprouting pointing to a HIF-2alpha-dependent mechanism. In addition, reduction of uPA contributed to reduced endothelial tube formation in a fibrin matrix during prolonged hypoxia. PMID- 27490120 TI - Prediction of scaffold proteins based on protein interaction and domain architectures. AB - BACKGROUND: Scaffold proteins are known for being crucial regulators of various cellular functions by assembling multiple proteins involved in signaling and metabolic pathways. Identification of scaffold proteins and the study of their molecular mechanisms can open a new aspect of cellular systemic regulation and the results can be applied in the field of medicine and engineering. Despite being highlighted as the regulatory roles of dozens of scaffold proteins, there was only one known computational approach carried out so far to find scaffold proteins from interactomes. However, there were limitations in finding diverse types of scaffold proteins because their criteria were restricted to the classical scaffold proteins. In this paper, we will suggest a systematic approach to predict massive scaffold proteins from interactomes and to characterize the roles of scaffold proteins comprehensively. RESULTS: From a total of 10,419 basic scaffold protein candidates in protein interactomes, we classified them into three classes according to the structural evidences for scaffolding, such as domain architectures, domain interactions and protein complexes. Finally, we could define 2716 highly reliable scaffold protein candidates and their characterized functional features. To assess the accuracy of our prediction, the gold standard positive and negative data sets were constructed. We prepared 158 gold standard positive data and 844 gold standard negative data based on the functional information from Gene Ontology consortium. The precision, sensitivity and specificity of our testing was 80.3, 51.0, and 98.5 % respectively. Through the function enrichment analysis of highly reliable scaffold proteins, we could confirm the significantly enriched functions that are related to scaffold protein binding. We also identified functional association between scaffold proteins and their recruited proteins. Furthermore, we checked that the disease association of scaffold proteins is higher than kinases. CONCLUSIONS: In conclusion, we could predict larger volume of scaffold proteins and analyzed their functional characteristics. Deeper understandings about the roles of scaffold proteins from this study will provide a higher opportunity to find therapeutic or engineering applications of scaffold proteins using their functional characteristics. PMID- 27490121 TI - Surface Sites in Cu-Nanoparticles: Chemical Reactivity or Microscopy? AB - Copper nanoparticles are widely used in catalysis and electrocatalysis, and the fundamental understanding of their activity requires reliable methods to assess the number of potentially reactive atoms exposed on the surface. Herein, we provide a molecular understanding of the difference observed in addressing surface site titration using prototypical methods: transmission electron micrscopy (TEM), H2 chemisorption, and N2O titration by a combination of experimental and theoretical study. We show in particular that microscopy does not allow assessing the amount of reactive surface sites, while H2 and N2O chemisorptions can, albeit with slightly different stoichiometries (1 O/2CuS and 1 H2/2.2CuS), which can be rationalized by density functional theory calculations. High-resolution TEM shows that the origin of the observed difference between microscopy and titration methods is due to the strong metal support interaction experienced by small copper nanoparticles with the silica surface. PMID- 27490122 TI - The rich and the poor: environmental biodiversity protecting from allergy. AB - PURPOSE OF REVIEW: It has been proposed that biodiversity loss leads to reduced interaction between environmental and human microbiotas. This, in turn, may lead to immune dysfunction and impaired tolerance mechanisms in humans. That is, contact with environmental biodiversity is expected to protect from allergies. However, direct evidence linking contact with biodiversity and risk of allergy has been lacking. In this review, we consider the latest research on the biodiversity hypothesis of allergy. RECENT FINDINGS: It is becoming clear that what you eat, drink, inhale, and touch all contribute to the grand scheme of host microbial crosstalk that is needed for a balanced, healthy immune system to develop and maintain a healthy recognition between harmful and harmless invasions. Microbes can either communicate directly with host immune cells or affect the host via metabolism that can even lead to epigenetic modifications. Our living environment plays a key role in this process. Although especially, early exposure to diverse, beneficial microbiota from the environment is repeatedly found crucial, studies on immigrants demonstrate that condition in later life can also be decisive. CONCLUSION: We are still lacking a more detailed understanding of the interaction between natural, environmental biodiversity, and health, which calls for new innovative and more long-term investigations. The outcomes should be utilized in policy and urban planning efforts, promoting human interaction with natural biodiversity, and supporting a healthy lifestyle. PMID- 27490123 TI - An update on ocular allergy. AB - PURPOSE OF REVIEW: The update reviews prevalence, classification, cause, and treatment options for allergic eye disease. RECENT FINDINGS: The incidence of allergic eye disease is underreported but may affect almost all patients with allergic rhinitis. Increased rates of oculonasal symptoms have been reported in the United States resulting in significant economic expenditures. The spectrum of allergic conjunctivitis and its differential considerations include seasonal and perennial conjunctivitis, vernal and atopic keratoconjunctivitis, and giant papillary conjunctivitis. Patients with allergic conjunctivitis have classic immunoglobulin E-mediated pathophysiology and treatments directed at allergen avoidance, traditional pharmacotherapy with oral antihistamines, topical dual acting antihistamine/mast cell stabilizer agents, and treatment of tear film dysfunction are first-line management strategies. Immunotherapy is an effective treatment option and refractory cases may require ophthalmology comanagement for consideration of topical ester-based corticosteroid therapy and consideration of topical immunomodulators. SUMMARY: Ocular allergy involving specific modifiable and treatable environmental sensitizations is common and often underrecognized. It can impair quality of life to varying degrees. Some cases are quite refractory to management and may require multidisciplinary coordination of care between allergy and ophthalmology specialists. Understanding classification, triggers, and treatment options is important in designing the most appropriate patient tailored management plans. PMID- 27490125 TI - The 'omics' revolution: redefining the understanding and treatment of allergic skin diseases. AB - PURPOSE OF REVIEW: To evaluate how the genomic, transcriptomic, and proteomic profiles of allergic skin diseases, like atopic dermatitis and allergic contact dermatitis, contribute to their understanding and promote their therapeutic development. RECENT FINDINGS: The '-omics' revolution has facilitated the quantification of inflammatory skin diseases at the molecular level, expanding our understanding of disease pathogenesis. It has also greatly expanded once limited treatment options and improved the ability to define posttreatment improvements, beyond clinical scores. The findings on the genomic/transcriptomic level are also complemented by proteomic data, contributing to the understanding of the later changes taking place in the final stages of protein formation. Atopic dermatitis is defined as a Th2/Th22 polarized disease with some contributions of Th17 and Th1 pathways. In atopic dermatitis, studies of biologics and small molecules, targeting specific pathways upregulated in atopic dermatitis, seem to provide well tolerated alternatives to conventional immunosuppressive therapies (i.e. corticosteroids and cyclosporine A), particularly for severe patients. Allergic contact dermatitis is defined as having Th1/Th17-centered inflammation, especially with nickel-induced disease, but additional pathways, including Th2 and Th22, are upregulated with other allergens (i.e. fragrance). SUMMARY: Supplementing studies of allergic skin diseases with '-omics' approaches are transforming the pathogenic understanding, diagnosis and, perhaps, also the treatment of these diseases. PMID- 27490124 TI - Epidemiology of severe anaphylaxis: can we use population-based data to understand anaphylaxis? AB - PURPOSE OF REVIEW: The observed increase in incidence of allergic disease in many regions over the past 3 decades has intensified interest in understanding the epidemiology of severe allergic reactions. We discuss the issues in collecting and interpreting these data and highlight current deficiencies in the current methods of data gathering. RECENT FINDINGS: Anaphylaxis, as measured by hospital admission rates, is not uncommon and has increased in the United Kingdom, the United States, Canada, and Australia over the last 10-20 years. All large datasets are hampered by a large proportion of uncoded, 'unspecified' causes of anaphylaxis. Fatal anaphylaxis remains a rare event, but appears to be increasing for medication in Australia, Canada, and the United States. The rate of fatal food anaphylaxis is stable in the United Kingdom and the United States, but has increased in Australia. The age distribution for fatal food anaphylaxis is different to other causes, with data suggesting an age-related predisposition to fatal outcomes in teenagers and adults to the fourth decade of life. SUMMARY: The increasing rates of food and medication allergy (the latter exacerbated by an ageing population) has significant implications for future fatality trends. An improved ability to accurately gather and analyse population-level anaphylaxis data in a harmonized fashion is required, so as to ultimately minimize risk and improve management. PMID- 27490126 TI - A systematic review of the role of interleukin-17 and the interleukin-20 family in inflammatory allergic skin diseases. AB - PURPOSE OF REVIEW: Allergic skin diseases include atopic dermatitis/eczema, contact dermatitis, and drug hypersensitivity. Allergic skin diseases have a high prevalence. Atopic dermatitis is one of the most common inflammatory skin diseases and similar for allergic rhinitis and allergic asthma. Over a long period, allergic diseases have been regarded as immunoglobulin E-mediated T helper-2 (Th2)-driven. But new cytokines and T cells have been discovered within the last years. In this systematic review, the focus is laid on interleukin-17 (IL-17) and the interleukin-20 (IL-20) family which appear to be fine-tuning the Th2-driven answer. RECENT FINDINGS: IL-17 is a proinflammatory cytokine, which is produced by T cells. Primarily, IL-17 is produced by activated CD4+ cells, called Th-17 cells. IL-17 regulates keratinocyte expression of adhesion molecules and chemokines. IL-17 is involved in the pathogenesis of inflammatory diseases as psoriasis, arthritis, and inflammatory bowel diseases. In allergic diseases, the involvement of the TH17/IL17-pathway has only been recently described. Regarding the IL-20 family, IL-22 is the most interesting and the most studied cytokine in terms of allergic inflammatory disorders. IL-22 is produced by T-helper 22 cells, a new subset of CD4+ cells. SUMMARY: IL-17 as well as IL-22 seem to play a role in the pathogenesis of allergic skin diseases. PMID- 27490127 TI - Atopic dermatitis: new evidence on the role of allergic inflammation. AB - PURPOSE OF REVIEW: Atopic dermatitis is a chronic relapsing inflammatory skin disease. In the presence of a complex genetic background, there is increasing evidence for the role of specific allergenic trigger factors in perpetuating skin inflammation in sensitized atopic dermatitis patients. In this review, clinical and in-vitro data so far published on allergen-induced adaptive immune responses in atopic dermatitis are summarized. RECENT FINDINGS: Emerging new data have been published particularly on adaptive immune responses to inhalant allergens in atopic dermatitis. In a randomized controlled study, the induction of a flare-up by grass pollen exposure in sensitized atopic dermatitis patients could be demonstrated for the first time. T cells directed to the two major allergens of house dust mite have been characterized to display a Th2, and moreover, a Th17 and Th2/Th17 phenotype in sensitized atopic dermatitis patients. With regard to microbial antigens, T cell-mediated immune responses directed to proteins of the species themselves can be observed - as has been published for Staphylococcus aureus and Malassezia spp. Beyond this, specific T-cell activation to cross reacting human proteins might further trigger the disease in distinct patients. The role of 'autoallergic' phenomena in atopic dermatitis, because of human antigens without known cross-reactivity to environmental allergens, is currently under investigation as well. SUMMARY: Recent findings on immunological and clinical characteristics of adaptive immune responses to allergens in atopic dermatitis, but also on the identification of new, potentially relevant allergen sources might contribute to the development of effective treatment strategies 'customized' for allergic inflammation in atopic dermatitis in future. PMID- 27490128 TI - Leveraging Methylome-Environment Interaction to Detect Genetic Determinants of Disease. AB - OBJECTIVE: The association between DNA methylation and a trait of interest may depend on an environmental exposure, and incorrectly accounting for this dependence can lead to a reduction in power of the standard tests used in epigenome-wide association studies. We present the M-ME test to jointly test for the main effect of DNA methylation and methylation-environment interaction. METHODS: Through simulation, we compare the power and type 1 error of the M-ME test to a standard marginal test (M test) and a standard interaction test (ME test) under 1,800 different underlying models. These models allow for methylation environment correlation and measurement error in the exposure. RESULTS: In many true underlying models, either the M test or the ME test has very low power, but the M-ME test has optimal or nearly optimal power to detect a DNA methylation effect in all models considered, including those with methylation- environment dependence and measurement error in the exposure. Type 1 error inflation occurs in the tests when the exposure is measured with error and correlated with DNA methylation. CONCLUSION: The M-ME test is an attractive choice for studies aiming to detect any DNA methylation association when little is known about the epigenetic associations a priori. PMID- 27490129 TI - Predictors of Ventriculoperitoneal Shunt Failure in Children Undergoing Initial Placement or Revision. AB - BACKGROUND: Ventriculoperitoneal (VP) shunt placement, the mainstay of treatment for hydrocephalus, can place a substantial burden on patients and health care systems because of high complication and revision rates. We aimed to identify factors associated with 30-day VP shunt failure in children undergoing either initial placement or revision. METHODS: VP shunt placements performed on patients in the 2012-2013 American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Pediatric were identified. RESULTS: VP shunts were placed in 3,984 patients either as an initial placement (n = 1,093) or as a revision (n = 2,891). Compared to the initial-placement group, the revision group was significantly more likely to experience shunt failure (14 vs. 8%, p < 0.0001). In the initial-placement group, congenital hydrocephalus was independently associated with shunt failure (OR 1.83; 95% CI 1.01-3.31, p = 0.047). In the revision group, cardiac risk factors (OR 1.38; 95% CI 1.00-1.90, p = 0.047), a chronic history of seizures (OR 1.33; 95% CI 1.04-1.71, p = 0.022), and a history of neuromuscular disease (OR 0.61; 95% CI 0.41-0.90, p = 0.014) were independently associated with shunt failure. CONCLUSIONS: Identifying the factors associated with VP shunt failure may allow the development of interventions to decrease failures. Further refinement of the collected variables in the NSQIP Pediatric specific to neurosurgical procedures is necessary to identify modifiable risk factors. PMID- 27490130 TI - What Is the CT Dose Report Sheet and Why Is It Useful? PMID- 27490131 TI - Diagnostic and Management Strategies for Multiligament Knee Injuries: A Critical Analysis Review. AB - Multiligament knee injuries have a strong association with periarticular soft tissue and neurovascular injuries, which must not be overlooked in the initial evaluation of the patient. Even though magnetic resonance imaging (MRI) is imperative for a complete evaluation of the damaged ligamentous knee restraints, stress radiography aids in establishing the functional consequence of the MRI findings and may assist in directing reconstruction. Although cruciate ligament tears are generally reconstructed, a combined repair-reconstruction approach is most useful for collateral ligaments and extra-articular structures, with incorporation of local tissue into the reconstruction whenever possible. Regardless of the timing and operative technique chosen, patients with multiligament knee injuries are at high risk for complications and long-term disability. PMID- 27490132 TI - Surgical and Functional Outcomes After Limb-Preservation Surgery for Tumor in Pediatric Patients: A Systematic Review. AB - BACKGROUND: Limb-salvage surgery and segmental reconstruction for the treatment of lower extremity osseous tumors in the pediatric population have been described in the literature, but there is little consensus regarding the optimal surgical treatment for this patient population. METHODS: A systematic review of the literature was performed to identify studies focusing on limb-salvage procedures in pediatric patients who were managed with one of three reconstructions with use of a metallic endoprosthesis, allograft, or allograft-prosthesis composite. Data were segregated according to the excised and reconstructed anatomical location (proximal part of the femur, total femur, distal part of the femur, proximal part of the tibia) and were collated to assess modes of failure and functional outcomes of each reconstruction type for each anatomic location. RESULTS: Sixty articles met the inclusion criteria; all were Level-IV evidence, primarily consisting of small, retrospective case series. Infection was a primary mode of failure across all reconstruction types and locations, whereas allograft reconstructions were susceptible to structural failure as well. The rate of failure in the pediatric population correlated well with previously published results for adults. The incidence of subsequent amputation was lower in the pediatric population (5.2%) than has been reported in adults (9.5%) (p = 0.013). Meaningful growth of expandable metallic endoprostheses was reported in the literature, with an overall rate of leg-length discrepancy of 13.4% being noted at the time of the latest follow-up. The Musculoskeletal Tumor Society (MSTS) questionnaire was the most consistently used outcome measure in the literature, with average scores ranging from 71.0% to 86.8%, depending on reconstruction type and anatomic location. CONCLUSIONS: The current state of the literature detailing the surgical and functional outcomes of segmental reconstruction for the treatment of pediatric bone tumors is limited to Level-IV evidence and is complicated by under-segregation of the data by age and anatomical location of the reconstruction. Despite these limitations, pediatric limb-salvage surgery demonstrates satisfactory initial surgical and functional outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27490133 TI - The Effect of Diabetes Mellitus on Total Joint Arthroplasty Outcomes. AB - Diabetes has negative effects on the outcomes of total joint arthroplasty, including increased numbers of complications, decreased function, early revision, and higher costs. The prevalence of diabetes is increasing rapidly worldwide; therefore, the orthopaedic surgeon should have an understanding of how diabetes affects surgical outcomes. PMID- 27490134 TI - Is There a Genetic Predisposition to Frozen Shoulder?: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Frozen shoulder is a common disorder that leads to substantial functional loss for patients by impairing activities of daily living. It also adversely affects patients and society by impairing the ability to work. Its pathogenesis is not fully understood. The aim of the present study was to perform a systematic review and meta-analysis to assess the evidence suggesting a genetic link to frozen shoulder. METHODS: A literature search of MEDLINE, EMBASE, and CINAHL databases using relevant keywords revealed 5506 studies. After appropriate screening of titles, abstracts, and full studies, seven studies were analyzed. RESULTS: Three studies investigated rates of frozen shoulder among relatives. One study (n = 1828 twin pairs) showed an 11.6% prevalence in twin pairs and demonstrated a heritability of 42% for frozen shoulder after adjusting for age. A second study (n = 273) showed that 20% of patients with frozen shoulder had a positive family history involving a first-degree relative. The relative risk of frozen shoulder was 4:1 when all patients with frozen shoulder were compared with a control population. A third study (n = 87) showed that 29% of patients with frozen shoulder had a first-degree relative with frozen shoulder. Two studies evaluated racial predilection for frozen shoulder. One study (n = 50) reported a substantially higher number of white patients (76%) with frozen shoulder than black patients (24%). A second study (n = 87) showed that being born or having parents or grandparents born in the British Isles were risk factors for frozen shoulder. Four immunological studies investigated human leukocyte antigen (HLA) B27 as a risk factor for frozen shoulder. Meta-analysis of two of these studies with clearly defined controls showed significantly higher rates of HLA-B27 positivity in patients with frozen shoulder as compared with controls (p < 0.001). CONCLUSION: The limited evidence points toward a genetic link to frozen shoulder. We used family history and racial predilection as markers for genetic association, both of which indicated the presence of a genetic predisposition to frozen shoulder. However, as there is a lack of unbiased genetic approaches, there is an opportunity for genome-wide association studies to address definitively the molecular genetics of frozen shoulder. Such studies may eventually lead to a better understanding of the pathogenesis of frozen shoulder and the development of novel therapeutic interventions. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27490135 TI - First-Principles Study of the Role of O2 and H2O in the Decoupling of Graphene on Cu(111). AB - The structural and electronic properties of graphene coated on a Cu(111) surface can be strongly influenced by the arrangement of adsorbates at the graphene edges. Oxygen and water intercalation at the graphene edges could lead to oxidation and hydrolysis at the graphene/Cu(111) interface, eventually causing decoupling of graphene from the Cu substrate. However, the reaction pathways for oxygen or water (or both) intercalation at the graphene edges are not well understood at the molecular level. Using ab initio density functional theory calculations, we observed a strong hybridization of pi orbitals at a zigzag edge of a graphene nanoribbon (GNR) on a bare Cu(111) surface, whereas such hybridization was absent for the corresponding armchair edge under otherwise identical conditions. These results indicate that the edge type influences the oxidation chemistry beneath the GNR. Moreover, we demonstrate that the presence of oxygen species, as well as GNR, facilitates the propagation of H2O. The following decoupling mechanisms are discussed: (i) GNRs with armchair edge configurations on Cu(111) can be decoupled via a sequential reaction that involves O2 dissociation followed by H2O intercalation, whereas (ii) GNRs with zigzag edge configurations on Cu(111) can be decoupled by oxygen intercalation. PMID- 27490136 TI - Novel function of the endoplasmic reticulum degradation-enhancing alpha mannosidase-like proteins in the human hepatitis B virus life cycle, mediated by the middle envelope protein. AB - Cells replicating the human hepatitis B virus (HBV) express high levels of degradation-enhancing alpha-mannosidase-like proteins (EDEMs), a family of proteins involved in the endoplasmic reticulum associated degradation, one of the pathways activated during the unfolded protein response. Owing to their alpha-1,2 mannosidase activity, the EDEM1-3 proteins are able to process the N-linked glycans of misfolded or incompletely folded proteins, providing the recognition signal for their subsequent degradation. The HBV small (S), medium (M), and large (L) surface proteins bear an N-linked glycosylation site in the common S domain that is partially occupied in all proteins. The M protein contains an additional site in its preS2 domain, which is always functional. Here, we report that these oligosaccharides are processed by EDEMs, more efficiently by EDEM3, which induces degradation of L and S proteins, accompanied by a reduction of subviral particles production. In striking contrast, M not only is spared from degradation but its trafficking is also accelerated leading to an improved secretion. This unusual behavior of the M protein requires strictly the mannose trimming of the preS2 N linked glycan. Furthermore, we show that HBV secretion is significantly inhibited under strong endoplasmic reticulum stress conditions when M expression is prevented by mutagenesis of the viral genome. These observations unfold unique properties of the M protein in the HBV life cycle during unfolded protein response and point to alternative mechanisms employed by EDEMs to alleviate this stress in case of necessity by promoting glycoprotein trafficking rather than degradation. PMID- 27490137 TI - The Olympic Games and Athletic Sex Assignment. PMID- 27490138 TI - Fat-Containing Hypermetabolic Masses on FDG PET/CT: A Spectrum of Benign and Malignant Conditions. AB - OBJECTIVE: This article focuses on identifying the imaging appearances of hypermetabolic fatty masses and masslike lesions on PET/CT and understanding the diagnostic challenges radiologists may face while interpreting findings of these lesions on PET/CT. This article provides an approach to aid in the diagnosis of these lesions and the appropriate management of patients. CONCLUSION: Both malignant and benign fat-containing masses and masslike lesions can show hypermetabolic activity on PET/CT. Although the differential diagnosis is broad, clinical history, anatomic location, and knowledge of anatomic variants and imaging features can help radiologists avoid misinterpretation of benign fatty lesions as malignancy. PMID- 27490139 TI - An Azulene-Containing Low Bandgap Small Molecule for Organic Photovoltaics with High Open-Circuit Voltage. AB - A simple azulene-containing squaraine dye (AzUSQ) showing bandgap of 1.38 eV and hole mobility up to 1.25*10(-4) cm(2) V(-1) s(-1) was synthesized. With its low bandgap, an organic photovoltaic (OPV) device based on it has been made that exhibits an impressive open-circuit voltages (Voc ) of 0.80 V. Hence, azulene might be a promising structural unit to construct OPV materials with simultaneous low bandgap, high hole mobility and high Voc . PMID- 27490140 TI - Revisiting the scissor-like mechanism of activation for the erythropoietin receptor. AB - An interpretation of alternative crystal structures of the erythropoietin receptor, with and without ligand, led to the proposal of a scissor-like mechanism of activation. This model has been propagated in the literature and is still being used to interpret crystal structures of related type-I cytokine receptors. Here, we assess whether the model remains compatible with current knowledge on the family of type-I cytokine receptors, and consider whether the model, as initially presented, is truly supported by the crystal structures on which it was originally based. PMID- 27490141 TI - Myosin myopathy with external ophthalmoplegia associated with a novel homozygous mutation in MYH2. PMID- 27490142 TI - Medial Patellofemoral Ligament Reconstruction. PMID- 27490143 TI - Treatment of Glenoid Bone Deficiency in Total Shoulder Arthroplasty: A Critical Analysis Review. PMID- 27490144 TI - Osteochondritis Dissecans of the Knee. PMID- 27490145 TI - Jones Fractures: Pathophysiology and Treatment. PMID- 27490146 TI - Synthesis of Biaryl Ethers by the Copper-Catalyzed Chan-Evans-Lam Etherification from Benzylic Amine Boronate Esters. AB - The copper-catalyzed etherification of ortho-borylated benzylic amines with phenols has been achieved to provide biaryl ethers that are prevalent in biologically active compounds. A variety of substitution patterns on the aryl boronate ester and the phenol are tolerated under the reaction conditions, providing moderate to high yields. A competition reaction between phenol and aniline revealed condition-dependent selectivity in which the phenol could be highly favored over the aniline. PMID- 27490148 TI - Deterministic Migration-Based Separation of White Blood Cells. AB - Functional and phenotypic analyses of peripheral white blood cells provide useful clinical information. However, separation of white blood cells from peripheral blood requires a time-consuming, inconvenient process and thus analyses of separated white blood cells are limited in clinical settings. To overcome this limitation, a microfluidic separation platform is developed to enable deterministic migration of white blood cells, directing the cells into designated positions according to a ridge pattern. The platform uses slant ridge structures on the channel top to induce the deterministic migration, which allows efficient and high-throughput separation of white blood cells from unprocessed whole blood. The extent of the deterministic migration under various rheological conditions is explored, enabling highly efficient migration of white blood cells in whole blood and achieving high-throughput separation of the cells (processing 1 mL of whole blood less than 7 min). In the separated cell population, the composition of lymphocyte subpopulations is well preserved, and T cells secrete cytokines without any functional impairment. On the basis of the results, this microfluidic platform is a promising tool for the rapid enrichment of white blood cells, and it is useful for functional and phenotypic analyses of peripheral white blood cells. PMID- 27490147 TI - Inspiring change: humanities and social science insights into the experience and management of breathlessness. AB - PURPOSE OF REVIEW: Breathlessness can be debilitating for those with chronic conditions, requiring continual management. Yet, the meaning of breathlessness for those who live with it is poorly understood in respect of its subjective, cultural, and experiential significance. This article discusses a number of current issues in understanding the experience of breathlessness. RECENT FINDINGS: Effective communication concerning the experience of breathlessness is crucial for diagnosis, to identify appropriate treatment, and to provide patients with the capacity to self-manage their condition. However, there is an evident disconnect between the way breathlessness is understood between clinical and lay perspectives, in terms of awareness of breathlessness, the way symptoms are expressed, and acknowledgement of how it affects the daily lives of patients. SUMMARY: The review highlights the need for integrated multidisciplinary work on breathlessness, and suggests that effective understanding and management of breathlessness considers its wider subjective and social significance. PMID- 27490149 TI - Characterization of lower urinary tract symptoms in patients with idiopathic normal pressure hydrocephalus. AB - AIMS: The purpose of this study was to evaluate lower urinary tract symptoms (LUTS) in idiopathic normal pressure hydrocephalus (iNPH). METHODS: Patients with new-onset iNPH were prospectively evaluated for LUTS via detailed history and physical, and administration of questionnaires from the International Consultation on Incontinence to assess incontinence (ICIq-UI), overactive bladder (ICIq-OAB), and quality of life (ICIq-LUTqol), as well as the American Urological Association Symptom Score bother scale. All patients with moderate-to-severe LUTS were offered urodynamic testing. Sub-analysis was performed based on gender, medical comorbidities, and age. RESULTS: Fifty-five consecutive patients with iNPH completed the initial evaluation and surveys. Total urinary incontinence score was mild to moderate (8.71 +/- 0.64: 0-21 scale) with 90.9% experiencing leakage and 74.5% reporting urge incontinence. The most common OAB symptom was nocturia (2.2 +/- 0.14: 0-4 scale) with urge incontinence the most bothersome (3.71 +/- 0.44: 0-10 scale). Quality-of-life impact was moderate (4.47 +/- 0.4: 0 10 scale) and American Urological Association Symptom Score bother scale was 2.89 +/- 0.22 (0-6 scale). Urodynamics testing revealed 100% detrusor overactivity and mean bladder capacity of 200 mL. Several differences were identified based on gender, medical comorbidities, and age. CONCLUSIONS: Patients with iNPH present with mild-moderate incontinence of which nocturia is the most common symptom, urge incontinence the most bothersome, with 100% of patients having detrusor overactivity. Younger patients experienced greater bother related to LUTS. To our knowledge, this is the only prospective evaluation of urinary symptoms in patients with new-onset iNPH. PMID- 27490150 TI - Assessment and Treatment of Malnutrition in Orthopaedic Surgery. PMID- 27490151 TI - The Role of Evidence-Based Medicine in Clinical Practice Policy. PMID- 27490152 TI - Achilles Tendinopathy. PMID- 27490153 TI - Pathophysiology and Treatment of Spinal Tuberculosis. PMID- 27490154 TI - Prevention of Anterior Cruciate Ligament Rupture in Female Athletes: A Systematic Review. AB - BACKGROUND: A number of reports have been published on the effectiveness and design of intervention programs for the prevention of rupture of the anterior cruciate ligament (ACL) in female athletes. The purpose of this study was to systematically review the literature to determine the effectiveness of neuromuscular training programs in preventing ACL injury in female athletes. METHODS: A systematic review was performed with use of the PubMed, MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases. The search terms included "anterior cruciate ligament" and "ACL" combined with "prevention" and "intervention." The searches included material indexed by September 30, 2013. Data concerning study design, the characteristics of participants, the details of the neuromuscular programs, the types of sports, and number of ACL ruptures were extracted from the studies. Study heterogeneity was assessed with funnel plot and Egger regression methods. Pooled effects were calculated with use of a DerSimonian-Laird random-effects model. The number needed to treat was calculated on the basis of pooled incidence data. RESULTS: The risk of ACL rupture was 1.83 times higher for female athletes who did not participate in neuromuscular ACL prevention training programs (odds ratio [OR], 1.83; 95% confidence interval [95% CI], 1.08 to 3.10; p = 0.02). In studies that focused exclusively on soccer, the risk of ACL rupture was 2.62 times higher for nonparticipating athletes (OR, 2.62; 95% CI, 1.59 to 4.32; p < 0.01). When the data were analyzed according to the timing of the intervention, no significant effects were found. In studies in which the program took place both preseason and in-season, the risk (odds ratio) of ACL rupture for nonparticipating athletes was 2.34 (95% CI, 0.82 to 6.7; p = 0.11). In studies in which the intervention took place in-season only, the risk (odds ratio) of ACL rupture for nonparticipating athletes was 1.25 (95% CI, 0.23 to 6.75; p = 0.8). The number needed to treat to prevent a single ACL rupture was 128.7 athletes. We found no significant heterogeneity among the included studies. The I value was 35.40% (p = 0.11). No significant publication bias was found in our included studies. CONCLUSIONS: The results of this systematic review and meta analysis favor a protective effect of neuromuscular training programs on the risk of ACL rupture in female athletes. This protective effect is more pronounced in soccer players. Additional research is needed to design the optimal training program. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence. PMID- 27490155 TI - Smart Organic Two-Dimensional Materials Based on a Rational Combination of Non covalent Interactions. AB - Rational design of organic 2D (O2D) materials has made some progress, but it is still in its infancy. A class of self-assembling small molecules is presented that form nano/microscale supramolecular 2D materials in aqueous media. A judicial combination of four different intermolecular interactions forms the basis for the robust formation of these ultrathin assemblies. These assemblies can be programmed to disassemble in response to a specific protein and release its non-covalently bound guest molecules. PMID- 27490156 TI - Rising trends in surgery for rotator cuff disease in Western Australia. AB - BACKGROUND: Increasing rates of surgery for rotator cuff disease have been reported in the past decade in a number of countries worldwide. Rising surgery rates do not correspond with equivalent increases in shoulder pain prevalence. The aims of the study were: to investigate trends in population-adjusted surgical rates for rotator cuff disease in Western Australia (WA) from 2001 to 2013; to compare population-adjusted arthroscopic surgical trends between (i) private versus public hospital setting; (ii) sex and (iii) different age groups; and to evaluate rising health care costs associated with arthroscopic surgical rates for rotator cuff disease. METHODS: Numbers and costs for surgical procedures for rotator cuff disease performed in WA were extracted from the WA Department of Health database for the 13-year period, 2001-2013. RESULTS: Rising surgical trends were demonstrated with arthroscopic subacromial decompression (ASAD) and arthroscopic reconstruction showing large proportional increases of 108.7 and 68.4%, respectively. Increasing trends were mostly linear across private and public hospital settings, gender groups and different age groups. The rise in consumer price index-adjusted costs for ASAD in private and public hospitals was 273.7 and 320.8%, respectively, and for arthroscopic reconstruction 220.2 and 472.5%, respectively. CONCLUSION: The substantial increase in arthroscopic surgery rates for rotator cuff disease and associated costs in WA over the period 2001-2013 is in spite of evidence that surgical outcomes are no different to exercise interventions. Conservative treatments should be recommended as an initial treatment choice, to arrest escalating health care costs. PMID- 27490157 TI - Clostridial Gas Gangrene of the Abdominal Wall After Laparoscopic Cholecystectomy: A Case Report and Review. AB - Clostridial gas gangrene is a rare, yet severe, complication after laparoscopic cholecystectomy. We present a case report of a 48-year-old man with obesity, coronary artery disease, and diabetes, who developed clostridial gas gangrene of the abdominal wall after an uncomplicated laparoscopic cholecystectomy. Although the diagnosis was missed initially, successful radical surgical debridement was performed and the patient survived. Pathogenesis, symptoms, prognostic factors, and the best treatment are discussed. PMID- 27490158 TI - Visualization of the airway in infants with MRI using pointwise encoding time reduction with radial acquisition (PETRA). AB - PURPOSE: To assess airway visibility in infants using pointwise encoding time reduction with radial acquisition (PETRA). MATERIALS AND METHODS: PETRA was obtained in 37 infants (gestational age: 23-43 weeks; postconceptional age: 34-46 weeks) using 3T magnetic resonance imaging (MRI) without respiratory gating. The visibility of the branching point and the airway structures, including the trachea and bronchi, on PETRA was scored by two experienced pediatric radiologists using a four-point scale (0-3). The rates of good visibility (score 3 or 2) were calculated for each airway structure. Interrater agreement was evaluated by intraclass correlation coefficient (ICC). RESULTS: For readers 1 and 2, good visibility was achieved for the branching point of the main bronchi (76% and 95%, respectively), trachea (97% and 95%, respectively), right main bronchus (92% and 92%, respectively), and left main bronchus (97% and 84%, respectively). Lower rates of visibility were achieved for the lobar bronchi. There was substantial agreement (ICC: 0.61-0.79) between the two readers for all the airway structures, except for the branching point at the right upper/middle lobe bronchi, for which there was moderate agreement (ICC: 0.56). CONCLUSION: PETRA has the potential for good airway visibility in infants, particularly for the trachea and main bronchi. LEVEL OF EVIDENCE: 3 J. Magn. Reson. Imaging 2017;45:839-844. PMID- 27490159 TI - Solvent-Regulated Asymmetric Hydrogenation of Quinoline Derivatives in Oligo(Ethylene Glycol)s through Host-Guest Interactions. AB - The asymmetric hydrogenation of quinolines in oligo(ethylene glycol)s (OEGs) and poly(ethylene glycol)s (PEGs) with chiral cationic ruthenium diamine complexes has been investigated. Interestingly, in liquid PEGs or long-chain OEGs, the Ru catalysts lost their reactivity. Upon the addition of a little MeOH, the hydrogenation of quinoline was switched "ON". Evidence from mass spectrometry and control experiments revealed that encapsulation of the quinolinium salt by PEG or long-chain OEG molecules through supramolecular interactions is possibly the main reason for such a switchable hydrogenation reaction. Moreover, the asymmetric hydrogenation of 2-substituted quinoline derivatives was achieved in triethylene glycol (3-OEG), thereby affording 1,2,3,4-tetrahydroquinolines with excellent reactivities and enantioselectivities (up to 99 % ee). Furthermore, the Ru catalyst could be readily recycled for both pure 3-OEG and biphasic 3-OEG/n hexane systems without a clear loss of reactivity and enantioselectivity. PMID- 27490160 TI - From the Patient Perspective, Consent Forms Fall Short of Providing Information to Guide Decision Making. AB - OBJECTIVE: This study aimed to gather qualitative feedback on patient perceptions of informed consent forms and elicit recommendations to improve readability and utility for enhanced patient safety and engagement in shared decision making. METHODS: Sixty interviews in personal interviews were conducted consisting of a literacy and numeracy assessment, a comprehension quiz to assess retention of key information, and open-ended questions to determine reactions, clarity of information, and suggestions for improvement. RESULTS: Although 68% of the participants had education beyond high school, many still missed comprehension questions and found the forms difficult to read. Recurrent suggestions included specific formatting changes to enhance readability, a need for additional sources of information, mixed attitudes toward inclusion of risk information, and the recognized importance of physician-patient conversations. CONCLUSIONS: This study provides evidence from the patient perspective that consent forms are too complex and fail to achieve comprehension. Future studies should be conducted using patients' suggestions for form redesign and inclusion of supplemental educational tools to optimize communication and safety to achieve more informed health care decision making. PMID- 27490161 TI - Nickel Nanofoam/Different Phases of Ordered Mesoporous Carbon Composite Electrodes for Superior Capacitive Energy Storage. AB - Electrochemical energy storage devices based on electric double layer capacitors (EDLCs) have received considerable attention due to their high power density and potential for obtaining improved energy density in comparison to the lithium ion battery. Ordered mesoporous carbon (OMC) is a promising candidate for use as an EDLC electrode because it has a high specific surface area (SSA), providing a wider charge storage space and size-controllable mesopore structure with a long range order, suppling high accessibility to the electrolyte ions. However, OMCs fabricated using conventional methods have several drawbacks including low electronic conductivity and long ionic diffusion paths in mesopores. We used nickel nanofoam, which has a relatively small pore (sub-100 nm to subMUm) network structure, as a current collector. This provides a significantly shortened electronic/ionic current paths and plentiful surface area, enabling stable and close attachment of OMCs without the use of binders. Thus, we present hierarchical binder-free electrode structures based on OMC/Ni nanofoams. These structures give rise to enhanced specific capacitance and a superior rate capability. We also investigated the mesopore structural effect of OMCs on electrolyte transport by comparing the capacitive performances of collapsed lamellar, cylindrical, and spherical mesopore electrodes. The highly ordered and straightly aligned cylindrical OMCs exhibited the highest specific capacitance and the best rate capability. PMID- 27490162 TI - TIOtropium Safety and Performance In Respimat(r) (TIOSPIRTM ): Analysis of Asian cohort of COPD patients. AB - BACKGROUND AND OBJECTIVE: The TIOtropium Safety and Performance In Respimat (TIOSPIR) trial showed similar safety and exacerbation efficacy profiles for tiotropium Respimat and HandiHaler in patients with COPD. The TIOSPIR results for patients in Asia are presented here. METHODS: TIOSPIR evaluated once-daily tiotropium Respimat 5 and 2.5 ug with HandiHaler 18 ug in patients with COPD. Primary endpoints included time to death and time to first COPD exacerbation. Safety and exacerbation efficacy profiles were determined for the Asian region, and for Asia (all treatment arms pooled) versus the rest of the world (RoW). RESULTS: In Asia (n = 2356), time to death was similar for Respimat 5 and 2.5 ug versus HandiHaler 18 ug (hazard ratio (HR) (95% CI): 0.96 (0.67, 1.38) and 1.23 (0.87, 1.73)). Risk of COPD exacerbation was similar for Respimat 5 ug, but increased for 2.5 ug versus HandiHaler 18 ug (HR (95% CI): 0.99 (0.85, 1.15) and 1.17 (1.00, 1.35)). Time to death in Asia and RoW was similar (HR (95% CI): 1.15 (0.99, 1.35)). Time to first COPD exacerbation was longer (HR (95% CI): 0.84 (0.78, 0.89)) and exacerbation rates were lower in Asia, but severe exacerbations were more frequent than in the RoW. Risk of major adverse cardiovascular events was similar for both regions. CONCLUSION: Similar safety and exacerbation efficacy profiles were observed for tiotropium Respimat 5 ug and HandiHaler 18 ug in patients with COPD from Asia, analogous to the global analysis. Asian patients had lower risk of, and fewer exacerbations overall, but a higher proportion of severe exacerbations than in the RoW. PMID- 27490163 TI - Jabuticaba (Myrciaria cauliflora) Seeds: Chemical Characterization and Extraction of Antioxidant and Antimicrobial Compounds. AB - This study was aimed to assess the effect of time and temperature on the extraction of antioxidant compounds from jabuticaba seeds (Myrciaria cauliflora cv. Sabara), to optimize the solvent proportion (water, ethyl alcohol, and propanone), and to characterize the extract according to the chemical composition, antioxidant, and antimicrobial properties. Proximal composition, total phenolic content (TPC), antioxidant, and antimicrobial activities were analyzed. The optimized solvent ratio of 60% water and 40% propanone provided a mean TPC of 8.65 g GAE/100 g seeds and the antioxidant activity toward 2,2 diphenyl-1-picrylhydrazyl (DPPH) was 82.79% +/- 0.50%. Time and temperature parameters did not influence the yield of TPC. The gross seed extract was partially purified and both exhibited a high antioxidant activity and antimicrobial potential toward Gram-positive and Gram-negative bacteria. The purified jabuticaba seed lyophilized extract contained a higher (P < 0.05) TPC, o diphenols, flavonols, and antioxidant activity measured by the DPPH assay and total reducing capacity as compared to the gross lyophilized extract. Electrospray ionization coupled with tandem mass spectrometry (ESI-MS/MS) data showed the presence of ellagitannins and ellagic acid in the extracts, which are probably the responsible for the antimicrobial and antioxidant activities. PMID- 27490164 TI - The Use of "Literary Fiction" to Promote Mentalizing Ability. AB - Empathy is a multidimensional process that incorporates both mentalizing and emotional sharing dimensions. Empathic competencies are important for creating interpersonal relationships with other people and developing adequate social behaviour. The lack of these social components also leads to isolation and exclusion in healthy populations. However, few studies have investigated how to improve these social skills. In a recent study, Kidd and Castano (2013) found that reading literary fiction increases mentalizing ability and may change how people think about other people's emotions and mental states. The aim of our study was to evaluate the effects of reading literary fiction, compared to nonfiction and science fiction, on empathic abilities. Compared to previous studies, we used a larger variety of empathy measures and utilized a pre and post test design. In all, 214 healthy participants were randomly assigned to read a book representative of one of three literary genres (literary fiction, nonfiction, science fiction). Participants were assessed before and after the reading phase using mentalizing and emotional sharing tests, according to Zaki and Ochsner' s (2012) model. Comparisons of sociodemographic, mentalizing, and emotional sharing variables across conditions were conducted using ANOVA. Our results showed that after the reading phase, the literary fiction group showed improvement in mentalizing abilities, but there was no discernible effect on emotional sharing abilities. Our study showed that the reading processes can promote mentalizing abilities. These results may set important goals for future low-cost rehabilitation protocols for several disorders in which the mentalizing deficit is considered central to the disease, such as Autism Spectrum Disorders and Schizophrenia. PMID- 27490165 TI - CS-MINER: A Tool for Association Mining in Binding-Database. AB - This paper introduces the algorithms, implementation strategies, features, and applications of CS-MINER, a tool for visualization and analysis of drug-like chemical space. The CS-MINER is the abstract abbreviation for Chemical Space Miner and correlates the medicinal target space and chemical space, in a systematic way. The database in this software consists of a large collection of drug-like molecules. To prepare this database, a large number of molecules for 110 important biological targets were collected from Binding-DB. A total of 1497 physicochemical properties were calculated for each molecule. The CS-MINER uses the discriminant analysis techniques for tracing the collected data and finally separates the molecules based on their therapeutic targets and activities. The developed multivariate classifiers can be used for ligand-based virtual screening of more than 0.5 million random molecules of PubChem and ZINC databases. In order to validate the models, selected subspaces in CS-MINER were compared with DrugBank molecules. At the end of the analysis, the software provides an interactive environment for visualization of the selected chemical subspaces in the form of 2- and 3-dimensional plots. In general, CS-MINER is a tool for comparing the relative position of active biosimilar molecules in chemical space and is freely available at www.csminer.com. PMID- 27490166 TI - Discrete Biogeography Based Optimization for Feature Selection in Molecular Signatures. AB - Biomarker discovery from high-dimensional data is a complex task in the development of efficient cancer diagnoses and classification. However, these data are usually redundant and noisy, and only a subset of them present distinct profiles for different classes of samples. Thus, selecting high discriminative genes from gene expression data has become increasingly interesting in the field of bioinformatics. In this paper, a discrete biogeography based optimization is proposed to select the good subset of informative gene relevant to the classification. In the proposed algorithm, firstly, the fisher-markov selector is used to choose fixed number of gene data. Secondly, to make biogeography based optimization suitable for the feature selection problem; discrete migration model and discrete mutation model are proposed to balance the exploration and exploitation ability. Then, discrete biogeography based optimization, as we called DBBO, is proposed by integrating discrete migration model and discrete mutation model. Finally, the DBBO method is used for feature selection, and three classifiers are used as the classifier with the 10 fold cross-validation method. In order to show the effective and efficiency of the algorithm, the proposed algorithm is tested on four breast cancer dataset benchmarks. Comparison with genetic algorithm, particle swarm optimization, differential evolution algorithm and hybrid biogeography based optimization, experimental results demonstrate that the proposed method is better or at least comparable with previous method from literature when considering the quality of the solutions obtained. PMID- 27490167 TI - Enhancing the Reliability of GPCR Models by Accounting for Flexibility of Their Pro-Containing Helices: the Case of the Human mAChR1 Receptor. AB - To better investigate the GPCR structures, we have recently proposed to explore their flexibility by simulating the bending of their Pro-containing TM helices so generating a set of models (the so-called chimeras) which exhaustively combine the two conformations (bent and straight) of these helices. The primary objective of the study is to investigate whether such an approach can be exploited to enhance the reliability of the GPCR models generated by distant templates. The study was focused on the human mAChR1 receptor for which a presumably reliable model was generated using the congener mAChR3 as the template along with a second less reliable model based on the distant beta2-AR template. The second model was then utilized to produce the chimeras by combining the conformations of its Pro containing helices (i.e., TM4, TM5, TM6 and TM7 with 16 modeled chimeras). The reliability of such chimeras was assessed by virtual screening campaigns as evaluated using a novel skewness metric where they surpassed the predictive power of the more reliable mAChR1 model. Finally, the virtual screening campaigns emphasize the opportunity of synergistically combining the scores of more chimeras using a specially developed tool which generates highly predictive consensus functions by maximizing the corresponding enrichment factors. PMID- 27490168 TI - In Silico Estimation of Chemical Carcinogenicity with Binary and Ternary Classification Methods. AB - Carcinogenicity is one of the most concerned properties of chemicals to human health, thus it is important to identify chemical carcinogenicity as early as possible. In this study, 829 diverse compounds with rat carcinogenicity were collected from Carcinogenic Potency Database (CPDB). Using six types of fingerprints to represent the molecules, 30 binary and ternary classification models were generated to predict chemical carcinogenicity by five machine learning methods. The models were evaluated by an external validation set containing 87 chemicals from ISSCAN database. The best binary model was developed by MACCS keys and kNN algorithm with predictive accuracy at 83.91 %, while the best ternary model was also generated by MACCS keys and kNN algorithm with overall accuracy at 80.46 %. Furthermore, the best binary and ternary classification models were used to estimate carcinogenicity of tobacco smoke components containing 2251 compounds. 981 ones were predicted as carcinogens by binary classification model, while 110 compounds were predicted as strong carcinogens and 807 ones as weak carcinogens by ternary classification model. The results indicated that our models would be helpful for prediction of chemical carcinogenicity. PMID- 27490169 TI - Novel Uses of In Vitro Data to Develop Quantitative Biological Activity Relationship Models for in Vivo Carcinogenicity Prediction. AB - The availability of large in vitro datasets enables better insight into the mode of action of chemicals and better identification of potential mechanism(s) of toxicity. Several studies have shown that not all in vitro assays can contribute as equal predictors of in vivo carcinogenicity for development of hybrid Quantitative Structure Activity Relationship (QSAR) models. We propose two novel approaches for the use of mechanistically relevant in vitro assay data in the identification of relevant biological descriptors and development of Quantitative Biological Activity Relationship (QBAR) models for carcinogenicity prediction. We demonstrate that in vitro assay data can be used to develop QBAR models for in vivo carcinogenicity prediction via two case studies corroborated with firm scientific rationale. The case studies demonstrate the similarities between QBAR and QSAR modeling in: (i) the selection of relevant descriptors to be used in the machine learning algorithm, and (ii) the development of a computational model that maps chemical or biological descriptors to a toxic endpoint. The results of both the case studies show: (i) improved accuracy and sensitivity which is especially desirable under regulatory requirements, and (ii) overall adherence with the OECD/REACH guidelines. Such mechanism based models can be used along with QSAR models for prediction of mechanistically complex toxic endpoints. PMID- 27490170 TI - Multi-Component Protein - Protein Docking Based Protocol with External Scoring for Modeling Dimers of G Protein-Coupled Receptors. AB - In order to apply structure-based drug design techniques to GPCR complexes, it is essential to model their 3D structure. For this purpose, a multi-component protocol was derived based on protein-protein docking which generates populations of dimers compatible with membrane integration, considering all reasonable interfaces. At the next stage, we applied a scoring procedure based on up to eleven different parameters including shape or electrostatics complementarity. Two methods of consensus scoring were performed: (i) average scores of 100 best scored dimers with respect to each interface, and (ii) frequencies of interfaces among 100 best scored dimers. In general, our multi-component protocol gives correct indications for dimer interfaces that have been observed in X-ray crystal structures of GPCR dimers (opsin dimer, chemokine CXCR4 and CCR5 dimers, kappa opioid receptor dimer, beta1 adrenergic receptor dimer and smoothened receptor dimer) but also suggests alternative dimerization interfaces. Interestingly, at times these alternative interfaces are scored higher than the experimentally observed ones suggesting them to be also relevant in the life cycle of studied GPCR dimers. Further results indicate that GPCR dimer and higher-order oligomer formation may involve transmembrane helices (TMs) TM1-TM2-TM7, TM3-TM4-TM5 or TM4 TM5-TM6 but not TM1-TM2-TM3 or TM2-TM3-TM4 which is in general agreement with available experimental and computational data. PMID- 27490171 TI - On the Use of a Protic Ionic Liquid with a Novel Cation To Study Anion Basicity. AB - The need for reliable means of ordering and quantifying the Lewis basicity of anions is discussed and the currently available methods are reviewed. Concluding that there is need for a simple impurity-insensitive tool, we have sought, and here describe, a new method using NMR spectroscopy of a weak base, a substituted urea, 1,3-dimethyl-2-imidazolidinone (DMI), as it is protonated by Bronsted acids of different strengths and characters. In all cases studied the product of protonation is a liquid (hence a protic ionic liquid). NMR spectroscopy detects changes in the electronic structure of the base upon interaction with the proton donors. As the proton-donating ability, that is, acidity, increases, there is a smooth but distinct transition from a hydrogen-bonded system (with no net proton transfer) to full ionicity. The liquid state of the samples and high concentration of nitrogen atoms, despite the very low natural abundance of its preferred NMR-active isotope ((15) N), make possible the acquisition of (15) N spectra in a relatively short time. These (15) N, along with (13) C, chemical shifts of the carbonyl atom, and their relative responses to protonation of the carbonyl oxygen, can be used as a means, sensitive to anion basicity and relatively insensitive to impurities, to sort anions in order of increasing hydrogen bond basicity. The order is found to be as follows: SbF6 (-) ClO4 (-) >FSO3 (-) C (p.V175L) alteration in the proband. CONCLUSION: Overall, DES established a likely molecular genetic diagnosis for a post-mortem case after traditional testing methods were uninformative. The DES results allowed for reproductive options, such as preimplantation genetic diagnosis (PGD) and/or prenatal diagnosis, to be available to the parents in future pregnancies. PMID- 27490175 TI - Analytical Model for Estimating the Zenith Angle Dependence of Terrestrial Cosmic Ray Fluxes. AB - A new model called "PHITS-based Analytical Radiation Model in the Atmosphere (PARMA) version 4.0" was developed to facilitate instantaneous estimation of not only omnidirectional but also angular differential energy spectra of cosmic ray fluxes anywhere in Earth's atmosphere at nearly any given time. It consists of its previous version, PARMA3.0, for calculating the omnidirectional fluxes and several mathematical functions proposed in this study for expressing their zenith angle dependences. The numerical values of the parameters used in these functions were fitted to reproduce the results of the extensive air shower simulation performed by Particle and Heavy Ion Transport code System (PHITS). The angular distributions of ground-level muons at large zenith angles were specially determined by introducing an optional function developed on the basis of experimental data. The accuracy of PARMA4.0 was closely verified using multiple sets of experimental data obtained under various global conditions. This extension enlarges the model's applicability to more areas of research, including design of cosmic-ray detectors, muon radiography, soil moisture monitoring, and cosmic-ray shielding calculation. PARMA4.0 is available freely and is easy to use, as implemented in the open-access EXcel-based Program for Calculating Atmospheric Cosmic-ray Spectrum (EXPACS). PMID- 27490176 TI - Synthetic Site-Selectively Mono-6-O-Sulfated Heparan Sulfate Dodecasaccharide Shows Anti-Angiogenic Properties In Vitro and Sensitizes Tumors to Cisplatin In Vivo. AB - Heparan sulphate (HS), a ubiquitously expressed glycosaminoglycan (GAG), regulates multiple cellular functions by mediating interactions between numerous growth factors and their cell surface cognate receptors. However, the structural specificity of HS in these interactions remains largely undefined. Here, we used completely synthetic, structurally defined, alternating N-sulfated glucosamine (NS) and 2-O-sulfated iduronate (IS) residues to generate dodecasaccharides ([NSIS]6) that contained no, one or six glucosamine 6-O-sulfates (6S). The aim was to address how 6S contributes to the potential of defined HS dodecasaccharides to inhibit the angiogenic growth factors FGF2 and VEGF165, in vitro and in vivo. We show that the addition of a single 6S at the non-reducing end of [NSIS]6, i.e. [NSIS6S]-[NSIS]5, significantly augments the inhibition of FGF2-dependent endothelial cell proliferation, migration and sprouting in vitro when compared to the non-6S variant. In contrast, the fully 6-O-sulfated dodecasaccharide, [NSIS6S]6, is not a potent inhibitor of FGF2. Addition of a single 6S did not significantly improve inhibitory properties of [NSIS]6 when tested against VEGF165-dependent endothelial cell functions.In vivo, [NSIS6S] [NSIS]5 blocked FGF2-dependent blood vessel formation without affecting tumor growth. Reduction of non-FGF2-dependent ovarian tumor growth occurred when [NSIS6S]-[NSIS]5 was combined with cisplatin. The degree of inhibition by [NSIS6S]-[NSIS]5 in combination with cisplatin in vivo equated with that induced by bevacizumab and sunitinib when administered with cisplatin. Evaluation of post treatment vasculature revealed that [NSIS6S]-[NSIS]5 treatment had the greatest impact on tumor blood vessel size and lumen formation. Our data for the first time demonstrate that synthetic, structurally defined oligosaccharides have potential to be developed as active anti-angiogenic agents that sensitize tumors to chemotherapeutic agents. PMID- 27490178 TI - Alkali Niobate and Tantalate Perovskites as Alternative Photocatalysts. AB - Alkali tantalates and niobates are listed as important photocatalysts for the development of renewable energy technologies and environmental remediation. Herein, the photocatalytic degradation of methylene blue dye in aqueous solution by using highly crystalline particles with perovskite-like structures, LiTaO3 , LiNbO3 , NaTaO3 , NaNbO3 , KNbO3 , and KTaO3 , is investigated. It is demonstrated that ferroelectric KNbO3 is the most efficient photocatalyst of those tested because it combines an electronic band structure that can respond successfully to UVA light with a relatively high surface energy that enhances the catalytic properties. Additionally, the built-in electric field due to internal polarization of ferroelectric particles may contribute to the unique properties of this functional photocatalyst. This work provides an ideal platform for the rational design of more efficient ferroelectric-based photocatalytic devices. PMID- 27490177 TI - Human Serum-Specific Activation of Alternative Sigma Factors, the Stress Responders in Aggregatibacter actinomycetemcomitans. AB - Aggregatibacter actinomycetemcomitans, a known pathogen causing periodontal disease and infective endocarditis, is a survivor in the periodontal pocket and blood stream; both environments contain serum as a nutrient source. To screen for unknown virulence factors associated with this microorganism, A. actinomycetemcomitans was grown in serum-based media to simulate its in vivo environment. Different strains of A. actinomycetemcomitans showed distinct growth phenotypes only in the presence of human serum, and they were grouped into high- and low-responder groups. High-responders comprised mainly serotype c strains, and showed an unusual growth phenomenon, featuring a second, rapid increase in turbidity after 9-h incubation that reached a final optical density 2- to 7-fold higher than low-responders. Upon further investigation, the second increase in turbidity was not caused by cell multiplication, but by cell death. Whole transcriptomic analysis via RNA-seq identified 35 genes that were up-regulated by human serum, but not horse serum, in high-responders but not in low-responders, including prominently an alternative sigma factor rpoE (sigmaE). A lacZ reporter construct driven by the 132-bp rpoE promoter sequence of A. actinomycetemcomitans responded dramatically to human serum within 90 min of incubation only when the construct was carried by a high responder strain. The rpoE promoter is 100% identical among high- and low-responder strains. Proteomic investigation showed potential interactions between human serum protein, e.g. apolipoprotein A1 (ApoA1) and A. actinomycetemcomitans. The data clearly indicated a different activation process for rpoE in high- versus low-responder strains. This differential human serum-specific activation of rpoE, a putative extra cytoplasmic stress responder and global regulator, suggests distinct in vivo adaptations among different strains of A. actinomycetemcomitans. PMID- 27490180 TI - Direct vs. Microclimate-Driven Effects of Tree Species Diversity on Litter Decomposition in Young Subtropical Forest Stands. AB - Effects of tree species diversity on decomposition can operate via a multitude of mechanism, including alterations of microclimate by the forest canopy. Studying such effects in natural settings is complicated by the fact that topography also affects microclimate and thus decomposition, so that effects of diversity are more difficult to isolate. Here, we quantified decomposition rates of standard litter in young subtropical forest stands, separating effects of canopy tree species richness and topography, and quantifying their direct and micro-climate mediated components. Our litterbag study was carried out at two experimental sites of a biodiversity-ecosystem functioning field experiment in south-east China (BEF-China). The field sites display strong topographical heterogeneity and were planted with tree communities ranging from monocultures to mixtures of 24 native subtropical tree species. Litter bags filled with senescent leaves of three native tree species were placed from Nov. 2011 to Oct. 2012 on 134 plots along the tree species diversity gradient. Topographic features were measured for all and microclimate in a subset of plots. Stand species richness, topography and microclimate explained important fractions of the variations in litter decomposition rates, with diversity and topographic effects in part mediated by microclimatic changes. Tree stands were 2-3 years old, but nevertheless tree species diversity explained more variation (54.3%) in decomposition than topography (7.7%). Tree species richness slowed litter decomposition, an effect that slightly depended on litter species identity. A large part of the variance in decomposition was explained by tree species composition, with the presence of three tree species playing a significant role. Microclimate explained 31.4% of the variance in decomposition, and was related to lower soil moisture. Within this microclimate effect, species diversity (without composition) explained 8.9% and topography 34.4% of variance. Topography mainly affected diurnal temperature amplitudes by varying incident solar radiation. PMID- 27490179 TI - Loss of Gravitropism in Farnesene-Treated Arabidopsis Is Due to Microtubule Malformations Related to Hormonal and ROS Unbalance. AB - Mode of action of farnesene, a volatile sesquiterpene commonly found in the essential oils of several plants, was deeply studied on the model species Arabidopsis thaliana. The effects of farnesene on the Arabidopsis root morphology were evaluated by different microscopic techniques. As well, microtubules immunolabeling, phytohormone measurements and ROS staining helped us to elucidate the single or multi-modes of action of this sesquiterpene on plant metabolism. Farnesene-treated roots showed a strong growth inhibition and marked modifications on morphology, important tissue alterations, cellular damages and anisotropic growth. Left-handed growth of farnesene-treated roots, reverted by taxol (a known microtubule stabilizer), was related to microtubule condensation and disorganization. As well, the inhibition of primary root growth, lateral root number, lateral root length, and both root hairs length and density could be explained by the strong increment in ethylene production and auxin content detected in farnesene-treated seedlings. Microtubule alteration and hormonal unbalance appear as important components in the mode of action of farnesene and confirm the strong phytotoxic potential of this sesquiterpene. PMID- 27490181 TI - Time-to-Detection of Inducible Macrolide Resistance in Mycobacterium abscessus Subspecies and Its Association with the Erm(41) Sequevar. AB - Mutations in the erm(41) gene of M.abscessus group organisms are associated with differences in inducible macrolide resistance, with current recommendations being to hold rapidly growing isolates for up to 14 days in order to ensure that resistance which develops more slowly can be detected. This study aimed to determine the ideal incubation time for accurate identification of inducible macrolide resistance as well as to determine if there was an association between the time taken to detect inducible resistance in M.abscessus group organisms and their erm(41) sequevar. We amplified and sequenced the erm(41) genes of a total of 104 M.abscessus group isolates and determined their sequevars. The isolates were tested for phenotypic clarithromycin resistance at days 7, 10, 14 and 21, using Trek Diagnostics Sensititre RAPMYCO microbroth dilution plates. Associations between erm(41) gene sequevars and time to detection of resistance were evaluated using Fisher's exact test in R. The samples included in this study fell into 14 sequevars, with the majority of samples falling into Sequevar02 (16), Sequevar06 (15), Sequevar08 (7) and Sequvar 15 (31), and several isolates that were in small clusters, or unique. The majority (82.7%) of samples exhibiting inducible macrolide resistance were interpreted as resistant by day 7. Two isolates in Sequevar02, which has a T28C mutation that is associated with sensitivity, showed intermediate resistance at day 14, though the majority (13) were sensitive at day 14. The majority of isolates with inducible macrolide resistance fell into Sequevars 06,08 and 15, none of which contain the T28C mutation. These sequevars were analyzed to determine if there was any correlation between sequevar and time to detection of resistance. None was found. Based on these findings, we recommend the addition of a day 7 read to the CLSI guidelines to improve turn-around-times for these isolates. It is also recommended that erm(41) gene sequencing be added to routine phenotypic testing for the resolution of cases with difficult-to-interpret phenotypic results. PMID- 27490182 TI - Using Cellular Communication Networks To Detect Air Pollution. AB - Accurate real time monitoring of atmospheric conditions at ground level is vital for hazard warning, meteorological forecasting, and various environmental applications required for public health and safety. However, conventional monitoring facilities are costly and often insufficient, for example, since they are not representative of the larger space and are not deployed densely enough in the field. There have been numerous scientific works showing the ability of commercial microwave links that comprise the data transmission infrastructure in cellular communication networks to monitor hydrometeors as a potential complementary solution. However, despite the large volume of research carried out in this emerging field during the past decade, no study has shown the ability of the system to provide critical information regarding air quality. Here we reveal the potential for identifying atmospheric conditions prone to air pollution by detecting temperature inversions that trap pollutants at ground level. The technique is based on utilizing standard signal measurements from an existing cellular network during routine operation. PMID- 27490183 TI - Correction: DNA-catalyzed glycosylation using aryl glycoside donors. AB - Correction for 'DNA-catalyzed glycosylation using aryl glycoside donors' by Anthony R. Hesser et al., Chem. Commun., 2016, 52, 9259-9262. PMID- 27490184 TI - Corannulene-Helicene Hybrids: Chiral pi-Systems Comprising Both Bowl and Helical Motifs. AB - Two distinct structural elements that render pi-systems nonplanar, i.e., geodesic curvature and helical motifs, have been combined into new polyarenes that contain both features. The resultant corannulene-[n]helicenes (n = 5, 6) show unique molecular dynamics in their enantiomerization processes, including inversion motions of both the bowl and the helix. Optical resolution of a corannulene-based skeletally chiral molecule was also achieved for the first time, and the influence of the bowl-motif annulation on the chiroptical properties was investigated. PMID- 27490185 TI - Des-Acyl Ghrelin and Ghrelin O-Acyltransferase Regulate Hypothalamic-Pituitary Adrenal Axis Activation and Anxiety in Response to Acute Stress. AB - Ghrelin exists in two forms in circulation, acyl ghrelin and des-acyl ghrelin, both of which have distinct and fundamental roles in a variety of physiological functions. Despite this fact, a large proportion of papers simply measure and refer to plasma ghrelin without specifying the acylation status. It is therefore critical to assess and state the acylation status of plasma ghrelin in all studies. In this study we tested the effect of des-acyl ghrelin administration on the hypothalamic-pituitary-adrenal axis and on anxiety-like behavior of mice lacking endogenous ghrelin and in ghrelin-O-acyltransferase (GOAT) knockout (KO) mice that have no endogenous acyl ghrelin and high endogenous des-acyl ghrelin. Our results show des-acyl ghrelin produces an anxiogenic effect under nonstressed conditions, but this switches to an anxiolytic effect under stress. Des-acyl ghrelin influences plasma corticosterone under both nonstressed and stressed conditions, although c-fos activation in the paraventricular nucleus of the hypothalamus is not different. By contrast, GOAT KO are anxious under both nonstressed and stressed conditions, although this is not due to corticosterone release from the adrenals but rather from impaired feedback actions in the paraventricular nucleus of the hypothalamus, as assessed by c-fos activation. These results reveal des-acyl ghrelin treatment and GOAT deletion have differential effects on the hypothalamic-pituitary-adrenal axis and anxiety-like behavior, suggesting that anxiety-like behavior in GOAT KO mice is not due to high plasma des-acyl ghrelin. PMID- 27490186 TI - Neuropsychiatric Presentation of Wilson Disease in an Adolescent Male. PMID- 27490187 TI - Opening up the blackbox: an interpretable deep neural network-based classifier for cell-type specific enhancer predictions. AB - BACKGROUND: Gene expression is mediated by specialized cis-regulatory modules (CRMs), the most prominent of which are called enhancers. Early experiments indicated that enhancers located far from the gene promoters are often responsible for mediating gene transcription. Knowing their properties, regulatory activity, and genomic targets is crucial to the functional understanding of cellular events, ranging from cellular homeostasis to differentiation. Recent genome-wide investigation of epigenomic marks has indicated that enhancer elements could be enriched for certain epigenomic marks, such as, combinatorial patterns of histone modifications. METHODS: Our efforts in this paper are motivated by these recent advances in epigenomic profiling methods, which have uncovered enhancer-associated chromatin features in different cell types and organisms. Specifically, in this paper, we use recent state-of-the art Deep Learning methods and develop a deep neural network (DNN)-based architecture, called EP-DNN, to predict the presence and types of enhancers in the human genome. It uses as features, the expression levels of the histone modifications at the peaks of the functional sites as well as in its adjacent regions. We apply EP-DNN to four different cell types: H1, IMR90, HepG2, and HeLa S3. We train EP-DNN using p300 binding sites as enhancers, and TSS and random non DHS sites as non-enhancers. We perform EP-DNN predictions to quantify the validation rate for different levels of confidence in the predictions and also perform comparisons against two state-of-the-art computational models for enhancer predictions, DEEP-ENCODE and RFECS. RESULTS: We find that EP-DNN has superior accuracy and takes less time to make predictions. Next, we develop methods to make EP-DNN interpretable by computing the importance of each input feature in the classification task. This analysis indicates that the important histone modifications were distinct for different cell types, with some overlaps, e.g., H3K27ac was important in cell type H1 but less so in HeLa S3, while H3K4me1 was relatively important in all four cell types. We finally use the feature importance analysis to reduce the number of input features needed to train the DNN, thus reducing training time, which is often the computational bottleneck in the use of a DNN. CONCLUSIONS: In this paper, we developed EP-DNN, which has high accuracy of prediction, with validation rates above 90 % for the operational region of enhancer prediction for all four cell lines that we studied, outperforming DEEP-ENCODE and RFECS. Then, we developed a method to analyze a trained DNN and determine which histone modifications are important, and within that, which features proximal or distal to the enhancer site, are important. PMID- 27490188 TI - Improved Sugar Puckering Profiles for Nicotinamide Ribonucleoside for Hybrid QM/MM Simulations. AB - The coenzyme nicotinamide adenine dinucleotide (NAD+) and its reduced form (NADH) play ubiquitous roles as oxidizing and reducing agents in nature. The binding, and possibly the chemical redox step, of NAD+/NADH may be influenced by the cofactor conformational distribution and, in particular, by the ribose puckering of its nicotinamide-ribonucleoside (NR) moiety. In many hybrid quantum mechanics molecular mechanics (QM/MM) studies of NAD+/NADH dependent enzymes, the QM region is treated by semiempirical (SE) methods. Recent work suggests that SE methods do not adequately describe the ring puckering in sugar molecules. In the present work we adopt an efficient and practical strategy to correct for this deficiency for NAD+/NADH. We have implemented a cost-effective correction to a SE Hamiltonian by adding a correction potential, which is defined as the difference between an accurate benchmark density functional theory (DFT) potential energy surface (PES) and the SE PES. In practice, this is implemented via a B-spline interpolation scheme for the grid-based potential energy difference surface. We find that the puckering population distributions obtained from free energy QM(SE)/MM simulations are in good agreement with DFT and in fair accord with experimental results. The corrected PES should facilitate a more accurate description of the ribose puckering in the NAD+/NADH cofactor in simulations of biological systems. PMID- 27490189 TI - Notes from the Field: Fatal Infection Associated with Equine Exposure - King County, Washington, 2016. AB - On March 17, 2016, Public Health-Seattle & King County in Washington was notified of two persons who received a diagnosis of Streptococcus equi subspecies zooepidemicus (S. zooepidemicus) infections. S. zooepidemicus is a zoonotic pathogen that rarely causes human illness and is usually associated with consuming unpasteurized dairy products or with direct horse contact (1). In horses, S. zooepidemicus is a commensal bacterium that can cause respiratory, wound, and uterine infections (2). The health department investigated to determine the magnitude of the outbreak, identify risk factors, and offer recommendations. PMID- 27490190 TI - Respiratory syncytial virus hospitalization outcomes and costs of full-term and preterm infants. AB - OBJECTIVE: Infection with respiratory syncytial virus (RSV), which causes lower respiratory tract infections, is the leading cause of hospitalization among children <1 year old in the United States. Risk factors for RSV hospitalization include premature birth and younger chronologic age, along with several comorbid conditions. However, in terms of RSV hospitalization costs, premature infants are rarely studied separately from full-term infants. The objective of this study is to describe the cost and severity of RSV hospitalizations among preterm and full term infants without chronic lung disease or other high-risk conditions. STUDY DESIGN: This analysis used Truven Health Market Scan Multi-State Medicaid and Commercial Claims and Encounters databases, which contain a combined 4 million births from 2003 to 2013. Infants with comorbid conditions associated with increased risk for RSV infection were excluded. Infants were classified as preterm (<29, 29-30, 31-32, 33-34 and 35-36 weeks' gestational age (wGA)) or full term based on diagnostic coding. Health-care claims during the first year of life were evaluated for RSV hospitalizations, defined as inpatient claims with a diagnosis code for RSV in any position. Costs of RSV hospitalizations were captured and reported in 2014 USD. Inpatient claims for RSV hospitalizations were evaluated for the presence of codes indicating admission to the intensive care unit (ICU), use of mechanical ventilation (MV) and length of stay. These three measures were used to describe hospital severity. Chronologic age at the time of RSV hospitalization was also captured. Data were summarized and no statistical comparisons were conducted. RESULTS: There were 1 683 188 infants insured through Medicaid and 1 663 832 infants insured through commercial plans born from 1 July 2003 to 30 June 2013. Of those, 10.8 and 8.8% in each database, respectively, were born prematurely. There were 29 967 Medicaid-insured infants and 16 310 commercially insured infants with an RSV hospitalization during their first year of life. Mean first-year RSV hospitalization costs were higher for preterm infants, ranging from $8324 and $10 570 for full-term infants to $15 839 and $19 931 for preterm infants 33-34 wGA, and to $39 354 and $40 813 for preterm infants <29 wGA, among Medicaid-insured and commercially insured infants, respectively. RSV hospitalizations also tended to be more severe among preterm infants, with longer lengths of stay, a higher proportion of infants admitted to the intensive care unit (ICU) and increased use of MV compared with full-term infants. Mean costs of RSV hospitalizations with a PICU admission ranged from approximately $35 000 to $89 000. In both Medicaid and commercial groups, costs were greater for infants hospitalized at <90 days of age compared with older infants. CONCLUSIONS: Infants who were born prematurely and those hospitalized at <90 days of age have more costly and more severe RSV hospitalizations during the first year of life. These findings demonstrate important differences in the costs and severity of first-year RSV hospitalizations of premature and full-term infants. These differences are likely to be obscured in combined analysis, in which full-term infants predominate. Clinical guidelines and health-care policies relating to RSV would benefit from the availability of data obtained from separate analyses of these two infant subgroups. PMID- 27490191 TI - Compassion fatigue, burnout and compassion satisfaction in neonatologists in the US. AB - OBJECTIVE: Compassion fatigue (CF) is distress experienced by caregivers from ongoing contact with patients who are suffering. Burnout (BO) is occupational stress directly related to dissonance between job demands and available resources. Compassion satisfaction (CS) is professional fulfillment experienced through helping others. CF in physicians is not well studied. Neonatologists may be at particular risk for CF by virtue of recurrent exposure to distress in patients and their families. The objectives of this study were to determine the prevalence of CF, BO and CS, and to identify potential predictors for these phenomena in neonatologists. STUDY DESIGN: A modified Compassion Fatigue and Satisfaction Self-Test and a questionnaire of professional details and personal characteristics were distributed electronically to neonatologists nationally. Multivariable logistic and linear regression models for CF, BO and CS as a function of potential predictors were constructed. RESULTS: The survey response rate was 47%. The prevalence of CF, BO and CS was 15.7, 20.8 and 21.9%, respectively. Female gender, emotional depletion, distress from 'a clinical situation', 'co-workers', 'personal health issues' and 'not talking about distressing issues' were each significant determinants of CF. Emotional depletion, distress from the 'physical work environment' and 'co-workers', and 'not talking about distressing issues' were significant determinants of BO. Self identification as Hispanic; 'not currently feeling distressed'; talking about distressing issues; and utilization of pediatric palliative care services were significant determinants of higher CS. CONCLUSIONS: CF and BO may impact emotional well-being and professional performance of neonatologists. Enhancement of CS is a potential target for intervention. PMID- 27490192 TI - Transplacental passage of clindamycin from mother to neonate. AB - OBJECTIVE: To evaluate maternal and neonatal cord blood levels at delivery in patients receiving 900 mg of clindamycin intravenous (IV) every 8 h. STUDY DESIGN: Prospective study consented every mother that entered labor with a positive group B streptococcal culture, a high-risk penicillin allergy, and sensitivity to clindamycin and erythromycin. Maternal and cord blood clindamycin levels were obtained at delivery. Time from last dose completion to delivery, number of doses administered and body mass index (BMI) were assessed. RESULTS: Twenty-three patients were consented. All maternal clindamycin values were therapeutic and 22 (96%) of the 23 cord blood samples were therapeutic. The mean maternal level was of 4.46 MUg ml-1 (range of 0.7 to 8.4 MUg ml-1). The mean cord blood level was 3.35 MUg ml-1 (range of <0.5 to 6.4 MUg ml-1). CONCLUSION: These data show that the current dosing recommendation of 900 mg of clindamycin IV every 8 h produces therapeutic maternal and cord blood levels. PMID- 27490193 TI - Outcomes of Open-Approach Extracorporeal Septoplasty Without Simultaneous Rhinoplasty: Effects on Nasal Tip Projection and Rotation. AB - Importance: Performing an open-approach extracorporeal septoplasty (OAES) without simultaneous rhinoplasty could have adverse effects. We sought to understand the effects of OAES without simultaneous rhinoplasty on nasal tip projection and rotation in patients with severe septal deviation. Objectives: To evaluate the outcomes of OAES without simultaneous rhinoplasty in terms of nasal tip projection and rotation using objective measurements. Design, Setting, and Participants: This retrospective study was conducted at a training and research hospital using medical records of 32 adult patients who underwent OAES without simultaneous rhinoplasty between April 10, 2012 and June 12, 2015. Patients who underwent endonasal septoplasty, revision septal surgery, septorhinoplasty, open approach septoplasty with nasal tip plasty, or open-approach septoplasty without removal of the entire septal cartilage were excluded from the study. Postoperative photographs of the patients were taken at a mean (range) time of 16.4 (6-36) months after surgery. Nasolabial angle (NLA), nasofacial angle (NFA), and projection index (PI) were measured by the same surgeon on preoperative and postoperative lateral images. Main Outcomes and Measures: Projection index was measured using the Goode method; NLA and NFA were measured drawing lines between specific facial points according to the literature. All measurements were compared statistically. Results: Thirty-two adult patients (26 men and 6 women between ages 20 and 57 years) with severe septal deviation and underwent OAES without simultaneous rhinoplasty were included in the study. The postoperative values of NLA and NFA were observed to be decreased in all patients (100%). The PI was also determined to be decreased in 27 patients (84.6%) whereas it remained unchanged in 5 patients (15.4%). The overall postoperative mean values of NLA, NFA, and PI were found to be lower compared with preoperative mean values and the difference between them were determined to be statistically significant (NLA: 95% CI, 0.40-2.55, P = .005; NFA: 95% CI, 0.48-2.06, P = .003; and PI: 95% CI, 0.004 0.015, P = .002). Conclusions and Relevance: This study reveals that the nasal tip lost height from facial plane and rotated caudally in most patients who underwent OAES without simultaneous rhinoplasty. Patients demanding only relief of nasal obstruction and scheduled for OAES have to be informed about the potential cosmetic alterations when a simultaneous rhinoplasty is not requested. PMID- 27490194 TI - Association of Accelerometer-Assessed Sedentary Behavior With Diabetic Retinopathy in the United States. PMID- 27490195 TI - Zinc pyridinedicarboxylate micro-nanostructures: Promising anode materials for lithium-ion batteries with excellent cycling performance. AB - It is important to discover new, cheap and environmental friendly coordination polymer electrode materials for lithium-ion batteries. Zinc 2,6 pyridilinedicarboxylate particles show better cycling stability and higher discharge capacity than 2,5-pyridilinedicarboxylate micro-platelets when they are firstly tested as anode materials for lithium-ion batteries. The former can steadily cycle at current densities of 750, 1000 and 2000mAg(-1). It is also stable in multiple insertion/extraction processes at current densities of 750, 1500, 2000, 2500, 3000, and 750mAg(-1), and the capacity retention is 77.9% after 60cycles. While the latter is apt to show good cycling performance at smaller discharge current density. PMID- 27490196 TI - Phase behaviour and non-monotonic film drying kinetics of aluminium chlorohydrate glycerol-water ternary solutions. AB - We study the drying and film formation of a model ternary system comprising an inorganic salt (aluminium chlorohydrate, ACH), a humectant (glycerol) and water. Employing viscometric, X-ray diffraction, calorimetric, dynamic vapour sorption, spectroscopic, gravimetric and adhesion measurements, we examine the roles of humectant concentration, temperature and relative humidity (RH) in the phase behaviour and kinetics of film formation. Equilibrium film compositions are found to be non-monotonic with glycerol content. Around 15:4 ACH:glycerol mass ratio, films exhibit enhanced, albeit slower, desiccation, with water content lower than that of binary ACH-water solutions. At higher glycerol content, drying is faster, yet the resulting films have higher water content and remain tackier. Water adsorption/desorption is shown to be fully reversible, and share a similar non monotonic kinetic dependence on glycerol composition. These findings are rationalised in terms of the competitive binding of water and glycerol to ACH, the overall miscibility and glass formation within the ternary system. Our study is relevant to a range of salt formulations, employed in a variety of commercial applications, including lyoprotectants and personal care products. PMID- 27490197 TI - Neuromotor Noise Is Malleable by Amplifying Perceived Errors. AB - Variability in motor performance results from the interplay of error correction and neuromotor noise. This study examined whether visual amplification of error, previously shown to improve performance, affects not only error correction, but also neuromotor noise, typically regarded as inaccessible to intervention. Seven groups of healthy individuals, with six participants in each group, practiced a virtual throwing task for three days until reaching a performance plateau. Over three more days of practice, six of the groups received different magnitudes of visual error amplification; three of these groups also had noise added. An additional control group was not subjected to any manipulations for all six practice days. The results showed that the control group did not improve further after the first three practice days, but the error amplification groups continued to decrease their error under the manipulations. Analysis of the temporal structure of participants' corrective actions based on stochastic learning models revealed that these performance gains were attained by reducing neuromotor noise and, to a considerably lesser degree, by increasing the size of corrective actions. Based on these results, error amplification presents a promising intervention to improve motor function by decreasing neuromotor noise after performance has reached an asymptote. These results are relevant for patients with neurological disorders and the elderly. More fundamentally, these results suggest that neuromotor noise may be accessible to practice interventions. PMID- 27490198 TI - Madurella mycetomatis-Induced Massive Shoulder Joint Destruction: A Management Challenge. PMID- 27490199 TI - On the Nexus of the Spatial Dynamics of Global Urbanization and the Age of the City. AB - A number of concepts exist regarding how urbanization can be described as a process. Understanding this process that affects billions of people and its future development in a spatial manner is imperative to address related issues such as human quality of life. In the focus of spatially explicit studies on urbanization is typically a city, a particular urban region, an agglomeration. However, gaps remain in spatially explicit global models. This paper addresses that issue by examining the spatial dynamics of urban areas over time, for a full coverage of the world. The presented model identifies past, present and potential future hotspots of urbanization as a function of an urban area's spatial variation and age, whose relation could be depicted both as a proxy and as a path of urban development. PMID- 27490200 TI - Measuring Poverty in Southern India: A Comparison of Socio-Economic Scales Evaluated against Childhood Stunting. AB - INTRODUCTION: Socioeconomic status (SES) scales measure poverty, wealth and economic inequality in a population to guide appropriate economic and public health policies. Measurement of poverty and comparison of material deprivation across nations is a challenge. This study compared four SES scales which have been used locally and internationally and evaluated them against childhood stunting, used as an indicator of chronic deprivation, in urban southern India. METHODS: A door-to-door survey collected information on socio-demographic indicators such as education, occupation, assets, income and living conditions in a semi-urban slum area in Vellore, Tamil Nadu in southern India. A total of 7925 households were categorized by four SES scales-Kuppuswamy scale, Below Poverty Line scale (BPL), the modified Kuppuswamy scale, and the multidimensional poverty index (MDPI) and the level of agreement compared between scales. Logistic regression was used to test the association of SES scales with stunting. FINDINGS: The Kuppuswamy, BPL, MDPI and modified Kuppuswamy scales classified 7.1%, 1%, 5.5%, and 55.3% of families as low SES respectively, indicating conservative estimation of low SES by the BPL and MDPI scales in comparison with the modified Kuppuswamy scale, which had the highest sensitivity (89%). Children from low SES classified by all scales had higher odds of stunting, but the level of agreement between scales was very poor ranging from 1%-15%. CONCLUSION: There is great non-uniformity between existing SES scales and cautious interpretation of SES scales is needed in the context of social, cultural, and economic realities. PMID- 27490201 TI - Genome Skimming: A Rapid Approach to Gaining Diverse Biological Insights into Multicellular Pathogens. PMID- 27490202 TI - Multiparametric serological testing in autoimmune encephalitis using computer aided immunofluorescence microscopy (CAIFM). AB - Autoantibodies against neuronal cell surface antigens are tightly associated with immunotherapy-responsive autoimmune encephalitis, and a considerable number of corresponding autoantigens has been identified in recent years. Most patients initially present with overlapping symptoms, and a broad range of autoantibodies has to be considered to establish the correct diagnosis and initiate treatment as soon as possible to prevent irreversible and sometimes even life-threatening damage to the brain. Recombinant cell-based immunofluorescence allows to authentically present fragile membrane-associated surface antigens and, in combination with multiparametric analysis in the form of biochip mosaics, has turned out to be highly beneficial for parallel and prompt determination of anti neuronal autoantibodies and comprehensive differential diagnostics. For the evaluation of recombinant cell-based IIFT, a semi-automated novel function was introduced into an established platform for computer-aided immunofluorescence microscopy. The system facilitates the microscopic analysis of the tests and supports the laboratory personnel in the rapid issuance of diagnostic findings, which is of major importance for autoimmune encephalitis patients since timely initiation of treatment may lead to their full recovery. PMID- 27490203 TI - Multi-center harmonization of flow cytometers in the context of the European "PRECISESADS" project. AB - The innovative medicine initiative project called PRECISESADS will study 2.500 individuals affected by systemic autoimmune diseases (SADs) and controls. Among extensive OMICS approaches, multi-parameter flow cytometry analyses will be performed in eleven different centers. Therefore, the integration of all data in common bioinformatical and biostatistical investigations requires a fine mirroring of all instruments. We describe here the procedure elaborated to achieve this prerequisite. One flow cytometer chosen as reference instrument fixed the mean fluorescence intensities (MFIs) of 8 different fluorochrome conjugated antibodies (Abs) using VersaComp Ab capture beads. The ten other centers adjusted their own PMT voltages to reach the same MFIs. Subsequently, all centers acquired Rainbow 8-peak beads data on a daily basis to follow the stability of their instrument overtime. One blood sample has been dispatched and concomitantly stained in all centers. Comparison of leukocytes frequencies and cell surface marker MFIs demonstrated the close sensitivity of all flow cytometers, allowing a multicenter analysis. The effective multi-center harmonization enables the constitution of a workable wide flow cytometry database for the identification of specific molecular signatures in individuals with SADs. PMID- 27490204 TI - Critical review of the current recommendations for the treatment of systemic inflammatory rheumatic diseases during pregnancy and lactation. AB - The crucial issue for a better pregnancy outcome in women with autoimmune rheumatic diseases is appropriate planning, with counseling of the ideal timing and treatment adaptation. Drugs used to treat rheumatic diseases may interfere with fertility or increase the risk of miscarriages and congenital abnormalities. MTX use post-conception is clearly linked to abortions as well as major birth defects, so it should be stopped 3months before conception. Leflunomide causes abnormalities in animals even in low doses. Although in humans, it does not seem to be as harmful as MTX, when pregnancy is detected in a patient on leflunomide, cholestyramine is given for washout. Sulfasalazine can be used safely and is an option for those patients who were on MTX or leflunomide. Azathioprine is generally the immunosuppressive of choice in many high-risk pregnancy centers because of the safety profile and its steroid-sparing property. Cyclosporine and tacrolimus can also be used as steroid-sparing agents, but experience is smaller. Although prednisone and prednisolone are inactivated in the placenta, we try to limit the dose to the minimal effective one, to prevent side effects. Antimalarials have been broadly studied and are safe during pregnancy and breastfeeding. Among biologic disease modifying anti-rheumatic agents (bDMARD), the anti-TNFs that have been used for longer are the ones with greater experience. The large monoclonal antibodies do not cross the placenta in the first trimester, and after conception, the decision to continue medication should be taken individually. The experience is larger in women with inflammatory bowel diseases, where anti-TNF is generally maintained at least until 30weeks to reduce fetal exposure. Live vaccines should not be administrated to the infant in the first 6months of life. Pregnancy data for rituximab, abatacept, anakinra, tocilizumab, ustekinumab, belimumab, and tofacitinib are limited and their use in pregnancy cannot currently be recommended. PMID- 27490205 TI - From HBV to HPV: Designing vaccines for extensive and intensive vaccination campaigns worldwide. AB - HBsAg and HPV L1 proteins - the HBV and HPV antigens utilized in current vaccines - share amino acid sequences with human proteins such as cardiomyopathy associated protein 5, titin, protein-arginine deiminase, E3 ubiquitin-protein ligase RNF19A, bassoon, G-protein coupled receptor for fatty acids, insulin isoform 2, and mitogen-activated protein kinase kinase kinase 10, inter alia. Many shared peptides are also part of immunopositive epitopes. The data 1) support the possibility of crossreactions between the two viral antigens and human proteins that, when altered, may associate with neuropsychiatric, cardiovascular and metabolic diseases such as multiple sclerosis, amyotrophic lateral sclerosis, diabetes, and sudden death; 2) confirm the concept that only vaccines based on sequences unique to pathogens might nullify potential crossreactivity risks in vaccination protocols. PMID- 27490206 TI - Cardiovascular risk assessment in patients with rheumatoid arthritis: The relevance of clinical, genetic and serological markers. AB - Cardiovascular disease (CV) is the most common cause of premature mortality in patients with rheumatoid arthritis (RA). This is the result of an accelerated atherosclerotic process. Adequate CV risk stratification has special relevance in RA to identify patients at risk of CV disease. However, current CV risk screening and management strategies underestimate the actual CV risk in RA. Consequently, the search for additional tools that may help to identify those patients at high CV risk has become a key objective in the last years. In this regard, non invasive surrogates, such as carotid ultrasonography, have been found to be excellent predictors of future CV events. In addition, several studies have revealed the relevance of a genetic component in the development of CV disease in RA patients. Besides an association with HLA-DRB1* shared epitope alleles other gene polymorphisms located inside and outside the HLA seem to influence the risk of cardiovascular disease in RA. Moreover, serum levels of some metabolic syndrome-related biomarkers, adipokines such as adiponectin and biomarkers of endothelial cell activation and inflammation such as Osteoprotegerin and Asymmetric dimethylarginine have recently been found useful for the prediction of CV disease in these patients. An update of the current knowledge on these potential markers, especially focused on new genetic and serological biomarkers is shown in this review. PMID- 27490207 TI - Transmission of Lamb waves and resonance at an adhesive butt joint of plates. AB - The transmission behavior of Lamb waves and the possible occurrence of resonance at an adhesive butt joint of plates are studied experimentally. To this purpose, two 2.5-mm thick aluminum alloy plates are bonded at their edges using cyanoacrylate-based adhesive. Bonded plate specimens with different joint conditions are prepared by changing the bonding procedure. The measurements are performed for the transmission characteristics of the lowest-order symmetric (S0) and antisymmetric (A0) Lamb modes for the frequency range of 0.4-0.6MHz below the cut-off frequency of the higher-order modes. The experimental results show that the transmission coefficients of the S0 and A0 modes exhibit different frequency dependent characteristics depending on the joint condition. Furthermore, for the incidence of the S0 mode at the center frequency of 1MHz, the transmitted S0 mode in weakly bonded specimens shows a long oscillation tail due to the resonance effect. The experimental results are discussed in the light of the theoretical results based on the spring-type interface model. The interfacial stiffnesses identified from the transmission coefficients are shown to be correlated with the bonding condition of the joint and give reasonable estimates of the resonance frequencies of weakly bonded specimens. PMID- 27490208 TI - Prediction of compound-target interactions of natural products using large-scale drug and protein information. AB - BACKGROUND: Verifying the proteins that are targeted by compounds of natural herbs will be helpful to select natural herb-based drug candidates. However, this entails a great deal of effort to clarify the interaction throughout in vitro or in vivo experiments. In this light, in silico prediction of the interactions between compounds and target proteins can help ease the efforts. RESULTS: In this study, we performed in silico predictions of herbal compound target identification. First, data related to compounds, target proteins, and interactions between them are taken from the DrugBank database. Then we characterized six classes of compound-target interaction in humans including G protein-coupled receptors (GPCRs), ion channel, enzymes, receptors, transporters, and other proteins. Also, classification-prediction models that predict the interactions between compounds and target proteins through a machine learning method were constructed using these matrices. As a result, AUC values of six classes are 0.94, 0.93, 0.90, 0.89, 0.91, and 0.76 respectively. Finally, the interactions of compounds from natural products were predicted using the constructed classification models. Furthermore, from our predicted results, we confirmed that several important disease related proteins were predicted as targets of natural herbal compounds. CONCLUSIONS: We constructed classification prediction models that predict the interactions between compounds and target proteins. The constructed models showed good prediction performances, and numbers of potential natural compounds target proteins were predicted from our results. PMID- 27490209 TI - Effects of dietary green tea polyphenol supplementation on the health of workers exposed to high-voltage power lines. AB - Although it has been several decades since the focus on the effect of extremely low frequency electromagnetic fields (ELF-EMF) of high-voltage power lines on human health, no consistent conclusion has been drawn. The present study aimed to investigate the change in oxidative stress after exposure to ELF-EMFs, and potential protective effects of green tea polyphenol supplementation (GTPS) on ELF-EMFs induced oxidative stress. A total of 867 subjects, including workers with or without exposure to ELF-EMFs of 110-420kV power lines, participated and were randomized into GTPS and placebo treatment groups. Oxidative stress and oxidative damage to DNA were assessed by urinary tests of 8-isoprostane and 8 OHdG. Significant increased urinary 8-isoprostane and 8-OHdG were observed in workers with ELF-EMFs exposure, which were diminished after 12 months of GTPS. No protective effects of GTPS on oxidative stress and oxidative damage to DNA were observed after three months of GTPS withdraw. We found a negative impact of high voltage power lines on the health of workers. Long-term GTPS could be an efficient protection against the health issues induced by high-voltage power lines. PMID- 27490210 TI - Effects of inducers of cytochrome P450s on enrofloxacin N-deethylation in crucian carp Carassius auratus gibelio. AB - In this study with crucian carp (Carassius auratus gibelio), the effect on enrofloxacin (EF) and its metabolite ciprofloxacin (CF) and on the activity of cytochrome P450 1A (CYP1A) and cytochrome P450 3A (CYP3A) was estimated following the oral administration of rifampicin (RIF) (12mg/kg) and beta-naphthoflavone (BNF) (12mg/kg), respectively. First, reversed-phase high-performance liquid chromatography (RP-HPLC) was used to detect the pharmacokinetics of EF with continual blood sampling. In RIF-treated, BNF-treated and control groups, the value of the CmaxCF/CmaxEF ratio was 4.41, 0.81 and 0.95, and the corresponding value of the AUC0-t-CF/AUC0-t-EF ratio was 3.69, 1.84 and 1.76, respectively. In the RIF-treated, BNF-treated and control groups, the MRT values of EF were 26.57, 27.45 and 30.88h, and the corresponding values for CF were 5.79, 35.18 and 38.11h, respectively. Based on these results for crucian carp, the accumulation and elimination of EF and CF in the RIF-treated group were more rapid than in BNF treated and control groups. Second, liver microsomes were pretreated with the inducer of CYP1A for BNF and that of CYP3A for RIF, and then the enzymatic activities of CYP1A and CYP3A were measured, respectively. The activities of ethoxyresorufin-O-deethylation (EROD) and erythromycin-N-demethylation (ERND) increased significantly (P<0.05) for CYP1A and CYP3A, respectively. However, in further experiments on the formation of CF, the level of EF N-deethylation was significantly induced by RIF and inhibited by ketoconazole (KTZ) for CYP3A but had no influence for CYP1A, BNF and berberine chloride (BER). We concluded that CYP3A might be responsible for the N-deethylation of EF and because of this activity, could also serve as a toxicity biomarker in crucian carp. PMID- 27490211 TI - Tideglusib induces apoptosis in human neuroblastoma IMR32 cells, provoking sub G0/G1 accumulation and ROS generation. AB - Neuroblastoma is the most common tumor amongst children amounting to nearly 15% of cancer deaths. This cancer is peculiar in its characteristics, exhibiting differentiation, maturation and metastatic transformation leading to poor prognosis and low survival rates among children. Chemotherapy, though toxic to normal cells, has shown to improve the survival of the patient with emphasis given more towards targeting angiogenesis. Recently, Tideglusib was designed as an 'Orphan Drug' to target the neurodegenerative Alzheimer's disease and gained significant momentum in its function during clinical trials. Duffy et al. recently reported a reduction in cell viability of human IMR32 neuroblastoma cells when treated with Tideglusib at varying concentrations. We investigated the effects of Tideglusib, at various concentrations, compared to Lithium chloride at various concentrations, on IMR32 cells. Lithium, a known GSK-3 inhibitor, was used as a standard to compare the efficiency of Tideglusib in a dose-dependent manner. Cell viability was assessed by MTT assay. The stages of apoptosis were evaluated by AO/EB staining and nuclear damage was determined by Hoechst 33258 staining. Reactive oxygen species (ROS) and mitochondrial membrane potential (DeltaPsim) were assessed by DCFDA dye and Rhodamine-123 dye, respectively. Tideglusib reported a significant dose-dependent increase in pro-apoptotic proteins (PARP, Caspase-9, Caspase-7, Caspase-3) and tumor-related genes (FasL, TNF-alpha, Cox-2, IL-8, Caspase-3). Anti-GSK3 beta, pGSK3 beta, Bcl-2, Akt-1, p Akt1 protein levels were observed with cells exposed to Tideglusib and Lithium chloride. No significant dose-dependent changes were observed for the mRNA expression of collagenase MMP-2, the tumor suppressor p53, or the cell cycle protein p21. Our study also reports Tideglusib reducing colony formation and increasing the level of sub-G0/G1 population in IMR32 cells. Our investigations report the significance of Tideglusib as a promising apoptotic inducer in human neuroblastoma IMR32 cells. Our study also reports that LiCl reduced cell viability in IMR32 cells inducing apoptosis mediated by ROS generation. PMID- 27490212 TI - Shape memory thermoplastic polyurethane (TPU)/poly(epsilon-caprolactone) (PCL) blends as self-knotting sutures. AB - Thermally responsive shape memory polymers have promising applications in many fields, especially in biomedical areas. In this study, a simple method was purposed to prepare thermoplastic polyurethane (TPU)/poly(epsilon-caprolactone) (PCL) blends that possess shape memory attributes. TPU and PCL were melt compounded via a twin-screw extruder and injection molded at various ratios. Multiple test methods were used to characterize their shape memory properties and reveal the underling mechanism. The blends containing 25% TPU and 75% PCL possessed the best shape memory properties as indicated by a 98% shape fixing ratio and 90% shape recovery ratio. This was attributed to the hybrid crystalline and amorphous regions of PCL and TPU. We also found that PCL and TPU had good miscibility and that the PCL domain in TPU25% had higher crystallinity than neat PCL. The crystalline region in TPU25% could deform and maintain its temporary shape when stretched, which contributed to its high shape fixing attribute, while the rubbery TPU region assisted in the recovery of the sample upon heating by releasing the deformation energy stored. Moreover, the TPU25% string prepared could knot itself in a hot water bath, indicating a potential for suture applications. Lastly, the 3T3 fibroblast cells cultured on the TPU/PCL blends showed high viability and active substrate-cell interactions. PMID- 27490213 TI - Chronic pain disorders after critical illness and ICU-acquired opioid dependence: two clinical conundra. AB - PURPOSE OF REVIEW: Is to describe the potential for patients to undergo an acute to-chronic pain transition after ICU discharge as a result of pain they experienced in ICU and to explore the phenomenon of ICU-acquired opioid dependence. Both topics are timely, in that they can negatively influence patient recovery after critical illness and contribute to post-ICU syndrome. RECENT FINDINGS: Recognizing and treating pain in patients while they are in the ICU has always been important. However, new knowledge increases the importance of good pain management on patient welfare: recent basic science discoveries on mechanisms of chronic pain development; identification of myriad factors, occurring during the patient's hospital and ICU stay, that put patients at risk for development of chronic pain; the view that a multimodal analgesia treatment approach that is opioid sparing may be the optimum method for acute pain management. Furthermore, recent findings about ICU-acquired opioid dependence provide a foundation for promoting more rigorous assessment, prevention, and treatment of opioid withdrawal in ICU patients. SUMMARY: Providing sufficient analgesia to ICU patients while preventing opioid dependence and withdrawal is essential to promote comfort and rehabilitation. Obtaining this balance requires heightened ICU clinician attention and focused research. PMID- 27490214 TI - Why are we Still Dialyzing Overdoses to Tricyclic Antidepressants? A subanalysis of the NPDS database. AB - A recent analysis of the American Association of Poison Control Centers database, showed that poisonings from toxins not usually considered amenable to extracorporeal purification ("non-classic toxins" such as ethanol and tricyclic antidepressants) continue to be reported. This publication investigates factors that may explain these findings. Our results suggest that: 1) the relatively high absolute number of ECTR performed for non-classic toxins may simply reflect the large number of exposures to these toxins, 2) poisoning from another toxin may have been the reason for ECTR initiation in some exposures to non-classic toxins, 3) poisoning from non-classic toxins may receive ECTR for purposes other than toxin removal, and 4) the decisional threshold to initiate ECTR may be lower for non-classic toxins because of heightened toxicity. PMID- 27490215 TI - Atraumatic Hip Instability. AB - Atraumatic hip instability is an increasingly recognized source of pain and hip dysfunction. It can result from numerous causes, including femoroacetabular impingement, prior trauma, injury to the capsuloligamentous structures, and idiopathic etiologies. Occult hip instability can be a challenging diagnosis that requires careful attention to, and interpretation of, history, physical examination, and radiographic imaging findings. Iatrogenic hip instability is a potential complication of both open and arthroscopic hip-preserving surgical procedures that can have catastrophic results. Atraumatic hip instability is a pathologic entity that can be successfully addressed with open and arthroscopic procedures. PMID- 27490216 TI - Tendinopathy and Tendon Rupture Associated with Statins. AB - Use of statins may be associated with certain tendinopathies and tendon ruptures, especially of the Achilles, quadriceps, and distal biceps tendons. Tendinopathy usually occurs within the first year of statin use and improves after the drug therapy is stopped. Systemic conditions with a higher risk of tendon rupture include diabetes, gout, rheumatoid arthritis, and chronic kidney disease. Certain drugs, such as corticosteroids and fluoroquinolones, have also been implicated in tendon ruptures. Patients with these systemic conditions who are taking statins in combination with other drugs that increase the risk of tendon injury should be educated about this risk and alternative treatments, including diet and exercise. PMID- 27490217 TI - Problematic Pediatric Hand and Wrist Fractures. AB - Seymour fractures are open juxta-physeal fractures of the distal phalanx. A true lateral radiograph should be obtained for diagnosis, and treatment should include removal of the nail, irrigation and debridement of the fracture, and percutaneous Kirschner wire stabilization. Mallet fractures are more common in children than adults, and treatment is generally nonoperative for nondisplaced or minimally displaced fractures without volar subluxation of the distal phalanx; however, splinting compliance should be carefully assessed in younger populations. Phalangeal neck fractures have a limited potential to remodel and a propensity to redisplace. A true lateral radiograph will show displacement best; treatment is generally with percutaneous pinning. Open reduction should be avoided when possible because of the risk of osteonecrosis of the phalangeal condyles. The epidemiology of scaphoid fractures in children is changing, with waist fractures now the most common type. This may be due to an increase in body mass index (BMI) as well as high-level sports participation in today's pediatric population. Although the vast majority of acute scaphoid fractures can be treated successfully with cast immobilization, children who present with established nonunions should be offered open reduction and internal fixation as the primary treatment. PMID- 27490218 TI - Introduction of New Technologies in Orthopaedic Surgery. AB - The introduction of new devices, biologics, and combination products to the orthopaedic marketplace is increasing rapidly. The majority of these new technologies obtain clearance to market by demonstrating substantial equivalence to a predicate (previously approved device) according to the U.S. Food and Drug Administration (FDA) 510(k) process. Surgeons play a critical role in the introduction of new technologies to patients and must take a leadership role in promoting safe, efficacious, appropriate, and cost-effective care, especially for operative procedures. Surgeons should monitor and document their patients' clinical outcomes and adverse events when using new technology, to ensure that the new technology is performing as desired. PMID- 27490219 TI - Synovial Chondromatosis. AB - Synovial chondromatosis is a rare, benign condition of unknown etiology in which the synovium undergoes metaplasia leading to cartilaginous nodules that ultimately break free, mineralize, and even ossify. The most commonly involved joint is the knee. Patients may be asymptomatic or may present with pain, swelling, and limited range of motion. Plain radiographs can be diagnostic and mineralized nodules are pathognomonic. Recommended treatment involves arthroscopic or open removal of loose bodies with or without a synovectomy to prevent further articular and periarticular destruction and to relieve symptoms. PMID- 27490220 TI - Operative Treatment of Lateral Ankle Instability. AB - Chronic lateral ankle instability can occur in a subset of patients following ankle inversion sprains. Operative treatment to restore stability in the ankle and hindfoot and to prevent further degenerative changes may be indicated in cases in which nonoperative treatment has failed. Anatomical direct repair with use of native ligament remnants with or without reinforcement of the inferior retinaculum is the so-called gold standard operative strategy for the treatment of lateral ankle instability. The procedure has shown promising short and long term outcomes. Candidates for the procedure have ligament remnants of sufficient quality that are amendable to direct repair. Anatomical reconstruction with use of autograft or allograft is reserved for patients with insufficient ligament remnants to fashion a direct repair, failed previous lateral ankle repair, high body mass index, or generalized ligamentous laxity. A wide variety of autografts have been described, each with potential advantages and disadvantages. These procedures can provide good-to-excellent short-term outcomes. However, there is no available information on their long-term clinical results. Non-anatomical lateral ligament reconstruction typically involves the use of the adjacent peroneal brevis tendon and has been applied in cases in which only poor-quality ligament remains. The procedure can provide good to excellent short-term outcomes, although reported long-term outcomes have differed among studies. The particular tendon used for the graft should be carefully considered given the potential alterations in the kinematics of the ankle and hindfoot. Arthroscopic ligament repair is becoming increasingly popular as it is minimally invasive. This procedure is restricted to patients who have good-quality ligament remnants. Good-to-excellent clinical outcomes have been reported after short and long-term follow-up, although a relatively high rate of complications-including nerve damage-has been reported following the procedure and therefore warrants further investigation before widespread adoption can be advocated. PMID- 27490221 TI - Design and validation of a near-infrared fluorescence endoscope for detection of early esophageal malignancy. AB - Barrett's esophagus is a known precursor lesion to esophageal adenocarcinoma. In these patients, early detection of premalignant disease, known as dysplasia, allows curative minimally invasive endoscopic therapy, but is confounded by a lack of contrast in white light endoscopy. Imaging fluorescently labeled lectins applied topically to the tissue has the potential to more accurately delineate dysplasia, but tissue autofluorescence limits both sensitivity and contrast when operating in the visible region. To overcome this challenge, we synthesized near infrared (NIR) fluorescent wheat germ agglutinin (WGA-IR800CW) and constructed a clinically translatable bimodal NIR and white light endoscope. Images of NIR and white light with a field of view of 63 deg and an image resolution of 182 MUm are coregistered and the honeycomb artifact arising from the fiber bundle is removed. A minimum detectable concentration of 110 nM was determined using a dilution series of WGA-IR800CW. We demonstrated ex vivo that this system can distinguish between gastric and squamous tissue types in mouse stomachs (p=0.0005) and accurately detect WGA-IR800CW fluorescence in human esophageal resections (compared with a gold standard imaging system, rs>0.90). Based on these findings, future work will optimize the bimodal endoscopic system for clinical trials in Barrett's surveillance. PMID- 27490222 TI - High-temporal-resolution, full-field optical angiography based on short-time modulation depth for vascular occlusion tests. AB - We developed high-temporal-resolution, full-field optical angiography for use in vascular occlusion tests (VOTs). In the proposed method, undersampled signals are acquired by a high-speed digital camera that separates the dynamic and static speckle signals. The two types of speckle signal are used to calculate the short time modulation depth (STMD) of each of the camera pixels. STMD is then used to realize high-temporal-resolution, full-field optical angiography. Phantom and biological experiments conducted and demonstrated the feasibility of using our proposed method to perform VOTs and to study the reaction kinetics in microfluidic systems. PMID- 27490223 TI - An Unusual Case of Intra-Abdominal Air. PMID- 27490224 TI - A Rare Cause of Ascites: Putting the Pieces.... PMID- 27490225 TI - A Rare Cause of Hepatitis: "Think Outta the Box!". PMID- 27490226 TI - Hematuria and Diarrhea: A Case Report. PMID- 27490227 TI - White Spots in the Rectum. PMID- 27490228 TI - An Unusual Cause of Life-Threatening Upper Gastrointestinal Bleeding. PMID- 27490229 TI - Unusual Gastric Nodules. PMID- 27490230 TI - Appropriate Timing of Rectal Indomethacin Administration and Patient Selection in Assessment of Post-ERCP Pancreatitis. PMID- 27490231 TI - An Unusual Cause of Hematochezia and Aneurysmal Small Bowel Dilatation. PMID- 27490232 TI - Statins for age-related macular degeneration. AB - BACKGROUND: Age-related macular degeneration (AMD) is a progressive, late-onset disorder of the macula affecting central vision. It is the leading cause of blindness in people over 65 years in industrialized countries. Recent epidemiologic, genetic, and pathological evidence has shown that AMD shares a number of risk factors with atherosclerosis, leading to the hypothesis that statins may exert protective effects in AMD. OBJECTIVES: The objective of this review was to examine the effectiveness of statins compared with other treatments, no treatment, or placebo in delaying the onset and progression of AMD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2016), EMBASE (January 1980 to March 2016), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2016), PubMed (January 1946 to March 2016), the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com) (last searched 5 June 2014), ClinicalTrials.gov (www.clinicaltrials.gov), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 31 March 2016. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-randomized trials that compared statins with other treatments, no treatment, or placebo in people who were diagnosed as having the early stages of AMD. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently evaluated the search results against the selection criteria, abstracted data, and assessed risk of bias. We did not perform meta-analysis due to heterogeneity in the interventions and outcomes between the included studies. MAIN RESULTS: Two RCTs with a total of 144 participants met the selection criteria. Both trials compared simvastatin versus placebo in older people (older than 50 or 60 years) with high risk of developing AMD (drusen present on examination). Overall, we judged the quality of the evidence to be low, as we downgraded all outcomes due to limitations in the designs of the trials and insufficient outcome reporting. The larger trial, with 114 participants, was conducted in Australia and used a higher dose (40 mg daily) of simvastatin for three years. Participants and study personnel in this trial were adequately masked, however data were missing for 30% of participants at three years' follow-up. The smaller trial, with 30 participants, was conducted in Italy and used a lower dose (20 mg) of simvastatin for three months. This trial reported insufficient details to assess the risk of bias.Neither trial reported data for change in visual acuity. Low-quality evidence from the smaller trial, with 30 participants, did not show a statistically significant difference between the simvastatin and placebo groups in visual acuity values at three months of treatment (decimal visual acuity 0.21 +/- 0.56 in simvastatin group and 0.19 +/- 0.40 in placebo group) or 45 days after the completion of treatment (decimal visual acuity 0.20 +/- 0.50 in simvastatin group and 0.19 +/- 0.48 in placebo group). The lack of a difference in visual acuity was not explained by lens or retina status, which remained unchanged during and after the treatment period for both groups.Preliminary analyses of 42 participants who had completed 12 months' follow-up in the larger trial did not show a statistically significant difference between simvastatin and the placebo groups for visual acuity, drusen score, or visual function (effect estimates and confidence intervals were not available). Complete data for these outcomes at three years' follow-up were not reported. At three years, low-quality evidence showed an effect of simvastatin in slowing progression of AMD compared with placebo to be uncertain (odds ratio 0.51, 95% confidence interval 0.23 to 1.09).One trial did not report adverse outcomes. The second trial reported no difference between groups in terms of adverse events such as death, muscle aches, and acute hepatitis. AUTHORS' CONCLUSIONS: Evidence from currently available RCTs is insufficient to conclude that statins have a role in preventing or delaying the onset or progression of AMD. PMID- 27490233 TI - Atypical Radiological Presentation of a Wingless-Type Pediatric Medulloblastoma. PMID- 27490234 TI - Consensus Statement of Society of Abdominal Radiology Disease-Focused Panel on Barium Esophagography in Gastroesophageal Reflux Disease. AB - OBJECTIVE: The Society of Abdominal Radiology established a panel to prepare a consensus statement on the role of barium esophagography in gastroesophageal reflux disease (GERD), as well as recommended techniques for performing the fluoroscopic examination and the gamut of findings associated with this condition. CONCLUSION: Because it is an inexpensive, noninvasive, and widely available study that requires no sedation, barium esophagography may be performed as the initial test for GERD or in conjunction with other tests such as endoscopy. PMID- 27490235 TI - Pediatric Chest Radiographs: Common and Less Common Errors. AB - OBJECTIVE: Radiographic imaging of the pediatric chest presents several unique challenges and nuances, stemming from congenital variants and pathologic processes specific to this population. Errors in interpretation may lead to inappropriate further imaging, incurring additional radiation exposure and cost, as well as psychologic effects on the patients and their families. CONCLUSION: Here, we aim to highlight some common and less common pitfalls in pediatric chest radiography, as well as some tools for avoiding potential mistakes. PMID- 27490236 TI - Orthogonal Dual-Triggered Shape-Memory DNA-Based Hydrogels. AB - DNA-based shape-memory hydrogels revealing switchable shape recovery in the presence of two orthogonal triggers are described. In one system, a shaped DNA/acrylamide hydrogel is stabilized by duplex nucleic acids and pH-responsive cytosine-rich, i-motif, bridges. Separation of the i-motif bridges at pH 7.4 transforms the hydrogel into a quasi-liquid, shapeless state, that includes the duplex bridges as permanent shape-memory elements. Subjecting the quasi-liquid state to pH 5.0 or Ag(+) ions recovers the hydrogel shape, due to the stabilization of the hydrogel by i-motif or C-Ag(+) -C bridged i-motif. The cysteamine-induced transformation of the duplex/C-Ag(+) -C bridged i-motif hydrogel into a quasi-liquid shapeless state results in the recovery of the shaped hydrogel in the presence of H(+) or Ag(+) ions as triggers. In a second system, a shaped DNA/acrylamide hydrogel is generated by DNA duplexes and bridging Pb(2+) or Sr(2+) ions-stabilized G-quadruplex subunits. Subjecting the shaped hydrogel to the DOTA or KP ligands eliminates the Pb(2+) or Sr(2+) ions from the respective hydrogels, leading to shapeless, memory-containing, quasi liquid states that restore the original shapes with Pb(2+) or Sr(2+) ions. PMID- 27490237 TI - Metal-Free Cross-Coupling of Arylboronic Acids and Derivatives with DAST-Type Reagents for Direct Access to Diverse Aromatic Sulfinamides and Sulfonamides. AB - We have developed a simple and convenient method for the cross-coupling of arylboronic acids and their derivatives with DAST-type reagents under mild and metal-free conditions to directly afford sulfinamides in moderate to good yields. Moreover, sulfonamides were obtained after a simple oxidation reaction. The reaction mechanism was investigated by (18) O-labeling experiments, and the synthetic utility was demonstrated by the sulfoxidation of natural products. PMID- 27490238 TI - Single Nucleotide Polymorphism Clustering in Systemic Autoimmune Diseases. AB - Systemic Autoimmune Diseases, a group of chronic inflammatory conditions, have variable symptoms and difficult diagnosis. In order to reclassify them based on genetic markers rather than clinical criteria, we performed clustering of Single Nucleotide Polymorphisms. However naive approaches tend to group patients primarily by their geographic origin. To reduce this "ancestry signal", we developed SNPClust, a method to select large sources of ancestry-independent genetic variations from all variations detected by Principal Component Analysis. Applied to a Systemic Lupus Erythematosus case control dataset, SNPClust successfully reduced the ancestry signal. Results were compared with association studies between the cases and controls without or with reference population stratification correction methods. SNPClust amplified the disease discriminating signal and the ratio of significant associations outside the HLA locus was greater compared to population stratification correction methods. SNPClust will enable the use of ancestry-independent genetic information in the reclassification of Systemic Autoimmune Diseases. SNPClust is available as an R package and demonstrated on the public Human Genome Diversity Project dataset at https://github.com/ThomasChln/snpclust. PMID- 27490239 TI - Enantioconvergent Nucleophilic Substitution Reaction of Racemic Alkyne-Dicobalt Complex (Nicholas Reaction) Catalyzed by Chiral Bronsted Acid. AB - Catalytic enantioselective syntheses enable a practical approach to enantioenriched molecules. While most of these syntheses have been accomplished by reaction at the prochiral sp(2)-hybridized carbon atom, little attention has been paid to enantioselective nucleophilic substitution at the sp(3)-hybridized carbon atom. In particular, substitution at the chiral sp(3)-hybridized carbon atom of racemic electrophiles has been rarely exploited. To establish an unprecedented enantioselective substitution reaction of racemic electrophiles, enantioconvergent Nicholas reaction of an alkyne-dicobalt complex derived from racemic propargylic alcohol was developed using a chiral phosphoric acid catalyst. In the present enantioconvergent process, both enantiomers of the racemic alcohol were transformed efficiently to a variety of thioethers with high enantioselectivity. The key to achieving success is dynamic kinetic asymmetric transformation (DYKAT) of enantiomeric cationic intermediates generated via dehydroxylation of the starting racemic alcohol under the influence of the chiral phosphoric acid catalyst. The present fascinating DYKAT involves the efficient racemization of these enantiomeric intermediates and effective resolution of these enantiomers through utilization of the chiral conjugate base of the phosphoric acid. PMID- 27490241 TI - The Ramachandran Number: An Order Parameter for Protein Geometry. AB - Three-dimensional protein structures usually contain regions of local order, called secondary structure, such as alpha-helices and beta-sheets. Secondary structure is characterized by the local rotational state of the protein backbone, quantified by two dihedral angles called phi and psi. Particular types of secondary structure can generally be described by a single (diffuse) location on a two-dimensional plot drawn in the space of the angles phi and psi, called a Ramachandran plot. By contrast, a recently-discovered nanomaterial made from peptoids, structural isomers of peptides, displays a secondary-structure motif corresponding to two regions on the Ramachandran plot [Mannige et al., Nature 526, 415 (2015)]. In order to describe such 'higher-order' secondary structure in a compact way we introduce here a means of describing regions on the Ramachandran plot in terms of a single Ramachandran number, [Formula: see text], which is a structurally meaningful combination of phi and psi. We show that the potential applications of [Formula: see text] are numerous: it can be used to describe the geometric content of protein structures, and can be used to draw diagrams that reveal, at a glance, the frequency of occurrence of regular secondary structures and disordered regions in large protein datasets. We propose that [Formula: see text] might be used as an order parameter for protein geometry for a wide range of applications. PMID- 27490240 TI - KIR and HLA Genotypes Implicated in Reduced Killer Lymphocytes Immunity Are Associated with Vogt-Koyanagi-Harada Disease. AB - Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are killer lymphocytes that provide defense against viral infections and tumor transformation. Analogous to that of CTL, interactions of killer-cell immunoglobulin-like receptors (KIR) with specific human leukocyte antigen (HLA) class I ligands calibrate NK cell education and response. Gene families encoding KIRs and HLA ligands are located on different chromosomes, and feature variation in the number and type of genes. The independent segregation of KIR and HLA genes results in variable KIR-HLA interactions in individuals, which may impact disease susceptibility. We tested whether KIR-HLA combinations are associated with Vogt Koyanagi-Harada (VKH) disease, a bilateral granulomatous panuveitis that has strong association with HLA-DR4. We present a case control study of 196 VKH patients and 209 controls from a highly homogeneous native population of Japan. KIR and HLA class I genes were typed using oligonucleotide hybridization method and analyzed using two-tailed Fisher's exact probabilities. The incidence of Bx KIR genotypes was decreased in VKH patients (odds ratio [OR] 0.58, P = 0.007), due primarily to a decrease in centromeric B-KIR motif and its associated KIRs 2DS2, 2DL2, 2DS3, and 2DL5B. HLA-B22, implicated in poor immune response, was increased in VKH (OR = 4.25, P = 0.0001). HLA-Bw4, the ligand for KIR3DL1, was decreased in VKH (OR = 0.59, P = 0.01). The KIR-HLA combinations 2DL2+C1/C2 and 3DL1+Bw4, which function in NK education, were also decreased in VKH (OR = 0.49, P = 0.012; OR = 0.59, P = 0.013). Genotypes missing these two inhibitory KIR-HLA combinations in addition to missing activating KIRs 2DS2 and 2DS3 were more common in VKH (OR = 1.90, P = 0.002). These results suggest that synergistic hyporesponsiveness of NK cells (due to poor NK education along with missing of activating KIRs) and CTL (due to HLA-B22 restriction) fail to mount an effective immune response against viral-infection that may trigger VKH pathogenesis in genetically susceptible individuals, such as HLA-DR4 carriers. PMID- 27490242 TI - Prevalence and Phylogenetic Analysis of Human Bocaviruses 1-4 in Pediatric Patients with Various Infectious Diseases. AB - OBJECTIVES: Viral infections caused by human bocaviruses 1-4 (HBoV1-4) are more complicated than previously believed. A retrospective, large-scale study was undertaken to explore the prevalence of HBoV1-4 in pediatric patients with various infectious diseases and delineate their phylogenetic characteristics. METHODS: Clinical samples from four specimen types, including 4,941 respiratory, 2,239 cerebrospinal fluid (CSF), 2,619 serum, and 1,121 fecal specimens, collected from pediatric patients with various infectious diseases were screened for HBoV1-4. A 690-nt fragment in each specimen was then amplified and sequenced for phylogenetic analysis. Clinical characteristics of HBoV-positive patients with different specimen types available were evaluated. RESULTS: Approximately 1.2% of patients were confirmed as HBoV-positive, with the highest positive rate in patients with gastrointestinal infection (2.2%), followed by respiratory (1.65%), central nervous system (0.8%), and hematological infections (0.2%). A single genetic lineage of HBoV1 circulated among children over the 8-year period, while a new cluster of HBoV2, via intra-genotype recombination between HBoV2A and HBoV2B, was prevalent. Some patients had HBoV1-positive respiratory and serum specimens or fecal specimens. Several cases became HBoV1-positive following the appearance of respiratory infection, while several cases were positive for HBoV2 only in CSF and serum specimens, rather than respiratory specimens. CONCLUSIONS: A single genetic lineage of HBoV1 is speculated as a viral pathogen of respiratory infection and causes both comorbid infection and acute gastroenteritis. Additionally, a new cluster of HBoV2 is prevalent in China, which may infect the host through sites other than the respiratory tract. PMID- 27490244 TI - Effect of Additives on the Selectivity and Reactivity of Enzymes. AB - Enzymes have been widely used as efficient, eco-friendly, and biodegradable catalysts in organic chemistry due to their mild reaction conditions and high selectivity and efficiency. In recent years, the catalytic promiscuity of many enzymes in unnatural reactions has been revealed and studied by chemists and biochemists, which has expanded the application potential of enzymes. To enhance the selectivity and activity of enzymes in their natural or promiscuous reactions, many methods have been recommended, such as protein engineering, process engineering, and media engineering. Among them, the additive approach is very attractive because of its simplicity to use and high efficiency. In this paper, we will review the recent developments about the applications of additives to improve the catalytic performances of enzymes in their natural and promiscuous reactions. These additives include water, organic bases, water mimics, cosolvents, crown ethers, salts, surfactants, and some particular molecular additives. PMID- 27490243 TI - N-glycosylation in the thermoacidophilic archaeon Sulfolobus acidocaldarius involves a short dolichol pyrophosphate carrier. AB - N-glycosylation is a post-translational modification that occurs across evolution. In the thermoacidophilic archaea Sulfolobus acidocaldarius, glycoproteins are modified by an N-linked tribranched hexasaccharide reminiscent of the N-glycans assembled in Eukarya. Previously, hexose-bearing dolichol phosphate was detected in a S. acidocaldarius Bligh-Dyer lipid extract. Here, we used a specialized protocol for extracting lipid-linked oligosaccharides to detect a dolichol pyrophosphate bearing the intact hexasaccharide, as well as its biosynthetic intermediates. Furthermore, evidence for N-glycosylation of two S. acidocaldarius proteins by the same hexasaccharide and its derivatives was collected. These findings thus provide novel insight into archaeal N glycosylation. PMID- 27490245 TI - Outcome after ileal pouch-anal anastomosis in ulcerative colitis patients: experience during a 27-year period. AB - BACKGROUND: No previous study describes the postoperative outcome and functional results after ileal pouch-anal anastomosis (IPAA), performed in ulcerative colitis by the same surgical team with the different anastomotic techniques adopted in a 27-year period. METHODS: Prospectively, consecutive 333 ulcerative colitis patients operated adopting different IPAA techniques during the open surgery period 1984-2011 were enrolled. IPAA was performed using single stapling (SS) technique in 38 patients, double stapling (DS) technique in 235 patients (TIA stapler 42 patients, Endo-GIA 131 patients, Contour 62 patients) and handsewn IPAA in 60 patients. RESULTS: Statistically different early and late complications were recorded among the different IPAA techniques. A lower frequency of daily and nocturnal defecations and a higher level of continence were observed in the DS-IPAA compared to handsewn IPAA. The distance between the anastomotic line and the anal verge was significantly lower in DS Endo-GIA or DS Contour groups than in the DS TIA and SS. In SS IPAA group, 31.6% developed cuffitis compared to 14.4% belonging to DS group, at a mean follow-up of 140.4 months. CONCLUSIONS: Technical improvements changed the IPAA technique. Stapled IPAA is characterized by better functional outcome than handsewn IPAA. DS Endo GIA and Contour IPAA are followed by lower risk of cuffitis. PMID- 27490246 TI - High-rate, High Temperature Acetotrophic Methanogenesis Governed by a Three Population Consortium in Anaerobic Bioreactors. AB - A combination of acetate oxidation and acetoclastic methanogenesis has been previously identified to enable high-rate methanogenesis at high temperatures (55 to 65 degrees C), but this capability had not been linked to any key organisms. This study combined RNA-stable isotope probing on 13C-labelled acetate and 16S amplicon sequencing to identify the active micro-organisms involved in high-rate methanogenesis. Active biomass was harvested from three bench-scale thermophilic bioreactors treating waste activated sludge at 55, 60 and 65 degrees C, and fed with 13-C labelled and 12C-unlabelled acetate. Acetate uptake and cumulative methane production were determined and kinetic parameters were estimated using model-based analysis. Pyrosequencing performed on 13C- enriched samples indicated that organisms accumulating labelled carbon were Coprothermobacter (all temperatures between 55 and 65 degrees C), acetoclastic Methanosarcina (55 to 60 degrees C) and hydrogenotrophic Methanothermobacter (60 to 65 degrees C). The increased relative abundance of Coprothermobacter with increased temperature corresponding with a shift to syntrophic acetate oxidation identified this as a potentially key oxidiser. Methanosarcina likely acts as both a hydrogen utilising and acetoclastic methanogen at 55 degrees C, and is replaced by Methanothermobacter as a hydrogen utiliser at higher temperatures. PMID- 27490247 TI - Quantitatively Verifying the Results' Rationality for Farmland Quality Evaluation with Crop Yield, a Case Study in the Northwest Henan Province, China. AB - Evaluating the assessing results' rationality for farmland quality (FQ) is usually qualitative and based on farmers and experts' perceptions of soil quality and crop yield. Its quantitative checking still remains difficult and is likely ignored. In this paper, FQ in Xiuwu County, the Northwest Henan Province, China was evaluated by the gray relational analysis (GRA) method and the traditional analytic hierarchy process (AHP) method. The consistency rate of two results was analysed. Research focused on proposing one method of testing the evaluation results' rationality for FQ based on the crop yield. Firstly generating a grade map of crop yield and overlying it with the FQ evaluation maps. Then analysing their consistency rate for each grade in the same spatial position. Finally examining the consistency effects and allowing for a decision on adopting the results. The results showed that the area rate consistency and matching evaluation unit numbers between the two methods were 84.68% and 87.29%, respectively, and the space distribution was approximately equal. The area consistency rates between crop yield level and FQ evaluation levels by GRA and AHP were 78.15% and 74.29%, respectively. Therefore, the verifying effects of GRA and AHP were near, good and acceptable, and the FQ results from both could reflect the crop yield levels. The evaluation results by GCA, as a whole, were slightly more rational than that by AHP. PMID- 27490248 TI - Copper-Catalyzed Oxirane-Opening Reaction with Aryl Iodides and Se Powder. AB - Using Se powder as the selenating reagent, the copper-catalyzed double C-Se cross coupling of aryl iodides, epoxides, and elemental selenium has been developed. This strategy provides a straightforward approach to the synthesis of beta hydroxy phenylselenides with excellent regioselectivity of the ring opening reaction. This process proceeds in generally good yields and is compatible with a broad range of functional groups. PMID- 27490249 TI - The HOMA-Adiponectin (HOMA-AD) Closely Mirrors the HOMA-IR Index in the Screening of Insulin Resistance in the Brazilian Metabolic Syndrome Study (BRAMS). AB - BACKGROUND: The major adverse consequences of obesity are associated with the development of insulin resistance (IR) and adiposopathy. The Homeostasis Model Assessment-Adiponectin (HOMA-AD) was proposed as a modified version of the HOMA1 IR, which incorporates adiponectin in the denominator of the index. OBJECTIVES: To evaluate the performance of the HOMA-AD index compared with the HOMA1-IR index as a surrogate marker of IR in women, and to establish the cutoff value of the HOMA-AD. SUBJECTS/METHODS: The Brazilian Metabolic Syndrome Study (BRAMS) is a cross-sectional multicenter survey. The data from 1,061 subjects met the desired criteria: 18-65 years old, BMI: 18.5-49.9 Kg/m2 and without diabetes. The IR was assessed by the indexes HOMA1-IR and HOMA-AD (total sample) and by the hyperglycemic clamp (n = 49). Metabolic syndrome was defined using the IDF criteria. RESULTS: For the IR assessed by the clamp, the HOMA-AD demonstrated a stronger coefficient of correlation (r = -0.64) compared with the HOMA1-IR (r = 0.56); p < 0.0001. In the ROC analysis, compared with the HOMA1-IR, the HOMA-AD showed higher values of the AUC for the identification of IR based on the clamp test (AUC: 0.844 vs. AUC: 0.804) and on the metabolic syndrome (AUC: 0.703 vs. AUC: 0.689), respectively; p < 0.001 for all. However, the pairwise comparison did not show evidence of superiority for the HOMA-AD in comparison with the HOMA1 IR in the diagnosis of IR and metabolic syndrome (p > 0.05). The optimal cutoff identified for the HOMA-AD for the diagnosis of IR was 0.95. CONCLUSIONS: The HOMA-AD index was demonstrated to be a useful surrogate marker for detecting IR among adult women and presented a similar performance compared with the HOMA1-IR index. These results may assist physicians and researchers in determining which method to use to evaluate IR in light of the available facilities. PMID- 27490250 TI - Characteristic microglial features in patients with hereditary diffuse leukoencephalopathy with spheroids. AB - OBJECTIVE: To clarify the histopathological alterations of microglia in the brains of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS) caused by mutations of the gene encoding the colony stimulating factor-1 receptor (CSF-1R). METHODS: We examined 5 autopsied brains and 1 biopsy specimen from a total of 6 patients with CSF-1R mutations. Detailed immunohistochemical, biochemical, and ultrastructural features of microglia were examined, and quantitative analyses were performed. RESULTS: In layers 3 to 4 of the frontal cortex in HDLS brains, microglia showed relatively uniform and delicate morphology, with thin and winding processes accompanying knotlike structures, and significantly smaller areas of Iba1 immunoreactivity and lower numbers of Iba1 positive cells were evident in comparison with control brains. On the other hand, in layers 5 to 6 and the underlying white matter, microglia were distributed unevenly; that is, in some areas they had accumulated densely, whereas in others they were scattered. Immunoblot analyses of microglia-associated proteins, including CD11b and DAP12, revealed that HDLS brains had significantly lower amounts of these proteins than diseased controls, although Ki-67-positive proliferative microglia were not reduced. Ultrastructurally, the microglial cytoplasm and processes in HDLS showed vesiculation of the rough endoplasmic reticulum and disaggregated polyribosomes, indicating depression of protein synthesis. On the other hand, macrophages were immunonegative for GLUT-5 or P2ry12, indicating that they were derived from bone marrow. INTERPRETATION: The pathogenesis of HDLS seems to be associated with microglial vulnerability and morphological alterations. Ann Neurol 2016;80:554-565. PMID- 27490252 TI - The Thrower's Shoulder: An Update. PMID- 27490251 TI - The Representation of Prediction Error in Auditory Cortex. AB - To survive, organisms must extract information from the past that is relevant for their future. How this process is expressed at the neural level remains unclear. We address this problem by developing a novel approach from first principles. We show here how to generate low-complexity representations of the past that produce optimal predictions of future events. We then illustrate this framework by studying the coding of 'oddball' sequences in auditory cortex. We find that for many neurons in primary auditory cortex, trial-by-trial fluctuations of neuronal responses correlate with the theoretical prediction error calculated from the short-term past of the stimulation sequence, under constraints on the complexity of the representation of this past sequence. In some neurons, the effect of prediction error accounted for more than 50% of response variability. Reliable predictions often depended on a representation of the sequence of the last ten or more stimuli, although the representation kept only few details of that sequence. PMID- 27490253 TI - Osseous Sarcoidosis. PMID- 27490254 TI - Acute Achilles Tendon Rupture: A Critical Analysis Review. PMID- 27490255 TI - Degenerative Lumbar Scoliosis. PMID- 27490256 TI - Silica Wastes to High-Performance Lithium Storage Materials: A Rational Designed Al2 O3 Coating Assisted Magnesiothermic Process. AB - Si/C yolk-shell structures have been developed to deal with the major issues associated with Si anodes: the huge volume changes and the low electrical conductivity. However, the fabrication process often involves expensive starting materials and/or simultaneously generates insulated SiC, which is harmful for Si anodes. Here, silica wastes from the optical fibers industry are used as starting materials to prepare high performance Si/C materials with Si@void@C yolk-shell structure via a rational designed Al2 O3 coating assisted magnesiothermic process. The obtained yolk-shell Si@void@C materials have a capacity of more than 1450 mA h g-1 after 100 cycles at 0.4 A g-1 . Thanks to the easily coated and removed Al2 O3 layer, the general formation of SiC can be avoided which is beneficial for improving the rate performances, and a capacity of ~800 mA h g-1 is still kept after 200 cycles at a high rate of 10 A g-1 with a low capacity loss of 0.08% per cycle. PMID- 27490257 TI - Changes in Dietary Fat Intake and Projections for Coronary Heart Disease Mortality in Sweden: A Simulation Study. AB - OBJECTIVE: In Sweden, previous favourable trends in blood cholesterol levels have recently levelled off or even increased in some age groups since 2003, potentially reflecting changing fashions and attitudes towards dietary saturated fatty acids (SFA). We aimed to examine the potential effect of different SFA intake on future coronary heart disease (CHD) mortality in 2025. METHODS: We compared the effect on future CHD mortality of two different scenarios for fat intake a) daily SFA intake decreasing to 10 energy percent (E%), and b) daily SFA intake rising to 20 E%. We assumed that there would be moderate improvements in smoking (5%), salt intake (1g/day) and physical inactivity (5% decrease) to continue recent, positive trends. RESULTS: In the baseline scenario which assumed that recent mortality declines continue, approximately 5,975 CHD deaths might occur in year 2025. Anticipated improvements in smoking, dietary salt intake and physical activity, would result in some 380 (-6.4%) fewer deaths (235 in men and 145 in women). In combination with a mean SFA daily intake of 10 E%, a total of 810 (-14%) fewer deaths would occur in 2025 (535 in men and 275 in women). If the overall consumption of SFA rose to 20 E%, the expected mortality decline would be wiped out and approximately 20 (0.3%) additional deaths might occur. CONCLUSION: CHD mortality may increase as a result of unfavourable trends in diets rich in saturated fats resulting in increases in blood cholesterol levels. These could cancel out the favourable trends in salt intake, smoking and physical activity. PMID- 27490258 TI - Assessment of the Broader Economic Consequences of HPV Prevention from a Government-Perspective: A Fiscal Analytic Approach. AB - BACKGROUND: Cervical cancer poses a substantial burden in terms of morbidity, mortality, and economic losses, especially in low/middle-income countries. HPV vaccination and/or cervical cancer screening among females may reduce the burden of HPV-related diseases, including cervical cancer. However, limited funds may impede the implementation of population-based programmes. Governmental investments in the prevention of infectious disease may have broader economic and fiscal benefits, which are not accounted in conventional economic analyses. This study estimates the broader economic and fiscal impacts of implementing HPV vaccination and/or cervical cancer screening in Indonesia from the perspective of the government. METHODS: A government-perspective quantitative analytic framework was applied to assess the Net Present Value (NPV) of investment on cervical cancer prevention strategies including HPV vaccination, cervical screening and its combination in Indonesia. All monetary values were presented in International Dollars (I$). RESULTS: Based on a cohort of 10,000,000 Indonesian 12-year-old females, it was estimated that HPV vaccination and/or cervical cancer screening result in a positive NPV for the Indonesian government. The combination of cervical screening and HPV vaccination generated a substantial reduction of cervical cancer incidence and HPV-related mortality of 87,862 and 19,359, respectively. It was estimated that HPV vaccination in combination with cervical screening is the most favorable option for cervical cancer prevention (NPV I$2.031.786.000), followed by HPV vaccination alone (NPV I$1.860.783.000) and cervical screening alone (NPV I$375.244.000). CONCLUSION: In addition to clinical benefits, investing in HPV vaccination and cervical screening may yield considerable fiscal benefits for the Indonesian governments due to lifelong benefits resulting from reduction of cervical cancer-related morbidity and mortality. PMID- 27490260 TI - Proceedings of the 8th Annual Conference on the Science of Dissemination and Implementation : Washington, DC, USA. 14-15 December 2015. PMID- 27490259 TI - Apicoplast-Localized Lysophosphatidic Acid Precursor Assembly Is Required for Bulk Phospholipid Synthesis in Toxoplasma gondii and Relies on an Algal/Plant Like Glycerol 3-Phosphate Acyltransferase. AB - Most apicomplexan parasites possess a non-photosynthetic plastid (the apicoplast), which harbors enzymes for a number of metabolic pathways, including a prokaryotic type II fatty acid synthesis (FASII) pathway. In Toxoplasma gondii, the causative agent of toxoplasmosis, the FASII pathway is essential for parasite growth and infectivity. However, little is known about the fate of fatty acids synthesized by FASII. In this study, we have investigated the function of a plant like glycerol 3-phosphate acyltransferase (TgATS1) that localizes to the T. gondii apicoplast. Knock-down of TgATS1 resulted in significantly reduced incorporation of FASII-synthesized fatty acids into phosphatidic acid and downstream phospholipids and a severe defect in intracellular parasite replication and survival. Lipidomic analysis demonstrated that lipid precursors are made in, and exported from, the apicoplast for de novo biosynthesis of bulk phospholipids. This study reveals that the apicoplast-located FASII and ATS1, which are primarily used to generate plastid galactolipids in plants and algae, instead generate bulk phospholipids for membrane biogenesis in T. gondii. PMID- 27490261 TI - Internal Concentration and Time Are Important Modifiers of Toxicity: The Case of Chlorpyrifos on Caenorhabditis elegans. AB - The internal concentration of chemicals in exposed organisms changes over time due to absorption, distribution, metabolism, and excretion processes since chemicals are taken up from the environment. Internal concentration and time are very important modifiers of toxicity when biomarkers are used to evaluate the potential hazards and risks of environmental pollutants. In this study, the responses of molecular biomarkers, and the fate of chemicals in the body, were comprehensively investigated to determine cause-and-effect relationships over time. Chlorpyrifos (CP) was selected as a model chemical, and Caenorhabditis elegans was exposed to CP for 4 h using the passive dosing method. Worms were then monitored in fresh medium during a 48-h recovery regime. The mRNA expression of genes related to CYP metabolism (cyp35a2 and cyp35a3) increased during the constant exposure phase. The body residue of CP decreased once it reached a peak level during the early stage of exposure, indicating that the initial uptake of CP rapidly induced biotransformation with the synthesis of new CYP metabolic proteins. The residual chlorpyrifos-oxon concentration, an acetylcholinesterase (AChE) inhibitor, continuously increased even after the recovery regime started. These delayed toxicokinetics seem to be important for the extension of AChE inhibition for up to 9 h after the start of the recovery regime. Comprehensive investigation into the molecular initiation events and changes in the internal concentrations of chemical species provide insight into response causality within the framework of an adverse outcome pathway. PMID- 27490262 TI - Nanoparticle Assembly of Surface-Modified Proteins. AB - Nature's biomaterials such as peptides and proteins represent a valuable source of highly defined macromolecules. Herein we developed a nanoparticle drug delivery system based on the assembly of surface-modified proteins that can be transferred into organic solvents and represent the structural material of the carrier system. The particles are prepared by an oil-in-water nanoemulsion technique without the need of additional denaturation or cross-linking steps for stabilization. We achieve the necessary lipophilic solubility switch of the protein material by high surface PEGylation under conservation of the native three-dimensional protein structure. This study focuses on lysozyme as model enzyme for the preparation of empty and doxorubicin-loaded nanoparticles with an average diameter of 100 nm. The particles are stable in physiological buffers and only release their therapeutic payload into cancer cells after a time-dependent cellular uptake. We also transferred this approach to various proteins, exemplifying the universal applicability of our new preparation method for protein-based nanoparticles. PMID- 27490263 TI - The association of dopamine pathway gene score, nicotine dependence and smoking cessation in a rural male population of Shandong, China. AB - BACKGROUND AND OBJECTIVES: Smoking and smoking cessation are both psychological and physiological traits. We aimed to investigate the interaction between dopamine pathway gene scores and nicotine dependence on smoking cessation in a rural Chinese male population. METHODS: Participants were recruited from 17 villages in Shandong, China. DNA was extracted from blood sample of 819 participants. 25 single nucleotide polymorphisms (SNPs) in 8 dopamine (DA) pathway genes were genotyped. Weighted gene score of each gene is used to analyze the whole gene effect. Logistic regression was used to calculate odds ratios (OR) and multivariate-adjusted OR of each gene score for smoking cessation. Multiplicative model interaction was assessed through a cross-product interaction term of gene score by nicotine dependence in a multivariate logistic regression model. RESULTS: After adjusting for age, occupation, education, marital status, self-rating anxiety score, and disease status, we observed significant negative associations of catechol-O-methyltransferase (COMT), dopamine receptor D2 (DRD2) gene score and smoking cessation, as well as significant positive associations between ankyrin repeat and kinase domain containing 1 (ANKK1), dopamine transporter (SLC6A3), dopamine receptor D4 (DRD4) gene score and smoking cessation. A significant multiplicative model interaction between nicotine dependence and the SLC6A3 gene score on smoking cessation was also observed (p = .03). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: There is a significant multiplicative model interaction of SLC6A3 gene score and nicotine dependence on smoking cessation. This finding could help to identify smokers who may be at high risk of relapse, and thus to develop more professional and personalized smoking cessation treatment. (Am J Addict 2016;25:493-498). PMID- 27490265 TI - Pharmacogenetics of cystic fibrosis treatment. AB - Cystic fibrosis (CF) is genetic autosomal recessive disease caused by reduced or absent function of CFTR protein. Treatments for patients with CF have primarily focused on the downstream end-organ consequences of defective CFTR. Since the discovery of the CFTR gene that causes CF in 1989 there have been tremendous advances in our understanding of the genetics and pathophysiology of CF. This has recently led to the development of new CFTR mutation-specific targeted therapies for select patients with CF. This review will discuss the characteristics of the CFTR gene, the CFTR mutations that cause CF and the new mutation specific pharmacological treatments including gene therapy that are contributing to the dawning of a new era in cystic fibrosis care. PMID- 27490266 TI - Paracrine effects of human adipose-derived mesenchymal stem cells in inflammatory stress-induced senescence features of osteoarthritic chondrocytes. AB - Aging and exposure to stress would determine the chondrocyte phenotype in osteoarthritis (OA). In particular, chronic inflammation may contribute to stress induced senescence of chondrocytes and cartilage degeneration during OA progression. Recent studies have shown that adipose-derived mesenchymal stem cells exert paracrine effects protecting against degenerative changes in chondrocytes. We have investigated whether the conditioned medium (CM) from adipose-derived mesenchymal stem cells may regulate senescence features induced by inflammatory stress in OA chondrocytes. Our results indicate that CM down regulated senescence markers induced by interleukin-1beta including senescence associated beta-galactosidase activity, accumulation of gammaH2AX foci and morphological changes with enhanced formation of actin stress fibers. Treatment of chondrocytes with CM also decreased the production of oxidative stress, the activation of mitogen-activated protein kinases, and the expression of caveolin-1 and p21. The effects of CM were related to the reduction in p53 acetylation which would be dependent on the enhancement of Sirtuin 1 expression. Therefore, CM may exert protective effects in degenerative joint conditions by countering the premature senescence of OA chondrocytes induced by inflammatory stress. PMID- 27490264 TI - Transmission Dynamics of Visceral Leishmaniasis in the Indian Subcontinent - A Systematic Literature Review. AB - BACKGROUND: As Bangladesh, India and Nepal progress towards visceral leishmaniasis (VL) elimination, it is important to understand the role of asymptomatic Leishmania infection (ALI), VL treatment relapse and post kala-azar dermal leishmaniasis (PKDL) in transmission. METHODOLOGY/ PRINCIPAL FINDING: We reviewed evidence systematically on ALI, relapse and PKDL. We searched multiple databases to include studies on burden, risk factors, biomarkers, natural history, and infectiveness of ALI, PKDL and relapse. After screening 292 papers, 98 were included covering the years 1942 through 2016. ALI, PKDL and relapse studies lacked a reference standard and appropriate biomarker. The prevalence of ALI was 4-17-fold that of VL. The risk of ALI was higher in VL case contacts. Most infections remained asymptomatic or resolved spontaneously. The proportion of ALI that progressed to VL disease within a year was 1.5-23%, and was higher amongst those with high antibody titres. The natural history of PKDL showed variability; 3.8-28.6% had no past history of VL treatment. The infectiveness of PKDL was 32-53%. The risk of VL relapse was higher with HIV co-infection. Modelling studies predicted a range of scenarios. One model predicted VL elimination was unlikely in the long term with early diagnosis. Another model estimated that ALI contributed to 82% of the overall transmission, VL to 10% and PKDL to 8%. Another model predicted that VL cases were the main driver for transmission. Different models predicted VL elimination if the sandfly density was reduced by 67% by killing the sandfly or by 79% by reducing their breeding sites, or with 4-6y of optimal IRS or 10y of sub-optimal IRS and only in low endemic setting. CONCLUSION/ SIGNIFICANCE: There is a need for xenodiagnostic and longitudinal studies to understand the potential of ALI and PKDL as reservoirs of infection. PMID- 27490267 TI - Aviation Emissions Impact Ambient Ultrafine Particle Concentrations in the Greater Boston Area. AB - Ultrafine particles are emitted at high rates by jet aircraft. To determine the possible impacts of aviation activities on ambient ultrafine particle number concentrations (PNCs), we analyzed PNCs measured from 3 months to 3.67 years at three sites within 7.3 km of Logan International Airport (Boston, MA). At sites 4.0 and 7.3 km from the airport, average PNCs were 2- and 1.33-fold higher, respectively, when winds were from the direction of the airport compared to other directions, indicating that aviation impacts on PNC extend many kilometers downwind of Logan airport. Furthermore, PNCs were positively correlated with flight activity after taking meteorology, time of day and week, and traffic volume into account. Also, when winds were from the direction of the airport, PNCs increased with increasing wind speed, suggesting that buoyant aircraft exhaust plumes were the likely source. Concentrations of other pollutants [CO, black carbon (BC), NO, NO2, NOx, SO2, and fine particulate matter (PM2.5)] decreased with increasing wind speed when winds were from the direction of the airport, indicating a different dominant source (likely roadway traffic emissions). Except for oxides of nitrogen, other pollutants were not correlated with flight activity. Our findings point to the need for PNC exposure assessment studies to take aircraft emissions into consideration, particularly in populated areas near airports. PMID- 27490268 TI - Extending rule-based methods to model molecular geometry and 3D model resolution. AB - BACKGROUND: Computational modeling is an important tool for the study of complex biochemical processes associated with cell signaling networks. However, it is challenging to simulate processes that involve hundreds of large molecules due to the high computational cost of such simulations. Rule-based modeling is a method that can be used to simulate these processes with reasonably low computational cost, but traditional rule-based modeling approaches do not include details of molecular geometry. The incorporation of geometry into biochemical models can more accurately capture details of these processes, and may lead to insights into how geometry affects the products that form. Furthermore, geometric rule-based modeling can be used to complement other computational methods that explicitly represent molecular geometry in order to quantify binding site accessibility and steric effects. RESULTS: We propose a novel implementation of rule-based modeling that encodes details of molecular geometry into the rules and binding rates. We demonstrate how rules are constructed according to the molecular curvature. We then perform a study of antigen-antibody aggregation using our proposed method. We simulate the binding of antibody complexes to binding regions of the shrimp allergen Pen a 1 using a previously developed 3D rigid-body Monte Carlo simulation, and we analyze the aggregate sizes. Then, using our novel approach, we optimize a rule-based model according to the geometry of the Pen a 1 molecule and the data from the Monte Carlo simulation. We use the distances between the binding regions of Pen a 1 to optimize the rules and binding rates. We perform this procedure for multiple conformations of Pen a 1 and analyze the impact of conformation and resolution on the optimal rule-based model. CONCLUSIONS: We find that the optimized rule-based models provide information about the average steric hindrance between binding regions and the probability that antibodies will bind to these regions. These optimized models quantify the variation in aggregate size that results from differences in molecular geometry and from model resolution. PMID- 27490270 TI - Enhancing the Bipolar Redox Cycling Efficiency of Plane-Recessed Microelectrode Arrays by Adding a Chemically Irreversible Interferent. AB - The individual electrochemical anodic responses of dopamine (DA), epinephrine (EP), and pyrocatechol (CT) were investigated at arrays of recessed gold disk microelectrodes arrays (MEAs) covered by a gold plane electrode and compared to those of their binary mixture (CT and EP) when the top-plane electrode was operated as a bipolar electrode or as a collector. The interferent species (EP) displays a chemically irreversible wave over the same potential range as the chemically reversible ones of DA or CT. As expected, in the generator-collector (GC) mode, EP did not contribute to the redox cycling amplification that occurred only for DA or CT. Conversely, in the bipolar mode, the presence of EP drastically increased the bipolar redox cycling efficiency of DA and CT. This evidenced that the chemically irreversible oxidation of EP at the anodic poles of the top plane floating electrode provided additional electron fluxes that were used to more efficiently reduce the oxidized DA or CT species at the cathodic poles. This suggests an easy experimental strategy for enhancing the bipolar efficiency of MEAs up to reach a performance identical to that achieved when the same MEAs are operated in a GC mode. PMID- 27490271 TI - Corrigendum to "A joint compressed-sensing and super-resolution approach for very high-resolution diffusion imaging". PMID- 27490272 TI - A Branch-and-Bound Approach for Tautomer Enumeration. AB - Knowledge about tautomer forms of a structure is important since, e.g., a property prediction for a molecule can yield to different results which depend on the individual tautomer. Tautomers are isomers that can be transformed to each other through chemical equilibrium reactions. In this paper the first exact Branch-and-Bound (B&B) algorithm to calculate tautomer structures is proposed. The algorithm is complete in the sense of tautomerism and generates all possible tautomers of a structure according to the tautomer definition, it is initialized with. To be efficient, the algorithm takes advantage of symmetric and formation properties. Some restrictions are used to enable an early pruning of some branches of the B&B tree. This is important, since a simple enumeration strategy would lead to number of candidate tautomers that is exponentially increasing with the number of hydrogen atoms and their attachment sites. The proposed implementation of the B&B algorithm covers the majority of the prototropic tautomer cases, but can be adapted to other kinds of tautomerism too. Furthermore, a computer processable definition of tautomerism is given in the form of the moving hydrogen atom problem. PMID- 27490273 TI - Establishing Good Computer Modelling Practice (GCMP) in the Prediction of Chemical Toxicity. AB - This paper suggests guidelines for good computer modelling practice (GCMP) when predicting chemical toxicity, with similar purposes to those for Good Laboratory Practice (GLP). The purpose of GCMP is not to specify what should be delivered with models or predictions but to set out what must be done to ensure that work can be audited, on site, in a way analogous to the auditing of studies conforming to GLP; it is intended to confirm that work has been done properly, as distinct from providing advice on how to do it. Comments are made on the guidelines and how they might be followed, based on practical experience with the implementation of such a scheme in the development of knowledge-based and quantitative structure activity relationship models. It is hoped that publication of this paper will encourage wider discussion of the subject leading to adoption of measures to ensure the trustworthiness of computer modelling work that is carried out in connection with regulatory submissions. PMID- 27490274 TI - Assessing Confidence in Predictions Using Veracity and Utility - A Case Study on the Prediction of Mammalian Metabolism by Meteor Nexus. AB - A previous paper1 described new metrics, veracity and utility, for assessing the performance of toxicity prediction systems that report confidence in their predictions. Assessing the performance of systems that predict mammalian metabolism is complicated by the absence of comprehensive sets of negative observations and predictions. This paper presents an approach to assessing the performance of such systems using veracity and utility. PMID- 27490275 TI - Virtually Designed Triclosan-Based Inhibitors of Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis and of Plasmodium falciparum. AB - We report here new chemical structures of predicted nanomolar triclosan-based inhibitors (TCLs) of Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA) virtually proposed by computer-assisted molecular design. 3D models of InhA-TCL complexes were prepared by in situ modifications of the reference crystal structure (PDB entry 1P45) for a training set of 15 TCLs with known InhA inhibitory activities. A QSAR model was built leading to linear correlation between the calculated free energies of complexation (DeltaDeltaGcom ) and experimental values IC50 (exp) : pIC50 =-0.0657*DeltaDeltaGcom +3.0502, R(2) =0.96. In addition, ligand-based quantitative pharmacophore model (PH4) was built from bound conformations of the training set compounds and confirmed the correlation between molecular models and observed activities: pIC50 (exp=) 0.8929*pIC50 (pre) -0.441, R(2) =0.95. Structural information from both models helped us to propose new TCL analogues. A virtual library of TCLs with known predicted activities against enoyl-acyl carrier protein reductase of Plasmodium falciparum (PfENR) was evaluated, revealing dual target TCLs. Moreover, analysis of binding site interactions suggested enriching substitutions, which led to more potent TCLs with predicted pIC50 (pre) as low as 7 nM. The computational approach, which used both free energy estimated from molecular modeling and 3D QSAR pharmacophore model, was helpful in virtually proposing the dual-targeted drugs and provided valuable information for the design of novel potential antituberculotic agents. PMID- 27490276 TI - Towards Better BBB Passage Prediction Using an Extensive and Curated Data Set. AB - In the present report, the challenging task of drug delivery across the blood brain barrier (BBB) is addressed via a computational approach. The BBB passage was modeled using classification and regression schemes on a novel extensive and curated data set (the largest to the best of our knowledge) in terms of log BB. Prior to the model development, steps of data analysis that comprise chemical data curation, structural, cutoff and cluster analysis (CA) were conducted. Linear Discriminant Analysis (LDA) and Multiple Linear Regression (MLR) were used to fit classification and correlation functions. The best LDA-based model showed overall accuracies over 85 % and 83 % for the training and test sets, respectively. Also a MLR-based model with acceptable explanation of more than 69 % of the variance in the experimental log BB was developed. A brief and general interpretation of proposed models allowed the estimation on how 'near' our computational approach is to the factors that determine the passage of molecules through the BBB. In a final effort some popular and powerful Machine Learning methods were considered. Comparable or similar performance was observed respect to the simpler linear techniques. Most of the compounds with anomalous behavior were put aside into a set denoted as controversial set and discussion regarding to these compounds is provided. Finally, our results were compared with methodologies previously reported in the literature showing comparable to better results. The results could represent useful tools available and reproducible by all scientific community in the early stages of neuropharmaceutical drug discovery/development projects. PMID- 27490277 TI - Physicochemical Profiles of the Marketed Agrochemicals and Clues for Agrochemical Lead Discovery and Screening Library Development. AB - Combinatorial chemistry, high-throughput and virtual screening technologies have been extensively used for discovering agrochemical leads from chemical libraries. The knowledge of the physicochemical properties of the marketed agrochemicals is useful for guiding the design and selection of such libraries. Since the earlier profiling of marketed agrochemicals, the number and types of marketed agrochemicals have significantly increased. Recent studies have shown the change of some physicochemical properties of oral drugs with time. There is a need to also profile the physicochemical properties of the marketed agrochemicals. In this work, we analyzed the key physicochemical properties of 1751 marketed agrochemicals in comparison with the previously-analyzed herbicides and insecticides, 106 391 natural products and 57 548 diverse synthetic libraries compounds. Our study revealed the distribution profiles and evolution trend of different types of agrochemicals that in many respects are broadly similar to the reported profiles for oral drugs, with the most marked difference being that agrochemicals have a lower number of hydrogen bond donors. The derived distribution patterns provided the rule of thumb guidelines for selecting potential agrochemical leads and also provided clues for further improving the libraries for agrochemical lead discovery. PMID- 27490278 TI - Difficulties in Performing Mesalazine Enemas and Factors Related to Discontinuation Among Patients With Ulcerative Colitis. AB - Current first-line treatment of ulcerative colitis consists of a combination of mesalazine enemas and oral mesalazine; however, many patients may discontinue mesalazine enemas. In this single-center, cross-sectional study, 165 outpatients with ulcerative colitis completed a self-administered questionnaire regarding the frequency of mesalazine enemas, difficulties in performing these enemas, and factors possibly associated with their discontinuation, as well as patient clinical and demographic characteristics. Of 165 patients, 34 (20.6%) discontinued mesalazine enemas because of a lack of efficacy. Five of the 13 items assessing difficulties were answered affirmatively by the majority of patients. Discontinuation of enema application was associated with a perceived lack of efficacy, four or more bowel movements per day, and lower scores on measurement of the doctor-patient relationship. Application of mesalazine enemas by patients with ulcerative colitis may be improved by discussions with peers and healthcare professionals and by adjusting the frequency of application or the time of starting the enema based on worsening of ulcerative colitis. PMID- 27490279 TI - Laxative Use and Self-Reported Constipation in a Community-Dwelling Elderly Population: A Community-Based Survey From Australia. AB - The objectives of this study were to (1) determine the prevalence of laxative use and self-reported constipation and (2) identify risk factors associated with constipation in a community-dwelling elderly population. A retrospective cross sectional survey using data from the Australian Longitudinal Study of Ageing was used to explore laxative use and constipation in a cohort of community-dwelling older persons. The prevalence of laxative use was 15% and the prevalence of self reported constipation was 21%. Females were more likely to report constipation and use laxatives. Of those using laxatives, men were more likely to have their laxatives prescribed by a doctor whereas women were more likely to self-medicate. Poor self-rated health and a higher need for assistance with activities of daily living were identified as risk factors for constipation. Constipation is a common condition affecting the community-dwelling elderly. There is a need to optimize the management of constipation and use of laxatives in such populations. PMID- 27490280 TI - Confined Water Determines Transport Properties of Guest Molecules in Narrow Pores. AB - We computed the transport of methane through 1 nm wide slit-shaped pores carved out of solid substrates. Models for silica, magnesium oxide, and alumina were used as solid substrates. The pores were filled with water. The results show that the methane permeability through the hydrated pores is strongly dependent on the solid substrate. Detailed analysis of the simulated systems reveals that local properties of confined water, including its structure, and more importantly, evolution of solvation free energy and hydrogen bond structure are responsible for the pronounced differences observed. The simulations are extended to multicomponent systems representative of natural gas, containing methane, ethane, and H2S. The results show that all pores considered have high affinity for H2S, moderate affinity for methane, and low affinity for ethane. The H2S/methane transport selectivity through the hydrated alumina pore is comparable, or superior, to that reported for existing commercial membranes. A multiscale approach was then implemented to demonstrate that a Smoluchowski one-dimensional model is able to reproduce the molecular-level results for short pores when appropriate values for the local self-diffusion coefficients are used as input parameters. We propose that the model can be extended to predict methane transport through uniform hydrated pores of macroscopic length. When verified by experiments, our simulation results could have important implications in applications such as natural gas sweetening and predictions of methane migration through hydraulically fractured shale formations. PMID- 27490282 TI - Erratum: Vol. 65, No. 26. AB - In the report, "Notes from The Field: Ebola Virus Disease Cluster - Northern Sierra Leone, January 2016," the name of a member of The Interagency Investigation Team was incorrect and should have read as follows: "Matthew Cotten, PhD, Wellcome Trust Sanger Institute, United Kingdom." PMID- 27490281 TI - Three-Dimension Hierarchical Al2O3 Nanosheets Wrapped LiMn2O4 with Enhanced Cycling Stability as Cathode Material for Lithium Ion Batteries. AB - A three dimensional (3D) Al2O3 coating layer was synthesized by a facile approach including stripping and in situ self-assembly of gamma-AlOOH. The uniform flower like Al2O3 nanosheets with high specific area largely sequesters acidic species produced by side reaction between electrode and electrolyte. The inner coating layer wrapping spinel LiMn2O4 effectively inhibits the dissolution of Mn by suppressing directive contact with electrolyte to enhance cycling stability. The rate performance is improved because of the better electrolyte storage of the assembled hierarchical architecture of the 3D coating layer affording unimpeded Li(+) diffusion from electrode to electrolyte. The electrochemical results reveal the as-prepared coated LiMn2O4 sample with the amount of Al2O3 at 1 wt % exhibits superior cycle stability under room temperature even at elevated temperature. The initial specific discharge capacity is 128.5 mAh g(-1) at 0.1 C and retains 89.8% of the initial capacity after 800 cycles at 1 C rate. When cycling at 55 degrees C, the composite shows 93.6% capacity retention after 500 cycles. This facile surface modification and effective structure of coating layer can be adopted to enhance the cycling performance and thermal stability of other electrode materials for which Al2O3 plays its role. PMID- 27490283 TI - Correction: A narrow amide I vibrational band observed by sum frequency generation spectroscopy reveals highly ordered structures of a biofilm protein at the air/water interface. AB - Correction for 'A narrow amide I vibrational band observed by sum frequency generation spectroscopy reveals highly ordered structures of a biofilm protein at the air/water interface' by Zhuguang Wang et al., Chem. Commun., 2016, 52, 2956 2959. PMID- 27490284 TI - Origin of axonal proteins: Is the axon-schwann cell unit a functional syncytium? AB - The structural homeostasis is challenging for neurons, whose axons extend up to meters in large animals, and the axoplasmic mass reaches over a thousand times that of the cell body. Thus, the protein demand may overcome the capacity of the cell body to supply the right protein species, to the right place, in the right time. In this context, a body of evidence indicates that glial cells support the axonal maintenance and regenerative responses by diverse mechanisms of intercellular communication. We showed recently that Schwann cells (SC) transfer ribosomes to axons and also enhance regeneration by means of extracellular vesicles known as exosomes that contain mRNAs, miRNAs and proteins. These findings strongly suggest that the nucleus of the SC supports the machinery for protein synthesis of the axon and participates in the specification of the phenotype of the underlying axon. That the genetic programs of many nuclei modulate the axoplasm on a local basis is akin to a syncytium but at variance with it, the nuclei belong to satellite cells. We propose that the SC-axon unit is a functional syncytium. This intercellular organization opens a novel understanding of the nervous system and a new avenue of research into its physiology and disorders (c) 2016 Wiley Periodicals, Inc. PMID- 27490285 TI - Miniaturized fibre-top cantilevers on etched fibres. AB - Fibre-top probes are self-aligned, all optical devices obtained by carving a cantilever on top of a 125-MUm diameter single-mode optical fibre. In this paper, we show that this design can be adapted to smaller fibres as well. We evaluated the performance of a 20-MUm diameter probe in contact mode atomic force microscopy (AFM) and that of a 50-MUm diameter probe in nanoindentation measurements. AFM images proved to be accurate both in air and water, although some distortion was observed because of the mechanical bending of the fibre during scanning. Indentation curves resembled those obtained with larger devices. The maximum indentation depth, however, is limited by the small dimensions of the cantilever. PMID- 27490286 TI - Remarkable points for discussing outcomes of urodynamic studies. PMID- 27490287 TI - Physician Assistant Genomic Competencies. AB - Genomic discoveries are increasingly being applied to the clinical care of patients. All physician assistants (PAs) need to acquire competency in genomics to provide the best possible care for patients within the scope of their practice. In this article, we present an updated version of PA genomic competencies and learning outcomes in a framework that is consistent with the current medical education guidelines and the collaborative nature of PAs in interprofessional health care teams. PMID- 27490288 TI - Educational Needs Assessment Highlights Several Areas of Emphasis in Teaching Evidence-Based Medicine Skills to Physician Assistant Students. AB - PURPOSE: An assessment of educational needs is essential for curricular reform in medical education. Using the conceptual framework of needs assessment, this study aimed to determine which content should be emphasized in teaching evidence-based medicine (EBM) skills to physician assistant (PA) students. METHODS: Key content areas were identified from the published literature and objectives for previous courses. A questionnaire-type needs assessment instrument was created and given to a graduating class of PA students (n = 21) at the University of North Dakota. The response format had two 5-option scales, one to assess current skill levels and the other to assess ideal skill levels. Means for each category were calculated, and a mean difference analysis was performed. RESULTS: An average mean difference of 0.5 was noted in 3 domains (information retrieval skills, writing skills, and overall gains), and a mean difference of 0.7 was noted in one domain (statistical skills). Items with a mean difference of >= 0.7 were identified for prioritization for curricular reform. Open-ended input from respondents substantiated the need for greater emphasis on these content areas. CONCLUSION: Several content areas related to EBM skills can be identified and prioritized through a systematically conducted educational needs assessment. This method can be used to identify discrepancies between the existing and ideal states of affairs in PA education. PMID- 27490289 TI - Beyond the Clinic: Physician Assistant Student Perspectives on Careers in Physician Assistant Education. AB - PURPOSE: Professional training programs for physician assistants (PAs) have been rapidly expanding. The profession therefore needs to develop a sufficiently robust teaching workforce. METHODS: This study surveyed current PA students from all Physician Assistant Education Association member programs to ascertain their level of interest in and understanding of careers in PA education, including faculty and precepting roles. RESULTS: The study revealed that interest was greatest in precepting roles. A higher level of education before attending a PA program correlated with a higher interest in PA education roles, although an education-related degree did not show a significant relationship with such roles. CONCLUSION: These and other study findings are important to consider as the profession continues to develop a pipeline to education careers for students and clinicians. PMID- 27490290 TI - What Do Physician Assistant Students Know About Nutrition? A Survey of Attitudes, Self-Perceived Proficiency, and Knowledge During Three Stages of Physician Assistant Education. AB - PURPOSE: This study applied a cross-sectional design and analyzed the nutrition knowledge and attitudes of physician assistant (PA) students during 3 stages of PA education. METHODS: The PA students from the class of 2014, 2015, and 2016 attending a midwestern university were surveyed using Qualtrics. Descriptive statistics and analysis of variance tests were performed to determine the difference between the 3 cohorts on "previous nutrition knowledge," "attitudes," and "knowledge" subscores and total scores. A post hoc analysis was performed to determine the differences between groups. RESULTS: A statistically significant difference was found in the mean total score between classes, with the class of 2014 scoring 17 points higher on average than the class of 2016. CONCLUSION: These results suggest that positive nutrition attitudes and knowledge among PA students from this sample were lacking. This study suggests a possible need for revision of nutrition education provided by PA programs. PMID- 27490291 TI - Durability of Expanded Physician Assistant Training Positions Following the End of Health Resources and Services Administration Expansion of Physician Assistant Training Funding. AB - PURPOSE: The purpose of this study was to assess the number of Health Resources and Services Administration Expansion of Physician Assistant Training (EPAT) funded physician assistant (PA) programs planning to maintain class size at expanded levels after grant funds expire and to report proposed financing methods. The 5-year EPAT grant expired in 2015, and the effect of this funding on creating a durable expansion of PA training seats has not yet been investigated. METHODS: The study used an anonymous, 9-question, Web-based survey sent to the program directors at each of the PA programs that received EPAT funding. Data were analyzed in Excel and using SAS statistical analysis software for both simple percentages and for Fisher's exact test. RESULTS: The survey response rate was 81.48%. Eighty-two percent of responding programs indicated that they planned to maintain all expanded positions. Fourteen percent will revert to their previous student class size, and 4% will maintain a portion of the expanded positions. A majority of the 18 programs (66%) maintaining all EPAT seats will be funded by tuition pass-through, and one program (6%) will increase tuition. There was no statistical association between the program type and the decision to maintain expanded positions (P = .820). CONCLUSIONS: This study demonstrates that the one-time EPAT PA grant funding opportunity created a durable expansion in PA training seats. Future research should focus on the effectiveness of the program in increasing the number of graduates choosing to practice in primary care and the durability of expansion several years after funding expiration. PMID- 27490292 TI - Critical Appraisal of the Randomized Controlled Trial. PMID- 27490293 TI - Reinventing the Hospital Handoff for Clinical Education. PMID- 27490294 TI - Telemedicine and Clinical Rotations: Worth Investigating? PMID- 27490295 TI - Burn Management in Orthopaedic Trauma: A Critical Analysis Review. PMID- 27490296 TI - A Strategy for Successful Implementation of Bundled Payments in Orthopaedic Surgery. PMID- 27490297 TI - Reverse Shoulder Arthroplasty for the Treatment of Proximal Humeral Fractures. PMID- 27490298 TI - Decision-Making in the Treatment of the Spastic Shoulder and Elbow: Tendon Release Versus Tendon Lengthening. PMID- 27490300 TI - Where do uncertainties reside within environmental risk assessments? Expert opinion on uncertainty distributions for pesticide risks to surface water organisms. AB - A reliable characterisation of uncertainties can aid uncertainty identification during environmental risk assessments (ERAs). However, typologies can be implemented inconsistently, causing uncertainties to go unidentified. We present an approach based on nine structured elicitations, in which subject-matter experts, for pesticide risks to surface water organisms, validate and assess three dimensions of uncertainty: its level (the severity of uncertainty, ranging from determinism to ignorance); nature (whether the uncertainty is epistemic or aleatory); and location (the data source or area in which the uncertainty arises). Risk characterisation contains the highest median levels of uncertainty, associated with estimating, aggregating and evaluating the magnitude of risks. Regarding the locations in which uncertainty is manifest, data uncertainty is dominant in problem formulation, exposure assessment and effects assessment. The comprehensive description of uncertainty described will enable risk analysts to prioritise the required phases, groups of tasks, or individual tasks within a risk analysis according to the highest levels of uncertainty, the potential for uncertainty to be reduced or quantified, or the types of location-based uncertainty, thus aiding uncertainty prioritisation during environmental risk assessments. In turn, it is expected to inform investment in uncertainty reduction or targeted risk management action. PMID- 27490299 TI - Collaboration and entanglement: An actor-network theory analysis of team-based intraprofessional care for patients with advanced heart failure. AB - Despite calls for more interprofessional and intraprofessional team-based approaches in healthcare, we lack sufficient understanding of how this happens in the context of patient care teams. This multi-perspective, team-based interview study examined how medical teams negotiated collaborative tensions. From 2011 to 2013, 50 patients across five sites in three Canadian provinces were interviewed about their care experiences and were asked to identify members of their health care teams. Patient-identified team members were subsequently interviewed to form 50 "Team Sampling Units" (TSUs), consisting of 209 interviews with patients, caregivers and healthcare providers. Results are gathered from a focused analysis of 13 TSUs where intraprofessional collaborative tensions involved treating fluid overload, or edema, a common HF symptom. Drawing on actor-network theory (ANT), the analysis focused on intraprofessional collaboration between specialty care teams in cardiology and nephrology. The study found that despite a shared narrative of common purpose between cardiology teams and nephrology teams, fluid management tools and techniques formed sites of collaborative tension. In particular, care activities involved asynchronous clinical interpretations, geographically distributed specialist care, fragmented forms of communication, and uncertainty due to clinical complexity. Teams 'disentangled' fluid in order to focus on its physiological function and mobilisation. Teams also used distinct 'framings' of fluid management that created perceived collaborative tensions. This study advances collaborative entanglement as a conceptual framework for understanding, teaching, and potentially ameliorating some of the tensions that manifest during intraprofessional care for patients with complex, chronic disease. PMID- 27490302 TI - 500-fold enhancement of in situ (13)C liquid state NMR using gyrotron-driven temperature-jump DNP. AB - A 550-fold increase in the liquid state (13)C NMR signal of a 50MUL sample was obtained by first hyperpolarizing the sample at 20K using a gyrotron (260GHz), then, switching its frequency in order to apply 100W for 1.5s so as to melt the sample, finally, turning off the gyrotron to acquire the (13)C NMR signal. The sample stays in its NMR resonator, so the sequence can be repeated with rapid cooling as the entire cryostat stays cold. DNP and thawing of the sample are performed only by the switchable and tunable gyrotron without external devices. Rapid transition from DNP to thawing in one second time scale was necessary especially in order to enhance liquid (1)H NMR signal. PMID- 27490303 TI - Effect of ionic interaction between a hyperpolarized magnetic resonance chemical probe and a gadolinium contrast agent for the hyperpolarized lifetime after dissolution. AB - In hyperpolarization of (13)C-enriched magnetic resonance chemical probes in the solid-state, a trace amount of gadolinium (Gd) contrast agent can be used to maximize polarization of the (13)C nuclear spins. Here, we report systematic measurement of the spin-lattice relaxation time (T1) and enhancement level of (13)C-enriched chemical probes in the presence of various Gd contrast agents in the liquid-state after dissolution. Using two different (13)C probes having opposite electric charges at neutral pH, we clearly show the T1 of hyperpolarized (13)C was barely affected by the use of a Gd complex that displays repulsive interaction with the (13)C probe in solution, whilst T1 was drastically shortened when there was ionic attraction between probe and complex. PMID- 27490301 TI - Associations of gestational and early life exposures to ambient air pollution with childhood atopic eczema in Shanghai, China. AB - Whether ambient air pollution is associated with childhood atopic eczema is controversial. In this paper, we selected 3358 preschool children who had not altered residences since pregnancy from a cross-sectional study during 2011-2012 in Shanghai, China, and obtained parent-reported data regarding childhood atopic eczema using an improved ISAAC questionnaire. We recorded daily concentrations of SO2, NO2, and PM10 throughout the child's lifetime (2006-2012), and calculated period-averaged concentrations for each district where the child lived to represent the child's exposure levels of these pollutants during different periods. In the multiple logistic regression analyses adjusted for potential confounders as well as for the other pollutants in the same periods, childhood atopic eczema was significantly associated with increments of NO2 in the approximate interquartile range (20MUg/m3) during gestational period (adjusted OR, 95% CI for eczema lifetime-ever: 1.80, 1.29-2.49; for eczema in the year prior to the survey: 2.32, 1.57-3.43) and during the first year of life (2.00, 1.40-2.84; 2.16, 1.43-3.28). Exposure to elevated NO2 in the first two years, three years and total lifetime, as well as exposure to mixtures containing NO2 in each of these periods, were consistently associated with increased likelihood of childhood eczema. The highest odds ratios were found between exposure to a mixture of SO2 and NO2 during total lifetime (increment: 35MUg/m3) and childhood eczema (adjusted OR, 95% CI: 2.80, 1.75-4.48; 3.50, 1.98-6.19). No significant associations were found between childhood eczema and ambient SO2 and PM10 individually or in mixtures. This study indicates that gestational and lifetime exposures to ambient NO2 are risk factors for atopic eczema in childhood. Exposure to ambient SO2 and PM10 may enhance the effect of NO2 exposure on childhood eczema. PMID- 27490304 TI - Neural correlates of accelerated auditory processing in children engaged in music training. AB - Several studies comparing adult musicians and non-musicians have shown that music training is associated with brain differences. It is unknown, however, whether these differences result from lengthy musical training, from pre-existing biological traits, or from social factors favoring musicality. As part of an ongoing 5-year longitudinal study, we investigated the effects of a music training program on the auditory development of children, over the course of two years, beginning at age 6-7. The training was group-based and inspired by El Sistema. We compared the children in the music group with two comparison groups of children of the same socio-economic background, one involved in sports training, another not involved in any systematic training. Prior to participating, children who began training in music did not differ from those in the comparison groups in any of the assessed measures. After two years, we now observe that children in the music group, but not in the two comparison groups, show an enhanced ability to detect changes in tonal environment and an accelerated maturity of auditory processing as measured by cortical auditory evoked potentials to musical notes. Our results suggest that music training may result in stimulus specific brain changes in school aged children. PMID- 27490305 TI - Predictors of 30-day perioperative morbidity and mortality of unruptured intracranial aneurysm surgery. AB - INTRODUCTION: Large-scale studies examining the incidence and predictors of perioperative complications after surgical clipping of unruptured intracranial aneurysms (UIA) using nationally representative prospectively collected data are lacking in the literature. METHODS: Using the American College of Surgeons' National Surgical Quality Improvement Program (ACS-NSQIP) dataset, we conducted a retrospective analysis of the complications experienced by patients that underwent surgical management of a UIA between the years of 2007 and 2013. The primary outcomes of interest were mortality within the 30-day perioperative period and adverse discharge disposition to a location other than home. Predictors of morbidity and mortality were elucidated using multivariable logistic regression analyses controlling for available patient demographic, comorbidity, and operative characteristics. RESULTS: 662 patients were identified in the ACS-NSQIP dataset for operative management of an unruptured aneurysm. The observed rates of 30-day mortality and adverse discharge disposition were 2.27% and 19.47%, respectively. A hundred and eight (16.31%) patients developed at least one major complication. On multivariable analysis, death within 30days was significantly associated with increased operative time (OR 1.005 per minute, 95% CI 1.002-1.008) and chronic preoperative corticosteroid use (OR 28.4, 95% CI 1.68 480.42), whereas major complication development was associated with increased operative time (OR 1.004 per minute, 95% CI 1.002-1.006), age (OR 1.017 per year, 95% CI 1-1.034), preoperative dependency (OR 3.3, 95% CI 1.16-9.40) and diabetes mellitus (OR 2.89, 95% CI 1.45-5.75). Lastly, increasing age (OR 1.017 per year, 95% CI 1-1.034) as well as ASA Class 3 (OR 1.73, 95% CI 1.08-2.77) and 4 (OR 2.28, 95% CI 1.1-4.72) were independent predictors of discharge to a location other than home. CONCLUSION: Our study yields morbidity and mortality benchmarks for UIA surgery in a representative, national surgical registry. It will hopefully aid in recognizing those patients at greater risk for postoperative complications following surgical management, leading to appropriate changes in treatment strategies for this selected group of patients. PMID- 27490306 TI - Interactions of gut microbiota with dietary polyphenols and consequences to human health. AB - PURPOSE OF REVIEW: Dietary (poly)phenolic compounds have received attention over the last 20 years as antioxidants with preventive properties against chronic diseases. However, the evidence of these effects in clinical trials is weak, mainly because of a considerable interindividual variability. Polyphenols bioavailability is low, and gut microbiota metabolize them into simpler metabolites. As gut microbiota vary among individuals, such interindividual variability should be considered as a moderating factor in clinical trials. In this review, we show evidence of interactions with gut microbiota that help understanding polyphenols' health effects. RECENT FINDINGS: Recent studies indicate that dietary polyphenols are relevant in the modulation of gut microbiota and that these microorganisms convert polyphenols into active and bioavailable metabolites; hence, variations in gut microbiota can affect polyphenol activity. SUMMARY: The results show that study participants' stratification by their polyphenol-metabolizing phenotypes would be necessary for clinical trials as specific metabotypes produce the bioactive metabolites responsible for the health effects. Metabotypes can also reflect the gut microbiota composition and metabolic status, and could be biomarkers of the potential polyphenol health effects mediated through gut microbiota. PMID- 27490307 TI - Similarities in the Retinal Appearance of Patients With Zika Virus Compared With Cobalamin C Deficiency. PMID- 27490309 TI - TiCl4-Mediated Preparation of Thiophthalide Derivatives via Formal Thio-Passerini Reactions. AB - By the formal extension of the Passerini reaction to thiocarbonyl derivatives, the straightforward preparation of thiophthalides is disclosed. This method involves the intermediate formation of a sulfanyl-phthalide and a titanium tetrachloride mediated isocyanide insertion reaction. When tert-butyl thiol is used, thanks to the deprotection of the tert-butyl group, a thiophthalide resulting from a 1,5-Mumm rearrangement is isolated. Owing to the multifaceted activity of TiCl4, all steps may conveniently be performed in one pot, starting directly from 2-formylbenzoic acids, tert-butyl thiol, and various isocyanides. PMID- 27490310 TI - Association of Intraoperative Neuromonitoring With Reduced Recurrent Laryngeal Nerve Injury in Patients Undergoing Total Thyroidectomy. AB - Importance: Injury of the recurrent laryngeal nerve (RLN) is one of the most serious complications of thyroid surgery. Intraoperative neuromonitoring (IONM) has been introduced to verify RLN function integrity and may be a helpful adjunct in nerve dissection. Objective: To determine whether the use of IONM can reduce the incidence of RLN injury in patients undergoing total thyroidectomy. Design, Setting, and Participants: This cohort study included 2556 patients who underwent total thyroidectomy between January 2002 and December 2012 in the Department of Otolaryngology-Head and Neck Surgery of Venizeleio General Hospital, Heraklion, Greece. Patients who had IONM during the procedure (n = 1481) were compared with patients who underwent surgery with nerve visualization alone (n = 1075). All patients underwent indirect laryngoscopy-fiberoptic nasopharyngoscopy both preoperatively and on day 2 after surgery to assess vocal cord motility. Main Outcomes and Measures: Use of IONM and incidence of RLN injury. Results: A total of 2556 patients (2028 women and 528 men [5112 RLNs at risk]; mean [SD] age, 51.35 [14.18] years; age range, 18-89 years) underwent total thyroidectomy. Univariate analysis showed that the use of IONM resulted in a significant reduction in RLN injury incidence (3.3% vs 0.7%) with a relative risk reduction of 2.6% (odds ratio [OR], 5.15; 95% CI, 3.12-8.49; number needed to treat, 19). Multivariate logistic regression showed that no use of IONM was an independent risk factor for RLN injury in patients who underwent total thyroidectomy (adjusted OR [AOR], 5.44; 95% CI, 3.26-9.09). Additional risk factors for RLN injury were operative time (AOR, 12.91; 95% CI, 6.66-25.06), maximum diameter greater than 45 mm of right thyroid lobe (AOR, 4.91; 95% CI, 3.12-8.56) and left thyroid lobe (AOR, 2.24; 95% CI, 1.39-4.32), extrathyroid extension (AOR, 3.26; 95% CI, 1.62-6.59), incidental parathyroidectomy (AOR, 3.30; 95% CI, 2.13-5.09), and tumor size larger than 10 mm (AOR, 3.24; 95% CI, 1.59-6.62). Conclusions and Relevance: Our findings showed that the use of IONM decreased significantly both temporary and permanent RLN injuries. The technology of IONM is safe and reliable, and this technique is an important adjunct in nerve dissection and functional neural integrity. The routine use of IONM reduced pitfalls and provided guidance for our surgeons in difficult cases, reoperations, and high risk patients. PMID- 27490308 TI - Effects of Visible-Light Irradiation of Protoporphyrin IX on the Self-Assembly of Tubulin Heterodimers. AB - The formation and the effects of laser irradiation of the complex formed by protoporphyrin IX (PPIX) and tubulin was investigated. We have used tubulin as a model protein to investigate whether docked photoactive ligands can affect the structure and function of polypeptides upon exposure to visible light. We observed that laser irradiation in the Soret band prompts bleaching of the PPIX, which is accompanied by a sharp decrease in the intensity and average fluorescence lifetime of the protein (dominated by the four tryptophan residues of the tubulin monomer). The kinetics indicate non-trivial effects and suggest that the photosensitization of the PPIX bound to tubulin prompts structural alterations of the protein. These modifications were also observed through changes in the energy transfer between Trp residues and PPIX. The results suggest that laser irradiation produces localized partial unfolding of tubulin and that the changes prompt modification of the formation of microtubules in vitro. Measurements of singlet oxygen formation were inconclusive in determining whether the changes are prompted by reactive oxygen species or other excited state mechanisms. PMID- 27490311 TI - The Hydroxysteroid (17beta) Dehydrogenase Family Gene HSD17B12 Is Involved in the Prostaglandin Synthesis Pathway, the Ovarian Function, and Regulation of Fertility. AB - The hydroxysteroid (17beta) dehydrogenase (HSD17B)12 gene belongs to the hydroxysteroid (17beta) dehydrogenase superfamily, and it has been implicated in the conversion of estrone to estradiol as well as in the synthesis of arachidonic acid (AA). AA is a precursor of prostaglandins, which are involved in the regulation of female reproduction, prompting us to study the role of HSD17B12 enzyme in the ovarian function. We found a broad expression of HSD17B12 enzyme in both human and mouse ovaries. The enzyme was localized in the theca interna, corpus luteum, granulosa cells, oocytes, and surface epithelium. Interestingly, haploinsufficiency of the HSD17B12 gene in female mice resulted in subfertility, indicating an important role for HSD17B12 enzyme in the ovarian function. In line with significantly increased length of the diestrous phase, the HSD17B+/- females gave birth less frequently than wild-type females, and the litter size of HSD17B12+/- females was significantly reduced. Interestingly, we observed meiotic spindle formation in immature follicles, suggesting defective meiotic arrest in HSD17B12+/- ovaries. The finding was further supported by transcriptome analysis showing differential expression of several genes related to the meiosis. In addition, polyovular follicles and oocytes trapped inside the corpus luteum were observed, indicating a failure in the oogenesis and ovulation, respectively. Intraovarian concentrations of steroid hormones were normal in HSD17B12+/- females, whereas the levels of AA and its metabolites (6-keto prostaglandin F1alpha, prostaglandin D2, prostaglandin E2, prostaglandin F2alpha, and thromboxane B2) were decreased. In conclusion, our study demonstrates that HSD17B12 enzyme plays an important role in female fertility through its role in AA metabolism. PMID- 27490312 TI - Empathic Communication in Virtual Education for Nursing Students: I'm Sorry to Hear That. AB - The current study examined the communication strategies used by undergraduate nursing students (N = 343) to express empathy during simulated health history interviews. Interacting with a virtual patient, students encountered up to 9 information disclosures that warranted the expression of empathy but recognized few (33.54%). Sophistication of language to express empathy varied depending on the disclosure topic. These findings suggest that empathy as a learned skill can be incorporated into a variety of nursing contexts. PMID- 27490313 TI - Content Validation of a Quality and Safety Education for Nurses-Based Clinical Evaluation Instrument. AB - Quality and Safety Education for Nurses (QSEN) has been prominent in nursing education for 10 years. Since its inception, faculty have used the QSEN competencies as a framework for developing teaching strategies and tools, but there are few findings available to support this practice. This article describes the process of developing a QSEN-based clinical evaluation instrument for a prelicensure nursing program and establishing content validation for its items using the content validity index. PMID- 27490314 TI - Effective Learning of Interprofessional Teamwork. AB - Educators are actively identifying optimal teaching-learning strategies that afford future health care professionals opportunities to acquire skills necessary to function as a member of an interprofessional team. This article describes the development of an interprofessional team learning experience consisting of students from 6 health professions programs within 1 college of health professions. Student achievement of interprofessional team competencies were evaluated in a pretest-posttest format. Essential components of a 7-week program, teaching methodologies, and course evaluations are presented. PMID- 27490315 TI - Penalized weighted least-squares approach for multienergy computed tomography image reconstruction via structure tensor total variation regularization. AB - Multienergy computed tomography (MECT) allows identifying and differentiating different materials through simultaneous capture of multiple sets of energy selective data belonging to specific energy windows. However, because sufficient photon counts are not available in each energy window compared with that in the whole energy window, the MECT images reconstructed by the analytical approach often suffer from poor signal-to-noise and strong streak artifacts. To address the particular challenge, this work presents a penalized weighted least-squares (PWLS) scheme by incorporating the new concept of structure tensor total variation (STV) regularization, which is henceforth referred to as 'PWLS-STV' for simplicity. Specifically, the STV regularization is derived by penalizing higher order derivatives of the desired MECT images. Thus it could provide more robust measures of image variation, which can eliminate the patchy artifacts often observed in total variation (TV) regularization. Subsequently, an alternating optimization algorithm was adopted to minimize the objective function. Extensive experiments with a digital XCAT phantom and meat specimen clearly demonstrate that the present PWLS-STV algorithm can achieve more gains than the existing TV based algorithms and the conventional filtered backpeojection (FBP) algorithm in terms of both quantitative and visual quality evaluations. PMID- 27490316 TI - Surface reconstruction for planning and navigation of liver resections. AB - Computer-assisted systems for planning and navigation of liver resection procedures rely on the use of patient-specific 3D geometric models obtained from computed tomography. In this work, we propose the application of Poisson surface reconstruction (PSR) to obtain 3D models of the liver surface with applications to planning and navigation of liver surgery. In order to apply PSR, the introduction of an efficient transformation of the segmentation data, based on computation of gradient fields, is proposed. One of the advantages of PSR is that it requires only one control parameter, allowing the process to be fully automatic once the optimal value is estimated. Validation of our results is performed via comparison with 3D models obtained by state-of-art Marching Cubes incorporating Laplacian smoothing and decimation (MCSD). Our results show that PSR provides smooth liver models with better accuracy/complexity trade-off than those obtained by MCSD. After estimating the optimal parameter, automatic reconstruction of liver surfaces using PSR is achieved keeping similar processing time as MCSD. Models from this automatic approach show an average reduction of 79.59% of the polygons compared to the MCSD models presenting similar smoothness properties. Concerning visual quality, on one hand, and despite this reduction in polygons, clinicians perceive the quality of automatic PSR models to be the same as complex MCSD models. On the other hand, clinicians perceive a significant improvement on visual quality for automatic PSR models compared to optimal (obtained in terms of accuracy/complexity) MCSD models. The median reconstruction error using automatic PSR was as low as 1.03+/-0.23mm, which makes the method suitable for clinical applications. Automatic PSR is currently employed at Oslo University Hospital to obtain patient-specific liver models in selected patients undergoing laparoscopic liver resection. PMID- 27490317 TI - Watertight modeling and segmentation of bifurcated Coronary arteries for blood flow simulation using CT imaging. AB - Image-based simulation of blood flow using computational fluid dynamics has been shown to play an important role in the diagnosis of ischemic coronary artery disease. Accurate extraction of complex coronary artery structures in a watertight geometry is a prerequisite, but manual segmentation is both tedious and subjective. Several semi- and fully automated coronary artery extraction approaches have been developed but have faced several challenges. Conventional voxel-based methods allow for watertight segmentation but are slow and difficult to incorporate expert knowledge. Machine learning based methods are relatively fast and capture rich information embedded in manual annotations. Although sufficient for visualization and analysis of coronary anatomy, these methods cannot be used directly for blood flow simulation if the coronary vasculature is represented as a loose combination of tubular structures and the bifurcation geometry is improperly modeled. In this paper, we propose a novel method to extract branching coronary arteries from CT imaging with a focus on explicit bifurcation modeling and application of machine learning. A bifurcation lumen is firstly modeled by generating the convex hull to join tubular vessel branches. Guided by the pre-determined centerline, machine learning based segmentation is performed to adapt the bifurcation lumen model to target vessel boundaries and smoothed by subdivision surfaces. Our experiments show the constructed coronary artery geometry from CT imaging is accurate by comparing results against the manually annotated ground-truths, and can be directly applied to coronary blood flow simulation. PMID- 27490318 TI - Connexin43 Mimetic Peptide Improves Retinal Function and Reduces Inflammation in a Light-Damaged Albino Rat Model. AB - PURPOSE: Drugs that regulate connexin43 (Cx43) gap junction channels can reduce the spread of injury and improve functional outcomes after nervous system trauma. In the eye, Cx43 expression increases in the choroid following light damage. The aim of this study was to investigate whether Cx43 hemichannel block could preserve retinal function postinjury. METHODS: Light damage was induced by exposure of adult albino Sprague-Dawley rats to 2700 Lux light for 24 hours. Intravitreal injections of a Cx43 mimetic peptide hemichannel blocker, Peptide5, or sham were administered 2 hours after the onset and at the end of the light damage period. Retinal function was assessed by electroretinogram and inflammatory responses in the choroid and retina were assessed using immunohistochemistry (ionized calcium binding adaptor molecule 1 [Iba-1], leukocyte common antigen [CD45], glial fibrillary acidic protein [GFAP]). RESULTS: Light-damaged rat eyes had (1) reduced neuronal responses in both the rod and cone pathways and (2) marked inflammatory responses in the choroid and retina. Peptide5 significantly preserved function of photoreceptoral and postphotoreceptoral neurons in these animals. This was evident 24 hours after injury and 2 weeks later, as shown by improved mixed a-wave and mixed b-wave amplitudes, isolated rod PII and PIII amplitudes, and cone PII responses when compared with sham-treated controls. Retinal thinning and inflammation were also significantly reduced in Peptide5-treated eyes when compared with sham-treated controls. CONCLUSIONS: Blocking Cx43 hemichannels after light damage can significantly improve functional outcomes of neurons in both the rod and cone photo-transduction pathways in the light-damaged animal model, likely by reducing choroid inflammation and suppressing the glial-mediated inflammatory response. These data may have relevance for the treatment of conditions such as diabetic retinopathy and age-related macular degeneration. PMID- 27490319 TI - Functional and Morphologic Changes of Meibomian Glands in an Asymptomatic Adult Population. AB - PURPOSE: The aim of the study was to understand natural changes of meibomian glands (MG) that occur with aging in the absence of any ocular pathology or ocular discomfort symptoms, to differentiate between "age normal" and pathologic or dysfunctional changes of the MG. METHODS: A total of 185 subjects (109 females) with no pre-existing ocular and systemic abnormalities were recruited and divided into four age groups: 25 to 34, 35 to 44, 45 to 54, and 55 to 66 years. At a single visit, the following MG measures were collected: meibum quality (MQ) and MG expressibility (MGE) of the lower lid, and MG drop-out score (meiboscale) using infrared meibography of the upper and lower lids. Assessments of anterior eye, tear function variables, noninvasive and invasive tear breakup time (TBUT), corneal integrity, and lid wiper epitheliopathy were also performed during the visit. An Ocular Surface Disease Index (OSDI) questionnaire was used to record dry eye symptoms. Meibum lipids samples were collected and analyzed. RESULTS: A majority of the study population (61%) was asymptomatic. There was a significant worsening in the MQ (P< 0.048), MGE (P < 0.03), and meiboscale (P < 0.01) with increasing age. Significant increase was observed in anterior blepharitis (P < 0.001) and telangiectasia (P< 0.02) with aging. Interestingly, tear osmolarity decreased significantly (P < 0.001), while tear meniscus height (P < 0.001) and invasive TBUT (P = 0.02) increased with increase in age. There was no significant association between MG variables and sex, ocular discomfort symptoms, or meibum lipids classes. CONCLUSIONS: Progressive MG loss occurs normally with age accompanied by reduced quality and quantity of the meibum produced. However, clinical presentation of ocular discomfort symptoms is stalled without corresponding disruption to tear function. PMID- 27490320 TI - Characteristics of Retinal Nerve Fiber Layer Defect in Nonglaucomatous Eyes With Type II Diabetes. AB - PURPOSE: To investigate the characteristics of retinal nerve fiber layer (RNFL) defects associated with type II diabetes. METHODS: Forty nonglaucomatous eyes with type II diabetes and 54 eyes with early open angle glaucoma that exhibited a localized RNFL defect and 42 eyes from age- and sex-matched nondiabetic, nonglaucomatous controls were imaged with red-free fundus photography and optical coherence tomography (Cirrus HD-OCT, Carl Zeiss Meditec). The area under the receiver operating characteristic curves of eyes with diabetes was compared with that of eyes with glaucoma. When an RNFL defect on fundus photographs was identified in the quadrant, clock-hour, temporal-superior-nasal-inferior-temporal (TSNIT), deviation, and thickness maps, it was considered a true detection. RESULTS: In eyes with diabetes, the RNFL defects were located more frequently in the superior hemisphere than they were in those with glaucoma (P < 0.001). The angular locations of RNFL defects in eyes with diabetes (56.1 +/- 12.7 degrees ) were significantly farther from the fovea compared with those in glaucoma (44.3 +/- 17.3 degrees ; P < 0.001); in addition, the width of RNFL defects in diabetes (5.1 +/- 2.3 degrees ) was significantly narrower than those in glaucoma (20.8 +/ 12.3 degrees ; P < 0.001). The best parameter discriminating RNFL defects in diabetes from those in glaucoma was width of RNFL defect (0.955), followed by rim area (0.844), and average RNFL (0.791). The thickness map showed a sensitivity (70%) and specificity (69.1%), superior to those of all other maps in eyes with diabetes. CONCLUSIONS: The narrow width and identification of RNFL defect in thickness map obtained with Cirrus HD-OCT seems to be an effective tool for detecting RNFL defects in diabetes. PMID- 27490321 TI - Erratum. PMID- 27490322 TI - Phase Synchronization Analysis of Natural Wake and Sleep States in Healthy Individuals Using a Novel Ensemble Phase Synchronization Measure. AB - PURPOSE: Electrical activity in the brain is presumed to arise from a combination of tonic asynchronous neuronal firing during wake and a synchronized, burst-pause firing of large number of neurons during sleep. This study aims to compare the phase synchronization index (SI) across multiple channels during wake and various sleep stages on scalp electroencephalographic recordings. METHODS: Forty healthy subjects were subjected to overnight polysomnography using 8-channel electroencephalography. Electroencephalographic phase synchronization during awake, non-rapid eye movement (N1, N2, N3), and rapid eye movement sleep states was studied using ensemble measure (multichannel measure across all the eight channels based on Hilbert transformation between any two pairs). RESULTS: With the progression of states of wakefulness to non-rapid eye movement sleep, there was progressive increase in phase SI in delta band while SI decreased in alpha band (P < 0.001). The SI in delta band during rapid eye movement was comparable with that of awake state (P < 0.001). In theta band, SI tends to decrease in N2 and increase in N3 (P < 0.001). In beta band, there was progressive increase in SI from awake to non-rapid eye movement stages that decreased in rapid eye movement stage (P < 0.001). CONCLUSIONS: This is the first study that has used an ensemble measure to assess the long-range cortical phase synchronization during awake and various sleep stages. The findings support the previous view of increased delta synchrony during non-rapid eye movement sleep and alpha synchrony during wakefulness. Rapid eye movement stage was characterized by marked desynchrony in all frequency bands. These findings suggest the possible role of cortical synchronization in influencing the occurrence of epileptic activity during sleep and awake states. PMID- 27490323 TI - Maximizing the Yield of Rapid Eye Movement Sleep in the Epilepsy Monitoring Unit. AB - PURPOSE: Rapid eye movement (REM) sleep can help localize the epileptogenic zone in multifocal epilepsy when interictal discharges appear diffuse. However, REM sleep is reputedly rare and easily overlooked in the Epilepsy Monitoring Unit (EMU). The aims of this study are to determine the characteristics of REM sleep in a typical EMU and whether using automated artifact recognition can meaningfully enhance REM sleep detection. METHODS: Artifact-based REM sleep detection was applied to 581 nights of EMU recording from 100 patients over 12 months. REM sleep had been manually detected at the time of recording. The index of suspicion for manual detection was raised after 6 months. Artifact-based detection was compared with manual detection, and the impact on localization was assessed. RESULTS: REM sleep occurred in 77% of EMU nights. Thirty-six patients achieved REM sleep nightly and 62 patients on at least one night. Mean admission was 5.83 days. Mean REM sleep duration was 5.92 minutes over 1.88 mean nightly bouts. Raising the level of suspicion increased manual detection rates from 22.6% to 40.5%. The artifact-based detection rate was 96% and provided additional localizing information in 10% of epilepsy patients. CONCLUSIONS: REM sleep is common in the EMU, but bouts are few and brief. Capturing these bouts to maximize the yield of REM sleep in the EMU is made possible by automated artifact recognition whose results could enhance localization of the epileptogenic zone. PMID- 27490324 TI - Large Amplitude Cortical Evoked Potentials in Nonepileptic Patients. Reviving an Old Neurophysiologic Tool to Help Detect CNS Pathology. AB - PURPOSE: Although large amplitude evoked potentials (EPs) are typically associated with progressive myoclonic epilepsy patients, giant EPs imply central nervous system (CNS) hyperexcitability and can be seen in various nonepileptic disorders. METHODS: We performed a retrospective chart review including history, physical examination, imaging and diagnostic studies of nonepileptic patients with large amplitude somatosensory evoked potentials (SSEPs) and visual evoked potentials (VEPs) during 2007 to 2013. Large amplitude EPs were defined as follows: VEPs (N75-P100) >18 MUV; and SSEPs (N20-P25) >6.4 MUV. Recording montage for VEPs was Oz-Cz and SSEPs C3'/C4'-Fz. RESULTS: Fifty-two patients (33 females, 19 males; age range, 9-90 years) were identified. No CNS pathology was detected in 7 patients. All remaining patients were diagnosed with new CNS disorders including: vascular (37%); myelopathies (13%); demyelinating (11%); space occupying lesions (8.7%); syringomyelia (8.7%); hydrocephalus (6.5%); Vitamin B 12 deficiency (4.3%); multiple system atrophy (4.3%); and toxins (2.2%). CONCLUSIONS: This study supports the notion that large amplitude EP implies CNS hyperexcitability and CNS disease. These results confirm the utility of EP studies in patients with suspected CNS pathology. PMID- 27490325 TI - Hyperventilation in Patients With Focal Epilepsy: Electromagnetic Tomography, Functional Connectivity and Graph Theory - A Possible Tool in Epilepsy Diagnosis? AB - PURPOSE: Hyperventilation (HV) is a commonly used electroencephalogram activation method. METHODS: We analyzed EEG recordings in 22 normal subjects and 22 patients with focal epilepsy of unknown cause. We selected segments before (PRE), during (HYPER), and 5 minutes after (POST) HV. To analyze the neural generators of EEG signal, we used standard low-resolution electromagnetic tomography (sLORETA software). We then computed EEG lagged coherence, an index of functional connectivity, between 19 regions of interest. A weighted graph was built for each band in every subject, and characteristic path length (L) and clustering coefficient (C) have been computed. Statistical comparisons were performed by means of analysis of variance (Group X Condition X Band) for mean lagged coherence, L and C. RESULTS: Hyperventilation significantly increases EEG neural generators (P < 0.001); the effect is particularly evident in cingulate cortex. Functional connectivity was increased by HV in delta, theta, alpha, and beta bands in the Epileptic group (P < 0.01) and only in theta band in Control group. Intergroup analysis of mean lagged coherence, C and L, showed significant differences for Group (P < 0.001), Condition (P < 0.001), and Band (P < 0.001). Analysis of variance for L also showed significant interactions: Group X Condition (P = 0.003) and Group X Band (P < 0.001). CONCLUSIONS: In our relatively small group of epileptic patients, HV is associated with activation of cingulate cortex; moreover, it modifies brain connectivity. The significant differences in mean lagged coherence, path length, and clustering coefficient permit to hypothesize that this activation method leads to different brain connectivity patterns in patients with epilepsy when compared with normal subjects. If confirmed by other studies involving larger populations, this analysis could become a diagnostic tool in epilepsy. PMID- 27490326 TI - Unilateral Mu Rhythm and Associated Cortical Lesions on Brain MRI. AB - PURPOSE: The purpose of this study was to assess the frequency of occurrence of a unilateral mu rhythm and the associated neuroimaging findings on dedicated epilepsy protocol brain MRI. METHODS: We retrospectively reviewed the EEG reports database at the American University of Beirut Medical Center between 2011 and 2014 searching for the presence of a unilateral mu rhythm. For patients with a unilateral mu rhythm, we recorded the patients' demographics, number of EEGs performed, characteristics of the mu activity, and the findings on the epilepsy protocol brain MRIs. RESULTS: A total of 7986 patients underwent 9,509 EEG between 2011 and 2014. Four patients (0.05%) aged between 19 and 55 years had evidence of a unilateral mu rhythm. Three patients were diagnosed with localization-related epilepsy and one with syncope. The brain MRIs showed cortical lesions involving the parietal cortex, ipsilateral to the unilateral mu rhythm in the three patients with epilepsy. CONCLUSIONS: A unilateral mu rhythm is a rare phenomenon on the scalp EEG that should prompt a search for an ipsilateral lesion, even in the absence of additional EEG abnormalities. PMID- 27490327 TI - Measuring the Severity of Neonatal Seizures: Temporal-Spatial Burden. AB - PURPOSE: The American Clinical Neurophysiology Society recommends measuring neonatal seizures' severity by their frequency (number of seizures-anywhere per hour), burden (percentage of time with seizures-anywhere), or on a region-by region, temporal-spatial basis. This study compares two reduced-channel montages for temporal-spatial seizure burden analyses and examines the agreement of seizures' quantification among these three methodologies. METHODS: A convenience sample of 10 neonatal electroencephalograms was annotated for the beginnings and ends of seizures, which appeared anywhere in the full neonatal montage, then repeated on a more precise, region-by-region basis using 2 reduced-channel montages A and B. Seizure severity was measured by seizures-anywhere frequency, seizures-anywhere burden, and temporal-spatial seizure burdens using montages A and B. The results were compared by measuring their correlation and by linear regression modeling. RESULTS: Seizures-anywhere frequency was correlated with seizures-anywhere burden (rho = 0.77). However, a narrow range of seizures anywhere frequencies corresponded with a broad range of seizures-anywhere burdens. Although there was high correlation between seizures-anywhere burdens and temporal-spatial seizure burdens (rho = 0.92 montage A, rho = 0.90 montage B), seizures-anywhere burdens were insensitive to variations in the spatial aspects of seizures, which were highly prevalent even in this small sample set. After adjusting for intrareader variability, the temporal-spatial seizure burdens measured by montages A and B were not significantly different (P = 0.56). CONCLUSIONS: The severity of neonatal seizures is poorly represented by simple measures such as seizures-anywhere frequencies or burdens. The use of temporal spatial seizure burden measurements is supported in work where great precision in quantifying neonatal seizures is required. PMID- 27490328 TI - The effectiveness of a nurse practitioner-led pain management team in long-term care: A mixed methods study. AB - BACKGROUND: Considering the high rates of pain as well as its under-management in long-term care (LTC) settings, research is needed to explore innovations in pain management that take into account limited resource realities. It has been suggested that nurse practitioners, working within an inter-professional model, could potentially address the under-management of pain in LTC. OBJECTIVES: This study evaluated the effectiveness of implementing a nurse practitioner-led, inter professional pain management team in LTC in improving (a) pain-related resident outcomes; (b) clinical practice behaviours (e.g., documentation of pain assessments, use of non-pharmacological and pharmacological interventions); and, (c) quality of pain medication prescribing practices. METHODS: A mixed method design was used to evaluate a nurse practitioner-led pain management team, including both a quantitative and qualitative component. Using a controlled before-after study, six LTC homes were allocated to one of three groups: 1) a nurse practitioner-led pain team (full intervention); 2) nurse practitioner but no pain management team (partial intervention); or, 3) no nurse practitioner, no pain management team (control group). In total, 345 LTC residents were recruited to participate in the study; 139 residents for the full intervention group, 108 for the partial intervention group, and 98 residents for the control group. Data was collected in Canada from 2010 to 2012. RESULTS: Implementing a nurse practitioner-led pain team in LTC significantly reduced residents' pain and improved functional status compared to usual care without access to a nurse practitioner. Positive changes in clinical practice behaviours (e.g., assessing pain, developing care plans related to pain management, documenting effectiveness of pain interventions) occurred over the intervention period for both the nurse practitioner-led pain team and nurse practitioner-only groups; these changes did not occur to the same extent, if at all, in the control group. Qualitative analysis highlighted the perceived benefits of LTC staff about having access to a nurse practitioner and benefits of the pain team, along with barriers to managing pain in LTC. CONCLUSIONS: The findings from this study showed that implementing a nurse practitioner-led pain team can significantly improve resident pain and functional status as well as clinical practice behaviours of LTC staff. LTC homes should employ a nurse practitioner, ideally located onsite as opposed to an offsite consultative role, to enhance inter-professional collaboration and facilitate more consistent and timely access to pain management. PMID- 27490329 TI - Metastasis to the Heart: A Radiologic Approach to Diagnosis With Pathologic Correlation. AB - OBJECTIVE: Evaluating metastatic disease to the heart and pericardium, from detection to diagnosis, often requires a multimodality imaging approach. A radiologist's ability to evaluate cardiac metastases hinges on an understanding of the epidemiology, anatomy, and imaging features of this disease process. CONCLUSION: On surveillance imaging of patients with cancer or when metastatic disease is suspected, detection of metastatic disease may be greatly enhanced by an understanding of which primary tumors metastasize to the heart and the most common routes of spread. PMID- 27490330 TI - JOURNAL CLUB: Patient Perception of Radiology and Radiologists: A Survey Analysis of Academic and Community Institutions. AB - OBJECTIVE: The objective of the present study is to evaluate patient understanding of radiology and radiologists and to assess patient interest in direct consultation with a radiologist. MATERIALS AND METHODS: A total of 1976 adult radiology outpatients at both a university and a nearby community hospital were surveyed. After an initial survey was administered, educational material with an attached follow-up survey was distributed to the patients. A McNemar test was used to assess the difference between patients who correctly chose the radiologist as the image interpreter before and after educational material was provided, whereas a paired t test was used to test the difference between patient levels of comfort with various image interpreters. RESULTS: Of the respondents, 84% expressed interest in meeting with a radiologist, with 43% willing to pay $0, 37% willing to pay $10-$30, and 20% willing to pay $40 or more to do so. Small percentages of respondents incorrectly identified ultrasound (10%) and MRI (45%) examinations as using radiation, whereas larger percentages of respondents correctly identified radiography (87%), CT (63%), and nuclear medicine imaging (62%) examinations as using radiation. A total of 73% of respondents (1002/1369) initially chose the radiologist as the image interpreter; this percentage improved to 81% (1109/1369) after the respondents received educational material (p < 0.0001). Both before and after educational material was provided, respondents had a statistically significantly lower mean (+/- SD) comfort level score (scale, 1-10) when faced with the prospect of a nurse or physician assistant interpreting their examination versus a trained physician (i.e., a radiologist) (mean score, 5.2 +/- 3.27 and 9.4 +/- 1.47, respectively, before education [p < 0.0001] and 5.2 +/- 2.94 and 9.56 +/- 1.24, respectively, after education [p < 0.0001]). CONCLUSION: The level of comfort with radiologists as image interpreters was statistically significantly higher than the level of comfort with nonradiologist interpreters, and most patients were interested in meeting with radiologists. Educational material improved patient perception and knowledge of radiology. PMID- 27490331 TI - Melatonin Receptor 1 Deficiency Affects Feeding Dynamics and Pro-Opiomelanocortin Expression in the Arcuate Nucleus and Pituitary of Mice. AB - BACKGROUND/METHODS: Melatonin, the neurohormone for darkness, mediates photoperiod-dependent changes in physiology and behavior by targeting specific membrane-bound receptors (MT1 and MT2). In the present study, we investigated the impact of MT1 receptor deficiency on feeding behavior, locomotor activity and mRNA expression levels encoding for the polypeptide pro-opiomelanocortin (Pomc) and neuropeptide Y (Npy) in the hypothalamic arcuate nucleus (ARC) and the adenohypophysis [pars distalis (PD) and pars intermedia (PI)] in a comparison between wild-type (WT) and MT1-deficient (MT1-/-) mice. RESULTS: The MT1-/- mice spent significantly more time feeding than the WT mice, while the general locomotor behavior, body weight and the total amount of food consumed did not differ between both genotypes. The nocturnal expression levels of Pomc in the ARC and PD were significantly higher in WT as compared to MT1-/- mice and exogenous melatonin administered during the light phase stimulated Pomc expression in WT mice only. No differences were found between WT and MT1-/- mice with regard to Pomc expression levels in the PI. CONCLUSION: Thus, the MT1-mediated signaling stimulates Pomc expression in a region-specific pattern. Since the MT1-mediated changes in Pomc expression do not elicit direct orexigenic or anorexigenic effects, such effects are obviously mediated by regulatory systems downstream of the Pomc mRNA (e.g. cleavage and release of POMC derivatives), which are independent of MT1 signaling. PMID- 27490332 TI - Does Ventriculoperitoneal Shunting Improve Thyroid Hormone Levels in Hydrocephalic Newborns? AB - OBJECTIVE/AIM: The aim of this report was to investigate the effect of ventriculoperitoneal shunt insertion for the treatment of hydrocephalus on thyroid hormones in the first 3 months of life. METHODS: Thyroid-stimulating hormone (TSH), free T3 (fT3), and free T4 (fT4) levels were compared at 7 days (preoperatively) and at 30 and 90 days (postoperatively) after birth between 25 ventriculoperitoneal shunt-inserted hydrocephalic newborns and 20 healthy newborns. RESULTS: The TSH level at 7 days was higher in the hydrocephalic patient group (6.33 uIU) compared to the control group (3.76 uIU). This value was significantly decreased at 90 days in the ventriculoperitoneal shunt-inserted newborns (2.35 uIU) compared to the control group (3.33 uIU; p < 0.05). There were no significant differences between time points for fT4 and fT3 values in the patient group or for TSH, fT4, and fT3 values in the control group. CONCLUSION: We propose that a ventriculoperitoneal shunt inserted in the early period of life may have beneficial effects on thyroid hormones. PMID- 27490333 TI - Combination of a Cyano Migration Strategy and Alkene Difunctionalization: The Elusive Selective Azidocyanation of Unactivated Olefins. AB - A conceptually new, efficient, and metal-free approach for the challenging azidocyanation of unactivated alkenes is presented. The strategy of intramolecular distal cyano migration is combined with alkene difunctionalization for the first time. A variety of useful azido-substituted alkyl nitriles are prepared in good yields and, most importantly, with exquisite regio- and stereo selectivities. PMID- 27490334 TI - A novel screening method for 64 new psychoactive substances and 5 amphetamines in blood by LC-MS/MS and application to real cases. AB - Identification and quantification of new psychoactive substances (NPS), both in biological and non-biological samples, represent a hard challenge for forensic toxicologists. NPS are increasingly emerging on illegal drug market. Many cases of co-consumption of NPS and other substances have also been reported. Hence, the development of analytical methods aiming at the detection of a broad-spectrum of compounds (NPS and "traditional" drugs) could be helpful. In this paper, a fully validated screening method in blood for the simultaneous detection of 69 substances, including 64 NPS (28 synthetic cannabinoids, 19 synthetic cathinones, 5 phenethylamines, 3 indanes, 2 piperazines, 2 tryptamines, 2 phencyclidine, methoxetamine, ketamine and its metabolite) and 5 amphetamines (amphetamine, methamphetamine, MDMA, MDA, 3,4-methylenedioxy-N-ethylamphetamine - MDEA-) by a dynamic multiple reaction monitoring analysis through liquid chromatography - tandem mass spectrometry (LC-MS/MS) is described. This method is very fast, easy to perform and cheap as it only requires the deproteinization of 200MUL of blood sample with acetonitrile. The chromatographic separation is achieved with a C18 column. The analysis is very sensitive, with limits of quantification ranging from 0.1 to 0.5ng/mL. The method is linear from 1 to 100ng/mL and the coefficient of determination (R(2)) was always above 0.9900. Precision and accuracy were acceptable at any quality control level and recovery efficiency range was 72 110%. Matrix effects did not negatively affect the analytical sensitivity. This method was successfully applied to three real cases, allowing identification and quantification of: mephedrone and methamphetamine (post-mortem); ketamine, MDMA and MDA (post-mortem); AB-FUBINACA (ante-mortem). PMID- 27490336 TI - Luminescent Covalent Organic Frameworks Containing a Homogeneous and Heterogeneous Distribution of Dehydrobenzoannulene Vertex Units. AB - Finding new ways to construct crystalline multiple-component covalent organic frameworks (COFs) has become an important focus. Herein we report the synthesis of three novel COFs containing a homogeneous and heterogeneous distribution of pi conjugated dehydrobenzoannulene (DBA) vertex units. The COFs were synthesized by reacting different ratios of C3-symmetric DBA catechol monomers with C2-symmetric pyrene-2,7-diboronic acid (PDBA) to yield three COFs, Py-DBA-COF 1, Py-DBA-COF 2, and Py-MV-DBA-COF. All three materials are highly crystalline and display unique luminescent properties in the solid state. PMID- 27490335 TI - Sulfoxide-Based Enantioselective Nazarov Cyclization: Divergent Syntheses of (+) Isopaucifloral F, (+)-Quadrangularin A, and (+)-Pallidol. AB - The synthesis of enantiomerically pure 3-aryl substituted indanones is developed using an enantioselective sulfoxide-based Knoevenagel condensation/Nazarov cyclization procedure. After the reductive desulfonation of the methyl para-tolyl sulfoxide-containing chiral auxiliary under mild conditions, selected enantiomerically pure indanone is used for the divergent total syntheses of three resveratrol natural products (+)-isopaucifloral F, (+)-quadrangularin A, and (+) pallidol. PMID- 27490341 TI - Beyond GRACE: Using Satellite Data for Groundwater Investigations. PMID- 27490342 TI - Tracing the origin of beer samples by NMR and chemometrics: Trappist beers as a case study. AB - An NMR and chemometric analytical approach to classify beers according to their brand identity was developed within the European TRACE project (FP6-2003-FOOD-2 A, contract number: 0060942). Rochefort 8 Trappist beers (47 samples), other Trappist beers (76 samples) and non-Trappist beers (110 samples) were analyzed by 1 H NMR spectroscopy. Selected NMR signals were measured and used to build classification models. Three different classification problems were identified, namely Trappist versus non-Trappist, Rochefort versus Non-Rochefort, and Rochefort 8 versus non-Rochefort 8. In all the three cases, both a discriminant and a modeling approaches were followed, using partial least squares discriminant analysis (PLS-DA) and soft independent modeling of class analogies (SIMCA), respectively, leading to very high classification accuracy as evaluated by external validation. Information regarding chemical composition was also obtained: Trappist beers contain a higher amount of formic and pyruvic acids and a lower amount of acetic acid and alanine with respect to non-Trappist ones. Rochefort beers turned out to have also a higher content of propanol and isopentanol with respect to non-Rochefort samples. Finally, Rochefort 8, shows the highest content of pyruvic acid and the lowest content of gallic, fumaric, acetic acids, adenosine, uridine, 2-phenylethanol, GABA, and alanine. PMID- 27490343 TI - Microarray-Based Analysis of Methylation of 1st Trimester Trisomic Placentas from Down Syndrome, Edwards Syndrome and Patau Syndrome. AB - Methylation-based non-invasive prenatal testing of fetal aneuploidies is an alternative method that could possibly improve fetal aneuploidy diagnosis, especially for trisomy 13(T13) and trisomy 18(T18). Our aim was to study the methylation landscape in placenta DNA from trisomy 13, 18 and 21 pregnancies in an attempt to find trisomy-specific methylation differences better suited for non invasive prenatal diagnosis. We have conducted high-resolution methylation specific bead chip microarray analyses assessing more than 450,000 CpGs analyzing placentas from 12 T21 pregnancies, 12 T18 pregnancies and 6 T13 pregnancies. We have compared the methylation landscape of the trisomic placentas to the methylation landscape from normal placental DNA and to maternal blood cell DNA. Comparing trisomic placentas to normal placentas we identified 217 and 219 differentially methylated CpGs for CVS T18 and CVS T13, respectively (delta beta>0.2, FDR<0.05), but only three differentially methylated CpGs for T21. However, the methylation differences was only modest (delta beta<0.4), making them less suitable as diagnostic markers. Gene ontology enrichment analysis revealed that the gene set connected to theT18 differentially methylated CpGs was highly enriched for GO terms related to"DNA binding" and "transcription factor binding" coupled to the RNA polymerase II transcription. In the gene set connected to the T13 differentially methylated CpGs we found no significant enrichments. PMID- 27490345 TI - Liver resection for non-colorectal non-neuroendocrine metastases. AB - OBJECTIVE: Liver resections for non-colorectal non-neuroendocrine liver metastases (NCNELM) are gaining popularity. This study examines the outcomes of liver resections in patients with NCNELM in an Australian hospital. METHOD: A database search identified 21 attempted liver resections on 20 patients (12 men, eight women, mean age: 63.1) from 1998 to 2013. A retrospective analysis considered patient demographics and primary malignancy details. Complication rates were compared to those for colorectal metastases at the same institution. Kaplan-Meier curves were used to plot overall survival. RESULTS: Complete resection was achieved in 16 of the 21 operations with 13 cases having proven metastases (three cases were benign lesions on final histology). Primary cancers were gastric (n = 4), gall bladder/bile duct (n = 3), renal (n = 3), soft tissue sarcoma (n = 3), melanoma (n = 2), pancreatic (n = 2), anal (n = 2), breast (n = 1) and unknown (n = 1). Primary histology types were adenocarcinoma (n = 10), sarcoma (n = 3), renal cell (n = 3), squamous cell (n = 2), melanoma (n = 2) and gastrointestinal stromal tumour (n = 1). There was no peri-operative mortality. Significant post-operative complications (Clavien-Dindo Grade III or more) occurred in six patients (28.5%). Overall survival at 2 and 5 years was 46.2% and 30.8%, respectively, for all 21 cases of attempted resection, and 51.9% and 34.6%, respectively, for the 13 cases of complete resection of malignant metastases. CONCLUSIONS: This study produced comparable 5-year survival rates to those reported after liver resection for colorectal metastases and in other studies on NCNELM. Complication rates were comparable to those for colorectal liver metastasis resection at the same institution. PMID- 27490344 TI - E2F1 Hinders Skin Wound Healing by Repressing Vascular Endothelial Growth Factor (VEGF) Expression, Neovascularization, and Macrophage Recruitment. AB - BACKGROUND: Refractory surface of wound and dermal chronic ulcer are largely attributed to poor neovascularization. We have previously shown that E2F1 suppresses VEGF expression in the ischemic heart, and that genetic deletion of E2F1 leads to better cardiac recovery. However, whether E2F1 has a role in dermal wound healing is currently not known. METHODS AND RESULTS: Skin wounds were surgically induced in E2F1-null (E2F1-/-) mice and WT littermates. E2F1-/- displayed an accelerated wound healing including wound closure, dermal thickening and collagen deposition, which was associated with an increased endothelial cell proliferation and greater vessel density in the border zone of the wound. Furthermore, more macrophages were recruited to the skin lesions and the level of VEGF expression was markedly higher in E2F1-/- than in WT mice. CONCLUSIONS: E2F1 hinders skin wound healing by suppressing VEGF expression, neovascularization, and macrophage recruitment. Strategies that target E2F1 may enhance wound healing. PMID- 27490346 TI - The Influence of Sex and Season on Conspecific Spatial Overlap in a Large, Actively-Foraging Colubrid Snake. AB - Understanding the factors influencing the degree of spatial overlap among conspecifics is important for understanding multiple ecological processes. Compared to terrestrial carnivores, relatively little is known about the factors influencing conspecific spatial overlap in snakes, although across snake taxa there appears to be substantial variation in conspecific spatial overlap. In this study, we described conspecific spatial overlap of eastern indigo snakes (Drymarchon couperi) in peninsular Florida and examined how conspecific spatial overlap varied by sex and season (breeding season vs. non-breeding season). We calculated multiple indices of spatial overlap using 6- and 3-month utilization distributions (UD) of dyads of simultaneously adjacent telemetered snakes. We also measured conspecific UD density values at each telemetry fix and modeled the distribution of those values as a function of overlap type, sex, and season using generalized Pareto distributions. Home range overlap between males and females was significantly greater than overlap between individuals of the same sex and male home ranges often completely contained female home ranges. Male home ranges overlapped little during both seasons, whereas females had higher levels of overlap during the non-breeding season. The spatial patterns observed in our study are consistent with those seen in many mammalian carnivores, in which low male-male overlap and high inter-sexual overlap provides males with greater access to females. We encourage additional research on the influence of prey availability on conspecific spatial overlap in snakes as well as the behavioral mechanisms responsible for maintaining the low levels of overlap we observed. PMID- 27490347 TI - Saturated Heavier Group 14 Compounds as sigma -Electron-Acceptor (Z-Type) Ligands. AB - This review article describes the chemistry of transition-metal complexes containing heavier group 14 elements (Si, Ge, and Sn) as the sigma-electron acceptor (Z-type) ligands and discusses the characteristics of bonds between the transition metal and Z-type ligand. Moreover, we review the iridium hydride mediated cleavage of E-X bonds (E=Si, Ge; X=F, Cl), where the key intermediates are pentacoordinate silicon or germanium compounds bearing a dative M->E bond. PMID- 27490349 TI - [Not Available]. PMID- 27490348 TI - A Genome-Wide Search for Greek and Jewish Admixture in the Kashmiri Population. AB - The Kashmiri population is an ethno-linguistic group that resides in the Kashmir Valley in northern India. A longstanding hypothesis is that this population derives ancestry from Jewish and/or Greek sources. There is historical and archaeological evidence of ancient Greek presence in India and Kashmir. Further, some historical accounts suggest ancient Hebrew ancestry as well. To date, it has not been determined whether signatures of Greek or Jewish admixture can be detected in the Kashmiri population. Using genome-wide genotyping and admixture detection methods, we determined there are no significant or substantial signs of Greek or Jewish admixture in modern-day Kashmiris. The ancestry of Kashmiri Tibetans was also determined, which showed signs of admixture with populations from northern India and west Eurasia. These results contribute to our understanding of the existing population structure in northern India and its surrounding geographical areas. PMID- 27490350 TI - [Not Available]. PMID- 27490351 TI - [Higher - Further - Faster]. AB - The striated skeletal muscles consist of different myocytes that have different metabolic and contractile characteristics. They react in a specific way to difference training stimuli: adaptations as a result of endurance training trigger an increase in mitochondria and lead to an intensified oxidative metabolism. Adaptations as a result of strength training result in increased protein biosynthesis and hypertrophy of the skeletal myocytes. About 50 % of the adaptation associated with endurance training are due to genetic factors.The molecular mechanisms that underlie the training adaptations are currently the subject of intense research. They comprise complex interrelated systems with a series of key components. Understanding molecular switches and signalling pathways gives rise to the assumption that the combination of simultaneous strength training and endurance training is counterproductive. The combination of both these forms of training possible weakens the effect on muscle mass and muscle strength. Consequently the recommendation is to plan for enough of time intervals between strength training and endurance training. PMID- 27490352 TI - [Fast Response Training in Youth Soccer Players]. AB - BACKGROUND: Injuries of the knee and ankle joint are a serious ongoing problem in soccer. Although there is a variety of prevention programmes, a significant reduction of severe knee injuries has not been observed. Therefore, current strategies for diagnostics and training need to be re-evaluated. OBJECTIVE: Our study aimed to test a totally new intervention strategy (fast response training on the SpeedCourt). The efficiency of this method was evaluated with youth soccer athletes. MATERIALS AND METHODS: 24 young male class A athletes (mean age 18.0 +/ 0.7 years) of a local soccer team underwent SpeedCourt training for 7 weeks (1 training session per week = TS) during the regular season of competition. TS contained life-kinetic elements (time of exercise: 15 - 30 seconds, break: 2 minutes) and included a warm-up phase (15 minutes) and fast response training on the SpeedCourt (30 minutes). The players were tested on the SpeedCourt with different tests (Counter Movement Jump (CMJ), shuttle run, tapping, 10-second sprint) before and after the training programme. RESULTS: The univariate single factor analysis of variance showed significant improvements in all test parameters (eta(2)> 0.10). The range varied between eta(2) = 0.106 (time of ground contact right leg) und eta(2) = 0.730 (reaction time right leg). We did not find any relevant correlations between the tests and parameters. The number of injury-related accidents involving the lower extremities was reduced by about 50 % during defined periods of time. CONCLUSION: Our data revealed that training with fast responses at the SpeedCourt system clearly improved speed and speed strength performance of young soccer athletes, which is remarkable given the low intensity of influences (one TS per week). The increase in performance was accompanied by a significant reduction of the injury rate. PMID- 27490353 TI - [Characteristics of Nutrition in Competitive Sports, Ranging from Leisure Activities to High-Performance Athletics]. AB - Nutrition has a crucial influence on physical and mental performance ability and is an important measure along sidetraining in high-performance athletes. However, this form of nutritionis not applicable for every athlete and in every situation. The question of optimal nutrition requires involvement with the particular type of sports, an athlete's current training stage, and athletes' individual requirements and objectives. Implementation takes time and individual motivation on the part of athletes and the specialist staff who engage intensively with the nutritional needs of athletes. In addition to adequate energy provision, it is important to divide the energy sensibly among the energy sources carbohydrates, fats, and protein. Performance athletes' higher need for protein can usually be covered in their regular diet; supplements are needed only in exceptional cases. Studies have shown that small amounts of 15 - 25 g protein are sensible after weight training, in order to stimulate muscle protein synthesis. The need for carbohydrates increases dynamically with the intensity and duration of physical exertion. A sufficient supply is crucial for achieving maximum performance. Low carb diets are unsuitable for performance athletes. So called low-glycogen training, however, can lead to better adjustment/adaptation processes in selected training stages and can increase performance ability. PMID- 27490354 TI - [Zika Virus - Impact on the 2016 Olympic Games in Rio de Janeiro]. AB - There is an ongoing discussion in the media about the Zika virus and the question of whether or not athletes and visitors will be at risk of an infection during the Olympic Games in Rio de Janeiro in 2016. According to an assessment published on 31 May 2016 by the IOC and the WHO, participants and visitors have no reason to panic. However, increasing public pressure has caused the WHO to re-evaluate the current situation, and further recommendations will likely be given before the Olympic Games start. The current facts are as follows: 1) The Olympic Summer Games will be held during the winter months in Brazil, when the appearance of mosquitoes is expected to be low. 2) Extensive use of insecticides every 6 to 8 weeks in Rio de Janeiro and all Olympic venues has almost eradicated the mosquito population. 3) Individual protection of athletes, trainers and visitors is crucial (wearing appropriate clothing with skin coverage, sleeping under mosquito nets, using contact insecticides for clothing and mosquito nets, and applying insect repellents on a regular basis). 4) Pregnant women should avoid travelling to any country with current Zika virus activity. In sum, the risk to incur a Zika virus infection during the Olympic Games in Rio de Janeiro will likely be comparable to the risk in other countries where cases of Zika virus infections are registered. PMID- 27490355 TI - [Rehabilitation of Ligamentous Elbow Instability in Athletes]. AB - Ligamentous instability of the elbow is a common pathology affecting athletes in different types of sports. It may lead to a permanent impairment of an athlete's ability to train and compete. The advancements made in arthroscopic, biomechanical and clinical diagnostic procedures allow for a better understanding of the etiology of elbow discomfort. As a result, ligamentous instability has been increasingly identified as a reason for acute and chronic pain in athletes. This article provides an overview of the etiology as well as diagnostic and rehabilitative procedures for ligamentous instability of the elbow in athletes and presents principles of rehabilitation in patients with symptomatic elbow instability. PMID- 27490356 TI - Groin Pain and Muscular Imbalance of Quadriceps and Hamstrings in an Elite Soccer Player - A Case Study. AB - Soccer and football players are exposed to a high risk of groin pain. In some cases, the pubic symphysis is the origin of the problems.This article presents a case report of a young elite soccer player who, over a period of two years, suffered from pain in the groin and symphysis area. The right leg was the kicking leg. Imaging techniques did not reveal pathological findings. Sports hernia, osteomyelitis, enthesopathy, adductor tendonitis, and muscle sprains, as well as rheumatic or urogenital disorders were excluded.A 3 D posture analysis was performed to examine the statics of the body and pelvis. The maximum isometric strength of the left and right leg adductors and abductors, as well as the knee flexors and extensors were measured.We found a muscular imbalance resulting from the type of sport the athlete engaged in with an unfavourable ratio between the right knee extensor and flexor muscles. Comparing sides, an imbalance was also identified between the right and left knee extensor. This imbalance resulted in a one-sided forward tilt of the right hemi-pelvis. This pelvic torsion may lead to an increase in shear forces in the pubic symphysis, which we suspected to be the reason for the recurring problems.After three months of specific training exercises, the pelvic position was harmonised and the muscular imbalances were significantly reduced. Even 6 months after completion of the specific training exercises, the player remained without complaints despite his unvaried soccer training intensity.Causal treatment of functional pain in the groin or symphysis area should take into account the ipsilateral and contralateral strength ratios of the knee extensors and flexors as well as the three-dimensional position of the pelvis. PMID- 27490357 TI - Iodine-Catalyzed Cross Dehydrogenative Coupling Reaction: A Regioselective Sulfenylation of Imidazoheterocycles Using Dimethyl Sulfoxide as an Oxidant. AB - A regioselective formation of C-S bonds has been achieved using a cross dehydrogenative coupling (CDC) protocol using iodine as a catalyst and dimethyl sulfoxide as an oxidant under green chemistry conditions. This strategy employs the reaction of easily available heterocyclic thiols or thiones with imidazoheterocycles. This protocol provides an efficient, mild, and inexpensive method for sulfenylation of imidazoheterocycles with a diverse range of heterocyclic thiols and heterocyclic thiones. PMID- 27490358 TI - Is Satisfaction with the Acute-Care Experience Higher amongst Consumers Treated in the Private Sector? A Survey of Public and Private Sector Arthroplasty Recipients. AB - BACKGROUND: Consumer satisfaction with the acute-care experience could reasonably be expected to be higher amongst those treated in the private sector compared to those treated in the public sector given the former relies on high-level satisfaction of its consumers and their subsequent recommendations to thrive. The primary aims of this study were to determine, in a knee or hip arthroplasty cohort, if surgery in the private sector predicts greater overall satisfaction with the acute-care experience and greater likelihood to recommend the same hospital. A secondary aim was to determine whether satisfaction across a range of service domains is also higher in the private sector. METHODS: A telephone survey was conducted 35 days post-surgery. The hospital cohort comprised eight public and seven private high-volume arthroplasty providers. Consumers rated overall satisfaction with care out of 100 and likeliness to recommend their hospital on a 5-point Likert scale. Additional Likert-style questions were asked covering specific service domains. Generalized estimating equation models were used to analyse overall satisfaction (dichotomised as >= 90 or < 90) and future recommendations for care (dichotomised as 'definitely recommend' or 'other'), whilst controlling for covariates. The proportions of consumers in each sector reporting the best Likert response for each individual domain were compared using non-parametric tests. RESULTS: 457 survey respondents (n = 210 private) were included. Less patient-reported joint impairment pre-surgery [OR 1.03 (95% CI 1.01-1.05)] and absence of an acute complication (OR 2.13 95% CI 1.41-3.23) significantly predicted higher overall satisfaction. Hip arthroplasty [OR 1.84 (1.1-2.96)] and an absence of an acute complication [OR 2.31 (1.28-4.17] significantly predicted greater likelihood for recommending the hospital. The only care domains where the private out-performed the public sector were hospitality (46.7 vs 35.6%, p <0.01) and frequency of surgeon visitation (76.4 vs 65.8%, p = 0.03). CONCLUSIONS: Arthroplasty consumers treated in the private sector are not more satisfied with their acute-care experience nor are they more likely to recommend their hospital provider. Rather, avoidance of complications in either sector appears to result in improved satisfaction as well as a greater likelihood that patients would recommend their hospital provider. PMID- 27490359 TI - Constrained Cyclopeptides: Biaryl Formation through Pd-Catalyzed C-H Activation in Peptides-Structural Control of the Cyclization vs. Cyclodimerization Outcome. AB - A series of short tryptophan-phenylalanine peptides containing an iodo substituent on the phenyl ring was subjected to Pd-catalyzed CH activation reactions to give the corresponding aryl-indole coupled products. Two types of adducts were generated: cyclomonomer and cyclodimeric peptides; no evidence of oligo- or polymerization products was detected. Contrary to standard peptide macrocyclizations, the factors controlling the fate of the reaction are the number of amino acids between the aromatic residues and the regiochemistry of the parent iodo derivative, independent of both the concentration and the cyclization mode. The method is general and allows access to novel biaryl peptidic topologies, which have been fully characterized. PMID- 27490360 TI - Mycoplasma pneumoniae triggering the Guillain-Barre syndrome: A case-control study. AB - OBJECTIVE: Guillain-Barre syndrome (GBS) is an acute postinfectious immune mediated polyneuropathy. Although preceding respiratory tract infections with Mycoplasma pneumoniae have been reported in some cases, the role of M. pneumoniae in the pathogenesis of GBS remains unclear. We here cultured, for the first time, M. pneumoniae from a GBS patient with antibodies against galactocerebroside (GalC), which cross-reacted with the isolate. This case prompted us to unravel the role of M. pneumoniae in GBS in a case-control study. METHODS: We included 189 adults and 24 children with GBS and compared them to control cohorts for analysis of serum antibodies against M. pneumoniae (n = 479) and GalC (n = 198). RESULTS: Anti-M. pneumoniae immunoglobulin (Ig) M antibodies were detected in GBS patients and healthy controls in 3% and 0% of adults (p = 0.16) and 21% and 7% of children (p = 0.03), respectively. Anti-GalC antibodies (IgM and/or IgG) were found in 4% of adults and 25% of children with GBS (p = 0.001). Anti-GalC positive patients showed more-frequent preceding respiratory symptoms, cranial nerve involvement, and a better outcome. Anti-GalC antibodies correlated with anti-M. pneumoniae antibodies (p < 0.001) and cross-reacted with different M. pneumoniae strains. Anti-GalC IgM antibodies were not only found in GBS patients with M. pneumoniae infection, but also in patients without neurological disease (8% vs 9%; p = 0.87), whereas anti-GalC IgG was exclusively found in patients with GBS (9% vs 0%; p = 0.006). INTERPRETATION: M. pneumoniae infection is associated with GBS, more frequently in children than adults, and elicits anti GalC antibodies, of which specifically anti-GalC IgG may contribute to the pathogenesis of GBS. Ann Neurol 2016;80:566-580. PMID- 27490361 TI - Non-Smoking Tobacco Affects Endothelial Function in Healthy Men in One of the Largest Health Studies Ever Performed; The Nord-Trondelag Health Study in Norway; HUNT3. AB - BACKGROUND: Oral tobacco (snuff) is taking a large market share in Scandinavia, especially with young users. However, long-term health effects are unknown. Small studies show association between snuff and reduced endothelial function, representing an early stage of vascular injury that often precedes manifest cardiovascular disease by several years. We therefore determined the associations between snuff and endothelial function in a large sample of healthy Norwegian men. METHODS AND DESIGN: In the Fitness substudy of the Nord-Trondelag Health Study (HUNT3), endothelial function was measured by flow-mediated dilation (FMD). Aerobic fitness was measured by peak oxygen uptake (VO2peak). A cross-sectional design including 1 592 self-reported healthy men compared these observations with records of present tobacco use, standard cardiovascular risk factors, and socioeconomic status, using general linear models. RESULTS: FMD was lower in snuff users (FMD: 4.12%, 3.63, 4.61) compared to non-users (FMD: 4.52%, 4.27, 4.78) after adjustment for age (difference: -0.57%, -1.12, -0.01). After further adjustment for potential confounders, FMD still tended to be lower in snuff users than in non-users (difference: -0.53%, -1.09, 0.02). This difference was even more pronounced in the inactive snuff users (-0.83%, -1.59, -0.06) and in the low fit snuff users (-0.74%, CI -0.55, 0.079). CONCLUSIONS: Oral tobacco is associated with a tendency towards reduced endothelial function, indicating vascular changes that precede cardiovascular disease. The strongest associations were found in men with low physical activity or reduced aerobic fitness. PMID- 27490362 TI - Remarkable In Vivo Nonlinear Photoacoustic Imaging Based on Near-Infrared Organic Dyes. AB - Two near-infrared dyes featuring good dispersion and light-harvesting property present a remarkable nonlinear photoacoustic response in vitro and in vivo comparing with conventional gold nanorods. This study benefits the fabrication of drug delivery platforms with accurate targeting and control effect under photoacoustic image guidance. PMID- 27490363 TI - Stability Analysis of SIR Model with Distributed Delay on Complex Networks. AB - In this paper, by taking full consideration of distributed delay, demographics and contact heterogeneity of the individuals, we present a detailed analytical study of the Susceptible-Infected-Removed (SIR) epidemic model on complex population networks. The basic reproduction number [Formula: see text] of the model is dominated by the topology of the underlying network, the properties of individuals which include birth rate, death rate, removed rate and infected rate, and continuously distributed time delay. By constructing suitable Lyapunov functional and employing Kirchhoff's matrix tree theorem, we investigate the globally asymptotical stability of the disease-free and endemic equilibrium points. Specifically, the system shows threshold behaviors: if [Formula: see text], then the disease-free equilibrium is globally asymptotically stable, otherwise the endemic equilibrium is globally asymptotically stable. Furthermore, the obtained results show that SIR models with different types of delays have different converge time in the process of contagion: if [Formula: see text], then the system with distributed time delay stabilizes fastest; while [Formula: see text], the system with distributed time delay converges most slowly. The validness and effectiveness of these results are demonstrated through numerical simulations. PMID- 27490365 TI - Racial/Ethnic Disparities in Primary Care Quality Among Type 2 Diabetes Patients, Medical Expenditure Panel Survey, 2012. AB - INTRODUCTION: Racial and ethnic disparities exist in diabetes prevalence, access to diabetes care, diabetes-related complications and mortality rates, and the quality of diabetes care among Americans. We explored racial and ethnic disparities in primary care quality among Americans with type 2 diabetes. METHODS: We analyzed data on adults with type 2 diabetes derived from the household component of the 2012 Medical Expenditure Panel Survey. Multiple regression and multivariate logistic regressions were used to examine the association between race/ethnicity and primary care attributes related to first contact, longitudinality, comprehensiveness, and coordination, and clusters of confounding factors were added sequentially. RESULTS: Preliminary findings indicated differences in primary care quality between racial/ethnic minorities and whites across measures of first contact, longitudinality, comprehensiveness, and coordination. After controlling for confounding factors, these differences were no longer apparent; all racial/ethnic categories showed similar rates of primary care quality according to the 4 primary care domains of interest in the study. CONCLUSION: Results indicate equitable primary care quality for type 2 diabetes patients across 4 key domains of primary care after controlling for socioeconomic characteristics. Additional research is necessary to support these findings, particularly when considering smaller racial/ethnic groups and investigating outcomes related to diabetes. PMID- 27490366 TI - Health and Nutrition Literacy and Adherence to Treatment in Children, Adolescents, and Young Adults With Chronic Kidney Disease and Hypertension, North Carolina, 2015. AB - INTRODUCTION: Adherence to treatment and dietary restrictions is important for health outcomes of patients with chronic/end-stage kidney disease and hypertension. The relationship of adherence with nutritional and health literacy in children, adolescents, and young adults is not well understood. The current study examined the relationship of health literacy, nutrition knowledge, nutrition knowledge-behavior concordance, and medication adherence in a sample of children and young people with chronic/end-stage kidney disease and hypertension. METHODS: We enrolled 74 patients (aged 7-29 y) with a diagnosis of chronic/end stage kidney disease and hypertension from the University of North Carolina Kidney Center. Participants completed instruments of nutrition literacy (Disease Specific Nutrition Knowledge Test), health literacy (Newest Vital Sign), nutrition behavior (Nutrition Knowledge-Behavior Concordance Scale), and medication adherence (Morisky Medication Adherence Scale). Linear and binary logistic regressions were used to test the associations. RESULTS: In univariate comparisons, nutrition knowledge was significantly higher in people with adequate health literacy. Medication adherence was related to nutrition knowledge and nutrition knowledge-behavior concordance. Multivariate regression models demonstrated that knowledge of disease-specific nutrition restrictions did not significantly predict nutrition knowledge-behavior concordance scores. In logistic regression, knowledge of nutrition restrictions did not significantly predict medication adherence. Lastly, health literacy and nutrition knowledge behavior concordance were significant predictors of medication adherence. CONCLUSION: Nutrition knowledge and health literacy skills are positively associated. Nutrition knowledge, health literacy, and nutrition knowledge behavior concordance are positively related to medication adherence. Future research should focus on additional factors that may predict disease-specific nutrition behavior (adherence to dietary restrictions) in children and young people with chronic conditions. PMID- 27490367 TI - Lessons From the Community-Centered Health Home Demonstration Project: Patient Centered Medical Homes Can Improve Health Conditions in Their Surrounding Communities. PMID- 27490364 TI - High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model. AB - Investigations on the influence of nature vs. nurture on Alcoholism (Alcohol Use Disorder) in human have yet to provide a clear view on potential genomic etiologies. To address this issue, we sequenced a replicated animal model system bidirectionally-selected for alcohol preference (AP). This model is uniquely suited to map genetic effects with high reproducibility, and resolution. The origin of the rat lines (an 8-way cross) resulted in small haplotype blocks (HB) with a corresponding high level of resolution. We sequenced DNAs from 40 samples (10 per line of each replicate) to determine allele frequencies and HB. We achieved ~46X coverage per line and replicate. Excessive differentiation in the genomic architecture between lines, across replicates, termed signatures of selection (SS), were classified according to gene and region. We identified SS in 930 genes associated with AP. The majority (50%) of the SS were confined to single gene regions, the greatest numbers of which were in promoters (284) and intronic regions (169) with the least in exon's (4), suggesting that differences in AP were primarily due to alterations in regulatory regions. We confirmed previously identified genes and found many new genes associated with AP. Of those newly identified genes, several demonstrated neuronal function involved in synaptic memory and reward behavior, e.g. ion channels (Kcnf1, Kcnn3, Scn5a), excitatory receptors (Grin2a, Gria3, Grip1), neurotransmitters (Pomc), and synapses (Snap29). This study not only reveals the polygenic architecture of AP, but also emphasizes the importance of regulatory elements, consistent with other complex traits. PMID- 27490368 TI - Electronic Cigarette Use Among High School Students and Its Association With Cigarette Use And Smoking Cessation, North Carolina Youth Tobacco Surveys, 2011 and 2013. AB - INTRODUCTION: Although adolescent cigarette use continues to decline in the United States, electronic cigarette (e-cigarette) use among adolescents has escalated rapidly. This study assessed trends and patterns of e-cigarette use and concurrent cigarette smoking and the relationships between e-cigarette use and smoking cessation intentions and behaviors among high school students in North Carolina. METHODS: Data came from high school students who completed the school based, cross-sectional North Carolina Youth Tobacco Survey in 2011 (n = 4,791) and 2013 (n = 4,092). This study assessed changes in prevalence of e-cigarette and cigarette use from 2011 through 2013, and cessation-related factors associated with those students' current and past use of e-cigarettes in 2013. RESULTS: The prevalence of current e-cigarette use (use in the past 30 days) significantly increased from 1.7% (95% CI, 1.3%-2.2%) in 2011 to 7.7% (95% CI, 5.9%-10.0%) in 2013. Among dual users, current e-cigarette use was negatively associated with intention to quit cigarette smoking for good (relative risk ratio [RRR] = 0.51; 95% CI, 0.29-0.87) and with attempts to quit cigarette smoking in the past 12 months (RRR = 0.69; 95% CI, 0.49-0.97). Current e-cigarette smokers were less likely than those who only smoked cigarettes to have ever abstained from cigarette smoking for 6 months (RRR = 0.42; 95% CI, 0.21-0.82) or 1 year (RRR = 0.21; 95% CI, 0.09-0.51) and to have used any kind of aids for smoking cessation (RRR = 0.46; 95% CI, 0.29-0.74). CONCLUSION: Public health practitioners and cessation clinic service providers should educate adolescents about the risks of using any nicotine-containing products, including e cigarettes, and provide adequate tobacco cessation resources and counseling to adolescent tobacco users. PMID- 27490369 TI - Circumventing Diffusion in Kinetically Controlled Solid-State Metathesis Reactions. AB - Solid-state diffusion is often the primary limitation in the synthesis of crystalline inorganic materials and prevents the potential discovery and isolation of new materials that may not be the most stable with respect to the reaction conditions. Synthetic approaches that circumvent diffusion in solid state reactions are rare and often allow the formation of metastable products. To this end, we present an in situ study of the solid-state metathesis reactions MCl2 + Na2S2 -> MS2 + 2 NaCl (M = Fe, Co, Ni) using synchrotron powder X-ray diffraction and differential scanning calorimetry. Depending on the preparation method of the reaction, either combining the reactants in an air-free environment or grinding homogeneously in air before annealing, the barrier to product formation, and therefore reaction pathway, can be altered. In the air-free reactions, the product formation appears to be diffusion limited, with a number of intermediate phases observed before formation of the MS2 product. However, grinding the reactants in air allows NaCl to form directly without annealing and displaces the corresponding metal and sulfide ions into an amorphous matrix, as confirmed by pair distribution function analysis. Heating this mixture yields direct nucleation of the MS2 phase and avoids all crystalline binary intermediates. Grinding in air also dissipates a large amount of lattice energy via the formation of NaCl, and the crystallization of the metal sulfide is a much less exothermic process. This approach has the potential to allow formation of a range of binary, ternary, or higher-ordered compounds to be synthesized in the bulk, while avoiding the formation of many binary intermediates that may otherwise form in a diffusion-limited reaction. PMID- 27490370 TI - XPS Study of Ion Irradiated and Unirradiated UO2 Thin Films. AB - XPS determination of the oxygen coefficient kO = 2 + x and ionic (U(4+), U(5+), and U(6+)) composition of oxides UO2+x formed on the surfaces of differently oriented (hkl) planes of thin UO2 films on LSAT (Al10La3O51Sr14Ta7) and YSZ (yttria-stabilized zirconia) substrates was performed. The U 4f and O 1s core electron peak intensities as well as the U 5f relative intensity before and after the (129)Xe(23+) and (238)U(31+) irradiations were employed. It was found that the presence of uranium dioxide film in air results in formation of oxide UO2+x on the surface with mean oxygen coefficients kO in the range 2.07-2.11 on LSAT and 2.17-2.23 on YSZ substrates. These oxygen coefficients depend on the substrate and weakly on the crystallographic orientation. On the basis of the spectral parameters it was established that uranium dioxide films AP2,3 on the LSAT substrates have the smallest kO values, and from the XRD and EBSD results it follows that these samples have a regular monocrystalline structure. The XRD and EBSD results indicate that samples AP5-7 on the YSZ substrates have monocrystalline structure; however, they have the highest kO values. The observed difference in the kO values was probably caused by the different nature of the substrates: the YSZ substrates provide 6.4% compressive strain, whereas (001) LSAT substrates result only in 0.03% tensile strain in the UO2 films. (129)Xe(23+) irradiation (92 MeV, 4.8 * 10(15) ions/cm(2)) of uranium dioxide films on the LSAT substrates was shown to destroy both long-range ordering and uranium close environment, which results in an increase of uranium oxidation state and regrouping of oxygen ions in uranium close environment. (238)U(31+) (110 MeV, 5 * 10(10), 5 * 10(11), 5 * 10(12) ions/cm(2)) irradiations of uranium dioxide films on the YSZ substrates were shown to form the lattice damage only with partial destruction of the long-range ordering. PMID- 27490371 TI - IMAGING DIAGNOSIS-RADIOGRAPHY AND ULTRASONOGRAPHY OF BILATERAL CONGENITAL URETEROVESICAL JUNCTION STENOSIS CAUSING HYDRONEPHROSIS AND HYDROURETER IN A FERRET (MUSTELA PUTORIUS FURO). AB - An 8-month-old neutered male ferret was presented for vaccination and preventive treatment for adrenal gland disease. Abdominal ultrasound revealed severe bilateral hydronephrosis and hydroureter. Excretory urography and negative contrast cystography showed bilateral ureterovesical junction stenosis. Positive retrograde cystography demonstrated right ureteral reflux. A subcutaneous ureteral bypass was placed in the left kidney; however, it had to be removed 3 months later due to an obstruction and persistent urinary tract infection. Bilateral ureteroneocystotomy was performed. Although congenital strictures are uncommon in veterinary patients, they should be included in the differential diagnosis in ferrets presenting with hydronephrosis and hydroureter of undetermined cause. PMID- 27490372 TI - Terahertz Time-Domain Spectroscopy of Thermoresponsive Polymers in Aqueous Solution. AB - The behavior of highly concentrated aqueous solutions of two thermoresponsive polymers poly(N-isopropylacrylamide) (PNIPAm) and poly(N-vinylcaprolactam) (PVCL) have been investigated by terahertz time-domain spectroscopy (THz-TDS). Measurements have been performed for concentrations up to 20 wt %, over a frequency range from 0.3 to 1.5 THz and for temperatures from 20 to 45 degrees C including the zone for lower critical solution temperature (LCST). THz-TDS enables the study of the behavior of water present in the solution (i.e., free or bound to the polymer). From these measurements, in addition to phase transition temperature, thermodynamic data such as variation of enthalpy and entropy can be inferred. Thanks to these data, further insights upon the mechanism involved during the dehydration phenomenon were obtained. These results were compared to the ones issued from dynamic light scattering, spectroscopy, or microscopy techniques to underline the interest to use THz-TDS as a powerful tool to characterize the behavior of thermoresponsive polymers in highly concentrated solutions. PMID- 27490373 TI - Optimising Translational Research Opportunities: A Systematic Review and Narrative Synthesis of Basic and Clinician Scientists' Perspectives of Factors Which Enable or Hinder Translational Research. AB - INTRODUCTION: Translational research is central to international health policy, research and funding initiatives. Despite increasing use of the term, the translation of basic science discoveries into clinical practice is not straightforward. This systematic search and narrative synthesis aimed to examine factors enabling or hindering translational research from the perspective of basic and clinician scientists, a key stakeholder group in translational research, and to draw policy-relevant implications for organisations seeking to optimise translational research opportunities. METHODS AND RESULTS: We searched SCOPUS and Web of Science from inception until April 2015 for papers reporting scientists' views of the factors they perceive as enabling or hindering the conduct of translational research. We screened 8,295 papers from electronic database searches and 20 papers from hand searches and citation tracking, identifying 26 studies of qualitative, quantitative or mixed method designs. We used a narrative synthesis approach and identified the following themes: 1) differing concepts of translational research 2) research processes as a barrier to translational research; 3) perceived cultural divide between research and clinical care; 4) interdisciplinary collaboration as enabling translation research, but dependent on the quality of prior and current social relationships; 5) translational research as entrepreneurial science. Across all five themes, factors enabling or hindering translational research were largely shaped by wider social, organisational, and structural factors. CONCLUSION: To optimise translational research, policy could consider refining translational research models to better reflect scientists' experiences, fostering greater collaboration and buy in from all types of scientists. Organisations could foster cultural change, ensuring that organisational practices and systems keep pace with the change in knowledge production brought about by the translational research agenda. PMID- 27490374 TI - Plant-Mediated Effects on Mosquito Capacity to Transmit Human Malaria. AB - The ecological context in which mosquitoes and malaria parasites interact has received little attention, compared to the genetic and molecular aspects of malaria transmission. Plant nectar and fruits are important for the nutritional ecology of malaria vectors, but how the natural diversity of plant-derived sugar sources affects mosquito competence for malaria parasites is unclear. To test this, we infected Anopheles coluzzi, an important African malaria vector, with sympatric field isolates of Plasmodium falciparum, using direct membrane feeding assays. Through a series of experiments, we then examined the effects of sugar meals from Thevetia neriifolia and Barleria lupilina cuttings that included flowers, and fruit from Lannea microcarpa and Mangifera indica on parasite and mosquito traits that are key for determining the intensity of malaria transmission. We found that the source of plant sugar meal differentially affected infection prevalence and intensity, the development duration of the parasites, as well as the survival and fecundity of the vector. These effects are likely the result of complex interactions between toxic secondary metabolites and the nutritional quality of the plant sugar source, as well as of host resource availability and parasite growth. Using an epidemiological model, we show that plant sugar source can be a significant driver of malaria transmission dynamics, with some plant species exhibiting either transmission-reducing or -enhancing activities. PMID- 27490376 TI - Associations between functional FCGR2A R131H and FCGR3A F158V polymorphisms and responsiveness to TNF blockers in spondyloarthropathy, psoriasis and Crohn's disease: a meta-analysis. AB - AIM: The aim of the current study was to investigate whether FCGR polymorphisms are associated with responsiveness to anti-TNF-alpha therapy in patients with spondyloarthropathy, psoriasis, and Crohn's disease. MATERIALS & METHODS: We conducted a meta-analysis to evaluate the association between the functional FCGR3A F158V and FCGR2A R131H polymorphisms and responsiveness to TNF blockers. RESULTS: The meta-analysis indicated that responsiveness to TNF blockers was associated with the FCGR3A V allele (odds ratio: 3.308; 95% CI: 1.053-10.39; p = 0.040) and the FCGR2A RR + RH genotype (odds ratio: 3.904; p = 0.027) in patients with a follow-up time of >=6 months. CONCLUSION: FCGR3A V and FCGR2A R allele carriers show better responsiveness to anti-TNF-alpha therapy in patients with follow-up times >=6 months. PMID- 27490375 TI - Gateway Vectors for Simultaneous Detection of Multiple Protein-Protein Interactions in Plant Cells Using Bimolecular Fluorescence Complementation. AB - Bimolecular fluorescence complementation (BiFC) is widely used to detect protein protein interactions, because it is technically simple, convenient, and can be adapted for use with conventional fluorescence microscopy. We previously constructed enhanced yellow fluorescent protein (EYFP)-based Gateway cloning technology-compatible vectors. In the current study, we generated new Gateway cloning technology-compatible vectors to detect BiFC-based multiple protein protein interactions using N- and C-terminal fragments of enhanced cyan fluorescent protein (ECFP), enhanced green fluorescent protein (EGFP), and monomeric red fluorescent protein (mRFP1). Using a combination of N- and C terminal fragments from ECFP, EGFP and EYFP, we observed a shift in the emission wavelength, enabling the simultaneous detection of multiple protein-protein interactions. Moreover, we developed these vectors as binary vectors for use in Agrobacterium infiltration and for the generate transgenic plants. We verified that the binary vectors functioned well in tobacco cells. The results demonstrate that the BiFC vectors facilitate the design of various constructions and are convenient for the detection of multiple protein-protein interactions simultaneously in plant cells. PMID- 27490377 TI - Development of melt electrohydrodynamic 3D printing for complex microscale poly (epsilon-caprolactone) scaffolds. AB - The replication of native hierarchical structures into synthetic scaffolds is important to direct cell growth and tissue regeneration. However, most of the existing scaffold strategies lack the capability to simultaneously realize the controlled fabrication of macroscopic geometries as well as microscale architectures with the scale similar to living cells. Here we developed a melt electrohydrodynamic printing platform and verified its feasibility to fabricate three-dimensional (3D) tissue-engineered scaffolds with complex curved geometries and microscale fibrous structures. Melting temperature was studied to stably print poly (epsilon-caprolactone) (PCL) filaments with the size of about 10 MUm, which was precisely stacked into 3D straight walls with fine surface quality. By adjusting stage moving speed and directions, 3D PCL scaffolds with curved contours and predefined fiber orientations or spacing were successfully printed. Biological experiments showed that the printed microscale scaffolds had good biocompatibility and facilitated cellular proliferation and alignment in vitro. It is envisioned that the melt electrohydrodynamic printing can potentially provide an innovative tool to fabricate hierarchical scaffolds that mimic the native tissue architectures in a multiscale level. PMID- 27490378 TI - Ring Expansion and Skeletal Rearrangement of Propargyl Alcohol Substituted Aziridines Induced by Ruthenium Complexes. AB - The ring expansion and skeletal rearrangement of two types of propargyl alcohol substituted aziridines with or without cycloalkane moieties was induced by a ruthenium cyclopentadienyl phosphine complex. In the simple aziridine system with no cycloalkane, the unique cycloisomerization process altered the absolute connectivity of the two-carbon unit in the three-membered ring to give organometallic products with substituted pyridine or dihydropyridine ligands. For the aziridine on a cyclohexyl ring, the cycloisomerization process was controlled by an interchange process between vinylidene and allenylidene species, thus creating a better relative configuration of the aziridinyl and the alkynyl units. This determines the stereochemistry of the metal carbene products of the octahydroindole derivatives. The structures of five products were determined by X ray diffraction analysis. PMID- 27490379 TI - Two-Color Lateral Flow Assay for Multiplex Detection of Causative Agents Behind Acute Febrile Illnesses. AB - Acute undifferentiated febrile illnesses (AFIs) represent a significant health burden worldwide. AFIs can be caused by infection with a number of different pathogens including dengue (DENV) and Chikungunya viruses (CHIKV), and their differential diagnosis is critical to the proper patient management. While rapid diagnostic tests (RDTs) for the detection of IgG/IgM against a single pathogen have played a significant role in enabling the rapid diagnosis in the point-of care settings, the state-of-the-art assay scheme is incompatible with the multiplex detection of IgG/IgM to more than one pathogen. In this paper, we present a novel assay scheme that uses two-color latex labels for rapid multiplex detection of IgG/IgM. Adapting this assay scheme, we show that 4-plex detection of the IgG/IgM antibodies to DENV and CHIKV is possible in 10 min by using it to correctly identify 12 different diagnostic scenarios. We also show that blue, mixed, and red colorimetric signals corresponding to IgG, IgG/IgM, and IgM positive cases, respectively, can be associated with distinct ranges of hue intensities, which could be exploited by analyzer systems in the future for making accurate, automated diagnosis. This represents the first steps toward the development of a single RDT-based system for the differential diagnosis of numerous AFIs of interest. PMID- 27490380 TI - 20(th) EuroQSAR: Understanding Chemical-Biological Interactions. PMID- 27490381 TI - GTM-Based QSAR Models and Their Applicability Domains. AB - In this paper we demonstrate that Generative Topographic Mapping (GTM), a machine learning method traditionally used for data visualisation, can be efficiently applied to QSAR modelling using probability distribution functions (PDF) computed in the latent 2-dimensional space. Several different scenarios of the activity assessment were considered: (i) the "activity landscape" approach based on direct use of PDF, (ii) QSAR models involving GTM-generated on descriptors derived from PDF, and, (iii) the k-Nearest Neighbours approach in 2D latent space. Benchmarking calculations were performed on five different datasets: stability constants of metal cations Ca(2+) , Gd(3+) and Lu(3+) complexes with organic ligands in water, aqueous solubility and activity of thrombin inhibitors. It has been shown that the performance of GTM-based regression models is similar to that obtained with some popular machine-learning methods (random forest, k-NN, M5P regression tree and PLS) and ISIDA fragment descriptors. By comparing GTM activity landscapes built both on predicted and experimental activities, we may visually assess the model's performance and identify the areas in the chemical space corresponding to reliable predictions. The applicability domain used in this work is based on data likelihood. Its application has significantly improved the model performances for 4 out of 5 datasets. PMID- 27490382 TI - Prediction of PARP Inhibition with Proteochemometric Modelling and Conformal Prediction. AB - Poly(ADP-ribose) polymerases (PARPs) play a key role in DNA damage repair. PARP inhibitors act as chemo- and radio- sensitizers and thus potentiate the cytotoxicity of DNA damaging agents. Although PARP inhibitors are currently investigated as chemotherapeutic agents, their cross-reactivity with other members of the PARP family remains unclear. Here, we apply Proteochemometric Modelling (PCM) to model the activity of 181 compounds on 12 human PARPs. We demonstrate that PCM (R0 (2) test =0.65-0.69; RMSEtest =0.95-1.01 degrees C) displays higher performance on the test set (interpolation) than Family QSAR and Family QSAM (Tukey's HSD, alpha 0.05), and outperforms Inductive Transfer knowledge among targets (Tukey's HSD, alpha 0.05). We benchmark the predictive signal of 8 amino acid and 11 full-protein sequence descriptors, obtaining that all of them (except for SOCN) perform at the same level of statistical significance (Tukey's HSD, alpha 0.05). The extrapolation power of PCM to new compounds (RMSE=1.02+/-0.80 degrees C) and targets (RMSE=1.03+/-0.50 degrees C) is comparable to interpolation, although the extrapolation ability is not uniform across the chemical and the target space. For this reason, we also provide confidence intervals calculated with conformal prediction. In addition, we present the R package conformal, which permits the calculation of confidence intervals for regression and classification caret models. PMID- 27490383 TI - Data Mining and Machine Learning Tools for Combinatorial Material Science of All Oxide Photovoltaic Cells. AB - Growth in energy demands, coupled with the need for clean energy, are likely to make solar cells an important part of future energy resources. In particular, cells entirely made of metal oxides (MOs) have the potential to provide clean and affordable energy if their power conversion efficiencies are improved. Such improvements require the development of new MOs which could benefit from combining combinatorial material sciences for producing solar cells libraries with data mining tools to direct synthesis efforts. In this work we developed a data mining workflow and applied it to the analysis of two recently reported solar cell libraries based on Titanium and Copper oxides. Our results demonstrate that QSAR models with good prediction statistics for multiple solar cells properties could be developed and that these models highlight important factors affecting these properties in accord with experimental findings. The resulting models are therefore suitable for designing better solar cells. PMID- 27490384 TI - An Ab Initio Method for Designing Multi-Target Specific Pharmacophores using Complementary Interaction Field of Aspartic Proteases. AB - For past few decades, key objectives of rational drug discovery have been the designing of specific and selective ligands for target proteins. Infectious diseases like malaria are continuously becoming resistant to traditional medicines, which inculcates need for new approaches to design inhibitors for antimalarial targets. A novel method for ab initio designing of multi target specific pharmacophores using the interaction field maps of active sites of multiple proteins has been developed to design 'specificity' pharmacophores for aspartic proteases. The molecular interaction field grid maps of active sites of aspartic proteases (plasmepsin II & IV from Plasmodium falciparum, plasmepsin from Plasmodium vivax, pepsin & cathepsin D from human) are calculated and common pharmacophoric features for favourable binding spots in active sites are extracted in the form of cliques of graphs using inductive logic programming (ILP). The two pharmacophore ensembles are constructed from largest common cliques by imposing size of receptor active site (L) and domain-specific receptor ligand information (S). The overlap of chemical space between two ensembles and the results of virtual screening of inhibitor database with known activities show that this method can design efficient pharmacophores with no prior ligand information. PMID- 27490385 TI - Molecular Docking Study on Galantamine Derivatives as Cholinesterase Inhibitors. AB - A training set of 22 synthetic galantamine derivatives binding to acetylcholinesterase was docked by GOLD and the protocol was optimized in terms of scoring function, rigidity/flexibility of the binding site, presence/absence of a water molecule inside and radius of the binding site. A moderate correlation was found between the affinities of compounds expressed as pIC50 values and their docking scores. The optimized docking protocol was validated by an external test set of 11 natural galantamine derivatives and the correlation coefficient between the docking scores and the pIC50 values was 0.800. The derived relationship was used to analyze the interactions between galantamine derivatives and AChE. PMID- 27490386 TI - Perspectives of Halogen Bonding Description in Scoring Functions and QSAR/QSPR: Substituent Effects in Aromatic Core. AB - Halogen bonding (XB) is a new promising interaction pattern in medicinal chemistry. It has predominantly electrostatic nature - high electrostatic potential anisotropy. However to fully unleash the potential of XB in rational drug design fast and robust empirical methods of XB description should be developed. Current approaches rely heavily on ab initio calculation for each molecule studied. Thus fast prediction of electrostatic parameters for description of XB for arbitrary organic molecules is of paramount importance to promptly establish QSAR/QSPR, virtual screening and molecular docking pipelines suitable for today's agile development requirements. The two most promising approaches to describe anisotropic electrostatic models - the extra point (EP) charge model and the multipole expansion (ME) model - were studied on their ability (1) to describe ab initio molecular electrostatic potential (MEP) and (2) to produce parameters that can be predicted for each molecule empirically rather than estimated via ab initio calculations. The reference ab initio MEP was calculated for a set of 730 substituted halobenzenes. Parameters for anisotropic electrostatics of both empirical models (EP and ME) studied were extracted from ab initio MEP. The Free?Wilson and Hansch type QSPR models relating XB parameters with aromatic substituents were built and analyzed, providing the guidelines for further development. PMID- 27490387 TI - In silico Prediction of Aqueous Solubility: a Comparative Study of Local and Global Predictive Models. AB - 32 Quantitative Structure-Property Relationship (QSPR) models were constructed for prediction of aqueous intrinsic solubility of liquid and crystalline chemicals. Data sets contained 1022 liquid and 2615 crystalline compounds. Multiple Linear Regression (MLR), Support Vector Machine (SVM) and Random Forest (RF) methods were used to construct global models, and k-nearest neighbour (kNN), Arithmetic Mean Property (AMP) and Local Regression Property (LoReP) were used to construct local models. A set of the best QSPR models was obtained: for liquid chemicals with RMSE (root mean square error) of prediction in the range 0.50-0.60 log unit; for crystalline chemicals 0.80-0.90 log unit. In the case of global models the large number of descriptors makes mechanistic interpretation difficult. The local models use only one or two descriptors, so that a medicinal chemist working with sets of structurally-related chemicals can readily estimate their solubility. However, construction of stable local models requires the presence of closely related neighbours for each chemical considered. It is probable that a consensus of global and local QSPR models will be the optimal approach for construction of stable predictive QSPR models with mechanistic interpretation. PMID- 27490388 TI - In Silico Predictions of Drug - Drug Interactions Caused by CYP1A2, 2C9 and 3A4 Inhibition - a Comparative Study of Virtual Screening Performance. AB - The cytochrome P450 (CYP) superfamily represents the major enzyme class responsible for the metabolism of exogenous compounds. Investigation of clearance pathways is therefore an integral part in early drug development, as any alteration of metabolic enzymes may markedly influence the toxicological profile and efficacy of novel compounds. In silico methods are widely applied in drug development to complement experimental approaches. Several different tools are available for that purpose, however, for CYP enzymes they have only been applied retrospectively so far. Within this study, pharmacophore- and shape-based models and a docking protocol were generated for the prediction of CYP1A2, 2C9, and 3A4 inhibition. All theoretically validated models, the validated docking workflow, and additional external bioactivity profiling tools were applied independently and in parallel to predict the CYP inhibition of 29 compounds from synthetic and natural origin. After subsequent experimental assessment of the in silico predictions, we analyzed and compared the prospective performance of all methods, thereby defining the suitability of the applied techniques for CYP enzymes. We observed quite substantial differences in the performances of the applied tools, suggesting that the rational selection of that virtual screening method that proved to perform best can largely improve the success rates when it comes to CYP inhibition prediction. PMID- 27490390 TI - Peptide Binding Prediction to Five Most Frequent HLA-DQ Proteins - a Proteochemometric Approach. AB - Major histocompatibility complex (MHC) proteins class II, are glycoproteins binding within the cell to short peptides with foreign origin, called epitopes, and present them at the cell surface for inspection by T-cells. Apart from presenting foreign antigens, they are able to present also common self-antigens and trigger autoimmune diseases as coeliac disease and diabetes mellitus type 1. The MHC proteins are extremely polymorphic. The polymorphism is located mainly in the peptide binding site. In the present study, we apply a proteochemometric approach to derive a model for prediction of peptide binding to human MHC class II proteins from locus HLA-DQ. Proteochemometrics was applied on 2624 peptides binding to five most frequent HLA-DQ proteins. The sequences of peptides and proteins were described by three z-descriptors relating to hydrophobicity, steric effects and polarity of amino acids. Cross-terms accounting for the protein peptide interactions also were included. The derived model was validated by external test set of 660 peptides and showed rpred (2) =0.808, AUC=0.965, 92.5 % accuracy at threshold of pIC50 =5.3 and average sensitivity of 83 % among the top 10 % best predicted nonamers. The model is implemented in the server for MHC binding prediction EpiTOP and is freely available at http://www.ddg pharmfac.net/epitop. PMID- 27490389 TI - Pharmacophore-Based Virtual Screening to Discover New Active Compounds for Human Choline Kinase alpha1. AB - Choline kinase (CK) catalyses the transfer of the ATP gamma-phosphate to choline to generate phosphocholine and ADP in the presence of magnesium leading to the synthesis of phosphatidylcholine. Of the three isoforms of CK described in humans, only the alpha isoforms (HsCKalpha) are strongly associated with cancer and have been validated as drug targets to treat this disease. Over the years, a large number of Hemicholinium-3 (HC-3)-based HsCKalpha biscationic inhibitors have been developed though the relevant common features important for the biological function have not been defined. Here, selecting a large number of previous HC-3-based inhibitors, we discover through computational studies a pharmacophore model formed by five moieties that are included in the 1-benzyl-4 (N-methylaniline)pyridinium fragment. Using a pharmacophore-guided virtual screening, we then identified 6 molecules that showed binding affinities in the low MUM range to HsCKalpha1. Finally, protein crystallization studies suggested that one of these molecules is bound to the choline and ATP-binding sites. In conclusion, we have developed a pharmacophore model that not only allowed us to dissect the structural important features of the previous HC-3 derivatives, but also enabled the identification of novel chemical tools with good ligand efficiencies to investigate the biological functions of HsCKalpha1. PMID- 27490391 TI - Integrative Modeling Strategies for Predicting Drug Toxicities at the eTOX Project. AB - Early prediction of safety issues in drug development is at the same time highly desirable and highly challenging. Recent advances emphasize the importance of understanding the whole chain of causal events leading to observable toxic outcomes. Here we describe an integrative modeling strategy based on these ideas that guided the design of eTOXsys, the prediction system used by the eTOX project. Essentially, eTOXsys consists of a central server that marshals requests to a collection of independent prediction models and offers a single user interface to the whole system. Every of such model lives in a self-contained virtual machine easy to maintain and install. All models produce toxicity relevant predictions on their own but the results of some can be further integrated and upgrade its scale, yielding in vivo toxicity predictions. Technical aspects related with model implementation, maintenance and documentation are also discussed here. Finally, the kind of models currently implemented in eTOXsys is illustrated presenting three example models making use of diverse methodology (3D-QSAR and decision trees, Molecular Dynamics simulations and Linear Interaction Energy theory, and fingerprint-based QSAR). PMID- 27490392 TI - Virtual Screening for HIV Protease Inhibitors Using a Novel Database Filtering Procedure. AB - A virtual screening to find novel inhibitors for HIV protease was performed on the ZINC database.1 A critical part in virtual screening and associated techniques is preliminary database filtering and size reduction and for that purpose a novel feature matrix matching procedure was used. The reduction of ~14 million available ligands to a subset of 14299 ligands was achieved with a structure based approach where the analysis of the 3D structure of the active site of the protease produced a graph with hydrogen bond donor, hydrogen bond acceptor and hydrophobic subsites represented as graph nodes. A similar treatment was also applied to the compound database content and the comparison of binding site and ligand graphs was used to preselect potentially active ligands. The resulting set was further subjected to docking. The algorithm used was able to find several novel as well as previously known and experimentally tested ligands, demonstrating the validity of the approach. PMID- 27490393 TI - The Permeability of an Artificial Membrane for Wide Range of pH in Human Gastrointestinal Tract: Experimental Measurements and Quantitative Structure?Activity Relationship. AB - In silico models for membrane permeability have been based on values measured for single pH. Depending on the diet (fasted/fed state) and part of human intestine the range of pH varies approximately from 2.4 to 8.0. This motivated to study and model the membrane permeability of chemicals considering the whole range of pH in the human intestine. For this, effective membrane permeability values were measured for 65 drugs and drug-like compounds using PAMPA method at four pHs (3, 5, 7.4, 9) over 48 h, introducing technological innovations for the time dependence measurement. The highest permeability value of a compound from four pHs was used to derive QSAR analyzing a large pool of molecular descriptors and introducing new descriptor. Using stepwise forward selection approach a significant QSAR model was derived that included only two mechanistically relevant descriptors, the logarithmic octanol-water partition coefficient and hydrogen bonding surface area. Prediction confidence of the model was blind tested with a true external validation set of 15 compounds. The resulting QSAR model shows potential to combine permeability values from various pH-s into one descriptive and predictive model for estimating maximum permeability in human gastrointestinal tract. The QSAR model and data are available through the QsarDB repository (http://dx.doi.org/10.15152/QDB.137). PMID- 27490395 TI - Welcome to JBJS Reviews! PMID- 27490396 TI - Allografts in Foot and Ankle Surgery: A Critical Analysis Review. PMID- 27490394 TI - Compounds Derived from the Bhutanese Daisy, Ajania nubigena, Demonstrate Dual Anthelmintic Activity against Schistosoma mansoni and Trichuris muris. AB - BACKGROUND: Whipworms and blood flukes combined infect almost one billion people in developing countries. Only a handful of anthelmintic drugs are currently available to treat these infections effectively; there is therefore an urgent need for new generations of anthelmintic compounds. Medicinal plants have presented as a viable source of new parasiticides. Ajania nubigena, the Bhutanese daisy, has been used in Bhutanese traditional medicine for treating various diseases and our previous studies revealed that small molecules from this plant have antimalarial properties. Encouraged by these findings, we screened four major compounds isolated from A. nubigena for their anthelmintic properties. METHODOLOGY/PRINCIPAL FINDINGS: Here we studied four major compounds derived from A. nubigena for their anthelmintic properties against the nematode whipworm Trichuris muris and the platyhelminth blood fluke Schistosoma mansoni using the xWORM assay technique. Of four compounds tested, two compounds-luteolin (3) and (3R,6R)-linalool oxide acetate (1)-showed dual anthelmintic activity against S. mansoni (IC50 range = 5.8-36.9 MUg/mL) and T. muris (IC50 range = 9.7-20.4 MUg/mL). Using scanning electron microscopy, we determined luteolin as the most efficacious compound against both parasites and additionally was found effective against the schistosomula, the infective stage of S. mansoni (IC50 = 13.3 MUg/mL). Luteolin induced tegumental damage to S. mansoni and affected the cuticle, bacillary bands and bacillary glands of T. muris. Our in vivo assessment of luteolin (3) against T. muris infection at a single oral dosing of 100 mg/kg, despite being significantly (27.6%) better than the untreated control group, was markedly weaker than mebendazole (93.1%) in reducing the worm burden in mice. CONCLUSIONS/SIGNIFICANCE: Among the four compounds tested, luteolin demonstrated the best broad-spectrum activity against two different helminths-T. muris and S. mansoni-and was effective against juvenile schistosomes, the stage that is refractory to the current gold standard drug, praziquantel. Medicinal chemistry optimisation including cytotoxicity analysis, analogue development and structure activity relationship studies are warranted and could lead to the identification of more potent chemical entities for the control of parasitic helminths of humans and animals. PMID- 27490397 TI - Measuring Value in Orthopaedic Surgery. PMID- 27490398 TI - Pitfalls, Errors, and Unintended Consequences in Musculoskeletal Oncology: How They Occur and How They Can Be Avoided. PMID- 27490399 TI - Diagnosis of Periprosthetic Infection After Shoulder Arthroplasty: A Critical Analysis Review. PMID- 27490400 TI - The decrease of consistence probability: at the crossroad of catastrophic transition of a biological system. AB - BACKGROUND: Unlike traditional detection of a disease state in which there are clear phenomena, it is usually a challenge to identify the pre-disease state during the progression of a complex disease just before the serious deterioration, not only because of the high complexity of the biological system, but there may be few clues and apparent changes appearing until the catastrophic critical transition occurs. RESULTS: In this work, by exploiting the different dynamical features between the normal and pre-disease states, we present a hidden Markov-model (HMM) based computational method to identify the pre-disease state and elucidate the essential mechanisms during the critical transition at the network level. Specifically, by considering the network variation and regarding that the pre-disease state is the end or shift-point of a stationary Markov process, a consistence score is proposed to measure the probability that a system is in consistency with the normal state. As validation, this approach is applied to detect the upcoming critical transition of complex systems based on both the dataset generated from a simulated network and the rich information provided by high-throughput microarray data. The effectiveness of our method has been demonstrated by the identification of the pre-disease states for two real datasets including HCV-induced hepatocellular carcinoma and virus-induced influenza infection. CONCLUSION: From dynamical view point, the critical transition phenomena in many biological processes are of some generic properties, which can be detected by the established method. PMID- 27490401 TI - Understanding Diffusion in Hierarchical Zeolites with House-of-Cards Nanosheets. AB - Introducing mesoporosity to conventional microporous sorbents or catalysts is often proposed as a solution to enhance their mass transport rates. Here, we show that diffusion in these hierarchical materials is more complex and exhibits non monotonic dependence on sorbate loading. Our atomistic simulations of n-hexane in a model system containing microporous nanosheets and mesopore channels indicate that diffusivity can be smaller than in a conventional zeolite with the same micropore structure, and this observation holds true even if we confine the analysis to molecules completely inside the microporous nanosheets. Only at high sorbate loadings or elevated temperatures, when the mesopores begin to be sufficiently populated, does the overall diffusion in the hierarchical material exceed that in conventional microporous zeolites. Our model system is free of structural defects, such as pore blocking or surface disorder, that are typically invoked to explain slower-than-expected diffusion phenomena in experimental measurements. Examination of free energy profiles and visualization of molecular diffusion pathways demonstrates that the large free energy cost (mostly enthalpic in origin) for escaping from the microporous region into the mesopores leads to more tortuous diffusion paths and causes this unusual transport behavior in hierarchical nanoporous materials. This knowledge allows us to re-examine zero length-column chromatography data and show that these experimental measurements are consistent with the simulation data when the crystallite size instead of the nanosheet thickness is used for the nominal diffusional length. PMID- 27490403 TI - Mimickers of Cervical Radiculopathy. PMID- 27490402 TI - New laparoscopic approach to the pudendal nerve for neuromodulation based on an anatomic study. AB - AIMS: The aim was to develop a new laparoscopic technique for placement of a pudendal lead. METHODS: Development of a direct, feasible and reliable minimal invasive laparoscopic approach to the pudendal nerve (PN). Thirty-one embalmed human specimens were dissected for the relevant anatomic structures of the pelvis. Step-by-step documentation and analysis of the laparoscopic approach in order to locate the PN directly in its course around the medial part of the sacrospinous ligament and test this approach for feasibility. Landmarks for intraoperative navigation towards the PN as well as the possible position of an lead were selected and demonstrated. RESULTS: The visible medial umbilical fold, the intrapelvine part of the internal pudendal artery, the coccygeus muscle and the sacrospinous ligament are the main landmarks. The PN traverses the medial part of the sacrospinous ligament dorsally, medially to the internal pudendal artery. The medial part of the sacrospinous ligament has to be exposed in order to display the nerve. An lead can be placed ventrally on the nerve or around it, depending on the lead type or shape. CONCLUSIONS: A precise and reliable identification of the PN by means of laparoscopy is feasible with an easy four step approach: (1) identification of the medial umbilical fold; (2) identification of the internal iliac artery; (3) identification of the internal pudendal artery and incision of the coccygeus muscle ('white line', arcuated line); and (4) exposition of the medial part of the sacrospinous ligament to display the PN. PMID- 27490404 TI - Elbow Injuries in the Throwing Athlete. PMID- 27490405 TI - The Evaluation and Treatment of Polyostotic Lesions. PMID- 27490406 TI - Orthopaedic Graduate Medical Education: A Changing Paradigm. PMID- 27490407 TI - QuickStats: Percentage* of Preterm Births(?) Among Teens Aged 15-19 Years, by Race/Ethnicity - National Vital Statistics System, United States, 2007-2014(S). AB - During 2007-2014, the percentage of births among teens aged 15-19 years that were preterm declined for each racial/ethnic group, except for non-Hispanic Asian or Pacific Islander teens, where the change was not significant. In 2014, the percentage of births that were preterm was higher among non-Hispanic black and non-Hispanic Asian or Pacific Islander teens (10.6% for both) than non-Hispanic white (8.6%), non-Hispanic American Indian or Alaska Native (8.2%), and Hispanic (7.9%) teens. PMID- 27490408 TI - "Quitting like a Turk:" How political priority developed for tobacco control in Turkey. AB - In recent years, tobacco control emerged as a political priority in Turkey and today the country is widely regarded as one of the global leaders in tackling tobacco use. Although political priority is considered a facilitating factor to the success of addressing public health issues, there is a paucity of research to help us understand how it is developed in middle-income countries. The primary aim of this study is to understand the process and determinants of how tobacco control became a political priority in Turkey using the Multiple Streams Framework. A mixed-methods case study approach was used whereby data were gathered from three different sources: in-depth interviews (N = 19), document reviews (N = 216), and online self-administered surveys (N = 61). Qualitative data were collected for the purpose of understanding the processes and determinants that led to political prioritization of tobacco control and were analyzed using deductive and inductive coding. Quantitative data were collected to examine the actors and were analyzed using descriptive statistics and network nominations. Data were triangulated. Findings revealed that tobacco control achieved political priority in Turkey as a result of the development and convergence of multiple streams, including a fourth, separate global stream. Findings also shed light on the importance of Turkey's foreign policy in the transformation of the political stream. The country's desire for European Union accession and global visibility helped generate a political environment that was receptive to global norms for tobacco control. A diverse but cohesive network of actors joined forces with global allies to capitalize on this opportunity. Results suggest (1) the importance of global-agenda setting activities on political priority development, (2) the utility of aligning public health and foreign policy goals and (3) the need to build a strong global incentive structure to help entice governments to take action on public health issues. PMID- 27490410 TI - Islet Transplantation Provides Superior Glycemic Control With Less Hypoglycemia Compared With Continuous Subcutaneous Insulin Infusion or Multiple Daily Insulin Injections. AB - BACKGROUND: The aim was to compare efficacy of multiple daily injections (MDI), continuous subcutaneous insulin infusion (CSII) and islet transplantation to reduce hypoglycemia and glycemic variability in type 1 diabetes subjects with severe hypoglycemia. METHODS: This was a within-subject, paired comparison of MDI and CSII and CSII with 12 months postislet transplantation in 10 type 1 diabetes subjects referred with severe hypoglycemia, suitable for islet transplantation. Individuals were assessed with HbA1c, Edmonton Hypoglycemia Score (HYPOscore), continuous glucose monitoring (CGM) and in 8 subjects measurements of glucose variability using standard deviation of glucose (SD glucose) from CGM and continuous overlapping net glycemic action using a 4 hour interval (CONGA4). RESULTS: After changing from MDI to CSII before transplantation, 10 subjects reduced median HYPOscore from 2028 to 1085 (P < 0.05) and hypoglycemia events from 24 to 8 per patient-year (P < 0.05). While HbA1c, mean glucose and median percent time hypoglycemic on CGM were unchanged with CSII, SD glucose and CONGA4 reduced significantly (P < 0.05). At 12 months posttransplant 9 of 10 were C peptide positive, (5 insulin independent). Twelve months postislet transplantation, there were significant reductions in all baseline parameters versus CSII, respectively, HbA1c (6.4% cf 8.2%), median HYPOscore (0 cf 1085), mean glucose (7.1 cf 8.6 mmol L), SD glucose (1.7 cf 3.2 mmol/L), and CONGA4 (1.6 cf 3.0). CONCLUSIONS: In subjects with severe hypoglycemia suitable for islet transplantation, CSII decreased hypoglycemia frequency and glycemic variability compared with MDI whereas islet transplantation resolved hypoglycemia and further improved glycemic variability regardless of insulin independence. PMID- 27490411 TI - Predicting Outcomes on the Liver Transplant Waiting List in the United States: Accounting for Large Regional Variation in Organ Availability and Priority Allocation Points. AB - BACKGROUND: The probability of liver transplant and death on the waiting list in the United States varies greatly by donation service area (DSA) due to geographic differences in availability of organs and allocation of priority points, making it difficult for providers to predict likely outcomes after listing. We aimed to develop an online calculator to report outcomes by region and patient characteristics. METHODS: Using the Scientific Registry of Transplant Recipients database, we included all prevalent US adults aged 18 years or older waitlisted for liver transplant, examined on 24 days at least 30 days apart over a 2-year period. Outcomes were determined at intervals of 30 to 365 days. Outcomes are reported by transplant program, DSA, region, and the nation for comparison, and can be shown by allocation or by laboratory model for end-stage liver disease (MELD) score (6-14, 15-24, 25-29, 30-34, 35-40), age, and blood type. RESULTS: Outcomes varied greatly by DSA; for candidates with allocation MELD 25-29, the 25th and 75th percentiles of liver transplant probability were 30% and 67%, respectively, at 90 days. Corresponding percentiles for death or becoming too sick to undergo transplant were 5% and 9%. Outcomes also varied greatly for candidates with and without MELD exception points. CONCLUSIONS: The waitlist outcome calculator highlights ongoing disparities in access to liver transplant and may assist providers in understanding and counseling their patients about likely outcomes on the waiting list. PMID- 27490412 TI - Successful Renal Transplantation of Deceased Donor Kidneys With 100% Glomerular Fibrin Thrombi and Acute Renal Failure Due to Disseminated Intravascular Coagulation. AB - BACKGROUND: Disseminated intravascular coagulation (DIC)-positive kidneys have historically been turned down for fear of poor outcomes. Higher severity injuries, which are prone to DIC, are typically seen in younger, otherwise healthy potential donors. The continued kidney allograft shortage has generated interest in the use of these DIC-positive grafts. There have been some reports of acceptable outcomes of renal transplantation using kidneys from donors with DIC. There are multiple clinical series demonstrating good outcomes from DIC-positive kidneys when the extent of glomeruli containing fibrin thrombi is less than 50% and donor renal function is preserved. These grafts are frequently associated with a period of delayed graft function. METHODS: We report 2 transplants with kidneys from brain dead donors with known DIC. RESULTS: Both donors had renal failure and pretransplant renal biopsies showing 100% of the glomeruli containing fibrin thrombi. The recipients experienced delayed graft function requiring hemodialysis which was discontinued on postoperative days 18 and 39 for cases 1 and 2, respectively. Both patients are now over 14 months posttransplant with stable allograft function. CONCLUSIONS: Until clearer organ selection criteria are established, caution should be exercised when considering the use of kidneys with a similar phenotype and allocation decisions made by a multidisciplinary transplant team on a case-by-case basis. PMID- 27490409 TI - Impact of Immune-Modulatory Drugs on Regulatory T Cell. AB - Immunosuppression strategies that selectively inhibit effector T cells while preserving and even enhancing CD4FOXP3 regulatory T cells (Treg) permit immune self-regulation and may allow minimization of immunosuppression and associated toxicities. Many immunosuppressive drugs were developed before the identity and function of Treg were appreciated. A good understanding of the interactions between Treg and immunosuppressive agents will be valuable to the effective design of more tolerable immunosuppression regimens. This review will discuss preclinical and clinical evidence regarding the influence of current and emerging immunosuppressive drugs on Treg homeostasis, stability, and function as a guideline for the selection and development of Treg-friendly immunosuppressive regimens. PMID- 27490413 TI - Clinical and Economic Consequences of Early Cancer After Kidney Transplantation in Contemporary Practice. AB - BACKGROUND: Current clinical and economic consequences of cancer after kidney transplantation are incompletely defined. METHODS: We examined United States Renal Data System records of Medicare-insured kidney transplant recipients in 2000 to 2011 to determine clinical and economic impacts of cancer diagnosed within the first 3 years posttransplantation. Cancer diagnoses were identified using Medicare billing codes and categorized as nonmelanoma skin cancer (NMSC), viral-linked and "other" cancers. Associations of cancers with mortality and graft loss were estimated by time-varying Cox regression. Impacts of cancer diagnoses on inpatient and outpatient costs within each year were quantified by multivariate linear regression modeling. RESULTS: Among 67 157 recipients, by 3 years posttransplant, NMSC was diagnosed in 5.7%, viral-linked cancer in 1.9%, and "other" cancers in 6.3%. Viral-linked cancer was associated with more than 3 fold increased risk in subsequent mortality until the third transplant anniversary, and nearly twice the mortality risk after year 3. "Other" cancers had similar associations with death and graft loss, whereas NMSC was associated with 33% higher mortality beyond the third year posttransplant. Viral-linked cancer had the largest inpatient and outpatient cost impacts per case, followed by "other" cancer, whereas NMSC impacted only outpatient costs. Care of new cancer diagnoses was generally more costly than care of previously established diagnoses. Cancer accounted for 3% to 5.5% of total inpatient Medicare expenditures and 1.5% to 3.3% of outpatient expenditures in the first 3 years posttransplant. CONCLUSIONS: Early posttransplant malignancy is an expensive and morbid condition that warrants attention in efforts to improve pretransplant screening and management protocols before and after transplant. PMID- 27490414 TI - Utility of Applying Quality Assessment Tools for Kidneys With KDPI >=80. AB - BACKGROUND: Kidneys with "high" Kidney Donor Profile Index (KDPI) are often biopsied and pumped, yet frequently discarded. METHODS: In this multicenter study, we describe the characteristics and outcomes of kidneys with KDPI of 80 or greater that were procured from 338 deceased donors. We excluded donors with anatomical kidney abnormalities. RESULTS: Donors were categorized by the number of kidneys discarded: (1) none (n = 154, 46%), (2) 1 discarded and 1 transplanted (n = 48, 14%), (3) both discarded (n = 136, 40%). Donors in group 3 were older, more often white, and had higher terminal creatinine and KDPI than group 1 (all P < 0.05). Biopsy was performed in 92% of all kidneys, and 47% were pumped. Discard was associated with biopsy findings and first hour renal resistance. Kidney injury biomarker levels (neutrophil gelatinase-associated lipocalin, IL-18, and kidney injury molecule-1 measured from donor urine at procurement and from perfusate soon after pump perfusion) were not different between groups. There was no significant difference in 1-year estimated glomerular filtration rate or graft failure between groups 1 and 2 (41.5 +/- 18 vs 41.4 +/- 22 mL/min per 1.73 m; P = 0.97 and 9% vs 10%; P = 0.76). CONCLUSIONS: Kidneys with KDPI of 80 or greater comprise the most resource consuming fraction of our donor kidney pool and have the highest rates of discard. Our data suggest that some discarded kidneys with KDPI of 80 or greater are viable; however, current tools and urine and perfusate biomarkers to identify these viable kidneys are not satisfactory. We need better methods to assess viability of kidneys with high KDPI. PMID- 27490417 TI - Prevalence and Clinical Impact of Donor-Specific Alloantibody Among Intestinal Transplant Recipients. AB - BACKGROUND: Rejection remains the leading cause of allograft loss, and a major barrier to improving long-term outcomes after intestinal transplantation. Our aim is to define the prevalence and investigate the role of donor-specific antibody (DSA) on intestinal graft outcomes. METHODS: The study includes 109 transplants performed in 95 recipients at a single center. Patients were screened for DSA pretransplant, monitored regularly posttransplant and when clinically indicated using the single-antigen bead Luminex assay. Standard induction immunosuppression was with interleukin-2 receptor antagonists, and antithymocyte globulin in high risk recipients. Maintenance regimens were tacrolimus-based. RESULTS: Pretransplant DSA was detected in 12 (11%) recipients with 50% continuing to have circulating antibodies posttransplant. An additional 24 (25%) patients developed de novo DSA, and of these, 71% had persistent antibodies. Recipients with preformed DSA demonstrated elevated risks of early graft failure, whereas those with de novo DSA experienced accelerated graft loss once DSA was detected, reaching a 28% failure rate within 2 years. HLA-DQ mismatch is a significant risk factor for de novo DSA emergence, whereas the persistence of antibodies is predicted by DSA strength and specificity. Although inclusion of the liver in the intestinal allograft imparts an immunological advantage against rejection-related graft loss, this protective effect was lost among recipients with persistent DSA. CONCLUSIONS: The presence of DSA is associated with inferior graft outcomes among intestinal transplant recipients. An enhanced understanding of the mechanisms by which DSA causes allograft injury, and effective strategies targeting humoral immune reactivity are needed to improve long-term intestinal graft outcomes. PMID- 27490416 TI - Proangiogenic Function of T Cells in Corneal Transplantation. AB - BACKGROUND: Corneal neovascularization increases the risk of T cell-mediated allograft rejection. Here, we investigate whether T cells promote angiogenesis in transplantation. METHODS: Conventional effector T cells were collected from draining lymph nodes of allogeneic or syngeneic corneal transplanted BALB/c mice. T cells were either cocultured with vascular endothelial cells (VECs) to assess VEC proliferation or used in a mixed lymphocyte reaction assay. Messenger RNA (mRNA) expression of vascular endothelial growth factor (VEGF)-A, -C, and VEGF receptor 2 (VEGF-R2) in VECs was assessed by real-time PCR. VEGF-A protein expression was determined by enzyme-linked immunosorbent assay. Flow cytometry was used to analyze VEGF-R2 expression in corneal CD31 cells, and VEGF-A and IFNgamma expression in corneal CD4 T cells. RESULTS: Allogeneic T cells from high risk (HR) grafted mice induced more VEC proliferation than those from syngeneic transplant recipients (P = 0.03). Vascular endothelial growth factor-A mRNA and protein expression were higher in T cells from draining lymph nodes (P = 0.03 and P = 0.04, respectively) and cornea (protein; P = 0.04) of HR compared with low risk (LR) grafted hosts. Vascular endothelial growth factor-A, VEGF-C, and VEGF R2 mRNA expression were increased in VECs when cocultured with T cells from HR transplants compared with LR transplants and naive mice. In addition, IFNgamma blockade in T cell/VEC coculture increased VEC proliferation and VEGF-A protein expression, whereas blocking VEGF-A significantly reduced VEC proliferation (P = 0.04). CONCLUSIONS: Allogeneic T cells from corneal transplant hosts promote VEC proliferation, probably via VEGF-A signaling, whereas IFNgamma shows an antiangiogenic effect. Our data suggest that T cells are critical mediators of angiogenesis in transplantation. PMID- 27490418 TI - Wound Healing Complications in Kidney Transplant Recipients Receiving Everolimus. AB - BACKGROUND: De novo use of mammalian target of rapamycin inhibitors after kidney transplantation is associated with a concentration-dependent incidence of wound healing adverse events (WHAE). The objective of this analysis was to compare the incidence of WHAE in patients receiving everolimus (EVR) or mycophenolate sodium (MPS). METHODS: This was a predefined subanalysis of a single-center prospective randomized study in which 288 kidney transplant recipients receiving tacrolimus and prednisone were randomized for 3 different regimens: rabbit antithymocyte globulin (r-ATG)/EVR (N = 85); basiliximab (BAS)/EVR (N = 102); BAS/MPS (N = 101). Clinical WHAE were prospectively collected using a prespecified case report form in all study visits. Abdominal ultrasound was performed at 30 days posttransplant to capture subclinical abnormalities. Surgeons were blinded to randomized treatment and no specific surgical procedures were implemented. RESULTS: A higher proportion of patients in BAS/EVR showed at least 1 clinical WHAE (22.3% vs 35.3% vs 22.0%, P = 0.03) and total clinical and subclinical WHAE (35% vs 42% vs 26%, P = 0.014) compared with BAS/MPS, respectively. A higher proportion of patients in r-ATG/EVR showed subclinical WHAE (13% vs 7% vs 4%, P = 0.025) compared with BAS/MPS, respectively. Patients receiving EVR showed a higher risk of developing clinical or subclinical WHAE (r-ATG/EVR vs BAS/MPS hazard ratio 1.30; BAS/EVR vs BAS/MPS hazard ratio 1.73, P = 0.028). CONCLUSIONS: In this cohort of de novo kidney transplant recipients receiving tacrolimus and prednisone, the use of EVR was associated with higher incidence of combined clinical and subclinical WHAE compared with MPS. PMID- 27490419 TI - Increased Risk of Death for Patients on the Waitlist for Liver Transplant Residing at Greater Distance From Specialized Liver Transplant Centers in the United States. AB - BACKGROUND: We have previously shown that patients listed for orthotopic liver transplantation (OLT) in United Network for Organ Sharing Region 4 (Texas and Oklahoma) have higher waitlist mortality rates when residing more than 30 miles from specialized liver transplant centers (LTC). Considering that findings might only be exclusive for this region with its peculiarities in terms of having the highest land surface extensions, lowest population densities, and largest rural populations. We investigated the entire OLT patient population in the United States to assess if our previous regional findings are nationally validated and if a rural, micropolitan, or metropolitan residence location affects outcome of waitlisted OLT patients in the nation. METHODS: Patients waiting for OLT in the United States from 2002 to 2012 were stratified by distance from the patients' residence to LTC and by Rural Urban Commuting Area (RUCA) codes classification. Statistical analyses were performed to evaluate risk of mortality on the waitlist and the likelihood to receive an OLT using a Cox proportional hazards model and a generalized additive model with a logistic link. RESULTS: Survival time and probability of death while on the waitlist for OLT using distance to LTC showed significant increased risk with the distance (P = 0.001 and P < 0.0001, respectively). At the same time, using RUCA classification as the variable did not show significance (P = 0.14 and P = 0.73, respectively). CONCLUSIONS: Distance from an LTC is a risk factor of mortality on the waitlist for OLT, whereas RUCA classification is not a significant factor. PMID- 27490420 TI - Owning Up to Negative Ingroup Traits: How Personal Autonomy Promotes the Integration of Group Identity. AB - OBJECTIVE: Our experiences, attributes, and behaviors are diverse, inconsistent, and often negative. Consequently, our capacity to assimilate divergent experiences-particularly negative aspects-is important to the development of a unified self. Whereas this process of integration has received attention at the level of personal identity, it has not been assessed at the level of group identity. OBJECTIVE: We examined the mechanisms involved in integrating positive and negative ingroup identities, as well as related outcomes. METHOD: In three experiments, participants (N = 332) high and low in autonomy identified either positive or negative aspects of their ingroup and then indicated the extent to which they integrated the attribute. RESULTS: Those high in personal autonomy integrated both positive and negative identities, whereas those low in autonomy acknowledged only positive identities. Study 2 showed that, regardless of identity valence, those high in autonomy felt satisfied and close with their group. Conversely, those low in autonomy felt less close and more dissatisfied with their group after reflecting on negative identities. Finally, reflecting on a negative identity reduced prejudice, but only for those high in autonomy. CONCLUSIONS: Owning up to negative group traits is facilitated by autonomy and demonstrates benefits for ingroup and intergroup processes. PMID- 27490421 TI - Perception of occlusion by young infants: Must the occlusion event be congruent with the occluder? AB - Four-month-old infants perceive continuity of an object's trajectory through occlusion, even when the occluder is illusory, and several cues are apparently needed for young infants to perceive a veridical occlusion event. In this paper we investigated the effects of dislocating the spatial relation between the occlusion events and the visible edges of the occluder. In two experiments testing 60 participants, we demonstrated that 4-month-olds do not perceive continuity of an object's trajectory across an occlusion if the deletion and accretion events are spatially displaced relative to the occluder edges (Experiment 1) or if deletion and accretion occur along a linear boundary that is incorrectly oriented relative to the occluder's edges (Experiment 2). Thus congruence of these cues is apparently important for perception of veridical occlusion. These results are discussed in relation to an account of the development of perception of occlusion and object persistence. PMID- 27490422 TI - Ion Dynamics in a Mixed-Cation Alkoxy-Ammonium Ionic Liquid Electrolyte for Sodium Device Applications. AB - The ion dynamics in a novel sodium-containing room-temperature ionic liquid (IL) consisting of an ether-functionalised quaternary ammonium cation and bis(trifluoromethylsulfonyl)amide [NTf2 ] anion with various concentrations of Na[NTf2 ] have been characterised using differential scanning calorimetry, impedance spectroscopy, diffusometry and NMR relaxation measurements. The IL studied has been specifically designed to dissolve a relatively large concentration of Na[NTf2 ] salt (over 2 mol kg-1 ) as this has been shown to improve ion transport and conductivity. Consistent with other studies, the measured ionic conductivity and diffusion coefficients show that the overall ionic mobility decreases with decreasing temperature and increasing salt content. NMR relaxation measurements provide evidence for correlated dynamics between the ether-functionalised ammonium and Na cations, possibly with the latter species acting as cross-links between multiple ammonium cations. Finally, preliminary cyclic voltammetry experiments show that this IL can undergo stable electrochemical cycling and could therefore be potentially useful as an electrolyte in a Na-based device. PMID- 27490423 TI - Editorial Comment. PMID- 27490424 TI - Reply by Authors. PMID- 27490425 TI - Perioperative Hearing Evaluations for Patients Undergoing Tympanostomy Tube Placement. AB - Importance: Obtaining hearing thresholds is an important step in the evaluation of a child with otitis media because decreased hearing in the presence of a chronic middle ear effusion factors into the decision to place tympanostomy tubes (TTs). Objective: To provide evidence regarding appropriate use of perioperative hearing evaluations in conjunction with TTs. Design, Setting, and Participants: Case series with medical record review of all patients aged 0 to 24 years who received TTs at a tertiary pediatric care facility from June 1, 2010, through June 1, 2011. Medical records were abstracted by 1 researcher for surgical, audiometric, tympanometric, clinical, and patient demographic data. The data analysis was performed between December 1, 2014, and June 1, 2015. Main Outcomes and Measures: Audiometric data were examined to determine the number of patients with hearing loss preoperatively and postoperatively, with the intention to describe the population with no prior hypothesis regarding results. Results: Of 2274 patients identified, 910 (40.0%) were female. Median (interquartile range) age at TT placement was 2.62 (1.48-4.94) years. A total of 1757 (77.3%) underwent audiometric evaluation preoperatively, 1742 (76.6%) postoperatively, and 1395 (61.3%) both preoperatively and postoperatively; 170 (7.5%) had no audiometric testing. Within 1 year after surgery, 271 (11.9%) of patients had evidence of nonfunctional tubes. Postoperatively, 19.9% (347 of the 1742 patients who received a postoperative evaluation) had hearing loss. In all, 89 (3.9%) patients had a permanent sensorineural hearing loss, and 15 (0.66%) had a persistent conductive hearing loss. Conclusions and Relevance: A postoperative audiometric examination should be performed in children who have hearing loss when evaluated before TT placement to determine whether resolution of the hearing loss was obtained. PMID- 27490426 TI - Understanding spinal cord compression. PMID- 27490429 TI - How to encourage trial reporting. PMID- 27490427 TI - Prevalence of Sleep-Disordered Breathing and Patient Characteristics in a Coronary Artery Disease Cohort Undergoing Cardiovascular Rehabilitation. AB - PURPOSE: Coronary artery disease (CAD) is a leading cause of death and identification of risk factors for CAD is crucial. One such potential risk factor is sleep-disordered breathing (SDB). This prospective cohort study investigated the prevalence of SDB and determined risk factors for the presence of SDB in a large CAD cohort undergoing cardiac rehabilitation. METHODS: A total of 1425 patients with confirmed CAD starting rehabilitation were screened for SDB using cardiorespiratory polygraphy (n = 921) or polygraphy plus pulse oximetry (n = 484). RESULTS: A total of 1408 patients were included; 69.5% were male, 78% had acute coronary syndrome, and 22% had stable CAD. The prevalence of SDB (apnea hypopnea index [AHI] >=5/h) was 83%. Moderate to severe SDB (AHI >=15/h) was present in 53%. Up to 70% of coronary artery bypass graft (CABG) recipients had an AHI >=15/h versus 33% of those who had not undergone CABG. SDB severity did not vary significantly in patients with stable CAD or on the basis of left ventricular ejection fraction. SDB was more severe and the frequency of oxygen desaturation was higher in men than in women. Multivariate logistic regression identified age, sex, body mass index, and CABG as independent risk factors for severe SDB. CONCLUSION: SDB is a highly prevalent comorbidity in patients with CAD, particularly those who have undergone CABG. These results strengthen existing associations and emphasize the importance of diagnosing and monitoring SDB in patients with CAD entering a cardiac rehabilitation program. Early diagnosis and intervention has the potential to have a beneficial effect on CAD prognosis. PMID- 27490430 TI - A second look: Efforts to repurpose old drugs against Zika cast a wide net. PMID- 27490431 TI - Networking for resistance detection: FDA and CDC build repository of drug resistant microbes. PMID- 27490432 TI - Disease drivers: Global consortia aim to unpack genetics of diabetes and obesity. PMID- 27490434 TI - CBLB ubiquitin ligase: a major regulator of antifungal immunity. PMID- 27490433 TI - Understanding human immune function using the resources from the Human Functional Genomics Project. PMID- 27490435 TI - The brain's reward circuitry regulates immunity. PMID- 27490436 TI - The role of muscle stem cell-niche interactions during aging. PMID- 27490437 TI - Corrigendum: Nod2-mediated recognition of the microbiota is critical for mucosal adjuvant activity of cholera toxin. PMID- 27490438 TI - New Methodology for Known Metabolite Identification in Metabonomics/Metabolomics: Topological Metabolite Identification Carbon Efficiency (tMICE). AB - A new, simple-to-implement and quantitative approach to assessing the confidence in NMR-based identification of known metabolites is introduced. The approach is based on a topological analysis of metabolite identification information available from NMR spectroscopy studies and is a development of the metabolite identification carbon efficiency (MICE) method. New topological metabolite identification indices are introduced, analyzed, and proposed for general use, including topological metabolite identification carbon efficiency (tMICE). Because known metabolite identification is one of the key bottlenecks in either NMR-spectroscopy- or mass spectrometry-based metabonomics/metabolomics studies, and given the fact that there is no current consensus on how to assess metabolite identification confidence, it is hoped that these new approaches and the topological indices will find utility. PMID- 27490439 TI - Informing climate models with rapid chamber measurements of forest carbon uptake. AB - Models predicting ecosystem carbon dioxide (CO2 ) exchange under future climate change rely on relatively few real-world tests of their assumptions and outputs. Here, we demonstrate a rapid and cost-effective method to estimate CO2 exchange from intact vegetation patches under varying atmospheric CO2 concentrations. We find that net ecosystem CO2 uptake (NEE) in a boreal forest rose linearly by 4.7 +/- 0.2% of the current ambient rate for every 10 ppm CO2 increase, with no detectable influence of foliar biomass, season, or nitrogen (N) fertilization. The lack of any clear short-term NEE response to fertilization in such an N limited system is inconsistent with the instantaneous downregulation of photosynthesis formalized in many global models. Incorporating an alternative mechanism with considerable empirical support - diversion of excess carbon to storage compounds - into an existing earth system model brings the model output into closer agreement with our field measurements. A global simulation incorporating this modified model reduces a long-standing mismatch between the modeled and observed seasonal amplitude of atmospheric CO2 . Wider application of this chamber approach would provide critical data needed to further improve modeled projections of biosphere-atmosphere CO2 exchange in a changing climate. PMID- 27490440 TI - Cerium(III) Complex Modified Gold Electrode: An Efficient Electrocatalyst for the Oxygen Evolution Reaction. AB - Exploring efficient and inexpensive electrocatalysts for the oxidation of water is of great importance for various electrochemical energy storage and conversion technologies. In the present study, a new water-soluble [Ce(III)(DMF) (HSO4)3] complex was synthesized and characterized by UV-vis, photoluminescence, and high resolution X-ray photoelectron spectroscopy techniques. Owing to classic 5d -> 4f transitions, an intense photoluminescence in the UV region was observed from the water-soluble [Ce(III)(DMF) (HSO4)3] complex. A stacking electrode was designed where self-assembled l-cysteine monolayer modified gold was immobilized with the synthesized cerium complex and was characterized by scanning electron microscopy, electrochemical impedance spectroscopy, and cyclic voltammetry. The resulting electrode, i.e., [Ce(III)(DMF) (HSO4)3]-l-cysteine-Au stacks shows high electrocatalytic water oxidation behavior at an overpotential of eta ~ 0.34 V under neutral pH conditions. We also demonstrated a way where the overpotential is possible to decrease upon irradiation of UV light. PMID- 27490441 TI - Genetic diversity and association analysis of leafminer (Liriomyza langei) resistance in spinach (Spinacia oleracea). AB - Leafminer (Liriomyza langei) is a major insect pest of many important agricultural crops, including spinach (Spinacia oleracea). Use of genetic resistance is an efficient, economic, and environment-friendly method to control this pest. The objective of this research was to conduct association analysis and identify single nucleotide polymorphism (SNP) markers associated with leafminer resistance in spinach germplasm. A total of 300 USDA spinach germplasm accessions were used for the association analysis of leafminer resistance. Genotyping by sequencing (GBS) was used for genotyping and 783 SNPs from GBS were used for association analysis. The leafminer resistance showed a near normal distribution with a wide range from 1.1 to 11.7 stings per square centimeter leaf area, suggesting that the leafminer resistance in spinach is a complex trait controlled by multiple genes with minor effect in this spinach panel. Association analysis indicated that five SNP markers, AYZV02040968_7171, AYZV02076752_412, AYZV02098618_4615, AYZV02147304_383, and AYZV02271373_398, were associated with the leafminer resistance with LOD 2.5 or higher. The SNP markers may be useful for breeders to select plants and lines for leafminer resistance in spinach breeding programs through marker-assisted selection. PMID- 27490442 TI - The influence of flue gas desulphurization gypsum additive on characteristics and evolution of humic substance during co-composting of dairy manure and sugarcane pressmud. AB - For the purpose of evaluating the effect of flue gas desulphurization gypsum (FGDG) additive on characteristics and evolution of humic substance (HS) during composting, HS from composts with FGDG (CPG) and without FGDG (CP) were extracted and assessed with respect to their particle size, elemental analysis, FTIR and UV vis spectroscopy, and the molecular composition of HS was characterized via pyrolysis-GC/MS as well. The particle size of HS ranged between 300 and 600nm, representing a bimodal distribution. As composting proceeded, the C/H of HS increased, and C/N decreased. The FTIR and UV-vis spectroscopy indicated that the aromatization of HS was promoted over the composting process. Adding FGDG increased the unsaturated degree and aromatization of HS. Pyrolysis-GC/MS showed the level of alkane decreased, and the level of benzene and nitrogen compounds increased upon the addition of FGDG. The nitrogen compounds of HS in CPG was significantly higher than that in CP. PMID- 27490443 TI - A study on pyrolysis of Canada thistle (Cirsium arvense) with titania based catalysts for bio-fuel production. AB - The catalytic pyrolysis of Cirsium arvense was performed with titania supported catalysts under the operating conditions of 500 degrees C, 40 degrees C/min heating rate, 100mL/min N2 flow rate in a fixed bed reactor for biofuel production. The effect of catalysts on product yields was investigated. The amount of pyrolysis products (bio-char, bio-oil, gas) and the composition of the produced bio-oils were determined by proton nuclear magnetic resonance ((1)H NMR), Fourier transform infrared spectroscopy (FT-IR), gas chromatography/mass spectrometry (GC-MS) and elemental analysis (EA) techniques. Thistle bio-oils had lower O/C and H/C molar ratios compared to feedstock. The highest bio-char and bio-oil yields of 29.32wt% and 36.71wt% were obtained in the presence of Ce/TiO2 and Ni/TiO2 catalysts respectively. GC-MS identified 97 different compounds in the bio-oils obtained from thistle pyrolysis. (1)H NMR analysis showed that the bio-oils contained ~55-77% aliphatic and ~6-19% aromatic structural units. PMID- 27490444 TI - Current status of the influence of osteoporosis on periodontology and implant dentistry. AB - PURPOSE OF REVIEW: This review summarizes recent evidence on the impact of osteoporosis on periodontonlogy and implant dentistry, prevalence of diseases, pathophysiology and treatment outcomes. RECENT FINDINGS: Patients with osteoporosis should be advised about the importance of returning for periodical periodontal maintenance as inadequate oral care may lead to a faster development of periodontitis. There is no definitive information on the development of bisphosphonate-related osteonecrosis of the jaw associated with dental implant therapy. Patients presenting severe periodontitis, undergoing intravenous bisphosphonate therapy (for long-term periods) and submitted to more invasive periodontal/peri-implant surgical procedures (that can promote superior dentoalveolar surgical trauma) might be advised about the possibility of developing bisphosphonate-related osteonecrosis of the jaw following dental therapy. Thus, individualized risk evaluation must be undertaken by both the medical and dental teams prior to any dental treatment. SUMMARY: The most recent literature on the impact of osteoporosis on the periodontal and peri-implant tissues was reviewed to emphasize the importance of oral hygiene measures, and the combined medical/dental assessment of importance when osteoporotic patients are in need of dentoalveolar surgical procedures (e.g. tooth extraction and dental implant placement). PMID- 27490445 TI - Similarities in the Retinal Appearance of Patients With Zika Virus Compared With Cobalamin C Deficiency-Reply. PMID- 27490448 TI - Assessment of Early Treatment Response With DWI After CT-Guided Radiofrequency Ablation of Functioning Adrenal Adenomas. AB - OBJECTIVE: The objective of this study was to establish the suitability of the apparent diffusion coefficient (ADC) as a parameter for evaluating early treatment response after percutaneous ablation of functional adrenal adenomas. SUBJECTS AND METHODS: Seventeen adult patients with functioning adrenal adenomas underwent radiofrequency ablation. Serum hormone levels were analyzed before and up to 6 months after ablation. MRI findings (nodule size in cm, signal intensity index, ADC maps, and nodule-to-muscle ADC ratio) were analyzed before and up to 30 days after ablation. A consensus review of all scans was performed by two attending abdominal imaging radiologists. The procedure was considered successful if serum hormone levels normalized and no contrast enhancement of the adrenal lesion was seen on follow-up MRI. RESULTS: Of 17 patients who underwent radiofrequency ablation, complete response was achieved in 16 patients with partial response in one patient. Of the four parameters of interest, only ADC maps and nodule-to-muscle ADC ratio showed statistically significant differences (p < 0.05). CONCLUSION: This prospective study suggests that apparent diffusion coefficient values may help radiologists monitor early treatment response after CT-guided radiofrequency ablation of functioning adrenal adenomas. PMID- 27490446 TI - Imaging lymphoid tissues in nonhuman primates to understand SIV pathogenesis and persistence. AB - CD4+ T cells are the primary HIV-1 target cell, with the vast majority of these cells residing within lymphoid tissue compartments throughout the body. Predictably, HIV-1 infection, replication, localization, reservoir establishment and persistence, as well as associated host immune and inflammatory responses and disease pathology principally take place within the tissues of the immune system. By virture of the fact that the virus-host struggle is played out within lymphoid and additional tissues compartments in HIV-1 infected individuals it is critical to understand HIV-1 infection and disease within these relevant tissue sites; however, there are obvious limitations to studying these dynamic processes in humans. Nonhuman primate (NHP) research has provided a vital bridge between basic and preclinical research and clinical studies, with experimental SIV infection of NHP models offering unique opportunities to understand key processes of HIV-1 infection and disease that are either not practically feasible or ethical in HIV 1 infected humans. In this review we will discuss current approaches to studying the tissue based immunopathogenesis of AIDS virus infection in NHPs, including both analyses of tissues obtained at biopsy or necropsy and complementary non invasive imaging approaches that may have practical utility in monitoring HIV-1 disease in the clinical setting. PMID- 27490450 TI - Reducing Gender Discrepancies in Academic Radiology. PMID- 27490449 TI - A statistical assessment of pesticide pollution in surface waters using environmental monitoring data: Chlorpyrifos in Central Valley, California. AB - Pesticides are routinely monitored in surface waters and resultant data are analyzed to assess whether their uses will damage aquatic eco-systems. However, the utility of the monitoring data is limited because of the insufficiency in the temporal and spatial sampling coverage and the inability to detect and quantify trace concentrations. This study developed a novel assessment procedure that addresses those limitations by combining 1) statistical methods capable of extracting information from concentrations below changing detection limits, 2) statistical resampling techniques that account for uncertainties rooted in the non-detects and insufficient/irregular sampling coverage, and 3) multiple lines of evidence that improve confidence in the final conclusion. This procedure was demonstrated by an assessment on chlorpyrifos monitoring data in surface waters of California's Central Valley (2005-2013). We detected a significant downward trend in the concentrations, which cannot be observed by commonly-used statistical approaches. We assessed that the aquatic risk was low using a probabilistic method that works with non-detects and has the ability to differentiate indicator groups with varying sensitivity. In addition, we showed that the frequency of exceedance over ambient aquatic life water quality criteria was affected by pesticide use, precipitation and irrigation demand in certain periods anteceding the water sampling events. PMID- 27490451 TI - Synthesis of meta-Terphenyl-2,2''-diols by Anodic C-C Cross-Coupling Reactions. AB - The anodic C-C cross-coupling reaction is a versatile synthetic approach to symmetric and non-symmetric biphenols and arylated phenols. We herein present a metal-free electrosynthetic method that provides access to symmetric and non symmetric meta-terphenyl-2,2''-diols in good yields and high selectivity. Symmetric derivatives can be obtained by direct electrolysis in an undivided cell. The synthesis of non-symmetric meta-terphenyl-2,2''-diols required two electrochemical steps. The reactions are easy to conduct and scalable. The method also features a broad substrate scope, and a large variety of functional groups are tolerated. The target molecules may serve as [OCO](3-) pincer ligands. PMID- 27490452 TI - Recognition and Management of Perioperative Stroke in Hospitalized Patients. AB - We sought to characterize stroke management and outcomes in a postoperative population. By using the electronic medical records, we identified 39 patients suffering perioperative stroke after noncardiac and nonneurosurgical procedures for whom documentation of management and outcomes was available. Thirty-three strokes occurred during admission, whereas 6 occurred after discharge and were recognized upon return to the hospital. Perioperative stroke was associated with delayed recognition, infrequent intervention, and significant rates of morbidity and mortality, suggesting the need for improved screening and more rapid treatment. There may be disparities in care and outcomes between in-hospital and out-of hospital stroke patients, though further study is warranted. PMID- 27490455 TI - Cellular uptake and anticancer activity of salvianolic acid B phospholipid complex loaded nanoparticles in head and neck cancer and precancer cells. AB - Salvianolic acid B (SalB) was demonstrated to be a promising chemopreventive agent for head and neck squamous cell carcinoma (HNSCC) in the previous studies by our and other research institution, but the properties like low efficacy, poor systemic delivery, and low bioavailability has hampered its clinical applications. To continue our research program focused on the use of natural compounds on cancer chemoprevention, we propose a first example of phospholipid complex loaded nanoparticles (PLC-NPs) encapsulating SalB as a potential carrier for intervention of HNSCC (HN13, HN30) cells and precancer Leuk1 cells in this study. Qualitative and quantitive studies of cellular uptake showed that intracellular accumulation of SalB was significantly higher when HN13, HN30 and Leuk1 cells were incubated with SalB-PLC-NPs complex (nano-SalB) as against free SalB. Cell viability assay revealed that the cell growth of HN13 and HN30 cells was significantly inhibited of 56.1% and 29.3%, respectively, for nano-SalB compared to an equivalent amount of free-SalB (P<0.001). Moreover, cell cycle and apoptosis assay showed that a clear trend of cell cycle arrest and induction of apoptosis was also observed within the HNSCC cells treated with nano-SalB. Collectively, this study demonstrated that nano-SalB was significantly more potent had an anticancer effect against HNSCC cells, which serves as the first step toward establishing SalB nano-formulations as promising cancer chemopreventive agents. The current study could pave a new way for the development of drugs that target HNSCC in the future. PMID- 27490454 TI - A humanized osteopontin mouse model and its application in immunometabolic obesity studies. AB - Osteopontin (OPN) is a multifunctional protein involved in several inflammatory processes and pathogeneses including obesity-related disorders and cancer. OPN binds to a variety of integrin receptors and CD44 resulting in a proinflammatory stimulus. Therefore, OPN constitutes a novel interesting target to develop new therapeutic strategies, which counteract OPN's proinflammatory properties. We established a humanized SPP1 (hSPP1) mouse model and evaluated its suitability as a model for obesity and insulin resistance. Unchallenged hSPP1 animals did not significantly differ in body weight and gross behavioral properties compared to wild-type (WT) animals. High-fat diet-challenged hSPP1 similarly developed obesity and inflammation, whereas insulin resistance was markedly changed. However, OPN expression profile in tissues was significantly altered in hSPP1 compared to WT depending on the diet. In conclusion, we developed a versatile humanized model to study the action of OPN in vivo and to develop strategies that target human OPN in a variety of pathologies. PMID- 27490453 TI - Microbiome, trimethylamine N-oxide, and cardiometabolic disease. AB - There is increasing appreciation that changes in microbiome composition and function can promote long-term susceptibility for cardiometabolic risk. Gut microbe-derived metabolites that are biologically active, such as trimethylamine N-oxide (TMAO), are now recognized as contributors to atherogenesis. This review summarizes our current understanding of the role of TMAO in the pathogenesis of cardiometabolic diseases and will discuss current findings, controversies, and further perspectives in this new area of investigation. Better appreciation of the interactions between dietary nutrient intake with gut microbiota-mediated metabolism may provide clinical insights into defining individuals at risk for disease progression in cardiometabolic diseases, as well as additional potential therapeutic targets for reducing risks for cardiometabolic disease progression. PMID- 27490456 TI - Spironolactone nanocrystals for oral administration: Different pharmacokinetic performances induced by stabilizers. AB - Nanocrystal (NC) technology is an effective strategy to enhance the oral bioavailability for poorly water-soluble drugs. Stabilizers are essential and important in NC formulations due to its ability to decrease the system energy. Studies have revealed that stabilizers can affect the particle size and stability of the system. However, whether stabilizers can affect the in vivo behaviors of the NCs is unknown. To investigate the effects of stabilizers on the in vitro and in vivo performances of NCs, four types of spironolactone (SPN) NCs with similar diameters but different stabilizers were prepared. All the NCs were spherical in shape with a size of about 370nm. In addition, the NCs were also characterized by differential scanning calorimetry, X-ray diffraction, and Raman spectroscopy, the results obtained showed that the SPN in all the formulations was partially amorphous. In fasted state simulated intestinal fluid, all the SPN-NCs showed similar dissolution profiles. However, the dissolution for SPN-NCs/NaDC was suppressed in 0.1M HCl. Importantly, the AUC(0-48h)total for SPN-NCs/F127, SPN NCs/F68, SPN-NCs/HPMC-E5, and SPN-NCs/NaDC was 4.96-, 3.91-, 2.88- and 1.72-fold higher than that of the SPN suspension, respectively. These results demonstrated that stabilizers in NCs played an important role for the in vivo pharmacokinetic behaviors. It is highly suggested that the ionic stabilizers are not suitable to stabilize drug nanocrystals alone because it may induce aggregation and agglomeration of drug crystals when transferring through the whole gastrointestinal tract and experiencing the different pH levels. PMID- 27490457 TI - A Structural Magnetic Resonance Imaging Study in Transgender Persons on Cross-Sex Hormone Therapy. AB - BACKGROUND: To date, research findings are inconsistent about whether the neuroanatomy in transgender persons resembles that of their natal sex or their gender identity. Moreover, few studies have examined the effects of long-term cross-sex hormonal treatment on neuroanatomy in this cohort. The purpose of the present study was to examine neuroanatomical differences in transgender persons after prolonged cross-sex hormone therapy. METHODS: Eighteen transgender men (female-to-male), 17 transgender women (male-to-female), 30 nontransgender men (natal men), and 27 nontransgender women (natal women) completed a high resolution structural magnetic resonance imaging scan at 3 T. Eligibility criteria for transgender persons were gender-affirming surgery and at least 2 years of cross-sex hormone therapy. Exclusion criteria for nontransgender persons were presence of psychiatric or neurological disorders. RESULTS: The mean neuroanatomical volume for the amygdala, putamen, and corpus callosum differed between transgender women and natal women but not between transgender women and natal men. Differences between transgender men and natal men were found in several brain structures, including the medial temporal lobe structures and cerebellum. Differences between transgender men and natal women were found in the medial temporal lobe, nucleus accumbens, and 3rd ventricle. Sexual dimorphism between nontransgender men and women included larger cerebellar volumes and a smaller anterior corpus callosum in natal men than in natal women. The results remained stable after correcting for additional factors including age, total intracranial volume, anxiety, and depressive symptoms. CONCLUSIONS: Neuroanatomical differences were region specific between transgender persons and their natal sex as well as their gender identity, raising the possibility of a localized influence of sex hormones on neuroanatomy. PMID- 27490459 TI - Noncovalent Dimerization after Enediyne Cyclization on Au(111). AB - We investigate the thermally induced cyclization of 1,2-bis(2 phenylethynyl)benzene on Au(111) using scanning tunneling microscopy and computer simulations. Cyclization of sterically hindered enediynes is known to proceed via two competing mechanisms in solution: a classic C(1)-C(6) (Bergman) or a C(1) C(5) cyclization pathway. On Au(111), we find that the C(1)-C(5) cyclization is suppressed and that the C(1)-C(6) cyclization yields a highly strained bicyclic olefin whose surface chemistry was hitherto unknown. The C(1)-C(6) product self assembles into discrete noncovalently bound dimers on the surface. The reaction mechanism and driving forces behind noncovalent association are discussed in light of density functional theory calculations. PMID- 27490458 TI - The roles of AtxA orthologs in virulence of anthrax-like Bacillus cereus G9241. AB - AtxA is a critical transcriptional regulator of plasmid-encoded virulence genes in Bacillus anthracis. Bacillus cereus G9241, which caused an anthrax-like infection, has two virulence plasmids, pBCXO1 and pBC210, that each harbor toxin genes and a capsule locus. G9241 also produces two orthologs of AtxA: AtxA1, encoded on pBCXO1, and AtxA2, encoded on pBC210. The amino acid sequence of AtxA1 is identical to that of AtxA from B. anthracis, while the sequences of AtxA1 and AtxA2 are 79% identical and 91% similar to one another. We found by qRT-PCR that AtxA1 and AtxA2 function as positive regulators of toxin (AtxA1) and capsule operon (both) transcription in G9241 and that a DeltaatxA1 mutant produced lower levels of the anthrax toxins and no hyaluronic acid capsule. Deletion of atxA1 or atxA2 decreased the virulence of spores administered intranasally or subcutaneously to C57BL/6 mice but not to A/J mice, and deletion of both genes rendered spores avirulent in A/J mice. In addition, unlike AtxA1, AtxA2 did not form stable homomultimers in vitro, although AtxA1 and AtxA2 formed heterodimers. Our data show that AtxA1 is the primary regulator of G9241 virulence factor expression and that AtxA1 and AtxA2 are both required for full virulence. PMID- 27490460 TI - Young Women's Contraceptive Decision Making: Do Preferences for Contraceptive Attributes Align with Method Choice? AB - CONTEXT: Understanding how women's preferences for certain attributes of contraceptive methods relate to their method choice can inform the content of contraceptive counseling. METHODS: Data from 715 women aged 18-29 who had ever used contraceptives were drawn from the 2009 National Survey of Reproductive and Contraceptive Knowledge. Chi-square tests and multivariable logistic regression analyses were used to examine how women's preferences for specific contraceptive attributes were related to their social and demographic characteristics and their current contraceptive choice. RESULTS: The majority of women considered it extremely important for a method to be very effective at preventing pregnancy (79%) and to be effective at preventing HIV and STDs (67%); fewer than one quarter felt similarly about a method's being hormone-free (22%). Women who felt it was quite or extremely important for a method to be very effective at preventing pregnancy were not more likely to use the most effective methods than were women who considered this attribute not at all or only slightly important. Women who considered it quite or extremely important for a method to be hormone free were less likely than others to use hormonal methods (odds ratio, 0.4), and women who considered STD protection quite or extremely important had elevated odds of relying on condoms alone, rather than on an effective contraceptive method alone (3.6). CONCLUSIONS: Most women desire a very effective method for pregnancy prevention, but it is unclear how this translates to their contraceptive use. The associations between women's preferred contraceptive attributes and method choice warrant further attention. PMID- 27490462 TI - Impact Factors and Prediction of Popular Topics in a Journal. AB - The impact factor (IF) for 2015 was recently released and this could be the time to once again reflect on its use as a metric of a journal. Problems and concerns regarding the IF have been addressed extensively elsewhere 1 2. The principle of the IF for a given year is that it represents the average number of citations of articles published in the journal in the two previous years.While authors frequently cite the IF as a determining factor for submission, the IF does not predict how many times individual articles will be cited. In a study from a peer reviewed cardiovascular journal, nearly half of all published articles were poorly cited, i. e., less than five citations in five years 3. A similar percentage seems to apply to our journal. In nearly all journals we estimate that the majority of citations relate to a minority of the articles. Some articles are never cited. 13 % of the articles published in our journal from 2010 to 2013 have never been cited. Even authors of poorly cited articles benefit from the IF since many institutions use the combined impact factors of their published papers to measure research activity and this may be reflected in their research budgets.The competition for the printed pages in the six annual issues of Ultraschall in der Medizin/European Journal of Ultrasound (UiM/EJU) has resulted in high rejection rates (between 80 % and 90 %). One negative review with recommendation of major revision may therefore result in rejection. Peer-review fraud where the submitting author listed recommended reviewers with fake email addresses supplying fabricated peer reviews has recently been described in the New England Journal of Medicine 4. Some of the editors of our journal believe they have experienced this as well. Fabricating reviews in order to get a high IF for an article is to be considered fraud and is inexcusable.One aspect of using impact factors as a measure of the quality of a journal is that the IF only goes back two years. There may be differences between journals for different medical specialties since the citations in some areas seem to "burn out" within a few years while some articles continue to be cited even after several years. Therefore, a citation window that is longer than 2 years has been proposed 5.For this editorial we took a look at the 60 articles published in UiM/EJU in 2010. Half of them were no longer being cited in 2015. However, 10 articles were cited more than 5 times in 2015, and 5 of these were cited more than 10 times 6 7 8 9 10. It therefore seems that many of our articles have a long scientific life and generate more citations than indicated by the IF. Moreover, some articles have the highest number of citations after three years when they are no longer contributing to the impact factor. The most frequently cited articles from 2010 were multicenter studies, recommendations, and papers on hot topics like contrast enhanced ultrasound (CEUS) and elastography, but it should be noted that there were also articles on the same topics that were poorly cited.The same trending topics continued into 2013 now topped by European guidelines and recommendations 11 12 13. 9 of the 10 most cited articles we published in 2014 were on CEUS or elastography 14 15 16 17 18 19 20 21 22, but the most cited article from that year so far has been on peripheral nerves 23. Surprisingly many good scientific papers on obstetrics/fetal US and musculoskeletal US have low citation rates 24 25 26. Our predictions for 2016 based on the topics of submitted articles in the last 12 months are that CEUS and elastography will continue to be popular topics.It is also worth mentioning that there can be a discrepancy between which titles are cited and which are accessed online. In addition to international guidelines, our CME articles are usually popular according to online access. CME articles are well established educational papers but they are rarely cited for the IF. Looking at the most read full-text recent articles on our journal's website shows that multicenter studies as well as recommendations backed by a national society or by the EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology) are still important 27 28 29 30 31 32 33. Upcoming important topics appear to be pediatric use of CEUS, simulation training and the introduction of ultrasound to medical students 34 35 36 37. Some of these are also backed by EFSUMB.A recent paper on the IF of radiology journals found that subspecialty radiology journals had a higher IF than general radiology journals 38. This could prove a challenge to interdisciplinary journals like ours but we take pride in continuing to cover all aspects of ultrasound in more than 15 fields.The distribution between reviews, original articles and case reports in a journal is worth addressing. An important aspect of a journal is the publication of original scientific research articles. CME articles, pictorials and letters are important for other reasons but are cited at a lower rate. The value of case reports with regard to the IF is low since they are rarely cited 39 and we have observed that some journals have abandoned the publication of case reports, thus leaving them to spin-off journals. The rationale is that keeping case reports in a journal will only increase the denominator, thereby decreasing the IF 39. At our journal we have seen a decline in case report submissions but still want to publish them and even put one case on the front cover of every issue. Case reports still hold an educational value 40 and are important to our readers.In conclusion, a healthy mix of original articles, CME articles, reviews and case reports combined with a few international guidelines and recommendations is important to UIM/EJU. Although we see popular topics like CEUS and elastography, it is not possible to predict which articles will be read or even cited based on the topic, with multicenter studies being the exception. PMID- 27490461 TI - Dyschloremia Is a Risk Factor for the Development of Acute Kidney Injury in Critically Ill Patients. AB - INTRODUCTION: Dyschloremia is common in critically ill patients, although its impact has not been well studied. We investigated the epidemiology of dyschloremia and its associations with the incidence of acute kidney injury and other intensive care unit outcomes. MATERIAL AND METHODS: This is a single center, retrospective cohort study at Mayo Clinic Hospital-Rochester. All adult patients admitted to intensive care units from January 1st, 2006, through December 30th, 2012 were included. Patients with known acute kidney injury and chronic kidney disease stage 5 before intensive care unit admission were excluded. We evaluated the association of dyschloremia with ICU outcomes, after adjustments for the effect of age, gender, Charlson comorbidity index and severity of illness score. RESULTS: A total of 6,025 patients were enrolled in the final analysis following the implementation of eligibility criteria. From the cohort, 1,970 patients (33%) developed acute kidney injury. Of the total patients enrolled, 4,174 had a baseline serum chloride. In this group, 1,530 (37%) had hypochloremia, and 257 (6%) were hyperchloremic. The incidence of acute kidney injury was higher in hypochloremic and hyperchloremic patients compared to those with a normal serum chloride level (43% vs.30% and 34% vs. 30%, respectively; P < .001). Baseline serum chloride was lower in the acute kidney injury group vs. the non-acute kidney injury group [100 mmol/L (96-104) vs. 102 mmol/L (98-105), P < .0001]. In a multivariable logistic regression model, baseline serum chloride of <=94 mmol/L found to be independently associated with the risk of acute kidney injury (OR 1.7, 95% CI 1.1-2.6; P = .01). DISCUSSION: Dyschloremia is common in critically ill patients, and severe hypochloremia is independently associated with an increased risk of development of acute kidney injury. PMID- 27490463 TI - EFSUMB Guidelines on Interventional Ultrasound (INVUS), Part V - EUS-Guided Therapeutic Interventions (short version). AB - The fifth section of the Guidelines on Interventional Ultrasound (INVUS) of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) assesses the evidence for all the categories of endoscopic ultrasound-guided treatment reported to date. Celiac plexus neurolysis and block, vascular intervention, drainage of fluid collections, drainage of biliary and pancreatic ducts, and experimental tumor ablation techniques are discussed. For each topic, all current evidence has been extensively analyzed and summarized into major recommendations for reader consultation (short version; the long version is published online). PMID- 27490464 TI - Nachlese Dreilandertreffen 2015. PMID- 27490465 TI - Mini-breast reconstruction with an omental flap: a retrospective clinical study. AB - INTRODUCTION: Potential challenges associated with immediate small breast reconstruction include an inadequate size of the donor site, a thinner skin envelope and limited selection of implants. We present immediate postmastectomy reconstruction of small breasts with a laparoscopically harvested pedicled omental flap (LHPOF) in five Korean women. METHODS: From December 2014 to July 2015, we performed immediate postmastectomy reconstruction with an LHPOF in five breast cancer patients. Data on the patients' age; body mass index; tumour size; site, type and weight of the mastectomy specimen; operative time; hospital stay; complications; postoperative chemotherapy or radiation therapy; and follow-up duration were reviewed in this retrospective clinical study. RESULTS: The mean mastectomy specimen weight was 212 g (range: 104-272 g). The mean operative time was 298 min (range: 240-380 min), and the mean harvesting time was 75 min (range: 65-90 min). There were no flap-related complications such as fat necrosis or flap loss and no donor site-related complications such as bowel dysfunction, an epigastric bulge or hernia during the follow-up period (average: 8.2 months, range: 5-11 months). The cosmetic results were satisfactory. DISCUSSION: The LHPOF can be useful for immediate postmastectomy reconstruction of small breasts, because it provides a soft and naturally ptotic appearance of the reconstructed breast (versus implant-based reconstruction) with low donor-site morbidity (versus other autologous tissue reconstruction approaches). PMID- 27490466 TI - Bis-Boron Compounds in Catalysis: Bidentate and Bifunctional Activation. AB - The development of metal-free catalysts as an alternative to the use of transition metals has gained tremendous interest in the past. In catalysis, Lewis acidity is one of the major principles used for the activation of organic compounds. Improving the reactivity and selectivity of Lewis acids by utilizing bidentate interactions was already proposed 50 years ago. Nevertheless, product inhibition due to strong binding has made applications of bidentate Lewis acids challenging for many years. Recently, bis-boron compounds have been found to be very effective and several applications in Diels-Alder reactions, carbon dioxide reduction, and ammonia-borane dehydrogenation were reported. All three transformations are enabled by the catalyst at different stages during the course of the reaction. These new and useful examples illustrate the great potential of the concept. PMID- 27490467 TI - HER-2 and EGFR mRNA Expression and Its Relationship with Versican in Malignant Matrix-Producing Tumors of the Canine Mammary Gland. AB - Versican expression promotes tumor growth by destabilizing focal cell contacts, thus impeding cell adhesion and facilitating cell migration. It not only presents or recruits molecules to the cell surface, but also modulates gene expression levels and coordinates complex signal pathways. Previously, we suggested that the interaction between versican and human epidermal growth factor receptors may be directly associated with tumor aggressiveness. Thus, the expression of EGFR and HER-2 in these neoplasms may contribute to a better understanding of the progression mechanisms in malignant mammary tumors. The purpose of this study was to correlate the gene and protein expressions of EGFR and HER2 by RNA In Situ Hybridization (ISH) and immunohistochemistry (IHC), respectively, and their relationship with the versican expression in carcinomas in mixed tumors and carcinosarcomas of the canine mammary gland. The results revealed that EGFR mRNA expression showed a significant difference between in situ and invasive carcinomatous areas in low and high versican expression groups. Identical results were observed in HER-2 mRNA expression. In immunohistochemistry analysis, neoplasms with low versican expression showed greater EGFR immunostaining in the in situ areas than in invasive areas, even as the group presenting high versican expression displayed greater EGFR and HER-2 staining in in situ areas. Significant EGFR and HER-2 mRNA and protein expressions in in situ carcinomatous sites relative to invasive areas suggest that these molecules play a role during the early stages of tumor progression. PMID- 27490469 TI - Disability Divides in India: Evidence from the 2011 Census. AB - BACKGROUND: Understanding the socioeconomic and regional divides in disability prevalence in India has considerable relevance for designing public health policies and programs. OBJECTIVES: The aim of the present study is to quantify the prevalence of disability by gender, region (rural and urban; states and districts), and caste. We also examine the association between disability prevalence and the major socio-demographic and socioeconomic characteristics of the districts in India. METHODS: Age-standardized disability prevalence (ASDP) was calculated using 2011 census data and applying the WHO World Standard Population. A regression analysis was carried out to examine the association between disability prevalence and demographic and socioeconomic characteristics across districts of India. RESULTS: The study found that ASDP varies substantially across districts and is higher among women, rural dwellers, and members of scheduled tribes (STs) and scheduled castes (SCs). The regression model showed that the disability rate in districts rises with increasing proportions of the population who are urban dwellers, aged 65 or older, members of STs, and living in dilapidated housing; and that the disability prevalence decreases with increasing proportions of the female population who are literate, and of the general population who are working and have access to safe drinking water. CONCLUSION: As the burden of disability falls disproportionately across geographic regions and socioeconomic groups, public health policies in India should take this variation into account. The definition of disability used in the census should be modified to generate internationally comparable estimates of disability prevalence. PMID- 27490468 TI - Bleeding Risk with Long-Term Low-Dose Aspirin: A Systematic Review of Observational Studies. AB - BACKGROUND: Low-dose aspirin has proven effectiveness in secondary and primary prevention of cardiovascular events, but is also associated with an increased risk of major bleeding events. For primary prevention, this absolute risk must be carefully weighed against the benefits of aspirin; such assessments are currently limited by a lack of data from general populations. METHODS: Systematic searches of Medline and Embase were conducted to identify observational studies published between 1946 and 4 March 2015 that reported the risks of gastrointestinal (GI) bleeding or intracranial hemorrhage (ICH) with long-term, low-dose aspirin (75 325 mg/day). Pooled estimates of the relative risk (RR) for bleeding events with aspirin versus non-use were calculated using random-effects models, based on reported estimates of RR (including odds ratios, hazard ratios, incidence rate ratios and standardized incidence ratios) in 39 articles. FINDINGS: The incidence of GI bleeding with low-dose aspirin was 0.48-3.64 cases per 1000 person-years, and the overall pooled estimate of the RR with low-dose aspirin was 1.4 (95% confidence interval [CI]: 1.2-1.7). For upper and lower GI bleeding, the RRs with low-dose aspirin were 2.3 (2.0-2.6) and 1.8 (1.1-3.0), respectively. Neither aspirin dose nor duration of use had consistent effects on RRs for upper GI bleeding. The estimated RR for ICH with low-dose aspirin was 1.4 (1.2-1.7) overall. Aspirin was associated with increased bleeding risks when combined with non-steroidal anti-inflammatory drugs, clopidogrel and selective serotonin reuptake inhibitors compared with monotherapy. By contrast, concomitant use of proton pump inhibitors decreased upper GI bleeding risks relative to aspirin monotherapy. CONCLUSIONS: The risks of major bleeding with low-dose aspirin in real-world settings are of a similar magnitude to those reported in randomized trials. These data will help inform clinical judgements regarding the use of low dose aspirin in prevention of cardiovascular events. PMID- 27490471 TI - Erratum. PMID- 27490472 TI - Posterior Shoulder Instability in Athletes. PMID- 27490470 TI - Effective Cellular Morphology Analysis for Differentiation Processes by a Fluorescent 1,3a,6a-Triazapentalene Derivative Probe in Live Cells. AB - Nuclear and cytoplasmic morphological changes provide important information about cell differentiation processes, cell functions, and signal responses. There is a strong desire to develop a rapid and simple method for visualizing cytoplasmic and nuclear morphology. Here, we developed a novel and rapid method for probing cellular morphological changes of live cell differentiation process by a fluorescent probe, TAP-4PH, a 1,3a,6a-triazapentalene derivative. TAP-4PH showed high fluorescence in cytoplasmic area, and visualized cytoplasmic and nuclear morphological changes of live cells during differentiation. We demonstrated that TAP-4PH visualized dendritic axon and spine formation in neuronal differentiation, and nuclear structural changes during neutrophilic differentiation. We also showed that the utility of TAP-4PH for visualization of cytoplasmic and nuclear morphologies of various type of live cells. Our visualizing method has no toxicity and no influence on the cellular differentiation and function. The cell morphology can be rapidly observed after addition of TAP-4PH and can continue to be observed in the presence of TAP-4PH in cell culture medium. Moreover, TAP-4PH can be easily removed after observation by washing for subsequent biological assay. Taken together, these results demonstrate that our visualization method is a powerful tool to probe differentiation processes before subsequent biological assay in live cells. PMID- 27490473 TI - Skeletal Repair in Distraction Osteogenesis: Mechanisms and Enhancements. PMID- 27490474 TI - Arthroscopic Treatment of Pincer-Type Impingement of the Hip. PMID- 27490475 TI - Advances in Pediatric Limb Lengthening: Part 1. PMID- 27490476 TI - Editorial for the Special Issue on Photocatalysis. PMID- 27490477 TI - Impact of Health System Inputs on Health Outcome: A Multilevel Longitudinal Analysis of Botswana National Antiretroviral Program (2002-2013). AB - OBJECTIVE: To measure the association between the number of doctors, nurses and hospital beds per 10,000 people and individual HIV-infected patient outcomes in Botswana. DESIGN: Analysis of routinely collected longitudinal data from 97,627 patients who received ART through the Botswana National HIV/AIDS Treatment Program across all 24 health districts from 2002 to 2013. Doctors, nurses, and hospital bed density data at district-level were collected from various sources. METHODS: A multilevel, longitudinal analysis method was used to analyze the data at both patient- and district-level simultaneously to measure the impact of the health system input at district-level on probability of death or loss-to-follow up (LTFU) at the individual level. A marginal structural model was used to account for LTFU over time. RESULTS: Increasing doctor density from one doctor to two doctors per 10,000 population decreased the predicted probability of death for each patient by 27%. Nurse density changes from 20 nurses to 25 nurses decreased the predicted probability of death by 28%. Nine percent decrease was noted in predicted mortality of an individual in the Masa program for every five hospital bed density increase. CONCLUSION: Considerable variation was observed in doctors, nurses, and hospital bed density across health districts. Predictive margins of mortality and LTFU were inversely correlated with doctor, nurse and hospital bed density. The doctor density had much greater impact than nurse or bed density on mortality or LTFU of individual patients. While long-term investment in training more healthcare professionals should be made, redistribution of available doctors and nurses can be a feasible solution in the short term. PMID- 27490478 TI - Inhibition of Pancreatic Cancer Cell-Induced Paracrine Hedgehog Signaling by Liver X Receptor Agonists and Oxy16, a Naturally Occurring Oxysterol. AB - The widespread involvement of the Hedgehog (Hh) signaling pathway in human malignancies has driven efforts to develop Hh pathway inhibitors as anti-cancer agents. The majority of these agents antagonize Smoothened (Smo), a plasma membrane-associated signal transducer molecule. However, several such Smo antagonists have failed in clinical trials to benefit patients with cancers that arise from aberrant Hh signaling (which often bypasses Smo). In this study, we report that a naturally occurring oxysterol, 20alpha, 22(R)-dihydroxycholesterol (Oxy16), a known metabolite in the biosynthesis of steroid hormones, strongly inhibits Hh signaling induced in C3H10T1/2 embryonic fibroblasts and NIH3T3-E1 fibroblasts through a mechanism that is independent of liver X receptor (LXR) activation. We demonstrate that Oxy16 inhibits Hh signaling in Suppressor of Fused (Sufu) null mouse embryonic fibroblast (MEF) cells, indicating that its inhibitory effect on Hh signaling is epistatic to Sufu. We further demonstrate that Oxy16 inhibits Gli1 transcriptional activity in NIH3T3-E1 cells overexpressing Gli1 and a Gli-dependent reporter construct. Altogether, data presented here suggest that Oxy16 may be a suitable starting point for the development of new drugs that inhibit Hh signaling downstream of Smo. By targeting aberrant Hh signaling, such novel Hh pathway inhibitors could significantly broaden the range of clinical applications compared to existing Smo antagonists. Furthermore, the present study adds a new facet to the spectrum of Hh pathway modulation that naturally occurring oxysterol derivatives are capable of, ranging from allosteric activation of the pathway via Smo binding to inhibition of the pathway downstream of Smo. J. Cell. Biochem. 118: 499-509, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27490479 TI - Structure of the ent-Copalyl Diphosphate Synthase PtmT2 from Streptomyces platensis CB00739, a Bacterial Type II Diterpene Synthase. AB - Terpenoids are the largest and most structurally diverse family of natural products found in nature, yet their presence in bacteria is underappreciated. The carbon skeletons of terpenoids are generated through carbocation-dependent cyclization cascades catalyzed by terpene synthases (TSs). Type I and type II TSs initiate cyclization via diphosphate ionization and protonation, respectively, and protein structures of both types are known. Most plant diterpene synthases (DTSs) possess three alpha-helical domains (alphabetagamma), which are thought to have arisen from the fusion of discrete, ancestral bacterial type I TSs (alpha) and type II TSs (betagamma). Type II DTSs of bacterial origin, of which there are no structurally characterized members, are a missing piece in the structural evolution of TSs. Here, we report the first crystal structure of a type II DTS from bacteria. PtmT2 from Streptomyces platensis CB00739 was verified as an ent copalyl diphosphate synthase involved in the biosynthesis of platensimycin and platencin. The crystal structure of PtmT2 was solved at a resolution of 1.80 A, and docking studies suggest the catalytically active conformation of geranylgeranyl diphosphate (GGPP). Site-directed mutagenesis confirmed residues involved in binding the diphosphate moiety of GGPP and identified DxxxxE as a potential Mg(2+)-binding motif for type II DTSs of bacterial origin. Finally, both the shape and physicochemical properties of the active sites are responsible for determining specific catalytic outcomes of TSs. The structure of PtmT2 fundamentally advances the knowledge of bacterial TSs, their mechanisms, and their role in the evolution of TSs. PMID- 27490480 TI - Nutrition Screening Tools and the Prediction of Clinical Outcomes among Chinese Hospitalized Gastrointestinal Disease Patients. AB - Nutrition risk Screening 2002 (NRS-2002) and Subjective Global Assessment (SGA) are widely used screening tools but have not been compared in a Chinese population. We conducted secondary data analysis of a cross-sectional study which included 332 hospitalized gastrointestinal disease patients, collected by the Gastrointestinal department of Peking Union Medical College Hospital (PUMCH) in 2008. Results of NRS-2002 and SGA screening tools, complications, length of stay (LOS), cost, and death were measured. The agreement between the tools was assessed via Kappa (kappa) statistics. The performance of NRS-2002 and SGA in predicting LOS and cost was assessed via linear regression. The complications and death prediction of tools was assessed using receiver operating characteristic (ROC) curves. NRS-2002 and SGA identified nutrition risk at 59.0% and 45.2% respectively. Moderate agreement (kappa >0.50) between the two tools was found among all age groups except individuals aged <= 20, which only slight agreement was found (kappa = 0.087). NRS-2002 (R square 0.130) and SGA (R square 0.140) did not perform differently in LOS prediction. The cost prediction of NRS-2002 (R square 0.198) and SGA (R square 0.190) were not significantly different. There was no difference between NRS-2002 (infectious complications: area under ROC (AUROC) = 0.615, death: AUROC = 0.810) and SGA (infectious complications: AUROC = 0.600, death: AUROC = 0.846) in predicting infectious complication and death, but NRS-2002 (0.738) seemed to perform better than SGA (0.552) in predicting non infectious complications. The risk of malnutrition among patients was high. NRS 2002 and SGA have similar capacity to predict LOS, cost, infectious complications and death, but NRS-2002 performed better in predicting non-infectious complications. PMID- 27490481 TI - Distinct roles of visual, parietal, and frontal motor cortices in memory-guided sensorimotor decisions. AB - Mapping specific sensory features to future motor actions is a crucial capability of mammalian nervous systems. We investigated the role of visual (V1), posterior parietal (PPC), and frontal motor (fMC) cortices for sensorimotor mapping in mice during performance of a memory-guided visual discrimination task. Large-scale calcium imaging revealed that V1, PPC, and fMC neurons exhibited heterogeneous responses spanning all task epochs (stimulus, delay, response). Population analyses demonstrated unique encoding of stimulus identity and behavioral choice information across regions, with V1 encoding stimulus, fMC encoding choice even early in the trial, and PPC multiplexing the two variables. Optogenetic inhibition during behavior revealed that all regions were necessary during the stimulus epoch, but only fMC was required during the delay and response epochs. Stimulus identity can thus be rapidly transformed into behavioral choice, requiring V1, PPC, and fMC during the transformation period, but only fMC for maintaining the choice in memory prior to execution. PMID- 27490483 TI - Structures of TorsinA and its disease-mutant complexed with an activator reveal the molecular basis for primary dystonia. AB - The most common cause of early onset primary dystonia, a neuromuscular disease, is a glutamate deletion (DeltaE) at position 302/303 of TorsinA, a AAA+ ATPase that resides in the endoplasmic reticulum. While the function of TorsinA remains elusive, the DeltaE mutation is known to diminish binding of two TorsinA ATPase activators: lamina-associated protein 1 (LAP1) and its paralog, luminal domain like LAP1 (LULL1). Using a nanobody as a crystallization chaperone, we obtained a 1.4 A crystal structure of human TorsinA in complex with LULL1. This nanobody likewise stabilized the weakened TorsinADeltaE-LULL1 interaction, which enabled us to solve its structure at 1.4 A also. A comparison of these structures shows, in atomic detail, the subtle differences in activator interactions that separate the healthy from the diseased state. This information may provide a structural platform for drug development, as a small molecule that rescues TorsinADeltaE could serve as a cure for primary dystonia. PMID- 27490482 TI - MYC activation and BCL2L11 silencing by a tumour virus through the large-scale reconfiguration of enhancer-promoter hubs. AB - Lymphomagenesis in the presence of deregulated MYC requires suppression of MYC driven apoptosis, often through downregulation of the pro-apoptotic BCL2L11 gene (Bim). Transcription factors (EBNAs) encoded by the lymphoma-associated Epstein Barr virus (EBV) activate MYC and silence BCL2L11. We show that the EBNA2 transactivator activates multiple MYC enhancers and reconfigures the MYC locus to increase upstream and decrease downstream enhancer-promoter interactions. EBNA2 recruits the BRG1 ATPase of the SWI/SNF remodeller to MYC enhancers and BRG1 is required for enhancer-promoter interactions in EBV-infected cells. At BCL2L11, we identify a haematopoietic enhancer hub that is inactivated by the EBV repressors EBNA3A and EBNA3C through recruitment of the H3K27 methyltransferase EZH2. Reversal of enhancer inactivation using an EZH2 inhibitor upregulates BCL2L11 and induces apoptosis. EBV therefore drives lymphomagenesis by hijacking long-range enhancer hubs and specific cellular co-factors. EBV-driven MYC enhancer activation may contribute to the genesis and localisation of MYC-Immunoglobulin translocation breakpoints in Burkitt's lymphoma. PMID- 27490484 TI - The selectivity of the Na(+)/K(+)-pump is controlled by binding site protonation and self-correcting occlusion. AB - The Na(+)/K(+)-pump maintains the physiological K(+) and Na(+) electrochemical gradients across the cell membrane. It operates via an 'alternating-access' mechanism, making iterative transitions between inward-facing (E1) and outward facing (E2) conformations. Although the general features of the transport cycle are known, the detailed physicochemical factors governing the binding site selectivity remain mysterious. Free energy molecular dynamics simulations show that the ion binding sites switch their binding specificity in E1 and E2. This is accompanied by small structural arrangements and changes in protonation states of the coordinating residues. Additional computations on structural models of the intermediate states along the conformational transition pathway reveal that the free energy barrier toward the occlusion step is considerably increased when the wrong type of ion is loaded into the binding pocket, prohibiting the pump cycle from proceeding forward. This self-correcting mechanism strengthens the overall transport selectivity and protects the stoichiometry of the pump cycle. PMID- 27490485 TI - Functional Translational Readthrough: A Systems Biology Perspective. AB - Translational readthrough (TR) has come into renewed focus because systems biology approaches have identified the first human genes undergoing functional translational readthrough (FTR). FTR creates functional extensions to proteins by continuing translation of the mRNA downstream of the stop codon. Here we review recent developments in TR research with a focus on the identification of FTR in humans and the systems biology methods that have spurred these discoveries. PMID- 27490486 TI - In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano graphene oxide. AB - Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ~120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. (64)Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of (64)Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates ((64)Cu-NOTA GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers with satisfactory drug loading capacity (e.g. for doxorubicin [DOX], 756 mg/g). Enhanced drug delivery efficiency in cbgLuc-MDA-MB-231 metastatic sites was demonstrated in DOX-loaded GO-FSHR-mAb by fluorescence imaging. This FSHR-targeted, GO-based nanoplatform can serve as a useful tool for early metastasis detection and targeted delivery of therapeutics. PMID- 27490487 TI - Predicting Molecular Crowding Effects in Ion-RNA Interactions. AB - We develop a new statistical mechanical model to predict the molecular crowding effects in ion-RNA interactions. By considering discrete distributions of the crowders, the model can treat the main crowder-induced effects, such as the competition with ions for RNA binding, changes of electrostatic interaction due to crowder-induced changes in the dielectric environment, and changes in the nonpolar hydration state of the crowder-RNA system. To enhance the computational efficiency, we sample the crowder distribution using a hybrid approach: For crowders in the close vicinity of RNA surface, we sample their discrete distributions; for crowders in the bulk solvent away from the RNA surface, we use a continuous mean-field distribution for the crowders. Moreover, using the tightly bound ion (TBI) model, we account for ion fluctuation and correlation effects in the calculation for ion-RNA interactions. Applications of the model to a variety of simple RNA structures such as RNA helices show a crowder-induced increase in free energy and decrease in ion binding. Such crowding effects tend to contribute to the destabilization of RNA structure. Further analysis indicates that these effects are associated with the crowder-ion competition in RNA binding and the effective decrease in the dielectric constant. This simple ion effect model may serve as a useful framework for modeling more realistic crowders with larger, more complex RNA structures. PMID- 27490488 TI - IMAGING DIAGNOSIS-MAGNETIC RESONANCE IMAGING FEATURES OF A MULTIFOCAL OLIGODENDROGLIOMA IN THE SPINAL CORD AND BRAIN OF A DOG. AB - An 8-year-old neutered male Toy Poodle was presented with chronic, progressive tetraparesis, and possible seizures. Magnetic resonance images demonstrated an extensive, T1 and T2 hyperintense contrast enhancing mass in the cervical spinal cord. Three nodules were present on the surface of the thalamus, with enhancement most evident on delayed images. A diagnosis of high-grade oligodendroglioma was confirmed with postmortem histopathology and immunohistochemical labeling. Oligodendroglioma should be considered as a differential for T1 hyperintense intraaxial or intramedullary lesions with contrast enhancement. If enhancement is not visualized on postcontrast images, delayed images may be beneficial. PMID- 27490489 TI - Binuclear Complexes and Extended Chains Featuring Pt(II)-Tl(I) Bonds: Influence of the Pyridine-2-Thiolate and Cyclometalated Ligands on the Self-Assembly and Luminescent Behavior. AB - Platinum solvate complexes [Pt(C6F5)(C^N)(S)] [C^N = phenylpyridinyl (ppy), S = dimethyl sulfoxide (DMSO) (A); C^N = benzoquinolinyl (bzq), S = CH3COCH3 (B)] react with [Tl(Spy)] (Spy = 2-pyridinethiolate) to afford binuclear [{Pt(C6F5)(C^N)}Tl(Spy)] [C^N = ppy (1) and bzq (2)] species containing a Pt-Tl bonding interaction, supported by a MU-Spy-kappaN,S bridging ligand, as confirmed by X-ray diffraction. However, the related reactions with [Tl(SpyCF3-5)] [SpyCF3 5 = 5-(trifluoromethyl)-2-pyridinethiolate] give neutral extended chains [{Pt(C6F5)(C^N)}Tl(SpyCF3-5)]n [C^N = ppy (3) and bzq (4)]. 3 features a zigzag Pt-Tl...S-Pt- chain, generated by Pt-Tl and Tl...S bonds, with the SpyCF3 acting as a MU-kappaN:kappa(2)S bridging ligand, whereas 4 displays an unsupported ...Tl Pt...Tl-Pt... backbone (angle of ca. 158.7 degrees ). The lowest-energy absorption bands in the UV-vis spectra in CH2Cl2, associated with (1)L'LCT transitions with minor (1)LC/(1)MLCT (L' = Spy or SpyCF3-5; L = C^N) character, are similar for all complexes 1-4, demonstrating that for 3 and 4 the chains break down in solution to yield similar bimetallic Pt-Tl units. For 2, two different forms, 2-o (orange) and 2-y (yellow), exhibiting different colors and emissions were found depending on the isolation conditions. Slow crystallization favors formation of the thermodynamically more stable yellow form (2-y), which exhibits a high-energy (HE) structured emission band, whereas fast crystallization gives rise to the orange form (2-o), with a remarkably lower energy structureless emission. Complexes 1 and 3 exhibit dual luminescence in the solid state at 298 K: an unstructured low-energy band associated with (3)pipi* excimeric emission due to pi...pi (C^N) interactions and a more structured HE band, assigned, with support of density functional theory calculations, to an intraligand (3)LC (C^N) excited state mixed with some ligand (SPy)/platinum-to ligand (C^N)(3)[(L' + M)LCT] charge transfer. Chain 4 only shows a HE band at 298 K, attributed to a (3)L'LCT (SpyCF3 -> bzq) excited state mixed with a minor (3)MLCT/(3)MM'CT (M = Pt; M' = Tl) contribution. At 77 K, the pipi*-stacking emission is predominant in all complexes, except in the form 2-y. Interestingly, 2-4 exhibit reversible mechanochromic color and luminescence changes, with remarkable red shift and increased quantum yields, and upon exposure to solvents, they are restored to their original color and emission. On the basis of powder X ray diffraction studies, a plausible mechanism of the mechanochromic processes is proposed, involving reversible crystalline-to-amorphous phase transitions. PMID- 27490490 TI - Lollipops in the Clinic: Information Dense Mutation Plots for Precision Medicine. AB - INTRODUCTION: Concise visualization is critical to present large amounts of information in a minimal space that can be interpreted quickly. Clinical applications in precision medicine present an important use case due to the time dependent nature of the interpretations, although visualization is increasingly necessary across the life sciences. In this paper we describe the Lollipops software for the presentation of panel or exome sequencing results. Source code and binaries are freely available at https://github.com/pbnjay/lollipops. Although other software and web resources exist to produce lollipop diagrams, these packages are less suited to clinical applications. The demands of precision medicine require the ability to easily fit into a workflow and incorporate external information without manual intervention. RESULTS: The Lollipops software provides a simple command line interface that only requires an official gene symbol and mutation list making it easily scriptable. External information is integrated using the publicly available Uniprot and Pfam resources. Heuristics are used to select the most informative components and condense them for a concise plot. The output is a flexible Scalable Vector Graphic (SVG) diagram that can be displayed in a web page or graphic illustration tool. CONCLUSION: The Lollipops software creates information-dense, publication-quality mutation plots for automated pipelines and high-throughput workflows in precision medicine. The automatic data integration enables clinical data security, and visualization heuristics concisely present knowledge with minimal user configuration. PMID- 27490491 TI - Mycobacterium tuberculosis DevR/DosR Dormancy Regulator Activation Mechanism: Dispensability of Phosphorylation, Cooperativity and Essentiality of alpha10 Helix. AB - DevR/DosR is a well-characterized regulator in Mycobacterium tuberculosis which is implicated in various processes ranging from dormancy/persistence to drug tolerance. DevR induces the expression of an ~48-gene dormancy regulon in response to gaseous stresses, including hypoxia. Strains of the Beijing lineage constitutively express this regulon, which may confer upon them a significant advantage, since they would be 'pre-adapted' to the environmental stresses that predominate during infection. Aerobic DevR regulon expression in laboratory manipulated overexpression strains is also reported. In both instances, the need for an inducing signal is bypassed. While a phosphorylation-mediated conformational change in DevR was proposed as the activation mechanism under hypoxia, the mechanism underlying constitutive expression is not understood. Because DevR is implicated in bacterial dormancy/persistence and is a promising drug target, it is relevant to resolve the mechanistic puzzle of hypoxic activation on one hand and constitutive expression under 'non-inducing' conditions on the other. Here, an overexpression strategy was employed to elucidate the DevR activation mechanism. Using a panel of kinase and transcription factor mutants, we establish that DevR, upon overexpression, circumvents DevS/DosT sensor kinase-mediated or small molecule phosphodonor dependent activation, and also cooperativity-mediated effects, which are key aspects of hypoxic activation mechanism. However, overexpression failed to rescue the defect of C-terminal-truncated DevR lacking the alpha10 helix, establishing the alpha10 helix as an indispensable component of DevR activation mechanism. We propose that aerobic overexpression of DevR likely increases the concentration of alpha10 helix-mediated active dimer species to above the threshold level, as during hypoxia, and enables regulon expression. This advance in the understanding of DevR activation mechanism clarifies a long standing question as to the mechanism of DevR overexpression-mediated induction of the regulon in the absence of the normal environmental cue and establishes the alpha10 helix as an universal and pivotal targeting interface for DevR inhibitor development. PMID- 27490493 TI - Psychophysiological Responses to Group Exercise Training Sessions: Does Exercise Intensity Matter? AB - Group exercise training programs were introduced as a strategy for improving health and fitness and potentially reducing dropout rates. This study examined the psychophysiological responses to group exercise training sessions. Twenty seven adults completed two group exercise training sessions of moderate and vigorous exercise intensities in a random and counterbalanced order. The %HRR and the exertional and arousal responses to vigorous session were higher than those during the moderate session (p<0.05). Consequently, the affective responses to vigorous session were less pleasant than those during moderate session (p<0.05). These results suggest that the psychophysiological responses to group exercise training sessions are intensity-dependent. From an adherence perspective, interventionists are encouraged to emphasize group exercise training sessions at a moderate intensity to maximize affective responses and to minimize exertional responses, which in turn may positively affect future exercise behavior. PMID- 27490492 TI - High Frequency and Diversity of Antimicrobial Activities Produced by Nasal Staphylococcus Strains against Bacterial Competitors. AB - The human nasal microbiota is highly variable and dynamic often enclosing major pathogens such as Staphylococcus aureus. The potential roles of bacteriocins or other mechanisms allowing certain bacterial clones to prevail in this nutrient poor habitat have hardly been studied. Of 89 nasal Staphylococcus isolates, unexpectedly, the vast majority (84%) was found to produce antimicrobial substances in particular under habitat-specific stress conditions, such as iron limitation or exposure to hydrogen peroxide. Activity spectra were generally narrow but highly variable with activities against certain nasal members of the Actinobacteria, Proteobacteria, Firmicutes, or several groups of bacteria. Staphylococcus species and many other Firmicutes were insusceptible to most of the compounds. A representative bacteriocin was identified as a nukacin-related peptide whose inactivation reduced the capacity of the producer Staphylococcus epidermidis IVK45 to limit growth of other nasal bacteria. Of note, the bacteriocin genes were found on mobile genetic elements exhibiting signs of extensive horizontal gene transfer and rearrangements. Thus, continuously evolving bacteriocins appear to govern bacterial competition in the human nose and specific bacteriocins may become important agents for eradication of notorious opportunistic pathogens from human microbiota. PMID- 27490494 TI - Adaptive local learning in sampling based motion planning for protein folding. AB - BACKGROUND: Simulating protein folding motions is an important problem in computational biology. Motion planning algorithms, such as Probabilistic Roadmap Methods, have been successful in modeling the folding landscape. Probabilistic Roadmap Methods and variants contain several phases (i.e., sampling, connection, and path extraction). Most of the time is spent in the connection phase and selecting which variant to employ is a difficult task. Global machine learning has been applied to the connection phase but is inefficient in situations with varying topology, such as those typical of folding landscapes. RESULTS: We develop a local learning algorithm that exploits the past performance of methods within the neighborhood of the current connection attempts as a basis for learning. It is sensitive not only to different types of landscapes but also to differing regions in the landscape itself, removing the need to explicitly partition the landscape. We perform experiments on 23 proteins of varying secondary structure makeup with 52-114 residues. We compare the success rate when using our methods and other methods. We demonstrate a clear need for learning (i.e., only learning methods were able to validate against all available experimental data) and show that local learning is superior to global learning producing, in many cases, significantly higher quality results than the other methods. CONCLUSIONS: We present an algorithm that uses local learning to select appropriate connection methods in the context of roadmap construction for protein folding. Our method removes the burden of deciding which method to use, leverages the strengths of the individual input methods, and it is extendable to include other future connection methods. PMID- 27490495 TI - Development and validation of a prognostic nomogram for acute-on-chronic hepatitis B liver failure. AB - BACKGROUND AND AIM: Determining individual risk of short-term mortality in patients with acute-on-chronic hepatitis B liver failure (ACHBLF) is a difficult task. We aimed to develop and externally validate a prognostic nomogram for ACHBLF patients. METHODS: The nomogram was built to estimate the probability of 30-day, 60-day, 90-day, and 60-month survival based on an internal cohort of 246 patients with ACHBLF. The predictive accuracy and discriminative ability of nomogram were determined by a concordance index (C-index), calibration curve, and time-dependent receiver operating characteristics (tdROC), comparing with model for end-stage liver disease (MELD) score. The results were validated using bootstrap resampling and an external cohort of 138 patients. Furthermore, we plotted decision curves to evaluate the clinical usefulness of nomogram. RESULTS: Independent factors derived from multivariable Cox analysis of training cohort to predict mortality were age, total bilirubin, serum sodium, and prothrombin activity, which were all assembled into nomogram. The calibration curves for probability of survival showed optimal agreement between nomogram prediction and actual observation. The C-index of nomogram was higher than that of MELD score for predicting survival (30-day, 0.809 vs 0.717, P < 0.001; 60-day, 0.792 vs 0.685, P < 0.001; 90-day, 0.779 vs 0.678, P < 0.001; 6-month, 0.781 vs 0.677, P < 0.001). Additionally, tdROC and decision curves also showed that nomogram was superior to MELD score. The results were confirmed in validation cohort. CONCLUSIONS: The prognostic nomogram provided an individualized risk estimate of short-term survival in patients with ACHBLF, offering to clinicians to improve their abilities to assess patient prognosis. PMID- 27490496 TI - Thermal Cycloisomerization of Putative Allenylpyridines for the Synthesis of Isoquinoline Derivatives. AB - A cascade (cyclo)isomerization/elimination process produces novel isoquinoline derivatives of potential interest for pharmaceutical, biomedical, and energy related research. Mechanistic experiments support a putative allenylpyridine (reminiscent of the Garratt-Braverman cyclization) as a key intermediate in the cascade process. PMID- 27490497 TI - NMR-Assisted Molecular Docking Methodologies. AB - Nuclear magnetic resonance (NMR) spectroscopy and molecular docking are regularly being employed as helpful tools of drug discovery research. Molecular docking is an extremely rapid method to evaluate possible binders from a large chemical library in a fast and cheap manner. NMR techniques can directly detect a protein ligand interaction, can determine the corresponding association constant, and can consistently identify the ligand binding cavity. Consequently, molecular docking and NMR techniques are naturally complementary techniques where the combination of the two has the potential to improve the overall efficiency of drug discovery process. In this review, we would like to summarize the state of the art of docking methods which have been recently bridged to NMR experiments to identify novel and effective therapeutic drug candidates. PMID- 27490498 TI - Structural Characteristics of the Allosteric Binding Site Represent a Key to Subtype Selective Modulators of Muscarinic Acetylcholine Receptors. AB - The high conservation of the orthosteric acetylcholine binding site of muscarinic receptors (MAChR) represents a considerable challenge in terms of designing subtype selective drugs. A promising approach to gain subtype selectivity is to include allosteric or dualsteric targeting that aims to address more specific extracellular binding sites. Despite recent advances in crystallography of G protein coupled receptors (GPCRs), structural information for all 5 MAChR subtypes is not yet available. Here we report structural models of the active and the inactive receptor state of all subtypes derived by homology modelling in combination with MD simulations. The comparison of the allosteric binding site unveils the characteristics for each subtype on a structural level and indicates anchor points for rational design of selective drugs. Additionally, homology models offer the possibility for a rational explanation of dualsteric subtype selectivity, as we show for the M2 over M5 selectivity of the dualsteric ligands Atr-6-naph and Iper-6-phth. PMID- 27490499 TI - Method for Systematic Assessment of Chemical Changes in Molecular Scaffolds with Conserved Topology and Application to the Analysis of Scaffold-Activity Relationships. AB - Sets of scaffolds with conserved molecular topology are abundant among drugs and bioactive compounds. Core structure topology is one of the determinants of biological activity. Heteroatom replacements and/or bond order variation render topologically equivalent scaffolds chemically distinct and also contribute to differences in the biological activity of compounds containing these scaffolds. Relationships between core structure topology, chemical modifications, and observed activity profiles are difficult to analyze. A computational method is introduced to consistently assess chemical transformations that distinguish scaffolds with conserved topology. The methodology is applied to quantify chemical differences in conserved topological environments and systematically relate chemical changes in topologically equivalent scaffolds to associated activity profiles. PMID- 27490500 TI - Acceleration of Binding Site Comparisons by Graph Partitioning. AB - The comparison of protein binding sites is a prominent task in computational chemistry and has been studied in many different ways. For the automatic detection and comparison of putative binding cavities the Cavbase system has been developed which uses a coarse-grained set of pseudocenters to represent the physicochemical properties of a binding site and employs a graph-based procedure to calculate similarities between two binding sites. However, the comparison of two graphs is computationally quite demanding which makes large-scale studies such as the rapid screening of entire databases hardly feasible. In a recent work, we proposed the method Local Cliques (LC) for the efficient comparison of Cavbase binding sites. It employs a clique heuristic to detect the maximum common subgraph of two binding sites and an extended graph model to additionally compare the shape of individual surface patches. In this study, we present an alternative to further accelerate the LC method by partitioning the binding-site graphs into disjoint components prior to their comparisons. The pseudocenter sets are split with regard to their assigned phyiscochemical type, which leads to seven much smaller graphs than the original one. Applying this approach on the same test scenarios as in the former comprehensive way results in a significant speed-up without sacrificing accuracy. PMID- 27490501 TI - Identification and Validation Novel of VIM-2 Metallo-beta-lactamase Tripeptide Inhibitors. AB - The development of novel inhibitors against metallo-beta-lactamase is essential to remedy metallo-beta-lactamase mediated bacterial resistance. A recently emerged metallo-beta-lactamase, VIM-2, has demonstrated resistance to existing beta-lactamase inhibitors in the clinic. In this study, a hybrid virtual screening protocol that combines pharmacophore modeling, molecular docking, and calculation of binding free energy was employed to screen an internal tripeptide database for novel inhibitors against VIM-2. This resulted in four tripeptides (WWC, WCW, MCW, YCW) as potential inhibitors, and their effects on VIM-2 metallo beta-lactamase were subsequently tested in vitro. Significantly, two peptides (MCW, YCW) exhibited potent inhibitory activities with IC50 values of 18.15 uM and 52.9 uM, respectively. To our knowledge, this is the first study that employed the hybrid virtual screening of combinational peptide database and discovered potent peptide inhibitors of VIM-2 metallo-beta-lactamase. PMID- 27490502 TI - Cross-Mapping of Protein - Ligand Binding Data Between ChEMBL and PDBbind. AB - The ChEMBL database is a valuable open data source, which provides a comprehensive collection of binding data, functional and ADMET properties of bioactive compounds. The PDBbind database has a more focused scope, i.e. collecting binding data for the protein-ligand complexes in the Protein Data Bank. Currently, the PDBbind collection of binding data is rather modest as compared to the ChEMBL collection (~13 000 versus ~1.3 million). One may suspect if the former is actually a subset of the latter. In this study, we mapped the molecular information and protein-ligand binding data in PDBbind to the records in ChEMBL, and then analyzed the overlap between the binding data recorded in these two databases. Our results indicate that only ~20 % of the binding data in PDBbind can find their counterparts in ChEMBL. Thus, the PDBbind collection of binding data is largely complementary to the ChEMBL collection. We also reveal two reasons accounting for the low overlap between two databases: First, only a minor fraction of the protein-ligand complexes in PDBbind is covered by ChEMBL; Second, the literature spaces screened by these two databases do not have a substantial overlap either. The value of focused databases versus more comprehensive ones is demonstrated by our study. PMID- 27490503 TI - Design Evolution of the Glenoid Component in Total Shoulder Arthroplasty. PMID- 27490504 TI - Limited Arthroplasty for Osteoarthritis of the Knee: A Critical Analysis Review. PMID- 27490505 TI - Blood Management for Patients Undergoing Total Joint Arthroplasty. PMID- 27490506 TI - Injectable Collagenase for the Treatment of Dupuytren Contracture: A Critical Analysis Review. PMID- 27490507 TI - The Effect of Articular Reduction After Fractures on Posttraumatic Degenerative Arthritis: A Critical Analysis Review. PMID- 27490508 TI - Failed Total Knee Arthroplasty. PMID- 27490509 TI - An Introduction to the Linear Mixed Model for Orthopaedic Research. PMID- 27490510 TI - Endoscopic Treatment of Greater Trochanteric Pain Syndrome of the Hip. PMID- 27490511 TI - Management of Syndesmotic Disruption in Ankle Fractures: A Critical Analysis Review. PMID- 27490512 TI - Tenodesis of the Long Head of the Biceps: A Review of Indications, Techniques, and Outcomes. PMID- 27490513 TI - Prevalence of Amyotrophic Lateral Sclerosis - United States, 2012-2013. AB - PROBLEM/CONDITION: Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a progressive and fatal neuromuscular disease for which no cure or viable treatment has been identified. ALS, like most noncommunicable diseases, is not a nationally notifiable disease in the United States. The prevalence of ALS in the United States during 2010-2011 was estimated to be 3.9 cases per 100,000 persons in the general population. Updated prevalence estimates are needed to help monitor disease status, better understand etiology, and identify risk factors for ALS. PERIOD COVERED: 2012-2013. DESCRIPTION OF SYSTEM: The National ALS Registry, established in 2009, collects data on ALS patients in the United States to better describe the incidence and prevalence of ALS, examine risk factors such as environmental and occupational exposures, and characterize the demographics of those living with ALS. To identify prevalent cases of ALS, data are compiled from four national administrative databases (maintained by the Centers for Medicare and Medicaid Services, the Veterans Health Administration, and the Veterans Benefits Administration). To identify cases not included in these databases and to better understand risk-factors associated with ALS and disease progression, the Registry also includes data that are collected from patients who voluntarily enroll and complete online surveys. RESULTS: During 2012 and 2013, the Registry identified 14,713 and 15,908 persons, respectively, who met the surveillance case definition of ALS. The estimated ALS prevalence rate was 4.7 cases per 100,000 U.S. population for 2012 and 5.0 per 100,000 for 2013. Due to revisions to the algorithm and use of death data from the National Death Index, an updated prevalence estimate has been calculated retrospectively for October 19, 2010-December 31, 2011. This updated estimate showed a prevalence rate of 4.3 per 100,000 population and a total of 13,282 cases. Since the inception of the Registry, the pattern of characteristics (e.g., age, sex, and race/ethnicity) among persons with ALS have remained unchanged. Overall, ALS was more common among whites, males, and persons aged 60-69 years. The age groups with the lowest number of ALS cases were persons aged 18-39 years and those aged >=80 years. Males had a higher prevalence rate of ALS than females overall and across all data sources. These findings remained consistent during October 2010 December 2013. INTERPRETATION: The Registry is the only available data source that can be used to estimate the national prevalence for ALS in the United States. Use of both administrative national databases and self-report from patients enables a comprehensive approach to estimate ALS prevalence. The overall increase in the prevalence rate from 4.3 per 100,000 persons (revised) during 2010-2011 to 4.7 and 5.0 per 100,000 persons, respectively, during 2012-2013 likely is not an actual increase in the number of ALS cases. Rather, this increase might be attributed to improved case ascertainment due to the refinement of the algorithm used to identify definite ALS cases, along with an increased public awareness of the Registry. Registry estimates of ALS prevalence are consistent with findings from long-established ALS registries in Europe and from smaller-scale epidemiologic studies previously conducted in the United States. PUBLIC HEALTH ACTIONS: Data collected by the National ALS Registry are being used to better describe the epidemiology of ALS in the United States and to help facilitate research. The combined approach of using national administrative databases and a self-enrollment web portal to collect data is novel and potentially could be used for other non-notifiable diseases such as Parkinson's disease or multiple sclerosis. Increased public awareness of the Registry might lead to more ALS cases being identified from the secure web portal (https://www.cdc.gov/als), which can ascertain cases apart from the national administrative databases. For example, in 2014, the ALS Ice Bucket Challenge, a social media-centered campaign, received extensive public visibility and created increased awareness of ALS. The Agency for Toxic Substances and Disease Registry (ATSDR) works closely with ALS advocacy and support groups, researchers, health care professionals, and others to promote the National ALS Registry and to identify all cases of ALS in the United States. In addition to estimating the prevalence of ALS, the Registry is being used to collect specimens from patient enrollees through a new biorepository, connect patient enrollees with new clinical trials and epidemiologic studies, and fund studies to help learn more about the etiology of ALS. Additional information about the National ALS Registry is available at http://www.cdc.gov/als or by calling toll-free at 1-877-442-9719. PMID- 27490514 TI - Medical and Surgical Treatments for Usual-Type Vulvar Intraepithelial Neoplasia. AB - Clinical Question: Which interventions are the most effective and tolerable for treating usual-type vulvar intraepithelial neoplasia? Bottom Line: Provided cancer is not suspected, usual-type vulvar intraepithelial neoplasia treatment, including medical and surgical options, can be individualized to take into account the site, extent of disease, and a woman's preferences, with a commitment to long-term follow-up. PMID- 27490515 TI - Childhood emotional maltreatment and mental disorders: Results from a nationally representative adult sample from the United States. AB - Child maltreatment is a public health concern with well-established sequelae. However, compared to research on physical and sexual abuse, far less is known about the long-term impact of emotional maltreatment on mental health. The overall purpose of this study was to examine the association of emotional abuse, emotional neglect, and both emotional abuse and neglect with other types of child maltreatment, a family history of dysfunction, and lifetime diagnoses of several Axis I and Axis II mental disorders. Data were from the National Epidemiological Survey on Alcohol and Related Conditions collected in 2004 and 2005 (n=34,653). The most prevalent form of emotional maltreatment was emotional neglect only (6.2%), followed by emotional abuse only (4.8%), and then both emotional abuse and neglect (3.1%). All categories of emotional maltreatment were strongly related to other forms of child maltreatment (odds ratios [ORs] ranged from 2.1 to 68.0) and a history of family dysfunction (ORs ranged from 2.2 to 8.3). In models adjusting for sociodemographic characteristics, all categories of emotional maltreatment were associated with increased odds of almost every mental disorder assessed in this study (adjusted ORs ranged from 1.2 to 7.4). Many relationships remained significant independent of experiencing other forms of child maltreatment and a family history of dysfunction (adjusted ORs ranged from 1.2 to 3.0). The effects appeared to be greater for active (i.e., emotional abuse) relative to passive (i.e., emotional neglect) forms of emotional maltreatment. Childhood emotional maltreatment, particularly emotionally abusive acts, is associated with increased odds of lifetime diagnoses of several Axis I and Axis II mental disorders. PMID- 27490516 TI - Is there a role for paediatric Sexual Assault Nurse Examiners in the management of child sexual assault in Australia? AB - In Australia, paediatricians and Child Protection Specialists provide the medical and forensic examinations of child victims of sexual assault. There are workforce challenges in the recruitment and retention of doctors to undertake child sexual assault (CSA) work particularly in remote and rural areas. Pediatric Sexual Assault Nurse Examiner (PSANE) programs have existed in the USA and the UK for many years. Using Rapid Evidence Assessment (REA) methodology, a systematic search of the literature was performed to ascertain what is known about SANE programs, to evaluate the evidence for their effectiveness across a number of domains (accessibility, health and legal outcomes and cost effectiveness) and to inform policy on models of care and elements of best practice which may be appropriate for local implementation in Australia. This review showed that despite the limited evidence available and significant gaps in the evidence, SANEs provide a high standard of medical care and are not detrimental to the legal process. By providing recommendations regarding the potential value, effectiveness and feasibility of establishing a PSANE program in Australia, this article may be of interest to other high income countries facing similar workforce challenges in meeting the needs of children with alleged sexual assault. PMID- 27490517 TI - Exploring child prostitution in a major city in the West African region. AB - The study explored the characteristics of child prostitution in a major city in the West African region. A convenience sample of children in prostitution, specifically girls below age 18 (n=243), were recruited on 83 prostitution sites identified in Ouagadougou, the capital city of Burkina Faso. A survey instrument, consisting of 71 closed-ended question items, was used to explore various variables including profile of children in prostitution, factors of vulnerability to prostitution; prostitution practices, compensations and related issues in child prostitution. The findings show that most children in prostitution in the city were from Burkina Faso (63%) and Nigeria (30%), two countries that do not share borders. Most native respondents practiced prostitution for survival and to support their families. In contrast, all the respondents from Nigeria practiced prostitution as victims of international sex trafficking. An important finding was that 77% of the children in prostitution surveyed were educated. Among the respondents, there were similarities in the major life events that contributed to their situation of prostitution. These life events include early separation with parents, sexual abuse, foster care, and forced marriage. Implications for policy, practice and research are discussed. PMID- 27490518 TI - Self-Powered Triboelectric Micro Liquid/Gas Flow Sensor for Microfluidics. AB - Liquid and gas flow sensors are important components of the micro total analysis systems (MUTAS) for modern analytical sciences. In this paper, we proposed a self powered triboelectric microfluidic sensor (TMS) by utilizing the signals produced from the droplet/bubble via the capillary and the triboelectrification effects on the liquid/solid interface for real-time liquid and gas flow detection. By alternating capillary with different diameters, the sensor's detecting range and sensitivity can be adjusted. Both the relationship between the droplet/bubble and capillary size, and the output signal of the sensor are systematically studied. By demonstrating the monitoring of the transfusion process for a patient and the gas flow produced from an injector, it shows that TMS has a great potential in building a self-powered micro total analysis system. PMID- 27490520 TI - Ultrasensitive Strain Sensor Produced by Direct Patterning of Liquid Crystals of Graphene Oxide on a Flexible Substrate. AB - Ultrasensitive flexible strain sensors were developed through the combination of shear alignment of a high concentration graphene oxide (GO) dispersion with fast and precise patterning of multiple rectangular features on a flexible substrate. Resistive changes in the reduced GO films were investigated under various uniaxial strain cycles ranging from 0.025 to 2%, controlled with a motorized nanopositioning stage. The devices uniquely combine a very small detection limit (0.025%) and a high gauge factor with a rapid fabrication process conducive to batch production. PMID- 27490519 TI - Human Proteome Project Mass Spectrometry Data Interpretation Guidelines 2.1. AB - Every data-rich community research effort requires a clear plan for ensuring the quality of the data interpretation and comparability of analyses. To address this need within the Human Proteome Project (HPP) of the Human Proteome Organization (HUPO), we have developed through broad consultation a set of mass spectrometry data interpretation guidelines that should be applied to all HPP data contributions. For submission of manuscripts reporting HPP protein identification results, the guidelines are presented as a one-page checklist containing 15 essential points followed by two pages of expanded description of each. Here we present an overview of the guidelines and provide an in-depth description of each of the 15 elements to facilitate understanding of the intentions and rationale behind the guidelines, for both authors and reviewers. Broadly, these guidelines provide specific directions regarding how HPP data are to be submitted to mass spectrometry data repositories, how error analysis should be presented, and how detection of novel proteins should be supported with additional confirmatory evidence. These guidelines, developed by the HPP community, are presented to the broader scientific community for further discussion. PMID- 27490521 TI - Correlation study between image features and mechanical properties of Han Chinese facial skin. AB - OBJECTIVE: Mechanical properties are considered to be vital factors that influence skin physiology during ageing. Wrinkles and skin roughness are the two main features in aged skin. The purpose of this study is to characterize the relationship between facial skin mechanical properties and image features using quantitative methods. METHODS: Two hundred and forty healthy male and female volunteers living in Shanghai, China (aged 20-70 years), were examined in this study. Facial images were photographed by VISIA-CR. Wrinkle volume of middle forehead and skin roughness of upper cheek were analysed by Skin Surface Analyzer (SSA) software. Mechanical parameters at the middle forehead and upper cheek were measured using Cutometer(r) MPA 580 and Reviscometer(r) RVM 600. RESULTS: Skin wrinkles and roughness increased during ageing, where men have a higher level and earlier manifestation than women. Skin mechanical parameters R2, R5, R7 and RRT were found decreased with age. Moreover, mechanical parameters including R2, R7, RRT and anisotropy showed significant correlations with wrinkle volume and/or skin roughness. CONCLUSION: The facial image features including wrinkle volume and skin roughness are significantly correlated with skin elasticity and anisotropy, which could well describe the skin features of Han Chinese. PMID- 27490522 TI - Intramolecular Chain Hydrosilylation of Alkynylphenylsilanes Using a Silyl Cation as a Chain Carrier. AB - Diorganyl[2-(trimethylsilylethynyl)phenyl]silanes 1a-c and methyl-substituted phenylsilanes 1d and 1e were treated with a small amount of trityl tetrakis(pentafluorophenyl)borate (TPFPB) as an initiator in benzene to afford the corresponding benzosiloles (2a-e) in moderate to good yields. However, no reaction was observed for the reaction using [2-(1 hexynyl)phenyl]diisopropylsilane lf. The methyl substituent was tolerated under the reaction conditions and increased the yield of the corresponding benzosilole depending on the substitution position. From the result using 1f, the current reaction was found to require the trimethylsilyl group, which can stabilize intermediary alkenyl carbocations by the beta-silyl effect. The current reaction can be considered an intramolecular chain hydrosilylation of alkynylarylsilanes involving silyl cations as chain carriers. Therefore, the silyl cations generated by hydride abstraction from hydrosilanes 1 with the trityl cation causes intramolecular electrophilic addition to the C-C triple bond to form ethenyl cations, which abstract a hydride from 1 to afford benzosiloles 2 with the regeneration of the silyl cations. PMID- 27490523 TI - Synthesis and Evaluation of New 1,3,4-Thiadiazole Derivatives as Antinociceptive Agents. AB - In the current work, new 1,3,4-thiadiazole derivatives were synthesized and investigated for their antinociceptive effects on nociceptive pathways of nervous system. The effects of these compounds against mechanical, thermal and chemical stimuli were evaluated by tail-clip, hot-plate and acetic acid-induced writhing tests, respectively. In addition, activity cage was performed to assess the locomotor activity of animals. The obtained data indicated that compounds 3b, 3c, 3d, 3e, 3g and 3h increased the reaction times of mice both in the hot-plate and tail-clip tests, indicating the centrally mediated antinociceptive activity of these compounds. Additionally, the number of writhing behavior was significantly decreased by the administration of compounds 3a, 3c, 3e and 3f, which pointed out the peripherally mediated antinociceptive activity induced by these four compounds. According to the activity cage tests, compounds 3a, 3c and 3f significantly decreased both horizontal and vertical locomotor activity of mice. Antinociceptive behavior of these three compounds may be non-specific and caused by possible sedative effect or motor impairments. PMID- 27490524 TI - In Vivo Monitoring of the Growth of Fertilized Eggs of Medaka Fish (Oryzias latipes) by Near-Infrared Spectroscopy and Near-Infrared Imaging-A Marked Change in the Relative Content of Weakly Hydrogen-Bonded Water in Egg Yolk Just before Hatching. AB - The present study develops further our previous study of in vivo monitoring at the molecular level of the embryonic development in Japanese medaka fish (Oryzias latipes) using near-infrared (NIR) spectroscopy and NIR imaging. NIR spectra were measured nondestructively for three major parts of fertilized medaka eggs (the embryonic body, oil droplets, and egg yolk) from the first day after fertilization to the day just before hatching (JBH). Changes in the contents of chemical components such as proteins, water, and lipids were monitored in situ during embryonic development. A marked change in the relative content of weakly hydrogen-bonded water was observed in the egg yolk JBH. Principal component analysis (PCA) was carried out using the NIR spectra data of the egg yolk and embryo on the fifth day after fertilization. The PCA clearly separates the egg yolk data from the embryo body parts. Principal component PC1 and PC2 loading plots suggest that the hydrogen bonding structure of water in the egg yolk is considerably different to those of the other parts and the fraction of weakly hydrogen-bonded water in the egg yolk is smaller than that in the embryonic body. NIR images developed from the intensities of peaks of second derivative spectra owing to water and proteins show their different distribution patterns. Images of the ratio of strongly and weakly hydrogen-bonded water confirmed that oil droplets and embryonic body parts have higher and lower ratios, respectively, of strongly hydrogen-bonded water than do the other parts. The images developed from the intensity of the peaks at 4864 and 4616 cm(-1) related to the proteins indicated that the egg yolk contains a higher concentration of protein than do the other parts. The peaks at 5756 and 4530 cm(-1) caused by the protein secondary structures of alpha-helix and beta-sheet showed the configuration of the egg cell membrane. The present study might lead to new understanding at the molecular level regarding the growth of fertilized eggs and provides a new tool to visualize egg development in a nondestructive manner. PMID- 27490525 TI - Microfluidic Devices in Advanced Caenorhabditis elegans Research. AB - The study of model organisms is very important in view of their potential for application to human therapeutic uses. One such model organism is the nematode worm, Caenorhabditis elegans. As a nematode, C. elegans have ~65% similarity with human disease genes and, therefore, studies on C. elegans can be translated to human, as well as, C. elegans can be used in the study of different types of parasitic worms that infect other living organisms. In the past decade, many efforts have been undertaken to establish interdisciplinary research collaborations between biologists, physicists and engineers in order to develop microfluidic devices to study the biology of C. elegans. Microfluidic devices with the power to manipulate and detect bio-samples, regents or biomolecules in micro-scale environments can well fulfill the requirement to handle worms under proper laboratory conditions, thereby significantly increasing research productivity and knowledge. The recent development of different kinds of microfluidic devices with ultra-high throughput platforms has enabled researchers to carry out worm population studies. Microfluidic devices primarily comprises of chambers, channels and valves, wherein worms can be cultured, immobilized, imaged, etc. Microfluidic devices have been adapted to study various worm behaviors, including that deepen our understanding of neuromuscular connectivity and functions. This review will provide a clear account of the vital involvement of microfluidic devices in worm biology. PMID- 27490526 TI - Agavins Increase Neurotrophic Factors and Decrease Oxidative Stress in the Brains of High-Fat Diet-Induced Obese Mice. AB - BACKGROUND: Fructans obtained from agave, called agavins, have recently shown significant benefits for human health including obesity. Therefore, we evaluated the potential of agavins as neuroprotectors and antioxidants by determining their effect on brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) as well as oxidative brain damage in of obese mice. METHODS: Male C57BL/6J mice were fed a high-fat diet (HFD) and treated daily with 5% (HFD/A5) or 10% (HFD/A10) of agavins or a standard diet (SD) for 10 weeks. The levels of BDNF and GDNF were evaluated by ELISA. The oxidative stress was evaluated by lipid peroxidation (TBARS) and carbonyls. SCFAs were also measured with GC-FID. Differences between groups were assessed using ANOVA and by Tukey's test considering p < 0.05. RESULTS: The body weight gain and food intake of mice HFD/A10 group were significantly lower than those in the HFD group. Agavins restored BDNF levels in HFD/A5 group and GDNF levels of HFD/A5 and HFD/A10 groups in cerebellum. Interestingly, agavins decreased TBARS levels in HFD/A5 and HFD/A10 groups in the hippocampus, frontal cortex and cerebellum. Carbonyl levels were also lower in HFD/A5 and HFD/A10 for only the hippocampus and cerebellum. It was also found that agavins enhanced SCFAs production in feces. CONCLUSION: Agavins may act as bioactive ingredients with antioxidant and protective roles in the brain. PMID- 27490527 TI - Potential Application of p-Coumaric Acid on Differentiation of C2C12 Skeletal Muscle and 3T3-L1 Preadipocytes-An in Vitro and in Silico Approach. AB - Coumaric acid (CA) is a phenolic acid of the hydroxycinnamic acid family, and it has many biological functions such as anti-oxidant, anti-inflammatory, antidiabetic, anti-ulcer, anti-platelet, anti-cancer activities, etc. In the present study, we planned to analyse the potential molecular function of CA on skeletal muscle and preadipocytes differentiation using PCR and Western blot techniques. First, we analysed the impact of CA on C2C12 skeletal muscle differentiation. It revealed that CA treatment inhibited horse serum-induced skeletal muscle differentiation as evidenced by the decreased expression of early myogenic differentiation markers such as Myogenin and myoD via the AMP activated protein kinase- alpha AMPK-alpha mediated pathway. Furthermore, the level of lipid accumulation and changes in genes and protein expressions that are associated with lipogenesis and lipolysis were analyzed in 3T3-L1 cells. The Oil Red O staining evidenced that CA treatment inhibited lipid accumulation at the concentration of 0.1 and 0.2 mM. Furthermore, coumaric acid treatment decreased the expression of main transcriptional factors such as CCAAT/enhancer binding protein-alpha (C/EBP-alpha) and peroxisome proliferator-activated receptor gamma 2 (PPAR-gamma2). Subsequently, CA treatment decreased the expression of sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthase (FAS), acetyl CoA carboxylase (ACC) and adiponectin. Finally, we identified conformational changes induced by CA in PPAR-gamma2 using computational biology tools. It revealed that CA might downregulate the PPAR-gamma2 expression by directly binding with amino acids of PPAR-gamma2 by hydrogen at 3.26 distance and hydrophobic interactions at 3.90 contact distances. These data indicated that CA suppressed skeletal muscle and preadipocytes differentiation through downregulation of the main transcriptional factors and their downstream targets. PMID- 27490528 TI - Effects on Nitric Oxide Production of Urolithins, Gut-Derived Ellagitannin Metabolites, in Human Aortic Endothelial Cells. AB - The consumption of foodstuffs yielding circulating compounds able to maintain endothelial function by improving nitric oxide (NO) bioavailability can be considered as an effective strategy for cardiovascular disease prevention. This work assessed the in vitro effects of urolithin A, urolithin B, and urolithin B glucuronide, ellagitannin-derived metabolites of colonic origin, on NO release and endothelial NO synthase (eNOS) activation in primary human aortic endothelial cells (HAECs). Urolithins were tested both individually at 15 MUM and as a mixture of 5 MUM each, at different time points. The biotransformation of these molecules in cell media due to cell metabolism was also evaluated by UHPLC-MS(n). The mix of urolithins at 5 MUM significantly increased nitrite/nitrate levels following 24 h of incubation, while single urolithins at 15 MUM did not modify NO bioavailability. Both the mix of urolithins at 5 MUM and urolithin B-glucuronide at 15 MUM activated eNOS expression. All urolithins underwent metabolic reactions, but these were limited to conjugation with sulfate moieties. This study represents a step forward in the understanding of cardiovascular health benefits of ellagitannin-rich foodstuffs and backs the idea that peripheral cells may contribute to urolithin metabolism. PMID- 27490529 TI - In Vivo Release Kinetics and Antibacterial Activity of Novel Polyphenols-Enriched Chewing Gums. AB - Chewing gums may be particularly effective means for delivering and maintaining bioactive molecules, included in the gum formulation, able to have an anti cariogenic effect. The purposes of this study were: to develop novel chewing gums containing quercetin (Qt); to evaluate their release using in vivo trial; finally, to test their in vivo antibacterial effect against oral Streptococcus mutans strains. A preliminary study was performed to produce new gums, enriched with the polyphenol quercetin. Then, a first in vivo experimental study was assessed to test the percentages of Qt released in the saliva of young volunteers. Moreover, a second clinical trial was performed to analyze the antibacterial capability of these enriched chewing gums against S. mutans strains after 14 days of daily consumption. The release analysis showed that a more effective release of Qt occurs in the first minutes of chewing, and it does not change saliva pH values. Moreover, Qt included in gums demonstrates an effective antibacterial activity, showing a reduction of the concentration of S. mutans strains in saliva samples, especially after 7 days. Qt included in experimental chewing gums could be efficiently released into the oral cavity and could promote an effective anti-caries concentration in volunteer's saliva, without changing salivary pH values. PMID- 27490530 TI - Preparation of Hydrochlorothiazide Nanoparticles for Solubility Enhancement. AB - Nanoparticles can be considered as a useful tool for improving properties of poorly soluble active ingredients. Hydrochlorothiazide (Class IV of the Biopharmaceutical Classification System) was chosen as a model compound. Antisolvent precipitation-solvent evaporation and emulsion solvent evaporation methods were used for preparation of 18 samples containing hydrochlorothiazide nanoparticles. Water solutions of surfactants sodium dodecyl sulfate, Tween 80 and carboxymethyl dextran were used in mass concentrations of 1%, 3% and 5%. Acetone and dichloromethane were used as solvents of the model compound. The particle size of the prepared samples was measured by dynamic light scattering. The selected sample of hydrochlorothiazide nanoparticles stabilized with carboxymethyl dextran sodium salt with particle size 2.6 nm was characterized additionally by Fourier transform mid-infrared spectroscopy and scanning electron microscopy. It was found that the solubility of this sample was 6.5-fold higher than that of bulk hydrochlorothiazide. PMID- 27490531 TI - Circulating Organ-Specific MicroRNAs Serve as Biomarkers in Organ-Specific Diseases: Implications for Organ Allo- and Xeno-Transplantation. AB - Different cell types possess different miRNA expression profiles, and cell/tissue/organ-specific miRNAs (or profiles) indicate different diseases. Circulating miRNA is either actively secreted by living cells or passively released during cell death. Circulating cell/tissue/organ-specific miRNA may serve as a non-invasive biomarker for allo- or xeno-transplantation to monitor organ survival and immune rejection. In this review, we summarize the proof of concept that circulating organ-specific miRNAs serve as non-invasive biomarkers for a wide spectrum of clinical organ-specific manifestations such as liver related disease, heart-related disease, kidney-related disease, and lung-related disease. Furthermore, we summarize how circulating organ-specific miRNAs may have advantages over conventional methods for monitoring immune rejection in organ transplantation. Finally, we discuss the implications and challenges of applying miRNA to monitor organ survival and immune rejection in allo- or xeno transplantation. PMID- 27490533 TI - Coordination Environment of Cu(II) Ions Bound to N-Terminal Peptide Fragments of Angiogenin Protein. AB - Angiogenin (Ang) is a potent angiogenic factor, strongly overexpressed in patients affected by different types of cancers. The specific Ang cellular receptors have not been identified, but it is known that Ang-actin interaction induces changes both in the cell cytoskeleton and in the extracellular matrix. Most in vitro studies use the recombinant form (r-Ang) instead of the form that is normally present in vivo ("wild-type", wt-Ang). The first residue of r-Ang is a methionine, with a free amino group, whereas wt-Ang has a glutamic acid, whose amino group spontaneously cyclizes in the pyro-glutamate form. The Ang biological activity is influenced by copper ions. To elucidate the role of such a free amino group on the protein-copper binding, we scrutinized the copper(II) complexes with the peptide fragments Ang(1-17) and AcAng(1-17), which encompass the sequence 1 17 of angiogenin (QDNSRYTHFLTQHYDAK-NH2), with free amino and acetylated N terminus, respectively. Potentiometric, ultraviolet-visible (UV-vis), nuclear magnetic resonance (NMR) and circular dichroism (CD) studies demonstrate that the two peptides show a different metal coordination environment. Confocal microscopy imaging of neuroblastoma cells with the actin staining supports the spectroscopic results, with the finding of different responses in the cytoskeleton organization upon the interaction, in the presence or not of copper ions, with the free amino and the acetylated N-terminus peptides. PMID- 27490532 TI - Serum Concentrations of Endothelin-1 and Matrix Metalloproteinases-2, -9 in Pre Hypertensive and Hypertensive Patients with Type 2 Diabetes. AB - Endothelin-1 (ET-1) is one of the most potent vasoconstrictors known to date. While its plasma or serum concentrations are elevated in some forms of experimental and human hypertension, this is not a consistent finding in all forms of hypertension. Matrix metalloproteinases -2 and -9 (MMP-2 and MMP-9), which degrade collagen type IV of the vascular basement membrane, are responsible for vascular remodeling, inflammation, and atherosclerotic complications, including in type 2 diabetes (T2D). In our study, we compared concentrations of ET-1, MMP-2, and MMP-9 in pre-hypertensive (PHTN) and hypertensive (HTN) T2D patients with those of healthy normotensive controls (N). ET-1, MMP-2, and MMP-9 were measured by ELISA. Concentrations of ET-1 in PHTN and N were very similar, while those in HTN were significantly higher. Concentrations of MMP-2 and MMP-9 in PHTN and HTN were also significantly higher compared to N. An interesting result in our study is that concentrations of MMP-2 and MMP-9 in HTN were lower compared to PHTN. In conclusion, we showed that increased production of ET-1 in patients with T2D can lead to long-lasting increases in blood pressure (BP) and clinical manifestation of hypertension. We also demonstrated that increased levels of MMP-2 and MMP-9 in pre-hypertensive and hypertensive patients with T2D mainly reflect the early vascular changes in extracellular matrix (ECM) turnover. PMID- 27490535 TI - Evaluation of Pulmonary Toxicity of Zinc Oxide Nanoparticles Following Inhalation and Intratracheal Instillation. AB - We conducted inhalation and intratracheal instillation studies of zinc oxide (ZnO) nanoparticles in order to examine their pulmonary toxicity. F344 rats were received intratracheal instillation at 0.2 or 1 mg of ZnO nanoparticles with a primary diameter of 35 nm that were well-dispersed in distilled water. Cell analysis and chemokines in bronchoalveolar lavage fluid (BALF) were analyzed at three days, one week, one month, three months, and six months after the instillation. As the inhalation study, rats were exposed to a concentration of inhaled ZnO nanoparticles (2 and 10 mg/m3) for four weeks (6 h/day, 5 days/week). The same endpoints as in the intratracheal instillation study were analyzed at three days, one month, and three months after the end of the exposure. In the intratracheal instillation study, both the 0.2 and the 1.0 mg ZnO groups had a transient increase in the total cell and neutrophil count in the BALF and in the expression of cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2, chemokine for neutrophil, and heme oxygenase-1 (HO-1), an oxidative stress marker, in the BALF. In the inhalation study, transient increases in total cell and neutrophil count, CINC-1,-2 and HO-1 in the BALF were observed in the high concentration groups. Neither of the studies of ZnO nanoparticles showed persistent inflammation in the rat lung, suggesting that well-dispersed ZnO nanoparticles have low toxicity. PMID- 27490536 TI - Impact of HIV Infection and Anti-Retroviral Therapy on the Immune Profile of and Microbial Translocation in HIV-Infected Children in Vietnam. AB - CD4+ T-lymphocyte destruction, microbial translocation, and systemic immune activation are the main mechanisms of the pathogenesis of human immunodeficiency virus type 1 (HIV) infection. To investigate the impact of HIV infection and antiretroviral therapy (ART) on the immune profile of and microbial translocation in HIV-infected children, 60 HIV vertically infected children (31 without ART: HIV(+) and 29 with ART: ART(+)) and 20 HIV-uninfected children (HIV(-)) aged 2-12 years were recruited in Vietnam, and their blood samples were immunologically and bacteriologically analyzed. Among the HIV(+) children, the total CD4+-cell and their subset (type 1 helper T-cell (Th1)/Th2/Th17) counts were inversely correlated with age (all p < 0.05), whereas regulatory T-cell (Treg) counts and CD4/CD8 ratios had become lower, and the CD38+HLA (human leukocyte antigen) DR+CD8+- (activated CD8+) cell percentage and plasma soluble CD14 (sCD14, a monocyte activation marker) levels had become higher than those of HIV(-) children by the age of 2 years; the CD4/CD8 ratio was inversely correlated with the plasma HIV RNA load and CD8+-cell activation status. Among the ART(+) children, the total CD4+-cell and Th2/Th17/Treg-subset counts and the CD4/CD8 ratio gradually increased, with estimated ART periods of normalization being 4.8 8.3 years, whereas Th1 counts and the CD8+-cell activation status normalized within 1 year of ART initiation. sCD14 levels remained high even after ART initiation. The detection frequency of bacterial 16S/23S ribosomal DNA/RNA in blood did not differ between HIV-infected and -uninfected children. Thus, in children, HIV infection caused a rapid decrease in Treg counts and the early activation of CD8+ cells and monocytes, and ART induced rapid Th1 recovery and early CD8+-cell activation normalization but had little effect on monocyte activation. The CD4/CD8 ratio could therefore be an additional marker for ART monitoring. PMID- 27490537 TI - Drought-Induced Leaf Proteome Changes in Switchgrass Seedlings. AB - Switchgrass (Panicum virgatum) is a perennial crop producing deep roots and thus highly tolerant to soil water deficit conditions. However, seedling establishment in the field is very susceptible to prolonged and periodic drought stress. In this study, a "sandwich" system simulating a gradual water deletion process was developed. Switchgrass seedlings were subjected to a 20-day gradual drought treatment process when soil water tension was increased to 0.05 MPa (moderate drought stress) and leaf physiological properties had expressed significant alteration. Drought-induced changes in leaf proteomes were identified using the isobaric tags for relative and absolute quantitation (iTRAQ) labeling method followed by nano-scale liquid chromatography mass spectrometry (nano-LC-MS/MS) analysis. Additionally, total leaf proteins were processed using a combinatorial library of peptide ligands to enrich for lower abundance proteins. Both total proteins and those enriched samples were analyzed to increase the coverage of the quantitative proteomics analysis. A total of 7006 leaf proteins were identified, and 257 (4% of the leaf proteome) expressed a significant difference (p < 0.05, fold change <0.6 or >1.7) from the non-treated control to drought-treated conditions. These proteins are involved in the regulation of transcription and translation, cell division, cell wall modification, phyto-hormone metabolism and signaling transduction pathways, and metabolic pathways of carbohydrates, amino acids, and fatty acids. A scheme of abscisic acid (ABA)-biosynthesis and ABA responsive signal transduction pathway was reconstructed using these drought induced significant proteins, showing systemic regulation at protein level to deploy the respective mechanism. Results from this study, in addition to revealing molecular responses to drought stress, provide a large number of proteins (candidate genes) that can be employed to improve switchgrass seedling growth and establishment under soil drought conditions (Data are available via ProteomeXchange with identifier PXD004675). PMID- 27490534 TI - The Impact of Anti-Epileptic Drugs on Growth and Bone Metabolism. AB - Epilepsy is a common neurological disorder worldwide and anti-epileptic drugs (AEDs) are always the first choice for treatment. However, more than 50% of patients with epilepsy who take AEDs have reported bone abnormalities. Cytochrome P450 (CYP450) isoenzymes are induced by AEDs, especially the classical AEDs, such as benzodiazepines (BZDs), carbamazepine (CBZ), phenytoin (PT), phenobarbital (PB), and valproic acid (VPA). The induction of CYP450 isoenzymes may cause vitamin D deficiency, hypocalcemia, increased fracture risks, and altered bone turnover, leading to impaired bone mineral density (BMD). Newer AEDs, such as levetiracetam (LEV), oxcarbazepine (OXC), lamotrigine (LTG), topiramate (TPM), gabapentin (GP), and vigabatrin (VB) have broader spectra, and are safer and better tolerated than the classical AEDs. The effects of AEDs on bone health are controversial. This review focuses on the impact of AEDs on growth and bone metabolism and emphasizes the need for caution and timely withdrawal of these medications to avoid serious disabilities. PMID- 27490538 TI - Association of Serum Uric Acid Concentration with Diabetic Retinopathy and Albuminuria in Taiwanese Patients with Type 2 Diabetes Mellitus. AB - Patients with type 2 diabetes mellitus (DM) may experience chronic microvascular complications such as diabetic retinopathy (DR) and diabetic nephropathy (DN) during their lifetime. In clinical studies, serum uric acid concentration has been found to be associated with DR and DN. The goal of this study was to evaluate the relationship between the increases in serum uric acid level and the severity of DR and albuminuria in Taiwanese patients with type 2 DM. We recorded serum uric acid concentration, the severity of DR, and the severity of albuminuria by calculating urinary albumin-to-creatinine ratio (UACR) in 385 patients with type 2 DM. In multivariate logistic regression analysis, a high uric acid concentration was a risk factor for albuminuria (odds ratio (OR), 1.227; 95% confidence interval (CI) = 1.015-1.482; p = 0.034) and DR (OR, 1.264; 95% CI = 1.084-1.473; p = 0.003). We also demonstrated that there was a higher concentration of serum uric acid in the patients with more severe albuminuria and DR. In conclusion, an increased serum uric acid level was significantly correlated with the severity of albuminuria and DR in Taiwanese patients with type 2 DM. PMID- 27490539 TI - Upregulation of Human ST8Sia VI (alpha2,8-Sialyltransferase) Gene Expression by Physcion in SK-N-BE(2)-C Human Neuroblastoma Cells. AB - In this research, we firstly demonstrated that physcion, an anthraquinone derivative, specifically increased the expression of the human alpha2,8 sialyltransferase (hST8Sia VI) gene in SK-N-BE(2)-C human neuroblastoma cells. To establish the mechanism responsible for the up-regulation of hST8Sia VI gene expression in physcion-treated SK-N-BE(2)-C cells, the putative promoter region of the hST8Sia VI gene was functionally characterized. Promoter analysis with serially truncated fragments of the 5'-flanking region showed that the region between -320 and -240 is crucial for physcion-induced transcription of hST8Sia VI in SK-N-BE(2)-C cells. Putative binding sites for transcription factors Pax-5 and NF-Y are located at this region. The Pax-5 binding site at -262 to -256 was essential for the expression of the hST8Sia VI gene by physcion in SK-N-BE(2)-C cells. Moreover, the transcription of hST8Sia VI induced by physcion in SK-N BE(2)-C cells was inhibited by extracellular signal-regulated protein kinase (ERK) inhibitor U0126 and p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, but not c-Jun N-terminal kinase (JNK) inhibitor SP600125. These results suggest that physcion upregulates hST8Sia VI gene expression via ERK and p38 MAPK pathways in SK-N-BE(2)-C cells. PMID- 27490540 TI - Salvianolic Acid A, as a Novel ETA Receptor Antagonist, Shows Inhibitory Effects on Tumor in Vitro. AB - Endothelin-1 (ET-1) autocrine and paracrine signaling modulate cell proliferation of tumor cells by activating its receptors, endothelin A receptor (ETAR) and endothelin B receptor (ETBR). Dysregulation of ETAR activation promotes tumor development and progression. The potential of ETAR antagonists and the dual-ETAR and ETBR antagonists as therapeutic approaches are under preclinical and clinical studies. Salvianolic acid A (Sal A) is a hydrophilic polyphenolic derivative isolated from Salvia miltiorrhiza Bunge (Danshen), which has been reported as an anti-cancer and cardio-protective herbal medicine. In this study, we demonstrate that Sal A inhibits ETAR activation induced by ET-1 in both recombinant and endogenous ETAR expression cell lines. The IC50 values were determined as 5.7 uM in the HEK293/ETAR cell line and 3.14 uM in HeLa cells, respectively. Furthermore, our results showed that Sal A suppressed cell proliferation and extended the doubling times of multiple cancer cells, including HeLa, DU145, H1975, and A549 cell lines. In addition, Sal A inhibited proliferation of DU145 cell lines stimulated by exogenous ET-1 treatment. Moreover, the cytotoxicity and cardio-toxicity of Sal A were assessed in human umbilical vein endothelial cells (HUVEC) and Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS CMs), which proved that Sal A demonstrates no cytotoxicity or cardiotoxicity. Collectively, our findings indicate that Sal A is a novel anti-cancer candidate through targeting ETAR. PMID- 27490541 TI - The Exon Junction Complex Controls the Efficient and Faithful Splicing of a Subset of Transcripts Involved in Mitotic Cell-Cycle Progression. AB - The exon junction complex (EJC) that is deposited onto spliced mRNAs upstream of exon-exon junctions plays important roles in multiple post-splicing gene expression events, such as mRNA export, surveillance, localization, and translation. However, a direct role for the human EJC in pre-mRNA splicing has not been fully understood. Using HeLa cells, we depleted one of the EJC core components, Y14, and the resulting transcriptome was analyzed by deep sequencing (RNA-Seq) and confirmed by RT-PCR. We found that Y14 is required for efficient and faithful splicing of a group of transcripts that is enriched in short intron containing genes involved in mitotic cell-cycle progression. Tethering of EJC core components (Y14, eIF4AIII or MAGOH) to a model reporter pre-mRNA harboring a short intron showed that these core components are prerequisites for the splicing activation. Taken together, we conclude that the EJC core assembled on pre-mRNA is critical for efficient and faithful splicing of a specific subset of short introns in mitotic cell cycle-related genes. PMID- 27490542 TI - Pharmacological Activities of Ruthenium Complexes Related to Their NO Scavenging Properties. AB - Angiogenesis is considered responsible for the growth of primary tumours and of their metastases. With the present study, the effects of three ruthenium compounds, potassiumchlorido (ethylendiamminotetraacetate)rutenate(III) (RuEDTA), sodium (bis-indazole)tetrachloro-ruthenate(III), Na[trans-RuCl4Ind2] (KP1339) and trans-imidazoledimethylsulphoxidetetrachloro-ruthenate (NAMI-A), are studied in vitro in models mimicking the angiogenic process. The ruthenium compounds reduced the production and the release of nitrosyls from either healthy macrophages and immortalized EA.hy926 endothelial cells. The effects of NAMI-A are qualitatively similar and sometimes quantitatively superior to those of RuEDTA and KP1339. NAMI A reduces the production and release of nitric oxide (NO) by the EA.hy926 endothelial cells and correspondingly inhibits their invasive ability; it also strongly inhibits the angiogenesis in matrigel sponges implanted subcutaneously in healthy mice. Taken together, these data support the anti-angiogenic activity of the tested ruthenium compounds and they contribute to explain the selective activity of NAMI-A against solid tumour metastases, the tumour compartment on which angiogenesis is strongly involved. This anti-angiogenic effect may also contribute to the inhibition of the release of metastatic cells from the primary tumour. Investigations on the anti-angiogenic effects of NAMI-A at this level will increase knowledge of its pharmacological properties and it will give a further impulse to the development of this class of innovative metal-based drugs. PMID- 27490543 TI - Electrochemical Determination of Food Preservative Nitrite with Gold Nanoparticles/p-Aminothiophenol-Modified Gold Electrode. AB - Due to the negative impact of nitrate and nitrite on human health, their presence exceeding acceptable levels is not desired in foodstuffs. Thus, nitrite determination at low concentrations is a major challenge in electroanalytical chemistry, which can be achieved by fast, cheap, and safe electrochemical sensors. In this work, the working electrode (Au) was functionalized with p aminothiophenol (p-ATP) and modified with gold nanoparticles (Au-NPs) to manufacture the final (Au/p-ATP-Aunano) electrode in a two-step procedure. In the first step, p-ATP was electropolymerized on the electrode surface to obtain a polyaminothiophenol (PATP) coating. In the second step, Au/p-ATP-Aunano working electrode was prepared by coating the surface with the use of HAuCl4 solution and cyclic voltammetry. Determination of aqueous nitrite samples was performed with the proposed electrode (Au/p-ATP-Aunano) using square wave voltammetry (SWV) in pH 4 buffer medium. Characteristic peak potential of nitrite samples was 0.76 V, and linear calibration curves of current intensity versus concentration was linear in the range of 0.5-50 mg.L(-1) nitrite with a limit of detection (LOD) of 0.12 mg.L(-1). Alternatively, nitrite in sausage samples could be colorimetrically determined with high sensitivity by means of p-ATP-modified gold nanoparticles (AuNPs) and naphthylethylene diamine as coupling agents for azo-dye formation due to enhanced charge-transfer interactions with the AuNPs surface. The slopes of the calibration lines in pure NO2(-) solution and in sausage sample solution, to which different concentrations of NO2(-) standards were added, were not significantly different from each other, confirming the robustness and interference tolerance of the method. The proposed voltammetric sensing method was validated against the colorimetric nanosensing method in sausage samples. PMID- 27490545 TI - Preprocessing the Nintendo Wii Board Signal to Derive More Accurate Descriptors of Statokinesigrams. AB - During the past few years, the Nintendo Wii Balance Board (WBB) has been used in postural control research as an affordable but less reliable replacement for laboratory grade force platforms. However, the WBB suffers some limitations, such as a lower accuracy and an inconsistent sampling rate. In this study, we focus on the latter, namely the non uniform acquisition frequency. We show that this problem, combined with the poor signal to noise ratio of the WBB, can drastically decrease the quality of the obtained information if not handled properly. We propose a new resampling method, Sliding Window Average with Relevance Interval Interpolation (SWARII), specifically designed with the WBB in mind, for which we provide an open source implementation. We compare it with several existing methods commonly used in postural control, both on synthetic and experimental data. The results show that some methods, such as linear and piecewise constant interpolations should definitely be avoided, particularly when the resulting signal is differentiated, which is necessary to estimate speed, an important feature in postural control. Other methods, such as averaging on sliding windows or SWARII, perform significantly better on synthetic dataset, and produce results more similar to the laboratory-grade AMTI force plate (AFP) during experiments. Those methods should be preferred when resampling data collected from a WBB. PMID- 27490544 TI - Examination of Inertial Sensor-Based Estimation Methods of Lower Limb Joint Moments and Ground Reaction Force: Results for Squat and Sit-to-Stand Movements in the Sagittal Plane. AB - Joint moment estimation by a camera-based motion measurement system and a force plate has a limitation of measurement environment and is costly. The purpose of this paper is to evaluate quantitatively inertial sensor-based joint moment estimation methods with five-link, four-link and three-link rigid body models using different trunk segmented models. Joint moments, ground reaction forces (GRF) and center of pressure (CoP) were estimated for squat and sit-to-stand movements in the sagittal plane measured with six healthy subjects. The five-link model and the four-link model that the trunk was divided at the highest point of the iliac crest (four-link-IC model) were appropriate for joint moment estimation with inertial sensors, which showed average RMS values of about 0.1 Nm/kg for all lower limb joints and average correlation coefficients of about 0.98 for hip and knee joints and about 0.80 for ankle joint. Average root mean square (RMS) errors of horizontal and vertical GRFs and CoP were about 10 N, 15 N and 2 cm, respectively. Inertial sensor-based method was suggested to be an option for estimating joint moments of the trunk segments. Inertial sensors were also shown to be useful for the bottom-up estimation method using measured GRFs, in which average RMS values and average correlation coefficients were about 0.06 Nm/kg and larger than about 0.98 for all joints. PMID- 27490546 TI - Passive Wireless Hermetic Environment Monitoring System for Spray Painting Workshop. AB - Passive wireless sensors have the advantages of operating without a power supply and remote sensing capability. Hence, they are very suitable for some harsh environments, such as hermetic environments, rotating parts, or very high temperature environments. The spray painting workshop is such a harsh environment, containing a large amount of flammable paint mist and organic gas. Aiming at this special environment of spray painting workshop, a passive wireless hermetic environment monitoring system was designed, fabricated, and demonstrated. The proposed system is composed of a transponder and a reader, and the circuit design of each part is given in detail in this paper. The power and the data transmission between the transponder and the reader are realized by the inductive coupling mechanism. Utilizing the back scatter modulation and channel multiplexing, the frequency signals generated by three different environmental sensors-together with their interfaces in the transponder-are wirelessly read out by the reader. Because of the harsh environment of the spray painting room, the package of the monitoring system is quite important. Three different kinds of filter films for the system package were compared. The experimental results show that the composite filter film aluminum anodic oxide/polytetrafluoroethylene (AAO/PTFE) has the best performance. After fabrication, the measured temperature, humidity, and pressure sensitivities were measured and found to be 180 Hz/ degrees C in the range of 0~60 degrees C, 100 Hz/%RH in the range of 15~95 %RH, and 42 Hz/hPa in the range of 600~1100 hPa, respectively. Additionally, the remote sensing distance of the monitoring system reaches 4 cm. Finally, the passive wireless hermetic environment monitoring system was installed on the glass wall of the spray painting workshop and was successfully demonstrated. PMID- 27490547 TI - Transducer Development and Characterization for Underwater Acoustic Neutrino Detection Calibration. AB - A short bipolar pressure pulse with "pancake" directivity is produced and propagated when an Ultra-High Energy (UHE) neutrino interacts with a nucleus in water. Nowadays, acoustic sensor networks are being deployed in deep seas to detect this phenomenon as a first step toward building a neutrino telescope. In order to study the feasibility of the method, it is critical to have a calibrator that is able to mimic the neutrino signature. In previous works the possibility of using the acoustic parametric technique for this aim was proven. In this study, the array is operated at a high frequency and, by means of the parametric effect, the emission of the low-frequency acoustic bipolar pulse is generated mimicking the UHE neutrino acoustic pulse. To this end, the development of the transducer to be used in the parametric array is described in all its phases. The transducer design process, the characterization tests for the bare piezoelectric ceramic, and the addition of backing and matching layers are presented. The efficiencies and directivity patterns obtained for both primary and parametric beams confirm that the design of the proposed calibrator meets all the requirements for the emitter. PMID- 27490548 TI - Quantitative Determination of Fluorine Content in Blends of Polylactide (PLA) Talc Using Near Infrared Spectroscopy. AB - Near-infrared spectroscopy (NIRS) has been widely used for quantitative and/or qualitative determination of a wide range of matrices. The objective of this study was to develop a NIRS method for the quantitative determination of fluorine content in polylactide (PLA)-talc blends. A blending profile was obtained by mixing different amounts of PLA granules and talc powder. The calibration model was built correlating wet chemical data (alkali digestion method) and NIR spectra. Using FT (Fourier Transform)-NIR technique, a Partial Least Squares (PLS) regression model was set-up, in a concentration interval of 0 ppm of pure PLA to 800 ppm of pure talc. Fluorine content prediction (R2cal = 0.9498; standard error of calibration, SEC = 34.77; standard error of cross-validation, SECV = 46.94) was then externally validated by means of a further 15 independent samples (R2EX.V = 0.8955; root mean standard error of prediction, RMSEP = 61.08). A positive relationship between an inorganic component as fluorine and NIR signal has been evidenced, and used to obtain quantitative analytical information from the spectra. PMID- 27490549 TI - Sine Rotation Vector Method for Attitude Estimation of an Underwater Robot. AB - This paper describes a method for estimating the attitude of an underwater robot. The method employs a new concept of sine rotation vector and uses both an attitude heading and reference system (AHRS) and a Doppler velocity log (DVL) for the purpose of measurement. First, the acceleration and magnetic-field measurements are transformed into sine rotation vectors and combined. The combined sine rotation vector is then transformed into the differences between the Euler angles of the measured attitude and the predicted attitude; the differences are used to correct the predicted attitude. The method was evaluated according to field-test data and simulation data and compared to existing methods that calculate angular differences directly without a preceding sine rotation vector transformation. The comparison verifies that the proposed method improves the attitude estimation performance. PMID- 27490550 TI - Seasonal Mass Changes and Crustal Vertical Deformations Constrained by GPS and GRACE in Northeastern Tibet. AB - Surface vertical deformation includes the Earth's elastic response to mass loading on or near the surface. Continuous Global Positioning System (CGPS) stations record such deformations to estimate seasonal and secular mass changes. We used 41 CGPS stations to construct a time series of coordinate changes, which are decomposed by empirical orthogonal functions (EOFs), in northeastern Tibet. The first common mode shows clear seasonal changes, indicating seasonal surface mass re-distribution around northeastern Tibet. The GPS-derived result is then assessed in terms of the mass changes observed in northeastern Tibet. The GPS derived common mode vertical change and the stacked Gravity Recovery and Climate Experiment (GRACE) mass change are consistent, suggesting that the seasonal surface mass variation is caused by changes in the hydrological, atmospheric and non-tidal ocean loads. The annual peak-to-peak surface mass changes derived from GPS and GRACE results show seasonal oscillations in mass loads, and the corresponding amplitudes are between 3 and 35 mm/year. There is an apparent gradually increasing gravity between 0.1 and 0.9 MUGal/year in northeast Tibet. Crustal vertical deformation is determined after eliminating the surface load effects from GRACE, without considering Glacial Isostatic Adjustment (GIA) contribution. It reveals crustal uplift around northeastern Tibet from the corrected GPS vertical velocity. The unusual uplift of the Longmen Shan fault indicates tectonically sophisticated processes in northeastern Tibet. PMID- 27490551 TI - INS/GNSS Tightly-Coupled Integration Using Quaternion-Based AUPF for USV. AB - This paper addresses the problem of integration of Inertial Navigation System (INS) and Global Navigation Satellite System (GNSS) for the purpose of developing a low-cost, robust and highly accurate navigation system for unmanned surface vehicles (USVs). A tightly-coupled integration approach is one of the most promising architectures to fuse the GNSS data with INS measurements. However, the resulting system and measurement models turn out to be nonlinear, and the sensor stochastic measurement errors are non-Gaussian and distributed in a practical system. Particle filter (PF), one of the most theoretical attractive non linear/non-Gaussian estimation methods, is becoming more and more attractive in navigation applications. However, the large computation burden limits its practical usage. For the purpose of reducing the computational burden without degrading the system estimation accuracy, a quaternion-based adaptive unscented particle filter (AUPF), which combines the adaptive unscented Kalman filter (AUKF) with PF, has been proposed in this paper. The unscented Kalman filter (UKF) is used in the algorithm to improve the proposal distribution and generate a posterior estimates, which specify the PF importance density function for generating particles more intelligently. In addition, the computational complexity of the filter is reduced with the avoidance of the re-sampling step. Furthermore, a residual-based covariance matching technique is used to adapt the measurement error covariance. A trajectory simulator based on a dynamic model of USV is used to test the proposed algorithm. Results show that quaternion-based AUPF can significantly improve the overall navigation accuracy and reliability. PMID- 27490552 TI - Modeling and Analysis of Phase Fluctuation in a High-Precision Roll Angle Measurement Based on a Heterodyne Interferometer. AB - Heterodyne interferometry is a high-precision method applied in roll angle measurements. Phase metering is essential for high precision. During a high precision measurement, a phase fluctuation appears even when the roll angle does not vary, which has never been analyzed before. Herein, the reason for the phase fluctuation is revealed, which results from the frequency-difference fluctuation and time difference between measurement and reference beams. A mathematical model of that phase-fluctuation mechanism is established, and that model provides a theoretical basis for analyzing and reducing the phase fluctuation. The impact that the main factors have on the phase metering is analyzed quantitatively, and experiments are carried out to validate the model. Finally, the phase fluctuation decreases to 0.02 degrees by frequency reduction, which conversely verifies the theoretical model. PMID- 27490554 TI - Bindings and RESTlets: A Novel Set of CoAP-Based Application Enablers to Build IoT Applications. AB - Sensors and actuators are becoming important components of Internet of Things (IoT) applications. Today, several approaches exist to facilitate communication of sensors and actuators in IoT applications. Most communications go through often proprietary gateways requiring availability of the gateway for each and every interaction between sensors and actuators. Sometimes, the gateway does some processing of the sensor data before triggering actuators. Other approaches put this processing logic further in the cloud. These approaches introduce significant latencies and increased number of packets. In this paper, we introduce a CoAP-based mechanism for direct binding of sensors and actuators. This flexible binding solution is utilized further to build IoT applications through RESTlets. RESTlets are defined to accept inputs and produce outputs after performing some processing tasks. Sensors and actuators could be associated with RESTlets (which can be hosted on any device) through the flexible binding mechanism we introduced. This approach facilitates decentralized IoT application development by placing all or part of the processing logic in Low power and Lossy Networks (LLNs). We run several tests to compare the performance of our solution with existing solutions and found out that our solution reduces communication delay and number of packets in the LLN. PMID- 27490553 TI - Identification of Quorum-Sensing Signal Molecules and a Biosynthetic Gene in Alicycliphilus sp. Isolated from Activated Sludge. AB - Activated sludge is a complicated mixture of various microorganisms that is used to treat sewage and industrial wastewater. Many bacteria produce N-acylhomoserine lactone (AHL) as a quorum-sensing signal molecule to regulate the expression of the exoenzymes used for wastewater treatment. Here, we isolated an AHL-producing bacteria from an activated sludge sample collected from an electronic component factory, which we named Alicycliphilus sp. B1. Clone library analysis revealed that Alicycliphilus was a subdominant genus in this sample. When we screened the activated sludge sample for AHL-producing strains, 12 of 14 the AHL-producing isolates were assigned to the genus Alicycliphilus. A putative AHL-synthase gene, ALISP_0667, was cloned from the genome of B1 and transformed into Escherichia coli DH5alpha. The AHLs were extracted from the culture supernatants of the B1 strain and E. coli DH5alpha cells harboring the ALISP_0667 gene and were identified by liquid chromatography-mass spectrometry as N-(3-hydroxydecanoyl)-l homoserine lactone and N-(3-hydroxydodecanoyl)-l-homoserine lactone. The results of comparative genomic analysis suggested that the quorum-sensing genes in the B1 strain might have been acquired by horizontal gene transfer within activated sludge. PMID- 27490555 TI - Topsensterols A-C, Cytotoxic Polyhydroxylated Sterol Derivatives from a Marine Sponge Topsentia sp. AB - Three new polyhydroxylated sterol derivatives topsensterols A-C (1-3) have been isolated from a marine sponge Topsentia sp. collected from the South China Sea. Their structures were elucidated by detailed analysis of the spectroscopic data, especially the NOESY spectra. Topsensterols A-C (l-3) possess novel 2beta,3alpha,4beta,6alpha-tetrahydroxy-14alpha-methyl Delta(9(11)) steroidal nuclei with unusual side chains. Compound 2 exhibited cytotoxicity against human gastric carcinoma cell line SGC-7901 with an IC50 value of 8.0 MUM. Compound 3 displayed cytotoxicity against human erythroleukemia cell line K562 with an IC50 value of 6.0 MUM. PMID- 27490556 TI - Severe and Moderate Asthma Exacerbations in Asthmatic Children and Exposure to Ambient Air Pollutants. AB - BACKGROUND: It is well established that short-term exposure to ambient air pollutants can exacerbate asthma, the role of early life or long-term exposure is less clear. We assessed the association between severe asthma exacerbations with both birth and annual exposure to outdoor air pollutants with a population-based cohort of asthmatic children in the province of Quebec (Canada). METHOD: Exacerbations of asthma occurring between 1 April 1996 and 31 March 2011 were defined as one hospitalization or emergency room visit with a diagnosis of asthma for children (<13 years old) already diagnosed with asthma. Annual daily average concentrations of ozone (O3) and nitrogen dioxide (NO2) were estimated at the child's residential postal code. Satellite based levels of fine particulate (PM2.5) estimated for a grid of 10 km by 10 km were also assigned to postal codes of residence for the whole province. Hazard ratios (HRs) were estimated from Cox models with a gap time approach for both birth and time-dependant exposure. RESULTS: Of the 162,752 asthmatic children followed (1,020,280 person-years), 35,229 had at least one asthma exacerbation. The HRs stratified by age groups and adjusted for the year of birth, the ordinal number of exacerbations, sex, as well as material and social deprivation, showed an interquartile range increase in the time-dependant exposure to NO2 (4.95 ppb), O3 (3.85 ppb), and PM2.5 (1.82 MUg/m3) of 1.095 (95% CI 1.058-1.131), 1.052 (95% CI 1.037-1.066) and 1.025 (95% CI 1.017 1.031), respectively. While a positive association was found to PM2.5, no associations were found between exposure at birth to NO2 or O3. CONCLUSIONS: Our results support the conclusion, within the limitation of this study, that asthma exacerbations in asthmatic children are mainly associated with time dependent residential exposures less with exposure at birth. PMID- 27490557 TI - Spatiotemporal Variability of Remotely Sensed PM2.5 Concentrations in China from 1998 to 2014 Based on a Bayesian Hierarchy Model. AB - With the rapid industrial development and urbanization in China over the past three decades, PM2.5 pollution has become a severe environmental problem that threatens public health. Due to its unbalanced development and intrinsic topography features, the distribution of PM2.5 concentrations over China is spatially heterogeneous. In this study, we explore the spatiotemporal variations of PM2.5 pollution in China and four great urban areas from 1998 to 2014. A space time Bayesian hierarchy model is employed to analyse PM2.5 pollution. The results show that a stable "3-Clusters" spatial PM2.5 pollution pattern has formed. The mean and 90% quantile of the PM2.5 concentrations in China have increased significantly, with annual increases of 0.279 MUg/m3 (95% CI: 0.083-0.475) and 0.735 MUg/m3 (95% CI: 0.261-1.210), respectively. The area with a PM2.5 pollution level of more than 70 MUg/m3 has increased significantly, with an annual increase of 0.26 percentage points. Two regions in particular, the North China Plain and Sichuan Basin, are experiencing the largest amounts of PM2.5 pollution. The polluted areas, with a high local magnitude of more than 1.0 relative to the overall PM2.5 concentration, affect an area with a human population of 949 million, which corresponded to 69.3% of the total population in 2010. North and south differentiation occurs in the urban areas of the Jingjinji and Yangtze Delta, and circular and radial gradient differentiation occur in the urban areas of the Cheng-Yu and Pearl Deltas. The spatial heterogeneity of the urban Jingjinji group is the strongest. Eighteen cities located in the Yangtze Delta urban group, including Shanghai and Nanjing, have experienced high PM2.5 concentrations and faster local trends of increasing PM2.5. The percentage of exposure to PM2.5 concentrations greater than 70 MUg/m3 and 100 MUg/m3 is increasing significantly. PMID- 27490558 TI - Correlation of CpG Island Methylation of the Cytochrome P450 2E1/2D6 Genes with Liver Injury Induced by Anti-Tuberculosis Drugs: A Nested Case-Control Study. AB - This study investigated the role of CpG island methylation of the CYP2E1 and CYP2D6 genes in liver injury induced by anti-TB drugs from an epigenetic perspective in a Chinese cohort. A 1:1 matched nested case-control study design was applied. Pulmonary tuberculosis (TB) patients, who underwent standard anti-TB therapy and developed liver injury were defined as cases, while those who did not develop liver injury were defined as control. The two groups were matched in terms of sex, treatment regimen, and age. In 114 pairs of cases, CpG island methylation levels of the CYP2E1 and CYP2D6 genes in plasma cell-free DNA were found to be significantly correlated with the occurrence of anti-TB drug-induced liver injury (ADLI), with odds ratio (OR) values of 2.429 and 3.500, respectively (p < 0.01). Moreover, through multivariate logistic regression analysis, CpG island methylation of the CYP2E1 and CYP2D6 genes in plasma cell-free DNA were found to be significantly correlated with the occurrence of ADLI, with adjusted OR values of 4.390 (95% confidence interval (CI): 1.982-9.724) and 9.193 (95% CI: 3.624-25.888), respectively (p < 0.001). These results suggest that aberrantly elevated methylation of CpG islands of the CYP2E1 and CYP2D6 genes in plasma cell free DNA may increase the risk of ADLI in Chinese TB patients. PMID- 27490559 TI - Effect of Hypoxia on Ldh-c Expression in Somatic Cells of Plateau Pika. AB - Sperm specific lactate dehydrogenases (LDH-C4) is a lactate dehydrogenase that catalyzes the conversion of pyruvate to lactate. In mammals, Ldh-c was originally thought to be expressed only in testes and spermatozoa. Plateau pika (Ochotona curzoniae), which belongs to the genus Ochotona of the Ochotonidea family, is a hypoxia-tolerant mammal living 3000-5000 m above sea level on the Qinghai-Tibet Plateau, an environment which is strongly hypoxic. Ldh-c is expressed not only in testes and sperm, but also in the somatic tissues of plateau pika. To reveal the effect of hypoxia on pika Ldh-c expression, we investigated the mRNA and protein level of Ldh-c as well as the biochemical index of anaerobic glycolysis in pika somatic tissues at the altitudes of 2200 m, 3200 m and 3900 m. Our results showed that mRNA and protein expression levels of Ldh-c in the tissues of pika's heart, liver, brain and skeletal muscle were increased significantly from 2200 m to 3200 m, but had no difference from 3200 m to 3900 m; the activities of LDH and the contents of lactate showed no difference from 2200 m to 3200 m, but were increased significantly from 3200 m to 3900 m. Hypoxia up-regulated and maintained the expression levels of Ldh-c in the pika somatic cells. Under the hypoxia condition, plateau pikas increased anaerobic glycolysis in somatic cells by LDH-C4, and that may have reduced their dependence on oxygen and enhanced their adaptation to the hypoxic environment. PMID- 27490560 TI - The Impact of Low-Level Lead Toxicity on School Performance among Hispanic Subgroups in the Chicago Public Schools. AB - BACKGROUND: Environmental lead exposure detrimentally affects children's educational performance, even at very low blood lead levels (BLLs). Among children in Chicago Public Schools (CPS), the severity of the effects of BLL on reading and math vary by racial subgroup (White vs. Hispanic vs. non-Hispanic Black). We investigated the impact of BLL on standardized test performance by Hispanic subgroup (Mexican, Puerto Rican, and Other Hispanic). METHODS: We examined 12,319 Hispanic children born in Chicago between 1994 and 1998 who were tested for BLL between birth and 2006 and enrolled in the 3rd grade at a CPS school between 2003 and 2006. We linked the Chicago birth registry, the Chicago Blood Lead Registry, and 3rd grade Illinois Standard Achievement Test (ISAT) scores to examine associations between BLL and school performance. Primary analyses were restricted to children with BLL below 10 ug/dL (0.483 umol/L). RESULTS: BLLs below 10 ug/dL (0.483 umol/L) were inversely associated with reading and math scores in all Hispanic subgroups. Adjusted Relative Risks (RRadj) and 95% confidence intervals (CI) for reading and math failure were 1.34 (95% CI = 1.25, 1.63) and 1.53 (95% CI = 1.32, 1.78), respectively, per each additional 5 ug/dL of lead exposure for Hispanic children; RRadj did not differ across subgroups. We estimate that 7.0% (95% CI = 1.8, 11.9) of reading and 13.6% (95% CI = 7.7, 19.2) of math failure among Hispanic children can be attributed to exposure to BLLs of 5-9 ug/dL (0.242 to 0.435 umol/L) vs. 0-4 ug/dL (0-0.193 umol/L). The RRadj of math failure for each 5 ug/dL (0.242 umol/L) increase in BLL was notably (p = 0.074) stronger among black Puerto Rican children (RRadj = 5.14; 95% CI = 1.65-15.94) compared to white Puerto Rican children (RRadj = 1.50; 95% CI = 1.12-2.02). CONCLUSIONS: Early childhood lead exposure is associated with poorer achievement on standardized reading and math tests in the 3rd grade for Mexican, Puerto Rican, and Other Hispanic children enrolled in Chicago Public Schools. While we did not see interactions between BLL and ISAT performance by Hispanic subgroup, the stronger association between BLL and math failure for Black Puerto Rican children is intriguing and warrants further study. PMID- 27490561 TI - Exposure to Flood Hazards in Miami and Houston: Are Hispanic Immigrants at Greater Risk than Other Social Groups? AB - Although numerous studies have been conducted on the vulnerability of marginalized groups in the environmental justice (EJ) and hazards fields, analysts have tended to lump people together in broad racial/ethnic categories without regard for substantial within-group heterogeneity. This paper addresses that limitation by examining whether Hispanic immigrants are disproportionately exposed to risks from flood hazards relative to other racial/ethnic groups (including US-born Hispanics), adjusting for relevant covariates. Survey data were collected for 1283 adult householders in the Houston and Miami Metropolitan Statistical Areas (MSAs) and flood risk was estimated using their residential presence/absence within federally-designated 100-year flood zones. Generalized estimating equations (GEE) with binary logistic specifications that adjust for county-level clustering were used to analyze (separately) and compare the Houston (N = 546) and Miami (N = 560) MSAs in order to clarify determinants of household exposure to flood risk. GEE results in Houston indicate that Hispanic immigrants have the greatest likelihood, and non-Hispanic Whites the least likelihood, of residing in a 100-year flood zone. Miami GEE results contrastingly reveal that non-Hispanic Whites have a significantly greater likelihood of residing in a flood zone when compared to Hispanic immigrants. These divergent results suggest that human-flood hazard relationships have been structured differently between the two MSAs, possibly due to the contrasting role that water-based amenities have played in urbanization within the two study areas. Future EJ research and practice should differentiate between Hispanic subgroups based on nativity status and attend to contextual factors influencing environmental risk disparities. PMID- 27490562 TI - Newborn Parent Based Intervention to Increase Child Safety Seat Use. AB - This paper intends to assess the effect of a maternity department intervention on improvement of knowledge and use of child safety seats (CSS) among newborn parents. An intervention study included three groups (one education plus free CSS intervention group, one education only group, and one control group). The participants were parents of newborns in the maternity department of two hospitals. Both of the intervention groups received a folded pamphlet of child passenger safety, a height chart and standardized safety education during their hospital stay after giving birth. The education plus free CSS intervention group received an additional free CSS and professional installation training at hospital discharge. The control group received a pamphlet with educational information about nutrition and food safety. Three months after enrollment, a telephone follow-up was conducted among participants in the three groups. Data on child passenger safety knowledge, risky driving behaviors, and use of CSS were evaluated before and after the intervention. A total of 132 newborn parents were enrolled in the study; of those, 52 (39.4%) were assigned into the education plus free CSS intervention group, 44 (33.3%) were in the education intervention only group, and 36 (27.3%) were in the control group. No significant differences existed in demographics among the three groups. There was a significant difference in newborn parents' child passenger safety knowledge and behaviors in the three groups before and after the intervention. In addition, the CSS use increased significantly in the education plus free CSS group after the intervention compared to parents in the education only or control groups. Education on safety, combined with a free CSS and professional installation training, were effective at increasing newborn parents' knowledge and use of CSS. Future studies with larger sample sizes and longer follow-up are needed to determine a long-term effect of the intervention. PMID- 27490563 TI - High Laccase Expression by Trametes versicolor in a Simulated Textile Effluent with Different Carbon Sources and PHs. AB - Textile effluents are highly polluting and have variable and complex compositions. They can be extremely complex, with high salt concentrations and alkaline pHs. A fixed-bed bioreactor was used in the present study to simulate a textile effluent treatment, where the white-rot fungus, Trametes versicolor, efficiently decolourised the azo dye Reactive Black 5 over 28 days. This occurred under high alkaline conditions, which is unusual, but advantageous, for successful decolourisation processes. Active dye decolourisation was maintained by operation in continuous culture. Colour was eliminated during the course of operation and maximum laccase (Lcc) activity (80.2 U?L(-1)) was detected after glycerol addition to the bioreactor. Lcc2 gene expression was evaluated with different carbon sources and pH values based on reverse transcriptase-PCR (polymerase chain reaction). Glycerol was shown to promote the highest lcc2 expression at pH 5.5, followed by sucrose and then glucose. The highest levels of expression occurred between three and four days, which corroborate the maximum Lcc activity observed for sucrose and glycerol on the bioreactor. These results give new insights into the use of T. versicolor in textile dye wastewater treatment with high pHs. PMID- 27490564 TI - Measles Virus Hemagglutinin Protein Epitopes: The Basis of Antigenic Stability. AB - Globally eliminating measles using available vaccines is biologically feasible because the measles virus (MV) hemagglutinin (H) protein is antigenically stable. The H protein is responsible for receptor binding, and is the main target of neutralizing antibodies. The immunodominant epitope, known as the hemagglutinating and noose epitope, is located near the receptor-binding site (RBS). The RBS also contains an immunodominant epitope. Loss of receptor binding correlates with an escape from the neutralization by antibodies that target the epitope at RBS. Another neutralizing epitope is located near RBS and is shielded by an N-linked sugar in certain genotype strains. However, human sera from vaccinees and measles patients neutralized all MV strains with similar efficiencies, regardless of the N-linked sugar modification or mutations at these epitopes. Two other major epitopes exist at a distance from RBS. One has an unstructured flexible domain with a linear neutralizing epitope. When MV-H forms a tetramer (dimer of dimers), these epitopes may form the dimer-dimer interface, and one of the two epitopes may also interact with the F protein. The neutralization mechanisms of antibodies that recognize these epitopes may involve inhibiting the H-F interaction or blocking the fusion cascade after MV-H binds to its receptors. PMID- 27490565 TI - Clomiphene and Its Isomers Block Ebola Virus Particle Entry and Infection with Similar Potency: Potential Therapeutic Implications. AB - The 2014 outbreak of Ebola virus (EBOV) in Western Africa highlighted the need for anti-EBOV therapeutics. Clomiphene is a U.S. Food and Drug Administration (FDA)-approved drug that blocks EBOV entry and infection in cells and significantly protects EBOV-challenged mice. As provided, clomiphene is, approximately, a 60:40 mixture of two stereoisomers, enclomiphene and zuclomiphene. The pharmacokinetic properties of the two isomers vary, but both accumulate in the eye and male reproductive tract, tissues in which EBOV can persist. Here we compared the ability of clomiphene and its isomers to inhibit EBOV using viral-like particle (VLP) entry and transcription/replication competent VLP (trVLP) assays. Clomiphene and its isomers inhibited the entry and infection of VLPs and trVLPs with similar potencies. This was demonstrated with VLPs bearing the glycoproteins from three filoviruses (EBOV Mayinga, EBOV Makona, and Marburg virus) and in two cell lines (293T/17 and Vero E6). Visual problems have been noted in EBOV survivors, and viral RNA has been isolated from semen up to nine months post-infection. Since the clomiphene isomers accumulate in these affected tissues, clomiphene or one of its isomers warrants consideration as an anti-EBOV agent, for example, to potentially help ameliorate symptoms in EBOV survivors. PMID- 27490566 TI - Novel Combination of Prebiotics Galacto-Oligosaccharides and Inulin-Inhibited Aberrant Crypt Foci Formation and Biomarkers of Colon Cancer in Wistar Rats. AB - The selectivity and beneficial effects of prebiotics are mainly dependent on composition and glycosidic linkage among monosaccharide units. This is the first study to use prebiotic galacto-oligosaccharides (GOS) that contains beta-1,6 and beta-1,3 glycosidic linkages and the novel combination of GOS and inulin in cancer prevention. The objective of the present study is to explore the role of novel GOS and inulin against various biomarkers of colorectal cancer (CRC) and the incidence of aberrant crypt foci (ACF) in a 1,2-dimethyl hydrazine dihydrochloride (DMH)-induced rodent model. Prebiotic treatments of combined GOS and inulin (57 mg each), as well as individual doses (GOS: 76-151 mg; inulin 114 mg), were given to DMH-treated animals for 16 weeks. Our data reveal the significant preventive effect of the GOS and inulin combination against the development of CRC. It was observed that inhibition of ACF formation (55.8%) was significantly (p <= 0.05) higher using the GOS and inulin combination than GOS (41.4%) and inulin (51.2%) treatments alone. This combination also rendered better results on short-chain fatty acids (SCFA) and bacterial enzymatic activities. Dose-dependent effects of prebiotic treatments were also observed on cecum and fecal bacterial enzymes and on SCFA. Thus, this study demonstrated that novel combination of GOS and inulin exhibited stronger preventive activity than their individual treatments alone, and can be a promising strategy for CRC chemoprevention. PMID- 27490567 TI - The Effect of Holder Pasteurization on Nutrients and Biologically-Active Components in Donor Human Milk: A Review. AB - When a mother's milk is unavailable, the best alternative is donor milk (DM). Milk delivered to Human Milk Banks should be pasteurized in order to inactivate the microbial agents that may be present. Currently, pasteurization, performed at 62.5 degrees C for 30 min (Holder Pasteurization, HoP), is recommended for this purpose in international guidelines. Several studies have been performed to investigate the effects of HoP on the properties of DM. The present paper has the aim of reviewing the published papers on this topic, and to provide a comparison of the reported variations of biologically-active DM components before and after HoP. This review was performed by searching the MEDLINE, EMBASE, CINHAL and Cochrane Library databases. Studies that clearly identified the HoP parameters and compared the same DM samples, before and after pasteurization, were focused on. A total of 44 articles satisfied the above criteria, and were therefore selected. The findings from the literature report variable results. A possible explanation for this may be the heterogeneity of the test protocols that were applied. Moreover, the present review spans more than five decades, and modern pasteurizers may be able to modify the degradation kinetics for heat-sensitive substances, compared to older ones. Overall, the data indicate that HoP affects several milk components, although it is difficult to quantify the degradation degree. However, clinical practices demonstrate that many beneficial properties of DM still persist after HoP. PMID- 27490568 TI - Selective Membrane Redistribution and Depletion of Galphaq-Protein by Pasteurella multocida Toxin. AB - Pasteurella multocida toxin (PMT), the major virulence factor responsible for zoonotic atrophic rhinitis, is a protein deamidase that activates the alpha subunit of heterotrimeric G proteins. Initial activation of G alpha-q-coupled phospholipase C-beta-1 signaling by PMT is followed by uncoupling of G alpha-q dependent signaling, causing downregulation of downstream calcium and mitogenic signaling pathways. Here, we show that PMT decreases endogenous and exogenously expressed G alpha-q protein content in host cell plasma membranes and in detergent resistant membrane (DRM) fractions. This membrane depletion of G alpha q protein was dependent upon the catalytic activity of PMT. Results indicate that PMT-modified G alpha-q redistributes within the host cell membrane from the DRM fraction into the soluble membrane and cytosolic fractions. In contrast, PMT had no affect on G alpha-s or G beta protein levels, which are not substrate targets of PMT. PMT also had no affect on G alpha-11 levels, even though G alpha-11 can serve as a substrate for deamidation by PMT, suggesting that membrane depletion of PMT-modified G-alpha-q has specificity. PMID- 27490569 TI - Putative Nonribosomal Peptide Synthetase and Cytochrome P450 Genes Responsible for Tentoxin Biosynthesis in Alternaria alternata ZJ33. AB - Tentoxin, a cyclic tetrapeptide produced by several Alternaria species, inhibits the F1-ATPase activity of chloroplasts, resulting in chlorosis in sensitive plants. In this study, we report two clustered genes, encoding a putative non ribosome peptide synthetase (NRPS) TES and a cytochrome P450 protein TES1, that are required for tentoxin biosynthesis in Alternaria alternata strain ZJ33, which was isolated from blighted leaves of Eupatorium adenophorum. Using a pair of primers designed according to the consensus sequences of the adenylation domain of NRPSs, two fragments containing putative adenylation domains were amplified from A. alternata ZJ33, and subsequent PCR analyses demonstrated that these fragments belonged to the same NRPS coding sequence. With no introns, TES consists of a single 15,486 base pair open reading frame encoding a predicted 5161 amino acid protein. Meanwhile, the TES1 gene is predicted to contain five introns and encode a 506 amino acid protein. The TES protein is predicted to be comprised of four peptide synthase modules with two additional N-methylation domains, and the number and arrangement of the modules in TES were consistent with the number and arrangement of the amino acid residues of tentoxin, respectively. Notably, both TES and TES1 null mutants generated via homologous recombination failed to produce tentoxin. This study provides the first evidence concerning the biosynthesis of tentoxin in A. alternata. PMID- 27490570 TI - Developmental Drift and the Role of Wnt Signaling in Aging. AB - Population aging is a public health problem affecting the majority of the developed world. As populations age, the incidence of degenerative diseases increases exponentially, leading to large increases in public spending on healthcare. Here we summarize recent findings on the developmental drift theory of aging, and the links that have been established between aging and the Wnt signaling pathways. We focus on insights derived from model organisms connecting the evolutionary basis of aging and the link to developmental programming. PMID- 27490571 TI - A Hypothesis: Life Initiated from Two Genes, as Deduced from the RNA World Hypothesis and the Characteristics of Life-Like Systems. AB - RNA played a central role in the emergence of the first life-like system on primitive Earth since RNA molecules contain both genetic information and catalytic activity. However, there are several drawbacks regarding the RNA world hypothesis. Here, I briefly discuss the feasibility of the RNA world hypothesis to deduce the RNA functions that are essential for forming a life-like system. At the same time, I have conducted a conceptual analysis of the characteristics of biosystems as a useful approach to deduce a realistic life-like system in relation to the definition of life. For instance, an RNA-based life-like system should possess enough stability to resist environmental perturbations, by developing a cell-like compartment, for instance. Here, a conceptual viewpoint is summarized to provide a realistic life-like system that is compatible with the primitive Earth environment and the capabilities of RNA molecules. According to the empirical and conceptual analysis, I propose the hypothesis that the first life-like system could have initiated from only two genes. PMID- 27490572 TI - Lariophagus distinguendus (Hymenoptera: Pteromalidae) (Forster)-Past, Present, and Future: The History of a Biological Control Method Using L. distinguendus against Different Storage Pests. AB - Legal requirements and consumer demands for residue-free products pose a big challenge for pest control in grain stores. One possible alternative to chemical insecticides is biological pest control with the pteromalid wasp Lariophagus distinguendus against the weevils Sitophilus granarius, S. oryzae (Coleoptera: Dryophtoridae), and many other storage pest beetles. The use of this wasp as a biocontrol agent was already suggested in 1919 by Prof. Dr. Hase [1]. Despite many studies on host-finding and behavioral biology, the applied aspect was neglected until 1994. Nowadays the wasps are commercially available and can now even be reared on-site, facilitating their use tremendously. This review highlights the milestones in L. distinguendus research, gives insights in current studies, and ventures a glimpse into the future. PMID- 27490573 TI - Evaluation of Low versus High Volume per Minute Displacement CO2 Methods of Euthanasia in the Induction and Duration of Panic-Associated Behavior and Physiology. AB - Current recommendations for the use of CO 2 as a euthanasia agent for rats require the use of gradual fill protocols (such as 10% to 30% volume displacement per minute) in order to render the animal insensible prior to exposure to levels of CO 2 that are associated with pain. However, exposing rats to CO 2 , concentrations as low as 7% CO 2 are reported to cause distress and 10%-20% CO 2 induces panic-associated behavior and physiology, but loss of consciousness does not occur until CO 2 concentrations are at least 40%. This suggests that the use of the currently recommended low flow volume per minute displacement rates create a situation where rats are exposed to concentrations of CO 2 that induce anxiety, panic, and distress for prolonged periods of time. This study first characterized the response of male rats exposed to normoxic 20% CO 2 for a prolonged period of time as compared to room air controls. It demonstrated that rats exposed to this experimental condition displayed clinical signs consistent with significantly increased panic-associated behavior and physiology during CO 2 exposure. When atmospheric air was then again delivered, there was a robust increase in respiration rate that coincided with rats moving to the air intake. The rats exposed to CO 2 also displayed behaviors consistent with increased anxiety in the behavioral testing that followed the exposure. Next, this study assessed the behavioral and physiologic responses of rats that were euthanized with 100% CO 2 infused at 10%, 30%, or 100% volume per minute displacement rates. Analysis of the concentrations of CO 2 and oxygen in the euthanasia chamber and the behavioral responses of the rats suggest that the use of the very low flow volume per minute displacement rate (10%) may prolong the duration of panicogenic ranges of ambient CO 2 , while the use of the higher flow volume per minute displacement rate (100%) increases agitation. Therefore, of the volume displacement per minute rates evaluated, this study suggests that 30% minimizes the potential pain and distress experienced by the animal. PMID- 27490574 TI - Antioxidant Properties of Water-Soluble Gum from Flaxseed Hulls. AB - Soluble flaxseed gum (SFG) was extracted from flax (Linum usitatissimum) hulls using hot water, and its functional groups and antioxidant properties were investigated using infrared spectroscopy and different antioxidant assays (2,2 diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulphonic acid (ABTS), reducing power capacity, and beta-carotene bleaching inhibition assay), respectively. The antioxidant capacity of SFG showed interesting DPPH radical-scavenging capacity (IC50 SFG = 2.5 mg.mL(-1)), strong ABTS radical scavenging activity (% inhibition ABTS = 75.6% +/- 2.6% at 40 mg.mL( 1)), high reducing power capacity (RPSFG = 5 mg.mL(-1)), and potent beta-carotene bleaching inhibition activity (IC50 SFG = 10 mg.mL(-1)). All of the obtained results demonstrate the promising potential use of SFG in numerous industrial applications, and a way to valorize flaxseed hulls. PMID- 27490576 TI - Mental Health Difficulties and Help-Seeking Beliefs within a Sample of Female Partners of UK Veterans Diagnosed with Post-Traumatic Stress Disorder. AB - In the UK there is a paucity of research about the needs of partners who are supporting ex-service personnel with mental health difficulties. In this study, we surveyed the mental health needs and barriers to help-seeking within a sample of partners of UK veterans who had been diagnosed with PTSD. Our sample included 100 participants. Forty-five percent met criteria for alcohol problems, 39% for depression, 37% for generalised anxiety disorder and 17% for symptoms of probable PTSD. Participants who met case criteria for depression, anxiety and problems with alcohol were more likely to report a greater number of help-seeking barriers. Participants who were experiencing mental health difficulties were more likely to endorse barriers connected to stigmatising beliefs than those associated with practical issues around accessing mental health services. The evidence presented suggests there may be a considerable burden of mental illness within this population. It would seem prudent to conduct further work to understand how best to address this clinical need. PMID- 27490575 TI - Highly-Immunogenic Virally-Vectored T-cell Vaccines Cannot Overcome Subversion of the T-cell Response by HCV during Chronic Infection. AB - An effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV) infection, as an adjunct to newly developed directly-acting antivirals (DAA), or for the prevention of reinfection, would significantly reduce the global burden of disease associated with chronic HCV infection. A recombinant chimpanzee adenoviral (ChAd3) vector and a modified vaccinia Ankara (MVA), encoding the non-structural proteins of HCV (NSmut), used in a heterologous prime/boost regimen induced multi-specific, high-magnitude, durable HCV-specific CD4+ and CD8+ T-cell responses in healthy volunteers, and was more immunogenic than a heterologous Ad regimen. We now assess the immunogenicity of this vaccine regimen in HCV infected patients (including patients with a low viral load suppressed with interferon/ribavirin therapy), determine T-cell cross-reactivity to endogenous virus, and compare immunogenicity with that observed previously in both healthy volunteers and in HCV infected patients vaccinated with the heterologous Ad regimen. Vaccination of HCV infected patients with ChAd3 NSmut/MVA-NSmut was well tolerated. Vaccine-induced HCV-specific T-cell responses were detected in 8/12 patients; however, CD4+ T-cell responses were rarely detected, and the overall magnitude of HCV-specific T-cell responses was markedly reduced when compared to vaccinated healthy volunteers. Furthermore, HCV-specific cells had a distinct partially-functional phenotype (lower expression of activation markers, granzyme B, and TNFalpha production, weaker in vitro proliferation, and higher Tim3 expression, with comparable Tbet and Eomes expression) compared to healthy volunteers. Robust anti-vector T-cells and antibodies were induced, showing that there is no global defect in immunity. The level of viremia at the time of vaccination did not correlate with the magnitude of the vaccine-induced T-cell response. Full-length, next-generation sequencing of the circulating virus demonstrated that T-cells were only induced by vaccination when there was a sequence mismatch between the autologous virus and the vaccine immunogen. However, these T-cells were not cross-reactive with the endogenous viral variant epitopes. Conversely, when there was complete homology between the immunogen and circulating virus at a given epitope T-cells were not induced. T-cell induction following vaccination had no significant impact on HCV viral load. In vitro T-cell culture experiments identified the presence of T cells at baseline that could be expanded by vaccination; thus, HCV-specific T cells may have been expanded from pre-existing low-level memory T-cell populations that had been exposed to HCV antigens during natural infection, explaining the partial T-cell dysfunction. In conclusion, vaccination with ChAd3 NSmut and MVA-NSmut prime/boost, a potent vaccine regimen previously optimized in healthy volunteers was unable to reconstitute HCV-specific T-cell immunity in HCV infected patients. This highlights the major challenge of overcoming T-cell exhaustion in the context of persistent antigen exposure. PMID- 27490577 TI - pH-Responsive PLGA Nanoparticle for Controlled Payload Delivery of Diclofenac Sodium. AB - Poly(lactic-co-glycolic acid) (PLGA) based nanoparticles have gained increasing attention in delivery applications due to their capability for controlled drug release characteristics, biocompatibility, and tunable mechanical, as well as degradation, properties. However, thorough study is always required while evaluating potential toxicity of the particles from dose dumping, inconsistent release and drug-polymer interactions. In this research, we developed PLGA nanoparticles modified by chitosan (CS), a cationic and pH responsive polysaccharide that bears repetitive amine groups in its backbone. We used a model drug, diclofenac sodium (DS), a nonsteroidal anti-inflammatory drug (NSAID), to study the drug loading and release characteristics. PLGA nanoparticles were synthesized by double-emulsion solvent evaporation technique. The nanoparticles were evaluated based on their particle size, surface charge, entrapment efficacy, and effect of pH in drug release profile. About 390-420 nm of average diameters and uniform morphology of the particles were confirmed by scanning electron microscope (SEM) imaging and dynamic light scattering (DLS) measurement. Chitosan coating over PLGA surface was confirmed by FTIR and DLS. Drug entrapment efficacy was up to 52%. Chitosan coated PLGA showed a pH responsive drug release in in vitro. The release was about 45% more at pH 5.5 than at pH 7.4. The results of our study indicated the development of chitosan coating over PLGA nanoparticle for pH dependent controlled release DS drug for therapeutic applications. PMID- 27490579 TI - Dissociation and Re-Aggregation of Multicell-Ensheathed Fragments Responsible for Rapid Production of Massive Clumps of Leptothrix Sheaths. AB - Species of the Fe/Mn-oxidizing bacteria Leptothrix produce tremendous amounts of microtubular, Fe/Mn-encrusted sheaths within a few days in outwells of groundwater that can rapidly clog water systems. To understand this mode of rapid sheath production and define the timescales involved, behaviors of sheath-forming Leptothrix sp. strain OUMS1 were examined using time-lapse video at the initial stage of sheath formation. OUMS1 formed clumps of tangled sheaths. Electron microscopy confirmed the presence of a thin layer of bacterial exopolymer fibrils around catenulate cells (corresponding to the immature sheath). In time-lapse videos, numerous sheath filaments that extended from the periphery of sheath clumps repeatedly fragmented at the apex of the same fragment, the fragments then aggregated and again elongated, eventually forming a large sheath clump comprising tangled sheaths within two days. In this study, we found that fast microscopic fragmentation, dissociation, re-aggregation and re-elongation events are the basis of the rapid, massive production of Leptothrix sheaths typically observed at macroscopic scales. PMID- 27490578 TI - Electrochemical, Electrochemiluminescence, and Photoelectrochemical Aptamer-Based Nanostructured Sensors for Biomarker Analysis. AB - Aptamer-based sensors have been intensively investigated as potential analytical tools in clinical analysis providing the desired portability, fast response, sensitivity, and specificity, in addition to lower cost and simplicity versus conventional methods. The aim of this review, without pretending to be exhaustive, is to give the readers an overview of recent important achievements about electrochemical, electrochemiluminescence, and photoelectrochemical aptasensors for the protein biomarker determination, mainly cancer related biomarkers, by selected recent publications. Special emphasis is placed on nanostructured-based aptasensors, which show a substantial improvement of the analytical performances. PMID- 27490580 TI - Immunization of Health-Care Providers: Necessity and Public Health Policies. AB - Health-care providers (HCPs) are at increased risk for exposure to vaccine preventable diseases (VPDs) in the workplace. The rationale for immunization of HCPs relies on the need to protect them and, indirectly, their patients from health-care-associated VPDs. Published evidence indicates significant immunity gaps for VPDs of HCPs globally. Deficits in knowledge and false perceptions about VPDs and vaccines are the most common barriers for vaccine uptake and may also influence communication about vaccines between HCPs and their patients. Most countries have immunization recommendations for HCPs; however, there are no universal policies and significant heterogeneity exists between countries in terms of vaccines, schedules, frame of implementation (recommendation or mandatory), and target categories of HCPs. Mandatory influenza immunization policies for HCPs have been implemented with high vaccine uptake rates. Stronger recommendations for HCP immunization and commitment at the level of the health care facility are critical in order to achieve high vaccine coverage rates. Given the importance to health, mandatory immunization policies for VPDs that can cause serious morbidity and mortality to vulnerable patients should be considered. PMID- 27490581 TI - Illustrating the Multi-Faceted Dimensions of Group Therapy and Support for Cancer Patients. AB - In cancer support groups, choice of therapy model, leadership style, and format can impact patients' experiences and outcomes. Methodologies that illustrate the complexity of patients' group experiences might aid in choosing group style, or testing therapeutic mechanisms. We used this naturalistic study as a beginning step to explore methods for comparing cancer group contexts by first modifying a group-experience survey to be cancer-specific (Group Experience Questionnaire (GEQ)). Hypothesizing that therapist-led (TL) would differ from non-therapist-led (NTL), we explored the GEQ's multiple dimensions. A total of 292 patients attending three types of groups completed it: 2 TL groups differing in therapy style ((1) Supportive-Expressive (SET); (2) The Wellness Community (TWC/CSC)); (3) a NTL group. Participants rated the importance of "Expressing True Feelings" and "Discussing Sexual Concerns" higher in TL than NTL groups and "Discussing Sexual Concerns" higher in SET than other groups. They rated "Developing a New Attitude" higher in TWC/CSC compared to NTL. In addition, we depict the constellation of group qualities using radar-charts to assist visualization. These charts facilitate a quick look at a therapy model's strengths and weaknesses. Using a measure like the GEQ and this visualization technique could enable health-service decision making about choice of therapy model to offer. PMID- 27490582 TI - Evaluation of an Education and Training Program to Prevent and Manage Patients' Violence in a Mental Health Setting: A Pretest-Posttest Intervention Study. AB - Workplace violence can lead to serious consequences for victims, organizations, and society. Most workplace violence prevention programs aim to train staff to better recognize and safely manage at-risk situations. The Omega education and training program was developed in Canada in 1999, and has since been used to teach healthcare and mental health workers the skills needed to effectively intervene in situations of aggression. The present study was designed to assess the impact of Omega on employee psychological distress, confidence in coping, and perceived exposure to violence. This program was offered to 105 employees in a psychiatric hospital in Montreal, Canada. Eighty-nine of them accepted to participate. Questionnaires were completed before the training, after a short period of time (M = 109 days) and at follow-up (M = 441 days). Repeated-measures ANOVAs and Cohen's d effect sizes were calculated. Results demonstrated statistically significant improvements in short-term and follow-up posttest scores of psychological distress, confidence in coping, and in levels of exposure to violence. This study is one of very few to demonstrate the positive impact of this training program. Further research is needed to understand how to improve the effectiveness of the program, especially among participants resistant to change. PMID- 27490583 TI - Postpartum Bonding Disorder: Factor Structure, Validity, Reliability and a Model Comparison of the Postnatal Bonding Questionnaire in Japanese Mothers of Infants. AB - Negative attitudes of mothers towards their infant is conceptualized as postpartum bonding disorder, which leads to serious health problems in perinatal health care. However, its measurement still remains to be standardized. Our aim was to examine and confirm the psychometric properties of the Postnatal Bonding Questionnaire (PBQ) in Japanese mothers. We distributed a set of questionnaires to community mothers and studied 392 mothers who returned the questionnaires at 1 month after childbirth. Our model was compared with three other models derived from previous studies. In a randomly halved sample, an exploratory factor analysis yielded a three-factor structure: Anger and Restrictedness, Lack of Affection, and Rejection and Fear. This factor structure was cross-validated by a confirmatory factor analysis using the other halved sample. The three subscales showed satisfactory internal consistency. The three PBQ subscale scores were correlated with depression and psychological abuse scores. Their test-retest reliability between day 5 and 1 month after childbirth was measured by intraclass correlation coefficients between 0.76 and 0.83. The Akaike Information Criteria of our model was better than the original four-factor model of Brockington. The present study indicates that the PBQ is a reliable and valid measure of bonding difficulties of Japanese mothers with neonates. PMID- 27490584 TI - From Biomass-Derived Furans to Aromatics with Ethanol over Zeolite. AB - We report a novel catalytic conversion of biomass-derived furans and alcohols to aromatics over zeolite catalysts. Aromatics are formed via Diels-Alder cycloaddition with ethylene, which is produced in situ from ethanol dehydration. The use of liquid ethanol instead of gaseous ethylene, as the source of dienophile in this one-pot synthesis, makes the aromatics production much simpler and renewable, circumventing the use of ethylene at high pressure. More importantly, both our experiments and theoretical studies demonstrate that the use of ethanol instead of ethylene, results in significantly higher rates and higher selectivity to aromatics, due to lower activation barriers over the solid acid sites. Synchrotron-diffraction experiments and proton-affinity calculations clearly suggest that a preferred protonation of ethanol over the furan is a key step facilitating the Diels-Alder and dehydration reactions in the acid sites of the zeolite. PMID- 27490585 TI - Smart Hydrogels with Inhomogeneous Structures Assembled Using Nanoclay-Cross Linked Hydrogel Subunits as Building Blocks. AB - A novel and facile assembly strategy has been successfully developed to construct smart nanocomposite (NC) hydrogels with inhomogeneous structures using nanoclay cross-linked stimuli-responsive hydrogel subunits as building blocks via rearranged hydrogen bonding between polymers and clay nanosheets. The assembled thermoresponsive poly(N-isopropylacrylamide-co-acrylamide) (poly(NIPAM-co-AM)) hydrogels with various inhomogeneous structures exhibit excellent mechanical properties due to plenty of new hydrogen bonding interactions created at the interface for locking the NC hydrogel subunits, which are strong enough to tolerate external forces such as high levels of elongations and multicycles of swelling/deswelling operations. The proposed approach is featured with flexibility and designability to build assembled hydrogels with diverse architectures for achieving various responsive deformations, which are highly promising for stimuli-responsive manipulation such as actuation, encapsulation, and cargo transportation. Our assembly strategy creates new opportunities for further developing mechanically strong hydrogel systems with complex architectures that composed of diverse internal structures, multistimuli responsive properties, and controllable shape deformation behaviors in the soft robots and actuators fields. PMID- 27490586 TI - Introduction. PMID- 27490587 TI - Pediatric Cardiac Intensive Care: A Transition to Maturity. PMID- 27490588 TI - Function of the Left and Right Ventricles and the Interactions Between Them. AB - OBJECTIVES: There has been a recent increase in our understanding of mechanisms whereby the two sides of the heart interact and modulate each other that may be particularly relevant to patients in the ICU. For this review, our objectives are to examine the function of the left ventricle, consider some of the ways in which the function of the right ventricle differs from that of the left, and examine the effects of the left ventricle on the function of the right and vice versa. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: There are fundamental differences between the function of the left and right ventricles, which relate to a significant extent to differences in their respective arterial loads. Although traditionally it has been usual to consider the function of the left and right ventricle in isolation, it is now recognized that this approach is flawed and as a result there is an increasing appreciation of the continual cross talk between the two sides of the heart in both the normal and diseased states. A more rational approach to the use of standard therapies frequently used in the cardiac ICU will come from a better understanding of these important fundamental concepts, and novel therapeutic concepts are already emerging from new data regarding biventricular interactions. PMID- 27490589 TI - Chronic Heart Failure. AB - OBJECTIVES: The objectives of this review are to discuss the paradigms used to stage heart failure in children, the classification and physiologic profile of cardiomyopathies, and the acute and chronic pharmacologic management of heart failure. DATA SOURCE: MEDLINE, PubMed. CONCLUSION: The etiology of chronic heart failure in pediatrics is vast. The paradigm of extrapolating adult clinical trials and technological advancements to treat heart failure in children has become a nonsustainable model. The field of pediatric heart failure continues to advance with more robust guideline-directed care and the imminent creation of a dynamic, contemporary international database. As the field involves a markedly heterogeneous patient population, it is imperative to use pediatric specific descriptors of disease impact. The fields of pediatric heart failure and critical care medicine will continue to evolve together as childhood specific registries, quality improvement guidelines, and research will lead to practice models eliciting optimal therapy for patients with heart failure in the intensive care setting. PMID- 27490590 TI - Critical Heart Failure and Shock. AB - OBJECTIVES: The objectives of this review are to discuss the clinical assessment, pathophysiology, and management of shock, with an emphasis on circulatory physiology, cardiopulmonary interactions, and pharmacologic strategies to optimize systemic oxygen delivery. These principles will then be applied to the clinical syndromes of heart failure and cardiogenic shock that are seen in children. DATA SOURCE: MEDLINE, PubMed. CONCLUSION: An understanding of essential circulatory physiology and the pathophysiology of shock are necessary for managing patients at risk for or in a state of shock. A timely and accurate assessment of cardiac function, cardiac output, and tissue oxygenation and the means by which to enhance the relationship between oxygen delivery and consumption are essential in order to optimize outcomes. PMID- 27490591 TI - Aortic and Mitral Valve Disease and Left Ventricular Dysfunction in Children. AB - OBJECTIVES: In this review, we will discuss aortic stenosis, aortic regurgitation, mitral regurgitation, and mitral stenosis. We will review the etiology, anatomy, pathophysiology, presentation, and treatment of aortic and mitral valve disease. Age and lesion specific treatments are outlined based on the severity of valve disease with an aim at long-term preservation of left ventricular function. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: Mitral and aortic valve disease leads to unique hemodynamic burdens that can impact left ventricular function, quality of life, and longevity. The primary challenge in the management of mitral and aortic valve disease is to apply appropriate medical management and identify that point in time at which the surgery is necessary. Although guidelines have been established for the management of aortic and mitral valve disease in adults, the challenges of early presentation, maintenance of growth potential, and apparent increased tolerance of hemodynamic burden in children makes decision making challenging. PMID- 27490593 TI - Arrhythmias in Cardiac Critical Care. AB - OBJECTIVES: Here, we characterize the frequency, mechanisms, clinical impact, and potential treatment options for several arrhythmias commonly encountered in pediatric cardiac critical care. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: Arrhythmias among children in the cardiac critical care setting are common and clinically important, associated independently with prolonged mechanical ventilation, critical care unit stay, and an increase in mortality. The precise characterization of an arrhythmia may provide clues as to an underlying mechanism as well as serve to guide treatment. Arrhythmia therapy, pharmacologic or otherwise, is directed toward addressing the underlying mechanism, and as such may be applicable to the treatment of more than one specific rhythm disturbance. Decisions concerning therapy must call into consideration an arrhythmia's underlying etiology, mechanism, and associated hemodynamic embarrassment, along with the potential for adverse effects of treatment. PMID- 27490592 TI - Pulmonary Hypertension. AB - OBJECTIVES: To review the clinical classification, diagnosis, and pathophysiology of pulmonary hypertension in children, emphasizing the role of right ventricular function, ventricular interaction, and congenital heart disease in the evolution and progression of disease, as well as management strategies and therapeutic options. DATA SOURCE: MEDLINE, PubMed. CONCLUSIONS: Critically ill children with pulmonary hypertension associated with congenital heart disease are a high-risk population. Congenital cardiac defects resulting in either increased pulmonary blood flow or impaired pulmonary venous drainage predispose patients to developing structural and functional aberrations of the pulmonary vasculature. Mortality from pulmonary hypertension is most directly related to right ventricular failure. PMID- 27490594 TI - Extracorporeal Membrane Oxygenation for Cardiac Indications in Children. AB - OBJECTIVES: The objectives of this review are to discuss the use of extracorporeal membrane oxygenation following surgery for congenital heart disease, myocarditis and as a bridge to cardiac transplantation. In addition, the latest in circuit equipment, the management of anticoagulation and blood transfusions, and short- and long-term outcomes are reviewed. DATA SOURCE: MEDLINE, PubMed. CONCLUSIONS: The use of extracorporeal membrane oxygenation to support children with heart disease is increasing. There is wide variability in the use and management of extracorporeal membrane oxygenation between centers. Many areas of extracorporeal membrane oxygenation management warrant additional research to inform clinical practice and improve patient outcomes, including the use of extracorporeal membrane oxygenation in patients undergoing single ventricle palliation, optimizing strategies for monitoring and titrating anticoagulation therapies, and efforts directed at minimizing the risk of neurologic injury. PMID- 27490595 TI - Ventricular Assist Devices in Pediatric Cardiac Intensive Care. AB - OBJECTIVES: The objectives of this review are to discuss the process of patient and mechanical device selection, operative management, and postoperative care with a focus on the management of right ventricular failure, anticoagulation strategies, device-related infections and neurologic sequelae. DATA SOURCES: MEDLINE, PubMed. CONCLUSION: The number of patients with advanced heart failure due to either acquired or congenital heart disease continues to increase, necessitating in some mechanical circulatory support and in others cardiac transplantation. With a limited cardiac donor pool, mechanical circulatory support is playing a greater role in the management of this population. The perioperative morbidity associated with mechanical circulatory support has lessened with improved postoperative management strategies. PMID- 27490596 TI - Heart Transplantation-The Pediatric Cardiac Critical Care Perspective. AB - OBJECTIVES: Although there have been tremendous advancements in the care of severe pediatric cardiovascular disease, heart transplantation remains the standard therapy for end-stage heart disease in children. As such, these patients comprise an important and often complex subset of patients in the ICU. The purpose of this article is to review the causes and management of allograft dysfunction and the medications used in the transplant population. DATA SOURCES: MEDLINE, PubMed, and Cochrane Database of systemic reviews. CONCLUSIONS: Pediatric heart transplant recipients represent a complex group of patients that frequently require critical care. Their immunosuppressive medications, while being vital to maintenance of allograft function, are associated with significant short- and long-term complications. Graft dysfunction can occur from a variety of etiologies at different times following transplantation and remains a major limitation to long-term posttransplant survival. PMID- 27490597 TI - Pulmonary Edema and Hypoxic Respiratory Failure. AB - OBJECTIVES: The purpose of this chapter is to outline the causes, physiology, pathophysiology, and management strategies for hydrostatic and permeability pulmonary edema and hypoxic respiratory failure. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: The pulmonary parenchyma and vasculature are at high risk in conditions where injury occurs to the lung and or heart. A targeted approach that uses strategies that optimize the particular pathophysiology of the parenchyma and vasculature is required. PMID- 27490599 TI - Cardiopulmonary Resuscitation in Congenital and Acquired Heart Disease. AB - OBJECTIVES: The Pediatric Advanced Life Support recommendations were developed for otherwise healthy infants and children with normal cardiac anatomy. Patients with acquired and congenital heart disease require specific considerations that may differ from the Pediatric Advanced Life Support recommendations. Our aim is to present prearrest, arrest, and postarrest considerations that are unique to children with congenital and acquired heart disease. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: A clear understanding of the underlying anatomy and physiology of congenital and acquired heart disease is imperative in order to employ the appropriate modifications to the current Pediatric Advanced Life Support recommendations and to optimize outcomes. PMID- 27490598 TI - Cardiopulmonary Interactions. AB - OBJECTIVES: The objectives of this review are to discuss the mechanisms by which respiration impacts cardiovascular function and vice versa, with an emphasis on the impact of these interactions in pediatric cardiac critical care. DATA SOURCE: A search of MEDLINE was conducted using PubMed. CONCLUSIONS: In the presence of underlying cardiac and respiratory disease, the interplay between these two systems is significant and plays a pivotal role in the pathophysiology of acute and chronic phases of a wide spectrum of diseases. An understanding of these relationships is essential to optimizing the care of critically ill patients. PMID- 27490600 TI - Near Infrared Spectroscopy as a Hemodynamic Monitor in Critical Illness. AB - OBJECTIVES: The objectives of this review are to discuss the technology and clinical interpretation of near infrared spectroscopy oximetry and its clinical application in patients with congenital heart disease. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: Near infrared spectroscopy provides a continuous noninvasive assessment of tissue oxygenation. Over 20 years ago, near infrared spectroscopy was introduced into clinical practice for monitoring cerebral oxygenation during cardiopulmonary bypass in adults. Since that time, the utilization of near infrared spectroscopy has extended into the realm of pediatric cardiac surgery and is increasingly being used in the cardiac ICU to monitor tissue oxygenation perioperatively. PMID- 27490601 TI - Hemodynamic Monitoring. AB - OBJECTIVES: In this review, we discuss hemodynamic monitoring modalities, including their application, the interpretation of data, limitations, and impact on outcomes. DATA SOURCE: MEDLINE, PubMed. CONCLUSIONS: One of the tenets of critical care medicine is to ensure adequate tissue oxygenation. This assessment must be timely and accurate to optimize outcomes. The clinical assessment of cardiac function, cardiac output, and tissue oxygenation based on the physical examination and standard hemodynamic variables, although an indispensable part of this exercise, has significant limitations. The use of adjunctive hemodynamic monitoring modalities provides a much more objective, accurate, and timely assessment of the patient's hemodynamic profile and is invaluable for assessing the patient's clinical status, clinical trajectory, and response to interventions. PMID- 27490602 TI - Biomarkers in Pediatric Cardiac Critical Care. AB - OBJECTIVES: In this review, we discuss the physiology, pathophysiology, and clinical role of troponin, lactate, and B-type natriuretic peptide in the assessment and management of children with critical cardiac disease. DATA SOURCE: MEDLINE, PubMed. CONCLUSION: Lactate, troponin, and B-type natriuretic peptide continue to be valuable biomarkers in the assessment and management of critically ill children with cardiac disease. However, the use of these markers as a single measurement is handicapped by the wide variety of clinical scenarios in which they may be increased. The overall trend may be more useful than any single level with a persistent or rising value of more importance than an elevated initial value. PMID- 27490603 TI - Echocardiography and Focused Cardiac Ultrasound. AB - OBJECTIVES: The following review will describe the use of focused cardiac ultrasound performed by noncardiologists and its role as an acute hemodynamic monitoring tool in pediatric cardiac critical care. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: The use of focused cardiac ultrasound has grown tremendously over recent years, and is increasingly being performed and interpreted by intensivists, anesthesiologists, and emergency medicine physicians. These imaging techniques are useful in establishing etiologies of cardiac dysfunction and should compliment the physical examination and standard hemodynamic monitoring. PMID- 27490604 TI - Sedation and Analgesia in Pediatric Cardiac Critical Care. AB - OBJECTIVES: This review will focus on the pharmacokinetics (with an emphasis on the context-sensitive half-time), pharmacodynamics, and hemodynamic characteristics of the most commonly used sedative/hypnotic, analgesic, and IV anesthetics used in cardiac intensive care. In addition, the assessment of pain and agitation and withdrawal will be reviewed. DATA SOURCE: MEDLINE, PubMed. CONCLUSIONS: Children in the cardiac ICU often require one or more components of general anesthesia: analgesia, amnesia (sedation and hypnosis), and muscle relaxation to facilitate mechanical ventilation, to manage postoperative pain, to perform necessary procedures, and to alleviate fear and anxiety. Furthermore, these same children are often vulnerable to hemodynamic instability due to unique underlying physiologic vulnerabilities. An assessment of hemodynamic goals, postoperative procedures to be performed, physiologic vulnerabilities, and the intended duration of mechanical ventilation should be made. Based on this assessment, the optimal selection of sedatives, analgesics, and if necessary, muscle relaxants can then be made. PMID- 27490606 TI - Nutrition and Mesenteric Issues in Pediatric Cardiac Critical Care. AB - OBJECTIVES: The objectives of this review are to discuss the challenges of delivering adequate nutrition to children with congenital heart disease, including pre- and postoperative factors and the role of enteral and parenteral nutrition, as well as the evidence supporting current practices. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: Providing adequate nutritional support is paramount for critically ill infants with congenital heart disease, a population at particular risk for malnutrition. Improved nutritional support has been associated with increased survival and reduction in overall morbidity. Further gains can be achieved by creating a clinical culture that emphasizes optimal perioperative nutritional support. Additional research is required to identify the specific nutrient composition, optimal mode, and timing of delivery to maximize clinical benefit. PMID- 27490607 TI - Acute Kidney Injury and Cardiorenal Syndromes in Pediatric Cardiac Intensive Care. AB - OBJECTIVES: The objectives of this review are to discuss the definition, diagnosis, and pathophysiology of acute kidney injury and its impact on immediate, short-, and long-term outcomes. In addition, the spectrum of cardiorenal syndromes will be reviewed including the pathophysiology on this interaction and its impact on outcomes. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: The field of cardiac intensive care continues to advance in tandem with congenital heart surgery. As mortality has become a rare occurrence, the focus of cardiac intensive care has shifted to that of morbidity reduction. Acute kidney injury adversely impact outcomes of patients following surgery for congenital heart disease as well as in those with heart failure (cardiorenal syndrome). Patients who become fluid overloaded and/or require dialysis are at a higher risk of mortality, but even minor degrees of acute kidney injury portend a significant increase in mortality and morbidity. Clinicians continue to seek methods of early diagnosis and risk stratification of acute kidney injury to prevent its adverse sequelae. PMID- 27490605 TI - Neurodevelopmental Outcomes in Children With Congenital Heart Disease-What Can We Impact? AB - OBJECTIVES: The objectives of this review are to discuss the scope of neurologic injuries in newborns with congenital heart disease, the mechanisms of injury, including prenatal, pre-, intra-, and postoperative factors, neurodevelopmental outcomes, and therapeutic strategies for the timely intervention and prevention of neurologic injury. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: At the current time, important research is underway to 1) better understand the developing brain in the fetus with complex congenital heart disease, 2) to identify modifiable risk factors in the operating room and ICU to maximize long-term neurodevelopmental outcomes, and 3) develop strategies to improve family psychosocial health, childhood development, and health-related quality of life following hospital discharge. Crucial in this effort is the identification of an early postoperative surrogate variable with good predictive validity for long term outcomes. If an appropriate surrogate variable for long-term outcomes can be identified, and measured relatively early after surgical intervention for complex congenital heart disease, reliable clinical trials can be undertaken to improve upon current outcomes. PMID- 27490608 TI - Fluid Management: Pharmacologic and Renal Replacement Therapies. AB - OBJECTIVES: Focusing on critically ill children with cardiac disease, we will review common causes of fluid perturbations, clinical recognition, and strategies to minimize and treat fluid-related complications. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: Meticulous fluid management is vital in critically ill children with cardiac disease. Fluid therapy is important to maintain adequate blood volume and perfusion pressure in order to support cardiac output, tissue perfusion, and oxygen delivery. However, fluid overload and acute kidney injury are common and are associated with increased morbidity and mortality. Understanding the etiologies for disturbances in volume status and the pathophysiology surrounding those conditions is crucial for providing optimal care. PMID- 27490610 TI - Cardiopulmonary Bypass-Induced Inflammatory Response: Pathophysiology and Treatment. AB - OBJECTIVES: The objectives of this review are to discuss the pathophysiology of the pro-inflammatory response to the cardiopulmonary bypass circuit, the impact of ischemia reperfusion injury on post-operative organ function, the compensatory anti-inflammatory response and the evidence for immune-modulatory strategies and their impact on outcomes. DATA SOURCE: MEDLINE, PubMed. CONCLUSION: Innovations such as the development of more biocompatible surfaces and miniaturized circuits, as well as the increasing expertise of surgeons, anesthesiologists and perfusionists has transformed cardiac surgery and the use of cardiopulmonary bypass into a relatively routine procedure with favorable outcomes. Despite these refinements, the attendant inflammatory response to bypass, ischemia reperfusion injury and the compensatory anti-inflammatory response contribute to post operative morbidity and mortality. Additional studies are needed to further delineate the impact of immunomodulatory strategies on outcomes. PMID- 27490611 TI - Avoidance of Hospital-Acquired Infections in Pediatric Cardiac Surgical Patients. AB - OBJECTIVES: The objectives of this review are to discuss the prevalence and risk factors associated with the development of hospital-acquired infections in pediatric patients undergoing cardiac surgery and the published antimicrobial prophylaxis regimens and rational approaches to the diagnosis, prevention, and treatment of nosocomial infections in these patients. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: Hospital-acquired infections remain a significant source of potentially preventable morbidity and mortality in pediatric cardiac surgical patients. Through improved understanding of these conditions and implementation of avoidance strategies, centers caring for these patients may improve outcomes in this vulnerable population. PMID- 27490609 TI - Sepsis in Pediatric Cardiac Intensive Care. AB - OBJECTIVES: In this review, we will discuss risk factors for developing sepsis; the role of biomarkers in establishing an early diagnosis, in monitoring therapeutic efficacy, in stratification, and for the identification of sepsis endotypes; and the pathophysiology and management of severe sepsis and septic shock, with an emphasis on the impact of sepsis on cardiovascular function. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: There is a lot of excitement in the field of sepsis research today. Scientific advances in the diagnosis and clinical staging of sepsis, as well as a personalized approach to the treatment of sepsis, offer tremendous promise for the future. However, at the same time, it is also evident that sepsis mortality has not improved enough, even with progress in our understanding of the molecular pathophysiology of sepsis. PMID- 27490612 TI - Bleeding and Thrombosis in Pediatric Cardiac Intensive Care. AB - OBJECTIVES: The objective of this article is to review the particular tendencies as well as specific concerns of bleeding and clotting in children with critical cardiac disease. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: Children with critical heart disease are at particular risk for bleeding and clotting secondary to intrinsic as well as extrinsic factors. We hope that this review will aid the clinician in managing the unique challenges of bleeding and clotting in this patient population, and serve as a springboard for much needed research in this area. PMID- 27490613 TI - Endocrinologic Diseases in Pediatric Cardiac Intensive Care. AB - OBJECTIVES: The objectives of this review are to discuss the pathophysiology, clinical impact and treatment of hyperglycemia, and disturbances in thyroid and adrenal function prior to and following cardiac surgery in children. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: Disturbances in glucose metabolism and thyroid and adrenal function are common in critically ill children with cardiac disease and in particular in children undergoing cardiac surgery for complex congenital heart disease. An understanding of the pathophysiology, clinical impact and treatment of these disturbances is essential for the management of these at risk patients. PMID- 27490614 TI - Shunt Lesions Part I: Patent Ductus Arteriosus, Atrial Septal Defect, Ventricular Septal Defect, and Atrioventricular Septal Defect. AB - OBJECTIVES: This review summarizes the current understanding of the pathophysiology and perioperative management of patent ductus arteriosus, atrial septal defect, ventricular septal defect, and atrioventricular septal defect. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: The four congenital cardiac lesions that are the subject of this review, patent ductus arteriosus, atrial septal defect, ventricular septal defect, and atrioventricular septal defect, are the most commonly found defects causing a left-to-right shunt. These defects frequently warrant transcatheter or surgical intervention. Although the perioperative care is relatively straightforward for many of these patients, there are a number of management strategies and complications associated with each intervention. The treatment outcomes for all of these lesions are very good in the current era. PMID- 27490615 TI - Shunt Lesions Part II: Anomalous Pulmonary Venous Connections and Truncus Arteriosus. AB - OBJECTIVES: The objectives of this review are to describe the anatomy, pathophysiology, perioperative therapeutic strategies, and operative procedures for patients with anomalous pulmonary venous connections and truncus arteriosus. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: An understanding of the anatomy and pathophysiology of anomalous pulmonary venous connections and truncus arteriosus is essential for the optimal perioperative management of these complex and challenging congenital lesions. PMID- 27490616 TI - Left Ventricular Outflow Tract Obstruction: Coarctation of the Aorta, Interrupted Aortic Arch, and Borderline Left Ventricle. AB - OBJECTIVES: The objectives of this review are to discuss the perioperative management of coarctation of the aorta, interrupted aortic arch, and the borderline left ventricle. METHODS: MEDLINE and PubMed. CONCLUSIONS: Successful management of systemic obstructive lesions involves a thorough evaluation of the anatomy and pathophysiology to determine the most effective management strategy. PMID- 27490617 TI - Hypoplastic Left Heart Syndrome and Other Shunt-Dependent Single Ventricles. AB - OBJECTIVES: In this review, we discuss the pathophysiology, treatment, and outcomes of patients with the hypoplastic left heart syndrome and other single ventricle variants prior to and following surgery. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: Patients with shunted single ventricle physiology are at increased risk for acute hemodynamic decompensation owing to the increased myocardial workload, the dynamic balance between systemic and pulmonary circulations, and the potential for shunt obstruction. Understanding of the physiology and anticipatory management are critical to prevent hemodynamic compromise and cardiac arrest. PMID- 27490618 TI - Right Ventricular Outflow Tract Obstruction: Pulmonary Atresia With Intact Ventricular Septum, Pulmonary Stenosis, and Ebstein's Malformation. AB - OBJECTIVES: The objectives of this review are to discuss the anatomy, pathophysiology, clinical course, and current treatment strategies for pulmonary atresia with intact ventricular septum, pulmonary stenosis, and Ebstein's anomaly. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: Considerable advances have been made in management strategies for these complex congenital heart lesions, which have led to improved outcomes. PMID- 27490619 TI - Tetralogy of Fallot and Its Variants. AB - OBJECTIVES: The objectives of this review are to discuss the anatomy, pathophysiology, surgical repair, and perioperative management strategies for tetralogy of Fallot and its variants. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: Significant refinements have been made in the repair strategy for tetralogy of Fallot, based on improved understanding of postrepair physiology. Important considerations for timing and technique of surgery and perioperative management have been presented, and continued evolution is expected. Expanded use of the pulmonary valve reconstruction technique outlined herein, whatever the age of repair, may improve long-term outcome. PMID- 27490620 TI - Transposition of the Great Arteries and Common Variants. AB - OBJECTIVES: The objectives of this review are to discuss the physiology, perioperative management, surgical correction, and outcomes of infants with transposition of the great arteries and common variants undergoing the arterial switch operation. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: The widespread adoption of the arterial switch operation for transposition of great arteries has been one of the more gratifying advances in pediatric cardiovascular care, and represents the simultaneous improvements in diagnostics, surgical and bypass techniques, anesthesia in the neonate, improvements in intensive care technology, nursing strategies, and system-wide care delivery. Many of the strategies adopted for the neonate with transposition of the great arteries have been translated to neonatal care for other congenital heart lesions. Continued work is necessary to investigate the effects of perioperative care on long-term neurodevelopmental outcomes, as well as collaboration between centers to spread "best practices" for outcome, cost, and morbidity reduction. PMID- 27490621 TI - L-Transposition of the Great Arteries. AB - OBJECTIVES: To describe the various surgical options, perioperative management strategies, and outcomes for this complex lesion. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: L-transposition of the great arteries is a relatively rare defect, comprising less than 1% of all congenital heart defects. There is considerable heterogeneity in clinical presentation depending on the presence of associated defects. Surgery for this rare and complex defect has evolved from "physiologic" repair in which the right ventricle remains in the systemic position to the "anatomic" repair, which restores the left ventricle as the systemic ventricle. There has been a great interest in performing the anatomic repair or "double switch" operation, a rather complex operation that presents unique challenges in the postoperative period. PMID- 27490622 TI - Clinical-Physiological Considerations in Patients Undergoing Staged Palliation for a Functionally Single Ventricle. AB - OBJECTIVES: The objectives of this review are to discuss the pathophysiology of the circulation with a functionally univentricular heart, with a focus on the unique physiologic characteristics, which provide the underpinnings for the management of these complex patients. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: The circulation of the patient with a functionally univentricular heart displays unique physiologic characteristics, which are quite different from those of the normal biventricular circulation. There are profound differences within the heart itself in terms of ventricular function, interventricular interactions, and myocardial architecture, which are likely to have significant implications for the efficiency of ventricular ejection and metabolism. The coupling between the systemic ventricle and the aorta also displays unique features. The 3D orientation of the Fontan anastomosis itself can profoundly impact cardiac output, although the "portal" pulmonary arterial bed is a crucial determinant of overall cardiovascular function. As a result, disease-specific approaches to improve cardiovascular function are required at all stages during the care of these complex patients. PMID- 27490623 TI - Acquired and Congenital Coronary Artery Diseases. AB - OBJECTIVES: The objectives of this review are to discuss the spectrum of coronary artery anomalies and the evidence behind current treatment strategies. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: Coronary artery anomalies exist in up to 1% of the population and most of these do not cause symptoms or ischemia and do not require any surgical intervention whereas others are potentially fatal. The type of surgical intervention is often dictated by the type of lesion, and upon the unique anatomic and physiologic variables associated with each lesion. Postoperative care can be challenging particularly after surgical repair of anomalous left coronary artery from the pulmonary artery. PMID- 27490624 TI - Outcomes Analysis and Quality Improvement in Children With Congenital and Acquired Cardiovascular Disease. AB - OBJECTIVES: In this review, the current state of outcomes analysis and quality improvement in children with acquired and congenital cardiovascular disease will be discussed, with an emphasis on defining and measuring outcomes and quality in pediatric cardiac critical care medicine and risk stratification systems. DATA SOURCE: MEDLINE and PubMed CONCLUSION: : Measuring quality and outcomes in the pediatric cardiac critical care environment is challenging owing to many inherent obstacles, including a diverse patient mix, difficulty in determining how the care of the ICU team contributes to outcomes, and the lack of an adequate risk adjustment method for pediatric cardiac critical care patients. Despite these barriers, new solutions are emerging that capitalize on lessons learned from other quality improvement initiatives, providing opportunities to build upon previous successes. PMID- 27490625 TI - Comorbid Conditions in Neonates With Congenital Heart Disease. AB - OBJECTIVES: The objectives of this review are to discuss the pathophysiology, clinical impact and treatment of major noncardiac anomalies, and prematurity in infants with congenital heart disease. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: Mortality risk is significantly higher in patients with congenital heart disease and associated anomalies compared with those in whom the heart defect occurs in isolation. Although most noncardiac structural anomalies do not require surgery in the neonatal period, several require surgery for survival. Management of such infants poses multiple challenges. Premature infants with congenital heart disease face challenges imposed by their immature organ systems, which are susceptible to injury or altered function by congenital heart disease and abnormal circulatory physiology independent of congenital heart disease. For optimal outcomes in premature infants or in infants with multiple congenital anomalies, a collaborative interdisciplinary approach is necessary. PMID- 27490626 TI - Intensive Care in the Adult With Congenital Heart Disease. AB - OBJECTIVES: The purpose of this review is to discuss current outcomes for patients with adult congenital heart disease, assess the level of knowledge regarding the impact of comorbidities, and discuss the various models of care with a view to establish the optimal environment for the care of these patients in the future. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: There is an increasingly large population of adults with previously operated congenital heart disease. Consequently, there are increasing numbers of adults requiring intensive care support after re-do surgery, or as a consequence of medical complications of their underlying cardiac disease. There is relatively little data specific to this population to guide optimal disposition and care models. PMID- 27490627 TI - Nursing Considerations in Pediatric Cardiac Critical Care. AB - OBJECTIVE: The objectives of this review are to describe the education and critical thinking skills that characterize pediatric critical care nursing and how these skills impact patient care and outcomes in pediatric cardiac critical care. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: Pediatric cardiac critical care nurses manage complex and vulnerable patients requiring various levels of support. Effective care of these patients requires knowledge about the complex anatomy and physiology associated with congenital and acquired heart disease, as well as the effects of mechanical ventilation, mechanical circulatory support, and vasoactive medications. Strong physical examination skills, accurate interpretation of hemodynamic and laboratory data, active participation in bedside rounds, excellent communication skills, meticulous care of invasive monitoring catheters and tubes, and compassionate support of families are among the skills that distinguish a cardiac critical care nurse. PMID- 27490628 TI - Global Perspectives On Pediatric Cardiac Critical Care. AB - OBJECTIVES: The objectives of this review are to discuss the global epidemiology of cardiovascular disease, emphasizing congenital heart disease; to discuss the concept of epidemiologic transition and its role in studying the evolving epidemiology of disease; and to assess and address the global burden of congenital heart disease including its prevention and treatment. DATA SOURCE: MEDLINE and PubMed. CONCLUSIONS: Despite impressive reductions in mortality from congenital and acquired cardiovascular disease in high-income countries, these reductions have not been observed on a global scale. It will be necessary to continue our attempts to extend rational programs of care to middle- and low income countries based on community empowerment, economics, and population health. The specialist in pediatric cardiac critical care can be a central driver of these programs. PMID- 27490629 TI - The cosmopolitan contradictions of planetary urbanization. AB - This paper explores the empirical, conceptual and theoretical gains that can be made using cosmopolitan social theory to think through the urban transformations that scholars have in recent years termed planetary urbanization. Recognizing the global spread of urbanization makes the need for a cosmopolitan urban sociology more pressing than ever. Here, it is suggested that critical urban sociology can be invigorated by focusing upon the disconnect that Henri Lefebvre posits between the planetarization of the urban - which he views as economically and technologically driven - and his dis-alienated notion of a global urban society. The first aim of this paper is to highlight the benefits of using 'cosmopolitan' social theory to understand Lefebvre's urban problematic (and to establish why this is also a cosmopolitan problematic); the second is to identify the core cosmopolitan contradictions of planetary urbanization, tensions that are both actually existing and reproduced in scholarly accounts. The article begins by examining the challenges presented to urban sociology by planetary urbanization, before considering how cosmopolitan sociological theory helps provide an analytical 'grip' on the deep lying social realities of contemporary urbanization, especially in relation to questions about difference, culture and history. These insights are used to identify three cosmopolitan contradictions that exist within urbanized (and urbanizing) space; tensions that provide a basis for a thoroughgoing cosmopolitan investigation of planetary urbanization. PMID- 27490630 TI - Genome editing comes of age. AB - Genome editing harnesses programmable nucleases to cut and paste genetic information in a targeted manner in living cells and organisms. Here, I review the development of programmable nucleases, including zinc finger nucleases (ZFNs), TAL (transcription-activator-like) effector nucleases (TALENs) and CRISPR (cluster of regularly interspaced palindromic repeats)-Cas9 (CRISPR-associated protein 9) RNA-guided endonucleases (RGENs). I specifically highlight the key advances that set the foundation for the rapid and widespread implementation of CRISPR-Cas9 genome editing approaches that has revolutionized the field. PMID- 27490631 TI - Looking to the future following 10 years of induced pluripotent stem cell technologies. AB - The development of induced pluripotent stem cells (iPSCs) has fundamentally changed our view on developmental cell-fate determination and led to a cascade of technological innovations in regenerative medicine. Here we provide an overview of the progress in the field over the past decade, as well as our perspective on future directions and clinical implications of iPSC technology. PMID- 27490632 TI - Cell-type-specific profiling of protein-DNA interactions without cell isolation using targeted DamID with next-generation sequencing. AB - This protocol is an extension to: Nat. Protoc. 2, 1467-1478 (2007); doi:10.1038/nprot.2007.148; published online 7 June 2007The ability to profile transcription and chromatin binding in a cell-type-specific manner is a powerful aid to understanding cell-fate specification and cellular function in multicellular organisms. We recently developed targeted DamID (TaDa) to enable genome-wide, cell-type-specific profiling of DNA- and chromatin-binding proteins in vivo without cell isolation. As a protocol extension, this article describes substantial modifications to an existing protocol, and it offers additional applications. TaDa builds upon DamID, a technique for detecting genome-wide DNA binding profiles of proteins, by coupling it with the GAL4 system in Drosophila to enable both temporal and spatial resolution. TaDa ensures that Dam-fusion proteins are expressed at very low levels, thus avoiding toxicity and potential artifacts from overexpression. The modifications to the core DamID technique presented here also increase the speed of sample processing and throughput, and adapt the method to next-generation sequencing technology. TaDa is robust, reproducible and highly sensitive. Compared with other methods for cell-type specific profiling, the technique requires no cell-sorting, cross-linking or antisera, and binding profiles can be generated from as few as 10,000 total induced cells. By profiling the genome-wide binding of RNA polymerase II (Pol II), TaDa can also identify transcribed genes in a cell-type-specific manner. Here we describe a detailed protocol for carrying out TaDa experiments and preparing the material for next-generation sequencing. Although we developed TaDa in Drosophila, it should be easily adapted to other organisms with an inducible expression system. Once transgenic animals are obtained, the entire experimental procedure-from collecting tissue samples to generating sequencing libraries-can be accomplished within 5 d. PMID- 27490634 TI - Reply to "Reducing Gender Discrepancies in Academic Radiology". PMID- 27490633 TI - High-quality full-length immunoglobulin profiling with unique molecular barcoding. AB - High-throughput sequencing analysis of hypermutating immunoglobulin (IG) repertoires remains a challenging task. Here we present a robust protocol for the full-length profiling of human and mouse IG repertoires. This protocol uses unique molecular identifiers (UMIs) introduced in the course of cDNA synthesis to control bottlenecks and to eliminate PCR and sequencing errors. Using asymmetric 400+100-nt paired-end Illumina sequencing and UMI-based assembly with the new version of the MIGEC software, the protocol allows up to 750-nt lengths to be sequenced in an almost error-free manner. This sequencing approach should also be applicable to various tasks beyond immune repertoire studies. In IG profiling, the achieved length of high-quality sequence covers the variable region of even the longest chains, along with the fragment of a constant region carrying information on the antibody isotype. The whole protocol, including preparation of cells and libraries, sequencing and data analysis, takes 5 to 6 d. PMID- 27490635 TI - Does asymptomatic recurrent diffuse capillary C4d complement deposition impair cardiac allograft function? AB - BACKGROUND: The aim of this study was to evaluate whether asymptomatic recurrent (>=2) antibody-mediated rejection (pAMR 1+), defined as diffuse capillary C4d immunostaining (rAMR) on endomyocardial biopsies (EMBs), during the first year after heart transplantation impairs left ventricular (LV) function. METHODS: Fifty-four consecutive heart transplant patients who survived well (New York Heart Association <=2 and EF>=55%) the first month after transplantation were enrolled and prospectively underwent 490 echocardiographies and EMB. Asymptomatic rAMR without histopathologic findings was evaluated as a risk factor for deterioration of graft function. Primary endpoint, assessed 1 year after transplantation, was development of LV dysfunction and/or adverse remodeling according to pre-specified echo parameters. RESULTS: During the first year from transplantation, rAMR occurred in five patients. Recurrent AMR was associated with a significant higher risk to develop LV concentric hypertrophy (OR 3.6, 95% CI: 1.8-7.0, P=.02) or reduced lateral S' peak velocity (OR 2.3, 95% CI: 1.5-3.6, P=.03). Patients with rAMR showed significative adverse graft remodeling (DeltaLV end-diastolic volume: +16+/-12.3 vs -0.2+/-14.4 mL; P=.02) and deterioration of graft function (Deltalateral S' peak velocity: -3.3+/-3 vs -0.4+/-2.9 cm/s; P=.03). CONCLUSIONS: Recurrent asymptomatic diffuse capillary C4d immunostaining may play a role in the early development of cardiac allograft adverse remodeling and dysfunction. PMID- 27490636 TI - EUCheMS Lecture Award: G. Ferey and C. Moberg / August Wilhelm von Hofmann Memorial Medal: B. L. Feringa / Catalan-Sabatier Prize: J.-M. Tarascon / Elhuyar Goldschmidt Lectureship: N. Martin and F. Wurthner / European Federation for Medicinal Chemistry Awards: F. Diederich and P. J. Hergenrother / Eni Awards: J. A. Lercher and D. Milstein. PMID- 27490637 TI - Advancing HIV research with pregnant women: navigating challenges and opportunities. AB - OBJECTIVE: Concerns about including pregnant women in research have led to a dearth of evidence to guide safe and effective treatment and prevention of HIV in pregnancy. To better understand why these evidence gaps persist and inform guidance for responsible inclusion of pregnant women in the HIV research agenda, we aimed to learn what HIV experts perceive as barriers and constraints to conducting this research. METHODS: We conducted a series of group and one-on-one consultations with 62 HIV investigators and clinicians to elicit their views and experiences conducting HIV research involving pregnant women. Thematic analysis was used to identify priorities and perceived barriers to HIV research with pregnant women. RESULTS: Experts discussed a breadth of needed research, including safety, efficacy, and appropriate dosing of: newer antiretrovirals for pregnant women, emerging preventive strategies, and treatment for coinfections. Challenges to conducting research on pregnancy and HIV included ethical concerns, such as how to weigh risks and benefits in pregnancy; legal concerns, such as restrictive interpretations of current regulations and liability issues; financial and professional disincentives, including misaligned funder priorities and fear of reputational damage; and analytical and logistical complexities, such as challenges recruiting and retaining pregnant women to sufficiently power analyses. CONCLUSION: Investigators face numerous challenges to conducting needed HIV research with pregnant women. Advancing such research will require clearer guidance regarding ethical and legal uncertainties; incentives that encourage rather than discourage investigators to undertake such research; and a commitment to earlier development of safety and efficacy data through creative trial designs. PMID- 27490639 TI - Associations between antiretroviral use and subclinical coronary atherosclerosis. AB - OBJECTIVES: HIV infection is associated with increased prevalence of subclinical coronary plaque. The extent to which such plaque reflects effects of HIV infection or effects of long-term antiretroviral therapy (ART) use remains unclear and was the goal of this analysis. DESIGN AND METHODS: We compared the prevalence and extent of coronary plaque and stenosis between users of specific ART drugs or drug classes using coronary computed tomography (CT) among HIV infected men in the Multicenter AIDS Cohort Study. To account for time-dependent confounders, including cardiovascular disease risk factors and time-varying reasons for using specific treatments, we conducted fully adjusted logistic and linear models with inverse probability of treatment weighting. RESULTS: There were 618 men who underwent noncontrast coronary CT; 450 also underwent coronary CT angiography. At the time of scanning, 81% had undetectable plasma HIV RNA. In fully adjusted models, cumulative use of zidovudine, abacavir, darunavir, and protease inhibitors as a drug class were inconsistently associated with specific forms of plaque presence or extent. CONCLUSION: Among virally suppressed HIV infected men with extensive ART exposure, no consistent associations between use of specific ART drugs and both subclinical coronary plaque presence and extent were apparent. Our findings support the hypothesis that, among virally suppressed persons, type of ART used is not in general a major determinant of subclinical coronary plaque risk. PMID- 27490638 TI - Prevalence and predictors of low muscle mass in HIV/viral hepatitis coinfection. AB - OBJECTIVE: Low muscle mass is associated with reduced survival in HIV, possibly mediated by systemic inflammation. Viral hepatitis coinfection can induce additional inflammation and hepatic dysfunction that may exacerbate low muscle mass. We determined the prevalence of and risk factors for low muscle mass in HIV/viral hepatitis coinfection. DESIGN AND METHODS: A cross-sectional study of participants in the Multicenter AIDS Cohort Study and Women's Interagency HIV Study with anthropometry performed after 1 January 2000. Viral hepatitis defined by positive hepatitis B virus surface antigen and/or hepatitis C virus RNA. Low muscle mass defined as less than 10th percentile of age-matched and sex-matched reference values for mid-upper arm circumference. Using multivariable logistic regression, we determined adjusted odds ratios with 95% confidence intervals (CIs) of the association of HIV/viral hepatitis coinfection with low muscle mass and factors associated with low muscle mass in coinfected persons. Analyses adjusted for age, race, BMI, alcohol use, and IDU (also, nadir CD4 cell count and HIV RNA where appropriate). RESULTS: Among 3518 participants (164 HIV/viral hepatitis, 223 viral hepatitis alone, 1070 HIV alone, and 2061 uninfected), HIV/viral hepatitis-coinfected persons had a 3.50-fold (95% CI, 1.51-8.09), 1.93 fold (1.17-3.20), and 2.65-fold (1.62-4.35) higher odds of low muscle mass than viral hepatitis-monoinfected, HIV-monoinfected, and uninfected persons, respectively. Lack of HIV RNA suppression [odds ratio, 2.26 (95% CI, 1.10-4.63)] was the only factor associated with low muscle mass in coinfected persons. CONCLUSION: HIV/viral hepatitis-coinfected persons have a higher likelihood of low muscle mass than those with viral hepatitis monoinfection, HIV monoinfection, or neither infection. HIV viremia is an important risk factor for low muscle mass among coinfected persons. PMID- 27490641 TI - Acute HIV infection transmission among people who inject drugs in a mature epidemic setting. AB - OBJECTIVE: Estimates for the contribution of transmission arising from acute HIV infections (AHIs) to overall HIV incidence vary significantly. Furthermore, little is known about AHI-attributable transmission among people who inject drugs (PWID), including the extent to which interventions targeting chronic infections (e.g. HAART as prevention) are limited by AHI transmission. Thus, we estimated the proportion of transmission events attributable to AHI within the mature HIV epidemic among PWID in New York City (NYC). DESIGN: Modeling study. METHODS: We constructed an interactive sexual and injecting transmission network using an agent-based model simulating the HIV epidemic in NYC between 1996 and 2012. Using stochastic microsimulations, we cataloged transmission from PWID based on the disease stage of index agents to determine the proportion of infections transmitted during AHI (in primary analyses, assumed to last 3 months). RESULTS: Our calibrated model approximated the epidemiological features of the mature HIV epidemic in NYC between 1996 and 2012. Annual HIV incidence among PWID dropped from approximately 1.8% in 1996 to 0.7% in 2012. Over the 16-year period, AHI accounted for 4.9% (10th/90th percentile: 0.1-12.3%) of incident HIV cases among PWID. The annualized contribution of AHI increased over this period from 3.6% in 1996 to 5.9% in 2012. CONCLUSION: Our results suggest that, in mature epidemics such as NYC, between 3% and 6% of transmission events are attributable to AHI among PWID. Current HIV treatment as prevention strategies are unlikely to be substantially affected by AHI-attributable transmission among PWID populations in mature epidemic settings. PMID- 27490644 TI - Double trouble: a rare case of bilateral intratonsillar abscess. PMID- 27490643 TI - Neonatal Acute Kidney Injury and the Risk of Intraventricular Hemorrhage in the Very Low Birth Weight Infant. AB - Despite improvements in survival of premature infants, many have comorbid conditions. The role of the kidney in multiorgan dysfunction is unclear, particularly in regard to intraventricular hemorrhage (IVH). We hypothesized that infants diagnosed with acute kidney injury (AKI) have an increased risk of IVH independent of gestational age (GA) and other variables associated with both comorbidities. This prospective cohort study consisted of 125 infants with a birth weight <=1,200 g and/or GA <=31 weeks. A definition of AKI was used from KDIGO, not including urine output as nonoliguria is common in this population. IVH was based on serial head ultrasounds. Neonates with AKI had a higher trend towards having IVH compared to those without [14/35 (40%) vs. 22/83 (26.5%), p = 0.1]. Infants with AKI were more likely to have stage 2 IVH or higher than those without AKI [12/36 (33.3%) vs. 6/82 (7.3%); p < 0.01]. AKI was associated with a 3.6-fold increased risk of a grade 2 or higher IVH [hazard ratio (HR) 3.55, 95% confidence interval (CI) 1.39-9.07] and over 4-fold increase in risk of a grade 3 or higher IVH (HR 4.34, 95% CI 1.43-13.21). While there was no association between AKI and IVH overall, those with AKI had a higher hazard ratio to develop a grade 2 or higher IVH even when controlling for birth weight, antenatal steroid use, and 5-min Apgar score. Future studies are indicated to expand sample size and to control for other clinical variables that could be associated with both AKI and IVH. PMID- 27490642 TI - Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti programed death-ligand 1 (Avelumab). AB - OBJECTIVE: The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target. METHODS: Lymph node biopsies from HIV-infected patients (n = 23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques. RESULTS: PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment. CONCLUSION: Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans. PMID- 27490646 TI - pH-Responsive Relaxometric Behaviour of Coordination Polymer Nanoparticles Made of a Stable Macrocyclic Gadolinium Chelate. AB - Lanthanide-containing nanoscale particles have been widely explored for various biomedical purposes, however, they are often prone to metal leaching. Here we have created a new coordination polymer (CP) by applying, for the first time, a stable Gd(III) chelate as building block in order to prevent any fortuitous release of free lanthanide(III) ion. The use of the Gd-DOTA-4AmP complex as a design element in the CP allows not only for enhanced relaxometric properties (maximum r1 =16.4 mm(-1) s(-1) at 10 MHz), but also for a pH responsiveness (Deltar1 =108 % between pH 4 and 6.5), beyond the values obtained for the low molecular weight Gd-DOTA-4AmP itself. The CP can be miniaturised to the nanoscale to form colloids that are stable in physiological saline solution and in cell culture media and does not show cytotoxicity. PMID- 27490645 TI - Single nucleotide polymorphisms in an intergenic chromosome 2q region associated with tissue factor pathway inhibitor plasma levels and venous thromboembolism. AB - Essentials Tissue factor pathway inhibitor (TFPI) regulates the blood coagulation cascade. We replicated previously reported linkage of TFPI plasma levels to the chromosome 2q region. The putative causal locus, rs62187992, was associated with TFPI plasma levels and thrombosis. rs62187992 was marginally associated with TFPI expression in human aortic endothelial cells. Click to hear Ann Gil's presentation on new insights into thrombin activatable fibrinolysis inhibitor SUMMARY: Background Tissue factor pathway inhibitor (TFPI) regulates fibrin clot formation, and low TFPI plasma levels increase the risk of arterial thromboembolism and venous thromboembolism (VTE). TFPI plasma levels are also heritable, and a previous linkage scan implicated the chromosome 2q region, but no specific genes. Objectives To replicate the finding of the linkage region in an independent sample, and to identify the causal locus. Methods We first performed a linkage analysis of microsatellite markers and TFPI plasma levels in 251 individuals from the F5L Family Study, and replicated the finding of the linkage peak on chromosome 2q (LOD = 3.06). We next defined a follow-up region that included 112 603 single nucleotide polymorphisms (SNPs) under the linkage peak, and meta-analyzed associations between these SNPs and TFPI plasma levels across the F5L Family Study and the Marseille Thrombosis Association (MARTHA) Study, a study of 1033 unrelated VTE patients. SNPs with false discovery rate q values of < 0.10 were tested for association with TFPI plasma levels in 892 patients with coronary artery disease in the AtheroGene Study. Results and Conclusions One SNP, rs62187992, was associated with TFPI plasma levels in all three samples (beta = + 0.14 and P = 4.23 * 10-6 combined; beta = + 0.16 and P = 0.02 in the F5L Family Study; beta = + 0.13 and P = 6.3 * 10-4 in the MARTHA Study; beta = + 0.17 and P = 0.03 in the AtheroGene Study), and contributed to the linkage peak in the F5L Family Study. rs62187992 was also associated with clinical VTE (odds ratio 0.90, P = 0.03) in the INVENT Consortium of > 7000 cases and their controls, and was marginally associated with TFPI expression (beta = + 0.19, P = 0.08) in human aortic endothelial cells, a primary site of TFPI synthesis. The biological mechanisms underlying these associations remain to be elucidated. PMID- 27490647 TI - Experience with Lumbar Puncture Following Endoscopic Third Ventriculostomy for Obstructive Hydrocephalus. AB - Background and Objective The increase in intracranial pressure (ICP) in some patients in the immediate postoperative period following endoscopic third ventriculostomy (ETV) is not well understood. This study explored the effect of lumbar puncture following ETV for obstructive hydrocephalus on outcome. Materials and Methods A total of 145 patients with obstructive hydrocephalus underwent ETV between 2009 and 2014. Following ETV, all patients underwent lumbar puncture on postoperative days 1 and 3. Results In 106 patients, ICP returned to normal levels accompanied by symptom relief. In 39 patients, ICP remained high on postoperative days 3, and lumbar puncture was continued every alternate postoperative day for 11 days. ICP always returned to normal. These 39 patients were divided into two groups for analysis: group A (age < 18 years) and group B (age >= 18 years). Peak values of ICP for groups A and B were recorded on days 3 and 5, respectively. Conclusions Our study suggests an important role for postoperative lumbar puncture in ensuring successful treatment results after ETV. In most of the symptomatic patients with obstructive hydrocephalus, lumbar puncture appears to contribute to rapid ICP normalization, to alleviation of symptoms, and prevention of complications. PMID- 27490648 TI - Special Series on Mental Health. PMID- 27490649 TI - One-Visit Behavioral Intervention for Older Primary Care Patients with Mild to Moderate Depressive Symptoms. AB - OBJECTIVES: We pilot tested a one-visit behavioral intervention with telephone follow-up for older primary care patients with mild to moderate depressive symptoms. METHODS: A total of 16 English-speaking primary care patients aged 60 years and older who scored 5 to 14 on the Patient Health Questionnaire-9 (PHQ-9) engaged in the intervention visit. Outcomes were assessed at baseline and 4 weeks: activity goals, readiness to change (University of Rhode Island Change Assessment), PHQ-9, Generalized Anxiety Disorder-7, World Health Organization Disability Assessment Schedule 2.0, and satisfaction. RESULTS: The 14 participants who completed the study met or exceeded 73% of activity goals on average. They also improved on all outcomes (P < 0.05) with medium (University of Rhode Island Change Assessment, GAD-7) to large effect sizes (PHQ-9, World Health Organization Disability Assessment Schedule 2.0), and they were satisfied. CONCLUSIONS: This pilot study provided preliminary evidence that a one-visit behavioral activation intervention is acceptable and feasible and improves outcomes. If findings are confirmed, then this intervention could be integrated into existing collaborative care programs. PMID- 27490650 TI - Commentary on "One-Visit Behavioral Intervention for Older Primary Care Patients with Mild to Moderate Depressive Symptoms". PMID- 27490651 TI - Conversion Disorder in an Appalachian Community. AB - OBJECTIVES: Conversion disorder (CD) is believed to be the manifestation of physical and/or neurological symptoms for primary gain without an identifiable organic cause. Although it is believed to be more common in rural areas, the literature examining this claim is sparse. To our knowledge, no study has been published evaluating the prevalence of CD in a rural Appalachian population. The aim of this study was to characterize and determine the prevalence of CD per Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria in a rural Appalachian psychiatric consultation service and to compare this population with control patients from the same service. METHODS: We performed a retrospective chart review of all patients diagnosed as having CD per Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria on a psychiatric consultation service at a rural Appalachian academic medical center during a 13-month time period. For each case, two consecutive control patients were selected from the same service and time span. RESULTS: There were 21 cases and 42 controls in this study, with a CD prevalence rate of 6.0% (N = 21/351). Sociodemographic, comorbidity, and recent symptomatology data were obtained. Compared with controls, cases were significantly younger and were more likely to have a history of sexual abuse, seizure disorder, antiepileptic use, neurologic referral, electroencephalogram, magnetic resonance imaging of the brain, and history of CD. We found it interesting that fewer cases reported alcohol and drug use. CONCLUSIONS: The observed prevalence of 6.0% does not support the historical theory that CD is more prevalent in rural or lower socioeconomic populations. Our data add to the characterization of the Appalachian CD population. PMID- 27490652 TI - Impact of Nutrition on Neurocognition. PMID- 27490653 TI - Commentary on "Impact of Nutrition on Neurocognition". PMID- 27490655 TI - Homelessness and Emergency Psychiatric Evaluations. PMID- 27490654 TI - Mental Health Impact of Hosting Disaster Refugees: Analyses from a Random Sample Survey Among Haitians Living in Miami. AB - OBJECTIVES: Studies on the mental health of families hosting disaster refugees are lacking. This study compares participants in households that hosted 2010 Haitian earthquake disaster refugees with their nonhost counterparts. METHODS: A random sample survey was conducted from October 2011 through December 2012 in Miami-Dade County, Florida. Haitian participants were assessed regarding their 2010 earthquake exposure and impact on family and friends and whether they hosted earthquake refugees. Using standardized scores and thresholds, they were evaluated for symptoms of three common mental disorders (CMDs): posttraumatic stress disorder, generalized anxiety disorder, and major depressive disorder (MDD). RESULTS: Participants who hosted refugees (n = 51) had significantly higher percentages of scores beyond thresholds for MDD than those who did not host refugees (n = 365) and for at least one CMD, after adjusting for participants' earthquake exposures and effects on family and friends. CONCLUSIONS: Hosting refugees from a natural disaster appears to elevate the risk for MDD and possibly other CMDs, independent of risks posed by exposure to the disaster itself. Families hosting refugees deserve special attention. PMID- 27490656 TI - Does Timing of Internal Medicine Residency Interview Affect Likelihood of Matching? AB - OBJECTIVES: Applicants to our internal medicine (IM) residency program consistently have shared concerns about whether the interview date influences their ability to match via the National Residency Matching Program. We performed a retrospective study to assess whether interview timing was associated with successful matching at our IM program. METHODS: We identified all of the applicants who interviewed for a first-year position with our IM residency program from 2010 to 2014. Each year's interview dates were totaled and divided equally into three categories: early, middle, or late. Baseline demographics, United States Medical Licensing Examination scores, and type of medical school (American or international) were compared among the interview date groups and between those who did and did not match at our program. RESULTS: Of 914 interviewees, 311 interviewed early (October/November), 299 interviewed in the middle (December), and 304 interviewed late (January). The proportion to match at our program was similar in each interview group (12.5%, 18.4%, 15.1%, respectively; P = 0.133). Logistic regression analysis showed that the middle interview group had increased odds to match compared with the early group (odds ratio 1.590; P = 0.044). The late-versus-early group showed no difference (P = 0.362). No significant differences were found with type of medical school or United States Medical Licensing Examination scores. Of all of the interviewees participating in the match, nearly all matched into a program somewhere, with no significant difference based on interview timing. CONCLUSIONS: When considering all of the interviewees, interview date showed no major influence on matching. Only the middle interview time period showed a slight increased chance of matching to our IM program, but the significance was marginal. PMID- 27490657 TI - Fostering Clinical Excellence Across an Academic Health System. AB - OBJECTIVES: Changes in the US healthcare economic system are requiring academic health centers (AHCs) to restructure in pursuit of their traditional tripartite missions; engaging the individuals focused on clinical care is becoming more important. We conducted this study to guide our institution's transformation by identifying ways to formally recognize clinicians who are excelling in patient care and understand which forms of acknowledgment would be acceptable and motivating. METHODS: A survey was developed by a large committee with representation spanning the AHC and was sent electronically in spring 2014 to stakeholders across the institution. Items assessed perceptions of the importance and present state of valuing clinical excellence, the utility of 14 potential metrics to assess clinical excellence, and the meaningfulness of seven potential rewards for clinical excellence. Bivariate and multivariate logistic regression models analyzed differences (P < 0.05) by respondent sex, ethnicity, academic rank, primary clinical affiliation, and time spent in patient care and research activities. RESULTS: A total of 1716 of 3168 (54%) stakeholders responded, including 1198 of 2151 (56%) individuals from academic hospitals, 114 of 276 (41%) from the outpatient affiliated practices, and 304 of 741 (54%) from satellite locations. Nearly everyone (96%) agreed that clinical accomplishments should be recognized, although a minority (47%) believed that clinicians were already valued. Most respondents selected 7 or more of 14 metrics as valid and reasonable for assessing clinical excellence. Popular metrics (eg, clinical productivity) were not believed to represent clinical excellence as much as others (eg, professionalism). Multivariate analysis found the least agreement among stakeholders on using published scholarship as evidence for clinical excellence, with the widest differences comparing senior faculty versus nonfaculty (88% vs 27%) and those with >75% of their time spent in patient care versus others (37% vs 73%). Most (six of seven) types of reward were perceived as meaningful by the majority of respondents, with little variation among subgroups across bivariate and multivariate analyses. CONCLUSIONS: This system-wide assessment was successful at identifying new strategies for recognizing clinical excellence. Other AHCs seeking institutional transformation may wish to perform a similar assessment. PMID- 27490658 TI - Patient Perceptions of Oseltamivir for the Treatment of Influenza. AB - OBJECTIVES: Oseltamivir (Tamiflu) is approved by the Food and Drug Administration and is advertised for the treatment of influenza types A and B. Patient perceptions of its efficacy have not been adequately studied. Recent systematic reviews have called the benefits of this drug into question relative to the cost and adverse effect profile. We hypothesized that most people would be unaware of the efficacy, cost, or adverse effect profile of the drug. Our objective was to determine patient perceptions of efficacy, cost, and adverse effect profile of oseltamivir for the treatment of influenza. METHODS: This was a cross-sectional, multiple-choice, open-response survey of adult patients and adult caregivers of pediatric patients who presented to the emergency department (ED) with flu-like symptoms. Flu-like symptoms were defined as any respiratory symptom plus fever or body aches. The study took place during the 2014-2015 flu season at a rural ED. We analyzed the data, with descriptive statistics reported as frequencies/percentages for categorical data. Survey data collected as Likert scale data were summarized using mean, median, and mode. RESULTS: During the 4 month period, 70 surveys were completed. A total of 67% of the participants were women, with 84% younger than 40 years. Subjects younger than 40 years were more likely to have seen advertising for oseltamivir (31% vs 0%, P = 0.04). Less than half reported having received the flu vaccine that year. Most reported that oseltamivir was an effective treatment for the flu. Most overstated the perceived efficacy of oseltamivir. Most were not willing to take the medication if it had adverse effects, with the most deterring adverse effects being potential kidney and liver injury. CONCLUSIONS: In our study most patients reported overly positive expectations for the efficacy of oseltamivir for treating influenza. Most reported that commonly listed adverse effects would deter their use of the medication. PMID- 27490659 TI - Clinical Features of Respiratory Viral Infections Among Inpatients at a Major US Tertiary Care Hospital. AB - OBJECTIVES: Respiratory viral illnesses (RVI) are reliably diagnosed by respiratory viral panel using polymerase chain reaction (RVP-PCR); however, owing to the scant data, clinical presentation alone is unreliable in establishing viral etiology. The primary objective of this study was to characterize signs and symptoms of RVI among inpatients in a major tertiary care hospital. METHODS: Between 2013 and 2015, adult inpatients with RVI undergoing RVP-PCR were prospectively enrolled in our study. Clinical data were collected by interviews and electronic medical record reviews. Data analysis was performed using chi(2) testing, analysis of variance for continuous variables, and logistic regression modeling. RESULTS: Of 421 patients analyzed, 175 (41.7%) had a positive RVP-PCR. Patients were evenly matched at baseline except for renal disease. Multivariate logistic regression modeling demonstrated the following positive correlations: positive RVP-PCR with renal disease (odds ratio [OR] 2.08), cough (OR 2.28), and wheezing (OR 1.8); influenza with cough (OR 5.04), and renal disease (OR 2.17); metapneumovirus with age older than 65 (OR 3.24); respiratory syncytial viruses with wheezing (OR 3.42) and immunosuppression (OR 3.11); and parainfluenza with smoking (OR 3.16). Negative correlations included influenza with anosmia (OR 0.41); rhinovirus/enterovirus with feeling confined to bed (OR 0.3); metapneumovirus with smoking (OR 0.29); and parainfluenza with male sex (OR 0.22). CONCLUSIONS: In this descriptive study, we noted specific viral associations with clinical signs and symptoms among 421 inpatients with RVIs. With increasing RVP-PCR use, studies similar to ours may be able to better define the clinical presentation of RVIs and lead to evidence-based, clinical presentation-guided diagnostic and management algorithms. PMID- 27490660 TI - Determinants of Elevated Alkaline Phosphatase in Patients Infected with HIV. AB - OBJECTIVES: A retrospective cross-sectional study was performed to assess the prevalence of elevated alkaline phosphatase (ALP) in patients infected with human immunodeficiency virus (HIV) and to determine the relation between ALP and specific antiretroviral therapy (ART). METHODS: A total of 2990 patients were included in this study. Data were collected from a major academic institution's HIV clinic using the most recent searchable values from patients' medical records. Included patients were 18 to 89 years old, had HIV, and their ALP results were available. Elevated ALP was defined as ALP >120 IU/L. Logistic regression analyses were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for predictors of elevated ALP level. RESULTS: In our total population of 2990, 15.4% (n = 459) had elevated ALP. In the bivariate analyses, older age (>=60 years; OR 4.1, 95% CI 2.6-6.4), female sex (OR 1.6, 95% CI 1.3-1.9), Other race (not African American) vs white (OR 1.9, 95% CI 1.8-3.3), elevated creatinine (OR 2.9, 95% CI 2.1-4.1), laboratory evidence of liver disease (OR 2.1, 95% CI 1.7-2.6), CD4 count <200 cells per cubic millimeter (OR 2.5, 95% CI 2.0-3.2), hepatitis C infection (OR 1.9, 95% CI 1.4-2.5), laboratory markers of bone turnover (OR 1.9, 95% CI 1.2-3.1), and non-nucleoside reverse transcriptase inhibitors use (OR 1.2, 95% CI 1.02-1.15) were significantly associated with elevated ALP. Only the association with laboratory markers of bone turnover remained significant in the multivariate analysis, however. CONCLUSIONS: The results suggest that comorbidities and demographic variables have stronger associations with elevated ALP than specific antiretroviral therapy. Future research should be conducted to define the clinical significance of elevated ALP among patients infected with HIV. PMID- 27490661 TI - How Is Zika Transmitted? PMID- 27490662 TI - Life-Long Radar Tracking of Bumblebees. AB - Insect pollinators such as bumblebees play a vital role in many ecosystems, so it is important to understand their foraging movements on a landscape scale. We used harmonic radar to record the natural foraging behaviour of Bombus terrestris audax workers over their entire foraging career. Every flight ever made outside the nest by four foragers was recorded. Our data reveal where the bees flew and how their behaviour changed with experience, at an unprecedented level of detail. We identified how each bee's flights fit into two categories-which we named exploration and exploitation flights-examining the differences between the two types of flight and how their occurrence changed over the course of the bees' foraging careers. Exploitation of learned resources takes place during efficient, straight trips, usually to a single foraging location, and is seldom combined with exploration of other areas. Exploration of the landscape typically occurs in the first few flights made by each bee, but our data show that further exploration flights can be made throughout the bee's foraging career. Bees showed striking levels of variation in how they explored their environment, their fidelity to particular patches, ratio of exploration to exploitation, duration and frequency of their foraging bouts. One bee developed a straight route to a forage patch within four flights and followed this route exclusively for six days before abandoning it entirely for a closer location; this second location had not been visited since her first exploratory flight nine days prior. Another bee made only rare exploitation flights and continued to explore widely throughout its life; two other bees showed more frequent switches between exploration and exploitation. Our data shed light on the way bumblebees balance exploration of the environment with exploitation of resources and reveal extreme levels of variation between individuals. PMID- 27490664 TI - Social reasoning abilities in preterm and full-term children aged 5-7years. AB - BACKGROUND: Literature has evidenced behavioral and socio-emotional problems in preterm children, as well as long-term difficulties to establish and maintain social relationships in preterm population. Several studies have shown relations between behavior and social reasoning abilities in typically developing children and adults. AIM: The present study aimed to investigate the social understanding and social reasoning abilities in preterm children aged between 5 and 7years in comparison to their full-term peers. STUDY DESIGN: A social resolution task (SRT) was used to assess abilities to judge, identify and reason about others' behavior in relation to conventional and moral rules knowledge. SUBJECTS: 102 preterm children and 88 full-term children were included in the study. RESULTS: Compared with their full-term peers, preterm children exhibited difficulties to understand and reason about inappropriate social behavior, particularly for situations related to the transgression of conventional rules. They used more irrelevant information and exhibited less social awareness when reasoning about the transgression of social rules. The only significant predictor for global SRT and social reasoning scores was the mental processing composite of the K-ABC, but the part of the variance of the SRT that could be explained by the general cognitive abilities was relatively small. CONCLUSION: Preterm children demonstrated poorer social knowledge and social reasoning abilities compared with full-term children at early school age. Improving such abilities may reduce behavioral difficulties and peer relationship problems often described in the preterm population. These findings emphasize the need to early identify children at risk for impaired social development. PMID- 27490663 TI - Lipid Body Organelles within the Parasite Trypanosoma cruzi: A Role for Intracellular Arachidonic Acid Metabolism. AB - Most eukaryotic cells contain varying amounts of cytosolic lipidic inclusions termed lipid bodies (LBs) or lipid droplets (LDs). In mammalian cells, such as macrophages, these lipid-rich organelles are formed in response to host-pathogen interaction during infectious diseases and are sites for biosynthesis of arachidonic acid (AA)-derived inflammatory mediators (eicosanoids). Less clear are the functions of LBs in pathogenic lower eukaryotes. In this study, we demonstrated that LBs, visualized by light microscopy with different probes and transmission electron microscopy (TEM), are produced in trypomastigote forms of the parasite Trypanosoma cruzi, the causal agent of Chagas' disease, after both host interaction and exogenous AA stimulation. Quantitative TEM revealed that LBs from amastigotes, the intracellular forms of the parasite, growing in vivo have increased size and electron-density compared to LBs from amastigotes living in vitro. AA-stimulated trypomastigotes released high amounts of prostaglandin E2 (PGE2) and showed PGE2 synthase expression. Raman spectroscopy demonstrated increased unsaturated lipid content and AA incorporation in stimulated parasites. Moreover, both Raman and MALDI mass spectroscopy revealed increased AA content in LBs purified from AA-stimulated parasites compared to LBs from unstimulated group. By using a specific technique for eicosanoid detection, we immunolocalized PGE2 within LBs from AA-stimulated trypomastigotes. Altogether, our findings demonstrate that LBs from the parasite Trypanosoma cruzi are not just lipid storage inclusions but dynamic organelles, able to respond to host interaction and inflammatory events and involved in the AA metabolism. Acting as sources of PGE2, a potent immunomodulatory lipid mediator that inhibits many aspects of innate and adaptive immunity, newly-formed parasite LBs may be implicated with the pathogen survival in its host. PMID- 27490665 TI - Effect of Halide Composition on the Photochemical Stability of Perovskite Photovoltaic Materials. AB - The photochemical stability of encapsulated films of mixed halide perovskites with a range of MAPb(I1-x Brx )3 (MA=methylammonium) compositions (solid solutions) was investigated under accelerated stressing using concentrated sunlight. The relevance of accelerated testing to standard operational conditions of solar cells was confirmed by comparison to degradation experiments under outdoor sunlight exposure. We found that MAPbBr3 films exhibited no degradation, while MAPbI3 and mixed halide MAPb(I1-x Brx )3 films decomposed yielding crystallization of inorganic PbI2 accompanied by degradation of the perovskite solar light absorption, with faster absorption degradation in mixed halide films. The crystal coherence length was found to correlate with the stability of the films. We postulate that the introduction of Br into the mixed halide solid solution stressed its structure and induced more structural defects and/or grain boundaries compared to pure halide perovskites, which might be responsible for the accelerated degradation. Hence, the cause for accelerated degradation may be the increased defect density rather than the chemical composition of the perovskite materials. PMID- 27490666 TI - Medical-Grade Channel Access and Admission Control in 802.11e EDCA for Healthcare Applications. AB - In this paper, we deal with the problem of assuring medical-grade quality of service (QoS) for real-time medical applications in wireless healthcare systems based on IEEE 802.11e. Firstly, we show that the differentiated channel access of IEEE 802.11e cannot effectively assure medical-grade QoS because of priority inversion. To resolve this problem, we propose an efficient channel access algorithm. The proposed algorithm adjusts arbitrary inter-frame space (AIFS) in the IEEE 802.11e protocol depending on the QoS measurement of medical traffic, to provide differentiated near-absolute priority for medical traffic. In addition, based on rigorous capacity analysis, we propose an admission control scheme that can avoid performance degradation due to network overload. Via extensive simulations, we show that the proposed mechanism strictly assures the medical grade QoS and improves the throughput of low-priority traffic by more than several times compared to the conventional IEEE 802.11e. PMID- 27490667 TI - Limb girdle muscular dystrophies: classification, clinical spectrum and emerging therapies. AB - PURPOSE OF REVIEW: The aim of the study was to describe the clinical spectrum of limb girdle muscular dystrophies (LGMDs), the pitfalls of the current classification system for LGMDs, and emerging therapies for these conditions. RECENT FINDINGS: Close to half of all LGMD subtypes have been discovered within the last 6 years of the 21-year-period in which the current classification system for LGMD has existed. The number of letters for annotation of new recessive LGMD conditions is exhausted, and multiple already classified LGMDs do not strictly fulfill diagnostic criteria for LGMD or are registered in other classification systems for muscle disease. On the contrary, diseases that fulfill classical criteria for LGMD have found no place in the LGMD classification system. These shortcomings call for revision/creation of a new classification system for LGMD. The rapidly expanding gene sequencing capabilities have helped to speed up new LGMD discoveries, and unveiled pheno-/genotype relations. Parallel to this progress in identifying new LGMD subtypes, emerging therapies for LGMDs are under way, but no disease-specific treatment is yet available for nonexperimental use. SUMMARY: The field of LGMD is rapidly developing from a diagnostic and therapeutic viewpoint, but a uniform and universally agreed classification system for LGMDs is needed. PMID- 27490668 TI - Treatment of Humeral Shaft Fractures: A Critical Analysis Review. PMID- 27490670 TI - Advances in Pediatric Limb Lengthening: Part 2. PMID- 27490669 TI - Recommendations for Perioperative Management of Patients on Existing Anticoagulation Therapy. PMID- 27490671 TI - Arthroscopic Treatment of Cam-Type Impingement of the Hip. PMID- 27490672 TI - Prophylaxis Against Venous Thromboembolism After Total Hip and Knee Arthroplasty: A Critical Analysis Review. PMID- 27490673 TI - Monomer Dynamics of Alzheimer Peptides and Kinetic Control of Early Aggregation in Alzheimer's Disease. AB - The rate of reconfiguration-or intramolecular diffusion-of monomeric Alzheimer (Abeta) peptides is measured and, under conditions that aggregation is more likely, peptide diffusion slows down significantly, which allows bimolecular associations to be initiated. By using the method of Trp-Cys contact quenching, the rate of reconfiguration is observed to be about five times faster for Abeta40 , which aggregates slowly, than that for Abeta42 , which aggregates quickly. Furthermore, the rate of reconfiguration for Abeta42 speeds up at higher pH, which slows aggregation, and in the presence of the aggregation inhibitor curcumin. The measured reconfiguration rates are able to predict the early aggregation behavior of the Abeta peptide and provide a kinetic basis for why Abeta42 is more prone to aggregation than Abeta40 , despite a difference of only two amino acids. PMID- 27490674 TI - Estimating Retinal Blood Flow Velocities by Optical Coherence Tomography. AB - Importance: While optical coherence tomography (OCT) angiography has been considered to evaluate retinal capillary blood flow instead of fluorescein angiography, the reflectance pattern of blood vessels on structural OCT might also provide retinal capillary flow data in the absence of fluorescein angiography. This potential has been insufficiently explored, despite promising data concerning a possible relationship between the reflectance pattern of blood vessels and their perfusion velocity in a laboratory setting. Objective: To evaluate the potential of retinal blood flow velocity estimation by structural OCT. Design, Setting, and Participants: Cross-sectional observational study conducted from June to November 2015 at a tertiary clinical referral center. Sixty arteries (the superior and inferior temporal arteries) from 30 eyes of 30 patients (17 female, 13 male) were included in the study. Main Outcomes and Measures: Based on the intraluminal contrast patterns of retinal arteries on OCT, 3 independent graders categorized the blood flow velocities as low, medium, or high. These results and the results from a software-based intraluminal contrast analysis were compared with the retinal blood flow velocities measured by video fluorescein angiography. Results: Among the 30 eyes of 30 patients (mean [SD] age, 72.6 [12.3] years; 17 female, 13 male), 15 were controls without retinal occlusion, 6 had a branch retinal artery occlusion, and 9 had a central retinal artery occlusion. When discriminating between low flow velocities and medium or high flow velocities, the graders' sensitivity ranged from 88.2% to 100% (grader 1: 88.2%; 95% CI, 63.6%-98.5%; grader 2: 88.2%; 95% CI, 63.6%-98.5%; and grader 3: 100%; 95% CI, 69.8%-100%) and their specificity ranged from 97.6% to 100% (grader 1: 100%; 95% CI, 87.7%-100%; grader 2: 97.6%; 95% CI, 87.4%-99.9%; and grader 3: 100%; 95% CI, 87.7%-100%). The kappa coefficients of the comparison between the 3 graders and the angiography were 0.77 (95% CI, 0.60-0.93; P < .001), 0.64 (95% CI, 0.44-0.83; P < .001), and 0.87 (95% CI, 0.74-0.99; P < .001). In the computer-based assessment, the contrast reduction of the intraluminal pattern could be numerically expressed in a specific coefficient in the model (I2, describing the angular change of the backscattering intensity in the model), which presented nonoverlapping intervals between low flow velocities and medium or high flow velocities (mean [SD] I2, 0.3 [5.3], 20.4 [6.4], and 21.7 [4.0], respectively). Conclusions and Relevance: This study suggests that a low retinal blood flow velocity reflects in a visually distinct contrast reduction of the intraluminal pattern of retinal vessels on OCT. Larger studies are required to assess the clinical benefits. PMID- 27490675 TI - Cell Surface Proteome of Dental Pulp Stem Cells Identified by Label-Free Mass Spectrometry. AB - Multipotent mesenchymal stromal cells (MSCs) are promising tools for regenerative medicine. They can be isolated from different sources based on their plastic adherence property. The identification of reliable cell surface markers thus becomes the Holy Grail for their prospective isolation. Here, we determine the cell surface proteomes of human dental pulp-derived MSCs isolated from single donors after culture expansion in low (2%) or high (10%) serum-containing media. Cell surface proteins were tagged on intact cells using cell impermeable, cleavable sulfo-NHS-SS-biotin, which allows their enrichment by streptavidin pull down. For the proteomic analyses, we first compared label-free methods to analyze cell surface proteomes i.e. composition, enrichment and proteomic differences, and we developed a new mathematical model to determine cell surface protein enrichment using a combinatorial gene ontology query. Using this workflow, we identified 101 cluster of differentiation (CD) markers and 286 non-CD cell surface proteins. Based on this proteome profiling, we identified 14 cell surface proteins, which varied consistently in abundance when cells were cultured under low or high serum conditions. Collectively, our analytical methods provide a basis for identifying the cell surface proteome of dental pulp stem cells isolated from single donors and its evolution during culture or differentiation. Our data provide a comprehensive cell surface proteome for the precise identification of dental pulp-derived MSC populations and their isolation for potential therapeutic intervention. PMID- 27490676 TI - A delayed foreign body granuloma associated with polypropylene sutures used in tendon transfer. A case report. AB - INTRODUCTION: A delayed foreign body reaction to polypropylene sutures has not been previously reported following tendon repair. PRESENTATION OF CASE: A 12-year old boy underwent tendon transfer. Tendon repair was done using polypropylene sutures. Five months later, a slowly growing granuloma was seen at the tendon repair site. Skin testing did not show an allergic reaction to the suture. Excision of the granuloma and removal of sutures were curative. Histology confirmed a foreign body granuloma. DISCUSSION: A mass developing several months at the site of tendon repair indicates either an allergic or foreign body reaction to the suture. Skin testing (for allergy) and histological examination of the mass differentiate allergic from foreign body reactions. CONCLUSION: We report on a rare case of a giant granuloma caused by a delayed foreign body reaction to polypropylene sutures used in tendon repair. PMID- 27490677 TI - Isolated rectus abdominis metastasis from melanoma-An extremely rare case. AB - INTRODUCTION: Melanoma is a health problem world-wide. Its incidence has tripled in the last decade. The main cause of death in melanoma patients is widespread metastases. It can metastasize to almost every organ. However, melanoma skeletal muscle metastases (MSMM) are exceptional, and only two cases of MSMM to rectus abdominis muscles have been previously published. Regardless of all new advances seen in melanoma therapy, cure for most MSMM is still elusive. Surgical approaches are still not well defined. PRESENTATION OF CASE: A 35-year-old woman had been previously operated of an ulcerated scapular melanoma (Clark level III, Breslow 2.3mm) in January 2014. Subsequently she underwent a sentinel lymph node which resulted negative. Twenty months later, a CT scan revealed a well-enhanced nodule of 25mm in the right rectus abdominis, without any other metastases. The PET-CT uptake was pathologic (SUV maximum of 13.16). An ultrasound-guided biopsy confirmed it was a metastatic melanoma. A radical compartmental resection of the right rectus abdominis muscle was performed. The abdominal wall was reconstructed with two polypropylene meshes buried preperitoneally. The final histologic diagnosis of the specimen proved to be a metastasis of melanoma. DISCUSSION: Surgery is the only potentially curative therapy for patients with isolated MSMM. The ultimate goal of negative resection margins, in order to avoid local recurrences, is paramount in those difficult cases. CONCLUSION: Radical compartmental surgery should be considered for selected stage IV melanoma patients whose disease could be amenable to complete resection, in order to extend median survival. PMID- 27490678 TI - Total vertebrectomy (Th2) and dissection of the subclavian artery for a superior sulcus tumor invading the spine: A case report. AB - INTRODUCTION: Surgery for primary lung cancer invading the spine remains challenging. Here, we present a case of superior sulcus tumor (SST) with vertebral invasion, successfully resected with total vertebrectomy (Th2) and dissection of involved apical chest wall and the subclavian artery (SCA). PRESENTATION OF CASE: A 62-year-old man was referred with the diagnosis of lung squamous cell carcinoma originating from left upper lobe (clinical stage IIIA/T4N0M0) involving the thoracic vertebrae (Th2) as well as the apical chest wall including three ribs (1st, 2nd and 3rd) and SCA. After induction concurrent chemo-radiotherapy, we achieved complete resection by three-step surgical procedures as follows: first, the anterior portion of involved chest wall including SCA was dissected through the trans-manubrial approach (TMA); next, the posterior portion of involved chest wall including ribs was dissected and left upper lobectomy with nodal dissection was performed through posterolateral thoracotomy; finally, total vertebrectomy (Th2) was performed through posterior mid-line approach. DISCUSSION: This tumor was existence of anterior and posterior position in pulmonary apex region. So that, it is very important for complete resecting this complicated tumor to work out operation's strategy. CONCLUSION: Surgery may be indicated for SST invading the spine, when complete resection is expected. PMID- 27490679 TI - A case of abdominal compartment syndrome derived from simple elongated sigmoid colon in an elderly man. AB - INTRODUCTION: Abdominal compartment syndrome or intra-abdominal hypertension may occur after intra-abdominal events, but their etiology and clinical signs remain unclear. We report a case of abdominal compartment syndrome in an elderly patient without other risk factors. PRESENTATION OF CASE: An 86-year-old man had been admitted to our hospital several times for a dilated sigmoid colon with elongation, and had complained about abdominal pain and abdominal fullness. At every admission we decompressed the sigmoid colon gas by colonoscopy, resulting in early discharge the following day. Recently, the patient developed dementia and experienced reduced activities of daily living that are common with aging. He frequently complained of severe abdominal distension with hypotension, tachycardia and tachypnea, and finally entered hospital twice a week. We decided to perform elective surgery, which showed abdominal compartment syndrome caused by elongated sigmoid colon without volvulus (the first reported case). DISCUSSION AND CONCLUSION: Considering the increase in the aging population, we must bear in mind that abdominal compartment syndrome may occur in simple elongated sigmoid colon without other risk factors. PMID- 27490680 TI - A new hybrid sutureless patch repair utilizing chitosan for left ventricle rupture after myocardial infarction: A case report. AB - INTRODUCTION: There are many publications reporting the use of TachoSil sheets for sutureless repair. Trauma doctors have recently reported that chitosan-based sheets can efficiently achieve hemostasis for active bleeding. PRESENTATION OF CASE: An 85-year-old man was diagnosed with left ventricle free wall rupture that caused cardiac tamponade and cardiogenic shock. Extracorporeal membrane oxygenator (ECMO) was started immediately and surgical repair was planned. Bleeding occurred from a 1-cm tear in the center of the necrotic area in the territory of the left circumflex artery. The tear was treated with a chitosan based HemCon Bandage. After hemostasis of the myocardium was achieved, the bandage was peeled off and a patch repair was performed using collagen fleece with fibrinogen-based impregnation. His condition subsequently improved. The tracheal tube was extubated and ECMO was removed 2days after the surgery. One month later, the patient had no complications at his postoperative follow-up visit. DISCUSSION: To our knowledge, this is the first report of a hybrid patch repair utilizing chitosan-based sheets for a left ventricle rupture after myocardial infarction. Further studies are necessary to evaluate the short- and long-term efficacy of this procedure, and these results must be compared with those of classical surgical repairs. CONCLUSION: The new hybrid sutureless patch utilizing chitosan was demonstrated as safe, easy and effective. PMID- 27490682 TI - General and Mild Cobalt-Catalyzed C-Alkylation of Unactivated Amides and Esters with Alcohols. AB - The borrowing hydrogen or hydrogen autotransfer methodology is an elegant and sustainable or green concept to construct carbon-carbon bonds. In this concept, alcohols, which can be obtained from barely used and indigestible biomass, such as lignocellulose, are employed as alkylating reagents. An especially challenging alkylation is that of unactivated esters and amides. Only noble metal catalysts based on iridium and ruthenium have been used to accomplish these reactions. Herein, we report on the first base metal-catalyzed alpha-alkylation of unactivated amides and esters by alcohols. Cobalt complexes stabilized with pincer ligands, recently developed in our laboratory, catalyze these reactions very efficiently. The precatalysts can be synthesized easily from commercially available starting materials on a multigram scale and are self-activating under the basic reaction conditions. This Co catalyst class is also able to mediate alkylation reactions of both esters and amides. In addition, we apply the methodology to synthesize ketones and to convert alcohols into aldehydes elongated by two carbon atoms. PMID- 27490681 TI - Two cases of laparoscopic simultaneous resection of colorectal cancer and synchronous liver metastases in elderly patients. AB - INTRODUCTION: The laparoscopic resection of colorectal cancer and laparoscopic liver surgery are widely considered to be safe. Recently, it has been reported that the simultaneous laparoscopic resection of primary colorectal cancer and liver metastasis is technically feasible and safe when it is performed at experienced centers. However, the feasibility of simultaneous laparoscopic procedures for colorectal cancer and synchronous colorectal liver metastases in elderly patients has not been studied sufficiently. In this study, two cases in which elderly patients with colorectal cancer and synchronous liver metastases were treated with simultaneous laparoscopic resection are reported. PRESENTATION OF CASES: An 83-year-old female was diagnosed with ascending colon cancer and synchronous hepatic metastases. Simultaneous laparoscopic resection of the primary colon cancer and the liver metastasis was performed. Another tiny hepatic metastasis was subsequently detected in the right hepatic lobe. It was treated with hand-assisted radiofrequency ablation (RFA). The total operative time was 470min, and 340g of intraoperative blood loss occurred. The other case involved a 78-year-old male who was diagnosed with ascending colon cancer and synchronous hepatic metastasis in the right hepatic lobe. Simultaneous laparoscopic resection of the primary colon tumor and liver metastasis was performed. The total operative time was 471min, and 240g of intraoperative blood loss occurred. The postoperative courses of both patients were uneventful. DISCUSSION AND CONCLUSION: Our results indicate that simultaneous laparoscopic resection of colorectal cancer and synchronous liver metastases is feasible and safe in elderly patients. PMID- 27490684 TI - Use of Cepheid Xpert Carba-R(r) for Rapid Detection of Carbapenemase-Producing Bacteria in Abdominal Septic Patients Admitted to Intensive Care Unit. AB - Early institution of effective antibiotic therapy and source control are pivotal to improve survival of abdominal septic patients. Xpert(r) Carba-R is a real time polymerase chain reaction assay for rapid detection and differentiation of five genes (blaKPC, blaVIM, blaOXA-48, blaIMP-1, blaNDM) responsible for carbapenem resistance. We performed an observational study investigating the clinical usefulness and applicability of Xpert(r) Carba-R to detect carbapenem resistance in abdominal septic patients admitted to intensive care unit. We compared the results of Xpert(r) Carba-R with standard microbiological culture. We collected a set of two rectal/stomia swabs and two swabs from abdominal drainage fluid for each patient. We included 20 patients for a total of 45 comparisons between the two methods. In our clinical setting, the overall performance of Xpert(r) Carba-R for detection of carbapenem resistance in the presence of genes detectable and non-detectable by the method was: sensitivity 50% (95% CI 24.6-75.3); specificity 93.1% (95% CI 77.2-99.1); positive predictive value (PPV) 80% (95% CI 44.4-97.5); negative predictive value (NPV) 77.1% (95% CI 56.9-89.6). The inter-rater agreement was 0.47 (SE 0.14; 95% CI 0.20-0.74). When considering the only 5 mechanisms of resistance detected by both methods, the overall diagnostic performance was: sensitivity 100% (95% CI 69.1-100), specificity 94.2 (95% CI 80.8-99.3), PPV 83.3 (95% CI 59.6-97.9) and NPV 100% (95% CI 89.4-100). The inter rater agreement was 0.88 (SE 0.08; 95% CI 0.71-1). Xpert(r) Carba-R may be considered an additional diagnostic tool for early diagnosis of carbapenem resistance in abdominal septic patients. Clinicians should be aware of their epidemiology before its introduction in the diagnostic protocol of their intensive care units. PMID- 27490685 TI - Biomarkers for Presymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients. AB - Cardiotoxicity of doxorubicin (DOX) remains an important health concern. DOX cardiotoxicity is cumulative-dose-dependent and begins with the first dose of chemotherapy. No biomarker for presymptomatic detection of DOX cardiotoxicity has been validated. Our hypothesis is that peripheral blood cells (PBC) gene expression induced by the early doses of DOX-based chemotherapy could identify potential biomarkers for presymptomatic cardiotoxicity in cancer patients. PBC gene expression of 33 breast cancer patients was conducted before and after the first cycle of DOX-based chemotherapy. Cardiac function was evaluated before the start of chemotherapy and at its completion. Differentially expressed genes (DEG) of patients who developed DOX-associated cardiotoxicity after the completion of chemotherapy were compared with DEG of patients who did not. Ingenuity database was used for functional analysis of DEG. Sixty-sevens DEG (P<0.05) were identified in PBC of patients with DOX-cardiotoxicity. Most of DEG encode proteins secreted by activated neutrophils. The functional analysis of the DEG showed enrichment for immune- and inflammatory response. This is the first study to identify the PBC transcriptome signature associated with a single dose of DOX based chemotherapy in cancer patients. We have shown that PBC transcriptome signature associated with one dose of DOX chemotherapy in breast cancer can predict later impairment of cardiac function. This finding may be of value in identifying patients at high or low risk for the development of DOX cardiotoxicity during the initial doses of chemotherapy and thus to avoid the accumulating toxic effects from the subsequent doses during treatment. PMID- 27490687 TI - The Femoral Intercondylar Notch During Life: An Anatomic Redefinition With Patterns Predisposing to Cruciate Ligament Impingement. AB - OBJECTIVE: The goals of this study were to test whether age- and sex-dependent variations in the size and shape of the intercondylar notch exist and to define the landmarks and measurements best suited for assessment of the intercondylar notch on MR images. MATERIALS AND METHODS: In this retrospective cross-sectional study, 329 patients were divided into six age groups, and their MR images (3-T coronal T2-weighted fat-suppressed spectral attenuated inversion recovery [SPAIR], sagittal proton density-weighted, axial T2-weighted fat-suppressed SPAIR) were evaluated. The intercondylar notch was measured and its shape evaluated on coronal images. Three shapes of intercondylar notch were defined. RESULTS: The intercondylar notch is subject to change throughout life, narrowing more distally and widening more proximally. Its width ranges from 16.23 +/- 2.71 mm before the age of 11 years to 19.38 +/- 2.90 mm in middle age and then decreases to 18.6 +/- 2.36 mm after the age of 60 years. Its shape changes from an A shape in the early stages of life to an Omega shape in the later stages. CONCLUSION: The term "intercondylar space" is introduced as a morphologic description of the osseous intercondylar notch and adjacent structures. The femur as a whole is subject to substantial plastic deformation throughout life, not only in its proximal part, with respect to torsion, but also in its distal extent. PMID- 27490686 TI - Neuroimaging of the bilingual brain: Structural brain correlates of listening and speaking in a second language. AB - Diffusion tensor imaging was used to compare white matter structure between American monolingual and Spanish-English bilingual adults living in the United States. In the bilingual group, relationships between white matter structure and naturalistic immersive experience in listening to and speaking English were additionally explored. White matter structural differences between groups were found to be bilateral and widespread. In the bilingual group, experience in listening to English was more robustly correlated with decreases in radial and mean diffusivity in anterior white matter regions of the left hemisphere, whereas experience in speaking English was more robustly correlated with increases in fractional anisotropy in more posterior left hemisphere white matter regions. The findings suggest that (a) foreign language immersion induces neuroplasticity in the adult brain, (b) the degree of alteration is proportional to language experience, and (c) the modes of immersive language experience have more robust effects on different brain regions and on different structural features. PMID- 27490688 TI - IMAGING DIAGNOSIS-COMPUTED TOMOGRAPHY OF TRACTION BRONCHIECTASIS SECONDARY TO PULMONARY FIBROSIS IN A PATTERDALE TERRIER. AB - An 8-year-old, Patterdale terrier was referred for evaluation of tachypnoea, exercise intolerance, and weight loss. Computed tomographic images showed pneumomediastinum, diffuse pulmonary ground glass opacity, and marked dilatation of peripheral bronchi, but no evidence of thickened bronchial walls. The histopathologic diagnosis was diffuse pulmonary interstitial fibrosis, type II pneumocyte hyperplasia, and bronchiectasis. The lack of evidence of primary bronchitis supported a diagnosis of traction bronchiectasis. Traction bronchiectasis can occur as a sequela to pulmonary fibrosis in dogs. PMID- 27490689 TI - Proton-Coupled Electron Transfer in a Series of Ruthenium-Linked Tyrosines with Internal Bases: Evaluation of a Tunneling Model for Experimental Temperature Dependent Kinetics. AB - Photoinitiated proton-coupled electron transfer (PCET) kinetics has been investigated in a series of four modified tyrosines linked to a ruthenium photosensitizer in acetonitrile, with each tyrosine bearing an internal hydrogen bond to a covalently linked pyridine or benzimidazole base. After correcting for differences in driving force, it is found that the intrinsic PCET rate constant still varies by 2 orders of magnitude. The differences in rates, as well as the magnitude of the kinetic isotope effect (KIE = kH/kD), both generally correlate with DFT calculated proton donor-acceptor distances. An Arrhenius analysis of temperature dependent data shows that the difference in reactivity arises primarily from differences in activation energies. We use this kinetic data to evaluate a commonly employed theoretical model for proton tunneling which includes a harmonic distribution of proton donor-acceptor distances due to vibrational motions of the molecule. Applying this model to the experimental data yields the conclusion that donor-acceptor compression is more facile in the compounds with shorter PT distance; however, this is contrary to independent calculations for the same compounds. This discrepancy is likely because the assumption in the model of Morse-shaped proton potential energy surfaces is inappropriate for (strongly) hydrogen-bonded systems. These results question the general applicability of this model. The results also suggest that a correlation of rate vs proton tunneling distance for the series of compounds is complicated by a concomitant variation of other relevant parameters. PMID- 27490691 TI - Steric and Electronic Influence on Proton-Coupled Electron-Transfer Reactivity of a Mononuclear Mn(III)-Hydroxo Complex. AB - A mononuclear hydroxomanganese(III) complex was synthesized utilizing the N5 amide-containing ligand 2-[bis(pyridin-2-ylmethyl)]amino-N-2-methyl-quinolin-8-yl acetamidate (dpaq(2Me) ). This complex is similar to previously reported [Mn(III)(OH)(dpaq(H))](+) [Inorg. Chem. 2014, 53, 7622-7634] but contains a methyl group adjacent to the hydroxo moiety. This alpha-methylquinoline group in [Mn(III)(OH)(dpaq(2Me))](+) gives rise to a 0.1 A elongation in the Mn N(quinoline) distance relative to [Mn(III)(OH)(dpaq(H))](+). Similar bond elongation is observed in the corresponding Mn(II) complex. In MeCN, [Mn(III)(OH)(dpaq(2Me))](+) reacts rapidly with 2,2',6,6'-tetramethylpiperidine-1 ol (TEMPOH) at -35 degrees C by a concerted proton-electron transfer (CPET) mechanism (second-order rate constant k2 of 3.9(3) M(-1) s(-1)). Using enthalpies and entropies of activation from variable-temperature studies of TEMPOH oxidation by [Mn(III)(OH)(dpaq(2Me))](+) (DeltaH(?) = 5.7(3) kcal(-1) M(-1); DeltaS(?) = 41(1) cal M(-1) K(-1)), it was determined that [Mn(III)(OH)(dpaq(2Me))](+) oxidizes TEMPOH ~240 times faster than [Mn(III)(OH)(dpaq(H))](+). The [Mn(III)(OH)(dpaq(2Me))](+) complex is also capable of oxidizing the stronger O-H and C-H bonds of 2,4,6-tri-tert-butylphenol and xanthene, respectively. However, for these reactions [Mn(III)(OH)(dpaq(2Me))](+) displays, at best, modest rate enhancement relative to [Mn(III)(OH)(dpaq(H))](+). A combination of density function theory (DFT) and cyclic voltammetry studies establish an increase in the Mn(III)/Mn(II) reduction potential of [Mn(III)(OH)(dpaq(2Me))](+) relative to [Mn(III)(OH)(dpaq(H))](+), which gives rise to a larger driving force for CPET for the former complex. Thus, more favorable thermodynamics for [Mn(III)(OH)(dpaq(2Me))](+) can account for the dramatic increase in rate with TEMPOH. For the more sterically encumbered substrates, DFT computations suggest that this effect is mitigated by unfavorable steric interactions between the substrate and the alpha-methylquinoline group of the dpaq(2Me) ligand. The DFT calculations, which reproduce the experimental activation free energies quite well, provide the first examination of the transition-state structure of mononuclear Mn(III)(OH) species during a CPET reaction. PMID- 27490690 TI - Intra-Animal Comparison between Three-dimensional Molecularly Targeted US and Three-dimensional Dynamic Contrast-enhanced US for Early Antiangiogenic Treatment Assessment in Colon Cancer. AB - Purpose To perform an intra-animal comparison between (a) three-dimensional (3D) molecularly targeted ultrasonography (US) by using clinical-grade vascular endothelial growth factor receptor 2 (VEGFR2)-targeted microbubbles and (b) 3D dynamic contrast material-enhanced (DCE) US by using nontargeted microbubbles for assessment of antiangiogenic treatment effects in a murine model of human colon cancer. Materials and Methods Twenty-three mice with human colon cancer xenografts were randomized to receive either single-dose antiangiogenic treatment (bevacizumab, n = 14) or control treatment (saline, n = 9). At baseline and 24 hours after treatment, animals were imaged with a clinical US system equipped with a clinical matrix array transducer by using the following techniques: (a) molecularly targeted US with VEGFR2-targeted microbubbles, (b) bolus DCE US with nontargeted microbubbles, and (c) destruction-replenishment DCE US with nontargeted microbubbles. VEGFR2-targeted US signal, peak enhancement, area under the time-intensity curve, time to peak, relative blood volume (rBV), relative blood flow, and blood flow velocity were quantified. VEGFR2 expression and percentage area of blood vessels were assessed ex vivo with quantitative immunofluorescence and correlated with corresponding in vivo US parameters. Statistical analysis was performed with Wilcoxon signed rank tests and rank sum tests, as well as Pearson correlation analysis. Results Molecularly targeted US signal with VEGFR2-targeted microbubbles, peak enhancement, and rBV significantly decreased (P <= .03) after a single antiangiogenic treatment compared with those in the control group; similarly, ex vivo VEGFR2 expression (P = .03) and percentage area of blood vessels (P = .03) significantly decreased after antiangiogenic treatment. Three-dimensional molecularly targeted US signal correlated well with VEGFR2 expression (r = 0.86, P = .001), and rBV (r = 0.71, P = .01) and relative blood flow (r = 0.78, P = .005) correlated well with percentage area of blood vessels, while other US perfusion parameters did not. Conclusion Three-dimensional molecularly targeted US and destruction replenishment 3D DCE US provide complementary molecular and functional in vivo imaging information on antiangiogenic treatment effects in human colon cancer xenografts compared with ex vivo reference standards. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27490692 TI - Copula-Based Approach to Synthetic Population Generation. AB - Generating synthetic baseline populations is a fundamental step of agent-based modeling and simulation, which is growing fast in a wide range of socio-economic areas including transportation planning research. Traditionally, in many commercial and non-commercial microsimulation systems, the iterative proportional fitting (IPF) procedure has been used for creating the joint distribution of individuals when combining a reference joint distribution with target marginal distributions. Although IPF is simple, computationally efficient, and rigorously founded, it is unclear whether IPF well preserves the dependence structure of the reference joint table sufficiently when fitting it to target margins. In this paper, a novel method is proposed based on the copula concept in order to provide an alternative approach to the problem that IPF resolves. The dependency characteristic measures were computed and the results from the proposed method and IPF were compared. In most test cases, the proposed method outperformed IPF in preserving the dependence structure of the reference joint distribution. PMID- 27490693 TI - Mutational Biases Drive Elevated Rates of Substitution at Regulatory Sites across Cancer Types. AB - Disruption of gene regulation is known to play major roles in carcinogenesis and tumour progression. Here, we comprehensively characterize the mutational profiles of diverse transcription factor binding sites (TFBSs) across 1,574 completely sequenced cancer genomes encompassing 11 tumour types. We assess the relative rates and impact of the mutational burden at the binding sites of 81 transcription factors (TFs), by comparing the abundance and patterns of single base substitutions within putatively functional binding sites to control sites with matched sequence composition. There is a strong (1.43-fold) and significant excess of mutations at functional binding sites across TFs, and the mutations that accumulate in cancers are typically more disruptive than variants tolerated in extant human populations at the same sites. CTCF binding sites suffer an exceptionally high mutational load in cancer (3.31-fold excess) relative to control sites, and we demonstrate for the first time that this effect is seen in essentially all cancer types with sufficient data. The sub-set of CTCF sites involved in higher order chromatin structures has the highest mutational burden, suggesting a widespread breakdown of chromatin organization. However, we find no evidence for selection driving these distinctive patterns of mutation. The mutational load at CTCF-binding sites is substantially determined by replication timing and the mutational signature of the tumor in question, suggesting that selectively neutral processes underlie the unusual mutation patterns. Pervasive hyper-mutation within transcription factor binding sites rewires the regulatory landscape of the cancer genome, but it is dominated by mutational processes rather than selection. PMID- 27490694 TI - AP-1 Inhibition by SR 11302 Protects Human Hepatoma HepG2 Cells from Bile Acid Induced Cytotoxicity by Restoring the NOS-3 Expression. AB - The harmful effects of bile acid accumulation occurring during cholestatic liver diseases have been associated with oxidative stress increase and endothelial nitric oxide synthase (NOS-3) expression decrease in liver cells. We have previously reported that glycochenodeoxycholic acid (GCDCA) down-regulates gene expression by increasing SP1 binding to the NOS-3 promoter in an oxidative stress dependent manner. In the present study, we aimed to investigate the role of transcription factor (TF) AP-1 on the NOS-3 deregulation during GCDCA-induced cholestasis. The cytotoxic response to GCDCA was characterized by 1) the increased expression and activation of TFs cJun and c-Fos; 2) a higher binding capability of these at position -666 of the NOS-3 promoter; 3) a decrease of the transcriptional activity of the promoter and the expression and activity of NOS 3; and 4) the expression increase of cyclin D1. Specific inhibition of AP-1 by the retinoid SR 11302 counteracted the cytotoxic effects induced by GCDCA while promoting NOS-3 expression recovery and cyclin D1 reduction. NOS activity inhibition by L-NAME inhibited the protective effect of SR 11302. Inducible NOS isoform was no detected in this experimental model of cholestasis. Our data provide direct evidence for the involvement of AP-1 in the NOS-3 expression regulation during cholestasis and define a critical role for NOS-3 in regulating the expression of cyclin D1 during the cell damage induced by bile acids. AP-1 appears as a potential therapeutic target in cholestatic liver diseases given its role as a transcriptional repressor of NOS-3. PMID- 27490696 TI - Modification of human serum albumin by the nerve agent VX: microbore liquid chromatography/electrospray ionization high-resolution time-of-flight tandem mass spectrometry method for detection of phosphonylated tyrosine and novel cysteine containing disulfide adducts. AB - RATIONALE: Organophosphorus nerve agents still constitute a considerable threat to the health of military personnel and the civilian population. Long-term biomarkers are crucial for reliable verification of exposure to banned substances. Therefore, current research focuses on identification of endogenous protein targets showing covalent modifications by organophosphorus nerve agents (adducts). METHODS: Purified human serum albumin and human plasma were incubated with the nerve agent VX followed by enzymatic proteolysis with pronase. Resulting peptide cleavage products were separated by microbore liquid chromatography (MULC) online coupled to positive electrospray ionization (ESI) with subsequent high-resolution time-of-flight tandem mass spectrometry (HR MS/MS) allowing identification of known and novel adducts. RESULTS: In addition to known phosphonylation of various tyrosine residues, albumin was found to be modified at diverse cysteine residues by covalent attachment of the leaving group of VX. These novel disulfide adducts were cleaved from at least two regions of the intact protein as dipeptides containing cysteine and proline either as CP or PC. A rapid and sensitive method was developed for simultaneous detection of the diverse covalent modifications of human albumin by VX. CONCLUSIONS: Identification of the novel leaving group adducts with human albumin expands the basic knowledge on molecular toxicology of the nerve agent VX. Furthermore, the presented MULC/ESI HR MS/MS method might be of relevance for verification of VX poisoning. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27490695 TI - Nosocomial Outbreak of OXA-48-Producing Klebsiella pneumoniae in a Chinese Hospital: Clonal Transmission of ST147 and ST383. AB - BACKGROUND: In China, the spread and outbreak of OXA-48-producing Enterobacteriaceae remains largely unknown. METHODS: OXA-48-producing isolates were analyzed for genetic relatedness by pulsed-field gel electrophoresis (PFGE), antimicrobial susceptibility by E-test, and sequence type (ST) by multilocus sequence typing. S1-PFGE and southern blotting were used for plasmid profiling, and PCR and subsequent sequencing were performed to determine the genetic environment of blaOXA-48 gene. RESULTS: In total, 37 non-duplicated OXA-48 producing K. pneumoniae (OXAKp) isolates were recovered. From December 2013 to August 2014, an outbreak was observed at a respiratory ICU. The 37 isolates of K. pneumoniae were categorized into four PFGE types (A, B, C, and D). The predominant strains associated with the outbreak were strains with PFGE type A and B, which belonged to ST383 and ST147, respectively. Plasmid sequencing revealed that the blaOXA-48-carrying plasmid is 69,069 bp in length and belongs to the IncL/M incompatibility group. Sequence analysis revealed that the IS1999 element was located upstream of the blaOXA-48 gene and was truncated by IS1R. CONCLUSIONS: In this study, the dissemination and outbreak of OXAKp isolates were clonal, and ST147 and ST383 K. pneumoniae were the predominant clones that were associated with the outbreak. Meanwhile, the horizontal transfer of plasmids potentially mediate the spread of blaOXA-48 gene between different K. pneumoniae strains. PMID- 27490697 TI - petal: Co-expression network modelling in R. AB - BACKGROUND: Networks provide effective models to study complex biological systems, such as gene and protein interaction networks. With the advent of new sequencing technologies, many life scientists are grasping for user-friendly methods and tools to examine biological components at the whole-systems level. Gene co-expression network analysis approaches are frequently used to successfully associate genes with biological processes and demonstrate great potential to gain further insights into the functionality of genes, thus becoming a standard approach in Systems Biology. Here the objective is to construct biologically meaningful and statistically strong co-expression networks, the identification of research dependent subnetworks, and the presentation of self contained results. RESULTS: We introduce petal, a novel approach to generate gene co-expression network models based on experimental gene expression measures. petal focuses on statistical, mathematical, and biological characteristics of both, input data and output network models. Often over-looked issues of current co-expression analysis tools include the assumption of data normality, which is seldom the case for hight-throughput expression data obtained from RNA-seq technologies. petal does not assume data normality, making it a statistically appropriate method for RNA-seq data. Also, network models are rarely tested for their known typical architecture: scale-free and small-world. petal explicitly constructs networks based on both these characteristics, thereby generating biologically meaningful models. Furthermore, many network analysis tools require a number of user-defined input variables, these often require tuning and/or an understanding of the underlying algorithm; petal requires no user input other than experimental data. This allows for reproducible results, and simplifies the use of petal. Lastly, this approach is specifically designed for very large high throughput datasets; this way, petal's network models represent as much of the entire system as possible to provide a whole-system approach. CONCLUSION: petal is a novel tool for generating co-expression network models of whole-genomics experiments. It is implemented in R and available as a library. Its application to several whole-genome experiments has generated novel meaningful results and has lead the way to new testing hypothesizes for further biological investigation. PMID- 27490698 TI - Neutropenia as an Adverse Event following Vaccination: Results from Randomized Clinical Trials in Healthy Adults and Systematic Review. AB - BACKGROUND: In the context of early vaccine trials aimed at evaluating the safety profile of novel vaccines, abnormal haematological values, such as neutropenia, are often reported. It is therefore important to evaluate how these trials should be planned not to miss potentially important safety signals, but also to understand the implications and the clinical relevance. METHODOLOGY: We report and discuss the results from five clinical trials (two with a new Shigella vaccine in the early stage of clinical development and three with licensed vaccines) where the absolute neutrophil counts (ANC) were evaluated before and after vaccination. Additionally, we have performed a systematic review of the literature on cases of neutropenia reported during vaccine trials to discuss our results in a more general context. PRINCIPAL FINDINGS: Both in our clinical trials and in the literature review, several cases of neutropenia have been reported, in the first two weeks after vaccination. However, neutropenia was generally transient and had a benign clinical outcome, after vaccination with either multiple novel candidates or well-known licensed vaccines. Additionally, the vaccine recipients with neutropenia frequently had lower baseline ANC than non-neutropenic vaccinees. In many instances neutropenia occurred in subjects of African descent, known to have lower ANC compared to western populations. CONCLUSIONS: It is important to include ANC and other haematological tests in early vaccine trials to identify potential safety signals. Post-vaccination neutropenia is not uncommon, generally transient and clinically benign, but many vaccine trials do not have a sampling schedule that allows its detection. Given ethnic variability in the level of circulating neutrophils, normal ranges taking into account ethnicity should be used for determination of trial inclusion/exclusion criteria and classification of neutropenia related adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT02017899, NCT02034500, NCT01771367, NCT01765413, NCT02523287. PMID- 27490699 TI - The Myeloablative Drug Busulfan Converts Cysteine to Dehydroalanine and Lanthionine in Redoxins. AB - The myeloablative agent busulfan (1,4-butanediol dimethanesulfonate) is an old drug that is used routinely to eliminate cancerous bone marrow prior to hematopoietic stem cell transplant. The myeloablative activity and systemic toxicity of busulfan have been ascribed to its ability to cross-link DNA. In contrast, here we demonstrate that incubation of busulfan with the thiol redox proteins glutaredoxin or thioredoxin at pH 7.4 and 37 degrees C results in the formation of putative S-tetrahydrothiophenium adducts at their catalytic Cys residues, followed by beta-elimination to yield dehydroalanine. Both proteins contain a second Cys, in their catalytic C-X-X-C motif, which reacts with the dehydroalanine, the initial Cys adduct with busulfan, or the S tetrahydrothiophenium, to form novel intramolecular cross-links. The reactivity of the dehydroalanine (DHA) formed is further demonstrated by adduction with glutathione to yield a lanthionine and by a novel reaction with the reducing agent tris(2-carboxyethyl)phosphine (TCEP), which yields a phosphine adduct via Michael addition to the DHA. Formation of a second quaternary organophosphonium salt via nucleophilic substitution with TCEP on the initial busulfan-protein adduct or on the THT(+)-Redoxin species is also observed. These results reveal a rich potential for reactions of busulfan with proteins in vitro, and likely in vivo. It is striking that several of the chemically altered protein products retain none of the atoms of busulfan, in contrast to typical drug-protein adducts or traditional protein modification reagents. In particular, the ability of a clinically used drug to convert Cys to dehydrolanine in intact proteins, and its subsequent reaction with biological thiols, is unprecedented. PMID- 27490700 TI - Clinical Relevance of ASC-H Cytologies: Experience in a Single Tertiary Hospital. AB - OBJECTIVES: To review the cases of atypical squamous cells (ASC), cannot exclude squamous intraepithelial lesion (ASC-H) diagnosed at a single institution and to discuss the interpretation challenges and clinical management of these cases. STUDY DESIGN: The ASC-H cases diagnosed at our institution from 2006 to 2015 were studied retrospectively; of 159,000 Pap smears, there were 959 cases of ASC of undetermined significance (ASC-US) and 148 cases of ASC-H. We have reviewed the clinical records of the ASC-H cases, and data have been analyzed using SPSS 20.0. RESULTS: Median age was 43.1 years; 49.6% of the patients had previous cervical cytologies, and 55.9% of them were negative. Following ASC-H diagnosis, another smear was obtained in 97.1% of the cases and in 67.6% a biopsy was performed. Biopsy revealed low-grade dysplasia in 18.8% of the cases, high-grade dysplasia in 27.8%, and infiltrating carcinoma in 2.3%. Patients with significant lesions in histology were younger than patients with negative results (p = 0.08). A diagnosis of ASC-H/squamous intraepithelial lesion in the repeated cytology had a sensitivity of 74.2%, specificity of 39.6%, positive predictive value of 44.8%, and negative predictive value of 70% for the diagnosis of dysplasia. CONCLUSIONS: ASC-H diagnosis is associated with a high incidence of histological high-grade lesions. A repeat cytology can aid in the selection of high-risk patients, but there may be false-negative results. PMID- 27490701 TI - Commentary on USPSTF Final Statement on Universal Screening for Autism. PMID- 27490702 TI - Liver stiffness measurement predicts high-grade post-hepatectomy liver failure: A prospective cohort study. AB - BACKGROUND AND AIM: Liver stiffness measurement using transient elastography appears to be an excellent tool for detection of liver fibrosis and cirrhosis with high accuracy. The aim of this study is to evaluate the efficacy of preoperative liver stiffness measurement in predicting post-hepatectomy liver failure. METHODS: A prospective cohort study of all consecutive patients undergoing hepatectomy for hepatocellular carcinoma from February 2010 to August 2014 was studied. All patients received detailed preoperative assessments including liver stiffness measurement. The primary outcome was post-hepatectomy liver failure according to the International Study Group of Liver Surgery definition. RESULTS: A total of 255 patients were included. Liver stiffness measurement showed significant correlation with grade B or C post-hepatectomy liver failure. (P = 0.003) Using the cutoff at 12 kPa, liver stiffness measurement had a sensitivity of 52.4% and specificity of 73.3% in predication of high-grade (grade B or C) post-hepatectomy liver failure. Liver stiffness measurement > 12 kPa was also an independent prognostic factor for both high grade post-hepatectomy liver failure and major postoperative complications by multivariate analysis. The diagnostic accuracy was better in patients without right lobe tumor with an area under the receiver operating characteristic of 0.83 compared with an area under the receiver operating characteristic of only 0.62 in patients with right lobe tumor. CONCLUSIONS: Liver stiffness measurement using Fibroscan is good to predict high-grade post-hepatectomy liver failure especially in patients without right lobe tumor. PMID- 27490703 TI - Gram Scale Synthesis of Benzophenanthroline and Its Blue Phosphorescent Platinum Complex. AB - The design, synthesis, and characterization of 12 phenylbenzo[f][1,7]phenanthroline, Bzp, is reported. Its use as a fluorine-free ligand for sky blue phosphorescence is demonstrated in a cyclometalated platinum complex, BzpPtDpm. BzpPtDpm phosphoresces at the same wavelength as its analogous 4,6-difluorophenylpyridine complex at both room temperature (466 nm) and 77 K (458 nm). Finally, production of a conformationally restricted derivative of BzpPtDpm with greatly increased quantum yield (46%) validates the versatility of the synthetic route. PMID- 27490704 TI - Improving Metabolic Pathway Efficiency by Statistical Model-Based Multivariate Regulatory Metabolic Engineering. AB - Metabolic engineering entails target modification of cell metabolism to maximize the production of a specific compound. For empowering combinatorial optimization in strain engineering, tools and algorithms are needed to efficiently sample the multidimensional gene expression space and locate the desirable overproduction phenotype. We addressed this challenge by employing design of experiment (DoE) models to quantitatively correlate gene expression with strain performance. By fractionally sampling the gene expression landscape, we statistically screened the dominant enzyme targets that determine metabolic pathway efficiency. An empirical quadratic regression model was subsequently used to identify the optimal gene expression patterns of the investigated pathway. As a proof of concept, our approach yielded the natural product violacein at 525.4 mg/L in shake flasks, a 3.2-fold increase from the baseline strain. Violacein production was further increased to 1.31 g/L in a controlled benchtop bioreactor. We found that formulating discretized gene expression levels into logarithmic variables (Linlog transformation) was essential for implementing this DoE-based optimization procedure. The reported methodology can aid multivariate combinatorial pathway engineering and may be generalized as a standard procedure for accelerating strain engineering and improving metabolic pathway efficiency. PMID- 27490706 TI - Dosing of Milrinone in Preterm Neonates to Prevent Postligation Cardiac Syndrome: Simulation Study Suggests Need for Bolus Infusion. AB - BACKGROUND: Milrinone has been suggested as a possible first-line therapy for preterm neonates to prevent postligation cardiac syndrome (PLCS) through decreasing systemic vascular resistance and increasing cardiac contractility. The optimal dosing regimen, however, is not known. OBJECTIVE: To model the dosing of milrinone in preterm infants for prevention of PLCS after surgical closure of patent ductus arteriosus (PDA). METHODS: Milrinone time-concentration profiles were simulated for 1,000 subjects using the volume of distribution and clearance estimates based on one compartmental population pharmacokinetic model by Paradisis et al. [Arch Dis Child Fetal Neonatal Ed 2007;92:F204-F209]. Dose optimization was based on retrospectively collected demographic data from neonates undergoing PDA ligation in Estonian PICUs between 2012 and 2014 and existing pharmacodynamic data. The target plasma concentration was set at 150-200 ng/ml. RESULTS: The simulation study used demographic data from 31 neonates who underwent PDA ligation. The median postnatal age was 13 days (range: 3-29) and weight was 760 g (range: 500-2,351). With continuous infusion of milrinone 0.33 MUg/kg/min, the proportion of subjects within the desired concentration range was 0% by 3 h, 36% by 6 h, and 61% by 8 h; 99% of subjects exceeded the range by 18 h. The maximum proportion of total simulated concentrations in the target range was attained with a bolus infusion of 0.73 MUg/kg/min for 3 h followed by a 0.16 MUg/kg/min maintenance infusion. CONCLUSION: Mathematical simulations suggest that in preterm neonates the plasma time-concentration profile of milrinone can be optimized with a slow loading dose followed by maintenance infusion. PMID- 27490707 TI - All-Elastomer-Based Triboelectric Nanogenerator as a Keyboard Cover To Harvest Typing Energy. AB - The drastic expansion of consumer electronics (like personal computers, touch pads, smart phones, etc.) creates many human-machine interfaces and multiple types of interactions between human and electronics. Considering the high frequency of such operations in our daily life, an extraordinary amount of biomechanical energy from typing or pressing buttons is available. In this study, we have demonstrated a highly flexible triboelectric nanogenerator (TENG) solely made from elastomeric materials as a cover on a conventional keyboard to harvest biomechanical energy from typing. A dual-mode working mechanism is established with a high transferred charge density of ~140 MUC/m(2) due to both structural and material innovations. We have also carried out fundamental investigations of its performance dependence on various structural factors for optimizing the electric output in practice. The fully packaged keyboard-shaped TENG is further integrated with a horn-like polypyrrole-based supercapacitor as a self-powered system. Typing in normal speed for 1 h, ~8 * 10(-4) J electricity could be stored, which is capable of driving an electronic thermometer/hydrometer. Our keyboard cover also performs outstanding long-term stability, water resistance, as well as insensitivity to surface conditions, and the last feature makes it useful to research the typing behaviors of different people. PMID- 27490708 TI - alpha-Regioselective Barbier Reaction of Carbonyl Compounds and Allyl Halides Mediated by Praseodymium. AB - The first utility of praseodymium as a mediating metal in the Barbier reaction of carbonyl compounds with allyl halides was reported in this paper. In contrast to the traditional metal-mediated or catalyzed Barbier reactions, exclusive alpha adducts were obtained in this one-pot reaction with a broad scope of substrates and feasible reaction conditions. PMID- 27490705 TI - Small Molecules in Development for the Treatment of Spinal Muscular Atrophy. AB - Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease resulting from pathologically low levels of survival motor neuron (SMN) protein. The majority of mRNA from the SMN2 allele undergoes alternative splicing and excludes critical codons, causing an SMN protein deficiency. While there is currently no FDA-approved treatment for SMA, early therapeutic efforts have focused on testing repurposed drugs such as phenylbutyrate (2), valproic acid (3), riluzole (6), hydroxyurea (7), and albuterol (9), none of which has demonstrated clinical effectiveness. More recently, clinical trials have focused on novel small-molecule compounds identified from high-throughput screening and medicinal chemistry optimization such as olesoxime (11), CK-2127107, RG7800, LMI070, and RG3039 (17). In this paper, we review both repurposed drugs and small molecule compounds discovered following medicinal chemistry optimization for the potential treatment of SMA. PMID- 27490709 TI - Chemoinformatics in the United Kingdom. PMID- 27490710 TI - The Evolution of Digital Chemistry at Southampton. AB - In this paper we take a historical view of e-Science and e-Research developments within the Chemical Sciences at the University of Southampton, showing the development of several stages of the evolving data ecosystem as Chemistry moves into the digital age of the 21(st) Century. We cover our research on aspects of the representation of chemical information in the context of the world wide web (WWW) and its semantic enhancement (the Semantic Web) and illustrate this with the example of the representation of quantities and units within the Semantic Web. We explore the changing nature of laboratories as computing power becomes increasing powerful and pervasive and specifically look at the function and role of electronic or digital notebooks. Having focussed on the creation of chemical data and information in context, we finish the paper by following the use and reuse of this data as facilitated by the features provided by digital repositories and their importance in facilitating the exchange of chemical information touching on the issues of open and or intelligent access to the data. PMID- 27490711 TI - Chemoinformatics at the University of Sheffield 2002-2014. AB - This paper summarises work in chemoinformatics carried out in the Information School of the University of Sheffield during the period 2002-2014. Research studies are described on fingerprint-based similarity searching, data fusion, applications of reduced graphs and pharmacophore mapping, and on the School's teaching in chemoinformatics. PMID- 27490712 TI - Designing Hydroxamates and Reversed Hydroxamates to Inhibit Zinc-containing Proteases but not Cytochrome P450s: Insights from Quantum Mechanics and Protein ligand Crystal Structures. AB - The Hydroxamate is a useful functional group that binds to metals in a range of enzymes, notably zinc in matrix metalloproteases and histone deacetylases. The group is also able to form interactions with iron leading to inhibition of the cytochromes P450, particularly the 3A4 isoform. We have studied the available crystal structures of zinc-containing proteins bound to hydroxamates and compared the observed geometries with those found by quantum mechanical calculations. This has revealed the likely binding mode preferences for neutral and anionic protonation states and highlighted the importance of electrostatic complementarity. Calculations were also performed for the interaction of the hydroxamate with iron in a heme environment, as found in the cytochromes P450. These reveal that the preferred binding mode of hydroxamates in this environment involves the s-trans conformation. These calculations provide design guidelines for those interested in designing inhibitors of metalloenzymes that do not block metabolism of other drugs. The ability to predict the geometries and energies of binding modes that cannot be studied experimentally is an advantage offered by this kind of study. PMID- 27490713 TI - Greedy and Linear Ensembles of Machine Learning Methods Outperform Single Approaches for QSPR Regression Problems. AB - The application of Machine Learning to cheminformatics is a large and active field of research, but there exist few papers which discuss whether ensembles of different Machine Learning methods can improve upon the performance of their component methodologies. Here we investigated a variety of methods, including kernel-based, tree, linear, neural networks, and both greedy and linear ensemble methods. These were all tested against a standardised methodology for regression with data relevant to the pharmaceutical development process. This investigation focused on QSPR problems within drug-like chemical space. We aimed to investigate which methods perform best, and how the 'wisdom of crowds' principle can be applied to ensemble predictors. It was found that no single method performs best for all problems, but that a dynamic, well-structured ensemble predictor would perform very well across the board, usually providing an improvement in performance over the best single method. Its use of weighting factors allows the greedy ensemble to acquire a bigger contribution from the better performing models, and this helps the greedy ensemble generally to outperform the simpler linear ensemble. Choice of data preprocessing methodology was found to be crucial to performance of each method too. PMID- 27490714 TI - Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans. AB - OBJECTIVE: Although posttraumatic stress disorder (PTSD) and chronic pain frequently occur in tandem, the pathophysiological mechanisms mediating this comorbidity are poorly understood. Because excessive inflammation occurs in both conditions, we examined the cerebrospinal fluid (CSF) concentrations of inflammatory response mediators interleukin 1-beta (IL-1beta), interleukin 6 (IL 6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNFalpha) and interleukin 10 (IL-10) after prolonged suprathreshold pain stimulus in 21 male combat veterans; 10 with PTSD and 11 combat controls (CC). METHODS: After completing baseline quantitative sensory testing (QST) and psychological profiling, all patients received an injection of capsaicin into the quadriceps muscle. Spontaneously reported pain was measured for 30min after the capsaicin injection. The evoked pain measure of temporal summation was tested between 70 and 110min post capsaicin injection. Inflammatory (IL-1beta, IL-6, IL-8 TNFalpha) and anti inflammatory (IL-10) CSF cytokines were measured before (baseline) and after capsaicin injection over a time frame of 110min. RESULTS: Following intramuscular capsaicin injection, pro-inflammatory cytokines [TNFalpha, IL-6, IL-8] significantly increased (percent rise from baseline) in both groups, whereas IL 1beta significantly increased in the PTSD group only. The anti-inflammatory cytokine IL-10 showed an immediate (within 10min) increase in the CC group; however, the IL-10 increase in the PTSD group was delayed and not consistently elevated until 70min post injection. CONCLUSION: These findings show significant central nervous system (CNS) differences in the inflammatory response to a deep pain stimulus in combat veterans with and without PTSD. They support the concept that abnormally elevated neuroinflammatory response to pain stimuli may be one CNS mechanism accounting for the high co-occurrence of PTSD and pain. PMID- 27490715 TI - Chemoradiation for Locally Advanced Unresectable Pancreatic Cancer-What Now? PMID- 27490716 TI - Non-insulated smooth motion, micro-needles RF fractional treatment for wrinkle reduction and lifting of the lower face: International study. AB - INTRODUCTION: Skin aging occurs through both intrinsic and extrinsic processes. Fractional radiofrequency (RF) with a microneedling array is the newest form of fractional therapy to be useful in treating aging skin. The current study utilized a noninsulated fractional RF microneedling system. METHODS: This multicenter clinical trial saw 49 patients complete 3 monthly treatments with the new fractional RF microneedling treatments and be followed for 3 months following their last treatment. Pain during treatment was recorded as well as overall improvement using a GAIS scale. Adverse events were also noted. RESULTS: Forty nine patients completed all of the treatments and follow-ups. Mild to moderate erythema were reported immediately after treatment which lasted up to 12 hours after the treatment. Pain, as measured on a 1-10 VAS, was noted to 4, on average. The average Fitzpatrick's wrinkle scale score at baseline was 5.04 +/- 1.22, 1 month after 3 treatments 3.829 +/- 1.69 and 3 months after 3 treatments 3.5 +/- 1.66. These results are statistically highly significant (correlated T-test, P < 0.001). Improvement was shown in 100% of patients while 65% of patients had significant improvement (GAIS levels 3-5). Significant skin tightening and skin lifting were also observed. No unusual adverse events were noted throughout the course of the study. CONCLUSION: This multicenter study showed significant wrinkle reduction, skin tightening, and lifting of the mid and lower face with the noninsulated fractional RF microneedling system. Lasers Surg. Med. 48:727 733, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27490717 TI - Mechanisms of triple whammy acute kidney injury. AB - Pre-renal acute kidney injury (AKI) results from glomerular haemodynamic alterations leading to reduced glomerular filtration rate (GFR) with no parenchymal compromise. Renin-angiotensin system inhibitors, such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor antagonists (ARAs), non-steroidal anti-inflammatory drugs (NSAIDs) and diuretics, are highly prescribed drugs that are frequently administered together. Double and triple associations have been correlated with increased pre-renal AKI incidence, termed "double whammy" and "triple whammy", respectively. This article presents an integrative analysis of the complex interplay among the effects of NSAIDs, ACEIs/ARAs and diuretics, acting alone and together in double and triple therapies. In addition, we explore how these drug combinations alter the equilibrium of regulatory mechanisms controlling blood pressure (renal perfusion pressure) and GFR to increase the odds of inducing AKI through the concomitant reduction of blood pressure and distortion of renal autoregulation. Using this knowledge, we propose a more general model of pre-renal AKI based on a multi whammy model, whereby several factors are necessary to effectively reduce net filtration. The triple whammy was the only model associated with pre-renal AKI accompanied by a course of other risk factors, among numerous potential combinations of clinical circumstances causing hypoperfusion in which renal autoregulation is not operative or is deregulated. These factors would uncouple the normal BP-GFR relationship, where lower GFR values are obtained at every BP value. PMID- 27490718 TI - Macular Ganglion Cell Imaging Study: Covariate Effects on the Spectral Domain Optical Coherence Tomography for Glaucoma Diagnosis. AB - PURPOSE: To evaluate the effect of multiple covariates on the diagnostic performance of the Cirrus high-definition optical coherence tomography (HD-OCT) for glaucoma detection. METHODS: A prospective case-control study was performed and included 173 recently diagnosed glaucoma patients and 63 unaffected individuals from the Macular Ganglion Cell Imaging Study. Regression analysis of receiver operating characteristic were conducted to evaluate the influence of age, spherical equivalent, axial length, optic disc size, and visual field index on the macular ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (RNFL) measurements. RESULTS: Disease severity, as measured by visual field index, had a significant effect on the diagnostic performance of all Cirrus HD-OCT parameters. Age, axial length and optic disc size were significantly associated with diagnostic accuracy of average peripapillary RNFL thickness, whereas axial length had a significant effect on the diagnostic accuracy of average GCIPL thickness. CONCLUSIONS: Diagnostic performance of the Cirrus HD-OCT may be more accurate in the advanced stages of glaucoma than at earlier stages. A smaller optic disc size was significantly associated with improved the diagnostic ability of average RNFL thickness measurements; however, GCIPL thickness may be less affected by age and optic disc size. PMID- 27490720 TI - Associations of various perceived-stress situations with depressive symptoms in >=50-year old Taiwanese men and women: Results from the Taiwan Longitudinal Study on Aging. AB - This study was aimed to evaluate the cross-sectional and longitudinal associations between various perceived-stress and depressive symptoms in old Taiwanese men and women aged 50 years and over. Data were derived from the Taiwan Longitudinal Study on Aging. Stress for health, finance, and family members' related issues were all cross-sectionally associated with concurrent depressive symptoms for men and women (all P<0.05). Increased/constant-high health stress was positively associated with subsequent depressive symptoms in both genders (all P<0.05). Constantly high job stress and increased stress over family members' problems were associated with higher likelihood of subsequent depressive symptoms in men (P<0.05). Constantly high/increased financial stress and relationship strain with family members were positively associated with subsequent depressive symptoms in women (all P<0.05). The results suggest that stress for health, job, finance, and family members-related issues are unequally associated with depressive symptoms among Taiwanese men and women aged 50 years and over. Changes of health stress even reduced are significantly associated with subsequent depressive symptoms. Long-term job stress and increased stress over family members' problems increase occurrences of men's depressive symptoms, while increased/long-term financial stress and relationship-strain with family members increase occurrences of women's depressive symptoms. Long-term high health stress has more impacts on men's depressive symptoms than women's, while long-term high relationship strain with family members has more impacts on women's depressive symptoms than men's. PMID- 27490722 TI - Tailoring Graphene Nanosheets for Highly Improved Dispersion Stability and Quantitative Assessment in Nonaqueous Solvent. AB - Aggregation is a critical limitation for the practical application of graphene based materials. Herein, we report that graphene oxide (GO) nanosheets chemically modified with ethanolamine (EA), ethylene glycol (EG), and sulfanilic acid (SA) demonstrate superior dispersion stability in organic solvents, specifically EG, based on the differences in their covalent chemistries. Functionalized GO was successfully dispersed in EG at a concentration of 9.0 mg mL(-1) (0.50 vol %), the highest dispersion concentration reported to date. Moreover, our study introduces a unique analytical method for the assessment of dispersion stability and successfully quantifies the instability index based on transmission profiles under centrifugation cycles. Interestingly, GO-EG and GO-EA exhibited highly improved dispersion stabilities approximately 96 and 48 times greater than that of GO in EG solvent, respectively. This finding highlights the critical role of surface functional groups in the enhancement of chemical affinity and miscibility in the surrounding media. We anticipate that the novel structural designs and unique tools presented in this study will further the understanding and application of chemically functionalized carbon materials. PMID- 27490721 TI - Antiviral activity of Thiosemicarbazones derived from alpha-amino acids against Dengue virus. AB - The endemicity and seasonal outbreaks of Dengue disease in most tropical and subtropical countries underscores an urgent need to develop effective prevention and control measures. Development of a Dengue vaccine, which is complicated by the Antibody Dependent Enhancement effect (ADE), a viral inhibitor, seems prudent as it would inhibit the spread of the virus. In vitro methods such as MTT assay and plaque formation unit reduction assays were employed for screening the viral inhibitory property of alpha-amino acid based Thiosemicarbazides. The results elicits that at concentrations not exceeding the maximum non cytotoxic concentration (MNCC), these compounds completely prevented Dengue virus infection in vero cells as indicated by the absence of cytopathic effects in a dose dependent manner. The high potency of Bz-Trp-TSC against all four types of Dengue virus infection elevates Thiosemicarbazide as a lead antiviral agent for Dengue disease. Screening small molecules for antiviral activity against the most rapidly spreading mosquito-borne viral disease is being explored by several research groups. Our findings would help to augment the efforts to identify the lead compounds for antiviral therapy to combat the Dengue disease. J. Med. Virol. 89:546-552, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27490723 TI - Subacute Myopericarditis Without Myocardial Infarction Treated With Intravenous Immunoglobulin in a Child With Marked Elevation of Plasma Cardiac Troponin I. PMID- 27490719 TI - Literature-Informed Analysis of a Genome-Wide Association Study of Gestational Age in Norwegian Women and Children Suggests Involvement of Inflammatory Pathways. AB - BACKGROUND: Five-to-eighteen percent of pregnancies worldwide end in preterm birth, which is the major cause of neonatal death and morbidity. Approximately 30% of the variation in gestational age at birth can be attributed to genetic factors. Genome-wide association studies (GWAS) have not shown robust evidence of association with genomic loci yet. METHODS: We separately investigated 1921 Norwegian mothers and 1199 children from pregnancies with spontaneous onset of delivery. Individuals were further divided based on the onset of delivery: initiated by labor or prelabor rupture of membranes. Genetic association with ultrasound-dated gestational age was evaluated using three genetic models and adaptive permutations. The top-ranked loci were tested for enrichment in 12 candidate gene-sets generated by text-mining PubMed abstracts containing pregnancy-related keywords. RESULTS: The six GWAS did not reveal significant associations, with the most extreme empirical p = 5.1 * 10-7. The top loci from maternal GWAS with deliveries initiated by labor showed significant enrichment in 10 PubMed gene-sets, e.g., p = 0.001 and 0.005 for keywords "uterus" and "preterm" respectively. Enrichment signals were mainly caused by infection/inflammation-related genes TLR4, NFKB1, ABCA1, MMP9. Literature informed analysis of top loci revealed further immunity genes: IL1A, IL1B, CAMP, TREM1, TFRC, NFKBIA, MEFV, IRF8, WNT5A. CONCLUSION: Our analyses support the role of inflammatory pathways in determining pregnancy duration and provide a list of 32 candidate genes for a follow-up work. We observed that the top regions from GWAS in mothers with labor-initiated deliveries significantly more often overlap with pregnancy-related genes than would be expected by chance, suggesting that increased sample size would benefit similar studies. PMID- 27490725 TI - Impact of Chest Radiography on Antibiotic Treatment for Children With Suspected Pneumonia. AB - OBJECTIVE: National guidelines discourage routine chest radiographs (CXRs) to confirm suspected pneumonia in children managed as outpatients. However, limiting CXRs may lead to antibiotic overuse. We examined the impact of CXRs and clinical suspicion on antibiotic treatment for children with suspected pneumonia. METHODS: Children aged 3 months to 18 years undergoing CXR for suspected pneumonia in a pediatric emergency department were prospectively enrolled. Before CXR, physicians indicated their initial plan for antibiotics (yes or no) and clinical suspicion for radiographic pneumonia (<5%, 5-10%, 11-20%, 21-50%, 51-75%, >75%). Subjects had radiographic pneumonia if their CXRs demonstrated definite or possible findings of pneumonia. We compared antibiotic treatment according to pre CXR antibiotic plan and suspicion for pneumonia and CXR results. RESULTS: Among the 107 children with a plan for antibiotics before CXR, 72% ultimately received antibiotics compared with 19% of the 1503 children without a pre-CXR plan for antibiotics (P < 0.001). Among those patients with a pre-CXR plan for antibiotics, 96% of children with radiographic pneumonia were ultimately treated compared with 54% without radiographic pneumonia (P < 0.001). If antibiotics were not initially planned, 37% with radiographic pneumonia were treated compared with 8% without radiographic pneumonia (P < 0.001). The use of CXR was more likely to influence antibiotic prescribing patterns when the clinical suspicion of pneumonia was low (<20%). CONCLUSIONS: Among children with high suspicion for pneumonia, CXRs infrequently altered the initial plan for antibiotics. However, when clinical suspicion for pneumonia was low, the use of CXR may reduce unnecessary antibiotic use. PMID- 27490724 TI - Evaluation of Anaphylaxis Management in a Pediatric Emergency Department. AB - OBJECTIVE: In 2006, the National Institute of Allergy and Infectious Disease established evidence-based treatment guidelines for anaphylaxis. The purpose of our study was to evaluate provider adherence to guidelines-based management for anaphylaxis in a tertiary care pediatric emergency department (ED). METHODS: Retrospective chart review was conducted of patients (0-18 years) presenting to the Arkansas Children Hospital ED from 2004 to 2011 for the treatment of anaphylaxis using International Classification of Diseases, Ninth Edition, codes. Multiple characteristics including demographics, clinical features, allergen source, and anaphylaxis management were collected. Fisher exact or chi tests were used to compare proportion of patients treated with intramuscular (IM) epinephrine in the preguideline versus postguideline period. Relative risk (RR) statistics were computed to estimate the ratio of patients who received self injectable epinephrine prescription and allergy follow-up in the preguideline and postguideline groups. RESULTS: A total of 187 patients (median [range] age, 7 [1 18] years; 67% male; 48% African American) were evaluated. Food (44%) and hymenoptera stings (22%) were commonly described culprit allergens, whereas 29% had no identifiable allergen. Only 47% (n = 87) received epinephrine in the ED and 31% (n = 27) via the preferred IM route. Comparing postguideline (n = 126) versus preguideline (n = 61) periods demonstrated increase in the usage of the IM route (46% postguideline vs 6% preguideline; risk ratio (RR), 7.64; 95% confidence interval [CI], 2.04-46.0; P < 0.001). Overall, 61% (n = 115) of the patients received self-injectable epinephrine upon discharge, and there were no significant differences between the groups (64% postguideline vs 56% preguideline, P = 0.30). Postguideline patients were more likely to receive a prescription compared with preguideline patients (64% postguideline vs 56% preguideline; RR, 1.15; 95% CI, 0.89-1.55; P = 0.30). Only 45% (n = 85) received an allergy referral. Postguideline patients were more likely to receive an allergy referral than preguideline patients (48% postguideline vs 41% preguideline; RR, 1.16; 95% CI, 0.81-1.73; P = 0.40). CONCLUSIONS: Provider use of IM epinephrine has improved since anaphylaxis guidelines were published. However, more provider education is needed to improve overall adherence of guidelines in a tertiary care pediatric ED. PMID- 27490726 TI - A Misdirected Patient Transfer Raises Emergency Medical Treatment and Labor Act Liability Issues. AB - Children often require transfer to pediatric hospital emergency departments (EDs) after evaluation in community hospital EDs. Such transfers are regulated by the federal Emergency Medical Treatment and Labor Act. Unusual circumstances, such as logistical errors in the physical transfer of the patient, may increase Emergency Medical Treatment and Labor Act-related liability risks for hospitals and ED physicians. PMID- 27490727 TI - Deep Vein Thrombus Occurring Immediately After Blunt Abdominal Trauma. AB - CASE: A 13-year-old adolescent girl with blunt abdominal injury was transferred to our hospital. Enhanced computed tomography (CT) showed not only retroperitoneal hematoma around the inferior vena cava and left common iliac vein but also thrombus extending from the left common iliac vein to the femoral vein. OUTCOME: Enhanced CT performed on the second day revealed no increase in retroperitoneal hematoma and a new small thrombus in the popliteal vein. Anticoagulant therapy was therefore started with administration of unfractionated heparin. Administration of warfarin was started on the 12th day and heparin administration was stopped on the 14th day. The patient was discharged on the 19th day with continuation of warfarin administration. Enhanced CT performed 10 months after injury showed no thrombus, and the administration of warfarin was then stopped. CONCLUSIONS: She was successfully treated with the appropriate start time and control of anticoagulation therapy based on careful evaluation of her general condition. PMID- 27490728 TI - Accidental Burn by Intentional Laxative Use. AB - OBJECTIVE: The purpose of this study was to present a case report and review the relevant literature on laxative-induced dermatitis being mistaken for scald injury and child abuse. CASE: A 33-month-old girl presented with partial thickness burn to the buttocks and perineum, which were suspected to be caused by child abuse. On further investigation, the parents had been administering large doses of laxatives to the child for chronic constipation. DISCUSSION: Child abuse by burning has characteristic physical examination findings, which differ from the pattern of laxative-induced dermatitis that has been reported in the literature. Diapers appear to be a risk factor for laxative-induced dermatitis. Surprisingly, the dose of laxative does not correlate with the severity of the burn injury. All physicians must be aware of the possibility of laxative-induced dermatitis mimicking scald burn injury to the buttocks. Parents should be educated about the risk of administering over-the-counter laxatives to children. PMID- 27490729 TI - Point-of-Care Ultrasound to Assess Anuria in Children. AB - Anuria in children may arise from a host of causes and is a frequent concern in the emergency department. This review focuses on differentiating common causes of obstructive and nonobstructive anuria and the role of point-of-care ultrasound in this evaluation. We discuss some indications and basic techniques for bedside ultrasound imaging of the urinary system. PMID- 27490730 TI - Point-of-Care Ultrasound to Assess Anuria in Children. PMID- 27490731 TI - Essentials of Pediatric Emergency Medicine Fellowship: Part 4: Beyond Clinical Education. AB - This article is the third in a 7-part series that aims to comprehensively describe the current state and future directions of pediatric emergency medicine fellowship training from the essential requirements to considerations for successfully administering and managing a program to the careers that may be anticipated upon program completion. This article focuses on the skills beyond clinical training required of pediatric emergency medicine physicians including teaching, leadership, teamwork, and communication. PMID- 27490732 TI - Emergency Department Point-of-Care Hip Ultrasound and Its Role in the Diagnosis of Septic Hip Arthritis: A Case Report. AB - We present a case of an 11-year-old girl with eye swelling and hip pain and the use of point-of-care hip ultrasound (US) to facilitate diagnosis of a septic hip. We review the US technique, sonographic findings, and relevant literature regarding point-of-care hip US. PMID- 27490733 TI - Diagnosis of Cystic Teratoma Facilitated by Point-of-Care Ultrasonography. AB - Abdominal pain and constipation are common chief complaints in the pediatric emergency department. We present a case of a child with pain, abdominal distention, and constipation ultimately diagnosed with an ovarian teratoma and the role of point-of-care ultrasonography in the evaluation. PMID- 27490734 TI - Pediatric Emergency Medicine: Legal Briefs. PMID- 27490735 TI - PEMNetwork: Barriers and Enablers to Collaboration and Multimedia Education in the Digital Age. AB - In January 2005, PEMFellows.com was created to unify fellows in pediatric emergency medicine. Since then, the website has expanded, contracted, and focused to adapt to the interests of the pediatric emergency medicine practitioner during the internet boom. This review details the innovation of the PEMNetwork, from the inception of the initial website and its evolution into a needs-based, user directed educational hub. Barriers and enablers to success are detailed with unique examples from descriptive analysis and metrics of PEMNetwork web traffic as well as examples from other online medical communities and digital education websites. PMID- 27490736 TI - Pediatric Emergency Department Return: A Literature Review of Risk Factors and Interventions. AB - BACKGROUND AND OBJECTIVE: Children discharged from emergency departments (EDs) are often at risk for ED return. The objective was to identify risk factors and interventions to mitigate or prevent ED return among this patient population. METHODS: Structured literature review of PubMed and clinicaltrials.gov was conducted to identify relevant studies. Inclusion criteria were studies evaluating ED returns by identifying risk factors and interventions in the pediatric population. Emergency department return was defined as returning to the ED within 1 year after initial visit. Abstract and full text articles were reviewed, and data were abstracted by 2 independent authors. RESULTS: A total of 963 articles were screened and yielded 42 potential relevant articles involving pediatric population. After full text review, a total of 12 articles were included in the final analysis (6 on risk factors and 6 on interventions). Risk factors for pediatric ED return included behavioral/psychiatric problems, younger age, acuity of illness, medical history of asthma, and social factors. Interventions included computer-generated instructions, postdischarge telephone coaching, ED-made appointments, case management, and home environment intervention. Emergency department-made appointments and postdischarge telephone coaching plus monetary incentive improved outpatient follow-up rate but not ED return. Home environment assessment coupled with case management reduced ED returns specifically among asthma patients. CONCLUSIONS: Several patient and visit characteristics can help predict children at risk for ED return. Although some interventions are successful at improving postdischarge follow-up, most did not reduce ED returns. PMID- 27490737 TI - ECGs in the ED. PMID- 27490738 TI - Precipitant induced porosity augmentation of polystyrene preserves the chondrogenicity of human chondrocytes. AB - Cells constantly sense and receive chemical and physical signals from neighboring cells, interstitial fluid, and extracellular matrix, which they integrate and translate into intracellular responses. Thus, the nature of the surface on which cells are cultured in vitro plays an important role for cell adhesion, proliferation, and differentiation. Autologs chondrocyte implantation is considered the treatment of choice for larger cartilage defects in the knee. To obtain a sufficient number of chondrocytes for implantation multiple passaging is often needed, which raises concerns about the changes in the chondrogenic phenotype. In the present study, we analyzed the effect at cellular and molecular level of precipitant induced porosity augmentation (PIPA) of polystyrene surfaces on proliferation and differentiation of human chondrocytes. Human chondrocytes were isolated from healthy patients undergoing anterior cruciate ligament reconstruction and cultured on PIPA modified polystyrene surfaces. Microscopical analysis revealed topographically arranged porosity with micron pores and nanometer pits. Chondrocytes cultured on PIPA surfaces revealed no difference in cell viability and proliferation, but gene- and protein expressions of collagen type II were pronounced in the first passage of chondrocytes when compared to chondrocytes cultured on control surfaces. Additionally, an analysis of 40 kinases revealed that chondrocytes expanded on PIPA caused upregulated PI3K/mTOR pathway activation and inhibition of mTORC1 resulted in reduced sGAG synthesis. These findings indicate that PIPA modified polystyrene preserved the chondrogenicity of expanded human chondrocytes at gene and protein levels, which clinically may be attractive for the next generation of cell-culture surfaces for ex vivo cell growth. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3073-3081, 2016. PMID- 27490739 TI - Does quality of developmental care in NICUs affect health-related quality of life in 5-y-old children born preterm? AB - BACKGROUND: Preterm birth and Neonatal Intensive Care Unit (NICU) stay are early adverse experiences, which may affect health-related quality of life (HRQoL) even in the absence of prematurity-related morbidities. The aim of this multicenter longitudinal study was to examine the relation between quality levels of NICU Developmental Care (DC) and HRQoL at 60 mo in children who were born preterm. METHODS: HRQoL of 102 very preterm (VPT) children from 20 NICUs and 110 full-term controls was assessed using TNO-AZL Preschool Children's Quality of Life Questionnaire (TAPQOL). In VPT children, we compared HRQoL by splitting NICUs into units with high- and low-quality of DC according to the following two factors: (i) the infant centered care (ICC), and (ii) the infant pain management (IPM). RESULTS: Compared to VPT children from NICUs with high-quality of ICC, VPT children from NICUs with low-quality in ICC scored lower in HRQoL component which resulted from the aggregation of lively, positive emotionality, social and motor functioning. No differences were found between VPT children from high-quality ICC NICUs and full-term children and for the IPM index. CONCLUSION: Findings suggest that higher quality of DC in NICU related to ICC might mitigate long-term negative quality of life outcomes. PMID- 27490743 TI - Medicolegal-Malpractice and Ethical Issues in Radiology. PMID- 27490742 TI - A validated protocol to quantify severity of male urogenital feminization using the MOUSE (Mouse objective urethral severity evaluation). AB - BACKGROUND: Congenital abnormalities vary in presentation, yet studies using model organisms tend to focus on occurrence rather than severity of the defect. Scoring severity of abnormalities in model systems allows explicit hypothesis testing during basic, translational, and reverse translational studies. We developed and validated a protocol to quantify severity of male urogenital feminization (hypospadias) in the mouse model. Hypospadias is one of the most common birth defects in the world. METHODS: To induce genital feminization, pregnant mice were exposed to different concentrations of the antiandrogen vinclozolin. Genitalia were photographed at gestational age 18.5. A dichotomous scoring system to evaluate genital feminization was developed, and validated against histological measurements of urethral length. A training protocol was developed for novice scorers, and criteria were defined to evaluate precision and accuracy of scores. RESULTS: Vinclozolin induced variation in hypospadias severity. Severity scores were tightly correlated with histologically determined urethral length and both techniques showed similar dose-response relationships. Novice observers were trained to precisely and accurately score hypospadias severity. CONCLUSION: This standardized scoring system advances the mouse as a model to study urogenital development, and will facilitate research on the mechanisms driving genital feminization in males, and aid translational hypospadias research. PMID- 27490744 TI - Open and Arthroscopic Anterior Shoulder Stabilization. PMID- 27490741 TI - Gestational diabetes is associated with changes in placental microbiota and microbiome. AB - BACKGROUND: The human microbiota is a modulator of the immune system. Variations in the placental microbiota could be related with pregnancy disorders. We profiled the placental microbiota and microbiome in women with gestational diabetes (GDM) and studied its relation to maternal metabolism and placental expression of anti-inflammatory cytokines. METHODS: Placental microbiota and microbiome and expression of anti-inflammatory cytokines (IL10, TIMP3, ITGAX, and MRC1MR) were analyzed in placentas from women with GDM and from control women. Fasting insulin, glucose, O'Sullivan glucose, lipids, and blood cell counts were assessed at second and third trimester of pregnancy. RESULTS: Bacteria belonging to the Pseudomonadales order and Acinetobacter genus showed lower relative abundance in women with GDM compared to control (P < 0.05). In GDM, lower abundance of placental Acinetobacter associated with a more adverse metabolic (higher O'Sullivan glucose) and inflammatory phenotype (lower blood eosinophil count and lower placental expression of IL10 and TIMP3) (P < 0.05 to P = 0.001). Calcium signaling pathway was increased in GDM placental microbiome. CONCLUSION: A distinct microbiota profile and microbiome is present in GDM. Acinetobacter has been recently shown to induce IL-10 in mice. GDM could constitute a state of placental microbiota-driven altered immunologic tolerance, making placental microbiota a new target for therapy in GDM. PMID- 27490740 TI - Inotropes do not increase cardiac output or cerebral blood flow in preterm piglets. AB - BACKGROUND: The preterm newborn is at high risk of developing cardiovascular compromise during the first day of life and this is associated with increased risk of brain injury. Standard treatments are volume expansion and administration of inotropes, typically dopamine and/or dobutamine, but there is limited evidence that inotropes improve clinical outcomes. This study investigated the efficacy of dopamine and dobutamine for the treatment of cardiovascular compromise in the preterm newborn using a piglet model. METHODS: Preterm and term piglets were assigned to either dopamine, dobutamine or control infusions. Heart rate, left ventricular contractility, cardiac output, blood pressure, and cerebral and regional blood flows were measured during baseline, low (10 ug/kg/h), and high (20 ug/kg/h) dose infusions. RESULTS: At baseline, preterm piglets had lower cardiac contractility, cardiac output, blood pressure, and cerebral blood flow compared to term piglets. The response of preterm piglets to either dopamine or dobutamine administration was less than in term piglets. In both preterm and term piglets, cardiac output and cerebral blood flow were unaltered by either inotrope. CONCLUSION: In order to provide better cardiovascular support, it may be necessary to develop treatments that target receptors with a more mature profile than adrenoceptors in the preterm newborn. PMID- 27490745 TI - Risks and Benefits of Simultaneous Bilateral Total Knee Arthroplasty: A Critical Analysis Review. PMID- 27490746 TI - Open Tibial Fractures: Updated Guidelines for Management. PMID- 27490747 TI - Imaging Criteria for the Quantification of Disc Degeneration: A Systematic Review. PMID- 27490748 TI - Balancing C=C Functionalization and C=O Reduction in Cu-H Catalysis. AB - Coppercabana: The copper(I) hydride catalyzed functionalization of unactivated alkenes has been shown to be compatible with conventional carbonyl reduction. Through the combination of both pathways or complete suppression of C=O reduction in favor of C=C functionalization, methods for the stereoselective synthesis of a variety of chiral molecules have been developed. PMID- 27490749 TI - Fast Diagnostics of BRAF Mutations in Biopsies from Malignant Melanoma. AB - According to the American skin cancer foundation, there are more new cases of skin cancer than the combined incidence of cancers of the breast, prostate, lung, and colon each year, and malignant melanoma represents its deadliest form. About 50% of all cases are characterized by a particular mutation BRAF(V600E) in the BRAF (Rapid Acceleration of Fibrosarcoma gene B) gene. Recently developed highly specific drugs are able to fight BRAF(V600E) mutated tumors but require diagnostic tools for fast and reliable mutation detection to warrant treatment efficiency. We completed a preliminary clinical trial applying cantilever array sensors to demonstrate identification of a BRAF(V600E) single-point mutation using total RNA obtained from biopsies of metastatic melanoma of diverse sources (surgical material either frozen or fixated with formalin and embedded in paraffin). The method is faster than the standard Sanger or pyrosequencing methods and comparably sensitive as next-generation sequencing. Processing time from biopsy to diagnosis is below 1 day and does not require PCR amplification, sequencing, and labels. PMID- 27490750 TI - Thermodynamic Stability and Defect Chemistry of Bismuth-Based Lead-Free Double Perovskites. AB - Bismuth- or antimony-based lead-free double perovskites represented by Cs2 AgBiBr6 have recently been considered promising alternatives to the emerging lead based perovskites for solar cell applications. These new perovskites belong to the Fm3? m space group and consist of two types of octahedra alternating in a rock-salt face-centered cubic structure. We show, by density functional theory calculations, that the stable chemical potential region for pure Cs2 AgBiBr6 is narrow. Ag vacancies are a shallow accepters and can easily form, leading to intrinsic p-type conductivity. Bi vacancies and AgBi antisites are deep acceptors and should be the dominant defects under the Br-rich growth conditions. Our results suggest that the growth of Cs2 AgBiBr6 under Br-poor/Bi-rich conditions is preferred for suppressing the formation of the deep defects, which is beneficial for maximizing the photovoltaic performance. PMID- 27490751 TI - Focal segmental glomerulosclerosis in pediatric kidney transplantation: 30 years' experience. AB - : From 1982 to 2011, 53 kidney transplantations (KT) for pediatric focal segmental glomerulosclerosis (FSGS) were recorded in the National Israeli Kidney Transplant Registry (NIKTR): 22-primary (1?) FSGS, 25-proved/suspected genetic secondary (2?) FSGS, six lost/incomplete files/other. Half (56%) of 23 patients with 2? FSGS were Israeli-Arabs vs 29% of 1? FSGS KT recipients. 1? FSGS recurrence occurred in 64% (14/22) of 22 KT in 17 patients aged (median) 14 years vs 1/25 of 2? FSGS (P<.001). Early graft days/nonfunction occurred in 9/14 (64%), 2/8 (25%) and 2/25 (4%) of recurrent 1? FSGS (rFSGS), nonr1? FSGS and 2? FSGS, respectively. Twelve biopsies performed in nine of these grafts at (median) 8 days (range 5-60 days) post-KT showed: ATN-5, suspected rejection-4, rFSGS-2, normal kidney-1; rFSGS was diagnosed eventually in 8/9. Dialysis need during the first month post-KT was significantly associated with FSGS recurrence: 6/14 (43%) for rFSGS vs 2/8 (25%) for non-rFSGS. Plasmapheresis (PP) achieved complete and partial rFSGS remission in 5/9 and 2/9 grafts, respectively. Three grafts were excised during the first 60 days post-KT for: nonfunction (1) and bleeding (2). Remaining grafts' GFR was: 78, 42, and 91 mL/min (median) at 5.3, 4.75, and 8 years follow-up for non-rFSGS, rFSGS, and 2? FSGS grafts, respectively. CONCLUSIONS: Early PP implementation should be considered after KT for 1? FSGS patients with early graft dysfunction despite delayed proteinuria and nonspecific biopsy. PMID- 27490753 TI - The Use of Augment Devices in Revision Acetabular Surgery. PMID- 27490754 TI - Wrong-Level Spine Surgery. PMID- 27490752 TI - Bilateral tDCS on Primary Motor Cortex: Effects on Fast Arm Reaching Tasks. AB - BACKGROUND: The effects produced by transcranial direct current stimulation (tDCS) applied to the motor system have been widely studied in the past, chiefly focused on primary motor cortex (M1) excitability. However, the effects on functional tasks are less well documented. OBJECTIVE: This study aims to evaluate the effect of tDCS-M1 on goal-oriented actions (i.e., arm-reaching movements; ARM), in a reaction-time protocol. METHODS: 13 healthy subjects executed dominant ARM as fast as possible to one of two targets in front of them while surface EMG was recorded. Participants performed three different sessions. In each session they first executed ARM (Pre), then received tDCS, and finally executed Post, similar to Pre. Subjects received three different types of tDCS, one per session: In one session the anode was on right-M1 (AR), and the cathode on the left-M1 (CL), thus termed AR-CL; AL-CR reversed the montage; and Sham session was applied likewise. Real stimulation was 1mA-10min while subjects at rest. Three different variables and their coefficients of variation (CV) were analyzed: Premotor times (PMT), reaction-times (RT) and movement-times (MT). RESULTS: triceps-PMT were significantly increased at Post-Sham, suggesting fatigue. Results obtained with real tDCS were not different depending on the montage used, in both cases PMT were significantly reduced in all recorded muscles. RT and MT did not change for real or sham stimulation. RT-CV and PMT-CV were reduced after all stimulation protocols. CONCLUSION: tDCS reduces premotor time and fatigability during the execution of fast motor tasks. Possible underlying mechanisms are discussed. PMID- 27490755 TI - Congenital Clubfoot. PMID- 27490756 TI - Shared Decision Making in Total Joint Replacement. PMID- 27490758 TI - Quantification of Estrogen Receptor Expression in Normal Breast Tissue in Postmenopausal Women With Breast Cancer and Association With Tumor Subtypes. AB - Estrogen exposure is important in the pathogenesis of breast cancer and is a contributing risk factor. In this study we quantified estrogen receptor (ER) alpha expression in normal breast epithelium (NBR) in women with breast cancer and correlated it with breast cancer subtypes. Tissue microarrays were constructed from 204 breast cancer patients for whom normal breast tissue away from tumor was available. Slides stained with ER were scanned and expression in normal terminal duct lobular epithelium was quantitated using computer-assisted image analysis. ER expression in normal terminal duct lobular epithelium of postmenopausal women with breast cancer was significantly associated with estrogen and triple (estrogen, progesterone receptors, and HER2) negative phenotypes. Also increased age at diagnosis was significantly associated with ER expression in NBR. ER positivity in normal epithelium did not vary by tumor size, lymph node status, tumor grade, or stage. On the basis of quantitative image analysis, we confirm that ER expression in NBR increases with age in women with breast cancer, and report for the first time, a significant association between ER expression in NBR with ER-negative and triple-negative cancers in postmenopausal women. PMID- 27490757 TI - Manufacturing Man-Made Magnetosomes: High-Throughput In Situ Synthesis of Biomimetic Magnetite Loaded Nanovesicles. AB - A new synthetic method for the production of artificial magnetosomes, i.e., lipid coated vesicles containing magnetic nanoparticles, is demonstrated. Magnetosomes have considerable potential in biomedical and other nanotechnological applications but current production methods rely upon magnetotactic bacteria which limits the range of sizes and shapes that can be generated as well as the obtainable yield. Here, electrohydrodynamic atomization is utilized to form nanoscale liposomes of tunable size followed by electroporation to transport iron into the nanoliposome core resulting in magnetite crystallization. Using a combination of electron and fluorescence microscopy, dynamic light scattering, Raman spectroscopy, and magnetic susceptibility measurements, it is shown that single crystals of single-phase magnetite can be precipitated within each liposome, forming a near-monodisperse population of magnetic nanoparticles. For the specific conditions used in this study the mean particle size is 58 nm (+/-8 nm) but the system offers a high degree of flexibility in terms of both the size and composition of the final product. PMID- 27490759 TI - Parafibromin, APC, and MIB-1 Are Useful Markers for Distinguishing Parathyroid Carcinomas From Adenomas. AB - BACKGROUND: Differentiation of parathyroid carcinoma (PC) from parathyroid adenoma (PA) relies solely on the pathologic determination of invasion of surrounding structures and/or distant metastasis. Parathyroid lesions with atypical histologic features with no demonstration of invasion or metastasis present a diagnostic dilemma. Different authors report a parafibromin and adenomatous polyposis coli (APC) loss or reduction in PC cases. High proliferative activity of MIB-1 and increased galectin 3 expression are reported in PC. There is no clear cutoff for the sensitivity, specificity, or predictive value for all these markers. METHODS: The immunohistochemical expression of parafibromin, APC, MIB-1, and galectin 3 was studied in 73 adenomas, 21 PCs, and 3 atypical adenomas. The presence or absence of each marker was identified through the use of a comprehensive scoring system based on multiplying the percentage of tumor cells stained (0 to 100) and the staining intensity (0 to 3) on each biopsy. The highest score that any slide could reach was 300. A cutoff of >100 was used to consider the specimen positive for parafibromin, APC, or galectin 3 staining. MIB-1 proliferation indices were calculated using image cytometry; proliferation indices >5% were considered positive. RESULTS: We identified parafibromin loss in 7/21 (33%) carcinomas and 1/73 (1%) adenomas. Loss of APC was seen in 20/21 (95%) carcinomas and 38/73 (52%) adenomas. MIB-1 indices were elevated in 18/21 (86%) carcinomas. MIB-1 indices were <5% in all (100%) adenomas. MIB-1 indices were elevated in 2/3 (67%) atypical adenomas. CONCLUSIONS: Our study presents a clear cutoff to determine the practicality of using parafibromin, APC, and MIB-1 as immunohistochemical markers to differentiate between PCs and PAs. Loss of parafibromin and a high MIB-1 index are both independently sensitive and specific markers for the diagnosis of PC. Loss of APC was only specific for PC. This panel of markers provides a novel, useful approach in the diagnosis and differentiation of PCs from PAs. PMID- 27490760 TI - Prognostic Significance of High Ki-67 Index and Histogenetic Subclassification in Primary Central Nervous System Lymphoma. AB - In diffuse large B-cell lymphoma (DLBCL), the germinal center B-cell (GCB) subtype is associated with a better prognosis compared with the nongerminal center B-cell-like (non-GCB) subtype. However, validity of this immunohistochemical subgrouping in primary DLBCL of the central nervous system is unclear. A total 45 cases of primary central nervous system lymphoma (PCNS)/DLBCL were selected, and immunohistochemistries for CD10, Bcl-6, MUM1, and Ki-67 were performed. Each of the cases was subclassified as either GCB or non-GCB based on its immunoprofile. Among clinical and immunologic markers, patients under 70 years of age and who had methotrexate chemotherapy showed a significantly better overall survival (OS). High Ki-67 (ie, a Ki-67 index >=90%) was an independent prognostic factor for a poor OS in the whole cohort and in the patients with non GCB subtype tumors (P=0.017, HR=4.267, 95% CI, 1.3-14.0; P=0.031, HR=3.752, 95% CI, 1.3-12.5). Tumors were dominantly non-GCB subtype (41/45, 91.1%); only 4 (8.9%) were GCB subtype. The 2-year OS rates for these groups were 73% and 100%. There was, however, no statistically significant difference between these groups for OS and progression-free survival. The subclassification of PCNS/DLBCL into GCB and non-GCB subtypes did not seem to have a prognostic value. In non-GCB subtype PCNSL patients, high Ki-67 index was an adverse independent prognostic marker that could be used to stratify patients for more suitable management. PMID- 27490761 TI - Factors Associated With Detection of Helicobacter pylori in Gastric Biopsies: A Case-Control Study of 396 Biopsies. AB - AIM OF THE STUDY: Helicobacter pylori (HP) infection is associated with significant gastric mucosal inflammation. We aimed to determine the clinicopathologic features associated with HP in gastric biopsy. METHODS AND RESULTS: Three hundred ninety-six gastric biopsies were evaluated including 165 HP-positive cases and 231 randomly selected HP-negative controls. HP was detected using hematoxylin and eosin (H&E), Giemsa, and immunohistochemistry staining. The univariate and multivariate analyses were conducted to study the relationship of clinicopathologic characteristics and HP infection. Among the HP-positive cases, 131 cases were confirmed by H&E staining and 34 cases were confirmed by Giemsa or immunohistochemistry staining. Compared with chronic inactive gastritis, chronic active gastritis was more likely associated with having HP detected by H&E. Males were more likely to have HP gastritis than females (odds ratio: 1.72, P=0.01). The patients who had chronic active gastritis or chronic gastritis (moderate or severe) were more likely to have HP infection than patients with mild chronic gastritis (P<0.001). Conversely, patients who had intestinal metaplasia were less likely to have HP infection than patients without intestinal metaplasia (odds ratio: 0.22, P<0.001). However, concurrent atrophic gastritis was not related to HP infection (P=0.37). HP infection history was not associated with HP infection (P=0.74). CONCLUSIONS: HP detection in gastric biopsies is associated with active inflammation, male sex, and the lack of intestinal metaplasia, but not atrophic gastritis or HP infection history. Routine ancillary staining may not be required for HP detection in all biopsy specimens. We do not recommend ancillary staining for mild chronic inactive gastritis. PMID- 27490762 TI - HER2 Status in Gastric and Gastroesophageal Junction Cancer: Results of the Large, Multinational HER-EAGLE Study. AB - Human epidermal growth factor receptor 2 (HER2) dysregulation is associated with tumorigenesis in gastric/gastroesophageal junction cancer; however, the number of patients with HER2-positive disease is unclear, possibly due to differing scoring criteria/assays. Data are also lacking for early disease. We aimed to assess the HER2-positivity rate using approved testing criteria in a large, real-life multinational population. HER2-positivity was defined as an immunohistochemistry staining score of 3+, or immunohistochemistry 2+ and HER2 amplification detected by in situ hybridization. A total of 4949 patients were enrolled and results showed that 14.2% of 4920 samples with immunohistochemistry results were HER2 positive. HER2-positivity was significantly higher in males (16.1% vs. 9.6% in females), in gastroesophageal versus stomach tumors (22.1% vs. 12.9%), in biopsy versus surgical samples (18.3% vs. 13.0%), in intestinal tumor subtypes versus diffuse (21.5% vs. 4.8%) and mixed types (21.5% vs. 8.5%) (P<0.001), in mixed versus diffuse types (8.5% vs. 4.8%), and in "other" versus diffuse types (11.7% vs. 4.8%; P=0.002). There were no significant differences between stages. Patients in the youngest age percentile had significantly lower HER2-positivity rates than patients in the remaining percentiles (9.2% vs. 15.9%, 15.7%, and 15.1%; P<0.001). HER2-positivity was highest in France (20.2%) and lowest in Hong Kong (10.4%). In conclusion, HER-EAGLE, the first study of its kind to be conducted in a large, multinational population of almost 5000 patients, gives valuable insights into the real-world HER2-positivity rate in a gastric/gastroesophageal junction cancer patient population not selected for disease stage or histology. PMID- 27490763 TI - CD44 Immunoexpression is Unfavorable Predictor in Ovarian Serous Cancer. AB - The aim of this study was to clarify the clinical role of CD44 expression in ovarian serous cancer, and its relation to clinicopathologic prognostic factors, disease free survival and overall survival (OS). Immunohistochemical staining for CD44 was performed on 81 formalin-fixed, paraffin-embedded tumor sections. CD44 expression was found in 43% of ovarian carcinoma samples. Correlations between categorical variables were studied using the chi and the Mann-Whitney U test. For survival analysis, the Kaplan-Meier method, the log-rank test and the Cox proportional hazard regression model were used. We did not find any statistically significant difference in the distribution of respondents according to clinical stage of the disease, tumor grade or the presence of vascular invasion in relation to the expression of CD44. According to the results of uninominal analysis, early International Federation of Gynecology and Obstetrics (FIGO) stage of the disease (P=0.003) was associated with longer disease free survival, while the expression of CD44 (P<0.001), FIGO stage III and IV (P=0.009) and the finding of vascular invasion (P=0.005) was related to a shorter OS. In conclusion, we proved that positive CD44 immunoexpression is a independent prognostic indicator of shorter OS of patients with ovarian serous cancer. PMID- 27490764 TI - The p16-Ki-67-HMB45 Immunohistochemistry Scoring System is Highly Concordant With the Fluorescent In Situ Hybridization Test to Differentiate Between Melanocytic Nevi and Melanomas. AB - The treatment of melanoma requires early diagnosis and extensive surgical removal of the primary tumor. The differential diagnosis between a melanoma and a nevus is sometimes difficult from a histopathologic point of view and could require ancillary diagnostic tools. Recently, both fluorescent in situ hybridization (FISH) and p16-Ki67-HMB45 combined immunohistochemistry have been proposed as examples of ancillary diagnostic methods to help classify melanocytic tumors as benign or malignant. In this study, we compare FISH and p16-Ki-67-HMB45 immunohistochemistry in a set of melanomas and nevi. A total of 101 formalin fixed and paraffin-embedded tumor samples (44 melanomas and 57 nevi) were analyzed using FISH for chromosomes 6, 8, 9, and 11 and p16-Ki-67-HMB45 immunohistochemistry. Any chromosomal imbalances and/or a p16-Ki-67-HMB45 immunohistochemistry combined score of 4 or higher were considered to reflect a "favor" malignant tumor. Using FISH, 42 out of 44 melanomas presented at least 1 chromosomal imbalance, whereas 2 melanomas and all nevi did not. Each melanoma, including 6 challenging tumors, had a p16-Ki-67-HMB45 immunohistochemistry combined score of 4 or higher and every nevus had a score inferior to 4. This reflects an excellent strength of agreement between FISH, immunohistochemistry, and definitive histopathologic diagnosis in our tumor set. We conclude that both FISH and p16-Ki67-HMB45 combined immunohistochemistry are valuable ancillary diagnostic tools to help pathologists classify melanocytic tumors as nevi or melanomas. PMID- 27490765 TI - Another Point of View About Cyclin D1 and p16 Expression in Blue Nevi and Malignant Melanomas. PMID- 27490766 TI - The Stem Cell-associated Transcription Factor SOX2 as a Diagnostic Marker of High grade Squamous Intraepithelial Lesion of the Uterine Cervix in Comparison With p16 and Ki-67. AB - The transcription factor SOX2 has been identified as an oncogene involved in the pathogenesis of squamous cell carcinoma (SCC) of multiple sites, including the uterine cervix. The relationship between SOX2 overexpression and the continuum of precancerous lesions of the cervix has not been previously elucidated. We evaluated SOX2 immunohistochemical expression in normal cervix, low-grade squamous intraepithelial lesion (LSIL) (mild squamous dysplasia), high-grade squamous intraepithelial lesion (HSIL) (moderate and severe dysplasia) and SCC of the cervix in comparison with p16 and Ki-67. Staining patterns were scored as negative, basal one third of the epithelium, lower two third, or full thickness. The results showed that SOX2 expression was limited to the basal one third in 84% of LSIL cases, whereas 95% of HSIL showed SOX2 expression up to two third or full thickness (P<0.0001). p16 and Ki-67 displayed similar results. The difference in SOX2 expression between moderate and severe dysplasia was not statistically significant (P=0.53). Invasive SCC positivity was as follows: SOX2 94%; p16 89%; and Ki-67 100%. Our findings support a role for SOX2 in the progression of squamous dysplasia to SCC. The Lower Anogenital Standardization Terminology Project's recent assertion of a lack of a biological correlate to cervical intraepithelial neoplasia II is also upheld by SOX2. For equivocal situations in which a diagnosis of cervical intraepithelial neoplasia II would have been made, Lower Anogenital Standardization Terminology recommends p16, or other biomarkers such as Ki-67 to clarify the diagnosis. SOX2, with a clean nuclear staining pattern, may also be suitable for this role. PMID- 27490767 TI - Geographical disparity in breast reconstruction following mastectomy has reduced over time. AB - BACKGROUND: Breast reconstruction (BR) following mastectomy for breast cancer has been shown to improve quality of life and body image; however, there is significant geographic variation in BR rates. We explored factors associated with BR following mastectomy. METHODS: This is a population-based data linkage study consisting of cancer registry records linked to hospital inpatient episodes for 4104 women aged 20 years and over-diagnosed with a first primary invasive localized stage breast cancer between 1997 and 2012 in Queensland, Australia, who underwent a mastectomy. Multivariate logistic regression was used to model predictors of BR. RESULTS: Overall, 481 women (11.7%) underwent reconstruction. Proportions increased over time and were higher for younger women. Younger age, more recent diagnosis, living in high or very high accessibility areas or less disadvantaged areas, smaller tumours and attending a private or high-volume hospital independently increased the odds of reconstruction. The geographical disparity reduced significantly over time. CONCLUSION: Geographical barriers to accessing BR have reduced; however, continued monitoring and further research to inform strategies to further reduce subgroup disparities remain a priority. PMID- 27490768 TI - New Thieme Research Awards: Call for Pacesetting Contributions to Drug Research. PMID- 27490769 TI - The Effect of Early Excessive Weight Gain on the Development of Hypertension in Pregnancy. AB - Background Previous studies have shown an association between total excessive gestational weight gain and hypertension in pregnancy. However, this may be a reflection of excessive water retention associated with the pathophysiology of hypertensive disorders of pregnancy. Early excessive weight gain, prior to the third trimester, results in greater maternal fat deposition and inflammation, which has also been associated with the development of hypertension. By focusing on early excessive weight gain, the association between maternal weight gain and the future development of hypertension can be examined. Objective To evaluate the association between early excessive maternal weight gain and the development of hypertension during pregnancy. Study Design This was a secondary analysis of a longitudinal cohort study of 1,441 women without chronic hypertension who were enrolled in a prospective study evaluating maternal angiogenic factors and the prediction of preeclampsia. Initial body mass index (BMI) was calculated by weight and height at the first study visit. Early excessive maternal weight gain was defined as weight gain by 28 weeks that exceeded the Institute of Medicine (IOM) guidelines and was calculated utilizing the maximum amount of weight gain per week recommended by the IOM based on the patient's starting BMI (normal: 0.45 kg; overweight: 0.32 kg; obese: 0.27 kg). Hypertension was defined as a sustained systolic blood pressure of >=140 mm Hg or a diastolic blood pressure of >=90 mm Hg. Logistic regression was used to determine the association between early excessive weight gain, initial BMI, and the development of hypertension, including gestational hypertension and preeclampsia, during pregnancy. Results Of 1,441 women, 767 (53.2%) had weight gain that exceeded the IOM guidelines in the first 28 weeks and 154 (10.8%) developed hypertension during pregnancy. Women whose weight gain exceeded the IOM guidelines were more likely to develop hypertension even after adjusting for relevant confounders (12.5 vs. 8.6%; p = 0.02; adjusted odds ratio [OR] = 1.70; 95% confidence interval [CI]: 1.18-2.44; p < 0.01). Obese women had a 2.4-fold increased risk of developing hypertension, even after controlling for excessive weight gain (adjusted OR = 2.44; 95% CI: 1.66-3.59; p < 0.01) Conclusions Early excessive maternal weight gain and initial BMI are independently associated with the diagnosis of a hypertensive disorder of pregnancy. Women should be counseled regarding the benefits of achieving a normal BMI prior to pregnancy and appropriate weight gain during pregnancy, as well as the potential harms of excessive weight gain related to perinatal outcomes. PMID- 27490770 TI - Endocrine Disruptors: A Potential Risk Factor for Gestational Diabetes Mellitus. AB - Gestational diabetes mellitus (GDM) has increased dramatically in the past 20 years together with the obesity epidemic. Mirroring the increase in incidence of GDM is increasing use of endocrine disrupting chemicals (EDCs). EDCs are structurally similar to endogenous hormones and interfere with synthesis, secretion, activity, or elimination of natural hormones, resulting in adverse health effects, including diabetes, obesity, developmental disorders, etc. Although the association between bisphenol A (BPA), a well-studied EDC, and type 2 diabetes has been repeatedly investigated in epidemiological and animal studies, there is a dearth of studies examining EDCs and GDM. In fact, the impact of environmental toxins on perinatal health outcomes has largely been overlooked.Recognizing this research gap, the American College of Obstetricians and Gynecologists, American Society for Reproductive Medicine, and International Federation of Gynecology and Obstetrics recently joined leading scientists and clinicians in a call for action to prioritize research in the consequences of exposure to toxic environmental agents on women's health. Evidence is emerging to suggest signaling molecules and EDCs are involved in the control of microRNA (miRNA) expression in trophoblast cells. We reviewed existing scientific evidence of EDCs as a risk factor for GDM as well as the potential role of miRNA in this association. PMID- 27490772 TI - Management of Supplemental Oxygen for Infants with Persistent Pulmonary Hypertension of Newborn: A Survey. AB - Objective To evaluate practice variations amongst neonatologists regarding oxygen management in neonates with persistent pulmonary hypertension of newborn (PPHN). Study Design An online survey was administered to neonatologists to assess goal oxygenation targets and oxygen titration practices in PPHN. Response variations were assessed and intergroup comparisons performed. Results Thirty-three percent (492) of neonatologists completed the survey. Twenty-eight percent reported using specific oxygen titration guidelines. Majority of respondents used a combination of oxygen saturation (SpO2) and arterial oxygen tension (PaO2) initially to titrate oxygen. Seventy percent of the respondents used higher goal SpO2 > 95% or 95 to 98% and thirty-eight percent of the respondents used PaO2 > 80 mm Hg. Physicians with extracorporeal membrane oxygenation experience and those with greater than ten years neonatal intensive care unit experience inclined toward use of SpO2 alone for oxygen titration and aimed for lower range of SpO2 and PaO2 targets. Greater proportion of neonatologists who employed specific oxygen titration guidelines used lower SpO2 targets. Conclusion Wide practice variations exist amongst neonatologists regarding optimal SpO2 and PaO2 targets and oxygen titration practices in the management of PPHN. PMID- 27490771 TI - Sex-Specific Associations of Maternal Gestational Glycemia with Hormones in Umbilical Cord Blood at Delivery. AB - Background Few studies have examined sex-specific associations of maternal gestational glycemia with cord blood hormones, which might predict later health. Methods In 976 women without pre-existing diabetes in the Project Viva cohort, we used linear regression to examine associations of maternal gestational glycemia with cord hormone concentrations, adjusted for maternal characteristics and stratified by infant sex. Results A total of 6.1% of women had gestational diabetes mellitus (GDM), 8.8% isolated hyperglycemia, 3.2% gestational impaired glucose tolerance, and 81.9% were normoglycemic. In boys, compared with infants of normoglycemic mothers, infants of GDM mothers had higher cord levels of IGF-2 (beta 35.55 ng/mL; 95% CI: 2.60, 68.50), IGFBP-3 (111.2 ng/mL; 5.53, 216.8), insulin (4.66 uU/mL; 2.38, 6.95), C-peptide (0.46 ng/mL; 0.25, 0.67), and leptin (3.51 ng/mL; 1.37, 5.64), but lower IGF-1 (-6.71 ng/mL; -12.7, - 0.76, adjusted for IGFBP-3). In girls, GDM offspring had higher cord blood levels of IGF-1 adjusted for IGFBP-3 (12.45 ng/mL; 4.85, 20.04). Boys, but not girls, of mothers with abnormal glucose tolerance but not GDM also had higher levels of some hormones. Conclusion GDM was associated with growth factors and adipokines in cord blood from boys, but only IGF-1 in girls. These findings suggest sex differences in responses to fetal overnutrition. PMID- 27490773 TI - Neonatal Hospital Course and Outcomes of Live-born Infants with Trisomy 18 at Two Tertiary Care Centers in the United States. AB - Objectives Trisomy 18 is presumed to be a lethal chromosomal abnormality; medical management of infants with this aneuploidy is controversial. Our objective was to describe our approach and experience with trisomy 18 infants. Study Design We reviewed the initial hospital course, management, and factors predicting discharge from the hospital from two large tertiary care neonatal intensive care units in the southern United States over 26 years. Results Of the 29 infants with trisomy 18, 21 (72%) died in the hospital and 8 (28%) were discharged home. 19 (66%) infants received mechanical ventilation and 10 (34%) received inotropic medications. Eight infants had critical congenital heart defects; only one survived to discharge. Three infants underwent major surgeries; one cardiac surgery, one tracheoesophageal fistula repair, and one myelomeningocele repair. Median length of hospital stay was 14 days (range, 0-78) for all the infants and 31 days (range, 18-66) for those that were discharged home. Factors associated with discharge from the hospital were female sex, higher gestational age, and absence of critical congenital heart defects. Median survival time was 13 days and was significantly longer for females compared with males. Our 1-month and 1 year survival rates were 31% and 3.9% respectively. Conclusion A significant proportion of infants with trisomy 18 were discharged home. These data are helpful in counseling parents of infants with trisomy 18. PMID- 27490774 TI - First Trimester Detection of Placental Disease: Challenges and Opportunities. AB - It is generally agreed that placental pathology accounts for the majority of perinatal morbidity and mortality. If a placental prodrome could be diagnosed in vivo, risk for maternal or fetal complications could be estimated and acted upon before clinical symptoms are apparent. This is especially relevant in early diagnoses of gestational diabetes mellitus, which can be controlled through carefully monitored diet and activity changes. To meet this important need, there have been increased efforts to identify early gestation biomarkers of placental dysfunction using innovative imaging technologies. Here we outline innovative quantitative markers of placental shape and their relationship to placental function, clinical implications of these quantifiers, and the most recent mathematical models that utilize placental images to delineate at risk from normal pregnancies. We propose that novel contexts of readily available placental measures and routine collection of in vivo placental images in all pregnancies may be all that are needed to advance the identification of early risk determination of complicated pregnancies from placental images. PMID- 27490775 TI - Longitudinal Patterns of Glycemic Control and Blood Pressure in Pregnant Women with Type 1 Diabetes Mellitus: Phenotypes from Functional Data Analysis. AB - Objective To identify phenotypes of type 1 diabetes control and associations with maternal/neonatal characteristics based on blood pressure (BP), glucose, and insulin curves during gestation, using a novel functional data analysis approach that accounts for sparse longitudinal patterns of medical monitoring during pregnancy. Methods We performed a retrospective longitudinal cohort study of women with type 1 diabetes whose BP, glucose, and insulin requirements were monitored throughout gestation as part of a program-project grant. Scores from sparse functional principal component analysis (fPCA) were used to classify gestational profiles according to the degree of control for each monitored measure. Phenotypes created using fPCA were compared with respect to maternal and neonatal characteristics and outcome. Results Most of the gestational profile variation in the monitored measures was explained by the first principal component (82-94%). Profiles clustered into three subgroups of high, moderate, or low heterogeneity, relative to the overall mean response. Phenotypes were associated with baseline characteristics, longitudinal changes in glycohemoglobin A1 and weight, and to pregnancy-related outcomes. Conclusion Three distinct longitudinal patterns of glucose, insulin, and BP control were found. By identifying these phenotypes, interventions can be targeted for subgroups at highest risk for compromised outcome, to optimize diabetes management during pregnancy. PMID- 27490776 TI - The relationship between attentional bias toward safety and driving behavior. AB - As implicit cognitive processes garner more and more importance, studies in the fields of healthy psychology and organizational safety research have focused on attentional bias, a kind of selective allocation of attentional resources in the early stage of cognitive processing. However, few studies have explored the role of attentional bias on driving behavior. This study assessed drivers' attentional bias towards safety-related words (ABS) using the dot-probe paradigm and self reported daily driving behaviors. The results revealed significant negative correlations between attentional bias scores and several indicators of dangerous driving. Drivers with fewer dangerous driving behaviors showed greater ABS. We also built a significant linear regression model between ABS and the total DDDI score, as well as ABS and the number of accidents. Finally, we discussed the possible mechanism underlying these associations and several limitations of our study. This study opens up a new topic for the exploration of implicit processes in driving safety research. PMID- 27490777 TI - Structural and Dynamic Characterization of the Molecular Hub Early Region 1A (E1A) from Human Adenovirus. AB - The small-DNA human adenovirus encodes one of the most versatile molecular hubs, the E1A protein. This protein is essential for productive viral infection in human cells and a vast amount of biologically relevant data are available on its interactions with host proteins. Up to now, however, no high-resolution structural and dynamic information on E1A is available despite its important biological role. Among the different spliced variants of E1A, two are expressed at high level in the early stage of infection. These are 243 and 289 residues isoforms. Herein, we present their NMR characterization, showing that they are both highly disordered, but also demonstrate a certain heterogeneous behavior in terms of structural and dynamic properties. Furthermore, we present the characterization of the isolated domain of the longer variant, known as CR3. This study opens the way to understanding at the molecular level how E1A functions. PMID- 27490778 TI - CSTMP induces apoptosis and mitochondrial dysfunction in human myeloma RPMI8226 cells via CHOP-dependent endoplasmic reticulum stress. AB - BACKGROUND: The natural product tetramethylpyrazine (TMP) and resveratrol have a variety of biologic activities, including anti-cancer effects. However the pharmacological function of CSTMP (a newly designed and synthesized TMP and resveratrol derivative) in cancer have not been elucidated. METHODS: In RPMI8226 cells, the cytotoxic effects and apoptosis were detected by MTT and Double staining for Annexin V-FITC and propidium iodide (PI). The protein and mRNA expression levels were detected by Real Time PCR and Western blot, respectively. The localization of cleaved caspase-12 was evaluated by immunofluorescent staining. The activation of caspase were measured by colorimetric assays and Western blot. RESULTS: CSTMP showed significantly cytotoxic effects and induced apoptosis in RPMI8226 cells. Caspase activation, Cytochrome c release and Bax, Bcl-2 and Bcl-XL levels analyses demonstrated that the anti-cancer effect of CSTMP in RPMI8226 cells was mediated by promoting caspase- and mitochondria dependent apoptosis. In addition, CSTMP induced the increased expression of endoplasmic reticulum (ER) stress related proteins (CHOP, GRP78, GRP94 and cleaved caspase-12) and the activation of multiple branches of ER stress transducers (PERK-eIF2alpha, IRE1alpha and ATF6). Moreover, knockdown of CHOP by siRNA markedly inhibited CSTMP-induced cytotoxic effects, caspases activity and mitochondrial dysfunction in RPMI8226 cells. CONCLUSIONS: Our results indicated that CSTMP could induce apoptosis and mitochondrial dysfunction in RPMI8226 cells via CHOP-dependent ER stress. PMID- 27490780 TI - miR-1299 suppresses cell proliferation of hepatocellular carcinoma (HCC) by targeting CDK6. AB - microRNA (miRNA) plays critical role in HCC initiation and development, many miRNAs have been reported to regulate HCC progression. In this study, we studied the role of miR-1299 in cell proliferation of HCC. We found miR-1299 was significantly downregulated in HCC cells and tissues. miR-1299 overexpression inhibited cell proliferation and arrested cell cycle in G0/G1 phase analyzed by MTT assay, soft agar assay, BrdU cell proliferation assay and cell cycle assay, while miR-1299 knockdown promoted cell proliferation and accelerated G1/S transition. Further analysis suggested the key regulator of G1/S transition, cyclin-dependent kinase 6 (CDK6) was the target of miR-1299, miR-1299 inhibited CDK6 expression and bound to the 3'UTR of CDK6. When double knockdown of miR-1299 and CDK6 promoted cell proliferation copied the phenotype caused by miR-1299 overexpression, suggesting miR-1299 inhibits cell proliferation by targeting CDK6. In summary, our data revealed miR-1299 inhibits cell proliferation, and might be a target for HCC therapy. PMID- 27490779 TI - Swertiamarin ameliorates oleic acid induced lipid accumulation and oxidative stress by attenuating gluconeogenesis and lipogenesis in hepatic steatosis. AB - Swertiamarin, a bitter secoiridoid glycoside, is an antidiabetic drug with lipid lowering activity meliorates insulin resistance in Type 2 Diabetes condition. Therefore, the study was designed to explore the antioxidant and hypolipidemic activity of swertiamarin in ameliorating NAFLD caused due to hepatic lipid accumulation, inflammation and insulin resistance. Steatosis was induced in HepG2 cells by supplementing 1mM oleic acid (OA) for 24h which was marked by significant accumulation of lipid droplets. This was determined by Oil Red O (ORO) staining and triglyceride accumulation. Swertiamarin (25MUg/ml) decreased triglyceride content by 2 folds and effectively reduced LDH release (50%) activity by protecting membrane integrity thus, preventing apoptosis evidenced by reduced cleavage of Caspase 3 and PARP1. We observed that swertiamarin significantly increased the expressions of major insulin signaling proteins like Insulin receptor (IR), PI(3)K, pAkt with concomitant reduction in p307 IRS-1. AMPK was activated by swertiamarin action, thus restoring insulin sensitivity in hepatocytes. In addition, qPCR results confirmed OA up-regulated Sterol Regulatory Element Binding Protein (SREBP)-1c and fatty acid synthase (FAS), resulting in increased fatty acid synthesis. Swertiamarin effectively modulated PPAR-alpha, a major potential regulator of carbohydrate metabolism which, in turn, decreased the levels of the gluconeogenic enzyme PEPCK, further restricting hepatic glucose production and fatty acid synthesis. Cumulatively, swertiamarin targets potential metabolic regulators AMPK and PPAR-alpha, through which it regulates hepatic glycemic burden, fat accumulation, insulin resistance and ROS in hepatic steatosis which emphasizes clinical significance of swertiamarin in regulating metabolism and as a suitable candidate for treating NAFLD. PMID- 27490782 TI - The role of short-chain fatty acid on blood pressure regulation. AB - PURPOSE OF REVIEW: The gut microbiota and its metabolites have been implicated in the regulation of host physiological functions such as inflammatory and metabolic responses. The short-chain fatty acid (SCFA) receptor is expressed in the kidney and blood vessels as well, and has been reported to function as a regulator of blood pressure (BP). This review highlights the role of SCFAs derived from gut microbial fermentation in the regulation of BP. RECENT FINDINGS: Olfactory receptor 78 (Olfr78) is a member of the G-protein-coupled receptor family, and it plays a key role as a chemosensor in various tissues. Both Olfr78 and G protein coupled receptor 41 (GPR41) are expressed in smooth muscle cells of blood vessels and they recognize SCFAs. Oral administration of SCFAs was found to change BP in vivo, an effect that was altered in Olfr78 and GPR41-deficient mice. SUMMARY: The regulation of BP via SCFA receptors has provided new insights into the interactions between the gut microbiota and BP control systems. We summarize these interactions and describe their contributions to a novel pathway involved in BP regulation. These recent findings could open new avenues for the development of therapeutic strategies for the treatment of cardiovascular diseases. PMID- 27490781 TI - Homology modeling and virtual screening for inhibitors of lipid kinase PI(4)K from Plasmodium. AB - Malaria parasite strains have emerged to tolerate the therapeutic effects of the prophylactics and drugs presently available. Recent studies have shown that KAI715 and its analogs inhibit malaria parasites growth by binding to lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) of the parasites. Therefore, targeting PI(4)K may open up new avenues of target-based drug discovery to identify novel anti-malaria drugs. In this investigation, we describe the discovery of novel potent PfPI(4)K (PI(4)K from P. falciparum) inhibitors by employing a proposed hybrid virtual screening (VS) method, including pharmacophore model, drug-likeness prediction and molecular docking approach. 3D structure of PfPI(4)K has been established by homology modeling. Pharmacophore model HypoA of PfPI(4)K inhibitors has been developed based on the ligand complexed with its corresponding receptor. 174 compounds with good ADMET properties were carefully selected by a hybrid virtual screening method. Finally, the 174 hits were further validated by using a new pharmacophore model HypoB built based on the docking pose of BQR685, and 95 compounds passed the last filter. These compounds would be further evaluated by biological activity assays. The molecular interactions of the top two potential inhibitors with the active site residues are discussed in detail. These identified hits can be further used for designing the more potent inhibitors against PfPI(4)K by scaffold hopping, and deserve consideration for further structure-activity relationship (SAR) studies. PMID- 27490783 TI - Neuroinflammatory mechanisms of hypertension: potential therapeutic implications. AB - PURPOSE OF REVIEW: Inflammation of forebrain and hindbrain nuclei has recently been highlighted as an emerging factor in the pathogenesis of neurogenic hypertension. The aim of this review is to summarize the state of the art in this field and to discuss recently discovered pathophysiological mechanisms, opening new perspectives for therapeutic application. RECENT FINDINGS: Microglia Toll like receptor 4 causally links angiotensin II (AngII)-mediated microglia cell activation and oxidative stress within the hypothalamic paraventricular nucleus (PVN). Toll-like receptor 4 can also be activated by lipopolysaccharides. PVN infusion of nuclear factor kappaB inhibitor lowers the blood pressure and ameliorates cardiac hypertrophy. Ang-(1-7) exerts direct effects on microglia, causing a reduction in both baseline and prorenin-induced release of proinflammatory cytokines. A compromised blood-brain barrier (BBB) constitutes a complementary mechanism that exacerbates AngII-driven neurohumoral activation, contributing to the development of hypertension. SUMMARY: PVN and BBB seem to be pivotal targets for therapeutic intervention in hypertension. Recent advances in imaging techniques enable visualization of the inflammatory state in microglia and BBB integrity in humans. AngII type I receptor blockers and AngII-converting enzyme inhibitors are the most likely candidates for controlled randomized trials in humans aimed at amelioration of brain inflammation in the forthcoming years. PMID- 27490785 TI - Public Attitudes About Eye and Vision Health. AB - Importance: Understanding the importance of eye health to the US population across ethnic and racial groups helps guide strategies to preserve vision in Americans and inform policy makers regarding priority of eye research to Americans. Objective: To understand the importance and awareness of eye health in the US population across ethnic and racial groups. Design, Setting, and Participants: Online nationwide poll created by experienced policy makers in August 2014 designed to understand the importance of eye health in the US population, although the poll was not subjected previously to formal construct validity testing. The population survey comprised 2044 US adults including non Hispanic white individuals and minority groups with minority oversampling to provide predicted margins of error no greater than 5%. Main Outcomes and Measures: Respondent attitudes on the importance of eye health, concerns about losing vision, support for eye health research, and awareness of eye diseases and risk factors. Results: Of the 2044 survey respondents, the weighten mean age was 46.2 years, 48% were male, and 11% were uninsured. Sixty three percent reported wearing glasses. Most individuals surveyed (87.5%; 95% CI, 84.5%-90%) believed that good vision is vital to overall health while 47.4% (95% CI, 43.7%-51.1%) rated losing vision as the worst possible health outcome. Respondents ranked losing vision as equal to or worse than losing hearing, memory, speech, or a limb. When asked about various possible consequences of vision loss, quality of life ranked as the top concern followed by loss of independence. Nearly two thirds of respondents were aware of cataracts (65.8%) or glaucoma (63.4%); only half were aware of macular degeneration; 37.3% were aware of diabetic retinopathy; and 25% were not aware of any eye conditions. Approximately 75.8% and 58.3%, respectively, identified sunlight and family heritage as risk factors for losing vision; only half were aware of smoking risks on vision loss. Conclusions and Relevance: In this well-characterized survey across all US ethnic and racial groups, vision health was a priority with high support for ongoing research for vision and eye health. Many Americans were unaware of important eye diseases and their behavioral or familial risk factors. The consistency of these findings among the varying ethnic/racial groups underscores the importance of educating the public on eye health and mobilizing public support for vision research. PMID- 27490786 TI - Activation of H2 over the Ru-Zn Bond in the Transition Metal-Lewis Acid Heterobimetallic Species [Ru(IPr)2(CO)ZnEt](.). AB - Reaction of [Ru(IPr)2(CO)H]BAr(F)4 with ZnEt2 forms the heterobimetallic species [Ru(IPr)2(CO)ZnEt]BAr(F)4 (2), which features an unsupported Ru-Zn bond. 2 reacts with H2 to give [Ru(IPr)2(CO)(eta(2)-H2)(H)2ZnEt]BAr(F)4 (3) and [Ru(IPr)2(CO)(H)2ZnEt]BAr(F)4 (4). DFT calculations indicate that H2 activation at 2 proceeds via oxidative cleavage at Ru with concomitant hydride transfer to Zn. 2 can also activate hydridic E-H bonds (E = B, Si), and computed mechanisms for the facile H/H exchange processes observed in 3 and 4 are presented. PMID- 27490784 TI - Paracellular transport in the collecting duct. AB - PURPOSE OF REVIEW: The paracellular pathway through the tight junction provides an important route for chloride reabsorption in the collecting duct of the kidney. This review describes recent findings of how defects in paracellular chloride permeation pathway may cause kidney diseases and how such a pathway may be regulated to maintain normal chloride homeostasis. RECENT FINDINGS: The tight junction in the collecting duct expresses two important claudin genes - claudin-4 and claudin-8. Transgenic knockout of either claudin gene causes hypotension, hypochloremia, and metabolic alkalosis in experimental animals. The claudin-4 mediated chloride permeability can be regulated by a protease endogenously expressed by the collecting duct cell - channel-activating protease 1. Channel activating protease 1 regulates the intercellular interaction of claudin-4 and its membrane stability. Kelch-like 3, previously identified as a causal gene for Gordon's syndrome, also known as pseudohypoaldosteronism II, directly interacts with claudin-8 and regulates its ubiquitination and degradation. The dominant pseudohypoaldosteronism-II mutation (R528H) in Kelch-like 3 abolishes claudin-8 binding, ubiquitination, and degradation. SUMMARY: The paracellular chloride permeation pathway in the kidney is an important but understudied area in nephrology. It plays vital roles in renal salt handling and regulation of extracellular fluid volume and blood pressure. Two claudin proteins, claudin-4 and claudin-8, contribute to the function of this paracellular pathway. Deletion of either claudin protein from the collecting duct causes renal chloride reabsorption defects and low blood pressure. Claudins can be regulated on posttranslational levels by several mechanisms involving protease and ubiquitin ligase. Deregulation of claudins may cause human hypertension as exemplified in the Gordon's syndrome. PMID- 27490787 TI - Medial Patellofemoral Reconstruction in Children and Adolescents. PMID- 27490788 TI - Improving Operating Room Efficiency, Part 1: General Managerial and Preoperative Strategies. PMID- 27490789 TI - Improving Operating Room Efficiency, Part 2: Intraoperative and Postoperative Strategies. PMID- 27490790 TI - Treatment of Syndesmotic Injuries of the Ankle: A Critical Analysis Review. PMID- 27490791 TI - Magnetic Resonance Imaging Following Spine Trauma. PMID- 27490792 TI - Operative and Nonoperative Treatment of Acromioclavicular Dislocation: A Critical Analysis Review. PMID- 27490793 TI - Effect of mitomycin c and 5-flurouracil adjuvant therapy on the outcomes of Ahmed glaucoma valve implantation. AB - BACKGROUND: To examine the effect of mitomycin c and 5-flurouracil on treatment outcomes following Ahmed glaucoma valve implantation. DESIGN: Retrospective consecutive case series. PARTICIPANTS: Fifty patients who received Ahmed glaucoma valve implantation from 1999 to 2013 in the San Francisco Veterans Administration Hospital. METHODS: The +INJECTION group received intraoperative mitomycin c followed by postoperative mitomycin c and/or 5-flurouracil, whereas the INJECTION group did not. MAIN OUTCOME MEASURES: Primary outcome was treatment success at 1 year post-implantation. Intraocular pressure, hypertensive phase, and the number of glaucoma medications were also examined. RESULTS: Twenty-six patients/eyes in the +INJECTION group and 24 patients/eyes in the -INJECTION group were included. Treatment success was higher in the +INJECTION compared with the -INJECTION group (86 vs. 58%; P = 0.04). Intraocular pressure was lower in the +INJECTION compared with the -INJECTION group at 1, 3, 6 and 12 months (P ? 0.00001, P = 0.00003, 0.0008 and 0.024). Hypertensive phase occurred less often in the +INJECTION compared with the -INJECTION group (3.8 vs. 54%; P = 0.021). The +INJECTION group required fewer medications compared with the -INJECTION group (P = 0.02, 0.002, 0.003 and 0.008 at 1, 3, 6 and 12 months). Complication rates were comparable between groups (46.2 and 54.2%; P = 0.63). CONCLUSIONS: Adjuvant treatment with antifibrotics following Ahmed glaucoma valve implantation decreased the hypertensive phase and improved surgical outcomes without impacting complication rates at 1 year. This study postulates a role for antifibrotics in the postoperative management of Ahmed glaucoma valves. PMID- 27490796 TI - Coupling Capillary Zone Electrophoresis to a Q Exactive HF Mass Spectrometer for Top-down Proteomics: 580 Proteoform Identifications from Yeast. AB - We used reversed-phase liquid chromatography to separate the yeast proteome into 23 fractions. These fractions were then analyzed using capillary zone electrophoresis (CZE) coupled to a Q-Exactive HF mass spectrometer using an electrokinetically pumped sheath flow interface. The parameters of the mass spectrometer were first optimized for top-down proteomics using a mixture of seven model proteins; we observed that intact protein mode with a trapping pressure of 0.2 and normalized collision energy of 20% produced the highest intact protein signals and most protein identifications. Then, we applied the optimized parameters for analysis of the fractionated yeast proteome. From this, 580 proteoforms and 180 protein groups were identified via database searching of the MS/MS spectra. This number of proteoform identifications is two times larger than that of previous CZE-MS/MS studies. An additional 3,243 protein species were detected based on the parent ion spectra. Post-translational modifications including N-terminal acetylation, signal peptide removal, and oxidation were identified. PMID- 27490795 TI - Six-SOMAmer Index Relating to Immune, Protease and Angiogenic Functions Predicts Progression in IPF. AB - RATIONALE: Biomarkers in easily accessible compartments like peripheral blood that can predict disease progression in idiopathic pulmonary fibrosis (IPF) would be clinically useful regarding clinical trial participation or treatment decisions for patients. In this study, we used unbiased proteomics to identify relevant disease progression biomarkers in IPF. METHODS: Plasma from IPF patients was measured using an 1129 analyte slow off-rate modified aptamer (SOMAmer) array, and patient outcomes were followed over the next 80 weeks. Receiver operating characteristic (ROC) curves evaluated sensitivity and specificity for levels of each biomarker and estimated area under the curve (AUC) when prognostic biomarker thresholds were used to predict disease progression. Both logistic and Cox regression models advised biomarker selection for a composite disease progression index; index biomarkers were weighted via expected progression-free days lost during follow-up with a biomarker on the unfavorable side of the threshold. RESULTS: A six-analyte index, scaled 0 to 11, composed of markers of immune function, proteolysis and angiogenesis [high levels of ficolin-2 (FCN2), cathepsin-S (Cath-S), legumain (LGMN) and soluble vascular endothelial growth factor receptor 2 (VEGFsR2), but low levels of inducible T cell costimulator (ICOS) or trypsin 3 (TRY3)] predicted better progression-free survival in IPF with a ROC AUC of 0.91. An index score >= 3 (group >= 2) was strongly associated with IPF progression after adjustment for age, gender, smoking status, immunomodulation, forced vital capacity % predicted and diffusing capacity for carbon monoxide % predicted (HR 16.8, 95% CI 2.2-126.7, P = 0.006). CONCLUSION: This index, derived from the largest proteomic analysis of IPF plasma samples to date, could be useful for clinical decision making in IPF, and the identified analytes suggest biological processes that may promote disease progression. PMID- 27490797 TI - Etiology and Features of Eyes with Rubeosis Iridis among Korean Patients: A Population-Based Single Center Study. AB - PURPOSE: To estimate the etiology and features of the eyes with rubeosis iridis among Korean patients. MATERIALS AND METHODS: This study is a retrospective review of 533 Korean patients with rubeosis iridis who visited an eye hospital in Seoul, Korea. We defined rubeosis iridis as visible blood vessels on the iris surface detected during a slit-lamp examination. All cases were reviewed for age at the time of diagnosis, medical history, the most likely cause of rubeosis iridis, visual acuity, and intraocular pressure. RESULTS: The most commonly observed cause of rubeosis iridis was diabetic retinopathy (DR; n = 337, 63.2%), followed by retinal vein occlusion (RVO; n = 101, 18.9%), ocular ischemic syndrome (OIS; n = 24, 4.5%), retinal detachment (n = 17, 3.2%), and uveitis (n = 15, 2.8%). The cause was classified as miscellaneous in 18 cases (3.4%); in 21 eyes (3.9%), the cause was not clear. Age at the time of rubeosis iridis diagnosis was lower in patients with DR (56.5 years) than in those with RVO (61.0 years) and OIS (64.8 years; P < 0.01). Intraocular pressure of the eyes with DR (37.3 mmHg) and RVO (39.5 mmHg) was higher than that of the eyes with OIS (25.8 mmHg; P < 0.01). CONCLUSION: In our population-based single center study, DR was the leading cause of rubeosis iridis followed by RVO and OIS among Korean patients. The clinical characteristics of the eyes with rubeosis iridis differed according to etiology. This finding may be useful when assessing eyes with rubeosis iridis. PMID- 27490798 TI - Cyclic Triradicals Composed of Iminonitroxide-Gold(I) with Intramolecular Ferromagnetic Interactions. AB - A triangular gold(iminonitroxide-2-ide) trimer complex (5) was prepared and investigated to determine its magnetic properties. The results showed that the metalloid triradical is highly stable, even in solution under aerated conditions. The intramolecular exchange interaction of 5 was found to be positive (Jintra /kB ~+29 K), thus showing that 5 is in a quartet ground state. In addition, a silver sandwich complex (5-Ag(+) -5) was prepared and its electronic and magnetic properties were also clarified. PMID- 27490799 TI - Correction: Normal Lung Quantification in Usual Interstitial Pneumonia Pattern: The Impact of Threshold-based Volumetric CT Analysis for the Staging of Idiopathic Pulmonary Fibrosis. AB - [This corrects the article DOI: 10.1371/journal.pone.0152505.]. PMID- 27490800 TI - Human Management of a Wild Plant Modulates the Evolutionary Dynamics of a Gene Determining Recessive Resistance to Virus Infection. AB - This work analyses the genetic variation and evolutionary patterns of recessive resistance loci involved in matching-allele (MA) host-pathogen interactions, focusing on the pvr2 resistance gene to potyviruses of the wild pepper Capsicum annuum glabriusculum (chiltepin). Chiltepin grows in a variety of wild habitats in Mexico, and its cultivation in home gardens started about 25 years ago. Potyvirus infection of Capsicum plants requires the physical interaction of the viral VPg with the pvr2 product, the translation initiation factor eIF4E1. Mutations impairing this interaction result in resistance, according to the MA model. The diversity of pvr2/eIF4E1 in wild and cultivated chiltepin populations from six biogeographical provinces in Mexico was analysed in 109 full-length coding sequences from 97 plants. Eleven alleles were found, and their interaction with potyvirus VPg in yeast-two-hybrid assays, plus infection assays of plants, identified six resistance alleles. Mapping resistance mutations on a pvr2/eIF4E1 model structure showed that most were around the cap-binding pocket and strongly altered its surface electrostatic potential, suggesting resistance-associated costs due to functional constraints. The pvr2/eIF4E1 phylogeny established that susceptibility was ancestral and resistance was derived. The spatial structure of pvr2/eIF4E1 diversity differed from that of neutral markers, but no evidence of selection for resistance was found in wild populations. In contrast, the resistance alleles were much more frequent, and positive selection stronger, in cultivated chiltepin populations, where diversification of pvr2/eIF4E1 was higher. This analysis of the genetic variation of a recessive resistance gene involved in MA host-pathogen interactions in populations of a wild plant show that evolutionary patterns differ according to the plant habitat, wild or cultivated. It also demonstrates that human management of the plant population has profound effects on the diversity and the evolution of the resistance gene, resulting in the selection of resistance alleles. PMID- 27490801 TI - Screening women for cervical cancer carcinoma with a HPV mRNA test: first results from the Venice pilot program. AB - BACKGROUND: HPV DNA-based screening is more effective than a Pap test in preventing cervical cancer, but the test is less specific. New HPV tests have been proposed for primary screening. The HPV mRNA test showed a similar or slightly lower sensitivity than the HPV DNA tests but with a higher specificity. We report the results of an organised HPV mRNA-based screening pilot program in Venice, Italy. METHODS: From October 2011 to May 2014, women aged 25-64 years were invited to undergo a HPV mRNA test (Aptima). Those testing positive underwent cytological triage. Women with positive cytology were referred to colposcopy, whereas those with negative cytology were referred to repeat the HPV mRNA test 1 year later. The results of the HPV mRNA test program were compared with both the local historical cytology-based program and with four neighbouring DNA HPV-based pilot projects. RESULTS: Overall, 23 211 women underwent a HPV mRNA test. The age-standardised positivity rate was 7.0%, higher than in HPV DNA programs (6.8%; relative rate (RR) 1.11, 95% confidence interval (CI) 1.05-1.17). The total colposcopy referral was 5.1%, double than with cytology (2.6%; RR 2.02, 95% CI 1.82-2.25) but similar to the HPV DNA programs (4.8%; RR 1.02; 95% CI 0.96 1.08). The cervical intraepithelial neoplasia grade 2+ detection rate with HPV mRNA was greater than in the HPV DNA programs at baseline (RR 1.50; 95% CI 1.19 1.88) and not significantly lower at the 1-year repeat (RR 0.70; 95% CI 0.40 1.16). The overall RR was 1.29 (95% CI 1.05-1.59), which was much higher than with cytology (detection rate 5.50/00 vs 2.10/00; RR 2.50, 95% CI 1.76-3.62). CONCLUSIONS: A screening programme based on the HPV mRNA obtained results similar to those observed with the HPV DNA test. In routine screening programmes, even a limited increase in HPV prevalence may conceal the advantage represented by the higher specificity of HPV mRNA. PMID- 27490802 TI - CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer. AB - BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are associated with improved survival in several epithelial cancers. The two chemokines CXCL9 and CXCL10 facilitate chemotactic recruitment of TILs, and their intratumoral accumulation is a conceivable way to improve TIL-dependent immune intervention in cancer. However, the prognostic impact of CXCL9 and CXCL10 in high-grade serous ovarian cancer (HGSC) is largely unknown. METHODS: One hundred and eighty four cases of HGSC were immunohistochemically analyzed for CXCL9, CXCL10. TILs were assessed using CD3, CD56 and FOXP3 staining. Chemokine regulation was investigated using the ovarian cancer cell lines OV-MZ-6 and SKOV-3. RESULTS: High expression of CXCL9 and CXCL10 was associated with an approximately doubled overall survival (n=70, CXCL9: HR 0.41; P=0.006; CXCL10: HR 0.46; P=0.010) which was confirmed in an independent validation set (n=114; CXCL9: HR 0.60; P=0.019; CXCL10: HR 0.52; P=0.005). Expression of CXCR3 ligands significantly correlated with TILs. In human ovarian cancer cell lines the cyclooxygenase (COX) metabolite Prostaglandin E2 was identified as negative regulator of chemokine secretion, whereas COX inhibition by indomethacin significantly upregulated CXCL9 and CXCL10. In contrast, celecoxib, the only COX inhibitor prospectively evaluated for therapy of ovarian cancer, suppressed NF-kappaB activation and inhibited chemokine release. CONCLUSION: Our results support the notion that CXCL9 and CXCL10 exert tumour-suppressive function by TIL recruitment in human ovarian cancer. COX inhibition by indomethacin, not by celecoxib, may be a promising approach to concomitantly improve immunotherapies. PMID- 27490803 TI - Symptoms and patient factors associated with longer time to diagnosis for colorectal cancer: results from a prospective cohort study. AB - BACKGROUND: The objective of this study is to investigate symptoms, clinical factors and socio-demographic factors associated with colorectal cancer (CRC) diagnosis and time to diagnosis. METHODS: Prospective cohort study of participants referred for suspicion of CRC in two English regions. Data were collected using a patient questionnaire, primary care and hospital records. Descriptive and regression analyses examined associations between symptoms and patient factors with total diagnostic interval (TDI), patient interval (PI), health system interval (HSI) and stage. RESULTS: A total of 2677 (22%) participants responded; after exclusions, 2507 remained. Participants were diagnosed with CRC (6.1%, 56% late stage), other cancers (2.0%) or no cancer (91.9%). Half the cohort had a solitary first symptom (1332, 53.1%); multiple first symptoms were common. In this referred population, rectal bleeding was the only initial symptom more frequent among cancer than non-cancer cases (34.2% vs 23.9%, P=0.004). There was no evidence of differences in TDI, PI or HSI for those with cancer vs non-cancer diagnoses (median TDI CRC 124 vs non-cancer 138 days, P=0.142). First symptoms associated with shorter TDIs were rectal bleeding, change in bowel habit, 'feeling different' and fatigue/tiredness. Anxiety, depression and gastro-intestinal co-morbidities were associated with longer HSIs and TDIs. Symptom duration-dependent effects were found for rectal bleeding and change in bowel habit. CONCLUSIONS: Doctors and patients respond less promptly to some symptoms of CRC than others. Healthcare professionals should be vigilant to the possibility of CRC in patients with relevant symptoms and mental health or gastro-intestinal comorbidities. PMID- 27490804 TI - Genome-wide measures of DNA methylation in peripheral blood and the risk of urothelial cell carcinoma: a prospective nested case-control study. AB - BACKGROUND: Global DNA methylation has been reported to be associated with urothelial cell carcinoma (UCC) by studies using blood samples collected at diagnosis. Using the Illumina HumanMethylation450 assay, we derived genome-wide measures of blood DNA methylation and assessed them for their prospective association with UCC risk. METHODS: We used 439 case-control pairs from the Melbourne Collaborative Cohort Study matched on age, sex, country of birth, DNA sample type, and collection period. Conditional logistic regression was used to compute odds ratios (OR) of UCC risk per s.d. of each genome-wide measure of DNA methylation and 95% confidence intervals (CIs), adjusted for potential confounders. We also investigated associations by disease subtype, sex, smoking, and time since blood collection. RESULTS: The risk of superficial UCC was decreased for individuals with higher levels of our genome-wide DNA methylation measure (OR=0.71, 95% CI: 0.54-0.94; P=0.02). This association was particularly strong for current smokers at sample collection (OR=0.47, 95% CI: 0.27-0.83). Intermediate levels of our genome-wide measure were associated with decreased risk of invasive UCC. Some variation was observed between UCC subtypes and the location and regulatory function of the CpGs included in the genome-wide measures of methylation. CONCLUSIONS: Higher levels of our genome-wide DNA methylation measure were associated with decreased risk of superficial UCC and intermediate levels were associated with reduced risk of invasive disease. These findings require replication by other prospective studies. PMID- 27490805 TI - The utility of urine-circulating miRNAs for detection of prostate cancer. AB - BACKGROUND: In this paper, the utility of urine-circulating microRNAs (miRNAs) as the potential biomarker of prostate cancer (PCa), the second most prevalent male cancer worldwide, was evaluated. METHODS: Cancerous (N=56) and non-cancerous (N=16) prostate tissues were analysed on TaqMan Low Density Array, with the initial screening of 754 miRNAs in a subset of the samples. The abundance of selected miRNAs was analysed in urine specimens from two independent cohorts of patients with PCa (N=215 overall), benign prostatic hyperplasia (BPH; N=23), and asymptomatic controls (ASC; N=62) by means of quantitative reverse transcription PCR. RESULTS: Over 100 miRNAs were found deregulated in PCa as compared with non cancerous prostate tissue. After thorough validation, four miRNAs were selected for the analysis in urine specimens. The abundance of miR-148a and miR-375 in urine was identified as specific biomarkers of PCa in both cohorts. Combined analysis of urine-circulating miR-148a and miR-375 was highly sensitive and specific for PCa in both cohorts (AUC=0.79 and 0.84) and strongly improved the diagnostic power of the PSA test (AUC=0.85, cohort PCa1), including the grey diagnostic zone (AUC=0.90). CONCLUSIONS: Quantitative measurement of urine circulating miR-148a and miR-375 can serve as the non-invasive tool for sensitive and specific detection of PCa. PMID- 27490806 TI - Medical treatment of renal cancer: new horizons. AB - Renal cell carcinoma (RCC) makes up 2-3% of adult cancers. The introduction of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors in the mid-2000s radically changed the management of RCC. These targeted treatments superseded immunotherapy with interleukin-2 and interferon. The pendulum now appears to be shifting back towards immunotherapy, with the evidence of prolonged overall survival of patients with metastatic RCC on treatment with the anti programmed cell death 1 ligand monoclonal antibody, nivolumab. Clinical prognostic criteria aid prediction of relapse risk for resected localised disease. Unfortunately, for patients at high risk of relapse, no adjuvant treatment has yet shown benefit, although further trials are yet to report. Clinical prognostic models also have a role in the management of advanced disease; now there is a pressing need for predictive biomarkers to direct therapy. Treatment selection for metastatic disease is currently based on histology, prognostic group and patient preference based on side effect profile. In this article, we review the current medical and surgical management of localised, oligometastatic and advanced RCC, including side effect management and the evidence base for management of poor-risk and non-clear cell disease. We discuss recent results from clinical trials and how these are likely to shape future practice and a renaissance of immunotherapy for renal cell cancer. PMID- 27490807 TI - Digital vs screen-film mammography in population-based breast cancer screening: performance indicators and tumour characteristics of screen-detected and interval cancers. AB - BACKGROUND: Full-field digital mammography (FFDM) has replaced screen-film mammography (SFM) in most breast cancer screening programs due to technological advantages such as possibilities to adjust contrast, better image quality and transfer capabilities. This study describes the performance indicators during the transition from SFM to FFDM and the characteristics of screen-detected and interval cancers. METHODS: Data of the Dutch breast cancer screening program, region North from 2004 to 2010 were linked to The Netherlands Cancer Registry (N=902 868). Performance indicators and tumour characteristics of screen-detected and interval cancers were compared between FFDM and SFM. RESULTS: After initial screens, recall rates were 2.1% (SFM) and 3.0% (FFDM; P<0.001). The positive predictive values (PPV) were 25.6% (SFM) and 19.9% (FFDM; P=0.002). Detection rates were similar, as were all performance indicators after subsequent screens. Similar percentages of low-grade ductal carcinoma in situ (DCIS) were found for SFM and FFDM. Invasive cancers diagnosed after subsequent screens with FFDM were more often of high-grade (P=0.024) and ductal type (P=0.030). The incidence rates of interval cancers were similar for SFM and FFDM after initial (2.69/1000 vs 2.51/1000; P=0.787) and subsequent screens (2.30 vs 2.41; P=0.652), with similar tumour characteristics. CONCLUSIONS: FFDM resulted in similar rates of screen detected and interval cancers, indicating that FFDM performs as well as SFM in a breast cancer screening program. No signs of an increase in low-grade DCIS (which might connote possible overdiagnosis) were seen. Nonetheless, after initial screening, which accounts for 12% of all screens, FFDM resulted in higher recall rate and lower PPV that requires attention. PMID- 27490809 TI - Use of Hemostatic Agents in Hip and Knee Arthroplasty: A Critical Analysis Review. PMID- 27490810 TI - Treatment of Monteggia and Transolecranon Fracture-Dislocations of the Elbow: A Critical Analysis Review. PMID- 27490808 TI - Polyunsaturated fatty acids and prostate cancer risk: a Mendelian randomisation analysis from the PRACTICAL consortium. AB - BACKGROUND: Prostate cancer is a common cancer worldwide with no established modifiable lifestyle factors to guide prevention. The associations between polyunsaturated fatty acids (PUFAs) and prostate cancer risk have been inconsistent. Using Mendelian randomisation, we evaluated associations between PUFAs and prostate cancer risk. METHODS: We used individual-level data from a consortium of 22 721 cases and 23 034 controls of European ancestry. Externally weighted PUFA-specific polygenic risk scores (wPRSs), with explanatory variation ranging from 0.65 to 33.07%, were constructed and used to evaluate associations with prostate cancer risk per one standard deviation (s.d.) increase in genetically-predicted plasma PUFA levels using multivariable-adjusted unconditional logistic regression. RESULTS: No overall association was observed between the genetically-predicted PUFAs evaluated in this study and prostate cancer risk. However, risk reductions were observed for short-chain PUFAs, linoleic (ORLA=0.95, 95%CI=0.92, 0.98) and alpha-linolenic acids (ORALA=0.96, 95%CI=0.93, 0.98), among men <62 years; whereas increased risk was found among men ?62 years for LA (ORLA=1.04, 95%CI=1.01, 1.07). For long-chain PUFAs (i.e., arachidonic, eicosapentaenoic, and docosapentaenoic acids), increased risks were observed among men <62 years (ORAA=1.05, 95%CI=1.02, 1.08; OREPA=1.04, 95%CI=1.01, 1.06; ORDPA=1.05, 95%CI=1.02, 1.08). CONCLUSION: Results from this study suggest that circulating omega-3 and omega-6 PUFAs may have a different role in the aetiology of early- and late-onset prostate cancer. PMID- 27490811 TI - Hand Transplantation. PMID- 27490812 TI - Pathogenesis of Adolescent Idiopathic Scoliosis. PMID- 27490814 TI - "Smoking Does Not Go With Yoga:" A Qualitative Study of Women's Phenomenological Perceptions During Yoga and Smoking Cessation. AB - INTRODUCTION: Smoking cessation is often accompanied by withdrawal symptoms, cigarette craving, increased negative affect, and increased experience of stress. Because yoga has been shown to reduce stress and negative affect, it may be an effective aid to smoking cessation. The objective of this study was to examine women's phenomenological experiences of vinyasa yoga as part of a smoking cessation program. METHODS: Focus groups were conducted post-intervention with women (n = 20) who participated in a pilot randomized controlled trial of yoga as a complementary therapy for smoking cessation. The 8-week vinyasa yoga intervention included twice weekly 60-minute classes that involved breathing exercises, postures (asanas), and relaxation techniques. Focus groups were audio recorded and transcribed. Thematic analysis focused on descriptions of yoga, breathing, and bodily sensations including cigarette craving. RESULTS: Focus group participants described vinyasa yoga as physically challenging. Most reported deliberate use of yogic breathing to cope with cigarette craving and stress. Other perceived effects included relaxation and an increased sense of body awareness and wellbeing. CONCLUSIONS: Participants viewed yoga as positive and potentially helpful for quitting smoking. Yoga may be an effective adjunct for smoking cessation. PMID- 27490813 TI - Identification of Antigenic Proteins from Lichtheimia corymbifera for Farmer's Lung Disease Diagnosis. AB - The use of recombinant antigens has been shown to improve both the sensitivity and the standardization of the serological diagnosis of Farmer's lung disease (FLD). The aim of this study was to complete the panel of recombinant antigens available for FLD serodiagnosis with antigens of Lichtheimia corymbifera, known to be involved in FLD. L. corymbifera proteins were thus separated by 2D electrophoresis and subjected to western blotting with sera from 7 patients with FLD and 9 healthy exposed controls (HEC). FLD-associated immunoreactive proteins were identified by mass spectrometry based on a protein database specifically created for this study and subsequently produced as recombinant antigens. The ability of recombinant antigens to discriminate patients with FLD from controls was assessed by ELISA performed with sera from FLD patients (n = 41) and controls (n = 43) recruited from five university hospital pneumology departments of France and Switzerland. Forty-one FLD-associated immunoreactive proteins from L. corymbifera were identified. Six of them were produced as recombinant antigens. With a sensitivity and specificity of 81.4 and 77.3% respectively, dihydrolipoyl dehydrogenase was the most effective antigen for discriminating FLD patients from HEC. ELISA performed with the putative proteasome subunit alpha type as an antigen was especially specific (88.6%) and could thus be used for FLD confirmation. The production of recombinant antigens from L. corymbifera represents an additional step towards the development of a standardized ELISA kit for FLD diagnosis. PMID- 27490815 TI - Oyster's cells regulatory volume decrease: A new tool for evaluating the toxicity of low concentration hydrocarbons in marine waters. AB - Human activities require fossil fuels for transport and energy, a substantial part of which can accidentally or voluntarily (oil spillage) flow to the marine environment and cause adverse effects in human and ecosystems' health. This experiment was designed to estimate the suitability of an original cellular biomarker to early quantify the biological risk associated to hydrocarbons pollutants in seawater. Oocytes and hepatopancreas cells, isolated from oyster (Crassostrea gigas), were tested for their capacity to regulate their volume following a hypo-osmotic challenge. Cell volumes were estimated from cell images recorded at regular time intervals during a 90min-period. When exposed to diluted seawater (osmolalities from 895 to 712mosmkg(-1)), both cell types first swell and then undergo a shrinkage known as Regulatory Volume Decrease (RVD). This process is inversely proportional to the magnitude of the osmotic shock and is best fitted using a first-order exponential decay model. The Recovered Volume Factor (RVF) calculated from this model appears to be an accurate tool to compare cells responses. As shown by an about 50% decrease in RVF, the RVD process was significantly inhibited in cells sampled from oysters previously exposed to a low concentration of diesel oil (8.4mgL(-1) during 24h). This toxic effect was interpreted as a decreased permeability of the cell membranes resulting from an alteration of their lipidic structure by diesel oil compounds. In contrast, the previous contact of oysters with diesel did not induce any rise in the gills glutathione S-transferase specific activity. Therefore, this work demonstrates that the study of the RVD process of cells selected from sentinel animal species could be an alternative bioassay for the monitoring of hydrocarbons and probably, of various chemicals in the environment liable to alter the cellular regulations. Especially, given the high sensitivity of this biomarker compared with a proven one, it could become a relevant and accurate tool to estimate the biological hazards of micropollutants in the water. PMID- 27490817 TI - Effect of bike-fit in the perception of comfort, fatigue and pain. AB - The aim of this study was to assess the influence of different bike positions on the perception of fatigue, pain and comfort. Twenty cyclists underwent three tests that involved cycling for 45 min at their individual 50% peak aerobic power output while adopting different positions on the bike. Participants performed the cycling tests adopting three positions defined by two parameters (knee flexion angle [20 degrees , 30 degrees , 40 degrees ] and trunk flexion angle [35 degrees , 45 degrees , 55 degrees ]) in random order. Angles were measured using a 2D motion analysis system during cycling and applying Fonda's correction factor. Perceptions of comfort, fatigue and pain were reported before the end of each test. The combination of 40 degrees knee flexion and 35 degrees trunk flexion was perceived as the most uncomfortable position. Moreover, greater knee flexion had a negative effect on trunk comfort, accompanied by greater levels of fatigue and pain perception in the anterior part of the thigh and knee. In conclusion, cyclists perceived the most comfortable position to be when the saddle height was within the recommended knee angle (30 degrees calculated from the offset position or 40 +/- 4.0 degrees of absolute value). Upright trunk was found to be the most comfortable position for recreational cyclists, where aerodynamics is not so important. Cyclists' bike perceptions should be taken into account when it comes to choosing the most beneficial position, since this can play a role in injury prevention and enhance cycling performance. PMID- 27490816 TI - Post-Decision Wagering Affects Metacognitive Awareness of Emotional Stimuli: An Event Related Potential Study. AB - The present research investigated metacognitive awareness of emotional stimuli and its psychophysiological correlates. We used a backward masking task presenting participants with fearful or neutral faces. We asked participants for face discrimination and then probed their metacognitive awareness with confidence rating (CR) and post-decision wagering (PDW) scales. We also analysed psychophysiological correlates of awareness with event-related potential (ERP) components: P1, N170, early posterior negativity (EPN), and P3. We have not observed any differences between PDW and CR conditions in the emotion identification task. However, the "aware" ratings were associated with increased accuracy performance. This effect was more pronounced in PDW, especially for fearful faces, suggesting that emotional stimuli awareness may be enhanced by monetary incentives. EEG analysis showed larger N170, EPN and P3 amplitudes in aware compared to unaware trials. It also appeared that both EPN and P3 ERP components were more pronounced in the PDW condition, especially when emotional faces were presented. Taken together, our ERP findings suggest that metacognitive awareness of emotional stimuli depends on the effectiveness of both early and late visual information processing. Our study also indicates that awareness of emotional stimuli can be enhanced by the motivation induced by wagering. PMID- 27490819 TI - Effects of Dual-Energy Technique on Radiation Exposure and Image Quality in Pediatric Body CT. AB - OBJECTIVE: The purpose of this study was to assess the effects of dual-energy CT (DECT) on radiation exposure and image quality in pediatric body CT. MATERIALS AND METHODS: This retrospective study included 79 children (median age, 10.1 years; range, 12 days-18 years) who underwent thoracic or abdominal-pelvic CT or CT angiography with dual-energy technique between October 2014 and March 2015. The delivered volume CT dose index (CTDIvol) from DECT was recorded and compared with the estimated CTDIvol had the patient undergone scanning with a standard single-energy CT (SECT) protocol. Size-specific dose estimates were calculated for both DECT and SECT. Image quality was subjectively scored (scale, 1-4). For 16 of 79 patients who underwent both DECT and SECT, image contrast and noise were measured and contrast-to-noise ratio calculated. Parametric and nonparametric testing of independent and paired samples was performed. RESULTS: For all 79 studies, actual median CTDIvol and size-specific dose estimate were 3.7 and 5.9 mGy for DECT versus prescanning estimates of 4.4 and 7.7 mGy for SECT, resulting in 12.5% and 11.2% radiation exposure reduction (p < 0.01). Diagnostic image quality was achieved in all patients. In the 16-patient subset, the median CTDIvol values of DECT and SECT were 3.1 and 3.4 mGy (p < 0.05). Median noise was greater with DECT than with SECT (p < 0.01), but the mean contrast-to-noise ratios for the liver and portal vein were similar (liver, p = 0.32; portal vein, p = 0.21). CONCLUSION: In pediatric body CT, the use of DECT results in radiation exposures comparable to or less than those of SECT while maintaining contrast and contrast-to-noise ratio. PMID- 27490818 TI - Branched-Chain Amino Acids as New Biomarkers of Major Depression - A Novel Neurobiology of Mood Disorder. AB - BACKGROUND: The proteinogenic branched-chain amino acids (BCAAs) valine, leucine and isoleucine might play an unrecognised crucial role in the development of depression through their activation of the mammalian target of rapamycin (mTor) pathway. The aim of this research project is to evaluate whether BCAAs are altered in patients with major depression and might thus be appropriate biomarkers for major depression. METHODS: The concentrations of valine, leucine and isoleucine were determined in 71 in-patients with major depression and 48 healthy controls by high-pressure liquid chromatography. Psychiatric and laboratory assessments were obtained at the time of in-patient admittance. RESULTS: The BCAAs are significantly decreased in patients with major depression in comparison with healthy subjects (valine: Mann-Whitney-U: 968.0; p <0.0001, leucine: Mann-Whitney-U: 1246.5; p = 0.013, isoleucine: Mann-Whitney-U: 1252.5; p = 0.014). Furthermore, as shown by Spearman's rank correlation coefficients, there is a significant negative correlation between valine, leucine and isoleucine concentrations and the Hamilton Depression Rating Scale (HAMD-17) as well as Beck Depression Inventory (BDI-II) scores. CONCLUSIONS: Our study results are strong evidence that in patients with major depression, BCAAs might be appropriate biomarkers for depression. Reduced activation of the mammalian target of rapamycin (mTor) due to a reduction of BCAAs might play a crucial unrecognised factor in the etiology of depression and may evoke depressive symptomatology and lower energy metabolism in patients with major depression. In the future, mTor and its up- and downstream signalling partners might be important targets for the development of novel antidepressants. PMID- 27490821 TI - Arylboration of 1-Arylalkenes by Cooperative Nickel/Copper Catalysis. AB - A method for the arylboration of 1-arylalkenes with bis(pinacolato)diboron and aryl chlorides or tosylates by cooperative Ni/Cu catalysis has been developed, which affords 2-boryl-1,1-diarylalkanes in high regio- and stereoselectivity. Under the applied conditions, this method is tolerant toward various functional groups, including silyl ether, alkoxycarbonyl, and aminocarbonyl moieties. PMID- 27490820 TI - Linking Genes and Brain Development of Honeybee Workers: A Whole-Transcriptome Approach. AB - Honeybees live in complex societies whose capabilities far exceed those of the sum of their single members. This social synergism is achieved mainly by the worker bees, which form a female caste. The worker bees display diverse collaborative behaviors and engage in different behavioral tasks, which are controlled by the central nervous system (CNS). The development of the worker brain is determined by the female sex and the worker caste determination signal. Here, we report on genes that are controlled by sex or by caste during differentiation of the worker's pupal brain. We sequenced and compared transcriptomes from the pupal brains of honeybee workers, queens and drones. We detected 333 genes that are differently expressed and 519 genes that are differentially spliced between the sexes, and 1760 genes that are differentially expressed and 692 genes that are differentially spliced between castes. We further found that 403 genes are differentially regulated by both the sex and caste signals, providing evidence of the integration of both signals through differential gene regulation. In this gene set, we found that the molecular processes of restructuring the cell shape and cell-to-cell signaling are overrepresented. Our approach identified candidate genes that may be involved in brain differentiation that ensures the various social worker behaviors. PMID- 27490822 TI - Wnt signal transduction pathways: modules, development and evolution. AB - BACKGROUND: Wnt signal transduction pathway (Wnt STP) is a crucial intracellular pathway mainly due to its participation in important biological processes, functions, and diseases, i.e., embryonic development, stem-cell management, and human cancers among others. This is why Wnt STP is one of the highest researched signal transduction pathways. Study and analysis of its origin, expansion and gradual development to the present state as found in humans is one aspect of Wnt research. The pattern of development and evolution of the Wnt STP among various species is not clear till date. A phylogenetic tree created from Wnt STPs of multiple species may address this issue. RESULTS: In this respect, we construct a phylogenetic tree from modules of Wnt STPs of diverse species. We term it as the 'Module Tree'. A module is nothing but a self-sufficient minimally-dependent subset of the original Wnt STP. Authenticity of the module tree is tested by comparing it with the two reference trees. CONCLUSIONS: The module tree performs better than an alternative phylogenetic tree constructed from pathway topology of Wnt STPs. Moreover, an evolutionary emergence pattern of the Wnt gene family is created and the module tree is tallied with it to showcase the significant resemblances. PMID- 27490823 TI - Comparison of Ai Chi and Impairment-Based Aquatic Therapy for Older Adults With Balance Problems: A Clinical Study. AB - BACKGROUND AND PURPOSE: Older adults with balance deficits often fear falling and limit their mobility. Poor balance is multifactorial, influenced by medication interactions, musculoskeletal and sensory system changes, and poor neuromuscular response to changes in body positions. Aquatic physical therapy (APT) is an intervention used to improve balance and decrease falls. Ai Chi is a water-based exercise program. It incorporates slow movements of progressive difficulty utilizing the upper and lower extremities and trunk coordinated with deep breathing. It is used for relaxation, strengthening, and balance training. The purpose of this study was to determine whether Ai Chi provides better results than conventional impairment-based aquatic therapy (IBAT) for older adults with balance deficits. METHODS: Thirty-two community-dwelling adults, 65 to 85 years old, were referred to 2 different community pools for APT. Fifteen participants received Ai Chi-based aquatic interventions and 17 participants received an IBAT program. Physical therapists trained in both programs completed interventions and determined discharge. Physical balance measures, which included the Berg Balance Scale (BBS) and Timed Up and Go (TUG), were collected pre- and posttherapy. Self reported outcome measures, the Activities-Specific Balance Confidence Scale (ABC) and Numerical Pain Rating Scale (NPRS), were collected pre- and posttherapy and 3 and 6-month postdischarge. RESULTS: A 2-way (group by time) mixed-model analysis of covariance with initial outcome scores as a covariate revealed no difference between groups in any of the outcome measures (BBS, P = .53; TUG, P = .39; ABC, P = .63; NPRS, P = .27). Repeated-measures analysis and dependent t tests showed significant improvements in the BBS (P = .00) and TUG (P = .03) after APT. The ABC and NPRS did not improve significantly (ABC, P = .27; NPRS, P = .77). CONCLUSIONS: There were no significant differences found in balance measures, balance confidence, or pain levels for community-dwelling older adults between the Ai Chi and IBAT programs. Physical outcome measures improved with APT but patient-reported measures did not. Further study is indicated to determine the most effective treatment frequency and duration for this population. PMID- 27490824 TI - On Sublimation. AB - Although it encapsulates the Freudian theory of art, the theory of sublimation has become outmoded. What is more, since its inception there has always been something ill-defined about it. Does it use sexualized or de-sexualized drive energy? Is it a defence or an alternative to defence? Does it serve Eros or Thanatos? Is it useful in clinical work or is it unusable? The only, albeit uncertain, aid to a definition relies on the extrinsic criterion of concrete artistic realization. My aim here to revisit and possibly 'reinvent' sublimation in the light of certain principles of the pre-Romantic aesthetics of the sublime. Both are theories of spiritual elevation, in other words, elevation that moves towards abstract thinking, and of man's 'moral' achievement; and both attempt to explain the mystery of aesthetic experience. On the one hand, the aesthetics of the sublime offers a modern myth that helps us articulate a series of factors occasionally referred to by various authors as constitutive of sublimation but which have not been incorporated into a single organic framework: loss and early mourning work; the earlier existence of a catastrophic factor - to be regarded, depending on the situation, as either traumatic or simply 'negative'; the correspondence with a process of somatopsychic categorization which coincides with subjectivity. On the other hand, it also helps us grasp the experience of negative pleasure empathically, living it 'from the inside'. PMID- 27490826 TI - Identification and characterization of the missing phosphatase on the riboflavin biosynthesis pathway in Arabidopsis thaliana. AB - Despite the importance of riboflavin as the direct precursor of the cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), the physiologically relevant catalyst dephosphorylating the riboflavin biosynthesis pathway intermediate 5-amino-6-ribitylamino-2,4(1H,3H) pyrimidinedione 5' phosphate (ARPP) has not been characterized from any organism. By using as the query sequence a previously identified plastidial FMN hydrolase AtcpFHy1 (At1g79790), belonging to the haloacid dehalogenase (HAD) superfamily, seven candidates for the missing ARPP phosphatase were found, cloned, recombinantly expressed, and purified. Activity screening showed that the enzymes encoded by AtcpFHy1, At4g11570, and At4g25840 catalyze dephosphorylation of ARPP. AtcpFHy1 was renamed AtcpFHy/PyrP1, At4g11570 and At4g25840 were named AtPyrP2 and AtGpp1/PyrP3, respectively. Subcellular localization in planta indicated that AtPyrP2 was localized in plastids and AtGpp1/PyrP3 in mitochondria. Biochemical characterization of AtcpFHy/PyrP1 and AtPyrP2 showed that they have similar Km values for the substrate ARPP, with AtcpFHy/PyrP1 having higher catalytic efficiency. Screening of 21 phosphorylated substrates showed that AtPyrP2 is specific for ARPP. Molecular weights of AtcpFHy/PyrP1 and AtPyrP2 were estimated at 46 and 72 kDa, suggesting dimers. pH and temperature optima for AtcpFHy/PyrP1 and AtPyrP2 were ~7.0-8.5 and 40-50 degrees C. T-DNA knockout of AtcpFHy/PyrP1 did not affect the flavin profile of the transgenic plants, whereas silencing of AtPyrP2 decreased accumulation of riboflavin, FMN, and FAD. Our results strongly support AtPyrP2 as the missing phosphatase on the riboflavin biosynthesis pathway in Arabidopsis thaliana. The identification of this enzyme closes a long-standing gap in understanding of the riboflavin biosynthesis in plants. PMID- 27490825 TI - In-Cell Enzymology To Probe His-Heme Ligation in Heme Oxygenase Catalysis. AB - Heme oxygenase (HO) is a ubiquitous enzyme with key roles in inflammation, cell signaling, heme disposal, and iron acquisition. HO catalyzes the oxidative conversion of heme to biliverdin (BV) using a conserved histidine to coordinate the iron atom of bound heme. This His-heme interaction has been regarded as being essential for enzyme activity, because His-to-Ala mutants fail to convert heme to biliverdin in vitro. We probed a panel of proximal His mutants of cyanobacterial, human, and plant HO enzymes using a live-cell activity assay based on heterologous co-expression in Escherichia coli of each HO mutant and a fluorescent biliverdin biosensor. In contrast to in vitro studies with purified proteins, we observed that multiple HO mutants retained significant activity within the intracellular environment of bacteria. X-ray crystallographic structures of human HO1 H25R with bound heme and additional functional studies suggest that HO mutant activity inside these cells does not involve heme ligation by a proximal amino acid. Our study reveals unexpected plasticity in the active site binding interactions with heme that can support HO activity within cells, suggests important contributions by the surrounding active site environment to HO catalysis, and can guide efforts to understand the evolution and divergence of HO function. PMID- 27490828 TI - Molecular dynamics techniques for modeling G protein-coupled receptors. AB - G protein-coupled receptors (GPCRs) constitute a major class of drug targets and modulating their signaling can produce a wide range of pharmacological outcomes. With the growing number of high-resolution GPCR crystal structures, we have the unprecedented opportunity to leverage structure-based drug design techniques. Here, we discuss a number of advanced molecular dynamics (MD) techniques that have been applied to GPCRs, including long time scale simulations, enhanced sampling techniques, water network analyses, and free energy approaches to determine relative binding free energies. On the basis of the many success stories, including those highlighted here, we expect that MD techniques will be increasingly applied to aid in structure-based drug design and lead optimization for GPCRs. PMID- 27490827 TI - Discovery and Preclinical Characterization of 6-Chloro-5-[4-(1 hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577), a Direct Activator of Adenosine Monophosphate-activated Protein Kinase (AMPK), for the Potential Treatment of Diabetic Nephropathy. AB - Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF 06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy. PMID- 27490830 TI - The confusion of psychiatric comorbidity. PMID- 27490829 TI - Preoperative Predictors in Chronic Suppurative Otitis Media for Ossicular Chain Discontinuity: A Cross-Sectional Study. AB - OBJECTIVE: Ossicular discontinuity may result from chronic suppurative otitis media and is usually detected intraoperatively. Our objective is to determine whether a preoperative audiogram can preoperatively predict the presence or absence of ossicular discontinuity. METHODS: A cross-sectional study was prospectively run on our patients, aged 12-75 years, ultimately operated on for chronic suppurative otitis media. Preoperative audiograms were analyzed to measure frequency-specific air-bone gap (ABG) cutoff values. Intraoperatively, ossicular chain integrity was carefully checked. Logistic regression analysis was done to obtain a predictive model. RESULTS: A total of 270 patients (306 ears) were included. Frequency-specific ABG cutoff values can predict ossicular discontinuity, namely: high ABGs at 1,000 Hz (>27.5 dB) and 2,000 Hz (>17.5 dB) are the most reliable variables associated with ossicular discontinuity. CONCLUSION: Preoperative audiograms can predict the presence of ossicular discontinuity in chronic suppurative otitis media. Large ABGs at both 1,000 and 2,000 Hz can predict ossicular discontinuity with a great degree of certainty. PMID- 27490831 TI - Efficacy of stimulants for psychiatric symptoms in individuals with traumatic brain injury. AB - BACKGROUND: The objective of this systematic review is to summarize data from published randomized controlled trials (RCTs) on the efficacy of stimulants for psychiatric symptoms in individuals with traumatic brain injury (TBI). METHODS: A literature search was conducted of 5 major databases (PubMed, MEDLINE, PsycINFO, Embase, and Cochrane Collaboration) that identified RCTs on the use of stimulants for human patients with a diagnosis of TBI. RESULTS: A total of 176 articles were identified, of which 18 matched the inclusion criteria and were reviewed in their entirety. The majority (17) of studies assessed methylphenidate (MPH), 1 assessed dextroamphetamine and MPH, and 1 assessed modafinil. One study showed significant improvement in depressive symptoms with MPH. Seven studies showed significant improvement in reaction time, whereas 4 studies showed significant improvement in accuracy with MPH compared with placebo. Of the 2 studies that included follow up, only 1 found significant differences in disability ratings, attention concentration, and motor memory at 30 days but not 90 days between the stimulant and placebo groups. The majority of studies demonstrated significant treatment effects immediately (ie, within minutes to hours) after first-time stimulant administration. Five of the 18 studies (3 adult, 2 pediatric) did not find benefit for stimulants when compared with placebo. Two studies that evaluated self-reported side effects found no significant difference between treatment groups, although 1 study showed a significant increase in mean arterial pressure in the stimulant group. CONCLUSIONS: There is limited evidence to suggest efficacy of stimulants for psychiatric symptoms in individuals with TBI. However, stimulants appear to improve attention after first-time administration and for short time periods in these individuals. PMID- 27490832 TI - Longitudinal assessment of clinical risk factors for depression in schizophrenia spectrum disorders. AB - BACKGROUND: During initial assessment of individuals with schizophrenia and related disorders (schizophrenia spectrum disorders [SSDs]), clinicians tend to pay greater attention to psychotic symptoms than mood symptoms, including depression. Depression is reported to influence the course of SSDs, but not much is known about the risk factors for depression in SSDs. In the present study, we examined clinical predictors of depression in SSDs. METHODS: The sample included 71 patients with SSDs followed in a modified Assertive Community Treatment program, the Community Support Network of Springfield, Illinois. The study design was naturalistic, prospective, and longitudinal (mean follow-up = 8.3 years; SD = 7.3). The GENMOD procedure appropriate for repeated measures analysis with dichotomous outcome variables followed longitudinally was computed. RESULTS: Rates of depression ranged from 18% to 41% over the differing assessment periods. Schizophrenia and schizoaffective disorder did not vary by depression rate. Depression independent of SSD diagnosis was associated with greater hospitalization rates. Clinical variables predict- ing depression were auditory hallucinations, delusions, poor insight, and poor judgment. CONCLUSIONS: Psychotic symptoms in the course of SSDs are risk factors for depression. As a consequence, the mental status examination of patients with SSDs with active psychosis should include assessment of mood changes. Further research is warranted to determine if treatment of depression among patients with SSDs may reduce their rates of hospitalization. PMID- 27490833 TI - Does comorbidity matter in body-focused repetitive behavior disorders? AB - BACKGROUND: Trichotillomania (TTM) and skin-picking disorder (SPD) have been characterized as body-focused repetitive behavior disorders (BFRBs). Because BFRBs frequently co-occur, we sought to discover the similarities and differences for individuals having both TTM and SPD as opposed to 1 of these disorders. METHODS: Participants with primary TTM (N = 421) were evaluated regarding the comorbidity of SPD, and participants with primary SPD (N = 124) were evaluated regarding the comorbidity of TTM. The effects of comorbidity overlap on demographic and clinical measures were evaluated. RESULTS: Of the 421 participants with primary TTM, 61 (14.5%) had co-occurring SPD. Of 124 participants with primary SPD, 21 (16.9%) had comorbid TTM. Participants with primary TTM and comorbid SPD had significantly more severe trichotillomania symptoms and were more likely to have major depressive disorder than those with TTM alone. Participants with primary SPD and comorbid TTM reported significantly more severe skin-picking symptoms than those who had only SPD. CONCLUSIONS: Individuals with co-occurring TTM and SPD may have more problematic symptoms with the primary repetitive behavior. Hair pullers with comorbid SPD were more likely to have comorbid depression. Evaluating patients for multiple BFRBs may be important to assess the severity of symptoms and may have treatment implications. PMID- 27490834 TI - Expanded conceptualization of multimorbidity to encompass substance use disorders and other psychiatric illness. AB - BACKGROUND: Traditionally, the study of medicine has focused on individual diseases. In reality, however, diseases tend to co-occur in individual patients, a concept known as multimorbidity. Multimorbidity most often is seen in geriatric practice. Empirical data on patients with multiple chronic disorders and clinical care guidelines based on single conditions are insufficient to inform medical care of patients with >1 medical condition. METHODS: This article reviews concepts of multimorbidity in the published literature in the context of substance use disorders, other psychiatric disorders, and associated social and environmental problems in other populations, including public sector service populations. RESULTS: Besides historically recognized co-occurrence of 3 dimensions of illness, including multiple medical illnesses, psychiatric disorders, and substance use disorders in varying combinations with one another, a fourth dimension of multimorbidity that includes associated social and environmental conditions fits within this construction. CONCLUSIONS: Additional steps are needed to address more effectively the needs of patients with substance use and other psychiatric disorders in the public sector psychiatric systems of care. These efforts will need to address the systems theory approach to multimorbidity that entails the socioeconomic and environmental aspects of their conditions. PMID- 27490835 TI - Placebo-controlled augmentation trials of the antioxidant NAC in schizophrenia: A review. AB - BACKGROUND: Several studies have reported that schizophrenia is associated with mitochondrial abnormalities, glutathione deficit, and increased brain oxidative stress (free radicals). N-acetylcysteine (NAC) is a strong antioxidant with potential therapeutic benefit in schizophrenia, according to some reports. We conducted a review of the published controlled studies, with the goal of determining the efficacy profile of NAC as an adjunctive treatment for schizophrenia. METHODS: An online search was conducted for all placebo controlled, double-blind, randomized clinical trials of NAC in schizophrenia, and a review was conducted. RESULTS: Two studies met the criteria for inclusion. Berk et al (2008) used NAC as an adjunctive treatment to atypical antipsychotics in subjects with chronic schizophrenia who were stable on antipsychotic medications. Treatment at 8 weeks was less efficacious than placebo, but at 24 weeks produced significant reductions vs placebo in Positive and Negative Syndrome Scale (PANSS) negative (d = 0.52), general (d = 0.46), and total (d = 0.57) scores. Farokhnia et al (2013) used NAC as an adjunctive treatment to risperidone in subjects with chronic schizophrenia who were experiencing an acute exacerbation episode. Eight weeks of treatment led to clinically significant reductions vs placebo in PANSS negative (d = 0.96), general (d = 0.59), and total (d = 0.88) scores. CONCLUSIONS: The data suggest that adjunctive NAC may be efficacious in reducing negative and general symptoms in schizophrenia. PMID- 27490836 TI - The evolution of PTSD criteria across editions of DSM. AB - BACKGROUND: The diagnosis of posttraumatic stress disorder (PTSD) has remained controversial from the time of its first inclusion in DSM-III. No reviews have fully documented the shifting PTSD definitions across editions of the criteria. This article chronicles the evolution of PTSD across editions of the DSM. METHODS: Diagnostic precursors to PTSD in DSM-I and DSM-II were briefly described, followed by systematic review of PTSD in subsequent editions of the DSM. Sections of the criteria and accompanying text were sorted into tables permitting visual comparisons across the editions. Research findings related to specific changes in the editions were provided from available research literature identified through specific PubMed searches using keywords relevant to each specific change. RESULTS: Fundamental topics of debate identified in this review are validity of the diagnosis, the trauma criterion, the role of symptoms in defining its psychopathology, differentiation from other disorders, and specifiers such as delayed onset. CONCLUSIONS: DSM-5 has corrected several major ambiguities and errors of the former editions that are fundamental to the construct of PTSD as a disorder that is defined conditionally in relation to exposure to trauma, but problems remain in DSM-5 trauma criteria, especially inconsistencies between exposure criteria and the definition of trauma. Discerning the critical distinctions required to understand PTSD depends on underlying clarity in terminology and precision in application of the diagnosis by academicians and clinicians. Trauma must be differentiated from other kinds of stressful events and conceptualized as an incident defined by physical injury rather than by emotional response. PMID- 27490837 TI - Anxiety or agitation in mood disorder with mixed features: A review with a focus on validity as a dimensional criterion. AB - BACKGROUND: The diagnostic validity of mixed features, excluding anxiety or psychomotor agitation in mood disorders, has not yet been fully examined. METHOD: PubMed and relevant English-language literature (regardless of year) were searched. Keywords were mixed or mixed state or mixed features or mixed episode and anxious or anxiety or agitation and bipolar disorder or depressive disorder or mood disorder or affective disorder. RESULTS: Most studies on anxiety or psychomotor agitation have included a significant correlation relevant to the "with mixed features" specifier, although it is common in both poles of mood episodes regardless of the predominant polarity. There is some confusion between the characteristic of classical mixed states and the definition of the mixed features specifier with the newly added anxious distress specifier in DSM-5, specifically, whether to include anxiety and agitation as significant characteristics. This change is of concern because a large proportion of patients with mixed features are now unspecified, and this may influence treatment planning and prognosis. CONCLUSIONS: The findings of our review suggest that anxiety and psychomotor agitation can be core symptoms in mood episodes with mixed features and important clinical clues for prediction of treatment effects and disease course. PMID- 27490838 TI - DSM-5-defined attenuated psychosis syndrome and conversion to full-scale schizophrenia spectrum disorders: An institution-wide retrospective review. AB - BACKGROUND: The objective of the study was to determine if DSM-5-defined attenuated psychosis syndrome (APS) could identify individuals with prodromal psychosis and predict conversion to schizophrenia spectrum disorders at a rate similar to that observed in previous studies that utilized structured interviews and specialized rating scales. METHODS: A retrospective review of patients' medical records was used to identify individuals meeting diagnostic criteria for the APS, followed by further evaluation 2 to 3 years after the initial diagnosis, to determine if they converted to schizophrenia spectrum disorders. Results then were compared with previous studies. RESULTS: Of our study population, 43.4% converted to schizophrenia or schizoaffective disorder 2 to 3 years after initial diagnosis of APS. Comparison at the 3-year mark indicated that there was no significant difference between our observed rates and previously published conversion rates (P = .066). Three covariates were found to increase significantly the rates of conversion when added to the APS criteria: Cannabis use (P = .048), lack of previous Axis I diagnosis (P = .005), and lack of previous treatment with psychotropic medications (P = .009). CONCLUSIONS: APS accurately predicts conversion to full-scale schizophrenia spectrum disorders at a rate similar to that observed in previous studies using structured interviews and specialized rating scales. PMID- 27490839 TI - Diagnosis Accuracy of Transcutaneous Bilirubinometry in Very Preterm Newborns. AB - BACKGROUND: Transcutaneous bilirubin (TcB) is a validated test for systematic screening of neonatal hyperbilirubinemia and monitoring term and near-term infants under phototherapy. OBJECTIVES: To evaluate TcB diagnostic accuracy for very preterm neonates. METHODS: Total serum bilirubin (TSB) and TcB measurements were performed prospectively in a multicenter sample of newborns <30 weeks of gestational age (GA). TcB sensitivity, specificity, predictive values, and likelihood ratios for the detection of neonates requiring phototherapy were calculated over the first 15 days of life, with or without phototherapy, with the expectation of achieving a detection rate of hyperbilirubinemia of over 95%. The potential influence of neonatal characteristics on the discordance between TcB and TSB in very preterm newborns was analyzed using multivariate multilevel logistic regression analyses. RESULTS: Altogether, 481 measurements were analyzed in 167 preterm patients. Mean GA was 27.6 +/- 1.6 weeks. The rates of newborns requiring phototherapy were 52% in the first 3 days, 16% from the 4th to the 7th day, and 2% during the second week. Diagnostic performance was similar among babies with or without phototherapy. TcB sensitivity decreased over time from 100% (93.9-100.0) to 50% (1.3-98.7). Specificity showed an inverse evolution from 14.8% (7.0-26.2) to 80.7% (72.2-89.2). The best performance was that of negative predictive values which varied from 95.5 to 100.0. False negatives were rare throughout the study (0.8% of measurements). In a multivariate analysis, the only factor significantly influencing discordance between TcB and TSB was postnatal age. We did not find any impact of GA and skin color. CONCLUSION: Among very preterm babies, TcB measurements might be useful for screening for neonatal jaundice in the first 2 weeks of life. In case of a TcB value below the phototherapy threshold, invasive TSB quantification could be unnecessary, with potential avoidance of blood drawing. PMID- 27490840 TI - Click-Dimerized Cinchona Alkaloids. AB - A series of Cinchona alkaloid-derived dimers were obtained in high yields in copper-catalyzed 1,3-dipolar "click" cycloaddition using bis(TMS)butadiyne and other bivalent alkynes. The products with bitriazole linkers were effective ligands for asymmetric copper-catalyzed Michael addition. It was shown that the presence of such linker was responsible for effective chirality transfer. PMID- 27490842 TI - Probabilistic evaluation of n traces with no putative source: A likelihood ratio based approach in an investigative framework. AB - Analysis of marks recovered from different crime scenes can be useful to detect a linkage between criminal cases, even though a putative source for the recovered traces is not available. This particular circumstance is often encountered in the early stage of investigations and thus, the evaluation of evidence association may provide useful information for the investigators. This association is evaluated here from a probabilistic point of view: a likelihood ratio based approach is suggested in order to quantify the strength of the evidence of trace association in the light of two mutually exclusive propositions, namely that the n traces come from a common source or from an unspecified number of sources. To deal with this kind of problem, probabilistic graphical models are used, in form of Bayesian networks and object-oriented Bayesian networks, allowing users to intuitively handle with uncertainty related to the inferential problem. PMID- 27490841 TI - What are the appropriate indicators of surgical difficulty during laparoscopic cholecystectomy? Results from a Japan-Korea-Taiwan multinational survey. AB - BACKGROUND: Serious complications continue to occur in laparoscopic cholecystectomy (LC). The commonly used indicators of surgical difficulty such as the duration of surgery are insufficient because they are surgeon and institution dependent. We aimed to identify appropriate indicators of surgical difficulty during LC. METHODS: A total of 26 Japanese expert LC surgeons discussed using the nominal group technique (NGT) to generate a list of intraoperative findings that contribute to surgical difficulty. Thereafter, a survey was circulated to 61 experts in Japan, Korea, and Taiwan. The questionnaire addressed LC experience, surgical strategy, and perceptions of 30 intraoperative findings listed by the NGT. RESULTS: The response rate of the survey was 100%. There was a statistically significant difference among nations regarding the duration of surgery and adoption rate of safety measures and recognition of landmarks. The criteria for conversion to an open or subtotal cholecystectomy were at the discretion of each surgeon. In contrast, perceptions of the impact of 30 intraoperative findings on surgical difficulty (categorized by factors related to inflammation and additional findings of the gallbladder and other intra-abdominal factors) were consistent among surgeons. CONCLUSIONS: Intraoperative findings are objective and considered to be appropriate indicators of surgical difficulty during LC. PMID- 27490843 TI - Multimodal imaging for nonmelanoma skin cancer margin delineation. AB - BACKGROUND AND OBJECTIVE: Nonmelanoma skin cancer (NMSC) is the most common form of cancer worldwide. The most effective form of treating this cancer is its surgical removal. As NMSC rarely metastasize, its complete excision is often curative. We investigated the potential of combining Terahertz Pulsed Imaging (TPI) with polarization enhanced reflectance optical imaging for the accurate intraoperative delineation of NMSC. MATERIALS AND METHODS: Fresh thick samples with residual cancer were obtained from surgeries. The samples were imaged within two hours using polarization optical and TPI systems without remounting. Analysis of the TPI results was performed in the frequency domain. Co- and cross-polarized optical images were acquired at 410 nm. Superficial optical images were obtained by subtracting cross-polarized from the respective co-polarized images. Terahertz, optical, and histological images were overlaid and compared. RESULTS AND CONCLUSIONS: Our results show that the frequency powers of diseased and normal skin tissues differ significantly at 0.47 THz. While TPI has demonstrated contrast between diseased and normal tissue, it can also highlight normal structures. As TPI alone lacks the resolution necessary to distinguish between tissue types morphologically, polarization optical imaging was used for the inspection of the suspicious areas highlighted by TPI. Combined TPI and optical imaging has the potential for quick intraoperative delineation of cancers. Lasers Surg. Med. 49:319-326, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27490844 TI - Correlation between "hourglass-like fascicular constriction" and idiopathic anterior interosseous nerve palsy. AB - INTRODUCTION: In recent operative cases of anterior interosseous nerve palsy (AINP), hourglass-like fascicular constrictions have been reported. We prospectively investigated the ultrasonographic history of these lesions to better understand the role of this lesion in AINP. METHODS: Seven patients who were diagnosed with idiopathic AINP based on classic clinical findings and had hourglass-like fascicular constrictions found on ultrasonography were included. All but 1 patient selected surgery, and we followed up all patients clinically and with ultrasonography. RESULTS: In the 5 patients treated surgically in whom paralysis recovered to a level greater than M4, postoperative ultrasonography revealed less constriction. The other patient experienced little recovery after surgery, and the severe constriction remained. In a conservatively treated patient, the paralysis recovered completely, and upon ultrasonography, the constriction had lessened. CONCLUSIONS: Although the mechanism is still unknown, hourglass-like fascicular constriction lessened with relief of motor weakness both in operatively and conservatively treated patients. Muscle Nerve 55: 508 512, 2017. PMID- 27490846 TI - Cu,N-codoped Hierarchical Porous Carbons as Electrocatalysts for Oxygen Reduction Reaction. AB - It remains a huge challenge to develop nonprecious electrocatalysts with high activity to substitute commercial Pt catalysts for oxygen reduction reactions (ORR). Here, the Cu,N-codoped hierarchical porous carbon (Cu-N-C) with a high content of pyridinic N was synthesized by carbonizing Cu-containing ZIF-8. Results indicate that Cu-N-C shows excellent ORR electrocatalyst properties. First of all, it nearly follows the four-electron route, and its electron transfer number reaches 3.92 at -0.4 V. Second, both the onset potential and limited current density of Cu-N-C are almost equal to those of a commercial Pt/C catalyst. Third, it exhibits a better half-wave potential (~16 mV) than a commercial Pt/C catalyst. More importantly, the Cu-N-C displays better stability and methanol tolerance than the Pt/C catalyst. All of these good properties are attributed to hierarchical structure, high pyridinic N content, and the synergism of Cu and N dopants. The metal-N codoping strategy can significantly enhance the activity of electrocatalysts, and it will provide reference for the design of novel N-doped porous carbon ORR catalysts. PMID- 27490845 TI - Race and mortality risk after radiation therapy in men treated with or without androgen-suppression therapy for favorable-risk prostate cancer. AB - BACKGROUND: African American (AA) men are more likely than non-AA men to have a comorbid illness that could interact with androgen-deprivation therapy (ADT) and shorten survival. This study assessed the impact that race had on the risk of all cause mortality (ACM) and other-cause mortality (OCM) among men definitively treated for favorable-risk prostate cancer (PC). METHODS: Between 1997 and 2013, 7252 men with low-risk or favorable intermediate-risk PC were treated with brachytherapy with neoadjuvant ADT (n = 1501) or without neoadjuvant ADT (n = 5751) for a 4-month median duration. Cox and Fine-Gray multivariate regressions were used to analyze whether the risk of ACM and OCM increased among AA men versus non-AA men receiving ADT; adjustments were made for the age at brachytherapy, year of brachytherapy, cardiometabolic comorbidity status, risk group, and ADT treatment propensity score. RESULTS: After a median follow-up of 8.04 years, 869 men (12.0%) died: 48 (5.52%) of PC and 821 (94.48%) of other causes. There was a significant association between AA race and an increased risk of both ACM (adjusted hazard ratio [AHR], 1.77; 95% confidence interval [CI], 1.06-2.94; P = .028) and OCM (AHR, 1.86; 95% CI, 1.08-3.19; P = .024) among AA men versus non-AA men who received ADT but not among those who did not receive ADT (AHR for ACM, 1.33; 95% CI, 0.93-1.91; P = .12; AHR for OCM, 1.39; 95% CI, 0.96-2.02; P = .08). CONCLUSIONS: ADT use may shorten survival in AA men with favorable-risk PC; therefore, its reservation for the treatment of higher risk PC, for which level 1 evidence supports its use, should be considered. Cancer 2016;122:3608-14. (c) 2016 American Cancer Society. PMID- 27490847 TI - Market Structure, Financial Dependence and Industrial Growth: Evidence from the Banking Industry in Emerging Asian Economies. AB - In this study, we examine the role of market structure for growth in financially dependent industries from 10 emerging Asian economies over the period of 1995 2011. Our approach departs from existing studies in that we apply four alternative measures of market structure based on structural and non-structural approaches and compare their outcomes. Results indicate that higher bank concentration may slow down the growth of financially dependent industries. Bank competition on the other hand, allows financially dependent industries to grow faster. These findings are consistent across a number of sensitivity checks such as alternative measures of financial dependence, institutional factors (including property rights, quality of accounting standards and bank ownership), and endogeneity consideration. In sum, our study suggests that financially dependent industries grow more in more competitive/less concentrated banking systems. Therefore, regulatory authorities need to be careful while pursuing a consolidation policy for banking sector in emerging Asian economies. PMID- 27490848 TI - Effects of a Soluble Epoxide Hydrolase Inhibitor on Lipopolysaccharide-Induced Acute Lung Injury in Mice. AB - OBJECTIVES: Inflammation plays a key role in the pathogenesis of acute lung injury (ALI). Soluble epoxide hydrolase (sEH) is suggested as a vital pharmacologic target for inflammation. In this study, we determined whether a sEH inhibitor, AUDA, exerts lung protection in lipopolysaccharide (LPS)-induced ALI in mice. METHODS: Male BALB/c mice were randomized to receive AUDA or vehicle intraperitoneal injection 4 h after LPS or phosphate buffered saline (PBS) intratracheal instillation. Samples were harvested 24 h post LPS or PBS administration. RESULTS: AUDA administration decreased the pulmonary levels of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha. Improvement of oxygenation and lung edema were observed in AUDA treated group. AUDA significantly inhibited sEH activity, and elevated epoxyeicosatrienoic acids (EETs) levels in lung tissues. Moreover, LPS induced the activation of nuclear factor (NF)-kappaB was markedly dampened in AUDA treated group. CONCLUSION: Administration of AUDA after the onset of LPS-induced ALI increased pulmonary levels of EETs, and ameliorated lung injury. sEH is a potential pharmacologic target for ALI. PMID- 27490849 TI - A Longitudinal Relationship Between Depressive Symptoms and Development of Metabolic Syndrome: The Coronary Artery Risk Development in Young Adults Study. AB - OBJECTIVE: Despite variability in the burden of elevated depressive symptoms by sex and race and differences in the incidence of metabolic syndrome, few prior studies describe the longitudinal association of depressive symptoms with metabolic syndrome in a diverse cohort. We tested whether baseline and time varying depressive symptoms were associated with metabolic syndrome incidence in black and white men and women from the Coronary Artery Risk Development in Young Adults study. METHODS: Participants reported depressive symptoms using the Center for Epidemiologic Studies Depression Scale at four examinations between 1995 and 2010. At those same examinations, metabolic syndrome was determined. Cox proportional hazards models were used to examine the associations of depressive symptoms on the development of metabolic syndrome in 3208 participants without metabolic syndrome at baseline. RESULTS: For 15 years, the incidence rate of metabolic syndrome (per 10,000 person-years) varied by race and sex, with the highest rate in black women (279.2), followed by white men (241.9), black men (204.4), and white women (125.3). Depressive symptoms (per standard deviation higher) were associated with incident metabolic syndrome in white men (hazard ratio = 1.25, 95% confidence interval = 1.08-1.45) and white women (hazard ratio = 1.17, 95% confidence interval = 1.00-1.37) after adjustment for demographic characteristics and health behaviors. There was no significant association between depression and metabolic syndrome among black men or black women. CONCLUSIONS: Higher depressive symptoms contribute modestly to the onset of metabolic syndrome among white adults. PMID- 27490850 TI - Suggestions to Reduce Clinical Fibromyalgia Pain and Experimentally Induced Pain Produce Parallel Effects on Perceived Pain but Divergent Functional MRI-Based Brain Activity. AB - OBJECTIVE: Hypnotic suggestion is an empirically validated form of pain control; however, the underlying mechanism remains unclear. METHODS: Thirteen fibromyalgia patients received suggestions to alter their clinical pain, and 15 healthy controls received suggestions to alter experimental heat pain. Suggestions were delivered before and after hypnotic induction with blood oxygen level-dependent (BOLD) activity measured concurrently. RESULTS: Across groups, suggestion produced substantial changes in pain report (main effect of suggestion, F2, 312 = 585.8; p < .0001), with marginally larger changes after induction (main effect of induction, F1, 312 = 3.6; p = .060). In patients, BOLD response increased with pain report in regions previously associated with pain, including thalamus and anterior cingulate cortex. In controls, BOLD response decreased with pain report. All changes were greater after induction. Region-of-interest analysis revealed largely linear patient responses with increasing pain report. Control responses, however, were higher after suggestion to increase or decrease pain from baseline. CONCLUSIONS: Based on behavioral report alone, the mechanism of suggestion could be interpreted as largely similar regardless of the induction or type of pain experience. The functional magnetic resonance imaging data, however, demonstrated larger changes in brain activity after induction and a radically different pattern of brain activity for clinical pain compared with experimental pain. These findings imply that induction has an important effect on underlying neural activity mediating the effects of suggestion, and the mechanism of suggestion in patients altering clinical pain differs from that in controls altering experimental pain. Patient responses imply that suggestions altered pain experience via corresponding changes in pain-related brain regions, whereas control responses imply suggestion engaged cognitive control. PMID- 27490851 TI - Association of Depressed Mood With Herpes Simplex Virus-2 Immunoglobulin-G Levels in Pregnancy. AB - OBJECTIVE: Depressed mood is common in pregnancy, is associated with stress, and could result in immune suppression that may lead to latent herpes viral reactivation. This study investigated whether depressed mood is associated with higher herpes viral IgG levels in pregnant women. METHODS: Complete cross sectional data from 247 pregnant women were available for this substudy. The data included demographics, scores on the Perceived Stress Scale and Profile of Mood States (POMS), and a panel of serum IgG levels for human herpesviruses. RESULTS: Only the herpes simplex virus type 2 (HSV-2) (genital herpes) IgG level was associated with Perceived Stress Scale and POMS-Depression/Dejection (POMS-D) score. Hierarchical multiple regression analysis was used to examine the association of POMS-D with herpesviral IgG levels adjusting for demographic variables. In the final model, African American race (beta = .251, p < .001), older age (beta = .199, p = .002), single marital status (beta = -.304, p < .001), and depressed mood (beta = .122, p = .04) were associated with HSV-2 IgG levels. In logistic regression, the strongest correlates of HSV IgG positivity were single marital status, followed by POMS-D scores and African American race. CONCLUSION: Genital herpes is a concern in pregnancy. Antibody titers may indicate asymptomatic viral shedding, viral reactivation, or primary viral infection. Antibody levels may be higher because of the immune changes during pregnancy and potential immune effects of depressed mood causing reactivation of latent HSV-2. PMID- 27490852 TI - Risk for Incident Hypertension Associated With Posttraumatic Stress Disorder in Military Veterans and the Effect of Posttraumatic Stress Disorder Treatment. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) increases cardiovascular disease and cardiovascular mortality risk. Neither the prospective relationship of PTSD to incident hypertension risk nor the effect of PTSD treatment on hypertension risk has been established. METHODS: Data from a nationally representative sample of 194,319 veterans were drawn from the Veterans Administration (VA) roster of United States service men and women. This included veterans whose end of last deployment was from September 2001 to July 2010 and whose first VA medical visit was from October 1, 2001 to January 1, 2009. Incident hypertension was modeled as 3 events: (1) a new diagnosis of hypertension and/or (2) a new prescription for antihypertensive medication, and/or (3) a clinic blood pressure reading in the hypertensive range (>=140/90 mm Hg, systolic/diastolic). Posttraumatic stress disorder diagnosis was the main predictor. Posttraumatic stress disorder treatment was defined as (1) at least 8 individual psychotherapy sessions of 50 minutes or longer during any consecutive 6 months and/or (2) a prescription for selective serotonin reuptake inhibitor medication. RESULTS: Over a median 2.4 year follow-up, the incident hypertension risk independently associated with PTSD ranged from hazard ratio (HR), 1.12 (95% confidence interval [CI], 1.08-1.17; p < .0001) to HR, 1.30 (95% CI, 1.26-1.34; p < .0001). The interaction of PTSD and treatment revealed that treatment reduced the PTSD-associated hypertension risk (e.g., from HR, 1.44 [95% CI, 1.38-1.50; p < .0001] for those untreated, to HR, 1.20 [95% CI, 1.15-1.25; p < .0001] for those treated). CONCLUSIONS: These results indicate that reducing the long-term health impact of PTSD and the associated costs may require very early surveillance and treatment. PMID- 27490854 TI - Lymphocyte enrichment using CD81-targeted immunoaffinity matrix. AB - In mass cytometry, the isolation of pure lymphocytes is very important to obtain reproducible results and to shorten the time spent on data acquisition. To prepare highly purified cell suspensions of peripheral blood lymphocytes for further analysis on mass cytometer, we used the new CD81+ immune affinity chromatography cell isolation approach. Using 21 metal conjugated antibodies in a single tube we were able to identify all basic cell subsets and compare their relative abundance in final products obtained by density gradient (Ficoll-Paque) and immune affinity chromatography (CD81+ T-catchTM) isolation approach. We show that T-catch isolation approach results in purer final product than Ficoll-Paque (P values 0.0156), with fewer platelets bound to target cells. As a result acquisition time of 105 nucleated cells was 3.5 shorter. We then applied unsupervised high dimensional analysis viSNE algorithm to compare the two isolation protocols, which allowed us to evaluate the contribution of unsupervised analysis over supervised manual gating. ViSNE algorithm effectively characterized almost all supervised cell subsets. Moreover, viSNE uncovered previously overseen cell subsets and showed inaccuracies in MaxparTM Human peripheral blood phenotyping panel kit recommended gating strategy. These findings emphasize the use of unsupervised analysis tools in parallel with conventional gating strategy to mine the complete information from a set of samples. They also stress the importance of the impurity removal to sensitively detect rare cell populations in unsupervised analysis. (c) 2016 International Society for Advancement of Cytometry. PMID- 27490855 TI - Current Guidelines for the Diagnosis and Management of Hepatocellular Carcinoma: A Comparative Review. AB - OBJECTIVE: The purpose of this article is to review aspects of guidelines pertinent to radiologists involved in the diagnosis or treatment of hepatocellular carcinoma. CONCLUSION: Early diagnosis and treatment of hepatocellular carcinoma are important because only 10% of patients meet the criteria for curative therapy at the time of diagnosis. Several organizations have developed guidelines for screening, diagnosis, and treatment of hepatocellular carcinoma. Radiologists play a pivotal role in every aspect of these guidelines. PMID- 27490853 TI - Low-Grade Inflammation and Ambulatory Cortisol in Adolescents: Interaction Between Interviewer-Rated Versus Self-Rated Acute Stress and Chronic Stress. AB - OBJECTIVE: To determine whether the association between self-rated or interviewer rated recent acute stress exposures and low-grade inflammation and daily cortisol production in adolescents is moderated by chronic stress ratings. METHODS: Acute and chronic stress exposures were assessed in 261 adolescents aged 13 to 16 years using a semistructured life stress interview. The negative impact of acute stressors was independently rated by both adolescents (self-rated) and interviewers (interviewer-rated). Markers of inflammation (interleukin (IL)-6, IL 1ra, C-reactive protein) were measured from peripheral blood samples obtained via antecubital venipuncture. Participants collected 4 saliva samples at home on each of 6 consecutive days for the analysis of diurnal salivary cortisol profiles. RESULTS: There were no main effects of acute stressors (self- and interviewer rated) and chronic family or peer stress on adolescent inflammation markers and cortisol (p values > .10). However, the interaction between interviewer-rated acute stress and chronic family stress was significantly associated with adolescent inflammation markers (IL-6, IL-1ra). Specifically, as chronic family stress increased, the association between acute stressor impact (interviewer rated) and inflammation markers became more positive (IL-6 (B = .054, SE = .023, p = .022); IL-1ra (B = .030, SE = .014, p = .034)). Interactions between self rated acute stress and chronic family stress were not associated with any biological measures (p values > .10). Interactions between acute stressor impact (both self- and interviewer-rated) and chronic peer stress were also not significantly associated with any biological measures (p values > .05). CONCLUSIONS: Among adolescents, interviewer-based ratings of acute stressor impact may allow for better prediction of health-relevant inflammation markers than adolescents' own ratings. PMID- 27490856 TI - A Hidden Portrait by Edgar Degas. AB - The preservation and understanding of cultural heritage depends increasingly on in-depth chemical studies. Rapid technological advances are forging connections between scientists and arts communities, enabling revolutionary new techniques for non-invasive technical study of culturally significant, highly prized artworks. We have applied a non-invasive, rapid, high definition X-ray fluorescence (XRF) elemental mapping technique to a French Impressionist painting using a synchrotron radiation source, and show how this technology can advance scholarly art interpretation and preservation. We have obtained detailed technical understanding of a painting which could not be resolved by conventional techniques. Here we show 31.6 megapixel scanning XRF derived elemental maps and report a novel image processing methodology utilising these maps to produce a false colour representation of a "hidden" portrait by Edgar Degas. This work provides a cohesive methodology for both imaging and understanding the chemical composition of artworks, and enables scholarly understandings of cultural heritage, many of which have eluded conventional technologies. We anticipate that the outcome from this work will encourage the reassessment of some of the world's great art treasures. PMID- 27490857 TI - Systems Approaches and Big Data in Molecular Informatics. PMID- 27490858 TI - PseDNA-Pro: DNA-Binding Protein Identification by Combining Chou's PseAAC and Physicochemical Distance Transformation. AB - Identification of DNA-binding proteins is an important problem in biomedical research as DNA-binding proteins are crucial for various cellular processes. Currently, the machine learning methods achieve the-state-of-the-art performance with different features. A key step to improve the performance of these methods is to find a suitable representation of proteins. In this study, we proposed a feature vector composed of three kinds of sequence-based features, including overall amino acid composition, pseudo amino acid composition (PseAAC) proposed by Chou and physicochemical distance transformation. These features not only consider the sequence composition of proteins, but also incorporate the sequence order information of amino acids in proteins. The feature vectors were fed into Support Vector Machine (SVM) for DNA-binding protein identification. The proposed method is called PseDNA-Pro. Experiments on stringent benchmark datasets and independent test datasets by using the Jackknife test showed that PseDNA-Pro can achieve an accuracy of higher than 80 %, outperforming several state-of-the-art methods, including DNAbinder, DNA-Prot, and iDNA-Prot. These results indicate that the combination of various features for DNA-binding protein prediction is a suitable approach, and the sequence-order information among residues in proteins is relative for discrimination. For practical applications, a web-server of PseDNA-Pro was established, which is available from http://bioinformatics.hitsz.edu.cn/PseDNA-Pro/. PMID- 27490859 TI - Illuminating Flash Point: Comprehensive Prediction Models. AB - Flash point is an important property of chemical compounds that is widely used to evaluate flammability hazard. However, there is often a significant gap between the demand for experimental flash point data and their availability. Furthermore, the determination of flash point is difficult and costly, particularly for some toxic, explosive, or radioactive compounds. The development of a reliable and widely applicable method to predict flash point is therefore essential. In this paper, the construction of a quantitative structure - property relationship model with excellent performance and domain of applicability is reported. It uses the largest data set to date of 9399 chemically diverse compounds, with flash point spanning from less than -130 degrees C to over 900 degrees C. The model employs only computed parameters, eliminating the need for experimental data that some earlier computational models required. The model allows accurate prediction of flash point for a broad range of compounds that are unavailable or not yet synthesized. This single model with a very broad range of chemical and flash point applicability will allow accurate predictions of this important property to be made for a broad range of new materials. PMID- 27490861 TI - A Machine Learning Approach to Explain Drug Selectivity to Soluble and Membrane Protein Targets. AB - Improved understanding of the forces that determine drug specificity to their targets is important for drug design and discovery, as well as for gaining knowledge about molecular recognition. Here, we present a machine learning approach that includes all approved drugs with a known protein target. The drugs were characterized using easily interpretable physico-chemical descriptors. Employing the Random Forest method, we were able to predict whether a drug binds to a soluble or membrane protein with an average accuracy of 84 % and an average area under curve of 0.91. The high average performance suggests that there exist some general physico-chemical differences between drugs that bind to membrane and soluble protein targets. Variable importance measures in combination with permutation tests were used to find the most influential descriptors. This resulted in six outstanding descriptors, that all involve drug flexibility and lipophilicity, suggesting that drugs binding to membrane protein targets are in general more flexible and lipophilic, and conversely, drugs binding to soluble protein targets are more rigid and hydrophilic. With the notion that ligands in general are blueprints of their protein pockets, we may also draw general conclusions about the protein-pocket properties which may add to the understanding of molecular recognition. PMID- 27490860 TI - 3-Chlorotyramine Acting as Ligand of the D2 Dopamine Receptor. Molecular Modeling, Synthesis and D2 Receptor Affinity. AB - We synthesized and tested 3-chlorotyramine as a ligand of the D2 dopamine receptor. This compound displayed a similar affinity by this receptor to that previously reported for dopamine. In order to understand further the experimental results we performed a molecular modeling study of 3-chlorotyramine and structurally related compounds. By combining molecular dynamics simulations with semiempirical (PM6), ab initio and density functional theory calculations, a simple and generally applicable procedure to evaluate the binding energies of these ligands interacting with the D2 dopamine receptors is reported here. These results provided a clear picture of the binding interactions of these compounds from both structural and energetic view points. A reduced model for the binding pocket was used. This approach allowed us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the Quantum Theory of Atoms in Molecules (QTAIM) technique. Molecular aspects of the binding interactions between ligands and the D2 dopamine receptor are discussed in detail. A good correlation between the relative binding energies obtained from theoretical calculations and experimental IC50 values was obtained. These results allowed us to predict that 3-chlorotyramine possesses a significant affinity by the D2 -DR. Our theoretical predictions were experimentally corroborated when we synthesized and tested 3-chlorotyramine which displayed a similar affinity by the D2 -DR to that reported for DA. PMID- 27490862 TI - Predictive QSPR Modelling for the Second Virial Coefficient of the Pure Organic Compounds. AB - In this article we developed a system of the predictive models for the second virial coefficients of the pure compounds. Second virial coefficient is the property derived from the virial equation of state, and is of particular interest as it describes pair intermolecular interactions. The two-layer QSPR models were developed, which exploited the well-known physical equations and allowed us to include this information into traditional QSPR methodology. This shows some new perspectives for work with temperature-dependent properties. It was shown that 2D descriptors can be successfully used for modeling of complex thermodynamic properties like virial coefficients. PMID- 27490863 TI - Multi-Server Approach for High-Throughput Molecular Descriptors Calculation based on Multi-Linear Algebraic Maps. AB - The present report introduces a novel module of the QuBiLS-MIDAS software for the distributed computation of the 3D Multi-Linear algebraic molecular indices. The main motivation for developing this module is to deal with the computational complexity experienced during the calculation of the descriptors over large datasets. To accomplish this task, a multi-server computing platform named T arenal was developed, which is suited for institutions with many workstations interconnected through a local network and without resources particularly destined for computation tasks. This new system was deployed in 337 workstations and it was perfectly integrated with the QuBiLS-MIDAS software. To illustrate the usability of the T-arenal platform, performance tests over a dataset comprised of 15 000 compounds are carried out, yielding a 52 and 60 fold reduction in the sequential processing time for the 2-Linear and 3-Linear indices, respectively. Therefore, it can be stated that the T-arenal based distribution of computation tasks constitutes a suitable strategy for performing high-throughput calculations of 3D Multi-Linear descriptors over thousands of chemical structures for posterior QSAR and/or ADME-Tox studies. PMID- 27490864 TI - Sequential kidney-liver transplantation from the same living donor for lecithin cholesterol acyl transferase deficiency. AB - BACKGROUND: Lecithin cholesterol acyl transferase (LCAT) deficiency is a rare autosomal recessive disorder of lipoprotein metabolism that results in end-stage renal disease (ESRD) necessitating transplantation. As LCAT is produced in the liver, combined kidney and liver transplantation was proposed to cure the clinical syndrome of LCAT deficiency. METHODS: A 29-year-old male with ESRD secondary to LCAT deficiency underwent a sequential kidney-liver transplantation from the same living donor (LD). One year following the kidney transplant, auxiliary partial orthotopic liver transplant (APOLT) of a left lateral segment from the same donor was performed. RESULTS: At 5 years follow-up, there have been no major complications, readmissions, or rejection episodes. Serum lipid abnormalities recurred within the first year, but liver and kidney allograft function remains intact. CONCLUSION: Few cases of sequential transplantation from the same LD have been performed in adults. This is the first APOLT and multi organ transplant performed for LCAT deficiency. Sequential organ transplant from the same LD for ESRD secondary to a metabolic disorder of the liver is feasible in adults and should be further investigated. PMID- 27490865 TI - Failure of the IDA in FRET Systems at Close Inter-Dye Distances Is Moderated by Frequent Low kappa(2) Values. AB - Forster resonance energy transfer (FRET) is analyzed in terms of distance- and orientation-dependent interactions between the transition dipole moments of the involved donor and acceptor molecules. However, the ideal dipole approximation (IDA) is known to fail at short donor-acceptor distances. In this work, we model FRET in a Cy5- and Alexa Fluor 488-labeled double-stranded RNA by means of combined molecular dynamics (MD) simulations and quantum-chemical calculations involving the IDA as well as the more sophisticated monomer transition density (MTD) approach. To this end, the relaxed ground-state geometries of the dyes were fitted to the MD-based structures. Although substantial deviations between IDA and MTD results can be observed for individual snapshots, the statistical impact of the failure on the FRET rates is negligible in the chosen examples. Our results clearly demonstrate that the IDA-based Forster model can still be applied to systems with small donor-acceptor distances, provided that the dyes are not trapped in arrangements with a high IDA failure and that the distribution of the relative transition dipole orientations is fairly isotropic. PMID- 27490867 TI - Dehydration of Methanediol in Aqueous Solution: An ONIOM(QM/MM) Study. AB - We used ONIOM(QM/MM) method to examine the dehydration of a methanediol in aqueous solution. A methanediol and a small number of water molecules in the proximity of the methanediol are calculated with quantum mechanics (QM), while a number of water molecules far from the methanediol are calculated with molecular mechanics (MM). A molecular dynamical simulation shows that 12 water molecules are located within the hydration shell of a methanediol. The energy barrier for the dehydration of a methanediol decreases when we increase the number of water molecules in the QM region and converges toward a finite value when 12 water molecules are included in the QM region. This indicates a significant effect of water molecules within the hydration shell on the dehydration process of a methanediol in aqueous solution. The dehydration rate calculated with the ONIOM(QM/MM) method agrees well with that obtained from a laboratory experiment. PMID- 27490868 TI - Versatility of peptide nucleic acids (PNAs): role in chemical biology, drug discovery, and origins of life. AB - This review briefly discussed nomenclature, synthesis, chemistry, and biophysical properties of a plethora of PNA derivatives reported since the discovery of aegPNA. Different synthetic methods and structural analogs of PNA synthesized till date were also discussed. An insight was gained into various chemical, physical, and biological properties of PNA which make it preferable over all other classes of modified nucleic acid analogs. Thereafter, various approaches with special attention to the practical constraints, characteristics, and inherent drawbacks leading to the delay in the development of PNA as gene therapeutic drug were outlined. An explicit account of the successful application of PNA in different areas of research such as antisense and antigene strategies, diagnostics, molecular probes, and so forth was described along with the current status of PNA as gene therapeutic drug. Further, the plausibility of the existence of PNA and its role in primordial chemistry, that is, origin of life was explored in an endeavor to comprehend the mystery and open up its deepest secrets ever engaging and challenging the human intellect. We finally concluded it with a discussion on the future prospects of PNA technology in the field of therapeutics, diagnostics, and origin of life. PMID- 27490869 TI - Negative-Pressure Wound Therapy in Acute Traumatic and Surgical Wounds in Orthopaedics. PMID- 27490870 TI - Treatment of Proximal Humeral Fractures: A Critical Analysis Review. PMID- 27490871 TI - Treatment of Traumatic Segmental Long-Bone Defects: A Critical Analysis Review. PMID- 27490873 TI - Tunnel Placement for the ACL During Reconstructive Surgery of the Knee: A Critical Analysis Review. PMID- 27490872 TI - Pathogenesis and Treatment of Dupuytren Disease. PMID- 27490875 TI - From the Editor. PMID- 27490874 TI - Advances in organ preservation for transplantation. AB - Organ transplantation provides the best available therapy for a myriad of medical conditions, including end-stage renal disease, hepatic failure and type I diabetes mellitus. The current clinical reality is, however, that there is a significant shortage of organs available for transplantation with respect to the number of patients on organ waiting lists. As such, methods to increase organ supply have been instituted, including improved donor management, organ procurement and preservation strategies, living organ donation, transplantation education and the increased utilization of donation after circulatory death and expanded criteria donors. In particular, especially over the last decade, we have witnessed a significant change in the way donor organs are preserved, away from static cold storage methods to more dynamic techniques centred on machine perfusion (MP). This review highlights the current state and future of organ preservation for transplantation, focusing on both abdominal and thoracic organs. In particular, we focus on MP preservation of renal, hepatic, pancreatic, cardiac and lung allografts, also noting relevant advances in Australasia. MP of organs after procurement holds considerable promise, and has the potential to significantly improve graft viability and function post-transplantation, especially in donors in whom acceptance criteria have been expanded. PMID- 27490876 TI - Marginalization: A Revisitation With Integration of Scholarship on Globalization, Intersectionality, Privilege, Microaggressions, and Implicit Biases. AB - In 1994, the concept of marginalization was explored in an article in Advances in Nursing Science. This is a revisitation of the concept incorporating new scholarship. This update is founded on feminism, postcolonialism, critical race theory, and discourse deconstruction, all viewpoints that have been explicated in nursing. The purpose of this analysis is to look at new scholarship and concepts useful to applying marginalization in nursing knowledge development from the standpoint of Bourdieu's macro, meso, and micro levels. New scholarship includes globalization, intersectionality, privilege, microaggressions, and implicit bias. Implications for decreasing health disparities through this new scholarship are discussed. PMID- 27490877 TI - Social Justice as a Lens for Understanding Workplace Mistreatment. AB - Workplace mistreatment can be viewed as a social injustice that prohibits one from achieving optimal well-being. Cognitive and interpersonal skills required of nurses can be impacted by workplace mistreatment, thus extending injustices by violating the rights of patients to optimal care. The purpose of this article is to view workplace mistreatment through the lens of Powers and Faden's theory of social justice. Workplace mistreatment is explored through the 6 dimensions of well-being, including health, personal security, reasoning, respect, attachment, and self-determination, identified in the theory. The implications for practice and policy are discussed and recommendations for research made. PMID- 27490878 TI - Mixed-Methods Research in the Discipline of Nursing. AB - In this review article, we examined the prevalence and characteristics of 294 mixed-methods studies in the discipline of nursing. Creswell and Plano Clark's typology was most frequently used along with concurrent timing. Bivariate statistics was most often the highest level of statistics reported in the results. As for qualitative data analysis, content analysis was most frequently used. The majority of nurse researchers did not specifically address the purpose, paradigm, typology, priority, timing, interaction, or integration of their mixed methods studies. Strategies are suggested for improving the design, conduct, and reporting of mixed-methods studies in the discipline of nursing. PMID- 27490879 TI - Using Theory Integration to Explore Complex Health Problems. AB - Although nursing leaders call for theory utilization in research, use remains low within the discipline. The purpose of this article is to explore the application of interdisciplinary integration of models and theories to nursing research. An example of theory integration for the purposes of guiding a study relevant to school nursing is described. A conceptual-theoretical-empirical structure based on the Neuman's systems model, a nursing theory, integrated with the social communication model of pain, a psychology model, was developed to guide the study to examine pain assessment for schoolchildren with intellectual and developmental disabilities. PMID- 27490880 TI - A Framework of Complex Adaptive Systems: Parents As Partners in the Neonatal Intensive Care Unit. AB - Advances in neonatal care are allowing for increased infant survival; however, neurodevelopmental complications continue. Using a complex adaptive system framework, a broad analysis of the network of agents most influential to vulnerable infants in the neonatal intensive care unit (NICU) is presented: parent, nurse, and organization. By exploring these interconnected relationships and the emergent behaviors, a model of care that increases parental caregiving in the NICU is proposed. Supportive parent caregiving early in an infant's NICU stay has the potential for more sensitive caregiving and enhanced opportunities for attachment, perhaps positively impacting neurodevelopment. PMID- 27490881 TI - Nurses' Knowledge About Transgender Patient Care: A Qualitative Study. AB - This study explored practicing nurses' knowledge of the needs of transgender patients. Structured interviews were conducted with 268 nurses in the San Francisco Bay Area. This study focused on the responses to 1 item in the 16-item interview, "Describe health care issues that are particular to transgender patients." Three themes emerged from the data: discomfort, transition, and harsh consequences of being transgender. These findings revealed nurses' discomfort and lack of knowledge about transgender people and their health care needs. Nursing curricula must challenge the gender binary to better prepare nurses to provide quality care for patients of all genders. PMID- 27490882 TI - Teen Mothers' Experience of Intimate Partner Violence: A Metasynthesis. AB - Pregnant and parenting teens suffer higher rates of intimate partner violence (IPV) than older mothers. This qualitative metasynthesis explores teen mothers' experience with IPV during pregnancy and postpartum. Organized by the metaphor of a web, findings highlight how pervasive violence during childhood contributes to teen pregnancy and the risk of IPV as violence is normalized. The web constricts through the partner's control as violence emerges or worsens with pregnancy. Young mothers become increasingly isolated, and live with the physical and psychological consequences of IPV. Trauma-informed nursing practice is needed to support teen mothers in violent intimate relationships to spin a new web. PMID- 27490883 TI - Interpretation of Hospital Nurse Fatigue Using Latent Profile Analysis. AB - There has been a lack of consensus in the literature related to the conceptualization, definition, and measurement of hospital nurse fatigue. Using latent profile analysis, the Hospital Nurse Force Theory provided a conceptual format to identify 3 profiles of nurse fatigue from subjective reports of hospital patient care nurses in a survey cohort. All fatigue and adaptation variables demonstrated significant inverse relationships. Describing nurse fatigue in profiles that include measures of acute, chronic, physical, and mental fatigue dimensions provided a new and expanded view of nurse fatigue to monitor trends comprehensively and evaluate fatigue risk management strategies. PMID- 27490884 TI - Internet Recruitment of Asian American Breast Cancer Survivors. AB - The purpose of this article is to identify practical issues in Internet recruitment of racial/ethnic minorities by analyzing an Internet intervention study conducted with Asian American breast cancer survivors, and to propose directions for recruitment of racial/ethnic minorities for future Internet research. Six practical issues were identified: (a) a relatively fewer number of Internet communities/groups; (b) hindrances in establishing authenticity; PMID- 27490886 TI - Understanding Influence within the Context of Nursing: Development of the Adams Influence Model Using Practice, Research, and Theory. AB - Acquiring influence, and knowing how to use it, is a required competency for nurse leaders, yet the concept of influence and how it works is not well described in the nursing literature. In this article, the authors examine what is known about influence and present an influence model specific to nurse leaders. The Adams Influence Model was developed through an iterative process and is based on a comprehensive review of the influence literature, expert commentary, multiple pilot studies, evaluation of nursing theories, and validation by an external data source. Rather than defining "how to" influence, the model serves as a guide for personal reflection, helping nurse leaders understand and reflect on the influence process and factors, tactics, and strategies they can use when seeking to influence others. PMID- 27490885 TI - Clinical Growth: An Evolutionary Concept Analysis. AB - Clinical growth is an essential component of nursing education, although challenging to evaluate. Considering the paradigm shift toward constructivism and student-centered learning, clinical growth requires an examination within contemporary practices. A concept analysis of clinical growth in nursing education produced defining attributes, antecedents, and consequences. Attributes included higher-level thinking, socialization, skill development, self reflection, self-investment, interpersonal communication, and linking theory to practice. Identification of critical attributes allows educators to adapt to student-centered learning in the clinical environment. These findings allow educators to determine significant research questions, develop situation-specific theories, and identify strategies to enhance student learning in the clinical environment. PMID- 27490887 TI - Atypical Fractures of the Femur: Evaluation and Treatment. PMID- 27490888 TI - Association Between Intervertebral Disc Degeneration and Cigarette Smoking: Clinical and Experimental Findings. PMID- 27490889 TI - Use of Locking Plates in Orthopaedic Trauma Surgery. PMID- 27490890 TI - Acute Fractures of the Tarsal Navicular: A Critical Analysis Review. PMID- 27490891 TI - Spinopelvic Fixation in Complex Sacral Fractures. PMID- 27490892 TI - The Metabolic Responses to L-Glutamine of Livers from Rats with Diabetes Types 1 and 2. AB - There are several claims about the beneficial effects of supplementing L glutamine to both type 1 and type 2 diabetes. The purpose of the present study was to provide detailed knowledge about the fate of this amino acid in the liver, the first organ that receives the compound when ingested orally. The study was done using the isolated perfused rat liver, an experimental system that preserves the microcirculation of the organ and that allows to measured several parameters during steady-state and pre steady-state conditions. L-Glutamine was infused in the portal vein (5 mM) and several parameters were monitored. Livers from type 1 diabetic rats showed an accelerated response to L-glutamine infusion. In consequence of this accelerated response livers from type 1 diabetic rats presented higher rates of ammonia, urea, glucose and lactate output during the first 25-30 minutes following L-glutamine infusion. As steady-state conditions approached, however, the difference between type 1 diabetes and control livers tended to disappear. Measurement of the glycogen content over a period of 100 minutes revealed that, excepting the initial phase of the L-glutamine infusion, the increased glucose output in livers from type 1 diabetic rats was mainly due to accelerated glycogenolysis. Livers from type 2 diabetic rats behaved similarly to control livers with no accelerated glucose output but with increased L-alanine production. L-Alanine is important for the pancreatic beta-cells and from this point of view the oral intake of L-glutamine can be regarded as beneficial. Furthermore, the lack of increased glucose output in livers from type 2 diabetic rats is consistent with observations that even daily L-glutamine doses of 30 g do not increase the glycemic levels in well controlled type 2 diabetes patients. PMID- 27490893 TI - Structural Implications on the Properties of Self-Assembling Supramolecular Hosts for Fluorescent Guests. AB - Nine amphiphilic macromolecules with decyl and oligo(ethylene glycol) side chains, randomly distributed along a common poly(methacrylate) backbone, were synthesized from the radical copolymerization of appropriate methacrylate monomers. The resulting amphiphilic constructs differ in (1) the ratio between their hydrophobic and hydrophilic components, (2) the length of their oligo(ethylene glycol) chains, and/or (3) the molecular weight. When the ratio between hydrophobic and hydrophilic segments is comprised between 6:1 and 1:2, the macromolecules assemble spontaneously into particles with nanoscaled dimensions in neutral buffer and capture hydrophobic borondipyrromethene chromophores in their interior. However, the critical concentration required for the assembly of these supramolecular hosts as well as their hydrodynamic diameter, supramolecular weight, and number of constituent macromolecular building blocks all vary monotonically with the ratio between hydrophobic and hydrophilic components. Specifically, the critical concentration decreases and the other three parameters increase as the relative hydrophobic content raises. Furthermore, an increase in the relative hydrophobic content also discourages interchromophoric interactions between entrapped guests in both ground and excited states as well as delays access of potential quenchers. In fact, these observations demonstrate that the hydrophobic components must be in excess over their hydrophilic counterparts for optimal supramolecular hosts to assemble. Indeed, a ratio of 6:1 between the numbers of decyl and oligo(ethylene glycol) side chains appears to be ideal for this particular structural design. Under these conditions, supramolecular hosts assemble spontaneously even at relatively low polymer concentrations and their fluorescent guests do not escape into the bulk aqueous solution, despite the reversibility of the noncovalent interactions holding the supramolecular container together. Thus, these systematic investigations provide invaluable structural guidelines to design self-assembling supramolecular hosts with optimal composition for the effective encapsulation of fluorescent guests and can lead to ideal delivery vehicles for the transport of imaging probes to target locations in biological samples. PMID- 27490894 TI - Taking advanced endovascular techniques out of the hospital: Ready for prime time? PMID- 27490895 TI - Redundancy and specificity in jasmonate signalling. AB - Jasmonates (JAs) are essential phytohormones regulating plant development and environmental adaptation. Many components of the JA-signalling pathway have been identified. However, our insight into the mechanisms by which a single bioactive JA hormone can regulate a myriad of physiological processes and provide specificity in the response remains limited. Recent findings on molecular components suggest that, despite apparent redundancy, specificity is achieved by (1) distinct protein-protein interactions forming unique JAZ/transcription factor complexes, (2) discrete spatiotemporal expression of specific components, (3) variable hormone thresholds for the formation of multiple JA receptor complexes and (4) integration of several signals by JA-pathway components. The molecular modularity that is thereby created enables a single bioactive hormone to specifically modulate multiple JA-outputs in response to different environmental and developmental cues. PMID- 27490896 TI - Renal Sympathetic Denervation in Rats Ameliorates Cardiac Dysfunction and Fibrosis Post-Myocardial Infarction Involving MicroRNAs. AB - BACKGROUND The role of renal sympathetic denervation (RSD) in ameliorating post myocardial infarction (MI) left ventricular (LV) fibrosis via microRNA-dependent regulation of connective tissue growth factor (CTGF) remains unknown. MATERIAL AND METHODS MI and RSD were induced in Sprague-Dawley rats by ligating the left coronary artery and denervating the bilateral renal nerves, respectively. Norepinephrine, renin, angiotensin II and aldosterone in plasma, collagen, microRNA21, microRNA 101a, microRNA 133a and CTGF in heart tissue, as well as cardiac function were evaluated six weeks post-MI. RESULTS In the RSD group, parameters of cardiac function were significantly improved as evidenced by increased LV ejection fraction (p<0.01), LV end-systolic diameter (p<0.01), end diastolic diameter (p<0.05), LV systolic pressure (p<0.05), maximal rate of pressure rise and decline (dP/dtmax and dP/dtmin, p<0.05), and decreased LV end diastolic pressure (p<0.05) when compared with MI rats. Further, reduced collagen deposition in peri-infarct myocardium was observed in RSD-treated rats along with higher microRNA101a and microRNA133a (p<0.05) and lower microRNA21 expression (p<0.01) than in MI rats. CTGF mRNA and protein levels were decreased in LV following RSD (p<0.01), accompanied by decreased expression of norepinephrine, renin, angiotensin II and aldosterone in plasma (p<0.05) compared with untreated MI rats. CONCLUSIONS The potential therapeutic effects of RSD on post-MI LV fibrosis may be partly mediated by inhibition of CTGF expression via upregulation of microRNA 101a and microRNA 133a and downregulation of microRNA21. PMID- 27490897 TI - Elevated expression of human papillomavirus antigen in brain tissue of patients with Rasmussen's encephalitis. AB - OBJECTS: To investigate the expression of human papillomavirus (HPV)-specific antigen in the brain tissue of patients with Rasmussen's Encephalitis (RE) and its possible link to the clinical manifestation of RE. METHODS: The correlation between RE and HPV antigen expression in brain tissue sections was investigated using immunohistochemical (IHC) staining, pathological examination, MRI and clinical manifestations. RESULTS: HPV antigen expression was elevated in three out of four patients with RE, whereas there were no detectable HPV antigens in six control patients. Significant staining for HPV antigen was located mainly around or in the nucleus and cytoplasm of neurons. Among these RE patients, three with elevated expression of HPV antigens had obvious hemisphere atrophy, whereas the patient with negative staining for HPV antigens had mild atrophy. CONCLUSIONS: Elevated expression of HPV antigens was observed in the brain tissue of RE patients, which may correlate with hemisphere atrophy. Thus, our results may suggest that HPV infection or being a carrier of HPV may play a role in the initiation and progression of RE. PMID- 27490898 TI - Glycyrrhizin ameliorates oxidative stress and inflammation in hippocampus and olfactory bulb in lithium/pilocarpine-induced status epilepticus in rats. AB - Glycyrrhizin (GL) is a triterpene present in the roots and rhizomes of Glycyrrhiza glabra that has anti-inflammatory, hepatoprotective and neuroprotective effects. Recently, it was demonstrated that GL produced neuroprotective effects on the postischemic brain as well as on the kainic acid injury model in rats. In addition to this, GL also prevented excitotoxic effects on primary cultures. The aims of the present study were to evaluate GL scavenging properties and to investigate GL's effect on oxidative stress and inflammation in the lithium/pilocarpine-induced seizure model in two cerebral regions, hippocampus and olfactory bulb, at acute time intervals (3 or 24h) after status epilepticus (SE). Fluorometric methods showed that GL scavenged three reactive oxygen species: hydrogen peroxide, peroxyl radicals and superoxide anions. In contrast, GL was unable to scavenge peroxynitrite, hydroxyl radicals, singlet oxygen and 2,2-diphenil-1-picrylhydrazyl (DPPH) radicals suggesting that GL is a weak scavenger. Additionally, administration of GL (50mg/kg, i.p.) 30min before pilocarpine administration significantly suppressed oxidative stress. Moreover, malondialdehyde levels were diminished and glutathione levels were maintained at control values in both cerebral regions at 3 and 24 after SE. At 24h after SE, glutathione S-transferase and superoxide dismutase activity increased in the hippocampus, while both glutathione reductase and glutathione peroxidase activity were unchanged in the olfactory bulb at that time. In addition, GL suppressed the induction of the proinflammatory cytokines interleukin-1 beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) in both cerebral regions evaluated. These results suggest that GL confers protection against pilocarpine damage via antioxidant and anti-inflammatory effects. PMID- 27490899 TI - Sex determination by three-dimensional geometric morphometrics of craniofacial form. AB - SUMMARY: The purpose of the present study is to define which regions of the cranium, the upper-face, the orbits and the nasal are the most sexually dimorphic, by using three-dimensional geometric morphometric methods, and investigate the effectiveness of this method in determining sex from the shape of these regions. The study sample consisted of 176 crania of known sex (94 males, 82 females) belonging to individuals who lived in Greece during the 20(th) century. The three-dimensional co-ordinates of 31 ecto-cranial landmarks were digitized using a MicroScribe 3DX contact digitizer. Goodall's F-test was performed in order to compare statistical differences in shape between males and females. Generalized Procrustes Analysis (GPA) was used to obtain size and shape variables for statistical analysis. Shape, Size and Form analyses were carried out by logistic regression and discriminant function analysis. The results indicate that there are shape differences between the sexes in the upper-face and the orbits. The highest shape classification rate was obtained from the upper face region. The centroid size of the caraniofacial and the orbital regions was smaller in females than males. Moreover, it was found that size is significant for sexual dimorphism in the upper-face region. As anticipated, the classification accuracy improves when both size and shape are combined. The findings presented here constitute a firm basis upon which further research can be conducted. PMID- 27490901 TI - A Scheduling Algorithm for Cloud Computing System Based on the Driver of Dynamic Essential Path. AB - To solve the problem of task scheduling in the cloud computing system, this paper proposes a scheduling algorithm for cloud computing based on the driver of dynamic essential path (DDEP). This algorithm applies a predecessor-task layer priority strategy to solve the problem of constraint relations among task nodes. The strategy assigns different priority values to every task node based on the scheduling order of task node as affected by the constraint relations among task nodes, and the task node list is generated by the different priority value. To address the scheduling order problem in which task nodes have the same priority value, the dynamic essential long path strategy is proposed. This strategy computes the dynamic essential path of the pre-scheduling task nodes based on the actual computation cost and communication cost of task node in the scheduling process. The task node that has the longest dynamic essential path is scheduled first as the completion time of task graph is indirectly influenced by the finishing time of task nodes in the longest dynamic essential path. Finally, we demonstrate the proposed algorithm via simulation experiments using Matlab tools. The experimental results indicate that the proposed algorithm can effectively reduce the task Makespan in most cases and meet a high quality performance objective. PMID- 27490900 TI - Limited Genetic Connectivity between Gorgonian Morphotypes along a Depth Gradient. AB - Gorgonian species show a high morphological variability in relation to the environment in which they live. In coastal areas, parameters such as temperature, light, currents, and food availability vary significantly with depth, potentially affecting morphology of the colonies and the structure of the populations, as well as their connectivity patterns. In tropical seas, the existence of connectivity between shallow and deep populations supported the hypothesis that the deep coral reefs could potentially act as (reproductive) refugia fostering re colonization of shallow areas after mortality events. Moreover, this hypothesis is not so clear accepted in temperate seas. Eunicella singularis is one of the most common gorgonian species in Northwestern Mediterranean Sea, playing an important role as ecosystem engineer by providing biomass and complexity to the coralligenous habitats. It has a wide bathymetric distribution ranging from about 10 m to 100 m. Two depth-related morphotypes have been identified, differing in colony morphology, sclerite size and shape, and occurrence of symbiotic algae, but not in mitochondrial DNA haplotypes. In the present study the genetic structure of E. singularis populations along a horizontal and bathymetric gradient was assessed using microsatellites and ITS1 sequences. Restricted gene flow was found at 30-40 m depth between the two Eunicella morphotypes. Conversely, no genetic structuring has been found among shallow water populations within a spatial scale of ten kilometers. The break in gene flow between shallow and deep populations contributes to explain the morphological variability observed at different depths. Moreover, the limited vertical connectivity hinted that the refugia hypothesis does not apply to E. singularis. Re-colonization of shallow water populations, occasionally affected by mass mortality events, should then be mainly fueled by larvae from other shallow water populations. PMID- 27490903 TI - Radiotherapy Deferral in Medulloblastoma. PMID- 27490904 TI - Prone sleeping and SUDEP risk: The dynamics of body positions in nonfatal convulsive seizures. AB - BACKGROUND: Most victims of sudden unexpected death in epilepsy (SUDEP) are found prone with signs suggestive of an unwitnessed convulsive seizure (CS). Prone sleeping has been proposed as a risk factor for SUDEP. Little is known, however, about the change of body position during the course of CSs. METHODS: We retrospectively reviewed video-EEG data and assessed body positions during the course of CSs, until there was a physical interaction by nursing staff with the subject. RESULTS: We identified 180 CSs in 90 individuals. In 16 of the 180 CSs (9%), the subject started in or turned to the prone position. Of the seven CSs that started in the prone position, three turned to a lateral position during the CS. In 13 CSs, the subject was in prone position at time of nursing intervention; nine (69%) of these started in a nonprone position. DISCUSSION: Our data suggest that the prone position occurs infrequently in closely supervised nonfatal CSs, a notable contrast to the number of victims of SUDEP found prone. Whether prone sleeping prior to CSs increases SUDEP risk, however, remains speculative, as body position during the course of a CS appeared to be dynamic. PMID- 27490902 TI - Interaction with PALB2 Is Essential for Maintenance of Genomic Integrity by BRCA2. AB - Human breast cancer susceptibility gene, BRCA2, encodes a 3418-amino acid protein that is essential for maintaining genomic integrity. Among the proteins that physically interact with BRCA2, Partner and Localizer of BRCA2 (PALB2), which binds to the N-terminal region of BRCA2, is vital for its function by facilitating its subnuclear localization. A functional redundancy has been reported between this N-terminal PALB2-binding domain and the C-terminal DNA binding domain of BRCA2, which undermines the relevance of the interaction between these two proteins. Here, we describe a genetic approach to examine the functional significance of the interaction between BRCA2 and PALB2 by generating a knock-in mouse model of Brca2 carrying a single amino acid change (Gly25Arg, Brca2G25R) that disrupts this interaction. In addition, we have combined Brca2G25R homozygosity as well as hemizygosity with Palb2 and Trp53 heterozygosity to generate an array of genotypically and phenotypically distinct mouse models. Our findings reveal defects in body size, fertility, meiotic progression, and genome stability, as well as increased tumor susceptibility in these mice. The severity of the phenotype increased with a decrease in the interaction between BRCA2 and PALB2, highlighting the significance of this interaction. In addition, our findings also demonstrate that hypomorphic mutations such as Brca2G25R have the potential to be more detrimental than the functionally null alleles by increasing genomic instability to a level that induces tumorigenesis, rather than apoptosis. PMID- 27490905 TI - Diagnostic accuracy of audio-based seizure detection in patients with severe epilepsy and an intellectual disability. AB - We evaluated the performance of audio-based detection of major seizures (tonic clonic and long generalized tonic) in adult patients with intellectual disability living in an institute for residential care. METHODS: First, we checked in a random sample (n=17, 102 major seizures) how many patients have recognizable sounds during these seizures. In the second part of this trial, we followed 10 patients (who had major seizures with recognizable sounds) during four weeks with an acoustic monitoring system developed by CLB ('CLB-monitor') and video camera. In week 1, we adapted the sound detection threshold until, per night, a maximum of 20 sounds was found. During weeks 2-4, we selected the epilepsy-related sounds and performed independent video verification and labeling ('snoring', 'laryngeal contraction') of the seizures. The video images were also fully screened for false negatives. In the third part, algorithms in the CLB-monitor detected one specific sound (sleep-related snoring) to illustrate the value of automatic sound recognition. RESULTS: Part 1: recognizable sounds (louder than whispering) occurred in 23 (51%) of the 45 major seizures, 20 seizures (45%) were below this threshold, and 2 (4%) were without any sound. Part 2: in the follow-up group (n=10, 112 major seizures; mean: 11.2, range: 1-30), we found a mean sensitivity of 0.81 (range: 0.33-1.00) and a mean positive predictive value of 0.40 (range: 0.06-1.00). All false positive alarms (mean value: 1.29 per night) were due to minor seizures. We missed 4 seizures (3%) because of lack of sound and 10 (9%) because of sounds below the system threshold. Part 3: the machine-learning algorithms in the CLB-monitor resulted in an overall accuracy for 'snoring' of 98.3%. CONCLUSIONS: Audio detection of major seizures is possible in half of the patients. Lower sound detection thresholds may increase the proportion of suitable candidates. Human selection of seizure-related sounds has a high sensitivity and moderate positive predictive value because of minor seizures which do not need intervention. Algorithms in the CLB-monitor detect seizure related sounds and may be used alone or in multimodal systems. PMID- 27490906 TI - Ezio Sciamanna: The Italian contribution to the origin of cortical stimulation mapping in humans. AB - Influenced by Ferrier's 1873 publication documenting his initial experience with cortical stimulation mapping (CSM) across several species, 19th-century experiments applying electric current to exposed human brain soon followed. Bartholow is commonly credited with the first report of CSM in a conscious human in 1874. What is not well established is that prominent Italian neurologist, Ezio Sciamanna, localized sensorimotor function in a human demonstration of CSM shortly thereafter in 1882. Sciamanna was in the vanguard of functional localization of brain function through direct stimulation of human gray matter. Unlike Bartholow, who has been canonized in the annals of CSM, Sciamanna has remained relatively obscure, despite the fact that his case may represent a better example of true subdural CSM than his better known contemporary. PMID- 27490907 TI - Use of thrombin-based haemostatic matrix in head and neck reconstructions: a potential risk factor for pulmonary embolism. AB - BACKGROUND: Haemostatic agents including thrombin-based haemostatic matrix are widely used in patients undergoing cardiac, vascular and spinal surgery. These agents promote local haemostasis through activation of the clotting cascade. To our knowledge, this case series is the first report of pulmonary embolization associated with FloSeal following head and neck oncology resection and free flap reconstruction. METHODS: We present five patients who were diagnosed with symptomatic pulmonary embolism after oncologic head and neck free flap reconstructions in 2014 and 2015. RESULTS: There were five patients consisting of three males and two females. The mean age was 67 years, ranging from 60 to 74 years. Pulmonary embolism occurred between 3 and 30 days with a mean of 12 days. Four out of the five reported cases showed involvement of more than one lobe, and two cases had bilateral pulmonary involvement. All but one patient underwent infratemporal fossa dissections as part of the cancer resection. Ten millilitres of FloSeal was applied to the pterygoid plexi in the four patients to achieve haemostasis. All patients received heparin infusion followed by warfarin therapy for at least 6 months with no mortality or complications relating to pulmonary embolism to date. CONCLUSION: Although inconclusive due to study design and small numbers, this series raises the possibility that there may be an association between the use of haemostatic matrix in head and neck oncologic reconstructions and pulmonary embolism. Haemostatic matrix must be used in caution when there is a direct contact with venous endolumens such as the pterygoid plexus and soleus. PMID- 27490909 TI - Multimorbidity in people with chronic kidney disease: implications for outcomes and treatment. AB - PURPOSE OF REVIEW: With ageing populations, the prevalence of multimorbidity is increasing. This review discusses recent developments in the understanding of multimorbidity in the context of chronic kidney disease (CKD). It explores the associated treatment burden and the implications for key outcomes and patient care. RECENT FINDINGS: Comorbidity and polypharmacy are common in CKD, even at early stages, and are associated with significant treatment burden. Both 'concordant' and 'discordant' comorbidities have a negative impact on mortality, cardiovascular disease, hospitalisation and length of stay. In addition, quality of life is influenced by many factors beyond CKD, including comorbidities and certain medications. Several factors may reduce treatment burden for people with CKD, though research on this is at an early stage. Although patient activation is desirable to support self-management amongst people with multimorbidity, there are significant challenges that impact patient capacity amongst elderly populations with complex needs. SUMMARY: Comorbidities are common in CKD and have important implications for patients, clinicians and health services. PMID- 27490908 TI - Epidemiologic Trends of Chemical Ocular Burns in the United States. AB - Importance: Determining the national epidemiologic trends of chemical ocular burns can assist physicians and policy makers in appropriate allocation of resources for treatment and prevention. Objective: To describe the epidemiologic trends and risk factors for chemical burns of the eye. Design, Setting, and Participants: Between August 1, 2015, and April 25, 2016, data from the Nationwide Emergency Department Sample were analyzed from January 1, 2010, through December 31, 2013. A sample of 900 emergency departments (EDs) across the United States was used. Patients presenting to EDs with a diagnosis of alkali or acid ocular burn, chemical conjunctivitis, or a combination of nonspecific ocular chemical burn and chemical poisoning or toxic effects were eligible for inclusion. Injured patients' age, sex, primary health care insurance, income quartile, and other demographics were described. A subset consisting of those injuries identified as alkaline or acidic burns was further characterized. Main Outcomes and Measures: Age-specific rates of ED presentation for chemical ocular burn injuries, independent factors associated with all, alkali, and acid injuries, and total ED-associated charges. Results: From January 1, 2010, through December 31, 2013, a total of 144 149 chemical ocular burns were diagnosed at EDs nationwide. Men represented 56.6% of all cases (n = 81 496). Median age was 32 years, with female patients presenting at a younger age than male patients (median of 32 vs 34 years; P < .001). Injury rates were highest among children aged 1 to 2 years (28.61 and 23.49 injuries per 100 000 population, respectively). Adults aged between 18 and 64 years also have these injuries at an increased rate, although this rate was half that of infants (mean, 13.28 per 100 000 population). Alkali injuries were more common than acid injuries (53.6% [n = 9137; 95% CI, 51.6%-56.0%] vs 46.4% [n = 7909; 95% CI, 44.0%-48.9%]), and all chemical eye injuries most commonly occur in residential locations (10.3% [n = 14 772]; 95% CI, 9.6%-10.9%) and among individuals in the first and second (lowest and second-lowest) income quartiles (<=$48 749) (56.0% [n = 80 691]; 95% CI, 54.4%-57.7%). Injuries most commonly occurred among those who had private health care insurance (31.9% [n = 45 900]; 95% CI, 30.9%-32.9%), and occurred more in the South (36.8% [n = 53 008]; 95% CI, 34.6%-39.1%). Emergency department charges due to these injuries totaled $106.7 million. Conclusions and Relevance: Young children represent the single highest-risk group for ocular chemical injuries. Education and other interventions concerned with preventing these injuries will be most effective if used accordingly. PMID- 27490910 TI - Gunshot Injuries to the Spine. PMID- 27490911 TI - Femoral Head Fractures. PMID- 27490912 TI - A Review of Current Graft Options for Anterior Cruciate Ligament Reconstruction. PMID- 27490913 TI - Avoiding Complications in Periacetabular Osteotomy. PMID- 27490914 TI - Structure of Chiral Au44(2,4-DMBT)26 Nanocluster with an 18-Electron Shell Closure. AB - The 18-electron shell closure structure of Au nanoclusters protected by thiol ligands has not been reported until now. Herein, we synthesize a novel nanocluster bearing the same gold atom number but a different thiolate number as another structurally resolved nanocluster Au44(TBBT)28 (TBBTH = 4-tert butylbenzenelthiol). The new cluster was determined to be Au44(2,4-DMBT)26 (2,4 DMBTH = 2,4-dimethylbenzenethiol) using multiple techniques, including mass spectrometry and single crystal X-ray crystallography (SCXC). Au44(2,4-DMBT)26 represents the first 18-electron closed-shell gold nanocluster. SCXC reveals that the atomic structure of Au44(2,4-DMBT)26 is completely different from that of Au44(TBBT)28 but is similar to the structure of Au38Q. The arrangement of staples (bridging thiolates) and part of the Au29 kernel atom induces the chirality of Au44(2,4-DMBT)26. The finding that a small portion of the gold kernel exhibits chirality is interesting because it has not been previously reported to the best of our knowledge. Although Au44(2,4-DMBT)26 bears an 18-electron shell closure structure, it is less thermostable than Au44(TBBT)28, indicating that multiple factors contribute to the thermostability of gold nanoclusters. Surprisingly, the small difference in Au/thiolate molar ratio between Au44(2,4-DMBT)26 and Au44(TBBT)28 leads to a dramatic distinction in Au 4f X-ray photoelectron spectroscopy, where it is found that the charge state of Au in Au44(2,4-DMBT)26 is remarkably more positive than that in Au44(TBBT)28 and even slightly more positive than the charge states of gold in Au-(2,4-DMBT) or Au-TBBT complexes. PMID- 27490915 TI - Dapagliflozin as Additional Treatment to Liraglutide and Insulin in Patients With Type 1 Diabetes. AB - CONTEXT: It is imperative that novel approaches to treatment of type 1 diabetes (T1D) are devised. OBJECTIVE: The objective of the study was to investigate whether addition of dapagliflozin to insulin and liraglutide results in a significant reduction in glycemia and body weight. DESIGN: This was a randomized clinical trial. SETTING: The study was conducted at a single academic medical center. PARTICIPANTS: Participants included T1D patients on liraglutide therapy for at least last 6 months. INTERVENTION: Thirty T1D patients were randomized (in 2:1 ratio) to receive either dapagliflozin 10 mg or placebo daily for 12 weeks. MAIN OUTCOME MEASURE: Change in mean glycated hemoglobin after 12 weeks of dapagliflozin when compared with placebo was measured. RESULTS: In the dapagliflozin group, glycated hemoglobin fell by 0.66% +/- 0.08% from 7.8% +/- 0.21% (P < .01 vs placebo), whereas it did not change significantly in the placebo group from 7.40% +/- 0.20% to 7.30% +/- 0.20%. The body weight fell by1.9 +/- 0.54kg (P < .05 vs placebo). There was no additional hypoglycemia (blood glucose < 3.88 mmol/L; P = .52 vs placebo). In the dapagliflozin group, there were significant increases in the plasma concentrations of glucagon by 35% +/- 13% (P < .05), hormone-sensitive lipase by 29% +/- 11% (P < .05), free fatty acids by 74% +/- 32% (P < .05), acetoacetate by 67% +/- 34% (P < .05), and beta hydroxybutyrate by 254% +/- 81% (P < .05). Urinary ketone levels also increased significantly (P < .05). None of these changes was observed in the placebo group. Two patients in the dapagliflozin group developed diabetic ketoacidosis. CONCLUSIONS: Addition of dapagliflozin to insulin and liraglutide in patients with T1D results in a significant improvement in glycemia and weight loss while increasing ketosis. If it is decided to use this approach, then it must be used only by a knowledgeable patient along with an endocrinologist who is well versed with it. PMID- 27490916 TI - Use of Estrogen-Containing Contraception Is Associated With Increased Concentrations of 25-Hydroxy Vitamin D. AB - CONTEXT: Small studies suggest exogenous estrogen may improve vitamin D status, but the etiology is unclear because women who use hormones may make lifestyle choices that differentially affect vitamin D status. OBJECTIVE: Our objective was to investigate the association between use of hormonal contraception and 25 hydroxy-vitamin D (25(OH)D). DESIGN: We used linear regression modeling of cross sectional data to estimate percent change in season-adjusted serum 25(OH)D with estrogen use after adjustment for other factors. SETTING: At the enrollment clinic visit (2010-2012) into a cohort study of uterine fibroids, each subject provided a blood sample, had anthropomorphic variables and skin reflectance measured, and answered questionnaires on demographics, dietary and supplement intake, contraceptive use, reproductive and medical history, and behaviors. PARTICIPANTS: A total of 1662 African American women, community volunteers, 23-34 years old, living in the Detroit, Michigan, area were included. INTERVENTIONS: None. MAIN OUTCOMES AND MEASURES: Serum 25(OH)D was measured. RESULTS: Serum 25(OH)D concentrations were low (70% <20 ng/ml). Current use of an estrogen containing contraceptive was associated with a 20% (95% confidence interval: 14 27) increase in 25(OH)D after adjustment. There was no increase in 25(OH)D among participants who had used estrogen in the past, but were not current users, indicating that results were unlikely to be due to unmeasured confounding by factors related to contraceptive choice. CONCLUSIONS: The increase in 25(OH)D with use of estrogen-containing contraceptives raise mechanistic questions regarding the biological pathways involved, and highlights the need for studies that examine possible endogenous estrogen effects on vitamin D. PMID- 27490917 TI - A Probabilistic Model for Cushing's Syndrome Screening in At-Risk Populations: A Prospective Multicenter Study. AB - CONTEXT: Cushing's syndrome (CS) is challenging to diagnose. Increased prevalence of CS in specific patient populations has been reported, but routine screening for CS remains questionable. To decrease the diagnostic delay and improve disease outcomes, simple new screening methods for CS in at-risk populations are needed. OBJECTIVE: To develop and validate a simple scoring system to predict CS based on clinical signs and an easy-to-use biochemical test. DESIGN: Observational, prospective, multicenter. SETTING: Referral hospital. PATIENTS: A cohort of 353 patients attending endocrinology units for outpatient visits. INTERVENTIONS: All patients were evaluated with late-night salivary cortisol (LNSC) and a low-dose dexamethasone suppression test for CS. MAIN OUTCOME MEASURES: Diagnosis or exclusion of CS. RESULTS: Twenty-six cases of CS were diagnosed in the cohort. A risk scoring system was developed by logistic regression analysis, and cutoff values were derived from a receiver operating characteristic curve. This risk score included clinical signs and symptoms (muscular atrophy, osteoporosis, and dorsocervical fat pad) and LNSC levels. The estimated area under the receiver operating characteristic curve was 0.93, with a sensitivity of 96.2% and specificity of 82.9%. CONCLUSIONS: We developed a risk score to predict CS in an at-risk population. This score may help to identify at-risk patients in non endocrinological settings such as primary care, but external validation is warranted. PMID- 27490918 TI - The Effects of Soy Isoflavones on Metabolic Status of Patients With Polycystic Ovary Syndrome. AB - CONTEXT: Limited data are available evaluating the effects of soy isoflavones on metabolic status of patients with polycystic ovary syndrome (PCOS). OBJECTIVE: The current study was performed to determine the effects of soy isoflavones on metabolic status of patients with PCOS. METHODS: This randomized, double-blind, placebo-controlled trial was performed on 70 women diagnosed with PCOS according to the Rotterdam criteria who were 18-40 years old. Participants were randomly allocated into two groups to take either 50 mg/d soy isoflavones (n = 35) or placebo (n = 35) for 12 weeks. Metabolic, endocrine, inflammation, and oxidative stress biomarkers were quantified at the beginning of the study and after the 12 week intervention. RESULTS: After 12 weeks of intervention, compared to the placebo group, soy isoflavone administration significantly decreased circulating serum levels of insulin (-1.2 +/- 4.0 vs +2.8 +/- 4.7 MUIU/mL; P < .001) and homeostasis model of assessment-estimated insulin resistance (-0.3 +/- 1.0 vs +0.6 +/- 1.1; P < .001) and increased the quantitative insulin sensitivity check index (+0.0009 +/- 0.01 vs -0.01 +/- 0.03; P = .01). Supplementation with soy isoflavones resulted in significant reductions in free androgen index (-0.03 +/- 0.04 vs +0.02 +/- 0.03; P < .001) and serum triglycerides (-13.3 +/- 62.2 vs +10.3 +/- 24.5 mg/dL; P = .04) compared to the placebo group. There was a significant increase in plasma total glutathione (+96.0 +/- 102.2 vs +22.7 +/- 157.8 MUmol/L; P = .04) and a significant decrease in malondialdehyde levels ( 0.7 +/- 0.8 vs +0.8 +/- 2.3 MUmol/L; P = .001) by soy isoflavone intake compared with the placebo group. We did not observe any significant effect of soy isoflavone intake on other lipid profiles and inflammatory and oxidative stress markers. CONCLUSION: Soy isoflavone administration for 12 weeks in women with PCOS significantly improved markers of insulin resistance, hormonal status, triglycerides, and biomarkers of oxidative stress. PMID- 27490919 TI - Energy Metabolic Adaptation and Cardiometabolic Improvements One Year After Gastric Bypass, Sleeve Gastrectomy, and Gastric Band. AB - CONTEXT: It is not known whether the magnitude of metabolic adaptation, a greater than expected drop in energy expenditure, depends on the type of bariatric surgery and is associated with cardiometabolic improvements. OBJECTIVE: To compare changes in energy expenditure (metabolic chamber) and circulating cardiometabolic markers 8 weeks and 1 year after Roux-en-y bypass (RYGB), sleeve gastrectomy (SG), laparoscopic adjustable gastric band (LAGB), or a low-calorie diet (LCD). Design, Setting, Participants, and Intervention: This was a parallel arm, prospective observational study of 30 individuals (27 females; mean age, 46 +/- 2 years; body mass index, 47.2 +/- 1.5 kg/m2) either self-selecting bariatric surgery (five RYGB, nine SG, seven LAGB) or on a LCD (n = 9) intervention (800 kcal/d for 8 weeks, followed by weight maintenance). RESULTS: After 1 year, the RYGB and SG groups had similar degrees of body weight loss (33-36%), whereas the LAGB and LCD groups had 16 and 4% weight loss, respectively. After adjusting for changes in body composition, 24-hour energy expenditure was significantly decreased in all treatment groups at 8 weeks (-254 to -82 kcal/d), a drop that only persisted in RYGB (-124 +/- 42 kcal/d; P = .002) and SG (-155 +/- 118 kcal/d; P = .02) groups at 1 year. The degree of metabolic adaptation (24-hour and sleeping energy expenditure) was not significantly different between the treatment groups at either time-point. Plasma high-density lipoprotein and total and high molecular weight adiponectin were increased, and triglycerides and high sensitivity C-reactive protein levels were reduced 1 year after RYGB or SG. CONCLUSIONS: Metabolic adaptation of approximately 150 kcal/d occurs after RYGB and SG surgery. Future studies are required to examine whether these effects remain beyond 1 year. PMID- 27490920 TI - Higher Prevalence of Type 2 Diabetes in Men Than in Women Is Associated With Differences in Visceral Fat Mass. AB - CONTEXT: We have previously found that visceral fat is a stronger predictor for cardiovascular risk factors than body mass index (BMI). OBJECTIVE: This study sought to investigate the prevalence of diabetes in elderly men and women in relation to objectively assessed visceral fat volume. DESIGN AND SETTING: The cohort consisted of a population-based sample of 705 men and 688 women, all age 70 y at the time of examination. MAIN OUTCOME MEASURES: Associations between body fat estimates, plasma glucose level, and diabetes prevalence were investigated using multivariable-adjusted statistical models. RESULTS: The prevalence of type 2 diabetes was 14.6% in men and 9.1% in women (P < .001). Mean BMI was slightly higher in men than in women (27.3 vs 26.6 kg/m2; P = .01), with a greater difference in mean visceral fat mass (1987 vs 1077 g; P < .001). After adjustment for physical activity and smoking, men had about/approximately twice the odds of having type 2 diabetes compared with women (odds ratio [OR], 1.95; 95% confidence interval [CI], 1.38-2.76). The inclusion of BMI in this model did not change the risk associated with male sex (OR, 1.93; 95% CI, 1.34-2.77). However, when visceral fat was included as a covariate, male sex was not associated with increased risk of type 2 diabetes (OR, 0.77; 95% CI, 0.51-1.18). CONCLUSIONS: The higher prevalence of type 2 diabetes in older men than in older women was associated with larger amount of visceral fat in men. In contrast, differences in BMI was not associated with this difference. PMID- 27490921 TI - Effects of Hydrocortisone on the Regulation of Blood Pressure: Results From a Randomized Controlled Trial. AB - CONTEXT: Cardiovascular risk is increased in patients with secondary adrenal insufficiency, which may be ascribed to an unfavorable metabolic profile consequent to a relatively high hydrocortisone replacement dose. OBJECTIVE: We determined the effects of a higher versus a lower glucocorticoid replacement dose on blood pressure (BP), the renin-angiotensin-aldosterone system, 11beta hydroxysteroid dehydrogenase enzyme activity and circulating (nor)metanephrines. DESIGN, SETTING, AND PATIENTS: Forty-seven patients with secondary adrenal insufficiency from the University Medical Center Groningen participated in this randomized double-blind crossover study. INTERVENTIONS: Patients randomly received 0.2-0.3 mg hydrocortisone/kg body weight followed by 0.4-0.6 mg hydrocortisone/kg body weight, or vice versa, each during 10 weeks. MAIN OUTCOME MEASURE(S): BP and regulating hormones were measured. RESULTS: The higher hydrocortisone dose resulted in an increase in systolic BP of 5 (12) mm Hg (P = .011), diastolic BP of 2 (9) mm Hg (P = .050), and a median [interquartile range] drop in plasma potassium of -0.1 [-0.3; 0.1] nmol/liter (P = .048). The higher hydrocortisone dose led to decreases in serum aldosterone of -28 [-101; 9] pmol/liter (P = .020) and plasma renin of -1.3 [-4.5; 1.2 ] pg/mL (P = .051), and increased the ratio of plasma and urinary cortisol to cortisone (including their metabolites) (P < .001 for all). Furthermore, on the higher dose, plasma and urinary normetanephrine decreased by -0.101 [-0.242; 0.029] nmol/liter (P < .001) and -1.48 [-4.06; 0.29] MUmol/mol creatinine (P < .001) respectively. CONCLUSIONS: A higher dose of hydrocortisone increased systolic and diastolic BP and was accompanied by changes in the renin-angiotensin-aldosterone system, 11beta-hydroxysteroid dehydrogenase enzyme activity, and circulating normetanephrine. This demonstrates that hydrocortisone dose even within the physiological range affects several pathways involved in BP regulation. PMID- 27490922 TI - omega-3 Fatty Acid Ethyl Esters Diminish Postprandial Lipemia in Familial Hypercholesterolemia. AB - CONTEXT: Impaired postprandial chylomicron metabolism induces hypertriglyceridemia and may increase the risk of atherosclerotic cardiovascular disease. Omega-3 fatty acid ethyl ester (omega-3 FAEE) supplementation decreases plasma triglycerides. However, its effect on postprandial chylomicron metabolism in familial hypercholesterolemia (FH) has not yet been investigated. OBJECTIVE: We aimed to examine the effect of omega-3 FAEE supplementation on postprandial responses in plasma triglycerides, very-low-density lipoprotein (VLDL) apolipoprotein B (apoB)-100, and apoB-48 in FH patients receiving standard cholesterol-lowering treatment. DESIGN, SETTING, AND PATIENTS: We carried out an 8-week open-label, randomized, crossover intervention trial to test the effect of oral supplementation with 4 g/d omega-3 FAEE (46% eicosapentaenoic acid and 38% docosahexaenoic acid) on postprandial triglyceride, VLDL-apoB-100, and apoB-48 responses in FH patients after ingestion of an oral fat load. OUTCOMES MEASURES: Plasma total and incremental triglyceride, VLDL-apoB-100, and apoB-48 0- to 10 hour area under the curve (AUC). RESULTS: omega-3 FAEE supplementation significantly (P < .05 in all) reduced concentrations of fasting plasma triglyceride (-20%), apoB (-8%), VLDL-apoB-100 (-26%), and apoB-48 (-36%); as well as systolic blood pressure (-6%) and diastolic blood pressure (-6%). Postprandial triglyceride and VLDL-apoB-100 total AUCs (-19% and -26%, respectively; P < .01) and incremental AUCs (-18% and -35%, respectively; P < .05), as well as postprandial apoB-48 total AUC (-30%; P < .02) were significantly reduced by omega-3 FAEE supplementation. CONCLUSION: Supplementation with omega-3 FAEEs improves postprandial lipemia in FH patients receiving standard care; this may have implications for further reducing atherosclerotic cardiovascular disease in this high-risk patient group. PMID- 27490923 TI - Nanostructured Antagonist of Extrasynaptic NMDA Receptors. AB - Glutamatergic cytotoxicity mediated by overactivation of N-methyl-d-aspartate receptors (NMDARs) is implicated in numerous neurological disorders. To be therapeutically viable, NMDAR antagonists must preserve physiological role of synaptic NMDARs (sNMDARs) in synaptic transmission and block only excessive pathological activation of NMDARs. Here we present a novel NMDAR antagonist that satisfies this two-fold requirement by exploiting spatial differences in NMDAR subcellular locations. Specifically, we designed a hybrid nanodrug (AuM) to be larger than the synaptic cleft by attaching memantine, NMDAR antagonist, via polymer linkers to a gold nanoparticle. We show that AuM efficiently and selectively inhibited extrasynaptic NMDARs (eNMDARs), while having no effect on sNMDARs and synaptic transmission. AuM exhibited neuroprotective properties both in vitro and ex vivo during such neurotoxic insults as NMDAR-mediated cytotoxicity in cerebrocortical cell culture and oxygen-glucose deprivation in acute hippocampal slices. Furthermore, AuM prevented dendritic spine loss triggered by Abeta oligomers in organotypic hippocampal slices and was more effective than free memantine. Using a novel rational design strategy, we demonstrate a proof of concept for a new class of neuroprotective drugs that might be beneficial for treatment of several neurological disorders. PMID- 27490925 TI - Correction: Gendist: An R Package for Generated Probability Distribution Models. AB - [This corrects the article DOI: 10.1371/journal.pone.0156537.]. PMID- 27490924 TI - Effects of Salt Stress on Three Ecologically Distinct Plantago Species. AB - Comparative studies on the responses to salt stress of taxonomically related taxa should help to elucidate relevant mechanisms of stress tolerance in plants. We have applied this strategy to three Plantago species adapted to different natural habitats, P. crassifolia and P. coronopus-both halophytes-and P. major, considered as salt-sensitive since it is never found in natural saline habitats. Growth inhibition measurements in controlled salt treatments indicated, however, that P. major is quite resistant to salt stress, although less than its halophytic congeners. The contents of monovalent ions and specific osmolytes were determined in plant leaves after four-week salt treatments. Salt-treated plants of the three taxa accumulated Na+ and Cl- in response to increasing external NaCl concentrations, to a lesser extent in P. major than in the halophytes; the latter species also showed higher ion contents in the non-stressed plants. In the halophytes, K+ concentration decreased at moderate salinity levels, to increase again under high salt conditions, whereas in P. major K+ contents were reduced only above 400 mM NaCl. Sorbitol contents augmented in all plants, roughly in parallel with increasing salinity, but the relative increments and the absolute values reached did not differ much in the three taxa. On the contrary, a strong (relative) accumulation of proline in response to high salt concentrations (600 800 mM NaCl) was observed in the halophytes, but not in P. major. These results indicate that the responses to salt stress triggered specifically in the halophytes, and therefore the most relevant for tolerance in the genus Plantago are: a higher efficiency in the transport of toxic ions to the leaves, the capacity to use inorganic ions as osmotica, even under low salinity conditions, and the activation, in response to very high salt concentrations, of proline accumulation and K+ transport to the leaves of the plants. PMID- 27490926 TI - Transgelin is a TGFbeta-inducible gene that regulates osteoblastic and adipogenic differentiation of human skeletal stem cells through actin cytoskeleston organization. AB - Regenerative medicine is a novel approach for treating conditions in which enhanced bone regeneration is required. We identified transgelin (TAGLN), a transforming growth factor beta (TGFbeta)-inducible gene, as an upregulated gene during in vitro osteoblastic and adipocytic differentiation of human bone marrow derived stromal (skeletal) stem cells (hMSC). siRNA-mediated gene silencing of TAGLN impaired lineage differentiation into osteoblasts and adipocytes but enhanced cell proliferation. Additional functional studies revealed that TAGLN deficiency impaired hMSC cell motility and in vitro transwell cell migration. On the other hand, TAGLN overexpression reduced hMSC cell proliferation, but enhanced cell migration, osteoblastic and adipocytic differentiation, and in vivo bone formation. In addition, deficiency or overexpression of TAGLN in hMSC was associated with significant changes in cellular and nuclear morphology and cytoplasmic organelle composition as demonstrated by high content imaging and transmission electron microscopy that revealed pronounced alterations in the distribution of the actin filament and changes in cytoskeletal organization. Molecular signature of TAGLN-deficient hMSC showed that several genes and genetic pathways associated with cell differentiation, including regulation of actin cytoskeleton and focal adhesion pathways, were downregulated. Our data demonstrate that TAGLN has a role in generating committed progenitor cells from undifferentiated hMSC by regulating cytoskeleton organization. Targeting TAGLN is a plausible approach to enrich for committed hMSC cells needed for regenerative medicine application. PMID- 27490927 TI - TLR and NLRP3 inflammasome-dependent innate immune responses to tumor-derived autophagosomes (DRibbles). AB - Autophagosomes derived from tumor cells, also referred to as defective ribosomal products in blebs (DRibbles), have been previously shown to stimulate potent T cell responses and mediate tumor regression when used as therapeutic cancer vaccines in multiple preclinical cancer models. In this report, we investigated the underlining mechanisms by which DRibbles induced T-cell activation, particularly how DRibbles activated antigen-presenting cells (APCs). We found that DRibbles could induce a rapid differentiation of monocytes and DC precursor (pre-DC) cells into functional APCs. DRibbles triggered innate receptor signaling via Toll-like Receptors (TLR)-2, TLR4, TLR7, TLR8, and nucleotide-binding oligomerization domain-containing protein 2 (NOD2), but not TLR3, TLR5, or TLR9. DRibbles induced PBMCs to produce pro-inflammatory cytokines, such as IL-6, IL 10, TNF-alpha, and IL-1beta. DRibbles induced IL-1beta release from PBMC or THP-1 cells without LPS priming, but required the core machinery of NLRP3 inflammasomes. Active endocytosis was required for inflammasome activation and cross presentation, and blocking endosome acidification or the ER-associated degradation (ERAD) pathway resulted in opposite effects on these two processes. Our data show that DRibbles could induce strong innate immune responses via multiple pattern recognition receptors, and explain why DRibbles could function as excellent antigen carriers to induce adaptive immune responses to both tumor cells and viruses. In contrast to the well-established inhibitory effect of autophagy on the inflammasome activation of APCs, our study demonstrates that isolated autophagosomes (DRibbles) from antigen donor cells activate inflammasomes by providing first and second signals required for IL-1beta production by PMBC. PMID- 27490928 TI - TMEM166/EVA1A interacts with ATG16L1 and induces autophagosome formation and cell death. AB - The formation of the autophagosome is controlled by an orderly action of ATG proteins. However, how these proteins are recruited to autophagic membranes remain poorly clarified. In this study, we have provided a line of evidence confirming that EVA1A (eva-1 homolog A)/TMEM166 (transmembrane protein 166) is associated with autophagosomal membrane development. This notion is based on dotted EVA1A structures that colocalize with ZFYVE1, ATG9, LC3B, ATG16L1, ATG5, STX17, RAB7 and LAMP1, which represent different stages of the autophagic process. It is required for autophagosome formation as this phenotype was significantly decreased in EVA1A-silenced cells and Eva1a KO MEFs. EVA1A-induced autophagy is independent of the BECN1-PIK3C3 (phosphatidylinositol 3-kinase, catalytic subunit type 3) complex but requires ATG7 activity and the ATG12 ATG5/ATG16L1 complex. Here, we present a molecular mechanism by which EVA1A interacts with the WD repeats of ATG16L1 through its C-terminal and promotes ATG12-ATG5/ATG16L1 complex recruitment to the autophagic membrane and enhances the formation of the autophagosome. We also found that both autophagic and apoptotic mechanisms contributed to EVA1A-induced cell death while inhibition of autophagy and apoptosis attenuated EVA1A-induced cell death. Overall, these findings provide a comprehensive view to our understanding of the pathways involved in the role of EVA1A in autophagy and programmed cell death. PMID- 27490931 TI - The Medical and Surgical Treatment of ARCO Stage-I and II Osteonecrosis of the Femoral Head: A Critical Analysis Review. PMID- 27490929 TI - Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and systemic chemotherapy is the major treatment strategy for late stage HCC patients. Poor prognosis following chemotherapy is the general outcome owing to recurrent resistance. Recent studies have suggested that in addition to cytotoxic effects on tumor cells, chemotherapy can induce an alternative cascade that supports tumor growth and metastasis. In the present investigation, we showed that thyroid hormone (TH), a potent hormone-mediating cellular differentiation and metabolism, acts as an antiapoptosis factor upon challenge of thyroid hormone receptor (TR)-expressing HCC cells with cancer therapy drugs, including cisplatin, doxorubicin and tumor necrosis factor-related apoptosis inducing ligand (TRAIL). TH/TR signaling promoted chemotherapy resistance through negatively regulating the pro-apoptotic protein, Bim, resulting in doxorubicin induced metastasis of chemotherapy-resistant HCC cells. Ectopic expression of Bim in hepatoma cells challenged with chemotherapeutic drugs abolished TH/TR triggered apoptosis resistance and metastasis. Furthermore, Bim expression was directly transactivated by Forkhead box protein O1 (FoxO1), which was negatively regulated by TH/TR. TH/TR suppressed FoxO1 activity through both transcriptional downregulation and nuclear exclusion of FoxO1 triggered by Akt-mediated phosphorylation. Ectopic expression of the constitutively active FoxO1 mutant, FoxO1-AAA, but not FoxO1-wt, diminished the suppressive effect of TH/TR on Bim. Our findings collectively suggest that expression of Bim is mediated by FoxO1 and indirectly downregulated by TH/TR, leading to chemotherapy resistance and doxorubicin-promoted metastasis of hepatoma cells. PMID- 27490932 TI - Coracoid Process Transfer for Recurrent Instability of the Shoulder: A Critical Analysis Review. PMID- 27490930 TI - Inhibitor of apoptosis protein expression in glioblastomas and their in vitro and in vivo targeting by SMAC mimetic GDC-0152. AB - Glioblastomas (GBMs) are the most aggressive primary brain tumors in adult and remain a therapeutic challenge. Targeting key apoptosis regulators with the ultimate aim to restore apoptosis in tumor cells could be an interesting therapeutic strategy. The inhibitors of apoptosis proteins (IAPs) are regulators of cell death and represent attractive targets, especially because they can be antagonized by SMAC mimetics. In this study, we first investigated the expression of cIAP1, cIAP2, XIAP and ML-IAP in human GBM samples and in four different cell lines. We showed that all GBM samples and GBM cell lines expressed all these IAPs, although the expression of each IAP varied from one case to another. We then showed that high level of ML-IAP predicted worse progression-free survival and overall survival in both univariate and multivariate analyses in two independent cohorts of 58 and 43 primary human GBMs. We then used GDC-0152, a SMAC mimetic that antagonizes these IAPs and confirmed that GDC-0152 treatment in vitro decreased IAPs in all the cell lines studied. It affected cell line viability and triggered apoptosis, although the effect was higher in U87MG and GL261 than in GBM6 and GBM9 cell lines. In vivo, GDC-0152 effect on U87MG orthotopic xenografts was dose dependent; it postponed tumor formation and slowed down tumor growth, significantly improving survival of GBM-bearing mice. This study revealed for the first time that ML-IAP protein expression correlates with GBM patient survival and that its antagonist GDC-0152 improves outcome in xenografted mouse. PMID- 27490933 TI - Use of Irradiated and Non-Irradiated Allograft Tissue in Anterior Cruciate Ligament Reconstruction Surgery: A Critical Analysis Review. PMID- 27490934 TI - Metal Hypersensitivity in Patients with Conventional Orthopaedic Implants. PMID- 27490935 TI - Conjoint FTLD-FUS of the neuronal intermediate filament inclusion disease type, progressive supranuclear palsy and Alzheimer's pathology presenting as parkinsonism with early falls and late hallucinations, psychosis and dementia. PMID- 27490936 TI - Determination of Ginkgolides A, B, C, J and Bilobalide in Plasma by LC-ESI ( )/MS/MS (QQQ) and its Application to the Pharmacokinetic Study of Ginkgo Biloba Extract in Rats. AB - A simple, rapid, and specific high-performance liquid chromatograph coupled with a tandem mass spectrometry method has been developed and validated for the quantification of ginkgolides in rat plasma, and the main pharmacokinetic parameters of ginkgolides after oral administration of Ginkgo biloba extract (GBE) was acquired. Methods: Plasma samples were pretreated with ethyl acetate extraction. Sulfamethoxazole was used as the internal standard (IS). Chromatographic separation was achieved on an Eclipse XDB-C18 column (2.1 mm*150 mm, 5 MUm) with a mobile phase consisting of methanol/0.1% formic acid water (gradient elution: 0~25 min (77:23)->(60:40), V/V) at a flow rate of 0.3 mL.min 1. The detection was performed on a triple quadruple tandem mass spectrometer using an electrospray ionization (ESI) source for 25 min. The detection was operated by multiple reaction monitoring(MRM) under negative ionization mode of the transitions of m/z 325->163 for BB, 469->423 for GJ, 439->125 for GC, 453 >351 for GA, 423->367 for GB and of m/z 252->156 for sulfamethoxazole (IS) respectively. Results: The pharmacokinetic properties of BB, GJ, GA, GB and GC were in line with the open 2-compartment model after oral administration of GBE in rats; The pharmacokinetic parameters of various lactones were calculated, and drugs-time curve and the curve fitting diagram of 5 ginkgolides were drew; The absorption and distribution rate of BB, GJ, GA, GB and GC were fast in rats in vivo, and half-life of absorption was less than 3 h. Conclusion: The developed LC ESI (-)/MS/MS (QQQ) method was successfully applied to assess the pharmacokinetic parameters and oral bioavailability of ginkgolides in rats after administration of GBE, which can provide basis for further clinical efficacy studies. PMID- 27490937 TI - Predictions of the Pharmacokinetics in Burn Injury Patients using Regression Models - Case Study with Levofloxacin. AB - Owing to its excellent safety, tolerability, pharmacokinetic and pharmacodynamic profile levofloxacin is widely used. Although pharmacokinetics of levofloxacin was somewhat more variable in burn injury patients, it appeared to be comparable to healthy subjects or other patients. Linear regression model was established for Cmax or Cmin vs. [AUCtau, CL and Vd] of levofloxacin using individual values from burn injury patients. Appropriate regression lines for Cmax or Cmin were subjected to internal and external validation on the ability to predict CL, Vd and AUCtau parameters. The mean absolute error (MAE) and root mean square error (RMSE) of the predictions were used to judge the appropriateness of either Cmax or Cmin models. Cmax models developed for levofloxacin showed moderate to strong correlations with the various parameters such as CL, Vd and AUCtau. The Cmin models showed strong correlation for CL and AUCtau but not for Vd where the correlation was weak. Internal validation using data from individual burn patients showed RMSE of 13.47-25.42% for various predictions. External validation that used mean data from healthy subjects showed RMSE of 13.86-27.13%. Despite the pharmacokinetic variability, linear regression models using either Cmax or Cmin were established for levofloxacin rendering predictions of several key pharmacokinetic parameters. Although there was limitation of Cmin model for predicting Vd, both models may be used as a prospective tool for the prediction of levofloxacin pharmacokinetics in burn care patients. PMID- 27490938 TI - A Tightly Stretched Ultralong Supramolecular Multiporphyrin Array Propagated by Double-Strand Formation. AB - A shape-programmed linearity through supramolecular polymerization is demonstrated by a step-growth double-strand formation of a telechelic oligomeric porphyrin array in which two alternating pyridyl-porphyrin sequenced units are held together by self-complementary ligand-to-metal coordination. The stiff rod like structure and sufficiently large binding constant of the double-strand unit considerably extended a supramolecular array in the one dimension, which produced a tightly stretched string with a length that exceeded several micrometers. PMID- 27490939 TI - The in vitro generation of multi-tumor antigen-specific cytotoxic T cell clones: Candidates for leukemia adoptive immunotherapy following allogeneic stem cell transplantation. AB - Adoptive T-cell immunotherapy is a promising approach to manage and maintain relapse-free survival of leukemia patients, especially following allogeneic stem cell transplantation. Post-transplant adoptive immunotherapy using cytotoxic T lymphocytes (CTLs) of the donor origin provide graft-versus-tumor effects, with or without graft-versus-host disease. Myeloid leukemias express immunogenic leukemia associated antigens (LAAs); such as WT-1, PRAME, MAGE, h-TERT and others, most of them are able to induce specific T cell responses whenever associated with the proper co-stimulation. We investigated the ability of a LAA expressing hybridoma cell line to induce CTL clones in PBMCs of HLA-matched healthy donors in vitro. The CTL clones were induced by repetitive co-culture with LAAs-expressing, HLA-A*0201(+) hybrid cell line, generated by fusion of leukemia blasts to human immortalized APC (EBV-sensitized B-lymphoblastoid cell line; HMy2). The induced cytotoxic T cell clones were phenotypically and functionally characterized by pentamer analysis, IFN-gamma release ELISPOT and cellular cytotoxicity assays. All T cell lines showed robust peptide recognition and functional activity when sensitized with HLA-A*0201-restricted WT-1235-243, hTERT615-624 or PRAME100-108 peptides-pulsed T2 cells, in addition to partially HLA-matched leukemia blasts. This study demonstrates the feasibility of developing multi-tumor antigen-specific T cell lines in allogeneic PBMCs in vitro, using LAA-expressing tumor/HMy2 hybrid cell line model, for potential use in leukemia adoptive immunotherapy in partially matched donor-recipient setting. PMID- 27490940 TI - Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene. AB - C3 glomerulopathy (C3G) is an ultra-rare complement-mediated renal disease characterized histologically by the predominance of C3 deposition within in the glomerulus. Familial cases of C3G are extremely uncommon and offer unique insight into the genetic drivers of complement dysregulation. In this report, we describe a patient who presented with C3G. Because a relative carried the same diagnosis, we sought an underlying genetic commonality to explain the phenotype. As part of a comprehension genetic screen, we completed multiplex ligation-dependent probe amplification across the complement factor H related region and identified amplification alterations consistent with a genomic rearrangement. Using comparative genomic hybridization, we narrowed and then cloned the rearrangement breakpoints thereby defining a novel fusion gene that is translated into a serum protein comprised of factor H related-5 (short consensus repeats 1 and 2) and factor H-related-2 (short consensus repeats 1-4). These data highlight the role of factor H related proteins in the control of complement activity and illustrate how perturbation of that control leads to C3G. PMID- 27490941 TI - Diagnostic Accuracy of CT for Local Staging of Colon Cancer: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The purpose of this article is to determine the accuracy of CT in the detection of tumor invasion beyond the bowel wall and nodal involvement of colon carcinomas. A literature search was performed to identify studies describing the accuracy of CT in the staging of colon carcinomas. Studies including rectal carcinomas that were inseparable from colon carcinomas were excluded. Publication bias was explored by using a Deeks funnel plot asymmetry test. A hierarchic summary ROC model was used to construct a summary ROC curve and to calculate summary estimates of sensitivity, specificity, and diagnostic odds ratios (ORs). CONCLUSION: On the basis of a total of 13 studies, pooled sensitivity, specificity, and diagnostic ORs for detection of tumor invasion beyond the bowel wall (T3-T4) were 90% (95% CI, 83-95%), 69% (95% CI, 62-75%), and 20.6 (95% CI, 10.2-41.5), respectively. For detection of tumor invasion depth of 5 mm or greater (T3cd-T4), estimates from four studies were 77% (95% CI, 66-85%), 70% (95% CI, 53-83%), and 7.8 (95% CI, 4.2-14.2), respectively. For nodal involvement (N+), 16 studies were included with values of 71% (95% CI, 59-81%), 67% (95% CI, 46-83%), and 4.8 (95% CI, 2.5-9.4), respectively. Two studies using CT colonography were included with sensitivity and specificity of 97% (95% CI, 90 99%) and 81% (95% CI, 65-91%), respectively, for detecting T3-T4 tumors. CT has good sensitivity for the detection of T3-T4 tumors, and evidence suggests that CT colonography increases its accuracy. Discriminating between T1-T3ab and T3cd-T4 cancer is challenging, but data were limited. CT has a low accuracy in detecting nodal involvement. PMID- 27490943 TI - Effect of light exposure on linalool biosynthesis and accumulation in grape berries. AB - Linalool is an important compound that contributes to the floral aroma in wines. This study showed the effect of light exposure on linalool accumulation in berries. The grape bunches were covered with films that block the full light spectrum (Shade) and the UV spectrum (UV-block), and a transparent film (Control). The linalool content was significantly higher in juice from Control covered berries than in juice from Shade- and UV-block-covered berries, and the expression levels of the representative genes in linalool biosynthesis in Shade- and UV-block-covered berries were markedly lower than in Control-covered berries. These findings suggest that exposing berries to light is essential for linalool biosynthesis. To reflect sunlight onto grape clusters, reflective sheets were placed on the ground of a vineyard. The linalool content in berries exposed to sunlight reflected from the reflective sheets was higher than those in the control. PMID- 27490942 TI - Solid-Vapor Reaction Growth of Transition-Metal Dichalcogenide Monolayers. AB - Two-dimensional (2D) layered semiconducting transition-metal dichalcogenides (TMDCs) are promising candidates for next-generation ultrathin, flexible, and transparent electronics. Chemical vapor deposition (CVD) is a promising method for their controllable, scalable synthesis but the growth mechanism is poorly understood. Herein, we present systematic studies to understand the CVD growth mechanism of monolayer MoSe2 , showing reaction pathways for growth from solid and vapor precursors. Examination of metastable nanoparticles deposited on the substrate during growth shows intermediate growth stages and conversion of non stoichiometric nanoparticles into stoichiometric 2D MoSe2 monolayers. The growth steps involve the evaporation and reduction of MoO3 solid precursors to sub oxides and stepwise reactions with Se vapor to finally form MoSe2 . The experimental results and proposed model were corroborated by ab initio Car Parrinello molecular dynamics studies. PMID- 27490944 TI - Cortical blindness post coronary angiogram: A rare but frightening complication. AB - Cortical blindness is a rare but frightening complication following coronary angiogram probably due to contrast penetration in occipital lobes in susceptible individuals [1, 2]. PMID- 27490945 TI - Multiclass method for the determination of 62 antibiotics in milk. AB - A multiclass method for screening and confirmatory analysis of antimicrobial residues in milk has been developed and validated. Sixty-two antibiotics belonging to ten different drug families (amphenicols, cephalosporins, lincosamides, macrolides, penicillin, pleuromutilins, quinolones, rifamycins, sulfonamides and tetracyclines) have been included. After the addition of an aqueous solution of EDTA, the milk samples were extracted twice with acetonitrile, evaporated and dissolved in ammonium acetate. After centrifugation, 10 ul were analysed using LC-Q-Orbitrap operating in positive electrospray ionization mode. The method was validated in bovine milk in the range 2-150 ug kg(-1) for all antibiotics; for four compounds with maximum residue limits higher than 100 ug kg(-1) , the validation interval has been extended until 333 ug kg( 1) . The estimated performance characteristics were satisfactory complying with the requirements of Commission Decision 2002/657/EC. Good accuracies were obtained also taking advantage from the versatility of the hybrid mass analyser. Identification criteria were achieved verifying the mass accuracy and ion ratio of two ions, including the pseudomolecular one, where possible. Finally, the developed procedure was applied to 13 real cases of suspect milk samples (microbiological assay) confirming the presence of one or more antibiotics, although frequently, the maximum residue limits were not exceeded. The availability of rapid multiclass confirmatory methods can avoid wastes of suspect, but compliant, raw milk samples. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27490946 TI - Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2. AB - Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC. PMID- 27490947 TI - Mirror-Touch Synaesthesia Is Not Associated with Heightened Empathy, and Can Occur with Autism. AB - Research has linked Mirror-Touch (MT) synaesthesia with enhanced empathy. We test the largest sample of MT synaesthetes to date to examine two claims that have been previously made: that MT synaesthetes (1) have superior empathy; and (2) only ever experience their MT synaesthesia in response to viewing a person being touched. Given that autism has been suggested to involve deficits in cognitive empathy, we also test two predictions: that MT synaesthetes should (3) be less likely than general population individuals without MT synaesthesia to have an autism spectrum condition (ASC), if MT is characterized by superior empathy; and (4) have fewer autistic traits. We selected three groups: a pure MT synaesthesia group (N = 46), a pure grapheme-colour (GC) synaesthesia group (N = 36), and a typical control group without synaesthesia (N = 46). Participants took three measures of empathy and one measure of autistic traits. MT synaesthetes did not show enhanced empathy. In addition, 30% of all MT synaesthetes recruited into this study (N = 135) reported also having ASC, and MT synaesthetes showed higher autistic trait scores than controls. Finally, some MT experiences were reported in response to viewing objects being touched. Our findings dispute the views that MT synaesthesia is linked with enhanced empathy, is less likely to occur with ASC or elevated autistic traits, and is specific to seeing a person being touched. PMID- 27490948 TI - A Single-Flask Synthesis of Morita-Baylis-Hillman Adducts from Ethoxyacetylene and Carbonyl Compounds: Synthesis of Subamolides D and E. AB - Sequential treatment of (ethoxyethynyl)lithium with aldehydes and/or ketones (2 and 4) and BF3.OEt2 gives rise to beta-hydroxyenoates 5 in good to excellent overall yields. Similarly, the combination of 1 (M = Li) and dicarbonyl compounds 6 (X = O) or keto/aldehyde acetals (X = OMe) followed by the addition of a Lewis acid leads to five-, six-, and seven-membered hydroxycycloalkene carboxyates. The utility of this method is demonstrated in the synthesis of the alpha-alkylidene lactone natural products subamolide D and E. PMID- 27490951 TI - Feasibility and reliability of carotid intima-media thickness measurements in nonsedated infants. AB - INTRODUCTION: Carotid intima-media thickness (CIMT) is a surrogate marker for atherosclerosis. It is increased in adolescents and young adults at risk for future cardiovascular disease. However, it remains unclear if it can be considered as a surrogate marker for atherosclerosis in infancy as very few studies have been performed in infants. OBJECTIVES: Our objective was to assess the feasibility and interobserver reproducibility of CIMT measurement in nonsedated infants. METHODS: We measured CIMT in 81 infants less than 1 year of age. Repeated measurements were obtained by a second observer in 24 children. The analysis was performed with semiautomated edge detection software. Measurements with over 95% edge detection over a length of 1 cm were considered as valid. We further compared the measurements using the semiautomated method with measurements using the manual electronic caliper method in a subgroup of 10 infants. RESULTS: Carotid ultrasound recordings and intima-media thickness measurements were obtained in 79% of infants (n = 64). Mean CIMT of the 64 infants measured by the first observer was 0.44 mm (SD: 0.04). In the 24 participants with measurements by two observers, the mean interobserver difference was 0.001 mm (SD: 0.026). The interobserver coefficient of variation was 5.9%. CIMT measurements obtained with the manual method (mean: 0.35; range: 0.29-0.39) were slightly lower than measurements obtained with the semiautomated method (mean: 0.38; range: 0.32-0.44). Measurements with both methods were highly correlated (r: 0.87). CONCLUSION: Measurement of CIMT in nonsedated infants less than 1 year of age is feasible in the majority of infants with good interobserver variability. PMID- 27490950 TI - Can arterial wave augmentation in young adults help account for variability of cardiovascular risk in different British ethnic groups? AB - OBJECTIVE: Traditional cardiovascular risk factors do not fully account for ethnic differences in cardiovascular disease. We tested if arterial function indices, particularly augmentation index (AIx), and their determinants from childhood could underlie such ethnic variability among young British adults in the 'DASH' longitudinal study. METHODS: DASH, at http://dash.sphsu.mrc.ac.uk/, includes representative samples of six main British ethnic groups. Pulse wave velocity (PWV) and AIx were recorded using the Arteriograph device at ages 21-23 years in a subsample (n = 666); psychosocial, anthropometric, and blood pressure (BP) measures were collected then and in two previous surveys at ages 11-13 years and 14-16 years. For n = 334, physical activity was measured over 5 days (ActivPal). RESULTS: Unadjusted values and regression models for PWVs were similar or lower in ethnic minority than in White UK young adults, whereas AIx was higher - Caribbean (14.9, 95% confidence interval 12.3-17.0%), West African (15.3, 12.9-17.7%), Indian (15.1, 13.0-17.2%), and Pakistani/Bangladeshi (15.7, 13.7-17.7%), compared with White UK (11.9, 10.2-13.6%). In multivariate models, adjusted for sex, central SBP, height, and heart rate, Indian and Pakistani/Bangladeshi young adults had higher AIx (beta = 3.35, 4.20, respectively, P < 0.01) than White UK with a similar trend for West Africans and Caribbeans but not statistically significant. Unlike PWV, physical activity, psychosocial or deprivation measures were not associated with AIx, with borderline associations from brachial BP but no other childhood variables. CONCLUSION: Early adult AIx, but not arterial stiffness, may be a useful tool for testing components of excess cardiovascular risk in some ethnic minority groups. PMID- 27490949 TI - Cholinergic profiles in the Goettingen miniature pig (Sus scrofa domesticus) brain. AB - Central cholinergic structures within the brain of the even-toed hoofed Goettingen miniature domestic pig (Sus scrofa domesticus) were evaluated by immunohistochemical visualization of choline acetyltransferase (ChAT) and the low affinity neurotrophin receptor, p75NTR . ChAT-immunoreactive (-ir) perikarya were seen in the olfactory tubercle, striatum, medial septal nucleus, vertical and horizontal limbs of the diagonal band of Broca, and the nucleus basalis of Meynert, medial habenular nucleus, zona incerta, neurosecretory arcuate nucleus, cranial motor nuclei III and IV, Edinger-Westphal nucleus, parabigeminal nucleus, pedunculopontine nucleus, and laterodorsal tegmental nucleus. Cholinergic ChAT-ir neurons were also found within transitional cortical areas (insular, cingulate, and piriform cortices) and hippocampus proper. ChAT-ir fibers were seen throughout the dentate gyrus and hippocampus, in the mediodorsal, laterodorsal, anteroventral, and parateanial thalamic nuclei, the fasciculus retroflexus of Meynert, basolateral and basomedial amygdaloid nuclei, anterior pretectal and interpeduncular nuclei, as well as select laminae of the superior colliculus. Double immunofluorescence demonstrated that virtually all ChAT-ir basal forebrain neurons were also p75NTR -positive. The present findings indicate that the central cholinergic system in the miniature pig is similar to other mammalian species. Therefore, the miniature pig may be an appropriate animal model for preclinical studies of neurodegenerative diseases where the cholinergic system is compromised. J. Comp. Neurol. 525:553-573, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27490952 TI - Significance of masked and nocturnal hypertension in normotensive women coursing a high-risk pregnancy. AB - OBJECTIVE: The aim was to evaluate the prevalence of nocturnal and masked hypertension and the prognostic values of these blood pressure (BP) abnormalities in normotensive women coursing a high-risk pregnancy. METHODS: The study was performed in pregnant women with 20 or more weeks of gestation coursing a high risk pregnancy, sent to a specialized hypertension department to perform a prospective defined protocol of BP evaluation. Women with office BP at least 140/90 mmHg were excluded. An ambulatory monitoring of BP was performed to identify masked and nocturnal hypertension (defined according to the current guidelines). The adjusted risk for development of preeclampsia/eclampsia (PEEC) was estimated using logistic regression. The ability of SBP and DBP to identify risk of PEEC was estimated using area under the receiver-operating characteristic curves. RESULTS: Eighty-seven women (29 +/- 7 years old, 30 +/- 5 weeks of pregnancy) were included in this analysis. The prevalence of masked hypertension was 33.3%. Nocturnal hypertension was found in 42.5% of the women. Remarkably, 27.0% of the women with nocturnal hypertension had normal 24-h values according to ambulatory BP monitoring. Twenty-two patients developed PEEC; adjusted relative risks increased with the presence of nocturnal (odds ratio = 4.72, 95% confidence interval 1.25-19.43, P = 0.023) or masked hypertension (odds ratio = 7.81, 95% confidence interval 2.6-22.86, P = 0.001). Nocturnal SBP and DBP had the highest abilities to predict PEEC (area under the curve = 0.77 and 0.80, respectively). CONCLUSION: Masked and nocturnal hypertension are frequent findings in normotensive women coursing a high-risk pregnancy, and their presence implies an increased risk to develop PEEC. PMID- 27490954 TI - A double-mutant collection targeting MAP kinase related genes in Arabidopsis for studying genetic interactions. AB - Mitogen-activated protein kinase cascades are conserved in all eukaryotes. In Arabidopsis thaliana there are approximately 80 genes encoding MAP kinase kinase kinases (MAP3K), 10 genes encoding MAP kinase kinases (MAP2K), and 20 genes encoding MAP kinases (MAPK). Reverse genetic analysis has failed to reveal abnormal phenotypes for a majority of these genes. One strategy for uncovering gene function when single-mutant lines do not produce an informative phenotype is to perform a systematic genetic interaction screen whereby double-mutants are created from a large library of single-mutant lines. Here we describe a new collection of 275 double-mutant lines derived from a library of single-mutants targeting genes related to MAP kinase signaling. To facilitate this study, we developed a high-throughput double-mutant generating pipeline using a system for growing Arabidopsis seedlings in 96-well plates. A quantitative root growth assay was used to screen for evidence of genetic interactions in this double-mutant collection. Our screen revealed four genetic interactions, all of which caused synthetic enhancement of the root growth defects observed in a MAP kinase 4 (MPK4) single-mutant line. Seeds for this double-mutant collection are publicly available through the Arabidopsis Biological Resource Center. Scientists interested in diverse biological processes can now screen this double-mutant collection under a wide range of growth conditions in order to search for additional genetic interactions that may provide new insights into MAP kinase signaling. PMID- 27490955 TI - Microbiota Characterization of Compost Using Omics Approaches Opens New Perspectives for Phytophthora Root Rot Control. AB - Phytophthora root rot caused by Phytophthora nicotianae is an economically important disease in pepper crops. The use of suppressive composts is a low environmental impact method for its control. Although attempts have been made to reveal the relationship between microbiota and compost suppressiveness, little is known about the microorganisms associated with disease suppression. Here, an Ion Torrent platform was used to assess the microbial composition of composts made of different agro-industrial waste and with different levels of suppressiveness against P. nicotianae. Both bacterial and fungal populations responded differently depending on the chemical heterogeneity of materials used during the composting process. High proportions (67-75%) of vineyard pruning waste were used in the most suppressive composts, COM-A and COM-B. This material may have promoted the presence of higher relative abundance of Ascomycota as well as higher microbial activity, which have proved to be essential for controlling the disease. Although no unique fungi or bacteria have been detected in neither suppressive nor conducive composts, relatively high abundance of Fusarium and Zopfiella were found in compost COM-B and COM-A, respectively. To the best of our knowledge, this is the first work that studies compost metabolome. Surprisingly, composts and peat clustered together in principal component analysis of the metabolic data according to their levels of suppressiveness achieved. This study demonstrated the need for combining the information provided by different techniques, including metagenomics and metametabolomics, to better understand the ability of compost to control plant diseases. PMID- 27490956 TI - Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening. AB - The mediator complex-associated cyclin dependent kinase CDK8 regulates beta catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl 1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies. PMID- 27490957 TI - Fragility Fracture Incidence in Chronic Obstructive Pulmonary Disease (COPD) Patients Associates With Nanoporosity, Mineral/Matrix Ratio, and Pyridinoline Content at Actively Bone-Forming Trabecular Surfaces. AB - Chronic obstructive pulmonary disease (COPD) is associated with low areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) and altered microstructure by bone histomorphometry and micro-computed tomography. Nevertheless, not all COPD patients sustain fragility fractures. In the present study, we used Raman microspectroscopic analysis to determine bone compositional properties at actively forming trabecular surfaces (based on double fluorescent labels) in iliac crest biopsies from 19 postmenopausal COPD patients (aged 62.1 +/- 7.3 years). Additionally, we analyzed trabecular geometrical centers, representing tissue much older than the forming surfaces. Eight of the patients had sustained fragility fractures, and 13 had received treatment with inhaled glucocorticoids. None of the patients had taken oral glucocorticoids. The monitored parameters were mineral/matrix ratio (MM), nanoporosity, and relative glycosaminoglycan (GAG), lipid, and pyridinoline contents (PYD). There were no significant differences between the glucocorticoid-treated patients and those who did not receive any. On the other hand, COPD patients sustaining fragility fractures had significantly lower nanoporosity and higher MM and PYD values compared with COPD patients without fragility fractures. To the best of our knowledge, this is the first study to discriminate between fracture and non fracture COPD patients based on differences in the material properties of bone matrix. Given that these bone material compositional differences are evident close to the cement line (a major bone interface), they may contribute to the inferior bone toughness and coupled with the lower lumbar spine bone mineral density values result in the fragility fractures prevalent in these patients. (c) 2016 American Society for Bone and Mineral Research. PMID- 27490953 TI - Protocols for Molecular Modeling with Rosetta3 and RosettaScripts. AB - Previously, we published an article providing an overview of the Rosetta suite of biomacromolecular modeling software and a series of step-by-step tutorials [Kaufmann, K. W., et al. (2010) Biochemistry 49, 2987-2998]. The overwhelming positive response to this publication we received motivates us to here share the next iteration of these tutorials that feature de novo folding, comparative modeling, loop construction, protein docking, small molecule docking, and protein design. This updated and expanded set of tutorials is needed, as since 2010 Rosetta has been fully redesigned into an object-oriented protein modeling program Rosetta3. Notable improvements include a substantially improved energy function, an XML-like language termed "RosettaScripts" for flexibly specifying modeling task, new analysis tools, the addition of the TopologyBroker to control conformational sampling, and support for multiple templates in comparative modeling. Rosetta's ability to model systems with symmetric proteins, membrane proteins, noncanonical amino acids, and RNA has also been greatly expanded and improved. PMID- 27490958 TI - The Predentary Bone and Its Significance in the Evolution of Feeding Mechanisms in Ornithischian Dinosaurs. AB - The characteristic predentary bone in ornithischian dinosaurs is a unique, unpaired element located at the midline of the mandibular symphysis. Although traditionally thought to only be a plant "nipping" bone, the true functional significance of this bone among feeding mechanisms of ornithischian dinosaurs is poorly known. Recent studies of a select few ornithischian genera have suggested rotation of the mandibular corpora around their long axes relative to their midline joint articulation with the predentary bone. This study aims to re evaluate these hypotheses as well as provide in-depth qualitative comparative descriptions of predentary bone morphology in ornithischian genera throughout all subclades, including heterodontosaurids, thyreophorans, ornithopods, and marginocephalians. Descriptions evaluate overall shape of the predentary, its articular surfaces contacting the rostral ends of the dentaries, and the morphology of the rostral extent of the dentaries and their midline symphysis. Functionally relevant morphologies in each predentary morphotype are accentuated for further speculation of feeding mechanisms. Three predentary morphotypes are described throughout ornithischian subclades and each plays a unique role in feeding adaptations. Most notably, the predentary likely evolved as a midline axial point of the mandibular symphysis for simultaneous variable movement or rotation of the mandibular corpora in many, but not all, taxa. This simultaneous movement of the hemimandibles would have aided in feeding on both sides of the jaw at once. The function of the predentary as well as other jaw adaptations is discussed for genera throughout all subclades, focusing on both general shape and joint morphology. Anat Rec, 299:1358-1388, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27490959 TI - Uptake, distribution in different tissues, and genotoxicity of imidacloprid in the freshwater fish Australoheros facetus. AB - The neonicotinoid imidacloprid is under re-evaluation by regulatory agencies because of the poor current information available regarding its potential effects. One of the goals of the present study was to determine imidacloprid uptake and distribution in the freshwater fish Australoheros facetus experimentally exposed for 24 h and 48 h to 100 MUg/L, 300 MUg/L, and 2500 MUg/L. The toxicity of imidacloprid to fish reported in the literature is in the milligrams per liter or gram per liter range, but sublethal effects at micrograms per liter in some groups other than fish have been described. Another goal of the present study was to evaluate imidacloprid's potential genotoxicity and to compare it between the individual compound and a commercial formulation. Concentrations of imidacloprid were measured in water, brain, muscle, gills, gut, liver, and blood by liquid chromatography-tandem mass spectrometry. Imidacloprid was detected in all the tissues tested. Concentrations were higher after 48 h than after 24 h in liver, gills, gut, and muscle, whereas in brain and blood they were similar at both exposure times. Although there was no accumulation, only uptake, of imidacloprid, genotoxicity was observed. In fish exposed to IMIDA NOVA 35(r) , increased micronucleus frequency at 100 ug/L and 1000 ug/L was detected, whereas in the imidacloprid active ingredient bioassay it increased only at 1000 ug/L imidacloprid. The present findings warn of the possible consequences that fish living in freshwater ecosystems can suffer. Environ Toxicol Chem 2017;36:699 708. (c) 2016 SETAC. PMID- 27490960 TI - One-Pot Synthesis of 2-Cyano-1,4-diketones: Applications to Synthesis of Cyanosubstituted Furans, Pyrroles, and Dihydropyridazines. AB - A convenient synthetic route for the construction of functionalized 2-cyano-1,4 diketones has been established from the nucleophilic substitution of 2 bromoacetophenones with NaCN via the in situ-generated beta-ketonitriles. This method was further applied to the synthesis of cyanosubstituted furans, pyrroles, or dihydropyridazines, which were obtained in good to excellent yields using Bi(OTf)3, NH4OAc, or N2H4. The key structures were confirmed by X-ray single crystal diffraction analysis. PMID- 27490961 TI - New Perspectives in Multiple Primary Colorectal Cancer: A Surgical Approach. AB - BACKGROUND: We identify the features of multiple primary colorectal cancer (MPCC), synchronous colorectal cancer (SCRC) and metachronous colorectal cancer (MCRC), and distinguish between the cases that require a more extensive surgery and those where the parameters of SCRC might be important to prevent the development of MCRC. METHODS: We gathered up consecutive individuals with MPCC, 50 for each category, and 100 consecutive individuals diagnosed with 'single' colorectal cancer. Clinical and familiar information was obtained. We classified both SCRC and MCRC according to locations. RESULTS: MPCC were associated with polyps, both in earlier stages and as sporadic forms. SCRC located in the right colon were most frequently of the mucinous type. MCRC developed SCRC in 24%, along the entire colon, with familiar cancer antecedents. SCRC patients undergoing a total colectomy were younger, with the cancer spread throughout the entire colon and a larger number of polyps, whereas MCRC were predominantly adenomatous polyps. We found 2 risk factors for SCRC that led to the development of MCRC: rectal location and higher number of polyps. CONCLUSIONS: SCRC possibly involves more than an environmental component. MCRC appears to be the producer of polyps that evolve into cancer at different times, emphasising the idea of a genetic predisposition. Studies are required to find biomarkers that define patients with higher risk of developing MCRC within SCRC. PMID- 27490962 TI - Glasgow Gloom or Leeds Glue? Dialect-Specific Vowel Duration Constrains Lexical Segmentation and Access. AB - Timing cues are important in many aspects of speech processing, fromidentifying segments to locating word and phrase boundaries. They vary across accents, yet representation and processing of this variation are poorly understood. We investigated whether an accent difference in vowel duration affects lexical segmentation and access. In Glasgow English (GE), /i u e o/ are shorter than in Leeds English (LE), especially for /i u/ before voiced stops and nasals. In a word-spotting experiment, GE and LE participants heard nonsense sequences (e.g. pobegloomezh) containing embedded words (gloom, glue), with segmental qualities intermediate between GE and LE. Critical vowel durations were manipulated according to accent (GE-appropriate vowels shorter than LE-appropriate ones) and phonological context (vowels shortest before voiceless stops < voiced stops/nasals < voiced fricatives). GE participants generally spotted words like gloom more accurately with GE-appropriate than LE-appropriate vowels. LE participants were less accurate than GE participants to spot words like gloom with GE-appropriate vowels, but more likely to spot embeddings like glue. These results were broadly as predicted based on the accent differences, but depended less than expected on the accent-specific phonological constraints. We discuss theoretical implications regarding the representation of duration and the time course of lexical access. PMID- 27490963 TI - Comprehension of texts by deaf elementary school students: The role of grammatical understanding. AB - BACKGROUND: The aim of this study was to analyze how the reading process of deaf Spanish elementary school students is affected both by those components that explain reading comprehension according to the Simple View of Reading model: decoding and linguistic comprehension (both lexical and grammatical) and by other variables that are external to the reading process: the type of assistive technology used, the age at which it is implanted or fitted, the participant's socioeconomic status and school stage. DESIGN: Forty-seven students aged between 6 and 13 years participated in the study; all presented with profound or severe prelingual bilateral deafness, and all used digital hearing aids or cochlear implants. Students' text comprehension skills, decoding skills and oral comprehension skills (both lexical and grammatical) were evaluated. RESULTS: Logistic regression analysis indicated that neither the type of assistive technology, age at time of fitting or activation, socioeconomic status, nor school stage could predict the presence or absence of difficulties in text comprehension. Furthermore, logistic regression analysis indicated that neither decoding skills, nor lexical age could predict competency in text comprehension; however, grammatical age could explain 41% of the variance. Probing deeper into the effect of grammatical understanding, logistic regression analysis indicated that a participant's understanding of reversible passive object-verb-subject sentences and reversible predicative subject-verb-object sentences accounted for 38% of the variance in text comprehension. CONCLUSIONS: Based on these results, we suggest that it might be beneficial to devise and evaluate interventions that focus specifically on grammatical comprehension. PMID- 27490964 TI - Astigmatism corrected common path probe for optical coherence tomography. AB - BACKGROUND AND OBJECTIVES: Optical coherence tomography (OCT) catheters for intraluminal imaging are subject to various artifacts due to reference-sample arm dispersion imbalances and sample arm beam astigmatism. The goal of this work was to develop a probe that minimizes such artifacts. MATERIALS AND METHODS: Our probe was fabricated using a single mode fiber at the tip of which a glass spacer and graded index objective lens were spliced to achieve the desired focal distance. The signal was reflected using a curved reflector to correct for astigmatism caused by the thin, protective, transparent sheath that surrounds the optics. The probe design was optimized using Zemax, a commercially available optical design software. Common path interferometric operation was achieved using Fresnel reflection from the tip of the focusing graded index objective lens. The performance of the probe was tested using a custom designed spectrometer-based OCT system. RESULTS: The probe achieved an axial resolution of 15.6 MUm in air, a lateral resolution 33 MUm, and a sensitivity of 103 dB. A scattering tissue phantom was imaged to test the performance of the probe for astigmatism correction. Images of the phantom confirmed that this common-path, astigmatism corrected OCT imaging probe had minimal artifacts in the axial, and lateral dimensions. CONCLUSIONS: In this work, we developed an astigmatism-corrected, common path probe that minimizes artifacts associated with standard OCT probes. This design may be useful for OCT applications that require high axial and lateral resolutions. Lasers Surg. Med. 49:312-318, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27490965 TI - The effects of short-term JNK inhibition on the survival and growth of aged sympathetic neurons. AB - During the course of normal aging, certain populations of nerve growth factor (NGF)-responsive neurons become selectively vulnerable to cell death. Studies using dissociated neurons isolated from neonates have shown that c-Jun N-terminal kinases (JNKs) are important in regulating the survival and neurite outgrowth of NGF-responsive sympathetic neurons. Unlike neonatal neurons, adult sympathetic neurons are not dependent on NGF for their survival. Moreover, the NGF precursor, proNGF, is neurotoxic for aging but not young adult NGF-responsive neurons. Because of these age-related differences, the effects of JNK inhibition on the survival and growth of sympathetic neurons isolated from aged mice were studied. Aged neurons, as well as glia, were found to be dependent on JNK for their growth but not their survival. Conversely, proNGF neurotoxicity was JNK-dependent and mediated by the p75-interacting protein NRAGE, whereas neurite outgrowth was independent of NRAGE. These results have implications for the potential use of JNK inhibitors as therapies for ameliorating age-related neurodegenerative disease. PMID- 27490966 TI - Cheminformatics Based Machine Learning Models for AMA1-RON2 Abrogators for Inhibiting Plasmodium falciparum Erythrocyte Invasion. AB - Malaria remains a dreadful disease by putting every year about 3.4 billion people at risk and resulting into mortality of 627 thousand people worldwide. Existing therapies based upon Quinines and Artemisinin-based combination therapies have started showing resistance, pressing the need for search of anti-malarials with different mechanisms of action. In this respect erythrocyte invasion by Plasmodium is immensely crucial, as being obligate intracellular parasite it must invade host cells. This process is mediated by interaction between conserved Apical Membrane Antigen (AMA1) and Rhoptry Neck (RON2) protein, which is compulsory for successful invasion of erythrocyte by Plasmodium and manifestation of the disease Malaria. Here, using the physicochemical properties of the compounds available from a confirmatory high throughput screening, which were tested for their disruption capability of this crucial molecular interaction, we trained supervised classifiers and validated their robustness by various statistical parameters. Best model was used for screening new compounds from Traditional Chinese Medicine Database. Some of the best hits already find their use as anti-malarials and the model predicts that an essential part of their effectiveness is likely due to inhibition of AMA1-RON2 interaction. Pharmacophoric features have also been identified to ease further designing of possible leads in an effective way. PMID- 27490967 TI - Structural Models for the Design of PKMzeta Inhibitors with Neurobiological Indications. AB - An atypical protein kinase C, PKMzeta has become an attractive target for various neurological disorders including long term potentiation, cognition, neuropathic pain and cancer. Drug discovery efforts have been hindered due to the non availability of the protein structure and hence in the present study we attempted to build the open and closed models of the protein PKMzeta using homology modeling. The models were then used to identify PKMzeta inhibitors utilizing a high-throughput virtual screening protocol from a large commercial chemical database. Compounds were selected based on the binding interactions and Glide score. Compounds were then subjected to in vitro luminescent based kinase assay for their inhibitory activity on targeted protein. Seven compounds exhibited IC50 s less than or equal to 10 uM. Cell based assays revealed that Lead C3 and Lead C6 exhibited selectivity towards methylmercury treated neuroblastoma growth inhibition and suppressed reactive oxygen species with IC50 s of 0.89 and 0.17 uM, respectively. Furthermore, Lead C3 exhibited attenuation of proinflammatory response with least energy in dynamic simulation studies and thus emerged as a prototypical lead for further development as novel inhibitor of PKMzeta for neurological implications. PMID- 27490968 TI - Quantitative Regression Models for the Prediction of Chemical Properties by an Efficient Workflow. AB - Rapid safety assessment is more and more needed for the increasing chemicals both in chemical industries and regulators around the world. The traditional experimental methods couldn't meet the current demand any more. With the development of the information technology and the growth of experimental data, in silico modeling has become a practical and rapid alternative for the assessment of chemical properties, especially for the toxicity prediction of organic chemicals. In this study, a quantitative regression workflow was built by KNIME to predict chemical properties. With this regression workflow, quantitative values of chemical properties can be obtained, which is different from the binary classification model or multi-classification models that can only give qualitative results. To illustrate the usage of the workflow, two predictive models were constructed based on datasets of Tetrahymena pyriformis toxicity and Aqueous solubility. The qcv (2) and qtest (2) of 5-fold cross validation and external validation for both types of models were greater than 0.7, which implies that our models are robust and reliable, and the workflow is very convenient and efficient in prediction of various chemical properties. PMID- 27490969 TI - Identification of Lead Compounds as Inhibitors of STAT3: Design, Synthesis and Bioactivity. AB - STAT3 belongs to the signal transducers and activators of transcription (STAT) family. It has been demonstrated that STAT3 is constitutively activated in many tumors, playing a role in carcinogenesis and tumor progression. For this reason, it has being considered a potential target for cancer therapy. In this context, we have designed, synthesized and evaluated 1,4-dimethyl-carbazole derivatives, targeting the STAT3 protein. Moreover, MTT assay performed on A375 and HeLa, showed significant antiproliferative activity of some of synthesized compounds (3 5). The same compounds (3-5) considerably reduced STAT3 expression, as demonstrated by Western blot analysis. Our multidisciplinary approach shows that 1,4-dimethyl-carbazoles are potential building blocks to develop more affinity ligands of STAT3. PMID- 27490970 TI - Pred-hERG: A Novel web-Accessible Computational Tool for Predicting Cardiac Toxicity. AB - The blockage of the hERG K(+) channels is closely associated with lethal cardiac arrhythmia. The notorious ligand promiscuity of this channel earmarked hERG as one of the most important antitargets to be considered in early stages of drug development process. Herein we report on the development of an innovative and freely accessible web server for early identification of putative hERG blockers and non-blockers in chemical libraries. We have collected the largest publicly available curated hERG dataset of 5,984 compounds. We succeed in developing robust and externally predictive binary (CCR~0.8) and multiclass models (accuracy~0.7). These models are available as a web-service freely available for public at http://labmol.farmacia.ufg.br/predherg/. Three following outcomes are available for the users: prediction by binary model, prediction by multi-class model, and the probability maps of atomic contribution. The Pred-hERG will be continuously updated and upgraded as new information became available. PMID- 27490971 TI - Coupled Biosynthesis of Volatiles and Salinosporamide A in Salinispora tropica. AB - Terrestrial bacteria, especially actinomycetes, are known to be prolific producers of volatile compounds. We show here that bacteria from ocean sediments can also release complex bouquets of volatiles. The actinomycete Salinispora tropica produces cyclohexenyl compounds not previously known in nature, such as methyl cyclohex-2-ene-1-carboxylate (9), methyl 2-(cyclohex-2-en-1-yl)acetate (10), methyl (E/Z)-2-(cyclohex-2-en-1-ylidene)acetate (11/12), and related alcohols 8 and 13. These compounds were identified by GC/MS and confirmed by synthesis. In addition, rare spiroacetals, aromatic compounds, short-chain acids and esters, alcohols, and various cyclic compounds were produced by the bacteria. The biosynthesis of the cyclohexenyl compounds is closely coupled to that of cyclohexenylalanine (4), a building block of salinosporamide A, a proteasome inhibitor produced by S. tropica. Analysis of S. tropica strains that harbor knockouts of the salinosporamide biosynthetic genes salX and salD, coupled with feeding experiments, revealed that 3-(cyclohex-2-en-1-yl)-2-oxopropanoic acid (60) and 3-(cyclohex-2-en-1-ylidene)-2-oxopropanoic acid (isomers 61 and 62) are important intermediates in the biosynthesis of salinosporamide A, 4, and 8-13. PMID- 27490972 TI - Effects of a stocking on plantar sensation in individuals with and without ankle instability. AB - INTRODUCTION: It is unknown whether footwear has a beneficial or deleterious effect on cutaneous sensitivity. We aimed to test a preliminary model of footwear and its effect on tactile perception among groups of controls, copers, and chronic ankle instability participants. METHODS: Light-touch thresholds were obtained for 45 participants (age: 20.2 +/- 2.8 years; height: 167.6 +/- 9.8 cm; mass: 66.3 +/- 14.7 kg) using Semmes-Weinstein monofilaments at the head of the first metatarsal (1MT), base of the fifth metatarsal (5MT), and calcaneus (CAL). Baseline measurements were compared with those taken after wearing a nylon stocking for 5 min. RESULTS: Thresholds were increased at all 3 sites when the stocking was worn (P < 0.05). Controls had an increase at 1MT, copers had an increase at 5MT and CAL, and chronic ankle instability had an increase at CAL. CONCLUSIONS: Cutaneous thresholds increase when subjects wear a nylon stocking, a model for the sensory effects of footwear. A history of ankle injury appears to influence which sites have altered sensibility. Muscle Nerve, 2016. Muscle Nerve 55: 513-519, 2017. PMID- 27490973 TI - Anti-ApoA-1 IgG serum levels predict worse poststroke outcomes. AB - BACKGROUND: Autoantibodies to apolipoprotein A-1 (anti-ApoA-1 IgG) were shown to predict major adverse cardiovascular events and promote atherogenesis. However, their potential relationship with clinical disability and ischaemic lesion volume after acute ischaemic stroke (AIS) remains unexplored. MATERIALS AND METHODS: We included n = 76 patients admitted for AIS and we investigated whether baseline serum anti-ApoA-1 IgG levels could predict (i) AIS-induced clinical disability [assessed by the modified Rankin Scale (mRS)], and (ii) AIS-related ischaemic lesion volume [assessed by Computed Tomography (CT)]. We also evaluated the possible pro-apoptotic and pro-necrotic effects of anti-ApoA-1 IgG on human astrocytoma cell line (U251) using flow cytometry. RESULTS: High levels of anti ApoA-1 IgG were retrieved in 15.8% (12/76) of patients. Increased baseline levels of anti-ApoA-1 IgG were independently correlated with worse mRS [beta = 0.364; P = 0.002; adjusted odds ratio (OR): 1.05 (95% CI 1.01-1.09); P = 0.017] and CT assessed ischaemic lesion volume [beta = 0.333; P < 0.001; adjusted OR: 1.06 (95% CI 1.01-1.12); P = 0.048] at 3 months. No difference in baseline clinical, biochemical and radiological characteristics was observed between patients with high vs. low levels of anti-ApoA-1 IgG. Incubating human astrocytoma cells with anti-ApoA-1 IgG dose dependently induced necrosis and apoptosis of U251 cells in vitro. CONCLUSION: Anti-ApoA-1 IgG serum levels at AIS onset are associated with poorer clinical recovery and worse brain lesion volume 3 months after AIS. These observations could be partly explained by the deleterious effect of anti-ApoA-1 IgG on human brain cell survival in vitro and may have clinical implication in the prediction of poor outcome in AIS. PMID- 27490974 TI - Electrical Conductivity, Thermoelectric Power, and Equilibration Kinetics of Nb Doped TiO2. AB - This work considers the equilibration kinetics of Nb-doped TiO2 single crystal (0.066 atom % Nb) during oxidation and reduction within a wide range of temperature (1073-1298 K) and oxygen activity (10(-14)-10(5) Pa). The associated semiconducting properties were determined using simultaneous measurements of both electrical conductivity and thermoelectric power. It is shown that the chemical diffusion coefficient in the strongly reducing regime, p(O2) < 10(-5) Pa, is 4 orders of magnitude larger than that in the reducing and oxidizing regimes, 10 Pa < p(O2) < 22 kPa. The derived theoretical model considers the gas/solid kinetics for the TiO2/O2 system in terms of two diffusion regimes: the fast regime related to fast defects (oxygen vacancies and titanium interstitials) and leading to quasi-equilibrium, and the slow regime associated with slow defects (titanium vacancies) resulting in the gas/solid equilibrium. It has been shown that incorporation of donor-type elements, such as niobium, and imposition of oxygen activity above a certain critical value, results in a substantial reduction in the concentration of high mobility defects and leads to slowing down the equilibration kinetics. In consequence, the fast kinetic regime is not observed. Comparison of the kinetic data for Nb-doped TiO2 single crystal (this work) and polycrystalline Nb-doped TiO2 (reported before) indicates that the gas/solid kinetics for the polycrystalline specimen at higher oxygen activities is rate controlled by the transport of oxygen within individual grains. PMID- 27490975 TI - Reply. PMID- 27490976 TI - PEMBROLIZUMAB ADMINISTRATION ASSOCIATED WITH POSTERIOR UVEITIS. AB - PURPOSE: To describe the development of uveitis and retinal vasculitis in association with pembrolizumab treatment for metastatic uveal melanoma. METHODS: A case report and a brief review of the literature are presented. Information collected and reported include the patient's clinical course, physical examination findings, fluorescein angiogram images, retinal photographs, and her response to treatment. RESULTS: A 54-year-old woman was diagnosed with a large choroidal malignant melanoma and had the affected eye enucleated. Pathology confirmed a mixed cell choroidal melanoma, and gene expression profiling was Class 2. Seventeen months after enucleation, the patient was diagnosed with metastatic uveal melanoma to the liver. Disease progression was observed during ipilimumab treatment. Pembrolizumab treatment was initiated, and after four infusions, she presented to clinic complaining of floaters and blurred vision. Examination revealed a nongranulomatous panuveitis characterized by perivascular retinal pigment epithelium pigmentary changes, retinal venous sheathing, 1+ anterior chamber and vitreous cellular reaction, 2+ vitreous haze, and optic disk edema. A dexamethasone sustained-release implant was administered and the uveitis regressed. A relapse in symptoms occurred but quickly subsided with a repeat injection. CONCLUSION: Pembrolizumab may induce a uveitic reaction. There is mounting evidence that patients using prembrolizumab should be educated and monitored for signs of uveitis. PMID- 27490977 TI - BRANCH RETINAL ARTERY OCCLUSION ASSOCIATED WITH PARACENTRAL ACUTE MIDDLE MACULOPATHY IN A PATIENT WITH LIVEDO RETICULARIS. AB - PURPOSE: To report the occurrence of a branch retinal artery occlusion with paracentral acute middle maculopathy in an otherwise healthy young man with a history of livedo reticularis (LR). METHODS: Retrospective case report. PATIENTS: A 21-year-old man with a history of LR being treated with pentoxifylline developed an acute branch retinal artery occlusion with initial best-corrected visual acuity at presentation of 20/80. RESULTS: A thorough diagnostic work up was negative for potential causes of branch retinal artery occlusion or LR. The patient was continued on pentoxifylline and started on aspirin 81 mg daily. At five-month follow-up, vision had improved to 20/25. Optical coherence tomography testing showed a hyperreflective band in the inner nuclear layer and outer plexiform layers in the affected eye that ultimately thinned, consistent with paracentral acute middle maculopathy. CONCLUSION: To our knowledge, this is the first case of branch retinal artery occlusion occurring in a patient with a history of LR. This could potentially be an early manifestation of Sneddon syndrome, a rare entity characterized by LR and cerebrovascular disease, which has been previously associated with central retinal artery occlusions. PMID- 27490978 TI - Correspondence. PMID- 27490979 TI - Chemodiversity of the Essential Oil from Leaves of Abies nebrodensis (Lojac.) Mattei. AB - Abies nebrodensis (Lojac.) Mattei (Pinaceae) is a species occurring in a very small population only in a restricted area of Sicily. Its taxonomic classification as different species has been object of discussion. In this work the chemical composition of the essential oil from the leaves is presented for the first time and compared to the essential oils from other euroasiatic species reported in literature. Peculiar characteristics of the essential oil of A. nebrodensis are highlighted. PMID- 27490980 TI - Multi-disciplinary management of complex pressure sore reconstruction: 5-year review of experience in a spinal injuries centre. AB - INTRODUCTION In our regional spinal injuries unit, complex pressure ulcer reconstruction is facilitated by a monthly multidisciplinary team clinic. This study reviews a series of the more complex of these patients who underwent surgery as a joint case between plastics and other surgical specialties, aiming to provide descriptive data as well as share the experience of treating these complex wounds. MATERIALS AND METHODS Patients operated on as a joint case from 2010 to 2014 were identified through a locally held database and hospital records were then retrospectively reviewed for perioperative variables. Descriptive statistics were collected. RESULTS 12 patients underwent 15 procedures as a joint collaboration between plastic surgery and other surgical specialties: one with spinal surgery, 12 with orthopaedic and two with both orthopaedic and urology involvement. Ischial and trochanteric wounds accounted for 88% of cases with five Girdlestone procedures being performed and 12 requiring soft-tissue flap reconstruction. Mean operative time was 3.8hours. Four patients required high dependency care and 13 patients received long-term antibiotics. Only three minor complications (20%) were seen with postoperative wound dehiscence. DISCUSSION The multidisciplinary team clinic allows careful assessment and selection of patients appropriate for surgical reconstruction and to help match expectations and limitations imposed by surgery, which are likely to influence their current lifestyle in this largely independent patient group. Collaboration with other specialties gives the best surgical outcome both for the present episode as well as leaving avenues open for potential future reconstruction. PMID- 27490981 TI - The use of FloSeal haemostatic sealant in the management of epistaxis: a prospective clinical study and literature review. AB - INTRODUCTION It is standard practice in the UK that if conservative measures or chemical cautery fail to control epistaxis, patients receive nasal packing which is often uncomfortable, requires admission and has well documented associated morbidity. Our study aims to evaluate the use of FloSeal haemostatic sealant in managing patients with epistaxis. MATERIALS AND METHODS Patients were identified from those referred with active epistaxis. A successful outcome was defined as complete haemostasis with FloSeal alone, with no further significant bleeding requiring admission or further interventions in the subsequent 7 days. Patients reported satisfaction using a ten-point visual analogue scale. Ear, nose and throat doctors recorded patient demographics, time to prepare FloSeal, length of stay, need for further treatment and adverse events on an electronic database. RESULTS 30 patients were enrolled in the study. The mean time to prepare FloSeal was 5 minutes. The success rate of FloSeal was 90%. The mean length of stay was 2.75 hours. The mean patient satisfaction with FloSeal was 8.4/10. No adverse events occurred. DISCUSSION FloSeal was found to be effective in controlling anterior epistaxis. There was a single case of posterior epistaxis which required operative management. The literature largely supports FloSeal in anterior epistaxis, but indicates sphenopalatine artery ligation as the definitive management of posterior epistaxis. CONCLUSIONS Our data support the use of FloSeal in patients with anterior epistaxis not controlled with conservative measures or chemical cautery. It was found to be easy to use, is well tolerated by patients and is efficient in financial terms. PMID- 27490983 TI - A folded up treatment sheet is preferable to a sandbag. PMID- 27490982 TI - Correlation of Ki-67 indices from biopsy and resection specimens of neuroendocrine tumours. AB - INTRODUCTION Neuroendocrine tumours (NETs) are a heterogeneous group of tumours with a highly variable presentation and prognosis. Management decisions are complex. Ki-67 levels in tissue samples are a key indicator used to grade tumours and guide treatment. This study assessed whether the Ki-67 index and tumour grade generated from tissue samples correlated with that assessed in resection specimens. METHODS This was a retrospective cohort analysis of all patients who had both a tissue sample and a resection specimen analysed in our trust, a tertiary referral centre, during 2012 and 2013. RESULTS Data from 36 patients were reviewed. Ki-67 indices from tissue samples and resection specimens showed strong correlation (r=0.95, p<0.001). Tumour grading was the same in the tissue sample and resection specimens for 22 patients (61.1%). In four patients (11.1%), the tissue sample overestimated the grade while in ten (27.8%), the sample underestimated the grade. CONCLUSIONS In most cases, the Ki-67 index and tumour grade from the tissue sample matched that of the resection specimen. However, in nearly 40% of cases, the tissue sample grading did not match the resection tumour grading. In the majority of these, the tissue sample underestimated disease activity. A low Ki-67 index in a tissue sample should therefore be taken as provisional and should not, in isolation, persuade clinicians to choose a more conservative treatment approach if there is clinical, biochemical or radiological evidence suggestive of a more aggressive disease pathology. PMID- 27490984 TI - A case series of a magnetic bone conduction hearing implant. AB - The objective of the study was to retrospectively review the postoperative outcomes of patients from a single centre who were implanted with a magnetic bone conduction hearing implant system. The medical and audiological case notes of all patients (n = 34) in a tertiary referral centre ENT department who had been implanted with a Baha(r) 4 Attract System between October 2013 and April 2015 were reviewed retrospectively. The main outcome measures were use of the aid and complications from implantation or use of the aid. Results indicated that 23 patients had no significant postoperative problems; 5 required an alteration in magnet strength; 1 reported troublesome tinnitus; 1 had the implant changed to an abutment system; 1 had the magnet removed; 1 has ongoing skin problems; 2 have been changed to a newer, lighter sound processor. The majority of patients had good outcomes from the magnetic bone conduction aid. A proportion of patients had significant problems requiring medical attention. PMID- 27490985 TI - Mechanisms, patterns and outcomes of paediatric polytrauma in a UK major trauma centre. AB - Introduction Paediatric trauma is a significant burden to healthcare worldwide and accounts for a large proportion of deaths in the UK. Methods This retrospective study examined the epidemiological data from a major trauma centre in the UK between January 2012 and December 2014, reviewing all cases of moderate to severe trauma in children. Patients were included if aged <=16 years and if they had an abbreviated injury scale score of >=2 in one or more body region. Results A total of 213 patients were included in the study, with a mean age of 7.8 years (standard deviation [SD]: 5.2 years). The most common cause of injury was vehicle related incidents (46%). The median length of hospital stay was 5 days (interquartile range [IQR]: 4-10 days). Approximately half (52%) of the patients had to stay in the intensive care unit, for a median of 1 day (IQR: 0-2 days). The mortality rate was 6.6%. The mean injury severity score was 19 (SD: 10). Pearson's correlation coefficient showed a positive correlation for injury severity score with length of stay in hospital (p<0.001). Conclusions There is significant variation in mechanism of injury, severity and pattern of paediatric trauma across age groups. A multidisciplinary team approach is imperative, and patients should be managed in specialist centres to optimise their care and eventual functional recovery. Head injury remained the most common, with significant mortality in all age groups. Rib fractures and pelvic fractures should be considered a marker for the severity of injury, and should alert doctors to look for other associated injuries. PMID- 27490986 TI - Contemporary characteristics of blunt abdominal trauma in a regional series from the UK. AB - INTRODUCTION Blunt abdominal trauma (BAT) is a common injury in recent trauma series. The characteristics of patients with BAT have changed following the reconfiguration of UK trauma services. The aim of this study was to build a new profile for BAT patients undergoing immediate or delayed laparotomy. METHODS All 5,401 consecutive adults presenting with major trauma between April 2012 and April 2014 in the 3 major trauma centres in the West Midlands were analysed to identify all patients with BAT. A total of 2,793 patients with a mechanism of injury or symptomatology consistent with BAT were identified (52%). Outcomes were analysed using local electronic clinical results systems and notes. RESULTS Of the 2,793 patients, 179 (6.4%) had a mesenteric or hollow viscus injury, 168 (6.0%) had a hepatobiliary injury, 149 (5.4%) had a splenic injury and 46 (1.6%) had a vascular injury. Overall, 103 patients (3.7%) underwent an early (<12 hours) laparotomy while 30 (1.1%) underwent a delayed (>12 hours) laparotomy. Twenty (66.7%) of those undergoing a delayed laparotomy had a hollow viscus injury. In total, 170 deaths occurred among the BAT patients (6.1%). In the early laparotomy group, 53 patients died (51.5%) whereas in the delayed laparotomy group, 6 patients died (20.0%). CONCLUSIONS This series has attempted to provide the characteristics of patients with BAT in a large contemporary UK cohort. BAT was found to be a common type of injury. Early and delayed laparotomy occurred in 3.7% and 1.1% of these patients respectively, mostly because of hollow viscus injury in both cases. Outcomes were comparable with those in the international literature from regions with mature trauma services. PMID- 27490987 TI - Mandibular sagittal split osteotomy - A modified technique to reduce postoperative labiomental paraesthesia. PMID- 27490988 TI - A giant testicular mixed germ cell tumour. AB - We present a case that we believe to be the largest mixed germ cell testicular tumour reported in the United Kingdom. A 23-year-old male was admitted to our urology department with a large scrotal swelling. The patient was found to have a giant left testicular tumour and a solitary lung metastasis at presentation. He underwent an emergency radical orchidectomy and subsequently received four cycles of bleomycin, etoposide and cisplatin chemotherapy. Four months after starting treatment, the tumour markers had normalised and a repeat staging computed tomography showed no active disease. The tumour reached that size because of the patient's failure to seek medical attention due to fear and embarrassment. PMID- 27490989 TI - Surgical management of complex intra-articular distal femoral and bicondylar Hoffa fracture. AB - Bicondylar Hoffa's fractures of distal femur are rare. We report the case of an 18-year-old male who sustained a closed complex fracture of both femoral condyles of the left femur on the sagittal plane (Hoffa fracture), combined with distal metaphyseal fracture. He was treated using parallel plates and interdigitating screws, with our technique based on an extrapolation of the principles of distal humerus fixation. The fracture united clinically and radiologically at 16 weeks. Twelve months postoperatively, the range of movement in the knee was 5 degrees 115 degrees . In this complex case, our technique provided stable fixation of the fragments and a satisfactory final functional outcome. PMID- 27490990 TI - AVCpred: an integrated web server for prediction and design of antiviral compounds. AB - Viral infections constantly jeopardize the global public health due to lack of effective antiviral therapeutics. Therefore, there is an imperative need to speed up the drug discovery process to identify novel and efficient drug candidates. In this study, we have developed quantitative structure-activity relationship (QSAR) based models for predicting antiviral compounds (AVCs) against deadly viruses like human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV), human herpesvirus (HHV) and 26 others using publicly available experimental data from the ChEMBL bioactivity database. Support vector machine (SVM) models achieved a maximum Pearson correlation coefficient of 0.72, 0.74, 0.66, 0.68, and 0.71 in regression mode and a maximum Matthew's correlation coefficient 0.91, 0.93, 0.70, 0.89, and 0.71, respectively, in classification mode during 10-fold cross-validation. Furthermore, similar performance was observed on the independent validation sets. We have integrated these models in the AVCpred web server, freely available at http://crdd.osdd.net/servers/avcpred. In addition, the datasets are provided in a searchable format. We hope this web server will assist researchers in the identification of potential antiviral agents. It would also save time and cost by prioritizing new drugs against viruses before their synthesis and experimental testing. PMID- 27490991 TI - Increasing prevalence of overweight and obesity among children in Vilnius, Lithuania: comparison of two longitudinal data sets of children born in 1990 and 1996. AB - SUMMARY: The aim of this study was to assess changes in prevalence of overweight and obesity among children born in 1996 and 1990 in Vilnius city. The results were based on comparison of two longitudinal data sets (N = 624 and N = 389) collected from the personal health records of children born in 1996 and 1990 respectively. No statistically significant differences in final height and BMI were established between children born in 1990 and 1996; however, both boys and girls born in 1996 appeared to be higher and heavier at different ages compared to their peers born in 1990. After controlling for tempo, the differences in height between the two cohorts have become insignificant for girls, with exceptions at the age of 3 and 10 years; for boys, the differences between the cohorts have remained significant, however at a slightly lower level. More children born in 1996 tended to be overweight and obese. In six years, the prevalence of overweight in Vilnius children has more than doubled; the prevalence of obesity has increased up to five times in some age groups. PMID- 27490993 TI - Treatment of Proximal Interphalangeal Joint Fracture-Dislocations. PMID- 27490992 TI - Induction immunosuppression for combined heart-lung transplantation. AB - BACKGROUND: Research on induction immunosuppression in patients undergoing combined heart-lung transplantation (HLTx) is limited. METHODS: The United Network for Organ Sharing database was queried from 2000 to 2013 to examine the influence of induction immunosuppression for combined HLTx in adult (>=18 years) and adolescent (>=12 and <18 years) recipients. RESULTS: Of 394 eligible combined HLTx cases (361 adults, 33 adolescents), 384 were included in univariate Cox analysis and 116 in the multivariate Cox model. Univariate analysis demonstrated no differences in survival by induction medication and no difference among the most common maintenance immunosuppression regimens. Adjusting for use of corticosteroids, multivariate analysis demonstrated no benefit of basiliximab (HR=3.582; 95% CI: 0.966, 13.279; P=.056), thymoglobulin/antilymphocyte globulin (ALG)/antithymocyte globulin (ATG) (HR=0.808; 95% CI: 0.134, 4.888; P=.817), alemtuzumab (HR=0.369; 95% CI: 0.087, 1.563; P=.176), or other induction medications (HR=1.511; 95% CI: 0.146, 15.610; P=.729), compared to no induction medication, with respect to mortality hazard post-HLTx. There were also no differences in treated acute rejection episodes by type of induction immunosuppression. CONCLUSIONS: Induction immunosuppression with contemporary agents does not improve survival after combined HLTx. PMID- 27490994 TI - The Cavovarus Foot in Hereditary Motor and Sensory Neuropathies. PMID- 27490995 TI - Venous Thromboembolic Disease in Foot and Ankle Surgery. PMID- 27490996 TI - Neurological and Vascular Complications Associated with Supracondylar Humeral Fractures in Children. PMID- 27490997 TI - The Assessment and Treatment of High-Grade Lumbosacral Spondylolisthesis and Spondyloptosis in Children and Young Adults. PMID- 27490998 TI - Phase Structure Transition and Properties of Salt-Free Phosphoric Acid/Non-ionic Surfactants in Water. AB - Precise control of phase structure transition for the synthesis of multi dimensional soft materials is a fascinating target in amphiphilic molecule self assembly. Here, we demonstrate a spontaneous formation of a closely packed lamellar phase consisting of uni- and multi-lamellar vesicles through the incorporation of a small amount of an extractant, di(2-ethylhexyl)phosphoric acid (DEHPA), into the highly swollen, planar lamellar phase of a non-ionic tetraethylene glycol monododecyl ether (C12EO4) surfactant in water. It is figured out that the introduction of negative membrane charges results in the electrostatic repulsion among the lamellae, which suppresses the Helfrich undulation and induces a phase structure transition from planar lamellae to closely packed vesicles. Our results provide important insight into amphiphilic molecule self-assembly, where additives and pH can satisfy the opportunities for the precise tuning of the lamellar structures, which makes a way for the development of lamellar soft materials. PMID- 27490999 TI - Gap junction as an intercellular glue: Emerging roles in cancer EMT and metastasis. AB - Metastasis is a common phenomenon in the progression and dissemination of cancer. It is estimated that metastasis accounts for 90% cancer-related mortality. Although the formation of tumor metastasis is relatively well understood, the underlying molecular mechanisms responsible for the emergence of aggressive cancer phenotype are still elusive. Figuring out the mechanisms by which cancer cells evade from the tumor is beneficial for obtaining novel and effectively therapeutic approaches. Primary tumors are composed of various subpopulations of cells with heterogeneous metastatic characteristics and the occurrence of metastatic dissemination is mainly dependent upon the interactions between tumor and the surrounding microenvironment. Tumor microenvironment (TME) such as extracellular matrix, macrophages, fibroblasts, stem cells and endothelial cells can orchestrate events critical to tumor evolution toward metastasis. GJ serves as an important communication between tumor cells and stromal cells. Increased GJs coupling blocks metastatic potential in some cancer animal models such as breast cancer and melanoma. Besides, epithelial-to-mesenchymal transition (EMT) is also a crucial step in the metastatic process and there are signs that GJs contribute to cell adhesion and migration (the pathological feature of EMT) in breast cancer. Therefore, we propose that GJ serves as an intercellular glue to suppress EMT and cancer metastasis. PMID- 27491000 TI - Corrigendum to 'Ca2+/calmodulin-dependent protein kinase IIgamma, a critical mediator of the NF-kappaB network, is a novel therapeutic target in non-small cell lung cancer' [Cancer Lett. 344 (1), 119-128; March 1, 2014]. PMID- 27491001 TI - Pickering emulsions with alpha-cyclodextrin inclusions: Structure and thermal stability. AB - This paper explores structural, interfacial and thermal properties of two types of Pickering emulsions containing alpha-cyclodextrin inclusion complexes: on one hand, emulsions were obtained between aqueous solutions of alpha-cyclodextrin and different oils (fatty acids, olive oil, silicone oil) and on the other hand, emulsions were obtained between these oils, water and micro or nano-platelet suspensions with inclusion complexes of hydrophobically-modified polysaccharides. The emulsions exhibit versatile properties according to the molecular architecture of the oils. Experiments were performed by microcalorimetry, X-ray diffraction and confocal microscopy. The aptitude of oil molecules to be threaded in alpha-cyclodextrin cavity is a determining parameter in emulsification and thermal stability. The heat flow traces and images showed dissolution, cooperative melting and de-threading of inclusion complexes which take place progressively, ending at high temperatures, close or above 100 degrees C. Another important feature observed in the emulsions with micro-platelets is the partial substitution of the guest molecules occurring at room temperature at the oil/water interfaces without dissolution, possibly by a diffusion mechanism of the oil. Accordingly, the dissolution and the cooperative melting temperatures of the inclusion crystals changed, showing marked differences upon the type of guest molecules. The enthalpies of dissolution of crystals were measured and compared with soluble inclusions. PMID- 27491002 TI - Fabrication and efficient visible light photocatalytic properties of novel zinc indium sulfide (ZnIn2S4) - graphitic carbon nitride (g-C3N4)/bismuth vanadate (BiVO4) nanorod-based ternary nanocomposites with enhanced charge separation via Z-scheme transfer. AB - Novel ZnIn2S4-g-C3N4/BiVO4 nanorod-based ternary nanocomposite photocatalysts with enhanced visible light absorption were synthesized and systematically characterized to confirm the formation of ZnIn2S4 marigold flowers, the layered structure of the g-C3N4, BiVO4 nanorods, and the formation of binary and ternary nanocomposites. The visible light absorption of BiVO4 was significantly improved after coupling with g-C3N4 and ZnIn2S4, which was confirmed by UV-visible diffuse reflectance spectroscopic analysis. Ternary ZnIn2S4-g-C3N4/BiVO4 nanocomposites exhibited excellent visible light photocatalytic decomposition efficiency (VL PDE) when used for the degradation of congo red (CR) dye and metronidazole (MTZ) pharmaceutical, as well as excellent stability and reusability. The ternary 5%ZnIn2S4-50%-g-C3N4/BiVO4 nanocomposite showed higher VL-PDE for CR (81.5%) and MTZ (59%) degradation than the binary composites, g-C3N4 and BiVO4. Radical quenching experiments showed that h(+), OH, and O2(-) were the reactive radicals, validating that the Z-scheme charge carrier transfer mechanism was responsible for the enhanced VL-PDE of the ternary ZnIn2S4-g-C3N4/BiVO4 nanocomposites, which was further confirmed by photoluminescence analysis. Furthermore, kinetic studies showed that the degradation followed pseudo-first-order kinetics, and that the ternary photocatalysts could be reused up to three times with good stability. The enhanced visible light absorption, high surface area, high adsorption capacity, Z scheme charge carrier transfer, and increased lifetime of photo-produced electron hole pairs were responsible for the increased visible light photocatalytic decomposition efficiency. PMID- 27491003 TI - Neuron-like gold-palladium alloy nanostructures: Rapid synthesis and applications in electrocatalysis and surface-enhanced Raman scattering. AB - Neuron-like gold-palladium (AuPd) alloy nanostructures were synthesized by simultaneous reduction of AuCl4(-) and PdCl4(2-) with ascorbic acid, using N methylimidazole as the structure-director and stabilizing agent. The synthesis method was simple and seedless, without any template or polymer. The architectures strongly depended on the concentration of N-methylimidazole, reaction temperature and time, and hence the formation mechanism was described in detail. The as-obtained architectures exhibited superior electrocatalytic activity for ethanol oxidation and surface-enhanced Raman scattering (SERS) responses, owing to their unique nanostructures with high density of steps, edges, and corners on their branches, along with the synergetic functions between Au and Pd. PMID- 27491004 TI - Improved sensing response of photo activated ZnO thin film for hydrogen peroxide detection. AB - The nanostructured ZnO thin films were deposited using spray pyrolysis technique. Formation of polycrystalinity with hexagonal wurtzite structure was observed from the structural study. Highly dense spherical shaped nanoparticles with fine crystallites were observed from the surface morphological studies. The light induced hydrogen peroxide vapour sensing was done using chemi-resistive method and its effect on the sensing response was studied and reported. PMID- 27491005 TI - Site-Specific Photolabeling of the IgG Fab Fragment Using a Small Protein G Derived Domain. AB - Antibodies are widely used reagents for recognition in both clinic and research laboratories all over the world. For many applications, antibodies are labeled through conjugation to different reporter molecules or therapeutic agents. Traditionally, antibodies are covalently conjugated to reporter molecules via primary amines on lysines or thiols on cysteines. While efficient, such labeling is variable and nonstoichiometric and may affect an antibody's binding to its target. Moreover, an emerging field for therapeutics is antibody-drug conjugates, where a toxin or drug is conjugated to an antibody in order to increase or incorporate a therapeutic effect. It has been shown that homogeneity and controlled conjugation are crucial in these therapeutic applications. Here we present two novel protein domains developed from an IgG-binding domain of Streptococcal Protein G. These domains show obligate Fab binding and can be used for site-specific and covalent attachment exclusively to the constant part of the Fab fragment of an antibody. The two different domains can covalently label IgG of mouse and human descent. The labeled antibodies were shown to be functional in both an ELISA and in an NK-cell antibody-dependent cellular cytotoxicity assay. These engineered protein domains provide novel tools for controlled labeling of Fab fragments and full-length IgG. PMID- 27491006 TI - A low frequency persistent reservoir of a genomic island in a pathogen population ensures island survival and improves pathogen fitness in a susceptible host. AB - The co-evolution of bacterial plant pathogens and their hosts is a complex and dynamic process. Host resistance imposes stress on invading pathogens that can lead to changes in the bacterial genome enabling the pathogen to escape host resistance. We have observed this phenomenon with the plant pathogen Pseudomonas syringae pv. phaseolicola where isolates that have lost the genomic island PPHGI 1 carrying the effector gene avrPphB from its chromosome are infective against previously resistant plant hosts. However, we have never observed island extinction from the pathogen population within a host suggesting the island is maintained. Here, we present a mathematical model which predicts different possible fates for the island in the population; one outcome indicated that PPHGI 1 would be maintained at low frequency in the population long term, if it confers a fitness benefit. We empirically tested this prediction and determined that PPHGI-1 frequency in the bacterial population drops to a low but consistently detectable level during host resistance. Once PPHGI-1-carrying cells encounter a susceptible host, they rapidly increase in the population in a negative frequency dependent manner. Importantly, our data show that mobile genetic elements can persist within the bacterial population and increase in frequency under favourable conditions. PMID- 27491008 TI - Protective immune responses of major Vgamma2Vdelta2 T-cell subset in M. tuberculosis infection. AB - Recent observation that prenyl pyrophosphates bind the Ig superfamily protein butyrophilin 3A1 (BTN3A1) suggests that modifying BTN3A1 activates major gammadelta T-cell subset, Vgamma2Vdelta2 T cells. Studies also show that microbial phosphoantigen HMBPP is required for expansion, pulmonary response, effector functions and memory polarization of Vgamma2Vdelta2 T cells during infections. Broad repertoires of cytokines involve expansion, recall-like expansion and effector functions of Vgamma2Vdelta2 T cells after Mtb infection or vaccination. Finally, mechanistic studies in nonhuman primate TB model demonstrate early expansion and differentiation of Vgamma2Vdelta2 T cells during Mtb infection can increase immune resistance to TB in macaques, with a potential mechanism of early/sustained IFN-gamma production and CTL killing. PMID- 27491007 TI - Tuning the anticancer activity of a novel pro-apoptotic peptide using gold nanoparticle platforms. AB - Pro-apoptotic peptides induce intrinsic apoptosis pathway in cancer cells. However, poor cellular penetration of the peptides is often associated with limited therapeutic efficacy. In this report, a series of peptide-gold nanoparticle platforms were developed to evaluate the anticancer activity of a novel alpha-lipoic acid-peptide conjugate, LA-WKRAKLAK, with respect to size and shape of nanoparticles. Gold nanoparticles (AuNPs) were found to enhance cell internalization as well as anticancer activity of the peptide conjugates. The smaller nanospheres showed a higher cytotoxicity, morphological change and cellular uptake compared to larger nanospheres and nanorods, whereas nanorods showed more hemolytic activity compared to nanospheres. The findings suggested that the anticancer and biological effects of the peptides induced by intrinsic apoptotic pathway were tuned by peptide-functionalized gold nanoparticles (P AuNPs) as a function of their size and shape. PMID- 27491009 TI - Postoperative Radiotherapy Patterns of Care and Survival Implications for Medulloblastoma in Young Children. AB - Importance: Postoperative radiotherapy to the craniospinal axis is standard-of care for pediatric medulloblastoma but is associated with long-term morbidity, particularly in young children. With the advent of modern adjuvant chemotherapy strategies, postoperative radiotherapy deferral has gained acceptance in children younger than 3 years, although it remains controversial in older children. Objective: To analyze recent postoperative radiotherapy national treatment patterns and implications for overall survival in patients with medulloblastoma ages 3 to 8 years. Design, Setting, and Exposures: Using the National Cancer Data Base, patients ages 3 to 8 years diagnosed as having histologically confirmed medulloblastoma in 2004 to 2012, without distant metastases, who underwent surgery and adjuvant chemotherapy with or without postoperative radiotherapy at facilities nationwide accredited by the Commission on Cancer were identified. Patients were designated as having "postoperative radiotherapy upfront" if they received radiotherapy within 90 days of surgery or "postoperative radiotherapy deferred" otherwise. Factors associated with postoperative radiotherapy deferral were identified using multivariable logistic regression. Overall survival (OS) was compared using Kaplan-Meier analysis with log-rank tests and multivariable Cox regression. Statistical tests were 2-sided. Main Outcomes and Measures: Postoperative radiotherapy utilization and overall survival. Results: Among 816 patients, 123 (15.1%) had postoperative radiotherapy deferred, and 693 (84.9%) had postoperative radiotherapy upfront; 36.8% of 3-year-olds and 4.1% of 8-year olds had postoperative radiotherapy deferred (P < .001). On multivariable logistic regression, variables associated with postoperative radiotherapy deferral were age (odds ratio [OR], 0.57 per year; 95% CI, 0.49-0.67 per year) and year of diagnosis (OR, 1.18 per year; 95% CI, 1.08-1.29 per year). On survival analysis, with median follow-up of 4.8 years, OS was improved for those receiving postoperative radiotherapy upfront vs postoperative radiotherapy deferred (5-year OS: 82.0% vs 63.4%; P < .001). On multivariable analysis, variables associated with poorer OS were postoperative radiotherapy deferral (hazards ratio [HR], 1.95; 95% CI, 1.15-3.31); stage M1-3 disease (HR, 1.86; 95% CI, 1.10-3.16), and low facility volume (HR, 1.75; 95% CI, 1.04-2.94). Conclusions and Relevance: Our national database analysis reveals a higher-than expected and increasing rate of postoperative radiotherapy deferral in children with medulloblastoma ages 3 to 8 years. The analysis suggests that postoperative radiotherapy deferral is associated with worse survival in this age group, even in the modern era of chemotherapy. PMID- 27491010 TI - Pediatric pseudotumor cerebri. AB - PURPOSE OF REVIEW: Recent findings in the literature regarding the epidemiology, diagnosis, and treatment of pediatric pseudotumor cerebri (PTC) are described. In the past, children with PTC have been treated like adult cases; however, the literature highlights important differences between children and adults with PTC. RECENT FINDINGS: Revised diagnostic criteria define an opening cerebrospinal fluid pressure greater than 28 cm water as elevated in the pediatric population. Obesity is an important risk factor for primary and secondary PTC in post pubertal children. Magnetic resonance imaging shows findings suggestive of elevated intracranial pressure in children with PTC, similar to those of adults with PTC. Diamox and weight loss are effective treatments for PTC patients with mild visual field loss. Severe papilledema, decreased vision, and optical coherence tomography measures at presentation identify patients at increased risk for subsequent visual loss. SUMMARY: Findings summarized in the recent literature may change practice patterns in the diagnosis and treatment of pediatric PTC. Although there are many similarities between the adult and pediatric populations, the differences should be considered when managing children with PTC. PMID- 27491011 TI - Evidence-Based Medicine vs Traditional Healers in Africa. PMID- 27491012 TI - Is Trying to Quit Associated With Tooth Loss and Delayed Yearly Dental Visit Among Smokers? Results of the 2014 Behavioral Risk Factor Surveillance System. AB - BACKGROUND: The rate of periodontitis in the US population has been estimated to be close to 50%. Patients with periodontitis, especially those who smoke, suffer from a high rate of tooth loss. The purpose of this analysis is to evaluate predictors of poor oral health and oral health habits among smokers and determine if trying to quit smoking is associated with better oral health or oral health habits in smokers in the United States. METHODS: Data from the 2014 Behavioral Risk Factor Surveillance System (BRFSS) were used in the analysis. After limiting the dataset to smokers, the designated exposure was respondent's report of trying to quit smoking (yes/no). Two logistic regression models were developed. One model identified factors associated with having a most recent dental visit longer than 1 year before the survey. The second model identified factors associated with loss of six or more teeth. Both models were controlled for confounding factors. RESULTS: After controlling for confounding, among smokers in the 2014 BRFSS, trying to quit was associated with significantly lower odds of respondents having their most recent dental visit longer than a year before the survey (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90 to 0.97) and was a significant risk factor for having lost six or more teeth (OR: 1.06; 95% CI: 1.02 to 1.10). CONCLUSIONS: Among smokers in the United States, trying to quit is associated with compliance with yearly dental visits and higher odds of lost teeth. Future research should investigate optimal approaches for providing smoking cessation services in the dental setting. PMID- 27491013 TI - Vitamin D Receptor Gene Polymorphism and Smoking in the Risk of Chronic Periodontitis. AB - BACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in susceptibility to infections and bone-related diseases. However, their relationship with periodontal disease remains unclear. This cross-sectional study investigates whether susceptibility to chronic periodontitis (CP) in a Thai population is associated with VDR polymorphisms. METHODS: Genomic DNA was obtained from 1,460 participants, aged 39 to 66 years. Genotyping of VDR polymorphisms (FokI, BsmI, ApaI, and TaqI) was performed using real-time polymerase chain reaction. Participants were categorized into three groups: 1) no/mild; 2) moderate; and 3) severe CP. Multinomial logistic regression was used to determine degree of association between VDR polymorphisms and periodontal status adjusted for known confounders. RESULTS: The CC+CT genotypes of FokI polymorphism were associated with severe CP with an odds ratio (OR) of 1.9 (95% confidence interval [CI]: 1.3 to 2.8). Compared with genotype-negative (TT) non smokers, positivity for the risk genotypes (CC+CT) alone and current smoking alone were associated with severe CP with ORs of 1.8 (95% CI: 1.1 to 3.2) and 2.5 (95% CI: 1.0 to 6.2), respectively. The combination of being genotype positive and smoking further increased the OR to 9.6 (95% CI: 4.5 to 20.4). This combined effect was 3.7 times (95% CI: 1.2 to 11.1) greater than expected from the sum of their individual effects, indicating a synergistic interaction. No significant association was observed between other polymorphisms and CP. CONCLUSION: FokI CC+CT genotypes were associated with increased susceptibility to severe CP, which was aggravated further when combined with smoking. PMID- 27491014 TI - Associations of emotional arousal, dissociation and symptom severity with operant conditioning in borderline personality disorder. AB - Those with borderline personality disorder (BPD) display altered evaluations regarding reward and punishment compared to others. The processing of rewards is basal for operant conditioning. However, studies addressing operant conditioning in BPD patients are rare. In the current study, an operant conditioning task combining learning acquisition and reversal was used. BPD patients and matched healthy controls (HCs) were exposed to aversive and neutral stimuli to assess the influence of emotion on learning. Picture content, dissociation, aversive tension and symptom severity were rated. Error rates were measured. Results showed no group interactions between aversive versus neutral scenes. The higher emotional arousal, dissociation and tension, the worse the acquisition, but not reversal, scores were for BPD patients. Scores from the Borderline Symptom List were associated with more errors in the reversal, but not the acquisition phase. The results are preliminary evidence for impaired acquisition learning due to increased emotional arousal, dissociation and tension in BPD patients. A failure to process punishment in the reversal phase was associated with symptom severity and may be related to neuropsychological dysfunctioning involving the ventromedial prefrontal cortex. Conclusions are limited due to the correlational study design and the small sample size. PMID- 27491015 TI - A case of flying insects visiting an anatomy and embalming laboratory in Medellin, Colombia. AB - From July to September of 2012, the fauna of flying insects visiting the anatomy and embalming laboratory of the Tecnologico de Antioquia, Faculty of Forensic Sciences, located in the city of Medellin, Colombia, were recorded. The first checklist in the literature of incidental flying insects occurring in this type of locale is provided, and a brief discussion is given of their behavioral habits related to this uncommon case. PMID- 27491016 TI - Scope or scalpel? A matched study of the treatment of large colorectal polyps. AB - BACKGROUND: Large colorectal polyps can be treated either endoscopically or by formal resection. The aim of this study was to clarify the relative advantages and disadvantages of surgical resection and colonoscopic snaring as means of treating large colorectal polyps. METHODS: This is a matched cohort study, comparing cases of surgical resection of benign colorectal polyps with endoscopic resection. Cases drawn from pathology and endoscopy databases were matched for the size and site of polyps, and the groups were compared for the end points of complications, length of hospital stay and completeness of the removal of the polyp. RESULTS: There were 78 patients in each group, with mean ages of 65.6 years (colonoscopy) and 66.8 years (surgery). A total of 39 of the surgery group and 47 of the colonoscopy group were men. Mean polyp size was 34.1 mm (colonoscopy) and 32.1 mm (surgery). There was an exact match for polyp location. Complications occurred in eight colonoscopy patients (10.3%) and 42 surgery patients (56.0%) (P < 0.001, chi-square). Length of hospital stay was 0 days for colonoscopy patients and 7.3 +/- 4.7 days for surgery (P < 0.001). The surgery group was separated into laparoscopic (n = 35) and open (n = 43) surgery. There was no difference in complication rates (42.4 versus 53.5%, respectively) but laparoscopic had shorter length of stay (5.8 days +/- 4.9 SD versus 8.4 days +/- 4.3 SD). Recurrence of surgically resected polyps was zero; at last follow-up 13% of snared polyps persisted. CONCLUSION: Although resection is a more certain and absolute way of treating benign polyps, endoscopic polypectomy is preferable. PMID- 27491017 TI - Disparities in Adult Cigarette Smoking - United States, 2002-2005 and 2010-2013. AB - Although cigarette smoking has substantially declined since the release of the 1964 Surgeon General's report on smoking and health,* disparities in tobacco use exist among racial/ethnic populations (1). Moreover, because estimates of U.S. adult cigarette smoking and tobacco use are usually limited to aggregate racial or ethnic population categories (i.e., non-Hispanic whites [whites]; non-Hispanic blacks or African Americans [blacks]; American Indians and Alaska Natives [American Indians/Alaska Natives]; Asians; Native Hawaiians or Pacific Islanders [Native Hawaiians/Pacific Islanders]; and Hispanics/Latinos [Hispanics]), these estimates can mask differences in cigarette smoking prevalence among subgroups of these populations. To assess the prevalence of and changes in cigarette smoking among persons aged >=18 years in six racial/ethnic populations and 10 select subgroups in the United States,(?) CDC analyzed self-reported data collected during 2002-2005 and 2010-2013 from the National Survey on Drug Use and Health (NSDUH) (2) and compared differences between the two periods. During 2010-2013, the overall prevalence of cigarette smoking among the racial/ethnic populations and subgroups ranged from 38.9% for American Indians/Alaska Natives to 7.6% for both Chinese and Asian Indians. During 2010-2013, although cigarette smoking prevalence was relatively low among Asians overall (10.9%) compared with whites (24.9%), wide within-group differences in smoking prevalence existed among Asian subgroups, from 7.6% among both Chinese and Asian Indians to 20.0% among Koreans. Similarly, among Hispanics, the overall prevalence of current cigarette smoking was 19.9%; however, within Hispanic subgroups, prevalences ranged from 15.6% among Central/South Americans to 28.5% among Puerto Ricans. The overall prevalence of cigarette smoking was higher among men than among women during both 2002-2005 (30.0% men versus 23.9% women) and 2010-2013 (26.4% versus 21.1%) (p<0.05). These findings highlight the importance of disaggregating tobacco use estimates within broad racial/ethnic population categories to better understand and address disparities in tobacco use among U.S. adults. PMID- 27491018 TI - Single Cobalt Atoms with Precise N-Coordination as Superior Oxygen Reduction Reaction Catalysts. AB - A new strategy for achieving stable Co single atoms (SAs) on nitrogen-doped porous carbon with high metal loading over 4 wt % is reported. The strategy is based on a pyrolysis process of predesigned bimetallic Zn/Co metal-organic frameworks, during which Co can be reduced by carbonization of the organic linker and Zn is selectively evaporated away at high temperatures above 800 degrees C. The spherical aberration correction electron microscopy and extended X-ray absorption fine structure measurements both confirm the atomic dispersion of Co atoms stabilized by as-generated N-doped porous carbon. Surprisingly, the obtained Co-Nx single sites exhibit superior ORR performance with a half-wave potential (0.881 V) that is more positive than commercial Pt/C (0.811 V) and most reported non-precious metal catalysts. Durability tests revealed that the Co single atoms exhibit outstanding chemical stability during electrocatalysis and thermal stability that resists sintering at 900 degrees C. Our findings open up a new routine for general and practical synthesis of a variety of materials bearing single atoms, which could facilitate new discoveries at the atomic scale in condensed materials. PMID- 27491019 TI - Fragment Coupling with Tertiary Radicals Generated by Visible-Light Photocatalysis. AB - Convergent synthesis strategies in which a target molecule is prepared by a branched approach wherein two or more complex fragments are combined at a late stage are almost always preferred over a linear approach in which the overall yield of the target molecule is eroded by the efficiency of each successive step in the sequence. As a result, bimolecular reactions that are able to combine complex fragments in good yield and, where important, with high stereocontrol are essential for implementing convergent synthetic strategies. Although intramolecular reactions of carbon radicals have long been exploited to assemble polycyclic ring systems, bimolecular coupling reactions of structurally complex carbon radicals have rarely been employed to combine elaborate fragments in the synthesis of structurally intricate molecules. We highlight in this Account recent discoveries from our laboratories that demonstrate that bimolecular reactions of structurally elaborate tertiary carbon radicals and electron deficient alkenes can unite complex fragments in high yield using nearly equimolar amounts of the two coupling partners. Our discussion begins by considering several aspects of the bimolecular addition of tertiary carbon radicals to electron-deficient alkenes that commend these transformations for the union of structurally complex, sterically bulky fragments. We then discuss how in the context of synthesizing rearranged spongian diterpenoids we became aware of the exceptional utility of coupling reactions of alkenes and tertiary carbon radicals to unite structurally complex synthetic intermediates. Our initial investigations exploit the early report of Okada that N-(acyloxy)phthalimides reductively fragment at room temperature in the presence of visible light and catalytic amounts of the photocatalyst Ru(bpy)3Cl2 to form carbon radicals that react with alkenes. We show that this reaction of a tertiary radical precursor and an enone can combine two elaborate enantioenriched fragments in good yield with the formation of new quaternary and secondary stereocenters. As a result of the ready availability of tertiary alcohols, we describe two methods that were developed, one in collaboration with the MacMillan group, to generate tertiary radicals from tertiary alcohols. In the method that will be preferred in most instances, the tertiary alcohol is esterified in high yield to give a tert-alkyl hemioxalate salt, which-without purification-reacts with electron-deficient alkenes in the presence of visible light and an Ir(III) photocatalyst to give coupled products having a newly formed quaternary carbon in high yield. Hemioxalate salts containing Li, Na, K, and Cs countercations can be employed in this reaction, whose only other product is CO2. These reactions are carried out using nearly equimolar amounts of the addends, making them ideal for coupling of complex fragments at the late stage in a synthetic sequence. The attractive attributes of the fragment-coupling chemistry that we discuss in this Account are illustrated by an enantioselective total synthesis of a tricyclic trans-clerodane diterpenoid in eight steps and 34% overall yield from commercially available precursors. We anticipate that bimolecular reactions of carbon radicals will be increasingly used for fragment coupling in the future. PMID- 27491020 TI - Changes in grape polyphenols (V. vinifera L.) as a consequence of post-harvest withering by high-resolution mass spectrometry: Raboso Piave versus Corvina. AB - Grape dehydration is an oenological process used for the production of high quality reinforced and sweet wines. Corvina and Raboso Piave are two red grape varieties used for production of high-quality Italian wines, such as Recioto, Amarone di Valpolicella and Raboso Passito. Changes of polyphenolic composition of the grapes as a consequence of the withering were studied by ultra-high performance liquid chromatography-quadrupole time of flight mass spectrometry (UHPLC/QTOF); for identification of compounds a homemade HR-MS database of grape and wine metabolites, was used. Concomitant with trans-resveratrol and viniferins, relevant increases of other stilbenes (piceatannol, resveratrol trimers and tetramers) and antioxidant compounds (quercetin, syringetin and tamarixetin) were observed. These compounds are part of the induced metabolism occurring during the withering process and in general improve the nutraceutical properties of grapes and wines. On the other hand, longer processes showed to decrease flavan-3-ols and glycoside flavonols. Constant increase of E/Z epsilon viniferin ratio was observed in all samples, and this parameter can be used to monitor the process. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27491022 TI - Molecular characterization and functional analysis of pheromone binding protein 1 from Cydia pomonella (L.). AB - A full-length cDNA encoding Cydia pomonella pheromone binding protein 1 (CpomPBP1) was cloned and characterized. CpomPBP1, possessing the typical characteristics of lepidopteran odorant binding proteins, was detected to be specifically expressed in the antennae of male and female moths at the mRNA and protein level. Soluble recombinant CpomPBP1 was subjected to in vitro binding to analyse its binding properties and to search for potentially active semiochemicals. A competitive binding assay showed that three 12-carbon ligands, codlemone, 1-dodecanol and E,E-2,4-dodecadienal, were able to bind to CpomPBP1 in decreasing order of affinity. Moreover, unlike the wild-type CpomPBP1, the C terminus truncated CpomPBP1 exhibited high affinity to ligands even in an acidic environment, suggesting that the C-terminus plays a role in preventing ligands from binding to CpomPBP1 in a lower pH environment. PMID- 27491021 TI - Structural basis for cholinergic regulation of neural circuits in the mouse olfactory bulb. AB - Odor information is regulated by olfactory inputs, bulbar interneurons, and centrifugal inputs in the olfactory bulb (OB). Cholinergic neurons projecting from the nucleus of the horizontal limb of the diagonal band of Broca and the magnocellular preoptic nucleus are one of the primary centrifugal inputs to the OB. In this study, we focused on cholinergic regulation of the OB and analyzed neural morphology with a particular emphasis on the projection pathways of cholinergic neurons. Single-cell imaging of a specific neuron within dense fibers is critical to evaluate the structure and function of the neural circuits. We labeled cholinergic neurons by infection with virus vector and then reconstructed them three-dimensionally. We also examined the ultramicrostructure of synapses by electron microscopy tomography. To further clarify the function of cholinergic neurons, we performed confocal laser scanning microscopy to investigate whether other neurotransmitters are present within cholinergic axons in the OB. Our results showed the first visualization of complete cholinergic neurons, including axons projecting to the OB, and also revealed frequent axonal branching within the OB where it innervated multiple glomeruli in different areas. Furthermore, electron tomography demonstrated that cholinergic axons formed asymmetrical synapses with a morphological variety of thicknesses of the postsynaptic density. Although we have not yet detected the presence of other neurotransmitters, the range of synaptic morphology suggests multiple modes of transmission. The present study elucidates the ways that cholinergic neurons could contribute to the elaborate mechanisms involved in olfactory processing in the OB. J. Comp. Neurol. 525:574-591, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27491023 TI - Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family. AB - Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7 substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation. PMID- 27491025 TI - 5-year follow-up of a randomized clinical study comparing everolimus plus reduced dose cyclosporine with mycophenolate mofetil plus standard-dose cyclosporine in de novo kidney transplantation: Retrospective single center assessment. AB - The aim of this study is to evaluate the efficacy and safety of everolimus plus reduced-dose cyclosporine compared with mycophenolate mofetil plus standard-dose cyclosporine 5years after living donor kidney transplantation. Between March 2008 and August 2009, 24 living donor kidney transplantations were enrolled in a 2 year, multicenter, randomized phase 3 study (RAD001A1202 study). 24 recipients were randomly classified into two groups and closely observed for 5years. 13 recipients were administered steroid, reduced-dose cyclosporine, everolimus and basiliximab (EVR group). 11 recipients were administered steroid, standard-dose cyclosporine, mycophenolate mofetil and basiliximab (STD group). Two groups were compared not only in graft function including estimated glomerular filtration rate (eGFR), and proteinuria, but also in adverse events such as de novo donor specific antibody (DSA) production, rejection, new-onset diabetes, hyperlipidemia, and cytomegalovirus (CMV) infection. No graft loss was identified in 5years. The incidences of acute T cell rejection, de novo DSA production, hyperlipidemia, and new-onset diabetes were similar. eGFR levels throughout the observation periods were similar. Three cases of proteinuria were identified in STD group. One case of proteinuria observed in EVR group was well controlled with angiotensin receptor blocker. Incidence of CMV infection in CMV antibody-positive recipients was significantly lower in EVR group. The safety and efficacy of reduced-dose cyclosporine and everolimus protocol were similar to those of standard-dose cyclosporine and mycophenolate mofetil other than for superior prevention of CMV infection. PMID- 27491026 TI - A Comparative Study of Intratesticular Ductules in the Spermatogenically Active Testes of Shortfin Mako and Thresher Sharks. AB - This comparative study of the radial testes of sexually mature thresher sharks (Alopias vulpinus) and shortfin mako sharks (Isurus oxyrinchus) describes the histology of the three-tiered network of sperm-carrying ductules in the testis and the lymphomyeloid tissue associated with it, namely the epigonal organ. In both species, a testis -> epigonal gradient was evident regarding the thickness of the ductule epithelial lining and subepithelial investment of connective tissue. Ductules straddling the testis-epigonal border often displayed luminal leukocytes and various signs of regression, including the progressive thickening of the ductule epithelial lining, dissolution of the cytoplasm, and loss of normal histoarchitecture. In Isurus, large amorphous areas formed due to the fusion of neighboring regressing ductules. The epigonal organ of Alopias additionally revealed circular degenerative sperm-containing, Hassall-like bodies with either a degenerate or cellular appearance, the latter the result of cell proliferative activity (as shown by proliferating cell nuclear antigen (PCNA) immunohistochemistry) in an expanding outer border comprising cells with intensely PCNA immunoreactive slender and oblong nuclei. The latter cells exhibited a periphery-to-center transformation of their nuclei, at which stage they were PCNA-negative and most likely in a terminally differentiated state as they phagocytized the cell debris in the degenerate core. Intermediate stages of these circular bodies were a rarity. The relationship between these degenerate bodies, and the common occurrence of blind pockets in the epithelial linings and non-apoptosis-related degenerate patches in the apical cytoplasmic regions of the irregular shaped ductules in Alopias is unclear, and needs further elucidation. Anat Rec, 299:1435-1448, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27491024 TI - Deletion of FoxO1, 3, and 4 in Osteoblast Progenitors Attenuates the Loss of Cancellous Bone Mass in a Mouse Model of Type 1 Diabetes. AB - Type 1 diabetes is associated with osteopenia and increased fragility fractures, attributed to reduced bone formation. However, the molecular mechanisms mediating these effects remain unknown. Insulin promotes osteoblast formation and inhibits the activity of the FoxO transcription factors. FoxOs, on the other hand, inhibit osteoprogenitor proliferation and bone formation. Here, we investigated whether FoxOs play a role in the low bone mass associated with type 1 diabetes, using mice lacking FoxO1, 3, and 4 in osteoprogenitor cells (FoxO1,3,4DeltaOsx1-Cre ). Streptozotocin-induced diabetes caused a reduction in bone mass and strength in FoxO-intact mice. In contrast, cancellous bone was unaffected in diabetic FoxO1,3,4DeltaOsx1-Cre mice. The low bone mass in the FoxO-intact diabetic mice was associated with decreased osteoblast number and bone formation, as well as decreased expression of the anti-osteoclastogenic cytokine osteoprotegerin (OPG) and increased osteoclast number. FoxO deficiency did not alter the effects of diabetes on bone formation; however, it did prevent the decrease in OPG and the increase in osteoclast number. Addition of high glucose to osteoblastic cell cultures decreased OPG mRNA, indicating that hyperglycemia in and of itself contributes to diabetic bone loss. Taken together, these results suggest that FoxOs exacerbate the loss of cancellous bone mass associated with type 1 diabetes and that inactivation of FoxOs might ameliorate the adverse effects of insulin deficiency. (c) 2016 American Society for Bone and Mineral Research. PMID- 27491027 TI - Detailed analysis of adverse events and surgical interventions in a large prospective trial of sacral neuromodulation therapy for overactive bladder patients. AB - INTRODUCTION: The InSite trial is a prospective, multicenter study of sacral neuromodulation (SNM) therapy with the InterStim(r) System in subjects with overactive bladder (OAB). One of the primary aims of the study is to report on long-term safety of the tined lead. This analysis provides detailed descriptions of device-related adverse events (AEs) and surgical interventions to 12 months. METHODS: Analysis included those subjects who completed test stimulation with a tined lead, received a full implant, and reported device-related AEs out to 12 months. A Clinical Events Committee (CEC) adjudicated AEs to 12 months. RESULTS: Device-related AEs occurred in 30% (82/272) of subjects, with only one considered serious. Fifty-six percent of the device-related AEs occurred between implant and 3 months. The most frequent device-related AEs were undesirable change in stimulation (12%, 32/272); implant site pain (7%, 20/272); and implant site infection (3%, 9/272). Of the 26 events of implant site pain, 13 required surgical intervention, with only two resulting in explant. Ten subjects experienced 13 events of a surgical site infection (including an additional cellulitis), five of which resolved with antibiotics and eight required explantation. The overall surgical intervention rate was 13% with the most common reasons being pain at the surgical site (4%), lack/loss of efficacy (4%), and infection (3%). CONCLUSIONS: Although a 30% AE rate was reported, most AEs were minor and were resolved without surgical intervention. Surgical intervention was required in 13% of subjects, with the majority being revision or replacement. Neurourol. Urodynam. 36:1136-1139, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27491028 TI - Assessment of the capability of remote sensing and GIS techniques for monitoring reclamation success in coal mine degraded lands. AB - The objective of the present study is to monitor reclamation activity in mining areas. Monitoring of these reclaimed sites in the vicinity of mining areas and on closed Over Burden (OB) dumps is critical for improving the overall environmental condition, especially in developing countries where area around the mines are densely populated. The present study evaluated the reclamation success in the Block II area of Jharia coal field, India, using Landsat satellite images for the years 2000 and 2015. Four image processing methods (support vector machine, ratio vegetation index, enhanced vegetation index, and normalized difference vegetation index) were used to quantify the change in vegetation cover between the years 2000 and 2015. The study also evaluated the relationship between vegetation health and moisture content of the study area using remote sensing techniques. Statistical linear regression analysis revealed that Normalized Difference Vegetation Index (NDVI) coupled with Normalized Difference Moisture Index (NDMI) is the best method for vegetation monitoring in the study area when compared to other indices. A strong linear relationship (r(2) > 0.86) was found between NDVI and NDMI. An increase of 21% from 213.88 ha in 2000 to 258.9 ha in 2015 was observed in the vegetation cover of the reclaimed sites for an open cast mine, indicating satisfactory reclamation activity. NDVI results indicated that vegetation health also improved over the years. PMID- 27491029 TI - Protective effect of gelatin polypeptides from Pacific cod (Gadus macrocephalus) against UV irradiation-induced damages by inhibiting inflammation and improving transforming growth factor-beta/Smad signaling pathway. AB - Exposure to ultraviolet (UV) radiation results in skin damage, collagen reduction in the dermis, and consequently, premature skin aging (photoaging). The goal of this study was to examine the effect of gelatin hydrolysate (CH) from pacific cod (Gadus macrocephalus) skin on UV irradiation-induced inflammation and collagen reduction of photoaging mouse skin. The effect of CH on the activities of endogenous antioxidant enzymes was investigated. The expressions of nuclear factor-kappaB (NF-kappaB), proinflammatory cytokines, type I and type III procollagen, transforming growth factor-beta1 (TGF-beta1), type II receptor of TGF-beta1 (TGF-betaRII), and Smad7 were determined using quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and ELISA. The results showed that oral administration of CH suppressed UV irradiation-induced damages to skin by inhibiting the depletion of endogenous antioxidant enzyme activity, and by suppressing the expression of NF-kappaB as well as NF-kappaB-mediated proinflammatory cytokines expression. Furthermore, CH inhibited type I procollagen synthesis reduction by up-regulating TbetaRII level and down regulating Smad7 level, which demonstrates that CH is involved in matrix collagen synthesis by activating the TGF-beta/Smad pathway in the photoaging skin. Based on these results, we conclude that CH protected skin from UV irradiation-induced photodamages, and CH may be a potentially effective agent for the prevention of photoaging. PMID- 27491030 TI - Application of UV-Vis spectrophotometric process for the assessment of indoloacridines as free radical scavenger. AB - A conventional approach has been used to synthesis Indole fused acridine, 4a-e. In this paper to achieve the target molecule, 4 the reaction was performed via two steps. In step 1, there was a reaction between Carbazolone, 1 and benzophenone, 2 to get dihydroindoloacridine, 3. In step 2, compound, 3 was treated with 5% Palladium/Carbon in the presence of diphenyl ether for 5h to give a dark brown product, 4. The column chromatography was used to purify final product, 4. All the synthesized compounds such as 3 and 4 were characterized by melting point, FTIR, (1)H NMR, and Mass spectra. Further to check the purity of the compounds it was subjected to CHN analyzer. The target molecules such as 3 and 4 were screened for antimicrobial studies against bacteria such as Bacillus subtilis (B. subtilis), Staphylococcus aureus (S. aureus), Klebsiella pneumonia (K. pneumonia), Salmonella typhi (S. typhi); and fungi like Aspergillus niger (A. niger), Aspergillus fumigatus (A. fumigatus). The obtained results clearly proves that the target molecules shown reasonable activity against K. pneumonia and A. niger. Further the compounds were screened for free radical scavenging activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH). The free radical scavenging property was performed using UV-Visible spectroscopy. The results were compared with the standard BHT (Butylated Hydroxy Toluene). Compounds, 4a and 4e were shown higher percentage of inhibition when compare to the standard. The result confirms that further research on indoloacridine will leads effective drug to the market. PMID- 27491031 TI - One-pot biogenic fabrication of silver nanocrystals using Quisqualis indica: Effectiveness on malaria and Zika virus mosquito vectors, and impact on non target aquatic organisms. AB - Currently, mosquito vector control is facing a number of key challenges, including the rapid development of resistance to synthetic pesticides and the recent spread of aggressive arbovirus outbreaks. The biosynthesis of silver nanoparticles (AgNPs) is currently considered an environmental friendly alternative to the employ of pyrethroids, carbamates and microbial agents (e.g. Bacillus thuringiensis var. israelensis), since AgNPs are easy to produce, effective and stable in the aquatic environment. However, their biophysical features showed wide variations according to the botanical agent using for the green synthesis, outlining the importance of screening local floral resources used as reducing and stabilizing agents. In this study, we focused on the biophysical properties and the mosquitocidal action of Quisqualis indica fabricated AgNPs. AgNPs were characterized using spectroscopic (UV, FTIR, XRD) and microscopic (AFM, SEM, TEM and EDX) techniques. AFM, SEM and TEM confirmed the synthesis of poly-dispersed AgNPs with spherical shape and size ranging from 1 to 30nm. XRD shed light on the crystalline structure of these AgNPs. The acute toxicity of Quisqualis indica extract and AgNPs was evaluated against malaria, arbovirus, and filariasis vectors, Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus, as well as on three important non-target aquatic organisms. The Q. indica leaf extract showed moderate larvicidal effectiveness on Cx. quinquefasciatus (LC50=220.42), Ae. aegypti (LC50=203.63) and An. stephensi (LC50=185.98). Q. indica-fabricated AgNPs showed high toxicity against Cx. quinquefasciatus (LC50=14.63), Ae. aegypti (LC50=13.55) and An. stephensi (LC50=12.52), respectively. Notably, Q. indica-synthesized AgNPs were moderately toxic to non-target aquatic mosquito predators Anisops bouvieri (LC50=653.05MUg/mL), Diplonychus indicus (LC50=860.94MUg/mL) and Gambusia affinis (LC50=2183.16MUg/mL), if compared to the targeted mosquitoes. Overall, the proposed one-pot biogenic fabrication of AgNPs using Q. indica is a low-cost and eco-friendly tool in the fight against Zika virus, malaria and filariasis vectors, with little impact against non-target aquatic mosquito predators. PMID- 27491032 TI - Predicting Melting Points of Organic Molecules: Applications to Aqueous Solubility Prediction Using the General Solubility Equation. AB - In this work we make predictions of several important molecular properties of academic and industrial importance to seek answers to two questions: 1) Can we apply efficient machine learning techniques, using inexpensive descriptors, to predict melting points to a reasonable level of accuracy? 2) Can values of this level of accuracy be usefully applied to predicting aqueous solubility? We present predictions of melting points made by several novel machine learning models, previously applied to solubility prediction. Additionally, we make predictions of solubility via the General Solubility Equation (GSE) and monitor the impact of varying the logP prediction model (AlogP and XlogP) on the GSE. We note that the machine learning models presented, using a modest number of 2D descriptors, can make melting point predictions in line with the current state of the art prediction methods (RMSE>=40 degrees C). We also find that predicted melting points, with an RMSE of tens of degrees Celsius, can be usefully applied to the GSE to yield accurate solubility predictions (log10 S RMSE<1) over a small dataset of drug-like molecules. PMID- 27491033 TI - Adaptive Particle Swarm Optimizer with Varying Acceleration Coefficients for Finding the Most Stable Conformer of Small Molecules. AB - A novel parameter automation strategy for Particle Swarm Optimization called APSO (Adaptive PSO) is proposed. The algorithm is designed to efficiently control the local search and convergence to the global optimum solution. Parameters c1 controls the impact of the cognitive component on the particle trajectory and c2 controls the impact of the social component. Instead of fixing the value of c1 and c2 , this paper updates the value of these acceleration coefficients by considering time variation of evaluation function along with varying inertia weight factor in PSO. Here the maximum and minimum value of evaluation function is use to gradually decrease and increase the value of c1 and c2 respectively. Molecular energy minimization is one of the most challenging unsolved problems and it can be formulated as a global optimization problem. The aim of the present paper is to investigate the effect of newly developed APSO on the highly complex molecular potential energy function and to check the efficiency of the proposed algorithm to find the global minimum of the function under consideration. The proposed algorithm APSO is therefore applied in two cases: Firstly, for the minimization of a potential energy of small molecules with up to 100 degrees of freedom and finally for finding the global minimum energy conformation of 1,2,3 trichloro-1-flouro-propane molecule based on a realistic potential energy function. The computational results of all the cases show that the proposed method performs significantly better than the other algorithms. PMID- 27491034 TI - Prediction of Nucleotide Binding Peptides Using Star Graph Topological Indices. AB - The nucleotide binding proteins are involved in many important cellular processes, such as transmission of genetic information or energy transfer and storage. Therefore, the screening of new peptides for this biological function is an important research topic. The current study proposes a mixed methodology to obtain the first classification model that is able to predict new nucleotide binding peptides, using only the amino acid sequence. Thus, the methodology uses a Star graph molecular descriptor of the peptide sequences and the Machine Learning technique for the best classifier. The best model represents a Random Forest classifier based on two features of the embedded and non-embedded graphs. The performance of the model is excellent, considering similar models in the field, with an Area Under the Receiver Operating Characteristic Curve (AUROC) value of 0.938 and true positive rate (TPR) of 0.886 (test subset). The prediction of new nucleotide binding peptides with this model could be useful for drug target studies in drug development. PMID- 27491035 TI - Streptococcus pneumoniae Genome-wide Identification and Characterization of BOX Element-binding Domains. AB - The BOX elements are short repetitive DNA sequences that distribute randomly in intergenic regions of the Streptococcus pneumoniae genome. The function and origin of such elements are still unknown, but they were found to modulate expression of neighboring genes. Evidences suggested that the modulation's mechanism can be fulfilled by sequence-specific interaction of BOX elements with transcription factor family proteins. However, the type and function of these BOX binding proteins still remain largely unexplored to date. In the current study we described a synthetic protocol to investigate the recognition and interaction between a highly conserved site of BOX elements and the DNA-binding domains of a variety of putative transcription factors in the pneumococcal genome. With the protocol we were able to predict those high-affinity domain binders of the conserved BOX DNA site (BOX DNA) in a high-throughput manner, and analyzed sequence-specific interaction in the domain?DNA recognition at molecular level. Consequently, a number of putative transcription factor domains with both high affinity and specificity for the BOX DNA were identified, from which the helix turn-helix (HTH) motif of a small heat shock factor was selected as a case study and tested for its binding capability toward the double-stranded BOX DNA using fluorescence anisotropy analysis. As might be expected, a relatively high affinity was detected for the interaction of HTH motif with BOX DNA with dissociation constant at nanomolar level. Molecular dynamics simulation, atomic structure examination and binding energy analysis revealed a complicated network of intensive nonbonded interactions across the complex interface, which confers both stability and specificity for the complex architecture. PMID- 27491036 TI - Inferring Association between Compound and Pathway with an Improved Ensemble Learning Method. AB - Emergence of compound molecular data coupled to pathway information offers the possibility of using machine learning methods for compound-pathway associations' inference. To provide insights into the global relationship between compounds and their affected pathways, a improved Rotation Forest ensemble learning method called RGRF (Relief & GBSSL - Rotation Forest) was proposed to predict their potential associations. The main characteristic of the RGRF lies in using the Relief algorithm for feature extraction and regarding the Graph-Based Semi Supervised Learning method as classifier. By incorporating the chemical structure information, drug mode of action information and genomic space information, our method can achieve a better precision and flexibility on compound-pathway prediction. Moreover, several new compound-pathway associations that having the potential for further clinical investigation have been identified by database searching. In the end, a prediction tool was developed using RGRF algorithm, which can predict the interactions between pathways and all of the compounds in cMap database. PMID- 27491037 TI - Improving tRNAscan-SE Annotation Results via Ensemble Classifiers. AB - tRNAScan-SE is a tRNA detection program that is widely used for tRNA annotation; however, the false positive rate of tRNAScan-SE is unacceptable for large sequences. Here, we used a machine learning method to try to improve the tRNAScan SE results. A new predictor, tRNA-Predict, was designed. We obtained real and pseudo-tRNA sequences as training data sets using tRNAScan-SE and constructed three different tRNA feature sets. We then set up an ensemble classifier, LibMutil, to predict tRNAs from the training data. The positive data set of 623 tRNA sequences was obtained from tRNAdb 2009 and the negative data set was the false positive tRNAs predicted by tRNAscan-SE. Our in silico experiments revealed a prediction accuracy rate of 95.1 % for tRNA-Predict using 10-fold cross validation. tRNA-Predict was developed to distinguish functional tRNAs from pseudo-tRNAs rather than to predict tRNAs from a genome-wide scan. However, tRNA Predict can work with the output of tRNAscan-SE, which is a genome-wide scanning method, to improve the tRNAscan-SE annotation results. The tRNA-Predict web server is accessible at http://datamining.xmu.edu.cn/~gjs/tRNA-Predict. PMID- 27491038 TI - Targeting Yes-associated Protein with Evolved Peptide Aptamers to Disrupt TGF beta Signaling Pathway: Therapeutic Implication for Bone Tumor. AB - The binding of transcription coactivator Yes-associated protein (YAP) to Smad transcription factors is an important event in activating transforming growth factor-beta (TGF-beta) signaling pathway, which is involved in the tumorigenicity and metastasis of bone tumor. Design of peptide aptamers to disrupt YAP?Smad interaction has been established as a promising approach for bone tumor therapy. Here, an evolution strategy was used to optimize Smad-derived peptides for high potency binding to YAP WW2 domain, resulting in an improved peptide population, from which those high-scoring candidates were characterized rigorously using molecular dynamics (MD) simulations and interaction free energy calculations. With the computational protocol we were able to generate a number of potential domain binders, which were then substantiated by using fluorescence spectroscopy assay. Subsequently, the complex structure of YAP WW2 domain with a high-affinity peptide was modeled and examined in detail, which was then used to guide structure-based peptide optimization to obtain several strong domain binders. Structural and energetic analysis revealed that electrostatic complementarity is primarily responsible for domain?peptide recognition, while other nonbonded interactions such as hydrogen bonding and salt bridges can contribute significantly to the recognition specificity. PMID- 27491039 TI - Variable sensory nerve conduction parameters in late onset Friedreich ataxia. PMID- 27491040 TI - Akt mediates TIGAR induction in HeLa cells following PFKFB3 inhibition. AB - Neoplastic cells metabolize higher amounts of glucose relative to normal cells in order to cover increased energetic and anabolic needs. Inhibition of the glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) diminishes cancer cell proliferation and tumour growth in animals. In this work, we investigate the crosstalk between PFKFB3 and TIGAR (TP53-Induced Glycolysis and Apoptosis Regulator), a protein known to protect cells from oxidative stress. Our results show consistent TIGAR induction in HeLa cells in response to PFKFB3 knockdown. Upon PFKFB3 silencing, cells undergo oxidative stress and trigger Akt phosphorylation. This leads to induction of a TIGAR-mediated prosurvival pathway that reduces both oxidative stress and cell death. As TIGAR is known to have a role in DNA repair, it could serve as a potential target for the development of effective antineoplastic therapies. PMID- 27491041 TI - Diagnostic and Therapeutic Challenges. PMID- 27491042 TI - PERIPHERAL RETINAL VASCULITIS: Analysis of 110 Consecutive Cases and a Contemporary Reappraisal of Tubercular Etiology. AB - PURPOSE: Describe the clinical features and outcomes of patients with peripheral retinal vasculitis (RV) and describe clinical characteristics of presumed tubercular RV in a nonendemic setting. METHODS: Retrospective cohort study of 110 consecutive patients with peripheral RV at a tertiary referral eye care center in the United Kingdom. Retinal vasculitis was defined as RV with vitritis associated with peripheral retinal ischemia. Patients who also had positive Quantiferon Gold in Tube test, positive tuberculin skin test, and/or other evidence of systemic tuberculosis such as biopsy were labeled with presumed tubercular RV. Treatment success was defined as resolution of inflammation, and successful tapering of oral corticosteroids to less than 10 mg/day or topical steroids to less than twice a day. RESULTS: Mean age of the study population was 42.69 +/- 14.95 years. Patients were predominantly Asian (49.1%) and Male (67.0%). A total of 73.2% had bilateral involvement. Sixty-nine (62.72%) patients had presumed tubercular RV. A total of 52.8% patients received antitubercular therapy, 65.5% received oral corticosteroids, and 17.3% required steroid-sparing oral immunosuppressive agents. A total of 85.19% of patients with presumed tubercular RV achieved treatment success with concurrent antitubercular therapy as against 75.61% of patients with nontubercular RV. CONCLUSION: This is the largest study of the epidemiology, clinical features, and outcomes of both peripheral RV and presumed tubercular RV to date. Presumed tubercular RV commonly seems to affect young males of Asian descent and had vitreous hemorrhage as common clinical findings and also demonstrated a good treatment outcome with antitubercular therapy. PMID- 27491043 TI - METAMORPHOPSIA AND TANGENTIAL RETINAL DISPLACEMENT AFTER EPIRETINAL MEMBRANE SURGERY. AB - PURPOSE: To determine whether the degree of metamorphopsia significantly correlated with the distance of the tangenital retinal displacement after epiretinal membrane surgery. METHODS: The M-CHARTS were used to measure the vertical metamorphopsia score and the horizontal score. The distances between the intersections of two sets of retinal vessels situated vertically or horizontally were measured in the near-infrared Spectralis images. RESULTS: Fifty eyes of 50 patients (22 men; age, 69.5 +/- 7.8 years) were retrospectively studied. The vertical and horizontal metamorphopsia scores significantly improved at 1 month after the surgery, and the vertical and horizontal retinal distances increased. The baseline horizontal and vertical metamorphopsia scores significantly correlated with the ratio of the pre- and postoperative vertical and horizontal retinal displacements, respectively (P = 0.038 and P = 0.015 at 1 week; P = 0.036 and P = 0.036 at 1 month). The postoperative horizontal metamorphopsia score at 1 month and the vertical metamorphopsia score at 3 months significantly correlated with the vertical displacement at 1 month (P = 0.034) and the horizontal displacement at 3 months (P = 0.001), respectively. CONCLUSION: The degree of metamorphopsia significantly correlated with the tangential retinal displacement. Dislocated Muller cells may stimulate the photoreceptors located away from original positions, which consequently results in the sensation of metamorphopsia in patients with an epiretinal membrane. PMID- 27491044 TI - CLOSING MACULAR HOLES WITH "MACULAR PLUG" WITHOUT GAS TAMPONADE AND POSTOPERATIVE POSTURING. AB - PURPOSE: To investigate the surgical results of macular hole surgery without gas tamponade or postoperative posturing in patients with Stage 3 and Stage 4 macular holes with >=500 MUm mean base diameter. DESIGN: Retrospective interventional case series. PARTICIPANTS: Twenty-six patients with Stage 3 and Stage 4 macular holes. METHODS: Twenty-six eyes of 26 patients with Stage 3 and Stage 4 macular holes and a mean base diameter of 892.8 +/- 349 MUm underwent pars plana 23-gauge vitrectomy with broad internal limiting membrane peel (ILM peel), inverted ILM flap repositioning (ILMR), and use of autologous gluconated blood clumps as a macular plug to close the macular hole. No fluid-air exchange, endotamponade, or postoperative posturing was used. The subjects were followed up for 12 months. The anatomical outcome of the procedure was evaluated by fundus examination and optical coherence tomography. Spectral domain optical coherence tomography was used to study the restoration of the outer retinal layer integrity in the postoperative period. The preoperative and postoperative best-corrected visual acuities in logMAR units were compared to evaluate functional outcome. MAIN OUTCOME MEASURE: Macular hole closure and best-corrected visual acuity before and after surgery. RESULTS: Twenty-six patients with mean age 62.8 +/- 7.3 years, preoperative median best-corrected visual acuity 6/60 (1.0 logMAR units), and a mean base diameter of 892.8 +/- 349 MUm underwent surgery to close macular holes without gas tamponade or postoperative posturing. Twenty patients (76.9%) were phakic. Twenty eyes (76.92%) had Stage 3 macular holes and 6 eyes (23.10%) had Stage 4 macular holes. After a single surgery, hole closure was achieved in 100% of eyes. The median best-corrected visual acuity improved from 6/60 (1.0 logMAR units) to 6/18 (0.50 logMAR units) (P < 0.001). Three patients needed cataract surgery at 12-month follow-up. No major intraoperative or postoperative complications were observed. CONCLUSION: Twenty-three-gauge pars plana vitrectomy combined with broad ILM peeling, use of ILMR and autologous gluconated blood clumps as a macular plug is effective in achieving satisfactory hole closure with statically significant functional improvement for large Stage 3 and Stage 4 macular holes. PMID- 27491045 TI - Leukemic Optic Nerve Infiltration Complicated by Retinal Artery and Vein Occlusions. PMID- 27491046 TI - CLINICAL EVALUATION OF THE RAPID ACCESS VITREAL INJECTION GUIDE: A Handheld Instrument for Assisting Intravitreal Injections. AB - PURPOSE: The Rapid Access Vitreal Injection (RAVI) guide combines the function of an eyelid speculum and measuring caliper into a single instrument for assisting intravitreal injections. This study clinically evaluated the RAVI guide with respect to patient acceptance, complication rates, and operative goals. METHODS: A prospective study was performed on 54 patients undergoing intravitreal injections using the RAVI guide (n = 32) or the speculum/caliper (n = 22). Device related pain was assessed using the Wong-Baker scoring system, scaled from 0 (no pain) to 10 (agonizing pain). RESULTS: Mean device-related pain score did not differ significantly between the 2 groups, with scores of 0.6 and 0.7 for the RAVI guide and speculum groups, respectively. The rate of significant pain (score of >=2) was twice as high in the speculum group (7 of 22, 32%) compared with the RAVI guide group (5 of 32, 16%), but this difference was not statistically significant (P = 0.19, Fisher's exact test). Operative goals of avoiding needle touch to lashes/lids and guiding needle insertion to the intended site were achieved in all patients. CONCLUSION: The RAVI guide appeared equivalent to the eyelid speculum in achieving operative goals, with similarly low pain scores. It has the potential for facilitating efficient, accurate, and safe intravitreal injections. PMID- 27491048 TI - Long-term Results of Combined Rhinoplasty and Septal Perforation Repair. AB - Importance: Combined rhinoplasty and septal perforation repair is a technically challenging procedure, and few studies have reported the outcomes. Objective: To present the long-term surgical results of rhinoplasty with concurrent septal perforation repair. Design, Setting, and Participants: This retrospective study included 17 patients who underwent rhinoplasty with concurrent septal perforation repair at a tertiary academic medical center from March 2005, through March 2015. Patients had a mean postoperative follow-up duration of 50.9 months. The etiology of the deformity, presenting symptoms, perforation size, intraoperative surgical techniques, and complications were analyzed. Final follow-up was completed on March 31, 2015. Main Outcomes and Measures: Postoperative subjective (telephone survey of patient satisfaction) and objective (Objective Rhinoplasty Outcome Score) patient satisfaction and endoscopic nasal cavity examination at the last follow-up. Results: Among the 17 patients (14 men; 3 women; mean [SD] age, 40 [16] years), 12 (71%) had previously undergone septoplasty and/or septorhinoplasty, 4 (24%) had nasal trauma, and 1 (6%) had an unknown cause. The main aesthetic reasons for rhinoplasty were a saddle nose deformity (10 patients [59%]) and deviated nose related to a previous surgery or trauma (5 patients [29%]). The functional reasons for surgery included nasal obstruction (14 patients [82%]) crusting (2 patients [12%]), epistaxis (1 patient [6%]), and whistling (1 patient [6%]). The perforation size varied from 2 to 30 mm, with a mean of 14.3 mm. Surgery was performed through the open rhinoplasty approach. Perforations were first closed with an advancement flap in 6 patients, rotation flap in 6 patients, a combination of both in 4 patients, and a combination of advancement flap and free mucosal graft in 1 patient, with or without interposition grafts. Rhinoplasty was performed with various grafts, maneuvers, and septal reconstruction. Complete closure with symptom relief was achieved in 15 patients (88%). The mean objective score evaluating the rhinoplasty results was 3.4 (on a scale of 0-4, where 3.4 is good to excellent). No serious complications occurred after surgery. Conclusions and Relevance: Concurrent rhinoplasty and nasal septal perforation repair is a safe and effective option when necessary. The open rhinoplasty approach facilitated septal perforation closure, whereas septal perforation repair did not affect the surgical result of rhinoplasty. Level of Evidence: 4. PMID- 27491049 TI - Recreational marijuana use is not associated with worse outcomes after renal transplantation. AB - As marijuana (MJ) legalization is increasing, kidney transplant programs must develop listing criteria for marijuana users. However, no data exist on the effect of MJ on kidney allograft outcomes, and there is no consensus on whether MJ use should be a contraindication to transplantation. We retrospectively reviewed 1225 kidney recipients from 2008 to 2013. Marijuana use was defined by positive urine toxicology screen and/or self-reported recent use. The primary outcome was death at 1 year or graft failure (defined as GFR<20 mL/min/1.73 m2 ). The secondary outcome was graft function at 1 year. Using logistic regression analyses, we compared these outcomes between MJ users and non-users. Marijuana use was not associated with worse primary outcomes by unadjusted (odds ratio 1.07, 95% CI 0.45-2.57, P=.87) or adjusted (odds ratio 0.79, 95% CI 0.28-2.28, P=.67) analysis. Ninety-two percent of grafts functioned at 1 year. Among these, the mean creatinine (1.52, 95% CI 1.39-1.69 vs 1.46, 95% CI 1.42-1.49; P=.38) and MDRD GFR (50.7, 95% CI 45.6-56.5 vs 49.5, 95% CI 48.3-50.7; P=.65) were similar between groups. Isolated recreational MJ use is not associated with poorer patient or kidney allograft outcomes at 1 year. Therefore, recreational MJ use should not necessarily be considered a contraindication to kidney transplantation. PMID- 27491050 TI - Genomics- and Transcriptomics-Based Patient Selection for Cancer Treatment With Immune Checkpoint Inhibitors: A Review. AB - Importance: Checkpoint blockade therapy targeting cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathways (PD-1/PD-L1) have achieved success in treating a number of malignancies. However, only a subset of patients responds to these therapies, and optimization of patient selection for treatment is imperative to avoid adverse effects without clinical benefit and keep costs manageable. Observations: The past few years have witnessed checkpoint inhibition becoming a first-line treatment option with US Food and Drug Administration approvals for various tumor types. Genomic analyses (whole genome, exome, and transcriptome) have been instrumental in identifying a genetic profile associated with sensitivity to checkpoint inhibitors. Therapy outcome is determined at various levels: (1) the degree of tumor "foreignness," as reflected by mutational burden and expression of viral genes, (2) the composition and activity of a preexisting immune infiltrate, and (3) mechanisms of tumor escape from immune surveillance. In addition, there are opportunities for genomic analyses of genetic polymorphisms and the gut microbiome that may be associated with clinical response to therapy. Conclusions and Relevance: Genomics provides powerful tools for the identification of biomarkers for response to immune checkpoint blockade, given their potential to analyze multiple parameters simultaneously in an unbiased manner. This offers the opportunity for genomics- and transcriptomics-based selection of patients for rationally designed therapy with immune checkpoint inhibitors. PMID- 27491051 TI - Concurrent validity and reliability of using ground reaction force and center of pressure parameters in the determination of leg movement initiation during single leg lift. AB - Postural adjustment evaluations during single leg lift requires the initiation of heel lift (T1) identification. T1 measured by means of motion analyses system is the most reliable approach. However, this method involves considerable workspace, expensive cameras, and time processing data and setting up laboratory. The use of ground reaction forces (GRF) and centre of pressure (COP) data is an alternative method as its data processing and setting up is less time consuming. Further, kinetic data is normally collected using frequency samples higher than 1000Hz whereas kinematic data are commonly captured using 50-200Hz. This study describes the concurrent-validity and reliability of GRF and COP measurements in determining T1, using a motion analysis system as reference standard. Kinematic and kinetic data during single leg lift were collected from ten participants. GRF and COP data were collected using one and two force plates. Displacement of a single heel marker was captured by means of ten Vicon((c)) cameras. Kinetic and kinematic data were collected using a sample frequency of 1000Hz. Data were analysed in two stages: identification of key events in the kinetic data, and assessing concurrent validity of T1 based on the chosen key events with T1 provided by the kinematic data. The key event presenting the least systematic bias, along with a narrow 95% CI and limits of agreement against the reference standard T1, was the Baseline COPy event. Baseline COPy event was obtained using one force plate and presented excellent between-tester reliability. PMID- 27491052 TI - Postural instability in Charcot-Marie-Tooth 1A disease. AB - The aim of this study was to evaluate the influence of somatosensory impairment, distal muscle weakness and foot deformities on the balance in 21 CMT1A patients using a baropodometric platform. Stabilometric analysis by measuring sway area and velocity of a centre of pressure (CoP) both at open and closed eyes were used to assess postural imbalance. Static analysis, by measuring the load and the plantar surface of forefoot, midfoot and hindfoot was used to define the footprint shape and to assess as a whole foot deformities. Stabilometric and static results were compared with those of a control group. In CMT1A patients, stabilometric findings were correlated with static parameters, Achilles' tendon retraction, distal muscle strength and CMT examination score (CMTES). CMT1A patients compared to controls had lower plantar surface and load on midfoot, and higher load on a forefoot. CMT1A patients had a greater postural instability, since they had a higher CoP velocity, both at open and closed eyes. Moreover, the CoP velocity correlated inversely with the strength of ankle dorsi-flexion muscles and directly with CMTES as whole and with the item "motor symptoms legs". Postural imbalance was not correlated with sensory impairment and foot deformities as expressed by static analysis and Achilles' tendon retraction. In this study we demonstrated an altered balance in CMT1A patients during upright standing. The imbalance in our CMT patients seems to be related to the weakness of ankle dorsi-flexor muscles rather than sensory impairment or foot deformities. These results could be due to a mildly affected CMT1A population, evaluated in an early stage of the disease. PMID- 27491053 TI - Hypokinetic gait changes induced by bilateral pallidal deep brain stimulation for segmental dystonia. AB - BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been established as an effective and safe treatment for dystonia. In general, side effects are rare, but there is increasing evidence that GPi DBS in dystonia can induce hypokinetic symptoms like micrographia or freezing of gait. We aimed to evaluate and quantify possible changes of gait following bilateral chronic GPi DBS for dystonia by computerized gait analyses. METHODS: We prospectively performed computerized gait analysis in ten consecutive patients (mean age 57.8+/ 14.3 years) with segmental dystonia but without involvement of lower trunk or legs who were treated with bilateral GPi DBS. Using pressure sensitive insoles, several parameters were measured preoperatively (pre-OP) and at a median of 7 months postoperatively. RESULTS: The mean step length significantly decreased from 60.0+/-6.9cm pre-OP to 54.3+/-6.4cm with GPi DBS (p<0.01). Due to only small changes of walking distance and gait velocity, the cadence correspondingly increased from 105.6+/-9.2 steps/min to 111.3+/-11.4 steps/min (p<0.05). More importantly, the variance of several gait parameters significantly decreased postoperatively. CONCLUSIONS: In patients with segmental dystonia, chronic DBS of the posteroventral lateral GPi is associated with only mild hypokinesia of gait, but with a relevant decrease in gait variability. Given other recently reported hypokinetic effects of GPi DBS for dystonia and recent results of electrophysiological coherence studies, these findings support the hypothesis of a general alteration of neuronal activity in striato-pallido-thalamo-cortical motor pathways following chronic stimulation of the posteroventral lateral GPi. PMID- 27491054 TI - Endoscopy Dyspnea and Ulcerative Colitis. PMID- 27491055 TI - Prevalence of Diphyllobothrium latum (Cestoda: Diphyllobothriidae) plerocercoids in fish species from four Italian lakes and risk for the consumers. AB - In recent years there has been a re-emergence of diphyllobothriasis by Diphyllobothrium latum (Cestoda: Diphyllobothriidae) in Italy, France and Switzerland, where in the past this fish-borne zoonosis was widespread and then virtually disappeared. A change in eating habits such as the consumption of raw/undercooked freshwater fish, has led to an increased risk for consumers of ingesting infective larvae of D. latum. A survey on the factors responsible for the re-emergence of human diphyllobothriasis in Italy was carried out from March 2013 to December 2014. The aim of this study was to assess the diffusion of D. latum plerocercoids in the fish populations of the sub-alpine lakes of Maggiore, Como, Iseo and Garda, updating the scarce historical data and assessing a preliminary "risk level" of the lacustrine environments and fish species under investigation. A total of 2228 fish belonging to 5 species, 690 from Lake Maggiore, 500 from Lake Como, 655 from Lake Iseo and 383 from Lake Garda were submitted to parasitological examination. The presence of D. latum plerocercoid larvae was detected in 6.6%, 25.4% and 7.6% of perch (Perca fluviatilis) from Lakes Maggiore, Como and Iseo respectively. The parasite was also present in pike (Esox lucius) with prevalence values ranging from 71.4 to 84.2% and in 3.6-3.8% of burbot (Lota lota) from Lakes Iseo and Como. Fish from Lake Garda were negative as well as sampled whitefish (Coregonus lavaretus) and shad (Alosa fallax lacustris). The results of this survey showed a widespread presence of D. latum plerocercoid larvae in Maggiore, Como and Iseo fish populations. Urban fecal contamination of water is still a key issue to be resolved, together with the improvement of communication with consumers regarding the best dietary habits and the most effective processes of parasite inactivation, required for the consumption of raw/undercooked fish caught in high-risk areas. PMID- 27491057 TI - Magnetic Resonance Imaging of the Native Hip Joint. PMID- 27491056 TI - Integrative taxonomy of Anisakidae and Raphidascarididae (Nematoda) in Paralichthys patagonicus and Xystreurys rasile (Pisces: Teleostei) from Brazil. AB - Thirty-six Paralichthys patagonicus and 30 Xystreurys rasile were collected in the state of Rio de Janeiro, Brazil to investigate the presence of anisakid and raphidascaridid nematodes. Anisakis typica, Terranova sp., Contracaecum sp., Hysterothylacium deardorffoverstreetorum, and Raphidascaris sp. were identified using integrative taxonomy of morphological and genetic data. Morphological and morphometric analysis was conducted using bright field microscopy with scanning electron microscopy for topographic characterization of the cuticular surface. Phylogenetic analysis, using ITS and cox2 molecular targets, clearly demonstrated the species identification of A. typica and H. deardorffoverstreetorum and the high diversity of H. deardorffoverstreetorum. This is the first report of A. typica, H. deardorffoverstreetorum, and Raphidascaris sp. parasitizing P. patagonicus and X. rasile. PMID- 27491058 TI - An Introduction to Clinical Significance in Orthopaedic Outcomes Research. PMID- 27491059 TI - Spine Surgery in an Ambulatory Setting: What Can Be Done Safely? PMID- 27491060 TI - Proximal Interphalangeal Joint Arthroplasty: A Critical Analysis Review. PMID- 27491061 TI - Intra-cochlear lipoma: a rare case diagnosed with specific magnetic resonance imaging protocols. PMID- 27491062 TI - CDC Grand Rounds: Adolescence - Preparing for Lifelong Health and Wellness. AB - Approximately 42 million adolescents aged 10-19 years, representing 13% of the population, resided in the United States in 2014 (1). Adolescence is characterized by rapid and profound physical, intellectual, emotional, and psychological changes (2), as well as development of healthy or risky behaviors that can last a lifetime. Parents have strong influence on their adolescent children's lives, and family-based programs can help parents support healthy adolescent development. Because schools are natural learning environments, implementing and improving school-based policies and programs are strategic ways to reinforce healthy behaviors and educate adolescents about reducing risky behaviors. Health care during adolescence should be tailored to meet the changing developmental needs of the adolescent while providing welcoming, safe, and confidential care. Parents, educators, care providers, public health officials, and communities should collaborate in fostering healthy environments for all adolescents, now and into the future. PMID- 27491063 TI - [62]Tetradecaphyrin and Its Mono- and Bis-Zn(II) Complexes. AB - A coiled structure of meso-pentafluorophenyl-substituted [62]tetradecaphyrin 1 was revealed by X-ray structural analysis. Synthetic protocols were devised to form mono- and bis-Zn(II) complexes, 1 Zn and 1 Zn2 , selectively. The former displayed a trigonal-bipyramidal pentacoordinated Zn(II) ion as a rare case and a cyclic voltammogram exhibiting eleven reversible redox waves. The latter showed a Ci-symmetric structure with modest Huckel aromaticity owing to a 62 pi-electronic circuit as the largest aromatic molecule to date. PMID- 27491064 TI - Direct Synthesis of Silylamine from N2 and a Silane: Mediated by a Tridentate Phosphine Molybdenum Fragment. AB - A homogeneous system which is able to yield silylamine from N2 and bis(silane) in one pot is reported. Mechanistically a {(triphosphine)molybdenum(I)} fragment, generated in situ, splits N2 into the corresponding nitrido complex at room temperature. Then, functionalization of the molybdenum nitrido is achieved by double Si-H addition under mild reaction conditions. Moreover, the bis(silyl)amine product is decoordinated from the metal center. PMID- 27491065 TI - Pre-clinical investigation of plasma pharmacokinetics and biodistribution of a novel antithrombotic agent S002-333 in mice using LC-MS/MS. AB - S002-333 [2-(4-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-b-carboxylic acid amide] is a novel and potent antithrombotic agent developed by CSIR-CDRI, India. The present study was aimed to develop a sensitive LC-MS/MS method for the quantification of S002-333 in mice plasma and tissues. The extraction of S002-333 from relatively small amount of mouse biomatrices (50MUL) was accomplished using protein precipitation followed by liquid-liquid extraction and the separation of analytes was achieved on C18 reversed phase column using acetonitrile and triple distilled water (75:25, v/v) as mobile phase at a flow rate of 0.6mL/min. The instrument was operated in the multiple reaction monitoring (MRM) mode using electrospray ionization (ESI) in the positive scan mode. For all the biomatrices, linear relationship was attained over the concentration range of 0.39-200ng/mL with correlation coefficients >=0.992. The lower limit of quantification for mouse plasma and tissue homogenates was 0.39ng/mL. The bioanalytical method was reproducible and reliable for all the matrices with inter-day and intra-day variability in precision being less than 15% and accuracy within +/-15%. The assay was successfully applied to pharmacokinetics and tissue distribution of S002-333 in mice. The pharmacokinetic study revealed adequate gastrointestinal absorption of S002-333 into the systemic circulation of mice with absolute oral bioavailability of 45.8%. Tissue distribution data showed rapid and wide distribution of S002-333 in the following order: small intestine>liver>kidney~lungs>heart>spleen>brain. The present findings may provide meaningful basis for further clinical development of this new chemical entity. PMID- 27491066 TI - Teaching artificial intelligence to read electropherograms. AB - Electropherograms are produced in great numbers in forensic DNA laboratories as part of everyday criminal casework. Before the results of these electropherograms can be used they must be scrutinised by analysts to determine what the identified data tells us about the underlying DNA sequences and what is purely an artefact of the DNA profiling process. A technique that lends itself well to such a task of classification in the face of vast amounts of data is the use of artificial neural networks. These networks, inspired by the workings of the human brain, have been increasingly successful in analysing large datasets, performing medical diagnoses, identifying handwriting, playing games, or recognising images. In this work we demonstrate the use of an artificial neural network which we train to 'read' electropherograms and show that it can generalise to unseen profiles. PMID- 27491067 TI - Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. AB - The gut microbiota interacts with the host via neuroimmune, neuroendocrine and neural pathways. These pathways are components of the brain-gut-microbiota axis and preclinical evidence suggests that the microbiota can recruit this bidirectional communication system to modulate brain development, function and behaviour. The pathophysiology of depression involves neuroimmune-neuroendocrine dysregulation. However, the extent to which changes in gut microbiota composition and function mediate the dysregulation of these pathways is unknown. Thirty four patients with major depression and 33 matched healthy controls were recruited. Cytokines, CRP, Salivary Cortisol and plasma Lipopolysaccharide binding protein were determined by ELISA. Plasma tryptophan and kynurenine were determined by HPLC. Fecal samples were collected for 16s rRNA sequencing. A Fecal Microbiota transplantation was prepared from a sub group of depressed patients and controls and transferred by oral gavage to a microbiota-deficient rat model. We demonstrate that depression is associated with decreased gut microbiota richness and diversity. Fecal microbiota transplantation from depressed patients to microbiota-depleted rats can induce behavioural and physiological features characteristic of depression in the recipient animals, including anhedonia and anxiety-like behaviours, as well as alterations in tryptophan metabolism. This suggests that the gut microbiota may play a causal role in the development of features of depression and may provide a tractable target in the treatment and prevention of this disorder. PMID- 27491068 TI - Effects of emotional acceptance and rumination on media-induced body dissatisfaction in anorexia and bulimia nervosa. AB - INTRODUCTION: Body dissatisfaction is an important risk and maintaining factor for eating disorders. The aim of the present study was to experimentally test the effects of two emotion regulation strategies - acceptance and rumination - on media-induced body dissatisfaction in eating disorders. METHOD: After watching pictures of thin models, women with anorexia nervosa (AN; n = 39) and bulimia nervosa (BN; n = 39) were encouraged to either use emotional acceptance or rumination to cope with their feelings. Body dissatisfaction and mood were repeatedly assessed. RESULTS: Acceptance significantly improved body dissatisfaction in women with BN. Rumination led to a significant increase of body dissatisfaction in both eating disorder groups. Results were independent from mood changes. DISCUSSION: Findings highlight the importance ruminative thinking may have in the aggravation of dissatisfaction with the own body in AN and BN. Results suggest that emotional acceptance is a useful strategy to regulate body dissatisfaction after exposure to thin-ideal media in BN. PMID- 27491069 TI - Association between seizures and mortality in patients with aneurysmal subarachnoid hemorrhage: A nationwide retrospective cohort analysis. AB - PURPOSE: The impact of seizures on outcomes in patients with subarachnoid hemorrhage (SAH) is not well understood, with conflicting results published in the literature. METHOD: For this retrospective cohort analysis, data from the Nationwide Inpatient Samples (NIS) for 2006-2011 were utilized. All patients aged >=18 years with a primary admitting diagnosis of subarachnoid hemorrhage were included. Patients with a diagnosis of seizure were segregated from the initial cohort. Multivariable logistic regression modeled the risk of death while adjusting for severity of SAH as well as co-morbidities. The primary outcome of this analysis was in-hospital mortality. RESULTS: 12,647 patients met inclusion criteria for the study, of which 1336 had a diagnosis of seizures. The unadjusted in-hospital mortality was higher for patients with seizures compared to those without (16.2% vs 11.6%, p<0.01). Compared to patients without seizures, patients with seizures were younger (52.4 years SD 13.9 vs 54.8 years, SD 13.6; p<0.01), more likely to be male (35.6% vs 31.0%, p<0.01) and had longer hospital stays (18.3 days, IQR 12.0-27.5 vs 14.8 days, IQR 10.0-21.9; p<0.01). After adjusting for the severity of SAH, seizures were found to be associated with increased mortality (OR 1.57, 95% CI 1.32-1.87, p<0.01). CONCLUSION: In this large nationwide analysis, the presence of seizures in patients with SAH was associated with higher in-hospital mortality. This finding has potentially important implications for goals of care decision-making and prognostication, but further study in the area is needed. PMID- 27491070 TI - Seeking out the sweet spot in cancer therapeutics: an interview with Lewis Cantley. AB - Lewis C. Cantley, Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, is a world leader in cancer and metabolic disease research. His seminal discoveries have shed light on the regulation of ion pumps and other transport proteins, insulin-mediated regulation of glucose metabolism and the role of signal transduction networks in cell transformation. At Tufts University in the 1980s, Lewis and his collaborators unveiled and characterized the phosphoinositide 3-kinase (PI3K) signaling pathway; a discovery that revolutionized the field of lipid signaling. In this interview, he documents his journey from serendipitous discovery of the pathway to determining its diverse physiological functions and role in cancer - an incredible odyssey that has laid the groundwork for clinical trials based on PI3K inhibitors. He also discusses the impact his early life had in spurring a thirst to understand biological processes at the molecular level, highlights how his multiple collaborations have helped in translating his basic discoveries to the clinic and explains why eating a high-sugar diet can be harmful. Ongoing studies in the Cantley lab are aimed at determining the mechanistic underpinnings of pancreatic, colorectal, ovarian and breast cancers, particularly the role of cellular metabolic pathways. The group has recently shown, amongst other breakthroughs, that vitamin C could provide a promising therapy for certain hard-to-treat cancers. PMID- 27491072 TI - A knockin mouse model for human ATP4aR703C mutation identified in familial gastric neuroendocrine tumors recapitulates the premalignant condition of the human disease and suggests new therapeutic strategies. AB - By whole exome sequencing, we recently identified a missense mutation (p.R703C) in the human ATP4a gene, which encodes the proton pump responsible for gastric acidification. This mutation causes an aggressive familial type I gastric neuroendocrine tumor in homozygous individuals. Affected individuals show an early onset of the disease, characterized by gastric hypoacidity, hypergastrinemia, iron-deficiency anemia, gastric intestinal metaplasia and, in one case, an associated gastric adenocarcinoma. Total gastrectomy was performed as the definitive treatment in all affected individuals. We now describe the generation and characterization of a knockin mouse model for the ATP4a(R703C) mutation to better understand the tumorigenesis process. Homozygous mice recapitulated most of the phenotypical alterations that were observed in human individuals, strongly suggesting that this mutation is the primary alteration responsible for disease development. Homozygous mice developed premalignant condition with severe hyperplasia, dysplasia and glandular metaplasia in the stomach. Interestingly, gastric acidification in homozygous mice, induced by treatment with 3% HCl acid in the drinking water, prevented (if treated from birth) or partially reverted (if treated during adulthood) the development of glandular metaplasia and dysplasia in the stomach and partially rescued the abnormal biochemical parameters. We therefore suggest that, in this model, achlorhydria contributes to tumorigenesis to a greater extent than hypergastrinemia. Furthermore, our mouse model represents a unique and novel tool for studying the pathologies associated with disturbances in gastric acid secretion. PMID- 27491071 TI - Progressive neurologic and somatic disease in a novel mouse model of human mucopolysaccharidosis type IIIC. AB - Mucopolysaccharidosis type IIIC (MPSIIIC) is a severe lysosomal storage disease caused by deficiency in activity of the transmembrane enzyme heparan-alpha glucosaminide N-acetyltransferase (HGSNAT) that catalyses the N-acetylation of alpha-glucosamine residues of heparan sulfate. Enzyme deficiency causes abnormal substrate accumulation in lysosomes, leading to progressive and severe neurodegeneration, somatic pathology and early death. There is no cure for MPSIIIC, and development of new therapies is challenging because of the unfeasibility of cross-correction. In this study, we generated a new mouse model of MPSIIIC by targeted disruption of the Hgsnat gene. Successful targeting left LacZ expression under control of the Hgsnat promoter, allowing investigation into sites of endogenous expression, which was particularly prominent in the CNS, but was also detectable in peripheral organs. Signs of CNS storage pathology, including glycosaminoglycan accumulation, lysosomal distension, lysosomal dysfunction and neuroinflammation were detected in 2-month-old animals and progressed with age. Glycosaminoglycan accumulation and ultrastructural changes were also observed in most somatic organs, but lysosomal pathology seemed most severe in liver. Furthermore, HGSNAT-deficient mice had altered locomotor and exploratory activity and shortened lifespan. Hence, this animal model recapitulates human MPSIIIC and provides a useful tool for the study of disease physiopathology and the development of new therapeutic approaches. PMID- 27491073 TI - A mouse model for ulcerative colitis based on NOD-scid IL2R gammanull mice reconstituted with peripheral blood mononuclear cells from affected individuals. AB - Animal models reflective of ulcerative colitis (UC) remain a major challenge, and yet are crucial to understand mechanisms underlying the onset of disease and inflammatory characteristics of relapses and remission. Mouse models in which colitis-like symptoms are induced through challenge with toxins such as oxazolone, dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) have been instrumental in understanding the inflammatory processes of UC. However, these neither reflect the heterogeneous symptoms observed in the UC affected population nor can they be used to test the efficacy of inhibitors developed against human targets where high sequence and structural similarity of the respective ligands is lacking. In an attempt to overcome these problems, we have developed a mouse model that relies on NOD-scid IL2R gamma(null) mice reconstituted with peripheral blood mononuclear cells derived from UC-affected individuals. Upon challenge with ethanol, mice developed colitis-like symptoms and changes in the colon architecture, characterized by influx of inflammatory cells, edema, crypt loss, crypt abscesses and epithelial hyperplasia, as previously observed in immune-competent mice. TARC, TGFbeta1 and HGF expression increased in distal parts of the colon. Analysis of human leucocytes isolated from mouse spleen revealed an increase in frequencies of CD1a+, CD64+, CD163+ and TSLPR+ CD14+ monocytes, and antigen-experienced CD44+ CD4+ and CD8+ T-cells in response to ethanol. Analysis of human leucocytes from the colon of challenged mice identified CD14+ monocytes and CD11b+ monocytes as the predominant populations. Quantitative real-time PCR (RT-PCR) analysis from distal parts of the colon indicated that IFNgamma might be one of the cytokines driving inflammation. Treatment with infliximab ameliorated symptoms and pathological manifestations, whereas pitrakinra had no therapeutic benefit. Thus, this model is partially reflective of the human disease and might help to increase the translation of animal and clinical studies. PMID- 27491074 TI - Development of a subset of forelimb muscles and their attachment sites requires the ulnar-mammary syndrome gene Tbx3. AB - In the vertebrate limb over 40 muscles are arranged in a precise pattern of attachment via muscle connective tissue and tendon to bone and provide an extensive range of motion. How the development of somite-derived muscle is coordinated with the development of lateral plate-derived muscle connective tissue, tendon and bone to assemble a functional limb musculoskeletal system is a long-standing question. Mutations in the T-box transcription factor, TBX3, have previously been identified as the genetic cause of ulnar-mammary syndrome (UMS), characterized by distinctive defects in posterior forelimb bones. Using conditional mutagenesis in mice, we now show that TBX3 has a broader role in limb musculoskeletal development. TBX3 is not only required for development of posterior forelimb bones (ulna and digits 4 and 5), but also for a subset of posterior muscles (lateral triceps and brachialis) and their bone eminence attachment sites. TBX3 specification of origin and insertion sites appears to be tightly linked with whether these particular muscles develop and may represent a newly discovered mechanism for specification of anatomical muscles. Re examination of an individual with UMS reveals similar previously unrecognized muscle and bone eminence defects and indicates a conserved role for TBX3 in regulating musculoskeletal development. PMID- 27491075 TI - A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease. AB - Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase alpha-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a fucosidosis mouse model, in which the gene for lysosomal alpha-L fucosidase (Fuca1) was disrupted by gene targeting. Homozygous knockout mice completely lack alpha-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(alpha1,6) GlcNAc(beta1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS). On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for fucosidosis. PMID- 27491076 TI - Autocrine IL-10 activation of the STAT3 pathway is required for pathological macrophage differentiation in polycystic kidney disease. AB - Polycystic kidney disease (PKD) is characterized by slow expansion of fluid filled cysts derived from tubules within the kidney. Cystic expansion results in injury to surrounding parenchyma and leads to inflammation, scarring and ultimately loss of renal function. Macrophages are a key element in this process, promoting cyst epithelial cell proliferation, cyst expansion and disease progression. Previously, we have shown that the microenvironment established by cystic epithelial cells can 'program' macrophages, inducing M2-like macrophage polarization that is characterized by expression of markers that include Arg1 and Il10 Here, we functionally characterize these macrophages, demonstrating that their differentiation enhances their ability to promote cyst cell proliferation. This observation indicates a model of reciprocal pathological interactions between cysts and the innate immune system: cyst epithelial cells promote macrophage polarization to a phenotype that, in turn, is especially efficient in promoting cyst cell proliferation and cyst growth. To better understand the genesis of this macrophage phenotype, we examined the role of IL-10, a regulatory cytokine shown to be important for macrophage-stimulated tissue repair in other settings. Herein, we show that the acquisition of the pathological macrophage phenotype requires IL-10 secretion by the macrophages. Further, we demonstrate a requirement for IL-10-dependent autocrine activation of the STAT3 pathway. These data suggest that the IL-10 pathway in macrophages plays an essential role in the pathological relationship between cysts and the innate immune system in PKD, and thus could be a potential therapeutic target. PMID- 27491077 TI - A high-fat jelly diet restores bioenergetic balance and extends lifespan in the presence of motor dysfunction and lumbar spinal cord motor neuron loss in TDP 43A315T mutant C57BL6/J mice. AB - Transgenic transactivation response DNA-binding protein 43 (TDP-43) mice expressing the A315T mutation under control of the murine prion promoter progressively develop motor function deficits and are considered a new model for the study of amyotrophic lateral sclerosis (ALS); however, premature sudden death resulting from intestinal obstruction halts disease phenotype progression in 100% of C57BL6/J congenic TDP-43(A315T) mice. Similar to our recent results in SOD1(G93A) mice, TDP-43(A315T) mice fed a standard pellet diet showed increased 5' adenosine monophosphate-activated protein kinase (AMPK) activation at postnatal day (P)80, indicating elevated energetic stress during disease progression. We therefore investigated the effects of a high-fat jelly diet on bioenergetic status and lifespan in TDP-43(A315T) mice. In contrast to standard pellet-fed mice, mice fed high-fat jelly showed no difference in AMPK activation up to P120 and decreased phosphorylation of acetly-CoA carboxylase (ACC) at early stage time points. Exposure to a high-fat jelly diet prevented sudden death and extended survival, allowing development of a motor neuron disease phenotype with significantly decreased body weight from P80 onward that was characterised by deficits in Rotarod abilities and stride length measurements. Development of this phenotype was associated with a significant motor neuron loss as assessed by Nissl staining in the lumbar spinal cord. Our work suggests that a high-fat jelly diet improves the pre-clinical utility of the TDP-43(A315T) model by extending lifespan and allowing the motor neuron disease phenotype to progress, and indicates the potential benefit of this diet in TDP-43-associated ALS. PMID- 27491079 TI - Update on Vaccine-Derived Polioviruses - Worldwide, January 2015-May 2016. AB - In 1988, the World Health Assembly resolved to eradicate poliomyelitis worldwide (1). One of the main tools used in polio eradication efforts has been the live, attenuated, oral poliovirus vaccine (OPV) (2), an inexpensive vaccine easily administered by trained volunteers. OPV might require several doses to induce immunity, but provides long-term protection against paralytic disease. Through effective use of OPV, the Global Polio Eradication Initiative (GPEI) has brought wild polioviruses to the threshold of eradication (1). However, OPV use, particularly in areas with low routine vaccination coverage, is associated with the emergence of genetically divergent vaccine-derived polioviruses (VDPVs) whose genetic drift from the parental OPV strains indicates prolonged replication or circulation (3). VDPVs can emerge among immunologically normal vaccine recipients and their contacts as well as among persons with primary immunodeficiencies (PIDs). Immunodeficiency-associated VDPVs (iVDPVs) can replicate for years in some persons with PIDs. In addition, circulating vaccine-derived polioviruses (cVDPVs) (3) can emerge in areas with low OPV coverage and can cause outbreaks of paralytic polio. This report updates previous summaries regarding VDPVs (4). PMID- 27491078 TI - A human pluripotent stem cell model of catecholaminergic polymorphic ventricular tachycardia recapitulates patient-specific drug responses. AB - Although beta-blockers can be used to eliminate stress-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), this treatment is unsuccessful in ~25% of cases. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from these patients have potential for use in investigating the phenomenon, but it remains unknown whether they can recapitulate patient-specific drug responses to beta blockers. This study assessed whether the inadequacy of beta-blocker therapy in an individual can be observed in vitro using patient-derived CPVT iPSC-CMs. An individual with CPVT harboring a novel mutation in the type 2 cardiac ryanodine receptor (RyR2) was identified whose persistent ventricular arrhythmias during beta-blockade with nadolol were abolished during flecainide treatment. iPSC-CMs generated from this patient and two control individuals expressed comparable levels of excitation-contraction genes, but assessment of the sarcoplasmic reticulum Ca(2+) leak and load relationship revealed intracellular Ca(2+) homeostasis was altered in the CPVT iPSC-CMs. beta-adrenergic stimulation potentiated spontaneous Ca(2+) waves and unduly frequent, large and prolonged Ca(2+) sparks in CPVT compared with control iPSC-CMs, validating the disease phenotype. Pursuant to the patient's in vivo responses, nadolol treatment during beta-adrenergic stimulation achieved negligible reduction of Ca(2+) wave frequency and failed to rescue Ca(2+) spark defects in CPVT iPSC-CMs. In contrast, flecainide reduced both frequency and amplitude of Ca(2+) waves and restored the frequency, width and duration of Ca(2+) sparks to baseline levels. By recapitulating the improved response of an individual with CPVT to flecainide compared with beta-blocker therapy in vitro, these data provide new evidence that iPSC-CMs can capture basic components of patient-specific drug responses. PMID- 27491080 TI - Assessment of periodontal mechano-nociceptive function in healthy Chinese individuals. AB - OBJECTIVE: Few clinical techniques are available for the description of mechano nociceptive function in human periodontal tissues. The objective of this study was to test a new technique for assessment of periodontal mechano-nociceptive function by direct application of controlled forces to the teeth and quantify site, side and gender differences in healthy individuals. DESIGN: Twenty healthy young adults (ten males and ten females) participated. A handheld pressure algometer was used to assess pressure pain threshold (PPT) on the maxillary and mandibular central incisors, canines and first premolars on the left and the right side from two directions: lateral and vertical. Statistical analysis was performed using analyses of variance (ANOVA) with repeated measures to compare data. RESULTS: There were significant gender differences of PPT for both lateral (Plateral=0.007) and vertical (Pvertical=0.001) directions with lower thresholds in females (higher sensitivity) than in males. A significant site effect (Plateral=0.002, Pvertical<0.001) was observed with less sensitivity at the first premolar compared to the anterior teeth. No significant right-to-left side differences (P=0.082) were found for the PPTs. There were significant PPT differences between maxillary and mandibular teeth (Plateral=0.020, Pvertical=0.041,) and significant differences between lateral and vertical direction (P<0.001). CONCLUSION: The novel application of PPTs directly to the teeth indicated an adequate and practical method with potential value for clinical assessment of painful conditions affecting the periodontal ligament. PMID- 27491081 TI - Characterization of a novel mutation in PAX9 gene in a family with non-syndromic dental agenesis. AB - BACKGROUND: Dental agenesis is the most common developmental anomaly in man and may present either as an isolated trait or as part of a syndrome, such as ectodermal dysplasia. Until now, the underlying molecular pathogenic mechanisms responsible for dental agenesis are still largely unknown. Several genetic and molecular studies have demonstrated that at least 300 genes are involved in tooth formation and development, coding for specific transcriptional factors, receptors or growth factors that are expressed at specific developmental stages. Dental agenesis in this respect is believed to result from altered expression of one or more of these factors during initiation and early morphogenesis of the tooth germ, and the first actors identified were MSX1 and PAX9. DESIGN: In this study, we focalized on a Tunisian family with a non-syndromic autosomal dominant form of tooth agenesis. In order to screen for the eventual genetic cause of dental agenesis in this family we sequenced 4 genes; PAX9, WNT10A, MSX1 and AXIN2 using Sanger sequencing. RESULTS: Direct Screening analysis of PAX9 gene, revealed a novel mutation p.Asp200Serfs*13. It consists of a duplication of 5 basepairs leading to a codon stop 13 position downstream. This novel mutation was found in all affected family members. CONCLUSIONS: In this report, we present the first genetic study of a Tunisian family with a non-syndromic autosomal dominant form of tooth agenesis, in which we identified in PAX9 gene a novel mutation. It most likely results in nonsense mediated RNA decay and haploinsifficiency that reduce the transactivation capacity of PAX9. PMID- 27491083 TI - Cancer risk in siblings of children with congenital malformations. AB - PURPOSE: Cancer and birth defects cluster in families more often than expected by chance, but the reasons are neither well known nor well studied. METHODS: From singletons born alive in Denmark between 1 January 1977 and 31 December 2007, we identified children who had no congenital malformations but had a full or half sibling with a congenital malformation (CM) diagnosed in the first year of life; this constituted the exposed group, while children whose siblings had no such condition constituted a reference group. We estimated cancer risks for children who had a full sibling or a half sibling with a CM using a Cox proportional hazards regression model. To control for confounding related to change of family structure, we estimated cancer risks for children from core families and children from broken families separately. Children were followed from birth up to 30 years of age (median follow-up 13.6 years). We obtained information on CMs and cancer from the Danish National Hospital Register and the Danish Cancer Registry. RESULTS: We identified 991,454 (78%) children from core families with 53,995 children who had a full sibling with a CM and 277,773 (22%) children from broken families with 7200 children who had a full sibling with a CM and 6194 children who had a half sibling with a CM. Children who had a full sibling with a CM from both core and broken families showed, in general, no increased cancer risk compared with children whose siblings had no CM, except in the case of children who had a full sibling with a CM in the nervous system (HR=2.61, 95%CI:1.60-4.27) or in the eye, ear, face, or neck (HR=2.47, 95%CI: 1.46-4.18). Children who had a half sibling with a CM seemed to have a higher cancer risk in early adulthood (HR=1.87, 95%CI: 0.98-3.56). CONCLUSIONS: Children who had a full sibling with a CM had no increased risk of cancer except for those who had a full sibling with a CM in the nervous system or in the eye, ear, face or neck. Children with a half sibling with a CM tended to have an increased cancer risk in early adulthood, perhaps a result of chance. This study should be replicated using other data sources. PMID- 27491082 TI - Histologic characterization of regenerated tissues after pulp revascularization of immature dog teeth with apical periodontitis using tri-antibiotic paste and platelet-rich plasma. AB - INTRODUCTION: This study evaluates histologically the efficacy of 4 revascularization protocols in necrotic-infected immature dog teeth with apical periodontitis (AP). METHODS: Forty double-rooted immature premolar teeth from 4 female Beagle dogs aged 5 months were used. Four teeth were left untouched as negative controls; the other 36 teeth were infected to develop pulp necrosis and AP. Four teeth were left untreated and assigned to the positive control group. The last 28 teeth were randomly assigned into four experimental groups of 8 teeth, each one treated with a different treatment protocol: A1, sodium hypochlorite (SH)+blood clot (BC); A2, SH+platelet-rich plasma (PRP); B1, SH+modified tri-antibiotic paste (mTAP)+BC; B2, SH+mTAP+PRP. The animals were sacrificed, histologic sections were prepared and three parameters were assessed: (1) presence or absence of new hard tissue on the internal root dentinal walls, (2) presence or absence of continued apical closure, and (3) presence or absence of vital tissue within the canal space. RESULTS: Significant differences (p<0.05) between the four experimental groups were evident in the percentage of teeth showing histological apical closure (34.5%) and vital tissue within the canal space (68.8%). Group B2 showed the maximal improvement in the three variables assessed (p<0.05). Group A1 showed the minimum percentages in the three parameters assessed (p<0.05). CONCLUSIONS: These results suggest that an intracanal dressing of mTAP, and the use of PRP as scaffold, improves the success rate of the revascularization procedure. PMID- 27491086 TI - Reply. PMID- 27491084 TI - Model systems of protein-misfolding diseases reveal chaperone modifiers of proteotoxicity. AB - Chaperones and co-chaperones enable protein folding and degradation, safeguarding the proteome against proteotoxic stress. Chaperones display dynamic responses to exogenous and endogenous stressors and thus constitute a key component of the proteostasis network (PN), an intricately regulated network of quality control and repair pathways that cooperate to maintain cellular proteostasis. It has been hypothesized that aging leads to chronic stress on the proteome and that this could underlie many age-associated diseases such as neurodegeneration. Understanding the dynamics of chaperone function during aging and disease-related proteotoxic stress could reveal specific chaperone systems that fail to respond to protein misfolding. Through the use of suppressor and enhancer screens, key chaperones crucial for proteostasis maintenance have been identified in model organisms that express misfolded disease-related proteins. This review provides a literature-based analysis of these genetic studies and highlights prominent chaperone modifiers of proteotoxicity, which include the HSP70-HSP40 machine and small HSPs. Taken together, these studies in model systems can inform strategies for therapeutic regulation of chaperone functionality, to manage aging-related proteotoxic stress and to delay the onset of neurodegenerative diseases. PMID- 27491087 TI - [The beginnings of kidney transplantation in Debrecen, Hungary]. PMID- 27491088 TI - Change: the Forerunner of Progress. PMID- 27491090 TI - A Valuable Year. PMID- 27491089 TI - Real-Time Assessment of Osseous Tissue Changes After Guided Bone Regeneration. PMID- 27491085 TI - Loss of vhl in the zebrafish pronephros recapitulates early stages of human clear cell renal cell carcinoma. AB - Patients with von Hippel-Lindau (VHL) disease harbor a germline mutation in the VHL gene leading to the development of several tumor types including clear cell renal cell carcinoma (ccRCC). In addition, the VHL gene is inactivated in over 90% of sporadic ccRCC cases. 'Clear cell' tumors contain large, proliferating cells with 'clear cytoplasm', and a reduced number of cilia. VHL inactivation leads to the stabilization of hypoxia inducible factors 1a and 2a [HIF1a and HIF2a (HIF2a is also known as EPAS1)] with consequent up-regulation of specific target genes involved in cell proliferation, angiogenesis and erythropoiesis. A zebrafish model with a homozygous inactivation in the VHL gene (vhl(-/-)) recapitulates several aspects of the human disease, including development of highly vascular lesions in the brain and the retina and erythrocytosis. Here, we characterize for the first time the epithelial abnormalities present in the kidney of the vhl(-/-) zebrafish larvae as a first step in building a model of ccRCC in zebrafish. Our data show that the vhl(-/-) zebrafish kidney is characterized by an increased tubule diameter, disorganized cilia, the dramatic formation of cytoplasmic lipid vesicles, glycogen accumulation, aberrant cell proliferation and abnormal apoptosis. This phenotype of the vhl(-/-) pronephros is reminiscent of clear cell histology, indicating that the vhl(-/-) mutant zebrafish might serve as a model of early stage RCC. Treatment of vhl(-/-) zebrafish embryos with a small-molecule HIF2a inhibitor rescued the pronephric abnormalities, underscoring the value of the zebrafish model in drug discovery for treatment of VHL disease and ccRCC. PMID- 27491091 TI - Home field advantage... PMID- 27491092 TI - Troubleshooting Tips. PMID- 27491093 TI - Confronting a crisis: An open letter to America's physicians on the opioid epidemic. PMID- 27491094 TI - AARP Now Advocates for APRNs, but Does it Still Advocate for Seniors? PMID- 27491095 TI - Immunization Awareness Month. PMID- 27491097 TI - Best Friend... PMID- 27491098 TI - The Undescended Testicles of West Virginia: A Single Center Experience. AB - OBJECTIVE: To determine the age of pediatric patients who underwent surgical intervention for undescended testicles (UDT) at our institution. METHODS: We retrospectively reviewed all pediatric patients who underwent orchiopexy and/or diagnostic laparoscopy for undescended or non-palpable testicles with our pediatric urologist from January 2013-March 2014. Patients were separated into those undergoing surgical intervention at 6-12 months, 13-24 months, 25-48 months, and >48 months of age. RESULTS: 70 patients underwent surgical intervention. Only 15 patients (21.4%) underwent surgical intervention within the recommended time period of 6-12 months. Orchiopexy was performed on 21 patients (30.0%) from 13-24 months, 12 patients (17.1%) from 25-48 months, and 22 patients (31.5%) after 48 months of age. CONCLUSIONS: Current American Urologic Association (AUA) recommendations advocate orchiopexy between 6-12 months of age. Improved parent and primary care education and access to pediatric urological evaluation of UDT will hopefully improve the timeliness of intervention within our state. PMID- 27491099 TI - Pre-operative Identification and Surgical Management of the Appendiceal Mucocele: A Case Report. AB - An appendiceal mucocele (AM) is an uncommon differential in the patient being evaluated for acute appendicitis. Although often asymptomatic, AMs can clinically mimic acute appendicitis, and preoperative distinction between these processes facilitates optimal management. We report the case of a 60-year-old male with an AM presenting with nausea and periumbilical pain radiating to the right lower quadrant. Literature relevant to the diagnosis and treatment of AMs is reviewed, with emphasis on diagnosis through radiographic imaging and surgical management. Abdominal CT scan or ultrasound are useful in identifying AMs preoperatively. A decision to perform a right hemicolectomy should be influenced by the criteria reported by Gonzalez-Moreno. The safety of the laparoscopic resection relative to an open appendectomy is debated. PMID- 27491100 TI - Bone Mineral Density and Vitamin D Level Compared to Lifestyle in Resident Physicians. AB - Due to the demands of resident education and long periods of time spent indoors, resident physicians may have poorer bone quality than would be expected. Forty four resident physicians underwent dual-energy X-ray absorptiometry (DEXA) and 25 hydroxyvitamin D level testing at our institution. Results were correlated with a survey of self-reported duty hours, physical activity, and sun exposure. The average 25-hydroxyvitamin D level for all participants was 29 ng/dL, which fell into the insufficient range, and 31.5% of all participants were in the deficient range, with a 25-hydroxyvitamin D level < 20 ng/ dL. For the 40 subjects who underwent DEXA, 17 were found to be osteopenic and three were found to be osteoporotic. Greater awareness of bone health, with routine use of vitamin D supplementation and increased time spent outdoors during peak sunlight hours, may be indicated in this cohort. PMID- 27491101 TI - Inconspicuous Presentation of Metastatic Neuroblastoma. AB - Neuroblastoma is a malignant tumor arising from nerve tissue that accounts for approximately 15 percent of pediatric cancer fatalities. Primary tumors most commonly arise in sympathetic nervous tissue of the abdomen and metastasize to the bone marrow, liver, and lymph nodes. This case report depicts a 3-year-old girl who presented with a recurring fever, runny nose, and a positive test for rhinovirus suggesting a simple case of the common cold. Further investigation, however, revealed stage 4 neuroblastoma. This patient experience emphasizes the importance of having a high level of suspicion to rule out more serious underlying pathology in a seemingly unremarkable patient presentation. PMID- 27491102 TI - Implementing Universal Pulse Oximetry Screening in West Virginia: Findings from Year One. AB - BACKGROUND: In March 2012 the West Virginia legislature passed a law that mandates birth hospitals to perform pulse oximetry screening for all well-babies in the newborn nursery to improve the detection of critical congenital heart disease (CCHD). CCHD screening data collection began on September 1, 2012 at all 28 birthing hospitals. The purpose of this study was to review the first year of pulse oximetry screening outcomes and identify barriers to implementation and solutions to improve tracking and policy. METHODS: All WV birth hospitals were provided with the U.S. Department of Health and Human Services recommendations for CCHD screening, and the Center for Disease Control's recommended screening algorithm for review and reference. 20,115 infants were entered into the Birth Score database between September 1, 2012 and August 31, 2013. 19,283 (91%) infants were screened for CCHD. RESULTS: 17,101 (88.5%) infants passed, 19 infants failed, and 2,163 (11.2%) infants had missing data for the screening. 832 infants were not screened due to being admitted to the neonatal intensive care unit for reasons unknown. 17 of the 19 infants who failed the screening had a transthoracic echo report available for review. Of those 17 infants reviewed, seven were diagnosed with CCHD. CONCLUSIONS: 85% of the infants born in WV who received a Birth Score during the year reviewed were screened for CCHD. Given that the goal is to have 100% compliance with the pulse oximetry screening, additional investigations into factors affecting compliance may be necessary. PMID- 27491103 TI - Lyme Disease in West Virginia: An Assessment of Distribution and Clinicians' Knowledge of Disease and Surveillance. AB - Lyme disease case misclassification, a top public health concern, may be attributed to the current disconnect between clinical diagnosis and surveillance. This study examines Lyme disease distribution in West Virginia (WV) and determines clinicians' knowledge of both disease and surveillance. Lyme disease surveillance data for 2013 were obtained from the WV Bureau for Public Health. A validated survey, distributed to clinicians at an academic medical center, assessed clinicians' knowledge of disease diagnosis and surveillance. There were 297 adult Lyme disease cases of which 83 were confirmed. Clinician survey responses resulted in a correct response rate of 70% for Lyme disease knowledge questions. Fewer than half of all clinicians were aware of the surveillance criteria for confirming Lyme disease cases. Neither medical specialty nor previous treatment of patients with Lyme disease were significantly associated with clinicians' knowledge of the disease. Clinicians in WV are familiar with symptoms and clinical management of Lyme disease. However, they are less knowledgeable about diagnosis and public health surveillance comprising reporting and confirming cases of the disease. Clinicians and public health authorities should collaborate more closely to promote education and awareness as a key step to successfully reducing the burden of Lymne disease. PMID- 27491104 TI - DISASTER PREPAREDNESS: ARE YOU READY? PMID- 27491105 TI - BACK TO SCHOOL. PMID- 27491106 TI - Monogenic Diabetes: Not Your "Typical" Diabetes. PMID- 27491107 TI - DINNER TO YOUR DOOR. PMID- 27491108 TI - SUPERMARKET SMARTS. BEANS, PEAS and LENTILS. PMID- 27491109 TI - IN THE KITCHEN WITH THE DIABETIC CHEF. CHRIS SMITH SHARES HIS PERSONAL JOURNEY WITH DIABETES AND HIS APPROACH TO HEALTHY COOKING. PMID- 27491111 TI - Take 5. Posture and Core Strength. PMID- 27491110 TI - Summer portion control: from beach to barbecue. PMID- 27491113 TI - WHAT PEOPLE LIVING WITH HIV SAY ABOUT NOT COMING IN FOR HEALTH CARE. PMID- 27491112 TI - Getting to Know You. Sierra Sandison. PMID- 27491114 TI - A SUCCESS STORY IN HIV LINKAGE TO CARE AND RETENTION. PMID- 27491115 TI - MAGICAL THINKING IN HIV: MUCH MORE THAN DENIAL. PMID- 27491116 TI - TAKING THE HILL. PMID- 27491118 TI - YOU'VE LOST THAT GUTSY FEELING, WHOA, THAT GUTSY FEELING. PMID- 27491117 TI - HEPATITIS C AT CROI. PMID- 27491119 TI - RECONNECTING WITH HER COMMUNITY. FEELING FREE WITH THE RIDE FOR AIDS CHICAGO. PMID- 27491120 TI - STAYING IN THE GAME. PMID- 27491122 TI - NOT SO FAST. PMID- 27491121 TI - ALL SYSTEMS GO. PMID- 27491123 TI - JESSE PEEL IS AGING SWIMMINGLY. PMID- 27491124 TI - HELL IN A HOT FLASH? PMID- 27491126 TI - FOR ME AND MY BROTHER. PMID- 27491125 TI - CAN OLDER PEOPLE GET SOME... SATISFACTION? PMID- 27491127 TI - ALONE TIME. PMID- 27491128 TI - TRANSFORMING LIVES. PMID- 27491129 TI - PLANNING AHEAD. PMID- 27491130 TI - Bridgepoint Active Healthcare: Stantec Architecture, KPMB Architects, HDR Architecture, Diamond Schmitt Architects, Toronto. PMID- 27491131 TI - Baby Its Cold Outside. PMID- 27491133 TI - An Interview with the President-Elect: Dr. Barsley. PMID- 27491132 TI - Does Hiring an Advertising Agency Cost My Dental Practice Money? PMID- 27491134 TI - When the price of the blood-pressure drug Nitropress leaped from $215 to $881 last year, an increase of 310%, it triggered public outrage: What's behind the gouging?. PMID- 27491136 TI - BIG INNOVATION IN SMALL PLACES. PMID- 27491135 TI - New U.S. nutrition labels will emphasize calories and sugar. PMID- 27491137 TI - INTO THE LIGHT. PMID- 27491138 TI - Integrated Disability Management: Implementing a Customized Whole-Person Approach. AB - This article describes how incorporating integrated disability management can address business challenges. It includes case studies featuring organizations that used a "whole-person approach" to result in (1) greater and more effective communication and reporting, (2) more satisfied and productive employees and (3) cost savings through quicker return to work when legally and medically appropriate, all in alignment with the particular needs of a given firm. One size most definitely does not fit all. PMID- 27491139 TI - A Generation With Income to Protect. AB - From an employee benefits perspective, generational differences undoubtedly play a big role in not only how to communicate with employees about their benefits but what benefits to offer. Yet while there's been a lot of talk about how to reach other generations, information about connecting with Generation X is harder to come by. This article discusses the state of Generation X's unique income protection and financial concerns. The author shows how offering income protection to Generation Xers not only helps them deal with today's expenses and prepare for the future but can also help employers meet business objectives such as attracting and retaining top talent. PMID- 27491140 TI - Don't Let Disability Derail Long-Term Financial Security: Enhancing Retirement Security in a DC World. AB - Long-term disability (LTD) protection, such as a defined contribution (DC) disability supplement, is critical for good long-term security in a DC environment. For those with a strong LTD program already in place, this challenge can be addressed by providing a DC disability benefit that replaces DC contributions during periods of LTD. If there is no LTD program, that is needed first. Appropriate disability coverage is vital if the DC system truly is to deliver long-term retirement security. This article discusses issues in achieving such coverage and provides ideas to help in developing programs. Few such programs exist today, but it is hoped that this article will encourage more employers to adopt them. PMID- 27491141 TI - Engagement and Empowerment Through Self-Service. AB - Self-service tools represent the next frontier for leave and disability. This article discusses several critical com- ponents of a successful leave and disability self-service tool. If given the proper investment and thoughtfully designed, self-service tools have the potential to augment an organization's existing interaction channels, im- proving the employee experience while delivering efficiencies for an administrative model. In an operating en- vironment in which cost savings sometimes are at the expense of employee experience, such a win-win solution should not be taken lightly and, more importantly, should not be missed. PMID- 27491142 TI - Pharmacies Denied Injunction Against Pharmacy Benefit Manager. Grasso Enterprises, LLC v. Express Scripts, Inc., 809 F.3d 1033 (8th Cir. Jan. 11,2016). PMID- 27491143 TI - [PROBLEM OF ENDOMETRIUM HYPERPLASTIC PROCESSES IN REPRODUCTIVE AGE WOMEN]. AB - The article presents the risk factors of endometrium hyperplastic processes (EHP) in reproduc- tive age women. It is shown that EHP occur in response to hormonal homeostasis violations of the target tissues. It is established that the biologically active substances, which are closely related to immune mechanisms of the reproductive system functioning take place in regulatory mechanisms of cell growth and differentiation of endometrium. PMID- 27491144 TI - [ERRORS IN DIAGNOSIS AND TREATMENT OF IMMUNODEPENDENT PATHOLOGY (ORIGINAL CONCEPT)]. AB - Based on many years of experience in 2009, we developed the original concept of a mixed approach to the treatment of infectious diseases in patients. During 2.5 years(from 2013 to June 2015) to have applied for consultative-diagnostic help of 3965 patients who had not verified the primary diagnosis. The basic principle of verification of the pathology of the removal of various causes immunosuppression. Based on our extensive, research and observation was often found in patients ascaridosis (55%) and giardiasis (65%), as a possible cause of immunosuppression. In 13% of patients was found the mucosal candidiasis. Among frequently and chronically ill persons we identified the active forms of Epstein-Barr virus (quantitative polymerase chain reaction in saliva) in 40%. The criterion for assessing performance immunogram was a decrease of two sigmal deviation from the lower age limit. In the study of neutrophil myeloperoxidase content observed decline (< 60%) in 99 (9.7%) of 1015 patients, indicating a fairly common cause of long-term permit infection in the tissues and persistence C. albicans. In the study of lymphocyte subpopulations often demonstrated reduction in the number of natural killer cells (26.7% of subjects), which shows a decline of one of the most important factors of congenital immunity. Among the humoral immune disorders often noted the decrease of total IgG (2.4%) and its subclass IgG1 (22.1%), indicating a significant diagnostic value determination of IgG subclasses it even with normal serum total. Thus, approximately 76% of patients often suffer set of a decrease immunity. Patients developed with mixed infections caused by various bacterial, fungal, viral and protozoan agents and worms. Immunological study of patients should be redynamics after eliminating the causes immunosuppression and sanitation foci of infection. Only multi-level examination of the patient will determine the final diagnosis and adequate treatment. PMID- 27491145 TI - [REGRESSION OF LEFT VENTRICULAR HYPERTROPHY IN PATIENTS WITH ESSENTIAL HYPERTENSION AND LONG-TERM THERAPY WITH LOSARTAN]. AB - In 106 patients with essential hypertension stage II losartan effectively lowers systolic and diastolic blood pressure during the day, thus contributing to the normalization of the circadian blood pressure profile in patients with initial breach, and does not affect the normal circadian rhythm. Long losartan promotes regression remodeling processes of cardiac muscle and reduce preload and afterload. PMID- 27491147 TI - [EFFICIENCY OF CONCOMITANT USE OF POLICOSANOL AND ROSUVASTATIN IN PATIENTS WITH STABLE CORONARY ARTERY DISEASE AND MODERATE HEPATIC DYSFUNCTION]. AB - The article presents the results for the study of lipid correction capacity and safety of concomitant use of policosanol and rosuvastatin compared with rosuvastatin monotherapy in patients with stable coronary artery disease and moderate hepatic dysfunction. Fifty-seven subjects aged 37 to 72 years (mean age 54.4 years +/- 6.5 years) have been enrolled into the study with the following inclusion criteria: therapy with statins for more than 8 weeks, failure to achieve target LDL cholesterol levels and moderately elevated liver enzymes. The following laboratory tests were performed at baseline and after 12 weeks of follow-up: blood lipid profile (total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), high density lipoprotein cholesterol (HDL-C) and triglycerides (TG), lipid peroxidation (ma- Ionic dialdehyde (MDA), glycosylated hemoglobin HbAlc (%) and liver function tests (gamma-glutamyl transpeptidase-gamma-GTP) and alanine aminotransferase (ALT). Concomitant use of policosanol with rosuvastatin was superior to rosuvastatin monotherapy in terms of reduction of pro-aterogenicity of lipid metabolism by decreasing serum TC, LDL-C and TG, increasing serum HDL-C and decreasing the pro-oxidative activity (MDA) with simultaneous substantial improvement of hepatic function. Concomitant use of policosanol at the dose of 20 mg/day and rosuvastatin at 10-20 mg/day was favorably tolerated. None of the subjects had any discontinuations of therapy due to adverse events. PMID- 27491146 TI - [EFFICACY OF STANDARD TWO-YEAR COMPREHENSIVE THERAPY TO ACHIEVE TARGET BLOOD PRESSURE AND REGRESSION DEGREES OF REMODELING OF THE LEFT VENTRICULAR HYPERTROPHY IN PATIENTS AFTER ACUTE MYOCARDIAL INFARCTION WITH COMORBID HYPERTENSION]. AB - The study involved 23 men after acute myocardial infarction (AMI) with comorbid arterial hypertension (AH). Mean age of patients was 56.7 years. Recurrent myocardial infarction was determined in 38.4%, cardiac failure I-III functional classes--100% of the cases. All patients underwent clinical examination, electrocardiography and echocardiography, blood lipid profile. Standard comprehensive treatment for two years included an perindopril 5-10 mg/day, beta blocker bisoprolol--5-10 mg/day, antisclerotic drug atorvastatin--20 mg/day and aspirin--75 mg/day. The patients after treatment was determined by a gradual increase towards the target of AT at 3, 6 and 12 to 24 months. Concentric left ventricular hypertrophy (LVH) before treatment was determined in 47.8%, eccentric -in 52.2% of patients. In the study of degrees of LVH I (initial) the extent to treatment was determined by 4.3%, II (moderate)--26.1%, III (large)--at 69.6%, indicating the development of cardiac remodeling. After the treatment was determined by marked reduction III (large) degree and transfer it in the II (moderate) and I (small) degree of left ventricular hypertrophy due to more or less pronounced changes remodeling left ventricular. The obtained data allow a more detailed and adequately assess the structural and functional outcome variables and determine the regression of myocardial hypertrophy in the background to achieve target blood pressure, which is important in practical cardiology. PMID- 27491148 TI - [OVERWEIGHT CAUSES A DECREASE STOCKS CARDIOVASCULAR SYSTEM]. AB - Examined 117 students of the National Pedagogical Dragomanov University to assess body mass index and indicators of the functional state of the cardiovascular system. Was established that regulatory mechanisms in students with overweight and underweight are in a state of tension and functionalities of the cardiovascular system are reduced under normal conditions of learning. PMID- 27491150 TI - [PATOGENETIC VALUE OF VIOLATIONS FROM GLUTATHIONE SYSTEM AT THE PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS ON A BACKGROUND OF DIABETES MELLITUS TYPE II]. AB - At the patients with nonalcoholic steatohepatitis on a background of diabetes mellitus type II, after completion of the generally accepted medical treatment there was no normalization of indexes of the glutation system (the level of recovered glutation and activity of enzymes the glutation redox-system was saved decreased), that in a clinical plan was represented in.a presence unstable clinical and biochemical remission of disease. PMID- 27491149 TI - [EXPRESSION OF PFKFB, HK2, NAMPT, TSPAN13 AND HSPB8 GENES IN PEDIATRIC GLIOMA]. AB - We studied the peculiarity of the expression of several key genes related to dysregulation of cell proliferation and surviving processes in pediatric glioma (glioblastoma multiforme) tissue from five children with age from 5 to 8 years as well a sin corresponding nonmalignant tissue counterparts as control from the same patients. RNA was isolated from glioma tissue and corresponding non malignant tissue counterparts and PFKFB1, PFKFB2, PFKFB3, PFKFB4, HK2, NAMPT, TSPAN13, and HSPB8 gene expressions were studied by quantitative polymerase chain reaction. It was shown that the expression level of genes PFKFB1, PFKFB2, PFKFB3, PFKFB4, HK2, NAMPT, TSPAN13, and HSPB8 is increased in pediatric gliomas as compared to corresponding non-malignant tissue counterparts, but in different grade. More significant changes were demonstrated for PFKFB3, PFKFB4 HK2, NAMPT, TSPAN13, and HSPB8 genes. Thus, the changes in pediatric glioma tissues of the expression of PFKFB1, PFKFB2, PFKFB3, PFKFB4, HK2, NAMPT, TSPAN13, and HSPB8 genes, which control cell proliferation and apoptosis, possibly contribute to enhance the tumor growth, because these genes control cell proliferation and surviving. PMID- 27491152 TI - [THE LEVELS OF OSTEOCALCIN AND PYRIDINOLINE IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: THE RELATIONSHIP WITH STRUCTURAL AND FUNCTIONAL STATE OF BONE TISSUE AND COURSE OF THE DESEASE]. AB - The article presents data on levels of osteocalcin and pyridinoline in patients with systemic lupus erythematosus (SLE), their comparison with structural and functional state of bone tissue and course of the disease. Bone metabolism derangements were found in 65.8% of women with SLE. Herewith, the increase of pyridinoline content was observed in 43.9% of patients, the reduction of osteocalcinin 39% of individuals. The deterioration of bone metabolism was associated with the severity of the disease, especially high levels of C-reactive protein (CRP) and interleukin-6 (IL-6) (r = 0.3-0.32), cumulative dose of glucocorticoids (GC) and low body mass index (BMI). Among patients with signs of biosynthetic inhibition and increasing of destructive processes in bone tissue were more often met people with osteopenia and osteoporosis. osteoporosis. PMID- 27491151 TI - [THE APPLICATION OF ANTIHOMOTOXIC DRUG PREPARATIONS IN THE COMPLEX TREATMENT IN PATIENTS WITH NEUROLOGICAL MANIFESTATIONS OF LUMBAR OSTEOCHONDROSIS]. AB - The expediency of application homeosyniatry by preparations of Traumel S and Placenta Compositum after the offered chart in relation to a complex with classic acupuncture and in relation to the group of the generally accepted treatment has been proved in complex treatment patients with reflex syndromes of lumbar osteochondrosis. A similar conclusion was done after the statistically reliable (P < 0.05) dynamics of parameters of endogenous intoxication, liperoxydation and antioxydant systems of the protection (by the level of katalase, superoxyddismutase, SH-groups, ceruloplasmine). PMID- 27491153 TI - [THE ROLE OF OSTEOCALCIN IN COURSE OF OSTEOARTHRITIS AND TYPE 2 DIABETES MELLITUS]. AB - We studied the level of osteocalcin and its relationships with carbohydrate metabolism and clinical and radiographic changes in patients with osteoarthritis (OA) and type 2 diabetes mellitus (DM 2) and their combination. Significant negative correlation between the level of osteocalcin and carbohydrate metabolism, and clinical and radiographic changes in patients with OA and DM 2 was found. We determined, that negative correlation of osteocalcin with carbohydrate metabolism and radiographic changes, and more pronounced pain in OA maybe an indication that the lack of production of osteocalcin leads to more severe changes during the OA on the background of DM 2 diabetes mellitus. PMID- 27491154 TI - [METHODS IN ABDOMINAL OBESITY]. AB - This article describes the anatomical and physiological, histological and topographic features of adipose tissue on the relationship of metabolic syndrome, insulin resistance and cardiovascular disease. An advanced diagnostic techniques of total body fat and visceral fat content quantification as the most metabolically active are described. PMID- 27491155 TI - [THE INFLUENCE OF A COMBINATION OF MODERN DRUGS NUCLEINAT AND ALFAGIN ON THE CONCENTRATION OF CIRCULATING IMMUNE COMPLEXES AND THEIR MOLECULAR COMPOSITION IN THE SERUM OF PATIENTS WITH IRRITABLE BOWEL SYNDROME ON THE BACKGROUND OF NEUROCIRCULATORY DYSTONIA IN COMPLEX MEDICAL REHABILITATION]. AB - The effect of the combination nucleinat and alfagin in a complex of medical rehabilitation at the level of circulating immune complexes (CIC) in serum of patients and their molecular composition with irritable bowel syndrome (IBS), against neurocirculatory dystonia (NeD). It is established that the combination of nucleinat and alfagin in medical rehabilitation of patients with this comorbid disorders contributes to the normalization of the total concentration of the CEC and their molecular composition, which indicates the validity of the application of the pathogenesis combinations of drugs in complex medical rehabilitation of patients with lBS against NCD. PMID- 27491156 TI - [COMPARATIVE EVALUATION OF THE EFFECTIVENESS OF THE USE OF 13C-LABELED MIXED TRIGLYCERIDE AND 13C-STARCH BREATH TESTS IN PATIENTS WITH CHRONIC PANCREATITIS AFTER CHOLECYSTECTOMY]. AB - The results of a comprehensive study of 96 patients after cholecystectomy are provided. The higher sensitivity and informativeness of the 13C-labeled mixed triglyceride breath .test compared with 13C-starch breath test for determining functional pancreatic insufficiency in patients after cholecystectomy in early stages of its formation was set. PMID- 27491157 TI - [THE LEVEL OF LACTATE DEHYDROGENASE AS A MARKER OF RENAL DYSFUNCTION IN NEONATES WITH ASPHYXIA]. AB - The article examines the possibility of determining the level of lactate dehydrogenase (LD) in biological fluids as a marker of renal dysfunction and energy supply in neonates with asphyxia. Investigation included 200 full-term newborns with disturbance kidney function: 100 infants who had severe asphyxia, and 100--with moderate asphyxia. LD activity was determined by kinetic spectrophotometric method. Determination of the activity of LD in the urine in the early neonatal period it is advisable to use as a non-invasive marker for the diagnosis of renal dysfunction in neonates with asphyxia. The content of LD in the blood serum can be used as one of the early markers of kidney damage in newborns with asphyxia. PMID- 27491158 TI - [A MODERN APPROACH TO THE TREATMENT OF DIABETIC POLYNEUROPATHY]. AB - In this paper, the authors conducted research on the application of a new drug for the treatment of diabetic polyneuropathy in patients with diabetes mellitus type 1 and 2. Established an effective influence on the hemodynamic, metabolic, biochemical parameters, improved sensory-motor conduction in nerve fibers. Recommended for widespread use in patients with diabetes mellitus. PMID- 27491159 TI - [FEATURES MICROECOLOGY GENITAL TRACT IN WOMEN OF REPRODUCTIVE AGE WITH BENIGN CERVICAL PATHOLOGY]. AB - In the article we may see the results of microbiological investigation of secretion from genital tracts in women with the benign pathology of uterus cervix. The outcomes specify the disorders of microecology of genital tracts in these women following the proliferation of conditionally pathogenic flora, the increase of viral infection and the increase in the frequency of diagnostic of sexually transmitted infections. PMID- 27491160 TI - [ULTRASOUND CRITERIA OR THE OPERABILITY AND EFFICACY OF THE TREATMENT OF THE MALIGNANT EPITHELIAL OVARIAN TUMOURS]. AB - In order to isolate the main sonographic criteria of ovarian cancer operability the dynamical U.S. examination was performed on 65 women with epithelial tumors of II-III stages before and during 5 years after treatment beginning, which included (in different combinations) cytoreductive surgery and neoadjuvant chemotherapy. Only total 14 (21.5%) relapses were revealed. The U.S. prognostic criteria of the ovarian cancer treatment efficacy with and without neoadjuvant chemotherapy were defined. PMID- 27491161 TI - [STUDY EFFECT OF ASSOSIATED PATHOLOGY ON THE DEVELOPMENT OF OPTIC NERVE ATROPHY]. AB - Studied effect of assosiated pathology on the development of optic nerve atrophy (ONA). The basis of population study was comparison some factors in the groups with ONA and without ONA (analysis case-control) and evaluation of relative risk. Analysis showed that the risk of development of ONA increased in coronary heart disease, hypertension, diabetes, atherosclerosis. A functional-organizational model of care for patients with ONA was proposed. PMID- 27491162 TI - [THE MANIFESTATIONS OF THE PATHOLOGICAL CHANGES OF THE INTERNAL ORGANS IN PATIENTS WITH DISEASES OF TEMPOROMANDIBULAR JOINT]. AB - The results of a survey of 248 patients (mean age--26.0 years +/- 7.4 years), from which 222 patients (mean age--26.3 years +/- 8.0 years) with diseases of temporomandibular joint. Identified and visceral connection between the local changes in the iris, the state of the body's connective tissue, the presence of visceral disease (cardiovascular, respiratory, digestive, urinary system), diseases of the temporomandibular joints. Key words: temporomandibular joint, connective tissue, iris, iridodiagnostic, internal organs, concomitant diseases, topical. diagnostics. PMID- 27491163 TI - [EVALUATION OF CHANGES OF GEOMETRICAL PARAMETERS OF ALGINATE DENTAL IMPRESSIONS DUE TO THE INFLUENCE OF CHEMICAL AND MICROWAVE DISINFECTION METHOD USING 3D TECHNOLOGIES]. AB - This clinical and laboratory study evaluated the effect of two methods of disinfection in different modes at the volume changes of alginate dental impressions and plaster models poured from them, as compared to the same parameters of plastic master models (PMM), using three-dimensional non-contact laser scanner and software. Immersion chemical disinfection for 15 min, microwave disinfection at 354 W for 10 minutes and combined disinfection with the power of 319 W for 4 minutes did not significantly affect the volumetric dimensional accuracy of the alginate impressions (P > 0.05). PMID- 27491164 TI - [INVESTIGATION OF THE LEVEL OF MINERAL DENSITY OF SKELETAL OSSEOUS TISSUE IN PATIENTS WITH PERIODONTAL TISSUE DISEASES]. AB - Results of investigation of mineral density condition of skeletal osseous tissue in patients with inflammatory and dystrophic-inflammatory diseases of periodontal tissues with ultrasound densitometry method have been presented. Various changes of osseous tissue of skeletal bones have been detected: osteopenia, osteoporosis and osteosclerosis, which correlated with the severity of pathological process in periodontium. Analysis of the obtained results has been carried out depending on patients' sex as well as form and severity degree of the course of periodontal diseases. It has been established that the peak of detected impairments of mineral density in the skeleton is due to osteopenia, the degree of severity of which deteriorates with the severity of pathological process in periodontal tissues, especially in women. PMID- 27491165 TI - [CHANGING THE PHYSIOLOGICAL PROPERTIES OF ORAL LIQUID FOR OBESITY]. AB - The study of oral fluid homeostasis is a valuable noninvasive technique for diagnosing the general state of the organism, as well as the initial stages of the pathological processes in the tissues oral cavity. The results of studies of changes in the physiological properties of the oral fluid (pH, salivary flow rate, viscosity) in obesity. PMID- 27491166 TI - [THE CORRECTION WITH NOOPHEN OF AUTONOMIC DYSFUNCTION IN YOUNG MEN WITH HYPERTENSION]. AB - The aim of this study was to investigate the influence of antihypertensive therapy with adding of gamma-amino-beta-phenylbutyric acid hydrochloride on the autonornic regulation of tcardiovascular system and the psychoemotional status in young men with hypertension. The study included 58 male with hypertension, aged 18-39 years (mean age 31.7 yearst 2.3 years), of them 28 patients (group I) administered beta-blocker and the other received a complex therapy which included beta-blocker and gamma-amino-beta-phenylbutyric acid hydrochiotide--Noofen ("OlainFarm", Latvia) 250 mg 3 times a day for 4 weeks. The control group consisted of 20 healthy indi&iduals aged 18-39 years (mean age 31.5 years +/- 2.5 years). The examination included of standard clinical; biochemical and instrumental investigatIons. We conducted a clinical measurement of blorid pressure, ambulatory blood pressure monitoring (ABPM), Doppler echocardiography, heart rate variability, autononlic symptoms questionnaire and Spielberger--Hanina Anxiety Scale. Analysis of circadian blbod pressure profile arid autonomic nervous system state in young men with hypertension, in spite of the short disenle history demonstratnl violations of the blood pressure circadian rhythm associated with the violation of the autonomic regulation of cardiovascular system as indreased sympathetic activity and decreased parasympathetic activity heart tate. In hypertensive patients with autonomic dysfunction we noted a reduction of level of mental health, which was reflected in an increase in'the number of people with high and moderate levels of reactive and personal anxiety It has been demonstratedthat the use of combination therapy with adding Noofen in young hypertensive men and autonomic dysfunction helped significantly improve the HRV parameters and restore autonomic balance on time parameters of heart rate variability reduced the level of reactive anxiety and imprdved the psychoemotional state. PMID- 27491169 TI - [EXPERIMENTAL GROUNDS ON POSSIBILITY TO MAKE AND TO USE PREDICTION MODELS OF PESTICIDES DESIGN STANDARD IN THE WATER OF PONDS USED FOR HOUSEHOLD AND DRINKING WATER SUPPLY]. AB - Taking into account the fact that current calculation methods for substantiation of standards in the water of water reservoirs valid in Ukraine are outdated the aim of our research was to scientifically substantiate the possibility to make and to use prediction models of pesticides design standard in the water of ponds used for household and drinking water supply. Array of experimentally substantiated and approved to use in Ukraine maximum allowable concentrations (MAC) of organic pesticides active ingredients in the water was analyzed (n = 201). Analysis of dependence between MAC value of pesticides in the water and its physical and chemical properties, indices of ecotoxicological hazard and persistency in the water was carried out using correlation and regression analysis methods. Twelve regression equations to establish design value of pesticides MAC in the water were proposed on the grounds of performed analysis. The results of reliability testing of proposed procedure on pesticides design tentatively allowable levels (TAL) in the water indicate on needs to apply the least value of TAL obtained in the process of calculations using proposed equations. It was proved that mathematical models proposed for prediction of pesticide design standard in the water are adequate and significant by Fisher's test (P < 0.05). Proposed algorithm allows considerably simplify procedure of obtaining temporary hygienic standard in the water for new pesticides. PMID- 27491167 TI - [EFFICIENCY OF COCARNIT IN COMPLEX THERAPY OF PATIENTS WITH SYSTEM DISEASES OF CONNECTING FABRIC WITH DEFEAT OF MYOCARDIUM AND DISPLAYS OF CARDIAC INSUFFICIENCY]. AB - In clinical trial included 41 patient with clinic-instrumental dates, which said about myocardium dysfunction and system diseases of connecting fabric and displays of CCI I-III of functional class (FC). Including of complex metabolic drug Cocarnit in standard therapy of systemdiseases of connecting fabric was instrumental in more expressed clinical improvement of patientsclinical dates in 15 days of supervision: a weakness diminished on 66.67%, shortbreathing at the insignificant physical loading--on 23.81%, at the ordinary physical loading--on 47.62%, at the megascopic physical loading--on 19.05%, pain in area of heart--on 42.85%, there are interruptions in-process heart--on 28.57%, oedematousness of shins--on 57.14%, sense of numbness, burning, sensitiveness to cold of extremities--on 57.14%. Quantity of patients with III FC diminished on 5 (23.81%), in a control group--on 2 (10%). It implementation of test with the 6 minute walking more expressed increase of the overcame distance is set for the patients of basicgroup--on 15.46% as compared to a control group--on 7.01%. Cocarnit patients estimatedpositively; side effects with subsequent abolition of drug, were not. Laboratory indexes (AlAT, AsAT, bilirubin, kreatinine, haemoglobin) at the end of trial did not change considerably, that confirmed good bearableness of drug. PMID- 27491168 TI - [CHANGES IN THE METABOLISM IN THE MYOCARDIUM OF RATS WITH ARTERIAL HYPERTENSION]. AB - In the myocardium of the rats with arterial hypertension marked increase in the amount of unsaturated fatty acids and polyunsaturated fatty acids. Reducing the concentration of palmitic acid and increased levels of arachidonic acid is considered as one of the factors that lead to the development of energy deficit and oxidative stress. In rats, with hypertension myocardial lactate concentration increases in the cytoplasmic fraction and reducing the amount of ATP. The level in the cytoplasmic and mitochondrial fractions above benchmarks, indicating about the change of antioxidant systems of the body In the cytoplasm and mitochondria of cardiomyocytes of the rats with arterial hypertension marked decrease in the activity of antioxidant enzymes: NO-synthase, catalase, glutathione reductase, which causes metabolic changes of the myocardium. PMID- 27491170 TI - [DEVELOPMENT OF THE LOCAL CLINICAL PATHWAY "PREVENTION OF CARDIOVASCULAR DISEASE" (SCIENTIFIC STATEMENT AND PRACTICAL APPROACH)]. AB - An overview of scientific data on current approaches to the prevention of cardiovascular diseases has been exposed. The results of proceedings on development of the local clinical pathway "Prevention of cardiovascular disease" in the State Institution of Science "Research and Practical Center of Preventive and Clinical Medicine" State Administrative Department has been generalized. PMID- 27491171 TI - [EPIDEMIOLOGIC ASPECTS OF HUMAN GRANULOCYTIC ANAPLASMOSIS IN THE WESTERN REGION OF UKRAINE]. AB - This article presents data of complex study of human granulocytic anaplasmosis the human granulocytic anaplasmosis (HGA) in the western region of Ukraine. Natural HGA foci were identified, where the prevalence of A. phagocytophilum in the main vector (I. ricinus) amount to (12.0 +/- 0.7) %, and seroprevalence of HGA among the healthy population--(28.6 +/- 1.6) %. It's shown that A. phagocytophilum is the etiologic agent of (33.7 +/- 4.9) % of undiagnosed cases of seasonal febrile diseases. Principal characteristics of HGA epidemiology: spring-summer scasonality, the prevalence of disease in the age structure of people of active age (45.30 +/- 1.95 years), a significant level combination with (60.4 +/- 2.2) % Lyme-horreliosis and other tick-borne infections (mixed infections), the different level of activity of HGA epidemic process in forest and steppe geographical landscape zones--were revealed. PMID- 27491172 TI - [Early achievements of the Danish pharmaceutical industry--8. Lundbeck]. AB - The article series provides a written and pictorial account of the Danish pharmaceutical industry's products from their introduction until about 1950. Part 8 deals with products from Lundbeck. Lundbeck which today is known as a considerable international pharmaceutical company could in 2015 celebrate its 100 years' jubilee. Among the early Danish medicinal companies H. Lundbeck & Co. is in many ways an exception as the company was not originally established as a pharmaceutical company. Not until several years after the foundation the company began to import foreign ready-made medicinal products and later-on to manufacture these medicinal products in own factory and even later to do research and development of own innovative products. When Lundbeck was established in 1915 several Danish medicinal companies, not only the well-known such as Alfred Benzon and Lovens kemiske Fabrik (LEO Pharma), but also Skelskor Frugtplantage, Ferrin and Ferraton, had emerged due to the respective enterprising pharmacy owners who had expanded their traditional pharmacy business and even with commercial success. Other medicinal companies, such as C.R. Evers & Co., Leerbeck & Holms kemiske Fabriker, Chr. F. Petri, Erslevs kemiske Laboratorium, Edward Jacobsen, Th. Fallesen-Schmidt, and yet other companies which were named after the founder had all been established by pharmacists with the primary intention to manufacture and sell medicinal products. Also for the limited companies Medicinalco, Ferrosan, Pharmacia, and GEA the primary task was to manufacture and sell medicinal products, and also in these companies pharmacists were involved in the foundation. Not until 1924, fully 9 years after the foundation, Lundbeck started to be interested in medicinal products and initiated import and sale of foreign medicinal products manufactured by a.o. German and French companies which had not established their own sales companies in Denmark. Almost all contemporary Danish manufacturers of medicinal products could exclusively determine own proprietary names of the articles and could themselves make their own homogeneous and easily recognisable design, a.o. by frequent use of prefixes as Afa, Asa, Gea, Ido, Leo, and Meco which associated to for instance the company name. However, it goes without saying that Lundbeck had to market the articles in commission according to the different contracts with their partners. Consequently their range of products appeared heterogeneously. The international financial crisis and the consequent unemployment in the 1920s and 1930s had in Denmark a.o. resulted in national regulation in order to complicate import of ready-made goods and thus support the domestic manufacture of such articles. This was one of the reasons why Lundbeck decided to initiate its own manufacture of medicinal products in Denmark instead of continuing only with the import business which had been obstructed by the authorities. This article does not mention all Lundbeck's medicinal products which were marketed in Denmark until 1955 where a new Pharmacy Act came into force though undoubtedly a lot of interest can be written about all of them. The products mentioned in this article have been carefully selected, not only because they are representative for Lundbeck's development during the first decades, but also because the Danish Collection of the History of Pharmacy has acquired consumer packages of many of the articles. Several of these packages include patient information leaflets with an instruction for use and/or other information, and especially these leaflets represent a source material which has not previously been given much attention. It does not appear from the available source material whether these earliest medicinal products from Lundbeck were assembled in Danish packages on the production sites, or whether they were repacked in Copenhagen. It is not unlikely that the assembling originally was finalized abroad, and that instructions for the production of packaging material with Danish text were supplied by Lundbeck to the respective manufacturers. However, it is not unlikely either that the currency restrictions which were made after 1932 encouraged Lundbeck, where possible, first of all to import raw materials and bulk products and then manufacture the finished products in Valby. This was the case with Anusol, which Lundbeck certainly emphazised in the advertisement. It has to be pointed out that at that time there were no legal requirements regarding dating, neither of the user instructions nor of advertisements. Thus it is not due to mistakes or omissions made by Lundbeck that these materials are undated. The user instructions which Lundbeck had inserted in the packages were made and distributed at a time where no legal restrictions were in force neither regarding form nor content of such. The user instructions for products marketed after 1932 had probably been presented to the Pharmacopoeia Commission as this was statutory. It is, however, uncertain whether the Commission has dealt with the contents and the look of the user instructions. The most important task of the Commission was besides of the work with maintaining the Pharmacopoeia to look after the economic interests of the pharmacies so that only new drug substances could be marketed by the pharmaceutical industry, cf. below. In order to find out whether, and if so to which extent, the Pharmacopoeia Commission has been occupied in evaluating the informative and promoting printed matters of the industry, would require studies of the unprinted files of the Commission, and that is outside the scope of this article. At that time it was not against the law to inform in a user instruction that in case of a longer period of treatment, it would be more economical for the patient to buy a larger package. If you look at these patient information leaflets with today's eyes in the light of the present detailed, comprehensive and rigid regulations which the EU Commission has stated regarding patient information leaflets, you will find that Lundbeck's patient information leaflets were both simple and easy to read. On a free sample of Gelonida meant for the prescribing physician Lundbeck stated, besides of indication, dosage and warnings, also that the article was "Manufactured in Denmark". At that time it was not required to print information of production sites on packaging materials, however, it was not unusual to use this sales promoting claim in times of unemployment. In 1949 the original packaging material for Beatin was modified because certain text elements, the therapeutic indications were removed as it appeared that they since 1933 had violated the Pharmacy Act against advertisements for medicinal products aimed at the public. The packaging material for Beatin is a model example of the possibilities to combine practical information about the use of a medicinal product with sales claims in a reliable way. The above text modification and thus the legalisation of the packaging material took place upon request from the company as the violation of the advertising rules of the Pharmacy Act apparently had not resulted in any legal problems. Studies of unpublished files from the National Board of Health may possibly explain the background of this sequence of events, however, that is outside the scope of this article. The paragraph of the Pharmacy Act of 1932, stating that a medicinal product containing a common commodity as the active ingredient could not be marketed as a proprietary medicinal product, was meant to protect the pharmacies against the increasing competition from the industry. At first the paragraph did put a strain on the industry which from then on either had to manufacture own originator products or to copy other originator products without breaking patents. In the long run it has probably caused that not only Lundbeck, but also other Danish pharmaceutical companies became research-oriented and thus have been able to develop a relatively large number of originator products. In this context a product like Lucamid can hardly be regarded as an example of such a compulsory development of an originator product, an acetylsalicylic acid analogue. There were already such products on the market, but the wish to develop a better active ingredient has probably been bigger. From the three first editions of The Tariff of Medicines from 1935, 1937 and 1939 respectively it appears how Lundbeck's business within the area of medicines developed during the last half of the 1930s. In 1935 Lundbeck had placed 36 different medicinal products on the market, and all of them were in-licensing products. 4 years later, in 1939 Lundbeck had placed 40 different medicinal products on the market, and the number of in-licensing products had been reduced to 18 and 22 products were Lundbeck products. However, the increased focus on the development of own new medicinal products as Epicutan and Klianyl did not stop the in-licensing activities. Varex which Lundbeck brought on the market in 1942 came from a German pharmaceutical company with which Lundbeck had not previously collaborated. In Denmark Lundbeck had the intention to market 4 of Goedecke's 6 different medicinal products which all had Gelonida as part of the proprietary name. However, only one of these products got a longer life and with a simplified name, namely Gelonida. The fixed combination with three compounds of acetylsalicylic acid, phenacetin and codeine was without doubt effective, however, already at the end of the 1950s concern was raised about the safety of phenacetin. The Card Index of Medicines is a primary source of knowledge of how Lundbeck marketed the earliest medicinal products to the prescribing physicians. (ABSTRACT TRUNCATED) PMID- 27491173 TI - "We're Not Done". PMID- 27491174 TI - Working Feverishly to FEND OFF DENGUE. PMID- 27491175 TI - THE CONFIDENCE BOOSTER. PMID- 27491176 TI - "Brexit is no quick fix for the NHS's problems". PMID- 27491177 TI - Nurses' views on impact of referendum revealed. PMID- 27491179 TI - Study looks at health visiting key attributes. PMID- 27491178 TI - What would voting to leave or stay in the EU mean for nursing? PMID- 27491180 TI - Most student nurses drop out at end of course or before it starts. PMID- 27491181 TI - DH announces plans to dissolve nursing policy unit to cut costs. PMID- 27491182 TI - London Assembly votes to fight against plans to scrap bursary. PMID- 27491184 TI - Are black and minority ethnic nurses discriminated against? PMID- 27491183 TI - Nursing staff removed from duty by trust. PMID- 27491185 TI - "Wise use of our resources will improve hospital dementia care". PMID- 27491186 TI - How dementia differs from normal ageing. AB - Dementia is a collective name for a set of symptoms that include memory loss, mood changes, confusion and increasing difficulty with everyday tasks. This four part series provides an overview of dementia and its treatment, from its causes and pathophysiology to diagnosis and the nurse's role in its management. This first article reviews the main forms of dementia and how research is shedding new light on the differences between dementia and normal ageing. PMID- 27491187 TI - Developing a clinical research career. AB - The National Institute for Health Research helps to promote clinical research careers for health professionals working in clinical practice, and has developed a structure to support new researchers. This article explains how nurses can get involved in clinical research and the support available to them. PMID- 27491188 TI - Evidence base for managing neurogenic bowel dysfunction. PMID- 27491189 TI - Management of pruritus in palliative care. AB - Pruritis (severe itching of the skin) is a relatively rare symptom in palliative care, but it can have a negative impact on patients' physical, psychological and social wellbeing. It can also be distressing for family members. Holistic assessment is needed to inform an individual plan of care to alleviate the itching, which will involve general skin-care measures and a combination of topical and systemic treatments. PMID- 27491190 TI - 60 seconds with Paula Crick. PMID- 27491191 TI - Leading future leaders. PMID- 27491192 TI - The fall of Theranos and the future of science in Silicon Valley. PMID- 27491193 TI - HOW TO BEAT THE VIRUS--AND THE MOSQUITOES THAT CARRY IT. PMID- 27491194 TI - So should we just kill them all?. PMID- 27491195 TI - Wicked Problem Solvers. AB - Companies today increasingly rely on teams that span many industries for radical innovation, especially to solve "wicked problems." So leaders have to understand how to promote collaboration when roles are uncertain, goals are shifting, expertise and organizational cultures are varied, and participants have clashing or even antagonistic perspectives. HBS professor Amy Edmondson has studied more than a dozen cross-industry innovation projects, among them the creation of a new city, a mango supply-chain transformation, and the design and construction of leading-edge buildings. She has identified the leadership practices that make successful cross-industry teams work: fostering an adaptable vision, promoting psychological safety, enabling knowledge sharing, and encouraging collaborative innovation. Though these practices are broadly familiar, their application within cross-industry teams calls for unique leadership approaches that combine flexibility, open-mindedness, humility, and fierce resolve. PMID- 27491196 TI - Leading the Team You Inherit. AB - Most leaders don't have the luxury of building their teams from scratch. Instead they're put in charge of an existing group, and they need guidance on the best way to take over and improve performance. Watkins, an expert on transitions, suggests a three-step approach: Assess. Act quickly to size up the personnel you've inherited, systematically gathering data from one-on-one chats, team meetings, and other sources. Reflect, too, on the business challenges you face, the kinds of people you want in various roles, and the degree to which they need to collaborate. Reshape. Adjust the makeup of the team by moving people to new positions, shifting their responsibilities, or replacing them. Make sure that everyone is aligned on goals and how to achieve them--you may need to change the team's stated direction. Consider also making changes in the way the team operates (reducing the frequency of meetings, for example, or creating new subteams). Then establish ground rules and processes to sustain desired behaviors, and revisit those periodically. Accelerate team development. Set your people up for some early wins. Initial successes will boost everyone's confidence and reinforce the value of your new operating model, thus paving the way for ongoing growth. PMID- 27491197 TI - The Secrets of Great Teamwork. AB - Over the years, as teams have grown more diverse, dispersed, digital, and dynamic, collaboration has become more complex. But though teams face new challenges, their success still depends on a core set of fundamentals. As J. Richard Hackman, who began researching teams in the 1970s, discovered, what matters most isn't the personalities or behavior of the team members; it's whether a team has a compelling direction, a strong structure, and a supportive context. In their own research, Haas and Mortensen have found that teams need those three "enabling conditions" now more than ever. But their work also revealed that today's teams are especially prone to two corrosive problems: "us versus them" thinking and incomplete information. Overcoming those pitfalls requires a new enabling condition: a shared mindset. This article details what team leaders should do to establish the four foundations for success. For instance, to promote a shared mindset, leaders should foster a common identity and common understanding among team members, with techniques such as "structured unstructured time." The authors also describe how to evaluate a team's effectiveness, providing an assessment leaders can take to see what's working and where there's room for improvement. PMID- 27491199 TI - House Republicans' win on ACA lawsuit doesn't change much--yet. PMID- 27491198 TI - How to Preempt Team Conflict. AB - Team conflict can add value or destroy it. Good conflict fosters respectful debate and yields mutually agreed-upon solutions that are often far superior to those first offered. Bad conflict occurs when team members simply can't get past their differences, killing productivity and stifling innovation. Destructive conflict typically stems not from differences of opinion but from a perceived incompatibility between the way certain team members think and act. The conventional approach to working through such conflict is to respond to clashes as they arise. But this approach routinely fails because it allows frustrations to build for too long, making it difficult to reset negative impressions and restore trust. In their research on team dynamics and experience working with executive teams, Toegel and Barsoux have found a proactive approach to be much more effective. In this article, they introduce a methodology that focuses on how people look, act, speak, think, and feel. Team leaders facilitate five conversations--one focused on each category--before the team gets under way, to build a shared understanding of the process, rather than the content, of work and lay the foundation for effective collaboration. PMID- 27491200 TI - Clinton's Medicare buy-in concept revives debate on public option. PMID- 27491201 TI - Aetna, Anthem face shareholder rebuke over political spending. PMID- 27491202 TI - When the addict is a doctor. PMID- 27491203 TI - Institutional investors fight for more sway at healthcare companies. PMID- 27491204 TI - What, me buy insurance?. PMID- 27491205 TI - Medical science's debt to the hibakusha. PMID- 27491206 TI - Effective population health strategies require leadership diversity. PMID- 27491207 TI - Making 3-D medical imaging a reality. PMID- 27491208 TI - 'I certainly don't think Obamacare is going away, nor would I want it to'. PMID- 27491209 TI - Overcoming the Next Barriers to Successful Therapy. PMID- 27491210 TI - Brain Targeting in MPS-IIIA. AB - Mucopolysaccharidosis type IIIA (MPS-IIIA) is a childhood metabolic neuropathology caused by the inherited deficiency of the lysosomal enzyme sulfamidase and is characterized by the accumulation of undegraded glycosaminoglycans in the lysosomes of cells and tissues of affected patients. MPS-IIIA represents one of the most common forms of lysosomal storage disorders (LSDs) and to date there is no cure. Since neurodegeneration is the most relevant pathological feature in MPS-IIIA patients, the treatment of the central nervous system (CNS) lesions represents the goal of any effective therapy for this devastating disorder. During the last years many advances have been made in developing and testing new therapies for brain involvement in MPS-IIIA. These studies have been possible because of the availability of mouse and dog models that recapitulate the MPS-IIIA neuropathological features. Some of these approaches are based on direct CNS administration routes through which the therapeutic molecules access the CNS via the parenchyma (intracerebral injections) or via the cerebrospinal fluid (intraventricular/intrathecal injections). These approaches are highly invasive and poorly suited for clinical use. Minimally invasive approaches are based on systemic injections into the blood stream of therapeutics capable of crossing the blood-brain barrier (BBB). This review will present the background of the clinic and pathology aspects of MPS-IIIA and will describe the current MPS-IIIA preclinical and clinical studies focusing on how a systemic therapeutic strategy based on crossing the BBB has been successfully used to treat CNS pathology and behavioral abnormalities in a mouse model of MPS-IIIA. Future clinical applications of this approach to MPS IIIA patients will be also discussed together with the possibility of using similar strategies in other LSDs with neurological involvement. PMID- 27491212 TI - Prevention is the Best Therapy: The Geneticist's Approach. AB - Abstract During the last two decades prenatal genetic screening and diagnosis has become the cornerstone of medical care for family planning to prevent genetic disease. Carrier screening programs for genetic disorders that are prevalent in various populations identify couples and pregnancies at risk of having an affected child. These couples can proceed with a choice of invasive prenatal diagnosis tests of the fetus (chorionic villous sampling and amniocentesis), or non-invasive prenatal testing of free fetal DNA circulation in the maternal blood which has emerged within the last few years and is currently available for fetal sexing for X Linked disorders. Despite the advances in prenatal diagnosis, couples found to have a fetus affected with a genetic disorder may need to face the dilemma of pregnancy termination. Preimplantation genetic diagnosis (PGD) is an alternative to preempt risk of having a child affected with a life-altering genetic disorder. This technique allows biopsy and genetic diagnosis of embryos obtained from in vitro fertilization by analysis of the genetic material from one or a few embryonic cells. Only unaffected embryos are returned to the mother to establish the pregnancy. We present our experience using PGD for four Lysosomal storage disorders: Tay Sachs, Gaucher type 1, Hunter and Fabry disease with some of the couples being carriers of more than one genetic disorder. PGD is applicable to most disorders for which the gene and the familial mutation are known and should be presented to couples as an alternative to invasive prenatal testing. PMID- 27491211 TI - Combination Therapies for Lysosomal Storage Diseases: A Complex Answer to a Simple Problem. AB - Abstract Lysosomal storage diseases (LSDs) are a group of 40-50 rare monogenic disorders that result in disrupted lysosomal function and subsequent lysosomal pathology. Depending on the protein or enzyme deficiency associated with each disease, LSDs affect an array of organ systems and elicit a complex set of secondary disease mechanisms that make many of these disorders difficult to fully treat. The etiology of most LSDs is known and the innate biology of lysosomal enzymes favors therapeutic intervention, yet most attempts at treating LSDs with enzyme replacement strategies fall short of being curative. Even with the advent of more sophisticated approaches, like substrate reduction therapy, pharmacologic chaperones, gene therapy or stem cell therapy, comprehensive treatments for LSDs have yet to be achieved. Given the limitations with individual therapies, recent research has focused on using a combination approach to treat LSDs. By coupling protein-, cell-, and gene- based therapies with small molecule drugs, researchers have found greater success in eradicating the clinical features of disease. This review seeks to discuss the positive and negatives of singular therapies used to treat LSDs, and discuss how, in combination, studies have demonstrated a more holistic benefit on pathological and functional parameters. By optimizing routes of delivery, therapeutic timing, and targeting secondary disease mechanisms, combination therapy represents the future for LSD treatment. PMID- 27491213 TI - Juvenile NCL (CLN3 Disease): Emerging Disease-Modifying Therapeutic Strategies. AB - Abstract Juvenile Neuronal Ceroid Lipofuscinosis is a lysosomal storage disease characterized pathologically by intracellular accumulation of autofluorescent storage material and neurodegeneration. Caused by mutations in the CLN3 gene on chromosome 16p12, the precise functions of the encoded protein remain unclear. Yet, recent preclinical discovery has established new therapeutic targets in development, including immunosuppressants, anti-inflammatories, and gene replacement therapies. Development of robust clinical trial endpoints appropriate for this poly-symptomatic disease, clinical trial design optimized for small samples, and adequate and efficient participant recruitment are challenges that lay ahead. PMID- 27491215 TI - Types A and B Niemann-Pick Disease. AB - Two distinct metabolic abnormalities are included under the eponym Niemann-Pick disease (NPD). The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM). Patients with ASM deficiency are classified as having types A and B Niemann-Pick disease (NPD). Type A NPD patients exhibit hepatosplenomegaly, frequent pulmonary infections, and profound central nervous system involvement in infancy. They rarely survive beyond two years of age. Type B patients also have hepatosplenomegaly and progressive alterations of their lungs, but there are usually no central nervous system signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Recently, patients with phenotypes intermediate between types A and B NPD also have been identified. These individuals represent the expected continuum caused by inheriting different mutations in the ASM gene (SMPD1). Patients in the second category are designated as having type C NPD. Impaired intracellular trafficking of cholesterol causes type C NPD, and two distinct gene defects have been found. In this chapter only types A and B NPD will be discussed. PMID- 27491216 TI - CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis). AB - CLN2 disease is an inherited metabolic storage disorder caused by the deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1). The disease affects mainly the brain and the retina and is characterized by progressive dysfunction of the central nervous system, leading to dementia, epilepsy, loss of motor function and blindness. The classical late infantile type begins at around three years of age with epilepsy and/or a standstill of psychomotor development, followed by a rapid loss of all abilities and death in childhood. A late onset form in a small proportion of patients starts at the age of 4 to 10 years, but also leads to severe neurological deterioration. The deficiency of TPP1 causes the lysosomal accumulation of a material called ceroid lipofuscin. The natural substrate of TPP1 is not known, nor is the connection between storage process and neurodegeneration, which is characterized by loss of neurons. Among various experimental approaches to treatment, enzyme replacement therapy (ERT) and gene therapy have developed remarkably. Enzyme delivery through the cerebrospinal fluid led to wide distribution of enzyme activity in the brain and to attenuated neuropathology and disease progression in a TPP1-deficient mouse model as well as in a natural TPP1-deficient dog model. Safety of the intrathecal delivery, pharmacokinetics, and tissue distribution of the administered enzyme studied in non-human primates were encouraging, and a phase I/II clinical trial for intraventricular ERT in CLN2 patients is ongoing. A second approach uses intracerebral injection of viral vectors containing normal coding segments of the CLN2 gene. In a CLN2 mouse model, this procedure resulted in cerebral enzyme expression, reduced brain pathology and increased survival. A small number of patients have been treated the same way using an AAV2-vector for gene transfer to the brain. Although there were no serious adverse events unequivocally attributable to the vector used, there were some serious adverse effects, and a clinical benefit was not clearly evident under the conditions of the experiment. A phase I/phase II study using a AAVrh10 vector is presently recruiting patients. PMID- 27491214 TI - The GM1 and GM2 Gangliosidoses: Natural History and Progress toward Therapy. AB - The gangliosidoses are lysosomal storage disorders caused by accumulation of GM1 or GM2 gangliosides. GM1 gangliosidosis has both central nervous system and systemic findings; while, GM2 gangliosidosis is restricted primarily to the central nervous system. Both disorders have autosomal recessive modes of inheritance and a continuum of clinical presentations from a severe infantile form to a milder, chronic adult form. Both are devastating diseases without cure or specific treatment however, with the use of supportive aggressive medical management, the lifespan and quality of life has been extended for both diseases. Naturally occurring and engineered animal models that mimic the human diseases have enhanced our understanding of the pathogenesis of disease progression. Some models have shown significant improvement in symptoms and lifespan with enzyme replacement, substrate reduction, and anti-inflammatory treatments alone or in combination. More recently gene therapy has shown impressive results in large and small animal models. Treatment with FDA-approved glucose analogs to reduce the amount of ganglioside substrate is used as off-label treatments for some patients. Therapies also under clinical development include small molecule chaperones and gene therapy. PMID- 27491217 TI - Insights into the Pathogenesis and Treatment of Krabbe Disease. AB - Krabbe disease (globoid cell leukodystrophy, GLD) is an inherited disease caused by a deficiency in the lysosomal enzyme galactocerebrosidase (GALC). The major galactosylated lipid degraded by GALC is galactosylceramide. However, GALC is also responsible for the degradation of galactosylsphingosine (psychosine), a highly cytotoxic glycolipid. It has been hypothesized that GALC-deficiency leads to psychosine accumulation that preferentially kills oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Krabbe disease has traditionally been considered a white matter disease characterized by the loss and disorganization of myelin, infiltration of multinucleated monocytes/macrophages (globoid cells) and lymphocytes, and dysregulation of pro inflammatory cytokines and chemokines. However, new studies have revealed unexpected neuronal deficiencies. Infantile Krabbe disease is believed to be the most common and aggressive form. However, juvenile and adult onset forms have been described. Children affected with infantile Krabbe disease present with motor dysfunction, cognitive decline, intractable seizures, and premature death between two to five years of age. Murine, canine, and primate models of GALC deficiency have been described and have played an important role in our understanding of this invariably fatal disease. Although there is no cure for Krabbe disease, hematopoietic stem cell transplantation can slow the progression of disease. Recent pre-clinical data indicate that simulataneously targeting multiple pathogenic mechanisms greatly increases efficacy in the murine model of Krabbe disease. A better understanding of the underlying pathogenesis will identify new therapeutic targets that may further increase efficacy. PMID- 27491218 TI - Therapy Development for the Lysosomal Storage Disease Fucosidosis using the Canine Animal Model. AB - Abstract Fucosidosis (OMIM 23000) is an inherited neurodegenerative lysosomal storage disease caused by a deficiency of the lysosomal hydrolase a-L-fucosidase due to mutations in the FUCA1 gene. Without enzyme-targeted therapy patients rarely survive beyond the first decade of life, and therapy options other than supportive care are limited. Hematopoietic transplants, first developed in the fucosidosis dog model, are the only treatment option available capable of delaying the disease course. However, due to the risks and exclusion criteria of this treatment additional therapies are required. The development of additional therapies including intravenous and intra-cerebrospinal fluid enzyme replacement therapy and gene therapy, which have been trialed in the canine model, will be discussed. PMID- 27491219 TI - [Clinical Guidelines for Diagnosis and Treatment of Liver Injury Related to Chinese Herbal Medicine]. PMID- 27491221 TI - [Study on the Distribution of Constitutions of Chinese Medicine in Patients with Osteonecrosis of Femoral Head]. AB - OBJECTIVE: To observe the distribution of constitution types of Chinese medicine (CM) in patients with osteonecrosis of femoral head (ONFH). METHODS: Totally 130 ONFH patients were recruited. Constitution types of CM were identified in all patients. Distribution features of constitution types of CM in ONFH patients were observed. The differences of distribution in gender, age, single or bilateral hips, course of disease, staging, cause, and region were also analyzed. RESULTS: Seventy patients were of complicated constitutions, while 60 patients were of single constitution. Among the 60 single constitution cases, yang-deficiency constitution [18 (13.9%)], damp-heat constitution [10 (7.7%)], blood-stasis constitution [7 (5.4%)], and qi-deficiency constitution [7 (5.4%)] were mainly distributed. Of the complicated constitutions, yang-deficiency dominated constitution occupied the top ratio [30 (23.1%)], followed by blood-stasis dominated constitution [15 (11.5%)], damp-heat dominated constitution [9 (6.9%)]. By putting them together, yang-deficiency constitution occupied the top constitution of CM [48 (36.9%)], followed by blood-stasis constitution [ 22 (16.9%)] and damp-heat constitution [19 (14.6%)]. The aforesaid three constitutions accounted for 68.5% of the total. There were no statistical distribution differences in gender, age, single or bilateral hips, course of disease, staging, or cause. CONCLUSION: Yang-deficiency constitution, damp-heat constitution, and blood-stasis constitution were liable constitutions of CM in ONFH patients. PMID- 27491220 TI - [Effects of Scalp Acupuncture on Serum NSE and S-100beta Concentrations and Postoperative Cogni- tive Function of Elderly Patients Undergoing Hip Replacement]. AB - OBJECTIVE: To explore the effect of Scalp acupuncture on serum neuron specific enolase (NSE) and S-100beta concentrations, and incidence rates of postoperative delirium (POD) and postoperative cognitive function (POCD) of elderly patients undergoing hip replacement. METHODS: Eighty-four patients undergoing scheduled hip replacement under combined spinal-epidural anesthesia (CSEA) were assigned to the control group (group C) and the scalp acupuncture group (group S) according to random digit table, 42 cases in each group. In group S, scalp acupuncture was additionally performed according to International Standardized Scheme for Scalp Acupuncture. Scalp acupuncture was performed during the operation from the MS1 middle line of forehead [1 cun before Shenting (GV24), including Shenting (GV24)] and MS5 middle line of vertex [from Baihui (DU20) to Qianding (DU21), including Baihui (DU20) and Qianding (DU21)]. The operation time and post-operative length of stay were observed. The midazolam dosage, hemorrhage amount, fluid transfusion amount, urine amount, use rates of ephedrine and atropine during the operation were also observed and compared between the two groups. The occurrence rate of POD and POCD at post-operative day 3 (T1), week 1 (T2), month 3 (T3), and month 6 (T4) were measured. Eighteen patients were randomly selected to collect blood from internal jugular vein before anesthesia t0), immediately after ending the surgery (t1), 6 h after operation (t2), 24 h after operation (t3), and 48 h after operation (t4), respectively. Serum levels of NSE and S-100beta were correspondingly measured. RESULTS: There was no statistical difference in the operation time, midazolam dosage used during the operation, hemorrhage amount, fluid transfusion amount, urine amount, use rates of ephedrine and atropine (P > 0.05). Compared with group C, the post-operative length of stay was shortened in group S (P < 0.05). The incidence rate of POD and that of POCD at each time point were lower in group S (P < 0.05). The expression level of NSE decreased at t2, t3, and t4, and the expression level of S100beta also decreased at t1, t2, t3, and t4(P < 0.05). There was no statistical difference in expression levels of NSE or S100beta between the two groups at other time points (P > 0.05). CONCLUSION: Scalp acupuncture could attenuate central nervous system lesion and improve POCD of elderly patients undergoing hip replacement. PMID- 27491222 TI - [Efficacy Observation for Treating Ankylosing Spondylitis by Chinese Herbs and Recombinant Hu- man Tumor Necrosis Factor Receptor II-Antibody Fusion Protein]. AB - OBJECTIVE: To observe the clinical effect of Chinese medical (CM) syndrome differentiation based Chinese herbs and recombinant human tumor necrosis factor receptor II-antibody fusion protein (etanercept) for treating ankylosing spondylitis (AS) patients. METHODS: Totally 35 AS patients were treated with syndrome differentiation based Chinese herbs and etanercept. Reinforcing Shen and strengthening Du channel, activating meridians to stop pain was principle used in syndrome differentiation based treatment. Etanercept was subcutaneously injected, 25 mg each time; twice per week for the first three months and once a week for the latter three months. The clinical efficacy was evaluated after 3 and 6 months of treatment. Meanwhile, ASAS20 and ASAS50 standards arriving rates were also observed. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), visual analog score (VAS) for spine pain, VAS for night pain, patient global assessment (PGA), VAS for physician global assessment, CM syndrome score, finger-ground distance, thoracic activity, tragus-wall distance, lumbar scoliosis, cervical rotation, Schober improved test, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were observed before treatment, 3 and 6 months after treatment. RESULTS: Compared with before treatment, BASDAI, BASFI, VAS for spine pain, night pain, physician global assessment, PGA, CM syndrome score, finger-ground distance, thoracic activity, tragus-wall distance, lumbar scoliosis, Schober improved test, ESR, and CRP all decreased after 3 and 6 months of treatment, with statistical difference (P < 0.05). Cervical rotation also decreased after 6 months of treatment, with statistical difference (P < 0.05). Compared with 3 months of treatment, total effective rate of CM syndrome, ASAS20 and ASAS50 standards arriving rates increased after 6 months of treatment, with statistical difference (P < 0.05). There were statistical differences in all indices mentioned above between after 3 months of treatment and after 6 months of treatment (P < 0.05). CONCLUSION: Syndrome differentiation based Chinese herbs combined etanercept could alleviate inflammatory reaction favorably, control the progression of active AS, and improve joint functions. PMID- 27491223 TI - [Research on Life Quality Scale for Patients with Idiopathic Pulmonary Fibrosis]. AB - OBJECTIVE: To develop a life quality scale suitable for idiopathic pulmonary fibrosis (IPF) patients, objectively reflecting its changes. METHODS: Authors first put forward a theoretical structure model of a scale according to patient reported outcome (PRO) scale formulation principle by combining basic theories of Chinese medicine (CM). Then authors developed an initial scale on the basis of various life quality scales for respiratory disease patients by using structural decision making. Totally 34 patients with confirmed diagnosis of IPF were tested by questionnaire. Items were screened using expert importance scoring method, factor analysis, correlation coefficient method, Cronbach's alpha coefficient method. IPF patient reported outcomes (IPF PRO, IP) were finally defined. RESULTS: A new IP scale was developed covering three areas and 38 items. Pearson correlation coefficient for correlation analysis of clinical symptom scores in ST George Respiratory Questionnaire and IP scale was 0.828 (P < 0.01). Pearson correlation coefficient for correlation analysis of activity ability scores was 0.929 (P < 0.01). Pearson correlation coefficient for correlation analysis of total scores was 0.862 (P < 0.01). By reliability of IP scale itself (reliability) analysis, Cronbach's alpha coefficient was 0.713. By using factor analysis method for data analysis, KMO statistics was 0.902. CONCLUSION: IP scale fully reflected the connotation of IPF patients' quality of life, so it could be used as CM clinical therapeutic effect evaluation tool. PMID- 27491224 TI - [Treatment of Early Diabetic Retinopathy by Liuwei Dihuang Pill Combined Ginkao Leaf Tablet]. AB - OBJECTIVE: To observe the prevention and clinical efficacy of combination of Liuwei Dihuang Pill (LDP) and Ginkgo Leaf Tablet (GLT) for early diabetic retinopathy (DR). METHODS: Using randomized, double-blind, double simulation, parallel controlled clinical trial, 140 type 2 diabetes mellitus (T2DM) outpatients were recruited and assigned to the treatment group and the control group, 70 in each group. All patients received basic Western medicine treatment (such as blood glucose and pressure control). Patients in the treatment group took LDP (8 pills each time, 3 times per day) and GLT (19.2 mg each time, 3 times per day), while those in the control group took LDP placebos and GLT placebos. All treatment lasted for 24 consecutive months. All subjects were followed-up every month. The general clinical data as sex, age, and metabolic data such as blood glucose, blood pressure, blood lipid, and DR prevalence rate were collected and statistically analyzed. RESULTS: There was no significant difference in levels of blood glucose, blood pressure, or blood lipid between the two groups (P > 0.05). After treatment the DR incidence rate was significantly lower in the treatment group than in the control group [3.1% (2/64) vs 18.6% (11/59), P < 0.05)]. Meanwhile, the DR prevalence rate of the treatment group was also significantly lower than that of the control group [6.3% (4/64) vs 20.0% (13/59), P < 0.05]. CONCLUSION: Combination of LDP and GLT could effectively prevent and treat the development of DR in T2DM patients. PMID- 27491225 TI - [Distribution of Syndrome Types of Chinese Medicine in Acute Infectious Diarrhea]. AB - OBJECTIVE: To observe syndrome types of Chinese medicine (CM) and distribution features of acute infectious diarrhea patients. METHODS: A retrospective study was performed in 465 acute infectious diarrhea patients. The distribution of CM syndrome and syndrome types in different seasons and genders were analyzed. RESULTS: Lack of appetite [381 (81.94%)], fatigue [350 (75.27%)], abdominal pain [338 (72.69%)], tenesmus [325 (69.89%)], anal scorching hot [276 (59.35%)], nausea [25 (55.48%)], diarrhea [249 (53.55%)], short yellow-urine [240 (51.61%)], thirsty [210 (45.16%)], and abdominal distention [206 (44.30%)] were most often seen. The syndrome distribution were sequenced as intestinal damp heat syndrome [268 (57.63%)], dyspeptic retention in intestine and stomach syndrome [106 (22.80%)], cold-damp invading exterior syndrome [47 (10.11%)], Pi-Wei qi deficiency syndrome [23 (4.95%)], cold-damp disturbing Pi syndrome [21 (4.52%)]. The incidence ratio of intestinal damp heat syndrome was the highest in autumn (P < 0.01), while that of cold-damp invading exterior syndrome was the highest in winter (P < 0.01). Cold-damp disturbing Pi syndrome was more often seen in females than in males (P < 0.01), and its incidence ratio was the highest in autumn (P < 0.05). The incidence ratio of dyspeptic retention in intestine and stomach syndrome was the highest in winter (P < 0.01). CONCLUSIONS: Intestinal damp heat syndrome was the most often seen in acute infectious diarrhea. Incidence ratios of in- testinal damp heat syndrome and cold-damp disturbing Pi syndrome were higher in autumn, while those of cold-damp invading exterior syndrome and dyspeptic retention in intestine and stomach syndrome were higher in winter. Cold-damp disturbing Pi syndrome was more often seen in females. PMID- 27491227 TI - [Effects of Cangfu Congxian Decoction on Oxidative Stress in Polycystic Ovary Syndrome Patients]. AB - OBJECTIVE: To observe the effect of Cangfu Congxian Decoction (CCD) on oxidative stress in granulosa cells of polycystic ovary syndrome (PCOS) patients. METHODS: Forty PCOS patients underwent in vitro fertilization-embryo transfer (IVF-ET) were assigned to the treatment group and the control group 1 according to random digit table, 20 in each group. Patients in the treatment group took CCD (200 mL, once in the morning and once in the afternoon) 2 months before IVF-ET, while those in the control group 1 took no Chinese medical decoction. Recruited were another 20 patients undergoing IVF-ET for tubal factors (as the control group 2). The clinical effect of IVF-ET were observed, including oocyte retrieval number, 2 pronuclear (2PN) fertilization rate, good quality embryo rate, clinical pregnancy rate, and ovarian hyperstimulation syndrome (OHSS) induced transplantation cancel rate. The expression of relative oxygen species (ROS) in granulosa cells was detected using cell immunofluorescence combined with confocal microscopy and FCM. RESULTS: Compared with the control group 1, occyte retrieval number, 2PN fertilization rate, and good quality embryo rate increased in the control group 2 and the treatment group (P <0. 05). OHSS induced transplantation cancel rate decreased in the control group 2 (P < 0.05). Fluorescence intensity of ROS decreased in the treatment group and the control group 2, as compared with the control group 1 (P < 0.01). CONCLUSION: CCD increased good quality embryo rate by down-regulating the expression of ROS protein in ovarian granulosa cells, and correcting in vivo oxidative stress. PMID- 27491226 TI - [Therapeutic Effects of Berberine Capsule on Patients with Mild Hyperlipidemia]. AB - OBJECTIVE: To observe the therapeutic effects of Berberine Capsule (BC) on patients with mild hyperlipidemia. METHODS: Totally 102 mild hyperlipemia patients were recruited. All patients were suggested to have proper diet and physical activity as basic therapy for 1 month of run-in period. Totally 97 patients completed it. Then they were randomly assigned to the berberine group (the treatment group, 49 cases) and the placebo group (the control group, 48 cases). Patients in the treatment group took BC 300 mg, while those in the control group took placebo 300 mg, thrice per day for 3 successive months. Then placebos and BC were interrupted for 2 months (as washout period). All subjects received only diet control and physical activity during washout period. After washout period, placebos and BC were re-administered to all patients in the same way for 3 months. Body mass index (BMI), fasting plasma glucose (FPG), TG, TC, LDL-C, and HDL-C were assessed after run-in period, washout period, at month 1, 2, 3 after the first therapy, at month 1, 2, 3 after second treatment, respectively. RESULTS: Compared with the end of run-in period, TG, TC, and LDL-C decreased, and HDL-C increased in the treatment group (P < 0.05) after first 3 months of treatment. Compared with 3 months after the first therapy, TG, TC, and LDL-C increased and HDL-C decreased in the treatment group after washout period (P < 0.05). Compared with the end of wash- out period, TC and LDL-C decreased in the treatment group at month 2 after second treatment (P < 0.05); TG, TC, and LDL C decreased (P < 0.01, P < 0.05), and HDL-C increased (P < 0.05) at month 3 after second treatment. Compared with the control group at month 3 after second treatment, TG, TC, and LDL-C all decreased, and HDL-C increased in the treatment group (all P < 0.05). CONCLUSION: BC was effective in improving blood lipid level in mild hyperlipidemia patients. PMID- 27491228 TI - [Analgesic Effect and Mechanism of Electroacupuncture on Rats with Chronic Inflammatory Pain]. AB - OBJECTIVE: To observe analgesic effect of electroacupuncture ( EA) on rats with chronic inflammatory pain and its regulatory mechanism on ispilateral dorsal root ganglion (DRG) and spinal dorsal horn (SDH) Mas-related G protein-coupled C receptor (MrgprC). METHODS: Totally 40 healthy male SD rats were divided into 4 groups according to random number table, i.e., the normal (N) group, the model (M) group, the acupuncture (Acu) group, the EA group, 10 rats in each group. The model of chronic inflammatory pain was established by subcutaneous injecting 0. 1 mL complete Freund's adjuvant (CFA) into right hind paw. Paw withdrawal thresholds (PWTs) were measured before modeling, at day 1, 3, 5, 7, and after CFA injection, respectively. Expression levels of MrgprC in ispilateral DRG and SDH were detected by Western blot. The content of bovine adrenal medulla 22 (BAM22) in SDH was detected by immunohistochemical assay. RESULTS: Compared with N group at each time point, PWTs significantly decreased in M group (P <0. 01). Compared with M group, PWTs significantly increased at day 5 of EA and after EA in EA group (P < 0.05, P < 0.01). Compared with Acu group at each time point, post-EA PWTs significantly increased in the EA group (P < 0.05). Compared with N group, expression of MrgprC in ispilateral DRG and ratio of BAM22 positive cells in ispilateral SDH increased in M group (P < 0.01). Compared with M group, expression of MrgprC in ispilateral DRG and ratio of BAM22 positive cells in ispilateral SDH increased in the EA group (P < 0.05). CONCLUSION: EA had favorable analgesic effect on chronic inflammatory pain induced by CFA, and its mechanism might be possibly associated with up-regulating MrgprC expression in ispilateral DRG and BAM22 content in ispilateral SDH. PMID- 27491229 TI - [Effect of Borneol on the Permeability of Blood Tumor Barrier Model and its Mechanism Study]. AB - OBJECTIVE: To observe the effect of natural borneol on the permeability of blood tumor barrier (BTB) model and the expression and activation of mitogen-activated protein kinase (MAPKs) signal transduction pathway related protein kinase in vitro. METHODS: C6 rat glioma cells and human umbilical vein endothelial cells (HUVECs) were co-cultured to establish BTB model. Then 4 groups were set up, the blank control group, low, middle, and high dose borneol groups (25, 50, 100 ug/mL), 3 samples collected at 7 time points (0, 10, 30, 60, 120, 180, 240 min, respectively). Blank culture medium was exchanged in the blank control group while medication. Different doses of natural borneol were administered to the 3 borneol groups. Cells were collected at different time points. BTB permeability was determined using horseradish peroxidase (HRP). Expression levels of extracellular signal regulated protein kinase (ERK), phosphorylation extracellular signal regulated protein kinase (P-ERK), P38MAPK, phosphor-P38MAPK, c-Jun N-terminal kinase (JNK), and phosphorylation c-Jun N-terminal kinase (P JNK) were detected using Western blot. RESULTS: Compared with the same group at min 0, the permeation rate obviously increased (P < 0.01) in the 3 borneol groups at the rest time points. P-ERK expression was elevated first, reached the peak at 30 min, and gradually recovered to the initial level (P > 0.05). Compared with the blank control group, HRP permeation rate increased from 10 min to 240 min (P < 0.01), and expression of P-ERK protein increased at 30 min and 60 min (P < 0.05) in the low dose borneol group; expression of P-JNK protein decreased in the 3 borneol groups at 180 min and 240 min (P < 0.05). Compared with the low dose borneol group, expression of P-ERK protein increased from 10 min to 180 min (P < 0.05), HRP permeation rate increased from 30 min to 180 min (P < 0.05), expression of P-JNK protein decreased at 180 and 240 min (P < 0.05) in the middle dose borneol group. Compared with the middle dose borneol group, HRP permeation rate increased from 10 min to 180 min (P < 0.05), expression of P-ERK protein increased from 10 min to 180 min (P < 0.05), expression of P-JNK protein increased at 180 min and decreased at 240 min (both P < 0.05) in the high dose borneol group. CONCLUSION: Natural borneol arrived at the effect of regulating reversible BTB patency possibly through activating phosphorylation of ERK in MAPKs signal transduction pathway, and further reversibly down-regulating expression of associated proteins. PMID- 27491230 TI - [Danlou Tablet Fought against Inflammatory Reaction in Atherosclerosis Rats with Intermingled Phlegm and Blood Stasis Syndrome and Its Mechanism Study]. AB - OBJECTIVE: To observe the effects of Danlou Tablet (DT) on inflammatory reaction, and expressions of lipoprotein-associated phospholipase A2 (LP-PLA2), secretory phospholipase A2 (sPLA2), and to analyze potential mechanisms. METHODS: Forty male Wistar rats were randomly and equally divided into five groups, i.e., the normal control group, the model group, the Western medicine (WM) group, the low dose DT group, the high dose DT group, 8 in each group. Rats in the normal control group were fed with basic forage for 12 successive weeks, while AS rat model was established in rats of the other four groups by feeding high fat and sugar forage plus intraperitoneal injection of vitamin D3. Normal saline, atorvastatin calcium suspension (at the daily dose of 1.8 mg/kg), low dose DT suspension (at the daily dose of 450 mg/kg), and high dose DT suspension (at the daily dose of 900 mg/kg) were administered to rats in the model group, the WM group, the low dose DT group, the high dose DT group respectively by gastragavage for 8 successive weeks. The general condition of all rats was observed. Rats were sacrificed after gastric administration and their serum collected. Serum levels of lipids (TC, TG, HDL-C, LDL-C) and inflammatory factors [IL-6, TNF-alpha, monocyte chemoattractant protein 1 (MCP-1), oxidized low-density lipoprotein (ox LDL), lipoprotein-associated phospholipase A2 (LP-PLA2), secretory phospholipase A2 (sPLA2)] were detected. Pathological changes of thoracic aorta were observed by HE staining. Protein and gene expressions of LP-PLA2 and sPLA2 in thoracic aorta were measured by Western blot and real-time fluorescent quantitative PCR respectively. RESULTS: Compared with the normal control group, rats in the model group were in low spirits and responded poorly. Typical atherosclerotic plaque could be seen in thoracic aorta of rats in the model group. Serum levels of TC, TG, LDL-C, IL-6, TNF-alpha, MCP-1, ox-LDL, LP-PLA2, and sPLA2 significantly increased (P < 0.05); protein and gene expressions of LP-PLA2 and sPLA2 in rat thoracic aorta increased (P < 0.05) in the model group. After 8 weeks of intervention, rats in 3 medication groups appeared active, and HE staining showed subsidence of plaque in rat thoracic aorta. Compared with the model group, serum levels of TC, TG, LDL-C, IL-6, TNF-alpha, MCP-1, ox-LDL, and LP-PLA2 decreased in 3 medication groups (P < 0.01, P < 0.05); serum sPLA2 level decreased, protein and mRNA expressions of LP-PLA2 and sPLA2 in rat thoracic aorta decreased in the WM group (P < 0.01, P < 0.05); protein and mRNA expressions of LP-PLA2 in rat thoracic aorta significantly decreased in the low dose DT group (P < 0.01, P < 0.05), and those of LP-PLA2 and sPLA2 decreased in the high dose DT group (P < 0.01, P < 0.05). CONCLUSION: DT could fight against inflammatory reaction and AS possibly through inhibiting LP-PLA2 expression and reducing ox-LDL production. PMID- 27491231 TI - [Effect of Tongxinluo on Apoptosis of Rat Cardiac Microvascular Endothelial Cells]. AB - OBJECTIVE: To observe the protective effects of Tongxinluo (TXL) on apoptosis of rat cardiac microvascular endothelial cells (RCMECs) resulting from homocysteine (Hcy) induced endoplasmic reticulum stress (ERS), and to determine the signaling pathway behind its protection. METHODS: Primary cultured RCMECs were isolated from neonatal rats using tissue explant method. The morphology of RCMECs was observed using inverted microscope, identified and differentiated by CD31 immunofluorescence method. Selected were well growing 2nd-4th generations of RCMECs. The optimal action time was determined by detecting the expression of glucose regulated protein 78 (GRP78) using immunofluorescence method. In the next experiment RCMECs were divided into 5 groups, i.e., the blank control group, the Hcy induced group (Hcy 10 mmol/L, 10 h), the Hcy + TXL group (Hcy 10 mmol/L + TXL 400 ug/mL), the Hcy +LY294002 group (Hcy 10 mmol/L + LY294002 5 umol/L, LY294002 as the inhibitor of PI3K), the Hcy + LY294002 + TXL group (Hcy 10 mmol/L + LY294002 5 umol/L + TXL 400 ug/mL). The apoptosis rate of RCMECs was detected by flow cytometry. mRNA and protein expressions of GRP78, C/ EBP homologous protein (CHOP), and cysteinyl aspartate specific proteinase-12 (caspase12) were detected by real-time reverse transcription PCR (RT-PCR) and Western blot respectively. Expression levels of phosphorylation of phosphatidylinositol 3-kinase (P-PI3K), total phosphatidylinositol 3-kinase (T- P13K) , phosphorylation of kinase B (P Akt) , and total kinase B (T-Akt) were detected by Western blot. RESULTS: Ten hours Hcy action time was determined. Compared with the blank control group, the apoptosis rate was increased (22.77%), mRNA and protein expressions of GRP78, CHOP, and Caspase-12 were increased, protein expressions of P-PI3K and P Akt,ratios of P-PI3K/T-PI3K and P-Akt/T-Akt were decreased in the Hcy induced group (P < 0.05, P < 0.01). Compared with the Hcy induced group, the apoptosis rate was decreased (10.17%), mRNA and protein expressions of GRP78, CHOP, and Caspase-12 were decreased, and expression levels of P-PI3K, P-Akt, P-PI3K/T-PI3K, and P-Akt/T-Akt were increased in the Hcy + TXL group (P < 0.05, P < 0.01). Compared with the Hcy + TXL group, the apoptosis rate was increased (17.9%), mRNA and protein expressions of GRP78, CHOP, and Caspase-12 were increased, expression levels of P-PI3K and P-Akt, ratios of P-PI3K/T-PI3K and P-Akt/T-Akt were decreased in the Hcy + TXL + LY294002 group (P < 0.05, P < 0.01). CONCLUSION: TXL could inhibit the apoptosis of RCMECs resulting from Hcy-induced ERS and its mechanism might be associated with activating PI3K/Akt signaling pathway. PMID- 27491232 TI - [Ligustrazine Promoted the Migration of Bone Marrow Mesenchymal Stem Cells by Up regulating MMP-2 and MMP-9 Expressions]. AB - OBJECTIVE: To explore the effect of ligustrazine on the migration of bone marrow mesenchymal stem cells (BMSCs) and protein expressions of matrix metalloproteinase-2 and-9 (MMP-2 and MMP-9) in vitro. METHODS: BMSCs were in vitro isolated and cultured using whole bone marrow adherent method, and phenotypes [surface positive antigens (CD29 and CD90) and negative antigens (CD34 and CD45)] identified using flow cytometry. BMSCs were divided into the blank control group, 25, 50, 100 umol/L ligustrazine group, and the GM6001 group (100 umol/L ligustrazine +MMPs inhibitor GM6001 ). The migration of BMSCs was tested by Transwell chamber test and wound healing assay after treated with ligustrazine for 24 h. The protein expressions of MMP-2 and MMP-9 were detected by Western blot. RESULTS: The third passage BMSCs grew well in uniform morphology. The expression rate of CD29, CD90, CD34, and CD45 was 96.9%, 97.3%, 0.2%, and 3.0%, respectively. Compared with the blank control group, the number of migrated cells and relative distance of cell invasion increased, and the protein expressions of MMP-2 and MMP-9 were elevated in each ligustrazine group (P < 0.05, P < 0.01). Compared with 100 umol/L ligustrazine group, the number of migrated cells and relative distance of cell invasion decreased in 25 and 50 umol/L ligustrazine groups and the GM6001 group (P < 0.01). Protein expression of MMP-2 decreased in 25 and 50 umol/L ligustrazine groups (P < 0.01). CONCLUSION: Ligustrazine could promote the migration of BMSCs in vitro, and its mechanism might be related to up regulating expression levels of MMP-2 and MMP-9 protein. PMID- 27491233 TI - [Brain Protection of Muscone in Rats with Brain Injury]. AB - OBJECTIVE: To observe cerebral protective effect of muscone (nasal administration) on traumatic brain injury model rats. METHODS: SD rats were divided into the sham-operation group, the model group, and the treatment groups according to random digit table, 50 in each group. Traumatic brain injury model was established by controlled cortical strike. Rats in the sham-operation group received surgery and anesthesia procedures only, with no strike. Muscone (1.8 mg/kg) was delivered to rats in the treatment group using in situ nasal perfusion, 30 min each time, twice daily for 7 successive days. Water content of brain tissue was detected in each group before intervention (T1), at day 3 of intervention (T2), day 5 of intervention (T3), and after intervention (T4), respectively. Expression levels of brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were detected using immunohistochemical analysis. RESULTS: Compared with the sham-operated group, water content of brain tissue increased (P < 0.05), and expression levels of NGF and BDNF decreased in the model group at T1, T2, T3, and T4 (P <0. 01). Compared with the model group, water content of brain tissue decreased (P < 0.05), and expression levels of NGF and BDNF increased (P < 0.01) in the treatment group at T1, T2, and T3. CONCLUSION: Nasal administration of muscone could reduce water content of brain tissue, alleviate cerebral edema, promote secretion of BDNF and NGF by olfactory ensheathing cells in traumatic brain injury rats. PMID- 27491235 TI - [Effects of Jianpi Jiedu Recipe on TCRVbetaCDR3 Spectratyping of Liver Cancer Rats with Pi Deficiency Syndrome]. AB - OBJECTIVE: To observe anti-cancer effects of Jianpi Jiedu Recipe (JJR) on liver cancer (LC) rats with Pi deficiency syndrome (PDS) and its relation with the third complementary-determining region gene spectratyping of TCRVbeta-chain (TCRVbetaCDR3). METHODS: Rats were divided into 8 groups according to random digit table, i.e., the blank control group (normal), the PDS group, the LC model group, the LC-PDS group, high, middle, and low dose JJR groups (75.00, 37.50, 18.75 g/kg, respectively by gastrogavage, once per day), the thymus pentapeptide group (5 mg/kg, intramuscular injection, twice per week), 8 in each group. Rats in the normal group were administered with physiological saline by gastrogavage once per day. PDS rat model was prepared by bitter-cold purgation. LC model was prepared by orthotopic transplantation method. Twenty gene subfamilies of TCRbetaCDR3 in the thymus, liver, and LC tissues were detected by Gene Scan. RESULTS: High and middle dose JJR could postpone the growth of LC volume (P < 0.05), with equivalent liver index and thymus index to those of the normal group (P > 0.05). In thymus and liver tissue of the normal group, the number of clones (20 and 19), gene fragment number (220 and 113), Quasi-Gaussian distribution ratio of TCRVbetaCDR3 gene repertoire (100.0% and 42.1%), and fragment fluorescence peak area (6,539 +/- 2,325 and 1,238 +/- 439) were at the highest level among the 8 groups. TCRVbetaCDR3 expressions in thymus and liver tissue of high and middle dose JJR groups were approximate to those of the normal group. They were in the middle of the thymus pentapeptide group, the PDS group, the LC model group, and poorest in the LC-PDS group. TCRVbetaCDR3 in liver tissue expressed the best in the thymus pentapeptide group. CONCLUSION: JJR might inhibit the growth of LC cells, and its mechanism might be related to enhancing TCRVbetaCDR3 spectratype expression. PMID- 27491234 TI - [Inhibition of Combination of Icaritin and Doxorubicin on Human Osteosarcoma MG 63 Cells in vitro]. AB - OBJECTIVE: To explore the inhibition and molecular mechanism of icaritin (ICT) combined doxorubicin (DOX) on human osteosarcoma MG-63 cells in vitro. METHODS: The control group, ICT groups (10, 20, 40, 80, and 160 umol/L), DOX groups (1, 2, 4, 8, and 16 ug/mL), and combination groups (20 umol/ L ICT +1 ug/mL DOX, 20 umol/L ICT +2 ug/mL DOX, 20 umol/L ICT +4 ug/mL DOX, 40 umol/L ICT +1 ug/mL DOX, 40 umol/L ICT +2 ug/mL DOX, 40 umol/L ICT +4 ug/mL DOX, 80 umol/L ICT +1 ug/mL DOX, 80 umol/L ICT +2 ug/mL DOX, 80 umol/L ICT +4 ug/mL DOX) were set up. Human osteosarcoma MG-63 cells were respectively cultured and their effects on morphological changes were observed using inverted phase contrast microscope after 24-and 48-h intervention. The cell proliferation inhibition rate of each group was de- termined using CCK-8, and IC50 calculated. The MG-63 apoptosis rate was detected using Annexin V-FITC/ PI double dye flow cytometry. Expression levels of bcl-2, caspase-3, and p21 were detected using RT-PCR. RESULTS: ICT and DOX could obviously inhibit the proliferation of MG-63 cell. Along with ICT concentration increasing from 10 umol/L to 160 umol/L, the cell proliferation inhibition rate also increased gradually from 9.67% +/- 3.62% to 89.18% +/- 9.66%. The IC50 was 46.93 umol/L and 3.87 ug/mL respectively. ICT and DOX could cause either early or late stage apoptosis, down-regulate Bcl-2 gene expression, and up-regulate gene expressions of Caspase-3 and p21 respectively (P < 0.05). Aforesaid changes were more obviously seen in combination groups than in lCT groups and DOX groups (P < 0.05). CONCLUSION: CT combined DOX had additive or synergistic inhibition effect for the proliferation of osteosarcoma MG-63 cells, which might be related with regulating gene expressions of bcl-2, caspase-3, and p21. PMID- 27491236 TI - [Study on the Fingerprint of Kingkong Zedoary Turmeric Oil]. AB - OBJECTIVE: To study the fingerprint of Zedoary Turmeric Oil (ZTO) as the bulk drug of Kingkong Elemene for making it safe, effective, stable, and controllable. METHODS: Fingerprints were detected by gas chromatography. beta-elemene peak was regarded as reference peak (S). The relative peak area of each common peak and the relative retention time were calculated. With a total of modes for reference, the fingerprints of 10 batches of Kingkong ZTO were detected, and their similarity was calculated by traditional Chinese medicine (TCM) fingerprint similarity calculation software. RESULTS: The determination method was stable and reliable. Totally 19 common characteristic peaks of Kingkong ZTO was found. The fingerprint similarity of these batches of Kingkong ZTO were not lower than 0.96. CONCLUSIONS: Gas chromatography for detecting the fingerprint of Kingkong ZTO was reliable and repeatable. The established fingerprint of Kingkong ZTO could guarantee the quality stability and safety of different product batches. PMID- 27491237 TI - [Staging Based Strategies and Practice for Prostate Cancer]. AB - Authors raised that staging based strategies and practice of integrative medicine (IM) by combining syndrome typing and disease identification, and choosing suitable measures in accordance with different persons and seasonal conditions after more than ten years' clinical practice and researches. Radical operation as prior (as evil eliminating) and strengthening vital qi in perioerative period are best strategy for promoting rapid rehabilitation of early stage prostate cancer patients. Strengthening body resistance to eliminate evil was used in treating advanced prostate cancer patients. For example, a comprehensive treatment program for hormone-dependent patients was combined with endocrinotherapy and Chinese herbs for synergisic efficacy-enhancing actions. In this way, these patients' quality of life (QOL) were improved and time to castration resistant prostate cancer (CRPC) was delayed, even some patients were clinically cured. There are lack of effective medicines and methods for CRPC patients. Greatly tonifying original qi is mainly used for improving their clinical symptoms and prolonging survivals. Practice has proved staging based strategies and practice of IM has favorable advantages in treating prostate cancer, especially showing prospect in prolonging survival and postponing progression of advanced prostate cancer patients. Besides, it also could provide beneficial considerations and inspiration for combination of syndrome typing and disease identification. PMID- 27491238 TI - [Acupoint Selection Laws for Massage Therapy of Infantile Anorexia: an Analysis Based on Data Mining]. AB - Massage prescriptions for treating infantile anorexia in Chinese Academic Journal Full-Text Database (CNKI, 1979-2012), Chinese Scientific and Technological Journal Full-Text Database (VIP, 1989-2012) and Wanfang Database (1990-2012) were collected. By using Chinese Medicine Inheritance Auxiliary Platform (Version 2.0) Software, 286 massage prescriptions for treatment of infantile anorexia were screened involved 76 acupoints, 20 commonly used acupoints, and 57 core acupoint combinations. Infantile Tuina specific points were used as main acupoints in massage therapy for infantile anorexia, and core acupoints covered Jizhu, Pi meridian, abdomen, Nei-Bagua, Zusanli (ST36), and Ban-men. PMID- 27491239 TI - [Communicative Translation of Chinese Patent Medical Instruction]. PMID- 27491240 TI - [Progress of Chinese Medicine and Western Medicine in Diagnosis and Treatment of Poor Ovarian Response in IVF-ET Cycle]. PMID- 27491241 TI - TALES FROM THE INSIDE. PMID- 27491242 TI - INFLAMED. PMID- 27491244 TI - 24 HOURS IN THE LIVES OF PEOPLE AFFECTED BY HIV. PMID- 27491243 TI - A CALL TO ACTION BY THE TRANSGENDER COMMUNITY. PMID- 27491246 TI - Editorial: EHealth Law: The Final Frontier? PMID- 27491245 TI - DEAR DOCTOR... WHAT ABOUT CANCER? AND OTHER QUESTIONS ANSWERED. PMID- 27491247 TI - Legal Status of Telemedicine in the Internal Market. AB - Health services enjoy freedom of movement within the European Union (EU). This freedom also applies to information society services (ISS). This article presents a legal framework within which it is possible to provide qualifying health services with the help of information and telecommunications technology (ICT) as iss. Due to the ambiguity of EU regulation, the problem regarding how to determine whether a particular medical service corresponds to favourable structural iss conditions is considered. Since telemedicine makes a wide application of electronic devices possible, a new element appears in the relationship between physicians and their patients. Therefore, using electronic devices may cause numerous doubts regarding the normative status of these devices, since they modify the physician's responsibility and affect the scope of his duty with regard to information. At the same time, the complexity of functional elements (actions) necessary to provide health services using ICT can, in some cases, prevent them from being recognised as ISS. PMID- 27491248 TI - Data Protection Compliance in the Age of Digital Health. AB - Advances in technology are transforming the way that health data is collected and used. This includes improvements in existing technology as well as innovations in mobile technology such as smartphone apps and wearables. Health data is strictly regulated under the EU Data Protection Directive 95/46/EC. Under current data protection rules, health data is broadly interpreted and will, in most circumstances not connected to the provision of healthcare, require organisations to obtain explicit consent from individuals for its collection and use. Further data protection compliance issues arise such as identifying who is a controller, ensuring transparency, using health data for research purposes and keeping health data secure. As the EU data protection landscape is due to change in the next few years and will affect the collection and use of health data, the forthcoming Data Protection Regulation also deserves attention. PMID- 27491249 TI - Electronic Health Record in Italy and Personal Data Protection. AB - The present article deals with the Italian Electronic Health Record (hereinafter EHR), recently introduced by Act 221/2012, with a specific focus on personal data protection. Privacy issues--e.g., informed consent, data processing, patients' rights and minors' will--are discussed within the framework of recent e-Health legislation, national Data Protection Code, the related Data Protection Authority pronouncements and EU law. The paper is aimed at discussing the problems arising from a complex, fragmentary and sometimes uncertain legal framework on e-Health. PMID- 27491250 TI - Exceptions and Exclusions: The Right to Informed Consent for Medical Treatment of People with Psychosocial Disabilities in Europe. AB - This article examines the relevant international law relating to informed consent to treatment for individuals with psychosocial disabilities and reflects on the protection offered in this respect by the European Convention on Human Rights (ECHR) and the Council of Europe Convention on Human Rights and Biomedicine. The article argues that while the UN Convention on the Rights of Persons with Disabilities is beginning to influence case law of the European Court of Human Rights, only 'weak' protection has been afforded to people with psychosocial disabilities by the ECHR and the Court in relation to informed consent for medical treatment. PMID- 27491251 TI - European Court of Human Rights. ECHR 2016/14 Case of Vasileva v. Bulgaria, 17 March 2016, no. 23796/10 (Fifth Section). PMID- 27491252 TI - European Court of Human Rights. ECHR 2016/15 Case of Elena Cojocaru v. Romania, 22 March 2016, no. 7417412 (Fourth Section). PMID- 27491253 TI - European Court of Human Right. ECHR 2016/16 Case of Kolesnikovich v. Russia, 22 March 2016, no. 4469413 (Third Section). PMID- 27491254 TI - European Court of Human Rights. ECHR 2016/17 Case of Blokhin v. Russia, 23 March 2016, no. 47152/06 (Grand Chamber). PMID- 27491255 TI - [Endocrine and Metabolic Emergencies; Points of Initial Management. Editorial: Endocrine and metabolic emergencies]. PMID- 27491256 TI - [Endocrine and Metabolic Emergencies; Points of Initial Management. Topics: I. Acute adrenal insufficiency (Adrenal crisis)]. PMID- 27491258 TI - [Endocrine and Metabolic Emergencies; Points of Initial Management. Topics: III. Thyroid storm]. PMID- 27491257 TI - [Endocrine and Metabolic Emergencies; Points of Initial Management. Topics II. Pheochromocytoma crisis]. PMID- 27491259 TI - [Endocrine and Metabolic Emergencies: Points of Initial Management. Topics: IV. Emergency medical care for patients with hypercalcemia or hypocalcemia]. PMID- 27491260 TI - [Endocrine and Metabolic Emergencies; Points of Initial Management. Topics: V. Hyponatremic encephalopathy]. PMID- 27491261 TI - [Endocrine and Metabolic Emergencies; Points of Initial Management. Topics: VI. Emergency treatment for eating disorders and refeeding syndrome]. PMID- 27491262 TI - [Endocrine and Metabolic Emergencies; Points of Initial Management. Topics: VII. Hypoglycemic coma]. PMID- 27491263 TI - [Endocrine and Metabolic Emergencies; Points of Initial Management. Topics: VIII. Hyperglycemic emergencies]. PMID- 27491264 TI - [Case Report; A case of type B insulin-resistance syndrome ameliorated with immune-suppression therapies]. PMID- 27491265 TI - [Case Report; A case of disseminated Mycobacterium shigaense infection]. PMID- 27491266 TI - [Case Report; A case of platypnea orthodeoxia syndrome after transcatheter Amplatzer device closure in a patient with persistent foramen ovale]. PMID- 27491267 TI - [Case Report; A case of Streptococcus suis meningitis which caused bilateral sensorineural hearing loss was improved due to the cochlear implantation]. PMID- 27491268 TI - [The Cutting-edge of Medicine; Latest evolution of family doctors' roles outside of Japan]. PMID- 27491269 TI - [The Cutting-edge of Medicine; Innate immunity and autoimmune disease]. PMID- 27491270 TI - Nanobubble Skin Supersolidity. AB - Water nanobubbles manifest fascinatingly higher mechanical strength, higher thermal stability, and longer lifetime than macroscopic bubbles; thus, they provide an important impact in applications in the biomedical and chemical industries. However, a detailed understanding of the mechanism behind these mysteries of nanobubbles remains a challenge. Consistency between quantum computations and Raman spectrometric measurements confirmed our predictions that a nanobubble skin shares the same supersolidity with molecular clusters, skins of bulk water, and water droplets because of molecular undercoordination (fewer than four nearest molecular neighbors). Molecular undercoordination (coordination number Zcluster < Zsurface < Zbubble < Zbulk = 4) shortens/extends the H-O/O:H bond and stiffens/softens its corresponding stretching phonons, whose frequency shift is proportional to the square root of the cohesive energy and inversely proportional to the segmental length. The strongly polarized O:H-O bond slows the molecular dynamics and increases the viscosity. The freezing temperature is lowered by the softened O:H bond, and the melting temperature is enhanced by the stiffened H-O bond. Therefore, the supersolid skin makes the nanobubbles thermally more stable, less dense, and stiffer and slows the dynamics of their molecular motion. PMID- 27491271 TI - Effect of hospital caseload on long-term outcome after standardization of rectal cancer surgery in the Spanish Rectal Cancer Project. AB - INTRODUCCIoN: The purpose of this prospective multicentre multilevel study was to investigate the influence of hospital caseload on long-term outcomes following standardization of rectal cancer surgery in the Rectal Cancer Project of the Spanish Society of Surgeons. METHODS: Data relating to 2910 consecutive patients with rectal cancer treated for cure between March 2006 and March 2010 were recorded in a prospective database. Hospitals were classified according to number of patients treated per year as low-volume, intermediate-volume, or high volume hospitals (12-23, 24-35, or >=36 procedures per year). RESULTS: After a median follow-up of 5 years, cumulative rates of local recurrence, metastatic recurrence and overall survival were 6.6 (CI95% 5.6-7.6), 20.3 (CI95% 18.8-21.9) and 73.0 (CI95% 74.7 - 71.3) respectively. In the multilevel regression analysis overall survival was higher for patients treated at hospitals with an annual caseload of 36 or more patients (HR 0,727 [CI95% 0,556-0,951]; P=.02). The risk of local recurrence and metastases were not related to the caseload. Moreover, there was a statistically significant variation in overall survival (median hazard ratio [MHR] 1.184 [CI95% 1.071-1,333]), local recurrence (MHR 1.308 [CI95% 1.010 1.668]) and metastases (MHR 1.300 [CI95% 1.181; 1.476]) between all hospitals. CONCLUSIONS: Overall survival was higher for patients treated at hospitals with an annual caseload of 36 or more patients. However, local recurrence was not influenced by caseload. PMID- 27491272 TI - Carbon nanotube membranes to predict skin permeability of compounds. AB - In the present study, carbon nanotube (CNT) membranes were prepared to predict skin penetration properties of compounds. A series of penetration experiments using Franz diffusion cells were performed with 16 different membrane compositions for model chemicals. Similar experiments were also carried out with same model molecules using five different commercially available synthetic membranes and human skins for the comparison. Model chemicals were selected as diclofenac, dexketoprofen and salicylic acid. Their permeability coefficients and flux values were calculated. Correlations between permeability values of model compounds for human skins and developed model membranes were investigated. Good correlations were obtained for CNT membrane, isopropyl myristate-treated CNT membrane (IM-CNT membrane) and bovine serum albumin-cholesterol, dipalmitoyl phosphatidyl choline-treated membrane (BSA-Cholesterol-DPPC-IM-CNT membrane). An artificial neural network (ANN) model was developed using some molecular properties and penetration coefficients from pristine CNT membranes to predict skin permeability values and quite good predictions were made. PMID- 27491273 TI - Quirks of dye nomenclature. 6. Malachite green. AB - Malachite green was discovered independently by two researchers in Germany in the 19(th) century and found immediate employment as a dye and a pigment. Subsequently, other uses, such as staining biological specimens, emerged. A much later application was the control of fungal and protozoan infections in fish, for which the dye remains popular, although illegal in many countries owing to a variety of toxicity problems. In solution, malachite green can exist as five different species depending on the pH. The location of the positive charge of the colored cation on a carbon atom or a nitrogen atom is still debated. The original names of this dye, and their origins, are briefly surveyed. PMID- 27491274 TI - The OH-Initiated Oxidation of CS2 in the Presence of NO: FTIR Matrix-Isolation and Theoretical Studies. AB - We studied the photochemistry of the carbon disulfide-nitrous acid system with the help of Fourier transform infrared (FTIR) matrix isolation spectroscopy and theoretical methods. The irradiation of the CS2...HONO complexes, isolated in solid argon, with the filtered output of the mercury lamp (lambda > 345 nm) was found to produce OCS, SO2, and HNCS; HSCN was also tentatively identified. The (13)C, (15)N, and (2)H isotopic shifts as well as literature data were used for product identifications. The evolution of the measured FTIR spectra with irradiation time and the changes in the spectra after matrix annealing indicated that the identified molecules are the products of different reaction channels: OCS being a product of another reaction path than SO2 and HNCS or HSCN. The possible reaction channels between SC(OH)S/SCS(OH) radicals and NO were studied using DFT/B3LYP/aug-cc-pVTZ method. The SC(OH)S and/or SCS(OH) intermediates are formed when HONO attached to CS2 photodissociates into OH and NO. The calculations indicated that SC(OH)S radical can form with NO two stable adducts. The more stable SC(OH)S...NO structure is a reactant for a simple one-step process leading to OCS and HONS molecules. An alternative, less-stable complex formed between SC(OH)S and NO leads to formation of OCS and HSNO. The calculations predict only one stable complex between SCS(OH) radical and NO, which can dissociate along two channels leading to HNCS and SO2 or HSCN and SO2 as the end products. The identified photoproducts indicate that both SC(OH)S and SCS(OH) adducts are intermediates in the CS2 + OH + NO reaction leading to different reaction products. PMID- 27491275 TI - Type XIX collagen: A new partner in the interactions between tumor cells and their microenvironment. AB - Type XIX collagen is a minor collagen that is associated with the basement membrane zone that belongs to the FACIT family (Fibril-Associated Collagens with Interrupted Triple helices). The FACIT family is composed of type IX, XII, XIV, XVI, XX, XXI, XXII and XIX collagens, which share many highly conserved structural motifs: a short NC1 domain, a thrombospondin-like N-terminal domain (TSPN), and numerous cysteine residues. The main role of FACITs is to ensure the integrity and stability of the extracellular matrix and its fibrillar collagen network by regulating the formation and size of the collagen fibrils. Type XIX collagen was discovered in a human rhabdomyosarcoma cell line. The collagen alpha1(XIX) chain is composed of 5 triple-helical domains (COL) interrupted by 6 non-triple-helical (NC) domains with a short, C-terminal, 19 amino acid non collagenous domain (NC1). This collagen is involved in the differentiation of muscle cells, central nervous system development, and formation of the esophagus. Type XIX collagen is associated with the basement membrane zone, like type XVIII and XV collagens. Its short NC1(XIX) C-terminal domain inhibits the migration and invasion of melanoma cells. It also exerts a strong anti-angiogenic effect by inhibiting MMP-14 and VEGF expression. NC1(XIX) binding to alphavbeta3 integrin decreases the phosphorylation of proteins involved in the FAK (Focal Adhesion Kinase)/PI3K (PhosphoInositide 3-Kinase)/Akt (protein kinase B)/mTOR (Mammalian Target Of Rapamycin) pathway. On the other hand, NC1(XIX) induces an increase in GSK3beta activity by decreasing its level of phosphorylation. The inhibition of this pathway could explain the anti-tumor properties of the NC1(XIX) domain. PMID- 27491276 TI - Simplified and standardized intrapartum management can yield high rates of successful VBAC in spontaneous labor. AB - OBJECTIVE: To examine the outcomes of vaginal birth after cesarean (VBAC) in women, in spontaneous labor, delivering after 37 weeks' gestation at an institution where trial of labor after a previous cesarean delivery (TOLAC) is encouraged and management of labor is standardized. METHODS: This retrospective cohort study included 3071 women with one previous cesarean only and no vaginal delivery who underwent a trial of labor from 2001 to 2011. Women were managed using the standardized "active management of labor" intrapartum protocol. Outcomes and characteristics of women who delivered vaginally were compared with those who required cesarean delivery. RESULTS: In spontaneous labor in their second pregnancy, those who attempted TOLAC had a 72.5% (1611/2222) rate of successful VBAC. Women who had a successful VBAC had smaller babies (3584 +/- 452 g versus 3799 +/- 489 g; p < 0.0001) at earlier gestations than those who had a repeat intrapartum cesarean delivery. They also required less intrapartum intervention, such as oxytocin augmentation (14.5% [234/1611] versus 41% [251/611]; p < 0.0001) and epidural anesthesia (64.8% [1044/1611] versus 82.8% [506/611]; p < 0.0001). The rate of uterine rupture was 0.54% (12/2222), while the rate of peri-partum hysterectomy was 0.18% (4/2222). CONCLUSION: This study shows that serious complications associated with TOLAC are rare providing intrapartum care and decision-making is made simple for the benefit of staff and patients alike. This is achieved through a standardized labor management protocol. PMID- 27491277 TI - Neuropsychological functioning in heart transplant candidates. AB - OBJECTIVE: This study provides age stratified neuropsychological test data for a large sample of heart transplant candidates. Patients with and without neurological co-morbidities were compared to better isolate the effects of congestive heart failure (CHF) on brain functioning. METHOD: Between 1988 and 2011, 956 patients (717 males, 239 females) with end-stage CHF and other life threatening cardiac diseases underwent neuropsychological assessment as a requirement of the heart transplant workup. Intellectual, memory, executive, language, attentional and psychomotor abilities were assessed, and standard cardiac measures were concurrently collected. Independent t-tests were used to compare subgroups with and without neurological co-morbidities on cardiac, neuropsychological and MMPI-2 measures. Chi-square tests were used for categorical items to compare demographic data between the two groups. RESULTS: Significant cognitive impairments across all domains assessed were typical in all age groups. Neurological co-morbidities, such as CVA and cardiac arrest were common, with 28% of the sample having one or more condition. That subgroup scored lower on measures of processing speed, memory, and executive measures, but the pattern of deficits was similar for both groups and not explainable by depression. Depression prevalence per MMPI-2 findings was comparable to that of the general population. CONCLUSIONS: End stage heart disease/heart failure is associated with global, mild to moderate cognitive impairment, regardless of age or neurological co-morbidities. Contributing factors likely include cerebrovascular hypoperfusion, multiorgan failure, systemic co-morbidities, and lifestyle issues. PMID- 27491278 TI - Hospitalizations and Other Health Care Resource Utilization Among Patients with Deep Vein Thrombosis Treated with Rivaroxaban Versus Low-molecular-weight Heparin and Warfarin in the Outpatient Setting. AB - PURPOSE: Compared with low-molecular-weight heparin (LMWH) and warfarin, the oral anticoagulant rivaroxaban has advantages, such as simplified care, that may lead to less health care resource utilization. METHODS: A retrospective, matched cohort analysis was conducted using claims dated between January 2011 and December 2013 from the Truven Health Analytics MarketScan databases. Adult patients who had a primary diagnosis of deep vein thrombosis (DVT) during an outpatient or emergency room (ER) visit after November 2, 2012, and who were treated with rivaroxaban or LMWH/warfarin on the same day, were identified. Patients were observed over 1, 2, 3, and 4 weeks after the DVT diagnosis. The mean numbers of hospitalizations for all causes and for venous thromboembolism (VTE) (which included those for DVT or pulmonary embolism), as well as other health care resource utilization (ER, outpatient, and other visits), and the associated health care costs and pharmacy costs, were evaluated and compared between cohorts using the Lin method. FINDINGS: All of the 512 rivaroxaban treated patients were well matched with the LMWH/warfarin-treated patients. The mean numbers of all-cause hospitalizations were significantly lower in the rivaroxaban users compared with those in the LMWH/warfarin users over 1 week (0.012 vs 0.032; P = 0.044) and 2 weeks (0.022 vs 0.048; P = 0.040). The corresponding mean numbers of VTE-related hospitalizations were significantly lower with rivaroxaban over 1 week (0.008 vs 0.028; P = 0.020), 2 weeks (0.016 vs 0.042; P = 0.020), and 4 weeks (0.034 vs 0.068; P = 0.036). The mean numbers of all-cause and VTE-related outpatient visits were also significantly lower in rivaroxaban users compared with those in LMWH/warfarin users over 1, 2, 3, and 4 weeks (all, P < 0.001). In terms of all-cause and VTE-related ER and other visits, no statistically significant differences were found between cohorts over the first 4 weeks. The associated mean all-cause total health care costs were significantly lower in the rivaroxaban users compared with those in the LMWH/warfarin users over 1 week (US $2332 vs $3428; P < 0.001) and 2 weeks ($3108 vs $4524; P < 0.001); moreover, significantly lower mean costs related to all cause hospitalizations (weeks 1 and 2) and pharmacy (weeks 1-4) were observed in patients treated with rivaroxaban, while no differences were found in costs related to ER visits (weeks 1-4), outpatient visits (weeks 1-4), or other visits (with the exception of week 1). IMPLICATIONS: Patients with DVT treated with rivaroxaban after an outpatient/ER visit had significantly lower mean numbers of hospitalizations and outpatient visits, as well as lower mean total, hospitalization, and pharmacy costs during the first 2 weeks of treatment compared with those in matched LMWH/warfarin users. PMID- 27491279 TI - Demographic and Clinical Characteristics of Patients With Type 2 Diabetes Mellitus Initiating Dipeptidyl Peptidase 4 Inhibitors: A Retrospective Study of UK General Practice. AB - PURPOSE: The majority of people with type 2 diabetes mellitus (T2DM) will develop chronic kidney disease in their lifetime. Because most dipeptidyl peptidase (DPP) 4 inhibitors require dose adjustment in patients with T2DM and renal impairment, we aimed to understand how these treatments are prescribed in UK clinical practice, and to determine whether recommended dose adjustments are being made at initial prescription. METHODS: This retrospective, descriptive cohort study analyzed data from the Clinical Practice Research Datalink (CPRD). Patients of interest were those with T2DM and renal impairment initiated on a DPP-4 inhibitor between 2014 and 2015. Patients under 40 years of age and with type 1 diabetes were excluded. Descriptive statistics were calculated for baseline demographic and clinical characteristics, and the study protocol was approved by the Independent Scientific Advisory Committee for Medicines and Healthcare products Regulatory Agency database research. FINDINGS: A total of 3425 patients diagnosed with T2DM and renal impairment and initiated on a DPP-4 inhibitor were identified. The percentages of patients prescribed the high dose of saxagliptin, alogliptin,sitagliptin, and vildagliptin were 48%, 43%, 41%, and 27%, respectively, which is not recommended given their renal dysfunction. These are conservative estimates, as they do not include patients with severe renal impairment on sitagliptin and alogliptin, whose doses should be further reduced. No patients were prescribed an inappropriately high dose of linagliptin, as there is no requirement for dose adjustment in patients with renal impairment. IMPLICATIONS: In this study, a considerable number of patients with T2DM and renal impairment were prescribed an inappropriately high dose of saxagliptin, alogliptin, sitagliptin, or vildagliptin for their level of renal impairment at treatment initiation. This prescribing could have been due to the complexity of different dosing requirements, or a lack of awareness of the need for dose adjustment of most DPP-4 inhibitors in patients with renal impairment. Linagliptin may be used in patients with moderate or severe renal impairment without dose adjustment. PMID- 27491280 TI - Lack of a Pharmacokinetic Interaction Between Saxagliptin and Dapagliflozin in Healthy Subjects: A Randomized Crossover Study. AB - PURPOSE: This single-dose, open-label, randomized, 3-period, 3-treatment crossover drug-drug interaction study was conducted to evaluate differences in the pharmacokinetic properties of saxagliptin and dapagliflozin when coadministered. METHODS: Healthy subjects (N = 42) were randomized to receive saxagliptin 5 mg alone, dapagliflozin 10 mg alone, or saxagliptin 5 mg plus dapagliflozin 10 mg coadministered; there was a washout period of >=6 days between treatments. Serial blood samples for determining saxagliptin, 5-hydroxy saxagliptin (5-OH saxagliptin; major active metabolite) and dapagliflozin plasma concentrations and pharmacokinetic parameters were collected before and up to 60 hours after the dose. No interaction was to be concluded if the 90% CIs for the geometric mean ratios of the combination compared with each drug given alone for Cmax and AUCinf were within 0.80 to 1.25. FINDINGS: The results indicated that dapagliflozin had no effect on the pharmacokinetic properties of saxagliptin, 5 OH saxagliptin, or saxagliptin total active moiety and vice versa. The 90% CIs for Cmax and AUCinf for all comparisons were contained entirely within the 0.80 to 1.25 equivalence intervals. Other pharmacokinetic parameters (apparent oral clearance or half-life) of saxagliptin or dapagliflozin were similar when each medicine was administered alone or when coadministered. No safety profile or tolerability findings of concern were observed during the study. All adverse events were mild, and no serious adverse events were reported. IMPLICATIONS: These data indicate that coadministration of saxagliptin and dapagliflozin exhibits no pharmacokinetic interaction and is well tolerated. ClinicalTrials.gov identifier: NCT01662999. PMID- 27491281 TI - Superbugs, Colistin, and Related Issues. PMID- 27491282 TI - Prescribing Patterns of Oral Antineoplastic Therapies Observed in the Treatment of Patients With Advanced Prostate Cancer Between 2012 and 2014: Results of an Oncology EMR Analysis. AB - PURPOSE: The purpose of this study was to examine, using a US electronic medical records (EMR) database, the clinical characteristics and real-world treatment sequences in men with advanced prostate cancer who initiated treatment with abiraterone acetate or enzalutamide. METHODS: This retrospective, observational study evaluated adult male patients with a diagnosis of prostate cancer (International Classification of Diseases, Ninth Revision, Clinical Modification code 185) in the EMR database between July 1, 2011, and March 31, 2014, who had initiated first-line treatment with abiraterone acetate or enzalutamide between September 1, 2012, and March 31, 2014. The first record for a patient initiating abiraterone acetate or enzalutamide was the index date. Patients had 6 months of pre-index medical record history and a variable length follow-up period, extending from the index date to the end of medical record data availability or date of the end of the study (March 31, 2014). The sequence of first- and second line therapies for advanced prostate cancer therapy was reported. FINDINGS: A total of 809 patients met study inclusion and exclusion criteria. This study found that the majority of patients who initiated treatment with either abiraterone acetate or enzalutamide between September 1, 2012, and March 31, 2014, received a single line of therapy (72%); abiraterone acetate was the most common first-line treatment (74% of first-line patients). A subset of patients treated first-line with either abiraterone acetate or enzalutamide were transitioned to an oral second-line agent (17% of first-line abiraterone acetate treated patients transitioned to second-line enzalutamide, and 16% of first-line enzalutamide-treated patients transitioned to second-line abiraterone acetate). Chemotherapy with docetaxel was also a commonly observed second-line treatment selection, occurring in 8% of first-line abiraterone acetate-treated patients and in 7% of first-line enzalutamide-treated patients. IMPLICATIONS: This EMR study is among the first to present evidence of US physician practice prescribing patterns regarding initiation of oral antineoplastic agents and use of subsequent therapies in patients with advanced prostate cancer. PMID- 27491283 TI - Integrative Review: Delivery of Healthcare Services to Adolescents and Young Adults During and After Foster Care. AB - The purpose of this integrative review is to summarize evidence describing delivery of healthcare services to adolescents while in foster care and to young adults after they exit foster care. The long-term, deleterious effect of abuse and/or neglect by caregivers among youth who have been placed in foster care is grounded in empirical evidence demonstrating the relationship between long-term health needs and exposure to trauma in childhood. Evidence is needed to provide culturally-specific care and also to identify knowledge gaps in the care of adolescents and young adults who have been in the foster care system. Peer reviewed research studies published between 2004 and 2014 that include samples of youth 12 to 30 years of age are included in the review. Eighteen studies met inclusion criteria for the review. Physical and behavioral healthcare needs among youth with foster care experience are significant. The ability to adequately meet health needs are inextricable from the ability to negotiate resources and to successfully interact with adults. Challenges that youth with foster care histories experience when transitioning into young adulthood are comparable to other populations of vulnerable youth not in foster care. Nurses must use each healthcare encounter to assess how the social determinants of health facilitate or impede optimal health among youth with foster care experience. The development of integrated intervention strategies to inform best practice models is a priority for current and former foster care youth as they transition into young adulthood. PMID- 27491284 TI - Squamous cell carcinoma in chronic osteomyelitis: a case report and review of the literature. AB - BACKGROUND: Chronic osteomyelitis is a challenging problem, and malignant transformation is a rare occurrence. We report a case of a patient with squamous cell carcinoma arising from an osteomyelitic hotbed and discuss through a literature review the etiopathogenesis, diagnosis, and treatment of this lesion. CASE PRESENTATION: A 69-year-old Italian man had sustained an exposed tibial fracture 40 years ago during a road accident, for which he had undergone various surgical osteosynthesis treatments with multiple antibiotic therapies. He presented to our hospital because of recurrence of a fistula at the proximal third of the anterior region of the tibia. For 2 months, we treated the lesion with antibiotics, and local medication with curettage. We saw no evidence of lesion improvement, and we advised the patient to undergo a knee amputation, which he refused. The alternative we chose was a surgical toilet of the osteomyelitic hotbed and used bioglass as a bone substitute. After 2 months of follow-up, we noticed a fulminating, budding formation in the area of the surgical wound that turned out to be a squamous cell carcinoma on biopsy. The patient again refused the amputation and underwent a wide-margin surgical debridement. After 2 months, the carcinoma recurred, and an above-the-knee amputation was performed. CONCLUSIONS: Our experience with this case indicates that amputation is the most appropriate treatment for squamous carcinoma occurring in patients with chronic osteomyelitis. To avoid risks of lymphonodular and organ metastasization, this radical surgical procedure should not be delayed. Early diagnosis and timely therapy can prevent amputation only in selected cases. Surgeons who treat osteomyelitis and chronic wounds should be aware of the risk of tumor degeneration. Squamous cell carcinoma associated with chronic osteomyelitis has a low-grade malignancy, but implications of lymphonodular involvement and organ metastasis should not be excluded. PMID- 27491286 TI - Influence of bisphosphonate therapy on bone geometry, volumetric bone density and bone strength of femoral shaft in postmenopausal women with rheumatoid arthritis. AB - BACKGROUND: There is evidence that postmenopausal women with rheumatoid arthritis (RA) on glucocorticoid (GC) therapy and bisphosphonate (BP) have an increased risk for atypical subtrochanteric and atypical diaphyseal femoral fracture (AFF). The underlying mechanism has not been elucidated so far. Using peripheral quantitative computed tomography (pQCT), the aim of the present study was to compare bone geometry, volumetric bone mineral density (vBMD) and bone strength of femoral shaft in BP-treated and BP-naive postmenopausal women with RA. METHODS: Prospective cross-sectional pQCT scans were taken at 33 % of total femur of BP-treated and BP-naive RA patients. Bone parameters of the two groups were compared and correlated to disease characteristics and muscle cross-sectional area (CSA). RESULTS: A total of 60 consecutive postmenopausal RA patients, 20 with BP therapy and 40 BP-naive, were included in the study. The median age of the subjects was 63.5 years (range 48-85 years), and median disease duration (RA) was 12.0 years (range 2-47 years). Height and weight of the patients of the two groups were comparable. Women in the BP group were on average 4.3 years older (p = 0.044), and duration since menopause was on average 5.76 years longer (p = 0.045). In the BP group, there was a 13.31 % reduced muscle cross-sectional area around the proximal thigh (p = 0.013); cortical CSA was smaller by 5.3 % (p = 0.043); however, total and medullary CSA, as well as cortical vBMD and the polar bone stress-strain index of the femoral shaft were similar in the two groups. In regression analysis, age, time since menopause and muscular CSA were significant factors determining cortical CSA, cortical thickness and femoral index (p < 0.05). Regression model showed no significant effect of BP therapy on bone geometry and density of the femoral diaphysis at 33 %. CONCLUSION: Differences in cortical CSA between BP-treated and BP-naive postmenopausal RA patients were found to be associated only with differences in age, time since menopause and muscle cross-sectional area around the proximal thigh. In interpreting our results, it should be kept in mind that BP was given only to patients with increased fracture risk. This fact might have a confounding effect on our findings of differences between the two groups. PMID- 27491287 TI - Cost-effectiveness of granulocyte colony-stimulating factor prophylaxis in chemotherapy-induced febrile neutropenia among breast cancer and Non-Hodgkin's lymphoma patients under Taiwan's national health insurance system. AB - RATIONALE, AIM AND OBJECTIVE: The beneficial effects of granulocyte colony stimulating factor (G-CSF) prophylaxis on reducing the risk of chemotherapy induced febrile neutropenia (CIFN) were well documented throughout the literature. However, existing data regarding its cost-effectiveness were conflicting. We estimated the cost-effectiveness of G-CSF prophylaxis in CIFN under Taiwan's National Health Insurance (NHI) system. METHODS: Data on clinical outcomes and direct medical costs were derived for 5179 newly diagnosed breast cancer and 629 non-Hodgkin's lymphoma (NHL) patients from the NHI claims database. Patients were further categorized into three subgroups as "primary-", "secondary-" and "no -" prophylaxis based on their patterns of G-CSF use. Generalized estimating equations were applied to estimate the impact of G-CSF use on the incidence of CIFN. The incremental cost-effectiveness ratios of primary and secondary prophylactic G-CSF use were calculated and sensitivity analyses were performed. RESULTS: Primary prophylaxis of G-CSF decreased the incidence of CIFN by 27% and 83%, while secondary prophylaxis by 34% and 22% in breast cancer and NHL patients, respectively. Compared with those with no prophylaxis, the incremental cost per CIFN reduced in primary prophylaxis is $931 and $52 among patients with breast cancer and NHL, respectively. In contrast, secondary prophylaxis is dominated by no prophylaxis and primary prophylaxis in both cancer patients. CONCLUSION: Primary but not secondary prophylactic use of G-CSF was cost-effective in CIFN in breast cancer and NHL patients under Taiwan's NHI system. PMID- 27491285 TI - S6Ks isoforms contribute to viability, migration, docetaxel resistance and tumor formation of prostate cancer cells. AB - BACKGROUND: The S6 Kinase (S6K) proteins are some of the main downstream effectors of the mammalian Target Of Rapamycin (mTOR) and act as key regulators of protein synthesis and cell growth. S6K is overexpressed in a variety of human tumors and is correlated to poor prognosis in prostate cancer. Due to the current urgency to identify factors involved in prostate cancer progression, we aimed to reveal the cellular functions of three S6K isoforms-p70-S6K1, p85-S6K1 and p54 S6K2-in prostate cancer, as well as their potential as therapeutic targets. METHODS: In this study we performed S6K knockdown and overexpression and investigated its role in prostate cancer cell proliferation, colony formation, viability, migration and resistance to docetaxel treatment. In addition, we measured tumor growth in Nude mice injected with PC3 cells overexpressing S6K isoforms and tested the efficacy of a new available S6K1 inhibitor in vitro. RESULTS: S6Ks overexpression enhanced PC3-luc cell line viability, migration, resistance to docetaxel and tumor formation in Nude mice. Only S6K2 knockdown rendered prostate cancer cells more sensitive to docetaxel. S6K1 inhibitor PF 4708671 was particularly effective for reducing migration and proliferation of PC3 cell line. CONCLUSIONS: These findings demonstrate that S6Ks play an important role in prostate cancer progression, enhancing cell viability, migration and chemotherapy resistance, and place both S6K1 and S6K2 as a potential targets in advanced prostate cancer. We also provide evidence that S6K1 inhibitor PF-4708671 may be considered as a potential drug for prostate cancer treatment. PMID- 27491288 TI - MAHILA: a protocol for evaluating a nurse-delivered mHealth intervention for women with HIV and psychosocial risk factors in India. AB - BACKGROUND: Women living with HIV are vulnerable to a variety of psychosocial barriers that limit access and adherence to treatment. There is little evidence supporting interventions for improving access and treatment adherence among vulnerable groups of women in low- and middle-income countries. The M obile Phone Based A pproach for H ealth I mprovement, L iteracy and A dherence (MAHILA) trial is assessing the feasibility, acceptability and preliminary efficacy of a novel, theory-guided mobile health intervention delivered by nurses for enhancing self care and treatment adherence among HIV-infected women in India. METHODS/DESIGN: Women (n = 120) with HIV infection who screen positive for depressive symptoms and/or other psychosocial vulnerabilities are randomly assigned in equal numbers to one of two treatment arms: treatment as usual plus the mobile phone intervention (experimental group) or treatment as usual (control group). In addition to treatment as usual, the experimental group receives nurse-delivered self-care counselling via mobile phone at fixed intervals over 16 weeks. Outcome measures are collected at baseline and at 4, 12, 24 and 36 weeks post-baseline. Outcomes include antiretroviral treatment adherence, HIV-1 RNA, depressive symptoms, illness perceptions, internalized stigma and quality of life. DISCUSSION: The MAHILA trial will provide information about how a mobile health counselling intervention delivered by non specialist nurses may improve access to care and support the adherence and clinical outcomes of women with HIV infection living in low- and middle-income countries such as India. TRIAL REGISTRATION: NCT02319330 (First received: July 30, 2014; Last verified: January 2016). PMID- 27491289 TI - Phylogeny of tick-derived Crimean-Congo hemorrhagic fever virus strains in Iran. AB - The presence of Crimean-Congo hemorrhagic fever virus (CCHFV) in Iran was assessed by collecting ticks from Golpayegan, Isfahan Province. Real time RT-PCR was used to detect the CCHFV RNA in the tick population and the origins of the viral sequences were determined. The CCHFV RNA was detected in 5.2% of 492 ticks collected from livestock in different regions of Golpayegan. The tick species that tested positive for the presence of CCHFV RNA included Hyalomma, Rhipicephalus and Haemaphysalis species. Phylogenetic analysis using the partial S-segment indicated that eight sequences clustered in clade IV (Asia-1) and three other sequences aligned within clade VI (Europe) with other CCHFV strains from Kosovo (Kosova1917) and Russia (Kashmanov). PMID- 27491290 TI - Erratum to "A review of reverse vaccinology approaches for the development of vaccines against ticks and tick borne diseases" [Ticks Tick-borne Dis. 7 (4) (2016) 573-585]. PMID- 27491291 TI - Primary pure spindle cell carcinoma (sarcomatoid carcinoma) of the ovary: A case report with immunohistochemical study. AB - BACKGROUND: In the ovary, sarcomatoid carcinoma has been reported only as mural nodules in epithelial malignant or borderline serous or mucinous cystic neoplasms, and in teratomas. In this paper we report a rare case of a solid sarcomatoid carcinoma of the ovary, without accompanying component of giant cells, pleomorphic cells, or glandular and other epithelial structures. CASE PRESENTATION: This case report refers to a sarcomatoid carcinoma of the ovary in in a 57 year-old woman with abdominal pain. Macroscopically, the neoplasm was a 15x10x5 cm ovarian mass that featured gray white solid fleshy areas, interspersed with areas of necrosis, hemorrhage and cystic spaces filled with thick fluid. The epithelial differentiation of the tumor was demonstrated by strong and diffuse reactivity to CAM5.2 and focal immunoreactivity to EMA. A diagnosis of malignant mesenchymal tumor was excluded due to negativity for desmin, smooth muscle actin, caldesmon, CD34, CD10, and myoglobin. Neural, neuroendocrine neoplasm, melanoma and Perivascular Epithelioid Cell Tumor (PEComa) were excluded because of negativity for S100, chromogranin, synaptophysin and HMB45. CONCLUSION: Primary ovarian spindle cell carcinoma is a rare neoplasm, which must be considered in the differential diagnosis of solid ovarian mass with spindle cell appearance. This case adds to our knowledge of the biological behavior of these rare neoplasms. The distinction from true sarcomas and carcinosarcomas is important because of the more favorable prognosis of the spindle cell carcinomas. However their diagnosis necessitates a careful tissue sampling and immunohistochemical staining. PMID- 27491292 TI - Short sleep duration is associated with increased risk of pre-hypertension and hypertension in Chinese early middle-aged females. AB - PURPOSE: The aim of this study is to investigate the relationship between sleep duration and hypertension in a middle-aged Chinese population. METHODS: Cross sectional data of 20,505 individuals aged 35-64 years from Taizhou longitudinal study was used. Logistic regression models were used to calculate odds ratios (ORs) for the risk of pre-hypertension and hypertension in association with sleep duration. RESULTS: Short sleep duration was associated with high systolic and diastolic blood pressure in comparison with sleep duration of 7-8 h in females. Short sleep duration was also associated with an increased risk of hypertension in females. Age-stratified analysis showed that as compared with sleep duration of 7-8 h, sleep duration <6 h increased risk of hypertension after controlling for multiple covariates with an OR of 1.766 (1.024-2.775) in early middle-aged females of 35-44 years. More importantly, sleeping less than 6 h is associated with increased risk of pre-hypertension in females of this age category, after controlling for multiple covariates with an OR of 1.769 (1.058-2.958). CONCLUSIONS: Sleeping less than 6 h a day is associated with increased risk of pre-hypertension and hypertension in Chinese early middle-aged females. The high risk populations require sufficient sleep, which could probably prevent the increased risk of pre-hypertension as well as hypertension. PMID- 27491293 TI - A Pilot Study on Telephone Cognitive Behavioral Therapy for Patients Six-Months Post-Bariatric Surgery. AB - OBJECTIVE: This study aimed to determine the feasibility and preliminary efficacy of a post-operative telephone-based cognitive behavioral therapy intervention (Tele-CBT) in improving eating pathology and psychosocial functioning. METHODS: Six-month post-operative bariatric surgery patients (n = 19) received six sessions of Tele-CBT. Study outcome variables included binge eating (BES), emotional eating (EES), depressive symptoms (PHQ-9), and anxiety symptoms (GAD 7). RESULTS: Retention was 73.7 % post-intervention. Tele-CBT resulted in significant reductions in mean difference scores on BES, EES-Total, EES-Anxiety, EES-Anger, PHQ9, and GAD7. Tele-CBT patients experienced a mean weight loss of 8.62 +/- 15.02 kg between 6-months post-surgery (pre-Tele-CBT) and 12-months post surgery. CONCLUSIONS: These preliminary results suggest that post-surgery Tele CBT is feasible and can improve post-surgery symptoms of psychopathology in this uncontrolled study, supporting the need for a randomized controlled trial. PMID- 27491294 TI - Micronutrient Status in Morbidly Obese Patients Prior to Laparoscopic Sleeve Gastrectomy and Micronutrient Changes 5 years Post-surgery. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has become more popular in recent years. The aim of this study was to determine the vitamin and mineral status in patients up to 5 years after LSG and to explore changes that occurred from pre-operatively to 1, 2 and 5 years after surgery. METHODS: Data reviewed included age, sex, weight and body mass index (BMI), micronutrient supplements consumed and blood levels of 25 hydroxyvitamin D (25 (OH) D), PTH (parathyroid hormone), ferritin, haemoglobin, folate and vitamin B12, prior to and post-LSG. Data was collated from medical records of morbidly obese patients who had undergone LSG surgery. RESULTS: There were a maximum of 336 patients with pre operative and 1 year after surgery values, n = 272 for 2 years and n = 116 for 5 years after surgery. At 5 years, only 54 % (58/107) of patients reported taking daily multivitamin supplements. Whilst most patients had values within the reference range for haemoglobin, vitamin B12, folate and vitamin D 5 years after LSG, 36 % (34/94) of the patients had serum ferritin below reference value. CONCLUSION: This study has highlighted a low micronutrient supplementation adherence. Ferritin levels decreased over time even with multivitamin supplementation. To improve micronutrient guidelines prior to and after LSG, more research, including controlled supplementation studies, are necessary. PMID- 27491295 TI - Reactive oxygen species in organ-specific autoimmunity. AB - Reactive oxygen species (ROS) have been extensively studied in the induction of inflammation and tissue damage, especially as it relates to aging. In more recent years, ROS have been implicated in the pathogenesis of autoimmune diseases. Here, ROS accumulation leads to apoptosis and autoantigen structural changes that result in novel specificities. ROS have been implicated not only in the initiation of the autoimmune response but also in its amplification and spreading to novel epitopes, through the unmasking of cryptic determinants. This review will examine the contribution of ROS to the pathogenesis of four organ specific autoimmune diseases (Hashimoto thyroiditis, inflammatory bowel disease, multiple sclerosis, and vitiligo), and compare it to that of a better characterized systemic autoimmune disease (rheumatoid arthritis). It will also discuss tobacco smoking as an environmental factor endowed with both pro-oxidant and anti-oxidant properties, thus capable of differentially modulating the autoimmune response. PMID- 27491298 TI - N-linked glycosite profiling and use of Skyline as a platform for characterization and relative quantification of glycans in differentiating xylem of Populus trichocarpa. AB - Our greater understanding of the importance of N-linked glycosylation in biological systems has spawned the field of glycomics and development of analytical tools to address the many challenges regarding our ability to characterize and quantify this complex and important modification as it relates to biological function. One of the unmet needs of the field remains a systematic method for characterization of glycans in new biological systems. This study presents a novel workflow for identification of glycans using Individuality Normalization when Labeling with Isotopic Glycan Hydrazide Tags (INLIGHTTM) strategy developed in our lab. This consists of monoisotopic mass extraction followed by peak pair identification of tagged glycans from a theoretical library using an in-house program. Identification and relative quantification could then be performed using the freely available bioinformatics tool Skyline. These studies were performed in the biological context of studying the N-linked glycome of differentiating xylem of the poplar tree, a widely studied model woody plant, particularly with respect to understanding lignin biosynthesis during wood formation. Through our workflow, we were able to identify 502 glycosylated proteins including 12 monolignol enzymes and 1 peroxidase (PO) through deamidation glycosite analysis. Finally, our novel semi-automated workflow allowed for rapid identification of 27 glycans by intact mass and by NAT/SIL peak pairing from a library containing 1573 potential glycans, eliminating the need for extensive manual analysis. Implementing Skyline for relative glycan quantification allowed for improved accuracy and precision of quantitative measurements over current processing tools which we attribute to superior algorithms correction for baseline variation and MS1 peak filtering. Graphical abstract Workflow for FANGS-INLIGHT glycosite profiling of plant xylem and monolignol proteins followed by INLIGHT tagging with semi-automated identification of glycans by light-heavy peak pairs. Finally, manual validation and relative quantification was performed in Skyline. PMID- 27491297 TI - Environmental factors in autoimmune diseases and their role in multiple sclerosis. AB - An increase in autoimmune diseases poses a socioeconomic challenge worldwide. Predisposing genetic risk has been identified, yet environmental factors make up a significant part of the risk in disease initiation and propagation. Next to improved hygiene and a gross reduction of infections, changes in dietary habits are one of the most evident Western lifestyle factors potentially associated with the increase in autoimmune diseases. Growing evidence suggests that particularly a typical 'Western diet', rich in saturated fat and salt and related pathologies can have a profound impact on local and systemic immune responses under physiologic and autoimmune conditions such as in multiple sclerosis (MS). In this review, we discuss recent findings on environmental factors influencing autoimmunity with an emphasis on the impact of 'Western diet' on immune homeostasis and gut microbiota in MS. PMID- 27491299 TI - Raman spectroscopy as a process analytical technology for pharmaceutical manufacturing and bioprocessing. AB - Adoption of Quality by Design (QbD) principles, regulatory support of QbD, process analytical technology (PAT), and continuous manufacturing are major factors effecting new approaches to pharmaceutical manufacturing and bioprocessing. In this review, we highlight new technology developments, data analysis models, and applications of Raman spectroscopy, which have expanded the scope of Raman spectroscopy as a process analytical technology. Emerging technologies such as transmission and enhanced reflection Raman, and new approaches to using available technologies, expand the scope of Raman spectroscopy in pharmaceutical manufacturing, and now Raman spectroscopy is successfully integrated into real-time release testing, continuous manufacturing, and statistical process control. Since the last major review of Raman as a pharmaceutical PAT in 2010, many new Raman applications in bioprocessing have emerged. Exciting reports of in situ Raman spectroscopy in bioprocesses complement a growing scientific field of biological and biomedical Raman spectroscopy. Raman spectroscopy has made a positive impact as a process analytical and control tool for pharmaceutical manufacturing and bioprocessing, with demonstrated scientific and financial benefits throughout a product's lifecycle. PMID- 27491296 TI - BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer. AB - Chronic inflammation drives pathologies associated with type 2 diabetes (T2D) and breast cancer. Obesity-driven inflammation may explain increased risk and mortality of breast cancer with T2D reported in the epidemiology literature. Therapeutic approaches to target inflammation in both T2D and cancer have so far fallen short of the expected improvements in disease pathogenesis or outcomes. The targeting of epigenetic regulators of cytokine transcription and cytokine signaling offers one promising, untapped approach to treating diseases driven by inflammation. Recent work has deeply implicated the Bromodomain and Extra Terminal domain (BET) proteins, which are acetylated histone "readers", in epigenetic regulation of inflammation. This review focuses on inflammation associated with T2D and breast cancer, and the possibility of targeting BET proteins as an approach to regulating inflammation in the clinic. Understanding inflammation in the context of BET protein regulation may provide a basis for designing promising therapeutics for T2D and breast cancer. PMID- 27491300 TI - An interface for online coupling capillary electrophoresis to dielectric barrier discharge ionization mass spectrometry. AB - The online combination of capillary electrophoresis (CE) with mass spectrometry (MS) has long been desired for the capability of direct and simultaneous separation and detection with high efficiency, accuracy, and throughput. In this work, a novel CE-MS interface was developed, using dielectric barrier discharge ionization (DBDI). The interface employed a spray tip with a coaxial three-layer structure, into which the CE sample solution, the sheath liquid, and the nebulizing gas were introduced. The spray tip was put between the DBDI outlet and the MS inlet, thus the CE sample solution could be blended with the sheath liquid, then nebulized. The nebulized sample could be ionized by DBDI, and finally analyzed by MS. The key parameters of the interface were optimized. Then, proof-of-concept experiments separating and detecting the mixture of metronidazole and acetaminophen solutions were conducted. The results showed high separation efficiency, low time consumption, high reproducibility, and convenience in operation. In addition, the interface exhibited a high tolerance of non-volatile salts and surfactants, which would be widely used in CE analyses. All of these results demonstrated that the newly developed CE-DBDI-MS interface could be successfully used in CE-MS studies, and could be further utilized in multiple areas involving efficient separation and detection. PMID- 27491301 TI - Novel diffusive gradients in thin films technique to assess labile sulfate in soil. AB - A novel diffusive gradients in thin films (DGT) technique for sampling labile soil sulfate was developed, based on a strong basic anion exchange resin (Amberlite IRA-400) for sulfate immobilization on the binding gel. For reducing the sulfate background on the resin gels, photopolymerization was applied instead of ammonium persulfate-induced polymerization. Agarose cross-linked polyacrylamide (APA) hydrogels were used as diffusive layer. The sulfate diffusion coefficient in APA gel was determined as 9.83 * 10(-6) +/- 0.35 * 10( 6) cm(2) s(-1) at 25 degrees C. The accumulated sulfate was eluted in 1 mol L( 1) HNO3 with a recovery of 90.9 +/- 1.6 %. The developed method was tested against two standard extraction methods for soil sulfate measurement. The obtained low correlation coefficients indicate that DGT and conventional soil test methods assess differential soil sulfate pools, rendering DGT a potentially important tool for measuring labile soil sulfate. PMID- 27491304 TI - EPR-correlated dipolar spectroscopy by Q-band chirp SIFTER. AB - While two-dimensional correlation spectra contain more information as compared to one-dimensional spectra, typical spectral widths encountered in electron paramagnetic resonance (EPR) spectroscopy largely restrict the applicability of correlation techniques. In essence, the monochromatic excitation pulses established in pulsed EPR often cannot uniformly excite the entire spectrum. Here, this restriction is alleviated for nitroxide spin labels at Q-band microwave frequencies around 35 GHz. This is achieved by substitution of monochromatic pulses by frequency-swept chirp pulses tailored for uniform excitation. Unwanted interference effects brought by this substitution are analyzed for a pair of electron spins with secular dipolar coupling. Experimentally, the dipole-dipole interaction can be separated from other interactions by a constant-time Zeeman-compensated solid echo sequence called SIFTER. Such SIFTER experiments usually yield a one-dimensional dipolar spectrum. EPR-correlated dipolar spectra can be obtained when the four pulses are replaced by chirp pulses. These two-dimensional spectra encode additional information on the geometrical arrangement of the two spin labels. With the excitation parameters achieved by a home-built Q-band spectrometer capable of frequency swept excitation, unwanted interference effects can be largely neglected for the examined model compound with a spin-spin distance of 4 nm. The experimentally obtained correlation pattern conforms to the expectation based on the inter-spin geometry of the investigated rigid model compound. PMID- 27491303 TI - Effects of physical therapy and relaxation techniques on the parameters of pain in university students with tension-type headache: A randomised controlled clinical trial. AB - INTRODUCTION: Non-pharmacological treatments help control tension-type headache; however, evidence about their effectiveness is still limited. This study evaluates the effectiveness of physical therapy based on cervical spine kinesiotherapy and posture correction exercises compared to a programme of relaxation techniques only (Schultz's Autogenic Training, AT). METHODS: Tension type headache is very common among university students. We randomly selected 152 university students with a diagnosis of tension-type headache according to the criteria of the International Headache Society. Eighty-four were women (55.3%) and 68 were men (44.7%). Mean age was 20.42+/-2.36 years. The study design is a randomised controlled trial of a non-pharmacological intervention with a blinded evaluation of response variables. We compared the results of two independent samples: AT was used in one of the groups while the other group received AT plus cervical spine kinesiotherapy and posture correction training. Patients recorded any changes in the parameters of pain (frequency, intensity, and duration) and drug consumption in a headache diary before treatment, at 4 weeks, and at 3 months. RESULTS: Both interventions achieved a decrease in all the parameters of pain; however, decreases in frequency and intensity were more significant in the combined treatment group (P<0.01) (d=0.4). CONCLUSIONS: Such active, non-invasive therapies as AT and cervical spine kinesiotherapy, and especially the combination of both, effectively reduce tension-type headache by preventing and managing the potential psychophysical causes of this disorder. Future research should aim to assess the long-term effects of these interventions. PMID- 27491302 TI - Quantitative patterns of Hsps in tubular adenoma compared with normal and tumor tissues reveal the value of Hsp10 and Hsp60 in early diagnosis of large bowel cancer. AB - Large bowel carcinogenesis involves accumulation of genetic alterations leading to transformation of normal mucosa into dysplasia and, lastly, adenocarcinoma. It is pertinent to elucidate the molecular changes occurring in the pre-neoplastic lesions to facilitate early diagnosis and treatment. Heat shock proteins (Hsps), many of which are molecular chaperones, are implicated in carcinogenesis, and their variations with tumor progression encourage their study as biomarkers. There are many reports on Hsps and cancer but none to our knowledge on their systematic quantification in pre-neoplastic lesions of the large bowel. We performed immunohistochemical determinations of Hsp10, Hsp60, Hsp70, and Hsp90 in biopsies of large bowel tubular adenomas with moderate grade of dysplasia and compared to normal mucosa and adenocarcinoma with a moderate grade of differentiation (G2). A significant elevation of Hsp10 and Hsp60 only, i.e., in the absence of elevation of Hsp70 or Hsp90, in both epithelium and lamina propria was found in tubular adenoma by comparison with normal mucosa. In contrast, adenocarcinoma was characterized by the highest levels of Hsp10 and Hsp60 in epithelium and lamina propria, accompanied by the highest levels of Hsp70 only in epithelium and of Hsp90 only in lamina propria, by comparison with normal and tubular adenoma counterparts. Hsp10 and Hsp60 are promising biomarkers for early diagnosis of tubular adenoma and for its differentiation from more advanced malignant lesions. Hsp10 and Hsp60 may be implicated in carcinogenesis from its very early steps and, thus, are potentially convenient targets for therapy. PMID- 27491305 TI - Immigrants as Research Partners: A Review of Immigrants in Community-Based Participatory Research (CBPR). AB - Community-based participatory research (CBPR) is uniquely suited to engage immigrants in all aspects of research, from research question development to data collection to interpretation and dissemination of results. An increasing number of research studies have utilized the methodology for exploring complex health issues for immigrants. In the current manuscript, we present a review of peer reviewed articles in health-related research where CBPR was conducted in partnership with immigrants. We examined the role of immigrants in the CBPR process and how immigrant involvement improved/enhanced the research rigor. A total of 161 articles met the inclusion criteria. The results of this literature review enhance our understanding of how CBPR can be used in direct collaboration with immigrants and highlights the many potential benefits for both researchers and immigrant communities. PMID- 27491306 TI - Proteomic Profiling and the Predicted Interactome of Host Proteins in Compatible and Incompatible Interactions Between Soybean and Fusarium virguliforme. AB - Sudden death syndrome (SDS) is a complex of two diseases of soybean (Glycine max), caused by the soil borne pathogenic fungus Fusarium virguliforme. The root rot and leaf scorch diseases both result in significant yield losses worldwide. Partial SDS resistance has been demonstrated in multiple soybean cultivars. This study aimed to highlight proteomic changes in soybean roots by identifying proteins which are differentially expressed in near isogenic lines (NILs) contrasting at the Rhg1/Rfs2 locus for partial resistance or susceptibility to SDS. Two-dimensional gel electrophoresis resolved approximately 1000 spots on each gel; 12 spots with a significant (P < 0.05) difference in abundance of 1.5 fold or more were picked, trypsin-digested, and analyzed using quadruple time-of flight tandem mass spectrometry. Several spots contained more than one protein, so that 18 distinct proteins were identified overall. A functional analysis performed to categorize the proteins depicted that the major pathways altered by fungal infection include disease resistance, stress tolerance, and metabolism. This is the first report which identifies proteins whose abundances are altered in response to fungal infection leading to SDS. The results provide valuable information about SDS resistance in soybean plants, and plant partial resistance responses in general. More importantly, several of the identified proteins could be good candidates for the development of SDS-resistant soybean plants. PMID- 27491307 TI - Application of active edible coatings made from basil seed gum and thymol for quality maintenance of shrimp during cold storage. AB - BACKGROUND: To improve the quality of Pacific white shrimp (Litopenaeus vannamei), active coating solutions were prepared by dissolving 10 g L-1 of basil seed gum (BSG) and adding various levels of thymol (6%, 8% and 10% w/w based on gum weight) and glycerol (3.5 g L-1 ) as plasticizer. The effects of coating solutions (CS1-4) on the quality changes of shrimps during refrigerated storage over 20 days were investigated. RESULTS: The total volatile basic nitrogen (TVB N) value in shrimps coated with CS4 (containing 10% w/w thymol) was slightly higher than the upper threshold of 300 mg kg-1 on day 18, whereas that of uncoated shrimps increased to, or over, the threshold value on day 7. Active coatings significantly reduced (P < 0.05) microbial growth in shrimps during the cold storage without a negative impact on the organoleptic properties. Using CS4 on the shrimp samples immediately reduced total viable count and psychrotrophic bacteria count by 2 and 1 log colony forming units g-1 , respectively, compared to controls. CONCLUSION: The results of the present study revealed that the active edible coatings based on BSG activated with thymol had good potential to be used in the production of active packaging for various food applications. (c) 2016 Society of Chemical Industry. PMID- 27491308 TI - Ameloblastoma Phenotypes Reflected in Distinct Transcriptome Profiles. AB - Ameloblastoma is a locally invasive benign neoplasm derived from odontogenic epithelium and presents with diverse phenotypes yet to be characterized molecularly. High recurrence rates of 50-80% with conservative treatment in some sub-types warrants radical surgical resections resulting in high morbidity. The objective of the study was to characterize the transcriptome of ameloblastoma and identify relevant genes and molecular pathways using normal odontogenic tissue (human "dentome") for comparison. Laser capture microdissection was used to obtain neoplastic epithelial tissue from 17 tumors which were examined using the Agilent 44 k whole genome microarray. Ameloblastoma separated into 2 distinct molecular clusters that were associated with pre-secretory ameloblast and odontoblast. Within the pre-secretory cluster, 9/10 of samples were of the follicular type while 6/7 of the samples in the odontoblast cluster were of the plexiform type (p < 0.05). Common pathways altered in both clusters included cell cycle regulation, inflammatory and MAPkinase pathways, specifically known cancer driving genes such as TP53 and members of the MAPkinase pathways. The pre secretory ameloblast cluster exhibited higher activation of inflammatory pathways while the odontoblast cluster showed greater disturbances in transcription regulators. Our results are suggestive of underlying inter-tumor molecular heterogeneity of ameloblastoma sub-types and have implications for the use of tailored treatment. PMID- 27491310 TI - Intraocular foreign body removal: a novel technique using intraoperative imaging. AB - We describe a case illustrating a new technique of using intraoperative optical coherence tomography (IOCT) for foreign body removal from the limbus and cornea. In this case, fragments of a fish hook in the temporal limbus and cornea were identified on the OCT. The residual pieces were then removed, assisted by high resolution, real-time cross-sectional imaging, IOCT. While this technique involves steep learning curve, we believe that it is safe for the patient and helps surgeon with instant decision making and reduce orbital manipulation. PMID- 27491311 TI - John Garrow. PMID- 27491312 TI - Glycosaminoglycans contribute to extracellular matrix fiber recruitment and arterial wall mechanics. AB - Elastic and collagen fibers are well known to be the major load-bearing extracellular matrix (ECM) components of the arterial wall. Studies of the structural components and mechanics of arterial ECM generally focus on elastin and collagen fibers, and glycosaminoglycans (GAGs) are often neglected. Although GAGs represent only a small component of the vessel wall ECM, they are considerably important because of their diverse functionality and their role in pathological processes. The goal of this study was to study the mechanical and structural contributions of GAGs to the arterial wall. Biaxial tensile testing was paired with multiphoton microscopic imaging of elastic and collagen fibers in order to establish the structure-function relationships of porcine thoracic aorta before and after enzymatic GAG removal. Removal of GAGs results in an earlier transition point of the nonlinear stress-strain curves [Formula: see text]. However, stiffness was not significantly different after GAG removal treatment, indicating earlier but not absolute stiffening. Multiphoton microscopy showed that when GAGs are removed, the adventitial collagen fibers are straighter, and both elastin and collagen fibers are recruited at lower levels of strain, in agreement with the mechanical change. The amount of stress relaxation also decreased in GAG-depleted arteries [Formula: see text]. These findings suggest that the interaction between GAGs and other ECM constituents plays an important role in the mechanics of the arterial wall, and GAGs should be considered in addition to elastic and collagen fibers when studying arterial function. PMID- 27491309 TI - Tyrosine hydroxylase (TH), its cofactor tetrahydrobiopterin (BH4), other catecholamine-related enzymes, and their human genes in relation to the drug and gene therapies of Parkinson's disease (PD): historical overview and future prospects. AB - Tyrosine hydroxylase (TH), which was discovered at the National Institutes of Health (NIH) in 1964, is a tetrahydrobiopterin (BH4)-requiring monooxygenase that catalyzes the first and rate-limiting step in the biosynthesis of catecholamines (CAs), such as dopamine, noradrenaline, and adrenaline. Since deficiencies of dopamine and noradrenaline in the brain stem, caused by neurodegeneration of dopamine and noradrenaline neurons, are mainly related to non-motor and motor symptoms of Parkinson's disease (PD), we have studied human CA-synthesizing enzymes [TH; BH4-related enzymes, especially GTP-cyclohydrolase I (GCH1); aromatic L-amino acid decarboxylase (AADC); dopamine beta-hydroxylase (DBH); and phenylethanolamine N-methyltransferase (PNMT)] and their genes in relation to PD in postmortem brains from PD patients, patients with CA-related genetic diseases, mice with genetically engineered CA neurons, and animal models of PD. We purified all human CA-synthesizing enzymes, produced their antibodies for immunohistochemistry and immunoassay, and cloned all human genes, especially the human TH gene and the human gene for GCH1, which synthesizes BH4 as a cofactor of TH. This review discusses the historical overview of TH, BH4-, and other CA related enzymes and their genes in relation to the pathophysiology of PD, the development of drugs, such as L-DOPA, and future prospects for drug and gene therapy for PD, especially the potential of induced pluripotent stem (iPS) cells. PMID- 27491314 TI - A self-reported survey on the confidence levels and motivation of New South Wales practice nurses on conducting advance-care planning (ACP) initiatives in the general-practice setting. AB - Nurses are well positioned to initiate and conduct advance-care planning (ACP) conversations; however, there has been limited research on practice nurses performing this role in Australia. The aim of the present study was to understand the beliefs, attitudes, perceptions, confidence, training and educational needs of New South Wales practice nurses with regards to involvement in ACP. A cross sectional online survey was conducted in August to October 2014. Nurses were recruited through nursing organisations and Medicare Locals. There were 147 completed surveys (n=147). Participants were mostly female registered nurses, with a median age of 50, and 6 years of practice-nurse experience. Practice nurses were generally positive towards their involvement in ACP and believed it would be beneficial for the community. Their confidence in initiating ACP increased as their familiarity with patients increased. They showed a high level of interest in participating in training and education in ACP. Barriers to their involvement in ACP included the lack of a good documentation system, limited patient-education resources and unclear source of remuneration. Nurses were also concerned over legalities of ACP, ethical considerations and their understanding of end-of-life care options. Nevertheless, they were highly receptive of integrating ACP discussions and were willing to enhance their skills. These findings uncover a need for further training and development of practice nurses for ACP discussions. PMID- 27491313 TI - Catechol-O-methyltransferase Val158Met polymorphism is associated with increased risk of multiple uterine leiomyomas either positive or negative for MED12 exon 2 mutations. AB - AIMS: To study the possible association of catechol-O-methyltransferase (COMT) Val158Met polymorphism with multiple and solitary uterine leiomyomas (ULs) and to check whether the COMT Val/Val genotype is associated with MED12 exon 2 mutations in fibroids. METHODS: The COMT Val158Met allele and genotype frequencies were compared between age-matched women with ULs (n=104) and controls (n=59). Patients with UL were subcategorised by diagnosis of solitary (n=59) or multiple (n=45) fibroids and by the presence of somatic MED12 exon 2 mutations in at least one fibroid (n=32) or in neither fibroid (n=26). The association of COMT Val/Val genotype with the presence of any ULs, solitary/multiple ULs and ULs positive/negative for MED12 exon 2 mutations was evaluated by chi2 tests using a dominant genotype model (G/G vs G/A+A/A) and expressed as ORs and 95% CIs. RESULTS: The COMT Val/Val genotype frequency did not differ between the patients with UL and the controls (28.8% vs 18.6%, p=0.149, OR 1.77; CI 0.81 to 3.86). However, it was significantly higher in the patients who had multiple UL compared with the solitary UL (40% vs 20.3%, p=0.028, OR 2.61; CI 1.09 to 6.24) and to the controls (40% vs 18.6%, p=0.016, OR 2.91; CI 1.20 to 7.06). No association of the COMT Val/Val genotype with UL-specific MED12 exon 2 mutations was found (p=0.662, OR 0.77; CI 0.23 to 2.53). CONCLUSIONS: Women with COMT Val/Val genotype are at high risk of developing multiple uterine fibroids either positive or negative for MED12 exon 2 mutations. These data are important to design new strategies for UL prophylaxis and treatment. PMID- 27491315 TI - Prevalence of chronic kidney disease after preeclampsia. AB - BACKGROUND: Preeclampsia (PE), an endothelial disease that affects kidney function during pregnancy, is correlated to an increased future risk of cardiovascular and chronic kidney disease. The Kidney Disease Improving Global Outcomes (KDIGO) 2012 guideline emphasizes the combined role of glomerular filtration rate (GFR) and albuminuria in determining the frequency of monitoring of kidney function. OBJECTIVES: In this study we evaluated the prevalence of CKD in women with a history of PE. We investigated how many seemingly healthy women required monitoring of kidney function according to the KDIGO guideline. METHODS: We included 775 primiparous women with a history of PE. They were at least 4 months postpartum, and had no pre-existing hypertension, diabetes or kidney disease. We estimated GFR by the CKD-Epidemiology equation and urinary albumin loss by albumin creatinine ratio in a 24-h urine collection. RESULTS: Most women, 669 (86.3 %), had a normal GFR and absent albuminuria. Based on the KDIGO guideline, 13.7 % would require at least yearly monitoring of kidney function. Only 1.4 % were classified to be at high risk for kidney function deterioration. CONCLUSION: Monitoring of kidney function seems relevant for about one in seven women with a history of PE, mainly due to albuminuria. Albuminuria should be evaluated postpartum to identify those women that need further monitoring of kidney function. PMID- 27491316 TI - Fluoroless catheter ablation of various right and left sided supra-ventricular tachycardias in children and adolescents. AB - Electrophysiology study (EPS) and catheter ablation (CA) in children and adolescents carries a potentially harmful effect of radiation exposure when performed with the use of fluoroscopy. Our aim was to evaluate the feasibility, safety and effectiveness of fluoroless EPS and CA of various supra-ventricular tachycardias (SVTs) with the use of the 3D mapping system and intracardiac echocardiography (ICE). Forty-three consecutive children and adolescents (age 13 +/- 3 years) underwent fluoroless EPS and CA for various supra-ventricular tachycardias. A three-dimensional (3D) mapping system NavXTM was used for guidance of diagnostic and ablation catheters in the heart. ICE was used as a fundamental imaging tool for transseptal punctures. Acute procedural success rate was 100 %. There were no procedure related complications and short-term follow up (10 +/- 3 months) revealed 93 % arrhythmia free survival rate. Fluoroless CA of various SVTs in the paediatric population is feasible, safe and can be performed successfully with 3D mapping system and ICE. PMID- 27491317 TI - [Femoral neck fractures in young patients]. AB - Femoral neck fractures in young patients are rare but of high clinical relevance due to the complexity of risk factors and complications. Early stabilization and accurate reduction are of high priority. Femoral head-preserving stabilization by dynamic hip screws or threefold screw osteosynthesis are the methods of choice. Postoperative results should be closely controlled in every case in order to be able to treat possible complications in time. PMID- 27491318 TI - Primary surgery results in no survival benefit compared to primary radiation for oropharyngeal cancer patients stratified by high-risk human papilloma virus status. AB - We changed the primary oropharynx squamous cell carcinoma (OPSCC) treatment recommendation from primary radiation therapy (RT) to tumor surgery and neck dissection, followed by RT around the year 2000 with apparently improved survival. However, high-risk human papilloma virus (hr-HPV)-16-caused OPSCCs have increased during this period. Furthermore, hr-HPV+ OPSCC carry a better prognosis than hr-HPV-negative patients. We have, therefore, evaluated the 5-year survival in the period from 1992 to 1999 versus 2000 to 2008 stratified by hr-HPV tumor infection status. Ninety-six OPSCC patients were treated from 1992 to 1999 compared with 136 patients from 2000 to 2008. The 5-year disease-specific survival (DDS) and overall survival (OS) were recorded, while the health-related quality of life (HRQoL) scores were obtained from some of the cured patients. Thirty-eight (40 %) in the first period and 86 OPSCCs (63 %) in the second period were hr-HPV+. In the first period, 16 versus 62 patients in the last period were treated by neck dissection, primary tumor surgery, and RT. DSS among all the hr HPV-negative patients in the first period was 51 versus 55 % in the second period, and the corresponding OS was 33 versus 31 %, respectively. The DSS among all the hr-HPV+ patients was 78 % in the first period versus 77 % in the second period, while the OS was 71 versus 69 %, respectively. The HRQoL scores among successfully treated patients were worse following surgery, plus RT than RT only. The hr-HPV-adjusted 5-year survival in OPSCC patients was similar between the two time periods. A decreased HRQoL was associated with surgical therapy, which indicates that hr-HPV+ OPSCC patients may be treated by primary RT followed by major surgery only if RT treatment fails. PMID- 27491320 TI - CYP2E1 polymorphisms and nasopharyngeal carcinoma risk: a meta-analysis. AB - The cytochrome P450 2E1 (CYP2E1) polymorphisms have been implicated in susceptibility to nasopharyngeal carcinoma (NPC). However, the results are inconsistent. The aim of this meta-analysis is to evaluate the association between the CYP2E1 polymorphisms and NPC risk. All eligible case-control studies published up to April 4, 2016 were identified by searching PubMed, Web of Science, CNKI, Wanfang and Weipu databases. The NPC risk associated with the CYP2E1 polymorphism was estimated for each study by odds ratios (OR) together with its 95 % confidence interval (CI), respectively. Seven case-control studies were included. Of those, there were seven studies (1302 cases and 1319 controls) for RsaI/PstI polymorphism and three studies (732 cases and 642 controls) for DraI polymorphism. Overall, a significant association was found for RsaI/PstI polymorphism under recessive and homozygote comparison models (OR = 2.72, 95 % CI 1.73-4.25; OR = 2.64, 95 % CI 1.68-4.16, respectively), while there was no significant association for RsaI/PstI polymorphism under other two genetic models. When stratified by ethnicity, similar results were observed between them. As for DraI polymorphism, we also observed a significant association under recessive and homozygote comparison models, but not for the other two models. This meta-analysis suggests that the CYP2E1 polymorphisms contributed to the susceptibility of NPC, especially in Asian populations. PMID- 27491319 TI - Will the mininvasive approach challenge the old paradigms in oral cancer surgery? AB - In the genome era, the achievement of a safe and complete resection of oral cancers remains a challenge for surgeons. Margin length at histopathological examination is still considered the main indicator of oncological radicality. However, this parameter is fraught by major limitations. Cancer aggressiveness, and in particular its ability to spread in the surrounding tissue, most probably influences loco-regional control and prognosis more than margin length. Unfortunately, no molecular markers are currently available to predict tumor aggressiveness pre-operatively. However, additional histopathological parameters, beside margin length, could be considered to better stratify oral tumors, including depth of invasion (DOI), perineural invasion or composite scores. Recent advances in laser technology have established a novel surgical trend toward a minimalist approach, named transoral laser microsurgery (TLM). TLM provides a local control rate comparable to the one achieved by larger resections if the margin appears disease free, independent from its length. In addition, the clinical availability of innovative optical technologies, such as narrow band imaging (NBI) or autofluorescence, allows more precise and tailored resections, not simply based on clinical observation and ruler measurement. This review will propose the possible implementation of novel procedures toward a mini-invasive surgical approach, providing a satisfactory control rate but significantly improving the quality of life of the patients compared to conventional surgery. PMID- 27491321 TI - Phonoarticulation in spinocerebellar ataxia type 3. AB - Phonoarticulation is characterized by changes in resonance, diadochokinesis, prosody, sound frequency, vocal quality, and intraoral pressure. The main aim of this study was to characterize the phonoarticulation in spinocerebellar ataxia type 3 (SCA3) and correlate it with clinical and genetic factors. Thirty-one patients with SCA3 who were subjected to spontaneous speech recordings and phonoarticulatory diadochokinesis (DDK) participated in the study. Speech analyses were performed starting after 10 s of spontaneous speech, by three experienced speech therapists, using a protocol for dysarthria adapted from the Mayo Clinic. The intra-evaluator reliability was analyzed. The lower the patient's age at disease onset was, the more frequent the occurrences of monofrequency and altered speech rhythm were. Articulation, DDK, resonance, and prosody showed a moderate correlation with the number of "CAG" triplet repeats. We conclude that the phonoarticulation of patients with Machado-Joseph disease (MJD) is characterized by mixed dysarthrophonia with cerebellar and hypokinetic components, and that there is a tendency toward higher frequency of dysarthrophonia symptoms with lower age of disease onset, longer time since onset and higher number of "CAG" triplet repeats. PMID- 27491322 TI - Looking for the Word "Angiogenesis" in the History of Health Sciences: From Ancient Times to the First Decades of the Twentieth Century. AB - This review deals with the origin of the term "angiogenesis", with an attention to John Hunter who is credited with this neologism. A part of the literature refers to a Hunter's work dating 1787, and the other part claims the first use of the term "angiogenesis" in the Hunter's masterpiece published in 1794. Since we were unable to find the term "angiogenesis" in Hunter's works, this review attempts to bring a new contribution to the historical research of this important concept, moving from ancient times to the first decades of the twentieth century, when "angiogenesis" begun to appear on titles of scientific articles. The development of the knowledge on the cardiocirculatory system and the principal steps of this fascinating subject were examined, with particular regard to microvascular bed and vessel sprouting, and to the intriguing observations on blood vessel neoformation that have been also made in the premicroscopic era. In Hunter's works, the concept of angiogenesis indeed emerges, but not the term "angiogenesis". The scientific language occurring during Hunter's time was still old-fashioned, and the term "angiogenesis" was not one of those he used, rather a much later neologism that sounds too modern to appear in that context. Would the first appearance of the term "angiogenesis" occur in late nineteenth century in studies dealing with embryogenesis and organ vascularization? The present study aims to explore the scientific literature and to open a debate to better define this matter. PMID- 27491323 TI - Robotic Enucleation for Benign or Borderline Tumours of the Pancreas: A Retrospective Analysis and Comparison from a High-Volume Centre in Asia. AB - BACKGROUND: Enucleation is increasingly performed for benign or borderline tumours of the pancreas because it is a parenchyma-sparing and less invasive procedure compared to conventional pancreatectomy, which reduces the risk of exocrine and endocrine insufficiency. This study retrospectively evaluated and compared the pre-, intra-, and post-operative clinical characteristics after open and robotic approaches for pancreatic enucleation. METHODS: Fifty-six cases of enucleation for benign or borderline tumours of the pancreas treated from March 2010 to July 2015 were identified by a retrospective search. These included 25 patients who underwent an open approach and 31 patients who underwent a robotic approach. The clinical characteristics were extracted and compared. RESULTS: The two groups had a similar location and pathology of the tumour. The robotic group had a significantly shorter operation time and significantly less blood loss than the open group. The rates of clinical pancreatic fistula (PF) formation and major complications were similar. The robotic approach could be applied for a tumour on the right side of the pancreas without increasing the incidence of clinical PF or other major complications. The patients with clinical PF had a significantly shorter distance between the lesion and the main pancreatic duct (MPD). CONCLUSION: Robotic enucleation appears to be a feasible and safe approach for benign or borderline tumours of the pancreas and was associated with similarly favourable surgical outcomes as the open approach. Identifying and avoiding the MPD is an important step during enucleation. PMID- 27491324 TI - Effect of Sitagliptin and Metformin on Prediabetes Progression to Type 2 Diabetes - A Randomized, Double-Blind, Double-Arm, Multicenter Clinical Trial: Protocol for the Sitagliptin and Metformin in PreDiabetes (SiMePreD) Study. AB - BACKGROUND: The high prevalence and incidence of type 2 diabetes mellitus (DM), and its associated morbidity and mortality, has prompted growing international interest and effort in the primary prevention of this disease. Primary prevention is possible since type 2 DM is preceded by prediabetes, offering a window opportunity to treat patients, and prevent the emergence of advanced disease. Sitagliptin is an oral dipeptidyl peptidase-IV inhibitor that preserves existing beta cell function and increases beta cell mass. These two effects have been demonstrated both in vitro and in animal studies, and current clinical data show that sitagliptin is safe. Metformin, a biguanide, reduces insulin resistance and inhibits hepatic gluconeogenesis, and has an excellent safety profile. The combination of metformin and sitagliptin, targeting both characteristics of prediabetes (insulin resistance and progressive beta cell degeneration), may potentially slow or halt the progression from prediabetes to type 2 DM. This paper describes the rationale and design of the Sitagliptin and Metformin in PreDiabetes (SiMePreD) study. OBJECTIVE: The aim of this study is to determine the effect of sitagliptin and metformin on progression from prediabetes to type 2 DM. The objectives of the study are to determine the effects of metformin and placebo on glycemic endpoints, the effects of sitagliptin and metformin on glycemic endpoints, the effects of metformin and placebo on incidence of cardiovascular disease and death, and the effects of sitagliptin and metformin on incidence of cardiovascular disease and death. METHODS: This is a randomized, double-blind, multicenter clinical study that will determine if the combination of metformin and sitagliptin is effective in preventing the progression from prediabetes to type 2 DM. The study will contain two arms (metformin/sitagliptin and metformin/placebo). Primary endpoints include the number of subjects progressing from prediabetes to type 2 DM, the number of cardiovascular events, and the number of deaths. The planned duration of the study is five years, and 410 subjects will be included in each group. Data analyses will include clinically relevant measures (eg, numbers needed to treat and numbers needed to harm) and will be performed according to the intention-to-treat principle. RESULTS: This study is currently in the process of acquiring research funding. CONCLUSIONS: The SiMePreD study is the first study to investigate the utility of sitagliptin in combination with metformin for the primary prevention of type 2 DM. . PMID- 27491325 TI - How to justify a ban on doping? AB - BACKGROUND: This article deals with arguments that challenge the possibility of an ethical justification for a doping ban. HYPOTHESIS/PURPOSE: It shows that a justification for the doping ban is only possible if its implementation can be safeguarded. STUDY DESIGN: Systematic review. METHODS: Based on the proposition of the game theory, this article examines the scope of the arguments of naturalness, health, equal opportunity and fairness used in scientific literature. RESULTS/CONCLUSIONS: Ceteris paribus, athletes will always prefer a situation that presents no health risk to a situation in which they face a threat to their health. They will therefore consent to a doping ban on the condition that it is ensured that all parties are bound to this rule, so that anyone complying with the rules will not be afraid of losing the competition as a result. For even if we condoned self-harm, it could still be argued plausibly that the individual should not suffer more disadvantages than absolutely necessary for the sake of gaining an advantage over others. Of course, it is possible to plead for a restricted approval of doping measures with acceptable risk. But even taking minor risks would not seem sensible under the condition that all participants without exception adhere to the same conditions when there is the option to renounce the (avoidable) risks. So as far as the use of performance-enhancing substances or methods is concerned, we can maintain that even if minor health risks are to be expected, a ban on doping can be justified from an ethical point of view. PMID- 27491327 TI - First digit macrodactyly and carpal tunnel syndrome caused by giant median nerve with macrodystrophia lipomatosa. PMID- 27491326 TI - Complex regional pain syndrome. AB - INTRODUCTION: Complex regional pain syndrome (CRPS) is a chronic pain condition that can occur after a minor trauma or surgery. It is a multifactorial condition with a complex cause and even more complex pathophysiology. There are disturbances and changes in the sympathetic, somatosensory and motor nervous system, resulting in severe pain and disability. Patients with CRPS can have their quality of life and functional ability greatly affected and they need appropriate and interdisciplinary interventions. PURPOSE: This article contributes towards an up-to-date knowledge and an overall view of CRPS, which can contribute to a structured and systematic rehabilitation process for patients. IMPLICATIONS: This Masterclass describes a functional restoration algorithm to assist therapists in the development of a treatment plan based on the available evidence and international guidelines. Early diagnosis and treatment is of great importance as patients (adults and children), can be severely affected in their functional capacity and quality of life. PMID- 27491328 TI - Life Sciences Discovery and Technology Highlights. PMID- 27491330 TI - Macromol. Biosci. 8/2016. AB - Back Cover: The authors have created polymers which release insulin using light. These materials utilize insulin itself as the primary monomer and therefore achieve a very high density (85% w/w insulin). This near perfect density makes them ideal as photoactivated depots of insulin. Further details can be found in the article by Bhagyesh R. Sarode, Piyush K. Jain, Simon H. Friedman on page 1138. PMID- 27491333 TI - Adaptive finite difference for seismic wavefield modelling in acoustic media. AB - Efficient numerical seismic wavefield modelling is a key component of modern seismic imaging techniques, such as reverse-time migration and full-waveform inversion. Finite difference methods are perhaps the most widely used numerical approach for forward modelling, and here we introduce a novel scheme for implementing finite difference by introducing a time-to-space wavelet mapping. Finite difference coefficients are then computed by minimising the difference between the spatial derivatives of the mapped wavelet and the finite difference operator over all propagation angles. Since the coefficients vary adaptively with different velocities and source wavelet bandwidths, the method is capable to maximise the accuracy of the finite difference operator. Numerical examples demonstrate that this method is superior to standard finite difference methods, while comparable to Zhang's optimised finite difference scheme. PMID- 27491332 TI - Use of the physical environment to support everyday activities for people with dementia: A systematic review. AB - Difficulty with everyday activities is a key symptom and defining feature of dementia, relating to subjective reports of well-being and overall quality of life. One way to support individuals in their daily activities is by modifying the physical environment to make it easier to interact with during activity performance. This systematic review explores the range of studies available using physical environmental strategies to support performance in everyday activities for people with dementia. Seventy-two relevant studies were identified by the search. Physical environmental strategies included changes to the global environment and to architectural features, use of moveable environmental aids and tailored individual approaches. Strategies supported general everyday activity functioning (N = 19), as well as specific activities, particularly mealtimes (N = 15) and orientation in space (N = 16); however, few studies were found that focused on aspects of personal care such as dressing (N = 1) and showering or the preferred hobbies of individuals (N = 0). Overall, there appeared to be a lack of research within private home environments, and of studies which specify the dementia syndrome or the whole neuropsychological profile of people with dementia. More work is needed to extend theoretical understandings of how people with dementia interact with their environments so that these spaces can be designed to further support activities of daily living performance. Future work in this field could also incorporate the perspectives and preferences of those living with dementia. PMID- 27491334 TI - Developing a Data Visualization System for the Bank of America Chicago Marathon (Chicago, Illinois USA). AB - As one of the largest marathons worldwide, the Bank of America Chicago Marathon (BACCM; Chicago, Illinois USA) accumulates high volumes of data. Race organizers and engaged agencies need the ability to access specific data in real-time. This report details a data visualization system designed for the Chicago Marathon and establishes key principles for event management data visualization. The data visualization system allows for efficient data communication among the organizing agencies of Chicago endurance events. Agencies can observe the progress of the race throughout the day and obtain needed information, such as the number and location of runners on the course and current weather conditions. Implementation of the system can reduce time-consuming, face-to-face interactions between involved agencies by having key data streams in one location, streamlining communications with the purpose of improving race logistics, as well as medical preparedness and response. Hanken T , Young S , Smilowitz K , Chiampas G , Waskowski D . Developing a data visualization system for the Bank of America Chicago Marathon (Chicago, Illinois USA). Prehosp Disaster Med. 2016;31(5):572 577. PMID- 27491337 TI - Thermalized connectivity networks of jammed packings. AB - Jammed packings of repulsive elastic spheres have emerged as a rich model system within which the elastic properties of disordered glassy materials may be elucidated. Most of the work on these packings has focused on the case of vanishing temperature. Here, we explore the elastic properties of the associated connectivity network for finite temperatures, ignoring the breaking of bonds and the formation of new ones. Using extensive Monte Carlo simulations, we find that, as the temperature is increased, the resulting spring network shrinks and exhibits a rapidly softening bulk modulus via a cusp. Moreover, the shear modulus stiffens in a fixed volume ensemble but not in a fixed pressure ensemble. These counter-intuitive behaviors may be understood from the characteristic spectrum of soft modes near isostaticity, which resembles the spectrum of a rod near its buckling instability. Our results suggest a generic mechanism for negative thermal expansion coefficients in marginal solids. We discuss some consequences of bond breaking and an apparent analogy between thermalization and shear. PMID- 27491335 TI - Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE(-/-) mice. AB - Atherosclerosis is a chronic inflammatory disease characterized by formation of lipid-rich plaques on the inner walls of arteries. ADAMTS4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase that regulates versican turnover in the arterial wall and atherosclerotic plaques. Recent reports indicated elevated ADAMTS4 level in human atherosclerotic plaques and in the plasma of acute coronary syndrome patients. Nevertheless, whether increased ADAMTS4 is a consequence of atherosclerosis or ADAMTS4 has a causal role in atherogenesis remains unknown. In this work, we investigated the role of ADAMTS4 in diet induced atherosclerosis using apolipoprotein E deficient (ApoE(-/ )) and Adamts4 knockout mice. We show that ADAMTS4 expression increases in plaques as atherosclerosis progresses in ApoE(-/-) mice. ApoE(-/-)Adamts4(-/-) double knockout mice presented a significant reduction in plaque burden at 18 weeks of age. Loss of ADAMTS4 lead to a more stable plaque phenotype with a significantly reduced plaque vulnerability index characterized by reduced lipid content and macrophages accompanied with a significant increase in smooth muscle cells, collagen deposition and fibrotic cap thickness. The reduced atherosclerosis is accompanied by an altered plasma inflammatory cytokine profile. These results demonstrate for the first time that ADAMTS4 contributes to diet induced atherosclerosis in ApoE(-/-) mice. PMID- 27491336 TI - Effect of alpha-linolenic acid-modified low molecular weight chondroitin sulfate on atherosclerosis in apoE-deficient mice. AB - METHODS: 8-week-age male ApoE(-/-) mice were fed with the atherogenic diet together with or without tested compounds (rosuvastatin calcium, alpha-LNA-LMWCS, LMWCS and alpha-LNA) for 16 weeks. When the animals were killed, blood plasma was isolated to test the level of TC, LDL-C, TNF-alpha, IL-6 and CRP by biochemistry analysis and ELISA method. The whole aorta and aortic root sections were also collected to study atherogenesis level and reveal the possible mechanism by histological examination, real-time PCR and Western blot analysis. RESULTS: The level of TC, LDL-C, TNF-alpha, IL-6 and CRP in plasma in H-LNA-LMWCS group were significantly lower than those of the control group (rosuvastatin calcium). Plaques in H-LNA-LMWCS group showed higher content of smooth muscle cells, lower content of lipid and macrophages, and lower mRNA levels of TNF-alpha, IL-6, CRP, MCP-1, VCAM-1 and ICAM-1 than those in the control group. In addition, alpha-LNA LMWCS could reduce the nuclear translocation of NF-kappaB, inhibit expressions of p-ERK1/2, p-p38, MCP-1, VCAM-1 and ICAM-1 in mice aorta. CONCLUSION: alpha-LNA LMWCS exhibited anti-atherosclerosis effect through regulating the lipid metabolism and diminishing the synthesis of pro-inflammatory cytokines. The possible mechanism may be that alpha-LNA-LMWCS could influence MAPK/ NF-kappaB related signal pathway. GENERAL SIGNIFICANCE: The results may provide significant suggestions for the application of alpha-LNA-LMWCS in anti-atherosclerosis. PMID- 27491338 TI - Zero-temperature quantum annealing bottlenecks in the spin-glass phase. AB - A promising approach to solving hard binary optimization problems is quantum adiabatic annealing in a transverse magnetic field. An instantaneous ground state initially a symmetric superposition of all possible assignments of N qubits-is closely tracked as it becomes more and more localized near the global minimum of the classical energy. Regions where the energy gap to excited states is small (for instance at the phase transition) are the algorithm's bottlenecks. Here I show how for large problems the complexity becomes dominated by O(log N) bottlenecks inside the spin-glass phase, where the gap scales as a stretched exponential. For smaller N, only the gap at the critical point is relevant, where it scales polynomially, as long as the phase transition is second order. This phenomenon is demonstrated rigorously for the two-pattern Gaussian Hopfield model. Qualitative comparison with the Sherrington-Kirkpatrick model leads to similar conclusions. PMID- 27491339 TI - Evolutionary Developmental Biology (Evo-Devo) Research in Latin America. AB - Famous for its blind cavefish and Darwin's finches, Latin America is home to some of the richest biodiversity hotspots of our planet. The Latin American fauna and flora inspired and captivated naturalists from the nineteenth and twentieth centuries, including such notable pioneers such as Fritz Muller, Florentino Ameghino, and Leon Croizat who made a significant contribution to the study of embryology and evolutionary thinking. But, what are the historical and present contributions of the Latin American scientific community to Evo-Devo? Here, we provide the first comprehensive overview of the Evo-Devo laboratories based in Latin America and describe current lines of research based on endemic species, focusing on body plans and patterning, systematics, physiology, computational modeling approaches, ecology, and domestication. Literature searches reveal that Evo-Devo in Latin America is still in its early days; while showing encouraging indicators of productivity, it has not stabilized yet, because it relies on few and sparsely distributed laboratories. Coping with the rapid changes in national scientific policies and contributing to solve social and health issues specific to each region are among the main challenges faced by Latin American researchers. The 2015 inaugural meeting of the Pan-American Society for Evolutionary Developmental Biology played a pivotal role in bringing together Latin American researchers eager to initiate and consolidate regional and worldwide collaborative networks. Such networks will undoubtedly advance research on the extremely high genetic and phenotypic biodiversity of Latin America, bound to be an almost infinite source of amazement and fascinating findings for the Evo-Devo community. PMID- 27491340 TI - The Association Between Sexual Health and Physical, Mental, and Social Health in Adolescent Women. AB - PURPOSE: Developmental models link sexual well-being to physical, mental/emotional, and social well-being, yet little empirical literature evaluates these relationships in adolescents. Better understanding of how and when sexuality complements other aspects of health may yield important points to enhance existing health education and prevention efforts. METHODS: Data were drawn from a 10-year longitudinal cohort study of sexual relationships and sexual behavior among adolescent women (N = 387; 14-17 years at enrollment). Sexual health data were drawn from quarterly partner-specific interviews and were linked to physical, mental/emotional, and social health information in annual questionnaires. Random intercept, mixed effects linear, ordinal logistic, or binary logistic regression were used to estimate the influence of sexual health on health and well-being outcomes (Stata, v.23, StataCorp, College Station, TX). All models controlled for participant age and race/ethnicity. RESULTS: Higher sexual health was significantly associated with less frequent nicotine and substance use, lower self-reported depression, lower thrill seeking, higher self esteem, having fewer friends who use substances, higher religiosity, better social integration, lower frequency of delinquent behavior and crime, and more frequent community group membership. Sexual health was not associated with the number of friends who used cigarettes. CONCLUSIONS: Positive sexually related experiences in romantic relationships during adolescence may complement physical, mental/emotional, and social health. Addressing specific aspects of healthy sexual development during clinical encounters could dually help primary prevention and health education address other common adolescent health issues. PMID- 27491341 TI - Rapid detection of European orthobunyaviruses by reverse transcription loop mediated isothermal amplification assays. AB - The development of reverse transcriptase loop-mediated isothermal amplification (RT-LAMP) assays are described herein for the detection of two orthobunyaviruses (Bunyaviridae), which represent the two main serogroups found in mosquitoes in Central Europe. The RT-LAMP assays were optimized for the detection of Tahyna virus (a California encephalitis group virus found in Aedes sp or Ochlerotatus sp mosquitoes) and Batai virus (also called Calovo virus, a Bunyamwera group virus found in Anopheles maculipennis s.l. mosquitoes) nucleic acid using endemic European virus isolates. The sensitivity of the RT-LAMP assays was determined to be comparable to that of conventional tests, with a limit of detection<0.1 pfu per reaction. The assays can be performed in 60min under isothermal conditions using very simple equipment. Furthermore, it was possible to proceed with the assays without nucleic acid extraction, albeit at a 100-fold loss of sensitivity. The RT-LAMP assays are a sensitive, cost-efficient method for both arbovirus surveillance as well as diagnostic laboratories to detect the presence of these endemic orthobunyaviruses. PMID- 27491342 TI - Prevalence of Plasmodium falciparum transmission reducing immunity among primary school children in a malaria moderate transmission region in Zimbabwe. AB - Malaria continues to cause alarming morbidity and mortality in more than 100 countries worldwide. Antigens in the various life cycle stages of malaria parasites are presented to the immune system during natural infection and it is widely recognized that after repeated malaria exposure, adults develop partially protective immunity. Specific antigens of natural immunity represent among the most important targets for the development of malaria vaccines. Immunity against the transmission stages of the malaria parasite represents an important approach to reduce malaria transmission and is believed to become an important tool for gradual elimination of malaria. Development of immunity against Plasmodium falciparum sexual stages was evaluated in primary school children aged 6-16 years in Makoni district of Zimbabwe, an area of low to modest malaria transmission. Malaria infection was screened by microscopy, rapid diagnostic tests and finally using nested PCR. Plasma samples were tested for antibodies against recombinant Pfs48/45 and Pfs47 by ELISA. Corresponding serum samples were used to test for P. falciparum transmission reducing activity in Anopheles stephensi and An. gambiae mosquitoes using the membrane feeding assay. The prevalence of malaria diagnosed by rapid diagnostic test kit (Paracheck)TM was 1.7%. However, of the randomly tested blood samples, 66% were positive by nested PCR. ELISA revealed prevalence (64% positivity at 1:500 dilution, in randomly selected 66 plasma samples) of antibodies against recombinant Pfs48/45 (mean A 405nm=0.53, CI=0.46-0.60) and Pfs47 (mean A405nm=0.91, CI=0.80-1.02); antigens specific to the sexual stages. The mosquito membrane feeding assay demonstrated measurable transmission reducing ability of the samples that were positive for Pfs48/45 antibodies by ELISA. Interestingly, 3 plasma samples revealed enhancement of infectivity of P. falciparum in An. stephensi mosquitoes. These studies revealed the presence of antibodies with transmission reducing immunity in school age children from a moderate transmission area of malaria, and provide further support to exploit target antigens such as Pfs48/45 for further development of a malaria transmission blocking vaccine. PMID- 27491344 TI - Acute effects of walking and combined exercise on oxidative stress and vascular function in peripheral artery disease. AB - The aim of this study was to compare the effects of a single session of walking and combined exercise on oxidative stress and vascular function in peripheral arterial disease patients. Thirteen patients with peripheral arterial disease underwent two experimental sessions in random order: walking (ten sets of 2-min walking at the speed corresponding to the onset of claudication pain with 2-min interval between sets) and combined exercise (1 * 10 reps in eight resistance exercises plus five-two-minute sets of walking). Before and after the exercise, vascular function (blood flow, leg vascular resistance and blood-flow postreactive hyperaemia) and oxidative stress (malondialdehyde and plasma nitrite levels) were obtained. Blood flow increased similarly after both sessions, whilst leg vascular resistance decreased similarly after both sessions. Plasma nitrite increased only after the combined exercise. Malondialdehyde decreased after both sessions, and the decrease was greater after combined exercise. As a conclusion, a single session of combined exercise improves blood flow and leg vascular resistance similarly to walking session; however, combined exercise promoted better effects on oxidative stress. PMID- 27491343 TI - Culicoides species composition and environmental factors influencing African horse sickness distribution at three sites in Namibia. AB - African horse sickness (AHS) is one of the most lethal infectious, non contagious, vector-borne disease of equids. The causative agent, African horse sickness virus (AHSV) is transmitted via Culicoides midges (Diptera: Ceratopogonidae). AHS is endemic to Namibia but detailed studies of Culicoides communities and influencing environmental parameters are limited. This study aims to determine the Culicoides species composition at three different sites and to assess environmental parameters influencing the geographical distribution of AHS in Namibia. Weekly collections of Culicoides were made during the AHS peak season from January to May for 2013 and 2014 using the Onderstepoort 220V UV-light trap. Out of 397 collections made, 124 collections (3287 Culicoides) were analysed for AHSV presence with RT-qPCR. A total of 295 collections were analysed for total Culicoides (all collected Culicoides individuals) and in 75% of these collections the Culicoides were identified to species level. C. imicola was the dominant species with proportional representation of 29.9%. C. subschultzei, C. exspectator and C. ravus each contribute more than 10% to the species composition. The lowest number of Culicoides was collected at Aus 9980, a total of 21819 at Windhoek and the highest number at Okahandja 47343. AHSV was present at all three sites during 2013 but only in Windhoek and Okahandja during 2014. Multivariate analyses of data from the two year survey indicate the environmental parameters in order of importance for the distribution of AHS in Namibia as precipitation>temperature>clay>relative humidity>NDVI. The implication of these findings is that any precipitation event increases Culicoides numbers significantly. Together with these results the high number of species found of which little is known regarding their vector competence, add to the complexity of the distribution of AHS in Namibia. PMID- 27491345 TI - In Vivo Imaging of Retinal Hypoxia in a Model of Oxygen-Induced Retinopathy. AB - Ischemia-induced hypoxia elicits retinal neovascularization and is a major component of several blinding retinopathies such as retinopathy of prematurity (ROP), diabetic retinopathy (DR) and retinal vein occlusion (RVO). Currently, noninvasive imaging techniques capable of detecting and monitoring retinal hypoxia in living systems do not exist. Such techniques would greatly clarify the role of hypoxia in experimental and human retinal neovascular pathogenesis. In this study, we developed and characterized HYPOX-4, a fluorescence-imaging probe capable of detecting retinal-hypoxia in living animals. HYPOX-4 dependent in vivo and ex vivo imaging of hypoxia was tested in a mouse model of oxygen-induced retinopathy (OIR). Predicted patterns of retinal hypoxia were imaged by HYPOX-4 dependent fluorescence activity in this animal model. In retinal cells and mouse retinal tissue, pimonidazole-adduct immunostaining confirmed the hypoxia selectivity of HYPOX-4. HYPOX-4 had no effect on retinal cell proliferation as indicated by BrdU assay and exhibited no acute toxicity in retinal tissue as indicated by TUNEL assay and electroretinography (ERG) analysis. Therefore, HYPOX 4 could potentially serve as the basis for in vivo fluorescence-based hypoxia imaging techniques, providing a tool for investigators to understand the pathogenesis of ischemic retinopathies and for physicians to address unmet clinical needs. PMID- 27491347 TI - Oil-in-Water Emulsions Stabilized by Carboxymethylated Lignins: Properties and Energy Prospects. AB - We take advantage of the amphiphilic properties of technical lignin macromolecules and their inherent high calorific values to formulate oil-in-water (O/W) fuel emulsions with high internal-phase ratios. For the oil phase, we used a combustible hydrocarbon (kerosene) with a measured equivalent alkane carbon number of 12. To adjust the balance of affinity with the oil and water phases and their surface activity, pine kraft lignins were carboxymethylated to different degrees, as quantified by (13) C NMR spectroscopy, potentiometric titrations, and zeta potential measurements. Carboxymethylated lignins (CMLs) with a degree of substitution of 30 % displayed a critical aggregation concentration of 3 %. The salinity and pH of the aqueous phase were chosen as formulation variables and adjusted within the Winsor framework. The O/W emulsions were produced by following standard protocols. The drop-size distributions of emulsions with varying pH, degree of substitution, and composition (water-to-oil ratio, WOR) were determined, and the long-term stabilities and rheological behavior of these emulsions were analyzed. Most of the obtained O/W fuel emulsions showed shear thinning behavior with a drop size of approximately 2.5 MUm and were stable for over 30 days. The combustion of the lignins and their respective emulsions was performed, and their higher heating values (HHVs) were quantified. The HHVs of CML and a high-internal-phase (WOR=30:70) O/W emulsion were 20 and 30 MJ kg(-1) , respectively. Overall, we propose the stabilization of O/W fuel emulsions by lignin as an important avenue in the utilization of this abundant biomacromolecule. PMID- 27491346 TI - Patient Perspectives Regarding Ethics of Spinal Column Stimulators in the Surgical Management of Persistent Postoperative Neuropathic Pain. AB - OBJECTIVE: The aim of this study is to better understand perspectives of patients with persistent postoperative neuropathic pain (PPNP) and assess perceptions of the ethical issues surrounding their structural spinal surgeon also performing spinal cord stimulation (SCS). METHODS: Semistructured face-to-face interviews with 20 neurosurgical spine patients were conducted. Patients were recruited from the neurosurgery clinics at Toronto Western Hospital and were seen in consultation for PPNP. Interviews were transcribed and subjected to thematic analysis using open and axial coding. RESULTS: The range of the duration of participants' preoperative symptoms varied from one month to more than 20 years, and was primarily back dominant (13/20). The median time since patients most recently underwent spinal surgery was three years. The majority of patients (15/20) do not view their current condition of PPNP as a failure of their initial spine surgeon. The most commonly reported reason for this is that patients trusted their physician and clear communication between the physician and the patient, prior to their surgery, ensured an understanding of the goals of the procedure. Nearly unanimously (19/20), patients did not perceive an ethical problem with a surgeon performing a structurally corrective spinal surgery and subsequently also implanting a SCS device if the same patient that develops medically refractory PPNP. CONCLUSIONS: This is the first clinical qualitative study of values and ethical perceptions of patients with medically refractory PPNP. Our findings provide a framework for understanding the values of patients with PPNP and demonstrate that a strong surgeon-patient relationship can ameliorate concerns surrounding PPNP and SCS implantation. PMID- 27491348 TI - Richter's Hernia After Laparoscopic Surgery. PMID- 27491350 TI - Ever HRD a ubiquitin-gated channel? AB - Elimination of misfolded proteins of the endoplasmic reticulum (ER) requires their retrotranslocation from the ER to the cytosol via membrane-bound ubiquitin ligase complexes. Baldridge and Rapoport now reconstitute a key step of retrotranslocation, demonstrating a protein conduit gated by ubiquitination. PMID- 27491349 TI - Synthesis of (18) F-Difluoromethylarenes from Aryl (Pseudo) Halides. AB - A general method for the synthesis of [(18) F]difluoromethylarenes from [(18) F]fluoride for radiopharmaceutical discovery is reported. The method is practical, operationally simple, tolerates a wide scope of functional groups, and enables the labeling of a variety of arenes and heteroarenes with radiochemical yields (RCYs, not decay-corrected) from 10 to 60 %. The (18) F-fluorination precursors are readily prepared from aryl chlorides, bromides, iodides, and triflates. Seven (18) F-difluoromethylarene drug analogues and radiopharmaceuticals including Claritin, fluoxetine (Prozac), and [(18) F]DAA1106 were synthesized to show the potential of the method for applications in PET radiopharmaceutical design. PMID- 27491351 TI - Reliability of immunocytochemistry and fluorescence in situ hybridization on fine needle aspiration cytology samples of breast cancers: methodological issues. PMID- 27491352 TI - Substituent effects of N4 Schiff base ligands on the formation of fluoride bridged dicobalt(ii) complexes via B-F abstraction: structures and magnetism. AB - We report the synthesis of two fluoride bridged cobalt(ii) dimers - [Co(MU F)(pnN4-PhCl)2(OH2)(MeCN)](BF4)3 (1) and [Co(MU-F)2(pnN4-PhCl)2](BF4)2 (2) - and related complexes derived from propyl-bridged N4 Schiff base plus pyridine ligands. Notably, the bridging fluoride ion(s) emanate from B-F abstraction processes on the BF4 anions in the starting salt, [Co(H2O)6](BF4)2. Two types of bridging motifs are generated - mono-bridged (MU-F) or di-bridged (MU-F)2- synthetically differentiated by the absence or presence of pyridine, respectively, during metalation. The synergistic roles of pyridine and the (ClPh)N4 ligand in promoting B-F abstraction were clarified by the isolation and crystallization of the simple tetrakis-pyridine monomeric complex [Co(py)4(MeCN)2](BF4)2 (4) [no B-F abstraction]; subsequent addition of the (ClPh)N4 ligand to 4 resulted in formation of the dimeric, di-bridged complex 2. Omission of pyridine during metalation resulted in formation of the mono-bridged dimer 1. The bulky chlorophenyl substituents were obligate for B-F abstraction, as metalation of the unsubstituted N4 ligand resulted in the non-fluoride-bridged dimer, [Co(pnN4)3](BF4)4 (3). In magnetic studies, complexes 1 (MUeff = 6.24MUB, 298 K) and 2 (MUeff = 7.70MUB, 298 K) both exhibit antiferromagnetic (AFM) coupling, but to different extents. Temperature-dependent magnetic susceptibility measurements (SQUID, 2 -> 300 K) reveal that the linearity of the mono-fluoride bridge in 1 [?Co-F-Co = 159.47(11) degrees ] results in very strong AFM coupling (J = -14.9 cm(-1)). In contrast, the more acute Co2F2 diamond core [?Co-F-Co = 98.8(2) degrees , 99.1(2) degrees ] results in a smaller extent of AFM coupling (J = -2.97 cm(-1)). Overall, the results indicate the 'non-innocence' of the BF4 counterion in cobalt(ii) chemistry, and dimers 1 and 2 affirm the effect of the geometry of the bridging fluoride ion(s) in determining the extent of AFM coupling. PMID- 27491353 TI - Laminin-111 Inhibits Bovine Fertilization but Improves Embryonic Development in vitro, and Receptor Integrin-beta1 is Involved in Sperm-Oocyte Binding. AB - This study detected the distribution of laminin during embryonic formation by immunofluorescence. To determine the possible function of laminin on developmental ability of in vitro fertilized embryos, the presumptive zygotes were divided and transferred to CR1aa medium supplemented with different concentrations (0 MUg/ml, 5 MUg/ml, 10 MUg/ml and 20 MUg/ml) of laminin. To explore the association with sperm-oocyte fusion, oocytes and/or sperm were pre incubated with laminin or anti-beta1 antibody before insemination. Laminin was absent in mature oocytes and could be detected first at the 8-cell stage and then displayed an increasing tendency. Adding 10 MUg/ml laminin to the culture medium improved embryonic development including cleavage rate, blastocyst rate, total cell numbers in the blastocyst and cell numbers in the inner cell mass. Laminin inhibited sperm-oocyte fusion when incubated with oocytes and/or sperm before in vitro fertilization, and only integrin-beta1 of sperm was involved in sperm oocyte binding. Inhibition may be caused by blocking beta1, but why laminin inhibits fertilization is still unknown. The results suggest that laminin plays an important role during embryonic formation and has a negative function in sperm oocyte fusion, but improves embryonic development. However, only integrin-beta1 is involved in sperm-oocyte binding. PMID- 27491354 TI - User survey finds rapid evidence reviews increased uptake of evidence by Veterans Health Administration leadership to inform fast-paced health-system decision making. AB - BACKGROUND: To provide evidence synthesis for faster-paced healthcare decision making, rapid reviews have emerged as a streamlined alternative to standard systematic reviews. In 2012, the Veterans Affairs Evidence-based Synthesis Program (VA ESP) added rapid reviews to support Veterans Health Administration (VHA) operational partners' more urgent decision-making needs. VHA operational partners play a substantial role in dissemination of ESP rapid reviews through a variety of routes, including posting on the VA ESP's public website ( http://www.hsrd. RESEARCH: va.gov/publications/esp/ ). As demand for rapid reviews rises, much progress has been made in characterizing methods and practices. However, evidence synthesis organizations still seek to better understand how and when rapid reviews are being used. METHODS: The VA ESP administered an online survey to rapid review operational partners. The survey assessed the nature of decision-making needs, overall perception of review content, resulting actions, and implementation timeframe. We use descriptive statistics and narrative methods to summarize findings. RESULTS: Between October 2011 and April 2015, we completed 12 rapid reviews for 35 operational partners. Operational partners were primarily non-academic subject matter experts with VA operations' decision-making authority. The most common topic categories reviewed were policy or system (50 %) or process of care (42 %) initiatives. Median report completion time was 14.5 weeks. Survey response rate was 46 %, with at least one operational partner responding for 92 % of reports. Reviews served multiple purposes including policy directive or regulation (72 %), supporting program development and evaluation (55 %), identifying future research needs (45 %), and determining implementation strategy (45 %). Overall, operational partners' perception of report content was positive. A majority of rapid reviews were used immediately and informed actions ranking high on the Institute of Medicine's Degrees of Impact framework: 45.4 % effected change, 18.2 % inspired action, 18.2 % informed the field, 9.1 % received recognition, and 9.1 % spread a message. CONCLUSIONS: VA ESP rapid reviews have increased the VHA's uptake of evidence to inform time-sensitive system-level decision-making. Key areas of interest for future evaluation include assessing user perception of our streamlined methods and the quality of our efforts to inform users of these methods, as well as comparing the usability and impact of our rapid and standard systematic reviews. PMID- 27491355 TI - A case of epidemic myalgia with symptoms resembling acute purulent spondylitis and discitis. AB - BACKGROUND: Epidemic myalgia is a disease that presents with fever and extreme myalgia of the trunk due to an acute enterovirus infection. The trunk pain is mainly in the chest or in the epigastrium. We aimed to highlight a case of epidemic myalgia where initial diagnosis needed differentiation from acute purulent spondylitis and discitis. CASE PRESENTATION: A 33-year-old woman presented with fever, chills, and acute episodes of low back pain. The sole unusual finding was pain upon spinal percussion, limited to the 4th and 5th lumbar vertebrae. Spinal MRI showed no abnormality. Paired serum samples from disease days 4 and 15 showed a significant increase in coxsackievirus B3 neutralizing antibodies. Based on this course, we diagnosed epidemic myalgia. CONCLUSIONS: Epidemic myalgia should be considered when differentiating acute low back pain accompanied by fever. PMID- 27491356 TI - Clinical application of whole-genome low-coverage next-generation sequencing to detect and characterize balanced chromosomal translocations. AB - Individuals carrying balanced translocations have a high risk of birth defects, recurrent spontaneous abortions and infertility. Thus, the detection and characterization of balanced translocations is important to reveal the genetic background of the carriers and to provide proper genetic counseling. Next generation sequencing (NGS), which has great advantages over other methods such as karyotyping and fluorescence in situ hybridization (FISH), has been used to detect disease-associated breakpoints. Herein, to evaluate the application of this technology to detect balanced translocations in the clinic, we performed a parental study for prenatal cases with unbalanced translocations. Eight candidate families with potential balanced translocations were investigated using two strategies in parallel, low-coverage whole-genome sequencing (WGS) followed-up by Sanger sequencing and G-banding karyotype coupled with FISH. G-banding analysis revealed three balanced translocations, and FISH detected two cryptic submicroscopic balanced translocations. Consistently, WGS detected five balanced translocations and mapped all the breakpoints by Sanger sequencing. Analysis of the breakpoints revealed that six genes were disrupted in the four apparently healthy carriers. In summary, our result suggested low-coverage WGS can detect balanced translocations reliably and can map breakpoints precisely compared with conventional procedures. WGS may replace cytogenetic methods in the diagnosis of balanced translocation carriers in the clinic. PMID- 27491357 TI - Controlled drug release to cancer cells from modular one-photon visible light responsive micellar system. AB - We present a one-photon visible light-responsive micellar system for efficient, on-demand delivery of small molecules. Release is mediated by a novel class of photochromic material - donor-acceptor Stenhouse adducts (DASAs). We demonstrate controlled delivery of small molecules such as the chemotherapeutic agent (paclitaxel) to human breast cancer cells triggered by micellar switching with low intensity, visible light. PMID- 27491358 TI - Open questions: what about the 'other' Rho GTPases? AB - Rho GTPases have many and diverse roles in cell physiology, and some family members are very well studied, including RhoA, Rac1 and Cdc42. But many are relatively neglected, and fundamental questions about their mechanisms and functions remain open. PMID- 27491359 TI - Repeatability of swept-source optical coherence tomography retinal and choroidal thickness measurements in neovascular age-related macular degeneration. AB - BACKGROUND: The aim was to determine the intrasession repeatability of swept source optical coherence tomography (SS-OCT)-derived retinal and choroidal thickness measurements in eyes with neovascular age-related macular degeneration (nAMD). METHODS: A prospective study consisting of patients with active nAMD enrolled in the Distance of Choroid Study at Moorfields Eye Hospital, London. Patients underwent three 12*9 mm macular raster scans using the deep range imaging (DRI) OCT-1 SS-OCT (Topcon) device in a single imaging session. Retinal and choroidal thicknesses were calculated for the ETDRS macular subfields. Repeatability was calculated according to methods described by Bland and Altman. RESULTS: 39 eyes of 39 patients with nAMD were included with a mean (+/-SD) age of 73.9 (+/-7.2) years. The mean (+/-SD) retinal thickness of the central macular subfield was 225.7 MUm (+/-12.4 MUm). The repeatability this subfield, expressed as a percentage of the mean central macular subfield thickness, was 23.2%. The percentage repeatability of the other macular subfields ranged from 13.2% to 28.7%. The intrasession coefficient of repeatability of choroidal thickness of the central macular subfield was 57.2 MUm with a mean choroidal thickness (+/-SD) of 181 MUm (+/-15.8 MUm). CONCLUSIONS: This study suggests that a change >23.2% of retinal thickness and 57.2 MUm choroidal thickness in the central macular subfield is required to distinguish true clinical change from measurement variability when using the DRI OCT-1 device to manage patients with nAMD. PMID- 27491360 TI - Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. AB - Stargardt disease (STGD1; MIM 248200) is the most prevalent inherited macular dystrophy and is associated with disease-causing sequence variants in the gene ABCA4 Significant advances have been made over the last 10 years in our understanding of both the clinical and molecular features of STGD1, and also the underlying pathophysiology, which has culminated in ongoing and planned human clinical trials of novel therapies. The aims of this review are to describe the detailed phenotypic and genotypic characteristics of the disease, conventional and novel imaging findings, current knowledge of animal models and pathogenesis, and the multiple avenues of intervention being explored. PMID- 27491362 TI - Synthesis of Breathing Metallopolymer Hollow Spheres for Redox-Controlled Release. AB - A convenient synthetic approach for the preparation of uniform metallopolymer containing hollow spheres based on 2-(methacryloyloxy)ethyl ferrocenecarboxylate (FcMA) as monomer by sequential starved feed emulsion polymerization is described. Core/shell particles consisting of a noncrosslinked poly(methyl methacrylate) core and a slightly crosslinked ferrocene-containing shell allows for the simple dissolution of core material and, thus, monodisperse metallopolymer hollow spheres are obtained. Since PFcMA is incorporated in the particle shell, herein investigated hollow spheres can be addressed by external triggers, i.e., solvent variation and redox chemistry in order to change the particle swelling capability. PFcMA-containing core/shell particles and hollow spheres are characterized by transmission electron microscope (TEM), scanning electron microscopy, cryogenic TEM, thermogravimetric analysis, and dynamic light scattering in terms of size, size distribution, hollow sphere character, redox responsiveness, and composition. Moreover, the general suitability of prepared stimulus-responsive nanocapsules for the use in catch-release systems is demonstrated by loading the nanocapsules with malachite green as model payload followed by release studies. PMID- 27491361 TI - Efficacy of night-time compression for breast cancer related lymphedema (LYNC): protocol for a multi-centre, randomized controlled efficacy trial. AB - BACKGROUND: Lymphedema is a prevalent long-term effect of breast cancer treatment that is associated with reduced quality of life. More recent observational data suggest that the addition of night-time compression to day-time use of a compression garment results in better long-term control of arm lymphedema. The primary objectives of the randomized controlled phase of the trial are to determine the efficacy of night-time compression on arm lymphedema volume maintenance and quality of life in breast cancer survivors who have completed intensive reduction treatment for their lymphedema. METHODS/DESIGN: The study will be a parallel 3-arm, multi-centre randomized fast-track trial. A total of 120 women with breast cancer related lymphedema will be recruited from 3 centres in Canada and randomized to group 1: Day-time compression garment alone or Group 2: Day-time compression garment + night-time compression bandaging or Group 3: Day-time compression garment + use of a night-time compression system garment. The duration of the primary intervention period will be 12 weeks. The follow-up period after the intervention (weeks 13 to 24) will follow a longitudinal observational design. The primary outcome variables: differences from baseline to week 12 in arm volume and quality of life (Lymphoedema Functioning, Disability and Health Questionnaire: Lymph-ICF). Secondary outcomes include bioimpedance analysis, sleep disturbance and self-efficacy. All measurements are standardized and will be performed prior to randomization, and at weeks 6, 12, 18 and 24. DISCUSSION: The use of night-time compression as a self-management strategy for chronic breast cancer related lymphedema is seen as an innovative approach to improve long-term control over the condition. This trial aims to advance the knowledge on self-management strategies for lymphedema. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov on July 9(th), 2014 ( NCT02187289 ). PMID- 27491363 TI - Seasonal and spatial variations of water quality and trophic status in Daya Bay, South China Sea. AB - Coastal water quality and trophic status are subject to intensive environmental stress induced by human activities and climate change. Quarterly cruises were conducted to identify environmental characteristics in Daya Bay in 2013. Water quality is spatially and temporally dynamic in the bay. Cluster analysis (CA) groups 12 monitoring stations into two clusters. Cluster I consists of stations (S1, S2, S4-S7, S9, and S12) located in the central, eastern, and southern parts of the bay, representing less polluted regions. Cluster II includes stations (S3, S8, S10, and S11) located in the western and northern parts of the bay, indicating the highly polluted regions receiving a high amount of wastewater and freshwater discharge. Principal component analysis (PCA) identified that water quality experience seasonal change (summer, winter, and spring-autumn seasons) because of two monsoons in the study area. Eutrophication in the bay is graded as high by Assessment of Estuarine Trophic Status (ASSETS). PMID- 27491364 TI - An integrative biomarker approach to assess the environmental stress in the north coast of Shandong Peninsula using native oysters, Crassostrea gigas. AB - An integrative biomarker approach was employed to evaluate the environmental quality of the north coast of Shandong Peninsula along the southern Bohai Sea of China, where pollution is an imminent threat due to rapid urbanization and industrialization. A battery of biomarkers and the metal bioaccumulation in tissues of native oyster Crassostrea gigas were measured under field conditions. Integrative biomarker index (IBR) and metal body burden were calculated to differentiate the pollution status of seven sampling sites. According to our results, Xinzhuang (XZ) site was the most severely contaminated, with the highest IBR value of 3.58, while the lowest IBR value (0.04) was obtained at Penglai (PL). Such an integrated biomarker approach was proved as a useful method for environmental quality assessment in the study area. PMID- 27491365 TI - Anthropogenic microfibres pollution in marine biota. A new and simple methodology to minimize airborne contamination. AB - Research studies on the effects of microlitter on marine biota have become more and more frequent the last few years. However, there is strong evidence that scientific results based on microlitter analyses can be biased by contamination from air transported fibres. This study demonstrates a low cost and easy to apply methodology to minimize the background contamination and thus to increase results validity. The contamination during the gastrointestinal content analysis of 400 fishes was tested for several sample processing steps of high risk airborne contamination (e.g. dissection, stereomicroscopic analysis, and chemical digestion treatment for microlitter extraction). It was demonstrated that, using our methodology based on hermetic enclosure devices, isolating the working areas during the various processing steps, airborne contamination reduced by 95.3%. The simplicity and low cost of this methodology provide the benefit that it could be applied not only to laboratory but also to field or on board work. PMID- 27491366 TI - Distribution and contamination of heavy metals in surface sediments of the Daya Bay and adjacent shelf, China. AB - Heavy metal (arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), lead (Pb), and zinc (Zn)) concentrations from the Daya Bay and adjacent shelf were determined to evaluate their levels and spatial distributions. The measured concentrations ranged from 1.94-13.67mg/kg for As, 0.03-0.13mg/kg for Cd, 10-85mg/kg for Cr, 1-39.5mg/kg for Cu, 0.01-0.09mg/kg for Hg, 11-56mg/kg for Pb, and 13-125mg/kg for Zn. The spatial distributions exhibited a gradual decrease from west to east, and the concentrations of the seven heavy metals met the China Marine Sediment Quality criteria. Both metal enrichment factor (EF) and geo-accumulation index (Igeo) values showed that Cd, Cr, Cu, Hg, and Zn were not at pollution levels in the region. Multivariate analysis (PCA) revealed that lithogenic factors dominated the distribution of most of the metals, whereas As and Hg were clearly influenced by anthropogenic input. PMID- 27491367 TI - A novel biomarker for marine environmental pollution of HSP90 from Mytilus coruscus. AB - Heat shock protein 90 (HSP90) is a conserved molecular chaperone contributing to cell cycle control, organism development and the proper regulation of cytosolic proteins. The full-length HSP90 cDNA of Mytilus coruscus (McHSP90, KT946644) was 2420bp, including an ORF of 2169bp encoding a polypeptide of 722 amino acids with predicted pI/MW 4.89/83.22kDa. BLASTp analysis and phylogenetic relationship strongly suggested McHSP90 was a member of HSP90 family, and it was highly conserved with other known HSP90, especially in the HSP90 family signatures, ATP/GTP-Binding sites and 'EEVD' motif. The mRNA of McHSP90 in haemolymph was upregulated in all treatments including Vibrio alginolyticus and Vibrio harveyi challenge, metals stresses (copper and cadmium) and 180 CST fuel exposure. All the results implied the expression of McHSP90 could be affected by Vibrio challenge and environmental stress, which might help us gain more insight into the molecular mechanism of HSP against adverse stresses in mollusca. PMID- 27491368 TI - Suspended micro-sized PVC particles impair the performance and decrease survival in the Asian green mussel Perna viridis. AB - Marine bivalves are known to ingest microplastics, but information on the consequences for their physiological performance is limited. To investigate a potential exposure pathway that has not yet been addressed, we mimicked the resuspension of microplastics from the sediment in a laboratory exposure experiment. For this, we exposed the Asian green mussel Perna viridis to 4 concentrations (0mg/l, 21.6mg/l, 216mg/l, 2160mg/l) of suspended polyvinylchloride (PVC) particles (1-50MUm) for two 2-hour-time-periods per day. After 44days, mussel filtration and respiration rates as well as byssus production were found to be a negative function of particle concentration. Furthermore, within 91days of exposure, mussel survival declined with increasing PVC abundance. These negative effects presumably go back to prolonged periods of valve closure as a reaction to particle presence. We suggest that microplastics constitute a new seston component that exerts a stress comparable to natural suspended solids. PMID- 27491369 TI - An unusual case of uterine cotyledonoid dissecting leiomyoma with adenomyosis. AB - BACKGROUND: Cotyledonoid dissecting leiomyoma is a rare variant of uterine smooth muscle tumor with an unusual growth pattern that shows intramural dissection within uterine myometrium and often a placenta-like appearance in its extrauterine components. CASE PRESENTATION: We present a unique case of cotyledonoid dissecting leiomyoma with adenomyosis. A 40-year-old Japanese female presented with prolonged menorrhagia and severe anemia. She had a pelvic mass followed-up for 6 years with a diagnosis of leiomyoma. However, increase in tumor size and cystic changes with hemorrhage were found by magnetic resonance imaging, and total abdominal hysterectomy with bilateral salpingectomy was performed. Macroscopically, the placenta-like exophytic mass protruding from the posterior uterine wall was composed of multiple nodules containing numerous hemorrhagic cysts. The mass showed continuity as a white multinodular dissecting mass infiltrating the posterolateral myometrium. Microscopically, both extra-and intrauterine portions of the mass were composed of nodules that contained swirled neoplastic smooth muscle cells with marked hyalinized degeneration, as observed in cotyledonoid dissecting leiomyomas of conventional type. In addition, numerous non-neoplastic glands of endometrial type surrounded by abundant endometrium-like stromal cells and non-neoplastic smooth muscle cells were found in the tumor, suggesting that it involved a part of concomitant adenomyosis originating from the nontumoral myometrium. CONCLUSIONS: Thus far, over 30 cases of cotyledonoid dissecting leiomyoma have been reported, none of which have described the presence of adenomyosis within the tumor. The present case suggested that cotyledonoid dissecting leiomyoma might have a unique clinical presentation involving concomitant uterine adenomyosis. It is critical for pathologists, gynecologists, and radiologists to be cognizant of cotyledonoid dissecting leiomyoma variants for timely and appropriate diagnosis and treatment. PMID- 27491370 TI - Search for a new economic optimum in the management of household waste in Tiaret city (western Algeria). AB - In household waste matters, the objective is always to conceive an optimal integrated system of management, where the terms 'optimal' and 'integrated' refer generally to a combination between the waste and the techniques of treatment, valorization and elimination, which often aim at the lowest possible cost. The management optimization of household waste using operational methodologies has not yet been applied in any Algerian district. We proposed an optimization of the valorization of household waste in Tiaret city in order to lower the total management cost. The methodology is modelled by non-linear mathematical equations using 28 variables of decision and aims to assign optimally the seven components of household waste (i.e. plastic, cardboard paper, glass, metals, textiles, organic matter and others) among four centres of treatment [i.e. waste to energy (WTE) or incineration, composting (CM), anaerobic digestion (ANB) or methanization and landfilling (LF)]. The analysis of the obtained results shows that the variation of total cost is mainly due to the assignment of waste among the treatment centres and that certain treatment cannot be applied to household waste in Tiaret city. On the other hand, certain techniques of valorization have been favoured by the optimization. In this work, four scenarios have been proposed to optimize the system cost, where the modelling shows that the mixed scenario (the three treatment centres CM, ANB, LF) suggests a better combination of technologies of waste treatment, with an optimal solution for the system (cost and profit). PMID- 27491371 TI - Exploring social and infrastructural factors affecting open burning of municipal solid waste (MSW) in Indian cities: A comparative case study of three neighborhoods of Delhi. AB - Open municipal solid waste (MSW)-burning is a major source of particulate matter emissions in developing world cities. Despite a legal ban, MSW-burning is observed ubiquitously in Indian cities with little being known about the factors shaping it. This study seeks to uncover social and infrastructural factors that affect MSW-burning at the neighborhood level. We couple physical assessments of the infrastructure provision and the MSW-burning incidences in three different neighborhoods of varying socio-economic status in Delhi, with an accompanying study of the social actors (interviews of waste handlers and households) to explore the extent to which, and potential reasons why, MSW-burning occurs. The observed differences in MSW-burning incidences range from 130 km-2 day-1 in low income to 30 km-2 day-1 in the high-income areas. However, two high-income areas neighborhoods with functional infrastructure service also showed statistical differences in MSW-burning incidences. Our interviews revealed that, while the waste handlers were aware of the health risks associated with MSW-burning, it was not a high priority in the context of the other difficulties they faced. The awareness of the legal ban on MSW-burning was low among both waste handlers and households. In addition to providing infrastructure for waste pickup, informal restrictions from residents and neighborhood associations can play a significant role in restricting MSW-burning at the neighborhood scale. A more efficient management of MSW requires a combined effort that involves interplay of both social and infrastructural systems. PMID- 27491372 TI - Optimizing emissions targets for residential recycling programmes: Why 'more' is not necessarily better with respect to diversion. AB - This study highlights the economic and environmental challenges of recycling in Ontario, specifically examining the effect of attempting to increase the emissions target for the province's household recycling programme. The findings from the cost model analysis found that Ontario's Blue Box programme reduces overall carbon emissions by approximately 1.8 million tonnes every year. This study also found that targeting specific materials for recovery could result in a scenario where the province could improve both overall diversion and emissions offsets while reducing material management costs. Under our modelled scenario, as the tonnes of greenhouse gases (GHGs) avoided increases, the system cost per tonne of GHG avoided initial declines. However, after avoiding 2.05 million tonnes of GHGs, the system cost/tonne GHG avoided increases. To achieve an emissions target in excess of 2.05 million tonnes, the province will have to start recycling higher cost non-core materials (composite materials, other plastics, etc.). PMID- 27491373 TI - Epidemiological characteristics and methodological quality of meta-analyses on diabetes mellitus treatment: a systematic review. AB - OBJECTIVE: Well-conducted meta-analyses (MAs) are considered as one of the best sources of clinical evidence for treatment decision. MA with methodological flaws may introduce bias and mislead evidence users. The aim of this study is to investigate the characteristics and methodological quality of MAs on diabetes mellitus (DM) treatments. DESIGN: Systematic review. METHODS: Cochrane Database of Systematic Review and Database of Abstract of Reviews of Effects were searched for relevant MAs. Assessing methodological quality of systematic reviews (AMSTAR) tool was used to evaluate the methodological quality of included MAs. Logistic regression analysis was used to identify association between characteristics of MA and AMSTAR results. RESULTS: A total of 252 MAs including 4999 primary studies and 13,577,025 patients were included. Over half of the MAs (65.1%) only included type 2 DM patients and 160 MAs (63.5%) focused on pharmacological treatments. About 89.7% MAs performed comprehensive literature search and 89.3% provided characteristics of included studies. Included MAs generally had poor performance on the remaining AMSTAR items, especially in assessing publication bias (39.3%), providing lists of studies (19.0%) and declaring source of support comprehensively (7.5%). Only 62.7% MAs mentioned about harm of interventions. MAs with corresponding author from Asia performed less well in providing MA protocol than those from Europe. CONCLUSIONS: Methodological quality of MA on DM treatments was unsatisfactory. There is considerable room for improvement, especially in assessing publication bias, providing lists of studies and declaring source of support comprehensively. Also, there is an urgent need for MA authors to report treatment harm comprehensively. PMID- 27491374 TI - Limited value for urinary 5-HIAA excretion as prognostic marker in gastrointestinal neuroendocrine tumours. AB - OBJECTIVE: To determine if urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion is of prognostic value for overall survival (OS) in patients with a gastrointestinal neuroendocrine tumour (NET) and to compare the prognostic value with patient characteristics, ENETS/WHO grading, ENETS TNM staging and biomarkers. DESIGN AND METHODS: Data was collected from patients with a gastrointestinal NET or a NET with gastrointestinal metastases and available 5 HIAA excretion in 24-h urine samples. Laboratory results were stratified for urinary 5-HIAA and chromogranin A (CgA): <2* upper limit of normal (ULN), 2-10* ULN, or >10* ULN. For neuron-specific enolase (NSE), this was the reference range or >1* ULN. OS was compared using Kaplan-Meier and log-rank tests, and hazard ratios were calculated using Cox regression for univariate and multivariate analyses. RESULTS: A total of 371 patients were included, 46.6% female with a mean age of 59.9 years. OS was shortest in patients with urinary 5-HIAA excretion >10* ULN vs reference range (median 83 months vs 141 months, P = 0.002). In univariate analysis, urinary 5-HIAA excretion >10* ULN was a negative predictor (HR 1.62, 95% CI: 1.09-2.39). However, in multivariate analysis, only age (HR 1.04, 95% CI: 1.01-1.08), grade 3 disease (HR 5.09, 95% CI: 2.20-11.79), NSE >1* ULN (HR 2.36, 95% CI: 1.34-4.14) and CgA >10* ULN (HR 3.61, 95% CI: 1.56-8.34) remained as the predictors. CONCLUSION: Urinary 5-HIAA excretion >10* ULN is a negative predictor for OS. However, when added to other biomarkers and grading, it is no longer a predictor for OS. Therefore, it should only be determined to assess carcinoid syndrome and not for prognostic value. PMID- 27491375 TI - Biomarkers of subclinical inflammation and increases in glycaemia, insulin resistance and beta-cell function in non-diabetic individuals: the Whitehall II study. AB - OBJECTIVE: Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional. DESIGN AND METHODS: We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers. RESULTS: Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin. CONCLUSIONS: Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function. PMID- 27491376 TI - Exploring the Interactions of the Dietary Plant Flavonoids Fisetin and Naringenin with G-Quadruplex and Duplex DNA, Showing Contrasting Binding Behavior: Spectroscopic and Molecular Modeling Approaches. AB - Guanine-rich sequences have the propensity to fold into a four-stranded DNA structure known as a G-quadruplex (G4). G4 forming sequences are abundant in the promoter region of several oncogenes and become a key target for anticancer drug binding. Here we have studied the interactions of two structurally similar dietary plant flavonoids fisetin and naringenin with G4 as well as double stranded (duplex) DNA by using different spectroscopic and modeling techniques. Our study demonstrates the differential binding ability of the two flavonoids with G4 and duplex DNA. Fisetin more strongly interacts with parallel G4 structure than duplex DNA, whereas naringenin shows stronger binding affinity to duplex rather than G4 DNA. Molecular docking results also corroborate our spectroscopic results, and it was found that both of the ligands are stacked externally in the G4 DNA structure. C-ring planarity of the flavonoid structure appears to be a crucial factor for preferential G4 DNA recognition of flavonoids. The goal of this study is to explore the critical effects of small differences in the structure of closely similar chemical classes of such small molecules (flavonoids) which lead to the contrasting binding properties with the two different forms of DNA. The resulting insights may be expected to facilitate the designing of the highly selective G4 DNA binders based on flavonoid scaffolds. PMID- 27491377 TI - Efficacy of zinc supplementation on serum calprotectin, inflammatory cytokines and outcome in neonatal sepsis - a randomized controlled trial. AB - OBJECTIVE: To find out the efficacy of zinc supplementation in decreasing the levels of serum calprotectin and inflammatory cytokines with improvement in outcome in neonatal sepsis. METHODS: Neonates with clinical signs suggestive of sepsis and at least two screening tests positive were randomized into two groups zinc group and control group. The zinc group received 3 mg/kg of zinc sulfate monohydrate twice a day orally for 10 days along with antibiotics. The control group received antibiotics and supportive care. Serum zinc, calprotectin, TNF alpha and IL-6 were estimated in serum at recruitment and 10 days later after completion of antibiotics. The babies were monitored daily till discharge and mortality rate was compared between the groups. RESULTS: Baseline characteristics were similar between the groups. Serum zinc levels were considerably increased in the zinc group after supplementation. There was significant decline in concentrations of serum calprotectin, TNF-alpha and IL-6 (p < 0.05) in the zinc group. In the control group also, serum calprotectin and IL-6 levels were found to be decreased significantly after antibiotic treatment (p < 0.05), while TNF alpha showed insignificant reduction. Kaplan-Meier analysis was performed to assess the survival time between the groups. The mortality was lower in the zinc group compared to the control group 5 versus 11, p= 0.12. CONCLUSION: Neonates with sepsis who received zinc in addition to antibiotics showed significant reduction in serum calprotectin and inflammatory cytokines. Although mortality was lower in zinc group, it was not statistically significant. PMID- 27491378 TI - Active recovery of the finger flexors enhances intermittent handgrip performance in rock climbers. AB - This study aimed to (1) evaluate the effect of hand shaking during recovery phases of intermittent testing on the time-force characteristics of performance and muscle oxygenation, and (2) assess inter-individual variability in the time to achieve the target force during intermittent testing in rock climbers. Twenty two participants undertook three finger flexor endurance tests at 60% of their maximal voluntary contraction until failure. Performances of a sustained contraction and two intermittent contractions, each with different recovery strategies, were analysed by time-force parameters and near-infrared spectroscopy. Recovery with shaking of the forearm beside the body led to a significantly greater intermittent test time (? 22%, P < .05), force-time integral (? 28%, P < .05) and faster muscle re-oxygenation (? 32%, P < .05), when compared to the hand over hold condition. Further, the ratio of intermittent to continuous test time distinguished specific aerobic muscular adaptations among sport climbers (2.02), boulderers (1.74) and lower grade climbers (1.25). Lower grade climbers and boulderers produced shorter duration contractions due to the slower development of target force during the intermittent test, indicating worse kinaesthetic differentiation. Both the type of recovery and climbing discipline determined muscle re-oxygenation and intermittent performance in rock climbers. PMID- 27491379 TI - Preparation and evaluation of novel hydrogel based on polysaccharide isolated from Bletilla striata. AB - Natural polysaccharides are highly valued and extensively applied in drug delivery system for their desirable physical properties and unique bioactivities. In this work, natural polysaccharides from Bletilla striata (BSP) were successfully extracted and incorporated with Carbopol 940 to prepare hydrogels. Rheological behavior, skin permeation properties and bioactivities of the BSP hydrogels were evaluated. The rheological test showed the better viscoelasticity and physical strength of BSP gels from Carbopol gel. The scanning laser confocal microscope (CLSM) and the trans-epidermal water loss (TEWL) examinations indicated that the BSP hydrogels significantly improved skin permeability. The improvement directly related with the BSP concentration in the gels. Atomic force microscope (AFM) examinations revealed that the BSP hydrogels modified the surface properties of corneocytes and resulted in the promotion effect. Furthermore, bioactivity evaluations indicated the hemostatic activates of BSP hydrogels. In conclusion, this work demonstrates the skin permeation enhancement and plasma coagulation effects of BSP hydrogels, which show great potential in transdermal drug delivery system and wound dressing. PMID- 27491380 TI - Phycobiliproteins: A Novel Green Tool from Marine Origin Blue-Green Algae and Red Algae. AB - Marine species are comprising about a half of the whole global biodiversity; the sea offers an enormous resource for novel bioactive compounds. Several of the marine origin species show multifunctional bioactivities and characteristics that are useful for a discovery and/or reinvention of biologically active compounds. For millennia, marine species that includes cyanobacteria (blue-green algae) and red algae have been targeted to explore their enormous potential candidature status along with a wider spectrum of novel applications in bio- and non-bio sectors of the modern world. Among them, cyanobacteria are photosynthetic prokaryotes, phylogenetically a primitive group of Gramnegative prokaryotes, ranging from Arctic to Antarctic regions, capable of carrying out photosynthesis and nitrogen fixation. In the recent decade, a great deal of research attention has been paid on the pronouncement of bio-functional proteins along with novel peptides, vitamins, fine chemicals, renewable fuel and bioactive compounds, e.g., phycobiliproteins from marine species, cyanobacteria and red algae. Interestingly, they are extensively commercialized for natural colorants in food and cosmetics, antimicrobial, antioxidant, anti-inflammatory, neuroprotective, hepatoprotective agents and fluorescent neo-glycoproteins as probes for single particle fluorescence imaging fluorescent applications in clinical and immunological analysis. However, a comprehensive knowledge and technological base for augmenting their commercial utilities are lacking. Therefore, this paper will provide an overview of the phycobiliproteins-based research literature from marine cyanobacteria and red algae. This review is also focused towards analyzing global and commercial activities with application oriented-based research. Towards the end, the information is also given on the potential biotechnological and biomedical applications of phycobiliproteins. PMID- 27491381 TI - Marine-Derived Bioactive Peptides for Biomedical Sectors: A Review. AB - Marine-based resources such as algae and other marine by-products have been recognized as rich sources of structurally diverse bioactive peptides. Evidently, their structural characteristics including unique amino acid residues are responsible for their biological activity. Several of the above-mentioned marine origin species show multi-functional bioactivities that are useful for a new discovery and/or reinvention of biologically active ingredients, nutraceuticals and/or pharmaceuticals. Therefore, in recent years, marine-derived bioactive peptides have gained a considerable attention with high-value biomedical and/or pharmaceutical potentials. Furthermore, a wider spectrum of bioactive peptides can be produced through proteolytic-assisted hydrolysis of various marine resources under controlled physicochemical (pH and temperature of the reaction media) environment. Owing to their numerous health-related beneficial effects and therapeutic potential in the treatment and/or prevention of many diseases, such marine-derived bioactive peptides exhibit a wider spectrum of biological activities such as anti-cancerous, anti-proliferative, anti-coagulant, antibacterial, antifungal, and anti-tumor activities among many others. Based on emerging evidence of marine-derived peptide mining, the above-mentioned marine resources contain noteworthy levels of high-value protein. The present review article mainly summarizes the marine-derived bioactive peptides and emphasizing their potential applications in biomedical and/or pharmaceutical sectors of the modern world. In conclusion, recent literature has provided evidence that marine derived bioactive peptides play a critical role in human health along with many possibilities of designing new functional nutraceuticals and/or pharmaceuticals to clarify potent mechanisms of action for a wider spectrum of diseases. PMID- 27491382 TI - Acupuncture for amnestic mild cognitive impairment: a meta-analysis of randomised controlled trials. AB - OBJECTIVE: Mild cognitive impairment (MCI) is a pre-dementia state; 5-10% of cases per year will evolve into dementia. MCI can be amnestic (AMCI) or non amnestic. AMCI is associated with a higher risk of progression. In recent years, interest in acupuncture as a potential treatment for AMCI has grown. The aim of this meta-analysis was to estimate the clinical effectiveness and safety of acupuncture for AMCI. METHODS: Randomised controlled trials (RCTs) of acupuncture versus medical treatment for AMCI were identified using the following databases from inception to July 2015: PubMed; Medline; CENTRAL; Chinese Scientific Journal Database; The Chinese Acupuncture Trials Register; China National Knowledge Infrastructure (CNKI); and Wanfang database. Data were extracted from RCTs meeting the inclusive criteria according to Cochrane methods. Meta-analyses were conducted using Rev Man V.5.3 software. RESULTS: Five trials involving 568 subjects were included. Meta-analysis showed that participants receiving acupuncture had better outcomes than those receiving nimodipine with greater clinical efficacy rates (odds ratio (OR) 1.78, 95% CI 1.19 to 2.65; p<0.01), mini mental state examination (MMSE) scores (mean difference (MD) 0.99, 95% CI 0.71 to 1.28; p<0.01), and picture recognition score (MD 2.12, 95% CI 1.48 to 2.75; p<0.01). Meta-analysis also showed acupuncture in conjunction with nimodipine significantly improved MMSE scores (MD 1.09, 95% CI 0.29 to 1.89; p<0.01) compared to nimodipine alone. Three trials reported adverse events. Methodological quality of the included studies was judged to be generally poor. CONCLUSIONS: Acupuncture appears effective for AMCI when used as an alternative or adjunctive treatment; however, caution must be exercised given the low methodological quality of included trials. Further, more rigorously designed studies are needed. PMID- 27491383 TI - Nociceptin/orphanin FQ receptor gene variation is associated with smoking status in Japanese. AB - AIM: The endogenous opioid system has been reportedly implicated in tobacco/nicotine dependence. MATERIALS & METHODS: We examined the genetic effects of eight SNPs in opioid receptor-related genes on smoking status and smoking related traits in Japanese. RESULTS: The genotypic and allelic variations of the rs2229205 SNP in the OPRL1 gene were significantly associated with smoking status, but no significant differences were found in the genetic variations of any of the SNPs with regard to smoking-related traits. The rs2229205 SNP did not show high linkage disequilibrium with the other SNPs in the linkage disequilibrium block that contained the SNP. CONCLUSION: The rs2229205 SNP in the OPRL1 gene may be a genetic factor that contributes to individual differences in the vulnerability to smoking in Japanese individuals. PMID- 27491384 TI - Newly arrived refugee children with Helicobacter pylori are thinner than their non-infected counterparts. AB - The hypothesis of this study was that those refugee children with Helicobacter pylori are thinner than their non-infected counterparts. This cross-sectional study investigated the height and weight of newly arrived refugee children up to age 19 years, who were screened for H. pylori using a stool antigen test at the Migrant Health Service in Adelaide between August 2010 and October 2013. Of 460 children, 21% were infected with H. pylori. After adjusting for vitamin B12 and iron levels, ethnicity, age and sex, the odds of being thin in the 10- to 19-year old age group was 4.28-fold higher (95% CI 1.48-12.4) if they were H. pylori positive compared with those who were H. pylori negative. The difference between the two groups is statistically significant (P=0.01). Screening and treatment for H. pylori in the general population in developed countries is not recommended unless there are symptoms such as dyspepsia or risk of peptic ulcer, duodenal ulcer or gastric cancer. Given the findings of this study, a recommendation could be made that newly arrived refugee children who are thin should be tested for H. pylori. Thinness in children may influence their cognitive ability, school performance, physical endurance and hence their ability to successfully settle into their new country. PMID- 27491385 TI - A multisite evaluation of summer camps for children with cancer and their siblings. AB - Summer camps for pediatric cancer patients and their families are ubiquitous. However, there is relatively little research, particularly studies including more than one camp, documenting outcomes associated with children's participation in summer camp. The current cross-sectional study used a standardized measure to examine the role of demographic, illness, and camp factors in predicting children's oncology camp-related outcomes. In total, 2,114 children at 19 camps participated. Campers were asked to complete the pediatric camp outcome measure, which assesses camp-specific self-esteem, emotional, physical, and social functioning. Campers reported high levels of emotional, physical, social, and self-esteem functioning. There were differences in functioning based on demographic and illness characteristics, including gender, whether campers/siblings were on or off active cancer treatment, age, and number of prior years attending camp. Results indicated that summer camps can be beneficial for pediatric oncology patients and their siblings, regardless of demographic factors (e.g., gender, treatment status) and camp factors (e.g., whether camp sessions included patients only, siblings only, or both). Future work could advance the oncology summer camp literature by examining other outcomes linked to summer camp attendance, using longitudinal designs, and including comparison groups. PMID- 27491386 TI - A large two-centre study in to rates of influenza and pneumococcal vaccination and infection burden in rheumatoid arthritis in the UK. AB - BACKGROUND: Infections are a common complication of RA with associated morbidity and mortality. The aetiology of increased risk is complex and multifactorial. Despite this, strategies to mitigate against risk of infection including vaccination are not always addressed in primary or secondary care with wide variation in practice from multiple small single centre audits. This study was a large two-centre survey of vaccine uptake in routine clinical practice and evaluated the relationship between vaccination and the burden of infection in RA patients. METHODS: A patient questionnaire was devised and disseminated through postal, clinic and phone survey at 2 UK rheumatology centres, detailing past vaccination history, reasons for non-vaccination, and history of recent infection. In a subset of patients, primary care vaccination data were also obtained. RESULTS: In total 929 patients responded to the survey. Over 85 % of patients were vaccinated against influenza, however only 44 % were vaccinated against pneumococcus. The vast majority of vaccination was undertaken in primary care. In the 12 months prior to the survey, 7.7 % of subjects recalled at least one episode of severe infection requiring admission, and nearly 40 % reported receiving at least one course of antibiotics. CONCLUSIONS: Infections are common in RA and Rheumatologists need to be adept at recognising at risk patients and managing them appropriately. Influenza vaccination uptake is good whilst pneumococcal vaccination rates are comparatively poor. Collaborative approaches between primary and secondary care are required to maximise vaccine uptake, which is safe and recommended in RA patients. PMID- 27491388 TI - Lung-specific RNA interference of coupling factor 6, a novel peptide, attenuates pulmonary arterial hypertension in rats. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive and life threatening disease associated with high morbidity and mortality rates. However, the exact regulatory mechanism of PAH is unknown. Although coupling factor 6 (CF6) is known to function as a repressor, its role in PAH has not been explored. Here, we investigated the involvement of endogenous CF6 in the development of PAH. METHODS: PAH was induced with monocrotaline (MCT), as demonstrated by significant increases in pulmonary artery pressure and vessel wall thickness. The adeno-associated virus (AAV) carrying CF6 short hairpin RNA (shRNA) or control vector (2*10(10) gp) was intratracheally transfected into the lungs of rats 2 weeks before or after MCT injection. RESULTS: A 2-6-fold increase in CF6 was observed in the lungs and circulation of the MCT-injected rats as confirmed by qRT-PCR and ELISA. Immunohistochemistry analysis revealed a small quantity of CF6 localized to endothelial cells (ECs) under physiological conditions spread to surrounding tissues in a paracrine manner in PAH lungs. Notably, CF6 shRNA effectively inhibited CF6 expression, abolished lung macrophage infiltration, reversed endothelial dysfunction and vascular remodeling, and ameliorated the severity of pulmonary hypertension and right ventricular dysfunction at 4 weeks both as a pretreatment and rescue intervention. In addition, the circulating and lung levels of 6-keto-PGF1a, a stable metabolite of prostacyclin, were reversed by CF6 inhibition, suggesting that the effect of CF6 inhibition may partly be mediated through prostacyclin. CONCLUSIONS: CF6 contributes to the pathogenesis of PAH, probably in association with downregulation of prostacyclin. The blockage of CF6 might be applied as a novel therapeutic approach for PAH and PA remodeling. PMID- 27491390 TI - The wizard behind the curtain: programmers as providers. AB - It is almost universally accepted that traditional provider-patient relationships should be governed, at least in part, by the ethical principles set forth by Beauchamp and Childress (Beauchamp and Childress, Principles of biomedical ethics, 1979). These principles include autonomy, beneficence, non-maleficence and justice (Beauchamp and Childress, Principles of biomedical ethics, 1979). Recently, however, the nature of medial practice has changed. The pervasive presence of computer technology in medicine raises interesting ethical questions. In this paper we argue that some software designers should be considered health care providers and thus be subject the ethical principles incumbent upon "traditional" providers. We argue that these ethical responsibilities should be applied explicitly rather than as a passive, implicit, set of guidelines. PMID- 27491387 TI - A practical community-based response strategy to interrupt Ebola transmission in sierra Leone, 2014-2015. AB - BACKGROUND: The Ebola virus disease spread rapidly in West Africa in 2014, leading to the loss of thousands of lives. Community engagement was one of the key strategies to interrupt Ebola transmission, and practical community level measures needed to be explored in the field and tailored to the specific context of communities. METHODS: First, community-level education on Ebola virus disease (EVD) prevention was launched for the community's social mobilizers in six districts in Sierra Leone beginning in November 2014. Then, from January to May of 2015, in three pilot communities, local trained community members were organized to engage in implementation of EVD prevention and transmission interruption measures, by involving them in alert case report, contact tracing, and social mobilization. The epidemiological indicators of transmission interruption in three study communities were evaluated. RESULTS: A total of 6 016 community social mobilizers from 185 wards were trained by holding 279 workshops in the six districts, and EVD message reached an estimated 631 680 residents. In three pilot communities, 72 EVD alert cases were reported, with 70.8 % of them detected by trained local community members, and 14 EVD cases were finally identified. Contact tracing detected 64.3 % of EVD cases. The median duration of community infectivity for the cases was 1 day. The secondary attack rate was 4.2 %, and no third generation of infection was triggered. No health worker was infected, and no unsafe burial and noncompliance to EVD control measures were recorded. The community-based measures were modeled to reduce 77 EVD cases, and the EVD-free goal was achieved four months earlier in study communities than whole country of Sierra Leone. CONCLUSIONS: The community-based strategy of social mobilization and community engagement was effective in case detection and reducing the extent of Ebola transmission in a country with weak health system. The successfully practical experience to reduce the risk of Ebola transmission in the community with poor resources would potentially be helpful for the global community to fight against the EVD and the other diseases in the future. PMID- 27491391 TI - All-optical transistor- and diode-action and logic gates based on anisotropic nonlinear responsive liquid crystal. AB - In this paper, we show that anisotropic photosensitive nematic liquid crystals (PNLC) made by incorporating anisotropic absorbing dyes are promising candidates for constructing all-optical elements by virtue of the extraordinarily large optical nonlinearity of the nematic host. In particular, we have demonstrated several room-temperature 'prototype' PNLC-based all-optical devices such as optical diode, optical transistor and all primary logic gate operations (OR, AND, NOT) based on such optical transistor. Owing to the anisotropic absorption property and the optical activity of the twist alignment nematic cell, spatially non-reciprocal transmission response can be obtained within a sizeable optical isolation region of ~210 mW. Exploiting the same mechanisms, a tri-terminal configuration as an all-optical analogue of a bipolar junction transistor is fabricated. Its ability to be switched by an optical field enables us to realize an all-optical transistor and demonstrate cascadability, signal fan-out, logic restoration, and various logical gate operations such as OR, AND and NOT. Due to the possibility of synthesizing anisotropic dyes and wide ranging choice of liquid crystals nonlinear optical mechanisms, these all-optical operations can be optimized to have much lower thresholds and faster response speeds. The demonstrated capabilities of these devices have shown great potential in all optical control system and photonic integrated circuits. PMID- 27491389 TI - Statin use and breast cancer survival: a nationwide cohort study in Scotland. AB - BACKGROUND: Preclinical evidence suggests that statins could delay cancer progression. Previous epidemiological findings have been inconsistent and some have been limited by small sample sizes, as well as certain time-related biases. This study aimed to investigate whether breast cancer patients who were exposed to statins had reduced breast cancer-specific mortality. METHODS: We conducted a retrospective cohort study of 15,140 newly diagnosed invasive breast cancer patients diagnosed from 2009 to 2012 within the Scottish Cancer Registry. Dispensed medication usage was obtained from linkages to the Scottish Prescribing Information System and breast cancer-specific deaths were identified from National Records of Scotland Death Records. Using time-dependent Cox regression models, hazard ratios (HR) and 95 % confidence intervals (CI) were calculated for the association between post-diagnostic exposure to statins (including simvastatin) and breast cancer-specific mortality. Adjustments were made for a range of potential confounders including age at diagnosis, year of diagnosis, cancer stage, grade, cancer treatments received, comorbidities, socioeconomic status and use of aspirin. RESULTS: A total of 1,190 breast cancer-specific deaths occurred up to January 2015. Overall, after adjustment for potential confounders, there was no evidence of an association between statin use and breast cancer-specific death (adjusted HR 0.93, 95 % CI 0.77, 1.12). No significant associations were observed in dose-response analyses or in analysis of all-cause mortality. For simvastatin use specifically, a weak non-significant reduction in breast cancer-specific mortality was observed compared to non-users (adjusted HR 0.89, 95 % CI 0.73, 1.08). Statin use before diagnosis was weakly associated with a reduction in breast cancer-specific mortality (adjusted HR 0.85, 95 % CI 0.74, 0.98). CONCLUSION: Overall, we found little evidence of a protective association between post-diagnostic statin use and cancer-specific mortality in a large nation-wide cohort of breast cancer patients. These findings will help inform the decision whether to conduct randomised controlled trials of statins as an adjuvant treatment in breast cancer. PMID- 27491392 TI - Self-assembled oxide films with tailored nanoscale ionic and electronic channels for controlled resistive switching. AB - Resistive switches are non-volatile memory cells based on nano-ionic redox processes that offer energy efficient device architectures and open pathways to neuromorphics and cognitive computing. However, channel formation typically requires an irreversible, not well controlled electroforming process, giving difficulty to independently control ionic and electronic properties. The device performance is also limited by the incomplete understanding of the underlying mechanisms. Here, we report a novel memristive model material system based on self-assembled Sm-doped CeO2 and SrTiO3 films that allow the separate tailoring of nanoscale ionic and electronic channels at high density (~10(12) inch(-2)). We systematically show that these devices allow precise engineering of the resistance states, thus enabling large on-off ratios and high reproducibility. The tunable structure presents an ideal platform to explore ionic and electronic mechanisms and we expect a wide potential impact also on other nascent technologies, ranging from ionic gating to micro-solid oxide fuel cells and neuromorphics. PMID- 27491394 TI - Self-assembled half-sandwich polyhedral cages via flexible Schiff-base ligands: an unusual macrocycle-to-cage conversion. AB - An edge-directed strategy was adopted to construct highly ordered polyhedral structures using flexible functions. Half-sandwich M6(L1)4 octahedral and M8(L2)4 cubic cages have been assembled by flexible Schiff-base ligands upon coordination to Cp*Rh(iii) organometallic acceptors. In particular, the rearrangement from a Rh(iii)-based half-sandwich M2(HL1)2 macrocycle to M6(L1)4 cage was found to occur in a solution. PMID- 27491393 TI - Global Expressions Landscape of NAC Transcription Factor Family and Their Responses to Abiotic Stresses in Citrullus lanatus. AB - Watermelon (Citrullus lanatus) is one xerophyte that has relative higher tolerance to drought and salt stresses as well as more sensitivity to cold stress, compared with most model plants. These characteristics facilitate it a potential model crop for researches on salt, drought or cold tolerance. In this study, a genome-wide comprehensive analysis of the ClNAC transcription factor (TF) family was carried out for the first time, to investigate their transcriptional profiles and potential functions in response to these abiotic stresses. The expression profiling analysis reveals that several NAC TFs are highly responsive to abiotic stresses and development, for instance, subfamily IV NACs may play roles in maintaining water status under drought or salt conditions, as well as water and metabolites conduction and translocation toward fruit. In contrast, rapid and negative responses of most of the ClNACs to low-temperature adversity may be related to the sensitivity to cold stress. Crosstalks among these abiotic stresses and hormone (abscisic acid and jasmonic acid) pathways were also discussed based on the expression of ClNAC genes. Our results will provide useful insights for the functional mining of NAC family in watermelon, as well as into the mechanisms underlying abiotic tolerance in other cash crops. PMID- 27491395 TI - Chiral recognition at self-assembled multivalent (SAMul) nanoscale interfaces - enantioselectivity in polyanion binding. AB - Self-assembled multivalent (SAMul) ligands based on palmitic acid functionalised with cationic l/d-lysine bind polyanionic heparin or DNA with no chiral preference. Inserting a glycine spacer unit switches on chiral discrimination - a rare example of controlled chiral recognition at a SAMul nanoscale interface. PMID- 27491398 TI - Electrocatalytic Efficiency Analysis of Catechol Molecules for NADH Oxidation during Nanoparticle Collision. AB - Electrocatalysis of molecules is a hot research topic in biological and energy related chemistry. Here, we develop a new system to study the electrocatalytic efficiency of a single catechol molecule for NADH oxidation by single functionalized nanoparticle collision at ultramicroelectrodes (UMEs). The proposed system is composed of gold nanoparticles (AuNPs) functionalized with catechol molecules and a carbon-fiber ultramicroelectrode. In the absence of NADH, when a functionalized AuNP collides with an UME at a suitable voltage, a small current spike is generated due to the oxidation of catechol molecules modified on the surface of AuNP. In the presence of NADH, the current spike is significantly amplified by the combined effects of the oxidation and electrocatalysis for NADH of catechol molecules. By analyzing the variations of the average peak charges and durations without or with NADH, we calculate that around five thousands NADH molecules could be catalyzed per second by a single catechol molecule, suggesting the successful establishment of this novel catalytic system. Thus, the proposed strategy could be used as a promising platform for research of other molecular electrocatalytic systems. PMID- 27491396 TI - Risk Score for Predicting Treatment-Requiring Retinopathy of Prematurity (ROP) in the Telemedicine Approaches to Evaluating Acute-Phase ROP Study. AB - PURPOSE: To develop a risk score for predicting treatment-requiring retinopathy of prematurity (TR-ROP) in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) study. DESIGN: Second analyses of an observational cohort study. PARTICIPANTS: Infants with birth weight (BW) <1251 g who had >=1 imaging session by 34 weeks of postmenstrual age (PMA) and >=1 subsequent retinopathy of prematurity (ROP) examination for determining TR-ROP by study-certified ophthalmologists. METHODS: Nonphysician trained readers evaluated wide-field retinal image sets for characteristics of ROP, pre-plus/plus disease, and retinal hemorrhage. Risk score points for predicting TR-ROP were derived from the regression coefficients of significant predictors in a multivariate logistic regression model. MAIN OUTCOME MEASURES: TR-ROP. RESULTS: Eighty-five of 771 infants (11.0%) developed TR-ROP. In a multivariate model, significant predictors for TR-ROP were gestational age (GA) (odds ratio [OR], 5.7; 95% confidence interval [CI], 1.7-18.9 for <=25 vs. >=28 weeks), need for respiratory support (OR, 7.0; 95% CI, 1.3-37.1 for high-frequency oscillatory ventilation vs. no respiratory support), slow weight gain (OR, 2.4; 95% CI, 1.2-4.6 for weight gain <=12 g/day vs. >15 g/day), and image findings at the first image session including number of quadrants with pre-plus (OR, 3.8; 95% CI, 1.5-9.7 for 4 pre plus quadrants vs. no pre-plus), stage and zone of ROP (OR, 4.7; 95% CI, 2.1-11.8 for stage 1-2 zone I, OR, 5.9; 95% CI, 2.1-16.6 for stage 3 zone I vs. no ROP), and presence of blot hemorrhage (OR, 3.1; 95% CI, 1.4-6.7). Image findings predicted TR-ROP better than GA (area under receiver operating characteristic curve [AUC] = 0.82 vs. 0.75, P = 0.03). The risk of TR-ROP steadily increased with higher risk score and predicted TR-ROP well (AUC = 0.88; 95% CI, 0.85-0.92). Risk score >=3 points for predicting TR-ROP had a sensitivity of 98.8%, specificity of 40.1%, and positive and negative predictive values of 17.0% and 99.6%, respectively. CONCLUSIONS: Image characteristics at 34 PMA weeks or earlier independently predict TR-ROP. If externally validated in other infants, risk score, calculated from image findings, GA, weight gain, and respiratory support, enables early identification of infants in need of increased surveillance for TR-ROP. PMID- 27491397 TI - Characterization of Chorioretinopathy Associated with Mitochondrial Trifunctional Protein Disorders: Long-Term Follow-up of 21 Cases. AB - PURPOSE: To assess long-term effects of genotype on chorioretinopathy severity in patients with mitochondrial trifunctional protein (MTP) disorders. DESIGN: Retrospective case series. PARTICIPANTS: Consecutive patients with MTP disorders evaluated at a single center from 1994 through 2015, including 18 patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and 3 patients with trifunctional protein deficiency (TFPD). METHODS: Local records from all visits were reviewed. Every participant underwent a complete ophthalmic examination and was evaluated by a metabolic physician and dietitian. Nine patients underwent ancillary funduscopic imaging including optical coherence tomography (OCT) and OCT angiography. MAIN OUTCOME MEASURES: The primary outcome measure was best-corrected visual acuity at the final visit. Secondary outcome measures included spherical equivalent refraction, visual fields, electroretinography B-wave amplitudes, and qualitative imaging findings. RESULTS: Participants were followed up for a median of 5.6 years (range 0.3-20.2 years). The median age of LCHADD participants at initial and final visits was 2.3 and 11.9 years, whereas that for TFPD participants at initial and final visits was 4.7 and 15.5 years, respectively. Four long-term survivors older than 16 years were included (3 with LCHADD and 1 with TFPD). The LCHADD participants demonstrated a steady decline in visual acuity from an average of 0.23 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/34) at baseline to 0.42 logMAR (Snellen equivalent, 20/53) at the final visit, whereas TFPD patients maintained excellent acuity throughout follow-up. Participants with LCHADD, but not TFPD, showed an increasing myopia with a mean decrease in spherical equivalent refraction of 0.24 diopters per year. Visual fields showed sensitivity losses centrally associated with defects on OCT. Multimodal imaging demonstrated progressive atrophy of the outer retina in LCHADD, often preceded by the formation of outer retinal tubulations and choriocapillaris dropout. Electroretinography findings support the more severe clinical profile of LCHADD patients compared with TFPD patients; the function of both rods and cones are attenuated diffusely in LCHADD patients, but are within normal limits for TFPD patients. CONCLUSIONS: Despite improved survival with early diagnosis, medical management, and dietary treatment, participants with the LCHADD subtype of MTP disorder continue to demonstrate visually disabling chorioretinopathy. Multimodal imaging is most consistent with choriocapillaris loss exceeding photoreceptor loss. PMID- 27491399 TI - The synergy and mode of action of quercetin plus amoxicillin against amoxicillin resistant Staphylococcus epidermidis. AB - BACKGROUND: Staphylococcus epidermidis is one of the most multiple resistances to antibiotics in the recent years. Therefore, practically-prescribed antibiotics in the treatment of these strains are not effective. Plant-derived antibacterial is one of the most interesting sources of new therapeutics. The present study was to investigate antibacterial, synergy and modes of action of quercetin and amoxicillin against amoxicillin-resistant Staphylococcus epidermidis (ARSE). METHODS: The MICs, checkerboard assay, viability curves, cytoplasmic membrane (CM) permeability, enzyme assay, transmission electron microscopy, confocal microscopy and FT-IR microspectroscopy measurement was performed. RESULTS: The MICs of amoxicillin, penicillin, quercetin and kaempferol against all ARSE strains were 16, 200, 256-384 and >1024 MUg/mL respectively. Synergistic effects were exhibited on amoxicillin plus quercetin and penicillin plus kaempferol against these strains at FIC index 0.50 and <0.38 respectively. The synergistic activity of quercetin plus amoxicillin was confirmed by the viable count. This combination increased CM permeability, caused marked morphological, peptidoglycan and cytoplasmic membrane damage, increased protein amide I and II, but decreased fatty acid in bacterial cells. The quercetin had an inhibitory activity against beta-lactamase. CONCLUSIONS: So, these findings are the first report that quercetin has the synergistic effect with amoxicillin against ARSE via four modes of actions, inhibit peptidoglycan synthesis and beta-lactamases activity, increase CM permeability and protein amide I and II but decrease fatty acid in bacterial cells. Of course, this flavonol has the dominant potential to develop a brand-new collateral phytochemical agent plus amoxicillin to treat ARSE. Future work should focus on the bioavailability, efficacy and toxicity in animal and human studies, as well as, the synergistic effect on blood and tissue should be evaluated and achieved. PMID- 27491400 TI - A locking compression plate as an external fixator for treating infected nonunion of the humeral diaphysis. AB - BACKGROUND: Infected nonunion of the humeral diaphysis is a challenging problem for orthopedic surgeons. This study aimed to evaluate the outcome of using a locking compression plate (LCP) as a definitive external fixator in the management of infected nonunion of the humeral diaphysis after failure of internal fixation. METHODS: We retrospectively reviewed a series of seven patients with infected nonunion of the humeral diaphysis treated with an LCP as an external fixator between June 2010 and August 2014. There were five males and two females, with an average age of 40.9 years. Six out of seven patients had been definitively diagnosed with infection due to known bacteria by germiculture. The clinical and radiographic outcomes were retrospectively evaluated. RESULTS: All patients were followed-up for a mean period of 26.3 months (range 12-48 months). All fractures obtained complete bone union, and the average time to bone union was 7.9 months (range 3.5-15 months). All infections were eventually resolved without any recurrence of deep infection. Pin tract infection was only seen in one case. Only one patient had transient radial nerve palsy after surgery for traction. The average shortening length of the affected upper limb was 3 cm (range 2-4 cm) compared with the contralateral limb. At the last follow-up, the average Disabilities of the Arm, Shoulder and Hand score of the involved limbs was 3.2 (range 0-13.4). All patients obtained excellent or good functional results, and returned to their original work. CONCLUSIONS: The novel use of an LCP as a definitive external fixator was an effective method for treating infected nonunion of the humeral diaphysis. However, a large-scale prospective clinical study is still needed to verify these findings. PMID- 27491401 TI - Collective dynamics of identical phase oscillators with high-order coupling. AB - In this paper, we propose a framework to investigate the collective dynamics in ensembles of globally coupled phase oscillators when higher-order modes dominate the coupling. The spatiotemporal properties of the attractors in various regions of parameter space are analyzed. Furthermore, a detailed linear stability analysis proves that the stationary symmetric distribution is only neutrally stable in the marginal regime which stems from the generalized time-reversal symmetry. Moreover, the critical parameters of the transition among various regimes are determined analytically by both the Ott-Antonsen method and linear stability analysis, the transient dynamics are further revealed in terms of the characteristic curves method. Finally, for the more general initial condition the symmetric dynamics could be reduced to a rigorous three-dimensional manifold which shows that the neutrally stable chaos could also occur in this model for particular parameters. Our theoretical analysis and numerical results are consistent with each other, which can help us understand the dynamical properties in general systems with higher-order harmonics couplings. PMID- 27491402 TI - EGFR and EML4-ALK Updated Therapies in Non-Small Cell Lung Cancer. AB - BACKGROUND: Non-small cell lung cancer is the leading cancer-related cause of death. OBJECTIVE: We review the latest therapies for NSCLC with EGFR and ELM4-ALK mutations as well as the most relevant studies and promising patents. METHOD: A literature search of PubMed database was carried out to identify recent Clinical Trials using EGFR therapies and novel patents involving diagnosis and therapies on NSCLC. We conducted a search to find new therapy strategies, new biomarkers, and selected five patents we find relevant. RESULTS: Over the last few years, identification of cancer harboring epidermal growth factor receptor mutations (EGFR) or chromosomal rearrangements of anaplastic lymphoma kinase (ALK) led to new ways in classifying and treating NSCLC. On the other hand, acquired resistance are a constantly challenge in the management of patients with these mutations and new drugs options are in development to improve and amplify treatment strategies. CONCLUSIONS: Currently, EGFR TKIs (e.g.: erlotinib, gefitinib, osimertinib) and ALK inhibitors (crizotinib, ceritinib, alectinib) provided a new face for advanced NSCLC outcomes. To understand the disease molecular profile is mandatory to define the best approach for each patient. PMID- 27491403 TI - Cactus thorn detection using bedside ultrasound. PMID- 27491404 TI - An Assessment of the Results of European Parliament Elections in Greece and European Union Under the Shadow of Economic Crisis. AB - On January 1, 1981, Greece became the tenth member of the European Economic Community and, 20 years later, on January 1, 2001, joined the euro area. In May of 2010 and February of 2012, Greece signed the first and the second economic adjustment programs and adopted austerity policies throughout the public sector in order to avoid the economic collapse, affecting residents' income and health status. We studied the questionnaires of polls conducted in Greece before the elections of the European Parliament (May 25, 2014) and the "Europeans 2014" Eurobarometer's survey in March of 2014. The responses of Greek voters from the Greek polls were alarming, pointing out their declining personal economic situation and Greece's national economic situation, with a sense that the country was heading in the wrong direction, declaring themselves unsatisfied and insecure. The responses of Greek voters from the "Europeans 2014" survey were even more alarming. Health was the first priority for the voters. As the Greek polls and the Eurobarometer's survey forecasted, but more significantly as the results of the Euro-elections showed, Greek voters preferred to put their hopes in something new. PMID- 27491405 TI - Novel Use of a Pneumatic Compression Device for Haemostasis of Haemodialysis Fistula Access Catheterisation Sites. AB - PURPOSE: Transradial pneumatic compression devices can be used to achieve haemostasis following radial artery puncture. This article describes a novel technique for acquiring haemostasis of arterio-venous haemodialysis fistula access sites without the need for suture placement using one such compression device. MATERIALS AND METHODS: A retrospective review of fistulograms with or without angioplasty/thrombectomy in a single institution was performed. 20 procedures performed on 12 patients who underwent percutaneous intervention of failing or thrombosed arterio-venous fistulas (AVF) had 27 puncture sites. Haemostasis was achieved using a pneumatic compression device at all access sites. Procedure details including size of access sheath, heparin administration and complications were recorded. RESULTS: Two diagnostic fistulograms, 14 fistulograms and angioplasties and four thrombectomies were performed via access sheaths with an average size (+/-SD) of 6 Fr (+/-1.12). IV unfractionated heparin was administered in 11 of 20 procedures. Haemostasis was achieved in 26 of 27 access sites following 15-20 min of compression using the pneumatic compression device. One case experienced limited bleeding from an inflow access site that was successfully treated with reinflation of the device for a further 5 min. No other complication was recorded. CONCLUSIONS: Haemostasis of arterio-venous haemodialysis fistula access sites can be safely and effectively achieved using a pneumatic compression device. This is a technically simple, safe and sutureless technique for acquiring haemostasis after AVF intervention. PMID- 27491406 TI - Phase I/II Multi-Institutional Study of Percutaneous Radiofrequency Ablation for Painful Osteoid Osteoma (JIVROSG-0704). AB - PURPOSE: This multicenter prospective study was conducted to evaluate the safety and efficacy of percutaneous radiofrequency ablation (RFA) for painful osteoid osteoma (OO). MATERIALS AND METHODS: Patients with OO (femur: n = 17, tibia: n = 2, humerus: n = 1, rib: n = 1) were enrolled and treated with RFA. In phase I, nine patients were evaluated for safety. In phase II, 12 patients were accrued, and an intent-to-treat analysis was performed on all patients. The primary endpoint was to evaluate the treatment safety. The secondary endpoint was to evaluate the efficacy for pain relief by the visual analogue scale (VAS) at 4 weeks after RFA. Treatment efficacy was classified as significantly effective (SE) when VAS score decreased by >=5 or score was <2, moderately effective when VAS score decreased by <5->=2 and score was >=2, and not effective (NE) when VAS score decreased by <2 or score was increased. Cases where the need for analgesics increased after treatment were also NE. RESULTS: RFA procedures were completed in all patients. Minor adverse effects (AEs) were observed as 4.8-14.3 % in 12 patients, and no major AEs were observed. Mean VAS score was 7.1 before treatment, 1.6 at 1 week, 0.3 at 4 weeks, and 0.2 at 3 months. All procedures were classified as SE. Pain recurrence was not noted in any patient during follow up (mean: 15.1 months). CONCLUSION: RFA is a safe, highly effective, and fast acting treatment for painful extraspinal OO. Future studies with a greater number of patients are needed. PMID- 27491407 TI - Visualization of precut DSAEK and pre-stripped DMEK donor corneas by intraoperative optical coherence tomography using the RESCAN 700. AB - BACKGROUND: To report the feasibility of intraoperative spectral domain optical coherence tomography (OCT) using the RESCAN 700 for the visualization and evaluation of precut Descemet's stripping automated endothelial keratoplasty (DSAEK) and prestripped Descemet's membrane endothelial keratoplasty (DMEK) donor tissue. METHODS: Precut DSAEK (n = 11), prestripped DMEK (n = 4) preserved in a viewing chamber were examined by intraoperative OCT. Wholly intact donor corneas for penetrating keratoplasty (PK) (n = 8) were also examined as controls. The obtained images were analyzed qualitatively for characteristics of each type of donor. RESULTS: For each type of donor, characteristic images were consistently obtained by intraoperative OCT in both the front and back views through the viewing chamber. In wholly intact donors for PK, appearance of normal corneal curvature and stromal texture with high reflectivity of epithelium and endothelium cell layers were clearly visualized. In precut DSAEK donors, precut lines were characteristically visualized in addition to the intact donor cornea images. In prestripped DMEK donors, identical OCT images to the intact donor cornea were noted when observed from the anterior surface. However, peripheral partial detachments of Descemet's membrane were characteristically observed in all prestripped DMEK donors when viewed from the back of the viewing chamber. CONCLUSION: Rapid visualization and rough evaluation of donor tissues for PK, precut DSAEK and prestripped DMEK donor corneas by intraoperative OCT was consistently possible through the viewing chamber. Therefore, this device may be used as an alternative of AS-OCT when the eyebank does not have their own AS-OCT. Although the peripheral detachment in DMEK donors are quite common and clinically non-problematic in DMEK donor quality and subsequent DMEK surgeries, it may be useful to distinguish between wholly intact PK donors and prestripped DMEK donors, enabling to prevent mix-ups of donors, especially when several different types of keratoplasties are scheduled in a same day in one operating theater. PMID- 27491409 TI - Two-photon excited fluorescence of intrinsic fluorophores enables label-free assessment of adipose tissue function. AB - Current methods for evaluating adipose tissue function are destructive or have low spatial resolution. These limit our ability to assess dynamic changes and heterogeneous responses that occur in healthy or diseased subjects, or during treatment. Here, we demonstrate that intrinsic two-photon excited fluorescence enables functional imaging of adipocyte metabolism with subcellular resolution. Steady-state and time-resolved fluorescence from intracellular metabolic co factors and lipid droplets can distinguish the functional states of excised white, brown, and cold-induced beige fat. Similar optical changes are identified when white and brown fat are assessed in vivo. Therefore, these studies establish the potential of non-invasive, high resolution, endogenous contrast, two-photon imaging to identify distinct adipose tissue types, monitor their functional state, and characterize heterogeneity of induced responses. PMID- 27491410 TI - The p90 ribosomal S6 kinase 2 specifically affects mitotic progression by regulating the basal level, distribution and stability of mitotic spindles. AB - RSK2, also known as RPS6KA3 (ribosomal protein S6 kinase, 90 kDa, polypeptide 3), is a downstream kinase of the mitogen-activated protein kinase (MAPK) pathway, which is important in regulating survival, transcription, growth and proliferation. However, its biological role in mitotic progression is not well understood. In this study, we examined the potential involvement of RSK2 in the regulation of mitotic progression. Interestingly, depletion of RSK2, but not RSK1, caused the accumulation of mitotic cells. Time-lapse analysis revealed that mitotic duration, particularly the duration for metaphase-to-anaphase transition was prolonged in RSK2-depleted cells, suggesting activation of spindle assembly checkpoint (SAC). Indeed, more BubR1 (Bub1-related kinase) was present on metaphase plate kinetochores in RSK2-depleted cells, and depletion of BubR1 abolished the mitotic accumulation caused by RSK2 depletion, confirming BubR1 dependent SAC activation. Along with the shortening of inter-kinetochore distance, these data suggested that weakening of the tension across sister kinetochores by RSK2 depletion led to the activation of SAC. To test this, we analyzed the RSK2 effects on the stability of kinetochore-microtubule interactions, and found that RSK2-depleted cells formed less kinetochore microtubule fibers. Moreover, RSK2 depletion resulted in the decrease of basal level of microtubule as well as an irregular distribution of mitotic spindles, which might lead to observed several mitotic progression defects such as increase in unaligned chromosomes, defects in chromosome congression and a decrease in pole-to-pole distance in these cells. Taken together, our data reveal that RSK2 affects mitotic progression by regulating the distribution, basal level and the stability of mitotic spindles. PMID- 27491411 TI - Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy. AB - Nephronophthisis-related ciliopathy (NPHP-RC) is a common genetic cause of end stage renal failure during childhood and adolescence and exhibits an autosomal recessive pattern of inheritance. Genetic diagnosis is quite limited owing to genetic heterogeneity in NPHP-RC. We designed a novel approach involving the step wise screening of Sanger sequencing and targeted exome sequencing for the genetic diagnosis of 55 patients with NPHP-RC. First, five NPHP-RC genes were analyzed by Sanger sequencing in phenotypically classified patients. Known pathogenic mutations were identified in 12 patients (21.8%); homozygous deletions of NPHP1 in 4 juvenile nephronophthisis patients, IQCB1/NPHP5 mutations in 3 Senior-Loken syndrome patients, a CEP290/NPHP6 mutation in 1 Joubert syndrome patient, and TMEM67/MKS3 mutations in 4 Joubert syndrome patients with liver involvement. In the remaining undiagnosed patients, we applied targeted exome sequencing of 34 ciliopathy-related genes to detect known pathogenic mutations in 7 (16.3%) of 43 patients. Another 18 likely damaging heterozygous variants were identified in 13 NPHP-RC genes in 18 patients. In this study, we report a variety of pathogenic and candidate mutations identified in 55 patients with NPHP-RC in Korea using a step-wise application of two genetic tests. These results support the clinical utility of targeted exome sequencing to resolve the issue of allelic and genetic heterogeneity in NPHP-RC. PMID- 27491412 TI - Cardiovascular autonomic alterations in hospitalized patients with community acquired pneumonia. AB - BACKGROUND: Alterations of cardiac autonomic control (CAC) are associated with poor outcomes in patients with infectious and non-infectious diseases. No evaluation of CAC in patients with community-acquired pneumonia (CAP) has been performed so far. The aim of the study was to assess CAC in patients with CAP and evaluate the impact of its alterations on disease severity and clinical outcomes in a multicenter, prospective, observational study. METHODS: Consecutive patients hospitalized for CAP were enrolled between 2011 and 2013 two university hospitals in Italy. CAC was assessed by linear spectral and non-linear symbolic analysis of heart rate variability. The presence of severe CAP was evaluated on hospital admission. The primary study outcome was time to clinical stability (TCS) during hospitalization. RESULTS: Among the 75 patients enrolled (median age: 75 years; 57 % males), a significantly lower total variability and reduction of sympathetic rhythmical component with predominant respiratory modulation was detected in comparison to controls. Among CAP patients affected by a severe CAP on admission, CAC showed a lower sympathetic modulation and predominant parasympathetic oscillatory rhythm. At the multivariate analysis, variables independently correlated with a TCS >7 days were total power, as marker of total variability, [OR (95 % CI): 0.997 (0.994-1.000), p = 0.0454] and sympathetic modulation [OR (95 % CI): 0.964 (0.932-0.998), p = 0.0367]. CONCLUSIONS: Loss of sympathetic rhythmical oscillation is associated with a more severe disease and worse early clinical outcome in hospitalized patients with CAP. PMID- 27491413 TI - Multi-parametric surface plasmon resonance platform for studying liposome-serum interactions and protein corona formation. AB - When nanocarriers are administered into the blood circulation, a complex biomolecular layer known as the "protein corona" associates with their surface. Although the drivers of corona formation are not known, it is widely accepted that this layer mediates biological interactions of the nanocarrier with its surroundings. Label-free optical methods can be used to study protein corona formation without interfering with its dynamics. We demonstrate the proof-of concept for a multi-parametric surface plasmon resonance (MP-SPR) technique in monitoring the formation of a protein corona on surface-immobilized liposomes subjected to flowing 100 % human serum. We observed the formation of formulation dependent "hard" and "soft" coronas with distinct refractive indices, layer thicknesses, and surface mass densities. MP-SPR was also employed to determine the affinity (K D ) of a complement system molecule (C3b) with cationic liposomes with and without polyethylene glycol. Tendency to create a thick corona correlated with a higher affinity of opsonin C3b for the surface. The label-free platform provides a fast and robust preclinical tool for tuning nanocarrier surface architecture and composition to control protein corona formation. PMID- 27491414 TI - Lipopolysaccharide suppresses human immunodeficiency virus 1 reverse transcription in macrophages. AB - HIV-1-infected macrophages are long-lived and act as human immunodeficiency virus 1 (HIV-1) virus reservoirs. Lipopolysaccharide (LPS) has been demonstrated to suppress HIV-1 replication in macrophages, but the mechanism is not clear. Previous research suggested that downregulation of CD4 and CCR5 as well as blockage of the interaction of HIV-1 with cells are major causes of inhibition of HIV-1 replication in macrophages by LPS. In order to study whether LPS blocks the post-entry event of HIV-1 replication, we developed a macrophage HIV-1 infection model by using VSV-G pseudotyped HIV-1-luciferase virus to infect THP-1 differentiated macrophage-like cells. We found that LPS can suppress HIV-1 replication at post-entry steps. Further study suggested that HIV-1 reverse transcription was blocked by LPS, but addition of exogenous deoxyribonucleosides led to only partial recovery of HIV-1 replication. However, the inhibition of pro inflammatory pathway completely rescued HIV-1 replication. Thus, our study shows that LPS can suppress the events of HIV-1 replication post-entry, including reverse transcription, and this restriction is mediated by more than one mechanism. PMID- 27491415 TI - Morphological and physiological differences between dehiscent and indehiscent anthers of Chrysanthemum morifolium. AB - Spray cut chrysanthemums ornamental value and vase life are rapidly reduced with an increase in the pollen dispersal of the middle tubular bisexual flowers, and excessive pollen grains floating in the air are usually harmful to people. Thus, two cultivars were selected: the dehiscent 'Qx-097' and the indehiscent 'Qx-007', to investigate the morphological, structural and physiological differences in anthers. (1) Prior to the opening of the tubular flower, the anther was completely dehisced, and the pollen grains of 'Qx-097' were then released. 'Qx 007' inflorescences showed no pollen dispersal, and this cultivar was therefore not contaminated by its own pollen grains during flowering. (2) The anther cell structure of 'Qx-007' was abnormal, such that the entire anther wall exhibited hypertrophy due to the non-selective thickening of the endothecium cell size in different areas. Moreover, cracks did not form in the 'Qx-007' anther due to failure of septum degradation and stomium breakage, which resulted in the anther locules being inwardly crushed. Besides, the indehiscent anther accompanies partial pollen abortion due to the impairment of tapetum development, this is not conducive to pollen dispersal. (3) The 'Qx-007' anther contained higher water levels compared with 'Qx-097', and the dehydration of the 'Qx-007' anther was relatively moderate. Furthermore, the 'Qx-007' anther exhibited higher Ca2+ and Mg2+ levels compared with 'Qx-097' during dehiscing periods. (4) The 'Qx-007' anther showed significantly lower jasmonic acid levels and higher indole-3-acetic acid levels compare with the 'Qx-097' anther. These results suggest that the endothecium, septum and stomium constituent of the anther structure exhibit developmental abnormalities, which likely serve as the cellular basis of anther indehiscence. In addition, anther dehydration, the enhancement of anther cell toughness due to a high level of ions, and JA (IAA) dysregulation may be the determining physiological factors of anther indehiscence. PMID- 27491416 TI - Cross-Cultural Perspectives on Parent-Adolescent Discrepancies: Existing Findings and Future Directions. AB - As summarized in this commentary, the first generation of cross-informant agreement research focused on perceptions of child and adolescent mental health. Contributions of this research include demonstrating that modest cross-informant agreement is a very robust phenomenon, utilizing numerous statistical approaches to measure degree of agreement, and identifying many factors that moderate agreement. An important focus of this work has been using multi-society international comparisons to examine cross-cultural similarities and differences in cross-informant agreement. The articles in this Special Issue represent a significant paradigm shift in which cross-informant agreement is examined as an independent variable predicting a wide variety of outcomes. Furthermore, moving beyond perceptions of adolescent mental health, these articles compare parent and adolescent perceptions of diverse aspects of family functioning (e.g., family conflict, parent-adolescent communication, family relationships, parental authority). Additionally, the research presented in this Special Issue employs innovative and sophisticated statistical techniques. Although the Special Issue represents some first steps toward considering cross-cultural aspects of perceptions of family functioning, much work still needs to be done in this area. Some suggestions for future research strategies to accomplish this goal conclude this commentary. PMID- 27491417 TI - Evaluation of environmental quality of two estuaries in Ilha do Maranhao, Brazil, using histological and genotoxic biomarkers in Centropomus undecimalis (Pisces, Centropomidae). AB - Estuaries are subjected to continual environmental impacts from activities in the catchment areas. This research assessed the quality of two estuarine habitats located in Ilha do Maranhao, Brazil, through histological and genotoxic biomarkers in Centropomus undecimalis, comparing the data obtained to metal, physical, and chemical concentrations of water samples. The gill histological alterations were analyzed by the histological alteration index and genotoxic lesions in erythrocytes were detected by the Micronucleus Test. The analysis of metals revealed that all water samples contained at least two elements with concentrations higher than that allowed by the current Brazilian law. For gill histological analysis, snook of both areas assessed exhibited moderate lesions, indicating that the local fish are affected by environmental stress. Micronucleus analysis of snook showed that the Bacanga river basin is the most affected. In addition to assessing the health of commercial fish populations, the information about the biomarkers used for the species can serve to contribute to the preparation and/or application of health assessment models and implementation of environmental recovery policies for coastal aquatic environments. PMID- 27491418 TI - Valorisation of tuna processing waste biomass for recovery of functional and antioxidant peptides using enzymatic hydrolysis and membrane fractionation process. AB - The enzymatic hydrolysis using Prolyve BS coupled to membrane process (Ultrafiltration (UF) and nanofiltration (NF)) is a means of biotransformation of tuna protein waste to Tuna protein hydrolysate (TPH) with higher added values. This method could be an effective solution for the production of bioactive compounds used in various biotechnological applications and minimizing the pollution problems generated by the seafood processing industries. The amino acid composition, functional and antioxidant properties of produced TPH were evaluated. The results show that the glutamic acid, aspartic acid, glycine, alaline, valine and leucine were the major amino acids detected in the TPH profile. After membrane fractionation process, those major amino acids were concentrated in the NF retentate (NFR). The NFR and NF permeate (NFP) have a higher protein solubility (>95 %) when compared to TPH (80 %). Higher oil and water binding capacity were observed in TPH and higher emulsifying and foam stability was found in UF retentate. The NFP showed the highest DPPH radical scavenging activity (65 %). The NFR contained antioxidant amino acid (30.3 %) showed the highest superoxide radical and reducing power activities. The TPH showed the highest iron chelating activity (75 %) compared to other peptide fractions. The effect of the membrane fractionation on the molecular weight distribution of the peptide and their bioactivities was underlined. We concluded that the TPH is a valuable source of bioactive peptides and their peptide fractions may serve as useful ingredients for application in food industry and formulation of nutritional products. PMID- 27491419 TI - Potential ecological and human health risks of heavy metals in surface soils associated with iron ore mining in Pahang, Malaysia. AB - The composition of heavy metals (and metalloid) in surface soils of iron ore mine impacted areas has been evaluated of their potential ecological and human health risks. The mining areas included seven selected locations in the vicinity of active and abandoned iron ore-mining sites in Pahang, Malaysia. Heavy metals such as Fe, Mn, Cu, Zn, Co, Pb, Cr, Ni, and Cd and metalloid As were present in the mining soils of the studied area, while Cu was found exceeding the soil guideline value at all sampling locations. However, the assessment of the potential ecological risk index (RI) indicated low ecological risk (RI between 44 and 128) with respect to Cd, Pb, Cu, As, Zn, Co, and Ni in the surface soils. Contributions of potential ecological risk [Formula: see text]by metal elements to the total potential ecological RI were evident for Cd, As, Pb, and Cu. Contribution of Cu appears to be consistently greater in the abandoned mining area compared to active iron ore-mining site. For non-carcinogenic risk, no significant potential health risk was found to both children and adults as the hazard indices (HIs) were all below than 1. The lifetime cancer risk (LCR) indicated that As has greater potential carcinogenic risk compared to other metals that may induce carcinogenic effects such as Pb, Cr, and Cd, while the LCR of As for children fell within tolerable range for regulatory purposes. Irrespective of carcinogenic or non-carcinogenic risk, greater potential health risk was found among children (by an order of magnitude higher for most metals) compared to adults. The hazard quotient (HQ) and cancer risk indicated that the pathways for the risk to occur were found to be in the order of ingestion > dermal > inhalation. Overall, findings showed that some metals and metalloid were still present at comparable concentrations even long after cessation of the iron ore-mining activities. PMID- 27491420 TI - Assessment of polybrominated diphenyl ethers in sediment of Asunle stream of the Obafemi Awolowo University, Ile-Ife, Nigeria. AB - Assessment of levels of polybrominated diphenyl ethers (PBDEs) from the sediment of Asunle stream, an adjourning stream of the Obafemi Awolowo University dumpsite, has been carried out. Sediment samples were collected from the stream at six locations for a period of 8 months, composed of 4 months each of wet (May Aug) and dry (Nov-Feb) seasons. Soxhlet extraction was employed for the isolation of all the target compounds from the sediment samples. Extracts were further subjected to multi-layer column chromatography employing different forms of silica gel. The prepared samples were analyzed using GC-MS. The overall mean concentrations of the total PBDEs ranged from 1.80 to 9.46 ng/g. The results showed that the concentrations of the PBDEs were slightly higher during the wet season than those during the dry season. In all the studied locations, BDE28, BDE47, BDE99, BDE100, BDE153, and BDE154 were detected in all the sediment samples at concentrations that ranged from 0.73 to 10.43 ng/g. Results of this study indicated that BDE153 was the major pollutant of the Asunle stream sediments. PMID- 27491421 TI - Physiological and biochemical mechanisms of spermine-induced cadmium stress tolerance in mung bean (Vigna radiata L.) seedlings. AB - The role of exogenous spermine (0.25 mM Spm, a type of polyamine (PA) in reducing Cd uptake and alleviating Cd toxicity (containing 1 and 1.5 mM CdCl2 in the growing media) effects was studied in the mung bean (Vigna radiata L. cv. BARI Mung-2) plant. Exogenously applied Spm reduced Cd content, accumulation, and translocation in different plant parts. Increasing phytochelatin content, exogenous Spm reduced Cd accumulation and translocation. Spm application reduced the Cd-induced oxidative damage which was reflected from the reduction of H2O2 content, O2*- generation rate, lipoxygenase (LOX) activity, and lipid peroxidation level and also reflected from the reduction of spots of H2O2 and O2* from mung bean leaves (compared to control treatment). Spm pretreatment increased non-enzymatic antioxidant contents (ascorbate, AsA, and glutathione, GSH) and activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), and glutathione reductase (GR) which reduced oxidative stress. The cytotoxicity of methylglyoxal (MG) is also reduced by exogenous Spm because it enhanced glyoxalase system enzymes and components. Through osmoregulation, Spm maintained a better water status of Cd-affected mung bean seedlings. Spm prevented the chl damage and increased its content. Exogenous Spm also modulated the endogenous free PAs level which might have the roles in improving physiological processes including antioxidant capacity, osmoregulation, and Cd and MG detoxification capacity. The overall Spm-induced tolerance of mung bean seedlings to Cd toxicity was reflected through improved growth of mung bean seedlings. PMID- 27491422 TI - Combination of biochar amendment and phytoremediation for hydrocarbon removal in petroleum-contaminated soil. AB - Remediation of soils contaminated with petroleum is a challenging task. Four different bioremediation strategies, including natural attenuation, biochar amendment, phytoremediation with ryegrass, and a combination of biochar and ryegrass, were investigated with greenhouse pot experiments over a 90-day period. The results showed that planting ryegrass in soil can significantly improve the removal rate of total petroleum hydrocarbons (TPHs) and the number of microorganisms. Within TPHs, the removal rate of total n-alkanes (45.83 %) was higher than that of polycyclic aromatic hydrocarbons (30.34 %). The amendment of biochar did not result in significant improvement of TPH removal. In contrast, it showed a clear negative impact on the growth of ryegrass and the removal of TPHs by ryegrass. The removal rate of TPHs was significantly lower after the amendment of biochar. The results indicated that planting ryegrass is an effective remediation strategy, while the amendment of biochar may not be suitable for the phytoremediation of soil contaminated with petroleum hydrocarbons. PMID- 27491423 TI - Use of the Modified Checklist for Autism, Revised with Follow Up-Albanian to Screen for ASD in Albania. AB - The Modified Checklist for Autism in Toddlers Revised-Albanian screener (M-CHAT-R A) was used to screen 2594 toddlers, aged 16-30 months, at well-child visits. Two hundred fifty-three (9.75 %) screened positive; follow up on failed items were conducted by phone with 127 (50 %); the remainder were lost to follow-up. Twenty six toddlers (21 %) continued to screen positive; 19 received full evaluations, which assessed for ASD with the Autism Diagnostic Observation Schedule and developmental delays with the Parents Assessment of Developmental Status Developmental Milestones. All evaluated children had significant delays; 17 of the 19 met criteria for Autism/ASD. Removal of three items improved performance. Although Albania and the US are quite different in culture and language, key features of ASD appeared very similar. PMID- 27491425 TI - ? PMID- 27491424 TI - Bone Density in Adolescents and Young Adults with Autism Spectrum Disorders. AB - Patients with autism spectrum disorder (ASD) are at increased risk for fracture, and peri-pubertal boys with ASD have lower bone mineral density (BMD) than controls. Data are lacking regarding BMD in older adolescents with ASD. We compared BMD using dual-energy X-ray absorptiometry in 9 adolescents/young adults with ASD against 9 typically developing matched controls. Patients with ASD and controls were excluded if they had other underlying conditions that may affect bone. Compared to controls, patients with ASD had (i) lower femoral neck and hip BMD Z-scores, and (ii) lower spine, femoral neck and hip height adjusted BMD Z scores even after controlling for BMI. Understanding the underlying pathophysiology will be key to developing therapies to improve BMD and reduce fracture risk. PMID- 27491426 TI - Systematic review of ixabepilone for treating metastatic breast cancer. AB - BACKGROUND: Ixabepilone is now a Food and Drug Administration-approved therapeutic option for patients with metastatic breast cancer (MBC) whose disease has progressed despite prior anthracycline and taxane therapy. We conducted a systematic review and meta-analysis to systematically evaluate the efficacy and safety of ixabepilone for treating metastatic breast cancer. METHODS: A systematic review and meta-analysis were conducted. Randomized controlled studies applying ixabepilone for treating MBC were included. The primary outcome was Overall Survival (OS). The authors of primary articles were contacted and methodological quality was evaluated. Subgroups were drawn based on intervention measures; heterogeneity and bias were discussed. RESULTS: Eight studies with 5247 patients were included. Compared with a weekly schedule, a triweekly schedule of ixabepilone was better at improving overall response rate (ORR), while there were no differences in improving OS and progression-free survival (PFS). Ixabepilone plus capecitabine was superior to capecitabine monotherapy in improving OS, PFS and ORR. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. There was no difference in the improvement of ORR, clinical benefit rate (CBR) and disease control rate (DCR) between ixabepilone and eribulin. CONCLUSIONS: Current evidence suggests that a triweekly schedule of ixabepilone is more effective than weekly dosing in improving ORR. Use of ixabepilone in combination with capecitabine possesses superior clinical efficacy to the use of capecitabine alone. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. The efficacy and safety between ixabepilone and eribulin were identical. PMID- 27491427 TI - Implementation of a post-arrest care team: understanding the nuances of a team based intervention. AB - BACKGROUND: Despite advances in the management of sudden cardiac arrest, mortality for patients admitted to hospital is still greater than 50 %. Lack of familiarity and experience with post-cardiac arrest patients and lack of interdisciplinary collaboration between emergency and ICU staff have been highlighted as potential barriers to optimal care. To address these barriers, a specialized Post Arrest Consult Team (PACT) was implemented at two urban academic centers. Our objective was to describe the PACT implementation from the participant perspective in order to explore potentially mitigating factors on effectiveness of the intervention and inform other institutions who may be considering a similar approach. METHODS: Using an ethnographic style approach, we collected data throughout the implementation period using both key informant interviews and non-participant observation. The data were analyzed using interpretive descriptive analysis techniques. RESULTS: The PACT intervention was taken up differently in each of the two participating institutions. Participants spoke about the difficulty in maintaining a dynamic interaction between the team members and a shared sense of purpose, the challenge of off-service consulting and the impact of the lack of data feedback to support whether the project was effecting change. CONCLUSIONS: It appears that purposefully creating a "sense of team," the team composition and organizational culture and provision of performance feedback are important facilitators to ensuring uptake of a team based intervention like the PACT model. Reporting of the intervention design and actual implementation experience like we have done here is crucial to allow readers to judge the quality of the study, to properly replicate it, and to contemplate how various factors may influence the outcome of a complex intervention. PMID- 27491430 TI - Quasisolitons in self-diffusive excitable systems, or Why asymmetric diffusivity obeys the Second Law. AB - Solitons, defined as nonlinear waves which can reflect from boundaries or transmit through each other, are found in conservative, fully integrable systems. Similar phenomena, dubbed quasi-solitons, have been observed also in dissipative, "excitable" systems, either at finely tuned parameters (near a bifurcation) or in systems with cross-diffusion. Here we demonstrate that quasi-solitons can be robustly observed in excitable systems with excitable kinetics and with self diffusion only. This includes quasi-solitons of fixed shape (like KdV solitons) or envelope quasi-solitons (like NLS solitons). This can happen in systems with more than two components, and can be explained by effective cross-diffusion, which emerges via adiabatic elimination of a fast but diffusing component. We describe here a reduction procedure can be used for the search of complicated wave regimes in multi-component, stiff systems by studying simplified, soft systems. PMID- 27491429 TI - Radiation exposure of the spleen during (177)Lu-DOTATATE treatment and its correlation with haematological toxicity and spleen volume. AB - BACKGROUND: Somatostatin analogue-based radionuclide therapy with (177)Lu DOTATATE is an important treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. In addition to the kidneys, the bone marrow is a major dose-limiting organ. The correlation between developed haematological toxicity and absorbed dose to the bone marrow is poor, which indicates that other factors affect haematological response. The spleen has an important role in the haematopoetic system, including being a reservoir for blood cells. It is also the organ that receives the highest mean absorbed dose during (177)Lu-DOTATATE treatment. The aim of this study was to analyse mean absorbed dose to the spleen and its correlation with haematological toxicity, and to explore changes in splenic volume. The study included 41 patients treated with 7.2 GBq (3.5-8.3 GBq) of (177)Lu-DOTATATE on two to five occasions. Following each fraction, planar whole-body scans were acquired at 2, 24, 48, and 168 h, and a SPECT/CT at 24 h post-injection. Mean absorbed spleen dose was calculated utilising planar images for time-activity data and SPECT to adjust activity amounts. Splenic volume information was collected from diagnostic CT scans at baseline and follow-up. RESULTS: Median and total absorbed spleen doses were estimated to 4.5 and 15 Gy, respectively. Total absorbed spleen dose correlated with decrease in Hb (p = 0.02), but not WBC (p = 0.31) or PLT (p = 0.65) counts. For patients without bone metastases, mean absorbed spleen dose correlated with decrease in PLT (p = 0.04) but not Hb (p = 0.16) or WBC (p = 0.42) counts. The spleen volume was reduced to 75 % (p < 0.001) of original values (200 vs. 260 ml) at a mean follow-up of 36 months. CONCLUSIONS: Haematological toxicity according to Hb counts was moderately but significantly correlated with total absorbed spleen dose. This supports the possibility that radiation exposure of the spleen affects overall haematological response during (177)Lu-DOTATATE treatment. PMID- 27491431 TI - Power and glory: applying participatory action research in public health. PMID- 27491432 TI - Time trends in health inequalities due to care in the context of the Spanish Dependency Law. AB - OBJECTIVE: In Spain, responsibility for care of old people and those in situations of dependency is assumed by families, and has an unequal social distribution according to gender and socioeconomic level. This responsibility has negative health effects on the carer. In 2006, the Dependency Law recognised the obligation of the State to provide support. This study analyses time trends in health inequalities attributable to caregiving under this new law. METHODS: Study of trends using two cross-sectional samples from the 2006 and 2012 editions of the Spanish National Health Survey (27,922 and 19,995 people, respectively). We compared fair/poor self-rated health, poor mental health (GHQ-12 >2), back pain, and the use of psychotropic drugs between non-carers, carers sharing care with other persons, and those providing care alone. We obtain prevalence ratios by fitting robust Poisson regression models. RESULTS: We observed no change in the social profile of carers according to gender or social class. Among women, the difference in all health indicators between carers and non-carers tended to decrease among those sharing care but not among lone carers. Inequalities tend to decrease slightly in both groups of men carers. CONCLUSIONS: Between 2006 and 2012, trends in health inequalities attributable to informal care show different trends according to gender and share of responsibility. It is necessary to redesign and implement policies to reduce inequalities that take into account the most affected groups, such as women lone carers. Policies that strengthen the fair social distribution of care should also be adopted. PMID- 27491433 TI - Advances and Challenges in Genomic Selection for Disease Resistance. AB - Breeding for disease resistance is a central focus of plant breeding programs, as any successful variety must have the complete package of high yield, disease resistance, agronomic performance, and end-use quality. With the need to accelerate the development of improved varieties, genomics-assisted breeding is becoming an important tool in breeding programs. With marker-assisted selection, there has been success in breeding for disease resistance; however, much of this work and research has focused on identifying, mapping, and selecting for major resistance genes that tend to be highly effective but vulnerable to breakdown with rapid changes in pathogen races. In contrast, breeding for minor-gene quantitative resistance tends to produce more durable varieties but is a more challenging breeding objective. As the genetic architecture of resistance shifts from single major R genes to a diffused architecture of many minor genes, the best approach for molecular breeding will shift from marker-assisted selection to genomic selection. Genomics-assisted breeding for quantitative resistance will therefore necessitate whole-genome prediction models and selection methodology as implemented for classical complex traits such as yield. Here, we examine multiple case studies testing whole-genome prediction models and genomic selection for disease resistance. In general, whole-genome models for disease resistance can produce prediction accuracy suitable for application in breeding. These models also largely outperform multiple linear regression as would be applied in marker assisted selection. With the implementation of genomic selection for yield and other agronomic traits, whole-genome marker profiles will be available for the entire set of breeding lines, enabling genomic selection for disease at no additional direct cost. In this context, the scope of implementing genomics selection for disease resistance, and specifically for quantitative resistance and quarantined pathogens, becomes a tractable and powerful approach in breeding programs. PMID- 27491428 TI - Molecular mechanisms involved in dendritic cell dysfunction in cancer. AB - Dendritic cells (DC) play a pivotal role in the tumor microenvironment (TME). As the primary antigen-presenting cells in the tumor, DCs modulate anti-tumor responses by regulating the magnitude and duration of infiltrating cytotoxic T lymphocyte responses. Unfortunately, due to the immunosuppressive nature of the TME, as well as the inherent plasticity of DCs, tumor DCs are often dysfunctional, a phenomenon that contributes to immune evasion. Recent progresses in our understanding of tumor DC biology have revealed potential molecular targets that allow us to improve tumor DC immunogenicity and cancer immunotherapy. Here, we review the molecular mechanisms that drive tumor DC dysfunction. We discuss recent advances in our understanding of tumor DC ontogeny, tumor DC subset heterogeneity, and factors in the tumor microenvironment that affect DC recruitment, differentiation, and function. Finally, we describe potential strategies to optimize tumor DC function in the context of cancer therapy. PMID- 27491434 TI - Quarantine Regulations and the Impact of Modern Detection Methods. AB - Producers worldwide need access to the best plant varieties and cultivars available to be competitive in global markets. This often means moving plants across international borders as soon as they are available. At the same time, quarantine agencies are tasked with minimizing the risk of introducing exotic pests and pathogens along with imported plant material, with the goal to protect domestic agriculture and native fauna and flora. These two drivers, the movement of more plant material and reduced risk of pathogen introduction, are at odds. Improvements in large-scale or next-generation sequencing (NGS) and bioinformatics for data analysis have resulted in improved speed and accuracy of pathogen detection that could facilitate plant trade with reduced risk of pathogen movement. There are concerns to be addressed before NGS can replace existing tools used for pathogen detection in plant quarantine and certification programs. Here, we discuss the advantages and possible pitfalls of this technology for meeting the needs of plant quarantine and certification. PMID- 27491435 TI - Fungal and Oomycete Diseases of Tropical Tree Fruit Crops. AB - The tropics produce a range of fruit from tree crops that cannot be grown in colder climates. Bananas, mangos, several nuts, spices, coffee, and cacao are widely traded and much sought after around the world. However, the sustainable production of these tropical tree fruit crops faces significant challenges. Among these, losses due to pests and diseases play a large part in reducing yields, quality, and profitability. Using bananas and cacao as key examples, we outline some of the reasons fungal and oomycete diseases cause such significant losses to tropical tree crops. Cultivation of monocultures derived from limited genetic diversity, environmental conditions conducive for disease development, high levels of disease incidence and severity, a lack of disease resistance in planting materials, shortages of labor, and inadequate infrastructure and investment pose significant challenges, especially for smallholder producers. The expansion of travel and trade has given rise to emerging infectious plant diseases that add further insecurity and pressure. We conclude that holistic actions are needed on multiple fronts to address the growing problem of disease in tropical fruit tree crops. PMID- 27491436 TI - DNA Methylation and Demethylation in Plant Immunity. AB - Detection of plant and animal pathogens triggers a massive transcriptional reprogramming, which is directed by chromatin-based processes, and ultimately results in antimicrobial immunity. Although the implication of histone modifications in orchestrating biotic stress-induced transcriptional reprogramming has been well characterized, very little was known, until recently, about the role of DNA methylation and demethylation in this process. In this review, we summarize recent findings on the dynamics and biological relevance of DNA methylation and demethylation in plant immunity against nonviral pathogens. In particular, we report the implications of these epigenetic regulatory processes in the transcriptional and co-transcriptional control of immune responsive genes and discuss their relevance in fine-tuning antimicrobial immune responses. Finally, we discuss the possible yet elusive role of DNA methylation and demethylation in systemic immune responses, transgenerational immune priming, and de novo epiallelism, which could be adaptive. PMID- 27491437 TI - Criteria for recommendation and expert consensus papers: from the European Association of Cardiovascular Imaging Scientific Documents Committee. AB - The recommendations given in this document are intended as a guide for the writing committees with the aim to harmonize the style and content of EACVI expert consensus and recommendation documents. PMID- 27491438 TI - Small aortic root in aortic valve stenosis: clinical characteristics and prognostic implications. AB - Aims: In aortic valve stenosis (AS), having a small aortic root may influence both the assessment of AS severity and the treatment strategy. The aim was to test the prognostic implications of having a small aortic root in AS within a large prospective study. Methods and results: We used data from 4.3-year follow up of 1560 patients with asymptomatic, initially mostly moderate AS enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis study. A small aortic root was defined as inner aortic sinotubular junction diameter indexed for body height <1.4 cm/m in women and <1.5 cm/m in men. A small aortic root was found in 270 patients (17.3%) at baseline. Having a small aortic root was associated with larger aortic root wall thickness, higher pressure recovery, lower systemic arterial compliance, left ventricular mass index, and female sex in a multivariable logistic regression analysis (all P < 0.05). In the Cox regression analysis, having a small aortic root at baseline was associated with higher hazard rates of ischaemic cardiovascular events (n = 268; HR 1.55, 95% CI 1.16 2.06), non-haemorrhagic stroke (n = 55; HR 1.88, 95% CI 1.04-3.41), and cardiovascular death (n = 81; HR 2.08, 95% CI 1.28-3.39) (all P < 0.05) after adjusting for confounders, including randomized study treatment, sex, hypertension, AS severity, and aortic valve replacement. Conclusion: In AS patients without known cardiovascular disease or diabetes, having a small aortic root was associated with increased ischaemic cardiovascular events and mortality. The results suggest a relation between the presence of a small aortic root and that of subclinical atherosclerosis. Clinical trial registration: ClinicalTrials.gov identifier: NCT00092677. PMID- 27491439 TI - Multi-subtype influenza virus-like particles incorporated with flagellin and granulocyte-macrophage colony-stimulating factor for vaccine design. AB - Virus-like particle (VLP) technology is an attractive platform for seasonal and pandemic influenza vaccine development. We previously showed that influenza VLPs can be modified using M2 fusion with molecular adjuvants such as Salmonella typhimurium flagellin (FliC) to enhance VLP immunogenicity. For this study, three types of chimeric VLPs were incorporated with FliC, granulocyte-macrophage colony stimulating factor (GM-CSF), or both GM-CSF and FliC (GM-CSF/FliC) to enhance anti-influenza immunogenicity. Our results indicate that immunizations with the chimeric FliC VLPs and GM-CSF/FliC H5N1 VLPs elicited more potent and broadly neutralizing antibodies and neuraminidase-inhibiting antibodies in sera, and induced higher numbers of hemagglutinin-specific antibody-secreting cells and germinal center B cell subsets in splenoctyes. Immunization with the chimeric GM CSF H5N1 VLPs induced stronger Th1 and Th2 cellular responses. The chimeric GM CSF/FliC H5N1 VLP constructs were further obtained to include H7 or H1H7 bi- or tri-subtype. It is our hope that these findings provide useful information for developing multi-subtype influenza vaccines. PMID- 27491440 TI - Functional evaluation of Heat Shock Proteins 70 (HSP70/HSC70) on Rhodnius prolixus (Hemiptera, Reduviidae) physiological responses associated with feeding and starvation. AB - Blood-sucking vectors must overcome thermal stress caused by intake of proportionally large amounts of warm blood from their hosts. In response to this, Heat Shock Proteins (HSPs) such as the widely studied HSP70 family (the inducible HSP70 and the cognate form HSC70, known for their role in preserving essential cellular functions) are rapidly up-regulated in their tissues. The triatomine Rhodnius prolixus is an important vector of Trypanosoma cruzi, the causative pathogen of Chagas' disease, and is also a model organism for studying insect biology and physiology. In this work, we observed that the expression of Rhodnius prolixus HSP70 was rapidly up-regulated in response to thermal shocks (0 degrees C and 40 degrees C) and also during the first hours after feeding on blood. HSP70/HSC70 RNAi knockdown elicited important alterations in R. prolixus physiological responses triggered by blood meal and starvation. HSP70/HSC70 knockdown insects showed lower resistance to prolonged starvation in comparison to appropriate controls, dying between 32 and 40 days after dsRNA injection. After blood feeding, the physiological effects of HSP70/HSC70 knockdown were more prominent and the insects died even earlier, within 14-20 days after feeding (21 27 days after dsRNA injection). These bugs showed impaired blood processing and digestion, reduced energetic metabolism and the midgut immune responses were compromised. Our findings suggest that HSP70/HSC70 depletion affected R. prolixus in starvation or fed conditions. After feeding, the arrival of blood in the digestive tract of knockdown insects fails to activate essential signaling pathways involved in blood processing, producing several alterations in their physiological processes enough to generate a premature death. PMID- 27491441 TI - Molecular and functional characterization of Bemisia tabaci aquaporins reveals the water channel diversity of hemipteran insects. AB - The Middle East-Asia Minor 1 (MEAM1) whitefly, Bemisia tabaci (Gennadius) is an economically important pest of food, fiber, and ornamental crops. This pest has evolved a number of adaptations to overcome physiological challenges, including 1) the ability to regulate osmotic stress between gut lumen and hemolymph after imbibing large quantities of a low nitrogen, sugar-rich liquid diet; 2) the ability to avoid or prevent dehydration and desiccation, particularly during egg hatching and molting; and 3) to be adapted for survival at elevated temperatures. One superfamily of proteins involved in the maintenance of fluid homeostasis in many organisms includes the aquaporins, which are integral membrane channel proteins that aid in the rapid flux of water and other small solutes across biological membranes. Here, we show that B. tabaci has eight aquaporins (BtAqps), of which seven belong to the classical aquaporin 4-related grade of channels, including Bib, Drip, Prip, and Eglps and one that belongs to the unorthodox grade of aquaporin 12-like channels. B. tabaci has further expanded its repertoire of water channels through the expression of three BtDrip2 amino-terminal splice variants, while other hemipteran species express amino- or carboxyl-terminal isoforms of Drip, Prip, and Eglps. Each BtAqp has unique transcript expression profiles, cellular localization, and/or substrate preference. Our phylogenetic and functional data reveal that hemipteran insects lost the classical glp genes, but have compensated for this by duplicating the eglp genes early in their evolution to comprise at least three separate clades of glycerol transporters. PMID- 27491442 TI - Two-trocar appendectomy in children - description of technique and comparison with conventional laparoscopic appendectomy. AB - BACKGROUND: The aim of the study was to describe the technique of two-trocar laparoscopic appendectomy and compare the outcome between two- and three-trocar techniques in children. METHODS: All children who underwent laparoscopic surgery for suspected appendicitis from 2006 to 2014 in a center for pediatric surgery were included in the study. Converted surgeries and patients with appendiceal abscess or concomitant intestinal obstruction were excluded. A total of 259 children underwent appendectomy with either two (35 %) or three (65 %) laparoscopic trocars according to the surgeons' preference and intraoperative judgment. Patient demographics, clinical symptoms, surgery characteristics, and complications were reviewed. RESULTS: The mean age of the children was 10.4 years (range, 1-14 years). The mean follow-up time was 41.2 months (SD +/- 29.2). No significant differences in age, gender, weight, or signs and symptoms were found between the two- and three-trocar groups. The mean surgery time was significantly shorter in the two-trocar group (47 min) than in the three-trocar group (66 min; p < 0.001). The rates of surgical complications were 2 % vs. 4 %, (p = 0.501), and the rates of postoperative complications were 0 % vs. 5 % (p = 0.054), in the two- and three-trocar groups. The overall incidence of postoperative wound infection was low (<1 %) and did not differ between groups. CONCLUSIONS: Two trocar laparoscopic appendectomy seems to be a safe and feasible technique with a low rate of postoperative wound infections. The present findings demonstrate that when the two-trocar technique could be applied, it is a good complement to the conventional three-trocar technique. PMID- 27491443 TI - Who Is Not a Candidate for a 1-Day Hospital-Based Total Knee Arthroplasty? AB - BACKGROUND: Short-stay total knee arthroplasty (TKA), defined as a 1-day length of stay (LOS), is feasible in many patients, yet variables identifying who are candidates for a short stay are not well described in literature. With an emphasis on cost-efficiency, we examined preoperative patient characteristics and perioperative hospital factors that correlated with a longer LOS. METHODS: A retrospective review of 381 primary TKAs was performed. Clinical measures differentiating a 1-day LOS group from that of a >=2-day LOS group were identified. RESULTS: Multiple logistic regression demonstrated older age (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.34-2.77; P < .001), female gender (OR, 4.22; 95% CI, 2.35-7.57; P < .001), American Society of Anesthesiologists score 3 or 4 (OR, 2.00; 95% CI, 1.01-3.95; P = .046), atrial fibrillation (OR, 8.87; 95% CI, 1.81-43.47; P = .007), and prior TKA on the contralateral side (OR, 3.57; 95% CI, 1.27-10.05; P = .016) as significant preoperative characteristics correlating with the >=2-day LOS group. The most significant hospital perioperative factor associated with longer stays was patients not ambulating on the day of surgery (OR, 4.09; 95% CI, 1.77-9.48; P = .001). Walking 150 ft (93% sensitive, 35% specific) on the day of surgery was predictive of patients in the 1-day LOS group. Hospital costs were US$1873 (P < .001) lower for patients in the 1-day group. CONCLUSION: Shorter stays decrease costs associated with TKA, and more refined predictive models are needed to optimize discharge protocols. Preoperative data help allocate limited healthcare resources toward patients more likely to leave in 1 day, while perioperative data facilitate learning to create a more efficient hospital process. PMID- 27491444 TI - Letter to the Editor on "Balancing Thromboprophylaxis and Bleeding in Total Joint Arthroplasty: Impact of Eliminating Enoxaparin and Predonation and Implementing Pneumatic Compression and Tranexamic Acid". PMID- 27491445 TI - Response to Letter to the Editor on "Large Metal Heads and Vitamin E Polyethylene Increase Frictional Torque in Total Hip Arthroplasty". PMID- 27491446 TI - Damage Patterns at the Head-Stem Taper Junction Helps Understand the Mechanisms of Material Loss. AB - BACKGROUND: Material loss at the taper junction of metal-on-metal total hip arthroplasties has been implicated in their early failure. The mechanisms of material loss are not fully understood; analysis of the patterns of damage at the taper can help us better understand why material loss occurs at this junction. METHODS: We mapped the patterns of material loss in a series of 155 metal-on metal total hip arthroplasties received at our center by scanning the taper surface using a roundness-measuring machine. We examined these material loss maps to develop a 5-tier classification system based on visual differences between different patterns. We correlated these patterns to surgical, implant, and patient factors known to be important for head-stem taper damage. RESULTS: We found that 63 implants had "minimal damage" at the taper (material loss <1 mm3), and the remaining 92 implants could be categorized by 4 distinct patterns of taper material loss. We found that (1) head diameter and (2) time to revision were key significant variables separating the groups. CONCLUSION: These material loss maps allow us to suggest different mechanisms that dominate the cause of the material loss in each pattern: (1) corrosion, (2) mechanically assisted corrosion, or (3) intraoperative damage or poor size tolerances leading to toggling of trunnion in taper. PMID- 27491447 TI - The European Knee Society, the Trans-Atlantic Counterpart of the American Knee Society. PMID- 27491448 TI - Letter to the Editor on "Large Metal Heads and Vitamin E Polyethylene Increase Frictional Torque in Total Hip Arthroplasty". PMID- 27491449 TI - Day of Surgery and Surgical Start Time Affect Hospital Length of Stay After Total Hip Arthroplasty. AB - BACKGROUND: The United States spends $12 billion each year on ~332,000 total hip arthroplasty (THA) procedures with the postoperative period accounting for ~40% of costs. The purpose of this study was to evaluate the effect of surgical scheduling (day of week and start time) on clinical outcomes, hospital length of stay (LOS), and rate of nonhome discharge in THA patients. METHODS: Analysis of perioperative variables was performed for patients who underwent THA at an urban tertiary care teaching hospital from 2009 to 2014. RESULTS: A total of 580 THA patients were included for analysis. LOS was higher for the Thursday/Friday cohort compared to Monday/Tuesday (3.7 vs 3.4 days; P = .03). Patients who had a surgical start time after 2 PM had longer LOS compared to patients operated on before 2 PM (3.9 vs 3.5 days; P = .03). After controlling for patient comorbidities and THA surgical approach (direct anterior vs posterior), Thursday/Friday THAs were associated with a 3.27 times risk of extended LOS (>75th percentile LOS) compared to Monday/Tuesday THAs (P < .001). Additionally, case start before 2 PM was protective and associated with a 0.46 times odds of extended LOS (P = .01). LOS reduction opportunity for changing surgical start time to before 2 PM was 0.9 days for high-risk patients (American Society of Anesthesiology class 3/4 and/or liver disease) and 0.2 days for low-risk patients (American Society of Anesthesiology class 1/2). CONCLUSION: Patients who underwent THA Thursday/Friday or had start times after 2 PM had significantly extended hospital LOS. Preoperative risk modification along with adjustments to surgical scheduling and/or perioperative staffing may reduce LOS and thus hospital expenditures for THA procedures. PMID- 27491450 TI - Resource allocation and post-reproductive degeneration in the freshwater cnidarian Hydra oligactis (Pallas, 1766). AB - Freshwater hydra are among the few animal groups that show negligible senescence and can maintain high survival and reproduction rates when kept under stable conditions in the laboratory. Yet, one species of Hydra (H. oligactis) undergoes a senescence-like process in which polyps degenerate and die after sexual reproduction. The ultimate factors responsible for this phenomenon are unclear. High mortality in reproducing animals could be the consequence of increased allocation of resources to reproduction at the expense of somatic maintenance. This hypothesis predicts that patterns of reproduction and survival are influenced by resource availability. To test this prediction we investigated survival and reproduction at different levels of food availability in 10 lineages of H. oligactis derived from a single Hungarian population. Sexual reproduction was accompanied by reduced survival, but a substantial proportion of animals regenerated after sexual reproduction and continued reproducing asexually. Polyps belonging to different lineages showed differences in their propensity to initiate sexual reproduction, gonad number and survival rate. Food availability significantly affected fecundity (number of eggs or testes produced), with the largest number of gonads being produced by animals kept on a high food regime. On the other hand, survival rate was not affected by the amount of food. These results show that survival is conserved at the expense of reproduction in this population when food is low. It remains a question still to be answered why survival is prioritized over reproduction in this population. PMID- 27491451 TI - Determination of Double Bond Positions and Geometry of Methyl Linoleate Isomers with Dimethyl Disulfide Adducts by GC/MS. AB - The dimethyl disulfide (DMDS) adduct method is one of the convenient and effective methods for determining double bond positions of unsaturated fatty acid methyl esters (FAME) except conjugated FAME. When analyzed using gas chromatography/electron ionization-mass spectrometry (GC/EI-MS), unsaturated FAME with DMDS added to the double bonds yields high intensity MS spectra of characteristic ions. The MS spectra of characteristic ions can then be used to easily confirm double bond positions. Here we explore the GC/EI-MS analysis of the DMDS adducts of methyl linoleate geometrical isomers isolated by high performance liquid chromatography (HPLC) with a silver nitrate column. For C18:2 c9, c12 and C18:2-t9, t12, DMDS randomly formed adducts with double bonds at either carbon 9-10 or carbon 12-13, but not both at the same time due to steric hindrance. For C18:2-c9, t12 and C18:2-t9, c12, however, DMDS only formed adducts with the double bond in the cis configuration. Consequently, when analyzing fatty acids with methylene interrupted double bonds, with one double bond in the cis and one in the trans configuration, double bond positions cannot be completely confirmed. PMID- 27491452 TI - Household composition and psychological health: Results of the Second Diabetes Attitudes, Wishes and Needs (DAWN2) study. AB - AIMS: 1) To explore the effect of household composition on the psychological health of adults with diabetes by comparing those living with other adult(s) including a partner with those living with neither partner nor other adult(s); 2) to examine potential mediation of social support in the association between household composition and psychological health. METHODS: The study is part of the DAWN2 study conducted in 17 countries. The population comprised 8596 people with diabetes (PWD). Multiple regression models (linear and binary) were applied. RESULTS: People living with 'other adult(s) but no partner' experienced significantly lower well-being, higher diabetes distress and worried more frequently about hypoglycaemic events than those with a partner or those not co habiting with another adult. However, participants living with 'other adult(s) but no partner' were more empowered compared to the other household composition groups. The association between household composition and psychological health was not mediated by diabetes-specific social support. CONCLUSIONS: The study indicates the psychological vulnerability of respondents living without a partner but with other adult(s). Appropriate support interventions must be developed and tested in order to enhance psychological health in people with diabetes living with other adults such as adult children, but with no partner. PMID- 27491453 TI - Comparing DTL microfiber and Neuroline skin electrode in the Mini Ganzfeld ERG. AB - BACKGROUND: In infant ERG recordings skin electrodes frequently result in a better compliance. In order to assess the quality of such recordings, we compared the recording characteristics of DTL microfiber and Neuroline surface electrodes using a modified ISCEV protocol in the Mini Ganzfeld ERG. METHODS: A prospective cohort study on healthy adult subjects was conducted at the Department of Ophthalmology, University of Basel, Switzerland. Thirty healthy volunteers were tested. The microfiber electrode (DTL Plus Electrode) was placed across the cornea, above the lower eyelid. The Neuroline skin electrode was placed on the surface of the lower lid on the opposite eye. The eye on which each electrode type was placed was randomised. Amplitudes of the rod, standard combined, standard flash cone, light-adapted 3.0 Hz flicker and red cone responses were analysed, as well as their respective implicit times. RESULTS: Both electrode recordings showed the same waveform characteristics. Responses with the Neuroline electrode were significantly weaker than those from the DTL electrode. Amplitudes of the rod, standard combined, standard flash cone, light-adapted 3.0 Hz flicker and red cone responses were up to four times larger when recorded with the DTL electrode (p < 0.005, ANOVA). Implicit times of the red cone ERGs were slightly faster for the Neuroline skin electrode recordings (p <= 0.039). CONCLUSIONS: Comparison of full-field ERG recordings with microfiber DTL and Neuroline skin electrodes showed that DTL electrodes produce larger ERGs. Hence, we provide evidence that both electrode types allow successful full-field ERG recording, although separate normative data for both electrodes are necessary. PMID- 27491454 TI - Molecular and antimicrobial susceptibility profiling of atypical Streptococcus species from porcine clinical specimens. AB - The Streptococcus species present broad phenotypic variation, making identification difficult using only traditional microbiological methods. Even though Streptococcus suis is the most important species for the worldwide swine industry, other Streptococcus species appear to be able to cause disease in swine and could represent a higher underestimated risk for porcine health. The aim of this study was to identify Streptococcus-like isolates by MALDI-TOF MS and 16S rRNA sequencing and further molecular and antibiotic susceptibility characterization of the atypical Streptococcus species capable of causing disease in swine. Fifty presumptive Streptococcus isolates from diseased pigs isolated from different Brazilian States between 2002 and 2014 were evaluated. Among the studied isolates, 26% were identified as Streptococcus hyovaginalis, 24% as Streptococcus plurianimalium, 12% as Streptococcus alactolyticus, 10% as Streptococcus hyointestinalis, and the remaining isolates belonged to Streptococcus henryi (6%), Streptococcus thoraltensis (6%), Streptococcus gallolyticus (6%), Streptococcus gallinaceus (4%), Streptococcus sanguinis (4%), and Streptococcus mitis (2%). The Streptococcus isolates were successfully identified by spectral cluster analysis and 16S rRNA sequencing with 96% of concordance between the techniques. The SE-AFLP analysis also supported Streptococcus species distinction and enabled further observation of higher genetic heterogeneity intra-species. The identified Streptococcus species presented variable MIC values to beta-lactams, enrofloxacin and florfenicol, and high resistance rates to tetracyclines and macrolides, which appear to be directly related to the industry's antimicrobial usage and resistance selection. PMID- 27491456 TI - Clinico-epidemiology and genetic diversity of Salivirus in acute gastroenteritis cases from Pune, Western India: 2007-2011. AB - Acute gastroenteritis is a leading cause of mortality in children from developing countries. Recently, Salivirus has been frequently detected in acute gastroenteritis patients, suggesting its possible aetiological role. Conflicting reports available on disease association of Salivirus have made it difficult to ascertain their causative role. The overall epidemiology and clinical features of Salivirus infections are poorly understood. The present five year study was undertaken to investigate the presence and genetic diversity of Salivirus in acute gastroenteritis cases from Pune, Western India and to determine the clinico epidemiological features of Salivirus infections. A total of 985 faecal samples (778 acute gastroenteritis and 207 asymptomatic controls), collected from three local hospitals (Jan2007-Dec2011) were examined for the presence of Salivirus by RT-PCR. Molecular characterization was performed by PCR amplification of the 3D and VP regions. Frequency of Salivirus detection in cases (2.6%) and controls (1.93%) was not significantly different (p = 0.57). Co-infection with other enteric viruses was seen in 50% of the cases. Comparison of clinical features between Salivirus mono and mixed infections revealed that Salivirus alone did not exacerbate gastroenteritis. The frequency of diarrhoea and overall clinical severity of mixed infections was significantly greater than mono infections (p = 0.02). Based on clinical findings, our study suggests that Salivirus does not cause severe gastroenteritis. Phylogenetic analysis indicated that study strains belonged to Salivirus A1 and formed 2 distinct clusters which shared nucleotide identities of 94.1-96.2% and 88.9-93.8% between themselves in 3D and VP regions, respectively. Interestingly, the more divergent Cluster2 strains shared a low nucleotide identity with the closest reference strain in both regions (~95% in 3D and ~92% in VP) suggesting that they could represent a variant type of Salivirus A1. The genetic diversity in strains detected from study region, emphasizes the need for Salivirus surveillance from other regions of India. PMID- 27491455 TI - Strong down-regulation of glycophorin genes: A host defense mechanism against rotavirus infection. AB - The mechanisms of rotavirus (RV) infection have been analyzed from different angles but the way in which RV modifies the transcriptome of the host is still unknown. Whole transcriptome shotgun sequencing of peripheral blood samples was used to reveal patterns of expression from the genome of RV-infected patients. RV provokes global changes in the transcriptome of infected cells, involving an over expression of genes involved in cell cycle and chromatin condensation. While interferon IFI27 was hyper-activated, interferon type II was not suggesting that RV has developed mechanisms to evade the innate response by host cells after virus infection. Most interesting was the inhibition of genes of the glycophorins A and B (GYPA/B) family, which are the major sialoglycoproteins of the human erythrocyte membrane and receptor of several viruses for host invasion. RV infection induces a complex and global response in the host. The strong inhibition of glycophorins suggests a novel defense mechanism of the host to prevent viral infection, inhibiting the expression of receptors used by the virus for infection. The present results add further support to the systemic nature of RV infection. PMID- 27491457 TI - Genetic variants in the regulatory region of SLC10A1 are not associated with the risk of hepatitis B virus infection and clearance. AB - The Na/taurocholate cotransporter NTCP (encoded by SLC10A1) was identified as a cellular entry receptor for the human hepatitis B virus (HBV), advancing our understanding of the molecular mechanism of HBV infection. An alternative hypothesis was put forward that regulatory variants in SLC10A1 might play an important role in HBV susceptibility by potentially influencing expression levels of NTCP. The three regulatory SNPs (rs8011311, rs7154439, rs111409076) were genotyped in 1023 HBV-persistent carriers, 735 subjects with HBV natural clearance and 732 HBV marker-negative subjects in a Han Chinese population. Real time reverse transcription PCR analysis and luciferase assays have been performed to dissect the potential functionality. In logistic regression analysis, when subjects with HBV natural clearance were compared with HBV marker-negative subjects, no significant associations with the risk of HBV infection were observed for any of the three SNPs after adjusting for age, sex, smoking status and alcohol consumption (P>0.05). Similar negative results were also found for the three SNPs when HBV-persistent carriers were compared with HBV marker negative subjects. Likewise, no significant associations with the risk of HBV clearance were observed when HBV-persistent carriers were compared with subjects with HBV natural clearance (P>0.05). Quantitative RT/PCR showed no significant difference in NTCP expression levels in normal liver tissue amongst individuals with different rs111409076 genotypes (P=0.317 for the general linear model). Moreover, no evident effect of the SLC10A1 rs111409076 AACA/- polymorphism on transcriptional activity was found by luciferase assay in either HepG2 (P=0.161) or Hep3b (P=0.129) cell lines. The present study indicated that the common variants in the regulatory region of SLC10A1 may not influence the expression of NTCP at the level of transcriptional regulation, and ultimately may not be associated with HBV susceptibility in this Chinese population. PMID- 27491458 TI - Zoonotic trypanosomes in South East Asia: Attempts to control Trypanosoma lewisi using human and animal trypanocidal drugs. AB - Beside typical human trypanosomes responsible of sleeping sickness in Africa and Chagas disease in Latin America, there is a growing number of reported atypical human infections due to Trypanosoma evansi, a livestock parasite, or Trypanosoma lewisi, a rat parasite, especially in Asia. Drugs available for the treatment of T. brucei ssp. in humans are obviously of choice for the control of T. evansi because it is derived from T. brucei. However, concerning T. lewisi, there is an urgent need to determine the efficacy of trypanocidal drugs for the treatment in humans. In a recent study, pentamidine and fexinidazole were shown to have the best efficacy against one stock of T. lewisi in rats. In the present study suramin, pentamidine, eflornitine, nifurtimox, benznidazole and fexinidazole, were evaluated at low and high doses, in single day administration to normal rats experimentally infected with a stock of T. lewisi recently isolated in Thailand. Because none of these treatments was efficient, a trial was made with the most promising trypanocide identified in a previous study, fexinidazole 100mg/kg, in 5 daily administrations. Results observed were unclear. To confirm the efficacy of fexinidazole, a mixed infection protocol was set up in cyclophosphamide immunosuppressed rats. Animals were infected successively by T. lewisi and T. evansi, and received 10 daily PO administrations of 200mg/kg fexinidazole. Drastic effects were observed against T. evansi which was cleared from the rat's blood within 24 to 48h; however, the treatment did not affect T. lewisi which remained in high number in the blood until the end of the experiment. This mixed infection/treatment protocol clearly demonstrated the efficacy of fexinidazole against T. evansi and its inefficacy against T. lewisi. Since animal trypanocides were also recently shown to be inefficient, other protocols as well as other T. lewisi stocks should be investigated in further studies. PMID- 27491459 TI - Stent-assisted coiling of very small wide-necked intracranial aneurysms: Complications, anatomical results and clinical outcomes. AB - BACKGROUND AND OBJECTIVE: Treatment of very small (<=3mm) wide-necked intracranial aneurysms remains controversial, we investigated the efficacy and safety of stent-assisted coiling of such aneurysms. METHODS: From September 2008 to December 2012, 112 very small wide-necked intracranial aneurysms in 108 patients were embolized with stent-assisted coiling. We assessed the initial neurological conditions, complications and anatomic results. The follow-up results were evaluated with DSA and mRS. RESULTS: Stent deployment was successful in 104 of 108 procedures (96.3%). 11 complications (10.2%) occurred during procedures, including 5 events of aneurysm rupture, 3 events of thromboembolism. The rate of complication, rupture and thromboembolism was not statistically different between the ruptured and unruptured patients (P=0.452, P=0.369, P=1.000, respectively). The initial aneurysmal occlusion was Raymond scale (RS) 1 in 34 patients (31.5%), RS2 in 53 patients (49.1%), and RS3 in 21 patients (19.4%). 79 aneurysms were available for anatomic follow-up of 12-47 months, stable occlusion in 45 aneurysms (57.0%), progressive complete occlusion in 34 aneurysms (43.0%). 95 patients(88.0%) were available for a clinical follow-up of 12-52 months, 92 patients (96.8%) had favorable clinical outcomes (mRS <=2), 3 patients (3.2%) had morbidity (mRS: 3-5). The morbidity was not statistically different between the ruptured and unruptured patients (P=1.000). CONCLUSIONS: Stent-assisted coiling of very small wide-necked intracranial aneurysms may be effective and safe. Because of low risk of rupture in such aneurysms, the coiling of unruptured such aneurysms must be selective. The long-term efficacy and safety of coiling such aneurysms remains to be determined in larger prospective series. PMID- 27491461 TI - Preconception weight management: an untapped area of women's health. AB - The aim of this study was to identify barriers to providing preconception weight management. Twenty health professionals participated in a semistructured phone interview regarding their beliefs on perceived barriers to providing preconception weight management. The interviews were recorded, transcribed verbatim and examined using thematic analysis to extract the key themes. Two themes were identified from the interviews: (1) barriers hindering women from accessing preconception weight management interventions (i.e. women's lack of awareness regarding the importance of preconception weight, and not being provided with weight management information or interventions by health professionals); and (2) barriers preventing health professionals from providing preconception weight management (i.e. an absence of implementation resources for preconception weight management, limited access to women of childbearing age who plan to conceive, and a high percentage of pregnancies being unplanned). There are significant client- and heath professional-based barriers to implementing preconception weight management. To begin to address these barriers, developing policy and preconception weight management programs based on evidence collected via a needs assessment, quantitative or mixed-method designs may be of benefit. Furthermore, these barriers are likely contributing to the paucity in research into preconception weight management services. PMID- 27491460 TI - Improvement of quality of life after therapeutic plasma exchange in patients with myasthenic crisis. AB - INTRODUCTION: We sought to evaluate quality of life patients with myasthenic crisis before and after therapeutic plasma exchange. MATERIALS AND METHODS: In our study we conducted an assessment of the quality of life with the use of the questionnaire SF-36, when executed eleven therapeutic plasma exchange. The assessment was made on baseline and after 4 weeks. We also did neurological clinical evaluation before and after TPE. RESULTS: Patients in the study showed significant improvement in quality of life after performed therapeutic plasma exchange. The changes were observed in physical functioning, which confirmed the results of the statistical significance of p<0.05. In the analysis, the assessment of mental functioning not obtained the results of statistical significance, but the results also showed improvement in self-assessment. We observed high correlation between general health and physical mental functioning, between the role limitations due to physical health problems and role limitations due to emotional problems, and general health perception and bodily pain. CONCLUSIONS: Therapeutic plasma exchange significantly improves the quality of life of patients with myasthenia gravis during the crisis. PMID- 27491462 TI - Dialysis-Related Spondyloarthropathy with Cervical Amyloidoma. PMID- 27491463 TI - Intestinal Angioedema in a Palliative Care Setting. PMID- 27491464 TI - Hospital Accreditation and Community Health. PMID- 27491465 TI - Digital Medicine: "O Brave New World". PMID- 27491466 TI - Intermittent Gastric Volvulus Mimicking Acute Coronary Syndrome. PMID- 27491468 TI - Changing Times in Cardiovascular Publications: A Commentary. PMID- 27491467 TI - A Case Report of Delayed Return of Spontaneous Circulation: Lazarus Phenomenon. PMID- 27491469 TI - Massive Spontaneous Subcutaneous Emphysema. PMID- 27491471 TI - Lack of existing guidelines for a large group of patients in Sweden: a national survey across the acute surgical care delivery chain. AB - RATIONALE, AIMS AND OBJECTIVES: Evidence-informed healthcare is the fundament for practice, whereby guidelines based on the best available evidence should assist health professionals in managing patients. Patients seeking care for acute abdominal pain form a common group in acute care settings worldwide, for whom decision-making and timely treatment are of paramount importance. There is ambiguity about the existence, use and content of guidelines for patients with acute abdomen. The objective was to describe and compare guidelines and management of patients with acute abdomen in different settings across the acute care delivery chain in Sweden. METHOD: A national cross-sectional design was used. Twenty-nine ambulance stations, 17 emergency departments and 33 surgical wards covering all six Swedish health regions were included, and 23 guidelines were quality appraised using the validated Appraisal of Guidelines for Research & Evaluation II tool. RESULTS: There is a lack of guidelines in use for the management of this large group of patients between and within different healthcare areas across the acute care delivery chain. The quality appraisal identified that several guidelines were of poor quality, especially the in hospital ones. Further, range orders for analgesics are common in the ambulance services and the surgical wards, but are seldom present in the emergency departments. Also, education in pain management is more common in the ambulance services. These findings are noteworthy as, hypothetically, the same patient could be treated in three different ways during the same care episode. CONCLUSIONS: There is an urgent need to develop high-quality evidence-based clinical guidelines for this patient group, with the entire care process in focus. PMID- 27491470 TI - Including alpha s1 casein gene information in genomic evaluations of French dairy goats. AB - BACKGROUND: Genomic best linear unbiased prediction methods assume that all markers explain the same fraction of the genetic variance and do not account effectively for genes with major effects such as the alpha s1 casein polymorphism in dairy goats. In this study, we investigated methods to include the available alpha s1 casein genotype effect in genomic evaluations of French dairy goats. METHODS: First, the alpha s1 casein genotype was included as a fixed effect in genomic evaluation models based only on bucks that were genotyped at the alpha s1 casein locus. Less than 1 % of the females with phenotypes were genotyped at the alpha s1 casein gene. Thus, to incorporate these female phenotypes in the genomic evaluation, two methods that allowed for this large number of missing alpha s1 casein genotypes were investigated. Probabilities for each possible alpha s1 casein genotype were first estimated for each female of unknown genotype based on iterative peeling equations. The second method is based on a multiallelic gene content approach. For each model tested, we used three datasets each divided into a training and a validation set: (1) two-breed population (Alpine + Saanen), (2) Alpine population, and (3) Saanen population. RESULTS: The alpha s1 casein genotype had a significant effect on milk yield, fat content and protein content. Including an alpha s1 casein effect in genetic and genomic evaluations based only on male known alpha s1 casein genotypes improved accuracies (from 6 to 27 %). In genomic evaluations based on all female phenotypes, the gene content approach performed better than the other tested methods but the improvement in accuracy was only slightly better (from 1 to 14 %) than that of a genomic model without the alpha s1 casein effect. CONCLUSIONS: Including the alpha s1 casein effect in a genomic evaluation model for French dairy goats is possible and useful to improve accuracy. Difficulties in predicting the genotypes for ungenotyped animals limited the improvement in accuracy of the obtained estimated breeding values. PMID- 27491473 TI - Deprescription in Advanced Cancer Patients Referred to Palliative Care. AB - In palliative care, drugs are considered futile if they do not have a short-term benefit in symptom control or quality of life. The authors examined pharmacotherapy prescribed for patients referred to palliative care to identify futile drugs. This was a retrospective analysis of patients referred over 6 months, focusing on the prescription of gastric protectants, antidiabetic agents, bisphosphonates, anticoagulants, antidementia drugs, statins, and antihypertensive agents. The sample consisted of 448 patients. Gastric protectants were prescribed futilely in 50% of cases (125/248), statins in 97% (69/71), antihypertensive agents in 27% (42/155), antidiabetic drugs in 1% (1/70), bisphosphonates in 27% (4/15), and antidementia drugs in 100% (9/9). This study reveals that many patients with advanced cancer continue to be treated with inappropriate drugs and points to the need for medical training in palliative care, drawing attention to the need for therapeutic review at each medical visit. PMID- 27491472 TI - Serum gamma-glutamyltransferase is not associated with subclinical atherosclerosis in patients with type 2 diabetes. AB - BACKGROUND: This study investigated the association between serum gamma glutamyltransferase (GGT) level and subclinical atherosclerosis in patients with type 2 diabetes. METHODS: This cross-sectional study involved 1024 patients with type 2 diabetes mellitus. Measurement of brachial-ankle pulse wave velocity (baPWV; as a marker of arterial stiffness) and an ultrasound assessment of carotid atherosclerosis were performed. Subclinical atherosclerosis was defined by the presence of a high baPWV (>=1720 cm/s), carotid atherosclerosis (intima media thickness >0.8 mm or the presence of plaques), and carotid stenosis (>=50 % of luminal narrowing). The subjects were stratified into quartiles according to GGT level, and the relationship between GGT level and subclinical atherosclerosis was analysed. RESULTS: Serum GGT levels were closely associated with obesity, atherogenic dyslipidemia, and metabolic syndrome. However, serum GGT levels did not show a linear association with baPWV, carotid intima-media thickness, or plaque grade. The prevalence of high baPWV, carotid atherosclerosis, and carotid stenosis did not differ between the quartiles in men and women. Multivariate logistic regression analyses revealed no association between GGT level and high baPWV, carotid atherosclerosis, and carotid stenosis, either as continuous variables or quartiles. CONCLUSIONS: Serum GGT levels were significantly associated with obesity, atherogenic dyslipidaemia, and metabolic syndrome, but not with the early and late stages of atherosclerotic vascular changes, in patients with type 2 diabetes. Serum GGT level may not be a reliable marker of subclinical atherosclerosis in type 2 diabetes. PMID- 27491474 TI - Fractions Learning in Children With Mathematics Difficulties. AB - Learning fractions is difficult for children in general and especially difficult for children with mathematics difficulties (MD). Recent research on developmental and individual differences in fraction knowledge of children with MD and typically achieving (TA) children has demonstrated that U.S. children with MD start middle school behind their TA peers in fraction understanding and fall further behind during middle school. In contrast, Chinese children, who like the MD children in the United States score in the bottom one third of the distribution in their country, possess reasonably good fraction understanding. We interpret these findings within the framework of the integrated theory of numerical development. By emphasizing the importance of fraction magnitude knowledge for numerical understanding in general, the theory proved useful for understanding differences in fraction knowledge between MD and TA children and for understanding how knowledge can be improved. Several interventions demonstrated the possibility of improving fraction magnitude knowledge and producing benefits that generalize to fraction arithmetic learning among children with MD. The reasonably good fraction understanding of Chinese children with MD and several successful interventions with U.S. students provide hope for the improvement of fraction knowledge among American children with MD. PMID- 27491475 TI - The association between multiple sclerosis and uveitis. AB - The association between multiple sclerosis (MS) and uveitis has been questioned. Nerve tissue and eye tissue develop from the same embryonic cells; thus, MS and uveitis could be etiologically associated. In published studies, the prevalence of MS in patients with uveitis differe from 0.7% to 30.4%, whereas the prevalence of uveitis in patients with MS differe from 0.65% to 36.7%. Based on the largest retrospective studies, the prevalence of uveitis among MS patients is ~1%, and the prevalence of MS among patients with uveitis is ~1%. This is considerably higher than in the general population; thus, more research on this topic is needed to further understand the relationship between MS and uveitis. PMID- 27491476 TI - Controversies over the role of internal limiting membrane peeling during vitrectomy in macular hole surgery. AB - Surgical management of an idiopathic macular hole consists of vitrectomy to release vitreofoveal traction and intraocular tamponade to flatten and reappose the hole's edges. The intentional atraumatic removal of the internal limiting membrane has been proposed as cost-effective option in macular hole surgery. The internal limiting membrane contributes to tangential traction at the edges of the hole and acts as a platform on which glial cells proliferate. Removal of the internal limiting membrane increases the elasticity of the denuded macula and improves the anatomical success rate; however, the visual consequences of this surgical maneuver are still not fully known. We discuss the beneficial and adverse effects associated with internal limiting membrane peeling in macular hole surgery, highlighting the internal limiting membrane's role in macular hole etiology and pathogenesis and the anatomical and functional findings after its removal. PMID- 27491477 TI - Revisiting the interpretation of casein micelle SAXS data. AB - An in-depth, critical review of model-dependent fitting of small-angle X-ray scattering (SAXS) data of bovine skim milk has led us to develop a new mathematical model for interpreting these data. Calcium-edge resonant soft X-ray scattering data provides unequivocal evidence as to the shape and location of the scattering due to colloidal calcium phosphate, which is manifested as a correlation peak centred at q = 0.035 A(-1). In SAXS data this feature is seldom seen, although most literature studies attribute another feature centred at q = 0.08-0.1 A(-1) to CCP. This work shows that the major SAXS features are due to protein arrangements: the casein micelle itself; internal regions approximately 20 nm in size, separated by water channels; and protein structures which are inhomogeneous on a 1-3 nm length scale. The assignment of these features is consistent with their behaviour under various conditions, including hydration time after reconstitution, addition of EDTA (a Ca-chelating agent), addition of urea, and reduction of pH. PMID- 27491478 TI - Cognitive inflexibility in Obsessive-Compulsive Disorder. AB - Obsessive-Compulsive Disorder (OCD) is characterized by maladaptive patterns of repetitive, inflexible cognition and behavior that suggest a lack of cognitive flexibility. Consistent with this clinical observation, many neurocognitive studies suggest behavioral and neurobiological abnormalities in cognitive flexibility in individuals with OCD. Meta-analytic reviews support a pattern of cognitive inflexibility, with effect sizes generally in the medium range. Heterogeneity in assessments and the way underlying constructs have been operationalized point to the need for better standardization across studies, as well as more refined overarching models of cognitive flexibility and executive function (EF). Neuropsychological assessments of cognitive flexibility include measures of attentional set shifting, reversal and alternation, cued task switching paradigms, cognitive control measures such as the Trail-Making and Stroop tasks, and several measures of motor inhibition. Differences in the cognitive constructs and neural substrates associated with these measures suggest that performance within these different domains should be examined separately. Additional factors, such as the number of consistent trials prior to a shift and whether a shift is explicitly signaled or must be inferred from a change in reward contingencies, may influence performance, and thus mask or accentuate deficits. Several studies have described abnormalities in neural activation in the absence of differences in behavioral performance, suggesting that our behavioral probes may not be adequately sensitive, but also offering important insights into potential compensatory processes. The fact that deficits of moderate effect size are seen across a broad range of classic neuropsychological tests in OCD presents a conceptual challenge, as clinical symptomatology suggests greater specificity. Traditional cognitive probes may not be sufficient to delineate specific domains of deficit in this and other neuropsychiatric disorders; a new generation of behavioral tasks that test more specific underlying constructs, supplemented by neuroimaging to provide insight into the underlying processes, may be needed. PMID- 27491480 TI - The integrated ultradian organization of behavior and physiology in mice and the contribution of orexin to the ultradian patterning. AB - Our series of rat experiments have shown that locomotor activity, arousal level, body and brown adipose tissue temperatures, heart rate and arterial pressure increase episodically in an integrated manner approximately every 100min (ultradian manner). Although it has been proposed that the integrated ultradian pattern is a fundamental biological rhythm across species, there are no reports of the integrated ultradian pattern in species other than rats. The aim of the present study was to establish a mouse model using simultaneous recording of locomotor activity, eating behavior, body temperature, heart rate and arousal in order to determine whether their behavior and physiology are organized in an ultradian manner in normal (wild-type) mice. We also incorporated the same recording in prepro-orexin knockout (ORX-KO) mice to reveal the role of orexin in the brain mechanisms underlying ultradian patterning. The orexin system is one of the key conductors required for coordinating autonomic functions and behaviors, and thus may contribute to ultradian patterning. In wild-type mice, locomotor activity, arousal level, body temperature and heart rate increased episodically every 93+/-18min (n=8) during 24h. Eating was integrated into the ultradian pattern, commencing 23+/-4min (n=8) after the onset of an electroencephalogram (EEG) ultradian episode. The integrated ultradian pattern in wild-type mice is very similar to that observed in rats. In ORX-KO mice, the ultradian episodic changes in locomotor activity, EEG arousal indices and body temperature were significantly attenuated, but the ultradian patterning was preserved. Our findings support the view that the ultradian pattern is common across species. The present results also suggest that orexin contributes to driving ultradian episodic changes, however, this neuropeptide is not essential for the generation of the ultradian pattern. PMID- 27491479 TI - Lateralized motor control processes determine asymmetry of interlimb transfer. AB - This experiment tested the hypothesis that interlimb transfer of motor performance depends on recruitment of motor control processes that are specialized to the hemisphere contralateral to the arm that is initially trained. Right-handed participants performed a single-joint task, in which reaches were targeted to 4 different distances. While the speed and accuracy was similar for both hands, the underlying control mechanisms used to vary movement speed with distance were systematically different between the arms: the amplitude of the initial acceleration profiles scaled greater with movement speed for the right dominant arm, while the duration of the initial acceleration profile scaled greater with movement speed for the left-non-dominant arm. These two processes were previously shown to be differentially disrupted by left and right hemisphere damage, respectively. We now hypothesize that task practice with the right arm might reinforce left-hemisphere mechanisms that vary acceleration amplitude with distance, while practice with the left arm might reinforce right-hemisphere mechanisms that vary acceleration duration with distance. We thus predict that following right arm practice, the left arm should show increased contributions of acceleration amplitude to peak velocities, and following left arm practice, the right arm should show increased contributions of acceleration duration to peak velocities. Our findings support these predictions, indicating that asymmetry in interlimb transfer of motor performance, at least in the task used here, depends on recruitment of lateralized motor control processes. PMID- 27491481 TI - Phase II trial of neoadjuvant letrozole and lapatinib in Asian postmenopausal women with estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2)-positive breast cancer [Neo-ALL-IN]: Highlighting the TILs, ER expressional change after neoadjuvant treatment, and FES-PET as potential significant biomarkers. AB - PURPOSE: Neo-ALL-IN (NCT 01275859) is a single-center, phase II study aimed to evaluate the efficacy and safety profiles of neoadjuvant letrozole plus lapatinib, as well as potential biomarkers, in postmenopausal women with ER- and HER2-positive (ER+HER2+) breast cancer. METHODS: Postmenopausal ER+HER2+ breast cancer of stages II-III was eligible. Daily 2.5 mg letrozole plus 1500 mg lapatinib were administered for 18-21 weeks before surgery. Clinical responses were assessed by palpation with caliper, breast ultrasonography, mammogram, and/or MRI. Biologic samples were collected for biomarker analyses at three time points (baseline, day 14, and before surgery). Baseline fluorine-18 fluorodeoxyglucose and fluorine-18 fluoroestradiol PET-CT scans were performed. RESULTS: Among 24 patients enrolled, 17 (70.8 %) completed planned neoadjuvant treatment, whereas 7 prematurely terminated the treatment and proceeded to surgery because of toxicity or progression; 2 patients showed definite progression, and 2 showed clinical regrowth by palpation regardless of minimal response. All patients eventually underwent breast cancer surgery. Toxicities were generally mild mostly within grades 1-2 except prolonged or recurrent grade 3 liver toxicities in 3 patients (13.6 %) regardless of sequential dose reduction, which finally led to discontinuation of treatment. The overall clinical response rates were 62.5 % (n = 15) including 1 CR in breast. However, no pathologic CR (ypT0-is N0) was achieved. SUVmax lower than 5.5 in baseline FES PET-CT (p = 0.007), baseline TILs over 20 % (p = 0.026), and decreased IHC ER Allred score after neoadjuvant treatment (p = 0.021) were significantly associated with adverse clinical response. CONCLUSIONS: When this chemo-free, combination neoadjuvant therapy with letrozole and lapatinib is given for Asian postmenopausal ER+HER2+ breast cancer, TILs, change of ER expression following neoadjuvant treatment, and SUVmax in baseline FES-PET are to be considered potential biomarkers in these patients. PMID- 27491482 TI - A method for optimizing dosage regimens in oncology by visualizing the safety and efficacy response surface: analysis of inotuzumab ozogamicin. AB - PURPOSE: The aim of this investigation was to develop a quantitative method to optimize inotuzumab ozogamicin (InO) dosage regimen in patients with indolent non Hodgkin lymphoma (NHL) by simultaneously balancing safety and efficacy. METHODS: Pharmacokinetics (PK), safety and efficacy data were obtained from a phase 2 trial of InO administered intravenously to patients (n = 81) with indolent NHL. The PK was described by a two-compartment model which was linked to: (1) an exponential tumor growth model to describe tumor size time course (efficacy determinant expressed as objective response rate) and (2) a precursor-dependent platelet inhibition model to describe platelet time course (safety determinant expressed as thrombocytopenia grade). The model was used to simulate virtual trials to construct safety and efficacy response surfaces. Using the simulated safety and efficacy contours, a clinical utility index (CUI) contour was then constructed, from which optimal InO regimens were then selected. RESULTS: The model-simulated efficacy response surface indicated near-optimal efficacy of InO at the dosage regimen used in the trial (1.8 mg/m(2) every 4 weeks). The model simulated safety response surface indicated that modifying the dosage regimen resulted in modest improvements in safety with little compromise in efficacy. The CUI contour identified 2 mg/m(2) every 10, 11, or 12 weeks as the "sweet spot" for optimal InO dosage regimen in patients with indolent NHL. CONCLUSION: An approach to dosage regimen optimization was developed for simultaneously balancing safety and efficacy. This approach allows objective identification of optimal dosage regimens from early trial information and thus has broad utility across oncology trials. PMID- 27491483 TI - Statistical Mechanical Model for pH-Induced Protein Folding: Application to Apomyoglobin. AB - Despite the major role of pH in protein folding and stability, a quantitative understanding of the pH-induced protein folding mechanism remains elusive. Two conventional models, the Monod-Wyman-Changeux and Linderstrom-Lang smeared charge models, respectively, have been used to analyze the formation/disruption of specific native structures and fluctuating non-native states. However, there are only a few models that can represent the overall kinetic events of folding/unfolding independent of the properties of relevant molecular species, which has hampered the efforts to systematically analyze pH-induced folding. Here, we constructed a statistical mechanical model that incorporates the protonation mechanism of conventional models along with a combined manual search and least-squares fitting procedure, which was used to investigate the folding of horse apomyoglobin over a wide pH range (2.2-6.7), with a time window ranging from ~40 MUs to ~100 s, using continuous-/stopped-flow fluorescence at 8 degrees C. Quantitative analysis assuming a five-state sequential scheme indicated that (1) pH-induced folding/unfolding is represented by both specific binding and Coulombic interactions; (2) kinetic folding/unfolding intermediates share kinetic mechanisms with the equilibrium intermediate, indicating their equivalence; and (3) native-like properties are acquired successively during folding by intermediates and in transition states. This model could also be applied to a variety of association/dissociation processes. PMID- 27491484 TI - Water ascent in trees and lianas: the cohesion-tension theory revisited in the wake of Otto Renner. AB - The cohesion-tension theory of water ascent (C-T) has been challenged over the past decades by a large body of experimental evidence obtained by means of several minimum or non-invasive techniques. The evidence strongly suggests that land plants acquire water through interplay of several mechanisms covered by the multi-force theory of (U. Zimmermann et al. New Phytologist 162: 575-615, 2004). The diversity of mechanisms includes, for instance, water acquisition by inverse transpiration and thermodynamically uphill transmembrane water secretion by cation-chloride cotransporters (L.H. Wegner, Progress in Botany 76:109-141, 2014). This whole plant perspective was opened by Otto Renner at the beginning of the last century who supported experimentally the strictly xylem-bound C-T mechanism, yet anticipated that the water ascent involves both the xylem conduit and parenchyma tissues. The survey also illustrates the known paradigm that new techniques generate new insights, as well as a paradigm experienced by Max Planck that a new scientific idea is not welcomed by the community instantly. PMID- 27491486 TI - The Case For and Against a Coronary Artery Calcium Trial: Means, Motive, and Opportunity. AB - Numerous observational studies have shown that coronary artery calcium (CAC) imaging can improve cardiovascular risk assessment in asymptomatic adults. Whether CAC imaging can improve cardiovascular outcomes as part of an overall risk reduction strategy compared to alternative care approaches has not been demonstrated in clinical trials. Therefore, the role of CAC imaging in primary prevention of cardiovascular disease is somewhat contentious. Advocates for expanded CAC testing offer the large amount of observational data as support for their position, while opponents to wider CAC testing propose that only a clinical trial can resolve the matter. This paper reviews the arguments for and against such a trial based on clinical, safety and economic considerations. We also propose potential trial approaches based on recent changes in clinical practice that could make a new CAC trial design feasible. PMID- 27491485 TI - Safety and Efficacy of Self-Expanding TAVR in Patients With Aortoventricular Angulation. AB - OBJECTIVES: The aim of this study was to determine the relationship between aortoventricular (AoV) angulation on clinical outcomes after self-expanding transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis who were deemed suboptimal for surgery. BACKGROUND: Multidetector computed tomographic (MDCT) imaging of the aortovalvular complex has become a prerequisite for case planning with self-expanding TAVR. The effect of aortic angulation, an index of an unfolded or "horizontal" aorta, on procedural outcome after self-expanding TAVR is not known. METHODS: The clinical course of 3,578 patients who received implants in the CoreValve US Clinical Trials and who had prospective MDCT estimation of the AoV angle before the procedure was reviewed. Clinical site echocardiogram assessments were used to determine the degree of residual aortic regurgitation 24 to 48 h after the procedure and at 30 days. On the basis of the measurement of the AoV angle on MDCT, patients were categorized into septiles, ranging from the lowest septile of an AoV angle <37.0 degrees to the highest AoV angle septile of >55.0 degrees . RESULTS: Patients were elderly (age 83.3 +/- 7.8 years) and were at high risk for surgical valve replacement (Society of Thoracic Surgeons Predicted Risk of Mortality 8.8 +/- 4.7). Greater degrees of AoV angulation were correlated with older age (p < 0.0001). Although procedure time was 6.9 min longer in the highest septile (59.4 +/- 35.9 min vs. 52.5 +/- 35.3 min in the lowest septile; p = 0.004), there were no linear trends (p > 0.05) in the frequencies of device success, procedural success, frequencies of moderate or greater aortic regurgitation at 30 days, number of valves implanted, or need for balloon post-dilation or new pacemakers among the AoV angle septiles. CONCLUSIONS: The degree of AoV angulation does not affect early clinical outcomes self-expanding transcatheter aortic valve replacement. (Safety and Efficacy Study of the Medtronic CoreValve(r) System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement [Medtronic CoreValve(r) U.S. Pivotal Trial]; NCT01240902). PMID- 27491487 TI - Arterial Remodeling and Endothelial Shear Stress Exhibit Significant Longitudinal Heterogeneity Along the Length of Coronary Plaques. PMID- 27491488 TI - When Is an Image Telling the Truth? Discordant Lessons From Imaging TAVR. PMID- 27491489 TI - Heart rate variability during sleep in children with autism spectrum disorder. AB - PURPOSE: Autonomic dysfunction has been reported in autism spectrum disorders (ASD). Less is known about autonomic function during sleep in ASD. The objective of this study is to provide insight into the autonomic cardiovascular control during different sleep stages in ASD. We hypothesized that patients with ASD have lower vagal and higher sympathetic modulation with elevated heart rate, as compared to typical developing children (TD). METHODS: We studied 21 children with ASD and 23 TD children during overnight polysomnography. Heart rate and spectral parameters were calculated for each vigilance stage during sleep. Data from the first four sleep cycles were used to avoid possible effects of different individual sleep lengths and sleep cycle structures. Linear regression models were applied to study the effects of age and diagnosis (ASD and TD). RESULTS: In both groups, HR decreased during non-REM sleep and increased during REM sleep. However, HR was significantly higher in stages N2, N3 and REM sleep in the ASD group. Children with ASD showed less high frequency (HF) modulation during N3 and REM sleep. LF/HF ratio was higher during REM. Heart rate decreases with age at the same level in ASD and in TD. We found an age effect in LF in REM different in ASD and TD. CONCLUSION: Our findings suggest possible deficits in vagal influence to the heart during sleep, especially during REM sleep. Children with ASD may have higher sympathetic dominance during sleep but rather due to decreased vagal influence. PMID- 27491490 TI - A case of idiopathic pure sudomotor failure associated with prolonged high levels of serum carcinoembryonic antigen. AB - We report a case of idiopathic pure sudomotor failure (IPSF) in which serum carcinoembryonic antigen (CEA) levels elevated at onset, and remained high while anhidrosis lasted. We considered that changes in serum levels of CEA were related to the disease activity of IPSF. PMID- 27491491 TI - Mixing positive and negative valence: Affective-semantic integration of bivalent words. AB - Single words have affective and aesthetic properties that influence their processing. Here we investigated the processing of a special case of word stimuli that are extremely difficult to evaluate, bivalent noun-noun-compounds (NNCs), i.e. novel words that mix a positive and negative noun, e.g. 'Bombensex' (bomb sex). In a functional magnetic resonance imaging (fMRI) experiment we compared their processing with easier-to-evaluate non-bivalent NNCs in a valence decision task (VDT). Bivalent NNCs produced longer reaction times and elicited greater activation in the left inferior frontal gyrus (LIFG) than non-bivalent words, especially in contrast to words of negative valence. We attribute this effect to a LIFG-grounded process of semantic integration that requires greater effort for processing converse information, supporting the notion of a valence representation based on associations in semantic networks. PMID- 27491492 TI - Sodium P-Aminosalicylic Acid Improved Manganese-Induced Learning and Memory Dysfunction via Restoring the Ultrastructural Alterations and gamma-Aminobutyric Acid Metabolism Imbalance in the Basal Ganglia. AB - Excessive intake of manganese (Mn) may cause neurotoxicity. Sodium para aminosalicylic acid (PAS-Na) has been used successfully in the treatment of Mn induced neurotoxicity. The gamma-aminobutyric acid (GABA) is related with learning and memory abilities. However, the mechanism of PAS-Na on improving Mn induced behavioral deficits is unclear. The current study was aimed to investigate the effects of PAS-Na on Mn-induced behavioral deficits and the involvement of ultrastructural alterations and gamma-aminobutyric acid (GABA) metabolism in the basal ganglia of rats. Sprague-Dawley rats received daily intraperitoneally injections of 15 mg/kg MnCl2.4H2O, 5d/week for 4 weeks, followed by a daily back subcutaneously (sc.) dose of PAS-Na (100 and 200 mg/kg), 5 days/week for another 3 or 6 weeks. Mn exposure for 4 weeks and then ceased Mn exposure for 3 or 6 weeks impaired spatial learning and memory abilities, and these effects were long-lasting. Moreover, Mn exposure caused ultrastructural alterations in the basal ganglia expressed as swollen neuronal with increasing the electron density in the protrusions structure and fuzzed the interval of neuropil, together with swollen, focal hyperplasia, and hypertrophy of astrocytes. Additionally, the results also indicated that Mn exposure increased Glu/GABA values as by feedback loops controlling GAT-1, GABAA mRNA and GABAA protein expression through decreasing GABA transporter 1(GAT-1) and GABA A receptor (GABAA) mRNA expression, and increasing GABAA protein expression in the basal ganglia. But Mn exposure had no effects on GAT-1 protein expression. PAS-Na treatment for 3 or 6 weeks effectively restored the above-mentioned adverse effects induced by Mn. In conclusion, these findings suggest the involvement of GABA metabolism and ultrastructural alterations of basal ganglia in PAS-Na's protective effects on the spatial learning and memory abilities. PMID- 27491494 TI - Redox-Dependent Transformation of a Hydrazinobuckybowl between Curved and Planar Geometries. AB - A red-fluorescent heterobuckybowl with an embedded hydrazine structure was synthesized from a cyclobiphenothiazine derivative via a strained cyclobicarbazole. The hydrazinobuckybowl was found to possess bowl and twist structures in the neutral state, a shallow bowl structure in the monocation state, and a planar structure in the dication state by means of X-ray crystallographic analysis, DFT calculations, and a comparison of experimental and calculated (13) C NMR chemical shifts. The hydrazinobuckybowl is the first buckybowl that changes its geometry between curved bowl/twist structures and a planar structure depending on the oxidation state. The drastic geometrical change was possible as a result of the presence of two heteroatoms in the bowl skeleton and the multiple reversible redox reactions of the compound. Owing to the two kinds of bowl and twist conformations, the bowl-inversion dynamics of the hydrazinobuckybowl were found to follow a triple-well potential model. PMID- 27491493 TI - Alcohol consumption, smoking, and drug use in pregnancy: Prevalence and risk factors in Southern Thailand. AB - INTRODUCTION: Substance use during pregnancy contributes to the risk of adverse health outcomes in mothers and children-in utero and during later development. In this study, we investigated the prevalence of substance use and associated factors in pregnant women receiving antenatal care in public hospitals in Thailand. METHODS: Women (3578) attending 7 antenatal care clinics in Songkhla for the first time during their current pregnancy were interviewed with a structured questionnaire focusing on demographic data, obstetric history, use of alcohol, tobacco, and other substances, and the General Health Questionnaire was administered. The use of substances was confirmed with the ultrarapid version of the Alcohol, Smoking, and Substance Involvement Screening Test and urine tests, which were also administered to 1 in 5 to 10 randomly selected women whose screening results were negative. RESULTS: Based on self-reports and General Health Questionnaire results, the weighted prevalence of alcohol, tobacco, or illicit substance use and that of "mental health problems" were 5.6% (95% confidence interval [CI], 4.9-6.4) and 29.2% (95% CI, 27.5-30.9), respectively. On the basis of the ultrarapid version of the Alcohol, Smoking, and Substance Involvement Screening Test and urine tests, the prevalence of likely substance use disorder during the 3 months prior to assessment was 1.2% (95% CI, 0.8-1.5) and 7.7% (95% CI, 4.6-10.7), respectively. Factors associated with substance use were religion, unmarried status, unplanned pregnancy, previous abortion, and current mental health problem. DISCUSSION: Our results emphasize the need for identification of substance use and mental health problems, with the help of questionnaires and biological markers, followed by early intervention. PMID- 27491495 TI - MYB expression: Potential role in separating adenoid cystic carcinoma (ACC) from pleomorphic adenoma (PA). AB - BACKGROUND: Basaloid tumors of the salivary gland both benign and malignant comprise ACC, cellular PA, basal cell adenoma (BCA), and basal cell adenocarcinoma. Rendering a diagnosis given a limited biopsy or fine needle aspiration (FNA) sample proves challenging. Activation of MYB by gene fusion has been found in salivary gland ACCs; therefore we investigated the utility of MYB immunohistochemistry (IHC) as a tool for distinguishing ACCs from other basaloid neoplasms. METHODS: We selected 48 cases of ACC (11 FNA blocks [CB]), 37 histologic resections [HR]), 74 PA (36 CB, 38 HR), and 18 BCA (7 CB, 11 HR). FNA CB showed 82% of ACCs (N = 9 of 11) as positive for MYB nuclear staining whereas 68% of ACCs (N = 25 of 37) were positive in HR. RESULTS: All PA were negative for MYB nuclear staining in both CB (N = 0 of 36) and HR (N = 0 of 38). CB showed 29% of BCA (N = 2 of 7) as positive for MYB nuclear staining and 55% (N = 6 of 11) positive in HR. Both ACC and BCA showed significantly higher mean staining intensity than PA in both CB and HR (P < 0.0001). When comparing ACC and BCA, significantly higher mean staining intensity was observed in CB (P = 0.02382) but not in HR (P = 0.42952). CONCLUSION: MYB nuclear staining may prove useful in separating ACC from PA and BCA, especially in limited cellular samples. Diagn. Cytopathol. 2016;44:799-804. (c) 2016 Wiley Periodicals, Inc. PMID- 27491496 TI - Metastatic Malignant Melanoma of the Urinary Bladder in a Patient With Benign Prostatic Hyperplasia and Urethral Stricture. PMID- 27491497 TI - New treatment approaches in CLL: Challenges and opportunities in the elderly. AB - The majority of patients with chronic lymphocytic leukemia (CLL) are over 70years old. These patients vary in their vulnerability toward treatment efforts. Heterogeneity in fitness of older patients with CLL is mainly determined by individual differences in physiological aging and pathological conditions such as comorbidities and geriatric syndromes. Various options exist to treat older patients with CLL outside and inside clinical trials. Among these are new treatment approaches, including chemoimmunotherapy with engineered CD20 antibodies (e.g., obinutuzumab), single agent therapy with kinase inhibitors (e.g., ibrutinib, idelalisib), other targeted drug therapy (e.g., venetoclax, lenalidomide), and combinations of these novel compounds. Treatment recommendations for older patients take patient-related as well as disease related risk factors into consideration. Emerging new treatment approaches in older patients offer novel opportunities, but also novel challenges which are discussed in this review. PMID- 27491498 TI - Weekly vinorelbine and paclitaxel in older patients with advanced non-small cell lung cancer: A phase II Fred and Pamela Buffet Cancer Center Clinical Trials Network study. AB - OBJECTIVE: Platinum-based doublet chemotherapy is the standard for most patients with advanced non-small cell lung cancer (NSCLC). Toxicity concerns limit chemotherapy for patients over 70years. Vinorelbine and paclitaxel are effective as single agents in advanced NSCLC. This phase II study evaluates safety and efficacy of a combination of these two agents in patients >70years with advanced NSCLC. MATERIALS AND METHODS: Patients with treatment naive metastatic NSCLC received two cycles comprising 6 weekly doses of vinorelbine and paclitaxel, with restaging scans at week 8. Patients with radiographic progression came off study. The estimated sample size was 29. Toxicity analyses were conducted after 10 patients and again after 19 patients were enrolled. Outcomes were safety and efficacy, progression free (PFS) and overall survival (OS) and quality of life (QOL). RESULTS: The study closed at second interim analysis as 6/19 patients had >=grade 4 non-hematologic toxicity (respiratory failure, sepsis, ischemic encephalopathy, pneumonia, hypoxemia, cardiopulmonary arrest, neutropenic fever, death). Of the 16 evaluable patients, 7 completed the study. Disease control rate (partial response+stable disease) was 47% (n=9); 37% (n=7) progressed. No complete responses were seen. Median PFS was 3.5months (95% CI: 1.4, 5.5) and OS 7.8months (95% CI: 1.9, 13.6). QOL did not change compared to baseline, at week 9, but increased at week 17. CONCLUSIONS: Although the combination met its response end points, increased toxicity makes this combination unsuitable for older patients. While QOL improved over the study, the small sample hinders interpretation. PMID- 27491499 TI - Renal assessment using CKD-EPI equation is useful as an early predictor of contrast- induced nephropathy in elderly patients with cancer. AB - OBJECTIVES: To assess respective roles of serum creatinine (SCr) alone and estimated glomerular filtration rate (eGFR) as an early predictor for contrast induced nephropathy (CIN) in elderly patients with cancer. MATERIALS AND METHODS: eGFR of 348 patients at 65years or older with malignancy who underwent contrast enhanced computed tomography (CECT) were calculated. eGFR was calculated based on the following three equations: Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI); Modification of Diet in Renal Disease Study (MDRD); Cockcroft Gault (CG). CIN was subdivided into two groups: CIN25% (SCr increase >25% but <=0.5mg/dl), and CIN0.5 (SCr increase >0.5mg/dl). The occurrence and clinical outcomes of CIN were determined according to SCr and eGFR. RESULTS: After CECT, CIN occurred in 50 (14.4%) patients, including 33 CIN25% patients and 17 CIN0.5 patients. CIN0.5 was significantly correlated with prolonged hospitalizations and increased in-hospital mortality, but not CIN25%. Despite SCr<1.5mg/dl, preexisting renal insufficiency (RI) was observed in 47 (13.5%) patients based on CKD-EPI equation, 50 (14.4%) patients based on MDRD equation, and 144 (41.4%) patients based on CG formula. In preexisting RI, the prevalence of CIN0.5 had an odds ratio of 15.02 (5.24 to 43.07) based on CKD-EPI equation, 13.73 (4.81 to 39.20) based on MDRD equation, and 5.03 (1.60 to 15.75) based on CG formula. CONCLUSION: In elderly patients with cancer who visit the emergency department, renal assessment before CECT using CKD-EPI equation was superior to SCr alone, MDRD equation, or CG formula in predicting the occurrence of CIN related CECT. PMID- 27491500 TI - The geriatrician's perspective on practical aspects of the multidisciplinary care of older adults with cancer. AB - Multidisciplinary teams (MDTs) have been incorporated into the practical care of elderly patients with cancer. Several geriatric oncology centres have attempted to determine the best way to implement MDTs by using geriatric assessment (GA). Developing a geriatric oncology service is a feasible work, which requires significant resources. The challenges of MDTs must be known so that better care planning for elderly patients with cancer can be devised. The aim of this paper is to discuss the practical aspects of the multidisciplinary care of older adults with cancer by considering a geriatric point of view and the recent literature. Reviewing data from recent studies helps enumerate the major challenges in establishing collaboration in geriatric oncology: evaluating the resources of your centre, knowing the role of each member of the team, establishing good communication both within the team and with the patients, and determining referral criteria and using screening tests to select which patients can benefit the most from the multidisciplinary evaluation and a more thorough GA. PMID- 27491501 TI - Remembrance of Professor Steven Wechsler (1948-2016). PMID- 27491502 TI - Cellular internalization and morphological analysis after intravenous injection of a highly hydrophilic octahedral rhenium cluster complex - a new promising X ray contrast agent. AB - The octahedral cluster compound Na2 H8 [{Re6 Se8 }(P(C2 H4 CONH2 )(C2 H4 COO)2 )6 ] has been shown to be highly radio dense, thus becoming a promising X-ray contrast agent. It was also shown that this compound had low cytotoxic effect in vitro, low acute toxicity in vivo and was eliminated rapidly from the body through the urinary tract. The present contribution describes a more detailed cellular internalization assay and morphological analysis after intravenous injection of this hexarhenium cluster compound at different doses. The median lethal dose (LD50 ) of intravenously administrated compound was calculated (4.67 +/- 0.69 g/kg). Results of the study clearly indicated that the cluster complex Hn [{Re6 Se8 }(P(C2 H4 CONH2 )(C2 H4 COO)2 )6 ]n-10 was not internalized into cells in vitro and induced only moderate morphological alterations of kidneys at high doses without any changes in morphology of liver, spleen, duodenum, or heart of mice. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27491503 TI - Macrophage Phenotype in Liver Injury and Repair. AB - Macrophages hold a critical position in the pathogenesis of liver injury and repair, in which their infiltrations is regarded as a main feature for both acute and chronic liver diseases. It is noted that, based on the distinct phenotypes and origins, hepatic macrophages are capable of clearing pathogens, promoting/or inhibiting liver inflammation, while regulating liver fibrosis and fibrolysis through interplaying with hepatocytes and hepatic stellate cells (HSC) via releasing different types of pro- or anti-inflammatory cytokines and growth factors. Macrophages are typically categorized into M1 or M2 phenotypes by adapting to local microenvironment during the progression of liver injury. In most occasions, M1 macrophages play a pro-inflammatory role in liver injury, while M2 macrophages exert an anti-inflammatory or pro-fibrotic role during liver repair and fibrosis. In this review, we focused on the up-to-date information about the phenotypic and functional plasticity of the macrophages and discussed the detailed mechanisms through which the phenotypes and functions of macrophages are regulated in different stages of liver injury and repair. Moreover, their roles in determining the fate of liver diseases were also summarized. Finally, the macrophage-targeted therapies against liver diseases were also be evaluated. PMID- 27491504 TI - Ruthenium-Catalyzed Methylation of Amines with Paraformaldehyde in Water under Mild Conditions. AB - Methylated amines are highly important for a variety of pharmaceutical and agrochemical applications. Existing routes for their formation result in the production of large amounts of waste or require high reaction temperatures, both of which impact the ecological and economical footprint of the methodologies. Herein, we report the ruthenium-catalyzed reductive methylation of a range of aliphatic amines, using paraformaldehyde as both substrate and hydrogen source, in combination with water. This reaction proceeds under mild aqueous reaction conditions. Additionally the use of a secondary phase for catalyst retention and recycling has been investigated with promising results. PMID- 27491505 TI - What are the most common first-trimester ultrasound findings in cases of Turner syndrome? AB - OBJECTIVES: To identify the most common first-trimester ultrasound findings in Turner syndrome (TS). To evaluate which first-trimester findings can be best used to predict the likelihood of TS. METHODS: This was a prospective study, based on singleton pregnancies. The referrals included 6210 patients. Scan protocol covered a review of the early fetal anatomy and markers of aneuploidy. RESULTS: Study population comprised 5644 pregnancies: 5613 with a normal karyotype and 31 cases of TS. Statistically significant differences (p < 0.05) were found between euploidy and TS groups in terms of nuchal translucency (NT; 1.7 mm versus 8.8 mm) and fetal heart rate (FHR; 160 versus 171 beats per minute). None of the TS cases demonstrated absent markers of aneuploidy as opposed to 5133 (91.4%) cases of euploidy. NT and abnormal DV flow (aDV or revDV) were the most common markers found in combination in TS cases (n = 17; 54.8%). 27 (0.5%) cases of euploidy and 17 (54.8%) cases of TS revealed congenital heart defects. Fetal hydrops was observed in 14 cases of TS (43.8%) and in 5 of euploidy (0.1%). In backward regression model, NT > 3.5 mm and right dominant heart (RDH) augmented the risk of TS risk by 991 and 314 times, respectively. CONCLUSIONS: First-trimester sonography is a feasible method to identify the most characteristic features of TS fenotype. When the first-trimester pattern of TS is considered, a highly thickened NT, FHR above the 95th percentile, abnormal ductus venosus velocimetry, fetal hydrops, and RDH should be specifically searched for. PMID- 27491506 TI - An assessment of lactobiopolymer-montmorillonite composites for dip coating applications on fresh strawberries. AB - BACKGROUND: The use of biopolymer coatings appears as a good alternative to preserve highly perishable fruits, as well as the environment. Proteins generally produce films with good mechanical properties, although their highly hydrophilic nature limits the use in many applications. Nanoparticles, such as nanoclays, can play a critical role in improving barrier properties. The present study evaluated the effect of the addition of montmorillonite (MMT)-nanoparticles to a lacto biopolymer coating, focusing on: (i) the morphological, thermal and barrier properties of the material and (ii) the shelf life of coated fresh strawberries. RESULTS: The addition of MMT improved the water vapor barrier property. Morphological and thermal analysis indicated a good interaction between the milk protein and the nanoclay, which was intercalated within the milk protein base (MPB) matrix, offering a more tortuous path to diffusing migrants. The MMT-MPB coating helped to significantly (P <= 0.05) reduce the weight loss, as well as oxygen uptake and the release of carbon dioxide, and improved the fruit firmness and reduced mould and yeast load compared to the uncoated fruits. The addition of MMT gave statistical difference (P <= 0.05) in terms of weight loss, subjective global appearance and purchase intention of coated fresh strawberries. CONCLUSION: The addition of nanofillers, such as MMT, into protein-based coating could improve its water vapour barrier and could affect, positively, some parameters of the shelf life of coated strawberries. (c) 2016 Society of Chemical Industry. PMID- 27491507 TI - Tuning the emission properties of a fluorescent polymer using a polymer microarray approach - identification of an optothermo responsive polymer. AB - Polymer microarrays were prepared using inkjet printing mixtures of acrylate monomers each with a common fluorescent fluorene co-polymer. Fluorescence analysis of each of the features on the array allowed identification of polymers that could tune the fluorescence under a variety of insults. The "hit" polymers were made into beads via reverse suspension polymerization and their fluorescence properties were analyzed. PMID- 27491508 TI - Peptides@mica: from affinity to adhesion mechanism. AB - Investigating the adsorption of peptides on inorganic surfaces, on the molecular level, is fundamental for medicinal and analytical applications. Peptides can be potent as linkers between surfaces and living cells in biochips or in implantation medicine. Here, we studied the adsorption process of the positively charged pentapeptide RTHRK, a recently identified binding sequence for surface oxidized silicon, and novel analogues thereof to negatively charged mica surfaces. Homogeneous formation of monolayers in the nano- and low micromolar peptide concentration range was observed. We propose an alternative and efficient method to both quantify binding affinity and follow adhesion behavior. This method makes use of the thermodynamic relationship between surface coverage, measured by atomic force microscopy (AFM), and the concomitant free energy of adhesion. A knowledge-based fit to the autocorrelation of the AFM images was used to correct for a biased surface coverage introduced by the finite lateral resolution of the AFM. Binding affinities and mechanisms were further explored by large scale molecular dynamics (MD) simulations. The combination of well validated MD simulations with topological data from AFM revealed a better understanding of peptide adsorption processes on the atomistic scale. We demonstrate that binding affinity is strongly determined by a peptide's ability to form salt bridges and hydrogen bonds with the surface lattice. Consequently, differences in hydrogen bond formation lead to substantial differences in binding affinity despite conservation of the peptide's overall charge. Further, MD simulations give access to relative changes in binding energy of peptide variations in comparison to a lead compound. PMID- 27491509 TI - Multidisciplinary Treatment of Severe Upper Incisor Root Resorption Secondary to Transposed Canine. AB - OBJECTIVE: Tooth transposition is a rare dental anomaly that could lead to undesirable side effects on other teeth. This case report aims to describe the multidisciplinary treatment of a patient with a severely resorbed permanent maxillary central incisor due to transposition with the permanent canine. CLINICAL CONSIDERATIONS: A girl aged 13 years and 7 months with a chief complaint of a pink spot on her maxillary left incisor with a slightly erupted tooth above it was referred to our clinic. Her left maxillary canine was transposed to her left central incisor site. The left canine was impacted and had caused severe resorption of the left central incisor root. Her maxillary left canine was substituted for the central incisor after the compulsory extraction of her left central incisor. The canine was prosthetically restored after orthodontic treatment. The results were stable 1 year after treatment had been completed. CONCLUSIONS: Orthodontic treatment in coordination with other dental specialties like prosthodontics, periodontology and oral and maxillofacial surgery can provide functional and esthetic outcome in cases of severely transposed canines. CLINICAL SIGNIFICANCE: This is a rare case of transposition that shows the significant root resorption on the maxillary central incisor due to the ectopic eruption of the canine. Canine substitution for the central incisor was chosen as a treatment plan instead of placing an implant. An esthetic smile and a functional occlusion were established at the end of the treatment. (J Esthet Restor Dent 29:5-12, 2017). PMID- 27491510 TI - A visible light-driven photocatalyst of a stable metal-organic framework based on Cu4Cl clusters and TIPE spacers. AB - A 3D new metal-organic framework (MOF) [Cu4Cl(TIPE)3].3Cl (1) has been synthesized and characterized. Compound 1 exhibits good chemical stability in aqueous solution with the pH ranging from 1 to 11. Interestingly, compound 1 shows high catalytic activities for the degradation of dyes (RhB, MB and MO) under LED and natural light irradiation. The Ea of 1 for RhB, MB and MO degradation is obtained to be 79.71, 66.14 and 87.26 kJ mol(-1), respectively. Furthermore, compound 1 can be reused in the catalytic process without the catalytic activity obviously decreasing. PMID- 27491511 TI - Work-related Injuries Among Emergency Medical Technicians in Western Turkey. AB - OBJECTIVES: Emergency medical technicians (EMTs) and paramedics are at serious risk for work-related injuries (WRIs) during work hours. Both EMTs and paramedics have higher WRI rates, according to the literature data. This study was designed to investigate causes and characteristics of WRIs involving EMTs and paramedics staffed in Western Turkey. METHODS: All health care personnel staffed in Emergency Medical Services (EMS) in the city were interviewed face-to-face in their off-duty hours to inform them about the study. Excluded from the study were those who declined to participate in the study, those who were not on duty during the two-month study period, and those who had been working in the EMS for less than one year. The subjects were asked to answer multiple-choice questions. RESULTS: A total of 163 personnel (117 EMTs and 46 paramedics) comprised the study sample. Eighty-three personnel (50.9%) were female and mean age was 29.7 years (SD=8.4 years). The most common mechanisms of WRI, as reported by the personnel, were motor vehicle accidents (MVAs; 31.9%), needlestick injuries (16.0%), ocular exposure to bodily fluids (15.4%), and sharp injuries (9.8%), respectively. Needlestick injuries commonly occurred during intravenous line procedures (59.4%) and inside the cruising ambulance (n=20; 62.5%). Working inside the cruising ambulance was the most commonly accused cause of the WRI (41.3%). CONCLUSION: Paramedic personnel and EMTs are under high risk of WRI. Motor vehicle accidents and needlestick injuries were the most common causes of WRI. Strict measures need to be taken to restructure the interior design to protect personnel from all kinds of WRIs. Yilmaz A , Serinken M , Dal O , Yaylaci S , Karcioglu O . Work-related injuries among emergency medical technicians in Western Turkey. Prehosp Disaster Med. 2016;31(5):505-508. PMID- 27491512 TI - Multimodal imaging of foveal cavitation in retinal dystrophies. AB - PURPOSE: Inherited retinal dystrophies and cone dysfunction syndromes may show a sharp hyporeflective interruption in the outermost retinal layers on optical coherence tomography (OCT), known as foveal cavitation (FC). The aim of the study was to describe the morpho-functional features of FC in patients affected by retinal dystrophies by means of multimodal imaging. METHODS: A consecutive series of patients affected by FC were prospectively recruited for the study. Patients underwent short-wavelength (SW) and near-infraRed (NIR) fundus autofluorescence (FAF), spectral domain OCT (SD-OCT), microperimetry (MP), and multifocal electroretinogram (mfERG). Mean size of FC on OCT was correlated with best corrected visual acuity (BCVA). RESULTS: Overall, 15 patients (30 eyes) were enrolled. Mean age was 38.2 +/- 14.5 years (range: 10-60), with nine females (60 %). Mean BCVA was 0.5 +/- 0.4 LogMAR. SD-OCT revealed focal loss of outer retinal layers and disruption of inner segment ellipsoid zone. Vertical height of FC (mean 27.77 +/- 18.77 MUm) was indirectly related to BCVA; complete forms of FC, with total loss of outer OCT bands, showed a poorer visual outcome. The FC size on NIR-FAF turned out to be larger with respect to SD-OCT and SW-FAF. CONCLUSION: Our data indicate that the presence of FC worsens functional outcome in patients affected by retinal disorders; complete and higher lesions are associated with a worse morpho-functional prognosis in these eyes. PMID- 27491513 TI - A review on prolificacy genes in sheep. AB - Ovulation rate and litter size are important reproduction traits in sheep and are of high economic value. Reproduction traits typically have low to medium heritabilities and do not exhibit a noticeable response to phenotypic selection. Therefore, inclusion of genetic information of the genes associated with reproductive ability could efficiently enhance the selection response. The most important major genes affecting prolificacy and their genetic diversities in different sheep breeds were reviewed. Different causative mutations with major effects on reproductive traits including ovulation rate and litter size have been found in various sheep breeds around the world. A general overview of the studies on main prolificacy genes showed that some alleles may express different phenotypic effects in different breeds, and thus, further studies on epistatic effects are necessary for more understanding of genetic control of reproductivity in sheep. Regarding the polygenic control of fertility traits, application of new high-throughput technologies to find new variants is essential for future studies. Moreover, genomewide association studies and genomic best linear unbiased predictions of breeding values are likely to be effective tools for genetic improvement of sheep reproductive performance traits. PMID- 27491514 TI - Aqueous photocatalytic degradation of selected micropollutants by Pd-modified titanium dioxide in three photoreactor types. AB - The goals of the present study were to synthesise highly efficient Pd-TiO2 photocatalyst, to characterise its performance in slurry in smaller scale and to investigate its performance in the aqueous photocatalytic oxidation of three antibiotics: doxycycline, sulphamethizole and amoxicillin. The performance of the photocatalyst was evaluated in an open batch slurry reactor equipped with a fluorescent long-wavelength ultraviolet (UVA) lamp (0.2 L). With the fastest degrading doxycycline, experimental research was continued in a fixed-bed continuous flow photoreactor (0.13 L), with the Pd-TiO2 photocatalyst attached to a glass plate, and a medium laboratory-scale three-phase fluidised-bed reactor (2 L) equipped with four fluorescent UVA lamps, with the photocatalyst attached to the surface of expanded clay granules employed as the bed material. While showing very high activity in the batch slurry reactor, far surpassing P25 Aeroxide, the performance of Pd-TiO2 with doxycycline was comparable to P25 in the semi continuous reactors. PMID- 27491515 TI - Single-electron induced surface plasmons on a topological nanoparticle. AB - It is rarely the case that a single electron affects the behaviour of several hundred thousands of atoms. Here we demonstrate a phenomenon where this happens. The key role is played by topological insulators-materials that have surface states protected by time-reversal symmetry. Such states are delocalized over the surface and are immune to its imperfections in contrast to ordinary insulators. For topological insulators, the effects of these surface states will be more strongly pronounced in the case of nanoparticles. Here we show that under the influence of light a single electron in a topologically protected surface state creates a surface charge density similar to a plasmon in a metallic nanoparticle. Such an electron can act as a screening layer, which suppresses absorption inside the particle. In addition, it can couple phonons and light, giving rise to a previously unreported topological particle polariton mode. These effects may be useful in the areas of plasmonics, cavity electrodynamics and quantum information. PMID- 27491517 TI - Vision in Plants via Plant-Specific Ocelli? AB - Although plants are sessile organisms, almost all of their organs move in space and thus require plant-specific senses to find their proper place with respect to their neighbours. Here we discuss recent studies suggesting that plants are able to sense shapes and colours via plant-specific ocelli. PMID- 27491516 TI - The Unexpected Diversity of Plant Organelle RNA Editosomes. AB - Flowering plants convert many hundreds of organelle cytidines (Cs) to uridines (Us) during post-transcriptional RNA editing. Pentatricopeptide repeat (PPR) proteins dictate specificity by recognizing RNA sequences near C targets. However, the complete mechanism of the editing machinery is not yet understood. Recently, non-PPR editing factors [RNA editing factor interacting proteins (RIPs)/multiple organellar RNA editing factors (MORFs), organelle RNA recognition motif (ORRM) proteins, organelle zinc-finger (OZ) proteins, and protoporphyrinogen oxidase 1 (PPO1)] have been identified as components of the plant RNA editosome, which is a small RNA-protein complex. Surprisingly, plant editosomes are highly diverse not only with regard to the PPR proteins they contain but also in the non-PPR components that are present. Here we review the most recent progress in the field and discuss the implications of the diversity of plant editosomes for the evolution of RNA editing and for possible future applications. PMID- 27491518 TI - Investigating the effect of landfill leachates on the characteristics of dissolved organic matter in groundwater using excitation-emission matrix fluorescence spectra coupled with fluorescence regional integration and self organizing map. AB - For the purpose of investigating the effect of landfill leachate on the characteristics of organic matter in groundwater, groundwater samples were collected near and in a landfill site, and dissolved organic matter (DOM) was extracted from the groundwater samples and characterized by excitation-emission matrix (EEM) fluorescence spectra combined with fluorescence regional integration (FRI) and self-organizing map (SOM). The results showed that the groundwater DOM comprised humic-, fulvic-, and protein-like substances. The concentration of humic-like matter showed no obvious variation for all groundwater except the sample collected in the landfill site. Fulvic-like substance content decreased when the groundwater was polluted by landfill leachates. There were two kinds of protein-like matter in the groundwater. One kind was bound to humic-like substances, and its content did not change along with groundwater pollution. However, the other kind was present as "free" molecules or else bound in proteins, and its concentration increased significantly when the groundwater was polluted by landfill leachates. The FRI and SOM methods both can characterize the composition and evolution of DOM in the groundwater. However, the SOM analysis can identify whether protein-like moieties was bound to humic-like matter. PMID- 27491519 TI - Outcomes of Sacral Neuromodulation in a Privately Insured Population. AB - OBJECTIVE: In this study, we analyzed claims data from the Ingenix data base to analyze outcomes of sacral neuromodulation with respect to both provider and patient factors. MATERIALS AND METHODS: We used the Ingenix (I3) data base to determine demographic, diagnosis, and procedure success information for years 2002-2007 for privately insured patients. Demographic information was obtained, as were the diagnoses given and procedures performed, based on ICD-9 diagnosis codes and Current Procedural Terminology procedure codes. Multivariate analysis was performed to identify specific predictors of success, as measured by progression to implantation of a pulse generator. RESULTS: Overall success, as defined by battery placement, was 49.1%. Fifty-one percent of staged procedures were followed by battery placement compared with 24.1% of percutaneous cases (p < 0.0001). Among the patient variables analyzed, women were more likely than men to progress to battery placement. After Stage I testing, patients treated by urologists were overall more likely than gynecologists to proceed to battery placement (I3: 54% vs. 47%, p < 0.0001). Unlike previous findings in other claims based data sets, we did not observe a provider-volume relationship in the i3 data set. CONCLUSIONS: Success of sacral neuromodulation, as defined by proceeding to battery placement, was much better after formal staged procedures, which leads us to question the utility of percutaneous techniques. Outcomes were also better among female patients and among those treated by a urologist. Specialty differences will likely diminish over time as more gynecologists adopt sacral neuromodulation. PMID- 27491520 TI - Non-Covalently Stabilized Alginate Hydrogels as Functional Cell Scaffold Material. AB - Biopolymers are an attractive class of compounds for being used in biomedical applications as they are widely available from biomass. Their drawback is the lack of mechanical stability and the ability to tune this properly. Covalent chemical cross-linking is an often used approach but it limits usability due to legislation as well as the need of advanced and specialized knowledge by end users such as clinicians. Here, increased and tunable mechanical properties are achieved of alginate-based hydrogels with non-covalent approaches using linear polyethyleneimine (LPEI) as a polyelectrolyte rather than only multivalent metal ions (Ca2+ ). Gel stiffness increases with increasing LPEI content. Gel morphology changes from a thin fibrous mesh for alginate-Ca2+ to thicker fibrous networks when LPEI is introduced. The gels are able to efficiently release encapsulated small molecular dyes and the gels are able to host cells. For the cell encapsulation human skin fibroblasts (HSkF) and human bone marrow-derived mesenchymal stem cells (hBM-MSC) are used. HSkF can be successfully incorporated without diminished viability while the matrix components and gel preparation method are not compatible with hBM-MSC. The newly developed alginate-based system is regarded as a potential candidate for wound dressing materials. PMID- 27491521 TI - Proteomic analysis of FFPE tissue: barriers to clinical impact. PMID- 27491522 TI - HEALTH TECHNOLOGY ASSESSMENTS REPORTING COST-EFFECTIVENESS OF TRANSCATHETER AORTIC VALVE IMPLANTATION. AB - OBJECTIVES: Made available since 2002, transcatheter aortic valve implantation (TAVI) is a minimally invasive new intervention which can provide significant survival improvement to patients with aortic stenosis. However, TAVI is expensive and currently not reimbursed by many governments. Some governments and institutions have been conducting health technology assessments (HTAs) to inform their reimbursement decisions. The aim of the present study is to review HTAs that have relied on a cost-effectiveness analysis to inform reimbursement decisions of TAVI. METHODS: A systematic literature review was conducted among published literature as well as reports released by HTA agencies. Predetermined inclusion and exclusion criteria, following the Preferred Reporting System for Systematic Reviews and Meta-Analysis guidelines, were used to select relevant HTAs. The selected papers were assessed against the Consolidated Health Economic Evaluation Reporting Standards. RESULTS: HTAs on TAVI from three countries were available for this review: Canada, Belgium, and the United Kingdom. All three HTAs used the Placement of Aortic Transcatheter Valve (PARTNER) trial data with Markov models to estimate the incremental cost effectiveness ratio. The three HTAs recommended conditional reimbursement for TAVI for otherwise inoperable patients. The HTAs did not use clear methods to estimate the health-related utility which ultimately affected their cost-effectiveness results. The UK HTA showed the best value for money (US$20,416 per quality-adjusted life-year). CONCLUSION: All studies found TAVI to be more costly and less effective for high risk patients suitable for surgery, whereas TAVI was consistently found to be cost effective for otherwise inoperable patients. PMID- 27491523 TI - Obituary: a tribute to Yoshihiro Kaneko, MD. PMID- 27491524 TI - Erratum: Increased neutrophil to lymphocyte ratio in persons suffering from hypertension with hyperhomocysteinemia. PMID- 27491525 TI - QQ-plots for assessing distributions of biomarker measurements and generating defensible summary statistics. AB - One of the main uses of biomarker measurements is to compare different populations to each other and to assess risk in comparison to established parameters. This is most often done using summary statistics such as central tendency, variance components, confidence intervals, exceedance levels and percentiles. Such comparisons are only valid if the underlying assumptions of distribution are correct. This article discusses methodology for interpreting and evaluating data distributions using quartile-quartile plots (QQ-plots) and making decisions as to how to treat outliers, interpreting effects of mixed distributions, and identifying left-censored data. The QQ-plot graph is shown to be a simple and elegant tool for visual inspection of complex data and deciding if summary statistics should be performed after log-transformation. PMID- 27491526 TI - Screening Caregivers of Children for Risky Drinking in KwaZulu-Natal, South Africa. AB - Background and Objectives Alcohol abuse, a significant health problem in South Africa, affects the ability of adults to care for children. Little is known regarding risky alcohol use among child caregivers there. A large population based study examined the prevalence of, and factors associated with, risky drinking among caregivers of young children in KwaZulu-Natal, South Africa comparing the use of the Alcohol Use Disorders Identification Test (AUDIT) and the AUDIT-C screens for hazardous or harmful drinking (referred to here as risky drinking). Methods 83 % of child caregivers from five tribal areas were interviewed using the 10-question AUDIT to screen for risky drinking. The AUDIT-C screen, a subset of AUDIT questions, targets alcohol consumption and binge drinking. Factors associated with risky drinking were investigated using logistic regression. Results 1434 caregivers participated, 98 % female. Sixteen percent reported ever drinking alcohol. Based on AUDIT criteria for risky drinking, 13 % of the sample scored as moderate drinkers, 2 % as hazardous users, and 1 % as harmful or dependent users (identifying 3 % as risky drinkers). Using AUDIT-C criteria to identify risky drinking significantly increased the proportion of caregivers identified as risky drinkers to 9 %. In multivariate analyses, factors associated with risky drinking were similar in both screens: partner violence, smoking, HIV-infection, caring for a child with disabilities. Conclusions for Practice Since the AUDIT-C identified risky alcohol use not otherwise detected with the full AUDIT, and since resources for screening in health care settings is limited, the AUDIT-C may be a more appropriate screen in populations where binge drinking is common. PMID- 27491527 TI - Unintended Childbearing and Child Growth in Northern Malawi. AB - Objective The study aims to assess whether unintended children experience slower growth than intended children. Methods We analysed longitudinal data linked to the Karonga Health and Demographic Surveillance Site collected over three rounds between 2008 and 2011 on women's fertility intentions and anthropometric data of children. Using the prospective information on fertility intention we assessed whether unintended children are more likely to be stunted than intended children. We applied Propensity Score Matching technique to control for endogenous factors affecting both the probability that a family has an unwanted birth and a child with poor health outcomes. Results We found that 24 % of children from unwanted pregnancies were stunted compared with 18 % of mistimed pregnancies and 17 % of those from wanted pregnancies. However, these differences in probability of children being stunted, though in the expected direction, were not significant either for large or small families, after controlling for age. The number of children in the household was associated with stunting and boys were substantially more likely to be stunted than girls. Conclusion We found no significance difference in probability of being stunted by mother's fertility intention. PMID- 27491528 TI - Medicare Competitive Bidding Program. AB - A recent study by the National Minority Quality Forum (NMQF) reported the failures and adverse health outcomes of the Medicare competitive bidding program as implemented by the Centers for Medicare & Medicaid Services (CMS) in 2011. CMS has repeatedly reported that the program caused no disruption of beneficiary access to needed medical products (including diabetes testing supplies) and that no adverse outcomes occurred. Although signals of disruption were seen early in the program implementation, economic modeling by McGeary and Katzman in 2004 demonstrated that the program design was significantly flawed. This article discusses the unintended consequences of competitive bidding program and provides a rationale for suspending the program until CMS can implement effective monitoring protocols to protect the safety of Medicare beneficiaries. PMID- 27491529 TI - Arm, Leg, and Foot Skin Water in Persons With Diabetes Mellitus (DM) in Relation to HbA1c Assessed by Tissue Dielectric Constant (TDC) Technology Measured at 300 MHz. AB - BACKGROUND: DM is associated with structural skin changes. However, few studies have investigated changes in dermal water and specifically its relationship to glucose control as measured by HbA1c. Our goal was to test the hypothesis that skin water, assessed by its tissue dielectric constant (TDC), is inversely related to HbA1c. METHODS: Water content of 3 skin sites (forearm, lower leg, and foot dorsum) of 50 persons with DM was estimated by measuring TDC at 300 MHz. TDC is the ratio of tissue dielectric constant to vacuum and depends on free and bound water in the measured volume. TDC was measured in triplicate to 4 depths, 0.5. 1.5, 2.5, and 5.0 mm to include different skin components. RESULTS: At each site increased measurement depth showed (1) a significant decrease in absolute TDC values and (2) a significant increase in foot-to-arm TDC ratios. TDC values at forearm were shown to be greater than at either leg or foot. However, testing of these 50 patients at 3 sites and 4 skin depths did not show any significant relationship between TDC and HbA1c or fasting glucose. CONCLUSIONS: The data indicate no relationship between TDC values, as indices for skin water, and HbA1c or fasting glucose. This implies that skin TDC values to assess skin property features and changes in persons with DM are not sensitive to recent glucose control. Furthermore, the results introduce a newly applied TDC technology useful to assess skin properties of persons with DM. PMID- 27491530 TI - mHealth Real-Time Blood Glucose Monitoring Facilitates Glycemic Management. PMID- 27491531 TI - Exposure-based cognitive-behavioural therapy via the internet and as bibliotherapy for somatic symptom disorder and illness anxiety disorder: randomised controlled trial. AB - BACKGROUND: In DSM-5 two new diagnoses, somatic symptom disorder (SSD) and illness anxiety disorder (IAD), have replaced DSM-IV hypochondriasis. There are no previous treatment studies for these disorders. Cognitive-behavioural therapy (CBT) delivered as therapist-guided or unguided internet treatment or as unguided bibliotherapy could be used to increase treatment accessibility. AIMS: To investigate the effect of CBT delivered as guided internet treatment (ICBT), unguided internet treatment (U-ICBT) and as unguided bibliotherapy. METHOD: A randomised controlled trial (RCT) where participants (n = 132) with a diagnosis of SSD or IAD were randomised to ICBT, U-ICBT, bibliotherapy or to a control condition on a waiting list (trial registration: Clinicaltrials.gov identifier NCT01966705). RESULTS: Compared with the control condition, all three treatment groups made large and significant improvements on the primary outcome Health Anxiety Inventory (between-group d at post-treatment was 0.80-1.27). CONCLUSIONS: ICBT, U-ICBT and bibliotherapy can be highly effective in the treatment of SSD and IAD. This is the first study showing that these new DSM-5 disorders can be effectively treated. PMID- 27491533 TI - Effectiveness of trauma-focused treatment for patients with psychosis with and without the dissociative subtype of post-traumatic stress disorder. AB - This study presents secondary analyses of a recently published trial in which post-traumatic stress disorder (PTSD) patients with psychosis (n = 108) underwent 8 sessions of trauma-focused treatment, either prolonged exposure (PE) or eye movement desensitisation and reprocessing (EMDR) therapy. 24.1% fulfilled the criteria for the dissociative subtype, a newly introduced PTSD subtype in DSM-5. Treatment outcome was compared for patients with and without the dissociative subtype of PTSD. Patients with the dissociative subtype of PTSD showed large reductions in clinician-administered PTSD scale (CAPS) score, comparable with patients without the dissociative subtype of PTSD. It is concluded that even in a population with severe mental illness, patients with the dissociative subtype of PTSD do benefit from trauma-focused treatments without a pre-phase of emotion regulation skill training and should not be excluded from these treatments. PMID- 27491532 TI - Longitudinal course of behavioural and psychological symptoms of dementia: systematic review. AB - BACKGROUND: More information about the pattern of behavioural and psychological symptoms of dementia (BPSD) in the course of dementia is needed to inform patients and clinicians and to design future interventions. AIMS: To determine the persistence and incidence of BPSD and their relation to cognitive function, in individuals with dementia or in cohorts investigated for dementia onset. METHOD: A systematic literature review analysed the baseline prevalence, persistence and incidence of 11 symptoms. The review was conducted according to established guidelines with the exception that we could not exclude the possibilities of bias in the studies examined. RESULTS: The 59 included studies showed considerable heterogeneity in their objectives and methods. The symptoms hyperactivity and apathy showed high persistence and incidence; depression and anxiety low or moderate persistence and moderate incidence; and psychotic symptoms low persistence with moderate or low incidence. CONCLUSIONS: Despite heterogeneity across studies in terms of setting, focus and length of follow-up, there were clinically relevant differences in the longitudinal courses of different BPSD. Apathy was the only symptom with high baseline prevalence, persistence and incidence during the course of dementia. PMID- 27491534 TI - Association of timing of menarche with depressive symptoms and depression in adolescence: Mendelian randomisation study. AB - BACKGROUND: Observational studies report associations between early menarche and higher levels of depressive symptoms and depression. However, no studies have investigated whether this association is causal. AIMS: To determine whether earlier menarche is a causal risk factor for depressive symptoms and depression in adolescence. METHOD: The associations between a genetic score for age at menarche and depressive symptoms at 14, 17 and 19 years, and depression at 18 years, were examined using Mendelian randomisation analysis techniques. RESULTS: Using a genetic risk score to indicate earlier timing of menarche, we found that early menarche is associated with higher levels of depressive symptoms at 14 years (odds ratio per risk allele 1.02, 95% CI 1.005-1.04, n = 2404). We did not find an association between the early menarche risk score and depressive symptoms or depression after age 14. CONCLUSIONS: Our results provide evidence for a causal effect of age at menarche on depressive symptoms at age 14. PMID- 27491535 TI - The use of thermographic imaging to evaluate therapeutic response in human tumour xenograft models. AB - Non-invasive methods to monitor tumour growth are an important goal in cancer drug development. Thermographic imaging systems offer potential in this area, since a change in temperature is known to be induced due to changes within the tumour microenvironment. This study demonstrates that this imaging modality can be applied to a broad range of tumour xenografts and also, for the first time, the methodology's suitability to assess anti-cancer agent efficacy. Mice bearing subcutaneously implanted H460 lung cancer xenografts were treated with a novel vascular disrupting agent, ICT-2552, and the cytotoxin doxorubicin. The effects on tumour temperature were assessed using thermographic imaging over the first 6 hours post-administration and subsequently a further 7 days. For ICT-2552 a significant initial temperature drop was observed, whilst for both agents a significant temperature drop was seen compared to controls over the longer time period. Thus thermographic imaging can detect functional differences (manifesting as temperature reductions) in the tumour response to these anti-cancer agents compared to controls. Importantly, these effects can be detected in the first few hours following treatment and therefore the tumour is observable non-invasively. As discussed, this technique will have considerable 3Rs benefits in terms of reduction and refinement of animal use. PMID- 27491536 TI - Metabolic activities of five botryticides against Botrytis cinerea examined using the Biolog FF MicroPlate. AB - Tobacco grey mold caused by Botrytis cinerea is an important fungal disease worldwide. Boscalid, carbendazim, iprodione, pyrimethanil and propiconazole are representative botryticides for grey mold management. This research investigated the sensitivities of B. cinerea from tobacco to these chemicals using the Biolog FF Microplate. All five chemicals showed inhibitory activity, with average EC50 values of 0.94, 0.05, 0.50, 0.61 and 0.31 MUg ml(-1), respectively. B. cinerea metabolized 96.8% of tested carbon sources, including 29 effectively and 33 moderately, but the metabolic fingerprints differed under pressures imposed by these botryticides. For boscalid, B. cinerea was unable to metabolize many substrates related to tricarboxylic acid cycle. For carbendazim, carbon sources related to glycolysis were not metabolized. For iprodione, use of most carbon substrates was weakly inhibited, and the metabolic profile was similar to that of the control. For propiconazole, no carbon substrates were metabolized and the physiological and biochemical functions of the pathogen were totally inhibited. These findings provide useful information on metabolic activities of these botryticides, and may lead to future applications of the Biolog FF Microplate for examining metabolic effects of other fungicides on other fungi, as well as providing a metabolic fingerprint of B. cinerea that could be useful for identification. PMID- 27491538 TI - Does the Use of Intraoperative Microelectrode Recording Influence the Final Location of Lead Implants in the Ventral Intermediate Nucleus for Deep Brain Stimulation? AB - To determine if the use of intraoperative microelectrode recording (MER) influences the final location of lead implant in deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM), and to evaluate the incidence of associated complications. The usefulness of intraoperative MER in DBS is debated, some centers suggesting it increases complications without additional benefit. We conducted a retrospective chart review of all patients who underwent VIM DBS with MER at the University of Texas Health Science Center in Houston from June 1, 2009 to October 1, 2013. Initial (MRI determined) and final (intraoperative MER determined) coordinates of implant were compared. To assess incidences of hemorrhagic and infectious complications, we reviewed postoperative CT scans and follow-up notes. Forty-five lead implants on 24 patients were reviewed. The mean age at implantation was 62.42 years (range 18-83). The average duration from diagnosis to surgery was 21.5 years (range 1-52). A statistically significant mean difference was observed in the superior-inferior plane (0.52 +/- 0.80 mm inferiorly, p < 0.05) and the anterior-posterior plane (0.45 +/- 0.86 mm posteriorly, p < 0.05). A non-statistically significant difference was also observed in the medial-lateral plane (0.02+/- 0.15 mm, p > 0.05). One patient developed an infectious complication (4.2 %) that required removal of leads; two patients had minimal asymptomatic intra-ventricular bleeding (8.3 %). In our DBS center, intraoperative MER in VIM DBS implant does not seem to have a higher rate of surgical complications compared to historical series not using MER, and might also be useful in determining the final lead location. PMID- 27491537 TI - [Social psychiatry and neurobiology : A long overdue convergence exemplified by schizophrenia]. AB - BACKGROUND: The proliferation of biological psychiatry has greatly increased over the last two decades. With the possibility to carry out brain research using modern technical methods, it seemed that social influencing factors would lose importance in the development of mental diseases; however, in actual fact this does not seem to be justified. It is necessary to overcome this separation, in that social factors are incorporated into a conceptual framework in the development of mental diseases, which simultaneously also takes the results of current neurobiological research into consideration. OBJECTIVES AND METHODS: The aims of this review article are to summarize the current state of sociopsychiatric research and to emphasize the perspectives of the biological principles and their validity with respect to the social dimensions of psychiatry, as exemplified by schizophrenic disorders. The article presents the options for a biosocial approach in social psychiatry and gives an overview of the currently available literature. RESULTS AND CONCLUSION: There is an abundance of neurobiological research approaches, which are closely associated with sociopsychiatric topics, such as social cognition. Social psychiatry and biological psychiatry should no longer be considered as diametrically opposed subdisciplines. On the contrary, the options which could emerge from a synthesis must be used in research and clinical practice. PMID- 27491539 TI - Minimally invasive direct coronary bypass compared with percutaneous coronary intervention for left anterior descending artery disease: a meta-analysis. AB - BACKGROUND: The clinical outcomes for left anterior descending (LAD) coronary artery lesion between minimally invasive direct coronary artery bypass (MIDCAB) and percutaneous coronary intervention (PCI) are still controversial. The objective was to compare safety and efficacy between MIDCAB and PCI for LAD. METHODS: Electronic databases and article references were systematically searched to access relevant studies. End points included mortality, myocardial infarction, target vessel revascularization (TVR), major adverse coronary events (MACE), angina recurrence, and stroke. RESULTS: Fourteen studies with 941 patients were finally involved in the present study. The mortality and incidence of myocardial infarction were similar in MIDCAB and PCI groups at 30 days, 6 months, and at follow-up beyond 1 year. Compared with PCI, MIDCAB decreased incidence of TVR and MACE at 6 months and beyond 1 year follow-up. MIDCAB was associated with a lower incidence of angina recurrence at 6 months compared with PCI. PCI was associated with higher risk of restenosis in target vessel. No significant difference was shown for stroke. CONCLUSION: Our meta-analysis indicates that there are no significant differences in the safety between MIDCAB and PCI in patients with LAD. However MIDCAB is superior to PCI for TVR and MACE. PMID- 27491541 TI - Hemodynamic deterioration after aortic valve replacement in a patient with mixed systemic amyloidosis. AB - We report a case of hemodynamic deterioration after aortic valve replacement in a patient with mixed systemic amyloidosis. A 77-year-old male with severe aortic valve stenosis and 19 years hemodialysis underwent aortic valve replacement. Postoperatively, the patient died of hemodynamic deterioration. Autopsy findings showed massive, whole-body edema and mixed systemic amyloidosis (dialysis-related and AA amyloidosis). Clinical and autopsy findings implied that hemodynamic deterioration was caused by increased vascular permeability. The amyloid deposit to the vessel causes inflammatory changes and increases vascular permeability. Mixed systemic amyloidosis occurs very rarely and could increases vascular permeability even more than each single type of amyloidosis. Systemic amyloidosis may be a risk factor for hemodynamic deterioration after cardiac surgery. Patients with longtime hemodialysis and a history associated with dialysis related amyloidosis would have at least single systemic amyloidosis, which should be considered a contraindication to cardiac surgery with cardiopulmonary bypass. PMID- 27491540 TI - Comprehensive analysis of the Co-structures of dipeptidyl peptidase IV and its inhibitor. AB - BACKGROUND: We comprehensively analyzed X-ray cocrystal structures of dipeptidyl peptidase IV (DPP-4) and its inhibitor to clarify whether DPP-4 alters its general or partial structure according to the inhibitor used and whether DPP-4 has a common rule for inhibitor binding. RESULTS: All the main and side chains in the inhibitor binding area were minimally altered, except for a few side chains, despite binding to inhibitors of various shapes. Some residues (Arg125, Glu205, Glu206, Tyr662 and Asn710) in the area had binding modes to fix a specific atom of inhibitor to a particular spatial position in DPP-4. We found two specific water molecules that were common to 92 DPP-4 structures. The two water molecules were close to many inhibitors, and seemed to play two roles: maintaining the orientation of the Glu205 and Glu206 side chains through a network via the water molecules, and arranging the inhibitor appropriately at the S2 subsite. CONCLUSIONS: Our study based on high-quality resources may provide a necessary minimum consensus to help in the discovery of a novel DPP-4 inhibitor that is commercially useful. PMID- 27491542 TI - Outcomes of surgical aortic valve replacement using Carpentier-Edwards PERIMOUNT bioprosthesis series in elderly patients with severe aortic valve stenosis: a retrospective cohort study. AB - OBJECTIVE: We sought to compare the outcomes of Carpentier-Edwards PERIMOUNT (CEP), Magna and Magna Ease valves in Japanese elderly patients with severe aortic valve stenosis (AS). METHODS: We retrospectively identified 136 patients (mean age 76.61 +/- 5.5 years old) who had undergone isolated surgical aortic valve replacement (SAVR) using CEP, Magna, and Magna Ease valves at a single institution, from January 2001 to December 2013. We compared the valves according to their survival rates, freedom from major adverse cardiovascular and cerebrovascular events (MACCE), and durability and hemodynamic performance by echocardiographic data. RESULTS: The thirty-day mortality after isolated SAVR in all the valve groups was "zero". The differences among the three groups in terms of survival rates, freedom from MACCE at 2 years, durability and hemodynamic performance of the valves by echocardiographic data was not statistically significant. CONCLUSION: All CEP, Magna and Magna Ease valves seemed to be similarly useful in Japanese elderly patients with severe AS. Our data did not clearly support the superiority of one valve over another. A longer follow-up period might be necessary to compare the durability and hemodynamic performance of these valves with more certainty. PMID- 27491543 TI - Structure of the Saccharomyces cerevisiae Hrr25:Mam1 monopolin subcomplex reveals a novel kinase regulator. AB - In budding yeast, the monopolin complex mediates sister kinetochore cross-linking and co-orientation in meiosis I. The CK1delta kinase Hrr25 is critical for sister kinetochore co-orientation, but its roles are not well understood. Here, we present the structures of Hrr25 and its complex with the monopolin subunit Mam1. Hrr25 possesses a "central domain" that packs tightly against the kinase C-lobe, adjacent to the binding site for Mam1. Together, the Hrr25 central domain and Mam1 form a novel, contiguous embellishment to the Hrr25 kinase domain that affects Hrr25 conformational dynamics and enzyme kinetics. Mam1 binds a hydrophobic surface on the Hrr25 N-lobe that is conserved in CK1delta-family kinases, suggesting a role for this surface in recruitment and/or regulation of these enzymes throughout eukaryotes. Finally, using purified proteins, we find that Hrr25 phosphorylates the kinetochore receptor for monopolin, Dsn1. Together with our new structural insights into the fully assembled monopolin complex, this finding suggests that tightly localized Hrr25 activity modulates monopolin complex-kinetochore interactions through phosphorylation of both kinetochore and monopolin complex components. PMID- 27491544 TI - Expression of Cystic Fibrosis Transmembrane Conductance Regulator in Ganglia of Human Gastrointestinal Tract. AB - CF is caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) which is an anion selective transmembrane ion channel that mainly regulates chloride transport, expressed in the epithelia of various organs. Recently, we have demonstrated CFTR expression in the brain, the spinal cord and the sympathetic ganglia. This study aims to investigate the expression and distribution of CFTR in the ganglia of the human gastrointestinal tract. Fresh tissue and formalin-fixed paraffin-embedded normal gastrointestinal tract samples were collected from eleven surgical patients and five autopsy cases. Immunohistochemistry, in situ hybridization, laser-assisted microdissection and nested reverse transcriptase polymerase chain reaction were performed. Expression of CFTR protein and mRNA was detected in neurons of the ganglia of all segments of the human gastrointestinal tract examined, including the stomach, duodenum, jejunum, ileum, cecum, appendix, colon and rectum. The extensive expression of CFTR in the enteric ganglia suggests that CFTR may play a role in the physiology of the innervation of the gastro-intestinal tract. The presence of dysfunctional CFTRs in enteric ganglia could, to a certain extent, explain the gastrointestinal symptoms frequently experienced by CF patients. PMID- 27491545 TI - Cost of diabetic retinopathy and macular oedema in a population, an eight year follow up. AB - BACKGROUND: Prospective, population-based study of an 8-year follow up. To determine the direct cost of diabetic retinopathy [DR], evaluating our screening programme and the cost of treating DR, focusing on diabetic macular oedema [DMO] after anti-vascular endothelial growth factor [anti-VEGF] treatment. METHODS: A total of 15,396 diabetes mellitus [DM] patients were studied. We determined the cost-effectiveness of our screening programme against an annual programme by applying the Markov simulation model. We also compared the cost-effectiveness of anti-VEGF treatment to laser treatment for screened patients with DMO. RESULTS: The cost of our 2.5-year screening programme was as follows: per patient with any DR, ?482.85 +/- 35.14; per sight-threatening diabetic retinopathy [STDR] patient, ?1528.26 +/- 114.94; and ?1826.98 +/- 108.26 per DMO patient. Comparatively, an annual screening programme would result in increases as follows: 0.77 in QALY per patient with any-DR and 0.6 and 0.44 per patient with STDR or DMO, respectively, with an incremental cost-effective ratio [ICER] of ?1096.88 for any-DR, ?4571.2 for STDR and ?7443.28 per DMO patient. Regarding diagnosis and treatment, the mean annual total cost per patient with DMO was ?777.09 +/- 49.45 for the laser treated group and ?7153.62 +/- 212.15 for the anti-VEGF group, with a QALY gain of 0.21, the yearly mean cost was ?7153.62 +/- 212.15 per patient, and the ICER was ?30,361. CONCLUSIONS: Screening for diabetic retinopathy every 2.5 years is cost-effective, but should be adjusted to a patient's personal risk factors. Treatment with anti-VEGF for DMO has increased costs, but the cost-utility increases to 0.21 QALY per patient. PMID- 27491546 TI - Engineering Saccharomyces cerevisiae with the deletion of endogenous glucosidases for the production of flavonoid glucosides. AB - BACKGROUND: Glycosylation of flavonoids is a promising approach to improve the pharmacokinetic properties and biological activities of flavonoids. Recently, many efforts such as enzymatic biocatalysis and the engineered Escherichia coli biotransformation have increased the production of flavonoid glucosides. However, the low yield of flavonoid glucosides can not meet the increasing demand for human medical and dietary needs. Saccharomyces cerevisiae is a generally regarded as safe (GRAS) organism that has several attractive characteristics as a metabolic engineering platform for the production of flavonoid glucosides. However, endogenous glucosidases of S. cerevisiae as a whole-cell biocatalyst reversibly hydrolyse the glucosidic bond and hinder the biosynthesis of the desired products. In this study, a model flavonoid, scutellarein, was used to exploit how to enhance the production of flavonoid glucosides in the engineered S. cerevisiae. RESULTS: To produce flavonoid glucosides, three flavonoid glucosyltransferases (SbGTs) from Scutellaria baicalensis Georgi were successfully expressed in E. coli, and their biochemical characterizations were identified. In addition, to synthesize the flavonoid glucosides in whole-cell S. cerevisiae, SbGT34 was selected for constructing the engineering yeast. Three glucosidase genes (EXG1, SPR1, YIR007W) were knocked out using homologous integration, and the EXG1 gene was determined to be the decisive gene of S. cerevisiae in the process of hydrolysing flavonoid glucosides. To further enhance the potential glycosylation activity of S. cerevisiae, two genes encoding phosphoglucomutase and UTP-glucose-1-phosphate uridylyltransferase involved in the synthetic system of uridine diphosphate glucose were over-expressed in S. cerevisiae. Consequently, approximately 4.8 g (1.2 g/L) of scutellarein 7-O glucoside (S7G) was produced in 4 L of medium after 54 h of incubation in a 10-L fermenter while being supplied with ~3.5 g of scutellarein. CONCLUSIONS: The engineered yeast harbouring SbGT with a deletion of glucosidases produced more flavonoid glucosides than strains without a deletion of glucosidases. This platform without glucosidase activity could be used to modify a wide range of valued plant secondary metabolites and to explore of their biological functions using whole-cell S. cerevisiae as a biocatalyst. PMID- 27491547 TI - Empirical determination of breed-of-origin of alleles in three-breed cross pigs. AB - BACKGROUND: Although breeding programs for pigs and poultry aim at improving crossbred performance, they mainly use training populations that consist of purebred animals. For some traits, e.g. residual feed intake, the genetic correlation between purebred and crossbred performance is low and thus including crossbred animals in the training population is required. With crossbred animals, the effects of single nucleotide polymorphisms (SNPs) may be breed-specific because linkage disequilibrium patterns between a SNP and a quantitative trait locus (QTL), and allele frequencies and allele substitution effects of a QTL may differ between breeds. To estimate the breed-specific effects of alleles in a crossbred population, the breed-of-origin of alleles in crossbred animals must be known. This study was aimed at investigating the performance of an approach that assigns breed-of-origin of alleles in real data of three-breed cross pigs. Genotypic data were available for 14,187 purebred, 1354 F1, and 1723 three-breed cross pigs. RESULTS: On average, 93.0 % of the alleles of three-breed cross pigs were assigned a breed-of-origin without using pedigree information and 94.6 % with using pedigree information. The assignment percentage could be improved by allowing a percentage (fr) of the copies of a haplotype to be observed in a purebred population different from the assigned breed-of-origin. Changing fr from 0 to 20 %, increased assignment of breed-of-origin by 0.6 and 0.7 % when pedigree information was and was not used, respectively, which indicates the benefit of setting fr to 20 %. CONCLUSIONS: Breed-of-origin of alleles of three-breed cross pigs can be derived empirically without the need for pedigree information, with 93.7 % of the alleles assigned a breed-of-origin. Pedigree information is useful to reduce computation time and can slightly increase the percentage of assignments. Knowledge on the breed-of-origin of alleles allows the use of models that implement breed-specific effects of SNP alleles in genomic prediction, with the aim of improving selection of purebred animals for crossbred offspring performance. PMID- 27491548 TI - Bioelectrical impedance vector analysis as a useful predictor of nutritional status in patients with short bowel syndrome. AB - BACKGROUND & AIMS: Short bowel syndrome (SBS) represents a serious intestinal absorption disorder. Therefore, patients with SBS may have severe malnutrition and excessive mineral and fluid losses. Once the assessment of nutritional status is important in their follow-up, body composition measurements and especially total body water (TBW) must be repeatedly evaluated for the assessment of changes in hydration and nutritional care. The aim of this study was to investigate if bioelectrical impedance vector analysis (BIVA) is a useful predictor of nutritional and hydration status in SBS patients. METHODS: In this observational study, 22 participants (12 women), 11 with SBS and 11 gender, age and BMI-matched controls, were evaluated using the bioelectrical impedance measurements (BIA) and BIVA to assess nutritional and hydration status. RESULTS: Participants age was 53 +/- 8 y (mean +/- SD). Body water, fat mass and lean mass as assessed by BIA did not differ between the two groups. However, BIVA showed important differences between the groups regarding hydration and amount of soft tissue (p < 0.0001 for women and p = 0.0015 for men). The results also evidenced that women's vectors were related to cachexia, while men's vectors were divided into lean and cachexia quadrants. The use of BIVA analysis also evidenced hydration disturbance and losses of soft tissue. CONCLUSIONS: BIVA may represent a better predictor of nutritional status for analysis and interpretation of body composition in patients with short bowel syndrome. This trial was registered at ClinicalTrials.gov as NCT02113228. PMID- 27491549 TI - [Mediastinal germ cell tumors]. AB - The mediastinum is among the most frequent anatomic region in which germ cell tumors (GCT) arise, second only to the gonads. Mediastinal GCT (mGCT) account for 16 % of all mediastinal neoplasms. Although the morphology and (according to all available data) the molecular genetics of mediastinal and gonadal GCT are identical, a number of unique aspects exist. There is a highly relevant bi-modal age distribution. In pre-pubertal children of both sexes, mGCT consist exclusively of teratomas and yolk sac tumors. The prognosis is generally favorable with modern treatment. In post-pubertal adults, virtually all patients with malignant mGCT are males; the prognosis is more guarded and depends (among other factors) on the histological GCT components and is similar to GCT in other organs. So-called somatic type malignancies (i. e. clonally related, non-germ cell neoplasias arising in a GCT) are much more frequent in mGCT than in other organs, and the association between mediastinal yolk sac tumors and hematological malignancies, such as myelodysplasias and leukemias, is unique to mediastinal tumors. The prognosis of GCT with somatic type malignancies is generally dismal. PMID- 27491550 TI - Physiological characteristics and metabolomics of transgenic wheat containing the maize C4 phosphoenolpyruvate carboxylase (PEPC) gene under high temperature stress. AB - In this paper, two transgenic wheat lines, PC27 and PC51, containing the maize PEPC gene and its wild-type (WT) were used as experimental material to study the effects of high temperature on their photosynthetic physiological characteristics and metabolome. The results showed that transgenic wheat lines had higher photosynthetic rate (P n) than WT under non-stress treatment (NT) and high temperature stress treatment (HT), and more significantly under HT. The change trends of F v/F m, F PSII, and q P were similar to P n, whereas that of non photochemical quenching (NPQ) was the opposite. Compared with WT, no differences in chlorophyll content between the transgenic wheat and WT were observed under NT, but two transgenic lines had relatively higher contents than WT under HT. The change trends of Chlorophyll a/b radio, the decreased values of F m, Wk, and Vj, and the activity of the antioxidant enzyme were consistent with the chlorophyll content. Compared with WT, transgenic wheat lines exhibited lower rate of superoxide anion production, H2O2 and malondialdehyde content under HT, and no significant differences were observed under NT. The expression pattern of the ZmPEPC gene and wheat endogenous photosynthesis-related genes were in agreement with that of P n. Compared with WT, about 13 different metabolites including one organic acid, six amino acids, four sugars, and two polyols were identified under NT; 25 different metabolites including six organic acids, 12 amino acids, four sugars, and three polyols were identified under HT. Collectively, our results indicate that ZmPEPC gene can enhance photochemical and antioxidant enzyme activity, upregulate the expression of photosynthesis-related genes, delay degradation of chlorophyll, change contents of proline and other metabolites in wheat, and ultimately improves its heat tolerance. PMID- 27491551 TI - Cortical miscommunication after prenatal exposure to alcohol. AB - We report on the effects of prenatal alcohol exposure on resting-state brain activity as measured by magnetoencephalography (MEG). We studied 37 subjects diagnosed with fetal alcohol spectrum disorder in one of three categories: fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder. For each subject, the MEG signal was recorded for 60 s during rest while subjects lay supine. Using time series analysis, we calculated the synchronous neural interactions for all pair-wise combinations of 248 MEG sensors resulting in 30,628 partial correlations for each subject. We found significant differences from control subjects in 6.19 % of the partial zero lag crosscorrelations (synchronous neural interactions; Georgopoulos et al. in J Neural Eng 4:349-355, 2007), with these differences localized in the right posterior frontal, right parietal, and left parietal/posterior frontal regions. These results show that MEG can detect functional brain differences in the individuals affected by prenatal exposure to alcohol. Furthermore, these differences may serve as a biomarker for future studies linking symptoms and signs to specific brain areas. This may lead to new insights into the neuropathology of fetal alcohol spectrum disorders. PMID- 27491552 TI - Quantitative and qualitative insights into the experiences of children with Rett syndrome and their families. AB - Rett syndrome is a rare neurodevelopmental disorder caused by a mutation in the MECP2 gene. It is associated with severe functional impairments and medical comorbidities such as scoliosis and poor growth. The population-based and longitudinal Australian Rett Syndrome Database was established in 1993 and has supported investigations of the natural history of Rett syndrome and effectiveness of treatments, as well as a suite of qualitative studies to identify deeper meanings. This paper describes the early presentation of Rett syndrome, including regression and challenges for families seeking a diagnosis. We discuss the importance of implementing strategies to enhance daily communication and movement, describe difficulties interpreting the presence of pain and discomfort, and argue for a stronger evidence base in relation to management. Finally, we outline a framework for understanding quality of life in Rett syndrome and suggest areas of life to which we can direct efforts in order to improve quality of life. Each of these descriptions is illustrated with vignettes of child and family experiences. Clinicians and researchers must continue to build this framework of knowledge and understanding with efforts committed to providing more effective treatments and supporting the best quality of life for those affected. PMID- 27491553 TI - Progress in Rett Syndrome: from discovery to clinical trials. AB - Fifty years ago, Andreas Rett described a disorder in 22 females featuring prominent regression of fine motor and communication skills, cognitive impairment, stereotypic movements, periodic breathing, and gait abnormalities. This disorder became known as Rett syndrome (RTT) following the report of Hagberg et al. in 1983. Although RTT was scarcely recognized at that time in the United States, here the efforts of Rett and Hagberg led to rapid progress in recognition and diagnosis, a clearer understanding of its clinical and pathological underpinnings, and, ultimately, identification of mutations in the methyl-CpG binding protein 2 (MECP2) gene as the primary cause of this unique and challenging neurodevelopmental disorder. Thereafter, a natural history study and critical translational research in animal models paved the way for potential disease-modifying agents to be assessed in human clinical trials. To be successful, the energies of the international community at all levels, including researchers in clinical and basic science, funding agencies, pharmaceutical companies, patient advocates, and, above all, parents and their children are essential. Otherwise, hopes for effective treatment, if not, a cure, will remain unfulfilled. PMID- 27491554 TI - The changing faces of corticotroph cell adenomas: the role of prohormone convertase 1/3. AB - The spectrum of corticotroph cell adenomas is very wide. Though rarely, silent corticotroph cell adenomas (SCA) may transform into corticotroph cell adenomas associated with Cushing's disease (CD). The aim of the study was to investigate the role of prohormone convertase 1/3 (PC1/3) in the transformation of SCA into CD. We reviewed the records of 1259 consecutive endoscopic endonasal procedures for pituitary adenomas from 1998 to 2013. Of these, 132 were CD and 44 were SCA. During the follow-up, three patients with SCA showed a clear transformation from SCA into CD and underwent surgery once again to remove the recurrent tumour. The PC1/3 expression was analysed by both immunohistochemistry and quantitative real time-polymerase chain reaction (qRT-PCR) in primary and recurrent tumours. The immunohistochemical PC1/3 expression was negative or weak in the three patients in the initial phase of SCA, while a strong expression was observed in the majority of neoplastic cells in tissue specimens obtained from the same three patients at the time of recurrence as CD. The immunohistochemical PC1/3 expression showed a strict correlation with the PC1/3 levels obtained by qRT-PCR. In 14 cases of SCA with no change of phenotype during the follow-up, the immunohistochemical PC1/3 expression was low and strictly associated with the level of PC1/3 obtained by qRT-PCR both in primary (14/14 cases) and in recurrent tumours (4/4 cases). Our study provides insight into the crucial role of the PC1/3 protein in the transformation of phenotype from SCA to CD. PMID- 27491555 TI - A hypothetical model to solve the controversy over the involvement of UCP2 in palmitate-induced beta-cell dysfunction. AB - The aim of this article is to solve an existing controversy over the involvement of uncoupling protein-2 in the impairment of glucose-stimulated insulin secretion induced by chronic exposure of beta-cells to palmitate. We analyzed and compared the results of studies that support and that deny the involvement of uncoupling protein-2 in this impairment. We observed that this impairment could occur in multiple stages. We provide a model in which palmitate-induced impairment of glucose-stimulated insulin secretion is proposed to occur in two stages, early stage and late stage, depending on the integrity of electron supply (glycolysis and Krebs cycle) and transport system through electron transport chain after palmitate treatment. Prolonged exposure of beta-cells to palmitate can impair this system. Early-stage impairment occurs due to uncoupling by uncoupling protein-2 when this system is still intact. When this system becomes impaired, late-stage impairment occurs mainly due to reduced glucose-stimulated adenosine triphosphate production independent of uncoupling by uncoupling protein-2. The change in glucose-stimulated oxygen uptake after palmitate treatment reflects the integrity of this system and can be used to differentiate between the two stages. Some beta-cells lines and islets appear to be more resistant to palmitate-induced impairment of electron supply and transport system than others, and therefore early stage is prominent in the more resistant cell lines and less prominent or absent in the less resistant cell lines. This may help to resolve the pathogenesis of diabetes and to monitor the progression of palmitate-induced beta cell dysfunction. PMID- 27491557 TI - In Search of Cognitive Dignity: The Diagnostic Challenges of Primary Care. PMID- 27491556 TI - WT1, MSH6, GATA5 and PAX5 as epigenetic oral squamous cell carcinoma biomarkers - a short report. AB - PURPOSE: Oral squamous cell carcinoma (OSCC) is a frequently occurring aggressive malignancy with a heterogeneous clinical behavior. Based on the paucity of specific early diagnostic and prognostic biomarkers, which hampers the appropriate treatment and, ultimately the development of novel targeted therapies, we aimed at identifying such biomarkers through a genetic and epigenetic analysis of these tumors. METHODS: 93 primary OSCCs were subjected to DNA copy number alteration (CNA) and methylation status analyses using methylation-specific multiplex ligation-dependent probe amplification (MS-MPLA). The genetic and epigenetic OSCC profiles obtained were associated with the patients' clinic-pathological features. RESULTS: We found that WT1 gene promoter methylation is a predictor of a better prognosis and that MSH6 and GATA5 gene promoter methylation serve as predictors of a worse prognosis. GATA5 gene promoter methylation was found to be significantly associated with a shorter survival rate. In addition, we found that PAX5 gene promoter methylation was significantly associated with tongue tumors. To the best of our knowledge, this is the first study that highlights this specific set of genes as epigenetic diagnostic and prognostic biomarkers in OSCC. CONCLUSIONS: Our data highlight the importance of epigenetically assessing OSCCs to identify key genes that may serve as diagnostic and prognostic biomarkers and, potentially, as candidate therapeutic targets. PMID- 27491558 TI - Risk Assessment for Venous Thromboembolism in Chemotherapy-Treated Ambulatory Cancer Patients. AB - OBJECTIVE: To design a precision medicine approach aimed at exploiting significant patterns in data, in order to produce venous thromboembolism (VTE) risk predictors for cancer outpatients that might be of advantage over the currently recommended model (Khorana score). DESIGN: Multiple kernel learning (MKL) based on support vector machines and random optimization (RO) models were used to produce VTE risk predictors (referred to as machine learning [ML]-RO) yielding the best classification performance over a training (3-fold cross validation) and testing set. RESULTS: Attributes of the patient data set ( n = 1179) were clustered into 9 groups according to clinical significance. Our analysis produced 6 ML-RO models in the training set, which yielded better likelihood ratios (LRs) than baseline models. Of interest, the most significant LRs were observed in 2 ML-RO approaches not including the Khorana score (ML-RO-2: positive likelihood ratio [+LR] = 1.68, negative likelihood ratio [-LR] = 0.24; ML-RO-3: +LR = 1.64, -LR = 0.37). The enhanced performance of ML-RO approaches over the Khorana score was further confirmed by the analysis of the areas under the Precision-Recall curve (AUCPR), and the approaches were superior in the ML-RO approaches (best performances: ML-RO-2: AUCPR = 0.212; ML-RO-3-K: AUCPR = 0.146) compared with the Khorana score (AUCPR = 0.096). Of interest, the best-fitting model was ML-RO-2, in which blood lipids and body mass index/performance status retained the strongest weights, with a weaker association with tumor site/stage and drugs. CONCLUSIONS: Although the monocentric validation of the presented predictors might represent a limitation, these results demonstrate that a model based on MKL and RO may represent a novel methodological approach to derive VTE risk classifiers. Moreover, this study highlights the advantages of optimizing the relative importance of groups of clinical attributes in the selection of VTE risk predictors. PMID- 27491559 TI - Neo-tanshinlactone selectively inhibits the proliferation of estrogen receptor positive breast cancer cells through transcriptional down-regulation of estrogen receptor alpha. AB - Breast cancer, the most frequent cancer in women, is the second leading cause of cancer-related death. Estrogens and estrogen receptors are well recognized to play predominant roles in breast cancer development and growth. Neo tanshinlactone is a natural product isolated from Salvia miltiorrhiza and showed selective growth inhibition of ER+ breast cancer cell lines as demonstrated by cell proliferation assay and colony formation assay. The selective anti proliferative effect of neo-tanshinlactone was associated with the induction of apoptosis in ER+ breast cancer cells. We also found that neo-tanshinlactone decreased steady state ESR1 mRNA levels in ER+ breast cancer cells, which was further confirmed by analysis of ER protein levels as well as the mRNA levels of target genes of this transcription factor, such as ESR2, BRCA1, CCND1, GREB1, TFF1, SERPINB9 and ABCA3. Furthermore, analysis of heterogeneous nuclear RNA (hnRNA) demonstrated that neo-tanshinlactone inhibited ESR1 mRNA de novo synthesis. The decrease of steady state ESR1 mRNA upon neo-tanshinlactone treatment was not abolished by protein synthesis inhibitor cycloheximide. And inhibition of mRNA synthesis with actinomycin D revealed no significant effect of neo-tanshinlactone on ESR1 mRNA stability. These results indicated that transcriptional down-regulation of ESR1 mRNA could contribute to the selective activity of neo-tanshinlactone on ER+ breast cancer cells. And as expected, the combination of neo-tanshinlactone and antiestrogen reagent tamoxifen showed a synergistic effect on growth of ER+ MCF7 cells. Our results suggest that neo tanshinlactone is a promising regimen for ER+ breast tumors. PMID- 27491560 TI - Stimulation of the histamine 4 receptor upregulates thymic stromal lymphopoietin (TSLP) in human and murine keratinocytes. AB - The cytokine thymic stromal lymphopoietin (TSLP) is involved in the development and the progression of allergic diseases. It is mainly released by epithelial cells at barriers such as skin and gut in response to danger signals. Overexpression of TSLP in keratinocytes (KC) can provoke the development of a type 2 inflammatory response. Additionally, TSLP directly acts on sensory neurons and thereby triggers itch. Since histamine is also increased in lesions of inflammatory skin diseases, the aim of this study was to investigate possible effects of histamine as well as different histamine receptor subtype agonists and antagonists on TSLP production in KC. We therefore stimulated human KC with histamine in the presence or absence of the known TSLP-inductor poly I:C and measured TSLP production at protein as well as mRNA level. Histamine alone did not induce TSLP production in human KC, but pre-incubation with histamine prior to challenge with poly I:C resulted in a significant increase of TSLP production compared to stimulation with poly I:C alone. Experiments with different histamine receptor agonists (H1R: 2-pyridylethylamine; H2R: amthamine; H2R/H4R: 4 methylhistamine (4MH)) revealed a dominant role for the H4R receptor, as 4-MH in combination with poly I:C displayed a significant increase of TSLP secretion, while the other agonists did not show any effect. The increase in TSLP production by 4MH was blocked with the H4R antagonist JNJ7777120. This effect was reproducible also in the murine KC cell line MSC. Taken together, our study indicates a new role for the H4 receptor in the regulation of TSLP in keratinocytes. Therefore, blocking of the H4R receptor in allergic diseases might be promising to alleviate inflammation and pruritus via TSLP. PMID- 27491561 TI - Epistemic injustice and responsibility in borderline personality disorder. AB - Miranda Fricker's concept of epistemic injustice has been quite a novel idea in epistemology. It brings something new to the fields of epistemology and ethics. Fricker draws our attention to a distinctive species of injustice, the epistemic injustice, in which someone is specifically wronged in his capacity as a knower. There has been a significant amount of work done in epistemic injustice, both in race and gender studies. The application of the concept in the context of mental health is less explored. Here, we aim to apply the concept of epistemic injustice in attributing responsibility to patients with borderline personality disorder. Attributing responsibility involves holding someone accountable for his presumed wrongdoings, making judgments on whether the agent has control on his action, on whether is aware of its consequences. It is generally agreed that in order to be morally responsible for an action the person should be worthy of praise or blame for it. Following Aristotle, we focus on epistemic condition in attribution of responsibility. We will discuss the role of epistemic injustice in assessment of epistemic condition of responsibility. We will show that we can misinterpret the agent's intentions because of the presence of systematic prejudices. We will focus on patients suffering from borderline personality disorder. We provide a case vignette to show a tendency in the professionals in holding these patients responsible for their action when it can be argued otherwise. We argue that prejudice against the patient with borderline personality disorder where the person is seen as manipulative plays a significant role in the process of epistemic injustice. The suggested manipulative nature of patients with borderline personality disorder leads to professionals to ascribe agency and knowledge where it is not due. PMID- 27491562 TI - Methadone analgesia in the critically ill. PMID- 27491563 TI - Use of ultrasound guidance for central venous catheterization: a national survey of intensivists and hospitalists. AB - PURPOSE: The purpose of the study is to evaluate the frequency and barriers to use of ultrasound guidance for central venous catheter (CVC) insertion by physicians specializing in critical care and hospital medicine. MATERIALS AND METHODS: A national cross-sectional electronic survey of intensivists and hospitalists was administered from November 2014 to January 2015. RESULTS: The survey response rate was 5.9% (1013/17 233). Moderate to very frequent use of ultrasound guidance varied by site: internal jugular vein (80%), subclavian vein (31%), and femoral vein (45%). Nearly all physicians (99%) who insert internal jugular CVCs daily use ultrasound guidance, whereas only 46% of physicians who insert subclavian CVCs daily use ultrasound guidance. Use of real-time ultrasound guidance varied by insertion site: internal jugular vein (73%), subclavian vein (28%), and femoral vein (42%). Most physicians (59%) reported not being comfortable with real-time needle tracking at the subclavian site. The most frequently reported barriers to use of ultrasound guidance were (1) limited availability of ultrasound equipment (28%), (2) perception of increased total procedure time (22%), and (3) concern for loss of landmark skills (13%). CONCLUSIONS: Most intensivists routinely use ultrasound guidance to insert internal jugular CVCs but not subclavian CVCs. The most commonly reported barrier to ultrasound use was limited access to an ultrasound machine. PMID- 27491564 TI - Retinoid-related orphan receptor gamma (RORgamma) adult induced knockout mice develop lymphoblastic lymphoma. AB - RORgamma is a nuclear hormone receptor which controls polarization of naive CD4+ T-cells into proinflammatory Th17 cells. Pharmacological antagonism of RORgamma has therapeutic potential for autoimmune diseases; however, this mechanism may potentially carry target-related safety risks, as mice deficient in Rorc, the gene encoding RORgamma, develop T-cell lymphoma with 50% frequency. Due to the requirement of RORgamma during development, the Rorc knockout (KO) animals lack secondary lymphoid organs and have a dysregulation in the generation of CD4+ and CD8+ T cells. We wanted to extend the evaluation of RORgamma deficiency to address the question whether lymphomas, similar to those observed in the Rorc KO, would develop in an animal with an otherwise intact adult immune system. Accordingly, we designed a conditional RORgamma knockout mouse (Rorc CKO) where the Rorc locus could be deleted in adult animals. Based on these studies we can confirm that these animals also develop lymphoma in a similar time frame as embryonic Rorc knockouts. This study also suggests that in animals where the gene deletion is incomplete, the thymus undergoes a rapid selection process replacing Rorc deficient cells with remnant thymocytes carrying a functional Rorc locus and that subsequently, these animals do not develop lymphoblastic lymphoma. PMID- 27491566 TI - Pitfalls in lupus. AB - "The objective of Pitfall!TM is to guide Harry through a maze of jungle scenes, jumping over or avoiding many deadly dangers... Harry has three lives in each game." If you exchange Harry's adventures with "Life with SLE," patients have to be guided through the jungle having just one life and the deadly dangers are flares, organ manifestations, and, e.g., consequences of immunosuppressive medications, especially glucocorticoids. Monitoring and treatment in line with recommendations and guidelines may be supportive to survive the first 3 to 5 levels in most cases, but for higher levels of the reality game, creativity is needed and life becomes more risky. The aim of this reflection is to identify common pitfalls and to stimulate further research and collaboration in specific areas of the lupus jungle. Topics like "Hidden Power Unit," "Looks similar ...," "Rev Meter for SLE," "Flare Prediction," "Level 2: Eminence Based," "Lupus=Lifelong Immunosuppression?!," "Glucocorticoids," "Antimalarials Are Contraindicated," "It Is All About Immunosuppression," "Prediction of Damage," and "Patient Global Assessment (PGA) versus Physician Global Assessment (PhGA)" are addressed. Raised ideas and thoughts are by no means complete or exclusive, but if taken up, they may hopefully lead to another approach in daily care and trials in SLE. PMID- 27491565 TI - Humoral and cellular autoimmunity in women with recurrent pregnancy losses and repeated implantation failures: A possible role of vitamin D. AB - Women with recurrent pregnancy losses (RPL) and repeated implantation failures (RIF) have auto- and cellular immune abnormalities. Approximately, 20% of women with RPL have autoimmune abnormalities, particularly antiphospholipid antibodies (APA). In addition, these women have a higher prevalence of antinuclear antibody, anti-thyroperoxidase and anti-thyroglobulin antibodies, and other non-organ specific autoantibodies. In women with RPL, the presence of autoimmunity is often associated with cellular immune abnormalities, such as increased NK cell levels and Th1/Th2 cell ratios. Vitamin D (VD) plays a major role in regulation of auto- and cellular immune abnormalities. VD deficiency is prevalent in women with RPL, and women with VD deficiency have increased auto- and cellular immune abnormalities as compared with women with normal VD levels. VD has immune regulatory effects on various immune effectors including T, B and NK cells. Potential therapeutic application of VD for RPL and RIF with auto- and cellular immune abnormalities should be explored. PMID- 27491567 TI - The viral paradigm in type 1 diabetes: Who are the main suspects? AB - Type 1 diabetes (T1D) is an autoimmune disease characterized by the loss of pancreatic beta cells in the islets of Langerhans. Although genetic predisposition plays an important role in T1D development, studies of identical twins suggest that environmental factors such as viruses and other pathogens may be critical triggers either through direct cytolytic effect and gradual beta cell destruction, or by bystander activation of the immune system. In addition, viruses may circumvent the host immune response and have the capacity to establish chronic lifelong infections. The association of various viral infections with the induction of T1D has been extensively studied at the serological and epidemiological level. However, there is still little evidence from studies of human pancreas to confirm their presence or a causal role in disease pathogenesis. In this review, we identify possible suspects for viral triggers of disease and explain their potential roles in the "viral paradigm" of T1D. PMID- 27491569 TI - Fc-gamma receptors: Attractive targets for autoimmune drug discovery searching for intelligent therapeutic designs. AB - Autoantibody immune complexes (ICs) mediate pathogenesis in multiple autoimmune diseases via direct interference with target function, complement fixation, and interaction with Fc-gamma receptors (FcgammaRs). Through high avidity interactions, ICs are able to crosslink low affinity FcgammaRs expressed on a wide variety of effector cells, leading to secretion of pro-inflammatory mediators and inducing cytotoxicity, ultimately resulting in tissue injury. Given their relevance in numerous autoimmune diseases, FcgammaRs have been considered as attractive therapeutic targets for the last three decades. However, a limited number of investigational drug candidates have been developed targeting FcgammaRs and only a few approved therapeutics have been associated with impacting FcgammaRs. This review provides a historical overview of the different therapeutic approaches used to target FcgammaRs for the treatment of autoimmune and inflammatory diseases. PMID- 27491568 TI - Anti-HMGCR antibodies as a biomarker for immune-mediated necrotizing myopathies: A history of statins and experience from a large international multi-center study. AB - In an effort to find naturally occurring substances that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins were first discovered by Endo in 1972. With the widespread prescription and use of statins to decrease morbidity from myocardial infarction and stroke, it was noted that approximately 5% of all statin users experienced muscle pain and weakness during treatment. In a smaller proportion of patients, the myopathy progressed to severe morbidity marked by proximal weakness and severe muscle wasting. Remarkably, Mammen and colleagues were the first to discover that the molecular target of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is an autoantibody target in patients that develop an immune-mediated necrotizing myopathy (IMNM). These observations have been confirmed in a number of studies but, until today, a multi-center, international study of IMNM, related idiopathic inflammatory myopathies (IIM), other auto-inflammatory conditions and controls has not been published. Accordingly, an international, multi-center study investigated the utility of anti-HMGCR antibodies in the diagnosis of statin associated IMNM in comparison to different forms of IIM and controls. This study included samples from patients with different forms of IIM (n=1250) and patients with other diseases (n=656) that were collected from twelve sites and tested for anti-HMGCR antibodies by ELISA. This study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of IIM who are older and have necrosis on muscle biopsy. Taken together, the data to date indicates that testing for anti-HMGCR antibodies is important in the differential diagnosis of IIM and might be considered for future classification criteria. PMID- 27491570 TI - The role of monocytes in ANCA-associated vasculitides. AB - The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of diseases causing inflammation in small blood vessels and linked by the presence of circulating ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). These antigens are present both in the cytoplasmic granules and on the surface of neutrophils, and the effect of ANCA on neutrophil biology has been extensively studied. In contrast, less attention has been paid to the role of monocytes in AAV. These cells contain PR3 and MPO in lysosomes and can also express them at the cell surface. Monocytes respond to ANCA by producing pro-inflammatory and chemotactic cytokines, reactive-oxygen-species and by up regulating CD14. Moreover, soluble and cell surface markers of monocyte activation are raised in AAV patients, suggesting an activated phenotype that may persist even during disease remission. The presence of monocyte-derived macrophages and giant cells within damaged renal and vascular tissue in AAV also attests to their role in pathogenesis. In particular, their presence in the tertiary lymphoid organ-like granulomas of AAV patients may generate an environment predisposed to maintaining autoimmunity. Here we discuss the evidence for a pathogenic role of monocytes in AAV, their role in granuloma formation and tissue damage, and their potential to both direct and maintain autoimmunity. ANCA activation of monocytes may therefore provide an explanation for the relapsing remitting course of disease and its links with infections. Monocytes may thus represent a promising target for the treatment of this group of life-threatening diseases. PMID- 27491571 TI - The result of surgical treatment of medial epicondylitis: analysis with more than a 5-year follow-up. AB - BACKGROUND: Angiofibroblastic changes of a musculotendinous origin at the medial epicondyle characterize medial epicondylitis of the elbow. Although nonsurgical treatment is the primary approach for medial epicondylitis, surgical treatment should be considered when conservative therapy fails. This study reports the results of surgical treatment of medial epicondylitis monitored for more than 5 years. METHODS: This study included 55 patients with 63 cases of medial epicondylitis between 2000 and 2010. The conservative treatment periods lasted for a minimum of 1 year, and steroid injections were administered more than twice before surgery. One surgeon conducted the surgical procedures. The Nirschl and Pettrone grades, visual analog scale (VAS) scores, Disabilities of the Arm, Shoulder and Hand (DASH) scores, Mayo Elbow Performance scores, and grip strengths were analyzed. Statistical analyses were performed using paired t tests. RESULTS: The mean VAS score improved from 8.5 to 2.4 (P <.001). Nirschl and Pettrone grades rated 43% (27 elbows) as excellent and 51% (32 elbows) as good. The Mayo Elbow Performance scores improved from 72 to 88 (P <.001) and DASH scores from 57 to 23 (P <.001). The mean grip strength of the affected side improved from 30 to 43 lb (P <.001). The mean time required to return to work and exercise was 2.8 months and 4.8 months, respectively. One case of heterotrophic ossification, which had no functional instability afterward, was seen. CONCLUSION: The results indicate that surgical treatment of medial epicondylitis could be an effective and safe treatment when conservative treatment fails. PMID- 27491572 TI - Erratum to "Genome-wide association study for rotator cuff tears identifies two significant single-nucleotide polymorphisms" [J Shoulder Elbow Surg 2016;25:174 179]. PMID- 27491573 TI - Spontaneous Osteonecrosis of the Jaw During Bisphosphonate Therapy: An Unusual Etiology of the Numb Chin Syndrome. AB - The numb chin syndrome is a rare manifestation of intractable pain in the palliative care setting and represents a major therapeutic challenge. The reported etiologies of the numb chin syndrome include trauma, infections, immune mediated systemic conditions, and malignancy, both through local infiltration or compression of the inferior alveolar nerve sheath. The authors present the case of a patient with long-standing multiple myeloma, suffering from numb chin syndrome caused by a spontaneous osteonecrosis of the jaw after bisphosphonate therapy. Intractable unilateral orofacial pain over the right chin and lower lip with associated numbness and paresthesia in the distribution area of the mental nerve were the clinical features. A complex pharmacological therapy, including methadone, carbamazepine, and dexamethasone was started, with insufficient pain control. In consideration of the prevalent neuropathic etiology, the authors opted for a locoregional nerve block of the mandibular nerve with bupivacaine and clonidine. The interdisciplinary approach was successful, and the patient was discharged with satisfactory pain control. The purpose of this report is to demonstrate the complexity of the therapeutic approach, which may include pharmacological measures and interventional procedures to improve symptom management in this challenging clinical condition. PMID- 27491574 TI - Impact of physical activity and sedentarism on hydration status and liquid intake in Spanish older adults. The PHYSMED study. AB - INTRODUCTION: Data on hydration status in older adults are scarce and there are very few studies focusing on the impact of physical activity (PA) on drinking behavior. OBJECTIVE: To assess the impact of physical activity and sedentarism on fluid intake in Spanish elderly. METHODS: 433 non-institutionalized Spanish older adults (58% females), aged 55-88 years, volunteered for the PHYSMED study. PA data were obtained by means of the Minnesota and EXERNET questionnaires. Population was divided into four groups: ILS (inactive and low sedentary), IHS (inactive and high sedentary), ALS (active and low sedentary) and AHS (active and high sedentary). Serum from fasting blood samples was analysed for osmolarity. RESULTS: The mean of total liquid intake was 1,751 +/- 628 mL/d. Significant differences were observed for total liquid intake between ILS/ALS and IHS/ALS (p < 0.001). ALS subjects consumed a higher amount of beverages such as water, juice, milk, coffee, sport drink, beer, wine and distilled drinks than the other PA groups. There was a significant difference for water intake between PA groups (p < 0.01). Serum osmolarity values were within references ranges in all subjects, and there was a signifi cant difference between PA groups (p < 0.01). CONCLUSIONS: Spanish older adults meet the DACH recommendations set by the German, Austrian and Swiss nutrition societies' liquid intake recommendations in the mean independently of PA and sedentary level. All participants are within reference ranges of serum osmolarity. Subjects in the active and low sedentary group consumed higher amounts of water and other beverages than in the other PA groups. PMID- 27491575 TI - Nutritional differences in malnourished patients according to their liquid-intake habits after hospital discharge. AB - INTRODUCTION: Malnutrition is a serious and relatively common problem among hospitalized patients; moreover, it is known that a good hydration state contributes to health and wellbeing. OBJECTIVE: The aim of this study was to determine the relationship between nutritional status, functional dependency, quality of life and liquid-intake habits in malnourished patients after hospital discharge. METHODS: Cross-sectional descriptive study in 91 patients (45 males) who presented malnutrition at hospital discharge. The patients were grouped according to their liquid intake estimated through the Mini Nutritional Assessment questionnaire: 3-5 glasses (n = 42), and > 5 glasses (n = 46); removing from analysis < 3 glasses of liquid intake (n = 3). The body mass index, weight, Malnutrition Universal Screening Tool (MUST), functional dependency (Barthel questionnaire), and quality of life (Short Form 12 Health Survey [SF 12]) were assessed 2-months after discharge. RESULTS: The > 5 glasses liquid intake group showed better nutritional status than the 3-5 glasses intake group, for weight (p < 0.001), body mass index (p = 0.001), and MUST scale (p = 0.020). Additionally, the > 5 glasses liquid intake group signifi cantly scored higher values in the total SF-12 questionnaire (p = 0.013), presenting better self reported quality of life, and higher functional independency in the Barthel index (p = 0.037) than the 3-5 glasses liquid intake group (p = 0.013). CONCLUSIONS: Although further research is needed to elucidate the characteristics of this relationship, descriptive comparisons between groups showed favorable nutritional status, functional independency and quality of life for the > 5 glasses of liquid intake compared with the 3-5 glasses of liquid intake group during a 2-months follow-up. PMID- 27491576 TI - Urinary hydration biomarkers and water sources in free-living elderly. AB - INTRODUCTION: Accurate estimates of water intake and hydration status in populations are essential to identify populations at risk of dehydration and define strategies to improve standards of water intake. OBJECTIVE: To evaluate the hydration status and the contribution of food and beverages to the total water intake in a sample of free-living physically active Portuguese elderly. METHODS: A sample of 74 individuals (28 men), aged 60 to 83 years, were included in this study. A 24 h urine sample was collected; 24 h urine volume and osmolality were quantifi ed in order to estimate the free water reserve (FWR) used to assess the hydration status. A 24 h food recall corresponding to the day of urine collection was obtained. Food and beverages were grouped according to their nutritional composition, namely water content. The contribution of those groups to total water intake and its association with the hydration status were estimated. Urinary markers and food groups' contribution to total water intake were compared between sexes and according to the median FWR, using the t-test and Mann Whitney test. RESULTS: Less than 10% of the participants were classifi ed as hypohydrated/at hypohydration risk. Water from food was nearly half of the total water intake (47% in females and 48% in males, p = 0.757). "Water" (22%) and "foods with reduced water content" (19%) were the groups that contributed the most to the total water intake in women and men, respectively. In men, the contribution of "alcoholic beverages" was signifi cantly higher than that of women (10.5% vs 1.7%, p < 0.001). CONCLUSIONS: Even though most of the study participants were classified as euhydrated, the contribution of water-rich and nutritionally dense food, and non-alcoholic beverages, particularly in men, should be promoted. PMID- 27491577 TI - The association between water intake, body composition and cardiometabolic factors among children - The Cuenca study. AB - INTRODUCTION: Beverage consumption and its possible association with current obesity epidemic and metabolic syndrome is under investigation in recent years, however water intake is probably the most underestimated of all beverages and could play an important role. OBJECTIVE: The aim of this study was to examine the association between water intake, body composition and cardiometabolic factors in a sample of Spanish children. METHODS: A cross-sectional study was conducted in 366 schoolchildren (53.5% girls) aged 9-11 years from the province of Cuenca in Spain. Data of anthropometrics, body composition, cardiometabolic risk factors and ardiorespiratory fi tness variables were collected. Beverage consumption was assessed using two non-consecutive 24 h dietary recalls. RESULTS: We found an inverse association between the consumption of water (ml)/kg per weight with BMI, body fat, fat-free mass, waist circumference, insulin levels, HOMA-IR (p < 0.001), and with arterial pressure parameters, systolic (p < 0.010) and diastolic blood pressure (p < 0.028), and mean arterial pressure (p < 0.012), as well as direct associations with HDL cholesterol (p < 0.001). In ANCOVA analyses, children who drank less water (ml)/kg per weight, had higher levels of LDL cholesterol (p < 0.050) and lower levels of HDL cholesterol (p < 0.042), and overweight-obesity subjects drank less water (ml)/kg per weight than normal peers (p < 0.011). Besides, children with lower levels of HDL cholesterol and higher levels of triglycerides and blood pressure had less water intake as a beverage. Finally, children who drank less water from beverages had high levels of LDL cholesterol. CONCLUSIONS: Higher consumption of water (ml)/kg per weight was negatively associated with BMI, body fat, fat-free mass, waist circumference, insulin levels, HOMA-IR, and positively with HDL cholesterol in children independently of age, sex and cardiorespiratory fi tness. In addition, overweight obese children drank less water (ml)/kg per weight than normoweight ones. Therefore, water consumption is associated with numerous health benefi ts and its adequate intake could contribute to prevent obesity and metabolic syndrome in childhood. PMID- 27491578 TI - Comparison of beverage consumption in adult populations from three different countries: do the international reference values allow establishing the adequacy of water and beverage intakes? AB - INTRODUCTION: Recommendations of adequate total water intake (aTWI) have been proposed by the European Food Safety Agency (EFSA) and the Institute of Medicine (IOM)of the United States of America. However, there are differences in the approach used to support them: IOM recommendation is based on average intakes observed in NHANES III (Third National Health and Nutrition Examination Survey) and EFSA recommendation on a combination of observed intakes from 13 different European countries. Despite these recommendations of aTWI, the currently available scientifi c evidence is not sufficient to establish a cut-off value that would prevent disease, reduce the risk for chronic diseases or improve health status. OBJECTIVE: To compare the average daily consumption of fluids (water and other beverages) in selective samples of population from Mexico, US and Spain, evaluating the quantity of fluid intake and understanding the contribution of each fluid type to the total fl uid intake. We also aim to determine if they reached adequate intake (AI) values, as defi ned by three different criteria: IOM, EFSA and water density. METHODS: Three studies were compared: from Mexico, the National Health and Nutrition Survey conducted in 2012 (NHNS 2012); from US, the NHANES III 2005-2010 and from Spain the ANIBES study leaded in 2013. Different categories of beverages were used to establish the pattern of energy intake for each country. Only adult population was selected. TWI of each study was compared with EFSA and IOM AI recommendations, as well as applying the criterion of water density (mL/kcal). RESULTS: The American study obtained the higher value of total kcal/day from food and beverages (2,437 +/- 13). Furthermore, the percentage of daily energy intake coming from beverages was, for American adults, 21%. Mexico was slightly behind with 19% and Spain ANIBES study registered only 12%. ANIBES showed signifi cantly low AI values for the overall population, but even more alarming in the case of males. Only 12% of men, in contrast with 21% of women, do satisfy the EFSA criterion. The IOM criterion reaches even less with higher recommended values for daily intake. In contrast, 60% of the American population reached the recommended intake of the IOM criterion. However, available data did not allow calculating the percentage reached by the EFSA criterion. Data from the Mexican study did not permit conducting comparisons with IOM or with EFSA. However, the water density criteria (mL/kcal) was higher than 1. CONCLUSION: There is a notable difference between all three populations in terms of TWI. Furthermore, within the same population, values of adequacy of TWI changed signifi cantly when they were assessed using different criteria. More scientifi c evidence is required for the production of better defined water intake recommendations in the future as well as more studies focusing on beverage consumption patterns in different settings. PMID- 27491579 TI - Urinary hydration biomarkers and dietary intake in children. AB - INTRODUCTION: The importance of hydration is undoubtable but reliable data on hydration status and its relation with diet is lacking. OBJECTIVES: We aimed to evaluate the hydration status and its relation to beverages and food intake in children. METHODS: A sample of 172 (50% male), 7-11 year-old children was included in this survey. Participants completed a 24 h urine collection; a 24 hours food recall corresponding to the day of urine collection was applied, weight and height were measured and parents/caregivers fi lled a lifestyle and socio-demographic questionnaire. The free water reserve was used to assess the hydration status. The intakes of food and beverages were compared according to hydration status using the t-test, Mann-Whitney test or unconditional regression models as appropriate. RESULTS: More than half of the participants were classifi ed as hypohydrated or at risk of hypohydration (57% in girls and 58% in boys). Compared to hypohydrated children, a signifi cant higher consumption of water (276.2 +/- 208.4 vs 188.2 +/- 187.4 g/day) and fruit juices (77.6 +/- 139.4 vs 14.4 +/- 57.2 g/day) was reported by euhydrated boys and girls, respectively. Lower consumers of water and fruit juices showed a higher risk of hypohydration (OR = 2.16, 95% CI: 1.02-4.58, p = 0.045), adjusting for confounders. CONCLUSIONS: Most of the children included in this analysis were classifi ed as at risk of hypohydration and those with higher water and fruit juices consumption showed a better hydration status. PMID- 27491580 TI - Dietary intake according to hydration status in 9-10 year-old soccer players. AB - INTRODUCTION: Children have an increased risk of voluntary dehydration especially during physical activity which may increase the risk of non-compensating water losses. OBJECTIVES: The aim of this study was to assess the hydration status and its relation to food intake in a children group of soccer players. METHOD: A sample of 36 boys aged 9-10 years was included in this study; 30 completed a 24 h urine collection. Participants completed a 24 h urine collection; a 24 hours food recall corresponding to the day of urine collection was applied, weight and height were measured and parents/caregivers fi lled a lifestyle and socio demographic questionnaire. The free water reserve (FWR [ml/24 h] = urine volume [ml/24 h] - obligatory urine volume [ml/24 h]) was used to assess the hydration status. Food and beverage groups were created and models of unconditional logistic regression were fi tted in order to estimate the magnitude of the association between the hydration status and diet. RESULTS: Forty three per cent of participants were classifi ed as at risk of hypohydration. Children who reported a high fruit and vegetables intake (above the median) were at decreased risk of hypohydration (OR = 0.19, 95% CI 0.04-0.94, p = 0.041), compared to children who reported a low fruit and vegetables intake. CONCLUSIONS: Almost half of the children were at risk of hypohydration. Our results suggested that water food sources such as fruit and vegetables may contribute to euhydration. PMID- 27491582 TI - Macronutrients contribution from beverages according to sex and age: findings from the ANIBES Study in Spain. AB - Methodologies and procedures used in dietary surveys have been widely developed with the aim of evaluating the nutritional status of a population. However, beverages are often either disregarded at national and international assessment of nutrients intake or poorly mentioned. Moreover, there is no standardized questionnaire developed as a research tool for the evaluation of beverages intake in the general population. Moreover, the contribution of different beverages to macronutrients intake is rarely provided. The latter in the context of a continuous expansion and innovation of the beverages market in Spain. Therefore, the main goal of the present study was to evaluate non-alcoholic and alcoholic beverages macronutrients contribution in the ANIBES study in Spain (9-75 years old).As expected, those contributed to dietary macronutrient intake mainly as total carbohydrates and sugar. The contribution to other macronutrients (proteins and lipids) by the beverage groups was of much less importance. For non-alcoholic beverages, contribution to carbohydrates was much higher in younger populations (children: 10.91 +/- 9.49%, mean +/- SD for boys and 9.46 +/- 8.83% for girls; adolescents: 11.97 +/- 11.26% for men and 13.77 +/- 10.55% in women) than in adults: 9.01 +/- 9.84% for men and 7.77 +/- 8.73% in women. Finally, a much lower contribution was observed in the elderly: 4.22 +/- 6.10% for men and 4.46 +/- 6.56% for women. No sex differences, however, across all age groups were found. Results for sugar contribution showed a similar trend: children (23.14 +/- 19.00% for boys and 19.77 +/- 17.35% for girls); adolescents (28.13 +/- 24.17% for men and 29.83 +/- 21.82% in women); adults 20.42 +/- 20.35% for men and 16.95 +/- 17.76% in women, p <= 0.01; and elderly: 14.63% +/- 9.97 for men and 9.33 +/- 12.86% in women. The main contribution corresponded to sugared soft drinks, juices and nectars, more relevant and significant in the younger populations. As for alcoholic beverages, the contribution of macronutrients to the total diet is low for carbohydrates and sugar. The main contribution of this group, as expected, is alcohol, being higher from low alcohol content beverages, and in men vs women (p <= 0.001). PMID- 27491581 TI - Fifty years of beverages consumption trends in Spanish households. AB - OBJECTIVES: To describe the evolution of non-alcoholic and alcoholic beverages consumption in the Spanish households from the 60's to nowadays. METHODS: This study is based on beverages and food consumption in Spanish households; the data sample consisted of consumption and distribution data, obtained from the Household Budget Survey (HBS) since 1964 to 1991 and from the Food Consumption Survey (FCS) since 2000 to 2014, in collaboration with the Spanish Nutrition Foundation (FEN). RESULTS: In 2014 the average consumption of non-alcoholic beverages was 332 g/person/day, whereas alcoholic beverages consumption represented 72.6 g/person/day. Consumption of non-alcoholic beverages has increased 721% (1964: 46 g/person/day; 1991: 96 g/person/day; 2000: 240 g/person/day and 2014: 332 g/person/day), whereas alcoholic beverages consumption has decreased roughly a 50% (1964: 145 g/person/day; 1991: 113 g/person/day; 2000: 78.4 g/person/day and 2014: 72.6 g/person/day). The most consumed alcoholic beverage in 2014 was beer (41.3 g/day), followed by wine (23.0 g/day). Regarding non-alcoholic beverages, the most consumed was water (144 g/day), followed by cola (ordinary: 30.7 g/day and diet: 20.5 g/day).According to Spanish regions, in 2014 non-alcoholic beverages were the most consumed in the islands (Balearic Islands 521 grams/person/day; Canary Islands 515 grams/person/day), as it was in the nineties (Balearic Islands 148 grams/person/day and Canary Islands 281 grams/person/day). However in 1980-81 the largest consumption of alcoholic beverages was that of Galicia, 408 g/person per day, and the lower in the Canary Islands, 63 g/person per day. In 2014, Murcia and Andalucia represented the regions with the highest consumption of alcoholic beverages. In 2014, alcoholic beverages provided roughly 1.89% of the total energy and 1.47% of sugars, whereas non-alcoholic beverages provided 3.28% of energy and 15.72% of sugars and, in 2000, alcoholic beverages contributed 2.29% of the energy and 1.47% of sugars and non-alcoholic drinks provided 3.76% of the energy and 22.7% of sugars. CONCLUSION: There have been signifi cant changes in the eating patterns at the Spanish homes, especially regarding beverages consumption, over the last five decades. In general, a higher consumption and variety for non-alcoholic drinks has occurred, especially in the islands. In parallel, a decline in alcoholic beverages consumption has been clearly observed. PMID- 27491583 TI - Effects of maternal hydration status on the osmolality of maternal milk. AB - BACKGROUND: It has been demonstrated that human milk osmolality (Mosm) is regulated within an established range, typically 290 to 300 mOsm/kg, and appears to be resistant to effects of maternal dehydration, as refl ected by high urinary osmolality (Uosm). OBJECTIVE: To determine the degree of association between Mosm and Uosm at a common point in time, as well as the reproducibility of both measures over a one-week interval of sampling. METHODS: Mosm and Uosm were measured with a Vogel Loser 450 osmometer on samples of the respective biological fluids collected concurrently in 31 lactating women, with infants aged between 30 and 340 days. In the first 15 women recruited, collections were repeated 7 days after the initial ones. RESULTS: The median Mosm for the 46 samples collected was 308 mOsm/kg with a range from 288 to 448 mOsm/kg. The corresponding values for Uosm were 598 mOsm/kg with a range from 93 to 1,678 mOsm/kg. The Spearman rank order correlation coeffi cient for within-individual association of Mosm and Uosm was r = 0.214 (p = 0.153). The median Mosm for the 15 repeat-subjects was 309 mOsm/kg on both occasions, with a within-individual Spearman coeffi cient of r = 0.326 (p = 0.118). By contrast, for the Uosm, the within-subject association was much stronger, with r = 0.699 (p = 0.002). CONCLUSIONS: The osmometry technique proved to be a highly stable and reproducible measurement technique. Mosm and Uosm are not significantly associated at a point in time. Intra-subject Mosm varies more across time than intra-subject Uosm. PMID- 27491584 TI - A new educational tool to learn about hydration: taste workshops for children. AB - INTRODUCTION: Nutrition education contributes to children's understanding and practice of healthy lifestyles behaviors. Having a well hydration status is an essential topic, especially since children are a vulnerable population who are much more prone to dehydration than adults are. The approval of the Report on the European Gastronomic Heritage: Cultural and Educational Aspects in 2014 served as starting point to work on innovative audio-visual and multimedia materials for children. The Spanish Nutrition Foundation (FEN) and the Royal Academy of Gastronomy (RAG), in collaboration with the Ministry of Education, Culture and Sport in Spain (MECD), developed educational videos for schoolchildren to learn about food, nutrition and gastronomy, specially, the importance of being hydrated. OBJECTIVES: To develop a serial of videos for children between 3 and 9 years old with nutrition and cooking lessons to be used as educational resources in the official curricula. METHODS: Fourteen chapters related to food, nutrition, gastronomy, physical activity and hydration to be used to record videos were designed and tested. A nutritionist, a chef and two puppets were the main characters acting in the videos. RESULTS: The chapters were assembled in nine videos that included five sections: introduction, video lesson, recipes -in case of hydration, recipes with different water content foods were recorded-, what have you learntand check your knowledge. A summary of the new educational material was officially presented at the Spain Pavilion during the Expo Milano 2015. Moreover, they are included as education tool for teachers in the new PANGEI Programme (Food, Nutrition and Gastronomy for Infantile Education) conjointly launched by FEN, RAG and MEDC. CONCLUSION: Taste workshops are useful as innovative nutrition education tools to reinforce language, listening and motor skills as well as food and nutrition concepts, and specially, the importance of being well hydrated. PMID- 27491585 TI - The use of moderated mediated analysis to study the influence of hypo-hydration on working memory. AB - INTRODUCTION: To date, dehydration has been typically reported to infl uence psychological parameters when there has been at least a 2% loss of body mass, although there has been little examination of those going about their everyday lives, those who have lost less than 1% of body mass. In such situations factors such as the initial hydration status and individual differences in the response to a reduced fl uid intake are likely to be infl uential. Yet to study the complexity added by such additional variables novel methods of statistical analysis are required. OBJECTIVES: The present study describes the use of moderated mediation, an approach that asks various questions: fi rstly, is drinking infl uential?; secondly, does a mediator (e.g.,thirst) sit between an independent and dependent variable?; and thirdly, does an effect only occur under certain conditions such as initial osmolality? METHOD: In the study, 118 subjects were exposed to 30 degrees C for four hours during which they half drank 300 ml water. The serial sevens test of working memory was performed before and at the end of the procedure. RESULTS: A 0.6% loss of body mass reduced the effi ciency of working memory. Those who consumed water had better working memory; working memory was worse in participants who lost more body mass or became thirstier, but only in those with higher levels of baseline osmolality. CONCLUSIONS: Small variations in hydration status infl uenced cognitive functioning although there were individual differences in the response. The parameters that influence an adverse response to hypo-hydration need to be established to allow giving appropriate advice. PMID- 27491586 TI - Frailty and sarcopenia: From theory to clinical implementation and public health relevance. AB - The sustainability of healthcare systems is threatened by the increasing (absolute and relative) number of older persons referring to clinical services. Such global phenomenon is questioning the traditional paradigms of medicine, pushing towards the need of new criteria at the basis of clinical decision algorithms. In this context, frailty has been advocated as a geriatric condition potentially capable of overcoming the weakness of chronological age in the identification of individuals requiring adapted care due to their increased vulnerability to stressors. Interestingly, frailty poses itself beyond the concept of nosological conditions due to the difficulties at correctly framing traditional diseases in the complex and heterogeneous scenario of elders. Thus, frailty may play a key role in public health policies for promoting integrated care towards biologically aged individuals, currently presenting multiple unmet clinical needs. At the same time, the term frailty has also been frequently used in the literature for framing a physical condition of risk for (mainly functional) negative endpoints. The combination of such physical impairment with an organ-specific phenotype (e.g., the age-related skeletal muscle decline or sarcopenia) may determine the assumptions for the development of a clinical condition to be used as potential target for ad hoc interventions against physical disability. In the present article, we present the background of frailty and sarcopenia, and discuss their potentialities for reshaping current clinical and research practice in order to promote holistic approach to older patients, solicit personalization of care, and develop new targets for innovative interventions. PMID- 27491588 TI - The beneficial effect of acute phase increase in serum ferritin. PMID- 27491587 TI - Validation of PROFUND prognostic index over a four-year follow-up period. AB - BACKGROUND/OBJECTIVES: The PROFUND index stratifies accurately the 12-month mortality risk of polypathological patients (PPs), but its fitness over a longer follow-up period remains unknown. We aimed to explore the calibration and discrimination power of PROFUND index over 4-years, in order to assess its follow up interval generalizability. DESIGN: Multicenter prospective cohort-study. SETTING: 33 Spanish hospitals. PARTICIPANTS: PPs included after hospital discharge, outpatient clinics, or home hospitalization. MEASUREMENTS: Mortality over a 4-year follow-up period. METHODS: PROFUND index calibration was assessed by risk-quartiles predicted/observed mortality (Hosmer-Lemeshow goodness-of-fit test), and its discrimination power by ROC curves. RESULTS: A total of 768 patients were included (630 [82%] of them completed the 4-year follow-up). Global mortality rate was 63.5%. When assessing individual patient scores, mortality was 52% in the lowest risk group (0-2 points in PROFUND score); 73.5% in the low intermediate risk group (3-6 points), 85% in the intermediate-high group (7-10 points); and 92% in the highest risk group (>=11 points). Accuracy testing of the PROFUND index showed good calibration (P=.8 in the Hosmer-Lemeshow goodness-of fit test), and also a good discrimination power (AUC=0.71 [0.67-0.77] in ROC curve). CONCLUSIONS: The PROFUND index maintained its accuracy in predicting mortality of polypathological patients over a 4-year follow-up period. This index may be of potential usefulness in deciding the most appropriate health-care interventions in populations with multimorbidity. PMID- 27491589 TI - Nicotinic receptor blockade decreases fos immunoreactivity within orexin/hypocretin-expressing neurons of nicotine-exposed rats. AB - Tobacco smoking is the leading cause of preventable death in the United States. Nicotine is the principal psychoactive ingredient in tobacco that causes addiction. The structures governing nicotine addiction, including those underlying withdrawal, are still being explored. Nicotine withdrawal is characterized by negative affective and cognitive symptoms that enhance relapse susceptibility, and suppressed dopaminergic transmission from ventral tegmental area (VTA) to target structures underlies behavioral symptoms of nicotine withdrawal. Agonist and partial agonist therapies help 1 in 4 treatment-seeking smokers at one-year post-cessation, and new targets are needed to more effectively aid smokers attempting to quit. Hypothalamic orexin/hypocretin neurons send excitatory projections to dopamine (DA)-producing neurons of VTA and modulate mesoaccumbal DA release. The effects of nicotinic receptor blockade, which is commonly used to precipitate withdrawal, on orexin neurons remain poorly investigated and present an attractive target for intervention. The present study sought to investigate the effects of nicotinic receptor blockade on hypothalamic orexin neurons using mecamylamine to precipitate withdrawal in rats. Separate groups of rats were treated with either chronic nicotine or saline for 7-days at which point effects of mecamylamine or saline on somatic signs and anxiety-like behavior were assessed. Finally, tissue from rats was harvested for immunofluorescent analysis of Fos within orexin neurons. Results demonstrate that nicotinic receptor blockade leads to reduced orexin cell activity, as indicated by lowered Fos-immunoreactivity, and suggest that this underlying cellular activity may be associated with symptoms of nicotine withdrawal as effects were most prominently observed in rats given chronic nicotine. We conclude from this study that orexin transmission becomes suppressed in rats upon nicotinic receptor blockade, and that behavioral symptoms associated with nicotine withdrawal may be aided by intervention upon orexinergic transmission. PMID- 27491590 TI - Behavioral deficits induced by third-trimester equivalent alcohol exposure in male C57BL/6J mice are not associated with reduced adult hippocampal neurogenesis but are still rescued with voluntary exercise. AB - Prenatal alcohol exposure can produce permanent alterations in brain structure and profound behavioral deficits. Mouse models can help discover mechanisms and identify potentially useful interventions. This study examined long-term influences of either a single or repeated alcohol exposure during the third trimester equivalent on survival of new neurons in the hippocampus, behavioral performance on the Passive avoidance and Rotarod tasks, and the potential role of exercise as a therapeutic intervention. C57BL/6J male mice received either saline or 5g/kg ethanol split into two s.c. injections, two hours apart, on postnatal day (PD)7 (Experiment 1) or on PD5, 7 and 9 (Experiment 2). All mice were weaned on PD21 and received either a running wheel or remained sedentary from PD35 PD80/81. From PD36-45, mice received i.p. injections of 50mg/kg bromodeoxyuridine (BrdU) to label dividing cells. Behavioral testing occurred between PD72-79. Number of surviving BrdU+ cells and immature neurons (doublecortin; DCX+) was measured at PD80-81. Alcohol did not affect number of BrdU+ or DCX+ cells in either experiment. Running significantly increased number of BrdU+ and DCX+ cells in both treatment groups. Alcohol-induced deficits on Rotarod performance and acquisition of the Passive avoidance task (Day 1) were evident only in Experiment 2 and running rescued these deficits. These data suggest neonatal alcohol exposure does not result in long-term impairments in adult hippocampal neurogenesis in the mouse model. Three doses of ethanol were necessary to induce behavioral deficits. Finally, the mechanisms by which exercise ameliorated the neonatal alcohol induced behavioral deficits remain unknown. PMID- 27491591 TI - Functional brain networks underlying latent inhibition of conditioned disgust in rats. AB - The present experiment examined the neuronal networks involved in the latent inhibition of conditioned disgust by measuring brain oxidative metabolism. Rats were given nonreinforced intraoral (IO) exposure to saccharin (exposed groups) or water (non-exposed groups) followed by a conditioning trial in which the animals received an infusion of saccharin paired (or unpaired) with LiCl. On testing, taste reactivity responses displayed by the rats during the infusion of the saccharin were examined. Behavioral data showed that preexposure to saccharin attenuated the development of LiCl-induced conditioned disgust reactions, indicating that the effects of taste aversion on hedonic taste reactivity had been reduced. With respect to cumulative oxidative metabolic activity across the whole study period, the parabrachial nucleus was the only single region examined which showed differential activity between groups which received saccharin-LiCl pairings with and without prior non-reinforced saccharin exposure, suggesting a key role in the effects of latent inhibition of taste aversion learning. In addition, many functional connections between brain regions were revealed through correlational analysis of metabolic activity, in particular an accumbens-amygdala interaction that may be involved in both positive and negative hedonic responses. PMID- 27491592 TI - Self-testing for Trichomonas vaginalis at home using a point-of-care test by women who request kits via the Internet. AB - We offered a point-of-care test for Trichomonas vaginalis to women via the Internet to determine if it was acceptable to women to perform the test at home. Most of the 102 participants felt that it was easy to collect the specimen, follow the instructions, and read and interpret the results for the trichomonas self-testing assay. PMID- 27491593 TI - Additive effects of levonorgestrel and ethinylestradiol on brain aromatase (cyp19a1b) in zebrafish specific in vitro and in vivo bioassays. AB - Estrogens and progestins are widely used in combination in human medicine and both are present in aquatic environment. Despite the joint exposure of aquatic wildlife to estrogens and progestins, very little information is available on their combined effects. In the present study we investigated the effect of ethinylestradiol (EE2) and Levonorgestrel (LNG), alone and in mixtures, on the expression of the brain specific ER-regulated cyp19a1b gene. For that purpose, recently established zebrafish-derived tools were used: (i) an in vitro transient reporter gene assay in a human glial cell line (U251-MG) co-transfected with zebrafish estrogen receptors (zfERs) and the luciferase gene under the control of the zebrafish cyp19a1b gene promoter and (ii) an in vivo bioassay using a transgenic zebrafish expressing GFP under the control of the zebrafish cyp19a1b gene promoter (cyp19a1b-GFP). Concentration-response relationships for single chemicals were modeled and used to design the mixture experiments following a ray design. The results from mixture experiments were analyzed to predict joint effects according to concentration addition and statistical approaches were used to characterize the potential interactions between the components of the mixtures (synergism/antagonism). We confirmed that some progestins could elicit estrogenic effects in fish brain. In mixtures, EE2 and LNG exerted additive estrogenic effects both in vitro and in vivo, suggesting that some environmental progestin could exert effects that will add to those of environmental (xeno-)estrogens. Moreover, our zebrafish specific assays are valuable tools that could be used in risk assessment for both single chemicals and their mixtures. PMID- 27491594 TI - Comparative Evaluation of Four Risk Scores for Predicting Mortality in Patients With Implantable Cardioverter-defibrillator for Primary Prevention. AB - INTRODUCTION AND OBJECTIVES: Several clinical risk scores have been developed to identify patients at high risk of all-cause mortality despite implantation of an implantable cardioverter-defibrillator. We aimed to examine and compare the predictive capacity of 4 simple scoring systems (MADIT-II, FADES, PACE and SHOCKED) for predicting mortality after defibrillator implantation for primary prevention of sudden cardiac death in a Mediterranean country. METHODS: A multicenter retrospective study was performed in 15 Spanish hospitals. Consecutive patients referred for defibrillator implantation between January 2010 and December 2011 were included. RESULTS: A total of 916 patients with ischemic and nonischemic heart disease were included (mean age, 62 +/- 11 years, 81.4% male). Over 33.4 +/- 12.9 months, 113 (12.3%) patients died (cardiovascular origin in 86 [9.4%] patients). At 12, 24, 36, and 48 months, mortality rates were 4.5%, 7.6%, 10.8%, and 12.3% respectively. All the risk scores showed a stepwise increase in the risk of death throughout the scoring system of each of the scores and all 4 scores identified patients at greater risk of mortality. The scores were significantly associated with all-cause mortality throughout the follow-up period. PACE displayed the lowest c-index value regardless of whether the population had heart disease of ischemic (c-statistic = 0.61) or nonischemic origin (c-statistic = 0.61), whereas MADIT-II (c-statistic = 0.67 and 0.65 in ischemic and nonischemic cardiomyopathy, respectively), SHOCKED (c-statistic = 0.68 and 0.66, respectively), and FADES (c-statistic = 0.66 and 0.60) provided similar c-statistic values (P >= .09). CONCLUSIONS: In this nontrial-based cohort of Mediterranean patients, the 4 evaluated risk scores showed a significant stepwise increase in the risk of death. Among the currently available risk scores, MADIT-II, FADES, and SHOCKED provide slightly better performance than PACE. PMID- 27491596 TI - A Highly Chemically Stable Metal-Organic Framework as a Luminescent Probe for the Regenerable Ratiometric Sensing of pH. AB - A heteroatom-rich 3D noninterpenetrating metal-organic framework (MOF) Cd-EDDA constructed from an ethylene glycol ether bridging tetracarboxylate ligand H4 EDDA (5,5'-(ethane-1,2-diylbis(oxy))diisophthalic acid) shows good chemical resistance to both acidic and alkaline solutions with a pH ranging from 2.0 to 12.2. There is a corresponding ratiometric luminescence response to pH from 2.0 to 11.5, and the sensing mechanism is also discussed through ion chromatography and molecular force field-based calculations. Importantly, the probe can easily be regenerated simply by modulating the pH of the solution, thus being the first example of a regenerable MOF-based ratiometric luminescent probe for pH. PMID- 27491595 TI - Ulnar Distraction Osteogenesis in the Treatment of Forearm Deformities in Children With Multiple Hereditary Exostoses. AB - PURPOSE: To report on the outcomes of using ulnar lengthening combined with acute angular correction for the treatment of forearm deformities in patients affected by multiple hereditary exostoses (MHE). Our hypothesis was that this procedure would improve both radiographic measurements and clinical outcomes with minimal complications. METHODS: A retrospective chart review was performed on patients who had a diagnosis of MHE and had undergone ulnar lengthening via a uniplanar external fixator over a 12-year period. Clinical outcomes such as range of motion, pain, and surgical complications were assessed. Radiographic changes were measured using interval radiographs. RESULTS: The series included 17 patients. Median age at surgery was 7 years (range, 3-14 years). Median follow up was 55 months (range, 5-125 months). Improvements occurred in radial and ulnar radii of curvature, carpal slip, ulnar variance, and carrying angle at the elbow. There was 1 major pin track infection. There were 2 failures of the external fixator requiring exchange. Premature consolidation occurred in 1 case. Elbow, forearm, and wrist motion was not affected. Radiocapitellar joint congruency did not change. No patient reported pain at final follow-up. CONCLUSIONS: Our approach of using distraction osteogenesis of the ulna with angular correction in the radius and ulna as needed is able to correct carpal slip as well as to improve forearm bowing and elbow carrying angle. All of the patients maintained congruency of the radiocapitellar joint with no postoperative dislocations. Because of the low complication rate, the resolution of pain in patients who presented with pain, and the improvement of forearm bowing, this approach should be considered as a treatment option for children with MHE who are at risk for radiocapitellar dislocation. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 27491597 TI - Dressed active particles in spherical crystals. AB - We investigate the dynamics of an active particle in two-dimensional spherical crystals, which provide an ideal environment to illustrate the interplay between active particles and crystallographic defects. A moving active particle is observed to be surrounded by localized topological defects, becoming a dressed active particle. Such a physical picture characterizes both the lattice distortion around the moving particle and the healing of the distorted lattice in its trajectory. We find that the dynamical behaviors of an active particle in both random and ballistic motions uniformly conform to this featured scenario, whether the particle is initially a defect or not. We further observe that the defect pattern around a dressed ballistic active particle randomly oscillates between two well-defined wing-like defect motifs regardless of its speed. The established physical picture of dressed active particles in this work partially deciphers the complexity of the intriguing nonequilibrium behaviors in active crystals, and opens the promising possibility of introducing the activity to engineer defects, which has strong connections with the design of materials. PMID- 27491598 TI - Using Laser-Induced Thermal Voxels to Pattern Diverse Materials at the Solid Liquid Interface. AB - We describe a high-resolution patterning approach that combines the spatial control inherent to laser direct writing with the versatility of benchtop chemical synthesis. By taking advantage of the steep thermal gradient that occurs while laser heating a metal edge in contact with solution, diverse materials comprising transition metals are patterned with feature size resolution nearing 1 MUm. We demonstrate fabrication of reduced metallic nickel in one step and examine electrical properties and air stability through direct-write integration onto a device platform. This strategy expands the chemistries and materials that can be used in combination with laser direct writing. PMID- 27491599 TI - Corrigendum to "Bluetongue virus surveillance in the Islamic Republic of Mauritania: Is serotype 26 circulating among cattle and dromedaries?" [Infect. Genet. Evol. (2016) 40:109-112]. PMID- 27491600 TI - Hepato-preferential insulins: Is this the end, or the end of the beginning? PMID- 27491601 TI - Combined Use of Bivalirudin and Radial Access in Acute Coronary Syndromes Is Not Superior to the Use of Either One Separately: Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVES: The aim of this meta-analysis was to study the relation between access site and bivalirudin use on outcomes in patients with acute coronary syndrome (ACS). BACKGROUND: Bivalirudin and radial access use are 2 strategies that are increasingly used to lower major bleeding in patients with ACS undergoing invasive approaches. The interaction between these 2 strategies and the benefit of using them in combination are unclear. METHODS: This analysis included randomized controlled trials that compared bivalirudin to heparin with or without glycoprotein IIb/IIIa inhibitors in patients with ACS and reported outcomes stratified by arterial access site. Meta-analyses of outcome data were performed on the basis of access site and anticoagulation regimen. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from event rates using random-effects models. RESULTS: Eight trials with a total of 27,491 patients were included. Bivalirudin reduced major bleeding risk in patients with femoral access (OR: 0.51; 95% CI: 0.46 to 0.6; p < 0.001) but not in patients with radial access (OR: 0.75; 95% CI: 0.45 to 1.26; p = 0.28). Moreover, radial access reduced major bleeding risk in patients treated with heparin (OR: 0.57; 95% CI: 0.43 to 0.77; p < 0.001) but not in patients treated with bivalirudin (OR: 0.96; 95% CI: 0.65 to 1.41; p = 0.83). There were no differences in major adverse cardiovascular events or all-cause mortality between bivalirudin and heparin, regardless of access site. CONCLUSIONS: Bivalirudin reduces bleeding risk only with femoral access, and radial access reduces bleeding risk only with heparin anticoagulation. Therefore, there is no additional benefit to the combined use of bivalirudin and radial access strategies in patients with ACS. PMID- 27491602 TI - The Fuzzy Math of Anticoagulation and Access Site: When 1 + 1 Does Not Always Equal 2. PMID- 27491603 TI - Prognostic Impact of Chronic Total Occlusions: A Report From SCAAR (Swedish Coronary Angiography and Angioplasty Registry). AB - OBJECTIVES: The aim of this study was to determine the prognostic impact of chronic total occlusion (CTO) on long-term mortality in a large prospective cohort. BACKGROUND: CTO is present in many patients with coronary artery disease and is difficult to treat with percutaneous coronary intervention. METHODS: The study population consisted of all consecutive patients who underwent coronary angiography in Sweden between January 1, 2005 and January 1, 2012, who were registered in SCAAR (Swedish Coronary Angiography and Angioplasty Registry). The patient population was heterogeneous with regard to indication for angiography (stable angina, ST-segment elevation myocardial infarction [STEMI], unstable angina or non-STEMI, and other) and treatment options. The long-term mortality rates of patients with and without CTO were compared by using shared frailty Cox proportional hazards regression adjusted for confounders. Tests were conducted for interactions between CTO and several pre-specified characteristics: indication for angiography and percutaneous coronary intervention (stable angina, STEMI, unstable angina or non-STEMI, and other), severity of coronary artery disease (1-, 2-, and 3-vessel and/or left main coronary artery disease), age, sex, and diabetes. RESULTS: During the study period, 14,441 patients with CTO and 75,431 patients without CTO were registered in SCAAR. CTO was associated with higher mortality (hazard ratio: 1.29; 95% confidence interval: 1.22 to 1.37; p < 0.001). In subgroup analyses, the risk attributable to CTO was lowest in patients with stable angina and highest in those with STEMI. In addition, CTO was associated with highest risk in patients under 60 years of age and with lowest risk in octogenarians. There was no interaction between CTO and either diabetes or sex, suggesting an equally adverse effect in both groups. CONCLUSIONS: In this large prospective observational study of patients with coronary artery disease, CTO was associated with increased mortality. This association was most prominent in younger patients and in those with acute coronary syndromes. PMID- 27491604 TI - Chronic Total Coronary Occlusions, Percutaneous Coronary Intervention, and Mortality: A "Hybrid Approach" to Interpretation. PMID- 27491605 TI - Individual Long-Term Mortality Prediction Following Either Coronary Stenting or Bypass Surgery in Patients With Multivessel and/or Unprotected Left Main Disease: An External Validation of the SYNTAX Score II Model in the 1,480 Patients of the BEST and PRECOMBAT Randomized Controlled Trials. AB - OBJECTIVES: The study sought to validate the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score II mortality prediction model after percutaneous coronary intervention (PCI) or coronary artery bypass grafting in a large pooled population of patients with multivessel coronary disease (MVD) and/or unprotected left main disease (UPLMD) enrolled in the PRECOMBAT (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease) and BEST (Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease) randomized controlled trials. BACKGROUND: For patients with MVD and/or UPLMD, the choice of the best revascularization strategy remains challenging. METHODS: Pooled individual patient-level data from PRECOMBAT and BEST were used to assess calibration and discrimination of the SYNTAX score II prediction model for all-cause mortality after PCI and coronary artery bypass grafting at 4-year follow-up. The study population comprised 1,480 patients (600 with UPLMD, 880 with MVD). RESULTS: The overall incidence of all cause mortality was 6.1% after a median follow-up period of 4.9 years. Validation plots showed good model calibration overall and across treatment groups but tended to overestimate all-cause mortality in the highest risk quintiles of patients in the whole population and the PCI arm. The SYNTAX score II showed moderate discrimination ability for the whole population (C index = 0.685) but better for patients receiving PCI than CABG (C index = 0.718 vs. 0.662 in patients with UPLMD, C index = 0.700 vs. 0.661 in those with MVD). Observed all cause mortality was higher when the treatment received was at variance with that recommended by the model and similar when it was concordant. CONCLUSIONS: The SYNTAX score II has good calibration but only moderate discrimination ability for long-term mortality prediction in this randomized population. This score provides an important tool to help guide the heart team's decision-making process regarding the selection of the best revascularization strategy for patients with MVD and/or UPLMD. (Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease, NCT00422968; Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease, NCT00997828). PMID- 27491606 TI - Coronary Revascularization: How Can Model-Derived Probabilities Inform Clinical Judgment? PMID- 27491608 TI - Harnessing the Potential of Human Autologous Stem Cells to Treat Refractory Angina. PMID- 27491607 TI - The RENEW Trial: Efficacy and Safety of Intramyocardial Autologous CD34(+) Cell Administration in Patients With Refractory Angina. AB - OBJECTIVES: This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34(+) cells would improve total exercise time (TET) and angina frequency in patients with refractory angina. BACKGROUND: IM administration of autologous CD34(+) cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials. METHODS: RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34(+) administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months. RESULTS: The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34(+) cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34(+)]). CONCLUSIONS: Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34(+) Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910). PMID- 27491610 TI - Examining Female-Specific Factors Lends Insight Into Women's More Favorable Prognosis in Transcatheter Aortic Valve Replacement. PMID- 27491609 TI - Acute and 30-Day Outcomes in Women After TAVR: Results From the WIN-TAVI (Women's INternational Transcatheter Aortic Valve Implantation) Real-World Registry. AB - OBJECTIVES: The study sought to examine the safety and performance of transcatheter aortic valve replacement (TAVR) using an all-female registry and to further explore the potential impact of female sex-specific characteristics on clinical outcomes after TAVR. BACKGROUND: Although women comprise 50% of patients with symptomatic severe aortic stenosis undergoing TAVR, the optimal treatment strategy remains undetermined. METHODS: The WIN-TAVI (Women's INternational Transcatheter Aortic Valve Implantation) registry is a multinational, prospective, observational registry of women undergoing TAVR for aortic stenosis, conducted without any external funding. The primary endpoint was the Valve Academic Research Consortium (VARC)-2 early safety endpoint at 30 days (composite of mortality, stroke, major vascular complication, life-threatening bleeding, stage 2 or 3 acute kidney injury, coronary artery obstruction, or repeat procedure for valve-related dysfunction). RESULTS: Between January 2013 and December 2015, 1,019 women were enrolled across 19 European and North American centers. The mean patient age was 82.5 +/- 6.3 years, mean EuroSCORE I was 17.8 +/- 11.7% and mean Society of Thoracic Surgeons score was 8.3 +/- 7.4%. TAVR was performed via transfemoral access in 90.6% and new-generation devices were used in 42.1%. In more than two-thirds of cases, an Edwards SAPIEN 23 mm (Edwards Lifesciences, Irvine, California) or Medtronic CoreValve <=26 mm (Medtronic Inc., Minneapolis, Minnesota) device was implanted. The 30-day VARC-2 composite endpoint occurred in 14.0% with 3.4% all-cause mortality, 1.3% stroke, 7.7% major vascular complications, and 4.4% VARC life-threatening bleeding. The independent predictors of the primary endpoint were age (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.00 to 1.08), prior stroke (OR: 2.02; 95% CI: 1.07 to 3.80), left ventricular ejection fraction <30% (OR: 2.62; 95% CI: 1.07 to 6.40), new device generation (OR: 0.59; 95% CI: 0.38 to 0.91), and history of pregnancy (OR: 0.57; 95% CI: 0.37 to 0.85). CONCLUSIONS: Women enrolled in this first ever all-female TAVR registry with collection of female sex-specific baseline parameters, were at intermediate-high risk and experienced a 30-day VARC-2 composite safety endpoint of 14.0% with a low incidence of early mortality and stroke. Randomized assessment of TAVR versus surgical aortic valve replacement in intermediate risk women is warranted to determine the optimal strategy. PMID- 27491612 TI - When Transcatheter Aortic Valve Replacement Is Not Enough: A Step Toward Understanding When Concomitant Mitral Regurgitation Needs Treatment. PMID- 27491611 TI - Mitral Regurgitation After Transcatheter Aortic Valve Replacement: Prognosis, Imaging Predictors, and Potential Management. AB - OBJECTIVES: This study sought to analyze the clinical impact of the degree and improvement of mitral regurgitation in TAVR recipients, validate the main imaging determinants of this improvement, and assess the potential candidates for double valve repair with percutaneous techniques. BACKGROUND: Many patients with severe aortic stenosis present with concomitant mitral regurgitation (MR). Cardiac imaging plays a key role in identifying prognostic factors of MR persistence after transcatheter aortic valve replacement (TAVR) and for planning its treatment. METHODS: A total of 1,110 patients with severe aortic stenosis from 6 centers who underwent TAVR were included. In-hospital to 6-month follow-up clinical outcomes according to the degree of baseline MR were evaluated. Off-line analysis of echocardiographic and multidetector computed tomography images was performed to determine predictors of improvement, clinical outcomes, and potential percutaneous alternatives to treat persistent MR. RESULTS: Compared with patients without significant pre-TAVR MR, 177 patients (16%) presented with significant pre-TAVR MR, experiencing a 3-fold increase in 6-month mortality (35.0% vs. 10.2%; p < 0.001). After TAVR, the degree of MR improved in 60% of them. A mitral annular diameter of >35.5 mm (odds ratio: 9.0; 95% confidence interval: 3.2 to 25.3; p < 0.001) and calcification of the mitral apparatus by multidetector computed tomography (odds ratio: 11.2; 95% confidence interval: 4.03 to 31.3; p < 0.001) were independent predictors of persistent MR. At least 14 patients (1.3% of the entire cohort, 13.1% of patients with persistent MR) met criteria for percutaneous mitral repair with either MitraClip (9.3%) or a balloon expandable valve (3.8%). CONCLUSIONS: Significant MR is not uncommon in TAVR recipients and associates with greater mortality. In more than one-half of patients, the degree of MR improves after TAVR, which can be predicted by characterizing the mitral apparatus with multidetector computed tomography. According to standardized imaging criteria, at least 1 in 10 patients whose MR persists after TAVR could benefit from percutaneous mitral procedures, and even more could be treated with MitraClip after dedicated pre-imaging evaluation. PMID- 27491613 TI - Valve Type, Size, and Deployment Location Affect Hemodynamics in an In Vitro Valve-in-Valve Model. AB - OBJECTIVES: The purpose of this study was to optimize hemodynamic performance of valve-in-valve (VIV) according to transcatheter heart valve (THV) type (balloon vs. self-expandable), size, and deployment positions in an in vitro model. BACKGROUND: VIV transcatheter aortic valve replacement is increasingly used for the treatment of patients with a failing surgical bioprosthesis. However, there is a paucity in understanding the THV hemodynamic performance in this setting. METHODS: VIV transcatheter aortic valve replacement was simulated in a physiologic left heart simulator by deploying a 23-mm SAPIEN, 23-mm CoreValve, and 26-mm CoreValve within a 23-mm Edwards PERIMOUNT surgical bioprosthesis. Each THV was deployed into 5 different positions: normal (inflow of THV was juxtaposed with inflow of surgical bioprosthesis), -3 and -6 mm subannular, and +3 and +6 mm supra-annular. At a heart rate of 70 bpm and cardiac output of 5.0 l/min, mean transvalvular pressure gradients (TVPG), regurgitant fraction (RF), effective orifice area, pinwheeling index, and pullout forces were evaluated and compared between THVs. RESULTS: Although all THV deployments resulted in hemodynamics that would have been consistent with Valve Academic Research Consortium-2 procedure success, we found significant differences between THV type, size, and deployment position. For a SAPIEN valve, hemodynamic performance improved with a supra annular deployment, with the best performance observed at +6 mm. Compared with a normal position, +6 mm resulted in lower TVPG (9.31 +/- 0.22 mm Hg vs. 11.66 +/- 0.22 mm Hg; p < 0.01), RF (0.95 +/- 0.60% vs. 1.27 +/- 0.66%; p < 0.01), and PI (1.23 +/- 0.22% vs. 3.46 +/- 0.18%; p < 0.01), and higher effective orifice area (1.51 +/- 0.08 cm(2) vs. 1.35 +/- 0.02 cm(2); p < 0.01) at the cost of lower pullout forces (5.54 +/- 0.20 N vs. 7.09 +/- 0.49 N; p < 0.01). For both CoreValve sizes, optimal deployment was observed at the normal position. The 26 mm CoreValve, when compared with the 23-mm CoreValve and 23-mm SAPIEN, had a lower TVPG (7.76 +/- 0.14 mm Hg vs. 10.27 +/- 0.18 mm Hg vs. 9.31 +/- 0.22 mm Hg; p < 0.01) and higher effective orifice area (1.66 +/- 0.05 cm(2) vs. 1.44 +/- 0.05 cm(2) vs. 1.51 +/- 0.08 cm(2); p < 0.01), RF (4.79 +/- 0.67% vs. 1.98 +/- 0.36% vs. 0.95 +/- 1.68%; p < 0.01), PI (29.13 +/- 0.22% vs. 6.57 +/- 0.14% vs. 1.23 +/- 0.22%; p < 0.01), and pullout forces (10.65 +/- 0.66 N vs. 5.35 +/- 0.18 N vs. 5.54 +/- 0.20 N; p < 0.01). CONCLUSIONS: The optimal deployment location for VIV in a 23 PERIMOUNT surgical bioprosthesis was at a +6 mm supra-annular position for a 23-mm SAPIEN valve and at the normal position for both the 23-mm and 26-mm CoreValves. The 26-mm CoreValve had lower gradients, but higher RF and PI than the 23-mm CoreValve and the 23-mm SAPIEN. In their optimal positions, all valves resulted in hemodynamics consistent with the definitions of Valve Academic Research Consortium-2 procedural success. Long-term studies are needed to understand the clinical impact of these hemodynamic performance differences in patients who undergo VIV transcatheter aortic valve replacement. PMID- 27491614 TI - Late Displacement After Transcatheter Mitral Valve Replacement for Degenerative Mitral Valve Disease With Massive Annular Calcification. PMID- 27491615 TI - More Stories. PMID- 27491616 TI - Interventional Treatment of a Failing Pulmonic and Tricuspid Bioprosthesis in Hedinger Syndrome. PMID- 27491617 TI - Late Presentation of a Semicomplete Occluded Right Coronary Artery by a Direct Flow Valve Preventing Interventional Therapy for ST-Segment Elevation Myocardial Infarction. PMID- 27491618 TI - Short-term interval training at both lower and higher intensities in the severe exercise domain result in improvements in VO2 on-kinetics. AB - PURPOSE: Although high-intensity interval training (HIT) seems to promote greater improvements in aerobic parameters than continuous training, the influence of exercise intensity on [Formula: see text] on-kinetics remains under investigation. METHODS: After an incremental test, twenty-one recreationally trained cyclists performed several time-to-exhaustion tests to determine critical power (CP), and the highest intensity (I HIGH), and the lowest exercise duration (T LOW) at which [Formula: see text] is attained during constant exercise. Subjects also completed a series of step transitions to moderate- and heavy intensity work rates to determine pulmonary [Formula: see text] on-kinetics. Surface electromyography (EMG) of vastus lateralis muscle and blood lactate accumulation (?BLC) was measured during heavy exercise. Subjects were assigned to one of two 4-week work-matched training groups: the lower [105 % CP: n = 11; 4 * 5 min at 105 % CP (218 +/- 39 W), 1 min recovery] or the upper [I HIGH: n = 10; 8 * 100 % I HIGH (355 +/- 60 W), 1:2 work:recovery ratio] intensity of the severe exercise domain. RESULTS: The two interventions were similarly effective in reducing the phase II [Formula: see text] time constant during moderate (105 % CP: 34 +/- 13 to 25 +/- 8 s; I HIGH: 31 +/- 9 to 23 +/- 6 s) and heavy exercise (105 % CP: 25 +/- 7 to 18 +/- 5 s; I HIGH: 27 +/- 7 to 16 +/- 5 s) and in reducing the amplitude of [Formula: see text] slow component, EMG amplitude, and ?BLC during heavy exercise. CONCLUSION: In conclusion, the short-term adjustments in response to step transitions to moderate and heavy exercise were independent of training intensity within the severe exercise domain. PMID- 27491619 TI - The effect of high-intensity cycling training on postural sway during standing under rested and fatigued conditions in healthy young adults. AB - PURPOSE: The purpose of this study was to investigate whether high-intensity cycling training leads to adapted responses of balance performance in response to exercise-induced muscle fatigue. METHODS: Eighteen healthy adults were assigned to either 3-weeks (n = 8, age 20.1 +/- 2.6 years, height 177 +/- 5 cm, mass 73.6 +/- 5.1 kg) or 6-weeks (n = 10, age 24.3 +/- 5.8 years, height 179 +/- 6 cm, mass 81.0 +/- 15.8 kg) of high-intensity training (HIT) on a cycle ergometer. The centre of pressure (COP) displacement in the anteroposterior (COPAP) direction and COP path length (COPL) were measured before and after the first and final high-intensity training sessions. RESULTS: Pre-training, exercise-induced fatigue elicited an increase in COPAP (3-weeks; p = 0.001, 6-weeks; p = 0.001) and COPL (3-weeks; p = 0.002, 6-weeks; p = 0.001) returning to pre-exercise levels within 10-min of recovery. Following 3-weeks of training, significant increases in COPAP (p = 0.001) and COPL (p = 0.002) were observed post-fatigue, returning to pre exercise levels after 15-min of recovery. After 6-weeks of training no significant increases in sway (COPAP; p = 0.212, COPL; p = 0.998) were observed following exercise-induced fatigue. CONCLUSIONS: In summary, 3 weeks of HIT resulted in longer recovery times following fatigue compared to pre-training assessments. After 6 weeks of HIT, postural sway following fatigue was attenuated. These results indicate that HIT could be included in injury prevention programmes, however, caution should be taken during early stages of the overreaching process. PMID- 27491621 TI - Using the dendritic polymer PAMAM to form gold nanoparticles in the protein cage thermosome. AB - The chaperonin thermosome (THS) is a protein cage that lacks binding sites for metal ions and inorganic nanoparticles. However, when poly(amidoamine) (PAMAM) is encapsulated into THS, gold nanoparticles (AuNP) can be prepared in the THS. The polymer binds HAuCl4. Subsequent reduction yields nanoparticles with narrow size distribution in the protein-polymer conjugate. PMID- 27491620 TI - The impact of sleeping with reduced glycogen stores on immunity and sleep in triathletes. AB - PURPOSE: We investigated the effects of a 3-week dietary periodization on immunity and sleep in triathletes. METHODS: 21 triathletes were divided into two groups with different nutritional guidelines during a 3-week endurance training program including nine twice a day sessions with lowered (SL group) or maintained (CON group) glycogen availability during the overnight recovery period. In addition to performance tests, sleep was monitored every night. Systemic and mucosal immune parameters as well as the incidence of URTI were monitored every week of the training/nutrition protocol. Two-ways ANOVA and effect sizes were used to examine differences in dependent variables between groups at each time point. RESULTS: The SL group significantly improved 10 km running performance (-1 min 13 s, P < 0.01, d = 0.38), whereas no improvement was recorded in the CON group (-2 s, NS). No significant changes in white blood cells counts, plasma cortisol and IL-6 were recorded over the protocol in both groups. The vitamin D status decreased in similar proportions between groups, whereas salivary IgA decreased in the SL group only (P < 0.05, d = 0.23). The incidence of URTI was not altered in both groups. All participants in both groups went to bed earlier during the training program (SL -20 min, CON -27 min, P < 0.05, d = 0.28). In the SL group, only sleep efficiency slightly decreased by 1.1 % (P < 0.05, d = 0.25) and the fragmentation index tended to increase at the end of the protocol (P = 0.06). CONCLUSION: Sleeping and training the next morning regularly with reduced glycogen availability has minimal effects on selected markers of immunity, the incidence of URTI and sleeping patterns in trained athletes. PMID- 27491622 TI - Core-Shell Silver/Polymeric Nanoparticles-Based Combinatorial Therapy against Breast Cancer In-vitro. AB - The current study aimed at preparing AgNPs and three different core-shell silver/polymeric NPs composed of Ag core and three different polymeric shells: polyvinyl alcohol (PVA), polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP). Thereafter, the core/shell NPs were loaded with a chemotherapeutic agent doxorubicin (DOX). Finally, the cytotoxic effects of the different core-shell Ag/polymeric NPs-based combinatorial therapeutics were tested in-vitro against breast cancer (MCF-7) and human fibroblast (1BR hTERT) cell lines. AgNPs, Ag/PVA and Ag/PVP NPs were more cytotoxic to MCF-7 cells than normal fibroblasts, as well as DOX-Ag, DOX-Ag/PVA, DOX-Ag/PEG and DOX-Ag/PVP nanocarriers (NCs). Notably, low dosage of core-shell DOX-loaded Ag/polymeric nanocarriers (NCs) exhibited a synergic anticancer activity, with DOX-Ag/PVP being the most cytotoxic. We believe that the prepared NPs-based combinatorial therapy showed a significant enhanced cytotoxic effect against breast cancer cells. Future studies on NPs-based combinatorial therapy may aid in formulating a novel and more effective cancer therapeutics. PMID- 27491625 TI - Cryogenic Trapping and Isotope Editing Identify a Protonated Water Cluster as an Intermediate in the Photosynthetic Oxygen-Evolving Reaction. AB - Internal water is known to play a catalytic role in several enzymes. In photosystem II (PSII), water is the substrate. To oxidize water, the PSII Mn4CaO5 cluster or oxygen evolving center (OEC) cycles through five oxidation states, termed Sn states. As reaction products, molecular oxygen is released, and protons are transferred through a ~25 A hydrogen-bonded network from the OEC to the thylakoid lumen. Previously, it was reported that a broad infrared band at 2880 cm(-1) is produced during the S1-to-S2 transition and accompanies flash-induced, S state cycling at pH 7.5. Here, we report that when the S2 state is trapped by continuous illumination under cryogenic conditions (190 K), an analogous 2740/2900 cm(-1) band is observed. The frequency depended on the sodium chloride concentration. This band is unambiguously assigned to a normal mode of water by D2(16)O and H2(18)O solvent exchange. Its large, apparent H2(18)O isotope shift, ammonia sensitivity, frequency, and intensity support assignment to a stretching vibration of a hydronium cation, H3O(+), in a small, protonated internal water cluster, nH2O(H3O(+)). Water OH stretching bands, which may be derived from the hydration shell of the hydronium ion, are also identified. Using the 2740 cm(-1) infrared marker, the results of calcium depletion and strontium reconstitution on the protonated water cluster are found to be pH dependent. This change is attributed to protonation of an amino acid side chain and a possible change in nH2O(H3O)(+) localization in the hydrogen-bonding network. These results are consistent with an internal water cluster functioning as a proton acceptor and an intermediate during the S1-to-S2 transition. Our experiments demonstrate the utility of this infrared signal as a novel functional probe in PSII. PMID- 27491624 TI - Insights into age-old questions of new dendritic spines: From form to function. AB - Principal neurons in multiple brain regions receive a vast majority of excitatory synaptic contacts on the tiny dendritic appendages called dendritic spines. These structures are believed to be the locus of memory storage in the brain. Indeed, neurological diseases leading to impairment in memory and cognitive capabilities are often associated with structural alteration of dendritic spines. While several landmark studies in the past have provided a great deal of information on the structure, function and molecular composition of prototypical mature dendritic spines, we still have a limited knowledge of nascent spines. In recent years there has been a surge of interest to understand the nascent spines and the increasing technical advances in the genetic, molecular and imaging methods have opened avenues for systematic and thorough investigation. In this review, by discussing studies from several labs including ours, we provide a systematic summary of the development, structure, molecular expression and function of nascent spines and highlight some of the potentially important and interesting research questions that remain to be answered. PMID- 27491626 TI - Merging thiophene with boron: new building blocks for conjugated materials. AB - This perspective highlights recent progress on the design, synthesis and applications of thienylboranes as building blocks for new functional materials. Well-controlled synthetic protocols, such as boron-tin and boron-silicon exchange reactions, hydroboration of alkynyl groups, and electrophilic borylations provide opportunities to access thiophene-boranes that are chemically robust and display desirable photophysical properties, redox characteristics, and solid-state assembly behavior. Diverse protocols for further functionalization allow for facile integration into larger conjugated structures and even polymeric systems. Moreover, the strong Lewis acid character that is characteristic of trivalent boranes facilitates intra- and intermolecular Lewis acid-base interactions that can further enrich the chemical and electronic properties of thiophene-borane materials. Recent advances with respect to applications in sensing, organic electronics, and the development of molecular switches are also discussed. PMID- 27491623 TI - Actin filament-microtubule interactions in axon initiation and branching. AB - Neurons begin life as spherical cells. A major hallmark of neuronal development is the formation of elongating processes from the cell body which subsequently differentiate into dendrites and the axon. The formation and later development of neuronal processes is achieved through the concerted organization of actin filaments and microtubules. Here, we review the literature regarding recent advances in the understanding of cytoskeletal interactions in neurons focusing on the initiation of processes from neuronal cell bodies and the collateral branching of axons. The complex crosstalk between cytoskeletal elements is mediated by a cohort of proteins that either bind both cytoskeletal systems or allow one to regulate the other. Recent studies have highlighted the importance of microtubule plus-tip proteins in the regulation of the dynamics and organization of actin filaments, while also providing a mechanism for the subcellular capture and guidance of microtubule tips by actin filaments. Although the understanding of cytoskeletal crosstalk and interactions in neuronal morphogenesis has advanced significantly in recent years the appreciation of the neuron as an integrated cytoskeletal system remains a frontier. PMID- 27491627 TI - Laparoscopic mesh repair for lumbar hernia after iliac crest bone harvest. AB - Lumbar hernia after iliac crest bone harvest is relatively rare. When it does occur, it presents as a flank abdominal protrusion through a lateroposterior abdominal wall defect. A laparoscopic approach for this type of hernia is reported to have advantages over the classic open method. Here, we present a case of a 49-year-old Caucasian man who presented with an enlarged left flank mass after iliac bone harvest for pseudarthrosis. He had undergone open onlay mesh repair for inferior lumbar hernia, but the hernia recurred 3 months postoperatively. Laparoscopic intraperitoneal onlay mesh repair using a composite mesh was performed 7 months after recurrence. The patient was discharged 6 days postoperatively without complications. No signs of recurrence were detected during 1-year follow-up period. The laparoscopic approach for lumbar hernia conferred excellent visualization of the hernia defect and enabled a safe mesh repair using intra-abdominal pressure to hold it in position. This approach provided all the benefits of minimally invasive surgery. PMID- 27491629 TI - Imaging the surface morphology, chemistry and conductivity of LiNi1/3Fe1/3Mn4/3O4 crystalline facets using scanning transmission X-ray microscopy. AB - Scanning transmission X-ray microscopy (STXM) using the X-ray fluorescence mode has been employed to elucidate the chemical structures at Ni, Fe, Mn and O sites from the (111) and (100) facets of micron-sized LiNi1/3Fe1/3Mn4/3O4 energy material particles. Furthermore, STXM imaging using electron yield mode has mapped out the surface conductivity of the crystalline particles. This study presents a novel approach that visualizes local element segregation, chemistry and conductivity variation among different crystal facets, which will assist further tailoring of the morphology and surface structure of this high voltage spinel lithium ion battery cathode material. PMID- 27491628 TI - Wastewater-Based Epidemiology To Monitor Synthetic Cathinones Use in Different European Countries. AB - Synthetic cathinones are among the most consumed new psychoactive substances (NPS), but their increasing number and interchangeable market make it difficult to estimate the real size of their consumption. Wastewater-based epidemiology (WBE) through the analysis of metabolic residues of these substances in urban wastewater can provide this information. This study applied WBE for the first time to investigate the presence of 17 synthetic cathinones in four European countries. A method based on solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry was developed, validated, and used to quantify the target analytes. Seven substances were found, with mephedrone and methcathinone being the most frequently detected and none of the analytes being found in Norway. Population-normalized loads were used to evaluate the pattern of use, which indicated a higher consumption in the U.K., followed by Spain and Italy, in line with the European prevalence data from population surveys. In the U.K., where an entire week was investigated, an increase of the loads was found during the weekend, indicating a preferential use in recreational contexts. This study demonstrated that WBE can be a useful additional tool to monitor the use of NPS in a population. PMID- 27491630 TI - Enantiodivergent Atroposelective Synthesis of Chiral Biaryls by Asymmetric Transfer Hydrogenation: Chiral Phosphoric Acid Catalyzed Dynamic Kinetic Resolution. AB - Reported herein is an enantiodivergent synthesis of chiral biaryls by a chiral phosphoric acid catalyzed asymmetric transfer hydrogenation reaction. Upon treatment of biaryl lactols with aromatic amines and a Hantzsch ester in the presence of chiral phosphoric acid, dynamic kinetic resolution (DKR) involving a reductive amination reaction proceeded smoothly to furnish both R and S isomers of chiral biaryls with excellent enantioselectivities by proper choice of hydroxyaniline derivative. This trend was observed in wide variety of substrates, and various chiral biphenyl and phenyl naphthyl adducts were synthesized with satisfactory enantioselectivities in enantiodivergent fashion. The enantiodivergent synthesis of synthetically challenging, chiral o tetrasubstituted biaryls were also accomplished, and suggests high synthetic potential of the present method. PMID- 27491632 TI - Erratum. PMID- 27491631 TI - Controversies in Surgical Management of Recalcitrant Enthesopathy of the Extensor Carpi Radialis Brevis. AB - Enthesopathy of the extensor carpi radialis brevis, often referred to as "tennis elbow," is common and responds to nonsurgical treatment in 80% to 90% of patients within 1 year. For those who proceed with surgery, much remains unclear regarding the ideal treatment. This paper discusses controversies in surgical management of extensor carpi radialis brevis enthesopathy including clinical outcomes of open versus arthroscopic techniques, the relevance of concomitant pathology addressed arthroscopically, and avenues for assessing comparative cost data. PMID- 27491633 TI - Compliance with cochlear implantation in children subsequently diagnosed with autism spectrum disorder. AB - OBJECTIVE: To assess the compliance with cochlear implantation (CI) in children subsequently diagnosed with autism spectrum disorder (ASD). METHODS: This was a retrospective case review and survey performed at a tertiary referral centre. Children meeting the criteria for CI who were implanted between 1989 and 2015 and who subsequently received a diagnosis of ASD were included. The primary outcome measure was to assess compliance with CI in children subsequently diagnosed with ASD. Secondary outcome measures included assessment of pre-CI risk factors that may have identified children at higher risk of a subsequent diagnosis of ASD, as well as the benefit obtained by these children following CI. RESULTS: 1050 children were implanted between 1989 and 2015. Of these, 22 children were diagnosed with ASD after receiving their CI. The average age at implantation was 2.6 years (median 3, range 1-8 years). The average age for diagnosis of ASD was 5 years, approximately 2 years (median 22 months, range 2-85 months) following CI. Of these, 16/22 (712.7%) regularly use their CI. 6/22 (27.2%) children became non users of their implant. Some degree of verbal communication was used by 13/22 (59%) of our studied group. CONCLUSION: There is a range of level of disabilities in ASD, with some relatively minor social communication difficulties through to severe language, cognitive, and behavioural difficulties. Compliance with CI is variable and appears to correlate with the severity of the ASD. Preoperative counselling should include information about the possible impact of later diagnosed disabilities such as ASD on performance. PMID- 27491634 TI - Effects of histidin-2-ylidene vs. imidazol-2-ylidene ligands on the anticancer and antivascular activity of complexes of ruthenium, iridium, platinum, and gold. AB - Couples of N-heterocyclic carbene complexes of ruthenium, iridium, platinum, and gold, each differing only in the carbene ligand being either 1,3-dimethylimidazol 2-ylidene (IM) or 1,3-dimethyl-N-boc-O-methylhistidin-2-ylidene (HIS), were assessed for their antiproliferative effect on seven cancer cell lines, their interaction with DNA, their cell cycle interference, and their vascular disrupting properties. In MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] assays only the platinum complexes were cytotoxic at single-digit micromolar IC50 concentrations with the (HIS)Pt complex being on average twice as active as the (IM)Pt complex. The former was highly efficacious against cisplatin-resistant HT-29 colon carcinoma cells where the latter had no effect. Both Pt complexes were accumulated by cancer cells and bound to double helical DNA equally well. Only the (HIS)Pt complex modified the electrophoretic mobility of circular DNA in vitro due to the HIS ligand causing greater morphological changes to the DNA. Both platinum complexes induced accumulation of 518A2 melanoma cells in G2/M and S phase of the cell cycle. A disruption of blood vessels in the chorioallantoic membrane of fertilized chicken eggs was observed for both platinum complexes and the (IM)gold complex. The (HIS)platinum complex was as active as cisplatin in tumor xenografted mice while being tolerated better. We found that the HIS ligand may augment the cytotoxicity of certain antitumoral metal fragments in two ways: by acting as a transmembrane carrier increasing the cellular accumulation of the complex, and by initiating a pronounced distortion and unwinding of DNA. We identified a new (HIS)platinum complex which was highly cytotoxic against cancer cells including cisplatin resistant ones. PMID- 27491635 TI - Associated ultrasonographic findings in fetuses with microcephaly because of suspected Zika virus (ZIKV) infection during pregnancy. AB - OBJECTIVE: To describe fetal ultrasonographic findings and outcomes in a series of cases of fetal microcephaly associated with Zika virus infection. METHODS: Retrospective case series of microcephaly with definite (laboratory evidence) or highly probable (specific neuroimaging findings and negative laboratory results) maternal Zika virus infection. Microcephaly was graded as mild if the head circumference was between 2 and 3 standard deviation (SD) below the mean, and severe if 3 or more SD below the mean. Associated central nervous system (CNS) and extracranial malformations are described. RESULTS: Nineteen singleton pregnancies fulfilling the inclusion criteria were identified. Severe microcephaly and mild microcephaly were identified in 14 and 5 fetuses, respectively. Additional CNS malformations were present in 17 cases and 7 had extracranial congenital anomalies. Symptoms were reported in 13/19 cases at a gestational age between 5 and 16 weeks. Mean (+/-SD) gestational age at ultrasound diagnosis was 32.3 +/- 5.1 weeks. Amniocentesis was performed in five cases at a median gestational age of 31 weeks (range 28-38) and was positive for Zika virus RT-PCR in two cases. There were three neonatal deaths and one stillbirth. CONCLUSION: In the presence of fetal microcephaly associated with Zika virus infection, CNS malformations are frequently detected. (c) 2016 John Wiley & Sons, Ltd. PMID- 27491637 TI - Nuclear respiratory factor-1 (NRF-1) regulated hypoxia-inducible factor-1alpha (HIF-1alpha) under hypoxia in HEK293T. AB - Hypoxia-inducible factor 1alpha (HIF-1alpha) is a master regulator of oxygen homeostasis. Under hypoxia, the active HIF1-alpha subunits are mainly regulated through increased protein stabilization. Little is known concerning HIF-1alpha transcriptional regulation. Nuclear respiratory factor 1 (NRF-1) is a DNA-binding transcription factor that regulates mitochondrial biogenesis. In this study, we showed that NRF-1was a repressor of HIF-1alpha. The cellular depletion of NRF-1 by siRNA targeting leads to increased HIF-1alphatranscriptional activity. EMSA, ChIP and luciferase activity allowed the identification of two functional NRF-1 binding sites within HIF-1alpha promoter. This study therefore identifies NRF-1 as a novel regulator of HIF-1alpha. (c) 2016 IUBMB Life, 68(9):748-755, 2016. PMID- 27491636 TI - Curcumin improves episodic memory in cadmium induced memory impairment through inhibition of acetylcholinesterase and adenosine deaminase activities in a rat model. AB - Curcumin, the main polyphenolic component of turmeric (Curcuma longa) rhizomes has been reported to exert cognitive enhancing potential with limited scientific basis. Hence, this study sought to evaluate the effect of curcumin on cerebral cortex acetylcholinesterase (AChE) and adenosine deaminase (ADA) activities in cadmium (Cd)-induced memory impairment in rats. Animals were divided into six groups (n = 6): saline/vehicle, saline/curcumin 12.5 mg/kg, saline/curcumin 25 mg/kg, Cd/vehicle, Cd/curcumin 12.5 mg/kg, and Cd/curcumin 25 mg/kg. Rats received Cd (2.5 mg/kg) and curcumin (12.5 and 25 mg/kg, respectively) by gavage for 7 days. The results of this study revealed that cerebral cortex AChE and ADA activities were increased in Cd-poisoned rats, and curcumin co-treatment reversed these activities to the control levels. Furthermore, Cd intoxication increased the level of lipid peroxidation in cerebral cortex with a concomitant decreased in functional sulfuhydryl (-SH) group and nitric oxide (NO), a potent neurotransmitter and neuromodulatory agent. However, the co-treatment with curcumin at 12.5 and 25 mg/kg, respectively increased the non-enzymatic antioxidant status and NO in cerebral cortex with a decreased in malondialdehyde (MDA) level. Therefore, inhibition of AChE and ADA activities as well as increased antioxidant status by curcumin in Cd-induced memory dysfunction could suggest some possible mechanism of action for their cognitive enhancing properties. PMID- 27491638 TI - Effective carbon and nitrogen removal with reduced sulfur oxidation in an anaerobic baffled reactor for fresh leachate treatment. AB - The application of an anaerobic baffled reactor (ABR) with four compartments was investigated for the simultaneous removal of carbon and nitrogen from leachate. The nitrified effluent was recycled to compartment 3 of the ABR, thereby avoiding the adverse influence of nitrogen oxides on anaerobic methanogenesis in compartment 1. Nitrified effluent recirculation not only enhanced chemical oxygen demand removal (>95.6%) but also improved the total nitrogen removal efficiency from 12.7% to 67.4% with increasing recirculation ratio from 0.25 to 2. The challenge of insufficient carbon sources for heterotrophic denitrification in compartment 3 with a high recirculation ratio could be overcome by step feeding of leachate. Moreover, various reduced sulfurs (e.g., sulfide, elemental sulfur, and organic sulfur) were involved in nitrate reduction via sulfur-based autotrophic denitrification. The addition of sulfide to compartment 3 further confirmed nitrate reduction using reduced sulfur as an electron donor. The interaction of organic carbon, reduced sulfur, and nitrate in leachate treatment needs further study. PMID- 27491639 TI - Is there a correlation between time of delivery and newborn cord pH? AB - PURPOSE: Since more senior and attending physicians work in labor wards during morning shifts, we expect a better delivery outcome during that time period. MATERIALS AND METHODS: A retrospective study was conducted between 1/2005 and 12/2014. Records of 56 428 singleton deliveries from a tertiary hospital in which cord blood pH was routinely measured at birth were analyzed. Time of birth was divided into shifts: 7 AM-3 PM (morning shift), 3 PM-11 PM (afternoon shift), and 11 PM-7 AM (night shift). Additional stratification compared weekdays and weekend deliveries. RESULTS: 19 601, 18 429, and 18 398 neonates were born during morning, afternoon, and night shifts, respectively. There was no significant difference in maternal age, neonatal weight, or mean 5-min Apgar score among the three shift periods. Furthermore, there was no correlation between shift time of delivery and newborn acidosis with respect to cord pH less than 7 (0.1% in each time periods, p = 0.67). Despite the above, instrumental deliveries and cesarean sections were more common in the morning shift compared to the afternoon and night shift, respectively (p = 0.001 each). CONCLUSIONS: Although shift time of delivery was found to be related to mode of delivery it was not related to either 5-min Apgar score or newborn acidosis as reflected by cord pH. PMID- 27491641 TI - Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. AB - The randomized phase 3 ENDEAVOR study (N=929) compared carfilzomib and dexamethasone (Kd) with bortezomib and dexamethasone (Vd) in relapsed multiple myeloma (RMM). We performed a subgroup analysis from ENDEAVOR in patients categorized by number of prior lines of therapy or by prior treatment. Median progression-free survival (PFS) for patients with one prior line was 22.2 months for Kd vs 10.1 months for Vd, and median PFS for patients with ?2 prior lines was 14.9 months for Kd vs 8.4 months for Vd. For patients with prior bortezomib exposure, the median PFS was 15.6 months for Kd vs 8.1 months for Vd, and for patients with prior lenalidomide exposure the median PFS was 12.9 months for Kd vs 7.3 months for Vd. Overall response rates (Kd vs Vd) were 81.9 vs 65.5% (one prior line), 72.0 vs 59.7% (?2 prior lines), 71.2 vs 60.3% (prior bortezomib) and 70.1 vs 59.3% (prior lenalidomide). The safety profile in the prior lines subgroups was qualitatively similar to that in the broader ENDEAVOR population. In RMM, outcomes are improved when receiving treatment with carfilzomib compared with bortezomib, regardless of the number of prior therapy lines or prior exposure to bortezomib or lenalidomide. PMID- 27491642 TI - Hypertension might be a risk factor for erectile dysfunction: a meta-analysis. AB - The study aimed to evaluate whether hypertension was a risk factor for erectile dysfunction (ED). Databases including PubMed and Embase were retrieved to identify studies related to hypertension in ED patients. Odds ratio (OR) and 95% confidence interval (CI) were used as the effect size. Subgroup analyses stratified by total number of enrolled subjects and research regions were performed. Sensitivity analysis was performed by removing a single study at one time. Egger's test was used to evaluate the publication bias. Totally, 40 studies including 121,641 subjects were included in the meta-analysis. As a result, hypertension was closely related to ED (OR = 1.74, 95% CI, 0.63-0.80, p < .01). Subgroup analysis indicated hypertension was the risk factor for ED whatever the participants numbers. When stratified by different regions, hypertension was a risk factor for ED in Africa (OR = 3.35, 95% CI, 1.45-7.77, p < .01), Americas (OR = 1.97, 95% CI, 1.68-2.31, p < 0.01), Asia (OR = 1.46, 95% CI, 1.16-1.84, p < .01) and Europe (OR = 1.83, 95% CI, 1.34-2.49, p < .01), but not in Australia. Hypertension may be a potential risk factor for ED. PMID- 27491640 TI - Enhanced CAR T-cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors. AB - Immunotherapy with T cell modified with gamma-retroviral or lentiviral (LV) vectors to express a chimeric antigen receptor (CAR) has shown remarkable efficacy in clinical trials. However, the potential for insertional mutagenesis and genotoxicity of viral vectors is a safety concern, and their cost and regulatory demands a roadblock for rapid and broad clinical translation. Here, we demonstrate that CAR T cells can be engineered through non-viral Sleeping Beauty (SB) transposition of CAR genes from minimalistic DNA vectors called minicircles (MCs). We analyzed genomic distribution of SB and LV integrations and show that a significantly higher proportion of MC-derived CAR transposons compared with LV integrants had occurred outside of highly expressed and cancer-related genes into genomic safe harbor loci that are not expected to cause mutagenesis or genotoxicity. CD19-CAR T cells engineered with our enhanced SB approach conferred potent reactivity in vitro and eradicated lymphoma in a xenograft model in vivo. Intriguingly, electroporation of SB MCs is substantially more effective and less toxic compared with conventional plasmids, and enables cost-effective rapid preparation of therapeutic CAR T-cell doses. This approach sets a new standard in advanced cellular and gene therapy and will accelerate and increase the availability of CAR T-cell therapy to treat hematologic malignancies. PMID- 27491643 TI - Contribution of Quantitative EEG to the Diagnosis of Early Cognitive Impairment in Patients With Idiopathic Parkinson's Disease. AB - Cognitive dysfunction can emerge during the clinical course of Parkinson's disease (PD) even beginning in early stages, which requires extended neuropsychological tests for diagnosis. There is need for rapid, feasible, and practical tests in clinical practice to diagnose and monitor the patients without causing any discomfort. We investigated the utility of quantitative analysis of digital EEG (qEEG) for diagnosing subtle cognitive impairment in PD patients without evident cognitive deficits (ie, "normal cognition"). We enrolled 45 patients with PD and age- matched 39 healthy controls in the study. All participants had Mini-Mental State Examination (MMSE) score greater than 25. qEEG analysis and extensive neuropsychological assessment battery were applied to all participants. Test scores for frontal executive functions, verbal memory processes, attention span, and visuospatial functions were significantly lower than healthy controls ( P < .01). qEEG analysis revealed a significant increase in delta, theta, and beta frequencies, and decrease in alpha frequency band in cerebral bioelectrical activity in patient group. In addition, power spectral ratios ([alpha + beta] / [delta + theta]) in frontal, central, temporal, parietal, and occipital regions were significantly decreased in patients compared with the controls. The slowing in EEG was moderately correlated with MMSE scores ( r = 0.411-0.593; P < .01). However, qEEG analysis and extensive neuropsychological assessment battery were only in weak correlation ( r = 0.230 0.486; P < .05). In conclusion, qEEG analysis could increase the diagnostic power in detecting subtle cognitive impairment in PD patients without evident cognitive deficit, perhaps years before the clinical onset of dementia. PMID- 27491644 TI - Live birth rate and number of blastomeres on day 2 transfer. AB - PURPOSE: To investigate whether the presence of large fragment (LF) and abnormal cell divisions (ACDs) has influenced the correlation between live birth rate and number of blastomeres detected on day 2 by conventional scoring. METHODS: This study included 578 embryos cultured in time lapse and selected for transfer by conventional scoring on day 2. By time-lapse recordings, embryos were reassessed to identify ACDs and/or LFs mistaken as blastomeres. The latter identifications were used to recalculate fragmentation rate and the number of blastomeres. Life birth rate according to number of blastomeres was compared in (a) embryos selected by conventional scoring and (b) embryos reassessed by time lapse. RESULTS: After conventional scoring, embryos with four cells had a significantly higher pregnancy rate than embryos with less than four cells and embryos with more than four cells. By time-lapse assessment, ACDs and/or recalculated fragmentation >25 % was recognized in 106/578 (18.3 %) of transferred embryos. None of them resulted in a live birth. After exclusion of these embryos, the number of blastomeres on the day of transfer did not have any impact on life birth rate. CONCLUSION: Conventional scoring on day 2 did not detect ACDs and LFs mistaken as blastomeres. LFs can lead to a recalculated fragmentation rate to >25 %. No significant correlation between live birth rate and number of blastomeres in day 2 embryos was observed when embryos with ACDs and fragmentation >25 % were excluded. Recognition of ACDs and fragmentation >25 % is more predictive of live birth than number of blastomeres. PMID- 27491645 TI - Barriers and Facilitators to Community CPR Education in San Jose, Costa Rica. AB - BACKGROUND: Bystander cardiopulmonary resuscitation (CPR) improves survival after prehospital cardiac arrest. While community CPR training programs have been implemented across the US, little is known about their acceptability in non-US Latino populations. OBJECTIVES: The purpose of this study was to identify barriers to enrolling in CPR training classes and performing CPR in San Jose, Costa Rica. METHODS: After consulting 10 San Jose residents, a survey was created, pilot-tested, and distributed to a convenience sample of community members in public gathering places in San Jose. Questions included demographics, CPR knowledge and beliefs, prior CPR training, having a family member with heart disease, and prior witnessing of a cardiac arrest. Questions also addressed barriers to enrolling in CPR classes (cost/competing priorities). The analysis focused on two main outcomes: likelihood of registering for a CPR class and willingness to perform CPR on an adult stranger. Odds ratios and 95% CIs were calculated to test for associations between patient characteristics and these outcomes. RESULTS: Among 371 participants, most were male (60%) and <40 years old (77%); 31% had a college degree. Many had family members with heart disease (36%), had witnessed a cardiac arrest (18%), were trained in CPR (36%), and knew the correct CPR steps (70%). Overall, 55% (95% CI, 50-60%) indicated they would "likely" enroll in a CPR class; 74% (95% CI, 70-78%) would perform CPR on an adult stranger. Cardiopulmonary resuscitation class enrollment was associated with prior CPR training (OR: 2.6; 95% CI, 1.6-4.3) and a prior witnessed cardiac arrest (OR: 2.0; 95% CI, 1.1-3.5). Willingness to perform CPR on a stranger was associated with a prior witnessed cardiac arrest (OR: 2.5; 95% CI, 1.2-5.4) and higher education (OR: 1.9; 95% CI, 1.1-3.2). Believing that CPR does not work was associated with a higher likelihood of not attending a CPR class (OR: 2.4; 95% CI, 1.7-7.9). Fear of performing mouth-mouth, believing CPR is against God's will, and fear of legal risk were associated with a likelihood of not attending a CPR class and not performing CPR on a stranger (range of ORs: 2.4-3.9). CONCLUSION: Most San Jose residents are willing to take CPR classes and perform CPR on a stranger. To implement a community CPR program, barriers must be considered, including misgivings about CPR efficacy and legal risk. Hands-only CPR programs may alleviate hesitancy to perform mouth-to-mouth. Schmid KM , Mould Millman NK , Hammes A , Kroehl M , Quiros Garcia R , Umana McDermott M , Lowenstein SR . Barriers and facilitators to community CPR education in San Jose, Costa Rica. Prehosp Disaster Med. 2016;31(5):509-515. PMID- 27491647 TI - Molecular Informatics: From Models to Systems and Beyond. PMID- 27491646 TI - Gartanin induces cell cycle arrest and autophagy and suppresses migration involving PI3K/Akt/mTOR and MAPK signalling pathway in human glioma cells. AB - In central nervous system, glioma is the most common primary brain tumour. The diffuse migration and rapid proliferation are main obstacles for successful treatment. Gartanin, a natural xanthone of mangosteen, suppressed proliferation, migration and colony formation in a time- and concentration-dependent manner in T98G glioma cells but not in mouse normal neuronal HT22 cells. Gartanin, at low micromole, led to cell cycle arrest in G1 phase accompanied by inhibited expression level of G1 cell cycle regulatory proteins cyclin D1, while increased expression level of cyclin-dependent kinase inhibitor p27Kip1. In addition, the secretion and activity of matrix metalloproteinases 2/9 (MMP-2/-9) were significantly suppressed in T98G cells treated with gartanin, and it might result from modulating mitogen-activated protein kinases (MAPK) signalling pathway in T98G glioma cells. Moreover, gartanin significantly induced autophagy in T98G cells and increased GFP-LC3 punctate fluorescence accompanied by the increased expression level of Beclin 1 and LC3-II, while suppressed expression level of p62. Gartanin treatment resulted in obvious inhibition of PI3K/Akt/mTOR signalling pathway, which is important in modulating autophagy. Notably, gartanin mediated anti-viability was significantly abrogated by autophagy inhibitors including 3-methyladenine (3-MA) and chloroquine (CQ). These results indicate that anti-proliferation effect of gartanin in T98G cells is most likely via cell cycle arrest modulated by autophagy, which is regulated by PI3K/Akt/mTOR signalling pathway, while anti-migration effect is most likely via suppression of MMP-2/-9 activity which is involved in MAPK signalling pathway. PMID- 27491648 TI - Deep Learning in Drug Discovery. AB - Artificial neural networks had their first heyday in molecular informatics and drug discovery approximately two decades ago. Currently, we are witnessing renewed interest in adapting advanced neural network architectures for pharmaceutical research by borrowing from the field of "deep learning". Compared with some of the other life sciences, their application in drug discovery is still limited. Here, we provide an overview of this emerging field of molecular informatics, present the basic concepts of prominent deep learning methods and offer motivation to explore these techniques for their usefulness in computer assisted drug discovery and design. We specifically emphasize deep neural networks, restricted Boltzmann machine networks and convolutional networks. PMID- 27491649 TI - Rational Design of Coumarin Derivatives as CK2 Inhibitors by Improving the Interaction with the Hinge Region. AB - Design of novel coumarin derivatives as CK2 inhibitors were attempted by targeting the interaction with the hinge region. A set of substituents capable of forming a hydrogen bond or halogen bond with the hinge region were screened in silico, and trifluoromethyl emerges as a promising motif by forming favorable electrostatic interaction and a presumable halogen bond with the hinge region. As proof of concept, three trifluoromethyl derivatives of coumarin were synthesized and tested in vitro. The results indicated that replacement of methyl by trifluoromethyl leads to a modest 5-fold improvement in potency, with the most active compound being 0.4 uM. The newly designed compounds were further screened on one lung cancer cell line A549, showing low micromolar anti-proliferative activity. PMID- 27491650 TI - In Silico Investigation of the Neurotensin Receptor 1 Binding Site: Overlapping Binding Modes for Small Molecule Antagonists and the Endogenous Peptide Agonist. AB - The neurotensin receptor 1 (NTSR1) belongs to the family of 7TM, G protein coupled receptors, and is activated by the 13-amino-acid peptide neurotensin (NTS) that has been shown to play important roles in neurological disorders and the promotion of cancer cells. Recently, a high-resolution x-ray crystal structure of NTSR1 in complex with NTS8-13 has been determined, providing novel insights into peptide ligand recognition by 7TM receptors. SR48692, a potent and selective small molecule antagonist has previously been used extensively as a tool compound to study NTSR1 receptor signaling properties. To investigate the binding mode of SR48692 and other small molecule compounds to NTSR1, we applied an Automated Ligand-guided Backbone Ensemble Receptor Optimization protocol (ALiBERO), taking receptor flexibility and ligand knowledge into account. Structurally overlapping binding poses for SR48692 and NTS8-13 were observed, despite their distinct chemical nature and inverse pharmacological profiles. The optimized models showed significantly improved ligand recognition in a large scale virtual screening assessment compared to the crystal structure. Our models provide new insights into small molecule ligand binding to NTSR1 and could facilitate the structure-based design of non-peptide ligands for the evaluation of the pharmacological potential of NTSR1 in neurological disorders and cancer. PMID- 27491651 TI - Combination of In Silico Analysis and In Vitro Assay to Investigate Drug Response to Human Epidermal Growth Factor Receptor 2 Mutations in Lung Cancer. AB - The epidermal growth factor receptor 2 (HER2) has been established as an important target of HER2-positive lung cancer, but somatic mutations in HER2 kinase domain are frequently observed that may cause drug resistance and sensitivity for tyrosine kinase inhibitors (TKIs). In this study, the response profile of 14 small-molecule TKIs upon 11 clinical HER2 mutations was investigated systematically using a synthetic strategy that integrated in silico analysis and in vitro assay to explore the structural basis, energetic property and biological implication underlying the intermolecular interactions of TKIs with wild-type and variant HER2. It is found that most clinical mutations are far away from HER2 active site and thus can only address modest or moderate effect on inhibitor binding. However, few single-point substations such as D769H and D769Y as well as the gatekeeper mutation T798 M were predicted to cause strong resistance for an array of TKIs by reshaping the geometric feature and physiochemical property of the active site. Furthermore, inhibitor response to the most common insertion mutation in HER2 exion 20 (HER2(YVMA) ) was examined in detail; the response can be grouped into three classes: sensitization, resistance and insusceptibility. The Bcr-Abl inhibitor bosutinib and EGFR inhibitor gefitinib were selected as the representatives of, respectively, sensitization and insusceptibility to perform kinase assay against the GST-tagged, recombinant kinase domains of wild-type HER2(WT) and HER2(YVMA) variant. As expected, the biological activity of bosutinib was improved by ~160-fold due to the insertion, while gefitinib exhibited low inhibitory potency on both HER2(WT) and HER2(YVMA) (IC50 >100 MUM). Structural analysis revealed an intensive network of hydrogen bonds and hydrophobic interactions in HER2(YVMA) ?bosutinib complex, whereas only few nonspecific van der Waals contacts were observed at the complex interface of HER2(YVMA) with gefitinib. PMID- 27491652 TI - Comparative Analysis of QSAR-based vs. Chemical Similarity Based Predictors of GPCRs Binding Affinity. AB - Ligand based virtual screening (LBVS) approaches could be broadly divided into those relying on chemical similarity searches and those employing Quantitative Structure-Activity Relationship (QSAR) models. We have compared the predictive power of these approaches using some datasets of compounds tested against several G-Protein Coupled Receptors (GPCRs). The k-Nearest Neighbors (kNN) QSAR models were built for known ligands of each GPCR target independently, with a fraction of tested ligands for each target set aside as a validation set. The prediction accuracies of QSAR models for making active/inactive calls for compounds in both training and validation sets were compared to those achieved by the Prediction of Activity Spectra for Substances' (PASS) and the Similarity Ensemble Approach (SEA) tools both available online. Models developed with the kNN QSAR method showed the highest predictive power for almost all tested GPCR datasets. The PASS software, which incorporates multiple end-point specific QSAR models demonstrated a moderate predictive power, while SEA, a chemical similarity based approach, had the lowest prediction power. Our studies suggest that when sufficient amount of data is available to develop and rigorously validate QSAR models such models should be chosen as the preferred virtual screening tool in ligand-based computational drug discovery as compared to chemical similarity based approaches. PMID- 27491653 TI - ADOMA: A Command Line Tool to Modify ClustalW Multiple Alignment Output. AB - We present ADOMA, a command line tool that produces alternative outputs from ClustalW multiple alignments of nucleotide or protein sequences. ADOMA can simplify the output of alignments by showing only the different residues between sequences, which is often desirable when only small differences such as single nucleotide polymorphisms are present (e.g., between different alleles). Another feature of ADOMA is that it can enhance the ClustalW output by coloring the residues in the alignment. This tool is easily integrated into automated Linux pipelines for next-generation sequencing data analysis, and may be useful for researchers in a broad range of scientific disciplines including evolutionary biology and biomedical sciences. The source code is freely available at https://sourceforge. net/projects/adoma/. PMID- 27491654 TI - Treatment outcome of PD-1 immune checkpoint inhibitor in Asian metastatic melanoma patients: correlative analysis with PD-L1 immunohistochemistry. AB - Overexpression of PD-L1 has been shown to be associated with better clinical responses to PD-1/PD-L1 blockade in melanoma. However, the utility of PD-L1 immunostaining as a predictive biomarker for anti-PD-1 treatment remains unclear, especially in melanoma of acral/mucosal origin. Materials and methods We collected and reviewed the medical records of 37 patients with metastatic melanoma who were treated with the anti-PD-1 antibodies pembrolizumab or nivolumab between January and December 2015. Patients with histologically diagnosed malignant melanoma and whose pretreatment tumor specimens were available for immunohistochemical staining of PD-L1 expression in tumor or immune cells were included. Results Of 37 patients, 26 patients had either acral or mucosal melanoma. The overall response rate was 10.8 % (95 % CI, 0.8-20.8 %). The response rate to PD-1 inhibitor was 11.5 % (95 % CI, 0-23.8 %) in acral/mucosal melanoma and that for cutaneous melanoma was 9.1 % (95 % CI, 0-26.1 %). Of these 37 patients, 18 had pre-treatment tumor specimens available for PD-L1 staining. Of 18 patients, 10 (55.5 %) were of acral/mucosal origin. In all patients with acral melanoma, the overall response rate (ORR) was 16.7 % (1 of 6 patients) and disease control rate (DCR) was 50 % (3 of 6 patients). In the PDL-1(+) melanoma group (1 % cut-off value), ORR was 20 % (2/10) and DCR was 80 %; for PDL-1 (-) group, ORR was 12.5 % (1/8) and DCR of 37.5 %. In the PDL-1 (+) group by 5 % cut off value, ORR was 33.3 % (2/6) and DCR was 83.3 %; for patients with PDL-1 (-), ORR was 8.3 % (1/12) and DCR was 50 %. The median PFS was 6.8 months in PDL-1(+) group and 1.9 months in PDL-1(-) group (p = 0.149). Anti-PD-1 treatment was very well tolerated without serious adverse events of grade 3 or 4 in all patients. Conclusions The treatment outcome to PD-1 antibody was not different in acral/mucosal melanoma when compared with cutaneous melanoma. The immunohistochemical PD-L1 expression seemed to be correlated with better clinical outcomes of anti-PD-1 treatment in limited cases. PMID- 27491655 TI - Simultaneous occurrence of metabolic, hematologic, neurologic and cardiac complications after Roux-en-Y gastric bypass for morbid obesity. AB - Roux-en-Y gastric bypass (RYGB) is a commonly performed procedure in the surgical treatment of morbid obesity. Since a major anatomical alteration is made, this procedure may lead to significant postoperative complications, including nutritional deficiencies related to malabsorption. As a consequence of micronutrient deficiencies, secondary metabolic, hematologic and neurologic complications might also develop. Each of these complications is well reported in the literature; however, there are limited data on the simultaneous occurrence of these complications in a single patient. In this report, we aimed to present the diagnosis and management of metabolic, hematologic, neurologic and cardiac complications, which occurred simultaneously in a 57-year-old female patient after undergoing laparoscopic RYGB procedure. PMID- 27491657 TI - Sharing experiences of clinical teaching: an evaluation of contrasting workshops. PMID- 27491656 TI - Understanding and responding when things go wrong: key principles for primary care educators. AB - Learning from events with unwanted outcomes is an important part of workplace based education and providing evidence for medical appraisal and revalidation. It has been suggested that adopting a 'systems approach' could enhance learning and effective change. We believe the following key principles should be understood by all healthcare staff, especially those with a role in developing and delivering educational content for safety and improvement in primary care. When things go wrong, professional accountability involves accepting there has been a problem, apologising if necessary and committing to learn and change. This is easier in a 'Just Culture' where wilful disregard of safe practice is not tolerated but where decisions commensurate with training and experience do not result in blame and punishment. People usually attempt to achieve successful outcomes, but when things go wrong the contribution of hindsight and attribution bias as well as a lack of understanding of conditions and available information (local rationality) can lead to inappropriately blame 'human error'. System complexity makes reduction into component parts difficult; thus attempting to 'find-and-fix' malfunctioning components may not always be a valid approach. Finally, performance variability by staff is often needed to meet demands or cope with resource constraints. We believe understanding these core principles is a necessary precursor to adopting a 'systems approach' that can increase learning and reduce the damaging effects on morale when 'human error' is blamed. This may result in 'human error' becoming the starting point of an investigation and not the endpoint. PMID- 27491658 TI - Can predilatation in transcatheter aortic valve implantation be omitted? - a prospective randomized study. AB - BACKGROUND: The use of a balloon expandable stent valve includes balloon predilatation of the aortic stenosis before valve deployment. The aim of the study was to see whether or not balloon predilatation is necessary in transcatheter aortic valve replacement (TAVI). METHODS: Sixty consecutive TAVI patients were randomized to the standard procedure or to a protocol where balloon predilatation was omitted. RESULTS: There were no significant differences between the groups regarding early hemodynamic results or complication rates. CONCLUSIONS: TAVI can be performed safely without balloon predilatation and with the same early results as achieved with the standard procedure including balloon predilatation. The reduction in the number of pacing periods required may be beneficial for the patient. PMID- 27491659 TI - [Alcohol and the heart : Anecdotes on the history of a checkered relationship]. AB - The cultural and natural scientific ambivalence of the heart and alcohol has long been the subject of philosophical, artistic, intellectual and emotional discussions, not uncommonly in a romanticizing manner. The indulgence of alcoholic beverages in moderation is contrasted by the inestimable risks and dangers of alcohol abuse with many cardiovascular implications, such as cardiac arrhythmia, cardiomyopathy and arterial hypertension. The inspirational mental effects of alcohol have been emphasized in many citations from Classical Antiquity through the Middle Ages and even in modern times. In addition to wine and beer many alcoholic drinks, such as Champagne, sparkling wines, whisky (or whiskey), brandy (Cognac) and fruit brandies have a nearly ritual culture of traditions and customs, without which social life would be unthinkable. The interplay between enjoyment and displeasure is emphasized in the year 2016 with the 500-year jubilee of the German purity requirements for beer with countless events, including the Bavarian State Exhibition 2016. Recently, evidence of a neuroprotective effect of alcohol was reported with an improvement of intellectual capacity, which could counteract the widely occurring dementia syndrome. Millions of people could profit from this effect. PMID- 27491660 TI - Three dimensional measurement of minimum joint space width in the knee from stereo radiographs using statistical shape models. AB - OBJECTIVES: An important measure for the diagnosis and monitoring of knee osteoarthritis is the minimum joint space width (mJSW). This requires accurate alignment of the x-ray beam with the tibial plateau, which may not be accomplished in practice. We investigate the feasibility of a new mJSW measurement method from stereo radiographs using 3D statistical shape models (SSM) and evaluate its sensitivity to changes in the mJSW and its robustness to variations in patient positioning and bone geometry. MATERIALS AND METHODS: A validation study was performed using five cadaver specimens. The actual mJSW was varied and images were acquired with variation in the cadaver positioning. For comparison purposes, the mJSW was also assessed from plain radiographs. To study the influence of SSM model accuracy, the 3D mJSW measurement was repeated with models from the actual bones, obtained from CT scans. RESULTS: The SSM-based measurement method was more robust (consistent output for a wide range of input data/consistent output under varying measurement circumstances) than the conventional 2D method, showing that the 3D reconstruction indeed reduces the influence of patient positioning. However, the SSM-based method showed comparable sensitivity to changes in the mJSW with respect to the conventional method. The CT-based measurement was more accurate than the SSM-based measurement (smallest detectable differences 0.55 mm versus 0. 82 mm, respectively). CONCLUSION: The proposed measurement method is not a substitute for the conventional 2D measurement due to limitations in the SSM model accuracy. However, further improvement of the model accuracy and optimisation technique can be obtained. Combined with the promising options for applications using quantitative information on bone morphology, SSM based 3D reconstructions of natural knees are attractive for further development.Cite this article: E. A. van IJsseldijk, E. R. Valstar, B. C. Stoel, R. G. H. H. Nelissen, N. Baka, R. van't Klooster, B. L. Kaptein. Three dimensional measurement of minimum joint space width in the knee from stereo radiographs using statistical shape models. Bone Joint Res 2016;320 327. DOI: 10.1302/2046-3758.58.2000626. PMID- 27491661 TI - Cost-Effectiveness of Deep Brain Stimulation for Advanced Parkinson's Disease in the United States. AB - OBJECTIVES: Deep brain stimulation (DBS), which uses an implantable device to modulate brain activity, is clinically superior to medical therapy for treating advanced Parkinson's disease (PD). We studied the cost-effectiveness of DBS in conjunction with medical therapy compared to best medical therapy (BMT) alone, using the latest clinical and cost data for the U.S. healthcare system. MATERIALS AND METHODS: We used a decision-analytic state-transition (Markov) model to project PD progression and associated costs for the two treatment strategies. We estimated the discounted incremental cost-effectiveness ratio (ICER) in U.S. dollars per quality-adjusted life-year (QALY) from the Medicare payer perspective, considering a ten-year horizon, and evaluated the robustness of our projections through extensive deterministic sensitivity analyses. RESULTS: Over ten years, DBS treatment led to discounted total costs of $130,510 compared to $91,026 for BMT and added 1.69 QALYs more than BMT, resulting in an ICER of $23,404 per QALY. This ICER was relatively insensitive to variations in input parameters, with neurostimulator replacement, costs for DBS implantation, and costs for treatment of disease-related falls having the greatest effects. Across all investigated scenarios, including a five-year horizon, ICERs remained under $50,000 per QALY. Longer follow-up periods and younger treatment age were associated with greater cost-effectiveness. CONCLUSIONS: DBS is a cost-effective treatment strategy for advanced PD in the U.S. healthcare system across a wide range of assumptions. DBS yields substantial improvements in health-related quality of life at a value profile that compares favorably to other well-accepted therapies. PMID- 27491662 TI - Prevalence of impaired glucose tolerance and other types of dysglycaemia among young twins and singletons in Guinea-Bissau. AB - BACKGROUND: Twins may be at increased risk of dysglycaemic disorders due to adverse fetal conditions. Data from Africa regarding this association is limited. We studied impaired glucose tolerance (IGT) and other types of dysglycemia among twins and singletons in Guinea-Bissau. METHODS: The study was conducted from February 2011 until March 2012 at the Bandim Health Project, a health and demographic surveillance system site in the capital Bissau. Twins (n = 209) and singletons (n = 182) were recruited from a previously established cohort. Oral glucose tolerance tests (OGTT) were performed, along with anthropometrics and collection of clinical and dietary data. RESULTS: Median age was 16.6 and 14.2 years between twins and singletons, respectively (P = 0.08). Mean birth weight was 2410 vs. 3090 g, respectively (P < 0.001). Twins had higher median fasting- and two hour capillary plasma glucose, 5.4(3.2-8.2) vs. 5.0(3.2-11.5) mmol/L (P < 0.001) and 6.8(3.4-11.3) vs. 6.2(3.2-12.1) mmol/L (P < 0.001), respectively, compared to singletons. The prevalence of IGT was 2.5 % (5/209) vs. 3.5 % (6/182) (RR = 0.73, 95 % CI: 0.20-2.64). 12 % (25/209) of twins had impaired fasting glucose (IFG), compared to 3.5 % (6/182) of singletons (3.63, 1.53-8.62). Dysglycemia (IGT and/or IFG or overt diabetes) was found in 17 % (35/209) vs. 9 % (16/182) (1.90, 1.08-3.37), respectively. CONCLUSIONS: Twins had higher glucose levels in both the fasting and postprandial state. This may indicate a detrimental effect of the twin fetal environment on glucose metabolism later in life, a result contrary to Scandinavian register studies. The IGT burden was low in this young age group and the risk was similar in twins and singletons. PMID- 27491663 TI - Electronically delivered, multicomponent intervention to reduce unnecessary antibiotic prescribing for respiratory infections in primary care: a cluster randomised trial using electronic health records-REDUCE Trial study original protocol. AB - INTRODUCTION: Respiratory tract infections (RTIs) account for about 60% of antibiotics prescribed in primary care. This study aims to test the effectiveness, in a cluster randomised controlled trial, of electronically delivered, multicomponent interventions to reduce unnecessary antibiotic prescribing when patients consult for RTIs in primary care. The research will specifically evaluate the effectiveness of feeding back electronic health records (EHRs) data to general practices. METHODS AND ANALYSIS: 2-arm cluster randomised trial using the EHRs of the Clinical Practice Research Datalink (CPRD). General practices in England, Scotland, Wales and Northern Ireland are being recruited and the general population of all ages represents the target population. Control trial arm practices will continue with usual care. Practices in the intervention arm will receive complex multicomponent interventions, delivered remotely to information systems, including (1) feedback of each practice's antibiotic prescribing through monthly antibiotic prescribing reports estimated from CPRD data; (2) delivery of educational and decision support tools; (3) a webinar to explain and promote effective usage of the intervention. The intervention will continue for 12 months. Outcomes will be evaluated from CPRD EHRs. The primary outcome will be the number of antibiotic prescriptions for RTIs per 1000 patient years. Secondary outcomes will be: the RTI consultation rate; the proportion of consultations for RTI with an antibiotic prescribed; subgroups of age; different categories of RTI and quartiles of intervention usage. There will be more than 80% power to detect an absolute reduction in antibiotic prescription for RTI of 12 per 1000 registered patient years. Total healthcare usage will be estimated from CPRD data and compared between trial arms. ETHICS AND DISSEMINATION: Trial protocol was approved by the National Research Ethics Service Committee (14/LO/1730). The pragmatic design of the trial will enable subsequent translation of effective interventions at scale in order to achieve population impact. TRIAL REGISTRATION NUMBER: ISRCTN95232781; Pre-results. PMID- 27491664 TI - Potentially disruptive life events: what are the immediate impacts on chronic disease management? A case-crossover analysis. AB - OBJECTIVE: To explore the association between unexpected potentially disruptive life events in a patient or family member that may challenge an individual's ability to take medications as prescribed and the discontinuation of evidence based medications for common, chronic conditions. Understanding the relationship between medication adherence and life stressors, especially those that can be identified using administrative data, may help identify patients at risk of non adherence. DESIGN: Observational self-controlled case-crossover design. SETTING: Individuals in a nationally representative US commercial health insurance database. PARTICIPANTS: Adult individuals who initiated an oral hypoglycaemic, antihypertensive and/or statin and subsequently stopped the medication for >=90 days. MAIN OUTCOME MEASURE: Potentially disruptive life events among patients and their family members measured in the 30 days just before the medication was discontinued ('hazard period') compared with the 30 days before this period ('control period'). These events included personal injury, hospitalisation, emergency room visits, changes in insurance coverage, acute stress or acute anxiety. RESULTS: Among the 326 519 patients meeting study criteria who discontinued their chronic disease medications, 88 896 (27.2%) experienced at least one potentially disruptive life event. Newly experiencing an injury (OR: 1.26, 95% CI 1.12 to 1.42), an emergency room visit (OR: 1.19, 95% CI 1.13 to 1.26) and acute stress (OR: 1.19, 95% CI 1.08 to 1.31) were associated with discontinuation. Life events among patients' family members did not appear to be associated with medication discontinuation or occurred less frequently just prior to discontinuation. CONCLUSIONS: Potentially disruptive life events among individuals identified using routinely collected claims data are associated with discontinuation of chronic disease medications. Awareness of these events may help providers or payers identify patients at risk of non-adherence to maximise patient outcomes. PMID- 27491665 TI - Protocol for a national blood transfusion data warehouse from donor to recipient. AB - INTRODUCTION: Blood transfusion has health-related, economical and safety implications. In order to optimise the transfusion chain, comprehensive research data are needed. The Dutch Transfusion Data warehouse (DTD) project aims to establish a data warehouse where data from donors and transfusion recipients are linked. This paper describes the design of the data warehouse, challenges and illustrative applications. STUDY DESIGN AND METHODS: Quantitative data on blood donors (eg, age, blood group, antibodies) and products (type of product, processing, storage time) are obtained from the national blood bank. These are linked to data on the transfusion recipients (eg, transfusions administered, patient diagnosis, surgical procedures, laboratory parameters), which are extracted from hospital electronic health records. APPLICATIONS: Expected scientific contributions are illustrated for 4 applications: determine risk factors, predict blood use, benchmark blood use and optimise process efficiency. For each application, examples of research questions are given and analyses planned. CONCLUSIONS: The DTD project aims to build a national, continuously updated transfusion data warehouse. These data have a wide range of applications, on the donor/production side, recipient studies on blood usage and benchmarking and donor-recipient studies, which ultimately can contribute to the efficiency and safety of blood transfusion. PMID- 27491666 TI - Ethnographic process evaluation of a quality improvement project to improve transitions of care for older people. AB - OBJECTIVES: Quality improvement projects to address transitions of care across care boundaries are increasingly common but meet with mixed success for reasons that are poorly understood. We aimed to characterise challenges in a project to improve transitions for older people between hospital and care homes. DESIGN: Independent process evaluation, using ethnographic observations and interviews, of a quality improvement project. SETTING AND PARTICIPANTS: An English hospital and two residential care homes for older people. DATA: 32 hours of non participant observations and 12 semistructured interviews with project members, hospital and care home staff. RESULTS: A hospital-based improvement team sought to reduce unplanned readmissions from residential care homes using interventions including a community-based geriatric team that could be accessed directly by care homes and a communication tool intended to facilitate transfer of information between homes and hospital. Only very modest (if any) impacts of these interventions on readmission rates could be detected. The process evaluation identified multiple challenges in implementing interventions and securing improvement. Many of these arose because of lack of consensus on the nature of the problem and the proper solutions: while the hospital team was keen to reduce readmissions and saw the problems as lying in poor communication and lack of community-based support for care homes, the care home staff had different priorities. Care home staff were unconvinced that the improvement interventions were aligned with their needs or addressed their concerns, resulting in compromised implementation. CONCLUSIONS: Process evaluations have a valuable role in quality improvement. Our study suggests that a key task for quality improvement projects aimed at transitions of care is that of developing a shared view of the problem to be addressed. A more participatory approach could help to surface assumptions, interpretations and interests and could facilitate the coproduction of solutions. This finding is likely to have broader applicability. PMID- 27491667 TI - Attitudes and factors affecting acceptability of self-administered cervicovaginal sampling for human papillomavirus (HPV) genotyping as an alternative to Pap testing among multiethnic Malaysian women. AB - OBJECTIVE: The objective of this study was to determine the attitudes and acceptability of self-administered cervicovaginal sampling compared with conventional physician-acquired Papanicolaou (Pap) smear among multiethnic Malaysian women. METHOD: A cross-sectional study was carried out via interviewer administered surveys from August 2013 through August 2015 at five government-run, urban health clinics in the state of Selangor. Subjects were participants from an ongoing community-based human papillomavirus (HPV) prevalence study who answered a standard questionnaire before and after self-sampling. The cervicovaginal self sampling for HPV genotyping was performed using a simple brush ('Just for Me'; Preventive Oncology International, Hong Kong). Detailed data on sociodemographics, previous Pap smear experience, and attitudes towards self administered cervicovaginal sampling were collected and analysed. Acceptability was inferred using a five-item Likert scale that included six different subjective descriptives: experience, difficulty, convenience, embarrassment, discomfort or pain, and confidence in collecting one's own sample. RESULTS: Of the 839 participants, 47.9% were Malays, followed by 30.8% Indians, 18.8% Chinese and 2.5% from other ethnicities. The median age of the participants was 38 years (IQR 30-48). Some 68.2% of participants indicated a preference for self-sampling over the Pap test, with 95% indicating willingness to follow-up a positive result at the hospital. Age, ethnicity and previous Pap test experience were significant independent factors associated with preference for self-sampling. The older the individual, the less likely they were to prefer self-sampling (adjusted OR 0.94, 95% CI 0.90 to 0.98). The Chinese were less likely to prefer self-sampling (72.6%) than the Malays (85.1%) (adjusted OR 0.57, 95% CI 0.33 to 0.98, p=0.004). Participants who had never undergone a Pap smear were also more likely to prefer self-sampling (88.5%) than women who had undergone a previous Pap (80.9%) (adjusted OR 0.06, 95% CI 0.35 to 0.87). CONCLUSIONS: Overall, urban Malaysian women from multiethnic backgrounds found self-sampling to be an acceptable alternative to Pap smear. PMID- 27491668 TI - Effectiveness and cost-effectiveness of the Salut Programme: a universal health promotion intervention for parents and children-protocol of a register-based retrospective observational study. AB - INTRODUCTION: There is inadequate evidence for the effectiveness and cost effectiveness of health promotion interventions. The Salut Programme aims to reach all parents and children in the Vasterbotten County of Sweden with a combination of health promotion interventions initiated during pregnancy and continued over the childhood period. This study protocol describes an effectiveness study and an economic evaluation study, where the ongoing Salut Programme is compared to care-as-usual over the periods of pregnancy, delivery and the child's first 2 years of life. METHODS: A register-based retrospective observational study design will be used with existing data sources with respect to exposures and outcomes. Outcomes of interest are clustered at 3 points: around the child's birth, 1 month after the child's birth and 2 years after the child's birth. We will simulate an experiment by retrospectively identifying and comparing children and their parents in the geographical areas where the Salut Programme was implemented since 2006 and onwards, and the areas where the Programme was not implemented before 2009. Outcomes will be analysed and compared for the premeasure period, and the postmeasure period for both groups. Our analysis combines difference-in-difference estimation with matching. A complementary analysis will be carried out on the longitudinal subsample of mothers who gave birth at least once during each of the time periods. The economic evaluation aims to capture the wider societal costs and benefits of the Salut Programme for the first 2 years of the children's lives. Incremental costs will be compared with incremental health gains and the results will be presented as a cost-consequence analysis. ETHICS AND DISSEMINATION: The Regional Ethical Review Board in Umea has given clearance for the Salut Programme research (2010 63-31M). No individual's identity will be revealed when presenting results. This study will provide information that can guide decision-makers to allocate resources optimally. PMID- 27491669 TI - Study design for a randomised controlled trial to explore the modality and mechanism of Tai Chi in the pulmonary rehabilitation of chronic obstructive pulmonary disease. AB - INTRODUCTION: Although pulmonary rehabilitation (PR) is associated with significant clinical benefits in chronic obstructive pulmonary disease (COPD) and has been recommended by guidelines, PR with conventional exercise training has not been widely applied in the clinic because of its inherent limitations. Alternative exercise such as Tai Chi has been investigated and the results are promising. However, the strengths and weaknesses of the exercise modality of Tai Chi, conventional PR and a combination of Tai Chi and conventional PR and the possible mechanisms underlying Tai Chi exercise remain unclear. This study aims to address the above research gaps in a well-designed clinical trial. METHODS AND ANALYSIS: This study is a single-blind, randomised controlled trial. Participants with stable COPD will be recruited and randomly assigned to one of four groups receiving Tai Chi exercise, conventional PR using a total body recumbent stepper (TBRS), combined Tai Chi and TBRS, or usual care (control) in a 1:1:1:1 ratio. Participants will perform 30 min of supervised exercise three times a week for 8 weeks; they will receive sequential follow-ups until 12 months after recruitment. The primary outcome will be health-related quality of life as measured by the St George's Respiratory Questionnaire. Secondary outcomes will include 6 min walking distance, pulmonary function, the modified Medical Research Council Dyspnoea Scale, the COPD Assessment Test, the Hospital Anxiety and Depression Scale, the Berg Balance Scale, exacerbation frequency during the study period, and systemic inflammatory and immune markers. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Clinical Trial and Biomedical Ethics Committee of West China Hospital of Sichuan University (No TCM-2015-82). Written informed consent will be obtained from each participant before any procedures are performed. The study findings will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ChiCTR-IOR-15006874; Pre-results. PMID- 27491670 TI - Investigating the accuracy of parentally reported weights and lengths at 12 months of age as compared to measured weights and lengths in a longitudinal childhood genome study. AB - BACKGROUND: Childhood obesity studies rely on parentally reported anthropometrics. However, the accuracy of such data has not been evaluated for 12 month-old children. Moreover, methods to improve the accuracy of reported data have not been assessed in prior studies. METHODS: A total of 185 children enrolled in a northern Virginia childhood longitudinal cohort genomic study had parentally completed surveys at 12 months. Measured weights and lengths were recorded for the same children from their 12-month paediatrician visit. Weight for length percentiles were calculated using World Health Organization gender specific growth charts. The agreement between reported and measured values was examined using Pearson's correlation, paired t-test and kappa statistics. The interquartile outlier rule was used to detect and remove outliers. RESULTS: Parentally reported weight was strongly associated with measured weight at 12 months (r=0.90). There was only a moderate correlation between parentally reported and measured lengths (r=0.52) and calculated weight for length percentiles (r=0.65). After removing outliers from parentally reported data, there was an increase in correlation between parentally reported and measured data for weight (r=0.93), length (r=0.69) and weight for length percentiles (r=0.76). Outliers removed compared to all children included were more likely to have maternal education less than a bachelor's degree (p=0.007). CONCLUSIONS: After removal of outliers from reported data, there is a strong correlation between calculated reported and measured weight for length percentiles suggesting that this may be an effective method to increase accuracy when conducting large scale obesity studies in young children where study costs benefit from using parentally reported data. PMID- 27491671 TI - Study protocol: first nationwide comparative audit of acute lower gastrointestinal bleeding in the UK. AB - INTRODUCTION: Acute lower gastrointestinal bleeding (LGIB) is a common indication for emergency hospitalisation worldwide. In contrast to upper GIB, patient characteristics, modes of investigation, transfusion, treatment and outcomes are poorly described. There are minimal clinical guidelines to inform care pathways and the use of endoscopy, including (diagnostic and therapeutic yields), interventional radiology and surgery are poorly defined. As a result, there is potential for wide variation in practice and clinical outcomes. METHODS AND ANALYSIS: The UK Lower Gastrointestinal Bleeding Audit is a large nationwide audit of adult patients acutely admitted with LGIB or those who develop LGIB while hospitalised for another reason. Consecutive, unselected presentations with LGIB will be enrolled prospectively over a 2-month period at the end of 2015 and detailed data will be collected on patient characteristics, comorbidities, use of anticoagulants, transfusion, timing and modalities of diagnostic and therapeutic procedures, clinical outcome, length of stay and mortality. These will be audited against predefined minimum standards of care for LGIB. It is anticipated that over 80% of all acute hospitals in England and some hospitals in Scotland, Wales and Northern Ireland will participate. Data will be collected on the availability and organisation of care, provision of diagnostic and therapeutic GI endoscopy, interventional radiology, surgery and transfusion protocols. ETHICS AND DISSEMINATION: This audit will be conducted as part of the national comparative audit programme of blood transfusion through collaboration with specialists in gastroenterology, surgery and interventional radiology. Individual reports will be provided to each participant site as well as an overall report and disseminated through specialist societies. Results will also be published in peer reviewed journals. The study has been funded by National Health Services (NHS) Blood and Transplant and the Bowel Disease Research Foundation and endorsed by the Association of Coloproctology of Great Britain and Ireland. PMID- 27491672 TI - Patterns of cancer screening, incidence and treatment disparities in China: protocol for a population-based study. AB - INTRODUCTION: Cancer has become the leading cause of death in China. Several knowledge gaps exist with respect to the patterns of cancer care and disparities in China. Chinese healthcare researchers do not have access to cancer research data of high quality. Only cancer incidence and mortality rates have been analysed in China while the patterns of cancer screening and treatment and disparities have not been rigorously examined. Potential disparities in cancer care by socioeconomic status have not been analysed in the previous literature. Population-based estimates of cancer care costs remain unexamined in China. This project will depict the pattern of cancer screening, incidence and treatment in Shandong province and enhance our understanding of causes of disparities in cancer control. METHODS AND ANALYSIS: We will create the first linked database of cancer registry and health insurance claims in China. We obtained cancer registry data on breast, gastrointestinal and lung cancer incidence from 2011 to 2014 and their health insurance claims information from 6 cities/counties of 10.63 million population and validated it with hospital discharge data. A 1600 participant survey will be administered to collect additional information of patients' socioeconomic status, employment and cancer care costs. Frequency analysis, spatial data exploratory analysis, multivariate logistic regression with instrumental variable, generalised linear regression and subgroup analysis will be used to analyse the following: the receipt of cancer screening, stage at diagnosis, guideline-concordant treatment and cancer care costs. Patient characteristics, tumour features, hospital characteristics, patient comorbidities and county-level descriptors will be used as covariates in the multivariate analysis. ETHICS AND DISSEMINATION: The Institutional Review Board of the School of Public Health of Shandong University approved this study (20140201). Data compiled from this project will be made available to all Chinese healthcare researchers. Study results will be disseminated through peer-reviewed publications and presentations at national and international meetings. PMID- 27491673 TI - A Contemporary Approach to Pulmonary Arterial Hypertension. AB - In recent years, there have been major changes in the landscape of pulmonary arterial hypertension therapy with the introduction of novel agents and innovative treatment strategies for this progressive disease. The aim of this review is to discuss the evolution in trial design in this field and highlight the salient features of recently published studies. We also summarize our approach to therapy selection in this chronic disease and identify areas for future exploration. The therapeutic armamentarium now includes 13 approved therapies. While most of these agents have been studied in small, short-term trials using the 6-min walk distance as a primary endpoint, there has been a shift in recent years toward larger, long-term, event-driven trials that utilize combined morbidity and mortality endpoints. The SERAPHIN and GRIPHON trials were two such studies, which led to the approval of the dual endothelin-receptor antagonist macitentan and the selective prostacyclin receptor antagonist selexipag, respectively. Other event-driven trials, like AMBITION and COMPASS-2, have provided valuable insight into the use of combined oral therapies in symptomatic patients. In conclusion, despite being a more manageable disease in the modern treatment era, pulmonary hypertension is still associated with considerable morbidity and much more work remains to be done in this field. Important questions remain about the most optimal way to manage patients and conduct trials going forward. PMID- 27491675 TI - EXPANDING EVIDENCE-BASED TECHNOLOGY ASSESSMENT FOR COVERAGE IN WASHINGTON STATE. AB - OBJECTIVES: We describe a new evidence-based method for screening and evaluating emerging medical technologies. Washington State agencies, under legislative direction, have granted authority to its agency Medical Directors and policy leaders to make coverage decisions on medical technologies using a "dossier" process. The dossier process is employed when technology advocates or manufacturers request Washington State healthcare purchasers to pay for new and emerging technologies. This offers the advocate an opportunity to submit scientific evidence and information classically associated with a more formal health technology assessment. METHODS: The submitted information is independently reviewed and summarized for Washington State's public healthcare purchasers allowing a more standardized coverage decision for all public purchasers in Washington State. RESULTS: This process has allowed Washington State to make twelve evidence-based coverage decisions at a fraction of the cost of classic technology assessment. To date, of twelve reviews over 6 years, one health technology was approved for coverage, ten were not covered and one did not require a coverage decision. CONCLUSIONS: This evidence-based dossier process has yielded high-value coverage decisions of new and emerging medical technologies for public healthcare purchasers in Washington State. PMID- 27491674 TI - The assessment of depression in people with multiple sclerosis: a systematic review of psychometric validation studies. AB - BACKGROUND: The prevalence of depression in people with multiple sclerosis (PwMS) is high; however, symptoms common to both conditions makes measurement difficult. There is no high quality overview of validation studies to guide the choice of depression inventory for this population. METHODS: A systematic review of studies validating the use of generic depression inventories in people with MS was conducted using MEDLINE and PsycINFO. Studies validating the use of depression inventories in PwMS and published in English were included; validation studies of tests for cognitive function and general mental health were excluded. Eligible studies were then quality assessed using the COSMIN checklist and findings synthesised narratively by instrument and validity domain. RESULTS: Twenty-one studies (N = 5,991 PwMS) evaluating 12 instruments were included in the review. Risk of bias varied greatly between instrument and validity domain. CONCLUSIONS: The review of validation studies was constrained by poor quality reporting and outcome reporting bias. Well-conducted evaluations of some instruments are unavailable for some validity domains. This systematic review provides an evidence base for trade-offs in the selection of an instrument for assessing self reported symptoms of depression in research or clinical practice involving people with MS. We make detailed and specific recommendations for where further research is needed. TRIAL REGISTRATION: PROSPERO CRD42014010597. PMID- 27491677 TI - Educational attainment, gender and health inequalities among older adults in Catalonia (Spain). AB - BACKGROUND: Health expectancies vary worldwide according to socioeconomic status (SES), with health disadvantages being evident among lower SES groups. Using educational attainment as a proxy of SES, we seek to identify trends in SES differentials in health by gender, with a particular focus on individuals with low educational attainment in the adult Catalan population (Spain) aged 55 or older. METHODS: Using cross-sectional data for 1994 and 2010-2014 drawn from the Catalan Health Survey, we examined three health indicators to document social health inequalities: self-perceived health, functional limitations, and restrictions on activities of daily living (ADL). We applied logistic models for each indicator, controlling for sociodemographic characteristics, health coverage and health behaviours. RESULTS: Among the less-educated, females presented a greater improvement in their self-perceived health over time than did their male counterparts, there being no significant variations among the medium/high educated. Regardless of education, males showed an increase in the prevalence of functional problems (as did the women, but the increase was not statistically significant). Both genders presented a higher prevalence of limitations when performing ADL in the second time period. The gender health gap was reduced slightly both for the low and the medium/high educated, expect in the case of ADL restrictions. Health and functioning differences by education level persisted, but showed significant signs of reduction. CONCLUSIONS: Less-educated females constitute the most disadvantaged group in terms of health and personal autonomy, though there are encouraging signs that the gap is closing both in terms of gender and level of education. Health policymakers need to devote particular attention to the aging population with low SES, especially to women. Public programmes promoting greater protection and equity, while fostering preventive and healthy practices, need to target the most underprivileged. PMID- 27491678 TI - Oestrous sheep serum balances ROS levels to supply in vitro capacitation of ram spermatozoa. AB - Reactive oxygen species (ROS) are fundamental for intracellular signalling. In spermatozoa, they are involved both to apoptosis and to capacitation, and changes in ROS levels can alter the balance between these two processes. Oestrous sheep serum (OSS) is considered an efficient agent for in vitro capacitation of ram spermatozoa. We have explored the effects of OSS on ram sperm physiology, especially on ROS production, during in vitro capacitation. Semen samples from 15 rams were cryopreserved. After thawing, samples were submitted to four treatments: control (CTL), 10% OSS supplementation for in vitro sperm capacitation, caspase inhibitor (INH, Z-VAD-FMK 100 MUM) and OSS (10%) plus caspase inhibitor (I + E). Sperm samples were incubated for 30 min at 38.5 degrees C and 5% CO2 and evaluated motility and kinetic parameters by computer assisted semen analysis (CASA) and viability (propidium iodide), apoptotic-like membrane changes (YO-PRO-1), acrosomal status (PNA-FITC), intracellular calcium (FLUO-3), membrane fluidity (M540) and ROS production (CM-H2 DCFDA) by flow cytometry. OSS induced changes in kinetic parameters compatible with capacitation, with a decrease in the percentage of progressive motility and linearity, and an increase in the amplitude of the lateral displacement of the sperm head (p < .05). Moreover, OSS increased the proportion of M540+ viable spermatozoa, YO-PRO-1+ and acrosome-reacted spermatozoa (p < .05). After incubation, OSS and I+E achieved lower ROS levels (p < .05). Ca(2+) levels did not change with the incubation, but were slightly higher (p < .05) when both OSS and the inhibitor were present. We suggest that OSS may modulate ROS levels, allowing intracellular signalling for capacitation to occur while preventing higher levels that could trigger apoptosis. PMID- 27491679 TI - Dual promoters of the major catalase (KatA) govern distinct survival strategies of Pseudomonas aeruginosa. AB - KatA is the major catalase required for hydrogen peroxide (H2O2) resistance and acute virulence in Pseudomonas aeruginosa PA14, whose transcription is driven from the promoter (katAp1) located at 155 nucleotide (nt) upstream of the start codon. Here, we identified another promoter (katAp2), the +1 of which was mapped at the 51 nt upstream of the start codon, which was responsible for the basal transcription during the planktonic culture and down-regulated upon H2O2 treatment under the control by the master regulator of anaerobiosis, Anr. To dissect the roles of the dual promoters in conditions involving KatA, we created the promoter mutants for each -10 box (p1m, p2m, and p1p2m) and found that katAp1 is required for the function of KatA in the logarithmic growth phase during the planktonic culture as well as in acute virulence, whereas katAp2 is required for the function of KatA in the stationary phase as well as in the prolonged biofilm culture. This dismantling of the dual promoters of katA sheds light on the roles of KatA in stress resistance in both proliferative and growth-restrictive conditions and thus provides an insight into the regulatory impacts of the major catalase on the survival strategies of P. aeruginosa. PMID- 27491680 TI - Post-translocational adaptation drives evolution through genetic selection and transcriptional shift in Saccharomyces cerevisiae. AB - Adaptation by natural selection might improve the fitness of an organism and its probability to survive in unfavorable environmental conditions. Decoding the genetic basis of adaptive evolution is one of the great challenges to deal with. To this purpose, Saccharomyces cerevisiae has been largely investigated because of its short division time, excellent aneuploidy tolerance and the availability of the complete sequence of its genome with a thorough genome database. In the past, we developed a system, named bridge-induced translocation, to trigger specific, non-reciprocal translocations, exploiting the endogenous recombination system of budding yeast. This technique allows users to generate a heterogeneous population of cells with different aneuploidies and increased phenotypic variation. In this work, we demonstrate that ad hoc chromosomal translocations might induce adaptation, fostering selection of thermo-tolerant yeast strains with improved phenotypic fitness. This "yeast eugenomics" correlates with a shift to enhanced expression of genes involved in stress response, heat shock as well as carbohydrate metabolism. We propose that the bridge-induced translocation is a suitable approach to generate adapted, physiologically boosted strains for biotechnological applications. PMID- 27491681 TI - BMP7 retards peripheral myelination by activating p38 MAPK in Schwann cells. AB - Schwann cell (SC) myelination is pivotal for the proper physiological functioning of the nervous system, but the underlying molecular mechanism remains less well understood. Here, we showed that the expression of bone morphogenetic protein 7 (BMP7) inversely correlates with myelin gene expression during peripheral myelination, which suggests that BMP7 is likely a negative regulator for myelin gene expression. Our experiments further showed that the application of BMP7 attenuates the cAMP induced myelin gene expression in SCs. Downstream pathway analysis suggested that both p38 MAPK and SMAD are activated by exogenous BMP7 in SCs. The pharmacological intervention and gene silence studies revealed that p38 MAPK, not SMAD, is responsible for BMP7-mediated suppression of myelin gene expression. In addition, c-Jun, a potential negative regulator for peripheral myelination, was up-regulated by BMP7. In vivo experiments showed that BMP7 treatment greatly impaired peripheral myelination in newborn rats. Together, our results established that BMP7 is a negative regulator for peripheral myelin gene expression and that p38 MAPK/c-Jun axis might be the main downstream target of BMP7 in this process. PMID- 27491682 TI - Prefrontal activity decline in women under a single dose of diazepam during rule guided responses: an fMRI study. AB - Daily life events confront us with new situations demanding responses to usual and unusual rules. Diazepam (DZ), a clinically important drug, facilitates the inhibitory activity of the GABAergic system. Prefrontal cortex, rich in DZ receptors, coordinates necessary resources to direct actions according to rules. The balance between excitatory and inhibitory activity is critical to achieve optimal function of brain systems leading to complex functions. Major sex differences in the physiological mechanisms of the GABAergic system have been reported. However, the differential influence of DZ on men and women in neural activity during behavior directed by frontal lobes remains unexplored. The ability of healthy volunteers to select responses following usual/congruent and novel/incongruent rules, and brain correlates were measured with fMRI under the administration of DZ and a placebo. 10 mg of DZ was enough to decrease the performance in a different manner between men and women. While reaction times increased in both men and women, women committed more errors selecting responses than men under DZ. Men demonstrated increased activity, while women demonstrated decreased activity in frontal regions involved in response selection of rules. These findings could have important consequences in understanding the differential influences of DZ between the sexes in complex daily life situations. More importantly, this study emphasizes the importance of understanding the differential effects on men and women of drugs widely employed by society, thereby achieves better therapeutic results and avoids side effects that the present study revealed to be different between sexes. PMID- 27491683 TI - Evidence of impaired neuromuscular responses in the support leg to a destabilizing swing phase perturbation in hemiparetic gait. AB - The neuromuscular mechanisms that underlie post-stroke impairment in reactive balance control during gait are not fully understood. Previous research has described altered muscle activations in the paretic leg in response to postural perturbations from static positions. Additionally, attenuation of interlimb reflexes after stroke has been reported. Our goal was to characterize post-stroke changes to neuromuscular responses in the stance leg following a swing phase perturbation during gait. We hypothesized that, following a trip, altered timing, sequence, and magnitudes of perturbation-induced activations would emerge in the paretic and nonparetic support legs of stroke survivors compared to healthy control subjects. The swing foot was interrupted, while subjects walked on a treadmill. In healthy subjects, a sequence of perturbation-induced activations emerged in the contralateral stance leg with mean onset latencies of 87-147 ms. The earliest latencies occurred in the hamstrings and hip abductor and adductors. The hamstrings, the adductor magnus, and the gastrocnemius dominated the relative balance of perturbation-induced activations. The sequence and balance of activations were largely preserved after stroke. However, onset latencies were significantly delayed across most muscles in both paretic and nonparetic stance legs. The shortest latencies observed suggest the involvement of interlimb reflexes with supraspinal pathways. The preservation of the sequence and balance of activations may point to a centrally programmed postural response that is preserved after stroke, while post-stroke delays may suggest longer transmission times for interlimb reflexes. PMID- 27491684 TI - Biosecurity for Translocations: Cirl Bunting (Emberiza cirlus), Fisher's Estuarine Moth (Gortyna borelii lunata), Short-Haired Bumblebee (Bombus subterraneus) and Pool Frog (Pelophylax lessonae) Translocations as Case Studies. AB - Exposure to parasites in conservation translocations increases the risks to recipient and translocated populations from disease, and therefore there has been interest in implementing biosecurity methods. Using four case examples we described how biosecurity was applied in practical translocation scenarios prior to and during a translocation and also post-release. We implemented biosecurity, including quarantine barriers, at specific points in the translocation pathway where hazards, identified by the disease risk analysis, had the potential to induce disease. Evidence that biosecurity protected translocated and recipient populations, included an absence of mortality associated with high-risk non native parasites, a reduction in mortality associated with endemic parasites, the absence of high-risk pathogenic parasites, or associated diseases, at the destination; and the apparent absence of diseases in closely related species at the destination site. The biosecurity protocols did not alter the level or duration of translocated species confinement and therefore probably did not act as a stressor. There is a monetary cost involved in biosecurity but the epidemiological evidence suggests that conservation translocation managers should carefully consider its use. Breakdowns in quarantine have occurred in human hospitals despite considerable investment and training for health professionals, and we therefore judge that there is a need for training in the objectives and maintenance of quarantine barriers in conservation translocations. Biosecurity protocols for conservation translocations should be continually updated in response to findings from disease risk analysis and post-release disease surveillance and we recommend further studies to evaluate their effectiveness. PMID- 27491685 TI - Laparoscopic Versus Open Resection for Gastrointestinal Stromal Tumors (GISTs). AB - PURPOSE: Primary gastrointestinal stromal tumors (GISTs) are typically treated with open resection. There is growing interest in laparoscopic GIST resection; however, data is limited. We report our experience with GIST resections using both open and laparoscopic techniques. MATERIALS AND METHODS: Twenty-nine GIST patients underwent definitive intent resection at the University of Missouri from 1990 to 2010. Patients who underwent laparoscopic resection (n = 7) were matched on the basis of tumor size, age, tumor location, and National Comprehensive Cancer Network (NCCN) risk stratification with seven patients who underwent open resection. The two groups were compared with respect to age, gender, BMI, tumor size, tumor site, mitotic rate, surgical margins, NCCN risk stratification, estimated blood loss, hospital stay, surgical complications, disease recurrence, and overall survival. RESULTS: The cohorts did not differ with respect to age, gender, BMI, tumor location, tumor size, or positive margins (p > 0.05). Patients who underwent open resection had more NCCN high-risk patients, but the difference was not statistically significant (p = 0.08). There was significantly less estimated blood loss (median 15 vs. 150 mL, p < 0.05) and significantly shorter hospital stay (median 4 vs. 7 days, p < 0.05) for the laparoscopy group. There were no recurrences in the laparoscopy group, but there was one in the open group with a median follow-up of 55 and 63 months, respectively (p > 0.05). Five-year disease-free survival was 100 % for the laparoscopic group and 83 % for the open resection group. CONCLUSIONS: Laparoscopic resection for appropriately selected GISTs is feasible and associated with significantly less blood loss and shorter hospitalizations compared to open resection. Further studies are needed to better define its role for GIST. PMID- 27491686 TI - Integrated plasmonic circuitry on a vertical-cavity surface-emitting semiconductor laser platform. AB - Integrated plasmonic sources and detectors are imperative in the practical development of plasmonic circuitry for bio- and chemical sensing, nanoscale optical information processing, as well as transducers for high-density optical data storage. Here we show that vertical-cavity surface-emitting lasers (VCSELs) can be employed as an on-chip, electrically pumped source or detector of plasmonic signals, when operated in forward or reverse bias, respectively. To this end, we experimentally demonstrate surface plasmon polariton excitation, waveguiding, frequency conversion and detection on a VCSEL-based plasmonic platform. The coupling efficiency of the VCSEL emission to waveguided surface plasmon polariton modes has been optimized using asymmetric plasmonic nanostructures. The plasmonic VCSEL platform validated here is a viable solution for practical realizations of plasmonic functionalities for various applications, such as those requiring sub-wavelength field confinement, refractive index sensitivity or optical near-field transduction with electrically driven sources, thus enabling the realization of on-chip optical communication and lab-on-a-chip devices. PMID- 27491688 TI - Different effects of BCG strains - A natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar formation in Guinea Bissau. AB - BACKGROUND: Different Bacillus Calmette-Guerin (BCG) vaccine strains may have different non-specific effects. We assessed the effect of two BCG strains (Danish and Russian) on childhood morbidity and BCG scarification in Guinea-Bissau. METHODS: During 2011-2013, infants in the Bandim Health Project's urban study area received the Danish or Russian BCG in a natural experiment. Health center consultations were registered at point of care and scar status and size at age 41/2 months. We assessed the effect of strain on consultation rates between vaccination and age 45days in Cox proportional hazards models. Scar prevalence and size were compared using binomial regression and ranksum tests. RESULTS: Among 1206 children, 18% received Danish BCG (n=215) and 82% Russian BCG (n=991). The adjusted hazard ratio (aHR) for consultations was 0.94 (95% CI 0.60-1.46) for Danish BCG compared with Russian BCG. Girls vaccinated with Danish BCG tended to have lower consultation rates compared with girls vaccinated with Russian BCG (aHR 0.56 (0.25-1.24)), whereas the effect was opposite for boys (aHR 1.24 (0.74 2.11)), p=0.09. Children vaccinated with Danish BCG were more likely to develop a scar (97%) than children vaccinated with Russian BCG (87%), the relative risk (RR) being 1.11 (1.06-1.16). The effect was stronger in girls, and BCG scar size was larger among infants vaccinated with the Danish strain. CONCLUSION: BCG strain influences scar prevalence and scar size, and may have sex differential effects on morbidity. BCG strains are currently used interchangeably, but BCG scarring has been linked to subsequent survival. Hence, more research into the health effects of different BCG strains is warranted. Small adjustments of BCG production could potentially lower childhood morbidity and mortality at low cost. PMID- 27491689 TI - Pathways to preterm birth: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data. PMID- 27491687 TI - Neonatal infections: Case definition and guidelines for data collection, analysis, and presentation of immunisation safety data. AB - Maternal vaccination is an important area of research and requires appropriate and internationally comparable definitions and safety standards. The GAIA group, part of the Brighton Collaboration was created with the mandate of proposing standardised definitions applicable to maternal vaccine research. This study proposes international definitions for neonatal infections. The neonatal infections GAIA working group performed a literature review using Medline, EMBASE and the Cochrane collaboration and collected definitions in use in neonatal and public health networks. The common criteria derived from the extensive search formed the basis for a consensus process that resulted in three separate definitions for neonatal blood stream infections (BSI), meningitis and lower respiratory tract infections (LRTI). For each definition three levels of evidence are proposed to ensure the applicability of the definitions to different settings. Recommendations about data collection, analysis and presentation are presented and harmonized with the Brighton Collaboration and GAIA format and other existing international standards for study reporting. PMID- 27491690 TI - Synergistic antioxidant action of vitamin E and rutin SNEDDS in ameliorating oxidative stress in a Parkinson's disease model. AB - PURPOSE: Oxidative stress is the leading cause in the pathogenesis of Parkinson's disease. Rutin is a naturally occurring strong antioxidant molecule with wide therapeutic applications. It suffers from the problem of low oral bioavailability which is due to its poor aqueous solubility. METHODS: In order to increase the solubility self-nanoemulsifying drug delivery systems (SNEDDS) of rutin were prepared. The oil, surfactant and co-surfactant were selected based on solubility/miscibility studies. Optimization was done by a three-factor, four level (34) Box-Behnken design. The independent factors were oil, surfactant and co-surfactant concentration and the dependent variables were globule size, self emulsification time, % transmittance and cumulative percentage of drug release. The optimized SNEDDS formulation (RSE6) was evaluated for various release studies. Antioxidant activity was assessed by various in vitro tests such as 2,2 diphenyl-1-picrylhydrazyl and reducing power assay. Oxidative stress models which had Parkinson's-type symptoms were used to determine the antioxidant potential of rutin SNEDDS in vivo. Permeation was assessed through confocal laser scanning microscopy. RESULTS: An optimized SNEDDS formulation consisting of Sefsol + vitamin E-Solutol HS 15-Transcutol P at proportions of 25:35:17.5 (w/w) was prepared and characterized. The globule size and polydispersity index of the optimized formulation was found to be 16.08 +/- 0.02 nm and 0.124 +/- 0.01, respectively. A significant (p < 0.05) increase in the percentage of drug release was achieved in the case of the optimized formulation as compared to rutin suspension. Pharmacokinetic study showed a 2.3-fold increase in relative oral bioavailability. The optimized formulation had significant in vitro and in vivo antioxidant activity. CONCLUSION: Rutin SNEDDS have been successfully prepared and they can serve as an effective tool in enhancing the oral bioavailability and efficacy of rutin, thus helping in ameliorating oxidative stress in neurodegenerative disorders like Parkinson's disease. PMID- 27491691 TI - Laminins and cancer stem cells: Partners in crime? AB - As one of the predominant protein families within the extracellular matrix both structurally and functionally, laminins have been shown to be heavily involved in tumor progression and drug resistance. Laminins participate in key cellular events for tumor angiogenesis, cell invasion and metastasis development, including the regulation of epithelial-mesenchymal transition and basement membrane remodeling, which are tightly associated with the phenotypic characteristics of stem-like cells, particularly in the context of cancer. In addition, a great deal of studies and reports has highlighted the critical roles of laminins in modulating stem cell phenotype and differentiation, as part of the stem cell niche. Stemming from these discoveries a growing body of literature suggests that laminins may act as regulators of cancer stem cells, a tumor cell subpopulation that plays an instrumental role in long-term cancer maintenance, metastasis development and therapeutic resistance. The accumulating evidence in this emerging research area suggests that laminins represent potential therapeutic targets for anti-cancer treatments against cancer stem cells, and that they may be used as predictive and prognostic markers to inform clinical management and improve patient survival. PMID- 27491692 TI - NF-kappaB activation in chronic lymphocytic leukemia: A point of convergence of external triggers and intrinsic lesions. AB - The nuclear factor-kappaB (NF-kappaB) pathway is constitutively activated in chronic lymphocytic leukemia (CLL) patients, and hence plays a major role in disease development and evolution. In contrast to many other mature B-cell lymphomas, only a few recurrently mutated genes involved in canonical or non canonical NF-kappaB activation have been identified in CLL (i.e. BIRC3, MYD88 and NFKBIE mutations) and often at a low frequency. On the other hand, CLL B cells seem 'addicted' to the tumor microenvironment for their survival and proliferation, which is primarily mediated by interaction through a number of cell surface receptors, e.g. the B-cell receptor (BcR), Toll-like receptors and CD40, that in turn activate downstream NF-kappaB. The importance of cell extrinsic triggering for CLL pathophysiology was recently also highlighted by the clinical efficacy of novel drugs targeting microenvironmental interactions through the inhibition of BcR signaling. In other words, CLL can be considered a prototype disease for studying the intricate interplay between external triggers and intrinsic aberrations and their combined impact on disease evolution. In this review, we will discuss the current understanding of mechanisms underlying NF kappaB deregulation in CLL, including micro-environmental, genetic and epigenetic events, and summarize data generated in murine models resembling human CLL. Finally, we will also discuss different strategies undertaken to intervene with the NF-kappaB pathway and its upstream mediators. PMID- 27491693 TI - A Comparison of Magnetization Transfer Methods to Assess Brain and Cervical Cord Microstructure in Multiple Sclerosis. AB - BACKGROUND: Demyelination is a core pathological feature of multiple sclerosis (MS) and spontaneous remyelination appears to be an important mechanism for repair in the disease. Magnetization transfer ratio imaging (MTR) has been used extensively to evaluate demyelination, although limitations to its specificity are recognized. MT saturation imaging (MTsat) removes some of the T1 dependence of MTR. We have performed a comparative evaluation of MTR and MTsat imaging in a mixed group of subjects with active MS, to explore their relative sensitivity to pathology relevant to explaining clinical outcomes. METHODS: A total of 134 subjects underwent MRI of their brain and cervical spinal cord. Isotropic 3 dimensional pre- and postcontrast T1-weighted and T2-weighted fluid-attenuated inversion recovery (FLAIR) volumes were segmented into brain normal appearing white matter (NAWM), brain WM lesions (WML), normal appearing spinal cord (NASC), and spinal cord lesions. Volumes and metrics for MTR and MTsat histograms were calculated for each region. RESULTS: Significant Spearman correlations were found with the Expanded Disability Status Scale and timed 25-foot walk for the whole brain and WML MTR, but not in that from the NAWM or any cervical spinal cord region. By contrast, the MTsat was correlated with both disability metrics in all these regions in both the brain and spine. CONCLUSIONS: This study extends prior work relating atrophy and lesion load with disability, by characterization of MTsat parameters. MTsat is practical in routine clinical applications and may be more sensitive to tissue damage than MTR for both brain and cervical spinal cord. PMID- 27491694 TI - Neuronal cholesterol metabolism increases dendritic outgrowth and synaptic markers via a concerted action of GGTase-I and Trk. AB - Cholesterol 24-hydroxylase (CYP46A1) is responsible for brain cholesterol elimination and therefore plays a crucial role in the control of brain cholesterol homeostasis. Altered CYP46A1 expression has been associated with several neurodegenerative diseases and changes in cognition. Since CYP46A1 activates small guanosine triphosphate-binding proteins (sGTPases), we hypothesized that CYP46A1 might be affecting neuronal development and function by activating tropomyosin-related kinase (Trk) receptors and promoting geranylgeranyl transferase-I (GGTase-I) prenylation activity. Our results show that CYP46A1 triggers an increase in neuronal dendritic outgrowth and dendritic protrusion density, and elicits an increase of synaptic proteins in the crude synaptosomal fraction. Strikingly, all of these effects are abolished by pharmacological inhibition of GGTase-I activity. Furthermore, CYP46A1 increases Trk phosphorylation, its interaction with GGTase-I, and the activity of GGTase-I, which is crucial for the enhanced dendritic outgrowth. Cholesterol supplementation studies indicate that cholesterol reduction by CYP46A1 is the necessary trigger for these effects. These results were confirmed in vivo, with a significant increase of p-Trk, pre- and postsynaptic proteins, Rac1, and decreased cholesterol levels, in crude synaptosomal fractions prepared from CYP46A1 transgenic mouse cortex. This work describes the molecular mechanisms by which neuronal cholesterol metabolism effectively modulates neuronal outgrowth and synaptic markers. PMID- 27491695 TI - Long-term Repeatability and Reproducibility of Phosphene Characteristics in Chronically Implanted Argus II Retinal Prosthesis Subjects. AB - PURPOSE: Previously published literatures of acute studies on few subjects have shown contradictory evidence on the reproducibility and characteristics of the elicited phosphenes, despite using the same stimulating parameters with epiretinal electrode arrays. In this study, we set out to investigate the long term repeatilibity and reproducibility of phosphenes in subjects chronically implanted with the Argus II retinal prosthesis (Second Sight Medical Products, Inc., Sylmar, CA, USA). DESIGN: Retrospective interventional case series and reliability study. METHODS: Six Argus II subjects of >5 years implantation from a single site participated. The 4-electrode cluster ("quad") closest to fovea was stimulated in each subject with a fixed biphasic current. Perceived phosphenes were depicted relative to subjective visual field center. The stimulus was applied at reducing time intervals from 20 minutes to 1 second. Two sets of stimulations were performed on the same day and 2 further sets repeated on a separate visit >1 week apart. RESULTS: Each subject depicted phosphenes of consistent shapes and sizes, and reported seeing the same colors with the fixed stimulating parameters, irrespective of the interstimuli intervals. However, there is a wide intersubject variation in the phosphene characteristics. Four subjects drew phosphenes in the same visual field quadrant, as predicted by the quad-fovea location. Two subjects depicted phosphenes in the same hemifield as the expected locations. CONCLUSION: Phosphenes for each subject were consistently reproducible in all our chronically implanted subjects. This has important implications in the development of long-term pixelated prosthetic vision for future devices. PMID- 27491696 TI - Same-site Trabeculectomy Revision for Failed Trabeculectomy: Outcomes and Risk Factors for Failure. AB - PURPOSE: To evaluate long-term tonometric outcomes of same-site trabeculectomy revision with mitomycin C (MMC) after failure of an initial trabeculectomy, and to identify risk factors for failure in patients with open-angle glaucoma. DESIGN: Retrospective cohort study. METHODS: One-hundred and seventeen patients (130 eyes) with primary open-angle, pseudoexfoliation, or pigmentary glaucoma, who failed a first trabeculectomy and who were >=40 years of age at the time of same-site trabeculectomy revision, were included. Three levels of success criteria were defined: (A) intraocular pressure (IOP) <=18 mm Hg and IOP reduction of 20%; (B) IOP <=15 mm Hg and IOP reduction of 25%; and (C) IOP <=12 mm Hg and IOP reduction of 30%. The primary outcome was the qualified Kaplan Meier success rate (with or without medications) for each criterion. Cox multivariate regression analysis was used to identify risk factors for failure. RESULTS: The success rates (+/- standard error) at the first, third, and fifth years of follow-up for criterion A were 69.7% (+/- 4.1%), 58.2% (+/- 4.6%), and 51.1% (+/- 5.0%); for criterion B these were 60.9% (+/- 4.4%), 47.8% (+/- 4.7%), and 44.0 (+/- 4.8%); and for criterion C, 44.6% (+/- 4.5%), 29.7% (+/- 4.4%), and 25.8% (+/- 4.3%). Mean follow-up was 5.2 (+/- 3.6) years. A time interval between the first and the same-site trabeculectomy revision of <3 years, worse baseline visual acuity, and dyslipidemia were significant risk factors for failure. CONCLUSIONS: Given the long-term tonometric success rates along with significant medication reduction, same-site trabeculectomy revision with MMC should be considered as a viable option to achieve reasonable IOP targets after a first failed trabeculectomy in open-angle glaucoma patients. PMID- 27491697 TI - Sequential Bilateral Corneal Transplantation and Graft Survival. AB - PURPOSE: To investigate graft survival and rejection following sequential bilateral corneal transplantation. DESIGN: Retrospective cohort study. METHODS: The study included patients with Fuchs endothelial dystrophy (FED), pseudophakic bullous keratopathy (PBK), or keratoconus who had undergone a penetrating keratoplasty (PK), endothelial keratoplasty (EK), or deep anterior lamellar keratoplasty (DALK) between 1999 and 2012. The main cohort included patients who had received a first transplant in both eyes for the same indication and a control cohort patients who had undergone a unilateral first corneal transplant. Main outcome measures were graft rejection or failure at 5 years. RESULTS: A total of 11 822 patients were included, of whom 9335 had a unilateral and 2487 bilateral corneal transplantation. For patients with FED (P < .005) and KC (P = .03) but not PBK (P = .19), a transplant in the second eye was associated with a 50% reduction in risk of graft failure within 5 years in the first eye (FED: hazard ratio [HR] 0.47, 95% confidence interval [CI]: 0.34-0.64; KC: HR 0.50, 95% CI: 0.24-1.02). For FED this was dependent on the type of transplant (EK: HR 0.30, 95% CI: 0.17-0.52; PK: HR 0.61, 95% CI: 0.42-0.88). We found no association between a transplant in the second eye and a rejection episode in the first eye (KC P = .19, FED P = .39, PBK P = .19). CONCLUSION: For FED and KC, a transplant in the second eye was associated with a reduced risk of graft failure in the first eye, independent of inter-transplant time. For FED this effect was pronounced following an EK in the first eye, where the risk of failure was reduced by 70%. PMID- 27491699 TI - HIV incidence among gay men and other men who have sex with men in 2020: where is the epidemic heading? AB - The goal to effectively prevent new HIV infections among gay, bisexual, and other men who have sex with men (MSM) is more challenging now than ever before. Despite declines in the late 1990s and early 2000s, HIV incidence among MSM is now increasing in many low- and high-income settings including the US, with young, adolescent, and racial/ethnic minority MSM being among those at highest risk. Potentiating HIV risks across all settings are individual-, network-, and structural-level factors such as stigma and lack of access to pre-exposure prophylaxis (PrEP) and antiretroviral treatment as prevention. To make a sustained impact on the epidemic, a concerted effort must integrate all evidence based interventions that will most proximally decrease HIV acquisition and transmission risks, together with structural interventions that will support improved coverage and retention in care. Universal HIV treatment, increased access to HIV testing, and daily oral PrEP have emerged as integral to the prevention of HIV transmission, and such efforts should be immediately expanded for MSM and other populations disproportionately affected by HIV. Respect for human rights and efforts to combat stigma and improve access to prevention services are needed to change the trajectory of the HIV pandemic among MSM. PMID- 27491698 TI - Localized Changes in Retinal Nerve Fiber Layer Thickness as a Predictor of Localized Functional Change in Glaucoma. AB - PURPOSE: To determine how well rates of localized retinal nerve fiber layer thickness (RNFLT) change correlate with rates of sensitivity change at corresponding locations in the visual field in glaucoma. DESIGN: Retrospective cohort study. METHODS: Three hundred and sixty-four eyes of 191 participants with suspected or confirmed glaucoma, as judged by experienced clinicians, were tested every 6 months with perimetry and optical coherence tomography (OCT). For each 24 2 visual field location, the corresponding sectoral peripapillary RNFLT was defined using a 30-degree sector, centered on the angle of nerve fiber entry into the optic nerve head. Rates of change of pointwise sensitivity and sectoral RNFLT were calculated over the last 8 visits at which reliable data were obtained. Passing-Bablok regression was used to predict the rate of pointwise sensitivity change from the rate of sectoral RNFLT change, for each location. RESULTS: Rates of sectoral RNFLT change were significantly predictive of rates of pointwise sensitivity change at all locations in the field. Correlations were modest, averaging 0.15, ranging from 0.03 to 0.25 depending on the location. A 1 MUm/y more rapid thinning in corresponding sectors was associated with 0.3 dB/y more rapid loss in the superior visual field but less than 0.1 dB/y more rapid loss at many locations in the inferior visual field. CONCLUSIONS: Localized RNFL thinning is associated with sensitivity loss at corresponding locations in the visual field, and their rates of change are significantly correlated. Peripapillary RNFLT may be used to monitor localized changes caused by glaucoma that have measurable consequences for a patient's vision. PMID- 27491700 TI - Adverse events related to the new psychoactive substance 3-fluorophenmetrazine - results from the Swedish STRIDA project. AB - BACKGROUND: New psychoactive substances (NPS) are often poorly pharmacologically documented and the production is unregulated, implying high risks for toxic side effects. This report from the STRIDA project describes analytically confirmed non fatal intoxications involving the phenmetrazine analogue 3-fluorophenmetrazine (3 FPM). STUDY DESIGN AND METHODS: Observational case series of patients with suspected acute NPS exposure requiring hospital care. Blood and urine samples were collected from patients presenting in emergency departments (ED) or intensive care units (ICU), after consultation with the Swedish Poisons Information Centre (PIC). Laboratory analysis was performed by multi-component liquid chromatography-mass spectrometry. Clinical data were collected during PIC consultations and retrieved from medical records. RESULTS: From November 2014 to October 2015, eight cases were registered as 3-FPM or "phenmetrazine" intoxications at the PIC after consultation. During the same period, analysis of STRIDA project samples confirmed 3-FPM use in a total of 19 patients (84% men) aged 22-54 (median 30) years. 3-FPM was detected in 15 out of 19 serum (2.7-1416 ng/mL) and in 14 out of 14 urine (1.0-6857 MUg/mmol creatinine) samples. All patients were also tested positive for other psychoactive substances, with benzodiazepines being most common (57% of the cases). Ten patients were monitored in the ED for <4 h, while six needed ICU monitoring of which five were graded as severe intoxications (Poisoning Severity Score 3). Prominent clinical signs were tachycardia (47%), depressed consciousness (42%), agitation/anxiety (37%), delirium (37%), dilated pupils (26%), and seizures (16%). All patients survived. CONCLUSION: In 19 patients testing positive for 3-FPM, a high incidence of severe clinical features was demonstrated. However, as all patients had also used other psychoactive substances, it was difficult to identify a unique toxidrome for 3 FPM. The results further showed that many 3-FPM intoxications would have been missed, if relying solely on information from PIC consultations. These results emphasize the importance of performing bioanalytical investigation in cases of suspected NPS intoxication. PMID- 27491701 TI - Arbuscular mycorrhizal fungi in the growth and extraction of trace elements by Chrysopogon zizanioides (vetiver) in a substrate containing coal mine wastes. AB - Vetiver (Chrysopogon zizanioides) is a fast-growing, high biomass producing plant employed for environmental rehabilitation. The study evaluated the effects of arbuscular mycorrhizal fungi (AMF) on the growth and trace element phytoextracting capabilities of vetiver in a substrate containing coalmine wastes in Southern Brazil. AMF included Acaulospora colombiana, Acaulospora morrowiae, Acaulospora scrobiculata, Dentiscutata heterogama, Gigaspora margarita, and Rhizophagus clarus. Among those, A. colombiana, G. margarita, and R. clarus promoted higher growth. AMF stimulated average increments in the accumulated P of 82% (roots), 194% (shoots first harvest-90 days) and 300% (shoots second harvest 165 days) and affected the phytoextraction of trace elements by vetiver, with larger concentrations in the roots. Plants inoculated with A. colombiana, A. morrowiae, and A. scrobiculata, in addition to the control, presented the highest levels of Cu and Zn in the roots. Overall, G. margarita stimulated the highest production of biomass, and, therefore, showed the most significant levels of trace elements in the plants. This work shows the benefits of certain AMF (especially A. morrowiae, G. margarita, and R. clarus) for the production of biomass and P uptake by vetiver, demonstrating the potential of those species for the rehabilitation of coal-mine-degraded soils. PMID- 27491702 TI - Secondary ion yields for vacuum-type electrospray droplet beams measured with a triple focus time-of-flight analyzer. AB - RATIONALE: We previously developed a massive cluster ion beam gun for secondary ion mass spectrometry (SIMS) in which the primary beam source is a vacuum electrospray. The secondary ion yields produced by this method had not yet been measured with a commercial time-of-flight (TOF) secondary ion mass spectrometer, and the ionization performance was unknown. METHODS: A vacuum-type electrospray droplet ion gun was connected to a triple-focus TOF analyzer. The flight time of the secondary ions was measured using a sample-bias pulsing method, because a short pulse of the electrospray droplet beam could not be obtained. The secondary ion yields of an amino acid sample produced by the electrospray droplet beams and atomic Ga ion beams were compared. RESULTS: TOF secondary ion spectra were measured for the amino acid and peptide samples with a mass resolution of ~500 using the sample-bias pulsing method. The secondary ion yield of the amino acid sample produced with the 10 kV vacuum-type electrospray droplet beams was much higher than that produced by 10 kV Ga ion beams. In addition, the secondary ion yields for the peptide sample and amino acid samples were almost similar. CONCLUSIONS: This is the first report on secondary ion yields produced with vacuum-type electrospray droplet ion beams and measured with a semi-commercial TOF analyzer. The enhancement of secondary ion yields, in particular for relatively high-mass molecules, would be very useful in the SIMS analysis of a wide variety of biological samples. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27491703 TI - Use of clinical practice guidelines by dentists: findings from the Japanese dental practice-based research network. AB - RATIONALE, AIMS AND OBJECTIVES: The objectives of this study were to: (1) examine differences in the use of dental clinical practice guidelines among Japanese dentists, and (2) identify characteristics associated with the number of guidelines used by participating dentists. METHODS: We conducted a cross sectional study consisting of a questionnaire survey in Japan between July 2014 and May 2015. The study queried dentists working in outpatient dental practices who are affiliated with the Dental Practice-Based Research Network Japan (n = 148). They were asked whether they have used each of 15 Japanese dental clinical guidelines. Associations between the number of guidelines used by participants and specific characteristics were analysed via negative binomial regression analysis. RESULTS: The mean number of guidelines used by participating dentists was 2.5 +/- 2.9 [standard deviation (SD)]. Rate of use of guidelines showed substantial variation, from 5% to 34% among dentists. The proportion of dentists that used guidelines was the highest among oral medicine specialists, who had the highest proportion for 10 of 15 guidelines. Negative binomial regression analysis identified three factors significantly associated with the number of guidelines used: 'years since graduation from dental school', 'specialty practice' and 'practice busyness'. CONCLUSIONS: These results suggest that the use of clinical practice guidelines by Japanese dentists may still be inadequate. Training in the use of the guidelines could be given to dental students as undergraduate education and to young clinicians as continuing education. PMID- 27491704 TI - Quantitative assessment of intrinsic noise for visually guided behaviour in zebrafish. AB - All sensory devices, whether biological or artificial, carry appreciable amounts of intrinsic noise. When these internally generated perturbations are sufficiently large, the behaviour of the system is not solely driven by the external stimulus but also by its own spontaneous variability. Behavioural internal noise can be quantified, provided it is expressed in relative units of the noise source externally applied by the stimulus. In humans performing sensory tasks at near threshold performance, the size of internal noise is roughly equivalent to the size of the response fluctuations induced by the external noise source. It is not known how the human estimate compares with other animals, because behavioural internal noise has never been measured in other species. We have adapted the methodology used with humans to the zebrafish, a small teleost that displays robust visually-guided behaviour. Our measurements demonstrate that, under some conditions, it is possible to obtain viable estimates of internal noise in this vertebrate species; the estimates generally fall within the human range, suggesting that the properties of internal noise may reflect general constraints on stimulus-response coupling that apply across animal systems with substantially different characteristics. PMID- 27491705 TI - Spatial frequency processing in the central and peripheral visual field during scene viewing. AB - Visuospatial attention and gaze control depend on the interaction of foveal and peripheral processing. The foveal and peripheral regions of the visual field are differentially sensitive to parts of the spatial-frequency spectrum. In two experiments, we investigated how the selective attenuation of spatial frequencies in the central or the peripheral visual field affects eye-movement behavior during real-world scene viewing. Gaze-contingent low-pass or high-pass filters with varying filter levels (i.e., cutoff frequencies; Experiment 1) or filter sizes (Experiment 2) were applied. Compared to unfiltered control conditions, mean fixation durations increased most with central high-pass and peripheral low pass filtering. Increasing filter size prolonged fixation durations with peripheral filtering, but not with central filtering. Increasing filter level prolonged fixation durations with low-pass filtering, but not with high-pass filtering. These effects indicate that fixation durations are not always longer under conditions of increased processing difficulty. Saccade amplitudes largely adapted to processing difficulty: amplitudes increased with central filtering and decreased with peripheral filtering; the effects strengthened with increasing filter size and filter level. In addition, we observed a trade-off between saccade timing and saccadic selection, since saccade amplitudes were modulated when fixation durations were unaffected by the experimental manipulations. We conclude that interactions of perception and gaze control are highly sensitive to experimental manipulations of input images as long as the residual information can still be accessed for gaze control. PMID- 27491706 TI - In vitro evaluation of the schistosomicidal effect of the extracts, fractions and major 3-hydroxy-2,6-dialkyl-substituted piperidine alkaloids from the flowers of Senna spectabilis (Fabaceae). AB - In this work, we present the in vitro schistosomicidal activity evaluation of the most active dichloromethane fraction (FDm) (ED50=83.5MUg/mL) and of a mixture of the major alkaloids ((-)-cassine/(-)-spectaline, C/E) (ED50=37.4MUg/mL) from the flowers of Senna spectabilis against adult worms and cercariae. We also demonstrate other toxic effects including paralysis of the adult worms, inhibition of the secretory activity, tegument lesions and cercaricidal activity. In the association test of Praziquantel (PZQ)-C/E, we observed up to 80% mortality of Schistosoma mansoni in comparison to PZQ monotherapy. Due to the diversity of the toxic effects, the schistosomicidal activity of C/E is likely a result of a multitarget mechanism involving the tegument, secretory system and neuromotor action. PMID- 27491707 TI - Novel nitric oxide-releasing spirolactone-type diterpenoid derivatives with in vitro synergistic anticancer activity as apoptosis inducer. AB - Herein, we reported the cytotoxicity, NO-releasing property, and apoptosis induced ability of two series of novel nitric oxide-releasing spirolactone-type diterpenoid derivatives (10a-f and 15a-f). All the title compounds were more potent than oridonin (7) and parent compound (9 or 14) against human tumor Bel 7402, K562, MGC-803 and CaEs-17 cells. SARs were concluded based on above data. Compound 15d exhibited the strongest antiproliferative activity with the IC50 of 0.86, 1.74, 1.16 and 3.75MUM, respectively, and could produce high level (above 25MUM) of NO at the time point of 60min. Further mechanism evaluation showed that 15d could induce S phase cell cycle arrest and apoptosis at low micromolar concentrations in Bel-7402 cells via mitochondria-related pathways. It was expected that the remarkable biological profile of the synthetic NO-releasing spirolactone-type diterpenoid analogs make them possible as promising candidates for the development of anticancer agents. PMID- 27491708 TI - Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors. AB - Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo. PMID- 27491709 TI - Synthesis and biological evaluation of novel imidazol-1-ylacetic acid derivatives as non-brain penetrant bombesin receptor subtype-3 (BRS-3) agonists. AB - Novel compounds based on 1a were synthesized with the focus of obtaining agonists acting upon peripheral BRS-3. To identify potent anti-obesity compounds without adverse effects on the central nervous system (CNS), a carboxylic acid moiety and a labile carboxylic ester with an antedrug functionality were introduced. Through the extensive synthetic exploration and the pharmacokinetic studies of intravenous administration in mice, the ester 2b was selected owing to its most suitable pharmacological profile. In the evaluation of food intake suppression in C57BL/6N mice, 2b showed significant in vivo efficacy and no clear adverse effects on blood pressure change in dogs administered the compound by intravenous infusion. PMID- 27491710 TI - Vialinin A and thelephantin G, potent inhibitors of tumor necrosis factor-alpha production, inhibit sentrin/SUMO-specific protease 1 enzymatic activity. AB - Several p-terphenyl compounds have been isolated from the edible Chinese mushroom Thelephora vialis. Vialinin A, a p-terphenyl compound, strongly inhibits tumor necrosis factor-alpha production and release. Vialinin A inhibits the enzymatic activity of ubiquitin-specific peptidase 5, one of the target molecules in RBL 2H3 cells. Here we examined the inhibitory effect of p-terphenyl compounds, including vialinin A, against sentrin/SUMO-specific protease 1 (SENP1) enzymatic activity. The half maximal inhibitory concentration values of vialinin A and thelephantin G against full-length SENP1 were 1.64+/-0.23MUM and 2.48+/-0.02MUM, respectively. These findings suggest that p-terphenyl compounds are potent SENP1 inhibitors. PMID- 27491711 TI - Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties. AB - Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer's disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility. PMID- 27491712 TI - The flexible feedstock concept in Industrial Biotechnology: Metabolic engineering of Escherichia coli, Corynebacterium glutamicum, Pseudomonas, Bacillus and yeast strains for access to alternative carbon sources. AB - Most biotechnological processes are based on glucose that is either present in molasses or generated from starch by enzymatic hydrolysis. At the very high, million-ton scale production volumes, for instance for fermentative production of the biofuel ethanol or of commodity chemicals such as organic acids and amino acids, competing uses of carbon sources e.g. in human and animal nutrition have to be taken into account. Thus, the biotechnological production hosts E. coli, C. glutamicum, pseudomonads, bacilli and Baker's yeast used in these large scale processes have been engineered for efficient utilization of alternative carbon sources. This flexible feedstock concept is central to the use of non-glucose second and third generation feedstocks in the emerging bioeconomy. The metabolic engineering efforts to broaden the substrate scope of E. coli, C. glutamicum, pseudomonads, B. subtilis and yeasts to include non-native carbon sources will be reviewed. Strategies to enable simultaneous consumption of mixtures of native and non-native carbon sources present in biomass hydrolysates will be summarized and a perspective on how to further increase feedstock flexibility for the realization of biorefinery processes will be given. PMID- 27491713 TI - Pellagra Secondary to Medication and Alcoholism: A Case Report and Review of the Literature. AB - Pellagra usually results from niacin deficiency and presents with the classic triad of dermatitis, diarrhea, and dementia. It is most commonly associated with malnutrition and poverty and is extremely rare in industrialized societies. Furthermore, pellagra can be induced by special clinical conditions that interfere with the intake, absorption, and metabolism of niacin. Because of its detrimental effects on health and its favorable prognosis after supplementation of nicotinamide, the importance of early diagnosis and treatment should be emphasized. Herein, we report a case of pellagra in a young alcoholic who underwent combined chemotherapy for tuberculosis. For the first time, a descriptive review of literature from 1957 to 2014 has been conducted to clarify potential etiologies of pellagra: alcoholism (35.24%, 37 articles), various medications (25.71%, 27 articles), inadequate oral intake (16.19%, 17 articles), malabsorption (13.33%, 14 articles), metabolic derangement (7.62%, 8 articles), excessive loss (0.95%, 1 article), and etiology unknown (0.95%, 1 article). PMID- 27491716 TI - Scenario analysis and disaster preparedness for port and maritime logistics risk management. AB - System Dynamics (SD) modelling is used to investigate the impacts of policy interventions on industry actors' preparedness to mitigate risks and to recover from disruptions along the maritime logistics and supply chain network. The model suggests a bi-directional relation between regulation and industry actors' behaviour towards Disaster Preparedness (DP) in maritime logistics networks. The model also showed that the level of DP is highly contingent on forecast accuracy, technology change, attitude to risk prevention, port activities, and port environment. PMID- 27491714 TI - Transition to a Tube Feeding Formula With Real Food Ingredients in Pediatric Patients With Intestinal Failure. AB - Due to concerns related primarily to allergic response and malabsorption, enteral nutrition therapy has traditionally relied on the use of elemental formulas in children with intestinal failure (IF). Blended food diets via a gastrostomy tube have been reported to improve feeding tolerance in pediatric populations receiving long-term enteral nutrition therapy. Complex macronutrients have been shown to stimulate intestinal adaptation in animal models. We report on our experience in children with IF who had an overall improvement in stool output when transitioned from an elemental formula to a tube feeding formula with real food ingredients (TFRF). Data were collected in a retrospective chart review of children with IF, >1 year of age, who were receiving enteral nutrition via continuous infusion, bolus feeding, or both. Indications for the TFRF trial were diarrhea or inconsistent stooling patterns. Ten children with a mean small bowel length of 48.3 cm were trialed on TFRF. Nine of 10 (90%) children tolerated the transition to 100% TFRF, of which 7 of 9 (78%) had their entire colon in continuity. The average age at successful transition was 29.2 months, and the average length of time to transition to 100% TFRF was 67.3 days. TFRF is well tolerated in children >1 year of age with IF; it also improves their stooling patterns. A commercially available TFRF is a cost-effective and nutritionally adequate means of providing nutrition to this patient population. PMID- 27491717 TI - Incidents between Straight-ahead Cyclists and Right-turning Motor Vehicles at Signalised Junctions. AB - Accidents between right-turning motor vehicles and straight-ahead cyclists are one of the most common accident types leading to cyclist injuries at signalised junctions in Denmark. A before-after safety evaluation of applying staggered stop lines in 189 arms at 123 signalised junctions is presented. The evaluation accounts for long-term accident trends and changes in motor vehicle traffic volumes. Applying staggered stop lines gives no decline in accidents between right-turning motor vehicles and straight-ahead cyclists. However, there is a statistical tendency to a decline of these right-turn accidents involving heavy vehicles. There are several questions about factors leading to right-turn accidents that cannot be answered by recorded accident data. A study of conflicting behaviour focuses on factors leading to conflicts. Video observations have been carried out in 10 arms at signalised junctions. A total of 45 situations with conflicting behaviour between right-turning motor vehicles and straight-ahead cyclists have been investigated and compared to a reference group of simultaneous arrivals. The relative risk is lowest when both parties stop on red before entering the junction. Upon simultaneous arrival of both parties at a green light, the relative risk is highest. Cyclists tend to have a higher relative risk of being involved in conflicts if they; a) ride through on yellow, b) have a time distance of at least 2seconds to other cyclists, c) wear a black jacket, and/or d) arrive at the junction at a speed of at least 25km/h. Much less can be said about the motor vehicles or their drivers on the basis of these video observations, but motor vehicles stopping in the cycle crossing in order to yield to pedestrians or cyclists have a higher relative risk of being involved in conflicts. PMID- 27491718 TI - Comparison of Thyroglobulin Measurements Using Three Different Immunoassay Kits: A BRAMHS Tg-Plus RIA Kit, a BRAMHS hTg Sensitive Kryptor Kit, and a Beckman Coulter ACCESS Immunoassay Kit. AB - BACKGROUND: Second-generation thyroglobulin immunometric assays (Tg-IMAs) have been developed with improved sensitivity. Our aim was to compare the diagnostic value of Tg-IMA measurements using a Kryptor (BRAHMS AG) kit (Tg-K) and an ACCESS (Beckman Coulter) kit (Tg-A) with that of the first-generation Tg measurement using a Tg-plus (BRAHMS AG) kit (Tg+). METHODS: We enrolled 82 differentiated thyroid cancer patients who underwent total thyroidectomy with radioactive iodine remnant ablation and who underwent diagnostic whole body scan using recombinant human thyroid stimulating hormone (rhTSH). The Tg+, Tg-K, and Tg-A were measured before rhTSH administration during levothyroxine treatment (suppressed Tg) from the same sample. Serum Tg+ was measured after rhTSH stimulation (stimulated Tg). RESULTS: Suppressed Tg+ was more significantly correlated with suppressed Tg-K (R2=0.919, P<0.001) than with suppressed Tg-A (R2=0.536, P<0.001). The optimal cut-off values of suppressed Tg+, Tg-K, and Tg-A for predicting stimulated Tg+ of 1 ng/mL were 0.3, 0.2, and 0.2 ng/mL, respectively. The sensitivity, specificity, and accuracy of suppressed Tg+ were 67%, 100%, and 90%, respectively; those of suppressed Tg-K were 83%, 90%, and 88%; those of suppressed Tg-A were 96%, 82%, and 87%, respectively. The positive predictive and negative predictive values of Tg+ were 100% and 87%, respectively; those of Tg-K were 79% and 92%; and those of Tg-A were 73% and 98%. CONCLUSION: We could not clearly demonstrate which kit had better diagnostic performance after comparison of first-generation Tg measurements with Tg-IMA measurements. Also, there were kit-to-kit variations between Tg-IMA kits. Suppressed Tg measured by Tg-IMA was insufficient to completely substitute for a stimulated Tg measurement. PMID- 27491719 TI - Prevalence of Reduced Kidney Function by Estimated Glomerular Filtration Rate Using an Equation Based on Creatinine and Cystatin C in Metabolic Syndrome and Its Components in Korean Adults. AB - BACKGROUND: It is known that metabolic syndrome (MetS) is associated with chronic kidney disease. We evaluated and compared the prevalence of reduced kidney function in MetS and its components by estimated glomerular filtration rate (eGFR) using an equation based on creatinine (eGFRcr), cystatin C (eGFRcys), and combined creatinine-cystatin C (eGFRcr-cys) in Korean adults. METHODS: We analyzed data from 3,649 adults who participated in a comprehensive health examination. RESULTS: Mean values of eGFRcys were higher compared with mean values of eGFRcr (96.1+/-18.2 mL/min/1.73 m2 vs. 91.2+/-13.6 mL/min/1.73 m2) in total subjects. The prevalence of reduced kidney function increased with age (9.6% for eGFRcys vs. 5.8% for eGFRcr-cys vs. 4.9% for eGFRcr, in subjects aged >=60 years), and significantly increased with MetS, abdominal obesity, hypertension, high triglyceride, low high density lipoprotein (HDL), and high insulin resistance. The prevalence of MetS, abdominal obesity, hypertension, high insulin resistance, low HDL, and hepatic steatosis was significantly increased in subjects with reduced kidney function. This increased prevalence and the odds ratio of reduced kidney function for prevalence of MetS was highest for eGFRcys, followed by those of eGFRcr-cys, and eGFRcr. CONCLUSION: The prevalence of reduced kidney function by eGFR was significantly increased in subjects with MetS and its related components. eGFRcys and eGFRcr-cys were superior to eGFRcr in detecting reduced kidney function. PMID- 27491720 TI - Macrophage Densities Correlated with CXC Chemokine Receptor 4 Expression and Related with Poor Survival in Anaplastic Thyroid Cancer. AB - BACKGROUND: Tumor associated macrophages (TAMs) and CXC chemokine receptor 4 (CXCR4) have emerged as potential biomarkers in various human cancers. The aims of this study were to investigate the clinical characteristics of anaplastic thyroid cancer (ATC) patients according to the TAM numbers in the tumor tissue, and to evaluate the associations between CXCR4 expressions and macrophage densities in ATC tumor microenvironment. METHODS: Total 14 ATC samples from thyroid tissue microarray were used. Immunohistochemical staining was performed using anti-CD163 and anti-CXCR4 antibodies. According to the immunoreactivity of CD163, all subjects were divided into two groups: low-CD163 (n=8) and high-CD163 (n=6) groups. RESULTS: The mean diagnostic age was 65+/-7 years and the median tumor size was 4.3 cm, ranging 2.5 to 15 cm. Clinicopathological characteristics were not significantly different between low-CD163 and high-CD163 groups, while age of diagnosis was younger in high-CD163 group than that of low-CD163 group with marginal significance (56.9+/-5.5 years vs. 67.5+/-6.8 years, P=0.09). However, overall survival was significantly reduced in high-CD163 group (5.5 months [range, 1 to 10]) compared with low-CD163 groups (8.8 months [range, 6 to 121); log-rank test, P=0.0443). Moreover, high-CD163 group showed strong CXCR4 expressions in both cancer and stromal compartments, while low-CD163 group showed relatively weak, stromal-dominant CXCR4 expressions. Additionally, CD163 and CXCR4 expressions showed a strong positive correlation (gamma2=0.432, P=0.013). CONCLUSION: Increased number of TAMs showed poor overall survival in ATC, suggesting TAMs are potentially a prognostic biomarker for ATC. CXCR4 expression was significantly correlated with CD163-positive TAM densities, which suggest the possible role of CXCR4 in TAM recruitments. PMID- 27491721 TI - Time to tackle the incumbency advantage in science: A survey of scientists shows strong support for funding policies that would distribute funds more evenly among laboratories and thereby benefit new and smaller research groups. PMID- 27491722 TI - What is the meaning of Brexit? PMID- 27491723 TI - The economic costs of mental disorders: Do our societies react appropriately to the burden of mental disorders? PMID- 27491724 TI - Management of type 2 diabetes: the current situation and key opportunities to improve care in the UK. AB - In common with global trends, the number of individuals with type 2 diabetes in the UK is rising, driven largely by obesity. The increasing prevalence of younger individuals with type 2 diabetes is of particular concern because of the accelerated course of diabetes-related complications that is observed in this population. The importance of good glycaemic control in the prevention of microvascular complications of diabetes is widely accepted, and there is a growing body of evidence to support a benefit in the reduction of cardiovascular events in the long term. Despite the importance of maintaining a healthy weight for the prevention of type 2 diabetes, the results from trials of lifestyle intervention strategies to reduce body weight have been disappointing. New glucose-lowering agents offer some promise in this regard, offering an opportunity to combat the dual burden of hyperglycaemia and obesity simultaneously. The timing and appropriate choice of glucose-lowering therapy has never been more complex as a result of rising prevalence of obesity in the young, concomitant obesity in some 90% of adults with type 2 diabetes and an ever increasing range of therapeutic options. The present review evaluates performance measures specific to weight and glycaemic control in type 2 diabetes in the UK using data from the Quality and Outcomes Framework in England and Wales, and the Scottish Diabetes Survey. Potential barriers to improvement in standards of care for people with type 2 diabetes are considered, including patient factors, clinical inertia and the difficulties in translating therapeutic guidelines into everyday clinical practice. PMID- 27491725 TI - Synthesis of 2,2'-biphenols through direct C(sp(2))-H hydroxylation of [1,1' biphenyl]-2-ols. AB - A novel synthesis of diversely substituted 2,2'-biphenols through Pd(ii) catalyzed, (t)BuOOH-oxidized, and hydroxyl-directed C(sp(2))-H hydroxylation of [1,1'-biphenyl]-2-ols has been developed. Notably, this finding is distinct from previous reports in which [1,1'-biphenyl]-2-ols underwent an intramolecular C-H activation and C-O bond formation to afford dibenzofurans under the promotion of Pd(ii) but in the absence of (t)BuOOH. PMID- 27491727 TI - Charging System Optimization of Triboelectric Nanogenerator for Water Wave Energy Harvesting and Storage. AB - Ocean waves are one of the most promising renewable energy sources for large scope applications due to the abundant water resources on the earth. Triboelectric nanogenerator (TENG) technology could provide a new strategy for water wave energy harvesting. In this work, we investigated the charging characteristics of utilizing a wavy-structured TENG to charge a capacitor under direct water wave impact and under enclosed ball collision, by combination of theoretical calculations and experimental studies. The analytical equations of the charging characteristics were theoretically derived for the two cases, and they were calculated for various load capacitances, cycle numbers, and structural parameters such as compression deformation depth and ball size or mass. Under the direct water wave impact, the stored energy and maximum energy storage efficiency were found to be controlled by deformation depth, while the stored energy and maximum efficiency can be optimized by the ball size under the enclosed ball collision. Finally, the theoretical results were well verified by the experimental tests. The present work could provide strategies for improving the charging performance of TENGs toward effective water wave energy harvesting and storage. PMID- 27491726 TI - Association of Gestational Hypertensive Disorders with Retinopathy of prematurity: A Systematic Review and Meta-analysis. AB - The role of gestational hypertensive disorders, which includes both pre-eclampsia and gestational hypertension, in the development of retinopathy of prematurity (ROP) has been controversial. Therefore, this systematic review and meta-analysis is to evaluate the association between gestational hypertensive disoders and ROP. Eligible studies published up to June 5, 2016 were identified from MEDLINE and EMBASE that evaluated the association between the two conditions. Totally 1142 published records were retrieved for screening, 925 of them eligible for detailed evaluation. Finally 19 studies involving 45281 infants with 5388 cases of ROP met our criteria for meta-analysis. Gestational hypertensive disorders were not associated with ROP (unadjusted OR: 0.89; P = 0.38; adjusted OR: 1.35; P = 0.18). Subgroup analyses also revealed no significant association between ROP with pre eclampsia (unadjusted OR: 0.85; P = 0.29; adjusted OR:1.29; P = 0.28) or with gestational hypertension (unadjusted OR: 1.10; P = 0.39; adjusted OR: 1.25; P = 0.60) separately. Sensitivity analysis indicated our results were robust. We concluded no significant association between gestational hypertensive disorders and ROP. More large scale well-conducted prospective cohorts on the topic are needed. PMID- 27491728 TI - Hydrogen bonding asymmetric star-shape derivative of bile acid leads to supramolecular fibrillar aggregates that wrap into micrometer spheres. AB - We report that star-shaped molecules with cholic acid cores asymmetrically grafted by low molecular weight polymers with hydrogen bonding end-groups undergo aggregation to nanofibers, which subsequently wrap into micrometer spherical aggregates with low density cores. Therein the facially amphiphilic cholic acid (CA) is functionalized by four flexible allyl glycidyl ether (AGE) side chains, which are terminated with hydrogen bonding 2-ureido-4[1H]pyrimidinone (UPy) end groups as connected by hexyl spacers, denoted as CA(AGE6-C6H12-UPy)4. This wedge shaped molecule is expected to allow the formation of a rich variety of solvent dependent structures due to the complex interplay of interactions, enabled by its polar/nonpolar surface-active structure, the hydrophobicity of the CA in aqueous medium, and the possibility to control hydrogen bonding between UPy molecules by solvent selection. In DMSO, the surfactant-like CA(AGE6-C6H12-UPy)4 self assembles into nanometer scale micelles, as expected due to its nonpolar CA apexes, solubilized AGE6-C6H12-UPy chains, and suppressed mutual hydrogen bonds between the UPys. Dialysis in water leads to nanofibers with lateral dimensions of 20-50 nm. This is explained by promoted aggregation as the hydrogen bonds between UPy molecules start to become activated, the reduced solvent dispersibility of the AGE-chains, and the hydrophobicity of CA. Finally, in pure water the nanofibers wrap into micrometer spheres having low density cores. In this case, strong complementary hydrogen bonds between UPy molecules of different molecules can form, thus promoting lateral interactions between the nanofibers, as allowed by the hydrophobic hexyl spacers. The wrapping is illustrated by transmission electron microscopy tomographic 3D reconstructions. More generally, we foresee hierarchically structured matter bridging the length scales from molecular to micrometer scale by sequentially triggering supramolecular interactions. PMID- 27491729 TI - Relationship between the surgical margin status, prognosis, and recurrence in extrahepatic bile duct cancer patients. AB - PURPOSE: The purpose of this retrospective study was to evaluate the relationship between the surgical margin status of the bile duct and the prognosis and recurrence of extrahepatic bile duct (EHBD) cancer. METHODS: The clinical data of 100 patients who underwent surgery for EHBD cancer between February 2002 and September 2014 were analyzed. The ductal margin status was classified into the following three categories: negative (D-N), positive with carcinoma in situ (D CIS), and positive with invasive carcinoma (D-INV). RESULTS: The number of patients with D-N, D-CIS, and D-INV was 69, 16, and 15, respectively. Local recurrence rates of patients with D-CIS (56.3 %) and D-INV (66.7 %) were significantly higher compared to those of patients with D-N (10.1 %; P < 0.001). D-CIS was a significant predictor of shorter recurrence-free survival (RFS). Lymph node metastasis (P = 0.037) and D-INV (P = 0.008) were independent predictors of shorter disease-specific survival (DSS). The prognostic relevance of the ductal margin status was high, particularly in patients without lymph node metastasis. CONCLUSION: The surgical margin status of the bile duct was significantly associated with RFS, DSS, and the recurrence site. PMID- 27491730 TI - Organizational Update: European Stroke Organisation. PMID- 27491731 TI - Good Intracranial Collaterals Trump Poor ASPECTS (Alberta Stroke Program Early CT Score) for Intravenous Thrombolysis in Anterior Circulation Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: In acute ischemic stroke, large early infarct size estimated by the Alberta Stroke Program Early CT Score (ASPECTS) is associated with poorer outcomes and is a relative contraindication for recanalization therapies. The state of the intracranial collateral circulation influences the functional outcome and may be a variable to consider before thrombolysis. We evaluated the prognostic effect of the collateral circulation in patients with thrombolyzed acute ischemic stroke who have large early infarct sizes as indicated by low ASPECTS. MATERIALS AND METHODS: Patients with anterior circulation acute ischemic stroke who received a computed tomographic angiogram and subsequent treatment with intravenous tissue-type plasminogen activator from 2010 to 2013 were studied. Two independent neuroradiologists determined their ASPECTS. We stratified patients using ASPECTS into 2 groups: large volume infarcts (ASPECTS<=7 points) and small volume infarcts (ASPECTS 8-10). In addition, we evaluated a third group with very large volume infarcts (ASPECTS<=5 points). We then analyzed the 3 subgroups using the Maas, Tan, and ASPECTS collaterals grading systems of the computed tomographic angiogram intracranial collaterals. Good outcomes were defined by modified Rankin Scale score of 0 to 2 at 3 months. RESULTS: A total of 300 patients were included in the final analysis. For patients with very large volume infarcts (ASPECTS<=5 points), univariable analysis showed that younger age, male sex, lower National Institute of Health Stroke Scale (NIHSS), lower systolic blood pressure, and good collaterals by Maas, Tan, or ASPECTS-collaterals grading were predictors of good outcomes. On multivariate analysis, younger age (odds ratio, 0.93; 95% confidence interval, 0.89-0.97; P=0.002) and good collaterals by ASPECTS-collaterals system (odds ratio, 1.34; 95% confidence interval, 1.15-1.57; P<0.001) were associated with good outcomes. CONCLUSIONS: In patients with large and very large volume infarcts, good collaterals as measured by the ASPECTS-collaterals system is associated with improved outcomes and can help select patients for intravenous thrombolysis. PMID- 27491732 TI - Does Increased Arterial Stiffness Herald Cognitive Impairment? PMID- 27491733 TI - FABS: An Intuitive Tool for Screening of Stroke Mimics in the Emergency Department. AB - BACKGROUND AND PURPOSE: A large number of patients with symptoms of acute cerebral ischemia are stroke mimics (SMs). In this study, we sought to develop a scoring system (FABS) for screening and stratifying SM from acute cerebral ischemia and to identify patients who may require magnetic resonance imaging to confirm or refute a diagnosis of stroke in the emergency setting. METHODS: We designed a scoring system: FABS (6 variables with 1 point for each variable present): absence of Facial droop, negative history of Atrial fibrillation, Age <50 years, systolic Blood pressure <150 mm Hg at presentation, history of Seizures, and isolated Sensory symptoms without weakness at presentation. We evaluated consecutive patients with symptoms of acute cerebral ischemia and a negative head computed tomography for any acute finding within 4.5 hours after symptom onset in 2 tertiary care stroke centers for validation of FABS. RESULTS: A total of 784 patients (41% SMs) were evaluated. Receiver operating characteristic curve (C statistic, 0.95; 95% confidence interval [CI], 0.93-0.98) indicated that FABS>=3 could identify patients with SM with 90% sensitivity (95% CI, 86%-93%) and 91% specificity (95% CI, 88%-93%). The negative predictive value and positive predictive value were 93% (95% CI, 90%-95%) and 87% (95% CI, 83% 91%), respectively. CONCLUSIONS: FABS seems to be reliable in stratifying SM from acute cerebral ischemia cases among patients in whom the head computed tomography was negative for any acute findings. It can help clinicians consider advanced imaging for further diagnosis. PMID- 27491734 TI - Use and Outcomes of Intravenous Thrombolysis for Acute Ischemic Stroke in Patients >=90 Years of Age. AB - BACKGROUND AND PURPOSE: Intravenous tissue-type plasminogen activator (tPA) is a proven treatment for acute ischemic stroke, but there has been limited evaluation among patients aged >=90 years. METHODS: We analyzed data from the Get With The Guidelines-Stroke national quality improvement registry from January 2009 to April 2013. Frequency, determinants, and outcomes of tPA use were compared among patients aged >=90 and 3 younger age groups (18-64, 65-79, and 80-89 years). RESULTS: Among 35 708 patients from 1178 sites who arrived within 2 hours of time last known well and received tPA, 2585 (7.2%) were >=90 years. Compared with younger patients, the rate of tPA use among patients without a documented contraindication was lower among patients aged >=90 years (67.4% versus 84.1% in 18-89-year olds; P<0.0001). Discharge outcomes among individuals aged >=90 years included discharge to home or acute rehabilitation in 31.4%, independent ambulation at discharge in 13.4%, symptomatic hemorrhage in 6.1%, and in-hospital mortality or hospice discharge in 36.4%. On multivariable analysis, good functional outcomes generally occurred less often and mortality more often among patients aged >=90 years. The risk of symptomatic hemorrhage was increased compared with patients <65 years but was not significantly different than the risk in 66- to 89-year olds. CONCLUSIONS: The use of intravenous tPA among those aged >=90 years is lower than in younger patients. When fibrinolytic therapy is used, the risk of symptomatic hemorrhage is not higher than in 66- to 89-year olds; however, mortality is higher and functional outcomes are lower. PMID- 27491735 TI - Aortic Stiffness and the Risk of Incident Mild Cognitive Impairment and Dementia. AB - BACKGROUND AND PURPOSE: Aortic stiffening increases the transfers of high pressure and flow pulsatility to small cerebral vessels potentially causing the accumulation of vascular brain injury. Our aim was to investigate the prospective association of aortic stiffness with the risks of incident mild cognitive impairment and dementia. METHODS: We studied 1101 dementia-free Framingham Offspring study participants (mean age, 69+/-6 years; 54% women). Aortic stiffness was measured as carotid-femoral pulse wave velocity using applanation tonometry and modeled as a linear variable and the top 2 quintiles (>11.4 m/s). Outcomes were the 10-year risk of incident mild cognitive impairment and dementia, including clinically characterized Alzheimer disease. We observed 106, 77, and 59 events of mild cognitive impairment, all-cause dementia, and clinical Alzheimer disease, respectively. RESULTS: After adjustment for age and sex, higher continuous aortic stiffness predicted an increased risk of mild cognitive impairment (hazard ratio, 1.40 [95% confidence interval, 1.13-1.73]), all-cause dementia (hazard ratio, 1.45 [95% confidence interval, 1.13-1.87]), and Alzheimer disease (hazard ratio, 1.41 [95% confidence interval, 1.06-1.87]). In risk factor adjusted statistical models, aortic stiffness remained a significant predictor of mild cognitive impairment but not incident dementia. In nondiabetic patients, the top 2 quintiles of aortic stiffness were associated with a higher risk of incident all-cause dementia across all statistical models. CONCLUSIONS: Aortic stiffness was an independent predictor of incident mild cognitive impairment in the whole sample and with incident dementia in nondiabetic patients. Our findings suggest aortic stiffness as a potentially modifiable risk factor for clinical cognitive impairment and dementia. PMID- 27491736 TI - The Capillary Index Score as a Marker of Viable Cerebral Tissue: Proof of Concept The Capillary Index Score in the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Trial. AB - BACKGROUND AND PURPOSE: The capillary index score (CIS) is based on the hypothesis that areas lacking capillary blush on pretreatment cerebral digital subtraction angiograms correspond to nonviable cerebral tissue. METHODS: Pretreatment digital subtraction angiograms and post-treatment noncontrast enhanced computed tomographic scans from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) trial were evaluated for areas lacking capillary blush and with tissue hypodensity, respectively. Because the superior and middle zones of the CIS correspond to the 7 cerebral cortex regions of the Alberta Stroke Program Early CT (ASPECT) score, capillary blush was scored in these 2 zones (0-2), called sub-CIS, and compared with the ASPECT score in these 7 regions (0-7), called hypodensity score. The presence and extent of hypodensity were compared between sub-CIS zones with contingency tables and nonparametric comparisons between groups, respectively. RESULTS: On the basis of a sample size of 50 subjects, 100% with sub-CIS <2 had the presence of hypodensity (hypodensity score >=1) versus 57% for sub-CIS=2 (P=0.004). The extent of hypodensity (numeric hypodensity score) was significantly lower for sub-CIS=2 than 0 or 1 (P=0.02). For 42 subjects with revascularization data, the presence and extent of hypodensity were significantly lower for sub-CIS=2 plus good revascularization than for other combinations of sub-CIS and revascularization (P=0.02 and 0.01, respectively). CONCLUSIONS: The absence of capillary blush on pretreatment digital subtraction angiogram seems to correspond to nonviable cerebral tissue. Successful revascularization reduces the chance of tissue hypodensity (infarction), when capillary blush is present. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR number 1804. URL: http://www.isrctn.com. Unique identifier: ISRCTN10888758. PMID- 27491737 TI - Blood Pressure, Carotid Flow Pulsatility, and the Risk of Stroke: A Community Based Study. AB - BACKGROUND AND PURPOSE: High blood pressure is a major cause of cardiovascular events, and carotid flow pulsatility may be associated with cardiovascular events. However, the combined effect of blood pressure and flow pulsatility on the development of stroke remains unclear. Therefore, we investigated the combined influence of central blood pressure and pulsatility index (PI) on the incidence of stroke. METHODS: Baseline data from 2033 adults (>=30 years) without stroke history in the Cardiovascular Disease Risk Factor Two-Township Study were linked to incident stroke. Common carotid flow PI was calculated by peak systolic velocity, end-diastolic velocity, and mean vessel velocity, which were measured in the common carotid artery. Hazard ratios for the risk of total stroke resulting from high central systolic blood pressure (CSBP) and high PI were calculated with Cox proportional hazard models. RESULTS: Over a median follow-up of 9.81 years, 132 people incurred stroke events. The incidence rates of stroke were 1.3, 6.4, and 13.2 per 1000 person-years for tertile groups of CSBP (P for trend<0.05) and 4.3, 7.0, and 9.4 per 1000 person-years for tertile groups of PI (P for trend<0.05). Compared with the first tertile of CSBP, hazard ratios were 4.88 (95% confidence interval, 2.29-10.43) for the second tertile and 10.42 (5.05 21.53) for the third tertile. Hazard ratios of PI were 2.18 (1.39-3.42; third tertile) and 1.64 (1.02-2.63; second tertile) compared with the first tertile. The individuals with a high CSBP and high PI had a 13-fold higher stroke risk compared with those with low CSBP and low PI (13.2; 1.75-99.71) after adjusting for age, sex, and traditional cardiovascular risk. CONCLUSIONS: CSBP and common carotid PI jointly and independently predicted future stroke. Carotid flow pulsatility may play an important role in the development of stroke. PMID- 27491738 TI - Leukoaraiosis, Cerebral Hemorrhage, and Outcome After Intravenous Thrombolysis for Acute Ischemic Stroke: A Meta-Analysis (v1). AB - BACKGROUND AND PURPOSE: We performed a meta-analysis to assess whether leukoaraiosis on brain computed tomographic scans of acute ischemic stroke patients treated with intravenous thrombolysis is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH) or poor functional outcome at 3 to 6 months after stroke, or both. METHODS: We searched PubMed and pooled relevant data in meta-analyses using random effects models. Using odds ratios (OR), we quantified the strength of association between the presence and severity of leukoaraiosis and post-thrombolysis sICH or 3- to 6-month modified Rankin Score >2. RESULTS: Eleven eligible studies (n=7194) were pooled in meta-analysis. The risk of sICH was higher in patients with leukoaraiosis (OR, 1.55; 95% confidence interval [CI], 1.17-2.06; P=0.002) and severe leukoaraiosis (OR, 2.53; 95% CI, 1.92-3.34; P<0.0001) compared with patients without leukoaraiosis. Leukoaraiosis was an independent predictor of sICH in 6 included studies (n=4976; adjusted OR, 1.75; 95% CI, 1.35-2.27; P<0.0001). OR for leukoaraiosis and poor 3- to 6-month outcome was 2.02 (95% CI, 1.54-2.65; P<0.0001), with significant statistical heterogeneity (I(2), 75.7%; P=0.002). In adjusted analyses, leukoaraiosis was an independent predictor of poor outcome (n=3688; adjusted OR, 1.61; 95% CI, 1.44-1.79; P<0.0001). In post hoc analyses, including only leukoaraiosis patients in randomized controlled trials (IST-3 [third International Stroke Trial], NINDS [National Institute of Neurological Disorders and Stroke], ECASS-1-2 [European Cooperative Acute Stroke Study]; n=2234), tissue type plasminogen activator versus control was associated with higher sICH risk (OR, 5.50; 95% CI, 2.49-12.13), but lower poor outcome risk (OR, 0.75; 95% CI, 0.60-0.95). CONCLUSIONS: Leukoaraiosis might increase post-intravenous thrombolysis sICH risk and poor outcome poststroke. Despite increased sICH risk, intravenous tissue-type plasminogen activator treatment has net clinical benefit in patients with leukoaraiosis. Given the risk of bias/confounding, these results should be considered hypothesis-generating and do not justify withholding intravenous thrombolysis. PMID- 27491739 TI - Protective Effects and Magnetic Resonance Imaging Temperature Mapping of Systemic and Focal Hypothermia in Cerebral Ischemia. AB - BACKGROUND AND PURPOSE: Hypothermia is potentially the most effective protective therapy for brain ischemia; however, its use is limited because of serious side effects. Although focal hypothermia (FH) has a significantly lower stress profile than systemic hypothermia (SH), its efficacy in ischemia has been poorly studied. We aimed to compare the therapeutic effects of each treatment on various short- and long-term clinically relevant end points. METHODS: Sprague-Dawley rats were subjected to transient (45 minutes) occlusion of the middle cerebral artery. One hour after arterial reperfusion, animals were randomly assigned to groups for treatment with SH or FH (target temperature: 32 degrees C) for 4 or 24 hours. Lesion volume, edema, functional recovery, and histological markers of cellular injury were evaluated for 1 month after ischemic injury. Effects of SH and FH on cerebral temperature were also analyzed for the first time by magnetic resonance thermometry, an approach that combines spectroscopy with gradient-echo-based phase mapping. RESULTS: Both therapeutic approaches reduced ischemic lesion volume (P<0.001), although a longer FH treatment (24 hours) was required to achieve similar protective effects to those induced by 4 hours of SH. In addition, magnetic resonance thermometry demonstrated that systemic hypothermia reduced whole-brain temperature, whereas FH primarily reduced the temperature of the ischemic region. CONCLUSIONS: Focal brain hypothermia requires longer cooling periods to achieve the same protective efficacy as SH. However, FH mainly affects the ischemic region, and therefore represents a promising and nonstressful alternative to SH. PMID- 27491740 TI - Determinants in Adolescence of Stroke-Related Hospital Stay Duration in Men: A National Cohort Study. AB - BACKGROUND AND PURPOSE: Physical and psychological characteristics in adolescence are associated with subsequent stroke risk. Our aim is to investigate their relevance to length of hospital stay and risk of second stroke. METHODS: Swedish men born between 1952 and 1956 (n=237 879) were followed from 1987 to 2010 using information from population-based national registers. Stress resilience, body mass index, cognitive function, physical fitness, and blood pressure were measured at compulsory military conscription examinations in late adolescence. Joint Cox proportional hazards models estimated the associations of these characteristics with long compared with short duration of stroke-related hospital stay and with second stroke compared with first. RESULTS: Some 3000 men were diagnosed with nonfatal stroke between ages 31 and 58 years. Low stress resilience, underweight, and higher systolic blood pressure (per 1-mm Hg increase) during adolescence were associated with longer hospital stay (compared with shorter) in ischemic stroke, with adjusted relative hazard ratios (and 95% confidence intervals) of 1.46 (1.08-1.89), 1.41 (1.04-1.91), and 1.01 (1.00 1.02), respectively. Elevated systolic and diastolic blood pressures during adolescence were associated with longer hospital stay in men with intracerebral hemorrhage: 1.01 (1.00-1.03) and 1.02 (1.00-1.04), respectively. Among both stroke types, obesity in adolescence conferred an increased risk of second stroke: 2.06 (1.21-3.45). CONCLUSIONS: Some characteristics relevant to length of stroke-related hospital stay and risk of second stroke are already present in adolescence. Early lifestyle influences are of importance not only to stroke risk by middle age but also to recurrence and use of healthcare resources among stroke survivors. PMID- 27491742 TI - In-Transit Telemedicine Speeds Ischemic Stroke Treatment: Preliminary Results. AB - BACKGROUND AND PURPOSE: Time to treatment is critically important in ischemic stroke. We compared the efficacy and cost of teleneurology evaluation during patient transport with that of mobile stroke transport units. METHODS: Using cellular-connected telemedicine devices, we assessed 89 presumptive stroke patients in ambulances in transit. Paramedics assisted remote teleneurologists in obtaining a simplified history and examination, then coordinating care with the receiving emergency department. We prospectively assessed door-to-needle and last known-well-to-needle times for all intravenous alteplase-treated stroke patients brought to our emergency departments by emergency medical services' transport, comparing those with and without in-transit telestroke. RESULTS: From January 2015 through March 2016, 111 stroke patients received intravenous alteplase at study emergency departments. Mean door to needle was 13 minutes less with in transit telestroke (28 versus 41; P=0.02). Although limitations in cellular communication degraded transmission quality, this did not prevent the completion of satisfactory patient evaluations. CONCLUSIONS: Improvement in time to treat seems comparable with in-transit telestroke and mobile stroke transport units. The low cost/unit makes this approach scalable, potentially providing rapid management of more patients. PMID- 27491741 TI - Inflammatory Biomarkers in Childhood Arterial Ischemic Stroke: Correlates of Stroke Cause and Recurrence. AB - BACKGROUND AND PURPOSE: Among children with arterial ischemic stroke (AIS), those with arteriopathy have the highest recurrence risk. We hypothesized that arteriopathy progression is an inflammatory process and that inflammatory biomarkers would predict recurrent AIS. METHODS: In an international study of childhood AIS, we selected cases classified into 1 of the 3 most common childhood AIS causes: definite arteriopathic (n=103), cardioembolic (n=55), or idiopathic (n=78). We measured serum concentrations of high-sensitivity C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor-alpha. We used linear regression to compare analyte concentrations across the subtypes and Cox proportional hazards models to determine predictors of recurrent AIS. RESULTS: Median age at index stroke was 8.2 years (interquartile range, 3.6-14.3); serum samples were collected at median 5.5 days post stroke (interquartile range, 3-10 days). In adjusted models (including age, infarct volume, and time to sample collection) with idiopathic as the reference, the cardioembolic (but not arteriopathic) group had higher concentrations of high-sensitivity C-reactive protein and myeloperoxidase, whereas both cardioembolic and arteriopathic groups had higher serum amyloid A. In the arteriopathic (but not cardioembolic) group, higher high-sensitivity C-reactive protein and serum amyloid A predicted recurrent AIS. Children with progressive arteriopathies on follow-up imaging had higher recurrence rates, and a trend toward higher high-sensitivity C-reactive protein and serum amyloid A, compared with children with stable or improved arteriopathies. CONCLUSIONS: Among children with AIS, specific inflammatory biomarkers correlate with cause and-in the arteriopathy group-risk of stroke recurrence. Interventions targeting inflammation should be considered for pediatric secondary stroke prevention trials. PMID- 27491743 TI - The action and mechanism of myrislignan on A549 cells in vitro and in vivo. AB - Myrislignan is a natural compound with little pharmacological study. In our investigation, we investigated the effect of myrislignan in the induction of apoptosis in A549 cells in vitro and in vivo. Myrislignan inhibited the proliferation of A549 cells in a dose- and time-dependent manner assayed by MTT. In addition, Hoechst flow cytometry showed that myrislignan significantly induced apoptosis and cell cycle arrest in A549 cells. The apoptosis and anti-cell proliferation was mediated by the activation of mitogen-activated protein kinase and the inhibition of epidermal growth factor receptor signal pathway, change of mitochondrial membrane potential, the releasing of c-Myc, the downregulation of the level of the anti-apoptotic protein Bcl-2, and the upregulation of the level of the pro-apoptotic protein Bax. In conclusion, those results reveal a potential mechanism for the anti-cancer effect of myrislignan on human lung cancer, while suggesting that myrislignan may be a promising compound for the treatment of lung cancer. PMID- 27491744 TI - Structure and hemolytic activity relationships of triterpenoid saponins and sapogenins. AB - We evaluated the hemolytic activity of 41 commercially available triterpenoid saponins and sapogenins derived from three types of structural skeletons. Structure-activity relationships were established by comparing the structural characteristics of both the aglycone and sugar moieties among the tested compounds. The majority of oleanane-type sapogenins had stronger hemolytic effects than those of the ursane and dammarane types. The presence of polar regions on sapogenins, such as a carboxyl (COOH) at position 28, an alpha hydroxyl (alpha-OH) at position 16, and/or a beta-hydroxyl (beta-OH) at position 2, significantly enhanced hemolysis. Meanwhile, the introduction of an alpha-OH at position 2 or a methyl hydroxyl (CH2OH) at positions 23 or 24 was closely associated with reduced activity. Our findings suggest that not only the complexity of sugar moieties but also the types and stereochemical configurations of functional groups at different positions, as well as the skeleton types, are important structural features affecting hemolytic potential. Our results provide a baseline in terms of the toxicity of saponins and sapogenins to erythrocytes, which holds promise for drug development. PMID- 27491747 TI - Health care and human rights: against the split duty gambit. AB - There are various grounds on which one may wish to distinguish a right to health care from a right to health. In this article, I review some old grounds before introducing some new grounds. But my central task is to argue that separating a right to health care from a right to health has objectionable consequences. I offer two main objections. The domestic objection is that separating the two rights prevents the state from fulfilling its duty to maximise the health it provides each citizen from its fixed health budget. The international objection is that separating a human right to health care fails the moral requirement that, for any given moral human right, the substance to which any two right-holders are entitled be of an equal standard. PMID- 27491748 TI - The right to preventive health care. AB - The right to health care is a right to care that (a) is not too costly to the provider, considering the benefits it conveys, and (b) is effective in bringing about the level of health needed for a good human life, not necessarily the best health possible. These considerations suggest that, where possible, society has an obligation to provide preventive health care, which is both low cost and effective, and that health care regulations should promote citizens' engagement in reasonable preventive health care practices. PMID- 27491749 TI - Diterpenoids from Callicarpa kwangtungensis and their NO inhibitory effects. AB - A phytochemical investigation of the leaves of Callicarpa kwangtungensis led to the isolation of three new diterpenoids (1-3), callipenes A-C, and eleven known analogues (4-14). Their structures were established on the basis of extensive analysis of NMR spectroscopic data, X-ray diffraction data, and experimental and calculated electronic circular dichroism spectra. Compounds 1 and 2 are rare abietane diterpenoids possessing a peroxide bridge. All of the isolates were found to inhibit LPS-induced NO production in BV-2 cells. PMID- 27491750 TI - Chemical structures, production and enzymatic transformations of sapogenins and saponins from Centella asiatica (L.) Urban. AB - Centella asiatica (L.) Urban is a medicinal herb traditionally used in Asiatic countries for its multiple therapeutic properties, essentially due to its accumulation of specific pentacylic triterpenoid saponins, mainly asiaticoside and madecassoside and the corresponding sapogenins. This review summarizes the updated knowledge about the chemical structures of about forty centelloids, found as minor metabolites in Centella, and all derived from ursane and oleane ring patterns. Similarly, the most recent genetic and enzymatic features involved in their biosynthesis is reviewed, in relation with their biotechnological production developed, either from in vitro plant cultures or undifferentiated cells, in order to be independent of natural sources and to provide a continuous and reliable source of centelloids. Finally, a short survey of the biotransformations of some centelloids, either in animal, human or microorganisms is reviewed. PMID- 27491751 TI - Poligalen, a new coumarin from Polygala boliviensis, reduces the release of TNF and IL-6 independent of NF-kB downregulation. AB - An unusually substituted coumarin, named poligalen, was isolated from a chloroform extract of the aerial parts of Polygala boliviensis. This coumarin was identified by one- and two-dimensional NMR techniques, and the structure of the compound was confirmed by X-ray diffraction. Poligalen exhibits immunomodulatory effects, reducing the levels of IL-6 and TNF after LPS stimulation in peritoneal macrophages. However, poligalen potentiates NF-kB activation. PMID- 27491752 TI - Tirucallane-type triterpenoids from the fruits of Phellodendron chinense Schneid and their cytotoxic activities. AB - Eleven triterpenoids were isolated from the fruits of Phellodendron chinense Schneid, and their structures were determined by spectroscopic analysis. The results show that four new tirucallane-type triterpenoids 1, 2, 5, and 6 and seven known compounds 3, 4, 7, 8, 9, 10, and 11 were isolated. Structurally, compound 6 was uncommon; it has a chlorine atom instead of a methyl group at the C-20 position. The cytotoxicities of the compounds was evaluated against the in vitro proliferation of four human tumor cell lines HEL, K562, MDA, and PC3 using adriamycin as the positive control. Compound 1 showed a similar cytotoxicity as the positive control; compounds 3 and 10 showed moderate cytotoxicities compared to the control (P<0.05). This indicates that these compounds have great potential for the development of new antitumor drugs. PMID- 27491753 TI - Sesquiterpenes of agarwood from Gyrinops salicifolia. AB - Six new sesquiterpenoids (1-6) and six known sesquiterpenoids (7-12) were isolated from agarwood originated from Gyrinops salicifolia Ridl. Most of them gave off aromatic odor, and all the compounds were isolated from this genus for the first time. The structures of 1-6 were elucidated by spectroscopic techniques (UV, IR, 1D and 2D NMR) and MS analysis, as well as by comparison with literature data. Compounds 1, 6 and 11-12 showed moderate acetylcholinesterase (AChE) inhibitory activity. PMID- 27491754 TI - New sesquiterpene lactones from Ambrosia cumanensis Kunth. AB - Eleven sesquiterpene lactones, including three new natural products (1-3), were isolated from the n-butanolic extract of Ambrosia cumanensis Kunth. aerial parts. The structure of all isolated compounds was elucidated by 1D- and 2D-NMR, and MS analyses. All compounds were tested for their antiproliferative activity on HeLa, Jurkat, and U937 cell lines. Compound 3, 2,3-dehydropsilostachyn C, showed cytotoxic activity with different potency in all cell lines. By means of flow cytometric studies, compound 3 was demonstrated to induce in Jurkat cells a G2/M cell cycle block, while in U937 elicited both cytostatic and cytotoxic responses. PMID- 27491755 TI - Characterization of diterpenoids from Caesalpinia decapetala and their anti-TMV activities. AB - Caesalpinia decapetala is a versatile medicinal plant belonging to the Fabaceae plant family. In our survey on plant secondary metabolites to obtain bioactive substances for the development of new agricultural anti-TMV agents, the chemical constituents of C. decapetala were investigated. This investigation led to the isolation of three new and ten known diterpenoids. Their structures including absolute configurations were elucidated based on the extensive NMR spectroscopic data analyses and the time-dependent density functional theory calculations. The following biological screenings revealed that most of these diterpenoids possessed anti-TMV activities. PMID- 27491756 TI - Yeast Ca(2+)-signal transduction inhibitors isolated from Dominican amber prevent the degranulation of RBL-2H3 cells through the inhibition of Ca(2+)-influx. AB - A new norlabdane compound, named kujigamberol has previously been isolated from Kuji amber (but not from Baltic amber) by activity guided fractionation. However, there has been no study of biological compounds in Dominican amber. Biological activities were examined using the hypersensitive mutant yeast (zds1Delta erg3Delta pdr1Delta pdr3Delta) with respect to Ca(2+)-signal transduction, enzymes and rat basophilic leukemia (RBL)-2H3 cells. The structures were elucidated on the basis of spectral analysis including high resolution (HR)-EI MS, 1D NMR and 2D NMR. Three diterpenoid compounds, 5(10)-halimen-15-oic acid (1), 3-cleroden-15-oic acid (2) and 8-labden-15-oic acid (3), which are different from the bioactive compounds in Kuji and Baltic ambers, were isolated from Dominican amber. They inhibited both calcineurin (CN) (IC50=40.0, 21.2 and 34.2MUM) and glycogen synthase kinase-3beta (GSK-3beta) (IC50=48.9, 43.8 and 41.1MUM) which are involved in the growth restored activity against the mutant yeast. The most abundant compound 2 showed inhibitory activity against both degranulation and Ca(2+)-influx in RBL-2H3 cells. The compounds having the growth restoring activity against the mutant yeast have potential as anti-allergic compounds. PMID- 27491757 TI - Domain motions and electron transfer dynamics in 2Fe-superoxide reductase. AB - Superoxide reductases are non-heme iron enzymes that represent valuable model systems for the reductive detoxification of reactive oxygen species. In the present study, we applied different theoretical methods to study the structural dynamics of a prototypical 2Fe-superoxide reductase and its influence on electron transfer towards the active site. Using normal mode and essential dynamics analyses, we could show that enzymes of this type are capable of well-defined, electrostatically triggered domain movements, which may allow conformational proofreading for cellular redox partners involved in intermolecular electron transfer. Moreover, these global modes of motion were found to enable access to molecular configurations with decreased tunnelling distances between the active site and the enzyme's second iron centre. Using all-atom classical molecular dynamics simulations and the tunnelling pathway model, however, we found that electron transfer between the two metal sites is not accelerated under these conditions. This unexpected finding suggests that the unperturbed enzymatic structure is optimized for intramolecular electron transfer, which provides an indirect indication of the biological relevance of such a mechanism. Consistently, efficient electron transfer was found to depend on a distinct route, which is accessible via the equilibrium geometry and characterized by a quasi conserved tyrosine that could enable multistep-tunnelling (hopping). Besides these explicit findings, the present study demonstrates the importance of considering both global and local protein dynamics, and a generalized approach for the functional analysis of these aspects is provided. PMID- 27491758 TI - Generalizing Treatment Effect Estimates From Sample to Population: A Case Study in the Difficulties of Finding Sufficient Data. AB - BACKGROUND: Given increasing concerns about the relevance of research to policy and practice, there is growing interest in assessing and enhancing the external validity of randomized trials: determining how useful a given randomized trial is for informing a policy question for a specific target population. OBJECTIVES: This article highlights recent advances in assessing and enhancing external validity, with a focus on the data needed to make ex post statistical adjustments to enhance the applicability of experimental findings to populations potentially different from their study sample. RESEARCH DESIGN: We use a case study to illustrate how to generalize treatment effect estimates from a randomized trial sample to a target population, in particular comparing the sample of children in a randomized trial of a supplemental program for Head Start centers (the Research Based, Developmentally Informed study) to the national population of children eligible for Head Start, as represented in the Head Start Impact Study. RESULTS: For this case study, common data elements between the trial sample and population were limited, making reliable generalization from the trial sample to the population challenging. CONCLUSIONS: To answer important questions about external validity, more publicly available data are needed. In addition, future studies should make an effort to collect measures similar to those in other data sets. Measure comparability between population data sets and randomized trials that use samples of convenience will greatly enhance the range of research and policy relevant questions that can be answered. PMID- 27491759 TI - Soil contamination with olive mill wastes negatively affects microbial communities, invertebrates and plants. AB - The aim of the present study was to evaluate the ecotoxicological effects of olive mill waste (OMW) on soil habitat function. To this end, soil samples from OMW evaporating ponds (S1-S5) located at Agareb (Sfax, Tunisia) and a reference soil (R) were collected. The effects of OMW on the springtails Folsomia candida (F.c.), the earthworm species Eisenia fetida (E.f.), Enchytraeus crypticus (E.c.) reproduction and on the soil living microbial communities were investigated. E.f. reproduction and tomato growth assays were performed in the reference soil amended with 0.43 to 7.60 % (wOMW/wref-soil) mass ratios of dried OMW. Changes in microbial function diversity were explored using sole-carbon-source utilization profiles (BiologEcoPlates(r)). E.f. absolutely avoided (100 %) the most polluted soil (S4) while the F.c. moderately avoided (37.5 +/- 7.5 %) the same soil. E.c. reproduction in S4 was significantly lower than in S1, S2, S3 and S5, and was the highest in R soil. Estimated effect concentration EC50 for juveniles' production by E.f., and for tomato fresh weight and chlorophyll content were 0.138, 0.6 and 1.13 %, respectively. Community level physiological profiles (CLPPs) were remarkably different in R and S4 and a higher similarity was observed between soils S1, S2, S3 and S5. Principal component analysis (PCA) revealed that differences between soil microbial functional diversity were mainly due to high polyphenol concentrations, while the salinity negatively affected E.c. reproduction in OMW contaminated soils. These results clearly reflect the high toxicity of dried OMW when added to agricultural soils, causing severe threats to terrestrial ecosystem functions and services provided by invertebrates and microbial communities. PMID- 27491760 TI - Effect of ultrasound training of physicians working in the prehospital setting. AB - BACKGROUND: Advances in technology have made ultrasound (US) devices smaller and portable, hence accessible for prehospital care providers. This study aims to evaluate the effect of a four-hour, hands-on US training course for physicians working in the prehospital setting. The primary outcome measure was US performance assessed by the total score in a modified version of the Objective Structured Assessment of Ultrasound Skills scale (mOSAUS). METHODS: Prehospital physicians participated in a four-hour US course consisting of both hands-on training and e-learning including a pre- and a post-learning test. Prior to the hands-on training a pre-training test was applied comprising of five videos in which the participants should identify pathology and a five-minute US examination of a healthy volunteer portraying to be a shocked patient after a blunt torso trauma. Following the pre-training test, the participants received a four-hour, hands-on US training course which was concluded with a post-training test. The US examinations and screen output from the US equipment were recorded for subsequent assessment. Two blinded raters assessed the videos using the mOSAUS. RESULTS: Forty participants completed the study. A significant improvement was identified in e-learning performance and US performance, (37.5 (SD: 10.0)) vs. (51.3 (SD: 5.9) p = < 0.0001), total US performance score (15.3 (IQR: 12.0-17.5) vs. 17.5 (IQR: 14.5-21.0), p = < 0.0001) and in each of the five assessment elements of the mOSAUS. CONCLUSION: In the prehospital physicians assessed, we found significant improvements in the ability to perform US examinations after completing a four-hour, hands-on US training course. PMID- 27491761 TI - Bacterial corneal ulcer associated with common variable immune deficiency. AB - Common variable immune deficiency (CVID) is one of the most commonly diagnosed primary immunodeficiencies. Generally, patients have a history of recurrent sinopulmonary infections, hypogammaglobulinemia of two or more immunoglobulin isotypes, and impaired functional antibody responses. Reports of corneal involvement associated with CVID are limited. We describe a case of corneal ulceration associated with methicillin-resistant Staphylococcus aureus in a patient with CVID that developed while on monthly intravenous immunoglobulin infusions and in which there were no common risk factors for bacterial keratitis, such as prior history of ocular surface disease, trichiasis, trauma, or contact lens wear. PMID- 27491763 TI - [Not Available]. PMID- 27491762 TI - [Not Available]. PMID- 27491764 TI - [Not Available]. PMID- 27491765 TI - [Not Available]. PMID- 27491766 TI - [Alcohol consumption in women and the elderly : When does it induce heart failure?]. AB - The association between alcohol consumption and the etiology and prognosis of cardiovascular diseases has been the focus of attention and also the subject of controversial discussions for many years. This is particularly true for heart failure, which can be induced by coronary artery disease (CAD), arterial hypertension, atrial and ventricular arrhythmias and cardiomyopathies. Acute effects of high doses of alcohol can lead to impairment of the cardiac contraction strength with rhythm disturbances (holiday heart syndrome), transient ischemic attacks and in rare cases to sudden cardiac death. The chronic effects of high alcohol consumption include in particular, ventricular dysfunction, chronic rhythm disturbances, alcoholic cardiomyopathy and CAD. In contrast, light to moderate consumption of alcohol is associated with a reduced risk of CAD and ischemic stroke; however, even moderate alcohol drinking is associated with a greater risk for atrial fibrillation. The unfavorable effects of alcohol occur at much lower levels of acute or chronic consumption in women than in men. In the elderly just as in young people, a moderate alcohol consumption is associated with a lower risk of heart failure. PMID- 27491767 TI - Temporal trends in transcatheter and surgical aortic valve replacement : An analysis of aortic valve replacements in Germany during 2012-2014. AB - This analysis of the data of the obligatory quality assurance programme AQUA shows the perioperative risk as well as the procedural outcome evaluated by the observed versus expected in-hospital mortality ratio (O/E ratio) of 62,872 patients undergoing isolated surgical (sAVR), transcatheter transvascular (TV-), or transapical (TA-) aortic valve replacement (TAVI) from 2012 to 2014 in Germany. The number of TAVI procedures increased from 9,352 in 2012 to 13,278 in 2014, whereas the number of sAVR remained constant (2012: 9,949; 2014: 9,953). Between 2012 and 2014, the number of TAVI implanted in patients with a logistic EuroScore I (logESI) of <=10 % (2012: 21 %; 2014: 26 %) as well as with a logESI <20 % (2012: 57 %; 2014: 64 %) increased. In-hospital mortality in TAVI patients decreased from 5.2 % (TV: 5.0 %; TA: 7.4 %) in 2012 to 4.2 % (TV: 3.8 %; TA: 5.5 %) in 2014, whereas it was stable for sAVR patients (2012: 2.8 %; 2014: 2.6 %). The O/E ratio of TAVI patients decreased from 0.91 (TV: 0.79; TA: 1.2) to 0.73 (TV: 0.69; TA: 0.89), whereas this ratio remained constant for sAVR patients (2012: 0.92; 2014: 0.93). In summary, estimated surgical risk, in-hospital mortality, as well as the O/E ratio for patients undergoing TAVI declined constantly during the last 3 years. PMID- 27491768 TI - Echocardiography in Pregnancy: Part 1. AB - Cardiovascular disease (CVD) remains the leading cause of maternal mortality, and clinical diagnosis of CVD in women during pregnancy is challenging. Pregnant women with known heart disease require careful multidisciplinary management by obstetric and medical teams to assess for maternal and fetal risk. Echocardiography is a safe and effective diagnostic tool indicated in pregnant women with cardiac symptoms or women with known cardiac disease for appropriate selection of women who require close monitoring of cardiac condition and valvular function. Echocardiography is the single most important clinical tool to diagnose and manage heart disease during pregnancy. Echocardiography is able to characterize cardiac structural abnormalities and corresponding hemodynamic changes, identifies heart diseases that are poorly tolerated in pregnancy, and helps select patients who may require a cesarean delivery because of hemodynamic instability. An understanding of the physiologic alterations including increased heart rate, blood volume, and cardiac output as well as the decreased vascular resistance is important for early recognition and monitoring of the consequences of cardiac disease in pregnancy. This review will focus on common acquired cardiac lesions encountered during pregnancy and the role of echocardiography in the diagnosis and management of these diseases. PMID- 27491769 TI - Depressive symptoms and functional decline following coronary interventions in older patients with coronary artery disease: a prospective cohort study. AB - BACKGROUND: Depressive symptoms are prevalent in patients with coronary artery disease (CAD). It is unclear, however, how depressive symptoms change over time and the impact of these changes on long-term functional outcomes. We examined the association between different trajectories of depressive symptoms over 1 year and change in functional status over 30 months among patients undergoing coronary angiography. METHODS: This was a prospective cohort study of 350 patients aged 60 and older undergoing non-emergent cardiac catheterization (October 2003-February 2007). A dynamic measure of significant depressive symptoms (i.e., Geriatric Depression Scale score 5+) capturing change over 12 months was derived that categorized patients into the following groups: (i) no clinically important depressive symptoms (at baseline, 6 and 12 months); (ii) baseline-only symptoms (at baseline but not at 6 and 12 months); (iii) new onset symptoms (not at baseline but present at either 6 or 12 months); and, (iv) persistent symptoms (at baseline and at either 6 or 12 month assessment). Primary outcomes were mean change in Older Americans Resources and Services (OARS) instrumental (IADL) and basic activities of daily living (BADL) scores (range 0-14 for each) across baseline (pre-procedure) and 6, 12, and 30 months post-procedure visits. RESULTS: Estimates for the symptom categories were 71 % (none), 9 % (baseline only), 8 % (new onset) and 12 % (persistent). In adjusted models, patients with persistent symptoms showed a significant decrease in mean IADL and BADL scores from baseline to 6 months (-1.32 [95 % CI -1.78 to -0.86] and -0.63 [-0.97 to -0.30], respectively) and from 12 to 30 months (-0.79 [-1.27 to -0.31] and -1.00 [-1.35 to -0.65], respectively). New onset symptoms were associated with a significant decrease in mean IADL scores at 6 months and from 6 to 12 months. Patients with no depressive symptoms showed little change in scores whereas those with baseline only symptoms showed significant improvement in mean IADL at 6 months. CONCLUSIONS: Patients with persistent depressive symptoms were at greatest risk for worse functional status 30 months following coronary interventions. Proactive screening and follow-up for depression in this population offers prognostic value and may facilitate the implementation of targeted interventions. PMID- 27491770 TI - Intrafollicular interleukin-8, interleukin-12, and adrenomedullin are the promising prognostic markers of oocyte and embryo quality in women with endometriosis. AB - PURPOSE: The study aimed to investigate key intrafollicular prognostic factors among various cytokines and angiogenic molecules for prediction of mature oocytes and good-quality embryos in women with endometriosis undergoing in vitro fertilization (IVF). METHODS: Paired follicular fluid and serum samples were collected from 200 women with advanced stage endometriosis and 140 normal ovulating women during oocyte retrieval. The concentrations of cytokines (pro inflammatory: IL-1beta, TNF-alpha, IL-2, IL-8, IL-12, IFN-gamma; anti inflammatory: IL-4, IL-6, IL-10) and angiogenic molecules (vascular endothelial growth factor (VEGF), adrenomedullin, angiogenin) were determined in follicular fluid and serum using ELISA. Expression of these molecules was subjected to multivariate analysis for the identification of major predictive markers of oocyte and embryo quality. Receiver operating characteristic (ROC) curve was applied to determine the best cutoff point for the discrimination between mature and immature oocytes in these women. RESULTS: Significant increases in levels of cytokines and angiogenic molecules were observed in women with endometriosis compared to controls (P < 0.001). From the validated partial least squares discriminant analysis (PLS-DA) model, IL-8, IL-12, and adrenomedullin were identified as the most important factors contributing to endometriosis and were negatively associated with oocyte maturity and embryo quality. CONCLUSION: The levels of IL-8, IL-12, and adrenomedullin may be good indicators of embryo and oocyte quality in endometriosis patients undergoing IVF. Further studies are necessary to ascertain the potential of these markers for oocyte and embryo developmental competence which may help improve the chances of a successful IVF in endometriosis patients. PMID- 27491771 TI - Pre-implantation genetic testing in ART: who will benefit and what is the evidence? AB - Pre-implantation genetic diagnosis for aneuploidy testing (PGD-A) is a tool to identify euploid embryos during IVF. The suggested populations of patients that can benefit from it are infertile women of advanced maternal age, with a history of recurrent miscarriages and/or IVF failures. However, a general consensus has not yet been reached.After the clinical failure of its first version based on cleavage stage biopsy and 9 chromosome-FISH analysis, PGD-A is currently performed by 24 chromosome screening techniques on trophectoderm (TE) biopsies. This approach has been clearly demonstrated to involve a higher clinical efficiency with respect to the standard care, in terms of sustained pregnancy rate per transfer and lower miscarriage rate. However, data about PGD-A efficacy calculated on a per intention-to-treat basis, as well as an analysis of its cost effectiveness, are still missing.TE biopsy is a safe and extensively validated approach with low biological and technical margin of error. Firstly, the prevalence of mosaic diploid/aneuploid blastocysts is estimated to be between 0 and 16 %, thus largely tolerable. Secondly, all the comprehensive chromosome screening (CCS) technologies adapted to, or designed to conduct PGD-A are highly concordant, and qPCR in particular has been proven to show the lowest false positive error rate (0.5 %) and a clinically recognizable error rate per blastocyst of just 0.21 %.In conclusion, there is a sufficient body of evidence to support the clinical application of CCS-based PGD-A on TE biopsies. The main limiting factor is the need for a high-standard laboratory to conduct blastocyst culture, biopsy and vitrification without impacting embryo viability. PMID- 27491773 TI - Parental migration and smoking behavior of left-behind children: evidence from a survey in rural Anhui, China. AB - BACKGROUND: Parental migration is most an important factor affecting children's behaviors. Few studies have addressed the association between parental migration and children's smoking behavior in China. This study aims to estimate the current smoking prevalence among children, evaluate the association of parental migration and the smoking behavior of children and identify factors associated with smoking behavior among left-behind children (LBC). METHODS: A cross-sectional study was conducted in 6 cities in Anhui province during July and August, 2012. All participants were interviewed face-to-face using a standardized questionnaire. Only children 10 to 14 years old that live in rural villages for at least 6 months during the previous year were included in the study. RESULTS: A total of 1343 children met the sampling criteria and participated in the study. Of these, 56 % are LBC and 44 % live with both parents. The average rate of smoking is 3.4 %. The rate of smoking is statistically higher for LBC with both parents out (rate = 6.1 %; OR = 5.59, P < 0.001) than for children living with both parents (1.4 %). Similarly, the rate of LBC with father home only (rate = 5.0 %; OR = 5.60, P = 0.005) is also statistically higher than for children living with both parents when controlling other variables. Factors affecting the smoking behavior of LBC, include gender (i.e., boys), (perceived) school performance and primary caregiver. CONCLUSIONS: Parental migration is associated with a significant increase in smoking behavior among children. Intervention studies that target LBC would help to develop strategies to reduce smoking among rural children. Gender specific strategies and anti-smoking education also appears to be needed to reduce tobacco use among rural LBC. PMID- 27491772 TI - Blastocyst culture using single versus sequential media in clinical IVF: a systematic review and meta-analysis of randomized controlled trials. AB - PURPOSE: The purpose of this study was to undertake a review of the available evidence comparing the use of a single medium versus sequential media for embryo culture to the blastocyst stage in clinical IVF. METHODS: We searched the Cochrane Central, PubMed, Scopus, ClinicalTrials.gov, Current Controlled Trials and WHO International Clinical Trials Registry Platform to identify randomized controlled trials comparing single versus sequential media for blastocyst culture and ongoing pregnancy rate. Included studies randomized either oocytes/zygotes or women. Eligible oocyte/zygote studies were analyzed to assess the risk difference (RD) and 95 % confidence intervals (CI) between the two media systems; eligible woman-based studies were analyzed to assess the risk ratio (RR) and 95 % CI for clinical pregnancy rate. RESULTS: No differences were observed between single and sequential media for either ongoing pregnancy per randomized woman (relative risk (RR) = 0.9, 95 % CI = 0.7 to 1.3, two studies including 246 women, I 2 = 0 %) or clinical pregnancy per randomized woman (RR = 1.0, 95 % CI = 0.7 to 1.4, one study including 100 women); or miscarriage per clinical pregnancy: RR = 1.3, 95 % CI = 0.4 to 4.3, two studies including 246 participants, I 2 = 0 %). Single media use was associated with an increase blastocyst formation per randomized oocyte/zygote (relative distribution (RD) = +0.06, 95 % CI = +0.01 to +0.12, ten studies including 7455 oocytes/zygotes, I 2 = 83 %) but not top/high blastocyst formation (RD = +0.05, 95 % CI = -0.01 to +0.11, five studies including 3879 oocytes/zygotes, I 2 = 93 %). The overall quality of the evidence was very low for all these four outcomes. CONCLUSIONS: Although using a single medium for extended culture has some practical advantages and blastocyst formation rates appear to be higher, there is insufficient evidence to recommend either sequential or single-step media as being superior for the culture of embryos to days 5/6. Future studies comparing these two media systems in well-designed trials should be performed. PMID- 27491774 TI - Prediction of drug interaction between oral adsorbent AST-120 and concomitant drugs based on the in vitro dissolution and in vivo absorption behavior of the drugs. AB - PURPOSE: AST-120 is used to decrease the abundance of serum uremic toxins in treatment of chronic kidney disease; however, it could also adsorb concomitantly administered drugs. This study aimed to develop a prediction method for drug interaction between AST-120 and concomitantly administered drugs based on in vitro dissolution and in vivo absorption behavior. METHODS: Sixty-eight drugs were selected for the analysis. For each drug, theoretical dissolution (R d) and absorption (R a) rates at estimated dosing intervals (1, 30, 60, 90, 120, and 240 min) were calculated using the Noyes-Whitney formula and compartment analysis, respectively. The optimal thresholds for R d and R a (R dth and R ath) were estimated by comparing the results with those of previous drug interaction studies for six drugs. Four drug interaction risk categories for 68 drugs at each dose interval were defined according to the indices of dissolution and absorption against their thresholds. RESULTS: The in vitro dissolution and in vivo absorption behavior of the selected drugs were well fitted to the Noyes-Whitney formula and one- or two-compartment models. The optimal R dth and R ath that gave the highest value of consistency with the equivalence of drug interaction studies were 90 and 30 %, respectively. As the dosing intervals were lengthened, the number of drugs classified into the low-risk categories increased. CONCLUSION: A new drug interaction prediction method based on the pharmacokinetic parameters of drugs was developed. The new model is useful for estimating the risk of drug interaction in clinical practice when AST-120 is used in combination with other drugs. PMID- 27491775 TI - Clinical relevance of the utilization of vital Lugol's iodine staining in detection and diagnosis of oral cancer and dysplasia. AB - OBJECTIVES: The aim of this study is to assess the clinical relevance of the utilization of vital Lugol's iodine staining in detection of oral cancer and dysplastic lesions as well as demarcation of the extent of these lesions. MATERIALS AND METHODS: A prospective, cross-sectional, hospital-based study was performed in Khartoum Teaching Dental Hospital, Sudan. Suspicious oral epithelial lesions indicating incisional biopsy were stained with 10 % Lugol's iodine solution and were clinically designated as "negative" for dysplasia or neoplasia when no unstained lesion (USL) area was observed, or as "positive" when a USL area is observed. Incisional biopsies involving both the unstained portion and the stained portion were obtained and histologically evaluated for definitive diagnosis. RESULTS: Forty-five biopsies were obtained from 28 patients. Histopathological examination of the specimens confirmed some degree of dysplasia or neoplasia in all clinically positive specimens with oral squamous cell carcinoma (OSCC) being the most common definitive diagnosis (17 patients, 60.7 %). Clinical relevance level of vital Lugol's iodine staining in detecting oral cancer and dysplasia was found to be 90.9 % (SE = 0.05, P = 0.05). CONCLUSION: The findings of this study showed that Lugol's iodine is an easy, safe, and effective method of visualizing oral epithelial lesions and differentiating epithelial carcinoma and dysplasia from other benign mucosal lesions. Despite certain limitations, its use is of great value in detection and diagnosis of oral cancer and dysplasia. CLINICAL RELEVANCE: Lugol's iodine staining can effectively be used in detection of the dysplastic and malignant superficial lesions of the oral epithelium. PMID- 27491776 TI - The impact of health insurance programs for children: evidence from Vietnam. AB - This study assesses the impact of children's health insurance programs on health care utilization and health care expenditures of children from 6 to 14 years old in Vietnam using four rounds of the Vietnam Household Living Standard Surveys from 2006 to 2012. We find a positive effect of both student and free health insurance programs on the number of health care visits. This positive impact tends to increase over time, and the impact of the free health insurance program is larger than the impact of the student health insurance program. Regarding out of-pocket health expenditures per visit, we find a reducing effect on this outcome of the free health insurance program but not the student health insurance program. PMID- 27491777 TI - Decatropis bicolor (Zucc.) Radlk essential oil induces apoptosis of the MDA-MB 231 breast cancer cell line. AB - BACKGROUND: Decatropis bicolor (Zucc.)Radlk is a plant that has been traditionally used for the treatment of breast cancer in some communities of Mexico. So, the aim of this study was to determine the cytotoxic and apoptotic effect of the essential oil of Decatropis bicolor against breast cancer cell line, MDA-MB-231. METHODS: The essential oil obtained from hydrodestillation of leaves of Decatropis bicolor was studied for its biological activity against breast cancer cells MDA-MB-231 by MTT assay, Hematoxylin-eosin stain, Annexin V FITC, TUNEL and western blot assays and for its chemical composition by GC-MS. RESULTS: The results showed a relevant cytotoxic effect of the essential oil towards MDA-MB-231 cells in a dose- and time- dependent manner, with an IC50 of 53.81 +/- 1.691 MUg/ml but not in the epithelial mammary cell line MCF10A (207.51 +/- 3.26 MUg/ml). Morphological examination displayed apoptotic characteristics in the treated cells like cell size reduction, membrane blebbing and apoptotic bodies. In addition, the apoptotic rate significantly increased as well as DNA fragmentation and western blot analysis revealed that the essential oil induced apoptosis in the MDA-MB-231 cells via intrinsic pathways due to the activation of Bax, caspases 9 and 3. Phytochemical analysis of the Decatropis bicolor essential oil showed the presence of twenty-three compounds. Major components of the oil were 1,5-cyclooctadiene,3-(methyl-2)propenyl (18.38 %), beta-terpineol (8.16 %) and 1-(3-methyl-cyclopent-2-enyl)-cyclohexene (6.12 %). CONCLUSIONS: This study suggests that essential oil of Decatropis bicolor has a potential cytotoxic and antitumoral effect against breast cancer cells, with the presence of potential bioactive compounds. Our results contribute to the validation of the anticancer activity of the plant in Mexican traditional medicine. PMID- 27491778 TI - Beneficial effects of dark chocolate on exercise capacity in sedentary subjects: underlying mechanisms. A double blind, randomized, placebo controlled trial. AB - In heart failure patients the consumption of (-)-epicatechin ((-)-Epi)-rich cocoa can restore skeletal muscle (SkM) mitochondrial structure and decrease biomarkers of oxidative stress. However, nothing is known about its effects on exercise capacity and underlying mechanisms in normal, sedentary subjects. Twenty normal, sedentary subjects (~50 years old) were randomized to placebo or dark chocolate (DC) groups and consumed 20 g of the products for 3 months. Subjects underwent before and after treatment, bicycle ergometry to assess VO2 max and work, SkM biopsy to assess changes in mitochondrial density, function and oxidative stress and blood sampling to assess metabolic endpoints. Seventeen subjects completed the trial. In the DC group (n = 9), VO2 max increased (17% increase, p = 0.056) as well as maximum work (watts) achieved (p = 0.026) with no changes with placebo (n = 8). The DC group evidenced increases in HDL levels (p = 0.005) and decreased triglycerides (p = 0.07). With DC, SkM evidenced significant increases in protein levels for LKB1, AMPK and PGC1alpha and in their active forms (phosphorylated AMPK and LKB1) as well as in citrate synthase activity while no changes were observed in mitochondrial density. With DC, significant increases in SkM reduced glutathione levels and decreases in protein carbonylation were observed. Improvements in maximum work achieved and VO2 max may be due to DC activation of upstream control systems and enhancement of SkM mitochondria efficiency. Larger clinical studies are warranted to confirm these observations. PMID- 27491779 TI - Ten-year change in sedentary behaviour, moderate-to-vigorous physical activity, cardiorespiratory fitness and cardiometabolic risk: independent associations and mediation analysis. AB - BACKGROUND: We aimed to study the independent associations of 10-year change in sedentary behaviour (SB), moderate-to-vigorous physical activity (MVPA) and objectively measured cardiorespiratory fitness (CRF), with concurrent change in clustered cardiometabolic risk and its individual components (waist circumference, fasting glucose, high-density lipoprotein (HDL) cholesterol, triglycerides and blood pressure). We also determined whether associations were mediated by change in CRF (for SB and MVPA), waist circumference (for SB, MVPA and CRF) and dietary intake (for SB). METHODS: A population-based sample of 425 adults (age (mean+/-SD) 55.83+/-9.40; 65% men) was followed prospectively for 9.62+/-0.52 years. Participants self-reported SB and MVPA and performed a maximal cycle ergometer test to estimate peak oxygen uptake at baseline (2002-2004) and follow-up (2012-2014). Multiple linear regression and the product of coefficients method were used to examine independent associations and mediation effects, respectively. RESULTS: Greater increase in SB was associated with more detrimental change in clustered cardiometabolic risk, waist circumference, HDL cholesterol and triglycerides, independently of change in MVPA. Greater decrease in MVPA was associated with greater decrease in HDL cholesterol and increase in clustered cardiometabolic risk, waist circumference and fasting glucose, independent of change in SB. Greater decrease in CRF was associated with more detrimental change in clustered cardiometabolic risk and all individual components. Change in CRF mediated the associations of change in SB and MVPA with change in clustered cardiometabolic risk, waist circumference and, only for MVPA, HDL cholesterol. Change in waist circumference mediated the associations between change in CRF and change in clustered cardiometabolic risk, fasting glucose, HDL cholesterol and triglycerides. CONCLUSIONS: A combination of decreasing SB and increasing MVPA, resulting in positive change in CRF, is likely to be most beneficial towards cardiometabolic health. PMID- 27491780 TI - Forward genetic screen of human transposase genomic rearrangements. AB - BACKGROUND: Numerous human genes encode potentially active DNA transposases or recombinases, but our understanding of their functions remains limited due to shortage of methods to profile their activities on endogenous genomic substrates. RESULTS: To enable functional analysis of human transposase-derived genes, we combined forward chemical genetic hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT1) screening with massively parallel paired-end DNA sequencing and structural variant genome assembly and analysis. Here, we report the HPRT1 mutational spectrum induced by the human transposase PGBD5, including PGBD5 specific signal sequences (PSS) that serve as potential genomic rearrangement substrates. CONCLUSIONS: The discovered PSS motifs and high-throughput forward chemical genomic screening approach should prove useful for the elucidation of endogenous genome remodeling activities of PGBD5 and other domesticated human DNA transposases and recombinases. PMID- 27491781 TI - Kawasaki disease incidence at Chandigarh, North India, during 2009-2014. AB - The aim of this study was to estimate incidence of Kawasaki disease (KD) in Chandigarh, North India, during 2009-2014. Diagnosis of KD was based on American Heart Association guidelines. Records of all children diagnosed with KD below 15 years at a large tertiary care referral centre from North India for paediatric immunology were analysed from January 2009 to December 2014. Children residing in Chandigarh were identified. Incidence rates were calculated based on population of Chandigarh in National Census 2011. Methodology was similar to our previously reported study from 1994 to 2008. Incidence of KD in children below 5 was also computed. A total of 258 children were diagnosed to have KD. Of these, 54 (43 boys, 11 girls) resided in Chandigarh. Coronary artery abnormalities on echocardiography were noted in 6. Incidence rate varied between 1.11 (in 2012) and 4.71/100,000 children below 15 (in 2009). In children below 5, incidence rate varied between 1.0 (in 2012) and 9.1/100,000 (in 2009). Peak incidence of KD was in third year of life. There was clustering of cases in February, April, June and October with a nadir in July. While the overall number of KD cases has increased, the 2009-2014 Chandigarh incidence is comparable to our previous figures. Our study is based on hospitalized children with KD and may be missing patients diagnosed elsewhere but that number is likely to be small. Further, patients in whom the diagnosis has never been made would also be missed. Median age at diagnosis has reduced as compared to our previous study. This is probably a reflection of increased awareness about KD amongst paediatricians and physicians in the region as a result of which the proportion of infants and young children diagnosed to have KD has shown a significant increase. Seasonal pattern of occurrence of KD is consistent with our previous observation. PMID- 27491782 TI - Safety and efficacy of a novel linear staple device with bioabsorbable polyglicolic acid felt in laparoscopic colorectal surgery. AB - INTRODUCTION: Laparoscopic surgery is widely used for the treatment of colorectal cancer, but it is often associated with postoperative anastomotic complications. Generally, gastrointestinal anastomosis for colorectal surgery is performed using mechanical anastomosis with a double stapling technique. Using the automatic suture device with bioabsorbable polyglycolic acid (PGA) felt is expected to adequately reinforce staple lines on fragile tissue, helping to prevent anastomotic complications, including leakage. METHODS: This study included 17 patients who underwent laparoscopic surgery after a diagnosis of colorectal cancer. The rectosigmoidal colon was resected toward the dentate line with a novel automatic PGA-felt suture device. RESULTS: None of the patients had any postoperative bleeding, and none developed grade III or higher postoperative complications based on the Clavien-Dindo classification. When the sigmoid colon, rectosigmoid, or rectum was anastomosed, holding the excess portion of the PGA felt, stapled with the automatic PGA-felt suture device, allowed us to adequately maneuver the part of the colon or rectum to be anastomosed. With this technique, we could easily and safely insert and remove the automatic anastomotic device. When the lower rectum was resected in a planned, two-step operation, the orientation of the PGA felt helped to determine the direction in which the automatic suture device was to be inserted in the second step. Thus, the resected rectum could easily be stapled in a straight line. CONCLUSION: The automatic PGA felt suture device is safe and effective for colorectal resections and anastomoses. PMID- 27491783 TI - Gastroesophageal Junction Tumors. PMID- 27491784 TI - Utility of Clinical Breast Examinations in Detecting Local-Regional Breast Events After Breast-Conservation in Women with a Personal History of High-Risk Breast Cancer. AB - BACKGROUND: Although breast cancer follow-up guidelines emphasize the importance of clinical examinations, prior studies suggest a small fraction of local regional events occurring after breast conservation are detected by examination alone. Our objective was to examine how local-regional events are detected in a contemporary, national cohort of high-risk breast cancer survivors. METHODS: A stage-stratified sample of stage II/III breast cancer patients diagnosed in 2006 2007 (n = 11,099) were identified from 1217 facilities within the National Cancer Data Base. Additional data on local-regional and distant breast events, method of event detection, imaging received, and mortality were collected. We further limited the cohort to patients with breast conservation (n = 4854). Summary statistics describe local-regional event rates and detection method. RESULTS: Local-regional events were detected in 5.5 % (n = 265) of patients. Eighty-three percent were ipsilateral or contralateral in-breast events, and 17 % occurred within ipsilateral lymph nodes. Forty-eight percent of local-regional events were detected on asymptomatic breast imaging, 29 % by patients, and 10 % on clinical examination. Overall, 0.5 % of the 4854 patients had a local-regional event detected on examination. Examinations detected a higher proportion of lymph node events (8/45) compared with in-breast events (18/220). No factors were associated with method of event detection. DISCUSSION: Clinical examinations, as an adjunct to screening mammography, have a modest effect on local-regional event detection. This contradicts current belief that examinations are a critical adjunct to mammographic screening. These findings can help to streamline follow-up care, potentially improving follow-up efficiency and quality. PMID- 27491785 TI - Primary Extremity Soft Tissue Sarcomas: Does Local Control Impact Survival? AB - BACKGROUND: The objective of this study was to evaluate the adequate margin in the local treatment of extremity soft tissue sarcomas (ESTS) and understand the relationship between local control and overall survival (OS). METHODS: All consecutive patients treated for a primary ESTS at a single center from 1993 to 2012 were reviewed. RESULTS: In all, 531 patients were included. Twelve (2 %) underwent a first-line amputation. The resections were R0/R1/not available in 434 (82 %), 92 (17 %), and 5 patients (1 %). The median tumor size was 8 cm, and the tumor grades were 1 (n = 132), 2 (n = 201), and 3 (n = 195). The median size of the minimal margin was 2 mm on fixed specimen. Preop or postop chemotherapy was administered to 222 patients, and 414 received radiotherapy. With a median follow up period of 7 years, the 5-year actuarial local recurrence (LR) rate and OS were 8 % (95 % CI, 6-11 %) and 80 % (95 % CI, 76-83 %). Predictors of worse OS were grade 3, leiomyosarcoma, male gender, and age >60 years, whereas tumor size, margin status, and LR were not. Among patients requiring re-excision (n = 252), the presence of residual cells correlated with OS but not LR. After preoperative treatment, a percentage of residual cells >=10 % correlated with OS but not LR. In the multivariate analysis, specific subtypes (epithelioid sarcoma and myxofibrosarcoma) and margin size <1 mm correlated with LR, whereas grade and the tissue constituting the surgical margins did not. CONCLUSIONS: Specific subtypes and surgical margin size <1 mm were correlated with a higher LR. Neither the margin status nor LR affect OS. PMID- 27491787 TI - Iron(III)-Catalyzed Ring-Closing Carbonyl-Olefin Metathesis. AB - Recent developments in catalytic carbonyl-olefin metathesis are summarized in this Highlight. Schindler and co-workers have reported that the environmentally benign FeCl3 catalyst promotes ring-closing carbonyl-olefin metathesis (RCCOM) in high yield under very mild conditions. PMID- 27491788 TI - [Not Available]. PMID- 27491786 TI - Thalamus Degeneration and Inflammation in Two Distinct Multiple Sclerosis Animal Models. AB - There is a broad consensus that multiple sclerosis (MS) represents more than an inflammatory disease: it harbors several characteristic aspects of a classical neurodegenerative disorder, i.e., damage to axons, synapses, and nerve cell bodies. While several accepted paraclinical methods exist to monitor the inflammatory-driven aspects of the disease, techniques to monitor progression of early and late neurodegeneration are still in their infancy and have not been convincingly validated. It was speculated that the thalamus with its multiple reciprocal connections is sensitive to inflammatory processes occurring in different brain regions, thus acting as a "barometer" for diffuse brain parenchymal damage in MS. To what extent the thalamus is affected in commonly applied MS animal models is, however, not known. In this article we describe direct and indirect damage to the thalamus in two distinct MS animal models. In the cuprizone model, we observed primary oligodendrocyte stress which is followed by demyelination, microglia/astrocyte activation, and acute axonal damage. These degenerative cuprizone-induced lesions were found to be more severe in the lateral compared to the medial part of the thalamus. In MOG35-55-induced EAE, in contrast, most parts of the forebrain, including the thalamus were not directly involved in the autoimmune attack. However, important thalamic afferent fiber tracts, such as the spinothalamic tract were inflamed and demyelinated on the spinal cord level. Quantitative immunohistochemistry revealed that this spinal cord inflammatory-demyelination is associated with neuronal loss within the target region of the spinothalamic tract, namely the sensory ventral posterolateral nucleus of the thalamus. This study highlights the possibility of trans-neuronal degeneration as one mechanism of secondary neuronal damage in MS. Further studies are now warranted to investigate involved cell types and cellular mechanisms. PMID- 27491789 TI - Defining Known Drug Space Using DFT. AB - A density functional theory (DFT) study was performed on a collection of clinically approved drugs, or Known Drug Space (KDS), to determine the statistical distribution of four properties: dipole moment (DM), polarisability (POL), ionisation potential (IP) and electron affinity (EA). The DM and POL are linked to cell permeability of drugs whereas IP and EA reflect their redox stability thus ease of metabolism. A benchmarking exercise showed a good correlation between experimental values and their predicted counterparts. It was found that KDS occupies the volume of chemical space defined by: DM<=10 D, POL<=68 A(3) , IP 6.0-9.0 V and EA-1.5-2.0 eV. Only 16 % of the drugs are outside one or more of these parameters. Three categories based on known oral absorption and bioavailability (low/medium/high) were established and compared. Predominately, drugs designated as 'low' were found outside the established parameters. The properties were compared with mainstream molecular descriptors and a strong correlation was seen for POL to MW (r(2) =0.899), which can explain the success of the latter since POL reflects the ability of molecules to interact with polar and non-polar environments such as water and interior of a membrane. PMID- 27491790 TI - The Comparison of the Combined Toxicity between Gram-negative and Gram-positive Bacteria: a Case Study of Antibiotics and Quorum-sensing Inhibitors. AB - Quorum-sensing inhibitors (QSIs) are being used increasingly in diverse fields, and are likely to end up in the environment, where they may encounter the antibiotics and consequently cause joint effects on biological systems. However, the potential joint effects of QSIs and antibiotics have received little attention. In this study, the joint effects of antibiotics, represented by sulfonamides (SAs) and penicillin, as well as three potential QSIs, were investigated using both Gram-negative (Escherichia coli, E. coli) and Gram positive bacteria (Bacillus subtilis, B. subtilis). It was found that E. coli tend to be more sensitive to the individual drugs than B. subtilis, whereas the joint effects on the two bacteria showed no difference regarding the same combination of antibiotics and QSIs. In general, SAs presented additive effects with gamma-Valerolactone and 2-Pyrrolidinone, but antagonistic effects with L-(+) Prolinol; penicillin exhibited antagonistic effects with all three QSIs. Moreover, it was found that the rate of resistance in E. coli against the individual antibiotics was reduced through the addition of the QSIs, which suggests a promising use of the QSIs in the bacterial infection treatment. This study also offers a valuable reference for the risk assessment of the antibiotics and QSIs in the real environment. PMID- 27491791 TI - Machine Learning Estimation of Atom Condensed Fukui Functions. AB - To enable the fast estimation of atom condensed Fukui functions, machine learning algorithms were trained with databases of DFT pre-calculated values for ca. 23,000 atoms in organic molecules. The problem was approached as the ranking of atom types with the Bradley-Terry (BT) model, and as the regression of the Fukui function. Random Forests (RF) were trained to predict the condensed Fukui function, to rank atoms in a molecule, and to classify atoms as high/low Fukui function. Atomic descriptors were based on counts of atom types in spheres around the kernel atom. The BT coefficients assigned to atom types enabled the identification (93-94 % accuracy) of the atom with the highest Fukui function in pairs of atoms in the same molecule with differences >=0.1. In whole molecules, the atom with the top Fukui function could be recognized in ca. 50 % of the cases and, on the average, about 3 of the top 4 atoms could be recognized in a shortlist of 4. Regression RF yielded predictions for test sets with R(2) =0.68 0.69, improving the ability of BT coefficients to rank atoms in a molecule. Atom classification (as high/low Fukui function) was obtained with RF with sensitivity of 55-61 % and specificity of 94-95 %. PMID- 27491792 TI - Predictive Models for Halogen-bond Basicity of Binding Sites of Polyfunctional Molecules. AB - Halogen bonding (XB) strength assesses the ability of an electron-enriched group to be involved in complexes with polarizable electrophilic halogenated or diatomic halogen molecules. Here, we report QSPR models of XB of particular relevance for an efficient screening of large sets of compounds. The basicity is described by pKBI2 , the decimal logarithm of the experimental 1 : 1 (B : I2 ) complexation constant K of organic compounds (B) with diiodine (I2 ) as a reference halogen-bond donor in alkanes at 298 K. Modeling involved ISIDA fragment descriptors, using SVM and MLR methods on a set of 598 organic compounds. Developed models were then challenged to make predictions for an external test set of 11 polyfunctional compounds for which unambiguous assignment of the measured effective complexation constant to specific groups out of the putative acceptor sites is not granted. At this stage, developed models were used to predict pKBI2 of all putative acceptor sites, followed by an estimation of the predicted effective complexation constant using the ChemEqui program. The best consensus models perform well both in cross-validation (root mean squared error RMSE=0.39-0.47 logKBI2 units) and external predictions (RMSE=0.49). The SVM models are implemented on our website (http://infochim.u strasbg.fr/webserv/VSEngine.html) together with the estimation of their applicability domain and an automatic detection of potential halogen-bond acceptor atoms. PMID- 27491793 TI - Pharmacophore-Map-Pick: A Method to Generate Pharmacophore Models for All Human GPCRs. AB - GPCR-based drug discovery is hindered by a lack of effective screening methods for most GPCRs that have neither ligands nor high-quality structures. With the aim to identify lead molecules for these GPCRs, we developed a new method called Pharmacophore-Map-Pick to generate pharmacophore models for all human GPCRs. The model of ADRB2 generated using this method not only predicts the binding mode of ADRB2-ligands correctly but also performs well in virtual screening. Findings also demonstrate that this method is powerful for generating high-quality pharmacophore models. The average enrichment for the pharmacophore models of the 15 targets in different GPCR families reached 15-fold at 0.5 % false-positive rate. Therefore, the pharmacophore models can be applied in virtual screening directly with no requirement for any ligand information or shape constraints. A total of 2386 pharmacophore models for 819 different GPCRs (99 % coverage (819/825)) were generated and are available at http://bsb.kiz.ac.cn/GPCRPMD. PMID- 27491794 TI - Variable resistance to freezing and thawing of CD34-positive stem cells and lymphocyte subpopulations in leukapheresis products. AB - BACKGROUND AIMS: Leukapheresis products for hematopoietic stem cell transplantation can be cryopreserved for various indications. Although it is known that CD34(+) cells tolerate cryopreservation well, a significant loss of CD3(+) cells has been observed, which has been ascribed to several factors, including transport, storage conditions and granulocyte-colony stimulating factor (G-CSF) administration. METHODS: To assess the tolerance of CD34(+) cells and lymphocyte subpopulations for cryopreservation and thawing, the post-thaw recoveries of CD34(+) cells, CD3(+)CD4(+) cells, CD3(+)CD8(+) cells, CD19(+) cells and CD16(+)CD56(+) cells were determined in 90 cryopreserved apheresis products, among which 65 were from G-CSF-mobilized donors, and 34 from unrelated donors that underwent transport before cryopreservation at our center. A controlled rate freezer and 5% dimethyl sulfoxide were used for cryopreservation. RESULTS: We could detect statistically significant differences for CD34(+) cell recovery (93.0 +/- 20.7%) when compared to CD3(+)CD4(+) cell (83.1 +/- 15.4%, P = 0.014), and CD3(+)CD8(+) cell recovery (83.3 +/- 13.9%, P = 0.001). Similarly, CD19(+) cell recovery (98.6 +/- 15.1%) was higher than CD3(+)CD4(+) cell (P = 2.5 * 10(-7)) and CD3(+)CD8(+) cell recovery (P = 1.2 * 10(-8)). Post-thaw recovery rates of all cell populations were not impaired in G-CSF-mobilized products compared with non-mobilized products nor in unrelated compared with related donor products. DISCUSSION: Our data suggest a lower tolerance of CD3(+) cells for cryopreservation and demonstrate that freezing-thawing resistance thawing is cell specific and independent from other factors that affect post-thaw recovery of cryopreserved cells. Thus, a clinical consequence may be the monitoring of post thaw CD3(+) cell doses of cryopreserved products, such as donor lymphocyte infusions. PMID- 27491795 TI - Metabolic fate of adenine in red blood cells during storage in SAGM solution. AB - BACKGROUND: Red blood cells (RBCs) are routinely stored and transfused worldwide. Recently, metabolomics have shown that RBCs experience a three-phase metabolic decay process during storage, resulting in the definition of three distinct metabolic phenotypes, occurring between Days 1 and 10, 11 and 17, and 18 and 46. Here we use metabolomics and stable isotope labeling analysis to study adenine metabolism in RBCs. STUDY DESIGN AND METHODS: A total of 6 units were prepared in SAGM or modified additive solutions (ASs) containing 15 N5 -adenine. Three of them were spiked with 15 N5 -adenine on Days 10, 14, and 17 during storage. Each unit was sampled 10 times spanning Day 1 to Day 32. At each time point metabolic profiling was performed. RESULTS: We increased adenine concentration in the AS and we pulsed the adenine concentration during storage and found that in both cases the RBCs' main metabolic pathways were not affected. Our data clearly show that RBCs cannot consume adenine after 18 days of storage, even if it is still present in the storage solution. However, increased levels of adenine influenced S-adenosylmethionine metabolism. CONCLUSION: In this work, we have studied in detail the metabolic fate of adenine during RBC storage in SAGM. Adenine is one of the main substrates used by RBCs, but the metabolic shift observed during storage is not caused by an absence of adenine later in storage. The rate of adenine consumption strongly correlated with duration of storage but not with the amount of adenine present in the AS. PMID- 27491796 TI - TRPV4 mediates afferent pathways in the urinary bladder. A spinal c-fos study showing TRPV1 related adaptations in the TRPV4 knockout mouse. AB - The role of transient receptor potential vanilloid subtype 4 (TRPV4) channels in urinary bladder afferent neural pathways was investigated using spinal c-fos measurements in mice. Anesthetized wild type and TRPV4 knockout (-/-) mice underwent noxious bladder distention and treatment with either intravesical instillation with lipopolysaccharide (LPS), or the TRPV1 agonist resiniferatoxin (RTX), vehicle or an intraperitoneal injected TRPV4 antagonist (HC067047). Mice underwent paraformaldehyde perfusion for rapid fixation and L6-S1 spinal cord sections were removed followed by immunohistochemical staining for c-fos. A number of c-fos expressing neurons in the dorsal horns of L6-S1 spinal cord transections were quantified. Groups were compared using univariate ANOVA. Even with the absence of bladder inflammation on H&E, the TRPV4 -/- mice still have a significant twofold higher c-fos expression (n = 39, SD 2) after noxious bladder distention compared to wild type mice (n = 20, SD 3). A twofold increase in c-fos expression was observed after LPS treatment in wild types (n = 42, SD 5), but no increase was seen in TRPV4 -/- mice (n = 42, SD 2). After desensitization of primary afferent C-nerve fibers with RTX, c-fos expression in TRPV4-/- mice decreased significantly (threefold) (n = 12, SD 4). Results imply that TRPV4 channels are important for bladder afferent signaling. TRPV4 -/- mice bladders generate more noxious sensory output, which is predominantly mediated through TRPV1 expressing high threshold nerve fibers. This study reveals TRPV1 related adaptive changes in afferent pathways of the TRPV4 -/- mouse. We propose that this effect is caused by a congenital impairment of low threshold nerves that mediate normal bladder filling sensations. PMID- 27491798 TI - Development in attention functions and social processing: Evidence from the Attention Network Test. AB - According to the attention network approach, attention is best understood in terms of three functionally and neuroanatomically distinct networks - alerting, orienting, and executive attention. Recent findings showed that social information influences the efficiency of these networks in adults. Using some social and non-social variants of the Attentional Network Test (ANT), this study was aimed to evaluate the development of the three attention networks in childhood, also assessing the development of the ability to manage social or non social conflicting information. Sixty-six children (three groups of 6, 8, and 10 years of age) performed three variants of the original ANT, using fish, schematic, or real faces looking to the left or right as target and flanker stimuli. Results showed an improvement from 6 to 8 and 10 years of age in reaction time (RT) and accuracy, together with an improvement of executive control and a decrement in alerting. These developmental changes were not unique to social stimuli, and no differences were observed between social and no-social variants of the ANT. However, independently from the age of the children, a real face positively affected the executive control (as indexed by RTs) as compared to both a schematic face and a fish. Findings of this study suggest that attentional networks are still developing from 6 to 10 years of age and underline the importance of face information in modulating the efficiency of executive control. Statement of contribution What is already known? Younger children made more errors and slower reaction times (RTs) than older children, in line with the majority of the past selective attention studies. Younger children showed both greater conflict and alerting effect than older children. The prediction that younger children would display larger interference effects than older children was supported. What does this study add? Extending the findings observed in adults and children, independently from their age, demonstrated greater cognitive interference (i.e., slower RTs and higher percentage of errors to incongruent relative to congruent conditions) when fish and schematic faces were presented than when photographs of real faces were used as stimuli. Like adults, children have a greater ability in the control of social information as compared to non social information. These results seem to indicate that the ability to handle social conflicts proceeds in parallel with the ability to manage non-social conflicting information. PMID- 27491797 TI - Development and psychometric evaluation of a condom use self-efficacy measure in Spanish and English. AB - BACKGROUND: Condom self-efficacy is an important construct for HIV/STI prevention and intervention. A psychometrically sound measure of the self-efficacy for using condoms that has been designed for Hispanic women to respond in Spanish or English is needed. OBJECTIVES: The goal of this study was to develop and evaluate a brief self-report measure of condom use self-efficacy. METHODS: We developed a 15-item measure of condom use self-efficacy based on expert knowledge of measurement and HIV/STI prevention with Hispanic women using a translation-back translation approach. Participants were 320 Hispanic women from the Southeastern US. RESULTS: Internal consistency of the full measure was 92. A short form of the instrument with a subset of five items also had acceptable internal consistency, alpha = .80, and was significantly correlated with the full scale, rs = .93, p < .001. A single latent factor explained 9-48% of the variation in these items. Evidence of construct validity of the short form was provided by correlations of the scale with two self-report measures of condom use: rs = .34** with condom use, rs = .37** with condom use during vaginal sex. CONCLUSIONS: Either the full measure or the five-item measure could be used in studies where condom use is an important behavioral outcome, such as evaluating prevention interventions, with Hispanic women. Future studies should examine the performance of this measure with other groups, including Hispanic men and members of other ethnic and language groups. PMID- 27491800 TI - Fatal cobalt toxicity after total hip arthroplasty revision for fractured ceramic components. AB - CONTEXT: Post-arthroplasty metallosis, which refers to metallic corrosion and deposition of metallic debris in the periprosthetic soft tissues of the body, is an uncommon complication. Systemic cobalt toxicity post-arthroplasty is extremely rare. The few known fatal cases of cobalt toxicity appear to be a result of replacing shattered ceramic heads with metal-on-metal or metal-on-polyethylene implants. Friction between residual shards of ceramic and cobalt-chromium implants allows release of cobalt into the synovial fluid and bloodstream, resulting in elevated whole blood cobalt levels and potential toxicity. CASE DETAILS: This is a single patient chart review of a 60-year-old woman with prior ceramic-on-ceramic right total hip arthroplasty complicated by fractured ceramic components and metallosis of the joint. She underwent synovectomy and revision to a metal-on-polyethylene articulation. Ten months post-revision, she presented to the emergency department (ED) with right hip pain, dyspnea, worsening hearing loss, metallic dysgeusia, and weight loss. Chest CTA revealed bilateral pulmonary emboli (PE), and echocardiogram revealed new cardiomyopathy with global left ventricular hypokinesis with an ejection fraction (EF) of 35-40% inconsistent with heart strain from PE. Whole blood cobalt level obtained two days into her admission was 424.3 mcg/L and 24-h urine cobalt level was 4830.5 mcg/L. Although the patient initially clinically improved with regard to her PE and was discharged to home on hospital day 5, she returned 10 days later with a right hip dislocation and underwent closed reduction of the hip. The patient subsequently decompensated, developing cardiogenic shock, and respiratory failure. She went into pulseless electrical activity (PEA) and expired. Autopsy revealed an extensive metallic effusion surrounding the right hip prosthesis that tested positive for cobalt (41,000 mcg/L). There was also cobalt in the heart muscle tissue (2.5 mcg/g). A whole blood cobalt level obtained two days before she expired was 641.6 mcg/L. DISCUSSION: This is a case of fatal cobalt-induced cardiomyopathy in a patient whose ceramic components of a total hip arthroplasty fractured causing metallosis with worsening cobalt toxicity. We recommend that when a fractured device is revised with a prosthesis with cobalt-chromium components, whole blood and urine cobalt measurements should be obtained and periodically monitored to evaluate for rising concentrations. Providers should be aware of clinical signs and symptoms of cobalt toxicity in patients who have prostheses with cobalt-chromium components. If suspected, toxicology and orthopedics should be involved for possible chelation and removal of the prosthesis. PMID- 27491799 TI - Consciousness and cortical responsiveness: a within-state study during non-rapid eye movement sleep. AB - When subjects become unconscious, there is a characteristic change in the way the cerebral cortex responds to perturbations, as can be assessed using transcranial magnetic stimulation and electroencephalography (TMS-EEG). For instance, compared to wakefulness, during non-rapid eye movement (NREM) sleep TMS elicits a larger positive-negative wave, fewer phase-locked oscillations, and an overall simpler response. However, many physiological variables also change when subjects go from wake to sleep, anesthesia, or coma. To avoid these confounding factors, we focused on NREM sleep only and measured TMS-evoked EEG responses before awakening the subjects and asking them if they had been conscious (dreaming) or not. As shown here, when subjects reported no conscious experience upon awakening, TMS evoked a larger negative deflection and a shorter phase-locked response compared to when they reported a dream. Moreover, the amplitude of the negative deflection a hallmark of neuronal bistability according to intracranial studies-was inversely correlated with the length of the dream report (i.e., total word count). These findings suggest that variations in the level of consciousness within the same physiological state are associated with changes in the underlying bistability in cortical circuits. PMID- 27491801 TI - In vivo imaging of DNA double-strand break induced telomere mobility during alternative lengthening of telomeres. AB - Repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) requires mobilization of chromatin for homology searches that allow interaction of the sequence to be repaired and its template DNA. Here we describe a system to rapidly induce DSBs at telomeres and track their movement, as well as a semi automated workflow for quantitative analysis. We have successfully used this approach to show that DSBs targeted to telomeres in cells utilizing the alternative lengthening of telomeres (ALT) mechanism increase their diffusion and subsequent long-range directional movement to merge with telomeres on other chromosomes. These methods are simple to implement and are compatible with almost any cell line or in vivo microscopy setup. The magnitude of DSB-induced telomere mobility allows the investigator to easily test for factors regulating telomere mobility during ALT. PMID- 27491802 TI - Lens opacity detection for serious posterior subcapsular cataract. AB - Cataract leads to visual impairment. Among different types of cataract, posterior subcapsular cataract (PSC) can develop rapidly and surgery is usually needed. An approach to detect PSC opacities in retro-illumination images is proposed. Watershed and Markov random fields (MRF) method are employed to opacities in anterior retro-illumination images. It results in a mixture of PSC, cortical opacities and noise. Then, information in both anterior and posterior retro illumination images is utilized. Two features are extracted to identify PSC: mean gradient comparison (MGC) between anterior and posterior retro-illumination images, and spatial location. This is the first time that comparison between anterior and posterior retro-illumination images is proposed and MGC is proposed as the feature of comparison in PSC detection. Experiments show that the sensitivity and specificity of PSC screening is 91.2 and 90.1 %, respectively, based on the 519 pairs of testing images. To the best of our knowledge, it is the best performance reported in automatic detection of PSC. Compared with the methods in the literatures, considerable improvement is achieved when there are large areas of PSC opacities. PMID- 27491803 TI - Finite element model of the impaction of a press-fitted acetabular cup. AB - Press-fit surgical procedures aim at providing primary stability to acetabular cup (AC) implants. Impact analysis constitutes a powerful approach to retrieve the AC implant insertion properties. The aim of this numerical study was to investigate the dynamic interaction occurring between the hammer, the ancillary and bone tissue during the impact and to assess the potential of impact analysis to retrieve AC implant insertion conditions. A dynamic two-dimensional axisymmetric model was developed to simulate the impaction of the AC implant into bone tissue assuming friction at the bone-implant interface and large deformations. Different values of interference fit (from 0.5 to 2 mm) and impact velocities (from 1 to 2 m.s-1) were considered. For each configuration, the variation of the force applied between the hammer and the ancillary was analyzed and an indicator I was determined based on the impact momentum of the signal. The simulated results are compared to the experiments. The value of the polar gap decreases with the impact velocity and increases with the interference fit. The bone-implant contact area was significantly correlated with the resonance frequency (R 2 = 0.94) and the indicator (R 2 = 0.95). The results show the potential of impact analyses to retrieve the bone-implant contact properties. PMID- 27491804 TI - Study of a water-soluble fluorescent sensor based on the Eu(III) pefloxacin complex. AB - The antibiotic type organic structure pefloxacin binds well with europium (III) ions as a useful scaffold for assembling optical probes and allows energy transfer from ligand to metal ions through coordination linkages. This water soluble chemosensor demonstrated significant 'off-on (red)' changes from an alkaline to a neutral environment (pH 14-8). The emission changed from red to blue under acidic conditions (pH 7-2). The whole process was completely reversible and effective within the pH range 2 to 14. Moreover, this probe system exhibited distinct luminescence quenching upon the addition of Cu2+ or Fe3+ . This general modular route will permit easy detection and the concept can be extended to a variety of quinolones for sensing purposes. PMID- 27491805 TI - Distribution of inflammation and association between active and chronic alterations within the endometrium of dairy cows. AB - Objectives of this study were twofold: (i) to assess the association between polymorphonuclear (PMN) counts and chronic alterations within the bovine endometrium and (ii) to determine the distribution of inflammation throughout the endometrium of clinically healthy dairy cows. Holstein-Friesian cows (n = 32) from a single dairy farm were selected for this experiment. Before slaughtering, a complete reproductive examination was performed to discard any type of clinical disease. After slaughtering, reproductive tracts were collected, and the endometrium was sampled at 8 pre-defined locations. At each location, endometrial biopsies (EBs) and cytology (CY) samples were harvested. Histopathology samples were stained with haematoxylin-eosin (EB-HE) and naphthol-AS-D-chloroacetate esterase (EB-naphthol), while CY samples were stained with Wright-Giemsa. In the EB-HE samples, parameters assessed were epithelium height, mononuclear cells infiltration, lymphocytic aggregates, periglandular fibrosis, angiosclerosis and haemorrhage. In EB-naphthol and CY slides, PMNs counts were evaluated. Binomial logistic regression was used to assess the association between the number of PMNs present in both the EB-naphthol and CY samples and alterations identified in the EB-HE samples and to analyse the distribution of the histopathological alterations (EB-HE). A Poisson mixed-effect model was used to analyse the distribution of PMNs within the endometrium. A significant positive association was found between the PMN counts and the mononuclear cells infiltration. The presence of erythrocytes was associated with higher odds to detect PMNs in the stratum compactum. Significantly, higher infiltration of PMNs and mononuclear cells were detected in the uterine body and the right horn region. Concluding, CY is a technique that allows the evaluation of PMN counts and therefore only evaluates active inflammation. A complete assessment of endometrial health can only be obtained using EB. To optimize the sensitivity to diagnose endometrial inflammation in cows, adjacencies of the corpus uteri should be considered as the preferred region to harvest samples. PMID- 27491806 TI - Promoting women's health in an era of globalization: a South Asian perspective. AB - Promoting the health of women requires an understanding of the full range of factors shaping their health, including globalization. Focusing on South Asia, I outline some of the critical global women's health issues that warrant further attention by health promotion researchers. I discuss the inadequacy of international approaches for improving the health of South Asian women, occupational health hazards associated with global industries targeting women, new forms of gender based violence, gendered ethical challenges arising as global and local forces collide and the rise of transnational feminist networks that can be harnessed for advancing women's health across the region. PMID- 27491807 TI - The Latin America and the Caribbean search strategy proposal. AB - Latin America and the Caribbean's public health literature is not widely recognized. Science in this region has even been compared to a night sky with just a few specks of light. To make those lights as reachable as possible, we developed the Latin America and the Caribbean Search Strategy (LACSS). This is a new method to utilize our region's health promotion results within MEDLINE/PubMed. In contrast to a typical MeSH query, LACSS retrieves up to six times more publication results regarding non-communicable diseases, neglected tropical diseases, injuries and other important public health relevant topics in the region. We believe that global health promotion will be improved in this region by improving its visibility, and this search strategy will contribute to this. PMID- 27491808 TI - The proposal of philosophical basis of the health care system. AB - The studies of health care systems are conducted intensively on various levels. They are important because the systems suffer from numerous pathologies. The health care is analyzed, first of all, in economic aspects but their functionality in the framework of systems theory is studied, as well. There are also attempts to work out some general values on which health care systems should be based. Nevertheless, the aforementioned studies, however, are fragmentary ones. In this paper holistic approach to the philosophical basis of health care is presented. The levels on which the problem can be considered are specified explicitly and relations between them are analyzed, as well. The philosophical basis on which the national health care systems could be based is proposed. Personalism is the basis for the proposal. First of all, the values, that are derived from the personalistic philosophy, are specified as the basic ones for health care systems. Then, general organizational and functional properties of the system are derived from the assumed values. The possibility of adaptation of solutions from other fields of social experiences are also mentioned. The existing health care systems are analyzed within the frame of the introduced proposal. PMID- 27491809 TI - Genetic events in the progression of adenoid cystic carcinoma of the breast to high-grade triple-negative breast cancer. AB - Adenoid cystic carcinoma of the breast is a rare histological type of triple negative breast cancer with an indolent clinical behavior, often driven by the MYB-NFIB fusion gene. Here we sought to define the repertoire of somatic genetic alterations in two adenoid cystic carcinomas associated with high-grade triple negative breast cancer. The different components of each case were subjected to copy number profiling and massively parallel sequencing targeting all exons and selected regulatory and intronic regions of 488 genes. Reverse transcription PCR and fluorescence in situ hybridization were employed to investigate the presence of the MYB-NFIB translocation. The MYB-NFIB fusion gene was detected in both adenoid cystic carcinomas and their associated high-grade triple-negative breast cancer components. Although the distinct components of both cases displayed similar patterns of gene copy number alterations, massively parallel sequencing analysis revealed intratumor genetic heterogeneity. In case 1, progression from the trabecular adenoid cystic carcinoma to the high-grade triple-negative breast cancer was found to involve clonal shifts with enrichment of mutations affecting EP300, NOTCH1, ERBB2 and FGFR1 in the high-grade triple-negative breast cancer. In case 2, a clonal KMT2C mutation was present in the cribriform adenoid cystic carcinoma, solid adenoid cystic carcinoma and high-grade triple-negative breast cancer components, whereas a mutation affecting MYB was present only in the solid and high-grade triple-negative breast cancer areas and additional three mutations targeting STAG2, KDM6A and CDK12 were restricted to the high-grade triple negative breast cancer. In conclusion, adenoid cystic carcinomas of the breast with high-grade transformation are underpinned by the MYB-NFIB fusion gene and, akin to other forms of cancer, may be constituted by a mosaic of cancer cell clones at diagnosis. The progression from adenoid cystic carcinoma to high-grade triple-negative breast cancer of no special type may involve the selection of neoplastic clones and/or the acquisition of additional genetic alterations. PMID- 27491810 TI - Molecular genetic heterogeneity in undifferentiated endometrial carcinomas. AB - Undifferentiated and dedifferentiated endometrial carcinomas are rare and highly aggressive subtypes of uterine cancer, not well characterized at a molecular level. To investigate whether dedifferentiated carcinomas carry molecular genetic alterations similar to those of pure undifferentiated carcinomas, and to gain insight into the pathogenesis of these tumors, we selected a cohort of 18 undifferentiated endometrial carcinomas, 8 of them with a well-differentiated endometrioid carcinoma component (dedifferentiated endometrioid carcinomas), and studied them by immunohistochemistry and massive parallel and Sanger sequencing. Whole-exome sequencing of the endometrioid and undifferentiated components, as well as normal myometrium, was also carried out in one case. According to The Cancer Genome Atlas classification, we distributed 95% of the undifferentiated carcinomas in this series as follows: (a) hypermutated tumors with loss of any mismatch repair protein expression and microsatellite instability (eight cases, 45%); (b) ultramutated carcinomas carrying mutations in the exonuclease domain of POLE (two cases, 11%); (c) high copy number alterations (copy-number high) tumors group exhibiting only TP53 mutations and high number of alterations detected by FISH (two cases, 11%); and (d) low copy number alterations (copy-number low) tumors with molecular alterations typical of endometrioid endometrial carcinomas (five cases, 28%). Two of the latter cases, however, also had TP53 mutations and higher number of alterations detected by FISH and could have progressed to a copy number high phenotype. Most dedifferentiated carcinomas belonged to the hypermutated group, whereas pure undifferentiated carcinomas shared molecular genetic alterations with copy-number low or copy-number high tumors. These results indicate that undifferentiated and dedifferentiated endometrial carcinomas are molecularly heterogeneous tumors, which may have prognostic value. PMID- 27491811 TI - Survival of buffalo bull spermatozoa: effect on structure and function due to alpha-lipoic acid and cholesterol-loaded cyclodextrin. AB - Sperm survival depending upon integral membranes and function is imperative for fertilization. This study was designed to augment survival of buffalo spermatozoa using alpha-lipoic acid (ALA) and cholesterol-loaded cyclodextrin (CLC) during cryopreservation. Semen was frozen using 0, 0.5, 1, 1.5, 2 and 2.5 mmol L-1 ALA (experiment 1) and ALA or CLC separately or together (experiment 2). Semen was assessed for post-thaw motility, plasma membrane integrity (PMI), intact acrosome and plasma membrane (IACR-IPM) and DNA integrity at 0, 1.5, 3 and 4.5 hr of incubation. In experiment 1, use of 0.5 mmol L-1 ALA enhanced the sperm cryosurvival and post-thaw longevity than other groups up to 4.5 hr of incubation, and this concentration of ALA was used in second experiment with CLC. The results revealed higher (p < .05) sperm survival function and time of sperm attributes due to use of ALA than CLC and control. However, the sperm quality did not improve (p > .05) when ALA was combined with CLC. In conclusion, survival of buffalo bull spermatozoa during freeze-thawing and post-thaw incubation can be enhanced more with ALA than CLC or control, followed by CLC than control. However, there is no synergistic effect on survival of buffalo bull spermatozoa due to ALA and CLC. PMID- 27491812 TI - In Situ Calibration of a New Chemcatcher Configuration for the Determination of Polar Organic Micropollutants in Wastewater Effluent. AB - Passive sampling is proposed as an alternative to traditional grab- and composite sampling modes. Investigated here is a novel passive sampler configuration, the Chemcatcher containing an Atlantic HLB disk covered by a 0.2 MUm poly(ether sulfone) membrane, for monitoring polar organic micropollutants (personal care products, pharmaceuticals, and illicit drugs) in wastewater effluent. In situ calibration showed linear uptake for the majority of detected micropollutants over 9 days of deployment. Sampling rates (RS) were determined for 59 compounds and were generally in the range of 0.01-0.10 L day(-1). The Chemcatcher was also suitable for collecting chiral micropollutants and maintaining their enantiomeric distribution during deployment. This is essential for their future use in developing more accurate environmental risk assessments at the enantiomeric level. Application of calibration data in a subsequent monitoring study showed that the concentration estimated for 92% of micropollutants was within a factor of 2 of the known concentration. However, their application in a legislative context will require further understanding of the properties and mechanisms controlling micropollutant uptake to improve the accuracy of reported concentrations. PMID- 27491813 TI - Fusarium and mycotoxin spectra in Swiss barley are affected by various cropping techniques. AB - Fusarium head blight is one of the most important cereal diseases worldwide. Cereals differ in terms of the main occurring Fusarium species and the infection is influenced by various factors, such as weather and cropping measures. Little is known about Fusarium species in barley in Switzerland, hence harvest samples from growers were collected in 2013 and 2014, along with information on respective cropping factors. The incidence of different Fusarium species was obtained by using a seed health test and mycotoxins were quantified by LC-MS/MS. With these techniques, the most dominant species, F. graminearum, and the most prominent mycotoxin, deoxynivalenol (DON), were identified. Between the three main Swiss cropping systems, Organic, Extenso and Proof of ecological performance, we observed differences with the lowest incidence and toxin accumulation in organically cultivated barley. Hence, we hypothesise that this finding was based on an array of growing techniques within a given cropping system. We observed that barley samples from fields with maize as previous crop had a substantially higher F. graminearum incidence and elevated DON accumulation compared with other previous crops. Furthermore, the use of reduced tillage led to a higher disease incidence and toxin content compared with samples from ploughed fields. Further factors increasing Fusarium infection were high nitrogen fertilisation as well as the application of fungicides and growth regulators. Results from the current study can be used to develop optimised cropping systems that reduce the risks of mycotoxin contamination. PMID- 27491815 TI - Examining the interaction between cognitive control and reward sensitivity in substance use dependence. AB - BACKGROUND: Drug dependence is characterized by altered reward processing and poor cognitive control, expressed as a preference for immediate rewards and impaired inhibitory control, respectively. To examine the interaction between reward processing (via the presence or absence of reward) and mechanisms of inhibitory control in drug dependence, the current study used the Monetary Incentive Control Task (MICT) to examine whether a group of opiate dependent persons demonstrated greater difficulty exerting control over immediate rewards compared to neutral stimuli. METHODS: The MICT is a Go/Stop paradigm that examines inhibitory control over immediate rewards. Performance of 32 opiate dependent individuals was compared to 29 healthy controls. RESULTS: Opiate users demonstrated poorer inhibitory performance than controls, irrespective of cues signaling immediate reward. Whereas control participants' responses were modulated by probability cues, the opiate group did not show a capacity to up regulate their cognitive control performance. CONCLUSIONS: The present results suggest a general decrease in cognitive control in opiate dependence, accompanied by a reduced ability to optimally modulate behavior in accordance with external cues. Opiate users and controls did not differ in the interaction between cognitive control and reward. The study highlights important issues for future research to consider when further examining this interaction in drug dependence. PMID- 27491816 TI - Prevalence of at-risk drinking among Brazilian truck drivers and its interference on the performance of executive cognitive tasks. AB - BACKGROUND: Binge drinking (BD) has been associated with an increase in the risk of alcohol-related injuries. Alcohol continues to be the main substance consumed by truck drivers, a population of special concern, since they are often involved in traffic accidents. The aim of this study was to estimate the prevalence of BD and its interference in the executive functioning among truck drivers in Sao Paulo, Brazil. METHODS: A non-probabilistic sample of 684 truck drivers was requested to answer a structured research instrument on their demographic data and alcohol use. They performed cognitive tests to assess their executive functioning and inventories about confounding variables. The participants were then divided according to their involvement in BD. RESULTS: 17.5% of the interviewees have reported being engaged in BD. Binge drinkers showed a better performance on one test, despite having done so at the expense of more mistakes and lower accuracy. More interestingly, binge drinkers took three seconds longer than non-binge drinkers to inhibit an inadequate response, which is worrisome in the context of traffic. Overall, the deleterious effect of BD on performance remained after controlling for the effects of confounding variables in regression logistic models. CONCLUSIONS: As the use of alcohol among truck drivers may be as a way to get by with their work conditions, we believe that a negotiation between their work organization and public authorities would reduce such use, preventing negative interferences on truck drivers' cognitive functioning, which by its turn may also prevent traffic accidents. PMID- 27491814 TI - Vagal nerve stimulation improves mitochondrial dynamics via an M3 receptor/CaMKKbeta/AMPK pathway in isoproterenol-induced myocardial ischaemia. AB - Mitochondrial dynamics-fission and fusion-are associated with ischaemic heart disease (IHD). This study explored the protective effect of vagal nerve stimulation (VNS) against isoproterenol (ISO)-induced myocardial ischaemia in a rat model and tested whether VNS plays a role in preventing disorders of mitochondrial dynamics and function. Isoproterenol not only caused cardiac injury but also increased the expression of mitochondrial fission proteins [dynamin related peptide1 (Drp1) and mitochondrial fission protein1 (Fis-1)) and decreased the expression of fusion proteins (optic atrophy-1 (OPA1) and mitofusins1/2 (Mfn1/2)], thereby disrupting mitochondrial dynamics and leading to increase in mitochondrial fragments. Interestingly, VNS restored mitochondrial dynamics through regulation of Drp1, Fis-1, OPA1 and Mfn1/2; enhanced ATP content and mitochondrial membrane potential; reduced mitochondrial permeability transition pore (MPTP) opening; and improved mitochondrial ultrastructure and size. Furthermore, VNS reduced the size of the myocardial infarction and ameliorated cardiomyocyte apoptosis and cardiac dysfunction induced by ISO. Moreover, VNS activated AMP-activated protein kinase (AMPK), which was accompanied by phosphorylation of Ca2+ /calmodulin-dependent protein kinase kinase beta (CaMKKbeta) during myocardial ischaemia. Treatment with subtype-3 of muscarinic acetylcholine receptor (M3 R) antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide or AMPK inhibitor Compound C abolished the protective effects of VNS on mitochondrial dynamics and function, suggesting that M3 R/CaMKKbeta/AMPK signalling are involved in mediating beneficial effects of VNS. This study demonstrates that VNS modulates mitochondrial dynamics and improves mitochondrial function, possibly through the M3 R/CaMKKbeta/AMPK pathway, to attenuate ISO induced cardiac damage in rats. Targeting mitochondrial dynamics may provide a novel therapeutic strategy in IHD. PMID- 27491818 TI - In a tertiary maternity hospital, when should a paediatrician be present in the delivery room? AB - OBJECTIVE: 10% of newborns require positive pressure ventilation (PPV) at birth. There are few data on prenatal or early postnatal factors that are predictive of the need for a paediatrician in the delivery room. The study analysed prenatal obstetric and early postnatal factors associated with the requirement for paediatrician assistance in this setting. METHODS: Over a three-month period, all consecutive births in a tertiary hospital's maternity unit were prospectively evaluated with regard to the need for paediatrician assistance (requested either before or after the delivery), the requirement for resuscitation, and transfer to a neonatal intensive care unit (NICU). RESULTS: For a total of 584 consecutive births, paediatrician assistance was requested before delivery in 170 cases (30.5%) and after in 78 cases (13.3%). 78% of the newborns requiring PPV, 95.8% of those requiring endotracheal intubation and 86.3% of those requiring transfer to the NICU matched recently published prenatal criteria for paediatrician assistance. Along with a low Apgar score and a cord blood pH <7.20, these criteria covered 95% of the prenatal and early postnatal requests for paediatrician assistance. CONCLUSIONS: These criteria for neonatal resuscitation in the delivery room would enable medical staff to anticipate the need for paediatrician assistance. PMID- 27491817 TI - Age, period, and cohort effects in synthetic cannabinoid use among US adolescents, 2011-2015. AB - BACKGROUND: Synthetic cannabinoids use has been a public health concern given association with hospitalization and death among users. While national reports estimate that reported use is declining among adolescents, differences by birth cohort may indicate subgroups who remain at higher risk, both in the overall adolescent population and among demographic subgroups. METHODS: We estimated age, period, and cohort models of self-reported past-year synthetic cannabinoid use (queried as "synthetic marijuana" ["K2," "Spice"]) among 54,865 adolescents aged 13-19 attending high school from 2011 to 2015. RESULTS: Past-year use decreased from 11.86% in 2011 to 4.75% in 2015. This decrease was best represented as a linear downward trend. When stratified by key covariates, however, results indicated evidence of a positive cohort effect for students of higher socioeconomic status (SES). For those students, use did not decrease at the same rate as the overall population; younger cohorts of high SES students remain at higher risk for synthetic cannabinoid use than older cohorts as well as lower SES peers. A similar and stronger association was found for frequent marijuana users (>=20 occasions of past-year use). Multi-level models indicated that groups at highest risk included older adolescents, Hispanics and other/mixed race students, cigarette users, and frequent marijuana users. CONCLUSION: Synthetic cannabinoid use is associated with morbidity as well as mortality; continued attention to reducing synthetic cannabinoid use remains an important public health priority to maximizing student health. PMID- 27491819 TI - Development of a Web-based GIS monitoring and environmental assessment system for the Black Sea: application in the Danube Delta area. AB - In this paper, the development of a Web-based GIS system for the monitoring and assessment of the Black Sea is presented. The integrated multilevel system is based on the combination of terrestrial and satellite Earth observation data through the technological assets provided by innovative information tools and facilities. The key component of the system is a unified, easy to update geodatabase including a wide range of appropriately selected environmental parameters. The collection procedure of current and historical data along with the methods employed for their processing in three test areas of the current study are extensively discussed, and special attention is given to the overall design and structure of the developed geodatabase. Furthermore, the information system includes a decision support component (DSC) which allows assessment and effective management of a wide range of heterogeneous data and environmental parameters within an appropriately designed and well-tested methodology. The DSC provides simplified and straightforward results based on a classification procedure, thus contributing to a monitoring system not only for experts but for auxiliary staff as well. The examples of the system's functionality that are presented highlight its usability as well as the assistance that is provided to the decision maker. The given examples emphasize on the Danube Delta area; however, the information layers of the integrated system can be expanded in the future to cover other regions, thus contributing to the development of an environmental monitoring system for the entire Black Sea. PMID- 27491821 TI - Cobalt-catalyzed C-H olefination of aromatics with unactivated alkenes. AB - A cobalt-catalyzed C-H olefination of aromatic and heteroaromatic amides with unactivated alkenes, allyl acetates and allyl alcohols is described. This method offers an efficient route for the synthesis of vinyl and allyl benzamides in a highly stereoselective manner. It is observed that the ortho substituent on the benzamide moiety is crucial for the observation of allylated products in unactivated alkenes. PMID- 27491820 TI - Annexin A4-nuclear factor-kappaB feedback circuit regulates cell malignant behavior and tumor growth in gallbladder cancer. AB - Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system. However, the mechanisms underlying its tumor initiation, progression, and metastasis are not yet fully understood. The annexin A4 (ANXA4) gene is highly expressed in GBC tissues and may play an important role in the initiation and progression of this disease. In this study, we examined the up-regulation of ANXA4 in human GBC tissues and cell lines. Elevated ANXA4 correlated well with invasion depth in GBC patients and predicted a poor prognosis. In vitro, GBC-SD and NOZ cells with ANXA4 knockdown demonstrated increased apoptosis and inhibited cell growth, migration, and invasion. Interactions between ANXA4 and nuclear factor-kappaB (NF-kappaB) p65 proteins were detected. In vivo, ANXA4 knockdown inhibited tumor growth of GBC cells in nude mice and down-regulated the expression of downstream factors in the NF-kappaB signaling pathway. Taken together, these data indicate that up-regulation of ANXA4 leads to activation of the NF-kappaB pathway and its target genes in a feedback regulatory mechanism via the p65 subunit, resulting in tumor growth in GBC. PMID- 27491825 TI - Anatomy, histology and elemental profile of long bones and ribs of the Asian elephant (Elephas maximus). AB - This study evaluated the morphology and elemental composition of Asian elephant (Elephas maximus) bones (humerus, radius, ulna, femur, tibia, fibula and rib). Computerized tomography was used to image the intraosseous structure, compact bones were processed using histological techniques, and elemental profiling of compact bone was conducted using X-ray fluorescence. There was no clear evidence of an open marrow cavity in any of the bones; rather, dense trabecular bone was found in the bone interior. Compact bone contained double osteons in the radius, tibia and fibula. The osteon structure was comparatively large and similar in all bones, although the lacuna area was greater (P < 0.05) in the femur and ulna. Another finding was that nutrient foramina were clearly present in the humerus, ulna, femur, tibia and rib. Twenty elements were identified in elephant compact bone. Of these, ten differed significantly across the seven bones: Ca, Ti, V, Mn, Fe, Zr, Ag, Cd, Sn and Sb. Of particular interest was the finding of a significantly larger proportion of Fe in the humerus, radius, fibula and ribs, all bones without an open medullary cavity, which is traditionally associated with bone marrow for blood cell production. In conclusion, elephant bones present special characteristics, some of which may be important to hematopoiesis and bone strength for supporting a heavy body weight. PMID- 27491824 TI - Partying Last Weekend: Factors Related to Heavy Episodic Drinking Among People Who Use Recreational Drugs. AB - BACKGROUND: Heavy episodic drinking (HED) has negative consequences for both the individual and society. Research on HED has focused mainly on the general population while research into HED and other drug use among recreational drug using populations is less developed. OBJECTIVES: This study explores factors related to HED on a previous weekend among male and female recreational drug users. METHODS: Cross-sectional interviews were undertaken with those age 19+ who regularly use recreational drugs in a nightlife setting in two cities in Canada (n = 931) between 2008 and 2014. Participants were asked about their alcohol and other drug use the previous Friday or Saturday. Chi-square bivariate tests were used to determine factors significantly associated with HED with significant variables then entered into multivariate logistic regression models to determine related factors for men and women. RESULTS: Results showed that 53.4% of all participants met criteria for HED the previous weekend and the majority of those had used at least one other drug. Multivariate models showed being in postsecondary full-time, being between 19 and 25, using cocaine and using tobacco the previous weekend was associated with HED for men. For women, using cocaine the previous weekend was associated with HED, while being 26 and over, married or common law and using marijuana was associated with lower odds of HED. CONCLUSION: HED is common among recreational drug users but different factors were associated HED for men and women. Interventions for recreational drug users should include both alcohol and other drug messaging and be gender specific. PMID- 27491822 TI - Introduction of a prognostic biomarker to strengthen risk stratification of acutely admitted patients: rationale and design of the TRIAGE III cluster randomized interventional trial. AB - BACKGROUND: Several biomarkers have shown to carry prognostic value beyond current triage algorithms and may aid in initial risk stratification of patients in the emergency department (ED). It has yet to be established if information provided by biomarkers can be used to prevent serious complications or deaths. Our aim is to determine whether measurement of the blood level of the biomarker soluble urokinase plasminogen activator receptor (suPAR) can enhance early risk stratification leading to reduced mortality, lower rate of complications, and improved patient flow in acutely admitted adult patients at the ED. The main hypothesis is that the availability of suPAR can reduce all-cause mortality, assessed at least 10 months after admission, by drawing attention towards patients with an unrecognized high risk, leading to improved diagnostics and treatment. METHODS: The study is designed as a cross-over cluster randomized interventional trial. SuPAR is measured within 2 h after admission and immediately reported to the treating physicians in the ED. All ED physicians are educated in the prognostic capabilities of suPAR prior to the inclusion period. The inclusion period began January 11(th) 2016 and ends June 6(th) 2016. The study aims to include 10.000 patients in both the interventional and control arm. The results will be presented in 2017. DISCUSSION: The present article aims to describe the design and rationale of the TRIAGE III study that will investigate whether the availability of prognostic information can improve outcome in acutely admitted patients. This might have an impact on health care organization and decision-making. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov (ID NCT02643459 , November 13, 2015) and at the Danish Data Protection agency (ID HGH-2015-042 I-Suite no. 04087). PMID- 27491827 TI - Reference values and repeatability of the Schirmer tear tests I and II in domesticated, clinically normal dromedary camels (Camelus dromedarius). AB - OBJECTIVE: To determine the normal values and repeatability for Schirmer tear test (STT) in clinically normal dromedary camels and to analyze the influence of the age and gender on these values. ANIMALS STUDIED: Thirty clinically normal dromedary camels of different ages (calves, immature, and mature). PROCEDURES: Schirmer tear tests I and II were performed using commercial STT strips. Three measurements were obtained from each eye over three consecutive weeks, and the variance of these measurements was determined. RESULTS: Mean values and coefficient of variation of STT I and STT II for the right and left eyes varied significantly among camel groups (P < 0.05). For STT I, the most frequently recorded values were >14-18, > 22-26, and >30-34 mm/min in calves, immature camels, and mature camels, respectively. For STT II, however, the most frequently recorded values were 7-14, >10-18, and >26-30 mm/min, respectively. The interassay coefficients of variation were 1.7-14.4% and were significantly lower in mature camels than in calves and immature camels (P < 0.05). Age was positively correlated with STT I (r = 0.81) and STT II values (r = 0.88). No significant variations were found between genders. CONCLUSIONS: This preliminary study reports STT I and II values and repeatability in normal dromedary camels. This information may assist veterinary practitioners in complete ophthalmic examinations and in accurate diagnosis of ocular surface diseases affecting the tear film in this species. PMID- 27491826 TI - Simultaneous targeted activation of Notch1 and Vhl-disruption in the kidney proximal epithelial tubular cells in mice. AB - Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, representing approximately 75% of all renal neoplasms. ccRCC is known to be strongly associated with silencing of the von Hippel Lindau (VHL) tumor suppressor gene, yet VHL deficiency alone does not seem to be sufficient to drive the oncogenic transformation of normal renal epithelium and induce renal tumorigenesis. We, and others, have previously suggested that constitutive activation of the Notch signaling pathway, alongside with VHL loss, contribute to the oncogenic features of ccRCC. Here we report a prevailing hyperactivation of the Notch1 receptor in human ccRCC relative to the healthy counterpart. To explore the consequences of the elevated Notch1 signaling observed in ccRCC patient material, we made use of a conditional mouse model based on concurrent ectopic expression of constitutively active Notch1 (NICD1) and deletion of the Vhl gene. Histological examination of the kidneys of the conditional mice demonstrate the existence of nests of dysplastic cells with a clear cytoplasm as a consequence of lipid accumulation, thus displaying a one important hallmark of human ccRCC. PMID- 27491828 TI - HIV-1 Tat exacerbates lipopolysaccharide-induced cytokine release via TLR4 signaling in the enteric nervous system. AB - The loss of gut epithelium integrity leads to translocation of microbes and microbial products resulting in immune activation and drives systemic inflammation in acquired immunodeficiency syndrome (AIDS) patients. Although viral loads in HIV patients are significantly reduced in the post-cART era, inflammation and immune activation persist and can lead to morbidity. Here, we determined the interactive effects of the viral protein HIV-1 Tat and lipopolysaccharide (LPS) on enteric neurons and glia. Bacterial translocation was significantly enhanced in Tat-expressing (Tat+) mice. Exposure to HIV-1 Tat in combination with LPS enhanced the expression and release of the pro-inflammatory cytokines IL-6, IL-1beta and TNF-alpha in the ilea of Tat+ mice and by enteric glia. This coincided with enhanced NF-kappaB activation in enteric glia that was abrogated in glia from TLR4 knockout mice and by knockdown (siRNA) of MyD88 siRNA in wild type glia. The synergistic effects of Tat and LPS resulted in a reduced rate of colonic propulsion in Tat+ mice treated with LPS. These results show that HIV-1 Tat interacts with the TLR4 receptor to enhance the pro-inflammatory effects of LPS leading to gastrointestinal dysmotility and enhanced immune activation. PMID- 27491829 TI - Effects of multiple types of stigma on the probability of HIV disclosure to sex partners: a systematic review. AB - Previous review studies explored factors related to the process of HIV disclosure. However, none of these review studies specifically focused on the effects of stigma on HIV disclosure to sex partners. A comprehensive systematic review of empirical studies on the effects of stigma on HIV disclosure to sex partners was conducted until December 2014. Twenty-seven articles published in English-language journals were selected, and study characteristics and findings were evaluated. Inconsistent findings in the assessment of impacts of stigma on HIV disclosure to sex partners were documented. Three underlying plausible reasons were identified, and these included: (1) different types of stigma may have different effects on HIV disclosure to sex partners; (2) studies used different measurement strategies; and (3) varied personal backgrounds and health factors that can mitigate, facilitate or moderate the effect of stigma on HIV disclosure to sex partners. Studies with precise definition measurements of specific types of stigma used them appropriately in a matching context to provide more consistent research results. This review identifies the need for further investigation into how the HIV disclosure process is shaped by particular types of stigma, types of sex partners and demographic characteristics of people living with HIV/AIDS. PMID- 27491831 TI - Evaluation of a novel strategy of triage in the haematology ambulatory care setting. AB - BACKGROUND: In 2010, wait-times for new patients referred to see a haematologist at our outpatient tertiary care centre clinic exceeded 6 months. The provision of written recommendations for a subset of referred patients was undertaken to reduce patient wait-times. These recommendation letters outlined possible causes of the abnormality for which the patient was being referred and suggested a course of action for follow-up, and patients were then managed by their referring practitioner. We sought to characterize the cohort of patients for whom written recommendations were written and assess whether written recommendations were a satisfactory alternative for the referring practitioner. METHODS: All haematology patient referrals managed with written recommendations in 2010 were included in the study and were assessed one year later. Referring practitioners who received written recommendations were sent a short survey to evaluate their satisfaction with this process. RESULTS: A total of 444 of 2400 referrals were managed with a letter. At 1-year follow-up, 58 (13%, 95% CI) of the abnormalities which prompted the referral had resolved and 201 (45%, 95%CI) had remained stable. There was a single haematology-related death during the 1-year follow-up and the haematological abnormality worsened in 4 (1%) patients. Of 203 (71%) referring practitioners who responded to the satisfaction survey, 90% (95% CI) indicated that they would be satisfied with written recommendations in the future. INTERPRETATION: The provision of written recommendations appears to be a safe and satisfactory alternative to an inperson outpatient assessment in certain well defined subsets of stable outpatients with haematologic abnormalities. PMID- 27491832 TI - BMI as a Predictor of Spinal Cord Stimulation Success in Chronic Pain Patients. AB - BACKGROUND: Spinal cord stimulation (SCS) is an effective method of treating chronic pain. Obese patients are overrepresented in chronic pain cases. We examine the effect of body mass index (BMI) on SCS success. METHODS: We prospectively follow outcome measures including visual analog score, Beck Depression Inventory (BDI), McGill Pain Questionnaire, Oswestry Disability Index (ODI), Pain Catastrophizing Scale (PCS), and the Insomnia Severity Index at baseline, six months, and one year postoperatively. Retrospectively, we examined whether our patients with a BMI above the 75th percentile (BMI >=36.5) had worse outcomes. RESULTS: Our analysis included thoracic and cervical SCS patients-19 with a BMI >=36.5 and 58 with a BMI <36.5. High BMI patients experienced less BDI improvement at 6 months (T(df) 2.257(36); p = 0.030; 95% CI [4.7%, 87.4%]) and one year (2.74(28); p = 0.011; 95% CI [18.1%, 125.0%]) post-SCS. High BMI patients had less improvement in pain as measured by the PCS at one year (U = 79.5; p = 0.045; 95% CI [-116.0%, 0.0%]). DISCUSSION: Each group experienced successful surgical outcomes. High BMI patients had less BDI improvement at six months and one year and less PCS improvement at one year. These data aid us in counseling our patients preoperatively. PMID- 27491830 TI - Diabetes and Cognitive Impairment. AB - Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with reduced performance on multiple domains of cognitive function and with evidence of abnormal structural and functional brain magnetic resonance imaging (MRI). Cognitive deficits may occur at the very earliest stages of diabetes and are further exacerbated by the metabolic syndrome. The duration of diabetes and glycemic control may have an impact on the type and severity of cognitive impairment, but as yet we cannot predict who is at greatest risk of developing cognitive impairment. The pathophysiology of cognitive impairment is multifactorial, although dysfunction in each interconnecting pathway ultimately leads to discordance in metabolic signaling. The pathophysiology includes defects in insulin signaling, autonomic function, neuroinflammatory pathways, mitochondrial (Mt) metabolism, the sirtuin-peroxisome proliferator-activated receptor-gamma co-activator 1alpha (SIRT-PGC-1alpha) axis, and Tau signaling. Several promising therapies have been identified in pre-clinical studies, but remain to be validated in clinical trials. PMID- 27491834 TI - Reductive exfoliation of substoichiometric MoS2 bilayers using hydrazine salts. AB - Substoichiometric molybdenum disulphide (MoSx) nanosheets are successfully synthesised following a novel reductive route using hydrazine salts. The resulting two dimensional crystals are found to be highly monodispersed in thickness, forming exclusively 1.9 +/- 0.2 nm thick bilayers. The lateral dimensions of the nanosheets are governed by the precursor bulk particle's size. Exploring a range of hydrazine derivatives with various degrees of steric hindrance leads to the conclusion that intercalation does not occur during the process and that exfoliation is instead facilitated by the reduction of Mo centres leading to the exfoliation of substoichiometric bilayers with distorted lattices. The lattice distortion is found to be persistent across all samples with XPS analysis pointing towards a S to Mo ratio of 1.2. The resulting material features an electronic bandgap of 2.1 eV, which is wider than that of pristine monolayer MoS2 with relatively longer radiative decay time. PMID- 27491833 TI - ANGPTL2 is associated with an increased risk of cardiovascular events and death in diabetic patients. AB - AIMS/HYPOTHESIS: A high serum angiopoietin-like 2 (ANGPTL2) concentration is an independent risk factor for developing diabetes and is associated with insulin resistance and atherosclerosis. In this work, we have examined the impact of serum ANGPTL2 on improving cardiovascular (CV) risk stratification in patients with type 2 diabetes. METHODS: A prospective, monocentric cohort of consecutive type 2 diabetes patients (the SURDIAGENE cohort; total of 1353 type 2 diabetes patients; 58% men, mean +/- SD age 64 +/- 11 years) was followed for a median of 6.0 years for death as primary endpoint and major adverse CV events (MACE; i.e. CV death, myocardial infarction or stroke) as a secondary endpoint. Patients with end-stage renal disease, defined as a requirement for dialysis or a history of kidney transplantation, were excluded. Patients were grouped into quartiles according to ANGPTL2 concentrations at inclusion: <11.2 (Q1), 11.2-14.7 (Q2), 14.8-19.5 (Q3) or >19.5 (Q4) ng/ml. RESULTS: During follow up, 367 patients (representing 4.5% of the total person-years) died and 290 patients (representing 3.7% of the total person-years) presented with MACE. Both the survival and MACE free survival rates were significantly different between ANGPTL2 quartiles (logrank 82.12, p < 0.0001 for death; and logrank 65.14, p < 0.0001 for MACE). Patients with ANGPTL2 concentrations higher than 19.5 ng/ml (Q4) had a significantly higher risk of death and MACE than those with ANGPTL2 levels of 19.5 ng/ml or less (Q1-3) (HR for death 2.44 [95% CI 1.98, 3.00], p < 0.0001; HR for MACE 2.43 [95% CI 1.92, 3.06], p < 0.0001) after adjustment for sex, age and established CV risk factors. Using ANGPTL2 concentrations, prediction of the risk of mortality, as assessed by integrated discrimination improvement (IDI), was significantly improved (IDI 0.006 +/- 0.002, p = 0.0002). CONCLUSIONS/INTERPRETATION: In patients with type 2 diabetes, serum ANGPTL2 concentrations were independently associated with death and MACE. Therefore, ANGPTL2 is a promising candidate biomarker for improving risk stratification in type 2 diabetes patients, and may prove to be a valuable therapeutic target. PMID- 27491835 TI - Variations in pelvic lymph node dissection in invasive bladder cancer: A Dutch nationwide population-based study during centralization of care. AB - OBJECTIVES: To assess temporal trends in radical cystectomy (RC) and pelvic lymph node dissection (PLND) and the effect of centralization of care in the Netherlands between 2006 and 2012. PATIENTS AND METHODS: This nationwide population-based study included 3524 patients from the Netherlands Cancer Registry who underwent RC as the primary treatment for cT1-4a, N0 or Nx, M0 urothelial carcinoma. Annual application rates of PLND, median LNC, and rates of node-positive disease (pN+) were compared by linear-by-linear association. Multivariable logistic regression was performed to identify patients' and hospital characteristics associated with PLND and LNC>=10, and to study associations between LNC and pN+disease. RESULTS: In total, 3,191 (91%) patients had PLND during RC and the use increased from 84% in 2006 to 96% in 2012 (P<0.001). Owing to centralization of care in 2010 (at least 10RCs/y/hospital), significantly more patients were treated in high-volume hospitals (>=20RC per year) in 2011 and 2012. PLND use was highest in males, younger patients and in academic, teaching, and high-volume hospitals (>=20RC per year). In 2012, PLND application rates were comparable for academic, teaching, and nonteaching hospitals (P = 0.344). Median LNC increased from 7 in 2006 to 13 in 2012 (P<0.001), 55% had an LNC>=10 (63% in 2012). Furthermore, lymph node count (LNC)>=10 was associated with cT3-4a and, pN+disease, R0 and treatment in academic, teaching, or high-volume hospitals (>=20RC per year). Rate of pN+disease increased from 18% to 24% between 2006 and 2012 (P = 0.014). This trend was significantly associated with increased LNC on a continuous scale (odds ratio = 1.03). CONCLUSIONS: After centralization of care, PLND during RC for cT1 4a, N0 or Nx, M0 urothelial carcinoma has become standard in all types of Dutch hospitals. The increase in LNC between 2006 and 2012 was associated with a higher incidence of pN+disease and suggests more adequate template extension and adherence to contemporary guidelines in recent years. PMID- 27491837 TI - Dynamic Predictive Scores for Cardiac Surgery-Associated Acute Kidney Injury. AB - BACKGROUND: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication with a poor prognosis. In order to identify modifiable perioperative risk factors for AKI, which existing risk scores are insufficient to predict, a dynamic clinical risk score to allow clinicians to estimate the risk of CSA-AKI from preoperative to early postoperative periods is needed. METHODS AND RESULTS: A total of 7233 cardiac surgery patients in our institution from January 2010 to April 2013 were enrolled prospectively and distributed into 2 cohorts. Among the derivation cohort, logistic regression was used to analyze CSA-AKI risk factors preoperatively, on the day of ICU admittance and 24 hours after ICU admittance. Sex, age, valve surgery combined with coronary artery bypass grafting, preoperative NYHA score >2, previous cardiac surgery, preoperative kidney (without renal replacement therapy) disease, intraoperative cardiopulmonary bypass application, intraoperative erythrocyte transfusions, and postoperative low cardiac output syndrome were identified to be associated with CSA-AKI. Among the other 1152 patients who served as a validation cohort, the point scoring of risk factor combinations led to area under receiver operator characteristics curves (AUROC) values for CSA-AKI prediction of 0.74 (preoperative), 0.75 (on the day of ICU admission), and 0.82 (postoperative), and Hosmer-Lemeshow goodness-of fit tests revealed a good agreement of expected and observed CSA-AKI rates. CONCLUSIONS: The first dynamic predictive score system, with Kidney Disease: Improving Global Outcomes (KDIGO) AKI definition, was developed and predictive efficiency for CSA-AKI was validated in cardiac surgery patients. PMID- 27491836 TI - Diagnosis and Management of Cardiovascular Disease in Advanced and End-Stage Renal Disease. PMID- 27491838 TI - Air pollution affects lung cancer survival. PMID- 27491839 TI - Air pollution affects lung cancer survival. AB - RATIONALE: Exposure to ambient air pollutants has been associated with increased lung cancer incidence and mortality, but due to the high case fatality rate, little is known about the impacts of air pollution exposures on survival after diagnosis. This study aimed to determine whether ambient air pollutant exposures are associated with the survival of patients with lung cancer. METHODS: Participants were 352 053 patients with newly diagnosed lung cancer during 1988 2009 in California, ascertained by the California Cancer Registry. Average residential ambient air pollutant concentrations were estimated for each participant's follow-up period. Cox proportional hazards models were used to estimate HRs relating air pollutant exposures to all-cause mortality overall and stratified by stage (localised only, regional and distant site) and histology (squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma and others) at diagnosis, adjusting for potential individual and area level confounders. RESULTS: Adjusting for histology and other potential confounders, the HRs associated with 1 SD increases in NO2, O3, PM10, PM2.5 for patients with localised stage at diagnosis were 1.30 (95% CI 1.28 to 1.32), 1.04 (95% CI 1.02 to 1.05), 1.26 (95% CI 1.25 to 1.28) and 1.38 (95% CI 1.35 to 1.41), respectively. Adjusted HRs were smaller in later stages and varied by histological type within stage (p<0.01, except O3). The largest associations were for patients with early-stage non-small cell cancers, particularly adenocarcinomas. CONCLUSIONS: These epidemiological findings support the hypothesis that air pollution exposures after lung cancer diagnosis shorten survival. Future studies should evaluate the impacts of exposure reduction. PMID- 27491840 TI - LOCAL HEALTH TECHNOLOGY ASSESSMENT IN CANADA: CURRENT STATE AND NEXT STEPS. AB - OBJECTIVES: Canada has witnessed expansion of the health technology assessment (HTA) infrastructure in the last 25 years. Local HTA entities at the hospital or regional level are emerging to assist decision makers in the acquisition, implementation, maintenance, and disinvestment of healthcare technologies. There is a need to facilitate collaboration and exchange of expertise and knowledge between these entities regarding the role of local HTA in Canada. METHODS: In November 2013, the pan-Canadian Collaborative hosted a symposium, Hospital/Regional HTA: Local Evidence-based Decisions for Health Care Sustainability, bringing together over 60 HTA producers, researchers, stakeholders, and manufacturers involved in local HTA across Canada. The objective was to showcase the diversity of local HTA in Canada, while highlighting common gaps to be addressed. RESULTS: The Symposium focused on current practices in local HTA in Canada to support informed decision making, and opportunities for information sharing and provide equal access to timely evidence based information to decision makers. The main themes included assessment of evidence for local HTA, contextualization, stakeholder engagement in local HTA, knowledge translation and impact of recommendations, and challenges and opportunities for local HTA. CONCLUSIONS: Local HTA in Canada complements HTAs conducted at the provincial and federal levels to improve the efficient and effective health service delivery in institutions or regions faced with limited resources. Some challenges faced by local HTA producers to influence hospital policies and clinical practice involve the engagement of healthcare professionals and potential lack of training and support necessary for the introduction of a new technology. PMID- 27491841 TI - Identification of survival-promoting OSIP108 peptide variants and their internalization in human cells. AB - The plant-derived decapeptide OSIP108 increases tolerance of yeast and human cells to apoptosis-inducing agents, such as copper and cisplatin. We performed a whole amino acid scan of OSIP108 and conducted structure-activity relationship studies on the induction of cisplatin tolerance (CT) in yeast. The use of cisplatin as apoptosis-inducing trigger in this study should be considered as a tool to better understand the survival-promoting nature of OSIP108 and not for purposes related to anti-cancer treatment. We found that charged residues (Arg, His, Lys, Glu or Asp) or a Pro on positions 4-7 improved OSIP108 activity by 10% or more. The variant OSIP108[G7P] induced the most pronounced tolerance to toxic concentrations of copper and cisplatin in yeast and/or HepG2 cells. Both OSIP108 and OSIP108[G7P] were shown to internalize equally into HeLa cells, but at a higher rate than the inactive OSIP108[E10A], suggesting that the peptides can internalize into cells and that OSIP108 activity is dependent on subsequent intracellular interactions. In conclusion, our studies demonstrated that tolerance/survival-promoting properties of OSIP108 can be significantly improved by single amino acid substitutions, and that these properties are dependent on (an) intracellular target(s), yet to be determined. PMID- 27491842 TI - Advances in LC: bioanalytical method transfer. AB - There are three main reasons for transferring from an existing bioanalytical assay to an alternative chromatographic method: speed, cost and sensitivity. These represent a challenge to the analyst in that there is an interplay between these three considerations and one factor is often improved at the expense of another. These three factors act as drivers to encourage technology development and support its uptake. The more recently introduced chromatographic technologies may show significant improvements against one of more of these factors relative to conventional 4.6-mm id reversed-phase HPLC. In this article, some of these new chromatographic approaches will be considered in terms of what they can offer the bioanalysts. PMID- 27491843 TI - A simple, effective approach for rapid development of high-throughput and reliable LC-MS/MS bioanalytical assays. AB - BACKGROUND: Rapidly developing LC-MS/MS assays with high-throughput and quality are challenging yet desired. Methodology & results: A simple method development approach was reported and demonstrated with the quantitative bioanalysis of BMS 984478, a hepatitis C virus nonstructural protein 5A inhibitor. An accurate, precise and robust LC-MS/MS method for the quantitation of BMS-984478 in rat and monkey plasma was developed and validated. Incurred sample reanalysis evaluation passed with 100% of samples meeting the acceptance criteria. The validated assay was successfully applied in toxicology studies without any failed runs. CONCLUSION: The approach was successfully applied to the bioanalysis of BMS 984478 in toxicology and clinical studies. This approach was shown to be effective and reliable in speeding the development of high-throughput and reliable LC-MS/MS assays. PMID- 27491844 TI - Running ahead of doping: analytical advances and challenges faced by modern laboratories ahead of Rio 2016. PMID- 27491845 TI - Determination of urinary aldosterone using a plasma aldosterone 2D ID LC-MS/MS method. AB - AIM: In the diagnosis for primary aldosteronism, the measurement of urinary aldosterone is part of the confirmation test but diagnostic accuracy may be blunted due to poor immunoassay performance for urinary aldosterone. Nowadays, plasma aldosterone concentrations are measured preferably by LC-MS/MS yet such methods for urinary aldosterone are lacking. METHODS & RESULTS: We show that plasma and urinary aldosterone can be measured with the same 2D isotope dilution LC-MS/MS method. The accuracy of the method was tested against a certified reference material. The reference values for plasma and urinary aldosterone were established. DISCUSSION & CONCLUSION: With this method, urinary aldosterone concentrations can be measured precisely, simply and accurately together with plasma samples with one set of calibration standards. PMID- 27491846 TI - LC-MS/MS assay of ropinirole in rat biological matrices: elimination of lysoglycerophosphocholines-based matrix effect. AB - AIM: To adequately support PK evaluation of ropinirole in rats following intranasal administration, it was desirable to determine ropinirole concentrations in rat plasma, brain homogenate and microdialysate. Results & methodology: A robust LC-MS/MS method has been developed for the determination of ropinirole in biological samples. Liquid-liquid extraction using ethyl acetate eliminated matrix effect due to significantly reduced levels of lysoglycerophosphocholines. The assay was fully validated with dynamic ranges of 0.01-20 ng/ml for plasma and brain homogenate samples and 0.1-200 ng/ml for microdialysate samples. CONCLUSION: The proposed method was accurate and precise for the quantification of ropinirole in biological samples and was successfully applied to a microdialysis study of ropinirole in rats. PMID- 27491847 TI - Case-based Learning Outperformed Simulation Exercises in Disaster Preparedness Education Among Nursing Trainees in India: A Randomized Controlled Trial. AB - OBJECTIVE: In resource-constrained environments, appropriately employing triage in disaster situations is crucial. Although both case-based learning (CBL) and simulation exercises (SEs) commonly are utilized in teaching disaster preparedness to adult learners, there is no substantial evidence supporting one as a more efficacious methodology. This randomized controlled trial (RCT) evaluated the effectiveness of CBL versus SEs in addition to standard didactic instruction in knowledge attainment pertaining to disaster triage preparedness. METHODS: This RCT was performed during a one-day disaster preparedness course in Lucknow, India during October 2014. Following provision of informed consent, nursing trainees were randomized to knowledge assessment after didactic teaching (control group); didactic plus CBL (Intervention Group 1); or didactic plus SE (Intervention Group 2). The educational curriculum used the topical focus of triage processes during disaster situations. Cases for the educational intervention sessions were scripted, identical between modalities, and employed structured debriefing. Trained live actors were used for SEs. After primary assessment, the groups underwent crossover to take part in the alternative educational modality and were re-assessed. Two standardized multiple-choice question batteries, encompassing key core content, were used for assessments. A sample size of 48 participants was calculated to detect a >=20% change in mean knowledge score (alpha=0.05; power=80%). Robustness of randomization was evaluated using X 2, anova, and t-tests. Mean knowledge attainment scores were compared using one- and two-sample t-tests for intergroup and intragroup analyses, respectively. RESULTS: Among 60 enrolled participants, 88.3% completed follow-up. No significant differences in participant characteristics existed between randomization arms. Mean baseline knowledge score in the control group was 43.8% (standard deviation=11.0%). Case-based learning training resulted in a significant increase in relative knowledge scores at 20.8% (P=0.003) and 10.3% (P=.033) in intergroup and intragroup analyses, respectively. As compared to control, SEs did not significantly alter knowledge attainment scores with an average score increase of 6.6% (P=.396). In crossover intra-arm analysis, SEs were found to result in a 26.0% decrement in mean assessment score (P < .001). CONCLUSIONS: Among nursing trainees assessed in this RCT, the CBL modality was superior to SEs in short-term disaster preparedness educational translation. Simulation exercises resulted in no detectable improvement in knowledge attainment in this population, suggesting that CBL may be utilized preferentially for adult learners in similar disaster training settings. Aluisio AR , Daniel P , Grock A , Freedman J , Singh A , Papanagnou D , Arquilla B . Case-based learning outperformed simulation exercises in disaster preparedness education among nursing trainees in India: a randomized controlled trial. Prehosp Disaster Med. 2016;31(5):516-523. PMID- 27491848 TI - Insight into the kinetics and thermodynamics of the hydride transfer reactions between quinones and lumiflavin: a density functional theory study. AB - The kinetics and equilibrium of the hydride transfer reaction between lumiflavin and a number of substituted quinones was studied using density functional theory. The impact of electron withdrawing/donating substituents on the redox potentials of quinones was studied. In addition, the role of these substituents on the kinetics of the hydride transfer reaction with lumiflavin was investigated in detail under the transition state (TS) theory assumption. The hydride transfer reactions were found to be more favorable for an electron-withdrawing substituent. The activation barrier exhibited a quadratic relationship with the driving force of these reactions as derived under the formalism of modified Marcus theory. The present study found a significant extent of electron delocalization in the TS that is stabilized by enhanced electrostatic, polarization, and exchange interactions. Analysis of geometry, bond-orders, and energetics revealed a predominant parallel (Leffler-Hammond) effect on the TS. Closer scrutiny reveals that electron-withdrawing substituents, although located on the acceptor ring, reduce the N-H bond order of the donor fragment in the precursor complex. Carried out in the gas-phase, this is the first ever report of a theoretical study of flavin's hydride transfer reactions with quinones, providing an unfiltered view of the electronic effect on the nuclear reorganization of donor-acceptor complexes. PMID- 27491849 TI - Photoinduced hydrogen-bonding dynamics. AB - Hydrogen bonding dynamics has received extensive research attention in recent years due to the significant advances in femtolaser spectroscopy experiments and quantum chemistry calculations. Usually, photoexcitation would cause changes in the hydrogen bonding formed through the interaction between hydrogen donor and acceptor molecules on their ground electronic states, and such transient strengthening or weakening of hydrogen bonding could be crucial for the photophysical transformations and the subsequent photochemical reactions that occurred on a time scale from tens of femtosecond to a few nanoseconds. In this article, we review the combined experimental and theoretical studies focusing on the ultrafast electronic and vibrational hydrogen bonding dynamics. Through these studies, new mechanisms and proposals and common rules have been put forward to advance our understanding of the hydrogen bondings dynamics in a variety of important photoinduced phenomena like photosynthesis, dual fluorescence emission, rotational reorientation, excited-state proton transfer and charge transfer processes, chemosensor fluorescence sensing, rearrangements of the hydrogen-bond network including forming and breaking hydrogen bond in water. Graphical Abstract We review the recent advances on exploring the photoinduced hydrogen bonding dynamics in solutions through a joint approach of laser spectroscopy and theoretical calculation. The reviewed studies have put forward a new mechanism, new proposal, and new rule for a variety of photoinduced phenomena such as photosynthesis, dual fluorescence emission, rotational reorientation, excited state proton transfer and charge transfer, chemosensor fluorescence sensing, and rearrangements of the hydrogen-bond network in water. PMID- 27491850 TI - In-silico studies on DegP protein of Plasmodium falciparum in search of anti malarials. AB - Despite encouraging progress over the past decade, malaria caused by the Plasmodium parasite continues to pose an enormous disease burden and is one of the major global health problems. The extreme challenge in malaria management is the resistance of parasites to traditional monochemotherapies like chloroquine and sulfadoxine-pyrimethamine. No vaccine is yet in sight, and the foregoing effective drugs are also losing ground against the disease due to the resistivity of parasites. New antimalarials with novel mechanisms of action are needed to circumvent existing or emerging drug resistance. DegP protein, secretory in nature has been shown to be involved in regulation of thermo-oxidative stress generated during asexual life cycle of Plasmodium, probably required for survival of parasite in host. Considering the significance of protein, in this study, we have generated a three-dimensional structure of PfDegP followed by validation of the modeled structure using several tools like RAMPAGE, ERRAT, and others. We also performed an in-silico screening of small molecule database against PfDegP using Glide. Furthermore, molecular dynamics simulation of protein and protein ligand complex was carried out using GROMACS. This study substantiated potential drug-like molecules and provides the scope for development of novel antimalarial drugs. PMID- 27491851 TI - Evolution of the hydrogen-bonding motif in the melamine-cyanuric acid co-crystal: a topological study. AB - The melamine (M)/cyanuric acid (CA) supramolecular system is perhaps one of the most exploited in the field of self-assembly because of the high complementarity of the components. However, it is necessary to investigate further the factors involved in the assembly process. In this study, we analyzed a set of 13 M n /CA m clusters (with n , m = 1, 2, 3), taken from crystallographic data, to characterize the nature of the hydrogen bonds involved in the self-assembly of these components as well as to provide greater understanding of the phenomenon. The calculations were performed at the B3LYP/6-311++G(d,p) and omega-B97XD (single point) levels of theory, and the interactions were analyzed within the framework of the quantum theory of atoms in molecules and by means of molecular electrostatic potential maps. Our results show that the stablest structure is the rosette-type motif and the aggregation mechanism is governed by a combination of cooperative and anticooperative effects. Our topological results explain the polymorphism in the self-assembly of coadsorbed monolayers of M and CA. Graphical abstract The aggregation steps of the melamine-cyanuric co-crystal is driven by a hydrogen-bonded network which is governed by a complex combination of cooperative and anticooperative effects. PMID- 27491852 TI - The dopamine D2 receptor dimer and its interaction with homobivalent antagonists: homology modeling, docking and molecular dynamics. AB - In order to apply structure-based drug design techniques to G protein-coupled receptor complexes, it is essential to model their 3D structure and to identify regions that are suitable for selective drug binding. For this purpose, we have developed and tested a multi-component protocol to model the inactive conformation of the dopamine D2 receptor dimer, suitable for interaction with homobivalent antagonists. Our approach was based on protein-protein docking, applying the Rosetta software to obtain populations of dimers as present in membranes with all the main possible interfaces. Consensus scoring based on the values and frequencies of best interfaces regarding four scoring parameters, Rosetta interface score, interface area, free energy of binding and energy of hydrogen bond interactions indicated that the best scored dimer model possesses a TM4-TM5-TM7-TM1 interface, which is in agreement with experimental data. This model was used to study interactions of the previously published dopamine D2 receptor homobivalent antagonists based on clozapine,1,4-disubstituted aromatic piperidines/piperazines and arylamidoalkyl substituted phenylpiperazine pharmacophores. It was found that the homobivalent antagonists stabilize the receptor-inactive conformation by maintaining the ionic lock interaction, and change the dimer interface by disrupting a set of hydrogen bonds and maintaining water- and ligand-mediated hydrogen bonds in the extracellular and intracellular part of the interface. Graphical Abstract Structure of the final model of the dopamine D2 receptor homodimer, indicating the distancebetween Tyr37 and Tyr 5.42 in the apo form (left) and in the complex with the ligand (right). PMID- 27491853 TI - H2 adsorption and dissociation on PdO(101) films supported on rutile TiO2 (110) facet: elucidating the support effect by DFT calculations. AB - To explore metal oxide-support interactions and their effect, H2 adsorption and dissociation on PdO(101)/TiO2(110) films with different film thicknesses, in comparison with that on pure PdO(101) surface without TiO2(110) support, were studied by density functional theory calculation. A monolayer PdO(101) film supported on TiO2 facet shows different properties to a pure PdO(101) surface. On the monolayer PdO(101)/TiO2(110) film, TiO2 support leads to stronger molecular adsorption of H2 on coordinatively unsaturated Pd top sites than that on a pure PdO surface. H2 dissociation with the formation of OH was preferred thermodynamically but slightly unfavorable kinetically on the monolayer PdO film due to the TiO2 support effect. Graphical abstract On the monolayer PdO(101)/TiO2(110) film, the TiO2 support effect leads to stronger H2 molecular adsorption on coordinatively unsaturated Pd top sites than on pure PdO surface. H2 dissociation with the formation of OH is preferred thermodynamically but slightly unfavorable kinetically on the film due to the TiO2 support effect. PMID- 27491854 TI - Fluorescein photodiagnosis of idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome: A case report and long-term outcome of photocoagulation therapy. AB - Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome is a disease characterized by multiple retinal macroaneurysms, neuroretinitis and peripheral capillary non-perfusion, leading to irreversible visual loss. It includes five stages and has previously been rarely reported. IRVAN syndrome is especially rare in Asia. In this report, we describe laser diagnosis and therapy in an Asian patient with IRVAN syndrome over two years of follow-up. We observed non-perfusion retina and dilated retinal capillaries in the contralateral eye. Photocoagulation is an effective therapy to control retinal macroaneurysms and nonperfusions and to prevent visual loss, particularly in the early stages of IRVAN syndrome (stages 2 & 3). To the best of our knowledge, this is the first long-term observation of photocoagulation in IRVAN syndrome. We discovered the early signs of such lesions, which may be beneficial for clinical diagnosis and therapy. PMID- 27491855 TI - Optical diagnosis of actinic cheilitis by infrared spectroscopy. AB - : Actinic cheilitis (AC) is considered a potentially malignant disorder of the lip. Biomolecular markers study is important to understand malignant transformation into squamous cell carcinoma. Fourier transform infra red (FT-IR) spectroscopy was used to analyze AC in this study. OBJECTIVES: The aim of the study was to evaluate if FT-IR spectral regions of nucleic acids and collagen can help in early diagnosis of malignant transformation. METHODS: Tissues biopsies of 14 patients diagnosed with AC and 14 normal tissues were obtained. FT-IR spectra were measured at five different points resulting in 70 spectra of each. Analysis of Principal components analysis (PCA) and linear discrimination analysis (LDA) model were also used. In order to verify the statistical difference in the spectra, Mann-Whitney U test was performed in each variable (wavenumber) with p value <0.05. RESULTS: After the Mann-Whitney U test the vibrational modes of CO (Collagen 1), PO2 (Nucleic Acids) and CO asymmetric (Triglycerides/Lipids) were observed as a possible spectral biomarker. These bands were chosen because they represent the vibrational modes related to collagen and DNA, which are supposed to be changed in AC samples. Based on the PCA-LDA results, the predictive model corresponding to the area under the curve was 0.91 for the fingerprint region and 0.83 for the high wavenumber region, showing the greater accuracy of the test. CONCLUSIONS: FT-IR changes in collagen and nucleic acids could be used as molecular biomarkers for malignant transformation. PMID- 27491856 TI - The effectiveness and cost-effectiveness of intraoperative imaging in high-grade glioma resection; a comparative review of intraoperative ALA, fluorescein, ultrasound and MRI. AB - BACKGROUND: Surgical resection of high-grade gliomas (HGG) is standard therapy because it imparts significant progression free (PFS) and overall survival (OS). However, HGG-tumor margins are indistinguishable from normal brain during surgery. Hence intraoperative technology such as fluorescence (ALA, fluorescein) and intraoperative ultrasound (IoUS) and MRI (IoMRI) has been deployed. This study compares the effectiveness and cost-effectiveness of these technologies. METHODS: Critical literature review and meta-analyses, using MEDLINE/PubMed service. The list of references in each article was double-checked for any missing references. We included all studies that reported the use of ALA, fluorescein (FLCN), IoUS or IoMRI to guide HGG-surgery. The meta-analyses were conducted according to statistical heterogeneity between studies. If there was no heterogeneity, fixed effects model was used; otherwise, a random effects model was used. Statistical heterogeneity was explored by chi2 and inconsistency (I2) statistics. To assess cost-effectiveness, we calculated the incremental cost per quality-adjusted life-year (QALY). RESULTS: Gross total resection (GTR) after ALA, FLCN, IoUS and IoMRI was 69.1%, 84.4%, 73.4% and 70% respectively. The differences were not statistically significant. All four techniques led to significant prolongation of PFS and tended to prolong OS. However none of these technologies led to significant prolongation of OS compared to controls. The cost/QALY was $16,218, $3181, $6049 and $32,954 for ALA, FLCN, IoUS and IoMRI respectively. CONCLUSIONS: ALA, FLCN, IoUS and IoMRI significantly improve GTR and PFS of HGG. Their incremental cost was below the threshold for cost effectiveness of HGG-therapy, denoting that each intraoperative technology was cost-effective on its own. PMID- 27491857 TI - [Arthroscopically assisted transcapsular refixation of the triangular fibrocartilage complex of the wrist]. AB - OBJECTIVE: Refixation of the triangular fibrocartilage complex (TFCC) to the ulnar capsule of the wrist. INDICATIONS: Distal TFCC tears without instability, proximal TFCC intact. Loose ulnar TFCC attachment without tear or instability. CONTRAINDICATIONS: Peripheral TFCC tears with instability of the distal radioulnar joint (DRUJ). Complex or proximal tears of the TFCC. Isolated, central degenerative tears without healing potential. SURGICAL TECHNIQUE: Arthroscopically guided, minimally invasive suture of the TFCC to the base of the sixth extensor compartment. POSTOPERATIVE MANAGEMENT: Above elbow plaster splint, 70 degrees flexion of the elbow joint, 45 degrees supination for 6 weeks. Skin suture removal after 2 weeks. No physiotherapy to extend pronation and supination during the first 3 months. RESULTS: In an ongoing long-term study, 7 of 31 patients who underwent transcapsular refixation of the TFCC between 1 January 2003 and 31 December 2010 were evaluated after an average follow-up interval of 116 +/- 34 months (range 68-152 months). All patients demonstrated an almost nearly unrestricted range of wrist motion and grip strength compared to the unaffected side. All distal radioulnar joints were stable. On the visual analogue scale (VAS 0-10), pain at rest was 1 +/- 1 (range 0-2) and pain during exercise 2 +/- 2 (range 0-5); the DASH score averaged 10 +/- 14 points (range 0-39 points). All patients were satisfied. The modified Mayo wrist score showed four excellent, two good, and one fair result. These results correspond to the results of other series. CONCLUSION: Transcapsular refixation is a reliable, technically simple procedure in cases with ulnar-sided TFCC tears without instability leading to good results. PMID- 27491858 TI - Pb-210 and fly ash particles in ombrotrophic peat bogs as indicators of industrial emissions. AB - Peat cores were collected from a Sphagnum-dominated Selisoo bog, which is located about 40 km from the large oil shale-fired power plants (PPs) in Estonia. These PPs have been operational from the 1960's and had the largest negative impact on the surrounding environment during the 1970's and 1980's. Nearby ombrotrophic peatlands are good indicators of atmospheric pollution due to their properties of effectively adsorbing mineral matter and pollutants. Collected peat cores (S1 and S2) from Selisoo peat bog were sliced into 1 cm thick layers and measured gamma spectrometrically. In addition, spherical fly ash particles (SFAP) originating from the combustion of the PPs were counted. The maximum concentrations (particles per cm3) of the SFAP remained between 7 and 12 cm for core S1 and between 11 and 17 cm for core S2. The concentration profiles of the SFAP reflect the combustion and emission history of the PPs. Pb-210 activity concentrations have the maximum values up to 500 Bq kg-1 and 413 Bq m-2 for S1 and for the S2 the values are 441 Bq kg-1 and 535 Bq m-2 (dry weight). The unsupported 210Pb inventory is around 4250 Bq m-2. This represents a 210Pb deposition flux of 133 Bq m-2 y-1. The estimated 210Pb deposition via fly ash from the PPs at Selisoo area remains between 0.2 and 2.2 Bq m-2 y-1. Considering the annual 210Pb deposition from the atmosphere (with a precipitation rate of 600 mm y-1) between 92 and 133 Bq m-2, which is regarded as the natural background value, we show that the radiological burden due to the power plants at these distances is negligible. As the peat cores exhibit noticeable differences from each other (in terms of radionuclide concentration distribution), the SFAP can provide a good additional parameter to improve the validity of results obtained only from radiometric methods in the chronological studies. SFAP can also act as a possible tool to estimate the radionuclide deposition rate via fly ash in the vicinity of the PPs. PMID- 27491859 TI - Spatial analysis of ambient gamma dose equivalent rate data by means of digital image processing techniques. AB - A detailed ambient gamma dose equivalent rate mapping based on field measurements at ground level and at 1 m height was carried out at 142 sites in 80 * 90 km area in Pest County, Hungary. Detailed digital image processing analysis was carried out to identify and characterise spatial features such as outlying points, anomalous zones and linear edges in a smoothed TIN interpolated surface. The applied method proceeds from the simple shaded relief model and digital cross sections to the more complex gradient magnitude and gradient direction maps, 2nd derivative profile curvature map, relief map and lineament density map. Each map is analysed for statistical characteristics and histogram-based image segmentation is used to delineate areas homogeneous with respect to the parameter values in these maps. Assessment of spatial anisotropy is implemented by 2D autocorrelogram and directional variogram analyses. The identified spatial features are related to underlying geological and tectonic conditions using GIS technology. Results show that detailed digital image processing is efficient in revealing the pattern present in field-measured ambient gamma dose equivalent rates and they are related to regional scale tectonic zones and surface sedimentary lithological conditions in the study area. PMID- 27491860 TI - Frequent detection of PIK3CA mutations in single circulating tumor cells of patients suffering from HER2-negative metastatic breast cancer. AB - Modern technologies enable detection and characterization of circulating tumor cells (CTC) in peripheral blood samples. Thus, CTC have attracted interest as markers for therapeutic response in breast cancer. First studies have incorporated CTC analyses to guide therapeutic interventions and stratification of breast cancer patients. Aim of this study was to analyze characteristic features of CTC as biomarker for predicting resistance to HER2-targeted therapies. Therefore, CTC from metastatic breast cancer patients with HER2 negative primary tumors screened for the prospective randomized phase III trial DETECT III were explored for their HER2 status and the presence of PIK3CA mutations. Detection and characterization of HER2 expression of CTC were conducted with the CellSearch((r)) system. Fifteen of 179 CTC-positive patients (8.4%) contained >=1 CTC with strong HER2 expression. Genomic DNA from individual CTC isolated by micromanipulation was propagated by whole genome amplification and analyzed for PIK3CA mutations in exons 9 and 20 by Sanger sequencing. One or more CTC/7.5 mL were detected in 179/290 patients (61.7%). In 109 patients (34.8%), >=5 CTC/7.5 mL were found. We detected at least one CTC with the mutation p.E542K, p.E545K, p.H1047R, p.H1047L or p.M1043V in 12/33 patients (36.4%). Thirty six of 114 CTC (31.6%) harbored one of these mutations. CTC in individual patients exhibited heterogeneity concerning PIK3CA mutations and HER2 expression. In conclusion, clinically relevant genomic aberrations such as mutations in the hotspot regions of exon 9 and 20 of the PIK3CA gene can be detected in single CTC and might provide insights into mechanisms of resistance to HER2-targeted therapies. PMID- 27491861 TI - LRG1 mRNA expression in breast cancer associates with PIK3CA genotype and with aromatase inhibitor therapy outcome. AB - BACKGROUND: PIK3CA is the most frequent somatic mutated oncogene in estrogen receptor (ER) positive breast cancer. We previously observed an association between PIK3CA genotype and aromatase inhibitors (AI) treatment outcome. This study now evaluates whether expression of mRNAs and miRs are linked to PIK3CA genotype and are independently related to AI therapy response in order to define potential expressed biomarkers for treatment outcome. MATERIALS AND METHODS: The miR and mRNA expression levels were evaluated for their relationship with the PIK3CA genotype in two breast tumor datasets, i.e. 286 luminal cancers from the TCGA consortium and our set of 84 ER positive primary tumors of metastatic breast cancer patients who received first line AI. BRB Array tools class comparison was performed to define miRs and mRNAs whose expression associate with PIK3CA exon 9 and 20 status. Spearman correlations established miR-mRNA pairs and mRNAs with related expression. Next, a third dataset of 25 breast cancer patients receiving neo-adjuvant letrozole was evaluated, to compare expression levels of identified miRs and mRNAs in biopsies before and after treatment. Finally, to identify potential biomarkers miR and mRNA levels were related with overall survival (OS) and progression free survival (PFS) after first-line AI therapy. RESULTS: Expression of 3 miRs (miR-449a, miR-205-5p, miR-301a-3p) and 9 mRNAs (CCNO, FAM81B, LRG1, NEK10, PLCL1, PGR, SERPINA3, SORBS2, VTCN1) was related to the PIK3CA status in both datasets. All except miR-301a-3p had an increased expression in tumors with PIK3CA mutations. Validation in a publicly available dataset showed that LRG1, PGR, and SERPINA3 levels were decreased after neo adjuvant AI-treatment. Six miR-mRNA pairs correlated significantly and stepdown analysis of all 12 factors revealed 3 mRNAs (PLCL1, LRG1, FAM81B) related to PFS. Further analyses showed LRG1 and PLCL1 expression to be unrelated with luminal subtype and to associate with OS and with PFS, the latter independent from traditional predictive factors. CONCLUSION: We showed in two datasets of ER positive and luminal breast tumors that the expression of 3 miRs and 9 mRNAs associate with the PIK3CA status. Expression of LRG1 is independent of luminal (A or B) subtype, decreased after neo-adjuvant AI-treatment, and is proposed as potential biomarker for AI therapy outcome. PMID- 27491862 TI - Cadmium resistance and uptake by bacterium, Salmonella enterica 43C, isolated from industrial effluent. AB - Cadmium resistant bacterium, isolated from industrial wastewater, was characterized as Salmonella enterica 43C on the basis of biochemical and 16S rRNA ribotyping. It is first ever reported S. enterica 43C bared extreme resistance against heavy metal consortia in order of Pb(2+)>Cd(2+)>As(3+)>Zn(2+)>Cr(6+)>Cu(2+)>Hg(2+). Cd(2+) stress altered growth pattern of the bacterium in time dependent manner. It could remove nearly 57 % Cd(2+) from the medium over a period of 8 days. Kinetic and thermodynamic studies based on various adsorption isotherm models (Langmuir and Freundlich) depicted the Cd(2+) biosorption as spontaneous, feasible and endothermic in nature. Interestingly, the bacterium followed pseudo first order kinetics, making it a good biosorbent for heavy metal ions. The S. enterica 43C Cd(2+) processivity was significantly influenced by temperature, pH, initial Cd(2+) concentration, biomass dosage and co-metal ions. FTIR analysis of the bacterium revealed the active participation of amide and carbonyl moieties in Cd(2+) adsorption confirmed by EDX analysis. Electron micrographs beckoned further surface adsorption and increased bacterial size due to intracellular Cd(2+) accumulation. An overwhelming increase in glutathione and other non-protein thiols levels played a significant role in thriving oxidative stress generated by metal cations. Presence of metallothionein clearly depicted the role of such proteins in bacterial metal resistance mechanism. The present study results clearly declare S. enterica 43C a suitable candidate for green chemistry to bioremediate environmental Cd(2+). PMID- 27491864 TI - Erratum. AB - In the article "Effect of Addition of Platelet-rich Plasma to Calcium Phosphosilicate Putty on Healing at 9 Months in Periodontal Intrabony Defects" by Sagrika Shukla, Ashi Chug, Lanka Mahesh, Harpreet Singh Grover, issue 17 volume 3, page 230. It erroneously appeared that: "...support was given to Dr. George A. Kotsakis DDS, Advanced Education Program in Periodontology, University of Minnesota and Dr. Bhanu K. Bhakri MD (Paediatrics), All India Institute of Medical Sciences for kind support and guidance." The correct statement is: "Acknowledgements: We thank Dr. George A. Kotsakis DDS, Advanced Education Program in Periodontology, University of Minnesota and Dr. Bhanu K. Bhakri MD (Paediatrics), All India Institute of Medical Sciences for kind support and guidance." PMID- 27491863 TI - Can Simulated Team Tasks be Used to Improve Nontechnical Skills in the Operating Room? AB - OBJECTIVE: The purpose of this study was to understand the effect of a team-based surgical skills intervention on the technical and nontechnical skills of surgery residents. DESIGN: This was a prospective cohort study with pretesting or posttesting. We designed basic tasks for the assessment and learning of nontechnical skills in the operating room (OR). A total of 15 postgraduate year 1 residents performed an open gastrojejunostomy in a simulated OR setting (pretest), followed by training in the 3 team-based tasks designed to teach communication and teamwork, followed by performance of a gastrojejunostomy in the simulated OR (posttest). SETTING: Tertiary care, university-based teaching institution. PARTICIPANTS: A total of 15 general surgery residents at the intern level. RESULTS: The mean nontechnical skills for surgeons (NOTSS) score improved postteam task training (10.04 +/- 0.33 vs. 12.14 +/- 1.33). There was a concomitant increase in the objective structured assessment of technical skills (OSATS) score (18.56 +/- 0.86 vs. 22.86 +/- 0.15, p = 0.006). The percentage increases in OSATS and NOTSS score for each resident was similar (19.49 +/- 4.8 % for NOTSS vs. 21.22 +/- 4.92 % for OSATS, p = 0.502). CONCLUSION: Nontechnical skills positively correlate with the technical performance of a surgeon. Simple, easily designed tasks can be used to improve NOTSS in the OR. These team tasks and development of curricula based on them can be used to explicitly address one of the most important components of ACGME core competencies for surgical residents, namely interpersonal skills and communication. PMID- 27491865 TI - Main causes of death in Dande, Angola: results from Verbal Autopsies of deaths occurring during 2009-2012. AB - BACKGROUND: The Dande Health and Demographic Surveillance System (HDSS) located in Bengo Province, Angola, covers nearly 65,500 residents living in approximately 19,800 households. This study aims to describe the main causes of deaths (CoD) occurred within the HDSS, from 2009 to 2012, and to explore associations between demographic or socioeconomic factors and broad mortality groups (Group I Communicable diseases, maternal, perinatal and nutritional conditions; Group II Non-communicable diseases; Group III-Injuries; IND-Indeterminate). METHODS: Verbal Autopsies (VA) were performed after death identification during routine HDSS visits. Associations between broad groups of CoD and sex, age, education, socioeconomic position, place of residence and place of death, were explored using chi-square tests and fitting logistic regression models. RESULTS: From a total of 1488 deaths registered, 1009 verbal autopsies were performed and 798 of these were assigned a CoD based on the 10(th) revision of the International Classification of Diseases (ICD-10). Mortality was led by CD (61.0 %), followed by IND (18.3 %), NCD (11.6 %) and INJ (9.1 %). Intestinal infectious diseases, malnutrition and acute respiratory infections were the main contributors to under five mortality (44.2 %). Malaria was the most common CoD among children under 15 years old (38.6 %). Tuberculosis, traffic accidents and malaria led the CoD among adults aged 15-49 (13.5 %, 10.5 % and 8.0 % respectively). Among adults aged 50 or more, diseases of the circulatory system (23.2 %) were the major CoD, followed by tuberculosis (8.2 %) and malaria (7.7 %). CD were more frequent CoD among less educated people (adjusted odds ratio, 95 % confidence interval for none vs. 5 or more years of school: 1.68, 1.04-2.72). CONCLUSION: Infectious diseases were the leading CoD in this region. Verbal autopsies proved useful to identify the main CoD, being an important tool in settings where vital statistics are scarce and death registration systems have limitations. PMID- 27491866 TI - Interaction of a standardized mistletoe (Viscum album) preparation with antitumor effects of Trastuzumab in vitro. AB - BACKGROUND: Besides conventional anticancer therapy many breast cancer patients use complementary and alternative medicine (CAM) like the medicinal herb mistletoe (Viscum album L.). To gain more knowledge about possible herb-drug interactions between CAM and conventional anticancer medications, in the present in vitro study we investigated the effect of a standardized mistletoe preparation on the action of Trastuzumab, a drug used for the treatment of Her-2 positive breast cancer. METHODS: The Her-2 positive human breast carcinoma cell line SK-BR 3 was treated with Trastuzumab. Different doses of the drug were combined with Viscum album extract (VAE) in clinically relevant doses. Proliferation, apoptosis, cell cycle and the secretion of vascular endothelial growth factor (VEGF) were analyzed. RESULTS: No inhibition of antitumor efficacy of Trastuzumab by VAE was detected. VAE and Trastuzumab, either alone or in combination, inhibited proliferation of SK-BR-3 cells in vitro. At higher concentrations VAE induced apoptosis, which was not observed for Trastuzumab. Cells treated with Trastuzumab underwent a G0/G1 cell cycle arrest and cells treated with VAE a G2/M arrest. After application of the two drugs in combination both G0/G1 and G2/M arrest was observed. VEGF secretion of SK-BR-3 cells was significantly inhibited by sole treatment with Trastuzumab or VAE. Combined treatment of Trastuzumab and VAE at clinically relevant doses showed additive inhibitory effects on VEGF secretion. CONCLUSIONS: VAE did not interfere with cytostatic effects of Trastuzumab on SK-BR-3 cells in vitro. Our in vitro results suggest that no risk of safety by herb drug interactions has to be expected from the exposition of cancer cells to Trastuzumab and VAE simultaneously. In contrast, VAE and Trastuzumab seem to exhibit complementary anti-cancer effects in vitro. PMID- 27491867 TI - Spine extra-osseous chordoma mimicking neurogenic tumors: report of three cases and review of the literatures. AB - BACKGROUND: For a long time, chordoma has been known as an osseous tumor mainly found at the clivus and sacrococcygeal region. However, spine extra-osseous chordoma (SEC) with a better prognosis than the classic type has been neglected. According to our literature review, only several case reports have been published in English literatures. Here in this article, three cases of SEC, plus a literature review, are presented. CASE PRESENTATION: Three cases of SEC were presented from our center. Surprisingly, neurologic tumors were considered as the first diagnosis. Thereafter, en bloc resection was performed in all the three cases. Especially, the dumbbell-shaped one in the cervical spine was removed by en bloc through the combined anterior and posterior approach for the first time. Follow-up within 12-58 months after surgeries proved no recurrence or metastasis. CONCLUSIONS: Spine extra-osseous chordoma, commonly located in the cervical and epidural region, is extremely rarely met. SEC is characterized with less aggressiveness, the lower rate of recurrence and metastasis, and better prognosis than those of the osseous origin. Though complete excision can be achieved generally, differential diagnosis of spine neurogenic tumors and the following en bloc resection should be made as carefully as possible. PMID- 27491868 TI - Comparative efficacy of oral nucleotide analogues for the prophylaxis of hepatitis B virus recurrence after liver transplantation: a network meta analysis. AB - BACKGROUND: Prophylactic nucleos(t)ide anologues against hepatitis B virus (HBV) recurrence after liver transplantation (LT) include lamivudine, entecavir, tenofovir, adefovir. Since the most effective strategies for post-LT remain inconclusive, we aimed to compare 6 different treatment options (lamivudine, entecavir, tenofovir, adefovir, lamivudine plus adefovir, lamivudine plus tenofovir) in terms of HBV recurrence after LT using network meta-analysis. METHODS: The search identified seventeen studies involving 6 different prophylactic regimens covering 7274 patients. RESULTS: Compared with entecavir, lamivudine plus tenofovir (OR 2.00, 95%CI 0.02-183.29), lamivudine plus adefovir, (OR 2.83, 95%CI 0.18-33.57), tenofovir (OR 1.11, 95%CI 0.22-5.80), adefovir (OR 3.78, 95%CI 0.59-22.16), lamivudine (OR 4.62, 95%CI 1.75-11.39) were associated with an increased risk of HBV recurrence. CONCLUSION: Entecavir resulted with the highest probability (31%) as the best prophylactic option on reducing the risk of HBV recurrence. Entecavir is the preferred oral NAs treatment compared to other five different prophylactic regimens in the prevention of HBV recurrence after LT. PMID- 27491869 TI - Erratum to: Antioxidant Rescue of Selenomethionine-Induced Teratogenesis in Zebrafish Embryos. PMID- 27491870 TI - Sub-lethal Effects of Chlorpyrifos on Big Brown Bats (Eptesicus fuscus). AB - We determined dose-response curves for sublethal effects of the organophosphorus (OP) insecticide, chlorpyrifos, on bats. Big brown bats (Eptesicus fuscus, n = 64) were given a single dose of chlorpyrifos (nominal concentrations) of 0, 5, 10, 15, 20, 25, 30, or 60 ug/g body weight and examined at 12 or 24 h after dosing. A second experiment dosed 32 bats with 0 or 60 ug/g body weight and examined 1, 3, 7, or 14 days after dosing. Skin temperature and behavioral changes were recorded, and brain and plasma cholinesterase (ChE) activity were measured. The benchmark dose (BMD10) of chlorpyrifos that altered brain and plasma ChE activity at 24 h was 3.7 and 10.1 ug/g, respectively. The 95 % lower confidence limit for the BMD10 (i.e., BMDL10) was 1.6 and 7.7 ug/g. The best of five models (as determined by AIC) for impaired flight, impaired movement, or presence of tremors provided a BMD10 of 6.2, 12.9, and 7.8 ug/g body weight of chlorpyrifos, respectively. BMDL10 for impaired flight, impaired movement, or presence of tremors was 3.5, 6.6, and 5.3 ug/g body weight, respectively. In the wild, impaired ability to fly or crawl could be life-threatening. Brain and plasma ChE activity remained low for 3 days after dosing. Gradual recovery of enzyme activity was observed by 7 days in survivors. Brain and plasma ChE activity were still significantly lower than that of the control group at 14 days after dosing. PMID- 27491871 TI - Enhanced spin-orbit coupling in core/shell nanowires. AB - The spin-orbit coupling (SOC) in semiconductors is strongly influenced by structural asymmetries, as prominently observed in bulk crystal structures that lack inversion symmetry. Here we study an additional effect on the SOC: the asymmetry induced by the large interface area between a nanowire core and its surrounding shell. Our experiments on purely wurtzite GaAs/AlGaAs core/shell nanowires demonstrate optical spin injection into a single free-standing nanowire and determine the effective electron g-factor of the hexagonal GaAs wurtzite phase. The spin relaxation is highly anisotropic in time-resolved micro photoluminescence measurements on single nanowires, showing a significant increase of spin relaxation in external magnetic fields. This behaviour is counterintuitive compared with bulk wurtzite crystals. We present a model for the observed electron spin dynamics highlighting the dominant role of the interface induced SOC in these core/shell nanowires. This enhanced SOC may represent an interesting tuning parameter for the implementation of spin-orbitronic concepts in semiconductor-based structures. PMID- 27491872 TI - Linear Multiple Epithelioid Hemangioma Associated With a Quiescent Vascular Malformation. PMID- 27491873 TI - Quantification of global myocardial function by cine MRI deformable registration based analysis: Comparison with MR feature tracking and speckle-tracking echocardiography. AB - OBJECTIVES: To evaluate deformable registration algorithms (DRA)-based quantification of cine steady-state free-precession (SSFP) for myocardial strain assessment in comparison with feature-tracking (FT) and speckle-tracking echocardiography (STE). METHODS: Data sets of 28 patients/10 volunteers, undergoing same-day 1.5T cardiac MRI and echocardiography were included. LV global longitudinal (GLS), circumferential (GCS) and radial (GRS) peak systolic strain were assessed on cine SSFP data using commercially available FT algorithms and prototype DRA-based algorithms. STE was applied as standard of reference for accuracy, precision and intra-/interobserver reproducibility testing. RESULTS: DRA showed narrower limits of agreement compared to STE for GLS (-4.0 [-0.9, 7.9]) and GCS (-5.1 [1.1,-11.2]) than FT (3.2 [11.2,-4.9]; 3.8 [13.9,-6.3], respectively). While both DRA and FT demonstrated significant differences to STE for GLS and GCS (all p<0.001), only DRA correlated significantly to STE for GLS (r=0.47; p=0.006). However, good correlation was demonstrated between MR techniques (GLS:r=0.74; GCS:r=0.80; GRS:r=0.45, all p<0.05). Comparing DRA with FT, intra-/interobserver coefficient of variance was lower (1.6 %/3.2 % vs. 6.4 %/5.7 %) and intraclass-correlation coefficient was higher. DRA GCS and GRS data presented zero variability for repeated observations. CONCLUSIONS: DRA is an automated method that allows myocardial deformation assessment with superior reproducibility compared to FT. KEY POINTS: * Inverse deformable registration algorithms (DRA) allow myocardial strain analysis on cine MRI. * Inverse DRA demonstrated superior reproducibility compared to feature-tracking (FT) methods. * Cine MR DRA and FT analysis demonstrate differences to speckle-tracking echocardiography * DRA demonstrated better correlation with STE than FT for MR derived global strain data. PMID- 27491874 TI - Multiparametric magnetic resonance imaging characteristics of normal, benign and malignant conditions in the prostate. AB - OBJECTIVES: To identify the multiparametric magnetic resonance imaging (mpMRI) characteristics of normal, benign and malignant conditions in the prostate. METHODS: Fifty-six histopathological whole-mount radical prostatectomy specimens from ten randomly selected patients with prostate cancer (PC) were matched with corresponding transverse mpMRI slices. The mpMRI was performed prior to biopsy and consisted of T2-weighted imaging (T2-WI), diffusion-weighted imaging (DWI), dynamic contrast-enhanced imaging (DCE) and magnetic resonance spectroscopic imaging (MRSI). RESULTS: In each prostate specimen, a wide range of histopathological conditions were observed. They showed consistent but overlapping characteristics on mpMRI. Normal glands in the transition zone showed lower signal intensity (SI) on T2-WI, lower ADC values and lower citrate peaks on MRSI as compared to the peripheral zone (PZ) due to sparser glandular elements and more prominent collagenous fibres. In the PZ, normal glands were iso-intense on T2-WI, while high SI areas represented cystic atrophy. Mimickers of well differentiated PC on mpMRI were inflammation, adenosis, HG-PIN and post-atrophic hyperplasia. CONCLUSION: Each prostate is a unique mix of normal, benign and/or malignant areas that vary in extent and distribution resulting in very heterogeneous characteristics on mpMRI. Understanding the main concepts of this mpMRI-histopathological correlation may increase the diagnostic confidence in reporting mpMRI. KEYPOINTS: * In each prostate specimen a wide range of histopathological conditions was observed. * Interpretation of mpMRI may be difficult because benign conditions may mimic PC. * High signal intensity areas in the PZ on T2-WI represented cystic atrophy. * The TZ showed sparser glands and more collagenous fibres than the PZ. PMID- 27491875 TI - Volumetric MRI study of the intrauterine growth restriction fetal brain. AB - OBJECTIVES: Intrauterine growth restriction (IUGR) is a pathologic fetal condition known to affect the fetal brain regionally and associated with future neurodevelopmental abnormalities. This study employed MRI to assess in utero regional brain volume changes in IUGR fetuses compared to controls. METHODS: Retrospectively, using MRI images of fetuses at 30-34 weeks gestational age, a total of 8 brain regions-supratentorial brain and cavity, cerebral hemispheres, temporal lobes and cerebellum-were measured for volume in 13 fetuses with IUGR due to placental insufficiency and in 21 controls. Volumes and their ratios were assessed for difference using regression models. Reliability was assessed by intraclass correlation coefficients (ICC) between two observers. RESULTS: In both groups, all structures increase in absolute volume during that gestation period, and the rate of cerebellar growth is higher compared to that of supratentorial structures. All structures' absolute volumes were significantly smaller for the IUGR group. Cerebellar to supratentorial ratios were found to be significantly smaller (P < 0.05) for IUGR compared to controls. No other significant ratio differences were found. ICC showed excellent agreement. CONCLUSIONS: The cerebellar to supratentorial volume ratio is affected in IUGR fetuses. Additional research is needed to assess this as a radiologic marker in relation to long-term outcome. KEY POINTS: * IUGR is a pathologic fetal condition affecting the brain * IUGR is associated with long-term neurodevelopmental abnormalities; fetal characterization is needed * This study aimed to evaluate regional brain volume differences in IUGR * Cerebellar to supratentorial volume ratios were smaller in IUGR fetuses * This finding may play a role in long-term development of IUGR fetuses. PMID- 27491876 TI - A simplified method for identifying early CRISPR-induced indels in zebrafish embryos using High Resolution Melting analysis. AB - BACKGROUND: The CRISPR/Cas9 system has become a regularly used tool for editing the genome of many model organisms at specific sites. However, two limiting steps arise in the process of validating guide RNA target sites in larvae and adults: the time required to identify indels and the cost associated with identifying potential mutant animals. RESULTS: Here we have combined and optimized the HotSHOT genomic DNA extraction technique with a two-steps Evagreen PCR, followed by a high-resolution melting (HRM) assay, which facilitates rapid identification of CRISPR-induced indels. With this technique, we were able to genotype adult zebrafish using genomic DNA extracted from fin-clips in less than 2 h. We were also able to obtain a reliable and early read-out of the effectiveness of guide RNAs only 4 h after the embryos were injected with the constructs for the CRISPR/Cas9 mutagenic system. Furthermore, through mutagenesis kinetic assay, we identified that the 2-cell stage is the earliest time point at which indels can be observed. CONCLUSIONS: By combining an inexpensive and rapid genomic DNA extraction method with an HRM-based assay, our approach allows for high throughput genotyping of adult zebrafish and embryos, and is more sensitive than standard PCR approaches, permitting early identification of CRISPR-induced indels and with applications for other model organisms as well. PMID- 27491877 TI - A special issue on CCN proteins and cancer. PMID- 27491878 TI - Transcranial Doppler as a Predictor of Ischemic Events in Carotid Artery Dissection. AB - BACKGROUND: We aim to evaluate clinical features and transcranial Doppler (TCD) elements, as predictors of the development of ischemic events (IEs) in patients suffering from spontaneous carotid arterial dissection without stroke (CCADW). METHODS: Consecutive patients with CCADW, seen in Clinica Alemana de Santiago between April 2004 and January 2015, were evaluated clinically, and with TCD, microembolic signals (MES) monitoring and breath hold Index (BHI) test were performed. RESULTS: Forty-one patients with 45 CCADW were included. Mean age 41.9 years, 31 male, and 12 (29.1%) patients present with multiple CCADW. At the moment of TCD evaluation, 17 (41.4%) patients were being treated with antiplatelets and the rest under Heparin. TCD monitoring lasted in average 53.3 minutes and demonstrated at the moment of evaluation, MES in four carotid arteries (11.1%) of 3 patients and 13 (28.8%) abnormal BHI in 11 patients. Six IEs occurred in 3 patients, 3 strokes, and 3 transient ischemic attacks. In the univariate analysis correlating IE with clinical and ultrasonographic findings, the degree of carotid stenosis, the presence of multiple CAD, and the presence of MES plus abnormalities of BHI were significantly associated with the risk of an IE. Multivariable analysis showed that only the presence of MES plus abnormal BHI were significant (P < .001). MES and abnormal BHI were present in the 3 patients and in four arterial territories that had IE. CONCLUSIONS: TCD can identify a subgroup of patients with CCADW who are at high risk of IE. PMID- 27491880 TI - Nanofibrillar cellulose wound dressing in skin graft donor site treatment. AB - BACKGROUND: Although new therapeutic approaches for burn treatment have made progress, there is still need for better methods to enhance wound healing and recovery especially in severely burned patients. Nanofibrillar cellulose (NFC) has gained attention due to its renewable nature, good biocompatibility and excellent physical properties that are of importance for a range of applications in pharmaceutical and biomedical fields. In the present study, we investigated the potential of a wood based NFC wound dressing in a clinical trial on burn patients. Previously, we have investigated NFC as a topical functionalized wound dressing that contributes to improve wound healing in mice. METHODS: Wood based NFC wound dressing was tested in split-thickness skin graft donor site treatment for nine burn patients in clinical trials at Helsinki Burn Centre. NFC dressing was applied to split thickness skin graft donor sites. The dressing gradually dehydrated and attached to donor site during the first days. During the clinical trials, physical and mechanical properties of NFC wound dressing were optimized by changing its composition. From patient 5 forward, NFC dressing was compared to commercial lactocapromer dressing, Suprathel(r) (PMI Polymedics, Germany). RESULTS: Epithelialization of the NFC dressing-covered donor site was faster in comparison to Suprathel(r). Healthy epithelialized skin was revealed under the detached NFC dressing. NFC dressing self-detached after 11-21days for patients 1 9, while Suprathel(r) self-detached after 16-28days for patients 5-9. In comparison studies with patients 5-9, NFC dressing self-detached on average 4days earlier compared with Suprathel(r). Lower NFC content in the material was evaluated to influence the enhanced pliability of the dressing and attachment to the wound bed. No allergic reaction or inflammatory response to NFC was observed. NFC dressing did not cause more pain for patients than the traditional methods to treat the skin graft donor sites. CONCLUSION: Based on the preliminary clinical data, NFC dressing seems to be promising for skin graft donor site treatment since it is biocompatible, attaches easily to wound bed, and remains in place until donor site has renewed. It also detaches from the epithelialized skin by itself. PMID- 27491879 TI - Reproductive age-associated fibrosis in the stroma of the mammalian ovary. AB - Under normal physiological conditions, tissue remodeling in response to injury leads to tissue regeneration without permanent damage. However, if homeostasis between synthesis and degradation of extracellular matrix (ECM) components is altered, fibrosis - or the excess accumulation of ECM - can disrupt tissue architecture and function. Several organs, including the heart, lung and kidney, exhibit age-associated fibrosis. Here we investigated whether fibrosis underlies aging in the ovary - an organ that ages chronologically before other organs. We used Picrosirius Red (PSR), a connective tissue stain specific for collagen I and III fibers, to evaluate ovarian fibrosis. Using bright-field, epifluorescence, confocal and polarized light microscopy, we validated the specific staining of highly ordered PSR-stained fibers in the ovary. We next examined ovarian PSR staining in two mouse strains (CD1 and CB6F1) across an aging continuum and found that PSR staining was minimal in ovaries from reproductively young adult animals, increased in distinct foci in animals of mid-to-advanced reproductive age, and was prominent throughout the stroma of the oldest animals. Consistent with fibrosis, there was a reproductive age-associated increase in ovarian hydroxyproline content. We also observed a unique population of multinucleated macrophage giant cells, which are associated with chronic inflammation, within the ovarian stroma exclusively in reproductively old mice. In fact, several genes central to inflammation had significantly higher levels of expression in ovaries from reproductively old mice relative to young mice. These results establish fibrosis as an early hallmark of the aging ovarian stroma, and this altered microenvironment may contribute to the age-associated decline in gamete quality. PMID- 27491881 TI - Immunomodulation of hematological malignancies using oligonucleotides based nanomedicines. AB - Hematological malignancies are a group of diseases characterized by clonal proliferation of blood-forming cells. Malignant blood cells are classified as myeloid or lymphoid cells depending on their stem cell origin. Lymphoid malignancies are characterized by lymphocyte accumulation in the blood stream, in the bone marrow, or in lymphatic nodes and organs. Several of these diseases are associated with chromosomal translocations, which cause gene fusion and amplification of expression, while others are characterized with aberrant expression of oncogenes. Overall, these genes play a major role in development and maintenance of malignant clones. The discovery of antisense oligonucleotides and RNA interference (RNAi) mechanisms offer new tools to specifically manipulate gene expression. Systemic delivery of inhibitory oligonucleotides molecules for manipulation of gene expression in lymphocytes holds a great potential for facilitating the development of an oligonucleotides -based therapy platform for lymphoid blood cancer. However, lymphocytes are among the most difficult targets for oligonucleotides delivery, as they are resistant to conventional transfection reagents and are dispersed throughout the body, making it difficult to successfully localize or deliver oligonucleotides payloads via systemic administration. In this review, we will survey the latest progress in the field of oligonucleotides based nanomedicine in the heterogeneous group of hematological malignancies with special emphasis on RNA based strategies. We will describe the most advanced non-viral nanocarriers for RNA delivery to malignant blood cells. We will also discuss targeted strategies for cell specific delivery of RNA molecules using nanoparticles and the therapeutic benefit of manipulating gene function in hematological malignancies. Finally, we will focus on the ex vivo, in vivo, and clinical trial strategies, that are currently under development in hematological malignancies - strategies that might increase the arsenal of drugs available to hematologists in the upcoming years. PMID- 27491882 TI - Therapeutic and diagnostic applications of extracellular vesicles. AB - During the past two decades, extracellular vesicles (EVs) have been identified as important mediators of intercellular communication, enabling the functional transfer of bioactive molecules from one cell to another. Consequently, it is becoming increasingly clear that these vesicles are involved in many (patho)physiological processes, providing opportunities for therapeutic applications. Moreover, it is known that the molecular composition of EVs reflects the physiological status of the producing cell and tissue, rationalizing their exploitation as biomarkers in various diseases. In this review the composition, biogenesis and diversity of EVs is discussed in a therapeutic and diagnostic context. We describe emerging therapeutic applications, including the use of EVs as drug delivery vehicles and as cell-free vaccines, and reflect on future challenges for clinical translation. Finally, we discuss the use of EVs as a biomarker source and highlight recent studies and clinical successes. PMID- 27491883 TI - Nilotinib reverses ABCB1/P-glycoprotein-mediated multidrug resistance but increases cardiotoxicity of doxorubicin in a MDR xenograft model. AB - The BCR-Abl tyrosine kinase inhibitor (TKI), nilotinib, was developed to surmount resistance or intolerance to imatinib in patients with Philadelphia-positive chronic myelogenous leukemia. Recent studies have shown that nilotinib induces potent sensitization to anticancer agents by blocking the functions of ABCB1/P glycoprotein (P-gp) in multidrug resistance (MDR). However, changes in P-gp expression or function affect the cardiac disposition and prolong the presence of both doxorubicin (DOX) and doxorubicinol (DOXol) in cardiac tissue, thus, enhancing the risk of cardiotoxicity. In this study, we used a MDR xenograft model to evaluate the antitumor activity, tissue distribution and cardiotoxicity of DOX when co-administered with nilotinib. This information will provide more insight into the pharmacological role of nilotinib in MDR reversal and the risk of DOX cardiotoxicity. Our results showed that nilotinib significantly enhanced DOX cytotoxicity and increased intracellular rhodamine 123 accumulation in MG63/DOX cells in vitro and strongly enhanced DOX inhibition of growth of P-gp overexpressing MG63/DOX cell xenografts in nude mice. Additionally, nilotinib significantly increased DOX and DOXol accumulation in serum, heart, liver and tumor tissues. Importantly, nilotinib induced a disproportionate increase in DOXol in cardiac tissue. In the co-administration group, CBR1 and AKR1A1 protein levels were significantly increased in cardiac tissue, with more severe necrosis and vacuole formation. These results indicate that nilotinib reverses P-gp- mediated MDR by blocking the efflux function and potentiates DOX-induced cardiotoxicity. These findings represent a guide for the design of future clinical trials and studies of pharmacokinetic interactions and may be useful in guiding the use of nilotinib in combination therapy of cancer in clinical practice. PMID- 27491884 TI - Estimation of bisphenol A-Human toxicity by 3D cell culture arrays, high throughput alternatives to animal tests. AB - Bisphenol A (BPA) has been widely used for manufacturing polycarbonate plastics and epoxy resins and has been extensively tested in animals to predict human toxicity. In order to reduce the use of animals for toxicity assessment and provide further accurate information on BPA toxicity in humans, we encapsulated Hep3B human hepatoma cells in alginate and cultured them in three dimensions (3D) on a micropillar chip coupled to a panel of metabolic enzymes on a microwell chip. As a result, we were able to assess the toxicity of BPA under various metabolic enzyme conditions using a high-throughput and micro assay; sample volumes were nearly 2,000 times less than that required for a 96-well plate. We applied a total of 28 different enzymes to each chip, including 10 cytochrome P450s (CYP450s), 10 UDP-glycosyltransferases (UGTs), 3 sulfotransferases (SULTs), alcohol dehydrogenase (ADH), and aldehyde dehydrogenase 2 (ALDH2). Phase I enzyme mixtures, phase II enzyme mixtures, and a combination of phase I and phase II enzymes were also applied to the chip. BPA toxicity was higher in samples containing CYP2E1 than controls, which contained no enzymes (IC50, 184+/-16MUM and 270+/-25.8MUM, respectively, p<0.01). However, BPA-induced toxicity was alleviated in the presence of ADH (IC50, 337+/-17.9MUM), ALDH2 (335+/-13.9MUM), and SULT1E1 (318+/-17.7MUM) (p<0.05). CYP2E1-mediated cytotoxicity was confirmed by quantifying unmetabolized BPA using HPLC/FD. Therefore, we suggest the present micropillar/microwell chip platform as an effective alternative to animal testing for estimating BPA toxicity via human metabolic systems. PMID- 27491887 TI - Introduction to the Special Section on Clinical Applications of Multi-Scale Modeling. PMID- 27491885 TI - Effects of Sialic Acid Modifications on Virus Binding and Infection. AB - Sialic acids (Sias) are abundantly displayed on the surfaces of vertebrate cells, and particularly on all mucosal surfaces. Sias interact with microbes of many types, and are the targets of specific recognition by many different viruses. They may mediate virus binding and infection of cells, or alternatively can act as decoy receptors that bind virions and block virus infection. These nine-carbon backbone monosaccharides naturally occur in many different modified forms, and are attached to underlying glycans through varied linkages, creating significant diversity in the pathogen receptor forms. Here we review the current knowledge regarding the distribution of modified Sias in different vertebrate hosts, tissues, and cells, their effects on viral pathogens where those have been examined, and outline unresolved questions. PMID- 27491888 TI - Persistent Luminescent Nanocarrier as an Accurate Tracker in Vivo for Near Infrared-Remote Selectively Triggered Photothermal Therapy. AB - Optical imaging-guidance of indocyanine green (ICG) for photothermal therapy (PTT) has great latent capacity in cancer therapy. However, the conventional optical image-guidance mode has caused strong tissue autofluorescence of the living tissue, which leads to the accurate infrared light irradiation cannot be conducted. In this article, ICG and persistent luminescence phosphors (PLPs) coloaded mesoporous silica nanocarriers ((ICG+PLPs)@mSiO2) were first designed and prepared for persistent luminescent imaging-guided PTT. The (ICG+PLPs)@mSiO2 nanocarriers could significantly improve signal-to-noise ratio during luminescence imaging-guided PTT, making the PLP promising for improving the accuracy of the tumor site for photothermal therapy in vivo. This paper is likely to develop a new way for accurately regulating cancer cell death based on luminescence imaging-guided PTT selectively triggered by near-infrared (NIR) remote. PMID- 27491889 TI - Attendance of cultural events and involvement with the arts-impact evaluation on health and well-being from a Swiss household panel survey. AB - OBJECTIVES: Although there is strong uptake of active or passive engagement with the cultural and creative activities as determinants of individual health, well being and social participation, few population studies report any causal influence on self-reported and physical health or life satisfaction from voluntary engagement with the arts (playing an instrument or singing, painting, sculpture) or passive cultural participation (attending the cinema, theatre, opera and exhibitions). This study set out to investigate any potential derived benefits to the Swiss population. STUDY DESIGN: The 2010 and 2013 waves of the Swiss Household Panel study were used for analysis. The data are representative for the Swiss population aged 14 years and older with respect to major demographic variables. METHODS: Using longitudinal data, the strengths of the two approaches to evaluating causal inference were simultaneously applied: propensity score matching and difference-in-differences. Propensity score matching attempted to eliminate selection bias by conditioning on confounding variables. Difference in-differences estimator was applied to remove unobserved fixed effects via intra individual comparisons over time by comparing the trends in a matched treatment and control group. RESULTS: The study showed that voluntary cultural activity-of any type, passive or active-did not seem to have any causative influence on health and well-being. Results showed that long-term health and well-being did not improve significantly as a result of any specific activity in the cultural arena. CONCLUSIONS: The investigation provided little evidence to justify health promotion messages for involvement with the arts. Nevertheless, these findings do not contest that active or passive participation in cultural- and arts-related activities may be beneficial to health and well-being when guided by qualified therapists to treat specific health-related problems. PMID- 27491886 TI - Natural Products and the Gene Cluster Revolution. AB - Genome sequencing has created unprecedented opportunities for natural-product discovery and new insight into the diversity and distributions of natural-product biosynthetic gene clusters (BGCs). These gene collectives are highly evolved for horizontal exchange, thus providing immediate opportunities to test the effects of small molecules on fitness. The marine actinomycete genus Salinispora maintains extraordinary levels of BGC diversity and has become a useful model for studies of secondary metabolism. Most Salinispora BGCs are observed infrequently, resulting in high population-level diversity while conforming to constraints associated with maximum genome size. Comparative genomics is providing a mechanism to assess secondary metabolism in the context of evolution and evidence that some products represent ecotype-defining traits while others appear selectively neutral. PMID- 27491890 TI - Shedding light on azopolymer brush dynamics by fluorescence correlation spectroscopy. AB - Understanding the response to illumination at a molecular level as well as characterising polymer brush dynamics are key features that guide the engineering of new light-stimuli responsive materials. Here, we report on the use of a confocal microscopy technique that was exploited to discern how a single molecular event such as the photoinduced isomerisation of azobenzene can affect an entire polymeric material at a macroscopic level leading to photodriven mass migration. For this reason, a set of polymer brushes, containing azobenzene (Disperse Red 1, DR) on the side chains of poly(methacrylic acid), was synthesised and the influence of DR on the polymer brush dynamics was investigated for the first time by Fluorescence Correlation Spectroscopy (FCS). Briefly, two dynamics were observed, a short one coming from the isomerisation of DR and a long one related to the brush main chain. Interestingly, photoinduced polymer aggregation in the confocal volume was observed. PMID- 27491891 TI - Pyrogallol, an absorbable microbial gallotannins-metabolite and mango polyphenols (Mangifera Indica L.) suppress breast cancer ductal carcinoma in situ proliferation in vitro. AB - Mango is rich in bioactive absorbable polyphenols, but also contains considerable amounts of unabsorbable gallotannins at varying degrees of polymerization. Gallotannins are not absorbable upon consumption and have rarely been considered in the discussion of health benefits of polyphenols. Therefore, the objective of this study was to investigate the anti-proliferative activities of the major microbial metabolite of gallotannins, pyrogallol (PG) and a low molecular weight fraction of mango (Mangifera Indica L.) polyphenols (ML) and involved pathways including the AKT/mTOR signaling axis in an in situ breast cancer cell line, MCF10DCIS.COM. Fluorouracil (5-FU), a widely used genotoxic cancer therapeutic, was used a positive control and in combination with ML and PG to assess potential interactions. Concentrations that were non-cytotoxic in non-cancer cells were identified in non-cancer mammary fibroblasts (MCF-12F) and only non-cytotoxic dietarily relevant concentrations were selected for the investigation in MCF10DCIS.COM cancer cells. In addition to proliferation and viability, mRNA and expression of total and phosphorylated protein were investigated. Results show that both, ML and PG significantly reduced proliferation in MCF10DCIS.COM, but did not significantly reduce viability following a 48 h exposure. ML significantly reduced mRNA expression of mTOR and HIF-1alpha, while PG significantly reduced mRNA of IGF-1R, AKT, mTOR and HIF-1alpha. ML and PG reduced total protein expression of IGF-1R, IR, AKT, mTOR, and P70S6K. In addition, PG reduced IRS protein. Both treatments also had an effect on phosphorylated protein levels, with PG significantly reducing IGF-1R, AKT, and P70S6K levels. ML had a similar effect and significantly decreased IR, AKT, and P70S6K phosphorylation levels. Within the low concentration-range, ML and PG did not interact with the cytotoxic activities of 5-FU. Overall, the AKT/mTOR signaling axis appears to be implicated as causal in decreased proliferation induced by diet-relevant concentrations of ML and PG. PMID- 27491892 TI - Genomic identification, rapid evolution, and expression of Argonaute genes in the tilapia, Oreochromis niloticus. AB - Argonaute proteins are key components of the small RNA-induced silencing complex and have multiple roles in RNA-directed regulatory pathways. Argonaute genes can be divided into two subfamilies: the Ago (interacting with microRNA/small interfering RNA) and Piwi subfamilies (interacting with piwi-interacting RNAs (piRNAs)). In the present study, genome-wide analyses firstly yielded the identification of different members of Agos and Piwis in the tilapia, coelacanth, spotted gar, and elephant shark. The additional teleost Ago3b was generated following the fish-specific genome duplication event. Selective pressure analysis on Agos and Piwis between cichlids and other teleosts showed an accelerated evolution of Piwil1 in the cichlid lineages, and the positive selected sites were located in the region of PIWI domain, suggesting that these amino acid substitutions are adapt to targeted cleavage of messenger RNA (mRNA) in cichlids. Ago1 and Ago4 were detected at higher levels at 5 days after hatching (dah) in both ovaries and testes compared with other stages, supporting the previously reported requirement of Ago-mediated pathways to clear the maternal mRNAs during the early embryogenesis. The Piwis were abundantly expressed in tilapia testes, indicating their essential roles in male germline, especially in spermatogenesis. Notable expression of Piwis was also detected in skeletal muscle, indicating that piRNA pathway may not only be confined to development and maintenance of the germline but may also play important roles in somatic tissues. The expression of Piwil1 and Piwil2 was examined by quantitative PCR (qPCR) and in situ hybridization (ISH) to validate the spatial and temporal expression profiles. Taken together, these results present a thorough overview of tilapia Argonaute family and provide a new perspective on the evolution and function of this family in teleosts. PMID- 27491894 TI - Optimal modified tracking performance for networked control systems with QoS constraint. AB - This paper investigates the optimal modified tracking performance of networked control systems with a constraint on quality of service (QoS). The QoS is characterized by two parameters of the system, viz. data dropout and the additive white Gaussian noise. The proposed modified tracking performance index prevents the probability of invalid data arising from the variations in the tracking error in the absence of an integrator in the plant. The derived optimal filter eliminates the influence of channel noise in the feedback channel. The optimal modified tracking performance expression is obtained by using the co-prime factorization. Results indicate that the optimal modified tracking performance is influenced by the non-minimum phase zeros, modification factor, packet dropout probability, and the characteristics of the reference signals. The obtained results will give some guidance for the design of networked control systems. The efficiency of the model is verified using some typical examples. PMID- 27491893 TI - Concurrent quantification of multiple biomarkers indicative of oxidative stress status using liquid chromatography-tandem mass spectrometry. AB - 8-Hydroxy-2-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NO2Gua), 8-iso prostaglandin F2alpha (8-IsoPGF2alpha), and N-acetyl-S-(tetrahydro-5-hydroxy-2 pentyl-3-furanyl)-L-cysteine (HNE-MA) are well-studied and representative biomarkers for oxidative DNA damage, inflammation, and lipid peroxidation; all of which have been associated with increases in risks of various diseases and cancers. A rapid and highly sensitive isotope-dilution liquid-chromatography tandem mass spectrometry (LC-MS/MS) method was developed to simultaneously quantify the aforementioned biomarkers in urine. Upon validation, this method shows excellent feasibility, sensitivity (0.008-0.03 ng/mL) and satisfactory recoveries (88.7-95.4%); the calibration curves displayed excellent linearity with coefficients of determination (R(2)) greater than 0.998. Additionally, low variations were observed in the relative standard deviation for intra- and inter day measurements for the four analytes. The relative matrix effects for all four analytes ranged from 2.04 to 3.27%, which signaled that interferences from endogenous levels of the analytes were deemed statistically insignificant. This study successfully developed an analytical method capable to simultaneously quantify urinary 8-OHdG, 8-NO2Gua, 8-IsoPGF2alpha, and HNE-MA. This analytical protocol can be applied towards conducting epidemiological studies to reveal the mechanisms related to disease development, and thus evaluate the associated risks of diseases. PMID- 27491895 TI - Meta-analysis of variance: an illustration comparing the effects of two dietary interventions on variability in weight. AB - Meta-analysis, which drives evidence-based practice, typically focuses on the average response of subjects to a treatment. For instance in nutritional research the difference in average weight of participants on different diets is typically used to draw conclusions about the relative efficacy of interventions. As a result of their focus on the mean, meta-analyses largely overlook the effects of treatments on inter-subject variability. Recent tools from the study of biological evolution, where inter-individual variability is one of the key ingredients for evolution by natural selection, now allow us to study inter subject variability using established meta-analytic models. Here we use meta analysis to study how low carbohydrate (LC) ad libitum diets and calorie restricted diets affect variance in mass. We find that LC ad libitum diets may have a more variable outcome than diets that prescribe a reduced calorie intake. Our results suggest that whilst LC diets are effective in a large proportion of the population, for a subset of individuals, calorie restricted diets may be more effective. There is evidence that LC ad libitum diets rely on appetite suppression to drive weight loss. Extending this hypothesis, we suggest that between-individual variability in protein appetite may drive the trends that we report. A priori identification of an individual's target intake for protein may help define the most effective dietary intervention to prescribe for weight loss. PMID- 27491896 TI - Tunable electronic structures of germanium monochalcogenide nanosheets via light non-metallic atom functionalization: a first-principles study. AB - Germanium monochalcogenides, i.e. GeS and GeSe sheets, are isoelectronic analogues of phosphorene, which have been synthesized in recent experiments (P. Ramasamy et al., J. Mater. Chem. C, 2016, 4, 479). Utilizing first-principles calculations, we have investigated their tunable electronic and magnetic properties via light non-metallic atom (B, C, N, O, Si, P, S) functionalization. We find that on these GeS and GeSe sheets O and S adatoms prefer to locate at the top site above the Ge atom, while the other ones like to occupy the anion site, which push the original S/Se atom to the hollow site instead. O and S adatoms slightly affect the semiconducting behaviour of the doped systems, while B, C, N, Si, P ones will drastically modify their band structures and induce versatile spintronic properties. Through the supercell calculations, B and C adatoms are found to induce a bipolar semiconducting behaviour in the decorated systems, while the N/P adatom will cause a spin-gapless-semiconducting/nearly-half metallic feature in them. The B/C/N/Si/P-substituted GeS/GeSe sheet can be formed by removing the hollow-site S/Se atom from the adatom-decorated structures, which exhibit an opposite semiconducting/metallic behaviour to their phosphorene counterparts. A general odd-even rule is proposed for this phenomenon, which shows that an odd (even) number of valence electron difference between the substitution and host atoms would cause a metallic (semiconducting) feature in the substituted systems. Our study demonstrates that atom functionalization is an efficient way to tailor the properties of GeS and GeSe nanosheets, which have adaptable electronic properties for potential applications in nanoelectronics and spintronics. PMID- 27491897 TI - Targeting Oxidative Stress in Central Nervous System Disorders. AB - There is widespread recognition that reactive oxygen species (ROS) play key roles in normal brain function and pathology in the context of neurological disease. Oxidative stress continues to be a key therapeutic target for neurological diseases. In developing antioxidant therapies for neurological disease, special attention should be given to the brain's unique vulnerability to oxidative insults and its architecture. Consideration of antioxidant therapy should be guided by a strong rationale for oxidative stress in a given neurological disease. This review provides an overview of processes that can guide the development of antioxidant therapies in neurological diseases, such as knowledge of basic redox mechanisms, unique features of brain pathophysiology, mechanisms and classes of antioxidants, and desirable properties of drug candidates. PMID- 27491898 TI - The Intratumoral Balance between Metabolic and Immunologic Gene Expression Is Associated with Anti-PD-1 Response in Patients with Renal Cell Carcinoma. AB - Pretreatment tumor PD-L1 expression has been shown to correlate with response to anti-PD-1/PD-L1 therapies. Yet, most patients with PD-L1(+) tumors do not respond to treatment. The current study was undertaken to investigate mechanisms underlying the failure of PD-1-targeted therapies in patients with advanced renal cell carcinoma (RCC) whose tumors express PD-L1. Formalin-fixed, paraffin embedded pretreatment tumor biopsies expressing PD-L1 were derived from 13 RCC patients. RNA was isolated from PD-L1(+) regions and subjected to whole genome microarray and multiplex quantitative (q)RT-PCR gene expression analysis. A balance between gene expression profiles reflecting metabolic pathways and immune functions was associated with clinical outcomes following anti-PD-1 therapy. In particular, the expression of genes involved in metabolic and solute transport functions such as UGT1A family members, also found in kidney cancer cell lines, was associated with treatment failure in patients with PD-L1(+) RCC. Conversely, tumors from responding patients overexpressed immune markers such as BACH2, a regulator of CD4(+) T-cell differentiation, and CCL3 involved in leukocyte migration. These findings suggest that tumor cell-intrinsic metabolic factors may contribute to treatment resistance in RCC, thus serving as predictive markers for treatment outcomes and potential new targets for combination therapy regimens with anti-PD-1. Cancer Immunol Res; 4(9); 726-33. (c)2016 AACRSee related Spotlight by Ohashi, p. 719. PMID- 27491899 TI - Retroviral particles are effectively purified on an affinity matrix containing peptides selected by phage-display. AB - Retroviral particles are expensive to manufacture, mostly due to the downstream processing steps which result in low recoveries (~30%) and concentration factors. In this work, a dodecapeptide phage-display library was panned against retrovirus like particles expressing the envelope protein Ampho4070A (VLPs-AMPHO) and VLPs without the target protein, used as a negative control (VLPs). A depletion/selection panning protocol was successfully used to deal with the structural complexity of the target, and a total of three distinct peptide sequences displaying preferential binding towards VLPs-AMPHO were found. Peptide 3 (CAAALAKPHTENHLLT), which appeared as one lead candidate, was synthesized and immobilized onto two purification matrices, cross-linked agarose and magnetic particles. The matrices selectively bound VLPs-AMPHO and in both cases recovery yields higher than 90% were obtained when employing mild elution conditions, while maintaining viral particle morphology and size. PMID- 27491900 TI - Cardiovascular Magnetic Resonance to Evaluate Aortic Regurgitation After Transcatheter Aortic Valve Replacement. AB - BACKGROUND: Residual aortic regurgitation (AR) following transcatheter aortic valve replacement (TAVR) is associated with greater mortality; yet, determining AR severity post-TAVR using Doppler echocardiography remains challenging. Cardiovascular magnetic resonance (CMR) is purported as a more accurate means of quantifying AR; however, no data exist regarding the prognostic value of AR as assessed by CMR post-TAVR. OBJECTIVES: This study sought to evaluate the effect of AR assessed with CMR on clinical outcomes post-TAVR. METHODS: We included 135 patients from 3 centers. AR was quantified using regurgitant fraction (RF) measured by phase-contrast velocity mapping CMR at a median of 40 days post-TAVR, and using Doppler echocardiography at a median of 6 days post-TAVR. Median follow up was 26 months. Clinical outcomes included mortality and rehospitalization for heart failure. RESULTS: Moderate-severe AR occurred in 17.1% and 12.8% of patients as measured by echocardiography and CMR, respectively. Higher RF post TAVR was associated with increased mortality (hazard ratio: 1.18 for each 5% increase in RF [95% confidence interval: 1.08 to 1.30]; p < 0.001) and the combined endpoint of mortality and rehospitalization for heart failure (hazard ratio: 1.19 for each 5% increase in RF; 95% confidence interval: 1.15 to 1.23; p < 0.001). Prediction models yielded significant incremental predictive value; CMR performed a median of 40 days post-TAVR had a greater association with post-TAVR clinical events compared with early echocardiography (p < 0.01). RF >=30% best predicted poorer clinical outcomes (p < 0.001 for either mortality or the combined endpoint of mortality and heart failure rehospitalization). CONCLUSIONS: Worse CMR-quantified AR was associated with increased mortality and poorer clinical outcomes following TAVR. Quantifying AR with CMR may identify patients with AR who could benefit from additional treatment measures. PMID- 27491901 TI - When Accurate Flow Quantitation Matters: The Case of CMR Assessment of Aortic Regurgitation After TAVR. PMID- 27491902 TI - Cerebral Embolism: A Silent Iatrogenic Complication of TAVR That Needs Voiced Consideration. PMID- 27491903 TI - Radial Artery as a Coronary Artery Bypass Conduit: 20-Year Results. AB - BACKGROUND: There is a lack of evidence for the choice of the second conduit in coronary surgery. The radial artery (RA) is a possible option, but few data on very-long-term outcomes exist. OBJECTIVES: This study describes 20-year results of RA grafts used for coronary artery bypass grafting and the effects of RA removal on forearm circulation. METHODS: We report the results of the prospective 20-year follow-up of the first 100 consecutive patients who received the RA as a coronary bypass conduit at our institution. RESULTS: Follow-up was 100% complete. There were 64 deaths, 23 (35.9%) from cardiovascular causes. Kaplan-Meier 20-year survival was 31%. Of the 36 survivors, 33 (91.6%) underwent RA graft control at a mean of 19.0 +/- 2.5 years after surgery. The RA was found to be patent in 24 cases (84.8% patency). In the overall population, probability of graft failure at 20 years was 19.0 +/- 0.2% for the left internal thoracic artery (ITA), 25.0 +/- 0.2% for the RA, and 55.0 +/- 0.2% for the saphenous vein (p = 0.002 for RA vs. saphenous vein, 0.11 for RA vs. ITA, and p < 0.001 for ITA vs. saphenous vein). Target vessel stenosis >90%, but not location of distal anastomosis, significantly influenced long-term RA graft patency. No patients reported hand or forearm symptoms. The ulnar artery diameter was increased in the operated arm (2.44 +/- 0.43 mm vs. 2.01 +/- 0.47 mm; p < 0.05) and correlated with the peak systolic velocity of the second palmar digital artery (Pearson coefficient: 0.621; p < 0.05). CONCLUSIONS: The 20-year patency rate of RA grafts is good, and not inferior to the ITA, especially when the conduit is used to graft a vessel with >90% stenosis. RA harvesting does not lead to hand or forearm symptoms, even at a very-long-term follow-up. PMID- 27491904 TI - The Radial Artery Graft: Clinical or Subclinical Benefits? PMID- 27491905 TI - Long-Term Trends in Newly Diagnosed Brugada Syndrome: Implications for Risk Stratification. AB - BACKGROUND: A proband of Brugada syndrome (BrS) is the first patient diagnosed in a family. There are no data regarding this specific, high-risk population. OBJECTIVES: This study sought to investigate the Brugada probands diagnosed from 1986 through the next 28 years. METHODS: We included 447 probands belonging to families with a diagnostic type 1 electrocardiogram Brugada pattern. The database was divided into 2 periods: the first period identified patients who were part of the initial cohort that became the consensus document on BrS in 2002 (early group); the second period reflected patients first diagnosed from 2003 to January 2014 (latter group). RESULTS: There were 165 probands in the early group and 282 in the latter group. Aborted sudden death as the first manifestation of the disease occurred in 12.1% of the early group versus 4.6% of the latter group (p = 0.005). Inducibility during programmed electrical stimulation was achieved in 34.4% and 19.2% of patients, respectively (p < 0.001). A spontaneous type 1 electrocardiogram pattern at diagnosis was present in 50.3% early versus 26.2% latter patients (p = 0.0002). Early group patients had a higher probability of a recurrent arrhythmia during follow-up (19%) than those of the latter group (5%) (p = 0.007). The clinical suspicion and use of a sodium-channel blocker to unmask BrS has allowed earlier diagnoses in many patients. CONCLUSIONS: Since being first described, the presentation of BrS has changed. There has been a decrease in aborted sudden cardiac death as the first manifestation of the disease among patients who were more recently diagnosed. These variations in initial presentation have important clinical consequences. In this setting, the value of inducibility to stratify individuals with BrS has changed. PMID- 27491906 TI - Brugada Syndrome: The Endless Conundrum. PMID- 27491907 TI - Predicting In-Hospital Mortality in Patients With Acute Myocardial Infarction. AB - BACKGROUND: As a foundation for quality improvement, assessing clinical outcomes across hospitals requires appropriate risk adjustment to account for differences in patient case mix, including presentation after cardiac arrest. OBJECTIVES: The aim of this study was to develop and validate a parsimonious patient-level clinical risk model of in-hospital mortality for contemporary patients with acute myocardial infarction. METHODS: Patient characteristics at the time of presentation in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry-GWTG (Get With the Guidelines) database from January 2012 through December 2013 were used to develop a multivariate hierarchical logistic regression model predicting in-hospital mortality. The population (243,440 patients from 655 hospitals) was divided into a 60% sample for model derivation, with the remaining 40% used for model validation. A simplified risk score was created to enable prospective risk stratification in clinical care. RESULTS: The in-hospital mortality rate was 4.6%. Age, heart rate, systolic blood pressure, presentation after cardiac arrest, presentation in cardiogenic shock, presentation in heart failure, presentation with ST-segment elevation myocardial infarction, creatinine clearance, and troponin ratio were all independently associated with in-hospital mortality. The C statistic was 0.88, with good calibration. The model performed well in subgroups based on age; sex; race; transfer status; and the presence of diabetes mellitus, renal dysfunction, cardiac arrest, cardiogenic shock, and ST-segment elevation myocardial infarction. Observed mortality rates varied substantially across risk groups, ranging from 0.4% in the lowest risk group (score <30) to 49.5% in the highest risk group (score >59). CONCLUSIONS: This parsimonious risk model for in-hospital mortality is a valid instrument for risk adjustment and risk stratification in contemporary patients with acute myocardial infarction. PMID- 27491908 TI - No One Size Fits All: Scoring Risk of In-Hospital Death After Myocardial Infarction. PMID- 27491909 TI - A Test in Context: Neprilysin: Function, Inhibition, and Biomarker. AB - Neprilysin is a zinc-dependent endopeptidase. It is ubiquitous in distribution and promiscuous in function, with >50 putative peptide substrates with varying levels of in vitro and/or in vivo evidence of functional relevance. In the first part of this review, we discuss the genetic, structural, substrate, and pathophysiological aspects of neprilysin. We incorporate information provided by genetically modified models, as well as pre-clinical and clinical data from investigations of synthetic neprilysin inhibitors. We next highlight the value of neprilysin as a biotarget and weigh the clinical benefits of synthetic neprilysin inhibitors, either alone or in combination with antagonists of the renin angiotensin system. Finally, we provide evidence about soluble neprilysin as a biomarker surrogate in patients with heart failure and identify important gaps that require further research before soluble neprilysin is used clinically. In sum, neprilysin is a versatile, veteran player returning yet again to center stage after an eventful career spanning >40 years. PMID- 27491910 TI - Aortic Valve Sparing in Different Aortic Valve and Aortic Root Conditions. AB - The development of aortic valve-sparing operations (reimplantation of the aortic valve and remodeling of the aortic root) expanded the surgical armamentarium for treating patients with aortic root dilation caused by a variety of disorders. Young adults with aortic root aneurysms associated with genetic syndromes are ideal candidates for reimplantation of the aortic valve, and the long-term results have been excellent. Incompetent bicuspid aortic valves with dilated aortic annuli are also satisfactorily treated with the same type of operation. Older patients with ascending aortic aneurysm and aortic insufficiency secondary to dilated sinotubular junction and a normal aortic annulus can be treated with remodeling of the aortic root or with reimplantation of the aortic valve. The first procedure is simpler, and both procedures are likely equally effective. As with any heart valve-preserving procedure, patient selection and surgical expertise are keys to successful and durable repairs. PMID- 27491911 TI - Brugada Syndrome and the Subcutaneous Implantable Cardioverter-Defibrillator. PMID- 27491912 TI - Community-Based Trends in Acute Myocardial Infarction From 2008 to 2014. PMID- 27491913 TI - Mean Arterial Pressure Estimation by a Non-Traditional Formula and Fractional Pulse Pressure. PMID- 27491914 TI - Reply: Mean Arterial Pressure Estimation by a Non-Traditional Formula and Fractional Pulse Pressure. PMID- 27491915 TI - A Prima Vista Ablation of Ventricular Tachycardia: Should We Abandon the Mapping of VT? PMID- 27491916 TI - Reply: A Prima Vista Ablation of Ventricular Tachycardia: Should We Abandon the Mapping of VT? PMID- 27491917 TI - Small angle x-ray scattering with edge-illumination. AB - Sensitivity to sub-pixel sample features has been demonstrated as a valuable capability of phase contrast x-ray imaging. Here, we report on a method to obtain angular-resolved small angle x-ray scattering distributions with edge illumination- based imaging utilizing incoherent illumination from an x-ray tube. Our approach provides both the three established image modalities (absorption, differential phase and scatter strength), plus a number of additional contrasts related to unresolved sample features. The complementarity of these contrasts is experimentally validated by using different materials in powder form. As a significant application example we show that the extended complementary contrasts could allow the diagnosis of pulmonary emphysema in a murine model. In support of this, we demonstrate that the properties of the retrieved scattering distributions are consistent with the expectation of increased feature sizes related to pulmonary emphysema. Combined with the simplicity of implementation of edge-illumination, these findings suggest a high potential for exploiting extended sub-pixel contrasts in the diagnosis of lung diseases and beyond. PMID- 27491918 TI - CNS Multiparameter Optimization Approach: Is it in Accordance with Occam's Razor Principle? AB - A detailed analysis of the possibility of using the Multiparameter Optimization approach (MPO) for CNS/non-CNS classification of drugs was carried out. This work has shown that MPO descriptors are able to describe only part of chemical transport in the CNS connected with transmembrane diffusion. Hence the "intuitive" CNS MPO approach with arbitrary selection of descriptors and calculations of score functions, search of thresholds of classification, and absence of any chemometric procedures, leads to rather modest accuracy of CNS/non CNS classification models. PMID- 27491919 TI - 3D Structure, Dimerization Modeling, and Lead Discovery by Ligand-protein Interaction Analysis of p60 Transcription Regulator Protein (p60TRP). AB - The p60 transcription regulator protein (p60TRP) is a basic helix-loop-helix (bHLH) domain-containing neuroprotective protein and a member of the G-protein coupled receptor (GPCR)-associated sorting protein (GPRASP) family. In the present study, multiple theoretical physico-chemical methods (e.g. Modeller v.9.13, I-TASSER, PROCHECK and ClusPro v2.0 with PIPER) were applied to unveil the three-dimensional (3D) protein structure of the p60TRP homo-dimer protein and explore potential ligand-protein interactions. Our results suggest a Mg(2+) containing 3D p60TRP dimer protein that potentially interacts with 5-(1 aziridinyl)-2,4-dinitrobenzamide (CB1954) and [2-(3-dodecylimidazolidin-1-yl)-1 phosphonoethyl] phosphonic acid (B73). The discovery of CB1954 and B73 may serve as a potential lead for further drug screening tests to normalize the p60TRP signaling pathway in neurodegenerative diseases. Interference with p60TRP signaling via CB1954/B73-related molecules might be a novel option for modifying neurodegenerative signaling pathways (e.g. RIN1, PP2A, RanBP5, CREB and SYNJ1) to treat various brain diseases. PMID- 27491920 TI - Classification of Mixtures of Chinese Herbal Medicines Based on a Self-organizing Map (SOM). AB - Chinese Herbal Medicines (CHMs) are typically mixtures of compounds and are often categorized into cold and hot according to the theory of Chinese Medicine. This classification is essential for guiding the clinical application of CHMs. In this study, three types of molecular descriptors were used to build models for classification of 59 CHMs with typical cold/hot properties in the training set taken from the original records on properties in China Pharmacopeia as reference. The accuracy and the Matthews correlation coefficient of the models were validated by a test set containing other 56 CHMs. The best model produced the accuracies of 94.92 % and 83.93 % on training set and test set, respectively. The MACCS fingerprint model is robust in predicting hot/cold properties of the CHMs from their major constituting compounds. This work shows how a classification model for data consisting of multi-components can be developed. The derived model can be used for the application of Chinese herbal medicines. PMID- 27491921 TI - Using Support Vector Machine (SVM) for Classification of Selectivity of H1N1 Neuraminidase Inhibitors. AB - Inhibition of the neuraminidase is one of the most promising strategies for preventing influenza virus spreading. 479 neuraminidase inhibitors are collected for dataset 1 and 208 neuraminidase inhibitors for A/P/8/34 are collected for dataset 2. Using support vector machine (SVM), four computational models were built to predict whether a compound is an active or weakly active inhibitor of neuraminidase. Each compound is represented by MASSC fingerprints and ADRIANA.Code descriptors. The predication accuracies for the test sets of all the models are over 78 %. Model 2B, which is the best model, obtains a prediction accuracy and a Matthews Correlation Coefficient (MCC) of 89.71 % and 0.81 on test set, respectively. The molecular polarizability, molecular shape, molecular size and hydrogen bonding are related to the activities of neuraminidase inhibitors. The models can be obtained from the authors. PMID- 27491922 TI - A Random Forest Model for Predicting Allosteric and Functional Sites on Proteins. AB - We created a computational method to identify allosteric sites using a machine learning method trained and tested on protein structures containing bound ligand molecules. The Random Forest machine learning approach was adopted to build our three-way predictive model. Based on descriptors collated for each ligand and binding site, the classification model allows us to assign protein cavities as allosteric, regular or orthosteric, and hence to identify allosteric sites. 43 structural descriptors per complex were derived and were used to characterize individual protein-ligand binding sites belonging to the three classes, allosteric, regular and orthosteric. We carried out a separate validation on a further unseen set of protein structures containing the ligand 2-(N cyclohexylamino) ethane sulfonic acid (CHES). PMID- 27491923 TI - In silico Prediction of Drug Induced Liver Toxicity Using Substructure Pattern Recognition Method. AB - Drug-induced liver injury (DILI) is a leading cause of acute liver failure in the US and less severe liver injury worldwide. It is also one of the major reasons of drug withdrawal from the market. Thus, DILI has become one of the most important concerns of drugs, and should be predicted in very early stage of drug discovery process. In this study, a comprehensive data set containing 1317 diverse compounds was collected from publications. Then, high accuracy classification models were built using five machine learning methods based on MACCS and FP4 fingerprints after evaluating by substructure pattern recognition method. The best model was built using SVM method together with FP4 fingerprint at the IG value threshold of 0.0005. Its overall predictive accuracies were 79.7 % and 64.5 % for the training and test sets, separately, which yielded overall accuracy of 75.0 % for the external validation dataset, consisting of 88 compounds collected from a benchmark DILI database - the Liver Toxicity Knowledge Base. This model could be used for drug-induced liver toxicity prediction. Moreover, some key substructure patterns correlated with drug-induced liver toxicity were also identified as structural alerts. PMID- 27491924 TI - Structural and Functional Diversities of the Hexadecahydro-1H cyclopenta[a]phenanthrene Framework, a Ubiquitous Scaffold in Steroidal Hormones. AB - Hexadecahydro-1H-cyclopenta[a]phenanthrene framework (HHCPF) has been considered as one of the privileged scaffolds due to its versatile presence in many biologically essential molecules. In our quest to unravel the privileged nature of this framework, we undertook a systematic analysis of target binding and Absorption, Distribution, Metabolism, Elimination, Toxicity (ADMET)/physicochemical properties of 110 drugs containing HHCPF reported in DrugBank. Effect of number and positions of double bonds in the framework and substitutions at each carbon position on the target selectivity as well as drug like properties of these drugs were studied. Fifteen different scaffolds based on the numbers and positions of double bonds in the HHCPF were identified among these drugs. The optimum number of double bonds present in the HHCPF scaffolds was observed to be one to three, and one particular positional isomer is predominant among many scaffolds with same numbers of double bonds. Docking studies reveal the role of substituents at different positions to make specific interactions with their respective targets. Based on the docking interactions, we proposed structure based e-Pharmacophore models for seven important targets of HHCPF drugs. Good correlations were observed between the substitutions carbon positions 3 and 17 of the scaffolds and ADMET properties of the HHCPF drugs. This work enables preliminary prediction of the target selectivity and ADMET properties of a new HHCPF molecule based on the scaffold, substituents and the pharmacophoric features. PMID- 27491925 TI - Microbiomic and Posttranslational Modifications as Preludes to Autoimmune Diseases. AB - Diagnosis and treatment of autoimmunity has mainly relied on adaptive immunity. Infection and inflammation induce cytokines and chemokines and activate myeloid cells to release enzymes. Proteases cleave host proteins into a molar excess of remnant peptides. Additional enzymes modify these peptides into putative autoantigens prior to T and B cell activation. We propose that post-translational modifications may be a means of generating auto-reactive peptides. Microbes also provide proteases and modifying enzymes to the host, and we posit that this may result in autoantigen generation. This could help explain, at least in part, the recently discovered connections between microbiota and autoimmunity. Better explorations of the innate prelude phase of autoimmunity in conjunction with environmental factors might provide novel, broadly applicable therapies. PMID- 27491927 TI - Hierarchical architecture of the inner layers of selected extant rhynchonelliform brachiopods. AB - In spite of several attempts for a best knowledge of the phylum, brachiopods remain, compared with molluscs, among those least analysed in terms of biomineralization. The lack of economic impact for extant species is probably liable for that situation. Much attention has been on the microstructure of calcite biomaterials (rhynchonelliforms and craniiforms). Here, we emphasize the sub-micrometric structure of selected examples of rhynchonelliform shells using Atomic Force Microscopy (AFM) to complement Scanning Electron Microscopy (SEM) and Energy Dispersive X-ray (EDX) analyses. The hierarchical organization of the shell layers (secondary and/or tertiary elements) is highlighted for species non yet observed from this point of view, and is compared to a few already mentioned in the literature. Previous analysis revealed that granules are composed of a complex aggregation of sub-units in intimate relation with an intracrystalline matrix. Their shape, size and probably early orientation depend on the species as well as age and living environments of the specimens studied. The control of the inorganic part of the composite fibrous elements is constrained by the deposition of nearly arched shape or polygonal protein membranes at the inner boundary of the primary layer, prior to the deposition of the first granules, membranes becoming proteinaceous sheathes progressively enshrining fibres. The diverse orientations of the granules in fibrous neighbours thus further increase arguments in favour of the tendency to improve the shell strength. PMID- 27491928 TI - Allergen-specific immune response suppresses interleukin 10 expression in B cells via increasing micro-RNA-17-92 cluster. AB - Interleukin (IL)-10-expressing B cells play a critical role in the immune homeostasis in the body; its regulation has not been fully understood. Micro-RNA (miR)-17-92 cluster has strong regulation in the immunity. This study tests a hypothesis that miR-17-92 cluster suppresses IL-10 expression in B cells. In this study, peripheral B cells were collected from patients with allergic rhinitis (AR). The B cells were treated with specific allergens, dust mite extracts, in the culture. The expressions of miR-17-92 cluster and IL-10 in the culture were assessed by real-time quantitative reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. The results showed that the levels of miR-19a, but not the rest of the 5 members (miR-17, miR-18a, miR-19b, miR-20a, and miR-92a), were significantly higher in peripheral B cells from AR patients as than in B cells from healthy participants. Exposure of B cells from AR patients to specific allergen, dust mite extracts, significantly increased the levels if miR-19a and suppressed the expression of IL-10 in B cells. The levels of histone deacetylase 11 and acetylated H3K9 were higher, and the RNA polymerase II and c-Maf (the IL-10 transcription factor) were lower, at the IL-10 promoter locus. In conclusion, miR-19a mediates the allergen-specific immune response decreased IL-10 expression in B cells. PMID- 27491929 TI - A Mathematical Model for Biocontrol of the Invasive Weed Fallopia japonica. AB - We propose a mathematical model for biocontrol of the invasive weed Fallopia japonica using one of its co-evolved natural enemies, the Japanese sap-sucking psyllid Aphalara itadori. This insect sucks the sap from the stems of the plant thereby weakening it. Its diet is highly specific to F. japonica. We consider a single isolated knotweed stand, the plant's size being described by time dependent variables for total stem and rhizome biomass. It is the larvae of A. itadori that damage the plant most, so the insect population is described in terms of variables for the numbers of larvae and adults, using a stage-structured modelling approach. The dynamics of the model depends mainly on a parameter h, which measures how long it takes for an insect to handle (digest) one unit of F. japonica stem biomass. If h is too large, then the model does not have a positive equilibrium and the plant biomass and insect numbers both grow together without bound, though at a lower rate than if the insects were absent. If h is sufficiently small, then the model possesses a positive equilibrium which appears to be locally stable. The results based on our model imply that satisfactory long term control of the knotweed F. japonica using the insect A. itadori is only possible if the insect is able to consume and digest knotweed biomass sufficiently quickly; if it cannot, then the insect can only slow down the growth which is still unbounded. PMID- 27491930 TI - Letter in response to "Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1)". PMID- 27491926 TI - Phage-Enabled Nanomedicine: From Probes to Therapeutics in Precision Medicine. AB - Both lytic and temperate bacteriophages (phages) can be applied in nanomedicine, in particular, as nanoprobes for precise disease diagnosis and nanotherapeutics for targeted disease treatment. Since phages are bacteria-specific viruses, they do not naturally infect eukaryotic cells and are not toxic to them. They can be genetically engineered to target nanoparticles, cells, tissues, and organs, and can also be modified with functional abiotic nanomaterials for disease diagnosis and treatment. This Review will summarize the current use of phage structures in many aspects of precision nanomedicine, including ultrasensitive biomarker detection, enhanced bioimaging for disease diagnosis, targeted drug and gene delivery, directed stem cell differentiation, accelerated tissue formation, effective vaccination, and nanotherapeutics for targeted disease treatment. We will also propose future directions in the area of phage-based nanomedicines, and discuss the state of phage-based clinical trials. PMID- 27491932 TI - Hereditary angioedema: death after a dental extraction. AB - Hereditary angioedema (HAE) is a group of three uncommon and potentially fatal conditions, each of which is transmitted as a somatic dominant trait. A recognized trigger to attacks is dental treatment, with tooth extraction frequently reported in the published work. The clinical symptoms may not manifest for many hours or even days after the procedure. We describe a recent case in Australia in which death resulted from HAE following dental extraction, and we discuss its post-mortem presentation and diagnosis, highlighting the need for dental practitioners to be aware of this condition. PMID- 27491933 TI - Impact of glyphosate-resistant corn, glyphosate applications and tillage on soil nutrient ratios, exoenzyme activities and nutrient acquisition ratios. AB - BACKGROUND: We report results of the last two years of a 7 year field experiment designed to test the null hypothesis: applications of glyphosate on glyphosate resistant (GR) and non-resistant (non-GR) corn (Zea mays L.) under conventional tillage and no-till would have no effect on soil exoenzymes and microbial activity. RESULTS: Bulk soil (BS) and rhizosphere soil (RS) macronutrient ratios were not affected by either GR or non-GR corn, or glyphosate applications. Differences observed between exoenzyme activities were associated with tillage rather than glyphosate applications. In 2013, nutrient acquisition ratios for bulk and rhizosphere soils indicated P limitations, but sufficient assimilable N. In 2014, P limitations were observed for bulk and rhizosphere soils, in contrast to balanced C and N acquisition ratios in rhizosphere soils. Stoichiometric relationships indicated few differences between glyphosate and non-glyphosate treatments. Negative correlations between C:P and N:P nutrient ratios and nutrient acquisition ratios underscored the inverse relation between soil nutrient status and microbial community exoenzyme activities. CONCLUSIONS: Inconsistent relationships between microbial community metabolic activity and exoenzyme activity indicated an ephemeral effect of glyphosate on BS exoenzyme activity. Except for ephemeral effects, glyphosate applications appeared not to affect the function of the BS and RS exoenzymes under conventional tillage or no till. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. PMID- 27491931 TI - Edible Ginger-derived Nano-lipids Loaded with Doxorubicin as a Novel Drug delivery Approach for Colon Cancer Therapy. AB - The use of nanotechnology for drug delivery has shown great promise for improving cancer treatment. However, potential toxicity, hazardous environmental effects, issues with large-scale production, and potential excessive costs are challenges that confront their further clinical applications. Here, we describe a nanovector made from ginger-derived lipids that can serve as a delivery platform for the therapeutic agent doxorubicin (Dox) to treat colon cancer. We created nanoparticles from ginger and reassembled their lipids into ginger-derived nanovectors (GDNVs). A subsequent characterization showed that GDNVs were efficiently taken up by colon cancer cells. Viability and apoptosis assays and electric cell-substrate impedance-sensing technology revealed that GDNVs exhibited excellent biocompatibility up to 200 MUmol/l; by contrast, cationic liposomes at the same concentrations decreased cell proliferation and increased apoptosis. GDNVs were capable of loading Dox with high efficiency and showed a better pH-dependent drug-release profile than commercially available liposomal Dox. Modified GDNVs conjugated with the targeting ligand folic acid mediated targeted delivery of Dox to Colon-26 tumors in vivo and enhanced the chemotherapeutic inhibition of tumor growth compared with free drug. Current experiments explore the feasibility of producing nature-derived nanoparticles that are effective as a treatment vehicle while potentially attenuating the issues related to traditional synthetic nanoparticles. PMID- 27491934 TI - A scoping review examining physical activity measurement and levels in the first 2 years of life. AB - BACKGROUND: The first few years of life have been identified as a critical stage in the development of activity behaviours, which have been shown to track into later life. This scoping review aims to assess the literature reporting on physical activity levels in the first 2 years of life in order to answer two main questions: (i) how is physical activity measured in this age group? and (ii) how active are infants and toddlers in the first 2 years of life? METHODS: A search strategy was employed using PubMed with restrictions only on age and language. After applying exclusion criteria, 20 papers were included in the results. RESULTS: Seventeen studies used some form of objective assessment of physical activity (accelerometers, actometers, direct observation, doubly labelled water or a metabolic chamber); while the remaining three relied on subjective assessments (parent reported questionnaires or interviews, and activity diaries). Nine studies exclusively assessed infants (<12 months), and five exclusively assessed toddlers (>12 months). Only six studies reported physical activity levels and patterns specifically; most included studies measured activity as a covariate or correlate. Therefore, much of the reported data was difficult to assess, as results were vague or incompletely described. Where data were reported sufficiently for analysis, results were equally conflicted regarding whether toddlers were meeting recommended physical activity guidelines. CONCLUSIONS: This scoping review re-iterates the fact that more studies need to be conducted, which focus primarily on measuring and reporting physical activity levels and patterns in this age group in a comprehensive and standardized way, so that more informed guidelines can be devised and interventions can be designed and implemented where necessary. PMID- 27491935 TI - 9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-11H indeno[1, 2-c]quinolin-11-one (BPIQ), A Quinoline Derivative Inhibits Human Hepatocellular Carcinoma Cells by Inducing ER Stress and Apoptosis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading cancers in the world, including Taiwan. The chemoresistance of advanced HCC frequently results in the poor prognosis of patients. Previous studies demonstrated the quinoline derivative, 9-bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1 yl)ethoxy]phenyl}-11Hindeno[ 1,2-c]quinolin-11-one (BPIQ) exerts the inhibitory potential against several cancer cells, including liver cancer cells. OBJECTIVE: We further investigated the anti-HCC effects of BPIQ, including apoptosis and the modulation of ER stress. METHODS: Both trypan blue exclusion assay and colony formation assay were performed to examine whether BPIQ affects the growth of HCC cell lines Ha22T and Huh7. Flow cytometry-based assay was performed for determining the cell cycle distribution and apoptosis. Western blot assay was conducted for detecting the changes in apoptosis- and endoplasmic reticulum (ER) stress-associated proteins. RESULTS: BPIQ inhibits cell growth and induces the apoptosis of both Ha22T and Huh7 cell lines significantly. The level of gammaH2AX, an endogenous DNA damage biomarker was dramatically increased suggesting the involvement of DNA damage pathway in BPIQ-induced apoptosis. Further, BPIQ down-regulates the pro-survival proteins, survivin, XIAP and cyclin D1. BPIQ also may regulate ER stress response through modulating the levels of ER stress-related proteins Glucose-regulated protein of 78 kD (GRP78), Inositol requiring kinase-1alpha (IREalpha), C/EBP homologous protein (Chop) and calnexin. CONCLUSIONS: The anti-HCC effect of BPIQ may occur through down-regulating pro survival proteins, and the modulation of ER stress may contribute to the BPIQ induced apoptosis of HCC cells. The chemotherapeutic or chemopreventive applications of BPIQ for HCC treatment will be worthy of further investigation in future. PMID- 27491937 TI - Synthesis and Evaluation of A New Series of Thiazole Derivatives as Potential Antitumor Agents and MMP Inhibitors. AB - BACKGROUND: In recent years, the relationship between overexpression of matrix metalloproteinases (MMPs) and tumor invasion/metastasis has prompted researchers to develop MMP inhibitors as anticancer drugs. OBJECTIVE: The aim of this study was to design and synthesize new thiazole-based anticancer agents targeting MMPs. METHOD: New thiazole derivatives were synthesized and investigated for their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cell lines using MTT assay. The potential inhibitory effects of the best candidates on gelatinases (MMP-2, MMP-9), and collagenases (MMP-1, MMP-8, MMP-13) were evaluated. RESULTS: Ethyl 2 [2-((4-amino-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)acetamido]-4 methylthiazole-5-carboxylate (3) was found to be the most promising anticancer agent against MCF-7 cell line due to its selective inhibitory effect on MCF-7 cells with an IC50 value of 20.6+/-0.3 MUg/mL when compared with cisplatin (IC50= 35.31+/-0.51 MUg/mL). Compound 3 also showed multiple MMP (MMP-1, MMP-8 and MMP 9) inhibitory activity (10.56+/-1.70, 20 and 7.28+/-1.49%, respectively). CONCLUSION: The notable anticancer activity and selectivity of compound 3 on MCF 7 cell line can be attributed to multiple MMP inhibition potential. PMID- 27491938 TI - Postpartum Depression and Social Support in China: A Cultural Perspective. AB - This study explored how Chinese culture affects the relationship between social support and postpartum depression. In-depth interviews with 38 mothers in mainland China showed that discrepancies between expected and perceived available social support and conflicts among social support providers are two major contributors to the stress associated with postpartum depression. These dynamics are deeply rooted in the context of Chinese culture with its distinctive gender roles and family dynamics. These cultural norms further prevent women from seeking social support. PMID- 27491936 TI - The Effects of 1,3,5-trisubstituted Indole Derivatives on Cell Growth, Apoptosis and MMP-2/9 mRNA Expression of MCF-7 Human Breast Cancer Cells. AB - BACKGROUND: Matrix metalloproteinases are known as extracellular matrix degrading enzymes and have important role on tumor progression. OBJECTIVE: This study reports the effects of 1,3,5-trisubstituted indole derivatives on cytotoxicity, apoptosis and MMP- 2/MMP-9 mRNA expression of MCF-7 human breast carcinoma cells. METHOD: The cytotoxic effects of the compounds on MCF-7 cells were performed by MTT test, and cell proliferation was determined via BrdU incorporation. The apoptotic effects were observed by cell death detection elisa. The effects of the compounds on MMP-2/-9 enzyme activity and mRNA expression were also performed. RESULTS: The compounds inhibited the proliferation of MCF-7 breast carcinoma cells significantly in a dose dependent manner. All compounds were able to induce DNA fragmentation, especially compound 1. The IC50 values of compound 2 and 4 for MMP-2 were 0.42 MUM and 1.88 MUM, respectively. MMP-2 mRNA expression results were correlated with the inhibition of enzyme activity, such compound 4 inhibited MMP-2 mRNA expression at all treated concentrations. Docking simulation has also been performed to analyze the binding mode of compounds and the results showed that compound 2, the most active compound, formed a hydrogen bond with Glu202 for binding to the MMP-2 active site. In addition, the hydrophobic parts of compound 2 are in contact with nonpolar surface areas of MMP-2, such as His201, His211, Tyr223 and Tyr193. CONCLUSION: According to the molecular docking results along with the biological assay data, it is suggested that compound 2 might be used for further design and development of MMP-2 inhibitors. PMID- 27491939 TI - Piptadenin, a Novel 3,4-Secooleanane Triterpene and Piptadenamide, a New Ceramide from the Stem Bark of Piptadeniastrum africanum (Hook.f.) Brenan. AB - Piptadenin (1), a new triterpene along with piptadenamide (10), a new ceramide, have been isolated from the AcOEt-soluble fraction of the MeOH extract of the stem bark of Piptadeniastrum africanum along with nine known compounds, 1-O [(3beta,22beta)-3,22-dihydroxy-28-oxoolean-12-en-28-yl]-beta-d-glucopyranose (2), 22beta-hydroxyoleanic acid (3), oleanic acid (4), lupeol (5), betulinic acid (6), 5alpha-stigmasta-7,22-dien-3beta-ol (7), 5alpha-stigmasta-7,22-dien-3-one (8), (3beta)-stigmast-5-en-3-yl beta-d-glucopyranoside (9) and 2,3-dihydroxypropyl hexacosanoate (11). Except for compound 11, all the isolated compounds are reported for the first time from this plant. The structures of the isolated compounds were elucidated by spectroscopic data including 1D and 2D NMR. The pure compounds 1 - 11 were subjected to the pharmacological screening and compounds 2, 5 - 7 and 9 exhibited potent urease inhibitory activity with IC50 value of 25.8, 28.9, 30.1, 31.8 and 32.7 MUm, respectively, whereas compound 1 showed moderate activity (IC50 = 98.7 MUm). The potent urease inhibitory activity supplemented the previous literature reports and medicinal uses of this plant. PMID- 27491940 TI - Identification and transcript profiles of citrus growth-regulating factor genes involved in the regulation of leaf and fruit development. AB - Growth-regulating factor (GRF) is an important protein in GA-mediated response, with key roles in plant growth and development. However, it is not known whether or how the GRF proteins in citrus to regulate organ size. In this study, nine citrus GRF genes (CsGRF1-9) were validated from the 'Anliu' sweet orange (AL, Citrus sinensis cv. Anliu) by PCR amplification. They all contain two conserved motifs (QLQ and WRC) and have 3-4 exons. The transcript levels of genes were detected by qRT-PCR. Transcript analysis showed that (1) CsGRF 1, 2, 5, 6, 7, and 9 expressed predominantly in young leaf, CsGRF 3 and 4 expressed predominantly in fruit immature juice sacs and CsGRF 8 expressed predominantly in root; (2) all citrus GRF genes had significantly higher expression in young leaves than mature leaf; (3) in juice sacs, the transcript levels of CsGRF1, 4, 5, 6, and 8 increased significantly while the transcript levels of CsGRF2, 3, 7, and 9 had no significant change from 80 DAF to 100 DAF. Besides, GA3 treatment did not affect the transcript levels of CsGRF5 and CsGRF6 but significantly increased the transcript levels of the other seven CsGRF genes in young leaves. These results suggested that all CsGRF genes involve in the leaf development, CsGRF1, 4, 5, 6, and 8 act developmentally whilst CsGRF2, 3, 7, and 9 play fundamental roles in fruit cell enlargement, which may be through GA pathway or GA-independent pathway. PMID- 27491941 TI - Obstetrical outcomes of emergency compared with elective cervical cerclage. AB - OBJECTIVE: To study obstetric outcomes of emergency cerclage compared with elective cerclage. STUDY DESIGN: Retrospective cohort study of pregnancy outcomes of patients who underwent cervical cerclage, performed according to ACOG guidelines, between January 2006 and December 2014. Patients who underwent emergency cerclage, due to cervical shortening or cervical dilation (emergency cerclage group) were compared with patients who underwent history-indicated cerclage (elective cerclage group). Emergency cerclage was not performed in patients with uterine contractions, vaginal bleeding, or signs of chorioamnionitis. Procedure-related complications were defined as rupture of membranes or chorioamnionitis occurring after cerclage placement and before 24 weeks of gestation. RESULTS: Overall, 154 patients with elective cerclage and 47 patients with emergency cerclage were included. Mean gestational age at cerclage operation was 13.1 +/- 1 and 20.2 +/- 3 weeks, respectively. There were no differences between the emergency cerclage group and the elective cerclage group regarding mean gestational age at delivery (36.1 +/- 3 versus 35.6 +/- 3, respectively, p = 0.7), rate of deliveries beyond 34 weeks of gestation (81.81% versus 78.72%, respectively, p = 0.67), rate of deliveries beyond 37 weeks of gestation (64.93% versus 59.57%, respectively, p = 0.6), cesarean deliveries (33.11% versus 39.13%, p = 0.48, respectively), or birthweight (2848 versus 2862 grams, respectively, p = 0.9). Regarding procedure-related complications, there were no differences between the elective and the emergency cerclage groups in the rate of chorioamnionitis (1.29% versus 4.34%, respectively, p = 0.22), or ruptured membranes (1.29% versus 4.34%, respectively, p = 0.22). CONCLUSION: Pregnancy outcomes of emergency cerclage are comparable with those of elective cerclage. PMID- 27491942 TI - Narrative as re-fusion: Making sense and value from sickle cell and thalassaemia trait. AB - The moral turn within sociology suggests that we need to be attentive to values and have a rapprochement with philosophy. The study of illness narratives is one area of sociology that has consistently addressed itself to moral domains but has tended to focus on stories of living with genetic or chronic illness per se rather than liminal states such as genetic traits. This article takes the case of genetic carriers within racialized minority groups, namely, those with sickle cell or thalassaemia trait, and takes seriously the notion that their narratives are ethical practices. In line with the work of Paul Ricoeur, such storied practices are found to link embodiment, social relationships with significant others and wider socio-cultural and socio-political relations. At the same time, such practices are about embodying values. These narratives may be considered as practices that re-fuse what genetic counselling has de-fused, in order to make sense of a life in its entirety and to strive ethically and collectively towards preferred social realities. PMID- 27491943 TI - Practices of partnership: Negotiated safety among couples who inject drugs. AB - Despite the majority of needle-syringe sharing occurring between sexual partners, the intimate partnerships of people who inject drugs have been largely overlooked as key sites of both hepatitis C virus prevention and transmission, and risk management more generally. Drawing on interviews with 34 couples living in inner city Australia, this article focuses on participants' accounts of 'sharing'. While health promotion discourses and conventional epidemiology have tended to interpret the practice of sharing (like the absence of condom use) in terms of 'noncompliance', we are interested in participants' socially and relationally situated 'rationalities'. Focussing on participants' lived experiences of partnership, we endeavour to make sense of risk and safety as the participants themselves do.How did these couples engage with biomedical knowledge around hepatitis C virus and incorporate it into their everyday lives and practices? Revisiting and refashioning the concept of 'negotiated safety' from its origins in gay men's HIV prevention practice, we explore participants' risk and safety practices in relation to multiple and alternative framings, including those which resist or challenge mainstream epidemiological or health promotion positions. Participant accounts revealed the extent to which negotiating safety was a complex and at times contradictory process, involving the balancing or prioritising of multifarious, often competing, risks. We argue that our positioning of participants' partnerships as the primary unit of analysis represents a novel and instructive way of thinking about not only hepatitis C virus transmission and prevention, but the complexities and contradictions of risk production and its negotiation more broadly. PMID- 27491944 TI - All care, but whose responsibility? Community juries reason about expert and patient responsibilities in prostate-specific antigen screening for prostate cancer. AB - General practitioners have implicitly been given responsibility for guiding men's decisions about prostate-specific antigen-based screening for prostate cancer, but patients' expectations of the bounds of this responsibility remain unclear. We sought to explore how well-informed members of the public allocate responsibilities in prostate-specific antigen screening decision-making. In 2014, we convened two Community juries in Sydney, Australia, to address questions related to the content and timing of information provision and respective roles of patients and general practitioners in screening decisions. Participants in the first jury were of mixed gender and of all ages (n = 15); the participants in the second jury were all male and of screening age (n = 12). Both juries were presented with balanced factual evidence on the harms and benefits of prostate specific antigen screening and expert perspectives on ethico-legal aspects of consent in medical practice. In their deliberations, jurors agreed that general practitioners should take responsibility for informing men of the options, risks and benefits of prostate-specific antigen testing, but arrived at different positions on whether or not general practitioners should also guide screening decisions. Jurors also disagreed on how much and when general practitioners should provide detailed information about biopsies and treatments. These responses suggest that for prostate-specific antigen testing, there is a public expectation that both the allocation of responsibility between general practitioners and their male patients, and the level of information provided will be tailored to individual men. In the presence of expert uncertainty, a well informed public may have reason to embrace or resist shared decision-making processes. PMID- 27491945 TI - Shape morphing Kirigami mechanical metamaterials. AB - Mechanical metamaterials exhibit unusual properties through the shape and movement of their engineered subunits. This work presents a new investigation of the Poisson's ratios of a family of cellular metamaterials based on Kirigami design principles. Kirigami is the art of cutting and folding paper to obtain 3D shapes. This technique allows us to create cellular structures with engineered cuts and folds that produce large shape and volume changes, and with extremely directional, tuneable mechanical properties. We demonstrate how to produce these structures from flat sheets of composite materials. By a combination of analytical models and numerical simulations we show how these Kirigami cellular metamaterials can change their deformation characteristics. We also demonstrate the potential of using these classes of mechanical metamaterials for shape change applications like morphing structures. PMID- 27491946 TI - Guidance from an in situ hot stage in TEM to synthesize magnetic metal nanoparticles from a MOF. AB - A series of in situ hot stage experiments using transmission electron microscopy (TEM) were studied to directly observe the transition of a Ni-MOF to Ni nanoparticles wrapped in carbon (Ni-NPC) over temperatures ranging from ambient temperature to 700 degrees C. Ni-NPC-600 displays high catalytic activity in 4 nitrophenol reduction and high conversion, even after 10 cycles. PMID- 27491947 TI - The cooperativity effect in the reaction of soluble quinoprotein (PQQ-containing) glucose dehydrogenase is not due to subunit interaction but to substrate-assisted catalysis. AB - : Soluble quinoprotein (PQQ-containing) glucose dehydrogenase (sGDH, EC 1.1.99.35) catalyzes the oxidation of beta-d-glucose to d-glucono-delta-lactone. Although sGDH has many analytical applications, the relationship between activity and substrate concentration is not well established. Previous steady-state kinetic studies revealed a negative cooperativity effect which has recently been ascribed to subunit interaction. To investigate this conclusion, stopped-flow kinetic experiments were carried out on the reaction in which oxidized enzyme (Eox ) was reduced with substrates to Ered . The appearance of Ered is observed to be preceded by formation of an intermediate enzyme form, Int, which is mono exponentially formed from Eox . However, the rate of conversion of Int into Ered depends hyperbolically on the concentration of substrate (leading to a 35-fold stimulation in the case of glucose). Evidence is provided that substrate not only binds to Eox but also to Int and Ered as well, and that the binding to Int causes the significant stimulation of Int decay. It is proposed that a proton shuffling step is involved in the decay, which is facilitated by binding of substrate to Int. Substituting the PQQ-activating Ca by a Ba ion lowered all reaction rates but did not change the stimulation factor. In summary, the previous proposal that the cooperativity effect of sGDH is due to interaction between its substrate loaded subunits is incorrect; it is due to substrate-assisted catalysis of the enzyme. ENZYMES: EC 1.1.99.35 - soluble quinoprotein glucose dehydrogenase. PMID- 27491948 TI - Prenatal metal exposure in the Middle East: imprint of war in deciduous teeth of children. AB - In war zones, the explosion of bombs, bullets, and other ammunition releases multiple neurotoxicants into the environment. The Middle East is currently the site of heavy environmental disruption by massive bombardments. A very large number of US military bases, which release highly toxic environmental contaminants, have also been erected since 2003. Current knowledge supports the hypothesis that war-created pollution is a major cause of rising birth defects and cancers in Iraq. We created elemental bio-imaging of trace elements in deciduous teeth of children with birth defects from Iraq. Healthy and naturally shed teeth from Lebanon and Iran were also analyzed for trace elements. Lead (Pb) was highest in teeth from children with birth defects who donated their teeth from Basra, Iraq (mean 0.73-16.74 (208)Pb/(43)Ca ppm, n = 3). Pb in healthy Lebanese and Iranian teeth were 0.038-0.382 (208)Pb/(43)Ca ppm (n = 4) and 0.041 0.31 (208)Pb/(43)Ca ppm (n = 2), respectively. Our hypothesis that increased war activity coincides with increased metal levels in deciduous teeth is confirmed by this research. Lead levels were similar in Lebanese and Iranian deciduous teeth. Deciduous teeth from Iraqi children with birth defects had remarkably higher levels of Pb. Two Iraqi teeth had four times more Pb, and one tooth had as much as 50 times more Pb than samples from Lebanon and Iran. PMID- 27491949 TI - Quantitative assessment of possible human health risk associated with consumption of arsenic contaminated groundwater and wheat grains from Ropar Wetand and its environs. AB - Arsenic (As) is a carcinogenic metalloid that enters food chain through food and water and poses health risk to living beings. It is important to assess the As status in the environment and risks associated with it. Hence, a risk assessment study was conducted across Ropar wetland, Punjab, India and its environs in pre monsoon season of 2013, to estimate the risk posed to adults and children via daily consumption of As contaminated groundwater and wheat grains. Arsenic concentrations determined in groundwater, soil and wheat grain samples using atomic absorption spectrometer ranged from 2.90 to 10.56 MUg L(-1), 0.06 to 0.12 mg kg(-1) and 0.03 to 0.21 mg kg(-1), respectively. Arsenic in wheat grains showed significant negative correlation with phosphate content in soil indicating a competitive uptake of arsenate and phosphate ions by plants. Principal component analysis and cluster analysis suggested that both natural and anthropogenic factors contribute to variation in As content and other variables studied in soil and groundwater samples. Total cancer risk and hazard index were higher than the USEPA safety limits of 1.00 * 10(-6) and 1, respectively, for both adults and children indicating a high risk of cancer and other health disorders. Consumption of As contaminated wheat grains was found to pose higher risk of cancer and non-cancer health disorders as compared to intake of As contaminated groundwater by both adults and children. Moreover, children were found to be more prone to cancer and other heath disorders due to As exposure via wheat grains and groundwater as compared to adults. PMID- 27491950 TI - The Impact of Nursing Home Pay-for-Performance on Quality and Medicare Spending: Results from the Nursing Home Value-Based Purchasing Demonstration. AB - OBJECTIVE: To evaluate the impact of the Nursing Home Value-Based Purchasing demonstration on quality of care and Medicare spending. DATA SOURCES/STUDY SETTING: Administrative and qualitative data from Arizona, New York, and Wisconsin nursing homes over the base-year (2008-2009) and 3-year (2009-2012) demonstration period. STUDY DESIGN: Nursing homes were randomized to the intervention in New York, while the comparison facilities were constructed via propensity score matching in Arizona and Wisconsin. We used a difference-in difference analysis to compare outcomes across the base-year relative to outcomes in each of the three demonstration years. To provide context and assist with interpretation of results, we also interviewed staff members at participating facilities. PRINCIPAL FINDINGS: Medicare savings were observed in Arizona in the first year only and Wisconsin for the first 2 years; no savings were observed in New York. The demonstration did not systematically impact any of the quality measures. Discussions with nursing home administrators suggested that facilities made few, if any, changes in response to the demonstration, leading us to conclude that the observed savings likely reflected regression to the mean rather than true savings. CONCLUSION: The Federal nursing home pay-for-performance demonstration had little impact on quality or Medicare spending. PMID- 27491951 TI - VCO2 calorimetry is a convenient method for improved assessment of energy expenditure in the intensive care unit. PMID- 27491952 TI - Transition from two-dimensional photonic crystals to dielectric metasurfaces in the optical diffraction with a fine structure. AB - We study experimentally a fine structure of the optical Laue diffraction from two dimensional periodic photonic lattices. The periodic photonic lattices with the C4v square symmetry, orthogonal C2v symmetry, and hexagonal C6v symmetry are composed of submicron dielectric elements fabricated by the direct laser writing technique. We observe surprisingly strong optical diffraction from a finite number of elements that provides an excellent tool to determine not only the symmetry but also exact number of particles in the finite-length structure and the sample shape. Using different samples with orthogonal C2v symmetry and varying the lattice spacing, we observe experimentally a transition between the regime of multi-order diffraction, being typical for photonic crystals to the regime where only the zero-order diffraction can be observed, being is a clear fingerprint of dielectric metasurfaces characterized by effective parameters. PMID- 27491953 TI - Pigment retinopathy in warmblood horses with equine degenerative myeloencephalopathy and equine motor neuron disease. AB - OBJECTIVE: A pigment retinopathy has been reported in adult horses with equine motor neuron disease (EMND) arising from chronic alpha-tocopherol (alpha-TP) deficiency. A pigment retinopathy has not been identified in horses with neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) that affects genetically susceptible young horses with alpha-TP deficiency. The objective of this report is to describe, for the first time, a pigment retinopathy in a family of alpha-TP-deficient Warmbloods (WB) with clinically apparent NAD/EDM or EMND. ANIMALS AND PROCEDURES: Twenty-five WB horses from one farm underwent complete neurologic and ophthalmic examinations and serum alpha-TP concentrations were assessed. Two of the most severely ataxic horses were euthanized and postmortem examinations performed. RESULTS: Alpha-TP deficiency was widespread on this farm (22 of 25 horses). Eleven of 25 horses were clinically normal (age range 2-12 years), one had signs of EMND (6 years of age), 10 had signs of ataxia consistent with NAD/EDM (1-10 years), and two of these were postmortem confirmed concurrent NAD/EDM and EMND. A pigment retinopathy characterized by varying amounts of granular dark pigment in the tapetal retina was observed in four clinically apparent NAD/EDM horses (two postmortem confirmed concurrent NAD/EDM and EMND) and one horse with clinical signs of EMND. CONCLUSIONS: A pigment retinopathy can be present in young alpha-TP-deficient Warmblood horses with clinical signs of EMND as well as those with signs of NAD/EDM. PMID- 27491956 TI - A Single Center Prospective Observational Study of Outcomes With Tonic Cervical Spinal Cord Stimulation. AB - BACKGROUND: Spinal cord stimulation (SCS) has been a valuable resource for the treatment of chronic, nonmalignant pain that persists in the face of maximal medical management. A recent study demonstrated efficacy of cervical SCS in a multicenter registry. Here, in our single center study, we are able to delve into patient specifics, explore outcomes with percutaneous vs. paddle implants, and examine impact of patient symptomatology. METHODS: We prospectively collected data on subjects who underwent cervical SCS via numeric rating scale (NRS), McGill Pain Questionnaire, Oswestry Disability Index (ODI), and Beck Depression Inventory. Subjects completed this battery pre-operatively, at six months and at one year. Data were analyzed via repeated measures ANOVA, bivariate correlation analysis, and paired t-tests. RESULTS: In 30 consecutive subjects, 24 had a complete data set. The diagnosis was failed neck surgery syndrome (13%), Complex regional pain syndrome (29%), and neuropathic pain (58%). Compared with baseline, NRS score significantly improved at six months (p = 0.021) and one year (p = 0.047). ODI score also improved at one year (p = 0.009). At both six months and one year, subjects with percutaneous implants reported significantly less disability on ODI (p = 0.016 and 0.034, respectively), as compared with those who received paddle implants. There was no difference in NRS score or any other outcome measure based on type of implant. Diagnosis or region of pain did not correlate with any measure of outcome. DISCUSSION: We demonstrate that neck and arm pain can be improved with cervical SCS at six month and one-year follow-ups. Both percutaneous and paddle implants have benefit. We tend to place percutaneous implants for radicular pain and retrograde C1-2 paddles for axial pain that is ineffectively treated during the trial. PMID- 27491957 TI - Understanding Systematic Reviews and Meta-Analyses [Formula: see text]. AB - Systematic reviews should be distinguished from narrative reviews. In the latter, an editor asks an expert to sum up all of the information that is known about a particular topic. However, the expert is under no constraints regarding what he or she does, or does not, choose to include in the review. As a result, his or her bias can influence the final message. A systematic review, which may or may not be written by experts, typically asks a narrower question, and then answers it using the entirety of the medical literature. The systematic review process includes computer searches to identify the pertinent literature, a statement of the inclusion and exclusion criteria for identified studies, a list of items of interest to extract from each study, a method to assess the quality of each study, a summary of the evidence that has been found (which may or may not involve attempts to combine data), a discussion of the evidence and the limitations of the conclusions, and suggestions for future research efforts. If the data are combined, that process is called meta-analysis. In meta-analysis, an estimate of the reliability of each study is made, and those that appear to be more reliable are weighed more heavily when the data are combined. While systematic reviews depend on a more preplanned method and thus, unlike narrative reviews, contain sections on method, they can be easily read once the reader becomes familiar with the vocabulary. PMID- 27491955 TI - Control of the heat stress-induced alternative splicing of a subset of genes by hnRNP K. AB - Pre-mRNA splicing is widely repressed upon heat shock in eukaryotic cells. However, it has been shown that HSP105 pre-mRNA is alternatively spliced in response to heat stress. Using RNAi screening in HeLa cells, we found that RNA binding proteins hnRNP K and PSF/SFPQ are necessary for the exon 12 exclusion of HSP105 during heat stress. Moreover, exon array analyses showed that a group of genes is alternatively spliced during heat stress in an hnRNP K-dependent manner, whereas hnRNP K is not necessary for the stress-induced alternative splicing of the remaining genes. Among the latter group, we found that SRp38/SRSF10 and SC35/SRSF2 are necessary for the inclusion of exon 13 of TNRC6A during heat stress. Thus, our study clearly showed that several RNA-binding proteins are involved in the splicing regulation in response to heat stress in mammalian cells. PMID- 27491954 TI - The Expression of Human Cytomegalovirus MicroRNA MiR-UL148D during Latent Infection in Primary Myeloid Cells Inhibits Activin A-triggered Secretion of IL 6. AB - The successful establishment and maintenance of human cytomegalovirus (HCMV) latency is dependent on the expression of a subset of viral genes. Whilst the exact spectrum and functions of these genes are far from clear, inroads have been made for protein-coding genes. In contrast, little is known about the expression of non-coding RNAs. Here we show that HCMV encoded miRNAs are expressed de novo during latent infection of primary myeloid cells. Furthermore, we demonstrate that miR-UL148D, one of the most highly expressed viral miRNAs during latent infection, directly targets the cellular receptor ACVR1B of the activin signalling axis. Consistent with this, we observed upregulation of ACVR1B expression during latent infection with a miR-UL148D deletion virus (DeltamiR UL148D). Importantly, we observed that monocytes latently infected with DeltamiR UL148D are more responsive to activin A stimulation, as demonstrated by their increased secretion of IL-6. Collectively, our data indicates miR-UL148D inhibits ACVR1B expression in latently infected cells to limit proinflammatory cytokine secretion, perhaps as an immune evasion strategy or to postpone cytokine-induced reactivation until conditions are more favourable. This is the first demonstration of an HCMV miRNA function during latency in primary myeloid cells, implicating that small RNA species may contribute significantly to latent infection. PMID- 27491958 TI - Parental presence at induction of anesthesia is feasible with minimal preparation and resources. PMID- 27491959 TI - Small molecule-assisted fabrication of black phosphorus quantum dots with a broadband nonlinear optical response. AB - Ultrathin BP QDs with a uniform size of ~3.4 nm were prepared via small molecule assisted liquid phase exfoliation and they exhibited superior broadband nonlinear saturable absorption promising for nonlinear optical applications. Laser photolysis measurement implied that the nonlinear response origin was related to the long-lived electron-hole pairs delocalized within the BP QDs. PMID- 27491960 TI - A Review of Hormonal Contraception and Venous Thromboembolism in Adolescents. AB - BACKGROUND: The number of adolescents who are prescribed hormonal contraception (HC) for contraceptive and noncontraceptive indications is increasing. Approximately 1 of 4 female adolescents will use some form of HC by age 19 years. Venous thromboembolism (VTE) is a rare, but life-threatening complication associated with HC use. Although adolescents aged 15 to 19 years have the lowest absolute HC-associated VTE risk, they still account for 5.9% of HC-associated VTE. The absolute HC-associated VTE risk for those younger than 15 years of age is not well described. OBJECTIVE: The objectives of this report are to describe the current literature regarding HC-associated VTE in adolescents, to review the coagulation cascade and in vivo coagulation, to highlight differences between the adolescent and adult coagulation profiles, to discuss coagulation profile changes related to HC use, and to identify knowledge deficits for future study. CONCLUSION: The mechanisms and confounding variables that lead to HC-associated VTE in all adolescents are not well understood because many large HC studies exclude female adolescents younger than 18 years of age. Because of the paucity of data in this age group, observational studies and randomized controlled trials of VTE risk in adolescents on varying forms of HC are needed. Studies should include female adolescents across the entire adolescent age span (12-21 years) to better understand HC-associated VTE risk in this population. PMID- 27491961 TI - Alcohol use among adults in Uganda: findings from the countrywide non communicable diseases risk factor cross-sectional survey. AB - BACKGROUND: There are limited data on levels of alcohol use in most sub-Saharan African countries. OBJECTIVE: We analyzed data from Uganda's non-communicable diseases risk factor survey conducted in 2014, to identify alcohol use prevalence and associated factors. DESIGN: The survey used the World Health Organization STEPS tool to collect data, including the history of alcohol use. Alcohol users were categorized into low-, medium-, and high-end users. Participants were also classified as having an alcohol-use-related disorder if, over the past 12 months, they were unable to stop drinking alcohol once they had started drinking, and/or failed to do what was normally expected of them because of drinking alcohol, and/or needed an alcoholic drink first in the morning to get going after a heavy drinking session the night before. Weighted logistic regression analysis was used to identify factors associated with medium- to high-end alcohol use. RESULTS: Of the 3,956 participants, 1,062 (26.8%) were current alcohol users, including 314 (7.9%) low-end, 246 (6.2%) medium-end, and 502 (12.7%) high-end users. A total of 386 (9.8%) were classified as having an alcohol-use-related disorder. Male participants were more likely to be medium- to high-end alcohol users compared to females; adjusted odds ratio (AOR)=2.34 [95% confidence interval (CI)=1.88-2.91]. Compared to residents in eastern Uganda, participants in central and western Uganda were more likely to be medium- to high-end users; AOR=1.47 (95% CI=1.01 2.12) and AOR=1.89 (95% CI=1.31-2.72), respectively. Participants aged 30-49 years and those aged 50-69 years were more likely to be medium- to high-end alcohol users, compared to those aged 18-29 years, AOR=1.49 (95% CI=1.16-1.91) and AOR=2.08 (95% CI=1.52-2.84), respectively. CONCLUSIONS: The level of alcohol use among adults in Uganda is high, and 9.8% of the adult population has an alcohol-use-related disorder. PMID- 27491962 TI - Barriers to successful treatment of alcohol addiction as perceived by healthcare professionals in Thailand - a Delphi study about obstacles and improvement suggestions. AB - BACKGROUND: Many Thai people experiencing alcohol addiction do not seek help, and those who do often have inadequate access to treatment. There are few research studies focusing on alcohol addiction treatment in Thailand. OBJECTIVE: The purpose of the current study was to identify barriers to the treatment of alcohol addiction and to collect experts' suggestions for improving treatment in Thailand. The Delphi technique was used to achieve consensual agreement among an expert panel within the field of alcohol addiction and treatment. DESIGN: Three rounds of a Delphi survey were completed by a panel of experts in alcohol addiction, including physicians, nurses, social workers, psychologists, healthcare officers, and an Alcoholics Anonymous member. The open-ended answers provided by 34 experts in the first round resulted in 60 statements, which were later grouped into three themes. After three rounds of questionnaires, 51 statements were accepted as consensus. RESULTS: Thirty-two experts participated in all three Delphi rounds. Over 80% of participants were particularly concerned about five obstacles to alcohol addiction treatment. The majority of suggestions from the expert panel were related to patients' right to treatment and the national policy for reducing the negative effects of alcohol. According to the results of the present study, the experts suggested that the treatment of alcohol addiction should be continuous from primary care to tertiary care, and convenient pathways should be established in healthcare services. The experts would also like to increase the number of healthcare providers and improve their knowledge and skills in working with people experiencing alcohol addiction. CONCLUSIONS: Equal rights to health and treatment for people experiencing alcohol addiction in Thailand require policy improvements, as well as acceptance and awareness of alcohol addiction from both the public and policymakers. PMID- 27491963 TI - HOSPITAL-BASED HEALTH TECHNOLOGY ASSESSMENT (HB-HTA): A 10-YEAR SURVEY AT ONE UNIT. AB - INTRODUCTION: Hospital-based health technology assessment (HB-HTA) has been introduced to help hospital management in decision making about the adoption of new health technologies (HTs). We reviewed the accuracy of the expected medical impact of HTs assessed at our hospital, as well as the acceptance of this process by clinicians. METHODS: For each HT adopted between 2002 and 2011, a semi structured interview with the involved clinician was conducted, assessing (i) the perceived utility of the HB-HTA process, (ii) the accuracy of the new HT's expected medical impact as compared with observed patient data from the year 2012, and (iii) the compliance with the indications of the HB-HTA report. RESULTS: Over the 10-year period, forty HB-HTAs were carried out, of which thirty four led to acceptance. Twenty-seven of the twenty-eight clinicians involved in these thirty-four HTs accepted the interview and 85 percent acknowledged the utility of the HB-HTA process. Five of the thirty-four HTs were no longer in use. For the twenty-nine remaining HTs, observed patients' number was as expected in eight, higher in four, lower in fifteen, and not available in two cases. Available average length of stay was 61 percent longer than expected. Two HTs had a higher complication rate and three a lower success rate. Indications evolved in 55 percent of HTs after a few years (seven restrictions, six broadenings, and three other changes). CONCLUSIONS: A HB-HTA process is useful to improve quality in decision making. Follow-up analysis should routinely be performed to adapt HB HTA reports' conclusions to practical experience and new scientific evidence. PMID- 27491964 TI - Development and Validation of a Quality Assurance Score for Robot-assisted Radical Cystectomy: A 10-year Analysis. AB - OBJECTIVE: To develop quality assessment tool to evaluate surgical performance for robot-assisted radical cystectomy program. METHODS: A prospectively maintained quality assurance database of 425 consecutive robot-assisted radical cystectomies performed by a single surgeon between 2005 and 2015 was retrospectively reviewed. Potentially modifiable factors, related to the management and perioperative care of patients, were used to evaluate patient care. Criteria included the following: preoperative (administration of neoadjuvant chemotherapy); operative (operative time <6.5 hours and estimated blood loss <500 cc); pathologic (negative soft tissue surgical margins and lymph node yield >=20); and postoperative (no high-grade complications, readmission, or noncancer-related mortality within 30 days).The Quality Cystectomy Score (QCS) was developed (1 star: achieving <=2 criteria or mortality within 30 days; 2 stars: 3 or 4 criteria met; 3 stars: 5 or 6 criteria met; and 4 stars: 7 or all criteria met). Univariate and multivariate Cox proportional hazard regression models were fitted to test for the association between QCS and survival outcomes. RESULTS: Most patients (85%) achieved at least 3 stars, and more patients achieved 4 stars with time. High QCS was associated with better recurrence-free, cancer-specific, and overall survival (P values <.05). None of the patients with 1-star were alive at 1 year. Patients with 4 stars achieved the best survival rates (recurrence-free survival [62%], cancer-specific survival [70%], and overall survival [53%] at 5 years) (log rank P < .0001). CONCLUSION: Continuous assessment for quality improvement facilitated implementation and maintenance of robot-assisted program for bladder cancer. PMID- 27491965 TI - Projecting the Urology Workforce Over the Next 20 Years. AB - OBJECTIVE: To forecast the size and composition of the urologist and urology advanced care provider (ACP; nurse practitioner, physicians' assistant) workforce over the next 20 years. METHODS: Current urologist workforce was estimated from the American Board of Urology certification data and the 2014 American Urological Association (AUA) Census. Incoming workforce was estimated from the American Board of Urology and AUA residency match data. Estimates of the ACP workforce were extracted from the 2012 AUA Physician Survey. Full-time equivalent (FTE) calculations were based on a 2014 urology workforce survey. Workforce projections were created using a stock and flow population model with multiple alternative forecast scenarios. RESULTS: Slight growth in overall (urologist + ACP) workforce FTEs is expected, from 14,792 in 2015 to 15,160 in 2035. A significant decline in urologist FTEs is likely, from 11,221 in 2015 to 8859 in 2035. ACPs should increase markedly, from 8,710 in 2015 to 15,369 in 2035. Female urologists should increase by 2035, from the current 7.0% to 18.6% of urologist workforce. Alternate scenarios were evaluated, with forecasted FTEs in 2035 ranging from 14,066 to 17,675. In 2035, workforce shortage predictions range from 12% to 46%. CONCLUSION: With a decrease in urologists over the coming decades, urologists and ACPs may not meet future demand. This forecast highlights the need for discussion and planning among leadership in the field to find creative solutions for this impending workforce shortage. PMID- 27491966 TI - Explanatory model of psychosis: impact on perception of self-stigma by patients in three sub-saharan African cities. AB - BACKGROUND: Most cultures in sub-Saharan Africa subscribe to the belief that the root cause of psychosis is supernatural. Individuals in the community who hold a religiomagical explanatory model of causation have been shown to exhibit more stigmatizing attitudes towards people with psychosis. Self-stigma among individuals with psychosis is less frequently studied. METHOD: We used a mixed method approach, consisting of key informant's interviews to elicit information on explanatory models of causation of psychosis and questionnaire assessment of internalized stigma with an adapted version of the Scale for Internalized Stigma of Mental Illness. Twenty-four, 31, and 30 subjects with recent experience of utilizing the service of traditional or faith healers for severe mental disorders in Ibadan (Nigeria), Kumasi (Ghana), and Nairobi (Kenya), respectively, were interviewed. RESULTS: About 44 % (42.1 %) of the Nigerian respondents had a high (severe) level of self-stigma with the respective proportions among Ghanaian and Kenyan respondents being 20.7 and 37.5 %. Compared with 4 out of a total of 12 respondents (33.3 %) who reported low self-stigma reported supernatural attribution, 14 out of 20 respondents (70 %) with the highest level of self stigma reported supernatural attribution across the three sites. When low scorers ascribed supernatural causation, it was often with a religious focus. CONCLUSION: There is a greater tendency for persons with high levels of self-stigma than those with low levels to ascribe supernatural attribution to their experience of a severe mental health condition. PMID- 27491967 TI - Social influences on eating and physical activity behaviours of urban, minority youths. AB - OBJECTIVE: Social relationships can impact youths' eating and physical activity behaviours; however, the best strategies for intervening in the social environment are unknown. The objectives of the present study were to provide in depth information on the social roles that youths' parents and friends play related to eating and physical activity behaviours and to explore the impact of other social relationships on youths' eating and physical activity behaviours. DESIGN: Convergent parallel mixed-methods design. SETTING: Low-income, African American, food desert neighbourhoods in Baltimore City, MD, USA. SUBJECTS: Data were collected from 297 youths (53 % female, 91 % African American, mean age 12.3 (sd 1.5) years) using structured questionnaires and combined with in-depth interviews from thirty-eight youths (42 % female, 97 % African American, mean age 11.4 (sd 1.5) years) and ten parents (80 % female, 50 % single heads of house, 100 % African American). RESULTS: Combined interpretation of the results found that parents and caregivers have multiple, dynamic roles influencing youths' eating and physical activity behaviours, such as creating health-promoting rules, managing the home food environment and serving as a role model for physical activity. Other social relationships have specific, but limited roles. For example, friends served as partners for physical activity, aunts provided exposure to novel food experiences, and teachers and doctors provided information related to eating and physical activity. CONCLUSIONS: Obesity prevention programmes should consider minority youths' perceptions of social roles when designing interventions. Specifically, future research is needed to test the effectiveness of intervention strategies that enhance or expand the supportive roles played by social relationships. PMID- 27491968 TI - Multiple timescale mixed bursting dynamics in a respiratory neuron model. AB - Experimental results in rodent medullary slices containing the pre-Botzinger complex (pre-BotC) have identified multiple bursting mechanisms based on persistent sodium current (I NaP) and intracellular Ca2+. The classic two timescale approach to the analysis of pre-BotC bursting treats the inactivation of I NaP, the calcium concentration, as well as the Ca2+-dependent inactivation of IP 3 as slow variables and considers other evolving quantities as fast variables. Based on its time course, however, it appears that a novel mixed bursting (MB) solution, observed both in recordings and in model pre-BotC neurons, involves at least three timescales. In this work, we consider a single compartment model of a pre-BotC inspiratory neuron that can exhibit both I NaP and Ca2+ oscillations and has the ability to produce MB solutions. We use methods of dynamical systems theory, such as phase plane analysis, fast-slow decomposition, and bifurcation analysis, to better understand the mechanisms underlying the MB solution pattern. Rather surprisingly, we discover that a third timescale is not actually required to generate mixed bursting solutions. Through our analysis of timescales, we also elucidate how the pre-BotC neuron model can be tuned to improve the robustness of the MB solution. PMID- 27491969 TI - Smaller tumor size is associated with poor survival in stage II colon cancer: An analysis of 7,719 patients in the SEER database. AB - BACKGROUND: We hypothesized that in patients with colon cancer showing heavy intestinal wall invasion without lymph node metastasis (stage II), small tumor size would correlate with more aggressive tumor behaviors and thus poorer cancer specific survival (CSS). METHODS: We analyzed Caucasian patients with stage II colon cancer based on data from the US Surveillance, Epidemiology, and End Results (SEER) database. Survival was analyzed using the Kaplan-Meier method, and the log-rank test was used to identify differences. Risk factors were analyzed using the Cox proportional hazard model. RESULTS: A total of 7719 stage II colon cancer patients from the SEER database were included in the analysis. The cutoff value (5.0 cm) was determined using the X-tile program. The Kaplan-Meier analysis showed that tumors <5.0 cm had a poorer CSS compared to tumors >=5.0 cm (p = 0.006). Multivariate analysis indicated that tumor size is an independent prognostic factor for stage II patients, and compared to tumors <5.0 cm, tumors >=5.0 cm were more likely to result in a better CSS (HR 0.775, 95% CI 0.691 0.870, p < 0.001). Tumor size was also analyzed as a continuous variable in the multivariate analysis, and the CSS decreased with decreasing tumor size (HR 0.958, 95% CI 0.936-0.981, p < 0.001). Subgroup analyses suggested that tumor size is also an independent prognostic factor for stage IIA (p = 0.002) and IIC (p < 0.001) patients. CONCLUSIONS: Smaller tumor size is associated with poor CSS in the stage II colon cancer and particularly in the stage IIA and IIC subgroups. PMID- 27491970 TI - Effects of hydrodynamic disturbances and resuspension characteristics on the release of tetrabromobisphenol A from sediment. AB - Tetrabromobisphenol A (TBBPA) exists widely in river and lake sediments; it has raised growing attention in recent years as emerging contaminant due to its possible threats to the aquatic environment and human health. Using a specialized simulator, the relationships between hydrodynamic disturbances and resuspension characteristics were simulated, with an emphasis on microscopic characteristics. Furthermore, TBBPA release from sediment was studied in relation to hydrodynamic disturbances and resuspension characteristics. The results show that stronger water disturbances caused an increase in suspended solids concentration (SSC) and produced different behaviors of particle size distribution (PSD) and media diameter (D50) in the slight and large-scale resuspension situations. As for microscopic resuspension characteristics, the specific surface area (SSA) of suspended particulate matter (SPM) was very different from that of smooth particles. This difference may result from the fractal nature of the SPM. The fractal dimension (FD) of SPM was found to have a significant correlation with turbulent kinetic energy. TBBPA release into overlying water and adsorption onto SPM both increased with hydrodynamic disturbances; but the release into overlying water is more dominant. The TBBPA concentrations in SPM under different hydrodynamic conditions were significant related to SSA, indicating that SSA is a key factor affecting the TBBPA adsorption capacity of SPM. TBBPA concentrations in sediment decreased slightly with the increased hydrodynamic dispersion. Findings from this research show the importance of considering the hydrodynamic disturbance and resuspension characteristics in understanding TBBPA release behavior in aquatic environment. PMID- 27491971 TI - Size-dependent depletion and community disturbance of phytoplankton under intensive oyster mariculture based on HPLC pigment analysis in Daya Bay, South China Sea. AB - In this study, we conducted a 14-month investigation in Daya Bay, southern China to understand the effects of oyster farming on phytoplankton community and biomass by using size-fractionated phytopigments. Results proved the filtering effects of oysters on phytoplankton biomass. During the oyster culture period, the average concentration of total chlorophyll a (sum of size-fractionated Chl a) within the farming area was approximately 60% lower than that at the reference site. Phytoplankton depletion in the aquaculture zone mainly occurred in micro sized fractions (>20 MUm) of Chl a, fucoxanthin, and peridinin. The influence of oyster filtration on nano-sized (2.7-20 MUm) pigments seemed less than that on micro-sized ones. The depletion of peridinin and 19'-hex-fucoxanthin in aquaculture zone was higher than those of the other pigments, which indicated that flagellated cells might be selectively filtered by oysters and could be more easily influenced by oyster aquaculture. The pico-sized Chl a (<2.7 MUm) comprised 24% of total Chl a on the average in the aquaculture zone during the cultural period compared to 6% in the reference site. Picoeukaryote abundance, which was determined via flow cytometry, was significantly higher in the aquaculture zone than in the non-aquaculture areas. The abundance of picoeukaryote is significantly and positively correlated with the concentrations of pico-sized prasinoxanthin, violaxanthin, and neoxanthin, indicating that picoeukaryote is dominated by those in prasinophyte. The results suggest that oyster aquaculture might stimulate the growth of prasinophyte, although the seasonal variations are mainly controlled by the water temperature in the study area. This research highlights the successful use of size-fractionated phytopigments to estimate size-specific phytoplankton biomass and community, which can be applied as a routine method to monitor the environmental effect and food resources of bivalve aquaculture. PMID- 27491972 TI - Prediction of intravenous immunoglobulin resistance in Kawasaki disease in an East China population. AB - The objectives of the study were to find the risk factors associated with intravenous immunoglobulin (IVIG) resistance and generate a prediction scoring system of IVIG resistance in patients with Kawasaki disease (KD). We retrospectively reviewed the clinical records of KD patients between January 2006 and December 2014. Multivariate logistic regression was performed to identify the risk factors of IVIG non-responders. The independent risk factors were used to construct a new scoring system and compared with Kobayashi and Egami scoring systems. Multivariate logistic regression analysis identified age <6 months, rash, edema of extremities, % neutrophils, and serum albumin as independent risk factors for IVIG non-responders. We assigned one point for rash, edema of extremities, and % neutrophils >=80 %. Two points were assigned for age <6 months and serum albumin <35 g/L. Using a cutoff point of three or more, we identified the IVIG non-responders with 71.4 % sensitivity and 76.0 % specificity. The new scoring system had a relatively better performance than Kobayashi and Egami scoring systems in the KD patients in East China. Clinical pediatricians must pay more attention to these high-risk patients, and use of additional therapies early in the course of their illness is necessary. PMID- 27491973 TI - Draft Genome Sequence of Geobacillus subterraneus Strain K, a Hydrocarbon Oxidizing Thermophilic Bacterium Isolated from a Petroleum Reservoir in Kazakhstan. AB - The draft genome sequence of Geobacillus subterraneus strain K, a thermophilic aerobic oil-oxidizing bacterium isolated from production water of the Uzen high temperature oil field in Kazakhstan, is presented here. The genome is annotated for elucidation of the genomic and phenotypic diversity of thermophilic alkane oxidizing bacteria. PMID- 27491974 TI - Complete Genome Sequence of Streptococcus agalactiae Strain S25 Isolated from Peritoneal Liquid of Nile Tilapia. AB - Streptococcus agalactiae (Lancefield group B; GBS) is one of the major pathogens in fish production, especially in Nile tilapia (Oreochromis niloticus). The genomic characteristics of GBS isolated from fish must be more explored. Thus, we present here the genome of GBS S25, isolated from Nile tilapia from Brazil. PMID- 27491975 TI - Complete Genome Sequence of a Novel Bacillus sp. VT 712 Strain Isolated from the Duodenum of a Patient with Intestinal Cancer. AB - We report here the complete genome sequence of the spore-forming Bacillus sp. strain VT 712 isolated from the duodenum of a patient with intestinal cancer. The genome is 3,921,583 bp, with 37.9% G+C content. It contains 3,768 predicted protein-coding genes for multidrug resistance transporters, virulence factors, and daunorubicin resistance. PMID- 27491976 TI - Draft Genome Sequences of Legionella pneumophila JR32 and Lp01 Laboratory Strains Domesticated in Japan. AB - We report here the draft genome sequences of two Legionella pneumophila variant strains (JR32 and Lp01_666) originally derived from a Philadelphia-1 clinical isolate, domesticated in Japan, with distinct susceptibility to amoebae. Detailed genomic analysis will allow us to better understand Legionella adaptation and survival mechanisms in host cells. PMID- 27491977 TI - Draft Genome Sequence of a Thermophilic Desulfurization Bacterium, Geobacillus thermoglucosidasius Strain W-2. AB - Geobacillus thermoglucosidasius strain W-2 is a thermophilic bacterium isolated from a deep-subsurface oil reservoir in northern China, which is capable of degrading organosulfur compounds. Here, we report the draft genome sequence of G. thermoglucosidasius strain W-2, which may help to elucidate the genetic basis of biodegradation of organosulfur pollutants under heated conditions. PMID- 27491978 TI - Draft Genome Sequence of Burkholderia stabilis LA20W, a Trehalose Producer That Uses Levulinic Acid as a Substrate. AB - Burkholderia stabilis LA20W produces trehalose using levulinic acid (LA) as a substrate. Here, we report the 7.97-Mb draft genome sequence of B. stabilis LA20W, which will be useful in investigations of the enzymes involved in LA metabolism and the mechanism of LA-induced trehalose production. PMID- 27491979 TI - Draft Genome Sequence of Escherichia coli S51, a Chicken Isolate Harboring a Chromosomally Encoded mcr-1 Gene. AB - We present the draft genome of Escherichia coli S51, a colistin-resistant extended-spectrum beta-lactamase-producing strain isolated in 2015 from raw chicken meat imported from Germany. Assembly and annotation of this draft genome resulted in a 4,994,918-bp chromosome and revealed a chromosomally encoded mcr-1 gene responsible for the colistin resistance of the strain. PMID- 27491980 TI - Permanent Improved High-Quality Draft Genome Sequence of Nocardia casuarinae Strain BMG51109, an Endophyte of Actinorhizal Root Nodules of Casuarina glauca. AB - Here, we report the first genome sequence of a Nocardia plant endophyte, N. casuarinae strain BMG51109, isolated from Casuarina glauca root nodules. The improved high-quality draft genome sequence contains 8,787,999 bp with a 68.90% GC content and 7,307 predicted protein-coding genes. PMID- 27491981 TI - Complete Genome Sequence of the Proteorhodopsin-Containing Marine Flavobacterium Dokdonia donghaensis DSW-1T, Isolated from Seawater off Dokdo in the East Sea (Sea of Korea). AB - Dokdonia spp. have been used for investigating the lifestyles of proteorhodopsin containing photoheterotrophs and for understanding marine photobiology. Here, we report the complete genome sequence of Dokdonia donghaensis DSW-1(T) using the PacBio sequencing platform. It should provide a valuable resource for comparative genomic studies of marine life harboring microbial rhodopsins among others. PMID- 27491982 TI - Draft Genome Sequences of Eight Obligate Methane Oxidizers Occupying Distinct Niches Based on Their Nitrogen Metabolism. AB - The genome sequences of Methylomonas methanica (NCIMB 11130(T), R-45363, and R 45371), Methylomonas koyamae (R-45378, R-45383, and R-49807), Methylomonas lenta (R-45370), and Methylosinus sp. (R-45379) were obtained. These aerobic methanotrophs were isolated from terrestrial ecosystems, and their distinct phenotypes related to nitrogen assimilation and dissimilation were previously reported. PMID- 27491983 TI - First Complete Genome Sequence of Chronic Bee Paralysis Virus Isolated from Honey Bees (Apis mellifera) in China. AB - Chronic bee paralysis virus (CBPV) is a serious viral disease affecting adult bees. We report here the complete genome sequence of CBPV, which was isolated from a honey bee colony with the symptom of severe crawling. The genome of CBPV consists of two segments, RNA 1 and RNA 2, containing respective overlapping fragments. PMID- 27491984 TI - A Narnavirus-Like Element from the Trypanosomatid Protozoan Parasite Leptomonas seymouri. AB - Genome sequences were determined for a novel RNA virus, Leptomonas seymouri Narna like virus 1 (LepseyNLV1). A 2.9-kb segment encodes an RNA-dependent RNA polymerase (RdRp), while a smaller 1.5-kb segment showed no database search matches. This is the first report of bisegmented Narnaviridae from insect trypanosomatids. PMID- 27491985 TI - A Novel Bunyavirus-Like Virus of Trypanosomatid Protist Parasites. AB - We report here the sequences for all three segments of a novel RNA virus (LepmorLBV1) from the insect trypanosomatid parasite Leptomonas moramango This virus belongs to a newly discovered group of bunyavirus-like elements termed Leishbunyaviruses (LBV), the first discovered from protists related to arboviruses infecting humans. PMID- 27491986 TI - Draft Genome Sequence of Pseudoalteromonas tetraodonis Strain MQS005, a Bacterium with Potential Quorum-Sensing Regulation. AB - We present here the draft genome sequence of Pseudoalteromonas tetraodonis strain MQS005, a bacterium possessing potential quorum-sensing regulatory activity. This strain was isolated from water from the South China Sea, People's Republic of China. The assembly consists of 4,252,538 bp and contains 144 contigs, with a G+C content of 41.85%. PMID- 27491987 TI - Draft Genome Sequence of Paenibacillus polymyxa KF-1, an Excellent Producer of Microbicides. AB - We report here the draft genome sequence of Paenibacillus polymyxa KF-1, which exhibits excellent antimicrobial activity. It encodes the synthase of bacitracin, kalimantacin, bacillomycin, iturin, fusaricidin, tridecaptin, and pelgipeptin and biosynthetic pathways of antiviral curldan and levan polysaccharides. Also, a novel prophage is involved in this genome that contains endolysin-encoding genes. PMID- 27491989 TI - Complete Genome Sequence of Zika Virus Isolated in Mexico, 2016. AB - Zika virus belongs to the genus Flavivirus, and its spread remains an international public health emergency. In this report, we describe the obtainment and molecular characterization of a complete viral genome through the direct metagenomic analysis from saliva from an autochthonous transmission case in Mexico. PMID- 27491988 TI - Draft Genome Sequence of Fonsecaea nubica Strain CBS 269.64, Causative Agent of Human Chromoblastomycosis. AB - On the basis of multilocus phylogenetic data, Fonsecaea nubica was described in 2010 as a molecular sibling of F. monophora, an established agent of the human skin disease chomoblastomycosis in tropical zones. Genome analysis of these pathogens is mandatory to identify genes involved in the interaction with host and virulence. PMID- 27491990 TI - Genome Sequence of Listeria monocytogenes Strain HPB2088 (Serotype 1/2a), an Environmental Isolate Collected in Canada in 1994. AB - Listeria monocytogenes is a foodborne pathogen that causes severe illness. Thus, ongoing efforts at real-time whole-genome sequencing are of utmost importance. However, it is also important that retrospective analyses that place these data into context be performed. Here, we present the genome sequence of strain HPB2088, which was collected in 1994. PMID- 27491991 TI - Draft Genome Sequence of Capniomyces stellatus, the Obligate Gut Fungal Symbiont of Stonefly. AB - Capniomyces stellatus is a host-specific endosymbiotic fungus, living in the hindgut of stoneflies (especially in Allocapnia). Here, we present the first draft genome sequence of the fungus, as well as the ab initio gene prediction and function analyses, which will facilitate the study and comparative analyses of insect-associated fungi. PMID- 27491992 TI - Draft Genome Sequences of Two Ureolytic Bacteria Isolated from Concrete Block Waste. AB - We sequenced genomes of two ureolytic bacteria, Bacillus sp. JH7 and Sporosarcina sp. HYO08, which were isolated from concrete waste and have a potential for biocementation applications. PMID- 27491993 TI - Draft Genome Sequence of Oil-Degrading Bacterium Gallaecimonas pentaromativorans Strain YA_1 from the Southwest Indian Ocean. AB - Gallaecimonas pentaromativorans has been previously reported to be capable of degrading crude oil and diesel oil. G. pentaromativorans strain YA_1 was isolated from the southwest Indian Ocean and can degrade crude oil. This study reports the draft genome sequence of G. pentaromativorans, which can provide insights into the mechanisms of microbial oil biodegradation. PMID- 27491994 TI - Genome Sequence of Arenibacter algicola Strain TG409, a Hydrocarbon-Degrading Bacterium Associated with Marine Eukaryotic Phytoplankton. AB - Arenibacter algicola strain TG409 was isolated from Skeletonema costatum and exhibits the ability to utilize polycyclic aromatic hydrocarbons as sole sources of carbon and energy. Here, we present the genome sequence of this strain, which is 5,550,230 bp with 4,722 genes and an average G+C content of 39.7%. PMID- 27491995 TI - Insights into the Genome Sequences of an N-Acyl Homoserine Lactone Molecule Producing Two Pseudomonas spp. Isolated from the Arctic. AB - We report for the first time the draft genome sequence of two psychrotrophic Pseudomonas species, Pseudomonas simiae RGCB 73 and Pseudomonas brenneri RGCB 108, from the Arctic that produce more than one acyl homoserine lactone molecule of varied N-acyl length. The study confirms the presence of a LuxR-LuxI (type) mediated quorum-sensing system in both the Pseudomonas species and enables us to understand the role of quorum sensing in their survival in extremely cold environments. PMID- 27491996 TI - Draft Genome Sequences of Two Avian Pathogenic Escherichia coli Strains of Clinical Importance, E44 and E51. AB - Avian pathogenic Escherichia coli strains have remarkable impacts on animal welfare and the production economy in the poultry industry worldwide. Here, we present the draft genomes of two isolates from chickens (E44 and E51) obtained from field outbreaks and subsequently investigated for their potential for use in autogenous vaccines for broiler breeders. PMID- 27491997 TI - Permanent Draft Genome Sequence of Nocardia sp. BMG111209, an Actinobacterium Isolated from Nodules of Casuarina glauca. AB - Nocardia sp. strain BMG111209 is a non-Frankia actinobacterium isolated from root nodules of Casuarina glauca in Tunisia. Here, we report the 9.1-Mbp draft genome sequence of Nocardia sp. strain BMG111209 with a G + C content of 69.19% and 8,122 candidate protein-encoding genes. PMID- 27491998 TI - Complete Genome Sequence of Highly Virulent Porcine Reproductive and Respiratory Syndrome Virus Variants That Recently Emerged in the United States. AB - A recent outbreak of particularly virulent disease caused by porcine reproductive and respiratory syndrome virus has occurred in swine herds across the United States. We report here the complete genome sequence of eight viral isolates from four Nebraska herds experiencing an outbreak of severe disease in 2016. PMID- 27491999 TI - Draft Genome Sequence of the Chloroperoxidase-Producing Fungus Caldariomyces fumago Woronichin DSM1256. AB - We report here the draft genome sequence of the chloroperoxidase (EC 1.11.1.10) producing ascomycete Caldariomyces fumago Its genome was assembled into 511 contigs with a total size of 25 Mb. The G+C content is 51.4%, and 9,806 putative protein-coding genes were predicted. Eight heme-thiolate peroxidase genes, including two chloroperoxidase genes, were found. PMID- 27492000 TI - Complete Genome Sequence of Chinese Yam Necrotic Mosaic Virus from Dioscorea opposita in the Republic of Korea. AB - The complete genome sequence of Chinese yam necrotic mosaic virus (ChYNMV) consisting of 8,213 nucleotides containing one open reading frame was determined by the transcriptome data generated from Discorea opposita This is the first report of the complete nucleotide sequence of ChYNMV from Dioscorea opposita in the Republic of Korea. PMID- 27492001 TI - Draft Genome Sequence of Planomonospora sphaerica JCM9374, a Rare Actinomycete. AB - Planomonospora sphaerica is a rare actinomycete that is a potential antibiotic producer. Here, we report the draft genome sequence of P. sphaerica strain JCM9374. This is the first genome report of a bacterium belonging to the genus Planomonospora The genome information of P. sphaerica will contribute to studies on the structure and function of antibiotics. PMID- 27492002 TI - Draft Genome Sequence of Streptomyces sp. F-3. AB - Streptomyces sp. F-3 is a kind of thermophilic Streptomyces strain that can produce cellulolytic enzymes and diverse secondary metabolites. Here, we report the complete genome of this organism, whose genome length is 5,303,958 bp, containing 6,041 protein-coding genes, 69 tRNA operons, and three rRNA operons. PMID- 27492003 TI - Draft Genome Sequence of Lactococcus garvieae Strain PAQ102015-99, an Outbreak Strain Isolated from a Commercial Trout Farm in the Northwestern United States. AB - We announce the draft genome assembly of Lactococcus garvieae strain PAQ102015 99, a recently isolated strain from an outbreak of lactococcosis at a commercial trout farm in the northwestern United States. The draft genome comprises 14 contigs totaling 2,068,357 bp with an N50 of 496,618 bp and average G+C content of 38%. PMID- 27492004 TI - [Pulmonary hypertension : What is new in therapy?]. AB - Pulmonary hypertension (PH) comprises a group of pulmonary vascular diseases that are characterized by progressive exertional dyspnea and right heart insufficiency ultimately resulting in right heart decompensation. The classification is into five clinical subgroups that form the absolutely essential basis for decisions on the indications for different pharmacological and non-pharmacological forms of treatment. The guidelines were updated in 2015 and in addition to the hitherto existing pharmacological treatment options of phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostacyclins, the soluble guanylate cyclase stimulator riociguat has now been incorporated for treatment of certain forms of PH. This article provides an overview of the new treatment recommendations in the current guidelines, e. g. for PH patients who are in intensive care units due to surgical interventions or progressive right heart insufficiency. PMID- 27492005 TI - Patterns of diaphragm function in critically ill patients receiving prolonged mechanical ventilation: a prospective longitudinal study. AB - BACKGROUND: In intensive care unit (ICU) patients, diaphragmatic dysfunction (DD) can occur on admission or during the subsequent stay. The respective incidence of these two phenomena has not been previously studied in humans. The study was designed to describe temporal trends in diaphragm function in mechanically ventilated (MV) patients. METHODS: Ancillary study of a prospective, 6-month, observational cohort study conducted in two ICUs. MV patients were studied within 24 h following intubation (day-1) and every 48-72 h thereafter. Diaphragm function was assessed by twitch tracheal pressure (Ptr,stim) in response to bilateral anterior magnetic phrenic nerve stimulation. Diaphragm dysfunction was defined as Ptr,stim < 11 cmH2O. Patients who received MV for at least 5 days were retained, and the first and the last measures were analysed. RESULTS: Forty-three patients were included. Overall, 79 % of patients developed DD at some point during their ICU stay: 23 (53 %) patients presented DD on initiation of mechanical ventilation, 14 (33 %) of whom had persistent DD, while diaphragm function improved in 9 (21 %). Among the remaining 20 (47 %) patients who did not present DD on initiation of MV, 11 (26 %) developed DD during the ICU stay, while 9 (21 %) did not. Mortality was higher in patients with DD either on initiation of mechanical ventilation or during the subsequent ICU stay than in those who never developed DD (35 vs. 0 %, p = 0.04). Duration of MV was higher in patients with DD on initiation of MV that subsequently persisted than in patients who never exhibited diaphragm dysfunction (18 vs. 5 days, p = 0.04). Factors associated with a change in Ptr,stim were: age [linear coefficient regression (Coeff.) -0.097, standard error (SD) 0.047, p = 0.046], PaO2/FiO2 ratio (Coeff. 0.014, SD 0.006, p = 0.0211) and the proportion of the time under MV with sedation (per 10 %, Coeff. -5.359, SD 2.451, p = 0.035). CONCLUSIONS: DD is observed in a large majority of MV patients >=5 days at some point of their ICU stay. Various patterns of DD are observed, including DD on initiation of mechanical ventilation and ICU-acquired DD. Trial registration clinicaltrials.gov Identifier # NCT00786526. PMID- 27492006 TI - Air pollution, aeroallergens and admissions to pediatric emergency room for respiratory reasons in Turin, northwestern Italy. AB - BACKGROUND: Air pollution can cause respiratory symptoms or exacerbate pre existing respiratory diseases, especially in children. This study looked at the short-term association of air pollution concentrations with Emergency Room (ER) admissions for respiratory reasons in pediatric age (0-18 years). METHODS: Daily number of ER admissions in a children's Hospital, concentrations of urban background PM2.5, NO2, O3 and total aeroallergens (Corylaceae, Cupressaceae, Gramineae, Urticaceae, Ambrosia, Betula) were collected in Turin, northwestern Italy, for the period 1/08/2008 to 31/12/2010 (883 days). The associations between exposures and ER admissions were estimated, at time lags between 0 and 5 days, using generalized linear Poisson regression models, adjusted for non meteorological potential confounders. RESULTS: In the study period, 21,793 ER admissions were observed, mainly (81 %) for upper respiratory tract infections. Median air pollution concentrations were 22.0, 42.5, 34.1 MUg/m(3) for urban background PM2.5, NO2, and O3, respectively, and 2.9 grains/m(3) for aeroallergens. We found that ER admissions increased by 1.3 % (95 % CI: 0.3-2.2 %) five days after a 10 MUg/m(3) increase in NO2, and by 0.7 % (95 % CI: 0.1-1.2 %) one day after a 10 grains/m(3) increase in aeroallergens, while they were not associated with PM2.5 concentrations. ER admissions were negatively associated with O3 and aeroallergen concentrations at some time lags, but these association shifted to the null when meteorological confounders were adjusted for in the models. CONCLUSIONS: Overall, these findings confirm adverse short-term health effects of air pollution on the risk of ER admission in children and encourage a careful management of the urban environment to health protection. PMID- 27492007 TI - Antidiarrheal activity of crude methanolic root extract of Idigofera spicata Forssk.(Fabaceae). AB - BACKGROUND: Till now many of medicinal plants having claimed therapeutic value traditionally are waiting scientific verification of their efficacy and safety. Accordingly this study is conducted to evaluate the antidiarrheal activity of hydromethanolic root extract of Indigofera spicata Forssk. in castor oil induced diarrhea model, misoprostol induced secretion model and its antimotility activity using charcoal as a marker. METHODS: In all the three models the animals were randomly allocated into five groups of six animals each and then group I mice were received 1 ml/100 g normal saline, group II were treated with standard drug as a positive control whereas group III, IV and V were treated with 100, 200 and 400 mg/kg extract doses, respectively. Statistical significance of differences in the mean of number of defecations, fluid content of faces, intestinal fluid accumulation ratio, intestinal fluid weight and distance travelled by charcoal between groups was analyzed by SPSS version-21 using one way ANOVA followed by Tukey's post hoc multiple comparison. RESULT: The hydromethanolic crude extract of Indigofera spicata at 200 and 400 mg/kg mg/kg doses showed statistically significant (p < 0.05) inhibition of the frequency of defecation and weight difference of the fluid content of the faces compared to the negative controls. For those doses the percentage inhibition of diarrheal feces was 43.62 and 53.51 %, respectively. The antisecretary activity of the extract in terms of fluid accumulation ratio was not found significant but in terms of intestinal fluid weight, all the extract doses revealed significant (p < 0.05) inhibition. Unlike the standard drug, the antimotility activity of the extract was not found statistically significant compared to the negative control. CONCLUSION: Root of Indigofera spicata Forssk. has shown promising antidiarrheal activity which validates its traditional use. Further studies are needed and possibly the plant may serve as a potential source of new agent in the therapeutic armamentarium of diarrhea. PMID- 27492009 TI - Hypovitaminosis D predicts the onset of orthostatic hypotension in older adults. AB - A number of small cross sectional studies have demonstrated that hypovitaminosis D (represented by low 25 hydroxyvitamin D (25OHD) levels) is associated with orthostatic hypotension (OH). We investigated if hypovitaminosis D is associated with the onset of OH in older adults over a follow-up of 4.4 years. 25OHD was categorized using sex-specific quartiles; OH was defined as a drop of <=20 mm Hg in systolic or <=10 mm Hg in diastolic blood pressure <3 minutes of standing. Among 1308 elderly without OH at baseline, using an adjusted logistic regression analysis and taking those with higher baseline serum 25OHD as reference, there was a significant increase in the onset of OH in those with lower serum 25OHD levels. The association was significant only in women when we stratified by sex. In conclusion, hypovitaminosis D predicts the onset of OH in older adults, particularly in women. PMID- 27492008 TI - Invasive micropapillary carcinoma of the breast had poor clinical characteristics but showed no difference in prognosis compared with invasive ductal carcinoma. AB - BACKGROUND: It is controversial for prognosis of invasive micropapillary carcinoma (IMPC) compared with invasive ductal carcinoma (IDC) of the breast. To better understand the difference between IMPC and IDC prognoses, we conducted this retrospective study. METHODS: Data from 33 patients with IMPC were retrospectively reviewed, and the clinicopathologic characteristics and survival status were compared with those of 347 patients with IDC who were treated during the same period. RESULTS: The IMPC cases were of larger tumor size, greater proportion of nodal involvement, and an increased incidence of lymphovascular invasion compared with IDC cases. The overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and failure-free survival (FFS) rates were not significantly different between IMPC and IDC. The 3 year OS rate was 97 vs 94.2 % for the IMPC and IDC patients, respectively. The 3 year FFS rate was 87.9 vs 86.2 % for the IMPC and IDC patients, respectively. For IMPC patients, the 3-year LRFS rate was 93.9 % and in IDC patients was 89.0 %. The 3-year DMFS rates of IMPC patients was 90.9 % and IDC patients was 89 %. CONCLUSIONS: IMPC had poor clinical characteristics, but it showed no difference in OS, FFS, LRFS, and DMFS compare with IDC. PMID- 27492010 TI - Analyses of genetic diversity of bacterial blight pathogen, Xanthomonas oryzae pv. oryzae using IS1112 in Bangladesh. AB - Bacterial blight (BB) is caused by Xanthomonas oryzae pv. oryzae (Xoo), a most destructive disease of rice, mostly in Asia, including Bangladesh. Altogether 96 isolates of Xoo were collected from 19 rice-growing districts of Bangladesh in both the rain-fed and irrigated seasons of 2014 to assess their pathotypic and genetic variation. Pathotypic analyses were carried out on a set of 12 Near Isogenic Lines (NILs) of rice containing a single resistance gene and two check varieties IR24 and TN1 by the leaf clipping inoculation method. A total of 24 pathotypes were identified based on their virulence patterns on the NILs tested. Among these, pathotypes VII, XII and XIV, considered as major, containing a maximum number of isolates (9.38% each), are frequently distributed in seven northern to mid-eastern districts of Bangladesh. The most virulent pathotype I was recorded in the Habiganj and Brahmanbaria districts. The molecular analysis of variability among the isolates was carried out through PCR analysis using multi-locus primers Jel1 and Jel2 (based on the repetitive element IS1112 in the Xoo genome). Using the genotypic data, a dendrogram was constructed with 17 clusters along with 17 molecular haplotypes at the 65% similarity index. Cluster I was composed of 46 isolates considered as major, whereas clusters X, XI, XII and XVII were represented by a single isolate. A phenogram was constructed based on virulence to interpret the relationship between the pathotypes and the molecular haplotypes. At the 50% similarity level, among 10 clusters, cluster I, considered as major, consisted of a maximum of 10 pathotypes out of 24. In case of haplotypes, a maximum of 7 haplotypes were obtained from pathotype XII, whereas pathotypes IX, X, XV, XXII and XXIV were represented by a single haplotype. However, the present study revealed that different isolates belonging to the same pathotypes belonged to different haplotypes. Conversely, genetically similar haplotypes were also detected from different pathotypes collected from separate districts. This relationship appeared due to a high degree of DNA polymorphism among strains within many pathotypes existing in Bangladesh. PMID- 27492011 TI - Plasmid pPCP1-derived sRNA HmsA promotes biofilm formation of Yersinia pestis. AB - BACKGROUND: The ability of Yersinia pestis to form a biofilm is an important characteristic in flea transmission of this pathogen. Y. pestis laterally acquired two plasmids (pPCP1and pMT1) and the ability to form biofilms when it evolved from Yersinia pseudotuberculosis. Small regulatory RNAs (sRNAs) are thought to play a crucial role in the processes of biofilm formation and pathogenesis. RESULTS: A pPCP1-derived sRNA HmsA (also known as sR084) was found to contribute to the enhanced biofilm formation phenotype of Y. pestis. The concentration of c-di-GMP was significantly reduced upon deletion of the hmsA gene in Y. pestis. The abundance of mRNA transcripts determining exopolysaccharide production, crucial for biofilm formation, was measured by primer extension, RT-PCR and lacZ transcriptional fusion assays in the wild-type and hmsA mutant strains. HmsA positively regulated biofilm synthesis-associated genes (hmsHFRS, hmsT and hmsCDE), but had no regulatory effect on the biofilm degradation-associated gene hmsP. Interestingly, the recently identified biofilm activator sRNA, HmsB, was rapidly degraded in the hmsA deletion mutant. Two genes (rovM and rovA) functioning as biofilm regulators were also found to be regulated by HmsA, whose regulatory effects were consistent with the HmsA-mediated biofilm phenotype. CONCLUSION: HmsA potentially functions as an activator of biofilm formation in Y. pestis, implying that sRNAs encoded on the laterally acquired plasmids might be involved in the chromosome-based regulatory networks implicated in Y. pestis-specific physiological processes. PMID- 27492012 TI - Complications associated with ureterorenoscopy (URS) related to treatment of urolithiasis: the Clinical Research Office of Endourological Society URS Global study. AB - INTRODUCTION: Ureterorenoscopy (URS) is a popular and growing option for management of ureteric and renal stones. The CROES URS Global Study was set up to assess the outcomes of URS in a large worldwide cohort of patients involving multiple centres. In this paper, we analysed the database for intra-operative and post-operative complications associated with ureterorenoscopy. METHODS: The CROES database was established via collaboration between 114 centres in 32 countries worldwide, and information on both intra-operative and post-operative complications was collected electronically between January 2010 and October 2012. RESULT: On analysis of a total of 11,885 patients, the overall complication and stone-free rates were found to be 7.4 and 85.6 %, respectively. The intra operative and post-operative complication rates were 4.2 and 2.6 %, respectively, and in total 5 deaths were reported in the study period. Taking into account different world economies, there were no differences in the complication rates between the developing and developed nations or between different centres from different continents. CONCLUSION: Ureterorenoscopy is a safe and effective procedure for treatment of stones, the outcomes of which are broadly comparable in different parts of the world for similar patient and stone demographics. PMID- 27492013 TI - Common medications and prostate cancer mortality: a review. AB - PURPOSE: Most prostate cancer patients also have comorbidities that are treated with both prescription and nonprescription medications; furthermore, many use dietary supplements. We assess their association with prognosis after prostate cancer diagnosis, and we discuss methodological challenges and clinical implications. METHODS: We reviewed high-quality observational studies investigating the association of commonly used medications and supplements with prostate cancer-specific mortality. RESULTS: There is preliminary evidence that statins and metformin use may be associated with lower risk of cancer-specific mortality after prostate cancer diagnosis; conversely, high calcium and multivitamin supplementation may be associated with increased risk. Evidence is inconclusive for nonsteroidal anti-inflammatory drugs, acetylsalicylic acid (aspirin), insulin, antihypertensives such as angiotensin-converting enzyme inhibitors and beta-blockers, digoxin, and warfarin. Common limitations of the internal validity of studies examined include unmeasured confounding and confounding by indication, competing risks, and time-related biases such as immortal time bias. The majority of studies focused on Caucasian men with specific comorbidities, while heterogeneity among patients and tumors was mostly not assessed. CONCLUSIONS: Commonly prescribed medications and over-the-counter supplements may influence prognosis among prostate cancer patients. Further well designed pharmacoepidemiologic studies and randomized controlled trials of selected medications in appropriate patient groups are necessary before these drugs can bear new indications for prostate cancer treatment. We discuss considerations when deciding about use of these drugs in clinical practice at the present time. PMID- 27492014 TI - Demand for radiotherapy in Spain. AB - AIM: Assessing the demand for radiotherapy in Spain based on existing evidence to estimate the human resources and equipment needed so that every person in Spain has access to high-quality radiotherapy when they need it. MATERIAL AND METHODS: We used data from the European Cancer Observatory on the estimated incidence of cancer in Spain in 2012, along with the evidence-based indications for radiotherapy developed by the Australian CCORE project, to obtain an optimal radiotherapy utilisation proportion (OUP) for each tumour. RESULTS: About 50.5 % of new cancers in Spain require radiotherapy at least once over the course of the disease. Additional demand for these services comes from reradiation therapy and non-melanoma skin cancer. Approximately, 25-30 % of cancer patients with an indication for radiotherapy do not receive it due to factors that include access, patient preference, familiarity with the treatment among physicians, and especially resource shortages, all of which contribute to its underutilisation. CONCLUSIONS: Radiotherapy is underused in Spain. The increasing incidence of cancer expected over the next decade and the greater frequency of reradiations necessitate the incorporation of radiotherapy demand into need-based calculations for cancer services planning. PMID- 27492015 TI - Salvage treatment with irinotecan/cisplatin versus pemetrexed/cisplatin in patients with non-small cell lung cancer pre-treated with a non-platinum-based regimen in the first-line setting: a randomized phase II study of the Hellenic Oncology Research Group (HORG). AB - BACKGROUND: Platinum-based chemotherapy is the standard front-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, non-platinum combinations of third-generation chemotherapeutic agents are considered an alternative therapeutic option for patients who cannot tolerate the toxic effects of platinum compounds. In this study, the efficacy and toxicity of the combination of irinotecan plus cisplatin (IC) was compared to pemetrexed plus cisplatin (PC) regimen, in platinum-naive patients with advanced NSCLC, who had been previously treated with the combination of a taxane plus gemcitabine. PATIENTS AND METHODS: A total of 124 patients with locally advanced or metastatic NSCLC were randomly assigned to either irinotecan 110 mg/m2 on day 1 and 100 mg/m2 on day 8 plus cisplatin 80 mg/m2 on day 8 every 3 weeks (IC arm) or pemetrexed 500 mg/m2 plus cisplatin 80 mg/m2 on day 1 every 3 weeks (PC arm). The primary endpoint of the study was the overall response rate (ORR). RESULTS: The ORR and median progression-free survival (PFS) in the IC arm were 18 % and 3.3 months, respectively, while in the PC arm were 19 % and 4.2 months (p = ns). Median overall survival (OS) was significantly higher in patients with PC (6.9 vs. 10.9; p = 0.013). PC regimen had a better toxicity profile compared to IC, with a statistically significant lower incidence of grade 3/4 neutropenia (3 vs. 31 %; p = 0.0001) and diarrhea (1.6 vs. 14.7 %, p = 0.018). CONCLUSIONS: In patients with advanced NSCLC pretreated with docetaxel/gemcitabine, the combination of pemetrexed/cisplatin is associated with increased OS and is better tolerated than the combination of irinotecan/cisplatin and should be considered as a valid therapeutic option for platinum-naive, previously treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT00614965. PMID- 27492016 TI - Self-emulsifying phospholipid pre-concentrates (SEPPs) for improved oral delivery of the anti-cancer genistein: Development, appraisal and ex-vivo intestinal permeation. AB - Genistein (GEN), a potent anticancer agent, suffers from scanty oral bioavailability due to poor solubility and extensive metabolism. This work endeavored to enhance GEN solubility and intestinal permeability via fabrication of self-emulsifying phospholipid pre-concentrates (SEPPs) using some bioactive surfactants. Moreover, the potential of surfactant-free SEPP to address GEN obstacles was investigated. SEPPs were prepared from Phosal((r)) 53MCT, oil/phosphatidylcholine mixture, alone or with only 30% of different surfactant/co-surfactant mixture (S/CO). In-vitro characterization encompassed globule size analysis, zeta potential (ZP), transmission electron microscopy, and in-vitro release. Ex-vivo intestinal permeation study was performed using non everted rat intestinal sac technique. Upon aqueous dilution, SEPPs were easily dispersed with spherical globules within a nano-range size (from 165+/-15 to 425+/-20nm) and adequate negative ZP (>-30mV). SEPPs demonstrated a significant enhancement in GEN release compared to drug suspension without superior effect due to added S/CO. Permeation study revealed that at least 12.13% free GEN was permeated after 120min from SEPPs compared to only 3.7% from drug suspension. Among different SEPPs, SEPP containing 30% Tween 80/Transcutol HP mixture showed the highest GEN permeation (18.54%). Conclusively, SEPP might be a promising nanocarrier that enhances GEN bioavailability via improving dissolution and inhibition of pre-systemic clearance. PMID- 27492017 TI - Oral dosage form administration practice in children under 6 years of age: A survey study of paediatric nurses. AB - The purpose of this study was to interview paediatric nurses on administration issues using extemporaneous capsules and marketed capsules and tablets in children younger than 6 years old, based on most frequently administered drugs in six participating wards. The 59 responding nurses estimated respectively at 7.7+/ 1.7 and 7.3+/-1.8years the age from which children would properly swallow extemporaneous capsules and marketed solids, with 33% and 37% of nurses considering that children under 6 would not get their prescribed treatment using these dosage forms. Refusal of the child to take the solid was the first reason to explain administration failure (85% of nurses for extemporaneous capsules, 89% for marketed solids). Although type of formulation and requirement of chewing were factors influencing the age at which children would take solid from nurses' experience, size of conventional tablets was not among these factors. All respondents use to crush tablets in children unable to swallow whole solids; 37% of nurses systematically split the tablets to ease the swallowing in children able to swallow. Only 11 nurses had an information tool at their disposal to guide manipulation of solids, with 7 of them using it in their daily practice. Providing specific-ward questionnaires, this study gives factual information on administration practices, perceptions and issues faced by paediatric nurses. PMID- 27492018 TI - Formulation of controlled-release pelubiprofen tablet using Kollidon((r)) SR. AB - To develop a matrix-type, controlled-release tablet formulation of pelubiprofen (PLB), a recently developed non-steroidal anti-inflammatory drug, polymeric excipients including hypromellose, hydroxypropylcellulose, Eudragit((r)) RS PO, and Kollidon((r)) SR were screened. A formulation containing 12.4% w/w Kollidon((r)) SR (K2 tablet) was found to be the most promising and stable for 6 months in an accelerated stability test. PLB release from K2 tablet was limited at pH 1.2, but gradually increased at pH 6.8 with a surface-erosion, resulting in the best fit to Hixson-Crowell equation. Comparative human PK studies were performed using a randomized, 2-way crossover design. LC-MS/MS assay revealed that the plasma level of PLB-transOH, an active metabolite, was significantly higher than that of PLB. After multiple dosing of immediate-release tablet (R) and K2 tablet (T), the T/R ratios of AUC were 1.02 and 1.04 for PLB and PLB transOH, respectively. Level A in vitro-in vivo correlation was established for the K2 tablet-administered group. PK profile of PLB-transOH was not influenced by food intake, while that of PLB was altered. We suggest that K2 tablet could be administered twice a day without being affected by food intake, thereby enhancing patient compliance. PMID- 27492019 TI - Potential of surface-eroding poly(ethylene carbonate) for drug delivery to macrophages. AB - Films composed of poly(ethylene carbonate) (PEC), a biodegradable polymer, were compared with poly(lactide-co-glycolide) (PLGA) films loaded with and without the tuberculosis drug rifampicin to study the characteristics and performance of PEC as a potential carrier for controlled drug delivery to macrophages. All drug loaded PLGA and PEC films were amorphous indicating good miscibility of the drug in the polymers, even at high drug loading (up to 50wt.%). Polymer degradation studies showed that PLGA degraded slowly via bulk erosion while PEC degraded more rapidly and near-linearly via enzyme mediated surface erosion (by cholesterol esterase). Drug release studies performed with polymer films indicated a diffusion/erosion dependent delivery behavior for PLGA while an almost zero-order drug release profile was observed from PEC due to the controlled polymer degradation process. When exposed to polymer degradation products the murine macrophage cell line J774A.1 showed less susceptibility to PEC than to PLGA. However, when seeding the macrophages on PLGA and PEC films no relevant difference in cell proliferation/growth kinetics was observed. Overall, this study emphasizes that PEC is an attractive polymer for controlled drug release and could provide superior performance to PLGA for some drug delivery applications including the treatment of macrophage infections. PMID- 27492020 TI - Supersaturated controlled release matrix using amorphous dispersions of glipizide. AB - Spray dried dispersions (SDDs) of glipizide, a BCS Class II model drug, were prepared using various grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone S-630 as carriers. The SDDs appeared as a single amorphous phase with up to 60% drug loading level as revealed by X-ray powder diffraction (XRPD), modulated differential scanning calorimetry (mDSC) and scanning electron microscopy (SEM). Supersaturated micro-dissolution testing of various SDDs in fasted state simulated intestinal fluid showed prolonged supersaturation state (up to 180min) with solubility increases of 5.2-13.9 fold relative to crystalline drug under similar conditions. Solubility and stability characteristics of the most desirable SDDs in terms of relative dissolution AUCs (AUC(SDD)/AUC(crystalline)) and supersaturated concentration ratios (C180/Cmax) were determined. Results show that HPMCAS-based SDDs achieve a higher degree of supersaturation compared to Copovidone S-630 and that SDDs comprising HPMCAS-M and HPMCAS-H maintained stable supersaturated concentration. Dissolution data showed that SDD-loaded CR tablets provide stable supersaturated concentration within the hydrated matrix with increased rate and extent of drug dissolution over 24h. Co-existence of HPMCAS and HPMC within the hydrating matrix showed strong suppression of drug crystallization and allowed achievement of zero-order and slow-first order release kinetics. PMID- 27492021 TI - Intracellular delivery of peptide cargos using polyhydroxybutyrate based biodegradable nanoparticles: Studies on antitumor efficacy of BCL-2 converting peptide, NuBCP-9. AB - Faster biodegradation, immunogenicity and lack of cell penetrative capabilities are hurdles in development of peptidyl drugs for cancer therapy. Polymeric carriers can be used to overcome these problems. The present study is focused on the use of polyhydroxybutyrate as a potential nanovehicle for the delivery of anticancer peptides. PHB (72kDa) was produced by thermal treatment of high molecular weight PHB (300kDa) under melt conditions and then conjugated with PEG (4kDa) by Steglich esterification reaction. Anticancer peptide NuBCP-9 (FSRSLHSLL) encapsulated PHB(72K)-PEG(4K) NPs were prepared by double emulsion solvent evaporation method. PHB(72K)-PEG(4K) NPs showed encapsulation efficiency of 61% and exhibited sustained release of peptide over a period of 26days at physiological pH. NuBCP-9 loaded PHB(72K)-PEG(4K) NPs showed an IC50 value of 2.2MUM & 1.6MUM in MCF-7 cells in 48h and 72h respectively. Confocal laser microscopy confirmed efficient cellular uptake and induction of apoptosis by peptide loaded NPs in a time dependent manner. In vivo intraperitonial administration of 20mg/kg NuBCP-9/NPs twice a week for three weeks triggered 90% tumor regression in Ehrlich syngeneic mouse model. Our results illustrated the potential of PHB(72K)-PEG(4K) based nanoformulation as a tool for targeting intracellular proteins. PMID- 27492023 TI - Nanoparticle-mediated siRNA delivery assessed in a 3D co-culture model simulating prostate cancer bone metastasis. AB - siRNA has emerged as a potential therapeutic for the treatment of prostate cancer but effective delivery remains a major barrier to its clinical application. This study aimed to develop and characterise a 3D in vitro co-culture model to simulate prostate cancer bone metastasis and to assess the ability of the model to investigate nanoparticle-mediated siRNA delivery and gene knockdown. PC3 or LNCaP prostate cancer cells were co-cultured with hFOB 1.19 osteoblast cells in 2D on plastic tissue culture plates and in 3D on collagen scaffolds mimicking the bone microenvironment. To characterise the co-culture model, cell proliferation, enzyme secretion and the utility of two different gene delivery vectors to mediate siRNA uptake and gene knockdown were assessed. Cell proliferation was reduced by~50% by day 7 in the co-culture system relative to monoculture (PC3 and LNCaP co-cultures, in 2D and 3D) and an enhanced level of MMP9 (a marker of bone metastasis) was secreted into the media (1.2-4-fold increase depending on the co culture system). A cationic cyclodextrin gene delivery vector proved significantly less toxic in the co-culture system relative to the commercially available vector Lipofectamine 2000((r)). In addition, knockdown of both the GAPDH gene (minimum 15%) and RelA subunit of the NF-kappaB transcription factor (minimum 20%) was achieved in 2D and 3D cell co-cultures. Results indicate that the prostate cancer-osteoblast in vitro co-culture model was more physiologically relevant vs the monoculture. This model has the potential to help improve the design and efficacy of gene delivery formulations, to more accurately predict in vivo performance and, therefore, to reduce the risk of product failure in late stage clinical development. PMID- 27492022 TI - Controlled curcumin release via conjugation into PBAE nanogels enhances mitochondrial protection against oxidative stress. AB - Mitochondria are considered to be the "power plants" of the cell, but can also initiate and execute cell death, stimulated by oxidative stress (OS). OS induced mitochondrial dysfunction is characterized by a loss in oxygen consumption and reduced ATP production. Curcumin, as a potential therapeutic, has been explored as a candidate for mitochondrial OS suppression, but rapid metabolism and aqueous insolubility has prevented it from being effective. Further, efficient delivery of curcumin via the incorporation into nanocarriers has again been limited due to low drug loading capacities and/or significant burst release, resulting in acute cytotoxicity. Hence, to increase the therapeutic potential and reduce the toxic effects of curcumin, curcumin conjugated poly(beta-amino ester) nanogels (CNGs) were synthesized using Michael addition chemistry. This approach provided easy control over the nanogel size, with CNGs showing a uniform release of active curcumin over 48h with no burst release. This controlled release system significantly increased the safety limit for curcumin, with a ten fold increase in the cytotoxic threshold, as compared to free curcumin. Further, real-time mitochondrial response analysis with the Seahorse XF96 showed effective and prolonged suppression of H2O2 induced mitochondrial oxidative stress upon pre treating endothelial cells with CNGs and this potential of nanogels was studied at different pre-treatment times prior to H2O2 exposure. PMID- 27492024 TI - Food Insecurity Is Associated with Cognitive Deficits Among HIV-Positive, But Not HIV-Negative, Individuals in a United States Sample. AB - People living with HIV/AIDS (PLWHA) in the United States (US) have disproportionately high rates of food insecurity (FI). In the general population, FI has been associated with cognitive impairment among older adults and may exacerbate HIV-associated neurocognitive disorders. The current study assessed the effects of FI and HIV infection on the neuropsychological performance of 61 HIV-positive and 36 HIV-negative adults in the US. While the main effects were minimal, the interactive effects revealed that FI was related to deficits in speed of information processing, learning, memory, motor function, and overall cognitive impairment for the HIV-positive group, but not the HIV-negative group. The interactive effects remained after controlling for relevant sociodemographic characteristics. Although bidirectional associations cannot be ruled out in a cross-sectional study, the results suggest that FI may contribute to cognitive impairment among HIV-positive adults in the US. Given the high rates of socioeconomic disadvantage among PLWHA in the US, addressing FI as part of routine clinical care may be warranted. PMID- 27492025 TI - Understanding HIV-Related Stigma Among Women in the Southern United States: A Literature Review. AB - Societal stigmatization of HIV/AIDS due to assumptions about transmission and associated behaviors plays a substantial role in the psychosocial well-being of people living with this chronic illness, particularly for women in traditionally conservative geographic regions. Known for social conservatism, the Southern United States (US) holds the highest incidence rate of HIV infection in the US. A systematic search of four databases was used to identify 27 relevant scientific articles pertaining to HIV-related stigma among women living with HIV/AIDS in the Southern US. These studies revealed a rudimentary understanding of stigma sources, effects, and stigma-reduction interventions in this population. Due to the cultural specificity of stigma, further differentiation of stigma in discrete sectors of the South as well as a dialogue about the moral implications of stigma is necessary to lay the groundwork for patient-centered interventions to mitigate the destructive effects of stigma experienced by women in this region. PMID- 27492026 TI - Design of Pluronic-Based Formulation for Enhanced Redaporfin-Photodynamic Therapy against Pigmented Melanoma. AB - The therapeutic outcome of photodynamic therapy (PDT) with redaporfin (a fluorinated sulfonamide bacteriochlorin, F2BMet or LUZ11) was improved using Pluronic-based (P123, F127) formulations. Neither redaporfin encapsulated in Pluronic nor micelles alone exhibited cytotoxicity in a broad concentration range. Comprehensive in vitro studies against B16F10 melanoma cells showed that redaporfin-P123 micelles enhanced cellular uptake and increased oxidative stress compared with redaporfin-F127 or photosensitizer alone after short incubation times. ROS-sensitive fluorescent probes showed that the increased oxidative stress is due, at least in part, to a more efficient formation of hydroxyl radicals, and causes strong light-dose dependent apoptosis and necrosis. Tissue distribution and pharmacokinetic studies in tumor-bearing mice show that the Pluronic P123 formulation of redaporfin increases its bioavailability as well as the tumor-to-muscle and tumor-to-skin ratios, in comparison with Cremophor EL and Pluronic F127 formulations. Redaporfin in P123 was most successful in the PDT of C57BL/6J mice bearing subcutaneously implanted B16F10 melanoma tumors. Vascular targeted PDT combining 1.5 mg kg(-1) redaporfin in P123 with a light dose of 74 J cm(-2) led to 100% complete cures (i.e., no tumor regrowth over one year post treatment). This remarkable result reveals that modification of redaporfin with Pluronic block copolymers overcomes the resistance of melanoma cells to PDT possibly via increased tumor selectivity and enhanced ROS generation. PMID- 27492027 TI - The revised guidelines of the Medical Council of India for academic promotions: Need for a rethink. PMID- 27492029 TI - Diabetic retinopathy and its risk factors in patients with type 2 diabetes attending rural primary healthcare facilities in Tamil Nadu. AB - BACKGROUND: India has a high burden of diabetic retinopathy ranging from 12.2% to 20.4% among patients with type 2 diabetes mellitus (T2DM). A T2DM management programme was initiated in the public sector in Tamil Nadu. We estimated the prevalence of diabetic retinopathy and its associated risk factors. METHODS: We did a cross-sectional survey among patients with T2DM attending two primary health centres for treatment and follow-up in Kancheepuram, Tamil Nadu in January March 2013. We did a questionnaire-based survey, and measured blood pressure and biochemical parameters (serum creatinine, plasma glucose, etc.) of the patients. We examined their eyes by direct and indirect ophthalmoscopy and defined diabetic retinopathy using a modified classification by Klein et al. We calculated the proportion and 95% CI for the prevalence and adjusted odds ratio (AOR) for risk factors associated with diabetic retinopathy. RESULTS: Among the 270 patients, the mean (SD) age was 54.5 (10) years. The median duration of T2DM was 48 months. The prevalence of diabetic retinopathy was 29.6%. Overall, 65.9% of patients had hypertension, 14.4% had nephropathy (eGFR <60 mg/dl) and 67.4% had neuropathy. Among patients with comorbid conditions, 60%, 48%, 32%, and 3% were already diagnosed to have hypertension, neuropathy, retinopathy, and nephropathy, respectively. The risk factors for diabetic retinopathy were hypertension (AOR 3.2, 95% CI 1.7-6.3), duration of T2DM >5 years (AOR 6.5, 95% CI 3.6-11.7), poor glycaemic control (AOR 2.4, 95% CI 1.4-4.4), and nephropathy (AOR 2.3, 95% CI 1.1 4.6). CONCLUSIONS: There was a high burden of undetected retinopathy and other comorbid conditions among patients with T2DM. Early detection of comorbid conditions and glycaemic control can be improved by training care-providers and educating patients. PMID- 27492030 TI - Guillain-Barre syndrome in a patient with neuropsychiatric systemic lupus erythematosus. AB - Guillain-Barre syndrome is a rare manifestation of neuropsychiatric systemic lupus erythematosus (SLE). Clinical and electrophysiological features of Guillain Barre syndrome in patients with SLE are different from those in patients without SLE. There is considerable variation in the management and prognosis. We present a patient with Guillain-Barre syndrome and SLE and review the recent knowledge on the various manifestations of neuropsychiatric SLE. PMID- 27492031 TI - Routine health check-ups: A boon or a burden? AB - Healthcare provider institutions in India now offer structured health check-up 'packages' for routine screening of common diseases. While some tests included within their ambit are in keeping with international and Indian recommendations, some are entirely unwarranted. Unnecessary and inappropriate screening tests may cause more harm than benefit. Besides financial and resource burden, there may be over-diagnosis and over-treatment, psychological distress due to false-positive test results, harm from invasive follow-up tests, and false reassurance due to false-negative test results. Clinicians must ensure a net benefit from tests and interventions in order to efficiently deliver preventive services. We reviewed current screening guidelines for cardiovascular disease and common cancers, and surveyed multiple 'packages' provided at 8 centres in Mumbai, India. We put forth our recommendations for routine health screening in asymptomatic adults in India. PMID- 27492032 TI - Control of scabies in endemic areas: Is mass drug administration the solution? PMID- 27492033 TI - Residents' working hours and patient safety: Have we finally laid the issue to rest! PMID- 27492034 TI - Total knee replacement or non-surgical therapy for osteoarthritis of the knee? PMID- 27492035 TI - Post-earthquake Nepal: Acute-on-chronic problems. PMID- 27492036 TI - Then and now: Teaching medicine at the patient's bedside. PMID- 27492037 TI - The art of letting go and the mandate of going further. PMID- 27492038 TI - Cytomegaloviral retinitis. PMID- 27492039 TI - Metachronous second primary of the oesophagus detected by FDG-PET/CT in a patient with follicular variant of papillary thyroid carcinoma. PMID- 27492040 TI - Elimination of lymphatic filariasis. PMID- 27492041 TI - Myelopathy complicating congenital atlanto-axial dislocation (A study of 28 cases). PMID- 27492042 TI - News from here and there. PMID- 27492044 TI - Dysplasia discrimination in intestinal-type neoplasia of the esophagus and colon via digital image analysis. AB - Determining gastrointestinal tract dysplasia level is clinically important but can be difficult, and given this challenge, we investigated colonic and esophageal dysplastic progression using digital image analysis (IA). Whole slide images were obtained for colonic normal mucosa (NCM), hyperplastic polyps (HP), conventional tubular adenomas (TA), and adenomas with high-grade dysplasia (HGD), and esophageal intestinal metaplasia negative for dysplasia (IM), indefinite for dysplasia (IFD), low-grade dysplasia (LGD), and HGD. Characteristic nuclei were circumscribed, and parameters discriminating groups included nuclear circumference (MUm), area (MUm(2)), and 15 positive pixel count (PPC) algorithm IA measurements. In colon polyps and esophageal lesions, average nuclear area and circumference ranged 30-108.6 MUm(2) and 27.5-48.9 MUm, respectively. Differences for average nuclear area and circumference met statistical significance (p < 0.05) between diagnostic groups in the esophagus and colon, except for IM versus IFD nuclear area. Pixel intensity (brightness) separated lesions within both groups with statistical significance except for colonic TAs versus HPs and esophageal LGD versus IM. HGD nuclei in both groups demonstrated more pixel staining heterogeneity than other lesions. Hierarchical clustering and principal component analysis demonstrated that lesions with similar diagnoses tended to cluster together on a low- to high-grade spectrum. Our results confirm that quantitative IA is an effective adjunct reflecting dysplasia in colon polyps and Barrett esophagus lesions. Nuclear area, circumference, and PPC algorithm findings distinguished lesions in a statistically significant manner. This suggests utility for future studies on similar methods, which may provide an adjunctive ancillary technique for pathologists and enhance patient care. PMID- 27492045 TI - A multifunctional extract from corn steep liquor: antioxidant and surfactant activities. AB - In the last few years the awareness of consumers and institutions about the impact that our industrial processes has on health and the environment has increased, demanding more natural products. In this work, a multifunctional bioactive extract with surfactant and antioxidant properties, composed mainly of C16 and C18 fatty acids, and phenolic compounds (vanillic acid, p-coumaric acid, ferulic acid, sinapic acid and quercetin) was obtained from corn steep liquor (CSL). Different liquid-liquid extraction protocols were evaluated obtaining a natural extract, which was able to reduce the surface tension of water by more than 30 units, showing antioxidant activity with an EC50 of 8.51 mg mL(-1) and a yield of 6.85 g of extract per kg of CSL. Additionally, it was observed that after liquid-liquid extraction with chloroform, the aqueous phase can be subjected to a hydrothermal treatment, followed by extraction with ethyl acetate, in order to obtain another extract (24.7 g of extract per kg of CSL) with a higher antioxidant capacity (EC50 of 4.02 mg mL(-1)). In this case the antioxidant extract is composed of protocatechuic acid, vanillic acid, caffeic acid, epicatechin, p-coumaric acid, ferulic acid, sinapic acid and quercetin. PMID- 27492046 TI - Treatment recommendations for single-unit crowns: Findings from The National Dental Practice-Based Research Network. AB - BACKGROUND: The objectives of this study were to quantify practitioner variation in likelihood to recommend a crown and test whether certain dentist, practice, and clinical factors are associated significantly with this likelihood. METHODS: Dentists in The National Dental Practice-Based Research Network completed a questionnaire about indications for single-unit crowns. In 4 clinical scenarios, practitioners ranked their likelihood of recommending a single-unit crown. The authors used these responses to calculate a dentist-specific crown factor (range, 0-12). A higher score implied a higher likelihood of recommending a crown. The authors tested certain characteristics for statistically significant associations with the crown factor. RESULTS: A total of 1,777 of 2,132 eligible dentists (83%) responded. Practitioners were most likely to recommend crowns for teeth that were fractured, cracked, or endodontically treated or had a broken restoration. Practitioners overwhelmingly recommended crowns for posterior teeth treated endodontically (94%). Practice owners, practitioners in the Southwest, and practitioners with a balanced workload were more likely to recommend crowns, as were practitioners who used optical scanners for digital impressions. CONCLUSIONS: There is substantial variation in the likelihood of recommending a crown. Although consensus exists in some areas (posterior endodontic treatment), variation dominates in others (size of an existing restoration). Recommendations varied according to type of practice, network region, practice busyness, patient insurance status, and use of optical scanners. PRACTICAL IMPLICATIONS: Recommendations for crowns may be influenced by factors unrelated to tooth and patient variables. A concern for tooth fracture-whether from endodontic treatment, fractured teeth, or large restorations-prompted many clinicians to recommend crowns. PMID- 27492047 TI - Pituitary dysfunction after aneurysmal subarachnoid hemorrhage in Japanese patients. AB - To elucidate the pituitary function of Japanese patients after aneurysmal subarachnoid hemorrhage (aSAH) and implicative factors related to growth hormone deficiency (GHD) after aSAH. We evaluated basal pituitary hormone levels among 59 consecutive aSAH patients with a modified Rankin Scale (mRS) ?4 at 3months after aSAH onset. Patients with low insulin-like growth factor 1 (IGF-1) SD score (SDS) or who seemed to develop pituitary dysfunction underwent provocative endocrine testing during a period of 3-36months after SAH onset. The relationship between IGF-1 SDS and clinical factors of the patients such as severity of SAH, aneurysm location, and treatment modalities, were assessed. Six patients (10.2%) demonstrated their IGF-1 SDS less than -2. Multiple logistic regression analyses revealed that patients who underwent surgical clipping had a significantly lower IGF-1 SDS (<-1SD) than patients who underwent endovascular embolization with an odds ratio of 5.83 (p=0.032). Thirty-three patients took provocative tests and five (15.6%) patients were identified as having GHD. The mean IGF-1 SDS of these five GHD patients was 0.08 SD. The aneurysms in all GHD patients were located in internal carotid artery (ICA) or anterior cerebral artery (ACA). To the best of our knowledge, this is the first report describing the prevalence of GHD in Japanese patients after aSAH, and it was not as high as that of previous European studies. We recommend that screening pituitary dysfunction for aSAH survivors with their aneurysms located in ICA or ACA. PMID- 27492048 TI - The efficacy and safety of teriflunomide based therapy in patients with relapsing multiple sclerosis: A meta-analysis of randomized controlled trials. AB - The aim of this study was to evaluate the efficacy and safety of teriflunomide in reducing the frequency of relapses and progression of physical disability in patients with relapsing multiple sclerosis (RMS). Literatures were searched in Pubmed, Medline and Embase to screen citations from January 1990 to April 2015. Studies of parallel group design comparing teriflunomide and placebo for RMS were screened. After independent review of 234 citations by two authors, seven studies were identified as meeting the inclusion criteria. The results showed teriflunomide (7 and 14mg) could significantly reduce annualized relapse rate and teriflunomide at the higher dose could also decrease the disability progression (risk ratio (RR)=0.69, 95% confidence interval (CI): 0.55-0.87). And teriflunomide significantly reduce annualized rates of relapses with sequelae EDSS/FS, relapses leading to hospitalization, and relapses requiring IV corticosteroids. Patients treated with teriflunomide 14mg have a lower annualized rate of relapses with sequelae-investigator (RR=0.37, 95% CI: 0.26-0.52). Teriflunomide 7mg has a higher incidence of diarrhea (RR=1.73, 95% CI: 1.32-2.26) and hair thinning (RR=1.99, 95% CI: 1.4-2.81), while teriflunomide 14mg has a higher incidence of diarrhea (RR=1.71, 95% CI: 1.34-2.18), hair thinning (RR=2.81, 95% CI: 2.02-3.91) and nausea (RR=1.65, 95% CI: 1.03-2.31) compared with placebo. The incidence of elevated alanine aminotransferase levels was also higher with teriflunomide than with placebo. However, the incidence of serious adverse events was similar across groups. In conclusion, teriflunomide significantly reduces annualized relapse rates and disability progression with a similar safety and tolerability profile to placebo. PMID- 27492049 TI - Breaking Down the Barriers to Precision Cancer Nanomedicine. AB - Nanomedicine offers unique advantages in treating human cancers. However, physiological and pathological barriers within normal and disease tissues, which are highly variable among individuals, often hinder its effectiveness. The body possesses specific innate responses to nanoparticles (NPs), which when combined with unique pathophysiological signatures in the tumor microenvironment, can severely limit the utility of nanomedicine in the oncological setting. Furthermore, with the successes of cancer immunotherapies, understanding nanoimmune interactions and developing immune-smart cancer nanomedicine that can take advantage of the body's immune functions will increasingly become clinically relevant. Therefore, a better understanding of the important native and acquired biological processes that dictate the fate of nanomedicine is integral to developing more effective individualized platforms for treating cancer patients. PMID- 27492050 TI - Interactions of rod-like particles on responsive elastic sheets. AB - What are the physical laws of the mutual interactions of objects bound to cell membranes, such as various membrane proteins or elongated virus particles? To rationalise this, we here investigate by extensive computer simulations mutual interactions of rod-like particles adsorbed on the surface of responsive elastic two-dimensional sheets. Specifically, we quantify sheet deformations as a response to adhesion of such filamentous particles. We demonstrate that tip-to tip contacts of rods are favoured for relatively soft sheets, while side-by-side contacts are preferred for stiffer elastic substrates. These attractive orientation-dependent substrate-mediated interactions between the rod-like particles on responsive sheets can drive their aggregation and self-assembly. The optimal orientation of the membrane-bound rods is established via responding to the elastic energy profiles created around the particles. We unveil the phase diagramme of attractive-repulsive rod-rod interactions in the plane of their separation and mutual orientation. Applications of our results to other systems featuring membrane-associated particles are also discussed. PMID- 27492052 TI - Endogenous Technology Adoption and Medical Costs. AB - Despite the claim that technology has been one of the most important drivers of healthcare spending growth over the past decades, technology variables are rarely introduced explicitly in cost equations. Furthermore, technology is often considered exogenous. Using 1996-2007 panel data on Swiss geographical areas, we assessed the impact of technology availability on per capita healthcare spending covered by basic health insurance whilst controlling for the endogeneity of health technology availability variables. Our results suggest that medical research, patent intensity and the density of employees working in the medical device industry are influential factors for the adoption of technology and can be used as instruments for technology availability variables in the cost equation. These results are similar to previous findings: CT and PET scanner adoption is associated with increased healthcare spending, whilst increased availability of percutaneous transluminal coronary angioplasty facilities is associated with reductions in per capita spending. However, our results suggest that the magnitude of these relationships is much greater in absolute value than that suggested by previous studies that did not control for the possible endogeneity of the availability of technologies. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27492053 TI - Prognostic value of computed tomography in acute pulmonary thromboembolism. AB - In addition to being the standard reference for the diagnosis of acute pulmonary thromboembolism, CT angiography of the pulmonary arteries can also provide valuable information about the patient's prognosis. Although which imaging findings are useful for prognosis remains controversial, signs of right ventricular dysfunction on CT are now included in clinical algorithms for the management of pulmonary thromboembolism. However, the optimal method for obtaining these measurements while maintaining a balance between the ease of use necessary to include their evaluation in our daily activity and the loss of precision in its predictive capacity remains to be determined. Moreover, other variables associated with pulmonary thromboembolism that often go unobserved can complement the prognostic information we can offer to clinicians. This review aims to clarify some of the more controversial aspects related to the prognostic value of CT in patients with pulmonary embolisms according to the available evidence. Knowing which variables are becoming more important in the prognosis, how to detect them, and why it is important to include them in our reports will help improve the management of patients with pulmonary embolism. PMID- 27492054 TI - Reduced CD161+ MAIT cell frequencies in HCV and HIV/HCV co-infection: Is the liver the heart of the matter? PMID- 27492055 TI - Joint society statement for the elimination of viral hepatitis. PMID- 27492057 TI - Probing non-covalent interactions with a second generation energy decomposition analysis using absolutely localized molecular orbitals. AB - An energy decomposition analysis (EDA) separates a calculated interaction energy into as many interpretable contributions as possible; for instance, permanent and induced electrostatics, Pauli repulsions, dispersion and charge transfer. The challenge is to construct satisfactory definitions of all terms in the chemically relevant regime where fragment densities overlap, rendering unique definitions impossible. Towards this goal, we present an improved EDA for Kohn-Sham density functional theory (DFT) with properties that have previously not been simultaneously attained. Building on the absolutely localized molecular orbital (ALMO)-EDA, this second generation ALMO-EDA is variational and employs valid antisymmetric electronic wavefunctions to produce all five contributions listed above. These contributions moreover all have non-trivial complete basis set limits. We apply the EDA to the water dimer, the T-shaped and parallel-displaced benzene dimer, the p-biphthalate dimer "anti-electrostatic" hydrogen bonding complex, the biologically relevant binding of adenine and thymine in stacked and hydrogen-bonded configurations, the triply hydrogen-bonded guanine-cytosine complex, the interaction of Cl(-) with s-triazine and with the 1,3-dimethyl imidazolium cation, which is relevant to the study of ionic liquids, and the water-formaldehyde-vinyl alcohol ter-molecular radical cationic complex formed in the dissociative photoionization of glycerol. PMID- 27492056 TI - Induction of DNA damage and erroneous repair can explain genomic instability caused by endosulfan. AB - Endosulfan (ES) is an organochlorine pesticide, speculated to be associated with chromosomal abnormalities and diseases in humans. However, very little is known about the mechanism of its genotoxicity. Using in vivo, ex vivo and in vitro model systems, we show that exposure to ES induces reactive oxygen species (ROS) in a concentration and time-dependent manner. The generation of ROS results in DNA double-strand breaks either directly or in a replication-dependent manner, both in mice and human cells. Importantly, ES-induced DNA damage evokes DNA damage response, resulting in elevated levels of classical non-homologous DNA endjoining (NHEJ), the predominant double-strand break repair pathway in higher eukaryotes. Sequence analyses of NHEJ junctions revealed that ES treatment results in extensive processing of broken DNA, culminating in increased and long junctional deletions, thereby favoring erroneous repair. We also find that exposure to ES leads to significant increase in microhomology-mediated end joining (MMEJ), a LIGASE III-dependent alternative repair pathway. Therefore, we demonstrate that ES induces DNA damage and genomic instability, alters DNA damage response thereby promoting erroneous DNA repair. PMID- 27492058 TI - Multiplex 16S rRNA-derived geno-biochip for detection of 16 bacterial pathogens from contaminated foods. AB - Foodborne diseases caused by various pathogenic bacteria occur worldwide. To prevent foodborne diseases and minimize their impacts, it is important to inspect contaminated foods and specifically detect many types of pathogenic bacteria. Several DNA oligonucleotide biochips based on 16S rRNA have been investigated to detect bacteria; however, a mode of detection that can be used to detect diverse pathogenic strains and to examine the safety of food matrixes is still needed. In the present work, a 16S rRNA gene-derived geno-biochip detection system was developed after screening DNA oligonucleotide specific capture probes, and it was validated for multiple detection of 16 pathogenic strains that frequently occur with a signature pattern. rRNAs were also used as detection targets directly obtained from cell lysates without any purification and amplification steps in the bacterial cells separated from 8 food matrixes by simple pretreatments. Thus, the developed 16S rRNA-derived geno-biochip can be successfully used for the rapid and multiple detection of the 16 pathogenic bacteria frequently isolated from contaminated foods that are important for food safety. PMID- 27492059 TI - Plant-mediated interactions between two herbivores differentially affect a subsequently arriving third herbivore in populations of wild cabbage. AB - Plants are part of biodiverse communities and frequently suffer from attack by multiple herbivorous insects. Plant responses to these herbivores are specific for insect feeding guilds: aphids and caterpillars induce different plant phenotypes. Moreover, plants respond differentially to single or dual herbivory, which may cascade into a chain of interactions in terms of resistance to other community members. Whether differential responses to single or dual herbivory have consequences for plant resistance to yet a third herbivore is unknown. We assessed the effects of single or dual herbivory by Brevicoryne brassicae aphids and/or Plutella xylostella caterpillars on resistance of plants from three natural populations of wild cabbage to feeding by caterpillars of Mamestra brassicae. We measured plant gene expression and phytohormone concentrations to illustrate mechanisms involved in induced responses. Performance of both B. brassicae and P. xylostella was reduced when feeding simultaneously with the other herbivore, compared to feeding alone. Gene expression and phytohormone concentrations in plants exposed to dual herbivory were different from those found in plants exposed to herbivory by either insect alone. Plants previously induced by both P. xylostella and B. brassicae negatively affected growth of the subsequently arriving M. brassicae. Furthermore, induced responses varied between wild cabbage populations. Feeding by multiple herbivores differentially activates plant defences, which has plant-mediated negative consequences for a subsequently arriving herbivore. Plant population-specific responses suggest that plant populations adapt to the specific communities of insect herbivores. Our study contributes to the understanding of plant defence plasticity in response to multiple insect attacks. PMID- 27492062 TI - Soft-tissue defects of the Achilles tendon region: Management and reconstructive ladder. Review of the literature. AB - INTRODUCTION: Defects of the Achilles tendon region represent a challenge for reconstructive surgeons. Several options are available but there is still no reconstructive ladder for this specific and tricky area. An up-to-date reconstructive ladder according to local and general conditions is proposed based on our multicentre experience and an extensive review of the English literature on PubMed. MATERIALS AND METHODS: An extensive review of the English literature was performed on PubMed using the following key-words: "Achilles region", "heel", "soft-tissue reconstruction", "flaps", "grafts" and "dermal substitutes". RESULTS: A total of 69 complete papers were selected, covering the last thirty years' literature. Although most of the studies were based on limited case series, local and general conditions were always reported. A comprehensive reconstructive ladder of all the available reconstructive techniques for the Achilles region has been created based on our personal multicentre experience and the results of the literature review. CONCLUSIONS: The reconstructive ladder is a concept that is still a mainstay in plastic surgery and guides decisions in the repair strategy for soft tissue defects. The optimal solution, according to the experience of the surgeon and the wishes of the patient, is the one that implies less sacrifice of the donor site. Perforator flaps should be the first-line option for small-to-moderate defects; the distally-based sural flap is the most reported for moderate-to-large defects of the Achilles region, and free flaps should be reserved mainly for complex and wide reconstructions. PMID- 27492061 TI - Long-range movement of large mechanically interlocked DNA nanostructures. AB - Interlocked molecules such as catenanes and rotaxanes, connected only via mechanical bonds have the ability to perform large-scale sliding and rotational movements, making them attractive components for the construction of artificial molecular machines and motors. We here demonstrate the realization of large, rigid rotaxane structures composed of DNA origami subunits. The structures can be easily modified to carry a molecular cargo or nanoparticles. By using multiple axle modules, rotaxane constructs are realized with axle lengths of up to 355 nm and a fuel/anti-fuel mechanism is employed to switch the rotaxanes between a mobile and a fixed state. We also create extended pseudo-rotaxanes, in which origami rings can slide along supramolecular DNA filaments over several hundreds of nanometres. The rings can be actively moved and tracked using atomic force microscopy. PMID- 27492063 TI - Minimally-invasive treatment of calcaneal fractures: A review of the literature and our experience. AB - The optimal treatment of calcaneal fractures (CF) is currently controversial and is still under debate. It is well established that conservative treatment of these fractures is associated with poor results. Several surgical techniques are described in the literature; however, there is no consensus on which of these is more effective. The main goals of surgery are to restore the subtalar joint congruence, and calcaneal width, height, shape and alignment, thus avoiding medial and lateral impingement and enabling the patient to resume a normal lifestyle. ORIF is the most popular technique for these fractures, but it is associated with high rates of wound complications, hardware failure and infections. Several minimally-invasive techniques have been developed recently for the treatment of CF, with the common aim to be as simple, effective and inexpensive as possible and to reduce surgical times, complications and length of hospital stay. PMID- 27492064 TI - Unblinded randomized control trial on prophylactic antibiotic use in gustilo II open tibia fractures at Kenyatta National Hospital, Kenya. AB - OBJECTIVE: To determine the difference in infection rate between 24h versus five days of prophylactic antibiotic use in management of Gustilo II open tibia fractures. DESIGN: Unblinded randomized control trial. SETTING: Accident and Emergency, orthopedic wards and outpatient clinics at Kenyatta National Hospital (KNH). PATIENTS: The study involved patients aged 18-80 years admitted through accident and emergency department with Gustilo II traumatic open tibia fractures. INTERVENTION: Patients were randomized into either 24hour or five day group and antibiotics started for 24hours or five days after surgical debridement. The wounds were exposed and scored using ASEPSIS wound scoring system for infection after 48h, 5days and at 14days. OUTCOME MEASURES: The main outcomes of interest were presence of infection at days 2, 5 and 14 and effect of duration to antibiotic administration on infection rate. RESULTS: There was no significant difference in infection rates between 24-hour and 5-day groups with infection rates of 23% (9/40) vs. 19% (7/37) respectively (p=0.699). The infection rate was significantly associated with time lapsed before administration of antibiotics (p=0.004). CONCLUSION: In the use of prophylactic antibiotics for the management of Gustilo II traumatic open tibia fractures, there is no difference in infection rate between 24hours and five days regimen but time to antibiotic administration correlates with infection rate. Antibiotic use for 24hours only has proven adequate prophylaxis against infection. This is underlined in our study which we hope shall inform practice in our setting. A larger, more appropriately controlled study would be useful. PMID- 27492066 TI - Extra-articular distal tibia facture (AO-43A): A retrospective study comparing modified MIPPO with IMN. AB - PURPOSE: We introduce a new MIPPO procedure which is simple and effective for the treatment of extra-articular distal tibia facture (AO-43A). The aim of this retrospective study was to compare our modified MIPPO with IMN. MATERIALS AND METHODS: This retrospective study included 64 patients treated with our modified MIPPO and 61 patients with IMN. The data of sex, age, operation time, blood loss, wound complications, mal-reduction, shortening and fracture healing was analyzed. RESULTS: The operation time was significantly shorter in the MIPPO group than in the IMN group (56.0min vs. 85.0min, P<0.001). There were 5 patients (8.2%) in the IMN group and 2 patients (3.1%) in the MIPPO group who had wound complications (P=0.399). Mal-reduction occurred in 17 patients (27.9%) managed with IMN and in 3 patients (4.7%) who had MIPPO (P<0.001). Furthermore, no patients had a left/right difference in the length of the tibia of >1cm and nonunion in both groups. CONCLUSIONS: Our results have shown that our modified MIPPO has enormous advantages over IMN for extra-articular distal tibia fracture (AO-43A). PMID- 27492065 TI - Comparative evaluation of MicroDTTect device and flocked swabs in the diagnosis of prosthetic and orthopaedic infections. AB - The evolution of new prosthetic and osteosynthetic devices has led to more surgical indications, and this is accompanied by an increased incidence of septic complications in orthopaedic and trauma surgery in the general population. The strategy for choosing surgical or therapeutic (conservative) treatment is based on the identification of the pathogen: knowledge of the aetiological agents is an essential element in the decision-making process to ensure the most effective treatment is administered. The pathogen also needs to be considered in the challenging case of doubtful infection, where perhaps the only sign is inflammation, for a more accurate prediction of progression to either sepsis or healing. Biofilm-related infections and low-grade infections may fall into this category. Biofilm slows the metabolism of microorganisms and prolongs their survival, which renders them resistant to antibiotics. Moreover, when microorganisms are embedded in the biofilm they are poorly recognised by the immune system and the infection becomes chronic. As recently demonstrated, isolation and identification of bacteria in biofilm is difficult as the bacteria are concealed. The development of an effective means of sample collection and laboratory methods that can dislodge bacteria from prosthetic surfaces has therefore become necessary. The primary aim of the study was to evaluate the reliability of an innovative technology (MicroDTTect), specifically applied to collect and transport explanted samples (prostheses, osteosynthetic devices, biological tissues), and compare with flocked swabs. The MicroDTTect system is quick and simple to use and, most importantly, is a closed system that is totally sterile and safe for the patient being treated. It contains a specific concentration of dithiotreitol (DTT) that can dislodge bacteria from the biofilm adhering to prosthetic surfaces. The numbers of positive and negative samples were measured to compare the MicroDTTect methodology with swab collection in 30 procedures. The results showed that MicroDTTect had a higher sensitivity compared to swabs (77% and 46%, respectively), and was associated with more positive results than swabs (35% and 20%, respectively). These preliminary results show that MicroDTTect is superior to swab collection for bacterial identification in orthopaedic surgery. The early identification of microorganisms that cause sepsis may help improve treatment strategies and the efficacy of therapy, which will lead to an increased healing rate, reduced severity of sequelae and improved quality of life. PMID- 27492067 TI - Automated visibility map of the internal colon surface from colonoscopy video. AB - PURPOSE: Optical colonoscopy is a prominent procedure by which clinicians examine the surface of the colon for cancerous polyps using a flexible colonoscope. One of the main concerns regarding the quality of the colonoscopy is to ensure that the whole colonic surface has been inspected for abnormalities. In this paper, we aim at estimating areas that have not been covered thoroughly by providing a map from the internal colon surface. METHODS: Camera parameters were estimated using optical flow between consecutive colonoscopy frames. A cylinder model was fitted to the colon structure using 3D pseudo stereo vision and projected into each frame. A circumferential band from the cylinder was extracted to unroll the internal colon surface (band image). By registering these band images, drift in estimating camera motion could be reduced, and a visibility map of the colon surface could be generated, revealing uncovered areas by the colonoscope. Hidden areas behind haustral folds were ignored in this study. The method was validated on simulated and actual colonoscopy videos. The realistic simulated videos were generated using a colonoscopy simulator with known ground truth, and the actual colonoscopy videos were manually assessed by a clinical expert. RESULTS: The proposed method obtained a sensitivity and precision of 98 and 96 % for detecting the number of uncovered areas on simulated data, whereas validation on real videos showed a sensitivity and precision of 96 and 78 %, respectively. Error in camera motion drift could be reduced by almost 50 % using results from band image registration. CONCLUSION: Using a simple cylindrical model for the colon and reducing drift by registering band images allows for the generation of visibility maps. The current results also suggest that the provided feedback through the visibility map could enhance clinicians' awareness of uncovered areas, which in return could reduce the probability of missing polyps. PMID- 27492068 TI - Electromagnetic navigation versus fluoroscopy in aortic endovascular procedures: a phantom study. AB - PURPOSE: To explore the possible benefits of electromagnetic (EM) navigation versus conventional fluoroscopy during abdominal aortic endovascular procedures. METHODS: The study was performed on a phantom representing the abdominal aorta. Intraoperative cone beam computed tomography (CBCT) of the phantom was acquired and merged with a preoperative multidetector CT (MDCT). The CBCT was performed with a reference plate fixed to the phantom that, after merging the CBCT with the MDCT, facilitated registration of the MDCT volume with the EM space. An EM field generator was stationed near the phantom. Navigation software was used to display EM-tracked instruments within the 3D image volume. Fluoroscopy was performed using a C-arm system. Five operators performed a series of renal artery cannulations using modified instruments, alternatingly using fluoroscopy or EM navigation as the sole guidance method. Cannulation durations and associated radiation dosages were noted along with the number of cannulations complicated by loss of guidewire insertion. RESULTS: A total of 120 cannulations were performed. The median cannulation durations were 41.5 and 34.5 s for the fluoroscopy- and EM guided cannulations, respectively. No significant difference in cannulation duration was found between the two modalities (p = 0.736). Only EM navigation showed a significant reduction in cannulation duration in the latter half of its cannulation series compared with the first half (p = 0.004). The median dose area product for fluoroscopy was 0.0836 [Formula: see text]. EM-guided cannulations required a one-time CBCT dosage of 3.0278 [Formula: see text]. Three EM-guided and zero fluoroscopy-guided cannulations experienced loss of guidewire insertion. CONCLUSION: Our findings indicate that EM navigation is not inferior to fluoroscopy in terms of the ability to guide endovascular interventions. Its utilization may be of particular interest in complex interventions where adequate visualization or minimal use of contrast agents is critical. In vivo studies featuring an optimized implementation of EM navigation should be conducted. PMID- 27492069 TI - Exosome cargo reflects TGF-beta1-mediated epithelial-to-mesenchymal transition (EMT) status in A549 human lung adenocarcinoma cells. AB - It has been suggested that tumor cells secrete exosomes to modify the local microenvironment, which then promotes intercellular communication and metastasis. Although exosomes derived from cancer cells may contribute to the epithelial mesenchymal transition (EMT) in untransformed cells, few studies have defined exosome cargo upon induction of EMT. In this study, we investigated the changes in exosomal cargo from the epithelial to mesenchymal cell phenotype by inducing EMT with transforming growth factor (TGF)-beta1 in A549 human lung adenocarcinoma cells. The protein content of the exosomes reflects the change in the cell phenotype. In addition, miR-23a was significantly enriched in the exosomes after mesenchymal transition. Following treatment of exosomes from mesenchymal cells via EMT induction with TGF-beta1 to the epithelial cell type, phenotypic changes in protein expression level and cell morphology were observed. Autologous treatment of exosomes enhanced the transcriptional activity and abundance of beta catenin. Our results suggest that the exosomal protein and miRNA content reflects the physiological condition of its source and that exosomes induce phenotypic changes via autocrine signaling. PMID- 27492071 TI - The nature of organic records in impact excavated rocks on Mars. AB - Impact ejected rocks are targets for life detection missions to Mars. The Martian subsurface is more favourable to organic preservation than the surface owing to an attenuation of radiation and physical separation from oxidising materials with increasing depth. Impact events bring materials to the surface where they may be accessed without complicated drilling procedures. On Earth, different assemblages of organic matter types are derived from varying depositional environments. Here we assess whether these different types of organic materials can survive impact events without corruption. We subjected four terrestrial organic matter types to elevated pressures and temperatures in piston-cylinder experiments followed by chemical characterisation using whole-rock pyrolysis-gas chromatography-mass spectrometry. Our data reveal that long chain hydrocarbon-dominated organic matter (types I and II; mainly microbial or algal) are unresistant to pressure whereas aromatic hydrocarbon-dominated organic matter types (types III and IV; mainly land plant, metamorphosed or degraded, displaying some superficial chemical similarities to abiotic meteoritic organic matter) are relatively resistant. This suggests that the impact excavated record of potential biology on Mars will be unavoidably biased, with microbial organic matter underrepresented while metamorphosed, degraded or abiotic meteoritic organic matter types will be selectively preserved. PMID- 27492070 TI - Amyloid-beta and tau pathology following repetitive mild traumatic brain injury. AB - Neurodegenerative diseases are characterized by distinctive neuropathological alterations, including the cerebral accumulation of misfolded protein aggregates, neuroinflammation, synaptic dysfunction, and neuronal loss, along with behavioral impairments. Traumatic brain injury (TBI) is believed to be an important risk factor for certain neurodegenerative diseases, such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). TBI represents a ubiquitous problem in the world and could play a major role in the pathogenesis and etiology of AD or CTE later in life. TBI events appear to trigger and exacerbate some of the pathological processes in these diseases, in particular, the formation and accumulation of misfolded protein aggregates composed of amyloid-beta (Abeta) and tau. Here, we describe the relationship between repetitive mild TBI and the development of Abeta and tau pathology in patients affected by AD or CTE on the basis of epidemiological and pathological studies in human cases, and a thorough overview of data obtained in experimental animal models. We also discuss the possibility that TBI may contribute to initiate the formation of misfolded oligomeric species that may subsequently spread the pathology through a prion like process of seeding of protein misfolding. PMID- 27492072 TI - Vascular Dysfunction in Leukoaraiosis. AB - BACKGROUND AND PURPOSE: The pathogenesis of leukoaraiosis has long been debated. This work addresses a less well-studied mechanism, cerebrovascular reactivity, which could play a leading role in the pathogenesis of this disease. Our aim was to evaluate blood flow dysregulation and its relation to leukoaraiosis. MATERIALS AND METHODS: Cerebrovascular reactivity, the change in the blood oxygen level dependent 3T MR imaging signal in response to a consistently applied step change in the arterial partial pressure of carbon dioxide, was measured in white matter hyperintensities and their contralateral spatially homologous normal-appearing white matter in 75 older subjects (age range, 50-91 years; 40 men) with leukoaraiosis. Additional quantitative evaluation of regions of leukoaraiosis was performed by using diffusion (n = 75), quantitative T2 (n = 54), and DSC perfusion MRI metrics (n = 25). RESULTS: When we compared white matter hyperintensities with contralateral normal-appearing white matter, cerebrovascular reactivity was lower by a mean of 61.2% +/- 22.6%, fractional anisotropy was lower by 44.9 % +/- 6.9%, and CBF was lower by 10.9% +/- 11.9%. T2 was higher by 61.7% +/- 13.5%, mean diffusivity was higher by 59.0% +/- 11.7%, time-to-maximum was higher by 44.4% +/- 30.4%, and TTP was higher by 6.8% +/- 5.8% (all P < .01). Cerebral blood volume was lower in white matter hyperintensities compared with contralateral normal-appearing white matter by 10.2% +/- 15.0% (P = .03). CONCLUSIONS: Not only were resting blood flow metrics abnormal in leukoaraiosis but there is also evidence of reduced cerebrovascular reactivity in these areas. Studies have shown that reduced cerebrovascular reactivity is more sensitive than resting blood flow parameters for assessing vascular insufficiency. Future work is needed to examine the sensitivity of resting-versus-dynamic blood flow measures for investigating the pathogenesis of leukoaraiosis. PMID- 27492074 TI - Neuroimaging Findings in Congenital Zika Syndrome. PMID- 27492075 TI - Reply. PMID- 27492073 TI - Progressing Bevacizumab-Induced Diffusion Restriction Is Associated with Coagulative Necrosis Surrounded by Viable Tumor and Decreased Overall Survival in Patients with Recurrent Glioblastoma. AB - BACKGROUND AND PURPOSE: Patients with recurrent glioblastoma often exhibit regions of diffusion restriction following the initiation of bevacizumab therapy. Studies suggest that these regions represent either diffusion-restricted necrosis or hypercellular tumor. This study explored postmortem brain specimens and a population analysis of overall survival to determine the identity and implications of such lesions. MATERIALS AND METHODS: Postmortem examinations were performed on 6 patients with recurrent glioblastoma on bevacizumab with progressively growing regions of diffusion restriction. ADC values were extracted from regions of both hypercellular tumor and necrosis. A receiver operating characteristic analysis was performed to define optimal ADC thresholds for differentiating tissue types. A retrospective population study was also performed comparing the overall survival of 64 patients with recurrent glioblastoma treated with bevacizumab. Patients were separated into 3 groups: no diffusion restriction, diffusion restriction that appeared and progressed within 5 months of bevacizumab initiation, and delayed or stable diffusion restriction. An additional analysis was performed assessing tumor O6-methylguanine-DNA methyltransferase methylation. RESULTS: The optimal ADC threshold for differentiation of hypercellularity and necrosis was 0.736 * 10-3mm2/s. Progressively expanding diffusion restriction was pathologically confirmed to be coagulative necrosis surrounded by viable tumor. Progressive lesions were associated with the worst overall survival, while stable lesions showed the greatest overall survival (P < .05). Of the 40% of patients with O6-methylguanine DNA-methyltransferase methylated tumors, none developed diffusion-restricted lesions. CONCLUSIONS: Progressive diffusion-restricted lesions were pathologically confirmed to be coagulative necrosis surrounded by viable tumor and associated with decreased overall survival. Stable lesions were, however, associated with increased overall survival. All lesions were associated with O6 methylguanine-DNA-methyltransferase unmethylated tumors. PMID- 27492076 TI - Comment on "SAPHO Syndrome: Imaging Findings of Vertebral Involvement". PMID- 27492077 TI - Insight into the Epigenetics of Alzheimer's Disease: A Computational Study from Human Interactome. AB - BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease throughout the world. Most of the clinical symptoms of AD appear at a very later stage, therefore, the identification of disease markers is essential which can help proper detection of AD at an earlier stage and slow down its progression. Studies have implicated that epigenetic biomarkers, such as DNA methylation, histone modification and non coding RNA mediated regulation serve crucial roles in several disease progression including AD. OBJECTIVE: The aim of our study was to identify the topologically significant AD-related proteins from experimentally validated human protein-protein interaction database, HPRD (interactome) and find out novel epigenetic biomarkers. METHOD: In this computational work, we constructed AD specific diseasome from AD genelist and interactome. Using this diseasome we screened the interactome with the help of novel parameters namely degree band and similarity index and identified AD related proteins. Regulatory network involving AD related proteins, not previously known to be associated with AD was constructed. Several network motifs and epigenetic modification patterns of regulators of these motifs were studied. RESULT: Our study identified computationally predicted 22 epigenetic genes and 11 epigenetic miRs, not previously known to be associated with AD, from the network motifs. Most of these genes and miRs show brain specific expression. Further study on the epigenetic modification patterns of these regulators regarding histone modification, CpG island and lncRNAs strengthened their association in AD. CONCLUSION: Computationally predicted genes and miRs identified in our study might provide insight into new epigenetic AD therapeutic targets. PMID- 27492078 TI - Environmental Variables That Influence Patient Satisfaction: A Review of the Literature. AB - Patient's perception of care-referred to as patient satisfaction-is of great interest in the healthcare industry, as it becomes more directly tied to the revenue of the health system providers. The perception of care has now become important in addition to the actual health outcome of the patient. The known influencers for the patient perception of care are the patient's own characteristics as well as the quality of service received. In patient surveys, the physical environment is noted as important for being clean and quiet but is not considered a critical part of patient satisfaction or other health outcomes. Patient perception of care is currently measured as patient satisfaction, a systematic collection of perceptions of social interactions from an individual person as well as their interaction with the environment. This exploration of the literature intends to explore the rigorous, statistically tested research conducted that has a spatial predictor variable and a health or behavior outcome, with the intent to begin to further test the relationships of these variables in the future studies. This literature review uses the patient satisfaction framework of components of influence and identifies at least 10 known spatial environmental variables that have been shown to have a direct connection to the health and behavior outcome of a patient. The results show that there are certain features of the spatial layout and environmental design in hospital or work settings that influence outcomes and should be noted in the future research. PMID- 27492080 TI - Transcription factor ZFP38 is essential for meiosis prophase I in male mice. AB - The production of haploid gametes by meiosis is a cornerstone of sexual reproduction and maintenance of genome integrity. Zfp38 mRNA is expressed in spermatocytes, indicating that transcription factor ZFP38 has the potential to regulate transcription during meiosis. In this study, we generated Zfp38 conditional knockout mice (Zfp38(flox/flox), Stra8-Cre, hereafter called Zfp38 cKO) and found that spermatogenesis did not progress beyond meiosis prophase I in Zfp38 cKO mice. Using a chromosomal spread technique, we observed that Zfp38 cKO spermatocytes exhibited a failure in chromosomal synapsis observed by SYCP1/SYCP3 double staining. Progression of DNA double-strand breaks (DSB) repair is disrupted in Zfp38 cKO spermatocytes, as revealed by gamma-H2AX, RAD51 and MLH1 staining. Furthermore, the mRNA and protein levels of DSB repair enzymes and factors that guide their loading onto sites of DSBs, such as RAD51, DMC1, RAD51, TEX15 and PALB2, were significantly reduced in Zfp38 cKO spermatocytes. Taken together, our data suggest that ZFP38 is critical for the chromosomal synapsis and DSB repairs partially via its regulation of DSB repair-associated protein expression during meiotic progression in mouse. PMID- 27492079 TI - Ovarian tissue transport to expand access to fertility preservation: from animals to clinical practice. AB - Primordial follicles dictate a female's reproductive life span and therefore are central to fertility preservation for both endangered species and individuals with fertility-threatening conditions. Ovarian tissue containing primordial follicles can be cryopreserved and later thawed and transplanted back into individuals to restore both endocrine function and fertility. Importantly, increasing numbers of human live births have been reported following ovarian tissue cryopreservation and transplantation. A current limitation of this technology is patient access to sites that are approved or equipped to process and cryopreserve ovarian tissue - especially in larger countries or low resource settings. Here, we review empirical evidence from both animal models and human studies that suggest that ovarian tissue can be transported at cold temperatures for several hours while still maintaining the integrity and reproductive potential of the primordial follicles within the tissue. In fact, several human live births have been reported in European countries using tissue that was transported at cold temperatures for up to 20 h before cryopreservation and transplantation. Ovarian tissue transport, if implemented widely in clinical practice, could therefore expand both patient and provider access to emerging fertility preservation options. PMID- 27492081 TI - Effect of kit ligand on natriuretic peptide precursor C and oocyte maturation in cattle. AB - In vitro maturation (IVM) of oocytes in cattle is inefficient, and there is great interest in the development of approaches to improve maturation and fertilization rates. Intraovarian signalling molecules are being explored as potential additives to IVM media. One such factor is kit ligand (KITL), which stimulates the growth of oocytes. We determined if KITL enhances oocyte maturation in cattle. The two main isoforms of KITL (KITL1 and KITL2) were expressed in bovine cumulus-oocyte complexes (COC), and levels of mRNA increased during FSH stimulated IVM. The addition of KITL to the culture medium increased the percentage of oocytes that reached meiosis II but did not affect cumulus expansion after 22 h of IVM. Addition of KITL reduced the levels of mRNA encoding natriuretic peptide precursor C (NPPC), a protein that holds oocytes in meiotic arrest, and increased the levels of mRNA encoding YBX2, an oocyte-specific factor involved in meiosis. Removal of the oocyte from the COC resulted in increased KITL mRNA levels and decreased NPPC mRNA levels in cumulus cells, and addition of denuded oocytes reversed these effects. Taken together, our results suggest that KITL enhances bovine oocyte nuclear maturation through a mechanism that involves NPPC, and that the oocyte regulates cumulus expression of KITL mRNA. PMID- 27492083 TI - Chemoinformatic Classification Methods and their Applicability Domain. AB - Classification rules are often used in chemoinformatics to predict categorical properties of drug candidates related to bioactivity from explanatory variables, which encode the respective molecular structures (i.e. molecular descriptors). To avoid predictions with an unduly large error probability, the domain the classifier is applied to should be restricted to the domain covered by the training set objects. This latter domain is commonly referred to as applicability domain in chemoinformatics. Conceptually, the applicability domain defines the region in space where the "normal" objects are located. Defining the border of the applicability domain may then be viewed as detecting anomalous or novel objects or as detecting outliers. Currently two different types of measures are in use. The first one defines the applicability domain solely in terms of the molecular descriptor space, which is referred to as novelty detection. The second type defines the applicability domain in terms of the expected reliability of the predictions which is referred to as confidence estimation. Both types are systematically differentiated here and the most popular measures are reviewed. It will be shown that all common chemoinformatic classifiers have built-in confidence scores. Since confidence estimation uses information of the class labels for computing the confidence scores, it is expected to be more efficient in reducing the error rate than novelty detection, which solely uses the information of the explanatory variables. PMID- 27492084 TI - Advances in Activity Cliff Research. AB - Activity cliffs, i.e. similar compounds with large potency differences, are of interest from a chemical and informatics viewpoint; as a source of structure activity relationship information, for compound optimization, and activity prediction. Herein, recent highlights of activity cliff research are discussed including studies that have further extended our understanding of activity cliffs, yielded unprecedented insights, or paved the way for practical applications. PMID- 27492082 TI - The roles of non-coding RNAs in Parkinson's disease. AB - Parkinson's disease (PD) is considered as a high prevalence neurodegenerative disorders worldwide. Pathologically, the demise of dopamine-producing cells, in large part due to an abnormal accumulation of the alpha-synuclein in the substantia nigra, is one of the main causes of the disease. Up until now, many de novo investigations have been conducted to disclose the mechanisms underlying in PD. Among them, impacts of non-coding RNAs (ncRNAs) on the pathogenesis and/or progression of PD need to be highlighted. microRNAs (miRNAs) and long ncRNAs (lncRNAs) are more noteworthy in this context. miRNAs are small ncRNAs (with 18 25 nucleotide in length) that control the expression of multiple genes at post transcriptional level, while lncRNAs have longer size (over 200 nucleotides) and are involved in some key biological processes through various mechanisms. Involvement of miRNAs has been well documented in the development of PD, particularly gene expression. Hence, in this current review, we will discuss the impacts of miRNAs in regulation of the expression of PD-related genes and the role of lncRNAs in the pathogenesis of PD. PMID- 27492085 TI - Designing Multi-target Compound Libraries with Gaussian Process Models. AB - We present the application of machine learning models to selecting G protein coupled receptor (GPCR)-focused compound libraries. The library design process was realized by ant colony optimization. A proprietary Boehringer-Ingelheim reference set consisting of 3519 compounds tested in dose-response assays at 11 GPCR targets served as training data for machine learning and activity prediction. We compared the usability of the proprietary data with a public data set from ChEMBL. Gaussian process models were trained to prioritize compounds from a virtual combinatorial library. We obtained meaningful models for three of the targets (5-HT2c , MCH, A1), which were experimentally confirmed for 12 of 15 selected and synthesized or purchased compounds. Overall, the models trained on the public data predicted the observed assay results more accurately. The results of this study motivate the use of Gaussian process regression on public data for virtual screening and target-focused compound library design. PMID- 27492086 TI - Development of Quantum Chemical Method to Calculate Half Maximal Inhibitory Concentration (IC50 ). AB - Till date theoretical calculation of the half maximal inhibitory concentration (IC50 ) of a compound is based on different Quantitative Structure Activity Relationship (QSAR) models which are empirical methods. By using the Cheng Prusoff equation it may be possible to compute IC50 , but this will be computationally very expensive as it requires explicit calculation of binding free energy of an inhibitor with respective protein or enzyme. In this article, for the first time we report an ab initio method to compute IC50 of a compound based only on the inhibitor itself where the effect of the protein is reflected through a proportionality constant. By using basic enzyme inhibition kinetics and thermodynamic relations, we derive an expression of IC50 in terms of hydrophobicity, electric dipole moment (MU) and reactivity descriptor (omega) of an inhibitor. We implement this theory to compute IC50 of 15 HIV-1 capsid inhibitors and compared them with experimental results and available other QASR based empirical results. Calculated values using our method are in very good agreement with the experimental values compared to the values calculated using other methods. PMID- 27492087 TI - Hydration Free Energy as a Molecular Descriptor in Drug Design: A Feasibility Study. AB - In this work the idea was investigated whether calculated hydration energy (DeltaGhyd ) can be used as a molecular descriptor in defining promising regions of chemical space for drug design. Calculating DeltaGhyd using the Density Solvation Model (SMD) in conjunction with the density functional theory (DFT) gave an excellent correlation with experimental values. Furthermore, calculated DeltaGhyd correlates reasonably well with experimental water solubility (r(2) =0.545) and also log P (r(2) =0.530). Three compound collections were used: Known drugs (n=150), drug-like compounds (n=100) and simple organic compounds (n=140). As an approximation only molecules, which do not de/protonate at physiological pH were considered. A relatively broad distribution was seen for the known drugs with an average at -15.3 kcal/mol and a standard deviation of 7.5 kcal/mol. Interestingly, much lower averages were found for the drug-like compounds (-7.5 kcal/mol) and the simple organic compounds (-3.1 kcal/mol) with tighter distributions; 4.3 and 3.2 kcal/mol, respectively. This trend was not observed for these collections when calculated log P and log S values were used. The considerable greater exothermic DeltaGhyd average for the known drugs clearly indicates in order to develop a successful drug candidate value of DeltaGhyd <-5 kcal/mol or less is preferable. PMID- 27492089 TI - Early identification of sepsis in hospital inpatients by ward nurses increases 30 day survival. AB - BACKGROUND: Systemic inflammatory response syndrome (SIRS) and sepsis are now frequently identified by observations of vital signs and detection of organ failure during triage in the emergency room. However, there is less focus on the effect on patient outcome with better observation and treatment at the ward level. METHODS: This was a before-and-after intervention study in one emergency and community hospital within the Mid-Norway Sepsis Study catchment area. All patients with confirmed bloodstream infection have been prospectively registered continuously since 1994. Severity of sepsis, observation frequency of vital signs, treatment data, length of stay (LOS) in high dependency and intensive care units, and mortality were retrospectively registered from the patients' medical journals. RESULTS: The post-intervention group (n = 409) were observed better and had higher odds of surviving 30 days (OR 2.7, 95 % CI 1.6, 4.6), lower probability of developing severe organ failure (0.7, 95 % CI 0.4, 0.9), and on average, 3.7 days (95 % CI 1.5, 5.9 days) shorter LOS than the pre-intervention group (n = 472). CONCLUSIONS: In a cohort with stable mortality rates, early sepsis recognition by ward nurses may have reduced progression of disease and improved survival for patients in hospital with sepsis. PMID- 27492090 TI - Corneal inlays for spectacle independence: Friend or foe? PMID- 27492088 TI - Coiled-coils: The long and short of it. AB - Coiled-coils are found in proteins throughout all three kingdoms of life. Coiled coil domains of some proteins are almost invariant in sequence and length, betraying a structural and functional role for amino acids along the entire length of the coiled-coil. Other coiled-coils are divergent in sequence, but conserved in length, thereby functioning as molecular spacers. In this capacity, coiled-coil proteins influence the architecture of organelles such as centrioles and the Golgi, as well as permit the tethering of transport vesicles. Specialized coiled-coils, such as those found in motor proteins, are capable of propagating conformational changes along their length that regulate cargo binding and motor processivity. Coiled-coil domains have also been identified in enzymes, where they function as molecular rulers, positioning catalytic activities at fixed distances. Finally, while coiled-coils have been extensively discussed for their potential to nucleate and scaffold large macromolecular complexes, structural evidence to substantiate this claim is relatively scarce. PMID- 27492091 TI - Scleral fixation of a foldable intraocular lens with polytetrafluoroethylene sutures through a Hoffman pocket. AB - Scleral fixation of intraocular lenses (IOLs) is traditionally performed after conjunctival dissection and preparation of scleral flaps. The Hoffman pocket technique creates scleral pockets without conjunctival dissection. We describe a technique that uses a Hoffman pocket and 7-0 polytetrafluoroethylene (Gore-Tex) sutures for scleral fixation of a foldable posterior chamber IOL in patients with insufficient capsule support. The technique eliminates the need for conjunctival dissection, scleral cauterization, knot rotation, and sutured wound closure. The favorable properties of the suture material and the use of a small incision to insert a foldable IOL are additional advantages. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492092 TI - Iris fixation of unstable anterior chamber intraocular lenses. AB - Cataract surgeons are sometimes challenged with a patient who has an unstable anterior chamber intraocular lens (AC IOL). Over time, an unstable AC IOL can lead to significant complications. This problem is most often addressed with an IOL exchange using an appropriately sized AC IOL or a posterior chamber IOL with iris or scleral fixation. We present a technique of 2-point iris fixation of unstable AC IOLs as a simpler and less traumatic alternative. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 27492093 TI - Through-focus performance with a corneal shape-changing inlay: One-year results. AB - PURPOSE: To evaluate improvement in the through-focus acuity and visual function provided by a corneal inlay designed to modify the surface shape of the central cornea. SETTING: Two clinical practices, United States. DESIGN: Prospective nonrandomized clinical trial. METHODS: Emmetropic patients with presbyopia who required a reading addition (add) from +1.50 to +2.00 diopters (D) had implantation of the Raindrop Near Vision Inlay in the nondominant eye. The inlay was designed to modify the anterior curvature of the central cornea with the intent to improve near and intermediate vision. At the preoperative and 1-year postoperative visits, the following visual functions were recorded: defocus curves in the nondominant eye, required add for best near vision, distance corrected binocular contrast sensitivity, and uncorrected and corrected visual acuity at 6 m, 80 cm, and 40 cm. RESULTS: The study comprised 30 patients. One year postoperatively, on average, distance-corrected near acuity improved by more than 3 lines, with patients achieving a distance-corrected acuity of 0.3 logMAR (20/40) or better across a 3.50 D range of defocus. Binocular uncorrected visual acuity of 0.2 logMAR (20/32) or better at distance, intermediate, and near distances was obtained in 97% of patients. The mean reduction in the reading add was 1.60 D. There was no significant change in binocular contrast sensitivity. Overall patient satisfaction was high. CONCLUSION: A corneal inlay in the nondominant eye of emmetropic patients provided a significant increase in the range of functional vision at intermediate and near, with no loss in binocular distance acuity. FINANCIAL DISCLOSURE: Drs. Whitman, Hovanesian, Steinert, and Koch received compensation for participating in the study from Revision Optics, Inc. Drs. Steinert and Koch are medical monitors for Revision Optics, Inc. None of the other authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492094 TI - American Society of Anesthesiologists classification in cataract surgery: Results from the Ophthalmic Surgery Outcomes Data Project. AB - PURPOSE: To explore the association of American Society of Anesthesiologists (ASA) classification with cataract surgery outcomes. SETTING: Five Veterans Affairs Medical Centers, United States. DESIGN: Retrospective observational cohort study. METHODS: The study analyzed the outcomes of cataract surgery cases. Corrected distance visual acuity (CDVA), unanticipated events, and vision-related quality of life (VRQL) were assessed using the National Eye Institute Visual Function Questionnaire (NEI-VFQ), comparing ASA classes I through IV. For some analyses, ASA classes I and II were designated as Group A and ASA classes III and IV were designated Group B. RESULTS: Of the 4923 cases, 875 (17.8%) were in Group A, 4032 (81.9%) were in Group B, and 16 (0.3%) had missing data. The mean CDVA and mean composite NEI-VFQ score improved after cataract surgery in both groups (P < .0001); however, Group A had a better mean postoperative CDVA and postoperative VFQ composite scores than Group B (P < .0001, both outcomes). A higher ASA class was associated with an increased risk for 2 unanticipated events; that is, clinically significant macular edema (CSME) (Group A: 4 [0.47%] versus Group B: 50 [1.28%]; adjusted odds ratio [OR], 3.02; 95% confidence interval [CI], 1.02-13.05; P = 0.04) and readmission to the hospital within 30 days (2 [0.23%] versus 56 [1.41%]; OR, 8.26; 95% CI, 1.71-148.62; P = .004) CONCLUSIONS: Among United States veterans, the ASA classification could be an important predictor of VRQL and visual outcomes. In this cohort, it was associated with an increased risk for 2 serious unanticipated events-CSME and readmission to the hospital-both costly, unwanted outcomes. FINANCIAL DISCLOSURE: Dr. Vollman is a consultant to Forsight Vision5. None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492095 TI - Ocular-surface temperature modification by cataract surgery. AB - PURPOSE: To analyze ocular-surface temperature changes after microincision cataract surgery and to correlate them with surgical, clinical, and laboratory parameters. SETTING: Ophthalmology Unit, Saint Orsola-Malpighi Hospital, Bologna, Italy. DESIGN: Prospective case series. METHODS: Patients affected by monolateral senile cataract were examined preoperatively and 7 days and 28 days postoperatively. Infrared thermography was used to measure the temperature soon after eye opening, the temperature after 10 seconds of sustained eye opening, and the difference between these 2 values in the central cornea, nasal limbus, and temporal limbus. The Ocular Surface Disease Index (OSDI), Schirmer test, vital staining, tear breakup time (TBUT), conjunctival scraping cytology, exudated tear serum albumin, and laser flare-cell meter examinations were performed. RESULTS: The study comprised 26 patients (10 men, 16 women). The temperature changed significantly after surgery. The temperature soon after eye opening showed cooling in the central cornea and nasal limbus and heating in the temporal limbus. The temperature after 10 seconds of sustained eye opening minus the temperature soon after eye opening increased in all regions. The temperature after 10 seconds of sustained eye opening minus the temperature soon after eye opening in the central cornea was inversely related to the OSDI and directly related to TBUT. The temperature soon after eye opening increased in the temporal limbus and was directly related to inflammatory indices. CONCLUSIONS: The ocular surface temperature changed after cataract surgery depending on the region analyzed. The cooling in the central cornea could be related to the increased tear-film instability. The heating in the temporal limbus could be related to postoperative inflammation. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492096 TI - Influence of ophthalmic viscosurgical devices on intraoperative aberrometry. AB - PURPOSE: To determine whether the presence of an ophthalmic viscosurgical device (OVD) in the anterior chamber influences intraoperative aberrometry and the suggested intraocular lens (IOL) power. SETTING: Advanced Vision Care, Los Angeles, and Specialty Surgery Center, Beverly Hills, California, USA. DESIGN: Prospective interventional case series. METHOD: Eyes scheduled for routine phacoemulsification and were divided into 6 equal groups, with each having 1 of 6 OVDs. After cataract removal, carefully controlled aberrometry was performed with the anterior chamber filled with balanced salt solution (BSS). Immediately thereafter, the BSS was replaced by 1 of the OVDs and the aberrometry repeated. The IOL power was selected from the BSS reading, and clinical manifest refraction was performed 3 weeks after surgery. The mean absolute error (MAE) was determined and compared with the extrapolated refraction had the IOL power been selected from the aberrometry reading under OVD. RESULTS: The study comprised 120 eyes, 20 in each group. The IOL power determination was lower with OVD filling the chamber. For Discovisc and Amvisc Plus, the MAE determinations were statistically different because the suggested IOL power was approximately 0.50 diopter less than with a BSS fill. For the remaining OVDs (Amvisc, Healon, Healon GV, and Provisc), the MAE differences were insignificant. The strong correlation between differences in the index of refraction between BSS and specific OVDs appeared to be causal. CONCLUSION: Surgeons should be aware of the influence of OVDs on the accuracy of intraoperative aberrometry because specific agents can alter the optical results and suggested IOL power. FINANCIAL DISCLOSURE: Dr. Masket is a consultant to Wavetec Vision Systems, Inc., and Alcon Laboratories, Inc., and has a research grant from Alcon Laboratories, Inc. Dr. Fram has a research grant from Wavetec Vision Systems, Inc. Dr. Holladay is a consultant to Wavetec Vision Systems, Inc. PMID- 27492097 TI - Femtosecond laser penetrating corneal relaxing incisions combined with cataract surgery. AB - PURPOSE: To evaluate the effectiveness of femtosecond laser penetrating corneal relaxing incisions (CRIs) in reducing corneal astigmatism during cataract surgery. SETTING: Shanxi Eye Hospital, Taiyuan, Shanxi Province, China. DESIGN: Prospective case series. METHODS: Using the Lensx laser, CRIs were placed at a diameter of 8.0 mm with a depth of 90%. Corneal astigmatism was measured before surgery and 1 and 3 months after surgery. Vector analyses were performed. To obtain the net corneal changes, the with-the-wound (WTR) and against-the-wound (ATR) changes were calculated along the meridian of the CRI. Multiple regression analysis with generalized estimating equations was used to evaluate the factors contributing to the effectiveness of CRIs. RESULTS: The study comprised 51 eyes. One and 3 months postoperatively, respectively, the mean keratometric astigmatism was reduced significantly by 0.65 diopter (D) and 0.67 D (both P < .05); compared with preoperative corneal astigmatism, the percentage of eyes within +/-0.50 D of refractive astigmatism significantly increased by 42.6% and 46.7% (both P < .05) and the mean refractive astigmatism was significantly decreased at 1 month (0.27 @ 93 versus 0.17 * 17) (P < .05) but not at 3 months (0.09 @ 138 versus 0.07 * 172) (P > .05). The mean WTW and ATW changes were -1.05 D and -1.00 D, respectively, and 14.9% and 6.7% of eyes, respectively, were overcorrected. Age, CRI length, and CRI location were factors contributing to net corneal changes. A nomogram is proposed. CONCLUSION: Femtosecond laser CRIs were effective in reducing corneal astigmatism during cataract surgery, and their long-term effectiveness should be evaluated. FINANCIAL DISCLOSURE: Dr. Koch is a consultant to Abbott Medical Optics, Inc., Alcon Laboratories, Inc., and Revision Optics, Inc. None of the other authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492098 TI - Comparison of vitreous loss rates between manual phacoemulsification and femtosecond laser-assisted cataract surgery. AB - PURPOSE: To compare the vitreous loss complication rate of manual phacoemulsification cataract surgery with that of femtosecond laser-assisted cataract surgery. SETTING: Mercy Eye Specialists, Springfield, Missouri, USA. DESIGN: Retrospective single-center case series. METHODS: Cataract surgeries from 2010 to 2014 performed by 4 surgeons were audited for rates of vitreous loss. Vitreous loss data were statistically analyzed with and without exclusions. RESULTS: Of the total 7155 cases from 2010 to 2014, 3784 were consecutively performed using manual phacoemulsification from 2010 to 2012 and 3371 were performed using femtosecond laser-assisted cataract surgery from 2013 to 2014. The rate of vitreous loss with exclusions was 1.17% in the manual phacoemulsification group and versus 0.65% femtosecond laser-assisted group; without exclusions, the rate was 1.40% versus 0.77%. In absolute terms, the rate decreased for every surgeon in the study. The chi-square test showed a statistically significant association between the date of surgery, and thus technique, and vitrectomy cases (P < .05). Odds ratio analysis with exclusions versus without exclusions indicated that surgeries performed from 2010 to 2012 using manual phacoemulsification were 1.6 times and 1.8 times, respectively, more likely to have vitreous loss than surgeries performed from 2013 to 2014 using the femtosecond laser-assisted cataract surgery technique. CONCLUSIONS: Conversion from manual phacoemulsification to femtosecond laser-assisted cataract surgery resulted in a statistically significant decrease in vitreous loss. Because vitreous loss increases the risk for other serious complications of cataract surgery, this new finding has important implications for the safety of cataract surgery. FINANCIAL DISCLOSURE: Proprietary or commercial disclosures are listed after the references. PMID- 27492099 TI - Accuracy of user-adjusted axial length measurements with optical biometry in eyes having combined phacovitrectomy for macular-off rhegmatogenous retinal detachment. AB - PURPOSE: To evaluate the accuracy of user-adjusted axial length (AL) measured by optical biometry for intraocular lens (IOL) calculations in eyes having combined phacovitrectomy for macula-off rhegmatogenous retinal detachment (RRD). SETTING: Ophthalmology Department, Calderdale Royal Hospital, Halifax, United Kingdom. DESIGN: Retrospective case series. METHODS: Consecutive eyes having phacovitrectomy for macula-off RRD were evaluated. The ALs were measured using optical biometry with user adjustment to identify a posterior peak corresponding to the eye's AL and ultrasound (US). These were compared with each other and with the postoperative optical biometry and analyzed for accuracy as an indication of the eye's AL. RESULTS: The study comprised 22 eyes of 22 patients. There was no statistically significant difference between the mean AL measurements derived from user-adjusted optical biometry and US AL (P = .964). The user-adjusted optical biometry was not statistically significantly different from the postoperative optical biometry (P = .242). Compared with the postoperative optical biometry, the IOL power was within +/-0.5 diopter in 12 (92%) of 13 cases (95% confidence interval [CI], 77.8 to 100.0) for user-adjusted optical biometry and in 10 (77%) of 13 cases (95% CI, 54.0 to 99.8) for US measurements. CONCLUSIONS: User-adjusted optical biometry could be used as an alternative method for measuring AL in macula-off RRD with combined phacovitrectomy. However, optical biometry would require assessment of agreement with US AL in cases in which a posterior peak is not easily identifiable. User-adjusted optical biometry might outperform US AL when calculating IOL power; however, a larger study should be performed to confirm this. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492100 TI - Comparative analysis of brilliant blue G and an intracameral illuminator in assisting visualization of the anterior capsule in eyes with vitreous hemorrhage. AB - PURPOSE: To compare the safety and efficacy of 0.025 mg/mL brilliant blue G (BBG) and an intracameral illuminator for visualizing the anterior capsule. SETTING: University-based tertiary referral center, South Korea. DESIGN: Retrospective cases series. METHODS: The medical records of patients with vitreous hemorrhage for which they had pars plana vitrectomy and cataract surgery were retrospectively reviewed. The patients were classified into 2 groups. The BBG group comprised patients having capsule staining with BBG. The illuminator group comprised patients who had capsulorhexis assisted with an intracameral illuminator. The status of the endothelial cells was analyzed. RESULTS: There were 27 eyes in the BBG group and 35 eyes in the illuminator group. In the BBG group, endothelial cell density (ECD) was reduced 3 months after surgery (10.6% loss) (P = .003). The illuminator group had no significant loss (1.5% loss) (P = .264). The ECD loss was greater in the BBG group than the illuminator group 3 months after surgery (P = .01). There was no statistically significant difference in the coefficient of variation of cell area or percentage of hexagonal cells between the 2 groups. CONCLUSIONS: The ECD loss was higher in eyes with 0.025 mg/mL BBG staining than in eyes using an intracameral illuminator. Further studies are necessary to establish the safety profile of BBG on the endothelium. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492101 TI - Optical quality and visual performance after cataract surgery with biaxial microincision intraocular lens implantation. AB - PURPOSE: To evaluate the time course of the optical quality and visual performance with a microincision monofocal intraocular lens (Incise). SETTING: Hospital Torrecardenas, Almeria, Spain. DESIGN: Prospective study. METHODS: The visual and refractive outcomes were evaluated in eyes with the microincision IOL preoperatively and 1, 3, and 6 months postoperatively. The modulation transfer function (MTF) cutoff frequency, Strehl ratio, and objective scatter index (OSI) were used to measure optical quality. The contrast sensitivity function (CSF) and the visual disturbance index characterized visual performance. RESULTS: In the 32 study eyes, the mean values preoperatively and 6 months postoperatively, respectively, were MTF cutoff frequency (11.40 cycles per degree [cpd] +/- 8.39 [SD] and 23.33 +/- 11.68 cpd; P < .001), Strehl ratio (0.078 +/- 0.32 and 0.15 +/ 0.07; P < .05), and OSI (7.44 +/- 3.25 and 1.57 +/- 0.26; P < .001). At each spatial frequency, the CSF significantly differed between preoperatively and postoperatively (P < .001). The mean visual disturbance index changed from 0.70 +/- 0.28 to 0.31 +/- 0.17 (P < .001). For all parameters studied, statistically significant differences were found between the preoperative and postoperatively values, with no differences between the results 1, 3, and 6 months after surgery (P > .05). CONCLUSIONS: Biaxial microincision cataract surgery provided optimum clinical outcomes. The optical quality and visual performance improved significantly 1 month after surgery, with the results remaining stable at 6 months. The postoperative visual function was similar to that in subjects of the same age with healthy eyes. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492102 TI - Using continuous intraoperative optical coherence tomography to classify swirling lens fragments during cataract surgery and to predict their impact on corneal endothelial cell damage. AB - PURPOSE: To quantify and classify swirling lens fragments during cataract surgery and record their impact on the corneal endothelium using continuous intraoperative optical coherence tomography (OCT). SETTING: Vienna Institute for Ocular Surgery, Hanusch Hospital, Vienna, Austria. DESIGN: Prospective case series. METHODS: Patients scheduled for cataract surgery without other ophthalmologic comorbidities were included. During surgery, continuous OCT recordings were performed to measure and score swirling lens fragments that came into contact with the corneal endothelium. Endothelial cell density (ECD) was measured preoperatively and 1 month postoperatively. In addition, the central corneal thickness and aqueous flare were measured preoperatively and 1 hour, 1 day, and 1 month postoperatively. RESULTS: Continuous intraoperative OCT video recordings showed 104 swirling lens fragments in 40 eyes that came into contact with the corneal endothelium. A mean of 2.6 lens fragments (range 0 to 6) that came into contact were observed per eye. Small fragments and fragments touching the center of the endothelium had a significantly greater effect on postoperative ECD than other fragment parameters. The predictive power of the fragment score on ECD was found to be moderate (r(2) = 0.6). CONCLUSIONS: Small swirling lens fragments touching the center of the corneal endothelium had a significant influence on ECD. With the newly developed fragment score, it was possible to predict the operative endothelial cell loss. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492103 TI - Immunohistochemical characteristics of the vitreolenticular interface in congenital unilateral posterior cataract. AB - PURPOSE: To gain insight into the histology of the vitreolenticular interface in congenital unilateral posterior cataract. SETTING: Antwerp University Hospital, Department of Ophthalmology, Edegem, and the University of Antwerp, Faculty of Medicine and Health Sciences, Antwerp, Belgium. DESIGN: Prospective case study. METHODS: Samples of the posterior lens capsule of patients with congenital posterior cataract (including opaque plaque on the anterior and adhesion to the vitreous on the posterior surface) were collected during the posterior capsulorhexis procedure. Staining for collagen types II and IV was performed using indirect immunohistochemistry. Results were compared with those of control posterior lens capsules of 3 children and 3 adults. RESULTS: Samples were collected from 3 patients. All posterior lens capsules contained collagen type IV. Samples from congenital posterior cataract patients all showed a narrow band of collagen type II on the outer surface, indicating strong adherence of the anterior hyaloid membrane to the center of the posterior lens capsule. Surprisingly, collagen type II was also found in the posterior capsule plaques. Collagen type II was not found in any control posterior lens capsule. CONCLUSION: The adherence of collagen type II to the center of the posterior lens capsule histologically supports the hypothesis that this subgroup of congenital cataract hints at an abnormality at the vitreolenticular interface. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492104 TI - Higher-order aberrations 1 year after corneal collagen crosslinking for keratoconus and their independent effect on visual acuity. AB - PURPOSE: To evaluate the effect of corneal collagen crosslinking (CXL) in progressive keratoconus patients on higher-order aberrations (HOAs) and the effect of change in HOAs on visual acuity between baseline and 1 year after CXL. SETTING: Tertiary academic referral center, Utrecht, the Netherlands. DESIGN: Prospective cohort study. METHODS: This study included consecutive keratoconus patients who were treated with epithelium-off CXL and followed for a minimum of 1 year. The following corneal HOAs were measured with Scheimpflug tomography (Pentacam HR type 70900): coma, trefoil, spherical aberration, and total corneal HOAs. A 2-tailed paired-samples t test was used to compare baseline and postoperative aberrations. Multivariable linear regression was applied to assess the independent effects of HOA subtypes on changes in uncorrected (UDVA) and corrected (CDVA) distance visual acuity. RESULTS: Overall, the degree of corneal HOAs in the patient cohort (N = 187) was relatively unchanged after CXL, with a mean change of -1.34% (P = .272). Horizontal coma contributed most to the total amount of HOAs but was virtually unchanged on average. The HOA subtype of spherical aberrations decreased significantly (-15.68%) (P < .001). There was no effect of the change in HOAs on the change in CDVA; however, there was a significant effect of the change in horizontal coma on the change in UDVA (P = .003; B -0.475). CONCLUSIONS: Corneal HOAs in general were relatively unchanged from baseline to 1 year after CXL in eyes with progressive keratoconus. A change in horizontal coma had a strong and independent effect on UDVA. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492105 TI - Natural history of corneal haze after corneal collagen crosslinking in keratoconus using Scheimpflug analysis. AB - PURPOSE: To analyze corneal haze after corneal collagen crosslinking (CXL) for progressive keratoconus using Scheimpflug densitometry. SETTING: Auckland District Health Board, Auckland, New Zealand. DESIGN: Prospective randomized controlled study. METHODS: Both eyes of all patients were examined preoperatively and 1, 3, 6, and 12 months postoperatively. One eye of each patient was treated with corneal CXL, with the contralateral eye serving as the control. Examinations included uncorrected distance visual acuity and corrected distance visual acuity (CDVA), slitlamp biomicroscopy, and Scheimpflug tomography (Pentacam). RESULTS: Thirty-six eyes of 36 patients were enrolled. The mean preoperative corneal densitometry was 19.0 +/- 3.2 (SD). Postoperatively, the mean densitometry peaked at 1 month, decreasing to baseline level after 6 months without application of topical corticosteroids. The development of haze was significant compared with the contralateral untreated eyes (P < .01). The anterior (120 MUm) and inner (central 0.0 to 2.0 mm) zones of the cornea had the highest densitometry after treatment. Lower preoperative central corneal thickness (CCT) was significantly correlated with higher corneal densitometry (P = .03). However, the preoperative CCT, keratometry, and astigmatism did not influence the difference in densitometry between the treated eyes and untreated eyes. There was no evidence of a relationship between densitometry and CDVA (P = .30). CONCLUSIONS: After corneal CXL, patients with keratoconus developed transient corneal haze in the anterior central cornea that might not require specific treatment. Thin corneas were associated with higher densitometry; thus, there might be a greater expectancy of corneal haze in patients with advanced keratoconus. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492106 TI - Outcome of primary intraocular lens implantation in infants: Complications and rates of additional surgery. AB - PURPOSE: To study the requirement of additional surgery and adverse events in infants having primary intraocular lens (IOL) implantation. SETTING: Tertiary care institute, Chandigarh, India. DESIGN: Prospective observational noncomparative case series. METHODS: Infants who had phacoaspiration, primary posterior capsulotomy, anterior vitrectomy, and primary IOL implantation were evaluated for complications and the need for additional surgery over a 3-year period. The main outcome measures were the rate of complications, adverse events, and need for additional surgery. RESULTS: Sixty infants (100 eyes) with a mean age of 7.13 months +/- 2.32 (SD) (range 3 to 12 months) were studied. The mean follow-up was 41.2 +/- 3.5 months. Indication of additional surgery included visual axis opacification in 13 eyes, pupillary membrane/IOL decentration in 4 eyes, and iris prolapse in 4 eyes. Adverse events included pigment on the IOL in 14 eyes and iridolenticular adhesions in 9 eyes. Ocular hypertension was observed in 2 eyes. The IOL was placed in sulcus or by optic capture in 14 eyes. There was no difference in additional surgery and adverse events between infants aged 6 months or younger versus those older than 6 months (P = .734). CONCLUSION: There was a low incidence of adverse events and additional surgery requirement in infants who had cataract surgery with primary IOL implantation. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492107 TI - Evaluation of long-term biocompatibility and capsular bag opacification with a new silicone-polyimide plate-type intraocular lens in the rabbit model. AB - PURPOSE: To evaluate the long-term biocompatibility and safety of the new SC9 intraocular lens (IOL) after implantation in rabbit eyes, in accordance with the requirements of the International Organization for Standardization 11979-5, Annex G:2006(E). SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Bilateral phacoemulsification was performed on 9 New Zealand white rabbits; 1 eye received the test IOL and the contralateral eye received a commercially available plate-type silicone control IOL (AA4204VL). Two rabbits were humanely killed at 2 months and the remaining at 6 months. After gross examination of the eyes from the posterior Miyake-Apple view, select IOLs were explanted and had surface staining for implant cytology. All globes were then sectioned and processed for complete histopathologic examination. RESULTS: Overall uveal biocompatibility was similar between the test IOLs and control IOLs throughout the study. The mean posterior capsule opacification at 6 months was 0.8 +/- 0.27 (SD) in the test group and 4.0 +/- 0 in the control group (P = .001, t test: paired 2-sample for means). The mean posterior synechiae formation at 6 months was 1.28 +/- 1.25 in the test group and 2.71 +/- 0.75 in the control group (P = .01). A histopathologic examination confirmed the relative lack of capsule opacification in the study eyes compared with the control eyes and the absence of untoward inflammatory reaction or toxicity in all eyes. CONCLUSION: The new IOL maintained an open capsular bag secondary to its design, which appeared to prevent overall capsular bag opacification and retain uveal and capsule biocompatibility. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492108 TI - Effects of genipin corneal crosslinking in rabbit corneas. AB - PURPOSE: To evaluate the effect of genipin, a natural crosslinking agent, in rabbit eyes. SETTING: Department of Ophthalmology, Universidad Nacional de Colombia Centro de Tecnologia Oftalmica, Bogota, Colombia. DESIGN: Experimental study. METHODS: Ex vivo rabbit eyes (16; 8 rabbits) were treated with genipin 1.00%, 0.50%, and 0.25% for 5 minutes with a vacuum device to increase corneal permeability. Penetration was evaluated using Scheimpflug pachymetry (Pentacam). In the in vivo model (20 rabbits; 1 eye treated, 1 eye with vehicle), corneas were crosslinked with genipin as described. Corneal curvature, corneal pachymetry, and intraocular pressure (IOP) assessments as well as slitlamp examinations were performed 0, 7, 30, and 60 days after treatment. RESULTS: In the ex vivo model, Scheimpflug pachymetry showed deep penetration in the rabbit corneas with an increase in corneal density and a dose-dependent relationship. Corneal flattening was observed in treated eyes (mean 4.4 diopters +/- 0.5 [SD]) compared with the control eyes. Pachymetry and IOP were stable in all evaluations. No eye showed toxicity in the anterior chamber or in the lens. CONCLUSIONS: Corneal crosslinking induced by genipin produced significant flattening of the cornea with no toxicity in rabbit eyes. This crosslinking could be useful in the treatment of corneal ectasia and in the modification of corneal curvature. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492109 TI - Clinical outcomes of small-incision lenticule extraction and femtosecond laser assisted wavefront-guided laser in situ keratomileusis. AB - Small-incision lenticule extraction and wavefront-guided femtosecond-assisted laser in situ keratomileusis (LASIK) provide good visual outcomes and an efficacious correction of myopia or myopic astigmatism with similar levels of safety. Some differences in predictability and the percentage of eyes gaining lines of corrected distance visual acuity are present. A higher level of coma is present after small-incision lenticule extraction, with no clear differences between techniques in spherical aberration. Better contrast sensitivity is achieved in the early postoperative period after wavefront-guided femtosecond laser-assisted LASIK, possibly because of less intrastromal light backscattering and Bowman layer microdistortions. Corneal sensitivity decreased less after small incision lenticule extraction because of less severe decrease in subbasal nerve density, which has a significant effect on symptomatology and dry-eye tests (P < .05). Significant corneal biomechanical changes occurred after both techniques (P < .05), with no scientific evidence supporting the superiority of 1 technique over the other. FINANCIAL DISCLOSURE: Dr. Pinero received an unrestricted educational grant from Abbott Medical Optics, Inc. Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 27492110 TI - Cataract in pseudohypoparathyroidism. AB - A 22-year-old white man presented with photopsia of 3-year duration despite a corrected distance visual acuity of 20/20 in both eyes. Ophthalmic examination revealed multiple irregularly shaped white cortical opacifications of the lens in both eyes but no other significant ocular findings. One year after the photopsia onset, the patient experienced an episode of seizures with generalized tonic clonic movements. Neurological follow-up examination demonstrated extensive brain calcification in the basal ganglia and frontal lobes, leading to a diagnosis of pseudohypoparathyroidism. Pseudohypoparathyroidism is a rare condition, and there are few reports of ocular findings with this underlying pathology. Our findings clearly demonstrate that even relatively unremarkable ocular signs can lead to diagnosis of severe systemic diseases. Therefore, the cataract surgeon should be aware of these conditions before removing the lens. FINANCIAL DISCLOSURE: None of the authors has a financial or proprietary interest in any material or method mentioned. PMID- 27492111 TI - Cataractous mountain on the corneal horizon: Swept-source optical coherence tomography. PMID- 27492112 TI - Tetracaine-enhanced transepithelial corneal collagen crosslinking. PMID- 27492113 TI - Reply. PMID- 27492115 TI - A Modern Menagerie of Mammalian Malaria. AB - Malaria parasites belong to the diverse apicomplexan order Haemospororida and use a variety of vertebrate and dipteran hosts worldwide. Recently, the utilization of molecular methods has resulted in a burst of newly discovered and rediscovered taxa infecting mammalian hosts, particularly in apes, ungulates, and bats. Additional study of these diverse mammal-infecting taxa is crucial for better understanding the evolutionary history of malaria parasites, especially given that most previous comparative phylogenetic analyses have tended to use both limited taxon sampling and a small set of genetic loci, resulting in weakly supported (and sometimes hotly contested) hypotheses. The ability to generate genomic data from these mammalian parasites, even from subpatent infections, will open up exciting prospects for research on malaria parasites. PMID- 27492114 TI - Ammonia stress under high environmental ammonia induces Hsp70 and Hsp90 in the mud eel, Monopterus cuchia. AB - The obligatory air-breathing mud eel (Monopterus cuchia) is frequently being challenged with high environmental ammonia (HEA) exposure in its natural habitats. The present study investigated the possible induction of heat shock protein 70 and 90 (hsp70, hsc70, hsp90alpha and hsp90beta) genes and more expression of Hsp70 and Hsp90 proteins under ammonia stress in different tissues of the mud eel after exposure to HEA (50 mM NH4Cl) for 14 days. HEA resulted in significant accumulation of toxic ammonia in different body tissues and plasma, which was accompanied with the stimulation of oxidative stress in the mud eel as evidenced by more accumulation of malondialdehyde (MDA) and hydrogen peroxide (H2O2) during exposure to HEA. Further, hyper-ammonia stress led to significant increase in the levels of mRNA transcripts for inducible hsp70 and hsp90alpha genes and also their translated proteins in different tissues probably as a consequence of induction of hsp70 and hsp90alpha genes in the mud eel. However, hyper-ammonia stress was neither associated with any significant alterations in the levels of mRNA transcripts for constitutive hsc70 and hsp90beta genes nor their translated proteins in any of the tissues studied. More abundance of Hsp70 and Hsp90alpha proteins might be one of the strategies adopted by the mud eel to defend itself from the ammonia-induced cellular damages under ammonia stress. Further, this is the first report of ammonia-induced induction of hsp70 and hsp90alpha genes under hyper-ammonia stress in any freshwater air-breathing teleost. PMID- 27492116 TI - A systematic review of tranexamic acid in hip fracture surgery. AB - AIM: To systematically examine and quantify the efficacy and safety of tranexamic acid in hip fracture surgery. METHODS: A systematic literature search was conducted using Medline, EMBASE, AMED, CiNAHL, and the Cochrane Central Registry of Controlled Trials. Two assessors independently screened search outputs for potentially relevant articles which met the eligibility criteria. The primary outcome measure was requirement of post-operative blood transfusion. Risk of bias assessment was performed using the Cochrane Collaboration's risk of bias tool for randomized controlled trials (RCTs) and the ROBINS-I tool for observational studies. Meta-analysis was performed to estimate risk ratio (RR), risk difference (RD) and mean difference (MD) values for dichotomous and continuous data outcomes, respectively. The interpretation of each outcome was made using the GRADE approach. RESULTS: Of 102 studies identified, seven met the inclusion criteria including a total of 770 participants (TXA: 341; Control: 429). On meta analysis, intravenous TXA resulted in a 46% risk reduction in blood transfusion requirement compared to a placebo/control group (RR: 0.54; 95% CI: 0.35-0.85; I2 : 78%; Inconsistency (chi2 ) P = <0.0001; n = 750). There was also a significantly higher post-operative haemoglobin for TXA versus placebo/control (MD: 0.81; 95% CI: 0.45-1.18; I2 : 46%; Inconsistency (chi2 ) P = 0.10; n = 638). There was no increased risk of thromboembolic events (RD: 0.01; 95% CI: -0.03, 0.05; I2 : 68%; Inconsistency (chi2 ) P = 0.007, n = 683). CONCLUSION: There is moderate quality evidence that TXA reduces blood transfusion in hip fracture surgery, with low quality evidence suggesting no increased risk of thrombotic events. These findings are consistent with TXA use in other orthopaedic procedures. PMID- 27492117 TI - Social Media and Internet Resources for Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). AB - The incorporation of Internet resources and the use of social media among patients, clinicians, advocates, and researchers in the field of hematology and oncology are growing in importance. Utilization of online information sharing is rising, especially among those involved in rare blood cancer fields, which have generally featured a paucity of reliable, updated information. In particular, blastic plasmacytoid dendritic cell neoplasm (BPDCN), an uncommon, but highly aggressive hematologic malignancy, is one example of a cancer with limited information readily available to the general public. The infrequent incidence of BPDCN, the challenges in recognizing the disease and making a clinico-pathologic diagnosis, and the lack of standard therapies are some of the reasons accounting for the dearth of expert opinion, scientific publications and discussion, and accessibility of online information for patients. This article highlights social media and Internet sources available for patients and other healthcare stakeholders in the field of BPDCN and discusses our efforts to increase awareness and propagation of BPDCN electronic resources, including the founding of an online Twitter community, #BPDCN. PMID- 27492118 TI - Social Media and Myeloproliferative Neoplasms (MPN): Analysis of Advanced Metrics From the First Year of a New Twitter Community: #MPNSM. AB - The social media platform Twitter has provided the hematology/oncology community with unprecedented, novel methods of interpersonal communication and increased ability for the dissemination of important updates in a rapidly moving field. The advent, and subsequent success, of disease-specific Twitter communities have further enabled interested healthcare stakeholders to become quickly organized around a unique set of rare medical conditions, such as hematologic malignancies, that, historically, generally lack large amounts of reliable online information. One example is the Twitter community #MPNSM (myeloproliferative neoplasms on social media), which was started approximately one and half years ago and has served as a recognized venue for discussion among many members of the MPN community, including patients, researchers, providers, and advocacy organizations. This article will focus on understanding the impact of the founding of this community via the analysis of advanced Twitter metrics of user experience, from the first year of use for this novel healthcare hashtag. PMID- 27492119 TI - Identification and expression analysis of IkappaB and NF-kappaB genes from Cyclina sinensis. AB - With the increasing economic importance of Cyclina sinensis aquaculture, interest in its defense mechanisms against pathogenic infection has grown in recent years. Inhibitor of nuclear factor-kappaB (IkappaB) and nuclear factor-kappaB (NF kappaB) are proteins with central roles in many important physiological and pathological processes, such as innate immune responses. In this study, we identified CsIkappaB and CsNF-kappaB genes from a C. sinensis transcriptome library. In healthy adult clams, CsIkappaB and CsNF-kappaB genes were widely expressed in various tissues and highly expressed in hemocytes. Further, the expression levels of these genes were significantly increased in hemocytes challenged by Vibrio anguillarum, Micrococcus luteus and poly I:C. Inhibition of CsMyD88 expression by RNAi technology significantly altered the mRNA expression patterns of CsIkappaB and CsNF-kappaB as measured using quantitative real-time PCR. These results collectively indicated that the NF-kappaB signaling pathway, including CsIkappaB and CsNF-kappaB genes, might be involved in early innate immune responses and may be regulated by a MyD88-dependent signaling pathway in C. sinensis. PMID- 27492120 TI - A high-mobility group box 1 that binds to DNA, enhances pro-inflammatory activity, and acts as an anti-infection molecule in black rockfish, Sebastes schlegelii. AB - High-mobility group box (HMGB) 1 is a chromosomal protein that plays critical roles in DNA transcription, replication and repair. In addition, HMGB1 functions as a pro-inflammatory molecule in many vertebrates and invertebrates. In teleosts, very limited studies of HMGB1 have been reported. In this study, we identified a HMGB1 homologue (SsHMGB1) from black rockfish (Sebastes schlegelii) and analyzed its structure, expression and biological function. The open reading frame of SsHMGB1 is 621 bp, with a 5'-untranslated region (UTR) of 62 bp and a 3' UTR of 645 bp. SsHMGB1 contains two typical HMG boxes and an acidic C-terminal tail. The deduced amino acid sequence of SsHMGB1 shares the highest overall identity (89.4%) with the HMGB1 of Anoplopoma fimbria. The expression of SsHMGB1 occurred in multiple tissues and was highest in the brain. Moreover, the mRNA level of SsHMGB1 in head kidney (HK) macrophages could be induced by Listonella anguillarum in a time-dependent manner. Recombinant SsHMGB1 purified from Escherichia coli (i) bound DNA fragments in a dose-dependent manner; and (ii) induced the expression of cytokines in HK macrophages, including a significant increase in TNF-alpha activity and enhanced mRNA level of TNF13B and IL-1 beta, which are known to be involved in antibacterial defense; moreover, (iii) significantly improved the macrophage bactericidal activity together with reduced pathogen dissemination and replication of bacteria in fish kidney. These results indicated that SsHMGB1 is a novel HMGB1 that possesses apparent immunoregulatory properties and is likely to be involved in fighting bacterial infection. PMID- 27492121 TI - The Dorsal/miR-1959/Cactus feedback loop facilitates the infection of WSSV in Litopenaeus vannamei. AB - miR-1959, a novel microRNA identified from Litopenaeus vannamei, mediates a positive feedback loop between Dorsal and Cactus that can continuously maintain the activation of the NF-kappaB pathway. It has been known that miR-1959 is involved in antibacterial immunity in shrimp, but its function in antiviral responses is still unknown. In this study, we focused on the role of miR-1959 in infection of white spot syndrome virus (WSSV), the major viral pathogen in shrimp worldwide. The expression of miR-1959 in shrimp hemocytes, gill, and hepatopancreas was significantly up-regulated upon WSSV infection. Dual luciferase reporter assays demonstrated that miR-1959 could enhance the activity of the promoter of WSSV immediate early gene ie1. In vivo experiments also showed that inhibition of miR-1959 led to decrease of the mortality of WSSV-infected shrimp and the genome copies of WSSV in tissues, meanwhile the expression of WSSV ie1 and VP28 genes was down-regulated. In contrast, increase of the miR-1959 level in shrimp by injection of miR-1959 mimics produced opposite results. These suggested that the Dorsal/miR-1959/Cactus feedback loop could favor the infection of WSSV in shrimp. Thus, our study helps further reveal the interaction between WSSV and shrimp immune system. PMID- 27492122 TI - Glucomannan's protective effect on the virulence of Vibrio splendidus in pacific oyster. AB - We examine the effect of Glucomannan, extracted from Candida utilis yeast, on immune parameters and resistance to Vibrio splendidus of Crassostreagigas. Our results showed that Glucomannan was a successful anti-adhesive molecule; it exhibited a stronger inhibitory effect on adhesion of Vibrio splendidus in infected Crassostreagigas. Vibrio splendidus viable cells number declined after incubation with Glucomannan. Furthermore, the Glucomannan diet showed higher activity to trigger the immune response against bacteria. Glucomannan applications, in biological control of seafood associated pathogens can be an alternative solution, providing consumer with a product of good quality owing to the use of 40 non-toxic compounds. Based on our results, Glucomannan could be used as a bio-protective culture in oyster's depuration to prevent Vibrio splendidus growth. PMID- 27492123 TI - Pinocembrin attenuates lipopolysaccharide-induced inflammatory responses in Labeo rohita macrophages via the suppression of the NF-kappaB signalling pathway. AB - Pinocembrin is a flavonoid that has been reported to exhibit various pharmacological and biological activities including antimicrobial, antioxidant, and anti-inflammatory. To explore the anti-inflammatory activity of pinocembrin in a fish cell line, we investigated its ability to regulate the inflammatory mediators elevated by lipopolysaccharide (LPS) in Labeo rohita head-kidney (HK) macrophages. HK macrophages of L. rohita were treated with LPS (1 MUg mL(-1)) in the presence or absence of pinocembrin. We examined the inhibitory effect of pinocembrin on LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production. The inhibitory effect of pinocembrin on nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) was investigated by RT-PCR and western blot. The effect of pinocembrin on pro-inflammatory cytokines (tumour necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta)) and anti-inflammatory cytokine IL 10 was investigated by ELISA and RT-PCR. The phosphorylation of three mitogen activated protein kinases (MAPKs) ERK, JNK, and p38 was analysed by western blot. Pinocembrin inhibited LPS-induced productions of NO and PGE2, and also markedly inhibited TNF-alpha, IL-1beta, iNOS, and COX-2 production in a concentration dependent manner. In addition, TNF-alpha and IL-1beta mRNA expression levels decreased significantly, while IL-10 mRNA expression increased (P < 0.05) with pinocembrin pre-treatment. RT-PCR and western blot analysis showed that pinocembrin decreased both the mRNA and protein expression levels of LPS-induced iNOS and COX-2 in HK macrophages. Pinocembrin suppressed the phosphorylation of MAPK in LPS-stimulated HK macrophages. Further, pinocembrin significantly inhibited LPS-induced NF-kappaB transcriptional activity via the attenuation of IkappaBalpha degradation. Taken together, pinocembrin reduced the levels of pro inflammatory mediators, such as iNOS, COX-2, TNF-alpha, and IL-1beta, by inhibiting NF-kappaB activation via the suppression of ERK and p38 phosphorylation, and by attenuating the degradation of IkappaBalpha. These results suggest that pinocembrin is a potential novel candidate for the treatment of inflammatory conditions in L. rohita macrophages. PMID- 27492124 TI - Transcriptome analysis of mud crab (Scylla paramamosain) gills in response to Mud crab reovirus (MCRV). AB - Mud crab (Scylla paramamosain) is an economically important marine cultured species in China's coastal area. Mud crab reovirus (MCRV) is the most important pathogen of mud crab, resulting in large economic losses in crab farming. In this paper, next-generation sequencing technology and bioinformatics analysis are used to study transcriptome differences between MCRV-infected mud crab and normal control. A total of 104.3 million clean reads were obtained, including 52.7 million and 51.6 million clean reads from MCRV-infected (CA) and controlled (HA) mud crabs respectively. 81,901, 70,059 and 67,279 unigenes were gained respectively from HA reads, CA reads and HA&CA reads. A total of 32,547 unigenes from HA&CA reads called All-Unigenes were matched to at least one database among Nr, Nt, Swiss-prot, COG, GO and KEGG databases. Among these, 13,039, 20,260 and 11,866 unigenes belonged to the 3, 258 and 25 categories of GO, KEGG pathway, and COG databases, respectively. Solexa/Illumina's DGE platform was also used, and about 13,856 differentially expressed genes (DEGs), including 4444 significantly upregulated and 9412 downregulated DEGs were detected in diseased crabs compared with the control. KEGG pathway analysis revealed that DEGs were obviously enriched in the pathways related to different diseases or infections. This transcriptome analysis provided valuable information on gene functions associated with the response to MCRV in mud crab, as well as detail information for identifying novel genes in the absence of the mud crab genome database. PMID- 27492125 TI - Suppressor of cytokine signaling 2 (SOCS2) negatively regulates the expression of antimicrobial peptides by affecting the Stat transcriptional activity in shrimp Marsupenaeus japonicus. AB - The suppressor of cytokine signaling (SOCS) family is a kind of negative regulators in the Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway in mammals and Drosophila. In kuruma shrimp, Marsupenaeus japonicus, SOCS2 is identified and its expression can be stimulated by peptidoglycan and polycytidylic acid. However, if SOCS2 participates in regulating Jak/Stat pathway in shrimp still needs further study. In this study, SOCS2 with Src homology 2 domain and SOCS box was identified in kuruma shrimp, M. japonicus. SOCS2 existed in hemocytes, heart, hepatopancreas, gills, stomach, and intestine, the expression of SOCS2 was upregulated significantly in the hemocytes and intestine of shrimp challenged with Vibrio anguillarum at 6 h. To analyze SOCS2 function in shrimp immunity, bacterial clearance and survival rate were analyzed after knockdown of SOCS2 in shrimp challenged with V. anguillarum. Results showed that bacterial clearance increased, and the survival rate improved significantly comparing with controls. The SOCS2 was expressed in Escherichia coli and the recombinant SOCS2 was injected into shrimp, and Stat phosphorylation and translocation were analyzed. The result showed that "overexpression" of SOCS2 declined Stat phosphorylation level and inhibited Stat translocation into the nucleus. After knockdown of SOCS2 in shrimp prior to V. anguillarum infection, the expression level of antimicrobial peptides, including anti-lipopolysaccharide factors C1, C2 and D1, and Crustin I was upregulated significantly, and the expression of the AMPs was declined after recombinant SOCS2 injection. The SOCS2 expression was also decreased in Stat-knockdown shrimp challenged by V. anguillarum at 6 and 12 h. Therefore, SOCS2 negatively regulates the AMP expression by inhibiting Stat phosphorylation and translocation into nucleus in shrimp, meanwhile, SOCS2 expression was also regulated by Jak/Stat pathway. PMID- 27492126 TI - Resonance-Assisted Hydrogen Bonding as a Driving Force in Synthesis and a Synthon in the Design of Materials. AB - Resonance-assisted hydrogen bonding (RAHB), a concept introduced by Gilli and co workers in 1989, concerns a kind of intramolecular H-bonding strengthened by a conjugated pi-system, usually in 6-, 8-, or 10-membered rings. This Review highlights the involvement of RAHB as a driving force in the synthesis of organic, coordination, and organometallic compounds, as a handy tool in the activation of covalent bonds, and in starting moieties for synthetic transformations. The unique roles of RAHB in molecular recognition and switches, E/Z isomeric resolution, racemization and epimerization of amino acids and chiral amino alcohols, solvatochromism, liquid-crystalline compounds, and in synthons for crystal engineering and polymer materials are also discussed. The Review can provide practical guidance for synthetic chemists that are interested in exploring and further developing RAHB-assisted synthesis and design of materials. PMID- 27492127 TI - Middle fascicle as a common retrograde limb in two left upper septal interfascicular reentrant ventricular tachycardias: a case report. PMID- 27492128 TI - Biological Activities of Triterpenoids and Phenolic Compounds from Myrica cerifera Bark. AB - Seven triterpenoids, 1 - 7, two diarylheptanoids, 8 and 9, four phenolic compounds, 10 - 13, and three other compounds, 14 - 16, were isolated from the hexane and MeOH extracts of the bark of Myrica cerifera L. (Myricaceae). Among these compounds, betulin (1), ursolic acid (3), and myricanol (8) exhibited cytotoxic activities against HL60 (leukemia), A549 (lung), and SK-BR-3 (breast) human cancer cell lines (IC50 3.1 - 24.2 MUm). Compound 8 induced apoptotic cell death in HL60 cells (IC50 5.3 MUm) upon evaluation of the apoptosis-inducing activity by flow cytometric analysis and by Hoechst 33342 staining method. Western blot analysis on HL60 cells revealed that 8 activated caspases-3, -8, and -9 suggesting that 8 induced apoptosis via both mitochondrial and death receptor pathways in HL60. Upon evaluation of the melanogenesis-inhibitory activity in B16 melanoma cells induced with alpha-melanocyte-stimulating hormone (alpha-MSH), erythrodiol (7), 4-hydroxy-2-methoxyphenyl beta-d-glucopyranoside (13), and butyl quinate (15) exhibited inhibitory effects (65.4 - 86.0% melanin content) with no, or almost no, toxicity to the cells (85.9 - 107.4% cell viability) at 100 MUm concentration. In addition, 8, myricanone (9), myricitrin (10), protocatechuic acid (11), and gallic acid (12) revealed potent DPPH radical-scavenging activities (IC50 6.9 - 20.5 MUm). PMID- 27492129 TI - Highly Efficient Synthesis of Fructooligosaccharides by Extracellular Fructooligosaccharide-Producing Enzymes and Immobilized Cells of Aspergillus aculeatus M105 and Purification and Biochemical Characterization of a Fructosyltransferase from the Fungus. AB - In this work, Aspergillus aculeatus M105 was obtained to produce high extracellular fructooligosaccharide-producing enzyme activity. The maximum yields of fructooligosaccharides produced by its extracellular enzymes and immobilized cells were 67.54 and 65.47% (w/w), respectively. A fructosyltransferase (FTase), AaFT32A, was purified from M105. The optimal pH and temperature of AaFT32A were pH 5.0-6.0 and 65 degrees C, respectively. The Km, Vmax, and kcat values for the transfructosylating activity of AaFT32A were 2267 mM, 1347 MUmol/min/mg protein, and 1550.2 s(-1), respectively, and those values for the hydrolytic activity of AaFT32A were 6.10 mM, 32.44 MUmol/min/mg protein, and 37.3 s(-1), respectively. The sequence of AaFT32A deduced from the cloned gene shared 99.4% identity with a FTase from Aspergillus japonicus CB05 and a fructofuranosidase from Aspergillus niger and 96.5% identity with a FTase (Aspacl_37092) from A. aculeatus ATCC 16872. The fungal strain and its FTase may have potential applications in the prebiotics industry. PMID- 27492131 TI - Two Decades of Laccases: Advancing Sustainability in the Chemical Industry. AB - Given the current state of environmental affairs and that our future on this planet as we know it is in jeopardy, research and development into greener and more sustainable technologies within the chemical and forest products industries is at its peak. Given the global scale of these industries, the need for environmentally benign practices is propelling new green processes. These challenges are also impacting academic research and our reagents of interest are laccases. These enzymes are employed in a variety of biotechnological applications due to their native function as catalytic oxidants. They are about as green as it gets when it comes to chemical processes, requiring O2 as their only co-substrate and producing H2 O as the sole by-product. The following account will review our twenty year journey on the use of these enzymes within our research group, from their initial use in biobleaching of kraft pulps and for fiber modification within the pulp and paper industry, to their current application as green catalytic oxidants in the field of synthetic organic chemistry. PMID- 27492132 TI - Twenty-four cases of imported zika virus infections diagnosed by molecular methods. AB - Zika virus is an emerging flavivirus widely spreading through Latin America. Molecular diagnosis of the infection can be performed using serum, urine and saliva samples, although a well-defined diagnostic algorithm is not yet established. We describe a series of 24 cases of imported zika virus infection into Catalonia (northeastern Spain). Based on our findings, testing of paired serum and urine samples is recommended. PMID- 27492130 TI - Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat. AB - Cold- and beta3-adrenoceptor agonist-induced sympathetic activation leads to angiogenesis and UCP1-dependent thermogenesis in mouse brown and white adipose tissues. Here we show that endothelial production of PDGF-CC during white adipose tissue (WAT) angiogenesis regulates WAT browning. We find that genetic deletion of endothelial VEGFR2, knockout of the Pdgf-c gene or pharmacological blockade of PDGFR-alpha impair the WAT-beige transition. We further show that PDGF-CC stimulation upregulates UCP1 expression and acquisition of a beige phenotype in differentiated mouse WAT-PDGFR-alpha(+) progenitor cells, as well as in human WAT PDGFR-alpha(+) adipocytes, supporting the physiological relevance of our findings. Our data reveal a paracrine mechanism by which angiogenic endothelial cells modulate adipocyte metabolism, which may provide new targets for the treatment of obesity and related metabolic diseases. PMID- 27492133 TI - Characterization of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella, Enterobacter, and Citrobacter obtained in environmental samples of a Tunisian hospital. AB - The assessment of the hospital environment as a reservoir of ESBL-producing Enterobacteriaceae in Tunisian hospitals is scarcely analyzed, except for Escherichia coli. The aim of this study was to evaluate the presence of ESBL producing non-E. coli Enterobacteriaceae (ESBL-EbNoEc) in 300 samples of abiotic surfaces and the hands of patients and staff of a Tunisian Hospital, and to characterize the ESBL genes of the recovered isolates. ESBL-EbNoEc were recovered in 28 of 300 (9.3%) analyzed samples and were identified as Klebsiella pneumoniae (n= 11), Enterobacter cloacae (n=11), Citrobacter freundii (n=4) and Klebsiella oxytoca (n=2). The bla genes identified by PCR and sequencing among the strains were as follows: 11 K.pneumoniae strains [blaCTX-M-15+ blaTEM-1+ blaSHV-11 (n=6); blaCTX-M-15+ blaTEM-1+ blaSHV-28 (n=3); blaCTX-M-15+ blaTEM-1+ blaSHV-1 (n=2)], 11 E. cloacae strains [blaCTX-M-15 (n=6); blaCTX-M-15+ blaTEM-1b (n=2); blaCTX-M 15+ blaTEM-1b+ blaOXA-1 (n=1);blaCTX-M-15+ blaOXA-1 (n=1);blaSHV-12 (n=1)], 4 C. freundii strains [blaCTX-M-15] and 2 K. oxytoca strains [blaCTX-M-15 (n=1); blaSHV-12 (n=1)]. The ISEcp1 and orf477 sequences were identified upstream and downstream of the blaCTX-M-15 gene, respectively, in 3 K. pneumoniae and 3 E. cloacae isolates. The PFGE analysis demonstrated three unrelated pulsotypes in K. pneumoniae strains and five pulsotypes in E. cloacae. The uncontrolled dissemination of ESBL-producing bacteria, even in the hospital environment, has become a real problem and new strategies and hygienic rules are needed to stop this bacterial dissemination. PMID- 27492134 TI - Postantifungal effect of caspofungin against the Candida albicans and Candida parapsilosis clades. AB - Killing and postantifungal effects could be relevant for the selection of optimal dosing schedules. This study aims to compare time-kill and postantifungal effects with caspofungin on Candida albicans (C. albicans, Candida dubliniensis, Candida africana) and Candida parapsilosis (C. parapsilosis, Candida metapsilosis, Candida orthopsilosis) clades. In the postantifungal effect experiments, strains were exposed to caspofungin for 1 h at concentrations 0.12-8 MUg/mL. Time-kill experiments were conducted at the same concentrations. Caspofungin exhibited a significant and prolonged postantifungal effect (>37 h) with 2 MUg/mL against the most strains of C. albicans clade. Against the C. parapsilosis clade, the postantifungal effect was <12 h at 8 MUg/mL, except for two strains. Caspofungin was fungicidal against C. albicans, C. dubliniensis and C. metapsilosis. PMID- 27492135 TI - Use of Low Dose Ziconotide as First-Line Intrathecal Monotherapy. AB - BACKGROUND: Ziconotide use in intrathecal drug therapy (IDT) has been limited by dosing related side effects. We examine our experience with ziconotide as a first line IDT monotherapy in patients with chronic pain and present our low and slow dosing algorithm aimed at reducing these patient experienced side effects while adequately managing pain. METHODS: We retrospectively reviewed demographics, dosing, and outcomes of 15 consecutive patients with complete three-month data sets implanted with intrathecal pain pumps more than three years utilizing ziconotide as a first-line monotherapy. RESULTS: Ziconotide response was assessed at visit 5 (69 +/- 10 days) and responders were characterized by having 30% or greater improvement in numerical rating scale scores (n = 7), or activities of daily living (ADL) (n = 7). Eight of our patients had a response in at least one measure (53%). In our eight responders, NRS score decreased from 8.4 +/- 0.7 at baseline (consult visit) to 2.4 +/- 1.0 at 2.6 months and 4.0 +/- 1.3 at most recent follow-up, mean of 12.9 months after implant. We noted that our responders tended to have neuropathic pain with an objective etiology. Initial dosing in 12 patients was 1.2 mcg/day (range for the other three patients was 0.6-1.4). Following initial dosing, visits were at 2-4 week intervals with mean titration doses between 1.1 and 2.8 mcg/day. Slight dizziness in two patients and transient urinary retention in one patient occurred, all resolving with dose reduction. No patients had discontinued use at three-month follow-up. DISCUSSION: We present our experience with low and slow ziconotide IDT as a first-line monotherapy, which showed no side effects resulting in discontinuation of the medication at three-month follow-up. Using a conservative dosing strategy, we were able to effectively treat 53% of patients. PMID- 27492136 TI - The first porphyrin-subphthalocyaninatoboron(iii)-fused hybrid with unique conformation and intramolecular charge transfer behavior. AB - Porphyrin and subphthalocyaninatoboron(iii) chromophores have been fused through a quinoxaline moiety, resulting in the first porphyrin subphthalocyaninatoboron(iii)-fused hybrid with intramolecular charge transfer from tetrapyrrole/tripyrrole chromophores to the quinoxaline moiety. The unique plane-bowl molecular structure of this hybrid was revealed based on single crystal X-ray diffraction analysis for the first time. PMID- 27492137 TI - [Tibial defects and infected non-unions : Treatment results after Masquelet technique]. AB - BACKGROUND: The treatment of non-unions with large bone defects or osteitis is a major challenge in orthopedic and trauma surgery. A new concept of therapy is a two-step procedure: Masquelet technique according to the diamond concept. METHODS: Between February 2010 and June 2014, 55 patients with tibia non-unions or infections were treated in a two-step Masquelet technique in our center. The patients' average age was 48 (median 50; minimum 15-maximum 72) with an average BMI (body mass index) of 28 (27; 18-52). There were 10 (18 %) female and 45 (82 %) male patients in the group. All study patients went through a follow up. Bone healing and clinical functional data were collected, as well as data according to subjective patient statements about pain and everyday limitations. RESULTS: In 42 cases (76.4 %) the outcome was a sufficient bony consolidation. On average, the time to heal was 10.3 (8, 5; 3-40) months, defect gaps were 4 cm (3 cm; 0,6-26 cm), and on average the patients had had 6 (median 4; range 1-31) previous operations . In all cases patients received osteosynthesis as well as a defect filling with RIA (reamer-irrigator-aspirator), and growth factor BMP-7 (bone morphogenetic protein-7). In 13 cases (23.6 %) there was no therapeutic success. In the evaluation of the SF12 questionnaire the mental health score increased from 47.4 (49.1; 27.6-65.7) to 49.8 (53.0; 28.7-69.4) and the well-being score from 32.7 (32.7;16.9-55.7) to 36.6 (36.5; 24.6-55.9). CONCLUSION: The two-step bone grafting method in the Masquelet technique used for tibia non-unions according to the diamond concept is a promising treatment option. Its application for tibia shaft non-unions with large bone defects or infections means a high degree of safety for the patient. PMID- 27492139 TI - Stanene: Atomically Thick Free-standing Layer of 2D Hexagonal Tin. AB - Stanene is one of most important of 2D materials due to its potential to demonstrate room temperature topological effects due to opening of spin-orbit gap. In this pursuit we report synthesis and investigation of optical properties of stanene up to few layers, a two-dimensional hexagonal structural analogue of graphene. Atomic scale morphological and elemental characterization using HRTEM equipped with SAED and EDAX detectors confirm the presence of hexagonal lattice of Sn atoms. The position of Raman peak along with the inter-planar 'd' spacing obtained from SAED for prepared samples are in good agreement with that obtained from first principles calculations and confirm that the sheets are not (111) alpha-Sn sheets. Further, the optical signature calculated using density functional theory at ~191 nm and ~233 nm for low buckled stanene are in qualitative agreement with the measured UV-Vis absorption spectrum. AFM measurements suggest interlayer spacing of ~0.33 nm in good agreement with that reported for epitaxial stanene sheets. No traces of oxygen were observed in the EDAX spectrum suggesting the absence of any oxidized phases. This is also confirmed by Raman measurements by comparing with oxidized stanene sheets. PMID- 27492138 TI - Conditional Deletion of Smad1 Ameliorates Glomerular Injury in Progressive Glomerulonephritis. AB - Matrix expansion and cell proliferation are concomitantly observed in various glomerular injuries. However, the molecular mechanisms responsible for these changes have not been fully elucidated. We have reported that Smad1 is a key signalling molecule that regulates the transcription of type IV collagen (Col4) in mesangial matrix expansion and is thereby involved in glomerular injury in an acute model of glomerulonephritis. In this study, we addressed the role of Smad1 signalling in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis, using conditional deletion of Smad1 in Rosa26CreERT2 mice (Smad1-CKO). Mesangial matrix expansion in the Smad1-CKO mice with NTN was significantly inhibited compared with that in wild type mice with NTN, which was consistent with the decrease in Col4 expression level. On the other hand, STAT3 activation and cell proliferation were not influenced by Smad1 deletion in the NTN model. Therefore, we investigated another factor that activates cell proliferation in the absence of Smad1. Id2 induced VEGF secretion and subsequent STAT3 activation, independently of Smad1 expression in mouse mesangial cells. Here we show that Smad1 plays an important role in the development of glomerular injury without affecting cell proliferation, in progressive glomerulonephritis. PMID- 27492140 TI - Azithromycin as an adjunct to non-surgical periodontal therapy: a systematic review. AB - The aim of this study was to investigate the current published work relating to the clinical benefits of the use of systemic azithromycin as an adjunct to non surgical periodontal therapy. A published work search of PubMed, EMBASE and Cochrane Register of Controlled Trials up to 27 April 2016 was undertaken. The large degree of heterogeneity in the types of studies, treatment protocols, test subjects, sample size and exclusion criteria indicated that the use of narrative synthesis of all relevant studies was a valid method of review. Of the 194 eligible studies, 15 were found to be of relevance. The majority of studies demonstrated an additional clinical benefit when azithromycin is used as an adjunct to non-surgical periodontal therapy, particularly in deeper pockets (>=6 mm). In conclusion, the current body of research on the adjunctive use of systemic azithromycin in non-surgical periodontal therapy suggests there is a clinical benefit and that this benefit is greatest in deeper initial pockets (>=6 mm). The findings also suggest that future studies need to be more careful in subject selection to identify susceptible patients or at risk sites, both the immunoregulatory effects and antibiotic resistance of azithromycin needs to be reported, and that study populations need to be more homogeneous. PMID- 27492142 TI - Chronic hepatitis C virus (HCV) burden in Rhode Island: modelling treatment scale up and elimination. AB - We utilized a disease progression model to predict the number of viraemic infections, cirrhotic cases, and liver-related deaths in the state of Rhode Island (RI) under four treatment scenarios: (1) current HCV treatment paradigm (about 215 patients treated annually, Medicaid reimbursement criteria fibrosis stage ?F3); (2) immediate scale-up of treatment (to 430 annually) and less restrictive Medicaid reimbursement criteria (fibrosis stage ?F2); (3) immediate treatment scale-up and no fibrosis stage-specific Medicaid reimbursement criteria (?F0); (4) an 'elimination' scenario (i.e. a continued treatment scale-up needed to achieve >90% reduction in viraemic cases by 2030). Under current treatment models, the number of cirrhotic cases and liver-related deaths will plateau and peak by 2030, respectively. Treatment scale-up with ?F2 and ?F0 fibrosis stage treatment criteria could reduce the number of cirrhotic cases by 21.7% and 10.0%, and the number of liver-related deaths by 19.3% and 7.4%, respectively by 2030. To achieve a >90% reduction in viraemic cases by 2030, over 2000 persons will need to be treated annually by 2020. This strategy could reduce cirrhosis cases and liver-related deaths by 78.9% and 72.4%, respectively by 2030. Increased HCV treatment uptake is needed to substantially reduce the burden of HCV by 2030 in Rhode Island. PMID- 27492141 TI - Preparedness for use of the rapid result HIV self-test by gay men and other men who have sex with men (MSM): a mixed methods exploratory study among MSM and those involved in HIV prevention and care. AB - OBJECTIVES: The aim of the study was to explore preparedness for the HIV self test among men who have sex with men (MSM) and those involved in HIV prevention and care. METHODS: A mixed methods exploratory research design was employed, detailing awareness and willingness to use the self-test and the perceived barriers and facilitators to implementation. Quantitative and qualitative data collection and analysis were completed in parallel. Descriptive and inferential analysis of cross-sectional bar-based survey data collected from MSM through a self-completed questionnaire and oral fluid specimen collection (n = 999) was combined with qualitative, thematic, analysis of data collected through 12 expert focus groups (n = 55) consisting of gay men, National Health Service (NHS) staff, community organizations, entrepreneurs and activists. Findings were subsequently combined and assessed for synergies. RESULTS: Among MSM, self-test awareness was moderate (55%). Greater awareness was associated with increased educational attainment [adjusted odds ratio 1.51; 95% confidence interval (CI) 1.00-2.30; P = 0.05] and previous history of sexually transmitted infection (STI) testing (adjusted odds ratio 1.63; 95% CI 1.11-2.39; P = 0.01). Willingness to use the test was high (89%) and associated with meeting sexual partners online (unadjusted odds ratio 1.96; 95% CI 1.31-2.94; P < 0.001). Experts highlighted the overall acceptability of self-testing; it was understood as convenient, discreet, accessible, and with a low burden to services. However, some ambivalence towards self-testing was reported; it could reduce opportunities to engage with wider services, wider health issues and the determinants of risk. CONCLUSIONS: Self-testing represents an opportunity to reduce barriers to HIV testing and enhance prevention and access to care. Levels of awareness are moderate but willingness to use is high. Self-testing may amplify health inequalities. PMID- 27492143 TI - Quantitative proteomic analysis exploring progression of colorectal cancer: Modulation of the serpin family. AB - Colorectal cancer (CRC) remains a major cause of cancer related-death in developed countries. The mortality risk is correlated with the stage of CRC determined at the primary diagnosis and early diagnosis is associated with enhanced survival rate. Currently, only faecal occult blood tests are used to screen for CRC. Consequently, there is an incentive to identify specific markers of CRC. We used quantitative proteomic analysis of serum samples to characterize protein profiles in adenoma, CRC and healthy control samples. We identified 89 distinct proteins modulated between normal, colorectal adenoma and carcinoma patients. This list emphasizes proteins involved in enzyme regulator activities and in particular the serpin family. In serum samples, protein profiles of three members of the serpin family (SERPINA1, SERPINA3 and SERPINC1) were confirmed by ELISA assays. We obtained sensitivity/specificity values of 95%/95% for both SERPINA1 and SERPINC1, and 95%/55% for SERPINA3. This study supports the idea that serum proteins can discriminate adenoma and CRC patients from unaffected patients and reveals a panel of regulated proteins that might be useful for selecting patients for colonoscopy. By evaluating SERPINA1, SERPINA3 and SERPINC1, we highlight the potential role of the serpin family during the development and progression of CRC. SIGNIFICANCE: Colorectal cancer (CRC) remains a major cause of cancer mortality throughout the world. However, very few CRC biomarkers have satisfactory sensitivity and specificity in clinical practice. To the best of our knowledge our study is the first to profile sera proteomes between adenoma, CRC and healthy patients. We report a comprehensive list of proteins that may be used as early diagnostic biomarkers of CRC. It is noteworthy that 17% of these modulated proteins have been previously described as candidate biomarkers in CRC. Enzyme regulator activity was found to be the main molecular function among these proteins and, in particular, there was an enrichment of members of the serpin family. The subsequent verification on a new cohort by ELISA demonstrates that these serpins could be useful to discriminate healthy from colorectal carcinoma patients with a high sensitivity and specificity. The combination of these biomarkers should increase predictive powers of CRC diagnosis. The remaining candidates form a reserve for further evaluation of additional biomarkers for CRC diagnosis. PMID- 27492144 TI - MicroRNA-155 is a critical regulator of type 2 innate lymphoid cells and IL-33 signaling in experimental models of allergic airway inflammation. AB - BACKGROUND: Allergic airway inflammation is triggered by allergen exposure through several steps including release of IL-33, which promotes cytokine (IL-5, IL-13) production by type 2 innate lymphoid cells (ILC2s). MicroRNA (miR)-155 has recently been described to regulate adaptive responses in allergic inflammation. However, the role of miR-155 in the regulation of ILC2s remains unexplored. OBJECTIVE: We sought to elucidate the contribution of miR-155 in ILC2 expansion using experimental murine models of allergic airway inflammation. METHODS: To determine the role of miR-155 in the regulation of ILC2s in allergic airway inflammation, miR-155 deficient (miR-155-/-) and wild-type (WT) mice were subjected to acute or chronic allergen-induced inflammation or treated with recombinant IL-33. RESULTS: miR-155 was 10-fold upregulated in WT-derived ILC2s in response to IL-33. Furthermore, miR-155-/- mice demonstrated impaired lung IL 33 levels in response to allergen challenge and the number of ILC2s was significantly reduced in allergen-challenged miR-155-/- mice compared with WT mice. Exogenous IL-33 treatment revealed that miR-155 is needed for IL-33-induced ILC2 expansion and eosinophilic airway inflammation. Indeed, ILC2s from IL-33 challenged miR-155-/- lungs exhibited impaired proliferation, GATA-3 expression, and IL-13 production as compared with IL-33-challenged WT ILC2s. CONCLUSIONS: Our findings for the first time demonstrate that ILC2s and IL-33 signaling are regulated by miR-155 in allergic airway inflammation. PMID- 27492145 TI - To compare growth outcomes and cost-effectiveness of "Kangaroo ward care" with "intermediate intensive care" in stable extremely low birth weight infants: randomized control trial. AB - AIMS: To compare growth outcome and cost-effectiveness of "Kangaroo ward care" (KWC) with "Intermediate intensive care" (IIC) in stable extremely low birth weight (ELBW) infants. MATERIALS AND METHODS: This is secondary analysis of the study and we analyzed 62 ELBW infants, 33 were randomized to KWC and 29 to IIC once the infant reached a weight of 1150 g. Infants in the KWC group were shifted to the Kangaroo ward immediately after randomization and in the IIC group received IIC care till they attain a weight of 1250 g before shifting to Kangaroo ward. RESULTS: The gain in weight (g/day), length (cm/week), and head circumference (cm/week) were comparable between the two groups. The mean weight, length, and head circumference were comparable at term gestational age. The infants in KWC group were shifted five days earlier to Kangaroo ward when compared to IIC group. The cost-effective analysis using "top-down" and "bottom up" accounting method showed that there was significant reduction of hospital and parents expenditure in KWC group (p < 0.001) with approximate saving of 452 USD for each patient in the KWC group. CONCLUSION: Early shifting of ELBW infants for KWC is very efficacious and cost-effective intervention when compared to IIC. (CTRI/2014/05/004625). PMID- 27492146 TI - Central Venous Occlusion in the Hemodialysis Patient. AB - Central venous stenosis (CVS) is encountered frequently among hemodialysis patients. Prior ipsilateral central venous catheterization and cardiac rhythm device insertions are common risk factors, but CVS can also occur in the absence of this history. Chronic CVS can cause thrombosis with partial or complete occlusion of the central vein at the site of stenosis. CVS is frequently asymptomatic and identified as an incidental finding during imaging studies. Symptomatic CVS presents most commonly as an upper- or lower-extremity edema ipsilateral to the CVS. Previously unsuspected CVS may become symptomatic after placement of an ipsilateral vascular access. The likelihood of symptomatic CVS may be affected by the central venous catheter (CVC) location; CVC side; duration of CVC dependence; type, location, and blood flow of the ipsilateral access; and extent of collateral veins. Venous angiography is the gold standard for diagnosis. Percutaneous transluminal angioplasty and stent placement can improve the stenosis and alleviate symptoms, but CVS typically recurs frequently, requiring repeated interventions. Refractory symptomatic CVS may require ligation of the ipsilateral vascular access. Because no available treatment option is curative, the goal should be to prevent CVS by minimizing catheters and central vein instrumentation in patients with chronic kidney disease and dialysis patients. PMID- 27492147 TI - Risk factors for coronary artery disease and acute coronary syndrome in patients <=40 years old. AB - OBJECTIVE: In this study, we assessed the risk factor profile in premature coronary artery disease (CAD) and acute coronary syndrome for adults <=40 years old. METHODS: A retrospective chart analysis of 397 patients <=40 years old admitted from 2005 to 2014 for chest pain and who underwent coronary arteriography. RESULTS: Of 397 patients that had undergone coronary arteriography, 54% had CAD while 46% had normal coronary arteries. When compared with patients with normal coronary arteries, patients with CAD were more likely to smoke tobacco, have dyslipidemia, be diabetic, have BMI >30 kg/m(2), have a family history of premature CAD and be male in gender. CONCLUSION: Healthcare intervention in the general population through screening, counseling and education regarding the risk factors is warranted to reduce premature CAD. PMID- 27492148 TI - PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer. AB - Pyruvate kinase M2 (PKM2) is a key driver of aerobic glycolysis in cancer cells and has been shown to be up-regulated by mTOR in vitro. Our previous proteomic profiling studies showed that PKM2 was significantly upregulated in cervical cancer tissues after treatment with neoadjuvant chemotherapy (NACT). Whether PKM2 expression predicts cisplatin-based NACT sensitivity and is mTOR dependent in cervical cancer patients remains unclear. Using paired tumor samples (pre- and post-chemotherapy) from 36 cervical cancer patients, we examined mTOR, HIF 1alpha, c-Myc, and PKM2 expression in cervical cancer samples and investigated the response to cisplatin-based NACT. In addition, we established PKM2 suppressed cervical cancer cell lines and evaluated their sensitivity to cisplatin in vitro. We found that the mTOR/HIF-1alpha/c-Myc/PKM2 signaling pathway was significantly downregulated in post-chemotherapy cervical cancer tissues. High levels of mTOR, HIF-1alpha, c-Myc, and PKM2 were associated with a positive chemotherapy response in cervical cancer patients treated with cisplatin-based NACT. In vitro, PKM2 knockdown desensitized cervical cancer cells to cisplatin. Moreover, PKM2 had complex interactions with mTOR pathways. mTOR, HIF1alpha, c-Myc, and PKM2 expression in cervical cancer may serve as predictive biomarkers to cisplatin based chemotherapy. PKM2 enhances chemosensitivity to cisplatin through interaction with the mTOR pathway in cervical cancer. PMID- 27492150 TI - Case report: progressive multifocal encephalopathy (PML) causing an isolated cerebellar syndrome. PMID- 27492149 TI - Characteristics of European adults who dropped out from the Food4Me Internet based personalised nutrition intervention. AB - OBJECTIVE: To characterise participants who dropped out of the Food4Me Proof-of Principle study. DESIGN: The Food4Me study was an Internet-based, 6-month, four arm, randomised controlled trial. The control group received generalised dietary and lifestyle recommendations, whereas participants randomised to three different levels of personalised nutrition (PN) received advice based on dietary, phenotypic and/or genotypic data, respectively (with either more or less frequent feedback). SETTING: Seven recruitment sites: UK, Ireland, The Netherlands, Germany, Spain, Poland and Greece. SUBJECTS: Adults aged 18-79 years (n 1607). RESULTS: A total of 337 (21 %) participants dropped out during the intervention. At baseline, dropouts had higher BMI (0.5 kg/m2; P<0.001). Attrition did not differ significantly between individuals receiving generalised dietary guidelines (Control) and those randomised to PN. Participants were more likely to drop out (OR; 95 % CI) if they received more frequent feedback (1.81; 1.36, 2.41; P<0.001), were female (1.38; 1.06, 1.78; P=0.015), less than 45 years old (2.57; 1.95, 3.39; P<0.001) and obese (2.25; 1.47, 3.43; P<0.001). Attrition was more likely in participants who reported an interest in losing weight (1.53; 1.19, 1.97; P<0.001) or skipping meals (1.75; 1.16, 2.65; P=0.008), and less likely if participants claimed to eat healthily frequently (0.62; 0.45, 0.86; P=0.003). CONCLUSIONS: Attrition did not differ between participants receiving generalised or PN advice but more frequent feedback was related to attrition for those randomised to PN interventions. Better strategies are required to minimise dropouts among younger and obese individuals participating in PN interventions and more frequent feedback may be an unnecessary burden. PMID- 27492151 TI - [Cases and duration of mechanical ventilation in German hospitals : An analysis of DRG incentives and developments in respiratory medicine]. AB - BACKGROUND: Diagnosis-related groups (DRGs) have been used to reimburse hospitals services in Germany since 2003/04. Like any other reimbursement system, DRGs offer specific incentives for hospitals that may lead to unintended consequences for patients. In the German context, specific procedures and their documentation are suspected to be primarily performed to increase hospital revenues. Mechanical ventilation of patients and particularly the duration of ventilation, which is an important variable for the DRG-classification, are often discussed to be among these procedures. OBJECTIVES: The aim of this study was to examine incentives created by the German DRG-based payment system with regard to mechanical ventilation and to identify factors that explain the considerable increase of mechanically ventilated patients in recent years. Moreover, the assumption that hospitals perform mechanical ventilation in order to gain economic benefits was examined. MATERIAL AND METHODS: In order to gain insights on the development of the number of mechanically ventilated patients, patient-level data provided by the German Federal Statistical Office and the German Institute for the Hospital Remuneration System were analyzed. The type of performed ventilation, the total number of ventilation hours, the age distribution, mortality and the DRG distribution for mechanical ventilation were calculated, using methods of descriptive and inferential statistics. Furthermore, changes in DRG-definitions and changes in respiratory medicine were compared for the years 2005-2012. RESULTS: Since the introduction of the DRG-based payment system in Germany, the hours of ventilation and the number of mechanically ventilated patients have substantially increased, while mortality has decreased. During the same period there has been a switch to less invasive ventilation methods. The age distribution has shifted to higher age-groups. A ventilation duration determined by DRG definitions could not be found. CONCLUSION: Due to advances in respiratory medicine, new ventilation methods have been introduced that are less prone to complications. This development has simultaneously improved survival rates. There was no evidence supporting the assumption that the duration of mechanical ventilation is influenced by the time intervals relevant for DRG grouping. However, presumably operational routines such as staff availability within early and late shifts of the hospital have a significant impact on the termination of mechanical ventilation. PMID- 27492152 TI - Serious engagement in sport and health benefits among Korean immigrants in the USA. AB - There is a dearth of information pertaining to ethnicity and serious leisure among immigrants. The purpose of our study was to explore the health benefits of serious engagement in sports among Korean immigrants who are part of club activities. Using semi-structured in-depth interviews, we identified three themes associated with the benefits of serious leisure: (a) coping with acculturative stress, (b) creating ethnic strength, and (c) personal benefits. Participants gain personal and social benefits by pursuing leisure activities in a serious manner within their ethnic in-group. PMID- 27492153 TI - Ommaya reservoir in the treatment of cryptococcal meningitis. AB - The objective is to study the role of Ommaya reservoir in the treatment of cryptococcal meningitis. The clinical data of 42 patients with cryptococcal meningitis were retrospectively studied. The Ommaya group included 20 patients, who were treated with Amphotericin B (Am B) and Ommaya reservoir implantation. The non-Ommaya group contained 22 patients, who were just treated with Amphotericin B (Am B). In the Ommaya group (surgical group), all 20 patients with Ommaya reservoir were fully recovered, and their average hospital stay period and average treatment period with Amphotericin B were 105.3 +/- 18.3 and 75.0 +/- 18.1 days, respectively. In the non-Ommaya group (control group), 16 patients were fully recovered and the average hospital stay period and average treatment period with Amphotericin B of these 22 patients were 139.6 +/- 29.5 and 150.0 +/- 32.2 days, respectively. In the surgical group, average period of cryptococcus disappearance was 20 +/- 8 days, while in the control group, that was 35 +/- 10 days. The clinical efficacy was better in surgical group than control group (P < 0.05). Ommaya reservoir implantation is a valuable approach in the treatment of cryptococcal meningitis and can improve the cure rate, decrease mortality, and shorten the period of treatment. PMID- 27492154 TI - Acta Neurologica Belgica: a youthful centenarian. PMID- 27492156 TI - Mental illness research in the Gulf Cooperation Council: a scoping review. AB - Rapid growth and development in recent decades has seen mental health and mental illness emerge as priority health concerns for the Gulf Cooperation Council (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates). As a result, mental health services in the region are being redefined and expanded. However, there is a paucity of local research to guide ongoing service development. Local research is important because service users' experience of mental illness and mental health services are linked to their sociocultural context. In order for service development to be most effective, there is a need for increased understanding of the people who use these services.This article aims to review and synthesize mental health research from the Gulf Cooperation Council. It also seeks to identify gaps in the literature and suggest directions for future research. A scoping framework was used to conduct this review. To identify studies, database searches were undertaken, regional journals were hand searched, and reference lists of included articles were examined. Empirical studies undertaken in the Gulf Cooperation Council that reported mental health service users' experience of mental illness were included. Framework analysis was used to synthesize results. Fifty-five studies met inclusion criteria and the following themes were identified: service preferences, illness (symptomology, perceived cause, impact), and recovery (traditional healing, family support, religion). Gaps included contradictory findings related to the supportive role of the Arabic extended family and religion, under-representation of women in study samples, and limited attention on illness management outside of the hospital setting.From this review, it is clear that the sociocultural context in the region is linked to service users' experience of mental illness. Future research that aims to fill the identified gaps and develop and test culturally appropriate interventions will aid practice and policy development in the region. PMID- 27492157 TI - Blended learning: how can we optimise undergraduate student engagement? AB - BACKGROUND: Blended learning is a combination of online and face-to-face learning and is increasingly of interest for use in undergraduate medical education. It has been used to teach clinical post-graduate students pharmacology but needs evaluation for its use in teaching pharmacology to undergraduate medical students, which represent a different group of students with different learning needs. METHODS: An existing BSc-level module on neuropharmacology was redesigned using the Blended Learning Design Tool (BLEnDT), a tool which uses learning domains (psychomotor, cognitive and affective) to classify learning outcomes into those taught best by self-directed learning (online) or by collaborative learning (face-to-face). Two online courses were developed, one on Neurotransmitters and the other on Neurodegenerative Conditions. These were supported with face-to-face tutorials. Undergraduate students' engagement with blended learning was explored by the means of three focus groups, the data from which were analysed thematically. RESULTS: Five major themes emerged from the data 1) Purpose and Acceptability 2) Structure, Focus and Consolidation 3) Preparation and workload 4) Engagement with e-learning component 5) Future Medical Education. CONCLUSION: Blended learning was acceptable and of interest to undergraduate students learning this subject. They expressed a desire for more blended learning in their courses, but only if it was highly structured, of high quality and supported by tutorials. Students identified that the 'blend' was beneficial rather than purely online learning. PMID- 27492155 TI - Gender differences and gender convergence in alcohol use over the past three decades (1984-2008), The HUNT Study, Norway. AB - BACKGROUND: To examine changes in men's and women's drinking in Norway over a 20 year period, in order to learn whether such changes have led to gender convergence in alcohol drinking. METHODS: Repeated cross-sectional studies (in 1984-86, 1995-97, and 2006-08) of a large general population living in a geographically defined area (county) in Norway. Information about alcohol drinking is based on self-report questionnaires. Not all measures were assessed in all three surveys. RESULTS: Adult alcohol drinking patterns have changed markedly over a 20-year period. Abstaining has become rarer while consumption and rates of recent drinking and problematic drinking have increased. Most changes were in the same direction for men and women, but women have moved towards men's drinking patterns in abstaining, recent drinking, problematic drinking and consumption. Intoxication (among recent drinkers) has decreased in both genders, but more in men than in women. The declines in gender differences, however, were age-specific and varied depending on which drinking behavior and which beverage was taken into account. CONCLUSIONS: There has been a gender convergence in most drinking behaviours, including lifetime history of problem drinking, over the past 2-3 decades in this Norwegian general population, but the reasons for this convergence appear to be complex. PMID- 27492158 TI - Doctors' reports about palliative systemic treatment: A medical record study. AB - BACKGROUND: Decisions about palliative systemic treatment are key elements of palliative and end-of-life care. Such decisions must often be made in complex, clinical situations. AIM: To explore the content of medical records of patients with advanced non-small cell lung cancer and pancreatic cancer with specific emphasis on doctors' notes about decisions on palliative systemic treatment. DESIGN: Medical record review (2009-2012) of 147 cancer patients containing 276 notes about palliative systemic treatment. We described the proportion of notes/medical records containing pre-specified items relevant to palliative systemic treatment. We selected patients using the nationwide Netherlands Cancer Registry. SETTING: Hospital based. RESULTS: About 75% of all notes reported doctors' considerations to start/continue palliative systemic treatment, including information about the prognosis (47%), possible survival gain (22%), patients' wish for palliative systemic treatment (33%), impact on quality of life (8%), and patient's age (3%). Comorbidity (82%), smoking status (78%) and drinking behaviour (63%) were more often documented than patients' performance status (16%). Conversations with the patient/family about palliative systemic treatment were reported in 49% of all notes. Response measurements and dose adaptations were documented in 75% and 71% of patients who received palliative systemic treatment respectively. CONCLUSION: Medical records provide insight into the decision-making process about palliative systemic treatment. The content and detail of doctors' notes, however, widely varies especially concerning their palliative systemic treatment considerations. Registries that aim to measure the quality of (end-of-life) care must be aware of this outcome. Future research should further explore how medical records can best assist in evaluating the quality of the decision-making process in the patient's final stage of life. PMID- 27492159 TI - What is the evidence for conducting palliative care family meetings? A systematic review. AB - BACKGROUND: Structured family meeting procedures and guidelines suggest that these forums enhance family-patient-team communication in the palliative care inpatient setting. However, the vulnerability of palliative patients and the resources required to implement family meetings in accordance with recommended guidelines make better understanding about the effectiveness of this type of intervention an important priority. Aim and design: This systematic review examines the evidence supporting family meetings as a strategy to address the needs of palliative patients and their families. The review conforms to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. DATA SOURCES: Six medical and psychosocial databases and "CareSearch," a palliative care-specific database, were used to identify studies reporting empirical data, published in English in peer-reviewed journals from 1980 to March 2015. Book chapters, expert opinion, and gray literature were excluded. The Cochrane Collaboration Tool assessed risk of bias. RESULTS: Of the 5051 articles identified, 13 met the inclusion criteria: 10 quantitative and 3 qualitative studies. There was low-level evidence to support family meetings. Only two quantitative pre- and post-studies used a validated palliative care family outcome measure with both studies reporting significant results post-family meetings. Four other quantitative studies reported significant results using non validated measures. CONCLUSION: Despite the existence of consensus-based family meeting guidelines, there is a paucity of evidence to support family meetings in the inpatient palliative care setting. Further research using more robust designs, validated outcome measures, and an economic analysis are required to build the family meeting evidence before they are routinely adopted into clinical practice. PMID- 27492160 TI - Current status of accurate prognostic awareness in advanced/terminally ill cancer patients: Systematic review and meta-regression analysis. AB - BACKGROUND: No systematic meta-analysis is available on the prevalence of cancer patients' accurate prognostic awareness and differences in accurate prognostic awareness by publication year, region, assessment method, and service received. AIM: To examine the prevalence of advanced/terminal cancer patients' accurate prognostic awareness and differences in accurate prognostic awareness by publication year, region, assessment method, and service received. DESIGN: Systematic review and meta-analysis. METHODS: MEDLINE, Embase, The Cochrane Library, CINAHL, and PsycINFO were systematically searched on accurate prognostic awareness in adult patients with advanced/terminal cancer (1990-2014). Pooled prevalences were calculated for accurate prognostic awareness by a random-effects model. Differences in weighted estimates of accurate prognostic awareness were compared by meta-regression. RESULTS: In total, 34 articles were retrieved for systematic review and meta-analysis. At best, only about half of advanced/terminal cancer patients accurately understood their prognosis (49.1%; 95% confidence interval: 42.7%-55.5%; range: 5.4%-85.7%). Accurate prognostic awareness was independent of service received and publication year, but highest in Australia, followed by East Asia, North America, and southern Europe and the United Kingdom (67.7%, 60.7%, 52.8%, and 36.0%, respectively; p = 0.019). Accurate prognostic awareness was higher by clinician assessment than by patient report (63.2% vs 44.5%, p < 0.001). CONCLUSION: Less than half of advanced/terminal cancer patients accurately understood their prognosis, with significant variations by region and assessment method. Healthcare professionals should thoroughly assess advanced/terminal cancer patients' preferences for prognostic information and engage them in prognostic discussion early in the cancer trajectory, thus facilitating their accurate prognostic awareness and the quality of end-of-life care decision-making. PMID- 27492161 TI - Eccentric Contraction-Induced Muscle Injury: Reproducible, Quantitative, Physiological Models to Impair Skeletal Muscle's Capacity to Generate Force. AB - In order to investigate the molecular and cellular mechanisms of muscle regeneration an experimental injury model is required. Advantages of eccentric contraction-induced injury are that it is a controllable, reproducible, and physiologically relevant model to cause muscle injury, with injury being defined as a loss of force generating capacity. While eccentric contractions can be incorporated into conscious animal study designs such as downhill treadmill running, electrophysiological approaches to elicit eccentric contractions and examine muscle contractility, for example before and after the injurious eccentric contractions, allows researchers to circumvent common issues in determining muscle function in a conscious animal (e.g., unwillingness to participate). Herein, we describe in vitro and in vivo methods that are reliable, repeatable, and truly maximal because the muscle contractions are evoked in a controlled, quantifiable manner independent of subject motivation. Both methods can be used to initiate eccentric contraction-induced injury and are suitable for monitoring functional muscle regeneration hours to days to weeks post-injury. PMID- 27492162 TI - Volumetric Muscle Loss. AB - Volumetric muscle loss (VML) injury is prevalent in severe extremity trauma and is an emerging focus area among orthopedic and regenerative medicine fields. VML injuries are the result of an abrupt, frank loss of tissue and therefore of different etiology from other standard rodent injury models to include eccentric contraction, ischemia reperfusion, crush, and freeze injury. The current focus of many VML-related research efforts is to regenerate the lost muscle tissue and thereby improve muscle strength. Herein, we describe a VML model in the anterior compartment of the hindlimb that is permissible to repeated neuromuscular strength assessments and is validated in mouse, rat, and pig. PMID- 27492163 TI - Freeze Injury of the Tibialis Anterior Muscle. AB - Freeze injury is physically induced by exposing skeletal muscle to an extremely cold probe, and results in a robust degenerative and inflammatory response. One unique aspect of freeze injury is that it destroys not only the muscle fiber cells, but also all of the mononuclear cells in the zone of injury. Repair of the muscle is accomplished by satellite cells from outside of the zone of injury, which must migrate in and which may interact with inflammatory cells, hence the length of time before apparent histological recovery of the most damaged zone is typically somewhat longer with freeze injury than with other physical or chemical methods of injury. In this chapter, we present a detailed protocol for the freeze injury of the tibialis anterior (TA) muscle in mouse. PMID- 27492164 TI - Synergist Ablation as a Rodent Model to Study Satellite Cell Dynamics in Adult Skeletal Muscle. AB - In adult skeletal muscles, satellite cells are the primary myogenic stem cells involved in myogenesis. Normally, they remain in a quiescent state until activated by a stimulus, after which they proliferate, differentiate, and fuse into an existing myofiber or form a de novo myofiber. To study satellite cell dynamics in adult murine models, most studies utilize regeneration models in which the muscle is severely damaged and requires the participation from satellite cells in order to repair. Here, we describe a model to study satellite cell behavior in muscle hypertrophy that is independent of muscle regeneration.Synergist ablation surgery involves the surgical removal of the gastrocnemius and soleus muscles resulting in functional overload of the remaining plantaris muscle. This functional overload results in myofiber hypertrophy, as well as the activation, proliferation, and fusion of satellite cells into the myofibers. Within 2 weeks of functional overload, satellite cell content increases approximately 275 %, an increase that is accompanied with a ~60 % increase in the number of myonuclei. Therefore, this can be used as an alternative model to study satellite cell behavior in adulthood that is different from regeneration, and capable of revealing new satellite cell functions in regulating muscle adaptation. PMID- 27492165 TI - Inducing and Evaluating Skeletal Muscle Injury by Notexin and Barium Chloride. AB - Models of skeletal muscle injury in animal models are invaluable tools to assess muscle stem cell (MuSC)-mediated tissue repair. The optimization and comprehensive evaluation of these approaches have greatly improved our ability to assess MuSC regenerative potential. Here we describe the procedures for skeletal muscle injury with notexin and BaCl2 and assessment of the dynamics of tissue regeneration. PMID- 27492167 TI - Fibrosis-Inducing Strategies in Regenerating Dystrophic and Normal Skeletal Muscle. AB - The excessive accumulation of collagens (fibrosis) impairs the function of vital tissues and organs. Fibrosis is a hallmark of severe muscular dystrophies, such as the incurable Duchenne Muscular Dystrophy (DMD), where skeletal muscle is substituted by scar (fibrotic) tissue as disease advances. One of the major obstacles in increasing our ability to combat fibrosis-driven muscular dystrophy progression is that no optimal in vivo models of muscle fibrosis are currently available, limiting fibrosis research and the development of novel therapies. In this chapter we describe different experimental strategies to accelerate and enhance muscle fibrosis in vivo in the widely used animal model for DMD, the mdx mouse. Since excessive tissue scarring also hampers the normal regeneration process after muscle injury, we have extended these fibrogenic strategies to the muscle of normal (non-diseased) mice. These strategies will allow fibrosis induction and assessment in a wide array of genetically modified mouse lines in physiological and pathological conditions of muscle regeneration. They should eventually improve our ability to combat fibrosis and foster muscle regeneration in DMD. PMID- 27492166 TI - Cardiotoxin Induced Injury and Skeletal Muscle Regeneration. AB - Skeletal muscles have a tremendous capacity for repair and regeneration in response to injury. This capacity for regeneration is largely due to a myogenic stem cell population, termed satellite cells, which are resident in adult skeletal muscles. In order to decipher the mechanisms that govern myogenic stem cell quiescence, activation, differentiation, and self-renewal, a reproducible injury model is required. Therefore, we have utilized the delivery of the myonecrotic agent, cardiotoxin, to examine the molecular mechanisms of myogenic stem cells in response to injury. Here, we describe our experience using cardiotoxin as a potent myonecrotic agent to study skeletal muscle regeneration. We provide a detailed protocol to examine skeletal muscle injury and regeneration using morphological analyses. PMID- 27492168 TI - Isolation, Cryosection and Immunostaining of Skeletal Muscle. AB - Adult skeletal muscle is maintained and repaired by resident stem cells called satellite cells, located between the plasmalemma of a muscle fiber, and the surrounding basal lamina. When needed, satellite cells are activated to form proliferative myoblasts, that then differentiate and fuse to existing muscle fibers, or fuse together to form replacement myofibers. In parallel, a proportion of satellite cells self-renew, to maintain the stem cell pool. To date, Pax7 is the marker of choice for identifying quiescent satellite cells. Co-immunostaining of skeletal muscle with Pax7 and laminin allows both identification of satellite cells, and the myofiber that they are associated with. Furthermore, satellite cells can be followed through the early stages of the myogenic program by co immunostaining with myogenic regulatory factors such as MyoD. To test genetically modified mice for satellite cell expression, co-immunostaining can be performed for Pax7 and reporter genes such as eGFP. Here, we describe a method for identification of satellite cells in skeletal muscle sections, including muscle isolation, cryosectioning and co-immunostaining for Pax7 and laminin. PMID- 27492169 TI - Isolation of Mouse Periocular Tissue for Histological and Immunostaining Analyses of the Extraocular Muscles and Their Satellite Cells. AB - The extraocular muscles (EOMs) comprise a group of highly specialized skeletal muscles controlling eye movements. Although a number of unique features of EOMs including their sparing in Duchenne muscular dystrophy have drawn a continuous interest, knowledge about these hard to reach muscles is still limited. The goal of this chapter is to provide detailed methods for the isolation and histological analysis of mouse EOMs. We first introduce in brief the basic anatomy and established nomenclature of the extraocular primary and accessory muscles. We then provide a detailed description with step-by-step images of our procedure for isolating (and subsequently cryosectioning) EOMs while preserving the integrity of their original structural organization. Next, we present several useful histological protocols frequently used by us, including: (1) a method for highlighting the general organization of periocular tissue, using the MyoD(Cre) * R26(mTmG) reporter mouse that elegantly distinguishes muscle (MyoD(Cre)-driven GFP(+)) from the non-myogenic constituents (Tomato(+)); (2) analysis by H&E staining, allowing for example, detection of the pathological features of the dystrophin-null phenotype in affected limb and diaphragm muscles that are absent in EOMs; (3) detection of the myogenic progenitors (i.e., satellite cells) in their native position underneath the myofiber basal lamina using Pax7/laminin double immunostaining. The EOM tissue harvesting procedure described here can also be adapted for isolating and studying satellite cells and other cell types. Overall, the methods described in this chapter should provide investigators the necessary tools for entering the EOM research field and contribute to a better understanding of this highly specialized muscle group and its complex micro anatomy. PMID- 27492170 TI - Skeletal Muscle Tissue Clearing for LacZ and Fluorescent Reporters, and Immunofluorescence Staining. AB - Skeletal muscle is a highly ordered yet complex tissue containing several cell types that interact with each other in order to maintain structure and homeostasis. It is also a highly regenerative tissue that responds to damage in a highly intricate but stereotypic manner, with distinct spatial and temporal kinetics. Proper examination of this process requires one to look at the three dimensional orientation of the cellular and subcellular components, which can be accomplished through tissue clearing. While there has been a recent surge of protocols to study biology in whole tissue, it has primarily focused on the nervous system. This chapter describes the workflow for whole mount analysis of murine skeletal muscle for LacZ reporters, fluorescent reporters and immunofluorescence staining. Using this technique, we are able to visualize LacZ reporters more effectively in deep tissue samples, and to perform fluorescent imaging with a depth greater than 1700 MUm. PMID- 27492171 TI - Isolation, Culture, Functional Assays, and Immunofluorescence of Myofiber Associated Satellite Cells. AB - Adult skeletal muscle stem cells, termed satellite cells, regenerate and repair the functional contractile cells in adult skeletal muscle called myofibers. Satellite cells reside in a niche between the basal lamina and sarcolemma of myofibers. Isolating single myofibers and their associated satellite cells provides a culture system that partially mimics the in vivo environment. We describe methods for isolating and culturing intact individual myofibers and their associated satellite cells from the mouse extensor digitorum longus muscle. Following dissection and isolation of individual myofibers we provide protocols for myofiber transplantation, satellite cell transfection, immune detection of satellite cell antigens, and assays to examine satellite cell self-renewal and proliferation. PMID- 27492172 TI - Flow Cytometry and Transplantation-Based Quantitative Assays for Satellite Cell Self-Renewal and Differentiation. AB - In response to muscle damage, satellite cells proliferate and undertake both differentiation and self-renewal, generating new functional muscle tissue and repopulating this new muscle with stem cells for future injury responses. For many questions relating to the physiological regulation of satellite cells, quantitative readouts of self-renewal and differentiation can be very useful. There is a particular need for a quantitative assay for satellite cell self renewal that does not rely solely upon sectioning, staining and counting cells in sections. In this chapter, we provide detailed methods for quantifying the self renewal and differentiation potential of a given population of satellite cells using an assay involving transplantation into injured, regenerating muscle together with specific markers for donor cell identity and state of differentiation. In particular, using the Pax7-ZsGreen transgene as a marker of satellite cell state, self-renewal can be quantified by FACS on transplanted muscle to actually count the total number of resident satellite cells at time points following transplantation. PMID- 27492173 TI - Noninvasive Tracking of Quiescent and Activated Muscle Stem Cell (MuSC) Engraftment Dynamics In Vivo. AB - Muscle stem cells play a central role in muscle regeneration. Most studies in the field of muscle regeneration focus on the unraveling of muscle stem cell biology to devise strategies for treating failing muscles as seen in aging and muscle related diseases. However, the common method used in assessing stem cell function in vivo is laborious, as it involves time-consuming immunohistological analyses by microscopy on serial cryo-sections of the muscle post stem cell transplantation. Here we describe an alternative method, which adapts the bioluminescence imaging (BLI) technique to allow noninvasive tracking of engrafted stem-cell function in vivo in real-time. This assay system enables longitudinal studies in the same mice over time and reveals parameters, not feasible by traditional analysis, such as the magnitude and dynamics of engrafted muscle stem cell expansion in vivo in response to a particular drug treatment or muscle injury. PMID- 27492174 TI - Myogenic Progenitors from Mouse Pluripotent Stem Cells for Muscle Regeneration. AB - Muscle homeostasis is maintained by resident stem cells which, in both pathologic and non-pathologic conditions, are able to repair or generate new muscle fibers. Although muscle stem cells have tremendous regenerative potential, their application in cell therapy protocols is prevented by several restrictions, including the limited ability to grow ex vivo. Since pluripotent stem cells have the unique potential to both self-renew and expand almost indefinitely, they have become an attractive source of progenitors for regenerative medicine studies. Our lab has demonstrated that embryonic stem cell (ES)-derived myogenic progenitors retain the ability to repair existing muscle fibers and contribute to the pool of resident stem cells. Because of their relevance in both cell therapy and disease modeling, in this chapter we describe the protocol to derive myogenic progenitors from murine ES cells followed by their intramuscular delivery in a murine muscular dystrophy model. PMID- 27492175 TI - Assaying Human Myogenic Progenitor Cell Activity by Reconstitution of Muscle Fibers and Satellite Cells in Immunodeficient Mice. AB - Comparing the functional myogenic potential of various human cell populations is an important step in the preclinical evaluation of cell transplantation as a means to treat human muscle disease and degeneration. Culture systems allow one to gage the potential of cell populations to proliferate and undergo myogenic differentiation under specific conditions. An in vivo assay evaluates the ability of cells to differentiate and generate muscle fibers within a natural environment, and importantly, evaluates the potential of donor cells to reconstitute the satellite cell niche. In this chapter, we describe a technique for isolating mononuclear cells from human muscle samples, and a method of xenotransplantation for assessing functional myogenic potential in vivo. Briefly, cell populations are injected into the pre-irradiated and regenerating muscle of immunodeficient mice. The injected muscle is frozen at specific time points after injection and cryosections analyzed by immunostaining. The number of human dystrophin-expressing fibers and the number of Pax7(+) human lamin A/C(+) nuclei are determined, which provides a quantitative method of comparing the in vivo functional potential of cell populations. PMID- 27492176 TI - Methods for Mitochondria and Mitophagy Flux Analyses in Stem Cells of Resting and Regenerating Skeletal Muscle. AB - Mitochondria generate most of the cell's supply of ATP as a source of energy. They are also implicated in the control of cell's growth and death. Because of these critical functions, mitochondrial fitness is key for cellular homeostasis. Often, however, mitochondria become defective following damage or stress. To prevent accumulation of damaged mitochondria, the cells clear them through mitophagy, which is defined as the selective degradation of mitochondria by autophagy (the process for degradation of long-lived proteins and damaged organelles in lysosomes). Recently, constitutive mitophagic activity has been reported in quiescent muscle stem cells (satellite cells), which sustain regeneration of skeletal muscle. In response to muscle damage, these cells activate, expand, and differentiate to repair damaged myofibers. Mitophagy was shown to be required for maintenance of satellite cells in their healthy quiescent state. Conversely, damaged mitochondria accumulated in satellite cells with aging and this was attributed to defective mitophagy. This caused increased levels of reactive oxygen species (ROS) and loss of muscle stem cell regenerative capacity at old age. In this chapter, we describe different experimental strategies to evaluate mitochondria status and mitophagy in muscle stem cells from mice. They should improve our ability to study muscle stem homeostasis in adult life, and their loss of function in aging and disease. PMID- 27492177 TI - Identification, Isolation, and Characterization of Mesenchymal Progenitors in Mouse and Human Skeletal Muscle. AB - Mesenchymal progenitors residing in the muscle interstitial space contribute to pathogeneses such as fat infiltration and fibrosis. Because fat infiltration and fibrosis are hallmarks of diseased muscle, it is important to establish an accurate and reproducible method for isolating mesenchymal progenitors for research on muscle diseases. In this chapter, we describe methods based on fluorescence-activated cell sorting (FACS) to purify mesenchymal progenitors from mouse and human skeletal muscle using the most reliable marker for mesenchymal progenitors, PDGFRalpha. These methods allow concurrent isolation of the muscle stem cells called satellite cells. The quality of isolated mesenchymal progenitors is confirmed by their remarkable adipogenic potential without myogenic capacity, while purified satellite cells possess robust myogenic activity with no adipogenic potential. Simultaneous isolation of both mesenchymal progenitors and satellite cells from mouse and human tissues provides a powerful platform for studying skeletal muscle regeneration and diseases. PMID- 27492178 TI - FACS Fractionation and Differentiation of Skeletal-Muscle Resident Multipotent Tie2+ Progenitors. AB - The skeletal muscle niche is complex and heterogeneous. Over the past few decades, various groups have reported the existence of multiple adult stem cell populations within this environment. Techniques commonly used to identify and assess the differentiation capacities of these cellular fractions, oftentimes rare populations, include the use of lineage tracers, immunofluorescence and histochemistry, flow cytometry, gene expression assays, and phenotypic analysis in culture or in vivo. In 2012, our lab identified and characterized a skeletal muscle resident Tie2+ progenitor that exhibits adipogenic, chondrogenic, and osteogenic differentiation potentials (Wosczyna et al., J Bone Miner Res 27:1004 1017, 2012). This Tie2+ progenitor also expresses the markers PDGFRalpha and Sca 1 which in turn label a population of muscle-resident fibro/adipogenic progenitors (FAPs) (Joe et al., Nat Cell Biol 12:153-163, 2010; Uezumi et al., Nat Cell Biol 12:143-152, 2010), suggesting similar identities or overlap in the two mesenchymal progenitor populations. Our study demonstrated that these Tie2 expressing mesenchymal progenitors contribute robustly to BMP-induced heterotopic ossification (HO) in mice, and therefore could represent a key cellular target for therapeutic intervention in HO treatment (Wosczyna et al., J Bone Miner Res 27:1004-1017, 2012). In this chapter, we provide a detailed description of our updated fluorescence-activated cell sorting (FACS) strategy and describe cell culture methods for differentiation of Tie2+ progenitors to adipogenic and osteogenic fates. This strategy is easily adaptable for the prospective isolation of other rare subpopulations resident in skeletal muscle. PMID- 27492179 TI - In Vitro Assays to Determine Skeletal Muscle Physiologic Function. AB - In vitro muscle contractile function assays are important to characterize the differences between different muscle types (e.g., slow vs. fast), between a diseased and non-diseased muscle, or importantly, to demonstrate the efficacy of a muscle treatment such as a drug, an overexpressed transgene, or knockout of a specific gene. Fundamental contractile properties can be assessed by twitch, tetanic, force-frequency, force-velocity, and fatigue assays. Many of these assays are conducted with the muscle at a constant length, e.g., an isometric contraction. However, to better represent the dynamic purpose of muscles in vivo (e.g., to move limbs), dynamic assays such as the force-velocity (concentric contractions) or stretch-injury (eccentric contractions) should also be obtained. Characterizing skeletal muscle function in vitro is a powerful approach to demonstrate efficacy of a treatment to rescue diseased muscle and to assess functional regeneration. PMID- 27492180 TI - In Vivo Assessment of Muscle Contractility in Animal Studies. AB - In patients with muscle injury or muscle disease, assessment of muscle damage is typically limited to clinical signs, such as tenderness, strength, range of motion, and more recently, imaging studies. Animal models provide unmitigated access to histological samples, which provide a "direct measure" of damage. However, even with unconstrained access to tissue morphology and biochemistry assays, the findings typically do not account for loss of muscle function. Thus, the most comprehensive measure of the overall health of the muscle is assessment of its primary function, which is to produce contractile force. The majority of animal models testing contractile force have been limited to the muscle groups moving the ankle, with advantages and disadvantages depending on the equipment. Here, we describe in vivo methods to measure torque, to produce a reliable muscle injury, and to follow muscle function within the same animal over time. We also describe in vivo methods to measure tension in the leg and thigh muscles. PMID- 27492181 TI - Functional Measurement of Respiratory Muscle Motor Behaviors Using Transdiaphragmatic Pressure. AB - The diaphragm muscle must be able to generate sufficient forces to accomplish a range of ventilatory and non-ventilatory behaviors throughout life. Measurements of transdiaphragmatic pressure (Pdi) can be conducted during eupnea, hypoxia (10 % O2)-hypercapnia (5 % CO2), chemical airway stimulation (i.e., sneezing), spontaneously occurring deep breaths (i.e., sighs), sustained airway or tracheal occlusion, and maximal efforts elicited via bilateral phrenic nerve stimulation, representing the full range of motor behaviors available by the diaphragm muscle. We provide detailed methods on the in vivo measurements of Pdi in mice. PMID- 27492183 TI - Analysis of Aerobic Respiration in Intact Skeletal Muscle Tissue by Microplate Based Respirometry. AB - Mitochondrial function is a key component of skeletal muscle health, and its dysfunction has been associated with a wide variety of diseases. Microplate-based respirometry measures aerobic respiration of live cells through extracellular changes in oxygen concentration. Here, we describe a methodology to measure aerobic respiration of intact murine skeletal muscle tissue. The tissues are not cultured, permeabilized, or enzymatically dissociated to single fibers, so there is minimal experimental manipulation affecting the samples prior to acquiring measurements. PMID- 27492182 TI - Assessment of the Contractile Properties of Permeabilized Skeletal Muscle Fibers. AB - Permeabilized individual skeletal muscle fibers offer the opportunity to evaluate contractile behavior in a system that is greatly simplified, yet physiologically relevant. Here we describe the steps required to prepare, permeabilize and preserve small samples of skeletal muscle. We then detail the procedures used to isolate individual fiber segments and attach them to an experimental apparatus for the purpose of controlling activation and measuring force generation. We also describe our technique for estimating the cross-sectional area of fiber segments. The area measurement is necessary for normalizing the absolute force to obtain specific force, a measure of the intrinsic force-generating capability of the contractile system. PMID- 27492184 TI - [Heterochromia and unilateral iris nodules]. PMID- 27492185 TI - Impact of disability status on suicide risks in South Korea: Analysis of National Health Insurance cohort data from 2003 to 2013. AB - BACKGROUND: The elevated risk of suicide in people with disability has been suggested in the previous studies; however, the majority of study results have been limited to specific disability types, and there is a lack of research comparing the risk of suicide in people with disability in general. OBJECTIVES: To examine the hazard ratio of suicide according to the presence and the types of disability and identify patterns in the results. METHODS: In this study, we used National Health Insurance Service-National Sample Cohort data on 990,598 people, and performed analysis on the cause of death from 2003 through 2013. A Cox proportional hazard model was used to estimate the hazard ratio of suicide associated with disability and its types. RESULTS: The hazard ratio of suicide among people with disability was 1.9-folds higher compared to people without disability. The risk of suicide among different disability types was higher in mental disorder, renal failure, brain injury and physical disability. The hazard ratio of suicide in people with disability was not varied by income. The time to death by suicide for people with disability from the onset of their disability was 39.8 months on average. CONCLUSIONS: Our findings suggest that when the government plans suicide prevention policies, early and additional interventions specific to people with disability are needed. Disability due to mental disorder, renal failure should be given priority. PMID- 27492187 TI - Practical Counseling Skills for the Pediatrician in the Indian Context: Correspondence. PMID- 27492186 TI - Corynebacterium glutamicum possesses beta-N-acetylglucosaminidase. AB - BACKGROUND: In Gram-positive Corynebacterium glutamicum and other members of the suborder Corynebacterianeae, which includes mycobacteria, cell elongation and peptidoglycan biosynthesis is mainly due to polar growth. C. glutamicum lacks an uptake system for the peptidoglycan constituent N-acetylglucosamine (GlcNAc), but is able to catabolize GlcNAc-6-phosphate. Due to its importance in white biotechnology and in order to ensure more sustainable processes based on non-food renewables and to reduce feedstock costs, C. glutamicum strains have previously been engineered to produce amino acids from GlcNAc. GlcNAc also is a constituent of chitin, but it is unknown if C. glutamicum possesses chitinolytic enzymes. RESULTS: Chitin was shown here not to be growth substrate for C. glutamicum. However, its genome encodes a putative N-acetylglucosaminidase. The nagA 2 gene product was active as beta-N-acetylglucosaminidase with 0.27 mM 4-nitrophenyl N,N'-diacetyl-beta-D-chitobioside as substrate supporting half-maximal activity. NagA2 was secreted into the culture medium when overproduced with TAT and Sec dependent signal peptides, while it remained cytoplasmic when overproduced without signal peptide. Heterologous expression of exochitinase gene chiB from Serratia marcescens resulted in chitinolytic activity and ChiB secretion was enhanced when a signal peptide from C. glutamicum was used. Colloidal chitin did not support growth of a strain secreting exochitinase ChiB and beta-N acetylglucosaminidase NagA2. CONCLUSIONS: C. glutamicum possesses beta-N acetylglucosaminidase. In the wild type, beta-N-acetylglucosaminidase activity was too low to be detected. However, overproduction of the enzyme fused to TAT or Sec signal peptides led to secretion of active beta-N-acetylglucosaminidase. The finding that concomitant secretion of endogenous NagA2 and exochitinase ChiB from S. marcescens did not entail growth with colloidal chitin as sole or combined carbon source, may indicate the requirement for higher or additional enzyme activities such as processive chitinase or endochitinase activities. PMID- 27492188 TI - Influence of sperm DNA damage on human preimplantation embryo metabolism. AB - Understanding the embryo metabolic response to sperm induced specific abnormalities could help in developing the metabolic markers to prevent the transfer of embryos carrying sperm mediated defects. In this study, NMR based metabolic profiling of the embryo spent media was employed in 34 patients undergoing ICSI cycles. Processed ejaculates were tested for DNA damage using comet assay. Relative intensities of the metabolites from 74 embryo spent media samples from 34 patients and 23 medium controls were profiled using 1H NMR and compared between 'male-factor' and control groups. Relative intensities in the subgroups which are independent of patients with male factor or tubal factors, but related to the extent of sperm DNA damage were also compared. Sperm characteristics including DNA damage levels (Olive tail moment, OTM) were significantly different between 'male factor' and control groups (P<0.001 0.0001). Of the metabolites analyzed, glutamine intensity was significantly lower in 'male factor' group (P<0.01) whereas, pyruvate intensity was significantly lower in embryos derived from the processed sperm fraction having <1.0 OTM (P=0.003). In contrast glutamine and alanine intensities were significantly higher in the embryos derived from sperm population having OTM <1.0. (P=0.03 & 0.005 respectively). Pyruvate to alanine ratio was significantly lower in <1.0 OTM group (P<0.0001). This study indicates that increased level of sperm DNA damage in the processed ejaculate affects embryo metabolism which could be related to embryonic genetic integrity. PMID- 27492189 TI - Posttraumatic Stress Disorder (PTSD) Patients Exhibit a Blunted Parasympathetic Response to an Emotional Stressor. AB - Diminished parasympathetic reactivity is a physiological feature of posttraumatic stress disorder (PTSD). The objective of this study was to compare female PTSD patients with non-traumatized healthy women with respect to autonomic cardiovascular regulation during exposure to two stressors. Hospitalized PTSD patients (n = 52) and controls (n = 37) completed standardized laboratory-based stress testing including a mental arithmetic test and a standardized audiotape recording of a crying infant. Controls and PTSD patients both showed a significantly increased heart rate and reduced pre-ejection period from baseline rest to the arithmetic stressor. However, as judged from nonsignificant changes in baroreflex sensitivity, parasympathetic activation caused by the crying infant stressor was blunted in PTSD patients as compared to healthy individuals. Under the crying infant condition, a vagal dominance was observed only in controls, and not in PTSD patients. Our data demonstrate that, in PTSD patients, diminished parasympathetic reactivity is not restricted to trauma-related events but can also be observed in response to a social stimulus such as listening to a crying infant. This finding suggests that the altered vagal reactivity in PTSD patients reflects the physiological consequences of a generally disturbed autonomous response to emotionally relevant stressors. PMID- 27492190 TI - Arguing against the proposed definition changes of PD. AB - As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article titled "Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease." In particular, we suggest that the 1-year rule distinguishing Parkinson's disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice and clinical and basic science research and when helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, "PD (dementia with Lewy bodies subtype)," will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions. (c) 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 27492192 TI - State diagram for adhesion dynamics of deformable capsules under shear flow. AB - Due to the significance of understanding the underlying mechanisms of cell adhesion in biological processes and cell capture in biomedical applications, we numerically investigate the adhesion dynamics of deformable capsules under shear flow by using a three-dimensional computational fluid dynamic model. This model is based on the coupling of the front tracking-finite element method for elastic mechanics of the capsule membrane and the adhesion kinetics simulation for adhesive interactions between capsules and functionalized surfaces. Using this model, three distinct adhesion dynamic states are predicted, such as detachment, rolling and firm-adhesion. Specifically, the effects of capsule deformability quantified by the capillary number on the transitions of these three dynamic states are investigated by developing an adhesion dynamic state diagram for the first time. At low capillary numbers (e.g. Ca < 0.0075), whole-capsule deformation confers the capsule a flattened bottom in contact with the functionalized surface, which hence promotes the rolling-to-firm-adhesion transition. It is consistent with the observations from previous studies that cell deformation promotes the adhesion of cells lying in the rolling regime. However, it is surprising to find that, at relatively high capillary numbers (e.g. 0.0075 < Ca < 0.0175), the effect of capsule deformability on its adhesion dynamics is far more complex than just promoting adhesion. High deformability of capsules makes their bottom take a concave shape with no adhesion bond formation in the middle. The appearance of this specific capsule shape inhibits the transitions of both rolling-to-firm-adhesion and detachment-to-rolling, and it means that capsule deformation no longer promotes the capsule adhesion. Besides, it is interesting to note that, when the capillary number exceeds a critical value (e.g. Ca = 0.0175), the rolling state no longer appears, since capsules exhibit large deviation from the spherical shape. PMID- 27492191 TI - Regulation of macrophage polarization and plasticity by complex activation signals. AB - Macrophages are versatile cells of the immune system that play an important role in both advancing and resolving inflammation. Macrophage activation has been described as a continuum, and different stimuli lead to M1, M2, or mixed phenotypes. In addition, macrophages expressing markers associated with both M1 and M2 function are observed in vivo. Using flow cytometry, we examine how macrophage populations respond to combined M1 and M2 activation signals, presented either simultaneously or sequentially. We demonstrate that macrophages exposed to a combination of LPS, IFN-gamma, IL-4, and IL-13 acquire a mixed activation state, with individual cells expressing both M1 marker CD86 and M2 marker CD206 instead of polarizing to discrete phenotypes. Over time, co stimulated macrophages lose expression of CD86 and display increased expression of CD206. In addition, we find that exposure to LPS/IFN-gamma potentiates the subsequent response to IL-4/IL-13, whereas pre-polarization with IL-4/IL-13 inhibits the response to LPS/IFN-gamma. Mathematical modeling of candidate regulatory networks indicates that a complex inter-dependence of M1- and M2 associated pathways underlies macrophage activation. Specifically, a mutual inhibition motif was not by itself sufficient to reproduce the temporal marker expression data; incoherent feed-forward of M1 activation as well as both inhibition and activation of M2 by M1 were required. Together these results corroborate a continuum model of macrophage activation and demonstrate that phenotypic markers evolve with time and with exposure to complex signals. PMID- 27492193 TI - Anti-inflammatory properties of pterocarpanquinone LQB-118 in mice. AB - Pterocarpanquinone (+/-)-LQB-118 presents antineoplastic and antiparasitic properties and also shows great inhibitory effect on TNF-alpha release in vitro. Here, its anti-inflammatory activity was evaluated in a lipopolysaccharide (LPS) induced lung inflammation model in C57BL/6 mice. LPS inhalation induced a marked neutrophil infiltration to the lungs which was reduced by intraperitoneal treatment with (+/-)-LQB-118 in a similar manner to that of dexamethasone and even better than that of acetylsalicylic acid. Moreover, (+/-)-LQB-118 administration resulted in decrease of NF-kappaB activation and KC level in lungs, with a pronounced inhibitory effect on TNF-alpha release, measured in bronchoalveolar lavage fluid. Trying to understand the anti-inflammatory mechanism by which (+/-)-LQB-118 acts, we performed a molecular modeling analysis, including docking to estrogen receptors alpha and beta. Results suggested that (+/-)-LQB-118 may bind to both receptors, with a similar orientation to 17-beta-estradiol. Together, these results showed that (+/-)-LQB 118 exhibits an anti-inflammatory effect, most likely by inhibiting TNF-alpha release and NF-kappaB activation, which may be related to the estrogen receptor binding. PMID- 27492194 TI - 3-Arylpropionylhydroxamic acid derivatives as Helicobacter pylori urease inhibitors: Synthesis, molecular docking and biological evaluation. AB - Helicobacter pylori urease is involved in several physiologic responses such as stomach and duodenal ulcers, adenocarcinomas and stomach lymphomas. Thus, inhibition of urease is taken for a good chance to treat H. pylori-caused infections, we have therefore focused our efforts on seeking novel urease inhibitors. Here, a series of arylpropionylhydroxamic acids were synthesized and evaluated for urease inhibition. Out of these compounds, 3-(2-benzyloxy-5 chlorophenyl)-3-hydroxypropionylhydroxamic acid (d24) was the most active inhibitor with IC50 of 0.15+/-0.05MUM, showing a mixed inhibition with both competitive and uncompetitive aspects. Non-linear fitting of kinetic data gives kinetics parameters of 0.13 and 0.12MUg.mL(-1) for Ki and Ki', respectively. The plasma protein binding assays suggested that d24 exhibited moderate binding to human and rabbit plasma proteins. PMID- 27492195 TI - Cholinesterase inhibitory activity of isoquinoline alkaloids from three Cryptocarya species (Lauraceae). AB - Alzheimer's disease is the most common form of dementia among older adults. Acetylcholinesterase and butyrylcholinesterase are two enzymes involved in the breaking down of the neurotransmitter acetylcholine. Inhibitors for these enzymes have potential to prolong the availability of acetylcholine. Hence, the search for such inhibitors especially from natural products is needed in developing potential drugs for Alzheimer's disease. The present study investigates the cholinesterase inhibitory activity of compounds isolated from three Cryptocarya species towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Nine alkaloids were isolated; (+)-nornantenine 1, (-)-desmethylsecoantofine 2, (+)-oridine 3, (+)-laurotetanine 4 from the leaves of Cryptocarya densiflora BI., atherosperminine 5, (+)-N-methylisococlaurine 6, (+)-N-methyllaurotetanine 7 from the bark of Cryptocarya infectoria Miq., 2-methoxyatherosperminine 8 and (+) reticuline 9 from the bark of Cryptocarya griffithiana Wight. In general, most of the alkaloids showed higher inhibition towards BChE as compared to AChE. The phenanthrene type alkaloid; 2-methoxyatherosperminine 8, exhibited the most potent inhibition against BChE with IC50 value of 3.95MUM. Analysis of the Lineweaver-Burk (LB) plot of BChE activity over a range of substrate concentration suggested that 2-methoxyatherosperminine 8 exhibited mixed-mode inhibition with an inhibition constant (Ki) of 6.72MUM. Molecular docking studies revealed that 2-methoxyatherosperminine 8 docked well at the choline binding site and catalytic triad of hBChE (butyrylcholinesterase from Homo sapiens); hydrogen bonding with Tyr 128 and His 438 residues respectively. PMID- 27492196 TI - The development of peptide ligands that target helix 69 rRNA of bacterial ribosomes. AB - Antibiotic resistance prevents successful treatment of common bacterial infections, making it clear that new target locations and drugs are required to resolve this ongoing challenge. The bacterial ribosome is a common target for antibacterials due to its essential contribution to cell viability. The focus of this work is a region of the ribosome called helix 69 (H69), which was recently identified as a secondary target site for aminoglycoside antibiotics. H69 has key roles in essential ribosomal processes such as subunit association, ribosome recycling, and tRNA selection. Conserved across phylogeny, bacterial H69 also contains two pseudouridines and one 3-methylpseudouridine. Phage display revealed a heptameric peptide sequence that targeted H69. Using solid-phase synthesis, peptide variants with higher affinity and improved selectivity to modified H69 were generated. Electrospray ionization mass spectrometry was used to determine relative apparent dissociation constants of the RNA-peptide complexes. PMID- 27492197 TI - The life cycle of Thelohanellus kitauei (Myxozoa: Myxosporea) infecting common carp (Cyprinus carpio) involves aurantiactinomyxon in Branchiura sowerbyi. AB - Thelohanellus kitauei is a freshwater myxosporean parasite causing intestinal giant cystic disease of common carp. To clarify the life cycle of T. kitauei, we investigated the oligochaete populations in China and Hungary. This study confirms two distinct aurantiactinomyxon morphotypes (Aurantiactinomyxon type 1 and Aurantiactinomyxon type 2) from Branchiura sowerbyi as developmental stages of the life cycle of T. kitauei. The morphological characteristics and DNA sequences of these two types are described here. Based on 18S rDNA sequence analysis, Aurantiactinomyxon type 1 (2048 bp) and Aurantiactinomyxon type 2 (2031 bp) share 99.2-99.4 %, 99.8-100 % similarity to the published sequences of T. kitauei, respectively. The 18S rDNA sequences of these two aurantiactinomyxon morphotypes share 99.4 % similarity, suggesting intraspecific variation within the taxon, possibly due to geographic origin. Phylogenetic analyses demonstrate the two aurantiactinomyxon types clustered with T. kitauei. Regardless, based on 18S rDNA synonymy, it is likely that Aurantiactinomyxon type 1 and 2 are conspecific with T. kitauei. This is the fourth elucidated two-host life cycle of Thelohanellus species and the first record of T. kitauei in Europe. PMID- 27492198 TI - Sinuolinea niloticus n. sp., a myxozoan parasite that causes disease in Nile tilapia (Oreochromis niloticus). AB - Sinuolinea species are myxozoans of the order Bivalvulida, suborder Variisporina, and family Sinuolineidae, which can be parasites for freshwater and marine fish. The aim of this study was to describe the occurrence of Sinuolinea niloticus n. sp. infecting Nile tilapia (Oreochromis niloticus) from aquaculture and from river sources with morphological and molecular analyses. Between March 2010 and November 2012, 116 Nile tilapia were randomly sampled from aquaculture net fishing (n = 56) in Mira Estrela, Sao Paulo, and from the Capivari River (n = 60) in Botucatu, Sao Paulo. The fishes that were sampled were examined by necropsy, microscopic observation and molecular techniques for detection and identification of the myxozoan causing disease in tilapia. All of the tissues that were sampled for analysis showed the presence of the parasite. It was observed by microscopy that the myxozoan belongs to the Sinuolinea genus. This identification was performed based on morphological characteristics and histopathology findings, such as structures consistent with myxozoan in the interstices in all analysed tissues, coagulative necrosis, haemorrhage, inflammatory processes, presence of melano-macrophages and eosinophils. The results of the molecular analyses revealed that the myxozoan detected and identified in this study is sister to a group of other Sinuolinea species. Because this is the first report of this parasite in Nile tilapia, the parasite was named S. niloticus n. sp. This is the first report of a Sinuolinea species in Brazil and in tilapia. PMID- 27492199 TI - Morphological and molecular identification of nasopharyngeal bot fly larvae infesting red deer (Cervus elaphus) in Austria. AB - Nasopharyngeal myiases are caused by larvae of bot flies (Diptera: Oestridae), which have evolved a high specificity for their hosts. Bot flies (n = 916) were collected from 137 (57.6 %) out of 238 red deer (Cervus elaphus) hunted in Vorarlberg and Tyrol (Western Austria). After being stored in 75 % ethanol, larvae were identified to species level and developmental stage using morphological and morphometric keys. Larvae were also molecularly characterized by polymerase chain reaction (PCR) amplification and partial sequencing of the mitochondrial cytochrome oxidase subunit I gene. Morphological and molecular analysis allowed identification of larvae as Cephenemyia auribarbis and Pharyngomyia picta. Genetic variations were also examined within the specimens collected in both geographical locations. PMID- 27492200 TI - Antimalarial potential of leaves of Chenopodium ambrosioides L. AB - In an effort to identify novel therapeutic alternatives for the treatment of malaria, the present study evaluated the antimalarial effect of the crude hydroalcoholic extract (HCE) from the leaves of Chenopodium ambrosioides L. For this purpose, the molecular affinity between the total proteins from erythrocytes infected with Plasmodium falciparum and HCE or chloroquine was evaluated by surface plasmon resonance (SPR). Subsequently, the plasmodicidal potential of HCE was assessed in a P. falciparum culture. Using BALB/c mice infected with Plasmodium berghei intraperitoneally (ip.), we evaluated the effects of ip. treatment, for three consecutive days (day 7, 8, and 9 after infection), with chloroquine (45 mg/kg) or HCE (5 mg/kg), considering the survival index and the parasitaemia. The groups were compared to an untreated control group that receives only PBS at the same periods. The results indicated that HCE could bind to the total proteins of infected erythrocytes and could inhibit the parasite growth in vitro (IC50 = 25.4 g/mL). The in vivo therapeutic treatment with HCE increased the survival and decreased the parasitaemia in the infected animals. Therefore, the HCE treatment exhibited a significant antiplasmodial effect and may be considered as a potential candidate for the development of new antimalarial drugs. PMID- 27492201 TI - Microbiota from Rhabditis regina may alter nematode entomopathogenicity. AB - Here we report the presence of the entomopathogenic nematode Rhabditis (Rhabditoides) regina affecting white grubs (Phyllophaga sp. and Anomala sp.) in Mexico and R. regina-associated bacteria. Bioassays were performed to test the entomopathogenic capacity of dauer and L2 and L3 (combined) larval stages. Furthermore, we determined the diversity of bacteria from laboratory nematodes cultivated for 2 years (dauer and L2-L3 larvae) and from field nematodes (dauer and L2-L3 larvae) in addition to the virulence in Galleria mellonella larvae of some bacterial species from both laboratory and field nematodes. Dauer and non dauer larvae of R. regina killed G. mellonella. Bacteria such as Serratia sp. (isolated from field nematodes) and Klebsiella sp. (isolated from larvae of laboratory and field nematodes) may explain R. regina entomopathogenic capabilities. Different bacteria were found in nematodes after subculturing in the laboratory suggesting that R. regina may acquire bacteria in different environments. However, there were some consistently found bacteria from laboratory and field nematodes such as Pseudochrobactrum sp., Comamonas sp., Alcaligenes sp., Klebsiella sp., Acinetobacter sp., and Leucobacter sp. that may constitute the nematode microbiome. Results showed that some bacteria contributing to entomopathogenicity may be lost in the laboratory representing a disadvantage when nematodes are cultivated to be used for biological control. PMID- 27492202 TI - Cardiac and respiration induced motion of mediastinal lymph node targets in lung cancer patients throughout the radiotherapy treatment course. AB - BACKGROUND AND PURPOSE: Involved mediastinal lymph nodes (LNs) are often included in the radiotherapy target for lung cancer patients. Their motion may differ from the primary tumor motion, possibly undermining the loco-regional control. This study determines the detailed differential target motion throughout the treatment course. MATERIAL AND METHODS: Ten lung cancer patients with 2-4 fiducial markers implanted in LN targets received IMRT with a daily pre-treatment cone-beam CT (CBCT) scan. Offline, the 3D trajectory of the markers was determined from their projected trajectory in the CBCT projections. Frequency analysis was performed to separate the intrafraction motion into a respiratory and cardiac component. The mean setup error of the markers and the motion range were used to calculate margins required for LN targets when setup is based on soft-tissue match. RESULTS: Respiration motion was largest in the CC direction and more prominent for more caudal LNs. Cardiac motion was often (73%) largest in the AP direction and tended to be largest for more cranial LNs. Margins for intrafraction motion and daily baseline shifts of LNs were 4.8mm (LR), 6.0mm (CC) and 6.7mm (AP). CONCLUSIONS: Detailed mapping showed that LN motion was in general governed by breathing, but some LNs had substantial cardiac induced motion. PMID- 27492203 TI - Comparative evaluation of respiratory-gated and ungated FDG-PET for target volume definition in radiotherapy treatment planning for pancreatic cancer. AB - OBJECTIVE: The purpose of this study was to evaluate the usefulness of respiratory-gated positron emission tomography (4D-PET) in pancreatic cancer radiotherapy treatment planning (RTTP). MATERIALS AND METHODS: Fourteen patients with 18F-fluorodeoxyglucose (FDG)-avid pancreatic tumours were evaluated between December 2013 and March 2015. Two sets of volumes were contoured for the pancreatic tumour of each patient. The biological target volume in three dimensional RTTP (BTV3D) was contoured using conventional respiratory un-gated PET. The BTV3D was then expanded using population-based margins to generate a series of internal target volume 3D (ITV3D) values. The ITV 4D (ITV4D) was contoured using 4D-PET. Each of the five phases of 4D-PET was used for 4D contouring, and the ITV4D was constructed by summing the volumes defined on the five individual 4D-PET images. The relative volumes and normalized volumetric overlap were computed between ITV3D and ITV4D. RESULTS: On average, the FDG-avid tumour volumes were 1.6 (range: 0.8-2.3) fold greater in the ITV4D than in the BTV3D. On average, the ITV3D values were 2.0 (range: 1.1-3.4) fold larger than the corresponding ITV4D values. CONCLUSION: The ITV generated from 4D-PET can be used to improve the accuracy or reduce normal tissue irradiation compared with conventional un-gated PET-based ITV. PMID- 27492204 TI - Post radiation hysterectomy in locally advanced cervical cancer: Outcomes and dosimetric impact. AB - PURPOSES: Firstly, to evaluate the impact of completion hysterectomy after chemoradiation and image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer. Secondly, to assess a potential differential dose effect relationship for the rectum and bladder according to the realization of hysterectomy. MATERIAL AND METHODS: Two cohorts of patients were identified, differing by the realization of completion hysterectomy. Inclusions were limited to FIGO stage I-II, with no para-aortic involvement. All patients received a combination of pelvic chemoradiation followed by IGABT. Their outcomes and morbidity were reviewed. Log-rank tests were used to compare survivals. Probit analyses were performed to study dose-volume effect relationships. RESULTS: The two cohorts comprised 54 patients in the completion surgery group and 157 patients in the definitive radiotherapy group. They were well balanced, except for the mean follow-up, significantly longer in the post hysterectomy cohort and the use of PET-CT in the work-up, more frequent in the definitive radiotherapy cohort. Although less local relapses were reported in the hysterectomy group, the 5-year disease-free and overall survival did not differ between groups. The cumulative incidence of severe late morbidity was significantly increased in the hysterectomy cohort: 22.5% versus 6.5% at 5years (p=0.016). Dose-volume effects were observed for the bladder, with the D2cm3 corresponding with a 10% probability of late severe morbidity urinary events (ED10) of 67.8Gy and 91.9Gy in the hysterectomy and definitive radiotherapy cohorts, respectively. A D90 CTVHR of 85Gy (planning aim) corresponded with a 93.3% rate of local control in the definitive radiotherapy cohort whereas it corresponded with a 77.3% chance to have a good histologic response (complete response or microscopic residual disease) in the hysterectomy group. CONCLUSION: No benefit from completion hysterectomy in terms of overall or disease-free survival rates was observed, which was moreover responsible for an increase of the severe late morbidity. The realization of post-radiation hysterectomy resulted in a shift of the ED10 of 24.1Gy. PMID- 27492205 TI - Measurement of transepidermal water loss (TEWL) in cats with experimental skin barrier dysfunction using a closed chamber system. AB - BACKGROUND: A closed chamber evaporimeter is suitable for measuring transepidermal water loss (TEWL) in cats because of the compact device size, tolerance to sudden movement and short measuring time. TEWL is a representative parameter for skin barrier dysfunction, which is one of the clinical signs of atopic dermatitis in humans and dogs. Measurement of feline TEWL has been reported, but applicability of this parameter has not been validated. HYPOTHESIS/OBJECTIVES: The aims of this study were to determine if tape stripping is a valid experimental model in cats for studying TEWL and to determine if a closed chambered system is a suitable measurement tool for cats. ANIMALS: Ten clinically normal cats. METHODS: In order to evaluate variation of the measured values, TEWL was measured at the right and left side of the three clipped regions (axillae, lateral thigh and groin). Subsequently, TEWL was measured using sequential tape stripping of the stratum corneum as a model of acute barrier disruption. RESULTS: The variations between both sides of the three regions showed no significant difference. Sequential tape stripping was associated with increasing values for TEWL. CONCLUSIONS AND CLINICAL IMPORTANCE: Feline TEWL was shown to reflect changes in the skin barrier in an experimental model using a closed chamber system and has the potential for evaluating skin barrier function in cats with skin diseases. PMID- 27492206 TI - Different Variants in Reverse Transcriptase Domain Determined by Ultra-deep Sequencing in Treatment-naive and Treated Indonesian Patients Infected with Hepatitis B Virus. AB - A nucleos(t)ide analog (NA) is the common antiviral drug available for directly treating hepatitis B virus (HBV) infection. However, its application has led to the emergence of NA-resistant mutations mostly in a conserved region of the reverse transcriptase domain of HBV polymerase. Harboring NA-resistant mutations decreases drug effectiveness and increases the frequency of end-stage liver disease. The invention of next-generation sequencing that can generate thousands of sequences from viral complex mixtures provides opportunities to detect minor changes and early viral evolution under drug stress. The present study used ultra deep sequencing to evaluate discrepant quasispecies in the reverse transcriptase domain of HBV including NA-resistant hotspots between seven treatment-naive Indonesian patients infected with HBV and five at the early phase of treatment. The most common sub-genotype was HBV B3 (83.34%). The substitution rate of variants determined among amino acids with a ratio of >= 1% changes was higher among the population in conserved regions (23.19% vs. 4.59%, P = 0.001) and in the inter-reverse transcriptase domain (23.95% vs. 2.94%, P = 0.002) in treatment naive, than in treated patients. Nine hotspots of antiviral resistance were identified in both groups, and the mean frequency of changes in all patients was < 1%. The known rtM204I mutation was the most frequent in both groups. The lower rate of variants in HBV quasispecies in patients undergoing treatment could be associated with virus elimination and the extinction of sensitive species by NA therapy. The present findings imply that HBV quasispecies dynamically change during treatment. PMID- 27492207 TI - Thrombospondin 1 Suppresses Insulin Signaling in C2C12 Myotubes. AB - Thrombospondin 1 (TSP-1) is abundantly expressed in visceral adipose tissue and this expression is up-regulated in obese humans and rodents. Recent studies showed that genetic deletion of TSP-1 protects mice from diet-induced insulin resistance. However, the molecular mechanism is largely unknown. In this study, we examined the effect of recombinant TSP-1 on insulin signaling in cultured cells from insulin sensitive tissues to investigate whether TSP-1 could act as an adipokine. Here we show that treatment with recombinant TSP-1 suppressed insulin signaling in cultured muscle cells, which was accompanied by the activation of stress signaling such as JNK, p38, and IKK. These results suggest that TSP-1 acts as an adipokine which is involved in the pathogenesis of obesity-induced insulin resistance. Thus, TSP-1 could be a potential target for the treatment of insulin resistance and metabolic disease related to insulin resistance. PMID- 27492208 TI - Recurrence of Enchondroma in a Middle Finger after Curettage and Back-filling with Calcium Phosphate Bone Cement: a Case Report. AB - We report a case of recurrence of enchondroma in a middle finger after curettage and back-filling with calcium phosphate bone cement (CPC). The radiograph showed a lytic lesion around the CPC filling which showed no signs of absorption after 12 years. The tumor was curated easily, however, a steel bar was needed to remove the CPC mass in a carefully manner not to break the cortex. CPC has an advantage of immediate biomechanical stability, on the other hand, a disadvantage of being unabsorbed inside of bone. Although enchondroma has a low recurrence rate after surgery generally, in consideration of recurrence, we recommend the use of absorbable materials when a use of artificial bone substitute to fill the defect is planned. PMID- 27492209 TI - A Case Report of Drug-Induced Thrombocytopenia after Living Donor Liver Transplantation. AB - There are few descriptions of severe thrombocytopenia during the early postoperative period after liver transplantation, and these have not been fully documented in the literature. Here, we report a case of drug-induced thrombocytopenia requiring transfusion of blood products after living donor liver transplantation. We determined that this was not caused by the interferon-free anti-viral therapy but by tacrolimus A 61-year-old woman with hepatitis C-related cirrhosis and hepatorenal syndrome underwent living donor liver transplantation using a left lobe graft from her son. After transplantation, immunosuppression consisted of tacrolimus and steroid. Seven weeks after transplantation, interferon-free therapy with daclatasvir and asunaprevir was started. Thirteen days thereafter, hepatitis C virus tested negative. However, the platelet count had begun to gradually decrease just before starting anti-viral therapy. Daclatasvir and asunaprevir were stopped because this was suspected to be a side effect of these drugs, but the patient nonetheless went on to develop severe thrombocytopenia (platelet count 17,000/MUL), which needed transfusions. Now suspecting tacrolimus as the inducer of this side effect, we changed to cyclosporin, after which the platelet count gradually recovered. Viral markers were still not detectable up to 2 months after discontinuation of the antiviral drugs. We conclude that when severe thrombocytopenia occurs, possible drug induced thrombocytopenia as well as other disorders must be investigated. PMID- 27492210 TI - Heterogeneous Effects of a Nonlinear Price Schedule for Outpatient Care. AB - Nonlinear price schedules generally have heterogeneous effects on health-care demand. We develop and apply a finite mixture bivariate probit model to analyze whether there are heterogeneous reactions to the introduction of a nonlinear price schedule in the German statutory health insurance system. In administrative insurance claims data from the largest German health insurance plan, we find that some individuals strongly react to the new price schedule while a second group of individuals does not react. Post-estimation analyses reveal that the group of the individuals who do not react to the reform includes the relatively sick. These results are in line with forward-looking behavior: Individuals who are already sick expect that they will hit the kink in the price schedule and thus are less sensitive to the co-payment. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27492211 TI - Polylactides in additive biomanufacturing. AB - New advanced manufacturing technologies under the alias of additive biomanufacturing allow the design and fabrication of a range of products from pre operative models, cutting guides and medical devices to scaffolds. The process of printing in 3 dimensions of cells, extracellular matrix (ECM) and biomaterials (bioinks, powders, etc.) to generate in vitro and/or in vivo tissue analogue structures has been termed bioprinting. To further advance in additive biomanufacturing, there are many aspects that we can learn from the wider additive manufacturing (AM) industry, which have progressed tremendously since its introduction into the manufacturing sector. First, this review gives an overview of additive manufacturing and both industry and academia efforts in addressing specific challenges in the AM technologies to drive toward AM-enabled industrial revolution. After which, considerations of poly(lactides) as a biomaterial in additive biomanufacturing are discussed. Challenges in wider additive biomanufacturing field are discussed in terms of (a) biomaterials; (b) computer-aided design, engineering and manufacturing; (c) AM and additive biomanufacturing printers hardware; and (d) system integration. Finally, the outlook for additive biomanufacturing was discussed. PMID- 27492212 TI - Electronic relaxation dynamics of PCDA-PDA studied by transient absorption spectroscopy. AB - Photo-curable polymers originating from 10,12-pentacosadiynoic acid (PCDA-PDA) are commonly used polydiacetylenes (PDAs). PCDA-PDA exhibits thermochromic properties undergoing a unique colorimetric transition from blue to red as the temperature is increased from low to high. In this work, we have carefully studied the temperature-dependent optical properties of PCDA-PDA by using UV visible absorption, FTIR, Raman, and transient absorption (TA) spectroscopy in combination with quantum chemical calculations. Temperature-dependent UV-visible absorption spectra indicate that PCDA-PDA exhibits reversible thermochromic properties up to 60 degrees C and its thermochromic properties become irreversible above 60 degrees C. Such distinct thermochromic properties are also manifested in TA signals so that the electronically excited PCDA-PDA relaxes to the ground state via an intermediate state at 20 degrees C (blue form) but it relaxes directly back to the ground state at 80 degrees C (red form). The electronic relaxation dynamics of PCDA-PDA are comprehensively analyzed based on different kinetic models by using the global fitting analysis method. The intermediate state in the blue form of PCDA-PDA is clearly found to be responsible for fluorescence quenching. FTIR and Raman spectroscopy and quantum chemical calculations confirm that the H-bonds between the carboxylic acid groups in PCDA-PDA are broken at high temperatures leading to an irreversible structural change of PCDA-PDA. PMID- 27492213 TI - Quantitative analysis of aromatics for synthetic biology using liquid chromatography. AB - The replacement of petrochemical aromatics with bio-based molecules is a key area of current biotechnology research. To date, a small number of aromatics have been produced by recombinant bacteria in laboratory scale while industrial production still requires further strain development. While each study includes some distinct analytical methodology to quantify certain aromatics, a method that can reliably quantify a great number of aromatic products and relevant pathway intermediates is needed to accelerate strain development. In this study, we developed a robust reverse phase high performance liquid chromatography method to quantify a wide range of aromatic metabolites present in host microorganisms using the shikimate pathway, which is the major metabolic pathway for biosynthesis of aromatics. Twenty-three metabolites can be quantified precisely with the optimized method using standard HPLC equipment and UV detection, with the mobile phase used for chromatography also compatible with mass spectrometry (MS). The limit of quantification/detection is as low as 10-10 to 10-13 mol, respectively, which makes this method feasible for quantification of intracellular metabolites. This method covers most metabolic routes for aromatics biosynthesis, it is inexpensive, robust, simple, precise and sensitive, and has been demonstrated on cell extracts from S. cerevisiae genetically engineered to overproduce aromatics. PMID- 27492214 TI - Resistance: How to resist immunotherapy. PMID- 27492216 TI - Metastasis: Setting up a new home. PMID- 27492217 TI - B-cell-specific depletion of tumour necrosis factor alpha inhibits atherosclerosis development and plaque vulnerability to rupture by reducing cell death and inflammation. AB - AIMS: B2 lymphocytes promote atherosclerosis development but their mechanisms of action are unknown. Here, we investigated the role of tumour necrosis factor alpha (TNF-alpha) produced by B2 cells in atherogenesis. METHODS AND RESULTS: We found that 50% of TNF-alpha-producing spleen lymphocytes were B2 cells and ~20% of spleen and aortic B cells produced TNF-alpha in hyperlipidemic ApoE(-/-) mice. We generated mixed bone marrow (80% MUMT/20% TNF-alpha(-/-)) chimeric LDLR(-/-) mice where only B cells did not express TNF-alpha. Atherosclerosis was reduced in chimeric LDLR(-/-) mice with TNF-alpha-deficient B cells. TNF-alpha expression in atherosclerotic lesions and in macrophages were also reduced accompanied by fewer apoptotic cells, reduced necrotic cores, and reduced lesion Fas, interleukin 1beta and MCP-1 in mice with TNF-alpha-deficient B cells compared to mice with TNF-alpha-sufficient B cells. To confirm that the reduced atherosclerosis is attributable to B2 cells, we transferred wild-type and TNF-alpha-deficient B2 cells into ApoE(-/-) mice deficient in B cells or in lymphocytes. After 8 weeks of high fat diet, we found that atherosclerosis was increased by wild-type but not TNF-alpha-deficient B2 cells. Lesions of mice with wild-type B2 cells but not TNF-alpha-deficient B2 cells also had increased apoptotic cells and necrotic cores. Transferred B2 cells were found in lesions of recipient mice, suggesting that TNF-alpha-producing B2 cells promote atherosclerosis within lesions. CONCLUSION: We conclude that TNF-alpha produced by B2 cells is a key mechanism by which B2 cells promote atherogenesis through augmenting macrophage TNF-alpha production to induce cell death and inflammation that promote plaque vulnerability. PMID- 27492218 TI - Efficacy of scalp hair decontamination following exposure to vapours of sulphur mustard simulants 2-chloroethyl ethyl sulphide and methyl salicylate. AB - Chemical warfare agents are an actual threat and victims' decontamination is a main concern when mass exposure occurs. Skin decontamination with current protocols has been widely documented, as well as surface decontamination. However, considering hair ability to trap chemicals in vapour phase, we investigated hair decontamination after exposure to sulphur mustard simulants methyl salicylate and 2-chloroethyl ethyl sulphide. Four decontamination protocols were tested on hair, combining showering and emergency decontamination (use of Fuller's earth or Reactive Skin Decontamination Lotion RSDL(r)). Both simulants were recovered from hair after treatment, but contents were significantly reduced (42-85% content allowance). Showering alone was the least efficient protocol. Concerning 2-chloroethyl ethyl sulphide, protocols did not display significant differences in decontamination efficacy. For MeS, use of emergency decontaminants significantly increased showering efficacy (10-20% rise), underlining their usefulness before thorough decontamination. Our results highlighted the need to extensively decontaminate hair after chemical exposure. Residual amounts after decontamination are challenging, as their release from hair could lead to health issues. PMID- 27492219 TI - Transient anomalous diffusion in periodic systems: ergodicity, symmetry breaking and velocity relaxation. AB - We study far from equilibrium transport of a periodically driven inertial Brownian particle moving in a periodic potential. As detected for a SQUID ratchet dynamics, the mean square deviation of the particle position from its average may involve three distinct intermediate, although extended diffusive regimes: initially as superdiffusion, followed by subdiffusion and finally, normal diffusion in the asymptotic long time limit. Even though these anomalies are transient effects, their lifetime can be many, many orders of magnitude longer than the characteristic time scale of the setup and turns out to be extraordinarily sensitive to the system parameters like temperature or the potential asymmetry. In the paper we reveal mechanisms of diffusion anomalies related to ergodicity of the system, symmetry breaking of the periodic potential and ultraslow relaxation of the particle velocity towards its steady state. Similar sequences of the diffusive behaviours could be detected in various systems including, among others, colloidal particles in random potentials, glass forming liquids and granular gases. PMID- 27492220 TI - Diffusion-weighted MRI for detection of hepatic osteodystrophy in primary sclerosing cholangitis: a comparison study with dual-energy X-ray absorptiometry. AB - PURPOSE: Osteodystrophy is a frequent complication in primary sclerosing cholangitis (PSC). The aim was to test the feasibility of vertebral bone diffusion-weighted imaging (DWI) in routine liver MRI for detection of osteoporosis using dual-energy X-ray absorptiometry (DXA) as gold standard. MATERIALS AND METHODS: Forty PSC patients (50 +/- 12.6 years) and ten controls (49.5 +/- 13.0 years) were scanned using a DWI spin echo echo-planar sequence (b factors 0-800 s/mm2) on a 3-T MRI system and DXA (76 kVp). The apparent diffusion coefficient (ADC) and T-score were correlated to laboratory and clinical details using Pearson correlation. RESULTS: In DXA-diagnosed osteoporosis (n = 3) and osteopenia (n = 12), the mean ADC was decreased (0.26 +/- 0.03 and 0.30 +/- 0.07 * 10-3 mm2/s) compared to patients with normal DXA scan results (n = 25; 0.32 +/- 0.06 * 10-3 mm2/s). No significant correlation of the ADC and T-score (r = 0.24; p = 0.13) was found, but the T-score correlated significantly to disease duration (r = -0.33; p = 0.04). In patients with prednisolone therapy (n = 7), the DXA T score was significantly lower (-1.46 +/- 0.49 vs. -0.16 +/- 0.23; p = 0.03). CONCLUSION: Diffusion-weighted MRI of the vertebral spine is a feasible technic to detect diffusion alterations caused by osteoporosis but lacks diagnostic capacities for diagnosing minor reductions of the bone mineral density detected by DXA. PMID- 27492215 TI - From Krebs to clinic: glutamine metabolism to cancer therapy. AB - The resurgence of research into cancer metabolism has recently broadened interests beyond glucose and the Warburg effect to other nutrients, including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting. PMID- 27492221 TI - Editor's Highlight: Evaluation of a Microelectrode Array-Based Assay for Neural Network Ontogeny Using Training Set Chemicals. AB - Thousands of compounds in the environment have not been characterized for developmental neurotoxicity (DNT) hazard. To address this issue, methods to screen compounds rapidly for DNT hazard evaluation are necessary and are being developed for key neurodevelopmental processes. In order to develop an assay for network formation, this study evaluated effects of a training set of chemicals on network ontogeny by measuring spontaneous electrical activity in neural networks grown on microelectrode arrays (MEAs). Rat (0-24 h old) primary cortical cells were plated in 48 well-MEA plates and exposed to 6 compounds: acetaminophen, bisindolylmaleimide-1 (Bis-1), domoic acid, mevastatin, sodium orthovanadate, and loperamide for a period of 12 days. Spontaneous network activity was recorded on days 2, 5, 7, 9, and 12 and viability was assessed using the Cell Titer Blue assay on day 12. Network activity (e.g. mean firing rate [MFR], burst rate [BR], etc), increased between days 5 and 12. Random Forest analysis indicated that across all compounds and times, temporal correlation of firing patterns (r), MFR, BR, number of active electrodes and % of spikes in a burst were the most influential parameters in separating control from treated wells. All compounds except acetaminophen (<= 30 uM) caused concentration-related effects on one or more of these parameters. Domoic acid and sodium orthovanadate altered several of these parameters in the absence of cytotoxicity. Although cytotoxicity was observed with Bis1, mevastatin, and loperamide, some parameters were affected by these compounds at concentrations below those resulting in cytotoxicity. These results demonstrate that this assay may be suitable for screening of compounds for DNT hazard identification. PMID- 27492222 TI - Effect of Repeated Daily Dosing with 2,4-Dinitrochlorobenzene on Glutathione Biosynthesis and Nrf2 Activation in Reconstructed Human Epidermis. AB - Glutathione (GSH) plays a major role in skin detoxification processes due to its ability to conjugate electrophilic exogenous compounds with, and sometimes without, catalysis by glutathione-s-transferase (GST). GST activity has been demonstrated both in skin and in most in vitro skin equivalents but so far studies have focussed on chemical clearance (conjugate identification and rate of conjugation) and did not consider the GSH lifecycle (conjugation, recycling, synthesis). We used the model skin sensitizer 2,4-dinitrochlorobenzene (DNCB) to investigate the effects of chemical exposure on GSH lifecycle in reconstructed human epidermis (RHE). We demonstrated that the RHE model is suitable to carry out repeated cycles of 2-h exposure to DNCB over a 3-day period. After each exposure to DNCB, the level of GSH is diminished in a dose dependent manner. After a 22-h recovery period, GSH is replenished back to initial levels. Accumulation of the nuclear factor E2-related factor 2 (Nrf2) in the cytosol also occurs within the 2 h of exposure to DNCB but returns to baseline during each recovery period, demonstrating that activation of the Nrf2 signaling pathway offers a rapid response to chemical stress. The amount of dinitrophenyl glutathione (DNP-SG) formed with DNCB (1) increased between the first and second exposure and (2) reached a plateau between the second and third exposure. Collectively, these data suggest that the metabolic capacity of skin may not be fixed in time but defence mechanisms might be activated in response to exposure to exogenous compounds, resulting in their accelerated clearance. PMID- 27492223 TI - Dietary Route of Exposure for Rabbit Developmental Toxicity Studies. AB - Dietary administration is a relevant route of oral exposure for regulatory toxicity studies of agrochemicals as it mimics potential human intake of the chemical via treated crops and commodities. Moreover, dietary administration of test compounds during a developmental toxicity study can deliver a prolonged and stable systemic exposure to the embryo or fetus at all stages of development. In this study, strategies were employed to optimize rabbit test material consumption via diet. Comparative toxicokinetic profiles of gavage versus dietary administration were evaluated in pregnant or non-pregnant New Zealand White rabbits for 2 novel agrochemicals with different plasma half-lives of elimination (sulfoxaflor, t1/2 = 13.5 h and halauxifen, t1/2 = 1 h). Dietary administration of sulfoxaflor resulted in stable 24-h plasma concentrations, whereas gavage administration resulted in a 3-fold fluctuation in plasma levels between Cmax and Cmin Dietary administration of sulfoxaflor resulted in a 2-fold higher nominal and diurnal systemic dose when compared with gavage dosing due to Cmax-related maternal toxicity following gavage. Results with the shorter half-life molecule, halauxifen, were more striking with a 6-fold diurnal fluctuation by the dietary route compared with a 368-fold fluctuation between Cmax and Cmin by gavage. Furthermore, plasma halauxifen was detectable only up to 12 h following gavage but up to 24 h following dietary administration. Finally, the presence of these compounds in fetal blood samples was demonstrated, confirming that dietary exposure is appropriate for achieving fetal exposure. Collectively, the results of these studies support the use of dietary exposure in rabbit developmental toxicity studies. PMID- 27492225 TI - From the Cover: Autophagy Induction Contributes to Cadmium Toxicity in Mesenchymal Stem Cells via AMPK/FOXO3a/BECN1 Signaling. AB - Mesenchymal stem cells (MSCs) are a valuable in vitro model for investigating the bone toxicity of cadmium (Cd). Autophagy has been proposed to play a pivotal role in Cd-mediated toxicity. The FOXO family proteins are important transcription factors that are essential to autophagy induction. This study investigated the role of autophagy in Cd-induced skeleton damage and its potential mechanism. We exposed MSCs to different concentrations of cadmium chloride (3.5, 7, and 14 MUM) for 24 h. We demonstrated that Cd treatment increased autophagic flux, and inhibition of autophagic process using BENC1 gene silencing blocked Cd-induced cell death. Cd treatment also significantly increased mRNA levels of various essential autophagy-related genes including ATG5, ATG12, BECN1, LC3, and ULK1. Specifically, Cd increased FOXO3a and FOXO1 expression at the mRNA and protein levels, and AMPK was demonstrated to enhance FOXO3a nuclear translocation and transcriptional activity by phosphorylating FOXO3a at specific serine residues (Ser588) in Cd-treated MSCs. Notably, knockdown of FOXO3a, but not FOXO1, prevented autophagy-related genes expression and autophagosome formation after Cd treatment. Taken together, our results demonstrate that Cd-induced cell death via the overactivation of FOXO3a-dependent autophagy. Modulation of the FOXO3a autophagy pathway may offer novel therapeutic approaches for the treatment of Cd induced bone damage. PMID- 27492224 TI - Comparative Developmental Toxicity of Flavonoids Using an Integrative Zebrafish System. AB - Flavonoids are a large, structurally diverse class of bioactive naturally occurring chemicals commonly detected in breast milk, soy based infant formulas, amniotic fluid, and fetal cord blood. The potential for pervasive early life stage exposures raises concerns for perturbation of embryogenesis, though developmental toxicity and bioactivity information is limited for many flavonoids. Therefore, we evaluated a suite of 24 flavonoid and flavonoid-like chemicals using a zebrafish embryo-larval toxicity bioassay-an alternative model for investigating developmental toxicity of environmentally relevant chemicals. Embryos were exposed to 1-50 uM of each chemical from 6 to 120 h postfertilization (hpf), and assessed for 26 adverse developmental endpoints at 24, 72, and 120 hpf. Behavioral changes were evaluated in morphologically normal animals at 24 and 72 hpf, at 120 hpf using a larval photomotor response (LPR) assay. Gene expression was comparatively evaluated for all compounds for effects on biomarker transcripts indicative of AHR (cyp1a) and ER (cyp19a1b, esr1, lhb, vtg) pathway bioactivity. Overall, 15 of 24 flavonoids elicited adverse effects on one or more of the developmental or behavioral endpoints. Hierarchical clustering and principle component analyses compared toxicity profiles and identified 3 distinct groups of bioactive flavonoids. Despite robust induction of multiple estrogen-responsive biomarkers, co-exposure with ER and GPER antagonists did not ameliorate toxicity, suggesting ER-independence and alternative modes of action. Taken together, these studies demonstrate that development is sensitive to perturbation by bioactive flavonoids in zebrafish that are not related to traditional estrogen receptor mode of action pathways. This integrative zebrafish platform provides a useful framework for evaluating flavonoid developmental toxicity and hazard prioritization. PMID- 27492226 TI - Dietary Omega-3 Polyunsaturated Fatty Acids Prevent Vascular Dysfunction and Attenuate Cytochrome P4501A1 Expression by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin. AB - Omega-3 polyunsaturated fatty acids (n-3 PUFAs) found in fish protect against cardiovascular morbidity and mortality; however, many individuals avoid fish consumption due to concerns about pollutants. We tested the hypothesis that n-3 PUFAs would prevent vascular dysfunction induced by 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD). C57Bl/6 male mice were fed a chow or n-3 PUFA diet for 10 weeks and were exposed to vehicle or 300 ng/kg/d TCDD during the final 2 weeks on each diet. Aortic vasoconstriction mediated by arachidonic acid (AA) +/- SKF525 (P450 inhibitor) or SQ29548 (thromboxane/prostanoid [TP] receptor antagonist) was assessed. RBC fatty acids and expression of n-3 and n-6 PUFA metabolites were analyzed. Cytochrome P4501A1 (CYP1A1), CYP1B1, and aryl hydrocarbon receptor (AHR) expression was measured. TCDD significantly increased AA-mediated vasoconstriction on a chow diet by increasing the contribution of P450s and TP receptor to the constriction response. In contrast, the n-3 PUFA diet prevented the TCDD-induced increase in AA vasoconstriction and normalized the contribution of P450s and TP receptor. Although TCDD increased the levels of AA vasoconstrictors on the chow diet, this increase was prevent by the n-3 PUFA diet. Additionally, the n-3 PUFA diet significantly increased the levels of n-3 PUFA-derived vasodilators and TCDD increased these levels further. Interestingly, the n-3 PUFA diet significantly attenuated CYP1A1 induction by TCDD without a significant effect on AHR expression. These data suggest that n-3 PUFAs can prevent TCDD-induced vascular dysfunction by decreasing vasoconstrictors, increasing vasodilators, and attenuating CYP1A1 induction, which has been shown previously to contribute to TCDD-induced vascular dysfunction. PMID- 27492228 TI - Helminth Infections and Cardiovascular Diseases: Toxocara Species is Contributing to the Disease. AB - Toxocariasis is the clinical term used to describe human infection with either the dog ascarid Toxocara canis or the feline ascarid Toxocara cati. As with other helminths zoonoses, the infective larvae of these Toxocara species cannot mature into adults in the human host. Instead, the worms wander through organs and tissues, mainly the liver, lungs, myocardium, kidney and central nervous system, in a vain attempt to find that, which they need to mature into adults. The migration of these immature nematode larvae causes local and systemic inflammation, resulting in the "larva migrans" syndrome. The clinical manifestations of toxocariasis are divided into visceral larva migrans, ocular larva migrans and neurotoxocariasis. Subclinical infection is often referred to as covert toxocariasis. One of the primary causes of death all around the world is cardiovascular disease that accounted for up to 30 percent of all-cause mortality. Cardiovascular disease and more precisely atherosclerotic cardiovascular disease, is predicted to remain the single leading cause of death (23.3 million deaths by 2030). A-quarter of people presenting the disease does not show any of the known cardiovascular risk factors. Therefore, there is considerable interest in looking for novel components affecting cardiovascular health, especially for those that could improve global cardiovascular risk prediction. This review endeavours to summarize the clinical aspects, new diagnostic and therapeutic perspectives of toxocaral disease with cardiovascular manifestations. PMID- 27492227 TI - Cardiac Imaging in Heart Failure with Comorbidities. AB - Imaging modalities stand at the frontiers for progress in congestive heart failure (CHF) screening, risk stratification and monitoring. Advancements in echocardiography (ECHO) and Magnetic Resonance Imaging (MRI) have allowed for improved tissue characterizations, cardiac motion analysis, and cardiac performance analysis under stress. Common cardiac comorbidities such as hypertension, metabolic syndromes and chronic renal failure contribute to cardiac remodeling, sharing similar pathophysiological mechanisms starting with interstitial changes, structural changes and finally clinical CHF. These imaging techniques can potentially detect changes earlier. Such information could have clinical benefits for screening, planning preventive therapies and risk stratifying patients. Imaging reports have often focused on traditional measures without factoring these novel parameters. This review is aimed at providing a synopsis on how we can use this information to assess and monitor improvements for CHF with comorbidities. PMID- 27492230 TI - Coccidioidomycosis in Patients with Selected Solid Organ Cancers: A Case Series and Review of Medical Literature. AB - Coccidioidomycosis is a common infection in the desert southwestern USA; approximately 3 % of healthy persons in Arizona alone become infected annually. Coccidioidomycosis may be severe in immunocompromised persons, but experience among patients with solid organ cancer has not been fully described. Therefore, we aimed to describe the clinical courses of patients whose cancers were complicated by coccidioidomycosis at our institution, which is located in an area with endemic Coccidioides. To do so, we conducted a retrospective review from January 1, 2000, through December 31, 2014, of all patients with breast, colorectal, or ovarian cancer whose cancer courses were complicated by coccidioidomycosis. We identified 17,576 cancer patients; 14 (0.08 %) of these patients met criteria for proven or probable coccidioidomycosis diagnosed within the first 2 years after the cancer diagnosis. All of these patients had primary pulmonary coccidioidomycosis, none had relapsed prior infection, and 1 had possible extrapulmonary dissemination. Five had active coccidioidal infection during chemotherapy, 1 of whom was hospitalized for coccidioidal pneumonia. All were treated with fluconazole, and all improved clinically. Eleven did not require prolonged courses of fluconazole. There were no clearly demonstrated episodes of relapsed infection. In conclusion, coccidioidomycosis was not a common complication of breast, colorectal, or ovarian cancers in patients treated at our institution, and it was not commonly complicated by severe or disseminated infection. PMID- 27492229 TI - Imaging Subclinical Atherosclerosis: Where Do We Stand? AB - The age of initiation and the rate of progression of atherosclerosis vary markedly among individuals and have been difficult to predict with traditional cardiovascular risk assessment models. Although these risk models provide good discrimination and calibration in certain populations, cardiovascular disease (CVD) risk may not be accurately estimated in low- and intermediate risk individuals. Therefore, imaging techniques such as Ankle-Brachial Index (ABI), Coronary Artery Calcium score (CAC), carotid Intima-Media Thickness (cIMT), flow mediated dilation (FMD) and Positron Emission Tomography (PET) have been developed and used to reclassify these individuals. In the present article we review the role of the most commonly used imaging techniques for CVD risk assessment. PMID- 27492231 TI - SEX-DETector: A Probabilistic Approach to Study Sex Chromosomes in Non-Model Organisms. AB - We propose a probabilistic framework to infer autosomal and sex-linked genes from RNA-seq data of a cross for any sex chromosome type (XY, ZW, and UV). Sex chromosomes (especially the non-recombining and repeat-dense Y, W, U, and V) are notoriously difficult to sequence. Strategies have been developed to obtain partially assembled sex chromosome sequences. Most of them remain difficult to apply to numerous non-model organisms, either because they require a reference genome, or because they are designed for evolutionarily old systems. Sequencing a cross (parents and progeny) by RNA-seq to study the segregation of alleles and infer sex-linked genes is a cost-efficient strategy, which also provides expression level estimates. However, the lack of a proper statistical framework has limited a broader application of this approach. Tests on empirical Silene data show that our method identifies 20-35% more sex-linked genes than existing pipelines, while making reliable inferences for downstream analyses. Approximately 12 individuals are needed for optimal results based on simulations. For species with an unknown sex-determination system, the method can assess the presence and type (XY vs. ZW) of sex chromosomes through a model comparison strategy. The method is particularly well optimized for sex chromosomes of young or intermediate age, which are expected in thousands of yet unstudied lineages. Any organisms, including non-model ones for which nothing is known a priori, that can be bred in the lab, are suitable for our method. SEX-DETector and its implementation in a Galaxy workflow are made freely available. PMID- 27492232 TI - Predictive Models of Recombination Rate Variation across the Drosophila melanogaster Genome. AB - In all eukaryotic species examined, meiotic recombination, and crossovers in particular, occur non-randomly along chromosomes. The cause for this non-random distribution remains poorly understood but some specific DNA sequence motifs have been shown to be enriched near crossover hotspots in a number of species. We present analyses using machine learning algorithms to investigate whether DNA motif distribution across the genome can be used to predict crossover variation in Drosophila melanogaster, a species without hotspots. Our study exposes a combinatorial non-linear influence of motif presence able to account for a significant fraction of the genome-wide variation in crossover rates at all genomic scales investigated, from 20% at 5-kb to almost 70% at 2,500-kb scale. The models are particularly predictive for regions with the highest and lowest crossover rates and remain highly informative after removing sub-telomeric and centromeric regions known to have strongly reduced crossover rates. Transcriptional activity during early meiosis and differences in motif use between autosomes and the X chromosome add to the predictive power of the models. Moreover, we show that population-specific differences in crossover rates can be partly explained by differences in motif presence. Our results suggest that crossover distribution in Drosophila is influenced by both meiosis-specific chromatin dynamics and very local constitutive open chromatin associated with DNA motifs that prevent nucleosome stabilization. These findings provide new information on the genetic factors influencing variation in recombination rates and a baseline to study epigenetic mechanisms responsible for plastic recombination as response to different biotic and abiotic conditions and stresses. PMID- 27492233 TI - A Genome-Scale Investigation of How Sequence, Function, and Tree-Based Gene Properties Influence Phylogenetic Inference. AB - Molecular phylogenetic inference is inherently dependent on choices in both methodology and data. Many insightful studies have shown how choices in methodology, such as the model of sequence evolution or optimality criterion used, can strongly influence inference. In contrast, much less is known about the impact of choices in the properties of the data, typically genes, on phylogenetic inference. We investigated the relationships between 52 gene properties (24 sequence-based, 19 function-based, and 9 tree-based) with each other and with three measures of phylogenetic signal in two assembled data sets of 2,832 yeast and 2,002 mammalian genes. We found that most gene properties, such as evolutionary rate (measured through the percent average of pairwise identity across taxa) and total tree length, were highly correlated with each other. Similarly, several gene properties, such as gene alignment length, Guanine Cytosine content, and the proportion of tree distance on internal branches divided by relative composition variability (treeness/RCV), were strongly correlated with phylogenetic signal. Analysis of partial correlations between gene properties and phylogenetic signal in which gene evolutionary rate and alignment length were simultaneously controlled, showed similar patterns of correlations, albeit weaker in strength. Examination of the relative importance of each gene property on phylogenetic signal identified gene alignment length, alongside with number of parsimony-informative sites and variable sites, as the most important predictors. Interestingly, the subsets of gene properties that optimally predicted phylogenetic signal differed considerably across our three phylogenetic measures and two data sets; however, gene alignment length and RCV were consistently included as predictors of all three phylogenetic measures in both yeasts and mammals. These results suggest that a handful of sequence-based gene properties are reliable predictors of phylogenetic signal and could be useful in guiding the choice of phylogenetic markers. PMID- 27492234 TI - Convergent Evolution of Fern-Specific Mitochondrial Group II Intron atp1i361g2 and Its Ancient Source Paralogue rps3i249g2 and Independent Losses of Intron and RNA Editing among Pteridaceae. AB - Mitochondrial intron patterns are highly divergent between the major land plant clades. An intron in the atp1 gene, atp1i361g2, is an example for a group II intron specific to monilophytes (ferns). Here, we report that atp1i361g2 is lost independently at least 4 times in the fern family Pteridaceae. Such plant organelle intron losses have previously been found to be accompanied by loss of RNA editing sites in the flanking exon regions as a consequence of genomic recombination of mature cDNA. Instead, we now observe that RNA editing events in both directions of pyrimidine exchange (C-to-U and U-to-C) are retained in atp1 exons after loss of the intron in Pteris argyraea/biaurita and in Actiniopteris and Onychium We find that atp1i361g2 has significant similarity with intron rps3i249g2 present in lycophytes and gymnosperms, which we now also find highly conserved in ferns. We conclude that atp1i361g2 may have originated from the more ancestral rps3i249g2 paralogue by a reverse splicing copy event early in the evolution of monilophytes. Secondary structure elements of the two introns, most characteristically their domains III, show strikingly convergent evolution in the monilophytes. Moreover, the intron paralogue rps3i249g2 reveals relaxed evolution in taxa where the atp1i361g2 paralogue is lost. Our findings may reflect convergent evolution of the two related mitochondrial introns exerted by co evolution with an intron-binding protein simultaneously acting on the two paralogues. PMID- 27492236 TI - Binding Kinetics in Drug Discovery. AB - Over the last years, researchers have increasingly become interested in measuring and understanding drugs' binding kinetics, namely the time in which drug and its target associate and dissociate. Historically, drug discovery programs focused on the optimization of target affinity as a proxy of in-vivo efficacy. However, often the efficacy of a ligand is not appropriately described by the in-vitro measured drug-receptor affinity, but rather depends on the lifetime of the in vivo drug-receptor interaction. In this review we review recent works that highlight the importance of binding kinetics, molecular determinants for rational optimization and the recent emergence of computational methods as powerful tools in measuring and understanding binding kinetics. PMID- 27492235 TI - Regular Higher Order Repeat Structures in Beetle Tribolium castaneum Genome. AB - Higher order repeats (HORs) containing tandems of primary and secondary repeat units (head-to-tail "tandem within tandem pattern"), referred to as regular HORs, are typical for primate alpha satellite DNAs and most pronounced in human genome. Regular HORs are known to be a result of recent evolutionary processes. In non primate genomes mostly so called complex HORs have been found, without head to tail tandem of primary repeat units. In beetle Tribolium castaneum, considered as a model case for genome studies, large tandem repeats have been identified, but no HORs have been reported. Here, using our novel robust repeat finding algorithm Global Repeat Map, we discover two regular and six complex HORs in T. castaneum. In organizational pattern, the integrity and homogeneity of regular HORs in T. castaneum resemble human regular HORs (with T. castaneum monomers different from human alpha satellite monomers), involving a wider range of monomer lengths than in human HORs. Similar regular higher order repeat structures have previously not been found in insects. Some of these novel HORs in T. castaneum appear as most regular among known HORs in non-primate genomes, although with substantial riddling. This is intriguing, in particular from the point of view of role of non coding repeats in modulation of gene expression. PMID- 27492237 TI - In silico Exploration of the Conformational Universe of GPCRs. AB - The structural plasticity of G protein coupled receptors (GPCRs) leads to a conformational universe going from inactive to active receptor states with several intermediate states. Many of them have not been captured yet and their role for GPCR activation is not well understood. The study of this conformational space and the transition dynamics between different receptor populations is a major challenge in molecular biophysics. The rational design of effector molecules that target such receptor populations allows fine-tuning receptor signalling with higher specificity to produce drugs with safer therapeutic profiles. In this minireview, we outline highly conserved receptor regions which are considered determinant for the establishment of distinct receptor states. We then discuss in-silico approaches such as dimensionality reduction methods and Markov State Models to explore the GPCR conformational universe and exploit the obtained conformations through structure-based drug design. PMID- 27492238 TI - Constructing and Validating 3D-pharmacophore Models to a Set of MMP-9 Inhibitors for Designing Novel Anti-melanoma Agents. AB - A receptor-independent (RI) four-dimensional structure-activity relationship (4D QSAR) formalism was applied to a set of sixty-four beta-N-biaryl ether sulfonamide hydroxamate derivatives, previously reported as potent inhibitors against matrix metalloproteinase subtype 9 (MMP-9). MMP-9 belongs to a group of enzymes related to the cleavage of several extracellular matrix components and has been associated to cancer invasiveness/metastasis. The best RI 4D-QSAR model was statistically significant (N=47; r(2) =0.91; q(2) =0.83; LSE=0.09; LOF=0.35; outliers=0). Leave-N-out (LNO) and y-randomization approaches indicated the QSAR model was robust and presented no chance correlation, respectively. Furthermore, it also had good external predictability (82 %) regarding the test set (N=17). In addition, the grid cell occupancy descriptors (GCOD) of the predicted bioactive conformation for the most potent inhibitor were successfully interpreted when docked into the MMP-9 active site. The 3D-pharmacophore findings were used to predict novel ligands and exploit the MMP-9 calculated binding affinity through molecular docking procedure. PMID- 27492239 TI - In silico and in vitro Studies on Begomovirus Induced Andrographolide Biosynthesis Pathway in Andrographis Paniculata for Combating Inflammation and Cancer. AB - Andrographolide and neoandrographolide are major bioactive molecules of Andrographis paniculata, a well-known medicinal plant. These molecules exhibited varying degrees of anti-inflammatory and anticancer activities in-vitro and in vivo. Role of begomovirus protein C2/TrAP in biosynthesis of andrographolide was identified through molecular modeling, docking and predicted results were substantiated by in vitro studies. Homology molecular modeling and molecular docking were performed to study the binding conformations and different bonding behaviors, in order to reveal the possible mechanism of action behind higher accumulation of andrographolide. It was concluded that C2/TrAP inhibit the activation of SNF1-Related Protein Kinase-1 (SnRK1) in terpenoid pathway and removes the negative regulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) by SnRK1, leading to higher accumulation of andrographolide and neoandrographolide in begomovirus infected plants. The binding site residues of SnRK1 docked with C2/TrAP were found to be associated with ATP binding site, substrate binding site and activation loop. Predicted results were also validated by HPTLC. This study provides important insights into understanding the role of viral protein in altering the regulation of biosynthesis of andrographolide and could be used in future research to develop biomimetic methods for increasing the production of such phytometabolites having anti-cancerous and anti-inflammatory properties. PMID- 27492240 TI - Derivation of Self-inhibitory Helical Peptides to Target Rho-kinase Dimerization in Cerebrovascular Malformation: Structural Bioinformatics Analysis and Peptide Binding Assay. AB - Rho-kinase dimerization is essential for its kinase activity and biological function; disruption of the dimerization has recently been established as a new and promising therapeutics strategy for cerebrovascular malformation (CM). Based on Rho-kinase dimer crystal structure we herein combined in silico analysis and in vitro assay to rationally derive self-inhibitory peptides from the dimerization interface. Three peptides namely Hlp1, Hlp2 and Hlp3 were successfully designed that have potential capability to rebind at the dimerization domain of Rho-kinase. Molecular dynamics (MD) simulations revealed that these peptides are helically structured when bound to Rho-kinase, but exhibit partially intrinsic disorder in unbound state. Binding free energy (BFE) analysis suggested that the peptides have a satisfactory energetic profile to interact with Rho-kinase. The computational findings were then substantiated by fluorescence anisotropy assays, conforming that the helical peptides can bind tightly to Rho-kinase with affinity KD at micromolar level. These designed peptides are considered as lead molecular entities that can be further modified and optimized to obtain more potent peptidomimetics as self-competitors to disrupt Rho-kinase dimerization in CM. PMID- 27492241 TI - Interaction of Tenebrio Molitor Antifreeze Protein with Ice Crystal: Insights from Molecular Dynamics Simulations. AB - Antifreeze proteins (AFP) observed in cold-adapting organisms bind to ice crystals and prevent further ice growth. However, the molecular mechanism of AFP ice binding and AFP-inhibited ice growth remains unclear. Here we report the interaction of the insect antifreeze protein (Tenebrio molitor, TmAFP) with ice crystal by molecular dynamics simulation studies. Two sets of simulations were carried out at 263 K by placing the protein near the primary prism plane (PP) and basal plane (BL) of the ice crystal. To delineate the effect of temperatures, both the PP and BL simulations were carried out at 253 K as well. The analyses revealed that the protein interacts strongly with the ice crystal in BL simulation than in PP simulation both at 263 K and 253 K. Further, it was observed that the interactions are primarily mediated through the interface waters. We also observed that as the temperature decreases, the interaction between the protein and the ice increases which can be attributed to the decreased flexibility and the increased structuring of the protein at low temperature. In essence, our study has shed light on the interaction mechanism between the TmAFP antifreeze protein and the ice crystal. PMID- 27492242 TI - Docking-based Design of Galantamine Derivatives with Dual-site Binding to Acetylcholinesterase. AB - The enzyme acetylcholinesterase is a key target in the treatment of Alzheimer's disease because of its ability to hydrolyze acetylcholine via the catalytic binding site and to accelerate the aggregation of amyloid-beta peptide via the peripheral anionic site (PAS). Using docking-based predictions, in the present study we design 20 novel galantamine derivatives with alkylamide spacers of different length ending with aromatic fragments. The galantamine moiety blocks the catalytic site, while the terminal aromatic fragments bind in PAS. The best predicted compounds are synthesized and tested for acetylcholinesterase inhibitory activity. The experimental results confirm the predictions and show that the heptylamide spacer is of optimal length to bridge the galantamine moiety bound in the catalytic site and the aromatic fragments interacting with PAS. Among the tested terminal aromatic fragments, the phenethyl substituent is the most suitable for binding in PAS. PMID- 27492243 TI - Guided Iterative Substructure Search (GI-SSS) - A New Trick for an Old Dog. AB - Substructure search (SSS) is a fundamental technique supported by various chemical information systems. Many users apply it in an iterative manner: they modify their queries to shape the composition of the retrieved hit sets according to their needs. We propose and evaluate two heuristic extensions of SSS aimed at simplifying these iterative query modifications by collecting additional information during query processing and visualizing this information in an intuitive way. This gives the user a convenient feedback on how certain changes to the query would affect the retrieved hit set and reduces the number of trial and-error cycles needed to generate an optimal search result. The proposed heuristics are simple, yet surprisingly effective and can be easily added to existing SSS implementations. PMID- 27492244 TI - Breast cancer biologic and etiologic heterogeneity by young age and menopausal status in the Carolina Breast Cancer Study: a case-control study. AB - BACKGROUND: Young-onset breast cancer (<40 years) is associated with worse prognosis and higher mortality. Breast cancer risk factors may contribute to distinct tumor biology and distinct age at onset, but understanding of these relationships has been hampered by limited representation of young women in epidemiologic studies and may be confounded by menopausal status. METHODS: We examined tumor characteristics and epidemiologic risk factors associated with premenopausal women's and young women's breast cancer in phases I-III of the Carolina Breast Cancer Study (5309 cases, 2022 control subjects). Unconditional logistic regression was used to assess heterogeneity by age (<40 vs. >=40 years) and menopausal status. RESULTS: In both premenopausal and postmenopausal strata, younger women had more aggressive disease, including higher stage, hormone receptor-negative, disease as well as increased frequency of basal-like subtypes, lymph node positivity, and larger tumors. Higher waist-to-hip ratio was associated with reduced breast cancer risk among young women but with elevated risk among older women. Parity was associated with increased risk among young women and reduced risk among older women, while breastfeeding was more strongly protective for young women. Longer time since last birth was protective for older women but not for young women. In comparison, when we stratified by age, menopausal status was not associated with distinct risk factor or tumor characteristic profiles, except for progesterone receptor status, which was more commonly positive among premenopausal women. CONCLUSIONS: Age is a key predictor of breast cancer biologic and etiologic heterogeneity and may be a stronger determinant of heterogeneity than menopausal status. Young women's breast cancer appears to be etiologically and biologically distinct from that among older women. PMID- 27492245 TI - The potential role of biomarkers in predicting gestational diabetes. AB - Gestational diabetes (GD) is a frequent complication during pregnancy and is associated with maternal and neonatal complications. It is suggested that a disturbing environment for the foetus, such as impaired glucose metabolism during intrauterine life, may result in enduring epigenetic changes leading to increased disease risk in adult life. Hence, early prediction of GD is vital. Current risk prediction models are based on maternal and clinical parameters, lacking a strong predictive value. Adipokines are mainly produced by adipocytes and suggested to be a link between obesity and its cardiovascular complications. Various adipokines, including adiponectin, leptin and TNF&, have shown to be dysregulated in GD. This review aims to outline biomarkers potentially associated with the pathophysiology of GD and discuss the role of integrating predictive biomarkers in current clinical risk prediction models, in order to enhance the identification of those at risk. PMID- 27492246 TI - Characterization of gonadotropic cells during continuous and seasonal spermatogenesis of two freshwater fish species: a histochemical and immunohistochemical study. AB - This work describes gonadotropic (GtH) cells and their morphological and immunohistochemical changes during the spermatogenic cycle of Serrasalmus maculatus (continuous spermatogenesis) and Pimelodus maculatus (seasonal spermatogenesis). GtH cells, widely distributed in the proximal pars distalis of the adenohypophysis, were characterized as round-shaped cells with eccentric nucleus, and cytoplasm with basophilic secretory granules and a variable number of vacuoles for both species. Immunohistochemistry against beta-follicle stimulating hormone (Fsh) and beta-luteinizing hormone (Lh) in adjacent sections showed two separated GtH-producing cell populations, and a third population where both GtHs are expressed in the same cell for both species. In the seasonal spermatogenesis of P. maculatus, GtH cells seemed to be more abundant during developing and spawning capable phases. In contrast, no cyclic changes were detected in the continuous spermatogenesis of S. maculatus, except for the strong immunoreaction for Fsh and Lh in males with intense spermiogenesis. We conclude that changes reported here might reflect the type of spermatogenic cycle (seasonal or continuous) which are under different regulatory mechanisms (environmental and internal cues) controlling the reproduction in these species. PMID- 27492247 TI - Within and beyond the communal turn to informed consent in industry-sponsored pharmacogenetics research: merits and challenges of community advisory boards. AB - The one-size-fits-all paradigm of drug development fails to address inter individual variability in drug response. Pharmacogenetics research aims at studying the role of genotypic differences in drug response. Recently, the pharmaceutical industry has shown interest to embed pharmacogenetics studies in the process of drug development. Nevertheless, population-based and commercial aspects of such future-oriented studies pose challenges for individually based informed consent (IC). As an exemplar of the communal turn to IC procedures, community advisory boards (CABs) have been integrated into different types of medical research. CABs hold the promise of organizing the relationship between participants and researchers in a more reciprocal and participatory way, offering possible means of overcoming the lapses of individualistic IC. However, the involvement of CABs with pharmacogenetics research might be rife with difficulties, uncertainties, and challenges. The current study first reviews the existing literature to discuss added values and challenges of relying on CABs as a supplement to individually based IC. Then, the particular moral and regulatory landscape of pharmacogenetics research will be delineated to argue that community engagement is both necessary and promising beyond the communal turn to IC processes. Three main features of the landscape include (1) new supportive stances that some regulatory bodies have adopted toward pharmacogenetics research, (2) the motivation of the industry to draw reception and trust from the subpopulations, and (3) the important role of the society in generating and embedding pharmacogenetics knowledge. Finally, some points to consider will be discussed to contextualize relying on CABs within this landscape. PMID- 27492248 TI - Delayed upper tract drainage on voiding cystourethrogram may not be associated with increased risk of urinary tract infection in children with vesicoureteral reflux. AB - INTRODUCTION: Urinary stasis in the setting of obstruction provides an opportunistic environment for bacterial multiplication and is a well-established risk factor for UTI. Vesicoureteral reflux (VUR) with delayed upper tract drainage (UTD) on VCUG has been reported to correlate with increased UTI risk. We sought to determine whether delayed UTD can be reliably classified, and whether it correlates with UTI incidence, VCUG, or endoscopic findings. METHODS: Children undergoing endoscopic surgery for primary VUR (2009-2012) were identified. VUR grade, timing, and laterality were abstracted. Demographics, hydrodistention (HD) grade, reported febrile and culture-proven UTI were assessed. UTD on VCUG was graded on post-void images as 1 = partial/complete UTD or 2 = no/increased UTD. Inter-observer agreement was calculated. Patients were excluded for incomplete imaging or inability to void during VCUG. RESULTS: The cohort included 128 patients (10M, 118F), mean age 4.1 +/- 2.1 years. Mean age at diagnosis was 2.8 +/- 2.8 years. Mean maximum VUR grade was 3 +/- 0.9: 1 (7.8%), 2 (20.3%), 3 (43%), 4 (25.8%), 5 (3.1%). UTD occurred in 45 (35%), and no drainage in 83 (65%) patients. Agreement coefficient between graders was 0.596 (p < 0.0001). Cultures were available in 100 patients (70 positive). Patients experienced a mean of 2 +/ 1.2 parent-reported fUTIs and 1.2 +/- 1.2 culture-proven UTIs from birth to surgery. UTI rate did not differ by UTD status for parent or culture-proven UTI (Table). On multivariate analysis, no patient characteristic was a significant predictor of UTI based on drainage status. Children diagnosed with VUR before 1 year of age had a higher verified UTI rate (p < 0.001). However, drainage was not a significant predictor of UTI rate and when testing the interaction of drainage and age. CONCLUSION: We sought to determine whether UTD was an accurate predictor of UTI risk to maximize available prognostic information from a single VCUG. Delayed UTD was not a predictor of infection in our patients, nor was it associated with previously described UTI risk factors, such as VUR timing or grade, and voiding dysfunction. Limitations included the retrospective nature of the study in patients undergoing endoscopic VUR treatment, and possible inaccurate UTI reports from parents and pediatricians. UTD can be reliably scored using a binary system with high inter-observer correlation. Our data call into question the previous finding that children with poor UTD are at increased risk of recurrent UTI. Delayed UTD is also not associated with higher HD, or VUR grade compared with those with more prompt UTD. PMID- 27492249 TI - Corrigendum to "Development of a DNA-based microarray for the detection of zoonotic pathogens in rodent species" [Mol. Cell. Probes 29 (6) (2015)]. PMID- 27492251 TI - Repeated movie viewings produce similar local activity patterns but different network configurations. AB - People seek novelty in everyday life, but they also enjoy viewing the same movies or reading the same novels a second time. What changes and what stays the same when re-experiencing a narrative? In examining this question with functional neuroimaging, we found that brain activity reorganizes in a hybrid, scale dependent manner when individuals processed the same audiovisual narrative a second time. At the most local level, sensory systems (occipital and temporal cortices) maintained a similar temporal activation profile during the two viewings. Nonetheless, functional connectivity between these same lateral temporal regions and other brain regions was stronger during the second viewing. Furthermore, at the level of whole-brain connectivity, we found a significant rearrangement of network partition structure: lateral temporal and inferior frontal regions clustered together during the first viewing but merged within a fronto-parietal cluster in the second. Our findings show that repetition maintains local activity profiles. However, at the same time, it is associated with multiple network-level connectivity changes on larger scales, with these changes strongly involving regions considered core to language processing. PMID- 27492250 TI - Role of thrombospondin 1 in liver diseases. AB - Thrombospondin 1 (TSP1) is a matricellular glycoprotein that can be secreted by many cell types. Through binding to extracellular proteins and/or cell surface receptors, TSP1 modulates a variety of cellular functions. Since its discovery in 1971, TSP1 has been found to play important roles in multiple biological processes including angiogenesis, apoptosis, latent transforming growth factor beta activation, and immune regulation. Thrombospondin 1 is also involved in regulating many organ functions. However, the role of TSP1 in liver diseases has not been extensively addressed. In this review, we summarize the findings about the possible role that TSP1 plays in chronic liver diseases focusing on non alcoholic fatty liver diseases, liver fibrosis, and hepatocellular carcinoma. PMID- 27492252 TI - Glycoluril-Derived Molecular Clips are Potent and Selective Receptors for Cationic Dyes in Water. AB - Molecular clip 1 remains monomeric in water and engages in host-guest recognition processes with suitable guests. We report the Ka values for 32 1?guest complexes measured by 1 H NMR, UV/Vis, and fluorescence titrations. The cavity of 1 is shaped by aromatic surfaces of negative electrostatic potential and therefore displays high affinity and selectivity for planar and cationic aromatic guests that distinguishes it from CB[n] receptors that prefer aliphatic over aromatic guests. Electrostatic effects play a dominant role in the recognition process whereby ion-dipole interactions may occur between ammonium ions and the C=O groups of 1, between the SO3- groups of 1 and pendant cationic groups on the guest, and within the cavity of 1 by cation-pi interactions. Host 1 displays a high affinity toward dicationic guests with large planar aromatic surfaces (e.g. naphthalene diimide NDI+ and perylene diimide PDI+) and cationic dyes derived from acridine (e.g. methylene blue and azure A). The critical importance of cation-pi interactions was ascertained by a comparison of analogous neutral and cationic guests (e.g. methylene violet vs. methylene blue; quinoline vs. N methylquinolinium; acridine vs. N-methylacridinium; neutral red vs. neutral red H+ ) the affinities of which differ by up to 380-fold. We demonstrate that the high affinity of 1 toward methylene blue (Ka =3.92*107 m-1 ; Kd =25 nm) allows for the selective sequestration and destaining of U87 cells stained with methylene blue. PMID- 27492253 TI - Targeting Splicing in the Treatment of Myelodysplastic Syndromes and Other Myeloid Neoplasms. AB - Genome sequencing of primary cells from patients with myelodysplastic syndromes (MDS) led to the identification of recurrent heterozygous mutations in gene encoding components of the spliceosome, the cellular machinery which processes pre-messenger RNA (mRNA) to mature mRNA during gene transcription. Splicing mutations are mutually exclusive with one another and collectively represent the most common mutation class in MDS, occurring in approximately 60 % of patients overall and more than 80 % of those with ring sideroblasts. Evidence from animal models suggests that homozygous splicing mutations are lethal, and that in heterozygously mutated models, any further disruption of splicing triggers apoptosis and cell death. MDS cells with spliceosome mutations are thus uniquely vulnerable to therapies targeting splicing, which may be tolerated by healthy cells. The spliceosome is emerging as a novel therapeutic target in MDS and related myeloid neoplasms, with the first clinical trial of a splicing modulator opening in 2016. PMID- 27492254 TI - Microfluidics: a transformational tool for nanomedicine development and production. AB - Microfluidic devices are mircoscale fluidic circuits used to manipulate liquids at the nanoliter scale. The ability to control the mixing of fluids and the continuous nature of the process make it apt for solvent/antisolvent precipitation of drug-delivery nanoparticles. This review describes the use of numerous microfluidic designs for the formulation and production of lipid nanoparticles, liposomes and polymer nanoparticles to encapsulate and deliver small molecule or genetic payloads. The advantages of microfluidics are illustrated through examples from literature comparing conventional processes such as beaker and T-tube mixing to microfluidic approaches. Particular emphasis is placed on examples of microfluidic nanoparticle formulations that have been tested in vitro and in vivo. Fine control of process parameters afforded by microfluidics, allows unprecedented optimization of nanoparticle quality and encapsulation efficiency. Automation improves the reproducibility and optimization of formulations. Furthermore, the continuous nature of the microfluidic process is inherently scalable, allowing optimization at low volumes, which is advantageous with scarce or costly materials, as well as scale up through process parallelization. Given these advantages, microfluidics is poised to become the new paradigm for nanomedicine formulation and production. PMID- 27492255 TI - Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth. AB - A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor. PMID- 27492256 TI - Distinct splicing signatures affect converged pathways in myelodysplastic syndrome patients carrying mutations in different splicing regulators. AB - Myelodysplastic syndromes (MDS) are heterogeneous myeloid disorders with prevalent mutations in several splicing factors, but the splicing programs linked to specific mutations or MDS in general remain to be systematically defined. We applied RASL-seq, a sensitive and cost-effective platform, to interrogate 5502 annotated splicing events in 169 samples from MDS patients or healthy individuals. We found that splicing signatures associated with normal hematopoietic lineages are largely related to cell signaling and differentiation programs, whereas MDS-linked signatures are primarily involved in cell cycle control and DNA damage responses. Despite the shared roles of affected splicing factors in the 3' splice site definition, mutations in U2AF1, SRSF2, and SF3B1 affect divergent splicing programs, and interestingly, the affected genes fall into converging cancer-related pathways. A risk score derived from 11 splicing events appears to be independently associated with an MDS prognosis and AML transformation, suggesting potential clinical relevance of altered splicing patterns in MDS. PMID- 27492258 TI - Aldo-X Bifunctional Building Blocks for the Synthesis of Heterocycles. AB - Compounds containing oxygen, nitrogen, or sulfur atoms inside the rings are attracting much attention and interest due to their biological importance. In recent years, several methods for the synthesis of such molecules have been reported by using aldo-X bifunctional building blocks (AXB3 s) as substrates; these are a wide class of organic molecules that contain at least two reactive sites, among them, one aldehyde, acetal, or semiacetal group was involved. Because of the multiple reactivities, AXB3 s are widely used in the one-pot synthesis of biologically important heterocycles. This review summarizes the synthesis of important heterocycles by using AXB3 s as pivotal components in establishing multicomponent reactions, tandem reactions, and so forth. In many cases, the established reaction systems with AXB3 s were characterized by some green properties, such as easy access to the substrate, mild and environmentally benign conditions, and wide scope of the substrate. PMID- 27492257 TI - Characterization of the tRNA ligases of pathogenic fungi Aspergillus fumigatus and Coccidioides immitis. AB - Yeast tRNA ligase (Trl1) is an essential trifunctional enzyme that repairs RNA breaks with 2',3'-cyclic-PO4 and 5'-OH ends. Trl1 is composed of C-terminal cyclic phosphodiesterase and central polynucleotide kinase domains that heal the broken ends to generate the 3'-OH, 2'-PO4, and 5'-PO4 termini required for sealing by an N-terminal ligase domain. Trl1 enzymes are found in all human fungal pathogens and they are promising targets for antifungal drug discovery because: (i) their domain structures and biochemical mechanisms are unique compared to the mammalian RtcB-type tRNA splicing enzyme; and (ii) there are no obvious homologs of the Trl1 ligase domain in mammalian proteomes. Here we characterize the tRNA ligases of two human fungal pathogens: Coccidioides immitis and Aspergillus fumigatus The biological activity of CimTrl1 and AfuTrl1 was verified by showing that their expression complements a Saccharomyces cerevisiae trl1Delta mutant. Purified recombinant AfuTrl1 and CimTrl1 proteins were catalytically active in joining 2',3'-cyclic-PO4 and 5'-OH ends in vitro, either as full-length proteins or as a mixture of separately produced healing and sealing domains. The biochemical properties of CimTrl1 and AfuTrl1 are similar to those of budding yeast Trl1, particularly with respect to their preferential use of GTP as the phosphate donor for the polynucleotide kinase reaction. Our findings provide genetic and biochemical tools to screen for inhibitors of tRNA ligases from pathogenic fungi. PMID- 27492259 TI - Leukocyte Adhesion Deficiency Type 1 (LAD1) with Expressed but Nonfunctional CD11/CD18. PMID- 27492261 TI - Absence of lung sliding is not a reliable sign of pneumothorax in patients with high positive end-expiratory pressure. PMID- 27492260 TI - Lymphoma Secondary to Congenital and Acquired Immunodeficiency Syndromes at a Turkish Pediatric Oncology Center. AB - The prevalence of lymphoma in primary immunodeficiency cases and autoimmune diseases, as well as on a background of immunodeficiency following organ transplants, is increasing. The lymphoma treatment success rate is known to be a low prognosis. Our study aimed to emphasize the low survival rates in immunodeficient vs. immunocompetent lymphoma patients and also to investigate the effect of rituximab in patients with ataxia telangiectasia and other immunodeficiencies. We summarized the clinical characteristics and treatment results of 17 cases with primary immunodeficiency that developed non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) retrospectively. Seven patients were diagnosed with ataxia-telangiectasia, two with common variable immunodeficiency, two with selective IgA deficiency, one with X-related lymphoproliferative syndrome, one with Wiskott-Aldrich syndrome, one with Epstein-Barr virus-related lymphoproliferative syndrome, one with interleukin-2-inducible T-cell kinase (ITK) deficiency, and one with lymphoma developing after autoimmune lymphoproliferative syndrome (ALPS). One patient underwent a renal transplant. Of the nine males and eight females (aged 3-12 years, median = 7) that developed lymphoma, seven were diagnosed with HL and ten with NHL (seven B-cell, three T cell). The NHL patients were started on the Berlin-Frankfurt-Munster, POG9317, LMB-96, or R-CHOP treatment protocols with reduced chemotherapy dosages. HL cases were started on the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and/or cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) protocol, also with modified dosages. Importantly, all seven cases of HL are alive and in remission, while six of the ten NHL patients have died. Primary immunodeficiency is a strong predisposing factor for developing lymphoma. Low treatment success rates relative to other lymphomas and difficulties encountered during treatment indicate that new treatment agents are needed. While some success has been achieved by combining rituximab with lymphoma treatment protocols in B-NHL cases with primary immunodeficiency, the need for new treatment approaches for these patients remains critical. PMID- 27492262 TI - Routine biological tests in self-poisoning patients: results from an observational prospective multicenter study. PMID- 27492263 TI - Cyclooctyne [60]fullerene hexakis adducts: a globular scaffold for copper-free click chemistry. AB - The synthesis of a new highly symmetric hexakis adduct of C60 appended with 12 cyclooctyne moieties has been carried out. This compound has been used for the copper-free strain-promoted cycloaddition reaction to a series of azides with excellent yields. This strategy for the obtention of clicked adducts of [60]fullerene is of special interest for biological applications. PMID- 27492265 TI - Influence of Onabotulinumtoxin A on testes of the growing rat. AB - Onabotulinumtoxin A (onabotA) is gaining wide medical use in children. The present study was planned to investigate the influence of its injection on the maturing testicular structures in rats. Immature rats were injected in the bilateral cremaster muscles by onabotA with three doses of (10, 20, and 40 U/kg) three times in a 2-week interval. The effect of these injections on fertility indices was examined. Levels of antisperm antibodies and several apoptosis parameters were also investigated. DNA content in form of ploidy and histopathological alterations were assessed. OnabotA-injected groups showed decreased sperm count and semen quality, while sperm vitality, morphology, and testosterone levels were not significantly affected. Furthermore, DNA flow cytometric analysis confirmed delayed sperm maturation. Apoptosis markers were significantly increased by the injections. In conclusion, onabotA injection in growing rats adversely affected sperm count and maturation. OnabotA testicular effects are mediated, at least partly, by apoptosis. PMID- 27492264 TI - The immunoglobulin G1 N-glycan composition affects binding to each low affinity Fc gamma receptor. AB - Immunoglobulin G1 (IgG1) is the most abundant circulating human antibody and also the scaffold for many therapeutic monoclonal antibodies (mAbs). The destruction of IgG-coated targets by cell-mediated pathways begins with an interaction between the IgG Fc region and multiple varieties of membrane-bound Fc gamma receptors (FcgammaRs) on the surface of leukocytes. This interaction requires the presence of an asparagine-linked (N-)glycan on the Fc, and variations in the N glycan composition can affect the affinity of CD16A binding (an FcgammaR). Contemporary efforts to glycoengineer mAbs focus on increasing CD16A affinity, and thus treatment efficacy, but it is unclear how these changes affect affinity for the other FcgammaRs. Here, we measure binding of the extracellular Fc-binding domains for human CD16A and B, CD32A, B and C, and CD64 to 6 well-defined IgG1 Fc glycoforms that cover ~85% of the pool of human IgG1 Fc glycoforms. Core alpha1-6 fucosylation showed the greatest changes with CD16B (8.5-fold decrease), CD16A (3.9-fold decrease) and CD32B/C (1.8-fold decrease), but did not affect binding to CD32A. Adding galactose to the non-reducing termini of the complex-type, biantennary glycan increased affinity for all CD16s and 32s tested by 1.7-fold. Sialylation did not change the affinity of core-fucosylated Fc, but increased the affinity of afucosylated Fc slightly by an average of 1.16-fold for all CD16s and CD32s tested. The effects of fucose and galactose modification are additive, suggesting the contributions of these residues to Fc gamma receptor affinity are independent. PMID- 27492266 TI - Stress-dependent phosphorylation of myocardin-related transcription factor A (MRTF-A) by the p38(MAPK)/MK2 axis. AB - Myocardin-related transcription factor A (MRTF-A) is a known actin-regulated transcriptional coactivator of serum response factor (SRF). Stimulation of actin polymerization activates MRTF-A by releasing it from G-actin and thus allowing it to bind to and activate SRF. Here, we compared protein phosphorylation in MK2/3 deficient cells rescued or not by ectopic expression of MK2 in two independent phosphoproteomic approaches using anisomycin-treated MEF cells and LPS-stimulated mouse macrophages, respectively. Two MRTF-A sites, Ser(351) (corresponding to Ser(312) in human) and Ser(371) (Ser(333) in human), showed significantly stronger phosphorylation (12-fold and 6-fold increase) in the cells expressing MK2. MRTF-A is phosphorylated at these sites in a stress-, but not in a mitogen induced manner, and p38(MAPK)/MK2 catalytic activities are indispensable for this phosphorylation. MK2-mediated phosphorylation of MRTF-A at Ser(312) and Ser(333) was further confirmed in an in vitro kinase assay and using the phospho-protein kinase-D (PKD)-consensus motif antibody (anti-LXRXXpS/pT), the p38(MAPK) inhibitor BIRB-796, MK2/3-deficient cells and MRTF-A phospho-site mutants. Unexpectedly, dimerization, subcellular localization and translocation, interaction with actin, SRF or SMAD3 and transactivating potential of MRTF-A seem to be unaffected by manipulating the p38(MAPK)/MK2-dependent phosphorylations. Hence, MRTF-A is stress-dependently phosphorylated by MK2 at Ser(312) and Ser(333) with so far undetected functional and physiological consequences. PMID- 27492267 TI - The N-myristoylome of Trypanosoma cruzi. AB - Protein N-myristoylation is catalysed by N-myristoyltransferase (NMT), an essential and druggable target in Trypanosoma cruzi, the causative agent of Chagas' disease. Here we have employed whole cell labelling with azidomyristic acid and click chemistry to identify N-myristoylated proteins in different life cycle stages of the parasite. Only minor differences in fluorescent-labelling were observed between the dividing forms (the insect epimastigote and mammalian amastigote stages) and the non-dividing trypomastigote stage. Using a combination of label-free and stable isotope labelling of cells in culture (SILAC) based proteomic strategies in the presence and absence of the NMT inhibitor DDD85646, we identified 56 proteins enriched in at least two out of the three experimental approaches. Of these, 6 were likely to be false positives, with the remaining 50 commencing with amino acids MG at the N-terminus in one or more of the T. cruzi genomes. Most of these are proteins of unknown function (32), with the remainder (18) implicated in a diverse range of critical cellular and metabolic functions such as intracellular transport, cell signalling and protein turnover. In summary, we have established that 0.43-0.46% of the proteome is N-myristoylated in T. cruzi approaching that of other eukaryotic organisms (0.5-1.7%). PMID- 27492268 TI - The editorial policy of Intensive Care Medicine. PMID- 27492269 TI - Ten things to know about critically ill elderly patients. PMID- 27492270 TI - Ten tips for managing critically ill patients with sickle cell disease. PMID- 27492271 TI - Antibiotic stewardship: do not rely on de-escalation alone. PMID- 27492272 TI - End-of-life care in the ICU: semper ad meliora (always strive for improvement). PMID- 27492274 TI - Direct carbon-carbon bond formation via reductive soft enolization: a syn selective Mannich addition of alpha-iodo thioesters. AB - The beta-amino carboxylic acid moiety is a key feature of numerous important biologically active compounds. We describe a syn-selective direct Mannich addition reaction that uses alpha-iodo thioesters and sulfonyl imines and produces beta-amino thioesters. Enolate formation is achieved by reductive soft enolization. The products of the reaction provide straightforward access to biologically important beta-lactams through a variety of known reactions. PMID- 27492273 TI - Proton Pump Inhibitors Are Not Associated With Acute Kidney Injury in Critical Illness. AB - Recent epidemiologic data linking proton pump inhibitor (PPI) use to acute and chronic kidney dysfunction is yet to be validated in other populations, and mechanisms have not been explored. Using a large, well phenotyped inception cohort of 15 063 critically ill patients, we examined the risk of acute kidney injury (AKI), as defined by the Kidney Disease Improving Global Outcomes criteria guidelines, according to prior use of a PPI, histamine-2 receptor antagonist (H2 RA), or neither. A total of 3725 (24.7%) patients reported PPI use prior to admission, while 905 (6.0%) patients reported H2 RA use. AKI occurred in 747 (20.0%) and 163 (18.0%) of PPI and H2 RA users respectively, compared to 1712 (16.2%) of those not taking acid suppressive medications. In unadjusted analysis, PPI and H2 RA users had a 28% (95%CI 1.17-1.41, P < .001) and 10% (95%CI 0.91 1.30, P = .31) higher risk of AKI compared to those taking neither class of medication. However, in sequential models that included adjustment for demographics, cardiovascular comorbidities, indications for PPI use, and severity of illness, the effect of PPI on the risk of AKI was attenuated, and in the adjusted analysis, PPI was not associated with AKI (OR 1.02; 95%CI 0.91-1.13, P = .73). The presence of sterile pyuria and hypomagnesemia did not modify the association between PPI use and AKI. In summary, after adjustment for demographics, illness severity, and the indication for PPI use, PPI use prior to admission is not associated with critical illness AKI. PMID- 27492275 TI - Emergency Medical Service Providers' Perspectives towards Management of the Morbidly Obese. AB - OBJECTIVE: Obesity is a growing epidemic in the United States with increasing burden to the health care system. Management and transport of the morbidly obese (MO) pose challenges for Emergency Medical Services (EMS) providers. Though equipment and resources are being directed to the transport of the obese, little research exists to guide these efforts. To address this, the author of this study sought to assess EMS providers' perspectives on the challenges of caring for MO patients. METHODS: An anonymous, web-based survey was distributed to all active providers of prehospital transport of a large, urban, fire-based EMS system to evaluate the challenges of MO patients. The definition of MO was left up to the provider. This survey looked at various components of transport: lifting, transport time, airway management, establishing intravenous access, drug administration, as well as demographics, equipment, and education needs. The survey contained yes/no, rank-order, and Likert scale questions. Data were analyzed using descriptive statistics. The study was approved by the University of Miami (Miami, Florida USA) Institutional Review Board. RESULTS: Of survey participants, 71.9% felt the average weight of their patients had increased, and 100% reported to have transported a MO patient. Of calls made to EMS, 25% were only for assistance in the house and another 25% were for non-emergent transport to a health care facility; shortness of breath was the most common emergent complaint. Of specific challenges to properly care for MO patients, 94.4 % ranked lifting and/or moving the patient highest, followed by airway management, intravenous access, and measuring vital signs. A total of 43.8% of respondents felt that MO patients require at least six to eight EMS personnel to transport patients while 31.8% felt more than eight providers were necessary. Greater than 81.3% felt it would be beneficial to receive more training and 90.4% felt more equipment was needed. Of participants, 68.8 % felt that MO patients did not receive the same standard of care. CONCLUSIONS: Surveyed participants reported that patient's weights are increasing with all having transported a MO patient. Despite the majority of transports being for non-emergent problems, providers felt more training would be beneficial, that equipment available does not meet needs, and that the MO pose challenges to appropriate patient care. Cienki JJ . Emergency Medical Service providers' perspectives towards management of the morbidly obese. Prehosp Disaster Med. 2016;31(5):471-474. PMID- 27492276 TI - The Role of Psychological Factors in the Perception of Postneedling Soreness and the Influence of Postneedling Intervention. AB - BACKGROUND: Myofascial trigger point dry needling is frequently associated with postneedling soreness, which can generate patient dissatisfaction and reduced treatment adherence. Psychological factors may influence the perception of postneedling soreness and the effectiveness of postneedling soreness treatments. OBJECTIVES: The objectives of the present study were to determine whether catastrophizing, kinesiophobia, pain anxiety, and fear of pain are significant predictors of postneedling soreness over time; and to analyze whether the relationships between psychological variables and postneedling soreness vary as a function of the postneedling soreness intervention, which included ischemic compression, placebo or control (without treatment). DESIGN: Repeated-measures observational study nested within a randomized controlled trial. SETTING: University community. PARTICIPANTS: Healthy volunteers (N = 90; 40 men and 50 women) 18 to 39 years of age (mean +/- standard deviation 22 +/- 3 years). METHODS: Catastrophizing, kinesiophobia, pain anxiety, and fear of pain were evaluated as possible predictors of postneedling pain before dry needling in a latent myofascial trigger point in the upper trapezius muscle. Participants were then divided into a treatment group that received ischemic compression as a postneedling intervention, a placebo group that received sham ischemic compression, and a control group that did not receive any treatment. MAIN OUTCOME MEASUREMENTS: Pain during needling and postneedling soreness were quantified using a visual analogue scale during needling, after treatment, and at 6, 12, 24, and 48 hours. RESULTS: A multilevel analysis revealed that individuals who exhibited more catastrophic thinking showed less postneedling soreness intensity immediately after needling in all participants (beta = -0.049). Pain-related anxiety was linked to greater immediate postneedling soreness in the compression condition (beta = 0.057). Finally, participants who exhibited more catastrophic thinking showed a slower rate of decline in postneedling soreness levels over time in the compression condition (beta = 0.038). CONCLUSIONS: Catastrophizing was associated with lower levels of postneedling soreness immediately after needling in all subjects. Although ischemic compression seems to be a useful procedure to reduce postneedling soreness, its efficacy could be slightly reduced in patients presenting higher scores of pain-related anxiety. Psychological procedures may help to correct the distorted pain expectancies associated with needling interventions and might also improve the effectiveness of ischemic compression. LEVEL OF EVIDENCE: II. PMID- 27492278 TI - Umbilical cord care: national survey, literature review and recommendations. AB - BACKGROUND: The basic principle of umbilical cord (UC) care is to keep it clean and dry, as this provides the fastest and safest UC healing. OBJECTIVE: To evaluate Slovenian UC care practice and compare its consistency with current international recommendations. METHODS: A questionnaire covering UC care from birth to complete healing of the umbilical wound was sent to all Slovenian primary-, secondary- and tertiary-level pediatric centers. Three different clinical conditions of the newborn's umbilicus were defined: healthy umbilicus (HU), umbilicus at risk (UR) and unhealthy umbilicus (UU). RESULTS: The study revealed a correlation between the clinical condition of the umbilicus, the frequency of UC care and the antiseptic usage in both the outpatient and inpatient UC care groups. HU was treated less frequently than UR and significantly less than UU. In both groups, these two conditions were also indications for UC care with antiseptic. The frequency of antiseptic usage for HU care was significantly lower in the outpatient care group. CONCLUSIONS: Slovenian UC care follows the general international recommendations. Based on these and our experience, we formulated recommendations for adjustments to UC care, depending on the clinical condition of the umbilicus, in order to prevent important complications. PMID- 27492277 TI - E-cigarette use among women of reproductive age: Impulsivity, cigarette smoking status, and other risk factors. AB - INTRODUCTION: The study aim was to examine impulsivity and other risk factors for e-cigarette use among women of reproductive age comparing current daily cigarette smokers to never cigarette smokers. Women of reproductive age are of special interest because of the additional risk that tobacco and nicotine use represents should they become pregnant. METHOD: Survey data were collected anonymously online using Amazon Mechanical Turk in 2014. Participants were 800 women ages 24 44years from the US. Half (n=400) reported current, daily smoking and half (n=400) reported smoking <100 cigarettes lifetime. Participants completed questionnaires regarding sociodemographics, tobacco/nicotine use, and impulsivity (i.e., delay discounting & Barratt Impulsiveness Scale). Predictors of smoking and e-cigarette use were examined using logistic regression. RESULTS: Daily cigarette smoking was associated with greater impulsivity, lower education, past illegal drug use, and White race/ethnicity. E-cigarette use in the overall sample was associated with being a cigarette smoker and greater education. E-cigarette use among current smokers was associated with increased nicotine dependence and quitting smoking; among never smokers it was associated with greater impulsivity and illegal drug use. E-cigarette use was associated with hookah use, and for never smokers only with use of cigars and other nicotine products. CONCLUSIONS: E cigarette use among women of reproductive age varies by smoking status, with use among current smokers reflecting attempts to quit smoking whereas among non smokers use may be a marker of a more impulsive repertoire that includes greater use of alternative tobacco products and illegal drugs. PMID- 27492279 TI - RpoE promotes invasion and intracellular survival by regulating SPI-1 and SPI-2 in Salmonella enterica serovar Typhi. AB - AIM: To demonstrate the role of RpoE during the later stage of hyperosmotic stress in Salmonella. MATERIALS & METHODS: Expressions of SPI-1 and SPI-2 under hyperosmotic stress for 120 min were investigated by a microarray, and the invasion and intracellular survival of wild-type and DeltarpoE strains were compared. The global differential expression of bacterial proteins between the wild-type and DeltarpoE strains was examined after 120 min of hyperosmotic stress. RESULTS: SPI-1 and SPI-2 were repressed, and the invasion and intracellular survival were defected in the DeltarpoE strain. Thirteen bacterial associated proteins and 11 secreted proteins differed significantly between the wild-type and DeltarpoE strains. CONCLUSION: RpoE may promote invasion and intracellular survival by regulating the expression of SPI-1 and SPI-2. PMID- 27492281 TI - Conserved Role of bFGF and a Divergent Role of LIF for Pluripotency Maintenance and Survival in Canine Pluripotent Stem Cells. AB - Dogs have been widely used as a preclinical model for human disease. With the successful generation of canine induced pluripotent stem cells (ciPSCs), the biomedical community has a unique opportunity to study therapeutic interventions using autologous stem cells that can benefit dogs and humans. Unlike mice and human pluripotent cells, which are leukemia inhibitory factor (LIF)- and basic fibroblast growth factor (bFGF)-dependent, respectively, dog iPSCs require both growth factors simultaneously. In an effort to elucidate the role of each factor in the control of ciPSC self-renewal, we performed a series of experiments aiming at understanding the signaling pathways activated by them. We found that bFGF regulates pluripotency by indirectly activating the SMAD2/3 pathway in the presence of feeder cells, exclusively targeting NANOG expression, and inhibiting spontaneous differentiation toward ectoderm and mesoderm. LIF activates the JAK STAT3 pathway but does not function in the typical manner described in mouse naive embryonic stem cells. These results show that a unique mechanism for maintenance of pluripotency is present in ciPSC. These findings should be taken into account when establishing stem cell differentiation protocols and may provide more insight into pluripotency regulation in species other than mice and humans. PMID- 27492280 TI - Research Review: Multi-informant integration in child and adolescent psychopathology diagnosis. AB - BACKGROUND: An empirically based, clinically usable approach to cross-informant integration in clinical assessment is needed. Although the importance of this ongoing issue is becoming increasingly recognized, little in the way of solid recommendations is currently provided to researchers and clinicians seeking to incorporate multiple informant reports in diagnosis of child psychopathology. The issue is timely because recent developments have created new opportunities for improved handling of this problem. For example, advanced theories of psychopathology and normal and abnormal child development provide theoretical guidance for how integration of multiple informants should be handled for specific disorders and at particular ages. In addition, more sophisticated data analytic approaches are now available, including advanced latent variable models, which allow for complex measurement approaches with consideration of measurement invariance. FINDINGS: The increasing availability and mobility of computing devices suggests that it will be increasingly feasible for clinicians to implement more advanced methods rather than being confined to the easily memorized algorithms of the DSM system. CONCLUSIONS: Development of models of cross-informant integration for individual disorders based on theory and tests of the incremental validity of more sophisticated cross-informant integration approaches in comparison to external validation criteria (e.g. longitudinal trajectories and outcomes, treatment response, and behavior genetic etiology) should be a focus of future work. PMID- 27492282 TI - Large-area, continuous and high electrical performances of bilayer to few layers MoS2 fabricated by RF sputtering via post-deposition annealing method. AB - We report a simple and mass-scalable approach for thin MoS2 films via RF sputtering combined with the post-deposition annealing process. We have prepared as-sputtered film using a MoS2 target in the sputtering system. The as-sputtered film was subjected to post-deposition annealing to improve crystalline quality at 700 degrees C in a sulfur and argon environment. The analysis confirmed the growth of continuous bilayer to few-layer MoS2 film. The mobility value of ~29 cm(2)/Vs and current on/off ratio on the order of ~10(4) were obtained for bilayer MoS2. The mobility increased up to ~173-181 cm(2)/Vs, respectively, for few-layer MoS2. The mobility of our bilayer MoS2 FETs is larger than any previously reported values of single to bilayer MoS2 grown on SiO2/Si substrate with a SiO2 gate oxide. Moreover, our few-layer MoS2 FETs exhibited the highest mobility value ever reported for any MoS2 FETs with a SiO2 gate oxide. It is presumed that the high mobility behavior of our film could be attributed to low charged impurities of our film and dielectric screening effect by an interfacial MoOxSiy layer. The combined preparation route of RF sputtering and post deposition annealing process opens up the novel possibility of mass and batch production of MoS2 film. PMID- 27492283 TI - Two-Color, Two-Photon Imaging at Long Excitation Wavelengths Using a Diamond Raman Laser. AB - We demonstrate that the second-Stokes output from a diamond Raman laser, pumped by a femtosecond Ti:Sapphire laser, can be used to efficiently excite red emitting dyes by two-photon excitation at 1,080 nm and beyond. We image HeLa cells expressing red fluorescent protein, as well as dyes such as Texas Red and Mitotracker Red. We demonstrate the potential for simultaneous two-color, two photon imaging with this laser by using the residual pump beam for excitation of a green-emitting dye. We demonstrate this for the combination of Alexa Fluor 488 and Alexa Fluor 568. Because the Raman laser extends the wavelength range of the Ti:Sapphire laser, resulting in a laser system tunable to 680-1,200 nm, it can be used for two-photon excitation of a large variety and combination of dyes. PMID- 27492284 TI - Supporting a 'bottom-up,' new, no-holds-barred, psycho-anthro-pediatrics: Making room (scientifically) for bedsharing families. PMID- 27492285 TI - SoyNet: a database of co-functional networks for soybean Glycine max. AB - Soybean (Glycine max) is a legume crop with substantial economic value, providing a source of oil and protein for humans and livestock. More than 50% of edible oils consumed globally are derived from this crop. Soybean plants are also important for soil fertility, as they fix atmospheric nitrogen by symbiosis with microorganisms. The latest soybean genome annotation (version 2.0) lists 56 044 coding genes, yet their functional contributions to crop traits remain mostly unknown. Co-functional networks have proven useful for identifying genes that are involved in a particular pathway or phenotype with various network algorithms. Here, we present SoyNet (available at www.inetbio.org/soynet), a database of co functional networks for G. max and a companion web server for network-based functional predictions. SoyNet maps 1 940 284 co-functional links between 40 812 soybean genes (72.8% of the coding genome), which were inferred from 21 distinct types of genomics data including 734 microarrays and 290 RNA-seq samples from soybean. SoyNet provides a new route to functional investigation of the soybean genome, elucidating genes and pathways of agricultural importance. PMID- 27492286 TI - Backmasking in the yeast genome: encoding overlapping information for protein coding and RNA degradation. AB - Backmasking is a recording technique used to hide a sound or message in a music track in reverse, meaning that it is only audible when the record is played backwards. Analogously, the compact yeast genome encodes for diverse sources of information such as overlapping coding and non-coding transcripts, and protein binding sites on the two complementary DNA strands. Examples are the consensus binding site sequences of the RNA-binding proteins Nrd1 and Nab3 that target non coding transcripts for degradation. Here, by examining the overlap of stable (SUTs, stable unannotated transcripts) and unstable (CUTs, cryptic unstable transcripts) transcripts with protein-coding genes, we show that the predicted Nrd1 and Nab3-binding site sequences occur at differing frequencies. They are always depleted in the sense direction of protein-coding genes, thus avoiding degradation of the transcript. However in the antisense direction, predicted binding sites occur at high frequencies in genes with overlapping unstable ncRNAs (CUTs), so limiting the availability of non-functional transcripts. In contrast they are depleted in genes with overlapping stable ncRNAs (SUTs), presumably to avoid degrading the non-coding transcript. The protein-coding genes maintain similar amino-acid contents, but they display distinct codon usages so that Nrd1 and Nab3-binding sites can arise at differing frequencies in antisense depending on the overlapping transcript type. Our study demonstrates how yeast has evolved to encode multiple layers of information-protein-coding genes in one strand and the relative chance of degrading antisense RNA in the other strand-in the same regions of a compact genome. PMID- 27492287 TI - Silencing of cryptic prophages in Corynebacterium glutamicum. AB - DNA of viral origin represents a ubiquitous element of bacterial genomes. Its integration into host regulatory circuits is a pivotal driver of microbial evolution but requires the stringent regulation of phage gene activity. In this study, we describe the nucleoid-associated protein CgpS, which represents an essential protein functioning as a xenogeneic silencer in the Gram-positive Corynebacterium glutamicum CgpS is encoded by the cryptic prophage CGP3 of the C. glutamicum strain ATCC 13032 and was first identified by DNA affinity chromatography using an early phage promoter of CGP3. Genome-wide profiling of CgpS binding using chromatin affinity purification and sequencing (ChAP-Seq) revealed its association with AT-rich DNA elements, including the entire CGP3 prophage region (187 kbp), as well as several other elements acquired by horizontal gene transfer. Countersilencing of CgpS resulted in a significantly increased induction frequency of the CGP3 prophage. In contrast, a strain lacking the CGP3 prophage was not affected and displayed stable growth. In a bioinformatics approach, cgpS orthologs were identified primarily in actinobacterial genomes as well as several phage and prophage genomes. Sequence analysis of 618 orthologous proteins revealed a strong conservation of the secondary structure, supporting an ancient function of these xenogeneic silencers in phage-host interaction. PMID- 27492290 TI - [Confronting the Health-Related Challenges of Climate Change: Nursing Education for the Future]. AB - Climate change is the greatest threat to public health in the 21st century. The increasing health impact of heat waves, the increasing magnitudes and spatial expansions of vector and water-borne diseases epidemics, and the increasing medical burdens of biological allergic illnesses, worsening local air pollution, and other related issues are expected to continue to increase in severity in the near future. All of these issues are global problems that must be faced. Adaptation strategies and action plans related to climate change are needed and emerging. Moreover, integrating the basic concepts, scientific evidences, and new technology into public and professional education systems is already recognized as a priority in the national adaptation program. Nurses stand on the frontlines of medical care and health communication. The integration of climate change and adaptation to climate change into nursing education and training is become increasingly important. This article reviews both the expected health impacts of climate change and the mitigation and adaptation strategies that have been proposed / adopted by medical care facilities around the world. Further, we outline the current, priority needs for action in medical care facilities in Taiwan in order to mitigate and adapt to climate-change-related healthcare issues. Additionally, we present an integrated strategic plan for educating healthcare professionals, including nurse, in the future. We hope that the ideas that are presented in this paper encourage multidisciplinary cooperation and help bridge the gap between technology development and practical application in Taiwan's medical care system. PMID- 27492288 TI - Evaluating the impact of single nucleotide variants on transcription factor binding. AB - Diseases and phenotypes caused by disrupted transcription factor (TF) binding are being identified, but progress is hampered by our limited capacity to predict such functional alterations. Improving predictions may be dependent on expanding the set of bona fide TF binding alterations. Allele-specific binding (ASB) events, where TFs preferentially bind to one of the two alleles at heterozygous sites, reveal the impact of sequence variations in altered TF binding. Here, we present the largest ASB compilation to our knowledge, 10 765 ASB events retrieved from 45 ENCODE ChIP-Seq data sets. Our analysis showed that ASB events were frequently associated with motif alterations of the ChIP'ed TF and potential partner TFs, allelic difference of DNase I hypersensitivity and allelic difference of histone modifications. For TF dimers bound symmetrically to DNA, ASB data revealed that central positions of the TF binding motifs were disproportionately important for binding. Lastly, the impact of variation on TF binding was predicted by a classification model incorporating all the investigated features of ASB events. Classification models using only DNase I hypersensitivity and sequence data exhibited predictive accuracy approaching the models with substantially more features. Taken together, the combination of ASB data and the classification model represents an important step toward elucidating regulatory variants across the human genome. PMID- 27492291 TI - [Implementing and Promoting Advance Care Planning for Community Older Adults]. AB - Advance care planning (ACP) is an emerging issue in the primary care system of Taiwan. Previous studies have attributed benefits to various types of ACP in diverse ranges of healthcare settings and populations. However, few older adults in Taiwan have had the opportunity to discuss ACP or to complete their advance directives. The present article takes the perspective of community health nursing to describe the international development and current status of ACP in the community in Taiwan. Furthermore, the intervention models and available resources of ACP are described. We look forward to healthcare professionals using ACP to assist greater numbers of community older adults, thus enhancing their terminal stage quality of life. PMID- 27492289 TI - Replication-dependent and independent mechanisms for the chromosome-coupled persistence of a selfish genome. AB - The yeast 2-micron plasmid epitomizes the evolutionary optimization of selfish extra-chromosomal genomes for stable persistence without jeopardizing their hosts' fitness. Analyses of fluorescence-tagged single-copy reporter plasmids and/or the plasmid partitioning proteins in native and non-native hosts reveal chromosome-hitchhiking as the likely means for plasmid segregation. The contribution of the partitioning system to equal segregation is bipartite- replication-independent and replication-dependent. The former nearly eliminates 'mother bias' (preferential plasmid retention in the mother cell) according to binomial distribution, thus limiting equal segregation of a plasmid pair to 50%. The latter enhances equal segregation of plasmid sisters beyond this level, elevating the plasmid close to chromosome status. Host factors involved in plasmid partitioning can be functionally separated by their participation in the replication-independent and/or replication-dependent steps. In the hitchhiking model, random tethering of a pair of plasmids to chromosomes signifies the replication-independent component of segregation; the symmetric tethering of plasmid sisters to sister chromatids embodies the replication-dependent component. The 2-micron circle broadly resembles the episomes of certain mammalian viruses in its chromosome-associated propagation. This unifying feature among otherwise widely differing selfish genomes suggests their evolutionary convergence to the common logic of exploiting, albeit via distinct molecular mechanisms, host chromosome segregation machineries for self-preservation. PMID- 27492292 TI - [The Impacts of Widowhood on the Health and Life of Elderly People and R elated Nursing Care]. AB - Widowhood, an unavoidable and stressful situation, has been associated with negative effects in elderly people during later life. This article reviews and summarizes the influences of widowhood on the health, daily life, and social life of elderly people. The influences of widowhood on elderly people may vary by gender, spousal relationship, and cohort background. In order to provide nursing care as early as possible, nurses must cooperate with professionals from social welfare and / or community-support systems to identify high-risk widowed elderly. When nurses assess the influences of widowhood on elderly people, they should consider the interactions among gender, spousal relationship, and cohort background. Furthermore, nurses may apply various strategies based on the needs of elderly people to improve the health and quality of life of patients. Suggestions include providing appropriate nursing care, offering positive social support, adjusting daily-life routines, and arranging activity programs based on care-recipient interests and resources. PMID- 27492293 TI - [The Use of Telemedicine Interventions to Improve Hypertension Management Among Racial Ethnic Minorities: A Systematic Review]. AB - BACKGROUND: Racial ethnic minorities are one of the fastest growing populations in Taiwan. In recent years, there has been an increase in literature addressing the efficacy of home blood-pressure (BP) management that uses telemedicine interventions in general healthcare and community settings. However, no study or systematic literature review has yet assessed the effectiveness of using telemedicine HTN interventions in Taiwan's indigenous, new-immigrant, and other minority populations. PURPOSE: The purpose of the present paper is to review the current literature on the use of telemedicine interventions to assist HTN management among racial ethnic minorities. METHODS: A comprehensive literature search was conducted for full-text articles that were published between January 2000 and December 2015 using the following databases: PubMed, WEB of Science, CINAHL (Cumulative Index to Nursing & Allied Health Literature), PsycINFO, Science Direct, ProQuest, Medline, Cochrane Library, National Dissertations and Theses, and airiti Library. The search used the following key search terms both alone and in combination: hypertension, blood pressure, management, telemedicine, telehealth, ehealth, and digital health. The studies were thoroughly assessed under the guidelines of Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA). A total of 6 articles met the criteria for using keywords related to racial ethnic minority populations and were used in the present review. RESULTS: Findings of this systematic review show that telemedicine interventions significantly improve HTN management. The intervention that combined home telemonitoring with culturally competent nurse counseling calls was identified as the best intervention for reducing BP. As the current literature on this topic is limited to African-Americans, more research is necessary to validate our findings. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Future studies should target racial ethnic minorities in Taiwan in order to better understand how to provide culturally appropriate, telemedicine-based HTN management to Taiwan's minority populations. Further studies with a long-term follow-up plan, randomized controlled trials, and larger sample sizes are required to support these results. PMID- 27492294 TI - [Nurse-Led Care Models in the Context of Community Elders With Chronic Disease Management: A Systematic Review]. AB - BACKGROUND: Longer average life expectancies have caused the rapid growth of the elderly as a percentage of Taiwan's population and, as a result of the number of elders with chronic diseases and disability. Providing continuing-care services in community settings for elderly with multiple chronic conditions has become an urgent need. PURPOSE: To review the nurse-led care models that are currently practiced among elders with chronic disease in the community and to further examine the effectiveness and essential components of these models using a systematic review method. METHODS: Twelve original articles on chronic disease care planning for the elderly or on nurse-led care management interventions that were published between 2000 and 2015 in any of five electronic databases: MEDLINE, PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature) Plus with Full Text, Cochrane Library, and CEPS (Chinese Electronic Periodicals Service)were selected and analyzed systematically. RESULTS: Four types of nurse-led community care models, including primary healthcare, secondary prevention care, cross-boundary models, and case management, were identified. Chronic disease-care planning, case management, and disease self-management were found to be the essential components of the services that were provided. The care models used systematic processes to conduct assessment, planning, implementation, coordination, and follow-up activities as well as to deliver services and to evaluate disease status. The results revealed that providing continuing-care services through the nurse-led community chronic disease-care model and cross boundary model enhanced the ability of the elderly to self-manage their chronic diseases, improved healthcare referrals, provided holistic care, and maximized resource utilization efficacy. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The present study cross-referenced all reviewed articles in terms of target clients, content, intervention, measurements, and outcome indicators. Study results may be referenced in future implementations of nurse-led community care models as well as in future research. PMID- 27492295 TI - [A Survey and Analysis of Exercise Among Pregnant Women Conducted Using the Theory of Reasoned Action]. AB - BACKGROUND: Prior research has highlighted the significant relationship between gestational weight gain and pregnancy outcomes. Exercise is one of the main factors that affects body weight. Therefore, exercising appropriately during pregnancy is an important activity for promoting healthy pregnancy outcomes. PURPOSE: To explore the status and features of maternal exercise during pregnancy and to analyze the related influence factors using the "theory of reasoned action" in order to provide evidence-based guidance on exercise during pregnancy. METHODS: Convenience sampling was used to recruit pregnant women from four hospitals of different administrative levels in Chengdu, China. A self-developed questionnaire was used to collect data. Data were input using Epidata and analyzed using SPSS 21.0. RESULTS: Data provided by 587 pregnant women in their first trimester, 522 in their second trimester, and 522 in their third trimester were used in analysis. Significant differences were found between the three groups in terms of housework loading and lifting. Further, participants in the third trimester were significantly more likely to exercise less than 3 times per week and less than 30 minutes per session than their first and second trimester peers (p < .001). Structural equation modeling identified that: behavior intention had a significant effect on level of physical activity; attitudes and norms affected behavior by affecting intention; monthly income and educational background affected behavior by influencing attitude; and educational background affected behavior by influencing perceived norms. CONCLUSIONS: The findings of the present study support that personal situation, the family, and social norms impact the behavior of women significantly more during pregnancy than before pregnancy. PMID- 27492296 TI - [Exploring the Experience of Dysmenorrhea and Life Adjustments of Women Undergoing Traditional Chinese Medicine Treatment]. AB - BACKGROUND: Previous studies of women with dysmenorrhea have focused on menstrual attitudes, the characteristics of menstrual pain, and self-care behavior. Traditional Chinese Medicine (TCM) studies on dysmenorrhea, on the other hand, have focused on the efficacy and safety of TCM treatments. Few studies have investigated how women perceive their own TCM-treatment experience of dysmenorrhea. PURPOSE: The objective of this study was to explore the experience of dysmenorrhea and life adjustments of women undergoing TCM treatment. METHODS: A semi-structured interviewing guide was used to collect data. A total of 40 dysmenorrheal women participated in the study. Individual, in-depth interviews were conducted for about 60-90 minutes with each participant. Their speech tone, facial expressions, and gestures during the interview process were also observed and recorded. The findings were analyzed using content analysis via ATLAS. ti 5.2 software. RESULTS: The process that the participants used to adjust to dysmenorrhea were distinguished into four progressive stages: "tip of the iceberg", "ice-breaking", "tug-of-war", and "blending-in". Initially, the participants perceived the symptoms of dysmenorrhea as the "tip of the iceberg". They attempted to hide / ignore the initial pain until the problem gradually worsened to the point that the symptoms began to significantly affect various aspects of life. It was only then that the participants began to pay attention to the problem and to seek help from TCM practitioners, which we defined as the "ice breaking" stage. If they encountered unexpected situations with regard to the treatment regimen, the participants entered the "tug-of-war" stage, during which they struggled over whether to continue with TCM treatments. Afterward, the participants gradually achieved a "blending-in" of new ideas, which allowed them to identify the strategies that best facilitated adjustment and rebalancing. Eventually, the participants achieved a new life balance. CONCLUSIONS: The outcomes of the present study may be referenced for nurse-patient communications that relate to dysmenorrhea and TCM treatment. PMID- 27492297 TI - [The Effect of Structured Group Reminiscence Therapy on the Life Satisfaction of Institutionalized Elderly]. AB - BACKGROUND: Long-term care institutions have become an option for older people who are dependent in daily living. However, insufficient attention has been focused on assessing the life satisfaction of those currently residing in these institutions in Taiwan. Previous research indicates that group reminiscence may improve the life satisfaction of older adults. However, there is currently no consensus regarding the implementation and evaluation of reminiscence interventions. PURPOSE: To examine the effect of a structured group reminiscence protocol on the life satisfaction of institutionalized older adults. METHODS: The study used a quasi-experimental design. A total of 48 older adults were conveniently recruited from two long-term care institutions in southern Taiwan. The experimental group (n = 23) received 8 weeks of structured-group reminiscence for 40 minutes weekly, while the control group (n = 25) received routine care from the institution. Both groups were evaluated using a life-satisfaction questionnaire before and after the intervention and again four weeks later. RESULTS: Life satisfaction scores were statistically similar on the pre-test and significantly different on both post-test questionnaires for the two groups. The scores for the experimental and control groups were pre-test: 24.22 vs 23.36 (p = .063); post-test I: 27.22 vs 23.32 (p < .001); and post-test II: 26.43 vs 23.00 (p < .001). The mean post-test scores for the experimental group were significantly higher than the pre-test score (p < .001). The generalized estimating equation test showed that the overall score of life satisfaction for the experimental group increased by 0.85-points (p = .042) more than the control group, which is a significant difference. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The results support that the 8-week structured group reminiscence protocol effectively enhances life satisfaction in older adults. The results of this study may be referenced in the continuing education of nurses working in long-term care institutions in the context of helping nurses organize, facilitate, and evaluate this protocol. PMID- 27492298 TI - [The Learning Effectiveness of Nurses Participating in a Simulated Radiation Therapy Skin Care Workshop]. AB - BACKGROUND: The skin reaction rate is 60-95% in cancer patients that receive radiation therapy. This therapy is likely to cause physical and mental discomfort and prolong treatment for patients. The current emphasis on lectures rather than practice to help nurses learn proper skin care practices likely imposes difficulties for nurses to handle various clinical situations. PURPOSE: To investigate the learning effectiveness of a simulated radiation therapy skin care workshop for nurses. METHODS: A total of 34 nurses at a hospital in one health system in northern Taiwan who had never used radiation therapy to provide care to patients were enrolled in this quasi-experimental study. A single group pretest, posttest and post-posttest (6 weeks after intervention) approach was used. At the simulated radiation therapy skin care workshop, we used teaching strategies including Ausubel's direct instruction teaching method and practice on simulated wounds on pig skins. Outcomes were evaluated using "the questionnaire of radiation therapy skin care" and "direct observation of procedural skills checklist". RESULTS: The results from the simulated radiation therapy skin care workshop were analyzed using GEE (generalized estimating equation). The post posttest and posttest scores increased significantly; knowledge mean score 3.14 (< .001) vs 2.64 (< .001), attitude mean score 2.06 (p < .05) vs 2.24 (p < .001), and skill mean score 2.79 (p < .001) vs 1.68 (p < .001). CONCLUSIONS: The simulated radiation therapy skin care workshop demonstrated significant and positive effects on learning outcomes. Therefore, we recommend incorporating this workshop into clinical nursing education and training strategies in the future. PMID- 27492299 TI - [Construction and Validation of a Chronic Kidney Disease Self-Care Scale]. AB - BACKGROUND: As the prevalence of chronic kidney disease (CKD) increases, it is important to understand the self-care behavior of CKD patients. OBJECTIVES: To construct a CKD self-care scale and evaluate its metric properties. METHODS: Through literature review and clinical experience, question items were constructed and validated using item analysis. Factors analysis was used to validate the reliability and validity of the resultant questionnaire in a cross sectional study. RESULTS: Six subscales containing a total of 20 items were extracted from the original CKD self-care scale using item and exploratory factor analysis. After performing three-time model goodness of fit, only five subscales including regular medication (5 items), diet control (4 items), regular exercise (3 items), smoking habits (2 items), and blood pressure management (2 items) were included in the final scale. The total explained variance of the final subscales was 74.96%. The reliability of the scale was examined and found to be satisfactory. Each absolute factor loading value fell between .72 and .94. The Cronbach's alpha for the overall scale was .83 and those for the five subscales were .83, .83, .94, .81, and .87, respectively. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Appropriate assessment tools that allow CKD health educators to evaluate the self-care behaviors of patients effectively are needed. The valid and reliable CKD self-care scale that was developed in the present study is able to assist CKD health educators to quickly evaluate the self-care behavior of patients and to make appropriate health plans. PMID- 27492300 TI - [A Chinese Philosophical Foundation for the Sacred Mission of Nurses: The Ways of Heaven and Life are Correlated]. AB - Clinical nursing practice uses professional nursing techniques, empathy, and moral judgment to help relieve the pain of patients who are suffering physically or mentally from trauma or illness. Thus, nursing involves sacred tasks. According to Confucian reasoning, morality is expressed through everyday actions. Providing care to patients arouses concern and sympathy in the caregiver, which induces him or her to fully apply professional knowledge to this task. This conduct demonstrates the moral conscience of nurses. The Chinese adage "Tian-tao hsing-ming hsiang kuan tung" (the way of heaven and life are correlated), attributed to Northern Song dynasty scholar Zhang Tsai, aptly explains the sacred mission of the nursing profession. Zhang held that all humans are born with a conscience that is given by heaven. However, human senses and desires may suppress this conscience. As Zhang Tsai suggested, the conscience must be cultivated in order to be manifested. The increase in recent years of international academic discussion / research related to the value and meaning of nursing and of exploration into how to promote the moral competence of nurses, not only provide support to Zhang's argument that "tian-tao" and "hsing-ming" are correlated but also provide positive momentum toward enhancing the self-worth of nurses and enabling patients to receive better care. PMID- 27492301 TI - [Application of the 6-Minute Walking Test and Shuttle Walking Test in the Exercise Tests of Patients With COPD]. AB - Exercise training improves the management of stable chronic obstructive pulmonary disease (COPD). COPD patients benefit from exercise training programs in terms of improved VO2 peak values and decreased dyspnea, fatigue, hospital admissions, and rates of mortality, increasing exercise capacity and health-related quality of life (HRQOL). COPD is often associated with impairment in exercise tolerance. About 51% of patients have a limited capacity for normal activity, which often further degrades exercise capacity, creating a vicious circle. Exercise testing is highly recommended to assess a patient's individualized functions and limitations in order to determine the optimal level of training intensity prior to initiating an exercise-training regimen. The outcomes of exercise testing provide a powerful indicator of prognosis in COPD patients. The six-minute walking test (6MWT) and the incremental shuttle-walking test (ISWT) are widely used in exercise testing to measure a patient's exercise ability by walking distances. While nursing-related articles published in Taiwan frequently cite and use the 6MWT to assess exercise capacity in COPD patients, the ISWT is rarely used. This paper introduces the testing method, strengths and weaknesses, and application of the two tests in order to provide clinical guidelines for assessing the current exercise capacity of COPD patients. PMID- 27492302 TI - [The Impact of Sunlight Exposure on the Health of Older Adults]. AB - Appropriate exposure to sunlight not only contributes to the production of vitamin D, which has been associated with enhanced bone health, mood, and cognitive functions, but also regulates the secretion of melatonin, which has been associated with the mediation of circadian rhythms, improved sleep quality, and optimized physical and social activity in the elderly. However, damage to the skin, eyes, and immune system has also been widely associated with long-term exposure to sunlight. Several studies have shown that many elderly, especially those that reside in institutions, do not receive sufficient sunlight exposure. Institutionalized elderly tend to participate in indoor activities and spend significant periods of time alone and asleep in front of the television. Furthermore, factors such as poor health, environmental design, indoor/outdoor preference, and activity design may impact the access of institutionalized elderly to sunlight more than their non-institutionalized peers. Therefore, we suggest that in addition to obtaining sufficient levels of vitamin D from their diet and from supplements, the elderly should perform outdoor activities for 20 30 minutes a day for five days each week. Furthermore, we suggest that the environment of the care facility should be made be more accessible and that some activities should be held outdoors. PMID- 27492303 TI - [To Push or Not to Push? Reflections on the Uterine Fundal Pressure Application in the Second Stage of Labor]. AB - Women who undergo vaginal birth apply uterine fundal pressure during the second stage of labor. Uterine fundal pressure is done manually with the practitioner's forearms, elbows, or palms pressed on the uterine fundus at a 30 degrees to 45 degrees angle to the maternal spine in the direction of the pelvis. The pressure is applied in the longitudinal direction. Gentle, firm, and steady pressure is recommended. The various side effects of applying uterine fundal pressure include: uterine rupture, postpartum urinary retention, severe perineal trauma and pain, rib fracture, postpartum dyspareunia, and potential neonatal distress or trauma. Therefore, caution is recommended in the application of uterine fundal pressure. Thus, only well-trained and experienced medical staff or nurses should be allowed to practice this intervention. PMID- 27492304 TI - [Exploration of Eating Difficulties of Patients With Dementia]. AB - The number of people living with dementia is growing as the average age of the population rises. Eating difficulties are a common problem for dementia patients and their caregivers. The etiology of these difficulties is often complicated. Weight loss, poor nutrition, aspiration pneumonia, and associated medical admissions or even mortality may occur as soon as an eating difficulty develops. This paper presents a literature review of the eating difficulties of dementia patients. The process of eating involves four stages: recognizing food, taking food into the mouth, chewing, and swallowing. We discuss the causes and clinical manifestations of eating difficulties at each of these stages and introduce an intervention for overcoming eating difficulties, aiming at providing choices of methods to improve eating behavior. The author hopes that this review will help medical personnel / caregivers enhance their understanding of the etiology and the clinical manifestation of eating difficulties in dementia patients, evaluate the overall condition of their patient(s), and provide an appropriate intervention in order to help these patients experience the most comfortable and non-invasive ways of eating or feeding, improve their quality of eating, and realize with their family improved spiritual well-being. PMID- 27492305 TI - [An Experience Promoting the Interdisciplinary Care Model for Dengue Fever]. AB - Emergency departments represent the first line in facing major healthcare events. During major epidemic outbreaks, patients crowding into the emergency departments increase the wait time for patients and overload the staffs that are on duty. The dengue fever outbreak in southern Taiwan during the summer 2015 presented a huge management challenge for physicians and nurses in local hospitals. We responded to this challenge by integrating resources from different hospital departments. This strategy successfully increased group cohesiveness among the medical team, ensuring that they could not only ultimately cope with the outbreak together but also effectively provide patient-centered care. This interdisciplinary care model may serve as a reference for medical professionals for the management of future epidemics and similar events. PMID- 27492306 TI - Alveolar bone loss in relation to toll-like receptor 4 and 9 genotypes and Porphyromonas gingivalis carriage. AB - Toll-like receptors (TLRs) are highly developed sensors to detect microbe associated molecular patterns. Functional polymorphisms of the genes TLR4 and TLR9 were found to be associated with alveolar bone loss in a Porphyromonas gingivalis-induced periodontitis model in mice. Our aim was to examine whether such an association can be detected in a group of Finnish adults. Polymorphisms of TLR4 Asp299Gly (rs4986790) and TLR9 rs187084 (1486 T/C) were genotyped by pyrosequencing and PCR from the saliva samples of 223 adults (age range 40-60 years). Alveolar bone loss, measured from panoramic radiographs, were compared between TLR genotype groups according to subjects' salivary carriage of P. gingivalis, measured using a single copy gene-based real-time PCR. The frequencies of TLR4 wild type and heterozygote variants were 87.4 % and 12.6 %, respectively, while those of TLR9 wild type, heterozygote, and homozygote variants were 25.6 %, 39.1 %, and 35.3 %, respectively. In the TLR4 heterozygote group, P. gingivalis-positive subjects had more alveolar bone loss than P. gingivalis-negative subjects (p = 0.027), while no difference was observed in the wild type group. P. gingivalis-negative individuals with TLR9 heterozygotes exhibited significantly less alveolar bone loss compared to those with TLR9 wild type (p = 0.007). Polymorphisms of TLR4 in P. gingivalis carriers seem to expose to alveolar bone loss. Polymorphisms of TLR9 can be protective against alveolar bone loss in the absence of P. gingivalis. PMID- 27492307 TI - IFITM3 and severe influenza virus infection. No evidence of genetic association. AB - Influenza virus infection (IVI) is typically subclinical or causes a self limiting upper respiratory disease. However, in a small subset of patients IVI rapidly progresses to primary viral pneumonia (PVP) with respiratory failure; a minority of patients require intensive care unit admission. Inherited and acquired variability in host immune responses may influence susceptibility and outcome of IVI. However, the molecular basis of such human factors remains largely elusive. It has been proposed that homozygosity for IFITM3 rs12252-C is associated with a population-attributable risk of 5.4 % for severe IVI in Northern Europeans and 54.3 % for severe H1N1pdm infection in Chinese. A total of 148 patients with confirmed IVI were considered for recruitment; 118 Spanish patients (60 of them hospitalized with PVP) and 246 healthy Spanish individuals were finally included in the statistical analysis. PCR-RFLP was used with confirmation by Sanger sequencing. The allele frequency for rs12252-C was found to be 3.5 % among the general Spanish population. We found no rs12252-C homozygous individuals in our control group. The only Spanish patient homozygous for rs12252-C had a neurological disorder (a known risk factor for severe IVI) and mild influenza. Our data do not suggest a role of rs12252-C in the development of severe IVI in our population. These data may be relevant to recognize whether patients homozygous for rs12252-C are at risk of severe influenza, and hence require individualized measures in the case of IVI. PMID- 27492308 TI - Freireich EJ, Miller A, Emerson CP, Ross JF. The effect of inflammation on the utilization of erythrocyte and transferrin bound radioiron for red cell production. Blood. 1957;12(11):972-983. PMID- 27492309 TI - I'm TORC1-ing platelets and thromboembolism. PMID- 27492310 TI - FBXO11: a novel germinal center B-cell regulator? PMID- 27492311 TI - Versican vs versikine: tolerance vs attack. PMID- 27492312 TI - ROS: novel regulators of thrombopoiesis. PMID- 27492313 TI - [Disability studies: social exclusion a research subject]. AB - The article presents disability studies and elaborates, as their central feature, the distinction between societal disability and impairment which can be described on an individual and medical level. Disability studies define disability as socially caused exclusion. Participation and inclusion, seen as sociopolitical control and counter-terms, do, in fact, have a different content, depending on usage and context. Using the example of the International Classification of Functioning (ICF) and the United Nations Convention on the Rights of Persons with Disabilities (UN CRPD), the respective understanding of disability is depicted. Against this background, the deficits of implementation of the UN CRPD, as criticized by the responsible UN Committee, are shown. Finally, a research agenda for disability studies is outlined, that deals with, among other things, implementation strategies and conflicts of interest in terms of inclusion, furthering widely unquestioned economic conditions and especially the negative impact of European austerity politics. PMID- 27492314 TI - [Impairment - disability - participation for all : New federal reporting in light of the UN Convention on the Rights of Persons with Disabilities]. AB - The new Federal Government's Report on Participation explores the contexts in which impairments become disabilities for those individuals who experience them. In parallel, it outlines the factors that foster inclusion and opportunities to act for everyone in society - despite existing impairments.From a sociopolitical and health policy perspective, disability refers to unequal opportunities based on impairment. Hence, the focus here is on the equalisation of these participation opportunities to match those of the entire population - but always from differentiated perspectives on the various social arenas. The human rights approach stresses protection against discrimination as well as dignity and self determination for all. From a human resources angle, the emphasis is on the performance of individuals in favourable conditions and the attainment of personal goals within their actual everyday circumstances.The new reporting concept is indebted to these perspectives and thus focuses on individual life circumstances, while referring to the WHO's International Classification of Functioning, Disability and Health (ICF) - an approach now validated on a global scale. Therefore, it does not only report on measures provided by services for persons with disabilities but, more crucially, investigates determinants on the personal and environmental levels, unequal opportunities and the interdependency between context and competence for particular sections of the population. Two groups are singled out in the process: elderly persons and individuals with mental health impairments.The participation report is part of the National Action Plan to implement the UN Convention on the Rights of Persons with Disabilities (UNCRPD). An independent scientific committee conceptualises the design of the report while accompanying and commenting upon its realisation. Currently, a second federal report on participation is emerging from the new concept. PMID- 27492315 TI - [Accessibility barriers in the German health care system : Supporting and inhibiting factors when establishing medical centres for mentally and multiply disabled persons]. AB - BACKGROUND: In addition to primary and secondary special care, a special type of care was created in the 2015 German Health Care Strengthening Act [GKV Versorgungsstarkungsgesetz]: medical care centres for adult people with mental and multiple disabilities (MCAMD). This closed a gap in the German healthcare system and part of Article 25 of the UN Convention on the Rights of Persons with Disabilities was implemented. OBJECTIVES: Experiences from pilot projects are useful while implementing these centres. The issue is therefore: which are the supporting (s) and inhibiting (i) factors when establishing MCAMDs in the view of health care providers? METHODS: Based on open guided expert interviews medical directors and initiators of existing and planned centres were interviewed. Data analysis was done by qualitative content analysis. RESULTS: Healthcare providers think reducing barriers in people's minds is most important. In the course of approval procedures, reservations from different actors and institutions were considered (i). During financial negotiations, health insurance companies requested a characterisation of the target group using the ICD-lists, which doesn't comply with the needs of the users (i). Implementation was only possible with a great effort from the initiators paired with willingness from actors of the association of statutory health insurance physicians and the health insurances (s). CONCLUSION: This paper describes the process used to implement MCAMDs. Potential centre providers can be inspired by these results. Further research on the process of implementation of these medical centres is needed, especially taking into account all involved parties. PMID- 27492316 TI - [Recommendation for the collection and analysis of data on participation and disability from the perspective of the World Health Organization]. AB - BACKGROUND: The Convention on the Rights of Persons with Disabilities (UNCRPD) demands actions to improve participation of people with disability and to remove barriers that hinder participation in society on an equal basis with others. Policymaking in this area requires reliable and detailed data on all aspects of disability. Up to now, there has been no standardized tool for collecting data on disability and participation in the general population. In November 2011, WHO, in collaboration with the World Bank, started the development of the Model Disability Survey (MDS). The MDS addresses WHO's conceptualization of disability as an outcome of interactions between a person with a health condition and contextual factors. OBJECTIVES: Presentation of the development and implementation of the MDS and the guidelines for standardized data analysis. METHODS: The development of the MDS was performed in three phases: (1) situation analysis and drafting an alpha version, (2) testing and piloting the alpha version and (3) implementation. RESULTS: The MDS is consequently designed as a survey for the general population without using filters. It has a modular structure and consists of two parts (household questionnaire and individual questionnaire with eight modules). This format allows for its use as a stand alone survey as well as its integration in other (national) surveys. The MDS has been cognitive tested, piloted and implemented in several countries. CONCLUSIONS: The MDS is the first general population survey that provides standardized, detailed and nuanced information on disability and participation of the general population to monitor the implementation of the UNCRPD. PMID- 27492317 TI - [Participation restrictions in substance use disorders : Registration by screening and assessment instruments]. AB - BACKGROUND: Substance use disorders can contribute to severe participation restrictions. Whether these participation restrictions are covered by assessment instruments that are frequently used in addiction treatment services is not known. The international Classification of Functioning, Disability and Health (ICF) provides a framework to compare the content of different assessments. OBJECTIVES: The aim of this study was to investigate whether assessments that are frequently used in German addiction treatment services, cover participation restrictions according to the ICF. MATERIALS AND METHODS: In the summer of 2015, we asked German addiction treatment services to participate in an online survey. Addiction treatment services were approached via the mailing lists of German associations of addiction treatment. Respondents were asked to indicate which assessments from a list of frequently used assessment instruments they were using in their treatment service. The most frequently used assessments were then linked to components of the ICF. RESULTS: A total of N = 177 addiction treatment services responded to the survey. Most of them offered long-term rehabilitation treatment (n = 97; 61 %) or counselling services (n = 44; 28 %). Twelve assessments were used by more than 10 % of the respondents. The analysis revealed a total of 491 so-called meaningful concepts that could be linked to components of the ICF. Of these, 95 (16 %) referred to the ICF component activity and participation. CONCLUSIONS: Frequently used assessments in addiction treatment services include contents of the ICF component activity and participation to a substantial degree. However, this does not mean by default that these assessments can be used to assess participation restriction in a meaningful way. PMID- 27492318 TI - Seroprevalence of Poliovirus Antibodies in the United States Population, 2009 2010. AB - BACKGROUND: Polio is eliminated in the United States, with the last indigenous transmission occurring in 1979. However, global eradication of polio has not yet been completed, so importation of poliovirus into the U.S. is still possible. Specimens from the 2009-10 National Health and Nutrition Examination Survey (NHANES) were analyzed to evaluate population seroprevalence and assess overall risk from a poliovirus importation. METHODS: We evaluated prevalence of serum antibodies to all three poliovirus types using the National Health and Nutrition Examination Survey during 2009-2010. RESULTS: The overall seroprevalence to poliovirus was 93.9 % for type 1, 97.0 % for type 2, and 83.1 % for type 3. Seroprevalence was higher for type 2 compared to the other types (p < 0.001) and lower for type 3 compared to the other types (p < 0.001). There was a tendency for higher seroprevalence in the younger age groups, but this varied by serotype. CONCLUSIONS: Seroprevalence was high (83.1 %-97.0 %) for all three types of poliovirus in the US population during 2009-2010. While there were observed differences by serotype with type 2 having the highest seroprevalence and type 3 having the lowest, consistent with previous observations, no large immunity gaps to poliovirus suggesting an imminent substantial population risk from a poliovirus importation were observed at a population level. PMID- 27492319 TI - Barriers to and Facilitators of Dietetics Education among Students of Diverse Backgrounds: Results of a Survey. PMID- 27492320 TI - Added Sugars Intake Across the Distribution of US Children and Adult Consumers: 1977-2012. AB - BACKGROUND: Public health organizations in the United States have recently increased focus on reducing population consumption of added sugars. OBJECTIVE: The objective of this study is to provide in-depth information on national trends in added sugars consumption and to examine both the mean and distribution of added sugars intake from 1977 to 2012. DESIGN: We conducted a descriptive study using six cross-sectional nationally representative surveys of food intake in the United States: the 1977-1978 National Food Consumption Survey (n=29,668), the 1989-1991 Continuing Survey of Food Intake by Individuals (n=14,827), the 1994 1998 Continuing Survey of Food Intake by Individuals (n=19,027), the 2003-2004 National Health and Nutrition Examination Survey (NHANES; n=8,273), the 2009-2010 NHANES (n=9,042), and the 2011-2012 NHANES (n=16,451). STATISTICAL ANALYSIS: We examined the key dependent variables, calories from added sugars and percentage of total energy intake from added sugars, at the mean and by quintiles of added sugars consumption for children (2 to 18 years) and adults (19 years and older) across the survey years. We also examined trends in added sugars intakes from foods and beverages. We used ordinary least squares regression to examine linear trends between survey years and multinomial logistic regressions to examine sociodemographic characteristics by quintile of added sugars consumption. We adjusted estimates by race, income, sex, and education. RESULTS: The US mean adjusted intake of added sugars remains high. In 2011-2012, children and adults consumed 326 kcal/day and 308 kcal/day, respectively, of added sugars, or 14% and 17%, respectively, of total their energy. For both children and adults, there was a considerable increase in calories from added sugars from 1977 to 2003, followed by a substantial decline from 2003 to 2012. There was no decline in the percentage of total energy intake from added sugars from 2003 to 2012. Changes over time were consistent across each quintile of added sugars consumption. The highest quintile of consumption was more likely to be male and in children was more likely to be non-Hispanic white. CONCLUSIONS: Despite a decline in consumption of added sugars since 2003 in the United States, mean adjusted added sugars intakes continue to be above the recommended level of 10% of the total energy intake. Changes in added sugars consumption from 1977 through 2012 occurred evenly across the distribution of added sugars intakes. PMID- 27492321 TI - Predictors of professional placement outcome: cultural background, English speaking and international student status. AB - Placements provide opportunities for students to develop practice skills in professional settings. Learning in placements may be challenging for culturally and linguistically diverse (CALD) students, international students, or those without sufficient English proficiency for professional practice. This study investigated whether these factors, which are hypothesized to influence acculturation, predict poor placement outcome. Placement outcome data were collected for 854 students who completed 2747 placements. Placement outcome was categorized into 'Pass' or 'At risk' categories. Multilevel binomial regression analysis was used to determine whether being CALD, an international student, speaking 'English as an additional language', or a 'Language other than English at home' predicted placement outcome. In multiple multilevel analysis speaking English as an additional language and being an international student were significant predictors of 'at risk' placements, but other variables tested were not. Effect sizes were small indicating untested factors also influenced placement outcome. These results suggest that students' English as an additional language or international student status influences success in placements. The extent of acculturation may explain the differences in placement outcome for the groups tested. This suggests that learning needs for placement may differ for students undertaking more acculturative adjustments. Further research is needed to understand this and to identify placement support strategies. PMID- 27492322 TI - The importance of mentoring during educational supervision. PMID- 27492323 TI - Basic science in integrated curricula : A medical student experience. PMID- 27492324 TI - Modulation of endogenous antioxidant defense and the progression of kidney disease in multi-heritage groups of patients with type 2 diabetes: PRospective EValuation of Early Nephropathy and its Treatment (PREVENT). AB - BACKGROUND: Diabetes is the western world's leading cause of end-stage renal disease. Glucose-dependent, oxidative stress is linked to the development of renal inflammation and sclerosis, which, in animal models of diabetes, can be prevented by anti-oxidative treatment. Patients of non-Caucasian heritage have low activity of the selenoprotein, antioxidant enzyme, glutathione peroxidase (GPx) and its co-factor vitamin E, which may be linked to their increased propensity to developing end-stage renal disease. RESEARCH DESIGN AND METHODS: We have designed a double-blind, randomized, placebo controlled study with selenium and/or vitamin E versus placebo as the interventions for patients with type 2 diabetes and chronic kidney disease (CKD) stages 1-3. A 2 * 2 factorial design will allow a balanced representation of the heritage groups exposed to each intervention. The primary biochemical outcome is change in GPx activity, and clinical outcome measure is the actual, rate of-and/or percentage change in estimated glomerular filtration rate (eGFR) from baseline. Analysis will be with a marginal model for longitudinal data using Generalized Estimating Equations corrected for measures of baseline serum antioxidant enzyme activities (GPx, superoxide dismutase and catalase), micronutrient levels (vitamins E and C), measures of inflammation (interleukin 6, c-reactive protein and monocyte chemoattractant protein-1) and markers of oxidative damage (plasma 8 isoprostaglandin F2alpha and urinary 8-hydroxydeoxyguanosine). EXPECTED RESULTS: The study will assess the relationship between GPx activity, oxidative stress, inflammation and eGFR. It will test the null hypothesis that antioxidant therapy does not influence the activity of GPx or other antioxidant enzymes and/or alter the rate of change in eGFR in these patient groups. CONCLUSIONS: Outcome data on the effect of antioxidants in human diabetic renal disease is limited. Previous post hoc analyses have not shown a beneficial effect of vitamin E on renal function. A recent trial of a pharmaceutical antioxidant agent, improved eGFR, but in patients with advanced diabetes-related chronic kidney disease its use was associated with an increased incidence of cardiovascular events. We will explore whether the nutritional antioxidants, vitamin E and selenium alone, or in combination in patients at high risk of renal disease progression, forestalls a reduction in eGFR. The study will describe whether endogenous antioxidant enzyme defenses can be safely modified by this intervention and how this is associated with changes in markers of oxidative stress. Trial registration ISRCTN 97358113. Registered 21st September 2009. PMID- 27492325 TI - The validity of a professional competence tool for physiotherapy students in simulation-based clinical education: a Rasch analysis. AB - BACKGROUND: Despite the recent widespread adoption of simulation in clinical education in physiotherapy, there is a lack of validated tools for assessment in this setting. The Assessment of Physiotherapy Practice (APP) is a comprehensive tool used in clinical placement settings in Australia to measure professional competence of physiotherapy students. The aim of the study was to evaluate the validity of the APP for student assessment in simulation settings. METHODS: A total of 1260 APPs were collected, 971 from students in simulation and 289 from students in clinical placements. Rasch analysis was used to examine the construct validity of the APP tool in three different simulation assessment formats: longitudinal assessment over 1 week of simulation; longitudinal assessment over 2 weeks; and a short-form (25 min) assessment of a single simulation scenario. Comparison with APPs from 5 week clinical placements in hospital and clinic-based settings were also conducted. RESULTS: The APP demonstrated acceptable fit to the expectations of the Rasch model for the 1 and 2 week clinical simulations, exhibiting unidimensional properties that were able to distinguish different levels of student performance. For the short-form simulation, nine of the 20 items recorded greater than 25 % of scores as 'not-assessed' by clinical educators which impacted on the suitability of the APP tool in this simulation format. CONCLUSION: The APP was a valid assessment tool when used in longitudinal simulation formats. A revised APP may be required for assessment in short-form simulation scenarios. PMID- 27492326 TI - [Light and noise: Environmental factors in intensive care units]. PMID- 27492327 TI - Chemopreventive effect of Phaleria macrocarpa on colorectal cancer aberrant crypt foci in vivo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Natural products are important ingredients for pharmaceutical applications specifically new entities for treating cancer and other diseases. Phaleria macrocarpa is native of Indonesia and considered as a prolific source of bioactive substances useful for chemoprevention. AIM OF THE STUDY: To investigate the chemopreventive properties of Phaleria macrocarpa on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rats. METHODS: The biological activities of the ethanol extract of P. macrocarpa fruits were evaluated both in vitro and in vivo. First the extract was investigated for its in vitro antioxidant activity by the total phenolic content and ferric reducing antioxidant power assay. Then the chemopreventive effect of P. macrocarpa was performed on AOM-induced aberrant crypt foci as colorectal carcinoma model in rats. RESULT: the crude ethanolic extract of P. macrocarpa has high antioxidant activity and modulated the oxidative stress as proved by the up-regulation of glutathione-s-transferase and superoxide dismutase. Immunohistochemical staining of the treated sections showed overexpression of PCNA and Bax, reduced crypt sizes and numbers, indicating the characteristic feature of apoptotic cancer cells. PCNA is a landmark of cell damage and turn-over and can be associated with clinical cancer mutation. The most potent doses were 250mg/kg and 500mg/kg as compared to 35mg/kg 5-fluorouracil. CONCLUSION: In this sense, the potential modulation of the colorectal pathophysiological pathway by P. macrocarpa natural compounds mostly flavonoids offer a great possibility for the discovery of new leads towards the colorectal cancer. PMID- 27492328 TI - Benzoate fraction from Gentiana rigescens Franch alleviates scopolamine-induced impaired memory in mice model in vivo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: G. rigescens Franch (Long Dan Cao in Chinese) is a well-known TCM herb. It is clinically used with other drugs for the treatment of brain diseases such as epilepsy, postherpetic neuralgia in China. AIM OF STUDY: In our previous study, the 11 dihydroxybenzoates compounds with NGF mimicking activity from G. rigescens Franch were found. In the present study, the neurogenesis and neuroprotection of a mixture of benzoates ( n-GS) were investigated in animal level. MATERIALS AND METHODS: The NGF mimicking activity of n-GS from G. rigescens Franch was examined in PC12 cells. The neurogenesis effects of n-GS were investigated in ICR mice with 5-bromo-2-deoxyuridine (BrdU) and neuronal neclei (NeuN) double immunostaining. Furthermore, the neuroprotection effects of n-GS on the memory in a scopolamine (SCO)-induced mouse model were evaluated with animal behavior tests. RESULTS: The NGF-mimicking function and neurogenesis of n-GS were observed in PC12 cells and in normal mice. Subsequently, we investigated the effects of n-GS on the memory in a SCO-induced mouse model. In Y-maze test, SCO significantly lowered the alternation. This finding was reversed by n-GS and donepezil (DONE). SCO significantly impaired the mice's performance in novel object recognition (NOR) and Morris water maze (MWM) tests. The time spent to explore the novel object was longer in the n-GS- and DONE-treated groups than in the SCO control group. In the MWM test, the escape latency of n-GS- and DONE-treated groups was shorter than that of the SCO control group. Mechanism study showed that SCO significantly reduced superoxide dismutase (SOD) but increased the activities of acetylcholinesterase (AChE) and the levels of malondialdehyde (MDA) in the hippocampus and cerebral cortex, which all can be improved by n-GS and DONE. Additionally, the phosphorylation of type 1 insulin like growth factor (IGF-1) receptor, extracellular signal-regulated kinase (ERK), and cAMP responsive element-binding (CREB) protein in the hippocampus was significantly up-regulated in the treatment group compared with that in the SCO group. CONCLUSIONS: n-GS could alleviate impaired memory of the SCO-induced mice model by inhibiting AChE activity and oxidative stress, and regulating the IGF 1R/ERK signaling pathway. PMID- 27492329 TI - Preterm infant gut microbiota affects intestinal epithelial development in a humanized microbiome gnotobiotic mouse model. AB - Development of the infant small intestine is influenced by bacterial colonization. To promote establishment of optimal microbial communities in preterm infants, knowledge of the beneficial functions of the early gut microbiota on intestinal development is needed. The purpose of this study was to investigate the impact of early preterm infant microbiota on host gut development using a gnotobiotic mouse model. Histological assessment of intestinal development was performed. The differentiation of four epithelial cell lineages (enterocytes, goblet cells, Paneth cells, enteroendocrine cells) and tight junction (TJ) formation was examined. Using weight gain as a surrogate marker for health, we found that early microbiota from a preterm infant with normal weight gain (MPI-H) induced increased villus height and crypt depth, increased cell proliferation, increased numbers of goblet cells and Paneth cells, and enhanced TJs compared with the changes induced by early microbiota from a poor weight gain preterm infant (MPI-L). Laser capture microdissection (LCM) plus qRT-PCR further revealed, in MPI-H mice, a higher expression of stem cell marker Lgr5 and Paneth cell markers Lyz1 and Cryptdin5 in crypt populations, along with higher expression of the goblet cell and mature enterocyte marker Muc3 in villus populations. In contrast, MPI-L microbiota failed to induce the aforementioned changes and presented intestinal characteristics comparable to a germ-free host. Our data demonstrate that microbial communities have differential effects on intestinal development. Future studies to identify pioneer settlers in neonatal microbial communities necessary to induce maturation may provide new insights for preterm infant microbial ecosystem therapeutics. PMID- 27492330 TI - A long noncoding RNA signature for ulcerative colitis identifies IFNG-AS1 as an enhancer of inflammation. AB - High-throughput technologies revealed new categories of genes, including the long noncoding RNAs (lncRNAs), involved in the pathogenesis of human disease; however, the role of lncRNAs in the ulcerative colitis (UC) has not been evaluated. Gene expression profiling was used to develop lncRNA signatures in UC samples. Jurkat T cells were activated by PMA/ionomycin subsequently interferon-gamma (IFNG) and tumor necrosis factor (TNF)-alpha protein levels were assessed by ELISA. Anti sense molecules were designed to block IFNG-AS1 expression. A unique set of lncRNAs was differentially expressed between UC and control samples. Of these, IFNG-AS1 was among the highest statistically significant lncRNAs (fold change: 5.27, P value: 7.07E-06). Bioinformatic analysis showed that IFNG-AS1 was associated with the IBD susceptibility loci SNP rs7134599 and its genomic location is adjacent to the inflammatory cytokine IFNG. In mouse models of colitis, active colitis samples had increased colonic expression of this lncRNA. Utilizing the Jurkat T cell model, we found IFNG-AS1 to positively regulate IFNG expression. Novel lncRNA signatures differentiate UC patients with active disease, patients in remission, and control subjects. A subset of these lncRNAs was found to be associated with the clinically validated IBD susceptibility loci. IFNG-AS1 was one of these differentially expressed lncRNAs in UC patients and found to regulate the key inflammatory cytokine, IFNG, in CD4 T cells. Taking these findings together, our study revealed novel lncRNA signatures deregulated in UC and identified IFNG-AS1 as a novel regulator of IFNG inflammatory responses, suggesting the potential importance of noncoding RNA mechanisms on regulation of inflammatory bowel disease-related inflammatory responses. PMID- 27492332 TI - Long noncoding RNAs: novel links to inflammatory bowel disease? PMID- 27492331 TI - Role of the sodium-dependent multivitamin transporter (SMVT) in the maintenance of intestinal mucosal integrity. AB - Utilizing a conditional (intestinal-specific) knockout (cKO) mouse model, we have recently shown that the sodium-dependent multivitamin transporter (SMVT) (SLC5A6) is the only biotin uptake system that operates in the gut and that its deletion leads to biotin deficiency. Unexpectedly, we also observed that all SMVT-cKO mice develop chronic active inflammation, especially in the cecum. Our aim here was to examine the role of SMVT in the maintenance of intestinal mucosal integrity [permeability and expression of tight junction (TJ) proteins]. Our results showed that knocking out the mouse intestinal SMVT is associated with a significant increase in gut permeability and with changes in the level of expression of TJ proteins. To determine whether these changes are related to the state of biotin deficiency that develops in SMVT-cKO mice, we induced (by dietary means) biotin deficiency in wild-type mice and examined its effect on the above-mentioned parameters. The results showed that dietary-induced biotin deficiency leads to a similar development of chronic active inflammation in the cecum with an increase in the level of expression of proinflammatory cytokines, as well as an increase in intestinal permeability and changes in the level of expression of TJ proteins. We also examined the effect of chronic biotin deficiency on permeability and expression of TJ proteins in confluent intestinal epithelial Caco-2 monolayers but observed no changes in these parameters. These results show that the intestinal SMVT plays an important role in the maintenance of normal mucosal integrity, most likely via its role in providing biotin to different cells of the gut mucosa. PMID- 27492335 TI - Transcultural Adaptation and Validation of the German Version of the Vocal Tract Discomfort Scale. AB - OBJECTIVES: Currently, there is no standardized German questionnaire to assess vocal tract discomfort in voice patients. The aim of this study was to evaluate the internal consistency, reliability, and validity of the German version of the Vocal Tract Discomfort (VTD) Scale. STUDY DESIGN: This is a cross-sectional study. METHODS: First, a cross-cultural translation and adaptation from English to German was performed. One hundred seven patients between the ages of 18 and 76 with voice disorders were divided into two different diagnosis-related groups (organic and functional voice disorder) and 50 vocally healthy adults were included. All participants completed the VTD Scale and the Voice Handicap Index (VHI). The internal consistency of the VTD Scale was analyzed through Cronbach's alpha coefficient. Pearson correlation between the VDT Scale and VHI total scores was used to determine criterion validity. The VDT Scale score differences related to diagnosis groups were assessed with analysis of variance. RESULTS: Excellent internal consistency was found (alpha = 0.919, P < 0.05), and criterion validity was confirmed by a high correlation between the total VTD Scale and VHI (r = 0.674). There was a significant difference between the diagnosis groups' total VTD Scale score (F[4.135] = 15.114, P = 0.000). Furthermore, the vocally healthy adults had significantly lower values than the two diagnosis groups (x-: 11.48, s = 8.340). CONCLUSIONS: The German version of the VTD Scale has an excellent internal consistency and reliability, and shows high clinical validity. Thus, it is a useful instrument in voice diagnostics. PMID- 27492334 TI - Pediatric intraventricular arachnoid cysts in the body of lateral ventricle: surgical outcome and its embryologic background. AB - PURPOSE: The aim of this study is for the surgical treatment and outcome of the endoscopic fenestration of the arachnoid cyst located in the ventricular body to trigone in the pediatric population. Special concern was paid for the developmental origin of the intraventricular cysts estimated from the postoperative follow-up neuroimagings. PATIENTS AND METHODS: Between July 2002 and June 2015, we performed endoscopic and partly CT/MRI navigated fenestrations of intraventricular arachnoid cysts located at the body to trigone of the lateral ventricle in ten pediatric patients aged 2 months to 5 years. Based on the long axis of the cyst, we have opted for two surgical approaches: anterior approach via burr hole at Kocher's point and posterior approach via burr hole at the posterior occipital region. Fenestration was performed based on the intraoperative findings, either ventriculocystostomy, ventriculocystoventriculostomy, or ventriculocystocisternostomy. RESULTS: Intraventricular arachnoid cysts located in the body-trigone region showed a favorable outcome after endoscopic fenestration. All of the cysts shrank postoperatively. Follow-up neuroimagings taken between 6 and 126 months after surgery strongly suggested its relationship with the midline cisterns. Of our ten cases, eight were suggestive for originating from the velum interpositum cistern while two seemed to root from the quadrigeminal cistern. CONCLUSION: In the present study, we found that endoscopic fenestration of intraventricular arachnoid cysts in the body to trigone is a safe procedure with a satisfactory outcome. In our limited experience, there are two anatomic backgrounds; velum interpositum cistern and quadrigeminal cistern. Differentiation can be possible by neuroimagings, especially those obtained after surgery. PMID- 27492333 TI - The serine protease-mediated increase in intestinal epithelial barrier function is dependent on occludin and requires an intact tight junction. AB - Barrier dysfunction is a characteristic of the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis. Understanding how the tight junction is modified to maintain barrier function may provide avenues for treatment of IBD. We have previously shown that the apical addition of serine proteases to intestinal epithelial cell lines causes a rapid and sustained increase in transepithelial electrical resistance (TER), but the mechanisms are unknown. We hypothesized that serine proteases increase barrier function through trafficking and insertion of tight junction proteins into the membrane, and this could enhance recovery of a disrupted monolayer after calcium switch or cytokine treatment. In the canine epithelial cell line, SCBN, we showed that matriptase, an endogenous serine protease, could potently increase TER. Using detergent solubility-based cell fractionation, we found that neither trypsin nor matriptase treatment changed levels of tight junction proteins at the membrane. In a fast calcium switch assay, serine proteases did not enhance the rate of recovery of the junction. In addition, serine proteases could not reverse barrier disruption induced by IFNgamma and TNFalpha. We knocked down occludin in our cells using siRNA and found this prevented the serine protease-induced increase in TER. Using fluorescence recovery after photobleaching (FRAP), we found serine proteases induce a greater mobile fraction of occludin in the membrane. These data suggest that a functional tight junction is needed for serine proteases to have an effect on TER, and that occludin is a crucial tight junction protein in this mechanism. PMID- 27492336 TI - Optimal Duration for Voice Rest After Vocal Fold Surgery: Randomized Controlled Clinical Study. AB - OBJECTIVES: Voice rest is commonly recommended after phonomicrosurgery to prevent worsening of vocal fold injuries. However, the most effective duration of voice rest is unknown. Recently, early vocal stimulation was recommended as a means to improve wound healing. The purpose of this study is to examine the optimal duration of voice rest after phonomicrosurgery. STUDY DESIGN: Randomized controlled clinical study. METHODS: Patients undergoing phonomicrosurgery for leukoplakia, carcinoma in situ, vocal fold polyp, Reinke's edema, and cyst were chosen. Participants were randomly assigned to voice rest for 3 or 7 postoperative days. Voice therapy was administered to both groups after voice rest. Grade, roughness, breathiness, asthenia, and strain (GRBAS) scale, stroboscopic examination, aerodynamic assessment, acoustic analysis, and Voice Handicap Index-10 (VHI-10) were performed pre- and postoperatively at 1, 3, and 6 months. Stroboscopic examination evaluated normalized mucosal wave amplitude (NMWA). Parameters were compared between both groups. RESULTS: Thirty-one patients were analyzed (3-day group, n = 16; 7-day group, n = 15). Jitter, shimmer, and VHI-10 were significantly better in the 3-day group at 1 month post operation. GRBAS was significantly better in the 3-day group at 1 and 3 months post operation, and NMWA was significantly better in the 3-day group at 1, 3, and 6 months post operation compared to the 7-day group. CONCLUSIONS: The data suggest that 3 days of voice rest followed by voice therapy may lead to better wound healing of the vocal fold compared to 7 days of voice rest. Appropriate mechanical stimulation during early stages of vocal fold wound healing may lead to favorable functional recovery. PMID- 27492337 TI - Transcatheter Aortic Valve Replacement Using the Portico System: 10 Things to Remember. AB - The Portico system (St. Jude Medical, Minneapolis, MN, USA) consists of a self expanding valve prosthesis and a delivery system designed for transcatheter aortic valve replacement (TAVR). We describe this system, its 10-steps implantation procedure, and provide tips and tricks based on our personal experience with this system. PMID- 27492338 TI - Implementing oxygen control in chip-based cell and tissue culture systems. AB - Oxygen is essential in the energy metabolism of cells, as well as being an important regulatory parameter influencing cell differentiation and function. Interest in precise oxygen control for in vitro cultures of tissues and cells continues to grow, especially with the emergence of the organ-on-a-chip and the desire to emulate in vivo conditions. This was recently discussed in this journal in a Critical Review by Brennan et al. (Lab Chip (2014). DOI: ). Microfluidics can be used to introduce flow to facilitate nutrient supply to and waste removal from in vitro culture systems. Well-defined oxygen gradients can also be established. However, cells can quickly alter the oxygen balance in their vicinity. In this Tutorial Review, we expand on the Brennan paper to focus on the implementation of oxygen analysis in these systems to achieve continuous monitoring. Both electrochemical and optical approaches for the integration of oxygen monitoring in microfluidic tissue and cell culture systems will be discussed. Differences in oxygen requirements from one organ to the next are a challenging problem, as oxygen delivery is limited by its uptake into medium. Hence, we discuss the factors determining oxygen concentrations in solutions and consider the possible use of artificial oxygen carriers to increase dissolved oxygen concentrations. The selection of device material for applications requiring precise oxygen control is discussed in detail, focusing on oxygen permeability. Lastly, a variety of devices is presented, showing the diversity of approaches that can be employed to control and monitor oxygen concentrations in in vitro experiments. PMID- 27492339 TI - Development and preliminary psychometric properties of the General Practitioner Attitudes and Confidence Scale (GPACS-D) for dementia. AB - BACKGROUND: International evidence suggests that dementia is under-diagnosed in the community and that General Practitioners (GPs) are often reluctant to engage to their fullest capability with patients who exhibit cognitive symptoms. This is potentially reflected by a lack of GP knowledge about the syndrome. However, it is also recognised that attitudes and confidence are important in relation to how and to what extent a GP approaches a person with dementia. This research sought to develop a reliable and valid measure of GPs attitudes and confidence towards dementia. METHODS: The General Practitioner Attitudes and Confidence Scale for Dementia (GPACS-D) was developed via a four stage process, including initial content development, pretesting, pilot testing and psychometric evaluation, including Principal Component Analysis (PCA). Participants were recruited for pre testing (n = 12), test-retest (n = 55), and dementia workshop pre-and post education evaluation (n = 215). RESULTS: The process of scale development and psychometric evaluation resulted in a 20-item measure of GP attitudes and confidence towards dementia, with 4 items removed due to poor reliability, low sensitivity, or lack of model fit. Among 55 respondents who completed the scale on two occasions with no intervening education, Kappa coefficient scores per item ranged from fair (n = 2, candidates for removal), moderate (n = 5), substantial (n = 15), and almost perfect (n = 2). A test of the sensitivity of item scores to change following dementia education among 215 GPs indicated that, with the exception of one item, all scale responses exhibited significant differences between pre-and post-workshop scores, indicating acceptable sensitivity. With one further item removed due to a low communality score, the final PCA undertaken with the remaining 20 items supports a four-component solution, which accounted for 51.9 % of the total variance. CONCLUSION: The GPACS-D provides a reliable and preliminarily valid measure of GP attitudes and confidence towards dementia. The scales provide useful information for medical educators and researchers who are interested in evaluating and intervening in GP perceptions of the syndrome and their capacity to provide effective care. PMID- 27492340 TI - Characteristic calcaneal ossification: an additional early radiographic finding in infants with fibrodysplasia ossificans progressiva. AB - BACKGROUND: We have clinically encountered children with fibrodysplasia ossificans progressiva who had abnormal calcaneal ossification. OBJECTIVE: To evaluate whether calcaneal ossification variants are significant radiographic findings in children with fibrodysplasia ossificans progressiva. MATERIALS AND METHODS: Lateral feet radiographs in nine children who fulfilled the diagnostic criteria of fibrodysplasia ossificans progressiva were reviewed. The studies were obtained during infancy or early childhood. RESULTS: Fourteen lateral foot radiographs of fibrodysplasia ossificans progressiva were available for this study (ages at examination: 1-104 months). Four children ages 2 months to 11 months showed double calcaneal ossification centers; 7 children had plantar calcaneal spurs that decreased in size with age. Overall, eight of nine children with fibrodysplasia ossificans progressiva demonstrated double calcaneal ossifications and/or plantar calcaneal spurs in infancy or childhood. CONCLUSION: Double calcaneal ossification centers in early infancy and plantar calcaneal spurs in childhood are frequently seen in children with fibrodysplasia ossificans progressiva and may be a useful radiologic indicator for early diagnosis. PMID- 27492342 TI - Identifying Important Attributes for Prognostic Prediction in Traumatic Brain Injury Patients. A Hybrid Method of Decision Tree and Neural Network. AB - BACKGROUND: Generally, traumatic brain injury (TBI) patients do not have a stable condition, particularly after the first week of TBI. Hence, indicating the attributes in prognosis through a prediction model is of utmost importance since it helps caregivers with treatment-decision options, or prepares the relatives for the most-likely outcome. OBJECTIVES: This study attempted to determine and order the attributes in prognostic prediction in TBI patients, based on early clinical findings. A hybrid method was employed, which combines a decision tree (DT) and an artificial neural network (ANN) in order to improve the modeling process. METHODS: The DT approach was applied as the initial analysis of the network architecture to increase accuracy in prediction. Afterwards, the ANN structure was mapped from the initial DT based on a part of the data. Subsequently, the designed network was trained and validated by the remaining data. 5-fold cross-validation method was applied to train the network. The area under the receiver operating characteristic (ROC) curve, sensitivity, specificity, and accuracy rate were utilized as performance measures. The important attributes were then determined from the trained network using two methods: change of mean squared error (MSE), and sensitivity analysis (SA). RESULTS: The hybrid method offered better results compared to the DT method. The accuracy rate of 86.3 % vs. 82.2 %, sensitivity value of 55.1 % vs. 47.6 %, specificity value of 93.6 % vs. 91.1 %, and the area under the ROC curve of 0.705 vs. 0.695 were achieved for the hybrid method and DT, respectively. However, the attributes' order by DT method was more consistent with the clinical literature. CONCLUSIONS: The combination of different modeling methods can enhance their performance. However, it may create some complexities in computations and interpretations. The outcome of the present study could deliver some useful hints in prognostic prediction on the basis of early clinical findings for TBI patients. PMID- 27492341 TI - Effect of hydration status on atrial and ventricular volumes and function in healthy adult volunteers. AB - BACKGROUND: Assessment of cardiac chamber volumes is a fundamental part of cardiac magnetic resonance (CMR) imaging. While the effects of inter- and intraobserver variability have been studied and have a recognized effect on the comparability of serial cardiac MR imaging studies, the effect of differences in hydration status has not been evaluated. OBJECTIVE: To evaluate the effects of volume administration on cardiac chamber volumes. MATERIALS AND METHODS: Thirteen healthy adults underwent a baseline cardiac MR to evaluate cardiac chamber volumes after an overnight fast. They were then given two saline boluses of 10 ml/kg of body weight and the cardiac MR was repeated immediately after each bolus. RESULTS: From the baseline scan to the final scan there was a significant increase in all four cardiac chamber end-diastolic volumes. Right atrial volumes increased 8.0%, from 61.1 to 66.0 ml/m2 (P<0.001), and left atrial volumes increased 10.0%, from 50.0 to 55.0 ml/m2 (P<0.001). Right ventricular volumes increased 6.0%, from 91.1 to 96.5 ml/m2 (P<0.001), and left ventricular volumes increased 3.2%, from 87.0 to 89.8 ml/m2 (P<0.001). CONCLUSION: Hydration status has a significant effect on the end-diastolic volumes of all cardiac chambers assessed by cardiac MR. Thus, hydration represents a "variable" that should be taken into account when assessing cardiac chamber volumes, especially when performing serial imaging studies in a patient. PMID- 27492343 TI - The Proposed ICD-11 Gender Incongruence of Childhood Diagnosis: A World Professional Association for Transgender Health Membership Survey. AB - ICD-11 (the eleventh edition of the World Health Organization International Statistical Classification of Diseases and Related Health Problems) is due for approval in 2018. For transgender health care, the most important proposals for ICD-11 are as follows: (1) the five ICD-10 diagnoses (most notably Transsexualism and Gender Identity Disorder of Childhood) currently in Chapter 5 (Mental and Behavioural Disorders) will be replaced by two Gender Incongruence diagnoses, one of Adolescence and Adulthood and the other of Childhood (GIC), and (2) these two diagnoses will be located in a new chapter provisionally named Conditions Related to Sexual Health. Debate on the GIC proposal has focused on whether there should be a diagnosis for young children exploring their identity and has drawn on a number of arguments for and against the proposal. The World Professional Association for Transgender Health conducted a survey to examine members' views concerning the GIC proposal, as well as an alternative framework employing non pathologizing Z Codes. The survey was completed by 241 (32.6 %) out of 740 members. Findings indicated an even split among members regarding the GIC proposal (51.0 % [n = 123] opposing and 47.7 % [n = 115] supporting the proposal). However, non-US members were overall opposed to the proposal (63.9 % [n = 46] opposing, 36.1 % [n = 26] supporting). Across the sample as a whole, and among those expressing a view about Z Codes, there was substantial support for their use in healthcare provision for children with gender issues (35.7 % [n = 86] of the sample supporting vs. 8.3 % [n = 20] rejecting). PMID- 27492344 TI - Colorectal cancer in Malaysia: Its burden and implications for a multiethnic country. AB - BACKGROUND: This study aims to provide an analytical overview of the changing burden of colorectal cancer and highlight the implementable control measures that can help reduce the future burden of colorectal cancer in Malaysia. METHODS: We performed a MEDLINE search via OVID with the Medical Subject Headings (MeSH) terms "Colorectal Neoplasms"[Mesh] and "Malaysia"[Mesh], and PubMed with the key words "colorectal cancer" and "Malaysia" from 1990 to 2015 for studies reporting any clinical, societal, and economical findings associated with colorectal cancer in Malaysia. Incidence and mortality data were retrieved from population-based cancer registries/databases. RESULTS: In Malaysia, colorectal cancer is the second most common cancer in males and the third most common cancer in females. The economic burden of colorectal cancer is substantial and is likely to increase over time in Malaysia owing to the current trend in colorectal cancer incidence. In Malaysia, most patients with colorectal cancer have been diagnosed at a late stage, with the 5-year relative survival by stage being lower than that in developed Asian countries. Public awareness of the rising incidence of colorectal cancer and the participation rates for colorectal cancer screening are low. CONCLUSION: The efficiency of different screening approaches must be assessed, and an organized national screening program should be developed in a phased manner. It is essential to maintain a balanced investment in awareness programs targeting general population and primary care providers, focused on increasing the knowledge on symptoms and risk factors of colorectal cancer, awareness on benefits of screening, and promotion of healthy life styles to prevent this important disease. PMID- 27492345 TI - Isolation, characterization, and marker utility of KCRE1, a transcriptionally active Ty1/copia retrotransposon from Kandelia candel. AB - Transposable elements are key players in eukaryotic genomic diversity. Due to their high abundance, great heterogeneity, and replicative transposition, long terminal repeat (LTR) retrotransposons are well suited as molecular markers for breeding and biodiversity studies, whereas their utilities in non-model organisms have been hindered by the lack of prior sequence knowledge. In this study, a putative complete (5362 bp) LTR retrotransposon was isolated and characterized in the mangrove species Kandelia candel (named KCRE1), and its transcription, insertional polymorphisms and copy number variations were also investigated. KCRE1 has all the features of a typical copia retroelement, and its transcription initiation and termination sites were identified by 5' and 3' rapid amplification of cDNA ends (RACE), respectively. KCRE1 exhibits high sequence similarity with the tomato retroelement Rider and is constitutively expressed in the leaf, root, flower, and hypocotyl tissues of K. candel. Based on KCRE1, sequence-specific amplification polymorphism (SSAP) markers were developed to explore genetic diversity across 30 individuals from three natural populations of K. candel in China. Six primer combinations yielded a total of 204 SSAP bands with an averaged percentage of polymorphic loci of 55.37 and 41.35 % at the species and population levels, respectively. Each individual had a distinct SSAP phenotype, and 14-23 unique bands were observed for each population. Accordingly, KCRE1 was highly abundant in the genome of K. candel and showed considerable copy number variation among the three populations. In conclusion, KCRE1 is the first transcriptionally active retrotransposon reported in K. candel, providing a useful tool for the elucidation of untapped genetic diversity in mangrove genomes. PMID- 27492346 TI - Nutrient production from dairy cattle manure and loading on arable land. AB - OBJECTIVE: Along with increasing livestock products via intensive rearing, the accumulation of livestock manure has become a serious issue due to the fact that there is finite land for livestock manure recycling via composting. The nutrients from livestock manure accumulate on agricultural land and the excess disembogues into streams causing eutrophication. In order to systematically manage nutrient loading on agricultural land, quantifying the amount of nutrients according to their respective sources is very important. However, there is a lack of research concerning nutrient loss from livestock manure during composting or storage on farms. Therefore, in the present study we quantified the nutrients from dairy cattle manure that were imparted onto agricultural land. METHODS: Through investigation of 41 dairy farms, weight reduction and volatile solids (VS), total nitrogen (TN), and total phosphorus (TP) changes of dairy cattle manure during the storage and composting periods were analyzed. In order to support the direct investigation and survey on site, the three cases of weight reduction during the storing and composting periods were developed according to i) experiment, ii) reference, and iii) theoretical changes in phosphorus content (DeltaP = 0). RESULTS: The data revealed the nutrient loading coefficients (NLCs) of VS, TN, and TP on agricultural land were 1.48, 0.60, and 0.66, respectively. These values indicated that the loss of nitrogen and phosphorus was 40% and 34%, respectively, and that there was an increase of VS since bedding materials were mixed with excretion in the barn. CONCLUSION: As result of nutrient-footprint analyses, the amounts of TN and TP particularly entered on arable land have been overestimated if applying the nutrient amount in fresh manure. The NLCs obtained in this study may assist in the development of a database to assess the accurate level of manure nutrient loading on soil and facilitate systematic nutrient management. PMID- 27492348 TI - Association of the Single Nucleotide Polymorphisms in RUNX1, DYRK1A, and KCNJ15 with Blood Related Traits in Pigs. AB - The aim of this study was to detect positional candidate genes located within the support interval (SI) regions based on the results of red blood cell, mean corpuscular volume (MCV), and mean corpuscular hemoglobin quantitative trait locus (QTL) in Sus scrofa chromosome 13, and to verify the correlation between specific single-nucleotide polymorphisms (SNPs) located in the exonic region of the positional candidate gene and the three genetic traits. The flanking markers of the three QTL SI regions are SW38 and S0215. Within the QTL SI regions, 44 genes were located, and runt-related transcription factor 1, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), and potassium inwardly rectifying channel, subfamily J, member 15 KCNJ15-which are reported to be related to the hematological traits and clinical features of Down syndrome-were selected as positional candidate genes. The ten SNPs located in the exonic region of the three genes were detected by next generation sequencing. A total of 1,232 pigs of an F2 resource population between Landrace and Korean native pigs were genotyped. To investigate the effects of the three genes on each genotype, a mixed-effect model which is the considering family structure model was used to evaluate the associations between the SNPs and three genetic traits in the F2 intercross population. Among them, the MCV level was highly significant (nominal p = 9.8*10-9) in association with the DYRK1A-SNP1 (c.2989 GC and (g.2988 A>G, g.3977-325 T>C) combinations of fatty acid-binding protein4 were the superior gene, and the superior genotype combinations across all economic traits were the CC genotype at g.3977-325 T>C and the AACC, GACC, GGCC genotypes of (g.2988 A>G, g.3977-325 T>C). PMID- 27492350 TI - Allelic variation of melanocortin-1 receptor locus in Saudi indigenous sheep exhibiting different color coats. AB - OBJECTIVE: This study was designed to characterize the DNA polymorphisms of the melanocortin-1 receptor (MC1R) gene in indigenous Saudi Arabian sheep breeds exhibiting different color coats, along with individuals of the Sawaknee breed, an exotic sheep imported from Sudan. METHODS: The complete coding region of MC1R gene including parts of 3' and 5' untranslated regions was amplified and sequenced from three the indigenous Saudi sheep; Najdi (generally black, n = 41), Naeimi (generally white with brown faces, n = 36) and Herri (generally white, n = 18), in addition to 13 Sawaknee sheep. RESULTS: Five single nucleotide polymorphisms (SNPs) were detected in the MC1R gene: two led to nonsynonymous mutations (c.218 T>A, p.73 Met>Lys and c.361 G>A, p.121 Asp>Asn) and three led to synonymous mutations (c.429 C>T, p.143 Tyr>Tyr; c.600 T>G, p.200 Leu>Leu, and c.735 C>T, p.245 Ile>Ile). Based on these five SNPs, eight haplotypes representing MC1R Ed and E+ alleles were identified among the studied sheep breeds. The most common haplotype (H3) of the dominant Ed allele was associated with either black or brown coat color in Najdi and Sawaknee sheep, respectively. Two other haplotypes (H6 and H7) of Ed allele, with only the nonsynonymous mutation A218T, were detected for the first time in Saudi indigenous sheep. CONCLUSION: In addition to investigating the MC1R allelic variation in Saudi indigenous sheep populations, the present study supports the assumption that the two independent nonsynonymous Met73Lys and Asp121Asn mutations in MC1R gene are associated with black or red coat colors in sheep breeds. PMID- 27492351 TI - Behaviour of mesotrione in maize and soil system and its influence on soil dehydrogenase activity. AB - The aim of this study was to investigate the dissipation of mesotrione and effect on dehydrogenase activity (DHA) in maize and soil system. The paper for the first time describes behaviour of this herbicide applied at various doses (separately or in mixture with other herbicide) in acidic and alkaline environment. The experiments were conducted using the method randomized blocks in four repetition cycles. Chemical application in seven variants at recommended doses of herbicide were performed. The sample preparation was performed by a modified QuEChERS method and the concentrations of mesotrione in maize and soil were determined by the liquid chromatography with tandem mass spectrometry (LC-MS/MS). The limit of detection was 0.0005mgkg(-1) and quantification 0.001mgkg(-1). The dissipation of mesotrione were described according to first-order (FO) kinetics equation with R(2) were between 0.8794 and 0.9934. The initial deposit of herbicide in soil and maize was higher in an acidic environment (0.06-0.18mgkg(-1)). A positive correlation between an alkaline pH and the rate of dissipation in soil was observed. The results showed that the time after which 50% (DT50) of substance has been degraded was different for both plant and soil. DT50 for soil was within the range 3.2-6.0days and 2.9-4.4days, for the maize 3.9-4.8days and 3.4-4.5days in an alkaline and an acidic environment, respectively. Concentration of mesotrione at applicable MRL level of 0.05mgkg(-1) in maize was achieved at 0.5 5.9days and at proposed MRL of 0.01mgkg(-1) at 8.8-15.8days. The results indicate that the application of mesotrione affected on DHA in the soil. One day after application this herbicide, concentration of DHA in soil was lower than in control plots, but after 21days was observed trend of increasing DHA. PMID- 27492352 TI - Diagnosis and Management of Oesophageal Cancer in Bariatric Surgical Patients. AB - BACKGROUND: Oesophageal cancer following bariatric surgery adds significant complexity to an already challenging disease. There is limited data on the diagnosis, presentation and management in these complex cases. METHODS: A retrospective cohort study on prospectively collected data over 10 years was conducted. The oesophago-gastric cancer database was searched for patients with prior bariatric surgery. Data were retrieved on bariatric and cancer management. RESULTS: We identified nine patients with oesophageal or gastro-oesophageal junction adenocarcinoma after bariatric surgery. Mean age was 58.3 +/- 6.9 years, and duration from bariatric surgery was 13.2 +/- 9.4 years. Weight loss at diagnosis was 30.6 +/- 23.3 kg (excess weight loss 58.1 % +/- 29.6). Modes of presentation were Barrett's surveillance (n = 3), reflux symptoms (n = 4) and incidental (n = 2). Management was surgical resection (n = 4), endoscopic mucosal resection (n = 2) and palliative (n = 3). Surgical resections were challenging due to adhesions, obesity, luminal dilatation and scarring on the stomach. There were two substantial leaks following gastroplasty. CONCLUSIONS: Oesophageal cancer following bariatric surgery is a challenging problem, and surgical resection carries high risk. A high index of suspicion is required and symptoms investigated precipitously. Technical challenges of operating on obese patients and the specific effects of previous bariatric procedures need to be understood, particularly the limitations on reconstructive options. PMID- 27492353 TI - Intussusception Involving the Roux-en-Y limb Following Gastric Bypass. PMID- 27492354 TI - A Combined Nissen Plus Hill Hybrid Repair for Paraesophageal Hernia Improves Clinical Outcomes and Reduces Long-Term Recurrences Compared with Laparoscopic Nissen Alone. AB - INTRODUCTION: We compared clinical and objective outcomes of combined Nissen-Hill hybrid (HYB) to Nissen fundoplication (LNF) for repair of paraesophageal hernia (PEH). METHODS: This study is a single-institution retrospective chart review of prospectively collected data for consecutive patients undergoing PEH repair from 2006 to 2015 with at least 6 months of follow-up. Quality of life metrics (QOLRAD, HRQL, and dysphagia), manometry, radiographic imaging, and pH testing were administered pre- and postoperatively. RESULTS: With 319 repairs (HYB = 141, LNF = 178), the groups were comparable in age and gender, but HYB had a higher BMI (30.95 vs 29.27, p < 0.05), larger hernia (6 vs 5 cm, p < 0.05), and more Barrett's esophagus (42 vs 29, p < 0.05). At a median follow-up of 22 months, DeMeester scores were equivalent but PPI use was higher in the LNF group. All three quality of life scores were better for HYB: GERD-HRQL 3.75 vs 7.49, p = 0.01; QOLRAD 6.59 vs 6.23, p = 0.04; and swallowing 40.71 vs 36.47, p = 0.01. At a median follow-up of 60 months (HYB = 39, LNF = 31), anatomic recurrences and reoperations were lower for HYB: 5 vs 45 % (p < 0.05), 2.6 vs 9.7 % (p = 0.2). CONCLUSION: Combining Nissen and Hill for PEH repair appears to result in better quality of life and fewer recurrences compared to LNF. PMID- 27492356 TI - Complex odontomas hindering eruption of maxillary permanent teeth: a radiological perspective. PMID- 27492355 TI - Non-Elective Paraesophageal Hernia Repair Portends Worse Outcomes in Comparable Patients: a Propensity-Adjusted Analysis. AB - INTRODUCTION: Patients undergoing non-elective paraesophageal hernia repair (PEHR) have worse perioperative outcomes. Because they are usually older and sicker, however, these patients may be more prone to adverse events, independent of surgical urgency. Our study aimed to determine whether non-elective PEHR is associated with differential postoperative outcome compared to elective repair, using propensity-score weighting. METHODS: We abstracted data for patients undergoing PEHR (n = 924; non-elective n = 171 (19 %); 1997-2010). Using boosted regression, we generated a propensity-weighted dataset. Odds of 30-day/in hospital mortality and major complications after non-elective surgery were determined. RESULTS: Patients undergoing non-elective repair were significantly older, had more adverse prognostic factors, and significantly more major complications (38 versus 18 %; p < 0.001) and death (8 versus 1 %; p < 0.001). After propensity weighting, median absolute percentage bias across 28 propensity score variables improved from 19 % (significant imbalance) to 5.6 % (well balanced). After adjusting propensity-weighted data for age and comorbidity score, odds of major complications were still nearly two times greater (OR 1.67, CI 1.07-2.61) and mortality nearly three times greater (OR 2.74, CI 0.93-8.1) than for elective repair. CONCLUSIONS: Even after balancing significant differences in baseline characteristics, non-elective PEHR was associated with worse outcomes than elective repair. Symptomatic patients should be referred for elective repair by experienced surgeons. PMID- 27492358 TI - Smoking and Cognition. AB - Given the large availability of nicotinic acetylcholine receptors (nAChRs) throughout the brain, and the wide range of neurotransmitter systems affected (norepinephrine, serotonin and dopamine), nicotine influences a wide variety of cognitive domains such as sensorial, motor, attention, executive function, learning and memory. This article reviews current state of the art research on the effects of nicotine upon cognition. There are different neurobiological mechanisms involved in acute/chronic smoking and nicotine abstinence. Smoking reinforcement could be due to the initial cognitive improvement, that is, individuals can learn that smoking temporarily increases cognitive functioning (improving some components of attention and memory). These acute nicotine effects improve (i) cognitive performance above smokers' normal levels, and (ii) cognitive disruption resulting from nicotine abstinence. Both neurobiological effects act as reinforcers to nicotine use, greatly contributing to the development of nicotine dependence. However, heavy smoking is associated with cognitive impairment and cognitive decline in middle age. Future clinical research should investigate the role of positive and negative cognitive effects of nicotine in smoking cessation treatment. This is clearly an important scientific issue, with insufficient current data from which to draw definitive conclusions. PMID- 27492357 TI - The multiple evolutionary origins of the eukaryotic N-glycosylation pathway. AB - BACKGROUND: The N-glycosylation is an essential protein modification taking place in the membranes of the endoplasmic reticulum (ER) in eukaryotes and the plasma membranes in archaea. It shares mechanistic similarities based on the use of polyisoprenol lipid carriers with other glycosylation pathways involved in the synthesis of bacterial cell wall components (e.g. peptidoglycan and teichoic acids). Here, a phylogenomic analysis was carried out to examine the validity of rival hypotheses suggesting alternative archaeal or bacterial origins to the eukaryotic N-glycosylation pathway. RESULTS: The comparison of several polyisoprenol-based glycosylation pathways from the three domains of life shows that most of the implicated proteins belong to a limited number of superfamilies. The N-glycosylation pathway enzymes are ancestral to the eukaryotes, but their origins are mixed: Alg7, Dpm and maybe also one gene of the glycosyltransferase 1 (GT1) superfamily and Stt3 have proteoarchaeal (TACK superphylum) origins; alg2/alg11 may have resulted from the duplication of the original GT1 gene; the lumen glycosyltransferases were probably co-opted and multiplied through several gene duplications during eukaryogenesis; Alg13/Alg14 are more similar to their bacterial homologues; and Alg1, Alg5 and a putative flippase have unknown origins. CONCLUSIONS: The origin of the eukaryotic N-glycosylation pathway is not unique and less straightforward than previously thought: some basic components likely have proteoarchaeal origins, but the pathway was extensively developed before the eukaryotic diversification through multiple gene duplications, protein co-options, neofunctionalizations and even possible horizontal gene transfers from bacteria. These results may have important implications for our understanding of the ER evolution and eukaryogenesis. REVIEWERS: This article was reviewed by Pr. Patrick Forterre and Dr. Sergei Mekhedov (nominated by Editorial Board member Michael Galperin). PMID- 27492359 TI - Substance-Related and Addictive Disorders as a Risk Factor of Suicide and Homicide among Patients with ADHD: A Mini Review. AB - OBJECTIVE: To discuss the role of substance-related and addictive disorders (SRAD) that lead patients with attention-deficit hyperactivity disorder (ADHD) to suicide and homicide. METHOD: Relevant articles were searched via PubMed using several keywords related to this issue. Most of the articles included in this review were published after 2000. RESULTS: Patients with ADHD often fall into crises of catastrophic life events such as suicide or homicide. SRAD play an important role in leading ADHD patients to such events. Because ADHD is characterized by inattentiveness and impulsivity, any kinds of substances, legal or illegal, can deteriorate ADHD symptoms, leading ADHD patients to such catastrophic events. There are several pathways that connect ADHD with SRAD, which are roughly divided into two ways: internalizing mental disorders and externalizing mental disorders. The former includes depression and anxiety disorders characterized by self-inhibition or withdrawal. The latter typically includes conduct disorder or oppositional defiant disorder, as well as antisocial personality disorder, characterized by aggressive or antisocial behaviors or emotions towards others. These comorbid psychiatric disorders are apt to lead ADHD patients to SRAD, and once these patients suffer from SRAD, risk of catastrophic life events seems to increase due to the irreversibility of their adverse mentality. Comorbid mental disorders with ADHD can act, at least partially, as mediators from ADHD to SRAD. CONCLUSION: SRAD can be a critical risk factor of suicide and homicide among patients with ADHD. Early interventions for families with ADHD and psychiatric comorbidities may work as effective preventive strategies against such events. PMID- 27492360 TI - Intron sequences that stimulate gene expression in Arabidopsis. AB - KEY MESSAGE: Related motifs strongly increase gene expression when added to an intron located in coding sequences. Many introns greatly increase gene expression through a mechanism that remains elusive. An obstacle to understanding intron mediated enhancement (IME) has been the difficulty of locating the specific intron sequences responsible for boosting expression because they are redundant, dispersed, and degenerate. Previously we used the IMEter algorithm in two independent ways to identify two motifs (CGATT and TTNGATYTG) that are candidates for involvement in IME in Arabidopsis. Here we show that both motifs are sufficient to increase expression. An intron that has little influence on expression was converted into one that increased mRNA accumulation 24-fold and reporter enzyme activity 40-fold relative to the intronless control by introducing 11 copies of the more active TTNGATYTG motif. This degree of stimulation is twice as large as that of the strongest of 15 natural introns previously tested in the same reporter gene. Even though the CGATT and TTNGATYTG motifs each increased expression, and CGATT matches the NGATY core of the longer motif, combining the motifs to make TTCGATTTG reduced the stimulating ability of the TTNGATYTG motif. Additional substitutions were used to test the contribution to IME of other residues in the TTNGATYTG motif. The verification that these motifs are active in IME will improve our ability to predict the stimulating ability of introns, to engineer any intron to increase expression to a desired level, and to explore the mechanism of IME by seeking factors that might interact with these sequences. PMID- 27492361 TI - Re A (A Child) and the United Kingdom Code of Practice for the Diagnosis and Confirmation of Death: Should a Secular Construct of Death Override Religious Values in a Pluralistic Society? AB - The determination of death by neurological criteria remains controversial scientifically, culturally, and legally, worldwide. In the United Kingdom, although the determination of death by neurological criteria is not legally codified, the Code of Practice of the Academy of Medical Royal Colleges is customarily used for neurological (brainstem) death determination and treatment withdrawal. Unlike some states in the US, however, there are no provisions under the law requiring accommodation of and respect for residents' religious rights and commitments when secular conceptions of death based on medical codes and practices conflict with a traditional concept well-grounded in religious and cultural values and practices. In this article, we analyse the medical, ethical, and legal issues that were generated by the recent judgement of the High Court of England and Wales in Re: A (A Child) [2015] EWHC 443 (Fam). Mechanical ventilation was withdrawn in this case despite parental religious objection to a determination of death based on the code of practice. We outline contemporary evidence that has refuted the reliability of tests of brainstem function to ascertain the two conjunctive clinical criteria for the determination of death that are stipulated in the code of practice: irreversible loss of capacity for consciousness and somatic integration of bodily biological functions. We argue that: (1) the tests of brainstem function were not properly undertaken in this case; (2) the two conjunctive clinical criteria set forth in the code of practice cannot be reliably confirmed by these tests in any event; and (3) absent authentication of the clinical criteria of death, the code of practice (in fact, although implicitly rather than explicitly) wrongly invokes a secular definition of death based on the loss of personhood. Consequently, the moral obligation of a pluralistic society to honor and respect diverse religious convictions to the greatest extent possible is being violated. Re A (A Child) is contrasted with the US case of Jahi McMath in which the court accommodated parental religious objection to the determination of neurological death codified in the Uniform Determination of Death Act. We conclude that the legal system in the United Kingdom should not favour a secular definition of death over a definition of death that is respectful of religious values about the inviolability and sanctity of life. We recommend the legal recognition of religious accommodation in death determination to facilitate cultural sensitivity and compassionate care to patients and families in a pluralistic society. PMID- 27492362 TI - Opioid Prescribing: How Well Do We Know Ourselves? PMID- 27492363 TI - Edaravone alleviates cisplatin-induced neurobehavioral deficits via modulation of oxidative stress and inflammatory mediators in the rat hippocampus. AB - Cisplatin is a chemotherapeutic agent used in the treatment of malignant tumors. A major clinical limitation of cisplatin is its potential toxic effects, including neurotoxicity. Edaravone, a potent free radical scavenger, has been reported to have the neuroprotective effect against neurological deficits. The aim of the present study was to determine the neuroprotective effect of edaravone against cisplatin-induced behavioral and biochemical anomalies in male Wistar rats. Our results showed that cisplatin (5mg/kg/week, i.p.) administration for seven weeks caused marked cognitive deficits and motor incoordination in rats. This was accompanied by oxido-nitrosative stress, neuroinflammation, NF-kappaB activation and down-regulation of Nrf2/HO-1 gene expression level in the hippocampus. Edaravone (10mg/kg/week, i.p.) treatment for seven weeks inhibited the aforementioned neurobehavioral and neurochemical deficits. Furthermore, edaravone was found to up-regulate the gene expression level of Nrf2/HO-1 and prevented the cisplatin-induced NF-kappaB activation. These findings demonstrated that oxido-nitrosative stress and inflammatory signaling mediators play a key role in the development of cisplatin-induced neurobehavioral deficits which were prevented by edaravone treatment. PMID- 27492364 TI - Remifentanil preconditioning protects rat cardiomyocytes against hypoxia reoxygenation injury via delta-opioid receptor mediated activation of PI3K/Akt and ERK pathways. AB - Remifentanil preconditioning has been demonstrated to reduce myocardial ischemia reperfusion injury in rat hearts, while the mechanisms are not fully understood. This study investigated the protective effects of remifentanil against hypoxia reoxygenation injury in adult rat cardiomyocytes and the mechanisms involving opioid receptors and downstream phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinase (ERK) signaling pathways. Adult rat cardiomyocytes were pretreated with remifentanil at different concentrations and then subjected to 90min hypoxia followed by 120min reoxygenation. The delta- (naltrindole), kappa- (nor-binaltorphimine), or MU opioid receptor antagonist (CTOP), as well as ERK inhibitor (PD98059) or PI3K inhibitor (wortmannin) was added before remifentanil preconditioning, respectively. Remifentanil showed significant protective effects against hypoxia reoxygenation injury by increasing cell survival (Trypan blue staining) while reducing LDH activity and cell apoptosis (Hoechst staining). These effects were markedly reversed by naltrindole and were partially blocked by nor binaltorphimine. Pretreatment of either PD98059 or wortmannin also abolished the protective effects of remifentanil. Following remifentanil preconditioning, the phosphorylation level of Akt reached peak at 10min of reoxygenation. ERK phosphorylation, however, was subsequently enhanced at 120min of reoxygenation. The phosphorylation levels of Akt and ERK were both blocked by naltrindole, but not nor-binaltorphimine or CTOP. Wortmannin inhibited the phosphorylation of both Akt and ERK, whereas PD98059 suppressed the phosphorylation of ERK only. In conclusion, our results suggested that remifentanil protected adult rat cardiomyocytes from hypoxia-reoxygenation injury and its effects appears to be dependent on the delta-opioid receptor mediated activation of PI3K/Akt and subsequent ERK signaling pathways. PMID- 27492365 TI - Ranolazine triggers pharmacological preconditioning and postconditioning in anesthetized rabbits through activation of RISK pathway. AB - We tested the hypothesis that ranolazine (Ran) is cardioprotective in a model of ischemia /reperfusion and we elucidated the intracellular mechanism. Anesthetized rabbits were subjected to is chemia and reperfusion and were divided into 5 groups: 1) Control, 2) Preconditioning (PreC), 3) Postconditioning (PostC), 4) RanA and 5) RanB, respectively treated with intravenous ranolazine, either 10min before or during index ischemia. Ranolazine was initially given over 60s and then from the beginning and throughout the whole reperfusion period. The infarcted to the risk ratio was calculated (%I/R). In a second series consisting of respective to the first series groups, the animals were subjected to the same interventions up to the 10th min of reperfusion where tissue samples were taken for immunoblotting of Akt, eNOS, ERK1/2 and GSK3beta (RISK pathway). In a third series, RanA+Wort, RanB+Wort and Wort groups were treated with ranolazine as RanA and RanB groups but with the addition of the PI3 inhibitor Wortmaninn (Wort) and %I/R calculated. Ranolazine reduced the % I/R in RanA and RanB compared to the Control (23.1+/-1.7%, 17.6+/-2.0% vs 47.6+/-1.0%, P<0.05). %I/R reduction achieved in the RanA and RanB groups was comparable to that observed in PreC and PostC (16.3+/-2.1%, 26.2+/-2.1%, respectively P<0.05 vs Control). Phosphorylation of Akt, ERK1/2, eNOS and GSK3beta were higher in PreC, PostC and in both ranolazine treated groups. Wortmannin abrogated ranolazine's %I/R reduction (RanA+Wort 31.4+/-1.7%, RanB+Wort 32.4+/-2.4%). Ranolazine reduces %I/R and triggers cardioprotection with a similar to conditioning mechanism which upregulates the RISK pathway. PMID- 27492366 TI - CellShape: A user-friendly image analysis tool for quantitative visualization of bacterial cell factories inside. AB - Visualization of the intracellular constituents of individual bacteria while performing as live biocatalysts is in principle doable through more or less sophisticated fluorescence microscopy. Unfortunately, rigorous quantitation of the wealth of data embodied in the resulting images requires bioinformatic tools that are not widely extended within the community-let alone that they are often subject to licensing that impedes software reuse. In this context we have developed CellShape, a user-friendly platform for image analysis with subpixel precision and double-threshold segmentation system for quantification of fluorescent signals stemming from single-cells. CellShape is entirely coded in Python, a free, open-source programming language with widespread community support. For a developer, CellShape enhances extensibility (ease of software improvements) by acting as an interface to access and use existing Python modules; for an end-user, CellShape presents standalone executable files ready to open without installation. We have adopted this platform to analyse with an unprecedented detail the tridimensional distribution of the constituents of the gene expression flow (DNA, RNA polymerase, mRNA and ribosomal proteins) in individual cells of the industrial platform strain Pseudomonas putida KT2440. While the CellShape first release version (v0.8) is readily operational, users and/or developers are enabled to expand the platform further. PMID- 27492367 TI - The rate of protein synthesis in hematopoietic stem cells is limited partly by 4E BPs. AB - Adult stem cells must limit their rate of protein synthesis, but the underlying mechanisms remain largely unexplored. Differences in protein synthesis among hematopoietic stem cells (HSCs) and progenitor cells did not correlate with differences in proteasome activity, total RNA content, mRNA content, or cell division rate. However, adult HSCs had more hypophosphorylated eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and 4E-BP2 as compared with most other hematopoietic progenitors. Deficiency for 4E-BP1 and 4E-BP2 significantly increased global protein synthesis in HSCs, but not in other hematopoietic progenitors, and impaired their reconstituting activity, identifying a mechanism that promotes HSC maintenance by attenuating protein synthesis. PMID- 27492368 TI - Transcription factors GAF and HSF act at distinct regulatory steps to modulate stress-induced gene activation. AB - The coordinated regulation of gene expression at the transcriptional level is fundamental to development and homeostasis. Inducible systems are invaluable when studying transcription because the regulatory process can be triggered instantaneously, allowing the tracking of ordered mechanistic events. Here, we use precision run-on sequencing (PRO-seq) to examine the genome-wide heat shock (HS) response in Drosophila and the function of two key transcription factors on the immediate transcription activation or repression of all genes regulated by HS. We identify the primary HS response genes and the rate-limiting steps in the transcription cycle that GAGA-associated factor (GAF) and HS factor (HSF) regulate. We demonstrate that GAF acts upstream of promoter-proximally paused RNA polymerase II (Pol II) formation (likely at the step of chromatin opening) and that GAF-facilitated Pol II pausing is critical for HS activation. In contrast, HSF is dispensable for establishing or maintaining Pol II pausing but is critical for the release of paused Pol II into the gene body at a subset of highly activated genes. Additionally, HSF has no detectable role in the rapid HS repression of thousands of genes. PMID- 27492369 TI - Relationship Between Antihypertensive Medications and Cognitive Impairment: Part II. Review of Physiology and Animal Studies. AB - PURPOSE OF REVIEW: There is an established association between hypertension and increased risk of poor cognitive performance and dementia including Alzheimer's disease; however, associations between antihypertensive medications (AHM) and dementia risk are less clear. An increased interest in AHM has resulted in expanding publications; however, none of the recent reviews provide comprehensive review. Our extensive review includes 24 mechanistic animal and human studies published over the last 5 years assessing relationship between AHM and cognitive function. RECENT FINDINGS: All classes of AHM showed similar result patterns in animal studies. The mechanism by which AHM exert their effect was extensively studied by evaluating well-established pathways of AD disease process, including amyloid beta (Abeta), vascular, oxidative stress and inflammation pathways, but only few studies evaluated the blood pressure lowering effect on the AD disease process. Methodological limitations of the studies prevent comprehensive conclusions prior to further work evaluating AHM in animals and larger human observational studies, and selecting those with promising results for future RCTs. PMID- 27492370 TI - Relationship Between Antihypertensive Medications and Cognitive Impairment: Part I. Review of Human Studies and Clinical Trials. AB - PURPOSE OF REVIEW: There is an established association between hypertension and increased risk of poor cognitive performance and dementia including Alzheimer's disease; however, associations between antihypertensive medications (AHMs) and dementia risk are less consistent. An increased interest in AHM has resulted in expanding publications; however, none of the recent reviews are comprehensive. Our extensive review includes 15 observational and randomized controlled trials (RCTs) published over the last 5 years, assessing the relationship between AHM and cognitive impairment. RECENT FINDINGS: All classes of AHM showed similar result patterns in human studies with the majority of study results reporting point estimates below one and only a small number of studies (N = 15) reporting statistically significant results in favor of a specific class. Only a small number of studies reported statistically significant results in favor of a specific class of AHM. Methodological limitations of the studies prevent definitive conclusions. Further work is now needed to evaluate the class of AHM and cognitive outcomes in future RCTs, with a particular focus on the drugs with the promising results in both animals and human observational studies. PMID- 27492371 TI - Simulated Microgravity and 3D Culture Enhance Induction, Viability, Proliferation and Differentiation of Cardiac Progenitors from Human Pluripotent Stem Cells. AB - Efficient generation of cardiomyocytes from human pluripotent stem cells is critical for their regenerative applications. Microgravity and 3D culture can profoundly modulate cell proliferation and survival. Here, we engineered microscale progenitor cardiac spheres from human pluripotent stem cells and exposed the spheres to simulated microgravity using a random positioning machine for 3 days during their differentiation to cardiomyocytes. This process resulted in the production of highly enriched cardiomyocytes (99% purity) with high viability (90%) and expected functional properties, with a 1.5 to 4-fold higher yield of cardiomyocytes from each undifferentiated stem cell as compared with 3D standard gravity culture. Increased induction, proliferation and viability of cardiac progenitors as well as up-regulation of genes associated with proliferation and survival at the early stage of differentiation were observed in the 3D culture under simulated microgravity. Therefore, a combination of 3D culture and simulated microgravity can be used to efficiently generate highly enriched cardiomyocytes. PMID- 27492372 TI - X-linked Inhibitor of Apoptosis Complicated by Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) and Granulomatous Hepatitis. AB - The X-linked inhibitor of apoptosis (XIAP) deficiency is a primary immunodeficiency characterized by Epstein-Barr virus (EBV)-driven hemophagocytic lymphohistiocytosis (HLH), splenomegaly, and colitis. Here, we present, for the first time, granulomatous hepatitis and granulomatous and lymphocytic interstitial lung disease (GLILD) as manifestations of XIAP deficiency. We report successful treatment of GLILD in XIAP deficiency with rituximab and azathioprine and discuss the role of XIAP deficiency in immune dysregulation. PMID- 27492373 TI - The invisible basal cell carcinoma: how reflectance confocal microscopy improves the diagnostic accuracy of clinically unclear facial macules and papules. AB - Difficult to diagnose and early non-melanoma skin cancer lesions are frequently seen in daily clinical practice. Besides precancerous lesions such as actinic keratosis, basal cell carcinomas (BCCs) score the highest frequency in skin tumors. While infiltrative and nodular BCCs require a surgical treatment with a significant impact on the patients' quality of life, early and superficial BCCs might benefit from numerous conservative treatments, such as topical immune modulators or photodynamic therapy. Dermoscopy has shown a high sensitivity and specificity in the diagnosis of early BCCs, and non-invasive imaging techniques like reflectance confocal microscopy (RCM) have proven to be helpful. The aim of our study was to investigate the importance of RCM in the diagnosis of BCCs with indistinct clinical and dermoscopic features. We retrospectively examined 27 histologically proven BCCs in which diagnosis was not possible based on naked eye examination; we separately reviewed clinical, dermoscopic, and confocal microscopy features and evaluated the lesions meeting the common diagnostic criteria for BCCs, and our diagnostic confidence. All lesions were clinically unclear, with no characteristic features suggestive for BCC; dermoscopy showed in most cases unspecific teleangiectasias (74 %) and micro-erosions (52 %). Confocal microscopy revealed in most of the cases the presence of specific criteria: peripheral palisading of the nuclei (89 %), clefting (70 %), stromal reaction (70 %), dark silhouettes (70 %), inflammatory particles (70 %), and tumor islands (67 %). In the absence of significant diagnostic clinical signs and with unclear dermoscopic features, specific confocal patterns were present in most of the lesions and enabled a correct diagnosis. In the absence of significant clinical features of BCC and in the case of uncertain dermoscopy, striking confocal features are detectable and easy to recognize in most cases. Confocal microscopy can therefore be instrumentful in the diagnosis of the so-called invisible BCCs. PMID- 27492374 TI - Polychromatic light-induced osteogenic activity in 2D and 3D cultures. AB - Photobiomodulation (PBM) has been applied to manipulate cellular responses by using monochromatic light in different wavelengths from ultraviolet (UV) to infrared (IR) region. Until now, an effective wavelength has not been revealed to induce proliferation and/or differentiation of cells. Therefore, in the presented study, we decided to use a specially designed plasma arc light source providing wavelengths between 590 and 1500 nm in order to investigate its biomodulatory effects on chitosan scaffold-supported three-dimensional (3D) cell cultures. For comparison, two-dimensional (2D) cell cultures were also carried out in tissue culture polystyrene dishes (TCPS). The results showed that light-induced temperature rise did not affect cells when the distance between the light source and the cells was 10 cm and the frequency of administration was daily. Moreover, light was applied for 5 and 10 min to the cells in TCPS and in chitosan scaffold groups, respectively. Cell culture studies under static conditions indicated that polychromatic light significantly stimulated bone nodule formation via the prolonged cell survival and stimulated differentiation of MC3T3-E1 preosteoblastic cells in both TCPS and chitosan scaffold groups. In conclusion, specially designed plasma arc light source used in this study induces formation of bone tissue and so, this light source is proposed as an appropriate system for in vitro bone tissue engineering applications. Statistical analyses were performed with one-way ANOVA by using GraphPad Instat software and standard deviations were calculated by using data of three parallel samples for each group. PMID- 27492375 TI - Time-resolved 3D rotational angiography: display of detailed neurovascular anatomy in patients with intracranial vascular malformations. AB - PURPOSE: The purpose of this pilot study was to demonstrate the applicability of time-resolved three-dimensional (3D) reconstructions from 3D digital subtraction angiography (DSA) rotational angiography (RA) datasets (four-dimensional (4D) DSA) to provide a more detailed display of the architecture of intracranial vascular malformations. METHODS: The experimental reconstruction software was applied to the existing 3D DSA datasets obtained with Siemens Artis zee biplane neuroangiography equipment. We included 27 patients with clinical indications for 3DRA for preinterventional or preoperative evaluation of intracranial dural arteriovenous fistulas (dAVFs, n=8) or arteriovenous malformations (AVMs, n=19). A modified DSA acquisition protocol covering an extended rotation angle of the C arm of 260 degrees during a scan time of 12 s was used. 4D volumes were displayed with up to 30 frames/s in a transparent volume rendering (VRT) mode and time-resolved multiplanar reconstructions (MPRs). Arterial feeders, fistulous points, or the shunt zone within the AVM nidus and venous drainage patterns as well as associated aneurysms were assessed after definition of a standardized evaluation procedure by consensus of two reviewers in comparison with 2D DSA and conventional 3D reconstructions. RESULTS: In all cases calculation of 4D reconstructions were technically feasible and evaluable. In two cases image quality was slightly compromised by movement artifacts. Compared with standard DSA projection images and 3D reconstructions, 4D VRTs and MPRs were rated significantly superior to define a proper projection and display of the shunt zone. In 12 out of 27 cases 4D reconstructions showed details of the angioarchitecture at the fistulous point or the nidus better than the other modalities and came close to the quality of superselective angiography. The efficacy of 3D and 4D applications was equal in the detection of pre- and intranidal aneurysms. The course of long arterial feeders and draining veins was difficult to assess on VRTs and MPRs. Especially for dAVFs, 2D DSA was clearly superior in identifying meningeal feeders. For detecting smaller vessels and for distinction between angiographic phases, 2D DSA is still considered to be superior to 4D imaging. Venous drainage was slightly better displayed in 4D reconstructions. CONCLUSIONS: Time-resolved 3DRA with 4D VRTs and MPRs is technically feasible and provides a detailed display of the angioarchitecture at the fistulous point or the nidus. Visualization of all angiographic features demands additional post-processing. Further standardization of evaluation tools and studies with blinded independent reviewers are necessary before the new technique can replace conventional neuroangiographic approaches. PMID- 27492376 TI - [Prophylactic meshes in the abdominal wall. German version]. AB - BACKGROUND: There is a high incidence of incisional hernias in specific high-risk patient populations. For these patients, the prophylactic placement of mesh during closure of the abdominal wall incision has been investigated in several prospective studies. OBJECTIVE: This article aims to summarize and synthetize the currently available evidence on prophylactic meshes in a narrative review. MATERIALS AND METHODS: Systematic reviews were performed on the use of prophylactic meshes in different indications: midline laparotomies, stoma reversal wounds, and permanent stoma. RESULTS: High-quality data from randomized trials shows that prophylactic synthetic non-absorbable mesh implantation is safe and effective, both in prevention of incisional hernias after midline laparotomies and during construction of an elective end colostomy. It should be considered in patients with a high risk for incisional hernia development, such as those receiving open abdominal aortic aneurysm, obesity, or colorectal cancer surgery. It is strongly recommended for construction of an elective permanent end colostomy. For midline laparotomies, both the retromuscular and onlay positions of a prophylactic mesh seem equally effective and safe. For parastomal hernia prevention, only the retromuscular prophylactic mesh and its use for end colostomies has been proven to be effective and safe. No data support the choice of a biological mesh or a synthetic absorbable mesh over a non-absorbable synthetic mesh, even in clean-contaminated surgical procedures. No data yet support the standard use of prophylactic mesh when closing the wound during closure of a temporary stoma. CONCLUSION: Prophylactic mesh implantation should be the standard of care during construction of an elective end colostomy and will become the standard of care for midline laparotomies in patients at high risk of incisional hernias. PMID- 27492377 TI - [Impact of perioperative nutritional therapy on risk and complication management in patients undergoing esophagectomy for cancer]. AB - Esophagectomy is considered to be a high risk procedure regarding postoperative morbidity and mortality. Therefore, in Germany, these operations are limited to hospitals fulfilling a minimum quantity. This systematic review focuses on risk and complication management regarding the impact of perioperative nutritional therapy, including the recent S3-guideline recommendations and comments of the German Working Group of Medical Societies (AWMF) which were established with contributions from the authors. PMID- 27492378 TI - [Multicystic intra-abdominal mass in a neonate]. PMID- 27492380 TI - Prospective Observational Post-marketing Study of Tafluprost 0.0015%/Timolol 0.5% Combination Ophthalmic Solution for Glaucoma and Ocular Hypertension: Short-Term Efficacy and Safety. AB - INTRODUCTION: The intraocular pressure (IOP)-lowering effect and safety of tafluprost 0.0015%/timolol maleate 0.5% combination ophthalmic solution (Taf-TFC) were investigated in a real-world clinical setting. METHODS: A prospective up to 2-year (more than 1 year) observational study has been initiated to collect data on the IOP, conjunctival hyperemia score, corneal staining score, and adverse events suffered by patients with glaucoma or ocular hypertension treated at 3 months, and up to 2 years (more than 1 year) after initiating treatment with Taf TFC. The 3-month findings are reported here. RESULTS: Among 439 patients enrolled at 100 institutions in Japan, most had normal tension glaucoma (45.3%) or primary open angle glaucoma (36.0%). Adverse drug reaction (ADR) occurred in 5.01%. The important ADRs were conjunctival hyperemia (five patients), blepharitis (four patients), and punctate keratitis (two patients). Serious adverse reactions occurred in two patients (three events). In 410 patients with data both before and after treatment, baseline mean IOP was 17.5 +/- 5.0 mmHg, and it was significantly decreased after 1, 2, and 3 months (all P < 0.05, paired-t test). IOP was significantly reduced in patients switched to Taf-TFC from either prostaglandin or beta-blocker monotherapy. IOP also decreased significantly in patients switched from a prostaglandin/timolol fixed combination, but not in patients switched from concomitant use of a prostaglandin analog and a beta blocker. The use of Taf-TFC did not worsen the adherence in most patients. CONCLUSION: Taf-TFC significantly reduced the IOP in patients with glaucoma or ocular hypertension treated in daily clinical practice with controllable or recoverable ADRs in short period. Taf-TFC was effective regardless of treatment patterns, and particularly, Taf-TFC significantly reduced IOP in cases in which requiring the second line therapy as insufficient of monotherapy. FUNDING: Santen Pharmaceutical Co., Ltd., Osaka, Japan. PMID- 27492379 TI - Trends in major risk factors and mortality from main non-communicable diseases in Lithuania, 1985-2013. AB - BACKGROUND: This study aimed to assess the trends in the prevalence and levels of risk factors and mortality from main non-communicable diseases in the Lithuanian population aged 45-64 years during 1985 to 2013. METHODS: Data from four general population surveys conducted between 1985 and 2008 were used. All these surveys were carried out in Kaunas city and five randomly selected municipalities of Lithuania. Risk factors measured at each survey included regular smoking, overweight, obesity, arterial hypertension, and high levels of blood lipids. In total, data of 10,719 subjects (4,965 men and 5,754 women) aged 45-64 were analysed. Trends in standardized all-cause mortality and mortality from cardiovascular disease (CVD), coronary heart disease (CHD), and malignant neoplasms were estimated for both sexes by joinpoint regression analysis. RESULTS: In 1985-2013, some favourable trends were observed in the age standardized mean levels and prevalence of risk factors and mortality from main non-communicable diseases in the Lithuanian middle-aged population. The mean values of blood lipids (with the exception of triglycerides) and the prevalence of dyslipidemias declined. In women, mean levels of systolic blood pressure and body mass index decreased, while in men, the levels of these factors increased. The prevalence of arterial hypertension and obesity increased in men. The proportion of obese women decreased. Smoking prevalence increased in both men and women. From 2007 to 2008, significant downward trends, which were steeper in women than in men, were observed in all-cause, CVD, and CHD mortality. CONCLUSIONS: Despite the favourable changes in some risk factors and mortality rates, the prevalence of risk factors and mortality from main non-communicable diseases in Lithuania are still high. This indicates the importance of the ongoing primary and secondary prevention and optimal treatment of these diseases. PMID- 27492381 TI - Physical activity after outpatient surgery and enhanced recovery for total knee arthroplasty. AB - PURPOSE AND HYPOTHESIS: The purpose of this study was to 'objectively' measure improvement of physical activity with the use of an activity monitor between patients who followed an enhanced recovery- or outpatient surgery pathway after total knee arthroplasty (TKA). It was hypothesized that both pathways will have comparable physical activity after TKA at 6-week follow-up. METHODS: This prospective observational comparative case study was designed to investigate activity parameters (e.g. physical activity, number of steps, sit-stand transfers) of two different pathways after 6 weeks with the use of a non-invasive triaxial accelerometer activity monitor. This study included 20 patients with a mean age of 65.5 years (SD 6.1) undergoing TKA who were allocated to follow one of the two pathways: enhanced recovery (n = 10) or outpatient surgery (n = 10). Patients were monitored for 4 days pre-, 4 days during and 4 days after 5 weeks postoperatively. Patient-reported outcome measures (PROMs) and range of knee motion were obtained pre- and 6 weeks postoperatively. RESULTS: The activity parameters recovered steeply during the first 4 postoperative days and continued to improve within both pathways (n.s.). Preoperative and during the first 4 days and 5 weeks postoperative, activity parameters were comparable (n.s.) between both pathways but did not reach preoperative levels of physical activity and range of motion (n.s.). PROMs improved within each pathway, and no difference between both pathways was observed (n.s.). CONCLUSIONS: This study demonstrates that the early physical activity parameters of patients after TKA, following the outpatient surgery pathway, were similar to patients who followed the standard enhanced recovery pathway. The activity monitor is an added value for a more detailed and objective analysis of the physical performance in patients after TKA. LEVEL OF EVIDENCE: III. PMID- 27492382 TI - The prevalence of proximal hamstring pathology on MRI in the asymptomatic population. AB - PURPOSE: Injury to the proximal hamstring complex (PHC) is becoming more frequently diagnosed. Patients attending our tertiary referral centre demonstrated 'pathological changes' in the unaffected normal contralateral PHC on MRI. The prevalence of PHC pathology, however, has not been previously documented in the literature in asymptomatic subjects. It is the hypothesis of this study that the natural history of asymptomatic pathological change on MRI in the PHC is not clear. The aim is to quantify the natural history of PHC degeneration. METHOD: Two hundred and fifty-three consecutive patients with an asymptomatic PHC were reviewed retrospectively between 2009 and 2010. The PHC was assessed in multiple MRI planes by a specialist musculoskeletal consultant radiologist. RESULTS: Five hundred and six proximal hamstrings complexes were reviewed. Eighty nine patients (35 %) were radiological normal both sides, median age 51 years (range 13-88). Thirty-four patients (13 %) had unilateral pathology, median age 55 years (range 25-89). Of these, 3 patients (1 %) had presence of a complete tear, median age 81 years (range 72-87). Sixteen patients (7 %) had tendinosis, median age 60 years (range 37-78). Fifteen patients (6 %) had a unilateral partial tear, median age 57 years (range 35-78). One hundred and thirty patients (52 %) had bilateral pathology, median age 65 years (range 25-89). Fifty-three patients (21 %) had the presence of bilateral tendinopathy alone, median age 56 years (range 25-89). Twenty-seven patients (11 %) had a partial tear on one side and tendinosis on the other, median age 68 years (range 38-89). Thirty-nine patients (15 %) had evidence of bilateral partial tears, median age 63 years (range 36-89), with 52 % demonstrating a torn conjoined and semi-membranosus tendon. The remaining 48 % had either an isolated tear of the conjoined or the semi-membranosus (the more commonly injured tendon 74 % of the time). Four patients (2 %) had bilateral complete ruptures with a median age of 68 years (range 59-78). Six patients (2 %) had a complete tear on one side and a partial tear on the other, median age 68 years (range 34-83). One patient had a complete tear on one side and tendinosis on the other, age 81 years. CONCLUSION: There is a higher prevalence of pathology in the asymptomatic population, 15 % have bilateral partial tears, and 2 % have bilateral complete tears. The semi membranosus being the most affected, this may help clinically stratify the need for surgical intervention. LEVEL OF EVIDENCE: I. PMID- 27492383 TI - Anterior hip capsuloligamentous reconstruction with Achilles allograft following gross hip instability post-arthroscopy. AB - The increasing use of hip arthroscopy has led to further development in our understanding of hip anatomy and potential post-operative complications. Iatrogenic gross hip instability following hip arthroscopy is a concerning complication described in recent orthopaedic literature. Post-arthroscopy hip instability is thought to be multifactorial, related to a variety of patient, surgical and post-operative factors. Given its infrequency, there is scarcity of literature describing appropriate surgical management and operative technique for addressing this instability. This study reports a case of gross hip instability following hip arthroscopy, describing a novel technique of management through anterior hip capsuloligamentous reconstruction with Achilles tendon allograft. Level of evidence V, Case Study. PMID- 27492384 TI - The accuracy of bony resection from patient-specific guides during total knee arthroplasty. AB - PURPOSE: In patient-specifically instrumented (PSI) total knee arthroplasty, the correlation between the pre-operative surgical plan, accuracy of the cutting block, and intra-operative resection size is unclear. The aim of this study was to evaluate the ability to accurately execute the PSI surgical plan and to add to the merging information with respect to this technology with the hypothesis that the PSI blocks would demonstrate good accuracy with regard to the bony thickness of the resections. METHODS: One hundred and thirty TKAs using PSI (MRI/long-leg radiographs) were retrospectively analysed. All surgeries were conducted via similar surgical approach and technique, with resection performed after guide placement and alignment assessment. The bony cut thicknesses of the medial (MTP) and lateral tibial plateau (LTP), distal medial (DM), distal lateral (DL), posterior medial (PM) and posterior lateral (PL) femur were measured with a vernier calliper. The measured resection thickness was subtracted from the planned resection. Errors were defined as <=1.5 mm (acceptable), 1.5-2.5 mm (borderline), and >2.5 mm (outliers). RESULTS: Overall, 81 (62.3 %) of the knees were free of outliers. The distal femur cut had the highest proportion of acceptable cut error with 209 of 260 total cuts acceptable (80.4 %). The tibial cuts had the lowest proportion of "acceptable" cuts (68.9 %). Tibial cuts had more outliers (33 of 260 cuts, 12.7 %) than the femur (39 of 520 cuts, 7.5 %) (p = 0.01). Pre-operative varus (n = 97) and valgus (n = 33) deformities demonstrated 7.7 % (45/482) and 13.6 % (27/198) of cuts which were outliers, respectively (p = 0.01). CONCLUSION: PSI showed only fair to moderate accuracy with 62.3 % of the knees presenting no outliers. The tibia cutting guide was less accurate than the femur. Specific attention is needed when cutting the tibia and in correction of valgus deformity. Moreover, intra-operative verifying measurements can provide feedback to the accuracy of the surgical plan. LEVEL OF EVIDENCE: IV, case series with no comparison group. PMID- 27492385 TI - Willingness to participate in health research: Tunisian survey. AB - BACKGROUND: Few studies have identified the willingness rate of developing countries population to be enrolled in clinical trials. METHODS: All participants including patients (n = 612), healthy volunteers (n = 354) and doctors (n = 134) completed a questionnaire to examine factors affecting the consent to participate in medical research. RESULTS: Overall, 80 % of the included population agree to participate in health research. This rate was lower for trials dealing with life threatening diseases (38 %). Altruism and perceived risk of harm were the main reason to respectively accept or refuse to participate in clinical trials. Factors significantly associated with willingness were: age <40 years (Odds Ratio (OR) 1.6 [95 % Confidence Interval (CI) 1.2-2.1]) and prior history of blood donation (OR 2.4 [95 % CI 1.7-3.5]). CONCLUSION: Most participants expressed their willingness to be included in medical research especially if they are young or if they have history of blood donation. However, consent to participate is low when medical research required acute care. PMID- 27492387 TI - Prescription drug misuse in Europe is higher than previously thought. PMID- 27492386 TI - Microbiota and chronic inflammatory arthritis: an interwoven link. AB - BACKGROUND: Only recently, the scientific community gained insights on the importance of the intestinal resident flora for the host's health and disease. Gut microbiota in fact plays a crucial role in modulating innate and acquired immune responses and thus interferes with the fragile balance inflammation versus tolerance. MAIN BODY: Correlations between gut bacteria composition and the severity of inflammation have been studied in inflammatory bowel diseases. More recently similar alterations in the gut microbiota have been reported in patients with spondyloarthritis, whereas in rheumatoid arthritis an accumulating body of evidence evokes a pathogenic role for the altered oral microbiota in disease development and course. In the context of dysbiosis it is also important to remember that different environmental factors like stress, smoke and dietary components can induce strong bacterial changes and consequent exposure of the intestinal epithelium to a variety of different metabolites, many of which have an unknown function. In this perspective, and in complex disorders like autoimmune diseases, not only the genetic makeup, sex and immunologic context of the individual but also the structure of his microbial community should be taken into account. CONCLUSIONS: Here we provide a review of the role of the microbiota in the onset, severity and progression of chronic inflammatory arthritis as well as its impact on the therapeutic management of these patients. Furthermore we point-out the complex interwoven link between gut-joint-brain and immune system by reviewing the most recent data on the literature on the importance of environmental factors such as diet, smoke and stress. PMID- 27492389 TI - Surgical outcome of the shunt: 15-year experience in a single institution. AB - PURPOSE: Surgical outcome after shunt insertion in pediatric hydrocephalus can vary greatly. Although first shunt survival rates and complications have been studied by several teams, much less is known about survival and complications of subsequent systems. The goals of this study were to evaluate the surgical outcome in a series of pediatric patients followed for a long time and establish the differences between first and subsequent extracranial shunt survival and complications. METHODS: We undertook a retrospective study in pediatric patients treated with ventriculoperitoneal shunts between 2000 and 2015 at our institution. Surgical outcome was assessed, and different shunt survival curves were studied with Kaplan-Meier. Complications related to each shunt failure were examined and compared. RESULTS: A total of 166 patients underwent 425 procedures, with a mean follow-up period of 93 months. The median number of shunt revision surgeries was 2. Shunt survival rates were better with the first shunt compared to those with the subsequent shunts. The main complication necessitating system revision surgery was overdrainage, the frequency of proximal and distal dysfunctions was similar in all the shunt failures, and isolated ventricle and infection were more frequent in younger patients. Shunt-related infections accounted for 7 % of the procedures, and the shunt independence rate was 10 %. CONCLUSIONS: The frequency of complications related to shunt failure in pediatric patients changes during follow-up. A strict protocol of overdrainage detection and active treatment could explain the need for repeat surgeries and the progressively shorter shunt survival time in our series. PMID- 27492390 TI - Sonography and Transthoracic Echocardiography for Diagnosis of Systemic Cardiovascular Metastatic Tumor Thrombi. AB - Sonography and transthoracic echocardiography (TTE) are seldom used for assessment of metastatic tumor thrombi in the cardiovascular system in routine clinical practice. We performed this retrospective study to evaluate the combination of sonography with TTE for diagnosis of metastatic tumor thrombi in heart and systemic vessels. Vascular, abdominal, pelvic, and small-part sonography was applied in 18 patients, and TTE was conducted simultaneously in 14 patients. Tumor thrombi invaded into the inferior vena cava system in 12 patients, superior vena cava system in 5 patients, and aorta in 1 patient; they extended to the right cardiac chambers in 11 patients. Six patients had diagnoses by pathologic examination. The primary neoplasms were identified by conventional imaging in 17 patients. The morphologic and echogenic characteristics of the tumor thrombi were diverse and depended on their original tumors. The thrombi were either contiguous or discrete from the original tumors. The neoplastic vascularity of the thrombi and the invasive extension were the primary characteristics that distinguished them from bland thrombi. Simultaneous application of sonography and TTE is a feasible way to comprehensively evaluate cardiovascular metastatic tumor thrombi in most patients. PMID- 27492388 TI - Feasibility, tolerability and safety of pediatric hyperpolarized 129Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis. AB - BACKGROUND: Hyperpolarized 129Xe is a promising contrast agent for MRI of pediatric lung function, but its safety and tolerability in children have not been rigorously assessed. OBJECTIVE: To assess the feasibility, safety and tolerability of hyperpolarized 129Xe gas as an inhaled contrast agent for pediatric pulmonary MRI in healthy control subjects and in children with cystic fibrosis. MATERIALS AND METHODS: Seventeen healthy control subjects (ages 6-15 years, 11 boys) and 11 children with cystic fibrosis (ages 8-16 years, 4 boys) underwent 129Xe MRI, receiving up to three doses of 129Xe gas prepared by either a commercially available or a homebuilt 129Xe polarizer. Subject heart rate and SpO2 were monitored for 2 min post inhalation and compared to resting baseline values. Adverse events were reported via follow-up phone call at days 1 and 30 (range +/-7 days) post-MRI. RESULTS: All children tolerated multiple doses of 129Xe, and no children withdrew from the study. Relative to baseline, most children who received a full dose of gas for imaging (10 of 12 controls and 8 of 11 children with cystic fibrosis) experienced a nadir in SpO2 (mean -6.0 +/- standard deviation 7.2%, P<=0.001); however within 2 min post inhalation SpO2 values showed no significant difference from baseline (P=0.11). There was a slight elevation in heart rate (mean +6.6 +/- 13.9 beats per minute [bpm], P=0.021), which returned from baseline within 2 min post inhalation (P=0.35). Brief side effects related to the anesthetic properties of xenon were mild and quickly resolved without intervention. No serious or severe adverse events were observed; in total, four minor adverse events (14.3%) were reported following 129Xe MRI, but all were deemed unrelated to the study. CONCLUSION: The feasibility, safety and tolerability of 129Xe MRI has been assessed in a small group of children as young as 6 years. SpO2 changes were consistent with the expected physiological effects of a short anoxic breath-hold, and other mild side effects were consistent with the known anesthetic properties of xenon and with previous safety assessments of 129Xe MRI in adults. Hyperpolarized 129Xe is a safe and well-tolerated inhaled contrast agent for pulmonary MR imaging in healthy children and in children with cystic fibrosis who have mild to moderate lung disease. PMID- 27492391 TI - Klippel-Trenaunay Syndrome: Need for Careful Clinical Classification. AB - Klippel-Trenaunay syndrome (KTS) is a rare congenital malformation characterized by a triad of clinical presentations: (1) capillary malformations manifesting as a "port wine stain"; (2) limb hypertrophy; and (3) venous varicosities. It is distinguished from Parkes-Weber syndrome by the absence of substantial arteriovenous shunting. Due to the clinical implications of an arteriovenous fistula, differentiation between the two syndromes is important, as the prognosis and treatment greatly differ. We present a series of 5 cases of suspected KTS, while emphasizing the difficulties in distinguishing KTS from Parkes-Weber syndrome without diagnostic imaging and underscoring the importance of accurately classifying patients with the appropriate syndrome. PMID- 27492392 TI - Is Brachial Artery Blood Flow Measured by Sonography During Early Postoperative Periods Predictive of Arteriovenous Fistula Failure in Hemodialysis Patients? AB - OBJECTIVES: The aim of our study was to determine a brachial artery blood flow level measured by sonography during early postoperative periods that is predictive of arteriovenous fistula failure in hemodialysis patients. METHODS: Doppler sonography was used to estimate the blood flow in the brachial artery of 103 patients at 1 and 14 days after arteriovenous fistula creation. The performance of brachial artery blood flow during early postoperative periods for predicting fistula failure was evaluated, and optimal cutoff values were determined. RESULTS: During a 6-month follow-up, 85 fistulas were classified as mature, and 18 were classified as failures. The reproducibility of blood flow measurements in the brachial artery was good (intraclass correlation coefficient, 0.912). The blood flow in the failure group was significantly lower than that in the mature group at both 1 and 14 days after fistula creation (P < .05). During the first 2 postoperative weeks, the blood flow increased by 40.7% in the failure group versus 78.3% in the mature group. The areas under the receiver operating characteristic curves of brachial artery blood flow for predicting failure were 0.77 (95% confidence interval, 0.66-0.87; optimal cutoff value, 310 mL/min)at 1 day and 0.91 (95% confidence interval, 0.83-0.99; 413 mL/min) at 14 days after fistula creation. CONCLUSIONS: Brachial artery blood flow measured by sonography during early postoperative periods may be predictive of forearm fistula failure. Blood flow of less than 310 mL/min at 1 day and 413 mL/min at 14 days after fistula creation may indicate a risk of failure to mature. PMID- 27492393 TI - Stenosis in Middle Cerebral Artery Duplication: Assessment With Transcranial Color-Coded Duplex Sonography. AB - Duplication of the middle cerebral artery is an unusual anatomic variant. Stenosis of one of its branches can be an exceptional cause of stroke and is very difficult to diagnose with transcranial duplex sonography. We report 2 patients with duplication of the middle cerebral artery in whom stenosis of one of its branches led to ischemic stroke and describe the sonographic findings in comparison to other neuroimaging modalities. These cases highlight the utility of adding a coronal insonation plane on top of the traditional axial plane to avoid identification pitfalls in patients with anatomic variants. PMID- 27492394 TI - Three-Dimensional Color/Power Doppler Sonography and HD live Silhouette Mode for Diagnosis of Molar Pregnancy. AB - We present our experience of using new 3-dimensional color/power Doppler sonography (HDliveFlow; GE Healthcare Japan, Tokyo, Japan) with the HD live silhouette mode for diagnosing complete molar pregnancy in the first trimester and differentiating it from missed abortion with hydropic degeneration. In the case of a complete mole, color Doppler sonography showed numerous vesicles without blood vessels, whereas HDliveFlow with the HD live silhouette mode clearly depicted these vesicles forming a mass with the clear demarcation of its edges and showed no blood flow inside the mass. In contrast to the hydropic abortion, which appeared as some vesicles with many blood vessels around them on color Doppler sonography, HDliveFlow with the HD live silhouette mode showed some vesicles embedded within the abundant blood vessels. The spatial relationship between the vesicles and surrounding highly vascularized uterus could be shown on HDliveFlow with the HD live silhouette mode. This technique might be beneficial as an additional diagnostic tool along with conventional color/power Doppler sonography, and it facilitates the early discrimination of these cases in the first trimester of pregnancy. PMID- 27492395 TI - Secondary structure and (1)H, (13)C and (15)N resonance assignments of Skint-1: a selecting ligand for a murine gammadelta T cell subset implicated in tumour suppression. AB - A study describing the (1)H, (13)C and (15)N backbone and side chain chemical shift assignments and secondary structure of Skint-1 a prototypic member of a family of mouse genes, of which Skint-1 is involved in the development of the dendritic epidermal T cell (DETC) subset of gammadelta T cells. PMID- 27492396 TI - Economic evaluation of pegylated interferon plus ribavirin for treatment of chronic hepatitis C in Thailand: genotype 1 and 6. AB - BACKGROUND: Pegylated interferon alpha 2a, alpha 2b and ribavirin have been included to the National List of Essential Medicines (NLEM) for treatment of only chronic hepatitis C genotypes 2 and 3 in Thailand. This reimbursement policy has not covered for other genotypes of hepatitis C virus infection (HCV) especially for genotypes 1 and 6 that account for 30-50 % of all HCV infection in Thailand. Therefore, this research determined whether pegylated interferon alpha 2a or alpha 2b plus ribavirin is more cost-effective than a palliative care for treatment of HCV genotype 1 and 6 in Thailand. METHODS: A cost-utility analysis using a model-based economic evaluation was conducted based on a societal perspective. A Markov model was developed to estimate costs and quality-adjusted life years (QALYs) comparing between the combination of pegylated interferon alpha 2a or alpha 2b and ribavirin with a usual palliative care for genotype 1 and 6 HCV patients. Health-state transition probabilities, virological responses, and utility values were obtained from published literatures. Direct medical and direct non-medical costs were included and retrieved from published articles and Thai Standard Cost List for Health Technology Assessment. The incremental cost effectiveness ratio (ICER) was presented as costs in Thai baht per QALY gained. RESULTS: HCV treatment with pegylated interferon alpha 2a or alpha 2b plus ribavirin was dominant or cost-saving in Thailand compared to a palliative care. The ICER value was negative with lower in total costs (peg 2a- 747,718vs. peg 2b- 819,921 vs. palliative care- 1,169,121 Thai baht) and more in QALYs (peg 2a- 13.44 vs. peg 2b- 13.14 vs. palliative care- 11.63 years) both in HCV genotypes 1 and 6. CONCLUSION: As cost-saving results, the Subcommittee for Development of the NLEM decided to include both pegylated interferon alpha 2a and alpha 2b into the NLEM for treatment of HCV genotype 1 and 6 recently. Economic evaluation for these current drugs can be further applied to other novel medications for HCV treatment. PMID- 27492397 TI - A Method for Quantitative Evaluation of the Results of Postural Tests. AB - A method for quantitative evaluation of the results of postural tests is proposed. The method is based on contact-free measurements of 3D coordinates of body point movements. The result can serve as an integral test based on the Mahalanobis distance. PMID- 27492399 TI - Comparative Culturing of 3T3 Swiss J2 Mouse Embryo Fibroblasts on Modified Chitosan Matrices. AB - Comparative culturing of mouse embryo fibroblasts on chitosan matrices and culture plastic was carried out. During the first 2 h of culturing (lag phase), cell adhesion to chitosan and chitosan-gelatin matrices was 20-30% higher than adhesion to culture plastic (control). During the stationary phase, 80% cells adhered to chitosan matrices (vs. 60% in the control). Cell culturing on chitosan matrices was carried out without medium replacement with fresh portions. The cells remained viable within 5 days of culturing. Cell death phase was observed on day 6 of culturing on chitosan matrices: cell adhesion dropped to 50%. Culturing on culture plastic was carried out with daily medium replacement with a fresh portion. Cell death phase (50% decrease in the number of adherent cell) under these condition was observed on day 5. It seems that the observed effect was a result of contact interactions of cell integrins and chitosan ligands, modulation of transmembrane signal, eventually modifying the expression of cell genes. This effect can be required in regenerative medicine for production of primary cell culture. PMID- 27492398 TI - Analysis of Polymorphism of Angiotensin System Genes (ACE, AGTR1, and AGT) and Gene ITGB3 in Patients with Arterial Hypertension in Combination with Metabolic Syndrome. AB - Changes in the frequencies of genotypes and mutant alleles of ACE, AGTR1, AGT, and ITGB3 genes were analyzed in patients with arterial hypertension coupled with metabolic syndrome (N=15) and compared with population data and corresponding parameters in patients with isolated hypertension (N=15). Increased frequency of genotype ID of ACE gene (hypertension predictor) was confirmed for both groups. In case of isolated hypertension, M235M genotype (gene AGT) was more frequent, in case of hypertension combined with metabolic syndrome, the frequency of genotypes A1166C and C1166C of the gene AGTR1 was higher in comparison with population data. Comparison of mutant allele frequencies in the two groups showed that at the 90% significance level allele T of the AGT gene was more frequent in hypertension coupled with metabolic syndrome (OR=1.26) and genotype A1166A of the AGTR1 gene was more frequent in the group with isolated hypertension. PMID- 27492400 TI - On Methods for the Analysis of Indefinite Stimuli Perception Characteristics: an fMRT Study of Gender-Specific Differences. AB - Comparative identification of cerebral regions activated in men and women during perception of indefinite images was carried out by fMRT and psychological testing. Nine men and nine women aged 20-26 years took part in the study. The volunteers examined simple geometric figures, slightly structurized images (tables from Rorschach's test), and images of impossible figures. Activation in the cerebellum and visual cortex (bilateral) was more pronounced in women in response to all types of images and less so in the right G. temporalis medius. The right frontal regions (G. precentralis, G. frontalis superior, G. frontalis medius) were also stronger activated in women in response to indefinite stimuli. PMID- 27492401 TI - Reflection of the State of Hunger in Impulse Activity of Nose Wing Muscles and Upper Esophageal Sphincter during Search behavior in Rabbits. AB - Reflection of the state of hunger in impulse activity of nose wing muscles and upper esophageal sphincter muscles was studied in chronic experiments on rabbits subjected to 24-h food deprivation in the absence of locomotion and during search behavior. In the absence of apparent behavioral activity, including sniffing, alai nasi muscles of hungry rabbits constantly generated bursts of action potentials synchronous with breathing, while upper esophageal sphincter muscles exhibited regular aperiodic low-amplitude impulse activity of tonic type. Latent form of food motivation was reflected in the structure of temporal organization of impulse activity of alai nasi muscles in the form of bimodal distribution of interpulse intervals and in temporal structure of impulse activity of upper esophageal sphincter muscles in the form of monomodal distribution. The latent form of food motivation was manifested in the structure of temporal organization of periods of the action potentials burst-like rhythm, generated by alai nasi muscles, in the form of monomodal distribution, characterized by a high degree of dispersion of respiratory cycle periods. In the absence of physical activity hungry animals sporadically exhibited sniffing activity, manifested in the change from the burst-like impulse activity of alai nasi muscles to the single-burst activity type with bimodal distribution of interpulse intervals and monomodal distribution of the burst-like action potentials rhythm periods, the maximum of which was shifted towards lower values, which was the cause of increased respiratory rate. At the same time, the monomodal temporal structure of impulse activity of the upper esophageal sphincter muscles was not changed. With increasing food motivation in the process of search behavior temporal structure of periods of the burst-like action potentials rhythm, generated by alai nasi muscles, became similar to that observed during sniffing, not accompanied by animal's locomotion, which is typical for the increased respiratory rhythm frequency. Increased hunger motivation was reflected in the temporal structure of impulse activity of upper esophageal sphincter muscles in the form of a shift to lower values of the maximum of monomodal distribution of interpulse intervals on the histogram, resulting in higher impulse activity frequency. The simultaneous increase in the frequency of action potentials bursts generation by alai nasi muscles and regular impulse activity of upper esophageal sphincter muscles is a reliable criterion for enhanced food motivation during search behavior in rabbits. PMID- 27492402 TI - Effect of Contamination with Perennial Permafrost Microorganisms on the Outcome of Closed Brain Neurotrauma. AB - We studied the effect of contamination with Bacillus genus microorganisms isolated from perennial permafrost samples on the outcome of closed brain neurotrauma in Wistar rats. It was found that contamination with different Bacillus strains produced different effects on the mortality of experimental animals with closed neurotrauma. The complex of metabolites from strain Ch2/9 - Bacillus spp. (pumilus) produced a protective effect in experimental closed brain neurotrauma. PMID- 27492403 TI - Dynamics of Erythropoiesis in Erythroblastic Islands in the Bone Marrow in Experimental Benzene-Induced Anemia. AB - In 14 days after triple subcutaneous injection of benzene to rats in a dose of 0.05 ml/100 g body weight, the number of erythroblastic islands in the bone marrow 2-fold decreased, de novo erythropoiesis ceased, de repeto erythropoiesis slowed down, and the number of lymphoid cells contacting with erythroblastic islands decreased. By day 56 of the experiment, proliferation of erythroid cells in the bone marrow start to recover due to erythropoiesis reconstitution, but the number of reticulocytes in the blood remained low. Analysis of phagocytic ability of macrophages in the erythroblastic islands showed that the intensity of phagocytosis of latex particles in mature islands decreased, which could affect denucleation of oxyphilic erythroblasts. PMID- 27492404 TI - Population Polymorphism of IFNL3 and IFNL4 Genes of Type 3 Interferon Associated with Spontaneous Clearance of Hepatitis C Virus in Representatives of Caucasian and Mongoloid Races. AB - The frequency of single nucleotide polymorphisms of IFNL3 gene (rsl12979860 and rs8099917) and dinucleotide polymorphism of IFNL4 gene (ss469415590) were estimated in healthy inhabitants of Mongolia and Irkutsk regions taking into account their races. Population and genetic studies were performed in 1520 conventionally healthy volunteers (blood donors), representatives of Caucasian and Mongoloid races. Significant race-related differences in the incidence of IFNL3 and IFNL4 gene polymorphisms associated with spontaneous clearance of hepatitis C virus were found in healthy volunteers. PMID- 27492405 TI - Circadian Rhythms of Carbohydrate Metabolism in Women with Different Types of Obesity. AB - Blood levels of glucose and immunoreactive insulin were assessed in women with android and gynoid types of obesity or normal body weight (control group) in the dynamics of oral glucose tolerance test in the morning and in the evening. In the control group, the mean concentrations of glucose and immunoreactive insulin were significantly higher in the evening at all test terms (0, 60 and 120 min), which is indicative of physiological insulin resistance in the evening. In the group of women with gynoid obesity, no difference in the levels of glucose and immunoreactive insulin was revealed in the morning and evening tests, but in the evening tests, glucose (60 and 120 min) and immunoreactive insulin (120 min) levels were lower than in the control group. In the group of women with android obesity, the evening glucose level on minutes 60 and 120 of the test was higher than in the morning, but immunoreactive insulin did not vary throughout the day and on minutes 60 and 120 it surpassed the corresponding parameter in the control group by 2-4 times. In case of gynoid obesity, glucose load was followed by hyperinsulinemia and hypoglycemia; in android obesity, it was followed by hyperinsulinemia, hyperglycemia, and insulin resistance irrespective of the time of the day. PMID- 27492406 TI - Effect of Opiate Receptors Blockade on Microbicidal Potential and Production of IL-1beta, TNFalpha, and IL-10 by Peritoneal Macrophages under Stress Conditions. AB - Rotation stress activated spontaneous and zymosan-induced ROS production. In animals receiving naloxone against the background of rotation stress, ROS production did not increase. Immobilization stress did not change the intensity of spontaneous and zymosan-induced ROS production, but inhibited stimulated ROS production against the background of naloxone treatment. Rotation produced a naloxone-independent inhibitory effect on spontaneous and stimulated IL-1beta and TNFalpha production by macrophages and naloxone-dependent stimulating effect on spontaneous IL-10 production. Rotation stress did not modulate stimulated IL-10 production. In case of immobilization stress, decreased IL-1beta and TNFalpha production was observed in mice exposed to stress under conditions of opiate receptors blockade; IL-10 production was not affected by immobilization stress. Both types of stress significantly increased plasma corticosterone levels, while naloxone had no effect on corticosterone production. PMID- 27492407 TI - Drugs Related to Oropharyngeal Dysphagia in Older People. AB - Scientific evidence on the impact of medication on the physiology of swallowing is scarce and mainly based on clinical case reports. To evaluate the association between oropharyngeal dysphagia (OD) and chronic exposure to medication in older patients admitted to the acute geriatric unit (AGU) of a secondary hospital, we performed a retrospective cross-sectional study of 966 patients admitted to an AGU from 2008 to 2011. We reviewed (a) diagnosis of OD (assessed with the volume viscosity swallow test, V- VST); (b) chronic patient medication classified by anatomical, therapeutic, chemical codes; and (c) demographic and clinical data. A univariate analysis was performed to determine which medications were associated with OD. A multivariate analysis adjusting for confounding clinical factors was performed to identify which of those medications were independently associated with OD. The age of patients included was 85.3 +/- 6.37 years and 59.4 % were women. A total of 41.9 % presented OD. We found a possible protective effect of beta blocking agents on OD after the multivariate analysis (OR 0.54, 95 % CI 0.35 0.85). None of the categories of drugs was associated with an altered swallowing function after adjusting for confounding variables. The present study is the first one to widely investigate the association between drugs and OD, increasing understanding of their association. The role of beta blockers in OD needs to be further studied as their potentially beneficial effects on the swallowing function in older patients could help to prevent complications. PMID- 27492410 TI - What Will It Take to Reduce the App Gap? PMID- 27492409 TI - Refined stratified-worm-burden models that incorporate specific biological features of human and snail hosts provide better estimates of Schistosoma diagnosis, transmission, and control. AB - BACKGROUND: Schistosoma parasites sustain a complex transmission process that cycles between a definitive human host, two free-swimming larval stages, and an intermediate snail host. Multiple factors modify their transmission and affect their control, including heterogeneity in host populations and environment, the aggregated distribution of human worm burdens, and features of parasite reproduction and host snail biology. Because these factors serve to enhance local transmission, their inclusion is important in attempting accurate quantitative prediction of the outcomes of schistosomiasis control programs. However, their inclusion raises many mathematical and computational challenges. To address these, we have recently developed a tractable stratified worm burden (SWB) model that occupies an intermediate place between simpler deterministic mean worm burden models and the very computationally-intensive, autonomous agent models. METHODS: To refine the accuracy of model predictions, we modified an earlier version of the SWB by incorporating factors representing essential in-host biology (parasite mating, aggregation, density-dependent fecundity, and random egg-release) into demographically structured host communities. We also revised the snail component of the transmission model to reflect a saturable form of human-to-snail transmission. The new model allowed us to realistically simulate overdispersed egg-test results observed in individual-level field data. We further developed a Bayesian-type calibration methodology that accounted for model and data uncertainties. RESULTS: The new model methodology was applied to multi-year, individual-level field data on S. haematobium infections in coastal Kenya. We successfully derived age-specific estimates of worm burden distributions and worm fecundity and crowding functions for children and adults. Estimates from the new SWB model were compared with those from the older, simpler SWB with some substantial differences noted. We validated our new SWB estimates in prediction of drug treatment-based control outcomes for a typical Kenyan community. CONCLUSIONS: The new version of the SWB model provides a better tool to predict the outcomes of ongoing schistosomiasis control programs. It reflects parasite features that augment and perpetuate transmission, while it also readily incorporates differences in diagnostic testing and human sub-population differences in treatment coverage. Once extended to other Schistosoma species and transmission environments, it will provide a useful and efficient tool for planning control and elimination strategies. PMID- 27492411 TI - Executive Summary of the Key Concepts. PMID- 27492408 TI - Effects of Change in Tongue Pressure and Salivary Flow Rate on Swallow Efficiency Following Chemoradiation Treatment for Head and Neck Cancer. AB - Patients treated with chemoradiation for head and neck cancer frequently develop dysphagia. Tissue damage to the oral tongue causing weakness along with decreases in saliva production may contribute to dysphagia. Yet, effects of these variables on swallowing-related measures are unclear. The purpose of this study was (1) to determine effects of chemoradiation on tongue pressures, as a surrogate for strength, and salivary flow rates and (2) to elucidate relationships among tongue pressures, saliva production, and swallowing efficiency by bolus type. Twenty-one patients with head and neck cancer treated with chemoradiation were assessed before and after treatment and matched with 21 healthy control participants who did not receive chemoradiation. Each participant was given a questionnaire to rate dysphagia symptoms. Videofluoroscopic Evaluation of Swallowing (VFES) was used to determine swallowing efficiency; the Saxon test measured salivary flow rate; and the Iowa Oral Performance Instrument (IOPI) was used for oral tongue maximum and endurance measures. Results revealed significantly lower tongue endurance measures for patients post-treatment as compared to controls (p = .012). Salivary flow rates also were lower compared to pre-treatment (p = .000) and controls (p = .000). Simple linear regression analyses showed that change in salivary flow rate was predictive of change in swallow efficiency measures from pre- to post-treatment for 1 mL thin liquid (p = .017), 3 mL nectar-thick liquid (p = .026), and 3 mL standard barium pudding (p = .011) boluses. Based on these findings, it appears that chemoradiation treatment affects tongue endurance and salivary flow rate, and these changes may impact swallow efficiency. These factors should be considered when planning treatment for dysphagia. PMID- 27492412 TI - Could Designing a Hospital Like a Medical Device Contribute to Patient Safety? PMID- 27492413 TI - Patient Safety: A Priority for Healthcare and for Healthcare Design. PMID- 27492414 TI - People Want to Know. PMID- 27492415 TI - Integrated Framework for Patient Safety and Energy Efficiency in Healthcare Facilities Retrofit Projects. AB - There is a growing focus on enhancing energy efficiency in healthcare facilities, many of which are decades old. Since replacement of all aging healthcare facilities is not economically feasible, the retrofitting of these facilities is an appropriate path, which also provides an opportunity to incorporate energy efficiency measures. In undertaking energy efficiency retrofits, it is vital that the safety of the patients in these facilities is maintained or enhanced. However, the interactions between patient safety and energy efficiency have not been adequately addressed to realize the full benefits of retrofitting healthcare facilities. To address this, an innovative integrated framework, the Patient Safety and Energy Efficiency (PATSiE) framework, was developed to simultaneously enhance patient safety and energy efficiency. The framework includes a step -: by -: step procedure for enhancing both patient safety and energy efficiency. It provides a structured overview of the different stages involved in retrofitting healthcare facilities and improves understanding of the intricacies associated with integrating patient safety improvements with energy efficiency enhancements. Evaluation of the PATSiE framework was conducted through focus groups with the key stakeholders in two case study healthcare facilities. The feedback from these stakeholders was generally positive, as they considered the framework useful and applicable to retrofit projects in the healthcare industry. PMID- 27492417 TI - Genomic and functional features of the biosurfactant producing Bacillus sp. AM13. AB - Genomic studies provide deeper insights into secondary metabolites produced by diverse bacterial communities, residing in various environmental niches. This study aims to understand the potential of a biosurfactant producing Bacillus sp. AM13, isolated from soil. An integrated approach of genomic and chemical analysis was employed to characterize the antibacterial lipopeptide produced by the strain AM13. Genome analysis revealed that strain AM13 harbors a nonribosomal peptide synthetase (NRPS) cluster; highly similar with known biosynthetic gene clusters from surfactin family: lichenysin (85 %) and surfactin (78 %). These findings were substantiated with supplementary experiments of oil displacement assay and surface tension measurements, confirming the biosurfactant production. Further investigation using LCMS approach exhibited similarity of the biomolecule with biosurfactants of the surfactin family. Our consolidated effort of functional genomics provided chemical as well as genetic leads for understanding the biochemical characteristics of the bioactive compound. PMID- 27492418 TI - Effects of constrained trunk movement on frontal plane gait kinematics. AB - Previously it has been shown that constraining step width in gait coincides with decreased trunk displacements. Conversely, external stabilization of the upper body in gait coincides with decreased step width, but this may in part be due to changes in passive dynamics of the leg. In the present study, trunk kinematics during gait were constrained without external stabilization by using an orthosis, to investigate whether step width and dynamic gait stability in the ML direction are changed in relation to trunk kinematics. Nine healthy young adults walked on a treadmill at three different speeds with no intervention and while wearing a thoracolumbar orthosis. Based on marker trajectories, trunk COM displacement, body COM displacement and velocity, step width, and margin-of-stability in ML direction were calculated. The results showed that the orthosis significantly reduced trunk and body COM displacements. As hypothesized, the restriction of trunk movement coincided with significantly decreased step width, while the margin-of-stability was not affected. These findings indicate that, when trunk movements are constrained, humans narrow step width, while maintaining a constant margin-of-stability. In conclusion, the present results in combination with previous work imply that in gait a reciprocal coupling between trunk kinematics and foot placement in the frontal plane subserves control of stability in the frontal plane. PMID- 27492420 TI - The bladder cancer drug market. PMID- 27492419 TI - The Cost-Effectiveness of Oral Nutrition Supplementation for Malnourished Older Hospital Patients. AB - BACKGROUND: Malnutrition, which is associated with increased medical complications in older hospitalized patients, can be attenuated by providing nutritional supplements. OBJECTIVE: This study evaluates the cost effectiveness of a specialized oral nutritional supplement (ONS) in malnourished older hospitalized patients. METHODS: We conducted an economic evaluation alongside a multicenter, randomized, controlled clinical trial (NOURISH Study). The target population was malnourished older hospitalized patients in the USA. We used 90 day (base case) and lifetime (sensitivity analysis) time horizons. The study compared a nutrient-dense ONS, containing high protein and beta-hydroxy-beta methylbutyrate to placebo. Outcomes included health-care costs, measured as the product of resource use and per unit cost; quality-adjusted life-years (QALYs) (90-day time horizon); life-years (LYs) saved (lifetime time horizon); and the incremental cost-effectiveness ratio (ICER). All costs were inflated to 2015 US dollars. RESULTS: In the base-case analysis, 90-day treatment group costs averaged US$22,506 per person, compared to US$22,133 for the control group. Treatment group patients gained 0.011 more QALYs than control group subjects, reflecting the treatment group's significantly greater probability of survival through 90 days' follow-up, as reported by the clinical trial. Hence, the 90-day follow-up period ICER was US$33,818/QALY. Assuming a lifetime time horizon, estimated treatment group life expectancy exceeded control group life expectancy by 0.71 years. Hence, the lifetime ICER was US$524/LY. The follow-up period for the trial was relatively short. Some of the patients were lost to follow-up, thus reducing collection of health-care utilization data during the clinical trial. CONCLUSION: Our findings suggest that the investigative ONS cost-effectively extends the lives of malnourished hospitalized patients. PMID- 27492421 TI - How Online Peer-to-Peer Conversation Shapes the Effects of a Message About Healthy Sleep. AB - Conversation about health messages and campaigns is common, and message-related conversations are increasingly recognized as a consequential factor in shaping message effects. The evidence base is limited, however, about the conditions under which conversation may help or hinder health communication efforts. In this study, college students (N = 301) first watched a short sleep video and were randomly assigned to either talk with a partner in an online chat conversation or proceed directly to a short survey. Unknown to participants, the chat partner was a confederate coached to say positive things about sleep and the message ('positive' chat condition), negative things ('negative' chat condition), or unrelated things ('natural' chat condition). All respondents completed a short survey on beliefs about sleep, reactions to the message, and intentions to get adequate sleep. Respondents had greater intentions to engage in healthy sleep when they engaged in positive conversation following message exposure than when they engaged in negative conversation after the message (p < 0.001). Positive emotion experienced in response to the message and positive chat perceptions were significant predictors (p < 0.05) of intentions to achieve healthy sleep. Health message designers may benefit from understanding how messages are exchanged in peer-to-peer conversation to better predict and explain their effects. PMID- 27492423 TI - International Cancer Education Conference 2016 Program and Abstracts. PMID- 27492422 TI - Human eccrine sweat gland cells reconstitute polarized spheroids when subcutaneously implanted with Matrigel in nude mice. AB - Increasing evidence indicates that maintenance of cell polarity plays a pivotal role in the regulation of glandular homeostasis and function. We examine the markers for polarity at different time points to investigate the formation of cell polarity during 3D reconstitution of eccrine sweat glands. Mixtures of eccrine sweat gland cells and Matrigel were injected subcutaneously into the inguinal regions of nude mice. At 2, 3, 4, 5 and 6 weeks post-implantation, Matrigel plugs were removed and immunostained for basal collagen IV, lateral beta catenin, lateroapical ZO-1 and apical F-actin. The results showed that the cell polarity of the spheroids appeared in sequence. Formation of basal polarity was prior to lateral, apical and lateroapical polarity. Collagen IV was detected basally at 2 weeks, beta-catenin laterally and ZO-1 lateroapically at 3 weeks, and F-actin apically at 4 weeks post-implantation. At week 5 and week 6, the localization and the positive percentage of collagen IV, beta-catenin, ZO-1 or F actin in spheroids was similar to that in native eccrine sweat glands. We conclude that the reconstituted 3D eccrine sweat glands are functional or potentially functional. PMID- 27492424 TI - Qualitative Exploration of Sexual Health Among Diverse Breast Cancer Survivors. AB - Although the physical and emotional impact of surgical removal of partial or complete removal of the breast as well as effects of breast cancer treatment on the individual have been well documented, little research is available on sexuality and sexual health of breast cancer survivors in a relationship context. Sexual health concerns of breast cancer survivors remain an unmet need for many. The present study consisted of qualitative interviews with 135 racially diverse, female breast cancer survivors who completed treatment to better understand their perspectives on sexual health and management of sexual problems in their potential and existing relationships after breast cancer. Key thematic findings include that breast cancer survivors have to (1) adapt to the physical and emotional traumas of breast cancer surgery and treatment, (2) navigate complicated sexual communications with potential and existing partners, and (3) negotiate intimacy and closeness without sexual intercourse with existing partners. This study demonstrates the need for healthcare providers to discuss sexual health after breast cancer with all of their patients as it is a concern that faces single and partnered breast cancer survivors months and years after treatment. PMID- 27492425 TI - How well Informed are Cancer Patients Prior to a Life Cycle of Injectable Chemotherapy Drug Treatment? AB - Cancer patient dissatisfaction, due to a long waiting time for chemotherapy treatment, is a common complaint. To improve patient satisfaction, our pharmaceutical team was prompted to design a series of information tools for injectable chemotherapy drug treatment (ICDT) patients. This study was based on French Health Authorities recommendations. All three stages were monitored: the preparation stage using a 204 patient survey, the design stage, and the assessment stage with a 12 point questionnaire patient evaluation. An information brochure and a 10-min film were designed which chronologically described key stages in the life cycle of ICDT. Both tools were assessed by 29 and 84 patients respectively. The questionnaire confirmed that this approach met the needs of more than 90 % of patients. The brochure and the film also accurately met the objectives and improved the understanding of the chemotherapy long waiting time which resulted in higher patient satisfaction. The designed tools will continue to evolve with changes in oncology practices based on various indicators defined in the study. Our study proposes an original method to assist health professionals to better inform cancer patients regarding the preparation of ICDT. It is also a part of a continuous quality program to assure quality outpatient healthcare. PMID- 27492426 TI - Update on the Management of Pancreatic Cancer in Older Adults. AB - Pancreatic cancer is more common in older adults, who are underrepresented in clinical trials and frequently under treated. Chronological age alone should not deter clinicians from offering treatment to geriatric patients, as they are a heterogeneous population. Geriatric assessment, frailty assessment tools, and toxicity risk scores help clinicians select appropriate patients for therapy. For resectable disease, surgery can be safe but should be done at a high-volume center. Adjuvant therapy is important; though there remains controversy on the role of radiation, chemotherapy is well studied and efficacious. In locally advanced unresectable disease, chemoradiation or chemotherapy alone is an option. Neoadjuvant therapy improves the chances of resectability in borderline resectable disease. Chemotherapy extends survival in metastatic disease, but treatment goals and risk-benefit ratios have to be clarified. Adequate symptom management and supportive care are important. There are now many new treatment strategies and novel therapies for this disease. PMID- 27492427 TI - Detection of spine structures with Bioimpedance Probe (BIP) Needle in clinical lumbar punctures. AB - Lumbar puncture is a relatively safe procedure, but some serious, even fatal, complications can occur. Needle guidance can increase puncture accuracy, decrease the number of attempts, and make the procedure easier. We tested the feasibility of a bioimpedance-based tissue-sensing technology for needle guidance in clinical use. The Bioimpedance Probe (BIP) Needle has a removable BIP stylet enabling measurement of bioimpedance spectra during the procedure. The BIP Needle is connected to a measurement device that uses tissue-classification software, and the device provides audiovisual feedback when it detects cerebrospinal fluid (CSF). We performed spinal anesthesia with the BIP Needle in 45 patients. The device performance and needle tip location were verified by an experienced anesthesiologist confirming CSF leakage. The device detected CSF in all cases (sensitivity of 100 %). Six cases with false detections lowered the specificity to 81 %, but in practice, most of these were easy to differentiate from true detections because their duration was short and they occurred during backward movement of the needle. The epidural spectrum differentiated as fatty tissue from surrounding tissues, but the ligamentum flavum was not clearly detectable in the data. The BIP Needle is a reliable tool for detecting CSF in lumbar puncture. It can make the puncture procedure smoother, as repeated CSF flow tests are avoided. The correct needle tip location is immediately detected, thus unnecessary needle movements close to spinal nerves are prevented. Physicians could benefit from the information provided by the BIP Needle, especially in patients with obesity or anatomic alterations. PMID- 27492428 TI - Observation of ventilation effects of I-gelTM, SupremeTM and Ambu AuraOnceTM with respiratory dynamics monitoring in small children. AB - The shortcomings of laryngeal mask airway (LMATM), such as upper airway obstruction and gastric distension or airway leakage, may limit its application in small children. The I-gelTM (I-gel), LMA-SupremeTM (LMA-S), and Ambu AuraOnceTM (Ambu) are three improvements upon these shortcomings. This study adopted respiratory dynamic monitoring to observe the ventilation parameters of the three laryngeal masks in small children. A total of 105 children were randomized into Ambu (n = 35), I-gel (n = 35), and LMA-S (n = 35) groups. Primary outcomes included leak pressure and respiratory dynamic data. Secondary outcomes included hemodynamic data and bispectral index values after induction (T0), time after successful laryngeal mask insertion (T1) and at three recording points every 10 min after insertion (T2, T3, and T4), as well as laryngeal mask related adverse reactions. The inspiratory/expiratory tidal volume per kilogram of body weight in the Ambu group was significantly different from those in the other groups (P < 0.05), while the leak pressure in the Ambu group was significantly lower (P < 0.05). At T3 and T4, the expiratory resistance values in the Ambu group were significantly lower than those in the LMA-S group (P < 0.05). We have shown that the three laryngeal masks provided secure ventilation in children <6 years of age by using continuous respiratory dynamic monitoring. We concluded that the I-gel presented a better sealing effect and fewer adverse reactions. PMID- 27492429 TI - Effective evaluation of arterial pulse waveform analysis by two-dimensional stroke volume variation-stroke volume index plots. AB - Arterial pulse waveform analysis (APWA) with a semi-invasive cardiac output monitoring device is popular in perioperative hemodynamic and fluid management. However, in APWA, evaluation of hemodynamic data is not well discussed. In this study, we analyzed how we visually interpret hemodynamic data, including stroke volume variation (SVV) and stroke volume (SV) derived from APWA. We performed arithmetic estimation of the SVV-SV relationship and applied measured values to this estimation. We then collected measured values in six anesthesia cases, including three liver transplantations and three other types of surgeries, to apply them to this SVV-SVI (stroke volume variation index) plot. Arithmetic analysis showed that the relationship between SVV and SV can be drawn as hyperbolic curves. Plotting SVV-SV values in the semi-logarithmic scale showed linear correlations, and the slopes of the linear regression lines theoretically represented average mean cardiac contractility. In clinical measurements in APWA, plotting SVV and SVI values in the linear scale and the semi-logarithmic scale showed the correlations represented by hyperbolic curves and linear regression lines. The plots approximately shifted on the rectangular hyperbolic curves, depending on blood loss and blood transfusion. Arithmetic estimation is close to real measurement of the SVV-SV interaction in hyperbolic curves. In APWA, using SVV as an index of preload and the cardiac index or SVI derived from arterial pressure-based cardiac output as an index of cardiac function, is likely to be appropriate for categorizing hemodynamic stages as a substitute for Forrester subsets. PMID- 27492430 TI - Safety analysis of laparoscopic endoscopic cooperative surgery versus endoscopic submucosal dissection for selected gastric gastrointestinal stromal tumors: a propensity score-matched study. AB - BACKGROUND: Laparoscopic endoscopic cooperative surgery (LECS) is a safe alternative to endoscopic submucosal dissection (ESD) for select gastric gastrointestinal stromal tumors (GISTs) that are <2 cm in size. To date, there have been no randomized studies comparing the feasibility of these two techniques. Therefore, we compared their feasibility and safety using the propensity score matching method in this study. METHODS: This was a single center, retrospective, propensity score-matched study of patients who underwent resection of selected gastric GISTs between 2004 and 2014. All patients underwent curative resection for pathologically diagnosed small gastric GISTs. The primary aim was to determine intraoperative complications and postoperative courses. To overcome selection biases, we performed a 1:1 match using five covariates, including age, gender, body mass index, Charlson comorbidity index, and tumor location, to generate propensity scores. RESULTS: In total, 32 patients treated with LECS and 102 patients treated with ESD were balanced into 30 pairs. The rate of intraoperative complications was significantly lower in the LECS group than in the ESD group (P = 0.029). LECS patients had less intraoperative bleeding than did ESD patients (15.0 ml [range 9.5-50.0 ml] vs. 43.5 ml [range 22.3-56.0 ml], P = 0.004). The two groups had similar postoperative courses. There was no difference in the reoperation rate between the two groups (P = 0.112). The ESD group had a shorter operating time than did the LECS group (41.5 min vs. 96.5 min, P < 0.001). However, during a follow-up of 57.9 (+/-28.9) months, the recurrence rate did not differ significantly between the two groups (0.0 vs. 6.7 %, respectively; P = 0.256). CONCLUSIONS: LECS for selected gastric GIST patients is feasible and is associated with a better intraoperative outcome and an equal postoperative course compared with the results of ESD. PMID- 27492431 TI - A new method (the "Pincers maneuver") for lymphadenectomy along the right recurrent laryngeal nerve during thoracoscopic esophagectomy in the prone position for esophageal cancer. AB - BACKGROUND: In esophageal squamous cell carcinoma, the number of dissected lymph nodes (LNs), including those along the recurrent laryngeal nerves (RLNs), influences prognosis and nodal staging accuracy. However, dissection of LNs along the RLN increases the risk of complications, especially RLN palsy. Therefore, complete dissection of these LNs with prevention of RLN palsy is recommended. We present herein a new method for lymphadenectomy along the right RLN, named the Pincers maneuver, during thoracoscopic esophagectomy in the prone position (TEP). METHODS: The fundamental concept in this new method is to first exfoliate the two dimensional membrane (lateral pedicle), which includes the right RLN, LNs along the right RLN, and the primary esophageal artery, from the right side of the trachea toward the neck. Using a Pincers strategy, closing in from the inner and outer sides of the two-dimensional membrane (lateral pedicle), lymphadenectomy along the right RLN toward the right inferior thyroid artery should be easy. This technique was evaluated in 30 consecutive cases of TEP for squamous cell cancer. RESULTS: There were 15 patients who underwent the new method (Pincers maneuver; Pm) and 15 patients who underwent the conventional method (Cm). There were no significant differences between the two groups in the duration of the thoracic procedure and dissection along the right RLN. No intraoperative and postoperative morbidity related to the right RLN was observed in either group. The Pm group had a higher number of dissected LNs along the right RLN than the Cm group (6.3 vs 3.1, p = 0.044). CONCLUSIONS: The Pincers maneuver for lymphadenectomy along the right RLN during TEP is technically safe and feasible. It increases the number of dissected LNs along the right RLN. PMID- 27492432 TI - Bilateral areolar endoscopic Sistrunk operation: a novel technique for thyroglossal duct cyst surgery. AB - BACKGROUND: Sistrunk operation of the thyroglossal duct is a procedure for the removal of a cyst, the middle part of the hyoid bone and tract towards the foramen caecum. Unavoidably, this procedure results in a scar on the skin in the neck area. By performing a bilateral areolar endoscopic Sistrunk operation, this study is the first to develop a procedure that can solve the aesthetic problem. This operation results in both an excellent cosmetic result and the successful treatment of TGDC. METHODS: A three-port technique was performed in this operation: 10-mm port for 30 degrees , 10-mm laparoscope, 5-mm port for the instrument at the left circumareolar area and 5-mm port located at the right circumareolar area. Insufflation pressure of CO2 gas was set at 6 mm Hg. The surgical working space was located over the breast tissue and pectoralis muscles, towards the anterior neck to the hyoid bone. The steps employed for resection were similar to a conventional Sistrunk operation using standard laparoscopic instruments and hook scissors. RESULTS: A series of 11 patients were successfully treated using this novel technique with neither conversion to open surgery nor surgical complications. Average operative time was 88.54 min (ranging from 60 to 130 min). Average blood loss was 35 mL. (ranging from 15 to 67 mL). Patients were discharged in an average of 2.36 days after the procedure (ranging from 2 to 3 days). CONCLUSION: This novel technique for TGDC Sistrunk surgery using an areolar approach is feasible, safe and effective. The benefit of this technique is the cosmetic result, which leaves no scarring on the neck after wound healing and may provide a new method for optimal aesthetic results. PMID- 27492433 TI - ? PMID- 27492434 TI - [Pyoderma gangrenosum]. AB - Pyoderma gangrenosum (PG) is an ulcerating, neutrophilic dermatosis of unknown etiology. Clinical appearance is characterized by sudden onset of sterile pustules that rapidly develop into very painful ulcerations with violaceous, undermined borders. Due to the lack of specific diagnostic and therapeutic markers, PG is a diagnosis of exclusion. An association with further diseases such as chronic inflammatory bowel disease, rheumatoid arthritis, diabetes, neoplasms, or metabolic syndrome exists in over 50 % of cases. Treatment of PG consists of suppression of inflammatory disease activity, treatment of associated morbidities, promotion of wound healing, and pain relief. Recommended first-line treatment consists of systemic glucocorticosteroids and additional or alternatively cyclosporine. A controlled trial on infliximab in PG points to efficacy of TNF-alpha antagonists. Due to chronicity, frequent recurrences, and often complicated courses, treatment with good tolerability is important. PMID- 27492435 TI - Prediction of hip osteoporosis by DXA using a novel pulse-echo ultrasound device. AB - : Pulse-echo ultrasonometry can be used as a pre-screen for hip osteoporosis before dual-energy x-ray absorptiometry (DXA), potentially allowing DXA to be avoided for the majority of post-menopausal women. Pulse-echo ultrasound measures of tibia cortical thickness are also associated with radiographically confirmed prior fractures, independent of femoral neck bone mineral density. INTRODUCTION: To estimate how well a pulse-echo ultrasound device discriminates those who have from those who do not have hip osteoporosis (femoral neck bone mineral density [BMD] or total hip BMD T-score <= -2.5), and to estimate the association of pulse echo ultrasound measures with prevalent (radiographically confirmed) clinical fractures. METHODS: Five hundred fifty-five post-menopausal women age 50 to 89 had femoral neck and total hip BMD measured by dual-energy x-ray absorptiometry (DXA), and pulse-echo ultrasound measures of distal radius, proximal tibia, distal tibia cortical thickness, and multi- and single-site density indices (DI). Using previously published threshold ultrasound values, we estimated the proportion of women who would avoid a follow-up DXA after pulse-echo ultrasonometry, and the sensitivity and specificity of this for the detection of hip osteoporosis. Logistic regression models were used to estimate the associations of pulse-echo ultrasound measures with radiographically confirmed clinical fractures within the prior 5 years. RESULTS: Using multi-site and single site DI measures, follow-up DXA could be avoided for 73 and 69 % of individuals, respectively, while detecting hip osteoporosis with 80-82 % sensitivity and 81 % specificity. Radiographically confirmed prior fracture was associated with ultrasound measures of single-site DI (odds ratio (OR) 1.55, 95 % confidence interval (CI). 1.06 to 2.26) and proximal tibia cortical thickness (OR 1.47, 95 % CI 1.10 to 1.96), adjusted for age, body mass index, and femoral neck BMD. CONCLUSIONS: Pulse-echo ultrasonometry can be used as an initial screening test for hip osteoporosis. Prospective studies of how well pulse-echo ultrasound measures predict subsequent clinical fractures are warranted. PMID- 27492436 TI - Osteogenesis imperfecta in children and adolescents-new developments in diagnosis and treatment. AB - Osteogenesis imperfecta (OI) is the most prevalent heritable bone fragility disorder in children. It has been known for three decades that the majority of individuals with OI have mutations in COL1A1 or COL1A2, the two genes coding for collagen type I alpha chains, but in the past 10 years defects in at least 17 other genes have been linked to OI. Almost all individuals with a typical OI phenotype have a mutation in one of the currently known genes. Regarding medical treatment, intravenous bisphosphonate therapy is the most widely used medical approach. This has a marked effect on vertebra in growing children and can lead to vertebral reshaping after compression fractures, but there is little effect of bisphosphonate therapy on the development of scoliosis. Bisphosphonate treatment decreases long-bone fracture rates, but such fractures are still frequent. Newer medications with anti-resorptive and bone anabolic action are being investigated in an attempt to improve on the efficacy of bisphosphonates but the safety and efficacy of these new approaches in children with OI is not yet established. PMID- 27492437 TI - Association between education and future leisure-time physical inactivity: a study of Finnish twins over a 35-year follow-up. AB - BACKGROUND: Education is associated with health related lifestyle choices including leisure-time physical inactivity. However, the longitudinal associations between education and inactivity merit further studies. We investigated the association between education and leisure-time physical inactivity over a 35-year follow-up with four time points controlling for multiple covariates including familial confounding. METHODS: This study of the population-based Finnish Twin Cohort consisted of 5254 twin individuals born in 1945-1957 (59 % women), of which 1604 were complete same-sexed twin pairs. Data on leisure-time physical activity and multiple covariates was available from four surveys conducted in 1975, 1981, 1990 and 2011 (response rates 72 to 89 %). The association between years of education and leisure-time physical inactivity (<1.5 metabolic equivalent hours/day) was first analysed for each survey. Then, the role of education was investigated for 15-year and 35-year inactivity periods in the longitudinal analyses. The co-twin control design was used to analyse the potential familial confounding of the effects. All analyses were conducted with and without multiple covariates. Odds Ratios (OR) with 95 % Confidence Intervals (CI) were calculated using logistic and conditional (fixed-effects) regression models. RESULTS: Each additional year of education was associated with less inactivity (OR 0.94 to 0.95, 95 % CI 0.92, 0.99) in the cross-sectional age- and sex-adjusted analyses. The associations of education with inactivity in the 15- and 35-year follow-ups showed a similar trend: OR 0.97 (95 % CI 0.93, 1.00) and OR 0.94 (95 % CI 0.91, 0.98), respectively. In all co-twin control analyses, each year of higher education was associated with a reduced likelihood of inactivity suggesting direct effect (i.e. independent from familial confounding) of education on inactivity. However, the point estimates were lower than in the individual-level analyses. Adjustment for multiple covariates did not change these associations. CONCLUSIONS: Higher education is associated with lower odds of leisure-time physical inactivity during the three-decade follow-up. The association was found after adjusting for several confounders, including familial factors. Hence, the results point to the conclusion that education has an independent role in the development of long-term physical inactivity and tailored efforts to promote physical activity among lower educated people would be needed throughout adulthood. PMID- 27492438 TI - Validation and comparison of instruments to identify frail patientes in primary care settings: Study protocol. AB - BACKGROUND: In the last few years several indices and tools, aimed at identifying frail subjects in various care settings have been developed. However, to date none of them has been incorporated into usual practice in the primary care setting. The purposes of this study are: 1) to evaluate the predictive capacity of the Tilburg Frailty Indicator (TFI), the Gerontopole Frailty Screening Tool (GFST) and the KoS model together with two biomarker levels (SOX2 and p16INK4a) for adverse events related to frailty; 2) to determine differences in the use of healthcare services according to frailty. METHODS/DESIGN: Prospective multicentre cohort study with a 2-year follow-up. The study will be performed in primary care centres of Gipuzkoa and Costa del Sol, both located in Spain. Autonomous, non institutionalized individuals aged 70 and over that agree to participate in this study will constitute the study population. A total of 900 individuals will be randomly selected from the healthcare administrative data bases of the participating health services. Data will be collected at baseline and at 1 and 2 years. The main independent variables assessed at baseline will be TFI outcomes, GFST and the KoS model, together with the expression of SOX2 and p16INK4a levels. During follow-up, loss of autonomy, the occurrence of death and consumption of healthcare resources will be assessed. DISCUSSION: The main focus of this work is the identification and evaluation of several instruments constructed under different rationales to identify frail subjects in primary care settings. The resulting outcomes have potential for direct application to the primary care practice. Early identification of the onset of functional impairment of elderly is an essential, still unresolved aspect in the prevention of dependence in the scope of primary care. PMID- 27492439 TI - Optimizing Silicon Oxide Embedded Silicon Nanocrystal Inter-particle Distances. AB - We demonstrate an analytical method to optimize the stoichiometry and thickness of multilayer silicon oxide films in order to achieve the highest density of non touching and closely spaced silicon nanocrystals after annealing. The probability of a nanocrystal nearest-neighbor distance within a limited range is calculated using the stoichiometry of the as-deposited film and the crystallinity of the annealed film as input parameters. Multiplying this probability with the nanocrystal density results in the density of non-touching and closely spaced silicon nanocrystals. This method can be used to estimate the best as-deposited stoichiometry in order to achieve optimal nanocrystal density and spacing after a subsequent annealing step. PMID- 27492441 TI - Erratum to: Novel nitrifiers and comammox in a full-scale hybrid biofilm and activated sludge reactor revealed by metagenomic approach. PMID- 27492440 TI - Classifying publications from the clinical and translational science award program along the translational research spectrum: a machine learning approach. AB - BACKGROUND: Translational research is a key area of focus of the National Institutes of Health (NIH), as demonstrated by the substantial investment in the Clinical and Translational Science Award (CTSA) program. The goal of the CTSA program is to accelerate the translation of discoveries from the bench to the bedside and into communities. Different classification systems have been used to capture the spectrum of basic to clinical to population health research, with substantial differences in the number of categories and their definitions. Evaluation of the effectiveness of the CTSA program and of translational research in general is hampered by the lack of rigor in these definitions and their application. This study adds rigor to the classification process by creating a checklist to evaluate publications across the translational spectrum and operationalizes these classifications by building machine learning-based text classifiers to categorize these publications. METHODS: Based on collaboratively developed definitions, we created a detailed checklist for categories along the translational spectrum from T0 to T4. We applied the checklist to CTSA-linked publications to construct a set of coded publications for use in training machine learning-based text classifiers to classify publications within these categories. The training sets combined T1/T2 and T3/T4 categories due to low frequency of these publication types compared to the frequency of T0 publications. We then compared classifier performance across different algorithms and feature sets and applied the classifiers to all publications in PubMed indexed to CTSA grants. To validate the algorithm, we manually classified the articles with the top 100 scores from each classifier. RESULTS: The definitions and checklist facilitated classification and resulted in good inter-rater reliability for coding publications for the training set. Very good performance was achieved for the classifiers as represented by the area under the receiver operating curves (AUC), with an AUC of 0.94 for the T0 classifier, 0.84 for T1/T2, and 0.92 for T3/T4. CONCLUSIONS: The combination of definitions agreed upon by five CTSA hubs, a checklist that facilitates more uniform definition interpretation, and algorithms that perform well in classifying publications along the translational spectrum provide a basis for establishing and applying uniform definitions of translational research categories. The classification algorithms allow publication analyses that would not be feasible with manual classification, such as assessing the distribution and trends of publications across the CTSA network and comparing the categories of publications and their citations to assess knowledge transfer across the translational research spectrum. PMID- 27492442 TI - Mx oligomer: a novel capsid pattern sensor? AB - Myxovirus resistance proteins represent a family of interferon-induced restriction factors of the innate and adaptive immune system. Human MxB acts as a novel restriction factor with antiviral activity against a range of HIV-1 and other retroviruses mainly by inhibiting the uncoating process after reverse transcription but prior to integration. Based on published data and conservation analysis, we propose a novel hypothesis, in which MxB dimers form higher order oligomers that restrict retroviral replication by binding to the viral capsid. Insights into the mechanistic basis of structural and functional characteristics of MxB will greatly advance our understanding of MxB. PMID- 27492444 TI - Resistive switching of alkanethiolated nanoparticle monolayers patterned by electron-beam exposure. AB - Carbon-based electronic devices are promising candidates for complementing silicon-based electronics in memory device applications. For example, sputtered thin films of amorphous carbon exhibit memristive behavior. The reported devices, however, have a minimal active area of about 50 nm diameter, leading to large set currents in the MUA range. Although power efficiency would benefit from reduced drive currents, resistive switching of amorphous carbon confined to a few cubic nanometers has remained largely unexplored. Here, we investigate resistive switching in 30 nm long and 25 nm wide monolayer arrays of 10 nm gold nanoparticles patterned by direct electron-beam exposure followed by a purpose designed emulsion-based development process. Electron-beam irradiation transforms the alkanethiol ligands of the gold nanoparticles into a solvent-resistant amorphous carbonaceous matrix allowing pattern development and imparting electronic function. We measure changes in conductivity of up to five orders of magnitude for set currents in the nA range. PMID- 27492443 TI - Age and time trends in eating frequency and duration of nightly fasting of German children and adolescents. AB - PURPOSE: To describe age and time trends in eating occasion frequency (EOF), meal frequency (MF), snack frequency (SF) and duration of nightly fasting (DNF) in German children and adolescents. METHODS: 9757 3-day dietary records of 1246 3-18 year-old participants of the open DONALD cohort study, collected 1985-2014, were analyzed for age and time trends using polynomial mixed-effects regression models. Eating occasions were either assigned to meals or snacks (>10 or <=10 % of daily total energy intake per eating occasion). DNF was defined as the longest time span without energy intake within one night. RESULTS: EOF, MF and SF decreased with age (EOF: linear, quadratic, cubic trend p < 0.0001; MF: linear trend p < 0.0001; SF: linear, quadratic trend p < 0.0001). Time trend analyses revealed a wavelike time course for EOF (linear trend p = 0.0580, quadratic trend = 0.0039, cubic trend = 0.0015) and SF (linear trend p = 0.0055, quadratic trend p = 0.0005, cubic trend p = 0.0003). MF slightly increased until 2000 and decreased thereafter (linear trend p = 0.0012, quadratic trend p = 0.0047). Effect sizes of time trends in EOF, MF and SF were small. Boys' and girls' DNF decreased with age (in both: linear, quadratic, cubic trend p < 0.0001) and increased over the study period (boys: linear trend p = 0.0011, interaction of age and time p < 0.0001; girls: linear trend p = 0.0167). CONCLUSION: EOF, MF and SF were higher in children than in adolescents, but, in contrast to other studies remained fairly stable over the study period. Decreasing DNF with age could reflect decreasing sleep durations. Additionally, DNF increased over the study period, probably due to an increase in breakfast skipping. PMID- 27492445 TI - Nonkeratinizing Squamous Cell Carcinoma In Situ of the Upper Aerodigestive Tract: An HPV-Related Entity. AB - The clinical and pathologic characteristics of human papillomavirus (HPV)-related premalignant lesions in the upper aerodigestive tract have not been adequately studied. There are a few reports of oral cavity HPV-related severe dysplasia with unique morphology (prominent apoptosis/karyorrhexis imparting a 'bowenoid' appearance) and a single case report of HPV-related squamous cell carcinoma in situ with nonkeratinizing histology distinct from the 'bowenoid' pattern that extensively involved the upper aerodigestive tract. The aim of this study was to characterize the morphologic and clinical features of HPV-related severe dysplasia/carcinoma in situ. All cases of upper aerodigestive tract severe dysplasia/carcinoma in situ (111 cases from 98 patients) at Washington University from July 2012 to March 2015 were categorized into histologic types: keratinizing, nonkeratinizing, mixed or 'bowenoid'. There were 83 (85 %) patients with keratinizing, 3 (3 %) nonkeratinizing and 12 (12 %) mixed patterns. The previously reported 'bowenoid' morphology was not identified. All 3 (100 %) nonkeratinizing and 6 (50 %) mixed cases were p16 and HPV RNA in situ hybridization (RNA ISH) positive (100 % concordance between p16 and RNA ISH). Only 2 of 73 keratinizing cases were p16 positive, 1 of which was also HPV RNA ISH positive (1.4 % of keratinizing cases HPV-related). Thus, nonkeratinizing morphology was a strong predictor of transcriptionally-active HPV in severe dysplasia/carcinoma in situ. HPV-related cases most commonly occurred in the floor of mouth and were frequently extensive (>=4 cm) or unresectable. PMID- 27492446 TI - Well-Differentiated Laryngeal/Hypopharyngeal Liposarcoma in the MDM2 Era Report of Three Cases and Literature Review. AB - Laryngeal/hypopharyngeal liposarcomas are very rare, fewer than 40 cases have been reported. These tumors are polypoid, with a male predisposition, and usually cause hoarseness and difficulty breathing. Their clinical course is characterized by multiple local recurrences. No distant metastasis has been reported, and dedifferentiation is extremely rare. In sum, the prognosis of these tumors is excellent; the 5-year survival rate is essentially 100 %. Pathologic diagnosis of these well-differentiated liposarcomas can be challenging. Many of them were initially diagnosed as benign lipoma, fibrovascular polyp, or "inflammatory polyp". The correct diagnosis is usually made after multiple recurrences. On the other hand, the literature bears out that these incorrect diagnoses do not impact disease-specific survival. Here, we report three patients with laryngeal/hypopharyngeal well-differentiated liposarcomas; this is the first documentation of MDM2 amplification in liposarcomas at this site. PMID- 27492448 TI - Caffeine discontinuation improves acute migraine treatment: a prospective clinic based study. AB - BACKGROUND: Caffeine has both excitatory and vasoconstrictive effects on central nervous system. Caffeine use might be associated with development and chronification of migraine. We aimed to evaluate the effect of caffeine cessation on the acute treatment of migraine. METHODS: We prospectively recruited migraine patients who consumed caffeine drinks daily and instructed them to discontinue their caffeine intake. Triptans were prescribed for acute treatment. Patients were followed up after at least two weeks after screening and evaluated the efficacy of acute treatment with the migraine assessment of current therapy (Migraine-ACT) questionnaire. Excellent efficacy was defined as Migraine-ACT score of 4. Chronic migraine, body mass index, allodynia, depression, anxiety, antiemetic use, and use of prophylactic medication were included in the multivariate analysis if the univariate p < 0.2. FINDINGS: Among 108 patients included, 36 completely discontinued their caffeine intake (abstinence group). The efficacy of acute treatment was assessed at median 34.5 days (interquartile range, 28-89) after the screening. Twenty-six patients (72.2 %) in the abstinence group and 29 (40.3 %) in the non-abstinence group reported an excellent efficacy (p = 0.002). The abstinence group also showed a trend toward greater reduction of headache impact test-6 (HIT-6) scores (p = 0.085). Caffeine abstinence was independently associated with an excellent efficacy of acute treatment (multivariate odds ratio, 3.2; 95 % confidence interval, 1.2-8.4; p = 0.018) after controlling for covariates. CONCLUSIONS: Caffeine abstinence is associated with better efficacy of acute migraine treatment. Our uncontrolled study results encourage a further confirmatory study on this issue. PMID- 27492449 TI - A profile of four patterns of vulnerability to functional decline in older general medicine patients in Victoria, Australia: a cross sectional survey. AB - BACKGROUND: There are limited published data reporting Australian hospitalized elders' vulnerability to functional decline to guide best practice interventions. The objectives of this study were to describe the prevalence of vulnerability to functional decline and explore profiles of vulnerability related to the performance of physical activity in a representative group of elders in a single centre in Victoria, Australia. METHODS: A cross-sectional survey of patients aged >= 70 years (Mean age 82.4, SD 7 years) admitted to a general medical ward of an Australian tertiary-referral metropolitan public hospital from March 2010 to March 2011 (n = 526). Patients were screened using the Vulnerable Elders Survey (VES-13). Distinct typologies of physical difficulties were identified using latent class analysis. RESULTS: Most elders scored >=3/10 on the VES-13 and were rated vulnerable to functional decline (n = 480, 89.5 %). Four distinct classes of physical difficulty were identified: 1) Elders with higher physical functioning (n = 114, 21.7 %); 2) Ambulant elders with diminished strength (n = 24, 4.6 %); 3) Elders with impaired mobility, strength and ability to stoop (n = 267, 50.8 %) and 4) Elders with extensive physical impairment (n = 121, 23 %) Vulnerable elders were distributed through all classes. CONCLUSIONS: Older general medicine patients in Victoria, Australia, are highly vulnerable to functional decline. We identified four distinct patterns of physical difficulties associated with vulnerability to functional decline that can inform health service planning, delivery and education. PMID- 27492450 TI - Obesity in Older People With and Without Conditions Associated With Weight Loss: Follow-up of 955,000 Primary Care Patients. AB - BACKGROUND: Moderate obesity in later life may improve survival, prompting calls to revise obesity control policies. However, this obesity paradox may be due to confounding from smoking, diseases causing weight-loss, plus varying follow-up periods. We aimed to estimate body mass index (BMI) associations with mortality, incident type 2 diabetes, and coronary heart disease in older people with and without the above confounders. METHODS: Cohort analysis in Clinical Practice Research Datalink primary care, hospital and death certificate electronic medical records in England for ages 60 to more than 85 years. Models were adjusted for age, gender, alcohol use, smoking, calendar year, and socioeconomic status. RESULTS: Overall, BMI 30-34.9 (obesity class 1) was associated with lower overall death rates in all age groups. However, after excluding the specific confounders and follow-up less than 4 years, BMI mortality risk curves at age 65-69 were U shaped, with raised risks at lower BMIs, a nadir between 23 and 26.9 and steeply rising risks above. In older age groups, mortality nadirs were at modestly higher BMIs (all <30) and risk slopes at higher BMIs were less marked, becoming nonsignificant at age 85 and older. Incidence of diabetes was raised for obesity 1 at all ages and for coronary heart disease to age 84. CONCLUSIONS: Obesity is associated with shorter survival plus higher incidence of coronary heart disease and type 2 diabetes in older populations after accounting for the studied confounders, at least to age 84. These results cast doubt on calls to revise obesity control policies based on the claimed risk paradox at older ages. PMID- 27492451 TI - Comorbidity Indices Versus Function as Potential Predictors of 30-Day Readmission in Older Patients Following Postacute Rehabilitation. AB - BACKGROUND: Information regarding the association of comorbidity indices with readmission risk for older adults receiving postacute care is limited. The purpose of this study was to compare the discriminatory ability of five comorbidity indices in predicting 30-day all-cause hospital readmission following discharge to the community from postacute inpatient rehabilitation facilities (IRF). METHODS: The sample included Medicare fee-for-service beneficiaries with stroke, lower extremity joint replacement, and fracture, discharged from IRF in 2011 (N = 75,582). Logistic regression models were used to predict 30-day all cause readmission. Impairment-specific base models included demographic characteristics and length of stay. Subsequent models included individual comorbidity indices: Tier, Charlson, Elixhauser, functional comorbidity index (FCI), and the hierarchical condition category (HCC). We then added discharge functional status to each model. Results were compared using C-statistics. RESULTS: Thirty-day readmission rates following discharge from an IRF ranged from 6.5% (joint replacement) to 14% (stroke). The C-statistics were 0.53, 0.56, and 0.55 for the base models in the stroke, joint replacement, and fracture groups, respectively. Adding the Tier, Charlson, FCI, or Elixhauser variables increased the C-statistics by 0.03-0.07 across the three impairment categories. Adding the HCC increased the C-statistics by 0.06-0.09. With the addition of discharge functional status in the model, the C-statistics further increased by 0.06-0.09. CONCLUSIONS: Comorbidity indices were weakly associated with 30-day readmission in older adults discharged from postacute inpatient rehabilitation. Adding patient-level functional status to the comorbidity indices further improved the discriminatory ability to predict readmission in our sample. PMID- 27492453 TI - Testing the role of glucose in self-control: A meta-analysis. AB - The glucose view of self-control posited glucose as the physiological substrate of self-control "resource", which results in three direct corollaries: 1) engaging in a specific self-control activity would result in reduced glucose level; 2) the remaining glucose level after initial exertion of self-control would be positively correlated with following self-control performance; 3) restoring glucose by ingestion would help to improve the impaired self-control performance. The current research conducted a meta-analysis to test how well each of the three corollaries of the glucose view would be empirically supported. We also tested the restoring effect of glucose rinsing on subsequent self-control performance after initial exertion. The results provided clear and consistent evidence against the glucose view of self-control such that none of the three corollaries was supported. In contrast, the effect of glucose rinsing turned out to be significant, but with alarming signs of publication bias. The implications and future directions are discussed. PMID- 27492452 TI - Diosmin Modulates the NF-kB Signal Transduction Pathways and Downregulation of Various Oxidative Stress Markers in Alloxan-Induced Diabetic Nephropathy. AB - Hyperglycaemia-mediated oxidative stress plays an imperative role in the progression of diabetic nephropathy. NF-kB is an important transcription factor in eukaryotes which regulates a diverse array of cellular process, including inflammation, immunological response, apoptosis, growth and development. Increased expression of NF-kB plays a vital role in the pathogenesis of many inflammatory diseases including diabetic nephropathy. Hence, the present study was designed to explore the nephroprotective nature of diosmin by assessing the various biochemical parameters, markers of oxidative stress and proinflammatory cytokine levels in alloxan-induced diabetic Wistar rats. Type 2 diabetes was induced in Wistar rats by single intraperitoneal injection of alloxan (120 mg/kg body weight). Seventy-two hours after the conformation of diabetes (blood glucose level >= 250 mg/dl), the rats were segregated into four groups, each group having six animals. Diabetic rats were treated with diosmin at a dose of 50 mg and 100 mg/kg body weight respectively. After the 28th day of treatment, rats were sacrificed, blood serum, plasma and kidney tissue were collected for various biochemical analysis. Inflammatory cytokine levels were measured through ELISA kit. Diosmin treatment produces significant reduction in the blood glucose and plasma insulin level and increases the body weight when compared with diabetic rats. Elevated level of malondialdehyde (MDA) and decrease levels of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and nitric oxide (NO) were significantly restored after 28 days of diosmin treatment. Diosmin treatment group also restores the normal architecture of the kidney tissue which was confirmed by histopathological examination. Moreover, oral administration of diosmin shows a significant normalization in the level of NF-kB, proving its pivotal role in maintaining renal function. The above ameliorative effects were more pronounced with diosmin at a dose of 100 mg/kg body weight. The above results permit us to conclude that treatment with diosmin halts hyperglycaemia mediated oxidative stress and decline in pro-inflammatory cytokines and thus has beneficial anti-diabetic activity. PMID- 27492454 TI - Predictors of health-related quality of life and association with survival may identify colorectal cancer patients at high risk of poor prognosis. AB - PURPOSE: To investigate the mediators of health-related quality of life (HR-QoL) in colorectal cancer (CRC) patients and effect on overall survival. METHODS: We analyzed baseline (within 1 year of diagnosis) SF-12v1 questionnaire data from 3734 CRC patients and assessed the differences in mental composite scores (MCS) and physical composite scores (PCS) by socio-demographics and risks of poor HR QoL by these factors. Hazard ratios were generated using univariate Cox regression for MCS and PCS dichotomized using the normalized scoring-based mean of 50 and survival estimates generated using the Kaplan-Meier method. RESULTS: Differences in MCS and PCS were identified by sex, age, education level, alcohol use, tobacco use, and stage. Race, marital status, and cancer site differed only by PCS. Being female, never married, former alcohol user, or with stage IV disease significantly increased risk of a poor HR-QoL, with magnitudes of risk from 1.25- to 1.97-fold. Higher education level had a protective effect (MCS: P trend = 2.32 * 10-7; PCS: P trend = 5.62 * 10-14). Hispanics and African Americans had a 1.35- and 1.57-fold risk of poor PCS, and increase in age had a protective effect for risk of poor MCS (P trend = 1.84 * 10-7). Poor MCS or PCS were associated with poor prognosis and decreased survival at 5 years (HRMCS 1.57, 95 % CI 1.41-1.76 and HRPCS 2.38, 95 % CI 2.08-2.72), and both remained significant when adjusting for age, gender, race, education level, tumor stage, and tumor site. CONCLUSIONS: Our findings identify potential mediators for HR-QoL and suggest that baseline HR-QoL assessment may be prognostic for CRC. PMID- 27492455 TI - MicroRNA-15a inhibits the growth and invasiveness of malignant melanoma and directly targets on CDCA4 gene. AB - MicroRNAs can affect behaviors of tumor cells by modulating the expression of the target genes that involve tumor growth, invasiveness, and death. The goal of this research is to examine the effects of miR-15a on the proliferation and invasiveness of malignant melanoma cells in vitro, as well as the therapeutic effect of miR-15a in a mouse melanoma model. miR-15a displayed inhibitory effects on proliferation and invasiveness of several malignant melanoma cell lines. miR 15a also caused cell cycle arrest at G1/G0 phase. miRNA 15a downregulated the expressions of CDCA4 and AKT-3 in melanoma cell lines. In vivo, experiment showed that miRNA 15a significantly retarded the growth of melanoma tumors in the mouse model. The luciferase reporter assay demonstrated that miR15a can suppress gene expression through the binding site in the 3 'UTR of CACD4, which is a bona fide target of miRNA 15a. In conclusion, miRNA 15a suppressed the growth and invasiveness of melanoma cells, suggesting that miRNA 15a may represent a viable microRNA-based therapy against melanoma. PMID- 27492456 TI - Extracellular HSP70-peptide complexes promote the proliferation of hepatocellular carcinoma cells via TLR2/4/JNK1/2MAPK pathway. AB - Heat shock protein 70 (HSP70) and HSP70-peptide complexes (HSP70-PCs) have been implicated in the pathogenesis of multiple tumors in humans and have been experimentally shown to increase the proliferation of cell lines derived from hepatocellular carcinoma. The goal of this study was to elucidate the molecular mechanisms through which extracellular HSP70/HSP70-PCs stimulate the proliferation of hepatocellular carcinoma (HCC). The molecular mechanisms of HSP70/HSP70-PC action were studied in the human hepatocellular carcinoma cell lines HepG2 and Huh-7, as well as tumor tissue collected from patients with HCC (n = 95). We found that HSP70/HSP70-PCs can stimulate the proliferation of HepG2 cells and that this effect is blocked by knocking down TLR2 and TLR4 expression by RNA interference. A physical interaction between HSP70/HSP70-PCs and TLR2/4 was established using co-immunoprecipitation and pull-down assays. Pharmacological inhibition of different branches of the MAPK intracellular signaling pathway indicated that the extracellular HSP70/HSP70-PC effect was mediated by the JNK1/2 signaling pathway within the cell. We also studied TLR2 and TLR expression at the protein and messenger RNA (mRNA) level in tumor and non tumor tissue in patients with HCC (n = 95), finding that TLR2 and 4 are increased in HCC tumor tissue and that the expression of TLR2 correlates with clinicopathologic features of HCC. Our data conclusively demonstrates that extracellular HSP70/HSP70-PCs can promote the proliferation of HCC cells through activation of TLR2 and TLR4 and subsequent activation of the intracellular JNK1/2/MAPK signaling pathway. PMID- 27492457 TI - Fibroblast activation protein alpha is expressed by transformed and stromal cells and is associated with mesenchymal features in glioblastoma. AB - Glioblastomas are deadly neoplasms resistant to current treatment modalities. Fibroblast activation protein (FAP) is a protease which is not expressed in most of the normal adult tissues but is characteristically present in the stroma of extracranial malignancies. FAP is considered a potential therapeutic target and is associated with a worse patient outcome in some cancers. The FAP localization in the glioma microenvironment and its relation to patient survival are unknown. By analyzing 56 gliomas and 15 non-tumorous brain samples, we demonstrate increased FAP expression in a subgroup of high-grade gliomas, in particular on the protein level. FAP expression was most elevated in the mesenchymal subtype of glioblastoma. It was neither associated with glioblastoma patient survival in our patient cohort nor in publicly available datasets. FAP was expressed in both transformed and stromal cells; the latter were frequently localized around dysplastic blood vessels and commonly expressed mesenchymal markers. In a mouse xenotransplantation model, FAP was expressed in glioma cells in a subgroup of tumors that typically did not express the astrocytic marker GFAP. Endogenous FAP was frequently upregulated and part of the FAP+ host cells coexpressed the CXCR4 chemokine receptor. In summary, FAP is expressed by several constituents of the glioblastoma microenvironment, including stromal non-malignant mesenchymal cells recruited to and/or activated in response to glioma growth. The limited expression of FAP in healthy tissues together with its presence in both transformed and stromal cells suggests that FAP may be a candidate target for specific delivery of therapeutic agents in glioblastoma. PMID- 27492458 TI - Disruption of clock gene expression in human colorectal liver metastases. AB - The circadian timing system controls about 40 % of the transcriptome and is important in the regulation of a wide variety of biological processes including metabolic and proliferative functions. Disruption of the circadian clock could have significant effect on human health and has an important role in the development of cancer. Here, we compared the expression levels of core clock genes in primary colorectal cancer (CRC), colorectal liver metastases (CRLM), and liver tissue within the same patient. Surgical specimens of 15 untreated patients with primary CRC and metachronous CRLM were studied. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of 10 clock genes: CLOCK, BMAL1, PER1, PER2, PER3, CRY1, CRY2, CSNK1E, TIM, TIPIN, and 2 clock-controlled genes: Cyclin-D1, and WEE1. Expression levels of 7 core clock genes were downregulated in CRLM: CLOCK (p = 0.006), BMAL1 (p = 0.003), PER1 (p = 0.003), PER2 (p = 0.002), PER3 (p < 0.001), CRY1 (p = 0.002), and CRY2 (p < 0.001). In CRC, 5 genes were downregulated: BMAL1 (p = 0.02), PER1 (p = 0.004), PER2 (p = 0.008), PER3 (p < 0.001), and CRY2 (p < 0.001). CSNK1E was upregulated in CRC (p = 0.02). Cyclin-D1 and WEE1 were both downregulated in CRLM and CRC. Related to clinicopathological factors, a significant correlation was found between low expression of CRY1 and female gender, and low PER3 expression and the number of CRLM. Our data demonstrate that the core clock is disrupted in CRLM and CRC tissue from the same patient. This disruption may be linked to altered cell cycle dynamics and carcinogenesis. PMID- 27492459 TI - MicroRNA target for MACC1 and CYR61 to inhibit tumor growth in mice with colorectal cancer. AB - Cysteine-rich protein 61 (CYR61) and metastasis associated in colon cancer (MACC1) protein promoted human colorectal cancer (CRC) cell metastasis and closely related to the patient's prognosis in colorectal cancer. The purpose of this article is to investigate whether CYR61 and MACC1 can serve as dual potential targets for gene therapy of human CRC. In this study, microRNA (miRNA) targeting for both CYR61 and MACC1 was used to investigate the mechanism and therapeutic effects for CRC cells and mice with CRC. We observed that silencing miRNA for CYR61 and MACC1 inhibited the epithelial-mesenchymal transition (EMT) process, and co-treatment strengthened this effect. MTT assay showed that the growth of colorectal tumor cells was decreased due to miRNA treatment. Apoptosis assay revealed that miRNA for CYR61 and MACC1 promoted CRC cells apoptotic. The animals' study results showed that the expression levels of CYR61 and MACC1 were significantly decreased after miRNA-100 and miRNA-143 treatment, respectively. The expression levels of apoptosis-promoting protein were increased significantly after treatment with miRNA-100 and miRNA-143, which suggested that both miRNA-100 and miRNA-143 may induce apoptosis by mitochondria-dependent pathway. In addition, metastasis and invasion assays showed that miRNA-100 and miRNA-143 treatment inhibited obviously migratory and invasive abilities of CRC cells. Furthermore, our data also showed that the tumor growth was significantly inhibited and survival rate of tumor-bearing mice was greatly improved by common treatments of miRNA-100 and miRNA-143. In conclusion, the abilities of apoptosis, metastasis, and invasion in CRC tumor cells were significantly suppressed by miRNA-100 and miRNA-143 targeting CYR61 and MACC1, respectively. As a result, CYR61 and MACC1 may serve as potential targets for gene therapy in human CRC treatments. PMID- 27492461 TI - Complete mitochondrial genome of the giant liver fluke Fascioloides magna (Digenea: Fasciolidae) and its comparison with selected trematodes. AB - BACKGROUND: Representatives of the trematode family Fasciolidae are responsible for major socio-economic losses worldwide. Fascioloides magna is an important pathogenic liver fluke of wild and domestic ungulates. To date, only a limited number of studies concerning the molecular biology of F. magna exist. Therefore, the objective of the present study was to determine the complete mitochondrial (mt) genome sequence of F. magna, and assess the phylogenetic relationships of this fluke with other trematodes based on the mtDNA dataset. FINDINGS: The complete F. magna mt genome sequence is 14,047 bp. The gene content and arrangement of the F. magna mt genome is similar to those of Fasciola spp., except that trnE is located between trnG and the only non-coding region in F. magna mt genome. Phylogenetic relationships of F. magna with selected trematodes using Bayesian inference (BI) was reconstructed based on the concatenated amino acid sequences for 12 protein-coding genes, which confirmed that the genus Fascioloides is closely related to the genus Fasciola; the intergeneric differences of amino acid composition between the genera Fascioloides and Fasciola ranged 17.97-18.24 %. CONCLUSIONS: The determination of F. magna mt genome sequence provides a valuable resource for further investigations of the phylogeny of the family Fasciolidae and other trematodes, and represents a useful platform for designing appropriate molecular markers. PMID- 27492462 TI - Preparation methods and applications behind alginate-based particles. AB - INTRODUCTION: Alginate-based particles have emerged as one of the most extensively searched drug delivery platforms due to their inherent properties, including good biocompatibility and biodegradability. Moreover, the low price, easy availability, natural origin, versatility and sol-gel transition properties, make alginate an ideal candidate to produce particles with different applications. Several techniques have been developed and optimized to prepare microparticles and nanoparticles in order to achieve more rational, coherent, efficient and cost-effective procedures. Alginate represents a suitable choice concerning delivery systems' safety, and therefore alginate-based particles have shown to be useful in the field of drug delivery with a special focus on biological encapsulants. Area covered: This review will provide an overview of alginate-based delivery systems, covering the innovative preparation methods of the last decade, the advantages and disadvantages of the most used methods, their wide diversity of applications and safety concerns. Expert opinion: The progression of nanotechnology over the last decades has stimulated the refinement of former microencapsulation methods and the exploration of new approaches towards the submicron scale with increased attention being focused on the safety of nanoparticles and product performance. Therefore, the design and optimization of the preparation methods of alginate-based microparticles and nanoparticles as well as their nontoxicity, biocompatibility and biodegradability to reach the desired application have been widely explored. PMID- 27492460 TI - MicroRNA-137 represses FBI-1 to inhibit proliferation and in vitro invasion and migration of hepatocellular carcinoma cells. AB - The pro-oncogene factor that binds to inducer of short transcripts-1 (FBI-1), which is encoded by ZBTB7A gene and belongs to POK (POZ/BTB and KrUppel) protein family, has been shown to enhance hepatocellular carcinoma (HCC) cells proliferation and multi-drug resistance (MDR) process. However, the possibility that FBI-1 is a therapeutic target for further HCC treatment remains poorly determined. In the current study, two microRNA (miRNA) target prediction programs (TargetScan and MiRanda) were used to identify miR-137 as a potential regulator of FBI-1. Our results showed that expression of miR-137 was downregulated, while FBI-1 was upregulated in clinical HCC specimens, compared with paired non-tumor specimens. Overexpression of miR-137 via adenoviral vector inhibited the proliferation and anchorage-independent growth of HCC cells, HepG2 and MHCC-97H. Our data also showed that miR-137 repressed endogenous expression level of FBI-1, as well as Notch-1 and Survivin. MiR-137 also inhibited in vitro invasion and migration of HCC cells and attenuated their epithelial-mesenchymal transition (EMT) process. Moreover, miR-137 suppressed the growth rate of HepG2 cells in nude mice model. Overexpression of miR-137 via its adenoviral vector enhanced the sensitivity of HepG2 cells to anti-tumor drugs and attenuated the MDR process of a resistance cell line HepG2/adriamycin (ADR). Thus, FBI-1 downregulation mediated by miR-137 overexpression may be a potential strategy for HCC treatment. PMID- 27492463 TI - Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future. AB - Osteoarthritis (OA) is the biggest unmet medical need among the many musculoskeletal conditions and the most common form of arthritis. It is a major cause of disability and impaired quality of life in the elderly. We review several ambitious but failed attempts to develop joint structure-modifying treatments for OA. Insights gleaned from these attempts suggest that these failures arose from unrealistic hypotheses, sub-optimal selection of patient populations or drug dose, and/or inadequate sensitivity of the trial endpoints. The long list of failures has prompted a paradigm shift in OA drug development with redirection of attention to: (1) consideration of the benefits of localized vs systemic pharmacological agents, as indicated by the increasing number of intra-articularly administered compounds entering clinical development; (2) recognition of OA as a complex disease with multiple phenotypes, that may each require somewhat different approaches for optimizing treatment; and (3) trial enhancements based on guidance regarding biomarkers provided by regulatory agencies, such as the Food and Drug Administration (FDA), that could be harnessed to help turn failures into successes. PMID- 27492465 TI - Cost utility modeling of early vs late total knee replacement in osteoarthritis patients. AB - : Given the dramatic increase in the number of total knee replacement (TKR) surgeries in developed countries, the issue of the best time for surgery needs to be addressed from an economic perspective. OBJECTIVE: To assess, from the perspective of the healthcare payer, the cost-utility of two surgical strategies in which knee replacement is performed at the early or late stage of the disease in patients with knee osteoarthritis (OA). DESIGN: Patient data and evidence from published literature on economic costs and outcomes in OA, including utilities, non-pharmacological, pharmacological and surgical options, combined with population life tables were entered in a Markov model of OA. The model represented the lifetime experience of a cohort of patients following their therapeutic management, discounting costs (euros) and utilities (quality-adjusted life-years) at 4% annually. RESULTS: In the base-case scenario, early TKR cost ?6,624 more than late TKR (?76,223 vs ?69,599) with a 0.15 gain in QALYs (18.675 vs 18.524). This yielded an incremental cost-utility ratio (ICUR) of 43,631 ?/QALY. Sensitivity analyses of the most influential uncertain parameters were performed and did not modify the direction of the conclusions: early TKR cost between ?3,655 and ?7,194 more than late TKR with a gain in QALYs between 0.15 and 0.39. The ICUR ranged from 17,131 ?/QALY to 48,241 ?/QALY. CONCLUSION: Our data do not support the early TKR strategy over the late TKR strategy in knee OA patients from a medico-economic perspective. PMID- 27492464 TI - The association of waist circumference with walking difficulty among adults with or at risk of knee osteoarthritis: the Osteoarthritis Initiative. AB - OBJECTIVE: Excess weight is a known risk factor for functional limitation and common in adults with knee osteoarthritis (OA). We asked to what extent high waist circumference was linked with developing difficulty with walking speed and distance over 4 years in adults with or at risk of knee OA. METHOD: Using data from the Osteoarthritis Initiative (OAI), we employed World Health Organization (WHO) categories for Body Mass Index (BMI) and waist circumference (small/medium and large). Difficulty with speed was defined by slow gait: <1.2 m/s during a 20 m walk, and difficulty with distance was defined by an inability to walk 400 m. We calculated risk ratios (RR) to examine the likelihood of developing difficulty with distance and speed using obesity and waist circumference as predictors with RRs adjusted for potential confounders (i.e., age, sex, race, education, physical activity, and OA status). RESULTS: Participants with obesity and large waists were 2.2 times more likely to have difficulty with speed at 4 years compared to healthy weight and small/medium waisted participants (Adjusted RR 2.2 [95% Confidence interval (CI) 1.6, 3.1], P < .0001). Participants with obesity and a large waist circumference had 2.4 times the risk of developing the inability to walk 400 m compared with those with a healthy BMI and small/medium waist circumference (Adjusted RR 0.9 [95% CI 1.6, 3.7], P < .0001). CONCLUSIONS: Waist circumference may be a main risk factor for developing difficulty with speed in adults with or at risk of knee OA. PMID- 27492466 TI - Comparative safety profile of hyaluronic acid products for knee osteoarthritis: a systematic review and network meta-analysis. AB - PURPOSE: Intra-articular (IA) hyaluronic acid (HA) is considered a safer alternative to oral Non-Steroidal Antiinflammatory Drugs (NSAIDs) and opioids for knee osteoarthritis (OA). A recent review raised potential safety concerns about HA, warranting further review of safety outcomes. We examined the risks of HA compared with IA placebo and investigated whether the risks vary among individual HA preparations. METHODS: We searched all relevant databases from inception to October 2015 and sought unpublished data. We included all knee OA trials which compared any of the 18 HA products and reported on adverse events (AEs) and withdrawals. We calculated odds ratios for safety data reported at the longest follow-up. Network meta-analysis was performed using a Bayesian hierarchical random effects model for mixed multiple treatment comparisons. RESULTS: We identified 74 studies involving 13,032 participants aged between 45 and 75 years. The proportion of women ranged from 28% to 100%. The overall incidence of local reactions reported across all products was 8.5%. Commonly reported AEs were transient local reactions, such as pain, swelling and arthralgia, which subsided rapidly. None of the HA products were statistically significantly different from IA placebo or from each other with regard to incidence of AEs. Three treatment related serious adverse events (SAEs) were reported among 9214 participants. CONCLUSIONS: Given the very low incidence of any particular AEs, we conclude that HA products are relatively well tolerated. These products have a similar safety profile compared to each other. This information along with the comparative effectiveness profile and relative cost would be helpful for clinicians in delivering individualized patient care. PMID- 27492467 TI - The influence of weather on the risk of pain exacerbation in patients with knee osteoarthritis - a case-crossover study. AB - OBJECTIVE: To quantify the risk of knee pain exacerbation associated with temperature, relative humidity, air pressure and precipitation in persons with knee osteoarthritis. METHOD: A web-based case-crossover study was conducted. Participants with a diagnosis of symptomatic, radiographic knee osteoarthritis were measured at baseline and followed for 3 months. Participants were instructed to log on to the study website if they perceived experiencing knee pain exacerbation (hazard period). Pain exacerbation was defined as an increase of >=2 on a 0-10 numeric rating scale (NRS) from the participant's mildest pain reported at baseline. A time-stratified case-crossover study was conducted to anchor the corresponding hazard date to four control periods within a particular 35-day interval. Data on maximum and minimum temperature ( degrees C), relative humidity (%), barometric pressure (hPa) and precipitation (mm) were obtained for the hazard and control periods from the publicly available meteorological database of the Australian Bureau of Meteorology. The associations were assessed using conditional logistic regression. RESULTS: Of the 345 participants recruited, 171 participants (women: 64%, mean age: 62 years, mean BMI: 30.2 kg/m2) experienced at least one episode of pain exacerbation, yielding 1,425 observations included in the analyses. There was no apparent association between temperature, relative humidity, air pressure or precipitation and risk of knee pain exacerbation. CONCLUSION: Despite anecdotal reports from patients, change in weather factors does not appear to influence the risk of pain exacerbation in persons with knee osteoarthritis. Additional studies should quantify the association of weather and risk of pain exacerbation in regions with more extreme weather conditions. PMID- 27492468 TI - Mating Disruption as a Suppression Tactic in Programs Targeting Regulated Lepidopteran Pests in US. AB - Mating disruption, the broadcast application of sex-attractant pheromone to reduce the ability of insects to locate mates, has proven to be an effective method for suppressing populations of numerous moth pests. Since the conception of mating disruption, the species-specificity and low toxicity of pheromone applications has led to their consideration for use in area-wide programs to manage invasive moths. Case histories are presented for four such programs where the tactic was used in the United States: Pectinophora gossypiella (pink bollworm), Lymantria dispar (gypsy moth), Epiphyas postvittana (light brown apple moth), and Lobesia botrana (European grapevine moth). Use of mating disruption against P. gossypiella and L. botrana was restricted primarily to agricultural areas and relied in part (P. gossypiella) or wholly (L. botrana) on hand-applied dispensers. In those programs, mating disruption was integrated with other suppression tactics and considered an important component of overall efforts that are leading toward eradication of the invasive pests from North America. By contrast, L. dispar and E. postvittana are polyphagous pests, where pheromone formulations have been applied aerially as stand-alone treatments across broad areas, including residential neighborhoods. For L. dispar, mating disruption has been a key component in the program to slow the spread of the infestation of this pest, and the applications generally have been well tolerated by the public. For E. postvittana, public outcry halted the use of aerially applied mating disruption after an initial series of treatments, effectively thwarting an attempt to eradicate this pest from California. Reasons for the discrepancies between these two programs are not entirely clear. PMID- 27492470 TI - Core competencies for UK occupational health nurses: a Delphi study. AB - Background: Occupational health nurses (OHNs) play a pivotal role in the delivery of occupational health (OH) services. Specific competency guidance has been developed in a number of countries, including the UK. While it is acknowledged that UK OHN practice has evolved in recent years, there has been no formal research to capture these developments to ensure that training and curricula remain up-to-date and reflect current practice. Aims: To identify current priorities among UK OHNs of the competencies required for OH practice. Methods: A modified Delphi study undertaken among representative OHN networks in the UK. This formed part of a larger study including UK and international occupational physicians. The study was conducted in two rounds using a questionnaire based on available guidance on training competencies for OH practice, the published literature, expert panel reviews and conference discussions. Results: Consensus among OHNs was high with 7 out of the 12 domains scoring 100% in rating. 'Good clinical care' was the principal domain ranked most important, followed by 'general principles of assessment & management of occupational hazards to health'. 'Research methods' and 'teaching & educational supervision' were considered least important. Conclusions: This study has established UK OHNs' current priorities on the competencies required for OH practice. The timing of this paper is opportune with the formal launch of the Faculty of Occupational Health Nursing planned in 2018 and should inform the development of competency requirements as part of the Faculty's goals for standard setting in OHN education and training. PMID- 27492469 TI - Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives. AB - Fibrous dysplasia (FD) is an uncommon and debilitating skeletal disorder resulting in fractures, deformity, functional impairment, and pain. It arises from post-zygotic somatic activating mutations in GNAS, in the cAMP-regulating transcript alpha-subunit, Gsalpha. Constitutive Gs signaling results in activation of adenylyl cyclase and dysregulated cAMP production. In the skeleton, this leads to the development of FD lesions with abnormal bone matrix, trabeculae, and collagen, produced by undifferentiated mesenchymal cells. FD may occur in isolation or in combination with extraskeletal manifestations, including hyperfunctioning endocrinopathies and cafe-au-lait macules, termed McCune Albright syndrome (MAS). This review summarizes current clinical and translational perspectives in FD/MAS, with an emphasis on FD pathogenesis, natural history, pre-clinical and clinical investigation, and future directions. PMID- 27492471 TI - Medical surveillance for occupational asthma-how are cases detected? AB - Background: In Finland, medical surveillance, including spirometry, is periodically performed for workers who are exposed to agents capable of causing occupational asthma (OA). Although it has been shown that surveillance can detect OA at an early stage, few studies have assessed its benefits or the role of surveillance spirometry. Aims: To assess the role of surveillance and spirometry in detecting OA and to evaluate the quality of spirometry. Methods: We retrospectively reviewed the medical files of patients in health surveillance programmes who were diagnosed with sensitizer-induced OA at the Finnish Institute of Occupational Health in 2012-14. We collected information on work exposure, respiratory symptoms, healthcare visits that initiated the diagnostic process, first spirometry and other diagnostic tests. Results: Sixty files were reviewed. Medical surveillance detected 11 cases (18%) and 49 cases (82%) were detected at doctors' appointments that were not related to surveillance. The median delay from the onset of asthma symptoms to diagnosis was 2.2 years. Delay did not differ between these groups. No cases were detected on the basis of abnormal spirometry without respiratory symptoms. However, five patients (8%) initially reported solely work-related rhinitis symptoms. Spirometry was normal in half of the cases and quality criteria were fulfilled in 86% of the tests. Conclusions: Fewer than one in five OA cases were detected through medical surveillance. Investigations were initiated by respiratory symptoms. No asymptomatic worker was referred because of abnormal spirometry. Our results highlight the importance of work-related nasal symptoms in detecting OA. PMID- 27492472 TI - [Clinical features of delayed endolymphatic hydrops and intralabyrinthine schwannoma : An imaging-confirmed comparative case series. German version]. AB - BACKGROUND: The aim of this study was to compare the clinical history and the findings in audiovestibular function tests in patients suffering from intralabyrinthine schwannoma or delayed endolymphatic hydrops (DEH). PATIENTS AND METHODS: Five patients diagnosed with intralabyrinthine schwannoma by magnetic resonance imaging (MRI) and five patients diagnosed with DEH by locally enhanced inner ear MRI (LEIM) were retrospectively studied. RESULTS: All patients with intralabyrinthine schwannoma or DEH initially presented with hearing loss. Vertigo occurred in two patients with intralabyrinthine schwannoma and in all patients with DEH. While audiometry achieved poorer results for patients with intralabyrinthine schwannomas, vestibular function tests revealed normal results in about half of the patients in both groups. CONCLUSION: Patients with intralabyrinthine schwannomas may present with clinical symptoms similar to patients suffering from other inner ear disorders like delayed endolymphatic hydrops and may obtain similar findings in audiovestibular function tests. High resolution MR imaging with locally applied contrast agent may provide evidence of both underlying pathologies. PMID- 27492473 TI - Clinical features of delayed endolymphatic hydrops and intralabyrinthine schwannoma : An imaging-confirmed comparative case series. English version. AB - BACKGROUND: The aim of this study was to compare the clinical history and audiovestibular function test results of patients suffering from intralabyrinthine schwannoma or delayed endolymphatic hydrops (DEH). PATIENTS AND METHODS: Five patients diagnosed with intralabyrinthine schwannoma by magnetic resonance imaging (MRI) and five patients diagnosed with DEH by locally enhanced inner ear MRI (LEIM) were retrospectively studied. RESULTS: All patients with intralabyrinthine schwannoma or DEH initially presented with hearing loss. Vertigo occurred in two patients with intralabyrinthine schwannoma and in all patients with DEH. While audiometry achieved poorer results for patients with intralabyrinthine schwannomas, vestibular function tests revealed normal results in about half of the patients in both groups. CONCLUSION: Patients with intralabyrinthine schwannomas may present with clinical symptoms similar to patients suffering from other inner ear disorders such as delayed endolymphatic hydrops and they may obtain similar findings in audiovestibular function tests. High-resolution magnetic resonance imaging with locally applied contrast agent may provide evidence of both underlying pathologies. PMID- 27492474 TI - Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems. AB - The generation of genetic variation (somatic hypermutation) is an essential process for the adaptive immune system in vertebrates. We demonstrate the targeted single-nucleotide substitution of DNA using hybrid vertebrate and bacterial immune systems components. Nuclease-deficient type II CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated) and the activation-induced cytidine deaminase (AID) ortholog PmCDA1 were engineered to form a synthetic complex (Target-AID) that performs highly efficient target specific mutagenesis. Specific point mutation was induced primarily at cytidines within the target range of five bases. The toxicity associated with the nuclease based CRISPR/Cas9 system was greatly reduced. Although combination of nickase Cas9(D10A) and the deaminase was highly effective in yeasts, it also induced insertion and deletion (indel) in mammalian cells. Use of uracil DNA glycosylase inhibitor suppressed the indel formation and improved the efficiency. PMID- 27492476 TI - Continental patterns of submarine groundwater discharge reveal coastal vulnerabilities. AB - Submarine groundwater discharge (SGD) delivers water and dissolved chemicals from continents to oceans, and its spatial distribution affects coastal water quality. Unlike rivers, SGD is broadly distributed and relatively difficult to measure, especially at continental scales. We present spatially resolved estimates of fresh (land-derived) SGD for the contiguous United States based on historical climate records and high-resolution hydrographic data. Climate controls regional patterns in fresh SGD, while coastal drainage geometry imparts strong local variability. Because the recharge zones that contribute fresh SGD are densely populated, the quality and quantity of fresh SGD are both vulnerable to anthropogenic disturbance. Our analysis unveils hot spots for contaminant discharge to marine waters and saltwater intrusion into coastal aquifers. PMID- 27492475 TI - Specification of tissue-resident macrophages during organogenesis. AB - Tissue-resident macrophages support embryonic development and tissue homeostasis and repair. The mechanisms that control their differentiation remain unclear. We report here that erythro-myeloid progenitors in mice generate premacrophages (pMacs) that simultaneously colonize the whole embryo from embryonic day 9.5 in a chemokine-receptor-dependent manner. The core macrophage program initiated in pMacs is rapidly diversified as expression of transcriptional regulators becomes tissue-specific in early macrophages. This process appears essential for macrophage specification and maintenance, as inactivation of Id3 impairs the development of liver macrophages and results in selective Kupffer cell deficiency in adults. We propose that macrophage differentiation is an integral part of organogenesis, as colonization of organ anlagen by pMacs is followed by their specification into tissue macrophages, hereby generating the macrophage diversity observed in postnatal tissues. PMID- 27492478 TI - Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing. AB - The Xist long noncoding RNA orchestrates X chromosome inactivation, a process that entails chromosome-wide silencing and remodeling of the three-dimensional (3D) structure of the X chromosome. Yet, it remains unclear whether these changes in nuclear structure are mediated by Xist and whether they are required for silencing. Here, we show that Xist directly interacts with the Lamin B receptor, an integral component of the nuclear lamina, and that this interaction is required for Xist-mediated silencing by recruiting the inactive X to the nuclear lamina and by doing so enables Xist to spread to actively transcribed genes across the X. Our results demonstrate that lamina recruitment changes the 3D structure of DNA, enabling Xist and its silencing proteins to spread across the X to silence transcription. PMID- 27492480 TI - Auto-brewery syndrome: Ethanol pseudo-toxicity in diabetic and hepatic patients. AB - Endogenous alcohol has been applied for spontaneous ethanol production via different metabolic pathways of the human body. Auto-brewery syndrome describes the patients with alcohol intoxication after ingesting carbohydrate-rich meals. The main objective of this study is to investigate the effect of diabetes mellitus (DM), liver cirrhosis (LC) and presence of both (DM and LC) on blood alcohol concentration (BAC) especially after carbohydrate ingestion. BAC has been measured by headspace gas chromatography-mass spectrometry in three groups of humans namely control, DM, LC and both (DM and LC) groups. The results showed that BAC in control group was 0.01-.3 mg/dL with mean 0.3 +/- 0.41 mg/dL. In patients with DM, BAC is significantly higher than that of control group 4.85 +/- 3.96 mg/dL. In patients with LC, BAC was 3.45 +/- 2.65 mg/dL. In patients with both DM and LC, BAC increases to reach 10.88 +/- 5.36 mg/dL. Endogenous ethanol production appears to increase in DM and LC. Also, it increased much more in patients with both diseases, but it did not reach toxic levels. On comparing BAC and blood glucose level in each group, all groups show insignificant correlations ( p > 0.05). PMID- 27492477 TI - Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys. AB - Zika virus (ZIKV) is responsible for a major ongoing epidemic in the Americas and has been causally associated with fetal microcephaly. The development of a safe and effective ZIKV vaccine is therefore an urgent global health priority. Here we demonstrate that three different vaccine platforms protect against ZIKV challenge in rhesus monkeys. A purified inactivated virus vaccine induced ZIKV-specific neutralizing antibodies and completely protected monkeys against ZIKV strains from both Brazil and Puerto Rico. Purified immunoglobulin from vaccinated monkeys also conferred passive protection in adoptive transfer studies. A plasmid DNA vaccine and a single-shot recombinant rhesus adenovirus serotype 52 vector vaccine, both expressing ZIKV premembrane and envelope, also elicited neutralizing antibodies and completely protected monkeys against ZIKV challenge. These data support the rapid clinical development of ZIKV vaccines for humans. PMID- 27492481 TI - Insurance statements related to regional anaesthesia: A French database analysis. AB - BACKGROUND: Adverse events in the perioperative period remain frequent, occurring in about 30% of the hospital admission and may be avoidable in nearly 50% of cases. Improving safety needs a continuous assessment of the risk level. MATERIAL AND METHODS: Data from the MACSF-Sou medical insurance company, including all the statements declared by anaesthesiologists and intensivists, were analyzed retrospectively by three experts, senior anaesthesiologists, of the SFAR, the French society of anesthesia and intensive care (Societe francaise d'anesthesie reanimation) to describe the risk associated with regional anaesthesia. RESULTS: One hundred and sixty-four events were analyzed, involving young patients (mean age of 48.3+/-15years; sex ratio: 0.57). The most involved surgical specialties were: orthopaedic surgery (61%) and obstetric surgery (13.4%). Reported events were predominantly peripheral nerve injury (64.6%). Mechanical complications of puncture (pneumothorax, haemothorax, complications of axial punctures) accounted for approximately 15% of events, infection for 11%. The revelation was predominant in the postoperative course (137 cases, 83.6%), particularly after the release of the operating room in over 47% of cases, including 39 cases (22%) after discharge from the hospital. CONCLUSION: Collaboration with insurance companies allows a relevant approach of the perioperative risk. In most cases, liability related to regional anaesthesia involved young patients in the perioperative course of scheduled surgery. One of the future challenges in managing, the anaesthetic and perioperative risks should be to invest more accurately the postoperative care both in the hospital or ambulatory settings. PMID- 27492479 TI - Modulatory role of betulinic acid in N-nitrosodimethylamine-induced hepatorenal toxicity in male Wistar rats. AB - N-nitrosodimethylamine (NDMA) is a toxicant found in foods and drinking water. Several synthetic agents used in alleviation of NDMA toxicity have been associated with serious side effects. Therefore, a safe and less toxic agent is desirable. In this study, betulinic acid (BA), a triterpenoid antioxidant, is proposed as a better and alternative agent to modulate NDMA-induced toxicity. Twenty-four Wistar rats were assigned into four groups of six rats each and treated with normal saline (control), BA (25 mg/kg), NDMA (5 mg/kg) and (BA + NDMA). BA was given by oral gavage for 14 consecutive days, while NDMA was administered intraperitoneally on days 7 and 12. Results showed that administration of NDMA significantly ( p < 0.05) elevated the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase and gamma-glutamyl transferase by 51%, 48% and 81%, respectively. Also, NDMA intoxication significantly ( p < 0.05) increased the levels of serum urea and creatinine by 64% and 82%, respectively, and decreased urinary creatinine by 67%. In addition, administration of NDMA significantly ( p < 0.05) increased the levels of hepatic and renal DNA fragmentation by 44% and 61%, respectively, relative to control. The number of micronucleated polychromatic erythrocytes (mnPCEs) in NDMA-treated rats (11.1 +/- 2.6 mnPCE/1000PCE) was significantly higher than control (4.3 +/- 1.1 mnPCE/1000 PCE). Immunohistochemistry revealed strong expressions of Bcl-2 and nuclear p53 in NDMA-intoxicated rats. Interestingly, pretreatment with BA significantly ( p < 0.05) ameliorated NDMA-induced changes in serum biochemical indices, mnPCEs, DNA fragmentation and expressions of Bcl-2 and p53 proteins. These findings suggest that BA protects against NDMA-induced toxicity via anti oxidative and anti-apoptotic activities. PMID- 27492482 TI - Prescription Opioid Abuse and its Potential Role in Gross Dental Decay. AB - INTRODUCTION: Prescription opioid abuse may have adverse dental effects that are irreversible, leaving younger populations with substantially decayed dentitions. This article explores the damaging effects of three years of prescription opioid abuse to a twenty-six-year-old's dentition and oral health. CASE PRESENTATION: A twenty-six-year-old Caucasian male presented to the University of Pennsylvania School of Dental Medicine with a past medical history of Percocet(r) abuse. He was consuming approximately twenty tablets per day for three years, and he had neglected to visit a dentist for over five years before arriving to the School of Dental Medicine. Management and Outcome: Intraoral examination revealed gross generalized decay along with generalized plaque accumulation. He was diagnosed with severe plaque induced gingivitis with localized chronic periodontitis and xerostomia. The dental treatment for this patient included periodontal maintenance and control, caries excavation, root canal therapy, extractions of non-restorable teeth, and continuous dental education. DISCUSSION: Prescription opioids are addictive, have high abuse potential, and dentists contribute to this problem by overprescribing these drugs. PMID- 27492483 TI - Automatic Identification of Physical Activity Intensity and Modality from the Fusion of Accelerometry and Heart Rate Data. AB - BACKGROUND: Physical activity (PA) is essential to prevent and to treat a variety of chronic diseases. The automated detection and quantification of PA over time empowers lifestyle interventions, facilitating reliable exercise tracking and data-driven counseling. METHODS: We propose and compare various combinations of machine learning (ML) schemes for the automatic classification of PA from multi modal data, simultaneously captured by a biaxial accelerometer and a heart rate (HR) monitor. Intensity levels (low / moderate / vigorous) were recognized, as well as for vigorous exercise, its modality (sustained aerobic / resistance / mixed). In total, 178.63 h of data about PA intensity (65.55 % low / 18.96 % moderate / 15.49 % vigorous) and 17.00 h about modality were collected in two experiments: one in free-living conditions, another in a fitness center under controlled protocols. The structure used for automatic classification comprised: a) definition of 42 time-domain signal features, b) dimensionality reduction, c) data clustering, and d) temporal filtering to exploit time redundancy by means of a Hidden Markov Model (HMM). Four dimensionality reduction techniques and four clustering algorithms were studied. In order to cope with class imbalance in the dataset, a custom performance metric was defined to aggregate recognition accuracy, precision and recall. RESULTS: The best scheme, which comprised a projection through Linear Discriminant Analysis (LDA) and k-means clustering, was evaluated in leave-one-subject-out cross-validation; notably outperforming the standard industry procedures for PA intensity classification: score 84.65 %, versus up to 63.60 %. Errors tended to be brief and to appear around transients. CONCLUSIONS: The application of ML techniques for pattern identification and temporal filtering allowed to merge accelerometry and HR data in a solid manner, and achieved markedly better recognition performances than the standard methods for PA intensity estimation. PMID- 27492484 TI - Treatment with cytokine thymic stromal lymphopoietin short hairpin RNA substantially reduces TGF-beta1-induced interstitial cellular fibrosis. AB - Thymic stromal lymphopoietin (TSLP) has previously been linked to allergic inflammatory diseases, and tissue fibrosis and organ dysfunction may also arise from such inflammation. It remains unclear, however, whether TSLP plays any role in the occurrence of renal fibrosis, so this study investigated that possibility. An in vitro fibrosis model was established by treating normal rat kidney fibroblast (NRK-49F) cells with transforming growth factor-beta1 (TGF-beta1), after which the levels of various fibrogenic markers (e.g., fibronectin) and downstream fibrogenic signal proteins (e.g., smad 7) were investigated. Also, TSLP shRNA was used to silence the effects of TSLP, while an ELISA was conducted to evaluate the fibronectin secretions. The level of fibronectin in the NRK-49F cells was dose- and time-dependently increased by the administration of exogenous TSLP (P<0.05). TSLP also significantly increased the level of fibrosis signaling, in addition to inducing a marked decrease in the down-regulation of Smad7. Interestingly, the application of TSLP shRNA caused a stark reversal of the TGF beta1-induced cellular fibrosis while simultaneously leading to the suppression of fibronectin and fibrogenic signal proteins. Taken together, these observations provide insights into how extracellular matrices develop and could thus lead to potential therapeutic interventions for the suppression of renal fibrosis. PMID- 27492486 TI - Transition and Dialectic: A Farewell, A Big Thank You, Some Medical Ethics and Some Reproduction. PMID- 27492485 TI - Divergent effects of Porcupine and Wntless on WNT1 trafficking, secretion, and signaling. AB - Loss-of-function studies have identified Porcupine (PORCN) and Wntless (WLS) as essential mediators of Wnt secretion and signaling. Whereas PORCN is thought to palmitoylate Wnt proteins, WLS is believed to transport palmitoylated Wnt proteins to the cell surface. However, little is known about how these two proteins cooperate to regulate Wnt palmitoylation, trafficking, secretion, and signaling. We first investigated possible interactions between PORCN, WLS, and WNT1, by carrying out co-immunoprecipitation studies. These studies demonstrate the existence of a complex containing PORCN and WLS. They further show that PORCN and WLS compete for binding to WNT1. Then, we used gain-of-function studies to investigate the cooperation between PORCN and WLS as well as possible biochemical interactions between PORCN, WLS, and WNT1. Consistent with the proposed roles for PORCN and WLS, we show that overexpression of PORCN promotes palmitoylation of WNT1 while overexpression of WLS does not. Overexpression of PORCN enhances the ability of WLS to promote WNT1 trafficking to the cell surface as well as secretion, but decreases the ability of WLS to activate WNT1 signaling in target cell. These observations suggest that the levels of WNT1 on the cell surface and in the media are not the sole determinants of the activation of Wnt signaling in target cells. PMID- 27492487 TI - The impact of fragility fractures on work and characteristics associated with time to return to work. AB - : We examined the impact of fragility fractures on the work outcomes of employed patients. The majority successfully returned to their previous jobs in a short amount of time, and productivity loss at work was low. Our findings underscore the fast recovery rates of working fragility fracture patients. INTRODUCTION: The purpose of this study is to describe the impact of fragility fractures on the work outcomes of patients who were employed at the time of their fracture. METHODS: A self-report anonymous survey was mailed to fragility fracture patients over 50 who were screened as part of the quality assurance programs of fracture clinics across 35 hospitals in Ontario, Canada. Measures of return to work (RTW), at-work productivity loss (Work Limitations Questionnaire), and sociodemographic, fracture-related, and job characteristics were included in the survey. Kaplan Meier estimates of the cumulative proportion of patients still off work were computed. Factors associated with RTW time following a fragility fracture were examined using Cox proportional hazards modeling. RESULTS: Of 275 participants, 242 (88 %) returned to work. Of these, the median RTW time was 20.5 days. About 86 % returned to the same job, duties, and hours as before their injury. Among full-time workers, the median number of lost hours due to presenteeism was 2.9 h (Q1-Q3 0.4-8.1 h). The median cost of presenteeism was $75.30 based on the month prior to survey completion. In multivariable analyses, female gender, needing surgery, and medium/heavy work requirements were associated with longer RTW time. Earlier RTW time was associated with elbow fracture and feeling completely better at time of survey completion. CONCLUSIONS: The majority of fragility fracture patients successfully returned to their previous jobs in a short amount of time, and productivity loss at work was low. Our findings underscore their fast recovery rates and give reason for optimism regarding the resilience of this population. PMID- 27492488 TI - Mothers' views of their preschool child's screen-viewing behaviour: a qualitative study. AB - BACKGROUND: Research on screen-viewing in preschool children has predominantly focused on television viewing. The rapid development of mobile devices (e.g. tablets, smart phones and e-readers) and the increase in their use by preschool children means there is a need to understand how and why these devices are used by this age group. The aim of this study was to explore mothers' views of their preschool children's screen viewing behaviour (including mobile devices) and investigate how preschool children use different screen-viewing devices. METHODS: One-to-one, semi-structured interviews with mothers of preschool children (aged between 2 and 4 years old). Mothers were recruited through preschools, nurseries, and mother and toddler groups located within four areas of varying socio-economic status within Bristol, UK. Data were analysed thematically using a framework approach. RESULTS: Twenty-six mothers were interviewed. Mobile devices were regularly used as a form of screen-viewing for most children but were used on an ad hoc basis rather than being a habitual activity. The reasons and influences of mobile device use described by mothers were similar to that of television viewing. However, the portability of mobile devices meant that they were often used outside of the home as a distraction tool. Their multi-functionality meant that they could be used as a portable television, or for purposeful learning through educational games and applications. Some mothers showed concerns over mobile device use by their child, whilst others felt it was an important and useful educational tool. Although the majority of mothers felt they needed to set rules and restrictions for mobile device use, many mothers felt that they are also a necessary and unavoidable part of life. CONCLUSIONS: Mothers in this study suggested that mobile device use by preschool children is common. More research is needed to determine the impact of mobile device use in preschool children, how much time preschool children spend using mobile devices and which activities their use may be replacing. PMID- 27492489 TI - Imaging features of iBalance, a new high tibial osteotomy: what the radiologist needs to know. AB - OBJECTIVE: To describe the post-surgical imaging appearance and complications of high tibial osteotomy in patients with the iBalance implant system (iHTO; Arthrex, Naples, FL, USA). MATERIALS AND METHODS: Retrospective, institutional review board-approved, Health Insurance Portability and Accountability Act compliant review of imaging after 24 iBalance procedures was performed with attention to: correction of varus malalignment, healing at the osteotomy site, resorption of the osteoinductive compound, and complications. RESULTS: Immediate correction of the varus deformity was present in all cases. Lobular radiolucency was present in all cases, more pronounced on the lateral knee radiograph, simulating infection or erosive disease. Four radiographic signs of healing were observed: blurring at the opposing osteotomy bony margins and at the osteoinductive compound and the adjacent bone interface, callus formation, and resorption of the osteoinductive compound. Complications were present in 33 % of cases, including fracture through the lateral tibial cortex (21 %), genu varum recurrence (8 %), painful exuberant bone formation (4 %), persistent pain, requiring total knee arthroplasty (4 %), and non-union (after >6 months' follow up), with suspected infection (4 %). CONCLUSION: Radiologists should be aware of the normal radiographic appearance following iBalance high tibial osteotomy, which may be confused with infection. Radiologists should also be aware of potential post-operative complications and compare all post-operative radiographs with the immediate post-operative examination to detect collapse of the osteotomy site and recurrence of varus angulation. PMID- 27492490 TI - The effects of the Norwegian Coordination Reform on the use of rehabilitation services: panel data analyses of service use, 2010 to 2013. AB - BACKGROUND: In 2012 the Norwegian Coordination Reform was implemented. The main motivation was to encourage municipalities to expand local, primary health care services. From 2012 to 2014, under the Municipal Co-Financing regime, municipalities were obliged to cover 20 % of the costs of health services provided at the specialist (hospital) level. Importantly, use of rehabilitation services in private institutions was not part of the cost-sharing mechanism of Municipal Co-Financing. Rehabilitation services may be seen as quite similar in nature whether they be provided by municipalities, hospitals or private institutions. Thus, with rehabilitation patients readily "transferrable" between levels, the question is whether the reform brought with it a sought after shift towards more municipal rehabilitation and less specialist rehabilitation. METHODS: Data from the Norwegian Patient Register and from Statistics Norway/KOSTRA were utilized to gauge annual expenditures and inputs in specialist, municipal and private institution rehabilitation services respectively. Fixed effects and first difference regression analyses for the period 2010-2013 were carried out to account for certain time-invariant traits of municipalities and/or hospital regions, and results were adjusted for contemporaneous trends in local needs. RESULTS: Expenditures in specialist rehabilitation services declined sharply (typically by 8-10 %) from 2011 (pre reform) to 2012 (post-reform), while expenditures in private rehabilitation services rose markedly in the same period (typically by 42-44 %). The results do not suggest any general expansion of municipal rehabilitation services. CONCLUSIONS: The results of the analyses suggest that municipalities shift away from the use of specialist rehabilitation services and towards the use of rehabilitation services in private institutions since the latter becomes relatively cheaper (free-of charge) than both municipal and specialist services in post-reform periods (as specialist services come at a cost to municipalities post-reform). While the main goal of the reform has not materialized the results nevertheless suggest that incentives (of cost-shifting) do play a significant role in rehabilitation service use. PMID- 27492491 TI - Is high waist circumference and body weight associated with high blood pressure in Iranian primary school children? AB - INTRODUCTION AND OBJECTIVES: The prevalence of overweight, abdominal obesity and hypertension among children has increased worldwide including Iran over several decades. We carried out a study to provide current estimates of the prevalence and trends of hypertension, overweight and obesity along with the relationship between weight status and hypertension in Iranian school-children. METHOD: This study was carried out among 1184 fifth-grade students, whose ages ranged from 11 to 14 years. Body weight, body mass index (BMI), height and waist circumference (WC), systolic (SBP) and diastolic blood pressure (DBP) were measured. RESULTS: 22.04 and 5.32 % of students were overweight and obese, respectively. The prevalence of overweight and obesity was significantly higher among girls than boys (all p = 0.02), whereas the prevalence of hypertension was significantly higher in boys than girls (p = 0.001). Although 27 % of boys and 24.32 % of girls had abdominal obesity, no significant associations were reported between abdominal obesity and sex (p = 0.12). The prevalence of hypertension in children with normal weight, overweight and obesity, was 3, 9.7 and 17.8 %, respectively (p < 0.01). We have obtained that the mean values of weight and WC were significantly higher in boys than girls. Based on linear regression, every 1 cm increase in abdominal circumference leads to an estimated DBP and SBP increase of 0.173 and 0.164 mmHg, respectively (p < 0.05). CONCLUSIONS: This study showed a high prevalence of hypertension and obesity in a school-based population in Tehran, Iran, in which the prevalence of hypertension was significantly and positively correlated with weight and WC. PMID- 27492492 TI - [Adaptation to physical activity and mental stress in the context of pain : Psychobiological aspects]. AB - The genesis of chronic pain is predominantly explained by a multidimensional pain model approach that is based on the dysfunctional influence of biological, psychological and social variables as key risk factors inducing aberrant long term changes. Biological facets comprise adaptation processes on the neuronal, musculoskeletal and (psycho) biological level that can be influenced by physical training or psychosocial factors, such as stress. These factors can play a causative role in developing dysfunctional adaptation mechanisms, which in turn prepare the biological ground to facilitate negative long-term changes in the peripheral and central nervous systems. Hence, these processes can be assumed to be fundamentally involved in the transition from acute to chronic and persistent pain. The aim of this review article is to discuss hypotheses for the genesis of chronic pain and possible treatment strategies. Selected research results about maladaptive processes in chronic pain due to psychological stress and physical activity are presented in order to inspire discussions about the ideal dose response relationship of physical activity and the combination of different therapeutic concepts. PMID- 27492493 TI - Ultrafast acousto-optic mode conversion in optically birefringent ferroelectrics. AB - The ability to generate efficient giga-terahertz coherent acoustic phonons with femtosecond laser makes acousto-optics a promising candidate for ultrafast light processing, which faces electronic device limits intrinsic to complementary metal oxide semiconductor technology. Modern acousto-optic devices, including optical mode conversion process between ordinary and extraordinary light waves (and vice versa), remain limited to the megahertz range. Here, using coherent acoustic waves generated at tens of gigahertz frequency by a femtosecond laser pulse, we reveal the mode conversion process and show its efficiency in ferroelectric materials such as BiFeO3 and LiNbO3. Further to the experimental evidence, we provide a complete theoretical support to this all-optical ultrafast mechanism mediated by acousto-optic interaction. By allowing the manipulation of light polarization with gigahertz coherent acoustic phonons, our results provide a novel route for the development of next-generation photonic-based devices and highlight new capabilities in using ferroelectrics in modern photonics. PMID- 27492497 TI - Gold Nanoshells: Combined Near Infrared Photothermal Therapy and Chemotherapy Using Gold Nanoshells Coated Liposomes to Enhance Antitumor Effect (Small 30/2016). AB - Gold nanoshell coated oleanolic acid liposomes mediating by chitosan (GNOLs), are designed and successfully synthesized for the first time by D. Gao and co-workers on page number 4103. An excellent near infrared (NIR) photothermal effect, pH responsive drug controlled release and tumor targeting properties are demonstrated. By combining NIR photothermal therapy and chemotherapy, the smart drug delivery system exhibits a superior antitumor property in vitro and in vivo. PMID- 27492494 TI - Novel Shank3 mutant exhibits behaviors with face validity for autism and altered striatal and hippocampal function. AB - Mutations/deletions in the SHANK3 gene are associated with autism spectrum disorders and intellectual disability. Here, we present electrophysiological and behavioral consequences in novel heterozygous and homozygous mice with a transcriptional stop cassette inserted upstream of the PDZ domain-coding exons in Shank3 (Shank3E13 ). Insertion of a transcriptional stop cassette prior to exon 13 leads to loss of the two higher molecular weight isoforms of Shank3. Behaviorally, both Shank3E13 heterozygous (HET) and homozygous knockout (KO) mice display increased repetitive grooming, deficits in social interaction tasks, and decreased rearing. Shank3E13 KO mice also display deficits in spatial memory in the Morris water maze task. Baseline hippocampal synaptic transmission and short term plasticity are preserved in Shank3E13 HET and KO mice, while both HET and KO mice exhibit impaired hippocampal long-term plasticity. Additionally, Shank3E13 HET and KO mice display impaired striatal glutamatergic synaptic transmission. These results demonstrate for the first time in this novel Shank3 mutant that both homozygous and heterozygous mutation of Shank3 lead to behavioral abnormalities with face validity for autism along with widespread synaptic dysfunction. Autism Res 2017, 10: 42-65. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27492500 TI - Erratum to: High field magnetic resonance imaging of rodents in cardiovascular research. PMID- 27492501 TI - Silver Ions in Non-canonical DNA Base Pairs: Metal-Mediated Mismatch Stabilization of 2'-Deoxyadenosine and 7-Deazapurine Derivatives with 2' Deoxycytidine and 2'-Deoxyguanosine. AB - Novel silver-mediated dA-dC, dA*-dC, and dA*-dG base pairs were formed in a natural DNA double helix environment (dA* denotes 7-deaza-dA, 7-deaza-7-iodo-dA, and 7-cyclopropyl-7-deaza-dA). 7-Deazapurine nucleosides enforce silver ion binding and direct metal-mediated base pair formation to their Watson-Crick face. New phosphoramidites were prepared from 7-deaza-dA, 7-deaza-7-iodo-dA, and 7 cyclopropyl-7-deaza-dA, which contain labile isobutyryl protecting groups. Solid phase synthesis furnished oligonucleotides that contain mismatches in near central positions. Increased thermal stabilities (higher Tm values) were observed for oligonucleotide duplexes with non-canonical dA*-dC and dA-dC pairs in the presence of silver ions. The stability of the silver-mediated base pairs was pH dependent. Silver ion binding was not observed for the dA-dG mismatch but took place when mismatches were formed between 7-deazaadenine and guanine. The specific binding of silver ions was confirmed by stoichiometric UV titration experiments, which proved that one silver ion is captured by one mismatch. The stability increase of canonical DNA mismatches might have an impact on cellular DNA repair. PMID- 27492502 TI - Absence of premature senescence in Werner's syndrome keratinocytes. AB - Werner's syndrome (WS) is an autosomal recessive genetic disorder caused by loss of function mutation in wrn and is a useful model of premature in vivo ageing. Cellular senescence is a plausible causal mechanism of mammalian ageing and, at the cellular level, WS fibroblasts show premature senescence resulting from a combination of telomeric attrition and replication fork stalling. Over 90% of WS fibroblast cultures achieve <20 population doublings (PD) in vitro compared to wild type human fibroblast cultures. It has been proposed that some cell types, capable of proliferation, will fail to show a premature senescence phenotype in response to wrn mutations. To test this hypothesis, human dermal keratinocytes (derived from both WS and wild type patients) were cultured long term. WS Keratinocytes showed a replicative lifespan in excess of 100 population doublings but maintained functional growth arrest mechanisms based on p16 and p53. The karyotype of the cells was superficially normal and the cultures retained markers characteristic of keratinocyte holoclones (stem cells) including p63 expression and telomerase activity. Accordingly we conclude that, in contrast to WS fibroblasts, WS keratinocytes do not demonstrate slow growth rates or features of premature senescence. These findings suggest that the epidermis is among the tissue types that do not display symptoms of premature ageing caused by loss of function of wrn. This is in support that Werner's syndrome is a segmental progeroid syndrome. PMID- 27492503 TI - Populus euphratica: an incompatible host for biotrophic pathogens? PMID- 27492504 TI - Postpartum education and lifestyle changes for preventing type 2 diabetes in Turkish women with previous gestational diabetes: A retrospective study. AB - BACKGROUND: Women with previous gestational diabetes mellitus (GDM) have at least sevenfold increased risk for developing type 2 diabetes compared with non-GDM mothers. The risk can be decreased by self-care measures. AIM: The aim of this study was to explore the postpartum education and lifestyle changes of Turkish women with previous GDM. METHOD: This was a retrospective descriptive epidemiological study. A total of 111 women who had given birth within the previous 3-4 years were interviewed by telephone between December 2013 and April 2014. RESULTS: The 83.8% of the women with GDM had not received education related to exercise, while 40.5% received no education regarding the importance of diet. More importantly, while 68.5% had been informed about testing blood glucose levels postpartum, a large majority, 69.3%, did not know for how long they would have had to continue testing their glucose levels. However, 31.3% of those who monitored their glucose levels had glucose intolerance. In terms of lifestyle changes, less than half of the women, 48.6%, had made changes in their diet and the majority, 51.4%, were inactive. CONCLUSION: Women need access to sustained education and supportive counselling both to motivate and to minimize the risk of type 2 diabetes after GDM. PMID- 27492505 TI - Emodin alleviates hepatic steatosis by inhibiting sterol regulatory element binding protein 1 activity by way of the calcium/calmodulin-dependent kinase kinase-AMP-activated protein kinase-mechanistic target of rapamycin-p70 ribosomal S6 kinase signaling pathway. AB - AIM: To investigate the effects of emodin on the treatment of non-alcoholic fatty liver and the underlying mechanisms. METHODS: In vitro, hepatocytes were treated with 1 mM free fatty acid together with various concentrations of emodin. In vivo, Sprague-Dawley rats were divided into a control group, high-fat diet (HFD) group, and three HFD groups treated with 40, 80, and 160 mg/kg emodin, respectively. After being fed a HFD for 4 weeks, rats were orally dosed with emodin once daily for 8 weeks. The biochemical parameters and histology features were examined. The expression of lipogenic and lipolytic gene and protein and the phosphorylation of calcium/calmodulin-dependent kinase kinase (CaMKK), AMP activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR) and p70 ribosomal S6 kinase (p70S6K) were measured in vitro and in vivo. RESULTS: Emodin improved lipid accumulation in vitro and in vivo. Emodin downregulated the levels of sterol regulatory element binding protein 1 (SREBP1) and its target enzymes but increased lipolysis-related proteins and mRNA. Phosphorylation of AMPK was increased, while phosphorylation of mTOR and p70S6K were suppressed by emodin. The nuclear translocation of SREBP1 was inhibited by emodin by AMPK and mTOR. Emodin activated AMPK by CaMKK and reversed the reduction of CaMKK in HFD-fed rats. CONCLUSION: Emodin effectively ameliorates hepatic steatosis through the CaMKK-AMPK-mTOR-p70S6K-SREBP1 signaling pathway. PMID- 27492506 TI - The KT Jeang Retrovirology prize 2016: Frank Kirchhoff. PMID- 27492507 TI - Long-term effects of azithromycin in patients with cystic fibrosis. AB - BACKGROUND: Low-dose azithromycin has beneficial effects on severity of the lung disease in cystic fibrosis (CF) patients for a period of 6-12 months after initiation of the treatment. Although its impact in the longer term is uncertain, this treatment is frequently used chronically. The aim of this retrospective study was to investigate the effects of low-dose azithromycin treatment on the progression of CF lung disease in patients treated for more than 12 months. METHODS: All of the CF patients followed in our pediatric center and who had been on low-dose azithromycin for more than 12 sequential months were included. The clinical data were collected for one year before and three years after the initiation of the azithromycin treatment. These data comprised lung function analyses, rates of exacerbations and of antibiotic courses, and changes in the airways' bacterial colonization. RESULTS: A total of 68 patients were included (mean age: 9.95 yrs (3.61)). After 12 months, significant reductions in the numbers of pulmonary exacerbations and antibiotic courses were present. However, this effect was not maintained in the subsequent periods, during which increased rates of both pulmonary exacerbations and antibiotic courses were observed. The lung function decline was not modified during the treatment, and a decreasing time-dependent trend typical of CF was observed for the various parameters. No differences in the airway colonization by pathogens such as Pseudomonas aeruginosa and methicillin-sensitive and/or -resistant Staphyloccocus aureus were observed during the treatment. However, isolated Staphyloccocus aureus strains became resistant to macrolides after 6 months of azithromycin and remained resistant thereafter. CONCLUSIONS: No clinical benefits of low-doses azithromycin were present after one year of treatment in young CF patients. Selection for macrolide-resistant strains of bacteria occurred, which should lead to a reconsideration of the duration of azithromycin treatment in CF. PMID- 27492508 TI - Comparison of ventilator-integrated end-tidal CO2 and transcutaneous CO2 monitoring in home-ventilated neuromuscular patients. AB - BACKGROUND: Non-invasive transcutaneous capnometry (TcCO2) is used to assess the home ventilation's efficiency. Recently, end-tidal CO2 (ETCO2) sensors have been integrated in life-support home ventilators. The purpose of this study was to compare the ventilator-integrated ETCO2 with TcCO2, in home-ventilated neuromuscular disease patients. METHODS: ETCO2 and TcCO2 were simultaneously measured during one night in 28 patients. Daytime blood gases were drawn on the following morning to measure arterial PCO2 (PaCO2). RESULTS: Compared to PaCO2 values, both ETCO2 and TcCO2 showed a small bias (-0.1 mmHg and 0.6 mmHg, respectively) and a similar critical difference (6.8 mmHg and 7.3 mmHg, respectively). We found a good correlation between ETCO2 and TcCO2, both considering the mean nocturnal PCO2 (r = 0.897, p < 0.001; bias -1.1 [- 9.0; 6.9] mmHg) and the maximal PCO2 value over the night (r = 0.905, p < 0.001; bias 3.1 [ 4.5; 10.8] mmHg). The concordance of the two techniques in detecting overnight PCO2 fluctuations was high, with r = 0.919 (p < 0.001) for the time spent with PCO2 >45 mmHg and r = 0.943 (p < 0.001) for the time with PCO2 >50 mmHg. CONCLUSIONS: The ventilator-integrated end-tidal CO2 monitoring is as reliable as the currently used transcutaneous measurement, resulting to be a valuable proxy of the overnight PCO2 evolution. This result opens the possibility of a simplification in the monitoring of home ventilated patients, since ETCO2 measurement can be performed directly at home, with a low additional cost. However, the accuracy of both these measurement techniques is not sufficient to replace blood gases, which remain the reference examination. ClinicalTrials.gov registration:NCT02068911. PMID- 27492509 TI - Combined pulmonary fibrosis and emphysema: The many aspects of a cohabitation contract. AB - Combined pulmonary fibrosis and emphysema (CPFE) is a clinical entity characterized by the coexistence of upper lobe emphysema and lower lobe fibrosis. Patients with this condition experience severe dyspnea and impaired gas exchange with preserved lung volumes. The diagnosis of the CPFE syndrome is based on HRCT imaging, showing the coexistence of emphysema and pulmonary fibrosis both in varying extent and locations within the lung parenchyma. Individual genetic background seem to predispose to the development of the disease. The risk of the development of pulmonary hypertension in patients with CPFE is high and related to poor prognosis. CPFE patients also present a high risk of lung cancer. Mortality is significant in patients with CPFE and median survival is reported between 2.1 and 8.5 years. Currently, no specific recommendations are available regarding the management of patients with CPFE. In this review we provide information on the existing knowledge on CPFE regarding the pathophysiology, clinical manifestations, imaging, complications, possible therapeutic interventions and prognosis of the disease. PMID- 27492510 TI - Angiopoietin-2 expression in patients with an acute exacerbation of idiopathic interstitial pneumonias. AB - BACKGROUND AND OBJECTIVE: We hypothesized that increased pulmonary vascular permeability may play a role in the pathogenesis of an acute exacerbation of the idiopathic interstitial pneumonias (AE-IIPs). Angiopoietin-2 (Ang-2) promotes endothelial activation, destabilization, and inflammation. The purpose of this study was to examine whether Ang-2 expression was associated with the pathogenesis of AE-IIPs. METHODS: Twenty-three patients with AE-IIP patients, 18 acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients, 37 idiopathic pulmonary fibrosis (IPF) patients, and 33 healthy volunteers (HVs) were enrolled. The serum level of Ang-2 was measured by an enzyme-linked immunosorbent assay. RESULTS: The serum levels of Ang-2 were higher in AE-IIPs and ALI/ARDS patients than in IPF patients and HVs; the BALF levels of Ang-2 were also higher than in IPF patients. There was a positive correlation between the serum level of Ang-2 and the CRP in patients with AE-IIP patients, whereas a significant positive correlation was found between the serum Ang-2 level and the CRP or SOFA scores of the ALI/ARDS patients. Although the baseline Ang-2 level was not related to survival, the Ang-2 levels significantly declined in survivors during treatment, while they did not change in non-survivors. CONCLUSIONS: Increased pulmonary vascular permeability and inflammation due to Ang-2 may play a role in the pathogenesis of AE-IIPs. PMID- 27492511 TI - Frequency of comorbidities in chronic obstructive pulmonary disease, and impact on all-cause mortality: A population-based cohort study. AB - BACKGROUND: In chronic obstructive pulmonary disease (COPD), the role of specific comorbidities on all-cause mortality is of major interest particularly with a database representative of the beneficiaries covered by the French health system. We investigated the frequency and the role of major comorbidities on all-cause mortality in a population-based cohort of COPD patients, and whether this impact was modulated by gender. METHODS: A historical cohort was identified in the French claims data. Patients aged >=45 years were selected in 2006 from the French national claims data (1/97(th) random sample) by at least one of the following criteria: (a) COPD-related hospitalisations, (b) long-term disease status for COPD, (c) dispensations of bronchodilators. Cardiovascular diseases, diabetes, depression and cancer were defined by specific therapy and/or long-term disease status. The impact of comorbidities on mortality was investigated during a seven-year follow-up period (2007-2013), using Cox models. RESULTS: In 4,237 patients (mean age 68 years, 55% males, mean annual death-rate 4.9%), cardiovascular diseases, diabetes, depression and cancers were identified in 68.7%, 15.2%, 14.2% and 10.6% of patients, respectively. Associations with mortality were significant for cardiovascular diseases (HR = 1.2, 95%CI = [1.0 1.4]), diabetes (HR = 1.2, 95%CI = [1.0-1.4]), depression (HR = 1.4, 95%CI = [1.2 1.6]) and cancers (HR = 1.6, 95%CI = [1.4-1.9]), with no difference between genders. CONCLUSIONS: In the French population, major comorbidities are common in COPD, particularly cardiovascular diseases that occur in over two thirds of patients. The impact of comorbidities on mortality was not related to their prevalence, with cancer having the largest impact. PMID- 27492512 TI - Nonspecific interstitial pneumonia preceding diagnosis of collagen vascular disease. AB - BACKGROUND: The aim of this study was to evaluate the incidence and clinical features of patients who developed collagen vascular disease (CVD) after an initial diagnosis of idiopathic nonspecific interstitial pneumonia (NSIP). METHODS: We conducted a retrospective review of 72 consecutive patients with NSIP who were diagnosed by surgical lung biopsy in our institution (idiopathic NSIP, n = 35; CVD-NSIP, n = 37 at initial diagnosis). No patients fulfilled the American College of Rheumatology criteria for a diagnosis with CVD within six months after the diagnosis of idiopathic NSIP. RESULTS: Of 35 patients initially diagnosed with idiopathic NSIP, six patients (17.1%) developed CVD during the follow-up period (5.5 +/- 5.0 years); three patients were diagnosed with dermatomyositis (DM), two patients with overlap syndrome (DM and Sjogren's syndrome), and one patient with rheumatoid arthritis. The mean time until CVD diagnosis was 2.0 years (six months - 3.5 years), and the one-, two- and three-year incidences of CVD development were 3.6%, 15.2% and 20.0%, respectively. There was no significant difference in clinical characteristics and survival among patients with NSIP preceding CVD diagnosis, those with idiopathic NSIP, or those with CVD NSIP. In addition, at the time of initial diagnosis, there was no significant difference for the fulfillment of previous criteria such as interstitial pneumonia with autoimmune feature (IPAF) between patients with NSIP preceding CVD diagnosis and those with idiopathic NSIP. CONCLUSIONS: It is difficult to predict CVD occurrence and careful attention is needed to detect the development of CVD in patients with idiopathic NSIP. PMID- 27492513 TI - Diagnostic value of (1 -> 3)-beta-D-glucan in bronchoalveolar lavage fluid for invasive fungal disease: A meta-analysis. AB - BACKGROUND: The serum (1 -> 3)-beta-D-glucan (BG) assay has been approved for diagnosing invasive fungal diseases (IFDs). However, the performance of (1 -> 3) beta-D-glucan assay in bronchoalveolar lavage (BAL) fluid is various among studies. The present study aimed to assess the accuracy of (1 -> 3)-beta-D-glucan assay in bronchoalveolar lavage fluid for the diagnosis of invasive fungal diseases by means of meta-analysis and systematic review of relevant studies. METHOD: The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (OR) and a summary receiver operating characteristic curve of BAL-BG for diagnosing invasive fungal diseases were pooled using meta-analysis. We also performed meta-regression analysis. RESULTS: A total of 838 patients (138 with proven or probable invasive fungal diseases), included in 6 studies, were analyzed. The pooled sensitivity, specificity, PLR, NLR and diagnostic odds ratio were 0.52 (95%CI, 0.38-0.53), 0.58 (95%CI, 0.55-0.61), 1.34 (95%CI, 1.08-1.66), 0.82 (95% CI, 0.63-1.07) and 1.71 (95%CI, 1.01-2.92) respectively. The area under the summary receiver operating characteristic curve, with 95% confidence intervals was 0.61 (95%CI, 0.67-0.55). CONCLUSION: The accuracy of (1 -> 3)-beta-D-glucan test in bronchoalveolar lavage fluid is marginal, so that the results should not be interpreted alone but can be used as a part of full assessment with clinical features, image findings and other laboratory results for the diagnosis of invasive fungal diseases. PMID- 27492514 TI - Swallowing function and chronic respiratory diseases: Systematic review. AB - BACKGROUND: The precise coordination between breathing and swallowing is an important mechanism to prevent pulmonary aspiration. Factors that alter breathing patterns and ventilation, such as chronic respiratory diseases, may influence that precise coordination of breathing and swallowing. PURPOSE: The purpose of this systematic literature review is to examine the effects of chronic respiratory diseases on swallowing function. METHOD: Literature searches were performed using the electronic databases PubMed and Embase. All articles meeting the eligibility criteria up to March 2016 were included. RESULTS: All articles included studied Chronic Obstructive Pulmonary Diseases (COPD) or Obstructive Sleep Apnea (OSA); no studies involving other respiratory diseases were found. A total of 1069 abstracts were retrieved, of which twenty-six studies met the inclusion criteria; eleven studies dealt with OSA and fifteen studies dealt with COPD. CONCLUSION: The outcome data indicate that chronic respiratory diseases increase the prevalence of oropharyngeal dysphagia (OD) in patients. However, the relative small number of studies, differences in selection criteria, definitions and assessment techniques used for diagnosing OSA, COPD, and OD point to the need for further research. PMID- 27492516 TI - Perioperative respiratory care in obese patients undergoing bariatric surgery: Implications for clinical practice. AB - Obesity is an increasing problem worldwide. The number of people with obesity doubled since the 1980's to affect an estimated 671 million people worldwide. Obese patients in general have an altered respiratory physiology and can have an impaired lung function, which leads to an increased risk of developing pulmonary complications during anaesthesia and after bariatric surgery (approximately 8%). Therefore the respiratory management of the bariatric surgical patient provides a number of challenges. This review will focus on the perioperative respiratory care in bariatric surgical patients discussing respiratory physiology in the obese and perioperative respiratory care in bariatric surgery. Finally the value of preoperative pulmonary function testing and preoperative OSAS screening will be discussed. PMID- 27492515 TI - Non-invasive screening for pulmonary hypertension in idiopathic pulmonary fibrosis. AB - BACKGROUND: Pulmonary hypertension (PH) is a common complication of idiopathic pulmonary fibrosis (IPF) that is associated with poor prognosis. Noninvasive screening for PH in IPF patients is challenging and a combination of several noninvasive determinations can improve discrimination. METHODS: We included 235 IPF patients who underwent right heart catheterization (RHC) as part of the lung transplant evaluation. We measured electrocardiographic (ECG) and echocardiographic variables as well as the pulmonary artery (PA) and ascending aorta (AA) diameters on chest CT. We recorded results of arterial blood gases (ABG), pulmonary function (PFT) and 6-min walk tests (6MWT). RESULTS: Several variables were predictors of PH in IPF patients in univariable models including a lower arterial oxygenation and 6MWT distance; worse right ventricular (RV) function, rightward deviation of the QRS axis and a higher FVC/DLCOc ratio, PA/AA diameter ratio, and estimated RV systolic pressure. In multivariable analysis, a worse RV function and higher PA/AA ratio remained predictors of PH (c-index 0.75 (0.65-0.84)). Similarly, a worse RV function, a higher PA/AA ratio and a rightward QRS axis deviation were independent predictors of precapillary PH (c index 0.86 (0.76-0.92)). A combination of PA/AA diameter ratio <1.1, a QRS axis <90 degrees and normal RV function showed a negative predictive value of 85% for precapillary PH. CONCLUSIONS: There are significant differences in ECG, echocardiographic, chest CT, PFT and ABG parameters between IPF patients with and without PH. However, these noninvasive tests alone or combination have limited discrimination ability for PH screening in IPF. PMID- 27492517 TI - Undernutrition state in patients with chronic obstructive pulmonary disease. A critical appraisal on diagnostics and treatment. AB - 'Undernutrition state' (UNS) is an ominous condition, in particular when associated with chronic obstructive pulmonary disease (COPD). In this review we discuss pathophysiological mechanisms and how UNS is defined and diagnosed. It seems unlikely that COPD-patients with established UNS have similar potential of reversibility (treatability) upon nutrition interventions as patients at a risk of developing such a condition, i.e. patients with low energy/nutrient intake, since pathophysiological, biochemical and metabolic conditions may differ substantially. We summarize the results of 7 of 17 published randomized controlled trials of nutritional supplementation in COPD-patients with defined UNS in the latest Cochrane review (2012). We thus excluded 10 of 17 trials included in review (2012), mostly because those studies also included patients with 'risk of' UNS. The seven included trials exhibit extensive heterogeneity for all studied variables. Most studies did not show beneficial effects of nutritional supplementation, although some reported minor increase in body weight and physical function of unclear clinical relevance. In contrast to the Cochrane review we conclude that it is difficult to draw firm conclusions regarding the effect of nutritional supplements in patients with COPD and UNS. Improved knowledge in this area is of utmost importance and some factors which should be considered in future studies are suggested. PMID- 27492518 TI - Clinical characteristics of adult asthma associated with small airway dysfunction. AB - Suboptimal asthma control is common despite modern asthma therapy. The degree of peripheral airway involvement remains unclear and poor medication delivery to these regions might be a contributing reason for this failure in obtaining adequate symptom control. A cohort of 196 adults (median (range) age 44 (18-61) years, 109 females, 54 ex-smokers, six current smokers) with physician-diagnosed asthma were recruited from primary care. Subjects were characterized clinically by interviews, questionnaires, skin prick tests (SPT) and blood eosinophil counts. Lung function was assessed by spirometry, impulse oscillometry (IOS) and nitrogen multiple breath washout (N2 MBW). IOS assessed peripheral airway resistance (FDR, frequency dependence of resistance). N2 MBW assessed global ventilation inhomogeneity (LCI, lung clearance index), specific indices of peripheral airway function (Scond * VT and Sacin * VT; VT, tidal volume), and inter-regional inhomogeneity (specific ventilation ratio). Never-smoking healthy cohorts of 158 and 400 adult subjects provided local reference values for IOS and N2 MBW variables, respectively. Peripheral airway dysfunction was detected in 31% (FDR or specific ventilation ratio) to 47% (Scond x VT) of subjects. Risk factors for peripheral airway dysfunction were identified. Among subjects with low FEV1 and either positive smoking history and/or blood eosinophilia (>4.0%), 63% had abnormality across all peripheral airway outcomes, whilst only one subject was completely normal. Abnormal peripheral airway function was present in a large proportion of adult asthmatics at baseline. Reduced FEV1, a positive smoking history, and/or blood eosinophilia identified "a small airway asthma subtype" that might benefit from peripheral airway targeted therapy. PMID- 27492519 TI - Observational study of lung transplant recipients surviving 20 years. AB - BACKGROUND: Lung transplant recipients have reduced long-term survival compared with other solid organ recipients. There is a lack of published data on the characteristics of very long term survivors. METHODS: We describe the demographics, clinical history and post-procedure function of all lung transplant recipients who have survived greater than 20 years at our centre. RESULTS: At the time of analysis there were 21 (16.4%) of 128 patients who survived over 20 years. The mean age at transplantation was 31.8 +/- 9.9 years. Five of 21 had undergone single-lung, eight double-lung and eight heart-lung transplant procedures. At the last evaluation, mean percentage predicted FEV1 in recipients of single and double lung were 51.3% and 57.9% respectively. By 20 years, 19 (90.5%) patients had developed bronchiolitis obliterans syndrome (BOS) with three (14%) BOS 1, six (29%) BOS 2 and 10 (48%) BOS 3 and two (9.5%) free from BOS. The median time to onset of BOS was 9.7 years (range 1.6-17.9). Of eight patients (38%) who required renal replacement, four (19%) had successfully undergone renal transplantation and four (19%) were on haemodialysis. Only one patient (5%) had symptomatic osteoporosis. Nineteen patients (90%) were treated for hypertension. Five patients (24%) had diabetes, all with an underlying diagnosis of cystic fibrosis and four of them developing diabetes post operatively. CONCLUSIONS: In our experience, 20-year survivors of lung transplantation had a delayed onset of BOS and morbidities due to immunosuppression that can be appropriately managed leading to long-term survival. PMID- 27492520 TI - Stepping down from combination asthma therapy: The predictors of outcome. AB - BACKGROUND: Stepping down from combination asthma therapy (inhaled corticosteroids (ICS) + long-acting beta2 agonists (LABA)) is often avoided due to fear of exacerbations, which may lead to overmedication in well-controlled asthma. A better knowledge about the predictors of outcome might encourage clinicians to start stepping down more often than previously. METHODS: In 55 subjects with well controlled asthma and combination therapy, LABAs were discontinued first, followed by ICS dose halving, and then cessation, in six weeks' intervals. The ability of Juniper's asthma control questionnaire (ACQ), ambulatory peak flow monitoring, spirometry, and hypertonic saline challenge to predict the outcomes of medication reductions were assessed. RESULTS: The proportions of subjects experiencing an exacerbation at each step were: 4 out of 55 subjects (7%) after LABA cessation, 4 out of 25 subjects (16%) after ICS dose halving, and 21 out of 46 subjects (46%) after ICS cessation. All exacerbations could be managed on an outpatient basis. There were 126 step-downs altogether. ACQ score < 0.29 (likelihood ratio 2.30 (1.05-5.05)), ACQ without spirometry < 0.15 (2.17 (0.96-4.90)) and FEV1 > 96% of predicted (2.18 (1.03-4.61)) predicted a successful outcome after step-down. Cough responsiveness to saline, bronchoconstrictive responsiveness to saline, and peak flow variation were not associated with the outcome. CONCLUSION: Combination therapy can often be reduced in controlled asthma but total cessation of ICSs must be carefully considered. Simple investigations, namely asthma control assessment by validated questionnaire and spirometry, help to predict the outcome of stepping down. TRIAL REGISTRY: The study was registered in ClinicalTrials.gov database (https://clinicaltrials.gov, KUH5801124). PMID- 27492521 TI - Improvement of physical activity after endobronchial valve treatment in emphysema patients. AB - RATIONALE: Bronchoscopic lung volume reduction using endobronchial valves is a promising treatment for severe emphysema patients without collateral ventilation. Physical activity is an important contributing factor for the autonomy, morbidity and mortality of these patients. OBJECTIVE: We investigated the impact of endobronchial valve treatment on physical activity in severe emphysema patients. METHODS: Physical activity was measured for 7 days by a triaxial accelerometer at baseline and 6 months follow-up after EBV treatment, and compared with standard medical care in a randomized controlled trial. RESULTS: Forty-three patients (77%female, age 59 +/- 9years, FEV1 30 +/- 7%pred, steps 3563 +/- 2213per/day) wore the accelerometer and were included in the analysis. Nineteen patients received EBV treatment and 24 standard medical care. At baseline, physical activity level was comparable between groups. After 6 months, the endobronchial valve group significantly improved compared to the controls in steps/day (+1252vs 148) and locomotion time (+17vs-2 min/day). Change in sit duration (0vs + 27 min/day) did not significantly differ. CONCLUSIONS: Physical activity significantly improved after endobronchial valve treatment in severe emphysema patients. This improvement was without any specific encouragement on physical activity. CLINICAL TRIAL NUMBER: Dutch trial register: NTR2876. PMID- 27492522 TI - Activity limitation and exertional dyspnea in adult asthmatic patients: What do we know? AB - Limitation of activity is the most cited symptom described by uncontrolled asthma patients. Assessment of activity limitation can be undertaken through several ways, more or less complex, subjective or objective. Yet little is known about the link between patients sensations and objective measurements. The present review reports the current knowledge regarding activity limitation and symptom perception (i.e., exertional dyspnea) in adult patients with asthma. This work is based on references indexed by PubMed, irrespective of the year of publication. Overall, patients with stable asthma do not have a more sedentary lifestyle than healthy subjects. However, during a cycle ergometric test, the maximal load is reduced when FEV1, FVC and muscle strengths are decreased. Additionally, during the six-minute walking test, mild asthma patients walk less than healthy subjects even if the minimal clinically important difference is not reached. The major complaint of asthma patients when exercising is dyspnea that is mainly related to the inspiratory effort and also to dynamic hyperinflation in some circumstances. Finally, the administration of bronchodilator does not improve the ventilatory pattern and the exercise capacity of asthma patients and little is known on its effect on exertional dyspnea. The present review allows to conclude that until now there is no gold standard test allowing the objective assessment of "activity limitation and exertional dyspnea" in asthma patients. PMID- 27492523 TI - Comparison of endobronchial ultrasound and high resolution computed tomography as tools for airway wall imaging in asthma and chronic obstructive pulmonary disease. AB - INTRODUCTION: Airway remodeling in asthma and chronic obstructive pulmonary disease (COPD) results in bronchial wall thickening. Bronchial wall thickness (BWT) can be assessed in high-resolution computed tomography (HRCT) and endobronchial ultrasound (EBUS). AIMS: To compare BWT measured by EBUS and HRCT in patients with mild-to-moderate asthma and COPD, and to evaluate the relationship between the BWT and pulmonary function. METHODS: The study included patients with mild-to-moderate asthma (n = 24), COPD (n = 36) and controls (n = 12). Bronchoscopy with EBUS (radial probe) and HRCT were performed to measure the BWT in the segmental bronchus. RESULTS: Good overall agreement between EBUS and HRCT measurements of BWT was demonstrated. Median HRCT-BWT did not reveal any significant differences between individuals with asthma and COPD, and control subjects: 1.56 (1.27-1.70) mm, 1.62 (1.45-1.90) mm, and 1.63 (1.41-1.77) mm, respectively (p = 0.315). In contrast, median BWT measured by EBUS was significantly higher in asthma and COPD groups when compared to controls: 1.20 (1.02-1.41) mm, 1.19 (1.10-1.48) mm, and 0.99 (0.90-1.08) mm, respectively (p = 0.006). There were no differences in BWT in mild-to-moderate asthma and COPD or significant correlations between BWT and the results of pulmonary function tests. CONCLUSIONS: The use of EBUS to assess BWT in asthma and COPD is feasible and it shows good compatibility with HRCT. A tendency towards lower BWT values in EBUS when compared to HRCT was observed. The finding that EBUS measurements demonstrated the differences between BWT in patients with obstructive lung diseases and controls, may suggest that EBUS is a more sensitive method to study the BWT than HRCT. PMID- 27492524 TI - Novel variants of SERPIN1A gene: Interplay between alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease. AB - Alpha1-antitrypsin (AAT) is one of the major circulating anti-protease whose levels in circulation are raised during excessive amount of proteases, especially neutrophil elastase (NE) released during the course of inflammation. Proteolytic attack of NE on peripheral organs, more exclusively on lung parenchyma has severe consequence that may precipitate pulmonary emphysema. Normally, human body has its own molecular and physiological mechanisms to synthesize and regulate the production of anti-protease like AAT to mitigate the extent of inflammatory damage. AAT coded by serine-protease inhibitor (SERPINA1) is predominantly expressed in hepatocytes and to some extent by macrophages, monocytes, lung tissue etc. The observation that persons with AAT deficiency developed chronic obstructive pulmonary disease (COPD) and early-onset of emphysema proposed a role for pathways connecting AAT in pathogenesis. Extensive studies have been done till now to bridge a connection between numerous genetic polymorphisms of SERPINA1 gene and the early onset of COPD. Here in this review, we have comprehensively discussed some of the variants of SERPINA1 gene discovered till date and their association with the exacerbation of obstructive pulmonary disease. PMID- 27492525 TI - Can bronchial asthma with an highly prevalent airway (and systemic) vagal tone be considered an independent asthma phenotype? Possible role of anticholinergics. AB - Recently, we studied occurrence and role of non-respiratory symptoms (n-RSs) before a worsening of asthma symptoms. Some n-RSs such as anxiety, reflux, heartburn, abdominal pain, which appeared within 3 h before the onset of an asthma attack, are the likely result of an imbalance between sympathetic/parasympathetic systems with an increase in cholinergic tone. Therefore, it is likely that some of these n-RSs induced by the increased cholinergic tone might be present related with specific parasympathetic associated respiratory symptoms such as those elicited by airway narrowing. It is likely that, at least in some categories of asthmatics, an increased cholinergic tone, rather than other well-known factors, might play a prevalent role in triggering bronchospasm. If this is the case, it is possible to speculate that the use of anticholinergic agents (mainly those with long-acting activity) in patients suffering from asthma should be more beneficial in individuals characterized by a higher degree of cholinergic tone that, consequently might be the ideal target for the use of long-acting anticholinergics and, possibly, represent a novel asthma phenotype. The presence of parasympathetic-associated n RSs might help the physician to identify this type of patients, although this might be followed by a more detailed assessment. PMID- 27492526 TI - Prevalence of depression in COPD: A systematic review and meta-analysis of controlled studies. AB - BACKGROUND: Depression is frequently reported in association with COPD. However, the prevalence of depression in these patients ranges largely. This study aimed to systematically review the prevalence of depression in COPD and controls and to explore remaining causes of inter-study variability in the reported prevalence. METHODS: A systemic review of the literature and a meta-analysis was performed to evaluate the source of variability in the reported rates of depression in stable COPD. Main eligibility criteria were: controlled studies with a sample size >100, outpatients with COPD diagnosed by spirometry and, use of a validated depression screening instrument. RESULTS: From 1613 studies identified, eight controlled studies were included in the review. The number of participants in the pooled studies was of 5.552 COPD subjects and 5.211 controls. Using stricter criteria for study selection reduced the variability of the depression prevalence in COPD and controls, which was 27.1% [25.9-28.3] in COPD subjects and 10.0% [9.2-10.8] in the control group. The pooled odds ratio and 95% CI was 3.74 [2.4-5.9]. However, the heterogeneity across studies was high. Possible explanatory factor included sample sizes, COPD/controls ratio, smoker's/nonsmokers ratio and qualitative differences (source of subjects, instruments to screen depression, COPD severity, smoking status, and comorbidities). CONCLUSION: The study highlights the variability in estimates of depression prevalence in COPD. It could be explained by methodological differences across the included studies. This suggests that a standardization is critical to improve precision of the estimates. PMID- 27492527 TI - The barriers to accessing primary care resulting in hospital presentation for exacerbation of asthma or chronic obstructive pulmonary disease in a large teaching hospital in London. AB - Asthma and chronic obstructive pulmonary disease (COPD) account direct costs of L1 billion each per year in the United Kingdom (UK). A national review of asthma deaths found that a significant proportion of patients die without seeking medical assistance or before emergency medical care could be provided. This study aims to establish the pathway that patients undertake to access care in the lead up to an accident and emergency (A&E) attendance and/or inpatient admission. Patients attending A&E and/or following an inpatient admission due to an exacerbation of asthma or COPD were reviewed by a specialist respiratory pharmacist during weekday working hours. Over a one-year period, 920 (224 asthma and 696 COPD) presentations for exacerbation of asthma and COPD were reviewed. Although the majority of the patients were registered with a general practitioner (GP), less than 50% received medical attention from their GP and/or had an active intervention prior to presenting to hospital. These findings correlate with those found in the national review of asthma deaths. At a time of increasing demands on healthcare resources, these results pose the question of how we can better triage patients to appropriate care settings to minimise unscheduled care and improve patient outcomes. PMID- 27492528 TI - Profile of difficult to treat asthma patients referred for systematic assessment. AB - AIM: We determined the proportion of asthma patients under specialist care who remain difficult-to-treat and might benefit from systematic assessment. We additionally report the characteristics and indications for referral in 90 patients who received systematic assessment for difficult asthma. METHODS: We conducted a three-month prospective audit of our hospital's general asthma clinic. We then analyzed consecutive patients over 18 months referred on for systematic assessment of difficult asthma. RESULTS: Over 3 months, 22/166 patients (13.3%) in the general asthma clinic were considered likely to benefit from systematic assessment of difficult asthma. These patients had higher inhaled steroid requirements (890 +/- 604 mg), lower lung function (FEV1: 65 +/- 18%), and more often received GINA step 5 treatment (22.7%). However, 7/22 (32%) of suitable patients were not referred for assessment, mainly due to patient factors. Over 18 months, 90 patients received systematic assessment for difficult asthma, on account of poor symptom control (62%), frequent exacerbations (44%), poor lung function (42%), patient factors (29%), and diagnostic uncertainty (26%). There was a high disease burden with a mean (+/-SD) asthma control test score and asthma quality of life questionnaire score of 14 +/- 5 and 4.26 +/- 1.45 respectively. 80% fulfilled criteria for severe asthma. The majority were either atopic (66.7%) or eosinophilic (54.4%); only 15.6% were neither. Patients had a median of three extra-pulmonary comorbidities, of which most were previously unrecognised. CONCLUSION: One-in-eight asthma patients already under specialist care were suitable for systematic assessment of difficult asthma, but a third of these were not referred due to patient factors. Diagnostic uncertainty and patient factors were important indications for systematic assessment. Most patients who underwent systematic assessment exhibited severe asthma phenotypes potentially responsive to targeted treatment, but also had multiple comorbidities. Our results highlight the importance of management strategies to address patient factors, severe asthma biology, and concurrent contributory conditions. PMID- 27492529 TI - Management of obese patients with respiratory failure - A practical approach to a health care issue of increasing significance. AB - In the general population, prevalence of obesity is increasing continuously. Concomitantly, a growing number of obese patients with severe illnesses presents at intensive care units (ICU). Particularly respiratory management of this patient group poses a challenge to intensive care physicians because of differences in respiratory anatomy and physiology in obese compared to non-obese individuals. Aim of this review is to present treatment options for critically ill obese patients requiring mechanical ventilation based on current studies concerning patient positioning, ventilatory regimen as well as extended therapy with veno-venous extracorporeal membrane oxygenation (ECMO). The ideal concept for respiratory management depends on multiple aspects and has to be determined individually. Knowledge of altered respiratory anatomy and physiology in obese patients and possible treatment options may facilitate respiratory management in this patient group. PMID- 27492530 TI - Challenges in managing Pseudomonas aeruginosa in non-cystic fibrosis bronchiectasis. AB - BACKGROUND: An Expert Forum was held at the 2014 European Respiratory Society International Congress to address issues involved in the management of Pseudomonas aeruginosa infection in patients with non-cystic fibrosis bronchiectasis (NCFB). Multiple studies have found that chronic P. aeruginosa infection is associated with more severe disease and higher morbidity and mortality. OVERVIEW: Participants discussed appropriate management of P. aeruginosa infection at three stages: 1) first isolation, including eradication protocols; 2) during exacerbations; and 3) during chronic infection, including long-term antibiotic therapy to reduce the severity of symptoms and frequency of exacerbations. Topics covered included frequency of sputum cultures, antibiotic treatment at first isolation and for exacerbations, optimal use of inhaled antibiotics, indications for long-term therapy, and treatment regimens that may reduce the frequency or severity of symptoms. Electronic polling and roundtable discussions followed by expert insights were used to address these topics. Significant diversity in management practices was reported among different countries and centres, and in many cases clinical management was at variance with published guidelines. CONCLUSIONS: This Expert Forum identified standardised terminology, clinician training, additional research into management strategies, and the development of new drugs as areas requiring improvement for the optimal management of P. aeruginosa in NCFB. PMID- 27492531 TI - The effect of N-acetylcysteine on biofilms: Implications for the treatment of respiratory tract infections. AB - OBJECTIVES: In airway infections, biofilm formation has been demonstrated to be responsible for both acute and chronic events, and constitutes a genuine challenge in clinical practice. Difficulty in eradicating biofilms with systemic antibiotics has led clinicians to consider the possible role of non-antibiotic therapy. The aim of this review is to examine current evidence for the use of N acetylcysteine (NAC) in the treatment of biofilm-related respiratory infections. METHODS: Electronic searches of PUBMED up to September 2015 were conducted, searching for 'biofilm', 'respiratory tract infection', 'N-acetylcysteine', 'cystic fibrosis', 'COPD', 'bronchiectasis', 'otitis', and 'bronchitis' in titles and abstracts. Studies included for review were primarily in English, but a few in Italian were also selected. RESULTS: Biofilm formation may be involved in many infections, including ventilator-associated pneumonia, cystic fibrosis, bronchiectasis, bronchitis, and upper respiratory airway infections. Many in vitro studies have demonstrated that NAC is effective in inhibiting biofilm formation, disrupting preformed biofilms (both initial and mature), and reducing bacterial viability in biofilms. There are fewer clinical studies on the use of NAC in disruption of biofilm formation, although there is some evidence that NAC alone or in combination with antibiotics can decrease the risk of exacerbations of chronic bronchitis, chronic obstructive pulmonary disease, and rhinosinusitis. However, the usefulness of NAC in the treatment of cystic fibrosis and bronchiectasis is still matter of debate. Most of the studies published to date have used oral or intramuscular NAC formulations. CONCLUSIONS: Evidence from in vitro studies indicates that NAC has good antibacterial properties and the ability to interfere with biofilm formation and disrupt biofilms. Results from clinical studies have provided some encouraging findings that need to be confirmed and expanded using other routes of administration of NAC such as inhalation. PMID- 27492532 TI - Tiotropium improves lung function, exacerbation rate, and asthma control, independent of baseline characteristics including age, degree of airway obstruction, and allergic status. AB - BACKGROUND: Many patients with asthma remain symptomatic despite treatment with inhaled corticosteroids (ICS) with or without long-acting beta2-agonists (LABAs). Tiotropium add-on to ICS plus a LABA has been shown to improve lung function and reduce exacerbation risk in patients with symptomatic asthma. OBJECTIVE: To determine whether the efficacy of tiotropium add-on therapy is dependent on patients' baseline characteristics. METHODS: Two randomized, double-blind, parallel-group, twin trials (NCT00772538 and NCT00776984) of once-daily tiotropium Respimat((r)) 5 MUg add-on to ICS plus a LABA were performed in parallel in patients with severe symptomatic asthma. Exploratory subgroup analyses of peak forced expiratory volume in 1 s (FEV1), trough FEV1, time to first severe exacerbation, time to first episode of asthma worsening, and seven question Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by baseline characteristics. RESULTS: 912 patients were randomized: 456 received tiotropium and 456 received placebo. Tiotropium improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, compared with placebo, independent of baseline characteristics including gender, age, body mass index, disease duration, age at asthma onset, and FEV1 % predicted at screening and reversibility. CONCLUSION: Once-daily tiotropium 5 MUg compared with placebo improved lung function, reduced the risk of asthma exacerbations and asthma worsening, and improved asthma symptom control, independent of a broad range of baseline characteristics, as add-on to ICS plus LABAs in patients with severe symptomatic asthma. TRIAL REGISTRY: ClinicalTrials.gov; numbers NCT00772538 and NCT00776984 URL: www.clinicaltrials.gov. PMID- 27492533 TI - Relationships between emphysema and airways metrics at High-Resolution Computed Tomography (HRCT) and ventilatory response to exercise in mild to moderate COPD patients. AB - BACKGROUND AND PURPOSE: In Chronic Obstructive Pulmonary Disease (COPD) patients, the opportunity to carry out a thoracic high-resolution CT (HRCT) scan and to perform an incremental cardiopulmonary exercise test (CPET) increases the possibility to identify the different clinical features of disease. The aim of our study was to evaluate the relationships between HRCT metrics (on emphysema by low attenuation areas-LAA% and airways by wall area-WA%) and CPET variables related to the dynamic response to exercise in terms of elastic balance (Delta rest-to-peak IC/TLC) and ventilation capacity for carbon dioxide output (VE/VCO2slope and VE/VCO2 intercept). METHODS: We prospectively enrolled COPD outpatients from the University Hospital of Parma. Data on anthropometrics characteristics, lung function, HRCT (LAA% and WA%) and CPET (Delta rest-to-peak IC/TLC, VE/VCO2 slope and VE/VCO2 intercept) were recorded. RESULTS: Fifty-one mild to moderate COPD patients (66% males; median age 70 y; mean FEV1 56% of pred.) were enrolled in the study. LAA% demonstrated a significant correlation with Delta rest-to-peak IC/TLC and VE/VCO2slope (r = 0.405, p = 0.005 and r = 0.453, p = 0.001, respectively), while WA% with VE/VCO2slope (r = -0.333, p = 0.020). In multivariate regression models, after adjustment for oxygen uptake (peak VO2) and physical capacity (peak workload), LAA was the only independent predictor of Delta rest-to-peak IC/TLC (beta 0.774, SE 0.334, p = 0.025) and VE/VCO2 slope (beta 0.155, SE 0.053, p = 0.005 and beta 0.305, SE 0.123, p = 0.018, respectively). VE/VCO2 intercept was instead predicted from FEV1 only (beta -0.097, SE 0.042, p = 0.027). CONCLUSION: In mild to moderate COPD patients, emphysema (LAA) and airways metrics (WA) have close relationships with the different characteristics of ventilatory response to exercise. In particular, we were able to show that LAA is an independent predictor of exercise-induced Delta rest-to-peak IC/TLC and VE/VCO2 slope. PMID- 27492534 TI - Pulmonary vein stenosis complicating radiofrequency catheter ablation for atrial fibrillation: A literature review. AB - Radiofrequency catheter ablation has become a widely used intervention in the treatment of atrial fibrillation. Pulmonary vein stenosis (PVS) is one of the most serious complications associated with this procedure; the degree of stenosis ranges from mild (<50%) to complete venous occlusion. The natural history of PVS and the risk of progression of existing PVS are uncertain. Symptomatic and/or severe PVS is a serious medical problem and can be easily misdiagnosed since it is an uncommon and relatively new medical problem, often has low clinical suspicion among clinicians, and has a non-specific presentation that mimics other more common respiratory or cardiac diseases. The estimated incidence varies in literature reports from 0% to 42% of ablation procedures, depending on technical aspects of the procedure and operator skill. Most patients with significant PVS remain asymptomatic or have few symptoms. Symptomatic patients usually present with dyspnea, chest pain, or hemoptysis and are usually treated with balloon angioplasty and/or stent placement. Little is known about the long term effect of PV stenosis/occlusion on the pulmonary circulation and the development of pulmonary hypertension. Evolving technology may reduce the frequency of this complication, but long term studies are needed to understand the effect of therapeutic atrial injury and adverse outcomes. This review summarizes the current literature and outlines an approach to the evaluation and management of these patients. PMID- 27492535 TI - A 12-year prognosis of adult-onset asthma: Seinajoki Adult Asthma Study. AB - RATIONALE: Long-term prognosis of adult-onset asthma is poorly known. OBJECTIVE: To evaluate 12-year prognosis of adult-onset asthma and the factors associated with disease prognosis. METHODS: Seinajoki Adult-onset Asthma Study (SAAS) is a 12-year real-life single-center follow-up study of new-onset asthma diagnosed at adult age and treated in primary and specialized care. Remission was defined by no symptoms and no asthma medication use for 6 months. Asthma control was evaluated according to Global Initiative for Asthma 2010. Factors associated with current asthma control were analyzed by multinomial multivariate logistic regression. MAIN RESULTS: A total of 203 patients (79% of the baseline population) were followed for 12 years. Remission occurred in 6 (3%) patients. In 34% asthma was controlled, in 36% it was partially controlled and in 30% uncontrolled. Uncontrolled asthma was predicted by elevated body-mass index at baseline, smoking (pack-years) and current allergic or persistent rhinitis. Elevated blood eosinophils and good lung function (FEV1) at baseline protected from uncontrolled asthma. In contrast, gender, age at the onset or baseline symptoms (Airways Questionnaire 20) were not significant predictors of uncontrolled disease. CONCLUSIONS: During a 12-year follow-up, remission of adult onset asthma was rare occurring in only 3% of patients. The majority of patients (66%) presented either with uncontrolled or partially controlled asthma. This study is registered at ClinicalTrials.gov with identifier number NCT02733016. PMID- 27492536 TI - Healthcare burden of obstructive sleep apnea and obesity among asthma hospitalizations: Results from the U.S.-based Nationwide Inpatient Sample. AB - BACKGROUND: Studies have highlighted the significant comorbidities of both obesity and obstructive sleep apnea (OSA) among asthma patients in outpatient settings, but such data in the inpatient setting is sparse. METHODS: Using 2009 2011 U.S. Nationwide Inpatient Sample; survey-weighted regression analyses were conducted to address the role of obesity, OSA, and both obesity and OSA on length of stay (LOS), total hospital charges, need for respiratory therapy, and disposition among adults with primary asthma hospitalization (n = 179,789). RESULTS: Males had a higher prevalence of OSA than females (5.23% vs. 3.88%), while females had a higher prevalence of obesity (17.21% vs. 8.95%) and both obesity and OSA (7.11% vs. 6.19%). Increased hospital LOS was associated with presence of obesity (incidence rate ratio [IRR] males = 1.07, IRR females = 1.08), OSA (IRR males = 1.07, IRR females = 1.14), and both obesity and OSA (IRR males = 1.19, IRR females = 1.24). Increased total hospital charges was related to obesity (8.64% for males and 9.61% for females), OSA (15.39% for males and 19.13% for females), and both comorbidities (24.94% for males and 28.50% for females). Presence of OSA alone increased odds of need for respiratory therapy for males (odds ratio [OR] = 2.56) and females (OR = 3.22), as did presence of both comorbidities (OR males = 2.85, OR females = 3.60). Odds of routine disposition was lower among females with both comorbidities (OR = 0.82). CONCLUSION: Compared to obesity alone, OSA and both obesity and OSA are associated with increased health resource utilization and poorer inpatient outcomes. This demonstrates the need for further clinical investigations of early detection of OSA among such at-risk populations. PMID- 27492537 TI - Impact of hyponatremia on mortality and morbidity in patients with COPD exacerbations. AB - Hyponatremia is the most common electrolyte disorder in hospitalized patients, being associated with increased morbidity and mortality in different clinical conditions. However, the prevalence and impact of this electrolytic disorder in patients hospitalized for an exacerbation of COPD still remains unknown. The aim of the present study was to clarify these points. A total of 424 patients hospitalized due to a COPD exacerbation were consecutively included, showing a frequency of hyponatremia of 15.8% (hyposmolar in most cases). Even though patients with and without hyponatremia showed a similar age, comorbidities, lung function impairment, presence of previous exacerbations, hospitalizations, most of the comorbidities and the overall severity index (APACHE II), their clinical outcomes were worse. Indeed, their hospitalization length, mechanical ventilation requirements and deaths (both during admission and within the months following discharge) were higher than those of non-hyponatremic patients. A sodium threshold lower than 129.7 mEq/L exhibited the better discriminatory power for death prediction. We conclude that hyponatremia (especially if severe) is a predictive marker for a bad clinical course in COPD exacerbations and therefore, patients with this electrolyte abnormality should be carefully monitored. PMID- 27492538 TI - Enhanced LPS-induced activation of IL-27 signalling in sarcoidosis. AB - RATIONALE: Granulomas in sarcoidosis have recently been described as containing Interleukin (IL)-27, one of the members of the IL-12 family of cytokines, which also includes IL-35. Levels of these cytokines and the IL-27 receptor subunits were hypothesised to differ between patients with sarcoidosis compared to healthy controls in peripheral blood. METHODS: Using a cross-sectional study design, plasma and peripheral blood mononuclear cells (PBMC) were collected from patients and control subjects. Protein and mRNA (in PBMC) levels for IL-27 and IL-35 (IL27, EBI3, IL12A subunits) as well as IL-27 receptor (IL6ST and IL27RA subunits) were assessed spontaneously and following direct (LPS) and indirect (anti-CD3/28 activation beads) macrophage stimulation using RT- PCR, ELISA and flow cytometry. RESULTS: Following stimulation with LPS, PBMC of patients with sarcoidosis displayed significantly enhanced expression of IL27 and EBI3 mRNA (p = 0.020 and p = 0.037 respectively) compared to PBMCs from healthy controls. There was also significantly enhanced production of IL-27 by PBMC from patients with sarcoidosis compared to healthy controls in response to LPS stimulation (p = 0.027). IL6ST mRNA and IL6ST protein were significantly lower in patients with sarcoidosis (mRNA p = 0.0002; MFI p = 0.0015) whilst IL27RA protein levels were significantly higher in patients with sarcoidosis compared to healthy controls (MFI p < 0.0001). Plasma IL-35 protein levels did not differ between control and sarcoidosis subjects (p = 0.23). CONCLUSION: These results suggest there may be exaggerated activation of IL-27 signalling in response to LPS in sarcoidosis. PMID- 27492539 TI - Ambrisentan response in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) - A subgroup analysis of the ARIES-E clinical trial. AB - OBJECTIVE: Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and early mortality and is an important complication in patients with connective tissue disease (CTD). Previously, the endothelin A selective receptor antagonist, ambrisentan, demonstrated efficacy and safety in treating patients with PAH due to WHO Group I etiologies. These analyses describe the 3-year efficacy and safety of ambrisentan in patients specifically with CTD associated PAH (CTD-PAH). METHODS: Patients with CTD-PAH participating in the ARIES-1 and -2 clinical trials and their long-term extension were evaluated. Efficacy evaluations including 6-min walk distance (6MWD), clinical worsening, and survival were collected at routine study visits. Additional analyses of 6MWD categorical (30 m) breakpoints were conducted to determine any relationship between 6MWD and a prognostic threshold for survival. RESULTS: 124 patients with CTD-PAH were evaluated. 62.6%, 57.3%, and 58.2% of CTD-PAH patients treated with ambrisentan exhibited increases in 6MWD at 1-, 2-, and 3- years respectively. At 3 years, 64% of patients were free from clinical worsening and 76% of patients were still alive (Kaplan-Meier estimates). Identified factors holding prognostic relevance for survival include: baseline functional class, CTD-PAH subgroup, patient sex, improvement in 6MWD >=30 m over the first 12 weeks of treatment, the most recent 6MWD, and a 6MWD absolute threshold of 222 m. CONCLUSION: These first analyses of the 3-year treatment of CTD-PAH patients with ambrisentan revealed fewer clinical worsening events and improved survival compared to historical controls. Key exercise parameters were also identified which appear important in guiding treatment. PMID- 27492540 TI - Women using bleach for home cleaning are at increased risk of non-allergic asthma. AB - BACKGROUND: Bleach is widely used for household cleaning. Although it is recognized that occupational use of bleach may have adverse respiratory health effects, it is unknown whether common domestic use of bleach may be a risk factor for asthma. AIM: To assess whether the domestic use of bleach for home cleaning is associated with asthma and other respiratory outcomes. METHODS: Questionnaire based information on respiratory symptoms and cleaning habits and data from skin prick-tests, bronchial responsiveness challenge and white blood cells were analyzed in 607 women participating in the follow-up of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). Bleach use was evaluated in 3 categories (<1 day/week; 1-3 days/week; 4-7 days/week "frequent"). RESULTS: Overall, 37% of the women reported using bleach weekly. Women using bleach frequently (11%) were more likely to have current asthma as compared to non-users (adjusted Odds-Ratio (aOR) = 1.7; 95% Confidence Interval (95%CI) 1.0-3.0). Among women with asthma, frequent use of bleach was significantly associated with higher blood neutrophil cell counts. Bleach use was significantly associated with non-allergic asthma (aOR 3.3; 95%CI 1.5-7.1), and more particularly with non allergic adult-onset asthma (aOR 4.9; 95%CI 2.0-11.6). Consistently, among women without allergic sensitization, significant positive associations were found between use of bleach and bronchial hyperresponsiveness, asthma like-symptoms and chronic cough. No association was observed for allergic asthma. CONCLUSIONS: Frequent use of bleach for home-cleaning is associated with non-allergic adult onset asthma, elevated neutrophil counts and lower-airway symptoms in women. PMID- 27492541 TI - Identification of five clusters of comorbidities in a longitudinal Japanese chronic obstructive pulmonary disease cohort. AB - BACKGROUND AND OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from various comorbidities. Recently, cluster analysis has been proposed to examine the phenotypic heterogeneity in COPD. In order to comprehensively understand the comorbidities of COPD in Japan, we conducted multicenter, longitudinal cohort study, called the Keio COPD Comorbidity Research (K-CCR). In this cohort, comorbid diagnoses were established by both objective examination and review of clinical records, in addition to self-report. We aimed to investigate the clustering of nineteen clinically relevant comorbidities and the meaningful outcomes of the clusters over a two-year follow-up period. MATERIAL AND METHODS: The present study analyzed data from COPD patients whose data of comorbidities were completed (n = 311). Cluster analysis was performed using Ward's minimum-variance method. RESULTS: Five comorbidity clusters were identified: less comorbidity; malignancy; metabolic and cardiovascular; gastroesophageal reflux disease (GERD) and psychological; and underweight and anemic. FEV1 did not differ among the clusters. GERD and psychological cluster had worse COPD assessment test (CAT) and Saint George's respiratory questionnaire (SGRQ) at baseline compared to the other clusters (CAT: p = 0.0003 and SGRQ: p = 0.00046). The rate of change in these scores did not differ within 2 years. The underweight and anemic cluster included subjects with lower baseline ratio of predicted diffusing capacity (DLco/VA) compared to the malignancy cluster (p = 0.036). CONCLUSIONS: Five clusters of comorbidities were identified in Japanese COPD patients. The clinical characteristics and health-related quality of life were different among these clusters during a follow-up of two years. PMID- 27492543 TI - A randomized controlled study comparing Prostaglandin E2 vaginal suppository with intra-cervical Foleys catheter balloon for preinduction cervical ripening at term. AB - BACKGROUND: Pre-induction ripening of an unfavourable cervix reduces the incidence of failed induction and associated maternal and perinatal morbidity and mortality. OBJECTIVE: The aim of this study is to compare the effectiveness of prostaglandin E2(PGE2) vaginal suppository with intra-cervical Foley's catheter balloon for pre-induction cervical ripening. METHODS: It is a prospective randomized study. Clients with unfavourable cervix (Bishop score<5) were randomly allocated into two groups. One group received 3mg PGE2 vaginal suppository and the second group had intra cervical Foley catheter insertion and balloon inflated with 30mls of sterile water. RESULTS: There were 38 patients in each arm.There was no difference in age, parity and educational level, p=0.9157, 0.8054 and 0.7568 respectively, in the two groups. There were significant changes in the Bishop scores following the application of Foley's catheter and Prostaglandin E2 (p= 0.0214 and 0.0105) respectively. The cervix became ripened (Bishop score e"5) in 92.1% of clients. There was no significant difference in cervical ripening effectiveness in the two groups (p=1.0000). The average time to onset of labour (latency interval) was 12.48+/-3.36 hours and was significantly shorter with the PGE2 group (p=0.0494). The mean induction to delivery interval for the women was 16.33+/-8.25hours. There was no significant difference between the two groups (p=0.7418). There were no differences between the two groups in mode of delivery, apgar sores and neonatal admission rate. CONCLUSIONS: PGE2 and Foley catheter balloon are equally effective as cervical ripening agents. PMID- 27492542 TI - The Secreted Protease PrtA Controls Cell Growth, Biofilm Formation and Pathogenicity in Xylella fastidiosa. AB - Pierce's disease (PD) is a deadly disease of grapevines caused by the Gram negative bacterium Xylella fastidiosa. Though disease symptoms were formerly attributed to bacteria blocking the plant xylem, this hypothesis is at best overly simplistic. Recently, we used a proteomic approach to characterize the secretome of X. fastidiosa, both in vitro and in planta, and identified LesA as one of the pathogenicity factors of X. fastidiosa in grapevines that leads to leaf scorching and chlorosis. Herein, we characterize another such factor encoded by PD0956, designated as an antivirulence secreted protease "PrtA" that displays a central role in controlling in vitro cell proliferation, length, motility, biofilm formation, and in planta virulence. The mutant in X. fastidiosa exhibited reduced cell length, hypermotility (and subsequent lack of biofilm formation) and hypervirulence in grapevines. These findings are supported by transcriptomic and proteomic analyses with corresponding plant infection data. Of particular interest, is the hypervirulent response in grapevines observed when X. fastidiosa is disrupted for production of PrtA, and that PD-model tobacco plants transformed to express PrtA exhibited decreased symptoms after infection by X. fastidiosa. PMID- 27492544 TI - Chlamydia Trachomatis Infection and Tubal Infertility in Port Harcourt, Southern,Nigeria. AB - BACKGROUND: Tubal occlusion remains one the commonest causes of infertility in our environment and previous pelvic infection have been implicated in the aetiology of the blockage Objective: To demonstrate prior chlamydia infection in women with tubal factor infertility and ascertain the relationship between chlamydia and tubal occlusion. METHODS: This was a case-control study consisting of 188 patients drawn from the University of Port Harcourt Teaching Hospital (UPTH) Port Harcourt, South-South Nigeria.The cases were 94 women with radiologically confirmed tubal occlusion and the controls were another 94 women with intrauterine pregnancy, all screened for the presence of chlamydia immunoglobin G antibody in the serum using Immunocomb Chlamydia Bivalent IgG kit, Orgenics, Israel.Their socio-demographic characteristics and the pattern of sexual behaviour were documented in the profoma provided. Statistical analysis was done using SPSS version 17 statistical software. RESULTS: The prevalence of Chlamydia antibodies was significantly higher in patients with tubal factor infertility (61.7%) than in the pregnant controls (34%) as p=0.001 and was associated with a three-fold risk of tubal factor infertility, with Odd's ratio (O.R) 3.12. CONCLUSION: There was a risk association between Chlamydia Trachomatis infection and tubal factor infertility. Early coitarche and previous pelvic inflammatory disease were other risk factors of Chlamydia trachomatis infection found to be positively associated with tubal factor infertility. PMID- 27492545 TI - Engaging Market Traders in Lassa Fever Campaign: Assessment of Knowledge and Risk Behaviour. AB - BACKGROUND: Markets provide a forum for reaching a large adult population with information on Lassa fever, and therefore understanding the food handling practices of traders may provide the foundation for an effective campaign against Lassa fever. This study was undertaken to provide baseline information on knowledge and food handling practices of traders in local markets in a Lassa fever endemic state of Nigeria. STUDY DESIGN: A structured questionnaire was used to obtain food handling habits that facilitate the transmission of Lassa virus from a cross sectional study involving 385 traders in three major markets in Edo state and data analyzed using SPSS version 15. RESULTS: Two hundred and ninety three (76.1%) had ever heard of Lassa fever, 27 (9.2%) had good knowledge. Good knowledge was significantly associated with higher educational status (p < 0.00) and male gender (p=0.03). Thirty seven (12.6%) respondents sun-dried their food frequently, 105 (35.8%) stored utensils in rodent proof containers, and 136 (46.4%) had the habit of eating garri soaked in water. One hundred and ninety (49.4%) respondents had food hygiene practices that were favorable for spread of Lassa fever. CONCLUSION: The observed gaps in knowledge of Lassa fever and food hygiene may be addressed through tailored health messages. In this way, market campaigns will be effective in increasing knowledge of Lassa fever, and traders can themselves become peer educators. PMID- 27492546 TI - Haemodynamic Changes during Awake Fibreoptic Bronchoscopy in Nigeria. AB - INTRODUCTION: There are no reports on haemodynamic changes on West African patients undergoing fibreoptic bronchoscopy (FOB). The aim of this study was to document these changes in West African patients undergoing awake FOB. MATERIALS AND METHODS: All consenting patients considered for awake FOB had their pulse rates, blood pressures and oxygen saturations documented at various phases of FOB, during procedures and up to 30 minutes after FOB to monitor any changes from pre-procedure levels. The values were analysed using SPSS version 16. RESULTS: One hundred and sixty FOB were performed on 145 patients. In non- sedated patients, the maximum oxygen saturation fall was 6% at the level of the vocal cord while the pulse rate rose as high as 13% at the carina. Bronchial washings exerted the most changes in sedated patients (SPO2 fell by 4.9%, and pulse rate rose by 11.9%). The mean arterial pressure increased occurred during bronchial washing for both groups (18.7% for non-sedated and 15.7% for sedated patients) CONCLUSION: Tachycardia, elevations in blood pressure and hypoxaemia are more pronounced and occur earlier during FOB in non-sedated patients. Traversing the vocal cords and bronchial washing evoke the most cardivascular changes during FOB. PMID- 27492547 TI - Knowledge of Secondary School Children in Edo State on Lassa Fever and its Implications for Prevention and Control. AB - BACKGROUND: Seasonal outbreaks of Lassa fever in West Africa cause significant morbidity and mortality across all ages. In addition to present efforts to raise awareness, school children can be targeted to become peer and family health educators. The study was carried out to determine the knowledge of Lassa fever among secondary school children, and household practices that increase risk of the infection. STUDY DESIGN: In a cross sectional survey, 561 secondary school students randomly selected from schools in Edo State were interviewed by means of a self - administered questionnaire that sought information on knowledge of Lassa fever and practices within the home that favour rodent contact . Data were analyzed using Statistical Package for Social Sciences version 15. RESULTS: Knowledge of Lassa fever was poor among 259 (49.4%) respondents, fair in 216 (41.2%) and good in 49 (9.4%). Female gender (< 0.01), monogamous family structure (p < 0.04) , and being in senior secondary class ( p=0.01) were predictors of high knowledge score. Self- reported Lassa fever risk conditions were found to be of low prevalence in 311(55.4%) and high in 250 (44.6%) homes, and associated with educational status of mother ( p=0.00) and father, (p =0.00). CONCLUSION: School children in endemic communities lack good knowledge of Lassa fever, but when properly guided, have the potential to become peer and family educators. PMID- 27492548 TI - Orbito-ocular tumors in Ibadan, South West Nigeria. AB - AIM: The aim of this study was to review the cases of orbito-ocular tumors in a single tertiary health facility, and determine changes in pattern of presentation. MATERIALS AND METHODS: Medical records of all patients with histologically confirmed orbito-ocular tumors between January 1992 and December 2011 in a tertiary center were reviewed. Patients' demographics, types of orbito ocular tumor and their presentation were recorded. RESULTS: Records of 205 patients were analyzed with a male to female ratio of 1.1:1 and median age of seven years. Retinoblastoma was the most common tumor followed by ocular surface squamous neoplasia. Squamous cell carcinoma was the most common eyelid tumor while rhabdomyosarcoma was the most common orbital tumor. No case of melanoma was seen during the period. More than two thirds of patients had lost vision at presentation due to delay in seeking appropriate medical attention Conclusion: There appears to be a reduction in the cases of orbito-ocular tumors in Ibadan, however, there is little variation in the pattern of presentation. Encouraging early presentation to the appropriate health facility may possibly reduce the morbidity in these patients. PMID- 27492549 TI - The Pattern of Uveitis In An African Tertiary Eye Care Centre. AB - OBJECTIVE: To determine the pattern of presentation of uveitis at the Guinness Eye Centre of the Lagos University Teaching Hospital, Lagos, Nigeria. MATERIALS AND METHODS: The case files of all patients with the diagnosis of uveitis who presented at the center from January 2006 to December 2010 were reviewed. Data on age, sex, ethnicity, symptoms, duration of symptoms before presentation, eye affected, anatomical type of uveitis and clinical type of uveitis were extracted onto a form for analysis. RESULTS: A total of 68 cases of uveitis were reviewed. There were 38(60.3%) males and 25 (39.7%) females. The range was from 12 to 90 years. The peak incidence occurred within the age range 21-40 years inclusive. Anterior uveitis and posterior uveitis occurred in 34(54.0%) and 17(27%) patients respectively. While reduction in vision was reported as a symptom by 54(85.7%) patients, only 41(65.1%) patients presented within 4 weeks of onset of symptoms. CONCLUSION: Anterior uveitis was the most common clinical type in this study. The highest incidence of uveitis occurred in the third and fourth decades of life. PMID- 27492550 TI - Visual acuity, safe/unsafe practices and self-reported road traffic crash experiences among commuter bus drivers from two motor parks in Lagos, Nigeria. AB - BACKGROUND: Road Traffic injuries remain a significant public health problem with serious health and economic implications. This study was conducted to determine visual acuity, safety practices and road traffic crash (RTC) experiences of commercial bus drivers in Lagos, Nigeria. METHODS: This cross-sectional study involved visual acuity screening and interviewer- administered questionnaire survey. Participating motor parks were selected by simple random sampling and all intercity, commercial minibus drivers were included. Data was analyzed with Epi info version 3.5.1. RESULTS: A total of 407 drivers participated with a mean age of 43.4 +/- 10.8 years. A total of 68 (16.7%) of the drivers did not meet the minimum VA standard required for driving; 8.6% of them use mobile phones while driving; 97% fasten their seatbelt, out of which almost 98% do so always. Fourteen percent also admitted eating while driving. Sixty two (15.2%) of drivers had been involved in RTC in the past 5 years prior to interview. CONCLUSION: A proportion of commercial minibus drivers did not meet the minimum VA required for driving. Some of them also practiced distracted driving. Free visual acuity screening within the motor park is recommended for commercial drivers at least once a year. There should be awareness campaigns to enlighten commercial drivers on the dangers of distracted driving in addition to strict enforcement of regulations and Highway Code. PMID- 27492551 TI - Acardius Acephalus in an Undiagnosed Twin Gestation; Case Report and review of Literature from Federal Medical Centre Gusau, Zamfara State, Northwestern Nigeria. AB - BACKGROUND: Acardiusacephalusfoetal anomaly is a rare abnormality occurring in multifoetal gestation particularly monozygous twin gestation. It is commonly characterized by varying gross structural malformations incompatible with extra uterine life. Reports on acardiusacephalusfoetal anomaly remain sparse. We report a case of acardiusacephalusin an undiagnosed twin with striking gross malformation delivered to a 28 year old un-booked multipara. Objective To report an acardiusacephalic anomaly in the second of an undiagnosed twin pregnancy delivered to a multipara and review relevant literature. METHOD: A Case was fully documentedat the Federal medical centre Gusau, Nigeria and local and international literature search conducted and reviewed. CONCLUSION: Acardiusacephalus may have additional malformations in the other organs. The current case, the first in our centre, shows yet other striking gross and severe malformations characterizing acardiusacephalus. PMID- 27492553 TI - Replication of alpha-amino acids via Strecker synthesis with amplification and multiplication of chiral intermediate aminonitriles. AB - Replication of chiral l- and d-alpha-(p-tolyl)glycine has been achieved in combination with the asymmetric induction, amplification and multiplication of their own chiral intermediates, l- and d-aminonitriles, in the solid-phase via the Strecker reaction between three achiral components, which is a plausible prebiotic mechanism for amino acid synthesis. PMID- 27492552 TI - The burden of maternal morbidity and mortality attributable to hypertensive disorders in pregnancy: a prospective cohort study from Uganda. AB - BACKGROUND: Hypertensive disorders of pregnancy are a major cause of morbidity and mortality. The objective was to estimate the disease burden attributable to hypertensive disorders of pregnancy in two referral hospitals in Uganda. METHODS: Through a prospective cohort study conducted in Jinja and Mulago hospitals in Uganda from March 1, 2013 and February 28, 2014, hypertension-related cases were analyzed. Maternal near miss cases were defined according to the WHO criteria. Maternal deaths were also analyzed. The maternal near miss incidence ratio, the case-specific severe maternal outcome ratio, the case-specific maternal mortality ratio and the case-fatality ratio were computed. RESULTS: Of 403 women with hypertensive disorders of pregnancy, 218 (54.1 %) had severe preeclampsia, 172 (42.7 %) had eclampsia, and 13 had chronic hypertension or Hemolysis, elevated liver enzymes or low platelets (HELLP) syndrome. The case-specific maternal near miss incidence ratios was 8.60 per 1,000 live births for all hypertensive disorders, 3.06 per 1,000 live births for severe preeclampsia and 5.11 per 1,000 live births for eclampsia. The case-specific severe maternal outcome ratio was 9.37 per 1,000 live births for all hypertensive disorders, and was 3.25 per 1,000 live births for severe preeclampsia and 5.61 per 1,000 live births for eclampsia. The case-specific maternal mortality ratio was 780 per 100,000 live births for all hypertensive disorders, and was 1940 per 100,000 live births for severe preeclampsia and 501 per 100,000 live births for eclampsia. The case-fatality ratio was 5.1 % overall (for all hypertensive disorders), but was 8 times higher for eclampsia compared to severe preeclampsia. Cyanosis, abnormal respiration, oliguria, circulatory collapse, coagulopathy, thrombocytopenia, and elevated serum lactate were significantly associated with severe maternal outcomes. CONCLUSION: There is high morbidity attributable to hypertensive disorders in pregnancy. Since some of the complications associated with morbidity can be recognized early, it is possible to prevent severe morbidity through early intervention with delivery, antihypertensive therapy and prophylactic magnesium sulphate treatment. The findings highlight the feasibility of implementing a facility-based surveillance system for severe maternal morbidity due to hypertensive disorders. PMID- 27492554 TI - Icariine Restores LPS-Induced Bone Loss by Downregulating miR-34c Level. AB - Bacteria-induced inflammatory responses cause excessive bone resorption in chronic inflammatory diseases such as septic arthritis, osteomyelitis, and orthopedic implant failure. Icariine has been reported to facilitate the bone healing and reduce the occurrence of osteoporosis in clinical, moreover, laboratory studies which have proved that Icariine promotes the proliferation and differentiation of osteoblasts in vitro. The present study aimed to evaluate the effects of Icariine on lipopolysaccharide (LPS)-induced bone loss via an osteogenic-in vitro model and to elucidate the underlying molecular mechanisms. Here, we showed that Icariine restored LPS-induced bone loss in a dose-dependent manner without any cytotoxicity even at 100 MUM in an osteogenic-in vitro model. Interestingly, Icariine restored the protein expression of Runx2, a key transcription factor for osteogenesis, but had no effect on its mRNA expression level. MiRNA-34c was dramatically upregulated after LPS stimulation; however, Icariine preincubation reversed miRNA-34c level. Western blot analysis showed that overexpression of miR-34c markedly inhibited the expression of osteogenic gene makers such as alkaline phosphatase (ALP), Runx2, OPN, and BMP2. ALP activity analysis and Alizarin Red S staining exhibited that both Icariine induced osteogenic differentiation and mineral nodule formation were significantly inverted by overexpression of miR-34c. Western blot results also showed that Icariine notably inhibited LPS-induced phosphorylation of JNKs, p38, IkBalpha, IKKbeta, and p65. Taken together, our studies suggested that Icariine restored LPS-induced bone loss by downregulating miR-34c level and suppressing JNKs, p38, and NF-kB pathways, which highlighted the potential use of Icariine as a therapeutic agent in the treatment of bacteria-induced bone loss diseases. PMID- 27492555 TI - Dual-time-point 18F-FDG PET/CT in the diagnosis of solitary pulmonary lesions in a region with endemic granulomatous diseases. AB - OBJECTIVE: Granulomatous diseases (GDs) can be metabolically active and indistinguishable from lung cancer on 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging. Evaluation of solitary pulmonary lesions remains a diagnostic challenge in regions with endemic GD. This study sought to determine the efficacy of dual-time-point (DTP) 18F-FDG PET/computed tomography (CT) imaging in diagnosing solitary pulmonary lesions from such regions. METHODS: A total of 50 patients with solitary pulmonary nodules or masses with confirmed histopathological diagnoses underwent DTP 18F-FDG PET/CT imaging at 1 and 3 h after tracer injection. The maximum standardized uptake value (SUVmax) on early and delayed scans (SUV1h and SUV3h, respectively) and retention index (RI) were calculated for each pulmonary lesion. Receiver operating characteristic analysis was performed to evaluate the discriminating validity of the parameters. RESULTS: There were 37 malignant and 13 benign solitary pulmonary lesions. Eight of the 13 (62 %) benign lesions were GDs. The sensitivity/specificity/accuracy of SUV1h, SUV3h and RI were 84/69/80 %, 84/85/84 %, and 81/54/74 %, respectively. SUV3h had the best diagnostic performance, especially regarding specificity. The values of SUV1h and SUV3h were significantly different between malignant lesions and GD, while the RI values of malignant lesions and GD were both high (18.6 +/- 19.5 and 18.7 +/- 15.3 %, respectively; P = not significant). CONCLUSION: SUV3h appeared to improve the diagnostic specificity of 18F-FDG PET/CT in evaluating solitary pulmonary lesions from regions with endemic GD. PMID- 27492556 TI - Extraction and derivatization of Leucaena leucocephala (Lam.) galactomannan: Optimization and characterization. AB - Water soluble gums also known as hydrocolloids are increasingly finding applications in the pharmaceutical and food industry due to their versatile functional properties. They possess considerable use in food and pharmaceutical industries as emulsifying, thickening and gelling agents. In the present investigation a heteropolysaccharide galactomannan was extracted from Leucaena leucocephala (Lam.) seeds by an aqueous method, characterized for its compositional analysis (mannose: galactose ratio), physicochemical and functional properties (solubility), and mechanical properties. The extracted gum was derivatized to form its carboxymethyl derivative and the method of its derivatization was optimized by varying the reaction parameters. The native and derivatized gum was characterized by FTIR, XRD, DSC, NMR, SEM and elemental analysis, etc. The yield of Leucaena leucocephala galactomannan (LLG) was found to be 20% (w/w). The optimized parameters for carboxymethylation reaction (degree of substitution 0.805) were found to be 6.0g NaOH, 10.0g MCA, at 60 degrees C for 4h. The physicochemical and functional characteristics of native and derivatized gum suggest its potential role in food and pharmaceutical industries. PMID- 27492557 TI - Preparation of pectin/silver nanoparticles composite films with UV-light barrier and properties. AB - Silver nanoparticles (AgNPs) was synthesized by a green method using an aqueous extract of Caesalpinia mimosoides Lamk (CMLE) as reducing and stabilizing agents, and they were used for the preparation of pectin-based antimicrobial composite films. The AgNPs were spherical in shape with the size in the range of 20-80nm and showed the absorption peak around 500nm. The pectin/AgNPs composite film exhibited characteristic absorption peak of AgNPs at 480nm. The surface color and light transmittance of the pectin films were greatly influenced by the addition of AgNPs. The lightness of the films decreased, however, redness and yellowness of the films increased after incorporation of AgNPs. UV-light barrier property of the pectin film increased significantly with a little decrease in the transparency. Though there were no structural changes in the pectin film by the incorporation of CMLE and AgNPs as indicated by the FTIR results, the film properties such as thermal stability, mechanical strength, and water vapor barrier properties of the pectin films increased. The pectin/AgNPs nanocomposite films exhibited strong antibacterial activity against food-borne pathogenic bacteria, Escherichia coli and Listeria monocytogenes. PMID- 27492558 TI - Kinetic and thermodynamic evaluation of adsorption of Cu(II) by thiosemicarbazide chitosan. AB - A modified biomacromolecule, chitosan-thiosemicarbazide framework (TSCS) as an adsorbent for Cu(II) was prepared from dialdehyde chitosan through condensation reaction with thiosemicarbazide, stabilized by the reduction reaction with sodium borohydride. TSCS was characterized by means of FT-IR and XPS. Surface morphologies were studied by FESEM and BET, which revealed the highly macro porous structure. The thermal analyses was done through TGA showing much stable chemical configuration at about >=400 degrees C. The experimental equilibrium data was evaluated by Langmuir, Freundlich and Dubinin-Radushkevich isotherm models. The Langmuir adsorption model was best fitted with experimental value, suggests the existence of monolayer coverage of adsorbed molecules with a maxima of 142.85mgg-1. The kinetic data was analyzed using pseudo-first-order, pseudo second-order and intraparticle diffusion models and the pseudo-second-order kinetics were found for all the concentrations. The calculated thermodynamic parameters such as DeltaGo, DeltaH and DeltaS were -2.33kJmol-1, 570.40Jmol-1 and 9.75Jmol-1K-1 respectively signifies the adsorption of Cu(II) onto TSCS is endothermic, spontaneous and a process of physisorption. The regeneration efficiency of the TSCS as an adsorbent was found to be >=90-95% using 0.1M EDTA. PMID- 27492559 TI - Application of Chitosan/PVA Nano fiber as a potential wound dressing for streptozotocin-induced diabetic rats. AB - Diabetes mellitus is a worldwide health problem affecting 1-2% of the population of world with noticeable morbidity and mortality. Vascular events such as hypertension, nephropathy, neuropathy and retinopathy are happened in diabetic patients. Decline in tissue blood circulation may causes hypoxia and finally may leads to slow wound healing and amputation. PVA/Chitosan Nano fiber wound dressings have high moisture vapor transmission rate and good antimicrobial activity1 PCNWD substrate does not have any recognized cytotoxicity effects and has excellent odor absorbing capability. In the present study, Streptozotocin (STZ) is used to induce diabetes in rats, Skin ulcers are produced experimentally in the experimentally induced diabetic and non-diabetic rats. Then PCNWD used as wound dressing for 2 weeks period to evaluate its macroscopic and microscopic effects on wound healing in comparison with untreated diabetic and non-diabetic rats experimental ulcers. The findings of current study indicate significant acceleration in diabetes wound healing on the rats treated by PVA/Chitosan Nano fiber. PMID- 27492561 TI - Evaluation of enzyme treatment conditions on extraction of anthocyanins from Prunus nepalensis L. AB - The study was designed to investigate the effect of enzyme assisted extraction of anthocyanins from Sohiong fruit (Prunus nepalensis) under varied time, temperature and treatment conditions. Highest anthocyanins yield was obtained by coupling enzymatic treatment along with solvent extraction simultaneously. Additionally, effect of enzyme type, enzyme concentration, reaction time and temperature were evaluated subsequently in following experiments. Cellulase treatment (10% E/S) for 180min at 4 degrees C exhibited highest yield of 984.40+/ 3.84mg C3G/100gdm which accounts to 14.61% higher yield when compared to conventional method (858.84+/-6.88mg C3G/100gdm). The study provides an economical alternative for commercial extraction of anthocyanins from Sohiong fruit which can be used as a colourant for various food and other products and owing to its antioxidizing properties can be effective for the prevention and treatment of diseases. PMID- 27492560 TI - KGM-based magnetic carbon aerogels matrix for the uptake of methylene blue and methyl orange. AB - In this study, the preparation of magnetic Fe and Mn oxides (Mag-FMBO) loaded carbon aerogels (CA) based on konjac glucomannan (KGM) and their performance for dyes adsorption were investigated. The prepared magnetic carbon aerogels (Mag-CA) materials were characterized by various methods, including BET surface area analysis, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and vibrating sample magnetometer (VSM). What's more, the Mag-CA materials were used as adsorbents to remove dyes [anionic methyl orange (MO) and cationic methylene blue (MB)] from aqueous solutions. The results showed that Mag-CA had an excellent adsorption performance towards MO and MB. The adsorption equilibrium data of both MO and MB can be well described by Langmuir model. The maximum MO and MB uptake capacity of Mag-CA reached 7.42mgg-1 and 9.37mgg-1 according to Langmuir isotherm at 303K, respectively. Thermodynamic parameters such as DeltaG, DeltaH and DeltaS were estimated to understand the adsorption mechanism of MO and MB. The adsorption processes of MO and MB could be well described by the pseudo second-order model. Moreover, Mag-CA with dyes (MO or MB) were successfully regenerated by ethanol and then easily separated from aqueous solution by applying magnetic field. PMID- 27492562 TI - Elucidating the impact of glucosylation on human serum albumin: A multi-technique approach. AB - Early glycation products as well as advance glycation end products are involved in pathogenesis of diabetes. Most of studies carried out on AGEs and their possible role in assessing diabetes complications, whereas only a few were focused to highlight the role of Amadori products. In this study, an attempt has been made to investigate a structural and immunological characterizations of Amadori-albumin upon early glucosylation because albumin undergoes fast glycation under hyperglycaemic condition. Amadori-albumin formation was determined by NBT assay and Amadori adducts in glycated samples were confirmed by LC-MS. Structural alterations in Amadori-albumin were characterized by loss in fluorescence intensity, loss in secondary and tertiary structures, exposure of hydrophobic patches, shifting in Amide bands and increment in hydrodynamic radius. Further, presence to autoantibodies against Amadori-albumin in diabetes patients were confirmed by direct binding ELISA and inhibition ELISA. Immunological studies results showed that autoantibodies present in diabetic patients with and without chronic kidney disease (CKD) showed significant binding with Amadori-albumin in comparison to the native protein. Anti Amadori-albumin antibodies predominantly present in CKD patients compare to without CKD patients. Band shift assay results showed true interaction between Amadori-albumin and autoantibodies present in CKD patients. Glucosylation results showed structural alterations in Amadori-albumin and hence generation of neo-epitopes in HSA molecule. Such modifications rendering the protein highly immunogenic that may be recognized as foreign molecule by immune cells and induced autoantibodies in diabetic patients. These finding signify the role of Amadori-albumin in kidney dysfunction in diabetes and raised level of autoantibodies may be used as biomarker for progression of CKD. PMID- 27492563 TI - Molecular characterization of Wolbachia infection in bed bugs (Cimex lectularius) collected from several localities in France. AB - Wolbachia symbionts are maternally inherited intracellular bacteria that have been detected in numerous insects including bed bugs. The objective of this study, the first epidemiological study in Europe, was to screen Wolbachia infection among Cimex lectularius collected in the field, using PCR targeting the surface protein gene (wsp), and to compare obtained Wolbachia strains with those reported from laboratory colonies of C. lectularius as well as other Wolbachia groups. For this purpose, 284 bed bug specimens were caught and studied from eight different regions of France including the suburbs of Paris, Bouches-du Rhone, Lot-et-Garonne, and five localities in Alpes-Maritimes. Among the samples, 166 were adults and the remaining 118 were considered nymphs. In all, 47 out of 118 nymphs (40%) and 61 out of 166 adults (37%) were found positive on wsp screening. Among the positive cases, 10 samples were selected randomly for sequencing. The sequences had 100% homology with wsp sequences belonging to the F supergroup strains of Wolbachia. Therefore, we confirm the similarity of Wolbachia strains detected in this epidemiological study to Wolbachia spp. reported from laboratory colonies of C. lectularius. PMID- 27492565 TI - AAOM Clinical Practice Statement: Subject: Oral lichen planus and oral cancer. PMID- 27492566 TI - Tooth autotransplantation in the anterior maxilla and mandible: retrospective results in young patients. AB - OBJECTIVE: This retrospective study evaluated survival rates, prognosis, and overall success of autotransplanted teeth in young patients missing anterior teeth as a result of trauma, agenesis, or developmental disturbances. STUDY DESIGN: Retrospective data were collected from the medical records of patients who had undergone tooth autotransplantations to anterior sites between January 2001 and December 2012. Clinical variables, such as gender, age, surgical indications, donor and recipient sites, type of anesthetics, bone augmentation, and complications during follow-up, were assessed. RESULTS: A total of 59 donor teeth in 46 patients (30 boys and 16 girls; average age 12.15 years) were autotransplanted to the anterior region of the maxilla and mandible. After a mean follow-up period of 17.35 months (range 10-61 months), all of the transplanted teeth remained in situ with no complications. CONCLUSIONS: This study supports the autotransplantation of teeth to the anterior alveolus as a viable option suitable in growing patients with missing anterior teeth. PMID- 27492564 TI - Prevalence of malaria, prevention measures, and main clinical features in febrile children admitted to the Franceville Regional Hospital, Gabon. AB - Recently, major progress has been made in controlling malaria in Africa. However, in Gabon, little information is available on the role of malaria in childhood febrile syndromes, the use and efficacy of preventive measures, and Plasmodium species distribution. Here, we characterized malaria in febrile children in Franceville, Gabon through a cross-sectional study at the pediatric unit of the Franceville Regional Hospital. We registered 940 febrile children. Their general condition was markedly altered in 11.7% of cases (n = 89/760); among them 19 (21.4%) had a severely altered condition. Malaria was the second most frequent etiology (22.0%; n = 162/738), after respiratory tract infections (37.3%; n = 275/738). Children with malaria (63 +/- 39 months) were older than children without malaria (40 +/- 37 months) (p = 0.0013). Hemoglobin, red blood cell, white blood cell, and platelet values were lower in children with malaria than in those without malaria (p < 0.0001). Anemia was the most common feature of severe malaria (70.6%; n = 12/17), followed by neurological involvement (23.5%; n = 4/17). The prevalence of malaria was significantly higher in children older than 60 months than in younger children (40% vs. 15.5%; p < 0.0001). Plasmodium falciparum accounted for 97.5% of cases (158/162), followed by Plasmodium malariae (2.5%; n = 4/162). Bed net use was high (74.4%; n = 697/936) and contributed to malaria prevention (p = 0.001). Good basic knowledge of malaria also had a preventive effect (p < 0.0001). The prevalence of malaria in children in Franceville did not decrease significantly from 2009 to 2012, remaining at about 20%, highlighting that preventive measures should be reinforced. PMID- 27492567 TI - Comparison of functional change in parotid gland after surgical excision of pleomorphic adenoma by two different types of parotidectomy. AB - OBJECTIVE: To compare the functional changes in parotid gland after surgical excision of pleomorphic adenoma by partial superficial parotidectomy (PSP), or conventional superficial parotidectomy (CSP). STUDY DESIGN: A prospective study including 117 patients undergoing CSP or PSP was performed. The uptake rate (UR) and excretion fraction (EF) of the parotid gland were measured by salivary gland scintigraphy before the surgery, as well as at months 3, 6, and 12 after the surgery; DeltaUR and DeltaEF, defined as the UR and EF differences between the contralateral side and the operated side, were also calculated. RESULTS: Either UR or EF of the operated side was lower than that in the contralateral side after surgery (P < .05). DeltaEF and DeltaUR values at months 6 and 12 were significantly smaller in the PSP group than those in the CSP group. CONCLUSIONS: PSP is preferable for preservation of the functions of the parotid gland. PMID- 27492568 TI - A versatile modular bioreactor platform for Tissue Engineering. AB - Tissue Engineering (TE) bears potential to overcome the persistent shortage of donor organs in transplantation medicine. Additionally, TE products are applied as human test systems in pharmaceutical research to close the gap between animal testing and the administration of drugs to human subjects in clinical trials. However, generating a tissue requires complex culture conditions provided by bioreactors. Currently, the translation of TE technologies into clinical and industrial applications is limited due to a wide range of different tissue specific, non-disposable bioreactor systems. To ensure a high level of standardization, a suitable cost-effectiveness, and a safe graft production, a generic modular bioreactor platform was developed. Functional modules provide robust control of culture processes, e.g. medium transport, gas exchange, heating, or trapping of floating air bubbles. Characterization revealed improved performance of the modules in comparison to traditional cell culture equipment such as incubators, or peristaltic pumps. By combining the modules, a broad range of culture conditions can be achieved. The novel bioreactor platform allows using disposable components and facilitates tissue culture in closed fluidic systems. By sustaining native carotid arteries, engineering a blood vessel, and generating intestinal tissue models according to a previously published protocol the feasibility and performance of the bioreactor platform was demonstrated. PMID- 27492569 TI - Predicting malignant neck lymphadenopathy using color duplex sonography based on multivariate analysis. AB - PURPOSE: To select the best predictors of cervical lymph node malignancy based on gray-scale and power Doppler sonography using multivariate analysis. METHODS: We evaluated sonographically a total of 97 lymph nodes in the neck that were subjected to fine-needle aspiration biopsy. The gray-scale and power Doppler sonography parameters that we analyzed using multivariate logistic regression included size, shape, echogenicity, echotexture, margins, hilum, presence of microcalcifications or necrosis, vascularization, and resistance index (RI). RESULTS: The three variables with a diagnostic accuracy exceeding 80% were an altered vascularization, heterogeneous echotexture, and abnormal hilum. Malignant nodes exhibited higher RI and larger sizes than benign nodes, and the best cutoff values to distinguish malignant from benign lymph nodes were an RI of 0.77 and a short axis >= 0.9 cm. Altered vascularization, a short axis >= 0.9 cm, and abnormal hilum were the best predictors of malignancy. CONCLUSIONS: The best sonographic predictors of lymph node malignancy are, in descending order, an altered vascularization, a short axis >= 0.9 cm, an abnormal hilum, and a heterogeneous echotexture. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:587-594, 2016. PMID- 27492570 TI - Clinical Interpretation of Variants from Next-Generation Sequencing: The 2016 Scientific Meeting of the Human Genome Variation Society. AB - The 2016 scientific meeting of the Human Genome Variation Society (HGVS; http://www.hgvs.org) was held on the 20th of May in Barcelona, Spain, with the theme of "Clinical Interpretation of Variants from Next-Generation Sequencing." PMID- 27492571 TI - Early U.S. Experience Following FDA Approval of the ABBOTT Vascular Bioresorbable Vascular Scaffold: Optimal Deployment Technique Using High Resolution Coronary Artery Imaging. AB - Drug eluting metallic stents have been the "gold standard" in the percutaneous management of coronary artery disease. Recent publications have suggested that the ABSORBTM bioresorbable vascular scaffold (BVS) may represent a reasonable alternative, in well selected cases. PMID- 27492572 TI - Developing Valid Measures of Emergency Management Capabilities within US Department of Veterans Affairs Hospitals. AB - Introduction Hospitals play a critical role in providing health care in the aftermath of disasters and emergencies. Nonetheless, while multiple tools exist to assess hospital disaster preparedness, existing instruments have not been tested adequately for validity. Hypothesis/Problem This study reports on the development of a preparedness assessment tool for hospitals that are part of the US Department of Veterans Affairs (VA; Washington, DC USA). METHODS: The authors evaluated hospital preparedness in six "Mission Areas" (MAs: Program Management; Incident Management; Safety and Security; Resiliency and Continuity; Medical Surge; and Support to External Requirements), each composed of various observable hospital preparedness capabilities, among 140 VA Medical Centers (VAMCs). This paper reports on two successive assessments (Phase I and Phase II) to assess the MAs' construct validity, or the degree to which component capabilities relate to one another to represent the associated domain successfully. This report describes a two-stage confirmatory factor analysis (CFA) of candidate items for a comprehensive survey implemented to assess emergency preparedness in a hospital setting. RESULTS: The individual CFAs by MA received acceptable fit statistics with some exceptions. Some individual items did not have adequate factor loadings within their hypothesized factor (or MA) and were dropped from the analyses in order to obtain acceptable fit statistics. The Phase II modified tool was better able to assess the pre-determined MAs. For each MA, except for Resiliency and Continuity (MA 4), the CFA confirmed one latent variable. In Phase I, two sub scales (seven and nine items in each respective sub-scale) and in Phase II, three sub-scales (eight, four, and eight items in each respective sub-scale) were confirmed for MA 4. The MA 4 capabilities comprise multiple sub-domains, and future assessment protocols should consider re-classifying MA 4 into three distinct MAs. CONCLUSION: The assessments provide a comprehensive and consistent, but flexible, approach for ascertaining health system preparedness. This approach can provide an organization with a clear understanding of areas for improvement and could be adapted into a standard for hospital readiness. Dobalian A , Stein JA , Radcliff TA , Riopelle D , Brewster P , Hagigi F , Der-Martirosian C . Developing valid measures of emergency management capabilities within US Department of Veterans Affairs hospitals. Prehosp Disaster Med. 2016;31(5):475 484. PMID- 27492573 TI - Decreased snake venom metalloproteinase effects via inhibition of enzyme and modification of fibrinogen. AB - Since the introduction of antivenom administration 120 years ago to treat venomous snake bit, it has been the gold standard for saving life and limb. However, this therapeutic approach is not always effective and not without potential life-threatening side effects. We tested a new paradigm to abrogate the plasmatic anticoagulant effects of fibrinogenolytic snake venom metalloproteinases by modification of fibrinogen with iron and carbon monoxide and by inhibiting these Zn(2+) dependent metalloproteinases directly with carbon monoxide exposure. Assessment of the fibrinogenolytic effects of venoms collected from Puff adder, Gaboon viper and Indian cobra snakes on plasmatic coagulation kinetics was performed with thrombelastography. Pretreatment of plasma with iron and carbon monoxide exposure markedly attenuated the effects of all three venoms, and direct pretreatment of each venom with carbon monoxide also significantly decreased the ability to compromise coagulation. These results demonstrated that the introduction of a transition metal (e.g., modulation of the alpha-chain of fibrinogen with iron), modulation of transition metal in heme (e.g., carbon monoxide modulation of fibrinogen-bound heme iron), and direct inhibition of transition metal containing venom enzymes (e.g., CO binding to Zn(2+) or displacing Zn(2+) from the catalytic site) significantly decreased fibrinogenolytic activity. This biometal modulation strategy to attenuate the anticoagulant effects of snake venom metalloproteinases could potentially diminish hemostatic injury in envenomed patients until antivenom can be administered. PMID- 27492574 TI - Sweet Taste Perception is Associated with Body Mass Index at the Phenotypic and Genotypic Level. AB - Investigations on the relationship between sweet taste perception and body mass index (BMI) have been inconclusive. Here, we report a longitudinal analysis using a genetically informative sample of 1,576 adolescent Australian twins to explore the relationship between BMI and sweet taste. First, we estimated the phenotypic correlations between perception scores for four different sweet compounds (glucose, fructose, neohesperidine dihydrochalcone (NHDC), and aspartame) and BMI. Then, we computed the association between adolescent taste perception and BMI in early adulthood (reported 9 years later). Finally, we used twin modeling and polygenic risk prediction analysis to investigate the genetic overlap between BMI and sweet taste perception. Our findings revealed that BMI in early adulthood was significantly associated with each of the sweet perception scores, with the strongest correlation observed in aspartame with r = 0.09 (p = .007). However, only limited evidence of association was observed between sweet taste perception and BMI that was measured at the same time (in adolescence), with the strongest evidence of association observed for glucose with a correlation coefficient of r = 0.06 (p = .029) and for aspartame with r = 0.06 (p = .035). We found a significant (p < .05) genetic correlation between glucose and NHDC perception and BMI. Our analyses suggest that sweet taste perception in adolescence can be a potential indicator of BMI in early adulthood. This association is further supported by evidence of genetic overlap between the traits, suggesting that some BMI genes may be acting through biological pathways of taste perception. PMID- 27492575 TI - Place-making with older persons: Establishing sense-of-place through participatory community mapping workshops. AB - Principles of aging-in-place emphasize the importance of creating sustainable environments that enable older people to maintain a sense of belonging, autonomy, independence, safety and security. Simply altering the built environment is insufficient for creating more inclusive environments for older persons, as creating 'meaningful' places for aging involves consideration of psychosocial and cultural issues that go beyond issues of physical space. This paper illustrates how applications of community-based participatory research methods, in particular, participatory community mapping workshops (PCMWs), can be used to access experiences of place, identify facilitators and barriers to accessing the built environment and co-create place-based solutions among older people and service providers in a new affordable housing development in Western Canada. Founded on tenets of empowerment and relationship building, four PCMWs were undertaken with 54 participants (N = 38 older people; N = 16 local service providers). PCMWs comprised (i) experiential group walks around the community to access understandings of place and community and (ii) mapping exercises, whereby participants articulated their place-based needs within the context of the new affordable housing development and surrounding neighbourhood. Dialogues were digitally recorded, transcribed and thematically analysed. Visual data, including photographs taken during experiential group walks were categorized and integrated into the narrative to illustrate place meanings. PCMWs enabled senior housing and social care professionals and decision-makers to co-construct knowledge with older tenants that facilitated place action and change. Key themes identified by participants included: identifying services and needs for health and wellbeing, having opportunities for social participation and overcoming cross-cultural challenges. PCMWs were found to be a nuanced method of identifying needs and resources and generating knowledge. PMID- 27492576 TI - Advancing the evidentiary base for tobacco warning labels: A commentary. PMID- 27492577 TI - Rapid and accurate identification of Xanthomonas citri subspecies citri by fluorescence in situ hybridization. AB - : Citrus canker is an economically important disease caused by the bacterial pathogen Xanthomonas citri subsp. citri (Xcc). This organism targets a wide range of citrus plants, including sweet orange, grapefruit, lemon and lime. As Xcc is spread by environmental factors such as wind and rain, it is difficult to control its movement once the disease has established. In order to facilitate monitoring of citrus canker we sought to design a novel diagnostic protocol based on fluorescence in situ hybridization (FISH) for identification of bacterial cells directly from canker pustules without cultivation or DNA extraction. This method was validated for specificity against a range of Xanthomonas species and strains. We show that our assay is extremely rapid (typically requiring between 2 and 3 h), and possesses a similar specificity to existing PCR diagnostic tools. The sensitivity of the assay is comparable to that of an existing PCR-based technique and sufficient for identifying Xcc in symptomatic plant material. The method is easily transferable to diagnosticians without prior experience using FISH. SIGNIFICANCE AND IMPACT OF THE STUDY: Xanthomonas citri subsp. citri (Xcc) is an aggressive and hardy pathogen of citrus plants worldwide. Outbreaks are difficult and costly to contain and the establishment of citrus canker results in restricted trade. In order to extend the existing toolkit for identification of Xcc we developed a novel diagnostic approach based on fluorescence in situ hybridization. Our approach is of comparable specificity and sensitivity to existing methods but can be performed directly on infected tissue making it significantly faster than existing PCRs, and requiring fewer laboratory resources. PMID- 27492578 TI - O6-Methylguanine-DNA methyltransferase (MGMT): A drugable target in lung cancer? AB - This manuscript addresses the role of O6-methylguanine-DNA methyltransferase (MGMT) as a biomarker in the oncogenesis of cancer and the opportunity of turning this gene into a drugable target in neuroendocrine tumours of the lung. Studies in brain tumours conclude that MGMT promoter methylation is considered a strong predictive factor for a favourable outcome for treatment with temozolomide, e.g. alkylating agent. We conducted a systematic review of MGMT in non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC) and other pulmonary neuroendocrine tumours (NETs) to evaluate whether MGMT is a prognostic and/or predictive factor to select patients with lung cancer who can benefit from treatment with temozolomide. In NSCLC MGMT promoter methylation is not a prognostic and predictive factor, hence temozolomide has no place. In SCLC and NET patients with a MGMT promoter methylation benefit of temozolomide has to be confirmed.Temozolomide can be considered a 'personalized' treatment if the predictive role of MGMT is further confirmed. PMID- 27492579 TI - Serum and xeno-free, chemically defined, no-plate-coating-based culture system for mesenchymal stromal cells from the umbilical cord. AB - OBJECTIVES: Umbilical cord mesenchymal stromal cells (UCMSCs) can be considered to become a new gold standard for MSC-based therapies. A serum and xeno-free, chemically defined and no-plate-coating-based culture system will greatly facilitate development of robust, clinically acceptable bioprocesses for reproducibly generating quality-assured UCMSCs. MATERIALS AND METHODS: In this study, we report for the first time, such a serum-free, xeno-free, completely chemically defined and no-plate-coating-based culture system for the isolation and expansion of UCMSCs, whose biological characteristics were evaluated and compared with serum-containing medium (SCM) methods. RESULTS: This culture system not only supported UCMSC primary cultures but also allowed for their expansion at low seeding density. Compared to SCM, UCMSCs in SFM exhibited (i) higher proliferative and colony-forming capacities; (ii) distinctly different morphologies; (iii) similar phenotype; (iv) similar pluripotency-associated marker expression; (v) superior osteogenic, but reduced adipogenic differentiation capacitities. In addition, UCMSCs cultured in SFM retained similar immunomodulatory properties to those in SCM. CONCLUSIONS: Our findings demonstrate the feasibility of isolating and expanding UCMSCs in a completely serum-free, xeno-free, chemically defined and no-plate-coating-based culture system and represent an important step forward for development of robust, clinically acceptable bioprocesses for UCMSCs. Further, this provides a superior study platform for UCMSCs biology in a controlled environment. PMID- 27492580 TI - Iridoids and phenylethanoid glycosides from the aerial parts of Ajuga tenorei, an endemic Italian species. AB - We report the first analysis in absolute, and in particular, concerning the phytochemical pattern, about an endemic Italian species, Ajuga tenorei C. Presl. The analysis, performed by means of techniques such as Column Chromatography and NMR spectroscopy and Mass spectrometry, led to the isolation and the identification of five compounds namely verbascoside (1), echinacoside (2), ajugoside (3), harpagide (4) and 8-O-acetylharpagide (5). The presence of these compounds is important from both chemotaxonomic and ethno-pharmacological point of view. For what concerns the first point is confirmed the correct botanical classification of the species. The isolated compounds are also known to exert peculiar pharmacological activities and their presence may give a rationale to the historical medicinal properties associated to the Ajuga genus in general, since these plants have a long traditional use in many parts of the world. Such fact might suggest the use of also this species in this sense. PMID- 27492581 TI - A distinct sortase SrtB anchors and processes a streptococcal adhesin AbpA with a novel structural property. AB - Surface display of proteins by sortases in Gram-positive bacteria is crucial for bacterial fitness and virulence. We found a unique gene locus encoding an amylase binding adhesin AbpA and a sortase B in oral streptococci. AbpA possesses a new distinct C-terminal cell wall sorting signal. We demonstrated that this C terminal motif is required for anchoring AbpA to cell wall. In vitro and in vivo studies revealed that SrtB has dual functions, anchoring AbpA to the cell wall and processing AbpA into a ladder profile. Solution structure of AbpA determined by NMR reveals a novel structure comprising a small globular alpha/beta domain and an extended coiled-coil heliacal domain. Structural and biochemical studies identified key residues that are crucial for amylase binding. Taken together, our studies document a unique sortase/adhesion substrate system in streptococci adapted to the oral environment rich in salivary amylase. PMID- 27492582 TI - The primary factor for suture configuration at rotator cuff repair: Width of mattress or distance from tear edge. AB - OBJECTIVES: The aims of this study was first to investigate whether the bite size or the bite distance from the tear edge is of primary importance in mattress suture configuration for rotator cuff repair. Secondly, whether the use of a 450 left side bent Arthro-PierceTM (Smith & Nephew, Andover, USA) during suture passage can be more effective on the strength of the configuration compared to a straight Arthro-PierceTM. MATERIALS AND METHODS: Twenty-eight bovine infraspinatus muscle tendons were randomized into four groups. Group 1; 5 mm wide 'bite size' * 15 mm length 'distance from the tear edge's mattress'; Group 2: 7.5 mm * 10 mm; Group 3: 15 mm * 5 mm 'using straight Arthro-PierceTM' and Group 4: 5 mm * 15 mm using left sided 450 bent Arthro-PierceTM. The repair specimens underwent cyclic loading prior to loading the failure testing. Cyclic elongation (mm), peak-to-peak displacement (mm), ultimate load (N), stiffness (N/mm) and failure mode were recorded for each specimen. RESULTS: The mean ultimate load in Group 1 was higher compared to group 3. The peak to peak displacement was higher in Group 4 compared to Group 1 (p < 0.05). The predominant failure mode in Groups 1, 2 and 4 was suture rupture. The Group 3 most specimens failed due to suture cut through the tendon. CONCLUSION: Bite size from the edge of the tendon seems to be more important than the width of the mattress. The curve of the suture passing device may also have an effect on the strength of the suture tendon interface. PMID- 27492583 TI - Total hip arthroplasty in patients with ankylosing spondylitis: Midterm radiologic and functional results. AB - INTRODUCTION: The aim of this study was to evaluate the clinical and radiological outcomes of total hip arthroplasty (THA) in patients with Ankylosing Spondylitis (AS). PATIENTS AND METHODS: One hundred five hips of 61 AS patients (mean age: 41.3 +/- 10.2 years) who underwent THA between 1997 and 2012 were included into the study. Dorr's classification of proximal femoral geometry, acetabular protrusio, bone ankylosis, acetabular protrusion, Brooker classification of heterotopic ossification (HO), Gruen and Charnley classifications of implant loosening were used in radiographic assessments. Patients were called back to return for an additional long-term follow-up for functional assessment. RESULTS: Cementless total hip arthroplasty was used in 83 hips (79%) and cemented TKA was used in 22 hips (21%). The overall rate of aseptic loosening was 7.6% at a mean follow-up of 5.4 years. Femoral loosening was statistically similar in cemented and cementless femoral components (14% vs. 8%, p = 0.089). Acetabular component loosening was statistically higher in patients with any degree of HO (p = 0.04). Regardless of the type of femoral implant (cemented or cementless), femoral component loosening was higher in Dorr's type C patients (p = 0.005). The average pre-operative HSS was 46.6 +/- 16.3, and it improved to 80.7 +/- 18.7 at last follow-up (p < 0.01). CONCLUSION: Revision incidence was similar in between ankylosed and non-ankylosed hips. While complication rates are high, significant functional improvement can be achieved after THA in patients with AS. PMID- 27492584 TI - Safety of modified Stoppa approach for Ganz periacetabular osteotomy: A preliminary cadaveric study. AB - OBJECTIVE: The aim of this cadaveric study was to investigate the efficacy of the modified Stoppa approach in Ganz periacetabular osteotomy (PAO). METHODS: The Ganz PAO was performed on 10 hemipelvises with normal hips, from 5 cadavers using the modified Stoppa approach through the Pfannenstiel incision. All of the osteotomies were performed under fluoroscopic control and direct visualizing the osteotomy site from the same incision. After the osteotomy, the acetabulum was medialized and redirected anterolaterally, and fixed with 2 screws. The neurovascular structures and the joints were examined by dissecting the soft tissues after fixation of the osteotomies. Outcome parameters were center-edge (CE) angle, the distances between the osteotomy and anterior superior iliac spine (ASIS), and between the osteotomy and the sciatic notch, neurovascular and joint penetrations. RESULTS: After the osteotomy, the mean CE angle was improved from 19.8 degrees to 25.2 degrees , mean distance between the osteotomy and ASIS was 3.1 cm, and the mean distance between the osteotomy and the sciatic notch was 10.2 mm. The neurovascular structures and the joints were examined by dissecting the soft tissues after fixation of the osteotomies. No damage to the joint, surrounding arteries, veins or nerves was detected in any of the cadavers. CONCLUSIONS: Bilateral dysplastic hips can be treated with a 10 cm, cosmetically more acceptable incision in the same session using this approach. Quadrilateral surface of the acetabulum can be directly seen using this approach and the osteotomy can be safely performed. PMID- 27492585 TI - Tyrosinase inhibitory flavonoid from Juniperus communis fruits. AB - The fruits of Juniperus communis have been traditionally used in the treatment of skin diseases. In our preliminary experiment, the MeOH extract of J. communis effectively suppressed mushroom tyrosinase activity. Three monoflavonoids and five biflavonoids were isolated from J. communis by bioassay-guided isolation and their inhibitory effect against tyrosinase was evaluated. According to the results of all isolates, hypolaetin 7-O-beta-xylopyranoside isolated from J. communis exhibited most potent effect of decreasing mushroom tyrosinase activity with an IC50 value of 45.15 MUM. Further study provided direct experimental evidence for hypolaetin 7-O-beta-D-xylopyranoside-attenuated tyrosinase activity in alpha-MSH-stimulated B16F10 murine melanoma cell. Hypolaetin 7-O-beta-D xylopyranoside from the EtOAc fraction of J. communis was also effective at suppressing alpha-MSH-induced melanin synthesis. This is the first report of the enzyme tyrosinase inhibition by J. communis and its constituent. Therapeutic attempts with J. communis and its active component, hypolaetin 7-O-beta-D xylopyranoside, might be useful in treating melanin pigmentary disorders. PMID- 27492586 TI - Artificial Force Induced Reaction Method for Systematic Determination of Complex Reaction Mechanisms. AB - Nowadays, computational studies are very important for the elucidation of reaction mechanisms and selectivity of complex reactions. However, traditional computational methods usually require an estimated reaction path, mainly driven by limited experimental implications, intuition, and assumptions of stationary points. However, the artificial force induced reaction (AFIR) method in the global reaction route mapping (GRRM) strategy can be used for unbiased and automatic reaction path searches for complex reactions. In this account, we highlight applications of the AFIR method to a variety of reactions (organic, organometallic, enzymatic, and photochemical) of complex molecular systems. In addition, the AFIR method has been successfully used to rationalise the origin of stereo- and regioselectivity. The AFIR method can be applied from small to large molecular systems, and will be a very useful tool for the study of complex molecular problems in many areas of chemistry, biology, and material sciences. PMID- 27492587 TI - Synthesis of "neoprofen", a rigidified analogue of ibuprofen, exemplifying synthetic methodology for altering the 3-D topology of pharmaceutical substances. AB - 3,3-Dimethylcyclopentanes (neopentylenes) are ubiquitous in Nature but largely absent from synthetic pharmaceutical libraries. Neopentylenes define a hydrophobic and rigid 3-D topology with distinct molecular pharmacology, as exemplified here with two neopentylene-fused analogues of the synthetic anti inflammatory drug, ibuprofen. PMID- 27492588 TI - Trends in the match rate and composition of candidates matching into categorical general surgery residency positions in the United States. AB - BACKGROUND: The aim of this study was to analyze the trends in the proportion of students from various educational backgrounds who matched into categorical general surgery (GS) residency positions. METHODS: National Resident Matching Program reports (1994 to 2014) were analyzed, and regression was used to estimate the trends for each group. RESULTS: The match rate into GS-categorical residency has remained stable; however, since 1994, we witnessed a 13% decrease in US seniors matching into GS. This has corresponded to proportional increases in matches for US citizens from international medical schools (US IMG, 1350%) and a 62% increase for non-US citizen international medical graduates (non-US IMG) into GS. In comparison, US IMG matches into all first-year postgraduate positions increased by 468%, whereas non-US IMG matches decreased by 15%. CONCLUSIONS: The stable match rates into categorical GS residencies are not because of US seniors but rather because of a rise in the number of IMGs. In contrast to the decreased reliance on non-US IMGs in all other specialties, GS is accepting a larger proportion of non-US IMGs. PMID- 27492589 TI - Motor Neuron Disease: New insights into genetic risk factors for amyotrophic lateral sclerosis. PMID- 27492590 TI - Brain imaging: Synaptic density directly visualized in human brains. PMID- 27492591 TI - What is the meaning of becoming PubMed Central journal? PMID- 27492592 TI - Human native kappa opioid receptor functions not predicted by recombinant receptors: Implications for drug design. AB - If activation of recombinant G protein-coupled receptors in host cells (by drugs or other ligands) has predictive value, similar data must be obtained with native receptors naturally expressed in tissues. Using mouse and human recombinant kappa opioid receptors transfected into a host cell, two selectively-acting compounds (ICI204448, asimadoline) equi-effectively activated both receptors, assessed by measuring two different cell signalling pathways which were equally affected without evidence of bias. In mouse intestine, naturally expressing kappa receptors within its nervous system, both compounds also equi-effectively activated the receptor, inhibiting nerve-mediated muscle contraction. However, whereas ICI204448 acted similarly in human intestine, where kappa receptors are again expressed within its nervous system, asimadoline was inhibitory only at very high concentrations; instead, low concentrations of asimadoline reduced the activity of ICI204448. This demonstration of species-dependence in activation of native, not recombinant kappa receptors may be explained by different mouse/human receptor structures affecting receptor expression and/or interactions with intracellular signalling pathways in native environments, to reveal differences in intrinsic efficacy between receptor agonists. These results have profound implications in drug design for kappa and perhaps other receptors, in terms of recombinant-to-native receptor translation, species-dependency and possibly, a need to use human, therapeutically-relevant, not surrogate tissues. PMID- 27492593 TI - MoS2 memristor with photoresistive switching. AB - A MoS2 nanosphere memristor with lateral gold electrodes was found to show photoresistive switching. The new device can be controlled by the polarization of nanospheres, which causes resistance switching in an electric field in the dark or under white light illumination. The polarization charge allows to change the switching voltage of the photomemristor, providing its multi-level operation. The device, polarized at a voltage 6 V, switches abruptly from a high resistance state (HRSL6) to a low resistance state (LRSL6) with the On/Off resistance ratio of about 10 under white light and smooth in the dark. Analysis of device conductivity in different resistive states indicates that its resistive state could be changed by the modulation of the charge in an electric field in the dark or under light, resulting in the formation/disruption of filaments with high conductivity. A MoS2 photomemristor has great potential as a multifunctional device designed by using cost-effective fabrication techniques. PMID- 27492594 TI - Development of immobilized-pepsin microreactors coupled to nano liquid chromatography and tandem mass spectrometry for the quantitative analysis of human butyrylcholinesterase. AB - Human butyrylcholinesterase is a serine hydrolase that reacts with organophosphorus compounds (OP) to form stable adducts. These adducts are valuable biomarkers for OP exposure and can be analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) after a preliminary digestion step in solution. However, this digestion step is time-consuming and cannot be directly coupled with LC-MS set ups. Therefore, the aim of this work was to develop pepsin based immobilized enzyme microreactors (IMERs) for the rapid digestion of human butyrylcholinesterase (HuBuChE). Various IMERs were synthesized by grafting different amounts of pepsin on a CNBr-sepharose gel and the grafting yield was measured by a bicinchoninic acid assay (BCA). A sensitive nanoLC-MS/MS method was developed to evaluate the digestion yields of HuBuChE on IMERs which was made possible by a synthetic peptide which was used as a calibrant. The digestion was optimized by studying the impact of different parameters such as the digestion time, the temperature and the amount of pepsin grafted on IMER. This optimization allowed HuBuChE to be digested with-in 20min without pretreatment and with digestion yields up to 20%. The repeatability of the IMER synthesis and HuBuChE digestion was highlighted with the characterization of 3 similar IMERs. Finally, the digestion yields of HuBuChE were higher with IMERs when compared to a typical in solution digestion. PMID- 27492595 TI - Sulfobutylether-beta-cyclodextrin as a chiral selector for separation of amino acids and dipeptides in chromatography. AB - Various amino acids, dipeptides and their isomers were (enantio)separated using sulfobutylether-beta-cyclodextrin as a chiral selector. Two different approaches were employed: first, dynamic coating of sulfobutylether-beta-cyclodextrin onto a strong anion-exchange stationary phase and, second, use of sulfobutylether-beta cyclodextrin as a mobile phase additive in a separation system with a C18 column. Measurements were carried out using RP-HPLC and hydrophilic interaction liquid chromatography. Mobile phases composed of organic modifier (methanol) and four different aqueous parts: (i) deionized water, (ii) an aqueous solution of formic acid (pH 2.1), (iii) ammonium acetate buffer (pH 4.7), and (iv) ammonium acetate buffer (pH 8.8) in various volume ratios. Under these separation conditions, out of 23 chiral analytes, 9 were baseline enantio-resolved and 7 were partially separated. Of 9 mixtures of dipeptide isomers, 8 were baseline-separated. Sulfobutylether-beta-cyclodextrin proved to be suitable for the separation of chiral and also achiral analytes. The use of sulfobutylether-beta-cyclodextrin as a dynamic coating agent or as a mobile phase additive depends on the particular chromatographic system and analytes of interest. PMID- 27492596 TI - Rapid method for the simultaneous detection of boar taint compounds by means of solid phase microextraction coupled to gas chromatography/mass spectrometry. AB - Because of animal welfare issues, the voluntary ban on surgical castration of male piglets, starting January 2018 was announced in a European Treaty. One viable alternative is the fattening of entire male pigs. However, this can cause negative consumer reactions due to the occurrence of boar taint and possibly lead to severe economic losses in pig husbandry. In this study, headspace solid phase microextraction (HS-SPME) coupled to GC-MS was used in the development and optimization of a candidate method for fast and accurate detection of the boar taint compounds. Remarkably fast extraction (45s) of the boar taint compounds from adipose tissue was achieved by singeing the fat with a soldering iron while released volatiles were extracted in-situ using HS-SPME. The obtained method showed good performance characteristics after validation according to CD 2002/657/EC and ISO/IEC 17025 guidelines. Moreover, cross-validation with an in house UHPLC-HR-Orbitrap-MS method showed good agreement between an in-laboratory method and the new candidate method for the fast extraction and detection of skatole and androstenone, which emphasizes the accuracy of this new SPME-GC-MS method. Threshold detection of the boar taint compounds on a portable GC-MS could not be achieved. However, despite the lack of sensitivity obtained on the latter instrument, a very fast method with run-to-run time of 3.5min for the detection of the boar taint compounds was developed. PMID- 27492597 TI - Characterization of thermal desorption with the Deans-switch technique in gas chromatographic analysis of volatile organic compounds. AB - This study presents a novel application based on the Deans-switch cutting technique to characterize the thermal-desorption (TD) properties for gas chromatographic (GC) analysis of ambient volatile organic compounds (VOCs). Flash heating of the sorbent bed at high temperatures to desorb trapped VOCs to GC may easily produce severe asymmetric or tailing GC peaks affecting resolution and sensitivity if care is not taken to optimize the TD conditions. The TD peak without GC separation was first examined for the quality of the TD peak by analyzing a standard gas mixture from C2 to C12 at ppb level. The Deans switch was later applied in two different stages. First, it was used to cut the trailing tail of the TD peak, which, although significantly improved the GC peak symmetry, led to more loss of the higher boiling compounds than the low boiling ones, thus suggesting compound discrimination. Subsequently, the Deans switch was used to dissect the TD peak into six 30s slices in series, and an uneven distribution in composition between the slices were found. A progressive decrease in low boiling compounds and increase in higher boiling ones across the slices indicated severe inhomogeneity in the TD profile. This finding provided a clear evidence to answer the discrimination problem found with the tail cutting approach to improve peak symmetry. Through the use of the innovated slicing method based on the Deans switch cutting technique, optimization of TD injection for highly resolved, symmetric and non-discriminated GC peaks can now be more quantitatively assessed and guided. PMID- 27492598 TI - Electrical field assisted matrix solid phase dispersion as a powerful tool to improve the extraction efficiency and clean-up of fluoroquinolones in bovine milk. AB - This work presents a new method by electrical matrix solid phase dispersion for the extraction and clean-up of marbofloxacin, ofloxacin, norfloxacin, ciprofloxacin, enrofloxacin, difloxacin and sarafloxacin in bovine milk. Composition and pH of the eluent, applied electrical potential and polarity were optimized by experimental designs. The combination of the chromatographic and electrophoretic mechanisms allowed the extraction and clean-up in one step with low organic solvent consumption, high extraction throughput and elution automation. Linearity, precision, trueness and limit of quantification were evaluated and provided values in accordance with other methods recently developed for the analysis of fluoroquinolones in milk. This technique proved to be promising for the extraction and clean-up of ionizable analytes in different milk matrices. PMID- 27492599 TI - Theoretical study of closed-loop recycling liquid-liquid chromatography and experimental verification of the theory. AB - The non-ideal recycling equilibrium-cell model including the effects of extra column dispersion is used to simulate and analyze closed-loop recycling counter current chromatography (CLR CCC). Previously, the operating scheme with the detector located before the column was considered. In this study, analysis of the process is carried out for a more realistic and practical scheme with the detector located immediately after the column. Peak equation for individual cycles and equations describing the transport of single peaks and complex chromatograms inside the recycling closed-loop, as well as equations for the resolution between single solute peaks of the neighboring cycles, for the resolution of peaks in the recycling chromatogram and for the resolution between the chromatograms of the neighboring cycles are presented. It is shown that, unlike conventional chromatography, increasing of the extra-column volume (the recycling line length) may allow a better separation of the components in CLR chromatography. For the experimental verification of the theory, aspirin, caffeine, coumarin and the solvent system hexane/ethyl acetate/ethanol/water (1:1:1:1) were used. Comparison of experimental and simulated processes of recycling and distribution of the solutes in the closed-loop demonstrated a good agreement between theory and experiment. PMID- 27492600 TI - Analysis of 4-bromo-3-fluorobenzaldehyde and separation of its regioisomers by one-dimensional and two-dimensional gas chromatography. AB - A starting material, 4-bromo-3-fluorobenzaldehyde, was used for active drug substance (API) AMG 369 production. The presence of the regioisomer impurities in the starting material 4-bromo-3-fluorobenzaldehyde presented significant challenges for the API synthetic route development due to the physical-chemical similarities of the impurities. These impurities significantly impact on the purity of the starting-material and final drug substance. Control of these impurities is important due to the potential genotoxicity of these impurities (p GTI). Analytical development was carried out to develop GC methods with high resolving power and high sensitivity to quantify the regioisomers presented in starting material and therefore to control the purity of the starting material and the final drug substance. In the study, complete resolution of the ten regioisomers by 1D-GC and heart-cutting two-dimensional GC (2D-GC) was achieved. A sensitive GC/micro electron capture detection (MU-ECD) method with high resolving power and sensitivity to fully resolve all the ten regioisomers of 4 bromo-3-fluorobenzaldehyde was obtained by using a CHIRALDEX GC column (1D- GC). To facilitate the systematic GC method development, heart-cutting two-dimensional gas chromatography (2D-GC) using a Deans switch was exploited for the separation of the ten regioisomers. The resulting heart-cutting 2D-GC method successfully separated all the ten regioisomers with better sensitivity and resolution. Regioisomer impurities in the starting material were identified and quantified by these GC methods. The sensitivity for the methods is in the range of 0.004ng to 0.02ng for the regioisomers. Linearity for the methods is: R(2)=0.999 to 1.000. The methods were suitable for control of the regioisomer impurities, p-GTIs, in the starting material and final drug substance. PMID- 27492601 TI - Neural correlates of olfactory and visual memory performance in 3D-simulated mazes after intranasal insulin application. AB - This fMRI study intended to establish 3D-simulated mazes with olfactory and visual cues and examine the effect of intranasally applied insulin on memory performance in healthy subjects. The effect of insulin on hippocampus-dependent brain activation was explored using a double-blind and placebo-controlled design. Following intranasal administration of either insulin (40IU) or placebo, 16 male subjects participated in two experimental MRI sessions with olfactory and visual mazes. Each maze included two separate runs. The first was an encoding maze during which subjects learned eight olfactory or eight visual cues at different target locations. The second was a recall maze during which subjects were asked to remember the target cues at spatial locations. For eleven included subjects in the fMRI analysis we were able to validate brain activation for odor perception and visuospatial tasks. However, we did not observe an enhancement of declarative memory performance in our behavioral data or hippocampal activity in response to insulin application in the fMRI analysis. It is therefore possible that intranasal insulin application is sensitive to the methodological variations e.g. timing of task execution and dose of application. Findings from this study suggest that our method of 3D-simulated mazes is feasible for studying neural correlates of olfactory and visual memory performance. PMID- 27492602 TI - Quality and Outcomes Framework: what have we learnt? PMID- 27492603 TI - Heavy-metal contamination and solid-phase fractionation in street dust. AB - Fourteen street-dust samples were collected from Hamedan, western Iran. Street dust samples received different amounts of heavy-metal pollution. The samples were analyzed for total cadmium (Cd), copper (Cu), lead (Pb), nickel (Ni), and zinc (Zn), and binding forms of heavy metal were determined in five fractions. The results showed Cd was the only metal present appreciably, 25.21% and 25.92%, in the exchangeable and carbonates fractions, respectively, and Cu was the only metal predominantly associated, 31.77%, with organic fraction. Zn, 45.84%, was present mainly in the Fe-Mn oxide fraction, and the residual fraction was the most dominant solid phase pool of Ni and Pb, respectively, with 42.56% and 41.31%. The order of apparent mobility and potential metal bioavailability for these contaminated street-dust samples is Cd > Zn > Cu > Pb > Ni. The risk assessment code results showed very high risk for Cd; medium risk for Cu, Pb, and Zn; and low risk for Ni. PMID- 27492605 TI - Hydrogen bonds in methane-water clusters. AB - Characterization of hydrogen bonds in CH4-(H2O)12 clusters was carried out by using several quantum chemistry tools. An initial stochastic search provided around 2 500 000 candidate structures, then, using a convex-hull polygon criterion followed by gradient based optimization under the Kohn-Sham scheme, a total of 54 well defined local minima were located in the Potential Energy Surface. These structures were further analyzed through second-order many-body perturbation theory with an extended basis set at the MP2/6-311++G(d,p) level. Our analysis of Gibbs energies at several temperatures clearly suggests a structural preference toward compact water clusters interacting with the external methane molecule, instead of the more commonly known clathrate-like structures. This study shows that CH4-(H2O)12 clusters may be detected at temperatures up to 179 K, this finding provides strong support to a recently postulated hypothesis that suggests that methane-water clusters could be present in Mars at these conditions. Interestingly, we found that water to water hydrogen bonding is strengthened in the mixed clusters when compared to the isolated water dimer, which in turn leads to a weakening of the methane to water hydrogen bonding when compared to the CH4-(H2O) dimer. Finally, our evidence places a stern warning about the abilities of popular geometrical criteria to determine the existence of hydrogen bonds. PMID- 27492604 TI - Depletion of Dicer promotes epithelial ovarian cancer progression by elevating PDIA3 expression. AB - Dicer is an essential component of the microRNA (miRNA) processing machinery whose low expression is associated with advanced stage and poor clinical outcome in epithelial ovarian cancer. To investigate the functional relevance of Dicer in epithelial ovarian cancer and to identify its downstream effectors, two dimensional gel electrophoresis combined with mass spectrometry was used for proteomic profiling. Dicer depletion promoted ovarian cancer cell proliferation and migration accompanied by a global upregulation of proteins. Twenty-six proteins, 7 upregulated and 19 downregulated, were identified. The functions of the identified proteins and their interactions were bioinformatically analyzed. Among them, protein disulfide-isomerase A3 (PDIA3) was considered to be a potential target protein of Dicer. PDIA3 repression by siRNA could significantly relieve the proliferation- and migration-promoting effect mediated by Dicer depletion in vitro and in vivo. Moreover, the miRNAs targeting PDIA3 were decreased in cells with Dicer depletion. In summary, low Dicer expression contributes to epithelial ovarian cancer progression by elevating PDIA3 expression. PMID- 27492606 TI - Expectations of younger patients concerning activities after knee arthroplasty: are we asking the right questions? AB - PURPOSE: Indications for total and unicondylar knee arthroplasty (KA) have expanded to younger patients, in which Patient-Reported Outcome Measures (PROMs) often show ceiling effects. This might be due to higher expectations. Our aims were to explore expectations of younger patients concerning activities in daily life, work and leisure time after KA and to assess to what extent PROMs meet and evaluate these activities of importance. METHODS: Focus groups were performed among osteoarthritis (OA) patients <65 years awaiting KA, in which they indicated what activities they expected to perform better in daily life, work and leisure time after KA. Additionally, 28 activities of daily life, 17 of work and 27 of leisure time were depicted from seven PROMS, which were rated on importance, frequency and bother. A total score, representing motivation for surgery, was also calculated. RESULTS: Data saturation was reached after six focus groups including 37 patients. Younger OA patients expect to perform better on 16 activities after KA, including high-impact leisure time activities. From the PROMs, daily life and work activities were rated high in both importance and motivation for surgery, but for leisure time activities importance varied highly between patients. All seven PROMs score activities of importance, but no single PROM incorporates all activities rated important. CONCLUSION: Younger patients expect to perform better on many activities of daily life, work and leisure time after KA, and often at demanding levels. To measure outcomes of younger patients, we suggest using PROMs that include work and leisure time activities besides daily life activities, in which preferably scored activities can be individualized. PMID- 27492608 TI - Synthesis and Spectroscopic Investigation of Diketopyrrolopyrrole - Spiropyran Dyad for Fluorescent Switch Application. AB - We report the synthesis and characterization of a new fluorescent dyad SP-DPP SP(9) via efficient palladium-catalyzed Sonogashira coupling of prop-2-yn-1-yl 3 (3',3'dimethyl-6-nitrospiro[chromene-2,2'-indolin]-1'-yl)propanoatespiropyran, SP(8), a well known photochromic accepter, with 3,6-bis(5-bromothiophen-2-yl)-2,5 bis((R)-2-ethylhexyl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione, DPP(4), a highly fluorescent donor. Under visible light exposure the SP unit is in a closed hydrophobic form, whereas under UV irradiation it converts to a polar, hydrophilic open form named Merocyanine (MC), which is responsible for functioning of photo-switch application. The photochemistry pertaining to fluorescence switch, 'on/off' behaviour, of model dyad SP-DPP-SP(9) is experimentally analyzed in solution as well as in solid state in polymer matrices by photoluminescence(PL) and absorption spectroscopy. After absorption of UV light the spiropyran unit of the dyad under goes the rupture of the spiro C-O bond leading to the formation of MC. The absorption band of MC fairly overlaps to the fluorescence of DPP unit resulting quenching of fluorescence via fluorescence resonance energy transfer from exited DPP unit to ground state MC. In contrary, the fluorescence of DPP is fully regained upon transformation of MC to SP by exposure to visible light or thermal stimuli. Hence, the fluorescence intensity of dyad 9 is regulated by reversible conversion among the two states of the photochromic spiropyran units and the fluorescence resonance energy transfer (FRET) between the MC form of SP and the DPP unit. Conversely, these scrutiny of the experiment express that the design of dyad 9 is viable as efficient fluorescent switch molecule in many probable commercial applications, such as, logic gates and photonic and optical communications. PMID- 27492607 TI - Defective DNA repair and chromatin organization in patients with quiescent systemic lupus erythematosus. AB - BACKGROUND: Excessive autoantibody production characterizing systemic lupus erythematosus (SLE) occurs irrespective of the disease's clinical status and is linked to increased lymphocyte apoptosis. Herein, we tested the hypothesis that defective DNA damage repair contributes to increased apoptosis in SLE. METHODS: We evaluated nucleotide excision repair at the N-ras locus, DNA double-strand breaks repair and apoptosis rates in peripheral blood mononuclear cells from anti dsDNA autoantibody-positive patients (six with quiescent disease and six with proliferative nephritis) and matched healthy controls following ex vivo treatment with melphalan. Chromatin organization and expression levels of DNA repair- and apoptosis-associated genes were also studied in quiescent SLE. RESULTS: Defective nucleotide excision repair and DNA double-strand breaks repair were found in SLE, with lupus nephritis patients showing higher DNA damage levels than those with quiescent disease. Melphalan-induced apoptosis rates were higher in SLE than control cells and correlated inversely with DNA repair efficiency. Chromatin at the N-ras locus was more condensed in SLE than controls, while treatment with the histone deacetylase inhibitor vorinostat resulted in hyperacetylation of histone H4, chromatin decondensation, amelioration of DNA repair efficiency and decreased apoptosis. Accordingly, genes involved in DNA damage repair and signaling pathways, such as DDB1, ERCC2, XPA, XPC, MRE11A, RAD50, PARP1, MLH1, MLH3, and ATM were significantly underexpressed in SLE versus controls, whereas PPP1R15A, BARD1 and BBC3 genes implicated in apoptosis were significantly overexpressed. CONCLUSIONS: Epigenetically regulated functional abnormalities of DNA repair machinery occur in SLE, regardless of clinical disease activity, and may promote lymphocyte apoptosis. Approaches to correct these abnormalities may be of therapeutic value in SLE. PMID- 27492609 TI - Effect of pi-Extended Substituents on Photophysical Properties of BODIPY Dyes in Solutions. AB - Four boron-dipyrrine (BODIPY) based dyes with pi-extended substituents in 8 position of dipyrrin ligand have been synthesized and characterized. Photophysical properties of the obtained compounds have been investigated in different individual solvents. Deposits of solvent polarity and viscosity were evaluated. BODIPY with 8-biphenyl substituent was found to be the fluorescent molecular rotor in contrast to more extended substituents. The complex nature of solvent-solute interactions leads to the poor applicability of standard multiparameter approaches to BODIPY solvatochromic properties. Fluorescence intensity was found to increase in case of solvent polarity growth, it is not typical for BODIPY. Taking that into account the BODIPY with pi-extended substituents could be used for fluorescence viscosity measurements, and as the fluorescent media polarity indicators in analytical chemistry and biochemistry. PMID- 27492610 TI - High-Risk Non-Muscle-Invasive Bladder Cancer-Therapy Options During Intravesical BCG Shortage. AB - Bladder cancer is the second commonest urinary tract malignancy with 70-80 % being non-muscle invasive (NMIBC) at diagnosis. Patients with high-risk NMIBC (T1/Tis, with high grade/G3, or CIS) represent a challenging group as they are at greater risk of recurrence and progression. Intravesical Bacilli Calmette-Guerin (BCG) is commonly used as first line therapy in this patient group but there is a current worldwide shortage. BCG has been shown to reduce recurrence in high-risk NMIBC and is more effective that other intravesical agents including mitomycin C, epirubicin, interferon-alpha and gemcitabine. Primary cystectomy offers a high change of cure in this cohort (80-90 %) and is a more radical treatment option which patients need to be counselled carefully about. Bladder thermotherapy and electromotive drug administration with mitomycin C are alternative therapies with promising short-term results although long-term follow-up data are lacking. PMID- 27492612 TI - Unemployment and mental health. PMID- 27492611 TI - ACVR1-Fc suppresses BMP signaling and chondro-osseous differentiation in an in vitro model of Fibrodysplasia ossificans progressiva. AB - Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease of heterotopic endochondral ossification (HEO), and currently no effective therapies are available for this disease. A recurrent causative heterozygous mutation (c.617 G>A; R206H) for FOP was identified in activin receptor type IA (ACVR1), a bone morphogenetic protein (BMP) type I receptor. This mutation aberrantly activates the BMP-Smad1/5/8 signaling pathway and leads to HEO in FOP patients. Here we report development of a soluble recombinant ACVR1 Fc fusion protein by combining the extracellular domain of human wild type ACVR1 and the Fc portion of human immunoglobulin gamma 1 (IgG1). The ACVR1-Fc fusion protein significantly down-regulated the dysregulated BMP signaling caused by the FOP ACVR1 mutation and effectively suppressed chondro-osseous differentiation in a previously described cellular FOP model, human umbilical vein endothelial cells (HUVECs) that were infected with adenovirus-ACVR1R206H (HUVECR206H). This ACVR1 Fc fusion protein holds great promise for prevention and treatment of HEO in FOP and related diseases. PMID- 27492613 TI - [Not Available]. PMID- 27492614 TI - Associations Between Health and Driving in an Older Adult Cohort in Rancho Bernardo. AB - OBJECTIVE: The purpose of this study was to identify the associations between health and health care utilization with driving patterns in a cohort of older adults. METHOD: In 2012, a total of 1,826 surviving participants in the Rancho Bernardo cohort were sent a health and driving pattern survey; 1,277 were returned. RESULTS: The majority of the respondents (1,151, 91%) were still driving. Older age, female sex, hospitalizations, emergency department (ED) visits and physical therapy visits, neurological disease, depression, limited vision, and limited hearing were associated with non-driving status. A total of 809 (71%) of drivers reported no citations or crashes in the last 5 years. DISCUSSION: The vast majority of older drivers in this cohort continued to drive, and did so safely. Health care utilization, medications, medical conditions, and self-assessment of health were associated with non-driving status. Prospective studies are needed to clarify the temporal relationships between these factors. PMID- 27492615 TI - A Survey of the Job Profiles of Biomedical Informatics Graduates. AB - BACKGROUND: In 2003, the University of Sao Paulo established the first Biomedical Informatics (BMI) undergraduate course in Brazil. Our mission is to provide undergraduate students with formal education on the fundamentals of BMI and its applied methods. This undergraduate course offers theoretical aspects, practical knowledge and scientifically oriented skills in the area of BMI, enab- ling students to contribute to research and methodical development in BMI. Course coordinators, professors and students frequently evaluate the BMI course and the curriculum to ensure that alumni receive quality higher education. OBJECTIVES: This study investigates (i) the main job activities undertake by USP BMI graduates, (ii) subjects that are fundamental important for graduates to pursue a career in BMI, and (iii) the course quality perceived by the alumni. METHODS: Use of a structured questionnaire to conduct a survey involving all the BMI graduates who received their Bachelor degree before July, 2015 (attempted n = 205). RESULTS: One hundred and forty-five graduates (71 %) answered the questionnaire. Nine out of ten of our former students currently work as informaticians. Seventy six graduates (52 %) work within the biomedical informatics field. Fifty-five graduates (38 %) work outside the biomedical informatics field, but they work in other IT areas. Ten graduates (7 %) do not work with BMI or any other informatics activities, and four (3 %) are presently unemployed. Among the 145 surveyed BMI graduates, 46 (32 %) and seven (5 %) hold a Master's degree and a PhD degree, respectively. Database Systems, Software Engineering, Introduction to Computer Science, Object-Oriented Programming, and Data Structures are regarded as the most important subjects during the higher education course. The majority of the graduates (105 or 72 %) are satisfied with the BMI education and training they received during the undergraduate course. CONCLUSIONS: More than half of the graduates from our BMI course work in their primary education area. Besides technical adequacy, the diverse job profiles, and the high level of satisfaction of our graduates indicate the importance of undergraduate courses specialized in the BMI domain are of utmost importance. PMID- 27492618 TI - Evaluation of a Laughter-based Exercise Program on Health and Self-efficacy for Exercise. AB - Background: Despite health benefits of physical activity (PA) and risks of physical inactivity, many older adults do not accumulate sufficient levels of PA to achieve associated health benefits. Lack of PA enjoyment may be a barrier to PA participation. Combining simulated laughter and PA for strength, balance, and flexibility is a potential solution for helping older adults maintain independence in activities of daily living through enjoyable participation in PA. Purpose of the study: The purpose of this study is to assess whether combining simulated laughter exercises with a moderate-intensity strength, balance, and flexibility PA program (i.e., LaughActive) increases participation in PA, health, and self-efficacy for PA among older adults residing in 4 assisted living facilities (ALFs). Design and methods: The 12-week wait list control pilot study used pre- and 6-week post-intervention comparisons within and between groups identified by paired sample t-test results among those who participated in twice weekly LaughActive classes (n = 27). Results: Significant improvements (p < .05 .10) were observed in mental health (SF-36v2), aerobic endurance (2-minute step test), and self-efficacy for exercise (OEE). Implications: PA programs that elicit positive emotions through simulated laughter have the potential to improve health, physical performance, and self-efficacy for PA among older adults and may positively influence participant adherence. PMID- 27492616 TI - Alcohol Consumption and Multiple Dysplastic Lesions Increase Risk of Squamous Cell Carcinoma in the Esophagus, Head, and Neck. AB - BACKGROUND & AIMS: Some patients develop multiple squamous cell carcinomas (SCCs) in the upper aerodigestive tract, attributed to field cancerization; alcohol consumption has been associated with this process. We examined the association between multiple areas of dysplastic squamous epithelium with the development of SCC of the esophagus or head and neck cancer, as well as alcohol consumption and smoking. METHODS: We examined 331 patients with early stage esophageal SCC using Lugol chromoendoscopy to evaluate the dysplastic squamous epithelium in the esophagus. Patients then were assigned to 3 groups, based on the number of Lugol voiding lesions: A, no lesion; B, 1-9 lesions; or C, 10 or more lesions. Participants completed lifestyle surveys on their history of drinking, smoking, and diet. All participants were evaluated by laryngopharyngoscopy before registration; only those without head and neck cancer were included, except for patients with superficial SCC limited to the subepithelial layer. Lesions detected in the esophagus and head and neck by surveillance were considered to be metachronous. The study end point was the cumulative incidence of metachronous SCCs in the esophagus and head and neck after endoscopic resection of esophageal SCC, according to the grade of Lugol-voiding lesions. At study entry, all patients were instructed to abstain from alcohol and smoking. RESULTS: Over the 2 year study period, metachronous SCCs of the esophagus were detected in 4% of patients in group A, in 9.4% of patients in group B, and in 24.7% of patients in group C (P < .0001 for patients in group A vs B or B vs C). Head and neck SCCs were detected in none of the patients in group A, in 1.7% of the patients in group B, and in 8.6% of the patients in group C (P = .016 for patients in group A vs C and P = .008 for patients in group B vs C). SCC of the esophagus or head and neck developed in 4.0% of patients in group A, in 10.0% of patients in group B, and in 31.4% of patients in group C (P < .0001 for group A vs B or A vs C). Alcohol abstinence decreased the risk of multiple SCCs of the esophagus (adjusted hazard ratio, 0.47, 95% confidence interval, 0.25-0.91; P = .025), whereas smoking abstinence did not. CONCLUSIONS: Multiple dysplastic lesions in the esophagus increase the risk of multiple SCCs. Alcohol abstinence reduces the risk of metachronous SCCs. Clinical Trials registry: UMIN000001676 and UMIN000005466. PMID- 27492619 TI - Confidant Availability (In)Stability and Emotional Well-Being in Older Men and Women. AB - Purpose of the study: The present study examined the role of stability and change in the availability of a family member and a friend as a confidant in older adults' emotional well-being. Method: Participants in two waves of the Wisconsin Longitudinal Study (N = 4,631; M = 64.3, 53.7% female) were assessed on depressive symptoms and the availability of a family member and friend as confidant. Using mixed linear effects models, four groups were compared over time and across gender on depressive symptoms: those with and without a family/friend confidant at both waves and those who lost and gained a family/friend confidant. Results: Those with stable availability of a family or friend confidant consistently scored the lowest on depressive symptoms; the gain of a family or friend confidant corresponded with a decrease in depressive symptoms, with a larger effect seen for the gain of a family confidant; the loss of a family confidant was associated with an increase in depressive symptoms over time; and stable availability of a family or friend confidant was more strongly linked to lower levels of depressive symptoms among women, whereas stable unavailability of a family confidant was linked to higher levels of depressive symptoms. Implications: Stable availability of either a family or friend confidant in late life is especially salient to emotional well-being, notably among women. Emotional well-being benefits from the gain of a confidant highlight the importance of supplementing or substituting a loss, especially of a family confidant, which is associated with a significant increase in depressive symptoms. PMID- 27492617 TI - A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition. AB - BACKGROUND & AIMS: Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). METHODS: Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. RESULTS: We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 * 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 * 10(-16)) and overweight individuals (P = 6.73 * 10(-16)). CONCLUSIONS: Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD. PMID- 27492621 TI - Sec16 alternative splicing dynamically controls COPII transport efficiency. AB - The transport of secretory proteins from the endoplasmic reticulum (ER) to the Golgi depends on COPII-coated vesicles. While the basic principles of the COPII machinery have been identified, it remains largely unknown how COPII transport is regulated to accommodate tissue- or activation-specific differences in cargo load and identity. Here we show that activation-induced alternative splicing of Sec16 controls adaptation of COPII transport to increased secretory cargo upon T-cell activation. Using splice-site blocking morpholinos and CRISPR/Cas9-mediated genome engineering, we show that the number of ER exit sites, COPII dynamics and transport efficiency depend on Sec16 alternative splicing. As the mechanistic basis, we suggest the C-terminal Sec16 domain to be a splicing-controlled protein interaction platform, with individual isoforms showing differential abilities to recruit COPII components. Our work connects the COPII pathway with alternative splicing, adding a new regulatory layer to protein secretion and its adaptation to changing cellular environments. PMID- 27492622 TI - In vitro acute and developmental neurotoxicity screening: an overview of cellular platforms and high-throughput technical possibilities. AB - Neurotoxicity and developmental neurotoxicity are important issues of chemical hazard assessment. Since the interpretation of animal data and their extrapolation to man is challenging, and the amount of substances with information gaps exceeds present animal testing capacities, there is a big demand for in vitro tests to provide initial information and to prioritize for further evaluation. During the last decade, many in vitro tests emerged. These are based on animal cells, human tumour cell lines, primary cells, immortalized cell lines, embryonic stem cells, or induced pluripotent stem cells. They differ in their read-outs and range from simple viability assays to complex functional endpoints such as neural crest cell migration. Monitoring of toxicological effects on differentiation often requires multiomics approaches, while the acute disturbance of neuronal functions may be analysed by assessing electrophysiological features. Extrapolation from in vitro data to humans requires a deep understanding of the test system biology, of the endpoints used, and of the applicability domains of the tests. Moreover, it is important that these be combined in the right way to assess toxicity. Therefore, knowledge on the advantages and disadvantages of all cellular platforms, endpoints, and analytical methods is essential when establishing in vitro test systems for different aspects of neurotoxicity. The elements of a test, and their evaluation, are discussed here in the context of comprehensive prediction of potential hazardous effects of a compound. We summarize the main cellular characteristics underlying neurotoxicity, present an overview of cellular platforms and read-out combinations assessing distinct parts of acute and developmental neurotoxicology, and highlight especially the use of stem cell-based test systems to close gaps in the available battery of tests. PMID- 27492620 TI - Physiological functions and clinical implications of the N-end rule pathway. AB - The N-end rule pathway is a unique branch of the ubiquitin-proteasome system in which the determination of a protein's half-life is dependent on its N-terminal residue. The N-terminal residue serves as the degradation signal of a protein and thus called N-degron. N-degron can be recognized and modifed by several steps of post-translational modifications, such as oxidation, deamination, arginylation or acetylation, it then polyubiquitinated by the N-recognin for degradation. The molecular basis of the N-end rule pathway has been elucidated and its physiological functions have been revealed in the past 30 years. This pathway is involved in several biological aspects, including transcription, differentiation, chromosomal segregation, genome stability, apoptosis, mitochondrial quality control, cardiovascular development, neurogenesis, carcinogenesis, and spermatogenesis. Disturbance of this pathway often causes the failure of these processes, resulting in some human diseases. This review summarized the physiological functions of the N-end rule pathway, introduced the related biological processes and diseases, with an emphasis on the inner link between this pathway and certain symptoms. PMID- 27492623 TI - Pharmacokinetic and pharmacodynamics of xylazine administered to exercised thoroughbred horses. AB - There is limited data describing xylazine serum concentrations in the horse and no reports of concentrations beyond 24 hours. The primary goal of the study reported here was to update the pharmacokinetics of xylazine following intravenous (IV) administration in order to assess the applicability of current regulatory recommendations. Pharmacodynamic parameters were determined using PK PD modeling. Sixteen exercised adult Thoroughbred horses received a single IV dose of 200 mg of xylazine. Blood and urine samples were collected at time 0 and at various times for up to 96 hours and analyzed using liquid chromatography tandem mass spectrometry. Xylazine serum concentrations were best fit by a 3 compartment model. Mean +/- SEM systemic clearance, volume of distribution at steady state, beta half-life and gamma half-life were 12.7 +/- 0.735 mL/min/kg, 0.660 +/- 0.053 L/kg, 2.79 +/- 0.105 hours and 26.0 +/- 1.9, respectively. Immediately following administration, horses appeared sedate as noted by a decrease in chin-to-ground distance, decreased locomotion and decreased heart rate (HR). Sedation lasted approximately 45 minutes. Glucose concentrations were elevated for 1-hour post administration. The EC50 (IC50) was 636.1, 702.2, 314.1 and 325.7 ng/mL for HR, atrioventricular block, chin-to-ground distance and glucose concentrations, respectively. The Emax (Imax) was 27.3 beats per minute, 47.5%, 42.4 cm and 0.28 mg/dL for HR, atrioventricular block, chin-to-ground distance and glucose concentrations, respectively. Pharmacokinetic parameters differ from previous reports and a prolonged detection time suggests that an extended withdrawal time, beyond current regulatory recommendations, is warranted to avoid inadvertent positive regulatory findings in performance horses. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27492624 TI - Antidotal Effects of Curcumin Against Agents-Induced Cardiovascular Toxicity. AB - Curcumin, the major phenolic compound in turmeric, shows preventive effects in various diseases. Curcumin is commonly found in rhizome of the Curcuma species and traditionally used in herbal medicine. Numeros studies has indicated that curcumin posses protective effects against toxic agents in various systems including cardiovascular. This study found that curcumin may be effective in cardiovascular diseases induced by toxic agents including Streptozotocin, Doxorubicin, Cyclosporin A, Methotrexate, Isoproterenol, Cadmium, Diesel exhaust particle, Nicotine, Hydrogen peroxide, and tert- Butyl hydroperoxide. However, due to the lake of information on human, further studies are needed to determine the efficacy of curcumin as an antidote agent. The present study aimed to critically review the recent literature data from that regarding the protective effects of curcumin against agents-induced cardiovascular toxicity. PMID- 27492625 TI - Introduction of nuclear medicine research in Japan. AB - There were many interesting presentations of unique studies at the Annual Meeting of the Japanese Society of Nuclear Medicine, although there were fewer attendees from Europe than expected. These presentations included research on diseases that are more frequent in Japan and Asia than in Europe, synthesis of original radiopharmaceuticals, and development of imaging devices and methods with novel ideas especially by Japanese manufacturers. In this review, we introduce recent nuclear medicine research conducted in Japan in the five categories of Oncology, Neurology, Cardiology, Radiopharmaceuticals and Technology. It is our hope that this article will encourage the participation of researchers from all over the world, in particular from Europe, in scientific meetings on nuclear medicine held in Japan. PMID- 27492626 TI - 2016 Young Investigators Meeting. PMID- 27492627 TI - Morphofunctional alterations in the olivocochlear efferent system of the genetic audiogenic seizure-prone hamster GASH:Sal. AB - The genetic audiogenic seizure hamster (GASH:Sal) is a model of a form of reflex epilepsy that is manifested as generalized tonic-clonic seizures induced by external acoustic stimulation. The morphofunctional alterations in the auditory system of the GASH:Sal that may contribute to seizure susceptibility have not been thoroughly determined. In this study, we analyzed the olivocochlear efferent system of the GASH:Sal from the organ of Corti, including outer and inner hair cells, to the olivocochlear neurons, including shell, lateral, and medial olivocochlear (LOC and MOC) neurons that innervate the cochlear receptor. To achieve this, we carried out a multi-technical approach that combined auditory hearing screenings, scanning electron microscopy, morphometric analysis of labeled LOC and MOC neurons after unilateral Fluoro-Gold injections into the cochlea, and 3D reconstruction of the lateral superior olive (LSO). Our results showed that the GASH:Sal exhibited higher auditory brain response (ABR) thresholds than their controls, as well as absence of distortion-product of otoacoustic emissions (DPOAEs) in a wide range of frequencies. The ABR and DPOAE results also showed differences between the left and right ears, indicating asymmetrical hearing alterations in the GASH:Sal. These alterations in the peripheral auditory activity correlated with morphological alterations. At the cochlear level, the scanning electron microscopy analysis showed marked distortions of the stereocilia from basal to apical cochlear turns in the GASH:Sal, which were not observed in the control hamsters. At the brainstem level, MOC, LOC, and shell neurons had reduced soma areas compared with control animals. This LOC neuron shrinkage contributed to reduction in the LSO volume of the GASH:Sal as shown in the 3D reconstruction analysis. Our study demonstrated that the morphofunctional alterations of the olivocochlear efferent system are innate components of the GASH:Sal, which might contribute to their susceptibility to audiogenic seizures. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic". PMID- 27492628 TI - Response to "Safety of repetitive transcranial magnetic stimulation in patients with epilepsy: A systematic review" by Luisa Santos Pereira and colleagues. PMID- 27492629 TI - Predictors of short-term mortality, cognitive and physical decline in older adults in northwest Russia: a population-based prospective cohort study. AB - BACKGROUND: The classical phenotype, accumulated deficit model and self-report approach of frailty were found not useful in older adults in northwest Russia. More research is needed to identify predictors of adverse outcomes in this population. AIM: The aim of this study is to identify predictors of mortality, autonomy and cognitive decline in a population that is characterized by a high cardiovascular morbidity and mortality rate. METHODS: A population-based prospective cohort study of 611 community-dwelling individuals 65+. Anthropometry, medical history nutritional status were recorded. An evaluation of cognitive, physical and autonomy function, spirometry, and laboratory tests were performed. The total follow-up was 5 years. Multiple imputation, backward stepwise Cox regression analysis, C-statistic, risk reclassification analysis and the bootstrapping techniques were used to analyze the data. RESULTS: We found that the combination of increasing age, male sex, low physical function, low mid arm muscle area, low forced expiratory volume in 1 s and anemia was associated with mortality for people 65+. The substitution of anemia with anemia + high level of C-reactive protein (hCRP) and the addition of high brain natriuretic peptide (hBNP) levels improved the classification of older persons at risk for mortality. DISCUSSION/CONCLUSION: The combination of low physical function, low mid-arm muscle area, low forced expiratory volume in 1 s, anemia with hCRP levels and hBNP identified older persons at a higher risk for mortality. These predictors may be used for the development of a prediction model to detect older people who are at risk for adverse health outcomes in northwest Russia. PMID- 27492631 TI - Motion Control of Micro-/Nanomotors. AB - As we progress towards employing self-propelled micro-/nanomotors in envisioned applications such as cargo delivery, environmental remediation, and therapeutic treatments, precise control of the micro-/nanomotors direction and their speed is essential. In this Review, major emerging approaches utilized for the motion control of micro-/nanomotors have been discussed, together with the lastest publications describing these approaches. Future studies could incorporate investigations on micro-/nanomotors motion control in a real-world environment in which matrix complexity might disrupt successful manipulation of these small scale devices. PMID- 27492630 TI - Modeling pollen time series using seasonal-trend decomposition procedure based on LOESS smoothing. AB - Analysis of airborne pollen concentrations provides valuable information on plant phenology and is thus a useful tool in agriculture-for predicting harvests in crops such as the olive and for deciding when to apply phytosanitary treatments as well as in medicine and the environmental sciences. Variations in airborne pollen concentrations, moreover, are indicators of changing plant life cycles. By modeling pollen time series, we can not only identify the variables influencing pollen levels but also predict future pollen concentrations. In this study, airborne pollen time series were modeled using a seasonal-trend decomposition procedure based on LOcally wEighted Scatterplot Smoothing (LOESS) smoothing (STL). The data series-daily Poaceae pollen concentrations over the period 2006 2014-was broken up into seasonal and residual (stochastic) components. The seasonal component was compared with data on Poaceae flowering phenology obtained by field sampling. Residuals were fitted to a model generated from daily temperature and rainfall values, and daily pollen concentrations, using partial least squares regression (PLSR). This method was then applied to predict daily pollen concentrations for 2014 (independent validation data) using results for the seasonal component of the time series and estimates of the residual component for the period 2006-2013. Correlation between predicted and observed values was r = 0.79 (correlation coefficient) for the pre-peak period (i.e., the period prior to the peak pollen concentration) and r = 0.63 for the post-peak period. Separate analysis of each of the components of the pollen data series enables the sources of variability to be identified more accurately than by analysis of the original non-decomposed data series, and for this reason, this procedure has proved to be a suitable technique for analyzing the main environmental factors influencing airborne pollen concentrations. PMID- 27492633 TI - Accurate application of a precontoured-locking plate for proximal humeral fractures in Asians: a cadaveric study. AB - OBJECTIVES: The purpose of this study was to identify the optimal position for a precontoured-locking plating (PHILOS((r))) of the proximal humerus in Asians in terms of conformity and to determine the prevalence of screw exits in the position of the highest conformity. METHODS: Twenty adult humeri and 14 cadaveric shoulders were included in this study. After placing the precontoured plate in the well-fitted position on the humerus, we measured the distance between the upper margin of the plate and the tip of greater tuberosity (GT) (distance A) and the distance between the anterior margin of the plate and lateral border of the bicipital groove (BG) (distance B). The prevalence of K-wire exits was assessed. In the 14 cadaver shoulders, the mutual relation between the most inferior locking sleeve of the optimally positioned plate and the axillary nerve was evaluated to assess the potential for axillary nerve injury. RESULTS: The precontoured plate was well-fitted and remained in a relatively constant position in all specimens. Distance A was an average of 3.6 mm (range 1.4-5.5 mm), and distance B was an average of 2.5 mm (range 0-4.6 mm). The K wire closest to the BG pierced it in four cases (20 %), and most inferior K wires exited at an average distance of 3.8 mm (range 1.6-9.0 mm) from the inferior articular margin of the humeral head. Regarding involvement of the BG, articular width was the only significant variable in the logistic regression model, with an odds' ratio of 0.610. The axillary nerve was located at an average vertical distance of 59.7 mm (range 51.8-66.9 mm) from the tip of the GT in a vertically neutral position. The results did not differ between the left and right sides (t = 0.326, p = 0.755). Although the axillary nerve was slightly inferior to the most inferior locking holes of the proximal humerus, it was located in the path of their locking sleeves on the deltoid muscle. CONCLUSION: The optimal position for the highest conformity led to ideal fixation of the proximal humerus and inferomedial support screw in Asians. However, the precontoured plate sometimes had screw exits that involved the BG, and articular width had a large impact on involvement of the BG. If locking sleeves for the most inferior holes were introduced on the deltoid muscle in a neutral position, there was high potential for injury to the axillary nerve in Koreans. PMID- 27492632 TI - Voluntary exercise blocks Western diet-induced gene expression of the chemokines CXCL10 and CCL2 in the prefrontal cortex. AB - Obesity increases inflammation, both peripherally and centrally, and exercise can ameliorate some of the negative health outcomes associated with obesity. Within the brain, the effect of obesity on inflammation has been well characterized in the hypothalamus and hippocampus, but has been relatively understudied in other brain regions. The current study was designed to address two primary questions; (1) whether western diet (high fat/high sucrose) consumption would increase markers of inflammation in the prefrontal cortex and (2) whether concurrent voluntary wheel running would ameliorate any inflammation. Adult male mice were exposed to a western diet or a control diet for 8weeks. Concurrently, half the animals were given running wheels in their home cages, while half did not have access to wheels. At the conclusion of the study, prefrontal cortex was removed and expression of 18 proinflammatory genes was assayed. Expression of a number of proinflammatory molecules was upregulated by consumption of the western diet. For two chemokines, chemokine (C-C motif) ligand 2 (CCL2) and C-X-C motif chemokine 10 (CXCL10), voluntary exercise blocked the increase in the expression of these genes. Cluster analysis confirmed that the majority of the tested genes were upregulated by western diet, and identified another small cluster of genes that were downregulated by either diet or exercise. These data identify a proinflammatory phenotype within the prefrontal cortex of mice fed a western diet, and indicate that chemokine induction can be blocked by voluntary exercise. PMID- 27492634 TI - Genetic associations with neuroendocrine tumor risk: results from a genome-wide association study. AB - The etiology of neuroendocrine tumors remains poorly defined. Although neuroendocrine tumors are in some cases associated with inherited genetic syndromes, such syndromes are rare. The majority of neuroendocrine tumors are thought to be sporadic. We performed a genome-wide association study (GWAS) to identify potential genetic risk factors for sporadic neuroendocrine tumors. Using germline DNA from blood specimens, we genotyped 909,622 SNPs using the Affymetrix 6.0 GeneChip, in a cohort comprising 832 neuroendocrine tumor cases from Dana Farber Cancer Institute and Massachusetts General Hospital and 4542 controls from the Harvard School of Public Health. An additional 241 controls from Dana-Farber Cancer Institute were used for quality control. We assessed risk associations in the overall cohort, and in neuroendocrine tumor subgroups. We identified no potential risk associations in the cohort overall. In the small intestine neuroendocrine tumor subgroup, comprising 293 cases, we identified risk associations with three SNPs on chromosome 12, all in strong LD. The three SNPs are located upstream of ELK3, a transcription factor implicated in angiogenesis. We did not identify clear risk associations in the bronchial or pancreatic neuroendocrine subgroups. This large-scale study provides initial evidence that presumed sporadic small intestine neuroendocrine tumors may have a genetic etiology. Our results provide a basis for further exploring the role of genes implicated in this analysis, and for replication studies to confirm the observed associations. Additional studies to evaluate potential genetic risk factors for sporadic pancreatic and bronchial neuroendocrine tumors are warranted. PMID- 27492635 TI - PYK2 via S6K1 regulates the function of androgen receptors and the growth of prostate cancer cells. AB - Androgen receptor (AR) is a steroid hormone receptor that functions as a transcription factor for regulating cell growth and survival. Aberrant AR function becomes a risk factor for promoting the progression of prostate cancer (PCa). In this study, we examined the roles of proline-rich tyrosine kinase 2 (PYK2) and ribosomal S6 kinase 1 (S6K1) in regulating AR expression and activity and growth properties in PCa cells. Compared with normal prostate tissues, PCa tumors exhibited high levels of PYK2 and S6K1 expression. Furthermore, the expression levels of PYK2 and S6K1 were significantly correlated with nuclear AR expression in PCa tissues. We further found the association between PYK2, S6K1, and AR in their protein expression and phosphorylation levels among normal prostate PZ-HPV-7 cells and prostate cancer LNCaP and 22Rv1 cells. Overexpression of the wild-type PYK2 in PZ-HPV-7 and LNCaP cells promoted AR and S6K1 expression and phosphorylation as well as enhanced cell growth. In contrast, expression of the mutated PYK2 or knockdown of PYK2 expression in LNCaP or 22Rv1 cells caused reduced expression or phosphorylation of AR and S6K1 as well as retarded cell growth. Under an androgen-deprived condition, PYK2-promoted AR expression and phosphorylation and PSA production in LNCaP cells can be abolished by knocking down S6K1 expression. In summary, our data suggested that PYK2 via S6K1 activation modulated AR function and growth properties in PCa cells. Thus, PYK2 and S6K1 may potentially serve as therapeutic targets for PCa treatment. PMID- 27492636 TI - Sleep Quality Predicts Persistence of Parental Postpartum Depressive Symptoms and Transmission of Depressive Symptoms from Mothers to Fathers. AB - BACKGROUND: Early parenthood is a time of chronic sleep disturbance and also of heightened depression risk. Poor sleep quality has been identified both as a predictor of postpartum depressive symptoms and as a consequence. PURPOSE: This study sought to clarify causal pathways linking sleep and postpartum depression via longitudinal path modeling. Sleep quality at 6 months postpartum was hypothesized to exacerbate depressive symptoms from 1 month through 1 year postpartum in both mothers and fathers. Within-couple associations between sleep and depression were also tested. METHODS: Data were drawn from a low-income, racially and ethnically diverse sample of 711 couples recruited after the birth of a child. Depressive symptoms were assessed at 1, 6, and 12 months postpartum, and sleep was assessed at 6 months postpartum. RESULTS: For both partnered mothers and fathers and for single mothers, depressive symptoms at 1 month postpartum predicted sleep quality at 6 months, which in turn predicted depressive symptoms at both 6 and 12 months. Results held when infant birth weight, breastfeeding status, and parents' race/ethnicity, poverty, education, and immigration status were controlled. Mothers' and fathers' sleep quality and depressive symptoms were correlated, and maternal sleep quality predicted paternal depressive symptoms both at 6 and at 12 months. CONCLUSIONS: Postpartum sleep difficulties may contribute to a vicious cycle between sleep and the persistence of depression after the birth of a child. Sleep problems may also contribute to the transmission of depression within a couple. Psychoeducation and behavioral treatments to improve sleep may benefit new parents. PMID- 27492637 TI - Incentivizing research into the effectiveness of medical devices. PMID- 27492638 TI - In-vivo characterization of left-ventricle pressure-volume telemetry system in swine model. AB - We present in-vivo study related to the use of our implantable RF telemetry system for pressure-volume (PV) cardiac monitoring in a animal subject. We implant a commercial MEMS PV sensor into the subject's heart left-ventricle (LV), while the telemetry system is implanted outside of the heart and connected to the sensor with a 7-microwires tether. The RF telemetry system is suitable for commercial application in medium sized subjects, its total volume of 2.475cm(3) and a weight of 4.0g. Our designed system is 58 % smaller in volume, 44 % in weight and has a 55 % reduction in sampling power over the last reported research in PV telemetry. In-vivo data was captured in both an acute and a freely moving setting over a 24 hour period. We experimentally demonstrated viability of the methodology that includes the surgical procedure and real-time monitoring of the in-vivo data in a freely moving subject. Further improvements in catheter design will improve the data quality and safety of the subject. This real-time implantable technology allows for researchers to quantify cardiac pathologies by extracting real-time pressure-volume loops, wirelessly from within freely moving subjects. PMID- 27492639 TI - August 2016 at a glance: the new ESC guidelines, and pathophysiology, epidemiology and prognosis of heart failure. PMID- 27492640 TI - Novel models and mechanisms of heart failure with preserved ejection fraction. PMID- 27492641 TI - Dose response characterization of the association of serum digoxin concentration with mortality outcomes in the Digitalis Investigation Group trial. AB - AIMS: Many patients with heart failure and reduced EF remain at high risk for hospitalization despite evidence-based therapy. Digoxin may decrease hospitalization; however, uncertainty persists concerning its proper administration and effect on mortality. This study investigated whether using dose response concepts to re-evaluate the relationship between serum digoxin concentration and key mortality outcomes in patients with reduced EF in the Digitalis Investigation Group trial would help clarify efficacy and safety. METHODS AND RESULTS: Multivariable Cox proportional hazards modelling and propensity score adjustment assessed the relationship between serum digoxin concentration (>=0.5 ng/mL) as a continuous variable and mortality outcomes. In patients treated with digoxin, a significant linear association was found between serum concentration and all-cause mortality [adjusted hazard ratio (HR) 1.25, 95% confidence interval (CI) 1.14-1.38, P < 0.001 per 0.5 ng/mL increase in serum concentration]. Based on this relationship, a bidirectional association was found between digoxin therapy and all-cause mortality when compared with placebo. The lowest serum concentrations (0.5-0.7 ng/mL) were associated with the lowest risk of all-cause mortality (adjusted HR 0.77, 95% CI 0.67-0.89, P < 0.001) while high serum concentrations (1.6-2.0 ng/mL) were associated with increased mortality (adjusted HR 1.33, 95% CI 1.12-1.58, P = 0.001). Consistent with this finding, lower serum concentrations (0.5-0.7 ng/mL) were associated with reduced death from worsening heart failure and a neutral effect on cardiovascular death not due to worsening heart failure. CONCLUSION: These findings favour targeting serum concentrations from 0.5 to 0.7 ng/mL when dosing digoxin in patients with heart failure and reduced EF. PMID- 27492642 TI - Targeting digoxin dosing to serum concentration: is the bullseye too small? PMID- 27492643 TI - Practice audit of the role of the Non-medical surgical assistant in Australia, an online survey. AB - The term Non-Medical Surgical Assistant (NMSA) encompasses all roles where healthcare clinicians without a medical degree provide clinical services during the perioperative cycle. The role of NMSA is gaining momentum within Australia. It is timely to ascertain who is preforming the role and quantify the practice setting and scope of practice to enable a nationally recognised platform for role evolution. For two months in 2015 a NMSA Practice Audit was available online. Sampling was initially of a convenience modality. A total of 83 clinicians responded. The majority of NMSAs were experienced RNs [>11yrs]; held post graduate qualifications [80%], practiced predominantly in metropolitan areas [65%] and had been performing the role for 8 years or less. The specialty with the highest uptake of the NMSAs is orthopaedic surgery. This paper provides an overview of NMSAs practicing in Australia and provides cost effective evidence of the need for this service in Australian healthcare. PMID- 27492644 TI - Reliability of the "Ten Test" for assessment of discriminative sensation in hand trauma. AB - "Ten Test" (TT) is a bedside measure of discriminative sensation, whereby the magnitude of abnormal sensation to moving light touch is normalized to an area of normal sensation on an 11-point Likert scale (0-10). The purposes of this study were to determine reliability parameters of the TT in a cohort of patients presenting to a hand trauma clinic with subjectively altered sensation post injury and to compare the reliability of TT to that of the Weinstein Enhanced Sensory Test (WEST). Study participants (n = 29, mean age = 37 +/- 12) comprised patients presenting to an outpatient hand trauma clinic with recent hand trauma and self reported abnormal sensation. Participants underwent TT and WEST by two separate raters on the same day. Interrater reliability, response stability and responsiveness of each test were determined by the intraclass correlation coefficient (ICC: 2, 1), standard error of measurement (SEM) with 95% confidence intervals (CI) and minimal detectable difference score, with 95% CI (MDD95), respectively. The TT displayed excellent interrater reliability (ICC = 0.95, 95% CI 0.89-0.97) compared to good reliability for WEST (ICC = 0.78, 95% CI 0.58 0.89). The range of true scores expected with 95% confidence based on the SEM (i.e. response stability), was +/-1.1 for TT and +/-1.1 for WEST. MDD95 scores reflecting test responsiveness were 1.5 and 1.6 for TT and WEST, respectively. The TT displayed excellent reliability parameters in this patient population. Reliability parameters were stronger for TT compared to WEST. These results provide support for the use of TT as a component of the sensory exam in hand trauma. PMID- 27492645 TI - Identification of a fourth ancient member of the IL-3/IL-5/GM-CSF cytokine family, KK34, in many mammals. AB - The related cytokine genes IL-3, IL-5 and GM-CSF map to the (extended) TH2 cytokine locus of the mammalian genome. For chicken an additional related cytokine gene, KK34, was reported downstream of the IL-3 plus GM-CSF cluster, but hitherto it was believed that mammalian genomes lack this gene. However, the present study identifies an intact orthologue of chicken KK34 gene in many mammals like cattle and pig, while remnants of KK34 can be found in human and mouse. Bovine KK34 was found to be transcribed, and its recombinant protein could induce STAT5 phosphorylation and proliferation of lymphocytes upon incubation with bovine PBMCs. This concludes that KK34 is a fourth functional cytokine of the IL-3/IL-5/GM-CSF/KK34-family (alias IL-5 family) in mammals. While analyzing KK34, the present study also made new identifications of cytokine genes in the extended TH2 cytokine loci for reptiles, birds and marsupials. This includes a hitherto unknown cytokine gene in birds and reptiles which we designated "IL 5famE". Other newly identified genes are KK34, GM-CSF(-like), IL-5, and IL-13 in reptiles, and IL-3 in marsupials. PMID- 27492646 TI - Molecular cloning of the rabbit interleukin 6 promoter: Functional characterization of rabbit hemorrhagic disease virus response elements in RK-13 cells. AB - Infection with rabbit hemorrhagic disease virus (RHDV) can cause acute liver failure (ALF), leading to severe mortality in rabbits. Inflammatory response, especially the expression of inflammatory cytokines such as interleukin (IL) 1beta, tumor necrosis factor (TNF)-alpha, and IL-6, may play major roles in mediating and amplifying the ALF. Among these cytokines, IL-6 is a multifunctional cytokine with a central role in various physiological inflammatory and immunological processes. In this study, we found that RHDV infection significantly upregulated IL-6 gene expression in vivo. Next, the rabbit IL-6 promoter was cloned and analyzed. Transfection of full-length RHDV cDNA in RK-13 cells upregulated the activity of the IL-6 promoter. A series of 5' deletion constructs demonstrated that AP-1 (activator protein 1), NF-IL6 (nuclear factor interleukin-6), and NF-kappaB (nuclear factor kappa B) elements were critical for RHDV-induced IL-6 transcription. Besides, the CREB (cAMP-response element binding protein) element may also play an accessory effect on RHDV induced IL-6 transcription. Collectively, the results elucidate the mechanism of IL-6 induction, and enrich the RHDV pathogenesis in rabbit. PMID- 27492647 TI - Percutaneous Balloon Aortic Valvuloplasty and Clinical Outcomes in Severe Aortic Stenosis: Correlation of Procedural Technique and Efficacy. AB - BACKGROUND: Percutaneous balloon aortic valvuloplasty (PBAV) is a palliative therapeutic option for relief of severe aortic stenosis (AS) in patients that are poor surgical or transcatheter aortic valve replacement (TAVR) candidates or as a bridge to definitive therapy. The outcomes following PBAV are highly variable and studies identifying factors that correlate with outcomes are sparse. The purpose of this study was to identify predictors at the time of the index procedures that can predict 1-year survival or need for repeat PBAV. METHODS: Demographic and procedural information of 505 PBAVs performed on 388 patients from January 1999 to December 2012 at the Deborah Heart and Lung Center were reviewed. Procedural data were compared across many variables and outcomes to identify predictors of outcomes. These predictors were statistically compared using chi-squared tests or Student's t-test. RESULTS: Of the 388 patients analyzed, 145 (37.4%) expired within 1 year following the index procedure. The cohort was then stratified into 3 groups based on the number of balloon inflations. They were similar with regard to baseline characteristics. The mean age was 81.9 +/- 9 years. Males constituted 51% of the cohort. Patients who underwent 2 and 3+ inflations had a 47.6% and 93.0% increase in the postprocedural aortic valve area compared to patients who had only 1 inflation. Patients who underwent 3+ inflations were significantly less likely to require a repeat PABV within a year and the repeat procedure free survival rate of 94.5% (P = 0.009). Despite improvement in valve area, there was no statistically significant difference in 1 year mortality between the groups (28.8% vs 42.9% vs 46.1% for 1 vs 2 vs 3+ inflations, respectively). CONCLUSIONS: PBAV provides a modest improvement in valve function and continues to be a safe and feasible option in experienced hands for select patients that are high risk for surgery or TAVR. The use of additional inflations during PBAV resulted in better long-term outcomes. PMID- 27492648 TI - Validity and reliability of the Bristol Stool Form Scale in healthy adults and patients with diarrhoea-predominant irritable bowel syndrome. AB - BACKGROUND: The Bristol Stool Form Scale (BSFS) is a 7-point scale used extensively in clinical practice and research for stool form measurement, which has undergone limited validity and reliability testing. AIM: To determine the validity and reliability of the BSFS in measuring stool form in healthy adults and patients with diarrhoea-predominant irritable bowel syndrome (IBS-D). METHODS: One hundred and sixty-nine healthy volunteers provided a stool sample and used the BSFS to classify stool form, which was compared with measured stool water content and with values from 19 patients with IBS-D. Eighty-six volunteers used the BSFS to classify 26 stool models to determine accuracy and reliability. RESULTS: Volunteers' classifications of stool type correlated with stool water (Spearman's rho = 0.491, P < 0.001), which increased in hard (Types 1-2), normal (Types 3-5) and loose stools (Types 6-7) (P < 0.001). The BSFS detected differences in stool form between healthy volunteers (mean 3.7, s.d. 1.5) and IBS D patients (mean 5.0, s.d. 1.2) (P < 0.001). Overall, 977/1204 (81%) stool models were correctly classified (substantial accuracy, kappa = 0.78), although <80% of Types 2, 3, 5 and 6 were classified correctly. On 852/1118 (76%) occasions, volunteers classified covert duplicate models to the same stool type (substantial reliability, kappa = 0.72), but with only moderate reliability for Types 2 (63%, kappa = 0.57) and 3 (62%, kappa = 0.55). CONCLUSIONS: The BSFS demonstrated substantial validity and reliability, although difficulties arose around clinical decision points (Types 2, 3, 5, 6) that warrant investigation in larger clinical populations. Potential for improving validity and reliability through modifications to the BSFS or training in its use should be explored. PMID- 27492649 TI - Mechanistic study of the radical SAM-dependent amine dehydrogenation reactions. AB - The radical SAM enzyme NosL catalyzes the conversion of l-Trp to 3-methyl-2 indolic acid, and this reaction is initiated by the 5'-deoxyadenosyl (dAdo) radical-mediated hydrogen abstraction from the l-Trp amino group. We demonstrate here that when d-Trp was used in the NosL reaction, hydrogen abstraction occurs promiscuously at both the amino group and Calpha of d-Trp. These results inspired us to establish the detailed mechanism of l-Trp amine dehydrogenation catalyzed by a NosL mutant, and to engineer a novel radical SAM-dependent l-Tyr amine dehydrogenase from the thiamine biosynthesis enzyme ThiH. PMID- 27492650 TI - A wide-necked extracranial internal carotid artery saccular aneurysm with ipsilateral proximal compression. AB - Extracranial internal carotid artery aneurysms (EICAA) are rare and can elicit various neurologic symptoms. Here, we present a case of a saccular EICAA compressing its proximal parent internal carotid artery (ICA). Ultrasonography demonstrated the proximal ICA stenosis and the "tardus-parvus" Doppler waveform downstream. The patient underwent aneurysmectomy and graft interposition. The histologic analysis highly supported an atypical fibromuscular dysplasia. Although this patient only showed a neck mass, the reduced ipsilateral cerebral blood supply was a potential cause for neurologic symptoms. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:116-120, 2017. PMID- 27492651 TI - Novel Genetic, Clinical, and Pathomechanistic Insights into TFG-Associated Hereditary Spastic Paraplegia. AB - Hereditary spastic paraplegias (HSPs) are genetically and clinically heterogeneous axonopathies primarily affecting upper motor neurons and, in complex forms, additional neurons. Here, we report two families with distinct recessive mutations in TFG, previously suggested to cause HSP based on findings in a single small family with complex HSP. The first carried a homozygous c.317G>A (p.R106H) variant and presented with pure HSP. The second carried the same homozygous c.316C>T (p.R106C) variant previously reported and displayed a similarly complex phenotype including optic atrophy. Haplotyping and bisulfate sequencing revealed evidence for a c.316C>T founder allele, as well as for a c.316_317 mutation hotspot. Expression of mutant TFG proteins in cultured neurons revealed mitochondrial fragmentation, the extent of which correlated with clinical severity. Our findings confirm the causal nature of bi-allelic TFG mutations for HSP, broaden the clinical and mutational spectra, and suggest mitochondrial impairment to represent a pathomechanistic link to other neurodegenerative conditions. PMID- 27492652 TI - Constructal approach to bio-engineering: the ocular anterior chamber temperature. AB - The aim of this work was to analyse the pressure inside the eyes anterior chamber, namedintraocular pressure (IOP), in relation to the biomechanical properties of corneas. The approach used was based on the constructal law, recently introduced in vision analysis. Results were expressed as the relation between the temperature of the ocular anterior chamber and the biomechanical properties of the cornea. The IOP, the elastic properties of the cornea, and the related refractive properties of the eye were demonstrated to be dependent on the temperature of the ocular anterior chamber. These results could lead to new perspectives for experimental analysis of the IOP in relation to the properties of the cornea. PMID- 27492653 TI - Extracorporeal Membrane Oxygenation (ECMO) for Hypothermic Cardiac Deterioration: A Case Series. AB - Accidental hypothermia can lead to untoward cardiac manifestations and arrest. This report presents a case series of severe accidental hypothermia with cardiac complications in three emergency patients who were treated with extracorporeal membrane oxygenation (ECMO) and survived after re-warming. The aim of this discussion was to encourage more clinicians to consider ECMO as a re-warming therapy for severe hypothermia with circulatory collapse and to prompt discussion about decreasing the barriers to its use. Niehaus MT , Pechulis RM , Wu JK , Frei S , Hong JJ , Sandhu RS , Greenberg MR . Extracorporeal membrane oxygenation (ECMO) for hypothermic cardiac deterioration: a case series. Prehosp Disaster Med. 2016;31(5):570-571. PMID- 27492654 TI - In silico and in vivo stability analysis of a heterologous biosynthetic pathway for 1,4-butanediol production in metabolically engineered E. coli. AB - Recently, several approaches have been published in order to develop a functional biosynthesis route for the non-natural compound 1,4-butanediol (BDO) in E. coli using glucose as a sole carbon source or starting from xylose. Among these studies, there was reported as high as 18 g/L product concentration achieved by industrial strains, however BDO production varies greatly in case of the reviewed studies. Our motivation was to build a simple heterologous pathway for this compound in E. coli and to design an appropriate cellular chassis based on a systemic biology approach, using constraint-based flux balance analysis and bi level optimization for gene knock-out prediction. Thus, the present study reports, at the "proof-of concept" level, our findings related to model-driven development of a metabolically engineered E. coli strain lacking key genes for ethanol, lactate and formate production (DeltapflB, DeltaldhA and DeltaadhE), with a three-step biosynthetic pathway. We found this strain to produce a limited quantity of 1,4-BDO (.89 mg/L BDO under microaerobic conditions and .82 mg/L under anaerobic conditions). Using glycerol as carbon source, an approach, which to our knowledge has not been tackled before, our results suggest that further metabolic optimization is needed (gene-introductions or knock-outs, promoter fine tuning) to address the redox potential imbalance problem and to achieve development of an industrially sustainable strain. Our experimental data on culture conditions, growth dynamics and fermentation parameters can consist a base for ongoing research on gene expression profiles and genetic stability of such metabolically engineered E. coli strains. PMID- 27492655 TI - Differences between prolonged weaning patients from medical and surgical intensive care units. AB - BACKGROUND: It is not clear whether patients entering a specialized, interdisciplinary weaning unit from surgical or medical intensive care units (ICU) distinguish substantially. The purpose of the present study was to assess differences in patients with prolonged weaning being referred from surgical and medical ICU. METHODS: Data collected from April 2013 to April 2014 was conducted for retrospective analysis. Mortality rates, demographic data, clinical, and microbial differences in 150 patients with prolonged weaning were assessed (80 surgical and 70 medical). RESULTS: Surgical ICU referrals tended to be older (70.7 +/- 11.3 vs. 67.3 +/- 12.3, P = 0.051) and had fewer underlying pulmonary diseases (45% vs. 60%, P = 0.067). Sodium values at the time of referral to the weaning unit were significantly higher in surgical (147.1 +/- 9.6) vs. medical (141.3 +/- 6.7 mmol/l) patients (P < 0.001). Each 10-unit increase in sodium at the time of referral to the weaning unit was associated with a 2.5-day (95% CI 0.4, 5.4; P = 0.09) prolongation of stay in the weaning unit. Although significant differences in microbiological agents from tracheal aspiration were seen, the infection rate on the weaning unit was similar in both groups. There was no difference in weaning unit mortality between surgical and medical ICU patients (18% vs. 23%; P = 0.41). CONCLUSION: Few differences were found between patients being referred to a specialized weaning unit from surgical vs. medical ICUs. Besides differences in microbiological characteristics of tracheal secretions, there were also differences in sodium levels, which appear to influence on treatment duration. PMID- 27492656 TI - Using L-STM to directly visualize enzymatic self-assembly/disassembly of nanofibers. AB - Self-assembly/disassembly is ubiquitous in nature and plays an important role in many biological events. But noninvasive characterization of this process in real time at molecular resolution remains challenging. Herein, using homebuilt liquid phase scanning tunneling microscopy (L-STM) with ultrahigh stability, we directly visualized enzymatic self-assembly/disassembly of oligopeptide nanofibers in real time for the first time. Static high-resolution L-STM images clearly showed the molecular packing details in the supramolecular nanofiber and the diameter of the nanofiber was consistent with that of cryo transmission electron microscopy (cryo TEM) observations. Moreover, the self-repairing behavior of the supramolecular nanofibers was also directly observed at high resolution for the first time. This work unprecedentedly revealed new insights into Nature-mimic self-assembly and disassembly at the molecular level. It also illustrates the potential of our homebuilt L-STM in studying delicate biological processes in physiological solution with high resolution. PMID- 27492657 TI - Effects of long-term iloprost treatment on right ventricular function in patients with Eisenmenger syndrome. AB - BACKGROUND: Right ventricular (RV) function is an important prognostic factor of pulmonary arterial hypertension (PAH), but there is insufficient data regarding RV function after long-term inhaled iloprost treatment. We evaluated the effect of long-term iloprost treatment on RV function in patients with Eisenmenger syndrome (ES). METHODS: Eleven consecutive patients with ES associated with congenital heart disease underwent echocardiographic measurements at baseline and 48 weeks after iloprost therapy. In addition, we recorded World Health Organization (WHO) functional class, 6-minute walk distance (6MWD), systemic arterial oxygen saturation (SaO2), and laboratory values such as hemoglobin, serum creatinine, and N-terminal pro-B natriuretic peptide. RESULTS: After 48 weeks of iloprost therapy, mean pulmonary arterial pressure (mPAP), pulmonary arterial systolic pressure (PASP), and pulmonary vascular resistance (PVR) were significantly decreased [mPAP, 42.5 (38.5-61.0) to 36.5 (29.1-40.0)mmHg; PASP, 92.6+/-19.9 to 74.5+/-23.8mmHg; PVR, 23.4 (19.8-26.0) to 23.4 (19.8-26.0)Wood unit respectively, all p<0.05]. There was also significant improvement in RV myocardial performance index [0.68 (0.61-0.80) to 0.52 (0.51-0.62), p=0.003] and RV longitudinal strain (-15.7+/-1.6 to -18.1+/-1.5%, p<0.001). In clinical assessment, WHO functional class (p=0.006), 6MWD (310.6+/-44.7 to 399.7+/-80.8m, p<0.001), and SaO2 (90.9+/-6.0% to 92.5+/-6.0%, p=0.022) were significantly improved. CONCLUSION: The improvement in echocardiographic parameters of the RV function after 48 weeks of iloprost therapy may provide insight on the efficacy of long-term iloprost treatment for RV functional improvement, which is a prognostic factor in patients with ES. PMID- 27492658 TI - Is a bare-metal stent still useful for improving the outcome of percutaneous coronary intervention? From the FU-Registry. AB - BACKGROUND: Percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) is increasingly being used for the treatment of coronary artery diseases. However, the role and effectiveness of PCI with a bare metal stent (BMS) have not yet been established. METHODS: Among the 2197 patients (2653 lesions) treated with PCI from 2003 to 2012 at three institutions in Fukuoka, 859 patients (1032 lesions) without acute coronary syndrome and in whom we were able to perform follow-up coronary angiography after stent placement and collect detailed data were selected for this study. Among the patients treated by BMS, the cut-off lesion reference for the development of in-stent restenosis (ISR) was calculated by comparing patients with and without ISR. In all patients with a lesion reference above/below the cut-off point of BMS-ISR, medium-term clinical and angiographic outcomes were compared between the BMS and DES groups. RESULTS: In patients treated with a BMS, the lesion reference [odds ratio 0.68, 95% confidence interval (CI) 0.43-0.97, p=0.03] was strongly correlated with ISR, and the area under the receiver operating characteristic curve was 0.704, with moderate accuracy. Calculation of the cut-off lesion reference for BMS-ISR, using a relative cumulative frequency distribution and a sensitivity/specificity curve, showed that the cut-off lesion reference for BMS-ISR was 3.08mm, and the sensitivity/specificity was 60.4%. For the DES and BMS groups in cases with a lesion reference over 3.08mm, BMS placement did not correlate with ISR (odds ratio 0.98, 95% CI 0.85-1.12), and there was also no correlation between BMS and major adverse cardiac events. CONCLUSION: In patients with a lesion reference?3.08mm, medium-term clinical and angiographic outcomes were equivalent between the use of a DES and BMS. Thus, BMS placement is well worth considering, especially in patients with a lesion reference?3.08mm, in whom double antiplatelet therapy needs to be stopped at an early stage. PMID- 27492660 TI - Efficient and stereocontrolled synthesis of chondroitin mono- and disaccharide linked to variously sulfated biotinylated trisaccharides of the linkage region of proteoglycans. AB - Efficient and stereocontrolled preparation of a library of variously sulfated biotinylated tetra- and pentasaccharides possessing the backbone of the partial linkage region plus the first chondroitin sulfate mono- or disaccharide unit (d GlcA)n-beta-d-(1,3)-GalNAc-beta-d-(1,4)-GlcA-beta-d-(1,3)-Gal-beta-d-(1,3)-Gal (n = 0 or 1) is reported herein for the first time. The synthesis of these compounds was achieved using common key intermediates and a disaccharide building block obtained by semisynthesis. Stereoselective glycosylation, selective protection/deprotection steps, efficient reduction of the N-trichloroacetyl group into the corresponding N-acetyl group, efficient sulfation strategy, deprotection and biotinylation afforded target oligomers in good yield with high purity. PMID- 27492659 TI - Severe prosthesis-patient mismatch after aortic valve replacement for aortic stenosis: Analysis of risk factors for early and long-term mortality. AB - BACKGROUND: Severe prosthesis-patient mismatch (PPM) is considered to further decrease survival compared to moderate PPM. This study aimed to assess the impact of severe PPM on survival after aortic valve replacement (AVR). METHODS: We retrospectively studied 2404 consecutive patients with PPM who underwent first time AVR for pure stenosis between January 2003 and December 2014. Mismatch was moderate for indexed effective valve orifice >0.65 to <0.85cm2/m2 and severe for indexed effective valve orifice <=0.65cm2/m2. Moderate mismatch occurred in 2165 patients (89%), and severe in 239 (11%) patients. Logistic multiple regression with bootstrapping and propensity score analyses were performed using 29 clinical and demographic data to assess the risk-adjusted impact of severe mismatch on mortality. The Cox proportional hazards model was constructed to process the long term outcome. RESULTS: Early mortality was 2.3% (51/2165) in moderate mismatch group and 3.7% (9/239) in severe mismatch group (p=0.2). Mortality at 5 and 10 years, was 218/1470 (14.8%) and 252/585 (43.1%) for moderate mismatch and 43/198 (21.7%) and 61/105 (58.1%) for severe mismatch (p=0.02 and p=0.006). Multivariable predictors of late mortality were as follows: age >=70 years, left ventricular ejection fraction <=40%, indexed left ventricular mass >220g/m2 and concomitant coronary artery revascularization. After propensity score matching, conditional logistic regression analysis demonstrated no relationship between severe mismatch and increased mortality at 5 postoperative years (HR, 0.9; 95% CI, 0.7-1.6; p=0.06), whereas it was significant at 10 postoperative years (HR, 1.9; 95% CI, 1.2-2.5; p=0.03). During the follow-up, severe mismatch was associated with more frequent hospital readmissions for cardiac events (0.12 vs. 0.08 events/patient/year, p=0.007). CONCLUSIONS: Patients with severe mismatch had lower long-term survival and higher incidence of hospital readmissions for cardiac events. However, the effect of severe mismatch on outcome appeared mainly related to the preoperative risk profile of each patient. PMID- 27492661 TI - Calls to suspend European sales of erlotinib for lung cancer. PMID- 27492662 TI - Open-Shell-Character-Based Molecular Design Principles: Applications to Nonlinear Optics and Singlet Fission. AB - Open-shell character, e. g., diradical character, is a quantum chemically well defined quantity in ground-state molecular systems, which is not an observable but can quantify the degree of effective bond weakness in the chemical sense or electron correlation strength in the physical sense. Because this quantity also correlates to specific excited states, physicochemical properties concerned with those states are expected to strongly correlate to the open-shell character. This feature enables us to open a new path to revealing the mechanism of these properties as well as to realizing new design principles for efficient functional molecular systems. This account explains the open-shell-character-based molecular design principles and introduces their applications to the rational design of highly efficient nonlinear optical and singlet fission molecular systems. PMID- 27492663 TI - Temporal evolution of urate crystal deposition over articular cartilage after successful urate-lowering therapy in patients with gout: An ultrasonographic perspective. AB - OBJECTIVE: To detect evolution of ultrasonographic signs of deposition of monosodium urate crystals (MSUC) in gouty joints by serial ultrasonography after initiation of urate-lowering therapy (ULT). METHODS: Adult gout patients were examined by serial ultrasonography after initiation of ULT with target serum uric acid (SUA) < 6 mg/dL. RESULTS: Thirty-eight male patients with gout with mean age of 50 +/- 11 years, median disease duration of 48 months and baseline mean SUA level of 8.8 +/- 1.5 mg/dL were recruited. Ultrasonographic evidence of MSUC deposition was detected in 89.74% of first metatarsophalangeal (MTP) joints and 27.63% of knee joints. Double contour sign (DCS), tophi, and hyperechoic spots (HES) were detected in 77.63%, 43.42%, and 19.74% of first MTPs, respectively. SUA level normalizes and plateaus after fourth month of follow-up. DCS thickness reduced significantly throughout the follow-up period. Overall, 86.25% DCS and 100% HES disappeared with median time of 6 months and 5.7 months, respectively. SUA normalization was the only significant predictor of DCS disappearance. CONCLUSIONS: Serial ultrasonographic determination of DCS, tophi, or HES during hypouricemic therapy is a noninvasive, effective method to detect the lowering of burden of urate load in gouty joints. PMID- 27492664 TI - A Novel Strategy for Preparation of Si-HA Coatings on C/C Composites by Chemical Liquid Vaporization Deposition/Hydrothermal Treatments. AB - A novel strategy for the preparation of Si-doped hydroxyapatite (Si-HA) coatings on H2O2-treated carbon/carbon composites (C/C) was developed. HA coating was prepared on C/C through chemical liquid vaporization deposition (CLVD)/hydrothermal treatment. HA coating was immersed in an H2SiO3 solution at an autoclave at 413 K for transformation into Si-HA coating. The effects of H2SiO3 mass contents on the phase, morphology, and composition of the Si-HA coatings were studied through SEM, EDS,XRD, and FTIR. Their bonding performance to C/C was measured through a scratch test. Under the optimal content condition, the in vitro skull osteoblast response behaviors of the Si-HA coating were evaluated. Results showed that SiO3(2-) could enter into the HA lattice and occupy the PO4(3-) sites. Doped SiO3(2-) significantly improved the bonding performance of the HA coating to C/C in comparison with the untreated HA. The adhesive strength of the coatings initially increased and then decreased with increasing H2SiO3 content. Meanwhile, the cohesive strength of the Si-HA coatings was almost nearly identical. The Si-HA coating achieved at a content of 90% H2SiO3 exhibited the best bonding performance, and its osteoblast compatibility in vitro was superior to that of the untreated HA coating on C/C through CLVD/hydrothermal treatment. PMID- 27492665 TI - Editorial Comment. PMID- 27492666 TI - Author Reply. PMID- 27492667 TI - Author Reply. PMID- 27492668 TI - Editorial Comment. PMID- 27492669 TI - The Society of Thoracic Surgeons Congenital Heart Surgery Database: 2016 Update on Research. AB - The Society of Thoracic Surgeons Congenital Heart Surgery Database (STS CHSD) is the largest congenital and pediatric cardiac surgical clinical data registry in the world. With more than 400,000 total operations from nearly all centers performing pediatric and congenital heart operations in North America, the STS CHSD is an unparalleled platform for clinical investigation, outcomes research, and quality improvement activities in this subspecialty. In 2015, several major original publications reported analyses of data in the CHSD pertaining to specific diagnostic and procedural groups, age-defined cohorts, or the entire population of patients in the database. Additional publications reported the most recent development, evaluation, and application of metrics for quality measurement and reporting of pediatric and congenital heart operation outcomes. This use of the STS CHSD for outcomes research and for quality measurement continues to expand as database participation and the available wealth of data in it continue to grow. This article reviews outcomes research and quality improvement articles published in 2015 based on STS CHSD data. PMID- 27492670 TI - The University of Minnesota Donor Lung Quality Index: A Consensus-Based Scoring Application Improves Donor Lung Use. AB - BACKGROUND: A simplified and consensus-based donor scoring process could improve donor lung use. METHODS: To develop the University of Minnesota Donor Lung Quality Index (UMN-DLQI), we used expert opinion to create an online survey that ranked 17 lung donor and recipient factors and graded their importance on a scale of 0 to 10. To arrive at consensus-based weights for each of the 17 factors, we used magnitude estimation (ME) methods. We performed receiver operating characteristic (ROC) analyses to evaluate predictive value. An application (app) was developed to simplify the scoring process. A second review process was instituted for every donor offer with an UMN-DLQI score greater than 40 as of September 2014 (post-donor score era). RESULTS: Worldwide, 11 transplantation centers (including ours) completed our survey. Results showed strong consensus among transplantation physicians across disparate practices. UMN-DLQI scores greater than 40 provided a sensitivity of 89%, a specificity of 55%, and a positive predictive value of 52% for donor offer acceptance. Number of transplants (63 versus 48) and donor lung use (15.1% versus 8.9%; p = 0.02) were significantly better in the post-donor score era without a penalty in transplantation outcomes. There was a trend toward a lower incidence of any primary graft dysfunction within 72 hours (40% versus 75%; p = 0.06) with a UMN DLQI greater than 40 but no difference in 30-day or 1-year survival. CONCLUSIONS: The UMN-DLQI scoring app is a simple tool for describing the attributes of a donor lung offer. More attention to scores greater than 40 safely improved donor lung use at a single institution. PMID- 27492672 TI - What about caregiving in spinal cord injury? PMID- 27492673 TI - Anxiety prevalence following spinal cord injury: a meta-analysis. PMID- 27492671 TI - Modeling the Myxomatous Mitral Valve With Three-Dimensional Echocardiography. AB - BACKGROUND: Degenerative mitral valve disease is associated with variable and complex defects in valve morphology. Three-dimensional echocardiography (3DE) has shown promise in aiding preoperative planning for patients with this disease but to date has not been as transformative as initially predicted. The clinical usefulness of 3DE has been limited by the laborious methods currently required to extract quantitative data from the images. METHODS: To maximize the utility of 3DE for preoperative valve evaluation, this work describes an automated 3DE image analysis method for generating models of the mitral valve that are well suited for both qualitative and quantitative assessment. The method is unique in that it captures detailed alterations in mitral leaflet and annular morphology and produces image-derived models with locally varying leaflet thickness. The method is evaluated on midsystolic transesophageal 3DE images acquired from 22 subjects with myxomatous degeneration and from 22 subjects with normal mitral valve morphology. RESULTS: Relative to manual image analysis, the automated method accurately represents both normal and complex leaflet geometries with a mean boundary displacement error on the order of one image voxel. A detailed quantitative analysis of the valves is presented and reveals statistically significant differences between normal and myxomatous valves with respect to numerous aspects of annular and leaflet geometry. CONCLUSIONS: This work demonstrates a successful methodology for the relatively rapid quantitative description of the complex mitral valve distortions associated with myxomatous degeneration. The methodology has the potential to significantly improve surgical planning for patients with complex mitral valve disease. PMID- 27492674 TI - Does an Online CBT Program for Anxiety Impact Upon Sleep Problems in Anxious Youth? AB - This study aimed to assess whether the transdiagnostic therapy elements of an online cognitive behaviour therapy anxiety program also impact on sleep-related problems (SRPs) in anxious youth. Participants were drawn from two previously published studies evaluating online cognitive behaviour therapy for child anxiety (BRAVE-ONLINE). The study included 63 children 7-12 years of age (M = 9.49, SD = 1.37) and 71 adolescents 12-18 years of age (M = 13.90, SD = 1.68). SRPs, severity of anxiety diagnosis, anxiety symptoms, number of diagnoses, depressive symptoms, and global functioning were assessed at pre-, post-, and 6-month follow up assessment points. SRPs were positively related to anxiety symptoms and severity for children and were positively related to depression for adolescents. SRPs did not differ between male and female participants, between children and adolescents, or between those who had generalised anxiety disorder in their profile and those who did not. Finally, children but not adolescents participating in the online program demonstrated a significantly greater reduction in SRPs from pre- to posttreatment compared to the waitlist group, and these gains were maintained at 6-month follow-up. Treatment focusing on child anxiety alone may reduce SRPs in children but not adolescents. Although further research is clearly needed, clinicians should ensure that they assess for SRPs in their teenage clients and directly target SRPs in treatment where required. PMID- 27492675 TI - Hallucinatory experience as aberrant event memory formation: Implications for the pathophysiology of schizophrenia. AB - If hallucinations are not fundamentally different from normal wakeful experiences, then the neural basis of hallucinations has to be essentially that of consciousness in general. The additional insight that consciousness reflects the formation (as opposed to consolidation) of event (episodic) memories links the pathophysiology of hallucinations to the hippocampus. Perceptions and misperceptions, insofar as they are consciously experienced, constitute contextualized and unitary phenomena (which are embedded as discrete events in the stream of consciousness); they are experiential manifestations of activity patters that recurrently emerge in the CA3 network of the hippocampus (and that are secondarily consolidated into retrievable and declarable memories). The hippocampus, forming allocentric representations of objects in their world context (event memories), is a point of convergence of neocortical sensory processing streams. Moreover, being extensively modulated by the organism's physiological state, the hippocampus embeds such representations in an emotional context and, through its output to the medial prefrontal cortex, guides decision making and goal-selection processes. Although sensory and associative processing in the neocortex makes an important contribution to the formation of behaviourally adaptive representations in the hippocampus, it is becoming clearer that pattern formation in the hippocampus is in itself the neural correlate of consciousness and that disruptions in relational memory processing in the hippocampus can give rise to hallucinations. Neurobiological and neuroimaging findings in schizophrenia research can be integrated within the proposed conceptual framework. PMID- 27492676 TI - Substance Abuse Treatment Patients in Housing Programs Respond to Contingency Management Interventions. AB - Use of homeless and transitional housing (e.g., recovery homes) programs can be associated with success in substance abuse treatment, perhaps because many of these programs encourage or mandate sobriety. In this study, we examined whether contingency management (CM) protocols that use tangible incentives for submission of drug-free specimens or other specific behaviors are effective for treatment seeking substance abusers whose behavior may also be shaped by housing programs. Of 355 participants in randomized trials of CM, 56 (16%) reported using transitional housing during the 12-week treatment period. Main and interaction effects of housing status and treatment condition were evaluated for the primary substance abuse treatment outcomes: a) longest duration of abstinence from alcohol, cocaine, and opioids, b) percentage of samples submitted that were negative for these substances, and c) treatment retention. After controlling for demographic and clinical characteristics, those who accessed housing programs submitted a higher percentage of negative samples (75%) compared to those who did not access housing programs (67%). Housing status groups did not differ in terms of longest duration of abstinence (accessed housing: M=3.1 weeks, SE=0.6; did not access housing: M=3.9 weeks, SE=0.3) or retention in substance abuse treatment (accessed housing: M=6.4 weeks, SE=0.6; did not access housing: M=6.6 weeks, SE=0.3). Regardless of housing status, CM was associated with longer durations of abstinence and treatment retention. No interactive effects of housing and treatment condition were observed (p>.05). Results suggest that those who accessed housing programs during substance abuse treatment benefit from CM to a comparable degree as their peers who did not use such programs. These effects suggest that CM remains appropriate for those accessing housing in community based programs. PMID- 27492677 TI - Diabetes drugs in England cost nearly L1bn last year. PMID- 27492679 TI - Celiac Disease Presenting as Profound Diarrhea and Weight Loss - A Celiac Crisis. AB - BACKGROUND Celiac disease is a hypersensitivity enteropathy that can have various presentations in adults. Rarely, patients can present with severe lab abnormalities, dehydration and weight loss caused by celiac disease - a celiac crisis. CASE REPORT A 46-year-old male with a past medical history significant for diabetes mellitus, type 2 (DM2) and recently treated Bell's Palsy presented to the emergency room complaining of weakness, diarrhea and lightheadedness. On presentation, the patient had a systolic blood pressure (SBP) of 60 mm Hg and a lactic acidosis with pH of 7.28. Infectious etiologies of diarrhea were ruled out. The patient had an EGD which showed erythema of the duodenal bulb. Serum anti-gliadin and anti-TTG IgA were both elevated suggesting Celiac disease. Biopsies showed histopathology consistent with celiac disease. The patient's diarrhea resolved after initiation of a gluten free diet. He gained 25 kilograms after discharge and did not require further hospitalizations for diarrhea. CONCLUSIONS Celiac crisis is a very rare presentation of celiac disease in adults but nonetheless should be considered in patients with marked metabolic derangements in the setting of osmotic diarrhea. Treatment consists of a gluten free diet and may require management with steroids and total parenteral nutrition (TPN). PMID- 27492678 TI - Economic growth, urbanization, globalization, and the risks of emerging infectious diseases in China: A review. AB - Three interrelated world trends may be exacerbating emerging zoonotic risks: income growth, urbanization, and globalization. Income growth is associated with rising animal protein consumption in developing countries, which increases the conversion of wild lands to livestock production, and hence the probability of zoonotic emergence. Urbanization implies the greater concentration and connectedness of people, which increases the speed at which new infections are spread. Globalization-the closer integration of the world economy-has facilitated pathogen spread among countries through the growth of trade and travel. High-risk areas for the emergence and spread of infectious disease are where these three trends intersect with predisposing socioecological conditions including the presence of wild disease reservoirs, agricultural practices that increase contact between wildlife and livestock, and cultural practices that increase contact between humans, wildlife, and livestock. Such an intersection occurs in China, which has been a "cradle" of zoonoses from the Black Death to avian influenza and SARS. Disease management in China is thus critical to the mitigation of global zoonotic risks. PMID- 27492680 TI - Size dependent microbial oxidation and reduction of magnetite nano- and micro particles. AB - The ability for magnetite to act as a recyclable electron donor and acceptor for Fe-metabolizing bacteria has recently been shown. However, it remains poorly understood whether microbe-mineral interfacial electron transfer processes are limited by the redox capacity of the magnetite surface or that of whole particles. Here we examine this issue for the phototrophic Fe(II)-oxidizing bacteria Rhodopseudomonas palustris TIE-1 and the Fe(III)-reducing bacteria Geobacter sulfurreducens, comparing magnetite nanoparticles (d ~ 12 nm) against microparticles (d ~ 100-200 nm). By integrating surface-sensitive and bulk sensitive measurement techniques we observed a particle surface that was enriched in Fe(II) with respect to a more oxidized core. This enables microbial Fe(II) oxidation to occur relatively easily at the surface of the mineral suggesting that the electron transfer is dependent upon particle size. However, microbial Fe(III) reduction proceeds via conduction of electrons into the particle interior, i.e. it can be considered as more of a bulk electron transfer process that is independent of particle size. The finding has potential implications on the ability of magnetite to be used for long range electron transport in soils and sediments. PMID- 27492681 TI - A Novel Fluorimetric Bulk Optode Membrane Based on NOS Tridentate Schiff Base for Selective Optical Sensing of Al3+ Ions. AB - A novel fluorimetric optode has been developed for the highly selective and sensitive for the determination of ultra trace amounts of Al3+ ions. The proposed fluorescent optode is based on the incorporation of a simple and effective fluorescent sensor tridentate NOS Schiff base N-(2-hydroxynaphthylidene)-2 aminothiophenol (H2L) in a plasticized PVC containing KTpClPB as a lipophilic anionic additive. H2L was synthesized by a facile one-step Schiff base reaction. The plasticized PVC-membrane displays a calibration response for Al3+ ions over a wide concentration range from 1.0 * 10-9 to 4.4 * 10-3 mol/L. The fluorescence signal of the optode membrane can be easily recovered by immersion in 0.01 M EDTA. In addition to high stability and reproducibility, the sensor shows a unique selectivity towards Al3+ ion with respect to common co-existing cations, particularly Ga3+and In3+. The proposed optode was applied successfully for determination of Al3+ in some real samples, including bottled drinking waters, bottled mineral waters and soft drinks. PMID- 27492682 TI - RhoGTPases at the synapse: An embarrassment of choice. AB - Activity-dependent modifications in the strength of excitatory synapses are considered to be major cellular mechanisms that contribute to the plasticity of neuronal networks underlying learning and memory. Key mechanisms for the regulation of synaptic efficacy involve the dynamic changes in size and number of dendritic spines, as well as the synaptic incorporation and removal of AMPA-type glutamate receptors (AMPAr). As key regulators of the actin cytoskeleton, the Rho subfamily of GTP-binding proteins play a critical role in synaptic development and plasticity. They shuttle between the active GTP-bound form and the inactive GDP-bound form under the regulation of dedicated guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). More than 80 human GEFs and 70 GAPs have been identified, most of which are expressed in the brain with a specific spatial and temporal expression pattern. However, the function of most GEFs and GAPs in the brain has not been elucidated. In this review, we highlight the novel neuronal function of the synaptic RhoGAP ARHGAP12 and the ID-associated RhoGEF TRIO and further propose 3 possible approaches of neurons utilizing Rho GTPase regulatory proteins to accurately modulate synaptic function. PMID- 27492683 TI - Antimicrobial susceptibility of lactic acid bacteria isolated from human and food producing animal feces in Khon Kaen Province, Thailand. AB - The aim of this study was to investigate the susceptibility of 93 Lactobacillus strains to seven antimicrobial agents, i.e., penicillin G, amoxicillin-clavulanic acid, vancomycin, tetracycline, streptomycin, ciprofloxacin, and sulfamethoxazole trimethoprim, by disk diffusion test. The Lactobacillus strains were isolated from fecal samples taken from 90 healthy, food-producing animals (fattening pigs, free-grazing ducks, and beef cattle) and 30 healthy human subjects (1- to 6-year olds) in Khon Kaen. The minimum inhibitory concentration (MIC) values of tetracycline and ciprofloxacin against all strains were determined using the E test. All 93 Lactobacillus isolates were identified at the species level using 16S rRNA gene sequencing. The most common species of Lactobacillus isolated from fattening pigs, free-grazing ducks, beef cattle, and humans were L. reuteri (30 %), L. salivarius (46.7 %), L. acetotolerans (20 %), and L. gasseri (33.3 %), respectively. A total of 83 Lactobacillus strains were resistant to the examined antibiotics. Some strains were resistant to two to six types of antibiotics. More than 50 % of Lactobacillus species were intrinsically resistant to vancomycin, streptomycin, ciprofloxacin, and sulfamethoxazole-trimethoprim. The prevalence of acquired resistance to tetracycline was observed for Lactobacillus isolates from fattening pigs, humans, free-grazing ducks, and beef cattle at 92.3, 85.7, 77.8, and 68.4 %, respectively. These results demonstrate the impact of antibiotic use in human and veterinary medicine on antibiotic treatment efficacy and may support the spread of transferable antibiotic resistant genes to other bacteria via the food chain. PMID- 27492684 TI - Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis. AB - Targeted disruption of leukocyte trafficking to the gut represents a promising approach for the treatment of inflammatory bowel diseases (IBDs). CCR5, the shared receptor for MIP1alpha and beta and RANTES, is expressed by multiple leukocytes. Here, we aimed to determine the role of CCR5 in mediating leukocyte trafficking in models of colitis, and evaluate the therapeutic potential of maraviroc, an orally active CCR5 antagonist used in the treatment of CCR5-tropic HIV. Acute and chronic colitis were induced by administration of DSS or TNBS to wild-type and CCR5(-/-) mice or adoptive transfer of splenic naive CD4(+) T-cells from wild type or CCR5(-/-) mice into RAG-1(-/-). CCR5 gene ablation reduced the mucosal recruitment and activation of CCR5-bearing CD4(+) and CD11b(+) leukocytes, resulting in profound attenuation of signs and symptoms of inflammation in the TNBS and transfer models of colitis. In the DSS/TNBS colitis and in the transfer model, maraviroc attenuated development of intestinal inflammation by selectively reducing the recruitment of CCR5 bearing leukocytes. In summary, CCR5 regulates recruitment of blood leukocytes into the colon indicating that targeting CCR5 may offer therapeutic options in IBDs. PMID- 27492685 TI - Neighborhood Stigma and Sleep: Findings from a Pilot Study of Low-Income Housing Residents in New York City. AB - The primary objective of this study was to investigate the relationship between neighborhood stigma and sleep in a sample of low-income housing residents in New York City. Data were derived from the NYC Low-Income Housing, Neighborhoods, and Health Study (N = 120). Adults living in low-income housing completed a survey consisting of measures of neighborhood stigma, sleep quality, and sleep duration. Neighborhood stigma and sleep were self-reported. Associations between neighborhood stigma and sleep health were analyzed using generalized linear models with cluster variance estimation. Multivariable models adjusted for age, gender, race/ethnicity, income, education, employment status, obesity, the census block percentage of non-Hispanic black residents, and the census block percentage median household income. Results indicate that a reported negative media perception of the neighborhood was negatively associated with sleep quality and duration (p < 0.01). However, additional research is needed to explore neighborhood stigma as it relates to sleep. PMID- 27492686 TI - Satisfying Results of Primary Hip Arthroplasty in Patients With Hip Dysplasia at a Mean Followup of 20 Years. AB - BACKGROUND: Developmental dysplasia of the hip (DDH) is a common cause of secondary osteoarthritis (OA) in younger patients, and when end-stage OA develops, a THA can provide a solution. Different options have been developed to reconstruct these defects, one of which is impaction bone grafting combined with a cemented cup. To determine the true value of a specific technique, it is important to evaluate patients at a long-term followup. As there are no long-term studies, to our knowledge, on THA in patients with DDH using impaction bone grafting with a cemented cup, we present the results of this technique at a mean of 15 years in patients with previous DDH. QUESTIONS/PURPOSES: We wished to determine (1) the long-term probability of cup revision at a minimum followup of 15 years for cemented acetabular impaction bone grafting in patients with DDH; (2) the radiographic appearance of the bone graft and radiographic signs of implant loosening; and (3) the complications and pre- and postoperative Harris hip scores with cemented THA combined with impaction bone grafting in patients with previous DDH. METHODS: Between January 1984 and December 1995 we performed 28 acetabular impaction bone grafting procedures for secondary OA believed to be caused by DDH in 22 patients; four patients died before 15 years, leaving 24 hips in 18 patients for retrospective analysis at a minimum of 15 years (mean, 20 years; range, 16-29 years). The diagnosis of DDH was made according to preoperative radiographs and intraoperative findings. All grades of dysplasia were included; five patients had Crowe Group I, eight had Group II, nine had Group III, and two had Group IV DDH. No patients were lost to followup. In all cases the acetabular defects were combined cavitary and segmental. Owing to the high number of deaths, we performed a competing-risk analysis to determine the probability of cup revision surgery. RESULTS: The competing-risk analysis showed cumulative incidences at 15 and 20 years, with endpoint revision for any reason of 7% (95% CI, 0%-17%), whereas this was 4% (95% CI, 0%-11%) with endpoint revision of the cup for aseptic loosening. Three revision surgeries were performed. Two cup revisions were performed for aseptic loosening at 12 and 26 years. Another cup revision was performed owing to sciatic nerve problems at 2 years. A stable radiographic appearance of the graft was seen in 19 of the 25 unrevised hips. Four hips showed acetabular radiolucent lines and two showed acetabular osteolysis. None of the unrevised cups showed migration or radiographic failure. Postoperative complications included a pulmonary embolus and a superficial wound infection. The Harris hip score improved from 37 (range, 9-72) preoperatively to 83 (range, 42-99) at latest followup. CONCLUSIONS: Cemented primary THA with the use of impaction bone grafting shows satisfying long-term results in patients with previous DDH. For future research it is important to evaluate this technique in a larger cohort with a long-term followup. Other techniques also should be evaluated at long-term followup to be able to compare different techniques in this important and specific patient group. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 27492687 TI - Novel Augmentation Technique for Patellar Tendon Repair Improves Strength and Decreases Gap Formation: A Cadaveric Study. AB - BACKGROUND: Patellar tendon ruptures commonly are repaired using transosseous patellar drill tunnels with modified-Krackow sutures in the patellar tendon. This simple suture technique has been associated with failure rates and poor clinical outcomes in a modest proportion of patients. Failure of this repair technique can result from gap formation during loading or a single catastrophic event. Several augmentation techniques have been described to improve the integrity of the repair, but standardized biomechanical evaluation of repair strength among different techniques is lacking. QUESTIONS/PURPOSES: The purpose of this study was to describe a novel figure-of-eight suture technique to augment traditional fixation and evaluate its biomechanical performance. We hypothesized that the augmentation technique would (1) reduce gap formation during cyclic loading and (2) increase the maximum load to failure. METHODS: Ten pairs (two male, eight female) of fresh-frozen cadaveric knees free of overt disorders or patellar tendon damage were used (average donor age, 76 years; range, 65-87 years). For each pair, one specimen underwent the standard transosseous tunnel suture repair with a modified-Krackow suture technique and the second underwent the standard repair with our experimental augmentation method. Nine pairs were suitable for testing. Each specimen underwent cyclic loading while continuously measuring gap formation across the repair. At the completion of cyclic loading, load to failure testing was performed. RESULTS: A difference in gap formation and mean load to failure was seen in favor of the augmentation technique. At 250 cycles, a 68% increase in gap formation was seen for the control group (control: 5.96 +/- 0.86 mm [95% CI, 5.30-6.62 mm]; augmentation: 3.55 +/- 0.56 mm [95% CI, 3.12-3.98 mm]; p = 0.02). The mean load to failure was 13% greater in the augmentation group (control: 899.57 +/- 96.94 N [95% CI, 825.06-974.09 N]; augmentation: 1030.70 +/- 122.41 N [95% CI, 936.61-1124.79 N]; p = 0.01). CONCLUSIONS: This biomechanical study showed improved performance of a novel augmentation technique compared with the standard repair, in terms of reduced gap formation during cyclic loading and increased maximum load to failure. CLINICAL RELEVANCE: Decreased gap formation and higher load to failure may improve healing potential and minimize failure risk. This study shows a potential biomechanical advantage of the augmentation technique, providing support for future clinical investigations comparing this technique with other repair methods that are in common use such as transosseous suture repair. PMID- 27492689 TI - A response to: "Evaluation of pain". PMID- 27492688 TI - When Can I Drive After Orthopaedic Surgery? A Systematic Review. AB - BACKGROUND: Patients often ask their doctors when they can safely return to driving after orthopaedic injuries and procedures, but the data regarding this topic are diverse and sometimes conflicting. Some studies provide observer reported outcome measures, such as brake response time or simulators, to estimate when patients can safely resume driving after surgery, and patient survey data describing when patients report a return to driving, but they do not all agree. We performed a systematic review and quality appraisal for available data regarding when patients are safe to resume driving after common orthopaedic surgeries and injuries affecting the ability to drive. QUESTIONS/PURPOSES: Based on the available evidence, we sought to determine when patients can safely return to driving after (1) lower extremity orthopaedic surgery and injuries; (2) upper extremity orthopaedic surgery and injuries; and (3) spine surgery. METHODS: A search was performed using PubMed and EMBASE(r), with a list of 20 common orthopaedic procedures and the words "driving" and "brake". Selection criteria included any article that evaluated driver safety or time to driving after major orthopaedic surgery or immobilization using observer-reported outcome measures or survey data. A total of 446 articles were identified from the initial search, 48 of which met inclusion criteria; abstract-only publications and non-English language articles were not included. The evidence base includes data for driving safety on foot, ankle, spine, and leg injuries, knee and shoulder arthroscopy, hip and knee arthroplasty, carpal tunnel surgery, and extremity immobilization. Thirty-four of the articles used observer-reported outcome measures such as total brake time, brake response time, driving simulator, and standardized driving track results, whereas the remaining 14 used survey data. RESULTS: Observer reported outcome measures of total brake time, brake response time, and brake force postoperatively suggested patients reached presurgical norms 4 weeks after right-sided procedures such as TKA, THA, and ACL reconstruction and approximately 1 week after left-sided TKA and THA. The collected survey data suggest patients resumed driving 1 month after right-sided and left-sided TKAs. Patients who had THA reported returning to driving between 6 days and 3 months postoperatively. Observer-reported outcome measures showed that patients' driving abilities often are impaired when wearing an immobilizing cast above or below the elbow or a shoulder sling on their dominant arm. Patients reported a return to driving on average 2 months after rotator cuff repair procedures and approximately 1-3 months postoperatively for total shoulder arthroplasties. Most patients with spine surgery had normal brake response times at the time of hospital discharge. Patients reported driving 6 weeks after total disc arthroplasty and anterior cervical discectomy and fusion procedures. CONCLUSIONS: The available evidence provides a best-case scenario for when patients can return to driving. It is important for observer-reported outcome measures to have normalized before a patient can consider driving, but other factors such as strength, ROM, and use of opioid analgesics need to be considered. This review can provide a guideline for when physicians can begin to consider evaluating these other factors and discussing a return to driving with patients. Survey data suggest that patients are returning to driving before observer-reported outcome measures have normalized, indicating that physicians should tell patients to wait longer before driving. Further research is needed to correlate observer-reported outcome measures with adverse events, such as motor vehicle accidents, and clinical tests that can be performed in the office. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 27492690 TI - Reimbursment of the serum CTX assay in France: the clinical biology nomenclature is incoherent. PMID- 27492691 TI - Interest of fecal calprotectine dosage in inflammatory bowel diseases, state of the art and perspectives. AB - Inflammatory bowel diseases are chronic diseases that result from an inflammation of the intestinal wall. They are suspected in any patient presenting with intestinal symptoms. Until recently, diagnosis was mainly based both on clinical and endoscopic arguments. The use of an easy, fast, reliable, non-invasive and inexpensive test must not only assist in the diagnosis but also contribute to their evolutionary and therapeutic monitoring. To date, fecal calprotectin is the most documented in this perspective. This marker allows to discriminate between functional and organic bowel processes with good sensitivity and good specificity. The determination of the fecal calprotectin level in stools contributes to the evaluation of the degree of disease activity and monitoring of therapeutic response. PMID- 27492692 TI - Circulating endothelial cells: a new biomarker of endothelial dysfunction in hematological diseases. AB - The endothelium and its integrity are in the center of numerous cardiovascular, pulmonary and tumoral diseases. Several studies identified different circulating cellular sub-populations, which allow a noninvasive exploration of endothelial dysfunction. Furthermore, angiogenesis plays a major role in the biology of benign and malignant hematologic diseases. Among these biomarkers, circulating endothelial cells could be considered as a marker of endothelial injury and/or endothelial activation as well as vascular remodeling, whereas circulating endothelial progenitor cells would be only involved in the vascular regeneration. In the future, the quantification of circulating endothelial cells in many diseases could be a noninvasive biomarker used in diagnosis, prognostic and therapeutic follow-up of lung vasculopathy and/or residual disease of hematological malignancies. PMID- 27492693 TI - Diagnosis of congenital fibrinogen disorders. AB - Congenital fibrinogen disorders comprise quantitative disorders defined by a complete absence (afibrinogenemia) or by a decreased level (hypofibrinogenemia) of circulating fibrinogen and qualitative disorders characterized by a discrepancy between the activity and the antigenic levels of fibrinogen (dysfibrinogenemia and hypodysfibrinogenemia). The biological diagnosis is based on a standard haemostasis assessment. All the coagulation tests that depend on the formation of fibrin as the end point are affected; although in dysfibrinogenemia the specificity and sensitivity of routine test depend on reagent and techniques. A genetic exploration permits to confirm the diagnosis and may enhance the prediction of the patient's phenotype. Homozygous or composite heterozygous null mutations are most often responsible for afibrinogenemia while hypofibrinogenemic patients are mainly heterozygous carrier of an afibrinogenemic allele. Heterozygous missense mutations are prevalent in dysfibrinogenemia, with two hot spot localized in exon 2 of the FGA and in the exon 8 of the FGG. The correlation between phenotype and genotype has been identified in some fibrinogen variants, including six mutations clustered in exons 8 and 9 of the FGG leading to hypofibrinogenemia with hepatic inclusions of abnormal fibrinogen aggregates as well as a few mutations associated with an increase risk of thrombotic events. A familial screening and additional functional assays should be carried out when possible. PMID- 27492694 TI - How to interpret cardiac biomarkers in renal failure and elderly? AB - New highly sensitive (hs) assays have challenged the interpretation of cardiac troponins (cTn) as markers of injury while natriuretic peptides remain the markers of choice for myocardial dysfunction. However, variability extracardiac factors such as age, gender and renal function may alter circulating levels. In chronic kidney disease (CKD), the increase in circulating levels of these biomarkers in the absence of cardiac disease underlines the problem of discriminative value for diagnosis as well as the need to redefine the thresholds. In addition, these biomarkers are of potential interest to stratify cardiovascular risk, the leading cause of death in CKD. The aim of this work is to clarify the effect of age and renal function on circulating levels of high sensitivity troponins and natriuretic peptides. PMID- 27492695 TI - Lactobacillus crispatus as biomarker of the healthy vaginal tract. AB - Decades of research have shown that the lactobacilli inhabiting the human vagina are the first line of defense in the female urogenital and reproductive tracts. In healthy cervicovaginal microbiota, Lactobacillus crispatus is prevalent and beneficial with production of copious amounts of lactic acid potent broad spectrum bactericide virucide and immunomodulator. Future and preventic approaches may need to include probiotics, prebiotics also have the potential to optimize and restore the vaginal ecosystem. PMID- 27492696 TI - IFM (Intergroupe francophone du myelome) recommendations for uniform interpretation of serum and urine protein electrophoresis in multiple myeloma diagnosis and follow-up. AB - Serum and urine proteins electrophoresis take a major place in multiple myeloma management, at time of diagnosis, during follow-up for treatment response evaluation and also in detection of relapse. The Intergroupe francophone du myelome (IFM) suggests recommendations to clinicians and biologists, to perform and interpret these biochemical analysis, with the objective of harmonizing practices between laboratories and improving patients' follow-up. PMID- 27492697 TI - Is it worth to report the presence of a single and additional band in the cerebrospinal fluid detected by isoelectrofocusing? AB - Despite the revisions of the Mac Donald criteria of multiple sclerosis (MS) in 2010, the cerebrospinal fluid (CSF) analysis by isoelectrofocusing (IEF) remains useful for atypical presentations of MS. The IEF is considered as positive when at least two or more additional bands are detected in the CSF by comparison with the patient's serum but sometimes, the IEF interpretation is more difficult. The goal of our study was to determine the significance when a single band in the CSF is detected by IEF. We conducted a retrospective study on 990 patients who underwent a lumbar puncture followed by a CSF analysis by IEF. Only 2% display such IEF profile (i.e. single and additional band in the CSF). A diagnosis of clinically isolated syndrome or MS was evidenced in 4 among those 21 patients. In conclusion, our data suggest that even if the presence of a single and additional band in the CSF is a rare situation, it should be mentioned to clinicians to not exclude the hypothesis of an inflammatory demyelinating disease of the central nervous system. PMID- 27492698 TI - Next generation sequencing with a semi-conductor technology (Ion Torrent PGMTM) for HLA typing: overall workflow performance and debate. AB - Current high resolution HLA typing technologies produce ambiguous results, and it is often necessary to perform additionnal tests to resolve these ambiguities. Next generation sequencing is a promising technology, which can overcome this problem. It is going to usher a new strategy to determine HLA compatibility between donor and recipient. It can lead to non ambiguous results by analysing the full amplified sequence of HLA genes and by eliminating heterozygote phase ambiguities. Instead, as many new techniques, we can face several problems, such as analysis difficulties because of incomplete HLA sequences in the database or errors related to the sequencing instrumentation. Moreover, the clinical relevance of analysing non coding regions of HLA genes is not well understood, but raise questions about the interest of getting HLA full sequence to understand drugs side effects or pathogenesis of infectious or auto-immune diseases. Our objective in this article is to present a commercial workflow for HLA typing by NGS, on Ion Torrent PGMTM sequencer, and to focus attention about pitfalls encountered during the analysis. PMID- 27492699 TI - PT, aPTT, TT and the hemostatic safety threshold of dabigatran and rivaroxaban. AB - The proposals of the Working group on perioperative hemostasis (Groupe d'interet en hemostase peri-operatoire (GIHP)) concerning the perioperative management of patients receiving the direct oral anticoagulants (DOACs) are based on the measure of their anticoagulant activities (anti-Xa for rivaroxaban and anti-IIa for dabigatran) with a safety threshold <= 30 ng/mL. If the dosage of the drug is not available, proposals are based on the combination of a PT >=80% and an aPTT <=1.20. The aim of our study was to evaluate the performance of PT, aPTT and thrombin time to predict values above or below the safety threshold. The measurement of DOACs concentration was carried out in 64 samples from patients treated with rivaroxaban and 48 samples from patients treated with dabigatran. The PT and aPTT were measured for all samples, while the TT was measured only for patients receiving dabigatran. The absence of agreement between the global hemostasis tests and the DOACs concentrations was observed for 10% of patients receiving dabigatran and 27% of patients with rivaroxaban treatment. Apart from dabigatran for which the predictive negative value of PT and aPTT or TT allows to exclude a concentration >30 ng/mL in 100% of cases, our results highlight the risk of misinterpretation when using global coagulation tests (PT and aPPT) for determination of the safety threshold for patients receiving the DOACs. PMID- 27492700 TI - 24 hours calciuria: normal values, regulations: about a cohort of 317 control subjects. AB - In a control population, we filed the 24-hour urinary calcium to set normal values, based on weight, BMI and menopause. By assessing calcium intake, 25OHD, PTH, CTX, GFR, we wanted to study how these could influence calcium excretion. A total of 317 subjects of 55.82 +/- 12.6 years were studied: 249 women (210 were postmenopausal) and 66 men. Mean urinary calcium 24h was 4.07 +/- 2.53 mmol: 3.99 +/- 2.89 in men, 3.54 +/- 2.44 in premenopausal women, 4.18 +/- 2.42 in postmenopausal women. 24-hour urine calcium was lower in overweight subjects whether they are men or women. It was positively correlated to 25OHD, CTX, GFR, serum calcium and negatively to PTH, BMI and weight. In conclusion, urinary calcium was lower in overweight subjects, it increases after menopause. Dietary calcium intake seems little involved in explaining variations in urinary calcium which depends essentially on bone remodeling (CTX), GFR, levels of vitamin D and PTH. PMID- 27492701 TI - Isolated methylmalonic acidemia: a case report. AB - Isolated methylmalonic acidemia (AMR) is an inborn error of metabolism due to an enzymatic deficit in methylmalonyl-CoA mutase. AMR lead to increased methylmalonic acid in plasma and urine without hyperhomocysteinemia. The clinical signs are recurrent episodes of ketoacidosis and bouts of vomiting, dehydration and mental retardation. These symptoms do not respond to the administration of vitamin B12. We report a case of a ten-months-old infant to whom the diagnosis was suspected in the presence of a metabolic acidosis, hyperammonemia, without hepatic impairment and ketosis. The chromatography of organic acids showed elevated methylmalonic acid levels. Molecular genetics allowed confirming the diagnosis of deficit in methylmalonyl-CoA mutase demonstrating the genetic abnormality of the gene MUT. PMID- 27492702 TI - A paperless autoimmunity laboratory: myth or reality? AB - Testing for antinuclear antibodies is the most frequently prescribed analysis for the diagnosis of rheumatic diseases. Indirect immunofluorescence remains the gold standard method for their detection despite the increasing use of alternative techniques. In order to standardize the manual microscopy reading, automated acquisition and interpretation systems have emerged. This publication enables us to present our method of interpretation and characterization of antinuclear antibodies based on a cascade of analyses and to share our everyday experience of the G Sight from Menarini. The positive/negative discrimination on Hep cells 2000 is correct in 85% of the cases. In most of the false negative results, it is a question of aspecific or low titers patterns, but a few cases of SSA speckled patterns of low titers demonstrated a probability index below 8. Regarding the pattern recognition, some types and mixed patterns are not properly recognized. Concerning the probability index correlated in some studies to final titer, the weak fluorescence of certain patterns and the random presence of artifacts that distort the index don't lead us to continue it in our daily practice. In conclusion, automated reading systems facilitate the reporting of results and traceability of patterns but still require the expertise of a laboratory technologist for positive/negative discrimination and for pattern recognition. PMID- 27492704 TI - Immunoanalytical profile of androstenedione. AB - Androstenedione is an androgen hormone and a precursor for testosterone and estrone synthesis. It is produced in both gonadal (testes and ovaries) and extragonadal levels (peripheral conversion of dehydroepiandrosterone). This hormone is useful in the assessment of virilism and hirsutism in women. In this paper, after a brief physiological reminder, the author presents the preanalytical and analytical considerations and the clinical utility of this hormone. PMID- 27492703 TI - High fasting serum insulin level due to autoantibody interference in insulin immunoassay discloses autoimmune insulin syndrome: a case report. AB - Insulin-antibodies are a cause of misleading results in insulin immunoassays. They may also mediate deleterious blood glucose variations. A patient presented with overtiredness, recurrent episodes of sweating, dizziness and fainting fits. A fasting serum insulin assay performed on a Modular platform (Modular analytic E170, Roche Diagnostic, Meylan, France) showed a highly elevated value of 194.7 mIU/L, whereas on the same sample glucose and C-peptide levels were normal. Other immunometric insulin assays were performed, as well as antibodies anti-insulin radiobinding assay (RBA) and gel filtration chromatography (GFC). While complementary insulin assays yielded closer to normal fasting levels, the free insulin concentration assessed after PEG precipitation was 14.0 mIU/L and the RBA was positive. GFC revealed that most of the insulin was complexed with a 150 kDa molecule, corresponding to an immunoglobulin G (IgG). A high fasting serum insulin level in a patient with neuroglucopenic symptoms was related to a high insulin-antibody level, suggesting an insulin autoimmune syndrome. PMID- 27492705 TI - Testez vos connaissances apres votre lecture. PMID- 27492708 TI - Systematic characterization of polycrystalline silica-carbonate helices. AB - Biomorphs are complex, life-like structures that emerge from the precipitation of barium carbonate and amorphous silica in alkaline media. Despite their inorganic nature, these microstructures have non-crystallographic morphologies such as helices and cardioid sheets. At the nanoscale, biomorphs arrange thousands of crystalline nanorods as hierarchical assemblies that resemble natural biominerals suggesting novel approaches towards the production of biomimetic materials. We report the synthesis of silica-carbonate biomorphs in single-phase, gradient-free solutions that differ markedly from the typical solution-gas or gel-solution setups. Our experimental approach significantly increases the duration of biomorph growth and hence assembles networks in which individual helices extend to several millimeters. These unusually long biomorphs allow the first quantitative measurements of mesoscopic parameters such as the helix wavelength, period, width, and linear as well as tangential growth velocities. We find that the latter quantities are system-specific and tightly conserved during many hours of growth. Moreover, the average double helix wavelength of (19 +/- 3) MUm and width of (9.6 +/- 0.8) MUm vary by less than 12% when the initial carbonate concentration is changed by three orders of magnitude. We also delineate the single helix growth mechanism and report the occurrence of ribbon-like structures and highly regular "superhelices". Our experiments clearly demonstrate the robustness and consistency of biomorph growth under stable chemical conditions. PMID- 27492707 TI - The molecular mechanism of thalidomide analogs in hematologic malignancies. AB - Thalidomide was sold in the 1950s as a sedative and was also used by pregnant women to treat morning sickness. It became notorious for causing severe birth defects and was removed from the market. More than four decades later, thalidomide had a renaissance in the treatment of cancer. Thalidomide and its more potent analogs, lenalidomide and pomalidomide, are nowadays approved treatments for multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. In addition, thalidomide and its analogs inhibit release of tumor necrosis factor-alpha and increase interleukin-2 (IL-2) and interferon-gamma release from T cells. The underlying molecular mechanisms for these pleiotropic effects remained obscure until the identification of the cereblon (CRBN) E3 ubiquitin ligase as the primary target of thalidomide and its analogs in 2010. Binding of thalidomide or lenalidomide increases the affinity of CRBN to the transcription factors IKZF1 and IKZF3 and casein kinase 1alpha (CK1alpha). Ubiquitination and degradation of these neo-substrates results in IL-2 release and growth arrest of multiple myeloma and MDS cells. The discovery of this previously undescribed mechanism for an approved drug provides a proof-of-concept for the development of new therapeutics that exploit ubiquitin ligases for specific degradation of disease-associated proteins. PMID- 27492709 TI - Oblique rift opening revealed by reoccurring magma injection in central Iceland. AB - Extension deficit builds up over centuries at divergent plate boundaries and is recurrently removed during rifting events, accompanied by magma intrusions and transient metre-scale deformation. However, information on transient near-field deformation has rarely been captured, hindering progress in understanding rifting mechanisms and evolution. Here we show new evidence of oblique rift opening during a rifting event influenced by pre-existing fractures and two centuries of extension deficit accumulation. This event originated from the Bardarbunga caldera and led to the largest basaltic eruption in Iceland in >200 years. The results show that the opening was initially accompanied by left-lateral shear that ceased with increasing opening. Our results imply that pre-existing fractures play a key role in controlling oblique rift opening at divergent plate boundaries. PMID- 27492706 TI - Oncolytic viruses-immunotherapeutics on the rise. AB - The oncolytic virus (OV) field has entered an exciting period in its evolution in which our basic understanding of viral biology and anti-cancer potential are being actively translated into viable therapeutic options for aggressive malignancies. OVs are naturally occurring or engineered viruses that are able to exploit cancer-specific changes in cellular signaling to specifically target cancers and their microenvironment. The direct cytolytic effect of OVs on cancer cells is known to release antigens, which can begin a cascade of events that results in the induction of anti-cancer adaptive immunity. This response is now regarded as the most critical mechanism of OV action and harnessing it can lead to the elimination of distant micrometastases as well as provide long-term anti cancer immune surveillance. In this review, we highlight the development of the OV field, why OVs are gaining an increasingly elevated standing as members of the cancer immunotherapy armamentarium, and finally, ongoing clinical studies that are aimed at translating unique OV therapies into approved therapies for aggressive cancers. PMID- 27492710 TI - Mechanistic Study on Gold-Catalyzed Highly Selective Hydroamination of Alkylidenecyclopropanes. AB - Density functional theory calculations have been carried out to study the mechanism of the gold-catalyzed highly selective hydroamination of alkylidenecyclopropanes. Two main mechanisms (i.e., double-bond activation-first and three-membered-ring activation-first mechanisms) have been examined. The double-bond activation-first mechanism results in the alkene hydroamination product, and it mainly consists of three steps: C-N bond formation, C-C bond rotation, and protodeauration (rate-determining step). Meanwhile, the three membered-ring activation-first mechanism finally produces allylic amines, and it occurs via the ring-opening (rate-determining step), C-N bond formation, and protodeauration steps. The calculation results show good agreement with the experimental outcomes on the chemo-, regio-, and diastereoselectivity. On this basis, we found that the regioselectivity is caused by the C-C bond rotation step, while the diastereoselectivity is determined by both the C-C bond rotation and the protodeauration steps in the double-bond activation-first mechanism. PMID- 27492711 TI - Double-balloon assisted trans-anal ERCP in a patient with Roux-en-Y choledochojejunostomy. PMID- 27492712 TI - Percutaneous transhepatic cholangioscopy for the diagnosis of biliary obstruction in a patient with Roux-en-Y partial gastrectomy. PMID- 27492713 TI - Successful treatment of a perforated duodenal ulcer with polyglycolic acid sheets. PMID- 27492714 TI - EUS-guided right hepatic bile duct drainage in complicated hilar stricture. PMID- 27492716 TI - Rafael Alvarez Cordero, MD. PMID- 27492715 TI - Cystic pancreatic neuroendocrine tumors: correlation of in vivo needle-based confocal endomicroscopic findings by ex vivo analysis. PMID- 27492717 TI - Exercise inducible laryngeal obstruction: diagnostics and management. AB - Obstruction of the central airways is an important cause of exercise-induced inspiratory symptoms (EIIS) in young and otherwise healthy individuals. This is a large, heterogeneous and vastly understudied group of patients. The symptoms are too often confused with those of asthma. Laryngoscopy performed as symptoms evolve during increasing exercise is pivotal, since the larynx plays an important role in symptomatology for the majority. Abnormalities vary between patients, and laryngoscopic findings are important for correct treatment and handling. The simplistic view that all EIIS is due to vocal cord dysfunction [VCD] still hampers science and patient management. Causal mechanisms are poorly understood. Most treatment options are based on weak evidence, but most patients seem to benefit from individualised information and guidance. The place of surgery has not been settled, but supraglottoplasty may cure well-defined severe cases. A systematic clinical approach, more and better research and randomised controlled treatment trials are of utmost importance in this field of respiratory medicine. PMID- 27492718 TI - Epigallocatechin-3-gallate inhibits angiotensin II-induced C-reactive protein generation through interfering with the AT1-ROS-ERK1/2 signaling pathway in hepatocytes. AB - Inflammation plays a key role in many chronic diseases such as cardiovascular diseases and liver diseases. As a representative inflammatory molecule, C reactive protein (CRP) is mainly produced in the liver. Hepatic CRP plays a direct role in the inflammatory hepatic diseases and in development of atherosclerosis when entering into the blood circulation. In the present study, we observed the effect of epigallocatechin-3-gallate (EGCG) on Ang II-induced CRP generation in hepatocytes and the molecular mechanism. Rats were delivered with the subcutaneous infusion of Ang II and/or intragastric administration of EGCG for 7 days. Hepatocytes were pretreated with EGCG before stimulation with Ang II in vitro. CRP level in the serum and liver was determined with ELISA and the immunohistochemical staining. RNA and protein expressions were determined using RT-PCR and Western blot. The in vivo experiment confirmed that EGCG reduced not only CRP generation in the liver of Ang II-infused rats but also serum CRP level. The in vitro results showed that pretreatment of hepatocytes with EGCG inhibited Ang II-induced mRNA and protein expression of CRP in a concentration-dependent manner. Further study exhibited that EGCG downregulated AT1 expression, attenuated Ang II-activated phosphorylation of ERK1/2, and upregulated Ang II inhibited peroxisome proliferator-activated receptor gamma (PPARgamma) expression in vitro and in vivo. In addition, EGCG decreased Ang II-stimulated reactive oxygen species (ROS) generation in hepatocytes. These demonstrate that EGCG is able to inhibit Ang II-induced CRP generation by interfering with AT1-ROS-ERK1/2 signal pathway in hepatocytes, which provides the new evidence and mechanism for the anti-inflammatory effect of EGCG. PMID- 27492719 TI - Identification of Limonol Derivatives as Heat Shock Protein 90 (Hsp90) Inhibitors through a Multidisciplinary Approach. AB - The identification of inhibitors of Hsp90 is currently a primary goal in the development of more effective drugs for the treatment of various types of multidrug resistant malignancies. In an attempt to identify new small molecules modulating the activity of Hsp90, we screened a small library of tetranortriterpenes. A high-affinity interaction with Hsp90 inducible form was uncovered for eight of these compounds, five of which are described here for the first time. By monitoring the ATPase activity and the citrate synthase thermal induced aggregation, compound 1 (cedrelosin A), 3 (7alpha-limonylacetate), and 5 (cedrelosin B), containing a limonol moiety, were found to be the most effective in compromising the Hsp90alpha chaperone activity. Consistent with these findings, the three compounds caused a depletion of c-Raf and pAkt Hsp90 client proteins in HeLa and MCF/7 cell lines. Induced fit docking protocol and molecular dynamics were used to rationalize the structural basis of the biological activity of the limonol derivatives. Taken together, these results point to limonol derivatives as promising scaffolds for the design of novel Hsp90alpha inhibitors. PMID- 27492720 TI - Dynamic expression of corticotropin-releasing hormone and urocortin in estrogen induced-cholestasis pregnant rat. AB - Intrahepatic cholestasis of pregnancy(ICP) is complicated by acute placental fetal hypoxia. Corticotropin-releasing hormone(CRH) and urocortin(UCN) are vasodilatory regulators of blood flow in the placenta. An ethinylestradiol(EE) induced cholestasis rat model was reproduced and serum/placental CRH/UCN were detected during 14-21days of gestation(DG). Maternal serum or placental CRH/UCN levels in the control rats were relatively consistent during 14-21DG. Serum CRH was reduced in the EE-treated rats compared with the control rats at 21DG. Regarding serum UCN, we observed a decrease at 17DG as well as an increase at 21DG in the EE-treated rats compared with the controls. Moreover, we observed a noticeable reduction of placental CRH/UCN expression at 17 or 19DG in the EE treated rats compared with the control rats. The serum bile acids levels exhibited an inverse correlation with placental CRH/UCN expression. EE-induced cholestasis rats might serve as a good model to further investigate the pathological mechanism underlying CRH/UCN dysregulation in ICP. PMID- 27492721 TI - Hyperglycemia induces mixed M1/M2 cytokine profile in primary human monocyte derived macrophages. AB - Hyperglycaemia is a key factor in diabetic pathology. Macrophages are essential regulators of inflammation which can be classified into two major vectors of polarisation: classically activated macrophages (M1) and alternatively activated macrophages (M2). Both types of macrophages play a role in diabetes, where M1 and M2-produced cytokines can have detrimental effects in development of diabetes associated inflammation and diabetic vascular complications. However, the effect of hyperglycaemia on differentiation and programming of primary human macrophages was not systematically studied. We established a unique model to assess the influence of hyperglycaemia on M1 and M2 differentiation based on primary human monocyte-derived macrophages. The effects of hyperglycaemia on the gene expression and secretion of prototype M1 cytokines TNF-alpha and IL-1beta, and prototype M2 cytokines IL-1Ra and CCL18 were quantified by RT-PCR and ELISA. Hyperglycaemia stimulated production of TNF-alpha, IL-1beta and IL-1Ra during macrophage differentiation. The effect of hyperglycaemia on TNF-alpha was acute, while the stimulating effect on IL-1beta and IL-1Ra was constitutive. Expression of CCL18 was supressed in M2 macrophages by hyperglycaemia. However the secreted levels remained to be biologically significant. Our data indicate that hyperglycaemia itself, without additional metabolic factors induces mixed M1/M2 cytokine profile that can support of diabetes-associated inflammation and development of vascular complications. PMID- 27492722 TI - The Masters of the Bolognese Orthopaedic School. AB - Bologna is one of the most ancient cradles of medical knowledge, as the city hosts one of the oldest medical faculties in the world. Among its best known institutions there is the Rizzoli Orthopaedic Institute, founded in the late nineteenth century, whose history is strictly connected with the evolution and development of the Italian orthopaedic practice of the last 120 years. The present manuscript acknowledges the main contributions by Francesco Rizzoli, Alessandro Codivilla and Vittorio Putti, who prompted the foundation and the international recognition of the Rizzoli Institute and the related Bolognese Orthopaedic School. PMID- 27492723 TI - Reliability of measurements performed on two dimensional and three dimensional computed tomography in glenoid assessment for instability. AB - PURPOSE: The main purpose of this study is to establish which of two methods is more reliable in glenoid assessment for instability in pre-operative planning. Accordingly, we have studied the intra- and inter-observer reliability of glenoid parameters with the use of two-dimensional (2D) and three-dimensional (3D) reconstructed computed tomography (CT) images. METHODS: One hundred glenoids were measured with the use of 2D-CT and 3D-CT (in 3D orientation) by two independent observers (one experienced and one inexperienced). Measurements were repeated after one week for 30 randomly selected glenoids. RESULTS: The intra-class correlation coefficient (ICC) for inter-observer reliability was significantly greater for 3D-CT (0.811 to 0.915) than for 2D-CT (0.523 to 0.925). All intra observer reliability values for 3D-CT were near perfect (0.835 to 0.997), while those for 2D-CT were less reliable (0.704 to 0.960). A dependent t-test showed that, for both observers, almost all glenoid parameters (except R and d) differed significantly (p < 0.05) between 2D and 3D measurement methods. CONCLUSIONS: Therefore, it can be concluded that 3D glenoid reconstructions are more reliable for glenoid bone loss assessment than 2D-CT. The results suggest that quantifying a glenoid defect with the use of 2D image only-even if performed by an experienced orthopaedic surgeon-is prone to errors. Differences in measurements between and within observers can be explained by plane setting and identifying glenoid rim in 2D-CT. Accordingly, we recommend that glenoid measurements should be performed in 3D orientation using 3D reconstruction obtained from CT images for pre-operative assessments, which are crucial for surgical planning. PMID- 27492724 TI - Tetanus toxin production is triggered by the transition from amino acid consumption to peptides. AB - Bacteria produce some of the most potent biomolecules known, of which many cause serious diseases such as tetanus. For prevention, billions of people and countless animals are immunised with the highly effective vaccine, industrially produced by large-scale fermentation. However, toxin production is often hampered by low yields and batch-to-batch variability. Improved productivity has been constrained by a lack of understanding of the molecular mechanisms controlling toxin production. Here we have developed a reproducible experimental framework for screening phenotypic determinants in Clostridium tetani under a process that mimics an industrial setting. We show that amino acid depletion induces production of the tetanus toxin. Using time-course transcriptomics and extracellular metabolomics to generate a 'fermentation atlas' that ascribe growth behaviour, nutrient consumption and gene expression to the fermentation phases, we found a subset of preferred amino acids. Exponential growth is characterised by the consumption of those amino acids followed by a slower exponential growth phase where peptides are consumed, and toxin is produced. The results aim at assisting in fermentation medium design towards the improvement of vaccine production yields and reproducibility. In conclusion, our work not only provides deep fermentation dynamics but represents the foundation for bioprocess design based on C. tetani physiological behaviour under industrial settings. PMID- 27492725 TI - Calcium hydroxyapatite crystal deposition with intraosseous penetration involving the posterior aspect of the cervical spine: a previously unreported cause of neck pain. AB - PURPOSE: Calcific tendinitis is a frequent disorder caused by hydroxyapatite crystal deposition; however, bone erosions from calcific tendinitis are unusual. The spinal manifestation of this disease is calcific tendinitis of the longus colli muscle; this disease has never been described in the posterior aspect of the spine. We report a case of calcium hydroxyapatite crystal deposition involving the posterior cervical spine eroding the bone cortex. METHODS: A 57 year-old woman presented with a 5-month history of left-sided neck pain. Radiographs showed C4-C5 interspinous calcification with lytic compromise of the posterior arch of C4. Magnetic resonance imaging confirmed a lytic lesion of the posterior arch of C4, with a soft tissue mass extending to the C4-C5 interspinous space; calcifications were observed as very low signal intensity areas on T1 and T2 sequences, surrounded by gadolinium-enhanced soft tissues. A computed tomography (CT) scan confirmed the bone erosions and the soft tissue calcifications. RESULTS: A CT-guided needle biopsy was performed; it showed vascularized connective tissue with inflammatory histiocytic infiltration and multinucleated giant cells; Alizarin Red stain confirmed the presence of hydroxyapatite crystals. The patient was treated with anti-inflammatories for 2 weeks. She has been asymptomatic in a 6-month follow-up; a CT scan at the last follow-up revealed reparative remodeling of bone erosions. CONCLUSION: This is the first report of calcium hydroxyapatite crystal deposition with intraosseous penetration involving the posterior aspect of the cervical spine. Considering that this unusual lesion can be misinterpreted as a tumor or infection, high suspicion is required to avoid unnecessary surgical procedures. PMID- 27492726 TI - HIV Infection and Myocardial Infarction. AB - BACKGROUND: After the advent of the potent combination antiretroviral therapy (cART) the incidence of acquired immune deficiency syndrome (AIDS) has declined dramatically and HIV infection became a chronic disease with a significant increase in the life expectancy of HIV-positive people. Consequently, chronic comorbidities as coronary heart disease raised an increasing concern in this population. OBJECTIVE: Aim of this editorial article is to review the most recent data about the cardiovascular disease risk among HIV-positive persons and to suggest an appropriate clinical management. RESULTS: An increased risk of myocardial infarction has been reported among HIVinfected subjects compared to the general population, but the pathogenic mechanism of this accelerated atherosclerotic process is complex and certainly multifactorial. The occurrence of myocardial infarction may be the consequence of traditional risk factors (that are overrepresented in the HIVinfected population), direct viral replication, and long-term toxicity of the antiretroviral drugs. Moreover, despite the persistent viral suppression induced by cART usually reduces the cardiovascular risk, several studies show in HIV-positive subjects a condition of chronic inflammation and immune activation that could lead to both accelerated endothelial dysfunction and atherosclerotic disease. CONCLUSION: The cardiovascular risk reduction and coronary heart disease prevention are today a leading challenge for all the clinicians involved in the HIV patients' care. PMID- 27492727 TI - Spatiotemporal Analysis of AIDS Incidence Among Adults in Brazil. AB - : AIDS is the fourth leading cause of death worldwide and, currently, the overall prevalence rate of HIV infection in Brazil is 0.5% among men and 0.3% among women. OBJECTIVE: To evaluate the spatiotemporal trend of AIDS in Brazil from 2006 to 2012 and its relationship with human development index (HDI) and their components income, education and life expectancy. METHODS: This ecological study evaluate the spatiotemporal trend of standardized incidence ratio of AIDS among adults in Brazil from 2006 to 2012 and its relationship with HDI by using a Bayesian analysis, considering the Brazilian Federal Units as units of analysis. The proposed statistical model allows obtaining a standardized incidence ratio (SIR, adjusted by gender and age). RESULTS: Among the men, our results show higher incidence rates in the States of the Southern regions as well as in the state of Amazonas (Northern Brazil). In females, we found other patterns for SIR, with higher incidence rates in the states of Rio de Janeiro (Southeast region), Rio Grande do Sul and Santa Catarina (both in Southern region). Among men it was observed as an expressive association between the SIR values and the overall HDI and income and education components, but it was observed to have an inverse association with the life expectancy component. Among women, it is noted that the SIR values are associated with the overall HDI and the education components only at the beginning of the studied period. DISCUSSION: AIDS remains a major public health problem in Brazil, mainly in the southern and southeastern regions of the country. Considering its association with HDI, it is noted that the disease still remains related to the pattern observed in the early years of the studied period, at least in the more developed regions of Brazil. This certainly happened because of the chronicity of the disease, thus affecting people with good socioeconomic status. PMID- 27492728 TI - The lasso-loop, lasso-mattress and simple-cinch stitch for arthroscopic rotator cuff repair: are there biomechanical differences? AB - PURPOSE: Various stitching techniques have been described to facilitate arthroscopic repair of rotator cuff tears. The aim of the present study was to compare the biomechanical properties of the lasso-loop, lasso-mattress and simple cinch stitch for rotator cuff repair. METHODS: Twelve infraspinatus tendons were harvested from sheep and split in half. The tendons were randomized into three different stitch configuration groups for biomechanical testing: lasso-loop, lasso-mattress and simple-cinch stitch. Each specimen was first cyclically loaded on a universal materials testing machine under force control from 5 to 30 N at 0.25 Hz for twenty cycles. Then, each specimen was loaded to failure under displacement control at a rate of 1 mm/s. Cyclic elongation, peak-to-peak displacement and ultimate tensile load were reported as mean +/- standard error and compared using one way analysis of variance. The type of failure was recorded. RESULTS: No differences in cyclic elongation (1.31 +/- 0.09 mm for the simple-cinch vs. 1.49 +/- 0.07 mm for the lasso-mattress vs. 1.61 +/- 0.09 mm for the lasso-loop stitch, p = 0.063) or peak-to-peak displacement (0.58 +/- 0.04 mm for the simple-cinch, 0.50 +/- 0.03 mm for the lasso-mattress and 0.62 +/- 0.06 mm for the lasso-loop stitch, p = 0.141) were seen between all tested stitch configurations. In the load-to-failure test, the simple cinch stitch (149.38 +/- 11.89 N) and the lasso-mattress (149.38 +/- 10.33 N) stitch demonstrated significantly higher ultimate load than the lasso-loop stitch (65.88 +/- 4.75 N, p < 0.001). All stitch configurations failed with suture pull out. CONCLUSIONS: The lasso-mattress and the simple-cinch stitch showed similar biomechanical properties with significant higher tensile loads needed for failure than the lasso-loop stitch. PMID- 27492729 TI - Surgically induced changes in retinal vessel diameter, retinal nerve fibre layer thickness, and the optic disc after 23-gauge pars plana vitrectomy. AB - The aim of the study is to investigate the retinal vascular calibre, retinal nerve fibre layer's thickness, and optic disc changes in patients after pars plana vitrectomy. We examined 40 eyes in 40 patients who had undergone unilateral pars plana vitrectomy at three time points: prior to surgery, and at 3 and 6 months after the operation. The diameters of central retinal arteries and veins were measured using retinal photographs. The central retinal arteriolar equivalent (CRAE) and central retinal venular equivalent (CRVE) were calculated using the revised Parr-Hubbard formula. Retinal nerve fibre layer thickness was obtained using Stratus optical coherence tomography. The cup-to-disc vertical ratio of the optic disc was evaluated using stereo optic disc photography. There were no significant differences between the eyes of individual patients before the operation. Cup-to-disc vertical ratios of the optic disc were significantly increased 3 and 6 months postoperatively (p < 0.01, p < 0.01), and there was a significant difference between the operative eye and fellow eye at the same time points (p < 0.01, p < 0.01). Changes in CRAE and CRVE in the operative eyes were significantly larger than the fellow eyes 6 months postoperatively (p < 0.01, p < 0.01). The retinal nerve fibre layer thickness showed no significant changes. While there were no changes in retinal nerve fibre layer thickness, vitrectomy induced changes in the cup-to-disc vertical ratio of the optic disc and retinal vessel diameter for at least 6 months after surgery. PMID- 27492730 TI - Incidence and risk factors associated with retinal redetachment after silicone oil removal in the African population. AB - The purpose of this study was to investigate the incidence and risk factors associated with retinal redetachment after silicone oil (SO) removal in the African population. A retrospective cohort study was performed on patients undergoing SO removal over a period of 4 years. The risk factors assessed were (1) characteristics of the retinal detachments including type of retinal detachment, type, number and location of the retinal tears, and proliferative vitreoretinopathy (PVR) score, and (2) surgical factors including type of silicone oil used, use of laser prior to SO removal, and location of the laser (360 degrees or around the tear only). SO was removed either through a pars plana approach or transpupillary approach and anterior limbal incision. Ninety nine eyes met the inclusion criteria during the study period. Twelve patients (12 %) had retinal redetachment after SO removal. Factors associated with redetachment were a preexisting macular hole, PVR grade B or worse, and no intraoperative endolaser photocoagulation. The incidence of redetachment in African population is similar to that reported from developed countries and other advanced vitreoretinal centers. Redetachment occurred at higher rates in patients with preexisting macular holes and tears who did not receive intraoperative endolaser photocoagulation and patients with a severe grade of PVR. PMID- 27492731 TI - Retina ganglion cell/inner plexiform layer and peripapillary nerve fiber layer thickness in patients with acromegaly. AB - Increased secretion of growth hormone and insulin-like growth factor-1 in acromegaly has various effects on multiple organs. However, the ocular effects of acromegaly have yet to be investigated in detail. The aim of the present study was to compare retina ganglion cell/inner plexiform layer (GCIPL) and peripapillary nerve fiber layer thickness (pRNFL) between patients with acromegaly and healthy control subjects using spectral domain optical coherence tomography (SD-OCT). This cross-sectional, comparative study included 18 patients with acromegaly and 20 control subjects. All participants underwent SD-OCT to measure pRNFL (in the seven peripapillary areas), GCIPL (in the nine ETDRS areas), and central macular thickness (CMT). Visual field (VF) examinations were performed using a Humphrey field analyzer in acromegalic patients. Measurements were compared between patients with acromegaly and control subjects. A total of 33 eyes of 18 patients with acromegaly and 40 eyes of 20 control subjects met the inclusion criteria of the present study. The overall calculated average pRNFL thickness was significantly lower in patients with acromegaly than in control subjects (P = 0.01), with pRNFL thickness significantly lower in the temporal superior and temporal inferior quadrants. Contrary to our expectations, pRNFL thickness in the nasal quadrant was similar between acromegalic and control subjects. The mean overall pRNFL thickness and superonasal, nasal, inferonasal, and inferotemporal quadrant pRNFL thicknesses were found to correlate with the mean deviation (MD) according to Spearman's correlation. However, other quadrants were not correlated with VF sensitivity. No significant difference in CMT values was observed (P = 0.6). GCIPL thickness was significantly lower in all quadrants of the inner and outer macula, except for central and inferior outer quadrants, in the acromegaly group than that in the control group (P < 0.05). GCIPL thicknesses of the inferior inner and outer macula quadrants were found to correlate with MD, whereas no correlation was observed between other quadrants and VF sensitivity. We demonstrated that GCIPL thickness decreased in patients with acromegaly compared with that in control subjects. However, the nasal quadrant pRNFL thickness was similar in acromegaly, in contrast to our expectations. SD-OCT may have utility in the assessment of the effects of acromegaly on retinal structures. PMID- 27492732 TI - Charlson comorbidity index predicts poor outcome in CML patients treated with tyrosine kinase inhibitor. AB - Although the Sokal and Hasford scoring systems are well-known prognostic models specific to chronic myeloid leukemia (CML), whether they can effectively predict outcomes in elderly CML patients with comorbidities has not been fully elucidated. We evaluated the association between comorbidity at diagnosis with treatment outcome and survival in chronic phase CML patients. A questionnaire was administered to patients diagnosed with CML between 2001 and 2012 and treated with tyrosine kinase inhibitors (TKIs). The Charlson comorbidity index (CCI) was used to determine concomitant diseases. In total, 79 patients (33 females; median age, 57 years) were enrolled. CCI scores at diagnosis were between 2 and 11. At the last follow-up, 46 patients showed a major molecular response. Complete cytogenetic response was achieved in 73.4 % of the cases 12 months after TKI administration. We observed only five deaths during the 55.5-month median follow up period. The risk categories (low/intermediate/high) associated with Sokal and Hasford scores were 33/27/7 and 21/43/3, respectively. The 27 cases with a CCI score >3 had significantly poorer survival after diagnosis (52 cases had a CCI score <2). CCI scores were inversely associated to overall survival. Concomitant comorbidity at diagnosis is associated with poor outcome in CML patients treated with TKIs. PMID- 27492733 TI - Dosing of loop diuretics in chronic heart failure: it's time for evidence. PMID- 27492734 TI - 3D printing of an interpenetrating network hydrogel material with tunable viscoelastic properties. AB - Interpenetrating network (IPN) hydrogel materials are recognized for their unique mechanical properties. While IPN elasticity and toughness properties have been explored in previous studies, the factors that impact the time-dependent stress relaxation behavior of IPN materials are not well understood. Time-dependent (i.e. viscoelastic) mechanical behavior is a critical design parameter in the development of materials for a variety of applications, such as medical simulation devices, flexible substrate materials, cellular mechanobiology substrates, or regenerative medicine applications. This study reports a novel technique for 3D printing alginate-polyacrylamide IPN gels with tunable elastic and viscoelastic properties. The viscoelastic stress relaxation behavior of the 3D printed alginate-polyacrylamide IPN hydrogels was influenced most strongly by varying the concentration of the acrylamide cross-linker (MBAA), while the elastic modulus was affected most by varying the concentration of total monomer material. The material properties of our 3D printed IPN constructs were consistent with those reported in the biomechanics literature for soft tissues such as skeletal muscle, cardiac muscle, skin and subcutaneous tissue. PMID- 27492735 TI - Biopsychosocial predictors of coping strategies of patients postmyocardial infarction. AB - Data from the Patients and Families Psychological Response to the Home Automated External Defibrillator Trial were used to examine the relationship between biopsychosocial variables and patients' coping strategies postmyocardial infarction. This study is the secondary data analysis of longitudinal observational study. A total of 460 patient-spouse pairs were recruited in January 2003 to October 2005. Hierarchical linear regression analysis examined biological/demographic, psychological and social variables regarding patients' coping scores using the Family Crisis Oriented Personal Evaluation Scale. Lower social support and social support satisfaction predicted lower total coping scores. Being younger, male gender and time since the myocardial infarction predicted lower positive coping strategy use. Higher anxiety and lower social support were related to fewer positive coping methods. Lower educational levels were related to increased use of negative coping strategies. Reduced social support predicted lower total coping scores and positive coping strategy use and greater passive coping style use. Social support from a broad network assisted with better coping; those living alone may need additional support. Social support and coping strategies should be taken into consideration for patients who have experienced a cardiac event. PMID- 27492736 TI - In vivo evaluation of shark teeth-derived bioapatites. AB - OBJECTIVE: The present work proposes the shark teeth as a new source of bioapatites for bone filler applications in maxillary sinus elevation, periodontal regeneration or implants placement. This abundant fishing by-product provides an improved hydroxyapatite (HA) with fluorine contributions. The in vivo evaluation of osteointegration and bone mineral density levels promoted by these marine bioapatites was the main objective. MATERIALS AND METHODS: Marine bioapatite granules of two sizes (1 mm, <20 MUm) were obtained and characterized (XRD, SEM, ICP-OES) to determine morphology and composition. In vivo evaluation was performed, after bioapatites implantation in critical defects of parietal bone of 25 rats, for 3 weeks. Commercial synthetic HA/betaTCP (60/40%) material and unfilled defects were used as controls. Radiology, micro-CT, histology and quantification of bone mineral density are presented. RESULTS: These marine bioapatites presented a globular porous morphology. A biphasic composition ~70% apatitic (HA, apatite-CaF, fluorapatite) and ~30% non-apatitic phase (whitlockite, tricalcium bis(orthophosphate)), with contributions of F (1.0 +/- 0.5%wt), Na (0.9 +/- 0.2%wt) and Mg (0.65 +/- 0.04%wt) was confirmed. After implantation period, higher osteointegration of 1-mm marine bioapatites than commercial synthetic granules was observed, together with bone formation from the defect surroundings but also at central area (potential osteoinductive properties). New bone cells penetrated inside pores and inter-granular cavities. Higher bone mineral density, in both 1-mm and <20-MUm granules, than on commercial synthetic graft was determined, being significant in 1-mm bioapatites (a P < 0.05). CONCLUSION: Shark teeth bioapatites were successfully validated as new functionally efficient bone filler in rat model, promoting significantly increased bone mineral density than synthetic control. PMID- 27492737 TI - Characterization of Acr2, an H-NS-like protein encoded on A/C2-type plasmids. AB - Conjugation plays an important role in the horizontal movement of DNA between bacterial species and even genera. Large conjugative plasmids in Gram-negative bacteria are associated with multi-drug resistance and have been implicated in the spread of these phenotypes to pathogenic organisms. A/C plasmids often carry genes that confer resistance to multiple classes of antibiotics. Recently, transcription factors were characterized that regulate A/C conjugation. In this work, we expanded the regulon of the negative regulator Acr2. We developed an A/C variant, pARK01, by precise removal of resistance genes carried by the plasmid in order to make it more genetically tractable. Using pARK01, we conducted RNA-Seq and ChAP-Seq experiments to characterize the regulon of Acr2, an H-NS-like protein. We found that Acr2 binds several loci on the plasmid. We showed, in vitro, that Acr2 can bind specific promoter regions directly and identify key amino acids which are important for this binding. This study further characterizes Acr2 and suggests its role in modulating gene expression of multiple plasmid and chromosomal loci. PMID- 27492738 TI - Impact of the implementation of an evidence-based guideline on diagnostic testing, management, and clinical outcomes for infants with bronchiolitis. AB - BACKGROUND: Although bronchiolitis poses a significant health problem in low- and middle-income countries (LMICs), to the best of our knowledge, to date it has not been determined whether evidence-based bronchiolitis clinical practice guidelines (CPGs) complemented by standardized educational strategies reduce the use of unnecessary diagnostic tests and medications and improve clinically important outcomes in LMICs. METHODS: In an uncontrolled before and after study, we assessed the impact of the implementation of an evidence-based bronchiolitis CPG on physician behavior and the care of infants with bronchiolitis by comparing pre guideline (March to August 2014) and post-guideline (March to August 2015) use of diagnostic tests and medications through an electronic medical record review in a children's hospital in Bogota, Colombia. We also sought to assess the impact of the implementation of the CPG on clinically important outcomes such as lengths of stay, hospital admissions, intensive care admissions, and hospital readmissions. RESULTS: Data from 662 cases of bronchiolitis (pre-guideline period) were compared with the data from 703 cases (post-guideline period). On comparing the pre- and post-guideline periods, it was seen that there was a significant increase in the proportion of patients with an appropriate diagnosis and treatment of bronchiolitis (36.4% versus 44.5%, p = 0.003), and there were statistically significant decreases in the use of a hemogram (33.2% versus 26.6%, p=0.010), procalcitonin (3.9% versus 1.6%, p=0.018), nebulized beta-2 agonists (45.6% versus 3.4%, p < 0.001), nebulized anticholinergics (3.3% versus 1.4%, p= 0.029), and nebulized epinephrine (16.2% versus 7.8%, p < 0.001). Likewise, a significant increase in the use of nebulized hypertonic saline was seen (79.6% versus 91.7%, p < 0.001). However, implementation of the CPG for bronchiolitis was not associated with significant changes in clinically important outcomes. CONCLUSIONS: The development and implementation of a good quality bronchiolitis CPG is associated with a significant increase in the proportion of cases with an appropriate diagnosis and treatment of the disease in the context of a university based hospital located in the capital of an LMIC. However, we could not demonstrate an improvement in clinically important outcomes such as any of the bronchiolitis severity parameters. PMID- 27492740 TI - New repellent effective against African malaria mosquito Anopheles gambiae: implications for vector control. AB - Anopheles gambiae Giles sensu stricto (Diptera: Culicidae) is a vector for Plasmodium, the causative agent of malaria. Current control strategies to reduce the impact of malaria focus on reducing the frequency of mosquito attacks on humans, thereby decreasing Plasmodium transmission. A need for new repellents effective against Anopheles mosquitoes has arisen because of changes in vector behaviour as a result of control strategies and concern over the health impacts of current repellents. The response of A. gambiae to potential repellents was investigated through an electroantennogram screen and the most promising of these candidates (1-allyloxy-4-propoxybenzene, 3c{3,6}) chosen for behavioural testing. An assay to evaluate the blood-host seeking behaviour of A. gambiae towards a simulated host protected with this repellent was then performed. The compound 3c{3,6} was shown to be an effective repellent, causing mosquitoes to reduce their contact with a simulated blood-host and probe less at the host odour. Thus, 3c{3,6} may be an effective repellent for the control of A. gambiae. PMID- 27492739 TI - Effect of selective serotonin reuptake inhibitors use on endocrine therapy adherence and breast cancer mortality: a population-based study. AB - The purpose of the study was to investigate whether the concomitant use of selective serotonin reuptake inhibitors (SSRI) with tamoxifen influences the risk of death due to breast cancer, and we also investigated the association between SSRI use and adherence to oral endocrine therapy (ET). We analyzed data from BCBaSe Sweden, which is a database created by the data linkage of Registries from three different regions of Sweden. To investigate the association between ET adherence and SSRI use, we included all women who were diagnosed with non-distant metastatic ER-positive invasive breast cancer from July 2007 to July 2011 and had at least one dispensed prescription of oral tamoxifen or aromatase inhibitor. To investigate the role of concurrent administration of SSRI and tamoxifen on breast cancer prognosis, we performed a nested case-control study. In the adherence cohort, 9104 women were included in the analyses. Women who received SSRI, either before or after breast cancer diagnosis, were at higher risk for low adherence to ET. However, when the overlapping period between SSRI use and ET was >50 %, no excess risk for low adherence was observed. Non-adherence (<80 %) to ET was significantly associated with worse breast cancer survival (OR 4.07; 95 % CI 3.27 5.06). In the case-control study, 445 cases and 11125 controls were included. The concomitant administration of SSRI and tamoxifen did not influence breast cancer survival, neither in short-term (OR 1.41; 95 % CI 0.74-2.68) nor in long-term SSRI users (OR 0.85; 95 % CI 0.35-2.08). Concomitant SSRI and tamoxifen use does not seem to increase risk for death due to breast cancer. Given the positive association between continuing antidepressive pharmacotherapy for a longer period of time and adherence to ET, it is essential to capture and treat depression in breast cancer patients to secure adherence to ET. PMID- 27492741 TI - Effect of Repetitive Intracutaneous Injections with Local Anesthetics and Steroids for Acute Thoracic Herpes Zoster and Incidence of Postherpetic Neuralgia. AB - Background: Treatment of established postherpetic neuralgia (PHN) is difficult and often disappointing. In this study, we assessed the efficacy of repetitive intracutaneous injections with local anesthetics and steroids in acute thoracic herpes zoster (HZ) pain, herpetic eruption, and incidence of PHN. Methods: Ninety three patients with acute thoracic HZ were randomly assigned to receive a standard treatment of antiviral medication with p.o. analgesics or the standard treatment with the addition of repetitive intracutaneous injections of a local anesthetic and steroid mixture. Patients were permitted to take tramadol when the visual analog scale (VAS) >= 4. Pain assessment using VAS was conducted at the initial visit, as well as 1, 2, 4, 12, and 24 weeks after the end of the treatments. Results: In comparison with the standard treatment group, the VAS scores of the intracutaneous injection group were significantly lower during the study. The intracutaneous injection group also reported shorter duration of pain and skin eruption than the control group ( P = 0.005 vs P < 0.001, respectively). At 1 month post-therapy, 12.8% patients in the intracutaneous injection group reported zoster-associated pain, compared with 47.8% in the standard treatment group ( P < 0.001). At 3 and 6 months post-therapy, the incidence of PHN was still significantly lower in the intracutaneous injection group than the standard treatment group. EuroQol VAS scores were significantly higher in the intracutaneous injection group vs standard treatment group (P < 0.001). Conclusion: Repetitive intracutaneous injections with local anesthetics and steroids along with standard treatment significantly reduce the duration of pain and herpetic eruption and incidence of PHN. PMID- 27492742 TI - A Different Approach to the Management of Osteoarthritis in the Knee: Ultrasound Guided Genicular Nerve Block. PMID- 27492743 TI - Psychological Treatment Needs for Chronic Pain in Singapore and the Relevance of the Psychological Flexibility Model. AB - Objective: The goals of the present study were (a) to assess the psychological treatment needs and treatment delivery preferences in people attending services or contacting a hospital website for chronic pain in Singapore, and (b) to explore potential relevance of the psychological flexibility (PF) model for this group by investigating associations between PF and pain-related outcomes. Design and Setting: This was a cross-sectional questionnaire study of people with chronic pain in Singapore. Subjects: Current users of treatment services at a tertiary pain management clinic (PMC), users of pain treatment services elsewhere, and non-treatment users. Methods: Participants were either recruited face-to-face at a pain clinic or via an online portal. All participants completed a questionnaire, including a survey of treatment barriers and needs, treatment delivery preferences for chronic pain, and standardized measures of PF, pain interference, emotional functioning, and health care use. Results: A total of 200 participants completed the study. Cost of treatment was identified as a main deterrent, while proof of treatment success was identified as a main facilitator for treatment uptake. A majority of participants (88.5%) indicated a preference for face-to-face treatment. In multiple regression analyses, after controlling for relevant demographic variables and pain intensity, PF explained 14% of the variance for pain interference and impact of depressive symptoms and 22% of the variance for depressive symptoms. Conclusion: A focus on meeting patients' needs at low cost, and providing proof of treatment success may increase psychological treatment uptake. Increasing PF for pain in people from Singapore may also contribute to better patient functioning. PMID- 27492744 TI - Acid-triggered release of doxorubicin from a hydrazone-linked Gd(3+)-texaphyrin conjugate. AB - The hydrazone-based Gd(3+)-texaphyrin doxorubicin conjugate 1, releases active doxorubicin at acidic pH values, allowing its components to be followed by two complementary imaging methods, namely Off-On fluorescence enhancement and MR imaging. It thus acts as a promising theranostic agent. PMID- 27492745 TI - A multidisciplinary approach to prenatal treatment of congenital long QT syndrome. AB - A 27-week fetus evaluated for bradycardia and hydrops was found to have anti-SSA negative 2 degrees atrioventricular block and ventricular tachycardia. A presumptive diagnosis of fetal long QT syndrome was made. Transplacental pharmacotherapy with intravenous magnesium and lidocaine restored sinus rhythm. At 30 6/7 weeks, the infant was delivered due to premature labor. Despite postnatal treatment with mexiletine and propranolol, she developed torsades de pointes. Ultimately, a de novo KCNH2 G628S mutation was diagnosed. She received an implantable cardiac defibrillator at 5 months of age. Early diagnosis and a multidisciplinary approach allowed successful in utero treatment and anticipatory postnatal management. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:168 170, 2017. PMID- 27492746 TI - [Management of symptoms associated with spasticity in patients with multiple sclerosis]. AB - OBJECTIVE: To describe the role of nurses in the management of symptoms related to spasticity in patients with multiple sclerosis (MS). METHOD: A descriptive study was developed based on a questionnaire on spasticity in MS patients. The questionnarie was completed through an anonymous tele-voting system at a national meeting with nurses involved in the management of these patients. RESULTS: Apart from fatigue, according to the opinion of the participants, the spasticity symptom associated with MS most notified by patients was difficulty in walking, followed by spasms and pain. Participants thought that it is important that nursing takes: 1) a role in identifying these symptoms, 2) should focus on the detection of the triggering or aggravating factors, and 3) on providing support in the assessment of the level of spasticity. It is important to inform about the correct use of anti-spasticity drugs, how to adjust the dosage and side effects of treatments, including cannabinoids via an oromucosal spray, titrating its doses according to each patient, and monitoring its tolerability, efficacy and adherence. Although there are usually resources to follow up these patients, there are still important gaps, including the lack of a specific follow-up protocol. CONCLUSIONS: Although all the participants are experts in the management of patients with MS, there is still diversity in the functions they perform, and the available resources they have in their hospitals. Nurses act as a key element in the process of identification of symptoms, training and monitoring of these patients with spasticity in EM. PMID- 27492748 TI - Simple Approach to Synthesize Amino-Functionalized Carbon Dots by Carbonization of Chitosan. AB - Carbon dots (CDs) as a new series of fluorescent nanomaterials have drawn great attention in recent years owning to their unique properties. In this paper, a simple carbonization approach to synthesize amino-functionalized CDs was developed by using chitosan as the carbon precursor. The as-prepared CDs possessed desirable amino function group on their surface and exhibited bright luminescence with absolute quantum yield (QY) of 4.34%, excitation-, pH-dependent and up-conversion fluorescence behaviors. Furthermore, we have investigated the cytotoxicity and biocompatibility of the as-prepared CDs, which demonstrated that the as-prepared CDs have the potential applications in biosensing, cellular imaging and drug delivery. PMID- 27492747 TI - Loss of Major DNase I Hypersensitive Sites in Duplicated beta-globin Gene Cluster Incompletely Silences HBB Gene Expression. AB - We report an infant with sickle cell disease phenotype by biochemical analysis whose beta-globin gene (HBB) sequencing showed sickle cell mutation (HBBS ) heterozygosity. The proband has a unique head-to-tail duplication of the beta globin gene cluster having wild-type (HBBA ) and HBBS alleles inherited from her father; constituting her HBBS /HBBS -HBBA genotype. Further analyses revealed that proband's duplicated beta-globin gene cluster (~650 kb) encompassing HBBA does not include the immediate upstream locus control region (LCR) or 3' DNase I hypersensitivity (HS) element. The LCR interacts with beta-globin gene cluster involving long range DNA interactions mediated by various transcription factors to drive the regulation of globin genes expression. However, a low level of HBBA transcript was clearly detected by digital PCR. In this patient, the observed transcription from the duplicated, distally displaced HBBA cluster demonstrates that the loss of LCR and flanking 3'HS sites do not lead to complete silencing of HBB transcription. PMID- 27492749 TI - Innovation in Graduate Education for Health Professionals in Humanitarian Emergencies. AB - The objective of this report was to show how the Center for Humanitarian Emergencies (the Center) at Emory University (Atlanta, Georgia USA) has trained graduate students to respond to complex humanitarian emergencies (CHEs) through innovative educational programs, with the goal of increasing the number of trained humanitarian workers. Natural disasters are on the rise with more than twice as many occurring from 2000-2009 as there were from 1980-1989. In 2012 alone, 144 million people were affected by a natural disaster or displaced by conflict worldwide. This has created an immense need for trained humanitarian workers to respond effectively to such disasters. The Center has developed a model for educational programming that targets learners along an educational continuum ranging from the undergraduate level through continuing professional education. These programs, based in the Rollins School of Public Health (RSPH) of Emory University, include: a competency-based graduate certificate program (the Certificate) in humanitarian emergencies; a fellowship program for mid-career professionals; and funded field practica. The competency-based Certificate program began in 2010 with a cohort of 14 students. Since then, 101 students have received the Certificate with 50 more due for completion in 2016 and 2017 combined. The fellowship program for mid-career professionals has hosted four fellows from conflict-affected or resource-poor countries, who have then gone on to assume leadership positions with humanitarian organizations. From 2009-2015, the field practicum program supported 34 students in international summer practicum experiences related to emergency response or preparedness. Students have participated in summer field experiences on every continent but Australia. Together the Certificate, funded field practicum opportunities, and the fellowship comprise current efforts in providing innovative education and training for graduate and post-graduate students of public health in humanitarian response. These modest efforts are just the beginning in terms of addressing the global shortage of skilled public health professionals that can coordinate humanitarian response. Evaluating existing programs will allow for refinement of current programs. Ultimately, these programs may influence the development of new programs and inform others interested in this area. Evans DP , Anderson M , Shahpar C , del Rio C , Curran JW . Innovation in graduate education for health professionals in humanitarian emergencies. Prehosp Disaster Med. 2016;31(5):532 538. PMID- 27492750 TI - Subacute pneumonia as a manifestation of acute fibrinous and organizing pneumonia. PMID- 27492751 TI - Endoscopic Cyanoacrylate for Persistent Air Leak from A Bronchopleural Fistula in A Patient with Idiopathic Pulmonary Fibrosis. PMID- 27492752 TI - Seasonal importance of flowers to Costa Rican capuchins (Cebus capucinus imitator): Implications for plant and primate. AB - OBJECTIVES: Our goal is to investigate flower foraging by capuchin monkeys, a behavior rarely studied in wild primates. We ask what drives seasonal variation in florivory rates: flower quality and abundance or fluctuations in fruit and invertebrate abundances. We explore how capuchins affect the reproductive success of flower food species by quantifying the potential pollination rate. MATERIALS AND METHODS: We followed capuchin groups from dawn to dusk and recorded all flower foraging bouts. Flower food nutritional composition was compared to fruit and invertebrate foods. We recorded overall flower, fruit, and invertebrate abundances and compared the rate of flower foraging to these. We estimated the likelihood of pollination from the proportion of flower patch visits to each plant species that satisfied minimum behavioral requirements. RESULTS: Flower eating was highly seasonal, and was significantly negatively related to overall fruit and invertebrate abundance but not flower abundance. Although smaller than most fruits, flowers were nutritionally comparable to fruit foods by dry mass and contained higher average concentrations of protein. Capuchins are likely pollinators for Luehea speciosa; most foraging visits to this species occurred in a manner that makes outcrossing or geitonogamous pollination likely. DISCUSSION: Flowers are an important seasonal resource for capuchins. Flowers likely act as fallback foods during periods of reduced fruit and invertebrate abundance, and may exert evolutionary pressure disproportionate to their consumption. Capuchin florivory likely affects the reproductive success of some plants, potentially shaping forest structure. Our study illustrates the value of assessing the importance of rare foods in the primate diet. PMID- 27492753 TI - Spatial clustering of average risks and risk trends in Bayesian disease mapping. AB - Spatiotemporal disease mapping focuses on estimating the spatial pattern in disease risk across a set of nonoverlapping areal units over a fixed period of time. The key aim of such research is to identify areas that have a high average level of disease risk or where disease risk is increasing over time, thus allowing public health interventions to be focused on these areas. Such aims are well suited to the statistical approach of clustering, and while much research has been done in this area in a purely spatial setting, only a handful of approaches have focused on spatiotemporal clustering of disease risk. Therefore, this paper outlines a new modeling approach for clustering spatiotemporal disease risk data, by clustering areas based on both their mean risk levels and the behavior of their temporal trends. The efficacy of the methodology is established by a simulation study, and is illustrated by a study of respiratory disease risk in Glasgow, Scotland. PMID- 27492754 TI - Immunopharmacology of fatty acids. PMID- 27492755 TI - Hemispheric specialization of mood processing is abnormal in patients with schizophrenia. PMID- 27492756 TI - Siderophores as molecular tools in medical and environmental applications. AB - Almost all life forms depend on iron as an essential micronutrient that is needed for electron transport and metabolic processes. Siderophores are low-molecular weight iron chelators that safeguard the supply of this important metal to bacteria, fungi and graminaceous plants. Although animals and the majority of plants do not utilise siderophores and have alternative means of iron acquisition, siderophores have found important clinical and agricultural applications. In this review, we will highlight the different uses of these iron chelating molecules. PMID- 27492757 TI - Metaproteomics reveals metabolic transitions between healthy and diseased stony coral Mussismilia braziliensis. AB - Infectious diseases such as white plague syndrome (WPS) and black band disease (BBD) have caused massive coral loss worldwide. We performed a metaproteomic study on the Abrolhos coral Mussismilia braziliensis to define the types of proteins expressed in healthy corals compared to WPS- and BBD-affected corals. A total of 6363 MS/MS spectra were identified as 361 different proteins. Healthy corals had a set of proteins that may be considered markers of holobiont homoeostasis, including tubulin, histone, Rab family, ribosomal, peridinin chlorophyll a-binding protein, F0F1-type ATP synthase, alpha-iG protein, calmodulin and ADP-ribosylation factor. Cnidaria proteins found in healthy M. braziliensis were associated with Cnidaria-Symbiodinium endosymbiosis and included chaperones (hsp70, hsp90 and calreticulin), structural and membrane modelling proteins (actin) and proteins with functions related to intracellular vesicular traffic (Rab7 and ADP-ribosylation factor 1) and signal transduction (14-3-3 protein and calmodulin). WPS resulted in a clear shift in the predominance of proteins, from those related to aerobic nitrogen-fixing bacteria (i.e. Rhizobiales, Sphingomonadales and Actinomycetales) in healthy corals to those produced by facultative/anaerobic sulphate-reducing bacteria (i.e. Enterobacteriales, Alteromonadales, Clostridiales and Bacteroidetes) in WPS corals. BBD corals developed a diverse community dominated by cyanobacteria and sulphur cycle bacteria. Hsp60, hsp90 and adenosylhomocysteinase proteins were produced mainly by cyanobacteria in BBD corals, which is consistent with elevated oxidative stress in hydrogen sulphide- and cyanotoxin-rich environments. This study demonstrates the usefulness of metaproteomics for gaining better comprehension of coral metabolic status in health and disease, especially in reef systems such as the Abrolhos that are suffering from the increase in global and local threatening events. PMID- 27492758 TI - Minority groups and the artificial pancreas: who is (not) in line? PMID- 27492759 TI - De-evolution of diagnostic testing for adrenal insufficiency. PMID- 27492760 TI - Choosing estimands in clinical trials with missing data. AB - Recent research has fostered new guidance on preventing and treating missing data. Consensus exists that clear objectives should be defined along with the causal estimands; trial design and conduct should maximize adherence to the protocol specified interventions; and a sensible primary analysis should be used along with plausible sensitivity analyses. Two general categories of estimands are effects of the drug as actually taken (de facto, effectiveness) and effects of the drug if taken as directed (de jure, efficacy). Motivated by examples, we argue that no single estimand is likely to meet the needs of all stakeholders and that each estimand has strengths and limitations. Therefore, stakeholder input should be part of an iterative study development process that includes choosing estimands that are consistent with trial objectives. To this end, an example is used to illustrate the benefit from assessing multiple estimands in the same study. A second example illustrates that maximizing adherence reduces sensitivity to missing data assumptions for de jure estimands but may reduce generalizability of results for de facto estimands if efforts to maximize adherence in the trial are not feasible in clinical practice. A third example illustrates that whether or not data after initiation of rescue medication should be included in the primary analysis depends on the estimand to be tested and the clinical setting. We further discuss the sample size and total exposure to placebo implications of including post-rescue data in the primary analysis. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27492762 TI - Comparison of apoptosis pathway following the use of two protocols for vitrification of immature mouse testicular tissue. AB - Our objective was to evaluate the apoptosis incidence in immature mouse testicular tissue after two different protocols of vitrification and short-term culture. Testes of 7-day-old Naval Medical Research Institute mice were isolated and distributed into control and vitrification groups. In vitrification 1 group, testes were vitrified using a combination of ethylene glycol and DMSO in three steps, and in vitrification 2 group, testes were vitrified using a combination of ethylene glycol and sucrose in five steps. Then, fresh and vitrified-warmed testis fragments were cultured for 20 hours. Morphology, cell viability, apoptosis incidence, and apoptosis gene expression (BAX, BCL2, Caspase 3, Fas, Fas ligand, p53) were evaluated at 0, 3, and 20 hours of culture by light microscopy, flow cytometry, and real-time polymerase chain reaction, respectively. Significant decrease of early apoptosis (annexin V+/PI- cells in vitrification 1 and 2 groups at 0 hours of culture, 37.34 +/- 0.91 and 30.72 +/- 2.2, and at 20 hours of culture, 1.46 +/- 0.28 and 0.76 +/- 0.11, respectively), increase of late apoptosis (annexin V+/PI+ cells in vitrification 1 group at 0 hours of culture, 14.46 +/- 0.86, and at 20 hours of culture, 37.18 +/- 2.34), and BAX/BCL-2 ratio (in vitrification 1 and 2 groups at 0 hours of culture, 7.31 +/- 0.31 and 6.83 +/- 1.38, and at 20 hours of culture, 24.08 +/- 4.32 and 9.35 +/- 1.91, respectively) were observed in vitrification groups during culture period. Caspase 3 expression was significantly decreased in all groups after 3 hours of culture (in control, vitrification 1, and vitrification 2 groups at 0 hours of culture, 1.00 +/- 0.0, 1.56 +/- 0.09, and 0.79 +/- 0.06, and at 20 hours of culture, 0.37 +/- 0.0, 0.96 +/- 0.10, and 0.12 +/- 0.03, respectively). Expression of p53 was significantly lower in vitrification 1 (0.32 +/- 0.02) and control (0.50 +/- 0.03) groups in 20 hours of culture as compared with vitrification 2 (0.88 +/- 0.14) group. Fas (in vitrification 1 and 2 groups at 0 hours of culture, 2.29 +/- 0.23 and 1.14 +/- 0.15, and at 20 hours of culture, 12.43 +/- 0.46 and 6.7 +/- 0.48, respectively) and Fas Ligand (in vitrification 1 and 2 groups at 0 hours of culture, 1.2 +/- 0.28 and 5.24 +/- 0.32, and at 20 hours of culture, 21.75 +/- 2.00 and 25.82 +/- 2.15, respectively) expressions significantly increased in vitrification groups after 20 hours of culture. Although both vitrification protocols cause cell death via apoptotic and necrotic pathway, it seems that vitrification 1 protocol induces cell death more via apoptotic pathway than via necrosis. The apoptosis incidence after vitrification may have occurred independent of p53. PMID- 27492761 TI - Impact of polymer-modified gold nanoparticles on brain endothelial cells: exclusion of endoplasmic reticulum stress as a potential risk factor. AB - A library of polymer-coated gold nanoparticles (AuNPs) differing in size and surface modifications was examined for uptake and induction of cellular stress responses in the endoplasmic reticulum (ER stress) in human brain endothelial cells (hCMEC/D3). ER stress is known to affect the physiology of endothelial cells (ECs) and may lead to inflammation or apoptosis. Thus, even if applied at non-cytotoxic concentrations ER stress caused by nanoparticles should be prevented to reduce the risk of vascular diseases and negative effects on the integrity of barriers (e.g. blood-brain barrier). We exposed hCMEC/D3 to twelve different AuNPs (three sizes: 18, 35, and 65 nm, each with four surface modifications) for various times and evaluated their effects on cytotoxicity, proinflammatory mediators, barrier functions and factors involved in ER stress. We demonstrated a time-dependent uptake of all AuNPs and no cytotoxicity for up to 72 h of exposure. Exposure to certain AuNPs resulted in a time-dependent increase in the proinflammatory markers IL-8, MCP-1, sVCAM, sICAM. However, none of the AuNPs induced an increase in expression of the chaperones and stress sensor proteins BiP and GRP94, respectively, or the transcription factors ATF4 and ATF6. Furthermore, no upregulation of the UPR stress sensor receptor PERK, no active splicing product of the transcription factor XBP1 and no upregulation of the transcription factor CHOP were detectable. In conclusion, the results of the present study indicate that effects of different-sized gold nanoparticles modified with various polymers were not related to the induction of ER stress in brain microvascular endothelial cells or led to apoptosis. PMID- 27492763 TI - Tracking Effects of Problematic Social Networking on Adolescent Psychopathology: The Mediating Role of Sleep Disruptions. AB - Concerns are growing about adolescents' problematic social networking and possible links to depressed mood and externalizing behavior. Yet there remains little understanding of underlying processes that may account for these associations, including the mediating role of sleep disruption. This study tests this putative mediating process and examines change in problematic social networking investment and disrupted sleep, in relation to change in depressed mood and externalizing behavior. A sample of 874 students (41% male; 57.2% Caucasian; baseline M age = 14.4 years) from 27 high schools were surveyed. Participants' problematic social networking, sleep disruption, and psychopathology (depressed mood, externalizing behaviors) were measured annually over 3 years. Longitudinal mediation was tested using latent trajectories of problematic social networking use, sleep disruption, and psychopathology. Both problematic social networking and sleep disruption underwent positive linear growth over time. Adolescents who increasingly invested in social networking reported increased depressed mood, with around 53% of this association explained by the indirect effect of increased sleep disruptions. Further, adolescents who increasingly invested in social networking also reported increased externalizing behavior; some of this relation was explained (13%) via increased sleep disruptions. However an alternative model in which increased externalizing was associated with increased social networking, mediated by sleep disruptions, indicated a reciprocal relation of similar magnitude. It is important for parents, teachers, and psychologists to minimize the negative effects of social networking on adolescents' psychopathology. Interventions should potentially target promoting healthy sleep habits through reductions in social networking investment and rescheduling usage away from bedtime. PMID- 27492764 TI - A multicenter 12-month experience with a new iliac side-branched device for revascularization of hypogastric arteries. AB - OBJECTIVE: The aim of this study was to investigate the 1-year safety and efficacy of a new iliac side-branched device (IBD) for revascularization of the hypogastric arteries. METHODS: Patients receiving the E-liac (Jotec GmbH, Hechingen, Germany) side-branched device at six German vascular centers either as a stand-alone procedure or in combination with abdominal aortic aneurysm exclusion were included in a prospectively created data bank. Collected data were analyzed for baseline characteristics, procedural events, and clinical follow-up; variables included endoleaks, reinterventions, and internal iliac artery (IIA) patency. RESULTS: Between January 2012 and January 2015, a total of 70 patients (69 men [98.6%]) with a median age of 74 years (range, 51-87 years) were consecutively treated; 66 patients had aneurysmatic disease of the iliac arteries, 2 patients had a para-anastomotic aneurysm after aortobi-iliac reconstruction, and another 2 patients had a type Ib endoleak after endovascular aneurysm repair. A total of 82 IIAs were revascularized, 12 bilaterally. Technical success was achieved in 100% (82/82) of the revascularized IIAs. All IBDs were patent at the end of the procedure. No instances of myocardial infarction, stroke, conversion to open repair, mesenteric or spinal cord infarction, or buttock necrosis were observed. There was one perioperative death (1.4%) in a 70-year-old patient with intraoperative gastrointestinal bleeding leading to multiple organ failure, which resulted in the patient's death on the fifth postoperative day. Within 30 days, one symptomatic occlusion of a treated common iliac artery (CIA) was observed. In two other patients, an asymptomatic kinking of the CIA segment of the IBD was revealed in the predischarge follow-up duplex ultrasound examination and corrected with relining. Median follow-up was 12 months (range, 6-16 months). One patient was lost during the follow-up period. Survival at 1 year was 98.5% with all IIAs remaining patent, whereas two CIA and two external iliac artery limb occlusions occurred. According to life-table analysis, the freedom from occlusion in a patient was 92% at 1 year, and freedom from type I endoleak was 87% at 1 year. CONCLUSIONS: This first ever 1-year study reports the results with the new E-liac device and shows that it can be safely applied for the treatment of aortoiliac aneurysmatic disease with low reintervention rates and high patency rates. Long-term data are needed to confirm the durability of the device. PMID- 27492765 TI - Electromobility Shift Assay Reveals Evidence in Favor of Allele-Specific Binding of RUNX1 to the 5' Hypersensitive Site 4-Locus Control Region. AB - In our previous studies on the Iranian beta-thalassemia (beta-thal) patients, we identified an association between the severity of the beta-thal phenotype and the polymorphic palindromic site at the 5' hypersensitive site 4-locus control region (5'HS4-LCR) of the beta-globin gene cluster. Furthermore, a linkage disequilibrium was observed between this region and XmnI-HBG2 in the patient population. Based on this data, it was suggested that the well-recognized phenotype-ameliorating role assigned to positive XmnI could be associated with its linked elements in the LCR. To investigate the functional significance of polymorphisms at the 5'HS4-LCR, we studied its influence on binding of transcription factors. Web-based predictions of transcription factor binding revealed a binding site for runt-related transcription factor 1 (RUNX1), when the allele at the center of the palindrome (TGGGG(A/G)CCCCA) was A but not when it was G. Furthermore, electromobility shift assay (EMSA) presented evidence in support of allele-specific binding of RUNX1 to 5'HS4. Considering that RUNX1 is a well-known regulator of hematopoiesis, these preliminary data suggest the importance of further studies to confirm this interaction and consequently investigate its functional and phenotypical relevance. These studies could help us to understand the molecular mechanism behind the phenotype modifying role of the 5'HS4-LCR polymorphic palindromic region (rs16912979), which has been observed in previous studies. PMID- 27492767 TI - Occurrence of the - -(SEA), - -(THAI) and - -(FIL) alpha-Thalassemia-1 Carriers from a 7-Year Study at Ramathibodi Hospital, Bangkok, Thailand. AB - alpha-Thalassemia (alpha-thal) is one of the most common genetic diseases in Thailand. Homozygosity of alpha-thal-1 (- -/- -) and compound heterozygosity of alpha-thal-1/alpha-thal-2 (- -/-alpha) leads to Hb Bart's (gamma4) hydrops fetalis and Hb H (beta4) disease, respectively. In order to better control and provide prevention of alpha-thal disease, the prevalence of alpha-thal-1 carriers and the types of genotypes in the Thai population should be known. A 7-year retrospective study, employing multiplex gap-polymerase chain reaction (gap-PCR) of 31,632 blood samples from Ramathibodi Hospital, Mahidol University, Bangkok, revealed an alpha-thal-1 carrier rate of 14.40% with the - -(SEA) (NG_000006.1: g.26264_45564del19301), - -(THAI) (NG_000006.1: g.10664_44164del33501) and - (FIL) (NG_000006.1: g.11684_43534del31851) genotypes, constituting frequencies of 14.21, 0.18 and 0.01%, respectively. Although the - -(FIL) genotype is rare in the Thailand, its detection should be included in future alpha-thal screening programs. PMID- 27492766 TI - Identification of a Novel beta-Globin Mutation (HBB: C.189_195delTCATGGC) in a Chinese Family. AB - beta-Thalassemia (beta-thal) is one of the most common genetic disorders worldwide. Molecular characterization of beta-thal is essential for prevention and understanding the biology of the disease. More and more rare and novel mutations are being reported. Here, we report a novel 7 bp deletion at codons 63 65 (HBB: c.189_195delTCATGGC) in exon 2 of the beta-globin gene in a family from Guangxi Province, China. This novel mutation causes a shift in the normal reading frame of the beta-globin coding sequence and created a stop codon at codon 87 in exon 2, which leads to a beta(0)-thal phenotype. PMID- 27492768 TI - The -(alpha)(5.2) Deletion Detected in a Uruguayan Family: First Case Report in the Americas. AB - In Uruguay, alpha-thalassemia (alpha-thal) mutations were introduced predominantly by Mediterranean European immigrant populations and by slave trade of African populations. A patient with anemia with hypochromia and microcytosis, refractory to iron treatment and with normal hemoglobin (Hb) electrophoresis was analyzed for alpha-thal mutations by multiplex gap-polymerase chain reaction (gap PCR), automated sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses. Agarose gel electrophoresis of the multiplex gap-PCR showed a band of unexpected size (approximately 700 bp) in the samples from the proband and mother. Automated sequencing of the amplified fragment showed the presence of the -(alpha)(5.2) deletion (NG_000006.1: g.32867_38062del5196) [an alpha-thal-1 deletion of 5196 nucleotides (nts)]. The MLPA analysis of the proband's sample also showed the presence of the -(alpha)(5.2) deletion in heterozygous state. We report here the presence of the -(alpha)(5.2) deletion, for the first time in the Americas, in a Uruguayan family with Italian ancestry, detected with a previously described multiplex gap-PCR. PMID- 27492769 TI - Is Vitamin C Supplementation in Patients with beta-Thalassemia Major Beneficial or Detrimental? AB - Globally, beta-thalassemia major (beta-TM) is one of the most common hereditary disorders. Multiple blood transfusions, that are a life-saving therapy in patients with beta-TM, is a major source of iron overload. Iron overload can lead to significant morbidity and mortality. Research evidence indicates that oxidative stress induced by iron overload, is one of the major precipitating causes of vitamin C deficiency in beta-TM patients. It has previously been shown that patients with beta-TM have significantly lower levels of vitamin C as compared to healthy individuals. It is believed that vitamin C can reduce both ferric (Fe(3+)) and ferrous (Fe(2+)) ions, and also facilitate the accessibility of iron to chelators through increase of iron release from the reticuloendothelial system. Despite the potential benefits of vitamin C in patients with beta-TM, several areas of concern exist that should be addressed by high quality research designs. Some recommendations have been provided through this study. PMID- 27492771 TI - Three-decade long fertilization-induced soil organic carbon sequestration depends on edaphic characteristics in six typical croplands. AB - Fertilizations affect soil organic carbon (SOC) content but the relative influences of the edaphic and climate factors on SOC storage are rarely studied across wide spatiotemporal scales. This study synthesized long-term datasets of fertilization experiments in six typical Chinese croplands, and calculated annual C input from crops and manure amendments, changes in SOC storage (DeltaSOC) and C sequestration efficiency (i.e. the percentage of soil C change per unit of C input, hereafter referred as CSE) in 0-20 cm soil over three decades. Three fertilization treatments include no fertilization (CK), chemical nitrogen, phosphorus and potassium fertilizers (NPK) and combined chemical fertilizers and manure (NPKM). Results showed significant fertilization effects on C input and DeltaSOC (NPKM>NPK>CK), and significantly higher CSE in Qiyang at Hunan than Zhengzhou at Henan and Heihe at Heilongjiang. The variance partitioning analysis (VPA) showed more variance of CSE can be explained by edaphic factors (up to 39.7%) than other factors. Furthermore, soil available N content and pH were identified as the major soil properties explaining CSE variance. This study demonstrated key controls of soil fertility factors on SOC sequestration and informs the need to develop strategic soil management plan to promote soil carbon sequestration under long-term intensive fertilization. PMID- 27492772 TI - Effects of fiber-glass-reinforced composite restorations on fracture resistance and failure mode of endodontically treated molars. AB - OBJECTIVES: The study evaluated the fracture resistance and fracture patterns of endodontically treated mandibular first molars restored with glass-fiber reinforced direct composite restorations. METHODS: In total, 60 extracted intact first molars were treated endodontically; a mesio-occluso-distal (MOD) cavity was prepared and specimens were then divided into six groups: sound teeth (G1), no restoration (G2), direct composite restoration (G3), fiber-post-supported direct composite restoration (G4), direct composite reinforced with horizontal mesio distal glass-fibers (G5), and buccal-palatal glass-fibers (G6). Specimens were subjected to 5000 thermocycles and 20,000 cycles of 45 degrees oblique loading force at 1.3Hz and 50N; they were then loaded until fracture. The maximum fracture loads were recorded in Newtons (N) and data were analyzed with one-way ANOVA and post-hoc Tukey tests (p<0.05). Fractured specimens were analyzed with a scanning electron microscope (SEM). RESULTS: The mean static loads (in Newtons) were: G1, 831.83; G2, 282.86; G3, 364.18; G4, 502.93; G5, 499.26; and G6, 582.22. Fracture resistance did not differ among G4, G5, and G6, but was significantly higher than G3 (p=0.001). All specimens fractured in a catastrophic way. In G6, glass fibers inducted a partial deflection of the fracture, although they were not able to stop crack propagation. CONCLUSIONS: For the direct restoration of endodontically treated molars, reinforcement of composite resins with glass fibers or fiber posts can enhance fracture resistance. The SEM analysis showed a low ability of horizontal glass-fibers to deviate the fracture, but this effect was not sufficient to lead to more favorable fracture patterns above the cement enamel junction (CEJ). CLINICAL SIGNIFICANCE: The fracture resistance of endodontically treated molars restored with direct composite restorations seems to be increased by reinforcement with fibers, even if it is insufficient to restore sound molar fracture resistance and cannot avoid vertical fractures. PMID- 27492773 TI - After 12 years, where next for QOF? PMID- 27492774 TI - Screening for Food Insecurity in Pediatric Clinical Settings: Opportunities and Barriers. AB - Food insecurity is a serious health concern among children in the United States with 15.3 million children living in food insecure households. The American Academy of Pediatrics recommends that pediatricians screen for food insecurity at health maintenance visits as identifying children at risk is a crucial step in the amelioration of food insecurity. Two surveys were administered in a Midwest pediatric clinic. A cross-sectional survey was electronically distributed to pediatric providers to assess perceptions of food insecurity among patients, provider readiness to conduct food security screenings, and barriers to conducting those screenings. A cross-sectional caregiver survey was administered to assess demographics, household food security status, participation in nutrition assistance programs, and barriers to getting enough food to eat. Descriptive statistics and odds ratios were calculated. Eighty-eight percent of physicians believe that food insecurity is a challenge for some of their patients. Only 15 % of providers reported screening for food insecurity, while 80 % were willing to screen. Physicians were most concerned with knowing how to handle a positive screen. Among caregivers, 57 % screened positive for food insecurity. Those experiencing food insecurity were more likely to be non-white, participate in SNAP and to feel discomfort towards the idea of talking to a doctor or nurse about food needs. Caregivers reporting food insecurity were significantly less likely to have a personal vehicle. Effective food insecurity screening requires addressing caregiver and health provider barriers in order to increase the likelihood of identifying households most at risk. PMID- 27492775 TI - Jayapura Teenagers Smoking Behavior. AB - Smoking behavior is a threat for Indonesian teenagers, including in the city of Jayapura, Papua province. The purpose of this study was to access Jayapura teenagers smoking behavior and knowledge including parents and other family members. The study was conducted on 78 respondents (grade 7, aged 11-14 years old), using cluster random sampling for selecting the public and private junior high school in Jayapura. The data collected was smoking behavior of respondents, parents and other family members (using self-reported questionnaire), and respondents' knowledge about the dangers of smoking (using tests with Cronbach's alpha 0.701). Data were analyzed descriptively and analytically using Chi-square, 95 % level of significant. The results showed 29.3 % of teenagers, 69.23 % of parents and 25.6 % of other family members were smokers, their knowledge was low (an average score of 60.81 out of 100), there was no significant statistical relationship between knowledge and smoking behavior among respondents (p = 0.079), and there is no significant relationship between teenagers behavior with the behavior of the parents (p = 0.609) and other family members (p = 0.578), 87 % of teenagers became smokers because there were individuals who smoke at home. PMID- 27492770 TI - Heterogeneity of B Cell Functions in Stroke-Related Risk, Prevention, Injury, and Repair. AB - It is well established that post-stroke inflammation contributes to neurovascular injury, blood-brain barrier disruption, and poor functional recovery in both animal and clinical studies. However, recent studies also suggest that several leukocyte subsets, activated during the post-stroke immune response, can exhibit both pro-injury and pro-recovery phenotypes. In accordance with these findings, B lymphocytes, or B cells, play a heterogeneous role in the adaptive immune response to stroke. This review highlights what is currently understood about the various roles of B cells, with an emphasis on stroke risk factors, as well as post-stroke injury and repair. This includes an overview of B cell functions, such as antibody production, cytokine secretion, and contribution to the immune response as antigen presenting cells. Next, evidence for B cell-mediated mechanisms in stroke-related risk factors, including hypertension, diabetes, and atherosclerosis, is outlined, followed by studies that focus on B cells during endogenous protection from stroke. Subsequently, animal studies that investigate the role of B cells in post-stroke injury and repair are summarized, and the final section describes current B cell-related clinical trials for stroke, as well as other central nervous system diseases. This review reveals the complex role of B cells in stroke, with a focus on areas for potential clinical intervention for a disease that affects millions of people globally each year. PMID- 27492776 TI - Primary non-refluxive megaureter in children: single-center experience and follow up of 212 patients. AB - PURPOSE: Primary non-refluxing megaureter (pMU) is a multifaceted and challenging congenital pathology of the urinary tract. We report our 23-year experience with this anomaly in terms of presentation, diagnostic work-up and management. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 212 children diagnosed with pMU between 1986 and 2009 at our institution. Mean follow up was 45.17 (0-192) months. RESULTS: Of the total, 168 (79 %) children presented with upper urinary tract dilation on perinatal ultrasound screening. In 44 (21 %) patients, the diagnosis was made following diagnostic work-up of a urinary tract infection (UTI, 18 %) or flank pain (3 %). In total, 203 of 254 pMUs (79.9 %) were successfully treated conservatively during the 23-year observation period. Forty-eight children (23 %) underwent ureteric reimplantation. UTIs occurred in 91 of 212 children (43 %). Of these, 41 (45 %) occurred despite antibacterial infection prophylaxis. Within the past three decades, there has been a marked shift from surgical toward conservative therapy at our institution. CONCLUSION: Neonatal renal ultrasound is the method of choice to timely identify children with pMU and, alongside dynamic renography, to monitor the clinical course. Nowadays, only a minor subset of children with asymptomatic course requires surgical correction. Antibacterial prophylaxis has the potential to reduce the risk of febrile UTIs. Prospective randomized studies are warranted to provide evidence of the beneficial effect of antibacterial prophylaxis. PMID- 27492777 TI - Beneath the tip of the iceberg: using electronic referrals to map the unquantified burden of clinical activity in a urology service. AB - INTRODUCTION: The aim of this study was to inform health policy by demonstrating the benefits of an electronic referral (e-referral) system to study inpatient referrals to urology departments. METHODS: London North West Healthcare NHS Trust has over 800 beds and several secondary and tertiary care services. In January 2014, we designed an e-referral form to requisition urology input for in-patients using the Integrated Clinical EnvironmentTM (ICE) platform. We retrospectively reviewed e-referral records from February to December 2014 for patient demography, the referring service and disease groups triggering a referral. RESULTS: There were 1192 referrals. There was a median of 107 e-referrals per month (IQR 97-123, range 91-132) and 4 per day (IQR 2-6, range 0-12). Weekend e referrals were 127 (median 1, IQR 0-2, range 0-5) with 1065 e-referrals on weekdays (median 4, IQR 3-6, range 0-12). A total of 848 (71.1 %) patients were male, and 344 (28.9 %) were female. Patients' mean age was 63 (SD 21) years. Almost half (550, 46 %) were acute referrals. Amongst the acute referrals, the majority (466, 84.7 %) arose from A&E. From the non-acute conditions, 381 (59.3 %) patients were from the medical specialities and 246 (38.3 %) from surgical disciplines. The three largest disease categories were urolithiasis (287, 24.1 %), haematuria (185, 15.5 %) and for ex-catheterisation (102, 8.6 %). A qualitative review showed the strengths and weaknesses of the system, enabling improvements in operational efficiency. CONCLUSION: An e-referral system monitors activity accurately. Systemic improvement in referral pathways would lead to better patient care and enable services to factor in the unseen component of workload and prompt realistic staffing. PMID- 27492778 TI - Retroperitoneal metastatic germ cell tumor presenting as a psoas abscess: a rare clinical occurrence and review of the literature. PMID- 27492779 TI - Seabird acoustic communication at sea: a new perspective using bio-logging devices. AB - Most seabirds are very noisy at their breeding colonies, when aggregated in high densities. Calls are used for individual recognition and also emitted during agonistic interactions. When at sea, many seabirds aggregate over patchily distributed resources and may benefit from foraging in groups. Because these aggregations are so common, it raises the question of whether seabirds use acoustic communication when foraging at sea? We deployed video-cameras with built in microphones on 36 Cape gannets (Morus capensis) during the breeding season of 2010-2011 at Bird Island (Algoa Bay, South Africa) to study their foraging behaviour and vocal activity at sea. Group formation was derived from the camera footage. During ~42 h, calls were recorded on 72 occasions from 16 birds. Vocalization exclusively took place in the presence of conspecifics, and mostly in feeding aggregations (81% of the vocalizations). From the observation of the behaviours of birds associated with the emission of calls, we suggest that the calls were emitted to avoid collisions between birds. Our observations show that at least some seabirds use acoustic communication when foraging at sea. These findings open up new perspectives for research on seabirds foraging ecology and their interactions at sea. PMID- 27492781 TI - Reaching Adolescent Gay, Bisexual, and Queer Men Online: Development and Refinement of a National Recruitment Strategy. AB - BACKGROUND: Using social networking websites to recruit research participants is increasingly documented in the literature, although few studies have leveraged these sites to reach those younger than 18 years. OBJECTIVE: To discuss the development and refinement of a recruitment protocol to reach and engage adolescent gay, bisexual, and other teenaged men who have sex with men (AGBM). Participants were recruited for development and evaluation activities related to Guy2Guy, a text messaging-based human immunodeficiency virus infection prevention program. METHODS: Eligibility criteria included being between 14 to 18 years old; being a cisgender male; self-identifying as gay, bisexual, and/or queer; being literate in English, exclusively owning a cell phone, enrolled in an unlimited text messaging plan, intending to keep their current phone number over the next 6 months, and having used text messaging for at least the past 6 months. Recruitment experiences and subsequent steps to refine the Internet-based recruitment strategy are discussed for 4 research activities: online focus groups, content advisory team, beta test, and randomized controlled trial (RCT). Recruitment relied primarily on Facebook advertising. To a lesser extent, Google AdWords and promotion through partner organizations working with AGBM youth were also utilized. RESULTS: Facebook advertising strategies were regularly adjusted based on preidentified recruitment targets for race, ethnicity, urban-rural residence, and sexual experience. The result was a diverse sample of participants, of whom 30% belonged to a racial minority and 20% were Hispanic. Facebook advertising was the most cost-effective method, and it was also able to reach diverse recruitment goals: recruitment for the first focus group cost an average of US $2.50 per enrolled participant, and it took 9 days to enroll 40 participants; the second focus group cost an average of US $6.96 per enrolled participant, and it took 11 days to enroll 40 participants. Recruitment for the first content advisory team cost an average of US $32.52 per enrolled participant; the second cost US $29.52 per participant. Both recruitment drives required 10 days to enroll 24 participants. For the beta test, recruitment cost an average of US $17.19 per enrolled participant, and it took 16 days to complete enrollment of 20 participants. For the RCT, recruitment cost an average of US $12.54 per enrolled participant, and it took 148 days to enroll 302 participants. Google AdWords campaigns did not result in any enrolled participants of whom the research staff members were aware. CONCLUSIONS: Internet-based strategies can be a cost-efficient means to recruit and retain hard-to-reach populations from across the country. With real-time monitoring of participant demographic characteristics, diverse samples can be achieved. Although Facebook advertising was particularly successful in this study, alternative social media strategies can be explored in future research as these media are ever-changing. PMID- 27492780 TI - miRNA143 Induces K562 Cell Apoptosis Through Downregulating BCR-ABL. AB - BACKGROUND Leukemia seriously threats human health and life. MicroRNA regulates cell growth, proliferation, apoptosis, and cell cycle. Whether microRNA could be treated as a target for leukemia is still unclear and the mechanism by which microRNA143 regulates K562 cells needs further investigation. MATERIAL AND METHODS miRNA143 and its scramble miRNA were synthesized and transfected to K562 cells. MTT assay was used to detect K562 cell proliferation. Flow cytometry and a caspase-3 activity detection kit were used to test K562 cell apoptosis. Western blot analysis was performed to determine breakpoint cluster region-Abelson (BCR ABL) expression. BCR-ABL overexpression and siRNA were used to change BCR-ABL level, and cell apoptosis was detected again after lipofection transfection. RESULTS miRNA143 transfection inhibited K562 cell growth and induced its apoptosis. miRNA143 transfection decreased BCR-ABL expression. BCR-ABL overexpression suppressed miRNA143-induced K562 cell apoptosis, while its reduction enhanced miRNA143-induced apoptosis. CONCLUSIONS miRNA143 induced K562 cell apoptosis through downregulating BCR-ABL. miRNA143 might be a target for a new leukemia therapy. PMID- 27492782 TI - Broadband multiple responses of surface modes in quasicrystalline plasmonic structure. AB - We numerically study the multiple excitation of surface modes in 2D photonic quasicrystal/metal/substrate structure. An improved rigorous coupled wave analysis method that can handle the quasicrystalline structure is presented. The quasicrystalline lattice, which refers to Penrose tiling in this paper, is generated by the cut-and-project method. The normal incidence spectrum presents a broadband multiple responses property. We find that the phase matching condition determines the excitation frequency for a given incident angle, while the depth of the reflection valley depends on the incident polarization. The modes will split into several sub-modes at oblique incidence, which give rise to the appearance of more responses on the spectrum. PMID- 27492784 TI - Reply to Prediction of Non-invasive Mechanical Ventilation Response. Moving from Art to Science. PMID- 27492783 TI - PTEN regulates EG5 to control spindle architecture and chromosome congression during mitosis. AB - Architectural integrity of the mitotic spindle is required for efficient chromosome congression and accurate chromosome segregation to ensure mitotic fidelity. Tumour suppressor PTEN has multiple functions in maintaining genome stability. Here we report an essential role of PTEN in mitosis through regulation of the mitotic kinesin motor EG5 for proper spindle architecture and chromosome congression. PTEN depletion results in chromosome misalignment in metaphase, often leading to catastrophic mitotic failure. In addition, metaphase cells lacking PTEN exhibit defects of spindle geometry, manifested prominently by shorter spindles. PTEN is associated and co-localized with EG5 during mitosis. PTEN deficiency induces aberrant EG5 phosphorylation and abrogates EG5 recruitment to the mitotic spindle apparatus, leading to spindle disorganization. These data demonstrate the functional interplay between PTEN and EG5 in controlling mitotic spindle structure and chromosome behaviour during mitosis. We propose that PTEN functions to equilibrate mitotic phosphorylation for proper spindle formation and faithful genomic transmission. PMID- 27492785 TI - Exciton coupling dynamics in syn- and anti-type beta-beta linked Zn(ii) porphyrin linear arrays. AB - The photophysical properties of molecular arrays are strongly dependent on a variety of structural factors: the constituent chromophores, dihedral angle, linkage length, linkage position, the center-to-center distance between chromophores, and the linker itself. Here, we investigated the exciton coupling dynamics of syn- and anti-type beta-beta directly linked Zn(ii) porphyrin linear arrays. Focusing on the relationship between the origin of the lowest excited electronic state and the linkage position, we evaluated the exciton coupling strength and carried out time-dependent density functional theory (TDDFT) calculations on model compounds as well as femtosecond transient absorption anisotropy (fs-TAA) measurements. Based on our experiments and calculations, we propose that a different origin of the lowest excited state leads to linkage position-dependent exciton coupling. In short, compared with syn-type porphyrin arrays, anti-type arrays induce distinct and stronger exciton coupling in the lowest excited state. PMID- 27492787 TI - Competing risk bias was common in a prominent medical journal. PMID- 27492786 TI - Variability between credit units dedicated to dental and clinical sciences in dental schools across the USA. AB - PURPOSE: The Commission of Dental Accreditation (CODA) does not set minimum standards for clock hours of training in Dental and Clinical sciences. The purpose of this evaluation was to compare United States (US) dental schools for variability in clock hours. The current paper utilizes the American Dental Association's survey of clock hours of all US dental schools which is publicly available data. Clock hours survey from 2010 to 2011 was utilized and the analysis tool, JMP, was utilized to visualize and report variability. PERSPECTIVE: The current paper highlights the large variation in clock hours of training among core clinical subjects in accredited dental schools around the United States. For example, teaching Physical Evaluations; Oral and Maxillofacial; and Oral Diagnosis and Treatment Planning were 97.0; 126.6; and 74.4 h. Moreover, upper limit for hours of Operative Dentistry teaching was 1410 h and lower limit was 129 h. Various other fields of education do enforce strict requirements on educational clock hours. For instance, Massachusetts' General Law states that both private and public schools must have 900 and 990 h in a school year for elementary and secondary schools, respectively. However, no such stipulation exists in the field of Dental Education. CODA's mission is "to serve the oral health care needs of the public" and CODA must consider if the average dental patient would consider a dentist who attended the school delivering 1410 h of Operative Dentistry to be the same standard as a graduate of the school delivering 129 h. PMID- 27492788 TI - Point of data saturation was assessed using resampling methods in a survey with open-ended questions. AB - OBJECTIVE: To describe methods to determine sample sizes in surveys using open ended questions and to assess how resampling methods can be used to determine data saturation in these surveys. STUDY DESIGN AND SETTING: We searched the literature for surveys with open-ended questions and assessed the methods used to determine sample size in 100 studies selected at random. Then, we used Monte Carlo simulations on data from a previous study on the burden of treatment to assess the probability of identifying new themes as a function of the number of patients recruited. RESULTS: In the literature, 85% of researchers used a convenience sample, with a median size of 167 participants (interquartile range [IQR] = 69-406). In our simulation study, the probability of identifying at least one new theme for the next included subject was 32%, 24%, and 12% after the inclusion of 30, 50, and 100 subjects, respectively. The inclusion of 150 participants at random resulted in the identification of 92% themes (IQR = 91 93%) identified in the original study. CONCLUSION: In our study, data saturation was most certainly reached for samples >150 participants. Our method may be used to determine when to continue the study to find new themes or stop because of futility. PMID- 27492789 TI - The effects of methylphenidate and propranolol on the interplay between induced anxiety and working memory. AB - RATIONALE: Research documents a reciprocal impact of anxiety on working memory (WM), although its strength and direction depend on factors like task difficulty. A better understanding of these factors may generate insights into cognitive mechanisms of action involved in anxiety, culminating into treatment implications. By blocking the physiological effects of anxiety, propranolol might also block anxiety interference on WM. Conversely, by improving task-directed attention, methylphenidate might reduce anxiety, or, alternatively, by improving cognitive efficiency and free up processing resources to compute anxiety. OBJECTIVES: To investigate the interplay between induced anxiety and WM, we pharmacologically manipulated either anxiety or cognition, using single doses of 40 mg propranolol (PRO), 20 mg methylphenidate (MPH), or placebo (PLA). In this double-blind parallel-group design study, 60 healthy volunteers (20/drug group) performed a verbal WM task under three loads, 1-, 2- and 3-back, and in two conditions, threat of shock and safety. Startle electromyography (EMG) was used to measure anxiety. RESULTS: Findings were twofold: (1) MPH blocked anxiety interference only on the 3-back WM performance, while PRO or PLA had no effects on anxiety-WM interference, and (2) drugs had no effects on anxiety, but, after controlling for baseline anxiety, MPH enhanced anxiety-potentiated startle during the 3-back task. CONCLUSIONS: These findings support that MPH-related improvement of cognitive efficiency permits anxiety to be processed and expressed. In conclusion, MPH may be a useful tool to investigate the mechanisms of interaction between anxiety and WM, particularly those under catecholaminergic control. PMID- 27492791 TI - Lewis Acids as Activators in CBS-Catalysed Diels-Alder Reactions: Distortion Induced Lewis Acidity Enhancement of SnCl4. AB - The effect of several Lewis acids on the CBS catalyst (named after Corey, Bakshi and Shibata) was investigated in this study. While (2) H NMR spectroscopic measurements served as gauge for the activation capability of the Lewis acids, in situ FT-IR spectroscopy was employed to assess the catalytic activity of the Lewis acid oxazaborolidine complexes. A correlation was found between the Deltadelta((2) H) values and rate constants kDA , which indicates a direct translation of Lewis acidity into reactivity of the Lewis acid-CBS complexes. Unexpectedly, a significant deviation was found for SnCl4 as Lewis acid. The SnCl4 -CBS adduct was much more reactive than the Deltadelta((2) H) values predicted and gave similar reaction rates to those observed for the prominent AlBr3 -CBS adduct. To rationalize these results, quantum mechanical calculations were performed. The frontier molecular orbital approach was applied and a good correlation between the LUMO energies of the Lewis acid-CBS-naphthoquinone adducts and kDA could be found. For the SnCl4 -CBS-naphthoquinone adduct an unusual distortion was observed leading to an enhanced Lewis acidity. Energy decomposition analysis with natural orbitals for chemical valence (EDA-NOCV) calculations revealed the relevant interactions and activation mode of SnCl4 as Lewis acid in Diels-Alder reactions. PMID- 27492790 TI - Reduction of methicillin-resistant Staphylococcus aureus infection in long-term care is possible while maintaining patient socialization: A prospective randomized clinical trial. AB - BACKGROUND: Antibiotic resistance is a challenge in long-term care facilities (LTCFs). The objective of this study was to demonstrate that a novel, minimally invasive program not interfering with activities of daily living or socialization could lower methicillin-resistant Staphylococcus aureus (MRSA) disease. METHODS: This was a prospective, cluster-randomized, nonblinded trial initiated at 3 LTCFs. During year 1, units were stratified by type of care and randomized to intervention or control. In year 2, all units were converted to intervention consisting of universal decolonization using intranasal mupirocin and a chlorhexidine bath performed twice (2 decolonization-bathing cycles 1 month apart) at the start of the intervention period. Subsequently, after initial decolonization, all admissions were screened on site using real-time polymerase chain reaction, and those MRSA positive were decolonized, but not isolated. Units received annual instruction on hand hygiene. Enhanced bleach wipe cleaning of flat surfaces was done every 4 months. RESULTS: There were 16,773 tests performed. The MRSA infection rate decreased 65% between baseline (44 infections during 365,809 patient days) and year 2 (12 infections during 287,847 patient days; P <.001); a significant reduction was observed at each of the LTCFs (P <.03). CONCLUSIONS: On-site MRSA surveillance with targeted decolonization resulted in a significant decrease in clinical MRSA infection among LTCF residents. PMID- 27492792 TI - Achieving Molecular Remission before Allogeneic Stem Cell Transplantation in Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Impact on Relapse and Long-Term Outcome. AB - Allogeneic stem cell transplantation (alloHSCT) in first complete remission (CR1) remains the consolidation therapy of choice in Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). The prognostic value of measurable levels of minimal residual disease (MRD) at time of conditioning is a matter of debate. We analyzed the predictive relevance of MRD levels before transplantation on the clinical outcome of Ph+ ALL patients treated with chemotherapy and imatinib in 2 consecutive prospective clinical trials. MRD evaluation before transplantation was available for 65 of the 73 patients who underwent an alloHSCT in CR1. A complete or major molecular response at time of conditioning was achieved in 24 patients (37%), whereas 41 (63%) remained carriers of any other positive MRD level in the bone marrow. MRD negativity at time of conditioning was associated with a significant benefit in terms of risk of relapse at 5 years, with a relapse incidence of 8% compared with 39% for patients with MRD positivity (P = .007). However, thanks to the post-transplantation use of tyrosine kinase inhibitors (TKIs), disease-free survival was 58% versus 41% (P = .17) and overall survival was 58% versus 49% (P = .55) in MRD-negative compared with MRD-positive patients, respectively. The cumulative incidence of nonrelapse mortality was similar in the 2 groups. Achieving a complete molecular remission before transplantation reduces the risk of leukemia relapse even though TKIs may still rescue some patients relapsing after transplantation. PMID- 27492793 TI - Novel Scoring Criteria for the Evaluation of Ocular Graft-versus-Host Disease in a Preclinical Allogeneic Hematopoietic Stem Cell Transplantation Animal Model. AB - Ocular complications occur after transplantation in 60% to 90% of chronic graft versus-host disease (GVHD) patients and significantly impair vision-related quality of life. Ocular surface inflammation and dry eye disease are the most common manifestations of ocular GVHD. Ocular GVHD can be viewed as an excellent preclinical model that can be studied to understand the immune pathogenesis of this common and debilitating disease. A limitation of this is that only a few experimental models mimic the ocular complications after hematopoietic stem cell transplantation (HSCT) and have focused on the acute GVHD process. To address this issue, we used a preclinical animal model developed by our group where ocular involvement was preceded by systemic GVHD to gain insight regarding the contributing immune mechanisms. Employing this "matched unrelated donor" model enabled the development of clinical scoring criteria, which readily identified different degrees of ocular pathology at both the ocular surface and adnexa, dependent on the level of conditioning before HSCT. As far as we are aware, we report for the first time that these clinical and immune responses occur not only on the ocular surface, but they also heavily involve the lid margin region. In total, the present study reports a preclinical scoring model that can be applied to animal models as investigators look to further explore GVHD's immunologic effects at the level of the ocular surface and eyelid adnexa compartments. We speculate that future studies will use this clinical scoring index in combination with what is recognized histologically and correlated with serum biomarkers identified in chronic/ocular GVHD. PMID- 27492795 TI - Comment on: Is high-intensity interval training more effective on improving cardiometabolic risk and aerobic capacity than other forms of exercise in overweight and obese youth? A meta-analysis. PMID- 27492794 TI - Haploidentical and Matched Sibling Donor Hematopoietic Cell Transplantation for Patients with HLA-Homozygous Haplotypes. AB - More than 1% of the Japanese population has HLA-homozygous haplotypes. For patients with such haplotypes, HLA-haploidentical family members who have no HLA mismatch in the graft-versus-host direction are readily available donor candidates for hematopoietic cell transplantation (HCT). In this study, the outcomes of patients with homozygous HLA-A, -B, and -DRB1 antigens who received HCT without T cell depletion from a haploidentical related donor with mismatches in the host-versus-graft direction only (hetero-to-homo, n = 78) or from an HLA matched sibling donor (MSD) (MSD-homo, n = 153) were compared with those in patients with heterozygous haplotypes who received HCT from an MSD (MSD-hetero, n = 7242). Transplant outcomes in the hetero-to-homo group were similar to those in the MSD-hetero group regarding neutrophil engraftment, grades III to IV acute graft-versus-host disease (aGVHD), nonrelapse mortality (NRM), relapse, and overall survival. On the other hand, the incidences of severe aGVHD and NRM in the MSD-homo group were significantly lower than those in the MSD-hetero group (grades III to IV aGVHD: aHR .50, P = .034; NRM: aHR .48, P = .004). In conclusion, patients with HLA-homozygous haplotypes achieved lower GVHD and NRM rates for MSD transplantation than those with HLA-heterozygous haplotypes. When an MSD or an appropriate alternative donor is not available for patients with HLA homozygous haplotypes who need immediate transplantation, transplantation from a haploidentical donor without T cell depletion is a viable option, given the comparable transplant outcomes for hetero-to-homo HCT and MSD-hetero HCT. PMID- 27492796 TI - Frequency and risks associated with Clostridium difficile-associated diarrhea after pediatric solid organ transplantation: a single-center retrospective review. AB - BACKGROUND: Morbidity and mortality related to Clostridium difficile infection (CDI) has increased, but epidemiology and risk factors within pediatric solid organ transplant (SOT) recipients are uncertain. METHODS: A retrospective cohort study of SOT recipients age <=18 years at transplantation from 2010 to 2013 was performed. Patients with CDI were compared with matched CDI-negative controls with diarrhea. RESULTS: Of 202 patients, the majority were male (58%) and Caucasian (77%). Kidney (42%) was the most common organ transplanted, followed by liver (38%), heart (17%), and multivisceral/intestine (3%). Age ranged from 3 weeks to 18 years (median 4.7 years, mean 6.6; interquartile range [IQR] 1.5 11.2). In 104 SOT recipients, at least 1 unformed stool was tested; 25 patients were positive for CDI. Most testing occurred by 60 days post transplant (mean 164, median 57, IQR 14-227). First negative tests occurred concurrently (mean 153, median 54, IQR 13-214) to the 25 patients with CDI (mean 199, median 65, IQR 32-238). In univariable analyses, age, gender, ethnicity, obesity, and calcineurin inhibitor choice were not associated with CDI. Liver recipients were more likely to have CDI (18.4% liver, 4.7% kidney, 8.8% heart, P < 0.01). Twenty CDI patients were matched to 35 controls. In multivariable analyses, neither recent hospitalization nor antibiotic duration or intensity was associated with CDI. Acid-blockade appeared protective (risk ratio 0.13, 95% confidence interval 0.02-0.78). CONCLUSIONS: CDI occurs in 12% of pediatric SOT recipients, but 24% of those tested with diarrhea were positive. In patients with diarrhea, prior hospitalization and antibiotic duration or intensity were not associated with CDI. PMID- 27492797 TI - Help-seeking behaviors for serious psychological distress among individuals with diabetes mellitus: The California Health Interview Survey, 2011-2012. AB - AIM: To investigate patterns of and factors associated with help-seeking behaviors among individuals with diabetes mellitus (DM) and/or serious psychological distress (SPD). METHODS: The analysis was conducted with the California Health Interview Survey (CHIS) 2011-2012 of 40,803 adults. Logistic regression was used to examine the associations between the multiple facilitating/preventing factors and outcome, guided by the Andersen's Health Care Utilization Model. RESULTS: The prevalence of DM and SPD were 10.9% and 3.4%, respectively, among participants in the survey. The participants with DM were more likely to experience SPD than those without DM (OR 1.46, 95% CI=1.11-1.91, p=0.006). Participants with combined DM and SPD, the most underserved, were less likely to perceive the need for mental health services and less likely to seek help, compared to those with only SPD. Need factors (SPD status and perceived need) were significantly associated with help-seeking behaviors for mental health, along with predisposing factors (age, gender, obesity, race, and employment), and enabling factors (insurance, English proficiency). CONCLUSIONS: Perceptions about need for seeking help seem to play an important role in receiving mental health services in addition to other predisposing or enabling factors. Identification of these factors may improve clinical outcomes related to DM and SPD. PMID- 27492798 TI - Bishop scoring: Perceived benefits of using in labour induction by Turkish midwives. AB - It is not always possible to achieve a successful induction. Bishop scoring system is an efficient method used in determining whether the induction will be effective or not. The aim of this study was to train midwives on the benefits and use of the Bishop scoring system and to minimize the unnecessary use of induction. This study was conducted as pretest-posttest quasi-experimental design. This study was conducted in a maternity hospital in Erzurum between 01 February and 31 July 2012. In the study, the midwives received training on the use of the Bishop scoring system, and changes in their knowledge levels and application during practice of induction were then evaluated. While only 20% of midwives were using the Bishop score before the training, 56.7% started to use this tool after the training. Comparing the examinations performed on pregnant women by the midwives in the pre-induction period before and after the training, the mean of the Bishop score changed from 7.26 to 9.68 after the training. It was determined that the training could increase the knowledge levels of midwives regarding the Bishop scoring system and their attention paid to the Bishop scoring system in the practice of induction. PMID- 27492799 TI - Microarray expression in peri-implant tissue next to different titanium implant surfaces predicts clinical outcomes: a split-mouth study. AB - OBJECTIVES: This split-mouth study evaluated miRNA expression of tissues around implants with different surface treatments. MATERIAL AND METHODS: Each patient of the sample (five men and five women) received two implants (one control and one test) into an edentulous quadrant to support fixed partial dentures. The control implants (Osseotite) had a dual acid-etched (DAE) surface in the apical portion and a machined coronal part, test implants (Full Osseotite, FOSS) were completely DAE. Machined healing abutments were placed on control implants and DAE abutments on test ones. All implants were assigned codes for blinding. Standardized periapical radiographs were taken at baseline, 2 and 6 months, and 1 year after surgery. Plaque index (PI), bleeding on probing (BOP), and probing depth (PD) were recorded at 3 and 6 weeks, and 2, 3, 6, and 12 months post-implant placement. After 3 months, a mini-invasive sample of soft tissue was collected from seven patients (four women and three men) for miRNA microarray analysis. RESULTS: Control implants showed greater bone resorption (BR) and lower PI: this was not statistically significant. No statistically significant differences in BOP and PD appeared. miRNA modulated by implant surfaces as well as by other clinical conditions has been identified. miRNA microarray analysis revealed that: (i) implant sites with low PI and absence of BOP had a miRNA expression profile similar to those with plaque and absence of BOP; sites with high PI and high BOP had a different profile. (ii) Implant sites with BOP presented similar profiles independently from implant surface. (iii) Implant sites with high PI and normal BR differed from others for miRNA expression profile. (iv) Implant sites with normal BR despite high BOP differed from others. This profile resembled that of FOSS implants. (v) Implant surface affected BR; groups having similar BR clusterized differently according to the implant type. CONCLUSIONS: DAE surfaces induced lower BR and more plaque accumulation: This did not affect the health of soft tissues. miRNA analysis indicated that soft tissue inflammation is more related to gene expression profile than to plaque or to implant surface. Specific miRNA profile can protect implant sites from bleeding and BR irrespective of plaque accumulation. PMID- 27492800 TI - Endogenous Factors in the Recovery of Reproductive Function After Testicular Injury and Cancer. AB - The testes are one of the most delicate organs in the male body and highly susceptible to the exogenous influences capable of inducing cell damage. Cancer therapies are well known to negatively affect the male reproductive tract with a severe impairment of spermatogenesis and infertility. The present work aimed to systematically review the available information about the different endogenous factors (hormonal and nonhormonal) that may have protective or advantageous properties on the recovery of male reproductive function after gonadal injury. Furthermore, the perspective that these endogenous molecules could act as cryoprotectants to improve the quality of cryopreserved semen samples was also discussed. The knowledge reviewed herein allowed to identify promising factors able to mitigate the male fertility problems arising either from oncological treatments or other gonadal damage, and opened new possibilities to ameliorate the recovery of spermatogenesis or to preserve fertility. PMID- 27492801 TI - Resistin-Like Molecule-alpha Causes Lung Injury in Rats with Acute Pancreatitis by Activating the PI-3K/Akt-NF-kappaB Pathway and Promoting Inflammatory Cytokine Release. AB - BACKGROUND: Resistin-like molecule-alpha (RELMalpha) has diverse regulatory functions in inflammation, but its role in severe acute pancreatitis (SAP) and acute pancreatitis associated lung injury (APALI) remains unclear. METHODS: SAP was induced in rats. RELMalpha protein expression was detected in lung tissue of rats to determine the relationship between APALI and RELMalpha. To investigate the effect of RELMalpha overexpression or knockdown on APALI, rats were given an intravenous injection of adenovirus vector before SAP induction. Lung and pancreatic samples were harvested 16 h after induction. After detection of RELMalpha protein levels, the severity of pancreatic and pulmonary injury was scored histologically, and serum and tissue levels of inflammatory mediators were measured. TUNEL assay and immunofluorescence were used to estimate pulmonary apoptosis and endothelial barrier integrity in lung tissue of SAP rats with RELMalpha knockdown. RESULTS: RELMalpha expression was significantly up-regulated in APALI and was related to the lung injury index. RELMalpha overexpression aggravated the release of inflammatory cytokines including interleukin (IL) 1beta, IL-6, IL-8, tumor necrosis factor-alpha, and serum C-reaction protein; the expression of inflammatory mediators phosphorylated (p)-AKT, p-P65, p-P38 mitogen activated protein kinase, p-extracellular regulated kinase, and intracellular adhesion molecule-1; and lung injury. RELMalpha knockdown had opposite effects. In addition, RELMalpha knockdown improved expression of proliferative cellular nuclear antigen, Bcl-2, zonal occluding-1 and Claudin-1 in lung tissue of SAP rats. CONCLUSION: RELMalpha is associated with lung injury severity in SAP. RELMalpha augments inflammatory activity by increasing inflammatory cytokine release. PMID- 27492802 TI - Correction to "Thermodynamic Resistance to Matter Flow at The Interface of a Porous Membrane". PMID- 27492803 TI - High-flow-mediated constriction in adults is not influenced by biomarkers of cardiovascular and metabolic risk. AB - PURPOSE: During reactive hyperemia, the brachial artery in some individuals constricts prior to dilation. Our aim was to describe the frequency of high-flow mediated constriction (H-FMC) in adults, and its relationship to body composition and biomarkers of cardiovascular and metabolic risk. METHODS: Two hundred forty six adults (124 male, 122 female; 36 +/- 7 years old) were assessed for H-FMC via sonographic imaging of the brachial artery. Blood pressure, glucose, insulin, lipids, and body composition assessed via dual energy X-ray absorptiometry were collected. H-FMC was characterized as a 10-second average of maximal postocclusion constriction. Independent t test was used to compare H-FMC versus non-H-FMC individuals. RESULTS: H-FMC was observed in approximately 69% of adult participants (54 obese, 57 overweight, and 59 normal weight). Total body mass (82.3 +/- 17.5 versus 76.3 +/- 16.3 kg, p = 0.012), fat mass (27.7 +/- 11.5 versus 23.8 +/- 10.5 kg, p = 0.012), body mass index (27.7 +/- 4.9 versus 26.1 +/ 5.0 kg/m2 , p = 0.018), and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (2.41 +/- 1.03 versus 2.09 +/- 0.72, p = 0.007) were higher in H-FMC than in non-H-FMC individuals. Flow-mediated dilatation (FMD) (6.12 +/- 3.48 versus 8.09 +/- 3.02%, p < 0.001) was lower in H-FMC subjects. However, there was no difference in brachial artery dilation between groups (7.57 +/- 3.69 versus 8.09 +/- 3.02%, p = 0.250) when H-FMC was added to FMD. CONCLUSIONS: Increased body mass, fat mass, and body mass index were associated with a greater H-FMC. When H-FMC was present, the FMD response to reactive hyperemia was significantly lower. Because H-FMC has been observed to negatively affect FMD response to reactive hyperemia, we suggest that H-FMC should be noted when analyzing and interpreting FMD data. H-FMC may be an ancillary measure of endothelial health. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:35-42, 2017. PMID- 27492804 TI - [Fungal biofilms: Confusion between tolerance and resistance drugs]. PMID- 27492805 TI - Molecular Chaperones in the Pathogenesis of Amyotrophic Lateral Sclerosis: The Role of HSPB1. AB - Genetic discoveries in amyotrophic lateral sclerosis (ALS) have a significant impact on deciphering molecular mechanisms of motor neuron degeneration but, despite recent advances, the etiology of most sporadic cases remains elusive. Several cellular mechanisms contribute to the motor neuron degeneration in ALS, including RNA metabolism, cellular interactions between neurons and nonneuronal cells, and seeding of misfolded protein with prion-like propagation. In this scenario, the importance of protein turnover and degradation in motor neuron homeostasis gained increased recognition. In this study, we evaluated the role of the candidate gene HSPB1, a molecular chaperone involved in several proteome maintenance functions. In a cohort of 247 unrelated Italian ALS patients, we identified two variants (c.570G>C, p.Gln190His and c.610dupG, p.Ala204Glyfs* 6). Functional characterization of the p.Ala204Glyfs* 6 demonstrated that the mutant protein alters HSPB1 dynamic equilibrium, sequestering the wild-type protein in a stable dimer and resulting in a loss of chaperone-like activity. Our results underline the relevance of identifying rare but pathogenic variations in sporadic neurodegenerative diseases, suggesting a possible correlation between specific pathomechanisms linked to HSPB1 mutations and the associated neurological phenotype. Our study provides additional lines of evidence to support the involvement of HSPB1 in the pathogenesis of sporadic ALS. PMID- 27492806 TI - Incidental Dose to Pelvic Nodal Regions in Prostate-Only Radiotherapy. AB - OBJECTIVES: Pelvic lymph nodal regions receive an incidental dose from conformal treatment of the prostate. This study was conducted to investigate the doses received by the different pelvic nodal regions with varying techniques used for prostate radiotherapy. METHODS AND MATERIALS: Twenty patients of high-risk node negative prostate cancer treated with intensity-modulated radiotherapy to the prostate alone were studied. Replanning was done for intensity-modulated radiotherapy, 3-dimensional conformal treatment, and 2-dimensional conventional radiotherapy with additional delineation of the pelvic nodal regions, namely, common iliac (upper and lower), presacral, internal iliac, obturator, and external iliac. Dose-volume parameters such as Dmean, D100%, D66%, D33%, V40, and V50 to each of the nodal regions were estimated for all patients. RESULTS: The obturator nodes received the highest dose among all nodal regions. The mean dose received by obturator nodal region was 44, 29, and 22 Gy from 2-dimensional conventional radiotherapy, 3-dimensional conformal treatment, and intensity modulated radiotherapy, respectively. The mean dose was significantly higher when compared between 2-dimensional conventional radiotherapy and 3-dimensional conformal treatment ( P < .001), 2-dimensional conventional radiotherapy and intensity-modulated radiotherapy ( P < .001), and 3-dimensional conformal treatment and intensity-modulated radiotherapy ( P < .001). The D33% of the obturator region was 64, 39, and 37 Gy from 2-dimensional conventional radiotherapy, 3-dimensional conformal treatment, and intensity-modulated radiotherapy, respectively. The dose received by all other pelvic nodal regions was low and not clinically relevant. CONCLUSION: The incidental dose received by obturator regions is significant especially with 2-dimensional conventional radiotherapy and 3-dimensional conformal treatment techniques as used in the trials studying elective pelvic nodal irradiation. However, with intensity modulated radiotherapy, this dose is lower, making elective pelvic irradiation more relevant. Advances in Knowledge: This study highlights that incidental dose received by obturator regions is significant especially with 2-dimensional conventional radiotherapy and 3-dimensional conformal treatment techniques. PMID- 27492807 TI - Development and Verification of a Mobile Shelter Assessment System "Rapid Assessment System of Evacuation Center Condition Featuring Gonryo and Miyagi (RASECC-GM)" for Major Disasters. AB - Introduction There were 5,385 deceased and 710 missing in the Ishinomaki medical zone following the Great East Japan Earthquake that occurred in Japan on March 11, 2011. The Ishinomaki Zone Joint Relief Team (IZJRT) was formed to unify the relief teams of all organizations joining in support of the Ishinomaki area. The IZJRT expanded relief activity as they continued to manually collect and analyze assessments of essential information for maintaining health in all 328 shelters using a paper-type survey. However, the IZJRT spent an enormous amount of time and effort entering and analyzing these data because the work was vastly complex. Therefore, an assessment system must be developed that can tabulate shelter assessment data correctly and efficiently. The objective of this report was to describe the development and verification of a system to rapidly assess evacuation centers in preparation for the next major disaster. Report Based on experiences with the complex work during the disaster, software called the "Rapid Assessment System of Evacuation Center Condition featuring Gonryo and Miyagi" (RASECC-GM) was developed to enter, tabulate, and manage the shelter assessment data. Further, a verification test was conducted during a large-scale Self Defense Force (SDF) training exercise to confirm its feasibility, usability, and accuracy. The RASECC-GM comprises three screens: (1) the "Data Entry screen," allowing for quick entry on tablet devices of 19 assessment items, including shelter administrator, living and sanitary conditions, and a tally of the injured and sick; (2) the "Relief Team/Shelter Management screen," for registering information on relief teams and shelters; and (3) the "Data Tabulation screen," which allows tabulation of the data entered for each shelter, as well as viewing and sorting from a disaster headquarters' computer. During the verification test, data of mock shelters entered online were tabulated quickly and accurately on a mock disaster headquarters' computer. Likewise, data entered offline also were tabulated quickly on the mock disaster headquarters' computer when the tablet device was moved into an online environment. CONCLUSIONS: The RASECC-GM, a system for rapidly assessing the condition of evacuation centers, was developed. Tests verify that users of the system would be able to easily, quickly, and accurately assess vast quantities of data from multiple shelters in a major disaster and immediately manage the inputted data at the disaster headquarters. Ishii T , Nakayama M , Abe M , Takayama S , Kamei T , Abe Y , Yamadera J , Amito K , Morino K . Development and verification of a mobile shelter assessment system "Rapid Assessment System of Evacuation Center Condition featuring Gonryo and Miyagi (RASECC-GM)" for major disasters. Prehosp Disaster Med. 2016;31(5):539-546. PMID- 27492808 TI - A Novel Adhesion Index for Verifying the Extent of Adhesion for the Extensor Digitorum Communis in Patients with Metacarpal Fractures. AB - This study aims to determine if the relative displacement between the extensor digitorum communis (EDC) tendon and its surrounding tissues can be used as an adhesion index (AI) for assessing adhesion in metacarpal fractures by comparing two clinical measures, namely single-digit-force and extensor lag (i.e., the difference between passive extension and full active extension). The Fisher Tippett block-matching method and a Kalman-filter algorithm were used to determine the relative displacements in 39 healthy subjects and 8 patients with metacarpal fractures. A goniometer was used to measure the extensor lag, and a force sensor was used to measure the single-digit-force. Measurements were obtained twice for each patient to evaluate the performance of the AI in assessing the progress of rehabilitation. The Pearson correlation coefficient was calculated to quantify the various correlations between the AI, extensor lag, and single-digit-force. The results showed strong correlations between the AI and the extensor lag, the AI and the single-digit-force, and the extensor lag and the single-digit-force (r = 0.718, -0.849, and -0.741; P = 0.002, P < 0.001, and P = 0.001, respectively). The AI in the patients gradually decreased after continuous rehabilitation, but remained higher than that of healthy participants. PMID- 27492809 TI - Cluster Analysis of Campylobacter jejuni Genotypes Isolated from Small and Medium Sized Mammalian Wildlife and Bovine Livestock from Ontario Farms. AB - Using data collected from a cross-sectional study of 25 farms (eight beef, eight swine and nine dairy) in 2010, we assessed clustering of molecular subtypes of C. jejuni based on a Campylobacter-specific 40 gene comparative genomic fingerprinting assay (CGF40) subtypes, using unweighted pair-group method with arithmetic mean (UPGMA) analysis, and multiple correspondence analysis. Exact logistic regression was used to determine which genes differentiate wildlife and livestock subtypes in our study population. A total of 33 bovine livestock (17 beef and 16 dairy), 26 wildlife (20 raccoon (Procyon lotor), five skunk (Mephitis mephitis) and one mouse (Peromyscus spp.) C. jejuni isolates were subtyped using CGF40. Dendrogram analysis, based on UPGMA, showed distinct branches separating bovine livestock and mammalian wildlife isolates. Furthermore, two-dimensional multiple correspondence analysis was highly concordant with dendrogram analysis showing clear differentiation between livestock and wildlife CGF40 subtypes. Based on multilevel logistic regression models with a random intercept for farm of origin, we found that isolates in general, and raccoons more specifically, were significantly more likely to be part of the wildlife branch. Exact logistic regression conducted gene by gene revealed 15 genes that were predictive of whether an isolate was of wildlife or bovine livestock isolate origin. Both multiple correspondence analysis and exact logistic regression revealed that in most cases, the presence of a particular gene (13 of 15) was associated with an isolate being of livestock rather than wildlife origin. In conclusion, the evidence gained from dendrogram analysis, multiple correspondence analysis and exact logistic regression indicates that mammalian wildlife carry CGF40 subtypes of C. jejuni distinct from those carried by bovine livestock. Future studies focused on source attribution of C. jejuni in human infections will help determine whether wildlife transmit Campylobacter jejuni directly to humans. PMID- 27492810 TI - Nervous system development in the fairy shrimp Branchinella sp. (Crustacea: Branchiopoda: Anostraca): Insights into the development and evolution of the branchiopod brain and its sensory organs. AB - Using immunohistochemical labeling against acetylated a-tubulin and serotonin in combination with confocal laser scanning microscopy and 3D-reconstruction, we investigated the temporary freshwater pond inhabitant Branchinella sp. (Crustacea: Branchiopoda: Anostraca) for the first time to provide detailed data on the development of the anostracan nervous system. Protocerebral sense organs such as the nauplius eye and frontal filament organs are present as early as the hatching stage L0. In the postnaupliar region, two terminal pioneer neurons grow from posterior to anterior to connect the mandibular neuromeres. The first protocerebral neuropil to emerge is not part of the central complex but represents the median neuropil, and begins to develop from L0+ onwards. In stage L3, the first evidence of developing compound eyes is visible. This is followed by the formation of the visual neuropils and the neuropils of the central complex in the protocerebrum. From the deutocerebral lobes, the projecting neuron tract proceeds to both sides of the lateral protocerebrum, forming a chiasma just behind the central body. In the postnaupliar region, the peripheral nervous system, commissures and connectives develop along an anterior-posterior gradient after the fasciculation of the terminal pioneer neurons with the mandibular neuromere. The peripheral nervous system in the thoracic segments consists of two longitudinal neurite bundles on each side which connect the intersegmental nerves, together with the ventral nervous system forming an orthogon-like network. Here, we discuss, among other things, the evidence of a fourth nauplius eye nerve and decussating projecting neuron tract found in Branchinella sp., and provide arguments to support our view that the crustacean frontal filament (organ) and onychophoran primary antenna are homologous. J. Morphol. 277:1423 1446, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27492811 TI - Elevated levels of circulating immunoglobulin E autoantibodies against BP180 and BP230 in an intractable case of bullous pemphigoid. PMID- 27492812 TI - Immunomodulation in cutaneous lupus erythematosus subsets. PMID- 27492813 TI - The many faces of Meckel's diverticulum and its complications. AB - Meckel's diverticulum is the most frequent congenital malformation of the gastrointestinal tract, occurring in 2% of the general population. Meckel's diverticulum is usually asymptomatic and found incidentally. However, the lifetime risk of complications is 4-40%. In this essay, we describe the clinical and imaging findings in 12 cases of Meckel's diverticula with complications over a 5-year period, which were confirmed pathologically. The major complications of Meckel's diverticulum include gastrointestinal bleeding, bowel obstruction, perforation and inflammation. Small bowel follow-through (SBFT), computed tomography (CT) including CT enterography and RI scintigraphy can be used to show typical imaging features of Meckel's diverticulum and its complications. Knowledge of the clinical and radiologic findings of Meckel's diverticulum can aid in the early and accurate diagnosis of this anomaly and its complications. PMID- 27492814 TI - One-pot construction of fused polycyclic heteroarenes involving 7-azaindoles and alpha,beta-unsaturated ketones. AB - A novel one-pot synthesis of pi-conjugated polycyclic compounds, which could undergo further facile transformation to form complex polycyclic heteroarene compounds, has been realized between 7-azaindoles and alpha,beta-unsaturated ketones. This distinctive cascade process proceeds via a rhodium(iii)-catalyzed alkylation/copper-catalyzed radical annulation-aromatization pathway. PMID- 27492816 TI - Community participation of youth with intellectual disability and autism spectrum disorder. AB - BACKGROUND: Community participation is associated with a range of positive developmental outcomes; however, the frequency, depth and resources associated with participation for youth with intellectual disability (ID) and autism spectrum disorder (ASD) are not well understood. METHOD: Caregivers of 212 youth with ASD and ID and only ID, aged 11-22 years, completed an online survey. Comparisons were made of caregiver reports of diversity and frequency of participation, levels of participation involvement and related environmental barriers and supports. RESULTS: The diversity and frequency of community participation of youth with ASD and ID approximated that of youth with ID only. Youth with ASD and ID were reported to be significantly less involved in the community activities in which they participated. Environmental features, and in particular, the social demands of community-based activities, were significant barriers to youths' participation. CONCLUSIONS: The current study highlights individual and environmental factors amenable to intervention that may foster successful community participation among youth with ASD and ID. PMID- 27492818 TI - Bridging the Gap Between Speech and Language: Using Multimodal Treatment in a Child With Apraxia. AB - Childhood apraxia of speech is a neurologic speech sound disorder in which children have difficulty constructing words and sounds due to poor motor planning and coordination of the articulators required for speech sound production. We report the case of a 3-year-old boy strongly suspected to have childhood apraxia of speech at 18 months of age who used multimodal communication to facilitate language development throughout his work with a speech language pathologist. In 18 months of an intensive structured program, he exhibited atypical rapid improvement, progressing from having no intelligible speech to achieving age appropriate articulation. We suspect that early introduction of sign language by family proved to be a highly effective form of language development, that when coupled with intensive oro-motor and speech sound therapy, resulted in rapid resolution of symptoms. PMID- 27492815 TI - Atrial fibrillation driver mechanisms: Insight from the isolated human heart. AB - Although there have been great technological advances in the treatment of atrial fibrillation (AF), current therapies remain limited due to a narrow understanding of AF mechanisms in the human heart. This review will highlight our recent studies on explanted human hearts where we developed and employed a novel functional-structural mapping approach by integrating high-resolution simultaneous endo-epicardial and panoramic optical mapping with 3D gadolinium enhanced MRI to define the spatiotemporal characteristics of AF drivers and their structural substrates. The results allow us to postulate that the primary mechanism of AF maintenance in human hearts is a limited number of localized intramural microanatomic reentrant AF drivers anchored to heart-specific 3D fibrotically insulated myobundle tracks, which may remain hidden to clinical single-surface electrode mapping. We suggest that ex vivo human heart studies, by using an integrated 3D functional and structural mapping approach, will help to reveal defining features of AF drivers as well as validate and improve clinical approaches to detect and target these AF drivers in patients with cardiac diseases. PMID- 27492817 TI - Discontinuation and Nonpublication of Randomized Clinical Trials Conducted in Children. AB - BACKGROUND: Trial discontinuation and nonpublication represent potential waste in research resources and lead to compromises in medical evidence. Pediatric trials may be particularly vulnerable to these outcomes given the challenges encountered in conducting trials in children. We aimed to determine the prevalence of discontinuation and nonpublication of randomized clinical trials (RCTs) conducted in pediatric populations. METHODS: Retrospective, cross-sectional study of pediatric RCTs registered in ClinicalTrials.gov from 2008 to 2010. Data were collected from the registry and associated publications identified (final search on September 1, 2015). RESULTS: Of 559 trials, 104 (19%) were discontinued early, accounting for an estimated 8369 pediatric participants. Difficulty with patient accrual (37%) was the most commonly cited reason for discontinuation. Trials were less likely to be discontinued if they were funded by industry compared with academic institutions (odds ratio [OR] 0.46, 95% confidence interval [CI] 0.27 0.77). Of the 455 completed trials, 136 (30%) were not published, representing 69 165 pediatric participants. Forty-two unpublished trials posted results on ClinicalTrials.gov. Trials funded by industry were more than twice as likely to result in nonpublication at 24 and 36 months (OR 2.21, 95% CI 1.35-3.64; OR 3.12, 95% CI 1.6-6.08, respectively) and had a longer mean time to publication compared with trials sponsored by academia (33 vs 24 months, P < .001). CONCLUSIONS: In this sample of pediatric RCTs, discontinuation and nonpublication were common, with thousands of children exposed to interventions that did not lead to informative or published findings. Trial funding source was an important determinant of these outcomes, with both academic and industry sponsors contributing to inefficiencies. PMID- 27492819 TI - Suppression of miR-19b enhanced the cytotoxic effects of mTOR inhibitors in human neuroblastoma cells. AB - BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors exert significant antitumor effects on several cancer cell types. In this study, we investigated the effects of mTOR inhibitors, in particular the regulation of the microRNA, in neuroblastoma cells. METHODS: AZD8055 (a new mTOR inhibitor)- or rapamycin induced cytotoxic effects on neuroblastoma cells were studied. Western blotting was used to investigate the expression of various proteins in the mTOR pathway. MicroRNA precursors and antagomirs were transfected into cells to manipulate the expression of target microRNA. RESULTS: AZD8055 exerted stronger cytotoxic effects than rapamycin in neuroblastoma cells (p<0.03). In addition, AZD8055 suppressed the mTOR pathway and increased the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in the neuroblastoma cells. AZD8055 significantly decreased miR-19b expression (p<0.005); in contrast, rapamycin increased miR-19b expression (p<0.05). Transfection of miR-19b antagomir into the neuroblastoma cells mimicked the effects of AZD8055 treatment, whereas miR-19b overexpression reversed the effects of AZD8055. Combination of miR-19b knockdown and rapamycin treatment significantly improved the sensitivity of neuroblastoma cells to rapamycin (p<0.02). CONCLUSION: Suppression of miR-19b may enhance the cytotoxic effects of mTOR inhibitors in neuroblastoma cells. PMID- 27492820 TI - Effect of democratic reforms on child mortality: a synthetic control analysis. AB - BACKGROUND: The effects of political regimes on health are unclear because empirical evidence is neither strong nor robust. Traditional econometric tools do not allow the direction of causality to be established clearly. We used a new method to investigate whether political transition into democracy affected child mortality. METHODS: We used a synthetic control method to assess the effects of democratisation on child mortality as a proxy of health in countries that underwent transition from autocracy to democracy that lasted for at least 10 years between 1960 and 2010. Democracy was indicated by a score greater than 0 in the Polity2 index. We constructed synthetic controls (counterfactuals) based on weighted averages for factors such as child mortality, economic development, openess to trade, conflict, rural population, and female education from a pool of countries that remained autocracies during the study period. RESULTS: Of 60 countries that underwent democratic transition in the study period, 33 met our inclusion criteria. We were able to construct good counterfactuals for 24 of these. On average, democratisation reduced child mortality, and the effect increased over time. Significant reductions in child mortality were seen in nine (38%) countries, with the average reduction 10 years after democratisation being 13%. In the other 15 countries the effects were not significant. At the country level yhe effects were heterogeneous, but the differences did not correlate with geographic, economic, or political indicators. The effect of democratisation, however, was stronger in countries with above average child mortality before transition than in countries with below average child mortality. INTERPRETATION: Our results are consistent with the interpretation that democratic reforms have the greatest effects when child mortality is a direct concern for a large part of the population. Future research could focus on identifying the precise mechanism through which the effects emerge. FUNDING: European Union 7th Framework Programme and KU Leuven Methusalem Fund. PMID- 27492821 TI - Towards parity democracy. PMID- 27492822 TI - Can pay for performance improve the quality of primary care? PMID- 27492823 TI - Parenting style and perceptions of children's weight among US Hispanics: a qualitative analysis. AB - Parental perceptions of their children's weight status may limit their willingness to participate in or acknowledge the importance of early interventions to prevent childhood obesity. This study aimed to examine potential differences in Hispanic mothers' and fathers' perceptions of childhood obesity, lifestyle behaviors and communication preferences to inform the development of culturally appropriate childhood obesity interventions. A qualitative study using focus groups was conducted. Groups (one for mothers and one for fathers) were composed of Hispanic parents (n = 12) with at least one girl and one boy (<= 10 years old) who were patients at a pediatric clinic in Tennessee, USA. Thirteen major themes clustered into four categories were observed: (i) perceptions of childhood obesity/children's weight; (ii) parenting strategies related to children's dietary behaviors/physical activity; (iii) perceptions of what parents can do to prevent childhood obesity and (iv) parental suggestions for partnering with child care providers to address childhood obesity. Mothers appeared to be more concerned than fathers about their children's weight. Fathers expressed more concern about the girls' weight than boys'. Mothers were more likely than fathers to congratulate their children more often for healthy eating and physical activity. Parents collectively expressed a desire for child care providers (e.g. caregivers, teachers, medical professionals and food assistance programs coordinators) to have a caring attitude about their children, which might in turn serve as a motivating factor in talking about their children's weight. Parental perceptions of their children's weight and healthy lifestyle choices are of potential public health importance since they could affect parental participation in preventive interventions. PMID- 27492824 TI - Resilience as a double-edged health promotion goal: examples from Lao PDR. AB - Individual and community resilience are undoubtedly important targets for health enhancement and invaluable aspirational outcomes in the health promotion endeavour especially in disaster contexts. However, overreliance on resilience as a proxy for positive well-being has serious personal and political implications in many contexts, as illustrated in research findings on women's quality of life in southern Lao PDR. Case studies derived from focus group interviews with ethnic minority Lao women about their quality of life are used to exemplify how overt signs of resilience may mask, rather than mirror, covert existential reality leaving women without a voice. The political implications of this silencing are profound. Private troubles remain hidden rather than being identified as public issues subject to public policy. This conundrum is not confined to third world countries. Structural limitations to achieving profound fulfilment abound in affluent countries also, yet neo-liberal governments rely heavily on the resilience of populations to minimize public spending. The challenge for health promotion researchers, policy makers and practitioners is to explore the nexus between individual agency and structural change in each specific context to ensure that health promotion initiatives do not inadvertently perpetuate disparities in access to power and resources. PMID- 27492825 TI - Unpacking complexity in public health interventions with the Actor-Network Theory. AB - This article proposes a sociologically informed theoretical and methodological framework to address the complexity of public health interventions (PHI). It first proposes three arguments in favour of using the Actor-Network Theory (ANT) for the framework. ANT: (1) deals with systems made of human and non-human entities and proposes a relational view of action; (2) provides an understanding of the intervention-context interactions and (3) is a tool for opening the intervention's black box. Three principles derived from ANT addressing theoretical problems with conceptualisation of PHI as complex systems are proposed: (1) to focus on the process of connecting the network entities instead of their stabilised form; (2) both human and non-human entities composing networks have performative capacities and (3) network and intervention shape one another. Three methodological guidelines are further derived: (1) the researcher's task consists in documenting the events that transform the network and intervention; (2) events must be ordered chronologically to represent the intervention's evolution and (3) a broad range of data is needed to capture complex interventions' evolution. Using ANT as a guide, this paper helps reconcile technicist and social views of PHI and provides a mean to integrate process and effect studies of interventions. PMID- 27492826 TI - Proposing a health promotion framework to address gambling problems in Australian Indigenous communities. AB - Gambling impacts affect Australian Indigenous families and communities in diverse and complex ways. Indigenous people throughout Australia engage in a broad range of regulated and unregulated gambling activities. Challenges in this area include the complexities that come with delivering services and programmes between the most remote regions, to highly populated towns and cities of Australia. There is little knowledge transfer between states and territories in Australia and no conceptual understanding or analysis of what constitutes 'best practice' in gambling service delivery for Indigenous people, families and communities. This article reviews health promotion approaches used in Australia, with a particular focus on Indigenous and gambling-based initiatives. Contributing to this review is an examination of health promotion strategies used in Indigenous gambling service delivery in the Northern Territory, New South Wales and Western Australia, demonstrating diversity and innovation in approaches. The article concludes by emphasizing the potential value of adopting health promotion strategies to underpin programme and service delivery for addressing gambling problems in Australian Indigenous communities. However, success is contingent on robust, evidence-based programme design, implementation and evaluation that adhere to health promotion principles. PMID- 27492827 TI - Tuberculosis care among refugees arriving in Europe: a ERS/WHO Europe Region survey of current practices. AB - No evidence exists on tuberculosis (TB) and latent TB infection (LTBI) management policies among refugees in European countries.A questionnaire investigating screening and management practices among refugees was sent to 38 national TB programme representatives of low and intermediate TB incidence European countries/territories of the WHO European Region.Out of 36 responding countries, 31 (86.1%) reported screening for active TB, 19 for LTBI, and eight (22.2%) reporting outcomes of LTBI treatment. Screening for TB is based on algorithms including different combinations of symptom-based questionnaires, bacteriology and chest radiography and LTBI screening on different combinations of tuberculin skin test and interferon-gamma release assays. In 22 (61.1%) countries, TB and LTBI screening are performed in refugee centres. In 22 (61.1%) countries, TB services are organised in collaboration with the private sector. 27 (75%) countries answered that screening for TB is performed as per national and international guidelines, while 19 (52.7%) gave the same answer with regards to LTBI screening. Infection control measures are inadequate in several of the countries surveyed.There is need for improved coordination of TB screening in Europe to implement the End TB Strategy and achieve TB elimination. PMID- 27492828 TI - Mechanisms of exertional dyspnoea in symptomatic smokers without COPD. AB - Dyspnoea and activity limitation can occur in smokers who do not meet spirometric criteria for chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are unknown.Detailed pulmonary function tests and sensory-mechanical relationships during incremental exercise with respiratory pressure measurements and diaphragmatic electromyography (EMGdi) were compared in 20 smokers without spirometric COPD and 20 age-matched healthy controls.Smokers (mean+/-sd post bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity 75+/ 4%, mean+/-sd FEV1 104+/-14% predicted) had greater activity-related dyspnoea, poorer health status and lower physical activity than controls. Smokers had peripheral airway dysfunction: higher phase-III nitrogen slopes (3.8+/-1.8 versus 2.6+/-1.1%.L(-1)) and airway resistance (difference between airway resistance measured at 5 Hz and 20 Hz 19+/-11 versus 12+/-7% at 5 Hz) than controls (p<0.05). Smokers had significantly (p<0.05) lower peak oxygen uptake (78+/-40 versus 107+/-45% predicted) and ventilation (61+/-26 versus 97+/-29 L.min(-1)). Exercise ventilatory requirements, operating lung volumes and cardio-circulatory responses were similar. However, submaximal dyspnoea ratings, resistive and total work of breathing were increased in smokers compared with controls (p<0.05); diaphragmatic effort (transdiaphragmatic pressure/maximumal transdiaphragmatic pressure) and fractional inspiratory neural drive to the diaphragm (EMGdi/maximal EMGdi) were also increased (p<0.05) mainly reflecting the reduced denominator.Symptomatic smokers at risk for COPD had greater exertional dyspnoea and lower exercise tolerance compared with healthy controls in association with greater airways resistance, contractile diaphragmatic effort and fractional inspiratory neural drive to the diaphragm. PMID- 27492829 TI - Clinical manifestations in primary ciliary dyskinesia: systematic review and meta analysis. AB - Few original studies have described the prevalence and severity of clinical symptoms of primary ciliary dyskinesia (PCD). This systematic review and meta analysis aimed to identify all published studies on clinical manifestations of PCD patients, and to describe their prevalence and severity stratified by age and sex.We searched PubMed, Embase and Scopus for studies describing clinical symptoms of >=10 patients with PCD. We performed meta-analyses and meta regression to explain heterogeneity.We included 52 studies describing a total of 1970 patients (range 10-168 per study). We found a prevalence of 5% for congenital heart disease. For the rest of reported characteristics, we found considerable heterogeneity (I2 range 68-93.8%) when calculating the weighted mean prevalence. Even after taking into account the explanatory factors, the largest part of the between-studies variance in symptom prevalence remained unexplained for all symptoms. Sensitivity analysis including only studies with test-proven diagnosis showed similar results in prevalence and heterogeneity.Large differences in study design, selection of study populations and definition of symptoms could explain the heterogeneity in symptom prevalence. To better characterise the disease, we need larger, multicentre, multidisciplinary, prospective studies that include all age groups, use uniform diagnostics and report on all symptoms. PMID- 27492830 TI - Predictive value of exhaled nitric oxide in the management of asthma: a systematic review. AB - The clinical value of measuring fractional exhaled nitric oxide (FeNO) in asthma is not clear. We aimed to assess whether FeNO can reliably predict clinical outcomes in asthma treated with inhaled corticosteroids (ICS). We also evaluated whether its predictive role is influenced by different inflammatory phenotypes of asthma.We conducted a systematic review focusing on five clinically relevant questions. Two authors independently screened search results, extracted data and assessed quality of the included studies. Data were synthesised by qualitative methods.12 prospective studies were included, answering partly three of the five questions. In steroid-naive asthma, a high FeNO level probably predicts good response to ICS. In ICS-treated asthmatics, a low FeNO level probably predicts low risk of exacerbation, and the patient is unlikely to benefit from increasing ICS dose. There were scarce data to conclude whether FeNO predicts exacerbations when ICS treatment is stopped in well-controlled asthma. Only one study reported results separately in different asthma phenotypes.The current evidence on the predictive value of FeNO and its role in the management of asthma is incomplete. Future studies should focus on clinically meaningful questions and probably target only eosinophilic phenotypes where FeNO is best associated with the activity of airway inflammation. PMID- 27492831 TI - Air pollution exposure is associated with restrictive ventilatory patterns. PMID- 27492832 TI - Blood granulocyte patterns as predictors of asthma phenotypes in adults from the EGEA study. AB - To what extent blood granulocyte patterns may predict asthma control remains under-studied. Our aim was to study associations between blood neutrophilia and eosinophilia and asthma control outcomes in adults.Analyses were conducted in 474 asthmatics from the first follow-up of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA2), including 242 asthmatics who were adults a decade earlier (EGEA1). At EGEA2, asthma control was assessed using the Global Initiative for Asthma definition (2015), and asthma exacerbations by use of urgent care or courses of oral corticosteroids in the past year. Blood EOSlo/EOShi was defined as =250 eosinophils.mm-3, respectively, and NEUlo/NEUhi as =5000 neutrophils.mm-3, respectively. Estimates were adjusted for age, sex and smoking.At EGEA2, NEUhi was associated with asthma exacerbations and poor asthma control (OR >2.10). EOShi was associated with higher bronchial hyperresponsiveness (BHR) (OR (95% CI) 2.21 (1.24-3.97)), poor lung function (p=0.02) and higher total IgE level (p=0.002). Almost 50% of asthmatics had a persistent pattern between surveys. Persistent NEUhi was associated with poor asthma control at EGEA2 (OR (95% CI) 3.09 (1.18-7.05)). EOShi at EGEA1 and persistent EOShi were associated with higher BHR (OR (95% CI) 2.36 (1.10-5.07) and 3.85 (1.11-13.34), respectively), poor lung function (p<0.06) and higher immunoglobulin E level (p<10-4) at EGEA2.Granulocyte patterns were differently associated with asthma outcomes, suggesting specific roles for each one, which could be tested as predictive signatures. PMID- 27492833 TI - Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study. AB - The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable, moderate-to-severe chronic obstructive pulmonary disease (COPD).AFFIRM COPD (Aclidinium and Formoterol Findings in Respiratory Medicine COPD) was a 24-week, double-blind, double-dummy, active-controlled study. Patients were randomised (1:1) to aclidinium/formoterol 400/12 ug twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 ug twice-daily via Accuhaler. The primary end-point was peak forced expiratory volume in 1 s (FEV1) at week 24. Other end-points included Transition Dyspnoea Index (TDI) focal score at week 24, TDI and St George's Respiratory Questionnaire (SGRQ) responders, COPD Assessment Test and SGRQ scores, assessment of COPD symptoms and exacerbations, use of reliever medication, and device preference. Adverse events were monitored throughout.In total, 933 patients were eligible (mean age 63.4 years, 65.1% male). Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV1 and noninferior in TDI. Health status and reduction in exacerbation risk were similar in both groups. While both treatments were well tolerated, pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone.In stable COPD, aclidinium/formoterol significantly improved bronchodilation versus salmeterol/fluticasone, with equivalent benefits in symptom control and reduction in exacerbation risk. Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol. PMID- 27492834 TI - The emerging role of epigenetics in pulmonary hypertension. AB - Epigenetics is usually defined as the study of changes in phenotype and gene expression not related to sequence alterations, but rather the chemical modifications of DNA and of its associated chromatin proteins. These modifications can be acquired de novo, being inherited, and represent the way in which genome and environment interact. Recent evidence points to the involvement of epigenetic changes in the pathogenesis of pulmonary hypertension, as they can partly explain how environmental and lifestyle factors can impose susceptibility to pulmonary hypertension and can explain the phenotypic alteration and maintenance of the disease state.In this article, we review the epigenetic regulatory mechanisms that are mediated by DNA methylation, the post translational modifications of histone tails and noncoding RNAs in the pathogenesis of pulmonary hypertension. Furthermore, pharmacological interventions aimed at epigenetic regulators/modifiers and their outcomes in different cellular and preclinical rodent models are discussed. Lastly, the remaining challenges and future directions in which to explore epigenetic-based therapies in pulmonary hypertension are discussed. PMID- 27492835 TI - Laparoscopic anti-reflux surgery for idiopathic pulmonary fibrosis at a single centre. AB - We sought to assess whether laparoscopic anti-reflux surgery (LARS) is associated with decreased rates of disease progression in patients with idiopathic pulmonary fibrosis (IPF).The study was a retrospective single-centre study of IPF patients with worsening symptoms and pulmonary function despite antacid treatment for abnormal acid gastro-oesophageal reflux. The period of exposure to LARS was September 1998 to December 2012. The primary end-point was a longitudinal change in forced vital capacity (FVC) % predicted in the pre- versus post-surgery periods.27 patients with progressive IPF underwent LARS. At time of surgery, the mean age was 65 years and mean FVC was 71.7% pred. Using a regression model, the estimated benefit of surgery in FVC % pred over 1 year was 5.7% (95% CI -0.9 12.2%, p=0.088) with estimated benefit in FVC of 0.22 L (95% CI -0.06-0.49 L, p=0.12). Mean DeMeester scores decreased from 42 to 4 (p<0.01). There were no deaths in the 90 days following surgery and 81.5% of participants were alive 2 years after surgery.Patients with IPF tolerated the LARS well. There were no statistically significant differences in rates of FVC decline pre- and post-LARS over 1 year; a possible trend toward stabilisation in observed FVC warrants prospective studies. The ongoing prospective randomised controlled trial will hopefully provide further insights regarding the safety and potential efficacy of LARS in IPF. PMID- 27492836 TI - Dosage of isoniazid and rifampicin poorly predicts drug exposure in tuberculosis patients. PMID- 27492838 TI - Task for Today: Complete the Puzzle of Circulating Stem Cells and the Atherosclerotic Burden. PMID- 27492837 TI - Diagnosing primary ciliary dyskinesia: an international patient perspective. AB - Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by progressive sino-pulmonary disease, with symptoms starting soon after birth. A European Respiratory Society (ERS) Task Force aims to address disparities in diagnostics across Europe by providing evidence-based clinical practice guidelines. We aimed to identify challenges faced by patients when referred for PCD diagnostic testing.A patient survey was developed by patient representatives and healthcare specialists to capture experience. Online versions of the survey were translated into nine languages and completed in 25 countries. Of the respondents (n=365), 74% were PCD-positive, 5% PCD-negative and 21% PCD uncertain/inconclusive. We then interviewed 20 parents/patients. Transcripts were analysed thematically.35% of respondents visited their doctor more than 40 times with PCD-related symptoms prior to diagnostic referral. Furthermore, the most prominent theme among interviewees was a lack of PCD awareness among medical practitioners and failure to take past history into account, leading to delayed diagnosis. Patients also highlighted the need for improved reporting of results and a solution to the "inconclusive" diagnostic status.These findings will be used to advise the ERS Task Force guidelines for diagnosing PCD, and should help stakeholders responsible for improving existing services and expanding provision for diagnosis of this rare disease. PMID- 27492839 TI - The All-Chemical Approach: A Solution for Converting Fibroblasts Into Myocytes. PMID- 27492840 TI - Karin Bornfeldt: Sticking With a Complicated Problem. PMID- 27492841 TI - Adaptions to Hypoxia and Redox Stress: Essential Concepts Confounded by Misleading Terminology. PMID- 27492843 TI - Correction. PMID- 27492842 TI - Responder Definition in Clinical Stem Cell Trials in Cardiology: Will the Real Responder Please Stand Up? PMID- 27492844 TI - Unusual FDG uptakes of mesenteric brown adipose tissue in a patient with pheochromocytomas. PMID- 27492845 TI - Synchronous presentation of nasopharyngeal carcinoma and abdominal paraganglioma with avid 18F-FDG and 68Ga-DOTA-TOC uptake in PET/CT by both tumours. PMID- 27492846 TI - Model averaging inconcentration-QT analyses. AB - This article describes how a frequentist model averaging approach can be used for concentration-QT analyses in the context of thorough QTc studies. Based on simulations, we have concluded that starting from three candidate model families (linear, exponential, and Emax) the model averaging approach leads to treatment effect estimates that are quite robust with respect to the control of the type I error in nearly all simulated scenarios; in particular, with the model averaging approach, the type I error appears less sensitive to model misspecification than the widely used linear model. We noticed also few differences in terms of performance between the model averaging approach and the more classical model selection approach, but we believe that, despite both can be recommended in practice, the model averaging approach can be more appealing because of some deficiencies of model selection approach pointed out in the literature. We think that a model averaging or model selection approach should be systematically considered for conducting concentration-QT analyses. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27492847 TI - Nanocrystalline calcium sulfate/hydroxyapatite biphasic compound as a TGF beta1/VEGF reservoir for vital pulp therapy. AB - OBJECTIVES: Vital pulp therapy aims to treat reversible pulpal injuries via protective dentinogenesis and to preserve more tooth structure. Mineral trioxide aggregate (MTA)-based capping materials demonstrate prolonged setting time increases the risk of pulpal infection during multi-visit treatment. Their non degradable property occupies pulp space and limits dentin-pulp regeneration. This study reports an inorganic degradable biomaterial that presents a short initial setting time and acts as a growth factor reservoir to promote reparative dentinogenesis. METHODS: We synthesize nanocrystalline calcium sulfate hemihydrate (nCS), hydroxyapatite (HAp) and calcium sulfate hemihydrate (CS) as a reservoir to which transforming growth factor-beta 1 (TGF-beta1) and vascular endothelial growth factor (VEGF) are added (denoted as nCS/HAp/CS/TGF beta1/VEGF). In vitro biocompatibility and mineralization (the activity and expression of alkaline phosphatase, ALP) were evaluated. Rat animal model was created to test in vivo efficacy. RESULTS: Cultured human dental pulp cells (HDPCs) showed that nCS/HAp/CS/TGF-beta1/VEGF cement has excellent biocompatibility and the potential to elevate the activity and expression of ALP. The in vivo efficacy (rat animal model) indicates protective dentin by micro computed tomography (MU-CT) measurements and histological analyses. The 3D MU-CT non-destructive analysis also determines volume changes during pulpotomy, suggesting that the degraded space of the nCS/HAp/CS/TGF-beta1/VEGF cement is repaired by the formation of dentin-pulp tissue. SIGNIFICANCE: These findings demonstrate that nCS/HAp/CS cement acts as a potent reservoir for the sustained release of growth factors, and that nCS/HAp/CS/TGF-beta1/VEGF cement has a high potential to form the reparative dentinogenesis in vivo. PMID- 27492848 TI - Findings in Historical Control Harlan RCCHanTM: WIST Rats from 104-week Oral Gavage Studies. AB - Vehicle control Harlan RCCHanTM:WIST rats were examined to provide control data for subsequent studies. The rats (180 male and 180 female) were dosed daily via oral gavage with reverse osmosis water for up to 104 weeks. At necropsy, body weights and macroscopic findings were recorded and tissues were collected for histopathology. The mean body weight at terminal sacrifice was 687 g for males and 466 g for females. The overall survival rate was 62% for males and 59% for females. The most common cause of death for males and females found dead or examined following unscheduled euthanasia was pituitary neoplasia with an incidence of 13.9% for males and 18.9% for females. Macroscopic and neoplastic and nonneoplastic microscopic findings are presented by body system. PMID- 27492849 TI - Aluminium ion-promoted radical-scavenging reaction of methylated hydroquinone derivatives. AB - The effect of the aluminium ion (Al(3+)) on the scavenging reaction of a 2,2 diphenyl-1-picrylhydrazyl radical (DPPH), as a reactivity model of reactive oxygen species, with hydroquinone (QH2) and its methylated derivatives (MenQH2, n = 1-4) was investigated using stopped-flow and electrochemical techniques in a hydroalcoholic medium. The second-order rate constants (k) for the DPPH scavenging reaction of the hydroquinones increased with the increasing number of methyl substituents. Upon addition of Al(3+), the k values significantly increased depending on the concentration of Al(3+). Such an accelerating effect of Al(3+) on the DPPH-scavenging rates of the hydroquinones results from the remarkable positive shift of the one-electron reduction potential (Ered) of DPPH in the presence of Al(3+). These results demonstrate that Al(3+), a strong Lewis acid, can act as a radical-scavenging promoter by stabilising the one-electron reduced species of the radical, although Al(3+) is reported not only to act as a pro-oxidant but also to strongly interact with biomolecules, showing toxicities. PMID- 27492850 TI - Aetiology of in-hospital cardiac arrest on general wards. AB - AIM: Aetiology of in-hospital cardiac arrests (IHCAs) on general wards has not been studied. We aimed to determine the underlying causes for IHCAs by the means of autopsy records and clinical judgement of the treating consultants. Furthermore, we investigated whether aetiology and preceding vital dysfunctions are associated with long-term survival. DESIGN AND SETTING: Prospective observational study between 2009-2011 including 279 adult IHCA patients attended by medical emergency team in a Finnish university hospital's general wards. RESULTS: The median age of the patients was 72 (64, 80) years, 185 (66%) were male, 178 (64%) of events were monitored/witnessed, first rhythm was shockable in 42 (15%) cases and 53 (19%) patients survived six months. Aetiology was determined as cardiac in 141 events, 73 of which were due to acute myocardial infarction. There were 138 non-cardiac IHCAs; most common causes were pneumonia (39) and exsanguination (16). No statistical difference was observed in the incidence of objective vital dysfunctions preceding the event between the cardiac and non-cardiac groups (40% vs. 44%, p=0.448). Subjective antecedents were more common in the cardiac cohort (47% vs. 32%, p=0.022), chest pain being an example (11% vs. 0.7%, p<0.001). Reviewing all 279 IHCAs, only shockable primary rhythm, monitored/witnessed event and low comorbidity score were independently associated with 180-day survival. CONCLUSIONS: Cardiac aetiology underlies half of the IHCAs on general wards. Both objective and subjective antecedents are common. However, neither the cardiac aetiology nor the absence of preceding deterioration of vital signs were factors independently associated with a favourable outcome. PMID- 27492851 TI - Examining emotion regulation in depression: A review and future directions. AB - Major Depressive Disorder (MDD) is an affective disorder with sustained negative affect and difficulties experiencing positive affect as its hallmark features. Previous work also highlights cognitive biases and deficits in cognitive control that accompany depression and suggestions have been made as to how cognitive and affective aspects of the disorder are linked. Recent work proposes that difficulties in the self-regulation of affect after experiencing negative life events may contribute to risk for the onset of depression, and indeed there is evidence that depressed patients exhibit more frequent use of maladaptive strategies when regulating affect and show difficulties effectively implementing adaptive strategies. Cognitive aspects of depression may play an important role in helping us understand these difficulties in self-regulation. This article reviews recent work on emotion regulation in depression and links cognitive biases and deficits associated with depression to difficulties in the self regulation of emotion. Importantly, a main goal of the article is to identify topics in need of future attention that could greatly help shed light on the relation between cognition and emotion regulation in this and other psychological disorders. PMID- 27492852 TI - Yttrium Siloxide Complexes Bearing Terminal Methyl Ligands: Molecular Models for Ln-CH3 Terminated Silica Surfaces. AB - Surface organometallic chemistry (SOMC) on silica materials is a prominent approach for the generation of highly active heterogenized polymerization catalysts. Despite advanced methods of characterization, the elucidation of the catalytically active surface species remains a challenging task. Alkylated rare earth metal siloxide complexes can be regarded as molecular models of respective covalently bonded alkylated surface species, primarily used for 1,3-diene polymerization. Here, we performed both salt metathesis reactions of [Y(MMe4 )3 ] (M = Al, Ga) with [K{OSi(OtBu)3 }] and alkylation reactions of [Y{OSi(OtBu)3 }3 ]2 with AlMe3 . The obtained complexes [Y(CH3 )[(AlMe2 ){OSi(OtBu)3 }2 ](AlMe4 )]2 , [Y(CH3 )[(AlMe2 ){OSi(OtBu)3 }2 ]-{OSi(OtBu)3 }], [Y{OSi(OtBu)3 }3 (MU Me)Y(MU-Me)2 Y{OSi(OtBu)3 }2 (AlMe4 )], and [Y(CH3 )(GaMe4 ){OSi(OtBu)3 }]2 represent rare examples of organoyttrium species with terminal methyl groups. The formation and purity of the mixed methyl/siloxy yttrium complexes could be enhanced by treating [Y(MMe4 )3 ] with [K(MMe2 ){OSi(OtBu)3 }2 ]n (M=Al: n=2; M=Ga: n=infinity). Complexes [K(MMe2 ){OSi(OtBu)3 }2 ]n were obtained by addition of [K{OSi(OtBu)3 }] to [Me2 M{OSi(OtBu)3 }]2 . Deeper insight into the fluxional behavior of the mixed methyl/siloxy yttrium complexes in solution was gained by (1) H and (13) C NMR spectroscopic studies at variable temperature and (1) H-(89) Y HSQC NMR spectroscopy. PMID- 27492853 TI - Retargeted adenoviruses for radiation-guided gene delivery. AB - The combination of radiation with radiosensitizing gene delivery or oncolytic viruses promises to provide an advantage that could improve the therapeutic results for glioblastoma. X-rays can induce significant molecular changes in cancer cells. We isolated the GIRLRG peptide that binds to radiation-inducible 78 kDa glucose-regulated protein (GRP78), which is overexpressed on the plasma membranes of irradiated cancer cells and tumor-associated microvascular endothelial cells. The goal of our study was to improve tumor-specific adenovirus mediated gene delivery by selectively targeting the adenovirus binding to this radiation-inducible protein. We employed an adenoviral fiber replacement approach to conduct a study of the targeting utility of GRP78-binding peptide. We have developed fiber-modified adenoviruses encoding the GRP78-binding peptide inserted into the fiber-fibritin. We have evaluated the reporter gene expression of fiber modified adenoviruses in vitro using a panel of glioma cells and a human D54MG tumor xenograft model. The obtained results demonstrated that employment of the GRP78-binding peptide resulted in increased gene expression in irradiated tumors following infection with fiber-modified adenoviruses, compared with untreated tumor cells. These studies demonstrate the feasibility of adenoviral retargeting using the GRP78-binding peptide that selectively recognizes tumor cells responding to radiation treatment. PMID- 27492854 TI - Overexpression of angiopoietin 2 promotes the formation of oral squamous cell carcinoma by increasing epithelial-mesenchymal transition-induced angiogenesis. AB - Oral squamous cell carcinoma (OSCC) is the most common cancer of the head and neck and is associated with a high rate of lymph node metastasis. The initial step in the metastasis and transition of tumors is epithelial-mesenchymal transition (EMT)-induced angiogenesis, which can be mediated by angiopoietin 2 (ANG2), a key regulatory factor in angiogenesis. In the present study, immunohistochemistry and real-time quantitative reverse transcriptase (qRT-PCR) were used to measure the expression of ANG2 in OSCC tissues. Plasmids encoding ANG2 mRNA were used for increased ANG2 expression in the OSCC cell line TCA8113. The short interfering RNA (siRNA)-targeting ANG2 mRNA sequences were used to inhibit ANG2 expression in TCA8113 cells. Subsequently, transwell assays were performed to examine the effects of ANG2 on TCA8113 cell migration and invasion. Furthermore, in vivo assays were performed to assess the effect of ANG2 on tumor growth. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays and immunohistochemistry were used to examine cell apoptosis and angiogenesis in tumor tissues, respectively. Finally, western blot analysis was performed to evaluate tumor formation-related proteins in OSCC tissues. We found that protein expression of ANG2 was remarkably upregulated in OSCC tissues. Overexpression of ANG2 increased the migration and invasion of TCA8113 cells by regulating EMT. Further investigations showed that overexpression of ANG2 increased tumor growth in nude mice, and angiogenesis of OSCC tissues increased in the presence of ANG2 overexpression. Overexpression of ANG2 also reduced cell apoptosis in tumor tissue cells. Finally, we found that overexpression of ANG2 resulted in changes in the expression of tumor formation-related proteins including vimentin, E-cadherin, Bim, PUMA, Bcl-2, Bax, Cyclin D1, PCNA and CD31. Our findings show that ANG2 has an important role in the migration and invasion of OSCC. More importantly, further investigations suggested that overexpression of ANG2 might increase OSCC metastasis by promoting angiogenesis in nude mice. This stimulatory effect could be achieved by inducing abnormal EMT and by reducing apoptosis and increasing proliferation of cells. PMID- 27492855 TI - Identification and characterization of novel natural pathogen of Drosophila melanogaster isolated from wild captured Drosophila spp. AB - Drosophila melanogaster is an emerging model system for the study of evolutionary ecology of immunity. However, a large number of studies have used non natural pathogens as very few natural pathogens have been isolated and identified. Our aim was to isolate and characterize natural pathogen/s of D. melanogaster. A bacterial pathogen was isolated from wild caught Drosophila spp., identified as a new strain of Staphylococcus succinus subsp. succinus and named PK-1. This strain induced substantial mortality (36-62%) in adults of several laboratory populations of D. melanogaster. PK-1 grew rapidly within the body of the flies post infection and both males and females had roughly same number of colony forming units. Mortality was affected by mode of infection and dosage of the pathogen. However mating status of the host had no effect on mortality post infection. Given that there are very few known natural bacterial pathogens of D. melanogaster and that PK-1 can establish a sustained infection across various outbred and inbred populations of D. melanogaster this new isolate is a potential resource for future studies on immunity. PMID- 27492856 TI - Diagnostic value of 18F-FDG PET/cardiac CT in late prosthetic aortic endocarditis with periprosthetic abscess. PMID- 27492857 TI - Usefulness of 18F-FDG PET/CT in a case of suspected vascular graft infection. AB - Vascular prosthetic graft infection (VPGI) is associated with high mortality and morbidity. An early and accurate diagnosis is essential in order to give the most appropriate treatment. The case is presented of a 74 year old male subjected to an aortobifemoral bypass graft, with clinical suspicion of VPGI with inconclusive tests. Later on an 18F-FDG PET/CT study showed a pathological uptake, suggestive of periprosthetic infection, as well as an incidental pulmonary lesion, suggestive of a primary neoplasm. A new 18F-FDG PET/CT showed a significant improvement in the uptake by the vascular graft after prolonged antibiotic treatment. 18F-FDG is a promising tracer for detecting VPGI as the accumulated activated white cells at the infection site have a high demand for 18F-FDG, and could help define the response to antibiotic treatment. PMID- 27492858 TI - Sleep and Social-Emotional Development in Infants and Toddlers. AB - The aim of this study was to examine the cross-sectional and longitudinal relationships among variables related to sleep patterns and both social-emotional problems (i.e., internalizing, externalizing, and dysregulation) and healthy social development (i.e., social competence). Assessments were completed at 6, 12, and 18 months across 5 cohorts of children for a total of 117 mother-child dyads. Mothers completed the Brief Infant Sleep Questionnaire at 6, 12, and 18 months, as well as the Infant Toddler Social Emotional Assessment at 12 and 18 months. Later bedtimes and less total sleep across the 24-hr period predicted higher internalizing problem scores, which includes indices of depression/withdrawal, general anxiety, separation distress, and inhibition. In contrast, sleep fragmentation was minimally associated with decreased social competence but not with any negative social-emotional outcomes. These results indicate that sleep patterns, primarily later bedtimes and less total sleep, appear to be associated with and predictive of social-emotional problem areas, namely, internalizing issues, in infants and toddlers. These findings add to the growing literature on the role of sleep in early social-emotional development and suggest that sleep schedule and duration should be addressed in clinical assessment and interventions for infant sleep. PMID- 27492859 TI - Interstitial microwave treatment for cancer: historical basis and current techniques in antenna design and performance. AB - The use of microwaves (MW) for thermal cancer treatment began in the late 1970s. At first, hyperthermia was induced by using single antennas applied interstitially. This was followed by arrays of multiple interstitial antennas driven synchronously at 915 or 2450 MHz. This early work focused on hyperthermia as an adjuvant therapy, but more recently has evolved into a thermally ablative monotherapy. Increased power required to thermally ablate tissues required additional developments such as internally cooled antennas. Larger tumours have also been ablated with MW antenna arrays activated synchronously or non synchronously. Numerical modelling has provided clinical treatment planning guidance and device design insight throughout this history. MW thermal therapy systems, treatment planning, navigation and image guidance continue to evolve to provide better tools and options for clinicians and patients in order to provide targeting optimisation with the goal of improved treatment for the patient and durable cancer eradication. This paper reviews the history and related technological developments, including antenna design, of MW heating for both hyperthermia and ablation. PMID- 27492860 TI - Pharmacy density in rural and urban communities in the state of Oregon and the association with hospital readmission rates. AB - OBJECTIVES: To characterize the pharmacy density in rural and urban communities with hospitals and to examine its association with readmission rates. DESIGN: Ecologic study. SETTING: Forty-eight rural and urban primary care service areas (PCSAs) in the state of Oregon. PARTICIPANTS: All hospitals in the state of Oregon. INTERVENTION: Pharmacy data were obtained from the Oregon Board of Pharmacy based on active licensure. Pharmacy density was calculated by determining the cumulative number of outpatient pharmacy hours in a PCSA. MAIN OUTCOME MEASURES: Oregon hospital 30-day all-cause readmission rates were obtained from the Centers for Medicare and Medicaid Services and were determined with the use of claims data of patients 65 years of age or older who were readmitted to the hospital within 30 days from July 2012 to June 2013. RESULTS: Readmission rates for Oregon hospitals ranged from 13.5% to 16.5%. The cumulative number of pharmacy hours in PCSAs containing a hospital ranged from 54 to 3821 hours. As pharmacy density increased, the readmission rates decreased, asymptotically approaching a predicted 14.7% readmission rate for areas with high pharmacy density. CONCLUSION: Urban hospitals were in communities likely to have more pharmacy access compared with rural hospitals. Future research should determine if increasing pharmacy access affects readmission rates, especially in rural communities. PMID- 27492862 TI - Influence of low-temperature nitriding on the strain-induced martensite and laser quenched austenite in a magnetic encoder made from 304L stainless steel. AB - We have investigated the possibility of producing a magnetic encoder by an innovative process. Instead of turning grooves in the encoder bar for precise positioning, we incorporated the information in 304L stainless steel by transforming the austenite to martensite after bar extrusion in liquid nitrogen and marking it with a laser, which caused a local transformation of martensite back into austenite. 304L has an excellent corrosion resistance, but a low hardness and poor wear resistance, which limits its range of applications. However, nitriding is a very promising way to enhance the mechanical and magnetic properties. After low-temperature nitriding at 400 degrees C it is clear that both epsilon- and alpha'-martensite are present in the deformed microstructure, indicating the simultaneous stress-induced and strain-induced transformations of the austenite. The effects of a laser surface treatment and the consequent appearance of a non-magnetic phase due to the alpha' -> gamma transformation were investigated. The EDS maps show a high concentration of nitrogen in the alternating hard surface layers of gammaN and alpha'N (expanded austenite and martensite), but no significantly higher concentration of chromium or iron was detected. The high surface hardness of this nitride layer will lead to steels and encoders with better wear and corrosion resistance. PMID- 27492861 TI - Negative control of TRAIL-R1 signaling by transforming growth factor beta1 in pancreatic tumor cells involves Smad-dependent down regulation of TRAIL-R1. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by both, overexpression of transforming growth factor (TGF)beta and resistance of the tumor cells to many apoptosis-inducing stimuli. The latter negatively impacts the outcome of therapeutic efforts and represents one important mechanism which tumor cells utilize to escape the immune surveillance. Since TGFbeta acts as a tumor promoter in advanced tumor stages and suppression of apoptosis is a known driver of tumor progression, it is possible that TGFbeta functions as a crucial determinant of tumor cell sensitivity to apoptosis in PDAC. Here, we have studied the impact of TGFbeta on TNF-related apoptosis inducing ligand (TRAIL)-induced signaling in PDAC cells. In TGFbeta-responsive Panc1 and Colo357 cells, TGFbeta1 reduced total and plasma membrane-associated levels of TRAIL-R1 but not those of TRAIL-R2. Consistent with the known predominant role of TRAIL-R1 in TRAIL-mediated signaling in PDAC, TGFbeta1 inhibited TRAIL-induced DISC formation and apoptosis as well as phosphorylation of MAPKs and IkappaBalpha. Similarly, it also reduced signaling of TRAIL-R1 following its specific activation with an agonistic antibody. In contrast, specific TRAIL-R2 signaling remained unchanged. The TGFbeta1 effect on TRAIL-R1 expression was mimicked by ectopic expression of a kinase-active version of the TGFbeta type I receptor ALK5 (ALK5-T204D) but not by ALK5 double mutant lacking the ability to phosphorylate Smad proteins (RImL45 T204D). Moreover, TGFbeta regulation of TRAIL-R1 was absent in two PDAC cell lines lacking the Smad4 gene DPC4 and siRNA-mediated silencing of Smad4 in Smad4 positive Panc1 cells abolished the TGFbeta-mediated decrease in TRAIL-R1 expression, together showing that ALK5/Smad4 signaling is crucial for TGFbeta regulation of TRAIL-R1 expression. Our results suggest a novel tumor-promoting function of TGFbeta1. By downregulating TRAIL-R1, TGFbeta1 may not only promote tumor escape from immune surveillance but also negatively impact on TRAIL- or TRAIL-R1-based therapy regimens for treatment of PDAC. PMID- 27492863 TI - Maternal lead exposure decreases the levels of brain development and cognition related proteins with concomitant upsurges of oxidative stress, inflammatory response and apoptosis in the offspring rats. AB - The presence of lead (Pb) in fetal brain may affect brain development-related proteins. We studied whether gestational/lactational Pb-exposure affects oxidative stress, proinflammatory response, apoptosis and levels of brain development/cognition-related proteins, including presynaptic synaptosome associated protein-25 (SNAP-25), postsynaptic density protein-95 (PSD-95), brain derived neurotropic factor (BDNF), tyrosine receptor-kinase protein B (TrkB) and vesicular acetylcholine transporter (VAChT) in the offspring. Female Wistar rats were randomly divided into control and Pb-exposed mother groups. The Pb-exposed rats received 0.1% (w/v) Pb acetate via drinking water during pregnancy and lactation. Milk and mammary glands were collected from lactating mothers to measure milk/mammary gland levels of lipid peroxide (LPO), as indicator of oxidative stress and proinflammatory TNF-alpha. Afterwards, the pups were sacrificed to determine brain levels of Pb, LPO, TNF-alpha, cytochrome C, SNAP 25, PSD-95, BDNF, TrkB and VAChT. The levels of LPO and TNF-alpha increased in the milk/mammary glands of the Pb-exposed mothers, concurrently with increases in the levels of Pb, LPO, TNF-alpha and cytochrome C and decreases in the levels of SNAP-25, PSD-95, BDNF, TrkB and VAChT in the brains of their offspring. Our results demonstrate that Pb-exposure during development reduces the brain levels of PSD-95 and SNAP-25 (synaptogenesis-markers), with concomitant upsurges of oxidative stress, TNF-alpha and apoptosis in the offspring. Furthermore, BDNF TrkB proteins that comprehend memory-related brain cognitions and/or VAChT that comprises cholinergic-neuromotor activities might be impaired by Pb-exposure. These findings provide evidence of toxic effects of Pb on brain development, at least, partially by decreasing the levels of PSD-95, SNAP-25 and other cognition related proteins. PMID- 27492864 TI - Electron-hole doping asymmetry of Fermi surface reconstructed in a simple Mott insulator. AB - It is widely recognized that the effect of doping into a Mott insulator is complicated and unpredictable, as can be seen by examining the Hall coefficient in high Tc cuprates. The doping effect, including the electron-hole doping asymmetry, may be more straightforward in doped organic Mott insulators owing to their simple electronic structures. Here we investigate the doping asymmetry of an organic Mott insulator by carrying out electric-double-layer transistor measurements and using cluster perturbation theory. The calculations predict that strongly anisotropic suppression of the spectral weight results in the Fermi arc state under hole doping, while a relatively uniform spectral weight results in the emergence of a non-interacting-like Fermi surface (FS) in the electron-doped state. In accordance with the calculations, the experimentally observed Hall coefficients and resistivity anisotropy correspond to the pocket formed by the Fermi arcs under hole doping and to the non-interacting FS under electron doping. PMID- 27492866 TI - Ophthalmologist who had an affair with patient avoids sanctions because of "unique" surgical skills. PMID- 27492865 TI - A telephone intervention to achieve differentiation in dietary intake: a randomized trial in paediatric primary care. AB - BACKGROUND: Telehealth offers opportunities to extend clinical and research interventions for paediatric obesity. OBJECTIVES: To assess utility of a telephone intervention, implemented through a national primary care paediatric research network, for promoting differentiation in dietary intake, consistent with either a low-glycemic load (Low GL) or Low Fat prescription, among overweight/obese school-age children. METHODS: Five-week telephone dietary counselling intervention for parents of overweight/obese school-age children recruited through the Slone Center Office-based Research Network. Parent-child dyads were randomized to Low GL or Low Fat diet. Primary outcomes were dietary GL and dietary fat, adjusted for energy intake and assessed by 24-h dietary recall. RESULTS: Subjects were randomized to Low GL (n = 11, 8.1 +/- 1.7 years, 45.5% male) or Low Fat (n = 11, 8.2 +/- 2.0 years, 36.4% male), with no baseline differences. Overall, 86% of subjects attended at least four of five counselling sessions, and study completion rate was 91% (based on completion of the final dietary recalls). Reported satisfaction was high. In adjusted analyses limited to 'recall completers,' reduction in dietary GL (g/1000 kcal) achieved within the Low GL group was significant (p = 0.01) and greater than the change in dietary GL in the Low Fat group (mean +/- SE; -12.9 +/- 4.4 vs. 5.1 +/- 4.9, p = 0.03). Similarly, reduction in dietary fat (% of total energy) within the Low Fat group was significant (-5.6 +/- 2.5, p = 0.046) but with no difference between groups (p = 0.25). CONCLUSION: A telephone-based dietary intervention for overweight/obese children, implemented through a national paediatric research network, fostered prescribed dietary changes. ClinicalTrials.gov registration: NCT00620152. PMID- 27492867 TI - Bariatric Radioembolization: A Pilot Study on Technical Feasibility and Safety in a Porcine Model. AB - PURPOSE: To evaluate feasibility of left gastric artery (LGA) yttrium-90 ((90)Y) radioembolization as potential treatment for obesity in a porcine model. MATERIALS AND METHODS: This study included 8 young female pigs (12-13 weeks, 21.8 28.1 kg). Six animals received infusions of (90)Y resin microspheres (46.3-105.1 MBq) into the main LGA and the gastric artery arising from the splenic artery. Animal weight and serum ghrelin were measured before treatment and weekly thereafter. Animals were euthanized 69-74 days after treatment, and histologic analyses of mucosal integrity and ghrelin immunoreactive cell density were performed. RESULTS: Superficial mucosal ulcerations < 3.0 cm(2) were noted in 5 of 6 treated animals. Ghrelin immunoreactive cell density was significantly lower in treated versus untreated animals in the stomach fundus (13.5 vs 34.8, P < .05) and stomach body (11.2 vs 19.8, P < .05). Treated animals gained less weight than untreated animals over the study duration (40.2 kg +/- 5.4 vs 54.7 kg +/- 6.5, P = .053). Average fundic parietal area (165 cm(2) vs 282 cm(2), P = .067) and average stomach weight (297.2 g vs 397.0 g, P = .067) were decreased in treated versus untreated animals. Trichrome staining revealed significantly more fibrosis in treatment animals compared with control animals (13.0 vs 8.6, P < .05). No significant differences were identified in plasma ghrelin concentrations (P = .24). CONCLUSIONS: LGA (90)Y radioembolization is promising as a potential treatment for obesity. A larger preclinical study is needed to evaluate the safety and efficacy of this procedure further. PMID- 27492868 TI - Multicentric Reticulohistiocytosis in a 5-Year-Old Girl. PMID- 27492869 TI - Unintentional Injuries in Children Up to Six Years of Age and Related Parental Knowledge, Attitudes, and Behaviors in Italy. AB - OBJECTIVES: To describe risk factors associated with unintentional injuries among children aged <6 years and to examine parents' level of knowledge, attitudes, and behaviors about pediatric injuries and related preventive measures. STUDY DESIGN: A cross-sectional survey was conducted between May and July 2015 on a random sample of 794 parents of 3- to 6-year-old children through a self-administered anonymous questionnaire. RESULTS: A total of 409 parents participated. Two-thirds of the children had experienced at least 1 unintentional injury in the previous 12 months. More than one-half of these children were boys. The leading cause was falls; the injuries occurred mainly at home, and only 9.2% were brought for attention to an emergency department. Parents who did not believe that it is possible to prevent unintentional injuries were more likely to have had a child injured. Approximately 70% of respondents were aware of security measures to prevent pediatric injuries, and this knowledge was more prevalent in older parents and in those with at least a college level of education compared with those with a middle school education. The perceived utility of education about preventive measures of pediatric injuries had a mean value of 8.9 on a Likert scale of 1-10 (1, not useful, to 10, very useful) and was significantly higher in mothers. CONCLUSIONS: This study highlights a clear need for public health educational programs for parents regarding prevention of unintentional injuries in children as a valuable tool to increase safety and injury prevention and to reduce risks, because the majority of such injuries occur at home. PMID- 27492870 TI - Pressure-Flow Analysis for the Assessment of Pediatric Oropharyngeal Dysphagia. AB - OBJECTIVES: To determine which objective pressure-impedance measures of pharyngeal swallowing function correlated with clinically assessed severity of oropharyngeal dysphagia (OPD) symptoms. STUDY DESIGN: Forty-five children with OPD and 34 control children without OPD were recruited and up to 5 liquid bolus swallows were recorded with a solid-state high-resolution manometry with impedance catheter. Individual measures of pharyngeal and upper esophageal sphincter (UES) function and a swallow risk index composite score were derived for each swallow, and averaged data for patients with OPD were compared with those of control children without OPD. Clinical severity of OPD symptoms and oral feeding competency was based on the validated Dysphagia Disorders Survey and Functional Oral Intake Scale. RESULTS: Those objective measures that were markers of UES relaxation, UES opening, and pharyngeal flow resistance differentiated patients with and without OPD symptoms. Patients demonstrating abnormally high pharyngeal intrabolus pressures and high UES resistance, markers of outflow obstruction, were most likely to have signs and symptoms of overt Dysphagia Disorders Survey (OR 9.24, P = .05, and 9.7, P = .016, respectively). CONCLUSION: Pharyngeal motor patterns can be recorded in children by the use of HRIM and pharyngeal function can be defined objectively with the use of pressure-impedance measures. Objective measurements suggest that pharyngeal dysfunction is common in children with clinical signs of OPD. A key finding of this study was evidence of markers of restricted UES opening. PMID- 27492871 TI - A cold plasma jet accelerates wound healing in a murine model of full-thickness skin wounds. AB - Cold plasma has been successfully applied in several fields of medicine that require, for example, pathogen inactivation, implant functionalization or alteration of cellular activity. Previous studies have provided evidence that plasma supports the healing of wounds owing to its beneficial mixtures of reactive species and modulation of inflammation in cells and tissues. To investigate the wound healing activity of an atmospheric pressure plasma jet in vivo, we examined the cold plasma's efficacy on dermal regeneration in a murine model of dermal full-thickness ear wound. Over 14 days, female mice received daily plasma treatment. Quantitative analysis by transmitted light microscopy demonstrated a significantly accelerated wound re-epithelialization at days 3-9 in comparison with untreated controls. In vitro, cold plasma altered keratinocyte and fibroblast migration, while both cell types showed significant stimulation resulting in accelerated closure of gaps in scratch assays. This plasma effect correlated with the downregulation of the gap junctional protein connexin 43 which is thought to be important in the regulation of wound healing. In addition, plasma induced profound changes in adherence junctions and cytoskeletal dynamics as shown by downregulation of E-cadherin and several integrins as well as actin reorganization. Our results theorize cold plasma to be a beneficial treatment option supplementing existing wound therapies. PMID- 27492873 TI - Suicide Risk Among Wounded U.S. Service Members. AB - The association between suicide and combat injuries sustained during the wars in Iraq and Afghanistan was examined. A retrospective population-based cohort design was conducted using official military records to identify combat injuries (October 7, 2001, to December 31, 2007). Those who were injured during combat had higher crude suicide rates than those who deployed and were not injured (incidence rate ratio [IRR] = 1.50; confidence interval [CI] = 1.06, 2.12), or never deployed (IRR = 1.46; CI = 1.04, 2.06). After adjusting for demographics, these findings were no longer statistically significant. Although our data did not support an elevated suicide risk among wounded service members, additional research is needed to examine the impact of injury severity. PMID- 27492874 TI - An optimised multi-host trematode life cycle: fishery discards enhance trophic parasite transmission to scavenging birds. AB - Overlapping distributions of hosts and parasites are critical for successful completion of multi-host parasite life cycles and even small environmental changes can impact on the parasite's presence in a host or habitat. The generalist Cardiocephaloides longicollis was used as a model for multi-host trematode life cycles in marine habitats. This parasite was studied to quantify parasite dispersion and transmission dynamics, effects of biological changes and anthropogenic impacts on life cycle completion. We compiled the largest host dataset to date, by analysing 3351 molluscs (24 species), 2108 fish (25 species) and 154 birds (17 species) and analysed the resultant data based on a number of statistical models. We uncovered extremely low host specificity at the second intermediate host level and a preference of the free-swimming larvae for predominantly demersal but also benthic fish. The accumulation of encysted larvae in the brain with increasing fish size demonstrates that parasite numbers level off in fish larger than 140mm, consistent with parasite-induced mortality at these levels. The highest infection rates were detected in host species and sizes representing the largest fraction of Mediterranean fishery discards (up to 67% of the total catch), which are frequently consumed by seabirds. Significantly higher parasite densities were found in areas with extensive fishing activity than in those with medium and low activity, and in fish from shallow lagoons than in fish from other coastal areas. For the first time, C. longicollis was also detected in farmed fish in netpens. Fishing generally drives declines in parasite abundance, however, our study suggests an enhanced transmission of generalist parasites such as C. longicollis, an effect that is further amplified by the parasite's efficient host-finding mechanisms and its alteration of fish host behaviour by larvae encysted in the brain. The anthropogenic impact on the distribution of trophically-transmitted, highly prevalent parasites likely results in a strong effect on food web structure, thus making C. longicollis an ideal bioindicator to compare food webs in natural communities versus those impacted by fisheries and aquaculture. PMID- 27492875 TI - Tracking adenovirus genomes identifies morphologically distinct late DNA replication compartments. AB - In adenoviral virions, the genome is organized into a chromatin-like structure by viral basic core proteins. Consequently viral DNAs must be replicated, chromatinized and packed into progeny virions in infected cells. Although viral DNA replication centers can be visualized by virtue of viral and cellular factors, the spatiotemporal regulation of viral genomes during subsequent steps remains to be elucidated. In this study, we used imaging analyses to examine the fate of adenoviral genomes and to track newly replicated viral DNA as well as replication-related factors. We show de novo formation of a subnuclear domain, which we termed Virus-induced Post-Replication (ViPR) body, that emerges concomitantly with or immediately after disintegration of initial replication centers. Using a nucleoside analogue, we show that viral genomes continue being synthesized in morphologically distinct replication compartments at the periphery of ViPR bodies and are then transported inward. In addition, we identified a nucleolar protein Mybbp1a as a molecular marker for ViPR bodies, which specifically associated with viral core protein VII. In conclusion, our work demonstrates the formation of previously uncharacterized viral DNA replication compartments specific for late phases of infection that produce progeny viral genomes accumulating in ViPR bodies. PMID- 27492876 TI - Detecting the Collapse of Cooperation in Evolving Networks. AB - The sustainability of biological, social, economic and ecological communities is often determined by the outcome of social conflicts between cooperative and selfish individuals (cheaters). Cheaters avoid the cost of contributing to the community and can occasionally spread in the population leading to the complete collapse of cooperation. Although such collapse often unfolds unexpectedly, it is unclear whether one can detect the risk of cheater's invasions and loss of cooperation in an evolving community. Here, we combine dynamical networks and evolutionary game theory to study the abrupt loss of cooperation with tools for studying critical transitions. We estimate the risk of cooperation collapse following the introduction of a single cheater under gradually changing conditions. We observe an increase in the average time it takes for cheaters to be eliminated from the community as the risk of collapse increases. We argue that such slow system response resembles slowing down in recovery rates prior to a critical transition. In addition, we show how changes in community structure reflect the risk of cooperation collapse. We find that these changes strongly depend on the mechanism that governs how cheaters evolve in the community. Our results highlight novel directions for detecting abrupt transitions in evolving networks. PMID- 27492877 TI - Oxidation of municipal wastewater by free radicals mechanism. A UV/Vis spectroscopy study. AB - This study investigates the oxidation of municipal wastewater (WW) by complexation with natural polyphenols having radical scavenging activity, such as (3,4,5 tri-hydroxy-benzoic acid) gallic acid (GA) in alkaline pH (>7), under ambient O2 and temperature. Physicochemical and structural characteristics of GA WW complex-forming are evaluated by UV/Vis spectroscopy. The comparative analysis among UV/Vis spectra of GA monomer, GA-GA polymer, WW compounds, and GA-WW complex reveals significant differences within 350-450 and 500-900 nm. According to attenuated total reflectance (ATR) spectroscopy and thermogravimetric analysis (TGA), these spectra differences correspond to distinct complexes formed. This study suggests a novel role of natural polyphenols on the degradation and humification of wastes. PMID- 27492878 TI - Joint damage and motor learning during unipedal stance in haemophilia arthropathy: report of two cases. PMID- 27492879 TI - Tunable dual emission in visible and near-infrared spectra using Co(2+)-doped PbSe nanocrystals embedded in a chalcogenide glass matrix. AB - Semimagnetic Pb1-xCoxSe nanocrystals were synthesized by a fusion protocol in a glass matrix and characterized by optical absorption (OA), transmission electron microscopy (TEM), and photoluminescence (PL) techniques. OA spectra and TEM images strongly indicated the formation of Pb1-xCoxSe magnetic phases in the glass system and the quantum dot size was manipulated by tuning the annealing time. The OA spectra together with crystal field theory indicate that Co(2+) is located in the tetrahedral site (Td) and the PL of the Pb1-xCoxSe nanocrystals presents characteristic recombination in the visible (~700 nm) and near-IR (1300 1600 nm) electromagnetic spectral range. With temperature decreasing, the PL spectra, in the visible spectral range, indicate an excited-state crossover yielding PL changes from (4)T1(P) -> (4)A2(F) broadband emission to (2)E(G) -> (4)A2(F) narrow-line emission. This phenomenon was explained on the basis of a configurational energy model. The OA and PL spectra of PbSe:Co(2+) indicate that the localized energy transition of Co(2+) ((4)A2(F) <-> (4)T1((4)F)) can be tuned from the band-gap energy to the conduction-band energy of PbSe NCs by changing the NC size by increasing the thermal annealing time. In the near-IR spectral range, the temperature-dependent PL spectra show that the process of thermal activation of localized electrons in Co(2+) states can be transferred to the conduction band of the NCs. This process depends on the energy distance between extended and localized states, which can be controlled by the sample annealing time. PMID- 27492880 TI - Depression Screening Using Daily Mental-Health Ratings from a Smartphone Application for Breast Cancer Patients. AB - BACKGROUND: Mobile mental-health trackers are mobile phone apps that gather self reported mental-health ratings from users. They have received great attention from clinicians as tools to screen for depression in individual patients. While several apps that ask simple questions using face emoticons have been developed, there has been no study examining the validity of their screening performance. OBJECTIVE: In this study, we (1) evaluate the potential of a mobile mental-health tracker that uses three daily mental-health ratings (sleep satisfaction, mood, and anxiety) as indicators for depression, (2) discuss three approaches to data processing (ratio, average, and frequency) for generating indicator variables, and (3) examine the impact of adherence on reporting using a mobile mental-health tracker and accuracy in depression screening. METHODS: We analyzed 5792 sets of daily mental-health ratings collected from 78 breast cancer patients over a 48 week period. Using the Patient Health Questionnaire-9 (PHQ-9) as the measure of true depression status, we conducted a random-effect logistic panel regression and receiver operating characteristic (ROC) analysis to evaluate the screening performance of the mobile mental-health tracker. In addition, we classified patients into two subgroups based on their adherence level (higher adherence and lower adherence) using a k-means clustering algorithm and compared the screening accuracy between the two groups. RESULTS: With the ratio approach, the area under the ROC curve (AUC) is 0.8012, indicating that the performance of depression screening using daily mental-health ratings gathered via mobile mental-health trackers is comparable to the results of PHQ-9 tests. Also, the AUC is significantly higher (P=.002) for the higher adherence group (AUC=0.8524) than for the lower adherence group (AUC=0.7234). This result shows that adherence to self-reporting is associated with a higher accuracy of depression screening. CONCLUSIONS: Our results support the potential of a mobile mental-health tracker as a tool for screening for depression in practice. Also, this study provides clinicians with a guideline for generating indicator variables from daily mental health ratings. Furthermore, our results provide empirical evidence for the critical role of adherence to self-reporting, which represents crucial information for both doctors and patients. PMID- 27492881 TI - Effect of regional versus local anaesthesia on outcome after arteriovenous fistula creation: a randomised controlled trial. AB - BACKGROUND: Arteriovenous fistulae are the optimum form of vascular access in end stage renal failure. However, they have a high early failure rate. Regional compared with local anaesthesia results in greater vasodilatation and increases short-term blood flow. This study investigated whether regional compared with local anaesthesia improved medium-term arteriovenous fistula patency. METHODS: This observer-blinded, randomised controlled trial was done at three university hospitals in Glasgow, UK. Adults undergoing primary radiocephalic or brachiocephalic arteriovenous fistula creation were randomly assigned (1:1; in blocks of eight) using a computer-generated allocation system to receive either local anaesthesia (0.5% L-bupivacaine and 1% lidocaine injected subcutaneously) or regional (brachial plexus block [BPB]) anaesthesia (0.5% L-bupivacaine and 1.5% lidocaine with epinephrine). Patients were excluded if they were coagulopathic, had no suitable vessels, or had a previous failed ipsilateral fistula. The primary endpoint was arteriovenous fistula patency at 3 months. We analysed the data on an intention-to-treat basis. This study was registered with ClinicalTrials.gov (NCT01706354) and is complete. FINDINGS: Between Feb 6, 2013, and Dec 4, 2015, 163 patients were assessed for eligibility and 126 patients were randomly assigned to local anaesthesia (n=63) or BPB (n=63). All patients completed follow-up on an intention-to-treat basis. Primary patency at 3 months was higher in the BPB group than the local anaesthesia group (53 [84%] of 63 patients vs 39 [62%] of 63; odds ratio [OR] 3.3 [95% CI 1.4-7.6], p=0.005) and was greater in radiocephalic fistulae (20 [77%] of 26 patients vs 12 [48%] of 25; OR 3.6 [1.4-3.6], p=0.03). There were no significant adverse events related to the procedure. INTERPRETATION: Compared with local anaesthesia, BPB significantly improved 3 month primary patency rates for arteriovenous fistulae. FUNDING: Regional Anaesthesia UK, Darlinda's Charity for Renal Research. PMID- 27492882 TI - Improving outcomes in dialysis fistulae. PMID- 27492883 TI - Observations of oral hygiene care interventions provided by nurses to hospitalized older people. AB - Dependent older hospitalized patients rely on nurses to assist them with the removal of plaque from their teeth, dentures, and oral cavities. Oral care interventions by 25 nurses on post-acute units, where patients have longer hospital stays, were observed during evening care. In addition to efforts to engage patients in oral care, nurses provided the following interventions: (a) supporting the care of persons with dentures; (b) supporting the care of natural teeth; (c) cleansing the tongue and oral cavity; and (d) moisturizing lips and oral tissues. Patients' oral hygiene care was supported in just over one-third of encounters. Denture care was inconsistently performed, and was infrequently followed by care of the oral cavity. Nurses did not encourage adequate self-care of natural teeth by patients, and infrequently moisturized tissues. Evidence based oral hygiene care standards are required to assist nurses to support patients in achieving optimal oral hygiene outcomes. PMID- 27492884 TI - Are nursing home care workers' health and presenteeism associated with implicit rationing of care? A cross-sectional multi-site study. AB - To explore associations between care workers' health and implicit rationing of care. Diverse studies have linked impaired health to reduced work performance - a factor measured through omission of required tasks. This cross-sectional study gathered data from 3239 care workers in 162 Swiss nursing homes. Data were analyzed via a linear logistic regression model using general estimating equations. Overall, rationing of care occurred "never" to "seldom." Rationing of activities of daily living was positively associated with care workers' joint pain (beta 0.04, CI 0.001-0.07), emotional exhaustion (beta 0.11, CI 0.07-0.15), and presenteeism (beta 0.05, CI 0.004-0.09). Rationing of caring, rehabilitation, and monitoring was positively associated with care workers' joint pain (beta 0.05, CI 0.01-0.09) and emotional exhaustion (beta 0.2, CI 1.16-0.24). Care workers health complaints are strongly associated with rationing of tasks directly related to resident care. PMID- 27492885 TI - Genetic evidence for a role of the SREBP transcription system and lipid biosynthesis in schizophrenia and antipsychotic treatment. AB - Schizophrenia is a serious psychotic disorder, with disabling symptoms and markedly reduced life expectancy. The onset is usually in late adolescence or early adulthood, which in time overlaps with the maturation of the brain including the myelination process. Interestingly, there seems to be a link between myelin abnormalities and schizophrenia. The oligodendrocyte-derived myelin membranes in the CNS are highly enriched for lipids (cholesterol, phospholipids and glycosphingolipids), thereby pointing at lipid homeostasis as a relevant target for studying the genetics and pathophysiology of schizophrenia. The biosynthesis of fatty acids and cholesterol is regulated by the sterol regulatory element binding protein (SREBP) transcription factors SREBP1 and SREBP2, which are encoded by the SREBF1 and SREBF2 genes on chromosome 17p11.2 and 22q13.2, respectively. Here we review the evidence for the involvement of SREBF1 and SREBF2 as genetic risk factors in schizophrenia and discuss the role of myelination and SREBP-mediated lipid biosynthesis in the etiology, pathophysiology and drug treatment of schizophrenia. PMID- 27492886 TI - Traumatic stress causes distinctive effects on fear circuit catecholamines and the fear extinction profile in a rodent model of posttraumatic stress disorder. AB - Central catecholamines regulate fear memory across the medial prefrontal cortex (mPFC), amygdala (AMYG), and hippocampus (HPC). However, inadequate evidence exists to address the relationships among these fear circuit areas in terms of the fear symptoms of posttraumatic stress disorder (PTSD). By examining the behavioral profile in a Pavlovian fear conditioning paradigm together with tissue/efflux levels of dopamine (DA) and norepinephrine (NE) and their reuptake abilities across the fear circuit areas in rats that experienced single prolonged stress (SPS, a rodent model of PTSD), we demonstrated that SPS-impaired extinction retrieval was concomitant with the changes of central DA/NE in a dissociable manner. For tissue levels, diminished DA and increased NE were both observed in the mPFC and AMYG. DA efflux and synaptosomal DA transporter were consistently reduced in the AMYG/vHPC, whereas SPS reduced NE efflux in the infralimbic cortex and synaptosomal NE transporter in the mPFC. Furthermore, a lower expression of synaptosomal VMAT2 was observed in the mPFC, AMYG, and vHPC after SPS. Finally, negative correlations were observed between retrieval freezing and DA in the mPFC/AMYG; nevertheless, the phenomena became invalid after SPS. Our results suggest that central catecholamines are crucially involved in the retrieval of fear extinction in which DA and NE play distinctive roles across the fear circuit areas. PMID- 27492887 TI - Enantioselective isothiourea-catalysed trans-dihydropyridinone synthesis using saccharin-derived ketimines: scope and limitations. AB - The catalytic enantioselective synthesis of a range of trans-dihydropyridinones from aryl-, heteroaryl- and alkenylacetic acids and saccharin-derived ketimines with good to excellent stereocontrol (15 examples, up to >95 : 5 dr, up to >99 : 1 er) is reported. After extensive optimisation, HyperBTM proved the optimal isothiourea catalyst for this transformation at -78 degrees C, giving trans dihydropyridones with generally excellent levels of diastereo- and enantioselectivity. PMID- 27492888 TI - Establishment of an appropriate fall prevention program: A community-based study. AB - AIM: To identify an appropriate community-based fall prevention program METHODS: We introduced two programs to 24 senior centers, "community salons," in a Japanese city, and carried out a prospective controlled trial between 2004 and 2005. Eight salons (185 participants aged 72.0 +/- 7.1 years) received a single visit program consisting of one multidisciplinary team visit that included fall risk assessment with feedback and a fall prevention lecture. A total of 16 salons (418 participants aged 73.6 +/- 7.4 years) received a year-round comprehensive program, with visits carried out every 3 months. We compared the fall rates for 1 year between the two programs. Based on the results, we implemented a modified program until 2014 and examined the long-term consequences. RESULTS: In the prospective controlled trial, fall rates did not differ significantly between programs (P = 0.449). Instead, fall rates for both programs decreased significantly by 0.89 (95% CI 0.84-0.94) times each month. Therefore, we implemented a modified version of the single-visit program. By March 2014, the programs had been delivered to 1863 individuals, and the total number of attendees was 6622. The average attendance frequency per participant was 0.62 times per year. The majority (85.3%) of salons requested the program every year. Overall, the risk of falling (fall rates in the preceding year) decreased significantly as the number of program attendances increased (incident rate ratio = 0.89, 95% CI 0.85-0.92) irrespective of initial program types. CONCLUSIONS: The programs including fall risk assessment with feedback and a fall prevention lecture reduced falls when embedded into the community, and they were accepted well over the course of 10 years. Geriatr Gerontol Int 2017; 17: 1081-1089. PMID- 27492889 TI - Composition, microstructure and element study of urinary calculi. AB - To better understand the basis of urinary calculi formation, we studied the composition, microstructure, and element analysis of different types of urinary calculi. Sixty people with urinary stones in Shanxi province were selected randomly. The composition of urinary stones was analyzed using Fourier transform infrared spectroscopy. The microstructure of material components was observed by a scanning electron microscopy and the elemental distribution and composition were analyzed by an X-ray energy spectrometer. Furthermore, general information, BMI, history of medicine, chronic medical history, family history, and recurrence rates were collected. Female-to-male ratio was 1:2.5; median age was 43.2 years old. Of the patients, 13.3% were found definite family history and 46.6% of patients for recurrence history. It was found that mixed stones account for the largest proportion (65%), followed by calcium oxalate monohydrate calculi (26.67%). In mixed stones, the mixture of calcium oxalate monohydrate and hydroxyapatite had the largest proportion, accounting for 71.79%. Stones showed different microcosmic characteristics and element distribution. Stones varied widely in distribution, infrared spectrum, microstructure, and element composition, which provided an important basis for urinary calculi research regarding urinary stone formation. PMID- 27492890 TI - Thermophysical properties of imidazolium tricyanomethanide ionic liquids: experiments and molecular simulation. AB - The low-viscous tricyanomethanide ([TCM](-))-based ionic liquids (ILs) are gaining increasing interest as attractive fluids for a variety of industrial applications. The thermophysical properties (density, viscosity, surface tension, electrical conductivity and self-diffusion coefficient) of the 1-alkyl-3 methylimidazolium tricyanomethanide [Cnmim][TCM] (n = 2, 4 and 6-8) IL series were experimentally measured over the temperature range from 288 to 363 K. Moreover, a classical force field optimized for the imidazolium-based [TCM](-) ILs was used to calculate their thermodynamic, structural and transport properties (density, surface tension, self-diffusion coefficients, viscosity) in the temperature range from 300 to 366 K. The predictions were directly compared against the experimental measurements. The effects of anion and alkyl chain length on the structure and thermophysical properties have been evaluated. In cyano-based ILs, the density decreases with increasing molar mass, in contrast to the behavior of the fluorinated anions, being in agreement with the literature. The contribution per -CH2- group to the increase of the viscosity presents the following sequence: [PF6](-) > [BF4](-) > [Tf2N](-) > [DCA](-) > [TCB](-) > [TCM](-). [TCM](-)-based ILs show lower viscosity than dicyanamide ([DCA](-))- and tetracyanoborate ([TCB](-))-based ILs, while the latter two exhibit a crossover which depends both on temperature and the alkyl chain length of the cation. The surface tension of the investigated ILs decreases with increasing alkyl chain length. [C2mim][TCM] shows an outlier behavior compared to other members of the homologous series. The surface enthalpies and surface entropies for all the studied systems have been calculated based on the experimentally determined surface tensions. The relationship between molar conductivity and viscosity was analyzed using the Walden rule. The experimentally determined self diffusion coefficients of the cations are in good agreement with the molecular simulation predictions, in which a decrease of the self-diffusion of the cations with increasing alkyl chain length is observed with a simultaneous increase in viscosity and for the longer alkyl lengths the anion becomes more mobile than the cation. PMID- 27492891 TI - Filaggrin gene loss-of-function variants modify the effect of breast-feeding on eczema risk in early childhood. PMID- 27492894 TI - A seminal molecular marker for sperm presence in non-obstructive azoospermia? PMID- 27492893 TI - Patient and caregiver expectations of emergency department care: A scoping literature review. AB - BACKGROUND: Communication between health care providers (HCPs) and patients and/or their caregivers in the chaotic emergency department (ED) context can be challenging and potentially impact health outcomes and patient satisfaction. Studies examining strategies to improve communication of patient and caregivers expectations of care in an ED are widely dispersed. METHODS: We conducted a scoping review of the published and grey literature to examine the extent, range and nature of existing research evidence regarding strategies to enhance communication of patient and caregiver expectations of care in an ED. RESULTS: Of the 599 articles retrieved, 24 met the inclusion criteria. Most of the studies identified included patients (n=9) or caregivers (n=8) as the population of interest, while the remainder examined the expectations of a mix of patients, parents/caregivers, and/or HCPs (n=7). The majority (n=21) of the studies did not communicate patient/caregiver expectations to HCPs. CONCLUSION: This scoping review highlights the paucity of available research literature evaluating strategies to communicate patient and caregiver ED expectations. Our findings identify the need for experimental designs in future studies to evaluate implementation strategies for ED expectation tools with a particular emphasis on measuring the impact of sharing patient expectations with HCPs. PMID- 27492892 TI - Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies. AB - Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC). The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE) cells. We identified frequent mutations involving a 40kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p<2(-16)), which was not found in patients without cancer (n=108). Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n=100), and common in BRCA1-BRCA2 mutation carriers (n=71) who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease. PMID- 27492896 TI - Socioeconomic Status in Relation to the Risk of Ovarian Cancer in African American Women: A Population-Based Case-Control Study. AB - We investigated the association between socioeconomic status and ovarian cancer in African-American women. We used a population-based case-control study design that included case patients with incident ovarian cancer (n = 513) and age- and area-matched control participants (n = 721) from 10 states who were recruited into the African American Cancer Epidemiology Study from December 2010 through December 2014. Questionnaires were administered via telephone, and study participants responded to questions about several characteristics, including years of education, family annual income, and risk factors for ovarian cancer. After adjustment for established ovarian cancer risk factors, women with a college degree or more education had an odds ratio of 0.71 (95% confidence interval (CI): 0.51, 0.99) when compared with those with a high school diploma or less (P for trend = 0.02); women with family annual incomes of $75,000 or more had an odds ratio of 0.74 (95% CI: 0.47, 1.16) when compared with those with incomes less than $10,000 (P for trend = 0.055). When these variables were dichotomized, compared with women with a high school diploma or less, women with more education had an adjusted odds ratio of 0.72 (95% CI: 0.55, 0.93), and compared with women with an income less than $25,000, women with higher incomes had an adjusted odds ratio of 0.86 (95% CI: 0.66, 1.12). These findings suggest that ovarian cancer risk may be inversely associated with socioeconomic status among African-American women and highlight the need for additional evidence to more thoroughly characterize the association between socioeconomic status and ovarian cancer. PMID- 27492895 TI - Parental Tobacco Smoking and Acute Myeloid Leukemia: The Childhood Leukemia International Consortium. AB - The association between tobacco smoke and acute myeloid leukemia (AML) is well established in adults but not in children. Individual-level data on parental cigarette smoking were obtained from 12 case-control studies from the Childhood Leukemia International Consortium (CLIC, 1974-2012), including 1,330 AML cases diagnosed at age <15 years and 13,169 controls. We conducted pooled analyses of CLIC studies, as well as meta-analyses of CLIC and non-CLIC studies. Overall, maternal smoking before, during, or after pregnancy was not associated with childhood AML; there was a suggestion, however, that smoking during pregnancy was associated with an increased risk in Hispanics (odds ratio = 2.08, 95% confidence interval (CI): 1.20, 3.61) but not in other ethnic groups. By contrast, the odds ratios for paternal lifetime smoking were 1.34 (95% CI: 1.11, 1.62) and 1.18 (95% CI: 0.92, 1.51) in pooled and meta-analyses, respectively. Overall, increased risks from 1.2- to 1.3-fold were observed for pre- and postnatal smoking (P < 0.05), with higher risks reported for heavy smokers. Associations with paternal smoking varied by histological type. Our analyses suggest an association between paternal smoking and childhood AML. The association with maternal smoking appears limited to Hispanic children, raising questions about ethnic differences in tobacco-related exposures and biological mechanisms, as well as study-specific biases. PMID- 27492898 TI - Antibody-drug conjugates: Current status and future perspectives. AB - Conventional cytotoxic agents used for the pharmacotherapy of cancer do not selectively localize at the tumor site, which may prevent dose escalation to therapeutically active regimens and may lead to undesired side effects and toxicity to normal organs. There has been a growing interest in the use of monoclonal antibodies as vehicles for the pharmacodelivery of potent cytotoxic drugs to neoplastic lesions. This novel class of targeted biopharmaceutical agents has the potential of improving activity and selectivity of cytotoxic agents. However, many technical aspects contribute to the success or failure of antibody-drug conjugates (ADCs). In this review, we summarize important pre clinical and clinical examples of early and current improvements in the field ADCs, including diversification of payloads, linkers, conjugation technologies, ADC formats and type of targets. Combination therapies of ADCs with checkpoint inhibitors are also discussed, in light of the exceptional expansion recorded in the latter space over the last five years. PMID- 27492899 TI - S100A8/A9: From basic science to clinical application. AB - Neutrophils and monocytes belong to the first line of immune defence cells and are recruited to sites of inflammation during infection or sterile injury. Both cells contain huge amounts of the heterodimeric protein S100A8/A9 in their cytoplasm. S100A8/A9 belongs to the Ca2+ binding S100 protein family and has recently gained a lot of interest as a critical alarmin modulating the inflammatory response after its release (extracellular S100A8/A9) from neutrophils and monocytes. Extracellular S100A8/A9 interacts with the pattern recognition receptors Toll-like receptor 4 (TLR4) and Receptor for Advanced Glycation Endproducts (RAGE) promoting cell activation and recruitment. Besides its biological function, S100A8/A9 (also known as myeloid related protein 8/14, MRP8/14) was identified as interesting biomarker to monitor disease activity in chronic inflammatory disorders including inflammatory bowel disease and rheumatoid arthritis. Furthermore, S100A8/A9 has been tested successfully in pre clinical imaging studies to localize sites of infection or sterile injury. Finally, recent evidence using small molecule inhibitors for S100A8/A9 also suggests that blocking S100A8/A9 activity exerts beneficial effects on disease activity in animal models of autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease. This review will provide a comprehensive and detailed overview into the structure and biological function of S100A8/A9 and also will give an outlook in terms of diagnostic and therapeutic applications targeting S100A8/A9. PMID- 27492900 TI - Platelet-vessel wall interactions and drug effects. PMID- 27492901 TI - Primary Triage in a Mass-casualty Event Possesses a Risk of Increasing Informational Confusion: A Simulation Study Using Shannon's Entropy. AB - Introduction Primary triage in a mass-casualty event setting using low-visibility tags may lead to informational confusion and difficulty in judging triage attribution of patients. In this simulation study, informational confusion during primary triage was investigated using a method described in a prior study that applied Shannon's Information Theory to triage. Hypothesis Primary triage using a low-visibility tag leads to a risk of informational confusion in prioritizing care, owing to the intermingling of pre- and post-triage patients. It is possible that Shannon's entropy evaluates the degree of informational confusion quantitatively and improves primary triage. METHODS: The Simple Triage and Rapid Treatment (START) triage method was employed. In Setting 1, entropy of a triage area with 32 patients was calculated for the following situations: Case 1 - all 32 patients in the triage area at commencement of triage; Case 2 - 16 randomly imported patients to join 16 post-triage patients; Case 3 - eight patients imported randomly and another eight grouped separately; Case 4 - 16 patients grouped separately; Case 5 - random placement of all 32 post-triage patients; Case 6 - isolation of eight patients of minor priority level; Case 7 - division of all patients into two groups of 16; and Case 8 - separation of all patients into four categories of eight each. In Setting 2, entropies in the triage area with 32 patients were calculated continuously with each increase of four post triage patients in Systems A and B (System A - triage conducted in random manner; and System B - triage arranged into four categories). RESULTS: In Setting 1, entropies in Cases 1-8 were 2.00, 3.00, 2.69, 2.00, 2.00, 1.19, 1.00, and 0.00 bits/symbol, respectively. Entropy increased with random triage. In Setting 2, entropies of System A maintained values the same as, or higher than, those before initiation of triage: 2.00 bits/symbol throughout the triage. The graphic waveform showed a concave shape and took 3.00 bits/symbol as maximal value when the probability of each category was 1/8, whereas the values in System B showed a linear decrease from 2.00 to 0.00 bits/symbol. CONCLUSION: Informational confusion in a primary triage area measured using Shannon's entropy revealed that random triage using a low-visibility tag might increase the degree of confusion. Methods for reducing entropy, such as enhancement of triage colors, may contribute to minimizing informational confusion. Ajimi Y , Sasaki M , Uchida Y , Kaneko I , Nakahara S , Sakamoto T . Primary triage in a mass-casualty event possesses a risk of increasing informational confusion: a simulation study using Shannon's entropy. Prehosp Disaster Med. 2016;31(5):498-504. PMID- 27492897 TI - Targeting the ROS-HIF-1-endothelin axis as a therapeutic approach for the treatment of obstructive sleep apnea-related cardiovascular complications. AB - Obstructive sleep apnea (OSA) is now recognized as an independent and important risk factor for cardiovascular diseases such as hypertension, coronary heart disease, heart failure and stroke. Clinical and experimental data have confirmed that intermittent hypoxia is a major contributor to these deleterious consequences. The repetitive occurrence of hypoxia-reoxygenation sequences generates significant amounts of free radicals, particularly in moderate to severe OSA patients. Moreover, in addition to hypoxia, reactive oxygen species (ROS) are potential inducers of the hypoxia inducible transcription factor-1 (HIF 1) that promotes the transcription of numerous adaptive genes some of which being deleterious for the cardiovascular system, such as the endothelin-1 gene. This review will focus on the involvement of the ROS-HIF-1-endothelin signaling pathway in OSA and intermittent hypoxia and discuss current and potential therapeutic approaches targeting this pathway to treat or prevent cardiovascular disease in moderate to severe OSA patients. PMID- 27492902 TI - Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells. AB - Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses. However, whether dectin-1 directs DCs to prime antitumour Th9 cells remains unclear. Here, we show that DCs activated by dectin-1 agonists potently promote naive CD4(+) T cells to differentiate into Th9 cells. Abrogation of dectin-1 in DCs completely abolishes their Th9-polarizing capability in response to dectin-1 agonist curdlan. Notably, dectin-1 stimulation of DCs upregulates TNFSF15 and OX40L, which are essential for dectin-1-activated DC-induced Th9 cell priming. Mechanistically, dectin-1 activates Syk, Raf1 and NF kappaB signalling pathways, resulting in increased p50 and RelB nuclear translocation and TNFSF15 and OX40L expression. Furthermore, immunization of tumour-bearing mice with dectin-1-activated DCs induces potent antitumour response that depends on Th9 cells and IL-9 induced by dectin-1-activated DCs in vivo. Our results identify dectin-1-activated DCs as a powerful inducer of Th9 cells and antitumour immunity and may have important clinical implications. PMID- 27492903 TI - Sex and Race/Ethnicity Differences in Implantable Cardioverter-Defibrillator Counseling and Use Among Patients Hospitalized With Heart Failure: Findings from the Get With The Guidelines-Heart Failure Program. AB - BACKGROUND: Previous studies have found that women and black patients eligible for a primary prevention implantable cardioverter-defibrillator (ICD) are less likely than men or white patients to receive one. METHODS: We performed an observational analysis of the Get With The Guidelines-Heart Failure Program from January 1, 2011, to March 21, 2014. Patients admitted with heart failure and an ejection fraction <=35% without an ICD were included. Rates of ICD counseling among eligible patients and ICD receipt among counseled patients were examined by sex and race/ethnicity. RESULTS: Among 21 059 patients from 236 sites, 4755 (22.6%) received predischarge ICD counseling. Women were counseled less frequently than men (19.3% versus 24.6%, P<0.001, adjusted odds ratio [OR], 0.84; 95% confidence interval [CI], 0.78-0.91). Racial and ethnic minorities were less likely to receive counseling than white patients (black 22.6%, Hispanic 18.6%, other race/ethnic group 14.4% versus white 24.3%, P<0.001 for each): adjusted OR versus white, 0.69; 95% CI, 0.63 to 0.76 for black patients; adjusted OR, 0.62; 95% CI, 0.55 to 0.70 for Hispanic patients; adjusted OR, 0.53; 95% CI, 0.43 to 0.65 for other patients. Among the 4755 counseled patients, 2977 (62.6%) received an ICD or had one planned for placement after hospital stay. Among those counseled, women and men were similarly likely to receive an ICD (adjusted OR, 1.13; 95% CI, 0.99-1.29). However, black (adjusted OR, 0.70; 95% CI, 0.56-0.88) and Hispanic patients (adjusted OR, 0.68; 95% CI, 0.46-1.01) were less likely to receive an ICD. CONCLUSIONS: Up to 4 of 5 hospitalized patients with heart failure eligible for ICD counseling did not receive it, particularly women and minority patients. Among counseled patients, ICD use differences by race and ethnicity persisted. PMID- 27492905 TI - CO2 Reduction to CO in Water: Carbon Nanotube-Gold Nanohybrid as a Selective and Efficient Electrocatalyst. AB - A gold-based nanostructure has been demonstrated as promising materials for the selective electroreduction of CO2 to CO in aqueous conditions. In this work, we present a carbon nanotube-gold nanohybrid as a selective and efficient electrocatalyst for the reduction of CO2 in 0.5 m NaHCO3 . The hybrid material exhibits remarkable activity with a current density of 10 mA cm(-2) at -0.55 V versus standard hydrogen electrode with a stable CO production rate (0.52 MUmol s(-1) ) after 4 h electrolysis. Monodispersed gold nanoparticles anchored on carbon nanotubes through a layer-by-layer method allows very little Au loading and thus minimization of the cost of electrode fabrication with a mass activity up to 100 A g(-1) at -0.55 V versus reversible hydrogen electrode. It is 33 times higher than a previous report for monodisperse Au nanoparticles (3 A g(-1) ) while ensuring selectivity (70 % faradaic yield of CO) at comparable reduction potential. PMID- 27492904 TI - Pregnancy and the Risk of Aortic Dissection or Rupture: A Cohort-Crossover Analysis. AB - BACKGROUND: Case series have described aortic dissection and rupture in pregnancy. Few population-based data exist to support an association. METHODS: We performed a cohort-crossover study using data on all emergency department visits and acute care hospitalizations at nonfederal healthcare facilities in California, Florida, and New York. We included women >=12 years of age with labor and delivery or abortive pregnancy outcome between 2005 and 2013. Our outcome was a composite of aortic dissection or rupture. Based on the timing of reported aortic complications during pregnancy, we defined the period of risk as 6 months before delivery until 3 months after delivery. We compared each patient's likelihood of aortic complications during this period with an equivalent 270-day period exactly 1 year later. Incidence rates and incidence rate ratios were computed using conditional Poisson regression with robust standard errors. RESULTS: Among 6 566 826 pregnancies in 4 933 697 women, we identified 36 cases of aortic dissection or rupture during the pregnancy or postpartum period and 9 cases during the control period 1 year later. The rate of aortic complications was 5.5 (95% confidence interval, 4.0-7.8) per million patients during pregnancy and the postpartum period, in comparison with 1.4 (95% confidence interval, 0.7 2.9) per million during the equivalent period 1 year later. Pregnancy was associated with a significantly increased risk of aortic dissection or rupture (incidence rate ratio, 4.0; 95% confidence interval, 2.0-8.2) in comparison with the control period 1 year later. CONCLUSIONS: The risk of aortic dissection or rupture is elevated during pregnancy and the postpartum period. PMID- 27492906 TI - HLA-A*23:01:19, a novel variant of HLA-A*23:01, discovered in a West African stem cell transplantation patient. AB - HLA-A*23:01:19 differs from HLA-A*23:01:01 by a single substitution in exon 4. PMID- 27492907 TI - Walking Throughout Your Day Keeps Depression (and a Host of Other Health Problems) Away. PMID- 27492908 TI - Effects of a Sedentary Behavior-Inducing Randomized Controlled Intervention on Depression and Mood Profile in Active Young Adults. AB - OBJECTIVE: To examine the effects of a free-living, sedentary behavior-inducing randomized controlled intervention on depression and mood profile. PATIENTS AND METHODS: Participants who were confirmed to be active via self-report and accelerometry were randomly assigned to either a sedentary behavior intervention group (n=26) or a control group (n=13) by using a 2:1 sample size ratio for intervention and control groups. The intervention group was asked to eliminate all exercise and minimize steps to 5000 or less steps/d for 1 week, whereas the control group was asked to continue normal physical activity levels for 1 week. Both groups completed a depression (Patient Health Questionnaire-9) and mood (Profile of Moods States) survey preintervention and immediately postintervention. The intervention group was asked to resume normal physical activity levels for 1 week postintervention and then completed the assessments for a third time. All data collection occurred between September 1, 2015, and December 1, 2015. RESULTS: Patient Health Questionnaire-9 group * time interaction analysis revealed that depression scores significantly increased from visit 1 to visit 2 (F=11.85; P=.001). Paired t tests comparing depression scores from visit 2 to visit 3 exhibited a significant decrease from visit 2 to visit 3 (P<.001). Profile of Moods States group * time interaction analysis paralleled depression results; mood scores significantly increased from visit 1 to visit 2 (F=10.03; P=.003) and significantly decreased from visit 2 to visit 3 (P<.001). CONCLUSION: A 1-week sedentary behavior-inducing intervention has deleterious effects on depression and mood. To prevent mental health decline in active individuals, consistent regular physical activity may be necessary. PMID- 27492909 TI - Physical Activity and Alzheimer Disease: A Protective Association. AB - OBJECTIVE: To explore whether being physically active can decrease Alzheimer disease (AD) risk. PARTICIPANTS AND METHODS: We conducted a meta-analysis of prospective observational cohort studies reporting the association between physical activity (PA) and incident AD. Relevant articles were identified by title and abstract in the electronic databases PubMed, ScienceDirect, and Scopus using the keywords Alzheimer, Alzheimer disease, Alzheimer's, Alzheimer's disease, physical activity, sport, exercise, sedentary, fitness, and combinations thereof for articles published in any language up to February 15, 2016. Criteria for consideration included division of the study cohort by PA levels and sample size specification for each PA level group, quantification (number) of persons who had development of AD, and PA assessment during time off work (not just work time). We followed the MOOSE (Meta-analyses of Observational Studies in Epidemiology) recommendations and used the Newcastle-Ottawa scale for study quality assessment. RESULTS: Ten high-quality studies were included in meta analysis I (23,345 participants). Follow-up ranged from 3.9 to 31 years, and the participants' age ranged from 70 to 80 years. The pooled odds ratio for development of AD in participants who were more vs less physically active was 0.65 (95% CI, 0.56-0.74; P<.001; no publication bias [P=.24] but with heterogeneity among studies [I(2)=31.32%]). We could identify participants' adherence to international PA recommendations in 5 studies, which constituted meta-analysis II (10,615 participants). The pooled odds ratio for development of AD in participants who were active vs those who were inactive was 0.60 (95% CI, 0.51-0.71; P<.001; no publication bias [P=.34] and no heterogeneity [I(2)=5.63%]). CONCLUSION: Although the limitations of self-reported PA data must be considered, regular PA performed by elderly people might play a certain protective role against AD. PMID- 27492910 TI - Effect of Preprocedural Thrombocytopenia on Prognosis After Percutaneous Coronary Intervention. AB - OBJECTIVE: To assess early and late outcomes, including bleeding, in patients with thrombocytopenia undergoing percutaneous coronary intervention (PCI). PATIENTS AND METHODS: We performed a retrospective single-center study of patients with preprocedural thrombocytopenia (platelet count <=100,000/MUL; n=204) undergoing PCI between 2003 and 2015. Inhospital and late outcomes were compared with those of a matched control group without thrombocytopenia (n=1281). RESULTS: The most common causes of thrombocytopenia were liver disease, immune mediated disease, and hematologic malignant neoplasms. Inhospital bleeding events after PCI were similar in patients with thrombocytopenia and matched controls (24 of 146 [16.4%] vs 179 of 1281 [14.0%]; P=.40) and were largely classified as minor using the Bleeding Academic Research Consortium (BARC) classification (89% BARC 1 or 2). There was no significant difference in inhospital death (4 of 146 [2.7%] vs 71 of 1281 [2.0%]; P=.56), but patients with thrombocytopenia had higher rates of platelet and red blood cell transfusion (18 of 146 [12.3%] vs 93 of 1281 [7.2%]; P=.05). During long-term follow-up, Kaplan-Meier estimated rates of bleeding events (BARC >=2) were higher for thrombocytopenia (at 5 years, 7.9% vs 3.6%; P=.03). Patients with thrombocytopenia had a similar risk of long-term cardiac mortality, but significantly higher rates of noncardiac mortality (at 5 years, 28% vs 21%; P=.02). CONCLUSION: This study suggests that short-term outcomes after PCI in patients with thrombocytopenia were favorable. On long-term follow-up, thrombocytopenia was associated with a higher risk of long-term noncardiac mortality and bleeding. PMID- 27492911 TI - Prophylactic Plasma Transfusion Before Interventional Radiology Procedures Is Not Associated With Reduced Bleeding Complications. AB - OBJECTIVE: To determine the association between prophylactic plasma transfusion and periprocedural red blood cell (RBC) transfusion rates in patients with elevated international normalized ratio (INR) values undergoing interventional radiology procedures. PATIENTS AND METHODS: In this retrospective cohort study, adult patients undergoing interventional radiology procedures with a preprocedural INR available within 30 days of the procedure during a study period of January 1, 2009, to December 31, 2013, were eligible for inclusion. Baseline characteristics, coagulation parameters, transfusion requirements, and procedural details were extracted. Univariate and multivariable propensity-matched analyses were used to assess the relationships between prophylactic plasma transfusion and the outcomes of interest, with a primary outcome assessed a priori of RBC transfusion occurring during the procedure or within the first 24 hours postprocedurally. RESULTS: A total of 18,204 study participants met inclusion criteria for this study, and 1803 (9.9%) had an INR of 1.5 or greater before their procedure. Of these 1803 patients, 196 patients (10.9%) received prophylactic plasma transfusion with a median time of 1.9 hours (interquartile range [IQR], 1.1-3.2 hours) between plasma transfusion initiation and procedure initiation. In multivariable propensity-matched analysis, plasma administration was associated with increased periprocedural RBC transfusions (odds ratio, 2.20; 95% CI, 1.38-3.50; P<.001) and postprocedural intensive care unit admission rates (odds ratio, 2.11; 95% CI, 1.41-3.14; P<.001) as compared with those who were not transfused preprocedurally. Similar relationships were seen at higher INR thresholds for plasma transfusion. CONCLUSION: In patients undergoing interventional radiology procedures, preprocedural plasma transfusions given in the setting of elevated INR values were associated with increased periprocedural RBC transfusions. Additional research is needed to clarify this potential association between preprocedural plasma transfusion and periprocedural RBC transfusion. PMID- 27492912 TI - Patient, Caregiver, and Physician Work in Heart Failure Disease Management: A Qualitative Study of Issues That Undermine Wellness. AB - OBJECTIVE: To identify factors underlying heart failure hospitalization. METHODS: Between January 1, 2012, and May 31, 2012, we combined medical record reviews and cross-sectional qualitative interviews of multiple patients with heart failure, their clinicians, and their caregivers from a large academic medical center in the Midwestern United States. The interview data were analyzed using a 3-step grounded theory-informed process and constant comparative methods. Qualitative data were compared and contrasted with results from the medical record review. RESULTS: Patient nonadherence to the care plan was the most important contributor to hospital admission; however, reasons for nonadherence were complex and multifactorial. The data highlight the importance of patient education for the purposes of condition management, timeliness of care, and effective communication between providers and patients. CONCLUSION: To improve the consistency and quality of care for patients with heart failure, more effective relationships among patients, providers, and caregivers are needed. Providers must be pragmatic when educating patients and their caregivers about heart failure, its treatment, and its prognosis. PMID- 27492913 TI - Incidence of Type 1 Diabetes Is Not Increasing in a Population-Based Cohort in Olmsted County, Minnesota, USA. AB - OBJECTIVES: To investigate the recent incidence of T1D in a US Midwestern county to determine whether this increase has been sustained and compare it with the incidence of celiac disease (CD) and also investigate the prevalence of CD, an associated autoimmune disease, within the cohort. PATIENTS AND METHODS: A broad search strategy was used to identify all incident cases of T1D in Olmsted County, Minnesota, between January 1, 1994, and December 31, 2010, using the Rochester Epidemiology Project. Diagnosis and residency status were confirmed through the medical record. Incidence rates were directly standardized to the 2010 US population. Poisson regression was used to test for a change in incidence rate. Clinical charts were reviewed to confirm case status. RESULTS: There were 233 incident cases of T1D. Directly adjusting for age and sex with respect to the 2010 US white population, the overall annual incidence of T1D was 9.2 (95% CI, 8.0-10.4) per 100,000 people per year among all ages and 19.9 (95% CI, 16.6-23.2) per 100,000 people per year for those younger than 20 years. There was no significant increase in the incidence of T1D over time (P=.45). Despite the overall stability in annual incidence, there was an initial increasing trend followed by a plateau. Of the 109 patients with T1D (47%) tested for CD, 12% (13) had biopsy-proven CD. CONCLUSION: The incidence of T1D has stopped increasing in Olmsted County, Minnesota, in the most recent decade. Further studies are needed to confirm this finding and explore reasons for this plateau. PMID- 27492914 TI - Duration of Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation in Patients With and Without Acute Coronary Syndrome: A Systematic Review of Randomized Controlled Trials. AB - In this systemic review we evaluated the efficacy and safety of long duration dual anti-platelet therapy (DAPT) (L-DAPT) compared with short duration DAPT (S DAPT) after drug-eluting stent (DES) implantation in patients who presented with or without acute coronary syndromes (ACS). We identified 8 randomized controlled trials in which 30,975 patients were randomized to S-DAPT versus L-DAPT (12,421 ACS and 18,554 non-ACS). Short duration dual anti-platelet therapy was associated with an increase in target vessel revascularization (TVR) in ACS patients, but the difference was not significant for non-ACS patients (odds ratio [OR] 5.04 [95% CI, 1.28-19.76], and OR, 0.89 [95% CI, 0.51-1.55], respectively). The risk of cardiac mortality was not significantly different with S-DAPT and L-DAPT for ACS (OR, 1.69 [95% CI, 0.82-3.50]) and non-ACS patients (OR, 0.89 [95% CI, 0.57 1.37]). For all cause mortality, myocardial infarction, and stent thrombosis, most of the events were derived from the DAPT study, thus a meta-analysis was not performed for these end points. Based on our review of the literature, we conclude that S-DAPT was associated with higher rates of stent thrombosis and myocardial infarction, and non-significant differences in all-cause mortality, with no significant interactions according to ACS vs non-ACS. However, in non-ACS patients, the benefit-risk profile favored S-DAPT, with lower all-cause mortality, whereas the trends were reversed in ACS. Additional studies are required to determine if the benefit-risk profile of S-DAPT vs L-DAPT varies according to clinical syndrome. PMID- 27492915 TI - Gas and Bloating-Controlling Emissions: A Case-Based Review for the Primary Care Provider. AB - The evaluation of the patient with gas and bloating can be complex and the treatment extremely challenging. In this article, a simplified approach to the history and relevant physical examination is presented and applied in a case oriented manner, suitable for application in the primary care setting. PMID- 27492916 TI - Common Functional Gastroenterological Disorders Associated With Abdominal Pain. AB - Although abdominal pain is a symptom of several structural gastrointestinal disorders (eg, peptic ulcer disease), this comprehensive review will focus on the 4 most common nonstructural, or functional, disorders associated with abdominal pain: functional dyspepsia, constipation-predominant and diarrhea-predominant irritable bowel syndrome, and functional abdominal pain syndrome. Together, these conditions affect approximately 1 in 4 people in the United States. They are associated with comorbid conditions (eg, fibromyalgia and depression), impaired quality of life, and increased health care utilization. Symptoms are explained by disordered gastrointestinal motility and sensation, which are implicated in various peripheral (eg, postinfectious inflammation and luminal irritants) and/or central (eg, stress and anxiety) factors. These disorders are defined and can generally be diagnosed by symptoms alone. Often prompted by alarm features, selected testing is useful to exclude structural disease. Identifying the specific diagnosis (eg, differentiating between functional abdominal pain and irritable bowel syndrome) and establishing an effective patient-physician relationship are the cornerstones of therapy. Many patients with mild symptoms can be effectively managed with limited tests, sensible dietary modifications, and over-the-counter medications tailored to symptoms. If these measures are not sufficient, pharmacotherapy should be considered for bowel symptoms (constipation or diarrhea) and/or abdominal pain; opioids should not be used. Behavioral and psychological approaches (eg, cognitive behavioral therapy) can be helpful, particularly in patients with chronic abdominal pain who require a multidisciplinary pain management program without opioids. PMID- 27492917 TI - Management of Hormone Deprivation Symptoms After Cancer. AB - Cancer survivors often experience symptoms related to hormone deprivation, including vasomotor symptoms, genitourinary symptoms, and sexual health concerns. These symptoms can occur due to natural menopause in midlife women, or they can be brought on by oncologic therapies in younger women or men. We searched PubMed for English-language studies from January 1990 through January 2016 to identify relevant articles on the management of hormone deprivation symptoms, including vasomotor, genitourinary, and sexual symptoms in patients with cancer. The search terms used included hormone deprivation, vasomotor symptoms, hot flash, vaginal dryness, sexual dysfunction, and breast cancer. This manuscript provides a comprehensive description of data supporting the treatment of symptoms associated with hormone deprivation. PMID- 27492918 TI - Gene Expression Profiling in Cutaneous Melanoma: Caveats for Clinicians. PMID- 27492919 TI - Time in Range: A Fourth Domain in Glycemic Control or a Glucose Variability Alternative? PMID- 27492920 TI - Yellowish Papules on the Palms After Water Immersion. PMID- 27492921 TI - Alzheimer Disease. PMID- 27492922 TI - The Mighty Mississippi, Summer Day, Morning on Monhegan, and Painting on Warf by Ken DeWaard. AB - Recognizing the contribution art has had in the Mayo Clinic environment since the original Mayo Clinic Building was finished in 1914, Mayo Clinic Proceedings features some of the numerous works of art displayed throughout the buildings and grounds on Mayo Clinic campuses as researched and interpreted by the author. PMID- 27492923 TI - Electroretinographic evaluations of retinal function before, just after, and after intravitreal injections. AB - Intravitreal injections (IVI) have become a part of daily practice for a growing number of procedures. We evaluated the retinal function by recording intraoperative photopic electroretinograms (ERGs) before an injection (T1), just after the injection (T2), and after the aspiration of the anterior chamber fluid (T3) of 19 eyes of 19 patients (mean age 70.6 years; men = 11) who received an IVI of an anti-vascular endothelial growth factor. The mean amplitudes of the b wave, photopic negative responses (PhNR), and oscillatory potentials (OPs) 1 and 2 at T2 were significantly smaller than that at T1, but no significant difference was observed between T3 and T1. The mean implicit times of the a-wave and OP1, 2, and 3 at T2 and the a-wave and the OP2 at T3 were significantly longer than that at T1. The mean intraocular pressure (IOP) at T2 (49.32 mm Hg) was significantly higher and the IOP at T3 (8.74 mm Hg) was significantly lower than that at T1 (21.05 mm Hg). The retinal function was reduced and the IOP elevated just after the IVI. The response of each ERG component was different suggesting a different sensitivity of each type of retinal neuron to IVI. PMID- 27492924 TI - The AMP analog AICAR modulates the Treg/Th17 axis through enhancement of fatty acid oxidation. AB - T cells must tightly regulate their metabolic processes to cope with varying bioenergetic demands depending on their state of differentiation. The metabolic sensor AMPK is activated in states of low energy supply and modulates cellular metabolism toward a catabolic state. Although this enzyme is known to be particularly active in regulatory T (Treg) cells, its impact on T helper (Th) cell differentiation is poorly understood. We investigated the impact of several AMPK activators on Treg-cell differentiation and found that the direct activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), but not the indirect activators metformin and 2-deoxyglucose, strongly enhanced Treg-cell induction by specifically enhancing Treg-cell expansion. Conversely, Th17 generation was impaired by the agent. Further investigation of the metabolic background of our observations revealed that AICAR enhanced both cellular mitochondrogenesis and fatty acid uptake. Consistently, increased Treg induction was entirely reversible on inhibition of fatty acid oxidation, thus confirming the dependence of AICAR's effects on metabolic pathways alterations. Translating our findings to an in vivo model, we found that the substance enhanced Treg cell generation on IL-2 complex induced immune stimulation. We provide a previously unrecognized insight into the delicate interplay between immune cell function and metabolism and delineate a potential novel strategy for metabolism-targeting immunotherapy.-Gualdoni, G. A., Mayer, K. A., Goschl, L., Boucheron, N., Ellmeier, W., Zlabinger, G. J. The AMP analog AICAR modulates the Treg/Th17 axis through enhancement of fatty acid oxidation. PMID- 27492926 TI - Ethics, Methods, and Measures in Intimate Partner Violence Research: The Current State of the Field. AB - Although intimate partner violence (IPV) is a well-studied topic, surprisingly little consensus among researchers has been reached with regard to the definition and measurement of its major typologies and constructs. The rigorous development and testing of prevention and intervention strategies on a large scale are hampered by many of these methodological difficulties as well as ethical considerations that make conducting IPV research difficult. The author presents a review of the current state of IPV research in these three areas (ethics, methods, and measurement) with suggestions for innovative research possibilities building from this status quo. Moving the field of IPV research forward is necessary to establish a broader evidence base for the prevention and treatment of abuse and to improve outcomes for survivors of IPV. PMID- 27492927 TI - "You Are a Part of the Solution": Negotiating Gender-Based Violence and Engendering Change in Urban Informal Settlements in Mumbai, India. AB - This article explores how women front-line workers engage with domestic and gender-based violence in the urban informal settlements of Dharavi in Mumbai, India. We conducted in-depth interviews with 13 voluntary front-line workers, along with ethnographic fieldwork in Dharavi, as a part of a pilot study. Our findings contribute to literature on context-specific approaches to understanding gender-based violence and "models" to prevent domestic violence in urban micro spaces. Furthermore, we also discuss notions of "change" ( badlaav) that the front-line workers experience. Finally, this article presents implications for socially engaged ethnographic research, as well as contextual and grounded insights on ways to reduce gender-based and domestic violence. PMID- 27492925 TI - A novel sphingomyelin/cholesterol domain-specific probe reveals the dynamics of the membrane domains during virus release and in Niemann-Pick type C. AB - We identified a novel, nontoxic mushroom protein that specifically binds to a complex of sphingomyelin (SM), a major sphingolipid in mammalian cells, and cholesterol (Chol). The purified protein, termed nakanori, labeled cell surface domains in an SM- and Chol-dependent manner and decorated specific lipid domains that colocalized with inner leaflet small GTPase H-Ras, but not K-Ras. The use of nakanori as a lipid-domain-specific probe revealed altered distribution and dynamics of SM/Chol on the cell surface of Niemann-Pick type C fibroblasts, possibly explaining some of the disease phenotype. In addition, that nakanori treatment of epithelial cells after influenza virus infection potently inhibited virus release demonstrates the therapeutic value of targeting specific lipid domains for anti-viral treatment.-Makino, A., Abe, M., Ishitsuka, R., Murate, M., Kishimoto, T., Sakai, S., Hullin-Matsuda, F., Shimada, Y., Inaba, T., Miyatake, H., Tanaka, H., Kurahashi, A., Pack, C.-G., Kasai, R. S., Kubo, S., Schieber, N. L., Dohmae, N., Tochio, N., Hagiwara, K., Sasaki, Y., Aida, Y., Fujimori, F., Kigawa, T., Nishibori, K., Parton, R. G., Kusumi, A., Sako, Y., Anderluh, G., Yamashita, M., Kobayashi, T., Greimel, P., Kobayashi, T. A novel sphingomyelin/cholesterol domain-specific probe reveals the dynamics of the membrane domains during virus release and in Niemann-Pick type C. PMID- 27492928 TI - Nanomechanical sandwich assay for multiple cancer biomarkers in breast cancer cell-derived exosomes. AB - The use of exosomes as cancer diagnostic biomarkers is technically limited by their size, heterogeneity and the need for extensive purification and labelling. We report the use of cantilever arrays for simultaneous detection of multiple exosomal surface-antigens with high sensitivity and selectivity. Exosomes from breast cancer were selectively identified by detecting over-expressed membrane proteins CD24, CD63, and EGFR. Excellent selectivity however, was achieved when targeting the cell-surface proteoglycan, Glypican-1 at extraordinary limits (~200 exosomes per mL, ~0.1 pg mL(-1)). PMID- 27492929 TI - Omnidirectional surface wave cloak using an isotropic homogeneous dielectric coating. AB - The field of transformation optics owes a lot of its fame to the concept of cloaking. While some experimental progress has been made towards free-space cloaking in three dimensions, the material properties required are inherently extremely difficult to achieve. The approximations that then have to be made to allow fabrication produce unsatisfactory device performance. In contrast, when surface wave systems are the focus, it has been shown that a route distinct from those used to design free-space cloaks can be taken. This results in very simple solutions that take advantage of the ability to incorporate surface curvature. Here, we provide a demonstration in the microwave regime of cloaking a bump in a surface. The distortion of the shape of the surface wave fronts due to the curvature is corrected with a suitable refractive index profile. The surface wave cloak is fabricated from a metallic backed homogeneous dielectric waveguide of varying thickness, and exhibits omnidirectional operation. PMID- 27492930 TI - Investigation of Disability Level, Leisure Satisfaction, and Quality of Life in Disabled Employees. AB - The purpose of this study is to investigate the disability level, leisure satisfaction, and quality of life in employees who were disabled. Six hundred twenty-seven employees who were disabled were included in this study and classified according to age, gender and disability level. In quality of life, there was significant difference between genders and age groups (p < .05). There was no significant difference neither in leisure satisfaction nor in disability level between groups (p > .05). In disability assessment, males were better and there was a significant difference in leisure satisfaction (p < .05). Age, gender, and disability level were important factors affecting disability, leisure satisfaction, and quality of life among employees who were disabled. PMID- 27492931 TI - Strength and Comprehensiveness of School Wellness Policies in Southeastern US School Districts. AB - BACKGROUND: In 2004, Congress passed legislation mandating that all public school districts participating in federal school meal programs develop a school wellness policy (SWP) to direct efforts related to nutrition and physical activity. We examined the extent to which SWPs varied in comprehensiveness and strength in a representative sample of school districts in the southeastern United States, the area of the country with the highest rates of childhood obesity. METHODS: Policies were assessed using an established 96-item coding tool by 2 raters to ascertain the comprehensiveness and strength of the policies as a whole, and across distinct subsections specified by federal legislation. In addition, variability in SWP comprehensiveness and strength was assessed based on district sociodemographic characteristics. RESULTS: Overall, SWPs in the southeastern states are weakly written, fragmented, and lack requirements necessary for healthy school environments. District size, which was the only sociodemographic factor related to policy characteristics, yielded an inverse association. CONCLUSIONS: To encourage continued promotion of healthy school environments, school districts will require technical support to improve the quality of their school wellness policies. PMID- 27492932 TI - Associations Between Adolescents' Weight and Maladjustment Differ With Deviation From Weight Norms in Social Contexts. AB - BACKGROUND: In line with the reflected self-appraisal hypothesis, previous research finds associations between weight and maladjustment are strongest when there is a mismatch between individuals' weight and the weight norm of their social contexts. However, research has not considered associations in more proximal social contexts. We examined differences in associations between weight and maladjustment for 2 proximal social contexts: grade-level peers and friendship groups. METHODS: We used sixth-graders (N = 565; Mage = 12 years) self-reported height and weight (used to calculate body mass index (BMI) z score), experiences of peer victimization, and depressive symptoms. Deviation from the normative weight was calculated as the students' BMI z-score minus the average BMI z-score for the context (grade-level peers or friendship group). RESULTS: Considering deviations from grade-level peers, greater BMI z-scores were associated with more self-reported peer victimization only for students above the weight norm. For the friendship group, greater weight was associated with more self-reported depressive symptoms only for those who were above the normative weight. CONCLUSIONS: Being heavier during adolescence may be especially problematic for students who differ from the norm in their proximal social contexts. Intervention efforts focused on weight and maladjustment may want to consider the contexts involved in adolescents' self-appraisals. PMID- 27492933 TI - "Headache Tools to Stay in School": Assessment, Development, and Implementation of an Educational Guide for School Nurses. AB - BACKGROUND: Headache is the most common type of pain reported in the pediatric population, and chronic headache is an increasingly prevalent and debilitating pain condition in children and adolescents. With large numbers of students experiencing acute headaches and more students with chronic headache reentering typical school settings, greater availability of tailored evidence-based practice guidelines for school nurses is imperative. METHODS: A 2-armed study was developed to assess the need for and evaluate the use and favorability of a headache-driven school nurse guide. Students and their parents were first surveyed on their school nurse's headache knowledge and management skills. School nurses were also interviewed on their desire for a headache educational tool. This feedback aided in developing a headache resource guide. Next, the guide was distributed to school nurses who provided feedback after a 3-month trial. RESULTS: Results indicate that "Headache Tools to Stay in School" is a useful resource in facilitating communication among health care providers, students, families, and school personnel on how to best meet the complex needs of students with headaches. CONCLUSIONS: Given the guide's favorability, we encourage school nurses to demand the creation of additional evidence-based resources. Continued dissemination of this guide may improve students' headache management under the informed care of school nurses, and may encourage the development of more evidence-based guides across various medical conditions. PMID- 27492934 TI - Bigger ? Better: The Comprehensiveness and Strength of School Wellness Policies Varies by School District Size. AB - BACKGROUND: District size has been shown to impact the anticipated barriers to wellness policy creation and implementation. Therefore, the purpose of the present study was to determine if strength and comprehensiveness of wellness policies differs among school districts of varying size. METHODS: Wellness policies were collected from 10 large, 29 medium, and 31 small school districts in a rural Midwest state. District size was categorized by the average daily membership in grades 9-11. Polices were coded using the Wellness School Assessment Tool (WellSAT). Strength and comprehensiveness of the full policy and policy sections were compared among small, medium, and large districts using 1 way analyses of variance (ANOVAs). Data are presented as mean +/- SD. Statistical significance was set at p <= .05. RESULTS: There was a difference in the total combined (p = .041), total comprehensiveness (p = .043), and total strength scores (p = .031) based on school district size, such that small districts had stronger, more comprehensive wellness policies than large districts. Section comparisons revealed the section focused on Standards for United States Department of Agriculture School Meals was primarily responsible for these differences. CONCLUSIONS: These data suggest smaller districts write policies that are more comprehensive to governmental standards and use more definitive language than larger districts. PMID- 27492935 TI - Support for Offering Sexual Health Services Through School-Based Health Clinics. AB - BACKGROUND: Numerous studies document support for sexuality education in the schools. However, there is a dearth of research assessing support for sexual health services offered through school-based health clinics (SBHCs). The purpose of this study was to assess voter support for offering 3 sexual health services (STI/HIV testing, STI/HIV treatment, condom distribution) through SBHCs. METHODS: The survey was developed after review of existing surveys on support for sexuality education and sexual health services. The university's Public Opinion Research Laboratory used random-digit-dialing to administer the survey to participants (N = 311) including residential and cell phone numbers. RESULTS: Most participants were supportive of offering sexual health services at both middle schools (MS) and high schools (HS): testing for STIs/HIV (61% MS, 76% HS), treatment for STIs/HIV (60% MS, 75% HS), and provision of condoms (44% MS, 63% HS). Analyses showed significant differences in support for sexual health services by a few demographic variables, opinions about sexuality education, and the percentage of students perceived to have had sexual intercourse. CONCLUSIONS: Results document support for offering sexual health services through SBHCs. These findings may benefit other communities looking to implement similar clinics. Such services have great potential for positively impacting the sexual health of youth. PMID- 27492936 TI - Implementation in Practice: Adaptations to Sexuality Education Curricula in California. AB - BACKGROUND: Local implementation of evidence-based curricula, including sex education, has received increasing attention. Although there are expectations that practitioners will implement evidence-based programs with fidelity, little is known regarding the experiences of instructors in meeting such standards. During 2005 to 2009, the California Department of Public Health funded local agencies through its Teen Pregnancy Prevention Programs (TPP) to provide comprehensive sex education. METHODS: To improve understanding of how agencies implemented curricula, in-depth telephone interviews with 128 coordinators were conducted in 2008 to 2009. Qualitative data were analyzed for content and themes. Selected data were quantified and analyzed to examine differences in curriculum adaptations across settings and curricula type. RESULTS: Whereas over half of the TPP agencies (59%) implemented evidence-based curricula, most agencies (95%) reported adapting the curriculum, with the majority (83%) adding content. Reasons for adaptations included ensuring that the material was accurate and appropriate; responding to logistical or time constraints; and other factors, such as parental and institutional support. CONCLUSION: These adaptations reflected agencies' efforts to balance state and local requirements, maintain curriculum fidelity, and provide more up-to-date and accessible information. These experiences highlight the need for guidelines that enable appropriate adaptations, while maintaining fidelity to the core components of the original curriculum. PMID- 27492937 TI - Reliability and Validity of the PAQ-C Questionnaire to Assess Physical Activity in Children. AB - BACKGROUND: Physical activity (PA) assessment by questionnaire is a cornerstone in the field of sport epidemiology studies. The Physical Activity Questionnaire for Children (PAQ-C) has been used widely to assess PA in healthy school populations. The aim of this study was to evaluate the reliability and validity of the PAQ-C questionnaire in Spanish children using triaxial accelerometry as criterion. METHODS: Eighty-three (N = 46 boys, N = 37 girls) healthy children (age 10.98 +/- 1.17 years, body mass index 19.48 +/- 3.51 kg/m(2) ) were volunteers and completed the PAQ-C twice and wore an accelerometer for 8 consecutive days. Reliability was analyzed by the intraclass correlation coefficient (ICC) and the internal consistency by the Cronbach's alpha coefficient. The PAQ-C was compared against total PA and moderate to vigorous PA (MVPA) obtained by accelerometry. RESULTS: Test-retest reliability showed an ICC = 0.96 for the final score of PAQ-C. Small differences between first and second questionnaire administration were detected. Few and low correlations (rho = 0.228 0.278, all ps < .05) were observed between PAQ-C and accelerometry. The highest correlation was observed for item 9 (rho = 0.311, p < .01). CONCLUSIONS: PAQ-C had a high reliability but a questionable validity for assessing total PA and MVPA in Spanish children. Therefore, PA measurement in children should not be limited only to self-report measurements. PMID- 27492938 TI - Association Between Physical Fitness and Academic Achievement in a Cohort of Danish School Pupils. AB - BACKGROUND: Time spent on physical activity in elementary school has been altered to improve core academics. However, little is known about the relationship between physical fitness and academic achievement. We examined the association between physical fitness and academic achievement and investigated the influence of parental socioeconomic status and ethnicity. METHODS: Participants were 542 girls and 577 boys aged 13 to 15 residing in the Danish municipality of Aalborg. A watt-max cycle ergometer test was completed to evaluate physical fitness as represented by VO2 max (mL.kg(-1) .min(-1) ). Academic achievement was measured 1 school year later through a series of mandatory exams within the humanities, sciences, and all obligatory defined exams. Parental income and education were drawn from nationwide registers. Linear regression models were used to investigate the association. RESULTS: Adjusting for ethnicity and parental socioeconomic status, the effect size of the humanities was 0.08 grad/VO2 max (95% Cl: 0.05 to 0.11) for girls and 0.06 grad/VO2 max (95% Cl:0.03 to 0.08) for boys. The effect size of the sciences was 0.09 grad/VO2 max (95% Cl:0.05 to 0.13) for girls and 0.06 grad/VO2 max (95% Cl:0.03 to 0.09) for boys. The effect size of the defined exams was 0.09 grad/VO2 max (95% Cl:0.06 to 0.11) for girls and 0.06 grad/VO2 max (95% Cl:0.03 to 0.08) for boys. CONCLUSION: We found a statistically significant positive association between physical fitness and academic achievement after adjusting for ethnicity and parental socioeconomic status. PMID- 27492939 TI - Blood pressure and complications in individuals with type 2 diabetes and no previous cardiovascular disease: national population based cohort study. AB - OBJECTIVES: To compare the risk associated with systolic blood pressure that meets current recommendations (that is, below 140 mm Hg) with the risk associated with lower levels in patients who have type 2 diabetes and no previous cardiovascular disease. DESIGN: Population based cohort study with nationwide clinical registries, 2006-12. The mean follow-up was 5.0 years. SETTING: 861 Swedish primary care units and hospital outpatient clinics. PARTICIPANTS: 187 106 patients registered in the Swedish national diabetes register who had had type 2 diabetes for at least a year, age 75 or younger, and with no previous cardiovascular or other major disease. MAIN OUTCOME MEASURES: Clinical events were obtained from the hospital discharge and death registers with respect to acute myocardial infarction, stroke, a composite of acute myocardial infarction and stroke (cardiovascular disease), coronary heart disease, heart failure, and total mortality. Hazard ratios were estimated for different levels of baseline systolic blood pressure with clinical characteristics and drug prescription data as covariates. RESULTS: The group with the lowest systolic blood pressure (110 119 mm Hg) had a significantly lower risk of non-fatal acute myocardial infarction (adjusted hazard ratio 0.76, 95% confidence interval 0.64 to 0.91; P=0.003), total acute myocardial infarction (0.85, 0.72 to 0.99; P=0.04), non fatal cardiovascular disease (0.82, 0.72 to 0.93; P=0.002), total cardiovascular disease (0.88, 0.79 to 0.99; P=0.04), and non-fatal coronary heart disease (0.88, 0.78 to 0.99; P=0.03) compared with the reference group (130-139 mm Hg). There was no indication of a J shaped relation between systolic blood pressure and the endpoints, with the exception of heart failure and total mortality. CONCLUSIONS: Lower systolic blood pressure than currently recommended is associated with significantly lower risk of cardiovascular events in patients with type 2 diabetes. The association between low blood pressure and increased mortality could be due to concomitant disease rather than antihypertensive treatment. PMID- 27492940 TI - Preparation and Characterization of Antimony and Arsenic Tricyanide and Their 2,2'-Bipyridine Adducts. AB - The arsenic(III) and antimony(III) cyanides M(CN)3 (M=As, Sb) have been prepared in quantitative yields from the corresponding trifluorides through fluoride cyanide exchange with Me3 SiCN in acetonitrile. When the reaction was carried out in the presence of one equivalent of 2,2'-bipyridine, the adducts [M(CN)3 ?(2,2' bipy)] were obtained. The crystal structures of As(CN)3 , [As(CN)3 ?(2,2'-bipy)] and [Sb(CN)3 ?(2,2'-bipy)] were determined and are surprisingly different. As(CN)3 possesses a polymeric three-dimensional structure, [As(CN)3 ?(2,2'-bipy)] exhibits a two-dimensional sheet structure, and [Sb(CN)3 ?(2,2'-bipy)] has a chain structure, and none of the structures resembles those found for the corresponding arsenic and antimony triazides. PMID- 27492941 TI - Cardiac rehabilitation increases physical capacity but not mental health after heart valve surgery: a randomised clinical trial. AB - OBJECTIVE: The evidence for cardiac rehabilitation after valve surgery remains sparse. Current recommendations are therefore based on patients with ischaemic heart disease. The aim of this randomised clinical trial was to assess the effects of cardiac rehabilitation versus usual care after heart valve surgery. METHODS: The trial was an investigator-initiated, randomised superiority trial (The CopenHeartVR trial, VR; valve replacement or repair). We randomised 147 patients after heart valve surgery 1:1 to 12 weeks of cardiac rehabilitation consisting of physical exercise and monthly psycho-educational consultations (intervention) versus usual care without structured physical exercise or psycho educational consultations (control). Primary outcome was physical capacity measured by VO2 peak and secondary outcome was self-reported mental health measured by Short Form-36. RESULTS: 76% were men, mean age 62 years, with aortic (62%), mitral (36%) or tricuspid/pulmonary valve surgery (2%). Cardiac rehabilitation compared with control had a beneficial effect on VO2 peak at 4 months (24.8 mL/kg/min vs 22.5 mL/kg/min, p=0.045) but did not affect Short Form 36 Mental Component Scale at 6 months (53.7 vs 55.2 points, p=0.40) or the exploratory physical and mental outcomes. Cardiac rehabilitation increased the occurrence of self-reported non-serious adverse events (11/72 vs 3/75, p=0.02). CONCLUSIONS: Cardiac rehabilitation after heart valve surgery significantly improves VO2 peak at 4 months but has no effect on mental health and other measures of exercise capacity and self-reported outcomes. Further research is needed to justify cardiac rehabilitation in this patient group. TRIAL REGISTRATION NUMBER: NCT01558765, Results. PMID- 27492942 TI - Clinical and prognostic value of poststenting fractional flow reserve in acute coronary syndromes. AB - OBJECTIVES: Fractional flow reserve (FFR) has been suggested to have value in acute coronary syndromes (ACSs). The clinical and prognostic value of ischaemia reduction assessed by post-percutaneous coronary intervention (PCI) FFR has not been studied in this population. METHODS: Consecutive stable ischaemic heart disease (SIHD) (N=390) and patients with ACS (N=189) who had pre-PCI FFR and post PCI FFR were followed for 2.4+/-1.5 years. Primary endpoint was major adverse cardiac events (MACE) (composite of myocardial infarction, target vessel revascularisation and death). RESULTS: In patients with ACS, PCI led to significant improvement in FFR from 0.62+/-0.15 to post-PCI FFR 0.88+/-0.08 (p<0.0001). Post-PCI FFR identified 29 patients (15%) who had persistently low FFR<0.80 (0.75+/-0.06) despite angiographically optimal results prompting subsequent interventions improving repeat FFR (0.85+/-0.06; p<0.0001). The difference in MACE events between patients with ACS and patients with SIHD varied according to the post-PCI FFR value (interaction p=0.044). Receiver operator curve analysis identified a final FFR cut-off of <=0.91 as having the best predictive accuracy for MACE in the ACS study population (30% vs 19%; p=0.03). Patients with ACS achieving final FFR of >0.91 had similar outcomes compared with patients who had SIHD (19% vs 16%; p=0.51). However, in patients with final FFR of <=0.91 there was increased MACE versus patients with SIHD (30% vs 16%; p<0.01). CONCLUSIONS: Post-PCI FFR is valuable in assessing the functional outcome of PCI in patients with ACS. Use of post-PCI FFR in patients with ACS allows for functional optimisation of PCI results and is predictive of long-term outcomes in patients with ACS. PMID- 27492943 TI - Left atrial appendage occlusion in high-risk patients with non-valvular atrial fibrillation. AB - OBJECTIVE: Percutaneous left atrial appendage (LAA) occlusion has been developed as a viable option for stroke and thromboembolism prevention in patients with non valvular atrial fibrillation (NVAF) and at high risk for cerebral cardioembolic events. Data on device implantation and long-term follow-up from large cohorts are limited. METHODS: 110 consecutive patients with NVAF and contraindications to oral anticoagulants (OACs) underwent LAA occlusion procedures and achieved a longer than 1 year follow-up. All patients were enrolled in a prospective registry. Procedures were performed using the Amplatzer Cardiac Plug or Amulet guided by fluoroscopy and intracardiac echocardiography. RESULTS: Mean age of the population was 77+/-6 years old; 68 were men. Atrial fibrillation was paroxysmal in 20%, persistent in 15.5% and permanent in 64.5% of cases, respectively. Mean CHA2DS2-VASc and HAS-BLED scores were 4.3+/-1.3 and 3.4+/-1, respectively. Technical success (successful deployment and implantation of device) was achieved in 100% of procedures. Procedural success (technical success without major procedure-related complications) was achieved in 96.4%, with a 3.6% rate of major procedural complications (three cases of pericardial tamponade requiring drainage and one case of major bleeding). Mean follow-up was 30+/-12 months (264 patient years). Annual rates for ischaemic stroke and for other thromboembolic events were respectively 2.2% and 0%, and annual rate for major bleeding was 1.1%. CONCLUSIONS: Our data suggest LAA occlusion in high-risk patients with NVAF not suitable for OACs is feasible and associated with low complication rates as well as low rates of stroke and major bleeding at long-term follow-up. PMID- 27492944 TI - Factors Affecting Attenuation of Dural Sinuses on Noncontrasted Computed Tomography Scan. AB - BACKGROUND AND PURPOSE: Noncontrasted computed tomography (NCCT) is used as the initial neuroimaging test of choice for patients who present with new-onset neurological symptoms. An apparently hyperattenuated venous sinus may lead to the suspicion of cerebral venous sinus thrombosis (CVST). Improved understanding of all factors that can affect attenuation of dural sinuses can guide triage of patients to or from further investigations of suspected CVST. The purpose of this retrospective study was to assess the effect of different factors including hematocrit (HCT), hemoglobin (Hb), age, BUN/Cr ratio (blood urea nitrogen-to creatinine ratio), and gender on the attenuation of dural sinuses on brain NCCT. METHODS: A total of 1293 patients with neurological symptoms who presented to the emergency department were included in this study. For each patient, clinical assessment, laboratory investigations, and brain NCCT were reviewed. For each brain NCCT, the average attenuation of superior sagittal sinus and both right and left sigmoid sinuses was measured. RESULTS: Positive significant correlations were found between average attenuation of dural sinuses on one hand and each of age, Hb, and HCT on the other hand. No significant correlation was found between average attenuation and BUN/Cr ratio. Gender discrepancy was also significant as higher attenuation was found in men. CONCLUSION: Age, gender, and Hb levels are the main factors that should be taken into account upon the assessment of dural sinuses on brain NCCT. The highest normal attenuation is predicted in an elderly polycythemic man and the lowest is predicted in a young anemic woman. PMID- 27492945 TI - Medical Decision Making: Hyposphagma Prior to Intravenous Tissue Plasminogen Activator in Acute Ischemic Stroke. AB - The decision to administer intravenous tissue plasminogen activator (IV tPA) is based on standard exclusion and inclusion criteria, which include laboratories, imaging, and time of last known well. When patients present with a clinical scenario that is not addressed in these standards, the decision to administer IV tPA is more complex. We present a case of a patient with an acute stroke syndrome that also included acute subconjunctival hemorrhage (i.e., hyposphagma). We provide the medical decision making that occurred prior to the administration. Ultimately, the finding of hyposphagma should not disqualify eligible patients from receiving IV tPA. PMID- 27492946 TI - Detection of Atrial Fibrillation with Intermittent Handheld Electrocardiogram in Patients with Ischemic Stroke and Transient Ischemic Attack. AB - BACKGROUND: Atrial fibrillation is an important risk factor for recurrent ischemic stroke and transient ischemic attack. Despite routine investigation, some patients' atrial fibrillation remains undetected. Intermittent handheld electrocardiogram (ECG) is an option for extended ECG monitoring aiming at enhancing detection rates. This study aimed to explore the detection rate of atrial fibrillation in stroke and transient ischemic attack patients with intermittent handheld ECG in the clinical setting of Halland Hospital Halmstad. METHODS: Patients discharged with a diagnosis of ischemic stroke or transient ischemic attack who underwent intermittent handheld ECG recording at Halland Hospital Halmstad from January 1, 2010, to March 31, 2014, were retrospectively studied; 370 patients in total. A positive investigation was defined as either atrial fibrillation for a minimum of 10 seconds or a short irregular supraventricular run. RESULTS: We found an overall atrial fibrillation detection rate of 7.6% (95% CI 5.1%-10.1%). The detection rate in stroke patients (11.0%) was significantly higher than in transient ischemic attack patients (5.0%), P = .032. The detection rate in patients aged less than 65 years was 4.2%, increasing to 9.8% in patients aged 65 years or older, P = .051. CONCLUSION: This retrospective study shows an atrial fibrillation detection rate of 7.6% in a stroke and transient ischemic attack population using prolonged intermittent monitoring with handheld ECG recording. The compliance to the monitoring was excellent. PMID- 27492947 TI - Continuous Monitoring of Spreading Depolarization and Cerebrovascular Autoregulation after Aneurysmal Subarachnoid Hemorrhage. AB - Delayed cerebral ischemia (DCI) is a prominent complication after aneurysmal subarachnoid hemorrhage (aSAH). Although vasospasm of proximal cerebral arteries has been regarded as the main cause of DCI, vasospasm of distal arteries, microthrombosis, impaired autoregulation, cortical spreading depolarization (CSD), and spreading ischemia are thought to be involved in DCI after aSAH. Here, we describe a patient with aSAH in whom CSD and cerebrovascular autoregulation were evaluated using simultaneous electrocorticography and monitoring of the pressure reactivity index (PRx) after surgical clipping of a ruptured posterior communicating artery aneurysm. In this patient, a prolonged duration of CSD and elevation of PRx preceded delayed neurological deficit. Based on this observation, we propose a relationship between these factors and DCI. Assessment of cerebrovascular autoregulation may permit detection of the inverse hemodynamic response to cortical depolarization. Detection of DCI may be achieved through simultaneous monitoring of CSD and PRx in patients with aSAH. PMID- 27492948 TI - Influence of sonophoresis on transdermal drug delivery of hydrophilic compound loaded lipid nanocarriers. AB - The effect of sonophoresis on the transdermal drug delivery of sodium fluorescein (NaFI)-loaded lipid nanocarriers such as liposomes (LI), niosomes (NI) and solid lipid nanoparticles (SLN) was investigated by confocal laser scanning microscopy (CLSM), fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The results showed that SN decreased the skin penetration of NaFI-loaded SLN (6.32-fold) and NI (1.79-fold), while it increased the penetration of NaFI-loaded LI (5.36-fold). CLSM images showed the red fluorescence of the LI and NI bilayer on the superficial layer of the stratum corneum. However, the red fluorescent probe of the SLN was not visualized in the skin. FTIR results of the LI and NI with SN showed no effect on lipid stratum corneum ordering, suggesting that the fragment of bilayer vesicles might repair the damaged skin. For SLN, the strengthening of stratum corneum by covering the disrupted skin with solid lipids was shown. SEM images show disrupted carriers of all the formulations adsorbed onto the damaged skin. In conclusion, the SN changed the properties of both the skin surface and lipid nanocarrier, demonstrating that disrupted skin might be repaired by a disrupted nanocarrier. PMID- 27492949 TI - An atypical role for the myeloid receptor Mincle in central nervous system injury. AB - The C-type lectin Mincle is implicated in innate immune responses to sterile inflammation, but its contribution to associated pathologies is not well understood. Herein, we show that Mincle exacerbates neuronal loss following ischemic but not traumatic spinal cord injury. Loss of Mincle was beneficial in a model of transient middle cerebral artery occlusion but did not alter outcomes following heart or gut ischemia. High functional scores in Mincle KO animals using the focal cerebral ischemia model were accompanied by reduced lesion size, fewer infiltrating leukocytes and less neutrophil-derived cytokine production than isogenic controls. Bone marrow chimera experiments revealed that the presence of Mincle in the central nervous system, rather than recruited immune cells, was the critical regulator of a poor outcome following transient middle cerebral artery occlusion. There was no evidence for a direct role for Mincle in microglia or neural activation, but expression in a subset of macrophages resident in the perivascular niche provided new clues on Mincle's role in ischemic stroke. PMID- 27492951 TI - Translational Relevance of Swine Models of Spinal Cord Injury. AB - Spinal cord injury (SCI) is a physically and psychologically devastating clinical condition. The typical treatment regimens of decompressive surgery and rehabilitation therapy still leave many patients with permanent disability. The development of new therapies and devices can be accelerated if relevant translational animal models are more effectively used in pre-clinical stages. Swine is a highly relevant model for SCI research, especially with respect to spine and spinal cord anatomy, spine vasculature, immune responses to injury, and functional assessments. Several spine injury models have recently been developed for swine and are beginning to be used to evaluate new therapies. Swine models of SCI offer tremendous advantages for efficient translation of pre-clinical discoveries and the development of new therapies and devices. Future swine models will also be enhanced by advances in gene-editing technology to further elucidate the complex pathophysiology associated with SCI and provide a means to engineer specific spinal pathologies. PMID- 27492952 TI - Analytical Eco-Scale for Assessing the Greenness of a Developed RP-HPLC Method Used for Simultaneous Analysis of Combined Antihypertensive Medications. AB - In the past few decades the analytical community has been focused on eliminating or reducing the usage of hazardous chemicals and solvents, in different analytical methodologies, that have been ascertained to be extremely dangerous to human health and environment. In this context, environmentally friendly, green, or clean practices have been implemented in different research areas. This study presents a greener alternative of conventional RP-HPLC methods for the simultaneous determination and quantitative analysis of a pharmaceutical ternary mixture composed of telmisartan, hydrochlorothiazide, and amlodipine besylate, using an ecofriendly mobile phase and short run time with the least amount of waste production. This solvent-replacement approach was feasible without compromising method performance criteria, such as separation efficiency, peak symmetry, and chromatographic retention. The greenness profile of the proposed method was assessed and compared with reported conventional methods using the analytical Eco-Scale as an assessment tool. The proposed method was found to be greener in terms of usage of hazardous chemicals and solvents, energy consumption, and production of waste. The proposed method can be safely used for the routine analysis of the studied pharmaceutical ternary mixture with a minimal detrimental impact on human health and the environment. PMID- 27492950 TI - Changes in intracranial venous blood flow and pulsatility in Alzheimer's disease: A 4D flow MRI study. AB - Cerebral blood flow, arterial pulsation, and vasomotion may be important indicators of cerebrovascular health in aging and diseases of aging such as Alzheimer's disease. Noninvasive markers that assess these characteristics may be helpful in the study of co-occurrence of these diseases and potential additive and interacting effects. In this study, 4D flow MRI was used to measure intra cranial flow features with cardiac-gated phase contrast MRI in cranial arteries and veins. Mean blood flow and pulsatility index as well as the transit time of the peak flow from the middle cerebral artery to the superior sagittal sinus were measured in a total of 104 subjects comprising of four groups: (a) subjects with Alzheimer's disease, (b) age-matched controls, (c) subjects with mild cognitive impairment, and (d) a group of late middle-aged with parental history of sporadic Alzheimer's disease. The Alzheimer's disease group exhibited: a significant decrease in mean blood flow in the superior sagittal sinus, transverse sinus, middle cerebral artery, and internal carotid arteries; a significant decrease of the peak and end diastolic blood flow in the middle cerebral artery and superior sagittal sinus; a faster transmission of peak flow from the middle cerebral artery to the superior sagittal sinus and increased pulsatility index along the carotid siphon. PMID- 27492953 TI - Posterior Distal Clavicle Beveling for Chronic Nonincarcerated Type IV Acromioclavicular Separations: Surgical Technique and Early Clinical Outcomes. AB - PURPOSE: To describe the arthroscopic partial posterior distal clavicle beveling technique for treatment of chronic nonincarcerated type IV acromioclavicular (AC) separations and report clinical outcomes and return to sport. METHODS: All patients who underwent the arthroscopic partial distal clavicle beveling technique and met eligibility criteria were identified and retrospectively reviewed. Inclusion criteria included the clinical diagnosis of a chronic nonincarcerated type IV AC separation and a minimum follow-up period of 24 months. Subjects completed the American Shoulder Elbow Surgeons shoulder assessment and a study-designed questionnaire. Radiographic images and clinical charts were also reviewed. RESULTS: This study identified 15 consecutive patients with 2 lost to follow-up, resulting in inclusion of 13 subjects (9 males and 4 females). Dominant arm was involved in 77% of cases. Mean age at operation was 33.2 years (range, 19-56 years). The mean period between injury and operation was 12.5 months (range, 3-37 months), and follow-up was 48.5 months (range, 24-126 months). The mean preoperative ASES score was 46.6 +/- 16.9 (range, 33-68), and the mean postoperative ASES score was 87.3 +/- 17.4 (range, 50-100) (P < .0001). All 9 athletes in the study returned to competition with a mean recovery period of 2.3 months (range, 2 weeks to 4 months). Mean timeframe for return to work was 2 weeks (range, 1 day to 2 months). One subject underwent a subsequent coracoclavicular ligament reconstruction for continued pain. The mean satisfaction level was 4.3 out of 5, and 91% would choose to have the surgery again. One subject indicated dissatisfaction with shoulder appearance. CONCLUSIONS: The arthroscopic partial distal clavicle beveling procedure for nonincarcerated type IV AC separations resulted in a significant reduction in pain, improved daily function, and early return to sport. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 27492954 TI - Genomic control of neuronal demographics in the retina. AB - The mature retinal architecture is composed of various types of neuron, each population differing in size and constrained to particular layers, wherein the cells achieve a characteristic patterning in their local organization. These demographic features of retinal nerve cell populations are each complex traits controlled by multiple genes affecting different processes during development, and their genetic determinants can be dissected by correlating variation in these traits with their genomic architecture across recombinant-inbred mouse strains. Using such a resource, we consider how the variation in the numbers of twelve different types of retinal neuron are independent of one another, including those sharing transcriptional regulation as well as those that are synaptically connected, each mapping to distinct genomic loci. Using the populations of two retinal interneurons, the horizontal cells and the cholinergic amacrine cells, we present in further detail examples where the variation in neuronal number, as well as the variation in mosaic patterning or in laminar positioning, each maps to discrete genomic loci where allelic variants modulating these features must be present. At those loci, we identify candidate genes which, when rendered non functional, alter those very demographic properties, and in turn, we identify candidate coding or regulatory variants that alter protein structure or gene expression, respectively, being prospective contributors to the variation in phenotype. This forward-genetic approach provides an alternative means for dissecting the molecular genetic control of neuronal population dynamics, with each genomic locus serving as a causal anchor from which we may ultimately understand the developmental principles responsible for the control of those traits. PMID- 27492955 TI - H-NS: an overarching regulator of the Vibrio cholerae life cycle. AB - Vibrio cholerae has become a model organism for studies connecting virulence, pathogen evolution and infectious disease ecology. The coordinate expression of motility, virulence and biofilm enhances its pathogenicity, environmental fitness and fecal-oral transmission. The histone-like nucleoid structuring protein negatively regulates gene expression at multiple phases of the V. cholerae life cycle. Here we discuss: (i) the regulatory and structural implications of H-NS chromatin-binding in the two-chromosome cholera bacterium; (ii) the factors that counteract H-NS repression; and (iii) a model for the regulation of the V. cholerae life cycle that integrates H-NS repression, cyclic diguanylic acid signaling and the general stress response. PMID- 27492961 TI - Novel super-resolution capable mitochondrial probe, MitoRed AIE, enables assessment of real-time molecular mitochondrial dynamics. AB - Mitochondria and mitochondrial dynamics play vital roles in health and disease. With the intricate nanometer-scale structure and rapid dynamics of mitochondria, super-resolution microscopy techniques possess great un-tapped potential to significantly contribute to understanding mitochondrial biology and kinetics. Here we present a novel mitochondrial probe (MitoRed AIE) suitable for live mitochondrial dynamics imaging and single particle tracking (SPT), together with a multi-dimensional data analysis approach to assess local mitochondrial (membrane) fluidity. The MitoRed AIE probe localizes primarily to mitochondrial membranes, with 95 ms fluorophore on-time delivering 106 photons/ms, characteristics which we exploit to demonstrate live cell 100 fps 3D time-lapse tracking of mitochondria. Combining our experimental and analytical approaches, we uncover mitochondrial dynamics at unprecedented time scales. This approach opens up a new regime into high spatio-temporal resolution dynamics in many areas of mitochondrial biology. PMID- 27492962 TI - Vonoprazan is superior to proton pump inhibitors in healing artificial ulcers of the stomach post-endoscopic submucosal dissection: A propensity score-matching analysis. AB - BACKGROUND AND AIM: Proton pump inhibitors (PPI) are effective at healing artificial ulcers after endoscopic submucosal dissection (ESD) for gastric neoplasms; however, the efficacy of vonoprazan is not completely understood. The aim of the present study was to determine the healing effect of vonoprazan on artificial ulcers post-gastric ESD relative to PPI. METHODS: Thirty-five patients who underwent gastric ESD between April and November 2015 were treated with vonoprazan 20 mg/day for 4 weeks and subsequently underwent endoscopy for evaluation of ulcer size (V group). Ulcer contraction rate was determined by the following formula: ([ESD specimen size] - [ulcer size at 4 weeks after ESD])/(ESD specimen size) * 100%. We compared the results with those of a historical control group treated with esomeprazole 20 mg/day for 4 weeks after gastric ESD and subsequently measured their ulcer size (33 patients, E group) by propensity score matching methods. RESULTS: Sixty-two subjects were enrolled after propensity score-matching. Ulcer contraction rate at 4 weeks after ESD in the V group was significantly higher than that of the E group (97.7 +/- 3.2% vs 94.5 +/- 6.7%, respectively, P = 0.025). Number of subjects with a scar-stage ulcer (100% contraction rate) tended to be higher in the V group relative to the E group (32% [10 of 31] vs 13% [4 of 31], respectively, P = 0.070, McNemar's chi-squared test). CONCLUSION: Vonoprazan has a faster post-gastric ESD artificial ulcer contraction rate than esomeprazole. Vonoprazan may supersede PPI in treating post ESD artificial ulcers of the stomach. PMID- 27492963 TI - Isolation and Physical Property Optimization of an Amorphous Drug Substance Utilizing a High Surface Area Magnesium Aluminometasilicate (Neusilin((r)) US2). AB - Control and optimization of the physical properties of a drug substance (DS) are critical to the development of robust drug product manufacturing processes and performance. A lack of isolatable, for example, crystalline, DS solid forms can present challenges to achieving this control. In this study, an isolation scheme for an amorphous DS was developed and integrated into the synthetic route producing DS with optimized properties. An inert absorbent excipient (Neusilin(r) US2) was used to isolate the DS via a novel antisolvent scheme as the final step of the route. Isolation was executed at kilogram scale utilizing conventional equipment. The resulting 50 wt% DS:Neusilin complex had improved physical stability and exceptional micromeritic and tableting properties. Improved dissolution was observed and attributed to enhanced dispersion and increased surface area. Characterization data suggest a high degree of penetration of the DS into the Neusilin, with DS occupying 70% of mesopore and 12% of macropore volume. This approach has application in the isolation and particle engineering of difficult to isolate DS without additional unit operation, such as spray drying, and has the potential for a high degree of optimization and control of physical properties over the course of DS development. PMID- 27492964 TI - Medication-induced diabetes mellitus. AB - Epidemiological studies and case reports have demonstrated an increased rate of development of diabetes mellitus consequent to taking diverse types of medication. This review explores this evidence linking these medications and development of diabetes and presents postulated mechanisms by which the medications might cause diabetes. Some medications are associated with a reduction in insulin production, some with reduction in insulin sensitivity, and some appear to be associated with both reduction in insulin production and insulin sensitivity. PMID- 27492965 TI - Agonist-induced internalization and desensitization of the apelin receptor. AB - Apelin acts via the G protein-coupled apelin receptor (APJ) to mediate effects on cardiovascular and fluid homeostasis. G protein-coupled receptor (GPCR) trafficking has an important role in the regulation of receptor signalling pathways and cellular functions, however in the case of APJ the mechanisms and proteins involved in apelin-induced trafficking are not well understood. We generated a stable HEK-293 cell line expressing N-terminus HA-tagged mouse (m) APJ, and used a semi-automated imaging protocol to quantitate APJ trafficking and ERK1/2 activation following stimulation with [Pyr1]apelin-13. The mechanisms of [Pyr1]apelin-13-induced internalization and desensitization were explored using dominant-negative mutant (DNM) cDNA constructs of G protein-coupled receptor kinase 2 (GRK2), beta-arrestin1, EPS15 and dynamin. The di-phosphorylated ERK1/2 (ppERK1/2) response to [Pyr1]apelin-13 desensitized during sustained stimulation, due to upstream APJ-specific adaptive changes. Furthermore, [Pyr1]apelin-13 stimulation caused internalization of mAPJ via clathrin coated vesicles (CCVs) and also caused a rapid reduction in cell surface and whole cell HA-mAPJ. Our data suggest that upon continuous agonist exposure GRK2-mediated phosphorylation targets APJ to CCVs that are internalized from the cell surface in a beta arrestin1-independent, EPS15- and dynamin-dependent manner. Internalization does not appear to contribute to the desensitization of APJ-mediated ppERK1/2 activation in these cells. PMID- 27492966 TI - Effects of thyroid hormone transporters MCT8 and MCT10 on nuclear activity of T3. AB - Transport of thyroid hormone (TH) across the plasma membrane is necessary for the genomic action of T3 mediated by its nuclear T3 receptor. MCT8 and MCT10 have been identified as important TH transporters. Mutations in MCT8 result in severe psychomotor retardation. In addition to TH transport into the cell, MCT8 and MCT10 also facilitate TH efflux from cells. Therefore, the aim of this study was to examine if MCT8 and MCT10 increase the availability of T3 for its nuclear receptor rather than generate a rapid equilibrium between cellular and serum T3. T3 action was investigated in JEG3 cells co-transfected with TRbeta1 and a T3 response element-driven luciferase construct, and T3 metabolism was analyzed in cells transfected with type 3 deiodinase (D3). In addition, cells were transfected with MCT8 or MCT10 and/or the cytoplasmic T3-binding protein mu crystallin (CRYM). Luciferase signal was markedly stimulated by incubating cells for 24 h with 1 nM T3, but this response was not augmented by MCT8 or MCT10 expression. Limiting the time of T3 exposure to 1-6 h and co-transfection with CRYM allowed for a modest increase in luciferase response to T3. In contrast, T3 metabolism by D3 was potently stimulated by MCT8 or MCT10 expression, but it was not affected by expression of CRYM. These results suggest that MCT8 and MCT10 by virtue of their bidirectional T3 transport have less effect on steady-state nuclear T3 levels than on T3 levels at the cell periphery where D3 is located. CRYM alters the dynamics of cellular TH transport but its exact function in the cellular distribution of TH remains to be determined. PMID- 27492968 TI - Water-Soluble Metallocene-Containing Polymers. AB - Metallocenes are organometallic compounds with reversible redox profiles and tunable oxidation and reduction potentials, depending on the metal and substituents at the cyclopentadienyl rings. Metallocenes have been introduced in macromolecules to combine the redox-activity with polymer properties. There are many examples of such hydrophobic polymer materials, but much fewer water-soluble examples are found scattered across the polymer literature. However, in terms of drug delivery and other biological applications, water solubility is essential. For this very reason, all the synthetic routes to water-soluble metallocene containing polymers are collected and discussed here. The focus is on neutral ferrocene- and ruthenocene-containing and charged cobaltocenium-containing macromolecules (i.e., symmetrical sandwich complexes). The synthetic protocols, self-assembly behavior, and other benefits of the obtained materials are discussed. PMID- 27492967 TI - Perinatal management: What has been learned through the network? AB - The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) has examined the effects of various obstetrical perinatal interventions and neonatal delivery room practices on the newborn with particular focus on those born preterm. Studies exploring the effects and safety of various antepartum maternal medications and the effects of the route and timing of delivery are examined. The NRN has contributed key studies to the evidence base for the International Liaison Committee on Resuscitation neonatal resuscitation guidelines. These studies are reviewed including research on timing of cord clamping, the importance of maintaining euthermia immediately after birth, delivery room ventilation strategies, outcomes following delivery room cardiopulmonary resuscitation, and the effects of prolonged resuscitation efforts. In addition, the NRN's detailed outcome data at the lowest gestational ages have greatly influenced on how providers counsel families regarding the appropriateness of resuscitation efforts at the lowest gestational ages. PMID- 27492970 TI - QT interval and drug therapy (Clinical review from Drug and Therapeutics Bulletin). PMID- 27492969 TI - The Arabidopsis SUMO E3 Ligase AtMMS21 Dissociates the E2Fa/DPa Complex in Cell Cycle Regulation. AB - Development requires the proper execution and regulation of the cell cycle via precise, conserved mechanisms. Critically, the E2F/DP complex controls the expression of essential genes during cell cycle transitions. Here, we discovered the molecular function of the Arabidopsis thaliana SUMO E3 ligase METHYL METHANESULFONATE SENSITIVITY GENE21 (AtMMS21) in regulating the cell cycle via the E2Fa/DPa pathway. DPa was identified as an AtMMS21-interacting protein and AtMMS21 competes with E2Fa for interaction with DPa. Moreover, DPa is a substrate for SUMOylation mediated by AtMMS21, and this SUMOylation enhances the dissociation of the E2Fa/DPa complex. AtMMS21 also affects the subcellular localization of E2Fa/DPa. The E2Fa/DPa target genes are upregulated in the root of mms21-1 and mms21-1 mutants showed increased endoreplication. Overexpression of DPa affected the root development of mms21-1, and overexpression of AtMMS21 completely recovered the abnormal phenotypes of 35S:E2Fa-DPa plants. Our results suggest that AtMMS21 dissociates the E2Fa/DPa complex via competition and SUMOylation in the regulation of plant cell cycle. PMID- 27492971 TI - Ethnic Differences in Bony Hip Morphology in a Cohort of 445 Professional Male Soccer Players. AB - BACKGROUND: Participation in high-impact athletic activities has recently been associated with a higher prevalence of cam deformity. Bony hip morphology has also emerged as an important factor in the development of hip osteoarthritis. However, it is unknown whether bony morphology differs between ethnicities in athletes participating in high-impact sports. PURPOSE: To investigate whether the prevalence of specific bony hip morphological abnormalities differed between professional male soccer players of diverse ethnic backgrounds. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Professional male soccer players from an entire league attending preparticipation screening were invited to participate in this study. Ethnicity was registered, and standardized radiographs of anteroposterior pelvic and Dunn views were obtained. Cam and pincer deformity, and acetabular dysplasia were quantified using the alpha angle, triangular index, and lateral center-edge angle (LCEA). Regression analyses with generalized estimating equations were used to determine prevalence differences in bony hip morphology. RESULTS: A total of 445 male soccer players (890 hips; mean age +/- SD, 25 +/- 4.9 years) participated in the study, representing the following ethnic groups: Arabic (59%), black (24%), Persian (7%), white (6%), East Asian (2%), and other (2%). The prevalence of cam deformity (alpha angle >60 degrees ) ranged from 57.5% to 71.7% across 4 of the groups, but East Asians had a significantly lower prevalence (18.8%; P <= .032). A large cam deformity (alpha angle >78 degrees ) was more prevalent in white (33.3%) compared with black soccer players (17.8%; P = .041) and was absent in East Asian players. Pincer deformity (LCEA >40 degrees ) was uncommon (3%) in all ethnicities. The prevalence of acetabular dysplasia (LCEA <20 degrees ) ranged from 8.0% to 16.7%, apart from the white group, in which prevalence was only 1.9% (P = .03). CONCLUSION: The prevalence of a cam deformity and acetabular dysplasia differed between ethnicities in this cohort of professional male soccer players. These findings suggest that there may be ethnic differences in both acetabular morphology and femoral bony response to athletic load. PMID- 27492972 TI - Twenty-Year Outcome of a Longitudinal Prospective Evaluation of Isolated Endoscopic Anterior Cruciate Ligament Reconstruction With Patellar Tendon or Hamstring Autograft. AB - BACKGROUND: Long-term prospective studies of isolated endoscopic anterior cruciate ligament (ACL) reconstruction are limited and may include confounding factors. PURPOSE: This study aimed to compare the outcomes of isolated ACL reconstruction using the patellar tendon (PT) autograft and the hamstring (HT) autograft in 180 patients over 20 years. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 180 participants undergoing isolated ACL reconstruction between 1993 and 1994 were prospectively recruited. Evaluation was performed at 1, 2, 5, 7, 10, 15, and 20 years after surgery and included the International Knee Documentation Committee (IKDC) knee ligament evaluation with radiographic evaluation, KT-1000 arthrometer side-to-side difference, and subjective scores. RESULTS: Over 20 years, there were 16 patients (18%) and 9 patients (10%) with an ACL graft rupture in the HT and PT groups, respectively (P = .13). ACL graft rupture was associated with male sex (odds ratio [OR], 3.9; P = .007), nonideal tunnel position (OR, 3.6; P = .019), and age <18 years at the time of surgery (OR, 4.6; P = .003). The odds of a contralateral ACL rupture were increased in patients with the PT graft compared with patients with the HT graft (OR, 2.2; P = .02) and those aged <18 years at the time of surgery (OR, 3.4; P = .001). The mean IKDC scores at 20-year follow-up were 86 and 89 for the PT and HT groups, respectively (P = .18). At 20 years, 53% and 57% of the PT and HT groups participated in strenuous or very strenuous activities (P = .55), kneeling pain was present in 63% and 20% of the PT and HT groups (P = .018), and radiographic osteoarthritic change was found in 61% and 41% of the PT and HT groups (P = .008), respectively. CONCLUSION: Compared with patients who received the HT graft, patients who received the PT graft had significantly worse outcomes with regard to radiologically detectable osteoarthritis, kneeling pain, and contralateral ACL injury. At 20-year follow-up, both HT and PT autografts continued to provide good subjective outcomes and objective stability. However, further ACL injury is common, particularly in male individuals, younger patients, and those with tunnel malposition. PMID- 27492973 TI - Anthelmintic Niclosamide Disrupts the Interplay of p65 and FOXM1/beta-catenin and Eradicates Leukemia Stem Cells in Chronic Myelogenous Leukemia. AB - PURPOSE: Leukemia stem cells (LSC), which are insensitive to tyrosine kinase inhibitors (TKI), are an important source of TKI resistance and disease relapse in chronic myelogenous leukemia (CML). Obstacles to eradicating LSCs include limited understanding of the regulation network of LSCs. The current study aimed to examine the interplay between NF-kappaB and FOXM1/beta-catenin, and the effect of its chemical intervention on CML LSCs. EXPERIMENTAL DESIGN: The interplay between NF-kappaB and FOXM1/beta-catenin was analyzed by reciprocal coimmunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP) assay in CML cells. The effect of disturbing NF-kappaB and FOXM1/beta-catenin by niclosamide on the self-renewal capacity and survival of LSCs was evaluated in vitro in human primary CML CD34+ cells and in vivo in CML mice. RESULTS: Reciprocal co-IP experiments showed physical interaction of p65 and FOXM1. p65 promoted transcription of FOXM1 gene. ChIP assay revealed recruitment of p65 on the promoter of FOXM1 gene. Conversely, FOXM1 and beta-catenin positively regulated the nuclear translocation and transcriptional activity of NF-kappaB in CML cells. Niclosamide disrupted the positive feedback loop between NF-kappaB and FOXM1/beta-catenin, thereby impairing the self-renewal capacity and survival of CML LSCs. Niclosamide decreased the long-term engraftment of human CML LSCs in NOD-SCID IL2Rgamma chain-deficient (NOG) mice, and prolonged the survival of CML mice. CONCLUSIONS: Interaction of p65 with FOXM1/beta-catenin is critical in CML and its disruption by niclosamide eradicates LSCs. These findings may improve the understanding of a self-renewal regulatory mechanism of LSCs and offer a rationale-based approach to eliminate LSCs in CML. Clin Cancer Res; 23(3); 789 803. (c)2016 AACR. PMID- 27492974 TI - Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-Associated Neutrophils through CCL15-CCR1 Axis. AB - PURPOSE: We have reported loss of SMAD4 promotes expression of CCL15 from colorectal cancer to recruit CCR1+ myeloid cells through the CCL15-CCR1 axis, which contributes to invasion and liver metastasis. However, the molecular mechanism of lung metastasis is yet to be elucidated. Our purpose is to determine whether similar mechanism is involved in the lung metastasis of colorectal cancer. EXPERIMENTAL DESIGN: In a mouse model, we examined whether SMAD4 could affect the metastatic activity of colorectal cancer cells to the lung through the CCL15-CCR1 axis. We immunohistochemically analyzed expression of SMAD4, CCL15, and CCR1 with 107 clinical specimens of colorectal cancer lung metastases. We also characterized the CCR1+ myeloid cells using several cell-type-specific markers. RESULTS: In a mouse model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1+ cells, promoting their metastatic activities to the lung. Immunohistochemical analysis of lung metastases from colorectal cancer patients revealed that CCL15 expression was significantly correlated with loss of SMAD4, and that CCL15-positive metastases recruited approximately 1.9 times more numbers of CCR1+ cells than CCL15-negative metastases. Importantly, patients with CCL15-positive metastases showed a significantly shorter relapse-free survival (RFS) than those with CCL15-negative metastases, and multivariate analysis indicated that CCL15 expression was an independent predictor of shorter RFS. Immunofluorescent staining showed that most CCR1+ cells around lung metastases were tumor-associated neutrophil, although a minor fraction was granulocytic myeloid-derived suppressor cell. CONCLUSIONS: CCL15-CCR1 axis may be a therapeutic target to prevent colorectal cancer lung metastasis. CCL15 can be a biomarker indicating poor prognosis of colorectal cancer patients with lung metastases. Clin Cancer Res; 23(3); 833-44. (c)2016 AACR. PMID- 27492975 TI - Effect of consumption of chicory inulin on bowel function in healthy subjects with constipation: a randomized, double-blind, placebo-controlled trial. AB - : Constipation is among the most common health impairments in Western countries. This study aimed to determine the effect of the chicory-derived fermentable dietary fiber Orafti(r) Inulin on stool frequency in healthy subjects with constipation. The study was conducted according to recent guidance documents for investigating bowel function and used a randomized, double-blind, placebo controlled, cross-over design with a 2-week wash-out phase. Each study period comprised a run-in phase followed by 4 weeks daily intake of 3 * 4g inulin or maltodextrin (placebo). Forty-four healthy volunteers with constipation documented stool frequency and consistency, gastrointestinal characteristics and quality of life. Consumption of Orafti(r) Inulin significantly increased stool frequency compared to placebo (median 4.0 [IQR 2.5-4.5] versus 3.0 [IQR 2.5-4.0] stools/week, p = 0.038). This was accompanied by a softening of stools and trend toward higher satisfaction versus placebo (p = 0.059). In conclusion, Orafti(r) Inulin was effective in volunteers with chronic constipation and significantly improved bowel function. CLINICAL TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov as NCT02548247. PMID- 27492977 TI - Mutagenic induction of an ultra-fast water-chain proton wire. AB - Replacement of the hydroxyl group of a hydrophilic sidechain by an H atom in the proton wire of GFP induces formation of a water-chain proton wire. Surprisingly, this "non-native" water chain functions as a proton wire with response times within 10 ps of the wild type protein. This remarkable rate retention is understood as a natural consequence of the well-known Grotthuss mechanism of proton transfer in water. PMID- 27492976 TI - Lectin inhibits antigen-antibody reaction in a glycoform-specific manner: Application for detecting alpha2,6sialylated-carcinoembryonic antigen. AB - Carcinoembryonic antigen (CEA) is a glycoprotein marker, which is widely used for diagnosing various cancers, especially colon adenocarcinoma. In addition, CEA mediates homotypic adhesion of colon adenocarcinoma cells, which appears to favor hematogenous metastasis. CEA carries alpha2,6sialyl residues on its N-glycans whereas a normal counterpart, normal fecal antigen-2, does alpha2,3sialyl residues, suggesting that cancer-specific alpha2,6sialylation on CEA may play a role for cell invasion and metastasis. A simple and rapid estimation of alpha2,6sialyled CEA in detergent extracts from formalin-fixed colon adenocarcinoma by "lectin inhibition" is reported. In the lectin inhibition method, Sambucus sieboldiana Agglutinin (SSA) lectin, an alpha2,6sialic acid binder, was used as a glycoform-specific inhibitor for antigen-antibody reaction in ELISA. Detergent extracts from colon adenocarcinoma showed a fair amount of ELISA signal in the absence of SSA whereas the signal was markedly reduced (45~74%) in the presence of SSA, suggesting that the extracts contains alpha2,6sialyled CEA. The presence of alpha2,6sialyled CEA in the extracts was confirmed by lectin microarray, in which SSA, Sambucus nigra agglutinin, and Trichosanthes japonica agglutinin I lectins were used as alpha2,6sialyl binders. Thus lectin inhibition is a simple and rapid method for detecting alpha2,6sialyled CEA even in crude detergent extracts from formalin-fixed adenocarcinoma tissue. PMID- 27492978 TI - Satisfaction Levels and Factors Influencing Satisfaction With Use of a Social App for Neonatal and Pediatric Patient Transfer Information Systems: A Questionnaire Study Among Doctors. AB - BACKGROUND: The treatment of neonatal and pediatric patients is limited to certain medical institutions depending on treatment difficulty. Effective patient transfers are necessary in situations where there are limited medical resources. In South Korea, the government has made a considerable effort to establish patient transfer systems using various means, such as websites, telephone, and so forth. However, in reality, the effort has not yet been effective. OBJECTIVE: In this study, we ran a patient transfer information system using a social app for effective patient transfer. We analyzed the results, satisfaction levels, and the factors influencing satisfaction. METHODS: Naver Band is a social app and mobile community application which in Korea is more popular than Facebook. It facilitates group communication. Using Naver Band, two systems were created: one by the Neonatal Intensive Care Unit and the other by the Department of Pediatrics at Chonbuk National University Children's Hospital, South Korea. The information necessary for patient transfers was provided to participating obstetricians (n=51) and pediatricians (n=90). We conducted a survey to evaluate the systems and reviewed the results retrospectively. RESULTS: The number of patients transferred was reported to increase by 65% (26/40) obstetricians and 40% (23/57) pediatricians. The time taken for transfers was reported to decrease by 72% (29/40) obstetricians and 59% (34/57) pediatricians. Satisfaction was indicated by 83% (33/40) obstetricians and 89% (51/57) pediatricians. Regarding factors influencing satisfaction, the obstetricians reported communication with doctors in charge (P=.03) and time reduction during transfers (P=.02), whereas the pediatricians indicated review of the diagnosis and treatment of transferred patients (P=.01) and the time reduction during transfers (P=.007). CONCLUSIONS: The users were highly satisfied and different users indicated different factors of satisfaction. This finding implies that users' requirements should be accommodated in future developments of patient transfer information systems. PMID- 27492979 TI - Human papillomavirus (HPV): making the case for 'Immunisation for All'. AB - Human papillomavirus (HPV) contributes to the most common sexually transmitted infections, with repeated and persistent infection with particular types causing disease in both men and women. Infection with low-risk HPV types can lead to genital warts and benign lesions of the oral cavity, while high-risk types can cause various HPV-related malignancies. The incidence of head and neck cancers has been rising in the past number of decades mostly due to oropharyngeal cancer linked to HPV infection. HPV vaccination has been shown to be effective for cervical and other anogenital HPV-related cancers, and there is significant potential for HPV vaccination to prevent oropharyngeal cancers, given that the HPV types implicated in this disease can be protected against by the HPV vaccine. Few countries have implemented a universal HPV vaccination programme for males and females, with many countries arguing that female-only vaccination programmes protect males via herd immunity and that men who have sex with men will be protected via targeted vaccination programmes. We argue these may be limited in their effectiveness. We propose that the most effective, practical, ethical and potentially cost-effective solution is universal HPV vaccination that might lead to control of HPV-related diseases in men and women alike. PMID- 27492980 TI - Complement C3a predicts outcome in cardiac resynchronization therapy of heart failure. AB - BACKGROUND: The chronic inflammation plays an important role in heart failure and complement components might be useful markers of the prognosis. We set out to evaluate their predictive value in the clinical outcomes of patients with cardiac resynchronization therapy (CRT). METHODS: We determined the complement levels C3, C3a, sC5b-9 and also the N-terminus of the prohormone brain natriuretic peptide (NT-proBNP) of 126 heart failure patients in a prospective, single-center observational study before and 6 months after CRT implantation. RESULTS: CRT reduced the C3a [212.5 (148.2-283.6) vs. 153 (119.8-218.3) ng/mL, p < 0.0001] and the sC5b-9 levels [296.9 (234.2-358.8) vs. 255.1 (210.1-319.0) ng/mL, p = 0.0006], but not the total C3 levels [1.43 (1.26-1.61) vs. 1.38 (1.23-1.57) g/L, p = 0.57]. C3a predicted the 5-year mortality of the patients [C3a > 165 ng/mL hazard ratio = 4.21 (1.65-10.72), p = 0.003] independent of the NT-proBNP and other factors. After reclassification, we observed a significant net reclassification improvement [NRI = 0.71 (0.43-0.98), p < 0.0001] and integrated discrimination improvement [IDI = 0.08 (0.03-0.12), p = 0.0002]. CONCLUSIONS: In patients with CRT, elevated C3a levels increase the risk of mortality independent of the NT-proBNP levels or other factors. CRT exerts anti-inflammatory effect by reducing the complement activation. PMID- 27492981 TI - Breastfeeding Support in Spanish Neonatal Intensive Care Units and the Baby Friendly Hospital Initiative. AB - BACKGROUND: The Baby-Friendly Hospital Initiative (BFHI) has a positive effect on breastfeeding in maternity wards; however, few studies have examined to what degree it affects care in neonatal intensive care units (NICUs). Recently, the BFHI has been adapted to the NICUs (Neo-BFHI). OBJECTIVE: This study aimed to compare breastfeeding support in Spanish NICUs in hospitals with BFHI accreditation or in the process of being accredited (group 1) with NICUs in hospitals that have not yet begun this initiative (group 2). METHODS: A validated questionnaire on breastfeeding support was distributed to level II and III NICUs in Spanish public hospitals. A univariate analysis and an analysis adjusted for the number of beds in NICUs were conducted. The results of the analysis of 36 breastfeeding support measures are presented in accordance with the Ten Steps to Successful Breastfeeding adapted to NICUs. RESULTS: Of the 141 participating NICUs, 129 (91%) responded to the questionnaire: 38 NICUs from group 1 and 91 NICUs from group 2. Group 1 had implemented a higher number of breastfeeding support measures than group 2. There were significant differences in 18 measures related to steps 2, 4, 5, 7, and 8 of the Neo-BFHI. In addition, a comparison of NICUs in hospitals with full accreditation (7 of 129) with those in group 2 revealed significant differences in 7 measures pertaining to steps 2, 5, 8, and 9. CONCLUSION: The Spanish NICUs in hospitals with BFHI accreditation or in the process of being accredited have better implementation of practices to promote and support breastfeeding. PMID- 27492982 TI - Developmental programmed cell death during asymmetric microsporogenesis in holocentric species of Rhynchospora (Cyperaceae). AB - Members of the Cyperaceae family exhibit an asymmetric microsporogenesis that results in the degeneration of three out of four meiotic products. Efforts have been made previously to describe the resulting structure, named the pseudomonad, but mechanisms concerning the establishment of cell domains, nuclear development, and programmed cell death are largely unknown. Using the Rhynchospora genus as a model, evidence for cell asymmetry, cytoplasmic isolation, and programmed cell death was obtained by a combination of electron microscopic, cytochemical, immunocytochemical, in situ hybridization, and flow cytometric methods. Degenerative cells were identified at the abaxial region, with the cytoskeleton marking their delimitation from the functional domain after meiosis. After attempting to initiate cell division with an unreplicated genome and abnormal spindle assembly, these cells exhibited a gradual process of cytoplasmic contraction associated with hypermethylation of cytosines and differential loss of DNA. These results indicate that the asymmetric tetrad establishes a functional cell, where one nucleus is preferentially selected to survive. Degenerative haploid cells are then eliminated in a multistep process associated with mitotic disorder, non-random elimination of repetitive DNA, vacuolar cell death, and DNA fragmentation. PMID- 27492983 TI - Virtual evaluation for CAD-CAM-fabricated complete dentures. AB - New treatment concepts for complete denture fabrication, including digital components, may increase the predictability of the treatment outcome. The reduced number of appointments, improved biocompatibility of the materials, opportunity to copy the outline of existing dentures, possibility of a virtual evaluation, and reduction of costs have changed the treatment workflow considerably. This becomes even more important against the background of an aging population. The innovative approach presented describes the combination of an impression-occlusal rim with a 3-dimesional face scan that allows a virtual evaluation, which might complement or even replace the traditional evaluation of a conventional tooth arrangement. PMID- 27492984 TI - Effect of incorporating seed oils on the antifungal property, surface roughness, wettability, weight change, and glucose sorption of a soft liner. AB - STATEMENT OF PROBLEM: The colonization of Candida albicans on soft liners causes the deterioration of material surface properties and denture stomatitis. PURPOSE: The purpose of this in vitro study was to investigate the effect of incorporating seed oil on the antifungal properties, surface roughness, wettability, weight changes, and glucose adsorption/absorption of a soft liner. MATERIAL AND METHODS: Centratherum anthelminticum, Ocimum sanctum Linn, and Linum usitatissimum seed oils were incorporated into a soft liner, and the diameter of the inhibition zone (DIZ) was calculated relative to the growth of C albicans at 24, 48, and 72 hours and 7 days. The effect of incorporating oil on wettability was evaluated with the contact angle analyzer, and effect on surface roughness was evaluated with scanning electron microscopy. Weight changes and absorption/adsorption of glucose to the soft liner were estimated. Data were analyzed by using paired Student t tests and 2-way ANOVA (alpha=.01). RESULTS: Soft liner with 800 MUL each of C anthelminticum and O sanctum oils showed complete inhibition at 72 hours; the DIZ on day 7 were 31.66 +/-1.20 mm and 29.66 +/-1.46 mm, respectively. The change in weight between time intervals differed significantly between conditions (P<.01). The addition of oils decreased the surface roughness and improved wettability significantly for O sanctum and C anthelminticum specimens (P<.01). At 72 hours, 5.5 mg of glucose was detected in the positive control, whereas no glucose was detected in the oil specimens. CONCLUSIONS: The addition of the seed oils of C anthelminticum and O sanctum to the soft liner significantly reduced the growth of C albicans, improved wettability, reduced surface roughness, and minimized the absorption and adsorption of glucose. PMID- 27492985 TI - Accuracy of torque-limiting devices: A comparative evaluation. AB - STATEMENT OF PROBLEM: To prevent the loosening of implant screws, clinicians should be aware of the output torque values needed to achieve the desired preload. Accurate torque-control devices are crucial in this regard; however, little information is currently available comparing the accuracy of mechanical with that of electronic torque-control devices. PURPOSE: The purpose of this in vitro study was to identify and compare the accuracy of different types of torque control devices. MATERIAL AND METHODS: Devices from 5 different dental implant manufacturers were evaluated, including 2 spring-type (Straumann, Implance) mechanical devices (MTLD), 2 friction-type (Biohorizons, Dyna) MTLDs, and 1 (Megagen) electronic torque-control device (ETLD). For each manufacturer, 5 devices were tested 5 times with a digital torque tester, and the average for each device was calculated and recorded. The percentage of absolute deviations from the target torque values (PERDEV) were calculated and compared by using 1 way ANOVA. A 1-sample t test was used to evaluate the ability of each device to achieve its target torque value within a 95% confidence interval for the true population mean of measured values (alpha=.05 for all statistical analyses). RESULTS: One-way ANOVAs revealed statistically significant differences among torque-control devices (P<.001). ETLD showed higher PERDEVs (28.33 +/-9.53) than MTLDs (P<.05), whereas PERDEVS of friction-type (7.56 +/-3.64) and spring-type (10.85 +/-4.11) MTLDs did not differ significantly. In addition, devices produced by Megagen had a significantly higher (P<.05) PERDEV (28.33 +/-9.53) other devices, whereas no differences were found in devices manufactured by Biohorizons (7.31 +/-5.34), Dyna (7.82 +/-1.08), Implance (8.43 +/-4.77), and Straumann (13.26 +/-0.79). However, 1-sample t tests showed none of the torque-control devices evaluated in this study were capable of achieving their target torque values (P<.05). CONCLUSIONS: Within the limitations of this in vitro study, MTLDs were shown to be significantly more accurate than ETLDs. However, none of the torque-control devices evaluated were able to meet their target torque values successfully. PMID- 27492986 TI - Percutaneous implant retention of a nasal prosthesis. AB - This report describes an approach to the simultaneous retention of a nasal prosthesis and an intraoral prosthesis for a patient who had undergone a total rhinectomy with resection of the upper lip and premaxilla. At the time of the nasal resection, 2 dental implants were placed adjacent to the resection margins in the first premolar positions. These were used to anchor an intraoral, milled titanium bar and overdenture to replace the missing anterior teeth and provide support for the upper lip, which had been reconstructed with a vascularized radial forearm free-flap. The titanium bar also incorporated a connection for a tissue-penetrating percutaneous nasal extension, which pierced the radial forearm flap near the junction with the hard palate. Magnetic attachments screwed to the nasal extension retained a nasal prosthesis. The predictable and straightforward implementation of this novel concept with digital design and manufacture of the titanium components and guided placement of the nasal extension was made possible with software planning. PMID- 27492987 TI - Oral rehabilitation of patients with Chediak-Higashi syndrome using zygoma and root form implant-supported fixed prostheses: A report of two patients. AB - Chediak-Higashi syndrome (CH-S) is a rare genetic immunodeficiency disorder. Fewer than 500 individuals with CH-S have been reported worldwide in the past 20 years. The dental management of patients in whom CH-S has been diagnosed has been rarely reported and only in the form of a case report. All reports addressed the severe periodontal disease found in those patients, and most studies concluded that periodontal treatment had an unfavorable prognosis. As a result, complete edentulism at an early age because of severe periodontal disease is expected. The purpose of this report was to present 2 patients with CH-S seeking oral rehabilitation after early tooth loss and severe bone resorption as a manifestation of severe periodontal disease. The treatment used bilateral zygoma implants and an all-on-4 concept. The complications encountered and management with a 5-year post-surgery follow-up are also presented. PMID- 27492988 TI - Clinical guidelines and procedures for provision of mandibular overdentures on 4 mini-dental implants. AB - This article describes the flapless placement of mini-dental implants (MDI) to retain mandibular overdentures. Clinical inclusion/exclusion criteria and clinical protocols for the flapless placement of MDIs and for retrofitting the overdenture are presented. A minimum bone height of 13 mm and a minimal flap are recommended. After drilling, the 4 implants are placed with a self-tapping process. A minimum of 15 Ncm of resistance upon final insertion indicates that immediate loading can be performed. The metal housings with O-rings are incorporated into the prosthesis using autopolymerizing resin. The technique and protocol for immediately loaded 4-mini-implant mandibular overdentures is minimally invasive and cost effective. PMID- 27492989 TI - WITHDRAWN: Comments regarding: Janyavula S, Lawson N, Cakir D, Beck P, Ramp LC, Burgess JO. The wear of polished and glazed zirconia against enamel. J Prosthet Dent 2013;109:22-9. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 27492990 TI - Computer-guided implant planning using a preexisting removable partial dental prosthesis. AB - Converting a conventional removable partial dental prosthesis (RPDP) into an implant-assisted removable partial dental prosthesis (IARPDP) may be facilitated by using data from the intaglio surface of the RPDP for proper implant placement. This procedure can be done by connecting the data from the intaglio surface of the RPDP to the residual ridge data of the cone beam computed tomography scan with implant planning software. However, although a misplaced implant under an RPDP can cause various complications, as yet, no technique has connected the information on a patient's existing RPDP to the implant planning software. This article presents computer-guided implant planning, using a patient's existing RPDP. PMID- 27492991 TI - Abdominal aortic aneurysm repair in New Zealand: a validation of the Australasian Vascular Audit. AB - BACKGROUND: In New Zealand (NZ), there are two major sources of operative data for abdominal aortic aneurysm (AAA) repair: the Australasian Vascular Audit (AVA) and the National Minimum Data Set (NMDS). Since the introduction of the AVA in NZ, there has not been any attempt at the validation of outcome data. The aims of this study were to report the outcomes of AAA repair and validate the AAA data captured by AVA using the NMDS. METHODS: AAA procedures performed in NZ from January 2010 to December 2014 were extracted from the AVA and NMDS. Patients identified from the AVA had their survival status matched to the NMDS. Only primary AAA procedures were included for the analysis, with re-interventions and graft infections excluded. Demographical, risk factors and outcome data were used for validation. RESULTS: The number of patients undergoing primary AAA procedure from AVA and NMDS was 1713 and 2078, respectively. The AVA inpatient mortality for elective and rupture AAA was 1.6 and 32.2%, respectively. The NMDS 30-day mortality from AAA was 2.5 and 31.5%. Overall, 1604 patients were available for matching, and the NMDS correctly reported 98.1% of endovascular aneurysm repair and 94.2% of elective AAA repairs; however, there were major differences in comorbidity reporting between the data sets. CONCLUSION: Both data sets were incomplete, but combining administrative (NMDS) and clinical (AVA) data sets provided a more accurate assessment of mortality figures. More than 80% of AAA repairs are captured by AVA, but further work to improve compliance and comorbidity documentation is required. PMID- 27492992 TI - Protocols for treating patients with end-stage renal disease: a survey of AEGD/GPR dental residencies. AB - RATIONALE/BACKGROUND: Approximately 14% of Americans are living with chronic kidney disease (CKD). The prevalence of end stage renal disease (ESRD), the result of progressing CKD continues to rise by 21,000 per year.Currently the only antibiotic prophylaxis guidelines for patients with end-stage renal disease undergoing dental treatment were published by the AHA in 2003. Presented in three parts, the first part of this study found no consistent protocols amongst U.S. dental schools. The goal of the second part of the project was to determine the current protocol being used to treat ESRD patients at accredited U.S. AEGD and GPR programs. METHODS AND MATERIALS: A 20 multiple choice question survey was e mailed to 262 directors of AEGDs and GPRs within the United States regarding renal treatment protocol details and antibiotic prophylaxis for patients with renal disease. RESULTS: 34% of respondents reported having an established renal treatment protocol. For programs with a protocol, 65.5% of programs reported following AHA guidelines. CONCLUSION: There is a lack of consistent, established protocols amongst U.S. AEGD and GPR programs. It is suggested that updated and evidence based guidelines for the safe treatment of patients be developed. PMID- 27492993 TI - Specific locations of linear furrows in patients with esophageal eosinophilia. AB - BACKGROUND AND AIM: Linear furrows are the most frequently found endoscopic abnormality in patients with esophageal eosinophilia (EE); however, the precise endoscopic features remain to be fully elucidated. Here, we aimed to clarify the endoscopic features of EE, essential for the diagnosis of eosinophilic esophagitis (EoE), by focusing on the specific locations of linear furrows in a Japanese population. METHODS: We enrolled 70 cases with EE (>=15 eosinophils/high power field) who were diagnosed at our hospital and related facilities. Information regarding endoscopic findings and clinical parameters was retrospectively reviewed. Next, the position of linear furrows in relation to esophageal longitudinal folds (ridge or valley) was evaluated in each case and compared with the position of mucosal breaks in patients with reflux esophagitis. Finally, the relationship between linear furrows and eosinophilic infiltration was evaluated. RESULTS: Of the 70 EE patients, 63 (90%) had linear furrows. Those occurred in a radial pattern and were widespread throughout the lower to upper esophagus, and exclusively found in esophageal longitudinal mucosal fold valleys, not on ridges, which was different from the position of mucosal breaks in patients with reflux esophagitis. Increased eosinophilic infiltration was significantly more frequent in linear furrows in the valleys (93%) as compared to mucosa on adjacent ridges (60%) (P < 0.05). CONCLUSION: Investigation of these endoscopic characteristics, especially by focusing on linear furrows in esophageal mucosal fold valleys, may provide important clues for more accurate diagnosis of EoE. PMID- 27492994 TI - Reference intervals for transthoracic echocardiography in the English springer spaniel: a prospective, longitudinal study. AB - OBJECTIVES: To establish transthoracic echocardiographic reference intervals in adult English springer spaniel dogs. METHODS: Forty-two healthy adult English springer spaniels were prospectively recruited from a general practice population in the UK. Animals were examined twice, at least 12 months apart, to exclude dogs with progressive cardiac disease. Reference intervals were calculated using Box Cox transformations and specific variables were depicted within an expert consensus range. Relationships of body mass, age and heart rate with cardiac structure and function were examined and functional assessments were compared with previous reports. Reference intervals were compared against published ratiometric indices and allometric scaling models. RESULTS: Thirty-nine dogs contributed to create the reference intervals. Significant relationships with bodyweight, age and heart rate were detected, although low coefficients of determination were found. Fractional shortening values were lower than has been reported in many breeds but Simpson-derived ejection fractions were similar to previously published breed-specific values. CLINICAL SIGNIFICANCE: Breed-specific reference intervals are reported allowing for more appropriate interpretation of echocardiographic assessments in the English springer spaniel. PMID- 27492995 TI - EPG Recordings Reveal Differential Feeding Behaviors in Sogatella furcifera in Response to Plant Virus Infection and Transmission Success. AB - Plant viruses are primarily transmitted by insect vectors and virus infection may influence on the vectors' feeding behaviors. Using an electrical penetration graph, we detected that infection with the Southern rice black-streaked dwarf virus (SRBSDV) in the white-backed planthopper (WBPH) and in rice plants both altered the vector's feeding behavior. When viruliferous WBPH (carrying SRBSDV) were fed on uninfected plants, they spent more time in salivation and phloem sap ingestion than non-viruliferous insects. In comparison with uninfected plants, infected plants showed an arrestant effect on non-viruliferous WBPH for phloem sap ingestion. Differential feeding behaviors were also detected between the WBPH that inoculated or acquired SRBSDV and those that failed to. The WBPH that inoculated SRBSDV exhibited more probing bouts, salivation events and phloem sap ingestion events and longer salivation than those that failed to. The WBPH that acquired SRBSDV were quicker to reach phloem and spent more time in phloem sap ingestion than those that failed to. These behavior alterations in the vector may have adaptive advantages for SRBSDV transmission and spread success because greater salivation by viruliferous vectors on uninfected hosts will promote virus inoculation, whereas more sap ingestion by non-viruliferous vectors on infected hosts will promote virus acquisition. PMID- 27492996 TI - [Cardiac amyloidosis: How to recognize them and manage them?] AB - Cardiac amyloidosis must be suspected in all cases of hypertrophic cardiomyopathy with preserved left ventricular ejection fraction to allow specific management. Final diagnosis needs pathological evidence, but bone scintigraphy may be an alternative for TTR amyloidosis. Invasive samplings are limited by new tools. Amyloidosis typing is required to start specific therapies if possible. Main specific treatments that are available are chemotherapy for AL; transthyretin stabilizer or gene therapy, studied for TTR-related cardiac amyloidosis. PMID- 27492997 TI - Low Molecular Weight Norbornadiene Derivatives for Molecular Solar-Thermal Energy Storage. AB - Molecular solar-thermal energy storage systems are based on molecular switches that reversibly convert solar energy into chemical energy. Herein, we report the synthesis, characterization, and computational evaluation of a series of low molecular weight (193-260 g mol(-1) ) norbornadiene-quadricyclane systems. The molecules feature cyano acceptor and ethynyl-substituted aromatic donor groups, leading to a good match with solar irradiation, quantitative photo-thermal conversion between the norbornadiene and quadricyclane, as well as high energy storage densities (396-629 kJ kg(-1) ). The spectroscopic properties and energy storage capability have been further evaluated through density functional theory calculations, which indicate that the ethynyl moiety plays a critical role in obtaining the high oscillator strengths seen for these molecules. PMID- 27492998 TI - Australian doctors condemn "horrific" treatment of children in juvenile detention. PMID- 27492999 TI - EDITORIAL. PMID- 27493000 TI - ERRATUM. PMID- 27493003 TI - Perinatal mental health in low- and middle-income country migrants. PMID- 27493004 TI - The use of a self-assembled aseptic splint for minor wrist injuries. PMID- 27493002 TI - LTbetaR controls thymic portal endothelial cells for haematopoietic progenitor cell homing and T-cell regeneration. AB - Continuous thymic homing of haematopoietic progenitor cells (HPCs) via the blood is critical for normal T-cell development. However, the nature and the differentiation programme of specialized thymic endothelial cells (ECs) controlling this process remain poorly understood. Here using conditional gene deficient mice, we find that lymphotoxin beta receptor (LTbetaR) directly controls thymic ECs to guide HPC homing. Interestingly, T-cell deficiency or conditional ablation of T-cell-engaged LTbetaR signalling results in a defect in thymic HPC homing, suggesting the feedback regulation of thymic progenitor homing by thymic products. Furthermore, we identify and characterize a special thymic portal EC population with features that guide HPC homing. LTbetaR is essential for the differentiation and homeostasis of these thymic portal ECs. Finally, we show that LTbetaR is required for T-cell regeneration on irradiation-induced thymic injury. Together, these results uncover a cellular and molecular pathway that governs thymic EC differentiation for HPC homing. PMID- 27493005 TI - Investigating the role of a poorly soluble surfactant in a thermally driven 2D microfoam. AB - Foam drainage dynamics is known to be strongly affected by the nature of the surfactants stabilising the liquid/gas interface. In the present work, we consider a 2D microfoam stabilized by both soluble (sodium dodecylsulfate) and poorly soluble (dodecanol) surfactants. The drainage dynamics is driven by a thermocapillary Marangoni stress at the liquid/gas interface [V. Miralles et al., Phys. Rev. Lett., 2014, 112, 238302] and the presence of dodecanol at the interface induces interface stress acting against the applied thermocapillary stress, which slows down the drainage dynamics. We define a damping parameter that we measure as a function of the geometrical characteristics of the foam. We compare it with predictions based on the interface rheological properties of the solution. PMID- 27493006 TI - Ecthyma gangrenosum in a renal transplant recipient. PMID- 27493007 TI - The need for genetic study to diagnose some cases of distal renal tubular acidosis. AB - We describe the case of a young woman who was diagnosed with advanced kidney disease, with an incidental finding of nephrocalcinosis of unknown aetiology, having been found asymptomatic throughout her life. The genetic study by panels of known genes associated with tubulointerstitial disease allowed us to discover autosomal dominant distal renal tubular acidosis associated with a de novo mutation in exon 14 of the SLC4A1 gene, which would have been impossible to diagnose clinically due to the advanced nature of the kidney disease when it was discovered. PMID- 27493008 TI - Can we use structural lesions seen on MRI of the sacroiliac joints reliably for the classification of patients according to the ASAS axial spondyloarthritis criteria? Data from the DESIR cohort. AB - OBJECTIVES: Investigating the utility of adding structural lesions seen on MRI of the sacroiliac joints to the imaging criterion of the Assessment of SpondyloArthritis (ASAS) axial SpondyloArthritis (axSpA) criteria and the utility of replacement of radiographic sacroiliitis by structural lesions on MRI. METHODS: Two well-calibrated readers scored MRI STIR (inflammation, MRI-SI), MRI T1-w images (structural lesions, MRI-SI-s) and radiographs of the sacroiliac joints (X-SI) of patients in the DEvenir des Spondyloarthrites Indifferenciees Recentes cohort (inflammatory back pain: >=3 months, <3 years, age <50). A third reader adjudicated MRI-SI and X-SI discrepancies. Previously proposed cut-offs for a positive MRI-SI-s were used (based on <5% prevalence among no-SpA patients): erosions (E) >=3, fatty lesions (FL) >=3, E/FL >=5. Patients were classified according to the ASAS axSpA criteria using the various definitions of MRI-SI-s. RESULTS: Of the 582 patients included in this analysis, 418 fulfilled the ASAS axSpA criteria, of which 127 patients were modified New York (mNY) positive and 134 and 75 were MRI-SI-s positive (E/FL>=5) for readers 1 and 2, respectively. Agreement between mNY and MRI-SI-s (E/FL>=5) was moderate (reader 1: kappa: 0.39; reader 2: kappa: 0.44). Using the E/FL>=5 cut-off instead of mNY classification did not change in 478 (82.1%) and 469 (80.6%) patients for readers 1 and 2, respectively. Twelve (reader 1) or ten (reader 2) patients would not be classified as axSpA if only MRI-SI-s was performed (in the scenario of replacement of mNY), while three (reader 1) or six (reader 2) patients would be additionally classified as axSpA in both scenarios (replacement of mNY and addition of MRI-SI-s). Similar results were seen for the other cut-offs (E>=3, FL>=3). CONCLUSIONS: Structural lesions on MRI can be used reliably either as an addition to or as a substitute for radiographs in the ASAS axSpA classification of patients in our cohort of patients with short symptom duration. PMID- 27493009 TI - SILAC-based quantitative proteomic analysis of secretome of Marc-145 cells infected with porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent of PRRS, which causes severe reproductive failure in sows, respiratory disease in young and growing pigs, and enormous economic losses to the global swine industry. In this study, SILAC combined with MS/MS was used to quantitatively identify the secretory proteins differentially expressed in PRRSV infected Marc-145 cells compared with mock-infected controls. In total, we identified 204 secretory proteins showing significant differences in infected cells (163 upregulated, 41 downregulated). Intensive bioinformatic analysis of secretome data revealed that PRRSV infection strongly activated nonclassical protein secretion, especially vesicle-mediated release of exosomal proteins, including different danger-associated molecular pattern molecules and the majority of secreted proteins involved in protein binding and transport, regulation of response to stimulus, metabolic processes, and immune responses. According to the functional proteins analysis, we speculate that proteins functioning in binding, transport, and the immune response are exploited by PRRSV to facilitate virus replication and immune evasion. Our study for the first time analyzes the secretory protein profile of PRRSV-infected Marc-145 cells and provides valuable insight into the host response to PRRSV infection. PMID- 27493010 TI - Virulence determinants in enteroaggregative Escherichia coli from North India and their interaction in in vitro organ culture system. AB - Enteroaggregative Escherichia coli (EAEC) is an important diarrhoeal pathogen causing diseases in multiple epidemiological and clinical settings. In developing countries like India, diarrhoeal diseases are one of the major killers among paediatric population and oddly, few studies are available from Indian paediatric population on the variability of EAEC virulence genes. In this study, we examined the distribution of plasmid and chromosomal-encoded virulence determinants in EAEC isolates, and analysed cytokines response generated against EAEC with specific aggregative adherence fimbriae (AAF) type in duodenal biopsies using in vitro organ culture (IVOC) mimicking in vivo conditions. Different virulence marker combinations among strains were reflected as a function of specific adhesins signifying EAEC heterogeneity. fis gene emerged as an important genetic marker apart from aggA and aap Further, EAEC infection in IVOC showed upregulation of IL-8, IL-1beta, IL-6, TNF-alpha and TLR-5 expression. EAEC with AAFII induced significant TLR-5 and IL-8 response, conceivably owing to more pathogenicity markers. This study sheds light on the pattern of EAEC pathotypes prevalent in North Indian paediatric population and highlights the presence of unique virulence combinations in pathogenic strains. Thus, evident diversity in EAEC virulence and multifaceted bacteria-host crosstalk can provide useful insights for the strategic management of diarrhoeal diseases in India, where diarrhoeal outbreaks are more frequent. PMID- 27493011 TI - Aeromonas salmonicida subsp. salmonicida strains isolated from Chinese freshwater fish contain a novel genomic island and possible regional-specific mobile genetic elements profiles. AB - Two strains of Aeromonas salmonicida, YK and BG, were isolated from largemouth bronze gudgeon and northern whitefish in China, and identified as A. salmonicida subsp. salmonicida based on phylogenetic analysis of vapA and 16S rRNA gene sequences. YK and BG originated from freshwater fish, one of which belonged to the cyprinid family, and the strains showed a difference in virulence. Subsequently, we performed whole genome sequencing of the strains, and comparison of their genomic sequences to the genome of the A449 reference strain revealed various genomic rearrangements, including a new variant of the genomic island AsaGEI in BG, designated as AsaGEI2c This is the first report on a GEI of A. salmonicida strain from China. Furthermore, both YK and BG strains contained a Tn7 transposon inserted at the same position in the chromosome. Finally, IS dependent rearrangements on pAsa5 are deemed likely to have occurred, with omission of the resD gene in both strains as well as omission of genes related to the IncF conjugal transfer system in the YK isolate. This study demonstrates that A. salmonicida subsp. salmonicida can infect non-salmonids (cyprinids) in addition to salmonids, and that AsaGEI2c might be useful as a geographical indicator of Chinese A. salmonicida subsp. salmonicida isolates. PMID- 27493012 TI - Superior adsorption performance for triphenylmethane dyes on 3D architectures assembled by ZnO nanosheets as thin as ~1.5nm. AB - The 3-dimensional hierarchical ZnO flower-like architectures have been synthesized in a Zn(Ac)2.2H2O-Na2SeO3-KBH4-pyridine solvothermal system at 100 degrees C for 24h. The flower-like architecture is assembled from ZnO nanosheets with a thickness of ~1.5nm, and the flower-like architecture specific surface area is 132m(2)/g. When the ZnO flower-like architecture is used as the adsorbent for acid fuschin (AF), malachite green (MG), basic fuchsin (BF), congo red (CR) and acid red (AR) in water, the adsorption capacities for AF, MG, BF, CR and AR are 7154.9, 2587.0, 1377.9, 85.0 and 38.0mg/g, respectively. Evidently, the as obtained ZnO flower-like architectures show excellent adsorption performances for triphenylmethane dyes, and the adsorption capacity of 7154.9mg/g for AF is the highest of all adsorbents for dyes. The adsorption mechanism can be attributed to the electrostatic attraction and the formation of ion-association complex between triphenylmethane dyes and ZnO hierarchical flower-like architectures. PMID- 27493013 TI - The suppression effect in visuospatial and verbal working memory span tasks in patients with Alzheimer's disease: a 2-year follow-up study. AB - This study adapted a new task to assess visuospatial and verbal working memory impairments in patients with Alzheimer Disease (AD), including an executive strategy of information suppression. The aim was to examine the visuospatial and verbal difficulties, and additionally to explore the average sex differences, during a 2-year follow-up study. The results indicated that patients with AD showed a significantly lower performance, compared with healthy elderly controls, especially with the suppression of information required in this new task. However, suppression did not lead to a significantly greater decline in the performance of patients when compared with the control group. PMID- 27493014 TI - The human microbiome in rheumatic autoimmune diseases: A comprehensive review. AB - The human microbiome consists of the total diversity of microbiota and their genes. High-throughput sequencing has allowed for inexpensive and rapid evaluation of taxonomic representation and functional capability of the microbiomes of human body sites. Autoimmune and inflammatory rheumatic diseases are characterized by dysbiosis of the microbiome. Microbiome dysbiosis can be influenced by host genetics and environmental factors. Dysbiosis is also associated with shifts in certain functional pathways. The goal of this article is to provide a current and comprehensive review of the unique characteristics of the microbiome of patients with autoimmune and inflammatory rheumatic diseases, measured using high-throughput sequencing. We also highlight the need for broader studies utilizing a longitudinal approach to better understand how the human microbiome contributes to disease susceptibility, and to characterize the role of the interaction between host genetics and microbial diversity in the pathogenesis of autoimmune diseases, disease manifestations, and progression. PMID- 27493016 TI - Evaluation of the dose-response relationship of oral robenacoxib in urate crystal induced acute stifle synovitis in dogs. AB - The objective of the study was to establish the dose-response relationship for robenacoxib, a selective cyclooxygenase (COX)-2 inhibitor, in a urate crystal model of acute synovitis. In a randomized partial Latin square design trial, 12 beagle dogs were administered orally single doses of robenacoxib (0.5, 1, 2, 4 and 8 mg/kg), placebo and the positive control meloxicam (0.1 mg/kg), 3 h after injection of sodium urate crystals into a stifle joint. Dogs were assessed for weight bearing on a force plate and by subjective clinical orthopaedic observations. Robenacoxib produced dose-dependent improvement in weight bearing, and decreased pain on palpation and joint swelling, over the dose range 0.5-2 mg/kg with no further increase in effect over the range 2-8 mg/kg. For weight bearing on the force plate, the ED50 of robenacoxib was 0.6-0.8 mg/kg. The onset of action and time to peak effect of robenacoxib were faster (respectively, 2-2.5 h and 3-5 h) than for meloxicam (respectively, 3 h and 6 h). Robenacoxib significantly inhibited COX-2 at all doses, with dose-related activity. Robenacoxib did not inhibit COX-1 over the dose range 0.5-4 mg/kg, but produced transient inhibition at 8 mg/kg. In conclusion, oral administration of robenacoxib over the dose range 0.5-8 mg/kg demonstrated significant analgesic and anti-inflammatory efficacy in dogs. PMID- 27493015 TI - Accelerating Enzymatic Catalysis Using Vortex Fluidics. AB - Enzymes catalyze chemical transformations with outstanding stereo- and regio specificities, but many enzymes are limited by their long reaction times. A general method to accelerate enzymes using pressure waves contained within thin films is described. Each enzyme responds best to specific frequencies of pressure waves, and an acceleration landscape for each protein is reported. A vortex fluidic device introduces pressure waves that drive increased rate constants (kcat ) and enzymatic efficiency (kcat /Km ). Four enzymes displayed an average seven-fold acceleration, with deoxyribose-5-phosphate aldolase (DERA) achieving an average 15-fold enhancement using this approach. In solving a common problem in enzyme catalysis, a powerful, generalizable tool for enzyme acceleration has been uncovered. This research provides new insights into previously uncontrolled factors affecting enzyme function. PMID- 27493017 TI - Three-Arm Branched Microporous Organic Nanotube Networks. AB - Here, a novel method is demonstrated for the preparation of three-arm branched microporous organic nanotube networks (TAB-MONNs) based on molecular templating of three-arm branched core-shell bottlebrush copolymers and Friedel-Crafts alkylation reaction. The unique three-arm branched bottlebrush copolymers are synthesized by a combination of atom transfer radical polymerization, reversible addition-fragmentation chain transfer polymerization, and ring-opening polymerization techniques. In this approach, the length and diameter of branched tube units can be well-controlled by rational molecular design. Moreover, the as prepared TAB-MONNs possess a high surface area and exhibit a superior adsorption capacity for Rhodamine 6G (R6G) and p-cresol. PMID- 27493018 TI - In vitro aerodynamic characteristics of aerosol delivered from different inhalation methods in mechanical ventilation. AB - Aerodynamic characteristics of aerosol delivery during invasive mechanical ventilation (IMV) are mostly determined by inserting cascade impactor in the circuit. Impactor might have some effect on airflow within IMV. Hence, the aim of the present study was to develop and evaluate new in vitro aerodynamic characterization methodology without affecting airflow in IMV. Breathing simulator was set in standard adult IMV circuit with inspiratory and expiratory pressures of 20 and 5 cm H2O, 1:3 inspiratory-expiratory ratio, 15 breaths min-1, and tidal volume of 500 ml. Two ml of salbutamol solution containing 10,000 MUg was nebulized using three different vibrating mesh nebulizers (VMNs) and Sidestream jet nebulizer (JET). Sixteen-metered doses, containing 100 MUg salbutamol each, were delivered using three different spacers. Each device was placed in inspiration limb of Y-piece of ventilator tubing. Aerodynamic characteristics of aerosol delivered were measured using cooled Andersen cascade impactor, with mixing inlet connected to it. VMNs used had significantly more total mass in the impactor (p < .001) and fine particle dose (p < .001) compared to JET. Spacers used had higher total mass in the impactor percent (p < .001) and fine particle fraction compared to nebulizers. The in vitro IMV methodology setting suggested here showed encouraging results in comparison of different aerosol delivery systems in intubated patient. PMID- 27493019 TI - What is the optimal duration of oral misoprostol treatment for cervical ripening? AB - OBJECTIVES: To evaluate the number of misoprostol tablets needed to obtain a Bishop score (BS) >= 6 or a significant cervical change (>=2 points in BS) during cervical ripening. METHODS: Retrospective study of women with term singleton pregnancies and a BS < 6 taking oral misoprostol (20 MUg first 2 doses followed by 40 MUg every 2 h) for cervical ripening. RESULTS: We included 400 women, 72% nulliparous, mean age of 31.3 +/- 5.9 years and 70% with a baseline BS <= 2. During cervical ripening, 61 (15.3%) achieved a BS >= 6 and 205 (51.3%) a significant change in BS. The incremental risk to achieve a BS >= 6 after 4 tablets was low (+3.25%) with an incremental probability of +12.75% for painful uterine contractions and +0.5% for abnormal fetal tracing (AFT). The incremental probability to achieve a significant change in BS after 7 tablets was low (+2.0%). 24.3% women delivered by cesarean section which likelihood significantly increased with maternal age <35 years, BMI >= 30, nulliparity, AFT, and baseline BS <= 2. CONCLUSIONS: The marginal benefit of giving more than 7 misoprostol tablets (14 h) during cervical ripening is very low. PMID- 27493020 TI - The Pressure induced by salt crystallization in confinement. AB - Salt crystallization is a major cause of weathering of rocks, artworks and monuments. Damage can only occur if crystals continue to grow in confinement, i.e. within the pore space of these materials, thus generating mechanical stress. We report the direct measurement, at the microscale, of the force exerted by growing alkali halide salt crystals while visualizing their spontaneous nucleation and growth. The experiments reveal the crucial role of the wetting films between the growing crystal and the confining walls for the development of the pressure. Our results suggest that the measured force originates from repulsion between the similarly charged confining wall and the salt crystal separated by a ~1.5 nm liquid film. Indeed, if the walls are made hydrophobic, no film is observed and no repulsive forces are detected. We also show that the magnitude of the induced pressure is system specific explaining why different salts lead to different amounts of damage to porous materials. PMID- 27493021 TI - The preparation of Cistanche phenylethanoid glycosides liquid proliposomes: Optimized formulation, characterization and proliposome dripping pills in vitro and in vivo evaluation. AB - Water-soluble Cistanche phenylethanoid glycosides (CPhGs) have poor permeability and low bioavailability. However, liposomes can improve the permeability of such drugs and their poor stability, and proliposomes have been used to overcome these problems. Based on this, Cistanche phenylethanoid glycoside liquid proliposomes (CPhGsP) and dripping(?) pills were prepared and optimized using response surface methodology. The properties of CPhGsP were evaluated in terms of their encapsulation efficiency, particle size, zeta potential, and morphology. The results obtained showed that the optimal formulation was drug/soybean phospholipid/poloxamer-188/sodium deoxycholate/propylene glycol 1:22.38:3.52:0.84:80 (w/w/w/w/v). This resulted in an encapsulation efficiency, particle size, and zeta potential of hydrated proliposomes with phosphate buffer solution (pH7.4) of 51.97%, 671.7nm, and -25.49mV, respectively. Stability testing of CPhGsP and CPhGs ordinary liposomes was carried out for 3months at 4+/ 2 degrees C, 25+/-2 degrees C, 40+/-2 degrees C, 75+/-5% RH. The results obtained showed that the stability of the proliposomes was better than that of ordinary liposomes at the same temperature, while a lower temperature of 4 degrees C is ideal for storage. Cistanche phenylethanoid glycoside liquid proliposomes dripping pills (CPhGsPD) are efficiently released in gastrointestinal solution as shown by in vitro release experiments and the structure of the liposomes does not destroy the proliposome dripping pills by hydration. In vivo experiments showed that the areas under the plasma level-time curves and peak concentrations of CPhGsPD and hydrated proliposomes were higher than those of CPhGs. Moreover, with CPhGsPD, the pharmacokinetic parameters were similar to those with hydrated proliposomes. These results showed that CPhGsPD offer a good way to improve the oral delivery of CPhGs. PMID- 27493022 TI - Geographic access to interventional cardiology services in one rural state. AB - OBJECTIVES: Explore (1) the characteristics of the Maine population with delayed geographic access to interventional cardiology (IC) services and (2) the effect of delayed geographic IC access on coronary mortality. BACKGROUND: Acute coronary syndrome (ACS), ST-segment elevated myocardial infarction (STEMI), and non-ST segment elevated myocardial infarction (NSTEMI) are highly prevalent. Coronary mortality is minimized when victims have prompt IC access. METHODS: The study design was (1) an exploration of census data to investigate disparities in geographic IC access and (2) a secondary analysis of administrative claims data to investigate coronary mortality relative to delayed geographic IC access. RESULTS: Delayed access was associated in the Maine population with rural residence, advanced age, high school education, and lack of health insurance. Delayed access was associated with increased unadjusted coronary mortality, but not age-adjusted coronary mortality. CONCLUSION: Delayed geographic IC access was associated with disparity but not with increased age-adjusted coronary mortality. PMID- 27493023 TI - Changes in physical function after hospitalization in patients with nursing and healthcare-associated pneumonia. AB - To clarify the functional changes after hospitalization due to pneumonia in elderly Japanese patients, we investigated the changes in physical functioning, nutritional routes, and diet that occurred after hospitalization in patients with nursing and healthcare-associated pneumonia (NHCAP). We analyzed 405 patients with NHCAP and compared findings with 448 patients with community-acquired pneumonia (CAP). Among the NHCAP patients, 140 (34%) patients showed a decline in activities of daily living function between baseline and discharge. After hospital discharge, 149 (37%) NHCAP patients did not return to the same residence location compared with where they were living prior to hospital admission. The frequency of this outcome was significantly higher in NHCAP patients than in CAP patients (p < 0.0001). After 6 months' follow-up, of the patients who transferred to different hospitals, 41 (73%) patients with CAP had returned to their own home, but only 16 (20%) patients with NHCAP could return home (p < 0.0001). Rates of alteration of nutritional route and type of diet from oral nutrition were significantly higher in NHCAP patients compared with CAP patients (22% vs 4%, p < 0.0001). Our results demonstrated that approximately one-third of hospitalized patients with NHCAP showed a decline in physical function. In addition, approximately one-fifth of NHCAP patients had changed their route of nutrition and type of diet. Our results indicated that physicians should attach greater importance to preventative measures against NHCAP rather than relying on antibiotic therapy post-infection in the management of pneumonia in elderly patients in order to extend their healthy life expectancy. PMID- 27493024 TI - Duration of fever and other symptoms after the inhalation of laninamivir octanoate hydrate for influenza treatment; comparison among the four Japanese influenza seasons from 2011-2012 to 2014-2015. AB - The duration of fever and other symptoms as markers of the clinical effectiveness of laninamivir octanoate hydrate (laninamivir) were investigated in the Japanese 2014-2015 influenza season and the results were compared with those of the previous three seasons, 2011-2012 to 2013-2014. From these four seasons, the data of 636 influenza A(H3N2) and 128 influenza B patients was available for analysis. No significant difference was found in their baseline characteristics. The median duration of fever for all A(H3N2) patients ranged from 32.0 to 41.0 h. The duration of fever in the 2014-2015 season was significantly shorter than that in the 2012-2013 and 2013-2014 seasons (p = 0.0204 and 0.0391, respectively), but the differences were within nine hours. The median duration of symptoms for A(H3N2) ranged from 80.0 to 89.0 h, with no significant difference among the four seasons (p = 0.2222). The median duration of fever for B patients ranged from 43.0 to 50.0 h, with no significant difference among the four seasons. The duration of the symptoms for B varied by season, but no significant difference was found among the four seasons. Over the four seasons, 44 adverse events were reported from among 921 patients, with all resolving without treatment. These results indicate the continuing effectiveness of laninamivir against influenza A(H3N2) and B, with no safety issues. It is unlikely that the clinical use of laninamivir has caused viral resistance in the currently epidemic viruses. PMID- 27493025 TI - Factors Influencing Adherence to Antiretroviral Therapy among People Living with HIV in Coastal South India. AB - BACKGROUND: Antiretroviral Therapy (ART) has transformed life threatening HIV/AIDS scenario into chronic manageable disease. METHODOLOGY: In this cross sectional, 409 People Living with Human Immunodeficiency Virus (PLHIV) aged >= 18 years, who were on ART, were assessed regarding the adherence to ART and factors affecting adherence using semi-structured questionnaire. The association between factors affecting adherence and the level of adherence were analyzed using multiple logistic regression model and odds ratio (OR) with 95% confidence intervals (CI) were reported. RESULTS: Among 409 PLHIV, 70.4% showed adherence to ART (>=95%). Univariate analysis yielded many factor associated with adherence (P < 0.05). However, on multivariate analysis, PLHIV who do not forget to take ART and not consuming alcohol were the factors consistent with adherence to ART (P < 0.05). CONCLUSION: Regular patient education and counseling regarding the usage of memory aids and abstinence from alcohol could be useful for adherence and long term success of ART among PLHIV. PMID- 27493026 TI - Disease modelling using human iPSCs. PMID- 27493027 TI - Myelinosomes act as natural secretory organelles in Sertoli cells to prevent accumulation of aggregate-prone mutant Huntingtin and CFTR. AB - Inappropriate deposition of insoluble aggregates of proteins with abnormal structures is a hallmark of affected organs in protein aggregation disease. Very rare, affected organs avoid aggregation naturally. This concerns atrophic testis in Huntington disease (HD). We aimed to understand how HD testis avoids aggregation. Using HD model R6/1 mice, we demonstrate that affected testis contain rare organelles myelinosomes. Myelinosomes secreted from testis somatic TM4 Sertoli cells provide the release of aggregate-prone mutant, but not normal Huntingtin (Htt) exon1. Myelinosomes also support the release of other aggregate prone mutant protein responsible for cystic fibrosis (CF), F508delCFTR. The traffic and discharge of myelinosomes is facilitated by multivesicular bodies (MVB)s. Inhibition of MVB excretion induced reversible retention of both misfolded proteins inside TM4 Sertoli cells. We propose that myelinosome-mediated elimination of mutant proteins is an unusual secretory process allowing Sertoli cells getting rid of misfolded proteins to avoid aggregation and to maintain cell proteostasis. PMID- 27493028 TI - Neuromuscular junctions are pathological but not denervated in two mouse models of spinal bulbar muscular atrophy. AB - Spinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease causing motor dysfunction in men. While the morphology of the neuromuscular junction (NMJ) is typically affected by neuromuscular disease, whether NMJs in SBMA are similarly affected by disease is not known. Such information will shed light on whether defective NMJs might contribute to the loss of motor function and represent a potential therapeutic target for treating symptoms of SBMA. To address this gap in information, the morphology of NMJs was examined in two mouse models of SBMA, a myogenic model that overexpresses wildtype androgen receptor (AR) exclusively in muscle fibres and a knockin (KI) model expressing a humanized mutant AR gene. The tripartite motor synapse consisting of motor nerve terminal, terminal Schwann cells (tSCs) and postsynaptic specialization were visualized and analysed using confocal microscopy. Counter to expectation, we found no evidence of denervation in either model, but junctions in both models show pathological fragmentation and an abnormal synaptophysin distribution consistent with functionally weak synapses. Neurofilament accumulations were observed only in the myogenic model, even though axonal transport dysfunction is characteristic of both models. The ultrastructure of NMJs revealed additional pathology, including deficits in docked vesicles presynaptically, wider synaptic clefts, and simpler secondary folds postsynaptically. The observed pathology of NMJs in diseased SBMA mice is likely the morphological correlates of defects in synaptic function which may underlie motor impairments associated with SBMA. PMID- 27493029 TI - The COQ2 genotype predicts the severity of coenzyme Q10 deficiency. AB - COQ2 (p-hydroxybenzoate polyprenyl transferase) encodes the enzyme required for the second step of the final reaction sequence of Coenzyme Q10 (CoQ) biosynthesis. Its mutations represent a frequent cause of primary CoQ deficiency and have been associated with the widest clinical spectrum, ranging from fatal neonatal multisystemic disease to late-onset encephalopathy. However, the reasons of this variability are still unknown.We have characterized the structure of human COQ2, defined its subcellular localization and developed a yeast model to validate all the mutant alleles reported so far.Our findings show that the main functional transcript of COQ2 is shorter than what was previously reported and that its protein product localizes to mitochondria with the C-terminus facing the intermembrane space. Complementation experiments in yeast showed that the residual activity of the mutant proteins correlates with the clinical phenotypes observed in patients.We defined the structure of COQ2 with relevant implications for mutation screening in patients and demonstrated that, contrary to other COQ gene defects such as ADCK3, there is a correlation between COQ2 genotype and patient's phenotype. PMID- 27493030 TI - New Insight in Copper-Ion Binding to Human Islet Amyloid: The Contribution of Metal-Complex Speciation To Reveal the Polypeptide Toxicity. AB - Type-2 diabetes (T2D) is considered to be a potential threat on a global level. Recently, T2D has been listed as a misfolding disease, such as Alzheimer's and Parkinson's diseases. Human islet amyloid polypeptide (hIAPP) is a molecule cosecreted in pancreatic beta cells and represents the main constituent of an aggregated amyloid found in individuals affected by T2D. The trace-element serum level is significantly influenced during the development of diabetes. In particular, the dys-homeostasis of Cu(2+) ions may adversely affect the course of the disease. Conflicting results have been reported on the protective role played by complex species formed by Cu(2+) ions with hIAPP or its peptide fragments in vitro. The histidine (His) residue at position 18 represents the main binding site for the metal ion, but contrasting results have been reported on other residues involved in metal-ion coordination, in particular those toward the N or C terminus. Sequences that encompass regions 17-29 and 14-22 were used to discriminate between the two models of the hIAPP coordination mode. Due to poor solubility in water, poly(ethylene glycol) (PEG) derivatives were synthesized. A peptide fragment that encompasses the 17-29 region of rat amylin (rIAPP) in which the arginine residue at position 18 was substituted by a histidine residue was also obtained to assess that the PEG moiety does not alter the peptide secondary structure. The complex species formed by Cu(2+) ions with Ac-PEG-hIAPP(17-29)-NH2 , Ac-rIAPP(17-29)R18H-NH2 , and Ac-PEG-hIAPP(14-22)-NH2 were studied by using potentiometric titrations coupled with spectroscopic methods (UV/Vis, circular dichroism, and EPR). The combined thermodynamic and spectroscopic approach allowed us to demonstrate that hIAPP is able to bind Cu(2+) ions starting from the His18 imidazole nitrogen atom toward the N-terminus domain. The stability constants of copper(II) complexes with Ac-PEG-hIAPP(14-22)-NH2 were used to simulate the different experimental conditions under which aggregate formation and oxidative stress of hIAPP has been reported. Speciation unveils: 1) the protective role played by increased amounts of Cu(2+) ions on the hIAPP fibrillary aggregation, 2) the effect of adventitious trace amounts of Cu(2+) ions present in phosphate-buffered saline (PBS), and 3) a reducing fluorogenic probe on H2 O2 production attributed to the polypeptide alone. PMID- 27493031 TI - Sustainable Pathways to Pyrroles through Iron-Catalyzed N-Heterocyclization from Unsaturated Diols and Primary Amines. AB - Pyrroles are prominent scaffolds in pharmaceutically active compounds and play an important role in medicinal chemistry. Therefore, the development of new, atom economic, and sustainable catalytic strategies to obtain these moieties is highly desired. Direct catalytic pathways that utilize readily available alcohol substrates have been recently established; however, these approaches rely on the use of noble metals such as ruthenium or iridium. Here, we report on the direct synthesis of pyrroles using a catalyst based on the earth-abundant and inexpensive iron. The method uses 2-butyne-1,4-diol or 2-butene-1,4-diol that can be directly coupled with anilines, benzyl amines, and aliphatic amines to obtain a variety of N-substituted pyrroles in moderate-to-excellent isolated yields. PMID- 27493032 TI - Confocal Raman Microscopy of Hybrid-Supported Phospholipid Bilayers within Individual C18-Functionalized Chromatographic Particles. AB - Measuring lipid-membrane partitioning of small molecules is critical to predicting bioavailability and investigating molecule-membrane interactions. A stable model membrane for such studies has been developed through assembly of a phospholipid monolayer on n-alkane-modified surfaces. These hybrid bilayers have recently been generated within n-alkyl-chain (C18)-modified porous silica and used in chromatographic retention studies of small molecules. Despite their successful application, determining the structure of hybrid bilayers within chromatographic silica is challenging because they reside at buried interfaces within the porous structure. In this work, we employ confocal Raman microscopy to investigate the formation and temperature-dependent structure of hybrid phospholipid bilayers in C18-modified, porous-silica chromatographic particles. Porous silica provides sufficient surface area within a confocal probe volume centered in an individual particle to readily measure, with Raman microscopy, the formation of an ordered hybrid bilayer of 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC) with the surface C18 chains. The DMPC surface density was quantified from the relative Raman scattering intensities of C18 and phospholipid acyl chains and found to be ~40% of a DMPC vesicle membrane. By monitoring Raman spectra acquired versus temperature, the bilayer main phase transition was observed to be broadened and shifted to higher temperature compared to a DMPC vesicle, in agreement with differential scanning calorimetry (DSC) results. Raman scattering of deuterated phospholipid was resolved from protonated C18 chain scattering, showing that the lipid acyl and C18 chains melt simultaneously in a single phase transition. The surface density of lipid in the hybrid bilayer, the ordering of both C18 and lipid acyl chains upon bilayer formation, and decoupling of C18 methylene C-H vibrations by deuterated lipid acyl chains all suggest an interdigitated acyl chain structure. The simultaneous melting of both layers is also consistent with an interdigitated structure, where immobility of surface grafted C18 chains decreases the cooperativity and increases the melting temperature compared to a vesicle bilayer. PMID- 27493039 TI - Serological survey finds evidence of bluetongue antibodies in UK cattle. PMID- 27493040 TI - 'Remarkable' horse awarded PDSA Dickin Medal. PMID- 27493044 TI - Animals pushed to their limits: what are the implications for welfare? AB - From working horses to dairy cows to dogs, animals are being pushed to their biological limits. But how far can we go before their health and welfare is compromised? This was one of the questions discussed at a recent meeting organised jointly by CABI and the Royal Veterinary College. Georgina Mills reports. PMID- 27493045 TI - Veterinary medicines update. AB - The following information has been produced for Veterinary Record by the Veterinary Medicines Directorate (VMD) to provide an update for veterinary surgeons on recent changes to marketing authorisations for veterinary medicines in the UK and on other relevant issues. PMID- 27493046 TI - Disease surveillance in England and Wales, July 2016. AB - ? Current and emerging issues? Highlights from the scanning surveillance network? Update on international disease threats? Botulism outbreaks in wild waterbirdsThese are among matters discussed in the Animal and Plant Health Agency's (APHA's) July disease surveillance report. PMID- 27493047 TI - Suspected avian botulism outbreaks in wild waterbirds during the summer. AB - The APHA Wildlife Expert Group reports on disease identified by the APHA Diseases of Wildlife Scheme and Avian Influenza Wild Bird Surveillance project. PMID- 27493048 TI - Does it matter that more boys aren't applying to vet school? PMID- 27493049 TI - Microchipping very small dogs. PMID- 27493050 TI - Measuring health-related quality of life in companion animals. PMID- 27493051 TI - Haemorrhagic bowel syndrome associated with ingestion of spoiled concentrate in two Brown Swiss cows. PMID- 27493052 TI - Increasing remission in diabetic cats. PMID- 27493060 TI - Working in industry using skills learned in practice. AB - After qualifying, Blaise Scott-Morris enjoyed working in small animal practice. In search of a new challenge, she joined Virbac where she is a technical adviser. PMID- 27493061 TI - Diary of a parliamentary intern. AB - With Brexit dominating the headlines, parliamentary intern Anthony Ridge considers some future implications for vets. PMID- 27493062 TI - Arthritis is developed in Borrelia-primed and -infected mice deficient of interleukin-17. AB - Interleukin-17 (IL-17) has been shown to participate in the development of Lyme arthritis in experimental mice. For example, neutralization of IL-17 with antibodies inhibits induction of arthritis in Borrelia-primed and -infected C57BL/6 wild-type mice. We hypothesized that mice lacking IL-17 would fail to develop Borrelia-induced arthritis. IL-17-deficient and wild-type C57BL/6 mice were primed with heat-inactivated Borrelia and then infected with viable spirochetes 3 weeks later. No swelling or major histopathological changes of the hind paws were detected in IL-17-deficient or wild-type mice that were primed with Borrelia or infected with viable spirochetes. By contrast, IL-17-deficient and wild-type mice that were primed and subsequently infected with heterologous Borrelia developed severe swelling and histopathological changes of the hind paws. In addition, Borrelia-primed and -infected IL-17-deficient mice exhibited elevated gamma-interferon (IFN-gamma) levels in sera and increased frequencies of IFN-gamma-expressing lymphocytes in popliteal lymph nodes compared to Borrelia primed and -infected wild-type mice. These results demonstrate that IL-17 is not required for development of severe pathology in response to infection with Borrelia burgdorferi, but may contribute to disease through an interaction with IFN-gamma. PMID- 27493063 TI - Inflammation-associated cytokine analysis identifies presence of respiratory bacterial pathogens in the nasopharynx. AB - We sought to determine if inflammatory cytokines are induced during asymptomatic nasopharyngeal (NP) colonization by the common respiratory bacteria Streptococcus pneumoniae (Spn), non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat). 85 serum samples were studied from 85 children 6-36 months of age when children were healthy and potentially NP colonized with Spn, NTHi or Mcat. Immunoassays were used to quantitate serum sICAM-1, IL-10 and S100A12 levels. Logistic regression was used to develop a predictive model for NP colonization probability for causative bacterial pathogen presence. Serum levels of sICAM-1, IL-10 and S100A12 increased during asymptomatic NP colonization by Spn, NTHi and Mcat. In a statistical model using risk scoring, we found high positive predictive and negative value, sensitivity and specificity when using these three cytokines to identify the presence of Spn, NTHi and Mcat in the NP. For the first time, we show that inflammatory cytokines are induced in serum during asymptomatic NP colonization by Spn, NTHi and Mcat. PMID- 27493065 TI - Fe3O4@mSiO2-FA-CuS-PEG nanocomposites for magnetic resonance imaging and targeted chemo-photothermal synergistic therapy of cancer cells. AB - In this work, a new multifunctional nanoplatform (Fe3O4@mSiO2-FA-CuS-PEG nanocomposite) for magnetic resonance imaging (MRI) and targeted chemo photothermal therapy, was firstly fabricated on the basis of magnetic mesoporous silica nanoparticles (Fe3O4@mSiO2), on which folic acid (FA) was grafted as the targeting reagent, CuS nanocrystals were attached as the photothermal agent, and polyethylene glycol (PEG) was coupled to improve biocompatibility. The characterization results demonstrated that the fabricated Fe3O4@mSiO2-FA-CuS-PEG nanocomposites not only showed strong magnetism and excellent MRI performance, but also had a high doxorubicin (DOX, an anticancer drug) loading capacity (22.1%). The loaded DOX can be sustainably released, which was apt to be controlled by pH adjustment and near infrared (NIR) laser irradiation. More importantly, targeted delivery of the DOX-loaded Fe3O4@mSiO2-FA-CuS-PEG nanocomposites could be accomplished in HeLa cells via the receptor-mediated endocytosis pathway, and this exhibited synergistic effect of chemotherapy and photothermal therapy against HeLa cells under irradiation with a 915 nm laser. Therefore, the fabricated multifunctional Fe3O4@mSiO2-FA-CuS-PEG nanocomposite has a great potential in image-guided therapy of cancers. PMID- 27493064 TI - Lipid Regulated Intramolecular Conformational Dynamics of SNARE-Protein Ykt6. AB - Cellular informational and metabolic processes are propagated with specific membrane fusions governed by soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNARE). SNARE protein Ykt6 is highly expressed in brain neurons and plays a critical role in the membrane-trafficking process. Studies suggested that Ykt6 undergoes a conformational change at the interface between its longin domain and the SNARE core. In this work, we study the conformational state distributions and dynamics of rat Ykt6 by means of single-molecule Forster Resonance Energy Transfer (smFRET) and Fluorescence Cross-Correlation Spectroscopy (FCCS). We observed that intramolecular conformational dynamics between longin domain and SNARE core occurred at the timescale ~200 MUs. Furthermore, this dynamics can be regulated and even eliminated by the presence of lipid dodecylphoshpocholine (DPC). Our molecular dynamic (MD) simulations have shown that, the SNARE core exhibits a flexible structure while the longin domain retains relatively stable in apo state. Combining single molecule experiments and theoretical MD simulations, we are the first to provide a quantitative dynamics of Ykt6 and explain the functional conformational change from a qualitative point of view. PMID- 27493066 TI - Toward Better Pain Management: The Development of a "Pain Stewardship Program" in a Tertiary Children's Hospital. AB - OBJECTIVE: Despite increased focus on pediatric pain, uncontrolled pain is still a problem for hospitalized pediatric inpatients. A program was designed to find patients with uncontrolled pain and develop a framework to oversee their pain management. This report details the development of a pain stewardship program with data from the first year of its activity. METHODS: Hospitalized inpatients in a tertiary care pediatric center in the mid-Atlantic region were included in the study. Pain scores are recorded every 4 hours in the hospital electronic health record. A report was constructed to find all patients with an average pain score >=7 in the preceding 12 hours. The charts of these patients were reviewed by our anesthesia pain service, and all patients were grouped into 1 of the following action categories: (1) no action required; (2) telephone call to the patient's attending physician; (3) one-time consultation; (4) consultation with ongoing management; or (5) patient was already on the anesthesia pain service. Demographic data, pain regimens, and outcomes were recorded in a prospectively collected database. RESULTS: There were 843 records on 441 unique patients. Only 22% required action to be taken by the anesthesia pain service. The pain stewardship database revealed that patients with sickle cell disease or abdominal pain required more frequent attention. CONCLUSIONS: An electronic health record based pain stewardship program is an important step in identifying all children in the hospital with undermanaged pain, and it provides a warning system that may improve patient care, outcomes, and satisfaction. PMID- 27493067 TI - Acceptability of a Community-Based Outreach HIV-Testing Intervention Using Oral Fluid Collection Devices and Web-Based HIV Test Result Collection Among Sub Saharan African Migrants: A Mixed-Method Study. AB - BACKGROUND: Late human immunodeficiency virus (HIV) diagnosis is common among sub Saharan African migrants. To address their barriers to HIV testing uptake and improve timely HIV diagnoses and linkage to care, the outreach HIV testing intervention, "swab2know," was developed. It combined a community-based approach with innovative testing methods: oral fluid self-sampling and the choice between Web-based HIV test result collections using a secured website or post-test counseling at a sexual health clinic. The sessions included an informational speech delivered by a physician of sub-Saharan African origin and testimonies by community members living with HIV. OBJECTIVES: The objectives of this study were to evaluate the intervention's acceptability among sub-Saharan African migrants and its potential to reach subgroups at higher risk for HIV infection and to identify facilitators and barriers for HIV testing uptake. METHODS: This mixed method study combined qualitative (participant observations and informal interviews with testers and nontesters) and quantitative data (paper-pencil survey, laboratory data, and result collection files). Data were analyzed using a content analytical approach for qualitative and univariate analysis for quantitative data. RESULTS: A total of 10 testing sessions were organized in sub Saharan African migrant community venues in the city of Antwerp, Belgium, between December 2012 and June 2013. Overall, 18.2% of all people present (N=780) underwent HIV testing; 29.8% of them tested for HIV for the first time, 22.3% did not have a general practitioner, and 21.5% reported 2 or more sexual partners (last 3 months). Overall, 56.3% of participants chose to collect their HIV test results via the protected website. In total, 78.9% collected their results. The qualitative analysis of 137 participant observation field notes showed that personal needs and Internet literacy determined the choice of result collection method. Generally, the oral fluid collection devices were well accepted mainly because sub-Saharan African migrants dislike blood taking. For some participants, the method raised concerns about HIV transmission via saliva. The combination of information sessions, testimonies, and oral fluid collection devices was perceived as effectively reducing thresholds to participation. Acceptability of the intervention differed between individual participants and settings. Acceptance was higher among women, in churches and settings where community leaders were engaged in HIV awareness raising. Higher preventive outcomes were observed in settings with lower acceptance. The presence of the intervention team visualized the magnitude of the HIV epidemic to the public and promoted HIV testing uptake at large, for example, those who declined indicated they would take up testing later. CONCLUSIONS: When accompanied by tailored provision of information, outreach HIV testing interventions adopting a community-based approach and innovative methods such as Web-based result collection and oral fluid collection devices are acceptable and reduce thresholds for HIV testing uptake. The swab2know intervention was able to reach sub-Saharan African migrants at risk of HIV infection, and with limited access to regular HIV testing. Among nontesters, the intervention contributed to awareness raising and therefore has a place in a multipronged HIV test promotion strategy. PMID- 27493068 TI - Badgers prefer cattle pasture but avoid cattle: implications for bovine tuberculosis control. AB - Effective management of infectious disease relies upon understanding mechanisms of pathogen transmission. In particular, while models of disease dynamics usually assume transmission through direct contact, transmission through environmental contamination can cause different dynamics. We used Global Positioning System (GPS) collars and proximity-sensing contact-collars to explore opportunities for transmission of Mycobacterium bovis [causal agent of bovine tuberculosis] between cattle and badgers (Meles meles). Cattle pasture was badgers' most preferred habitat. Nevertheless, although collared cattle spent 2914 collar-nights in the home ranges of contact-collared badgers, and 5380 collar-nights in the home ranges of GPS-collared badgers, we detected no direct contacts between the two species. Simultaneous GPS-tracking revealed that badgers preferred land > 50 m from cattle. Very infrequent direct contact indicates that badger-to-cattle and cattle-to-badger M. bovis transmission may typically occur through contamination of the two species' shared environment. This information should help to inform tuberculosis control by guiding both modelling and farm management. PMID- 27493069 TI - Gold Nanocups: Colloidal Gold Nanocups with Orientation-Dependent Plasmonic Properties (Adv. Mater. 30/2016). AB - On page 6322, J. F. Wang and co-workers report a wet-chemistry method for the preparation of colloidal Au nanocups and their plasmonic properties. The Au nanocups are prepared through single-vertex-initiated Au deposition on PbS nano octahedrons and subsequent selective dissolution of PbS. Owing to the orientation dependent coupling strengths, the obtained Au nanocups display orientation dependent plasmonic properties and Raman enhancements when deposited on substrates. PMID- 27493072 TI - Antimonene: Mechanical Isolation of Highly Stable Antimonene under Ambient Conditions (Adv. Mater. 30/2016). AB - On page 6332, J. Gomez-Herrero, F. Zamora, and co-workers describe the isolation of antimonene, a new allotrope of antimony that consists of a single layer of atoms. They obtain antimonene flakes by the scotch tape method; these flakes are highly stable in ambient conditions and even when immersed in water. The 1.2 eV gap calculated in this study suggests potential applications in optoelectronics. PMID- 27493071 TI - Zinc-Air Batteries: Flexible Rechargeable Zinc-Air Batteries through Morphological Emulation of Human Hair Array (Adv. Mater. 30/2016). AB - On page 6421, Z. Chen and co-workers describe an electrically rechargeable, nanoarchitectured air electrode that morphologically emulates a human-hair array for solid-state zinc-air batteries. Grown directly on a stainless-steel mesh, the hair-like array can effectively catalyze molecular oxygen to water. Batteries equipped with this electrode show tangible benefits, including improved flexibility and performance. PMID- 27493073 TI - Nanoscale Electrodes: Nanoscale Electrodes for Flexible Electronics by Swelling Controlled Cracking (Adv. Mater. 30/2016). AB - The fabrication of nanospaced electrodes on a flexible substrate is a great challenge. W. Wang, J. Shao, and co-workers propose a novel approach to fabricate nanogap electrodes for flexible electronics using a swelling-controlled cracking method, which is described on page 6337. This method has the advantages of high applicability, parallel manufacturing capacity, and compatibility with flexible substrates. It provides a new way to create high-performance flexible electronics in a cost-efficient fashion. PMID- 27493075 TI - Transgenic approach to express the channelrhodopsin 2 gene in arginine vasopressin neurons of rats. AB - Optogenetics provides a powerful tool to regulate neuronal activity by light sensitive ion channels such as channelrhodopsin 2 (ChR2). Arginine vasopressin (AVP; also known as the anti-diuretic hormone) is a multifunctional hormone which is synthesized in the magnocellular neurosecretory cells (MNCs) of the hypothalamus. Here, we have generated a transgenic rat that expresses an AVP-ChR2 enhanced green fluorescent protein (eGFP) fusion gene in the MNCs of the hypothalamus. The eGFP fluorescence that indicates the expression of ChR2-eGFP was observed in the supraoptic nucleus (SON) and in the magnocellular division of the paraventricular nucleus (PVN) that is known to contain AVP-secreting neurons. The eGFP fluorescence intensities in those nuclei and posterior pituitary were markedly increased after chronic salt loading (2% NaCl in drinking water for 5days). ChR2-eGFP was localized mainly in the membrane of AVP-positive MNCs. Whole-cell patch-clamp recordings were performed from single MNCs isolated from the SON of the transgenic rats, and blue light evoked repetitive action potentials. Our work provides for the first time an optogenetic approach to selectively activate AVP neurons in the rat. PMID- 27493076 TI - Advanced age negatively impacts survival in an experimental brain tumor model. AB - Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with an average age of 64 years at the time of diagnosis. To study GBM, a number of mouse brain tumor models have been utilized. In these animal models, subjects tend to range from 6 to 12 weeks of age, which is analogous to that of a human teenager. Here, we examined the impact of age on host immunity and the gene expression associated with immune evasion in immunocompetent mice engrafted with syngeneic intracranial GL261. The data indicate that, in mice with brain tumors, youth conveys an advantage to survival. While age did not affect the tumor infiltrating T cell phenotype or quantity, we discovered that old mice express higher levels of the immunoevasion enzyme, IDO1, which was decreased by the presence of brain tumor. Interestingly, other genes associated with promoting immunosuppression including CTLA-4, PD-L1 and FoxP3, were unaffected by age. These data highlight the possibility that IDO1 contributes to faster GBM outgrowth with advanced age, providing rationale for future investigation into immunotherapeutic targeting in the future. PMID- 27493077 TI - Polyphenols in dementia: From molecular basis to clinical trials. AB - Dementia is common in the elderly, but there are currently no effective therapies available to prevent or treat this syndrome. In the last decade, polyphenols (particularly curcumin, resveratrol and tea catechins) have been under very close scrutiny as potential therapeutic agents for neurodegenerative diseases, diabetes, inflammatory diseases and aging. Data were collected from Web of Science (ISI Web of Knowledge), Pubmed and Medline (from 2000 to 2015), by searching for the keywords "dementia" AND "curcumin", "resveratrol", "EGCG", "tea catechins". The same keywords were used to investigate the current state of clinical trials recorded in the NIH clinicaltrials.gov registry. Starting from the intrinsic properties of the compounds, we explain their specific action in patients with AD and the most common types of dementia. The pharmacological actions of curcumin, resveratrol and tea catechins have mainly been attributed to their antioxidant activity, interaction with cell signaling pathways, anti inflammatory effect, chelation of metal ions, and neuroprotection. Evidence from in vitro and in vivo studies on polyphenols have demonstrated that they may play an integral role in preventing and treating diseases associated with neurodegeneration. Furthermore, we critically analyze the clinical trials that we found, which investigate the real pharmacological actions and the possible side effects of these compounds. This review highlights the potential role of polyphenols in the prevention/treatment of dementia and describes the current limitations of research in this field. PMID- 27493078 TI - A highly reproducible mice model of chronic kidney disease: Evidences of behavioural abnormalities and blood-brain barrier disruption. AB - AIMS: In the present study, a novel mice model of chronic kidney disease (CKD) was developed, and psycho-motor behavioural abnormalities, blood-brain barrier (BBB) integrity and brain histology were studied. MAIN METHODS: Swiss albino female mice were given high adenine diet (0.3% w/w mixed with feed) for 4weeks. Serum urea and creatinine levels and renal histological studies were performed to validate the model. Psycho-motor behavioural abnormalities and neurological severity were studied. BBB integrity was assessed using Evans blue extravasation method. Nissl staining was performed to see possible morphological aberrations in brain. KEY FINDINGS: There was a significant increase in serum urea and creatinine levels in mice given high adenine diet, and the mice had abnormal kidney morphology. Deposition of adenine and 2,8-dihydroxyadenine crystals, and increased collagen deposits in the renal tissues were found, which validate induction of CKD in the mice. Motor behavioural abnormalities, depression-like and anxiolytic behaviour and increase in neurological severity were prevalent in mice with CKD. Evans Blue dye extravasation was found to occur in the brain, which signifies disruption of BBB. However, Nissl staining did not reveal any morphological aberration in brain tissue. SIGNIFICANCE: The present study puts forward a highly reproducible mice model of CKD validated with serum parameters and renal histopathological changes. The mice showed psycho-motor behavioural abnormalities and BBB disruption. It is a convenient model to study the disease pathology, and understanding the associated disorders, and their therapeutic interventions. PMID- 27493079 TI - Diabetes and exposure to peritoneal dialysis solutions alter tight junction proteins and glucose transporters of rat peritoneal mesothelial cells. AB - AIM: To evaluate alterations in tight junction (TJ) proteins and glucose transporters in rat peritoneal mesothelial cells (RPMC) from diabetic rats and after treatment with peritoneal dialysis solutions (PDS) in vitro. METHODS: Diabetes was induced in female Wistar rats by streptozotocin (STZ)-injection. Twenty-one days after STZ-injection, peritoneal thickness and mesothelial cell morphology were studied by light microscopy and microvilli length and density by atomic force microscopy. RPMC were obtained from healthy and diabetic rats. Mesothelial phenotype, evaluated by cytokeratin and pan-cadherin, epithelial to mesenchymal transition (EMT), evaluated by alpha-smooth muscle action (alpha-SMA) and vimentin, TJ proteins, claudins-1 and -2, and occludin, and glucose transporters, sodium and glucose co-transporters (SGLT) -1 and -2 and facilitative glucose transporters (GLUT) -1 and -2 were analyzed. Also, transepithelial electrical resistance (TER) was measured. Oxidative stress was estimated by measuring reactive oxygen species production, and protein carbonylation, receptor for advanced glycation end products (RAGE), nuclear factor erythroid related factor-2 (Nrf-2), and expression of antioxidant enzymes. KEY FINDINGS: Peritoneal damage was present 21days after STZ-injection. Diabetes induced changes in TJ and glucose transporters in RPMC together with decreased TER. RPMC from diabetic rats showed oxidative stress, which was enhanced by exposure to PDS. In addition, RPMC from diabetic rats showed early EMT. SIGNIFICANCE: To our knowledge, this is the first study that shows changes in TJ proteins and glucose transporters of RPMC from diabetic rats. All these alterations might explain the increased peritoneal permeability observed in diabetic patients undergoing peritoneal dialysis. PMID- 27493080 TI - Cytomorphology and Clinicopathologic Correlation of the Recurrent and Metastatic Adult Granulosa Cell Tumor of the Ovary: A Retrospective Review. AB - Granulosa cell tumors (GCT) of the ovary are low grade tumor with a potential ability of late pelvic recurrences and distant metastases. However, there is sparse literature on the cytopathologic features of metastatic granulosa cell tumors (MGCT). Between 2000 and 2014, eight cases of MGCT were diagnosed by FNA. Clinical, cytologic, and histopathologic features were reviewed. The age ranged from 34 to 84 years. Metastases were found in abdominal wall (4 cases), pelvic mass (1 case), liver (2 cases), and lung (1 case). The time to metastasis ranged from 1 to 14 years. All cases were hypercellular, with both large and small overlapping cell clusters and individual cells. The cytologic features included: naked nuclei (8/8 cases), Call-Exner bodies (2/8 cases), and prominent metachromatic stroma (3/8 cases). Moderate cytoplasm (4/8 cases) to scant delicate cytoplasm (4/8 cases) was seen. Cytoplasmic vacuoles were also noted (6/8 cases). N/C ratios were high although lower than small round cell tumors like lymphoma. Prominent, central nucleoli were also present (6/8 cases) as well as nuclear grooves (2/8 cases). Cell block was available in 3/8 cases and all were positive for inhibin immunostain. Histologic examination of the metastatic tissue confirmed MGCT. The important cytologic features of GCT like uniformity of tumor cells, nuclear grooves and Call-Exner bodies are occasionally present in MGCT. Prominent nucleoli and many naked nuclei were frequent. Therefore, the accurate interpretation of cytologic findings of MGCT requires cytohistologic correlation and inhibin positivity to avoid unnecessary surgical interventions for diagnostic purposes. The possibility of late recurrence of GCT should be kept in mind. Diagn. Cytopathol. 2016;44:1058-1063. (c) 2016 Wiley Periodicals, Inc. PMID- 27493081 TI - Host Th1/Th2 immune response to Taenia solium cyst antigens in relation to cyst burden of neurocysticercosis. AB - Neurocysticercosis (NCC), Taenia solium larval infection of the brain, is an important cause of acquired seizures in endemic countries, which relate to number, location and degenerating cysts in the brain. Multicyst infections are common in endemic countries although single-cyst infection prevails in India. Single-cyst infections in an endemic country suggest a role for host immunity limiting the infection. This study examined ex vivo CD4(+) T cells and in vitro Th1 and Th2 cytokine responses to T. solium cyst antigens of peripheral blood mononuclear cells of healthy subjects from endemic and nonendemic regions and of single- and multicyst-infected patients for association with cyst burden of NCC. T. solium cyst antigens elicited a Th1 cytokine response in healthy subjects of T. solium-endemic and T. solium-non-endemic regions and those with single-cyst infections and a Th2 cytokine response from subjects with multicyst neurocysticercosis. Multicyst neurocysticercosis subjects also exhibited low levels of effector memory CD4(+) T cells. Th1 cytokine response of T. solium exposure and low infectious loads may aid in limiting cyst number. Th2 cytokines and low effector T cells may enable multiple-cyst infections to establish and persist. PMID- 27493083 TI - Infective endocarditis in patients with bicuspid aortic valve: Clinical characteristics, complications, and prognosis. AB - INTRODUCTION: Bicuspid aortic valve (BAV) is the most frequent congenital cardiac disease. It is associated to a higher risk of cardiovascular complications, including infective endocarditis (IE). METHODS: Retrospective, observational and single centre study that included all patients with IE diagnosed between 1996 and 2014. An analysis was made of the epidemiological, clinical, microbiological and echocardiographic data, complications during hospital admission, need for surgery, in-hospital mortality, and 1-year follow-up. Cases with endocarditis on prosthetic valves or other locations were excluded, as well as those for which the aortic valve morphology had not been accurately defined. A comparative statistical analysis was performed between BAV and tricuspid (TAV). RESULTS: Of a total of 328 cases with IE, 118 (35.67%) were on aortic valve, with 18 (16.22%) of them being BAV. The BAV cases were younger than TAV (51+/-19.06 vs. 60.83+/ 15.73 years, P=.021) and they had less comorbidity (Charlson 0.67+/-0.77 vs. 1.44+/-1.64, P=.03).). There was a higher tendency of Staphylococcal origin (38.9 vs. 21.5%, P=.137), and 55.6% showed peri-valvular complications (TAV 16.1%, P=.001), in particular, abscesses (38.9 vs.16.1%, P=.047). BAV was the only predictive factor of peri-valvular complications (OR 7.87, 95% CI; 2.38-26.64, P=.001). Patients with BAV had more surgery during their admission (83.3 vs. 44.1%, P=.004), had less in-hospital mortality, with no statistical significance (5.6 vs. 25.8%, P=.069), and 1-year survival was significantly superior (93.8 vs 69.3%, P=.048). CONCLUSIONS: Patients with IE on BAV are young, with low comorbidity. They frequently present with peri-valvular complications and they often require early surgery. Compared to TAV cases, in-hospital mortality is lower and 1-year survival is significantly higher. PMID- 27493082 TI - Fibrous dysplasia of bone: craniofacial and dental implications. AB - Fibrous dysplasia (FD) is a rare bone disease caused by postzygotic somatic activating mutations in the GNAS gene, which lead to constitutive activation of adenylyl cyclase and elevated levels of cyclic AMP, which act on downstream signaling pathways and cause normal bone to be replaced with fibrous tissue and abnormal (woven) bone. The bone disease may occur in one bone (monostotic), multiple bones (polyostotic), or in combination with hyperfunctioning endocrinopathies and hyperpigmented skin lesions (in the setting of McCune Albright Syndrome). FD is common in the craniofacial skeleton, causing significant dysmorphic features, bone pain, and dental anomalies. This review summarizes the pathophysiology, clinical findings, and treatment of FD, with an emphasis on the craniofacial and oral manifestations of the disease. PMID- 27493084 TI - Life Lessons for Successful Leadership. PMID- 27493085 TI - How Hard Could It Be? PMID- 27493086 TI - The Fellowship Arms Race Revisited. PMID- 27493087 TI - Avoid "Short-Term": Use Units of Time for Follow-Up Recommendations. PMID- 27493088 TI - H/KDEL receptors mediate host cell intoxication by a viral A/B toxin in yeast. AB - A/B toxins such as cholera toxin, Pseudomonas exotoxin and killer toxin K28 contain a KDEL-like amino acid motif at one of their subunits which ensures retrograde toxin transport through the secretory pathway of a target cell. As key step in host cell invasion, each toxin binds to distinct plasma membrane receptors that are utilized for cell entry. Despite intensive efforts, some of these receptors are still unknown. Here we identify the yeast H/KDEL receptor Erd2p as membrane receptor of K28, a viral A/B toxin carrying an HDEL motif at its cell binding beta-subunit. While initial toxin binding to the yeast cell wall is unaffected in cells lacking Erd2p, binding to spheroplasts and in vivo toxicity strongly depend on the presence of Erd2p. Consistently, Erd2p is not restricted to membranes of the early secretory pathway but extends to the plasma membrane where it binds and internalizes HDEL-cargo such as K28 toxin, GFP(HDEL) and Kar2p. Since human KDEL receptors are fully functional in yeast and restore toxin sensitivity in the absence of endogenous Erd2p, toxin uptake by H/KDEL receptors at the cell surface might likewise contribute to the intoxication efficiency of A/B toxins carrying a KDEL-motif at their cytotoxic A-subunit(s). PMID- 27493089 TI - Anti-apoptotic effect of interleukin-22 on fibroblast-like synoviocytes in patients with rheumatoid arthritis is mediated via the signal transducer and activator of transcription 3 signaling pathway. AB - AIM: Inadequate apoptosis of fibroblast-like synoviocytes (FLS) plays a crucial role in the immunopathogenesis of rheumatoid arthritis (RA). Interleukin-22 (IL 22) is a novel member of the cytokine network that has been found to be involved in the immunological process underlying RA. In this study, we investigated the effect of IL-22 on the survival of RA-FLS from RA patients and examined the possible mechanism to determine new therapeutic strategies for RA. METHODS: FLS obtained from patients with RA were cultured in vitro and treated with sodium nitroprussiate (SNP) to induce apoptosis in the presence or absence of IL-22. RA FLS viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. RA-FLS apoptosis was analyzed by annexin V/propidium iodide staining (AV/PI). The levels of IL-22R1, pSTAT3-Y705, pSTAT3 S727, total STAT3, Bcl-xL and Bcl-2 were detected by Western blot analysis. RESULTS: IL-22R1 was expressed on RA-FLS. IL-22 pretreatment at concentrations ranging from 10 to 100 ng/mL increased RA-FLS viability and prevented SNP-induced apoptosis. Treatment with the STAT3 inhibitors, HO3867 or STA21, reversed the protective effect of IL-22 on SNP-induced apoptosis of RA-FLS. IL-22-induced phosphorylation of STAT3 (pSTAT3-Y705 and pSTAT3-S727) was increased in RA-FLS. Also IL-22 increased Bcl-2 expression in SNP-treated RA-FLS, and the effect was reversed by treatment with HO3867 or STA21. CONCLUSION: IL-22 protects against SNP-induced apoptosis in RA-FLS by activating the STAT3 pathway and the downstream target gene, Bcl-2. Therefore, therapeutic strategies that target the IL-22/STAT3 pathway are implicated as candidates for RA treatment. PMID- 27493090 TI - Early progression of proximal intramural hematoma to overt aortic dissection during initial computed tomographic evaluation. PMID- 27493091 TI - CASE 9-2016: Management of a Former Cardiac Anesthesiologist With Increasing Aortic Stenosis Requiring Aortic Valve Replacement. PMID- 27493092 TI - Efficacy and Safety of Fibrinogen Concentrate in Surgical Patients: A Meta Analysis of Randomized Controlled Trials. AB - OBJECTIVES: To investigate the efficacy and safety of fibrinogen concentrate (FC) in surgical patients. DESIGN: Meta-analysis of randomized controlled studies (RCTs). SETTING: Perioperative. PARTICIPANTS: Adult and pediatric surgical patients. INTERVENTIONS: A search of PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials, Transfusion Evidence Library, Google Scholar, and the proceedings from major international anesthesiology meetings up to February 1, 2016 for RCTs that compared FC with placebo or other comparators. MEASUREMENTS AND MAIN RESULTS: The primary outcome was all-cause mortality. Pooled risk ratios and mean differences (MDs) were computed with either fixed-effects or random effects models. The study included 14 RCTs comprising 1,035 patients; the majority of patients underwent cardiac surgery. All-cause mortality was lower in the fibrinogen group (4/432 [0.9%] v 15/430 [3.5%]; risk ratio 0.26; 95% confidence interval [CI] 0.09-0.78; p = 0.02; heterogeneity statistic (l2) = 0%). The use of FC was associated with reduced bleeding (MD -127 mL; 95% CI -207 to 47; p = 0.002; I2= 54%) and a lower number of red blood cells units transfused versus comparator (MD -0.9; 95% CI -1.3 to -0.5; p<0.001; I2 = 42%). There were no differences in the rates of thrombotic events and myocardial infarction. CONCLUSIONS: In surgical patients, FC was associated with reduced bleeding and a lower number of red blood cell units transfused, and it also might reduce mortality. However, none of the analyzed trials was powered for estimation of survival and adverse events with FC use. Half of the included studies were of high or moderate risk of bias. The evidence primarily came from cardiac surgery settings. PMID- 27493093 TI - A Pharmacokinetic Model for Protamine Dosing After Cardiopulmonary Bypass. AB - OBJECTIVE: This study investigated postoperative hemostasis of patients subjected to conventional protamine dosing compared with protamine dosing based on a pharmacokinetic (PK) model following cardiopulmonary bypass. DESIGN: Retrospective case-control study. SETTING: Tertiary university hospital. PARTICIPANTS: Patients undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: In 56 patients, protamine was dosed in a fixed ratio (CD), while 62 patients received protamine based on the PK model. MEASUREMENTS AND MAIN RESULTS: There was no difference in heparin administration (414+/-107 mg (CD) v 403+/-90 mg (PK); p = 0.54), whereas protamine dosing was considerably different with a protamine-to-heparin dosing ratio of 1.1+/-0.3 for the CD group and 0.5+/ 0.1 for the PK group (p<0.001). The changes in activated coagulation time (DeltaACT) values (ACT after protamine minus preoperative ACT;+17+/-77 s v+6+/-15 s; p = 0.31) were equal between groups. Yet, the thromboelastometric intrinsically activated coagulation test clotting time (CT; 250+/-76 s v 203+/-44 s; p<0.001) and intrinsically activated coagulation test without the heparin effect CT (275+/-105 v 198+/-32 s; p<0.001) were prolonged in the CD group. Median packed red blood cell transfusion (0 [0-2] v 0 [0-0]), fresh frozen plasma transfusion (1 [0-2] v 0 [0-0]), and platelet concentrate transfusion (0 [0-1] v 0 [0-0]) were different between the fixed ratio and PK group, respectively (all p<0.001). CONCLUSIONS: This study showed that patient-tailored protamine dosing based on a PK model was associated with a reduction in protamine dosing, with better hemostatic test results when compared with fixed-ratio protamine dosing. PMID- 27493094 TI - Hyperlactemia Predicts Surgical Mortality in Patients Presenting With Acute Stanford Type-A Aortic Dissection. AB - OBJECTIVE: Inspired by the limited facility of the Penn classification, the authors aimed to determine a rapid and optimal preoperative assessment tool to predict surgical mortality after acute Stanford type-A aortic dissection (AAAD) repair. DESIGN: Patients who underwent an attempted surgical repair of AAAD were determined using a de-identified single institution database. The charts of 144 patients were reviewed retrospectively for preoperative demographics and surrogates for disease severity and malperfusion. Bivariate analysis was used to determine significant (p<=0.05) predictors of in-hospital and 1-year mortality, the primary endpoints. Receiver operating characteristic curve generation was used to define optimal cut-off values for continuous predictors. SETTING: Single center, level 1 trauma, university teaching hospital. PARTICIPANTS: The study included 144 cardiac surgical patients with acute type-A aortic dissection presenting for surgical correction. INTERVENTIONS: Surgical repair of aortic dissection with preoperative laboratory samples drawn before patient transfer to the operating room or immediately after arterial catheter placement intraoperatively. MEASUREMENTS AND MAIN RESULTS: The study cohort comprised 144 patients. In-hospital mortality was 9%, and the 1-year mortality rate was 17%. Variables that demonstrated a correlation with in-hospital mortality included an elevated serum lactic acid level (odds ratio [OR] 1.5 [1.3-1.9], p<0.001), a depressed ejection fraction (OR 0.91 [0.86-0.96], p = .001), effusion (OR 4.8 [1.02-22.5], p = 0.04), neurologic change (OR 5.3 [1.6-17.4], p = 0.006), severe aortic regurgitation (OR 8.2 [2.0-33.9], p = 0.006), and cardiopulmonary resuscitation (OR 6.8 [1.7-26.9], p = 0.01). Only an increased serum lactic acid level demonstrated a trend with 1-year mortality using univariate Cox regression (hazard ratio 1.1 [1.0-1.1], p = 0.006). Receiver operating characteristic analysis revealed optimal cut-off lactic acid levels of 6.0 mmol/L and 6.9 mmol/L for in-hospital and 1-year mortality, respectively. CONCLUSION: Lactic acidosis, ostensibly as a surrogate for systemic malperfusion, represents a novel, accurate, and easily obtainable preoperative predictor of short-term mortality after attempted AAAD repair. These data may improve identification of patients who would not benefit from surgery. PMID- 27493095 TI - MicroRNA-3178 ameliorates inflammation and gastric carcinogenesis promoted by Helicobacter pylori new toxin, Tip-alpha, by targeting TRAF3. AB - BACKGROUND: Helicobacter pylori infection is the main cause of chronic gastritis, peptic ulcer, and gastric cancer. Tip-alpha is a newly identified carcinogenic factor present in H. pylori. TRAF3 can activate NF-kappaB by both canonical and noncanonical signaling pathways. In this study, we found that the expression of TRAF3 and NF-kappaB was upregulated, while microRNA-3178 (miR-3178) was decreased in H. pylori-positive gastric tissues but not in H. pylori-negative tissues. MATERIALS AND METHODS: GES-1 cells were incubated with 12.5 MUg/mL recombinant Tip-alpha (rTip-alpha) in RPMI1640 for 2 hours. After another 24 hours, the supernatant medium was designed as inflammatory-conditioned medium (ICM) and that from the untreated control cells was designed as untreated control medium. The release of proinflammatory cytokines from GES-1 cells and proliferation of gastric cancer cells was determined by ELISA and CCK-8 kits. Cells were transfected with the mimic, inhibitor, negative control of miR-3178, or TRAF3 siRNA control siRNA. The medium was then replaced with RPMI1640, 12.5 MUg/mL rTip alpha, and collected, and the total cellular RNA and protein were extracted for the following detection. RESULTS: MiR-3178 mimic prevented the increasement of TRAF3 and hence decreased activation of NF-kappaB signals, whereas miR-3178 inhibitor could not, in GES-1 cells with Tip-alpha treatment. The condition medium from miR-3178 mimic transfected GES-1 cells could inhibit proliferation and induce apoptosis of inflammation-related gastric cancer cells SGC7901 and MGC803 by decreasing the production of inflammatory cytokines TNF-alpha and IL-6, which were secreted by GES-1 cells. CONCLUSIONS: Taken all together, Tip-alpha might activate NF-kappaB to promote inflammation and carcinogenesis by inhibiting miR-3178 expression, which directly targeting TRAF3, during H. pylori infection in gastric mucosal epithelial cells. PMID- 27493097 TI - Analysis of allergic immune responses in humanized mice. AB - Nowadays, more than 25% of the population in industrial countries are affected by IgE-mediated (atopic) allergic diseases such as allergic rhinitis, asthma and atopic eczema. Due to intensive research on basis of in vitro studies with human immune cells and different murine in vivo models of allergy fundamental mechanisms of allergic immune responses have been elucidated during the last years. However, human studies are restricted and the immune system of mice differs from the human immune system in several aspects so that the transferability of experimental results from mice to men is limited. Humanized mice represent a new tool to analyze the interaction of human immune cells under physiological conditions as far as possible, particularly to test novel therapeutic strategies. This review summarizes the impact of humanized mouse models for the investigation and treatment of allergic diseases. PMID- 27493096 TI - Memory T cells in cutaneous leishmaniasis. AB - Leishmania causes a spectrum of diseases that range from self-healing to fatal infections. Control of leishmania is dependent upon generating CD4+ Th1 cells that produce IFNgamma, leading to macrophage activation and killing of the intracellular parasites. Following resolution of the disease, short-lived effector T cells, as well as long-lived central memory T cells and skin resident memory T cells, are retained and able to mediate immunity to a secondary infection. However, there is no vaccine for leishmaniasis, and the drugs used to treat the disease can be toxic and ineffective. While a live infection generates immunity, a successful vaccine will depend upon generating memory T cells that can be maintained without the continued presence of parasites. Since both central memory and skin resident memory T cells are long-lived, they may be the appropriate targets for a leishmaniasis vaccine. PMID- 27493098 TI - Nerve growth factor facilitates perivascular innervation in neovasculatures of mice. AB - It is well known that blood vessels including arterioles have a perivascular innervation. It is also widely accepted that perivascular nerves maintain vascular tone and regulate blood flow. Although there are currently prevailing opinions, unified views on the innervation of microcirculation in any organs have not been established. The present study was designed to investigate whether there are perivascular nerves innervated in microvessels and neovessels. Furthermore, we examined whether nerve growth factor (NGF) can exert a promotional effect on perivascular nerve innervation in neovessels of Matrigel plugs. A Matrigel was subcutaneously implanted in mouse. The presence of perivascular nerves in Matrigel on Day 7-21 after the implantation was immunohistochemically studied. NGF or saline was subcutaneously administered by an osmotic mini-pump for a period of 3-14 days. The immunostaining of neovasculatures in Matrigel showed the presence of perivascular nerves on Day 21 after Matrigel injection. Perivascular nerve innervation of neovessels within Matrigel implanted in NGF-treated mice was observed in Day 17 after Matrigel implantation. However, NGF treatment did not increase numbers of neovessels in Matrigel. These results suggest that perivascular nerves innervate neovessels as neovasculatures mature and that NGF accelerates the innervation of perivascular nerves in neovessels. PMID- 27493099 TI - Deletion of LR11 Attenuates Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation With Medial Thickening in Mice. AB - OBJECTIVE: We aimed to determine whether LR11 (low-density lipoprotein receptor with 11 binding repeats) is a potential key regulator of smooth muscle cell (SMC) proliferation during the progression of hypoxia-induced medial thickening in mice and whether sLR11 (soluble LR11) can serve as a biomarker in patients with pulmonary arterial hypertension. APPROACH AND RESULTS: The role of LR11 in pulmonary arterial hypertension was investigated using mouse and cell models of induced hypoxia. The expression of LR11 and of hypoxia-inducible factor-1alpha was significantly increased in lung tissues from C57Bl/6 mice after 3 weeks of exposure to hypoxia compared with normoxia. Serum sLR11 levels were also increased. Physiological and histochemical analyses showed that increased right ventricular systolic pressure, right ventricular hypertrophy, and medial thickening induced under hypoxia in wild-type mice were attenuated in LR11(-/-) mice. The proliferation rates stimulated by hypoxia or platelet-derived growth factor-BB were attenuated in SMC derived from LR11(-/-) mice, compared with those from wild-type mice. Exogenous sLR11 protein increased the proliferation rates of SMC from wild-type mice. The expression of LR11 and hypoxia-inducible factor 1alpha was increased in cultured SMC under hypoxic conditions, and hypoxia inducible factor-1alpha knockdown almost abolished the induction of LR11. Serum sLR11 levels were significantly higher in patients with, rather than without, pulmonary arterial hypertension. sLR11 levels positively correlated with pulmonary vascular resistance and mean pulmonary arterial pressure. CONCLUSIONS: LR11 regulated SMC proliferation during the progression of hypoxia-induced medial thickening in mice. The findings obtained from mice, together with those in humans, indicate that sLR11 could serve as a novel biomarker that reflects the pathophysiology of proliferating medial SMC in pulmonary arterial hypertension. PMID- 27493101 TI - The synergistic effect between vanillin and doxorubicin in ehrlich ascites carcinoma solid tumor and MCF-7 human breast cancer cell line. AB - Despite the remarkable anti-tumor activity of doxorubicin (DOX), its clinical application is limited due to multiple organ toxicities. Products with less side effects are therefore highly requested. The current study investigated the anti cancer activities of vanillin against breast cancer and possible synergistic potentiation of DOX chemotherapeutic effects by vanillin. Vanillin (100mg/kg), DOX (2mg/kg) and their combination were administered i.p. to solid Ehrlich tumor bearing mice for 21days. MCF-7 human breast cancer cell line was treated with vanillin (1 and 2mM), DOX (100MUM) or their combination. Protection against DOX induced nephrotoxicity was studied in rats that received vanillin (100mg/kg, ip) for 10days with a single dose of DOX (15mg/kg) on day 6. Vanillin exerted anticancer effects comparable to DOX and synergesticlly potentiated DOX anticancer effects both in-vivo and in-vitro. The anticancer potency of vanillin in-vivo was mediated via apoptosis and antioxidant capacity. It also offered an in-vitro growth inhibitory effect and cytotoxicity mediated by apoptosis (increased caspase-9 and Bax:Bcl-2 ratio) along with anti-metasasis effect. Vanillin protected against DOX-induced nephrotoxicity in rats. In conclusion, vanillin can be a potential lead molecule for the development of non-toxic agents for the treatment of breast cancer either alone or combined with DOX. PMID- 27493100 TI - Probucol in Albuminuric Type 2 Diabetes Mellitus Patients on Renin-Angiotensin System Blockade: A 16-Week, Randomized, Double-Blind, Placebo-Controlled Trial. AB - OBJECTIVE: To determine the effect of probucol on urine albumin excretion in type 2 diabetes mellitus patients with albuminuria using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. APPROACH AND RESULTS: This was a 16 week, phase II, randomized, placebo-controlled, parallel-group study in type 2 diabetes mellitus patients with a urinary albumin/creatinine ratio of >=300 mg/g using angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, conducted in 17 tertiary referral hospitals. Eligible patients were randomized to probucol 250 mg/d (n=44), probucol 500 mg/d (n=41), and placebo (n=41) groups in a ratio of 1:1:1 after block randomization procedures, keeping the treatment assignment blinded to the investigators, patients, and study assistants. The primary end point was change in the geometric mean of urinary albumin/creatinine ratio from baseline to week 16 (ClinicalTrials.gov identifier NCT01726816). The study was started on November 8, 2012, and completed on March 24, 2014. The least squares mean change+/-SE from baseline in urinary albumin/creatinine ratio at week 16 was -7.2+/-639.5 mg/g in the probucol 250 mg/d group (n=43; P=0.2077 versus placebo group), 9.3+/-587.4 mg/g in the probucol 500 mg/d group (n=40; P=0.1975 versus placebo group), and 259.0+/-969.1 mg/g in the placebo group (n=41). Although the majority of subjects were on statins, probucol treatment significantly lowered total cholesterol and low-density lipoprotein cholesterol levels. QT prolongation occurred in one and two subjects in control and probucol 250 mg/d groups, respectively. CONCLUSIONS: Four months of probucol up to 500 mg/d failed to reduce urinary albumin excretion. PMID- 27493102 TI - Involvement of mast cells and microvessels density in reactive lesions of oral cavity: A comparative immunohistochemical study. AB - In view of the similarity of clinicopathological features between reactive lesions of the oral cavity, the objective of the present study was to investigate the density of MCs (mast cells) and microvessels in a series of these lesions. Thirty-seven cases of reactive lesions including fibrous hyperplasia (FH, n=10), inflammatory fibrous hyperplasia (IFH, n=10), peripheral giant cell lesion (PGCL, n=10) and lobular capillary hemangioma (LCH, n=7) were investigated using immunohistochemistry for mast cell tryptase and CD34. For comparative purposes, central giant cell lesions (CGCL, n=5) were included. A higher MC density was observed in LCH (37.01), while CGCL exhibited the lowest density (n=8.14). There was a significant difference in MC density when all reactive lesions were compared to CGCL (p=0.001). The largest mean density of microvessels was observed in LCH (n=21.69). The smallest number was observed in CGCL (n=6.24). There was a significant difference in microvessel density when the reactive lesions were compared to CGCL (p=0.003). There was a significant and direct correlation between the density of MCs and microvessels only for IFH (p=0.048) and CGCL (p=0.005). A significant and direct correlation between the mean density of MCs and microvessels was observed when the reactive lesions were analyzed as a whole (p=0.005). Our results suggest that mast cells contribute to the connective tissue framework and angiogenic function, as well as the development, of reactive lesions of the oral cavity, including FH, IFH, LCH and PGCL. PMID- 27493103 TI - Diastolic dysfunction is associated with low urinary sodium excretion in patients with decompensated cirrhosis. AB - BACKGROUND/AIM: The pathogenesis and the clinical impact of diastolic dysfunction (DD) in cirrhosis remain unclear. Our aim was to investigate the factors significantly associated with the presence of DD in patients with decompensated cirrhosis on the waiting list for liver transplantation. MATERIAL AND METHODS: consecutive patients with decompensated cirrhosis, who admitted for transplant assessment, were prospectively evaluated. We assessed the independent factors associated with the presence of DD, while their discriminative ability was evaluated by AUC curve. The diagnosis of DD was based on Doppler echocardiography and classified into three categories according to the current guidelines. RESULTS: we evaluated 115 consecutive patients. Sixty six patients (57.3%-group 1) had DD and 49 (42.7%-group 2) had not DD. The 2 groups had similar Child Pugh/MELD scores and survival. In multivariable logistic regression analysis, pulse rate (OR: 1.082, 95% CI: 1.03-1.15, p = 0.004), and UNa24h (OR: 0.98, 95% CI: 0.97- 0.99, p = 0.004) were the only variables independently associated with the presence of DD. In the subgroup of consecutive patients (n = 31) with evaluation of cytokines, those (n = 22) with DD, compared to those (n = 9) without DD, had significantly higher levels of inteleukin-6 [145 (45-2000) vs. 56 (10-149)pg/mL, p = 0.043]. CONCLUSIONS: We found that DD was independently associated with lower 24-hour urine sodium. Although no correlation was found between DD and severity of liver disease or survival, further studies are needed for final conclusions. PMID- 27493104 TI - Economic growth leads to increase of obesity and associated hepatocellular carcinoma in developing countries. AB - Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer related death worldwide. In recent years, the prevalence of HCC has increased in both developing and developed countries. Most HCC cases develop in the presence of advanced chronic liver disease related to viral hepatitis. In particular hepatitis B virus and hepatitis C virus infections are considered as major HCC risk factors worldwide. However, current studies provide strong evidence for increasing numbers of HCC in nonalcoholic fatty liver disease (NAFLD). NAFLD represents the hepatic manifestation of metabolic syndrome which is based on obesity and insulin resistance. Epidemiologic data clearly demonstrates that NAFLD and obesity-related disorders are significant risk factors for tumor development in general and HCC in particular. As a consequence of life style changes towards higher calorie intake and less exercise, obesity and metabolic syndrome are spreading all over the world. Due to this increase in obesity and metabolic syndrome NAFLD-related HCC will become a major health care problem in the future. In conclusion, better understanding of the impact of NAFLD and obesity in the development of HCC will improve our treatment strategies of HCC and allow preventive measures. PMID- 27493105 TI - NASH: A glance at the landscape of pharmacological treatment. AB - The role of nonalcoholic fatty liver disease, namely nonalcoholic steatohepatitis (NASH), as risk factor for liver- and non-liver-related morbidity and mortality has been extensively reported. In addition to lifestyle changes, capable of removing the metabolic factors driving disease progression, there is an urgent need for drugs able to reduce hepatic necroinflammation without worsening of fibrosis. This goal is considered by regulatory agencies as surrogate marker to define the effectiveness in pharmacological compounds in NASH, and fast-track approval was granted by the Food and Drug Administration in consideration of disease severity and unmet medical needs. Several compounds are in the pipeline of pharmaceutical industries and are being studied in phase II trials, but only a few (obeticholic acid, elafibranor) have started phase III trials. This concise review is intended to offer a systematic analysis of the most promising therapeutic intervention in NASH. In conclusion, there is reasonable expectation that drug may help curb the burden of NASH, and we look forward to obtaining solid data on their long-term safety and effectiveness. However, we should not forget that behavioral interventions remain a mandatory background treatment, able to stop disease progression in compliant overweight/ obese patients, with results that compare favorably with - and add to - the beneficial effects of drug treatment. PMID- 27493106 TI - Assessment of intrahepatic regulatory T cells in children with autoimmune hepatitis. AB - Background. T-cell populations regulate the balance of immune responses. The CD (Cluster of differentiation) 4+CD25+ regulatory T cells (Tregs) are crucial for maintaining negative control of various immune responses. There are different T cell subpopulations with regulatory functions, as natural killer T cells, CD8+ and CD28. The forkhead box P3 (FOXP3) regulates Treg development and is required for its suppressive function. AIM: To evaluate the hepatic expression of the intrahepatic Tregs, Ig (immunoglobulin) G and IgM plasma cells in autoimmune hepatitis (AIH) and other chronic liver diseases (CLDs). MATERIAL AND METHODS: This study included 100 pediatric patients; 50 AIH and 50 CLDs other than AIH. All patients were subjected to routine investigations of CLDs plus immune staining of liver tissue for FOXp3, IgG and IgM plasma cells, CD4 and CD8 T cells. RESULTS: The FOXP3+ T cells in patients with AIH (6.3 +/- 5) were significantly higher than that in the non-AIH (2.1 +/- 2.6). FOXP3+ T cells were abundant in liver tissue with marked inflammatory cellular infiltrate. CD4+ and CD8+ infiltrating the liver tissue and IgG positive cells were significantly higher in AIH group, while the expression of IgM positive cells showed no significant difference. The IgG/IgM was significantly higher in the AIH treatment responders (3 +/- 3) than non-responders (1.6 +/- 0.5), while there was no significant difference regarding the intrahepatic expression of FOXP3+, CD4+, CD8+ cells, T-cells, IgG and IgM plasma cells. CONCLUSION: Intrahepatic Tregs were increased in number in patients with AIH in the initial presentation, and their presence is associated with increased activity and inflammation in liver biopsy. PMID- 27493107 TI - HAV and HBV seroprevalence in 1,000 patients with chronic HCV infection in a Tertiary Care Center in Sao Paulo, Brazil. AB - Background. Patients with chronic HCV infection and superinfection by hepatitis A virus (HAV) or hepatitis B virus (HBV) have higher morbidity and mortality when compared with those without HCV infection. Therefore, HAV and HBV active immunization has become mandatory in this population and hence their serological markers must be determined. The aim of this study was to evaluate the prevalence of serological markers of HAV and HBV infection in patients with chronic HCV. MATERIAL AND METHODS: One thousand chronic HCV patients at the University of Sao Paulo School of Medicine were evaluated for the prevalence of serological markers of HAV and HBV infection. RESULTS: Anti-HAV IgG was positive in 92.3% of patients. When stratified by age, anti-HAV IgG was found in 61% of patients between 20-29 years, 70% on patients between 30-39 years, 85% on patients between 40-49 years, 94% on patients between 50-59 years, and in 99% on patients over 60 years of age. Anti-HBc IgG was positive in 244 patients (24%). Stratified by age, in 4.3% of patients between 20-29 years, 17% 30-39 years, 21% 40-49 years, 24% 50 59 years, and in 28% of patients over 60 years. Of the 244 anti-HBc IgG positive patients, 0.8% were HBsAg positive, 8.5% were anti-HBc IgG isolated and 16% were also anti-HBs positive. CONCLUSIONS: In conclusion, the prevalence of anti-HAV IgG was similar to the general Brazilian population. However, anti-HBc IgG was higher in our patients, when compared to general population of Western countries, emphasizing the importance of immunization programs for this population. PMID- 27493108 TI - Resistance-associated polymorphisms in Dutch hepatitis C genotype 1a patients with and without HIV infection. AB - Background and aim. Resistance-associated variants (RAVs) on the NS3 region of the hepatitis C virus (HCV) may be relevant for antiviral therapy, but data in human immunodeficiency virus (HIV) coinfected patients are scarce. We assessed frequencies of NS3 RAVs in patients infected with HCV genotype 1a with or without HIV coinfection. MATERIAL AND METHODS: HCV NS3 amino acids 1-181 were sequenced by the Sanger method and analyzed for RAVs. RAVs and their distribution between HCV genotype 1a clade I and II viruses were compared between HIV-infected versus HIV-uninfected patients. RESULTS: 148 samples were available (n = 68 HIV and n = 80 non-HIV). Relative frequency of clade I and clade II was significantly different between HIV (85% and 15%) and non-HIV groups (49% and 51%). Overall, HIV infected patients exhibited significantly lower prevalence of RAVs than HIV uninfected patients (62% vs. 79%, p = 0.03). However, Q80K prevalence was significantly higher in HIV-infected subjects (50% vs. 24%, p = 0.001), whereas prevalence of S122D/G/N/S (2% vs. 16%, p = 0.002) and N174G/N/S (10% vs. 55%, p < 0.0001) polymorphisms were significantly lower. Q80K was found exclusively in clade I viruses. S122 (3% vs. 22%, p=0.001) and N174 (13% vs. 75%, p<0.0001) polymorphisms had significantly lower prevalence in clade I than clade II viruses. CONCLUSIONS: In the Netherlands, prevalence of clade I viruses and Q80K was significantly higher in HCV genotype 1a infected patients with HIV coinfection than in those without HIV coinfection. Prevalence of N174 and S122 polymorphisms was significantly higher in clade II than clade I viruses. PMID- 27493109 TI - Vaspin, resistin, retinol-binding protein-4, interleukin-1alpha and interleukin 6 in patients with nonalcoholic fatty liver disease. AB - Background and rational. Data on newer adipokines and interleukins in patients with nonalcoholic fatty liver disease (NAFLD) are inconclusive. The primary aim of this study was the evaluation of serum vaspin, resistin, retinol-binding protein (RBP)-4, interleukin (IL)-1alpha and IL-6 levels in NAFLD patients compared to matched controls, and their association with disease severity. MATERIAL AND METHODS: Twenty-nine consecutively enrolled NAFLD patients with histologically confirmed nonalcoholic simple steatosis (SS; n = 15) or steatohepatitis (NASH; n = 14) and 25 matched controls without NAFLD were recruited. Serum vaspin, resistin, RBP-4, IL-1alpha and IL-6 and biochemical tests were measured. RESULTS: Serum vaspin levels were lower and IL-6 levels higher in NASH patients than controls, but similar between controls and SS patients, or NASH and SS patients (vaspin, controls: 728.5 +/- 39.3; SS: 634.6 +/ 63.7; NASH: 531.5 +/- 52.0 pg/mL; p for trend 0.028; IL-6, controls: 1.5 +/- 0.2; SS: 2.5 +/- 0.6; NASH: 3.0 +/- 0.6 pg/mL; p for trend 0.032). However, after adjustment for body mass index or waist circumference, both vaspin and IL-6 did not remain significantly different between groups. Resistin, RBP-4 and IL-1alpha were not statistically different between groups. None of the selected adipokines or interleukins could independently differentiate NAFLD from SS, or patients with more severe from less severe histological lesions. CONCLUSION: Lower circulating vaspin, but higher IL-6 levels were observed in NASH patients than controls, whereas resistin, RBP-4 and IL-1alpha levels were similar between groups. However, these differences did not remain robust after adjustment for body mass index or waist circumference. PMID- 27493110 TI - The product of triglycerides and glucose as biomarker for screening simple steatosis and NASH in asymptomatic women. AB - Introduction and aim. Given that early identification of non-alcoholic fatty liver disease (NAFLD) is an important issue for primary prevention of hepatic disease, the objectives of this study were to evaluate the efficacy of the product of triglyceride and glucose levels (TyG) for screening simple steatosis and non-alcoholic steatohepatitis (NASH) in asymptomatic women, and to compare its efficacy vs. other biomarkers for recognizing NAFLD. MATERIAL AND METHODS: Asymptomatic women aged 20 to 65 years were enrolled into a cross-sectional study. The optimal values of TyG, for screening simple steatosis and NASH were established on a Receiver Operating Characteristic scatter plot; the sensitivity, specificity, and likelihood ratios of TyG index were estimated versus liver biopsy. According sensitivity and specificity, the efficacy of TyG was compared versus the well-known clinical biomarkers for recognizing NAFLD. RESULTS: A total of 50 asymptomatic women were enrolled. The best cutoff point of TyG for screening simple steatosis was 4.58 (sensitivity 0.94, specificity 0.69); in addition, the best cutoff point of TyG index for screening NASH was 4.59 (sensitivity 0.87, specificity 0.69). The positive and negative likelihood ratios were 3.03 and 0.08 for simple steatosis, and 2.80 and 0.18 for NASH. As compared versus SteatoTest, NashTest, Fatty liver index, and Algorithm, the TyG showed to be the best test for screening. CONCLUSIONS: TyG has high sensitivity and low negative likelihood ratio; as compared with other clinical biomarkers, the TyG showed to be the best test for screening simple steatosis and NASH. PMID- 27493111 TI - High prevalence of undiagnosed liver cirrhosis and advanced fibrosis in type 2 diabetic patients. AB - Background. Patients with type 2 diabetes mellitus (T2DM) are at risk for developing end-stage liver disease due to nonalcoholic steatohepatitis (NASH), the aggressive form of non-alcoholic fatty liver disease (NAFLD). Data on prevalence of advanced fibrosis among T2DM patients is scarce. AIM: To evaluate prevalence of steatosis, advanced fibrosis and cirrhosis using non-invasive methods in T2DM patients. MATERIAL AND METHODS: 145 consecutive T2DM patients (> 55 years-old) were prospectively recruited. Presence of cirrhosis and advanced fibrosis was evaluated by magnetic resonance imaging (MRI) and NAFLD fibrosis score (NFS) respectively. Exclusion criteria included significant alcohol consumption, markers of viral hepatitis infection or other liver diseases. Results are expressed in percentage or median (interquartile range). RESULTS: 52.6% of patients were women, the median age was 60 years old (57-64), mean BMI was 29.6 +/- 4.7 kg/m2 and diabetes duration was 7.6 +/- 6.9 years. A high prevalence of liver steatosis (63.9%), advanced fibrosis assessed by NFS (12.8%) and evidence of liver cirrhosis in MRI (6.0%) was observed. In a multivariate analysis GGT > 82 IU/L (P = 0.004) and no alcohol intake (P = 0.032) were independently associated to advanced fibrosis. CONCLUSION: A high frequency of undiagnosed advanced fibrosis and cirrhosis was observed in non-selected T2DM patients. Screening of these conditions may be warranted in this patient population. PMID- 27493113 TI - Schistosomal portal hypertension: Randomized trial comparing endoscopic therapy alone or preceded by esophagogastric devascularization and splenectomy. AB - Background. Upper gastrointestinal bleeding is a major cause of morbidity and mortality in patients with portal hypertension secondary to schistosomiasis mansoni. AIM: To evaluate the efficacy of combined surgery and sclerotherapy versus endoscopic treatment alone in the prophylaxis of esophageal variceal rebleeding due to portal hypertension in schistosomiasis. MATERIAL AND METHODS: During a two-years period consecutive patients with schistosomiasis and a recent bleeding history were evaluated for prospective randomization. Absolute exclusion criteria were alcoholism or other liver diseases, whereas platelet count < 50,000/mm3, INR > 1.5 or presence of gastric varices were relative exclusion criteria. By random allocation 25 (group A) have received endoscopic sclerotherapy for esophageal varices alone and 22 (group B) combined treatment: esophagogastric devascularization with splenectomy followed by sclerotherapy. Interim analysis at 24 months has shown significant statistical differences between the groups and the randomization was halted. RESULTS: Mean age was 38.9 +/- 15.4 years and 58.46% were male. Mean follow-up was 38.6 +/- 20.1 months. Endoscopic comparison of the size of esophageal varices before and after treatment did not show significant differences among the two groups. Treatment efficacy was assessed by the rate of recurrent esophageal variceal bleeding, that was more common in group A- 9/25 patients (36.0%) vs. 2/22 (9.0%) in group B (p = 0.029). Other complications were odynophagia, dysphagia and esophageal ulcer in group A and ascites and portal vein thrombosis in the surgical group. CONCLUSION: In portal hypertension due to schistosomiasis, combined surgical and endoscopic treatment was more effective for the prevention of recurrent esophageal variceal bleeding. PMID- 27493112 TI - Effects of combined genes of CTLA4Ig and IDO in post-liver transplantation immune tolerance of rats. AB - Background and rationale for the study. Previous studies showed that CTLA4Ig and indoleamine 2,3-dioxygenase (IDO) genes played regulatory role in organ transplantation but failed to reach satisfactory effects. In this study, we constructed an adenovirus- mediated gene expressing CTLA4Ig-IDO and established rat liver transplantation models. Recipients were randomly divided into four groups of 10 rats each. During the operation, CTLA4Ig, IDO, and CTLA4Ig-IDO genes, as well as a blank plasmid, were infused into different rat groups via portal vein to determine their effects on inducing immune tolerance. Survival rate of recipients, histological changes of graft liver, post-transplantation liver function, and cytokine levels were observed at day 14 after operation. RESULTS: Serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and total bilirubin level (TBIL) in the CTLA4Ig-IDO group were lower than those in the other three groups at 14 days post-transplantation (P < 0.05); mRNA and protein expressions of IL-2 and IFN-gamma were higher in the control group, but lower in the CTLA4Ig-IDO group (P < 0.05). By contrast, expressions of IL-4, TGF-b, IL-10, and T lymphocyte apoptosis were higher in the CTLA4Ig-IDO group than those in the other three groups (P < 0.05). The CTLA4Ig-IDO group exhibited mild acute rejection and higher survival rate compared with the other groups (P < 0.05). CONCLUSION: Compared with using CTLA4Ig or IDO alone, combined transfection of CTLA4Ig-IDO was more effective in inducing immune tolerance after liver transplantation. PMID- 27493114 TI - Risk factors contributing to early infection following transjugular intrahepatic portosystemic shunt in perioperative period. AB - Introduccion and aim. To investigate and identify the risk factors associated with early infection following a transjugular intrahepatic portosystemic shunt (TIPS)procedure in perioperative period. MATERIAL AND METHODS: The interventional radiology database at the West China Hospital in Sichuan, China was reviewed to identify all patients that underwent a TIPS procedure between January 30, 2013 and August 30, 2015. Four hundred and sixty-six TIPS patients with liver cirrhosis were enrolled in this study. Liver function was assessed using the Child-Pugh classification system and bacteremia was defined as patients that had a positive blood culture. Statistical analysis was performed using chi2 tests (include Fisher's exact tests chi2) and logistic regression analyses. A P< 0.05 was set as the threshold for statistical significance. RESULTS: One hundred and forty-eight of the 466 (31.7%) patients developed a fever. Eighty-three of the 148 fever patients subsequently had blood drawn for cultures and 9/83 (10.8%) patients developed bacteremia as defined by a blood culture analysis. Cholangiolithiasis (P = 0.006), Child-Pugh class A designation (P = 0.001), Child Pugh class C designation (P = 0.005) and hepatitis C virus infection (P = 0.011) were significantly correlated with fever in these patients. No statistically significant correlations were found between the other factors (age, gender, clinical manifestation, diabetes mellitus, cholangiolithiasis, etc.) and bacteremia, with the exception of periprocedure cholangiolithiasis, which was significantly correlated with blood culture-defined bacteremia (P < 0.05). CONCLUSIONS: Cholangiolithiasis is a risk factor for infection after a TIPS procedure in the periprocedure period. PMID- 27493115 TI - Efficacy and safety of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy. AB - Background and aims. Patients with intrahepatic cholestasis of pregnancy (ICP) benefit from ursodeoxycholic acid (UDCA) treatment. Since there is still certain reluctance to use UDCA in pregnant women, mainly due to warnings in the official SPC information in respective drug leaflets, our objective was to assess the efficacy and safety of UDCA during pregnancy. MATERIAL AND METHODS: Our retrospective multicentric study was performed on 191 consecutive pregnant women with ICP treated with UDCA. Any maternal and/or fetal complications of the UDCA treatment were searched for; healthy pregnant women (n = 256) served as controls. RESULTS: The UDCA treatment improved liver disease status in the majority of the affected women (86.1%). This treatment was well tolerated, with only negligible skin reactions (0.5%) and mild diarrhea (4.7%). No complications attributable to UDCA treatment were detected during the fetal life, delivery, or the early neonatal period. CONCLUSION: We confirmed the good efficacy and safety of UDCA treatment in pregnancy for both mothers and fetuses/neonates. PMID- 27493117 TI - Chilaiditi syndrome. An uncommon cause of crampy, upper abdominal pain. PMID- 27493116 TI - Fibrin-mediated integrin signaling plays a critical role in hepatic regeneration after partial hepatectomy in mice. AB - Background. The regenerative capacity of the liver is critical for proper responses to injury. Fibrin extracellular matrix (ECM) deposition is a common response to insult and contributes to inflammatory liver injury. However, the role of this matrix in hepatic regeneration has not been determined. OBJECTIVE: The purpose of this study was first to determine the role of fibrin ECM in hepatic regeneration followed by the role of the fibrin-binding alphavbeta3 integrin in mediating this effect. MATERIAL AND METHODS: C57Bl/6J (WT) or PAI-1 knockout (KO) mice underwent 70% partial hepatectomy (PHx); plasma and histologic indices of regeneration were determined, as well as expression of key genes involved in hepatic regeneration. RESULTS: PHx promoted transient fibrin deposition by activating coagulation and concomitantly decreasing fibrinolysis. Inhibiting fibrin deposition, either by blocking thrombin (hirudin) in WT mice or by knocking out PAI-1, was associated with a decrease in hepatocyte proliferation after PHx. This strongly suggested a role for fibrin ECM in liver regeneration. To investigate if alphavbeta3 integrin mediates this action, we tested the effects of the anti-alphavbeta3 cyclic peptide RGDfV in animals after PHx. As was observed with inhibition of fibrin deposition, competitive inhibition of alphavbeta3 integrin delayed regeneration after PHx, while not affecting fibrin deposition. These effects of RGDfV correlated with impaired angiogenesis and STAT3 signaling, as well as transient endothelial dysfunction. In conclusion, these data suggest that alphavbeta3 integrin plays an important role in coordinating hepatocyte division during liver regeneration after PHx via crosstalk with fibrin ECM. PMID- 27493118 TI - Early initiation of MARS(r) dialysis in Amanita phalloides-induced acute liver injury prevents liver transplantation. AB - Amanita phalloides is the most relevant mushroom intoxication leading to acute liver failure. The two principal groups of toxins, the amatoxins and the phallotoxins, are small oligopeptides highly resistant to chemical and physical influences. The amatoxins inhibit eukaryotic RNA polymerase II causing transcription arrest affecting mainly metabolically highly active cells like hepatocytes and renal cells. The clinically most characteristic symptom is a 6-40 h lag phase before onset of gastrointestinal symptoms and the rapid progression of acute liver failure leading to multi-organ failure and death within a week if left untreated. Extracorporeal albumin dialysis (ECAD) was reported to improve patient's outcome or facilitate bridging to transplantation. In our tertiary center, out of nine intoxicated individuals from five non-related families six patients presented with acute liver injury; all of them were treated with ECAD using the MARS(r) system. Four of them were listed on admission for high urgency liver transplantation. In addition to standard medical treatment for Amanita intoxication we initiated ECAD once patients were admitted to our center. Overall 16 dialysis sessions were performed. All patients survived with full native liver recovery without the need for transplantation. ECAD was well tolerated; no severe adverse events were reported during treatment. Coagulopathy resolved within days in all patients, and acute kidney injury in all but one individual. In conclusion, ECAD is highly effective in treating intoxication with Amanita phalloides. Based on these experiences we suggest early initiation and repeated sessions depending on response to ECAD with the chance of avoiding liver transplantation. PMID- 27493119 TI - An unusual type of biliar cyst: A case report. AB - We present the case of a 56-yr-old woman with vague abdominal pain of approximately 5 months duration. An ultrasound study showed moderate dilation of the common bile duct. Magnetic resonance cholangiopancreatography confirmed a cystic dilatation of the right hepatic duct with intra and extra hepatic component. The patient underwent right hepatectomy and complete excision of the cyst. Microscopically, the cyst wall was formed by fibrous tissue with mild acute and chronic inflammatory infiltrate, the inner surface showed a single layer of columnar epithelium and extensive squamous metaplasia without atypia, wich expressed p63 and high molecular weight cytoqueratin (34BE12). PMID- 27493120 TI - Bile salt export pump deficiency disease: two novel, late onset, ABCB11 mutations identified by next generation sequencing. AB - Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive cholestatic diseases of childhood and represents the main indication for liver transplantation at this age; PFIC2 involves ABCB11 gene, that encodes the ATPdependent canalicular bile salt export pump (BSEP). Benign intrahepatic cholestasis (BRIC) identifies a group of diseases involving the same genes and characterized by intermittent attacks of cholestasis with no progression to liver cirrhosis. Diagnosis with standard sequencing techniques is expensive and available only at a few tertiary centers. We report the application of next generation sequencing (NGS) in the diagnosis of the familial intrahepatic cholestasis with a parallel sequencing of three causative genes. We identified the molecular defects in ABCB11 gene in two different probands who developed a severe cholestatic disease of unknown origin. In the first patient a compound heterozygosity for the novel frameshift mutation p.Ser1100GlnfsX38 and the missense variant p.Glu135Lys was detected. In the second patient, triggered by contraceptive therapy, we identified homozygosity for a novel missense variant p.Ala523Gly. In conclusion, these mutations seem to have a late onset and a less aggressive clinical impact, acting as an intermediate form between BRIC and PFIC. PMID- 27493121 TI - How to screen NAFLD patients for diabetes? PMID- 27493122 TI - Effect of ezetimibe in HCV viral load after liver transplantation. PMID- 27493123 TI - Cell-based therapy to reverse advanced alcoholic liver fibrosis. PMID- 27493124 TI - Different interactomes for p70-S6K1 and p54-S6K2 revealed by proteomic analysis. AB - S6Ks are major effectors of the mTOR (mammalian target of rapamycin) pathway, signaling for increased protein synthesis and cell growth in response to insulin, AMP/ATP levels, and amino acids. Deregulation of this pathway has been related to disorders and diseases associated with metabolism, such as obesity, diabetes, and cancer. S6K family is composed of two main members, S6K1 and S6K2, which comprise different isoforms resulted from alternative splicing or alternative start codon use. Although important molecular functions have been associated with p70-S6K1, the most extensively studied isoform, the S6K2 counterpart lacks information. In the present study, we performed immunoprecipitation assays followed by mass spectrometry (MS) analysis of FLAG-tagged p70-S6K1 and p54-S6K2 interactomes, after expression in HEK293 cells. Protein lists were submitted to CRAPome (Contaminant Repository for Affinity Purification) and SAINT (Significance Analysis of INTeractome) analysis, which allowed the identification of high scoring interactions. By a comparative approach, p70-S6K1 interacting proteins were predominantly related to "cytoskeleton" and "stress response," whereas p54 S6K2 interactome was more associated to "transcription," "splicing," and "ribosome biogenesis." Moreover, we have found evidences for new targets or regulators of the S6K protein family, such as proteins NCL, NPM1, eIF2alpha, XRCC6, PARP1, and ILF2/ILF3 complex. This study provides new information about the interacting networks of S6Ks, which may contribute for future approaches to a better understanding of the mTOR/S6K pathway. PMID- 27493125 TI - Synthesis of surface-modified TREN-cored PAMAM dendrimers and their effects on the solubility of sulfamethoxazole (SMZ) as an analog antibiotic drug. AB - Sulfamethoxazole (SMZ) is a sulfonamide and used widely in the treatment of bacteriostatic and urinary tract infections with trimethoprim as an antibiotic. The problem with SMZ is its poor water solubility, therefore, low bioavailability in clinical applications. In this study, we synthesized new-generation Tris(2 aminoethyl)amine (TREN)-cored amine (NH2), Tris(hydroxymethyl)aminomethane (TRIS), and carboxyl (COOH) terminated different generations T2-T4 poly(amidoamine) PAMAM dendrimers. Synthesized PAMAMs were characterized by 1H NMR, 13C NMR, ATR-FTIR, spectroscopic titrations, and evaluated as potential solubility enhancers and drug carriers of sulfonamides by taking SMZ as a model drug. The effect of concentration, generation, and surface groups of PAMAMs on the solubility of SMZ was also investigated. Results showed that the solubility of SMZ improved significantly with an increasing generation size (T2-T4) and PAMAM dendrimer concentration (0-2 mM). The role of PAMAMs in the solubility enhancement of SMZ was in the order of T4.NH2 > T4.COOH > T3.NH2 > T4.TRIS > T2.NH2 > T3.COOH > T3.TRIS > T2.COOH > T2.TRIS, and in the ranges of 5- to 45 fold with maximum SMZ loading 7 to 61 mole/mole per PAMAM dendrimer molecule. In vitro release studies demonstrated that SMZ-PAMAM dendrimer complexes at the end of 2-h drug release (16-26%) was considerable slower than pure SMZ (38.8%). PMID- 27493126 TI - Three-dimensional transesophageal echocardiography incremental value in a rare case of a bileaflet tricuspid valve. AB - Detailed assessment of the tricuspid valve using two-dimensional echocardiography is always challenging, as only two of three leaflets can be seen at a time. Three dimensional echocardiography can provide the enface view of the tricuspid valve that allows simultaneous visualization of all of the three leaflets. In a 42-year old male patient scheduled for pulmonary endarterectomy, 3DTEE showed that the tricuspid valve is bileaflet, with one septal and another lateral leaflet. There were two commissures, one of them is anteriorly positioned and the other one is posterior. Our findings were confirmed intra-operatively by direct surgical visualization of the tricuspid valve. PMID- 27493128 TI - Fungal prosthetic valve endocarditis with mycotic aneurysm: Case report. AB - Fungal prosthetic valve endocarditis is an extremely severe form of infective endocarditis, with poor prognosis and high mortality despite treatment. Candida albicans is the most common etiological agent for this rare but increasingly frequent condition. We present a case of fungal prosthetic valve endocarditis due to C. albicans following aortic and pulmonary valve replacement in a 38-year-old woman with a history of surgically corrected tetralogy of Fallot, prior infective endocarditis and acute renal failure with need for catheter-based hemodialysis. Antifungal therapy with liposomal amphotericin B was initiated prior to cardiac surgery, in which the bioprostheses were replaced by homografts, providing greater resistance to recurrent infection. During hospitalization, a mycotic aneurysm was diagnosed following an episode of acute arterial ischemia, requiring two vascular surgical interventions. Despite the complications, the patient's outcome was good and she was discharged on suppressive antifungal therapy with oral fluconazole for at least a year. The reported case illustrates multiple risk factors for fungal endocarditis, as well as complications and predictors of poor prognosis, demonstrating its complexity. PMID- 27493127 TI - Dehydration of Glucose to 5-Hydroxymethylfurfural Using Nb-doped Tungstite. AB - Dehydration of glucose to 5-hydroxymethylfurfural (HMF) remains a significant problem in the context of the valorization of lignocellulosic biomass. Hydrolysis of WCl6 and NbCl5 leads to precipitation of Nb-containing tungstite (WO3 ?H2 O) at low Nb content and mixtures of tungstite and niobic acid at higher Nb content. Tungstite is a promising catalyst for the dehydration of glucose to HMF. Compared with Nb2 O5 , fewer by-products are formed because of the low Bronsted acidity of the (mixed) oxides. In water, an optimum yield of HMF was obtained for Nb-W oxides with low Nb content owing to balanced Lewis and Bronsted acidity. In THF/water, the strong Lewis acidity and weak Bronsted acidity caused the reaction to proceed through isomerization to fructose and dehydration of fructose to a partially dehydrated intermediate, which was identified by LC-ESI-MS. The addition of HCl to the reaction mixture resulted in rapid dehydration of this intermediate to HMF. The HMF yield obtained in this way was approximately 56 % for all tungstite catalysts. Density functional theory calculations show that the Lewis acid centers on the tungstite surface can isomerize glucose into fructose. Substitution of W by Nb lowers the overall activation barrier for glucose isomerization by stabilizing the deprotonated glucose adsorbate. PMID- 27493129 TI - Examining the relationship between antihypertensive medication satisfaction and adherence in older patients. AB - BACKGROUND: The relationship between medication adherence and treatment satisfaction has been consistently positive, however, this relationship has not been examined among older adults with hypertension. OBJECTIVES: The aim of this study was to examine the relationship between medication adherence and treatment satisfaction among a sample of older adults with hypertension. METHODS: This was a survey-based cross-sectional study in which seven community senior centers in the city of Memphis, Tennessee and its surrounding areas were visited. Individuals aged 60 years and older with self-reported hypertension who visited the community senior centers between August and December 2013 were asked to participate. The participants' satisfaction with their antihypertensive medications was assessed using a newly developed scale. The Short Form Health Survey (SF-12v2) was used to assess the health-related quality of life (HRQoL). The Primary Care Assessment Survey (PCAS) Communication scale was used to assess the satisfaction with health care provider communication. The Beliefs About Medicines Questionnaire (BMQ-General) was used to assess the participant beliefs about medications. The eight-item Morisky Medication Adherence Scale (MMAS-8) was used to assess adherence to antihypertensive medications. And the Single Item Literacy Screener (SILS) was used to assess health literacy. Multiple linear regression was conducted to examine the relationship between medication adherence and satisfaction with antihypertensive therapy controlling for multiple variables. RESULTS: One hundred and ninety participants with hypertension were included in the study. Most participants were white, women, aged >=70 years, taking >=2 prescription medications and having >=2 medical conditions. After adjusting for age, education, number of prescription medications, race, health literacy, sex, marital status, SF-12v2 Physical Component Summary (PCS-12) and Mental Component Summary (MCS-12), and PCAS-Communication scores, the overall satisfaction score of the antihypertensive medication regimen was positively and significantly associated with MMAS-8 sore (beta = 0.262; 95% confidence interval, 0.007-0.517; P = 0.043). CONCLUSIONS: Treatment satisfaction was associated with higher medication adherence among older adults with hypertension. PMID- 27493130 TI - Challenges in pediatric drug use: A pharmacist point of view. AB - The pediatric population is an enormously diverse segment of population varying both in size and age. The diversity caused pharmacists face various challenges primarily related to procuring, provision as well as use of drugs in this group of patients. Pediatric dose calculation is particularly a concern for pharmacists. Another challenge faced by pharmacists is unavailability of suitable formulations for pediatric use. This has also led many pharmacists to prepare extemporaneous liquid preparations, even though stability data on such preparations are scarce. Some extemporaneous preparations contain excipients which are potentially harmful in children. Besides that, inadequate labeling and drug information for pediatric drug use had not only challenged pharmacists in recommending and optimizing drug use in children, but also inadvertently caused many drugs used outside the approved terms of the product license (off-label use). Pharmacists are striving to stay connected to overcome the common and comparable challenges faced in their day to day duties and strive to maximize the safe and effective use of medicines for children. PMID- 27493132 TI - Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes: The ADJUNCT TWO Randomized Trial. AB - OBJECTIVE: To investigate the efficacy and safety of liraglutide added to capped insulin doses in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A 26 week, placebo-controlled, double-blind, parallel-group trial enrolling 835 subjects randomized 3:1 receiving once-daily subcutaneous liraglutide (1.8, 1.2, and 0.6 mg) or placebo added to an individually capped total daily dose of insulin. RESULTS: Mean baseline glycated hemoglobin (HbA1c) (8.1% [65.0 mmol/mol]) was significantly decreased with liraglutide versus placebo at week 26 (1.8 mg: -0.33% [3.6 mmol/mol]; 1.2 mg: -0.22% [2.4 mmol/mol]; 0.6 mg: -0.23% [2.5 mmol/mol]; placebo: 0.01% [0.1 mmol/mol]). Liraglutide significantly reduced mean body weight (-5.1, -4.0, and -2.5 kg for 1.8, 1.2, and 0.6 mg, respectively) versus placebo (-0.2 kg). Significant reductions in daily insulin dose and increases in quality of life were seen with liraglutide versus placebo. There were higher rates of symptomatic hypoglycemia (21.3 vs. 16.6 events/patient/year; P = 0.03) with liraglutide 1.2 mg vs. placebo and of hyperglycemia with ketosis >1.5 mmol/L with liraglutide 1.8 mg vs. placebo (0.5 vs. 0.1 events/patient/year; P = 0.01). CONCLUSIONS: In a broad population of subjects with long-standing type 1 diabetes, liraglutide added to capped insulin reduced HbA1c, body weight, and insulin requirements but with higher rates of hypoglycemia for liraglutide 1.2 mg and hyperglycemia with ketosis for liraglutide 1.8 mg. PMID- 27493133 TI - Impact of the Gather mHealth System on A1C: Primary Results of a Multisite Randomized Clinical Trial Among People With Type 2 Diabetes in India. PMID- 27493131 TI - The Platin-X series: activation, targeting, and delivery. AB - Anticancer platinum (Pt) complexes have long been considered to be one of the biggest success stories in the history of medicinal inorganic chemistry. Yet there remains the hunt for the "magic bullet" which can satisfy the requirements of an effective chemotherapeutic drug formulation. Pt(iv) complexes are kinetically more inert than the Pt(ii) congeners and offer the opportunity to append additional functional groups/ligands for prodrug activation, tumor targeting, or drug delivery. The ultimate aim of functionalization is to enhance the tumor selective action and attenuate systemic toxicity of the drugs. Moreover, an increase in cellular accumulation to surmount the resistance of the tumor against the drugs is also of paramount importance in drug development and discovery. In this review, we will address the attempts made in our lab to develop Pt(iv) prodrugs that can be activated and delivered using targeted nanotechnology-based delivery platforms. PMID- 27493134 TI - Risk of Cause-Specific Death in Individuals With Diabetes: A Competing Risks Analysis. AB - OBJECTIVE: Diabetes is a common cause of shortened life expectancy. We aimed to assess the association between diabetes and cause-specific death. RESEARCH DESIGN AND METHODS: We used the pooled analysis of individual data from 12 Spanish population cohorts with 10-year follow-up. Participants had no previous history of cardiovascular diseases and were 35-79 years old. Diabetes status was self reported or defined as glycemia >125 mg/dL at baseline. Vital status and causes of death were ascertained by medical records review and linkage with the official death registry. The hazard ratios and cumulative mortality function were assessed with two approaches, with and without competing risks: proportional subdistribution hazard (PSH) and cause-specific hazard (CSH), respectively. Multivariate analyses were fitted for cardiovascular, cancer, and noncardiovascular noncancer deaths. RESULTS: We included 55,292 individuals (15.6% with diabetes and overall mortality of 9.1%). The adjusted hazard ratios showed that diabetes increased mortality risk: 1) cardiovascular death, CSH = 2.03 (95% CI 1.63-2.52) and PSH = 1.99 (1.60-2.49) in men; and CSH = 2.28 (1.75 2.97) and PSH = 2.23 (1.70-2.91) in women; 2) cancer death, CSH = 1.37 (1.13 1.67) and PSH = 1.35 (1.10-1.65) in men; and CSH = 1.68 (1.29-2.20) and PSH = 1.66 (1.25-2.19) in women; and 3) noncardiovascular noncancer death, CSH = 1.53 (1.23-1.91) and PSH = 1.50 (1.20-1.89) in men; and CSH = 1.89 (1.43-2.48) and PSH = 1.84 (1.39-2.45) in women. In all instances, the cumulative mortality function was significantly higher in individuals with diabetes. CONCLUSIONS: Diabetes is associated with premature death from cardiovascular disease, cancer, and noncardiovascular noncancer causes. The use of CSH and PSH provides a comprehensive view of mortality dynamics in a population with diabetes. PMID- 27493137 TI - Isolation and characterization of atypical Listeria monocytogenes associated with a canine urinary tract infection. AB - Listeria monocytogenes, a well-described cause of encephalitis and abortion in ruminants and of food-borne illness in humans, is rarely associated with disease in companion animals. A case of urinary tract infection associated with an atypical, weakly hemolytic L. monocytogenes strain is described in a diabetic dog. The serotype of the L. monocytogenes isolate was determined to be 1/2a (3a), with the multilocus genotyping pattern 2.72_1/2a. A nucleotide substitution (Gly145Asp) was detected at residue 145 in the promoter prfA region. This residue is within the critical helix-turn-helix motif of PrfA. The source of the L. monocytogenes strain remains unknown, and the dog recovered after a 4-week course of cephalexin (30 mg/kg orally twice daily). PMID- 27493135 TI - Effect of Serotonin Transporter 5-HTTLPR Polymorphism on Gastrointestinal Intolerance to Metformin: A GoDARTS Study. AB - OBJECTIVE: The mechanism causing gastrointestinal intolerance to metformin treatment is unknown. We have previously shown that reduced-function alleles of organic cation transporter 1 (OCT1) are associated with increased intolerance to metformin. Considering recent findings that serotonin reuptake transporter (SERT) might also be involved in metformin intestinal absorption, and the role of serotonin in gastrointestinal physiology, in this study we investigated the association between a common polymorphism in the SERT gene and metformin gastrointestinal intolerance. RESEARCH DESIGN AND METHODS: We explored the effect of composite SERT 5-HTTLPR/rs25531 genotypes, L*L* (LALA), L*S* (LALG, LAS), and S*S* (SS, SLG, LGLG), in 1,356 fully tolerant and 164 extreme metformin intolerant patients by using a logistic regression model, adjusted for age, sex, weight, OCT1 genotype, and concomitant use of medications known to inhibit OCT1 activity. RESULTS: The number of low-expressing SERT S* alleles increased the odds of metformin intolerance (odds ratio [OR] 1.31 [95% CI 1.02-1.67], P = 0.031). Moreover, a multiplicative interaction between the OCT1 and SERT genotypes was observed (P = 0.003). In the analyses stratified by SERT genotype, the presence of two deficient OCT1 alleles was associated with more than a ninefold higher odds of metformin intolerance in patients carrying the L*L* genotype (OR 9.25 [95% CI 3.18-27.0], P < 10-4); however, it showed a much smaller effect in L*S* carriers and no effect in S*S* carriers. CONCLUSIONS: Our results indicate that the interaction between OCT1 and SERT genes might play an important role in metformin intolerance. Further studies are needed to replicate these findings and to substantiate the hypothesis that metformin gastrointestinal side effects could be related to the reduced intestinal serotonin uptake. PMID- 27493136 TI - Initial Combination of Empagliflozin and Metformin in Patients With Type 2 Diabetes. AB - OBJECTIVE: This study compared the efficacy and safety of initial combinations of empagliflozin + metformin with empagliflozin and metformin monotherapy in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The study randomized 1,364 drug-naive patients (HbA1c >7.5 to <=12% [>58 to <=108 mmol/mol]) for 24 weeks to empagliflozin 12.5 mg b.i.d. + metformin 1,000 mg b.i.d., empagliflozin 12.5 mg b.i.d. + metformin 500 mg b.i.d., empagliflozin 5 mg b.i.d + metformin 1,000 mg b.i.d., empagliflozin 5 mg b.i.d. + metformin 500 mg b.i.d., empagliflozin 25 mg q.d., empagliflozin 10 mg q.d., metformin 1,000 mg b.i.d., or metformin 500 mg b.i.d. The primary end point was change from baseline in HbA1c at week 24. RESULTS: At week 24, reductions in HbA1c (mean baseline 8.6-8.9% [70 73 mmol/mol]) were -1.9 to -2.1% with empagliflozin + metformin twice-daily regimens, -1.4% with both empagliflozin once-daily regimens, and -1.2 to -1.8% with metformin twice-daily regimens. Reductions in HbA1c were significantly greater with empagliflozin + metformin twice-daily regimens than with empagliflozin once-daily regimens (P < 0.001) and with metformin twice-daily regimens (P < 0.01). Reductions in weight at week 24 were significantly greater with empagliflozin + metformin twice-daily regimens (range -2.8 to -3.8 kg) than with metformin twice-daily regimens (-0.5 to -1.3 kg) (P < 0.001 for all). Adverse event (AE) rates were similar across groups (56.7-66.3%). No hypoglycemic AEs required assistance. CONCLUSIONS: Initial combinations of empagliflozin + metformin for 24 weeks significantly reduced HbA1c versus empagliflozin once daily and metformin twice daily, without increased hypoglycemia, reduced weight versus metformin twice daily, and were well tolerated. PMID- 27493138 TI - Rapid detection of Porcine circovirus 2 by recombinase polymerase amplification. AB - Porcine circovirus-associated disease, caused primarily by Porcine circovirus 2 (PCV-2), has become endemic in many pig-producing countries and has resulted in significant economic losses to the swine industry worldwide. Tests for PCV-2 infection include PCR, nested PCR, competitive PCR, and real-time PCR (rtPCR). Recombinase polymerase amplification (RPA) has emerged as an isothermal gene amplification technology for the molecular detection of infectious disease agents. RPA is performed at a constant temperature and therefore can be carried out in a water bath. In addition, RPA is completed in ~30 min, much faster than PCR, which usually takes >60 min. We developed a RPA-based method for the detection of PCV-2. The detection limit of RPA was 10(2) copies of PCV-2 genomic DNA. RPA showed the same sensitivity as rtPCR but was 10 times more sensitive than conventional PCR. Successful amplification of PCV-2 DNA, but not other viral templates, demonstrated high specificity of the RPA assay. This method was also validated using clinical samples. The results showed that the RPA assay had a diagnostic agreement rate of 93.7% with conventional PCR and 100% with rtPCR. These findings suggest that the RPA assay is a simple, rapid, and cost-effective method for PCV-2 detection, which could be potentially applied in clinical diagnosis and field surveillance of PCV-2 infection. PMID- 27493139 TI - A renal adenocarcinoma in a corn snake (Pantherophis guttatus) resembling human collecting duct carcinoma. AB - A 5-year-old male captive corn snake (Pantherophis guttatus) with caudal coelomic swelling was admitted for surgical treatment. Laparotomy revealed a 5 * 4 * 2.5 cm, firm, expansile, irregularly shaped mass arising from the middle portion of the right kidney with a mild lobulated pattern and mottled white-to-tan. Microscopically, the mass was composed of numerous bizarre angulated tubules of polygonal neoplastic cells separated by a scirrhous stroma with remarkable heterophilic infiltrates. The neoplastic cells were nonciliated and mucin secreting, with abundant brightly eosinophilic cytoplasm. There were marked cellular and nuclear atypia, frequent cell individualization, and stromal invasion, indicative of malignant behavior, which was confirmed by metastasis to the left kidney 1.5 months postoperatively. Both neoplastic epithelial cells and mesenchymal cells contributing to the scirrhous stroma had variable immunopositivity for pan-cytokeratin. The neoplasm was considered a renal adenocarcinoma resembling human collecting duct carcinoma. PMID- 27493140 TI - Development of a loop-mediated isothermal amplification method for detecting virulent Rhodococcus equi. AB - Rhodococcus equi is the most important causative bacterium of severe pneumonia in foals. We report herein the development of a specific loop-mediated isothermal amplification (LAMP) assay, which targets a gene encoding vapA for detecting virulent R. equi The detection limit of the LAMP assay was 10(4) colony forming units (CFU)/mL, which was equal to 10 CFU/reaction. The clinical efficacy of the LAMP assay was compared with those of 2 published PCR-based methods: nested PCR and quantitative real-time (q)PCR. Agreements between bacterial culture, which is the gold standard for detection of R. equi, and each of the 3 molecular tests were measured by calculating a kappa coefficient. The kappa coefficients of the LAMP (0.760), nested PCR (0.583), and qPCR (0.888) indicated substantial agreement, moderate agreement, and almost perfect agreement, respectively. Although the clinical efficacy of LAMP was not the best among the 3 methods tested, LAMP could be more easily introduced into less well-equipped clinics because it does not require special equipment (such as a thermocycler) for gene amplification. Veterinary practitioners could diagnose R. equi pneumonia more quickly by using LAMP and could use the results to select an appropriate initial treatment. PMID- 27493141 TI - Rice-produced MSP142 of Plasmodium falciparum elicits antibodies that inhibit parasite growth in vitro. AB - Many malaria antigens contain multiple disulphide bonds involved in the formation of inhibitory B-cell epitopes. Producing properly folded malaria antigens in sufficient quantities for vaccination is often a challenge. The 42-kDa fragment of Plasmodium falciparum merozoite surface protein 1 (MSP142 ) is such a kind of malaria antigen. In this study, we investigated the expression of MSP142 in a rice system (9522, a cultivar of Oryza sativa ssp. japonica), which was used as a bioreactor for protein production. The MSP142 gene was synthesized according to rice-preferred codons and transformed into rice plants via an Agrobacterium mediated method. The recombinant antigen was efficiently expressed in rice seeds with a level up to 1.56% of total soluble protein and was recognized by both the conformational monoclonal antibody 5.2 (mAb5.2) and the pooled sera of P. falciparum malaria patients. Rabbits were immunized intramuscularly with the purified MSP142 formulated with Freund's adjuvant. High antibody titres against MSP142 were elicited. The rabbit immune sera reacted well with the native protein of P. falciparum parasite and strongly inhibited the in vitro growth of blood stage P. falciparum parasites, demonstrating that transgenic rice can become an efficient bioreactor for the production of malaria vaccine antigens. PMID- 27493142 TI - Genetic determinants and postorthodontic external apical root resorption in Czech children. AB - OBJECTIVE: Genes, involved in the modulation of inflammatory response and bone remodeling, play a role in the development of postorthodontic external apical root resorption (EARR). The aim of our study was to analyze possible associations between seven single nucleotide polymorphisms (SNPs) in interleukin-17A (IL-17), osteopontin (SPP1), purinoreceptor P2X7 (P2RX7), and tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) genes and EARR in children after orthodontic treatment. SUBJECTS AND METHODS: This case-control study comprised 99 orthodontically treated patients (69 controls and 30 subjects with EARR). Genotype determinations of rs2275913, rs11730582, rs9138, rs208294, rs1718119, rs3102735, and rs2073618 were based on polymerase chain reaction using 5' nuclease TaqMan(r) assays. RESULTS: While no significant differences were observed in allele or genotype frequencies of all seven studied SNPs, specific haplotype of P2RX7 (rs208294 and rs1718119) modified the risk of EARR development (P < 0.05). In addition, the length of treatment with a fixed orthodontic appliance positively correlated with the presence of EARR (P < 0.05). CONCLUSIONS: Although the effect of individual SNPs studied on the EARR development was not confirmed in the Czech population, complex analysis suggested that variability in the P2RX7 gene and the length of orthodontic treatment may be important factors contributing to the etiopathogenesis of postorthodontic EARR. PMID- 27493144 TI - Calciotropic and phosphaturic hormones in heart failure. AB - AIMS: Despite adherence to evidence-based guidelines, heart failure [HF] still results in 5-year mortality rates of 50%, indicating a need to implement additional preventive/intervention strategies. This review summarizes data on alterations in the calciotropic and phosphaturic hormones 1,25-dihydroxyvitamin D [1,25(OH)2D] and fibroblast growth factors-23 [FGF-23] in HF and discusses non pharmacological measures for targeting these hormones. DATA SYNTHESIS: The role of 1,25(OH)2D in the regulation of calcium and phosphate homeostasis is central. 1,25(OH)2D also plays a pivotal role in cardiac function, but is downregulated by FGF-23. There is accumulating evidence from epidemiological data that HF is associated with decreased circulating 1,25(OH)2D and elevated FGF-23 levels. In patients with failing hearts, very low 1,25(OH)2D and extremely high FGF-23 levels have been reported. Experimental data support the assumption that vitamin D deficiency and high serum phosphate/FGF-23 levels increase the risk of HF. This review provides a hypothesis of how vitamin D deficiency, high calcium/phosphorus intake, physical inactivity, and age-related renal impairment may all contribute to HF by adversely affecting calcium- and phosphate-regulating hormones. Several case series in infants and a meta-analysis of randomized controlled trials in adults have already reported successful treatment of or a significant risk reduction in HF by vitamin D supplements. The association of calcium/phosphorus intake, physical activity, or renal function with calciotropic/phosphaturic hormones and HF is however less well documented. CONCLUSIONS: More attention should be paid in future to the association of circulating 1,25(OH)2D and FGF-23 levels with HF and to (non-pharmacological) measures for targeting these calciotropic/phosphaturic hormones. PMID- 27493143 TI - Neutrophil extracellular trap formation is increased in psoriasis and induces human beta-defensin-2 production in epidermal keratinocytes. AB - Neutrophil extracellular traps (NETs) have been implicated in the development of certain immune-mediated diseases, but their role in psoriasis has not been clearly defined. Human beta-defensin-2 (HBD-2) is an important antimicrobial peptide overexpressed in psoriasis epidermis. We evaluated whether the amount of NETs is increased in psoriasis and determined the effect of NETs on HBD-2 production in epidermal keratinocytes. Using fluorescent microscopy, we found that patients with psoriasis (n = 48) had higher amount of NETotic cells in their peripheral blood compared to healthy controls (n = 48) and patients with eczema (n = 35). Psoriasis sera showed increased ability to induce NET formation in control neutrophils but normal NET degradation ability. The amount of NETs in the peripheral blood correlated with psoriasis disease severity. NETosis was also observed in the majority (18 of 20) of psoriasis skin specimens. Furthermore, NETs induced HBD-2 mRNA and protein production in keratinocytes, and immunohistochemical analysis confirmed strong expression of HBD-2 in psoriasis lesional skin. In summary, NET formation is increased in peripheral blood and lesional skin of psoriasis patients and correlates with disease severity. Additionally, NET-induced HBD-2 production may provide a novel mechanism for the decreased susceptibility of psoriasis plaques to microbial infections. PMID- 27493145 TI - Differential hypersaline stress response in Zygosaccharomyces rouxii complex yeasts: a physiological and transcriptional study. AB - The Zygosaccharomyces rouxii complex comprises three distinct lineages of halotolerant yeasts relevant in food processing and spoilage, such as Z. sapae, Z. rouxii and a mosaic group of allodiploid strains. They manifest plastic genome architecture (variation in karyotype, ploidy level and Na(+)/H(+) antiporter encoding gene copy number), and exhibit diverse tolerances to salt concentrations. Here, we investigated accumulation of compatible osmolytes and transcriptional regulation of Na(+)/H(+) antiporter-encoding ZrSOD genes during salt exposure in strains representative for the lineages, namely Z. sapae ABT301(T) (low salt tolerant), Z. rouxii CBS 732(T) (middle salt tolerant) and allodiploid strain ATCC 42981 (high salt tolerant). Growth curve modelling in 2 M NaCl-containing media supplemented with or without yeast extract as nitrogen source indicates that moderate salt tolerance of CBS 732(T) mainly depends on nitrogen availability rather than intrinsic inhibitory effects of salt. All the strains produce glycerol and not mannitol under salt stress and use two different glycerol balance strategies. ATCC 42981 produces comparatively more glycerol than Z. sapae and Z. rouxii under standard growth conditions and better retains it intracellularly under salt injuries. Conversely, Z. sapae and Z. rouxii enhance glycerol production under salt stress and intracellularly retain glycerol less efficiently than ATCC 42981. Expression analysis shows that, in diploid Z. sapae and allodiploid ATCC 42981, transcription of gene variants ZrSOD2-22/ZrSOD2 and ZrSOD22 is constitutive and salt unresponsive. PMID- 27493146 TI - Evolutionary genomics of yeast pathogens in the Saccharomycotina. AB - Saccharomycotina comprises a diverse group of yeasts that includes numerous species of industrial or clinical relevance. Opportunistic pathogens within this clade are often assigned to the genus Candida but belong to phylogenetically distant lineages that also comprise non-pathogenic species. This indicates that the ability to infect humans has evolved independently several times among Saccharomycotina. Although the mechanisms of infection of the main groups of Candida pathogens are starting to be unveiled, we still lack sufficient understanding of the evolutionary paths that led to a virulent phenotype in each of the pathogenic lineages. Deciphering what genomic changes underlie the evolutionary emergence of a virulence trait will not only aid the discovery of novel virulence mechanisms but it will also provide valuable information to understand how new pathogens emerge, and what clades may pose a future danger. Here we review recent comparative genomics efforts that have revealed possible evolutionary paths to pathogenesis in different lineages, focusing on the main three agents of candidiasis worldwide: Candida albicans, C. parapsilosis and C. glabrata We will discuss what genomic traits may facilitate the emergence of virulence, and focus on two different genome evolution mechanisms able to generate drastic phenotypic changes and which have been associated to the emergence of virulence: gene family expansion and interspecies hybridization. PMID- 27493147 TI - MRI in patients with chronic pubalgia: Is precise useful information provided to the surgeon? A case-control study. AB - BACKGROUND: Recent studies described that MRI is a good examination to assess damage in chronic athletic pubalgia (AP). However, to our knowledge, no studies focus on systematic correlation of precise tendon or parietal lesion in MRI with surgery and histological assessment. Therefore, we performed a case-control study to determine if MRI can precisely assess Adductor longus (AL) tendinopathy and parietal lesion, compared with surgery and histology. HYPOTHESIS: MRI can determine if AP comes from pubis symphysis, musculotendinous or inguinal orifice structures. MATERIALS/METHODS: Eighteen consecutive patients were enrolled from November 2011 to April 2013 for chronic AP. To constitute a control group, we also enrolled 18 asymptomatic men. All MRI were reviewed in consensus by 2 skeletal radiologists for pubic symphysis, musculotendinous, abdominal wall assessment and compared to surgery and histology findings. RESULTS: Regarding pubis symphysis, we found 4 symmetric bone marrow oedema (14%), 2 secondary cleft (7%) and 2 superior ligaments lesions (7%). For AL tendon, we mainly found 13 asymmetric bone marrow oedema (46%), 15 hyperaemia (54%). Regarding abdominal wall, the deep inguinal orifice size in the group of symptomatic athletes and the control group was respectively 27.3+/-6.4mm and 23.8+/-6.3mm. The correlation between MRI and surgery/histology was low: 20% for the AL tendon and 9% for the abdominal wall. If we chose the criteria "affected versus unaffected", this correlation became higher: 100% for AL tendon and 73% for the abdominal wall. CONCLUSION: MRI chronic athletic pubalgia concerns preferentially AL tendinopathy and deep inguinal canal dehiscence with high correlation to surgery/histology when only considering the item "affected versus unaffected" despite low correlation when we try to precisely grade these lesions. LEVEL OF EVIDENCE: III: case-control study. PMID- 27493148 TI - Extraocular, Non-Visual, and Simple Photoreceptors: An Introduction to the Symposium. AB - It has been recognized for decades that animals sense light using photoreceptors besides those that are devoted strictly to vision. However, the nature of these receptors, their molecular components, their physiological responses, and their biological functions are often obscure. Only recently have researchers begun to learn how critical these non-visual or very simple visual responses are to organismal function. New approaches, including high-throughput molecular genetic techniques, have led to a revolution in our understanding of the evolution, anatomical distribution, physiology, and-in some cases-function of non-visual photoreception in diverse organisms. In the following papers, we bring together specialists from throughout the field to review the current state of knowledge regarding extraocular, non-visual, and simple photoreceptors in a large diversity of organisms ranging from protists through vertebrates and invertebrates. PMID- 27493149 TI - Microbiome Composition and Diversity of the Ice-Dwelling Sea Anemone, Edwardsiella andrillae. AB - Edwardsiella andrillae is a sea anemone (Cnidaria: Anthozoa: Actiniaria) only known to live embedded in the ice at the seawater interface on the underside of the Ross Ice Shelf, Antarctica. Although the anatomy and morphological characteristics of E. andrillae have been described, the adaptations of this species to the under-ice ecosystem have yet to be examined. One feature that may be important to the physiology and ecology of E. andrillae is its microbiome, which may play a role in health and survival, as has been deduced in other metazoans, including anthozoans. Here we describe the microbiome of five specimens of E. andrillae, compare the diversity we recovered to that known for temperate anemones and another Antarctic cnidarian, and consider the phylogenetic and functional implications of microbial diversity for these animals. The E. andrillae microbiome was relatively low in diversity, with seven phyla detected, yet included substantial phylogenetic novelty. Among the five anemones investigated, the distribution of microbial taxa varied; this trait appears to be shared by many anthozoans. Most importantly, specimens either appeared to be dominated by Proteobacteria-affiliated members or by deeply branching Tenericute sequences. There were few closely related sequence types that were common to temperate and Antarctic sea anemone microbiomes, the exception being an Acinetobacter-related representative. Similar observations were made between microbes associated with E. andrillae and an Antarctic soft coral; however, there were several closely-related, low abundance Gammaproteobacteria in both Antarctic microbiomes, particularly from the soft coral, that are also commonly detected in Southern Ocean seawater. Although this preliminary study leaves open many questions concerning microbiome diversity and its role in host ecology, we identify major lineages of microbes (e.g., diverse deep-branching Alphaproteobacteria, Epsilonproteobacteria, and divergent Tenericutes affiliates) that may play critical roles, and we highlight the current understanding and the need for future studies of sea anemone-microbiome relationships. PMID- 27493151 TI - Pseudoalteromonas profundi sp. nov., isolated from a deep-sea seamount. AB - A Gram-stain-negative, rod-shaped, strictly aerobic, motile bacterial strain, designated TP162T, was isolated from a seamount near the Yap Trench in the tropical western Pacific. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain TP162T was related to the genus Pseudoalteromonas and had highest 16S rRNA gene sequence similarities with the type strains Pseudoalteromonas shioyasakiensis SE3T (98.2 %), Pseudoalteromonas lipolytica LMEB 39T (97.7 %), Pseudoalteromonas arabiensis k53T (97.4 %) and Pseudoalteromonas aliena KMM 3562T (97.2 %). The predominant cellular fatty acids were summed feature 3 (composed of iso-C15 : 0 2-OH and/or C16 : 1omega7c), C17 : 1omega8c and C16 : 0. The quinone system for strain TP162T comprised predominantly ubiquinone-8, and the polar lipid profile contained phosphatidylethanolamine, phosphatidylglycerol, one unidentified phospholipid and four unidentified lipids. The genomic DNA G+C content of strain TP162T was 46.7 mol%. Strain TP162T shared 28 % DNA-DNA relatedness with P.shioyasakiensis JCM 18891T, 21 % with P. lipolytica JCM 15903T, 35 % with P.arabiensis JCM 17292T and 18 % with P.aliena LMG 22059T. Combined data from phenotypic, chemotaxonomic, phylogenetic and DNA-DNA relatedness studies demonstrated that strain TP162T is a representative of a novel species of the genus Pseudoalteromonas, for which we propose the name Pseudoalteromonas profundi sp. nov. (type strain TP162T=KACC 18554T=CGMCC 1.15394T). PMID- 27493150 TI - Accessory renal arteries: Prevalence in resistant hypertension and an important role in nonresponse to radiofrequency renal denervation. AB - OBJECTIVE: The aim of this study was to understand the role of accessory renal arteries in resistant hypertension, and to establish their role in nonresponse to radiofrequency renal denervation (RDN) procedures. BACKGROUND: Prior studies suggest a role for accessory renal arteries in hypertensive syndromes, and recent clinical trials of renal denervation report that these anomalies are highly prevalent in resistant hypertension. This study evaluated the relationships among resistant hypertension, accessory renal arteries, and the response to radiofrequency (RF) renal denervation. METHODS: Computed Tomography Angiography (CTA) and magnetic resonance imaging (MRI) scans from 58 patients with resistant hypertension undergoing RF renal denervation (RDN) were evaluated. Results were compared with CT scans in 57 healthy, normotensive subjects undergoing screening as possible renal transplant donors. All scans were carefully studied for accessory renal arteries, and were correlated with long term blood pressure reduction. RESULTS: Accessory renal arteries were markedly more prevalent in the hypertensive patients than normotensive renal donors (59% vs 32% respectively, p=0.004). RDN had an overall nonresponse rate of 29% (response rate 71%). Patients without accessory vessels had a borderline higher response rate to RDN than those with at least one accessory vessel (83% vs 62% respectively, p=0.076) and a higher RDN response than patients with untreated accessory arteries (83% vs 55%; p=0.040). For accessory renal arteries and nonresponse, the sensitivity was 76%, specificity 49%, with positive and negative predictive values 38% and 83% respectively. CONCLUSIONS: Accessory renal arteries were markedly over represented in resistant hypertensives compared with healthy controls. While not all patients with accessory arteries were nonresponders, nonresponse was related to both the presence and non-treatment of accessory arteries. Addressing accessory renal arteries in future clinical trials may improve RDN therapeutic efficacy. PMID- 27493152 TI - Abundance of Hepatic Transporters in Caucasians: A Meta-Analysis. AB - This study aimed to derive quantitative abundance values for key hepatic transporters suitable for in vitro-in vivo extrapolation within a physiologically based pharmacokinetic modeling framework. A meta-analysis was performed whereby data on abundance measurements, sample preparation methods, and donor demography were collated from the literature. To define values for a healthy Caucasian population, a subdatabase was created whereby exclusion criteria were applied to remove samples from non-Caucasian individuals, those with underlying disease, or those with subcellular fractions other than crude membrane. Where a clinically relevant active genotype was known, only samples from individuals with an extensive transporter phenotype were included. Authors were contacted directly when additional information was required. After removing duplicated samples, the weighted mean, geometric mean, standard deviation, coefficient of variation, and between-study homogeneity of transporter abundances were determined. From the complete database containing 24 transporters, suitable abundance data were available for 11 hepatic transporters from nine studies after exclusion criteria were applied. Organic anion transporting polypeptides OATP1B1 and OATP1B3 showed the highest population abundance in healthy adult Caucasians. For several transporters, the variability in abundance was reduced significantly once the exclusion criteria were applied. The highest variability was observed for OATP1B3 > OATP1B1 > multidrug resistance protein 2 > multidrug resistance gene 1. No relationship was found between transporter expression and donor age. To our knowledge, this study provides the first in-depth analysis of current quantitative abundance data for a wide range of hepatic transporters, with the aim of using these data for in vitro-in vivo extrapolation, and highlights the significance of investigating the background of tissue(s) used in quantitative transporter proteomic studies. Similar studies are now warranted for other ethnicities. PMID- 27493154 TI - Reading between the guidelines. PMID- 27493153 TI - Understanding patient access patterns for primary health-care services for Aboriginal and Islander people in Queensland: a geospatial mapping approach. AB - This paperexplores the patterns ofpatients'accessingsix Aboriginal and Islander CommunityControlled Health Services (AICCHSs) in Queensland. Between August 2011 and February 2014, 26199 patients made at least one visit over a 2-year period prior to at least one of six Queensland AICCHS - one urban service (RA 1) in south-east Queensland, and five services in regional towns (RA 3) in Far North Queensland. Geospatial mapping of addresses for these registered patients was undertaken. The outcomes analysed included travel times to, the proportion of catchment populations using each AICCHS and an assessment of alternative mainstream general practice availability to these patients was made. In brief, the use of AICCHS was higher than Australian Bureau of Statistics census data would suggest. Approximately 20% of clients travel more than 30min to seek Aboriginal Health services, but only 8% of patients travelled longer than 60min. In the major city site, many other general practitioner (GP) services were bypassed. The data suggest Aboriginal and Islander patients in Queensland appear to value community-controlled primary care services. The number of Indigenous clients in regional locations in the Far North Queensland registered with services is often higher than the estimated resident population numbers. PMID- 27493156 TI - JIFfy Pop. PMID- 27493158 TI - PALEONTOLOGY. Venezuela's woes hamper access to fossil trove. PMID- 27493159 TI - BIOMEDICINE. Antiaging trial using young blood stirs concerns. PMID- 27493155 TI - The CB1 Neutral Antagonist AM4113 Retains the Therapeutic Efficacy of the Inverse Agonist Rimonabant for Nicotine Dependence and Weight Loss with Better Psychiatric Tolerability. AB - BACKGROUND: Multiple studies suggest a pivotal role of the endocannabinoid system in regulating the reinforcing effects of various substances of abuse. Rimonabant, a CB1 inverse agonist found to be effective for smoking cessation, was associated with an increased risk of anxiety and depression. Here we evaluated the effects of the CB1 neutral antagonist AM4113 on the abuse-related effects of nicotine and its effects on anxiety and depressive-like behavior in rats. METHODS: Rats were trained to self-administer nicotine under a fixed-ratio 5 or progressive-ratio schedules of reinforcement. A control group was trained to self-administer food. The acute/chronic effects of AM4113 pretreatment were evaluated on nicotine taking, motivation for nicotine, and cue-, nicotine priming- and yohimbine induced reinstatement of nicotine-seeking. The effects of AM4113 in the basal firing and bursting activity of midbrain dopamine neurons were evaluated in a separate group of animals treated with nicotine. Anxiety/depression-like effects of AM4113 and rimonabant were evaluated 24h after chronic (21 days) pretreatment (0, 1, 3, and 10mg/kg, 1/d). RESULTS: AM4113 significantly attenuated nicotine taking, motivation for nicotine, as well as cue-, priming- and stress-induced reinstatement of nicotine-seeking behavior. These effects were accompanied by a decrease of the firing and burst rates in the ventral tegmental area dopamine neurons in response to nicotine. On the other hand, AM4113 pretreatment did not have effects on operant responding for food. Importantly, AM4113 did not have effects on anxiety and showed antidepressant-like effects. CONCLUSION: Our results indicate that AM4113 could be a promising therapeutic option for the prevention of relapse to nicotine-seeking while lacking anxiety/depression-like side effects. PMID- 27493160 TI - U.S. RESEARCH MANAGEMENT. NSF tries two-step review, drawing praise--and darts. PMID- 27493161 TI - INFECTIOUS DISEASE. Zika vaccine has a good shot. PMID- 27493162 TI - SCIENCE DIPLOMACY. Synchrotron aims to bridge divides in the Middle East. PMID- 27493163 TI - FRANCE. Dispute over president's age tears Pasteur Institute apart. PMID- 27493164 TI - The storyteller. PMID- 27493165 TI - The long road to LIGO. PMID- 27493166 TI - ANTHROPOLOGY. Emperor Yu's Great Flood. PMID- 27493167 TI - PHYSICS. Bringing order to the expanding fermion zoo. PMID- 27493168 TI - PLANT SCIENCE. How do sunflowers follow the Sun--and to what end? PMID- 27493169 TI - BIOTECHNOLOGY. Benefits of selective feeding. PMID- 27493170 TI - ANALYTICAL METHODS. A nanoview of battery operation. PMID- 27493171 TI - SCIENCE AND REGULATION. The FDA is prohibited from going germline. PMID- 27493172 TI - NUCLEAR ENERGY. China-U.S. cooperation to advance nuclear power. PMID- 27493173 TI - Deciphering P values: Beware false certainty. PMID- 27493174 TI - Deciphering P values: Defining significance. PMID- 27493175 TI - Expanding protected areas is not enough. PMID- 27493176 TI - Comment on "Open-ocean fish reveal an omnidirectional solution to camouflage in polarized environments". AB - Brady et al (Reports, 20 November 2015, p. 965) claimed that the silvery sides of certain fish are cryptic when viewed by animals with polarization sensitivity, which they termed "polarocrypsis." After examining their evidence, we find this claim to be unsupported due to (i) pseudoreplication, (ii) confounding polarization contrast with intensity contrast, and (iii) measurements taken at very shallow depths. PMID- 27493177 TI - Response to Comment on "Open-ocean fish reveal an omnidirectional solution to camouflage in polarized environments". AB - Cronin et al take issue with our evidence for polarocryptic carangid fish based on concerns of pseudoreplication, our contrast metric, and habitat. We clarify (i) the importance of camouflage in near-surface open ocean environments and (ii) the use of a Stokes contrast metric and further (iii) conduct individual-based statistics on our data set to confirm the reported polarocrypsis patterns. PMID- 27493178 TI - Grain-resolved analysis of localized deformation in nickel-titanium wire under tensile load. AB - The stress-induced martensitic transformation in tensioned nickel-titanium shape memory alloys proceeds by propagation of macroscopic fronts of localized deformation. We used three-dimensional synchrotron x-ray diffraction to image at micrometer-scale resolution the grain-resolved elastic strains and stresses in austenite around one such front in a prestrained nickel-titanium wire. We found that the local stresses in austenite grains are modified ahead of the nose cone shaped buried interface where the martensitic transformation begins. Elevated shear stresses at the cone interface explain why the martensitic transformation proceeds in a localized manner. We established the crossover from stresses in individual grains to a continuum macroscopic internal stress field in the wire and rationalized the experimentally observed internal stress field and the topology of the macroscopic front by means of finite element simulations of the localized deformation. PMID- 27493179 TI - Direct conversion of methane to aromatics in a catalytic co-ionic membrane reactor. AB - Nonoxidative methane dehydroaromatization (MDA: 6CH4 <-> C6H6 + 9H2) using shape selective Mo/zeolite catalysts is a key technology for exploitation of stranded natural gas reserves by direct conversion into transportable liquids. However, this reaction faces two major issues: The one-pass conversion is limited by thermodynamics, and the catalyst deactivates quickly through kinetically favored formation of coke. We show that integration of an electrochemical BaZrO3-based membrane exhibiting both proton and oxide ion conductivity into an MDA reactor gives rise to high aromatic yields and improved catalyst stability. These effects originate from the simultaneous extraction of hydrogen and distributed injection of oxide ions along the reactor length. Further, we demonstrate that the electrochemical co-ionic membrane reactor enables high carbon efficiencies (up to 80%) that improve the technoeconomic process viability. PMID- 27493180 TI - Origin and hysteresis of lithium compositional spatiodynamics within battery primary particles. AB - The kinetics and uniformity of ion insertion reactions at the solid-liquid interface govern the rate capability and lifetime, respectively, of electrochemical devices such as Li-ion batteries. Using an operando x-ray microscopy platform that maps the dynamics of the Li composition and insertion rate in Li(x)FePO4, we found that nanoscale spatial variations in rate and in composition control the lithiation pathway at the subparticle length scale. Specifically, spatial variations in the insertion rate constant lead to the formation of nonuniform domains, and the composition dependence of the rate constant amplifies nonuniformities during delithiation but suppresses them during lithiation, and moreover stabilizes the solid solution during lithiation. This coupling of lithium composition and surface reaction rates controls the kinetics and uniformity during electrochemical ion insertion. PMID- 27493181 TI - Permanent excimer superstructures by supramolecular networking of metal quantum clusters. AB - Excimers are evanescent quasi-particles that typically form during collisional intermolecular interactions and exist exclusively for their excited-state lifetime. We exploited the distinctive structure of metal quantum clusters to fabricate permanent excimer-like colloidal superstructures made of ground-state noninteracting gold cores, held together by a network of hydrogen bonds between their capping ligands. This previously unknown aggregation state of matter, studied through spectroscopic experiments and ab initio calculations, conveys the photophysics of excimers into stable nanoparticles, which overcome the intrinsic limitation of excimers in single-particle applications-that is, their nearly zero formation probability in ultra-diluted solutions. In vitro experiments demonstrate the suitability of the superstructures as nonresonant intracellular probes and further reveal their ability to scavenge reactive oxygen species, which enhances their potential as anticytotoxic agents for biomedical applications. PMID- 27493182 TI - Tuning the valley and chiral quantum state of Dirac electrons in van der Waals heterostructures. AB - Chirality is a fundamental property of electrons with the relativistic spectrum found in graphene and topological insulators. It plays a crucial role in relativistic phenomena, such as Klein tunneling, but it is difficult to visualize directly. Here, we report the direct observation and manipulation of chirality and pseudospin polarization in the tunneling of electrons between two almost perfectly aligned graphene crystals. We use a strong in-plane magnetic field as a tool to resolve the contributions of the chiral electronic states that have a phase difference between the two components of their vector wave function. Our experiments not only shed light on chirality, but also demonstrate a technique for preparing graphene's Dirac electrons in a particular quantum chiral state in a selected valley. PMID- 27493183 TI - Outburst flood at 1920 BCE supports historicity of China's Great Flood and the Xia dynasty. AB - China's historiographical traditions tell of the successful control of a Great Flood leading to the establishment of the Xia dynasty and the beginning of civilization. However, the historicity of the flood and Xia remain controversial. Here, we reconstruct an earthquake-induced landslide dam outburst flood on the Yellow River about 1920 BCE that ranks as one of the largest freshwater floods of the Holocene and could account for the Great Flood. This would place the beginning of Xia at ~1900 BCE, several centuries later than traditionally thought. This date coincides with the major transition from the Neolithic to Bronze Age in the Yellow River valley and supports hypotheses that the primary state-level society of the Erlitou culture is an archaeological manifestation of the Xia dynasty. PMID- 27493185 TI - Circadian regulation of sunflower heliotropism, floral orientation, and pollinator visits. AB - Young sunflower plants track the Sun from east to west during the day and then reorient during the night to face east in anticipation of dawn. In contrast, mature plants cease movement with their flower heads facing east. We show that circadian regulation of directional growth pathways accounts for both phenomena and leads to increased vegetative biomass and enhanced pollinator visits to flowers. Solar tracking movements are driven by antiphasic patterns of elongation on the east and west sides of the stem. Genes implicated in control of phototropic growth, but not clock genes, are differentially expressed on the opposite sides of solar tracking stems. Thus, interactions between environmental response pathways and the internal circadian oscillator coordinate physiological processes with predictable changes in the environment to influence growth and reproduction. PMID- 27493184 TI - Metabolic engineering of microbial competitive advantage for industrial fermentation processes. AB - Microbial contamination is an obstacle to widespread production of advanced biofuels and chemicals. Current practices such as process sterilization or antibiotic dosage carry excess costs or encourage the development of antibiotic resistance. We engineered Escherichia coli to assimilate melamine, a xenobiotic compound containing nitrogen. After adaptive laboratory evolution to improve pathway efficiency, the engineered strain rapidly outcompeted a control strain when melamine was supplied as the nitrogen source. We additionally engineered the yeasts Saccharomyces cerevisiae and Yarrowia lipolytica to assimilate nitrogen from cyanamide and phosphorus from potassium phosphite, and they outcompeted contaminating strains in several low-cost feedstocks. Supplying essential growth nutrients through xenobiotic or ecologically rare chemicals provides microbial competitive advantage with minimal external risks, given that engineered biocatalysts only have improved fitness within the customized fermentation environment. PMID- 27493186 TI - Macromolecular recognition directs calcium ions to coccolith mineralization sites. AB - Many organisms form elaborate mineralized structures, constituted of highly organized arrangements of crystals and organic macromolecules. The localization of crystals within these structures is presumably determined by the interaction of nucleating macromolecules with the mineral phase. Here we show that, preceding nucleation, a specific interaction between soluble organic molecules and an organic backbone structure directs mineral components to specific sites. This strategy underlies the formation of coccoliths, which are highly ordered arrangements of calcite crystals produced by marine microalgae. On combining the insoluble organic coccolith scaffold with coccolith-associated soluble macromolecules in vitro, we found a massive accretion of calcium ions at the sites where the crystals form in vivo. The in vitro process exhibits profound similarities to the initial stages of coccolith biogenesis in vivo. PMID- 27493187 TI - The inhibition mechanism of human 20S proteasomes enables next-generation inhibitor design. AB - The proteasome is a validated target for anticancer therapy, and proteasome inhibition is employed in the clinic for the treatment of tumors and hematological malignancies. Here, we describe crystal structures of the native human 20S proteasome and its complexes with inhibitors, which either are drugs approved for cancer treatment or are in clinical trials. The structure of the native human 20S proteasome was determined at an unprecedented resolution of 1.8 angstroms. Additionally, six inhibitor-proteasome complex structures were elucidated at resolutions between 1.9 and 2.1 angstroms. Collectively, the high resolution structures provide new insights into the catalytic mechanisms of inhibition and necessitate a revised description of the proteasome active site. Knowledge about inhibition mechanisms provides insights into peptide hydrolysis and can guide strategies for the development of next-generation proteasome-based cancer therapeutics. PMID- 27493189 TI - Working my way out. PMID- 27493188 TI - RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. AB - Mutations in the optineurin (OPTN) gene have been implicated in both familial and sporadic amyotrophic lateral sclerosis (ALS). However, the role of this protein in the central nervous system (CNS) and how it may contribute to ALS pathology are unclear. Here, we found that optineurin actively suppressed receptor interacting kinase 1 (RIPK1)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3, and mixed lineage kinase domain-like protein (MLKL). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1(G93A) transgenic mice and pathological samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration. Furthermore, inhibiting RIPK1 kinase may provide an axonal protective strategy for the treatment of ALS and other human degenerative diseases characterized by axonal degeneration. PMID- 27493190 TI - Diverse evolutionary roots and mechanistic variations of the CRISPR-Cas systems. AB - Adaptive immunity had been long thought of as an exclusive feature of animals. However, the discovery of the CRISPR-Cas defense system, present in almost half of prokaryotic genomes, proves otherwise. Because of the everlasting parasite host arms race, CRISPR-Cas has rapidly evolved through horizontal transfer of complete loci or individual modules, resulting in extreme structural and functional diversity. CRISPR-Cas systems are divided into two distinct classes that each consist of three types and multiple subtypes. We discuss recent advances in CRISPR-Cas research that reveal elaborate molecular mechanisms and provide for a plausible scenario of CRISPR-Cas evolution. We also briefly describe the latest developments of a wide range of CRISPR-based applications. PMID- 27493191 TI - Epithelioid sarcoma-like hemangioendothelioma on the chest wall. AB - Epithelioid sarcoma-like hemangioendothelioma is a rare vascular neoplasm that usually occurs in the distal extremities of young adults. Although the overall behavior of this neoplasm is usually indolent with a low risk of distant metastasis, the risk of local recurrence is significant. Therefore, initial surgical treatment with an adequate margin is important to improve the prognosis. However, epithelioid sarcoma-like hemangioendothelioma is frequently misdiagnosed. A preoperative misdiagnosis could result in resection without a sufficient margin. Herein, we describe a 68-year-old man with epithelioid sarcoma like hemangioendothelioma on the chest wall, which was treated by wide resection despite difficulties with the preoperative diagnosis. PMID- 27493192 TI - PcircRNA_finder: a software for circRNA prediction in plants. AB - MOTIVATION: Recent studies reveal an important role of non-coding circular RNA (circRNA) in the control of cellular processes. Because of differences in the organization of plant and mammal genomes, the sensitivity and accuracy of circRNA prediction programs using algorithms developed for animals and humans perform poorly for plants. RESULTS: A circRNA prediction software for plants (termed PcircRNA_finder) was developed that is more sensitive in detecting circRNAs than other frequently used programs (such as find_circ and CIRCexplorer), Based on analysis of simulated and real rRNA-/RNAase R RNA-Seq data from Arabidopsis thaliana and rice PcircRNA_finder provides a more comprehensive sensitive, precise prediction method for plants circRNAs. AVAILABILITY AND IMPLEMENTATION: http://ibi.zju.edu.cn/bioinplant/tools/manual.htm CONTACT: fanlj@zju.edu.cnSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27493193 TI - FARAO: the flexible all-round annotation organizer. AB - : With decreasing costs of generating DNA sequence data, genome and metagenome projects have become accessible to a wider scientific community. However, to extract meaningful information and visualize the data remain challenging. We here introduce FARAO, a highly scalable software for organization, visualization and integration of annotation and read coverage data that can also combine output data from several bioinformatics tools. The capabilities of FARAO can greatly aid analyses of genomic and metagenomic datasets. AVAILABILITY AND IMPLEMENTATION: FARAO is implemented in Perl and is supported under Unix-like operative systems, including Linux and macOS. The Perl source code is freely available for download under the MIT License from http://microbiology.se/software/farao/ CONTACT: johan.bengtsson-palme@microbiology.seSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27493194 TI - Detection of differentially methylated regions in whole genome bisulfite sequencing data using local Getis-Ord statistics. AB - MOTIVATION: DNA methylation is an important epigenetic modification that has essential role in gene regulation, cell differentiation and cancer development. Bisulfite sequencing is a widely used technique to obtain genome-wide DNA methylation profiles, and one of the key tasks of analyzing bisulfite sequencing data is to detect differentially methylated regions (DMRs) among samples under different treatment conditions. Although numerous tools have been proposed to detect differentially methylated single CpG site (DMC) between samples, methods for direct DMR detection, especially for complex study designs, are largely limited. RESULTS: We present a new software, GetisDMR, for direct DMR detection. We use beta-binomial regression to model the whole-genome bisulfite sequencing data, where variations in methylation levels and confounding effects have been accounted for. We employ a region-wise test statistic, which is derived from local Getis-Ord statistics and considers the spatial correlation between nearby CpG sites, to detect DMRs. Unlike existing methods, that attempt to infer DMRs from DMCs based on empirical criteria, we provide statistical inference for direct DMR detection. Through extensive simulations and an application to two mouse datasets, we demonstrate that GetisDMR achieves better sensitivities, positive predictive values, more exact locations and better agreement of DMRs with current biological knowledge. AVAILABILITY AND IMPLEMENTATION: It is available at https://github.com/DMU-lilab/GetisDMR CONTACTS: y.wen@auckland.ac.nz or zhiguangli@dlmedu.edu.cnSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27493195 TI - Novel methodology to perform sulfur hexafluoride (SF6)-based multiple-breath wash in and washout in infants using current commercially available equipment. AB - Multiple-breath inert gas washout (MBW) is ideally suited for early detection and monitoring of serious lung disease, such as cystic fibrosis, in infants and young children. Validated commercial options for the MBW technique are limited, and suitability of nitrogen (N2)-based MBW is of concern given the detrimental effect of exposure to pure O2 on infant breathing pattern. We propose novel methodology using commercially available N2 MBW equipment to facilitate 4% sulfur hexafluoride (SF6) multiple-breath inert gas wash-in and washout suitable for the infant age range. CO2, O2, and sidestream molar mass sensor signals were used to accurately calculate SF6 concentrations. An improved dynamic method for synchronization of gas and respiratory flow was developed to take into account variations in sidestream sample flow during MBW measurement. In vitro validation of triplicate functional residual capacity (FRC) assessments was undertaken under dry ambient conditions using lung models ranging from 90 to 267 ml, with tidal volumes of 28-79 ml, and respiratory rates 20-60 per minute. The relative mean (SD, 95% confidence interval) error of triplicate FRC determinations by washout was -0.26 (1.84, -3.86 to +3.35)% and by wash-in was 0.57 (2.66, -4.66 to +5.79)%. The standard deviations [mean (SD)] of percentage error among FRC triplicates were 1.40 (1.14) and 1.38 (1.32) for washout and wash-in, respectively. The novel methodology presented achieved FRC accuracy as outlined by current MBW consensus recommendations (95% of measurements within 5% accuracy). Further clinical evaluation is required, but this new technique, using existing commercially available equipment, has exciting potential for research and clinical use. PMID- 27493196 TI - Modeling age-related changes in muscle-tendon dynamics during cyclical contractions in the rat gastrocnemius. AB - Efficient muscle-tendon performance during cyclical tasks is dependent on both active and passive mechanical tissue properties. Here we examine whether age related changes in the properties of muscle-tendon units (MTUs) compromise their ability to do work and utilize elastic energy storage. We empirically quantified passive and active properties of the medial gastrocnemius muscle and material properties of the Achilles tendon in young (~6 mo) and old (~32 mo) rats. We then used these properties in computer simulations of a Hill-type muscle model operating in series with a Hookean spring. The modeled MTU was driven through sinusoidal length changes and activated at a phase that optimized muscle-tendon tuning to assess the relative contributions of active and passive elements to the force and work in each cycle. In physiologically realistic simulations where young and old MTUs started at similar passive forces and developed similar active forces, the capacity of old MTUs to store elastic energy and produce positive work was compromised. These results suggest that the observed increase in the metabolic cost of locomotion with aging may be in part due to the recruitment of additional muscles to compensate for the reduced work at the primary MTU. Furthermore, the age-related increases in passive stiffness coupled with a reduced active force capacity in the muscle can lead to shifts in the force length and force-velocity operating range that may significantly impact mechanical and metabolic performance. Our study emphasizes the importance of the interplay between muscle and tendon mechanical properties in shaping MTU performance during cyclical contractions. PMID- 27493197 TI - No difference in exogenous carbohydrate oxidation during exercise in children with and without impaired glucose tolerance. AB - The capacity to match carbohydrate (CHO) utilization with availability is impaired in insulin-resistant, obese adults at rest. Understanding exogenous carbohydrate (CHOexo) oxidation during exercise and its association to insulin resistance (IR) is important, especially in children at risk for type 2 diabetes. Our objective was to examine the oxidative efficiency of CHOexo during exercise in obese children with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). Children attended two visits and were identified as NGT (n = 22) or IGT (n = 12) based on 2-h oral glucose tolerance test (OGTT) glucose levels of <7.8 mmol/l or >=7.8 mmol/l, respectively. Anthropometry, body composition, and aerobic fitness (Vo2max) were assessed. Insulin and glucose at baseline, 30, 60, 90, and 120 min during the OGTT were used to calculate measures of insulin sensitivity. On a separate day, a (13)C-enriched CHO drink was ingested before exercise (3 * 20 min bouts) at 45% Vo2max Breath measurements were collected to calculate CHOexo oxidative efficiency. CHOexo oxidative efficiency during exercise was similar in IGT (17.0 +/- 3.6%) compared with NGT (17.1 +/- 4.4%) (P = 0.90) despite lower whole body insulin sensitivity in IGT at rest (P = 0.02). Area under the curve for insulin (AUCins) measured at rest during the OGTT was greater in IGT compared with NGT (P = 0.04). The ability of skeletal muscle to utilize CHOexo was not impaired during exercise in children with IGT. PMID- 27493199 TI - Comparing Trends Between Food Insecurity and Cigarette Smoking Among Adults in the United States, 1998 to 2011. AB - PURPOSE: Previous studies have shown that cigarette smoking is associated with higher rates and severity of food insecurity but do not address how population level smoking rates change in response to changes in food security. DESIGN: Trend analysis of serial cross-sectional data. SETTING: Data from a representative survey of US households. PARTICIPANTS: Adults within households participating in both the Food Security Supplement and Tobacco Use Supplement of the Current Population Survey during 5 overlapping administrations from 1998 to 2011. MEASURES: A "current smoker" is defined as someone who indicated that they currently smoke on "some days" or "every day." A household's food security is coded as "secure" or "insecure," according to responses to a food security scale, interpreted using a US Department of Agriculture standard. ANALYSIS: Descriptive comparison of the roughly triennial trends in the prevalence of food insecurity and current smoking from 1998 to 2011. RESULTS: The prevalence of food insecurity increased by 30% among adults overall versus 54% among current smokers, with most of the changes occurring following the economic recession of 2008 and 2009. Over this same period, the prevalence of current smoking declined by 33% among food secure adults and only 14% among food-insecure adults. CONCLUSION: Food insecurity increased more markedly among adult smokers than nonsmokers, and the prevalence of smoking declined more slowly in food-insecure households, indicating that more low-income smokers are facing hunger, which may at least partly be due to buying cigarettes. PMID- 27493198 TI - A single dose of histamine-receptor antagonists before downhill running alters markers of muscle damage and delayed-onset muscle soreness. AB - Histamine contributes to elevations in skeletal muscle blood flow following exercise, which raises the possibility that histamine is an important mediator of the inflammatory response to exercise. We examined the influence of antihistamines on postexercise blood flow, inflammation, muscle damage, and delayed-onset muscle soreness (DOMS) in a model of moderate exercise-induced muscle damage. Subjects consumed either a combination of fexofenadine and ranitidine (blockade, n = 12) or nothing (control, n = 12) before 45 min of downhill running (-10% grade). Blood flow to the leg was measured before and throughout 120 min of exercise recovery. Markers of inflammation, muscle damage, and DOMS were obtained before and at 0, 6, 12, 24, 48, and 72 h postexercise. At 60 min postexercise, blood flow was reduced ~29% with blockade compared with control (P < 0.05). Markers of inflammation were elevated after exercise (TNF alpha, IL-6), but did not differ between control and blockade. Creatine kinase concentrations peaked 12 h after exercise, and the overall response was greater with blockade (18.3 +/- 3.2 kU.l-1.h-1) compared with control (11.6 +/- 2.0 kU.l 1.h-1; P < 0.05). Reductions in muscle strength in control (-19.3 +/- 4.3% at 24 h) were greater than blockade (-7.8 +/- 4.8%; P < 0.05) and corresponded with greater perceptions of pain/discomfort in control compared with blockade. In conclusion, histamine-receptor blockade reduced postexercise blood flow, had no effect on the pattern of inflammatory markers, increased serum creatine kinase concentrations, attenuated muscle strength loss, and reduced pain perception following muscle-damaging exercise.NEW & NOTEWORTHY Histamine appears to be intimately involved with skeletal muscle during and following exercise. Blocking histamine's actions during muscle-damaging exercise, via common over-the-counter antihistamines, resulted in increased serum creatine kinase, an indirect marker of muscle damage. Paradoxically, blocking histamine's actions attenuated muscle strength loss and reduced perceptions of muscle pain for 72 h following muscle damaging exercise. These results indicate that exercise-induced histamine release may have a broad impact on protecting muscle from exercise-induced damage. PMID- 27493200 TI - The Relationship of Engagement in Improvement Practices to Outcome Measures in Large-Scale Quality Improvement Initiatives. AB - Hospital engagement networks (HENs) are part of the largest health care improvement initiative ever undertaken. This article explores whether engagement in improvement activities within a HEN affected quality measures. Data were drawn from 1174 acute care hospitals. A composite quality score was created from 10 targeted topic area measures multiplied by the number of qualifying topics. Scores improved from 5.4 (SD = 6.8) at baseline to 4.6 (5.9) at remeasurement; P < .0001. Hospitals with higher baseline scores demonstrated greater improvement ( P < .0001) than hospitals with lower baseline scores. Hospitals with larger Medicaid populations ( P = .023) and micropolitan ( P = .034) hospitals tended to have greater improvement, whereas hospitals in the West ( P = .0009) did not improve as much as hospitals in other regions. After adjusting for hospital characteristics, hospitals with improvement champions ( P = .008), a higher level of engagement with their state association ( P = .001), and more leadership involvement ( P = .005) in HEN demonstrated greater improvement. PMID- 27493201 TI - Comparative evaluation of the genomes of three common Drosophila-associated bacteria. AB - Drosophila melanogaster is an excellent model to explore the molecular exchanges that occur between an animal intestine and associated microbes. Previous studies in Drosophila uncovered a sophisticated web of host responses to intestinal bacteria. The outcomes of these responses define critical events in the host, such as the establishment of immune responses, access to nutrients, and the rate of larval development. Despite our steady march towards illuminating the host machinery that responds to bacterial presence in the gut, there are significant gaps in our understanding of the microbial products that influence bacterial association with a fly host. We sequenced and characterized the genomes of three common Drosophila-associated microbes: Lactobacillus plantarum, Lactobacillus brevis and Acetobacter pasteurianus For each species, we compared the genomes of Drosophila-associated strains to the genomes of strains isolated from alternative sources. We found that environmental Lactobacillus strains readily associated with adult Drosophila and were similar to fly isolates in terms of genome organization. In contrast, we identified a strain of A. pasteurianus that apparently fails to associate with adult Drosophila due to an inability to grow on fly nutrient food. Comparisons between association competent and incompetent A. pasteurianus strains identified a short list of candidate genes that may contribute to survival on fly medium. Many of the gene products unique to fly associated strains have established roles in the stabilization of host-microbe interactions. These data add to a growing body of literature that examines the microbial perspective of host-microbe relationships. PMID- 27493202 TI - RPGR, a prenylated retinal ciliopathy protein, is targeted to cilia in a prenylation- and PDE6D-dependent manner. AB - RPGR (retinitis pigmentosa GTPase regulator) is a ciliary protein associated with several forms of inherited retinal degenerative diseases. PDE6D is a ubiquitously expressed prenyl-binding protein and involved in ciliary targeting of prenylated proteins. The current working model for the RPGR function depicts that RPGR acts as a scaffold protein to recruit cargo-loaded PDE6D to primary cilia. Here, we present evidence demonstrating an alternative relationship between RPGR and PDE6D, in which RPGR is a cargo of PDE6D for ciliary targeting. We found that the constitutive isoform of RPGR, which is prenylated, requires prenylation for its ciliary localization. We also found that there are at least two independent ciliary targeting signals in RPGR: one within the N-terminal region that contains the RCC1-like domain and the other near the prenylation site at the C-terminus. Ablation of PDE6D blocked ciliary targeting of RPGR. Our study indicates that prenylated RPGR is one of the cargos of PDE6D for ciliary trafficking and provides insight into the mechanisms by which RPGR is targeted to cilia. PMID- 27493203 TI - Sulfur utilization of corals is enhanced by endosymbiotic algae. AB - Sulfur-containing compounds are important components of all organisms, but few studies have explored sulfate utilization in corals. Our previous study found that the expression of a sulfur transporter (SLC26A11) was upregulated in the presence of Symbiodinium cells in juveniles of the reef-building coral Acropora tenuis In this study, we performed autoradiography using (35)S-labeled sulfate ions ((35)SO4 (2-)) to examine the localization and amount of incorporated radioactive sulfate in the coral tissues and symbiotic algae. Incorporated (35)SO4 (2-) was detected in symbiotic algal cells, nematocysts, ectodermal cells and calicoblast cells. The combined results of (35)S autoradiography and Alcian Blue staining showed that incorporated (35)S accumulated as sulfated glycosaminoglycans (GAGs) in the ectodermal cell layer. We also compared the relative incorporation of (35)SO4 (2-) into coral tissues and endosymbiotic algae, and their chemical fractions in dark versus light (photosynthetic) conditions. The amount of sulfur compounds, such as GAGs and lipids, generated from (35)SO4 (2-) was higher under photosynthetic conditions. Together with the upregulation of sulfate transporters by symbiosis, our results suggest that photosynthesis of algal endosymbionts contributes to the synthesis and utilization of sulfur compounds in corals. PMID- 27493204 TI - Comparison of gamma-Aminobutyric Acid, Type A (GABAA), Receptor alphabetagamma and alphabetadelta Expression Using Flow Cytometry and Electrophysiology: EVIDENCE FOR ALTERNATIVE SUBUNIT STOICHIOMETRIES AND ARRANGEMENTS. AB - The subunit stoichiometry and arrangement of synaptic alphabetagamma GABAA receptors are generally accepted as 2alpha:2beta:1gamma with a beta-alpha-gamma beta-alpha counterclockwise configuration, respectively. Whether extrasynaptic alphabetadelta receptors adopt the analogous beta-alpha-delta-beta-alpha subunit configuration remains controversial. Using flow cytometry, we evaluated expression levels of human recombinant gamma2 and delta subunits when co transfected with alpha1 and/or beta2 subunits in HEK293T cells. Nearly identical patterns of gamma2 and delta subunit expression were observed as follows: both required co-transfection with alpha1 and beta2 subunits for maximal expression; both were incorporated into receptors primarily at the expense of beta2 subunits; and both yielded similar FRET profiles when probed for subunit adjacency, suggesting similar underlying subunit arrangements. However, because of a slower rate of delta subunit degradation, 10-fold less delta subunit cDNA was required to recapitulate gamma2 subunit expression patterns and to eliminate the functional signature of alpha1beta2 receptors. Interestingly, titrating gamma2 or delta subunit cDNA levels progressively altered GABA-evoked currents, revealing more than one kinetic profile for both alphabetagamma and alphabetadelta receptors. This raised the possibility of alternative receptor isoforms, a hypothesis confirmed using concatameric constructs for alphabetagamma receptors. Taken together, our results suggest a limited cohort of alternative subunit arrangements in addition to canonical beta-alpha-gamma/delta-beta-alpha receptors, including beta-alpha-gamma/delta-alpha-alpha receptors at lower levels of gamma2/delta expression and beta-alpha-gamma/delta-alpha-gamma/delta receptors at higher levels of expression. These findings provide important insight into the role of GABAA receptor subunit under- or overexpression in disease states such as genetic epilepsies. PMID- 27493205 TI - Structure of the Dispase Autolysis-inducing Protein from Streptomyces mobaraensis and Glutamine Cross-linking Sites for Transglutaminase. AB - Transglutaminase from Streptomyces mobaraensis (MTG) is an important enzyme for cross-linking and modifying proteins. An intrinsic substrate of MTG is the dispase autolysis-inducing protein (DAIP). The amino acid sequence of DAIP contains 5 potential glutamines and 10 lysines for MTG-mediated cross-linking. The aim of the study was to determine the structure and glutamine cross-linking sites of the first physiological MTG substrate. A production procedure was established in Escherichia coli BL21 (DE3) to obtain high yields of recombinant DAIP. DAIP variants were prepared by replacing four of five glutamines for asparagines in various combinations via site-directed mutagenesis. Incorporation of biotin cadaverine revealed a preference of MTG for the DAIP glutamines in the order of Gln-39 ? Gln-298 > Gln-345 ~ Gln-65 ? Gln-144. In the structure of DAIP the preferred glutamines do cluster at the top of the seven-bladed beta propeller. This suggests a targeted cross-linking of DAIP by MTG that may occur after self-assembly in the bacterial cell wall. Based on our biochemical and structural data of the first physiological MTG substrate, we further provide novel insight into determinants of MTG-mediated modification, specificity, and efficiency. PMID- 27493206 TI - Structure of the Tuberous Sclerosis Complex 2 (TSC2) N Terminus Provides Insight into Complex Assembly and Tuberous Sclerosis Pathogenesis. AB - Tuberous sclerosis complex (TSC) is caused by mutations in the TSC1 and TSC2 tumor suppressor genes. The gene products hamartin and tuberin form the TSC complex that acts as GTPase-activating protein for Rheb and negatively regulates the mammalian target of rapamycin complex 1 (mTORC1). Tuberin contains a RapGAP homology domain responsible for inactivation of Rheb, but functions of other protein domains remain elusive. Here we show that the TSC2 N terminus interacts with the TSC1 C terminus to mediate complex formation. The structure of the TSC2 N-terminal domain from Chaetomium thermophilum and a homology model of the human tuberin N terminus are presented. We characterize the molecular requirements for TSC1-TSC2 interactions and analyze pathological point mutations in tuberin. Many mutations are structural and produce improperly folded protein, explaining their effect in pathology, but we identify one point mutant that abrogates complex formation without affecting protein structure. We provide the first structural information on TSC2/tuberin with novel insight into the molecular function. PMID- 27493207 TI - Metabolite-driven Regulation of Heme Uptake by the Biliverdin IXbeta/delta Selective Heme Oxygenase (HemO) of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa acquires extracellular heme via the Phu (Pseudomonas heme uptake) and Has (heme assimilation system) systems. We have previously shown the catalytic actions of heme oxygenase (HemO) along with the cytoplasmic heme transport protein PhuS control heme flux into the cell. To further investigate the role of the PhuS-HemO couple in modulating heme uptake, we have characterized two HemO variants, one that is catalytically inactive (HemO H26A/K34A/K132A or HemOin) and one that has altered regioselectivity (HemO N19K/K34A/F117Y/K132A or HemOalpha), producing biliverdin IXalpha (BVIXalpha). HemOalpha similar to wild type was able to interact and acquire heme from holo-PhuS. In contrast, the HemOin variant did not interact with holo-PhuS and showed no enzymatic activity. Complementation of a hemO deletion strain with the hemOin or hemOalpha variants in combination with [(13)C]heme isotopic labeling experiments revealed that the absence of BVIXbeta and BVIXdelta leads to a decrease in extracellular levels of hemophore HasA. We propose BVIXbeta and/or BVIXdelta transcriptionally or post transcriptionally regulates HasA. Thus, coupling the PhuS-dependent flux of heme through HemO to feedback regulation of the cell surface signaling system through HasA allows P. aeruginosa to rapidly respond to fluctuating extracellular heme levels independent of the iron status of the cell. PMID- 27493209 TI - Carbon-Fixing Reactions of Photosynthesis. AB - plantcell;28/7/tpc.116.tt0716/FIG1F1fig1Photosynthesis in plants converts the energy of sunlight into chemical energy. Although photosynthesis involves many proteins and catalytic processes, it often is described as two sets of reactions, the light-dependent reactions and the carbon-fixing reactions. This lesson introduces the core biochemistry of the carbon-fixing reactions of photosynthesis, as well as its variations, C4 and CAM. Finally, it addresses how and why plants are affected by rising atmospheric CO2 levels, and research efforts to increase photosynthetic efficiency in current and future conditions. PMID- 27493208 TI - Identification of Two Conserved Residues Involved in Copper Release from Chloroplast PIB-1-ATPases. AB - Copper is an essential transition metal for living organisms. In the plant model Arabidopsis thaliana, half of the copper content is localized in the chloroplast, and as a cofactor of plastocyanin, copper is essential for photosynthesis. Within the chloroplast, copper delivery to plastocyanin involves two transporters of the PIB-1-ATPases subfamily: HMA6 at the chloroplast envelope and HMA8 in the thylakoid membranes. Both proteins are high affinity copper transporters but share distinct enzymatic properties. In the present work, the comparison of 140 sequences of PIB-1-ATPases revealed a conserved region unusually rich in histidine and cysteine residues in the TMA-L1 region of eukaryotic chloroplast copper ATPases. To evaluate the role of these residues, we mutated them in HMA6 and HMA8. Mutants of interest were selected from phenotypic tests in yeast and produced in Lactococcus lactis for further biochemical characterizations using phosphorylation assays from ATP and Pi Combining functional and structural data, we highlight the importance of the cysteine and the first histidine of the CX3HX2H motif in the process of copper release from HMA6 and HMA8 and propose a copper pathway through the membrane domain of these transporters. Finally, our work suggests a more general role of the histidine residue in the transport of copper by PIB-1-ATPases. PMID- 27493210 TI - Characterization of paramyosin and thin filaments in the smooth muscle of acorn worm, a member of hemichordates. AB - Paramyosin is a myosin-binding protein characteristic of invertebrate animals, while troponin is a Ca2+-dependent regulator of muscle contraction. Both proteins are widely distributed in protostomes, while in deuterostomes, their distribution is limited; namely, presence of paramyosin and absence of troponin are common features in echinoderm muscles, while muscles of chordates contain troponin but lack paramyosin. In this study, we examined the muscle of a hemichordate, acorn worm, to clarify whether this animal is like echinoderms or like the other deuterostome animals. We found a 100-kDa protein in the smooth muscle of acorn worm. This protein was identified with paramyosin, since the purified protein formed paracrystals with a constant axial periodicity in the presence of divalent cations as paramyosin of other animals, showed ability to interact with myosin and shared common antigenicity with echinoderm paramyosin. On the other hand, troponin band was not detected in isolated thin filaments, and the filaments increased myosin-ATPase activity in a Ca2+-independent manner. The results indicate that troponin is lacking in thin filaments of acorn worm muscle just as in those of echinoderms. The muscle of hemichordate acorn worm is quite similar to echinoderm muscles, but different from chordate muscles. PMID- 27493211 TI - Structure and function of [NiFe] hydrogenases. AB - Hydrogenases catalyze the reversible conversion of molecular hydrogen to protons and electrons via a heterolytic splitting mechanism. The active sites of [NiFe] hydrogenases comprise a dinuclear Ni-Fe center carrying CO and CN- ligands. The catalytic activity of the standard (O2-sensitive) [NiFe] hydrogenases vanishes under aerobic conditions. The O2-tolerant [NiFe] hydrogenases can sustain H2 oxidation activity under atmospheric conditions. These hydrogenases have very similar active site structures that change the ligand sphere during the activation/catalytic process. An important structural difference between these hydrogenases has been found for the proximal iron-sulphur cluster located in the vicinity of the active site. This unprecedented [4Fe-3S]-6Cys cluster can supply two electrons, which lead to rapid recovery of the O2 inactivation, to the [NiFe] active site. PMID- 27493212 TI - Shedding Light on Endometriosis. PMID- 27493213 TI - The Heat Stress Factor HSFA6b Connects ABA Signaling and ABA-Mediated Heat Responses. AB - Heat stress response (HSR) is a conserved mechanism developed to increase the expression of heat shock proteins (HSPs) via a heat shock factor (HSF)-dependent mechanism. Signaling by the stress phytohormone abscisic acid (ABA) is involved in acquired thermotolerance as well. Analysis of Arabidopsis (Arabidopsis thaliana) microarray databases revealed that the expression of HSFA6b, a class A HSF, extensively increased with salinity, osmotic, and cold stresses, but not heat. Here, we show that HSFA6b plays a pivotal role in the response to ABA and in thermotolerance. Salt-inducible HSFA6b expression was down-regulated in ABA insensitive and -deficient mutants; however, exogenous ABA application restored expression in ABA-deficient, but not -insensitive plants. Thus, ABA signaling is required for proper HSFA6b expression. A transcriptional activation assay of protoplasts revealed that ABA treatment and coexpression of an ABA signaling master effector, ABA-RESPONSIVE ELEMENT-BINDING PROTEIN1, could activate the HSFA6b promoter. In addition, HSFA6b directly bound to the promoter of DEHYDRATION-RESPONSIVE ELEMENT-BINDING PROTEIN2A and enhanced its expression. Analysis of ABA responses in seed germination, cotyledon greening, and root growth as well as salt and drought tolerance in HSFA6b-null, overexpression, and dominant negative mutants revealed that HSFA6b is a positive regulator participating in ABA-mediated salt and drought resistance. Thermoprotection tests showed that HSFA6b was required for thermotolerance acquisition. Our study reveals a network in which HSFA6b operates as a downstream regulator of the ABA mediated stress response and is required for heat stress resistance. This new ABA signaling pathway is integrated into the complex HSR network in planta. PMID- 27493214 TI - Histidine Regulates Seed Oil Deposition through Abscisic Acid Biosynthesis and beta-Oxidation. AB - The storage compounds are deposited into plant seeds during maturation. As the model oilseed species, Arabidopsis (Arabidopsis thaliana) has long been studied for seed oil deposition. However, the regulation of this process remains unclear. Through genetic screen with a seed oil body-specific reporter, we isolated low oil1 (loo1) mutant. LOO1 was mapped to HISTIDINE BIOSYNTHESIS NUMBER 1A (HISN1A). HISN1A catalyzes the first step of His biosynthesis. Oil significantly decreased, and conversely proteins markedly increased in hisn1a mutants, indicating that HISN1A regulates both oil accumulation and the oil-protein balance. HISN1A was predominantly expressed in embryos and root tips. Accordingly, the hisn1a mutants exhibited developmental phenotype especially of seeds and roots. Transcriptional profiling displayed that beta-oxidation was the major metabolic pathway downstream of HISN1A beta-Oxidation was induced in hisn1a mutants, whereas it was reduced in 35S:HISN1A-transgenic plants. In plants, seed storage oil is broken down by beta-oxidation, which is controlled by abscisic acid (ABA). We found that His activated genes of ABA biosynthesis and correspondingly advanced ABA accumulation. Exogenous ABA rescued the defects of hisn1a mutants, whereas mutation of ABA DEFICIENT2, a key enzyme in ABA biosynthesis, blocked the effect of His on beta-oxidation, indicating that ABA mediates His regulation in beta oxidation. Intriguingly, structural analysis showed that a potential His-binding domain was present in the general amino acid sensors GENERAL CONTROL NON DEREPRESSIBLE2 and PII, suggesting that His may serve as a signal molecule. Taken together, our study reveals that His promotes plant seed oil deposition through ABA biosynthesis and beta-oxidation. PMID- 27493216 TI - Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of alpha-dystroglycan. AB - The dystrophin glycoprotein complex, which connects the cell membrane to the basement membrane, is essential for a variety of biological events, including maintenance of muscle integrity. An O-mannose-type GalNAc-beta1,3-GlcNAc-beta1,4 (phosphate-6)-Man structure of alpha-dystroglycan (alpha-DG), a subunit of the complex that is anchored to the cell membrane, interacts directly with laminin in the basement membrane. Reduced glycosylation of alpha-DG is linked to some types of inherited muscular dystrophy; consistent with this relationship, many disease related mutations have been detected in genes involved in O-mannosyl glycan synthesis. Defects in protein O-linked mannose beta1,2-N acetylglucosaminyltransferase 1 (POMGnT1), a glycosyltransferase that participates in the formation of GlcNAc-beta1,2-Man glycan, are causally related to muscle-eye-brain disease (MEB), a congenital muscular dystrophy, although the role of POMGnT1 in postphosphoryl modification of GalNAc-beta1,3-GlcNAc-beta1,4 (phosphate-6)-Man glycan remains elusive. Our crystal structures of POMGnT1 agreed with our previous results showing that the catalytic domain recognizes substrate O-mannosylated proteins via hydrophobic interactions with little sequence specificity. Unexpectedly, we found that the stem domain recognizes the beta-linked GlcNAc of O-mannosyl glycan, an enzymatic product of POMGnT1. This interaction may recruit POMGnT1 to a specific site of alpha-DG to promote GlcNAc beta1,2-Man clustering and also may recruit other enzymes that interact with POMGnT1, e.g., fukutin, which is required for further modification of the GalNAc beta1,3-GlcNAc-beta1,4-(phosphate-6)-Man glycan. On the basis of our findings, we propose a mechanism for the deficiency in postphosphoryl modification of the glycan observed in POMGnT1-KO mice and MEB patients. PMID- 27493215 TI - Near-atomic cryo-EM structure of PRC1 bound to the microtubule. AB - Proteins that associate with microtubules (MTs) are crucial to generate MT arrays and establish different cellular architectures. One example is PRC1 (protein regulator of cytokinesis 1), which cross-links antiparallel MTs and is essential for the completion of mitosis and cytokinesis. Here we describe a 4-A-resolution cryo-EM structure of monomeric PRC1 bound to MTs. Residues in the spectrin domain of PRC1 contacting the MT are highly conserved and interact with the same pocket recognized by kinesin. We additionally found that PRC1 promotes MT assembly even in the presence of the MT stabilizer taxol. Interestingly, the angle of the spectrin domain on the MT surface corresponds to the previously observed cross bridge angle between MTs cross-linked by full-length, dimeric PRC1. This finding, together with molecular dynamic simulations describing the intrinsic flexibility of PRC1, suggests that the MT-spectrin domain interface determines the geometry of the MT arrays cross-linked by PRC1. PMID- 27493217 TI - Gram-negative trimeric porins have specific LPS binding sites that are essential for porin biogenesis. AB - The outer membrane (OM) of gram-negative bacteria is an unusual asymmetric bilayer with an external monolayer of lipopolysaccharide (LPS) and an inner layer of phospholipids. The LPS layer is rigid and stabilized by divalent cation cross links between phosphate groups on the core oligosaccharide regions. This means that the OM is robust and highly impermeable to toxins and antibiotics. During their biogenesis, OM proteins (OMPs), which function as transporters and receptors, must integrate into this ordered monolayer while preserving its impermeability. Here we reveal the specific interactions between the trimeric porins of Enterobacteriaceae and LPS. Isolated porins form complexes with variable numbers of LPS molecules, which are stabilized by calcium ions. In earlier studies, two high-affinity sites were predicted to contain groups of positively charged side chains. Mutation of these residues led to the loss of LPS binding and, in one site, also prevented trimerization of the porin, explaining the previously observed effect of LPS mutants on porin folding. The high resolution X-ray crystal structure of a trimeric porin-LPS complex not only helps to explain the mutagenesis results but also reveals more complex, subtle porin LPS interactions and a bridging calcium ion. PMID- 27493219 TI - From fire whirls to blue whirls and combustion with reduced pollution. AB - Fire whirls are powerful, spinning disasters for people and surroundings when they occur in large urban and wildland fires. Whereas fire whirls have been studied for fire-safety applications, previous research has yet to harness their potential burning efficiency for enhanced combustion. This article presents laboratory studies of fire whirls initiated as pool fires, but where the fuel sits on a water surface, suggesting the idea of exploiting the high efficiency of fire whirls for oil-spill remediation. We show the transition from a pool fire, to a fire whirl, and then to a previously unobserved state, a "blue whirl." A blue whirl is smaller, very stable, and burns completely blue as a hydrocarbon flame, indicating soot-free burning. The combination of fast mixing, intense swirl, and the water-surface boundary creates the conditions leading to nearly soot-free combustion. With the worldwide need to reduce emissions from both wanted and unwanted combustion, discovery of this state points to possible new pathways for reduced-emission combustion and fuel-spill cleanup. Because current methods to generate a stable vortex are difficult, we also propose that the blue whirl may serve as a research platform for fundamental studies of vortices and vortex breakdown in fluid mechanics. PMID- 27493218 TI - Alternative haplotypes of antigen processing genes in zebrafish diverged early in vertebrate evolution. AB - Antigen processing and presentation genes found within the MHC are among the most highly polymorphic genes of vertebrate genomes, providing populations with diverse immune responses to a wide array of pathogens. Here, we describe transcriptome, exome, and whole-genome sequencing of clonal zebrafish, uncovering the most extensive diversity within the antigen processing and presentation genes of any species yet examined. Our CG2 clonal zebrafish assembly provides genomic context within a remarkably divergent haplotype of the core MHC region on chromosome 19 for six expressed genes not found in the zebrafish reference genome: mhc1uga, proteasome-beta 9b (psmb9b), psmb8f, and previously unknown genes psmb13b, tap2d, and tap2e We identify ancient lineages for Psmb13 within a proteasome branch previously thought to be monomorphic and provide evidence of substantial lineage diversity within each of three major trifurcations of catalytic-type proteasome subunits in vertebrates: Psmb5/Psmb8/Psmb11, Psmb6/Psmb9/Psmb12, and Psmb7/Psmb10/Psmb13. Strikingly, nearby tap2 and MHC class I genes also retain ancient sequence lineages, indicating that alternative lineages may have been preserved throughout the entire MHC pathway since early diversification of the adaptive immune system ~500 Mya. Furthermore, polymorphisms within the three MHC pathway steps (antigen cleavage, transport, and presentation) are each predicted to alter peptide specificity. Lastly, comparative analysis shows that antigen processing gene diversity is far more extensive than previously realized (with ancient coelacanth psmb8 lineages, shark psmb13, and tap2t and psmb10 outside the teleost MHC), implying distinct immune functions and conserved roles in shaping MHC pathway evolution throughout vertebrates. PMID- 27493221 TI - Waltzing route toward double-helix formation in cholesteric shells. AB - Liquid crystals, when confined to a spherical shell, offer fascinating possibilities for producing artificial mesoscopic atoms, which could then self assemble into materials structured at a nanoscale, such as photonic crystals or metamaterials. The spherical curvature of the shell imposes topological constraints in the molecular ordering of the liquid crystal, resulting in the formation of defects. Controlling the number of defects, that is, the shell valency, and their positions, is a key success factor for the realization of those materials. Liquid crystals with helical cholesteric order offer a promising, yet unexplored way of controlling the shell defect configuration. In this paper, we study cholesteric shells with monovalent and bivalent defect configurations. By bringing together experiments and numerical simulations, we show that the defects appearing in these two configurations have a complex inner structure, as recently reported for simulated droplets. Bivalent shells possess two highly structured defects, which are composed of a number of smaller defect rings that pile up through the shell. Monovalent shells have a single radial defect, which is composed of two nonsingular defect lines that wind around each other in a double-helix structure. The stability of the bivalent configuration against the monovalent one is controlled by c = h/p, where h is the shell thickness and p the cholesteric helical pitch. By playing with the shell geometry, we can trigger the transition between the two configurations. This transition involves a fascinating waltz dynamics, where the two defects come closer while turning around each other. PMID- 27493220 TI - Crystal structure of a human neuronal nAChR extracellular domain in pentameric assembly: Ligand-bound alpha2 homopentamer. AB - In this study we report the X-ray crystal structure of the extracellular domain (ECD) of the human neuronal alpha2 nicotinic acetylcholine receptor (nAChR) subunit in complex with the agonist epibatidine at 3.2 A. Interestingly, alpha2 was crystallized as a pentamer, revealing the intersubunit interactions in a wild type neuronal nAChR ECD and the full ligand binding pocket conferred by two adjacent alpha subunits. The pentameric assembly presents the conserved structural scaffold observed in homologous proteins, as well as distinctive features, providing unique structural information of the binding site between principal and complementary faces. Structure-guided mutagenesis and electrophysiological data confirmed the presence of the alpha2(+)/alpha2(-) binding site on the heteromeric low sensitivity alpha2beta2 nAChR and validated the functional importance of specific residues in alpha2 and beta2 nAChR subunits. Given the pathological importance of the alpha2 nAChR subunit and the high sequence identity with alpha4 (78%) and other neuronal nAChR subunits, our findings offer valuable information for modeling several nAChRs and ultimately for structure-based design of subtype specific drugs against the nAChR associated diseases. PMID- 27493223 TI - Human serine racemase is allosterically modulated by NADH and reduced nicotinamide derivatives. AB - Serine racemase catalyzes both the synthesis and the degradation of d-serine, an obligatory co-agonist of the glutamatergic NMDA receptors. It is allosterically controlled by adenosine triphosphate (ATP), which increases its activity around 7 fold through a co-operative binding mechanism. Serine racemase has been proposed as a drug target for the treatment of several neuropathologies but, so far, the search has been directed only toward the active site, with the identification of a few, low-affinity inhibitors. Following the recent observation that nicotinamide adenine dinucleotide (reduced form) (NADH) inhibits serine racemase, here we show that the inhibition is partial, with an IC50 of 246 +/- 63 MUM, several-fold higher than NADH intracellular concentrations. At saturating concentrations of NADH, ATP binds with a 2-fold lower affinity and without co operativity, suggesting ligand competition. NADH also reduces the weak activity of human serine racemase in the absence of ATP, indicating an additional ATP independent inhibition mechanism. By dissecting the NADH molecule, we discovered that the inhibitory determinant is the N-substituted 1,4-dihydronicotinamide ring. Particularly, the NADH precursor 1,4-dihydronicotinamide mononucleotide exhibited a partial mixed-type inhibition, with a KI of 18 +/- 7 MUM. Docking simulations suggested that all 1,4-dihydronicotinamide derivatives bind at the interdimeric interface, with the ring positioned in an unoccupied site next to the ATP-binding site. This newly recognized allosteric site might be exploited for the design of high-affinity serine racemase effectors to finely modulate d serine homeostasis. PMID- 27493224 TI - Bridging the genotype-phenotype gap in 3D. PMID- 27493222 TI - Kinetic and thermodynamic framework for P4-P6 RNA reveals tertiary motif modularity and modulation of the folding preferred pathway. AB - The past decade has seen a wealth of 3D structural information about complex structured RNAs and identification of functional intermediates. Nevertheless, developing a complete and predictive understanding of the folding and function of these RNAs in biology will require connection of individual rate and equilibrium constants to structural changes that occur in individual folding steps and further relating these steps to the properties and behavior of isolated, simplified systems. To accomplish these goals we used the considerable structural knowledge of the folded, unfolded, and intermediate states of P4-P6 RNA. We enumerated structural states and possible folding transitions and determined rate and equilibrium constants for the transitions between these states using single molecule FRET with a series of mutant P4-P6 variants. Comparisons with simplified constructs containing an isolated tertiary contact suggest that a given tertiary interaction has a stereotyped rate for breaking that may help identify structural transitions within complex RNAs and simplify the prediction of folding kinetics and thermodynamics for structured RNAs from their parts. The preferred folding pathway involves initial formation of the proximal tertiary contact. However, this preference was only ~10 fold and could be reversed by a single point mutation, indicating that a model akin to a protein-folding contact order model will not suffice to describe RNA folding. Instead, our results suggest a strong analogy with a modified RNA diffusion-collision model in which tertiary elements within preformed secondary structures collide, with the success of these collisions dependent on whether the tertiary elements are in their rare binding competent conformations. PMID- 27493225 TI - Untapping root system architecture for crop improvement. PMID- 27493227 TI - Compulsive reading: Stars with addictions, to Star Wars. PMID- 27493228 TI - Psychiatric classification: Merely repetitive and problematic? PMID- 27493229 TI - Movies in Mind: Star Wars The consciousness 'awakens'. PMID- 27493226 TI - Dual transcriptome analysis reveals insights into the response to Rice black streaked dwarf virus in maize. AB - Maize rough dwarf disease (MRDD) is a viral infection that results in heavy yield losses in maize worldwide, particularly in the summer maize-growing regions of China. MRDD is caused by the Rice black-streaked dwarf virus (RBSDV). In the present study, analyses of microRNAs (miRNAs), the degradome, and transcriptome sequences were used to elucidate the RBSDV-responsive pathway(s) in maize. Genomic analysis indicated that the expression of three non-conserved and 28 conserved miRNAs, representing 17 known miRNA families and 14 novel miRNAs, were significantly altered in response to RBSDV when maize was inoculated at the V3 (third leaf) stage. A total of 99 target transcripts from 48 genes of 10 known miRNAs were found to be responsive to RBSDV infection. The annotations of these target genes include a SQUAMOSA promoter binding (SPB) protein, a P450 reductase, an oxidoreductase, and a ubiquitin-related gene, among others. Characterization of the entire transcriptome suggested that a total of 28 and 1085 differentially expressed genes (DEGs) were detected at 1.5 and 3.0 d, respectively, after artificial inoculation with RBSDV. The expression patterns of cell wall- and chloroplast-related genes, and disease resistance- and stress-related genes changed significantly in response to RBSDV infection. The negatively regulated genes GRMZM2G069316 and GRMZM2G031169, which are the target genes for miR169i-p5 and miR8155, were identified as a nucleolin and a NAD(P)-binding Rossmann-fold superfamily protein in maize, respectively. The gene ontology term GO:0003824, including GRMZM2G031169 and other 51 DEGs, was designated as responsive to RBSDV. PMID- 27493230 TI - An erudite encounter with: Jules Angst. PMID- 27493231 TI - Restoration of microRNA-212 causes a G0/G1 cell cycle arrest and apoptosis in adult T-cell leukemia/lymphoma cells by repressing CCND3 expression. AB - Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy. This study was designed to explore the expression and functional significance of microRNA (miR)-212 in ATL. The expression of miR-212 in human ATL tissues and cell lines were investigated. Gain-of-function experiments were carried out to determine the roles of miR-212 in cell proliferation, tumorigenesis, cell cycle progression, and apoptosis. We also identified and functionally characterized the target genes of miR-212 in ATL cells. Compared with normal lymph node biopsies, lymphoma samples from ATL patients displayed underexpression of miR-212 (p=0.0032). Consistently, miR-212 was downregulated in human ATL cell lines, compared with normal T lymphocytes. Restoration of miR-212 significantly (p<0.05) inhibited ATL cell proliferation and tumorigenesis in mice. Overexpression of miR 212 led to an accumulation of G0/G1-phase cells and a concomitant reduction of S phase cells. Moreover, enforced expression of miR-212-induced significant apoptosis in ATL cells. CCND3, which encodes a cell cycle regulator cyclin D3, was identified as a direct target of miR-212 in ATL cells. Rescue experiments with a miR-212-resistant variant of CCND3 demonstrated that overexpression of CCND3 restored cell-cycle progression and attenuated apoptotic response in miR 212-overexpressing ATL cells. Taken together, miR-212 exerts growth-suppressive effects in ATL cells largely by targeting CCND3 and may have therapeutic potential in ATL. PMID- 27493232 TI - Theory of mind predicts severity level in autism. AB - We investigated whether theory of mind skills can indicate autism spectrum disorder severity. In all, 62 children with autism spectrum disorder completed a developmentally sensitive theory of mind battery. We used intelligence quotient, Diagnostic and Statistical Manual of Mental Disorders (4th ed.) diagnosis and level of support needed as indicators of severity level. Using hierarchical cluster analysis, we found three distinct clusters of theory of mind ability: early-developing theory of mind (Cluster 1), false-belief reasoning (Cluster 2) and sophisticated theory of mind understanding (Cluster 3). The clusters corresponded to severe, moderate and mild autism spectrum disorder. As an indicator of level of support needed, cluster grouping predicted the type of school children attended. All Cluster 1 children attended autism-specific schools; Cluster 2 was divided between autism-specific and special needs schools and nearly all Cluster 3 children attended general special needs and mainstream schools. Assessing theory of mind skills can reliably discriminate severity levels within autism spectrum disorder. PMID- 27493233 TI - Experiences of posttraumatic growth in siblings of children with cancer. AB - As survival rates continue to improve for children diagnosed with cancer, strides in achieving better psychosocial outcomes for both children with cancer and their families have been accentuated. The current study aimed to explore the experiences of siblings of children diagnosed with cancer and attempted to overcome some of the limitations described in previous research. Primarily, the study considered the theoretical framework of posttraumatic growth (PTG) in the project design and analysis. Semi-structured interviews were completed with six siblings. Thematic analysis was employed to identify themes within the data set as a whole. The data revealed that siblings experienced a range of difficult emotions throughout the cancer trajectory as well as experiencing remarkable changes in their lives. This included both positive and negative changes. These changes included increased empathy and resilience, improved family relationships, disrupted routine, increased responsibility and perceived changes in the ill child. Siblings described factors which they found helpful and unhelpful in adjusting to these changes. The report ends with a discussion of the themes and their clinical and theoretical implications. The report also highlights the research limitations and areas for future investigation. PMID- 27493234 TI - Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine. AB - Background Application of inflammatory mediators to the cranial dura has been used as a method to activate and sensitize neurons in the meningeal sensory pathway in preclinical behavioral studies of headache mechanisms. However, the relatively high concentrations and volumes used in these studies raise the question of whether the applied agents might pass through the dura to act directly on central neurons, thus bypassing the dural afferent pathway. Methods We used a radiolabeling approach to quantify the meningeal permeability of two of the inflammatory mediators, 5-HT and PGE2, when applied to the cranial dura as part of an inflammatory mixture used in preclinical headache models. Results Both agents could be detected in samples taken four hours after dural application in the cerebrospinal fluid (CSF) and, in measurements made only for PGE2, in the central nervous system (CNS) as well. Based on our measurements, we made estimates of the CSF and CNS levels that would be attained with the higher concentrations and volumes of 5HT and PGE2 that were exogenously applied in previous pre-clinical headache studies. These estimated levels were comparable to or larger than normal endogenous levels, potentially large enough to have physiological effects. Conclusions The finding that the cranial meninges are permeable to the two tested inflammatory mediators PGE2 and 5-HT raises some uncertainty about whether the behavioral changes observed in prior pre-clinical headache studies with these as well as other agents can be attributed entirely to the activation of dural nociceptors, particularly when the agents are applied at concentrations several orders of magnitude above physiological levels. PMID- 27493235 TI - Reply to Chen et al. PMID- 27493236 TI - Heteroresistance of Mycobacterium tuberculosis Strains May Be Associated More Strongly With Poor Treatment Outcomes Than Within-Host Heterogeneity of M. tuberculosis Infection. PMID- 27493237 TI - Antibodies and Acidic Environment Do Not Enhance HIV-1 Transcytosis. AB - A limited number of human immunodeficiency virus type 1 (HIV-1) variants initially infect HIV-1-naive individuals. Recent studies imply that this may occur because generally inefficient transcytosis across intact mucosal surfaces could be enhanced for specific viruses with bound antibodies and in the presence of acidic pH. We found that transcytosis of both cell-free and cell-associated viruses with diverse envelopes was significantly decreased in the presence of either antibodies or plasma from chronically infected transmitting partners regardless of pH. Transmitted variants also did not have greater transmigration as compared to chronic-infection strains. Enhanced translocation capacity is unlikely to influence which HIV-1 variant establishes infection. PMID- 27493238 TI - Preexisting Antibody-Dependent Cellular Cytotoxicity-Activating Antibody Responses Are Stable Longitudinally and Cross-reactive Responses Are Not Boosted by Recent Influenza Exposure. AB - Cross-reactive influenza virus-specific antibody-dependent cellular cytotoxicity (ADCC)-activating antibodies are readily detected in healthy adults. However, little is known about the kinetics of these ADCC responses. We used retrospective serial blood samples from healthy donors to investigate this topic. All donors had ADCC responses against 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09) and avian influenza A(H7N9) virus hemagglutinins (HAs) despite being seronegative for these viruses in standard hemagglutination inhibition and microneutralization serological assays. A(H1N1)pdm09 exposure did not boost ADCC responses specific for H7 HA antigens. H7 HA ADCC responses were variable longitudinally within donors, suggesting that these cross-reactive antibodies are unstable. We found no correlation between ADCC responses to the H7 HA and either influenza virus specific immunoglobulin G1 concentration or age. PMID- 27493240 TI - Rearing Larvae of the Avian Nest Parasite, Philornis downsi (Diptera: Muscidae), on Chicken Blood-Based Diets. AB - Captive rearing of insect pests is necessary to understand their biology and to develop control methods. The avian nest fly, Philornis downsi Dodge and Aitken, is a blood-sucking parasite during its larval stage and a serious threat to endemic birds in the Galapagos Islands where it is considered invasive. In order to procure large numbers of flies for biological studies, rearing media and diets were trialed for rearing the larval stage of P. downsi under controlled conditions in the absence of its avian host. P. downsi eggs were obtained from field-caught female flies, and once eggs hatched they were reared on chicken blood for the first 3 d. Following this, three diets were tested on second- and third-instar larvae: 1) chicken blood only; 2) chicken blood, hydrolyzed protein and dried milk powder; and 3) chicken blood, hydrolyzed protein and brewer's yeast. Out of 385 P. downsi larvae tested, we were able to rear 50 larvae to the adult stage. The highest level of mortality was found in the first-instar larvae. Survivorship of second- and third-instar larvae was similar irrespective of diet and diet did not significantly influence larval or pupal development times; though larvae fed the diet with brewer's yeast developed marginally faster. Pupal weights were similar to those of larvae that had developed on bird hosts in the field. To our knowledge, this is the first effective protocol for rearing a hematophagous parasitic avian fly from egg to adult in the absence of a living host. PMID- 27493239 TI - An Adenovirus Vaccine Expressing Ebola Virus Variant Makona Glycoprotein Is Efficacious in Guinea Pigs and Nonhuman Primates. AB - A licensed vaccine against Ebola virus (EBOV) remains unavailable, despite >11 000 deaths from the 2014-2016 outbreak of EBOV disease in West Africa. Past studies have shown that recombinant vaccine viruses expressing EBOV glycoprotein (GP) are able to protect nonhuman primates (NHPs) from a lethal EBOV challenge. However, these vaccines express the viral GP-based EBOV variants found in Central Africa, which has 97.3% amino acid homology to the Makona variant found in West Africa. Our previous study showed that a recombinant adenovirus serotype 5 (Ad5) vectored vaccine expressing the Makona EBOV GP (MakGP) was safe and immunogenic during clinical trials in China, but it is unknown whether the vaccine protects against EBOV infection. Here, we demonstrate that guinea pigs immunized with Ad5 MakGP developed robust humoral responses and were protected against exposure to guinea pig-adapted EBOV. Ad5-MakGP also elicited specific B- and T-cell immunity in NHPs and conferred 100% protection when animals were challenged 4 weeks after immunization. These results support further clinical development of this candidate and highlight the utility of Ad5-MakGP as a prophylactic measure in future outbreaks of EBOV disease. PMID- 27493241 TI - M2-polarized and tumor-associated macrophages alter NK cell phenotype and function in a contact-dependent manner. AB - The crosstalk between NK cells and M1 macrophages has a vital role in the protection against infections and tumor development. However, macrophages in the tumor resemble an M2 phenotype, and, at present, their effect on NK cells is less clear. This study investigated whether tumor-associated macrophages (TAMs) have a role in altering NK cell function and phenotype using in vitro cocultures of murine NK cells with peritoneal or bone marrow-derived, M2-polarized macrophages or TAMs isolated from spontaneous mouse breast tumors. We report here that both peritoneal and bone marrow-derived M2 macrophages, as well as TAMs, substantially inhibit NK cell activation and concordant cytotoxicity against tumor cells. The mechanism for this inhibition was found to require contact between the respective cell types. Both M2 macrophages and TAMs are producers of the immunosuppressive cytokine TGF-beta. The inhibition of TGF-beta restored the cytotoxicity of NK cells in contact with M2 macrophages, implicating TGF-beta in the mechanism for NK cell inhibition. In addition to affecting NK cell function, TAMs also induced a CD27lowCD11bhigh-exhausted NK cell phenotype, which corresponds with the reduced activation and cytotoxicity observed. This study reveals a novel implication of TAMs in the tumor-associated inhibition of NK cell function by demonstrating their capacity to directly alter NK cell cytotoxicity and phenotype in a contact-dependent mechanism involving TGF-beta. These findings identify the interaction between NK cells and TAMs as a prospective therapeutic target to enhance NK cell effector function for effective NK cell cancer therapies. PMID- 27493242 TI - TLR2-mediated leukocyte trafficking to the developing brain. AB - Inflammation is a significant risk factor for brain injury in the perinatal period. In this study, we tested the hypothesis that activation of peripheral TLR induces inflammation in the brain, including leukocyte trafficking. Postnatal day 8 mice were injected intraperitoneally with a TLR1/2 (Pam3CSK4, P3C), TLR2/6 (FSL 1) or TLR4 (LPS) agonist, and the peripheral and central cytokine and chemokine response was determined. Infiltration of immune cells to the CSF and brain was examined by flow cytometry, and brain permeability was investigated by radioactively labeled sucrose. We report that peripheral administration of P3C to neonatal mice induces significant influx of leukocytes, mainly neutrophils and monocytes, to the CSF and brain. Infiltration of leukocytes was TLR2 and MyD88 dependent, but largely absent after administration of LPS or FSL-1. PC3-mediated accumulation of immune cells in the brain was observed in classic CNS-leukocyte gateways, the subarachnoid space and choroid plexus, as well as in the median eminence. Although P3C and LPS induced a similar degree of peripheral inflammatory responses, P3C provoked a distinct brain chemokine response and increased permeability, in particular, of the blood-CSF barrier. Collectively, our results do not support the hypothesis that TLR activation, in general, induces immune cell infiltration to the brain. Instead, we have discovered a specific TLR2-mediated mechanism of CNS inflammation and leukocyte invasion into the neonatal brain. This interaction between peripheral and central immune responses is to a large extent via the blood-CSF barrier. PMID- 27493244 TI - Murine liver-resident group 1 innate lymphoid cells regulate optimal priming of anti-viral CD8+ T cells. AB - The liver contains 2 transcriptionally distinct group 1 ILC subsets: CD49a+ ILC1s and CD49b+ NK cells. However, little is known about how group 1 ILCs contribute to hepatic immune responses. Therefore, we characterized murine liver-resident group 1 ILCs and found that CD49a+ ILC1s express high levels of the inhibitory receptor NKG2A and localize near DCs in perivascular spaces surrounding the portal triads. Upon hepatic viral infection, NKG2A signaling in group 1 ILCs, especially in CD49a+ ILC1s, inhibits CXCL9 expression required for robust accumulation of IFN-gamma+CD49b+ NK cells. As a consequence, NKG2A-/- mice showed increased numbers of IFN-gamma-producing NK cells that preferentially activate liver CD103+ DCs, leading to the sustained proliferation of adoptively transferred, virus-specific CD8+ T cells. Collectively, these data suggest that group 1 ILCs play a role in maintaining the liver as a tolerogenic site by limiting the recruitment of peripheral NK cells during the early phase of viral infection. Furthermore, our findings implicate that the inhibition of NKG2A signaling on group 1 ILCs may be a novel vaccine strategy to induce robust CD8+ T cell responses against persistent liver pathogens. PMID- 27493246 TI - Interleukin-6 gene knockout antagonizes high-fat-induced trabecular bone loss. AB - The purpose of the study was to determine the roles of interleukin-6 (IL6) in fat and bone communication. Male wild-type (WT) mice and IL6 knockout (IL6(-/-)) mice were fed with either regular diet (RD) or high-fat diet (HFD) for 12 weeks. Bone mass and bone microstructure were evaluated by micro-computed tomography. Gene expression related to lipid and bone metabolisms was assayed with real-time quantitative polymerase chain reaction. Bone marrow cells from both genotypes were induced to differentiate into osteoblasts or osteoclasts, and treated with palmitic acid (PA). HFD increased the body weight and fat pad weight, and impaired lipid metabolism in both WT and IL6(-/-) mice. The dysregulation of lipid metabolism was more serious in IL6(-/-) mice. Trabecular bone volume fraction, trabecular bone number and trabecular bone thickness were significantly downregulated in WT mice after HFD than those in the RD (P < 0.05). However, these bone microstructural parameters were increased by 53%, 34% and 40%, respectively, in IL6(-/-) mice than those in WT mice on the HFD (P < 0.05). IL6( /-) osteoblasts displayed higher alkaline phosphatase (ALP) activity and higher mRNA levels of Runx2 and Colla1 than those in WT osteoblasts both in the control and PA treatment group (P < 0.05). IL6(-/-) mice showed significantly lower mRNA levels of PPARgamma and leptin and higher mRNA levels of adiponectin in comparison with WT mice on HFD. In conclusion, these findings suggested that IL6 gene deficiency antagonized HFD-induced bone loss. IL6 might bridge lipid and bone metabolisms and could be a new potential therapeutic target for lipid metabolism disturbance-related bone loss. PMID- 27493245 TI - beta-Arrestin 1-dependent regulation of Rap2 is required for fMLP-stimulated chemotaxis in neutrophil-like HL-60 cells. AB - beta-Arrestins have emerged as key regulators of cytoskeletal rearrangement that are required for directed cell migration. Whereas it is known that beta-arrestins are required for formyl-Met-Leu-Phe receptor (FPR) recycling, less is known about their role in regulating FPR-mediated neutrophil chemotaxis. Here, we show that beta-arrestin 1 (ArrB1) coaccumulated with F-actin within the leading edge of neutrophil-like HL-60 cells during chemotaxis, and its knockdown resulted in markedly reduced migration within fMLP gradients. The small GTPase Ras-related protein 2 (Rap2) was found to bind ArrB1 under resting conditions but dissociated upon fMLP stimulation. The FPR-dependent activation of Rap2 required ArrB1 but was independent of Galphai activity. Significantly, depletion of either ArrB1 or Rap2 resulted in reduced chemotaxis and defects in cellular repolarization within fMLP gradients. These data strongly suggest a model in which FPR is able to direct ArrB1 and other bound proteins that are required for lamellipodial extension to the leading edge in migrating neutrophils, thereby orientating and directing cell migration. PMID- 27493247 TI - AMPK-dependent regulation of GLP1 expression in L-like cells. AB - This study examined whether AMPK, an evolutionarily conserved sensor of cellular energy status, determines the production of glucagon-like peptide-1 (GLP1). A negative relation existed between phosphorylation of AMPKalpha and the expression and secretion of GLP1 during changes in energy status in STC-1 cells, an L-like cell line. High concentration of glucose (25 mmol/L) decreased AMPKalpha phosphorylation, whereas it stimulated the expression and secretion of GLP1 relative to 5.6 mmol/L glucose. Serum starvation upregulated AMPKalpha phosphorylation, whereas it reduced GLP1 production significantly. Stimulation of AMPK phosphorylation by AICAR and overexpression of wild-type AMPKalpha1, constitutively active AMPKalpha1 plasmids, or AMPKalpha1 lentivirus particles suppressed proglucagon mRNA and protein contents in STC-1 cells. Inactivation of AMPK by Compound C, AMPKalpha1 siRNA or kinase-inactive AMPKalpha1 mutant increased the expression and secretion of GLP1. Our results suggest that AMPKalpha1 may link energy supply with the production of GLP1 in L-like cells. PMID- 27493243 TI - Autophagy in leukocytes and other cells: mechanisms, subsystem organization, selectivity, and links to innate immunity. AB - Autophagy is a fundamental biologic process that fulfills general and specialized roles in cytoplasmic homeostasis. The cell-autonomous antimicrobial functions of autophagy have been established in the macrophage. These cells and other leukocytes continue to be the cells of choice in studying autophagy in immunity and inflammation. This review uses several model examples that will be of interest to leukocyte and cell biologists alike. Furthermore, it comprehensively covers the subsystems in autophagy as they apply to all mammalian cells and incorporates the recent progress in our understanding of how these modules come together-a topic that should be of interest to all readers. PMID- 27493248 TI - Vector Competence of Anopheles kleini and Anopheles sinensis (Diptera: Culicidae) From the Republic of Korea to Vivax Malaria-Infected Blood From Patients From Thailand. AB - In total, 1,300 each of Anopheles kleini Rueda and Anopheles sinensis Wiedemann sensu stricto (s.s.) females (colonized from the Republic of Korea) and Anopheles dirus Peyton & Harrison (Thai strain) were allowed to feed on blood from Thai malaria patients naturally infected with Plasmodium vivax The overall oocyst infection rates for An. dirus, An. kleini, and An. sinensis s.s. were 77.4, 46.1, and 45.9%, respectively. The mean number of oocysts was significantly higher for An. dirus (82.7) compared with An. kleini (6.1) and An. sinensis s.s. (8.6), whereas the mean number of oocysts for An. kleini and An. sinensis s.s. was similar. The overall sporozoite infection rates for An. dirus, An. kleini, and An. sinensis s.s. dissected on days 14-15, 21, and 28 days post-feed were significantly higher for An. dirus (90.0%) than An. kleini (5.4%), whereas An. kleini sporozoite rates were significantly higher than An. sinensis s.s. (<0.1%). The overall sporozoite indices for positive females with +3 (100-1,000 sporozoites) and +4 (>1,000 sporozoites) salivary gland indices were significantly higher for An. dirus (85.7%), compared with An. kleini (47.1%). Only one An. sinensis s.s. had sporozoites (+2; >10-100 sporozoites). These results indicate that An. kleini is a competent vector of vivax malaria. Although An. sinensis s.s. develops relatively high numbers of oocysts, it is considered a very poor vector of vivax malaria due to a salivary gland barrier. PMID- 27493250 TI - Protein Self-Marking by Ectoparasites: A Case Study Using Bed Bugs (Hemiptera: Cimicidae). AB - The ability to mark individuals is a critical feature of many entomological investigations, including dispersal studies. Insect dispersal is generally investigated using mark-release-recapture techniques, whereby marked individuals are released at a known location and then captured at a measured distance. Ectoparasite dispersal has historically been challenging to study, in part because of the ethical concerns associated with releasing marked individuals. Here, we introduce the protein self-marking technique, whereby ectoparasites mark themselves in the field by feeding on the blood of an introduced host. We demonstrate the potential of this technique using laboratory-reared bed bugs (Cimex lectularius L.) that marked themselves by feeding on either rabbit or chicken blood. We then used enzyme-linked immunosorbent assays to detect host specific blood serum proteins in bed bugs. We assessed these protein markers' ability to 1) distinctively identify marked individuals, 2) persist following multiple feedings on an alternate diet, 3) persist over time across a range of temperatures, and 4) transfer from marked to unmarked individuals. Protein markers were detectable in bed bugs before and after molting, remained detectible after multiple feedings on an alternate diet, persisted regardless of whether an individual was starved or fed on an alternate diet following original mark acquisition, and did not transfer between individuals. The duration of detectability depended on temperature. Our results suggest that protein self marking is an effective technique for marking bed bugs and holds promise for use in dispersal studies of ectoparasitic insects. PMID- 27493249 TI - Mosquito Capture Rate Using CO2-Baited Traps in Relation to Distance From Water and Height: Implications for Avian Disease Transmission. AB - Accumulating evidence suggests that enzootic transmission of pathogens such as West Nile virus (WNV) by mosquitoes is governed by host-bird interactions, including mosquito preferences for specific species and developmental stages of host birds, host bird availability, and host defensive behavior. Here, we examined how the attack rate of five mosquito species in southern California was influenced by the position of CO2-baited traps in relation to distance from water and trap height. We identified 44,207 female mosquitoes representing five species: Aedes vexans Meigen, Anopheles franciscanus McCracken, Anopheles hermsi Barr & Guptavanij, and the two most abundant species which are also WNV vectors, Culex erythrothorax Dyar and Culex tarsalis Coquillett. Mosquito captures decreased markedly with trap height, and also decreased with distance from a riparian area but not with distance from an open water source lacking a vegetated border. The results of this study suggest that WNV-competent ornithophilic mosquitoes may amplify the virus especially in reservoir birds that roost or nest close to the ground and near riparian vegetation. PMID- 27493251 TI - Bionomics and Vector Potential of Culex thriambus (Diptera: Culicidae) Mosquitoes in Lake County, California. AB - California statewide West Nile virus (WNV) minimum infection rates in Culex thriambus Dyar mosquitoes are high; however, few specimens are submitted and tested each year, as their distribution seems limited to larval habitats along riparian systems. To evaluate the role of Cx. thriambus in the amplification, maintenance, and overwintering of WNV in Lake County, CA, the bionomics and vector potential of the species was investigated during 2014 and 2015. Culex thriambus was the most abundant mosquito species, with 1,153 adults and 7,624 immatures collected by vacuum aspiration and dip sampling, respectively, at the primary study site. Detection of WNV in four mosquito pools during September through November coincided with peak seasonality. Females entered and maintained a reproductive diapause during winter under field and seminatural conditions. Diapause was initiated in the majority of Cx. thriambus females by October and was terminated by 30 March. Some parous females (7.1%) and those in host-seeking arrest (7.1%) were collected throughout the winter period. An accrual of 679.51 degree-days ( degrees D) was necessary for diapause termination under seminatural conditions. Culex thriambus females fed on 16 different avian species during spring and summer, and no mammalian feeds were detected. West Nile viral RNA was detected in four of 42 Cx. thriambus pools tested during June through November and infection rates ranged from 3.53-28.15/1,000 tested. In summary, WNV transmission may be increased along riparian corridors throughout California where Cx. thriambus mosquitoes remain relatively abundant. PMID- 27493252 TI - Knockdown Resistance Mutations in Aedes aegypti (Diptera: Culicidae) From Puerto Rico. AB - Permethrin resistance is widespread in Aedes aegypti (L.), the main dengue, zika, and chikungunya virus vector in Latin America and the Caribbean. A common mechanism of resistance to pyrethroids-knockdown resistance (kdr)-is conferred through mutations in the insect's voltage-dependent sodium channel. In this mosquito, around 10 replacement substitutions in the voltage-gated sodium channel gene (vgsc) have been reported in pyrethroid-resistant strains. Two of these mutations, named Ile1,016 and Cys1,534, are widespread in mosquito populations from Latin America and the Caribbean. This study assessed the levels of permethrin resistance and the frequency of two kdr mutations in eight Ae. aegypti populations collected in Puerto Rico in 2013. Permethrin resistance factors ranged from 33-214-fold relative to the New Orleans reference strain. The frequency of kdr mutation Ile1,016 ranged from 0.65 to fixation (1.0), and for Cys1,534 frequencies varied from 0.8 to fixation. Alarmingly, two populations Carolina and Caguas-reached fixation at both loci. Our results suggest that permethrin effectiveness for Ae. aegypti control is compromised in these collections from Puerto Rico. PMID- 27493253 TI - Coexistence of Aedes aegypti and Aedes albopictus (Diptera: Culicidae) in Peninsular Florida Two Decades After Competitive Displacements. AB - The spread of Aedes albopictus (Skuse) eastward in the mid-1980s from its initial establishment in Houston, TX, was associated with rapid declines and local disappearances of Aedes aegypti (L.) in Gulf Coast states and Florida where annual larval surveillance during the early 1990s described temporal and spatial patterns of competitive displacements in cemeteries and tire shops. Approximately 20 yr later in 2013-2014, we re-visited former collection sites and sampled aquatic immatures of these two species from tire shops in 10 cities on State Route 441 and from 9 cemeteries from Lakeland to Miami in southwest Florida. In the recent samples Ae. aegypti was recovered from three central Florida cities where it had not been detected in 1994, but its northern limit on Rte. 441, Apopka, did not change. Other evidence, such as trends at a few cemeteries, suggested a moderate resurgence of this species since 1994. Cage experiments that exposed female progeny of Ae. aegypti from recent Florida collection sites to interspecific mating by Ae. albopictus males showed that females from coexistence sites had evolved resistance to cross-mating, but Ae. aegypti from sites with no Ae. albopictus were relatively susceptible to satyrization. Habitat classifications of collection sites were reduced by principal component (PC) analysis to four variables that accounted for > 99% of variances; PCs with strong positive loadings for tree cover and ground vegetation were associated with collection sites yielding only Ae. albopictus Within the coexistence range of the two species, the numbers of Ae. aegypti among total Aedes collected were strongly correlated in stepwise logistic regression models with two habitat-derived PCs, distance from the coast, and annual rainfall and mean maximum temperatures at the nearest weather station. Subtle increases in the range of Ae. aegypti since its previous displacements are interpreted in the context of the evolution of resistance to mating interference, realized versus fundamental niches of the two species, and persisting competition with Ae. albopictus. PMID- 27493254 TI - Predicting the Functionality and Form of a Dialysis Fistula. PMID- 27493255 TI - Value of Donor-Specific Anti-HLA Antibody Monitoring and Characterization for Risk Stratification of Kidney Allograft Loss. AB - The diagnosis system for allograft loss lacks accurate individual risk stratification on the basis of donor-specific anti-HLA antibody (anti-HLA DSA) characterization. We investigated whether systematic monitoring of DSA with extensive characterization increases performance in predicting kidney allograft loss. This prospective study included 851 kidney recipients transplanted between 2008 and 2010 who were systematically screened for DSA at transplant, 1 and 2 years post-transplant, and the time of post-transplant clinical events. We assessed DSA characteristics and performed systematic allograft biopsies at the time of post-transplant serum evaluation. At transplant, 110 (12.9%) patients had DSAs; post-transplant screening identified 186 (21.9%) DSA-positive patients. Post-transplant DSA monitoring improved the prediction of allograft loss when added to a model that included traditional determinants of allograft loss (increase in c statistic from 0.67; 95% confidence interval [95% CI], 0.62 to 0.73 to 0.72; 95% CI, 0.67 to 0.77). Addition of DSA IgG3 positivity or C1q binding capacity increased discrimination performance of the traditional model at transplant and post-transplant. Compared with DSA mean fluorescence intensity, DSA IgG3 positivity and C1q binding capacity adequately reclassified patients at lower or higher risk for allograft loss at transplant (category-free net reclassification index, 1.30; 95% CI, 0.94 to 1.67; P<0.001 and 0.93; 95% CI, 0.49 to 1.36; P<0.001, respectively) and post-transplant (category-free net reclassification index, 1.33; 95% CI, 1.03 to 1.62; P<0.001 and 0.95; 95% CI, 0.62 to 1.28; P<0.001, respectively). Thus, pre- and post-transplant DSA monitoring and characterization may improve individual risk stratification for kidney allograft loss. PMID- 27493256 TI - Preserving Residual Kidney Function in Hemodialysis Patients-Back in the Spotlight. PMID- 27493257 TI - Heme Oxygenase-1 Gene Polymorphisms-Toward Precision Medicine for AKI. PMID- 27493258 TI - Coronary Revascularization in Patients with CKD Stage 5D: Pragmatic Considerations. AB - Coronary revascularization decisions for patients with CKD stage 5D present a dilemma for clinicians because of high baseline risks of mortality and future cardiovascular events. This population differs from the general population regarding characteristics of coronary plaque composition and behavior, accuracy of noninvasive testing, and response to surgical and percutaneous revascularization, such that findings from the general population cannot be automatically extrapolated. However, this high-risk population has been excluded from all randomized trials evaluating outcomes of revascularization. Observational studies have attempted to address long-term outcomes after surgical versus percutaneous revascularization strategies, but inherent selection bias may limit accuracy. Compared with percutaneous strategies, surgical revascularization seems to have long-term survival benefit on the basis of observational data but associates with substantially higher short-term mortality rates. Percutaneous revascularization with drug-eluting and bare metal stents associates with a high risk of in-stent restenosis and need for future revascularization, perhaps contributing to the higher long-term mortality hazard. Off-pump coronary bypass surgery and the newest generation of drug-eluting stent platforms offer no definitive benefits. In this review, we address the nuances, complexities, and tradeoffs that clinicians face in determining the optimal method of coronary revascularization for this high-risk population. PMID- 27493260 TI - 18F-FDG PET/CT Imaging of Primary Gastric Lymphoma. AB - Primary gastric lymphoma (PGL) accounts for less than 4% of gastric neoplasms. 18F-FDG PET with simultaneously acquired CT (18F-FDG PET/CT) allows for staging and differentiation from other gastric cancers. Rapid diagnosis and staging are important because chemotherapeutic response is generally favorable. We describe a case of an 83-y-old woman with stage II1 PGL. 18F-FDG PET/CT can be helpful to differentiate various gastric masses and is an important factor in the staging of PGL. PMID- 27493259 TI - Variable Cyst Development in Autosomal Dominant Polycystic Kidney Disease: The Biologic Context. AB - Patients with autosomal dominant polycystic kidney disease (ADPKD) typically carry a mutation in either the PKD1 or PKD2 gene, which leads to massive cyst formation in both kidneys. However, the large intrafamilial variation in the progression rate of ADPKD suggests involvement of additional factors other than the type of mutation. The identification of these factors will increase our understanding of ADPKD and could ultimately help in the development of a clinically relevant therapy. Our review addresses the mechanisms by which various biologic processes influence cyst formation and cyst growth, thereby explaining an important part of the inter- and intrafamilial variability in ADPKD. Numerous studies from many laboratories provide compelling evidence for the influence on cyst formation by spatiotemporal gene inactivation, the genetic context, the metabolic status, the presence of existing cysts, and whether the kidneys were challenged by renal injury. Collectively, a solid basis is provided for the concept that the probability of cyst formation is determined by functional PKD protein levels and the biologic context. We model these findings in a graphic representation called the cystic probability landscape, providing a robust conceptual understanding of why cells sometimes do or do not form cysts. PMID- 27493261 TI - Scintigraphic Diagnosis of Intrathoracic Splenic Implants Masquerading as Malignancy. AB - After significant trauma to the spleen, small viable splenic fragments may exist in the peritoneal cavity or, less commonly, in the thorax. Thus, the appearance of splenules within the thorax on CT images can easily be mistaken for malignancy and lead to unnecessary intervention. Here, we present a case of multiple pulmonary masses that initially were presumed to be malignancy, leading to CT guided biopsy, but were eventually confirmed to be thoracic splenules through 99mTc-labeled sulfur colloid scintigraphy. PMID- 27493262 TI - Grouping of Metastatic Thyroid Carcinoma by Molecular Imaging Features to Allow for Individualized Treatment, with Emphasis on the TENIS Syndrome. AB - The process of radioiodine ((131)I) refractoriness, dedifferentiation, and development of thyroglobulin elevation and negative iodine scintigraphy (TENIS) syndrome in metastatic differentiated thyroid carcinoma (DTC) could be viewed as a disease continuum rather than a single event or an all-or-none phenomenon. In this report, the important role of molecular functional imaging in systematically exploring the disease biology and course of metastatic DTC is presented. Making this role the base, this report proposes a novel clinical classification for TENIS syndrome using molecular functional imaging. Such an endeavor, in our view, would aid in classification into subgroups and development of an individualized treatment strategy for patients with metastatic DTC. Case illustrations are presented that substantiate this viewpoint, including the value of combined assessment in selected cases and the requirement of a multipronged treatment approach for certain case scenarios. In addition to multiple other considerations, we believe that molecular functional imaging-based characterization of metastatic lesions could evolve as an important determinant for defining the optimal treatment strategy in patients with metastatic DTC, making the clinical management more rational and scientific. PMID- 27493263 TI - Increased Gastric Activity on Myocardial Perfusion Imaging. AB - We anecdotally observed an increased accumulation of (99m)Tc-tetrofosmin in the stomach of myocardial perfusion patients when their uptake phase coincided with preparation of hamburgers in an adjacent room for gastric emptying studies on other patients. The potential for a scent-stimulated alteration of gastric biodistribution required further investigation. METHODS: An experimental group and a control group were enrolled (20 patients per group). The experimental group could smell food being prepared during the uptake phase. Stomach, heart, and background regions were drawn in multiple projections, and the resulting data were evaluated. RESULTS: The experimental and control groups did not significantly differ in stomach counts per pixel, background-corrected counts per pixel, or heart-to-stomach ratio. Further analysis of the data revealed that women had a significantly higher increase in stomach counts (P = 0.022) and background-corrected stomach counts (P = 0.018) than men. CONCLUSION: Women had a greater increase in gastric (99m)Tc-tetrofosmin activity than men during the radiopharmaceutical uptake phase, but there was no causal relationship between an increase in activity and olfactory stimulation from the cooking of food. PMID- 27493264 TI - Subjecting Radiologic Imaging to the Linear No-Threshold Hypothesis: A Non Sequitur of Non-Trivial Proportion. AB - Radiologic imaging is claimed to carry an iatrogenic risk of cancer, based on an uninformed commitment to the 70-y-old linear no-threshold hypothesis (LNTH). Credible evidence of imaging-related low-dose (<100 mGy) carcinogenic risk is nonexistent; it is a hypothetical risk derived from the demonstrably false LNTH. On the contrary, low-dose radiation does not cause, but more likely helps prevent, cancer. The LNTH and its offspring, ALARA (as low as reasonably achievable), are fatally flawed, focusing only on molecular damage while ignoring protective, organismal biologic responses. Although some grant the absence of low dose harm, they nevertheless advocate the "prudence" of dose optimization (i.e., using ALARA doses); but this is a radiophobia-centered, not scientific, approach. Medical imaging studies achieve a diagnostic purpose and should be governed by the highest science-based principles and policies. The LNTH is an invalidated hypothesis, and its use, in the form of ALARA dosing, is responsible for misguided concerns promoting radiophobia, leading to actual risks far greater than the hypothetical carcinogenic risk purportedly avoided. Further, the myriad benefits of imaging are ignored. The present work calls for ending the radiophobia caused by those asserting the need for dose optimization in imaging: the low-dose radiation of medical imaging has no documented pathway to harm, whereas the LNTH and ALARA most assuredly do. PMID- 27493265 TI - Reply: 68Ga-DOTATATE PET/CT Versus MRI: Why the Comparison of 68Ga-DOTATATE PET/CT to an Appropriate MRI Protocol Is Essential. PMID- 27493266 TI - Liposomal Treatment of Experimental Arthritis Can Be Monitored Noninvasively with a Radiolabeled Anti-Fibroblast Activation Protein Antibody. AB - : Rheumatoid arthritis is a chronic autoimmune disorder resulting in synovial inflammation. Fibroblast activation protein (FAP) is overexpressed by fibroblastlike synoviocytes in arthritic joints. Radioimmunoimaging with an anti FAP antibody might be used to monitor the response to therapy, thus enabling tailored therapy strategies and therapeutic outcomes. The aim of this study was to assess whether a radiolabeled anti-FAP antibody could be used to monitor the efficacy of treatment with long-circulating liposomes (LCL) containing prednisolone phosphate (PLP-LCL) in a mouse model of arthritis. METHODS: Collagen induced arthritis (CIA) was induced in male DBA/1J mice. Mice were treated with a single injection (10 mg/kg) of PLP-LCL or empty LCL as a control. SPECT and CT images were acquired 24 h after injection of 99mTc-labeled succinimidyl hydrazinonicotinamide (99mTc-S-HYNIC)-conjugated anti-FAP antibody 28H1 at 2, 5, and 9 d after treatment. The uptake of 99mTc-S-HYNIC-28H1 in all joints was quantified and correlated with macroscopic arthritis scores. RESULTS: Treatment of CIA with PLP-LCL significantly suppressed joint swelling. At just 1 d after treatment, the macroscopic arthritis scores had decreased by 50%. Scores decreased further, to only 10% of the initial scores, at 5 and 9 d after treatment. In contrast, macroscopic arthritis scores had increased up to 600% in untreated mice at 9 d after the injection of empty LCL. 99mTc-S-HYNIC-28H1 uptake ranged from 1.5 percentage injected dose per gram in noninflamed joints to 22.6 percentage injected dose per gram in severely inflamed joints. The uptake of radiolabeled 28H1 in inflamed joints (percentage injected dose) correlated with the arthritis score (Spearman rho, 0.77; P < 0.0001). Moreover, the uptake of 99mTc-S-HYNIC-28H1 was slightly increased at 9 d after therapy but was not seen macroscopically, indicating that SPECT/CT imaging might be more sensitive than the macroscopic arthritis scoring method. CONCLUSION: SPECT/CT imaging with 99mTc S-HYNIC-28H1 specifically monitored the response to therapy, and tracer accumulation correlated with the severity of inflammation. In addition, SPECT/CT imaging was potentially more sensitive than the macroscopic arthritis scoring method. This study showed that SPECT/CT with 99mTc-S-HYNIC-28H1 could be used to noninvasively monitor the course of CIA in mice. PMID- 27493267 TI - Clinical Translation of a Dual Integrin alphavbeta3- and Gastrin-Releasing Peptide Receptor-Targeting PET Radiotracer, 68Ga-BBN-RGD. AB - : This study aimed to document the first-in-human application of a 68Ga-labeled heterodimeric peptide BBN-RGD (bombesin-RGD) that targets both integrin alphavbeta3 and gastrin-releasing peptide receptor (GRPR). We evaluated the safety and assessed the clinical diagnostic value of 68Ga-BBN-RGD PET/CT in prostate cancer patients in comparison with 68Ga-BBN. METHODS: Five healthy volunteers (4 men and 1 woman; age range, 28-53 y) were enrolled to validate the safety of 68Ga-BBN-RGD. Dosimetry was calculated using the OLINDA/EXM software. Thirteen patients with prostate cancer (4 newly diagnosed and 9 posttherapy) were enrolled. All the patients underwent PET/CT scans 15-30 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram of body weight of 68Ga-BBN-RGD and also accepted 68Ga-BBN PET/CT within 2 wk for comparison. RESULTS: With a mean injected dose of 107.3 +/- 14.8 MBq per patient, no side effect was found during the whole procedure and 2 wk follow-up, demonstrating the safety of 68Ga-BBN-RGD. A patient would be exposed to a radiation dose of 2.90 mSv with an injected dose of 129.5 MBq (3.5 mCi), which is much lower than the dose limit set by the Food and Drug Administration. In 13 patients with prostate cancer diagnosed by biopsy, 68Ga-BBN-RGD PET/CT detected 3 of 4 primary tumors, 14 metastatic lymph nodes, and 20 bone lesions with an SUVmax of 4.46 +/- 0.50, 6.26 +/- 2.95, and 4.84 +/- 1.57, respectively. Only 2 of 4 primary tumors, 5 lymph nodes, and 12 bone lesions were positive on 68Ga-BBN PET/CT, with the SUVmax of 2.98 +/- 1.24, 4.17 +/- 1.89, and 3.61 +/- 1.85, respectively. CONCLUSION: This study indicates the safety and efficiency of a new type of dual integrin alphavbeta3- and GRPR targeting PET radiotracer in prostate cancer diagnosis and staging. PMID- 27493268 TI - In Vivo Imaging of Antileukemic Drug Asparaginase Reveals a Rapid Macrophage Mediated Clearance from the Bone Marrow. AB - : The antileukemic drug asparaginase, a key component in the treatment of acute lymphoblastic leukemia, acts by depleting asparagine from the blood. However, little is known about its pharmacokinetics, and mechanisms of therapy resistance are poorly understood. Here, we explored the in vivo biodistribution of radiolabeled asparaginase, using a combination of imaging and biochemical techniques, and provide evidence for tissue-specific clearance mechanisms, which could reduce the effectiveness of the drug at these specific sites. METHODS: In vivo localization of 111In-labeled Escherichia coli asparaginase was performed in C57BL/6 mice by both small-animal SPECT/CT and ex vivo biodistribution studies. Mice were treated with liposomal clodronate to investigate the effect of macrophage depletion on tracer localization and drug clearance in vivo. Moreover, macrophage cell line models RAW264.7 and THP-1, as well as knockout mice, were used to identify the cellular and molecular components controlling asparaginase pharmacokinetics. RESULTS: In vivo imaging and biodistribution studies showed a rapid accumulation of asparaginase in macrophage-rich tissues such as the liver, spleen, and in particular bone marrow. Clodronate-mediated depletion of phagocytic cells markedly prolonged the serum half-life of asparaginase in vivo and decreased drug uptake in these macrophage-rich organs. Immunohistochemistry and in vitro binding assays confirmed the involvement of macrophagelike cells in the uptake of asparaginase. We identified the activity of the lysosomal protease cathepsin B in macrophages as a rate-limiting factor in degrading asparaginase both in vitro and in vivo. CONCLUSION: We showed that asparaginase is rapidly cleared from the serum by liver-, spleen-, and bone marrow-resident phagocytic cells. As a consequence of this efficient uptake and protease-mediated degradation, particularly bone marrow-resident macrophages may provide a protective niche to leukemic cells. PMID- 27493269 TI - Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood-Brain Barrier: A PET Study on Nonhuman Primates. AB - : The tyrosine kinase inhibitor erlotinib poorly penetrates the blood-brain barrier (BBB) because of efflux transport by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), thereby limiting its utility in the treatment of non-small cell lung cancer metastases in the brain. Pharmacologic strategies to inhibit ABCB1/ABCG2-mediated efflux transport at the BBB have been successfully developed in rodents, but it remains unclear whether these can be translated to humans given the pronounced species differences in ABCG2/ABCB1 expression ratios at the BBB. We assessed the efficacy of two different ABCB1/ABCG2 inhibitors to enhance brain distribution of 11C-erlotinib in nonhuman primates as a model of the human BBB. METHODS: Papio anubis baboons underwent PET scans of the brain after intravenous injection of 11C-erlotinib under baseline conditions (n = 4) and during intravenous infusion of high-dose erlotinib (10 mg/kg/h, n = 4) or elacridar (12 mg/kg/h, n = 3). RESULTS: Under baseline conditions, 11C-erlotinib distribution to the brain (total volume of distribution [VT], 0.22 +/- 0.015 mL/cm3) was markedly lower than its distribution to muscle tissue surrounding the skull (VT, 0.86 +/- 0.10 mL/cm3). Elacridar infusion resulted in a 3.5 +/- 0.9-fold increase in 11C-erlotinib distribution to the brain (VT, 0.81 +/- 0.21 mL/cm3, P < 0.01), reaching levels comparable to those in muscle tissue, without changing 11C-erlotinib plasma pharmacokinetics. During high-dose erlotinib infusion, 11C-erlotinib brain distribution was also significantly (1.7 +/- 0.2-fold) increased (VT, 0.38 +/- 0.033 mL/cm3, P < 0.05), with a concomitant increase in 11C-erlotinib plasma exposure. CONCLUSION: We successfully implemented ABCB1/ABCG2 inhibition protocols in nonhuman primates resulting in pronounced increases in brain distribution of 11C-erlotinib. For patients with brain tumors, such inhibition protocols may ultimately be applied to create more effective treatments using drugs that undergo efflux transport at the BBB. PMID- 27493271 TI - TERT Promoter Mutation Predicts Radioiodine-Refractory Character in Distant Metastatic Differentiated Thyroid Cancer. AB - : Telomerase reverse transcriptase (TERT) promoter mutation has been reported to be associated with aggressive characteristics in differentiated thyroid cancer (DTC). This study examined the status of TERT mutation in distant metastatic DTC and evaluated the correlation between TERT mutation and radioiodine uptake, as well as that between TERT mutation and therapy response. METHODS: TERT promoter and B-Raf proto-oncogene (BRAF) V600E mutation were retrospectively examined in primary tumors of 66 patients with distant metastatic DTC. Stimulated thyroglobulin (sTg) changes, radioiodine uptake status (avid or nonavid), and other imaging evidence were analyzed to evaluate therapy response. After a median follow-up of 46.5 mo (interquartile range, 29.0-70.5 mo), therapy response was classified as either disease control or refractory. RESULTS: The prevalence of TERT mutations was 22.73% (15/66), of which C228T mutation was more prevalent (13/15) than C250T mutation (2/15). Rising sTg was noticed in 93.33% (14/15) of the TERT mutation group. Of cases negative for both mutations, 78.12% (25/32) presented with decreased sTg. TERT mutation closely correlated with a poor response to radioiodine therapy (P < 0.001), and all 15 patients were classified as refractory to radioiodine therapy, with a positive predictive value of 100% at the endpoint of follow-up. TERT mutation was associated with older mean age at diagnosis (P < 0.001), larger mean tumor diameter (P = 0.013), and greater likelihood of both BRAF mutation coexistence (P = 0.044) and radioiodine refractory character (P < 0.001). In the 36 cases whose imaging results underwent semiquantitative analysis, TERT mutation significantly correlated with non radioiodine avidity, with a much lower mean tumor-to-background ratio (obtained from postradioiodine whole-body scanning) than in TERT wild-type cases (P < 0.001). In addition, patients with distant metastatic DTC with TERT mutation were more likely to lose radioiodine avidity at the initial radioiodine therapy than were those with only BRAF mutation (8/8 vs. 5/11; Fisher exact test, P = 0.018). CONCLUSION: TERT mutation closely associates with non-radioiodine avidity in distant metastatic DTC, and when compared with BRAF mutation, TERT mutation manifested a greater negative influence on radioiodine uptake. TERT mutation could also be used as an early predictor of radioiodine-refractory cases. PMID- 27493270 TI - Tumor-Absorbed Dose for Non-Hodgkin Lymphoma Patients Treated with the Anti-CD37 Antibody Radionuclide Conjugate 177Lu-Lilotomab Satetraxetan. AB - : 177Lu-lilotomab satetraxetan is a novel antibody radionuclide conjugate currently tested in a phase 1/2a first-in-human dosage escalation trial for patients with relapsed CD37+ indolent non-Hodgkin lymphoma. The aim of this work was to develop dosimetric methods and calculate tumor-absorbed radiation doses for patients treated with 177Lu-lilotomab satetraxetan. METHODS: Patients were treated at escalating injected activities (10, 15 and 20 MBq/kg) of 177Lu lilotomab satetraxetan and with different predosing, with or without 40 mg of unlabeled lilotomab. Eight patients were included for the tumor dosimetry study. Tumor radioactivity concentrations were calculated from SPECT acquisitions at multiple time points, and tumor masses were delineated from corresponding CT scans. Tumor-absorbed doses were then calculated using the OLINDA sphere model. To perform voxel dosimetry, the SPECT/CT data and an in-house-developed MATLAB program were combined to investigate the dose rate homogeneity. RESULTS: Twenty six tumors in 8 patients were ascribed a mean tumor-absorbed dose. Absorbed doses ranged from 75 to 794 cGy, with a median of 264 cGy across different dosage levels and different predosing. A significant correlation between the dosage level and tumor-absorbed dose was found. Twenty-one tumors were included for voxel dosimetry and parameters describing dose-volume coverage calculated. The investigation of intratumor voxel doses indicates that mean tumor dose is correlated to these parameters. CONCLUSION: Tumor-absorbed doses for patients treated with 177Lu-lilotomab satetraxetan are comparable to doses reported for other radioimmunotherapy compounds. Although the intertumor variability was considerable, a correlation between tumor dose and patient dosage level was found. Our results indicate that mean dose may be used as the sole dosimetric parameter on the lesion level. PMID- 27493272 TI - Theranostic Perspectives in Prostate Cancer with the Gastrin-Releasing Peptide Receptor Antagonist NeoBOMB1: Preclinical and First Clinical Results. AB - : We recently introduced the potent gastrin-releasing peptide receptor (GRPR) antagonist 68Ga-SB3 (68Ga-DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp Ala-Val-Gly-His-Leu-NHEt), showing excellent tumor localizing efficacy in animal models and in patients. By replacement of the C-terminal Leu13-Met14-NH2 dipeptide of SB3 by Sta13-Leu14-NH2, the novel GRPR antagonist NeoBOMB1 was generated and labeled with different radiometals for theranostic use. We herein report on the biologic profile of resulting 67/68Ga-, 111In-, and 177Lu-NeoBOMB1 radioligands in GRPR-expressing cells and mouse models. The first evidence of prostate cancer lesion visualization in men using 68Ga-NeoBOMB1 and PET/CT is also presented. METHODS: NeoBOMB1 was radiolabeled with 67/68Ga, 111In, and 177Lu according to published protocols. The respective metalated species natGa-, natIn , and natLu-NeoBOMB1 were also synthesized and used in competition binding experiments against [125I-Tyr4]BBN in GRPR-positive PC-3 cell membranes. Internalization of 67Ga-, 111In-, and 177Lu-NeoBOMB1 radioligands was studied in PC-3 cells at 37 degrees C, and their metabolic stability in peripheral mouse blood was determined by high-performance liquid chromatography analysis of blood samples. Biodistribution was performed by injecting a 67Ga-, 111In-, or 177Lu NeoBOMB1 bolus (74, 74, or 370 kBq, respectively, 100 MUL, 10 pmol total peptide +/- 40 nmol Tyr4-BBN: for in vivo GRPR blockade) in severe combined immunodeficiency mice bearing PC-3 xenografts. PET/CT images with 68Ga-NeoBOMB1 were acquired in prostate cancer patients. RESULTS: NeoBOMB1 and natGa-, natIn-, and natLu-NeoBOMB1 bound to GRPR with high affinity (half maximal inhibitory concentration, 1-2 nM). 67Ga-, 111In-, and 177Lu-NeoBOMB1 specifically and strongly bound on the cell membrane of PC-3 cells displaying low internalization, as expected for receptor antagonists. They showed excellent metabolic stability in peripheral mouse blood (>95% intact at 5 min after injection). After injection in mice, all 3 (67Ga-, 111In-, and 177Lu-NeoBOMB1) showed comparably high and GRPR-specific uptake in the PC-3 xenografts (e.g., 30.6 +/- 3.9, 28.6 +/- 6.0, and >35 percentage injected dose per gram at 4 h after injection, respectively), clearing from background predominantly via the kidneys. During a translational study in prostate cancer patients, 68Ga-NeoBOMB1 rapidly localized in pathologic lesions, achieving high-contrast imaging. CONCLUSION: The GRPR antagonist radioligands 67Ga-, 111In-, and 177Lu-NeoBOMB1, independent of the radiometal applied, have shown comparable behavior in prostate cancer models, in favor of future theranostic use in GRPR-positive cancer patients. Such translational prospects were further supported by the successful visualization of prostate cancer lesions in men using 68Ga-NeoBOMB1 and PET/CT. PMID- 27493273 TI - Preclinical Pharmacokinetics and Biodistribution Studies of 89Zr-Labeled Pembrolizumab. AB - : Pembrolizumab is a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1) found on T and pro-B cells. Pembrolizumab prevents PD-1 ligation by both PD-L1 and PD-L2, preventing the immune dysregulation that otherwise occurs when T-cells encounter cells expressing these ligands. Clinically, PD-1 blockade elicits potent antitumor immune responses, and antibodies blocking PD-1 ligation, including pembrolizumab, have recently received Food and Drug Administration approval for the treatment of advanced melanoma, renal cell cancer, and non-small cell lung cancer. METHODS: In this study, we evaluated the pharmacokinetics, biodistribution, and dosimetry of pembrolizumab in vivo, accomplished through radiolabeling with the positron emitter 89Zr. PET imaging was used to evaluate the whole-body distribution of 89Zr-deferoxamine (Df)-pembrolizumab in two rodent models (mice and rats). Data obtained from PET scans and biodistribution studies were extrapolated to humans to estimate the dosimetry of the tracer. As a proof of concept, the biodistribution of 89Zr-Df-pembrolizumab was further investigated in a humanized murine model. RESULTS: The tracer remained stable in blood circulation throughout the study and accumulated the greatest in liver and spleen tissues. Both mice and rats showed similar biodistribution and pharmacokinetics of 89Zr-Df pembrolizumab. In the humanized mouse model, T-cell infiltration into the salivary and lacrimal glands could be successfully visualized. CONCLUSION: These data will augment our understanding of the pharmacokinetics and biodistribution of radiolabeled pembrolizumab in vivo, while providing detailed dosimetry data that may lead to better dosing strategies in the future. These findings further demonstrate the utility of noninvasive in vivo PET imaging to dynamically track T cell checkpoint receptor expression and localization in a humanized mouse model. PMID- 27493275 TI - Lock-in camera based heterodyne holography for ultrasound-modulated optical tomography inside dynamic scattering media. AB - Ultrasound-modulated optical tomography (UOT) images optical contrast deep inside scattering media. Heterodyne holography based UOT is a promising technique that uses a camera for parallel speckle detection. In previous works, the speed of data acquisition was limited by the low frame rates of conventional cameras. In addition, when the signal-to-background ratio was low, these cameras wasted most of their bits representing an informationless background, resulting in extremely low efficiencies in the use of bits. Here, using a lock-in camera, we increase the bit efficiency and reduce the data transfer load by digitizing only the signal after rejecting the background. Moreover, compared with the conventional four-frame based amplitude measurement method, our single-frame method is more immune to speckle decorrelation. Using lock-in camera based UOT with an integration time of 286 MUs, we imaged an absorptive object buried inside a dynamic scattering medium exhibiting a speckle correlation time ([Formula: see text]) as short as 26 MUs. Since our method can tolerate speckle decorrelation faster than that found in living biological tissue ([Formula: see text] ~ 100 1000 MUs), it is promising for in vivo deep tissue non-invasive imaging. PMID- 27493274 TI - Discriminative Stimulus Effects of Binary Drug Mixtures: Studies with Cocaine, MDPV, and Caffeine. AB - Illicit drug preparations often include more than one pharmacologically active compound. For example, cocaine and synthetic cathinones [e.g., 3,4 methylenedioxypyrovalerone (MDPV)] are often mixed with caffeine before sale. Caffeine is likely added to these preparations because it is inexpensive and legal; however, caffeine might also mimic or enhance some of the effects of cocaine or MDPV. In these studies, male Sprague-Dawley rats were trained to discriminate 10 mg/kg cocaine from saline, and the discriminative stimulus effects of cocaine, caffeine, and MDPV were evaluated alone and as binary mixtures (cocaine and caffeine, MDPV and caffeine, and cocaine and MDPV) at fixed dose ratios of 3:1, 1:1, and 1:3 relative to the dose of each drug that produced 50% cocaine-appropriate responding. Dose-addition analyses were used to determine the nature of the drug-drug interactions for each mixture (e.g., additive, supra additive, or subadditive). Although additive interactions were observed for most mixtures, supra-additive interactions were observed at the 50% effect level for the 1:1 mixture of cocaine and caffeine and at the 80% effect level for all three mixtures of cocaine and caffeine, as well as for the 3:1 and 1:3 mixtures of cocaine and MDPV. These results demonstrate that with respect to cocaine-like discriminative stimulus effects, caffeine can function as a substitute in drug preparations containing either cocaine or MDPV, with enhancements of cocaine-like effects possible under certain conditions. Further research is needed to determine whether similar interactions exist for other abuse-related or toxic effects of drug preparations, including cocaine, synthetic cathinones, and caffeine. PMID- 27493276 TI - Air-coupled acoustic radiation force for non-contact generation of broadband mechanical waves in soft media. AB - A non-contact method for efficient, non-invasive excitation of mechanical waves in soft media is proposed, in which we focus an ultrasound (US) signal through air onto the surface of a medium under study. The US wave reflected from the air/medium interface provides radiation force to the medium surface that launches a transient mechanical wave in the transverse (lateral) direction. The type of mechanical wave is determined by boundary conditions. To prove this concept, a home-made 1 MHz piezo-ceramic transducer with a matching layer to air sends a chirped US signal centered at 1 MHz to a 1.6 mm thick gelatin phantom mimicking soft biological tissue. A phase-sensitive (PhS)-optical coherence tomography system is used to track/image the mechanical wave. The reconstructed transient displacement of the mechanical wave in space and time demonstrates highly efficient generation, thus offering great promise for non-contact, non-invasive characterization of soft media, in general, and for elasticity measurements in delicate soft tissues and organs in bio-medicine, in particular. PMID- 27493277 TI - Front-line action to protect amphibian biodiversity. PMID- 27493278 TI - Advances in veterinary practice. PMID- 27493279 TI - Ethical question of the month - August 2016. PMID- 27493280 TI - Epidemiology of toe tip necrosis syndrome (TTNS) of North American feedlot cattle. AB - Toe Tip Necrosis Syndrome (TTNS) is predominantly a hind limb lameness of feedlot cattle that develops early in the feeding period. Retrospective analyses of feedlot health records were conducted in order to describe the epidemiology of the disease at the level of the individual animal, lot, and feedyard. Analysis of 1904 lots (cohorts of > 100 head) of cattle, from 48 feedyards, found that TTNS occurred sporadically, but clustered by both lots and feedyards. Only 3.8% of lots had >= 1 case of TTNS; however, 26.4% of these lots were associated with 1 feedyard. Analysis of 702 cases of TTNS found that the disease clusters early in the feeding period; the mean (median; range) number of days on feed at death was 42.3 d (27.0 d; 4 to 302 d). The disease occurred in all months of the year and affected calves, yearlings, steers, and heifers. It was equivocal as to whether the source of the animals was associated with how quickly they died of TTNS in the feedyard. PMID- 27493281 TI - Erratum. AB - [This corrects the article on p. 1025 in vol. 56, PMID: 26483575.]. PMID- 27493282 TI - Augmentation of arthrodesis in dogs using a free autogenous omental graft. AB - A technique for using free autogenous omental grafting with arthrodesis in dogs is described and radiographic osseous union and complications after surgery are evaluated. This retrospective study matched body weight and procedure type for 8 cases of pancarpal arthrodesis, 4 cases of pantarsal arthrodesis, and 2 cases of partial tarsal arthrodesis in dogs with omental and cancellous bone autograft (OBG group) and with cancellous bone autograft alone (BG group). Radiographs were reviewed 9 to 12 weeks after surgery to compare scores of radiographic osseous union and it was found that the OBG group had higher scores than the BG group. The BG group had significantly more major complications that required re operation for implant removal or treatment of a deep infection compared to the OBG group. Overall, free autogenous omental grafts may be used to augment arthrodesis in dogs without significant morbidity and further investigation of its use to reduce major complications and speed bone healing are warranted. PMID- 27493284 TI - Post-operative complications associated with the Arthrex Canine Cranial Cruciate Ligament Repair Anchor System in small- to medium-sized dogs: A retrospective analysis (2009-2012). AB - This study classified and determined the post-operative complication rate associated with stabilization of cranial (CCL) ligament deficient stifles in small- to medium-sized dogs with the Arthrex Canine Cranial Cruciate Ligament Repair Anchor System (CCLRAS). Eighty-five medical records from 2009 to 2012 from 1 institution were evaluated. Complications were classified according to previously proposed definitions for orthopedic studies in veterinary medicine. Fifty-two owners were contacted by telephone at least 6 months after surgery and given a questionnaire to classify complications related to the implant. A visual analog scale was used to assess functionality and degree of pain. The overall complication rate was 30.3% with an inflammation-infection rate of 5.4% and a documented infection rate requiring implant removal of 1.8%. Owners reported full or acceptable function in 96% of cases with an average functional score of 86.5. Stabilization of CCL-deficient stifles in small- to medium-sized dogs with the Arthrex Canine CCLRAS is reliable with acceptable complication rates. PMID- 27493283 TI - Outcome and prognostic factors for dogs with a histological diagnosis of splenic hematoma following splenectomy: 35 cases (2001-2013). AB - Canine splenic hematoma can be indistinguishable from hemangiosarcoma on clinical presentation and grossly at the time of surgery. However, hemangiosarcoma represents an aggressive malignancy and a misdiagnosis of hematoma would forgo indications for chemotherapy. This study describes a long-term follow-up of cases with a histologic diagnosis of splenic hematoma following splenectomy to determine if the clinical course of the disease corroborated the diagnosis. Thirty-five dogs were evaluated to determine survival and prognostic associations with signalment and clinical data. Overall median survival time was 647 days (range: 0 to 3287 days). Statistically significant variables included a palpable abdominal mass during physical examination, sub-clinical coagulopathy, and metastasis. Four cases (11%) had reported evidence of metastasis at the time of euthanasia; 1 case was histologically confirmed. Overall prognosis for splenic hematoma appears excellent, as expected, but a small proportion of cases may have an undiagnosed malignant component. PMID- 27493285 TI - Long-term mechanical milking status of lacerated teat repaired surgically in cattle: 67 cases (2003-2013). AB - This study evaluated the long-term prognosis of return to normal mechanical milking after reconstructive teat surgery and determined the factors that have an impact on the outcome. A retrospective study of 67 dairy cows with teat lacerations was performed. Milking status at discharge and at long-term follow-up was adequate for 83% and 75% of the cows, respectively. No statistically significant differences were detected between the long-term prognosis and the age of the cow, the stage of lactation at presentation, or the configuration of the laceration. Lacerations repaired more than 24 hours after the trauma were more frequently associated with a negative outcome (P = 0.05). Mastitis was the most frequent complication (n = 17) and had a statistically significant negative impact on long-term prognosis (P = 0.02). Reconstructive surgery of lacerated teat in dairy cows can help establish return to normal mechanical milking. PMID- 27493286 TI - A cluster of trace-concentration methamphetamine identifications in racehorses associated with a methamphetamine-contaminated horse trailer: A report and analysis. AB - Three low concentration methamphetamine "positive" tests were linked to use of a methamphetamine-contaminated trailer to transport the affected horses. This incident establishes methamphetamine as a human-use substance that can inadvertently enter the environment of racing horses, resulting in urinary methamphetamine "positives;" an interim regulatory cut-off of 15 ng/mL for methamphetamine in post-race urine is proposed. PMID- 27493287 TI - A case of factor X deficiency in a Chihuahua dog. AB - A juvenile Chihuahua dog developed hemoperitoneum after routine ovariohysterectomy. She was managed with packed red blood cell and fresh frozen plasma transfusions as well as an exploratory laparotomy to verify ligature sites. No recurrence of hemorrhage occurred. Factor X deficiency was diagnosed and confirmed with repeat analysis including during times of health. PMID- 27493288 TI - Sialoendoscopy as a treatment for an obstructed mandibular salivary duct in a horse. AB - A 14-year-old Quarter Horse was examined for a draining tract of 8 months' duration on the right mandible that was non-responsive to antibiotic therapy and surgical therapy. Further investigation and subsequent treatment with sialoendoscopy and ultrasonography were performed to relieve an obstruction of plant awns in the mandibular salivary duct. PMID- 27493289 TI - Ventral rhinotomy in a pet rabbit (Oryctolagus cuniculus) with an odontogenic abscess and sub-obstructive rhinitis. AB - A rabbit was presented for severe dyspnea and was diagnosed with an odontogenic abscess obstructing the rostral nasopharynx using CT scan and oral endoscopy. The offending tooth was extracted intraorally, but due to persistent dyspnea, an endoscopic-guided ventral rhinotomy was performed. The dyspnea subsequently resolved, but the rabbit died 5 weeks later from a seemingly unrelated cause. PMID- 27493290 TI - Non-invasive magnetic resonance imaging diagnosis of presumed intermedioradial carpal bone avascular necrosis in the dog. AB - A 5-year-old, spayed female Weimaraner dog was evaluated for progressive left forelimb lameness localized to the carpus. Magnetic resonance imaging (MRI) was used to arrive at a presumptive diagnosis of intermedioradial carpal (IRC) bone fracture with avascular necrosis (AVN). To the authors' knowledge, this is the first report of naturally occurring AVN of the canine IRC diagnosed using MRI. PMID- 27493291 TI - Pain in human and non-human animals caused by electricity. PMID- 27493292 TI - Lessons for the first year in "practice". PMID- 27493293 TI - Clinical practice is not mandatory. PMID- 27493294 TI - Avoidance and enhancing screen-based communication. PMID- 27493295 TI - INHALED AEROSOL DOSIMETRY: SOME CURRENT RESEARCH NEEDS. AB - After the presentation of 60 papers at the conference "Advancing Aerosol Dosimetry Research" (October 24-25, 2014 in Irvine, CA, USA), attendees submitted written descriptions of needed research. About 40 research needs were submitted. The suggestions fell into six broad categories: 1) Access to detailed anatomic data; 2) Access to subject-specific aerosol deposition datasets; 3) Improving current inhaled aerosol deposition models; 4) Some current experimental data needs and hot topics; 5) Linking exposure and deposition modeling to health endpoints; and 6) Developing guidelines for appropriate validation of dosimetry and risk assessment models. Summaries of suggestions are provided here as an update on research needs related to inhaled aerosol dosimetry modeling. Taken together, the recommendations support the overarching need for increased collaborations between dose modelers and those that use the models for risk assessments, aerosol medicine applications, design of toxicology experiments, and extrapolation across species. This paper is only a snapshot in time of perceived research needs from the conference attendees; it does not carry the approval of any agency or other group that plans research priorities or that funds research. PMID- 27493296 TI - Total and regional deposition of inhaled aerosols in supine healthy subjects and subjects with mild-to-moderate COPD. AB - Despite substantial development of sophisticated subject-specific computational models of aerosol transport and deposition in human lungs, experimental validation of predictions from these new models is sparse. We collected aerosol retention and exhalation profiles in seven healthy volunteers and six subjects with mild-to-moderate COPD (FEV1 = 50-80%predicted) in the supine posture. Total deposition was measured during continuous breathing of 1 and 2.9 MUm-diameter particles (tidal volume of 1 L, flow rate of 0.3 L/s and 0.75 L/s). Bolus inhalations of 1 MUm particles were performed to penetration volumes of 200, 500 and 800 mL (flow rate of 0.5 L/s). Aerosol bolus dispersion (H), deposition, and mode shift (MS) were calculated from these data. There was no significant difference in total deposition between healthy subjects and those with COPD. Total deposition increased with increasing particle size and also with increasing flow rate. Similarly, there was no significant difference in aerosol bolus deposition between subject groups. Yet, the rate of increase in dispersion and of decrease in MS with increasing penetration volume was higher in subjects with COPD than in healthy volunteers (H: 0.798 +/- 0.205 vs. 0.527 +/- 0.122 mL/mL, p=0.01; MS: -0.271+/-0.129 vs. -0.145 +/- 0.076 mL/mL, p=0.05) indicating larger ventilation inhomogeneities (based on H) and increased flow sequencing (based on MS) in the COPD than in the healthy group. In conclusion, in the supine posture, deposition appears to lack sensitivity for assessing the effect of lung morphology and/or ventilation distribution alteration induced by mild-to-moderate lung disease on the fate of inhaled aerosols. However, other parameters such as aerosol bolus dispersion and mode shift may be more sensitive parameters for evaluating models of lungs with moderate disease. PMID- 27493297 TI - Characterization of an S-nitroso-N-acetylpenicillamine-based nitric oxide releasing polymer from a translational perspective. AB - Due to the role of nitric oxide (NO) in regulating a variety of biological functions in humans, numerous studies on different NO releasing/generating materials have been published over the past two decades. Although NO has been demonstrated to be a strong antimicrobial and potent antithrombotic agent, NO releasing (NOrel) polymers have not reached the clinical setting. While increasing the concentration of the NO donor in the polymer is a common method to prolong the NO-release, this should not be at the cost of mechanical strength or biocompatibility of the original material. In this work, it was shown that the incorporation of S-nitroso-penicillamine (SNAP), an NO donor molecule, into Elast eon E2As (a copolymer of mixed soft segments of polydimethylsiloxane and poly(hexamethylene oxide)), does not adversely impact the physical and biological attributes of the base polymer. Incorporating 10 wt % of SNAP into E2As reduces the ultimate tensile strength by only 20%. The inclusion of SNAP did not significantly affect the surface chemistry or roughness of E2As polymer. Ultraviolet radiation, ethylene oxide, and hydrogen peroxide vapor sterilization techniques retained approximately 90% of the active SNAP content, where sterilization of these materials did not affect the NO-release profile over an 18 day period. Furthermore, these NOrel materials were shown to be biocompatible with the host tissues as observed through hemocompatibility and cytotoxicity analysis. In addition, the stability of SNAP in E2As was studied under a variety of storage conditions, as they pertain to translational potential of these materials. SNAP-incorporated E2As stored at room temperature for over 6 months retained 87% of its initial SNAP content. Stored and fresh films exhibited similar NO release kinetics over an 18 day period. Combined, the results from this study suggest that SNAP-doped E2As polymer is suitable for commercial biomedical applications due to the reported physical and biological characteristics that are important for commercial and clinical success. PMID- 27493299 TI - A new horizon for the Sudanese Journal of Paediatrics. PMID- 27493298 TI - Financial Transfers to Husbands' and Wives' Elderly Mothers in Mexico: Do Couples Exhibit Preferential Treatment by Lineage? AB - The aim of this study was to contrast the likelihood that a husband's elderly mother receives financial assistance from a couple with that of a wife's mother. Prior U.S.-based research has documented a strong bias toward transfers to wives' parents. The authors aimed to extend this literature to Mexico, where financial help from adult children is a critical source of support for a rapidly aging population lacking institutional assistance. The authors' approach to modeling competition between mothers accounted for the nature of their need. The results demonstrate that among mothers of similar financial need, a husband's mother is twice as likely to receive financial assistance as a wife's mother. In contrast, when faced with personal care needs, a wife's mother is disproportionately favored. These results reflect gender differences in Mexican adult children's responsibility for family members' financial and physical well-being. The findings uncover new complexity in the patterns by which couples transfer money to parents of different lineage. PMID- 27493300 TI - Evaluation of Science. AB - Scientific achievement by publishing a scientific manuscript in a peer reviewed biomedical journal is an important ingredient of research along with a career enhancing advantages and significant amount of personal satisfaction. The road to evaluate science (research, scientific publications) among scientists often seems complicated. Scientist's career is generally summarized by the number of publications / citations, teaching the undergraduate, graduate and post-doctoral students, writing or reviewing grants and papers, preparing for and organizing meetings, participating in collaborations and conferences, advising colleagues, and serving on editorial boards of scientific journals. Scientists have been sizing up their colleagues since science began. Scientometricians have invented a wide variety of algorithms called science metrics to evaluate science. Many of the science metrics are even unknown to the everyday scientist. Unfortunately, there is no all-in-one metric. Each of them has its own strength, limitation and scope. Some of them are mistakenly applied to evaluate individuals, and each is surrounded by a cloud of variants designed to help them apply across different scientific fields or different career stages [1]. A suitable indicator should be chosen by considering the purpose of the evaluation, and how the results will be used. Scientific Evaluation assists us in: computing the research performance, comparison with peers, forecasting the growth, identifying the excellence in research, citation ranking, finding the influence of research, measuring the productivity, making policy decisions, securing funds for research and spotting trends. Key concepts in science metrics are output and impact. Evaluation of science is traditionally expressed in terms of citation counts. Although most of the science metrics are based on citation counts but two most commonly used are impact factor [2] and h-index [3]. PMID- 27493301 TI - The role of the health system in the prevention of hearing loss among children in Sub-Saharan Africa. AB - Around 1.2 million children living in Sub-Saharan Africa have a hearing impairment (HI) or hearing loss (HL). Limited attention and scarce resources dedicated to this condition means that such children often receive no management for their problem. This has substantial negative effects on their development, and ultimately results in poverty. Half of the number of cases of HI in such countries results from preventable causes. Formulation of effective prevention strategies to address the causes requires an understanding of the factors that lead to the causes of HI in Sub-Saharan Africa. A number of preventable causes were shown to significantly contribute to the prevalence of HI. The most significant causes include perinatal problems, middle ear problems, infective diseases, and ototoxic drugs. These causes persist because there are few effective prevention strategies in place, and those which exist are poorly implemented. There is little public and health care worker awareness about HL and its prevention. Few resources are allocated to the prevention of HL, meaning that these issues are not addressed. Evidence have shown that current failings in the prevention of HI from such causes include widespread limited resources, inadequate staff training, and absent or ineffectual prevention guidelines. The burden of HL has been shown to be significantly reduced through effective prevention strategies, both in the developed and developing world, justifying the need for increased attention and more resources in Sub-Saharan Africa. PMID- 27493302 TI - Recognition and diagnostic approach to acute metabolic disorders in the neonatal period. AB - Inborn errors of metabolism (IEM) constitute a group of inherited disorders that cause significant neonatal morbidity and mortality. This diverse group of diseases present with different clinical manifestations that make the diagnosis a real challenge. Early detection and appropriate investigations prevent complications and save lives. The aim of this review is to enable general paediatricians to clinically recognize IEM and plan relevant investigations at the appropriate time in a cost-effective manner, especially in countries where resources are limited. PMID- 27493303 TI - Recent intrauterine growth parameters of term Sudanese neonates in Khartoum compared to the findings three decades earlier. AB - The objective of this paper was to present anthropometric measurements of term Sudanese neonates which will reflect intrauterine growth. Secondly, to compare such parameters with that of a previous study done about three decades ago to show if there is any secular changes. Normal term neonates born to healthy mothers between the period of October 2010 to January 2011 at Khartoum Teaching Hospital were included in the study. There were certain criteria for inclusion and exclusion of the newborns and their mothers. Measurements of birth weight, crown-heel length and head circumferences were done in the first twenty four hours after birth. Statistical test of the difference between the means was used to show any significant difference. The means of birth weight, crown-heel length and head circumference for both sexes against gestational age were obtained. Comparing this study with the previous one showed no statistical significant difference for both sexes regarding the birth weight, crown-heel length but there is some difference between males head circumference. There is no evidence of upward secular trend regarding the intrauterine parameters. PMID- 27493304 TI - Pathologic causes of liver disease in Sudanese children: Results of 450 liver needle biopsies at a single children hospital. AB - The pathologic diagnoses of percutaneous 450 liver biopsies performed at the Gastroenterology Unit, Gaafar Ibnoof Specialized Children Hospital, Khartoum, Sudan during a five-year period (2005 to 2010) were reviewed. The cohort consisted of children aged between 1 month and 15 years, of whom 42% were less than 1 year of age. The male to female ratio was 1.4:1. The most common histological diagnosis was liver cirrhosis (26%), where no specific cause could be found, followed by neonatal hepatitis (20%), fatty liver (12%), billary atresia (10%), chronic hepatitis (8%), metabolic liver disease (6%), progressive intrahepatic cholestasis (5.5%), non-specific pathological changes (4.4%) and hepatocellular carcinoma in (4%). In conclusion, liver biopsy is a useful and practical tool for the appropriate diagnosis of pediatric liver diseases. Hepatocellular carcinoma has significantly higher prevalence in our pediatrics population. PMID- 27493305 TI - Sanjad-Sakati Syndrome in Sudanese children. AB - We report on the first 4 cases (3 girls and one boy belonging to 4 families) of Sanjad-Sakati syndrome from Sudan. They presented within the first 2 months of life with repeated hypocalcaemic convulsions, severe growth retardation and dysmorphic features. They all had low parathyroid hormone levels. All patients came from consanguineous families who are of Arab descent, and 8 of their siblings had similar condition and died without being diagnosed. PMID- 27493306 TI - Acute phase reactants in Sudanese children with severe protein-energy malnutrition. AB - The pre-dietary rehabilitation levels of acute phase proteins (APP) namely, alpha 1-antitrypsin (AAT), orosomucoid (ORO), haptoglobin (HAP), fibrinogen (FIB) and C reactive protein (CRP) in the plasma of Sudanese children with severe protein energy malnutrition (PEM) were compared with those of normal controls, and with the levels after dietary rehabilitation. Eighty one children were included in the study; 49 with severe PEM (23 with marasmus, 17 with marasmic-kwashiorkor and 9 with kwashiorkor), 13 with tuberculosis (TB) and 19 healthy children as controls. The study showed a high incidence of infections, especially acute respiratory infection (ARI), diarrhoeal diseases and intestinal parasites in the malnourished children. The mean plasma level of albumin was significantly lower in the malnourished children compared to controls (P<0.001), with kwashiorkor children showing the lowest mean level. This hypoalbuminaemia was significantly associated with the presence of ARI and intestinal parasites. The mean plasma levels of the APP, except FIB, were significantly higher in malnourished children than in controls, with higher levels associated with ARI and the presence of fever. Malnourished children with TB had significantly higher mean levels of the APP (AAT, HAP, FIB, CRP) compared to those without TB. The mean levels of HAP and AAT were significantly lower in the presence of diarrhoea, suggesting their loss in the stool. The mean levels of the APP after two weeks dietary rehabilitation and antimicrobial treatment showed a significant drop in only two of the APP, namely CRP, ORO, while FIB showed a significant rise. PMID- 27493307 TI - Classic ataxia-telangiectasia in a Sudanese boy: Case report and review of the literature. AB - Ataxia-telangiectasia (A-T) is a rare hereditary neurodegenerative disorder. Ataxia and telangiectasias are the hallmarks of the disease. A spectrum of manifestations may be seen in one family. There is no gold standard diagnostic test and diagnosis relies on clinical evaluation, exclusion of similar conditions, and supportive laboratory tests. More than 99% of individuals with classic A-T have mutations in ATM, the only gene known to be associated with ataxia-telangiectasia. We report a 28-months-old Sudanese boy who was presented with unsteady gait, frequent falls and telangectasias of the eyes. He also has had frequent episodes of respiratory tract infections. PMID- 27493308 TI - Tyrosinemia Typel: A case report. AB - Tyrosinemia type 1 is an inherited metabolic disorder attributable to deficiency of fumarylacetoacetate hydrolase enzyme. Here we report an eight month-old male Saudi infant who presented with jaundice, fever, and disturbed level of consciousness accompanied by abdominal distension, hepatomegaly and ascites with features suggestive of rickets. The diagnosis of tyrosinemia typ 1was confirmed based on clinical and biochemical findings. PMID- 27493309 TI - Ascaris Lumbricoides in a 13-year-old child. PMID- 27493310 TI - Pioneers of Paediatrics in Sudan: Professor Mahmoud Mohamed Hassan: FRCP (Edinburgh), FRCP (Glasgow), FAAP. PMID- 27493311 TI - Guidelines to Contributors. AB - To address the task of the expansion of the Sudanese Journal of Paediatrics (SJP) to encompass the scientific work dealing with child health locally and abroad, it will be the purpose of the Editorial Board of SJP to encourage authors to submit high-quality papers for the refereed publication and to make a more varied source of material to our readers. "Guidelines to contributors "are published to help the authors to present their data in accordance with the currently accepted uniform style for submitted manuscripts. It is based on the recommendations of the International Committee of Medical Journal Editors [1] with minor modifications to suit the local facilities in developing countries. PMID- 27493312 TI - Commitment to the wellbeing of children worldwide. PMID- 27493313 TI - Treatment strategies for acute metabolic disorders in neonates. AB - Acute metabolic emergencies in neonates represent a challenge to the medical and nursing staff. If not treated optimally, these disorders are associated with poor outcome. Early diagnosis, supportive therapy and specific measures addressing the derranged metabolic process are the gold standards for favorable results. This review highlights treatment strategies for Inborn Errors of Metabolism (IEM) presenting in the neonatal period. PMID- 27493314 TI - The effect of qat chewing and other factors on breast-feeding and child survival in a Yemeni society. AB - In a survey conducted in Dammar, Republic of Yemen, 755 mothers were interviewed to investigate the patterns and factors affecting childhood feeding practices. It was found that full breast-feeding rate (41.8%) and timely introduction of complementary feeding rate (57.4%) were low, bottle-feeding rate (25.1%) was high and timely first suckling rate was zero. It was also found that the more educated and older mothers tended to wean their children earlier than illiterate and younger mothers. A significant association between regular frequent qat chewing and history of child death was observed. The implications of these findings were discussed. PMID- 27493315 TI - Donkey milk-based formula: A substitute for patients with cow's milk protein allergy. AB - Cow's milk protein allergy affects 2-7% of children using cow's milk formulae. Fifty to eighty percent of them develop allergy to other food items and substitutes. On the search for a safe and affordable substitute, we reviewed the composition of milks of the domestic mammals in close contact with man. Milk constituents studied included fat, protein, lactose, minerals, water, pH, specific gravity and caloric value. Compared to others, donkey milk was found to be closest to breast milk when the amount of 16ml of sunflower is added to one liter of this milk. To our knowledge, no allergy to donkey milk has been reported yet. PMID- 27493316 TI - Characteristics associated with severe pneumonia in under-five children admitted to emergency units of two teaching hospitals in Khartoum, Sudan. AB - Pneumonia, defined as infection of lung parenchyma, is associated with severe complications especially in the very young and old patients. It is the world's leading cause of childhood mortality. The World Health Organization (WHO) classification and guidelines are commonly used in Sudan in the diagnosis and management of pneumonia patients. A group of 224 patients at Gaafar Ibn Oaf Children's Hospital and Omdurman Children's Hospital were assessed and managed for severe presentation of pneumonia. The data collected showed that most of the patients were of low socioeconomic class families. The vast majority (99%) of patients had chronic exposure to tobacco smoke at home. Female patients (52.7%) were more than males, with 42% of the presenting patients in the less than 12 months age group. Pneumonia is a dangerous childhood menace that is associated with severe presentations. Public health community outreach programs should be put in place to raise awareness. The case fatality rate during the study period was 4%. PMID- 27493317 TI - Infection and immunoglobulin levels in Sudanese children with severe protein energy malnutrition. AB - A hospital-based case control study was carried out to determine the pattern of infections and immunoblobulin levels in Sudanese children with severe protein energy malnutrition (PEM). The pre-dietary rehabilitation levels of the three major immunoglobulins (IgG, IgA and IgM) were compared with those of normal controls, and with the levels after dietary rehabilitation. Eighty one children were included in the study: 49 with severe PEM (23 with marasmus, 17 with marasmic - kwashiorkor and 9 with kwashiorkor), 13 with tuberculosis and 19 healthy children as controls. The study showed high incidence of infections, especially pneumonia and gastrointestinal infections in the malnourished children. Of special concern was the high incidence of urinary tract infection: 13 (26.5%) had significant pyuria and 9 of them had positive urine cultures, mainly Escherichia coli. Eight of the malnourished children also had pulmonary TB, and the ESR and Mantoux tests were not helpful in the diagnosis. The Mantoux test was negative in 88.8% of the malnourished group compared to 62.5% in those malnourished with TB. The malnourished groups had significantly higher plasma levels of the 3 immunoglobulins. While the maramic group attained significantly higher levels of IgG and IgA compared to the marasmic -kwashiorkor and kwashiorkor groups, the 3 groups of PEM showed a uniformly higher level of the IgM. After 2 weeks of rehabilitation, the levels of the 3 immunoglobulins showed no significant changes, except for the IgA which significantly decreased in all malnourished and the oedematous groups, and the IgM which increased significantly in the oedematous group. PMID- 27493318 TI - Button battery induced traumatic tracheoesophageal fistula: Case report and review of literature. AB - Although accidental ingestions by children of various household chemicals and medicines are well described and the treatment is supported by protocols and hotlines, the ingestion of button batteries is less publicized, and the dangers are less understood by both parents and health care providers. We describe the case of a three-year-old girl, who presented to hospital with respiratory distress, cough, and fever; three weeks after the ingestion of a button battery. Endoscopic examination revealed impacted 20 mm disc battery, which was removed, and a tracheoesophageal fistula (TOF) in the upper third of the oesophagus associated with severe oesophagitis, and oesophageal ulcers. There was also evidence of oesophageal fungal infection, and severe hyperemic pan-gastritis and duodenitis. Parents were counseled and conservative management advised, but they opted for surgical repair of the TOF. The operation was done and the child survived, but she ended up with a tracheal stricture and recurrent chest infections. In conclusion, oesophageal button battery impaction places the patient at high risk for tracheoesophageal fistula. The key to successful therapy is prompt diagnosis and removal, which saves life and decreases morbidity. Because of the complications associated with this condition, patients should be managed at an institution with skilled personnel and facilities for advanced life support. PMID- 27493319 TI - Dicephalus tribrachius conjoined twins: Case report and review of literature. AB - Conjoined twins is a phenomenon believed to be caused by either delayed splitting of the fertilized ovum or fusion of the embryonic stem cells. Disorganization of mutant genes is believed to be a cause in some cases. We report a case of stillborn dicephalus tribrachius female conjoined twins with features that are not reported previously in the literature with a single umbilical artery and two urinary bladders. The cause of intrauterine death in this case was probably multi factorial i.e. severe anemia in the mother, congestive heart failure, complications of obstructed labor and multiple skull fractures. PMID- 27493320 TI - Zellweger syndrome: A cause of neonatal hypotonia and seizures. AB - Zellweger syndrome, a paradigm of human peroxisomal disorders is characterized by dysmorphic features, hypotonia, severe neuro-developmental delay, hepatomegaly, renal cysts, sensorineural deafness and retinal dysfunction. This is a case report of a baby boy born with facial dysmorphism, profound hypotonia, seizures, and hepatomegaly. The diagnosis was not evident initially but only later when he presented with obstructive jaundiced and renal cysts. He died at the age of seven months. Biochemical studies revealed elevation of very long chain fatty acids and phytanic acid consistent with a peroxisomal disorder. The recognition of this syndrome is important since it is a fatal hereditary disease. Zellweger syndrome should be included in the differential diagnosis of infantile hypotonia and dysmorphism. PMID- 27493321 TI - Walker-Warburg Syndrome: A Case with multiple uncommon features. AB - Walker-Warburg syndrome (WWS) is a rare and lethal autosomal recessive disorder, caused by defective glycosylation of alpha-dystroglycan that is important for muscle integrity and neuronal migration. Mutations in six genes involved in the glycosylation of alpha-dystroglycan (POMT1, POMT2, POMGNT1, FCMD, FKRP and LARGE) have been identified in WWS patients, and others remain under study. Prenatal diagnosis may be possible by means of prenatal ultrasonography, or magnetic resonance imaging. We report a patient demonstrating the typical clinical features of lissencephaly, congenital muscular dystrophy and ocular abnormalities, in addition to other features including hydrocephalus, occipital encephalocele, agenesis of the corpus collosum, microphthalmia, ventricular septal defect, and rocker bottom feet deformity. PMID- 27493322 TI - Guidelines to Contributors. AB - To address the task of the expansion of the Sudanese Journal of Paediatrics (SJP) to encompass the scientific work dealing with child health locally and abroad, it will be the purpose of the Editorial Board of SJP to encourage authors to submit high-quality papers for the refereed publication and to make a more varied source of material to our readers. "Guidelines to contributors "are published to help the authors to present their data in accordance with the currently accepted uniform style for submitted manuscripts. It is based on the recommendations of the International Committee of Medical Journal Editors [1] with minor modifications to suit the local facilities in developing countries. PMID- 27493323 TI - Changing an old therapy of a historic human infection: Malaria. PMID- 27493324 TI - Time to switch from quinine. PMID- 27493325 TI - Drug-resistant malaria in Sudan: A review of evidence and scenarios for the future. AB - Resistance of falciparum malaria to chloroquine (CQ) has gradually emerged in the late 1970s, reaching unacceptably high proportions over the following three decades of use as frst line treatment in Sudan. By 2004-2006 CQ was replaced by artemisinin-based combination treatment (ACTs), with combination of sulfadoxine pyrimethamine (SP) and artesunate (AS) deployed as frst-line drug against falciparum malaria. The present review follows the evolution of CQ resistance in Sudan and the available evidence on the response to the present frst-line drugs. The fndings in Sudan are analyzed in view of developments in other African countries and at the global level, with the hope of elucidating possible scenarios for the course of events in the Sudan. Northern Sudan has been one of the areas where signals indicating the emergence of drug resistant malaria parasites have frst originated in Africa. The pattern of low endemicity and low population immunity to malaria, together with massive deployment and improper use of anti-malarial drugs created the ideal environment for creation of anti malarial drug resistance. Such an environment existed in certain areas in South East Asia that had historically been the epicenter from which falciparum malaria parasites resistant to pyrimethamine and chloroquine have spread to the rest of the world. The alarming recent reports about the emergence of artemisinin (ART) resistance in South East Asia have lead WHO to take specifc measures for prevention, early detection and containment of drug resistance. What could be applicable in Sudan in these measures is discussed here. PMID- 27493326 TI - Neonatal follow-up program: Where do we stand? AB - Neonatal follow-up program (NFP) is becoming the corner stone of standard, high quality care provided to newborns at risk of future neuorodevelopmental delay. Most of the recognized neonatal intensive care units in the developed countries are adopting NFP as part of their mandatory care for the best long term outcome of high risk infants, especially very low birth weight (VLBW) infants. Unfortunately, in the developing and in underdeveloped countries, such early detection and intervention programs are rarely existing, mainly because of the lack of awareness of and exposure to such programs in spite of the increasing numbers of surviving sick newborns due to advancement in neonatal care in these countries. This is a review article to explore the Neonatal follow-up programs looking at historical development, benefts and aims, and standard requirements for successful program development that can be adopted in our countries. In conclusion, proper Neonatal follow-up programs are needed to improve neonatal outcome. Therefore all professionals working in the feld of neonatal care in developing countries should cooperate to create such programs for early detection and hence early intervention for any adverse long term outcome in high-risk newborn infants. PMID- 27493327 TI - Childhood immune thrombocytopenia: Clinical presentation and management. AB - Immune thrombocytopenia (ITP) is an acquired hematological disorder that is developed secondary to the production of auto-antibodies against platelets leading to isolated thrombocytopenia, in the absence of other causes of thrombocytopenia such as drugs, infections, malignancy, or other autoimmune diseases [1-6]. ITP commonly affects children between one and seven years of age. Severe life threatening bleeding is rare (0.2-0.9%) [7-12]. Childhood primary ITP usually runs a benign, self-limiting course, with or without treatment. Complete remission occurs within six months from diagnosis, commonly within 6-12 weeks, in the majority of children with the diagnosis of ITP. However, 20-30% of children will continue to have persistent low platelets count with bleeding symptoms beyond six months from diagnosis [4, 12-18]. The diagnosis of ITP in children is essentially one of exclusion. The child is usually one to seven years old, develops skin bruises, petechiae, or mucosal bleeding, who is otherwise healthy and having no lymphadenopathy or organomegally. Full blood count reveals isolated thrombocytopenia with normal hemoglobin (Hb) level, white blood count (WBC) and normal peripheral blood smear. Initial management options for newly diagnosed childhood ITP include; observation only, the use of intravenous immunoglobulin (IVIG), steroids, anti-D immunoglobulin, each alone or in combination [6, 19.] Children who develop chronic ITP may benefit from splenectomy [19, 20-24]. Rituximab, a chimeric monoclonal antibody (anti-CD20), may lead to complete remission, and defers the need for splenectomy [25-27]. Recently, the thrombopoietin (TPO) agonists (Romiplostim and Eltrombopag) produced very good response in adult and pediatric patients with severe chronic ITP [28-30]. PMID- 27493328 TI - Morbidity and mortality amongst infants of diabetic mothers admitted into Soba university hospital, Khartoum, Sudan. AB - The prevalence of diabetes during pregnancy is increasing and this is associated with an increased risk of complications in both mother and fetus. The aim of this research is to study the neonatal complications of maternal diabetes. This was a prospective observational study that was conducted in Soba university hospital between September 2010 and March 2011. All infants born to diabetic mothers during the study period were admitted to the neonatal care unit for evaluation. Data on sex, gestational age, and birth weight, mode of delivery, complications, investigations, birth injury, and length of hospital stay were recorded. Maternal data were retrieved from records. Data was analyzed using Minitab 15. A total of 50 infants of diabetic mothers (IDMs) were included in the study. Thirty infants (60%) were females and 20 (40%) were males. Forty two (84%) of the neonates were born by caesarian section, only 7(14%) were born by spontaneous vaginal delivery. Birth injury was observed in 4% of them. The mean gestational age was 37.2+/ 2.051 weeks. The median birth weight was 3.5 kg. 14 (28%) of the babies were macrosomic, and 17 (34%) were large for gestational age (LGA). Congenital anomalies were found in 3 (6%), hypoglycemia in 6 (12%), hyperbillirubinaemia in 10 (20%), hypocalcaemia and hypomagnesaemia each occurred in 2%, transient tachypnea of the newborn occurred in 5 (10%) of the neonates and respiratory distress syndrome in 2%. Cardiomyopathy occurred in 2% and mortality was 4%. We concluded that macrosomia, LGA, and hyperbillirubinaemia were the commonest complications in IDMs, maternal glycaemic control was found to have a significant effect on a number of outcomes. PMID- 27493329 TI - Rickets and osteomalacia in Saudi children and adolescents attending endocrine clinic, Riyadh, Saudi Arabia. AB - This is a retrospective study in which we report our clinical experience during the period from January 1990 to December 2009, from a paediatric endocrine clinic at King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia. The diagnosis of rickets and oestomalacia was based on clinical, biochemical and radiological data. Eighty-one (34 males and 47 females) children and adolescents with rickets or osteomalacia aged 2 to 18 years (mean; 9.5 years) were evaluated. The commonest causes were nutritional; either low Vitamin D or calcium, or both. In 58 (71.60%) patients, eight patients (9.87%) were due to chronic use of anticonvulsant medications, while five (6.17%) patients were diagnosed to have celiac disease. Non-specific symptoms, such as bone pain and fatigue were the most common presenting symptoms which may indicate that other cases were possibly missed. Lack of direct sun exposure and malnutritional practices were evident. Several genetically inherited disorders were diagnosed; including; hypophosphataemic rickets in three (3.70%), vitamin D-dependent-rickets type 2 in five (6.17%) and pseudohypo-hyperparathyroidism in one (1.23%) child. Rickets was secondary to chronic renal failure in only one patient (1.23%). In conclusion, a diversity of disorders caused rickets or osteomalacia in our series. Paediatricians should be familiar with such different types and able to differentiate them from disorders mimicking rickets. rickets, such as hypophosphatasia, and metaphyseal dysplasias. An active plan should be put in place to prevent rickets and osteomalacia among young age groups. PMID- 27493330 TI - Prescription writing quality in paediatric teaching hospitals in Khartoum. AB - This study was conducted to analyze the quality of prescription writing of doctors in outpatient departments of paediatric teaching hospitals in Khartoum. This study is a descriptive cross- sectional, prospective, hospital based study. Nine hundred paediatric prescriptions collected from three paediatric teaching hospitals were analyzed. Three hundred prescriptions were also collected from doctors after giving them a case scenario for which they were asked to write appropriate prescriptions. These prescriptions were also analyzed for their completeness. Inadequate writing of the sex of the patient, weight, and height were notable regarding patient information. Generic names, concentration of the drug and treatment duration of the drug were poorly mentioned. Designation and identification of the prescriber were not adequately mentioned. In the case scenario 65.3 % of doctors wrote low quality prescriptions. Registrars wrote better prescriptions than medical officers who wrote better than house officers. Outpatient department prescriptions were unsatisfactory due to lack of necessary information for the ideal prescription. Also doctors, in response to case scenario, wrote low quality prescriptions. To improve prescription writing skills, we suggest that hospitals should provide standard prescription forms that contain the necessary fields for identification of both, patient and doctor. PMID- 27493331 TI - Cardiac manifestations of sickle cell anaemia in Sudanese children. AB - Sickle cell anaemia (SCA) is one of the commonest chronic hemolytic anaemias in the Sudan; it is a disease with high mortality and morbidity. This study was conducted aiming to observe the clinical pattern of cardiac abnormalities in children with sickle cell anaemia, and to assess the relationship between the cardiac abnormalities and the severity of the disease. The study was conducted in sickle cell disease clinic at Khartoum Children Emergency Hospital. The study group consisted of 289 patients with sickle cell anaemia, age range from 6 months to 18 years. Data were collected using a questionnaire which include full history, clinical examination findings, chest x-rays, and Electro-cardiography. Tachycardia, systolic murmurs, and cardiomegaly were detected in 28%, 61%, and 54% of patients with SCA respectively. Left ventricular dilatation was observed in 51% of the study group, while right ventricular dilatation was observed in 22% of the patients. Left and right atrial dilatations were observed in 16% and 6% of the patients respectively. Contractility, ejection fraction (EF) were found almost always normal in all study subjects. Chamber dilatations were not associated with any abnormality in Left ventricular functions. Hemglobin (Hb) levels correlated negatively with cardiomegaly. Left Ventricular End Diastolic Dimension (LVEDD) correlates negatively with Hb levels and positively with the severity index. Only four patients (1%) had abnormal valves. In conclusion, cardiac abnormalities in patients with SCA correlate with the age of the patients and the severity of the disease. PMID- 27493332 TI - Short stature in children: Pattern and frequency in a pediatric clinic, Riyadh, Saudi Arabia. AB - Longitudinal growth assessment is essential in child care. Short stature can be promptly recognized only with accurate measurements of growth and critical analysis of growth data. The objective of this study was to determine the pattern of short stature among patients referred to an endocrine pediatric clinic, King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia and to ascertain the aetiological profile of short stature. This is a retrospective review of patients referred to a pediatric endocrine clinic with short stature during the period January 1990 and December 2009. After a proper detailed medical history, growth analysis and physical examination, followed by a radiological (bone age) and laboratory screening (complete blood count and thyroid function). Growth hormone stimulation tests were performed when indicated. Magnetic resonance imaging (MRI) of the pituitary was performed when necessary. As well, celiac screening and small bowel biopsy were performed when appropriate. During the period under review, hundred and ten patients were evaluated for short stature. Their age ranged from 2 years and six months to 4 years. The male to female ratio was 1.3:1. The commonest etiology was genetic short stature found in 57 (51.8%) patients, while in the other 53 (48.2%) patients, variable endocrine and nutritional causes were noted. Short stature was a common referral. A wide variety of etiological diagnosis was noticed with genetic short stature being the commonest. A wide variety of endocrine causes were evident, with growth hormone deficiency, as a results of different etiologies, being the commonest. PMID- 27493333 TI - Incomplete Kawasaki disease: The usefulness of BCG reactivation as a diagnostic tool. AB - Kawasaki disease (KD) is an extremely rare condition in infants younger than 3 months old. Cardiovascular complications are unfortunately most common in young infants and it is in this age group, incomplete Kawasaki disease (IKD) is more frequently reported. Because IKD is a diagnostic dilemma, any sign that could help early diagnosis, such as BCG reactivation is useful. Here we report on an infant less than 3 months old with IKD wherein, BCG reactivation helped us in making the diagnosis. In this article, we highlight the usefulness of this sign for early diagnosis of IKD, especially in countries where BCG vaccination is still part of the immunization schedule. PMID- 27493334 TI - Breast carcinoma in a boy with metastatic axillary lymph nodes. AB - The purpose of this report is to highlight the clinicopathological features, diagnosis, management and prognosis of rare childhood breast cancer. We herein report a case of slowly growing, locally advanced secretory carcinoma of the breast in an 11-year-old boy with metastatic axillary lymph nodes, 12 of them were totally replaced by the tumor cells. No evidence of distant metastases was detected. Modified radical mastectomy with axillary clearance was done, with uneventful postoperative course. On searching the Sudan medical literature, no previous report of similar case was found. In conclusion, breast carcinoma, though a rare entity, yet should be borne in mind if a firm breast lump was found in a child. Fine needle aspiration cytology is effective to start with as a diagnostic tool. PMID- 27493335 TI - Meckel-Gruber syndrome: A rare and lethal anomaly. AB - Meckel-Gruber syndrome is a rare and lethal autosomal recessive disorder characterized by occipital encephalocele, postaxial polydactyly and bilateral dysplastic cystic kidneys. It can be associated with many other conditions. Antenatal ultrasound examination establishes the diagnosis by identifying at least two of the major features described. We describe a female baby who had the typical triad of Meckel-Gruber syndrome and died shortly after birth. PMID- 27493336 TI - Etiology and clinical pattern of cervical lymphadenopathy in Sudanese children. AB - Cervical lymphadenopathy (CLA) is a common childhood problem in clinical practice which poses diagnostic difficulties to pediatricians. The aims of this study were to determine the causes of CLA in Sudanese children and to evaluate the value of routine laboratory tests in determining the etiology. Demographic and clinical data were prospectively collected from eighty children with palpable cervical nodes. Children were then subjected to complete blood count, ESR, Mantoux test, aspiration cytology of a lymph node and serological tests for HIV agglutination test, ELISA for Epstein-Barr virus and toxoplasma gondii. The age ranged 1-13 years with a mean of 5.8 +/-3.1SD years with no gender difference. Specific etiologies of CLA were determined in 62.5% of patients. Ninety five percent of the causes were due to non-specific reactive hyperplasia of lymph nodes (NSRH) (37.5%), toxoplasmosis (27.5%), infectious mononucleosis due Epstein-Barr virus (13.8%), tuberculous adenitis (10%), acute adenitis (6.2%), whereas malignancy (Hodgkin's lymphoma) constituted 5% of causes of CLA. The clinical characteristics were insignificantly associated with the causes of lymphadenopathy (p>0.05). However, mobile lymph nodes were significantly associated with inflammatory conditions (P<0.05). Inflammatory causes accounted for the majority of the etiologies whereas Hodgkin's lymphoma was the only identified malignancy. Laboratory tests such as, ESR, TWBC, hemoglobin and Mantoux test should be used in adjunct with cytology and serology for diagnosis. PMID- 27493337 TI - Audit of acute asthma management at the Paediatric Emergency Department at Wad Madani Children's Hospital, Sudan. AB - This audit of hospital care of acute wheeze and asthma aimed to assess the degree of adherence of the acute care of the asthma patients to the published international guidelines. Information was collected in six key areas: patient demographics; initial asthma severity assessment; in-hospital treatment; asthma prophylaxis; asthma education and emergency planning; and follow-up arrangements. The area of initial asthma severity assessment showed defciencies in the clinical measures currently used to verify case severity. In- hospital treatment on the other hand was consistent with recommendations in the use of the inhaled beta-2 agonist salbutamol as bronchodilator, the discrete use of aminophylline and the small number of patients ordered chest X-ray. However, the treatment was incoherent with recommendations in the delivery method used for inhaled bronchodilator in relation to the age group of treated patients, absence of ipratropium bromide as a bronchodilator in the management and the large use of antibiotics. Assessment of the areas of asthma prophylaxis, asthma education and emergency- planning and follow-up arrangements illustrated that little efforts were made to assure safe discharge, although these measures have been shown to reduce morbidity after the exacerbation and reduce relapse rates and signifcantly reduce hospitalizations, unscheduled acute visits, missed work days, as well as improving quality of life. This audit emphasizes the need for the adoption of a management protocol for acute asthma care in the emergency department based on published international guidelines and the assurance of its implementation, monitoring and evaluation using the right tools to improve patient care. PMID- 27493339 TI - Managing the common and rare in paediatrics. PMID- 27493340 TI - Overview of diagnosis, management and outcome of congenital hypothyroidism: A call for a national screening programme in Sudan. AB - Congenital hypothyroidism (CH) is the commonest preventable cause of mental retardation in children worldwide. It continued to be a major health problem amongst Sudanese children. The lack of a screening programme in Sudan may be the major factor of missing the diagnosis in newborns with such a condition that can present very subtle clinically, yet with poor neurodevelopmental consequences. The outcome is very good when the condition is noticed early (in the first 2 - 3 weeks of life). However, the prognosis is guarded when the diagnosis is delayed, with a squeal of different degrees of developmental delay depending on the severity of the condition. In this overview, we tried to highlight the important issues of screening, diagnosis and outcome with and without early management, worldwide. We thereby send a call out for all paediatricians and endocrine clinicians who work locally or outside Sudan to collaborate with the Sudanese Society of Paediatrician as well as other stakeholders in Sudan to help establishing a national screening programme for all common and preventable causes of childhood illnesses which has devastating consequences such as CH. PMID- 27493341 TI - Managing wheeze in preschool children: How difficult can it be? AB - Wheeze is a common symptom in infants and preschool children. Up to 30% of children wheeze at least once before the age of 3 years and 2% of those have it severe enough to warrant hospital admission. Not only parents but also physicians have difficulty in recognizing wheeze. Wrong diagnosis of the underlying condition leads to inappropriate and unnecessary management and patient morbidity. Asthma is the commonest underlying condition in children with wheeze, but the differential diagnosis is quite broad and a systematic approach including a good clinical history, thorough physical examination and appropriate investigations are essential to reach the accurate diagnosis. PMID- 27493342 TI - A review and practical application of evidence based medicine (EBM): Testicular adrenal rest tumour. AB - Nowadays, Medical practice is largely based on the best available evidence. However, the evidence may not always be readily available and clinician and/or other health allied professionals may need to learn how to search for it. This article gives highlights on the very vast and growing subject of evidence based medicine (EBM), followed by a practical application of searching for it in the real life, in a situation when the available evidence is limited. PMID- 27493343 TI - Sudanese female doctors in paediatrics. AB - Though the number of female medical graduates has increased throughout the world, their postgraduate professional achievements are said to be suboptimal. Our aim is to look into the achievements of Sudanese female pediatricians and compare them with their male counterparts. A cross sectional study was undertaken using a questionnaire involving pediatricians working in the universities and Ministry of Health, Sudan. Ninety five (65.1%) out of 146 pediatricians responded; 73 (76.8%) were females and 22 (23.2%) were males. Thirty (41%) Of the females were in the academic career. Only 2 (8.3%) out of 24 assistant professors were promoted to associate professors and non of the four associate professors managed to become a professor compared to 68% and 25% among males, respectively. Twenty three (76.6%) of females compared to 31% of males had no publications. Nineteen out of 21 females (90.4%) who have been offered training opportunities abroad declined the offer for family reasons. Fifty four (93%) female pediatricians declined to work outside the capital state. No nursery facilities were available at work place. The main reasons for inadequate achievements included family issues, cultural obstacles, lack of mentorships and unsatisfying work environment and facilities. Suggestions were put forward to improve on these problems. Though female doctors are the majority of undergraduate and graduate students in Sudan, their professional and academic achievements after specialization are not optimal mainly for socio-cultural reasons and these need to be addressed. PMID- 27493344 TI - Prevalence of smoking among school adolescents in Khartoum State. AB - Tobacco is the single most important cause of chronic morbidity in the Developed World. Tobacco use primarily begins in early adolescence, reportedly before the time of high school graduation. By 2015 tobacco use is projected to cause 50% more deaths than AIDS. A cross sectional school based survey was conducted in primary and secondary school in Khartoum State. The study aimed to estimate the prevalence of smoking in school adolescents and associated personal and social factors. A total of 910 students with complete questionnaires were included in the analysis, of whom 13.6% were found to be current cigarette smokers. Factors that played role in initiation of smoking included smoking among parents, other family members and close friends. School adolescents who have friends or parents who smoke should be the main target for tobacco control. Smoking should become public health priority in Sudan to educate adolescents and parents regarding its hazards. PMID- 27493345 TI - Visual acuity testability of children in Bama and Banki towns of Borno State, Nigeria: The need to adopt HOTV protocol in school health programmes. AB - Despite the importance of visual acuity testing in children, no standard testing protocol was found for primary school pupils. Visual acuity screening was conducted on 400 primary school pupils in Nigeria using the HOTV protocol, nearly all the pupils 390/400 (97.5 %) had good binocular vision, only 10/400 (2.5 %) had poor vision which were monocular. Of those with poor monocular vision, 6/10 (60 %) involved the right eye while 4/10 (40 %) the left eye; these pupils were referred to the ophthalmologist for further evaluation. Because of its easy usage, the HOTV protocol can be adopted by school health programmes especially for the primary school pupils. PMID- 27493346 TI - Pattern and outcome of renal diseases in hospitalized children in Khartoum State, Sudan. AB - In developing countries, renal diseases in children constitute important causes of morbidity and mortality. In Sudan, data about patterns and outcome of these disorders is generally scanty. We conducted this study to provide basic renal data that may be utilized by researchers and health planners in a resource poor setting. A retrospective record review of all pediatric patients, followed in four teaching hospitals in Khartoum State over a five-year period (January 2000 June 2004), was achieved. In 150 hospitalized children a total of 200 renal diagnoses were recorded. Urinary tract infection (UTI), occurring with other underlying renal morbidities or isolated, was the commonest renal diagnosis (20%). The second common renal disorders were nephrotic syndrome (NS) and urolithiasis/stones accounting for 16% and 15.5% of cases, respectively. Acute glomerulonephritis (AGN) and congenital anomalies were relatively less common (12% and 10.5%, respectively). Other less frequently detected diseases were acute renal failure (ARF) in 6%, chronic renal failure (CRF) in 4%, hereditary nephropathies in 3.5% and renal tumors in 2.5%. There was a significant correlation between the pattern of renal diseases and age of patients (P =0.001) but not their gender or social class (P = 0.211 and 0.34, respectively). On follow up, 99 out of 150 patients (66%) recovered their normal renal function, 6/150 (4%) remained with persistent proteinuria, 30/150 (20%) progressed to CRF, 10/150 (6.7%) died, and 5/150 (3.3%) were referred to radiotherapy department for further management. Our data reflects geographical variations of patterns of renal diseases in Sudanese children as in other countries. Many of these diseases are preventable or potentially curable. Therefore, improvement of pediatric renal services and training of health workers would help in early detection and treatment of these conditions leading to reduction in their morbidity and mortality. PMID- 27493347 TI - Chronic immune thrombocytopenia in a child responding only to thrombopoietin receptor agonist. AB - Immune thrombocytopenia (ITP) is an acquired hematological disease in which the body produces antibodies against its own platelets leading to platelet destruction resulting in isolated thrombocytopenia. Childhood ITP may enter complete remission in the majority of cases within six months from diagnosis. However, 20-30% of affected children may develop chronic ITP (lasting for more than 12 months). First line treatment includes intravenous immunoglobulin (IVIG), corticosteroids or anti-D immunoglobulin. Second line treatment includes splenectomy, immunosuppressive therapy or Rituximab. Recently two thrombopoietin (TPO) receptor agonists (Romiplostim and Eltrombopag) are used to increase platelet count in refractory chronic ITP by increasing platelet production in bone marrow. Here is a case report on an 8 1/2 -year-old boy with refractory chronic ITP who failed therapy with IVIG, corticosteroids, splenectomy and Rituximab. He showed excellent response to treatment with TPO receptor agonist (Romiplostim). His platelet count increased from less than 10 x10(3)/dl and maintained between 100x10(3)/dl to 200x10(3)/dl after few weeks of starting Romiplostim therapy. PMID- 27493348 TI - Recurrent Kawasaki disease resistant to initial treatment with intravenous immunoglobulin. AB - Kawasaki disease (mucocutaneous lymph node syndrome) is a disease of unknown etiology characterized by vasculitis which may affect the coronary arteries. Young children are most commonly affected although the disease has been described in adults. Kawasaki disease (KD) was first described by Dr Tomisaku Kawasaki in 1967. Since then, more cases have been reported worldwide, the majority being from Japan. We report on a 6-year-old child with recurrent attacks of Kawasaki disease which was initially resistant to the conventional treatment. PMID- 27493349 TI - Meckel-Gruber syndrome: Antenatal diagnosis and ethical perspectives. AB - Meckel-Gruber syndrome (MGS) is an autosomal recessive disorder characterized by occipital encephalocele, polycystic kidneys and variable other congenital malformations. We report on a Sudanese patient with MGS diagnosed by antenatal ultrasound scan. Pregnancy was terminated at 25 weeks of gestation. PMID- 27493350 TI - Successful separation of craniopagus conjoined twins. AB - Craniopagus conjoined twins represent a rare phenom- enon of congenital malformation/ dysmorphism. The clinical pathology of this complex entity is reviewed and placed in perspective. Confusion surrounds the severity of craniopagus conjoined twins especially in relation to the difficulty of separation and subsequent outcome. Successful separation of craniopagus twins remains a rarity, however modern neurosurgical tech- niques have created opportunities for successful sepa- ration and brought hope for a normal survival of these children who in the past were often left as historical footnotes or put on display as oddities of nature. We report on a craniopagus conjoined twins from Sudan who had been successfully separated. PMID- 27493351 TI - Robert Archibald: A pioneer of tropical medicine in the Sudan: "I feel my heart is in that country and my work too" [] (Archibald, writing about being away from the Sudan during the First World War). PMID- 27493352 TI - Building civilization starts from childhood. PMID- 27493354 TI - Perinatal statistics of a 15-year period in the Central Region of Saudi Arabia. AB - Perinatal statistics are one of the most essential outcome indicators used by many developed countries in order to evaluate perinatal services provided to newborns. In this retrospective study, we collected 15 years of perinatal data at King Khalid University Hospital in Riyadh, Saudi Arabia in order to determine stillbirth and other mortality rates in our institute and compare them with international figures. A total of 58,073 babies were evaluated. Data were collected from maternal and neonatal registry books and from perinatal mortality and morbidity meeting reports between 1994 and 2008. Data were entered and analyzed using Microsoft Office Excel 2007. The stillbirth rate was 11.7/1000, early neonatal death rate was 3.4/1000, perinatal mortality rate (PMR) was 14.9/1000, and corrected PMR was 11.9/1000. Our rates were not significantly different from those of North American and European ones. We noticed a dramatic reduction in the corrected PMR in the last 3 years of the study because of greater advancement in perinatal and neonatal care. Our mortality rates were comparable to the North American and European rates which may reflect the quality of perinatal care provided in our institute. PMID- 27493353 TI - Surfactant therapy: the current practice and the future trends. AB - The efficacy of surfactant preparations used in the prevention and treatment of respiratory distress syndrome (RDS) is a well known fact; however, many controversies remain. The debate over which surfactant to be used, when and what is the best mode of delivery is still raging. Currently, animal-derived surfactants are preferred and clearly recommended by various practice guidelines, but new synthetic surfactants containing peptides that mimic the action of surfactant proteins are emerging and they seem to have a comparable efficacy profile to the natural surfactants. It is hoped that with further improvements, they will outperform their natural counterparts in terms of reliability and cost effectiveness. Early surfactant administration was shown to further reduce the risk of RDS and its complications. However, as nasal continuous positive airway pressure (nCPAP) is becoming increasingly the preferred first-line therapy for RDS, the less invasive approaches of respiratory support along with early selective surfactant administration (e.g. INSURE) appears to provide a better option. Although neonatal RDS is still the main indication of surfactant therapy, other pathological processes received considerable attention and major research has been dedicated to explore the role of surfactant in their management, Meconium aspiration syndrome (MAS) and congenital pneumonia are two worthy examples. The most updated practice guidelines do recommend the use of endotracheal instillation as the preferred mode of surfactant delivery. However, aerosolization and other non-invasive methods are being investigated with some success; nonetheless, further improvements are very much in need. PMID- 27493355 TI - Traditional and spiritual medicine among Sudanese children with epilepsy. AB - This cross sectional hospital based study, carried out simultaneously in Khartoum and in Wad Madani, Al Gezira State, aimed to study the impact of spiritual beliefs on explanation of the epilepsy etiology and the choices and methods of spiritual and traditional medicine used in the management of epilepsy in Sudan. The study included 180 care givers of whom 165 (91.7%) were mothers. Their ages ranged between 30-40 years. The majority (88.8%) were educated and 60 (33.3%) of them live in rural areas. Fifty eight (32.2%) attributed epilepsy to supernatural causes while 41 (22.8%) and 90 (50%) thought that epilepsy is an untreatable and contagious disorder, respectively. Traditional and spiritual medicine for the treatment of epilepsy was used by 70.5%. The common spiritual technique used was incantations (45.6%), spitting cure (37.2%) and ritual incensing (36.7%). Herbs, black cumin (Nigella sativa), honey and olive oil were mentioned among others as a traditional treatment for epilepsy. About two fifth (42.5%) started traditional or spiritual treatment before seeking any medical advice. Nevertheless, only 2.4% stopped the medical treatment as advised by the traditional healer. Fifty five (43.3%) thought that spiritual and/ or traditional treatment were effective in the management of epilepsy, 60(47.2%) found no difference while 12(9.45) got worse. The majority of patients with epilepsy, although on medical treatment, used traditional and spiritual methods as well. Traditional and spiritual healers may be involved positively in the management of epilepsy and extensive public educational programs are needed. PMID- 27493356 TI - State of personal hygiene among primary school children: A community based cohort study. AB - Good personal hygiene in primary school children could be effective towards preventing infectious diseases. This work examined personal cleanliness of primary school children in Banki based on the following variables: bathing, state of uniforms, hair, nails and oral hygiene. One hundred and fifty primary school children in Banki community were selected using the cluster random sampling method. Analysis of variance was used to compare means and to test for significance of data, and coefficient of correlation to investigate the relationship between cleanliness and age of subjects. There were 87 (58 %) boys and 63 (42 %) girls in a ratio of 1.4:1. Ninety six (64 %) pupils belong to low socioeconomic class. Whereas, 53 (35.3 %) were found within 11-13 years age group, the overall mean age was 9 years (Standard deviation [SD] was 2.2), 95 CI (7.0 - 11.0) years. Comparing means for the different categories of personal hygiene, there was significant difference (F= 61.47, p < 0.0001). General personal cleanliness in our participants improved with age, and a positive significant correlation was observed between age and personal cleanliness in (r = 0.971, p = 0.026). In conclusion, significant number of primary school pupils in Banki community had good personal hygiene, which was observed to be directly proportional with age. Therefore, all efforts towards quality health education on personal hygiene as a means of primary prevention of illnesses in primary school pupils should be sustained. PMID- 27493357 TI - Congenital neonatal chylothorax with hydrops fetalis treated with octreotide. AB - Congenital idiopathic chylothorax is the most common form of pleural effusion in neonates. It results from collection of lymphatic fluid in the pleural space secondary to leakage from the thoracic duct or one of its main tributaries. Chylothorax complicated by hydrops fetalis in a premature or term infant is an uncommon, serious clinical problem. We report on two cases with congenital chylothorax both treated with octreotide. One of the cases responded well to octreotide treatment, while the other did not. We conclude that octreotide should be considered in the treatment of neonatal chylothorax. PMID- 27493358 TI - Kasabach - Merritt syndrome: A case report. AB - Kasabach-Merritt syndrome is characterised by the combination of rapidly growing vascular tumour, thrombocytopenia, microangiopathic haemolytic anaemia and consumptive coagulopathy. The blood clotting disorder results from platelets and other clotting factors of the blood being used up within the tumor. We report a two- and- half month old Saudi female infant who presented with epistaxis, conjunctival haemorrage and bilateral periorbital ecchymosis. PMID- 27493359 TI - Marfan syndrome affecting a whole Sudanese family. AB - Marfan syndrome (MS, OMIM 154700) is an autosomal dominant disorder of fibrous connective tissue with striking pleiotropism and clinical variability. The cardinal features occur in skeletal, ocular, and cardiovascular systems. We describe a Sudanese family with the father and all his 4 children manifesting the syndrome. To our knowledge, there were no previously reported MS cases from Sudan. PMID- 27493360 TI - Pioneers of paediatrics: Professor Salah Abdelrahman Ali Taha, MD (U of K), DCH, PRCP (London), FRCP (Edin). AB - This article highlights the contributions of Professor Salah Abdelrahman Ali Taha (1927-1988), one of the pioneers in paediatrics in Sudan and Saudi Arabia. He graduated from Kitchener School of Medicine (renamed, Faculty of Medicine, University of Khartoum[U of K]) in 1952 and was awarded an MD from the U of K in 1973, having accomplished a survey on the prevalence and underlying causes of childhood malnutrition in 14 villages. His impact was remarkable in establishing child health services in Sudan and Saudi Arabia, and in laying the foundation of the Department of Pediatrics, College of Medicine, King Saud University. He was also an active researcher in various fields in child health, and was pioneering in those related to nutrition. Following his return to Sudan, Dr Salah A Taha was elected Member of Parliament from his rural district in Gezira State and was the Speaker of the House of Parliament in 1986. PMID- 27493361 TI - A pioneer of tropical medicine worldwide: Andrew Balfour, of Khartoum. AB - This is an archival account of the career of Sir Andrew Balfour in Khartoum, Sudan during the period 1902 to 1913. As the first director of the Wellcome Tropical Research Laboratories in Khartoum during the period, Andrew Balfour was tasked with establishing the laboratories and at the same time he was engaged in founding the health services in Khartoum. Balfour worked in close collaboration and support from Henry Wellcome and Reginald Wingate, the Governor General of the Sudan. The energetic and meticulous sanitary work of Balfour had a remarkable impact, with Khartoum declared mosquito-free by 1910. Establishing a research base in the laboratories was met with many challenges but eventually Balfour managed to recruit a team of dedicated researchers and to produce well-circulated publications in tropical medicine. Balfour's work in Khartoum later lead him to a distinguished career in tropical medicine. In 1923 he was appointed the first Director of London School of Hygiene and Tropical Medicine. He was also elected President of the Royal Society of Tropical Medicine and Hygiene (1925-27). Sir Andrew Balfour, KCMG, CB, LL D (1873 -1931). PMID- 27493362 TI - Professor Tigani El Mahi: Short biography and photos. PMID- 27493363 TI - First Tigani El Mahi Memorial Lecture. PMID- 27493364 TI - Food customs and cultural taboos. PMID- 27493365 TI - Family and child welfare in relation to urbanization. PMID- 27493366 TI - Report on a visit to Saudi Arabia. PMID- 27493367 TI - Biomedical Research: Child health and nation's health. PMID- 27493368 TI - Radiological imaging of disorders of sex development (DSD). AB - The birth of a child with ambiguous genitalia is a matter of a medical and social emergency to decide the appropriate sex rearing and eventually to prevent the associated metabolic disturbances. It must be taken with immediacy and great sensitivity. The pediatric endocrinologist should share the care with a team consists of a pediatric urologist, or surgeon, a pediatric radiologist, geneticist and a child psychiatrist or psychologist who should work closely with the family. Ultrasonograpy is the primary modality for demonstrating internal organs while genitography is used to assess the uterus, vagina, and any fistulas or complex tracts. Magnetic resonance imaging (MRI) is used as an adjunct modality to assess the internal gonads and genitalia. Early and appropriate gender assignment is necessary for healthy physical and psychological development of children with ambiguous genitalia. PMID- 27493369 TI - Type 2 diabetes in Sudanese children and adolescents. AB - The objective of this study was to determine the prevalence of T2 DM among children and adolescents attending a paediatric and adolescent diabetic clinic in Khartoum -Sudan and to find out the etiological factors, clinical presentation, management and associated co morbidities. This was a retrospective, descriptive hospital based study. The records of all children attending the clinic at Jabir Abu Izz Diabetic Center from January 2006 to December 2009 were reviewed and those who were diagnosed as type 2 DM were identified. Out of 985 patients 38 (4%) were labeled as having type 2 DM. Out of these, 35 (92.1%) had onset between 11-18 years of age and were all pubertal. Three patients (7.9%) were under 10. Female to male ratio was 1.2: 1. Thirty two (84.2%) were from tribes of Arab origin. There were no cases from tribes of southern Sudan of African origin. Risk factors for obesity included: diabetes during pregnancy 15 (39.5%), large for dates 16 (43%) small for dates 12(32%), family history of obesity 10 (26.3%), lack of exercise 32 (87.6%), TV watching for long hours 32(84.3%) and consumption of fast foods. Almost 70% were symptomatic at presentation. Co morbidities included hypertension 22(57.9%), microalbuminuria 7 (18.4%), hyperlipidaemia 6(7%) and none had retinopathy. The mean HbA1C was 9.1% gm/dl. This data confirms that T2 DM is emerging as a health problem among children and adolescents in Sudan mostly as a result of obesity particularly among high socioeconomic group in urban areas and more prevalent in certain ethnic groups. PMID- 27493370 TI - Diabetic Ketoacidosis in children admitted to Pediatric Intensive Care Unit of King Fahad Hospital, Al-Baha, Saudi Arabia: Precipitating factors, epidemiological parameters and clinical presentation. AB - Type I diabetes mellitus is the most common endocrine-metabolic disorder of childhood and adolescence and diabetic ketoacidosis (DKA) can be life threatening. The study aims at identifying precipitating factors, states epidemiological features and describes clinical presentations in children with DKA admitted to Pediatric Intensive Care Unit (PICU), King Fahad Hospital, Al Baha, Saudi Arabia. The hospital records of 80 children admitted to PICU with DKA between January 2000 and December 2004 were reviewed. Results were compared with published data from Saudi Arabia and other countries. Age at admission ranged between 8 months and 14 years (mean = 10.7 years). Female to male ratio was 1.22:1. Consanguinity was reported among 32(40%) of all admitted children's parents. A family history of diabetes (either type 1 or 2) was reported in 59 (74%). The leading precipitating factor for DKA was infections (82.1%). An episode of DKA was the first clinical presentation of diabetes among 52(65%). The common presenting symptoms were: vomiting in 57(71.3%) and abdominal pain in 53 (66.3%). All children were dehydrated. Other signs included acidotic breathing and tachypnea each in 60%. Only two children were comatose (2.5%). Three of presenting cases were initially misdiagnosed as acute appendicitis before correct diagnosis was established. Cerebral edema occurred in one child. There were no deaths. DKA is an important cause of hospital admissions in our hospital, and 65% of newly diagnosed cases present with DKA. More effort should be put to prevent and reduce the incidence of DKA at initial presentation and later. PMID- 27493371 TI - The pattern of anthropometric measurements among term newborn infants in Khartoum state in relation to maternal factors. AB - Anthropometric measurements of neonates are an important clinical tool for diagnosis of abnormally small or large neonates. This study aimed at finding the means of the anthropometric measurements among newborn babies in Khartoum state and to relate the tendency of the anthropometric parameters to maternal and paternal factors. This observational hospital-based study was carried out in 3 hospitals in Khartoum. Birth weights, crown-heel length and head circumference were taken from term neonates and questionnaire-based interviews were conducted with the mothers. Means of the sample and their associations with maternal and paternal factors were calculated using SPSS. In addition, the means were compared to WHO- MGRS (World health organization-multi growth reference standards). It was found that the average male newborn weighed 3.16kg with a range of 2.4kg to 4.1kg, measured 48.91cm in length with a range of 46.1cm to 51.4cm and measured 34.74cm in head circumference with a range of 32.3cm to 36.9cm. As for the females, the average newborn weighed 3.11kg with a range of 2.1kg to 4.2kg, measured 48.49cm in length with a range of 45.1cm to 51.7cm and measured 34.16cm in head circumference with a range of 32.3 to 36.4. These values were found to be statistically significant when compared with the WHO- MGR. We conclude that there was a difference observed in relation to Sudanese neonate's anthropometric parameters compared to WHO-MGR standards. Growth charts specific for Sudanese neonates are urgently needed. PMID- 27493372 TI - Early outcome of pre-term neonates delivered at Soba University Hospital. AB - In Sudan, several studies have been conducted on low birth weight, a few concentrated on pre-term births per se. The objectives of this study were to describe maternal and obstetric factors predisposing to pre-term delivery, to determine the incidence of early neonatal complications, to identify causes of early neonatal deaths and to determine survival rates relative to gestational age and birth weight. A descriptive hospital-based study was conducted at Soba University Hospital, over a seven months-period, from December 2003 to June 2004. One hundred consecutively born premature infants were followed up from the moment of delivery till the end of the first week of life. Chi squared tests and p values, using confidence intervals of 95%, were used for analysis. Eighty four mothers gave birth to 100 premature babies who were admitted to the Neonatal Unit of Soba University Hospital. Pregnancy induced hypertension (38.1%), multiple pregnancy ( 29%) and maternal infection ( 42.9%) were the main obstetric factors predisposing to premature birth. Morbidity among the pre-term birth population showed that respiratory distress syndrome was the main disease accounting for 36% and 46.2% of the deaths, respectively. Neonatal jaundice, apnoea, and neonatal infection occurred in 46%, 16% and 14% of the premature infants, respectively. However, respiratory distress syndrome and apnoea have been strongly associated with early neonatal mortality (P<0.05). A survival rate for the whole premature infant study was 74% and survival rates increased with increasing gestational age and increasing birth weight. PMID- 27493373 TI - Cigarette smoking among medical students in The National Ribat University, Sudan. AB - The problem of smoking among medical students is common worldwide, but the pattern and extent of the problem varies from place to place. Data from Sudanese medical students is limited. The aims of study was to know the extent of the problem of smoking among medical students, its routes and how it can be reduced. All students in the first and fifth year in the Faculty of Medicine, The National Ribat University were asked to fill a questionnaire regarding their knowledge and practice of smoking and when they started smoking. The questionnaire inquired about the role of their peers and the staff to help them stop smoking. Two hundred and forty (96%) of the first year students and 174 (94 %) of the fifth year students responded by filling the questionnaires. Around 10 % of all students smoke. Although non-smokers knew much about the problems of smoking, many of the smokers did not. The main influence on students to start smoking was from parents, siblings and friends. Eighty per cent of the smokers are willing to give up smoking and they tried many times. The study showed that little effort was made by the University Staff to help students stop smoking. Most students started smoking in the high secondary schools. There is a need for family community and institutional campaign to contain the problem of smoking. PMID- 27493374 TI - An in vitro anticoagulant effect of Fenugreek (Trigonella foenum-graecum) in blood samples of normal Sudanese individuals. AB - Haemostasis is the process of forming clots in the walls of damaged blood vessels to prevent abnormal bleeding and to maintain intravascular blood in a fluid state. Fenugreek is largely universal staple herb, popular throughout history and it has been consumed for treatment of different disorders. We aimed to study the possible anticoagulant effect of Fenugreek aqueous extract in vitro by using blood samples of normal individuals. In vitro anticoagulant effects of Fenugreek aqueous extract (5%) in different volumes (25, 50 and 75 MUL) were examined in the blood samples of normal individuals by measuring prothrombin time (PT). The aqueous extract of Fenugreek was found to inhibit coagulation process in vitro and significantly prolonged prothrombin time in a dose-dependent manner. Fenugreek aqueous extract in different concentrations inhibits clot formation and increases prothrombin time. Subject to further studies on efficacy and safety, It can well be used, in the future, as a supplementary anticoagulant agent in cardiovascular diseases and to prevent hypercoagulable states. PMID- 27493375 TI - Congenital cystic adenamatoid malformation: A case report. AB - We here report a rare case of congenital cystic adenamatoid malformation[CCAM]. This case presented early in the neonatal period with bilateral lung cysts and have favorable outcome. However, the patient continued to be oxygen dependent for more than six weeks. PMID- 27493376 TI - Dandy-Walker malformation and neurocutaneous melanosis in a three-month-old infant. AB - Dandy-Walker Malformation (DWM) is a rare congenital malformation of the brain. It is characterized by cystic enlargement of the fourth ventricle which is communicating with an enlarged posterior fossa, cerebellar dysgenesis, high tentorial insertion and hydrocephalus. Neurocutaneous Melanosis (NCM) is a congenital neurocutaneous syndrome characterized by large or multiple melanocytic nevi and benign or malignant melanocytic tumors of the leptomeninges. We report three months old boy who presented with projectile vomiting associated with a noticeable increase in head size. Several congenital nevi were seen all over his body with evident signs of hydrocephalus. The association of DWM and NCM is a rare complex, and to our knowledge, this is the eleventh case to be reported in the literature. In this article, we discuss the proposed pathogenesis, classification and management of the condition. PMID- 27493377 TI - Professor Mansour Ali Haseeb: Highlights from a pioneer of biomedical research, physician and scientist. AB - The article highlights the career of Professor Mansour Ali Haseeb (1910 - 1973; DKSM, Dip Bact, FRCPath, FRCP [Lond]), a pioneer worker in health, medical services, biomedical research and medical education in the Sudan. After his graduation from the Kitchener School of Medicine (renamed, Faculty of Medicine, University of Khartoum [U of K]) in 1934, he devoted his life for the development of laboratory medicine. He became the first Sudanese Director of Stack Medical Research Laboratories (1952 - 1962). He made valuable contributions by his services in the vaccine production and implementation programs, most notably in combating small pox, rabies and epidemic meningitis. In 1963 he became the first Sudanese Professor of Microbiology and Parasitology and served as the first Sudanese Dean of the Faculty of Medicine, U of K (1963-1969). He was an active loyal citizen in public life and served in various fields outside the medical profession. As Mayor of Omdurman, he was invited to visit Berlin in 1963 by Willy Brandt, Mayor of West Berlin (1957-1966) and Chancellor of the Federal Republic of Germany (1969 to 1974). Also as Mayor of Omdurman, he represented the City in welcoming Queen Elizabeth II during her visit to Sudan in February 1965. He also received State Medals from Egypt and Ethiopia. In 1973 he was appointed Chairman of the Sudan Medical Research Council, and was awarded the international Dr. Shousha Foundation Prize and Medal by the WHO for his contribution in the advancement of health, research and medical services. PMID- 27493378 TI - Remembering for tomorrow: Professor Mansour Ali Haseeb. AB - This is a highlight of the obituary ceremony in tribute to Professor Mansour Ali Haseeb (1910 - 1973), organized by the Medical Students Association of the Faculty of Medicine, the University of Khartoum (U of K). Professor Haseeb has been the first Sudanese Professor and first Dean of the Faculty of Medicine. He was an outstanding humane teacher, mentor and researcher, and was awarded the international Dr. Shousha Foundation Prize and Medal by the WHO. He was also an active citizen in public life and became Mayor of Omdurman City. The obituary ceremony reflected the feelings of the medical community and included speeches by Professor Abdalla El Tayeb, President of U of K; the Dean, Faculty of Medicine; the Late Professor Haseeb's colleagues and students, His family representative, and an elegy poem. PMID- 27493379 TI - Henry Solomon Wellcome: A philanthropist and a pioneer sponsor of medical research in the Sudan. AB - Henry Solomon Wellcome, the famous drug manufacturer had a fascinating association with the Sudan. Besides supporting tropical medicine research in this country, he established an extensive project in the Sudan that aimed at combining archeological excavations, philanthropy and social reform. This article is an archives-based account on this side of Wellcome's association with the Sudan. The article starts with Wellcome's early years in the American Midwest and the evolution of his career and his rise as a world-renowned drug manufacturer. After the battle of Omdurman, Wellcome visited Sudan in 1900 - 1901 where he offered to support the establishment of the research laboratories which later came to be known as the Wellcome Tropical Research Laboratories in Khartoum. He then became directly involved in the planning and running of extensive archeological excavations in the central Sudan. This project served as a field in which Wellcome found an outlet for his philanthropy. More than 4000 labourers were employed in Jebel Moya. Professional archeologists and anatomists were recruited by Wellcome to supervise the work, and all the requirements in terms of equipment were catered for. Wellcome devised a Savings Bank System whereby part of the earnings of each labourer were saved to him till the end of the season. He also introduced one of his innovations: aerial photography using box kite which was used for the first time in archeology. Wellcome made it a rule that no applicant should be turned away. The Camp Commandant had to find suitable work for each applicant, including the handicapped who were assigned to appropriate jobs like mending baskets or cutting grass for building huts. Wellcome's welfare work had a significant impact on the local inhabitants of Jebel Moya. Henry Solomon Wellcome, 1906. Oil painting by Hugh Goldwin Riviere. Credit: Wellcome Library. PMID- 27493380 TI - An outline of the history of Medical Research Institutes in the Sudan. PMID- 27493381 TI - Historical background and epidemiology of cerebrospinal meningitis (CSM). PMID- 27493382 TI - Higher Degrees on Medical and Related Subjects. PMID- 27493383 TI - Professionalism in medicine and hyposkillia. PMID- 27493384 TI - Hyposkillia: A sign of sagging medical profession-A pediatric perspective. AB - The practice of medicine since Hippocrates, the father of medicine (460-377 BC) had the care of the patient in the core of its ideals which included scholarship; confidentiality, altruism and no harm doing. These ideals evolved from individual physician adoption to professional organization adoption. The medical profession used to have autonomy, prestige, and values centered on patient care. With societal changing values and the appearance of managed care and bioethics the medical profession lost its autonomy, prestige and self regulation. This led to widespread dissatisfaction among the profession members and reflected in deficiency in education and training of medical students and young physicians and resulted in deficiency of clinical skills required to deliver health care. This situation has been referred to as hyposkillia. This sagging has been reported in many countries worldwide and brought concern to many medical education authorities and societies. In this paper nine cases are reported to demonstrate that hyposkillia is also prevalent in our part of the world and show some deficiencies in the clinical skills that are avoidable. Inadequacies in: accurate history taking, complete appropriate physical examination, pertinent investigation and sound critical reasoning in management planning, all precluded optimum health care delivery initially in these cases. Many professional and education authorities have suggested that the process of redemption of the medical profession should start before admission to medical school by change in admission requirements to include behavioral and social sciences, and that the curricula in the medical schools should be redesigned to meet the changing societal values and priorities. Teaching clinical skills should be a continuous lifelong learning process from the medical school through training and into practice. Modern technology is to complement and not to replace bedside teaching and the patient should remain the best teacher for the physician. PMID- 27493385 TI - The control of rheumatic fever and rheumatic heart disease: a call to raise the awareness. AB - Although the incidence of rheumatic fever (RF) and rheumatic heart disease (RHD) has declined in the developed world and many developing countries, yet it is still high in many countries including Sudan. The decline of frequency of RF in these countries is largely due to improved medical services leading to wide use of antibiotics to treat bacterial pharyngitis. In many developing countries, the incidence is decreased due to development of integrated control programs. Depending on secondary prophylaxis alone was shown to be ineffective, therefore, many countries, including Sudan initiated control programs that utilize both primary and secondary prevention together with increasing awareness and surveillance. The new program started in 2012 in Sudan in order to achieve its goal of reducing mortality of RHD by 25% in individual less than 25 years of age by year 2025. This article throws light on RF and RHD and its control program in Sudan. PMID- 27493386 TI - Patent ductus arteriosus in preterm infant: Basic pathology and when to treat. AB - The incidence of patent ductus arteriosus (PDA) in premature neonates varies according to the gestational age and respiratory status. Failure of PDA closure in preterm infants with respiratory distress syndrome results in a left to right shunt across the duct which may lead to pulmonary congestion and deterioration in respiratory status. Although indomethacin and ibuprofen are the main stay of medical treatment, conservative approach by restricted fluid and applying continuous positive airway pressure (CPAP) may be effective in prevention of PDA without complication. The daily clinical round debate on how to diagnose, when, and how to treat PDA in preterm neonates will be discussed with details in this review. PMID- 27493387 TI - Teaching professionalism in medicine: what, why and how? AB - The increased attention that "medical professionalism" has received lately exposes the deficit in our educational system and indicates the need for more work to be done to ensure an effective teaching and assessment of this competency. The concerted efforts made by many reputable organizations are great steps in the right direction. Nonetheless, many medical schools are still lagging behind. Literature has been clear about the importance of formal teaching in establishing professional behaviors in the medical school graduates; failing in this regard is certain to have unfavorable outcomes. Furthermore, current literature suggests many teaching strategies and assessment tools that can help in achieving this goal. However, many inadequacies are still there. Teaching professionalism requires, in addition to an explicit core curriculum that spans the continuum of medical education, special efforts in terms of imparting the non cognitive skills as well. Respectable role-models play a major part in this process. Helping students to reflect on the real life encounters in a safe environment is, probably, one of the most effective tools at our disposal. Many obstacles that may hinder this educational endeavor have been described in the literature. Negative role models and the "hidden curriculum" are among the most dreaded ones and they deserve an extra effort to overcome. PMID- 27493388 TI - Cystic fibrosis in Sudanese children: First report of 35 cases. AB - Cystic fibrosis is the most common severe genetic disorder among children of European descent. It is much less common in Africans and Asians. It affects most critically the lungs causing chronic lung disease, failure to thrive and social deprivation. This is a retrospective review of 35 Sudanese patients with confirmed cystic fibrosis. About 60% of cases presented before the age of 5 years and male to female ratio was 1.7:1.0. Consanguinity was reported in 25 of the families. The main presenting features were productive cough, wheeze and clubbing. The chest X-ray showed variable degrees of hyperinflation, collapse, cystic, fibrotic changes and bronchiectasis involving both upper and lower lobes with blurring of cardiac border and hilar vasculature in the majority of cases. The sweat chloride was between 70 and 140 mmol/l in 83% of the patients (positive > 60 mmol/l). Three patients underwent DNA study and confirmed to have cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. Gene study was not available for the rest of the patients. To our knowledge this is the first report of confirmed cases of cystic fibrosis in Sudanese patients. PMID- 27493389 TI - Vitamin A-rich porridge for Boarding Khalwa students with night blindness. AB - Khalwa is a non-governmental boarding school specialized in teaching Quran to Sudanese children. Food supply to Khalwa is completely dependent on donations. Students are fed on low cost and low nutritional value diet made of sorghum flour porridge and a stew made of dry okra, onion and oil. The incidence of night blindness among these students is reported by the Nutrition Department of the Federal Ministry of Health, Sudan, in 2005 as 0.9%. In this study we interviewed and examined 453 Khalwa students in Umbada area, however blood sampling for assay of vitamin A level was not acceptable by the Khalwa authorities. Thirty four students (7.5%) showed clinical evidence of Vitamin A Deficiency (VAD), 67.6% of them for a period of less than 6 months which was consistent with their stay in Khalwa. Vitamin A fortified sugar is used in Kenya, Zambia, South Africa and Honduras but it is costly and sugar-containing foods and drinks are not in common use by Khalwa students. To supply students with a good amount of vitamin A, we prepared a new porridge formed of sorghum flour; peeled, chopped and boiled pumpkins in addition to their traditional stew. One meal per student contained 250 grams of sorghum flour and 125 grams of pumpkin which supplies 611MUg (10891 I.U.) of vitamin A according to the USDA SR-25 composition tables (>100% Daily Value). Compared to the old porridge, there was significant differences (P <0.05) in vitamin A, carbohydrate, protein, fiber, fat, ash and moisture contents. All students accepted the taste of the new porridge and 91.2% agreed that it is not difficult to prepare. We conclude that adding pumpkins to Khalwa porridge is cost effective and may help preventing VAD and its deleterious effects on vision and health. PMID- 27493390 TI - The quality of life among Sudanese children with epilepsy and their care givers. AB - In the past few years, there has been a progressive increase in appreciation of the importance of quality of life (QOL) especially among patients with epilepsy. This issue had not been addressed in Sudanese children with epilepsy. We here aim to assess the quality of life in Sudanese children with epilepsy and their family care giver. This study was conducted in 2011 at the Epilepsy and Neurodisablity Out-patient Clinic at Saad Abualila University Hospital, Sudan. The study included 100 Children with epilepsy, and their care givers, whose age was between 6-18 years and had seizure for more than one year. The questionnaire used contains 27 questions; it was divided into four sections: impact of epilepsy and treatment, impact on the child development, impact on parents and impact on the family. For each question there were two dimensions: the frequency of the problem and the concerns that it causes. The total score ranges from 0 to 54. A combined total scale scores were calculated. The commonest concern regarding epilepsy was that the child may injure oneself, followed by that the child may stop breathing or develop brain damage or even die. The commonest concern regarding treatment was that medication may cause reduced alertness. The relevant mean scores in frequency and concern were 5.77 and 5.83 out of 10 respectively. In the child development domain, the commonest concern was that the child may become more moody and the related mean scores in frequency and concern were 9.36 and 9.32 out of 18. The commonest concern to parent was decreased ability for self care with relevant mean scores in frequency and concern of 3.14 and 3.16 out of 10. The commonest concern to the family was that the child needs to be more closely watched than other children. The mean scores here in frequency and concern were 5.37 and 5.44 out of 14. The group with epilepsy and associated co morbidities, longer seizure and treatment duration had consistently higher mean scores which were proved to significantly lower their QOL. There is a significant decline in the quality of life among Sudanese children with epilepsy and their family care giver. Psychosocial consultation, family support programs and health education for parent, teachers and publics about different aspects of epilepsy need to be addressed through mass media. PMID- 27493391 TI - Physical methods used by Sudanese mothers in rural settings to manage a child with fever. AB - Although the mainstays of antipyretic treatments are drugs such as paracetamol and ibuprofen, physical methods are also used. These include tepid sponging, removing clothes, and cooling the environment with fans to improve ventilation. The objective of this study is to assess the physical methods used by Sudanese rural mothers to manage a child with fever. A cross-sectional descriptive study was designed and conducted within 6 months; it involved 332 mothers of children under five. The data were collected through using a standardized administered questionnaire and focus group discussion and analyzed by statistical package for social science version 15.0 (SPSS). Tepid sponging was used by 47% of the interviewed mothers. 15% of the mothers increased fluid intake, 7% bathed the child and 5% put the child in light clothes. 59% of mothers applied tepid sponging on head, 33.9% on all the body, 3.7% and 2.2% on groin area and axilla, respectively. The majority of mothers (86%) used water from refrigerator or zeir [water clay pot] for applying tepid sponging, 9% used tap water, and 3% used ice water. In conclusion, this study revealed that the common physical treatment method for fever used by mothers was tepid sponging with inappropriate application. PMID- 27493392 TI - Neonatal respiratory distress in Omdurman Maternity Hospital, Sudan. AB - Neonatal respiratory distress (NRD) is a common neonatal problem, which is responsible for high morbidity and mortality. There are few published studies in developing countries addressing neonatal respiratory distress. There is no previously published study in Sudan on this problem. The objective of the study is to determine the frequency, different causes, immediate outcome. It was a prospective, descriptive, cross sectional hospital-based study which was carried out in neonatal intensive care unit (NICU) of Omdurman Maternity Hospital, between February-March 2013. The study enrolled all Sudanese newborns from 0-28 days including normal, low and high birth weight of different gestational ages admitted to the neonatal intensive care unit and diagnosed as neonatal respiratory distress. The frequency of NRD was calculated, the causes and immediate outcome were determined. Results showed that the frequency rate of NRD was (4.83%) among the total number of hospital (2071) live births during the period of the study. The commonest causes were transient tachypnoea of the newborn (TTN) in 28% of cases, sepsis in 24% of cases and hyaline membrane disease (HMD) in 15% of cases. The outcome of NRD was: cure in 56% of cases, death in 36% of cases, and patients discharged with complications in 8% of cases. In conclusion, the study confirmed the importance of NRD with a frequency rate of 4.83%, morbidity of 8% and mortality of 36% of cases. The causes and immediate outcome were determined and discussed. Some recommendations were suggested in order to reduce its frequency, morbidity and mortality. PMID- 27493393 TI - Fast food intake and prevalence of obesity in school children in Riyadh City. AB - Childhood obesity has become a new challenge for healthcare providers. The issue is not limited to certain parts of the world; its prevalence is increasing worldwide. The causes of obesity are poorly understood and continue to be debated and studied. It is a multifactorial disorder which involves dietary, behavioral, environmental as well as genetic factors. The increased consumption of more energy-dense, nutrient-poor foods with high levels of sugar and saturated fats, combined with reduced physical activity, have led to high obesity rates among children. The aim of this study was to assess the effect of dietary intake on the occurrence of childhood obesity, and study other associated factors including the education, occupation and income of parents and the living status. Normal healthy school girls (n =196) and school boys (n = 85) between the age of 6- 15 were recruited for the study. We found that obesity among children in Riyadh City was significantly associated with fast food intake (p = 0.0280). It was also observed that 72.5% of the overweight or obese students consumed fast food at least 4 times/week, and the other 15.9% were taking fast food 1- 3 times/week, while only 11.6% of the same overweight or obese group did not consume any fast food/ week. Father's and mother's occupations were not significantly correlated to their children's body weight. The prevalence of childhood obesity is changing and increasing yearly and is attributed to the nutritional risk factors for the Saudi school-age children. It is interesting to know that most of overweight or obese school students belonged to the families of highincome. Parents must take necessary precautions for the diet of their children and should adopt healthy life style in order to prevent or manage obesity of their children. PMID- 27493394 TI - Crimean-Congo hemorrhagic fever (CCHF) in Southern Kordofan. AB - Crimean-Congo hemorrhagic fever (CCHF) is a disease that poses a great threat to public health owing to its high mortality rate (30-70%), mode of transmission and geographic distribution. Here, we report on a nine years-old Sudanese boy from Southern Kordofan State who presented with Jaundice, high-grade fever, severe headache, abdominal pain and a history of hematemesis. The diagnosis of CCHF was confirmed based on clinical and serological findings. PMID- 27493395 TI - Pentalogy of Cantrell: case report and review of the literature. AB - Pentalogy of Cantrell is a syndrome that consists of five anomalies: a midline, upper abdominal wall abnormality; lower sternal defect; anterior diaphragmatic defect; diaphragmatic pericardial defect, and congenital abnormalities of the heart. The pathogenesis of this condition is not fully known yet, associations are common with this condition and treatment is extremely challenging. Prognosis and outcome depends on the type of the pentalogy of Cantrell and associated cardiac anomalies. It can be diagnosed reliably by antenatal ultrasound during the first trimester. We describe a Sudanese baby of undetermined sex who had the typical features of pentalogy of Cantrell and died shortly after birth. PMID- 27493396 TI - Managing traumatic brain injury in children: When do we need a computed tomography of the head? AB - Accidents still represent a major cause of death and disability in children. The resultant traumatic brain injury (TBI) usually needs a multidisciplinary approach of management. Although computed tomographic (CT) head scan is generally a preferred investigation in TBI, however, clear guidelines are required to help decision making by different team members on "when a head CT scan is needed", its limitations, and "when it is likely to be informative". The answers to these queries are highlighted, in the present article, with other aspects of treatment of children with TBI. This article discusses different worldwide-accepted approaches for managing children with TBI, and places special emphasis on the issue of "indications for a head CT scan". PMID- 27493397 TI - Albert Chalmers: Perpetual honours for a prominent tropical medicine career in the Sudan. AB - This article starts with brief review of Albert Chalmers' early career in tropical medicine until he was appointed Director of the Wellcome Tropical Research Laboratories in Khartoum (WTRLK) in 1913, succeeding Andrew Balfour. Then the article explores how Chalmers faced the challenges and managed to establish a solid research base under very harsh conditions. Most of his directorship was during the First World War, with shortage of staff and increased routine work load. In spite of these constraints, Chalmers managed to establish a base for research in tropical medicine in WTRK. Chalmers' research concentrated on the taxonomy and pathogenicity of bacteria and fungi but he also worked on miscellaneous dermatological disorders and on sleeping sickness. His papers reflect a wide range of knowledge and deep understanding of the topics he was covering. His work on the classification of pathogenic fungi was widely recognized. He tried different preparations of vaccines for cerebrospinal meningitis but with the technology available at the time he could not produce a potent vaccine. Chalmers' papers reflect the tremendous effort exerted in their production. Chamers resigned from WTRLK in 1920 and died of acute infective jaundice in the same year. In 1921 his widow, gave L500 to the Royal Society of Tropical Medicine and Hygiene (RSTMH) in memory of her husband. The RSTMH Council decided to devote this money to the foundation of the Chalmers Memorial Medal. PMID- 27493398 TI - Remembering the first doctors worldwide who offered their lives fighting Ebola virus epidemic. PMID- 27493399 TI - Health care professional development: Working as a team to improve patient care. AB - In delivering health care, an effective teamwork can immediately and positively affect patient safety and outcome. The need for effective teams is increasing due to increasing co-morbidities and increasing complexity of specialization of care. Time has gone when a doctor or a dentist or any other health practitioner in whatsoever health organization would be able to solely deliver a quality care that satisfies his or her patients. The evolution in health care and a global demand for quality patient care necessitate a parallel health care professional development with a great focus on patient centred teamwork approach. This can only be achieved by placing the patient in the centre of care and through sharing a wide based culture of values and principles. This will help forming and developing an effective team able to deliver exceptional care to the patients. Aiming towards this goal, motivation of team members should be backed by strategies and practical skills in order to achieve goals and overcome challenges. This article highlights values and principles of working as a team and principles and provides team players with a practical approach to deliver quality patient care. PMID- 27493400 TI - The prevalence and risk factors of retinopathy of prematurity among preterm babies admitted to Soba Neonatal Intensive Care Unit. AB - This is a prospective hospital based study conducted in Soba University Hospital (SUH), Neonatal Intensive Care Unit (NICU) between January 2012 and January 2013, to determine the prevalence and risk factors of retinopathy of prematurity (ROP) among preterm babies admitted to Soba NICU and to assess the outcome of those babies. Ninety-two neonates with gestational age less than 34 weeks at birth were included in the study. Thirty-three of them were males and 59 were females. All of them were admitted to the NICU due to prematurity. Data was collected in a structured questionnaire. Thirty-four infants (37%) developed ROP in one or both eyes; 12 (35.3%) of them developed stage 3 and underwent laser therapy, 2 of them had aggressive posterior form, which was treated with Evastin injection. Seven (20.3%) neonates diagnosed as stage 2, and 13 (37.7%) had stage 1. Statistically, there were significant relationships between ROP and gestational age, birth weight (BW), oxygen therapy, sepsis, and blood transfusion (p=0.000). No significant relationship was found between the occurrence of ROP and sex of the baby, respiratory distress syndrome (RDS), hyperbilirubineamia, intraventricular haemorrage (IVH) and necrotizing enterocolitis (NEC), p >0.000 in all of them. The prevalence of ROP in this study was 37%. Low BW, low gestational age, oxygen therapy, and blood transfusion were all significant risk factors for ROP. ROP should be highlighted in Sudan, and screening program should be recommended for all premature babies. PMID- 27493401 TI - Risk factors of low birth weight at three hospitals in Khartoum State, Sudan. AB - The aim of this study was to determine the percentage of women who give birth to low birth weight (LBW) children and to study the association of the different risk factors with LBW in three of large hospitals in Khartoum State, Sudan. This was a cross sectional study of 381 women. Three groups: 151, 130 and 100 women, who gave birth to live children, were selected from Alsuadi Teaching Hospital, Khartoum Teaching Hospital and Alribat University Hospital, respectively. Data were collected through structured interviews and the birth weights were recorded as measured by midwives. Uni-Multi variate analysis of the data was performed using SPSS 19. Permissions were taken from hospital administration and the participants before the conduction of the research. 13% of live born children were of low birth weight. The main risk factors for low birth weight in the study were the lack of adequate education (OR= 1.9) gestational age (OR= 5.5), type of pregnancy (OR= 9.6), presence of hypertension (OR= 3.6), renal disease (OR= 2.1), bleeding during pregnancy (OR= 6.1) and presence of moderate or severe anemia (OR= 3.19). While Adequacy of antenatal care (ANC) visits, presence of diabetes mellitus during pregnancy, smoking and malaria in the first three trimesters, presence of previous children and spacing were all found to be statistically not significant risk factors. Many of the risk factors are modifiable and can be prevented by improvement of the health care during pregnancy. PMID- 27493402 TI - Acute kidney injury in asphyxiated neonates admitted to a tertiary neonatal unit in Sudan. AB - Acute kidney injury (AKI) is a recognized complication of birth asphyxia. Early recognition of AKI is important in asphyxiated neonates as it helps in early intervention and appropriate management. The aim of this study was to determine the pattern of AKI in asphyxiated neonates and its relation to the grade of Hypoxic Ischemic Encephalopathy (HIE). This was a prospective hospital based study, conducted in the neonatal intensive care unit (NICU) at Gafaar Ibn Auf Children's Specialized Hospital during the period between January 2013 and December 2013. A total of 85 full term asphyxiated neonates who were admitted in NICU and diagnosed as HIE were enrolled in this study. with 50 (58.8%) less than 7 days of age, 31(36.5%) between (8-15) days and 4(4.7%) between (16-28) days. Males were found to be more affected than females (58.9% and 41.1%) respectively. Spontaneous vaginal delivery was the mode of delivery in 48(56.4%), assisted vaginal delivery in 14(16.5%), emergency caesarian in 19(22.4%) and elective caesarian section in. Percentage of AKI in those babies was 54.1%(46). With 30(65%) from those had non-oliguric type. Ten babies (21.7%) had serum creatinine between (1.5 - 2mg/dl), 29 (63.04%) between (2 - 3mg/dl) and 7(15.22%) between (3 4mg/ dl). This means that the majority of patients presented in injury stage. Hyperkalemia was found in (37.6%), hyponatremia in (27.1%) and hypocalceamia in (25.8%). Most of the babies with AKI had stage (ii) HIE. All babies were treated conservatively and 4(8.6%) died. In conclusion AKI was observed to be a common complication in asphyxiated neonates. PMID- 27493403 TI - The use of vital signs as predictors for serious bacterial infections in children with acute febrile illness in a pediatric emergency setting in Sudan. AB - Distinguishing children with serious infections from those with milder, self limiting febrile illnesses remains a daily challenge in primary care and hospital emergency department. Measurement of vital signs is recommended as part of this assessment. To determine whether vital signs can predict children with serious bacterial infections, we studied the data of children aged 1 month to < 16 years presented who with acute febrile illness to a Pediatric emergency department in Sudan. Sample size was 150 patients. The severity of infection was classified as serious or not serious bacterial infection. Vital signs and oxygen saturation were recorded and compared to the final outcome of these children. Data analyzed bivariably and multivariably using regression analysis. Ten percent of patients were classified as having serious bacterial infection. Tachycardia and tachypnea were the most sensitive and specific in predicting serious bacterial infections with (80%, 86.6 % sensitivity) and (97.4%, 83.7% specificity), respectively. High temperature, severe hypoxemia and hypotension were the least sensitive but highly specific signs of serious bacterial infections. As a conclusion, vital signs can be used to differentiate children with serious bacterial infections from those with non-serious bacterial infections in pediatric emergency departments and has comparable sensitivity to more complicated triage systems. PMID- 27493404 TI - Carbaodeim: A natural haematinic blend for treatment of dimorphic anemia of malnutrition. AB - Sudanese nomadic tribes living in the Sahara Region west of Khartoum State depend completely on food made of sour milk and other milk products cooked with onion and dried meat. This is usually added to a porridge made of sorghum flour. Goat and sheep milk is the main component and green vegetables are not commonly taken with this meal. Adults, who move out of their residential areas may have access to other types of food in towns and cities while mothers and children, staying always at home, do not have similar chances. Furthermore, in these dessert areas there is always difficulty in reaching health care facilities and getting medicines. Children from these areas who presented to Ombada Teaching Hospital - west of Omdurman- had very low hemoglobin and their peripheral blood picture showed dimorphic type of anemia. In the search for locally available ingredients that can prevent the occurrence of this type of anemia among the affected population, we studied the constituents of the commonly available fruits and vegetables in the area. We succeeded to formulate a blend (Carbaodeim) made of Carrots (25 gm), Baobab (100 gm) and Godeim (100 gm) which is found to contain iron (34.8 mg), folic acid (2.5 mg), ascorbic acid (372.8 mg), vitamin A (7000 mg), calcium (896.7 mg) and potassium (1910 mg), with many other components that have high nutritional value. This blend is easy to make, safe, nutritious, refreshing and cost effective. Carbaodeim is a naturally available and cost effective haematinic blend that might be added to the food menu of nomadic people as well as patients admitted to hospital with malnutrition or dimorphic type of anemia. PMID- 27493405 TI - Risk factors for neural tube defects in Riyadh City, Saudi Arabia: Case-control study. AB - Both genetic and non-genetic environmental factors are involved in the etiology of neural tube defects (NTD) which affect 0.5-2/1000 pregnancies worldwide. This study aimed to explore the risk factors for the development of NTD in Saudi population, and highlight identifiable and preventable causes. Similar studies are scarce in similar populations ofthe Arabian Peninsula and North Africa. This is an unmatched concurrent case-control study including NTD cases born at King Khalid University Hospital, Riyadh during a 4-year period (2002-2006). The case control study included 25 cases and 125 controls (case: control ratio of 1:5). Years of formal education, employment, household environment (including availability of air conditioning) and rate of parental consanguinity did not differ between mothers of cases and controls. Significantly higher proportion of mothers of cases had history of stillbirth compared to control mothers (16% vs 4.1%, P=0.02). Also family history of hydrocephalus and congenital anomalies were more prevalent in cases than controls (P values=0.0000 and 0.003, respectively). There was significant protective effect of periconceptional folic acid consumption both prior to conception (OR 0.02, 95% CI 0.00-0.07) and during the first 6 weeks of conception (OR 0.13, 95% CI 0.04-0.39). Further research, including a larger cohort, is required to enable ascertainment of gene-nutrient and gene environment interactions associated with NTD in Saudi Arabia. PMID- 27493406 TI - The neurologic aspects of hypomelanosis of Ito: Case report and review of the literature. AB - The term hypomelanosis of Ito (HI) is applied to individuals with skin hypopigmentation along the lines of Blaschko. Although it was originally described as a purely cutaneous disease, subsequent studies describing HI reported a 33% to 94% association with multiple extracutaneous manifestations, mostly of the central nervous and musculoskeletal systems. This leads to characterization of HI as a neurocutaneous disorder. We report a 10-year-old boy who presented with constellation of multiple congenital anomalies including facial dysmorphism, skin hypopigmentation, musculoskeletal, and nervous system abnormalities. The latter manifested as hypotonia, generalized seizures, and mild mental retardation. Cranial magnetic resonance imaging revealed normal finding initially, however; follow-up diffusion weighted images were suggestive of a possible iron accumulation. The facial phenotype coupled with the bilateral globus pallidi lesions were never been reported in association with HI. Thus, our patient represents a possible novel example of HI. PMID- 27493407 TI - Apert Syndrome: Late presentation and treatment challenges. AB - Apert syndrome is a rare autosomal dominant disorder characterized by craniosynostosis, craniofacial anomalies, and severe symmetrical syndactyly of the hands and feet. Anomalies of the viscera, skeleton and cardiovascular system have also been reported... Untreated craniosynostosis leads to inhibition of brain growth and an increase in intracranial and intraorbital pressure. Most cases are sporadic, resulting from new mutations with a paternal age effect. The prognosis of Apert Syndrome depends on the severity of brain malformation and early surgical interventions. We describe a Sudanese infant with Apert syndrome who presented for the first time at the age of three months and had limited options for intervention. PMID- 27493408 TI - Trisomy 18 syndrome: Towards a balanced approach. AB - Trisomy 18 is a relatively common autosomal trisomy syndrome. It is due to either full or partial presence of an extra copy of chromosome 18. Its prevalence correlates positively with advanced maternal age. Affected infants usually exhibit a variable pattern of anomalies including growth restriction, marked psychomotor and cognitive disability and an array of physical findings including characteristic craniofacial features, clenched fists with overriding fingers, small fingernails, underdeveloped thumbs, short sternum and heart and kidney anomalies. The majority of these infants die within the first year of life; only 5% to 10% of them survive longer. Their death is primarily due to cardio respiratory failure. In this case report of trisomy 18 we tried to highlight the importance of antenatal diagnosis and to emphasize the need for proper counseling at different points of time starting from the moment the condition is suspected until the point when diagnosis is confirmed and thereafter. PMID- 27493409 TI - Transient hyperphosphatasemia in children. AB - Transient Hyperphosphatasemia (TH) is a benign condition in which serum alkaline phosphatase (ALP) is transiently elevated in the absence of other systemic diseases. It mainly occurs in infants and children and very rarely seen in adults. The differential diagnosis may include liver, bone, kidney, intestinal, placental and blood diseases as well as other serious conditions as well as bone fracture due to accidental or non-accidental injuries. In this report, we present tow of our patients with TH and compare their clinical course with the natural history of TH described in literature. We also provide a focused review, in relevance to our presented cases, of this disease, which is rarely encountered in clinical practice. PMID- 27493410 TI - Dr Abdeen Khairy: The first doctor, worldwide, who gave his life fighting Ebola epidemic in 1976. PMID- 27493411 TI - Fighting the first Ebola virus epidemic in the World in 1976: Memoirs of a young doctor. PMID- 27493412 TI - Dr Mahgoub Osman Karrar who wrote the first clinical report on Ebola virus disease worldwide. PMID- 27493413 TI - A Clinical Report of The Outbreak of The Haemorrhagic Fever Which Occurred in Maridi Area, Equatoria Provinces, in The Southern Region of The Sudan. PMID- 27493414 TI - Loss of a Stethoscope: Ebola memoirs. AB - Loss of a Stethoscope is a real story highlighting the first epidemic of Ebola virus in the World, narrated by an eye witness. It occurred in southern Sudan (currently, South Sudan), mainly in Maridi. A Stethoscope that the people of Sudan are in an impelling need for was lost there. The hero is Dr. Abdeen Kairy, the doctor who managed the epidemic on his own at Maridi Hospital. He was an ebullient and graceful doctor who steps in confidence, determination and bravery towards his determined goal. He breaks through risks and disdains all hardships. He treated the lethal idiopathic disease. He got infected and died as the Martyr of Duty, Honor and Heroism. PMID- 27493415 TI - Paediatric neurology at the confluence of the Blue and White Niles. PMID- 27493416 TI - Managing childhood epilepsy in a resource-limited setting: A pragmatic approach. AB - Epilepsy is a complex neurological disorder. Its burden constitutes a major public health problem in resource-limited countries like Sudan. When it affects children, the challenges surrounding its diagnosis and management are enormous resulting in large numbers of patients missing out on adequate treatments. Epilepsy has the potential of not only adversely affecting the physical health of children but of also impacting negatively on their emotional, cognitive and social well-being. A pragmatic approach based on sound clinical skills of how to accurately diagnose epilepsy, as a priority, coupled with the choice of a cost effective, wide spectrum and efficient anti-epileptic drug, is recommended. PMID- 27493417 TI - Developmental regression in autism spectrum disorder. AB - The occurrence of developmental regression in autism spectrum disorder (ASD) is one of the most puzzling phenomena of this disorder. A little is known about the nature and mechanism of developmental regression in ASD. About one-third of young children with ASD lose some skills during the preschool period, usually speech, but sometimes also nonverbal communication, social or play skills are also affected. There is a lot of evidence suggesting that most children who demonstrate regression also had previous, subtle, developmental differences. It is difficult to predict the prognosis of autistic children with developmental regression. It seems that the earlier development of social, language, and attachment behaviors followed by regression does not predict the later recovery of skills or better developmental outcomes. The underlying mechanisms that lead to regression in autism are unknown. The role of subclinical epilepsy in the developmental regression of children with autism remains unclear. PMID- 27493418 TI - The results of different diagnostic imaging studies used in children with urinary tract infection. AB - Urinary tract infections (UTI) can cause significant renal scarring, which can be complicated by hypertension and renal impairment. This study describes the outcome of different imaging modalities in children with UTI and its relation to age, sex and type of UTI. Our objective was to describe the frequencies of different imaging studies, which were used to investigate children with UTI at King Fahad Hospital (KFH) between the years 2003 and 2008. This is a descriptive study of all children presenting with UTI at KFH from 2003 to 2008. The study population, 100 children , were divided into 3 age groups; first group (> 1 month to 2 years); second group (> 2 to 5 years) , third group (> 5 to 12 years). All enrolled children were confirmed to have had UTI via urinary cultures. Ninety seven (97%) patients underwent renal ultrasonography (US), 77 (77%) had a 99mTc dimercaptosuccinic acid (DMSA) scan within 2 months of presentation, and 60 (60%) patients underwent micturating cystourethrogram (MCUG), mainly those with an abnormal DMSA scan. A total of 100 patients screened, 10 (10%) were males and 90 (90%) were females, first age group constituted 10%, second age group was 25% , third age groups was 65%. E-coli was isolated in 84% of patients, 60% had recurrent UTI, 45% had pyelonephritis, 48.4% had abnormal renal US, 61% had an abnormal DMSA scan, and 26.6% had abnormal MCUG. UTI can cause significant morbidity in children if not managed properly. Imaging studies are useful in identifying children who require advanced medical intervention; however, such studies should be performed only when indicated. PMID- 27493419 TI - Zinc supplementation for the treatment of severe pneumonia in hospitalized children: A randomized controlled trial. AB - The objectives of this randomized controlled trial (RCT) were to compare the mean duration of hospital stay and mean time to relieve severe pneumonia signs and symptoms with or without zinc supplementation in hospitalized young children. This RCT was conducted from Oct 2011 to Mar 2012. in the paediatric department, PGM/Lahore General Hospital. Three hundred children (150 in each group) were randomly allocated to two groups: group A received zinc syrup (20 mg/day q 12 hourly) till discharge and group B received placebo syrup. This in addition to the antibiotic treatment. Data for severe pneumonia signs and symptoms i.e. oxygen saturation, respiratory rate, temperature and chest indrawing were recorded. The mean age of participants was 16.65+4.23 months in Group-A and15.96+5.11 months in Group-B. We found that the mean duration to relieve severe pneumonia signs and symptoms was 44.62+2.56 hours in Group-A and 48.73+3.124 hours in Group-B (p-value 0.023).Duration of hospital stay was 128.31+3.71 hours in Group-A and 137.67+2.56 in Group-B (p-value 0.001). We conclude that zinc supplementation for the treatment of children with pneumonia is an effective therapy along with standard treatment. PMID- 27493420 TI - Spectrum of attention deficit hyperactivity disorders (ADHD) among Sudanese children with epilepsy. AB - Epilepsy is commonly encountered in children with attention deficit hyperactivity disorder (ADHD). This study aims to determine the spectrum of ADHD among Sudanese children with epilepsy. The study was conducted at the Epilepsy and Neurodisabilities Outpatient Clinic for Children at Saad Abu Elila University Hospital, Khartoum, Sudan during the period January - July 2013. All patients with epilepsy who presented to the clinic during the study period were assessed for ADHD using psychometric questionnaire. According to the interpretation guide, the degree of probability of ADHD was identified. Out of 720 patients with epilepsy 77(10.6%) were identified as having ADHD. Of these 50 (19.50%) patients had a high probability of having ADHD, 29 (37.70%) above average, 29 (37.70%) average and 4 (5.20%) had low ADHD spectrum. PMID- 27493421 TI - Evaluation of quality of routine physical examination in urban public basic schools in Khartoum State, Sudan. AB - The objectives of this study are to identify the availability of the service logistics in basic public schools (structure as quality concept), to assess steps of physical examination according to the ministry of health guidelines (process as quality concept) and to measure satisfaction of service consumers (pupils) and service providers (teacher and doctors). The study involved seven localities in Sudan using questionnaires and observations. The structure in form of material and human resources was not well maintained, equally the process and procedure of medical examination did not well fit with rules of quality, however, the satisfaction level was within the accepted level. As far as structure, process and outcome were concerned, we are still below the standards in developed countries for many reasons but the level of satisfaction in the present study is more or less similar as in else studies. PMID- 27493422 TI - Familial hemophagocytic lymphohistiocytosis in two Saudi siblings. AB - Primary familial hemophagocytic lymphohistiocytosis (HLH; or familial erythrophagocytic lymphohistiocytosis [FEL]) is a heterogeneous autosomal recessive disorder more prevalent with parental consanguinity. There is aggressive proliferation of activated macrophages and histiocytes, which phagocytose red blood cells (RBCs), white blood cells (WBCs), and platelets, leading to anemia, neutropenia and thrombocytopenia. The exaggerated response of immune system in familial HLH can occur in the absence of infection. We report on two Saudi siblings with familial hemophagocytic lymphohistiocytosis. The first case was diagnosed and started on treatment but died after ten days of treatment while the second one was referred to a higher centre for treatment but died before commencing chemotherapy treatment. This rare inherited aggressive disease needs high index of suspicion and early treatment. Anti-inflammatory therapy consisting of steroids, etoposide or antithymocyte globulin (ATG), should be instituted promptly, followed by curative hematopoietic cell transplantation to get a better outcome. Without treatment, most patients with familial hemophagocytic lymphohistiocytosis survive only a few months. PMID- 27493424 TI - The boy who stopped walking.... PMID- 27493423 TI - Infantile cortical hyperostosis - a report of Saudi family. AB - A 2-weeks-old Saudi neonate was apparently well till the 10th day of life when a swelling of the right groin was noted accompanied by irritability and fever, without history of trauma. On examination: the girl was irritable and febrile, the mass was firm, ill defined, fixed and tender. The state of the underlying skin was normal. There was family history of 3 siblings with similar swellings in the neonatal period and one of them had recurrence of the condition till the age of 7 year. The radiological findings indicated diaphysis hyperostosis, sparring of the epiphysis and the benign course of the disease. With exclusion of syphilis, osteomyelitis and trauma, the likely diagnosis would be infantile cortical hyperostosis. Such diagnosis should not be overlooked when faced by bony swellings in neonates. PMID- 27493425 TI - The International Child Neurology Association (ICNA) Educational Meetng in Khartoum, Sudan. PMID- 27493426 TI - ICNA meeting: January 27-31, 2015. PMID- 27493427 TI - The orchestrated performance of the ICNA and first PET1 Course at the confluence of the Niles: Khartoum, January 2015. PMID- 27493428 TI - Welcome Speech of the International Child Neurology Association (ICNA) Educational Meeting in Khartoum, Sudan (January 27-31, 2015). PMID- 27493429 TI - Lessons to the World: Sudanese Youth and the Wellbeing of Children. PMID- 27493430 TI - Hawadith Street Initiative: A unique Sudanese childhood charity experience. AB - Due to escalating conflicts and resultant economic constraints, different social services in low income and low-middle income countries have witnessed a decline in its standards, and increase in the costs. This situation has led to emergence of large numbers of patients and their families who cannot afford the costs of health services provided by public hospitals. On this background, and the old heritage of the Sudanese to help the needy, the Hawadith Street Initiative (HSI) was established. Named after the street on which it was founded - which translates indirectly to "Accidents Lane", HSI was established in 2012 by a group of youths, most of them in their twenties of age, and recently graduated. The main activity of the initiative is helping the needy hospital patients, especially with regards to their treatment costs, in Khartoum and other cities in Sudan. Starting with recreational programs for cancer patients, and public campaigns for donation of blood, the initiative's youths changed their activities. Using the social media, Facebook, they adopted the strategy of communication with potential donors, after sending posts containing brief anonymous presentations and call of help for needy cases. Currently HSI includes more than 2000 volunteers in Khartoum and 17 other cities. The most important achievement of HSI is the establishment of an intensive care unit at a children hospital in Omdurman city costing 435,880 US dollars. HSI demonstrates the possibility of delivering great services with minimum resources, and constitutes a unique organization, worldwide, in a new wave of Internet-based initiatives. PMID- 27493431 TI - Beyond the guidelines of paediatric septic shock: A focused review. AB - Severe sepsis and septic shock continue to cause major morbidity and mortality among children, especially in the resource-limited areas. Guidelines that focus on these entities, such as "Surviving Sepsis" and "Paediatric Advanced Life Support" guidelines, are revised and updated on regular basis to incorporate new evidence based medicine. There is ongoing need to review these updated guidelines, and address potentially best available solutions for adapting them into suitable practical steps for paediatricians worldwide, especially those working in resource-limited areas. The available recommendations may help to improve sepsis management in middle- and low-income countries; however, guidelines must be wisely implemented according to the available resources, with follow up auditing to ensure appropriate implementation. PMID- 27493432 TI - Spinal cord schistosomiasis. AB - Acute myelopathy is increasingly being recognized as a common neurological complication of schistosomiasis. Schistosome eggs reach the spinal cord either as egg emboli or as eggs produced by ectopic worms. This leads to inflammatory reaction and granuloma formation around the eggs. Patients with spinal schistosomiasis may not have clinical evidence of schistosomiasis. The typical clinical picture is that of lumbar pain preceded by other symptoms by hours or up to 3 weeks. Patients may present with paraparesis, urinary retention or paraplegia. Definitive diagnosis of spinal cord schistosomiasis is by detection of the eggs in a spinal cord biopsy or at autopsy. However, most cases are diagnosed based on a presumptive diagnosis that depends on a suggestive clinical picture, history or evidence of active schistosomiasis and exclusion of other conditions. Investigations include stools and urine examination for schistosome eggs, blood tests, magnetic resonance imaging (MRI) and examination of the cerebrospinal fluid. Treatment of cases is mainly by praziquantel, corticosteroids, surgical intervention and rehabilitation. PMID- 27493433 TI - The prevalence and factors affecting attention deficit hyperactivity disorder among school children in Khartoum State. AB - Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children, characterized by age-inappropriate features of inattention, hyperactivity and impulsivity or both. The aim of this study is to determine the prevalence and socio demographic correlates of ADHD symptoms in general basic schoolchildren. A cross-sectional study conducted in Khartoum North. A random sample of 190 general basic schools was chosen, from which sample of 1000 students from both boys and girls were selected by systematic random sampling, their age ranges between 7 and 14 years. They were screened for different subtypes of ADHD symptoms using the SNAP-IV-C teacher and parent rating scale, which is a revision of the Swanson Nalon and Pelham (SNAP) questionnaire. The overall prevalence of ADHD was 9.4%. The prevalence of children with ADHD/inattentive sub type, ADHD/ hyperactive-impulsive sub type, ADHD/ combined subtype were 3.5%, 6.9 % and 1.0 %, respectively. The prevalence rate increased significantly with the increase in age. The study showed that the prevalence of ADHD symptoms among school children in Sudan was high as rated by both teacher and parents rather than what has been reported in other studies. ADHD symptoms are more common among boys than girls and more prevalent in late childhood and in those who lived in rural area. PMID- 27493434 TI - Evaluation of physicians' knowledge about prevention of rheumatic fever and rheumatic heart disease before and after a teaching session. AB - Rheumatic fever (RF) and rheumatic heart disease RHD remain as one of the major cardiovascular problems in Sudanese children. The cornerstones for control of RF and RHD are primary and secondary preventions as adopted by Sudan's programme. This study aimed to describe and raise the paediatric doctors' awareness about prevention of RF and RHD using lectures. It was a prospective, cross-sectional, hospital based study, conducted in Khartoum. The study populations were paediatric doctors including house officers, medical officers and registrars. Data were collected through self-administered questionnaire, which was constructed to assess the doctor's awareness about RF and RHD prevention before and after attending lectures. Eighty seven doctors participated in the study. The results showed that the overall doctors' awareness about prevention of rheumatic fever and rheumatic heart disease was at average level. It was raised by intervention through lectures to good level. It is recommended to introduce training programs for physicians in order to improve doctors' awareness about prevention of RF and RHD. Such activities need to be conducted at regular intervals. PMID- 27493435 TI - Pediatric pain management: More opportunities for better comfort. AB - Pediatric pain assessment is vital for optimal pediatric practice. After a year of implementation of pediatric pain assessment tools at a tertiary university hospital (King Saud University Medical City, Riyadh, Saudi Arabia), the physicians in the Department of Pediatrics were invited to participate in an interactive lecture about pediatric pain management to assess their awareness about using these tools. Their responses demonstrated that almost half of them were not using any pain scale in their daily practice. These findings highlight the need for a new strategy of implementation. The improvement of pain assessment and management necessitates extensive educational campaign for all health care providers and early audit in order to improve the physicians' awareness and compliance with these changes. PMID- 27493436 TI - Oxygen therapy in neonatal intensive care units in Khartoum State. AB - Oxygen is a drug that is essential in the treatment and prevention of neonatal hypoxia. The goal of oxygen therapy is to deliver sufficient oxygen to tissues while minimizing oxygen toxicity and oxidative stress. Improvement in monitoring technology of oxygen therapy has helped to improve clinicians' ability to appropriately apply and deliver oxygen. The objectives of this prospective observational descriptive hospital based study were: to evaluate the practice of oxygen therapy in the neonatal intensive care units (NICUs) in Khartoum State, to identify guidelines of oxygen therapy in NICUs, to determine the mode of oxygen delivery to the neonates, and to assess the practice of long term follow up of patients who used oxygen. During the period January - June 2014, 139 neonates were included. Oxygen was delivered to the neonates in the study depending on the clinical assessment. Saturation was not measured at the time of oxygen administration in 119 (85.6%) neonates. Oxygen was delivered by central device in 135 neonates (97.1%). The majority of the staff did not know the practice of long term follow up. Hundred and sixteen (83.5%) of the nursing staff knew that oxygen has complications but the majority didn't know the nature of the complications and what causes them. The study showed that there is lack of guidelines of oxygen therapy in the NICUs and lack of monitoring procedures, which is important to be highlighted to overcome the complications and to improve the practice of oxygen therapy. PMID- 27493437 TI - Dying for milk: A neonate with severe hypernatremia associated with inadequate breast feeding. AB - Inadequate breastfeeding may result in malnutrition, hypernatremic dehydration and catastrophic outcomes. We describe a case of severe breast feeding associated hypernatremia which was complicated by acute seizures and severe hyperglycemia. The baby's condition was initially confused with neonatal diabetes mellitus. PMID- 27493438 TI - Sturge-Weber syndrome: Continued vigilance is needed. AB - Sturge-Weber syndrome (SWS) is a non-hereditary congenital disorder due to somatic mosaic mutations in the GNAQ gene. The classical presentation relates to the brain lesion (cerebral angiomatous lesion of leptomeninges, which is responsible for epileptic seizures, hemiparesis and mental retardation), skin lesion (unilateral facial nevus), ocular and oral involvement. We present a 12 year-old boy who was referred to the Division of Pediatric Neurology, King Saud University Medical City, Riyadh, Saudi Arabia with left-sided hemiparesis. Physical examination showed a port wine stain involving the right side of the face, extending to the upper thorax, and enlargement of both the right eye globe and cornea (megalocornea), indicating the presence of glaucoma. Following urgent referral to ophthalmology service, his eye condition improved dramatically post surgery. Neuroradiological investigations, including cranial computed tomography (CT) and magnetic resonance angiography (MRI) revealed the classical brain lesions of SWS, as well as right leptomeningeal choroidal angioma. Ten months later, he developed focal-onset seizures which responded to treatment. His cognition is normal with good school performance. Continued vigilance is needed to identify and manage the complications of SWS. PMID- 27493439 TI - Approach to a child with recurrent pneumonia. AB - Pneumonia, or inflammation of the lungs parenchyma associated with consolidation of alveolar spaces, is a substantial cause of morbidity and mortality in childhood particularly among children below 5 years of age. It is one of the common causes of admission to the paediatric ward. The aim of this article is to provide a guide to a systemic approach for diagnosis and treatment of children with recurrent pneumonia while not over investigating those with common but usually unrecognised conditions such as asthma or recurrent simple viral infections. PMID- 27493440 TI - Incidental diaphragmatic hernia in an infant with cough. PMID- 27493441 TI - When history was made in Khartoum Civil Hospital: First introduction of chemotherapy for schistosomiasis. AB - John Brian Christopherson (1868-1955) was one of the first doctors to be recruited to serve in the Sudan under the British colonial rule. During his work in Sudan (1902-1919) he was key in establishing the civilian medical services in Sudan, including establishing Khartoum Civil Hospital (opened in 1909). The present article focuses on the work of Dr Christopherson in Khartoum Civil Hospital in which he introduced tartar emetic for the first time for the treatment of schistosomiasis. To validate this treatment, Christopherson conducted a series of clinical trials and published his findings in leading medical journals. He had to respond to priority claims over this discovery and to deal with skepticism about the safety of this new treatment. The publications of Christopherson covered not only the therapeutic efficacy of the drug but also discussed the epidemiology of the disease, the possible role of mass chemotherapy and also envisioned chemotherapy in school-age children as a possible strategy for future elimination of the disease. PMID- 27493442 TI - Building Gaafar Ibnauf Children's Hospital: Unprecedented story. PMID- 27493443 TI - The Editors of Sudanese Journal of Paediatrics would like to thank. PMID- 27493444 TI - Child and Parent Report of Parenting as Predictors of Substance Use and Suspensions from School. AB - This study examined how child and parent reports of parenting were related to early adolescent substance use and school suspensions. Data were from two time points six months apart on 321 families with an eighth grade student attending one of five schools in the Pacific Northwest. Child- and parent-report measures of family management practices were moderately correlated (r = .29). Child report, but not parent report, of more positive family management practices uniquely predicted a lower likelihood of adolescent substance use. Also, discrepancies between child and parent report of parenting predicted substance use, with child positive report of family management losing its protective association with adolescent substance use when parents had negative reports of their parenting. Parent report, but not child report, of better parenting predicted lower likelihood of suspensions, suggesting that the salience of child and parent report may depend on the type of behavioral outcome. PMID- 27493445 TI - A Multi-Cycle Q-Modulation for Dynamic Optimization of Inductive Links. AB - This paper presents a new method, called multi-cycle Q-modulation, which can be used in wireless power transmission (WPT) to modulate the quality factor (Q) of the receiver (Rx) coil and dynamically optimize the load impedance to maximize the power transfer efficiency (PTE) in two-coil links. A key advantage of the proposed method is that it can be easily implemented using off-the-shelf components without requiring fast switching at or above the carrier frequency, which is more suitable for integrated circuit design. Moreover, the proposed technique does not need any sophisticated synchronization between the power carrier and Q-modulation switching pulses. The multi-cycle Q-modulation is analyzed theoretically by a lumped circuit model, and verified in simulation and measurement using an off-the-shelf prototype. Automatic resonance tuning (ART) in the Rx, combined with multi-cycle Q-modulation helped maximizing PTE of the inductive link dynamically in the presence of environmental and loading variations, which can otherwise significantly degrade the PTE in multi-coil settings. In the prototype conventional 2-coil link, the proposed method increased the power amplifier (PA) plus inductive link efficiency from 4.8% to 16.5% at (RL = 1 kOmega, d23 = 3 cm), and from 23% to 28.2% at (RL = 100 Omega, d23 = 3 cm) after 11% change in the resonance capacitance, while delivering 168.1 mW to the load (PDL). PMID- 27493446 TI - Discovery and Validation of Hypermethylated Markers for Colorectal Cancer. AB - Colorectal carcinoma (CRC) is one of the most prevalent malignant tumors worldwide. Screening and early diagnosis are critical for the clinical management of this disease. DNA methylation changes have been regarded as promising biomarkers for CRC diagnosis. Here, we map DNA methylation profiling on CRC in six CRCs and paired normal samples using a 450 K bead array. Further analysis confirms the methylation status of candidates in two data sets from the Gene Expression Omnibus. Receiver operating characteristic (ROC) curves are calculated to determine the diagnostic performances. We identify 1549 differentially methylated regions (DMRs) showing differences in methylation between CRC and normal tissue. Two genes (ADD2 and AKR1B1), related to the DMRs, are selected for further validation. ROC curves show that the areas under the curves of ADD2 and AKR1B1 are higher than that of SEPT9, which has been clinically used as a screening biomarker of CRC. Our data suggests that aberrant DNA methylation of ADD2 and AKR1B1 could be potential screening markers of CRC. PMID- 27493447 TI - Circulating MicroRNAs as Potential Molecular Biomarkers in Pathophysiological Evolution of Pregnancy. AB - MicroRNAs represent nonprotein coding small RNA molecules that are very stable to degradation and responsible for gene silencing in most eukaryotic cells. Increased evidence has been accumulating over the years about their potential value as biomarkers for several diseases. MicroRNAs were predicted to be involved in nearly all biological processes from development to oncogenesis. In this review, we address the importance of circulating microRNAs in different conditions associated with pregnancy starting with the implantation period to preeclampsia and we shortly describe the correlation between placental circulating miRNAs and pregnancy status. We also discuss the importance of microRNAs in recurrent abortion and ectopic pregnancy. PMID- 27493448 TI - Aqueous Lanthanide Chemistry in Asymmetric Catalysis and Magnetic Resonance Imaging. AB - This account describes lanthanide coordination chemistry with a focus on the similarities between lanthanide complexes used in catalysis and those used as contrast agents in magnetic resonance imaging. PMID- 27493449 TI - Generation of Soluble Interleukin-11 and Interleukin-6 Receptors: A Crucial Function for Proteases during Inflammation. AB - The cytokines interleukin-11 (IL-11) and IL-6 are important proteins with well defined pro- and anti-inflammatory functions. They activate intracellular signaling cascades through a homodimer of the ubiquitously expressed signal transducing beta-receptor glycoprotein 130 (gp130). Specificity is gained through the cell- and tissue-specific expression of the nonsignaling IL-11 and IL-6 alpha receptors (IL-11R and IL-6R), which determine the responsiveness of the cell to these two cytokines. IL-6 is a rare example, where its soluble receptor (sIL-6R) has agonistic properties, so that the IL-6/sIL-6R complex is able to activate cells that are usually not responsive to IL-6 alone (trans-signaling). Recent evidence suggests that IL-11 can signal via a similar trans-signaling mechanism. In this review, we highlight similarities and differences in the functions of IL 11 and IL-6. We summarize current knowledge about the generation of the sIL-6R and sIL-11R by different proteases and discuss possible roles during inflammatory processes. Finally, we focus on the selective and/or combined inhibition of IL-6 and IL-11 signaling and how this might translate into the clinics. PMID- 27493450 TI - Evaluation of the Antioxidative, Antibacterial, and Anti-Inflammatory Effects of the Aloe Fermentation Supernatant Containing Lactobacillus plantarum HM218749.1. AB - Little work is done to develop Aloe vera (AV) using probiotics. To explore the potential benefits, the antioxidant effects and the antibacterial effects on foodborne pathogens of Aloe fermentation supernatant were evaluated in vitro. Our results indicated that the Aloe fermentation supernatant fermented by Lactobacillus plantarum HM218749.1 had very strong scavenging capacities of the DPPH (86%), O2 (*-) (85%), (*)OH (76%), and Fe(2+) chelation (82%) and reducing powers (242.5 mg/L), and the inhibition zones for Salmonella typhimurium, Salmonella enteritidis, Shigella flexneri, Escherichia coli, Listeria monocytogenes, S. dysenteriae 301, Staphylococcus aureus Cowan1, and Propionibacterium acnes were 16, 15, 19, 20, 21, 20, and 27 mm. Moreover, the low concentration of Aloe fermentation supernatant had significantly reduced the production of IL-1beta, TNF-alpha, and IL-6 in both mRNA and protein levels (P < 0.01). Therefore, the Aloe fermentation supernatant can be used as functional beverage or cosmetic ingredients to guard human intestinal health, delaying senescence, and prevent chronic diseases. PMID- 27493451 TI - Inflammation Thread Runs across Medical Laboratory Specialities. AB - We work on the assumption that four major specialities or sectors of medical laboratory assays, comprising clinical chemistry, haematology, immunology, and microbiology, embraced by genome sequencing techniques, are routinely in use. Medical laboratory markers for inflammation serve as model: they are allotted to most fields of medical lab assays including genomics. Incessant coding of assays aligns each of them in the long lists of big data. As exemplified with the complement gene family, containing C2, C3, C8A, C8B, CFH, CFI, and ITGB2, heritability patterns/risk factors associated with diseases with genetic glitch of complement components are unfolding. The C4 component serum levels depend on sufficient vitamin D whilst low vitamin D is inversely related to IgG1, IgA, and C3 linking vitamin sufficiency to innate immunity. Whole genome sequencing of microbial organisms may distinguish virulent from nonvirulent and antibiotic resistant from nonresistant varieties of the same species and thus can be listed in personal big data banks including microbiological pathology; the big data warehouse continues to grow. PMID- 27493453 TI - The Mystique of Brain Death. PMID- 27493452 TI - Circulating (CD3(-)CD19(+)CD20(-)IgD(-)CD27(high)CD38(high)) Plasmablasts: A Promising Cellular Biomarker for Immune Activity for Anti-PLA2R1 Related Membranous Nephropathy? AB - Membranous nephropathy (MN) is a kidney specific autoimmune disease mainly mediated by anti-phospholipase A2 receptor 1 autoantibody (PLA2R1 Ab). The adequate assessment of chimeric anti-CD20 monoclonal antibody, rituximab (RTX), efficacy is still needed to improve clinical outcome of patient with MN. We evaluated the modification of plasmablasts (CD3(-)CD19(+)CD20(-)IgD( )CD27(high)CD38(high)), a useful biomarker of RTX response in other autoimmune diseases, and memory (CD3(-)CD19(+)CD20(+)IgD(-)CD27(+)CD38(-)) and naive (CD3( )CD19(+)CD20(+)IgD(+)CD27(-)CD38(low)) B cells by fluorescence-activated cell sorter analysis in PLA2R1 related MN in one patient during the 4 years of follow up after RTX. RTX induced complete disappearance of CD19(+) B cells, plasmablasts, and memory B cells as soon as day 15. Despite severe CD19(+) lymphopenia, plasmablasts and memory B cells reemerged early before naive B cells (days 45, 90, and 120, resp.). During the follow-up, plasmablasts decreased more rapidly than memory B cells but still remained elevated as compared to day 0 of RTX. Concomitantly, anti-PLA2R1 Ab increased progressively. Our single case report suggests that, besides monitoring of serum anti-PLA2R1 Ab level, enumeration of circulating plasmablasts and memory B cells represents an attractive and complementary tool to assess immunological activity and efficacy of RTX induced B cells depletion in anti-PLA2R1 Ab related MN. PMID- 27493454 TI - Why are we Poor Organ Donors: A Survey Focusing on Attitudes of the Lay Public From Northern India. AB - BACKGROUND: Knowledge, sociocultural views, and awareness about organ donation in the general population are important for the success of deceased organ donation. There is an urgent need to gather this information in order to find out the reasons for poor organ donation rates in India. METHODS: A 30-item questionnaire was designed in the English and Hindi language and was administered to the lay people in order to assess their knowledge, views, and attitude regarding brain death and organ donation. RESULTS: Three hundred and fifty-two people (male:female = 202:150; mean age = 30.6 +/- 13.9 years) completed the questionnaire. Only 70% of the people were aware that the organs can be donated after brain death and only 44% thought that they understood the meaning of brain death. Media and Internet were the preferred sources for seeking information on brain death and organ donation. The majority of people (81.2%) were willing to donate organs after brain death but only 1.4% had registered for organ donation. Lack of awareness (80.1%), religious beliefs and superstitions (63.4%), and lack of faith in the healthcare system (40.3%) were believed to be the most important reasons for poor deceased organ donation rates in India. The survey also highlighted the importance of the opinion of family members and the religious leaders in making the decision for organ donation. Educational qualification above matriculation was significantly associated with the knowledge of brain death and the willingness for organ donation. CONCLUSION: Lack of awareness appears to be the most important factor for low donation rates in India. Educating people by using media and Internet and conducting awareness programs may help in improving the donation rates. PMID- 27493456 TI - Long-Term Outcomes of Liver Transplantation for Hepatic Sarcoidosis: A Single Center Experience. AB - AIM: Hepatic sarcoidosis is a rare indication for orthotopic liver transplantation (OLT). Hence, studies evaluating these patients are scarce. We present a single center experience with OLT for hepatic sarcoidosis in a case control study. METHODS: A retrospective chart review was performed on 970 patients with OLT at our center, and 13 patients (1.3%) were identified who underwent 14 OLTs for hepatic sarcoidosis. For each case, two controls matched for etiology of liver disease, recipient age (+/-5 years), and duration since transplant (within 5 years) were selected. RESULTS: For the 13 patients transplanted for sarcoidosis, the median age was 46 years. The majority were women (62%) and African-American (85%). Cholestatic liver disease was the primary manifestation. Portal hypertensive complications were present in 11 patients (84%). The median MELD score at transplantation was 19. Extra-hepatic manifestations were present in ten patients (77%). All patients received whole deceased 14 donor allografts. Six patients remain alive with a median post-OLT follow-up of 8.4 years. The 1-, 3-, 5-, and 10-year patient survival rates were 84.6%, 76.9%, 61.1%, and 51.3%, respectively for the sarcoidosis group and 82.1%, 78.6%, 78.6%, and 61.9%, respectively for the matched PSC/PBC group (P = 0.739). Re-graft free survival for sarcoidosis patients was 84.6%, 76.9%, 61.5%, and 51.3% for 1-, 3-, 5-, and 10-years and for the matched control group re-graft free survival was 78.6% at 1-, 3-, 5-years, and 64.8% at 10-years (P = 0.661). Recurrence of hepatic sarcoidosis was found in 4 patients at 11 days, 112 days, 222 days, and 6.6 years. CONCLUSIONS: Our study depicts the long-term benefit of liver transplantation in patients with end stage liver disease secondary to sarcoidosis. It shows statistically comparable graft and patient survival for such patients when compared to other cholestatic diseases. Disease recurrence, although possible, has not been shown to cause allograft dysfunction. PMID- 27493455 TI - Addition of Dexamethasone Alters the Bile Acid Composition by Inducing CYP8B1 in Primary Cultures of Human Hepatocytes. AB - BACKGROUND: Primary human hepatocytes offer the best human in vitro model for studies on human liver cell metabolism. Investigators use a variety of different media supplements and matrix biocoatings and the type of culture system used may influence the outcome. OBJECTIVES: To optimize in vitro conditions for primary human hepatocytes with regard to bile acid synthesis. METHODS: Human hepatocytes were isolated and cultured on collagen type I or EHS matrigel in cell media with or without dexamethasone. The glucocorticoid receptor (GR) antagonist RU486 was used to elucidate the involvement of GR. RESULTS: Hepatocytes cultured on EHS matrigel produced more bile acids and expressed higher levels of cholesterol 7alpha-hydroxylase (CYP7A1) than cells cultured on rat tail collagen. Supplementation with dexamethasone increased the formation of cholic acid (CA) and decreased chenodeoxycholic acid formation. In line with these results, the mRNA expression of sterol 12alpha-hydroxylase (CYP8B1) increased following dexamethasone treatment. Surprisingly, the mRNA expression of CYP7A1 and CYP27A1 was not increased to the same extent. By using the GR antagonist RU486, we concluded that CYP8B1 induction is mediated via a GR-independent pathway. An altered expression of retinoid-related orphan receptor (ROR) alpha and ROR alpha target gene Glucose-6-phosphatase (G6Pase) suggests that ROR alpha signaling may regulate CYP8B1 expression. CONCLUSION: Primary human hepatocytes have an increased bile acid synthesis rate when cultured on matrigel as compared to collagen. Exposure to glucocorticoid hormones stimulates the expression of CYP8B1, leading to an increased formation of CA and alteration of the bile acid composition. The effect is most likely mediated through a GR-independent pathway, possibly through ROR alpha. PMID- 27493457 TI - Limited Fibrosis Progression but Significant Mortality in Patients Ineligible for Interferon-Based Hepatitis C Therapy. AB - BACKGROUND: Individuals ineligible for interferon-based hepatitis C therapy may have a worse prognosis than patients who have failed or not received treatment. AIMS: To provide information about the limitations of medical treatment of hepatitis C in real-world patients. METHODS: We studied 969 treatment-ineligible patients and 403 treated patients enrolled between 1/1/01 and 6/30/06; data were collected until 3/31/13. Treatment barriers were grouped into five categories and classified as health-related or health-unrelated. Fibrosis stage was assessed initially and at the end of follow-up. Mortality was determined by search of the Social Security database. Death certificates of treatment-ineligible patients were reviewed. RESULTS: Initially, 288 individuals had advanced fibrosis and compensated disease; 87 untreated patients developed advanced fibrosis during follow-up. Health-related treatment barriers were more commonly associated with fibrosis progression and worse survival. During follow-up, 247 untreated patients died: 47% of liver-related and 53% of liver-unrelated causes. Patients with significant comorbid illness had the worst five- (70%) and ten-year (50.5%) survival. Despite high mortality (47%) in persons with decompensated liver disease, no treatment barrier was associated with a greater incidence of liver related death. Only significant comorbid medical illness was an independent predictor of disease progression; however, it was not associated with a greater incidence of liver-related death. Furthermore, treated patients had better 10 year survival than untreated patients on Kaplan-Meier analysis (80.3% vs. 74.5%, P = 0.005). CONCLUSION: Many patients with hepatitis C will die of non-liver related causes and may not be helped by anti-viral treatment. PMID- 27493458 TI - Donor Factors Including Donor Risk Index Predict Fibrosis Progression, Allograft Loss, and Patient Survival following Liver Transplantation for Hepatitis C Virus. AB - BACKGROUND: The utilization of liver transplantation (LT) is limited by the availability of suitable organs. This study aimed to assess the impact of the donor risk index (DRI) and other donor characteristics on fibrosis progression, graft, and patient survival in hepatitis C virus (HCV)-infected LT recipients. METHODS: HCV-infected LT recipients who had at least 2 post-LT protocol liver biopsy specimens available were included. Hazard ratio for bivariate analysis was computed using Cox proportional hazard regression analysis. RESULTS: Of 312 recipients, 26.6% died over a median follow-up of 58.5 months (95% CI: 46.5 67.3). Fourteen patients underwent re-transplantation. Mean time to graft failure was 84.3 months, median follow-up: 59 months, 95% CI (48.2, 68.3). DRI >1.5 was significantly associated with patient and graft survival (P = 0.04). Of the subset of 104 individuals who underwent histological analysis, 67.3% progressed to >=F2. On multivariate analysis, significant donor-specific predictors of fibrosis progression were: donor age >50 years and DRI >1.7. CONCLUSIONS: (1) Fibrosis progression in HCV-infected LT recipients is strongly associated with donor characteristics, specifically donor age and DRI. (2) DRI, an objective measure of donor quality, appears to correlate both with rate of histological progression and overall patient/graft survival. PMID- 27493459 TI - Anti-HBc Screening of Blood Donors in Bangladesh: Relevance to Containment of HBV Propagation. AB - OBJECTIVES: To avoid further transmission of hepatitis B virus (HBV) infection, blood is tested for hepatitis B surface antigen (HBsAg) before transfusion. However, post-transfusion hepatitis B has been detected in clinics after transfusion of HBsAg-negative blood. The study presented here was undertaken to assess if HBsAg-negative blood is free from HBV or not. METHODS: Sera were collected from 398 blood donors who were negative for HBsAg. Out of 398 blood samples, antibody to hepatitis B core antigen (ant-HBc) was detected in 82 sera samples. HBV DNA was evaluated in HBsAg-negative, anti-HBc-positive sera. HBsAg, hepatitis B e antigen (HBeAg), antibody to HBeAg (anti-HBe), and anti-HBc in the sera were measured by an enzyme-linked immunosorbent assay (ELISA). HBV DNA was quantified by a real time polymerase chain reaction (PCR). RESULTS: Out of 82 HBsAg-negative, anti-HBc-positive sera samples, HBV DNA were detected in the sera of 7 voluntary blood donors. Out of these 7 subjects, all were negative for HBeAg. The levels of ALT were more than 30 IU/L in 6 of 7 HBVDNA-positive subjects and it was above upper limit of normal (>42 IU/ml) in one subject. CONCLUSIONS: The present recommendation about blood transfusion of HBsAg-negative blood system is not capable of blocking HBV transmission to blood recipients. Although advanced countries have adopted nucleic acid testing (NAT) for preventing HBV transmission, developing countries may apply anti-HBc testing and ALT estimation before blood transmission. PMID- 27493461 TI - A Rare Presentation of Leishmaniasis. AB - Leishmaniasis or kala-azar is a protozoan disease that can present as cutaneous, mucocutaneous, visceral, and disseminated disease. In India, it is usually localized in distinct areas of Bihar, Jharkhand, West Bengal, and parts of Eastern Uttar Pradesh. Visceral leishmaniasis (VL) involves the visceral organs, mainly the liver, the spleen and bone marrow. VL is characterized by prolonged fever, massive splenomegaly, weight loss, progressive anemia, pancytopenia, and hypergammaglobulinemia, and can be complicated by serious infections. In most of the patient the diagnosis is made on bone marrow biopsy or splenic aspirate. We hereby present an unusual case of kala-azar in a 52-year-old patient non-resident of endemic area presenting with pyrexia of unknown origin, in whom bone marrow biopsy was negative for Leishmanin Donovan (LD) bodies, and diagnosis was made by liver biopsy in which LD bodies were seen. PMID- 27493462 TI - Innovative Approach of Using Esophageal Stent for Refractory Post-Band Ligation Esophageal Ulcer Bleed Following Living Donor Liver Transplantation. AB - Bleeding from post-banding esophageal ulcers is uncommon. It is associated with significant morbidity and mortality. The bleeding from post-banding ulcers is difficult to manage and may be refractory to endotherapy and pharmacological treatment; transjugular intrahepatic portosystemic shunt can be used in such cases. We present a case of refractory post-banding ulcer bleed in a liver transplant recipient, which was managed by placement of removable esophageal metal stent. PMID- 27493463 TI - Unusual Cause of Cholestatic Jaundice in a Young Immunocompetent Male. PMID- 27493460 TI - Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016. AB - India contributes significantly to the global burden of HCV. While the nucleoside NS5B inhibitor sofosbuvir became available in the Indian market in March 2015, the other directly acting agents (DAAs), Ledipasvir and Daclatasvir, have only recently become available in the India. The introduction of these DAA in India at a relatively affordable price has led to great optimism about prospects of cure for these patients as not only will they provide higher efficacy, but combination DAAs as all-oral regimen will result in lower side effects than were seen with pegylated interferon alfa and ribavirin therapy. Availability of these newer DAAs has necessitated revision of INASL guidelines for the treatment of HCV published in 2015. Current considerations for the treatment of HCV in India include the poorer response of genotype 3, nonavailability of many of the DAAs recommended by other guidelines and the cost of therapy. The availability of combination DAA therapy has simplified therapy of HCV with decreased reliance of evaluation for monitoring viral kinetics or drug related side effects. PMID- 27493464 TI - Hepatocyte Regeneration and Inhibition of Proliferation: Two Sides of a Coin. PMID- 27493465 TI - Hepatobiliary Quiz Answers - 18 (2016). PMID- 27493466 TI - Acute Liver Failure Caused by Hepatitis A Virus with Dengue Coinfection. PMID- 27493467 TI - Use of Barbed Sutures in Laparoscopic Gastrointestinal Single-Layer Sutures. AB - BACKGROUND AND OBJECTIVES: Laparoscopic anastomotic methods are not commonly used because of the cumbersome laparoscopic intracorporeal sutures and tying involved. The barbed suture is one of the various devices developed to simplify the placement of intracorporeal sutures. However, barbed sutures are not commonly used during reconstruction after radical gastrectomy in cancer patients or for single-layer entire-thickness running suturing for intestinal anastomoses. We describe the procedure for using barbed sutures and report on the short-term surgical outcomes. METHODS: Between August 2012 and March 2014, 15-cm-long barbed sutures (V-Loc 180; Covidien, Mansfield, MA, USA) were used for laparoscopic intestinal anastomoses, including intestinal hole closure for esophagojejunal and gastrojejunal anastomoses after mechanical anastomoses and gastric wall closure after partial resection. RESULTS: In total, 38 patients underwent 40 laparoscopic anastomoses (esophagojejunostomies, 26; gastrojejunostomies, 7; and simple closure of gastric defect, 7); no cases required conversion to open surgery. Two cases exhibited positive air leak test results during surgery (1 case of esophagojejunostomy and 1 case of simple closure of gastric defect). Two cases of intestinal obstruction were noted; of those, one patient with postoperative intestinal paresis (grade II) was managed conservatively, and the other underwent repeat laparoscopic surgery (grade IIIb) for internal herniation unrelated to V Loc use. No postoperative complications at the anastomosis site and no surgery related deaths were noted. CONCLUSION: Single-layer entire-thickness running suturing with the V-Loc 180 barbed suture after stapled side-to-side intestinal anastomosis was found to be safe and feasible in the reported cases. PMID- 27493468 TI - Laparoscopic Colorectal Training Gap in Colorectal and Surgical Residents. AB - BACKGROUND AND OBJECTIVES: Laparoscopic colorectal surgery is an established safe procedure with demonstrated benefits. Proficiency in this specialty correlates with the volume of cases. We examined training in this surgical field for both general surgery and colon and rectal surgery residents to determine whether the number of cases needed for proficiency is being realized. METHODS: We examined the Accreditation Council for Graduate Medical Education (ACGME) and American Board of Colorectal Surgeons (ABCRS) operative statistics for graduating general surgery and colon and rectal surgery residents. RESULTS: Although the number of advanced laparoscopy cases had increased for general surgery residents, there was still a significant gap in case volume between the average number of laparoscopic colorectal operations performed by graduating general surgery residents (21.6) and those performed by graduating colon and rectal surgery residents (81.9) in 2014. CONCLUSION: There is a gap between general surgery and colon and rectal surgery residency training for laparoscopic colorectal surgery. General surgery residents are not meeting the volume of cases necessary for proficiency in colorectal surgery. This deficit represents a structural difference in training. PMID- 27493469 TI - Quality of Communication in Robotic Surgery and Surgical Outcomes. AB - BACKGROUND AND OBJECTIVES: Robotic surgery has introduced unique challenges to surgical workflow. The association between quality of communication in robotic assisted laparoscopic surgery and surgical outcomes was evaluated. METHODS: After each gynecologic robotic surgery, the team members involved in the surgery completed a survey regarding the quality of communication. A composite quality-of communication score was developed using principal component analysis. A higher composite quality-of-communication score signified poor communication. Objective parameters, such as operative time and estimated blood loss (EBL), were gathered from the patient's medical record and correlated with the composite quality-of communication scores. RESULTS: Forty robotic cases from March through May 2013 were included. Thirty-two participants including surgeons, circulating nurses, and surgical technicians participated in the study. A higher composite quality-of communication score was associated with greater EBL (P = .010) and longer operative time (P = .045), after adjustment for body mass index, prior major abdominal surgery, and uterine weight. Specifically, for every 1-SD increase in the perceived lack of communication, there was an additional 51 mL EBL and a 31 min increase in operative time. The most common reasons reported for poor communication in the operating room were noise level (28/36, 78%) and console-to bedside communication problems (23/36, 64%). CONCLUSION: Our study demonstrates a significant association between poor intraoperative team communication and worse surgical outcomes in robotic gynecologic surgery. Employing strategies to decrease extraneous room noise, improve console-to-bedside communication and team training may have a positive impact on communication and related surgical outcomes. PMID- 27493470 TI - Robotic Trachelectomy After Supracervical Hysterectomy for Benign Gynecologic Disease. AB - BACKGROUND AND OBJECTIVES: A renewed interest in the supra cervical approach to hysterectomy has created a cohort of patients with a retained cervix at risk of persistent symptoms requiring a subsequent trachelectomy. The objective of this study was to evaluate the efficacy of robotic trachelectomy after a previous supracervical hysterectomy. METHODS: This is a retrospective chart review of women who had robotic trachelectomy after supracervical hysterectomy for benign gynecologic disease from January 2009 through October 2014. RESULTS: Eleven patients underwent robotic trachelectomy for benign conditions during the observed period. Prior supracervical hysterectomy had been performed for pelvic pain (8/11, 73%), abnormal uterine bleeding (7/11, 64%), and dysmenorrhea (5/11, 45%). In 10 of 11 patients, the symptoms leading to robotic trachelectomy were the same as those leading to supracervical hysterectomy. The time from hysterectomy to recurrence of symptoms ranged from 0.5 to 26 months (median, 6), whereas the time interval from previous surgery to robotic trachelectomy ranged from 1 to 57 months (median, 26). Mean age and body mass index at robotic trachelectomy were 42 +/- 5.4 years and 32 +/- 6.1 kg/m(2). Mean length of surgery was 218 +/- 88 minutes (range, 100-405). There was 1 major postoperative complication involving bladder perforation and subsequent vesicovaginal fistula (VVF). Endometriosis was seen in 27% of pathologic specimens and cervicitis in another 27%; 45% showed normal tissue histology. In 6 (55%) cases, symptoms leading to trachelectomy resolved completely after surgery, and the other 5 (45%) patients reported a significant improvement. CONCLUSIONS: Although trachelectomy can be a challenging surgery, our experience suggests that the robotic approach may be a valuable means of achieving safe and reproducible outcomes. PMID- 27493471 TI - Laparoscopic Total Extraperitoneal Hernia Repair Outcomes. AB - BACKGROUND AND OBJECTIVES: Laparoscopic inguinal hernia repair has become increasingly popular as an alternative to open surgery. The purpose of this study was to evaluate the safety and effectiveness of the laparoscopic total extraperitoneal procedure with the use of staple fixation and polypropylene mesh. METHODS: A retrospective chart review examined outcomes of 1240 laparoscopic hernia operations in 783 patients, focusing on intraoperative and early postoperative complications, pain, and time until return to work and normal physical activities. RESULTS: There were no intraoperative complications in this series; 106 patients experienced early postoperative complications across 8 evaluated categories: urinary retention (4.1%), seroma (3.0%), testicular/hemiscrotal swelling (1.9%), testicular atrophy (0%), hydrocele (0.6%), mesh infection (0.1%), and neurological symptoms (transient, 1.0%; persistent, 0.2%). Patients used an average of 5.6 Percocet pills after the procedure, and mean times until return to work and normal activities, including their routine exercise regimen, were 3.0 and 3.8 days, respectively. CONCLUSION: Complication rates and convalescence times were considered equivalent or superior to those found in other studies assessing both laparoscopic and open techniques. The usage of multiple Endostaples did not result in increased neurologic complications in the early postoperative period when compared with findings in the literature. In the hands of an experienced surgeon, total extraperitoneal repair is a safe, effective alternative to open inguinal hernia repair. PMID- 27493472 TI - Students' Interest in Surgery Affects Laparoscopic Practicing Performance. AB - BACKGROUND AND OBJECTIVE: Earlier exposure to laparoscopic techniques is thought to be beneficial for medical students. Reports have demonstrated that practice improves performance in laparoscopies. In this study, we intended to evaluate whether medical students' interest in surgery is affected by the amount of practice and the performance on a laparoscopic simulator. METHODS: A laparoscopic simulation curriculum was introduced at Taipei Medical University, Wan-Fang Medical Center. Study participants included 36 sixth-year and 14 seventh-year students who were divided according to whether they had indicated an interest (group A) or not (group B) in surgery. The students had twice-a-week practice sessions for 2 weeks. They underwent baseline measurement (BM) before training and posttraining measurement (PTM). Self-guided practice on the simulator was allowed. The learning outcomes were assessed comparing the BM and PTM scores by using the interquartile range (IQR) test. We also tested the correlation between total score and number of self-guided practice sessions. RESULTS: All study participants showed improvement. No differences were observed between BM and PTM scores and between 6th- and 7th-year medical students. Significant differences were found in PTM scores between groups A and B (P < .001). Analysis of variance with a post hoc test for different groups revealed that the PTMs were significantly higher for both the 6th- and 7th-year medical students in group A than for those in group B (P < .001). Total performance scores were improved with a higher number of self-guided practice sessions. Linear regression analysis demonstrated a significant correlation between the number of self-guided practice sessions and total performance score (P < .001). CONCLUSION: Those clerks and interns interested in surgery who had more sessions for self-guided practice, displayed more improvement than those not interested in surgery did. Improvement in performance correlated highly with trainees' number of self-guided practice sessions. PMID- 27493473 TI - Safety and Efficacy of Polymeric Clips for Appendiceal Stump Closure. AB - BACKGROUND AND OBJECTIVES: Laparoscopic appendectomy remains one of the most common emergency general surgical procedures in the United States. In an era of increasing focus on costs in medical care, we sought to evaluate the use of polymeric clips to secure the appendiceal base during laparoscopic appendectomy. METHODS: We performed a prospective cohort study of patients undergoing laparoscopic appendectomy from April 2013 through September 2014 at a single academic teaching institution. Polymeric clips were used to secure the appendiceal stump. Tissue dissection techniques and control of the mesoappendix were the operating surgeon's choice. Clinical outcomes are reported. RESULTS: A total of 25 patients (56% women; mean age, 41 y; body mass index of 29 kg/m(2)) were enrolled in our study and underwent laparoscopic appendectomy with polymeric clips. One patient was unable to have polymeric clips placed due to inflammation of the appendiceal base. There were no major perioperative complications. One patient developed a suture abscess in the umbilical incision, and another had prolonged ileus with computed tomography demonstrating persistent pelvic fluid that did not require intervention. Median length of stay was 1 d and mean length of follow-up was 81 d. The use of polymeric clips contributed ~ $32 to the overall operative cost. CONCLUSIONS: Polymeric clips are a safe alternative for securing the appendiceal base in laparoscopic appendectomy. They offer significant cost savings without any evidence of increased complications. PMID- 27493474 TI - Comparative Transcriptome Analysis Reveals Substantial Tissue Specificity in Human Aortic Valve. AB - RNA sequencing (RNA-seq) has revolutionary roles in transcriptome identification and quantification of different types of tissues and cells in many organisms. Although numerous RNA-seq data derived from many types of human tissues and cell lines, little is known on the transcriptome repertoire of human aortic valve. In this study, we sequenced the total RNA prepared from two calcified human aortic valves and reported the whole transcriptome of human aortic valve. Integrating RNA-seq data of 13 human tissues from Human Body Map 2 Project, we constructed a transcriptome repertoire of human tissues, including 19,505 protein-coding genes and 4,948 long intergenic noncoding RNAs (lincRNAs). Among them, 263 lincRNAs were identified as novel noncoding transcripts in our data. By comparing transcriptome data among different human tissues, we observed substantial tissue specificity of RNA transcripts, both protein-coding genes and lincRNAs, in human aortic valve. Further analysis revealed that aortic valve-specific lincRNAs were more likely to be recently derived from repetitive elements in the primate lineage, but were less likely to be conserved at the nucleotide level. Expression profiling analysis showed significant lower expression levels of aortic valve specific protein-coding genes and lincRNA genes, when compared with genes that were universally expressed in various tissues. Isoform-level expression analysis also showed that a majority of mRNA genes had a major isoform expressed in the human aortic valve. To our knowledge, this is the first comparative transcriptome analysis between human aortic valve and other human tissues. Our results are helpful to understand the transcriptome diversity of human tissues and the underlying mechanisms that drive tissue specificity of protein-coding genes and lincRNAs in human aortic valve. PMID- 27493476 TI - Quality Improvement in Critical Care: Selection and Development of Quality Indicators. AB - Background. Caring for critically ill patients is complex and resource intensive. An approach to monitor and compare the function of different intensive care units (ICUs) is needed to optimize outcomes for patients and the health system as a whole. Objective. To develop and implement quality indicators for comparing ICU characteristics and performance within and between ICUs and regions over time. Methods. Canadian jurisdictions with established ICU clinical databases were invited to participate in an iterative series of face-to-face meetings, teleconferences, and web conferences. Eighteen adult intensive care units across 14 hospitals and 5 provinces participated in the process. Results. Six domains of ICU function were identified: safe, timely, efficient, effective, patient/family satisfaction, and staff work life. Detailed operational definitions were developed for 22 quality indicators. The feasibility was demonstrated with the collection of 3.5 years of data. Statistical process control charts and graphs of composite measures were used for data display and comparisons. Medical and nursing leaders as well as administrators found the system to be an improvement over prior methods. Conclusions. Our process resulted in the selection and development of 22 indicators representing 6 domains of ICU function. We have demonstrated the feasibility of such a reporting system. This type of reporting system will demonstrate variation between units and jurisdictions to help identify and prioritize improvement efforts. PMID- 27493477 TI - Who Needs to Be Allocated in ICU after Thoracic Surgery? An Observational Study. AB - Background. The effective use of ICU care after lung resections has not been completely studied. The aims of this study were to identify predictive factors for effective use of ICU admission after lung resection and to develop a risk composite measure to predict its effective use. Methods. 120 adult patients undergoing elective lung resection were enrolled in an observational prospective cohort study. Preoperative evaluation and intraoperative assessment were recorded. In the postoperative period, patients were stratified into two groups according to the effective and ineffective use of ICU. The use of ICU care was considered effective if a patient experienced one or more of the following: maintenance of controlled ventilation or reintubation; acute respiratory failure; hemodynamic instability or shock; and presence of intraoperative or postanesthesia complications. Results. Thirty patients met the criteria for effective use of ICU care. Logistic regression analysis identified three independent predictors of effective use of ICU care: surgery for bronchiectasis, pneumonectomy, and age >= 57 years. In the absence of any predictors the risk of effective need of ICU care was 6%. Risk increased to 25-30%, 66-71%, and 93% with the presence of one, two, or three predictors, respectively. Conclusion. ICU care is not routinely necessary for all patients undergoing lung resection. PMID- 27493475 TI - Computational Identification of Novel Genes: Current and Future Perspectives. AB - While it has long been thought that all genomic novelties are derived from the existing material, many genes lacking homology to known genes were found in recent genome projects. Some of these novel genes were proposed to have evolved de novo, ie, out of noncoding sequences, whereas some have been shown to follow a duplication and divergence process. Their discovery called for an extension of the historical hypotheses about gene origination. Besides the theoretical breakthrough, increasing evidence accumulated that novel genes play important roles in evolutionary processes, including adaptation and speciation events. Different techniques are available to identify genes and classify them as novel. Their classification as novel is usually based on their similarity to known genes, or lack thereof, detected by comparative genomics or against databases. Computational approaches are further prime methods that can be based on existing models or leveraging biological evidences from experiments. Identification of novel genes remains however a challenging task. With the constant software and technologies updates, no gold standard, and no available benchmark, evaluation and characterization of genomic novelty is a vibrant field. In this review, the classical and state-of-the-art tools for gene prediction are introduced. The current methods for novel gene detection are presented; the methodological strategies and their limits are discussed along with perspective approaches for further studies. PMID- 27493478 TI - The Perception and Estimation of Others' Pain according to Children. AB - Accurate interpretation of pain expressed by others is important for socialization; however, the development of this skill in children is still poorly understood. Empathy for pain models propose two main components (affective and cognitive), which develop at different stages of life. The study's objective was to investigate the children's ability between 3 and 12 years of age to detect and assess the pain intensity in others using visual stimuli depicting either facial expressions of pain or hands in painful contexts. 40 preschool children and 62 school-aged children were recruited. Children observed series of stimuli and evaluated the pain intensity depicted. Results demonstrated that children as young as three years old were able to detect and assess pain in both types of stimuli and this ability continued to improve until the age of 12. Participants demonstrated better detection performance with hands than with faces. Results were coherent with the idea that the two types of stimuli presented recruit different processes. Pain detection in hands appears to rely mostly on affective sharing processes that are effective early in life, while older children's higher ability to perceive pain in facial expressions suggests that this ability is associated with the gradual development of cognitive processes. PMID- 27493479 TI - Wnt/Beta-Catenin Signal Inhibitor HC-1 Sensitizes Oral Squamous Cell Carcinoma Cells to 5-Fluorouracil through Reduction of CD44-Positive Population. AB - BACKGROUND: Oral squamous cell carcinoma is a prevalent and frequently lethal malignancy worldwide. Existence of treatment-resistant cancer stem cells is considered to be associated with tumor formation, recurrence and metastasis. Wnt/beta-catenin signal is one of the crucial signaling pathways for cancer stem cells. Wnt/beta-catenin signal inhibitor may reduce the population of cancer stem cells and improve therapeutic effects on the cancers. METHODS: The effects of three derivatives of Wnt/beta-catenin signal inhibitors, HC-1, IC-2 and PN3-13, which we recently developed, on oral squamous cell carcinoma cell line HSC2, were examined by luciferase reporter assay, WST assay, cell sorting assay and apoptosis assay. RESULTS: The reporter assay showed that these small molecule compounds reduced Wnt/beta-catenin transcriptional activity in HSC2 cells. Of these compounds, IC-2 and PN3-13 inhibited cell viability in a dose-dependent manner, whereas HC-1 did not at even higher concentrations. Notably, however, the cell-sorting assay revealed that HC-1 significantly reduces the CD44-positive population of oral squamous cell carcinoma cells, compared to other compounds without affecting cell viability. In addition, HC-1 increases the cytotoxicity of HSC2 cells to 5-fluorouracil. The combination treatment of HC-1 with 5 fluorouracil significantly increased the apoptotic cells whereas treatment by either compound did not. CONCLUSION: These data suggest that HC-1 is an effective compound to target cancer stem cells, and the combination treatment of HC-1 and 5 fluorouracil can stimulate the tumor suppressive effect on oral squamous cell carcinoma cells. PMID- 27493480 TI - Effect of Gingerol on Cisplatin-Induced Pica Analogous to Emesis Via Modulating Expressions of Dopamine 2 Receptor, Dopamine Transporter and Tyrosine Hydroxylase in the Vomiting Model of Rats. AB - BACKGROUND: Gingerol, the generic term for pungent constituents in ginger, has been used for treating vomiting in China. We are going to investigate the mechanisms of inhibitive effect of gingerol on cisplatin-induced pica behaviour by studying on both peripheral and central levels, and the effects of gingerol on homeostasis of dopamine (DA) transmission: dopamine D2 receptor (D2R), dopamine transporter (DAT) and tyrosine hydroxylase (TH). METHODS: The antiemetic effect of gingerol was investigated on a vomiting model in rats induced by cisplatin 3 mg.kg(-1) intraperitoneal injection (i.p.). Rats were randomly divided into the normal control group (C), simple gingerol control group (CG), cisplatin control group (V), cisplatin + metoclopramide group (M), cisplatin + low-dose gingerol group (GL), cisplatin + middle-dose gingerol group (GM) and cisplatin + high-dose gingerol group (GH). In observation period, rats in Groups C and V were pretreated with sterile saline 3 mL i.g.; rats in Group CG were pretreated with gingerol 40 mg.kg(-1) i.g.; rats in Group M were pretreated with metoclopramide 2.5 mg.kg(-1) i.g.; rats in Groups GL, GM and GH were pretreated with gingerol 10, 20 and 40 mg.kg(-1) i.g. for 3 days, respectively. Cisplatin (3 mg.kg(-1), i.p.) was administered one time after each treatment with the antiemetic agent or its vehicle except the Groups C and CG. The distribution of D2R, DAT and TH in the area postrema and ileum were measured by immunohistochemistry and quantitated based on the image analysis, and the expression of DAT and TH in the area postrema and ileum were measured by RT-PCR. The weights of kaolin eaten of the remaining rats were observed in every 6 h continuously for 72 h. RESULTS: The weight of kaolin eaten in rats induced by cisplatin was significantly reduced by pretreatment with gingerol in a dose-dependent manner during the 0-24 h and 24-72 h periods (P < 0.05). Gingerol markedly improved gastric emptying induced by cisplatin in a dose-dependent manner (P < 0.05), and exhibited effective dose dependent inhibition on the increase of expression levels of D2R and TH and the decrease of expression levels of DAT in both the ileum and area postrema (P < 0.05). CONCLUSION: Gingerol is effective on cisplatin-induced emesis in rats possibly by inhibiting central or peripheral increase of DA by inhibiting D2R, TH and accelerating DAT. PMID- 27493481 TI - Pharmacokinetic Interaction Study of Ranitidine and Daijokito in Healthy Volunteers. AB - BACKGROUND: Ranitidine is a histamine 2 receptor antagonist, and daijokito is a Kampo (Chinese herbal medicine as practiced in Japan) formula, which is traditionally used for treating constipation and digestive trouble. Previous study demonstrated that daijokito significantly affected the pharmacokinetics of ranitidine in rats; however, the doses of ranitidine and daijokito in that study were higher than in clinical practice. Therefore, we examined the pharmacokinetic interaction between ranitidine and daijokito in clinical practice doses in healthy volunteers. METHODS: This was a randomized, open label, two-period crossover study in healthy volunteers (n = 7). Volunteers received administrations of either a single dose of ranitidine 300 mg, or ranitidine 300 mg in combination with daijokito extract granules 2.5 g. Plasma concentrations of ranitidine were measured over 12 h by LC/MS/MS method. RESULTS: Plasma concentrations of ranitidine were lower with co-administration of daijokito compared with ranitidine alone. Co-administration of daijokito significantly decreased ranitidine area under the plasma concentration-time curve from 0 to 12 h (AUC0-12) and maximum plasma concentration (Cmax) with geometric mean (GM) ratio [90% confidence interval (CI)] for AUC0-12 of 0.609 (0.449, 0.826) and Cmax of 0.515 (0.345, 0.771). CONCLUSION: Co-administration of ranitidine with daijokito resulted in a significant decrease in plasma level of ranitidine in healthy volunteers. PMID- 27493482 TI - Clinical Diagnosis of Mendelian Disorders Using a Comprehensive Gene-Targeted Panel Test for Next-Generation Sequencing. AB - BACKGROUND: Genetic diagnoses provide beneficial information to patients and families. However, traditional genetic diagnoses are often difficult even for experienced clinicians and require recognition of characteristic patterns of signs or symptoms to guide targeted genetic testing for the confirmation of diagnoses. Next-generation sequencing (NGS) is a powerful genetic diagnostic tool. However, whole-genome and whole-exome sequencing (WES) are expensive, and the interpretation of results is difficult. Hence, target gene capture sequencing of gene panels has recently been applied to genetic diagnoses. Herein, we demonstrate that targeted sequencing approaches using gene panel testing are highly efficient for the diagnosis of Mendelian disorders. METHODS: NGS using TruSight one gene panel was performed in 17 families and 20 patients, and we developed a bioinformatic pipeline at our institution for detecting mutations. RESULTS: We detected causative mutations in 6 of 17 (35%) families. In particular, 11 (65%) families had syndromic diagnosis and 6 (35%) had no syndromic diagnosis before NGS testing. The number of positive diagnoses was 5 of 11 (45%) in the syndromic group and were 1 of 6 (17%) among patients of the no syndromic diagnosis group. CONCLUSION: Diagnostic yields in the present study were higher than in previous reports of genetic and chromosomal tests and WES. The present comprehensive gene-targeted panel test is a powerful diagnostic tool for Mendelian disorders. PMID- 27493483 TI - Prion Protein and Stage Specific Embryo Antigen 1 as Selection Markers to Enrich the Fraction of Murine Embryonic Stem Cell-Derived Cardiomyocytes. AB - BACKGROUND: The prion protein (PrP) might be useful as a tool to collect cardiac progenitor cells derived from embryonic stem (ES) cells. It is also possible that PrP(+) cells include undifferentiated cells with a capacity to develop into tumors. METHODS: PrP(+) cells isolated from embryoid bodies (EB) formed by mouse AB1 ES cells were examined using RT-PCR analysis and clonogeneic cell assay. To assess their potential to differentiate into cardiomyocytes, Nkx2.5(GFP/+) (hcgp7) cells, another ES cell line that carries the GFP reporter gene in the Nkx2.5 loci, were used. RESULTS: PrP(+) cells isolated from EB of day 7 and 14 did not express pluripotency markers, but expressed cardiac cell markers, while PrP(+) cells isolated from EB of day 21 expressed pluripotency markers. Cultured PrP(+) cells isolated from EB of day 21 expressed pluripotency markers to form colonies, whereas those isolated from EB of day 7 and 14 did not. To exclude proliferating cells from PrP(+) cells, stage specific embryo antigen 1 (SSEA1) was employed as a second marker. PrP(+)/SSEA1(-) cells did not proliferate and expressed cardiac cell markers, while PrP(+)/SSEA1(+) did proliferate. CONCLUSION: PrP(+) cells isolated from EB included undifferentiated cells in day 21. PrP(+)/SSEA1(-) cells included cardiomyoctes, suggesting PrP and SSEA1 may be useful as markers to enrich the fraction of cardiomyocytes. PMID- 27493484 TI - The First Pilot Comprehensive Evaluation of the Outcomes of Different Types of Robotic Surgeries in the Different Surgical Departments: The Penta, Tetra and Trifecta Achievements in Robotic Surgeries. AB - BACKGROUND: To ensure safe performance in robotic surgery, the Minimal Invasive Surgery Center (MISC) is composed of the anesthesiology department, five surgery departments and co-medical staff in our institution. The objective of this study was to evaluate the outcomes of different types of robotic surgeries for cancer treatment (n = 326) from different surgery departments in the MISC. METHODS: The outcomes of robot-assisted radical prostatectomy (RARP), partial nephrectomy (RAPN), transoral robotic surgery (TORS) for pharyngeal cancer, and robotic surgery for lung, gastric and rectal cancer were evaluated using the similar concept of pentafecta in RARP. RESULTS: The pentafecta rates of RARP and robotic surgery for rectal cancer were 33.3 and 56.5%, respectively. The tetrafecta rates of RARP (excluding potency evaluation from pentafecta) and TORS were 48.4 and 57.1%, respectively. The trifecta rates of RAPN, robotic surgeries for lung and gastric cancer were 75.9, 74.2 and 84.2%, respectively. The failure of tetrafecta in RARP achievement was significantly associated with high risk than with low risk according to National Comprehensive Cancer Network classification. CONCLUSION: This is the world's first comprehensive evaluation of different types of robotic surgeries for cancer treatment in the constitutional framework of an academic institution. MISC, which provides the constitutional framework of an academic institution, is providing immeasurable benefits in terms of robotic surgery quality, and it may ultimately lead to high penta-, tetra-, and trifecta rates for robotic surgeries for cancer treatment in all surgical departments. PMID- 27493485 TI - Transurethral En Bloc Resection of Bladder Tumor Using an Endoscopic Submucosal Dissection Technique: Preliminary Results in an Animal Model. AB - BACKGROUND: Transurethral resection of bladder tumor (TURBT) technique has been considered the routine method for removing most bladder tumors for decades. In contrast, endoscopic submucosal dissection (ESD) is the gold-standard treatment for gastrointestinal superficial tumors. We investigated the effectiveness and applicability of a new technique for en bloc bladder tumor resection using ESD procedure. METHODS: Four Landrace Large White Duroc female pigs were anesthetized with isoflurane prior endoscopic resection using a large-caliber prototype fiber bronchoscope. After local infiltration of the submucosa with sodium hyaluronate using an injector needle, a section of the target area (1.0-2.0 cm diameter circular area) was cut with the Dual Knife. RESULTS: In total, seven target sections were resected from the pigs. The median size of the resected sections was 1.8 cm (range 1.0-2.5 cm) and the median time taken to perform the resection of one section was 20 min (range 4-35 min). These target sections were completely resected en bloc. Although the small bladder perforations occurred on two occasions, no other short-term complications such as uncontrollable bleeding were observed. CONCLUSION: This procedure is a slightly difficult in the pigs with thin bladder walls. However, this procedure with the slim flexible cystoscope may allow us to be able to remove bladder tumors using only light sedation, especially for cases when small tumor recurrence is observed during routine cystoscopy for the patients with non-muscle invasive bladder cancer. PMID- 27493486 TI - Effect of Daisaikoto on Expressions of SIRT1 and NF-kappaB of Diabetic Fatty Liver Rats Induced by High-Fat Diet and Streptozotocin. AB - BACKGROUND: Daisaikoto (DSKT), a classical traditional Chinese herbal formula, has been used for treating digestive diseases for 1800 years in China. Therefore, in this study, we are going to investigate the effect of DSKT on diabetic fatty liver rats induced by a high-fat diet and streptozotocin (STZ), and the effects of DSKT on silent mating type information regulation 2 homolog 1 (SIRT1) and nuclear factor kappa B (NF-kappaB). METHODS: Diabetic fatty liver rat model was selected to establish a high-fat diet and STZ. Sixty Wistar rats were divided into six groups (n = 10): control group, high-fat diet + STZ group, simvastatin treatment group, DSKT low dose, medial dose and high dose treatment groups. After 8 weeks of drug intervention, body and liver weights, blood chemistry, blood glucose and insulin were examined. The expressions of sirtuin 1 and NF-kappaB in the liver were observed by RT-PCR and immunohistochemistry, respectively. RESULTS: A high-fat diet increased body, liver weights, and serum cholesterol concentrations. Intraperitoneal injection of STZ increased blood glucose and decreased body weights. DSKT improved them. Homeostasis model assessment estimated insulin resistance (HOMA-IR) indices were increased in the high-fat diet groups. DSKT improved them too. In histological examinations of the liver, we observed a significant improvement after treatment. Immunostaining expression of NF-kappaB in the liver was improved by DSKT and simvastatin. The mRNA expressions of SIRT1 in the liver were increased by DSKT and simvastatin. CONCLUSION: We have demonstrated that DSKT is capable of reversing dyslipidemia and insulin resistance induced by a high-fat diet and STZ. High dose DSKT reveals a stronger effect than simvastatin on the expressions of SIRT1 and NF-kappaB. Furthermore, DSKT has shown a strong dose-depended protective effect on diabetic fatty liver. PMID- 27493487 TI - Recipient Vessel Selection in Head and Neck Reconstruction Based on the Type of Neck Dissection. AB - BACKGROUND: Recipient vessel selection in head and neck reconstruction using free flap transfers has to be standardized. However, the recipient vessel selection based on the type of neck dissection has yet to be investigated. We describe the relationship between the type of neck dissection and recipient vessel. METHODS: Records of 107 consecutive patients who had undergone head and neck reconstruction using free flap transfers from 2011 to 2015 were reviewed retrospectively. Ninety-five were men and 12 were women, with a mean age of 65.6 years. Patients were divided into 5 groups based on the type of neck dissection: no neck dissection (NND, n = 17), upper jugular neck dissection, (UJND, n = 1), supraomohyoid neck dissection (SOND, n = 18), jugular neck dissection (JND, n = 39), and modified radical neck dissection (mRND, n = 32). We details the number of recipient vessels we selected for free tissue transfer in head and neck reconstruction depending on the type of neck dissection. RESULTS: The overall patency rate was 100%. The superficial temporal artery was used most frequently in NND; the superior thyroid artery in SOND; the transverse cervical artery in JND; and the transverse cervical artery in mRND. The superficial temporal vein was used most frequently in NND; The internal jugular vein in the SOND; and The external jugular vein in mRND. CONCLUSION: Microsurgeons should remember that proper recipient vessel selection depending on the type of neck dissection is important. We believe proper recipient vessel selection should improve results of head and neck reconstruction using free flap transfer. PMID- 27493488 TI - Correlation between Ultrasound Findings of Tumor Margin and Clinicopathological Findings in Patients with Invasive Ductal Carcinoma of the Breast. AB - BACKGROUND: Breast ultrasound findings regarding tumor margins are crucial in judging whether a tumor is malignant or benign. However, the relationships between the margins and clinicopathological characteristics remain largely unknown. In this study, we examined the clinicopathological characteristics of patients with invasive ductal carcinoma whose ultrasound images showed either well-defined and rough or indistinct margins. METHODS: Of all consecutive patients diagnosed with invasive ductal carcinoma at the Division of Breast and Endocrine Surgery of Tottori University Hospital from January 2012 to December 2014, 122 patients whose ultrasound images showed either "well-defined and rough" or "indistinct" tumor margins were included in this study. Mammography and ultrasound images taken at the initial examination were reviewed. Patients were divided into two groups based on ultrasound findings of the tumor margins: the "well-defined and rough group" and the "indistinct group." The relationships among ultrasound findings, mammography findings and clinicopathological findings were investigated in the two groups. RESULTS: The well-defined and rough group was more likely to contain solid-tubular carcinoma, while the indistinct group was more likely to contain scirrhous carcinoma. The MIB-1 index was higher in the well-defined and rough group than in the indistinct group. Additionally, the proportion of patients with nuclear grade 3, estrogen receptor negative/progesterone receptor-negative, and triple-negative breast cancer was greater in the well-defined and rough group than in the indistinct group. CONCLUSION: Invasive ductal carcinomas with well-defined and rough margins on ultrasound were likely to be malignant and proliferative than those with indistinct margins. PMID- 27493489 TI - EEG Power Spectrum Analysis in Children with ADHD. AB - BACKGROUND: Attention deficit disorder/hyperactivity disorder (ADHD) is a pathological condition that is not fully understood. In this study, we investigated electroencephalographic (EEG) power differences between children with ADHD and healthy control children. METHODS: EEGs were recorded as part of routine medical care received by 80 children with ADHD aged 4-15 years at the Department of Pediatric Neurology in Tottori University Hospital. Additionally, we recorded in 59 control children aged 4-15 years after obtaining informed consent. Specifically, awake EEG signals were recorded from each child using the international 10-20 system, and we used ten 3-s epochs on the EEG power spectrum to calculate the powers of individual EEG frequency bands. RESULTS: The powers of different EEG bands were significantly higher in the frontal brain region of those in the ADHD group compared with the control group. In addition, the power of the beta band in the ADHD group was significantly higher in all brain regions, except for the occipital region, compared with control children. With regard to developmental changes, the power of the alpha band in the occipital region showed an age-dependent decrease in both groups, with slightly lower power in the ADHD group. Additionally, the intergroup difference decreased in children aged 11 years or older. As with the alpha band in the occipital region, the beta band in the frontal region showed an age-dependent decrease in both groups. Unlike the alpha band, the power of the beta band was higher in the ADHD group than in the control group for children of all ages. CONCLUSION: The observed intergroup differences in EEG power may provide insight into the brain function of children with ADHD. PMID- 27493490 TI - Evaluation of an Hprt-Luciferase Reporter Gene on a Mammalian Artificial Chromosome in Response to Cytotoxicity. AB - BACKGROUND: Hypoxanthine guanine phosphoribosyltransferase (Hprt) is known as a house-keeping gene, and has been used as an internal control for real-time quantitative RT-PCR and various other methods of gene expression analysis. To evaluate the Hprt mRNA levels as a reference standard, we engineered a luciferase reporter driven by a long Hprt promoter and measured its response to cytotoxicity. METHODS: We constructed a reporter vector that harbored a phiC31 integrase recognition site and a mouse Hprt promoter fused with green-emitting luciferase (SLG) coding sequence. The Hprt-SLG vector was loaded onto a mouse artificial chromosome containing a multi-integrase platform using phiC31 integrase in mouse A9 cells. We established three independent clones. RESULTS: The established cell lines had similar levels of expression of the Hprt-SLG reporter gene. Hprt-SLG activity increased proportionately under growth conditions and decreased under cytotoxic conditions after blasticidin or cisplatin administration. Similar increases and decreases in the SLG luminescent were observed under growth and cytotoxic conditions, respectively, to those in the fluorescent obtained using the commercially available reagent, alamarBlue. CONCLUSION: By employing a reliable and stable expression system in a mammalian artificial chromosome, the activity of an Hprt-SLG reporter can reflect cell numbers under cell growth condition and cell viability in the evaluation of cytotoxic conditions. PMID- 27493491 TI - Melanoma of the Umbilicus: A Patient Report, Precaution in Operative Strategy, and the First Histopathological Review of Published Cases. AB - Umbilical melanoma is extremely rare. Among the past English reports on umbilical melanoma, there are only 8 reports in which histopathology was described in detail, and there has been no report with a review of the histopathology of previously reported cases. We experienced a case of umbilical melanoma and reviewed previously reported cases including our case. Because of the anatomical location, it is difficult to become aware of the umbilical melanoma unless there are some concomitant symptoms such as discharge or swelling. Even with these symptoms, patients tend to postpone a hospital visit for unknown reasons, resulting in increased risk of tumor growth and metastasis. When performing resection of umbilical melanoma, a portion of the peritoneum should also be removed. Sentinel lymph nodes can be axilla or inguinal lymph nodes. There is a possibility of metastasis to the preoperative abdominal cavity or to nearby skin through hematogenous spread. Preoperative evaluation of tumor spread and postoperative observation are important for umbilical melanoma in order to detect recurrence or metastasis because of its unique anatomical location. PMID- 27493492 TI - Mapping of the local environmental changes in proteins by cysteine scanning. AB - Protein conformational changes, which regulate the activity of proteins, are induced by the alternation of intramolecular interactions. Therefore, the detection of the local environmental changes around the key amino acid residues is essential to understand the activation mechanisms of functional proteins. Here we developed the methods to scan the local environmental changes using the vibrational band of cysteine S-H group. We validated the sensitivity of this method using bathorhodopsin, a photoproduct of rhodopsin trapped at liquid nitrogen temperature, which undergoes little conformational changes from the dark state as shown by the X-ray crystallography. The cysteine residues were individually introduced into 15 positions of Helix III, which contains several key amino acid residues for the light-induced conformational changes of rhodopsin. The shifts of S-H stretching modes of these cysteine residues and native cysteine residues upon the formation of bathorhodopsin were measured by Fourier transform infrared spectroscopy. While most of cysteine residues demonstrated no shift of S-H stretching mode, cysteine residues introduced at positions 117, 118, and 122, which are in the vicinity of the chromophore, demonstrated the significant changes. The current results are consistent with the crystal structure of bathorhodopsin, implying that the cysteine scanning is sensitive enough to detect the tiny conformational changes. PMID- 27493493 TI - alpha-helix formation rate of oligopeptides at subzero temperatures. AB - In 1999, Clarke et al. ((1999) Proc. Natl. Acad. Sci. USA 96, 7232-7237) reported that the nucleation rate of alpha-helix of oligopeptide AK16 is as slow as 60 ms. In the present study, we measured the nucleation rate of oligopeptide, C17 (DLTDDIMCVKKILDKVG, corresponding to alpha-helical region of 84th to 100th amino acids of bovine alpha-lactalbumin) using the same method as Clarke et al. We found only initial bursts of the increase of alpha-helices at temperatures higher than -50 degrees C in the presence of 70% methanol. The result with AK16 was the same as Clarke et al. reported. We also found that the folding rate of polyglutamic acid is too fast to be detected by the stopped-flow apparatus at 4 degrees C. These results demonstrate that the alpha-helix formation rates in C17, AK16 and polyglutamic acid are shorter than the dead time of the stopped-flow apparatus (6 ms). PMID- 27493494 TI - Optimal terminal sequences for continuous or serial isothermal amplification of dsRNA with norovirus RNA replicase. AB - The norovirus RNA replicase (NV3D(pol), 56 kDa, single chain monomeric protein) can amplify double-stranded (ds) RNA isothermally. It will play an alternative role in the in vitro evolution against traditional Qbeta RNA replicase, which cannot amplify dsRNA and consists of four subunits, three of which are borrowed from host E.coli. In order to identify the optimal 3'-terminal sequence of the RNA template for NV3D(pol), an in vitro selection using the serial transfer was performed for a random library having the 3'-terminal sequence of ---UUUUUUNNNN 3'. The population landscape on the 4-dimensional sequence space of the 17(th) round of transfer gave a main peak around ---CAAC-3'. In the preceding studies on the batch amplification reaction starting from a single-stranded RNA, a template with 3'-terminal C-stretch was amplified effectively. It was confirmed that in the batch amplification the ---CCC-3' was much more effective than the ---CAAC 3', but in the serial transfer condition in which the ----CAAC-3' was sustained stably, the ---CCC-3' was washed out. Based on these results we proposed the existence of the "shuttle mode" replication of dsRNA. We also proposed the optimal terminal sequences of RNA for in vitro evolution with NV3D(pol). PMID- 27493495 TI - Uncovering the mechanism for selective control of the visible and near-IR absorption bands in bacteriochlorophylls a, b and g. AB - Bacteriochlorophylls (BChls) play an important role as light harvesters in photosynthetic bacteria. Interestingly, bacteriochlorophylls (BChls) a, b, and g selectively tune their visible (Qx) and near IR (Qy) absorption bands by the substituent changes. In this paper, we theoretically study the mechanism for the selective control of the absorption bands. Density functional theory (DFT) and time-dependent DFT (TD-DFT) and four-orbital model analyses reveal that the selective red-shift of the Qy band with the substituent change from BChl a to b occurs with the lower-energy shift of the (HOMO, LUMO) excited state directly induced by the molecular-orbital energy changes. In contrast, the Qx band hardly shifts by the cancellation between the higher- and lower-energy shifts of the (HOMO-1, LUMO) excited state directly induced by the molecular-orbital energy changes and configuration interaction, respectively. On the other hand, with the substituent changes from BChl a to g, the Qx band selectively blue-shifts by the larger higher-energy shift of the (HOMO-1, LUMO) excited state directly induced by the molecular-orbital energy shifts than the lower-energy shift due to the configuration interaction. In contrast, the Qy band hardly shifts by the cancellation between the higher- and lower-energy shifts of the (HOMO, LUMO) excited state directly induced by the molecular-orbital energy changes and configuration interaction, respectively. Our work provides the important knowledge for understanding how nature controls the light-absorption properties of the BChl dyes, which might be also useful for design of porphyrinoid chromophores. PMID- 27493496 TI - Effect of the MotB(D33N) mutation on stator assembly and rotation of the proton driven bacterial flagellar motor. AB - The bacterial flagellar motor generates torque by converting the energy of proton translocation through the transmembrane proton channel of the stator complex formed by MotA and MotB. The MotA/B complex is thought to be anchored to the peptidoglycan (PG) layer through the PG-binding domain of MotB to act as the stator. The stator units dynamically associate with and dissociate from the motor during flagellar motor rotation, and an electrostatic interaction between MotA and a rotor protein FliG is required for efficient stator assembly. However, the association and dissociation mechanism of the stator units still remains unclear. In this study, we analyzed the speed fluctuation of the flagellar motor of Salmonella enterica wild-type cells carrying a plasmid encoding a nonfunctional stator complex, MotA/B(D33N), which lost the proton conductivity. The wild-type motor rotated stably but the motor speed fluctuated considerably when the expression level of MotA/B(D33N) was relatively high compared to MotA/B. Rapid accelerations and decelerations were frequently observed. A quantitative analysis of the speed fluctuation and a model simulation suggested that the MotA/B(D33N) stator retains the ability to associate with the motor at a low affinity but dissociates more rapidly than the MotA/B stator. We propose that the stator dissociation process depends on proton translocation through the proton channel. PMID- 27493497 TI - Reconstitution of intracellular environments in vitro and in artificial cells. AB - Toward reconstitution of living cells by artificial cells technology, it is critical process to understand the differences between mixtures of biomolecules and living cells. For the aim, we have developed procedures for preparation of an additive-free cell extract (AFCE) and for concentrating biomacromolecules in artificial cells. In this review, we introduce our recent progress to reconstitute intracellular environments in vitro and in artificial cells. PMID- 27493498 TI - Ultrasensitive enzyme-linked immunosorbent assay (ELISA) of proteins by combination with the thio-NAD cycling method. AB - An ultrasensitive method for the determination of proteins is described that combines an enzyme-linked immunosorbent assay (ELISA) and a thionicotinamide adenine dinucleotide (thio-NAD) cycling method. A sandwich method using a primary and a secondary antibody for antigens is employed in an ELISA. An androsterone derivative, 3alpha-hydroxysteroid, is produced by the hydrolysis of 3alpha hydroxysteroid 3-phosphate with alkaline phosphatase linked to the secondary antibody. This 3alpha-hydroxysteroid is oxidized to a 3-ketosteroid by 3alpha- hydroxysteroid dehydrogenase (3alpha-HSD) with a cofactor thio-NAD. By the opposite reaction, the 3-ketosteroid is reduced to a 3alpha-hydroxysteroid by 3alpha-HSD with a cofactor NADH. During this cycling reaction, thio-NADH accumulates in a quadratic function-like fashion. Accumulated thio-NADH can be measured directly at an absorbance of 400 nm without any interference from other cofactors. These features enable us to detect a target protein with ultrasensitivity (10(-19) mol/assay) by measuring the cumulative quantity of thio NADH. Our ultrasensitive determination of proteins thus allows for the detection of small amounts of proteins only by the application of thio-NAD cycling reagents to the usual ELISA system. PMID- 27493499 TI - Familial clustering of mice consistent to known pedigrees enabled by the genome profiling (GP) method. AB - Familial clustering without any prerequisite knowledge becomes often necessary in Behavioral Science, and forensic studies in case of great disasters like Tsunami and earthquake requiring body-identification without any usable information. However, there has been no well-established method for this purpose although conventional ones such as short tandem repeats (STR) and single nucleotide polymorphism (SNP), which might be applied with toil and moil to some extent. In this situation, we could find that the universal genome distance-measuring method genome profiling (GP), which is made up of three elemental techniques; random PCR, micro-temperature gradient gel electrophoresis (MUTGGE), and computer processing for normalization, can do this purpose with ease when applied to mouse families. We also confirmed that the sequencing approach based on the ccgf (commonly conserved genetic fragment appearing in the genome profile) was not completely discriminative in this case. This is the first demonstration that the familial clustering can be attained without a priori sequence information to the level of discriminating strains and sibling relationships. This method can complement the conventional approaches in preliminary familial clustering. PMID- 27493500 TI - Structural and mutation studies of two DNA demethylation related glycosylases: MBD4 and TDG. AB - Two mammalian DNA glycosylases, methyl-CpG binding domain protein 4 (MBD4) and thymine DNA glycosylase (TDG), are involved in active DNA demethylation via the base excision repair pathway. Both MBD4 and TDG excise the mismatch base from G:X, where X is uracil, thymine, and 5-hydroxymethyluracil (5hmU). In addition, TDG excises 5mC oxidized bases i.e. when X is 5-formylcytosine (5fC), and 5 carboxylcytosine (5caC) not 5-hydroxymethylcytosine (5hmC). A MBD4 inactive mutant and substrate crystal structure clearly explains how MBD4 glycosylase discriminates substrates: 5mC are not able to be directly excised, but a deamination process from 5mC to thymine is required. On the other hand, TDG is much more complicated; in this instance, crystal structures show that TDG recognizes G:X mismatch DNA containing DNA and G:5caC containing DNA from the minor groove of DNA, which suggested that TDG might recognize 5mC oxidized product 5caC like mismatch DNA. In mutation studies, a N157D mutation results in a more 5caC specific glycosylase, and a N191A mutation inhibits 5caC activity while that when X=5fC or T remains. Here I revisit the recent MBD4 glycos ylase domain co-crystal structures with DNA, as well as TDG glycosylase domain co crystal structures with DNA in conjunction with its mutation studies. PMID- 27493501 TI - Myosin V is a biological Brownian machine. AB - Myosin V is a vesicle transporter that unidirectionally walks along cytoskeletal actin filaments by converting the chemical energy of ATP into mechanical work. Recently, it was found that myosin V force generation is a composition of two processes: a lever-arm swing, which involves a conformational change in the myosin molecule, and a Brownian search-and-catch, which involves a diffusive "search" by the motor domain that is followed by an asymmetric "catch" in the forward actin target such that Brownian motion is rectified. Here we developed a system that combines optical tweezers with DNA nano-material to show that the Brownian search-and-catch mechanism is the energetically dominant process at near stall force, providing 13 kBT of work compared to just 3 kBT by the lever-arm swing. Our result significantly reconsiders the lever-arm swinging model, which assumes the swing dominantly produces work (>10 kBT), and sheds light on the Brownian search-and-catch as a driving process. PMID- 27493502 TI - Morphological and physiological characteristics of dermal photoreceptors in Lymnaea stagnalis. AB - Dermal photoreceptors located in the mantle of Lymnaea stagnalis were histologically and physiologically characterized. Our previous study demonstrated that the shadow response from dermal photoreceptors induces the whole-body withdrawal response. Through the interneuron, RPeD11, we detected that the light off response indirectly originated from a dermal photoreceptor. Previous observations, based on behavioral pharmacology, revealed that cyclic guanosine monophosphate acts as a second messenger in the dermal photoreceptor. Furthermore, gastropods possess dermal photoreceptors containing rhodopsin, as a photopigment, and another photo-sensitive protein, arrestin, responsible for terminating the light response. Thus, we chose three antibodies, anti-cGMP, anti rhodopsin, and anti-beta-arrestin, to identify the dermal photoreceptor molecules in Lymnaea mantle. Extracellular recording, using a suction electrode on the mantle, revealed a light off-response from the right parietal nerve. Overlapping structures, positive against each of the antibodies, were also observed. Numerous round, granular particles of 3-47 MUm in diameter with one nucleus were distributed around pneumostome and/or inside the mantle. The cells surrounding the pneumostome area, located 10 MUm beneath the surface, tended to have smaller cell soma ranging from 3 to 25 MUm in diameter, while cells located in other areas were distributed uniformly inside the mantle, with a larger diameter ranging from 12 to 47 MUm. The histological examination using back-filing Lucifer Yellow staining of the right parietal nerve with the three dermal photoreceptor antibodies confirmed that these overlapping-stained structures were dermal photoreceptors in Lymnaea. PMID- 27493503 TI - 3-D structural analysis of the crucial intermediate of skeletal muscle myosin and its role in revised actomyosin cross-bridge cycle. AB - Skeletal myosin S1 consists of two functional segments, a catalytic-domain and a lever-arm. Since the crystal structure of ADP/Vi-bound S1 exhibits a strong intramolecular flexure between two segments, inter-conversion between bent and extended forms; i.e. "tilting of the lever-arm" has been accepted as the established molecular mechanism of skeletal muscle contraction. We utilized quick freeze deep-etch replica electron microscopy to directly visualize the structure of in vitro actin-sliding myosin, and found the existence of a novel oppositely bent configuration, instead of the expected ADP/Vi-bound form. We also noticed that SH1-SH2 cross-linked myosin gives an aberrant appearance similar to the above structure. Since SH1-SH2-cross-linked myosin is a well-studied analogue of the transient intermediate of the actomyosin cross-bridge cycle, we devised a new image-processing procedure to define the relative view-angles between the catalytic-domain and the lever-arm from those averaged images, and built a 3-D model of the new conformer. The lever-arm in that model was bent oppositely to the ADP/Vi-bound form, in accordance with observed actin-sliding cross-bridge structure. Introducing this conformer as the crucial intermediate that transiently appears during sliding, we propose a revised scheme of the cross bridge cycle. In the scenario, the novel conformer keeps actin-binding in two different modes until it forms a primed configuration. The final extension of the lever-arm back to the original rigor-state constitutes the "power-stroke". Various images observed during sliding could be easily interpreted by the new conformer. Even the enigmatic behavior of the cross-bridges reported as "loose chemo-mechanical coupling" might be adequately explained under some assumptions. PMID- 27493504 TI - Cooperation between phenotypic plasticity and genetic mutations can account for the cumulative selection in evolution. AB - We propose the cooperative model of phenotype-driven evolution, in which natural selection operates on a phenotype caused by both genetic and epigenetic factors. The conventional theory of evolutionary synthesis assumes that a phenotypic value (P) is the sum of genotypic value (G) and environmental deviation (E), P=G+E, where E is the fluctuations of the phenotype among individuals in the absence of environmental changes. In contrast, the cooperative model assumes that an evolution is triggered by an environmental change and individuals respond to the change by phenotypic plasticity (epigenetic changes). The phenotypic plasticity, while essentially qualitative, is denoted by a quantitative value F which is modeled as a normal random variable like E, but with a much larger variance. Thus, the fundamental equation of the cooperative model is given as P=G+F where F includes the effect of E. Computer simulations using a genetic algorithm demonstrated that the cooperative model realized much faster evolution than the evolutionary synthesis. This accelerated evolution was found to be due to the cumulative evolution made possible by a ratchet mechanism due to the epigenetic contribution to the phenotypic value. The cooperative model can well account for the phenomenon of genetic assimilation, which, in turn, suggests the mechanism of cumulative selection. The cooperative model may also serve as a theoretical basis to understand various ideas and phenomena of the phenotype-driven evolution such as genetic assimilation, the theory of facilitated phenotypic variation, and epigenetic inheritance over generations. PMID- 27493505 TI - Microscopic heat pulse-induced calcium dynamics in single WI-38 fibroblasts. AB - Temperature-sensitive Ca(2+) dynamics occur primarily through transient receptor potential channels, but also by means of Ca(2+) channels and pumps on the endoplasmic reticulum membrane. As such, cytoplasmic Ca(2+) concentration ([Ca(2+)]cyt) is re-equilibrated by changes in ambient temperature. The present study investigated the effects of heat pulses (heating duration: 2 s or 150 s) on [Ca(2+)]cyt in single WI-38 fibroblasts, which are considered as normal cells. We found that Ca(2+) burst occurred immediately after short (2 s) heat pulse, which is similar to our previous report on HeLa cells, but with less thermosensitivity. The heat pulses originated from a focused 1455-nm infrared laser light were applied in the vicinity of cells under the optical microscope. Ca(2+) bursts induced by the heat pulse were suppressed by treating cells with inhibitors for sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) or inositol trisphosphate receptor (IP3R). Long (150 s) heat pulses also induced Ca(2+) bursts after the onset of heating and immediately after re-cooling. Cells were more thermosensitive at physiological (37 degrees C) than at room (25 degrees C) temperature; however, at 37 degrees C, cells were responsive at a higher temperature (ambient temperature+heat pulse). These results strongly suggest that the heat pulse-induced Ca(2+) burst is caused by a transient imbalance in Ca(2+) flow between SERCA and IP3R, and offer a potential new method for thermally controlling Ca(2+)-regulated cellular functions. PMID- 27493506 TI - Electrophysiological characteristics of feeding-related neurons after taste avoidance Pavlovian conditioning in Lymnaea stagnalis. AB - Taste avoidance conditioning (TAC) was carried out on the pond snail, Lymnaea stagnalis. The conditional stimulus (CS) was sucrose which elicits feeding behavior; while the unconditional stimulus (US) was a tactile stimulus to the head which causes feeding to be suppressed. The neuronal circuit that drives feeding behavior in Lymnaea is well worked out. We therefore compared the physiological characteristics on 3 classes of neurons involved with feeding behavior especially in response to the CS in conditioned vs. control snails. The cerebral giant cell (CGC) modulates feeding behavior, N1 medial neuron (N1M) is one of the central pattern generator neurons that organizes feeding behavior, while B3 is a motor neuron active during the rasp phase of feeding. We found the resting membrane potential in CGC was hyperpolarized significantly in conditioned snails but impulse activity remained the same between conditioned vs. control snails. There was, however, a significant increase in spontaneous activity and a significant depolarization of N1M's resting membrane potential in conditioned snails. These changes in N1M activity as a result of training are thought to be due to withdrawal interneuron RPeD11 altering the activity of the CGCs. Finally, in B3 there was: 1) a significant decrease in the amplitude and the frequency of the post-synaptic potentials; 2) a significant hyperpolarization of resting membrane potential in conditioned snails; and 3) a disappearance of bursting activity typically initiated by the CS. These neuronal modifications are consistent with the behavioral phenotype elicited by the CS following conditioning. PMID- 27493507 TI - Effects of serotonin on the heartbeat of pond snails in a hunger state. AB - Serotonin (5-hydroxytryptamine: 5-HT) is a multimodal transmitter that controls both feeding response and heartbeat in snails. However, the effects of 5-HT on the hunger state are still unknown. We therefore examined the relation among the hunger state, the heartbeat rate and the 5-HT action in food-starved snails. We found that the hunger state was significantly distinguished by the heartbeat rate in snails. The heartbeat rate was high in the food-satiated snails, whereas it was low in the food-starved snails. An increase in 5-HT concentration in the body boosted the heartbeat rate in the food-starved snails, but did not affect the rate in the food-satiated snails. These results suggest that 5-HT application may mimic the change from a starvation to a satiation state normally achieved by direct ingestion of food. PMID- 27493508 TI - Preface of Special Issue "TRP channels: their functional roles in medical sciences". PMID- 27493509 TI - Electrophysiological characteristics of IB4-negative TRPV1-expressing muscle afferent DRG neurons. AB - Muscle afferent neurons that express transient receptor potential vanilloid type I (TRPV1) are responsible for muscle pain associated with tissue acidosis. We have previously found that TRPV1 of isolectin B4 (IB4)-negative muscle nociceptors plays an important role in the acid-induced hyperalgesic priming and the development of chronic hyperalgesia in a mouse model of fibromyalgia. To understand the electrophysiological properties of the TRPV1-expressing muscle afferent neurons, we used whole-cell patch clamp recording to study the acid responsiveness and action potential (AP) configuration of capsaicin-sensitive neurons innervating to gastrocnemius muscle. Here we showed that IB4-negative TRPV1-expressing muscle afferent neurons are heterogeneous in terms of cell size, resting membrane potential, AP configuration, tetrodotoxin (TTX)-resistance, and acid-induced current (I acid), as well as capsaicin-induced current (I cap). TRPV1-expressing neurons were all acid-sensitive and could be divided into two acid-sensitive groups depending on an acid-induced sustained current (type I) or an acid-induced biphasic ASIC3-like current (type II). Type I TRPV1-expressing neurons were distinguishable from type II TRPV1-expressing neurons in AP overshoot, after-hyperpolarization duration, and all I acid parameters, but not in AP threshold, TTX-resistance, resting membrane potential, and I cap parameters. These differential biophysical properties of TRPV1-expressing neurons might partially annotate their different roles involved in the development and maintenance of chronic muscle pain. PMID- 27493510 TI - TRP channels in skin: from physiological implications to clinical significances. AB - TRP channels are expressed in various cells in skin. As an organ system to border the host and environment, many nonneuronal cells, including epidermal keratinocytes and melanocytes, express several TRP channels functionally distinct from sensory processing. TRPV1 and TRPV3 in keratinocytes of the epidermis and hair apparatus inhibit proliferation, induce terminal differentiation, induce apoptosis, and promote inflammation. Activation of TRPV4, 6, and TRPA1 promotes regeneration of the severed skin barriers. TRPA1 also enhances responses in contact hypersensitivity. TRPCs in keratinocytes regulate epidermal differentiation. In human diseases with pertubered epidermal differentiation, the expression of TRPCs are altered. TRPMs, which contribute to melanin production in melanocytes, serve as significant prognosis markers in patients with metastatic melanoma. In summary, not only act in sensory processing, TRP channels also contribute to epidermal differentiation, proliferation, barrier integration, skin regeneration, and immune responses. In diseases with aberrant TRP channels, TRP channels might be good therapeutic targets. PMID- 27493511 TI - Role of TRP channels in the induction of heat shock proteins (Hsps) by heating skin. AB - Transient receptor potential (TRP) channels in skin are crucial for achieving temperature sensitivity to maintain internal temperature balance and thermal homeostasis, as well as to protect skin cells from environmental stresses such as infrared (IR) or near-infrared (NIR) radiation via heat shock protein (Hsp) production. However, the mechanisms by which IR and NIR activate TRP channels and produce Hsps intracellularly have been independently reported. In this review, we discuss the relationship between TRP channel activation and Hsp production, and introduce the roles of several skin TRP channels in the regulation of HSP production by IR and NIR exposure. PMID- 27493512 TI - Thermodynamic implications of high Q 10 of thermo-TRP channels in living cells. AB - The activity of thermo-transient receptor potential (TRP) channels is highly dependent on temperature, and thus thermo-TRP reactions have a high temperature coefficient Q 10. In thermodynamics, a high value of Q 10 indicates the existence of a large activation energy (i.e., a large enthalpy) over a short period during the transition process between the closed and open states of the channels. The Gibbs free energy equation shows that a large entropy is required to compensate for this large enthalpy and permit activation of the channels, suggesting a large conformational change of the channels. These large values of enthalpy and entropy seem to be a match for the values of the unfolding process of globular proteins. We outline these thermodynamic issues in thermo-TRPs. PMID- 27493513 TI - FTIR study of CPD photolyase with substrate in single strand DNA. AB - Photolyases (PHRs) utilize near UV/blue light to specifically repair the major photoproducts (PPs) of UV-induced damaged DNA. The cyclobutane pyrimidine dimer (CPD)-PHR binds flavin adenine dinucleotide (FAD) as a cofactor and repairs CPD lesions in double-stranded DNA. To understand the activation and repair mechanism of CPD-PHR, we applied light-induced difference Fourier transform infrared (FTIR) spectroscopy to CPD-PHR, whose signals were identified by use of isotope labeling. To further investigate the enzymatic function, here we study the activation and repair mechanism of CPD-PHR with the substrate in single strand DNA, and the obtained FTIR spectra are compared with those in double-stranded DNA, the natural substrate. The difference spectra of photoactivation, the fully reduced (FADH(-)) minus semiquinone (FADH(*)) spectra, are almost identical in the presence of single strand and double-stranded DNA, except for slight spectral modification in the amide-I region. On the other hand, the difference spectra of photorepair were highly substrate dependent. Strong bands of the C=O stretch (1,720-1,690 cm(-1)) and phosphate vibrations (1,090-1,060 cm(-1)) of double stranded DNA may have disappeared in the case of single strand DNA. However, an isotope-labeled enzyme study revealed that spectral features upon DNA repair are similar between both substrates, and the main reason for the apparent spectral difference originates from structural flexibility of DNA after repair. PMID- 27493514 TI - Lever arm extension of myosin VI is unnecessary for the adjacent binding state. AB - Myosin VI is a processive myosin that has a unique stepping motion, which includes three kinds of steps: a large forward step, a small forward step and a backward step. Recently, we proposed the parallel lever arms model to explain the adjacent binding state, which is necessary for the unique motion. In this model, both lever arms are directed the same direction. However, experimental evidence has not refuted the possibility that the adjacent binding state emerges from myosin VI folding its lever arm extension (LAE). To clarify this issue, we constructed a myosin VI/V chimera that replaces the myosin VI LAE with the IQ3-6 domains of the myosin V lever arm, which cannot fold, and performed single molecule imaging. Our chimera showed the same stepping patterns as myosin VI, indicating the LAE is not responsible for the adjacent binding state. PMID- 27493515 TI - The activity of isolated snail neurons controlling locomotion is affected by glucose. AB - The involvement of serotonin in mediating hunger-related changes in behavioral state has been described in many invertebrates. However, the mechanisms by which hunger signals to serotonergic cells remain unknown. We tested the hypothesis that serotonergic neurons can directly sense the concentration of glucose, a metabolic indicator of nutritional state. In the snail Lymnaea stagnalis, we demonstrate that completely isolated pedal serotonergic neurons that control locomotion changed their biophysical characteristics in response to glucose application by lowering membrane potential and decreasing the firing rate. Additionally, the excitatory response of the isolated serotonergic neurons to the neuroactive microenvironment of the pedal ganglia was significantly lowered by glucose application. Because hunger has been reported to increase the activity of select neurons and their responses to the pedal ganglia microenvironment, these responses to glucose are in accordance with the hypothesis that direct glucose signaling is involved in the mediation of the hunger-related behavioral state. PMID- 27493516 TI - FTIR study of primate color visual pigments. AB - How do we distinguish colors? Humans possess three color pigments; red-, green-, and blue-sensitive proteins, which have maximum absorbance (lambdamax) at 560, 530, and 420 nm, respectively, and contribute to normal human trichromatic vision (RGB). Each color pigments consists of a different opsin protein bound to a common chromophore molecule, 11-cis-retinal, whereas different chromophore protein interactions allow preferential absorption of different colors. However, detailed experimental structural data to explain the molecular basis of spectral tuning of color pigments are lacking, mainly because of the difficulty in sample preparation. We thus started structural studies of primate color visual pigments using low-temperature Fourier-transform infrared (FTIR) spectroscopy, which needs only 0.3 mg protein for a single measurement. Here we report the first structural data of monkey red- (MR) and green- (MG) sensitive pigments, in which the information about the protein, retinal chromophore, and internal water molecules is contained. Molecular mechanism of color discrimination between red and green pigments will be discussed based on the structural data by FTIR spectroscopy. PMID- 27493517 TI - In vitro directed evolution of alpha-hemolysin by liposome display. AB - We have developed a method to enable in vitro directed evolution that can be applied to membrane proteins. This method, termed liposome display, uses liposomes as compartments in which membrane proteins are synthesized and as scaffolds for membrane protein integration. Thus, the synthesized membrane proteins are displayed on the surface of the liposome and exhibit their functions. A randomly mutated DNA library of the membrane protein was generated, encapsulated in the liposomes at the single-molecule level, and used to generate a liposome library. Liposomes displaying the desired membrane protein function were selected, thus accumulating the DNA molecule encoding the desired membrane protein. We have applied this method to alpha-hemolysin, a membrane protein derived from Staphylococcus aureus. Alpha-hemolysin forms a nanopore in the membrane, which allows the penetration of small molecules. We aimed to improve this nanopore activity by using the liposome display method. Consequently, alpha hemolysin evolved and attained a higher specific affinity for the liposome membrane. In this review, we describe the essential characteristics of liposome display and the properties of the evolved alpha-hemolysin obtained by this method. PMID- 27493518 TI - A new antigenic marker specifically labels a subpopulation of the class II Kenyon cells in the brain of the European honeybee Apis mellifera. AB - The mushroom bodies are the higher-order integration center in the insect brain and are involved in higher brain functions such as learning and memory. In the social hymenopteran insects such as honeybees, the mushroom bodies are the prominent brain structures. The mushroom bodies are composed of lobed neuropils formed by thousands of parallel-projecting axons of intrinsic neurons, and the lobes are divided into parallel subdivisions. In the present paper, we report a new antigenic marker to label a single layer in the vertical lobes of the European honeybee Apis mellifera. In the brain of A. mellifera, a monoclonal antibody (mAb) 15C3, which was originally developed against an insect ecdysone receptor (EcR) protein, immunolabels a single layer of the vertical lobes that correspond to the most dorsal layer of the gamma-lobe. The 15C3 mAb recognizes a single ~200 kDa protein expressed in the adult honeybee brain. In addition, the 15C3 mAb immunoreactivity was also observed in the lobes of the developing pupal mushroom bodies. Since gamma-lobe is well known to their extensive reorganization that occurs during metamorphosis in Drosophila, the novel antigenic marker for the honeybee gamma-lobe allows us to investigate morphological changes of the mushroom bodies during metamorphosis. PMID- 27493519 TI - A protocol for preparing nucleotide-free KaiC monomer. AB - The hexameric form of the KaiC protein is a core of the cyanobacterial biological clock, and its enzymatic activities exhibit circadian periodicity. The instability of the monomeric form of nucleotide-free KaiC has precluded its storage and detailed analyses of the activities of the reassembled hexamer. Here, we provide a protocol for preparing nucleotide-free KaiC monomer that is stable in solution and for triggering its reassembly into intact KaiC hexamer by the addition of ATP. A phosphate buffer containing glutamic acid and arginine enhanced the stability of KaiC monomer considerably. In addition, we found that reassembled KaiC hexamer was functionally active as the intact hexamer. This protocol provides a methodological basis for further analyses of first-turnover events of the ATPase/autokinase/autophosphatase activities of the KaiC hexamer. PMID- 27493520 TI - Experimental and theoretical bases for mechanisms of antigen discrimination by T cells. AB - Interaction only within specific molecules is a requisite for accurate operations of a biochemical reaction in a cell where bulk of background molecules exist. While structural specificity is a well-established mechanism for specific interaction, biophysical and biochemical experiments indicate that the mechanism is not sufficient for accounting for the antigen discrimination by T cells. In addition, the antigen discrimination by T cells also accompanies three intriguing properties other than the specificity: sensitivity, speed, and concentration compensation. In this work, we review experimental and theoretical works on the antigen discrimination by focusing on these four properties and show future directions towards understanding of the fundamental principle for molecular discrimination. PMID- 27493522 TI - Revealing the peptide presenting process of human leukocyte antigen through the analysis of fluctuation. AB - Structural fluctuation on microsecond to millisecond time scales has been reported to play an important role in proteins that undergo significant structural change during their expression of function. In these proteins, the structural change was obvious in the crystal structures. However, protein motions in solution could contribute to the function of proteins, even if no significant structural difference is observed in crystal structure of different states while they function. In this review, we introduce our recent report on the stabilization mechanism of human leukocyte antigen, and the possibility of fluctuation contributing to several biophysical properties of proteins. PMID- 27493521 TI - How do chaperonins fold protein? AB - Protein folding is a biological process that is essential for the proper functioning of proteins in all living organisms. In cells, many proteins require the assistance of molecular chaperones for their folding. Chaperonins belong to a class of molecular chaperones that have been extensively studied. However, the mechanism by which a chaperonin mediates the folding of proteins is still controversial. Denatured proteins are folded in the closed chaperonin cage, leading to the assumption that denatured proteins are completely encapsulated inside the chaperonin cage. In contrast to the assumption, we recently found that denatured protein interacts with hydrophobic residues at the subunit interfaces of the chaperonin, and partially protrude out of the cage. In this review, we will explain our recent results and introduce our model for the mechanism by which chaperonins accelerate protein folding, in view of recent findings. PMID- 27493523 TI - Chemomechanical coupling of F1-ATPase under hydrolysis conditions. AB - F1-ATPase (F1) is the smallest rotary motor protein that couples ATP hydrolysis/synthesis to rotary motion in a highly reversible manner. F1 is unique compared with other motor proteins because of its high efficiency and reversibility in converting chemical energy into mechanical work. To determine the energy conversion mechanism of F1-ATPase, we developed a novel single molecule manipulation technique with magnetic tweezers and determined the timing of Pi release, which was the last unknown piece of the chemomechanical coupling scheme of F1. The established fundamental chemomechanical coupling scheme provides evidence to explain the high reversibility between catalysis and mechanical work. PMID- 27493524 TI - GIRAF: a method for fast search and flexible alignment of ligand binding interfaces in proteins at atomic resolution. AB - Comparison and classification of protein structures are fundamental means to understand protein functions. Due to the computational difficulty and the ever increasing amount of structural data, however, it is in general not feasible to perform exhaustive all-against-all structure comparisons necessary for comprehensive classifications. To efficiently handle such situations, we have previously proposed a method, now called GIRAF. We herein describe further improvements in the GIRAF protein structure search and alignment method. The GIRAF method achieves extremely efficient search of similar structures of ligand binding sites of proteins by exploiting database indexing of structural features of local coordinate frames. In addition, it produces refined atom-wise alignments by iterative applications of the Hungarian method to the bipartite graph defined for a pair of superimposed structures. By combining the refined alignments based on different local coordinate frames, it is made possible to align structures involving domain movements. We provide detailed accounts for the database design, the search and alignment algorithms as well as some benchmark results. PMID- 27493526 TI - Comparative study of the different mechanisms for zinc ion stress sensing in two cyanobacterial strains, Synechococcus sp. PCC 7942 and Synechocystis sp. PCC 6803. AB - In response to an increased level of Zn(2+), Synechococcus sp. PCC 7942 expresses SmtA, a metallothionein-like metal-chelating protein, while Synechocystis sp. PCC 6803 expresses ZiaA, a transporter of Zn(2+). The gene expression of these proteins is regulated by repressor protein, SmtB and ZiaR, respectively. In spite of contributing to different response systems, both repressor proteins belong to the ArsR family and are highly homologous to each other. To understand the different systems responsible for dealing with excess Zn(2+), we examined the cis elements in the promoter regions of smtA and ziaA, as well as the binding affinities of recombinant SmtB and ZiaR proteins. The operator/promoter region of smtA included two palindromic sequences and that of ziaA included one. Electrophoretic mobility shift assay revealed that SmtB formed four different complexes with the operator/promoter region of smtA, whereas it formed only two different complexes with the corresponding region of ziaA. For ZiaR, the corresponding results were quite the same as those for SmtB. Furthermore, the complex formation between SmtB and operator/promoter regions is inhibited in the presence of Zn(2+) at higher concentrations than 16 MUM. On the other hand, the corresponding Zn(2+) concentration is 128 MUM. These results demonstrate that the degrees of protein-DNA complex formation between repressor proteins and the operator/promoter regions of regulated genes depend on the structures of the operator/promoter regions, and the effects of Zn(2+) on the dissociation of these complexes are mainly associated with the structures of the repressors. PMID- 27493525 TI - mDia1 and formins: screw cap of the actin filament. AB - Formin homology proteins (formins) are actin nucleation factors which remain bound to the growing barbed end and processively elongate actin filament (F actin). Recently, we have demonstrated that a mammalian formin mDia1 rotates along the long-pitch helix of F-actin during processive elongation (helical rotation) by single-molecule fluorescence polarization. We have also shown processive depolymerization of mDia1-bound F-actin during which helical rotation was visualized. In the cell where F-actins are highly cross-linked, formins should rotate during filament elongation. Therefore, when formins are tightly anchored to cellular structures, formins may not elongate F-actin. Adversely, helical rotation of formins might affect the twist of F-actin. Formins could thus control actin elongation and regulate stability of cellular actin filaments through helical rotation. On the other hand, ADP-actin elongation at the mDia1 bound barbed end turned out to become decelerated by profilin, in marked contrast to its remarkably positive effect on mDia1-mediated ATP-actin elongation. This deceleration is caused by enhancement of the off-rate of ADP-actin. While mDia1 and profilin enhance the ADP-actin off-rate, they do not apparently increase the ADP-actin on-rate at the barbed end. These results imply that G-actin-bound ATP and its hydrolysis may be part of the acceleration mechanism of formin-mediated actin elongation. PMID- 27493527 TI - Extraction and purification of a luminiferous substance from the luminous mushroom Mycena chlorophos. AB - Bioluminescence has attracted considerable attention in the area of biophysics, primarily because the phenomenon can fundamentally be interpreted as the conversion of chemical to light energy. Although the molecular mechanisms underlying luminescence have been studied extensively in fireflies and bacteria, few studies have been undertaken in luminous fungi. This relative lack of information is likely due to the absence of a common and species-specific reaction-type in the luminous fungi examined to date. We recently succeeded in extracting, for the first time, a luminiferous substance from the fungus Mycena chlorophos. The substance was purified and characterized according to its chemical and optical properties. It is hoped that this information will facilitate the clarification of a novel molecular mechanism in fungal bioluminescence systems. PMID- 27493528 TI - Full-Quantum chemical calculation of the absorption maximum of bacteriorhodopsin: a comprehensive analysis of the amino acid residues contributing to the opsin shift. AB - Herein, the absorption maximum of bacteriorhodopsin (bR) is calculated using our recently developed method in which the whole protein can be treated quantum mechanically at the level of INDO/S-CIS//ONIOM (B3LYP/6-31G(d,p): AMBER). The full quantum mechanical calculation is shown to reproduce the so-called opsin shift of bR with an error of less than 0.04 eV. We also apply the same calculation for 226 different bR mutants, each of which was constructed by replacing any one of the amino acid residues of the wild-type bR with Gly. This substitution makes it possible to elucidate the extent to which each amino acid contributes to the opsin shift and to estimate the inter-residue synergistic effect. It was found that one of the most important contributions to the opsin shift is the electron transfer from Tyr185 to the chromophore upon excitation. We also indicate that some aromatic (Trp86, Trp182) and polar (Ser141, Thr142) residues, located in the vicinity of the retinal polyene chain and the beta ionone ring, respectively, play an important role in compensating for the large blue-shift induced by both the counterion residues (Asp85, Asp212) and an internal water molecule (W402) located near the Schiff base linkage. In particular, the effect of Trp86 is comparable to that of Tyr185. In addition, Ser141 and Thr142 were found to contribute to an increase in the dipole moment of bR in the excited state. Finally, we provide a complete energy diagram for the opsin shift together with the contribution of the chromophore-protein steric interaction. PMID- 27493529 TI - A scoring function based on solvation thermodynamics for protein structure prediction. AB - We predict protein structure using our recently developed free energy function for describing protein stability, which is focused on solvation thermodynamics. The function is combined with the current most reliable sampling methods, i.e., fragment assembly (FA) and comparative modeling (CM). The prediction is tested using 11 small proteins for which high-resolution crystal structures are available. For 8 of these proteins, sequence similarities are found in the database, and the prediction is performed with CM. Fairly accurate models with average Calpha root mean square deviation (RMSD) ~ 2.0 A are successfully obtained for all cases. For the rest of the target proteins, we perform the prediction following FA protocols. For 2 cases, we obtain predicted models with an RMSD ~ 3.0 A as the best-scored structures. For the other case, the RMSD remains larger than 7 A. For all the 11 target proteins, our scoring function identifies the experimentally determined native structure as the best structure. Starting from the predicted structure, replica exchange molecular dynamics is performed to further refine the structures. However, we are unable to improve its RMSD toward the experimental structure. The exhaustive sampling by coarse-grained normal mode analysis around the native structures reveals that our function has a linear correlation with RMSDs < 3.0 A. These results suggest that the function is quite reliable for the protein structure prediction while the sampling method remains one of the major limiting factors in it. The aspects through which the methodology could further be improved are discussed. PMID- 27493530 TI - Virtual states introduced for overcoming entropic barriers in conformational space. AB - Free-energy landscape is an important quantity to study large-scale motions of a biomolecular system because it maps possible pathways for the motions. When the landscape consists of thermodynamically stable states (low-energy basins), which are connected by narrow conformational pathways (i.e., bottlenecks), the narrowness slows the inter-basin round trips in conformational sampling. This results in inaccuracy of free energies for the basins. This difficulty is not cleared out even when an enhanced conformational sampling is fairly performed along a reaction coordinate. In this study, to enhance the inter-basin round trips we introduced a virtual state that covers the narrow pathways. The probability distribution function for the virtual state was controlled based on detailed balance condition for the inter-state transitions (transitions between the real-state basins and the virtual state). To mimic the free-energy landscape of a real biological system, we introduced a simple model where a wall separates two basins and a narrow hole is pierced in the wall to connect the basins. The sampling was done based on Monte Carlo (MC). We examined several hole-sizes and inter-state transition probabilities. For a small hole-size, a small inter-state transition probability produced a sampling efficiency 100 times higher than a conventional MC does. This result goes against ones intuition, because one considers generally that the sampling efficiency increases with increasing the transition probability. The present method is readily applicable to enhanced conformational sampling such as multi-canonical or adaptive umbrella sampling, and extendable to molecular dynamics. PMID- 27493531 TI - Mechanistic insights from the recent structures of the CRM1 nuclear export complex and its disassembly intermediate. AB - CRM1 (also known as exportin 1 or Xpo1) is the most versatile nuclear export receptor (exportin) that carries a broad range of proteins and ribonucleoproteins from the nucleus to the cytoplasm through the nuclear pore complex. The majority of the export substrates of CRM1 contain a short peptide sequence, so-called leucine-rich nuclear export signal (NES), which typically harbor four or five characteristically spaced hydrophobic residues. The transport directionality is determined by the small GTPase Ran and Ran-binding proteins that control the binding and dissociation of cargo. Here we review recent structural studies that advanced understanding of how NES is specifically recognized by CRM1 in the nucleus, and how NES is rapidly dissociated from CRM1 in the cytoplasm. PMID- 27493532 TI - Proposed model for the flagellar rotary motor with shear stress transmission. AB - Most bacteria that swim are propelled by flagellar filaments, which are driven by a rotary motor powered by proton flux. The motor consists of the rotor and the stator. The stator consists of about 8 MotA-Mot B complex. There seems to be no definite information about the structure between the rotor and the stator, and it is examined whether the experimental data can be explained based upon the following assumptions. (a) There is viscoelastic medium between the rotor and the stator. (b) MotA-MotB complex has an electric dipole moment and produces shear stress in the electric field by a proton in the channel. Calculation results based upon these assumptions are in good agreement with the following experimental observations. (1) One revolution of the flagellar rotation consists of a constant number of steps. (2) The rotation velocity of the rotor is proportional to the trans-membrane potential difference. (3) When the rotational velocity of a flagellum is changed by adjusting the viscosity of the outer fluid, the torque for the cell to rotate a flagellum is practically constant but sharply decreases when the rotational velocity increases over a critical value. (4) The rotation direction remains the same when the sign of the electrochemical potential gradient is reversed. (5) The cell produces constant torque to rotate the flagellum even when the cell is rotated by externally applied torque. (6) A simple switch mechanism is proposed for chemotaxis. PMID- 27493533 TI - Self-oscillating gels beating like a heart muscle. AB - So far stimuli-responsive polymer gels and their application to smart materials have been widely studied. On the other hand, as a novel biomimetic gel, we developed gels with an autonomous self-oscillating function like a heart muscle, which was firstly reported in 1996. We designed the self-oscillating polymers and gels by utilizing the oscillating reaction, called the Belousov-Zhabotinsky (BZ) reaction. The self-oscillating polymer is composed of a poly(N isopropylacrylamide) network in which the catalyst for the BZ reaction is covalently immobilized. In the presence of the reactants, the polymer gel undergoes spontaneous cyclic swelling-deswelling changes without any on-off switching of external stimuli. Potential applications of the self-oscillating polymers and gels include several kinds of functional material systems, such as bio-mimetic actuators and mass transport surface. In this review, recent progress on the polymer gels is introduced. PMID- 27493534 TI - Phase dependency of long-term potentiation induction during the intermittent bursts of carbachol-induced beta oscillation in rat hippocampal slices. AB - The rodent hippocampus possesses theta (theta) and beta (beta) rhythms, which occur intermittently as bursts. Both rhythms are related to spatial memory processing in a novel environment. theta rhythm is related to spatial memory encoding process. beta rhythm is related to the match/mismatch process. In the match/mismatch process, rodent hippocampus detects a representation matching sensory inputs of the current place among the retrieved internal representations of places. Long-term synaptic potentiation (LTP) is induced in both processes. The cholinergic agent carbachol induces intermittent theta and beta oscillations in in vitro slices similar to in vivo bursts. LTP is facilitated during the generation of theta oscillation, suggesting that the facilitation of LTP is dependent upon the phases of intermittent burst (burst phases) of the oscillation. However, whether this is the case for beta oscillation has not yet been studied. In the present study, LTP-inducing theta-burst stimulation was administered at the different burst phases of carbachol-induced beta oscillations (CIBO), and the synaptic changes were measured at CA3-CA3 pyramidal cell synapses (CA3 synapse) and at CA3-CA1 pyramidal cell synapses (CA1 synapse). At the CA3 synapse, the largest magnitude of LTP was induced at the late burst phases of CIBO. At the CA1 synapse, LTP was induced only at the late burst phases. Modulation of LTP was suppressed when CIBO was blocked by the application of atropine at both synapses. The results suggest that the bursts of hippocampal beta rhythm can determine the optimal temporal period for completing with the match/mismatch process. PMID- 27493535 TI - Distinct Conformation of ATP Molecule in Solution and on Protein. AB - Adenosine triphosphate (ATP) is a versatile molecule used mainly for energy and a phosphate source. The hydrolysis of gamma phosphate initiates the reactions and these reactions almost always start when ATP binds to protein. Therefore, there should be a mechanism to prevent spontaneous hydrolysis reaction and a mechanism to lead ATP to a pure energy source or to a phosphate source. To address these questions, we extensively analyzed the effect of protein to ATP conformation based on the sampling of the ATP solution conformations obtained from molecular dynamics simulation and the sampling of ATP structures bound to protein found in a protein structure database. The comparison revealed mainly the following three points; 1) The ribose ring in ATP molecule, which puckers in many ways in solution, tends to assume either C2' exo or C2' endo when it binds to protein. 2) The adenine ring in ATP molecule, which takes open-book motion with the two ring structures, has two distinct structures when ATP binds to protein. 3) The glycosyl-bond and the bond between phosphate and the ribose have unique torsion angles, when ATP binds to protein. The combination of torsion angles found in protein-bound forms is under-represented in ATP molecule in water. These findings suggest that ATP-binding protein exerts forces on ATP molecule to assume a conformation that is rarely found in solution, and that this conformation change should be a trigger for the reactions on ATP molecule. PMID- 27493536 TI - Single turnovers of fluorescent ATP bound to bipolar myosin filament during actin filaments sliding. AB - The nucleotide turnover rates of bipolar myosin thick filament along which actin filament slides were measured by the displacement of prebound fluorescent ATP analog 2'(3')-O-[N-[2-[(Cy3)]amindo]ethyl] carbamoyl]-adenosine 5' triphosphate (Cy3-EDA-ATP) upon flash photolysis of caged ATP. The fluorescence of the thick filament where actin filament slides decayed with two exponential processes. The slower rate constant was the same as that without actin filament. Along bipolar myosin thick filament, actin filaments slide at a fast speed towards the central bare zone (forward), but more slowly away from the bare zone (backward). The displacement rate constant of fluorescent ATP from the myosin filament where actin filament moved forward was 5.0 s(-1), whereas the rate constant where the actin filament slid backward was 1.7 s(-1). These findings suggest that the slow ADP release rate is responsible for the slow backward sliding movement. PMID- 27493537 TI - Expression, purification and biochemical characterization of the cytoplasmic loop of PomA, a stator component of the Na(+) driven flagellar motor. AB - Flagellar motors embedded in bacterial membranes are molecular machines powered by specific ion flows. Each motor is composed of a stator and a rotor and the interactions of those components are believed to generate the torque. Na(+) influx through the PomA/PomB stator complex of Vibrio alginolyticus is coupled to torque generation and is speculated to trigger structural changes in the cytoplasmic domain of PomA that interacts with a rotor protein in the C-ring, FliG, to drive the rotation. In this study, we tried to overproduce the cytoplasmic loop of PomA (PomA-Loop), but it was insoluble. Thus, we made a fusion protein with a small soluble tag (GB1) which allowed us to express and characterize the recombinant protein. The structure of the PomA-Loop seems to be very elongated or has a loose tertiary structure. When the PomA-Loop protein was produced in E. coli, a slight dominant effect was observed on motility. We conclude that the cytoplasmic loop alone retains a certain function. PMID- 27493538 TI - Mechanism of the nucleotidyl-transfer reaction in DNA polymerase revealed by time resolved protein crystallography. AB - Nucleotidyl-transfer reaction catalyzed by DNA polymerase is a fundamental enzymatic reaction for DNA synthesis. Until now, a number of structural and kinetic studies on DNA polymerases have proposed a two-metalion mechanism of the nucleotidyl-transfer reaction. However, the actual reaction process has never been visualized. Recently, we have followed the nucleotidyl-transfer reaction process by human DNA polymerase eta using time-resolved protein crystallography. In sequence, two Mg(2+) ions bind to the active site, the nucleophile 3'-OH is deprotonated, the deoxyribose at the primer end converts from C2'-endo to C3' endo, and the nucleophile and the alpha-phosphate of the substrate dATP approach each other to form the new bond. In this process, we observed transient elements, which are a water molecule to deprotonate the 3'-OH and an additional Mg(2+) ion to stabilize the intermediate state. Particularly, the third Mg(2+) ion observed in this study may be a general feature of the two-metalion mechanism. PMID- 27493539 TI - Characterization of the ordered phase formed by sphingomyelin analogues and cholesterol binary mixtures. AB - The influences of structural alterations of sphingomyelin (SM) on its interactions with cholesterol (chol) and on ordered phase formation were examined by density measurements and surface pressure vs. molecular area isotherm measurements. In addition, we quantitatively characterized the ordered phase formed in each SM and chol binary mixture on the basis of the molecular compressional modulus of SM ( [Formula: see text]). Density measurements demonstrated that the ordered phase formation in threo-SM (tSM)/chol and dihydrosphingomyelin (DHSM)/chol binary bilayers shows similar chol concentration dependency to that of natural erythro-SM (eSM)/chol bilayers; the ordered phase formation was completed in the presence of 25 mol% chol. In contrast, SM bearing a triple bond in the place of a double bond (tripleSM) required a greater concentration of chol to completely transform the bilayer into the ordered phase (at 40 mol% chol). Surface pressure vs. molecular area isotherms showed that the DHSM molecule ( [Formula: see text] = 290 mN/m) is more rigid than eSM ( [Formula: see text] = 240 mN/m) above 30 mol% chol (in the ordered phase), although these values are similar (140-150 mN/m) in the absence of chol (liquid condensed phase). Most likely, the DHSM/chol mixture forms a more ordered membrane than the eSM/chol mixture does. Moreover, in the absence of chol, the rigidity of the tripleSM molecule ( [Formula: see text] = 250 mN/m) is significantly higher as compared with that of the eSM molecule ( [Formula: see text] = 150 mN/m), which is probably due to the presence of a triple bond. PMID- 27493540 TI - Rotary catalysis of FoF1-ATP synthase. AB - The synthesis of ATP, the key reaction of biological energy metabolism, is accomplished by the rotary motor protein; FoF1-ATP synthase (FoF1). In vivo, FoF1, located on the cell membrane, carries out ATP synthesis by using the proton motive force. This heterologous energy conversion is supposed to be mediated by the mechanical rotation of FoF1; however, it still remained unclear. Recently, we developed the novel experimental setup to reproduce the proton motive force in vitro and succeeded in directly observing the proton-driven rotation of FoF1. In this review, we describe the interesting working principles determined so far for FoF1 and then introduce results from our recent study. PMID- 27493541 TI - Crystal structure of channelrhodopsin, a light-gated cation channel - all cations lead through the monomer. AB - Channelrhodopsin (ChR) is a light-gated cation channel derived from green algae. Since the inward flow of cations triggers the neuron firing, neurons expressing ChRs can be optically controlled even within freely moving mammals. Although ChR has been broadly applied to neuro-science research, little is known about its molecular mechanisms. We determined the crystal structure of chimeric ChR at 2.3 A resolution and revealed its molecular architecture. The integration of structural, electrophysio-logical, and computational analyses provided insight into the molecular basis for the channel function of ChR, and paved the way for the principled design of ChR variants with novel properties. PMID- 27493542 TI - Role of the Dc domain of the bacterial hook protein FlgE in hook assembly and function. AB - The bacterial flagellar hook acts as a universal joint to smoothly transmit torque produced by the motor to the filament. The hook protein FlgE assembles into a 55 nm tubular structure with the help of the hook cap (FlgD). FlgE consists of four domains, D0, Dc, D1 and D2, arranged from the inner to the outer part of the tubular structure of the hook. The Dc domain contributes to the structural stability of the hook, but it is unclear how this Dc domain is responsible for the universal joint mechanism. Here, we carried out a deletion analysis of the FlgE Dc domain. FlgEDelta4/5 with deletion of residues 30 to 49 was not secreted into the culture media. FlgEDelta5 and FlgEDelta6 with deletions of residues 40 to 49 and 50 to 59, respectively, still formed hooks, allowing the export apparatus to export the hook-filament junction proteins FlgK and FlgL and flagellin FliC. However, these deletions inhibited the replacement of the FlgD hook cap by FlgK at the hook tip, thereby abolishing filament formation. Deletion of residues 50 to 59 significantly affected hook morphology. These results suggest that the Dc domain is responsible not only for hook assembly but also for FlgE export, the interaction with FlgK, and the polymorphic supercoiling mechanism of the hook. PMID- 27493543 TI - Responses of chromosome segregation machinery to mechanical perturbations. AB - For genome stability, the proper segregation of chromosomes is required. The exquisite process of chromosome segregation has charmed a lot of cell- and molecular biologists into watching what happens inside a mitotic cell and how each molecule contributes to this process for the accomplishment of accurate cell division1. The process to partition the duplicated genome to the daughter cells in each cell division is mediated by a self-organized structure called the mitotic spindle. It is well known that the mitotic spindle is a multi-component macromolecular machine composed of microtubules, molecular motors (kinesins, cytoplasmic dynein), and other regulatory molecules (microtubule-associated proteins, kinases, etc.). In recent years, most of the protein components of the mitotic spindle have been identified and the functions of these proteins have been characterized using molecular perturbations2,3. Thus, the mechanisms for spindle assembly and chromosome segregation are being revealed rapidly. However, the chromosome segregation machinery is poorly understood from the mechanical point of view, such as how the mitotic spindle within a cell responds to a variety of mechanical forces, originating from cell-cell interactions or environmental fluctuations. Recent advances in the controlled mechanical perturbation have indicated that the mitotic spindle possesses a structural pliability, size adaptability to the applied external forces, and a strong self organizing ability. Mechanical perturbations revealed also the mechanochemical regulation of chromosome segregation machinery, which responds to the applied forces. Here, we discuss the current progress in the biophysical research on the architectural and functional dynamics of the mitotic spindle. PMID- 27493544 TI - A new approach to detect small peptides clearly and sensitively by Western blotting using a vacuum-assisted detection method. AB - Western blotting is a widely used technique for the detection and quantification of proteins and peptides. However, it is challenging to detect small peptides efficiently by the conventional Western blotting method with shaking, in part because the peptides readily detach from the blotted membrane. Although some modified Western blotting protocols have been developed to overcome this problem, it remains difficult to prevent peptide detachment from the membrane. In this study, we show that the previously developed vacuum-assisted detection method greatly improves the detection of small peptides without additional protocol modification. The vacuum-assisted method was developed to shorten the time required for all immunodetection steps, and all the Western blotting solutions penetrated the membrane quickly and efficiently by this method. By using this vacuum method, we succeeded in detecting small peptides that were completely undetectable by the conventional Western blotting method. We also confirmed that peptide detachment was induced even by gentle shaking in the case of the conventional method, and the detachment was accelerated when detergent was present in the buffer. Unlike in the conventional method, there is no need to shake the membrane in solution in the vacuum method. Therefore, it is thought that the small peptides could be detected sensitively only by the vacuum method. PMID- 27493545 TI - Contribution of a visual pigment absorption spectrum to a visual function: depth perception in a jumping spider. AB - Absorption spectra of visual pigments are adaptively tuned to optimize informational capacity in most visual systems. Our recent investigation of the eyes of the jumping spider reveals an apparent exception: the absorption characteristics of a visual pigment cause defocusing of the image, reducing visual acuity generally in a part of the retina. However, the amount of defocus can theoretically provide a quantitative indication of the distance of an object. Therefore, we proposed a novel mechanism for depth perception in jumping spiders based on image defocus. Behavioral experiments revealed that the depth perception of the spider depended on the wavelength of the ambient light, which affects the amount of defocus because of chromatic aberration of the lens. This wavelength effect on depth perception was in close agreement with theoretical predictions based on our hypothesis. These data strongly support the hypothesis that the depth perception mechanism of jumping spiders is based on image defocus. PMID- 27493546 TI - Experimental thermodynamics of single molecular motor. AB - Molecular motor is a nano-sized chemical engine that converts chemical free energy to mechanical motions. Hence, the energetics is as important as kinetics in order to understand its operation principle. We review experiments to evaluate the thermodynamic properties of a rotational F1-ATPase motor (F1-motor) at a single-molecule level. We show that the F1-motor achieves 100% thermo dynamic efficiency at the stalled state. Furthermore, the motor reduces the internal irreversible heat inside the motor to almost zero and achieves a highly-efficient free energy transduction close to 100% during rotations far from quasistatic process. We discuss the mechanism of how the F1-motor achieves such a high efficiency, which highlights the remarkable property of the nano-sized engine F1 motor. PMID- 27493547 TI - Difference in hydration structures between F-actin and myosin subfragment-1 detected by small-angle X-ray and neutron scattering. AB - Hydration structures around F-actin and myosin subfragment-1 (S1), which play central roles as counterparts in muscle contraction, were investigated by small angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS). The radius of gyration of chymotryptic S1 was evaluated to be 41.3+/-1.1 A for SAXS, 40.1+/-3.0 A for SANS in H2O, and 37.8+/-0.8 A for SANS in D2O, respectively. The values of the cross-sectional radius of gyration of F-actin were 25.4+/-0.03 A for SAXS, 23.4+/-2.4 A for SANS in H2O, and 22.6 +/- 0.6 A for SANS in D2O, respectively. These differences arise from different contributions of the hydration shell to the scattering curves. Analysis by model calculations showed that the hydration shell of S1 has the average density 10-15% higher than bulk water, being the typical hydration shell. On the other hand, the hydration shell of F-actin has the average density more than 19% higher than bulk water, indicating that F-actin has a denser, unusual hydration structure. The results indicate a difference in the hydration structures around F-actin and S1. The unusual hydration structure around F-actin may have the structural property of so called "hyper-mobile water" around F-actin. PMID- 27493548 TI - Information-to-free-energy conversion: Utilizing thermal fluctuations. AB - Maxwell's demon is a hypothetical creature that can convert information to free energy. A debate that has lasted for more than 100 years has revealed that the demon's operation does not contradict the laws of thermodynamics; hence, the demon can be realized physically. We briefly review the first experimental demonstration of Maxwell's demon of Szilard's engine type that converts information to free energy. We pump heat from an isothermal environment by using the information about the thermal fluctuations of a Brownian particle and increase the particle's free energy. PMID- 27493549 TI - LigandBox: A database for 3D structures of chemical compounds. AB - A database for the 3D structures of available compounds is essential for the virtual screening by molecular docking. We have developed the LigandBox database (http://ligandbox.protein.osaka-u.ac.jp/ligandbox/) containing four million available compounds, collected from the catalogues of 37 commercial suppliers, and approved drugs and biochemical compounds taken from KEGG_DRUG, KEGG_COMPOUND and PDB databases. Each chemical compound in the database has several 3D conformers with hydrogen atoms and atomic charges, which are ready to be docked into receptors using docking programs. The 3D conformations were generated using our molecular simulation program package, myPresto. Various physical properties, such as aqueous solubility (LogS) and carcinogenicity have also been calculated to characterize the ADME-Tox properties of the compounds. The Web database provides two services for compound searches: a property/chemical ID search and a chemical structure search. The chemical structure search is performed by a descriptor search and a maximum common substructure (MCS) search combination, using our program kcombu. By specifying a query chemical structure, users can find similar compounds among the millions of compounds in the database within a few minutes. Our database is expected to assist a wide range of researchers, in the fields of medical science, chemical biology, and biochemistry, who are seeking to discover active chemical compounds by the virtual screening. PMID- 27493550 TI - Development of a rapid Buffer-exchange system for time-resolved ATR-FTIR spectroscopy with the step-scan mode. AB - Attenuated total reflectance (ATR)-FTIR spectroscopy has been widely used to probe protein structural changes under various stimuli, such as light absorption, voltage change, and ligand binding, in aqueous conditions. Time-resolved measurements require a trigger, which can be controlled electronically; therefore, light and voltage changes are suitable. Here we developed a novel, rapid buffer-exchange system for time-resolved ATR-FTIR spectroscopy to monitor the ligand- or ion-binding re-action of a protein. By using the step-scan mode (time resolution; 2.5 ms), we confirmed the completion of the buffer-exchange reaction within ~25 ms; the process was monitored by the infrared absorption change of a nitrate band at 1,350 cm(-1). We also demonstrated the anion-binding reaction of a membrane protein, Natronomonas pharaonis halorhodopsin (pHR), which binds a chloride ion in the initial anion-binding site near the retinal chromophore. The formation of chloride- or nitrate-bound pHR was confirmed by an increase of the retinal absorption band at 1,528 cm(-1). It also should be noted that low sample consumption (~1 ug of protein) makes this new method a powerful technique to understand ligand-protein and ion-protein interactions, particularly for membrane proteins. PMID- 27493551 TI - Recent structural studies on Dom34/aPelota and Hbs1/aEF1alpha: important factors for solving general problems of ribosomal stall in translation. AB - In the translation process, translating ribosomes usually move on an mRNA until they reach the stop codon. However, when ribosomes translate an aberrant mRNA, they stall. Then, ribosomes are rescued from the aberrant mRNA, and the aberrant mRNA is subsequently degraded. In eukaryotes, Pelota (Dom34 in yeast) and Hbs1 are responsible for solving general problems of ribosomal stall in translation. In archaea, aPelota and aEF1alpha, homologous to Pelota and Hbs1, respectively, are considered to be involved in that process. In recent years, great progress has been made in determining structures of Dom34/aPelota and Hbs1/aEF1alpha. In this review, we focus on the functional roles of Dom34/aPelota and Hbs1/aEF1alpha in ribosome rescue, based on recent structural studies of them. We will also present questions to be answered by future work. PMID- 27493552 TI - 3D structure of eukaryotic flagella/cilia by cryo-electron tomography. AB - Flagella/cilia are motile organelles with more than 400 proteins. To understand the mechanism of such complex systems, we need methods to describe molecular arrange-ments and conformations three-dimensionally in vivo. Cryo-electron tomography enabled us such a 3D structural analysis. Our group has been working on 3D structure of flagella/cilia using this method and revealed highly ordered and beautifully organized molecular arrangement. 3D structure gave us insights into the mechanism to gener-ate bending motion with well defined waveforms. In this review, I summarize our recent structural studies on fla-gella/cilia by cryo electron tomography, mainly focusing on dynein microtubule-based ATPase motor proteins and the radial spoke, a regulatory protein complex. PMID- 27493553 TI - Single molecule FRET observation of kinesin-1's head-tail interaction on microtubule. AB - Kinesin-1 (conventional kinesin) is a molecular motor that transports various cargo such as endoplasmic reticulum and mitochondria in cells. Its two head domains walk along microtubule by hydrolyzing ATP, while the tail domains at the end of the long stalk bind to the cargo. When a kinesin is not carrying cargo, its motility and ATPase activity is inhibited by direct interactions between the tail and head. However, the mechanism of this tail regulation is not well understood. Here, we apply single molecule fluorescence resonance energy transfer (smFRET) to observe this interaction in stalk-truncated kinesin. We found that kinesin with two tails forms a folding conformation and dissociates from microtubules, whereas kinesin with one tail remains bound to the micro-tubule and is immobile even in the presence of ATP. We further investigated the head-tail interaction as well as head-head coordination on the microtubule at various nucleotide conditions. From these results, we propose a two-step inhibition model for kinesin motility. PMID- 27493554 TI - Increase in cyclic AMP concentration in a cerebral giant interneuron mimics part of a memory trace for conditioned taste aversion of the pond snail. AB - Conditioned taste aversion (CTA) can be classically conditioned in the pond snail Lymnaea stagnalis and subsequently be consolidated into long-term memory (LTM). The neural trace that subserves CTA-LTM can be summarized as follows: A polysynaptic inhibitory postsynaptic potential recorded in the neuron 1 medial (N1M) cell in the conditioned snails as a result of activation of the cerebral giant cell (CGC) is larger and lasts longer than that in control snails. The N1M cell is ultimately activated by the CGC via the neuron 3 tonic (N3t) cell. That is, the inhibitory monosynaptic inputs from the N3t cell to the N1M cell are facilitated. The N1M and N3t cells are the members of feeding central pattern generator, whereas the CGC is a multimodal interneuron thought to play a key role in feeding behavior. Here we examined the involvement of a second messenger, cAMP, in the establishment of the memory trace. We injected cAMP into the CGC and monitored the potentials of the B3 motor neuron activated by the CGC. B3 activity is used as an index for the synaptic inputs from the N3t cell to the N1M cell. We found that the B3 potentials were transiently enlarged. Thus, when the cAMP concentration is increased in the CGC by taste aversion training, cAMP-induced changes may play a key role in the establishment of a memory trace in the N3t cell. PMID- 27493555 TI - Detection of a protein-bound water vibration of halorhodopsin in aqueous solution. AB - Protein-bound water molecules play crucial roles in their structure and function, but their detection is an experimental challenge, particularly in aqueous solution at room temperature. By applying attenuated total reflection (ATR) Fourier-transform infrared (FTIR) spectroscopy to a light-driven Cl(-) pump pharaonis halorhodopsin (pHR), here we detected an O-H stretching vibration of protein-bound water molecules in the active center. The pHR(Cl(-)) minus pHR(Br( )) ATR-FTIR spectra show random fluctuation at 3600-3000 cm(-1), frequency window of water vibration, which can be interpreted in terms of dynamical fluctuation of aqueous water at room temperature. On the other hand, we observed a reproducible spectral feature at 3617 (+)/3630 (-) cm(-1) in the pHR(Cl(-)) minus pHR(Br(-)) spectrum, which is absent in the pHR(Cl(-)) minus pHR(Cl(-)) and in the pHR(Br( )) minus pHR(Br(-)) spectra. The water O-H stretching vibrations of pHR(Cl(-)) and pHR(Br(-)) at 3617 and 3630 cm(-1), respectively, are confirmed by light induced difference FTIR spectra in isotope water (H2 (18)O) at 77 K. The observed water molecule presumably binds to the active center of pHR, and alter its hydrogen bond during the Cl(-) pumping photocycle. PMID- 27493558 TI - Feedback control of combustion instabilities from within limit cycle oscillations using [Formula: see text] loop-shaping and the nu-gap metric. AB - Combustion instabilities arise owing to a two-way coupling between acoustic waves and unsteady heat release. Oscillation amplitudes successively grow, until nonlinear effects cause saturation into limit cycle oscillations. Feedback control, in which an actuator modifies some combustor input in response to a sensor measurement, can suppress combustion instabilities. Linear feedback controllers are typically designed, using linear combustor models. However, when activated from within limit cycle, the linear model is invalid, and such controllers are not guaranteed to stabilize. This work develops a feedback control strategy guaranteed to stabilize from within limit cycle oscillations. A low-order model of a simple combustor, exhibiting the essential features of more complex systems, is presented. Linear plane acoustic wave modelling is combined with a weakly nonlinear describing function for the flame. The latter is determined numerically using a level set approach. Its implication is that the open-loop transfer function (OLTF) needed for controller design varies with oscillation level. The difference between the mean and the rest of the OLTFs is characterized using the nu-gap metric, providing the minimum required 'robustness margin' for an [Formula: see text] loop-shaping controller. Such controllers are designed and achieve stability both for linear fluctuations and from within limit cycle oscillations. PMID- 27493557 TI - Physical aspects of sensory transduction on seeing, hearing and smelling. AB - What is the general principle of sensory transduction? Sensory transduction is defined as energy transformation from the external world to the internal world. The energy of the external world, such as thermal energy (heat), electro-magnetic energy (light), mechanical energy (sound) and the energy from molecules (chemicals), is converted into electrochemical events in the animal nervous system. The following five classes of special sense receptors are utilized for energy conversion: vision (photo); audition (sound); taste and smell (chemo); and tactile (mechano). There are also other special sense receptors, including thermo and noxious receptors. The focus of this study is on photoreceptors, sound receptors and odorant-receptors because the transduction mechanisms of these receptors are explained biochemically and understood by a common physical principle; these biochemical models are well known in neuroscience. The following notable problems are inherent in these biochemical models: the cGMP ionophore model of the vertebrate photoreceptor cannot explain the fast photo-response (~msec); the tip links connection model of stereocilia in the basilar membrane for opening the K(+) channel on the tip of a hair has difficulty explaining the high frequency vibration of hair cells without a damping of the oscillation, and the odorant shape-specific receptor model for olfactory transduction has difficulty in discriminating the minute differences among similar fragrant smells of essential oils with different molecular shapes. These difficulties might arise from a lack of the physical sense when the transduction models were proposed. This article will reconsider these problems and propose rational models for visual, olfactory and auditory transduction. PMID- 27493559 TI - A topological study of gravity free-surface waves generated by bluff bodies using the method of steepest descents. AB - The standard analytical approach for studying steady gravity free-surface waves generated by a moving body often relies upon a linearization of the physical geometry, where the body is considered asymptotically small in one or several of its dimensions. In this paper, a methodology that avoids any such geometrical simplification is presented for the case of steady-state flows at low speeds. The approach is made possible through a reduction of the water-wave equations to a complex-valued integral equation that can be studied using the method of steepest descents. The main result is a theory that establishes a correspondence between different bluff-bodied free-surface flow configurations, with the topology of the Riemann surface formed by the steepest descent paths. Then, when a geometrical feature of the body is modified, a corresponding change to the Riemann surface is observed, and the resultant effects to the water waves can be derived. This visual procedure is demonstrated for the case of two-dimensional free-surface flow past a surface-piercing ship and over an angled step in a channel. PMID- 27493556 TI - The C-terminal periplasmic domain of MotB is responsible for load-dependent control of the number of stators of the bacterial flagellar motor. AB - The bacterial flagellar motor is made of a rotor and stators. In Salmonella it is thought that about a dozen MotA/B complexes are anchored to the peptidoglycan layer around the motor through the C-terminal peptidoglycan-binding domain of MotB to become active stators as well as proton channels. MotB consists of 309 residues, forming a single transmembrane helix (30-50), a stalk (51-100) and a C terminal peptidoglycan-binding domain (101-309). Although the stalk is dispensable for torque generation by the motor, it is required for efficient motor performance. Residues 51 to 72 prevent premature proton leakage through the proton channel prior to stator assembly into the motor. However, the role of residues 72-100 remains unknown. Here, we analyzed the torque-speed relationship of the MotB(Delta72-100) motor. At a low speed near stall, this mutant motor produced torque at the wild-type level. Unlike the wild-type motor, however, torque dropped off drastically by slight decrease in external load and then showed a slow exponential decay over a wide range of load by its further reduction. Since it is known that the stator is a mechano-sensor and that the number of active stators changes in a load-dependent manner, we interpreted this unusual torque-speed relationship as anomaly in load-dependent control of the number of active stators. The results suggest that residues 72-100 of MotB is required for proper load-dependent control of the number of active stators around the rotor. PMID- 27493560 TI - Nonlinear stratospheric variability: multifractal de-trended fluctuation analysis and singularity spectra. AB - Characterizing the stratosphere as a turbulent system, temporal fluctuations often show different correlations for different time scales as well as intermittent behaviour that cannot be captured by a single scaling exponent. In this study, the different scaling laws in the long-term stratospheric variability are studied using multifractal de-trended fluctuation analysis (MF-DFA). The analysis is performed comparing four re-analysis products and different realizations of an idealized numerical model, isolating the role of topographic forcing and seasonal variability, as well as the absence of climate teleconnections and small-scale forcing. The Northern Hemisphere (NH) shows a transition of scaling exponents for time scales shorter than about 1 year, for which the variability is multifractal and scales in time with a power law corresponding to a red spectrum, to longer time scales, for which the variability is monofractal and scales in time with a power law corresponding to white noise. Southern Hemisphere (SH) variability also shows a transition at annual scales. The SH also shows a narrower dynamical range in multifractality than the NH, as seen in the generalized Hurst exponent and in the singularity spectra. The numerical integrations show that the models are able to reproduce the low frequency variability but are not able to fully capture the shorter term variability of the stratosphere. PMID- 27493561 TI - H2 production by the photocatalytic reforming of cellulose and raw biomass using Ni, Pd, Pt and Au on titania. AB - Here, we report a method for sustainable hydrogen production using sunlight and biomass. It is shown that cellulose can be photoreformed to produce hydrogen, even in solid form, by use of metal-loaded titania photocatalysts. The experiments performed verified that the process is enabled by initial hydrolysis via glucose, which itself is shown to be efficiently converted to produce hydrogen by photocatalysis. Importantly, it is shown that not only precious metals such as Pt, Pd and Au can be used as the metal component, but also much more economic and less environmentally damaging Ni is effective. Even more importantly, we show for the first time, to the best our knowledge, that fescue grass as raw biomass can be effective for hydrogen production without significant pre-treatment. This provides additional benefits for the efficiency of biomass hydrogen production, because fewer processing steps for the raw material are required than in the production of purer forms of cellulose, for example. PMID- 27493562 TI - High-frequency homogenization for travelling waves in periodic media. AB - We consider high-frequency homogenization in periodic media for travelling waves of several different equations: the wave equation for scalar-valued waves such as acoustics; the wave equation for vector-valued waves such as electromagnetism and elasticity; and a system that encompasses the Schrodinger equation. This homogenization applies when the wavelength is of the order of the size of the medium periodicity cell. The travelling wave is assumed to be the sum of two waves: a modulated Bloch carrier wave having crystal wavevector [Formula: see text] and frequency omega1 plus a modulated Bloch carrier wave having crystal wavevector [Formula: see text] and frequency omega2. We derive effective equations for the modulating functions, and then prove that there is no coupling in the effective equations between the two different waves both in the scalar and the system cases. To be precise, we prove that there is no coupling unless omega1=omega2 and [Formula: see text] where Lambda=(lambda1lambda2...lambda d ) is the periodicity cell of the medium and for any two vectors [Formula: see text] the product a?b is defined to be the vector (a1b1,a2b2,...,adbd ). This last condition forces the carrier waves to be equivalent Bloch waves meaning that the coupling constants in the system of effective equations vanish. We use two-scale analysis and some new weak-convergence type lemmas. The analysis is not at the same level of rigour as that of Allaire and co-workers who use two-scale convergence theory to treat the problem, but has the advantage of simplicity which will allow it to be easily extended to the case where there is degeneracy of the Bloch eigenvalue. PMID- 27493563 TI - Influence of dopant substitution mechanism on catalytic properties within hierarchical architectures. AB - A range of hierarchically porous (HP) AlPO-5 catalysts, with isomorphously substituted transition metal ions, have been synthesized using an organosilane as a soft template. By employing a range of structural and spectroscopic characterization protocols, the properties of the dopant-substituted species within the HP architectures have been carefully evaluated. The resulting nature of the active site is shown to have a direct impact on the ensuing catalytic properties in the liquid-phase Beckmann rearrangement of cyclic ketones. PMID- 27493564 TI - Whispering Bloch modes. AB - We investigate eigenvalue problems for the planar Helmholtz equation in open systems with a high order of rotational symmetry. The resulting solutions have similarities with the whispering gallery modes exploited in photonic micro resonators and elsewhere, but unlike these do not necessarily require a surrounding material boundary, with confinement instead resulting from the geometry of a series of inclusions arranged in a ring. The corresponding fields exhibit angular quasi-periodicity reminiscent of Bloch waves, and hence we refer to them as whispering Bloch modes (WBMs). We show that if the geometry of the system is slightly perturbed such that the rotational symmetry is broken, modes with asymmetric field patterns can be observed, resulting in field enhancement and other potentially desirable effects. We investigate the WBMs of two specific geometries first using expansion methods and then by applying a two-scale asymptotic scheme. PMID- 27493565 TI - Movement of a finite body in channel flow. AB - A body of finite size is moving freely inside, and interacting with, a channel flow. The description of this unsteady interaction for a comparatively dense thin body moving slowly relative to flow at medium-to-high Reynolds number shows that an inviscid core problem with vorticity determines much, but not all, of the dominant response. It is found that the lift induced on a body of length comparable to the channel width leads to differences in flow direction upstream and downstream on the body scale which are smoothed out axially over a longer viscous length scale; the latter directly affects the change in flow directions. The change is such that in any symmetric incident flow the ratio of slopes is found to be [Formula: see text], i.e. approximately 0.900969, independently of Reynolds number, wall shear stresses and velocity profile. The two axial scales determine the evolution of the body and the flow, always yielding instability. This unusual evolution and linear or nonlinear instability mechanism arise outside the conventional range of flow instability and are influenced substantially by the lateral positioning, length and axial velocity of the body. PMID- 27493566 TI - North error estimation based on solar elevation errors in the third step of sky polarimetric Viking navigation. AB - The theory of sky-polarimetric Viking navigation has been widely accepted for decades without any information about the accuracy of this method. Previously, we have measured the accuracy of the first and second steps of this navigation method in psychophysical laboratory and planetarium experiments. Now, we have tested the accuracy of the third step in a planetarium experiment, assuming that the first and second steps are errorless. Using the fists of their outstretched arms, 10 test persons had to estimate the elevation angles (measured in numbers of fists and fingers) of black dots (representing the position of the occluded Sun) projected onto the planetarium dome. The test persons performed 2400 elevation estimations, 48% of which were more accurate than +/-1 degrees . We selected three test persons with the (i) largest and (ii) smallest elevation errors and (iii) highest standard deviation of the elevation error. From the errors of these three persons, we calculated their error function, from which the North errors (the angles with which they deviated from the geographical North) were determined for summer solstice and spring equinox, two specific dates of the Viking sailing period. The range of possible North errors DeltaomegaN was the lowest and highest at low and high solar elevations, respectively. At high elevations, the maximal DeltaomegaN was 35.6 degrees and 73.7 degrees at summer solstice and 23.8 degrees and 43.9 degrees at spring equinox for the best and worst test person (navigator), respectively. Thus, the best navigator was twice as good as the worst one. At solstice and equinox, high elevations occur the most frequently during the day, thus high North errors could occur more frequently than expected before. According to our findings, the ideal periods for sky polarimetric Viking navigation are immediately after sunrise and before sunset, because the North errors are the lowest at low solar elevations. PMID- 27493567 TI - Predicting the secondary dynamic mode interference phenomenon in thermoacoustic instability control. AB - This paper brings a novel mathematical perspective in assessing the rise of the secondary dynamic modes to prominence during the suppression of thermoacoustic instability. This phenomenon is observed by many earlier investigators; however, without a complete analytical reasoning. We consider a Rijke tube with both a passive Helmholtz resonator and an active feedback control to suppress instabilities. The core dynamics is represented as a linear time-invariant multiple time-delay system of neutral type. Parametric stability of the resulting infinite-dimensional dynamics is investigated using a recent analytical tool: cluster treatment of characteristic roots paradigm. This tool reveals the stability outlook of such systems exhaustively and non-conservatively in the parameter space of the system. First, we examine the stability with and without the Helmholtz resonator. We then select an unstable operation for the resonator mounted Rijke tube, impose a time-delayed integral feedback control over it and reveal the stabilizing controller parameters using the cluster treatment of characteristic roots methodology. When high control gains are inappropriately selected, the new analytical procedure declares how the secondary dynamic modes of the system exhibit instability although the initially unstable mode is now stabilized. All of these stability assessments are cross-validated using experimental results from a laboratory-scale Rijke tube set-up. PMID- 27493568 TI - Evidence of protein-free homology recognition in magnetic bead force-extension experiments. AB - Earlier theoretical studies have proposed that the homology-dependent pairing of large tracts of dsDNA may be due to physical interactions between homologous regions. Such interactions could contribute to the sequence-dependent pairing of chromosome regions that may occur in the presence or the absence of double-strand breaks. Several experiments have indicated the recognition of homologous sequences in pure electrolytic solutions without proteins. Here, we report single molecule force experiments with a designed 60 kb long dsDNA construct; one end attached to a solid surface and the other end to a magnetic bead. The 60 kb constructs contain two 10 kb long homologous tracts oriented head to head, so that their sequences match if the two tracts fold on each other. The distance between the bead and the surface is measured as a function of the force applied to the bead. At low forces, the construct molecules extend substantially less than normal, control dsDNA, indicating the existence of preferential interaction between the homologous regions. The force increase causes no abrupt but continuous unfolding of the paired homologous regions. Simple semi phenomenological models of the unfolding mechanics are proposed, and their predictions are compared with the data. PMID- 27493569 TI - Loose powder detection and surface characterization in selective laser sintering via optical coherence tomography. AB - Defects produced during selective laser sintering (SLS) are difficult to non destructively detect after build completion without the use of X-ray-based methods. Overcoming this issue by assessing integrity on a layer-by-layer basis has become an area of significant interest for users of SLS apparatus. Optical coherence tomography (OCT) is used in this study to detect surface texture and sub-surface powder, which is un-melted/insufficiently sintered, is known to be a common cause of poor part integrity and would prevent the use of SLS where applications dictate assurance of defect-free parts. To demonstrate the capability of the instrument and associated data-processing algorithms, samples were built with graduated porosities which were embedded in fully dense regions in order to simulate defective regions. Simulated in situ measurements were then correlated with the process parameters used to generate variable density regions. Using this method, it is possible to detect loose powder and differentiate between densities of +/-5% at a sub-surface depth of approximately 300 MUm. In order to demonstrate the value of OCT as a surface-profiling technique, surface texture datasets are compared with focus variation microscopy. Comparable results are achieved after a spatial bandwidth- matching procedure. PMID- 27493570 TI - Constitutive equation of friction based on the subloading-surface concept. AB - The subloading-friction model is capable of describing static friction, the smooth transition from static to kinetic friction and the recovery to static friction after sliding stops or sliding velocity decreases. This causes a negative rate sensitivity (i.e. a decrease in friction resistance with increasing sliding velocity). A generalized subloading-friction model is formulated in this article by incorporating the concept of overstress for viscoplastic sliding velocity into the subloading-friction model to describe not only negative rate sensitivity but also positive rate sensitivity (i.e. an increase in friction resistance with increasing sliding velocity) at a general sliding velocity ranging from quasi-static to impact sliding. The validity of the model is verified by numerical experiments and comparisons with test data obtained from friction tests using a lubricated steel specimen. PMID- 27493571 TI - Johnson-Kendall-Roberts adhesive contact for a toroidal indenter. AB - The unilateral axisymmetric frictionless adhesive contact problem for a toroidal indenter and an elastic half-space is considered in the framework of the Johnson Kendall-Roberts theory. In the case of a semi-fixed annular contact area, when one of the contact radii is fixed, while the other varies during indentation, we obtain the asymptotic solution of the adhesive contact problem based on the solution of the corresponding unilateral non-adhesive contact problem. In particular, the adhesive contact problem for Barber's concave indenter is considered in detail. In the case when both contact radii are variable, we construct the leading-order asymptotic solution for a narrow annular contact area. It is found that for a v-shaped generalized toroidal indenter, the pull-off force is independent of the elastic properties of the indented solid. PMID- 27493572 TI - Unidirectional invisibility and non-reciprocal transmission in two and three dimensions. AB - We explore the phenomenon of unidirectional invisibility in two dimensions, examine its optical realizations and discuss its three-dimensional generalization. In particular, we construct an infinite class of unidirectionally invisible optical potentials that describe the scattering of normally incident transverse electric waves by an infinite planar slab with refractive-index modulations along both the normal directions to the electric field. A by-product of this investigation is a demonstration of non-reciprocal transmission in two dimensions. To elucidate this phenomenon, we state and prove a general reciprocity theorem that applies to quantum scattering theory of real and complex potentials in two and three dimensions. PMID- 27493573 TI - Superalgebraically convergent smoothly windowed lattice sums for doubly periodic Green functions in three-dimensional space. AB - This work, part I in a two-part series, presents: (i) a simple and highly efficient algorithm for evaluation of quasi-periodic Green functions, as well as (ii) an associated boundary-integral equation method for the numerical solution of problems of scattering of waves by doubly periodic arrays of scatterers in three-dimensional space. Except for certain 'Wood frequencies' at which the quasi periodic Green function ceases to exist, the proposed approach, which is based on smooth windowing functions, gives rise to tapered lattice sums which converge superalgebraically fast to the Green function-that is, faster than any power of the number of terms used. This is in sharp contrast to the extremely slow convergence exhibited by the lattice sums in the absence of smooth windowing. (The Wood-frequency problem is treated in part II.) This paper establishes rigorously the superalgebraic convergence of the windowed lattice sums. A variety of numerical results demonstrate the practical efficiency of the proposed approach. PMID- 27493574 TI - The dynamic generalization of the Eshelby inclusion problem and its static limit. AB - The dynamic generalization of the celebrated Eshelby inclusion with transformation strain is the (subsonically) self-similarly expanding ellipsoidal inclusion starting from the zero dimension. The solution of the governing system of partial differential equations was obtained recently by Ni & Markenscoff (In press. J. Mech. Phys. Solids (doi:10.1016/j.jmps.2016.02.025)) on the basis of the Radon transformation, while here an alternative method is presented. In the self-similarly expanding motion, the Eshelby property of constant constrained strain is valid in the interior domain of the expanding ellipsoid where the particle velocity vanishes (lacuna). The dynamic Eshelby tensor is obtained in integral form. From it, the static Eshelby tensor is obtained by a limiting procedure, as the axes' expansion velocities tend to zero and time to infinity, while their product is equal to the length of the static axis. This makes the Eshelby problem the limit of its dynamic generalization. PMID- 27493575 TI - Surface plasmon resonances of arbitrarily shaped nanometallic structures in the small-screening-length limit. AB - According to the hydrodynamic Drude model, surface plasmon resonances of metallic nanostructures blueshift owing to the non-local response of the metal's electron gas. The screening length characterizing the non-local effect is often small relative to the overall dimensions of the metallic structure, which enables us to derive a coarse-grained non-local description using matched asymptotic expansions; a perturbation theory for the blueshifts of arbitrary-shaped nanometallic structures is then developed. The effect of non-locality is not always a perturbation and we present a detailed analysis of the 'bonding' modes of a dimer of nearly touching nanowires where the leading-order eigenfrequencies and eigenmode distributions are shown to be a renormalization of those predicted assuming a local metal permittivity. PMID- 27493576 TI - Global defect topology in nematic liquid crystals. AB - We give the global homotopy classification of nematic textures for a general domain with weak anchoring boundary conditions and arbitrary defect set in terms of twisted cohomology, and give an explicit computation for the case of knotted and linked defects in [Formula: see text], showing that the distinct homotopy classes have a 1-1 correspondence with the first homology group of the branched double cover, branched over the disclination loops. We show further that the subset of those classes corresponding to elements of order 2 in this group has representatives that are planar and characterize the obstruction for other classes in terms of merons. The planar textures are a feature of the global defect topology that is not reflected in any local characterization. Finally, we describe how the global classification relates to recent experiments on nematic droplets and how elements of order 4 relate to the presence of tau lines in cholesterics. PMID- 27493577 TI - Point vortex interactions on a toroidal surface. AB - Owing to non-constant curvature and a handle structure, it is not easy to imagine intuitively how flows with vortex structures evolve on a toroidal surface compared with those in a plane, on a sphere and a flat torus. In order to cultivate an insight into vortex interactions on this manifold, we derive the evolution equation for N-point vortices from Green's function associated with the Laplace-Beltrami operator there, and we then formulate it as a Hamiltonian dynamical system with the help of the symplectic geometry and the uniformization theorem. Based on this Hamiltonian formulation, we show that the 2-vortex problem is integrable. We also investigate the point vortex equilibria and the motion of two-point vortices with the strengths of the same magnitude as one of the fundamental vortex interactions. As a result, we find some characteristic interactions between point vortices on the torus. In particular, two identical point vortices can be locally repulsive under a certain circumstance. PMID- 27493578 TI - A non-classical Mindlin plate model incorporating microstructure, surface energy and foundation effects. AB - A non-classical model for a Mindlin plate resting on an elastic foundation is developed in a general form using a modified couple stress theory, a surface elasticity theory and a two-parameter Winkler-Pasternak foundation model. It includes all five kinematic variables possible for a Mindlin plate. The equations of motion and the complete boundary conditions are obtained simultaneously through a variational formulation based on Hamilton's principle, and the microstructure, surface energy and foundation effects are treated in a unified manner. The newly developed model contains one material length-scale parameter to describe the microstructure effect, three surface elastic constants to account for the surface energy effect, and two foundation parameters to capture the foundation effect. The current non-classical plate model reduces to its classical elasticity-based counterpart when the microstructure, surface energy and foundation effects are all suppressed. In addition, the new model includes the Mindlin plate models considering the microstructure dependence or the surface energy effect or the foundation influence alone as special cases, recovers the Kirchhoff plate model incorporating the microstructure, surface energy and foundation effects, and degenerates to the Timoshenko beam model including the microstructure effect. To illustrate the new Mindlin plate model, the static bending and free vibration problems of a simply supported rectangular plate are analytically solved by directly applying the general formulae derived. PMID- 27493579 TI - Interaction between mean flow and turbulence in two dimensions. AB - This short note is written to call attention to an analytic approach to the interaction of developed turbulence with mean flows of simple geometry (jets and vortices). It is instructive to compare cases in two and three dimensions and see why the former are solvable and the latter are not (yet). We present the analytical solutions for two-dimensional mean flows generated by an inverse turbulent cascade on a sphere and in planar domains of different aspect ratios. These solutions are obtained in the limit of small friction when the flow is strong while turbulence can be considered weak and treated perturbatively. I then discuss when these simple solutions can be realized and when more complicated flows may appear instead. The next step of describing turbulence statistics inside a flow and directions of possible future progress are briefly discussed at the end. PMID- 27493580 TI - A physical model for low-frequency electromagnetic induction in the near field based on direct interaction between transmitter and receiver electrons. AB - A physical model of electromagnetic induction is developed which relates directly the forces between electrons in the transmitter and receiver windings of concentric coaxial finite coils in the near-field region. By applying the principle of superposition, the contributions from accelerating electrons in successive current loops are summed, allowing the peak-induced voltage in the receiver to be accurately predicted. Results show good agreement between theory and experiment for various receivers of different radii up to five times that of the transmitter. The limitations of the linear theory of electromagnetic induction are discussed in terms of the non-uniform current distribution caused by the skin effect. In particular, the explanation in terms of electromagnetic energy and Poynting's theorem is contrasted with a more direct explanation based on variable filament induction across the conductor cross section. As the direct physical model developed herein deals only with forces between discrete current elements, it can be readily adapted to suit different coil geometries and is widely applicable in various fields of research such as near-field communications, antenna design, wireless power transfer, sensor applications and beyond. PMID- 27493581 TI - Origami mechanical metamaterials based on the Miura-derivative fold patterns. AB - This paper presents two new types of origami-inspired mechanical metamaterials based on the Miura-derivative fold patterns that consist of non-identical parallelogram facets. The analytical models to predict dimension changes and deformation kinematics of the proposed metamaterials are developed. Furthermore, by modelling the creases as revolute hinges with certain rotational spring constants, we derived analytical models for stretching and bulk moduli. The analytical models are validated through finite-element simulation results. Numerical examples reveal that the proposed metamaterials possess some intriguing properties, including negative Poisson's ratios and bulk modulus. The work presented in this paper can provide a highly flexible framework for the design of versatile tunable mechanical metamaterials. PMID- 27493582 TI - Turbulent jet manipulation using two unsteady azimuthally separated radial minijets. AB - The active manipulation of a turbulent round jet is experimentally investigated based on the injection of two radial unsteady minijets, prior to the issue of the main jet. The parametric study is conducted for the mass flow ratio Cm of the minijets to the main jet, and the ratio fe/f0 of the minijet frequency to the preferred-mode frequency of the main jet. It is found that the decay rate of the jet centreline mean velocity could be greatly increased if the two minijets are separated azimuthally by an angle theta=60 degrees , instead of by theta=180 degrees . This increase is a consequence of the flapping motion of the jet column, and the formation process and generation mechanism of this flapping motion are unveiled by careful analysis of the experimental data. PMID- 27493583 TI - A generalized optimization principle for asymmetric branching in fluidic networks. AB - When applied to a branching network, Murray's law states that the optimal branching of vascular networks is achieved when the cube of the parent channel radius is equal to the sum of the cubes of the daughter channel radii. It is considered integral to understanding biological networks and for the biomimetic design of artificial fluidic systems. However, despite its ubiquity, we demonstrate that Murray's law is only optimal (i.e. maximizes flow conductance per unit volume) for symmetric branching, where the local optimization of each individual channel corresponds to the global optimum of the network as a whole. In this paper, we present a generalized law that is valid for asymmetric branching, for any cross-sectional shape, and for a range of fluidic models. We verify our analytical solutions with the numerical optimization of a bifurcating fluidic network for the examples of laminar, turbulent and non-Newtonian fluid flows. PMID- 27493584 TI - Transient effects of drying creep in nanoporous solids: understanding the effects of nanoscale energy barriers. AB - The Pickett effect is the phenomenon of creep enhancement during transient drying. It has been observed for many nanoporous solids, including concrete, wood and Kevlar. While the existing micromechanical models can partially explain this effect, they have yet to consider nanoscale dynamic effects of water in nanopores, which are believed to be of paramount importance. Here, we examine how creep deformations in a slit pore are accelerated by the motion of water due to drying forces using coarse-grained molecular dynamics simulations. We find that the drying that drives water flow in the nanopores lowers both the activation energy of pore walls sliding past one another and the apparent viscosity of confined water molecules. This lowering can be captured with an analytical Arrhenius relationship accounting for the role of water flow in overcoming the energy barriers. Notably, we use this model and simulation results to demonstrate that the drying creep strain is not linearly dependent on the applied creep stress at the nanopore level. Our findings establish the scaling relationships that explain how the creep driving force, drying force and fluid properties are related. Thus, we establish the nanoscale origins of the Pickett effect and provide strategies for minimizing the additional displacements arising from this effect. PMID- 27493585 TI - It's Not Business, It's Personal: Implicit Religion in the Corporate Personhood Debate. AB - Debate surrounding the United States Supreme Court's 2010 decision in Citizens United v. FEC is ostensibly about the legal rights of corporations. However, I argue that the debate about corporate personhood is infused with religious concerns, rooted in the Protestant Reformation, about the proper identification of agentive subjects and the consequences of misidentification for human personhood. Focusing on the language used by opponents and defenders in the popular media, I show how both sides are animated by Protestant notions of human agency and share similar anxieties about the threats to that agency posed by abstract corporate or governmental entities. Attending to this fundamentally religious dimension not only improves our understanding of the moral stakes in the debate over corporations' legal rights but it also illuminates the implicit religious underpinnings of American political discourse. PMID- 27493586 TI - Patients' perceptions of the meaning of good care in surgical care: a grounded theory study. AB - BACKGROUND: Patients in surgical care have reported a fear of being discharged prior to sufficient recovery and a lack of control of their situation. Establishing the patient-nurse relationship is essential in the context of the care. The Swedish National Board of Health and Welfare has established indicators for good care for comparison, evaluation and improvement of the quality of the health care system. These indicators are knowledge-based, appropriate, safe, effective and equal health care, as well as care within a reasonable time and patient-centred care. Current core competence in nursing education include quality improvement, patient-centred care, teamwork and collaboration, using evidence-based practice, safety and informatics. This study investigates patients' perceptions of the meaning of good care in inpatient surgical care. METHODS: Grounded theory according to Charmaz was chosen as the study design. Interviews were conducted with 13 patients from six surgical wards in the south of Sweden in 2014-2015. RESULTS: The results showed that patients in surgical care perceived good care as being safe, as they were vulnerable and anxious. This could be achieved through accessible care, reliable care, caring attitudes and participating in one's own care. Patient participation was achieved by information and education and the possibility to affect their care. CONCLUSION: Patients need safety to experience good care. Caring attitudes and patient participation can be attained through patient-centred care. Bedside handover can improve patients' perceptions of accessible care and reliable care and can increase patient participation. Continuously maintaining competence and using evidence-based practice are needed to achieve reliable care. PMID- 27493587 TI - Nasal inflammation and its response to local glucocorticoid regular treatment in patients with persistent non-allergic rhinitis: a pilot study. AB - BACKGROUND: The pathogenesis of non-allergic rhinitis (NAR) is still largely unknown. Furthermore, it is unclear whether there is a correlation between the effect of nasal glucocorticoids on nasal inflammation and on nasal symptoms and quality of life. METHODS: In this pilot study we recruited 12 healthy subjects and 24 patients with recently diagnosed persistent NAR [12 untreated and 12 under regular treatment with nasal fluticasone furoate (two sprays of 27.5 MUg each in each nostril once daily, total daily dose = 110 MUg) for at least 20 days]. Each subject filled a mini rhinoconjunctivitis quality of life questionnaire (mini RQLQ). Nasal scrapings were obtained from each subject and used to prepare slides for Diff-Quik and immunocytochemical staining for inflammatory and epithelial cells count, MUC5AC expression and the general pro-inflammatory transcription factor nuclear factor kB (NF-kB) activation. RESULTS: The nasal score of the mini RQLQ, the number of nasal inflammatory cells (neutrophils, eosinophils) and the number of goblet cells are significantly higher in untreated patients with persistent NAR compared with control subjects and treated NAR patients. The percentage of MUC5AC+ nasal epithelial cells is significantly increased in untreated patients with persistent NAR compared with the control subjects (41.8 +/- 6.4 vs 22.3 +/- 4.8, respectively; p = 0.0403) without significant differences between control subjects and patients with persistent NAR on regular fluticasone furoate treatment (33.9 +/- 5.0 %; p = 0.0604) nor between the 2 groups of persistent NAR subjects (p = 0.3260). The number of cytosolic and/or nuclear p65+ nasal epithelial and inflammatory cells was not significantly different between the three groups. CONCLUSIONS: Patients with persistent untreated NAR, compared with normal control subjects and patients with persistent NAR under regular treatment with nasal fluticasone furoate by at least 20 days, have more nasal symptoms, worst quality of life and an increased number of nasal inflammatory cells (neutrophils, eosinophils), goblet cells and MUC5AC+ nasal epithelial cells. This nasal inflammation seems unrelated to NF-kB activation. PMID- 27493588 TI - Recognizing millions of consistently unidentified spectra across hundreds of shotgun proteomics datasets. AB - Mass spectrometry (MS) is the main technology used in proteomics approaches. However, on average 75% of spectra analysed in an MS experiment remain unidentified. We propose to use spectrum clustering at a large-scale to shed a light on these unidentified spectra. PRoteomics IDEntifications database (PRIDE) Archive is one of the largest MS proteomics public data repositories worldwide. By clustering all tandem MS spectra publicly available in PRIDE Archive, coming from hundreds of datasets, we were able to consistently characterize three distinct groups of spectra: 1) incorrectly identified spectra, 2) spectra correctly identified but below the set scoring threshold, and 3) truly unidentified spectra. Using a multitude of complementary analysis approaches, we were able to identify less than 20% of the consistently unidentified spectra. The complete spectrum clustering results are available through the new version of the PRIDE Cluster resource (http://www.ebi.ac.uk/pride/cluster). This resource is intended, among other aims, to encourage and simplify further investigation into these unidentified spectra. PMID- 27493589 TI - Leptospira Exposure and Patients with Liver Diseases: A Case-Control Seroprevalence Study. AB - The seroepidemiology of Leptospira infection in patients suffering from liver disease has been poorly studied. Information about risk factors associated with infection in liver disease patients may help in the optimal planning of preventive measures. We sought to determine the association of Leptospira IgG seroprevalence and patients with liver diseases, and to determine the characteristics of the patients with Leptospira exposure. We performed a case control study of 75 patients suffering from liver diseases and 150 age- and gender-matched control subjects. Diagnoses of liver disease included liver cirrhosis, steatosis, chronic hepatitis, acute hepatitis, and amoebic liver abscess. Sera of participants were analyzed for the presence of anti- Leptospira IgG antibodies using a commercially available enzyme immunoassay. Anti-Leptospira IgG antibodies were found in 17 (22.7%) of 75 patients and in 15 (10.0%) of 150 control subjects (OR = 2.32; 95% CI: 1.09-4.94; P=0.03). This is the first age- and gender-matched case control study about Leptospira seroprevalence in patients with liver diseases. Results indicate that Leptospira infection is associated with chronic and acute liver diseases. Results warrants for additional studies on the role of Leptospira exposure in chronic liver disease. PMID- 27493590 TI - IL-2 Expression and T lymphocyte Phenotyping in Young Children Suffering from Upper Respiratory Tract Infection with Streptococcus Pyogenes. AB - T cells are components of adaptive immunity and are involved in the resolution of respiratory infections, which are a major cause of morbidity and mortality in young children worldwide. Activation and differentiation of T cells is given mostly by the cytokine IL-2. This study aimed to determine the phenotype of T cells and IL-2 expression in children suffering from upper respiratory tract infection with Streptococcus pyogenes (S. pyogenes). For this purpose, IL-2 expression at its gene and protein levels and quantitation of CD4(+) and CD8(+) T lymphocytes were assessed in children aged 0-5 years old suffering from upper respiratory tract infection with S. pyogenes and healthy children of the same age. Children with S. pyogenes infection had a higher expression of IL-2 gene and a lower level of this cytokine expression at protein level than healthy children. The numbers of CD4(+) T lymphocytes were similar among the groups. In contrast, difference in the numbers of CD8(+) T lymphocytes among the groups was found. We conclude that infections by S. pyogenes in young children lead to an increased expression of IL-2 mRNA. PMID- 27493591 TI - Accessory Inferior Sulci of the Liver in an Afro-Caribbean Population. AB - INTRODUCTION: There have been no previous reports on the anatomic variations that exist on inferior surface of the liver in Caribbean populations. This information is important to optimize radiology and hepatobiliary surgical services in the region. METHODS: Two investigators independently observed 69 cadaveric dissections over five years and described the variations in surface anatomy. RESULTS: In this population 88% of cadaveric livers had conventional hepatic surface anatomy. However, 12% had accessory sulci present on the visceral surface of the liver, with a 7:1 male preponderance. When present, there was 100% correlation between the presence of Rouviere's sulcus and the right branch of portal pedicle. CONCLUSION: Abnormal surface anatomy is present in 12% of unselected specimens in this Caribbean population. Interventional radiologists and hepatobiliary surgeons practicing in the Caribbean must be cognizant of these differences in order to minimize morbidity during invasive procedures. PMID- 27493592 TI - Self-rated Health and Internet Addiction in Iranian Medical Sciences Students; Prevalence, Risk Factors and Complications. AB - INTRODUCTION: Self-rated health is a brief measure for general health. It is a comprehensive and sensitive index for prediction of health in future. Due to the high internet usage in medical students, the current study designed to evaluate the self-rated health (SRH) in relationship with internet addiction risk factors in medical students. METHODS: This cross sectional study conducted on 254 students of Qom University of Medical Sciences 2014. Participants selected by two stage sampling method including stratified and simple random sampling. The Young's questionnaire of internet addiction and SRH question used for data collection. Chi-square, t-test, and logistic regression used in data analysis. RESULTS: More than 79.9% of students reported their general health good and very good. The student's mean score of general health was higher than the average. In addition, the prevalence of internet addiction was 28.7%. An inverse significant correlation observed between SRH and internet addiction score (r=-0.198, p=0.002). Using internet for Entertainment, using private Email and chat rooms were the most important predictors of affecting to internet addiction. Moreover, internet addiction is the most predictors of SRH and increased the odds of bad SRH. CONCLUSION: The good SRH of medical students was higher than general population but in health faculty' students were lower than others. Due to the effect of internet addiction on SRH and increasing trend of internet use in medical students, as well as low age of participants, attention to psychological aspects and the job expectancy in future, can effective on increasing the good SRH. PMID- 27493594 TI - Focus on Endoscopy. PMID- 27493593 TI - Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats. AB - Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, beta-pinene, camphor, beta-caryophyllene, alpha-pinene and alpha-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, gamma-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats' liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes' activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition. PMID- 27493595 TI - Gastro-Hep News. PMID- 27493596 TI - A Systematic Review of Factors Associated With Utilization of Monitored Anesthesia Care for Gastrointestinal Endoscopy. AB - Utilization of monitored anesthesia care (MAC) for gastrointestinal endoscopy has increased markedly over the past decade, leading to significant additional health care expenditures. However, the extent to which certain patient-, provider-, and facility-level factors lead to MAC utilization is unclear. A systematic review of 13 studies evaluating influential factors associated with MAC utilization for colonoscopy and/or esophagogastroduodenoscopy was conducted. Multiple studies revealed significant increases in MAC utilization since the early 2000s, with substantial regional variation. The most influential patient-related factors associated with MAC utilization include female sex and diagnostic procedural indication. Other patient-related factors with weaker associations or conflicting evidence include older age, comorbidity, higher patient income, and white/non Hispanic race. The impact of patient substance use and/or prescription medication use has been minimally studied. The strongest provider- and facility-level factors associated with MAC use are a surgeon endoscopist and nonhospital site of service. Other factors with weaker associations include facility endoscopy volume and endoscopist years of experience. Further qualitative and quantitative health services research is needed to better understand the root cause of the rising trend of MAC utilization and to develop policies for encouraging appropriate use of MAC. PMID- 27493597 TI - Fecal Microbiota Transplantation for Inflammatory Bowel Disease. AB - The gut bacterial microbiome, particularly its role in disease and inflammation, has gained international attention with the successful use of fecal microbiota transplantation (FMT) in the treatment of Clostridium difficile infection. This success has led to studies exploring the role of FMT in other conditions, including inflammatory bowel disease (IBD). Both Crohn's disease and ulcerative colitis are chronic inflammatory conditions of the gastrointestinal system that have multifactorial etiologies. A shift in gut microbial composition in genetically susceptible individuals, an altered immune system, and environmental factors are all hypothesized to have a role in the pathogenesis of IBD. While numerous case reports and cohort studies have described the use of FMT in patients with IBD over the last 2 decades, the development of new sequencing techniques and results from 2 recent randomized, controlled trials have allowed for a better understanding of the relationship between the microbiome and the human host. However, despite these efforts, knowledge remains limited and the role of FMT in the management of IBD remains uncertain. Further investigation is necessary before FMT joins the current armamentarium of treatment options in clinical practice. PMID- 27493598 TI - Use of a Through-the-Scope Balloon System for Deep Enteroscopy. PMID- 27493599 TI - Surveillance for Hepatocellular Carcinoma. PMID- 27493600 TI - The Role of Bariatric Surgery in the Management of Nonalcoholic Steatohepatitis. PMID- 27493601 TI - Transoral Incisionless Fundoplication for the Treatment of Gastroesophageal Reflux Disease. PMID- 27493602 TI - The Transition From Pediatric to Adult Inflammatory Bowel Disease Care. PMID- 27493603 TI - The Transcription Cofactor Swi6 of the Fusarium graminearum Is Involved in Fusarium Graminearum Virus 1 Infection-Induced Phenotypic Alterations. AB - The transcription cofactor Swi6 plays important roles in regulating vegetative growth and meiosis in Saccharomyces cerevisiae. Functions of Swi6 ortholog were also characterized in Fusarium graminearum which is one of the devastating plant pathogenic fungi. Here, we report possible role of FgSwi6 in the interaction between F. graminearum and Fusarium graminearum virus 1 (FgV1) strain DK21. FgV1 perturbs biological characteristics of host fungi such as vegetative growth, sporulation, pigmentation, and reduction of the virulence (hypovirulence) of its fungal host. To characterize function(s) of FgSWI6 gene during FgV1 infection, targeted deletion, over-expression, and complementation mutants were generated and further infected successfully with FgV1. Deletion of FgSwi6 led to severe reduction of vegetative growth even aerial mycelia while over-expression did not affect any remarkable alteration of phenotype in virus-free isolates. Virus infected (VI) FgSWI6 deletion isolate exhibited completely delayed vegetative growth. However, VI FgSWI6 over-expression mutant grew faster than any other VI isolates. To verify whether these different growth patterns in VI isolates, viral RNA quantification was carried out using qRT-PCR. Surprisingly, viral RNA accumulations in VI isolates were similar regardless of introduced mutations. These results provide evidence that FgSWI6 might play important role(s) in FgV1 induced phenotype alteration such as delayed vegetative growth. PMID- 27493604 TI - Epidemiology and Control of Strawberry Bacterial Angular Leaf Spot Disease Caused by Xanthomonas fragariae. AB - Strawberry bacterial angular leaf spot (ALS) disease, caused by Xanthomonas fragariae has become increasingly problematic in the strawberry agro-industry. ALS causes small angular water-soaked lesions to develop on the abaxial leaf surface. Studies reported optimum temperature conditions for X. fragariae are 20 degrees C and the pathogen suffers mortality above 32 degrees C. However, at the nursery stage, disease symptoms have been observed under high temperature conditions. In the present study, results showed X. fragariae transmission was via infected maternal plants, precipitation, and sprinkler irrigation systems. Systemic infections were detected using X. fragariae specific primers 245A/B and 295A/B, where 300-bp and 615-bp were respectively amplified. During the nursery stage (from May to August), the pathogen was PCR detected only in maternal plants, but not in soil or irrigation water through the nursery stage. During the cultivation period, from September to March, the pathogen was detected in maternal plants, progeny, and soil, but not in water. Additionally, un-infected plants, when planted with infected plants were positive for X. fragariae via PCR at the late cultivation stage. Chemical control for X. fragariae with oxolinic acid showed 87% control effects against the disease during the nursery period, in contrast to validamycin-A, which exhibited increased efficacy against the disease during the cultivation stage (control effect 95%). To our knowledge, this is the first epidemiological study of X. fragariae in Korean strawberry fields. PMID- 27493605 TI - Visual Analysis for Detection and Quantification of Pseudomonas cichorii Disease Severity in Tomato Plants. AB - Pathogen infection in plants induces complex responses ranging from gene expression to metabolic processes in infected plants. In spite of many studies on biotic stress-related changes in host plants, little is known about the metabolic and phenotypic responses of the host plants to Pseudomonas cichorii infection based on image-based analysis. To investigate alterations in tomato plants according to disease severity, we inoculated plants with different cell densities of P. cichorii using dipping and syringe infiltration methods. High-dose inocula (>= 10(6) cfu/ml) induced evident necrotic lesions within one day that corresponded to bacterial growth in the infected tissues. Among the chlorophyll fluorescence parameters analyzed, changes in quantum yield of PSII (PhiPSII) and non-photochemical quenching (NPQ) preceded the appearance of visible symptoms, but maximum quantum efficiency of PSII (Fv/Fm) was altered well after symptom development. Visible/near infrared and chlorophyll fluorescence hyperspectral images detected changes before symptom appearance at low-density inoculation. The results of this study indicate that the P. cichorii infection severity can be detected by chlorophyll fluorescence assay and hyperspectral images prior to the onset of visible symptoms, indicating the feasibility of early detection of diseases. However, to detect disease development by hyperspectral imaging, more detailed protocols and analyses are necessary. Taken together, change in chlorophyll fluorescence is a good parameter for early detection of P. cichorii infection in tomato plants. In addition, image-based visualization of infection severity before visual damage appearance will contribute to effective management of plant diseases. PMID- 27493606 TI - Defense-Related Responses in Fruit of the Nonhost Chili Pepper against Xanthomonas axonopodis pv. glycines Infection. AB - Xanthomonas axonopodis pv. glycines (Xag ) is a necrotrophic bacterial pathogen of the soybean that causes bacterial pustules and is a nonhost pathogen of the chili pepper. In the current study, chili pepper fruit wound inoculated in planta with Xag 8ra formed necrotic lesions on the fruit surface and induced several structural and chemical barriers systemically in the fruit tissue. The initial defense response included programmed cell death of necrotizing and necrotized cells, which was characterized by nuclear DNA cleavage, as detected by TUNEL confocal laser scanning microscopy (CLSM), and phosphatidylserine exposure on cell walls distal to the infection site, as detected by Annexin V FLUOS-CLSM. These two responses may facilitate cell killing and enhance transportation of cell wall materials used for cell wall thickening, respectively. The cells beneath the necrotic tissue were enlarged and divided to form periclinal cell walls, resulting in extensive formation of several parallel boundary layers at the later stages of infection, accompanying the deposition of wall fortification materials for strengthening structural defenses. These results suggest that nonhost resistance of chili pepper fruit against the nonhost necrotrophic pathogen Xag 8ra is activated systematically from the initial infection until termination of the infection cycle, resulting in complete inhibition of bacterial pathogenesis by utilizing organ-specific in situ physiological events governed by the expression of genes in the plant fruit organ. PMID- 27493607 TI - The Effects of High Temperature on Infection by Potato virus Y, Potato virus A, and Potato leafroll virus. AB - We examined the effects of temperature on acquisition of Potato virus Y-O (PVY O), Potato virus A (PVA), and Potato leafroll virus (PLRV) by Myzus persicae by performing transmission tests with aphids that acquired each virus at different temperatures. Infection by PVY-O/PVA and PLRV increased with increasing plant temperature in Nicotiana benthamiana and Physalis floridana, respectively, after being transmitted by aphids that acquired them within a temperature range of 10 20 degrees C. However, infection rates subsequently decreased. Direct qRT-PCR of RNA extracted from a single aphid showed that PLRV infection increased in the 10 20 degrees C range, but this trend also declined shortly thereafter. We examined the effect of temperature on establishment of virus infection. The greatest number of plants became infected when N. benthamiana was held at 20 degrees C after inoculation with PVY-O or PVA. The largest number of P. floridana plants became infected with PLRV when the plants were maintained at 25 degrees C. PLRV levels were highest in P. floridana kept at 20-25 degrees C. These results indicate that the optimum temperatures for proliferation of PVY-O/PVA and PLRV differed. Western blot analysis showed that accumulations of PVY-O and PVA coat proteins (CPs) were lower at 10 degrees C or 15 degrees C than at 20 degrees C during early infection. However, accumulation increased over time. At 25 degrees C or 30 degrees C, the CPs of both viruses accumulated during early infection but disappeared as time passed. Our results suggest that symptom attenuation and reduction of PVY-O and PVA CP accumulation at higher temperatures appear to be attributable to increased RNA silencing. PMID- 27493608 TI - Short-Term Effects of Low-Level Heavy Metal Contamination on Soil Health Analyzed by Nematode Community Structure. AB - The short-term effects of low-level contamination by heavy metals (As, Cd, Cu, and Pb) on the soil health were examined by analyzing soil nematode community in soils planted with tomatoes. For this, the soils were irrigated with five metal concentrations ([1, 1/4, 1/4(2), 1/4(3), and 0] * maximum concentrations [MC] detected in irrigation waters near abandoned mine sites) for 18 weeks. Heavy metal concentrations were significantly increased in soils irrigated with MC of heavy metals, among which As and Cu exceeded the maximum heavy metal residue contents of soil approved in Korea. In no heavy metal treatment controls, nematode abundances for all trophic groups (except omnivorous-predatory nematodes [OP]) and colonizer-persister (cp) values (except cp-4-5) were significantly increased, and all maturity indices (except maturity index [MI] of plant parasitic nematodes) and structure index (SI) were significantly decreased, suggesting the soil environments might have been disturbed during 18 weeks of tomato growth. There were no concentration-dependent significant decreases in richness, abundance, or MI for most heavy metals; however, their significant decreases occurred in abundance and richness of OP and cp-4, MI2-5 (excluding cp 1) and SI, indicating disturbed soil ecosystems, at the higher concentrations (MC and MC/4) of Pb that had the most significant negative correlation coefficients for heavy metal concentrations and nematode community among the heavy metals. Therefore, the short-term effects of low-level heavy metal contamination on soil health can be analyzed by nematode community structures before the appearance of plant damages caused by the abiotic agents, heavy metals. PMID- 27493609 TI - Migration and Attacking Ability of Bursaphelenchus mucronatus in Pinus thunbergii Stem Cuttings. AB - To understand how Bursaphelenchus xylophilus kills pine trees, the differences between the effects of B. xylophilus and B. mucronatus on pine trees are usually compared. In this study, the migration and attacking ability of a non-pathogenic B. mucronatus in Pinus thunbergii were investigated. The distribution of B. mucronatus and the number of dead epithelial cells resulting from inoculation were compared with those of the pathogenic B. xylophilus. Although B. mucronatus is non-pathogenic in pines, its distribution pattern in P. thunbergii was the same as that of B. xylophilus. We therefore concluded that the non-pathogenicity of B. mucronatus could not be attributed to its migration ability. The sparse and sporadic attacking pattern of B. mucronatus was also the same as that of B. xylophilus. However, the number and area of the dead epithelial cells in pine cuttings inoculated with B. mucronatus were smaller than in those cuttings inoculated with B. xylophilus, meaning that the attacking ability of B. mucronatus is weaker than that of B. xylophilus. Therefore, we concluded that the weaker attacking ability of B. mucronatus might be the factor responsible for the non-pathogenicity. PMID- 27493610 TI - Identification and Expression Profiles of Six Transcripts Encoding Carboxylesterase Protein in Vitis flexuosa Infected with Pathogens. AB - Plants protect themselves from pathogen attacks via several mechanisms, including hypersensitive cell death. Recognition of pathogen attack by the plant resistance gene triggers expression of carboxylesterase genes associated with hypersensitive response. We identified six transcripts of carboxylesterase genes, Vitis flexuosa carboxylesterase 5585 (VfCXE5585), VfCXE12827, VfCXE13132, VfCXE17159, VfCXE18231, and VfCXE47674, which showed different expression patterns upon transcriptome analysis of V. flexuosa inoculated with Elsinoe ampelina. The lengths of genes ranged from 1,098 to 1,629 bp, and their encoded proteins consisted of 309 to 335 amino acids. The predicted amino acid sequences showed hydrolase like domains in all six transcripts and contained two conserved motifs, GXSXG of serine hydrolase characteristics and HGGGF related to the carboxylesterase family. The deduced amino acid sequence also contained a potential catalytic triad consisted of serine, aspartic acid and histidine. Of the six transcripts, VfCXE12827 showed upregulated expression against E. ampelina at all time points. Three genes (VfCXE5585, VfCXE12827, and VfCXE13132) showed upregulation, while others (VfCXE17159, VfCXE18231, and VfCXE47674) were down regulated in grapevines infected with Botrytis cinerea. All transcripts showed upregulated expression against Rhizobium vitis at early and later time points except VfCXE12827, and were downregulated for up to 48 hours post inoculation (hpi) after upregulation at 1 hpi in response to R. vitis infection. All tested genes showed high and differential expression in response to pathogens, indicating that they all may play a role in defense pathways during pathogen infection in grapevines. PMID- 27493612 TI - Antibacterial Activity of Cinnamaldehyde and Estragole Extracted from Plant Essential Oils against Pseudomonas syringae pv. actinidiae Causing Bacterial Canker Disease in Kiwifruit. AB - Pseudomonas syringae pv. actinidiae (Psa) causes bacterial canker disease in kiwifruit. Antibacterial activity of plant essential oils (PEOs) originating from 49 plant species were tested against Psa by a vapor diffusion and a liquid culture assays. The five PEOs from Pimenta racemosa, P. dioica, Melaleuca linariifolia, M. cajuputii, and Cinnamomum cassia efficiently inhibited Psa growth by either assays. Among their major components, estragole, eugenol, and methyl eugenol showed significant antibacterial activity by only the liquid culture assay, while cinnamaldehyde exhibited antibacterial activity by both assays. The minimum inhibitory concentrations (MICs) of estragole and cinnamaldehyde by the liquid culture assay were 1,250 and 2,500 ppm, respectively. The MIC of cinnamaldehyde by the vapor diffusion assay was 5,000 ppm. Based on the formation of clear zones or the decrease of optical density caused by these compounds, they might kill the bacterial cells and this feature might be useful for managing the bacterial canker disease in kiwifruit. PMID- 27493611 TI - A Rice Gene Homologous to Arabidopsis AGD2-LIKE DEFENSE1 Participates in Disease Resistance Response against Infection with Magnaporthe oryzae. AB - ALD1 (ABERRANT GROWTH AND DEATH2 [AGD2]-LIKE DEFENSE1) is one of the key defense regulators in Arabidopsis thaliana and Nicotiana benthamiana. In these model plants, ALD1 is responsible for triggering basal defense response and systemic resistance against bacterial infection. As well ALD1 is involved in the production of pipecolic acid and an unidentified compound(s) for systemic resistance and priming syndrome, respectively. These previous studies proposed that ALD1 is a potential candidate for developing genetically modified (GM) plants that may be resistant to pathogen infection. Here we introduce a role of ALD1-LIKE gene of Oryza sativa, named as OsALD1, during plant immunity. OsALD1 mRNA was strongly transcribed in the infected leaves of rice plants by Magnaporthe oryzae, the rice blast fungus. OsALD1 proteins predominantly localized at the chloroplast in the plant cells. GM rice plants over-expressing OsALD1 were resistant to the fungal infection. The stable expression of OsALD1 also triggered strong mRNA expression of PATHOGENESIS-RELATED PROTEIN1 genes in the leaves of rice plants during infection. Taken together, we conclude that OsALD1 plays a role in disease resistance response of rice against the infection with rice blast fungus. PMID- 27493613 TI - Development of Virus-Induced Gene Expression and Silencing Vector Derived from Grapevine Algerian Latent Virus. AB - Grapevine Algerian latent virus (GALV) is a member of the genus Tombusvirus in the Tombusviridae and infects not only woody perennial grapevine plant but also herbaceous Nicotiana benthamiana plant. In this study, we developed GALV-based gene expression and virus-induced gene silencing (VIGS) vectors in N. benthamiana. The GALV coat protein deletion vector, pGMG, was applied to express the reporter gene, green fluorescence protein (GFP), but the expression of GFP was not detected due to the necrotic cell death on the infiltrated leaves. The p19 silencing suppressor of GALV was engineered to inactivate its expression and GFP was successfully expressed with unrelated silencing suppressor, HC-Pro, from soybean mosaic virus. The pGMG vector was used to knock down magnesium chelatase (ChlH) gene in N. benthamaina and the silencing phenotype was clearly observed on systemic leaves. Altogether, the GALV-derived vector is expected to be an attractive tool for useful gene expression and VIGS vectors in grapevine as well as N. benthamiana. PMID- 27493614 TI - The Role of CDK 4/6 Inhibitors in Breast Cancer Treatment. PMID- 27493616 TI - Palbociclib: First CDK4/6 Inhibitor in Clinical Practice for the Treatment of Advanced HR-Positive Breast Cancer. AB - Palbociclib is the first inhibitor of the cyclin-dependent kinases (CDK) 4 and 6 to be introduced into clinical practice. Preclinical investigations led to its clinical development in advanced hormone receptor (HR)-positive breast cancer. To date, 2 significant clinical trials have been fully published. In this article, the results of these trials and their clinical relevance for the management of HR positive advanced breast cancer are discussed. PMID- 27493615 TI - Clinical Development of the CDK4/6 Inhibitors Ribociclib and Abemaciclib in Breast Cancer. AB - Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development. In this review, we will focus on clinical data on these 2 new drugs, highlighting their differences compared to palbociclib in terms of single-agent activity, central nervous system penetration, and common adverse events. In addition, we will present the ongoing clinical trials and discuss future directions in the field. PMID- 27493617 TI - Palbociclib - from Bench to Bedside and Beyond. AB - Endocrine therapy is the cornerstone in the treatment of hormone receptor positive breast cancer. During the last decades, much has been learned about the subtle regulation of the cell cycle. In this tightly regulated network, cyclin dependent kinases (CDKs) play a pivotal role. Especially CDK4/6 is the key regulator of the G1-S transition. Realizing its importance, specific inhibitors of CDK4/6 were developed. The drug most advanced in clinical development in this class is palbociclib (PD 0332991). This review highlights preclinical data and brings into focus early clinical trials that led to an accelerated approval by the US Food and Drug Administration (FDA) as first-line treatment in combination with letrozole in advanced hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Furthermore, ongoing clinical trials with palbociclib in advanced and in early breast cancer are outlined. In conclusion, inhibition of CDK4/6 using palbociclib in combination with endocrine therapy is an efficacious treatment option in hormone receptor-positive/HER2 negative advanced breast cancer. Ongoing clinical trials will show whether palbociclib is ready for prime time in early breast cancer. PMID- 27493618 TI - Implementation of the German Mammography Screening Program (German MSP) and First Results for Initial Examinations, 2005-2009. AB - BACKGROUND: The German Mammography Screening Program (German MSP) is population based and intended for women aged 50-69 years (approximately 10.5 million). The program started in 2005 and was implemented within 5 years. This article describes the implementation, structure, and screening process, and presents the results of initial examinations for the prevalence phase. METHODS: Data were collected annually from invitation centers (invitation, attendance), screening units (performance, outcomes), and cancer registries (incidence). RESULTS: In 2009, 92% of all annually eligible women were invited; 50% of the annually eligible population participated. The total cancer detection rate in the period of 2005-2009 was 8.1/1,000; the corresponding recall rate was 5.9%. 19.6% of detected cancers were ductal carcinoma in situ; 76.7% of invasive cancers were <= 20 mm in size, 30.2% were <= 10 mm, and 75.3% were node-negative. During the implementation period, incidence increased by 37 and 56% in the old and new federal states, respectively. Incidence rates decreased following the prevalence phase. CONCLUSION: The German MSP was successfully implemented. The results of the prevalence phase meet the target values of the European guidelines. Proper functioning of the program is also verified by its effects on breast cancer incidence. To draw reliable conclusions regarding the long-term effects of the program, results from the routine screening rounds have to be awaited. PMID- 27493619 TI - Factors Effecting Mastalgia. AB - BACKGROUND: Breast pain is one of the leading complaints that ends up with referral to breast surgery clinics. The purpose of the present study was to investigate the factors that cause mastalgia, and its relation with benign or malignant breast disease. METHODS: The study was performed in 700 patients. Data obtained from surveys, and imaging findings were prospectively recorded, and analyzed. RESULTS: The mean age was 45.20 +/- 10.78 years. The mastalgia group included 500 cases; the asymptomatic group comprised 200 individuals. Stressful lifestyle, caffeine consumption, and smoking were associated with mastalgia (p < 0.05). Rates of women who had breast fed 3 times or more were higher in the mastalgia group (p < 0.05). Increased breast density, and breast imaging reporting and data system (BI-RADS) 2 mammography findings were related with mastalgia (p < 0.05). Cysts and fibroadenomas were more common in the mastalgia group (p < 0.05). The incidence of a past history of malignant breast disease was significantly higher in the mastalgia group (p < 0.05). CONCLUSIONS: Stress, caffeine, smoking, lactation frequency, and benign disorders were factors detected to be related with mastalgia. Although a significant relation between mastalgia and malignant breast disease was detected in our study, more controlled studies are still required to investigate this issue further. PMID- 27493620 TI - Real-Time qPCR-Based Detection of Circulating Tumor Cells from Blood Samples of Adjuvant Breast Cancer Patients: A Preliminary Study. AB - BACKGROUND: Circulating tumor cells (CTCs) are cells that detach from a primary tumor, circulate through the blood stream and lymphatic vessels, and are considered to be the main reason for remote metastasis. Due to their origin, tumor cells have different gene expression levels than the surrounding blood cells. Therefore, they might be detectable in blood samples from breast cancer patients by real-time quantitative polymerase chain reaction (RT-qPCR). MATERIALS AND METHODS: Blood samples of healthy donors and adjuvant breast cancer patients were withdrawn and the cell fraction containing white blood cells and tumor cells was enriched by density gradient centrifugation. RNA was isolated and reverse transcribed to cDNA, which was then used in TaqMan real-time PCR against cytokeratin (CK)8, CK18 and CK19. 18S and GAPDH were used as controls. RESULTS: All 3 CKs were, on average, found to be significantly higher expressed in adjuvant breast cancer samples compared to negative controls, probably due to the presence of CTCs. Unfortunately, gene expression levels could not be correlated to tumor characteristics. CONCLUSIONS: RT-qPCR could make up a new approach for the detection of CTCs from blood samples of breast cancer patients, but a correlation of the PCR data to gold standard methods in CTC detection would help to further improve the informative value of the qPCR results. PMID- 27493622 TI - AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2016. PMID- 27493621 TI - Breast Tuberculosis after Chest Trauma - a Case Report and Review of the Literature. AB - BACKGROUND: Breast involvement of tuberculosis (TB) is well known but uncommon. It can resemble other diseases, including breast cancer, and diagnosis is quite difficult. So, when facing a breast lesion, a possible tubercular etiology should always be born in mind, relying on qualified laboratories to confirm the diagnosis. CASE REPORT: We describe a 42-year-old woman with a mammary fistula complicating a post-traumatic lump. A critical analysis of the diagnostic process was performed together with a review of the literature, also considering the potential role of trauma in inducing such a rare complication. PMID- 27493623 TI - AGO Recommendations for the Diagnosis and Treatment of Patients with Advanced and Metastatic Breast Cancer: Update 2016. PMID- 27493624 TI - Acceleration of Deep Neural Network Training with Resistive Cross-Point Devices: Design Considerations. AB - In recent years, deep neural networks (DNN) have demonstrated significant business impact in large scale analysis and classification tasks such as speech recognition, visual object detection, pattern extraction, etc. Training of large DNNs, however, is universally considered as time consuming and computationally intensive task that demands datacenter-scale computational resources recruited for many days. Here we propose a concept of resistive processing unit (RPU) devices that can potentially accelerate DNN training by orders of magnitude while using much less power. The proposed RPU device can store and update the weight values locally thus minimizing data movement during training and allowing to fully exploit the locality and the parallelism of the training algorithm. We evaluate the effect of various RPU device features/non-idealities and system parameters on performance in order to derive the device and system level specifications for implementation of an accelerator chip for DNN training in a realistic CMOS-compatible technology. For large DNNs with about 1 billion weights this massively parallel RPU architecture can achieve acceleration factors of 30, 000 * compared to state-of-the-art microprocessors while providing power efficiency of 84, 000 GigaOps/s/W. Problems that currently require days of training on a datacenter-size cluster with thousands of machines can be addressed within hours on a single RPU accelerator. A system consisting of a cluster of RPU accelerators will be able to tackle Big Data problems with trillions of parameters that is impossible to address today like, for example, natural speech recognition and translation between all world languages, real-time analytics on large streams of business and scientific data, integration, and analysis of multimodal sensory data flows from a massive number of IoT (Internet of Things) sensors. PMID- 27493627 TI - The Functional Networks of Prepulse Inhibition: Neuronal Connectivity Analysis Based on FDG-PET in Awake and Unrestrained Rats. AB - Prepulse inhibition (PPI) is a neuropsychological process during which a weak sensory stimulus ("prepulse") attenuates the motor response ("startle reaction") to a subsequent strong startling stimulus. It is measured as a surrogate marker of sensorimotor gating in patients suffering from neuropsychological diseases such as schizophrenia, as well as in corresponding animal models. A variety of studies has shown that PPI of the acoustical startle reaction comprises three brain circuitries for: (i) startle mediation, (ii) PPI mediation, and (iii) modulation of PPI mediation. While anatomical connections and information flow in the startle and PPI mediation pathways are well known, spatial and temporal interactions of the numerous regions involved in PPI modulation are incompletely understood. We therefore combined [(18)F]fluoro-2-deoxyglucose positron-emission tomography (FDG-PET) with PPI and resting state control paradigms in awake rats. A battery of subtractive, correlative as well as seed-based functional connectivity analyses revealed a default mode-like network (DMN) active during resting state only. Furthermore, two functional networks were observed during PPI: Metabolic activity in the lateral circuitry was positively correlated with PPI effectiveness and involved the auditory system and emotional regions. The medial network was negatively correlated with PPI effectiveness, i.e., associated with startle, and recruited a spatial/cognitive network. Our study provides evidence for two distinct neuronal networks, whose continuous interplay determines PPI effectiveness in rats, probably by either protecting the prepulse or facilitating startle processing. Discovering similar networks affected in neuropsychological disorders may help to better understand mechanisms of sensorimotor gating deficits and provide new perspectives for therapeutic strategies. PMID- 27493626 TI - The Autophagoproteasome a Novel Cell Clearing Organelle in Baseline and Stimulated Conditions. AB - Protein clearing pathways named autophagy (ATG) and ubiquitin proteasome (UP) control homeostasis within eukaryotic cells, while their dysfunction produces neurodegeneration. These pathways are viewed as distinct biochemical cascades occurring within specific cytosolic compartments owing pathway-specific enzymatic activity. Recent data strongly challenged the concept of two morphologically distinct and functionally segregated compartments. In fact, preliminary evidence suggests the convergence of these pathways to form a novel organelle named autophagoproteasome. This is characterized in the present study by using a cell line where, mTOR activity is upregulated and autophagy is suppressed. This was reversed dose-dependently by administering the mTOR inhibitor rapamycin. Thus, we could study autophagoproteasomes when autophagy was either suppressed or stimulated. The occurrence of autophagoproteasome was shown also in non-human cell lines. Ultrastructural morphometry, based on the stochiometric binding of immunogold particles allowed the quantitative evaluation of ATG and UP component within autophagoproteasomes. The number of autophagoproteasomes increases following mTOR inhibition. Similarly, mTOR inhibition produces overexpression of both LC3 and P20S particles. This is confirmed by the fact that the ratio of free vs. autophagosome-bound LC3 is similar to that measured for P20S, both in baseline conditions and following mTOR inhibition. Remarkably, within autophagoproteasomes there is a slight prevalence of ATG compared with UP components for low rapamycin doses, whereas for higher rapamycin doses UP increases more than ATG. While LC3 is widely present within cytosol, UP is strongly polarized within autophagoproteasomes. These fine details were evident at electron microscopy but could not be deciphered by using confocal microscopy. Despite its morphological novelty autophagoproteasomes appear in the natural site where clearing pathways (once believed to be anatomically segregated) co-exist and they are likely to interact at molecular level. In fact, LC3 and P20S co immunoprecipitate, suggesting a specific binding and functional interplay, which may be altered by inhibiting mTOR. In summary, ATG and UP often represent two facets of a single organelle, in which unexpected amount of enzymatic activity should be available. Thus, autophagoproteasome may represent a sophisticated ultimate clearing apparatus. PMID- 27493625 TI - Functional Relevance of Different Basal Ganglia Pathways Investigated in a Spiking Model with Reward Dependent Plasticity. AB - The brain enables animals to behaviorally adapt in order to survive in a complex and dynamic environment, but how reward-oriented behaviors are achieved and computed by its underlying neural circuitry is an open question. To address this concern, we have developed a spiking model of the basal ganglia (BG) that learns to dis-inhibit the action leading to a reward despite ongoing changes in the reward schedule. The architecture of the network features the two pathways commonly described in BG, the direct (denoted D1) and the indirect (denoted D2) pathway, as well as a loop involving striatum and the dopaminergic system. The activity of these dopaminergic neurons conveys the reward prediction error (RPE), which determines the magnitude of synaptic plasticity within the different pathways. All plastic connections implement a versatile four-factor learning rule derived from Bayesian inference that depends upon pre- and post-synaptic activity, receptor type, and dopamine level. Synaptic weight updates occur in the D1 or D2 pathways depending on the sign of the RPE, and an efference copy informs upstream nuclei about the action selected. We demonstrate successful performance of the system in a multiple-choice learning task with a transiently changing reward schedule. We simulate lesioning of the various pathways and show that a condition without the D2 pathway fares worse than one without D1. Additionally, we simulate the degeneration observed in Parkinson's disease (PD) by decreasing the number of dopaminergic neurons during learning. The results suggest that the D1 pathway impairment in PD might have been overlooked. Furthermore, an analysis of the alterations in the synaptic weights shows that using the absolute reward value instead of the RPE leads to a larger change in D1. PMID- 27493628 TI - Aesthetics by Numbers: Links between Perceived Texture Qualities and Computed Visual Texture Properties. AB - Our world is filled with texture. For the human visual system, this is an important source of information for assessing environmental and material properties. Indeed-and presumably for this reason-the human visual system has regions dedicated to processing textures. Despite their abundance and apparent relevance, only recently the relationships between texture features and high level judgments have captured the interest of mainstream science, despite long standing indications for such relationships. In this study, we explore such relationships, as these might be used to predict perceived texture qualities. This is relevant, not only from a psychological/neuroscience perspective, but also for more applied fields such as design, architecture, and the visual arts. In two separate experiments, observers judged various qualities of visual textures such as beauty, roughness, naturalness, elegance, and complexity. Based on factor analysis, we find that in both experiments, ~75% of the variability in the judgments could be explained by a two-dimensional space, with axes that are closely aligned to the beauty and roughness judgments. That a two-dimensional judgment space suffices to capture most of the variability in the perceived texture qualities suggests that observers use a relatively limited set of internal scales on which to base various judgments, including aesthetic ones. Finally, for both of these judgments, we determined the relationship with a large number of texture features computed for each of the texture stimuli. We find that the presence of lower spatial frequencies, oblique orientations, higher intensity variation, higher saturation, and redness correlates with higher beauty ratings. Features that captured image intensity and uniformity correlated with roughness ratings. Therefore, a number of computational texture features are predictive of these judgments. This suggests that perceived texture qualities-including the aesthetic appreciation-are sufficiently universal to be predicted-with reasonable accuracy-based on the computed feature content of the textures. PMID- 27493629 TI - Pyrrolidine Dithiocarbamate Prevents Neuroinflammation and Cognitive Dysfunction after Endotoxemia in Rats. AB - Systemic inflammation, for example as a result of infection, often contributes to long-term complications. Neuroinflammation and cognitive decline are key hallmarks of several neurological conditions, including advance age. The contribution of systemic inflammation to the central nervous system (CNS) remains not fully understood. Using a model of peripheral endotoxemia with lipopolysaccharide (LPS) we investigated the role of nuclear factor-kappaB (NF kappaB) activity in mediating long-term neuroinflammation and cognitive dysfunction in aged rats. Herein we describe the anti-inflammatory effects of pyrrolidine dithiocarbamate (PDTC), a selective NF-kappaB inhibitor, in modulating systemic cytokines including tumor necrosis factor (TNF)-alpha and interleukin-1beta (IL-1beta) and CNS markers after LPS exposure in aged rats. In the hippocampus, PDTC not only reduced neuroinflammation by modulating canonical NF-kappaB activity but also affected IL-1beta expression in astrocytes. Parallel effects were observed on behavior and postsynaptic density-95 (PSD95), a marker of synaptic function. Taken together these changes improved acute and long-term cognitive function in aged rats after LPS exposure. PMID- 27493631 TI - Paeonol Protects Rat Heart by Improving Regional Blood Perfusion during No Reflow. AB - No-reflow phenomenon, defined as inadequate perfusion of myocardium without evident artery obstruction, occurs at a high incidence after coronary revascularization. The mechanisms underlying no-reflow is only partially understood. It is commonly caused by the swelling of endothelial cells, neutrophil accumulation, and vasoconstriction, which are all related to acute inflammation. Persistent no-reflow can lead to hospitalization and mortality. However, an effective preventive intervention has not yet been established. We have previously found that paeonol, an active extraction from the root of Paeonia suffruticosa, can benefit the heart function by inhibiting tissue damage after ischemia, reducing inflammation, and inducing vasodilatation. To further investigate the potential cardioprotective action of paeonol on no-reflow, healthy male Wistar rats were randomly divided into four groups: sham, ischemia reperfusion (I/R) injury (left anterior descending coronary artery was ligated for 4 h followed by reperfusion for 8 h), and I/R injury pretreated with paeonol at two different doses. Real-time myocardial contrast echocardiography was used to monitor regional blood perfusion and cardiac functions. Our data indicated that paeonol treatment significantly reduces myocardial infarct area and no reflow area (n = 8; p < 0.05). Regional myocardial perfusion (A.beta) and cardiac functions such as ejection fraction, stroke volume, and fractional shortening were elevated by paeonol (n = 8; p < 0.05). Paeonol also lowered the serum levels of lactate dehydrogenase, creatine kinase, cardiac troponin T, and C-reactive protein, as indices of myocardial injury. Paeonol exerts beneficial effects on attenuating I/R-associated no-reflow injuries, and may be considered as a potential preventive treatment for cardiac diseases or post-coronary revascularization in which no-reflow often occurs. PMID- 27493632 TI - "Decoding" Angiogenesis: New Facets Controlling Endothelial Cell Behavior. AB - Angiogenesis, the formation of new blood vessels, is a unique and crucial biological process occurring during both development and adulthood. A better understanding of the mechanisms that regulates such process is mandatory to intervene in pathophysiological conditions. Here we highlight some recent argument on new players that are critical in endothelial cells, by summarizing novel discoveries that regulate notorious vascular pathways such as Vascular Endothelial Growth Factor (VEGF), Notch and Planar Cell Polarity (PCP), and by discussing more recent findings that put metabolism, redox signaling and hemodynamic forces as novel unforeseen facets in angiogenesis. These new aspects, that critically regulate angiogenesis and vascular homeostasis in health and diseased, represent unforeseen new ground to develop anti-angiogenic therapies. PMID- 27493630 TI - Animal-Free Chemical Safety Assessment. AB - The exponential growth of the Internet of Things and the global popularity and remarkable decline in cost of the mobile phone is driving the digital transformation of medical practice. The rapidly maturing digital, non-medical world of mobile (wireless) devices, cloud computing and social networking is coalescing with the emerging digital medical world of omics data, biosensors and advanced imaging which offers the increasingly realistic prospect of personalized medicine. Described as a potential "seismic" shift from the current "healthcare" model to a "wellness" paradigm that is predictive, preventative, personalized and participatory, this change is based on the development of increasingly sophisticated biosensors which can track and measure key biochemical variables in people. Additional key drivers in this shift are metabolomic and proteomic signatures, which are increasingly being reported as pre-symptomatic, diagnostic and prognostic of toxicity and disease. These advancements also have profound implications for toxicological evaluation and safety assessment of pharmaceuticals and environmental chemicals. An approach based primarily on human in vivo and high-throughput in vitro human cell-line data is a distinct possibility. This would transform current chemical safety assessment practice which operates in a human "data poor" to a human "data rich" environment. This could also lead to a seismic shift from the current animal-based to an animal free chemical safety assessment paradigm. PMID- 27493634 TI - Bubbles Quantified In vivo by Ultrasound Relates to Amount of Gas Detected Post mortem in Rabbits Decompressed from High Pressure. AB - The pathophysiological mechanism of decompression sickness is not fully understood but there is evidence that it can be caused by intravascular and autochthonous bubbles. Doppler ultrasound at a given circulatory location is used to detect and quantify the presence of intravascular gas bubbles as an indicator of decompression stress. In this manuscript we studied the relationship between presence and quantity of gas bubbles by echosonography of the pulmonary artery of anesthetized, air-breathing New Zealand White rabbits that were compressed and decompressed. Mortality rate, presence, quantity, and distribution of gas bubbles elsewhere in the body was examined postmortem. We found a strong positive relationship between high ultrasound bubble grades in the pulmonary artery, sudden death, and high amount of intra and extra vascular gas bubbles widespread throughout the entire organism. In contrast, animals with lower bubble grades survived for 1 h after decompression until sacrificed, and showed no gas bubbles during dissection. PMID- 27493633 TI - What Is the Arrhythmic Substrate in Viral Myocarditis? Insights from Clinical and Animal Studies. AB - Sudden cardiac death (SCD) remains an unsolved problem in the twenty-first century. It is often due to rapid onset, ventricular arrhythmias caused by a number of different clinical conditions. A proportion of SCD patients have identifiable diseases such as cardiomyopathies, but for others, the causes are unknown. Viral myocarditis is becoming increasingly recognized as a contributor to unexplained mortality, and is thought to be a major cause of SCD in the first two decades of life. Myocardial inflammation, ion channel dysfunction, electrophysiological, and structural remodeling may play important roles in generating life-threatening arrhythmias. The aim of this review article is to examine the electrophysiology of action potential conduction and repolarization and the mechanisms by which their derangements lead to triggered and reentrant arrhythmogenesis. By synthesizing experimental evidence from pre-clinical and clinical studies, a framework of how host (inflammation), and viral (altered cellular signaling) factors can induce ion electrophysiological and structural remodeling is illustrated. Current pharmacological options are mainly supportive, which may be accompanied by mechanical circulatory support. Heart transplantation is the only curative option in the worst case scenario. Future strategies for the management of viral myocarditis are discussed. PMID- 27493635 TI - The Phantom Vanish Magic Trick: Investigating the Disappearance of a Non-existent Object in a Dynamic Scene. AB - Drawing inspiration from sleight-of-hand magic tricks, we developed an experimental paradigm to investigate whether magicians' misdirection techniques could be used to induce the misperception of "phantom" objects. While previous experiments investigating sleight-of-hand magic tricks have focused on creating false assumptions about the movement of an object in a scene, our experiment investigated creating false assumptions about the presence of an object in a scene. Participants watched a sequence of silent videos depicting a magician performing with a single object. Following each video, participants were asked to write a description of the events in the video. In the final video, participants watched the Phantom Vanish Magic Trick, a novel magic trick developed for this experiment, in which the magician pantomimed the actions of presenting an object and then making it magically disappear. No object was presented during the final video. The silent videos precluded the use of false verbal suggestions, and participants were not asked leading questions about the objects. Nevertheless, 32% of participants reported having visual impressions of non-existent objects. These findings support an inferential model of perception, wherein top-down expectations can be manipulated by the magician to generate vivid illusory experiences, even in the absence of corresponding bottom-up information. PMID- 27493636 TI - Editorial: Mathematical and Statistics Anxiety: Educational, Social, Developmental and Cognitive Perspectives. PMID- 27493637 TI - Does Exercise Improve Cognitive Performance? A Conservative Message from Lord's Paradox. AB - Although extant meta-analyses support the notion that exercise results in cognitive performance enhancement, methodology shortcomings are noted among primary evidence. The present study examined relevant randomized controlled trials (RCTs) published in the past 20 years (1996-2015) for methodological concerns arise from Lord's paradox. Our analysis revealed that RCTs supporting the positive effect of exercise on cognition are likely to include Type I Error(s). This result can be attributed to the use of gain score analysis on pretest-posttest data as well as the presence of control group superiority over the exercise group on baseline cognitive measures. To improve accuracy of causal inferences in this area, analysis of covariance on pretest-posttest data is recommended under the assumption of group equivalence. Important experimental procedures are discussed to maintain group equivalence. PMID- 27493638 TI - Better Working Memory and Motor Inhibition in Children Who Delayed Gratification. AB - BACKGROUND: Despite the extensive research on delayed gratification over the past few decades, the neurocognitive processes that subserve delayed gratification remains unclear. As an exploratory step in studying these processes, the present study aims to describe the executive function profiles of children who were successful at delaying gratification and those who were not. METHODS: A total of 138 kindergarten students (65 males, 73 females; M age = 44 months, SD = 3.5; age range = 37-53 months) were administered a delayed gratification task, a 1-back test, a Day/night Stroop test and a Go/no-go test. The outcome measures of these tests were then analyzed between groups using a Multivariate Analysis of Variance, and subsequently a Multivariate Analysis of Covariance incorporating age as a covariate. RESULTS: Children who were successful in delaying gratification were significantly older and had significantly better outcomes in the 1-back test and go/no-go test. With the exception of the number of hits in the go/no-go test, all other group differences remained significant after controlling for age. CONCLUSION: Children who were successful in delaying gratification showed better working memory and motor inhibition relative to those who failed the delayed gratification task. The implications of these findings are discussed. PMID- 27493639 TI - How Parents Read Counting Books and Non-numerical Books to Their Preverbal Infants: An Observational Study. AB - Studies have stressed the importance of counting with children to promote formal numeracy abilities; however, little work has investigated when parents begin to engage in this behavior with their young children. In the current study, we investigated whether parents elaborated on numerical information when reading a counting book to their preverbal infants and whether developmental differences in numerical input exist even in the 1st year of life. Parents and their 5-10 months old infants were asked to read, as they would at home, two books to their infants: a counting book and another book that did not have numerical content. Parents' spontaneous statements rarely focused on number and those that did consisted primarily of counting, with little emphasis on labeling the cardinality of the set. However, developmental differences were observed even in this age range, such that parents were more likely to make numerical utterances when reading to older infants. Together, results are the first to characterize naturalistic reading behaviors between parents and their preverbal infants in the context of counting books, suggesting that although counting books promote numerical language in parents, infants still receive very little in the way of numerical input before the end of the 1st year of life. While little is known regarding the impact of number talk on the cognitive development of young infants, the current results may guide future work in this area by providing the first assessment of the characteristics of parental numerical input to preverbal infants. PMID- 27493640 TI - Erratum: How to Make the Ghosts in my Bedroom Disappear? Focused-Attention Meditation Combined with Muscle Relaxation (MR Therapy)-A Direct Treatment Intervention for Sleep Paralysis. AB - [This corrects the article on p. 28 in vol. 7, PMID: 26858675.]. PMID- 27493641 TI - The Exposed Proteomes of Brachyspira hyodysenteriae and B. pilosicoli. AB - Brachyspira hyodysenteriae and Brachyspira pilosicoli are well-known intestinal pathogens in pigs. B. hyodysenteriae is the causative agent of swine dysentery, a disease with an important impact on pig production while B. pilosicoli is responsible of a milder diarrheal disease in these animals, porcine intestinal spirochetosis. Recent sequencing projects have provided information for the genome of these species facilitating the search of vaccine candidates using reverse vaccinology approaches. However, practically no experimental evidence exists of the actual gene products being expressed and of those proteins exposed on the cell surface or released to the cell media. Using a cell-shaving strategy and a shotgun proteomic approach we carried out a large-scale characterization of the exposed proteins on the bacterial surface in these species as well as of peptides and proteins in the extracellular medium. The study included three strains of B. hyodysenteriae and two strains of B. pilosicoli and involved 148 LC MS/MS runs on a high resolution Orbitrap instrument. Overall, we provided evidence for more than 29,000 different peptides pointing to 1625 and 1338 different proteins in B. hyodysenteriae and B. pilosicoli, respectively. Many of the most abundant proteins detected corresponded to described virulence factors and vaccine candidates. The level of expression of these proteins, however, was different among species and strains, stressing the value of determining actual gene product levels as a complement of genomic-based approaches for vaccine design. PMID- 27493642 TI - Detection of Cronobacter Genus in Powdered Infant Formula by Enzyme-linked Immunosorbent Assay Using Anti-Cronobacter Antibody. AB - Cronobacter species (Cronobacter spp.) are hazardous foodborne pathogens associated with baby food, powdered infant formula (PIF). To develop a rapid and sensitive method for simultaneous detection of seven Cronobacter spp. in PIF, an indirect non-competitive enzyme-linked immunosorbent assay (INC-ELISA) was developed based on a novel immunoglobulin G (IgG), anti-Cronobacter IgG. The developed INC-ELISA was able to detect seven Cronobacter spp. at concentrations ranging from (5.6 +/- 0.30) * 10(3) to (2.1 +/- 0.01) * 10(5) colony forming unit (CFU)/mL in pure culture. Further, INC-ELISA employing anti-Cronobacter IgG was applicable for analysis of PIF samples contaminated with less than <10 cells of Cronobacter spp. per 25 g of PIF in 36 h. The developed antibody showed slight cross-reactivity with Franconibacter pulveris (LMG 24057) at high concentration (10(8) CFU/mL). The INC-ELISA method displayed excellent specificity without compromising cross-reactivity with other foodborne pathogens. The INC-ELISA assay method developed in this study using a novel anti-Cronobacter IgG facilitated highly sensitive, efficient, and rapid detection of Cronobacter spp. in baby food. PMID- 27493643 TI - Phylogenomic Analyses and Reclassification of Species within the Genus Tsukamurella: Insights to Species Definition in the Post-genomic Era. AB - Owing to the highly similar phenotypic profiles, protein spectra and 16S rRNA gene sequences observed between three pairs of Tsukamurella species (Tsukamurella pulmonis/Tsukamurella spongiae, Tsukamurella tyrosinosolvens/Tsukamurella carboxy divorans, and Tsukamurella pseudospumae/Tsukamurella sunchonensis), we hypothesize that and the six Tsukamurella species may have been misclassified and that there may only be three Tsukamurella species. In this study, we characterized the type strains of these six Tsukamurella species by tradition DNA DNA hybridization (DDH) and "digital DDH" after genome sequencing to determine their exact taxonomic positions. Traditional DDH showed 81.2 +/- 0.6% to 99.7 +/- 1.0% DNA-DNA relatedness between the two Tsukamurella species in each of the three pairs, which was above the threshold for same species designation. "Digital DDH" based on Genome-To-Genome Distance Calculator and Average Nucleotide Identity for the three pairs also showed similarity results in the range of 82.3 92.9 and 98.1-99.1%, respectively, in line with results of traditional DDH. Based on these evidence and according to Rules 23a and 42 of the Bacteriological Code, we propose that T. spongiae Olson et al. 2007, should be reclassified as a later heterotypic synonym of T. pulmonis Yassin et al. 1996, T. carboxydivorans Park et al. 2009, as a later heterotypic synonym of T. tyrosinosolvens Yassin et al. 1997, and T. sunchonensis Seong et al. 2008 as a later heterotypic synonym of T. pseudospumae Nam et al. 2004. With the advancement of genome sequencing technologies, classification of bacterial species can be readily achieved by "digital DDH" than traditional DDH. PMID- 27493645 TI - Transcriptomic Analysis of Staphylococcus epidermidis Biofilm-Released Cells upon Interaction with Human Blood Circulating Immune Cells and Soluble Factors. PMID- 27493644 TI - The New Antimicrobial Peptide SpHyastatin from the Mud Crab Scylla paramamosain with Multiple Antimicrobial Mechanisms and High Effect on Bacterial Infection. AB - SpHyastatin was first identified as a new cationic antimicrobial peptide in hemocytes of the mud crab Scylla paramamosain. Based on the amino acid sequences deduced, it was predicted that this peptide was composed of two different functional domains, a proline-rich domain (PRD) and a cysteine-rich domain (CRD). The recombinant product of SpHyastatin displayed potent antimicrobial activities against the human pathogen Staphylococcus aureus and the aquatic animal pathogens Aeromonas hydrophila and Pseudomonas fluorescens. Compared with the CRD of SpHyastatin, the PRD presented better antimicrobial and chitin binding activities, but both regions were essential for allowing SpHyastatin complete antimicrobial activity. The binding properties of SpHyastatin to different microbial surface molecules suggested that this might be an initial and crucial step for performing its antimicrobial activities. Evaluated using propidium iodide uptake assays and scanning electron microscopy images, the antimicrobial mechanism of SpHyastatin was found to be prone to disrupt cell membrane integrity. Interestingly, SpHyastatin exerted its role specifically on the surface of S. aureus and Pichia pastoris whereas it directly killed P. fluorescens through simultaneous targeting the membrane and the cytoplasm, indicating that SpHyastatin could use different antimicrobial mechanisms to kill different species of microbes. As expected, the recombinant SpHyastatin increased the survival rate of crabs challenged with Vibrio parahaemolyticus. In addition, SpHyastatin could modulate some V. parahaemolyticus-responsive genes in S. paramamosain. PMID- 27493646 TI - Analysis of the Changes in Expression Levels of Sialic Acid on Influenza-Virus Infected Cells Using Lectin-Tagged Polymeric Nanoparticles. AB - Viral infections affect millions around the world, sometimes leading to severe consequences or even epidemics. Understanding the molecular dynamics during viral infections would provide crucial information for preventing or stopping the progress of infections. However, the current methods often involve the disruption of the infected cells or expensive and time-consuming procedures. In this study, fluorescent polymeric nanoparticles were fabricated and used as bioimaging nanoprobes that can monitor the progression of influenza viral infection through the changes in the expression levels of sialic acids expressed on the cell membrane. The nanoparticles were composed of a biocompatible monomer to prevent non-specific interactions, a hydrophobic monomer to form the core, a fluorescent monomer, and a protein-binding monomer to conjugate lectin, which binds sialic acids. It was shown that these lectin-tagged nanoparticles that specifically target sialic acids could track the changes in the expression levels of sialic acids caused by influenza viral infections in human lung epithelial cells. There was a sudden drop in the levels of sialic acid at the initial onset of virus infection (t = 0~1 h) and at approximately 4~5 h post-infection. The latter drop correlated with the production of viral proteins that was confirmed using traditional techniques. Thus, the accuracy, the rapidity and the efficacy of the nanoprobes were demonstrated. Such molecular bioimaging tools, which allow easy handling and in situ monitoring, would be useful to directly observe and decipher the viral infection mechanisms. PMID- 27493647 TI - Molecular Underpinnings of Nitrite Effect on CymA-Dependent Respiration in Shewanella oneidensis. AB - Shewanella exhibit a remarkable versatility of respiration, with a diverse array of electron acceptors (EAs). In environments where these bacteria thrive, multiple EAs are usually present. However, we know little about strategies by which these EAs and their interaction affect ecophysiology of Shewanella. In this study, we demonstrate in the model strain, Shewanella oneidensis MR-1, that nitrite, not through nitric oxide to which it may convert, inhibits respiration of fumarate, and probably many other EAs whose reduction depends on quinol dehydrogenase CymA. This is achieved via the repression of cyclic adenosine monophosphate (cAMP) production, a second messenger required for activation of cAMP-receptor protein (Crp) which plays a primary role in regulation of respiration. If nitrite is not promptly removed, intracellular cAMP levels drop, and this impairs Crp activity. As a result, the production of nitrite reductase NrfA, CymA, and fumarate reductase FccA is substantially reduced. In contrast, nitrite can be simultaneously respired with trimethylamine N-oxide, resulting in enhanced biomass. PMID- 27493648 TI - Global Methylation Patterns and Their Relationship with Gene Expression and Small RNA in Rice Lines with Different Ploidy. AB - Whole genome duplication (WGD) is a major force in angiosperm evolution. Whether WGD is accompanied by the evolution of epigenetic regulators remains to be explored. Here we investigate whole genome methylation, gene expression, and miRNA regulation among monoploid, diploid, and triploid rice plants isolated from a twin-seedling population. The DNA methylation patterns in the three different ploidy plants were highly similar, with DNA methylation primarily enriched in the promoters. We examined the methylation of single genes and detected around 25,500 methylated genes, of which 22,751 were methylated in all three lines. Significantly divergent DNA methylation patterns between each pair of three lines were only detected in 64 genes, though more genes were found to exhibit differential expression. Analysis of DNA methylation and expression patterns showed that higher DNA methylation levels upstream of the transcription start sites are correlated with higher levels of expression of related genes; whereas higher DNA methylation levels in gene body regions are correlated with lower levels of expression. We also carried out high-throughput sequencing of small RNA libraries and identified 36 new miRNAs. These miRNAs have different expression levels depending on the ploidy. PMID- 27493649 TI - Nitrogen Mineralization of a Loam Soil Supplemented with Organic-Inorganic Amendments under Laboratory Incubation. AB - The quantification of nitrogen (N) supplying capacity of organic amendments applied to a soil is of immense importance to examine synchronization, N release capacity, and fertilizer values of these added materials. The aims of the present study was to determine the potential N mineralization and subsequent nitrification of separate and combined use of poultry manure (PM), wheat straw residues (WSR), and urea N (UN) applied to a loam soil incubated periodically over 140 days period. In addition, changes in total soil N and carbon contents were also monitored during the study. Treatments included: PM100, WSR100, PM50 + WSR50, UN100, UN50 + PM50, UN50 + WSR50, UN50 + PM25 + WSR25, and a control (unfertilized). All the amendments were applied on an N-equivalent basis at the rate of 200 mg N kg(-1). Results indicated that a substantial quantity of N had been released from the added amendments into the soil mineral pool and the net cumulative N mineralized varied between 39 and 147 mg N kg(-1), lowest in the WSR and highest in the UN50 + PM50. Significant differences were observed among the amendments and the net mineral N derived from a separate and combined use of PM was greater than the other treatments. The net cumulative N nitrified (NCNN) varied between 16 and 126 mg kg(-1), highest in UN50 + PM50 treatment. On average, percentage conversion of added N into available N by different amendments varied between 21 and 80%, while conversion of applied N into NO3 (-) N ranged between 9 and 65%, and the treatment UN50 + PM50 displayed the highest N recovery. Urea N when applied alone showed disappearance of 37% N (N unaccounted for) at the end while application of PM and WSR with UN reduced N disappearance and increased N retention in the mineral pool for a longer period. Organic amendments alone or in combination with UN improved organic matter buildup and increased soil N concentration. These results demonstrate the existence of substantial amounts of N reserves present in PM and WSR that can be utilized efficiently and effectively as potential N source for the management of nutrient poor soils and plant growth. PMID- 27493650 TI - Geminivirus-Mediated Genome Editing in Potato (Solanum tuberosum L.) Using Sequence-Specific Nucleases. AB - Genome editing using sequence-specific nucleases (SSNs) is rapidly being developed for genetic engineering in crop species. The utilization of zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats/CRISPR-associated systems (CRISPR/Cas) for inducing double-strand breaks facilitates targeting of virtually any sequence for modification. Targeted mutagenesis via non-homologous end-joining (NHEJ) has been demonstrated extensively as being the preferred DNA repair pathway in plants. However, gene targeting via homologous recombination (HR) remains more elusive but could be a powerful tool for directed DNA repair. To overcome barriers associated with gene targeting, a geminivirus replicon (GVR) was used to deliver SSNs targeting the potato ACETOLACTATE SYNTHASE1 (ALS1) gene and repair templates designed to incorporate herbicide-inhibiting point mutations within the ALS1 locus. Transformed events modified with GVRs held point mutations that were capable of supporting a reduced herbicide susceptibility phenotype, while events transformed with conventional T-DNAs held no detectable mutations and were similar to wild-type. Regeneration of transformed events improved detection of point mutations that supported a stronger reduced herbicide susceptibility phenotype. These results demonstrate the use of geminiviruses for delivering genome editing reagents in plant species, and a novel approach to gene targeting in a vegetatively propagated species. PMID- 27493651 TI - Multigenic Control of Pod Shattering Resistance in Chinese Rapeseed Germplasm Revealed by Genome-Wide Association and Linkage Analyses. AB - The majority of rapeseed cultivars shatter seeds upon maturity especially under hot-dry and windy conditions, reducing yield and gross margin return to growers. Here, we identified quantitative trait loci (QTL) for resistance to pod shatter in an unstructured diverse panel of 143 rapeseed accessions, and two structured populations derived from bi-parental doubled haploid (DH) and inter-mated (IF2) crosses derived from R1 (resistant to pod shattering) and R2 (prone to pod shattering) accessions. Genome-wide association analysis identified six significant QTL for resistance to pod shatter located on chromosomes A01, A06, A07, A09, C02, and C05. Two of the QTL, qSRI.A09 delimited with the SNP marker Bn A09-p30171993 (A09) and qSRI.A06 delimited with the SNP marker Bn-A06-p115948 (A06) could be repeatedly detected across environments in a diversity panel, DH and IF2 populations, suggesting that at least two loci on chromosomes A06 and A09 were the main contributors to pod shatter resistance in Chinese germplasm. Significant SNP markers identified in this study especially those that appeared repeatedly across environments provide a cost-effective and an efficient method for introgression and pyramiding of favorable alleles for pod shatter resistance via marker-assisted selection in rapeseed improvement programs. PMID- 27493652 TI - Multiple Evolutionary Events Involved in Maintaining Homologs of Resistance to Powdery Mildew 8 in Brassica napus. AB - The Resistance to Powdery Mildew 8 (RPW8) locus confers broad-spectrum resistance to powdery mildew in Arabidopsis thaliana. There are four Homologous to RPW8s (BrHRs) in Brassica rapa and three in Brassica oleracea (BoHRs). Brassica napus (Bn) is derived from diploidization of a hybrid between B. rapa and B. oleracea, thus should have seven homologs of RPW8 (BnHRs). It is unclear whether these genes are still maintained or lost in B. napus after diploidization and how they might have been evolved. Here, we reported the identification and sequence polymorphisms of BnHRs from a set of B. napus accessions. Our data indicated that while the BoHR copy from B. oleracea is highly conserved, the BrHR copy from B. rapa is relatively variable in the B. napus genome owing to multiple evolutionary events, such as gene loss, point mutation, insertion, deletion, and intragenic recombination. Given the overall high sequence homology of BnHR genes, it is not surprising that both intragenic recombination between two orthologs and two paralogs were detected in B. napus, which may explain the loss of BoHR genes in some B. napus accessions. When ectopically expressed in Arabidopsis, a C terminally truncated version of BnHRa and BnHRb, as well as the full length BnHRd fused with YFP at their C-termini could trigger cell death in the absence of pathogens and enhanced resistance to powdery mildew disease. Moreover, subcellular localization analysis showed that both BnHRa-YFP and BnHRb-YFP were mainly localized to the extra-haustorial membrane encasing the haustorium of powdery mildew. Taken together, our data suggest that the duplicated BnHR genes might have been subjected to differential selection and at least some may play a role in defense and could serve as resistance resource in engineering disease resistant plants. PMID- 27493653 TI - Comparative Transcriptome Analysis Revealed Genes Commonly Responsive to Varied Nitrate Stress in Leaves of Tibetan Hulless Barley. AB - Nitrogen (N) deprivation or excess can lead to dramatic phenotype change, disrupt important biological processes, and ultimately limit plant productivity. To explore genes in Tibetan hulless barley responsive to varied N stress, we utilized a comparative transcriptomics method to investigate gene expression patterns under three nitrate treatments. The transcriptome of the control (optimal-nitrate, ON) sample was compared with that of free-nitrate (FN), low nitrate (LN), and high-nitrate (HN) treatment samples, identifying 2428, 1274, and 1861 genes, respectively, that exhibited significant differences in transcript abundance. Among these, 9 genes encoding ribulose bisphosphate carboxylases exhibited up-regulated expression under varied N stress. We further compared FN vs. ON and LN vs. ON to investigate the impact of stress degree on gene expression. With the aggravation of stress, more genes were differentially expressed and thus possibly involved in the response to nitrogen deficiency. Cluster and functional enrichment analysis indicated that the differentially expressed genes (DEGs) in FN were highly enriched in response to stress, defense response, and gene expression regulation. Comprehensive comparison analysis further suggested that Tibetan hulless barley could respond to varied N stress by regulating multiple common biological processes and pathways such as nitrogen metabolism, carbon metabolism, and photosynthesis. A large number of specific DEGs involved in diverse biological processes were also detected, implying differences in the potential regulatory patterns of low- and high-N stress response. Notably, we also identified some NIN-like proteins and other transcription factors significantly modulated by these stresses, suggesting the involvement of these transcription factors in N stress response. To our knowledge, this study is the first investigation of the Tibetan hulless barley transcriptome under N stress. The identified N-stress-related genes may provide resources for genetic improvement and promote N use efficiency. PMID- 27493654 TI - A Tree-Centered Approach to Assess Impacts of Extreme Climatic Events on Forests. PMID- 27493656 TI - Sm-Like Protein-Mediated RNA Metabolism Is Required for Heat Stress Tolerance in Arabidopsis. AB - Sm-like proteins play multiple functions in RNA metabolism, which is essential for biological processes such as stress responses in eukaryotes. The Arabidopsis thaliana sad1 mutant has a mutation of sm-like protein 5 (LSM5) and shows impaired drought and salt stress tolerances. The lsm5/sad1 mutant also showed hypersensitivity to heat stress. GFP-fused LSM5/SAD1 was localized in the nucleus under optimal growth conditions. After heat stress treatment, GFP-fused LSM5/SAD1 fluorescence was also observed as small cytoplasmic dots, in addition to nuclear localization. Whole genome transcriptome analysis revealed that many genes in Arabidopsis were drastically changed in response to heat stress. More heat responsive genes were highly expressed in lsm5/sad1 mutant at both 2 and 6 h after heat stress treatment. Additionally, intron-retained and capped transcripts accumulated in the lsm5/sad1 mutant after heat stress treatment. In this study, we also identified non-Arabidopsis Genome Initiative transcripts that were expressed from unannotated regions. Most of these transcripts were antisense transcripts, and many capped non-AGI transcripts accumulated in the lsm5/sad1 mutant during heat stress treatment. These results indicated that LSM5/SAD1 functions to degrade aberrant transcripts through appropriate mRNA splicing and decapping, and precise RNA metabolic machinery is required for heat stress tolerance. PMID- 27493655 TI - Molecular Evolution and Association of Natural Variation in ZmARF31 with Low Phosphorus Tolerance in Maize. AB - Low-phosphorus (P) stress is one of the major factors constraining plant growth and yield. Improving plant tolerance to P starvation through molecular breeding is an efficient alternative to increase grain production. In the study, 331 diverse maize inbreds were used to detect nucleotide diversity and favorable alleles of ZmARF31, which plays a key role in low P responses and root architecture regulation. Significant phenotypic variation was found in each of 11 tested traits under both P and no-P treatments, and 30 single nucleotide polymorphisms (SNPs) and 14 insertion-deletions (InDels) were detected in ZmARF31 among the 331 maize inbreds. The 5'-untranslated region (UTR) of ZmARF31 showed a small linkage disequilibrium (LD) block under significant purifying selection, whereas the 3'-UTR showed the most abundant diversity and a larger LD block. Thirty, fourteen, and nine natural variations were identified in ZmARF31 that were associated with P-deficiency-tolerance traits (P <= 0.01) by using the general linear model (GLM), GLM incorporated with population structure, and mixed linear model, respectively. Four SNPs were significantly associated with the total dry weight (TDW) in the three models, of which SNPs S410 and S462 were located in a complete LD block. A further verification conducted in a recombinant inbred line population revealed that favorable allele G/G of non-synonymous mutation S410 and favorable allele with a 38 bp insertion of InDel S1442 exhibited positive genetic effects on the TDW and total root tips, respectively. Expression analysis further confirmed that ZmARF31 was highly expressed in the roots of low-P-tolerant inbred 178. The protein encoded by ZmARF31 was located both in the nucleus and cytoplasm. Haplotypes carrying more favorable alleles showed a greater effect on phenotypic variation than single loci. Such haplotypes should be helpful to develop valuable genetic markers and perform maize molecular breeding. PMID- 27493657 TI - De novo Assembly and Characterization of the Transcriptome of Broomcorn Millet (Panicum miliaceum L.) for Gene Discovery and Marker Development. AB - Broomcorn millet (Panicum miliaceum L.) is one of the world's oldest cultivated cereals, which is well-adapted to extreme environments such as drought, heat, and salinity with an efficient C4 carbon fixation. Discovery and identification of genes involved in these processes will provide valuable information to improve the crop for meeting the challenge of global climate change. However, the lack of genetic resources and genomic information make gene discovery and molecular mechanism studies very difficult. Here, we sequenced and assembled the transcriptome of broomcorn millet using Illumina sequencing technology. After sequencing, a total of 45,406,730 and 51,160,820 clean paired-end reads were obtained for two genotypes Yumi No. 2 and Yumi No. 3. These reads were mixed and then assembled into 113,643 unigenes, with the length ranging from 351 to 15,691 bp, of which 62,543 contings could be assigned to 315 gene ontology (GO) categories. Cluster of orthologous groups and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses assigned could map 15,514 unigenes into 202 KEGG pathways and 51,020 unigenes to 25 COG categories, respectively. Furthermore, 35,216 simple sequence repeats (SSRs) were identified in 27,055 unigene sequences, of which trinucleotides were the most abundant repeat unit, accounting for 66.72% of SSRs. In addition, 292 differentially expressed genes were identified between the two genotypes, which were significantly enriched in 88 GO terms and 12 KEGG pathways. Finally, the expression patterns of four selected transcripts were validated through quantitative reverse transcription polymerase chain reaction analysis. Our study for the first time sequenced and assembled the transcriptome of broomcorn millet, which not only provided a rich sequence resource for gene discovery and marker development in this important crop, but will also facilitate the further investigation of the molecular mechanism of its favored agronomic traits and beyond. PMID- 27493658 TI - A R2R3-MYB Transcription Factor Regulates the Flavonol Biosynthetic Pathway in a Traditional Chinese Medicinal Plant, Epimedium sagittatum. AB - Flavonols as plant secondary metabolites with vital roles in plant development and defense against UV light, have been demonstrated to be the main bioactive components (BCs) in the genus Epimedium plants, several species of which are used as materials for Herba Epimedii, an important traditional Chinese medicine. The flavonol biosynthetic pathway genes had been already isolated from Epimedium sagittatum, but a R2R3-MYB transcription factor regulating the flavonol synthesis has not been functionally characterized so far in Epimedium plants. In this study, we isolated and characterized the R2R3-MYB transcription factor EsMYBF1 involved in regulation of the flavonol biosynthetic pathway from E. sagittatum. Sequence analysis indicated that EsMYBF1 belongs to the subgroup 7 of R2R3-MYB family which contains the flavonol-specific MYB regulators identified to date. Transient reporter assay showed that EsMYBF1 strongly activated the promoters of EsF3H (flavanone 3-hydroxylase) and EsFLS (flavonol synthase), but not the promoters of EsDFRs (dihydroflavonol 4-reductase) and EsANS (anthocyanidin synthase) in transiently transformed Nicotiana benthamiana leaves. Both yeast two hybrid assay and transient reporter assay validated EsMYBF1 to be independent of EsTT8, or AtTT8 bHLH regulators of the flavonoid pathway as cofactors. Ectopic expression of EsMYBF1 in transgenic tobacco resulted in the increased flavonol content and the decreased anthocyanin content in flowers. Correspondingly, the structural genes involved in flavonol synthesis were upregulated in the EsMYBF1 overexpression lines, including NtCHS (chalcone synthase), NtCHI (chalcone isomerase), NtF3H and NtFLS, whereas the late biosynthetic genes of the anthocyanin pathway (NtDFR and NtANS) were remarkably downregulated, compared to the controls. These results suggest that EsMYBF1 is a flavonol-specific R2R3-MYB regulator, and involved in regulation of the biosynthesis of the flavonol-derived BCs in E. sagittatum. Thus, identification and functional characterization of EsMYBF1 provide insight into understanding the biosynthesis and regulation of the flavonol-derived BCs in Epimedium plants, and also provide an effective tool gene for genetic manipulation to improve the flavonol synthesis. PMID- 27493660 TI - Lack of Association Found between Helicobacter pylori Infection and Diarrhea Predominant Irritable Bowel Syndrome: A Multicenter Retrospective Study. AB - Aims. The association between Helicobacter pylori (H. pylori) infection and diarrhea-predominant irritable bowel syndrome (IBS-D) is still controversial. Here we performed a retrospective study to explore this issue. Methods. A total of 502 inpatients with Rome III confirmed IBS-D and known H. pylori status from 8 hospitals were enrolled. H. pylori-positive patients, hospitalized in the recent year, were followed up to evaluate the effects of H. pylori eradication on IBS-D clinical course. Results. Of the 502 IBS-D patients, 206 were H. pylori-positive, with an infection rate that has no significant difference with that of the general population in Guangdong province (p = 0.348). For patients followed up, no significant differences were noted as to overall symptoms (p = 0.562), abdominal pain/discomfort (p = 0.777), bloating (p = 0.736), stool frequency (p = 0.835), or stool characteristics (p = 0.928) between the H. pylori-eradicated group and the control group. The results were the same in long-term follow-up patients except the improvement of bloating, which showed that the bloating score in the H. pylori-eradicated group was significantly lower (p = 0.047). Conclusions. No significant correlation between H. pylori infection and IBS-D was noted. Overall, IBS-D patients may not benefit from H. pylori eradication. PMID- 27493661 TI - Chronic Kidney Disease Induced Intestinal Mucosal Barrier Damage Associated with Intestinal Oxidative Stress Injury. AB - Background. To investigate whether intestinal mucosal barrier was damaged or not in chronic kidney disease progression and the status of oxidative stress. Methods. Rats were randomized into two groups: a control group and a uremia group. The uremia rat model was induced by 5/6 kidney resection. In postoperative weeks (POW) 4, 6, 8, and 10, eight rats were randomly selected from each group to prepare samples for assessing systemic inflammation, intestinal mucosal barrier changes, and the status of intestinal oxidative stress. Results. The uremia group presented an increase trend over time in the serum tumor necrosis factor-alpha, interleukin-6 (IL-6) and IL-10, serum D-lactate and diamine oxidase, and intestinal permeability, and these biomarkers were significantly higher than those in control group in POW 8 and/or 10. Chiu's scores in uremia group were also increased over time, especially in POW 8 and 10. Furthermore, the intestinal malondialdehyde, superoxide dismutase, and glutathione peroxidase levels were significantly higher in uremia group when compared with those in control group in POW 8 and/or 10. Conclusions. The advanced chronic kidney disease could induce intestinal mucosal barrier damage and further lead to systemic inflammation. The underlying mechanism may be associated with the intestinal oxidative stress injury. PMID- 27493662 TI - A Clinicopathological Profile of Prostate Cancer in Trinidad and Tobago. AB - Aim. To conduct a clinicopathological review of all prostate biopsies performed in a tertiary referral centre in Trinidad and Tobago over a period of 30 months. Methods. The records of all patients who had prostate biopsies from January 2012 to July 2014 were reviewed. Clinical and pathologic data were compiled and subsequently analysed using SPSS version 20. Results. From January 2012 to July 2014, 617 transrectal ultrasound guided prostate biopsies were performed. Pathological data were found for 546 patients of whom 283 (51.8%) were confirmed carcinoma of the prostate. Moderately differentiated tumors (Gleason 7) were the most common group. Using the D'Amico risk classification, most cases were found to be high risk (63.1%). Afro-Trinidadians comprised 72.1% of the patients with prostate cancer. Afro-Trinidadians were also more likely to have high risk and high grade disease as well as high PSA values. Conclusion. This study demonstrates that over half of our biopsies are eventually positive for cancer and most cases were high risk. Afro-Trinidadians comprised a disproportionate number of those diagnosed with prostate cancer and had a greater risk of high risk disease. PMID- 27493663 TI - Does Frailty Predict Health Care Utilization in Community-Living Older Romanians? AB - Background. The predictive value of frailty assessment is still debated. We analyzed the predictive value of frailty of independent living elderly. The outcomes variables were visits to the general practitioner, hospital admission, and occurrence of new health problems. Methods. A one-year follow-up study was executed among 215 community-living old Romanians. General practitioners reported the outcome variables of patients, whose frailty was assessed one year before, using the Groningen Frailty Indicator. The predictive validity is analyzed by descriptive and regression analysis. Results. Three-quarters of all participants visited their general practitioner three times more last year and one-third were at least once admitted to a hospital. Patients who scored frail one year before were more often admitted to a hospital. Visits to the general practitioner and occurrence of new health problems were not statistically significant related to frailty scores. The frailty items polypharmacy, social support, and activities in daily living were associated with adverse outcomes. Conclusions. The predictive value of frailty instruments as the Groningen Frailty Indicator is still limited. More research is needed to predict health outcomes, health care utilization, and quality of life of frailty self-assessment instruments. Validation research on frailty in different "environments" is recommended to answer the question to what extent contextual characteristics influence the predictive value. PMID- 27493659 TI - Maintaining Genome Stability in Defiance of Mitotic DNA Damage. AB - The implementation of decisions affecting cell viability and proliferation is based on prompt detection of the issue to be addressed, formulation and transmission of a correct set of instructions and fidelity in the execution of orders. While the first and the last are purely mechanical processes relying on the faithful functioning of single proteins or macromolecular complexes (sensors and effectors), information is the real cue, with signal amplitude, duration, and frequency ultimately determining the type of response. The cellular response to DNA damage is no exception to the rule. In this review article we focus on DNA damage responses in G2 and Mitosis. First, we set the stage describing mitosis and the machineries in charge of assembling the apparatus responsible for chromosome alignment and segregation as well as the inputs that control its function (checkpoints). Next, we examine the type of issues that a cell approaching mitosis might face, presenting the impact of post-translational modifications (PTMs) on the correct and timely functioning of pathways correcting errors or damage before chromosome segregation. We conclude this essay with a perspective on the current status of mitotic signaling pathway inhibitors and their potential use in cancer therapy. PMID- 27493664 TI - A Combined Therapy with Myo-Inositol and D-Chiro-Inositol Improves Endocrine Parameters and Insulin Resistance in PCOS Young Overweight Women. AB - Introduction. We evaluated the effects of a therapy that combines myo-inositol (MI) and D-chiro-inositol (DCI) in young overweight women affected by polycystic ovary syndrome (PCOS), characterized by oligo- or anovulation and hyperandrogenism, correlated to insulin resistance. Methods. We enrolled 46 patients affected by PCOS and, randomly, we assigned them to two groups, A and B, treated, respectively, with the association of MI plus DCI, in a 40 : 1 ratio, or with placebo (folic acid) for six months. Thus, we analyzed pretreatment and posttreatment FSH, LH, 17-beta-Estradiol, Sex Hormone Binding Globulin, androstenedione, free testosterone, dehydroepiandrosterone sulphate, HOMA index, and fasting glucose and insulin. Results. We recorded a statistically significant reduction of LH, free testosterone, fasting insulin, and HOMA index only in the group treated with the combined therapy of MI plus DCI; in the same patients, we observed a statistically significant increase of 17-beta-Estradiol levels. Conclusions. The combined therapy of MI plus DCI is effective in improving endocrine and metabolic parameters in young obese PCOS affected women. PMID- 27493665 TI - From Guided Surgery to Final Prosthesis with a Fully Digital Procedure: A Prospective Clinical Study on 15 Partially Edentulous Patients. AB - Scope. To demonstrate guided implant placement and the application of fixed, implant-supported prosthetic restorations with a fully digital workflow. Methods. Over a 2-year period, all patients with partial edentulism of the posterior maxilla, in need of fixed implant-supported prostheses, were considered for inclusion in this study. The protocol required intraoral scanning and cone beam computed tomography (CBCT), the superimposition of dental-gingival information on bone anatomy, surgical planning, 3D-printed teeth-supported surgical templates, and modelling and milling of polymethylmethacrylate (PMMA) temporaries for immediate loading. After 3 months, final optical impression was taken and milled zirconia frameworks and 3D-printed models were fabricated. The frameworks were veneered with ceramic and delivered to the patients. Results. Fifteen patients were selected for this study. The surgical templates were stable. Thirty implants were placed (BTK Safe(r), BTK, Vicenza, Italy) and immediately loaded with PMMA temporaries. After 3 months, the temporaries were replaced by the final restorations in zirconia-ceramic, fabricated with a fully digital process. At 6 months, none of the patients reported any biological or functional problems with the implant-supported prostheses. Conclusions. The present procedure for fully digital planning of implants and short-span fixed implant-supported restorations has been shown to be reliable. Further studies are needed to validate these results. PMID- 27493666 TI - Characterization and Uncertainty Assessment of a Certified Reference Material of Chloramphenicol in Methanol (GBW(E)082557). AB - Prior to preparation of CRM candidate of chloramphenicol in methanol with a concentration of 100 mg/L, two independent methods including mass balance (MB) and quantitative nuclear magnetic resonance (qNMR) were employed to precisely measure the mass fraction of pure chloramphenicol materials. The mass fraction was assigned to be 99.8% with uncertainty of 0.3%. Homogeneity testing and stability study of chloramphenicol in methanol were examined by using high performance liquid chromatography. Additionally, the uncertainties originating from the process of CRM development were comprehensively evaluated. The experimental results indicate that the property value of this CRM is homogeneous and stable at 4 degrees C for at least six months. The new CRM (GBW(E)082557) can be applicable to calibration of instrument and assurance of accuracy and comparability of results in routine measurement. PMID- 27493667 TI - Severity of Osteoarthritis Is Associated with Increased Arterial Stiffness. AB - Objective. Osteoarthritis (OA) is associated with increased cardiovascular comorbidity and mortality. Evidence is lacking about whether arterial stiffness is involved in OA. The objective of our study was to find out associations between OA, arterial stiffness, and adipokines. Design. Seventy end-stage knee and hip OA patients (age 62 +/- 7 years) and 70 asymptomatic controls (age 60 +/- 7 years) were investigated using the applanation tonometry to determine their parameters of arterial stiffness. Serum adiponectin, leptin, and matrix metalloproteinase 3 (MMP-3) levels were determined using the ELISA method. Correlation between variables was determined using Spearman's rho. Multiple regression analysis with a stepwise selection procedure was employed. Results. Radiographic OA grade was positively associated with increased carotid-femoral pulse wave velocity (cf-PWV) (r = 0.272, p = 0.023). We found that OA grade was also associated with leptin and MMP-3 levels (rho = -0.246, p = 0.040 and rho = 0.235, p = 0.050, resp.). In addition, serum adiponectin level was positively associated with augmentation index and inversely with large artery elasticity index (rho = 0.293, p = 0.006 and rho = -0.249, p = 0.003, resp.). Conclusions. Our results suggest that OA severity is independently associated with increased arterial stiffness and is correlated with expression of adipokines. Thus, increased arterial stiffness and adipokines might play an important role in elevated cardiovascular risk in end-stage OA. PMID- 27493668 TI - Differentiation of Human Adipose Derived Stem Cells into Smooth Muscle Cells Is Modulated by CaMKIIgamma. AB - The multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is known to participate in maintenance and switches of smooth muscle cell (SMC) phenotypes. However, which isoform of CaMKII is involved in differentiation of adult mesenchymal stem cells into contractile SMCs remains unclear. In the present study, we detected gamma isoform of CaMKII in differentiation of human adipose derived stem cells (hASCs) into SMCs that resulted from treatment with TGF-beta1 and BMP4 in combination for 7 days. The results showed that CaMKIIgamma increased gradually during differentiation of hASCs as determined by real-time PCR and western blot analysis. The siRNA-mediated knockdown of CaMKIIgamma decreased the protein levels and transcriptional levels of smooth muscle contractile markers (a-SMA, SM22a, calponin, and SM-MHC), while CaMKIIgamma overexpression increases the transcriptional and protein levels of smooth muscle contractile markers. These results suggested that gamma isoform of CaMKII plays a significant role in smooth muscle differentiation of hASCs. PMID- 27493670 TI - Effects of Forest Bathing on Cardiovascular and Metabolic Parameters in Middle Aged Males. AB - In the present study, we investigated the effects of a forest bathing on cardiovascular and metabolic parameters. Nineteen middle-aged male subjects were selected after they provided informed consent. These subjects took day trips to a forest park in Agematsu, Nagano Prefecture, and to an urban area of Nagano Prefecture as control in August 2015. On both trips, they walked 2.6 km for 80 min each in the morning and afternoon on Saturdays. Blood and urine were sampled before and after each trip. Cardiovascular and metabolic parameters were measured. Blood pressure and pulse rate were measured during the trips. The Japanese version of the profile of mood states (POMS) test was conducted before, during, and after the trips. Ambient temperature and humidity were monitored during the trips. The forest bathing program significantly reduced pulse rate and significantly increased the score for vigor and decreased the scores for depression, fatigue, anxiety, and confusion. Urinary adrenaline after forest bathing showed a tendency toward decrease. Urinary dopamine after forest bathing was significantly lower than that after urban area walking, suggesting the relaxing effect of the forest bathing. Serum adiponectin after the forest bathing was significantly greater than that after urban area walking. PMID- 27493669 TI - Aggressiveness Niche: Can It Be the Foster Ground for Cancer Metastasis Precursors? AB - The relationship between tumor initiation and tumor progression can follow a linear projection in which all tumor cells are equally endowed with the ability to progress into metastasis. Alternatively, not all tumor cells are equal genetically and/or epigenetically, and only few cells are induced to become metastatic tumor cells. The location of these cells within the tumor can also impact the fate of these cells. The most inner core of a tumor where an elevated pressure of adverse conditions forms, such as necrosis-induced inflammation and hypoxia-induced immunosuppressive environment, seems to be the most fertile ground to generate such tumor cells with metastatic potential. Here we will call this necrotic/hypoxic core the "aggressiveness niche" and will present data to support its involvement in generating these metastatic precursors. Within this niche, interaction of hypoxia-surviving cells with the inflammatory microenvironment influenced by newly recruited mesenchymal stromal cells (MSCs), tumor-associated macrophages (TAMs), and other types of cells and the establishment of bidirectional interactions between them elevate the aggressiveness of these tumor cells. Additionally, immune evasion properties induced in these cells most likely contribute in the formation and maintenance of such aggressiveness niche. PMID- 27493671 TI - Berberine Inhibits Intestinal Polyps Growth in Apc (min/+) Mice via Regulation of Macrophage Polarization. AB - Antitumor effect of berberine has been reported in a wide spectrum of cancer, however, the mechanisms of which are not fully understood. The aim of this study was to investigate the hypothesis that berberine suppresses tumorigenesis in the familial adenomatous polyposis (FAP) by regulating the macrophage polarization in Apc (min/+) mouse model. Berberine was given to Apc (min/+) mice for 12 weeks. Primary macrophages were isolated; after berberine treatment, the change in signaling cascade was determined. The total number and size of polyps were reduced remarkably in berberine group, compared with control group. A significant decrease in protein levels of F4/80, mannose receptor (MR), and COX-2 in stroma of intestinal polyps and an increase in the level of iNOS were observed after berberine treatment. The mRNA level of MR and Arg-1 in berberine group was significantly lower than those in IL-10 or IL-4 group, while no significant difference in mRNA levels of iNOS and CXCL10 was observed. The migration and invasiveness assays in vitro showed that berberine could reduce the capability of migration and invasiveness. These findings suggest that berberine attenuates intestinal tumorigenesis by inhibiting the migration and invasion of colorectal tumor cells via regulation of macrophage polarization. PMID- 27493673 TI - Antitumor Effect of Zhihuang Fuzheng Soft Capsules on Tumor-Bearing Mice. AB - Chinese medicines (CMs) have been shown to have some advantages in preventing and controlling tumors. In this study, we investigated the antitumor effect of ZFSC by establishing a mouse model of HT-1080, A-549, and HCT-8 tumors. The result showed that tumor volumes of HT-1080 tumor-bearing nude mice in ZFSC low, medium, and high dose groups were lower significantly compared to the model group, and the high dose ZFSC showed the best antitumor effect. Tumor volumes of A-549 tumor bearing nude mice in ZFSC low, medium, and high dose groups were lower significantly compared to the model group and showed a good dose-response relationship. There was no significant effect on human colon cancer, although inhibition trends disappeared in the bar chart. In order to verify the immunomodulatory effect of ZFSC, ELISA was used to analyze serums IL-2, TNF alpha, and IFN in spleens. The results showed that ZFSC could enhance the immune function of tumor-bearing mice. ZFSC reduced IFN-gamma and TNF-alpha content in the serum of HT-1080 tumor-bearing mice and inhibit PD1 and PDL1 and suggested that the antitumor mechanism of ZFSC on human fibrosarcoma could be attributed to inhibition of the PDL1/PD1 pathway. PMID- 27493672 TI - Unsweetened Natural Cocoa Powder Has the Potential to Attenuate High Dose Artemether-Lumefantrine-Induced Hepatotoxicity in Non-Malarious Guinea Pigs. AB - Objective. This study investigated the elemental composition of unsweetened natural cocoa powder (UNCP), its effect on nitric oxide, and its hepatoprotective potential during simultaneous administration with high-dose artemether/lumefantrine (A/L). Method. Macro- and microelements in UNCP were analyzed with EDXRF spectroscopy. Thirty (30) male guinea-pigs were then divided into five groups. For groups 3 (low-dose), 4 (medium-dose), and 5 (high-dose), the animals received oral UNCP prophylactically for 14 days. Group 1 received distilled water (14 days) and group 2 A/L for the last 3 days (days 12 to 14). After euthanisation, biochemical and histopathological examinations were carried out in all groups. Results. Phytochemical analysis of UNCP showed the presence of saponins, flavonoids, tannins, and cardiac glycosides. Thirty-eight (38) macro- and microelements were found. UNCP produced significant decreases in ALT, ALP, GGT, and AST levels. A significant increase in total protein levels was observed during A/L+UNCP administration in comparison to 75 mg/kg A/L group. Histopathological examinations buttressed the protective effects of cocoa administration. UNCP administration increased nitric oxide levels 149.71% (P < 0.05) compared to controls. Conclusion. UNCP increases nitric oxide levels and has hepatoprotective potential during A/L administration. A high level of copper was observed which may be detrimental during high daily consumptions of UNCP. PMID- 27493674 TI - Chitosan and Sodium Alginate Combinations Are Alternative, Efficient, and Safe Natural Adjuvant Systems for Hepatitis B Vaccine in Mouse Model. AB - Hepatitis B viral (HBV) infections represent major public health problem and are an occupational hazard for healthcare workers. Current alum-adjuvanted HBV vaccine is the most effective measure to prevent HBV infection. However, the vaccine has some limitations including poor response in some vaccinee and being a frost-sensitive suspension. The goal of our study was to use an alternative natural adjuvant system strongly immunogenic allowing for a reduction in dose and cost. We tested HBV surface antigen (HBsAg) adjuvanted with chitosan (Ch) and sodium alginate (S), both natural adjuvants, either alone or combined with alum in mouse model. Mice groups were immunized subcutaneously with HBsAg adjuvanted with Ch or S, or triple adjuvant formula with alum (Al), Ch, and S, or double formulations with AlCh or AlS. These were compared to control groups immunized with current vaccine formula or unadjuvanted HBsAg. We evaluated the rate of seroconversion, serum HBsAg antibody, IL-4, and IFN-gamma levels. The results showed that the solution formula with Ch or S exhibited comparable immunogenic responses to Al-adjuvanted suspension. The AlChS gave significantly higher immunogenic response compared to controls. Collectively, our results indicated that Ch and S are effective HBV adjuvants offering natural alternatives, potentially reducing dose. PMID- 27493675 TI - Spirituality Concept by Health Professionals in Iran: A Qualitative Study. AB - Background. For years, researchers have sought to provide a clear definition of spirituality and its features and consequences, but the definitions provided of this concept still lack transparency. The present qualitative research was conducted to clarify this concept within the religious-cultural context of Iran. Materials and Methods. The present conventional qualitative content analysis was conducted with an inductive approach. Data were collected through semistructured interviews with 17 spiritual health experts and activists selected through purposive sampling. Results. Three themes emerged from the analysis of the data, including (1) the structure of spirituality, (2) defects in the conceptualization of spirituality, and (3) spirituality in practice, which are explained in this paper with their relevant subthemes and codes. The definition which this study proposes for this concept is that "spirituality is the sublime aspect of human existence bestowed on all humans in order for them to traverse the path of transcendence that is closeness to God (Allah)." Conclusion. The definition provided by this study is similar to the previous definitions of this concept in its main part (transcendence) and in incorporating a God-centered view of spirituality within the context of an Islamic society. This definition has implications for health services' education, research, and practice in similar societies. PMID- 27493676 TI - Ethnobotany: A Living Science for Alleviating Human Suffering. PMID- 27493679 TI - Development of a universal and simplified ddRAD library preparation approach for SNP discovery and genotyping in angiosperm plants. AB - BACKGROUND: The double digest restriction-site associated DNA sequencing technology (ddRAD-seq) is a reduced representation sequencing technology by sampling genome-wide enzyme loci developed on the basis of next-generation sequencing. ddRAD-seq has been widely applied to SNP marker development and genotyping on animals, especially on marine animals as the original ddRAD protocol is mainly built and trained based on animal data. However, wide application of ddRAD-seq technology in plant species has not been achieved so far. Here, we aim to develop an optimized ddRAD library preparation protocol be accessible to most angiosperm plant species without much startup pre-experiment and costs. RESULTS: We first tested several combinations of enzymes by in silico analysis of 23 plant species covering 17 families of angiosperm and 1 family of bryophyta and found AvaII + MspI enzyme pair produced consistently higher number of fragments in a broad range of plant species. Then we removed two purifying and one quantifying steps of the original protocol, replaced expensive consumables and apparatuses by conventional experimental apparatuses. Besides, we shortened P1 adapter from 37 to 25 bp and designed a new barcode-adapter system containing 20 pairs of barcodes of varying length. This is an optimized ddRAD strategy for angiosperm plants that is economical, time-saving and requires little technical expertise or investment in laboratory equipment. We refer to this simplified protocol as MiddRAD and we demonstrated the utility and flexibility of our approach by resolving phylogenetic relationships of two genera of woody bamboos (Dendrocalamus and Phyllostachys). Overall our results provide empirical evidence for using this method on different model and non-model plants to produce consistent data. CONCLUSIONS: As MiddRAD adopts an enzyme pair that works for a broad range of angiosperm plants, simplifies library constructing procedure and requires less DNA input, it will greatly facilitate designing a ddRAD project. Our optimization of this method may make ddRAD be widely used in fields of plant population genetics, phylogenetics, phylogeography and molecular breeding. PMID- 27493678 TI - Detecting N-myristoylation and S-acylation of host and pathogen proteins in plants using click chemistry. AB - BACKGROUND: The plant plasma membrane is a key battleground in the war between plants and their pathogens. Plants detect the presence of pathogens at the plasma membrane using sensor proteins, many of which are targeted to this lipophilic locale by way of fatty acid modifications. Pathogens secrete effector proteins into the plant cell to suppress the plant's defense mechanisms. These effectors are able to access and interfere with the surveillance machinery at the plant plasma membrane by hijacking the host's fatty acylation apparatus. Despite the important involvement of protein fatty acylation in both plant immunity and pathogen virulence mechanisms, relatively little is known about the role of this modification during plant-pathogen interactions. This dearth in our understanding is due largely to the lack of methods to monitor protein fatty acid modifications in the plant cell. RESULTS: We describe a rapid method to detect two major forms of fatty acylation, N-myristoylation and S-acylation, of candidate proteins using alkyne fatty acid analogs coupled with click chemistry. We applied our approach to confirm and decisively demonstrate that the archetypal pattern recognition receptor FLS2, the well-characterized pathogen effector AvrPto, and one of the best-studied intracellular resistance proteins, Pto, all undergo plant-mediated fatty acylation. In addition to providing a means to readily determine fatty acylation, particularly myristoylation, of candidate proteins, this method is amenable to a variety of expression systems. We demonstrate this using both Arabidopsis protoplasts and stable transgenic Arabidopsis plants and we leverage Agrobacterium-mediated transient expression in Nicotiana benthamiana leaves as a means for high-throughput evaluation of candidate proteins. CONCLUSIONS: Protein fatty acylation is a targeting tactic employed by both plants and their pathogens. The metabolic labeling approach leveraging alkyne fatty acid analogs and click chemistry described here has the potential to provide mechanistic details of the molecular tactics used at the host plasma membrane in the battle between plants and pathogens. PMID- 27493680 TI - Machine Learning Approach to Automated Quality Identification of Human Induced Pluripotent Stem Cell Colony Images. AB - The focus of this research is on automated identification of the quality of human induced pluripotent stem cell (iPSC) colony images. iPS cell technology is a contemporary method by which the patient's cells are reprogrammed back to stem cells and are differentiated to any cell type wanted. iPS cell technology will be used in future to patient specific drug screening, disease modeling, and tissue repairing, for instance. However, there are technical challenges before iPS cell technology can be used in practice and one of them is quality control of growing iPSC colonies which is currently done manually but is unfeasible solution in large-scale cultures. The monitoring problem returns to image analysis and classification problem. In this paper, we tackle this problem using machine learning methods such as multiclass Support Vector Machines and several baseline methods together with Scaled Invariant Feature Transformation based features. We perform over 80 test arrangements and do a thorough parameter value search. The best accuracy (62.4%) for classification was obtained by using a k-NN classifier showing improved accuracy compared to earlier studies. PMID- 27493681 TI - Anti-cholinesterases and memory improving effects of Vietnamese Xylia xylocarpa. AB - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia among the elderly and is characterized by loss of memory and other cognitive functions. An increase in AChE (a key enzyme in the cholinergic nervous system) levels around beta-amyloid plaques and neurofibrillary tangles is a common feature of AD neuropathology. Amnesic effects of scopolamine (acetylcholine receptor antagonist) can be investigated in various behavioral tests such as Morris water maze, object recognition, Y-maze, and passive avoidance. In the scope of this paper, we report the anti-AChE, anti-BChE properties of the isolated compound and the in vivo effects of the methanolic extract of Xylia xylocarpa (MEXX) on scopolamine-induced memory deficit. RESULTS: In further phytochemistry study, a new hopan-type triterpenoid, (3beta)-hopan-3-ol-28,22-olide (1), together with twenty known compounds were isolated (2-21). Compound 1, 2, 4, 5, 7-9, and 11-13 exhibited potent acetylcholinesterase (AChE) inhibitory activity in a concentration-dependent manner with IC50 values ranging from 54.4 to 94.6 MUM. Compound 13 was also shown anti-butyrylcholinesterase (BChE) activity with an IC50 value of 42.7 MUM. The Morris water Y-maze, Y-maze, and object recognition test were also carried out. CONCLUSIONS: It is noteworthy that MEXX is effective when administered orally to mice, experimental results are consistent with the traditional use of this medicinal plant species. PMID- 27493677 TI - Chronic over-nutrition and dysregulation of GSK3 in diseases. AB - Loss of cellular response to hormonal regulation in maintaining metabolic homeostasis is common in the process of aging. Chronic over-nutrition may render cells insensitive to such a hormonal regulation owing to overstimulation of certain signaling pathways, thus accelerating aging and causing diseases. The glycogen synthase kinase 3 (GSK3) plays a pivotal role in relaying various extracellular and intracellular regulatory signals critical to cell growth, survival, regeneration, or death. The main signaling pathway regulating GSK3 activity through serine-phosphorylation is the phosphoinositide 3-kinase (PI3K)/phosphoinositide-dependent kinase-1 (PDK1)/Akt relay that catalyzes serine phosphorylation and thus inactivation of GSK3. In addition, perilipin 2 (PLIN2) has recently been shown to regulate GSK3 activation through direct association with GSK3. This review summarizes current understanding on environmental and nutritional factors contributing to GSK3 regulation (or dysregulation) through the PI3K/PDK1/Akt/GSK3 axis, and highlights the newly discovered role that PLIN2 plays in regulating GSK3 activity and GSK3 downstream pathways. PMID- 27493682 TI - Simultaneous quantification of triterpenoic acids by high performance liquid chromatography method in the extracts of gum resin of Boswellia serrata obtained by different extraction techniques. AB - BACKGROUND: Boswellia serrata, also known as Indian frankincense is a commercially important medicinal plant which has been used for hundreds of years as an Ayurvedic medicine for the attempted treatment of arthritis. It contains naturally occurring triterpenoic acids, called as boswellic acids (BA's). RESULTS: A highly reproducible High performance liquid chromatography-ultraviolet diode array detection (HPLC-UV-DAD) method was developed for the simultaneous determination and quantitative analysis of eight major triterpenoic acids in Boswellia serrata gum resin obtained by different extraction techniques. All the calibration curves exhibited good linear regression (R(2) > 0.997) within the test ranges. The established method showed good precision and overall recoveries of the boswellic acids. CONCLUSIONS: The eight triterpenoic acids coded as BS-1 (11-keto-beta-boswellic acid), BS-2 (3-O-acetyl-11-keto-beta-boswellic acid), BS 3 (3-keto tirucallic acid), BS-4 (3-O-acetyl-alpha-tirucallic acid), BS-5 (3-O acetyl-beta-tirucallic acid), BS-6 (alpha-boswellic acid), BS-7 (beta-boswellic acid) and BS-8 (3-O-acetyl-beta-boswellic acid) were isolated from the processed gum resin of Boswellia serrata by column chromatography. The proposed HPLC method is simple, reliable and has been very useful for the qualitative as well as quantitative analysis of boswellic acids in the gum resin of Boswellia serrata. The proposed method allows to quantify boswellic acids in appreciable amounts by HPLC-UV (DAD) method in the extracts and the available marketed formulations.Graphical abstractIsolation & separation of eight Triterpenoic acids from Boswellia serrata. PMID- 27493683 TI - Microwave assisted synthesis, antifungal activity, DFT and SAR study of 1,2,4 triazolo[4,3-a]pyridine derivatives containing hydrazone moieties. AB - BACKGROUND: The increasing prevalence of multi-drug resistant fungal infections has encouraged the search for new antifungal agents. Hydrazone derivatives always exhibited diversity activities, including antifungal, anti-inflammatory, anti oxidation, anti-cancer activity. Regarding the heterocyclic moiety, 1,2,4 triazolo[4,3-a]pyridine derivatives also display broad activities, such as antifungal activity, anticonvulsant activity, herbicidal activity, antimicrobial activity and anticancer activity. RESULTS: A series of novel 1,2,4-triazolo[4,3 a]pyridine derivatives containing hydrazone moiety were designed and synthesized from 2,3-dichloropyridine, hydrazine hydrate by multi-step reactions under microwave irradiation condition, and their structures were characterized by FT IR, (1)H NMR, (13)C NMR, (19)F NMR, MS and elemental analysis. The antifungal activities of title compounds were determined. The results indicated that some of the title compounds exhibited good antifungal activity. Furthermore, DFT calculation was carried out for studying the structure-activity relationship (SAR). CONCLUSION: A practical synthetic route to obtain 1,2,4-triazolo[4,3 a]pyridine derivatives is presented. This study suggests that the 1,2,4 triazolo[4,3-a]pyridine derivatives exhibited good antifungal activity. PMID- 27493684 TI - A school mental health literacy curriculum resource training approach: effects on Tanzanian teachers' mental health knowledge, stigma and help-seeking efficacy. AB - BACKGROUND: Mental health literacy (MHL) is foundational for mental health promotion, prevention, stigma reduction, and care; School supported information pertaining to MHL in sub-Saharan Africa is extremely limited, including in Tanzania. Successful application of a school MHL curriculum resource may be an effective way to increase teacher MHL and therefore help to improve mental health outcomes for students. METHODS: Secondary school teachers in Tanzania were trained on the African Guide (AG) a school MHL curriculum resource culturally adapted from a Canadian MHL resource (The Guide) for use in Africa. Teacher training workshops on the classroom application of the AG were used to evaluate its impact on mental health literacy in a sample of Tanzanian Secondary school teachers. Pre-post training assessment of participant knowledge and attitudes was conducted. Help-seeking efficacy for teachers themselves and their interventions for students, friends, family members and peers were determined. RESULTS: Paired t test (n = 37) results demonstrate highly significant improvements in teacher's overall knowledge (p < 0.001; d = 1.14), including mental health knowledge, (p < 0.001; d = 1.14) and curriculum specific knowledge (p < 0.01; d = 0.63). Teachers' stigma against mental illness decreased significantly following the training (p < 0.001; d = 0.61). Independent t tests comparing the paired sample against unpaired sample also demonstrated significant differences between the groups for teacher's overall knowledge (p < 0.001). Teachers also reported high rates (greater than 3/4 of the sample) of positive help-seeking efficacy for themselves as well as for their students, friends, family members and peers. As a result of the training, the number of students teachers identified for potential mental health care totaled over 200. CONCLUSIONS: These positive results, when taken together with other research, suggest that the use of a classroom-based resource (the AG) that integrates MHL into existing school curriculum through training teachers may be an effective and sustainable way to increase the MHL (improved knowledge, decreased stigma and positive help-seeking efficacy) of teachers in Tanzania. As this study replicated the results of a previous intervention in Malawi, consideration could be given to scaling up this intervention in both countries and applying this resource and approach in other countries in East Africa. PMID- 27493685 TI - Effect of tungstate on acetate and ethanol production by the electrosynthetic bacterium Sporomusa ovata. AB - BACKGROUND: Microbial electrosynthesis (MES) and gas fermentation are bioenergy technologies in which a microbial catalyst reduces CO2 into organic carbon molecules with electrons from the cathode of a bioelectrochemical system or from gases such as H2. The acetogen Sporomusa ovata has the capacity of reducing CO2 into commodity chemicals by both gas fermentation and MES. Acetate is often the only product generated by S. ovata during autotrophic growth. RESULTS: In this study, trace elements in S. ovata growth medium were optimized to improve MES and gas fermentation productivity. Augmenting tungstate concentration resulted in a 2.9-fold increase in ethanol production by S. ovata during H2:CO2-dependent growth. It also promoted electrosynthesis of ethanol in a S. ovata-driven MES reactor and increased acetate production 4.4-fold compared to unmodified medium. Furthermore, fatty acids propionate and butyrate were successfully converted to their corresponding alcohols 1-propanol and 1-butanol by S. ovata during gas fermentation. Increasing tungstate concentration enhanced conversion efficiency for both propionate and butyrate. Gene expression analysis suggested that tungsten-containing aldehyde ferredoxin oxidoreductases (AORs) and a tungsten containing formate dehydrogenase (FDH) were involved in the improved biosynthesis of acetate, ethanol, 1-propanol, and 1-butanol. AORs and FDH contribute to the fatty acids re-assimilation pathway and the Wood-Ljungdahl pathway, respectively. CONCLUSIONS: This study presented here shows that optimization of microbial catalyst growth medium can improve productivity and lead to the biosynthesis of different products by gas fermentation and MES. It also provides insights on the metabolism of biofuels production in acetogens and demonstrates that S. ovata has an important untapped metabolic potential for the production of other chemicals than acetate via CO2-converting bioprocesses including MES. PMID- 27493686 TI - Enhancement of cellulosome-mediated deconstruction of cellulose by improving enzyme thermostability. AB - BACKGROUND: The concerted action of three complementary cellulases from Clostridium thermocellum, engineered to be stable at elevated temperatures, was examined on a cellulosic substrate and compared to that of the wild-type enzymes. Exoglucanase Cel48S and endoglucanase Cel8A, both key elements of the natural cellulosome from this bacterium, were engineered previously for increased thermostability, either by SCHEMA, a structure-guided, site-directed protein recombination method, or by consensus-guided mutagenesis combined with random mutagenesis using error-prone PCR, respectively. A thermostable beta-glucosidase BglA mutant was also selected from a library generated by error-prone PCR that will assist the two cellulases in their methodic deconstruction of crystalline cellulose. The effects of a thermostable scaffoldin versus those of a largely mesophilic scaffoldin were also examined. By improving the stability of the enzyme subunits and the structural component, we aimed to improve cellulosome mediated deconstruction of cellulosic substrates. RESULTS: The results demonstrate that the combination of thermostable enzymes as free enzymes and a thermostable scaffoldin was more active on the cellulosic substrate than the wild type enzymes. Significantly, "thermostable" designer cellulosomes exhibited a 1.7 fold enhancement in cellulose degradation compared to the action of conventional designer cellulosomes that contain the respective wild-type enzymes. For designer cellulosome formats, the use of the thermostabilized scaffoldin proved critical for enhanced enzymatic performance under conditions of high temperatures. CONCLUSIONS: Simple improvement in the activity of a given enzyme does not guarantee its suitability for use in an enzyme cocktail or as a designer cellulosome component. The true merit of improvement resides in its ultimate contribution to synergistic action, which can only be determined experimentally. The relevance of the mutated thermostable enzymes employed in this study as components in multienzyme systems has thus been confirmed using designer cellulosome technology. Enzyme integration via a thermostable scaffoldin is critical to the ultimate stability of the complex at higher temperatures. Engineering of thermostable cellulases and additional lignocellulosic enzymes may prove a determinant parameter for development of state-of-the-art designer cellulosomes for their employment in the conversion of cellulosic biomass to soluble sugars.Graphical abstractConversion of conventional designer cellulosomes into thermophilic designer cellulosomes. PMID- 27493687 TI - Dynamic flux balance modeling to increase the production of high-value compounds in green microalgae. AB - BACKGROUND: Photosynthetic organisms can be used for renewable and sustainable production of fuels and high-value compounds from natural resources. Costs for design and operation of large-scale algae cultivation systems can be reduced if data from laboratory scale cultivations are combined with detailed mathematical models to evaluate and optimize the process. RESULTS: In this work we present a flexible modeling formulation for accumulation of high-value storage molecules in microalgae that provides quantitative predictions under various light and nutrient conditions. The modeling approach is based on dynamic flux balance analysis (DFBA) and includes regulatory models to predict the accumulation of pigment molecules. The accuracy of the model predictions is validated through independent experimental data followed by a subsequent model-based fed-batch optimization. In our experimentally validated fed-batch optimization study we increase biomass and [Formula: see text]-carotene density by factors of about 2.5 and 2.1, respectively. CONCLUSIONS: The analysis shows that a model-based approach can be used to develop and significantly improve biotechnological processes for biofuels and pigments. PMID- 27493688 TI - Erratum to: Cost-effectiveness of clostridial collagenase ointment on wound closure in patients with diabetic foot ulcers: economic analysis of results from a multicenter, randomized, open-label trial. AB - [This corrects the article DOI: 10.1186/s13047-015-0065-x.]. PMID- 27493690 TI - Intravenous zoledronate for osteoporosis: less might be more. AB - Annual administration of 5 mg intravenous zoledronate is moderately effective in reducing fracture risk in older adults, decreasing the relative risk of clinical fracture by 33%. However, almost 10 years after its approval for use in clinical practice there remain very substantial uncertainties about the optimal treatment regimen, that is, the lowest dose and/or longest dosing interval that is efficacious. Several pieces of clinical research suggest that the current recommendation for annual administration of 5 mg zoledronate might represent overtreatment. Clinical trials to clarify the optimal use of zoledronate for reduction of fracture risk should be undertaken. PMID- 27493689 TI - Remission-induction therapies for early rheumatoid arthritis: evidence to date and clinical implications. AB - Recent guidelines on rheumatoid arthritis (RA) point to the importance of achieving remission as soon as possible during the course of the disease. The appropriate use of antirheumatic drugs is critical, particularly in early RA patients, before 24 weeks, since this is a 'window of opportunity' for treatment to modify disease progression. A treat-to-target strategy added to an aggressive therapeutic approach increases the chance of early remission, particularly in early RA patients. We conducted an overview of current therapeutic strategies leading to remission in early RA patients. We also provide interesting predictive factors that can guide the RA management strategy with regard to disease modifying treatment and/or drug-free remission. PMID- 27493692 TI - Selected aspects of the current management of myositis. AB - The idiopathic inflammatory myopathies (IIM) are a rare and heterogeneous group of acquired autoimmune muscle disorders, often referred to as 'myositis'. Clinical assessment, together with muscle biopsy findings and autoantibody status are key factors to consider when making a diagnosis of IIM, and in stratification of the 'IIM spectrum' into disease subgroups. Treatment stratified according to serotype (and in the future, likely also genotype) is increasingly being used to take account of the heterogeneity within the IIM spectrum. Subgroup classification is also important in terms of monitoring for complications, such as malignancy and interstitial lung disease. Disease monitoring should include the use of standardized tools such as the IMACS disease activity outcome measures. Other tools such as muscle MRI can be useful in identifying areas of active muscle inflammation. Treatment outcomes in IIM remain unsatisfactory. The evidence base to guide treatment decisions is remarkably limited. In addition to muscle inflammation, a number of noninflammatory cell-mediated mechanisms may contribute to weakness and disability, and for which no specific treatments are currently available. PMID- 27493691 TI - Maternal vitamin D levels during pregnancy and neonatal health: evidence to date and clinical implications. AB - Low maternal vitamin D levels during pregnancy have been associated with a plethora of adverse neonatal outcomes, including small for gestational age and preterm births, detrimental effect on offspring bone and teeth development, and risk of infectious diseases. Although most observational studies indicate a significant linear relationship between maternal 25-hydroxyvitamin D and the above outcomes, some randomized controlled trials to date are inconclusive, mostly due to differences in study design and supplementation regimen. The currently available results indicate that vitamin D supplementation during pregnancy reduces the risk of preterm birth, low birth weight, dental caries of infancy, and neonatal infectious diseases such as respiratory infections and sepsis. This narrative review aims to summarize available trial results regarding the effect of low maternal vitamin D levels during pregnancy, in conjunction with neonatal outcomes on the field, with a discourse on the appropriate clinical approach of this important issue. PMID- 27493693 TI - Treatment of hyperuricemia in gout: current therapeutic options, latest developments and clinical implications. AB - Despite being the most common type of inflammatory arthritis, gout is often poorly managed. Except for febuxostat and pegloticase, research in new therapeutic agents for the management of hyperuricemia in gout remained insufficient for several decades. With emerging evidence of possible roles of hyperuricemia in cardiometabolic comorbidities, as well as more convincing evidence regarding poor outcomes (e.g. disability, recurrent hospital admissions) in patients with uncontrolled gout, several agents are current under development. Increasing knowledge regarding renal urate transporters has resulted in the development of new generation uricosurics such as lesinurad and arhalofenate. This review aims at discussing current therapeutic strategies for gout, as well as their limitations and the possible role of emerging agents in the chronic management of hyperuricemia in gout. Drugs in phases I and II of development will be discussed, along with new agents and therapeutic classes, such as purine nucleoside phosphorylase inhibitors and dual-action drugs. These new developments are encouraging, and will hopefully contribute to a more adequate management of hyperuricemia in gout. PMID- 27493694 TI - Mobile and Wearable Device Features that Matter in Promoting Physical Activity. AB - BACKGROUND: As wearable sensors/devices become increasingly popular to promote physical activity (PA), research is needed to examine how and which components of these devices people use to increase their PA levels. AIMS: (1) To assess usability and level of engagement with the Fitbit One and daily SMS-based prompts in a 6-week PA intervention, and (2) to examine whether use/ level of engagement with specific intervention components were associated with PA change. METHODS: Data were analyzed from a randomized controlled trial that compared (1) a wearable sensor/ device (Fitbit One) plus SMS-based PA prompts, and (2) Fitbit One only, among overweight/ obese adults (N = 67). We calculated average scores from Likert-type response items that assessed usability and level of engagement with device features (e.g., tracker, website, mobile app, and SMS-based prompts), and assessed whether such factors were associated with change in steps/day (using Actigraph GT3X+). RESULTS: Participants reported the Fitbit One was easy to use and the tracker helped to be more active. Those who used the Fitbit mobile app (36%) vs. those who did not (64%) had an increase in steps at 6-week follow-up, even after adjusting for previous web/app use: +545 steps/ day (SE = 265) vs. -28 steps/ day (SE = 242) (p = .04). CONCLUSIONS: Level of engagement with the Fitbit One, particularly the mobile app, was associated with increased steps. Mobile apps can instantly display summaries of PA performance and could optimize self regulation to activate change. More research is needed to determine whether such modalities might be cost-effective in future intervention research and practice. PMID- 27493695 TI - Homology modeling and virtual screening studies of FGF-7 protein-a structure based approach to design new molecules against tumor angiogenesis. AB - Keratinocyte growth factor (KGF) protein is a member of the fibroblast growth factor (FGF) family, which is also known as FGF-7. The FGF-7 plays an important role in tumor angiogenesis. In the present work, FGF-7 is treated as a potential therapeutic target to prevent angiogenesis in cancerous tissue. Computational techniques are applied to evaluate and validate the 3D structure of FGF-7 protein. The active site region of the FGF-7 protein is identified based on hydrophobicity calculations using CASTp and Q-site Finder active site prediction tools. The protein-protein docking study of FGF-7 with its natural receptor FGFR2b is carried out to confirm the active site region in FGF-7. The amino acid residues Asp34, Arg67, Glu116, and Thr194 in FGF-7 interact with the receptor protein (FGFR2b). A grid is generated at the active site region of FGF-7 using Glide module of Schrodinger suite. Subsequently, a virtual screening study is carried out at the active site using small molecular structural databases to identify the ligand molecules. The binding interactions of the ligand molecules, with piperazine moiety as a pharmacophore, are observed at Arg67 and Glu149 residues of the FGF-7 protein. The identified ligand molecules against the FGF-7 protein show permissible pharmacokinetic properties (ADME). The ligand molecules with good docking scores and satisfactory pharmacokinetic properties are prioritized and identified as novel ligands for the FGF-7 protein in cancer therapy. PMID- 27493697 TI - JOCB Bulletin. PMID- 27493696 TI - Synthesis of a series of novel 2,5-disubstituted-1,3,4-oxadiazole derivatives as potential antioxidant and antibacterial agents. AB - A series of novel 2,5-disubstituted-1,3,4-oxadiazole derivatives were synthesized and screened for their antimicrobial and antioxidant activities. The assay indicated that compounds 3c, 3d, and 3i exhibited comparable antibacterial and antioxidant activity with first-line drugs. The structure activity relationship and molecular docking study of the synthesized compounds are also reported. PMID- 27493698 TI - Erratum to: Neural correlates of reward processing in adults with 22q11 deletion syndrome. AB - [This corrects the article DOI: 10.1186/s11689-016-9158-5.]. PMID- 27493699 TI - Tobacco smoking differently influences cell types of the innate and adaptive immune system-indications from CpG site methylation. AB - BACKGROUND: Tobacco smoke is worldwide one of the main preventable lifestyle inhalative pollutants causing severe adverse health effects. Epidemiological studies revealed association of tobacco smoking with epigenetic changes at single CpGs in blood. However, the biological relevance of the often only marginal methylation changes remains unclear. RESULTS: Comparing genome-wide changes in CpG methylation of three recently reported epidemiological datasets, two obtained on whole blood and one on peripheral blood mononuclear cells (PBMCs), it becomes evident that the majority of methylation changes (86.7 and 93.3 %) in whole blood account for changes in granulocytes. Analyzing, in more detail, seven highly significant reported smoking-induced methylation changes at single CpGs in different blood cell types of healthy volunteers (n = 32), we confirmatively found a strong cell-type specificity. Two CpGs in GFI1 and F2RL3 were significantly hypomethylated in granulocytes (-11.3 %, p = 0.001; -8.7 %, p = 0.001, respectively) but not in PBMCs of smokers while two CpGs in CPOX and GPR15 were found to be hypomethylated in PBMC (-4.3 %, p = 0.003; -4.2 %, P = 0.009, respectively) and their subtypes of GPR15 non-expressing (-3.2 %, p = 0.027; -2.5 %, p = 0.032, respectively) and smoking-evoked GPR15 expressing T cells (-15.8 %, p < 0.001; -13.8 %, p = 0.018, respectively) but not in granulocytes. In contrast, cg05575921 within AHRR was hypomethylated in every analyzed cell type of smokers, but with a different degree. Both, hypomethylation at cg05575921 in granulocytes (-55.2 % methylation change in smokers, p < 0.001) and the frequency of GPR15+ T cells (9.8-37.1 % in smokers), possessing a specific hypomethylation at cg19859270, were strongly associated with smoking behavior at individual level and could therefore serve as valuable biomarkers indicating a disturbed homeostasis in smokers. In contrast to the reported long-term persistent methylation changes in adult smokers after cessation, the hypomethylation at cg05575921 in prenatally tobacco smoke-exposed children (n = 13) from our LINA cohort was less stable and disappeared already within 2 years after birth. CONCLUSIONS: Studying cell type-specific methylation changes provides helpful information regarding the biological relevance of epigenetic modifications. Here, we could show that smoking differently affects both cells of the innate and adaptive immune systems. PMID- 27493700 TI - Erratum to: MSRE-HTPrimer: a high-throughput and genome-wide primer design pipeline optimized for epigenetic research. AB - [This corrects the article DOI: 10.1186/s13148-016-0190-9.]. PMID- 27493702 TI - Fabrication of anti-protein-fouling poly(ethylene glycol) microfluidic chip electrophoresis by sandwich photolithography. AB - Microfluidic chip electrophoresis (MCE) is a powerful separation tool for biomacromolecule analysis. However, adsorption of biomacromolecules, particularly proteins onto microfluidic channels severely degrades the separation performance of MCE. In this paper, an anti-protein-fouling MCE was fabricated using a novel sandwich photolithography of poly(ethylene glycol) (PEG) prepolymers. Photopatterned microchannel with a minimum resolution of 10 MUm was achieved. After equipped with a conventional online electrochemical detector, the device enabled baseline separation of bovine serum albumin, lysozyme (Lys), and cytochrome c (Cyt-c) in 53 s under a voltage of 200 V. Compared with a traditional polydimethylsiloxane MCE made by soft lithography, the PEG MCE made by the sandwich photolithography not only eliminated the need of a master mold and the additional modification process of the microchannel but also showed excellent anti-protein-fouling properties for protein separation. PMID- 27493701 TI - Flow of DNA in micro/nanofluidics: From fundamentals to applications. AB - Thanks to direct observation and manipulation of DNA in micro/nanofluidic devices, we are now able to elucidate the relationship between the polymer microstructure and its rheological properties, as well as to design new single molecule platforms for biophysics and biomedicine. This allows exploration of many new mechanisms and phenomena, which were previously unachievable with conventional methods such as bulk rheometry tests. For instance, the field of polymer rheology is at a turning point to relate the complex molecular conformations to the nonlinear viscoelasticity of polymeric fluids (such as coil stretch transition, shear thinning, and stress overshoot in startup shear). In addition, nanofluidic devices provided a starting point for manipulating single DNA molecules by applying basic principles of polymer physics, which is highly relevant to numerous processes in biosciences. In this article, we review recent progress regarding the flow and deformation of DNA in micro/nanofluidic systems from both fundamental and application perspectives. We particularly focus on advances in the understanding of polymer rheology and identify the emerging research trends and challenges, especially with respect to future applications of nanofluidics in the biomedical field. PMID- 27493703 TI - On-chip clearing of arrays of 3-D cell cultures and micro-tissues. AB - Three-dimensional (3-D) cell cultures are beneficial models for mimicking the complexities of in vivo tissues, especially in tumour studies where transport limitations can complicate response to cancer drugs. 3-D optical microscopy techniques are less involved than traditional embedding and sectioning, but are impeded by optical scattering properties of the tissues. Confocal and even two photon microscopy limit sample imaging to approximately 100-200 MUm depth, which is insufficient to image hypoxic spheroid cores. Optical clearing methods have permitted high-depth imaging of tissues without physical sectioning, but they are difficult to implement for smaller 3-D cultures due to sample loss in solution exchange. In this work, we demonstrate a microfluidic platform for high throughput on-chip optical clearing of breast cancer spheroids using the SeeDB, Clear(T2), and ScaleSQ clearing methods. Although all three methods are able to effectively clear the spheroids, we find that SeeDB and ScaleSQ more effectively clear the sample than Clear(T2); however, SeeDB induces green autofluorescence while ScaleS causes sample expansion. Our unique on-chip implementation permits clearing arrays of 3-D cultures using perfusion while monitoring the 3-D cultures throughout the process, enabling visualization of the clearing endpoint as well as monitoring of transient changes that could induce image artefacts. Our microfluidic device is compatible with on-chip 3-D cell culture, permitting the use of on-chip clearing at the endpoint after monitoring the same spheroids during their culture. This on-chip method has the potential to improve readout from 3-D cultures, facilitating their use in cell-based assays for high-content drug screening and other applications. PMID- 27493704 TI - Melatonin-Mediated Intracellular Insulin during 2-Deoxy-d-glucose Treatment Is Reduced through Autophagy and EDC3 Protein in Insulinoma INS-1E Cells. AB - 2-DG triggers glucose deprivation without altering other nutrients or metabolic pathways and then activates autophagy via activation of AMPK and endoplasmic reticulum (ER) stress. We investigated whether 2-DG reduced intracellular insulin increased by melatonin via autophagy/EDC3 in insulinoma INS-1E cells. p-AMPK and GRP78/BiP level were significantly increased by 2-DG in the presence/absence of melatonin, but IRE1alpha level was reduced in 2-DG treatment. Levels of p85alpha, p110, p-Akt (Ser473, Thr308), and p-mTOR (Ser2481) were also significantly reduced by 2-DG in the presence/absence of melatonin. Mn-SOD increased with 2-DG plus melatonin compared to groups treated with/without melatonin alone. Bcl-2 was decreased and Bax increased with 2-DG plus melatonin. LC3II level increased with 2-DG treatment in the presence/absence of melatonin. Intracellular insulin production increased in melatonin plus 2-DG but reduced in treatment with 2-DG with/without melatonin. EDC3 was increased by 2-DG in the presence/absence of melatonin. Rapamycin, an mTOR inhibitor, increased GRP78/BiP and EDC3 levels in a dose-dependent manner and subsequently resulted in a decrease in intracellular production of insulin. These results suggest that melatonin-mediated insulin synthesis during 2-DG treatment involves autophagy and EDC3 protein in rat insulinoma INS-1E cells and subsequently results in a decrease in intracellular production of insulin. PMID- 27493705 TI - Antioxidant and Antihyperlipidemic Effects of Campomanesia adamantium O. Berg Root. AB - Campomanesia adamantium O. Berg, popularly known as guavira, has been used in Brazilian traditional medicine for reduction of serum lipid. The present study was carried out to investigate the antioxidant and antihyperlipidemic effects of Campomanesia adamantium root aqueous extract (ExCA). Phenolic compounds were quantified in the ExCA and gallic and ellagic acids were identified by HPLC. ExCA showed efficiency in 2,2-diphenyl-1-picrylhydrazyl free radical scavenging, with IC50 similar to butylhydroxytoluene control, and protected the erythrocytes against lipid peroxidation induced by 2,2'-azobis(2-methylpropionamidine) dihydrochloride, reducing generated malondialdehyde. Hyperlipidemic Wistar rats treated daily by gavage during eight weeks with ExCA (200 mg/kg of body weight) showed reduced serum level of total cholesterol and triglycerides, similar to normolipidemic rats and hyperlipidemic rats treated with simvastatin (30 mg/kg of body weight) and ciprofibrate (2 mg/kg of body weight). Moreover, the treatment with ExCA also decreased malondialdehyde serum level in the hyperlipidemic rats. The body weight and organ mass were unmodified by ExCA in hyperlipidemic rats, except an increase of liver mass; however, the hepatic enzymes, alanine aminotransferase and aspartate aminotransferase, were unchanged. Together, these results confirm the potential value of Campomanesia adamantium root for lowering lipid peroxidation and lipid serum level, improving risk factors for cardiometabolic diseases development. PMID- 27493707 TI - The combination of breast necrosis and chylothorax following the OPCAB. AB - Due to long term patency, the internal mammary artery is considered as a conduit of choice for revascularization of the left anterior descending coronary artery. The internal mammary artery and its accessory branches in addition to perfusing the chest wall structures also contributes to supplying, part of the female breast arteries. In addition, due to the accompaniment of thoracic duct branches with the left internal mammary artery, harvesting may be associated with injury to these branches and contribute to chylothorax. We report a rare case of chylothorax and the breast necrosis following the coronary artery bypass grafting. The chylothorax was started in the second postoperative day and ceased gradually in the 12th day of operation. The breast necrosis appeared in the 3th weeks of operation with pain, and tenderness and black skin color change. The patient underwent total mastectomy in the 4th weeks of operation. PMID- 27493706 TI - Erythropoietin Restores Long-Term Neurocognitive Function Involving Mechanisms of Neuronal Plasticity in a Model of Hyperoxia-Induced Preterm Brain Injury. AB - Cerebral white and grey matter injury is the leading cause of an adverse neurodevelopmental outcome in prematurely born infants. High oxygen concentrations have been shown to contribute to the pathogenesis of neonatal brain damage. Here, we focused on motor-cognitive outcome up to the adolescent and adult age in an experimental model of preterm brain injury. In search of the putative mechanisms of action we evaluated oligodendrocyte degeneration, myelination, and modulation of synaptic plasticity-related molecules. A single dose of erythropoietin (20,000 IU/kg) at the onset of hyperoxia (24 hours, 80% oxygen) in 6-day-old Wistar rats improved long-lasting neurocognitive development up to the adolescent and adult stage. Analysis of white matter structures revealed a reduction of acute oligodendrocyte degeneration. However, erythropoietin did not influence hypomyelination occurring a few days after injury or long-term microstructural white matter abnormalities detected in adult animals. Erythropoietin administration reverted hyperoxia-induced reduction of neuronal plasticity-related mRNA expression up to four months after injury. Thus, our findings highlight the importance of erythropoietin as a neuroregenerative treatment option in neonatal brain injury, leading to improved memory function in adolescent and adult rats which may be linked to increased neuronal network connectivity. PMID- 27493708 TI - Ibrutinib in Waldenstrom macroglobulinemia: latest evidence and clinical experience. AB - Ibrutinib is an oral Bruton's tyrosine kinase (BTK) inhibitor, which has recently gained approval by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients with symptomatic Waldenstrom macroglobulinemia (WM). Herein, we review the role of BTK in the pathophysiology of WM, and present the results of the preclinical and clinical studies that led to the initial investigation and later approval of ibrutinib in WM. We also discuss aspects associated with ibrutinib therapy in WM patients, especially focusing on genomic profiling and the impact on response to ibrutinib, and the management of adverse events. PMID- 27493709 TI - Elotuzumab: the first approved monoclonal antibody for multiple myeloma treatment. AB - Elotuzumab is a monoclonal antibody directed against the SLAMF7 receptor, expressed on normal and malignant plasma cells with a lower expression on other lymphoid cells such as natural killer (NK) cells. Elotuzumab has no significant antimyeloma activity when given as a single agent to patients with relapsed or refractory multiple myeloma (RRMM). However, when combined with other antimyeloma agents, it results in improved response and outcome. Owing to the results from the landmark ELOQUENT-2 phase III clinical trial, which compared lenalidomide and dexamethasone with or without elotuzumab in patients with RRMM, elotuzumab in combination with lenalidomide and dexamethasone was approved by the American Food and Drug Administration (FDA) in November 2015 for multiple myeloma (MM) patients who received one to three prior lines of therapy. This review will give a brief description of the signaling lymphocytic activation molecule (SLAM) family receptors, the unique SLAMF7 receptor and the mechanism of action of elotuzumab. Thereafter, we will give an overview on its antimyeloma activity in preclinical and clinical trials, including its toxicity profile and management thereof. PMID- 27493710 TI - Bortezomib for the treatment of mantle cell lymphoma: an update. AB - Bortezomib is a first in class proteasome inhibitor, initially approved by the US Food and Drug Administration for the treatment of plasma cell myeloma. Bortezomib has been approved for the treatment of relapsed and refractory mantle cell lymphoma (MCL) and, more recently, in the upfront setting as well. Treatment algorithms for MCL have rapidly evolved over the past two decades, and the optimal regimen remains to be defined. The choice of treatment regimen is based on disease risk stratification models, the expected toxicity of antineoplastic agents, the perceived patient ability to tolerate the planned treatments and the availability of novel agents. As new drugs with novel mechanisms of action and variable toxicity profiles come into use, treatment decisions for a given patient have become increasingly complex. This article provides an overview of the evolving use of bortezomib in the rapidly changing management landscape of MCL. PMID- 27493711 TI - A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma. AB - Lenalidomide, an immunomodulatory drug that the US Food and Drug Administration (FDA) approved for the treatment of multiple myeloma, 5q- myelodysplasia and mantle-cell lymphoma (MCL), has encouraging efficacy in other B-cell malignancies. Its unique mechanism of action is in part due to altering the tumor microenvironment and potentiating the activity of T and natural-killer (NK) cells. Impressive clinical activity and excellent tolerability allows broad applicability. Lenalidomide has been used in a wide range of B-cell malignancies for years, but in 2013, the FDA marked its approval as a single agent only in relapsed/refractory mantle-cell lymphoma. Perhaps most impressive is the efficacy of lenalidomide when combined with monoclonal antibodies. Impressive efficacy and toxicity profiles with the combination of lenalidomide and rituximab in B-cell lymphomas in both the upfront and relapsed/refractory setting may allow a shift in our current treatment paradigm in both indolent and aggressive non-Hodgkin lymphoma (NHL). This review will summarize the current data in the relapsed/refractory and front-line setting of NHL with single-agent lenalidomide as well as its use in combination with other agents. PMID- 27493712 TI - Ofatumumab plus chlorambucil as a first-line therapy in less fit patients with chronic lymphocytic leukemia: analysis of COMPLEMENT1 and other monoclonal antibodies association data. AB - The management of patients with chronic lymphocytic leukemia (CLL) has radically improved over the last few years with the addition of anti-CD20 monoclonal antibodies (MoAbs) to chemotherapy. Chlorambucil has been considered for decades as a suitable therapeutic option for frail patients. Taking into account the advantage offered by the addition of MoAbs to chemotherapy, different studies up to now have explored the feasibility of chlorambucil-based chemoimmunotherapies in treatment-naive CLL. COMPLEMENT1 is a prospective, randomized, open-label trial evaluating the efficacy and safety of ofatumumab added to chlorambucil, compared with chlorambucil in monotherapy, in the setting of untreated patients with CLL considered unsuitable for a fludarabine-based approach. Progression-free survival was significantly longer in the chemoimmunotherapy arm when compared with the single-agent chlorambucil (22.4 months versus 13.1 months). Response rate and quality were also improved in the combination arm. Furthermore, the addition of ofatumumab did not lead to an unmanageable toxicity. While the employment of anti-CD20 antibodies represents an advantage in the treatment of the CLL symptomatic population, at present different patient selection and treatment schedules do not allow a reliable comparison between chlorambucil-based regimens. The addition of ofatumumab to chlorambucil represents a further therapeutic gain in CLL. Longer follow up and direct comparison with other MoAbs are warranted to establish the preferred first-line treatment in elderly and unfit patients. PMID- 27493713 TI - Unusual, spontaneous aneurysm formation in a patient being treated with ibrutinib for chronic lymphocytic leukemia. PMID- 27493714 TI - Osteogenic differentiation of human mesenchymal stem cells promotes mineralization within a biodegradable peptide hydrogel. AB - An attractive strategy for the regeneration of tissues has been the use of extracellular matrix analogous biomaterials. Peptide-based fibrillar hydrogels have been shown to mimic the structure of extracellular matrix offering cells a niche to undertake their physiological functions. In this study, the capability of an ionic-complementary peptide FEFEFKFK (F, E, and K are phenylalanine, glutamic acid, and lysine, respectively) hydrogel to host human mesenchymal stem cells in three dimensions and induce their osteogenic differentiation is demonstrated. Assays showed sustained cell viability and proliferation throughout the hydrogel over 12 days of culture and these human mesenchymal stem cells differentiated into osteoblasts simply upon addition of osteogenic stimulation. Differentiated osteoblasts synthesized key bone proteins, including collagen-1 (Col-1), osteocalcin, and alkaline phosphatase. Moreover, mineralization occurred within the hydrogel. The peptide hydrogel is a naturally biodegradable material as shown by oscillatory rheology and reversed-phase high-performance liquid chromatography, where both viscoelastic properties and the degradation of the hydrogel were monitored over time, respectively. These findings demonstrate that a biodegradable octapeptide hydrogel can host and induce the differentiation of stem cells and has the potential for the regeneration of hard tissues such as alveolar bone. PMID- 27493716 TI - Multipotent adult progenitor cells on an allograft scaffold facilitate the bone repair process. AB - Multipotent adult progenitor cells are a recently described population of stem cells derived from the bone marrow stroma. Research has demonstrated the potential of multipotent adult progenitor cells for treating ischemic injury and cardiovascular repair; however, understanding of multipotent adult progenitor cells in orthopedic applications remains limited. In this study, we evaluate the osteogenic and angiogenic capacity of multipotent adult progenitor cells, both in vitro and loaded onto demineralized bone matrix in vivo, with comparison to mesenchymal stem cells, as the current standard. When compared to mesenchymal stem cells, multipotent adult progenitor cells exhibited a more robust angiogenic protein release profile in vitro and developed more extensive vasculature within 2 weeks in vivo. The establishment of this vascular network is critical to the ossification process, as it allows nutrient exchange and provides an influx of osteoprogenitor cells to the wound site. In vitro assays confirmed the multipotency of multipotent adult progenitor cells along mesodermal lineages and demonstrated the enhanced expression of alkaline phosphatase and production of calcium-containing mineral deposits by multipotent adult progenitor cells, necessary precursors for osteogenesis. In combination with a demineralized bone matrix scaffold, multipotent adult progenitor cells demonstrated enhanced revascularization and new bone formation in vivo in an orthotopic defect model when compared to mesenchymal stem cells on demineralized bone matrix or demineralized bone matrix-only control groups. The potent combination of angiogenic and osteogenic properties provided by multipotent adult progenitor cells appears to create a synergistic amplification of the bone healing process. Our results indicate that multipotent adult progenitor cells have the potential to better promote tissue regeneration and healing and to be a functional cell source for use in orthopedic applications. PMID- 27493715 TI - Methods for culturing retinal pigment epithelial cells: a review of current protocols and future recommendations. AB - The retinal pigment epithelium is an important part of the vertebrate eye, particularly in studying the causes and possible treatment of age-related macular degeneration. The retinal pigment epithelium is difficult to access in vivo due to its location at the back of the eye, making experimentation with age-related macular degeneration treatments problematic. An alternative to in vivo experimentation is cultivating the retinal pigment epithelium in vitro, a practice that has been going on since the 1970s, providing a wide range of retinal pigment epithelial culture protocols, each producing cells and tissue of varying degrees of similarity to natural retinal pigment epithelium. The purpose of this review is to provide researchers with a ready list of retinal pigment epithelial protocols, their effects on cultured tissue, and their specific possible applications. Protocols using human and animal retinal pigment epithelium cells, derived from tissue or cell lines, are discussed, and recommendations for future researchers included. PMID- 27493717 TI - Differential protection of black-seed oil on econucleotidase, cholinesterases and aminergic catabolizing enzyme in haloperidol-induced neuronal damage of male rats. AB - BACKGROUND: The antipsychotic, haloperidol, is extremely efficient in the treatment of schizophrenia but its application is constrained because of irreversible adverse drug reactions. Hence, in this study, we investigate the differential effects of black seed oil on cholinesterase [acetylcholinesterase (AChE) and butrylcholinesterase (BuChE), ectonucleotidase (5'-nucleotidase), lactate dehydrogenase (LDH) and monoamine oxidase (MAO)] activities and relevant markers of oxidative stress in the cerebrum of haloperidol-induced neuronal damaged rats. METHODS: The animals were divided into six groups (n = 10): normal control rats; haloperidol-induced rats: induced rats were pre-, co- and post treated with black-seed oil respectively, while the last group was treated with extract oil only. The treatment was performed via oral administration and the experiment lasted 14 days. RESULTS: The results revealed an increase in 5(I) nucleotidase, a marker of adenosine triphosphate (ATP) and adenosine monophosphate (AMP) hydrolysis, as well as AChE, BuChE and MAO activities, with concomitant decrease in LDH activity of cerebrum in induced rats when compared with controls. Also, administration of haloperidol caused systemic oxidative damage and adverse histopathological changes in neuronal cells, indications of mental disorder. The differential treatments with black-seed oil prevented these alterations by increasing LDH and decreasing 5(I) nucleotidase, AChE, BuChE and MAO activities in the cerebrum. Essential oil post-treatment is most efficacious in reversing haloperidol-induced neuronal damage in rat; followed by pre- and cotreatment, respectively. CONCLUSIONS: We concluded that essential black-seed oil enhanced the wellness of aminergic, purinergic and cholinergic neurotransmissions of haloperidol-induced neuronal damage in rats. PMID- 27493719 TI - Making rational choices about how best to support consumers' use of medicines: a perspective review. AB - Inappropriate medicine use and polypharmacy create significant challenges for consumers and the health systems they live in, worldwide. In this review, we describe the evidence underpinning interventions directed primarily at healthcare consumers, including information provision, pharmacist-delivered interventions and practical supports, such as reminders to improve outcomes related to medicines. We identify a relatively small number of strategies that seem effective or promising: self-monitoring and self-management programmes, simplified dosing regimens and pharmacist-delivered interventions such as medication review. These interventions could be applied in practice to address some of the problems associated with inappropriate use of medicines, multimorbidity and polypharmacy. The evidence also indicates that success with many strategies is not consistent, suggesting that understanding the individual's context and their preferences will also be important for improving medicines' use. In addition, some strategies in current use are ineffective. Taken together, we argue that the evidence should inform deliberate, rational decisions between strategies to support consumers in using medicines safely and effectively. Future medicine-use research should likewise build rationally and constructively on what is known about promising interventions, avoiding duplication of past research, and working to help consumers negotiate the many challenges presented by polypharmacy. PMID- 27493718 TI - Medication-overuse headache: a perspective review. AB - Medication-overuse headache (MOH) is a debilitating condition in which frequent and prolonged use of medication for the acute treatment of pain results in the worsening of the headache. The purpose of this paper is to review the most recent literature on MOH and discuss future avenues for research. MOH accounts for a substantial share of the global burden of disease. Prevalence is often reported as 1-2% but can be as high as 7% overall, with higher proportions among women and in those with a low socioeconomic position. Management consists of withdrawing pain medication, focusing on prophylactic and nonmedical treatments, and limiting acute symptomatic medication. Stress reduction and lifestyle interventions may support the change towards rational pain medication use. Support, follow up, and education are needed to help patients through the detoxification period. There is fertile ground for research in MOH epidemiology, pathophysiology, and neuroimaging. Randomized and long-term follow-up studies on MOH treatment protocols are needed. Further focused research could be of major importance for global health. PMID- 27493720 TI - Nonmedical prescribing: where are we now? AB - Nonmedical prescribing has been allowed in the United Kingdom (UK) since 1992. Its development over the past 24 years has been marked by changes in legislation, enabling the progression towards independent prescribing for nurses, pharmacists and a range of allied health professionals. Although the UK has led the way regarding the introduction of nonmedical prescribing, it is now seen in a number of other Western-European and Anglophone countries although the models of application vary widely between countries. The programme of study to become a nonmedical prescriber (NMP) within the UK is rigorous, and involves a combination of taught curricula and practice-based learning. Prescribing is a complex skill that is high risk and error prone, with many influencing factors. Literature reports regarding the impact of nonmedical prescribing are sparse, with the majority of prescribing research tending to focus instead on prescribing by doctors. The impact of nonmedical prescribing however is important to evaluate, and can be carried out from several perspectives. This review takes a brief look back at the history of nonmedical prescribing, and compares this with the international situation. It also describes the processes required to qualify as a NMP in the UK, potential influences on nonmedical prescribing and the impact of nonmedical prescribing on patient opinions and outcomes and the opinions of doctors and other healthcare professionals. PMID- 27408687 TI - Case Report: Whole exome sequencing reveals a novel frameshift deletion mutation p.G2254fs in COL7A1 associated with autosomal recessive dystrophic epidermolysis bullosa. AB - Dystrophic epidermolysis bullosa simplex (DEB) is a phenotypically diverse inherited skin fragility disorder. It is majorly manifested by appearance of epidermal bullae upon friction caused either by physical or environmental trauma. The phenotypic manifestations also include appearance of milia, scarring all over the body and nail dystrophy. DEB can be inherited in a recessive or dominant form and the recessive form of DEB (RDEB) is more severe. In the present study, we identify a novel p.G2254fs mutation in COL7A1 gene causing a sporadic case of RDEB by whole exome sequencing (WES). Apart from adding a novel frameshift Collagen VII mutation to the repertoire of known mutations reported in the disease, to the best of our knowledge, this is the first report of a genetically characterized case of DEB from India. PMID- 27493721 TI - Different risk factor patterns for adult asthma, rhinitis and eczema: results from West Sweden Asthma Study. AB - BACKGROUND: Atopic diseases including asthma, rhinitis and eczema have increased in the second half of the past century. This has been well studied among children and adolescents but with the exception of asthma to a much lesser extent in adults. The adult risk factor pattern of atopic diseases, in particular of eczema, and their relation to allergic sensitization are yet to be fully elucidated. Studies among adults that have compared the risk factor pattern for these conditions in the same material are very few. The objective of this study was to compare the risk factor patterns for asthma, rhinitis and eczema in a randomly selected adult population. METHODS: A questionnaire survey on atopic diseases was dispatched by mail to 30,000 randomly selected individuals in West Sweden aged 16-75 years and 62 % participated. A subgroup of 2000 individuals was selected for clinical examinations including blood sampling for specific serum Immunoglobulin E to common airborne allergens and 1172 attended. RESULTS: The prevalence of current asthma was 11.8 %, current rhinitis 42.8 %, current eczema 13.5 and 2.3 % had all three conditions while 13.9 % had at least two conditions. No mutual risk factor was identified for all three conditions. Allergic sensitization was a strong risk factor for current asthma (OR 4.1 CI 2.7-6.3) and current rhinitis (OR 5.1 CI 3.8-6.9) but not so for current eczema. Obesity was a risk factor for current asthma and current rhinitis, while farm childhood decreased the risk for current asthma and current rhinitis. Occupational exposure to gas dust or fumes and female sex was associated with an increased risk of current asthma and current eczema. CONCLUSIONS: There are different risk factor patterns for asthma, rhinitis and eczema in adults but some risk factors are overlapping between some of the conditions. The effect of mutable risk factors should be assessed further in longitudinal studies. PMID- 27347383 TI - Where are the female science professors? A personal perspective. AB - The first woman to earn a Professorship at a University in Europe was Laura Maria Caterina Bassi, who earned a professorship in physics at the University of Bologna in 1732. Almost 300 years and three waves of feminism later, in 2016, women typically still only comprise 20% (or less) of the number of full professors in Europe. This opinion article will discuss the experiences of being a female academic today and the factors contributing to the academic gender gap from the perspective of a "young" natural scientist, as well as providing constructive suggestions for strategies to empower women in the academic world. PMID- 27493725 TI - Essential amino acid ratios and mTOR affect lipogenic gene networks and miRNA expression in bovine mammary epithelial cells. AB - BACKGROUND: The objective of this study was to study how changing the ratio of Lys to Thr, Lys to His, and Lys to Val affects the expression of lipogenic genes and microRNA (miRNA) in bovine mammary epithelial cells. RESULTS: Triplicate cultures with the respective "optimal" amino acid (AA) ratio (OPAA = Lys:Met 2.9:1; Thr:Phe 1.05:1; Lys:Thr 1.8:1; Lys:His 2.38:1; Lys:Val 1.23:1) plus rapamycin (OPAARMC; positive control), OPAA, Lys:Thr 2.1:1 (LT2.1), Lys:Thr 1.3:1 (LT1.3), Lys:His 3.05:1 (LH3.0), or Lys:Val 1.62:1 (LV1.6) were incubated in lactogenic medium for 12 h. The expression of 15 lipogenic genes and 7 miRNA were evaluated. Responses to LT2.1, LT1.3, LH3.0, and LV1.6 relative to the control (OPAARMC) included up-regulated expression of ACSS2, FABP3, ACACA, FASN, SCD, LPIN1, INSIG1, SREBF1, PPARD, and NR1H3 (commonly known as LXR-alpha). Furthermore, LV1.6 up-regulated expression of ACSL1, DGAT1, and RXRA and down regulated PPARG expression. Although no effect of OPAA on expression of PPARG was observed, compared with the control, OPAA up-regulated expression of the PPAR targets ACSS2, FABP3, ACACA, FASN, SCD, LPIN1, INSIG1, and SREBF1. Compared with the control, the expression of the anti-lipogenic MIR27AB was down-regulated by OPAA, LT2.1, LT1.3 and LH3.0. In contrast, compared with the control, the expression of the pro-lipogenic MIR21 was up-regulated by LT2.1, LT1.3, LH3.0, and LV1.6. CONCLUSIONS: The observed up-regulation of lipogenic gene networks and the changes in expression of key miRNA involved in the control of lipogenic balance are indicative of a potentially important role of EAA ratios and mTOR signaling in the regulation of milk fat synthesis. PMID- 27493724 TI - The IN/OUT assay: a new tool to study ciliogenesis. AB - BACKGROUND: Nearly all cells have a primary cilia on their surface, which functions as a cellular antennae. Primary cilia assembly begins intracellularly and eventually emerges extracellularly. However, current ciliogenesis assays, which detect cilia length and number, do not monitor ciliary stages. METHODS: We developed a new assay that detects antibody access to a fluorescently tagged ciliary transmembrane protein, which revealed three ciliary states: classified as 'inside,' 'outside,' or 'partial' cilia. RESULTS: Strikingly, most cilia in RPE cells only partially emerged and many others were long and intracellular, which would be indistinguishable by conventional assays. Importantly, these states switch with starvation-induced ciliogenesis and the cilia can emerge both on the dorsal and ventral surface of the cell. Our assay further allows new molecular and functional studies of the 'ciliary pocket,' a deep plasma membrane invagination whose function is unclear. Molecularly, we show colocalization of EHD1, Septin 9 and glutamylated tubulin with the ciliary pocket. CONCLUSIONS: Together, the IN/OUT assay is not only a new tool for easy and quantifiable visualization of different ciliary stages, but also allows molecular characterization of intermediate ciliary states. PMID- 27493726 TI - Use of near-infrared reflectance spectroscopy for the rapid determination of the digestible energy and metabolizable energy content of corn fed to growing pigs. AB - BACKGROUND: The ability of near-infrared reflectance spectroscopy (NIRS) to determine the digestible energy (DE) and metabolizable energy (ME) content of corn fed to growing pigs was tested. One hundred and seventeen corn samples, comprising different planting regions and varieties were collected from all over China in a three-year period. The samples were randomly split into a calibration set (n = 88) and a validation set (n = 29). The actual and calculated DE and ME content of the corn samples was determined by digestion-metabolism experiments and the prediction equations of Noblet and Perez (J Anim Sci. 71:3389-98,1993). The samples were then subjected to NIRS scanning and calibrations were performed by the modified partial least square (MPLS) regression method based on 77 different spectral pre-treatments. The NIRS equations based on the actually determined and calculated DE and ME were built separately and then validated using validation samples. RESULTS: The NIRS equations obtained from actually determined DE, the coefficient of determination for calibration (RSQcal), cross validation (R(2) CV), and validation (RSQv) were 0.89, 0.87 and 0.86, and these values for determined ME were 0.87, 0.86 and 0.86. For the NIRS equations built from calculated DE, the RSQcal, R(2) CV, and RSQv values were 0.88, 0.85 and 0.84, and these values for calculated ME were 0.86, 0.84 and 0.82. Except for the equation based on calculated ME (RPDv = 2.38, < 2.50), the other three equations built from actually determined energy and calculated DE produced good prediction performance (RPDv ranging from 2.53 to 2.69, > 2.50) when applied to validation samples. CONCLUSION: These results indicate that NIRS can be used as a quantitative method for the rapid determination of the available energy in corn fed to growing pigs, and the NIRS equations based on the actually determined energy produced better predictive performance than those built from calculated energy values. PMID- 27493727 TI - Malonate as a ROS product is associated with pyruvate carboxylase activity in acute myeloid leukaemia cells. AB - BACKGROUND: The role of anaplerotic nutrient entry into the Krebs cycle via pyruvate carboxylase has been the subject of increased scrutiny and in particular whether this is dysregulated in cancer. Here, we use a tracer-based NMR analysis involving high-resolution (1)H-(13)C-HSQC spectra to assess site-specific label incorporation into a range of metabolite pools, including malate, aspartate and glutamate in the acute myeloid leukaemia cell line K562. We also determine how this is affected following treatment with the redeployed drug combination of the lipid-regulating drug bezafibrate and medroxyprogesterone (BaP). RESULTS: Using the tracer-based approach, we assessed the contribution of pyruvate carboxylase (PC) vs. pyruvate dehydrogenase (PDH) activity in the derivation of Krebs cycle intermediates. Our data show that PC activity is indeed high in K562 cells. We also demonstrate a branched entry to the Krebs cycle of K562 cells with one branch running counterclockwise using PC-derived oxaloacetate and the other clockwise from the PDH activity. Finally, we show that the PC activity of K562 cells exclusively fuels the ROS-induced decarboxylation of oxaloacetate to malonate in response to BaP treatment; resulting in further Krebs cycle disruption via depletion of oxaloacetate and malonate-mediated inhibition of succinate dehydrogenase (SDH) resulting in a twofold reduction of fumarate. CONCLUSIONS: This study extends the interest in the PC activity in solid cancers to include leukaemias and further demonstrates the value of tracer-based NMR approaches in generating a more accurate picture of the flow of carbons and metabolites within the increasingly inappropriately named Krebs cycle. Moreover, our studies indicate that the PC activity in cancer cells can be exploited as an Achilles heel by using treatments, such as BaP, that elevate ROS production. PMID- 27493728 TI - Dial a Doctor: Improving lines of communication on the acute admissions unit. AB - The Royal London Hospital operates a system of 'specialty take triage', meaning that multiple teams provide patient care on the hospital's Acute Admission Unit (AAU). The aim of this project is to ensure the medical team for each patient can be promptly and easily contacted. An initial staff survey and engagement with key stakeholders assessed the baseline situation and guided a series of interventions, including the creation of ward whiteboards and funding for more portable phones. During further improvement cycles representatives from each profession were recruited to promote the new system, working groups held, and presentations made at staff meetings. The staff survey was repeated to gauge improvement. The initial survey of 33 staff revealed that there was no reliable system for ascertaining the specialty team to which a patient had been allocated or information on how to contact them. 39% of respondents reported experiencing a situation they felt was unsafe. Following the initial interventions, 25 staff responded to a second survey. 96% responded that the new system had made it easier to contact the correct medical team. The percentage of staff reporting difficulty knowing which medical team to contact most or everyday reduced from 66% to 32%. The percentage of those reporting difficulty contacting that team most or everyday reduced from 36% to 12%. There were 22 respondents to the survey following the second round of intervention. Less than 5% of staff reported difficulty most or everyday in both identifying the correct medical team and contacting them. There has been marked improvement in the ease of identifying and contacting the medical teams. This project is ongoing, recognising that further progress is required to ensure patient safety. PMID- 27493729 TI - Reducing mortality from hip fractures: a systematic quality improvement programme. AB - Hip fracture is one of the most serious consequences of falls in the elderly, with a mortality of 10% at one month and 30% at one year. Elderly patients with hip fractures have complex medical, surgical, and rehabilitation needs, and a well-coordinated multidisciplinary team approach is essential for the best outcome. The model of best practice for hip fracture care is set out in the Orthopaedic Blue Book and is incentivised by the best practice tariff. In 2009 to 2010, only 39.6% of our patients were being operated on within 36 hours, 19% achieved best practice tariff [1], and mortality was 7.8%. We were ranked as one of the worst hospitals to achieve best practice tariff [1] and our mortality was average. The orthogeriatrics team at Ashford & St Peter's NHS Trust (SPH) was implemented in 2010. Through a system redesign, regular governance meetings, audits and quality improvement projects, we have managed to improve care for our patients and reduce mortality. Over the last three years we have successfully achieved best care for our hip fracture patients, demonstrating a steady improvement in our attainment of the best practice tariff and a reduction in mortality to 5.3% in 2013, which ranks us amongst the best trusts nationally. PMID- 27493730 TI - Improving medical induction in obstetrics and gynaecology. AB - We present a year long quality improvement project to bring a new induction programme to the obstetrics and gynaecology (O&G) department of University Hospital Lewisham (UHL). Aimed at non-speciality junior doctors, including general practice and foundation trainees, the induction programme has sought to improve the quality of care delivered and experience of these transiting junior doctors. We have demonstrated a readily implementable and sustainable programme that requires only modest input of time from senior trainees (ST3+) periodically throughout the year. We have highlighted the specific need for senior consultant investment in the success and sustainability of such a project. We have demonstrated improvement of learning outcomes (p=0.01) in junior doctors undertaking the induction programme at Kirkpatrick's hierarchy level 2. PMID- 27493731 TI - Improving the quality of hospital discharge summaries utilising an electronic prompting system. AB - The discharge summary (DS) is a summary of an inpatient admission, patient's health state, and future treatment plans which is delivered to the patient's primary care provider. The DS is often incomplete, inaccurate, or unclear. The aim of this project was to improve the quality of the DS through the use of an electronic prompting system. The electronic prompting system was implemented in the acute medical and surgical wards of the hospital as an adjunct to a pre existing, widely used hospital program that documents all the patients in a ward or belonging to a particular treating team. When using the program, a doctor enters information (with the assistance of the treating consultant) from a drop down menu and is prompted to include common, departmental specific diagnoses, co morbidities, complications, and procedures that were commonly missed or documented incorrectly in the DS. Fifteen DSs were randomly selected from a two month period immediately prior to the intervention period and were rated by an external, experienced general practitioner (GP) using a scoring system consistent with the Australian Medical Association Guidelines for quality DSs. Fifteen random DSs from a two month period, four months post-implementation were also rated by the same GP. The quality of the DS improved in all categories evaluated. The overall quality improved from mean (+/- SD) 2.86 +/- 1.64 to 4.13 +/- 0.92 out of 5 (p = 0.031). Additionally the implementation of the system was associated with improvements in documentation of the diagnosis, co-morbidities and other relevant clinical information. In summary, electronic prompting systems can improve the quality of DSs to ensure the information contained within the DS is more accurate and complete. PMID- 27493732 TI - Recovery coaching in an acute older people rehabiliation ward. AB - Our patient, carer, and staff feedback clearly tells us that elderly patients are frequently disempowered by acute care provision, environments, and attitudes. This debilitates individuals mentally and physically, reducing their independent functioning, and may mean that they require prolonged care or are unfit to return home. We developed the concept of "recovery coaching" to support acute inpatient elderly care rehabilitation. We designed a training intervention to achieve "coaching conversations" between our staff and our patients. Data were collected from 46 participants; 22 in the pre-intervention stage and 24 in the post intervention stage. For the post-intervention patients, mean scores indicated that there was slightly higher increase in the patient's independence in terms of their Barthel (ADL) scores and that they reported higher feelings of self efficacy. For this patient group it was also found that more returned home with the same level of care as on their admission, and that fewer patients required residential care placements at discharge. This innovative intervention allowed us to challenge the fundamental basis of "I do it for you" to "I will do it with you", allowing the patient to become an integral partner in their health care. PMID- 27493733 TI - Developing a Platform for Learning from Mistakes: changing the culture of patient safety amongst junior doctors. AB - Junior doctors commonly make mistakes which may compromise patient safety. Despite the recent push by the NHS to encourage a "no blame" culture, mistakes are still viewed as shameful, embarrassing and demoralising events. The current model for learning from mistakes means that junior doctors only learn from their own errors. A survey was designed by the author for all the Foundation Year 1 doctors (FY1s) at Yeovil District Hospital to understand better the culture surrounding mistakes, and the types of mistakes that were being made. Using the results of the survey and the support of senior staff, a "Near misses" session has been introduced for FY1s once a month at which mistakes that have been made are discussed, with a consultant present to facilitate the proceedings. The aims of these sessions are to promote a culture of no blame, feedback information to clinical governance, and share learning experiences. 100% of the FY1s had made a mistake that could compromise patient safety. 63% discussed their mistakes with colleagues, 44% with seniors, and only 13% with their educational supervisor. Barriers to discussing mistakes included shame, embarrassment, fear of judgement, and unapproachable seniors. 94% thought a "Near misses" session would be useful. After the third session 100% of the FY1s agreed that the sessions were useful; 53% had changed their practice as a result of something they learned at the sessions. After discussing errors as a group we have worked with the clinical governance department, enacting strategies to avoid repetition of mistakes. Feedback from the junior doctors has been overwhelmingly positive and we have found these sessions to be a simple, inexpensive, and popular solution to cultural change in our organisation. PMID- 27493734 TI - Increasing uptake of bowel cancer screening. AB - Uptake of bowel cancer screening uptake at our practice is 32.72%, which is below the national target of 60%, but our cancer prevalence and death rate is higher than our CCG statistical mean. We examined reasons for non-response to bowel cancer screening in our patients and explored ways to promote engagement. From August 2013 to February 2014 we used three interventions in two patient groups: those turning 60 and eligible for screening (rising 60's) and non-responders to screening. Interventions used were; letter encouragement for rising 60's, staff education to increase opportunistic promotion of screening and calling non- responders to identify reasons for non-participation and encourage participation. Calls were made by either a Doctor or a Health Care Assistant (HCA); ethnicity, language spoken, caller and call outcome was recorded. Rising 60's (n=26) had an uptake of 46%, increased from 32.72%. From the non-responders (n = 73) we were unable to contact 38%, 46% was due to an incorrect or no phone number. Of those contacted main reasons for non-participation were not receiving a screening kit (n=19) and not wanting to be screened (n=14). Following calls 66% of non responders agreed to screening. From this 66% half (50%) completed screening with a negative result. 15 non-responders refused screening following our calls, the main reason given was not wanting to know if they had cancer (n =14). Calls from doctor and HCA had similar rates of screening uptake (39% and 33% respectively). Difficulty contacting patients was an unexpected barrier to screening and will be addressed. Actively encouraging screening appears beneficial with similar responses to Doctor and HCA. There appears to be a place for increased education regarding screening and early detection of malignancy amongst patients. Overall our interventions improved screening uptake at the practice and will be continued in future. PMID- 27493735 TI - Improving self-efficacy in spinal cord injury patients through "design thinking" rehabilitation workshops. AB - Advances in surgical and medical management have significantly reduced the length of time that patients with spinal cord injury (SCI) have to stay in hospital, but has left patients with potentially less time to psychologically adjust. Following a pilot in 2012, this project was designed to test the effect of "design thinking" workshops on the self-efficacy of people undergoing rehabilitation following spinal injuries. Design thinking is about understanding the approaches and methods that designers use and then applying these to think creatively about problems and suggest ways to solve them. In this instance, design thinking is not about designing new products (although the approaches can be used to do this) but about developing a long term creative and explorative mind-set through skills such as lateral thinking, prototyping and verbal and visual communication. The principles of "design thinking" have underpinned design education and practice for many years, it is also recognised in business and innovation for example, but a literature review indicated that there was no evidence of it being used in rehabilitation or spinal injury settings. Twenty participants took part in the study; 13 (65%) were male and the average age was 37 years (range 16 to 72). Statistically significant improvements were seen for EQ-5D score (t = -3.13, p = 0.007) and Patient Activation Measure score (t = -3.85, p = 0.001). Other outcome measures improved but not statistically. There were no statistical effects on length of stay or readmission rates, but qualitative interviews indicated improved patient experience. PMID- 27493736 TI - Improving pre-operative medicines reconciliation. AB - An audit of 143 surgical admissions showed that only 30% of general surgery and urology patients have complete medication charts on the day of surgery prior to going to theatre, compared to 94% of orthopaedic patients. This was despite having been seen previously in the pre-operative assessment clinic (POAC). These patients went to the wards post-operatively, where many then missed doses of their life-sustaining medications. Orthopaedic patients see a prescribing pharmacist in POAC who undertakes medicines reconciliation; this is performed by junior doctors for surgical patients. We designed three interventions to improve drug chart completion by junior doctors, and gathered prospective data for 22 weeks in the POAC. We also recorded attendance of junior doctors in the POAC and reasons for absence. Daily and weekly percentages of drug chart completion were plotted on a run chart. The baseline completion rate was 43%. This rose to 45% after the first and second interventions, and 51% after the third intervention. However, the completion rate remained markedly below our target of 94%. Junior doctors attended only 44% of POACs. They reported being "too busy to attend" 41% of the time, and could not be contacted on 11% of occasions. Junior doctors reported that they were unable to attend to both unwell inpatients and the POAC, the latter seeming less of a priority. This was despite a rota allocating doctors to attend POAC sessions free from clinical or teaching commitments. We were unable to increase the rate of drug chart completion with the resources available. We therefore recommend the employment of prescribing pharmacists in the POAC for general surgery and urology patients. PMID- 27493737 TI - Self-management of vaginal pessaries for pelvic organ prolapse. AB - Two thirds of women opt to use a vaginal pessary initially to manage the symptoms of pelvic organ prolapse. In the UK most women attend a health care professional at least every six months to change the pessary. This represents a significant burden both economically to the health care system and personally for the woman. Annually there are more than 300 appointments for pessary changes at our hospital. We developed a programme to teach women to self-manage their pessaries with the aim of improving patient experience and reducing outpatient attendances to free up outpatient capacity for new referrals. A physiotherapist was recuited to deliver this programme involving a one to one training session supplemented with written materials and an online video. Women using pessaries were offered the option of self-management. Eighty-eight women aged between 29 to 84 years enrolled in the programme. Sixty-three women (73% of those enrolled) successfully continued with self-management at six months, creating 126 extra outpatient appointment capacity in one year alone. Women self-managing reported higher levels of convenience (94% vs 81%), accessibility (97% vs 73%), support (100% vs. 83%), and comfort (86% vs. 53%) than those attending the hospital for GP practice for pessary change. Self-management appears to be an acceptable option for many women using vaginal pessaries, with personal benefits to the women and economic benefits to the hospital and commissioners. PMID- 27493738 TI - Working better together: joint leadership development for doctors and managers. AB - Traditionally, there have been tensions between frontline healthcare professionals and managers, with well-known stereotypes of difficult consultants and pen-pushing managers. Many junior doctors have limited management experience and have often never even met a manager prior to taking on a consultant role. Based on a successful programme pioneered by Dr Robert Klaber (Imperial, London) we have set-up an innovative scheme for Birmingham Children's Hospital, pairing junior doctors and managers to learn and work together. Our aim was to cultivate positive attitudes and understanding between the two groups, break down inter professional barriers, and to provide practical leadership experience and education. We recruited 60 managers and doctors to participate in shadowing, conversation, and quality improvement projects. Thought-provoking online materials, blogs, socials, and popular monthly workshops consisting of patient focused debate and discussion around key leadership themes, have helped to support learning and cement shared values. Formal evaluation has demonstrated an improvement in how participants perceive their knowledge and ability based on key NHS Leadership Framework competencies. Participant feedback has been extremely positive, and everyone plans to continue to incorporate Paired Learning into their continuing professional development. We are now embedding Paired Learning in the on-going educational programme offered at Birmingham Children's Hospital, whilst looking at extending the scheme to include different professional groups and other trusts across the region and nationally. PMID- 27493740 TI - Improving junior doctor handover between jobs. AB - Patient safety is one of the most important issues in healthcare. In recent years there has been much focus on "Black Wednesday"; the day that Foundation doctors start their first jobs. Great efforts have been made to ensure that patient safety on this day has improved, with the main example being that newly qualified doctors now use some of their free time between medical school and starting their first job to shadow their outgoing counterparts. However, because Foundation doctors start a brand new job approximately every four months for two years, subsequent job changeovers were identified as a time of potential problems and increased patient risk. It is not practical to shadow prior to every job because junior doctors are needed in their current post right up until changeover day, so a simple way to smooth this transition was needed. A handover lunch seemed to be a feasible solution. The day before Foundation doctors change jobs, an hour is dedicated for Foundation Year 1 doctors (F1's) to sit down together over lunch (provided by the mess) and take a formal handover of all relevant information about their forthcoming job and discuss current inpatients. Results showed that 100% of those surveyed mentioned face to face handover as essential, 93.75% said it was either helpful or extremely helpful to have a dedicated time for F1's to handover, and 12.5% said they would not have sought a face to face handover otherwise. Apart from being extremely simple and cheap, it was very popular with the F1's in the trust. It enables effective working from day one and is a great team building activity. PMID- 27493739 TI - Improving handover of patient care using a new weekend proforma with a focus on ceiling of care. AB - Patient handover is paramount for effective patient care and is often poorly documented or incomplete. North Bristol NHS Trust weekend handover proformas identify medical patients requiring weekend review. Many patients seen during on call shifts are not handed over. Our aim was to develop Friday ward round proforma sheets for medical patients, to encourage clear documentation of management plans in order to improve handover of important information, particularly ceiling of care decisions. Questionnaires were completed by F1 doctors regarding current handover systems. Baseline data collected by on-call F1s included time of understanding a patient's ceiling of care decision, and difficulty of comprehension of medical notes. Repeat data were collected with novel proformas in situ. Multiple cycles were performed to refine the sheets and target problems arising in their use. Ninety-three percent of F1s wanted improved patient handover, with ceiling of care (87%) and management plans (73%) being the most difficult areas to understand. Time taken to ascertain ceiling of care decisions improved with the introduction of Friday handover proformas; mean time 153 seconds before and 5 seconds after. Clarity and documentation of management plans improved, with 50% improvement in ease of understanding medical notes. Results demonstrate that introducing Friday ward round proformas for medical patients improves communication between weekday and on-call teams, highlights current escalation of care plans, and leads to faster decision-making. Future plans include the introduction of a short educational session to the new F1 doctors and continued progress with introduction into hospital stationary. PMID- 27493741 TI - Reducing non-attendance rates in a community mental health team. AB - The project aimed to improve productivity of psychiatric out patient clinic using quality improvement techniques through "Listening Into Action", a national programme designed to engage and support front-line clinicians to make improvements to patient care. We identified reasons as to why our patients missed appointments and then introduced a system to reduce "did not attend" (DNA) rates. Non-attendance at appointments results in a waste of resources and increases waiting times. It has been reported that DNA rates in mental health are higher compared to other settings. Therefore, reducing DNA rates are a priority for mental health care providers. We collected DNA rates over a period of months over May 2013 to September 2013. We conducted a patient survey to inquire why the patients missed their appointments. The aim of the project and results from the survey were presented and discussed at the multi-disciplinary team meeting to generate ideas for improvement and engage the team with the project. As the most frequent response from the survey was 'forgetting the appointment', we decided to introduce text messaging as an intervention to remind patients of their appointments. We also ensured that staff updated the mobile phone records for the patients at each appointment. We monitored the DNA rates after introducing this change on a monthly basis. Following our intervention, there was an overall reduction in DNA rates for all disciplines from 11.4% to 10.62% with the greatest change for medical DNA's from 17.7% to 11.8 %. Results from a patient survey showed that the reasons for non-attendance are multi-factorial and require a complex approach. Our intervention was a simple one but still it demonstrated some effectiveness. Reducing DNA rates requires interventions to be regularly monitored so that their effect is sustained over a period of time. PMID- 27493742 TI - Improving Mental Status Questionnaire (MSQ) completion on admission to the Acute Surgical Receiving Unit (ASRU), Ninewells Hospital, Dundee. AB - Delirium is common yet poorly identified in the UK. Early recognition is a key prognostic factor; delay here being associated with: increased mortality, increased morbidity, prolonged hospital stay, long term disability, and increased risk of developing dementia. Improvement in the diagnosis and management of delirium has scope to improve patient care, clinical outcomes, and ultimately an improved patient experience. As patients aged >=75 years are at an increased risk of developing delirium, we focused the improvement project to this age group. The baseline data demonstrated that the average >=75 year-old patient admitted to the Acute Surgical Receiving Unit (ASRU) at Ninewells Hospital had 5.4 out of 12 predisposing and precipitating risk factors for delirium; thus there was great potential for delirium to develop in these patients. During the analysis of the baseline data it became clear that we could not go ahead and implement the initial proposed improvement as the completion of the mental status questionnaire (MSQ) was inconsistent and low at 14.99%. Completion of the MSQ is vital in establishing any cognitive deficit at admission, and for providing a baseline for the continuing admission. As a consequence of this, we had to shift the main aim of the improvement project from improving the identification, diagnosis, and management of delirium, to improving the completion rate of the MSQ in our target age group. Consultations with members of the admission team were held to determine ways of improving the MSQ completion rate. It became clear that the completion of the MSQ relied on clinical staff remembering all 10 questions that constitute the test. The main intervention to facilitate improvement involved affixing a sticker with all 10 questions of the MSQ within the admissions document. The main aim was to increase the percentage of cognitive screening by the Mental State Questionnaire (MSQ) to 95% in patients aged >=75 on admission to ASRU at Ninewells Hospital by 11th July 2013. We achieved our main aim with 100% compliance on two days. Our average compliance over six days was however 81.33%, whilst not reaching our target this is still a substantial improvement. The introduction of the sticker detailing the 10 MSQ questions within the ASRU admissions document was well received by the admissions team. It has simplified the process as members of staff do not need to rely on their memory to remember the questions, and the sticker also acts as a prompt for them to consider further cognitive screening. PMID- 27493743 TI - Eliminating guidewire retention during ultrasound guided central venous catheter insertion via an educational program, a modified CVC set, and a drape with reminder stickers. AB - Guidewire retention is a severe but preventable complication from central venous catheter (CVC) insertion. There were three cases of guidewire retention during CVC insertion in the medical intensive care unit (MICU) in Singapore General Hospital, in the period between December 2011 and February 2012. The primary objective of this quality improvement project was to eliminate future incidences of guidewire retention during CVC insertion in the MICU and medical intermediate care area (MICA) via a structured educational program and a cost effective modified CVC set. The secondary objective was to perform a cost analysis and comparison between the use of the conventional hospital CVC set and drape with our newly modified CVC dressing kit. Root cause analysis of the three cases identified major factors leading to guidewire retention. Interventions were planned and tested using PDSA cycles. Internal medicine trainees rotating through MICU and MICA during the period between February 2012 and June 2013 underwent a multi-modal structured CVC insertion training program with hands on simulation. They also used a newly modified CVC dressing kit and drape. The CVC dressing kit was modified (CVC PLUS) to include a sterile drape with reminder stickers stating "REMOVE the GUIDEWIRE," as well as a sterile ultrasound sleeve. The total number of CVC insertions performed and guidewire retentions were monitored. During the period of study there were 320 CVC insertions in the MICU and MICA. Since this quality improvement project was initiated, and up to the submission of this article, there have not been any further cases of guidewire retention in the MICU and MICA. The total cost reduction per use of CVC PLUS was S$29.26 (Singaporean Dollars). A multi-modal structured training program, integrated with a modified, pre-packed CVC set, and drapes with reminder stickers (all included in CVC PLUS) were cost effective, and improved patient safety by eliminating guidewire retention during CVC insertion. PMID- 27493744 TI - The Participative Design of an Endoscopy Facility using Lean 3P. AB - In the UK, bowel cancer is the second largest cancer killer. Diagnosing people earlier can save lives but demand for endoscopies is increasing and this can put pressure on waiting times. To address this challenge, an endoscopy unit in North East England decided to improve their facilities to increase capacity and create environments that improve the experience of users. This presented a significant opportunity for step change improvement but also a problem in terms of creating designs that meet user requirements whilst addressing structural or space constraints. The Lean design process known as '3P' (standing for the production preparation process) was utilised as a participative design strategy to engage stakeholders in the design of the new department. This involved a time-out workshop (or 3P event) in which Lean and participative design tools were utilised to create an innovative design based on 'point of delivery' (POD) principles. The team created a design that demonstrated an increase in treatment room capacity by 25% and bed capacity by 70% whilst reducing travel distance for patients by 25.8% and staff by 27.1%. This was achieved with an increase in available space of only 13%. The Lean 3P method provided a structured approach for corporate and clinical staff to work together with patient representatives as cross-functional teams. This participative approach facilitated communication and learning between stakeholders about care processes and personal preferences. Lean 3P therefore appears to be a promising approach to improving the healthcare facilities design process to meet user requirements. PMID- 27493745 TI - Improving the safety and efficiency of outpatient lumbar puncture service. AB - Lumbar puncture (LP) is a commonly performed procedure in diagnosis and management of neurological conditions. LP is generally safe, however there are a number of potentially serious complications, including epidural haematoma and cerebral herniation. The risks of these should be considered and minimised prior to undertaking LP. Our regional neuroscience centre provides an outpatient LP service for patients throughout southeast England. Referrals from distant hospitals meant there was frequently no access to important clinical information, including indication for LP, past medical history, or medication history until the day of the procedure, and no access to results of investigations such as coagulation profile, platelet count, or intracranial imaging. Furthermore, there was limited capacity or time available in the day ward to perform these tests prior to LP. As a result, patients were either having LPs cancelled on the day of the procedure, were delayed by several hours on the day of the procedure for investigations, or were subject to the risk of having the LP performed without the knowledge of these key safety indicators. To address this issue we implemented an LP safety checklist to be completed by referring neurologists, providing details of the patient's medical history and results of investigations performed locally. In doing this, we increased the proportion of patients with an available platelet count prior to LP from 25% to 89%, and available coagulation profile from 18% to 82%. In addition, we saw a qualitative increase in the confidence of junior doctors in the safety of the LP clinic, as measured by a survey taken before and after the implementation of this system. This simple intervention made a rapid and remarkable difference to the safety and efficiency of this outpatient LP clinic. We would encourage other units to adopt this approach to address similar problems in a variety of outpatient settings. PMID- 27493746 TI - Improving Pre-emptive Prescribing to Relieve Patient Discomfort Occurring Out of Hours. AB - Junior doctors are commonly asked to prescribe simple medications for symptom relief for patients out of hours. Unfortunately, time constraints and other pressures may lead to delays before the medications are prescribed. A quality improvement project was conducted at a large university teaching hospital to establish the extent of the problem, with the aim of finding measures to improve preemptive prescribing for patients. Baseline data was gathered over three busy wards to calculate the total of new prescriptions made over the course of a weekend. There were 24 new prescriptions required over the weekend, a percentage increase of 14.9% compared to the existing prescriptions on a Friday. Following the first intervention this decreased to 10.2%, and by the second intervention the rate was 4.9%. Data collected several months later confirmed that the interventions remained successful, and preemptive prescribing continued. Overall, our interventions have shown that the number of new prescriptions required out of hours can be reduced by educating junior doctors on preemptive prescribing. PMID- 27493747 TI - Improving the Physical Health Monitoring of City & Hackney Assertive Outreach Service Patients. AB - Improving physical healthcare to reduce premature mortality in people with SMI (Serious Mental Illness) is a priority for ELFT (East London NHS Foundation Trust) and NHS England. It is well know that people with schizophrenia have a life expectancy which is approximately 20% shorter than that of the general population and a substantial mortality difference exists between people with schizophrenia and the general community.[1-2] Among other risk factors, such as poor diet, physical inactivity, and high rates of smoking, the iatrogenic effects of anti-psychotic medications have been found to increase the risk of metabolic syndrome. This can easily be detected through regular monitoring. Through this project, it was our aim to improve the physical health monitoring of City & Hackney Assertive Outreach Service (AOS) patients with a view to decrease mortality rate, increase life expectancy, increase the quality of life, and reduce harm from medication. This was done using quality improvement methods, including several change ideas, each of which started sequentially over the course of a nine month period from November 2014. Following QI methodology, this utilised cycles of iterative learning using PDSA methods and was supported by the Trust's extensive programme of quality improvement, including training provided by the Institute for Healthcare Improvement. The project involved setting a specific aim which was improving the physical health monitoring of AOS patients to 80% by July 2015 and for our patients to have physical health checks (blood tests, weight, ECG, BP) as a minimum annually. From baseline measurements of between 50-75%, we reached our target of 80% for weight, BP and blood tests monitoring, with 89%, 91%, and 84% achieved respectively by July 2015. Further progress still needs to be made on ECGs, with 77% achieved by July 2015, although the monitoring of ECG nearly doubled from 39% in November 2014 to 77% in July 2015. This project demonstrated that effective leadership, collaborative team work, embedding the project in our daily practice, generating local solutions, and improved communication between primary and secondary care can increase the physical health monitoring of this complex and challenging patient group. The team continues to identify other areas for change that may lead to further improvement in the physical health monitoring of AOS patients while making sure that the improvement is sustained. PMID- 27493748 TI - Red eyes and red-flags: improving ophthalmic assessment and referral in primary care. AB - Up to five percent of primary care consultations are eye-related, yet 96% of General Practitioners (GPs) do not undergo postgraduate ophthalmology training. Most do not feel assured performing eye assessments. Some red eye conditions can become sight threatening, and often exhibit red-flag features. These features include moderate pain, photophobia, reduced visual acuity (VA), eye-trauma, or unilateral marked redness. The aim of this project was to improve primary care assessment and referral of patients presenting with red-flag features based on the NICE 'Red Eye' Clinical Knowledge Summary recommendations. Data was collected retrospectively from 139 red eye consultations. A practice meeting highlighted poor awareness of red-flag features, low confidence levels in eye assessments, and time-constraints during appointments. Interventions were based on feedback from staff. These included a primary care teaching session on red-flag features, a VA measurement tutorial, and provision of a red eye toolkit, including VA equipment, to each consultation room. At baseline, each patient had on average 0.9 red-flag features assessed. Only 36.0% (9/25) of patients with red-flag features were appropriately referred to same-day ophthalmology services. Following two improvement cycles, a significant improvement was seen in almost every parameter. On average, each patient had 2.7 red-flag features assessed (vs 0.9, p<0.001). VA was assessed in 55.6% of consultations (vs 7.9%, p<0.001), pain was quantified in 81.5% (vs 20.9%, p=0.005), eye-trauma or foreign-body (51.8% vs 8.6%, p<0.001), extent of redness was documented in 66.7% (vs 14.4%, p<0.001). Only photophobia remained poorly assessed (18.5% vs 14.4%, p=0.75). Following this, 75.0% (6/8) of patients were appropriately referred. This project reflected the literature regarding low confidence and inexperience amongst GPs when faced with ophthalmic conditions. Improvements in education are required to ensure accurate assessments can be undertaken in a time-constrained environment. PMID- 27493749 TI - Reducing CBC Clotting Rates in the Neonatal Patient Care Areas. AB - Performing a complete blood count (CBC) is a common test performed in neonatal intensive care. Samples reported as "clotted" are not able to be analyzed and require redraw. A perceived "high" clotting rate elicits frustration among team members and has negative effects on patient flow and patient satisfaction. Process mapping and a root cause analysis determined that an educational intervention was required to optimize blood collection skills of front-line nurses. Through four rapid PDSA cycles over a three year period, the neonatal patient care areas were able to decrease their CBC clotting rates from 30% (monthly rate when the problem was identified) to 16% (yearly average at the end of the project). The CBC clotting rates continue to decease over time due to the integration of a multi-faceted educational plan into biannual education days designed for current staff nurses, as well as into the orientation plan for newly hired and student nurses. PMID- 27493750 TI - Developing psychological services following facial trauma. AB - Adults presenting to oral and maxillofacial surgery services are at high risk of psychological morbidity. Research by the Institute of Psychotrauma and the centre for oral and maxillofacial surgery trauma clinic at the Royal London hospital (2015) demonstrated nearly 40% of patients met diagnostic criteria for either depression, post traumatic stress disorder (PTSD), anxiety, alcohol misuse, or substance misuse, or were presenting with facial appearance distress. Most facial injury patients were not receiving mental health assessment or treatment, and the maxillofacial team did not have direct access to psychological services. Based on these research findings, an innovative one-year pilot psychology service was designed and implemented within the facial trauma clinic. The project addressed this need by offering collaborative medical and psychological care for all facial injury patients. The project provided brief screening, assessment, and early psychological intervention. The medical team were trained to better recognise and respond to psychological distress. PMID- 27493751 TI - Improving the communication between teams managing boarded patients on a surgical specialty ward. AB - Transferring patients from the ward of their specialty or consultant is described as boarding. 1 Boarding patients is becoming increasingly prevalent due to greater pressure on hospital capacity. This practice compromises patient safety through delayed investigations, prolonged hospital stays, and increased risk of hospital-acquired infections. 1 2 We evaluated how regularly boarded patients were reviewed, and how effectively information regarding their management was communicated from their primary specialty to ward staff. We aimed to improve the frequency of patient reviews by ensuring that each patient was reviewed every weekday and increase communication between primary specialty, and medical and nursing teams by 20% from baseline during the data collection period. The project was based in the Otolaryngology ward in Ninewells Hospital, Dundee, where there was a high prevalence of boarded patients. Baseline data showed a clear deficit in communication between the primary specialty and ward staff with only 31% of patient reviews being communicated to ward doctors. We designed and implemented a communication tool, in the form of a sticker, to be inserted into patients' medical notes for use by the primary specialty. Implementation of the sticker improved communication between teams as stickers were completed in 93% of instances. In 88% of patient reviews, the junior doctor was informed of the management plan, showing a large increase from baseline. Through PDSA cycles, we aimed to increase the sustainability and reliability of the sticker; however, we faced challenges with sustainability of sticker insertion. We aim to engage more stakeholders to raise awareness of the problem, brainstorm solutions together, and review the production and implementation of stickers with senior hospital management to discuss the potential use of this tool within practice. There is potentially a large scope for utilisation of this communication tool on a local level, which we hope will significantly improve patient safety. PMID- 27493752 TI - Promoting the role of patients in improving hand hygiene compliance amongst health care workers. AB - Hand hygiene is one of the fundamental measures necessary for reducing healthcare associated infections. The adherence of health care workers to safe hand hygiene practices is low worldwide, despite evidence showing compliance with hand hygiene guidelines decreases infection rate. This project focuses on the role of patients in promoting healthcare workers' compliance with hand hygiene practices. Several plan-do-study-act (PDSA) cycles were conducted to test interventions which aimed to empower patients and increase staff members' adherence to hand hygiene practices. The initial findings presented on the run chart demonstrate that compliance among healthcare workers increased with the interventions; there was an increase of 15% compliance during the 10 days of project testing. We will need to collect more data to show continued and sustained improvement. Patients can play an important role in promoting safe care and hand hygiene practices. PMID- 27493753 TI - Utilizing clinical pharmacists to improve delivery of evidence-based care for depression and anxiety in primary care. AB - Access to mental health providers has become an increasingly common challenge for many patients with depression and anxiety disorders. Primary care providers often manage this gap in care and currently provide solo care without the assistance of other team members. In order to provide quality care that aligns with best practice, we developed a depression and anxiety disorder treatment pathway utilizing a multidisciplinary team based on each members' individual skill set, or skill-task alignment. The main change to treatment implemented by the pathway was the addition of a clinical pharmacist in the management of patient care. This pathway was trialed over five months targeting two adult primary care teams (approximately 34 physicians and Advanced Registered Nurse Practitioners [ARNPs]) while the other five teams continued with current practice standards. Post implementation metrics indicated that clinical pharmacists successfully contacted 55% (406 of 738) of patients started on medication or who had a medication changed. Of these patients reached, 82 (20%) had an intervention completed. In addition, all physician leaders on the planning team (n=6) stated the new pathway was well received and delivered positive feedback from team members. PMID- 27493754 TI - Preliminary study of novel, timed walking tests for children with spina bifida or cerebral palsy. AB - OBJECTIVE: Walking assessment is an important aspect of rehabilitation practice; yet, clinicians have few psychometrically sound options for evaluating walking in highly ambulatory children. The purpose of this study was to evaluate the validity and reliability of two new measures of walking function-the Obstacles and Curb tests-relative to the 10-Meter Walk test and Timed Up and Go test in children with spina bifida or cerebral palsy. METHODS: A total of 16 ambulatory children with spina bifida (n=9) or cerebral palsy (n=7) (9 boys; mean age 7years, 7months; standard deviation 3years, 4months) and 16 age- and gender matched typically developing children participated. Children completed the walking tests, at both self-selected and fast speeds, twice. To evaluate discriminative validity, scores were compared between typically developing and spina bifida/cerebral palsy groups. Within the spina bifida/cerebral palsy group, inter-test correlations evaluated convergent validity and intraclass correlation coefficients evaluated within-session test-retest reliability. RESULTS: At fast speeds, all tests showed discriminative validity (p<0.006 for typically developing and spina bifida/cerebral palsy comparisons) and convergent validity (rho=0.81-0.90, p?0.001, for inter-test correlations). At self-selected speeds, only the Obstacles test discriminated between groups (p=0.001). Moderately strong correlations (rho=0.73-0.78, p?0.001) were seen between the 10-Meter Walk test, Curb test, and Timed Up and Go test. Intraclass correlation coefficients ranged from 0.81 to 0.97, with higher test-retest reliability for tests performed at fast speeds rather than self-selected speeds. CONCLUSION: The Obstacles and Curb tests are promising measures for assessing walking in this population. Performing tests at fast walking speeds may improve their validity and test-retest reliability for children with spina bifida/cerebral palsy. PMID- 27493755 TI - Non-invasive assessment of peripheral arterial disease: Automated ankle brachial index measurement and pulse volume analysis compared to duplex scan. AB - OBJECTIVES: This cross-sectional study aimed to individually and cumulatively compare sensitivity and specificity of the (1) ankle brachial index and (2) pulse volume waveform analysis recorded by the same automated device, with the presence or absence of peripheral arterial disease being verified by ultrasound duplex scan. METHODS: Patients (n=205) referred for lower limb arterial assessment underwent ankle brachial index measurement and pulse volume waveform recording using volume plethysmography, followed by ultrasound duplex scan. The presence of peripheral arterial disease was recorded if ankle brachial index <0.9; pulse volume waveform was graded as 2, 3 or 4; or if haemodynamically significant stenosis >50% was evident with ultrasound duplex scan. Outcome measure was agreement between the measured ankle brachial index and interpretation of pulse volume waveform for peripheral arterial disease diagnosis, using ultrasound duplex scan as the reference standard. RESULTS: Sensitivity of ankle brachial index was 79%, specificity 91% and overall accuracy 88%. Pulse volume waveform sensitivity was 97%, specificity 81% and overall accuracy 85%. The combined sensitivity of ankle brachial index and pulse volume waveform was 100%, specificity 76% and overall accuracy 85%. CONCLUSION: Combining these two diagnostic modalities within one device provided a highly accurate method of ruling out peripheral arterial disease, which could be utilised in primary care to safely reduce unnecessary secondary care referrals. PMID- 27493756 TI - Implementation and evaluation of Stanford Health Care direct-care teledermatology program. AB - INTRODUCTION: Teledermatology has proven to be an effective means of providing dermatologic care. The existing research has primarily evaluated its usefulness in a consultative model. Few academic centers have evaluated a patient-initiated model, and direct-to-consumer services remain the subject of controversy. Stanford Health Care recently launched a direct-care, patient-initiated teledermatology pilot program. This article evaluates the viability and patient satisfaction with this service. MATERIALS AND METHODS: During the pilot period, patients were able to seek remote dermatologic care using an eVisit tool in their MyHealth account. Patients initiated the consultation, answered questions regarding their complaint, and uploaded a picture if relevant. A Stanford dermatologist reviewed each eVisit and responded with an assessment and plan. The dermatologist noted whether they were able to make a diagnosis and their level of confidence in it. After the study, 10 patients participated in a focus group to provide feedback on the service. RESULTS: In all, 38 patients sought care during the pilot period. A dermatologist was able to make a diagnosis in 36 of 38 (95%) cases, with an average confidence level of 7.9 of 10. The average time to consultation was 0.8 days. Patients indicated high levels of satisfaction with the service although they had suggestions for improvement. DISCUSSION: Patients provided clinically useful images and information in a direct-care teledermatology model. Such services allow dermatology providers to increase access while maintaining high-quality care in an academic medical center. Further research is needed on standalone services that cannot integrate encounters with the patient's existing medical record. PMID- 27493757 TI - A randomized controlled trial studying the effectiveness of group medical appointments on self-efficacy and adherence in sickle cell disease (TEAM study): study protocol. AB - BACKGROUND: Sickle cell disease (SCD) is endemic in non-Western countries. Due to migration, the prevalence of SCD in the Netherlands has increased. Adherence to medical treatment is recognized as a major problem area. Therefore, new effective interventions to increase adherence are urgently needed. METHODS/DESIGN: The TEAM study is an ongoing randomized controlled trial (RCT) to compare protocolized individual medical appointments (IMA's; care-as-usual) with protocolized group medical appointments (GMA's; novel intervention) in pediatric (n = 40) and adult (n = 60) patients. The study aims to assess the effectiveness of GMA's (over a three year period) on patients' self-efficacy, adherence, quality of life, morbidity, hospital admissions and satisfaction with the treating professional; as well as to test the cost-effectiveness of GMA's. In both the IMA and GMA groups structured assessments will be performed at baseline (start of the study), after 1.5 and after 3 years. DISCUSSION: This is the first RCT to investigate the effectiveness of GMA's on self-efficacy and adherence in pediatric and adult patients with SCD, including a cost-effectiveness analysis. TRIAL REGISTRATION: NTR4750 (NL42182.000.12). Registered 13 August 2014. PMID- 27493758 TI - "Lachnoclostridium bouchesdurhonense," a new bacterial species isolated from human gut microbiota. AB - We report the main characteristics of "Lachnoclostridium bouchesdurhonense" strain AT5(T) (=CSUR P2181), a new bacterial species isolated from the gut microbiota of an obese patient from Marseille. PMID- 27493759 TI - Cardiovascular disease risk factors in relation to smoking behaviour and history: a population-based cohort study. AB - OBJECTIVE: To investigate how individual risk factors for cardiovascular disease (CVD) (blood pressure, lipid levels, body mass index, waist and hip circumference, use of antihypertensive or hypolipidemic medication, and diagnosed diabetes) differ in people aged 46 years with different smoking behaviour and history. METHODS: This population-based cohort study is based on longitudinal data from the Northern Finland Birth Cohort 1966 project. Data were collected at the 31-year and 46-year follow-ups, when a total of 5038 and 5974 individuals participated in clinical examinations and questionnaires. Data from both follow ups were available for 3548 participants. In addition to individual CVD risk factors, Framingham and Systematic Coronary Risk Evaluation (SCORE) algorithms were used to assess the absolute risk of a CVD event within the next decade. RESULTS: The differences in individual risk factors for CVD reached statistical significance for some groups, but the differences were not consistent or clinically significant. There were no clinically significant differences in CVD risk as measured by Framingham or SCORE algorithms between never smokers, recent quitters and former smokers (7.5%, 7.4%, 8.1% for men; 3.3%, 3.0%, 3.2% for women; p<0.001). CONCLUSIONS: The effect of past or present smoking on individual CVD risk parameters such as blood pressure and cholesterol seems to be of clinically minor significance in people aged 46 years. In other words, smoking seems to be above all an independent risk factor for CVD in the working-age population. Quitting smoking in working age may thus reduce calculated CVD risk nearly to the same level with people who have never smoked. PMID- 27493760 TI - Sudden cardiac death in adults with congenitally corrected transposition of the great arteries. AB - BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) is a rare congenital heart disease. There have been only few reports of sudden cardiac death (SCD) in patients with ccTGA and reasonable ventricular function. METHODS: A retrospective review of the medical records of all patients attending our adult congenital heart centre, with known ccTGA. RESULTS: From a database of over 3500 adult patients with congenital heart disease, we identified 39 (~1%) with ccTGA and 'two-ventricle' circulations. 65% were male. The mean age at diagnosis was 12.4+/-11.4 years and the mean age at last time of review was 34.3+/-11.3 years. 24 patients (56%) had a history of surgical intervention. 8 (19%) had had pacemaker implantation and 2 had had a defibrillator implanted for non-sustained ventricular tachycardia (NSVT). In 544 years of patient follow-up, there had been five cases of SCD in our population; 1 death per 109 patient years. Two of these patients had had previously documented supraventricular or NSVT. However, they were all classified as New York Heart Association (NYHA) class I or II, and systemic (right) ventricular function had been recorded as normal, mildly or mildly-moderately impaired, at most recent follow-up. CONCLUSIONS: Our experience suggests the need for improved risk stratification and/or surveillance for malignant arrhythmia in adults with ccTGA, even in those with reasonable functional class on ventricular function. PMID- 27493761 TI - Coronary sinus-based percutaneous annuloplasty as treatment for functional mitral regurgitation: the TITAN II trial. AB - OBJECTIVE: Functional (or secondary) mitral regurgitation (FMR) is associated with greater morbidity and worse outcomes in patients with congestive heart failure (CHF) and cardiomyopathy. The Carillon(r) Mitral Contour System(r) is a coronary sinus-based percutaneous therapy to reduce FMR. We evaluated the safety and efficacy of a modified version of the Carillon device in the treatment of patients with cardiomyopathy and FMR. METHODS: 36 patients with CHF, depressed left ventricular function (ejection fraction <40%) and at least moderate FMR underwent the Carillon device implant. RESULTS: There was 1 major adverse event within 30 days-a death (not device related)-occurring 17 days after the implant. Reductions in FMR and improvements in functional class and 6 min walk tests were seen, similar to prior studies. Device fractures in the high strain region of the proximal anchor (seen in prior studies) were not seen in this study. CONCLUSIONS: The modified Carillon device was associated with improvements in clinical and echocardiographic parameters in treating patients with FMR, while successfully addressing the issue of anchor fracture. This version of the Carillon device will be used in a blinded randomised trial of symptomatic patients with FMR. PMID- 27493762 TI - Circulating miRNA in patients with non-alcoholic fatty liver disease and coronary artery disease. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and coronary artery disease (CAD) is the cardiac manifestation of metabolic syndrome. NAFLD is strongly linked to CAD and hepatic steatosis is an independent risk factor for CAD and cardiac mortality. The pathogenic mechanism underlying this association remains poorly understood. In this study, we explored expression of circulating microRNAs (miRNAs) in patients with NAFLD and associated CAD. RESULTS: When compared to patients with NAFLD without CAD, patients with NAFLD and CAD had lower circulating levels of miR-132 (0.24+/-0.16 vs 0.30+/-0.11, p=0.03), while the circulating levels of miR 143 were higher (0.96+/-0.90 vs 0.64+/-0.77, p=0.02). The levels in circulation demonstrated trends opposite to previously observed intracellular levels in patients with CAD. In obese patients with NAFLD, lower circulating levels of miR 145 (1.42+/-1.00 vs 2.41+/-1.80), miR-211 (41.26+/-20.40 vs 57.56+/-25.45), miR 146a (2.13+/-1.40 vs 2.90+/-1.36) and miR-30c (6.92+/-4.99 vs 11.0+/-6.92) were detected when compared to lean patients with NAFLD. For miR-161 (0.59+/-1.19 vs 0.15+/-0.14) and miR-241 (0.28+/-0.29 vs 0.16+/-0.13), higher circulatory levels were detected in the obese patients with NAFLD. These observations suggest altered circulating levels of miRNAs that may serve to balance intracellular levels of miRNA in target tissues. Additional studies examining paired samples of target and producing tissues as well as respective plasma samples will help delineate the regulatory circuits governing the secretion and the uptake of miRNA in multitissue diseases. PMID- 27493763 TI - Sex differences in disease presentation, treatment and clinical outcomes of patients with hepatocellular carcinoma: a single-centre cohort study. AB - BACKGROUND: Although sex differences in hepatocellular carcinoma (HCC) risk are well known, it is unclear whether sex differences also exist in clinical presentation and survival outcomes once HCC develops. METHODS: We performed a retrospective cohort study of 1886 HCC patients seen in a US medical centre in 1998-2015. Data were obtained by chart review with survival data also by National Death Index search. RESULTS: The cohort consisted of 1449 male and 437 female patients. At diagnosis, men were significantly younger than women (59.9+/-10.7 vs 64.0+/-11.6, p<0.0001). Men had significantly higher rates of tobacco (57.7% vs 31.0%, p<0.001) and alcohol use (63.2% vs 35.1%, p<0.001). Women were more likely to be diagnosed by routine screening versus symptomatically or incidentally (65.5% vs 58.2%, p=0.03) and less likely to present with tumours >5 cm (30.2% vs 39.8%, p=0.001). Surgical and non-surgical treatment utilisation was similar for both sexes. Men and women had no significant difference in median survival from the time of diagnosis (median 30.7 (range=24.5-41.3) vs 33.1 (range=27.4-37.3) months, p=0.84). On multivariate analysis, significant predictors for improved survival included younger age, surgical or non-surgical treatment (vs supportive care), diagnosis by screening, tumour within Milan criteria and lower Model for End-Stage Liver Disease score, but not female sex (adjusted HR=1.01, CI 0.82 to 1.24, p=0.94). CONCLUSIONS: Although men have much higher risk for HCC development, there were no significant sex differences in disease presentation or survival except for older age and lower tumour burden at diagnosis in women. Female sex was not an independent predictor for survival. PMID- 27493764 TI - Is this scaling nonlinear? AB - One of the most celebrated findings in complex systems in the last decade is that different indexes y (e.g. patents) scale nonlinearly with the population x of the cities in which they appear, i.e. y~x (beta) ,beta?1. More recently, the generality of this finding has been questioned in studies that used new databases and different definitions of city boundaries. In this paper, we investigate the existence of nonlinear scaling, using a probabilistic framework in which fluctuations are accounted for explicitly. In particular, we show that this allows not only to (i) estimate beta and confidence intervals, but also to (ii) quantify the evidence in favour of beta?1 and (iii) test the hypothesis that the observations are compatible with the nonlinear scaling. We employ this framework to compare five different models to 15 different datasets and we find that the answers to points (i)-(iii) crucially depend on the fluctuations contained in the data, on how they are modelled, and on the fact that the city sizes are heavy tailed distributed. PMID- 27493765 TI - State-space reduction and equivalence class sampling for a molecular self assembly model. AB - Direct simulation of a model with a large state space will generate enormous volumes of data, much of which is not relevant to the questions under study. In this paper, we consider a molecular self-assembly model as a typical example of a large state-space model, and present a method for selectively retrieving 'target information' from this model. This method partitions the state space into equivalence classes, as identified by an appropriate equivalence relation. The set of equivalence classes H, which serves as a reduced state space, contains none of the superfluous information of the original model. After construction and characterization of a Markov chain with state space H, the target information is efficiently retrieved via Markov chain Monte Carlo sampling. This approach represents a new breed of simulation techniques which are highly optimized for studying molecular self-assembly and, moreover, serves as a valuable guideline for analysis of other large state-space models. PMID- 27493766 TI - New information on the braincase and inner ear of Euparkeria capensis Broom: implications for diapsid and archosaur evolution. AB - Since its discovery, Euparkeria capensis has been a key taxon for understanding the early evolution of archosaurs. The braincase of Euparkeria was described based on a single specimen, but much uncertainty remained. For the first time, all available braincase material of Euparkeria is re-examined using micro computed tomography scanning. Contrary to previous work, the parabasisphenoid does not form the posterior border of the fenestra ovalis in lateral view, but it does bear a dorsal projection that forms the anteroventral half of the fenestra. No bone pneumatization was found, but the lateral depression of the parabasisphenoid may have been pneumatic. We propose that the lateral depression likely corresponds to the anterior tympanic recess present in crown archosaurs. The presence of a laterosphenoid is confirmed for Euparkeria. It largely conforms to the crocodilian condition, but shows some features which make it more similar to the avemetatarsalian laterosphenoid. The cochlea of Euparkeria is elongated, forming a deep cochlear recess. In comparison with other basal archosauromorphs, the metotic foramen is much enlarged and regionalized into vagus and recessus scalae tympani areas, indicating an increase in its pressure-relief mechanism. The anterior semicircular canal is extended and corresponds to an enlarged floccular fossa. These aspects of the braincase morphology may be related to the development of a more upright posture and active lifestyle. They also indicate further adaptations of the hearing system of Euparkeria to terrestriality. PMID- 27493768 TI - Cold-stress responses in the Antarctic basidiomycetous yeast Mrakia blollopis. AB - Microbes growing at subzero temperatures encounter numerous growth constraints. However, fungi that inhabit cold environments can grow and decompose organic compounds under subzero temperatures. Thus, understanding the cold-adaptation strategies of fungi under extreme environments is critical for elucidating polar region ecosystems. Here, I report that two strains of the Antarctic basidiomycetous yeast Mrakia blollopis exhibited distinct growth characteristics under subzero conditions: SK-4 grew efficiently, whereas TKG1-2 did not. I analysed the metabolite responses elicited by cold stress in these two M. blollopis strains by using capillary electrophoresis-time-of-flight mass spectrometry. M. blollopis SK-4, which grew well under subzero temperatures, accumulated high levels of TCA-cycle metabolites, lactic acid, aromatic amino acids and polyamines in response to cold shock. Polyamines are recognized to function in cell-growth and developmental processes, and aromatic amino acids are also known to improve cell growth at low temperatures. By contrast, in TKG1-2, which did not grow efficiently, cold stress strongly induced the metabolites of the TCA cycle, but other metabolites were not highly accumulated in the cell. Thus, these differences in metabolite responses could contribute to the distinct abilities of SK-4 and TKG1-2 cells to grow under subzero temperature conditions. PMID- 27493767 TI - Pupil dilation as an index of preferred mutual gaze duration. AB - Most animals look at each other to signal threat or interest. In humans, this social interaction is usually punctuated with brief periods of mutual eye contact. Deviations from this pattern of gazing behaviour generally make us feel uncomfortable and are a defining characteristic of clinical conditions such as autism or schizophrenia, yet it is unclear what constitutes normal eye contact. Here, we measured, across a wide range of ages, cultures and personality types, the period of direct gaze that feels comfortable and examined whether autonomic factors linked to arousal were indicative of people's preferred amount of eye contact. Surprisingly, we find that preferred period of gaze duration is not dependent on fundamental characteristics such as gender, personality traits or attractiveness. However, we do find that subtle pupillary changes, indicative of physiological arousal, correlate with the amount of eye contact people find comfortable. Specifically, people preferring longer durations of eye contact display faster increases in pupil size when viewing another person than those preferring shorter durations. These results reveal that a person's preferred duration of eye contact is signalled by physiological indices (pupil dilation) beyond volitional control that may play a modulatory role in gaze behaviour. PMID- 27493769 TI - Optimal switching between geocentric and egocentric strategies in navigation. AB - Animals use a combination of egocentric navigation driven by the internal integration of environmental cues, interspersed with geocentric course correction and reorientation. These processes are accompanied by uncertainty in sensory acquisition of information, planning and execution. Inspired by observations of dung beetle navigational strategies that show switching between geocentric and egocentric strategies, we consider the question of optimal reorientation rates for the navigation of an agent moving along a preferred direction in the presence of multiple sources of noise. We address this using a model that takes the form of a correlated random walk at short time scales that is punctuated by reorientation events leading to a biased random walks at long time scales. This allows us to identify optimal alternation schemes and characterize their robustness in the context of noisy sensory acquisition as well as performance errors linked with variations in environmental conditions and agent-environment interactions. PMID- 27493770 TI - Camp stability predicts patterns of hunter-gatherer cooperation. AB - Humans regularly cooperate with non-kin, which has been theorized to require reciprocity between repeatedly interacting and trusting individuals. However, the role of repeated interactions has not previously been demonstrated in explaining real-world patterns of hunter-gatherer cooperation. Here we explore cooperation among the Agta, a population of Filipino hunter-gatherers, using data from both actual resource transfers and two experimental games across multiple camps. Patterns of cooperation vary greatly between camps and depend on socio-ecological context. Stable camps (with fewer changes in membership over time) were associated with greater reciprocal sharing, indicating that an increased likelihood of future interactions facilitates reciprocity. This is the first study reporting an association between reciprocal cooperation and hunter-gatherer band stability. Under conditions of low camp stability individuals still acquire resources from others, but do so via demand sharing (taking from others), rather than based on reciprocal considerations. Hunter-gatherer cooperation may either be characterized as reciprocity or demand sharing depending on socio-ecological conditions. PMID- 27493771 TI - Mating success and body condition not related to foraging specializations in male fur seals. AB - Individual specialization is widespread among wild populations. While its fitness consequences are central in predicting the ecological and evolutionary trajectories of populations, they remain poorly understood. Long-term individual foraging specializations occur in male Antarctic (Arctocephalus gazella) and Australian (A. pusillus doriferus) fur seals. Strong selective pressure is expected in these highly dimorphic and polygynous species, raising the question of the fitness payoffs associated with different foraging strategies. We investigated the relationship between individual isotopic niche (a proxy of foraging specialization), body size and condition, and an index of reproductive success (harem size) in territorial males. Individuals varied greatly in their skin and fur isotopic values reflecting a range of foraging strategies within the two populations. However, in both species, isotopic niche was not correlated to body size, condition or mating success (R (2)/rho < 0.06). Furthermore, no foraging niche was predominant in either species, which would have indicated a substantial long-term fitness benefit of a particular strategy via a higher survival rate. These results suggest that the fitness consequences of a foraging strategy depend not only on the quality of prey and feeding habitat but also on an individual's hunting efficiency and skills. PMID- 27493772 TI - Does density influence relative growth performance of farm, wild and F1 hybrid Atlantic salmon in semi-natural and hatchery common garden conditions? AB - The conditions encountered by Atlantic salmon, Salmo salar L., in aquaculture are markedly different from the natural environment. Typically, farmed salmon experience much higher densities than wild individuals, and may therefore have adapted to living in high densities. Previous studies have demonstrated that farmed salmon typically outgrow wild salmon by large ratios in the hatchery, but these differences are much less pronounced in the wild. Such divergence in growth may be explained partly by the offspring of wild salmon experiencing higher stress and thus lower growth when compared under high-density farming conditions. Here, growth of farmed, wild and F1 hybrid salmon was studied at contrasting densities within a hatchery and semi-natural environment. Farmed salmon significantly outgrew hybrid and wild salmon in all treatments. Importantly, however, the reaction norms were similar across treatments for all groups. Thus, this study was unable to find evidence that the offspring of farmed salmon have adapted more readily to higher fish densities than wild salmon as a result of domestication. It is suggested that the substantially higher growth rate of farmed salmon observed in the hatchery compared with wild individuals may not solely be caused by differences in their ability to grow in high-density hatchery scenarios. PMID- 27493773 TI - User-based representation of time-resolved multimodal public transportation networks. AB - Multimodal transportation systems, with several coexisting services like bus, tram and metro, can be represented as time-resolved multilayer networks where the different transportation modes connecting the same set of nodes are associated with distinct network layers. Their quantitative description became possible recently due to openly accessible datasets describing the geo-localized transportation dynamics of large urban areas. Advancements call for novel analytics, which combines earlier established methods and exploits the inherent complexity of the data. Here, we provide a novel user-based representation of public transportation systems, which combines representations, accounting for the presence of multiple lines and reducing the effect of spatial embeddedness, while considering the total travel time, its variability across the schedule, and taking into account the number of transfers necessary. After the adjustment of earlier techniques to the novel representation framework, we analyse the public transportation systems of several French municipal areas and identify hidden patterns of privileged connections. Furthermore, we study their efficiency as compared to the commuting flow. The proposed representation could help to enhance resilience of local transportation systems to provide better design policies for future developments. PMID- 27493774 TI - Active and reactive behaviour in human mobility: the influence of attraction points on pedestrians. AB - Human mobility is becoming an accessible field of study, thanks to the progress and availability of tracking technologies as a common feature of smart phones. We describe an example of a scalable experiment exploiting these circumstances at a public, outdoor fair in Barcelona (Spain). Participants were tracked while wandering through an open space with activity stands attracting their attention. We develop a general modelling framework based on Langevin dynamics, which allows us to test the influence of two distinct types of ingredients on mobility: reactive or context-dependent factors, modelled by means of a force field generated by attraction points in a given spatial configuration and active or inherent factors, modelled from intrinsic movement patterns of the subjects. The additive and constructive framework model accounts for some observed features. Starting with the simplest model (purely random walkers) as a reference, we progressively introduce different ingredients such as persistence, memory and perceptual landscape, aiming to untangle active and reactive contributions and quantify their respective relevance. The proposed approach may help in anticipating the spatial distribution of citizens in alternative scenarios and in improving the design of public events based on a facts-based approach. PMID- 27493775 TI - Contrast, contours and the confusion effect in dazzle camouflage. AB - 'Motion dazzle camouflage' is the name for the putative effects of highly conspicuous, often repetitive or complex, patterns on parameters important in prey capture, such as the perception of speed, direction and identity. Research into motion dazzle camouflage is increasing our understanding of the interactions between visual tracking, the confusion effect and defensive coloration. However, there is a paucity of research into the effects of contrast on motion dazzle camouflage: is maximal contrast a prerequisite for effectiveness? If not, this has important implications for our recognition of the phenotype and understanding of the function and mechanisms of potential motion dazzle camouflage patterns. Here we tested human participants' ability to track one moving target among many identical distractors with surface patterns designed to test the influence of these factors. In line with previous evidence, we found that targets with stripes parallel to the object direction of motion were hardest to track. However, reduction in contrast did not significantly influence this result. This finding may bring into question the utility of current definitions of motion dazzle camouflage, and means that some animal patterns, such as aposematic or mimetic stripes, may have previously unrecognized multiple functions. PMID- 27493776 TI - Gestational experience alters sex allocation in the subsequent generation. AB - Empirical tests of adaptive maternal sex allocation hypotheses have presented inconsistent results in mammals. The possibility that mothers are constrained in their ability to adjust sex ratios could explain some of the remaining variation. Maternal effects, the influence of the maternal phenotype or genotype on her developing offspring, may constrain sex allocation through physiological changes in response to the gestational environment. We tested if maternal effects constrain future parental sex allocation through a lowered gestational stress environment in laboratory mice. Females that experienced lowered stress as embryos in utero gave birth to female-biased litters as adults, with no change to litter size. Changes in offspring sex ratio was linked to peri-conceptual glucose, as those females that had increasing blood glucose peri-conceptionally gave birth to litters with a higher male to female sex ratio. There was, however, no effect of the lowered prenatal stress for developing male embryos and their sperm sex ratio when adult. We discuss the implications of maternal effects and maternal stress environment on the lifelong physiology of the offspring, particularly as a constraint on later maternal sex allocation. PMID- 27493777 TI - Alcohol discrimination and preferences in two species of nectar-feeding primate. AB - Recent reports suggest that dietary ethanol, or alcohol, is a supplemental source of calories for some primates. For example, slow lorises (Nycticebus coucang) consume fermented nectars with a mean alcohol concentration of 0.6% (range: 0.0 3.8%). A similar behaviour is hypothesized for aye-ayes (Daubentonia madagascariensis) based on a single point mutation (A294V) in the gene that encodes alcohol dehydrogenase class IV (ADH4), the first enzyme to catabolize alcohol during digestion. The mutation increases catalytic efficiency 40-fold and may confer a selective advantage to aye-ayes that consume the nectar of Ravenala madagascariensis. It is uncertain, however, whether alcohol exists in this nectar or whether alcohol is preferred or merely tolerated by nectarivorous primates. Here, we report the results of a multiple-choice food preference experiment with two aye-ayes and a slow loris. We conducted observer-blind trials with randomized, serial dilutions of ethanol (0-5%) in a standard array of nectar simulating sucrose solutions. We found that both species can discriminate varying concentrations of alcohol; and further, that both species prefer the highest available concentrations. These results bolster the hypothesized adaptive function of the A294V mutation in ADH4, and a connection with fermented foods, both in aye-ayes and the last common ancestor of African apes and humans. PMID- 27493778 TI - Anthropogenic noise, but not artificial light levels predicts song behaviour in an equatorial bird. AB - Birds in cities start singing earlier in the morning than in rural areas; commonly this shift is attributed to light pollution. Some studies have suggested that traffic noise has a stronger influence on singing activity than artificial light does. Changes in the timing of singing behaviour in relation to noise and light pollution have only been investigated in the temperate zones. Tropical birds, however, experience little seasonal variation in day length and may be less dependent on light intensity as a modifier for reproductive behaviours such as song. To test whether noise or light pollution has a stronger impact on the dawn chorus of a tropical bird, we investigated the singing behaviour of rufous collared sparrows (Zonotrichia capensis) in Bogota, Colombia at two times during the year. We found that birds in places with high noise levels started to sing earlier. Light pollution did not have a significant effect. Birds may begin to sing earlier in noisy areas to avoid acoustic masking by traffic later in the morning. Our results also suggest that some tropical birds may be less sensitive to variations in day length and thus less sensitive to light pollution. PMID- 27493779 TI - Network connections, dyadic bonds and fitness in wild female baboons. AB - In many social mammals, females who form close, differentiated bonds with others experience greater offspring survival and longevity. We still know little, however, about how females' relationships are structured within the social group, or whether connections beyond the level of the dyad have any adaptive value. Here, we apply social network analysis to wild baboons in order to evaluate the comparative benefits of dyadic bonds against several network measures. Results suggest that females with strong dyadic bonds also showed high eigenvector centrality, a measure of the extent to which an individual's partners are connected to others in the network. Eigenvector centrality was a better predictor of offspring survival than dyadic bond strength. Previous results have shown that female baboons derive significant fitness benefits from forming close, stable bonds with several other females. Results presented here suggest that these benefits may be further augmented if a female's social partners are themselves well connected to others within the group rather than being restricted to a smaller clique. PMID- 27493780 TI - Social networks predict selective observation and information spread in ravens. AB - Animals are predicted to selectively observe and learn from the conspecifics with whom they share social connections. Yet, hardly anything is known about the role of different connections in observation and learning. To address the relationships between social connections, observation and learning, we investigated transmission of information in two raven (Corvus corax) groups. First, we quantified social connections in each group by constructing networks on affiliative interactions, aggressive interactions and proximity. We then seeded novel information by training one group member on a novel task and allowing others to observe. In each group, an observation network based on who observed whose task-solving behaviour was strongly correlated with networks based on affiliative interactions and proximity. Ravens with high social centrality (strength, eigenvector, information centrality) in the affiliative interaction network were also central in the observation network, possibly as a result of solving the task sooner. Network-based diffusion analysis revealed that the order that ravens first solved the task was best predicted by connections in the affiliative interaction network in a group of subadult ravens, and by social rank and kinship (which influenced affiliative interactions) in a group of juvenile ravens. Our results demonstrate that not all social connections are equally effective at predicting the patterns of selective observation and information transmission. PMID- 27493781 TI - Overwintering evergreen oaks reverse typical relationships between leaf traits in a species spectrum. AB - The leaf economics spectrum has given us a fundamental understanding of the species variations in leaf variables. Across plant species, tight correlations among leaf mass per area (LMA), mass-based nitrogen (N m) and photosynthetic rate (A m) and leaf lifespan have been well known as trade-offs in leaf carbon economy. However, the regional or biome-level correlations may not be necessary to correspond with the global-scale analysis. Here, we show that almost all leaf variables in overwintering evergreen oaks in Japan were relatively well included within the evergreen-broadleaved trees in worldwide temperate forests, but N m was more consistent with that in deciduous broadleaved trees. Contrary to the universal correlations, the correlation between A m and N m among the evergreen oaks was negative and the correlation between A m and LMA disappeared. The unique performance was due to specific nitrogen allocation within leaves, i.e. the evergreen oaks with later leaf maturation had lower N m but higher nitrogen allocation to photosynthetic enzymes within leaves, to enhance carbon gain against the delayed leaf maturation and the shortened photosynthetic period due to cold winters. Our data demonstrate that correlations between leaf variables in a local scale are occasionally different from averaged global-scale datasets, because of the constraints in each biome. PMID- 27493782 TI - Population structure and historical demography of South American sea lions provide insights into the catastrophic decline of a marine mammal population. AB - Understanding the causes of population decline is crucial for conservation management. We therefore used genetic analysis both to provide baseline data on population structure and to evaluate hypotheses for the catastrophic decline of the South American sea lion (Otaria flavescens) at the Falkland Islands (Malvinas) in the South Atlantic. We genotyped 259 animals from 23 colonies across the Falklands at 281 bp of the mitochondrial hypervariable region and 22 microsatellites. A weak signature of population structure was detected, genetic diversity was moderately high in comparison with other pinniped species, and no evidence was found for the decline being associated with a strong demographic bottleneck. By combining our mitochondrial data with published sequences from Argentina, Brazil, Chile and Peru, we also uncovered strong maternally directed population structure across the geographical range of the species. In particular, very few shared haplotypes were found between the Falklands and South America, and this was reflected in correspondingly low migration rate estimates. These findings do not support the prominent hypothesis that the decline was caused by migration to Argentina, where large-scale commercial harvesting operations claimed over half a million animals. Thus, our study not only provides baseline data for conservation management but also reveals the potential for genetic studies to shed light upon long-standing questions pertaining to the history and fate of natural populations. PMID- 27493783 TI - Force and torque on spherical particles in micro-channel flows using computational fluid dynamics. AB - To delineate the influence of hemodynamic force on cell adhesion processes, model in vitro fluidic assays that mimic physiological conditions are commonly employed. Herein, we offer a framework for solution of the three-dimensional Navier-Stokes equations using computational fluid dynamics (CFD) to estimate the forces resulting from fluid flow near a plane acting on a sphere that is either stationary or in free flow, and we compare these results to a widely used theoretical model that assumes Stokes flow with a constant shear rate. We find that while the full three-dimensional solutions using a parabolic velocity profile in CFD simulations yield similar translational velocities to those predicted by the theoretical method, the CFD approach results in approximately 50% larger rotational velocities over the wall shear stress range of 0.1-5.0 dynes cm(-2). This leads to an approximately 25% difference in force and torque calculations between the two methods. When compared with experimental measurements of translational and rotational velocities of microspheres or cells perfused in microfluidic channels, the CFD simulations yield significantly less error. We propose that CFD modelling can provide better estimations of hemodynamic force levels acting on perfused microspheres and cells in flow fields through microfluidic devices used for cell adhesion dynamics analysis. PMID- 27493784 TI - A new method for reconstructing brain morphology: applying the brain-neurocranial spatial relationship in an extant lungfish to a fossil endocast. AB - Lungfish first appeared in the geological record over 410 million years ago and are the closest living group of fish to the tetrapods. Palaeoneurological investigations into the group show that unlike numerous other fishes-but more similar to those in tetrapods-lungfish appear to have had a close fit between the brain and the cranial cavity that housed it. As such, researchers can use the endocast of fossil taxa (an internal cast of the cranial cavity) both as a source of morphological data but also to aid in developing functional and phylogenetic implications about the group. Using fossil endocast data from a three-dimensional preserved Late Devonian lungfish from the Gogo Formation, Rhinodipterus, and the brain-neurocranial relationship in the extant Australian lungfish, Neoceratodus, we herein present the first virtually reconstructed brain of a fossil lungfish. Computed tomographic data and a newly developed 'brain-warping' method are used in conjunction with our own distance map software tool to both analyse and present the data. The brain reconstruction is adequate, but we envisage that its accuracy and wider application in other taxonomic groups will grow with increasing availability of tomographic datasets. PMID- 27493786 TI - Shared songs are of lower performance in the dark-eyed junco. AB - Social learning enables the adjustment of behaviour to complex social and ecological tasks, and underlies cultural traditions. Understanding when animals use social learning versus other forms of behavioural development can help explain the dynamics of animal culture. The dark-eyed junco (Junco hyemalis) is a songbird with weak cultural song traditions because, in addition to learning songs socially, male juncos also invent or improvise novel songs. We compared songs shared by multiple males (i.e. socially learned) with songs recorded from only one male in the population (many of which should be novel) to gain insight into the advantages of social learning versus invention or improvisation. Song types shared by multiple males were on average of lower performance, on aspects of vocal performance that have been implicated in agonistic communication in several species. This was not explained by cultural selection among socially learned songs (e.g. selective learning) because, for shared song types, song performance did not predict how many males shared them. We discuss why social learning does not maximize song performance in juncos, and suggest that some songbirds may add novel songs to culturally inherited repertoires as a means to acquire higher-quality signals. PMID- 27493785 TI - Force per cross-sectional area from molecules to muscles: a general property of biological motors. AB - We propose to formally extend the notion of specific tension, i.e. force per cross-sectional area-classically used for muscles, to quantify forces in molecular motors exerting various biological functions. In doing so, we review and compare the maximum tensions exerted by about 265 biological motors operated by about 150 species of different taxonomic groups. The motors considered range from single molecules and motile appendages of microorganisms to whole muscles of large animals. We show that specific tensions exerted by molecular and non molecular motors follow similar statistical distributions, with in particular, similar medians and (logarithmic) means. Over the 10(19) mass (M) range of the cell or body from which the motors are extracted, their specific tensions vary as M(alpha) with alpha not significantly different from zero. The typical specific tension found in most motors is about 200 kPa, which generalizes to individual molecular motors and microorganisms a classical property of macroscopic muscles. We propose a basic order-of-magnitude interpretation of this result. PMID- 27493787 TI - Effect of vitamin K2 on the anticoagulant activity of warfarin during the perioperative period of catheter ablation: Population analysis of retrospective clinical data. AB - BACKGROUND: Catheter ablation is a non-medication therapy for atrial fibrillation, and during the procedure, warfarin is withdrawn in the preoperative period to prevent the risk of bleeding. In case of emergency, vitamin K2 can be intravenously administered to antagonize the anticoagulant activity of warfarin. The aims of this study were to conduct population pharmacokinetic/pharmacodynamic modeling for retrospective clinical data and to investigate the effect of vitamin K2 on the anticoagulant activity of warfarin in the perioperative period of catheter ablation. METHODS: A total of 579 international normalized ratio (INR) values of prothrombin time from 100 patients were analyzed using the nonlinear mixed-effects modeling program NONMEM. A 1-compartment model was adapted to the pharmacokinetics of warfarin and vitamin K2, and the indirect response model was used to investigate the relationship between plasma concentration and the pharmacodynamic response of warfarin and vitamin K2. Since no plasma concentration data for warfarin and vitamin K2 were available, 3 literally available pharmacokinetic parameters were used to simultaneously estimate 1 pharmacokinetic parameter and 5 pharmacodynamic parameters. RESULTS: The population parameters obtained not only successfully explained the observed INR values, but also indicated an increase in sensitivity to warfarin in patients with reduced renal function. Simulations using these parameters indicated that vitamin K2 administration of more than 20 mg caused a slight dose-dependent decrease in INR on the day of catheter ablation and a delayed INR elevation after warfarin re-initiation. CONCLUSIONS: A pharmacokinetic/pharmacodynamic model was successfully built to explain the retrospective INR data during catheter ablation. Simulation studies suggest that vitamin K2 should be administered with care and that more than 20 mg is unnecessary in the preoperative period of catheter ablation. PMID- 27493788 TI - Paradoxical reactions under TNF-alpha blocking agents and other biological agents given for chronic immune-mediated diseases: an analytical and comprehensive overview. AB - Paradoxical adverse events (PAEs) have been reported during biological treatment for chronic immune-mediated diseases. PAEs are defined as the occurrence during biological agent therapy of a pathological condition that usually responds to this class of drug. A wide range of PAEs have been reported including dermatological, intestinal and ophthalmic conditions, mainly with antitumour necrosis factor alpha (TNF-alpha) agents. True PAEs include psoriasis, Crohn's disease and hidradenitis suppurativa. Other PAEs may be qualified as borderline and include uveitis, scleritis, sarcoidosis and other granulomatous diseases (granuloma annulare, interstitial granulomatous dermatitis), vasculitis, vitiligo and alopecia areata. Proposed hypotheses to explain these PAEs include an imbalance in cytokine production, the differential immunological properties between the monoclonal antibodies and TNF-alpha soluble receptor, an unopposed type I interferon production and a shift towards a Th1/Th2 profile. Data from registries suggest that the risk for paradoxical psoriasis is low and non significant. We discuss management of these PAEs, which depends on the type and severity of the adverse events, pre-existing treated conditions and the possibility of alternative therapeutic options for the underlying disease. Paradoxical adverse events are not restricted to anti-TNF-alpha agents and close surveillance of new available biological drugs (anti-interleukin-17/23, anti integrin) is warranted in order to detect the occurrence of new or as yet undescribed events. PMID- 27493789 TI - Educational needs and preferences of young European clinicians and physician researchers working in the field of rheumatology. AB - OBJECTIVES: To understand the educational needs and preferences of young clinicians and physician researchers in the field of rheumatology in Europe. METHODS: An international online survey was performed as a joint venture of ESCET and EMEUNET. The survey assessed the acceptance of and the access to the current European League Against Rheumatism (EULAR) educational portfolio, as well as the unmet educational needs and learning preferences among individuals below the age of 40 years working in rheumatology in Europe. RESULTS: Among 568 European clinicians and physician researchers, 65% indicated that the existing EULAR educational portfolio adequately covers their educational needs. Within the EULAR portfolio, the online course on rheumatic diseases and the postgraduate course were the most appreciated. Participants were very much in favour of new educational courses on imaging techniques, and 63% of participants indicated a particular interest in musculoskeletal ultrasound. A strong interest in refresher (60%) and general review (55%) courses was observed. Lack of funding was considered the major obstacle to participating in existing EULAR programmes. Finally, participants showed diverse preferences regarding learning modalities with common interests in live courses and conferences. CONCLUSIONS: EULAR's training opportunities are well appreciated among young clinicians and physician researchers in rheumatology. The results from this survey will help to develop EULAR's future educational portfolio. PMID- 27493790 TI - Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis. AB - INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24 months in methotrexate (MTX)-naive adult patients with RA. In this post hoc analysis, we compared efficacy and safety of tofacitinib in patients with early (disease duration <1 year) versus established (>=1 year) RA. METHODS: MTX-naive patients >=18 years with active RA received tofacitinib monotherapy (5 or 10 mg two times a day, or MTX monotherapy, in a 24 month Phase 3 trial. RESULTS: Of 956 patients (tofacitinib 5 mg two times a day, n=373; tofacitinib 10 mg two times a day, n=397; MTX, n=186), 54% had early RA. Baseline disease activity and functional disability were similar in both groups; radiographic damage was greater in patients with established RA. At month 24, clinical response rates were significantly greater in patients with early versus established RA in the tofacitinib 5 mg two times a day group. Both tofacitinib doses had greater effects on clinical, functional and radiographic improvements at 1 and 2 years compared with MTX, independent of disease duration. No new safety signals were observed. CONCLUSIONS: Treatment response was generally similar in early and established RA; significantly greater improvements were observed at month 24 with tofacitinib 5 mg two times a day in early versus established RA. Tofacitinib 5 and 10 mg two times a day demonstrated greater efficacy versus MTX irrespective of disease duration. No difference in safety profiles was observed between patients with early or established RA. TRIAL REGISTRATION NUMBER: NCT01039688; Results. PMID- 27493791 TI - Long-term efficiency of infliximab in patients with ankylosing spondylitis: real life data confirm the potential for dose reduction. AB - OBJECTIVE: To analyse the treatment outcome of patients with ankylosing spondylitis (AS) in the European AS infliximab cohort (EASIC) study after a total period of 8 years with specific focus on dosage and the duration of intervals between infliximab infusions. METHODS: EASIC included patients with AS who had received infliximab for 2 years as part of the ASSERT trial. After that period, rheumatologists were free to change the dose or the intervals of infliximab. Clinical data were status at baseline, end of ASSERT and for a total of 8 years of follow-up. RESULTS: Of the initially 71 patients with AS from EASIC, 55 patients (77.5%) had completed the 8th year of anti-tumour necrosis factor (TNF) treatment. Of those, 48 patients (87.3%) still continued on infliximab. The mean infusion interval increased slightly from 6 to 7.1+/-1.5 weeks, while 45.8% patients had increased the intervals up to a maximum of 12 weeks. The mean infliximab dose remained stable over time, with a minimum of 3.1 mg/kg and a maximum of 6.4 mg/kg. In patients receiving <5 mg/kg infliximab, the mean infusion interval increased to 7.0+/-1.2 weeks. In total, the mean cumulative dose per patient and per year decreased from 3566.30 to 2973.60 mg. CONCLUSIONS: We could observe that over a follow-up of 8 years of treatment with infliximab, >85% patients still remained on the same treatment, without any major safety events. Furthermore, both the infusion intervals and also the mean infliximab dose were modestly reduced in >=70% of the patients without the loss of clinical efficiency. PMID- 27493792 TI - Fatigue in primary Sjogren's syndrome is associated with lower levels of proinflammatory cytokines. AB - OBJECTIVES: This article reports relationships between serum cytokine levels and patient-reported levels of fatigue, in the chronic immunological condition primary Sjogren's syndrome (pSS). METHODS: Blood levels of 24 cytokines were measured in 159 patients with pSS from the United Kingdom Primary Sjogren's Syndrome Registry and 28 healthy non-fatigued controls. Differences between cytokines in cases and controls were evaluated using Wilcoxon test. Patient reported scores for fatigue were evaluated, classified according to severity and compared with cytokine levels using analysis of variance. Logistic regression was used to determine the most important predictors of fatigue levels. RESULTS: 14 cytokines were significantly higher in patients with pSS (n=159) compared to non fatigued healthy controls (n=28). While serum levels were elevated in patients with pSS compared to healthy controls, unexpectedly, the levels of 4 proinflammatory cytokines-interferon-gamma-induced protein-10 (IP-10) (p=0.019), tumour necrosis factor-alpha (p=0.046), lymphotoxin-alpha (p=0.034) and interferon-gamma (IFN-gamma) (p=0.022)-were inversely related to patient-reported levels of fatigue. A regression model predicting fatigue levels in pSS based on cytokine levels, disease-specific and clinical parameters, as well as anxiety, pain and depression, revealed IP-10, IFN-gamma (both inversely), pain and depression (both positively) as the most important predictors of fatigue. This model correctly predicts fatigue levels with reasonable (67%) accuracy. CONCLUSIONS: Cytokines, pain and depression appear to be the most powerful predictors of fatigue in pSS. Our data challenge the notion that proinflammatory cytokines directly mediate fatigue in chronic immunological conditions. Instead, we hypothesise that mechanisms regulating inflammatory responses may be important. PMID- 27493793 TI - The Utility of Routine Ultrasound Imaging after Elective Transplant Ureteric Stent Removal. AB - Background. Ureteric stent insertion during kidney transplantation reduces the incidence of major urological complications (MUCs). We evaluated whether routine poststent removal graft ultrasonography (PSRGU) was useful in detecting MUCs before they became clinically or biochemically apparent. Methods. A retrospective analysis was undertaken of clinical outcomes following elective stent removals from adult single renal transplant recipients (sRTRs) at our centre between 1 January 2011 and 31 December 2013. Results. Elective stent removal was performed for 338 sRTRs. Of these patients, 222 had routine PSRGU (median (IQR) days after stent removal = 18 (11-31)), 79 had urgent PSRGU due to clinical or biochemical indications, 12 had CT imaging, and 25 had no further renal imaging. Of the 222 sRTRs who underwent routine PSRGU, 210 (94.6%) had no change of management, three (1.4%) required repeat imaging only, and eight patients (3.6%) had incidental (nonureteric) findings. One patient (0.5%) had nephrostomy insertion as a result of routine PSRGU findings, but no ureteric stenosis was identified. Of 79 patients having urgent PSRGU after elective stent removal, three patients required transplant ureteric reimplantation. Conclusions. This analysis found no evidence that routine PSRGU at two to three weeks after elective stent removal provides any added value beyond standard clinical and biochemical monitoring. PMID- 27493795 TI - Comparison of Perioperative Ranibizumab Injections for Diabetic Macular Edema in Patients Undergoing Cataract Surgery. AB - Purpose. To compare the efficacy of perioperative ranibizumab injections on diabetic macular edema (DME) in patients undergoing cataract surgery. Methods. This study included 59 eyes of 59 patients. All patients had advanced cataract with DME and underwent an uneventful phacoemulsification surgery. There were 3 subgroups. The first group received intravitreal ranibizumab injection 2 weeks preoperatively, the second group received intraoperatively, and the third group received 2 weeks postoperatively. Follow-up examinations were performed at 1 week as well as at 1 and 3 months. Results. Baseline visual acuity showed a significant increase in all groups at 1 month. In group 1, compared to baseline value, foveal thickness (FT) increased significantly at 1 month and showed a significant decrease up to month 3. In group 2, FT increased at month 1 and this continued up to month 3. In group 3, FT increased at month 1 and was almost stable up to month 3. There were not any significant differences for visual acuity and FT between the groups. Conclusions. Although intrapostoperative ranibizumab injection for DME seems to be more effective than preoperative injections in patients undergoing cataract surgery, the treatment still needs to be continued following surgery. PMID- 27493794 TI - An Update on the Ophthalmologic Features in the Phakomatoses. AB - Neurofibromatosis type 1, tuberous sclerosis complex, and Von Hippel-Lindau disease, historically classified as the phakomatoses, are hereditary multisystem disorders characterized by the presence of hamartoma, which carry the risk of malignant transformation. The alteration of tumor suppressor genes seems to be at the basis of their pathophysiogenetic mechanism. Lisch and choroidal nodules in neurofibromatosis type 1, retinal astrocytomas in tuberous sclerosis complex, and retinal capillary hemangioma in Von Hippel-Lindau disease are the principal ophthalmic hamartomatous manifestations. The advent of novel imaging techniques such as near infrared reflectance and optical coherence tomography has provided unprecedented insight on the choroidal and retinal features of these diseases. These methods have improved early diagnosis and the ongoing surveillance in these conditions. Among an array of treatment modalities, antivascular endothelial growth factor therapy has been used in the management of retinal hamartomas but results have been varied. This review is an update on the pathophysiogenetic mechanisms, ophthalmic manifestations, and novel treatment strategies in the phakomatoses with emphasis on the role of imaging techniques. PMID- 27493796 TI - Optic Disc, Macula, and Retinal Nerve Fiber Layer Measurements Obtained by OCT in Thyroid-Associated Ophthalmopathy. AB - Aim. To compare the measurements of retinal nerve fiber layer (RNFL), macula and optic disc parameters obtained by optical coherence tomography (OCT), and intraocular pressure (IOP) between the patients with thyroid-associated ophthalmopathy (TAO) and healthy controls. Methods. One hundred and thirty-two eyes of 66 patients with TAO and 72 eyes of 36 healthy controls were included in the study. Proptosis level was determined by Hertel exophthalmometer. Optic disc, peripapillary retinal nerve fiber layer, and macula parameters were measured by OCT. All measurements of the patients were compared with those of age- and sex matched healthy controls. Results. No statistically significant difference was found between the patients with TAO and control group in terms of demographic characteristics (P > 0.05). Exophthalmometer measurements and IOP were higher in TAO group (P < 0.05). Mean macula thicknesses in TAO and control groups were 239.3 +/- 29.8 MUm and 246.6 +/- 31.8 MUm, respectively, and the difference between the groups was statistically significant (P = 0.000). TAO group had thinner inferior RNFL thickness and macular thicknesses (superior, inferior, temporal, and nasal) and higher disc area and C/D ratio when compared with the control group (P < 0.05). Conclusion. IOP, disc area, and C/D area ratio were higher in the patients with TAO and the thicknesses of macula and inferior RNFL were thinner when compared with healthy controls. This trial is registered with registration number at clinicaltrials.gov NCT02766660. PMID- 27493797 TI - Community Engaged Lifestyle Modification Research: Engaging Diabetic and Prediabetic African American Women in Community-Based Interventions. AB - Purpose. The I Am Woman (IAW) Program is a community-based, culturally responsive, and gender-specific nutrition, obesity, and diabetes educational prevention program designed for African American women (AAW). Chronic nutrition related health conditions such as excess body weight, diabetes mellitus, cardiovascular disease, and some forms of cancer are common among many African American women. Methods. IAW engaged AAW at risk for such deleterious health conditions by developing a health education intervention that aimed to support weight loss and management, improve knowledge about healthy lifestyle behavioral choices, and facilitate increased access to comprehensive healthcare. This Community Health Worker- (CHW-) led program enrolled 79 AAW aged 18 and older in a 7-week group health education intervention. Results. Following the intervention, results indicated that participants had greater knowledge about nutrition and health, strategies for prevention and management of obesity and diabetes, increased engagement in exercise and fitness activities, and decreased blood pressure, weight, body, and mass index. Cholesterol levels remained relatively unchanged. Additionally, AAW visited a primary care doctor more frequently and indicated greater interest in addressing their health concerns. Conclusion. This model of prevention appears to be a promising approach for increasing awareness about ways to improve the health and well-being of AAW. PMID- 27493798 TI - Liver Enzymes Abnormalities among Highly Active Antiretroviral Therapy Experienced and HAART Naive HIV-1 Infected Patients at Debre Tabor Hospital, North West Ethiopia: A Comparative Cross-Sectional Study. AB - Liver disease has emerged as the most common non-AIDS-related cause of death in HIV patients. However, there is limited data regarding this condition including our setting in Ethiopia. Hence, liver enzyme abnormalities among highly active antiretroviral therapy (HAART) experienced and HAART naive patients were assessed in this study. A total of 164 HAART experienced and 164 HAART naive patients were studied. Blood specimen was collected to determine alanine aminotransferase (ALT) and aspartate aminotransferase (AST), CD4 count, and viral hepatitis. The prevalence of liver enzyme abnormality was 20.1% and 22.0% among HAART experienced and HAART naive patients, respectively. The HAART experienced patients had higher mean ALT than HAART naive patients (P = 0.002). Viral hepatitis (AOR = 6.02; 95% CI = 1.87-19.39), opportunistic infections (AOR = 2.91; 95% CI = 1.04-8.19), current CD4 count <200 cells/mm(3) (AOR = 2.16; 95% CI = 1.06-4.39), and male sex (AOR = 1.83; 95% CI = 1.001-3.33) were associated with elevated ALT and/or AST. In conclusion, liver enzyme abnormalities were high in both HAART experienced and HAART naive HIV-1 infected patients. Hence, monitoring and management of liver enzyme abnormalities in HIV-1 infected patients are important in our setting. PMID- 27493799 TI - Determinants of Deescalation Failure in Critically Ill Patients with Sepsis: A Prospective Cohort Study. AB - Introduction. Deescalation refers to either discontinuation or a step-down of antimicrobials. Despite strong recommendations in the Surviving Sepsis Guidelines (2012) to deescalate, actual practices can vary. Our objective was to identify variables that are associated with deescalation failure. Methods. In this prospective study of patients with sepsis/septic shock, patients were categorized into 4 groups based on antibiotic administration: no change in antibiotics, deescalation, escalation (where antibiotics were changed to those with a broader spectrum of antimicrobial coverage), or mixed changes (where both escalation to a broader spectrum of coverage and discontinuation of antibiotics were carried out). Results. 395 patients were studied; mean APACHE II score was 24 +/- 7.8. Antimicrobial deescalation occurred in 189 (48%) patients; no changes were made in 156 (39%) patients. On multivariate regression analysis, failure to deescalate was significantly predicted by hematologic malignancy OR 3.3 (95% CI 1.4-7.4) p < 0.004, fungal sepsis OR 2.7 (95% CI 1.2-5.8) p = 0.011, multidrug resistance OR 2.9 (95% CI 1.4-6.0) p = 0.003, baseline serum procalcitonin OR 1.01 (95% CI 1.003-1.016) p = 0.002, and SAPS II scores OR 1.01 (95% CI 1.004-1.02) p = 0.006. Conclusions. Current deescalation practices reflect physician reluctance when dealing with complicated, sicker patients or with drug-resistance or fungal sepsis. Integrating an antibiotic stewardship program may increase physician confidence and provide support towards increasing deescalation rates. PMID- 27493800 TI - The Use of Xpert MTB/Rif for Active Case Finding among TB Contacts in North West Province, South Africa. AB - Introduction. Tuberculosis is a major cause of morbidity and mortality especially in high HIV burden settings. Active case finding is one strategy to potentially reduce TB disease burden. Xpert MTB/Rif has recently been recommended for diagnosis of TB. Methods. Pragmatic randomized trial to compare diagnosis rate and turnaround time for laboratory testing for Xpert MTB/Rif with TB microscopy and culture in household contacts of patients recently diagnosed with TB. Results. 2464 household contacts enrolled into the study from 768 active TB index cases. 1068 (44%) were unable to give sputum, but 24 of these were already on TB treatment. 863 (53%) participants sputum samples were tested with smear and culture and 2.7% (23/863; CI: 1.62-3.78) were diagnosed with active TB. Xpert MTB/Rif was used in 515 (21%) participants; active TB was diagnosed in 1.6% (8/515; CI: 0.52-2.68). Discussion and Conclusions. Additional 31 cases were diagnosed with contact tracing of household members. When Xpert MTB/Rif is compared with culture, there is no significant difference in diagnostic yield. PMID- 27493801 TI - Prevalence of Hypercalcaemia in a Renal Transplant Population: A Single Centre Study. AB - Introduction. Postrenal transplant bone disease is a significant problem. Factors influencing postrenal transplant bone status include high dose acute and low dose long-term steroid use, persistent hypercalcaemia, and graft failure. In this study, we aimed to determine the prevalence of hypercalcaemia and to evaluate the risk factors for postrenal transplant hypercalcaemia in long-term renal transplant patients at our centre. Methods. This is a biochemical audit in which we studied renal transplant recipients from the Central Northern Adelaide Renal Transplant Services, South Australia. Inclusion criteria include kidney transplant patients with functioning graft since 1971 and at least 3 months after transplantation at the time of analysis. Hypercalcaemia was defined as persistently elevated serum corrected calcium greater than or equal to 2.56 mmol/L for three consecutive months. Results. 679 renal transplant recipients with a functioning graft were studied and 101 were hypercalcaemic between March 2011 and June 2011 (15%). 60% of the hypercalcaemic patients were male and 40% were female, with chronic glomerulonephritis (39%) being the commonest cause of their end stage kidney disease (ESKD). Prevalence was similar in those that had haemodialysis and peritoneal dialysis pretransplantation. Hypercalcaemia in the renal transplant population was not secondary to suboptimal allograft function but secondary to pretransplantation hyperparathyroidism with persistent high parathyroid hormone (PTH) levels after transplantation. Conclusion. There is a high prevalence of hypercalcaemia (15%) in renal transplant recipients. The predominant cause for hypercalcaemia is pretransplantation hyperparathyroidism. The magnitude of pretransplantation hyperparathyroidism is the major determinant for long-term parathyroid function rather than graft function or pretransplantation duration on dialysis or mode of dialysis. PMID- 27493802 TI - Urinary Markers of Tubular Injury in HIV-Infected Patients. AB - Renal disease is a common complication of HIV-infected patients, associated with increased risk of cardiovascular events, progression to AIDS, AIDS-defining illness, and mortality. Early and accurate identification of renal disease is therefore crucial to improve patient outcomes. The use of serum creatinine, along with proteinuria, to detect renal involvement is essentially to screen for markers of glomerular disease and may not be effective in detecting earlier stages of renal injury. Therefore, more sensitive and specific markers are needed in order to early identify HIV-infected patients at risk of renal disease. This review article summarizes some new and important urinary markers of tubular injury in HIV-infected patients and their clinical usefulness in the renal safety follow-up of TDF-treated patients. PMID- 27493803 TI - Morphology and Functional Anatomy of the Recurrent Laryngeal Nerve with Extralaryngeal Terminal Bifurcation. AB - Anatomical variations of the recurrent laryngeal nerve (RLN), such as an extralaryngeal terminal bifurcation (ETB), threaten the safety of thyroid surgery. Besides the morphology of the nerve branches, intraoperative evaluation of their functional anatomy may be useful to preserve motor activity. We exposed 67 RLNs in 36 patients. The main trunk, bifurcation point, and terminal branches of bifid nerves were macroscopically determined and exposed during thyroid surgery. The functional anatomy of the nerve branches was evaluated by intraoperative nerve monitoring (IONM). Forty-six RLNs with an ETB were intraoperatively exposed. The bifurcation point was located along the prearterial, arterial, and postarterial segments in 11%, 39%, and 50% of bifid RLNs, respectively. Motor activity was determined in all anterior branches. The functional anatomy of terminal branches detected motor activity in 4 (8.7%) posterior branches of 46 bifid RLNs. The motor activity in posterior branches created a wave amplitude at 25-69% of that in the corresponding anterior branches. The functional anatomy of bifid RLNs demonstrated that anterior branches always contained motor fibres while posterior branches seldom contained motor fibres. The motor activity of the posterior branch was weaker than that of the anterior branch. IONM may help to differentiate between motor and sensory functions of nerve branches. The morphology and functional anatomy of all nerve branches must be preserved to ensure a safer surgery. PMID- 27493804 TI - High Dose Rate Brachytherapy as a Treatment Option in Endobronchial Tumors. AB - Purpose. To report our experience with high dose rate endobronchial brachytherapy (HDR-EBBT) and to assess its efficacy and tolerability with possibility of its use in selected cases with curative intent. Method. Retrospective review of patients with endobronchial tumors treated at our institution in 2007-2013 with HDR-EBBT. Subjective response and treatment related toxicity were extracted from patients' records. Clinical response was evaluated by chest CT +/- bronchoscopy 2 3 months after treatment. Local control (LC) and overall survival (OS) were analyzed. Results. Overall 23 patients were identified. Ten patients were treated with curative intent, in 8 of them HDR-EBBT was combined with external beam radiotherapy. Short term palliation was as follows: dyspnea (13/15), cough (12/14), and hemoptysis (3/3). Seventeen patients were evaluated, of whom 9 (53%) showed complete response. Four patients developed local failure (only 1 of them treated with curative intent) and were salvaged with HDR-EBBT (n = 1), chemotherapy (n = 2), and laser (n = 1). Among patients treated with curative intent, the 2-year LC and OS were 89% and 67%, respectively, and 2 out of 4 deaths were cancer-related. Late toxicity included bronchial stenosis (n = 1). Only 1 patient had fatal hemoptysis and postmortem examination indicated local recurrence. Conclusion. HDR-EBBT is promising treatment with tolerable complication if used in properly selected patients. PMID- 27493805 TI - Inhibition of DNA Methylation Impairs Synaptic Plasticity during an Early Time Window in Rats. AB - Although the importance of DNA methylation-dependent gene expression to neuronal plasticity is well established, the dynamics of methylation and demethylation during the induction and expression of synaptic plasticity have not been explored. Here, we combined electrophysiological, pharmacological, molecular, and immunohistochemical approaches to examine the contribution of DNA methylation and the phosphorylation of Methyl-CpG-binding protein 2 (MeCP2) to synaptic plasticity. We found that, at twenty minutes after theta burst stimulation (TBS), the DNA methylation inhibitor 5-aza-2-deoxycytidine (5AZA) impaired hippocampal long-term potentiation (LTP). Surprisingly, after two hours of TBS, when LTP had become a transcription-dependent process, 5AZA treatment had no effect. By comparing these results to those in naive slices, we found that, at two hours after TBS, an intergenic region of the RLN gene was hypomethylated and that the phosphorylation of residue S80 of MeCP2 was decreased, while the phosphorylation of residue S421 was increased. As expected, 5AZA affected only the methylation of the RLN gene and exerted no effect on MeCP2 phosphorylation patterns. In summary, our data suggest that tetanic stimulation induces critical changes in synaptic plasticity that affects both DNA methylation and the phosphorylation of MeCP2. These data also suggest that early alterations in DNA methylation are sufficient to impair the full expression of LTP. PMID- 27493806 TI - Axon Initial Segment Cytoskeleton: Architecture, Development, and Role in Neuron Polarity. AB - The axon initial segment (AIS) is a specialized structure in neurons that resides in between axonal and somatodendritic domains. The localization of the AIS in neurons is ideal for its two major functions: it serves as the site of action potential firing and helps to maintain neuron polarity. It has become increasingly clear that the AIS cytoskeleton is fundamental to AIS functions. In this review, we discuss current understanding of the AIS cytoskeleton with particular interest in its unique architecture and role in maintenance of neuron polarity. The AIS cytoskeleton is divided into two parts, submembrane and cytoplasmic, based on localization, function, and molecular composition. Recent studies using electron and subdiffraction fluorescence microscopy indicate that submembrane cytoskeletal components (ankyrin G, betaIV-spectrin, and actin filaments) form a sophisticated network in the AIS that is conceptually similar to the polygonal/triangular network of erythrocytes, with some important differences. Components of the AIS cytoplasmic cytoskeleton (microtubules, actin filaments, and neurofilaments) reside deeper within the AIS shaft and display structural features distinct from other neuronal domains. We discuss how the AIS submembrane and cytoplasmic cytoskeletons contribute to different aspects of AIS polarity function and highlight recent advances in understanding their AIS cytoskeletal assembly and stability. PMID- 27493807 TI - Emotion Dysregulation and Inflammation in African-American Women with Type 2 Diabetes. AB - C-reactive protein (CRP), a marker of systemic inflammation, has been associated with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Emotion dysregulation is a transdiagnostic risk factor for many psychological disorders associated with chronic inflammatory state. The objective of this study was to determine whether inflammation is associated with emotion dysregulation in women with type 2 diabetes mellitus (T2DM). We examined associations between trauma exposure, MDD, PTSD, emotion dysregulation, and CRP among 40 African American women with T2DM recruited from an urban hospital. Emotion dysregulation was measured using the Difficulties in Emotion Regulation Scale. PTSD and MDD were measured with structured clinical interviews. Child abuse and lifetime trauma load were also assessed. Analyses showed that both emotion dysregulation and current MDD were significantly associated with higher levels of CRP (p < 0.01). Current PTSD was not significantly related to CRP. In a regression model, emotion dysregulation was significantly associated with higher CRP (p < 0.001) independent of body mass index, trauma exposure, and MDD diagnosis. These findings suggest that emotion dysregulation may be an important risk factor for chronic inflammation beyond already known risk factors among women with T2DM, though a causal relationship cannot be determined from this study. PMID- 27493808 TI - Innovative trends and perspectives for erectile dysfunction treatment: A systematic review. AB - OBJECTIVE: To review contemporary knowledge concerning the innovative trends and perspectives in the treatment of erectile dysfunction (ED). METHODS: Medline was reviewed for English-language journal articles between January 2000 and March 2016, using the terms 'erectile dysfunction treatments', 'new trends' and 'perspectives'. In all, 114 original articles and 16 review articles were found to be relevant. Of the 76 cited papers that met the inclusion criteria, 51 papers had level of evidence of 1a-2b, whilst 25 had level of evidence of 3-4. Criteria included all pertinent review articles, randomised controlled trials with tight methodological design, cohort studies, and retrospective analyses. We also manually reviewed references from selected articles. RESULTS: Several interesting studies have addressed novel phosphodiesterase type 5 inhibitors (PDE5Is), orodispersible tablets, their recent chronic use, and combination with other agents. A few controlled studies have addressed herbal medicine as a sole or additional treatment for ED. Experimental studies and exciting review papers have addressed stem cells as novel players in the field of ED treatment. Other recent articles have revised the current status of low-intensity extracorporeal shockwave therapy in the field of ED. A few articles without long-term data have addressed new technologies that included: external penile support devices, penile vibrators, tissue engineering, nanotechnology, and endovascular tools for ED treatment. CONCLUSIONS: The current treatment of ED is still far from ideal. We expect to see new drugs and technologies that may revolutionise ED treatment, especially in complex cases. PMID- 27493809 TI - Internal versus external ureteric stents for uretero-ileal anastomosis after laparoscopic radical cystectomy with orthotopic neobladder: A prospective comparative study. AB - OBJECTIVE: To prospectively compare the use of external ureteric stents with internal JJ stenting of the uretero-ileal anastomosis in patients undergoing laparoscopic radical cystectomy (LRC) with a Y-shaped ileal orthotopic neobladder (ON). PATIENTS AND METHODS: The study included 69 patients undergoing LRC with ON. Patients were grouped according to the type of uretero-ileal stents used. An external ureteric stent was used in Group A (33 patients) and a JJ stent was used in Group B (36). We prospectively compared the duration of hospital stay, the incidence of short- and intermediate-term complications in the two study groups. RESULTS: The mean (SD) follow-up periods were 29.18 (3.94) and 28.19 (3.37) months for patients in Groups A and B, respectively. Perioperative patient characteristics were comparable in the two study groups. The use of JJ stenting was associated with a shorter hospital stay compared with external stenting, at a mean (SD) of 14.63 (3.74) and 6.8 (3.03) days in Groups A and B, respectively (P < 0.001). The incidence of urinary leakage was comparable in the two study groups, at 6.1% in Group A vs 8.3% in Group B (P = 1.0). Strictures of the uretero-ileal anastomosis occurred in two patients (6%) in Group A and confirmed by intravenous urography. All strictures were treated with antegrade JJ fixation. CONCLUSION: JJ stents could be used as an effective alternative to external ureteric stents to support the uretero-ileal anastomosis. JJ stenting is associated with a shorter hospital stay and similar complication rates compared with external stenting in patients undergoing LRC with ON. PMID- 27493810 TI - The embedded nipple: An optimal technique for re-implantation of primary obstructed megaureter in children. AB - OBJECTIVES: To present a novel ureteric re-implantation technique for primary obstructed megaureter (POM) that ensures success in the short- and long-term, as conventional techniques are not ideal for megaureters especially in children, with ureteric stenosis and reflux being common complications after re implantation. PATIENTS AND METHODS: Between 2009 and 2012, 22 paediatric patients with POM were enrolled. We performed a new technique for re-implantation of these ureters to ensure minimal incidence of ureteric strictures and easy subsequent endoscopic access. We performed follow-up voiding cystourethrography (VCUG) at 6 months postoperatively. RESULTS: The cohort comprised 14 boys and eight girls, with a median age of 22 months. Six patients underwent bilateral re-implantation. The mean (range) duration of indwelling ureteric catheterisation was 7.8 (4-14) days. There were no complications in the perioperative and postoperative periods. There was no reflux on follow-up VCUG in any of the patients. One patient developed Grade I reflux after 1 year and presented with a urinary tract infection. Diagnostic cystoscopy was performed in 13 patients showing that the nipple was directed similarly to the native ureteric orifice. CONCLUSION: The embedded-nipple technique for re-implantation of POM guarantees successful results and permits easy subsequent ureteroscopic access when needed. PMID- 27493811 TI - Paediatric Nonfunctioning Adrenocortical Carcinoma with Extension up to Right Side Heart: Cardiac Surgery Approach. AB - Adrenocortical carcinoma is a rare malignancy. Due to late diagnosis and no adequate effective adjuvant treatment, prognosis remains poor. Only approximately 30% of these malignancies are confined to the adrenal gland when they are diagnosed, as these tumors tend to be found years after their genesis. Cardiac involvement of adrenal carcinoma is very rare. We report a rare case of a 7-year old female with right adrenal cortical carcinoma, involving the right-side heart. PMID- 27493812 TI - Propofol Infusion Syndrome in Refractory Status Epilepticus: A Case Report and Topical Review. AB - Propofol infusion syndrome (PRIS) is a fatal complication when doses of propofol administration exceed 4 mg/kg/h for more than 48 hours. Propofol overdosage is not uncommon in patients with refractory status epilepticus (RSE). We describe a case of refractory status epilepticus complicated by propofol infusion syndrome and collect from 5 databases all reports of refractory status epilepticus cases that were treated by propofol and developed the syndrome and outline whether refractory status epilepticus treatment with propofol is standardized according to international recommendations, compare it with alternative medications, and discuss how this syndrome can be treated and prevented. A total of 21 patients who developed this syndrome reported arrhythmia in all cases (100%), rhabdomyolysis in 9 cases (42%), lactic acidosis in 13 cases (62%), renal failure in 8 cases (38%), lipemia in 7 cases (33%), and elevated hepatic enzymes in 6 cases (28%). 13 patients died (66%). Propofol is still given in a dosage higher than what is internationally recommended, and new treatment modalities such as renal replacement therapy, blood exchange, and extracorporeal membrane oxygenation seem to be promising. In conclusion, propofol should be carefully titrated, the maximal infusion rate needs to be reassessed, and combination of different sedative agents may be considered. PMID- 27493813 TI - Extranodal NK/T Cell Lymphoma Causing Cardiorespiratory Failure. AB - Extranodal NK/T cell lymphoma is an uncommon malignancy usually involving the sinonasal area. We report an unusual case of extranodal NK/T cell lymphoma diagnosed in a 62-year-old Caucasian male who died of progressive cardiorespiratory failure but had no clinically detectable upper respiratory system lesions. The initial diagnosis was made cytologically on a sample of pericardial fluid that contained neoplastic lymphoid cells. These cells were positive for CD2, cytoplasmic CD3, and Epstein-Barr virus and negative for CD56. The diagnosis was confirmed at the autopsy, which disclosed lymphoma infiltrates in the myocardium, lungs, stomach, and pancreas. The death was caused by heart and lung failure due to uncontrollable arrhythmia and respiratory insufficiency due to the lymphoma infiltrates. To the best of our knowledge, this is the first case of extranodal NK/T cell lymphoma presenting with cardiopulmonary failure. PMID- 27493814 TI - Spontaneous Bilateral Tubal Gestation: A Rare Case Report. AB - Here a case is presented where the woman after a positive pregnancy test underwent medical abortion for unwanted pregnancy without ultrasound confirmation of intrauterine pregnancy. On persistence of symptoms, a second opinion was procured, when examination and a transvaginal ultrasound scan revealed ruptured unilateral tubal ectopic pregnancy. However upon subsequent laparotomy (considering deteriorating hemodynamic status of the patient), intraoperatively it turned out to be a bilateral tubal ectopic gestation. PMID- 27493815 TI - Resuscitating the Baby after Shoulder Dystocia. AB - Background. To propose hypovolemic shock as a possible explanation for the failure to resuscitate some babies after shoulder dystocia and to suggest a change in clinical practice. Case Presentation. Two cases are presented in which severe shoulder dystocia was resolved within five minutes. Both babies were born without a heartbeat. Despite standard resuscitation by expert neonatologists, no heartbeat was obtained until volume resuscitation was started, at 25 minutes in the first case and 11 minutes in the second. After volume resuscitation circulation was restored, there was profound brain damage and the babies died. Conclusion. Unsuspected hypovolemic shock may explain some cases of failed resuscitation after shoulder dystocia. This may require a change in clinical practice. Rather than immediately clamping the cord after the baby is delivered, it is proposed that (1) the obstetrician delay cord clamping to allow autotransfusion of the baby from the placenta and (2) the neonatal resuscitators give volume much sooner. PMID- 27493816 TI - A Misguiding Osteoid Osteoma in the Bicipital Tuberosity of the Radius. AB - Osteoid osteoma is a benign bone tumor that appears most frequently in young patients. It is more common in males and it concerns mostly the long bones of the lower limb. A 20-year-old young woman presented to our outpatient department with pain in her left elbow. The symptoms began four years ago. At first, her symptoms were attributed to ulnar neuritis, confirmed by nerve conduction studies. In the following two years, she had undergone two surgical operations for decompression of the ulnar nerve. As a result, she reported poor results, which forced her to take frequently anti-inflammatory drugs for some years. When the patient presented to us, we planned a three-phase bone scan and an elbow MRI, which revealed the lesion. Based on the image findings of osteoid osteoma, we proceeded to the surgical removal of the tumor. Since then, the patient is pain-free and has a full range of motion of the affected elbow. Osteoid osteoma usually mimics multiple pathologies in the upper limb especially joint disease posing a challenge for the physician. The diagnosis requires high index of suspicion and a prompt diagnostic and surgical management. PMID- 27493817 TI - Morel-Lavallee Lesion of the Knee in a Recreational Frisbee Player. AB - Traumatic swelling/effusion in the knee region is a relatively common presenting complaint among athletes and nonathletes. Due to its broad differential diagnosis, a comprehensive evaluation beginning with history and physical examination are recommended. Knee joint effusion can be differentiated from other types of swelling by careful physical examination. Imaging, including plain radiography, ultrasound, and magnetic resonance imaging (MRI), is preferred modality. Aspiration of a local fluctuating mass may help with the diagnosis and management of some of these conditions. We present a case of a 26-year-old gentleman with superomedial Morel-Lavallee lesion (MLL) of the knee with history of a fall during a Frisbee game. His MLL was successfully treated with therapeutic aspiration and compression wrap without further sequelae. MLL is a rare condition consisting of a closed degloving injury caused by pressure and shear stress between the subcutaneous tissue and the superficial fascia or bone. Most commonly, MLL is found over the greater trochanter and sacrum but in rare cases can occur in other regions of the body. In most cases, concurrent severe injury mechanisms and concomitant fractures are present. MLL due to sports injuries are very rare. Therapeutic strategies may vary from compression wraps and aspiration to surgical evacuation. PMID- 27493818 TI - INFIX/EXFIX: Massive Open Pelvic Injuries and Review of the Literature. AB - Introduction. Open pelvic fractures make up 2-5% of all pelvic ring injuries. Their mortality has been reported to be as high as 50%. During Operation Enduring Freedom protocols for massive open pelvic injuries lead to the survival of injuries once thought to be fatal. The INFIX is a subcutaneous anterior fixator for pelvic stabilization which is stronger than external fixation. The purpose of this paper is to describe the use of INFIX and modern algorithms for massive open pelvic injuries. Methods. An IRB approved retrospective review describes 4 cases in civilian practice with massive open pelvic injuries. We also review the modern literature on open pelvic injures. Discussion. Key components in the care of massive open pelvic injuries include hemorrhage control by clamping of the aorta or REBOA when necessary and fecal/urinary diversion. The INFIX can be used internally, as a partial INFIX partial EXFIX, or as an EXFIX. Its low profile allows for easy application of wound vacs and wound care and when subcutaneous avoids pin tract infections. Conclusion. Massive open pelvic injuries are a difficult problem. Following modern protocols can help prevent mortality. PMID- 27493819 TI - Coracoid Process Avulsion Fracture at the Coracoclavicular Ligament Attachment Site in an Osteoporotic Patient with Acromioclavicular Joint Dislocation. AB - Coracoid fractures are uncommon, mostly occur at the base or neck of the coracoid process (CP), and typically present with ipsilateral acromioclavicular joint (ACJ) dislocation. However, CP avulsion fractures at the coracoclavicular ligament (CCL) attachment with ACJ dislocation have not been previously reported. A 59-year-old woman receiving glucocorticoid treatment fell from bed and complained of pain in her shoulder. Radiographs revealed an ACJ dislocation with a distal clavicle fracture. Three-dimensional computed tomography (3D-CT) reconstruction showed a small bone fragment at the medial apex of the CP. She was treated conservatively and achieved a satisfactory outcome. CP avulsion fractures at the CCL attachment can occur in osteoporotic patients with ACJ dislocations. Three-dimensional computed tomography is useful for identifying this fracture type. CP avulsion fractures should be suspected in patients with ACJ dislocations and risk factors for osteoporosis or osteopenia. PMID- 27493820 TI - Granulomatosis with Polyangiitis with Bilateral Facial Palsy and Severe Mixed Hearing Loss. AB - Granulomatosis with polyangiitis is autoimmune and rare disease. It affects many organs, but the most often affected organs are the nose, lungs, and kidneys. It is part of vasculitis and causes an autoimmune attack by an abnormal type of circulating antibody termed ANCAs against small blood vessels. Disease concerns both men and women with a peak age of presentation in the sixth and seven decades. Typically upper and lower respiratory tract and kidneys are involved. Otitis externa, otitis media, or mastoiditis rarely occurs in granulomatosis with polyangiitis. Deafness is the most dangerous aural complication. Histological examination of biopsy is often not specific. A case of GPA with bilateral otitis media, bilateral deafness, and bilateral facial palsy with fatal course is presented. PMID- 27493821 TI - Generalized Anxiety Disorder and Hypoglycemia Symptoms Improved with Diet Modification. AB - Observational evidence suggests that a relationship may exist between high glycemic index diets and the development of anxiety and depression symptoms; however, as no interventional studies assessing this relationship in a psychiatric population have been completed, the possibility of a causal link is unclear. AB is a 15-year-old female who presented with concerns of generalized anxiety disorder and hypoglycemia symptoms. Her diet consisted primarily of refined carbohydrates. The addition of protein, fat, and fiber to her diet resulted in a substantial decrease in anxiety symptoms as well as a decrease in the frequency and severity of hypoglycemia symptoms. A brief return to her previous diet caused a return of her anxiety symptoms, followed by improvement when she restarted the prescribed diet. This case strengthens the hypothesis that dietary glycemic index may play a role in the pathogenesis or progression of mental illnesses such as generalized anxiety disorder and subsequently that dietary modification as a therapeutic intervention in the treatment of mental illness warrants further study. PMID- 27493823 TI - Erratum to "Endobronchial Enigma: A Clinically Rare Presentation of Nocardia beijingensis in an Immunocompetent Patient". AB - [This corrects the article DOI: 10.1155/2015/970548.]. PMID- 27493822 TI - Dandy-Walker Malformation Presenting with Psychological Manifestations. AB - Dandy-Walker malformation, which is a congenital malformation of the cerebellum, is documented in literature to be associated with psychotic symptoms, obsessive compulsive symptoms, mood symptoms, hyperactivity, and impulsive behavior. The pathogenesis of psychiatric symptoms in Dandy-Walker malformation is thought to be due to disruption of the corticocerebellar tracts, resulting in what is known as cerebellar cognitive affective syndrome. We present a case of Dandy-Walker malformation presenting with psychiatric symptoms. This case highlights the necessity to be aware of psychiatric manifestations of cerebellar disease as it has an impact on the diagnosis and treatment. PMID- 27493824 TI - MRI Findings of Syndrome of Acute Bilateral Symmetrical Basal Ganglia Lesions in Diabetic Uremia: A Case Report and Literature Review. AB - The syndrome of acute bilateral basal ganglia lesions is an uncommon clinical occurrence exhibiting acute onset of movement abnormalities, which can be seen almost exclusively among patients with chronic renal failure, especially in the setting of concurrent diabetes mellitus. Symmetrical lesions located in basal ganglia demonstrated in MRI are typical manifestation of this syndrome. Our study includes routine MRI examination, MRS, 3D-ASL, and SWI findings, which have been rarely reported and will contribute to diagnosing more cases about this syndrome. PMID- 27493825 TI - Giant Cell Arteritis: An Atypical Presentation Diagnosed with the Use of MRI Imaging. AB - Giant cell arteritis (GCA) is the most common primary systemic vasculitis in western countries in individuals over the age of 50. It is typically characterised by the granulomatous involvement of large and medium sized blood vessels branching of the aorta with particular tendencies for involving the extracranial branches of the carotid artery. Generally the diagnosis is straightforward when characteristic symptoms such as headache, jaw claudication, or other ischemic complications are present. Atypical presentations of GCA without "overt" cranial ischemic manifestations have become increasingly recognised but we report for the first time a case of GCA presenting as mild upper abdominal pain and generalized weakness in the context of hyponatremia as the presenting manifestation of vasculitis that was subsequently diagnosed by MRI scanning. This case adds to the literature and emphasises the importance of MRI in the evaluation of GCA patients without "classic" cranial ischemic symptoms. PMID- 27493826 TI - Facilitators and Barriers to Linkage to HIV Care among Female Sex Workers Receiving HIV Testing Services at a Community-Based Organization in Periurban Uganda: A Qualitative Study. AB - Introduction. While four in ten female sex workers (FSWs) in sub-Saharan Africa are infected with HIV, only a small proportion is enrolled in HIV care. We explored facilitators and barriers to linkage to HIV care among FSWs receiving HIV testing services at a community-based organization in periurban Uganda. Methods. The cross-sectional qualitative study was conducted among 28 HIV positive FSWs from May to July 2014. Key informant interviews were conducted with five project staff and eleven peer educators. Data were collected on facilitators for and barriers to linkage to HIV care and manually analyzed following a thematic framework approach. Results. Facilitators for linkage to HIV care included the perceived good quality of health services with same-day results and immediate initiation of treatment, community peer support systems, individual's need to remain healthy, and having alternative sources of income. Linkage barriers included perceived stigma, fear to be seen at outreach HIV clinics, fear and myths about antiretroviral therapy, lack of time to attend clinic, and financial constraints. Conclusion. Linkage to HIV care among FSWs is influenced by good quality friendly services and peer support. HIV service delivery programs for FSWs should focus on enhancing these and dealing with barriers stemming from stigma and misinformation. PMID- 27493827 TI - Cost-Effectiveness and Validity Assessment of Cyscope Microscope, Quantitative Buffy Coat Microscope, and Rapid Diagnostic Kit for Malaria Diagnosis among Clinic Attendees in Ibadan, Nigeria. AB - Background. Unavailability of accurate, rapid, reliable, and cost-effective malaria diagnostic instruments constitutes major a challenge to malaria elimination. We validated alternative malaria diagnostic instruments and assessed their comparative cost-effectiveness. Method. Using a cross-sectional study design, 502 patients with malaria symptoms at selected health facilities in Ibadan between January and April 2014 were recruited consecutively. We examined malaria parasites using Cyscope(r), QBC, and CareStartTM and results were compared to light microscopy (LM). Validity was determined by assessing sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Costs per hour of use for instruments and turnaround time were determined. Result. Sensitivity of the instruments was 76.0% (CareStart), 95.0% (Cyscope), and 98.1% (QBC). Specificity was 96.0% (CareStart), 87.3% (Cyscope), and 85.5% (QBC). PPV were 65.2%, 67.5%, and 84.7%, while NPV were 93.6%, 98.6%, and 99.4% for CareStart, Cyscope, and QBC with Kappa values of 0.75 (CI = 0.68-0.82) for CareStart, 0.72 (CI = 0.65-0.78) for Cyscope, and 0.71 (CI = 0.64-0.77) for QBC. Average cost per hour of use was the lowest ($2.04) with the Cyscope. Turnaround time was the fastest with Cyscope (5 minutes). Conclusion. Cyscope fluorescent microscope had the shortest turnaround time and is the most cost-effective of all the malaria diagnostic instruments evaluated. PMID- 27493828 TI - The Effects of POWER Training in Young and Older Adults after Stroke. AB - Background. Approximately 35,000 strokes occur annually in adults below the age of 40, and there is disappointingly little data describing their responses to rehabilitation. The purpose of this analysis was to determine the effects of Poststroke Optimization of Walking using Explosive Resistance (POWER) training in young (<40 years) and older (>60 years) adults and to describe relationships between training-induced improvements in muscular and locomotor function. Methods. Data was analyzed from 16 individuals with chronic stroke who participated in 24 sessions of POWER training. Outcomes included muscle power generation, self-selected walking speed (SSWS), 6-minute walk test, Fugl-Meyer motor assessment, Berg Balance Scale, and Dynamic Gait Index. Results. There were no significant differences between groups at baseline. Within-group comparisons revealed significant improvements in paretic and nonparetic knee extensor muscle power generation in both groups. Additionally, young participants significantly improved SSWS. Improvements in SSWS were more strongly associated with improvements in power generation on both sides in young versus older participants. Conclusions. Younger adults after stroke seem to preferentially benefit from POWER training, particularly when increasing gait speed is a rehabilitation goal. Future research should aim to further understand age-related differences in response to training to provide optimal treatments for all individuals following stroke. PMID- 27493829 TI - Evaluation of Er,Cr:YSGG Laser Effect on Microshear Bond Strength of a Self Adhesive Flowable Composite in the Dentin of Permanent Molar: An In Vitro Study. AB - Aim and Background. Recently, new restorative materials such as self-adhesive flowable composites, because of their simple use and no need to bonding and etching, are considered important, particularly in pediatric dentistry. The aim of this study is to evaluate the effect of Er,Cr:YSGG laser on microshear bond strength of self-adhesive flowable composite on permanent teeth dentin in vitro. Material and Methods. In this experimental study, 40 dentin sections were prepared from healthy third molars and divided into two groups according to their surface preparation by Er,Cr:YSGG laser or without laser, only with silicon carbide paper. In each group, two groups of 10 teeth were treated with self adhesive flowable composite (Dyad) and conventional flowable composite (acid etch and bonding). Samples were stored in normal saline and after 48 hours their bond strength was measured. The failure mode of samples was observed on stereomicroscope. In order to analyse the results, the one way ANOVA and Tukey's test for multiple comparisons were used. Result. The maximum bond strength was related to conventional flowable composite with laser preparation group (24/21 Mpa). The lowest one was seen in Dyad composite without laser emitting (9/89 Mpa). The statistical difference between this two groups was significant (P value = 0/0038). The microshear bond strength differences between Dyad composite groups with laser preparation (mean = 16/427 +/- 1/79) and without laser preparation (mean = 12/85 +/- 1/90) were statistically significant too (P value = 0/01). Conclusion. Self-adhesive flowable composite has lower microshear bond strength than conventional flowable composite. Moreover, the laser irradiation as a surface treatment can improve this bond strength. PMID- 27493831 TI - Ischemia-induced Angiogenesis is Attenuated in Aged Rats. AB - To study whether focal angiogenesis is induced in aged rodents after permanent distal middle cerebral artery occlusion (MCAO), young adult (3-month-old) and aged (24-month-old) Fisher 344 rats underwent MCAO and sacrificed up to two months after MCAO. Immunohistochemistry and synchrotron radiation microangiography were performed to examine the number of newly formed blood vessels in both young adult and aged rats post-ischemia. We found that the number of capillaries and small arteries in aged brain was the same as young adult brain. In addition, we found that after MCAO, the number of blood vessels in the peri-infarct region of ipsilateral hemisphere in aged ischemic rats was significantly increased compared to the aged sham rats (p<0.05). We also confirmed that ischemia-induced focal angiogenesis occurred in young adult rat brain while the blood vessel density in young adult ischemic brain was significantly higher than that in the aged ischemic brain (p<0.05). Our data suggests that focal angiogenesis in aged rat brain can be induced in response to ischemic brain injury, and that aging impedes brain repairing and remodeling after ischemic stroke, possible due to the limited response of angiogenesis. PMID- 27493830 TI - Brain Atrophy, Anti-Smooth Muscle Antibody and Cognitive Impairment: An Association Study. AB - Cortical atrophy, neuronal loss, beta-amyloid deposition, neuritic plaques, and neurofibrillary tangles are neuropathological key features in the Alzheimer's disease (AD). Antibodies against beta-amyloid, neurotransmitters, microvascular endothelium components and microglial cells have been detected in AD serum suggesting that AD could be another autoimmune disease and provides a link between vascular pathology, endothelium dysfunction and neuronal cells death. Aim of the present study was to evaluate the association between autoantibody profile and cognitive impairment in geriatric patients, accounting for ApoE genotype as a potential confounding factor. Three hundred and forty-four geriatric patients, attending the clinic for the cognitive decline, underwent a biochemical and immunological profile, chest X-ray, cerebral computed tomography scan and complete cognitive evaluation. All patients were also screened for the ApoE genotype. A significantly higher prevalence of Anti-Smooth Muscle Antibody (ASMA) positivity was found in 89/204 (43.63%) patients with diagnosed neuroradiological signs of cerebral atrophy compared with 15/140 (10.71%) patients without the condition (p<0.001). Multivariable logistic model evidenced that such association was independent of patient's age, gender and Mini-Mental State Examination (OR=8.25, 95%CI: 4.26-15.99) and achieved a good discriminatory power (c statistic=0.783). Results were also independent of ApoE genotype, which resulted not associated both with the presence of brain atrophy and with the presence of ASMA positivity. Our results shows a strong association between brain atrophy and ASMA positivity and are consistent with several studies that focused attention on the mechanisms of endothelial immune response in the development of dementia. PMID- 27493832 TI - Deletion of Nuclear Factor kappa B p50 Subunit Decreases Inflammatory Response and Mildly Protects Neurons from Transient Forebrain Ischemia-induced Damage. AB - Transient forebrain ischemia induces delayed death of the hippocampal pyramidal neurons, particularly in the CA2 and medial CA1 area. Early pharmacological inhibition of inflammatory response can ameliorate neuronal death, but it also inhibits processes leading to tissue regeneration. Therefore, research efforts are now directed to modulation of post-ischemic inflammation, with the aim to promote beneficial effects of inflammation and limit adverse effects. Transcription factor NF-kappaB plays a key role in the inflammation and cell survival/apoptosis pathways. In the brain, NF-kappaB is predominantly found in the form of a heterodimer of p65 (RelA) and p50 subunit, where p65 has a transactivation domain while p50 is chiefly involved in DNA binding. In this study, we subjected middle-aged Nfkb1 knockout mice (lacking p50 subunit) and wild-type controls of both sexs to 17 min of transient forebrain ischemia and assessed mouse performance in a panel of behavioral tests after two weeks of post operative recovery. We found that ischemia failed to induce clear memory and motor deficits, but affected spontaneous locomotion in genotype- and sex-specific way. We also show that both the lack of the NF-kappaB p50 subunit and female sex independently protected CA2 hippocampal neurons from ischemia-induced cell death. Additionally, the NF-kappaB p50 subunit deficiency significantly reduced ischemia induced microgliosis, astrogliosis, and neurogenesis. Lower levels of hippocampal microgliosis significantly correlated with faster spatial learning. We conclude that NF-kappaB regulates the outcome of transient forebrain ischemia in middle aged subjects in a sex-specific way, having an impact not only on neuronal death but also specific inflammatory responses and neurogenesis. PMID- 27493833 TI - Mobility-Related Consequences of Reduced Lower-Extremity Peripheral Nerve Function with Age: A Systematic Review. AB - The objective of this study is to systematically review the relationship between lower-extremity peripheral nerve function and mobility in older adults. The National Library of Medicine (PubMed) was searched on March 23, 2015 with no limits on publication dates. One reviewer selected original research studies of older adults (>=65 years) that assessed the relationship between lower-extremity peripheral nerve function and mobility-related outcomes. Participants, study design and methods of assessing peripheral nerve impairment were evaluated and results were reported and synthesized. Eight articles were identified, including 6 cross-sectional and 2 longitudinal studies. These articles investigated 6 elderly cohorts (4 from the U.S. and 2 from Italy): 3 community-dwelling (including 1 with only disabled women and 1 without mobility limitations at baseline), 1 with both community-dwelling and institutionalized residents, 1 from a range of residential locations, and 1 of patients with peripheral arterial disease. Mean ages ranged from 71-82 years. Nerve function was assessed by vibration threshold (n=2); sensory measures and clinical signs and symptoms of neuropathy (n=2); motor nerve conduction (n=1); and a combination of both sensory measures and motor nerve conduction (n=3). Each study found that worse peripheral nerve function was related to poor mobility, although relationships varied based on the nerve function measure and mobility domain assessed. Six studies found that the association between nerve function and mobility persisted despite adjustment for diabetes. Evidence suggests that peripheral nerve function impairment at various levels of severity is related to poor mobility independent of diabetes. Relationships varied depending on peripheral nerve measure, which may be particularly important when investigating specific biological mechanisms. Future research needs to identify risk factors for peripheral nerve decline beyond diabetes, especially those common in late-life and modifiable. Interventions to preserve nerve function should be investigated with regard to their effect on postponing or preventing disability in older adults. PMID- 27493834 TI - Novel Insights into Acid-Sensing Ion Channels: Implications for Degenerative Diseases. AB - Degenerative diseases often strike older adults and are characterized by progressive deterioration of cells, eventually leading to tissue and organ degeneration for which limited effective treatment options are currently available. Acid-sensing ion channels (ASICs), a family of extracellular H(+) activated ligand-gated ion channels, play critical roles in physiological and pathological conditions. Aberrant activation of ASICs is reported to regulate cell apoptosis, differentiation and autophagy. Accumulating evidence has highlighted a dramatic increase and activation of ASICs in degenerative disorders, including multiple sclerosis, Parkinson's disease, Huntington's disease, intervertebral disc degeneration and arthritis. In this review, we have comprehensively discussed the critical roles of ASICs and their potential utility as therapeutic targets in degenerative diseases. PMID- 27493835 TI - Danggui-Shaoyao-San: New Hope for Alzheimer's Disease. AB - Danggui-Shaoyao-San (DSS), also called Toki-shakuyaku-san (TJ-23) or Dangguijakyak-san (DJS), is a well-known herbal formula (Angelica sinensis (Oliv.) Diels., Ligusticum chuanxiong Hort., Paeonia lactiflora pall., Poria cocos (Schw.) Wolf, Alisma orientalis (Sam.) Juzep., Atractylodes macrocephala Koidz.), which has been widely used in oriental countries for the treatment of various gynecological diseases. Recent studies show that DSS has an effect on free radical-mediated neurological diseases and exhibits anti-inflammatory and antioxidant activities and reduces cell apoptosis in the hippocampus. In addition, DSS mediates the modulation of central monoamine neurotransmitter systems and ameliorates dysfunction of the central cholinergic nervous system and scopolamine-induced decrease in ACh levels. DSS improves the function of the dopaminergic, adrenergic, and serotonergic nervous systems. Interestingly, DSS can alleviate cognitive dysfunction of Alzheimer's disease (AD) patients, suggesting that it is a useful therapeutic agent for AD. This paper reviews the mechanism of DSS for the treatment of AD. PMID- 27493837 TI - Population Aging in the European Information Societies: Towards a Comprehensive Research Agenda in eHealth Innovations for Elderly. AB - Population ageing is one of the major social and economic challenges of our contemporary societies. With the advent of the information society, new research and technological developments have been promoted in the field of assistive technologies and information and communication technologies of benefit to elderly people. This article examines the potentialities of new informatics developments in generating solutions to better address elderly people's daily-life, especially those with chronic illness and/or low autonomy. The authours attempt to propose a research agenda, by exposing various strengts and weaknesses of eHealth innovations for elderly, mainly grounded in secondary sources analysis. PMID- 27493836 TI - The Role of Bone Marrow Microenvironment in Governing the Balance between Osteoblastogenesis and Adipogenesis. AB - In the adult bone marrow, osteoblasts and adipocytes share a common precursor called mesenchymal stem cells (MSCs). The plasticity between the two lineages has been confirmed over the past decades, and has important implications in the etiology of bone diseases such as osteoporosis, which involves an imbalance between osteoblasts and adipocytes. The commitment and differentiation of bone marrow (BM) MSCs is tightly controlled by the local environment that maintains a balance between osteoblast lineage and adipocyte. However, pathological conditions linked to osteoporosis can change the BM microenvironment and shift the MSC fate to favor adipocytes over osteoblasts, and consequently decrease bone mass with marrow fat accumulation. This review discusses the changes that occur in the BM microenvironment under pathological conditions, and how these changes affect MSC fate. We suggest that manipulating local environments could have therapeutic implications to avoid bone loss in diseases like osteoporosis. PMID- 27493838 TI - Inhibition of Endoplasmic Reticulum Stress is Involved in the Neuroprotective Effect of bFGF in the 6-OHDA-Induced Parkinson's Disease Model. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder with complicated pathophysiologic mechanisms. Endoplasmic reticulum (ER) stress appears to play a critical role in the progression of PD. We demonstrated that basic fibroblast growth factor (bFGF), as a neurotropic factor, inhibited ER stress-induced neuronal cell apoptosis and that 6-hydroxydopamine (6-OHDA) induced ER stress was involved in the progression of PD in rats. bFGF administration improved motor function recovery, increased tyrosine hydroxylase (TH)-positive neuron survival, and upregulated the levels of neurotransmitters in PD rats. The 6-OHDA-induced ER stress response proteins were inhibited by bFGF treatment. Meanwhile, bFGF also increased expression of TH. The administration of bFGF activated the downstream signals PI3K/Akt and Erk1/2 in vivo and in vitro. Inhibition of the PI3K/Akt and Erk1/2 pathways by specific inhibitors partially reduced the protective effect of bFGF. This study provides new insight towards bFGF translational drug development for PD involving the regulation of ER stress. PMID- 27493840 TI - Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans. AB - BACKGROUND: Tocotrienols has been known to lower serum lipid parameters below 500 mg/d, while increase lipid parameters at higher dose of 750 mg/d. delta Tocotrienol has a novel inflammatory property of concentration-dependent inhibition and activation. Therefore, inhibition (anti-inflammatory) property of tocotrienols at low doses is useful for cardiovascular disease, whereas, activation (pro-inflammatory) property using high dose is found effective for treatments of various types of cancer. We have recently described plasma bioavailability of 125 mg/d, 250 mg/d and 500 mg/d doses of delta-tocotrienol in healthy fed subjects, which showed dose-dependent increases in area under the curve (AUC) and maximum concentration (Cmax). Hence, in the current study, higher doses of tocotrienols have used to analyze its effect on plasma pharmacokinetic parameters. AIMS: To evaluate the safety and bioavailability of higher doses (750 mg and 1000 mg) of annatto-based tocotrienols in healthy fed subjects. All four isomers (alpha-, beta-, gamma-, delta-) of tocols (tocotrienols and tocopherols) present in the plasmas of subjects were quantified and analyzed for various pharmacokinetic parameters. STUDY DESIGN: An open-label, randomized study was performed to analyze pharmacokinetics and bioavailability of delta-tocotrienol in 6 healthy fed subjects. All subjects (3/dose) were randomly assigned to one of each dose of 750 mg or 1000 mg. Blood samples were collected at 0, 1, 2, 4, 6, 8 h intervals and all isomers of alpha-,beta-,gamma-,delta-tocotrienols, and tocopherols in plasmas were quantified by HPLC. RESULTS: Oral administration of 750 and 1000 mg/d of tocotrienols resulted in dose-dependent increases in plasmas (ng/ml) AUCt0-t8 6621, 7450; AUCt0-infinity 8688, 9633; AUMC t0-infinity 52497, 57199; MRT 6.04, 5.93; Cmax 1444, 1592 (P<0.05), respectively, of delta tocotrienol isomer. Moreover, both doses also resulted in plasmas Tmax 3.33-4 h; elimination half-life (t1/2 h) 2.74, 2.68; time of clearance (Cl-T, l/h) 0.086, 0.078; volume of distribution (Vd/f, mg/h) 0.34, 0.30; and elimination rate constant (ke; h-1) 0.25, 0.17, respectively of delta- tocotrienol isomer. Similar results of these parameters were reported for gamma-tocotrienol, beta- tocotrienol, alpha-tocotrienol, delta-tocopherol, gamma-tocopherol, and beta tocopherol, except for alpha- tocopherol. CONCLUSIONS: This study has described pharmacokinetics using higher doses of 750 mg/d and 1000 mg/d of delta tocotrienol. These results confirmed earlier findings that Tmax was 3-4 h for all isomers of tocotrienols and tocopherols except for alpha-tocopherol (6 h). These higher doses of tocotrienols were found safe in humans and may be useful for treatments of various types of cancer, diabetes, and Alzheimer's disease. PMID- 27493839 TI - Pathophysiological Function of ADAMTS Enzymes on Molecular Mechanism of Alzheimer's Disease. AB - The extracellular matrix (ECM) is an environment that has various enzymes attended in regeneration and restoration processes which is very important to sustain physiological and biological functions of central nervous system (CNS). One of the participating enzyme systems in ECM turnover is matrix metalloproteinases. A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs (ADAMTS) is a unique family of ECM proteases found in mammals. Components of this family may be distinguished from the ADAM (A Disintegrin and Metalloproteinase) family based on the multiple copies of thrombospondin 1-like repeats. The considerable role of the ADAMTS in the CNS continues to develop. Evidences indicate that ADAMTS play an important role in neuroplasticity as well as nervous system pathologies such as Alzheimer's disease (AD). It is hopeful and possible that ADAMTS family members may be utilized to develop therapies for CNS pathologies, ischemic injuries, neurodegenerative and neurological diseases. To understand and provide definitive data on ADAMTS to improve structural and functional recovery in CNS injury and diseases, this review aimed to enlighten the subject extensively to reach certain information on metalloproteinases and related molecules/enzymes. It will be interesting to examine how ADAMTS expression and action would affect the initiation/progression of above-mentioned clinical situations, especially AD. PMID- 27493841 TI - Persistence of Neutralizing Antibody Against Dengue Virus 2 After 70 Years from Infection in Nagasaki. AB - This study aimed to investigate the duration of humoral immune responses to dengue virus (DENV) infection in Japanese who experienced acute febrile illness with hemorrhagic manifestations 70 years ago, when an epidemic of dengue occurred in Nagasaki, Japan, from 1942 to 1944. A Japanese volunteer requested serological diagnosis of DENV infection in 2014 and donated blood sample to measure the antibody titer against DENV by antiflavi IgG indirect ELISA, focus reduction neutralization test, and plaque reduction neutralization test. The serum sample of the volunteer was positive in flavi IgG ELISA and it indicated primary infection. In the neutralization test, the highest neutralizing titer was >=218 for DENV-2. We report here the existence of DENV-specific antibodies in the serum of a person after 70 years from infection. Published reports indicated that DENV 1 was responsible for the 1942-1944 outbreak in Nagasaki. However, our data suggested that DENV-2 also played a role in this Nagasaki dengue epidemic. PMID- 27493842 TI - Hemorrhagic Pilocytic Astrocytomas in Adults: A Case Report and Literature Review. AB - Pilocytic astrocytomas are histologically benign tumors, generally found in the pediatric population. Onset of symptoms is generally insidious, predominantly stemming from mass effect upon nearby structures. Patients harboring a pilocytic astrocytoma may present with gait disturbance, headaches, cranial nerve deficits, as well as hydrocephalus, depending on the exact location. Although cases of adult pilocytic astrocytomas in the adult population are described, they are quite uncommon. We present a case of an adult female presenting with acute neurological compromise resulting from an acutely hemorrhagic posterior fossa pilocytic astrocytoma. Her initial neurological assessment was consistent with a Glasgow coma scale of 4T, as the patient was experiencing decerebrate posturing. An emergent external ventricular drain was placed in the emergency department for acute hydrocephalus as a temporizing measure, prior to evacuation of the associated subdural and intratumoral hemorrhages, as well as resection of the mass. After a long hospital course and extensive rehabilitation, the patient made a remarkable recovery and eventually gave birth to a child via Caesarean section three years after her initial presentation. PMID- 27493843 TI - An Innovative and Portable Multimodal Pain Relief Device for the Management of Neuropathic Low Back Pain - a Study from Kashmir (Southeast Asia). AB - We developed a portable multimodal system with seven different mechanisms of pain relief incorporated into a lumbar belt called the Comfort-N-Harmony Belt (C&H belt). Here, we describe the technical details of the system and also summarize the effects of this multimodal pain relieving technology as an adjuvant to analgesics versus analgesics alone, on the level of pain, improvement of psychological status, disability, and the quality of life in the patients with neuropathic low back pain (LBP). We tracked the volunteers who were following up at a tertiary health care center for the complaints of neuropathic LBP of minimum three months duration and were on analgesics alone with no relief in the severity of the pain. Study group A (n = 45) consisted of volunteers with LBP on C&H belt therapy, along with the usually prescribed analgesic intake, and group B (n = 45) with LBP volunteers on analgesics, plus a similar looking but plain leather belt (placebo). For pain, the VAS (Visual Analogue Scale); for anxiety and depression, the (HADS) Hospital Anxiety-Depression Scale; for disability, the RMDQ (Roland Morris Disability Questionnaire); and for quality of life, (NHP) Nottingham Health-Profile were used before and after the study period. There were no significant differences in demographic variables between the groups (p < 0.05). After the study period of one month, VAS, RMDQ, NHP-pain, NHP-physical activity, and HADS scores in both groups were significantly improved compared to the pre treatment scores (p < 0.05). Group A also showed significant improvements in the scores of NHP-energy level and NHP-social isolation (p < 0.05). The post treatment scores did not significantly show any difference between the two groups (p > 0.05). However, in comparison of pre- and post-treatment scores, the pre treatment score values of RMDQ, NHP-pain, NHP-physical activity, and NHP-social isolation were much higher in group A compared to the group B, but still these scores were, in a statistically significant manner, improved in group A compared to the group B after the study period was over (p < 0.05). Multiple pain relieving mechanisms in a portable device-based system, when used along with analgesics, are effective in relieving pain, improving function and quality of life, and help in relieving the associated anxiety and depression in patients with chronic neuropathic LBP than the analgesics alone in the Kashmiri (Southeast Asian) population. PMID- 27493844 TI - A Prospective Cohort Evaluation of a Robotic, Auto-Navigating Operating Microscope. AB - The unique challenges inherent to microneurosurgery demand that we stay on the forefront of new surgical technologies. Many believe the next major technological advance in neurosurgery will be the widespread application of image-guided robotics in the operating room. We evaluated a novel technology for image-guided robotic auto-navigation of the operating microscope in a prospectively enrolled cohort of patients. Twenty patients were prospectively enrolled for analysis. Data were collected on the extent of resection, operative time, estimated blood loss, time taken to set up the new software, and complications encountered. Software accuracy, reliability, and usefulness in the case were subjectively evaluated. The most commonly treated pathologies were cavernous malformation (n = 5), arteriovenous malformation (n = 4), and meningioma (n = 4). The time to set up the new software interface before the start of the operation was <60 seconds in all cases. Subjective evaluation in each case revealed the robotic interface to be accurate, reliable, and useful. The new technology was significantly more useful in deeper lesions. The addition of image-guided robotic auto-positioning features to the operating microscope has a great potential to advance the field of neurosurgery. This study is the first prospective evaluation of such a technology in a patient cohort. The results suggest that the newest robotic auto positioning technology has the potential to improve the neurosurgeon's efficiency and efficacy, thereby positively impacting patient safety and surgical outcomes, especially in cases involving deep-seated lesions. PMID- 27493845 TI - Scleroderma in a Patient on Capecitabine: Is this a Variant of Hand-Foot Syndrome? AB - Drug-induced scleroderma is a rare adverse effect of some chemotherapeutic drugs, such as taxanes and bleomycin. Capecitabine, an oral fluoropyrimidine approved for the treatment of metastatic breast and colon cancer, commonly causes cutaneous side effects including the hand-and-foot syndrome (HFS). Scleroderma like skin changes associated with HFS associated with capecitabine is rare. However, diffuse scleroderma has never before been reported. We report a case of capecitabine-induced diffuse/systemic scleroderma in an 86-year-old female treated with capecitabine for metastatic colorectal cancer. She developed progressive skin and visceral sclerosis involving the lungs. We discuss the association between chemotherapy and scleroderma. We believe this is the first case of diffuse/systemic capecitabine-induced scleroderma without the presence of HFS. Early diagnosis is essential as fibrosis might be prevented in early stages. The capecitabine should be discontinued as early as possible. PMID- 27493846 TI - A Superior Cerebellar Convexity Two-Part Craniotomy to Access the Paramedian Supra and Infratentorial Space: Technical Note. AB - A craniotomy over the superior cerebellar convexity for approaches to this region typically involves a small infratentorial craniotomy and then drilling down of the bone to expose some portion of the transverse/sigmoid sinuses. The authors describe the anatomy of the region and the method for a two-part paramedian occipital and suboccipital craniotomy (supra and infratentorial) that may have time-saving, safety, and cosmetic advantages. For this technique, a supratentorial craniotomy is used to expose the transverse sinus from above, and subsequently, dissection across the sinus over the cerebellar convexity can be done under direct vision. The two bone pieces are joined on the inner table side while plates for fixation above the superior nuchal line can be counter-sunk to avoid post-operative pain from the prominence of screws. There is no need for cranioplasty materials since there is no burring down of bone for adequate exposure of the transverse sinus. The technique has been used by two senior surgeons over the years convincing them of the speed, safety, and utility of the technique. Here, the authors present a single example of the technique. PMID- 27493847 TI - A Rare Presentation of Ganglion Cyst of the Elbow. AB - INTRODUCTION: Ganglion cysts are benign soft tissue swellings commonly found in the wrist. The presence of these cysts in the elbow is uncommon, and few case reports have been reported for this condition at this location. These lesions can compress on the neighbouring structures or cause restriction of the joint movement. The awareness of this entity is a must, to arrive at an early diagnosis. MATERIALS AND METHOD: We report a patient with swelling in the anterolateral aspect of the elbow which had been causing intermittent pain for the last 13 months. The MRI revealed a fluid-filled cystic swelling which was communicating with the radio-capitellar joint. RESULTS: The lesion was excised in toto, using anterolateral approach for the elbow, and sent for histopathological examination which confirmed the diagnosis of a ganglion cyst. CONCLUSION: Thus, due to the infrequent presentation, an awareness of this condition is necessary to prevent a delay in diagnosis and its subsequent management. PMID- 27493848 TI - A Rare Giant Cell Tumor of the Distal Fibula and its Management. AB - Giant Cell Tumour (GCT) of the distal fibula is extremely rare and poses challenges in the surgical management. Wide excision or intralesional curettage, along with adjuvant chemical cauterisation can prevent the recurrence of GCT. The excised bone gap needs reconstruction using tricortical iliac autograft and supportive plate fixation. In addition to wide excision, preservation of ankle mortise is advisable in locally aggressive and large lesions of the distal fibula. We report a GCT of the distal fibula in a young female patient. As part of the treatment, en bloc resection, chemical cauterisation with phenol, and distal fibula reconstruction with a tricortical iliac crest bone graft was done. Eighteen months after the treatment, the patient has no recurrence and her ankle is stable with full range of movement. We suggest this method to be worthwhile for the treatment of this uncommon lesion in quantifying recurrence and functional outcome. PMID- 27493849 TI - Physicochemical origin of high correlation between thermal stability of a protein and its packing efficiency: a theoretical study for staphylococcal nuclease mutants. AB - There is an empirical rule that the thermal stability of a protein is related to the packing efficiency or core volume of the folded state and the protein tends to exhibit higher stability as the backbone and side chains are more closely packed. Previously, the wild type and its nine mutants of staphylococcal nuclease were compared by examining their folded structures. The results obtained were as follows: The stability was not correlated with the number of intramolecular hydrogen bonds, intramolecular electrostatic interaction energy, or degree of burial of the hydrophobic surface; though the empirical rule mentioned above held, it was not the proximate cause of higher stability; and the number of van der Waals contacts N vdW, or equivalently, the intramolecular van der Waals interaction energy was an important factor governing the stability. Here we revisit the wild type and its nine mutants of staphylococcal nuclease using our statistical-mechanical theory for hydration of a protein. A molecular model is employed for water. We show that the pivotal factor is the magnitude of the water entropy gain upon folding. The gain originates from an increase in the total volume available to the translational displacement of water molecules coexisting with the protein in the system. The magnitude is highly correlated with the denaturation temperature T m. Moreover, the apparent correlation between N vdW and T m as well as the empirical rule is interpretable (i.e., their physicochemical meanings can be clarified) on the basis of the water-entropy effect. PMID- 27493850 TI - Three-dimensional vertex model for simulating multicellular morphogenesis. AB - During morphogenesis, various cellular activities are spatiotemporally coordinated on the protein regulatory background to construct the complicated, three-dimensional (3D) structures of organs. Computational simulations using 3D vertex models have been the focus of efforts to approach the mechanisms underlying 3D multicellular constructions, such as dynamics of the 3D monolayer or multilayer cell sheet like epithelia as well as the 3D compacted cell aggregate, including dynamic changes in layer structures. 3D vertex models enable the quantitative simulation of multicellular morphogenesis on the basis of single cell mechanics, with complete control of various cellular activities such as cell contraction, growth, rearrangement, division, and death. This review describes the general use of the 3D vertex model, along with its applications to several simplified problems of developmental phenomena. PMID- 27493851 TI - The molecular dynamics of crawling migration in microtubule-disrupted keratocytes. AB - Cell-crawling migration plays an essential role in complex biological phenomena. It is now generally believed that many processes essential to such migration are regulated by microtubules in many cells, including fibroblasts and neurons. However, keratocytes treated with nocodazole, which is an inhibitor of microtubule polymerization - and even keratocyte fragments that contain no microtubules - migrate at the same velocity and with the same directionality as normal keratocytes. In this study, we discovered that not only these migration properties, but also the molecular dynamics that regulate such properties, such as the retrograde flow rate of actin filaments, distributions of vinculin and myosin II, and traction forces, are also the same in nocodazole-treated keratocytes as those in untreated keratocytes. These results suggest that microtubules are not in fact required for crawling migration of keratocytes, either in terms of migrating properties or of intracellular molecular dynamics. PMID- 27493852 TI - Protein-protein interactions of mitochondrial-associated protein via bioluminescence resonance energy transfer. AB - Protein-protein interactions are essential biological reactions occurring at inter- and intra-cellular levels. The analysis of their mechanism is generally required in order link to understand their various cellular functions. Bioluminescence resonance energy transfer (BRET), which is based on an enzymatic activity of luciferase, is a useful tool for investigating protein-protein interactions in live cells. The combination of the BRET system and biomolecular fluorescence complementation (BiFC) would provide us a better understanding of the hetero-oligomeric structural states of protein complexes. In this review, we discuss the application of BRET to the protein-protein interactions of mitochondrial-associated proteins and discuss its physiological relevance. PMID- 27493853 TI - Specific interactions between alkali metal cations and the KcsA channel studied using ATR-FTIR spectroscopy. AB - The X-ray structure of KcsA, a eubacterial potassium channel, displays a selectivity filter composed of four parallel peptide strands. The backbone carbonyl oxygen atoms of these strands solvate multiple K(+) ions. KcsA structures show different distributions of ions within the selectivity filter in solutions containing different cations. To assess the interactions of cations with the selectivity filter, we used attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. Ion-exchange-induced ATR-FTIR difference spectra were obtained by subtracting the spectrum of KcsA soaked in K(+) solution from that obtained in Li(+), Na(+), Rb(+), and Cs(+) solutions. Large spectral changes in the amide-I and -II regions were observed upon replacing K(+) with smaller-sized cations Li(+) and Na(+) but not with larger sized cations Rb(+) and Cs(+). These results strongly suggest that the selectivity filter carbonyls coordinating Rb(+) or Cs(+) adopt a conformation similar to those coordinating K(+) (cage configuration), but those coordinating Li(+) or Na(+) adopt a conformation (plane configuration) considerably different from those coordinating K(+). We have identified a cation-type sensitive amide-I band at 1681 cm(-1) and an insensitive amide-I band at 1659 cm(-1). The bands at 1650, 1639, and 1627 cm(-1) observed for Na(+)-coordinating carbonyls were almost identical to those observed in Li(+) solution, suggesting that KcsA forms a similar filter structure in Li(+) and Na(+) solutions. Thus, we conclude that the filter structure adopts a collapsed conformation in Li(+) solution that is similar to that in Na(+) solution but is in clear contrast to the X-ray crystal structure of KcsA with Li(+). PMID- 27493854 TI - Structural comparison between the open and closed forms of citrate synthase from Thermus thermophilus HB8. AB - The crystal structures of citrate synthase from the thermophilic eubacteria Thermus thermophilus HB8 (TtCS) were determined for an open form at 1.5 A resolution and for closed form at 2.3 A resolution, respectively. In the absence of ligands TtCS in the open form was crystalized into a tetragonal form with a single subunit in the asymmetric unit. TtCS was also co-crystallized with citrate and coenzyme-A to form an orthorhombic crystal with two homodimers in the asymmetric unit. Citrate and CoA are found in the active site situated between the large domain and the small domain in all subunit whereas the complex shows two distinct closed conformations, the fully closed form and partially closed form. Structural comparisons are performed to describe conformational changes associated with binding of products of TtCS. Upon binding of citrate, basic residues in the active site move toward citrate and make a hydrogen bond network in the active site, inducing a large-scale rotation of the small domain relative to the large domain. CoA is sandwiched between the small and large domains and then the cysteamine tail is inserted into the active site with a cooperative rotation around mainchain dihedrals in the hinge region connecting helices M and N. According to this rotation these helices are extended to close the active site completely. The considerable flexibility and structural rearrangements in the hinge region are crucial for an ordered bibi reaction in catalysis for microbial CSs. PMID- 27493856 TI - Time-resolved chemiluminescence of firefly luciferin generated by dissolving oxygen in deoxygenated dimethyl sulfoxide containing potassium tert-butoxide. AB - Chemiluminescence (CL) of firefly luciferin (Ln) consisting of red and green emission peaks can be generated by dissolving oxygen (O2) gas in deoxygenated dimethyl sulfoxide containing potassium tert-butoxide (t-BuOK) even without the enzyme luciferase. In this study, the characteristics of CL of Ln are examined by varying the concentrations of both Ln ([Ln]) and t-BuOK ([t-BuOK]). The time courses of the green and the red luminescence signals are also measured using a 32-channel photo sensor module. Interestingly, addition of 18-crown-6 ether (18 crown-6), a good clathrate for K(+), to the reaction solution before exposure to O2 changes the luminescence from green to red when [t-BuOK] = 20 mM and [18-crown 6] = 80 mM. Based on our experimental results, we propose a two-pathway model where K(+) plays an important role in the regulation of Ln CL to explain the two color luminescence observed from electronically excited oxyluciferin via dioxetanone. PMID- 27493855 TI - Investigation of glycan evolution based on a comprehensive analysis of glycosyltransferases using phylogenetic profiling. AB - Glycans play important roles in such cell-cell interactions as signaling and adhesion, including processes involved in pathogenic infections, cancers, and neurological diseases. Glycans are biosynthesized by multiple glycosyltransferases (GTs), which function sequentially. Excluding mucin-type O glycosylation, the non-reducing terminus of glycans is biosynthesized in the Golgi apparatus after the reducing terminus is biosynthesized in the ER. In the present study, we performed genome-wide analyses of human GTs by investigating the degree of conservation of homologues in other organisms, as well as by elucidating the phylogenetic relationship between cephalochordates and urochordates, which has long been controversial in deuterostome phylogeny. We analyzed 173 human GTs and functionally linked glycan synthesis enzymes by phylogenetic profiling and clustering, compiled orthologous genes from the genomes of other organisms, and converted them into a binary sequence based on the presence (1) or absence (0) of orthologous genes in the genomes. Our results suggest that the non-reducing terminus of glycans is biosynthesized by newly evolved GTs. According to our analysis, the phylogenetic profiles of GTs resemble the phylogenetic tree of life, where deuterostomes, metazoans, and eukaryotes are resolved into separate branches. Lineage-specific GTs appear to play essential roles in the divergence of these particular lineages. We suggest that urochordates lose several genes that are conserved among metazoans, such as those expressing sialyltransferases, and that the Golgi apparatus acquires the ability to synthesize glycans after the ER acquires this function. PMID- 27493857 TI - Subattomole detection of adiponectin in urine by ultrasensitive ELISA coupled with thio-NAD cycling. AB - Adiponectin is a hormone secreted from adipocytes, and it demonstrates antidiabetic, anti-atherosclerotic, antiobesity and anti-inflammatory effects. However, the patterns of change in urinary adiponectin levels in various diseases remain unknown, because only trace amounts of the hormone are present in urine. In the present study, we applied an ultrasensitive ELISA coupled with thio-NAD cycling to measure urinary adiponectin levels. Spikeand-recovery tests using urine confirmed the reliability of our ultrasensitive ELISA. The limit of detection for adiponectin in urine was 2.3*10(-19) moles/assay (1.4 pg/mL). The urinary adiponectin concentration ranged between 0.04 and 5.82 ng/mL in healthy subjects. The pilot study showed that the urinary adiponectin levels, which were corrected by the creatinine concentration, were 0.73+/-0.50 (ng/mg creatinine, N=6) for healthy subjects, versus 12.02+/-3.85 (ng/mg creatinine, N=3) for patients with diabetes mellitus (DM). That is, the urinary adiponectin levels were higher (P<0.05) in DM patients than in healthy subjects. Further, these urinary adiponectin levels tended to increase with the progression of DM accompanied with nephropathy. Our method is thus expected to provide a simple, rapid and reasonably priced test for noninvasive monitoring of the progression of DM without the requirement of special tools. PMID- 27493858 TI - Rotational motion of rhodamine 6G tethered to actin through oligo(ethylene glycol) linkers studied by frequency-domain fluorescence anisotropy. AB - Investigation of the rotational motion of a fluorescent probe tethered to a protein helps to elucidate the local properties of the solvent and protein near the conjugation site of the probe. In this study, we have developed an instrument for frequency-domain fluorescence (FDF) anisotropy measurements, and studied how the local properties around a protein, actin, can be elucidated from the rotational motion of a dye tethered to actin. Rhodamine 6G (R6G) was attached to Cys-374 using newly-synthesized R6G-maleimide with three different oligo(ethylene glycol) (OEG) linker lengths. The time-resolved anisotropy decay of R6G tethered to G-actin was revealed to be a combination of the two modes of the wobbling motion of R6G and the tumbling motion of G-actin. The rotational diffusion coefficient (RDC) of R6G wobbling was ~0.1 ns(-1) at 20 degrees C and increased with OEG linker length. The use of the three R6G-actin conjugates of different linker lengths was useful to not only figure out the linker length dependence of the rotational motion of R6G but also validate the analyses. In the presence of a cosolvent of glycerol, although the tumbling motion of G-actin was retarded in response to the bulk viscosity, the wobbling motion of R6G tethered to actin exhibited an increase of RDC as glycerol concentration increased. This finding suggests an intricate relationship between the fluid properties of the bulk solvent and the local environment around actin. PMID- 27493859 TI - Case study on the evolution of hetero-oligomer interfaces based on the differences in paralogous proteins. AB - We addressed the evolutionary trace of hetero-oligomer interfaces by comparing the structures of paralogous proteins; one of them is a monomer or homo-oligomer and the other is a hetero-oligomer. We found different trends in amino acid conservation pattern and hydrophobicity between homo-oligomer and hetero oligomer. The degree of amino acid conservation in the interface of homo-oligomer has no obvious difference from that in the surface, whereas the degree of conservation is much higher in the interface of hetero-oligomer. The interface of homo-oligomer has a few very conserved residue positions, whereas the residue conservation in the interface of hetero-oligomer tends to be higher. In addition, the interface of hetero-oligomer has a tendency of being more hydrophobic compared with the one in homo-oligomer. We conjecture that these differences are related to the inherent symmetry in homo-oligomers that cannot exist in hetero oligomers. Paucity of the structural data precludes statistical tests of these tendencies, yet the trend can be applied to the prediction of the interface of hetero-oligomer. We obtained putative interfaces of the subunits in CPSF (cleavage and polyadenylation specificity factor), one of the human pre-mRNA 3' processing complexes. The locations of predicted interface residues were consistent with the known experimental data. PMID- 27493860 TI - Liquid-theory analogy of direct-coupling analysis of multiple-sequence alignment and its implications for protein structure prediction. AB - The direct-coupling analysis is a powerful method for protein contact prediction, and enables us to extract "direct" correlations between distant sites that are latent in "indirect" correlations observed in a protein multiple-sequence alignment. I show that the direct correlation can be obtained by using a formulation analogous to the Ornstein-Zernike integral equation in liquid theory. This formulation intuitively illustrates how the indirect or apparent correlation arises from an infinite series of direct correlations, and provides interesting insights into protein structure prediction. PMID- 27493861 TI - Microbial rhodopsins: wide distribution, rich diversity and great potential. AB - One of the major topics in biophysics and physicobiology is to understand and utilize biological functions using various advanced techniques. Taking advantage of the photoreactivity of the seven-transmembrane rhodopsin protein family has been actively investigated by a variety of methods. Rhodopsins serve as models for membrane-embedded proteins, for photoactive proteins and as a fundamental tool for optogenetics, a new technology to control biological activity with light. In this review, we summarize progress of microbial rhodopsin research from the viewpoint of distribution, diversity and potential. PMID- 27493862 TI - Analysis of water channels by molecular dynamics simulation of heterotetrameric sarcosine oxidase. AB - A precise 100-ns molecular dynamics simulation in aquo was performed for the heterotetrameric sarcosine oxidase bound with a substrate analogue, dimethylglycine. The spatial region including the protein was divided into small rectangular cells. The average number of the water molecules locating within each cell was calculated based on the simulation trajectory. The clusters of the cells filled with water molecules were used to determine the water channels. The narrowness of the channels, the average hydropathy indices of the residues of the channels, and the number of migration events of water molecules through the channels were consistent with the selective transport hypothesis whereby tunnel T3 is the pathway for the exit of the iminium intermediate of the enzyme reaction. PMID- 27493863 TI - Structural role of two histidines in the (6-4) photolyase reaction. AB - Photolyases (PHRs) are DNA repair enzymes that revert UV-induced photoproducts, either cyclobutane pyrimidine dimers (CPD) or (6-4) photoproducts (PPs), into normal bases to maintain genetic integrity. (6-4) PHR must catalyze not only covalent bond cleavage, but also hydroxyl or amino group transfer, yielding a more complex mechanism than that postulated for CPD PHR. Previous mutation analysis revealed the importance of two histidines in the active center, H354 and H358 for Xenopus (6-4) PHR, whose mutations significantly lowered the enzymatic activity. Based upon highly sensitive FTIR analysis of the repair function, here we report that both H354A and H358A mutants of Xenopus (6-4) PHR still maintain their repair activity, although the efficiency is much lower than that of the wild type. Similar difference FTIR spectra between the wild type and mutant proteins suggest a common mechanism of repair in which (6-4) PP binds to the active center of each mutant, and is released after repair, as occurs in the wild type. Similar FTIR spectra also suggest that a decrease in volume by the H-to-A mutation is possibly compensated by the addition of water molecule( s). Such a modified environment is sufficient for the repair function that is probably controlled by proton-coupled electron transfer between the enzyme and substrate. On the other hand, two histidines must work in a concerted manner in the active center of the wild-type enzyme, which significantly raises the repair efficiency. PMID- 27493864 TI - Structures of the troponin core domain containing the cardiomyopathy-causing mutants studied by small-angle X-ray scattering. AB - Troponin (Tn), consisting of three subunits, TnC, TnI, and TnT, is a protein in the thin filaments in muscle, and, together with another thin-filament protein tropomyosin (Tm), plays a major role in regulation of muscle contraction. Various mutations of Tn cause familial hypertrophic cardiomyopathy. These mutations are directly related to aberrations in this regulatory mechanism. Here we focus on the mutations E244D and K247R of TnT, which reside in the middle of the pathway of the Ca(2+)-binding signal from TnC to Tm. These mutations induce an increase in the maximum tension of cardiac muscle without changes in Ca(2+)-sensitivity. As a first step toward elucidating the molecular mechanism underlying this functional aberration, we carried out small-angle X-ray scattering experiments on the Tn core domain containing the wild type subunits and those containing the mutant TnT in the absence and presence of Ca(2+). Changes in the overall shape induced by the mutations were detected for the first time by the changes in the radius of gyration and the maximum dimension between the wild type and the mutants. Analysis of the scattering curves by model calculations shows that TnC adopts a dumbbell structure regardless of the mutations, and that the mutations change the distributions of the conformational ensembles so that the flexible N- and C-terminal regions of TnT become close to the center of the whole moelcule. This suggests, since these regions are related to the Tn-Tm interactions, that alteration of the Tn-Tm interactions induced by the mutations causes the functional aberration. PMID- 27493865 TI - Diet composition as a source of variation in experimental animal models of cancer cachexia. AB - BACKGROUND: A variety of experimental animal models are used extensively to study mechanisms underlying cancer cachexia, and to identify potential treatments. The important potential confounding effect of dietary composition and intake used in many preclinical studies of cancer cachexia is frequently overlooked. Dietary designs applied in experimental studies should maximize the applicability to human cancer cachexia, meeting the essential requirements of the species used in the study, matched between treatment and control groups as well as also being generally similar to human consumption. METHODS: A literature review of scientific studies using animal models of cancer and cancer cachexia with dietary interventions was performed. Studies that investigated interventions using lipid sources were selected as the focus of discussion. RESULTS: The search revealed a number of nutrient intervention studies (n = 44), with the majority including n-3 fatty acids (n = 16), mainly eicosapentaenoic acid and/or docosahexaenoic acid. A review of the literature revealed that the majority of studies do not provide information about dietary design; food intake or pair-feeding is rarely reported. Further, there is a lack of standardization in dietary design, content, source, and overall composition in animal models of cancer cachexia. A model is proposed with the intent of guiding dietary design in preclinical studies to enable comparisons of dietary treatments within the same study, translation across different study designs, as well as application to human nutrient intakes. CONCLUSION: The potential for experimental endpoints to be affected by variations in food intake, macronutrient content, and diet composition is likely. Diet content and composition should be reported, and food intake assessed. Minimum standards for diet definition in cachexia studies would improve reproducibility of pre-clinical studies and aid the interpretation and translation of results to humans with cancer. PMID- 27493866 TI - Sarcopenic obesity and myosteatosis are associated with higher mortality in patients with cirrhosis. AB - BACKGROUND AND AIMS: Obesity is frequently associated with cirrhosis, and cirrhotic patients may develop simultaneous loss of skeletal muscle and gain of adipose tissue, culminating in the condition of sarcopenic obesity. Additionally, muscle depletion is characterized by both a reduction in muscle size and increased proportion of muscular fat, termed myosteatosis. In this study, we aimed to establish the frequency and clinical significance of sarcopenia, sarcopenic obesity and myosteatosis in cirrhotic patients. METHODS: We analysed 678 patients with cirrhosis. Sarcopenia, sarcopenic obesity and myosteatosis were analysed by CT scan using the third lumbar vertebrae skeletal muscle and attenuation indexes, using previously validated gender-and body mass index specific cutoffs. RESULTS: Patients were predominately men (n = 457, 67%), and cirrhosis aetiology was hepatitis C virus in 269 patients (40%), alcohol in 153 (23%), non-alcoholic steatohepatitis/cryptogenic in 96 (14%), autoimmune liver disease in 55 (8%), hepatitis B virus in 43 (6%), and others in 5 patients (1%). Sarcopenia was present in 292 (43%), 135 had sarcopenic obesity (20%) and 353 had myosteatosis (52%). Patients with sarcopenia (22 +/- 3 vs. 95 +/- 22 months, P < 0.001), sarcopenic obesity (22 +/- 3 vs. 95 +/- 22 months, P < 0.001), and myosteatosis (28 +/- 5 vs. 95 +/- 22 months, P < 0.001) had worse median survival than patients without muscular abnormalities. By multivariate Cox regression analysis, both sarcopenia [hazard ratio (HR) 2.00, 95% confidence interval (CI) 1.44-2.77, P < 0.001], and myosteatosis (HR 1.42, 95% CI 1.02-1.07, P = 0.04) were associated with mortality. CONCLUSIONS: Sarcopenia, sarcopenic obesity and myosteatosis are often present in patients with cirrhosis, and sarcopenia and myosteatosis are independently associated with a higher long-term mortality in cirrhosis. PMID- 27493867 TI - Prevalence of sarcopenia among community-dwelling elderly of a medium-sized South American city: results of the COMO VAI? study. AB - BACKGROUND: There is insufficient data concerning sarcopenia prevalence in South America. The aim of this study was to estimate sarcopenia prevalence and its clinical subgroups in a Southern Brazilian city. METHODS: A cross-sectional population-based study was performed among community-dwelling elderly aged 60 years or over. Subjects were evaluated according to the European Working Group on Sarcopenia in Older People established criteria. Muscle mass was estimated by calf circumference (CC). Cut-off CC points were defined by a subsample's dual X ray absorptiometry estimation of the appendicular skeletal muscle mass index (ASMI), which was subsequently compared with the values of a young adult population from the same city. Muscle strength was measured by manual dynamometry. Muscle performance was assessed through the 4 m gait speed test. RESULTS: The three diagnostic tests were performed in 1291 subjects. CC of <=34 cm (males) and <=33 cm (females) were defined as indicatives of low ASMI. The overall sarcopenia prevalence was 13.9% (CI95% 12.0; 15.8%). Its frequency was significantly higher among elderly with low schooling, without a partner, with low socioeconomic status, smokers, inactive, and with low body mass index. A higher prevalence of pre-sarcopenia was found in the youngest elderly; a higher prevalence of the clinical stages of the syndrome was found in older age groups. CONCLUSIONS: Approximately one in ten elderly aged 60-69 years was in the preclinical stage of the disease. This is the age group in which public policies should focus to establish early diagnosis and prevent clinical progression of the syndrome. PMID- 27493868 TI - Association of estimated glomerular filtration rate with all-cause and cardiovascular mortality: the role of malnutrition-inflammation-cachexia syndrome. AB - BACKGROUND: Previous studies have demonstrated that high estimated glomerular filtration rate (eGFR) is paradoxically associated with an increased risk of mortality, and the association becomes more predominant in older people. However, the role of malnutrition-inflammation-cachexia syndrome (MICS) in the association between eGFR and mortality has never been explored. METHODS: We conducted a community-based cohort study using data from the Taipei City Elderly Health Examination Database, collected during the period 2001-10. All participants aged >=65 years were included and stratified by the absence or presence of MICS, which is defined as the presence of at least one of the following markers: body mass index <22 kg/m(2), serum albumin <3.0 mg/dL, or Geriatric Nutritional Risk Index (GNRI) <98. The study endpoints were all-cause and cardiovascular mortality. RESULTS: A total of 131 354 participants were identified and categorized according to the chronic kidney disease stage based on eGFR. Compared with the reference eGFR of 60-89 mL/min/1.73 m(2), the overall and cardiovascular mortality risks were markedly high in the groups with eGFR of <30 mL/min/1.73 m(2) [overall: adjusted hazard ratio (aHR), 1.86; 95% confidence interval (CI), 1.72-2.00; cardiovascular: aHR, 1.87; 95% CI, 1.60-2.19] and >=90 mL/min/1.73 m(2) (overall: aHR, 1.23; 95% CI, 1.13-1.34; cardiovascular: aHR, 1.28; 95% CI, 1.06-1.54). In the absence of MICS, high eGFR was associated with lower mortality risk (aHR, 0.71; 95% CI, 0.62-0.80), and the U-shaped relationship disappeared. Subgroup analyses produced consistent results. CONCLUSIONS: MICS could influence the association observed between high eGFR and mortality in older people, particularly in those with low body mass index, albumin level, GNRI, and very low serum creatinine level. PMID- 27493869 TI - Muscle wasting and adipose tissue browning in infantile nephropathic cystinosis. AB - BACKGROUND: Muscle wasting is a common complication in patients with infantile nephropathic cystinosis, but its mechanism and association with energy metabolism is not known. We define the metabolic phenotype in Ctns(-/-) mice, an established murine model of infantile nephropathic cystinosis, with focus on muscle wasting and energy homeostasis. METHODS: Male Ctns(-/-) mice and wild-type (WT) controls were studied at 1, 4, 9, and 12 months of age. As Ctns(-/-) mice started to develop chronic kidney disease (CKD) at 9 months of age, 9- and 12-month-old Ctns(-/-) mice were also compared with age-matched WT mice with CKD. Serum and urine chemistry and energy homeostasis parameters were measured. Skeletal muscle histomorphometry and in vivo muscle function were measured. We studied expression of genes involved in muscle mass regulation, thermogenesis, energy metabolism, adipogenesis, and adipose tissue browning in Ctns(-/-) mice. RESULTS: Ctns(-/-) mice showed loss of weight and lean mass and increased energy expenditure. Ctns( /-) mice exhibited abnormal energy homeostasis before the onset of their CKD. Food intake in Ctns(-/-) mice was comparable with age-matched WT controls. However, significantly lower total body mass starting at 1 month of age and increased energy expenditure at 4 months of age preceded the onset of CKD at 9 months of age in Ctns(-/-) mice. Muscle accept content in 1- and 4-month-old Ctns(-/-) mice was significantly lower than that in age-matched WT controls. At 12 months of age, muscle fibre area and in vivo muscle strength was reduced in Ctns(-/-) mice than that in WT or CKD controls. Muscle wasting in Ctns(-/-) mice was associated with inhibition of myogenesis, activation of muscle proteolysis pathways, and overexpression of pro-inflammatory cytokines. Increased energy expenditure was associated with elevation of thermogenesis in skeletal muscle and adipose tissues. The development of beige adipocytes in Ctns(-/-) mice is a novel finding. Expression of beige adipose cell surface markers (CD137, Tmem26, and Tbx1) and uncoupling protein-1, which is a brown adipose tissue marker, was observed in inguinal white adipose tissue of Ctns(-/-) mice. Expression of key molecules implicated in the pathogenesis of adipose tissue browning (Cox2, cytochrome c oxidase subunit II; PGF2alpha, prostaglandin F2alpha; IL-1alpha, interleukin 1alpha; IL-6, interleukin 6; TNF-alpha, tumor necrosis factor alpha) was significantly increased in inguinal white adipose tissue of Ctns(-/-) mice than that in WT controls. CONCLUSION: This study describes a mouse model of nephropathic cystinosis presenting with profound muscle wasting. The mechanism for hypermetabolism in Ctns(-/-) mice may involve up-regulation of thermogenesis pathways in skeletal muscle and adipose tissues. This study demonstrates, for the first time, the development of beige adipocytes in Ctns(-/-) mice. Understanding the underlying mechanisms of adipose tissue browning in cystinosis may lead to novel therapy. PMID- 27493870 TI - Muscle RING-finger 2 and 3 maintain striated-muscle structure and function. AB - BACKGROUND: The Muscle-specific RING-finger (MuRF) protein family of E3 ubiquitin ligases is important for maintenance of muscular structure and function. MuRF proteins mediate adaptation of striated muscles to stress. MuRF2 and MuRF3 bind to microtubules and are implicated in sarcomere formation with noticeable functional redundancy. However, if this redundancy is important for muscle function in vivo is unknown. Our objective was to investigate cooperative function of MuRF2 and MuRF3 in the skeletal muscle and the heart in vivo. METHODS: MuRF2 and MuRF3 double knockout mice (DKO) were generated and phenotypically characterized. Skeletal muscle and the heart were investigated by morphological measurements, histological analyses, electron microscopy, immunoblotting, and real-time PCR. Isolated muscles were subjected to in vitro force measurements. Cardiac function was determined by echocardiography and working heart preparations. Function of cardiomyocytes was measured in vitro. Cell culture experiments and mass-spectrometry were used for mechanistic analyses. RESULTS: DKO mice showed a protein aggregate myopathy in skeletal muscle. Maximal force development was reduced in DKO soleus and extensor digitorum longus. Additionally, a fibre type shift towards slow/type I fibres occurred in DKO soleus and extensor digitorum longus. MuRF2 and MuRF3-deficient hearts showed decreased systolic and diastolic function. Further analyses revealed an increased expression of the myosin heavy chain isoform beta/slow and disturbed calcium handling as potential causes for the phenotype in DKO hearts. CONCLUSIONS: The redundant function of MuRF2 and MuRF3 is important for maintenance of skeletal muscle and cardiac structure and function in vivo. PMID- 27493871 TI - Degenerin channel activation causes caspase-mediated protein degradation and mitochondrial dysfunction in adult C. elegans muscle. AB - BACKGROUND: Declines in skeletal muscle structure and function are found in various clinical populations, but the intramuscular proteolytic pathways that govern declines in these individuals remain relatively poorly understood. The nematode Caenorhabditis elegans has been developed into a model for identifying and understanding these pathways. Recently, it was reported that UNC 105/degenerin channel activation produced muscle protein degradation via an unknown mechanism. METHODS: Generation of transgenic and double mutant C. elegans, RNAi, and drug treatments were utilized to assess molecular events governing protein degradation. Western blots were used to measure protein content. Cationic dyes and adenosine triphosphate (ATP) production assays were utilized to measure mitochondrial function. RESULTS: unc-105 gain-of-function mutants display aberrant muscle protein degradation and a movement defect; both are reduced in intragenic revertants and in let-2 mutants that gate the hyperactive UNC-105 channel. Degradation is not suppressed by interventions suppressing proteasome-mediated, autophagy-mediated, or calpain-mediated degradation nor by suppressors of degenerin-induced neurodegeneration. Protein degradation, but not the movement defect, is decreased by treatment with caspase inhibitors or RNAi against ced-3 or ced-4. Adult unc-105 muscles display a time dependent fragmentation of the mitochondrial reticulum that is associated with impaired mitochondrial membrane potential and that correlates with decreased rates of maximal ATP production. Reduced levels of CED-4, which is sufficient to activate CED-3 in vitro, are observed in unc-105 mitochondrial isolations. CONCLUSIONS: Constitutive cationic influx into muscle appears to cause caspase degradation of cytosolic proteins as the result of mitochondrial dysfunction, which may be relevant to ageing and sarcopenia. PMID- 27493872 TI - White adipose tissue cells and the progression of cachexia: inflammatory pathways. AB - BACKGROUND: Cachexia is a systemic syndrome leading to body wasting, systemic inflammation, and to metabolic chaos. It is a progressive condition, and little is known about its dynamics. Detection of the early signs of the disease may lead to the attenuation of the associated symptoms. The white adipose tissue is an organ with endocrine functions, capable of synthesising and secreting a plethora of proteins, including cytokines, chemokines, and adipokines. It is well established that different adipose tissue depots demonstrate heterogeneous responses to physiological and pathological stimuli. The present study aimed at providing insight into adipocyte involvement in inflammation along the progression of cachexia. METHODS: Eight-weeks-old male rats were subcutaneously inoculated with a Walker 256 carcinosarcoma cell suspension (2 * 10(7) cells in 1.0 mL; tumour-bearing, T) or Phosphate-buffered saline (control, C). The retroperitoneal, epididymal, and mesenteric adipose pads were excised on Days 0, 7, and 14 post-tumour cell injection, and the adipocytes were isolated. RESULTS: Mesenteric and epididymal adipocytes showed up-regulation of IL-1beta protein expression and activation of the inflammasome pathway, contributing for whole tissue inflammation. The stromal vascular fraction of the retroperitoneal adipose tissue, on the other hand, seems to be the major contributor for the inflammation in this specific pad. CONCLUSION: Adipocytes seem to play a relevant role in the establishment of white adipose tissue inflammation, through the activation of the NF-kappaB and inflammasome pathways. In epididymal adipocytes, induction of the inflammasome may be detected already on Day 7 post-tumour cell inoculation. PMID- 27493873 TI - p62/SQSTM1 but not LC3 is accumulated in sarcopenic muscle of mice. AB - AIM: We investigated the pathway of autophagy signaling linked to sarcopenia of mice. METHODS: Young adult (3-month) and aged (24- month) C57BL/6J mice were used. Using real-time PCR, Western blotting, and immunohistochemical microscopy, we evaluated the amounts of p62/SQSTM1, LC3, and Beclin-1 in the quadriceps muscle change with aging in mice. RESULTS: Marked fiber atrophy (30%) and many fibers with central nuclei were observed in the aged mice. Western blotting using homogenate of the cytosolic fraction clearly showed that the amounts of p62/SQSTM1 and Beclin-1 proteins were significantly increased in the aged skeletal muscle. The amounts of these proteins in both nuclear and membrane fractions did not change significantly with age. Immunofluorescence labeling indicated that aged mice more frequently possessed p62/SQSTM1-positive fibers in the cytosol in quadriceps muscle than young ones (aged: 14% vs. young: 1%). In aged muscle, p62/SQSTM1-positive fibers were significantly smaller than the surrounding p62/SQSTM1-negative fibers. Aging did not elicit significant changes in the mRNA levels of p62/SQSTM1 and Beclin-1, but decreased LC3 mRNA level. In aged muscle, the location of p62/SQSTM1 immunoreactivity was similar to that of Beclin-1 protein, but not LC3. CONCLUSION: Sarcopenia in mice appears to include a marked defect of autophagy signaling. PMID- 27493876 TI - The concept that focuses on oral motor and feeding function in cancer patients with muscle wasting: Skeletal muscle mass is associated with severe dysphagia in cancer patients. PMID- 27493875 TI - Salidroside alleviates cachexia symptoms in mouse models of cancer cachexia via activating mTOR signalling. AB - BACKGROUND: Cachexia has a devastating impact on survival and quality of life for many cancer patients and contributes to nearly one-third of all cancer deaths; also, it is associated with poor responses to chemotherapy and survival. A better understanding of the underlying mechanisms of cancer-associated cachexia (CAC), coupled with effective therapeutic approaches, will improve management of progressive functional impairment in cancer patients. Salidroside, a phenylpropanoid glycoside in Rhodiola rosea L, has been reported to possess potential anti-fatigue, anti-ageing, and anti-Alzheimer's disease properties. It is widely consumed as a nutritional supplement, but its effects on CAC and the possible mechanism remain a mystery. METHODS: In the murine models of cachexia induced by CT-26 and Lewis lung carcinoma (LLC) tumour, respectively, main features of CAC were determined after treatment of salidroside or chemotherapy. In vitro experiments were performed using murine C2C12 myotubes, which were treated by tumour necrosis factor-alpha. Levels of several critical muscle related signal proteins such as mammalian target of rapamycin (mTOR), p-mTOR, and myosin heavy chain (MyHC) were examined using western blot both in vitro and in vivo. RESULTS: In the present study, we showed the exciting effect of salidroside on the treatment of CAC. In CT-26 and LLC models, respectively, salidroside treatment could effectively preserve the tumour-free body weight, decrease loss of adipose and gastrocnemius muscles, alleviate tumour burden, and prolong their survival time. Additionally, in combined chemotherapy, salidroside could synergistically enhance the anti-tumour activity of cisplatin, especially decreased or eliminated chemotherapy-induced cachexia. Further analysis demonstrated that salidroside could significantly increase expression of mTOR, p mTOR, and MyHC in gastrocnemius muscle. Also, results in vitro showed that salidroside could not only obviously increase mTOR, p-mTOR, and MyHC expression in C2C12 myotubes but also effectively rescue their down-regulation induced by tumour necrosis factor-alpha. CONCLUSIONS: In the current study, the exciting effect of salidroside on CAC suggested that salidroside supplementation might be a promising approach for a multi-targeted therapy for the treatment of CAC. PMID- 27493874 TI - Diabetic mice exhibited a peculiar alteration in body composition with exaggerated ectopic fat deposition after muscle injury due to anomalous cell differentiation. AB - BACKGROUND: Sarcopenic obesity, age-related muscle loss, which is compensated by an increase in fat mass, impairs quality of life in elderly people. Although the increase in intramuscular fat is associated with decreased insulin sensitivity and increased metabolic risk factors, the origin of diabetes-associated intramuscular fat has not been elucidated. Here, we investigated intramuscular fat deposition using a muscle injury model in type 2 diabetic mice. METHODS: Male 8-week-old C57BL/6 and 8-week-old and 26-week-old KKAy underwent intramuscular injection of cardiotoxin (Ctx) (100 MUL/10 MUM) into the tibialis anterior (TA) muscles. After 2 weeks, the muscles were removed and evaluated. RESULTS: KKAy exhibited impaired muscle regeneration and ectopic fat deposition. Such impairment was more marked in older KKAy. These changes were also observed in another diabetic mouse model, db/db and diet-induced obese mice but not in streptozocin-induced diabetic mice. Deposited fat was platelet-derived growth factor (PDGF) receptor alpha positive and its cytoskeleton was stained with Masson's trichrome, indicating it to be of fibro-adipocyte progenitor cell origin. Expression of a myogenic marker, myoD, was lower and that of PDGF receptor alpha and CCAAT/enhancer binding protein (CEBP) alpha was higher in Ctx injured TA of KKAy compared with that of C57BL/6. Peroxisome proliferator activated receptor gamma (PPARgamma) was highly expressed in fat-forming lesions in older KKAy. Treatment with all-trans retinoic acid prevented the formation of intramuscular fat; however, treatment with GW9662, a PPARgamma antagonist, increased the fibrotic change in muscle. CONCLUSIONS: Diabetic mice showed impaired muscle regeneration with fat deposition, suggesting that diabetes may enhance sarcopenic obesity through a mechanism involving anomalous fibro adipocyte progenitor cell differentiation. PMID- 27493877 TI - Growth differentiation factor-15 as a prognostic biomarker in cancer patients. PMID- 27493878 TI - Opioid Use in the Twenty First Century: Similarities and Differences Across National Borders. AB - The global prevalence in the use of opiates and opioids has remained stable, though there were some unprecedented recent increases in opioid use and associated mortality and morbidity in the United States. Internationally, there is a strong tendency for consolidation of drug treatment strategies in favor of more systematic, structured and balanced approaches to regional and national drug policies. However, there are considerable differences in the scope, focus, and implementation of national drug policies and the political context is shaping drug prevention, treatment and rehabilitation efforts to an extent not typically observed in other public health domains. As a result, though in theory, there is a considerable multi-national agreement about the efficacy and effectiveness of different treatment modalities for opioid dependence, in practice, there are striking differences among different world regions and countries in the degree of implementation of these treatment modalities into clinical practice. Such discrepancies between theory and practice are observed even in high-income countries such as the United States and European Union member states, where evidence-based treatment modalities are still not well implemented into clinical practice. Despite the lack of evidence-based support for the role of detoxification as a stand-alone treatment for opioid use disorders, it appears to be the most widely used intervention for opioid use across the world. PMID- 27493879 TI - Response to: Letter to the Editor Regarding: The Expanding Phenotype of MELAS Caused by the m.3291 T > C tRNA Mutation E Kelland, C. A. Rupar, Asuri N. Prasad, K. Y. Tay, A. Downie and C. Prasad (1) by Josef Finsterer, MD, PhD [1], Sinda Zarrouk-Mahjoub, PhD [2] [1] Krankenanstalt Rudolfstiftung, Vienna [2] Genomics Platform, Pasteur Institute of Tunis, Tunisia. PMID- 27493880 TI - Barriers to drug adherence in the treatment of urea cycle disorders: Assessment of patient, caregiver and provider perspectives. AB - Patients and families living with metabolic disorders face challenging dietary and drug treatment regimens. On the hypothesis that poor palatability, volume and frequency of drug/formula administration contribute to treatment non-adherence and hyperammonemic episodes, a survey was conducted of patient, caregiver (CG) and physician perspectives on treatments used in urea cycle disorders (UCD). METHODS: A paper and online survey assessed experience with UCD medications, medical foods and dietary supplements. RESULTS: 25 physicians, 52 adult patients and 114 CG responded. In 2009, the most common UCD-specific intervention reported by patients included sodium phenylbutyrate (60%), followed by l-citrulline (46%), amino acid medical foods (15%), l-arginine preparations (18%), and sodium benzoate (8%). Only 36% of patients reported experiencing no hyperammonemic episodes in the last 2 years. The most commonly reported cause of hyperammonemic episodes was infection or other acute illnesses, followed by dietary indiscretion, side effects of medications, and drug non-adherence. Most patients, caregivers and physicians (> 75%) ranked nitrogen-scavenging medications, l citrulline, l-arginine, and medical foods as "effective" or "very effective." Non adherence was common (e.g. 18% of patients admitted to missing sodium phenylbutyrate "at least once a week" and "at least one a day"). Barriers to adherence included taste of medications, frequency of drug administration, number of pills, difficulty swallowing pills, side effects, forgetting to take medications, and high cost. Strategies to mitigate the gastrointestinal side effects of medications included the use of gastric tubes and acid reflux medications. Physicians indicated that 25% and 33% of pediatric and adult patients, respectively, were given less than the recommended dose of sodium phenylbutyrate due to concerns of tolerance, administration, and cost. CONCLUSIONS: Despite positive views of their effectiveness, respondents found medications, medical foods and dietary supplements difficult to take and viewed adherence as inadequate, thus contributing to hyperammonemic episodes. PMID- 27493881 TI - On the Origin of Cells and Derivation of Thyroid Cancer: C Cell Story Revisited. AB - We will highlight and put into perspective new lineage tracing data from genetic studies in mice indicating that the genuine progenitors to C cells arise in the endoderm germ layer. This overturns the current concept of a neural crest origin of thyroid C cells referred to in every textbook and dedicated paper to this very day. As will become apparent, except for a single experiment, the neural crest theory has little or no support when the evolution and development of calcitonin producing cells in the entire chordate family are considered. Instead, a unifying origin of all cells of the ultimobranchial bodies reopens questions on the histogenesis of certain thyroid pathologies previously difficult to explain. On this aspect, medullary thyroid cancer shows a stronger connection to gut neuroendocrine tumours than previously recognized. It is envisaged that novel factors implicated in C cell-derived tumour growth and progression will be discovered as the mechanisms that regulate lineage expansion of embryonic C cell precursors from pharyngeal endoderm are uncovered. We will not discuss why C cells go to the bother of burying themselves in the thyroid - this remains a mystery. PMID- 27493882 TI - Familiar Papillary Thyroid Carcinoma in a Large Brazilian Family Is Not Associated with Succinate Dehydrogenase Defects. AB - BACKGROUND: Thyroid cancer is the most common endocrine gland malignancy. Advances in understanding the genetic basis for thyroid cancer revealed the potential involvement of several genes in the formation of thyroid tumors. Mutations in the gene coding for succinate dehydrogenase subtype B (SDHB) have been implicated in papillary thyroid cancer (PTC). Succinate dehydrogenase (SDH) is a heterotetrameric protein composed of four subunits, SDHA, SDHB, SDHC, and SDHD, and participates in both the electron transport chain and the tricarboxylic acid cycle. The aim of the study was to evaluate the association between variants in the SDHA, SDHB, SDHC, and SDHD genes and familiar PTC in a large Brazilian family. METHOD: Four patients with PTC, 1 patient with PTC and gastrointestinal stromal tumor (GIST), 1 patient with GIST, and their relatives - several of them with different thyroid problems - from a large Brazilian family were screened for genetic variations of SDHx genes with the use of polymerase chain reaction-single stranded conformational polymorphism and direct sequencing. RESULTS: Only one rare variation in SDHA was found in some of the family members, but not segregating with the disease. No other genetic variants of these genes were detected in the family members that presented with PTC and/or GIST. CONCLUSION: Familiar PTC and a GIST were not associated with SDHx mutations; additional genetic defects, yet unknown, may be responsible for the development of tumor. PMID- 27493883 TI - Levothyroxine but Not Selenium Increases Endothelial Progenitor Cell Counts in Patients with Hypothyroidism. AB - BACKGROUND: Hypothyroidism is a common endocrine disease associated with increased oxidative stress, increased cardiovascular (CV) risk, CV events and endothelial dysfunction. Endothelial progenitor cells (EPCs) are a well-known marker of CV risk. OBJECTIVE: The aim of this work was to ascertain whether hypothyroidism is associated with lower EPC counts and if treatment with levothyroxine (LT4) or selenium (Se) improves EPC counts compared to placebo. METHODS: Hypothyrod patients (n = 100) were randomly divided into five groups to receive placebo (group A), LT4 (group B) or Se at doses of 83 ug (group C), 166 ug (group D) or 249 ug (group E) for 3 months. Each group comprised 20 patients: 10 with 'mild' hypothyroidism and 10 with 'severe' hypothyroidism. A healthy control group (group F) with 20 euthyroid subjects was also recruited. Subjects had to be free of CV disease, diabetes and drugs that interfere with EPCs. Anthropometric measurements (height, weight, BMI), blood pressure, fasting lipids and EPC analyses were performed at baseline and after 3 months. RESULTS: EPC counts were significantly lower in hypothyroid patients compared to controls. EPCs increased after 3 months of treatment with LT4, but not with Se at any dosage. CD133+ and CD34+ EPC counts were negatively correlated with thyroid stimulating hormone (TSH; r (2) = 0.523, p < 0.01 and r (2) = 0.517, p < 0.01, respectively) and positively correlated with FT4 (r (2) = 0.394, p < 0.01 and r (2) = 0.369, p < 0.01, respectively). TSH and FT4 were the only predictors of EPC counts. CONCLUSIONS: Hypothyroidism is associated with low EPC counts. Treatment with LT4, but not Se, can improve EPC counts. PMID- 27493884 TI - Comparison of Early Total Thyroidectomy with Antithyroid Treatment in Patients with Moderate-Severe Graves' Orbitopathy: A Randomized Prospective Trial. AB - BACKGROUND: The optimal therapeutic choice for Graves' hyperthyroidism in the presence of moderate-severe Graves' orbitopathy (GO) remains controversial. OBJECTIVES: We aimed to compare GO course in patients with moderate-severe GO treated with early total thyroidectomy (TTx) versus antithyroid drug (ATD) regimens, in a prospective, randomized manner. METHODS: Forty-two patients with moderate-severe GO were enrolled. A total of 4.5 g of pulse corticosteroids were given intravenously to all patients before randomization. Patients in the first group were given TTx, whereas patients in the second group were treated with ATDs. TSH was kept between 0.4 and 1 mIU/l. The clinical course of GO was evaluated with proptosis, lid aperture, clinical activity score (CAS), and diplopia. RESULTS: Eighteen and 24 patients were randomized to the TTx and ATD groups, respectively. Thyroid autoantibodies decreased significantly, and there were significant improvements in proptosis, lid aperture, and CAS in the TTx group. While in the ATD group the decrement in thyroid autoantibodies was not significant, there were significant improvements in proptosis and CAS. When the TTx group was compared with the ATD group, anti-TPO, anti-Tg, and TSH-receptor antibodies were significantly decreased in the TTx group (p < 0.01), but there was no significant difference with respect to proptosis, lid aperture, CAS, and diplopia between the two groups during a median (min.-max.) follow-up period of 60 months (36-72). CONCLUSION: Although no definitive conclusions could be drawn from the study, mainly due to limited power, early TTx and the ATD treatment regimens, followed by intravenous pulse corticosteroid therapy, seemed to be equally effective on the course of GO in this relatively small group of patients with moderate-severe GO during a median (min.-max.) follow-up period of 60 months (36-72). PMID- 27493885 TI - A 2015 Italian Survey of Clinical Practice Patterns in the Management of Graves' Disease: Comparison with European and North American Surveys. AB - BACKGROUND: Patients suffering from Graves' disease (GD) are quite frequent in endocrine clinical practice. In particular, overt hyperthyroidism may be complicated by serious adverse events and requires careful treatment, but its management has changed over the years in both the USA and European Union (EU). OBJECTIVES: To evaluate the current diagnosis and management of patient's with GD in Italy, and compare results with those obtained in previous similar surveys in the USA and EU. METHODS: Members of the Italian Association of Clinical Endocrinologists (AME) were asked to participate in a Web-based survey on management of GD. RESULTS: In total, 947 responses were obtained. The preferred diagnostic modality in Italy is TSH receptor antibody determination in conjunction with ultrasound, while radioactive iodine uptake/scan is preferred in the USA. Methimazole (MMI) 20-30 mg/day with a beta-blocker is the initial treatment of choice in Italy and the EU, whereas the USA opts more frequently for radioactive therapy. If Graves' orbitopathy occurs, orbit CT/MRI scans are more often obtained in Italy and the EU than in the USA. In case of planned pregnancy in 6-12 months, surgery is more frequently suggested in Italy than in the EU and USA. Propylthiouracil is generally preferred to MMI in the first trimester. CONCLUSIONS: Italian endocrinologists have shown significantly different patterns in diagnosis and management of GD compared to both the USA and EU. PMID- 27493886 TI - Serum Thyroglobulin Concentration Is a Weak Marker of Iodine Status in a Pregnant Population with Iodine Deficiency. AB - OBJECTIVE: To assess the reliability of thyroglobulin (Tg) as a marker of iodine status during pregnancy. DESIGN: 299 women aged 30.5 +/- 4.8 years (mean +/- SD) were studied. METHODS: In every subject, we measured urinary iodine concentration (UIC), serum thyrotropin (TSH), Tg, free thyroxine (fT4), Tg autoantibodies (TgAbs) and human chorionic gonadotropin (hCG) levels. We excluded samples with increased TgAbs from the analysis. RESULTS: According to WHO criteria, the study population was iodine deficient in every trimester. Serum Tg levels did not differ during the three trimesters of pregnancy. Serum hCG levels fell significantly as pregnancies advanced. A weak, significantly negative correlation (limited to the 3rd trimester) was found between Tg and UIC (rho = -0.187, p = 0.039). Serum fT4 decreased as pregnancies advanced and TSH increased. Serum fT4 was negatively correlated with TSH (rho = -0.161, p = 0.006) and positively with hCG (rho = +0.165, p = 0.005). The multiple regression equation of Tg based on hCG, TSH, UIC and trimester of pregnancy was significant but weak (F = 4.057, p = 0.003; R(2) = 0.055), with hCG as a significant predictor Tg (p for log hCG = 0.041). CONCLUSIONS: Tg cannot be considered as a valid marker of iodine deficiency in pregnancy, at least in a mildly iodine-deficient environment. Further studies in a larger patient cohort with differences in iodine status, as well as studies on Tg changes after improving iodine status in pregnant women, are needed in order to corroborate these results. PMID- 27493887 TI - Obesity Does Not Modify the Risk of Differentiated Thyroid Cancer in a Cytological Series of Thyroid Nodules. AB - BACKGROUND: A possible impact of obesity on the risk of thyroid cancer has been postulated in some studies, but it remains controversial. OBJECTIVE: To investigate the association between obesity and differentiated thyroid carcinoma in a population of unselected patients subjected to fine-needle aspiration cytology (FNAC) for thyroid nodules. METHODS: We retrospectively evaluated the results of FNAC of thyroid nodules in 4,849 patients (3,809 females and 1,040 males; mean age 55.9 +/- 14.1 years). Patients were stratified according to their body mass index (BMI). There were 1,876 (38.7%) normal-weight patients (BMI 18 24.9), 1,758 (36.2%) overweight (BMI 25-29.9), 662 (13.7%) grade 1 obese (BMI 30 34.9), 310 (6.4%) grade 2 obese (BMI 35-39.9) and 243 (5.0%) grade 3 obese (BMI >40). RESULTS: The prevalence of suspicious or malignant nodules (Thy4/Thy5) did not differ across the 5 BMI groups, i.e. it was 6.8% in normal-weight patients, 6.3% in overweight patients, 6.3% in grade 1 obese patients, 4.0% in grade 2 obese patients and 4.2% in grade 3 obese patients (p = 0.29). The prevalence of Thy4/Thy5 nodules did not differ when males and females were evaluated separately (p = 0.22 and p = 0.12, respectively). A significant, lower rate of Thy4/5 cytology was observed in female patients with grade 2-3 obesity (odds ratio 0.51; 95% confidence interval 0.284-0.920; p = 0.009). CONCLUSIONS: The results of this study, in a retrospective series of patients with thyroid nodules, do not confirm previous findings reporting an association between obesity and differentiated thyroid carcinoma. Thus, obese patients with nodular thyroid disease should be managed the same as normal-weight patients. PMID- 27493889 TI - Plasma Levels of Free Thyroxine and Risk of Major Bleeding in Bariatric Surgery. AB - BACKGROUND: In a recent study of patients using vitamin K antagonists, those with low free thyroxin (FT4) levels within the normal range had a 3- to 5-fold increased risk of major bleeding. We tested the hypothesis that low levels of preoperative FT4 within the reference range are associated with an increased risk of major bleeding during and after bariatric surgery. METHODS: The charts of 2,872 consecutive patients undergoing bariatric surgery were retrospectively screened for bleeding episodes. Patients with major bleeding until 1 month after surgery were compared to randomly selected control patients without bleeding, in a ratio of 1:4. We evaluated the association between preoperative FT4 levels and the risk of major bleeding by logistic regression. RESULTS: Seventy-two cases (2.5%) with major bleeding were identified and 288 controls were selected. The median plasma level of FT4 was 13 pmol/l (interquartile range: 12-14) in the cases as well as in the controls. No clear effect was observed of low levels of FT4 on the risk of major bleeding: odds ratio 1.48 (95% CI: 0.46-4.80) for patients with an FT4 level <11 pmol/l, 1.03 (0.49-2.18) for patients with an FT4 level <12 pmol/l, and 1.12 (0.65-1.94) for patients with an FT4 level <13 pmol/l as compared to patients with FT4 values greater than or equal to these cutoff levels. INTERPRETATION: We did not observe an increased risk of major bleeding with low levels of FT4 in patients undergoing bariatric surgery. PMID- 27493888 TI - Recreational Physical Activity and Differentiated Thyroid Cancer Risk: A Pooled Analysis of Two Case-Control Studies. AB - PURPOSE: Physical activity has been hypothesized to influence cancer occurrence through several mechanisms. To date, its relation with thyroid cancer risk has been examined in relatively few studies. We pooled 2 case-control studies conducted in Cuba and Eastern France to assess the relationship between self reported practice of recreational physical activity since childhood and thyroid cancer risk. METHODS: This pooled study included 1,008 cases of differentiated thyroid cancer (DTC) matched with 1,088 controls (age range 9-35 and 17-60 years in the French and Cuban studies, respectively). Risk factors associated with the practice of recreational physical activity were estimated using OR and 95% CI. Logistic regressions were stratified by age class, country, and gender and were adjusted for ethnic group, level of education, number of pregnancies for women, height, BMI, and smoking status. RESULTS: Overall, the risk of thyroid cancer was slightly reduced among subjects who reported recreational physical activity (OR = 0.8; 95% CI 0.5-1.0). The weekly frequency (i.e. h/week) seems to be more relevant than the duration (years). CONCLUSION: Long-term recreational physical activity, practiced since childhood, may reduce the DTC risk. However, the mechanisms whereby the DTC risk decreases are not yet entirely clear. PMID- 27493890 TI - Iodide Transport Defect and Breast Milk Iodine. AB - BACKGROUND: Iodide transport defect (ITD) is a dyshormonogenetic congenital hypothyroidism caused by sodium/iodide symporter (NIS) gene mutations. In the lactating mammary gland, iodide is concentrated by NIS, and iodine for thyroid hormone synthesis is thereby supplied to the infant in the breast milk. CASE DESCRIPTION: A 34-year-old Japanese woman was diagnosed with ITD caused by a homozygous NIS gene mutation T354P. She had begun treatment of primary hypothyroidism with levothyroxine at the age of 5. She delivered a baby at the age of 36. The iodine concentration in her breast milk was 54 ug/l. She took a 50 mg potassium iodide tablet daily to supply iodine in the breast milk, starting on the 5th day postpartum. Her breast milk iodine concentration increased to 90 ug/l (slightly above the minimum requirement level). The patient weaned her baby and stopped taking the daily potassium iodide tablet 6 weeks postpartum, and the baby began to be fed with relatively iodine-rich formula milk. The baby's thyroid function remained normal from birth until 6 months of age. CONCLUSION: Possible iodine deficiency in the infant breast-fed by an ITD patient should be kept in mind. Prophylactic iodine supplementation is essential for such infants in order to prevent severe iodine deficiency. PMID- 27493891 TI - Risk of Hepatocellular Carcinoma in Patients with Hepatitis C Virus Who Achieved Sustained Virological Response. PMID- 27493892 TI - Consensus for Radiotherapy in Hepatocellular Carcinoma from The 5th Asia-Pacific Primary Liver Cancer Expert Meeting (APPLE 2014): Current Practice and Future Clinical Trials. AB - A consensus meeting to develop practice guidelines and to recommend future clinical trials for radiation therapy (RT), including external beam RT (EBRT), and selective internal RT (SIRT) in hepatocellular carcinoma (HCC) was held at the 5th annual meeting of the Asia-Pacific Primary Liver Cancer Expert consortium. Although there is no randomized phase III trial evidence, the efficacy and safety of RT in HCC has been shown by prospective and retrospective studies using modern RT techniques. Based on these results, the committee came to a consensus on the utility and efficacy of RT in the management of HCC according to each disease stage as follows: in early and intermediate stage HCC, if standard treatment is not compatible, RT, including EBRT and SIRT can be considered. In locally advanced stage HCC, combined EBRT with transarterial chemoembolization or hepatic arterial infusion chemotherapy, and SIRT can be considered. In terminal stage HCC, EBRT can be considered for palliation of symptoms and reduction of morbidity caused by the primary tumor or its metastases. Despite the currently reported benefits of RT in HCC, the committee agreed that there is a compelling need for large prospective studies, including randomized phase III trial evidence evaluating the role of RT. Specifically studies evaluating the efficacy and safety of sequential combination of EBRT and SIRT are strongly recommended. PMID- 27493893 TI - Survival Benefit of Locoregional Treatment for Hepatocellular Carcinoma with Advanced Liver Cirrhosis. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) with decompensated liver cirrhosis (LC) is a life-threatening condition, which is amenable to liver transplantation (LT) as the standard first-line treatment. However, the application of LT can be limited due to a shortage of donor livers. This study aimed to clarify the effect of non-surgical therapy on the survival of patients with HCC and decompensated LC. METHODS: Of the 58,886 patients with HCC registered in the nationwide survey of the Liver Cancer Study Group of Japan (January 2000-December 2005), we included 1,344 patients with primary HCC and Child-Pugh (C-P) grade C for analysis in this retrospective study. Among the patients analyzed, 108 underwent LT, 273 were treated by local ablation therapy (LAT), 370 were treated by transarterial chemoembolization (TACE), and 593 received best supportive care (BSC). The effect of LT, LAT, and TACE on overall survival (OS) was analyzed using multivariate and propensity score analyses. RESULTS: Patient characteristics did not differ significantly between each treatment group and the BSC group, after propensity score matching. LAT (hazard ratio [HR]) =0.568; 95% confidence interval [CI], 0.40-0.80) and TACE (HR=0.691; 95% CI, 0.50-0.96) were identified as significant contributors to OS if the C-P score was less than 11 and tumor conditions met the Milan criteria. CONCLUSIONS: For patients with HCC within the Milan criteria and with a C-P score of 10 or 11, locoregional treatment can be used as a salvage treatment if LT is not feasible. PMID- 27493894 TI - Survival Analysis over 28 Years of 173,378 Patients with Hepatocellular Carcinoma in Japan. AB - BACKGROUND: Beginning in 1967, the Liver Cancer Study Group of Japan (LCSGJ) started a nationwide prospective registry of all patients with hepatocellular carcinoma (HCC) diagnosed at more than 700 institutions. To determine the effectiveness of surveillance and treatment methods longitudinally, we analyzed improvements over time in overall survival (OS) of 173,378 patients with HCC prospectively entered into the LCSGJ registry between 1978 and 2005. METHODS: All patients from more than 700 institutions throughout Japan with HCC were entered into the LCSGJ registry. Patients were grouped by years of diagnosis, with OS and 5-year OS rates being calculated. We also assessed OS and 5-year OS rates in patients who underwent resection, local ablation, transarterial chemoembolization (TACE), and hepatic arterial infusion chemotherapy (HAIC) and in those with baseline serum alpha-fetoprotein (AFP) levels >=400 ng/ml. RESULTS: The 5- and 10 year OS rates in the cohort of 173,378 patients were 37.9% and 16.5%, respectively. However, over time, the mean maximum tumor size decreased significantly, whereas 5-year OS rates and median survival time increased significantly. Similar findings were observed separately in patients who underwent resection, local ablation, TACE, and HAIC, as well as in patients with AFP levels >=400 ng/ml. CONCLUSION: The establishment of a nationwide HCC surveillance program in Japan has contributed to longer median OS and increased OS rates in patients diagnosed with this disease. These findings suggest that the establishment of a surveillance program in other countries with patients at risk for HCC may provide significant survival benefits. PMID- 27493896 TI - How to Improve Therapeutic Ratio in Radiotherapy of HCC. AB - BACKGROUND: During the past two decades, external-beam radiation technology has substantially changed from traditional two-dimensional to conformal three dimensional to intensity-modulated planning and stereotactic body radiotherapy (SBRT). SUMMARY: Modern techniques of radiotherapy (RT) are highly focused and capable of delivering an ablative dose to targeted hepatocellular carcinoma (HCC) tumors. SBRT is an option for selected patients with limited tumor volume and non eligibility for other invasive treatments. Moreover, RT combined with a radiation sensitizer (RS) to increase the therapeutic ratio has shown promising results in select studies, prompting further investigation of this combination. With the undetermined role of RT in treatment guidelines and variation in patterns of treatment failure after RT in patient with HCC, useful biomarkers to guide RT decision-making and selection of patients are needed and emerging. KEY MESSAGE: The objective of this review is to summarize the current RS with SBRT schemes and biomarkers for patient selection used to maximize the effect of RT on HCC. PMID- 27493895 TI - Liver-Directed Radiotherapy for Hepatocellular Carcinoma. AB - BACKGROUND: The incidence of hepatocellular carcinoma (HCC) continues to increase world-wide. Many patients present with advanced disease with extensive local tumor or vascular invasion and are not candidates for traditionally curative therapies such as orthotopic liver transplantation (OLT) or resection. Radiotherapy (RT) was historically limited by its inability to deliver a tumoricidal dose; however, modern RT techniques have prompted renewed interest in the use of liver-directed RT to treat patients with primary hepatic malignancies. SUMMARY: The aim of this review was to discuss the use of external beam RT in the treatment of HCC, with particular focus on the use of stereotactic body radiotherapy (SBRT). We review the intricacies of SBRT treatment planning and delivery. Liver-directed RT involves accurate target identification, precise and reproducible patient immobilization, and assessment of target and organ motion. We also summarize the published data on liver-directed RT, and demonstrate that it is associated with excellent local control and survival rates, particularly in patients who are not candidates for OLT or resection. KEY MESSAGES: Modern liver directed RT is safe and effective for the treatment of HCC, particularly in patients who are not candidates for OLT or resection. Liver-directed RT, including SBRT, depends on accurate target identification, precise and reproducible patient immobilization, and assessment of target and organ motion. Further prospective studies are needed to fully delineate the role of liver directed RT in the treatment of HCC. PMID- 27493897 TI - Personalized Clinical Trials in Hepatocellular Carcinoma Based on Biomarker Selection. AB - BACKGROUND: Since the approval of sorafenib there have been numerous failures of new agents in Phase III studies for treatment of advanced hepatocellular carcinoma (HCC). These studies have generally ignored the molecular heterogeneity of HCC and they have not enrolled patients based on predictive markers of response. The development of molecular targeted therapeutics in HCC needs to model the approach that has been taken with great success in other solid tumors, to decrease the likelihood of failure in future studies. SUMMARY: Here we review the paradigm taken with novel targeted agents in other solid tumors and highlight ongoing studies in HCC that are incorporating biomarkers in clinical development. KEY MESSAGES: With the appreciation of the molecular diversity of HCC, clinical development of new agents in HCC will need to be targeted towards those patients who are most likely to benefit. This strategy, based on biomarkers for patient selection, is more likely to yield positive results and mitigate the risk of continued negative Phase III studies. PMID- 27493898 TI - Anatomical and Functional Estimations of Brachial Artery Diameter and Elasticity Using Oscillometric Measurements with a Quantitative Approach. AB - Noninvasive vascular function measurement plays an important role in detecting early stages of atherosclerosis and in evaluating therapeutic responses. In this regard, recently, new vascular function measurements have been developed. These new measurements have been used to evaluate vascular function in coronary arteries, large aortic arteries, or peripheral arteries. Increasing vascular diameter represents vascular remodeling related to atherosclerosis. Attenuated vascular elasticity may be a reliable marker for atherosclerotic risk assessment. However, previous measurements for vascular diameter and vascular elasticity have been complex, operator-dependent, or invasive. Therefore, simple and reliable approaches have been sought. We recently developed a new automated oscillometric method to measure the estimated area (eA) of a brachial artery and its volume elastic modulus (VE). In this review, we further report on this new measurement and other vascular measurements. We report on the reliability of the new automated oscillometric measurement of eA and VE. Based on our findings, this measurement technique should be a reliable approach, and this modality may have practical application to automatically assess muscular artery diameter and elasticity in clinical or epidemiological settings. In this review, we report the characteristics of our new oscillometric measurements and other related vascular function measurements. PMID- 27493899 TI - Assessment of Arterial Stiffness Using the Cardio-Ankle Vascular Index. AB - BACKGROUND: Arterial stiffness is an independent predictor of outcomes for patients with cardiovascular disease. Although measurement of pulse wave velocity is a widely accepted, noninvasive approach for the assessment of arterial stiffness, its accuracy is affected by changes in blood pressure. SUMMARY: The cardio-ankle vascular index (CAVI) is an index of the overall stiffness of the artery from the origin of the aorta to the ankle and is theoretically independent of blood pressure at the time of measurement. CAVI increases linearly with age and is elevated even in mild arteriosclerotic disease. It can identify differences in the degree of arteriosclerosis among patients with severe arteriosclerotic disease and better reflects the severity of disease of the coronary artery than does brachial-ankle pulse wave velocity. Patients with higher CAVI values show a poor prognosis compared with those with lower CAVI values. Furthermore, CAVI can be lowered by controlling diabetes mellitus and hypertension. KEY MESSAGES: The primary aims of assessing arterial stiffness using CAVI are to assist in the early detection of arteriosclerosis, allowing timely treatment and lifestyle modification, and to quantitatively evaluate the progression of disease and the effectiveness of treatment. Whether CAVI-guided therapy can improve prognosis in high-risk patients needs to be further examined to confirm the clinical usefulness of this measure. PMID- 27493900 TI - Carotid Stiffness: A Novel Cerebrovascular Disease Risk Factor. AB - Carotid stiffening is considered an important element in the pathogenesis of cerebrovascular diseases. These include stroke as well as vascular dementia and depression. However, results of individual studies evaluating the association between carotid stiffening and incident stroke have been inconsistent. Therefore, we have conducted a systematic review and meta-analysis, showing that carotid stiffening is associated with incident stroke independently of cardiovascular risk factors and aortic stiffness. In addition, carotid stiffening improved stroke risk prediction beyond the Framingham stroke risk factors and aortic stiffness. Other studies have shown that carotid stiffening is associated with a higher incidence of vascular dementia and depressive symptoms. This suggests that carotid stiffness is a potential separate target for prevention strategies of cerebrovascular disease. PMID- 27493901 TI - Relation of Habitual Chocolate Consumption to Arterial Stiffness in a Community Based Sample: Preliminary Findings. AB - BACKGROUND: The consumption of chocolate and cocoa has established cardiovascular benefits. Less is known about the effects of chocolate on arterial stiffness, a marker of subclinical cardiovascular disease. The aim of this study was to investigate whether chocolate intakes are independently associated with pulse wave velocity (PWV), after adjustment for cardiovascular, lifestyle and dietary factors. METHODS: Prospective analyses were undertaken on 508 community-dwelling participants (mean age 61 years, 60% women) from the Maine-Syracuse Longitudinal Study (MSLS). Habitual chocolate intakes, measured using a food frequency questionnaire, were related to PWV, measured approximately 5 years later. RESULTS: Chocolate intake was significantly associated with PWV in a non-linear fashion with the highest levels of PWV in those who never or rarely ate chocolate and lowest levels in those who consumed chocolate once a week. This pattern of results remained and was not attenuated after multivariate adjustment for diabetes, cardiovascular risk factors and dietary variables (p = 0.002). CONCLUSIONS: Weekly chocolate intake may be of benefit to arterial stiffness. Further studies are needed to explore the underlying mechanisms that may mediate the observed effects of habitual chocolate consumption on arterial stiffness. PMID- 27493902 TI - Within-Home Blood Pressure Variability on a Single Occasion Has Clinical Significance. AB - There is growing evidence that diversely defined blood pressure variability (BPV) is an independent predictor of hypertensive target organ damage (TOD) and cardiovascular events. Several mechanisms have been speculated to underlie episodes of increased BPV, including the impairment of autonomic or hormonal regulation, renal dysfunction, and increased arterial stiffness. Within-home BPV, defined as differences in BP values obtained on a single occasion at home, could have prognostic significance for hypertensive TOD. It is typically thought that BP values are decreased with repeated measurements on a single occasion at home, but in the present subanalysis of 4,149 J-HOP (Japan Morning Surge-Home Blood Pressure) study patients, approximately 20% of the patients' home BP values were increased or unchanged by repeated measurements on a single occasion. In addition, those patients were likely to have hypertensive TOD. Thus, home BP measurement should be taken twice or more to detect the increase trend in home BP, which has been defined as within-home BPV. PMID- 27493903 TI - Molecular Mechanisms of Arterial Stiffening. AB - Stiffening of large arteries is a hallmark of vascular aging and one of the most important determinants of the age-related increase in blood pressure and cardiovascular disease events. Despite a substantial genetic component, the molecular mechanisms underlying phenotypic variability in arterial stiffness remain unknown. Previous genetic studies have identified several genetic variants that are associated with measures of arterial stiffness. Here, we review the relevant advances in the identification of pathways underlying arterial stiffness from genomic studies. PMID- 27493904 TI - The J-Curve Phenomenon in Hypertension. AB - Almost immediately after antihypertensive therapy was proven effective in preventing cardiovascular events, the J-curve issue emerged as a hot topic. The Hypertension Optimal Treatment (HOT) trial attempted to address this question (diastolic blood pressure <80, <85, and <90 mm Hg) but ended up with a post hoc analysis indicating a nadir of 138.5 mm Hg systolic and 82.6 mm Hg diastolic blood pressure. Nevertheless, this observational finding was supported by the results of observational studies in the general population and by post hoc analyses of antihypertensive treatment trials. The currently ongoing Systolic Hypertension Optimal Treatment (SHOT) trial investigates whether the relationship between systolic blood pressure and stroke recurrence is linear or J-shaped by treating systolic blood pressure to <125, <135, and <145 mm Hg in patients with a history of recent stroke. This trial may provide additional but probably inconclusive evidence, because optimal blood pressure might differ between individuals and across outcomes. Nevertheless, a universal beneficial, instead of optimal, level of blood pressure for antihypertensive treatment may exist approximating 130/80 mm Hg and should be investigated by comparing 130/80 mm Hg with 140/90 mm Hg as a target blood pressure in hypertensive patients with the simultaneous use of modern blood pressure measuring techniques, such as home and ambulatory blood pressure monitoring. PMID- 27493905 TI - The effect of low dose fentanyl as a premedication before induction of general anesthesia on the neonatal apgar score in cesarean section delivery: randomized, double-blind controlled trial. AB - BACKGROUND: The administration of opioids before induction of general anesthesia can be considered as a problem in cesarean section. The aim of this study was to compare the effects of intravenous Fentanyl as a premedication before induction of general anesthesia versus placebo on maternal hemodynamic parameters and on the first and fifth minutes Apgar score in the neonates in elective cesarean delivery. METHODS: This double- blinded, randomized, clinical trial study was conducted in 2014-2015 at Vali-e-Asr hospital, Birjand, Iran. Ninety full term pregnant women undergoing elective cesarean section delivery under general anesthesia were selected. The participants were randomly classified into two groups: The Fentanyl group and the placebo. Iintravenous Fentanyl 1MUg/kg was administrated three minutes before anesthesia induction for the Fentanyl group, and 2 milliliter normal saline was administered for the placebo group. Maternal mean arterial pressure, heart rate before the start of anesthesia induction and thirty seconds after intubation were measured. Also, the first and fifth minutes Apgar scores of the neonates were evaluated and recorded by a blinded anesthesiologist. The clinical trial registration number was IRCT2015010320112N3. RESULTS: Maternal mean arterial pressure was significantly lower in the Fentanyl group than the placebo group after intubation. Heart rate was significantly higher in the placebo group before the start of anesthesia induction and after intubation compared to the Fentanyl group. The first and fifth minutes' Apgar scores of the neonates were not statistically different between the two groups. CONCLUSION: Administration of 1MUg/Kg intravenous Fentanyl before the induction of anesthesia for cesarean section delivery decreases maternal hemodynamic changes after intubation. In addition, it does not have any effect on Apgar scores of the neonate in the 1st and 5th minutes after birth. PMID- 27493906 TI - Do ethical considerations influence any in HTA reports? A review of reports. AB - BACKGROUND: Dealing with ethical considerations is a major component of Health Technology Assessment (HTA) definitions. OBJECTIVES: Present study aimed to explore and describe the manner of ethical analyses in HTA reports and the effects it had on HTA-related decision making around the world. METHODS: By considering the contextual milieu of reports and searching for ethical themes and subjects in HTA full reports, a descriptive analysis of HTA reports' contents and related processes was conducted. The review focused on all English HTA reports issued in a year. All ethical aspects, criteria, approaches, and also decision- making related ethical issues were described and summarized in retrieved reports. The inclusion of ethical aspects in final decision-making criteria of HTA reports was also considered. RESULTS: Eighty-nine HTA reports issued in one year were included in this review and analyzed for ethical considerations. There was no trace of any ethical issues in 60.7% of retrieved HTA reports. Dimensions of equity in resource distribution, stakeholder engagement, social values, essence and nature of technology, and ethical issues about the method of assessment for decision making, and physician-patient relationship were raised and discussed in 38.2%, 3.4%, 3.4%, 3.4%, 34.8% and 3.4% of reports respectively. Those issues were also included in 44.1, 5.9, 2.9, 2.9, 0 and 2.9% of final reports, respectively. In overall, only in 16 cases (17.9%) of all 89 reports, ethical issues were included in HTA decision-making orientations. CONCLUSION: This review shows that ethical issues are occasionally raised and discussed in HTA reports. More importantly, the inclusion of ethical concerns as a decision criterion in HTAs is few and insufficient. PMID- 27493907 TI - Is the serum ferritin level a considerable predictor for hemorrhagic transformation of ischemic stroke? AB - BACKGROUND: Hemorrhagic Transformation (HT) of Ischemic Stroke (IS) is a detrimental complication. This study investigated the association between serum ferritin level and HT in patients with massive IS of middle cerebral artery. METHODS: Thirty patients with massive IS of middle cerebral artery were enrolled in this prospective cohort study. They were divided into two groups based on the serum ferritin level, lower or greater than 164.1ng/ml at the first 24 hours after admission. To investigate the incidence of HT in the two groups, we observed them for two weeks. RESULTS: During the two- week observation, the incidence of HT was two persons (13.3%) in the group with the serum ferritin level of lower than 164.1ng/ml, and eight persons (53.3%) in the other group. This difference was statistically significant between the two groups (p=0.02). The relative risk of HT was 4 (95% CI: 1.012- 15.8) in the patients with massive IS of middle cerebral artery and the serum ferritin level greater than 164.1ng/ml. CONCLUSION: This study revealed that the serum ferritin level greater than 164.1ng/ml in the first 24 hours after admission is a reasonably important predictor for HT of IS. Conducting studies on factors affecting the serum ferritin level are suggested. PMID- 27493908 TI - Comparing nurses' knowledge retention following electronic continuous education and educational booklet: a controlled trial study. AB - BACKGROUND: Training methods that enhance nurses' learning and retention will increase the quality of patient care. This study aimed to compare the effectiveness of electronic learning and educational booklet on the nurses' retention of diabetes updates. METHODS: In this controlled trial study, convenience sampling was used to select 123 nurses from the endocrinology and internal medicine wards of three hospitals affiliated to Tehran University of Medical Sciences (Tehran, Iran). The participants were allocated to three groups of manual, electronic learning, and control. The booklet and electronic learning groups were trained using educational booklet and electronic continuous medical education (CME) website, respectively. The control group did not receive any intervention. In all the three groups, the nurses' knowledge was measured before the intervention, and one and four weeks after the intervention. Data were collected by a questionnaire. RESULTS: Significant differences were observed between the mean scores of the three groups one and four weeks after the intervention (F=26.17, p=0.001 and F=4.07, p=0.020, respectively), and post hoc test showed that this difference was due to the higher score in e-learning group. Both e-learning and booklet methods could effectively improve nurses' knowledge (chi2=23.03, p=0.001 and chi2=51.71, p=0.001, respectively). CONCLUSION: According to the results of this study, electronic learning was more effective than booklet in enhancing the learning and retention of knowledge. Electronic learning is suggested as a more suitable method as it provides appropriate interactions and attractive virtual environments to motivate the learners and promote retention. PMID- 27493909 TI - A review on laboratory tests' utilization: A trigger for cutting costs and quality improvement in health care settings. AB - BACKGROUND: Considering the role of laboratory tests as a central part of controlling health expenditure, this study intends to investigate laboratory tests overutilization in Iran to pave the way for future interventions. METHODS: Inappropriate laboratory utilization was reviewed in a cross-sectional survey through the retrospective analysis of 384 medical records at a tertiary center. To pave the way for future intervention, overutilization tests were classified into two categories, inappropriate and inefficient, and then they were analyzed. Frequency analysis was used to analysis patient's age, gender, hospital wards, length of stay, and diagnosis as well as inappropriate test and inefficient tests. RESULTS: A total of 143 (1.50 %) of the tests were inefficient and was ordered due to laboratory errors including hemolysis, inefficient sampling, or absurd results. 2522 (26.40%) of the tests were inappropriate and stem from failure to meet medical/clinical appropriateness criteria. CONCLUSION: Whereas, inappropriate test ordering was more frequent than inefficient tests, the initial improvement strategy should focus on physicians' test ordering behavior through conducting proper teaching strategies, ongoing audit and educational feedback, implementing health information technology tools and employing laboratory practice guidelines (LPGs) and testing algorithms. Conducting continuous quality improvement cycle for laboratory services and training of personnel involved in blood sampling is recommended for inefficient tests. PMID- 27493910 TI - The effectiveness of FOBT vs. FIT: A meta-analysis on colorectal cancer screening test. AB - BACKGROUND: After lung and prostate cancers, colorectal cancer (CRC) is the third most common cancer in men and the second most common cancer in women after breast cancer worldwide. Every year, more than one million people are diagnosed with colorectal cancer worldwide and half of these patients die from this disease, making it the fourth leading cause of death in the world. This systematic review aimed to assess the effectiveness of the two colorectal diagnostic tests of FOBT (fecal occult blood test) and FIT (fecal immunochemical test)) in terms of technical performance. METHODS: To retrieve the relevant evidence, appropriate medical databases such as Cochrane library, NHSEED, Scopus and Google scholar were searched from February 2013 to July 2014, using free-texts and Mesh. In this study, inclusion/exclusion criteria of the papers, randomized controlled trials, economic evaluations, systematic reviews, meta-analyses and meta-syntheses of the effectiveness of FIT versus FOBT tests in moderate-risk populations (age: 50 to 70 years), which had reported the least of such outcomes as sensitivity, specificity and clinical outcomes were reviewed. The analyses of the effectiveness outcomes were performed in the form of meta-analysis. RESULTS: Five papers were eligible to be included in the final phase of the study for synthesis. FIT showed a better performance in participation and positivity rate. Moreover, in terms of false positive and negative rate, FIT showed fewer rates compared to FOBT (RR:-4.06; 95% CI (-7.89-0.24), and NN-scope (Number need to scope) (2.2% vs. 1.6%), and NN-screen (Number need to screen) (84% vs. 31-49% in different cut off levels) showed significant differences in FOBT vs. FIT, respectively. CONCLUSION: In the five included studies (3, 11-14), the acceptability of FIT was more than FOBT. However, in our meta-analysis, no difference was found between the two tests. FIT was significant in positivity rate and had a better performance in participation rate, and a fewer false negative numbers compared to FOBT. PMID- 27493911 TI - Radioprotective effects of selenium and vitamin-E against 6MV X-rays in human blood lymphocytes by micronucleus assay. AB - BACKGROUND: Critical macromolecules of cells such as DNA are in exposure to damage of free radicals that induced from the interaction of ionizing radiation with biological systems. Selenium and vitamin-E are natural compounds that have been shown to be a direct free radical scavenger. The aim of this study was to investigate the radioprotective effect of selenium and vitamin-E separately and synergistically against genotoxicity induced by 6MV x-rays irradiation in blood lymphocytes. METHODS: Fifteen volunteers were divided into three groups include A, B and C. These groups were given selenium (800IU), vitamin-E (100mg) and selenium (400IU) + vitamin-E (50mg), respectively. Peripheral blood samples were collected from each group before (0hr) and 1, 2 and 3hr after selenium and vitamin-E administration (separately and synergistically). Then the blood samples were irradiated to 200cGy of 6MV x-rays. After that lymphocyte samples were cultured with mitogenic stimulation to determine the chromosomal aberrations with micronucleus assay in cytokinesis-blocked binucleated cells. RESULTS: The lymphocytes in the blood samples collected at one hr after ingestion selenium and vitamin-E, exposed in vitro to x-rays exhibited a significant decrease in the incidence of micronuclei, compared with control group at 0hr. The maximum protection and decrease in frequency of micronuclei (50%) were observed at one hr after administration of selenium and vitamin-E synergistically. CONCLUSION: The data suggest that ingestion of selenium and vitamin-E as a radioprotector substance before exposures may reduce genetic damage caused by x-rays irradiation. PMID- 27493912 TI - Determinants of adherence to self-care behavior among women with type 2 diabetes: an explanation based on health belief model. AB - BACKGROUND: Self-care is an essential element in treating a person with diabetes; and managing diabetes is of prime importance. The aim of this study was to investigate the predictors of adherence to self-care behavior among women with Type 2 diabetes. METHODS: This cross-sectional study was conducted on 210 female patients aged 30 to 60. Data collection tool was an anonymous valid and reliable questionnaire designed based on the Health Belief Model (HBM), which acquired information about the followings: Perceived susceptibility, severity, benefits, barriers, self-efficacy and diabetes self-care behavior. Data were analyzed by t test, chisquare and regression analysis. RESULTS: The multiple regression models revealed 59.9% of the variance of self-care behavior with self-efficacy, perceived barrier, benefit and susceptibility. Additionally, the highest weight for beta (beta=0.87) was found for self-efficacy. Self-care behavior was positively correlated with all HBM variables except for perceived barriers showing a negative correlation. CONCLUSION: The Health Belief Model may be used as a framework to design intervention programs in an attempt to improve adherence to self-care behaviors of women with diabetes. In addition, the results indicated that self-efficacy might play a more crucial role in developing self-care behaviors than t other HBM components. Therefore, if the focus is placed on self efficacy when developing educational programs, it may increase the likelihood of adherence to self-care behavior. PMID- 27493913 TI - The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. AB - Many factors including genetic, environmental, and acquired are involved in breast cancer development across various societies. Among all of these factors in families with a history of breast cancer throughout several generations, genetics, like predisposing genes to develop this disease, should be considered more. Early detection of mutation carriers in these genes, in turn, can play an important role in its prevention. Because this disease has a high prevalence in half of the global population, female screening of reported mutations in predisposing genes, which have been seen in breast cancer patients, seems necessary. In this review, a number of mutations in two predisposing genes (BRCA1 and BRCA2) that occurred in patients with a family history was investigated. We studied published articles about mutations in genes predisposed to breast cancer between 2000 and 2015. We then summarized and classified reported mutations in these two genes to recommend some exons which have a high potential to mutate. According to previous studies, exons have been reported as most mutated exons presented in this article. Considering the large size and high cost of screening all exons in these two genes in patients with a family history, especially in developing countries, the results of this review article can be beneficial and helpful in the selection of exon to screen for patients with this disease. PMID- 27493914 TI - High frequency of metabolic syndrome in adult Zoroastrians in Yazd, Iran: a cross sectional study. AB - BACKGROUND: Metabolic syndrome (MS) is a cluster of metabolic disturbances, and its prevalence is increasing worldwide. MS exhibits variations among ethnic groups. Zoroastrianism is an ethnic minority which has maintained its isolation and endogamy up to now. So, we evaluated the frequency of MS in Zoroastrians of Yazd, Iran. METHODS: In this cross-sectional study, participants aged >=30 years were selected using a systematic random sampling. Weight, height, body mass index (BMI), waist circumference (WC), hip circumference (HC), waistto- hip ratio (WHR) and blood pressure (BP) were measured using standard methods. Also, blood levels of glucose, triglycerides (TG), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), urea, creatinine and uric acid (UA) were measured. Both revised National Cholesterol Education Program Adult Treatment Panel III (ATPIII) and Joint Interim Statement (JIS) criteria were used to diagnose the MS. RESULTS: The mean+/-SD age of the participants (n=403) was 56.9+/-12.8 years. The frequency of MS was 69.7% and 74.9% based on JIS and ATPIII criteria, respectively; this was significantly different by age, marital status, job, educational level, and menopausal status (p<0.05). The most prevalent abnormal parameters of MS according to ATPIII and JIS criteria were high WC (95%) and low HDL (87.9%), respectively. Mean LDL, systolic BP, WHR, UA, urea, and creatinine were different between men and women. The difference between the age groups was statistically significant for BMI, systolic BP, diastolic BP, TG, WHR and urea (p<0.05). CONCLUSION: This study showed a high frequency of MS in Zoroastrians of Yazd, Iran. PMID- 27493916 TI - Application of ultrasound in pulseless electrical activity (PEA) cardiac arrest. PMID- 27493915 TI - Outcomes of assisted reproduction treatment after dopamine agonist -cabergoline- for prevention of ovarian hyper stimulation syndrome. AB - BACKGROUND: Release of vascular endothelial growth factor (VEGF) by ovaries in response to HCG administration is one of the main mechanisms of ovarian hyper stimulation syndrome. Since Dopamine/dopamine receptor2 (Dp-r2) pathway activity mediated by VEGF/ Vascular endothelial growth factor receptor 2 (VEGFR- 2) signaling-, is associated with angiogenic events, dopamine agonists were used for the management of severe forms of OHSS. In order to assess the effects of Cabergoline on angiogenesis in the human endometrium, and subsequently its impacts on the implantation rate this study was conducted. METHODS: This historical cohort study was conducted based on existing data of 115 patients (20 40 years) whom underwent assisted reproductive treatment (ART) and with a high probability for developing OHSS between March 2007 and September 2008. Forty five cases received Cabergoline were compared to 70 control subjects. The statistical methods used were: Unpaired t-test for continuous variables and the chi-square test (or Fisher's exact test if required) for categorical variables. RESULTS: None of the patients (treatment or control group) developed OHSS. The etiologies of infertility and administration of GnRH agonist or antagonist protocols were similar in two groups (p>0.2). Number of transferred embryos and zygote intra fallopian transfer (ZIFT) did not differ between the two groups (p>=0.06). Implantation rate in treatment (3.1%) and control (6.6%) subjects was similar (p=0.4). No significant difference was observed in fertilization rate, chemical, clinical and ongoing pregnancies between the two groups (p>0.5). CONCLUSION: Cabergoline can be safely administered in ART protocols to prevent OHSS, without compromising ART outcomes. PMID- 27493918 TI - Length and weight growth trends for children less than two years old in Zanjan, Iran: Longitudinal modeling. AB - BACKGROUND: Growth failure in children less than five years old can lead to the serious complications such as increased mortality, learning difficulties or physical disability. The aim of this study was to investigate the nonorganic factors affecting the growth trend in less than two years children living in Zanjan, Iran. METHODS: This longitudinal study was conducted on a sample of 3566 children less than two years old in Zanjan. Weight and length growth trends were recorded as ordinal variables and analyzed by longitudinal marginal model. RESULTS: About 12% (n=289) and 8% (n=212) of children had at least one decline/stagnation in the weight and length growth curve, respectively. Based on the marginal model, the effect of the child's age and residence area on the weight and length growth trends were statistically significant (p<0.05). CONCLUSION: Given the relatively high prevalence of growth failure among studied children less than two years old in rural areas of Zanjan, raising the awareness of parents in rural areas about feeding and nutritional behaviors of children seems an important issue. Additionally, healthcare providers should mostly focus on monitoring the growth of children older than 12 months. PMID- 27493917 TI - Combined effect of botulinum toxin and splinting on motor components and function of people suffering a stroke. AB - BACKGROUND: Spasticity is one of the problems after a stroke. Due to this increase in muscle tone, patients are confronted with problems in motor control and difficulties in activities of daily living and complications such as shortness and contracture. The aim of this study was to examine the effects of the simultaneous use of both splint and botulinum toxin-A (BTX-A) injection on spasticity, range of motion and upper extremity function in a 3-month period. METHODS: In this study a comparison was done between three groups of interventions, conducted in rehabilitation clinics in Tehran. Sixty people with chronic stroke were recruited. Based on the inclusion criteria, a total of 39 stroke patients after completing the consent forms were entered to intervention groups; splint or botulinum toxin injection or combined splint/botulinum toxin injection. They were followed up about three months and the evaluations were done monthly. Goniometry was the method to measure the range of motion, and Modified Ashworth Scale was used to examine the spasticity and the upper extremity function was scored based on Fugl- Meyer Assessment. Statistical analysis was done using SPSS 17. And ANOVAs was used for comparison between groups and times. Significance was set at 0.05. RESULTS: All outcome measures were improved within each group but the differences between splint group and BTX-A group and the BTX-A splint group was not significant in most outcomes during the 3 periods (first evaluation until end of the first month, the end of first month until the end of second month, the end of second month until the end of the third month) (p>0.05). The results also showed that the changes in elbow's spasticity (p=0.05) and wrist's spasticity (p=0.007) and upper extremity function (p=0.04) were obvious between the three groups over the 3-months and the difference in the group of combined use of botulinum toxin, and the splint was more than other groups. CONCLUSION: In this study, the effects of botulinum toxin injection and Volar Dorsal Wrist/Hand Immobilization splint and the combined use of botulinum injection and splint were obvious in all groups but was not significantly different between the interventions in a 3-month follow-up. PMID- 27493919 TI - Is the status of diabetes socioeconomic inequality changing in Kurdistan province, west of Iran? A comparison of two surveys. AB - BACKGROUND: About 80% of deaths in 350 million cases of diabetes in the world occur in low and middle income countries. The aim of this study was to determine the status of diabetes socioeconomic inequality and the share of determinants of inequalities in Kurdistan Province, West of Iran, using two surveys in 2005 and 2009. METHODS: Data were collected from non-communicable disease surveillance surveys in Kurdistan in 2005 and 2009. In this study, the socioeconomic status (SES) of the participants was determined based on the residential area and assets using principal component analysis statistical method. We used concentration index and logistic regression to determine inequality. Decomposition analysis was used to determine the share of each determinant of inequality. RESULTS: The prevalence of diabetes expressed by individuals changed from 0.9% (95% CI: 0.6 1.3) in 2005 to 3.1% (95% CI: 2-4) in 2009. Diabetes Concentration Index changed from -0.163 (95% CI: -0.301- -0.024) in 2005 to 0.273 (95% CI: 0.101-0.445) in 2009. The results of decomposition analysis revealed that in 2009, 67% of the inequality was due to low socioeconomic status and 16% to area of residence; i.e., living in rural areas. CONCLUSION: The prevalence of diabetes significantly increased, and the diabetes inequality shifted from the poor people to groups with better SES. Increased prevalence of diabetes among the high SES individuals may be due to their better responses to diabetes control and awareness programs or due to the type of services they were provided during these years. PMID- 27493920 TI - Diet quality in obese/overweight individuals with/without metabolic syndrome compared to normal weight controls. AB - BACKGROUND: Metabolic syndrome (MetS) is a serious public health concern worldwide; however, the pathogenesis of this disease has not been yet cleared. This study aimed to compare diet quality in obese/overweight participants with/without metabolic syndrome with normal weight controls. METHODS: This was a comparative study on 147 Iranian adults under treatment at the Endocrinology Center of Tehran University of Medical Sciences. They were assigned into three groups (normal weight, obese weight with/without MetS) according to the inclusion exclusion criteria. Metabolic syndrome was defined according to the NCEP ATPIII consensus criteria. Healthy Eating Index Data were obtained from the validated FFQ to determine the diet quality index scores, using the Healthy Eating Index 2010. RESULTS: Our findings demonstrated that FBS, TG, SBP, WC and weight were higher among MetS patients compared to the both weight matched and non-weight matched participants, while HDL-c was lowest in this group (p<0.05). A statistically significant difference was found between healthy weight controls and obese/overweight participants with/without MetS in HEI-2010, and 9 of the 12 HEI-2010 components score (p<0.05). CONCLUSION: Our study revealed that low diet quality was a risk factor in developing MetS. PMID- 27493921 TI - The relationship between sodium intake and some bone minerals and osteoporosis risk assessment instrument in postmenopausal women. AB - BACKGROUND: The results of the studies on the effects of sodium on bone metabolism have been inconsistent. There is no definitive answer to the question of whether sodium restriction can be associated with a lower incidence of osteoporosis. What reinforces the necessity of designing this study is the lack of findings with the approach of examining the effects of sodium on bone in our country. METHODS: This was a cross-sectional study conducted on 185 retired female teachers aged 45 to 70. Sodium intake was evaluated using two methods: A 24-hour recall and a 12-hour urine sample. To assess bone health, ORAI index was calculated for each individual. Urinary calcium, phosphorus, potassium and serum vitamin D and PTH were measured as laboratory variables. To compare the general characteristics of the participants across tertiles of urinary sodium, the analysis of variance (ANOVA) was used for quantitative variables and the Chi square test for categorical variables. RESULTS: Phosphorous, calcium and potassium urinary excretion rate increased with the increase in urinary sodium (p<0.05). However, the changes in serum vitamin D, and PTH levels across tertiles of urinary sodium were not significant. Changes in urinary sodium levels were not significant (p=0.933) in ORAI groups (sorted by rating). The relationship between urinary calcium and sodium was apparent in low calcium intake (r=0.415, p<0.001), but not in higher calcium intake (r=0.144, p=0.177). CONCLUSION: Although urinary calcium and potassium increased with the increase in sodium intake, no relationship was found between sodium and ORAI. PMID- 27493922 TI - Does PTEN gene mutation play any role in Li-Fraumeni syndrome. AB - BACKGROUND: Li-Fraumeni syndrome (LFS) is one of the most serious hereditary cancer syndromes with a high risk of malignancy in childhood. This syndrome is an autosomal dominant cancer predisposing syndrome due to a germline mutation in the TP53 tumor suppressor gene. METHODS: In this study, a representative family case of Li-Fraumeni syndrome is described. The proband of this family was a 43-year old male who had osteosarcoma of the mandible and a positive family history of cancer. His mother died at the age of 29 of brain cancer; his sister died at the age of 18 of breast cancer; his brother died at the age of 36 of liver cancer; and another sister of his died at the age of 16 of leukemia. Complete sequence analysis of the TP53 and PTEN genes was performed in this family. We used standard diagnostic tools such as sequencing and multiplex ligation-dependent probe amplification (MLPA) to analyze these two genes in this family. The exons and flanking exon-intron junctions of the TP53 and PTEN genes were sequenced. RESULTS: We detected a germline mutation in the TP53 gene in this family that was previously reported as somatic mutation in LFS in the catalogue of somatic mutations in cancer (COSMIC). In addition, according to the International Agency for Research of Cancer (IARC) database, a 19-year-old male patient with sarcoma was recently reported to have this germline mutation. We also found two new IVS variations in the PTEN gene, one of which can be a suggestive evidence of an effect on the splicing of PTEN. CONCLUSION: Genomic modifications for tumor risk and genotype-phenotype correlations in LFS are still to be identified. We believe every new finding in this area can provide new insights into the pathogenesis and progression of Li-Fraumeni syndrome. PMID- 27493923 TI - Impact of endoscopic endonasal pituitary surgery on nasal airway patency. AB - BACKGROUND: Nose is used as a corridor in endoscopic endonasal transsphenoidal approach (EETSA) for pituitary adenoma. Thus, it may affect the nasal airway patency, function and sinonasal-related quality of life. The aim of this study is to objectively and subjectively evaluate these effects. METHODS: In this prospective study, 43 patients with pituitary adenoma who were candidates for EETSA from March 2012 to October 2013 were enrolled. The patients were evaluated preoperatively using acoustic rhinometry and rhinomanometry (with/without the use of decongestant drops) and asked to complete the 22-Item Sinonasal Outcome Test (SNOT-22) questionnaire. The tests were repeated at one and three months postoperatively. The preoperative data were compared with the first and second postoperative ones using paired-sample t-test. RESULTS: Without the use of decongestant drops, the total airway resistance increased significantly (p=0.016), and the nasal airflow decreased significantly (p=0.031) in the first postoperative evaluation. However, in the 3rd postoperative month, the difference was not significant. With the use of decongestant drops, the objective parameters showed no significant changes compared to preoperative data even at the first evaluation. The SNOT- 22 scores also did not differ significantly in 1st and 3rd postoperative months. The first postoperative SNOT-22 showed a strong correlation with the second minimal cross-sectional area on simultaneous evaluation, and with the preoperative total airway resistance. CONCLUSION: EETSA has a transient adverse effect on the nasal patency that quickly improves, making it a safe approach for the sinonasal system. Rhinomanometry is the most sensitive test for detecting these nasal functional changes objectively. PMID- 27493924 TI - The relationship between different diet quality indices and severity of airflow obstruction among COPD patients. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major public health problem worldwide. Smoking is the number one cause of COPD; however, genetic, environmental and dietary factors contribute to the etiology of this disease. In this study, we assessed the association between three diet quality indices -the Healthy Eating Index-2005 (HEI-2005), the Healthy Eating Index-2010 (HEI-2010), and Mediterranean Diet Score (MED)- and the severity of disease in COPD patients. METHODS: This cross-sectional study was performed at Rasul-e-Akram Hospital in Tehran on 121 COPD patients with the mean age of (SD) of 66.1(10.9) years. A pulmonary specialist diagnosed all participants based on a spirometry test. They were categorized into four groups (1, 2, 3, 4 stages of disease). Three diet quality indices, spirometry test and determination of disease severity were performed for all the participants. ANCOVA and Kruskal-Wallis test were used to assess the relationship between dietary quality indices and severity of the disease. The relationship between HEI-2010, HEI-2005, MED score, their components and lung function was assessed using a multiple linear regression analysis. All analyses were done using SPSS 18. RESULTS: Reduction of the Healthy Eating Index 2010 and MED score were observed along with the increase in disease severity, but they were not significant. The relationship between the three diet quality indices and lung function showed a significant association between MED score and Forced expiratory volume in one second (FEV1), The Forced Vital Capacity (FVC) (beta=2.9, 95% CI (1.1, 4.8), p=0.002), (beta=2.8, 95% CI (0.9, 4.8), p=0.007), respectively. CONCLUSION: Mediterranean dietary pattern and obtaining a better score on HEI-2010 diet were associated with a better lung function test. PMID- 27493925 TI - The effect of green tea extract supplementation on sputum smear conversion and weight changes in pulmonary TB patients: A randomized controlled trial. AB - BACKGROUND: Acceleration in sputum smear conversion helps faster improvement and decreased probability of the transfer of TB. In this study, we aimed to investigate the effect of green tea extract supplementation on sputum smear conversion and weight changes in smear positive pulmonary TB patients in Iran. METHODS: In this double blind clinical study, TB patients were divided into intervention, (n=43) receiving 500 mg green tea extract (GTE), and control groups (n=40) receiving placebo for two months, using balanced randomization. Random allocation and allocation concealment were observed. Height and weight were measured at the beginning, and two and six months post-treatment. Evaluations were performed on three slides, using the ZiehlNeelsen method. Independent and paired t test, McNemar's, Wilcoxon, Kaplan-Meier, Cox regression model and Log Rank test were utilized. Statistical significance was set at p<0.05. This trial was registered under IRCT201212232602N11. RESULTS: The interventional changes and the interactive effect of intervention on weight were not significant (p>0.05). In terms of shortening the duration of conversion, the case to control proportion showed a significant difference (p=0.032). Based on the Cox regression model, the hazard ratio of the relative risk of delay in sputum smear conversion was 3.7 (p=0.002) in the higher microbial load group compared to the placebo group and 0.54 (95% CI: 0.31-0.94) in the intervention compared to the placebo group. CONCLUSION: GTE decreases the risk of delay in sputum smear conversion, but has no effect on weight gain. Moreover, it may be used as an adjuvant therapy for faster rehabilitation for pulmonary TB patients. PMID- 27493926 TI - Incidence trends of colorectal cancer in Iran during 2000-2009: A population based study. AB - BACKGROUND: As the third leading cause of death, cancers have a special place in the Iranian health system. Several studies have been done in some regions of the country with few years of follow-ups, but this was the first standardized study to investigate the incidence trends of colorectal cancer in Iran in a one-decade period. METHODS: The registered data for colorectal cancer cases in National Cancer Registry System were extracted from the Center for Disease Control & Management of Ministry of Health. The codes from 18 to 21 among cancers were selected for colon and rectum cancers. Incidence rates were directly standardized, using WHO population. The significance of incidence rate trends was tested through Poisson regression. RESULTS: In this study, 36,650 cases of colorectal cancer were observed for 10 years in Iran, which increased from 813 cases in 2000 to 6,210 cases in 2009. Gender ratio of men to women was 1.39. Significant increasing trends of colorectal cancer were observed during the period of the study. The standardized incidence rate increased from 1.6 per 100,000 persons per year in 2000 to 11.3 in 2009 in males (p<0.001), and it increased from 1.6 per 100,000 persons per year in 2000 to 10.9 in 2009 in females (p<0.001). CONCLUSION: Colorectal cancer has an increasing trend in Iran. The rising trend of colorectal cancer as well as other types of cancers is partially due to improvement in cancer registry systems in the early years of registry. Moreover, westernized lifestyle and an increase in environmental risks could explain this rising trend. PMID- 27493927 TI - Economic inequalities in dental care utilizations in Iran: Evidence from an urban region. AB - BACKGROUND: Health utilization inequality is a major concern for health policymakers. Equality in utilization of services is very important for having a healthy society. The aim of this study was to describe inequality in dental care utilization in Iran, Therefore, concentration index, its curve, and the predictors of inequality in utilization of dental services and their spending were calculated. METHODS: Data of a health utilization survey which previously had been gathered in Shiraz, Iran were used for this study. Tobit and Poisson estimators were used to estimate utilization and out of pocket models. Furthermore, concentration index and curve was calculated to show inequality in dental care utilization. RESULTS: High inequalities was found in dental care utilization in Iran (concentration index=0.19). In the utilization model, the relationship between income and utilization was positive. People with higher income could utilize more services. Being covered by insurance increased the probability of dental care utilizations too. CONCLUSION: Policy makers must find solutions like increase the coverage of dental insurances to decrease inequality in dental care utilization. PMID- 27493928 TI - Health technology assessment on super oxidized water for treatment of chronic wounds. AB - BACKGROUND: Super oxidized water (SOW), as a novel antiseptic solution, is used with claims of effectiveness and cost effectiveness in healing chronic wounds such as diabetic foot, infectious postoperative ulcers and burn ulcers. We conducted a health technology assessment to evaluate the clinical evidence from clinical and randomized trials for this disinfection. This study aims to evaluate the safety, effectiveness and cost-effectiveness of this technology in Iran, for using as a wound disinfectant. METHODS: Systematic literature searches were conducted from October 2013 to March 2014 for the following medical databases: OVID MEDLINE, CINAHL, the Cochrane Library and the PICO terms were included and then analyzed by Cochrane assessment criteria. RESULTS: Out of 705 articles, twelve potentially relevant trials were identified. Others that didn't come with the PICO criteria were excluded. 5 randomized controlled trials, 5 clinical trials, a rapid HTA and a case series that had studied the effectiveness of super oxidized water on patients with different chronic wounds, were included. Most of these trials were assessing similar sets of outcomes as the Safety and Effect on Healing days to re-epithelization, healing rate, effect on Infection bacterial counts and infection rates. CONCLUSION: Super oxidized water is a safe, effective and cost effective irrigation and cleansing agent due to the performed analysis in comparison with current treatment as povidone iodine for treating wound infections. PMID- 27493929 TI - Religious experiences of Iranian transgenders: A qualitative study. AB - BACKGROUND: Gender identity disorder and its treatment with sex reassignment surgery is a profound experience, which can affect the mental, interpersonal, social and religious aspects of one's life. METHODS: This was a qualitative content analysis study focusing on the various dimensions of the experiences of seven patients suffering from gender identity disorder in a female-to-male subgroup. This study presents a report concerning the religious aspects of their experience. RESULTS: The findings of this study were categorized into the four following conceptual categories: sense of guilt; accomplishing a sense of submission to God's will as well as God's pleasing; practical commitment to religion; and rejection by the religious communities. CONCLUSION: Diminishing religion to spirituality comprised the core experiences of these patients having intimate relations with such concepts as secularism, stigma, and technocracy. PMID- 27493930 TI - The efficacy of a home-mechanical traction unit for patients with mild to moderate cervical osteoarthrosis: A pilot study. AB - BACKGROUND: Traction has been suggested to be an effective treatment for symptoms of neck disorder in patients with no contraindications. However, according to previous researches, the effectiveness of traction is controversial, particularly compared to other conservative treatments. This trial was conducted to evaluate the effect of sustained traction, using an over-the-door home cervical traction unit in combination with routine physical therapy on reducing cervical osteoarthrosis symptoms including neck pain, medication use and disability level compared to routine physical therapy alone. METHODS: In this double- blinded pilot study with a pre-post test design and a control group, 20 women with mild to moderate osteoarthrosis were systematically assigned to the over-the-door home cervical traction (mean+/-SD age: 50.5+/-4.45yrs) or control groups (mean+/-SD age: 55.6+/-7.34yrs). Pain, level of disability, and drug consumption were evaluated before and after 10 sessions of intervention. Data were analyzed using parametric or non-parametric statistic including the paired-sample t-test, independent sample t-test, and Wilcoxon and Mann-Whitney u test for intra and inter groups comparison based on the Kolmogorov-Smirnov test results. RESULTS: Patients in both groups showed a significant decrease in pain intensity and disability level (p<0.05). Despite the greater improvement in pain levels and disability in the experimental group compared to the controls, the differences were not significant (p>0.05). No significant differences were found in terms of drugs consumption within and between the groups at the end of the treatment (p>0.05). CONCLUSION: The results revealed that applying sustained traction using an over-the-door home cervical traction unit was not significantly superior to the routine physical therapy and ergonomic training to manage symptoms including neck pain and disability in a small group of mild to moderate cervical osteoarthrosis patients. PMID- 27493931 TI - Health system responsiveness after health sector evolution plan (HSEP): An inpatient survey in Kermanshah in 2015. AB - BACKGROUND: Responsiveness is one of the three main goals of the health system introduced by World Health Organization. This study aimed at examining health system responsiveness after Health Sector Evolution Plan in Kermanshah, Western Iran. METHODS: A sample of 335 hospitalized patients was selected using proportionate allocation to population size method in the city of Kermanshah (Iran) in 2015. World Health Survey (WHS) questionnaire was used to collect data. Data were analyzed using descriptive statistics and principal component analysis by STATA 12. RESULTS: The overall health system responsiveness score was 72.6. The best and worst performance for domains of dignity and autonomy were 82.2 and 62.5, respectively. Socio-demographic variables of the patients had no significant effect on the total health system responsiveness score. The principal component analysis findings indicated that 68% of the variance of the overall responsiveness score was explained by four components. CONCLUSION: The overall responsiveness score of each of the domains was higher than that of other similar previous studies in Iran. Although it is difficult to reach a conclusion, our findings may show better responsiveness of the health system compared to the previous reports. PMID- 27493932 TI - Quality of life in epileptic patients compared with healthy people. AB - BACKGROUND: Epilepsy is a common chronic neurological disorder that has a great impact on people's lives. Patients with epilepsy are at increased risk for poor Quality of Life (QoL). The objective of this study was to evaluate the QoL of epileptic patients in comparison to healthy persons. METHODS: This cross sectional study was conducted on 52 epileptic patients from Golbu region in Neyshabur (a city in northeast of Iran). Using Short Form Health Survey (SF-36) scale, the data were collected between April and Jun 2012. Every patient were compared with two healthy persons. Epileptic and healthy persons were similar for age, sex and local residence. Pearson's correlation coefficient and t-independent test applied for data analysis through SPSS v. 16 software. RESULTS: Of 52 epileptic patients, 24 were female (46.2%) and 28 were male (53.8%). The mean+/ SD age of epileptic patients was 40.92+/-20.33yr (Rang: 15-86yr). The total mean score of SF- 36 in patient group was 55.88 and in healthy group 68.52and this difference was statistically significant (p<0.001). Among the different subscales of SF-36 in epileptic patients, the highest and the lowest mean scores were found for social functioning and general health subscales, respectively. The mean scores in patient group in comparison to healthy group were lower in all subscales of SF-36 and these differences were statistically significant in all domains (except role limitations due to physical problems domain and role limitations due to emotional problems domain). CONCLUSION: The study showed that epilepsy disease has an important role in QoL of patients, thus some interventional programs are necessary to improve their QOL. PMID- 27493933 TI - How valid is the tallquist method in screening pregnant women with anemia in poor rural settings of southwestern Nigeria? AB - BACKGROUND: Diagnosis of anemia is challenging in resource-poor settings due to inadequate laboratory resources. This study assessed the validity of the Tallquist haemoglobinometer in assessing anemia among pregnant women in Osogbo, Southwestern Nigeria. METHODS: This was a cross - sectional study, in which 200 pregnant women of reproductive age were selected using multistage sapling method. A checklist was used to collect socio-demographic data and the results of the screening test. Blood collection and analysis were carried out using standardized referenced methods. RESULTS: Mean+/-SD age of the respondents was 28.9+3.9 yrs.; and 62 (62.6%) had up to primary level education. When Tallquist and Haematocrit methods were compared, there was 68.4%, 83.5% and 100% likelihood of Tallquist method (TM) diagnosing severe, moderate and mild anemia, respectively. The validity indices of the TM versus Haematocrit method as the gold standard revealed the sensitivity of 97.9%, specificity of 92.1%, positive predictive value of 92.4%, and negative predictive value of 97.9% and diagnostic accuracy of 95.0%. When compared to the Haemoglobin Cyanide method, the Tallquist method showed a calculated sensitivity of 96.6%, specificity of 87.4%, positive predictive value of 86.0%, and negative predictive value of 97.0% and diagnostic accuracy of 91.5%. CONCLUSION: The TM is a valid tool in screening anemia among pregnant women in resource- poor settings and rural primary health care centers in Southwestern Nigeria; therefore, its use should be encouraged, particularly to assess mild to moderate anemia. PMID- 27493934 TI - Cost-effectiveness analysis of dialysis and kidney transplant in patients with renal impairment using disability adjusted life years in Iran. AB - BACKGROUND: This cross-sectional study was conducted to compare the cost effectiveness of three therapeutic methods of long-term hemodialysis, kidney transplant from a living person and kidney transplant from a cadaver utilizing Disability Adjusted Life Years (DALY) using data from the records of patients referred to Afzalipour Hospital of Kerman in 2012. METHODS: This cross-sectional study utilizing Disability Adjusted Life Years (DALY) as outcome measure, used data from the records of patients referred to Afzalipour Hospital of Kerman in 2012. The decision tree model and decision tree software (Tree Age pro 11) were used for data analysis. In this research, costs and effects were studied from the patients and healthcare providers' perspective. RESULTS: In the patient's perspective, the CER of dialysis was 5.04 times greater than transplant from a living person and 6.15 times higher than transplant from a cadaveric donor. In the hospital's perspective, the average cost-effectiveness ratio of dialysis was 8.4 times greater than transplant from a living person and 14.07 times higher than transplant from a cadaver. The smaller the C-E ratio, the greater was the cost-effectiveness. In both perspectives, the order of effectiveness of treatment methods were transplant from a cadaver, transplant from a living person and dialysis. CONCLUSION: Considering the results obtained in this study, measures should be taken to increase the desire for organ donation from brain-dead patients, living people and patients' relatives. PMID- 27493936 TI - Comparative Brain and Central Nervous System Tumor Incidence and Survival between the United States and Taiwan Based on Population-Based Registry. AB - PURPOSE: Reasons for worldwide variability in the burden of primary malignant brain and central nervous system (CNS) tumors remain unclear. This study compares the incidence and survival of malignant brain and CNS tumors by selected histologic types between the United States (US) and Taiwan. METHODS: Data from 2002 to 2010 were selected from two population-based cancer registries for primary malignant brain and CNS tumors: the Central Brain Tumor Registry of the United States and the Taiwan Cancer Registry. Two registries had similar process of collecting patients with malignant brain tumor, and the quality of two registries was comparative. The age-adjusted incidence rate (IR), IR ratio, and survival by histological types, age, and gender were used to study regional differences. RESULTS: The overall age-adjusted IRs were 5.91 per 100,000 in the US and 2.68 per 100,000 in Taiwan. The most common histologic type for both countries was glioblastoma (GBM) with a 12.9% higher proportion in the US than in Taiwan. GBM had the lowest survival rate of any histology in both countries (US 1 year survival rate = 37.5%; Taiwan 1-year survival rate = 50.3%). The second largest group was astrocytoma, excluding GBM and anaplastic astrocytoma, with the distribution being slightly higher in Taiwan than in the US. CONCLUSION: Our findings revealed differences by histological type and grade of primary malignant brain and CNS tumors between two sites. PMID- 27493935 TI - The Gap Between Clinical Research and Standard of Care: A Review of Frailty Assessment Scales in Perioperative Surgical Settings. AB - The elderly population in the United States is increasing exponentially in tandem with risk for frailty. Frailty is described by a clinically significant state where a patient is at risk for developing complications requiring increased assistance in daily activities. Frailty syndrome studied in geriatric patients is responsible for an increased risk for falls, and increased mortality. In efforts to prepare for and to intervene in perioperative complications and general frailty, a universal scale to measure frailty is necessary. Many methods for determining frailty have been developed, yet there remains a need to define clinical frailty and, therefore, the most effective way to measure it. This article reviews six popular scales for measuring frailty and evaluates their clinical effectiveness demonstrated in previous studies. By identifying the most time-efficient, criteria comprehensive, and clinically effective scale, a universal scale can be implemented into standard of care and reduce complications from frailty in both non-surgical and surgical settings, especially applied to the perioperative surgical home model. We suggest further evaluation of the Edmonton Frailty Scale for inclusion in patient care. PMID- 27493937 TI - Nutrient Value of Leaf vs. Seed. AB - Major differences stand out between edible leaves and seeds in protein quality, vitamin, and mineral concentrations and omega 6/omega 3 fatty acid ratios. Data for seeds (wheat, rice, corn, soy, lentil, chick pea) are compared with corresponding data for edible green leaves (kale, spinach, broccoli, duckweed). An x/y representation of data for lysine and methionine content highlights the group differences between grains, pulses, leafy vegetables, and animal foods. Leaves come out with flying colors in all these comparisons. The perspective ends with a discussion on "So why do we eat mainly seeds?" PMID- 27493938 TI - Clinical Characteristics, Diagnostic Evaluation, and Antibiotic Prescribing Patterns for Skin Infections in Nursing Homes. AB - BACKGROUND: The epidemiology and management of skin infections in nursing homes has not been adequately described. We reviewed the characteristics, diagnosis, and treatment of skin infections among residents of nursing homes to identify opportunities to improve antibiotic use. METHODS: This was a retrospective study involving 12 nursing homes in the Denver metropolitan area. For residents at participating nursing homes diagnosed with a skin infection between July 1, 2013 and June 30, 2014, clinical and demographic information was collected through manual chart review. RESULTS: Of 100 cases included in the study, the most common infections were non-purulent cellulitis (n = 55), wound infection (n = 27), infected ulcer (n = 8), and cutaneous abscess (n = 7). In 26 cases, previously published minimum clinical criteria for initiating antibiotics (Loeb criteria) were not met. Most antibiotics (n = 52) were initiated as a telephone order following a call from a nurse, and 41 patients were not evaluated by a provider within 48 h after initiation of antibiotics. Nearly all patients (n = 95) were treated with oral antibiotics alone. The median treatment duration was 7 days (interquartile range 7-10); 43 patients received treatment courses of >=10 days. CONCLUSION: Most newly diagnosed skin infections in nursing homes were non purulent infections treated with oral antibiotics. Antibiotics were initiated by telephone in over half of cases, and lack of a clinical evaluation within 48 h after starting antibiotics was common. Improved diagnosis through more timely clinical evaluations and decreasing length of therapy are important opportunities for antibiotic stewardship in nursing homes. PMID- 27493939 TI - The Effects of Dietary Fat and Iron Interaction on Brain Regional Iron Contents and Stereotypical Behaviors in Male C57BL/6J Mice. AB - Adequate brain iron levels are essential for enzyme activities, myelination, and neurotransmitter synthesis in the brain. Although systemic iron deficiency has been found in genetically or dietary-induced obese subjects, the effects of obesity-associated iron dysregulation in brain regions have not been examined. The objective of this study was to examine the effect of dietary fat and iron interaction on brain regional iron contents and regional-associated behavior patterns in a mouse model. Thirty C57BL/6J male weanling mice were randomly assigned to six dietary treatment groups (n = 5) with varying fat (control/high) and iron (control/high/low) contents. The stereotypical behaviors were measured during the 24th week. Blood, liver, and brain tissues were collected at the end of the 24th week. Brains were dissected into the hippocampus, midbrain, striatum, and thalamus regions. Iron contents and ferritin heavy chain (FtH) protein and mRNA expressions in these regions were measured. Correlations between stereotypical behaviors and brain regional iron contents were analyzed at the 5% significance level. Results showed that high-fat diet altered the stereotypical behaviors such as inactivity and total distance traveled (P < 0.05). The high-fat diet altered brain iron contents and FtH protein and mRNA expressions in a regional-specific manner: (1) high-fat diet significantly decreased the brain iron content in the striatum (P < 0.05), but not other regions, and (2) thalamus has a more distinct change in FtH mRNA expression compared with other regions. Furthermore, high-fat diet resulted in a significant decreased total distance traveled and a significant correlation between iron content and sleeping in midbrain (P < 0.05). Dietary iron also decreased brain iron content and FtH protein expression in a regionally specific manner. The effect of interaction between dietary fat and iron was observed in brain iron content and behaviors. All these findings will lay foundations to further explore the links among obesity, behaviors, and brain iron alteration. PMID- 27493941 TI - Standards and Challenges of Care for Colorectal Cancer Today. PMID- 27493942 TI - Diagnostics and Epidemiology of Colorectal Cancer. AB - Colorectal cancer is one of the leading causes of cancer-related morbidity and mortality. Main risk factors include advanced age, family history, male sex, and lifestyle factors. Screening can reduce incidence and death from colorectal cancer. Therefore, prevention and early detection are crucial in order to detect and remove pre-neoplastic adenomas and to detect cancers at early stages. Colonoscopy, flexible sigmoidoscopy, and fecal occult blood tests are established tools for screening. Newer fecal immunochemical tests reveal higher sensitivities for advanced adenoma and cancer than guaiac-based hemoccult tests. Molecular stool and blood tests as well as virtual colonoscopy and colon capsule endoscopy are promising new developments so far not established as routine instruments for the prevention and early detection of colorectal cancer. Colonoscopy is the method of choice for the diagnosis of colorectal cancer and for adenoma removal. Prognosis is essentially dependent on the tumor stage at the time of the initial diagnosis. Proper staging based on imaging prior to therapy is a prerequisite. In rectal cancer, local staging is an essential requirement for the identification of appropriate candidates for neoadjuvant therapy. PMID- 27493940 TI - A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies. AB - Titin (TTN) is known as the largest sarcomeric protein that resides within the heart muscle. Due to alternative splicing of TTN, the heart expresses two major isoforms (N2B and N2BA) that incorporate four distinct regions termed the Z-line, I-band, A-band, and M-line. Next-generation sequencing allows a large number of genes to be sequenced simultaneously and provides the opportunity to easily analyze giant genes such as TTN. Mutations in the TTN gene can cause cardiomyopathies, in particular dilated cardiomyopathy (DCM). DCM is the most common form of cardiomyopathy, and it is characterized by systolic dysfunction and dilation of the left ventricle. TTN truncating variants have been described as the most common cause of DCM, while the real impact of TTN missense variants in the pathogenesis of DCM is still unclear. In a recent population screening study, rare missense variants potentially pathogenic based on bioinformatic filtering represented only 12.6% of the several hundred rare TTN missense variants found, suggesting that missense variants are very common in TTN and are frequently benign. The aim of this review is to understand the clinical role of TTN mutations in DCM and in other cardiomyopathies. Whereas TTN truncations are common in DCM, there is evidence that TTN truncations are rare in the hypertrophic cardiomyopathy (HCM) phenotype. Furthermore, TTN mutations can also cause arrhythmogenic right ventricular cardiomyopathy (ARVC) with distinct clinical features and outcomes. Finally, the identification of a rare TTN missense variant cosegregating with the restrictive cardiomyopathy (RCM) phenotype suggests that TTN is a novel disease-causing gene in this disease. Clinical diagnostic testing is currently able to analyze over 100 cardiomyopathy genes, including TTN; however, the size and presence of extensive genetic variation in TTN presents clinical challenges in determining significant disease causing mutations. This review discusses the current knowledge of TTN genetic variations in cardiomyopathies and the impact of the diagnosis of TTN pathogenic mutations in the clinical setting. PMID- 27493943 TI - Imaging Procedures for Colorectal Cancer. AB - BACKGROUND: Radiological imaging plays an important role in the setting of staging, follow-up, and imaging-guided treatment of colorectal carcinoma (CRC). METHODS: This review aims to summarize the current state of the art of the different radiological imaging procedures in CRC including an overview over recently published national and European guidelines and consensus statements concerning the imaging of CRC patients. RESULTS AND CONCLUSION: Radiological imaging is widely embedded in national and international guidelines, and structured reporting is recommended. PMID- 27493944 TI - Radiotherapy for Colorectal Cancer: Current Standards and Future Perspectives. AB - BACKGROUND: Multimodal treatment approaches are indispensable for patients with advanced-stage colorectal cancer. Radiotherapy has been established as essential part of perioperative concepts and was introduced as an option to face challenges such as local relapse or oligometastases. METHODS: A literature review was performed to summarize evidence and current standards of radiotherapeutic concepts in the treatment of colorectal cancer. RESULTS: For stage II/III rectal cancer, neoadjuvant radiotherapy is superior to adjuvant treatment. Two preoperative regimens have been established and are commonly used with different objectives: short-course radiotherapy (SC-RT) and long-course chemoradiotherapy (LC-CRT). Both reduce the risk of local relapse. Additionally, LC-CRT aims at downsizing the tumor to potentially reduce radicalness of surgery. There is increasing evidence that not all stage II/III rectal cancer patients need neoadjuvant irradiation but also that in some cases surgery might be omitted. Stereotactic body radiotherapy (SBRT) of the liver shows high rates of local control in oligometastatic patients. Intraoperative and particle radiotherapy extend the spectrum of treatment options for locally recurrent patients. CONCLUSION: Radiotherapeutic concepts are crucial for the primary management of locally advanced colorectal cancer and can essentially contribute to treatment approaches in locally recurrent, oligometastatic or palliative patients. PMID- 27493945 TI - Treatment of Metastatic Colorectal Cancer: Standard of Care and Future Perspectives. AB - Palliative chemotherapy for metastatic colorectal cancer has undergone substantial changes in recent years. The implementation of modern biologicals in the treatment has substantially improved overall survival up to 30 months. With the increasing number of therapeutic options, the question of optimal treatment sequence arises, which is addressed in current studies like FIRE 4 or STRATEGIC 1. Furthermore, clinical and molecular biomarkers to predict efficacy and tolerability are urgently needed. Today, the detection of activating RAS mutations is the only validated biomarker which precludes patients from anti-EGFR treatment. The detection of BRAF mutation V600E is associated with a very poor prognosis corresponding to a survival of 9-12 months. Prospective trials evaluating an optimal approach to this subgroup are still missing. First results from strategies targeting the aberrant signal transduction are promising and require further validation. Despite the advances so far, life expectancy unfortunately continues to be limited in the majority of patients with metastatic colorectal cancer. New strategies are needed to improve the prognosis. To this end, the identification of Her2/neu as a potential target and first experiences with checkpoint inhibition in patients with mismatch repair-deficient tumors are promising and also require further validation. PMID- 27493946 TI - Surgery for Colorectal Cancer - Trends, Developments, and Future Perspectives. AB - BACKGROUND: Although colorectal surgery is long established as the mainstay treatment for colon cancer, certain topics regarding technical fine-tuning to increase postsurgical recurrence-free survival have remained a matter of debate throughout the past years. These include complete mesocolic excision (CME), treatment strategies for metastatic disease, significance of hyperthermic intraperitoneal chemotherapy (HIPEC), and surgical techniques for the treatment of colorectal cancer recurrence. In addition, new surgical techniques have been introduced in oncologic colorectal surgery, and their potential to provide sufficiently radical resection has yet to be proven. METHODS: A structured review of the literature was performed to identify the current state of the art with regard to the mentioned key issues in colorectal surgery. RESULTS: This article provides a comprehensive review of the current literature addressing the above mentioned current challenges in colorectal surgery. The focus lies on the impact of CME and, in relation to this, on lymph node dissection, as well as on treatment of metastatic disease including peritoneal spread, and finally on the treatment of recurrent disease. CONCLUSION: Uniformly, the current literature reveals that surgery aiming at complete malignancy elimination within multimodal treatment approaches represents the fundamental quantum leap for the achievement of long-term tumor-free survival. PMID- 27493947 TI - Minimally Invasive Surgery for the Treatment of Colorectal Cancer. AB - BACKGROUND: Reduction in operative trauma along with an improvement in endoscopic access has undoubtedly occupied surgical minds for at least the past 3 decades. It is not at all surprising that minimally invasive colon surgery has come a long way since the first laparoscopic appendectomy by Semm in 1981. It is common knowledge that the recent developments in video and robotic technologies have significantly furthered advancements in laparoscopic and minimally invasive surgery. This has led to the overall acceptance of the treatment of benign colorectal pathology via the endoscopic route. Malignant disease, however, is still primarily treated by conventional approaches. METHODS AND RESULTS: This review article is based on a literature search pertaining to advances in minimally invasive colorectal surgery for the treatment of malignant pathology, as well as on personal experience in the field over the same period of time. Our search was limited to level I and II clinical papers only, according to the evidence-based medicine guidelines. We attempted to present our unbiased view on the subject relying only on the evidence available. CONCLUSION: Focusing on advances in colorectal minimally invasive surgery, it has to be stated that there are still a number of unanswered questions regarding the surgical management of malignant diseases with this approach. These questions do not only relate to the area of boundaries set for the use of minimally invasive techniques in this field but also to the exact modality best suited to the treatment of every particular case whilst maintaining state-of-the-art oncological principles. PMID- 27493949 TI - Effects of Platelet-Derived Endothelial Cell Growth Factor and Doppler Perfusion Index in Patients with Colorectal Hepatic Metastases. AB - BACKGROUND: We aimed to find out if there is a correlation between Doppler perfusion index (DPI) and platelet- derived endothelial cell growth factor (PD ECGF), which is an angiogenic factor with angiopoietic function, in patients with colorectal carcinoma. METHODS: 50 colorectal carcinoma patients (22 cases with liver metastases, 28 cases without liver metastases) and 50 healthy controls were assessed with Doppler ultrasound as a preoperative evaluation. PD-ECGF expression in postoperative specimens of the 50 cases with colorectal carcinoma was assayed by immunohistochemistry and real-time polymerase chain reaction methods. RESULTS: The mean DPI value was 0.29 +/- 0.05 in patients suffering from colon cancer with hepatic metastases and 0.12 +/- 0.03 in the healthy control group. The DPI value was significantly higher in patients with liver metastases (p < 0.05). PD-ECGF expression in patients with colorectal liver metastases was significantly higher than that in the group without liver metastases (p < 0.05). A positive correlation was found between DPI value and PD-ECGF expression in patients with liver metastases (p < 0.05). CONCLUSIONS: DPI and PD-ECGF may be valuable factors when screening hepatic metastases in patients with colorectal cancer and serve as practical measurements in postoperative follow-up. PMID- 27493948 TI - Physical Activity and Nutrition in Primary and Tertiary Prevention of Colorectal Cancer. AB - BACKGROUND: Lifestyle factors play a pivotal role in the primary and tertiary prevention of colorectal cancer. The purpose of this review article is to summarize data concerning the effect of the lifestyle factors physical activity (PA) and nutrition in primary and, more importantly, tertiary prevention of colorectal cancer (CRC). METHODS: Focusing on the influence of lifestyle factors on prognosis und quality of life (QOL), a comprehensive literature search of clinical studies published mainly in the years 2000 until 2015 was performed and the current knowledge based on these clinical studies reviewed. RESULTS: Besides avoiding risk factors (such as smoking and overindulgence in alcohol), healthy weight, regular and moderate PA as well as a diet which contains fruit, vegetables, poultry, and fish (so-called 'Mediterranean' diet) may reduce the risk of the disease significantly. Patients already diagnosed with CRC can also actively improve the prognosis of CRC and QOL by changing their lifestyle. Patients commencing moderate exercise and modifying their eating habits in terms of a 'Mediterranean' diet can reduce cancer-specific and overall mortality by up to 40% and significantly increase their quality of life already during chemotherapy. Therefore, moderate physical exercise, calorie restriction, and a Mediterranean dietary pattern for patients with CRC should be recommended by physicians treating these patients. In fact, the World Cancer Research Fund/American Institute for Cancer Research (AICR/WCRF) systematic literature review from 2007 shows that the lifestyle changes recommended after diagnosis are the same for primary prevention of this disease. CONCLUSION: Lifestyle changes such as moderate PA and a Mediterranean diet significantly improve the QOL as well as the prognosis of patients suffering from colorectal disease. However, the effect of lifestyle changes is mostly based on observational studies, while only few studies are prospective and none are randomized. Therefore, these observational studies warrant controlled randomized trials to prove the effectiveness of lifestyle interventions on QOL and cancer recurrence. PMID- 27493950 TI - Intussusception of the Appendix and Ileum Endometriosis: A Case Report. AB - BACKGROUND: Intussusception of the appendix is a very rare condition. It may clinically mimic acute or chronic abdominal diseases or can be asymptomatic. CASE REPORT: This paper describes our experience with intussusception of the appendix. We report a case of a female with appendiceal intussusception and ileum endometriosis. CONCLUSION: It is important to know about such a rare condition in order to avoid mistaking it with other abdominal diseases. However, diagnosis is rarely made preoperatively. PMID- 27493951 TI - mHealth self-care interventions: managing symptoms following breast cancer treatment. AB - BACKGROUND: Many women suffer from daily distressing symptoms related to lymphedema following breast cancer treatment. Lymphedema, an abnormal accumulation of lymph fluid in the ipsilateral body area or upper limb, remains an ongoing major health problem affecting more than 40% of 3.1 million breast cancer survivors in the United States. Patient-centered care related to lymphedema symptom management is often inadequately addressed in clinical research and practice. mHealth plays a significant role in improving self-care, patient-clinician communication, and access to health information. The-Optimal Lymph-Flow health IT system (TOLF) is a patient-centered, web-and-mobile-based educational and behavioral mHealth interventions focusing on safe, innovative, and pragmatic electronic assessment and self-care strategies for lymphedema symptom management. The purpose of this paper is to describe the development and test of TOLF system. METHODS: The development of TOLF was guided by the Model of Self-Care for Lymphedema Symptom Management and designed based on principles fostering accessibility, convenience, and efficiency of mHealth system to enhance training and motivating assessment of and self-care for lymphedema symptoms. Test of TOLF was accomplished by conducting a psychometric study to evaluate reliability, validity, and efficiency of the electronic version of Breast Cancer and Lymphedema Symptom Experience Index (BCLE-SEI), a usability testing and a pilot feasibility testing of mHealth self-care interventions. RESULTS: Findings from the psychometric study with 355 breast cancer survivors demonstrated high internal consistency of the electronic version of the instrument: a Cronbach's alpha coefficient of 0.959 for the total scale, 0.919 for symptom occurrence, and 0.946 for symptom distress. Discriminant validity of the instrument was supported by a significant difference in symptom occurrence (z=-6.938, P<0.000), symptom distress (z=-5.894, P<0.000), and total scale (z=-6.547, P<0.000) between breast cancer survivors with lymphedema and those without it. Findings of usability testing showed that breast cancer survivors were very satisfied with the mHealth self-care interventions: 90% rated the system having no usability problems; 10% noted minor cosmetic problems: spelling errors or text font size. The majority of participants 96.6% strongly agreed that the system was easy to use and effective in helping to learn about lymphedema, symptoms and self-care strategies. Feasibility testing demonstrated that a 12-week one group intervention using TOLF had significantly positive effects on less pain (P=0.031), less soreness (P=0.021), less aching (P=0.024), less tenderness (P=0.039), fewer numbers of lymphedema symptoms (P=0.003), and improved symptom distress (P=0.000) at 12 weeks after intervention. Themes from the qualitative data included empowerment, high quality information, loving avatar simulation videos, easy accessibility, and user-friendliness. CONCLUSIONS: TOLF system using the electronic version of the instrument is able to assess patients' lymphedema symptoms with high reliability and validity. TOLF system is also able to deliver self-care interventions to enhance self-care strategies for lymphedema symptom management. PMID- 27493952 TI - Influence of the Dermis Thickness on the Results of the Skin Treatment with Monopolar and Bipolar Radiofrequency Currents. AB - Electrically layered tissue structure significantly modifies distribution of radiofrequency (RF) current in the dermis and in the subcutaneous adipose tissue comparing to that in a homogeneous medium. On the basis of the simple model of RF current distribution in a two-layer skin containing dermis and subcutis, we assess the influence of the dermal thickness on the current density in different skin layers. Under other equal conditions, current density in the dermis is higher for the skin having thinner dermis. This contradicts the main paradigm of the RF theory stating that treatment results are mainly dependent on the maximal temperature reached in a target tissue, since the best short- and long-term clinical results of RF application to the skin were reported in the areas having thicker dermis. To resolve this contradiction, it is proposed that the long-term effect of RF can be realized through a structural modification of the subcutaneous fat depot adjacent to the treated skin area. Stimulation of these cells located near the interface dermis/subcutis will demand the concentration of applied RF energy in this area and will require the optimal arrangement of RF electrodes on the skin surface. PMID- 27493953 TI - A Tobacco-Derived Thymosin beta4 Concatemer Promotes Cell Proliferation and Wound Healing in Mice. AB - Thymosin beta4 (Tbeta4) is a peptide that is known to play important roles in protection, regeneration, and remodeling of injured tissues in humans, and that shows great promise in a range of clinical applications. However, current strategies to Tbeta4 are insufficient to meet growing demand and have a number of limitations. In this current study we investigated whether expression of recombinant Tbeta4 in plants, specifically in tobacco (Nicotiana tabacum) leaves, represents an effective approach. To address this question, a 168 bp Tbeta4 gene optimized for tobacco codon usage bias was constitutively expressed in tobacco as a 4-unit repeat concatemer, fused to a polyhistidine tag. Quantitative polymerase chain reaction and Western blot analyses were used to verify 4*Tbeta4 expression in 14 transgenic tobacco lines and enzyme-linked immunosorbent assay analysis indicated 4*Tbeta4 protein concentrations as high as 3 MUg/g of fresh weight in the leaves. We observed that direct administration of tobacco-derived Tbeta4 was more effective than Tbeta4 either obtained commercially or derived from expression in Escherichia coli at promoting splenocyte proliferation in vitro and wound healing in mice through an endothelial migration assay. This study provides new insights into the development of plant-derived therapeutic proteins and their application by direct administration. PMID- 27493954 TI - Cognitive Rehabilitation in Patients with Gliomas and Other Brain Tumors: State of the Art. AB - Disease prognosis is very poor in patients with brain tumors. Cognitive deficits due to disease or due to its treatment have an important weight on the quality of life of patients and caregivers. Studies often take into account quality of life as a fundamental element in the management of disease and interventions have been developed for cognitive rehabilitation of neuropsychological deficits with the aim of improving the quality of life and daily-life autonomy of patients. In this literature review, we will consider the published studies of cognitive rehabilitation over the past 20 years. PMID- 27493955 TI - Historical ESWT Paradigms Are Overcome: A Narrative Review. AB - Extracorporeal Shock Wave Therapy (ESWT) is a conservative treatment modality with still growing interest in musculoskeletal disorders. This narrative review aims to present an overview covering 20-year development in the field of musculoskeletal ESWT. Eight historical paradigms have been identified and put under question from a current perspective: energy intensity, focus size, anesthesia, imaging, growth plates, acuteness, calcifications, and number of sessions. All paradigms as set in a historical consensus meeting in 1995 are to be revised. First, modern musculoskeletal ESWT is divided into focused and radial technology and the physical differences are about 100-fold with respect to the applied energy. Most lesions to be treated are easy to reach and clinical focusing plays a major role today. Lesion size is no longer a matter of concern. With the exception of nonunion fractures full, regional, or even local anesthesia is not helpful in musculoskeletal indications. Juvenile patients can also effectively be treated without risk of epiphyseal damage. Further research is needed to answer the question about if and which acute injuries can be managed effectively. Treatment parameters like the number of sessions are still relying on empirical data and have to be further elucidated. PMID- 27493956 TI - Efficacy of Immediate Switching from Bicalutamide to Flutamide as Second-Line Combined Androgen Blockade. AB - We determined whether prostate specific antigen (PSA) would decrease with immediate antiandrogen switching from bicalutamide (BCL) to flutamide (FLT) in patients receiving combined androgen blockade for advanced prostate cancer. From 2002 to 2006, 20 patients who showed PSA failure after first-line hormonal therapy with a luteinizing hormone-release hormone (LH-RH) agonist and BCL were enrolled. All patients were immediately switched from BCL to FLT, administered with an LH-RH agonist, as second-line combined androgen blockade (CAB). We evaluated the PSA response to second-line CAB. Eight patients (40%) were responsive, showing PSA decreases of at least 50%. The median (range) duration of the PSA response was 18.4 (3-26) months. Second-line CAB using FLT was effective in 40% of patients who received first-line CAB using BCL. The lower Gleason scores at the initial prostate biopsy probably reflect the response to second line CAB. Responders showed significantly better OS and CSS in the determination of any PSA decline and 40% PSA decline. The median OS duration in nonresponders and responders (40% PSA decline) was 1433 days versus 3617 days. It is concluded that an immediate switch from BCL to FLT is effective for some CRPC patients after first-line CAB using BCL. PMID- 27493957 TI - Evaluation of Implant Collar Surfaces for Marginal Bone Loss: A Systematic Review and Meta-Analysis. AB - Background. It is important to understand the influence of different collar designs on peri-implant marginal bone loss, especially in the critical area. Objectives. The purpose of the present systematic review and meta-analysis was to compare dental implants with different collar surfaces, evaluating marginal bone loss and survival rates of implants. Methods. Eligibility criteria included clinical human studies, randomized controlled trials, and prospective and retrospective studies, which evaluated dental implants with different collar surface in the same study. Results. Twelve articles were included, with a total of 492 machined, 319 rough-surfaced, and 352 rough-surfaced microthreaded neck implants. There was less marginal bone loss at implants with rough-surfaced and rough-surfaced microthreaded neck than at machined-neck implants (difference in means: 0.321, 95% CI: 0.149 to 0.493; p < 0.01). Conclusion. Rough and rough surfaced microthreaded implants are considered a predictable treatment for preserving early marginal bone loss. PMID- 27493958 TI - Downregulation of ADAMTS8 by DNA Hypermethylation in Gastric Cancer and Its Clinical Significance. AB - A disintegrin and metallopeptidase with thrombospondin motif type 8 (ADAMTS8), a member of the ADAMTS family, was discovered as a novel angiogenesis inhibitor. We analyzed the expression and methylation of ADAMTS8 in primary gastric tumors and gastric cancer cell lines. We also examined the relationship between ADAMTS8 expression and methylation and clinicopathologic features. The results showed that the significant downregulation of ADAMTS8 mRNA expression was observed in gastric cancer cell lines and tissues, and its expression was related to invasive depth and lymph node metastasis. CpG was hypermethylated in gastric cancer cell lines MKN45, MGC803, and BGC823, as well as primary gastric cancer specimens. ADAMTS8 mRNA expression was significantly lower in methylated primary gastric tumors. A significant association was found between ADAMTS8 methylation status and lymph node metastasis in primary gastric cancer. Moreover, ADAMTS8 expression was upregulated in the gastric cancer cell lines MGC803, BGC823, and MKN45 after treatment with 5-aza-2'-deoxycytidine. Thus, our results demonstrate that expression of ADAMTS8 mRNA is significantly decreased and DNA methylation is frequent in gastric cancer. ADAMTS8 hypermethylation is associated with decreased expression in gastric cancer and may play an important role in the invasion and metastasis of gastric cancer. PMID- 27493959 TI - Distribution of Triamcinolone Acetonide after Intravitreal Injection into Silicone Oil-Filled Eye. AB - There is increasing use of the vitreous cavity as a reservoir for drug delivery. We study the intraocular migration and distribution of triamcinolone acetonide (TA) after injection into silicone oil tamponade agent during and after vitrectomy surgery ex vivo (pig eye) and in vitro (glass bottle). For ex vivo assessment, intraocular migration of TA was imaged using real-time FLASH MRI scans and high-resolution T2W imaging and the in vitro model was monitored continuously with a video camera. Results of the ex vivo experiment showed that the TA droplet sank to the interface of silicone oil and aqueous almost immediately after injection and remained inside the silicone oil bubble for as long as 16 minutes. The in vitro results showed that, after the shrinkage of the droplet, TA gradually precipitated leaving only a lump of whitish crystalline residue inside the droplet for about 100 minutes. TA then quickly broke the interface and dispersed into the underlying aqueous within 15 seconds, which may result in a momentary increase of local TA concentration in the aqueous portion and potentially toxic to the retina. Our study suggests that silicone oil may not be a good candidate as a drug reservoir for drugs like TA. PMID- 27493960 TI - Quantitative In Vitro and In Vivo Evaluation of Intestinal and Blood-Brain Barrier Transport Kinetics of the Plant N-Alkylamide Pellitorine. AB - Objective. To evaluate the gut mucosa and blood-brain barrier (BBB) pharmacokinetic permeability properties of the plant N-alkylamide pellitorine. Methods. Pure pellitorine and an Anacyclus pyrethrum extract were used to investigate the permeation of pellitorine through (1) a Caco-2 cell monolayer, (2) the rat gut after oral administration, and (3) the BBB in mice after intravenous and intracerebroventricular administration. A validated bioanalytical UPLC-MS(2) method was used to quantify pellitorine. Results. Pellitorine was able to cross the Caco-2 cell monolayer from the apical-to-basolateral and from the basolateral-to-apical side with apparent permeability coefficients between 0.6 . 10(-5) and 4.8 . 10(-5) cm/h and between 0.3 . 10(-5) and 5.8 . 10(-5) cm/h, respectively. In rats, a serum elimination rate constant of 0.3 h(-1) was obtained. Intravenous injection of pellitorine in mice resulted in a rapid and high permeation of pellitorine through the BBB with a unidirectional influx rate constant of 153 MUL/(g.min). In particular, 97% of pellitorine reached the brain tissue, while only 3% remained in the brain capillaries. An efflux transfer constant of 0.05 min(-1) was obtained. Conclusion. Pellitorine shows a good gut permeation and rapidly permeates the BBB once in the blood, indicating a possible role in the treatment of central nervous system diseases. PMID- 27493962 TI - An Effective and Feasible Method, "Hammering Technique," for Percutaneous Fixation of Anterior Column Acetabular Fracture. AB - Objective. The objective of this study was to evaluate the effectiveness and advantages of percutaneous fixation of anterior column acetabular fracture with "hammering technique." Materials and Methods. We retrospectively reviewed 16 patients with percutaneous fixation of anterior column acetabular fracture with "hammering technique." There were 11 males and 5 females with an average age of 38.88 years (range: 24-54 years) in our study. Our study included 7 nondisplaced fractures, 6 mild displaced fractures (<2 mm), and 5 displaced fractures (>2 mm). The mean time from injury to surgery was 4.5 days (range: 2-7 days). Results. The average of operation time was 27.56 minutes (range: 15-45 minutes), and the mean blood loss was 55.28 mL (range: 15-100 mL). The mean fluoroscopic time was 54.78 seconds (range: 40-77 seconds). The first pass of the guide wire was acceptable without cortical perforation or intra-articular perforation in 88.89% (16/18) of the procedures, and the second attempt was in 11.11% (2/18). Conclusion. Our study suggested that percutaneous fixation of anterior column acetabular fracture with "hammering technique" acquired satisfying surgical and clinical outcomes. It may be an alternative satisfying treatment for percutaneous fixation of anterior column acetabular fracture by 2D fluoroscopy using a C-arm with less fluoroscopic time. PMID- 27493963 TI - Effects of a Lifestyle-Based Physical Activity Intervention on Medical Expenditure in Japanese Adults: A Community-Based Retrospective Study. AB - Background. This study aimed to investigate whether a lifestyle-based physical activity program could contribute to reduced medical expenditure. Methods. The study participants were 60 adults aged 63.1 (standard deviation, 4.4) years in the intervention group; the case-control group consisted of 300 adults who were randomly selected from Japan's national health insurance system. This community based retrospective study incorporated a 3-year follow-up. Results. The total and outpatient medical expenditure in the intervention group were significantly lower than in the control group: total expenditure, $US640.4/year; outpatient expenditure, $369.1/year. The odds ratio for outpatient visiting was 6.47-fold higher in the control than in the intervention group. Conclusion. Our study suggests that a health program to promote physical activity can result in reduced total medical expenditure, outpatient medical expenditure, and possibly also inpatient medical expenditure. PMID- 27493961 TI - The Epithelial Sodium Channel and the Processes of Wound Healing. AB - The epithelial sodium channel (ENaC) mediates passive sodium transport across the apical membranes of sodium absorbing epithelia, like the distal nephron, the intestine, and the lung airways. Additionally, the channel has been involved in the transduction of mechanical stimuli, such as hydrostatic pressure, membrane stretch, and shear stress from fluid flow. Thus, in vascular endothelium, it participates in the control of the vascular tone via its activity both as a sodium channel and as a shear stress transducer. Rather recently, ENaC has been shown to participate in the processes of wound healing, a role that may also involve its activities as sodium transporter and as mechanotransducer. Its presence as the sole channel mediating sodium transport in many tissues and the diversity of its functions probably underlie the complexity of its regulation. This brief review describes some aspects of ENaC regulation, comments on evidence about ENaC participation in wound healing, and suggests possible regulatory mechanisms involved in this participation. PMID- 27493964 TI - Homocysteine Levels in Parkinson's Disease: Is Entacapone Effective? AB - Plasma homocysteine (Hcy) levels may increase in levodopa-treated patients with Parkinson's disease (PD) as a consequence of levodopa methylation via catechol-O methyltransferase (COMT). Results from previous studies that assessed the effect of COMT inhibitors on levodopa-induced hyperhomocysteinemia are conflicting. We aimed to evaluate the effects of levodopa and entacapone on plasma Hcy levels. A hundred PD patients were enrolled to the study and divided into three treatment groups (group I: levodopa and/or dopamine agonists; group II: levodopa, entacapone, and/or a dopamine agonist; and group III: dopamine agonist alone). We measured the serum B12, folic acid, and Hcy levels in all patients. There were no statistically significant differences between groups in terms of modified Hoehn and Yahr stages, Unified Parkinson's Disease Rating Scale II/III, Standardized Mini-Mental Test scores, and serum vitamin B12 and folic acid levels. Plasma median Hcy levels were found above the normal laboratory values in groups I and II, but they were normal in group III. However, there was no statistically significant difference in plasma Hcy levels between groups. Our results showed that levodopa treatment may cause a slight increase in the Hcy levels in PD compared with dopamine agonists and that COMT inhibitors may not have a significant effect on preventing hyperhomocysteinemia. PMID- 27493965 TI - In Vivo Corneal Biomechanical Properties with Corneal Visualization Scheimpflug Technology in Chinese Population. AB - Purpose. To determine the repeatability of recalculated corneal visualization Scheimpflug technology (CorVis ST) parameters and to study the variation of biomechanical properties and their association with demographic and ocular characteristics. Methods. A total of 783 healthy subjects were included in this study. Comprehensive ophthalmological examinations were conducted. The repeatability of the recalculated biomechanical parameters with 90 subjects was assessed by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Univariate and multivariate linear regression models were used to identify demographic and ocular factors. Results. The repeatability of the central corneal thickness (CCT), deformation amplitude (DA), and first/second applanation time (A1/A2-time) exhibited excellent repeatability (CV% <= 3.312% and ICC >= 0.929 for all measurements). The velocity in/out (V in/out), highest concavity- (HC-) radius, peak distance (PD), and DA showed a normal distribution. Univariate linear regression showed a statistically significant correlation between V in, V out, DA, PD, and HC-radius and IOP, CCT, and corneal volume, respectively. Multivariate analysis showed that IOP and CCT were negatively correlated with V in, DA, and PD, while there was a positive correlation between V out and HC-radius. Conclusion. The ICCs of the recalculated parameters, CCT, DA, A1-time, and A2-time, exhibited excellent repeatability. IOP, CCT, and corneal volume significantly influenced the biomechanical properties of the eye. PMID- 27493966 TI - Energetic Assessment of the Nonexercise Activities under Free-Living Conditions. AB - Nonexercise activities (NAs) are common types of physical activity in daily life and critical component in energy expenditure. However, energetic assessment of NA, particularly in free-living subjects, is a technical challenge. In this study, mechanical modeling and portable device were used to evaluate five common types of NA in daily life: sit to stand, lie to sit, bowing while standing, squat, and right leg over left. A human indirect calorimeter was used to measure the activity energy expenditure of NA. Mechanical work and mechanical efficiency of NA were calculated for mechanical modeling. Thirty-two male subjects were recruited for the study (20 subjects for the development of models and 12 subjects for evaluation of models). The average (mean +/- SD) mechanical work of 5 NAs was 2.31 +/- 0.50, 2.88 +/- 0.57, 1.75 +/- 0.55, 3.96 +/- 1.25, and 1.25 +/ 0.51 J/kg.m, respectively. The mean mechanical efficiencies of those activities were 22.0 +/- 3.3%, 26.5 +/- 5.1%, 19.8 +/- 3.7%, 24.0 +/- 5.5%, and 26.3 +/- 5.5%. The activity energy expenditure estimated by the models was not significantly different from the measurements by the calorimeter (p > 0.05) with accuracies of 102.2 +/- 20.7%, 103.7 +/- 25.8%, 105.6 +/- 14.6%, 101.1 +/- 28.0%, and 95.8 +/- 20.7%, respectively, for those activities. These findings suggest that the mechanical models combined with a portable device can provide an alternative method for the energetic analysis of nonexercise activities under free-living condition. PMID- 27493967 TI - A Shortest Dependency Path Based Convolutional Neural Network for Protein-Protein Relation Extraction. AB - The state-of-the-art methods for protein-protein interaction (PPI) extraction are primarily based on kernel methods, and their performances strongly depend on the handcraft features. In this paper, we tackle PPI extraction by using convolutional neural networks (CNN) and propose a shortest dependency path based CNN (sdpCNN) model. The proposed method (1) only takes the sdp and word embedding as input and (2) could avoid bias from feature selection by using CNN. We performed experiments on standard Aimed and BioInfer datasets, and the experimental results demonstrated that our approach outperformed state-of-the-art kernel based methods. In particular, by tracking the sdpCNN model, we find that sdpCNN could extract key features automatically and it is verified that pretrained word embedding is crucial in PPI task. PMID- 27493968 TI - In Vitro Bioactivity Study of RGD-Coated Titanium Alloy Prothesis for Revision Total Hip Arthroplasty. AB - Total hip arthroplasty (THA) is a common procedure for the treatment of end-stage hip joint disease, and the demand for revision THA will double by 2026. Ti6Al4V (Titanium, 6% Aluminum, and 4% Vanadium) is a kind of alloy commonly used to make hip prothesis. To promote the osseointegration between the prothesis and host bone is very important for the revision THA. The peptide Arg-Gly-Asp (RGD) could increase cell attachment and has been used in the vascular tissue engineering. In this study, we combined the RGD with Ti6Al4V alloy using the covalent cross linking method to fabricate the functional Ti6Al4V alloy (FTA). The distribution of RGD oligopeptide on the FTA was even and homogeneous. The FTA scaffolds could promote mouse osteoblasts adhesion and spreading. Furthermore, the result of RT qPCR indicated that the FTA scaffolds were more beneficial to osteogenesis, which may be due to the improvement of osteoblast adhesion by the RGD oligopeptide coated on FTA. Overall, the FTA scaffolds developed herein pave the road for designing and building more efficient prothesis for osseointegration between the host bone and prothesis in revision THA. PMID- 27493969 TI - Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis. AB - Atherosclerosis can be regarded as a chronic inflammatory state, in which macrophages play different and important roles. Phagocytic proinflammatory cells populate growing atherosclerotic lesions, where they actively participate in cholesterol accumulation. Moreover, macrophages promote formation of complicated and unstable plaques by maintaining proinflammatory microenvironment. At the same time, anti-inflammatory macrophages contribute to tissue repair and remodelling and plaque stabilization. Macrophages therefore represent attractive targets for development of antiatherosclerotic therapy, which can aim to reduce monocyte recruitment to the lesion site, inhibit proinflammatory macrophages, or stimulate anti-inflammatory responses and cholesterol efflux. More studies are needed, however, to create a comprehensive classification of different macrophage phenotypes and to define their roles in the pathogenesis of atherosclerosis. In this review, we provide an overview of the current knowledge on macrophage diversity, activation, and plasticity in atherosclerosis and describe macrophage based cellular tests for evaluation of potential antiatherosclerotic substances. PMID- 27493970 TI - The Impact of Type 2 Diabetes on the Efficacy of ADP Receptor Blockers in Patients with Acute ST Elevation Myocardial Infarction: A Pilot Prospective Study. AB - Background. The aim of this study was to validate the impact of type 2 diabetes (T2D) on the platelet reactivity in patients with acute ST elevation myocardial infarction (STEMI) treated with adenosine diphosphate (ADP) receptor blockers. Methods. A pilot prospective study was performed. Totally 67 patients were enrolled. 21 patients had T2D. Among all study population, 33 patients received clopidogrel and 34 patients received prasugrel. The efficacy of ADP receptor blocker therapy had been tested in two time intervals using light transmission aggregometry with specific inducer and vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) flow cytometry assay. Results. There were no significant differences in platelet aggregability among T2D and nondiabetic (ND) group. The platelet reactivity index of VASP-P did not differ significantly between T2D and ND group (59.4 +/- 30.9% versus 60.0 +/- 25.2% and 33.9 +/- 25.3% versus 38.6 +/- 29.3% in second testing). The number of ADP receptor blocker nonresponders did not differ significantly between T2D and ND patients. The time interval from ADP receptor blocker loading dosing to the blood sampling was similar in T2D and ND patients in both examinations. Conclusion. This prospective study did not confirm the higher platelet reactivity and higher prevalence of ADP receptor blocker nonresponders in T2D acute STEMI patients. PMID- 27493971 TI - HLA-E(*)01:03 Allele in Lung Transplant Recipients Correlates with Higher Chronic Lung Allograft Dysfunction Occurrence. AB - Lung transplantation (LTx) is a valid therapeutic option for selected patients with end-stage lung disease. HLA-E seems to play a major role in the immune response to different viral infections and to affect transplantation outcome, in Hematopoietic Stem Cell Transplantation, for example. Two nonsynonymous alleles, HLA-E(*)01:01 and HLA-E(*)01:03, have functional differences, involving relative peptide affinity, cell surface expression, and potential lytic activity of NK cells. The aim of this retrospective study was to determine the impact of these two alleles for LTx recipients on anti-HLA alloimmunization risk, overall survival, and chronic rejection (CLAD). HLA-E was genotyped in 119 recipients who underwent LTx from 1998 to 2010 in a single transplantation center. In univariate analysis, both HLA-E homozygous states were associated with impaired overall survival compared to heterozygous HLA-E alleles (p = 0.01). In multivariate analysis, HLA-E(*)01:03 allele showed increased CLAD occurrence when compared to homozygous HLA-E(*)01:01 status (HR: 3.563 (CI 95%, 1.016-12), p = 0.047). HLA-E allele did not affect pathogen infection or the production of de novo DSA. This retrospective study shows an uninvestigated, deleterious association of HLA-E alleles with LTx and requires verification using a larger cohort. PMID- 27493972 TI - Actions of Thyroid Hormone Analogues on Chemokines. AB - The extracellular domain of plasma membrane integrin alphavbeta3 contains a receptor for thyroid hormone (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3); this receptor also binds tetraiodothyroacetic acid (tetrac), a derivative of T4. Tetrac inhibits the binding of T4 and T3 to the integrin. Fractalkine (CX3CL1) is a chemokine relevant to inflammatory processes in the CNS that are microglia dependent but also important to normal brain development. Expression of the CX3CL1 gene is downregulated by tetrac, suggesting that T4 and T3 may stimulate fractalkine expression. Independently of its specific receptor (CX3CR1), fractalkine binds to alphavbeta3 at a site proximal to the thyroid hormone-tetrac receptor and changes the physical state of the integrin. Tetrac also affects expression of the genes for other CNS-relevant chemokines, including CCL20, CCL26, CXCL2, CXCL3, and CXCL10. The chemokine products of these genes are important to vascularity of the brain, particularly of the choroid plexus, to inflammatory processes in the CNS and, in certain cases, to neuroprotection. Thyroid hormones are known to contribute to regulation of each of these CNS functions. We propose that actions of thyroid hormone and hormone analogues on chemokine gene expression contribute to regulation of inflammatory processes in brain and of brain blood vessel formation and maintenance. PMID- 27493974 TI - Circulating Regulatory T-Cells in Monoclonal Gammopathies of Uncertain Significance and Multiple Myeloma: In Search of a Role. AB - The frequency and function of regulatory T-cells (Tregs) in multiple myeloma (MM) are still matter of debate. The percentage and absolute number of circulating Tregs (CD4(+)CD25(+high density)CD127(-/low density)) from 39 patients with untreated MM and 44 patients with monoclonal gammopathies of uncertain significance (MGUS) were tested and compared with 20 healthy subjects as controls. The mean percentage number of circulating Tregs was 2.1% +/- 1.0 (range 0.75-6.1%) in MM patients; 2.1% +/- 0.9 (range 0.3-4.4%) in MGUS; and 1.5% +/- 0.4 (range 0.9-2.1%) in controls (p ns). Mean absolute number of Tregs was 36.3/MUL +/- 23.7 (range 6.7-149/MUL) in MM; 38.8/MUL +/- 19.1 (range 4.3 87/MUL) in MGUS; and 39.4/MUL +/- 12.5 (range 18-63/MUL) in controls (p ns). After a median follow-up of 38 months, 5 MGUS and 2 smoldering MM (SMM) transformed into overt MM; however Tregs number did not predict this evolution. With respect to MM patients and after a median follow-up of 33 months, Tregs did not show any significant correlation with main clinical and laboratory characteristics. Finally, from a functional point of view, Tregs displayed an effective suppressor function, irrespective of disease status. This study indicates that the number of circulating Tregs does not differ in different monoclonal gammopathies and normal subjects and do not correlate with clinical features of MM. PMID- 27493973 TI - An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment. AB - Inflamm-aging is a challenging and promising new branch of aging-related research fields that includes areas such as immunosenescence. Increasing evidence indicates that inflamm-aging is intensively associated with many aging diseases, such as Alzheimer's disease, atherosclerosis, heart disease, type II diabetes, and cancer. Mounting studies have focused on the role of inflamm-aging in disease progression and many advances have been made in the last decade. However, the underlying mechanisms by which inflamm-aging affects pathological changes and disease development are still unclear. Here, we review studies of inflamm-aging that explore the concept, pathological features, mechanisms, intervention, and the therapeutic strategies of inflamm-aging in disease progression. PMID- 27493975 TI - Ovarian Carcinoma With Isolated Spinal Cord Metastasis. AB - Ovarian cancer metastasis to the spinal cord is quite rare, and few case reports have been published previously. Herein, we present a case of a patient who was treated for ovarian cancer and was thought to be disease free for 17 months, then presented with lower limb weakness. She was found to have a T11-T12 metastatic intramedullary spinal cord lesion. On pathology, the diagnosis of metastatic ovarian adenocarcinoma was made. This report highlights the importance of maintaining a low threshold for ovarian cancer metastases to the spinal cord when patients present with neurologic sequelae, even in the setting of normal laboratory values, as early detection can prevent permanent neurological consequences. PMID- 27493976 TI - Pseudoradial Nerve Palsy Caused by Acute Ischemic Stroke. AB - Pseudoperipheral palsy has been used to characterize isolated monoparesis secondary to stroke. Isolated hand nerve palsy is a rare presentation for acute cerebral stroke. Our patient presented with clinical features of typical peripheral radial nerve palsy and a normal computed tomography scan of the head, which, without a detailed history and neurological examination, could have been easily misdiagnosed as a peripheral nerve lesion deferring further investigation for a stroke. We stress the importance of including cerebral infarction as a critical differential diagnosis in patients presenting with sensory-motor deficit in an isolated peripheral nerve pattern. A good history and physical exam can differentiate stroke from peripheral neuropathy as the cause of radial nerve palsy. PMID- 27493977 TI - Prosthetic Arteriovenous Graft Contact Dermatitis Masquerading as an Arteriovenous Graft Infection in a Hemodialysis Patient. AB - Prosthetic arteriovenous (AV) graft is the second most common vascular access of choice in hemodialysis patients. Rare complications of such grafts are increasingly seen due to rising population of patients on hemodialysis. Infections and thrombosis are the most common complications. Though metallic implants are known to cause hypersensitivity skin reactions, prosthetic AV grafts are rarely known to cause such kind of reactions due to inert nature of materials used in their preparation. We present a case of 54-year-old male who developed contact dermatitis after AV graft creation which was mistreated initially as infection. PMID- 27493978 TI - Tear biomarkers for keratoconus. AB - Keratoconus is a progressive corneal thinning, ectatic condition, which affects vision. Recent advances in corneal topography measurements has helped advance proper diagnosis of this condition and increased research and clinical interests in the disease etiopathogenesis. Considerable progress has been achieved in understanding the progression of the disease and tear fluid has played a major role in the progress. This review discusses the importance of tear fluid as a source of biomarker for keratoconus and how advances in technology have helped map the complexity of tears and thereby molecular readouts of the disease. Expanding knowledge of the tear proteome, lipidome and metabolome opened up new avenues to study keratoconus and to identify probable prognostic or diagnostic biomarkers for the disease. A multidimensional approach of analyzing tear fluid of patients layering on proteomics, lipidomics and metabolomics is necessary in effectively decoding keratoconus and thereby identifying targets for its treatment. PMID- 27493979 TI - Dimensions of similarity in the mental lexicon. AB - During language production planning, multiple candidate representations are implicitly activated prior to articulation. Lexical representations that are phonologically related to the target (phonological neighbors) are known to influence phonetic properties of the target word. However, the question of which dimensions of phonological similarity contribute to such lexical-phonetic effects remains unanswered. In the present study, we reanalyze phonetic data from a previous study, examining the contrasting predictions of different definitions of phonological similarity. Our results suggest that similarity at the level of position-specific phonological segments best predicts the influence of neighbor activation on phonetic properties of initial consonants. PMID- 27493980 TI - Methodology for high-yield acquisition of functional near-infrared spectroscopy data from alert, upright infants. AB - Functional near-infrared spectroscopy (fNIRS) research to date has tended to publish group-averaged rather than individual infant data due to normative basic research goals. Acquisition of individual infant time courses holds interest, however, both for cognitive science and particularly for clinical applications. Infants are more difficult to study than adults as they cannot be instructed to remain still. In addressing this, upright infants pose several associated complications for the researcher. We identified and optimized the factors that affect the quality of fNIRS data from individual 6- to 9-month-old infants exposed to a visual stimulation paradigm. The fNIRS headpiece was reconfigured to reduce inertia, increase comfort, and improve conformity to the head, while preserving fiber density to avoid missing the visual cortex activation. The visual-stimulation protocol was modified to keep the attention of infants throughout the measurement, thus helping to reduce motion artifacts. Adequate optical contact was verified by checking power levels before each measurement. By revising our experimental process and our data rejection criteria to prioritize good optical contact, we report for the first time usable hemodynamic data from 83% of infants and that two-thirds of infants produced a statistically significant fNIRS response. PMID- 27493981 TI - Subject-specific four-dimensional liver motion modeling based on registration of dynamic MRI. AB - Magnetic resonance-guided high intensity focused ultrasound treatment of the liver is a promising noninvasive technique for ablation of liver lesions. For the technique to be used in clinical practice, however, the issue of liver motion needs to be addressed. A subject-specific four-dimensional liver motion model is presented that is created based on registration of dynamically acquired magnetic resonance data. This model can be used for predicting the tumor motion trajectory for treatment planning and to indicate the tumor position for treatment guidance. The performance of the model was evaluated on a dynamic scan series that was not used to build the model. The method achieved an average Dice coefficient of 0.93 between the predicted and actual liver profiles and an average vessel misalignment of 3.0 mm. The model performed robustly, with a small variation in the results per subject. The results demonstrate the potential of the model to be used for MRI-guided treatment of liver lesions. Furthermore, the model can possibly be applied in other image-guided therapies, for instance radiotherapy of the liver. PMID- 27493982 TI - Design of a practical model-observer-based image quality assessment method for x ray computed tomography imaging systems. AB - The use of a channelization mechanism on model observers not only makes mimicking human visual behavior possible, but also reduces the amount of image data needed to estimate the model observer parameters. The channelized Hotelling observer (CHO) and channelized scanning linear observer (CSLO) have recently been used to assess CT image quality for detection tasks and combined detection/estimation tasks, respectively. Although the use of channels substantially reduces the amount of data required to compute image quality, the number of scans required for CT imaging is still not practical for routine use. It is our desire to further reduce the number of scans required to make CHO or CSLO an image quality tool for routine and frequent system validations and evaluations. This work explores different data-reduction schemes and designs an approach that requires only a few CT scans. Three different kinds of approaches are included in this study: a conventional CHO/CSLO technique with a large sample size, a conventional CHO/CSLO technique with fewer samples, and an approach that we will show requires fewer samples to mimic conventional performance with a large sample size. The mean value and standard deviation of areas under ROC/EROC curve were estimated using the well-validated shuffle approach. The results indicate that an 80% data reduction can be achieved without loss of accuracy. This substantial data reduction is a step toward a practical tool for routine-task-based QA/QC CT system assessment. PMID- 27493983 TI - Usage and Attitudes Towards Natural Remedies and Homeopathy in General Pediatrics: A Cross-Country Overview. AB - In order to better understand the global approach and country differences in physicians' usage, knowledge, and attitudes towards natural remedies and homeopathy in pediatric practice, an online survey involving 582 general pediatricians and general practitioners treating pediatric diseases was conducted in 6 countries. Overall, 17% of the pediatric prescriptions refer to phytotherapy and 15% refer to homeopathic preparations. Natural remedies and homeopathic preparations are more frequently used in upper respiratory tract infections, infant colic, sleep disturbances, and recurrent infections. In the majority of cases, they are used together with chemical drugs. Both treatment options are typically used if parents are concerned about side effects of conventional drugs or prefer natural remedies for themselves. Physicians express high interest in natural remedies and homeopathy; however, their knowledge is variable. Lack of proven efficacy, knowledge on mechanism of action, and information on indications are main factors that limit their usage. PMID- 27493984 TI - The Effectiveness and Safety of a Homeopathic Medicinal Product in Pediatric Upper Respiratory Tract Infections With Fever: A Randomized Controlled Trial. AB - We investigated the clinical effectiveness of a homeopathic add-on therapy in a pediatric subpopulation with upper respiratory tract infections (URTI) in a randomized, controlled, multinational clinical trial. Patients received either on demand symptomatic standard treatment (ST-group) or the same ST plus a homeopathic medication (Influcid; IFC-group) for 7 days. Outcome assessment was based on symptom and fever resolution and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21). A total of 261 pediatric (<12 years) patients (130 IFC group; 131 ST-group) were recruited in Germany and the Ukraine. The IFC-group used less symptomatic medication, symptoms resolved significantly earlier (P = .0001), had higher proportions of fever-free children from day 3 onwards, and the WURSS-assessed global disease severity was significantly less (P < .0001) during the entire URTI episode. One adverse event (vomiting) was possibly related to IFC. IFC as add-on treatment in pediatric URTI reduced global disease severity, shortened symptom resolution, and was safe in use. PMID- 27493985 TI - A Study to Determine if Addition of Palatal Petechiae to Centor Criteria Adds More Significance to Clinical Diagnosis of Acute Strep Pharyngitis in Children. AB - Objective. A study to determine if addition of palatal petechiae to Centor criteria adds more value for clinical diagnosis of acute strep pharyngitis in children. Hypothesis. In children, Centor Criteria does not cover all the symptoms and signs of acute strep pharyngitis. We hypothesize that addition of palatal petechiae to Centor Criteria will increase the possibility of clinical diagnosis of group A streptococcal pharyngitis in children. Methods. One hundred patients with a complaint of sore throat were enrolled in the study. All the patients were examined clinically using the Centor Criteria. They were also examined for other signs and symptoms like petechial lesions over the palate, abdominal pain, and skin rash. All the patients were given rapid strep tests, and throat cultures were sent. No antibiotics were given until culture results were obtained. Results. The sample size was 100 patients. All 100 had fever, sore throat, and erythema of tonsils. Twenty of the 100 patients had tonsillar exudates, 85/100 had tender anterior cervical lymph nodes, and 86/100 had no cough. In total, 9 out of the 100 patients had positive throat cultures. We observed that petechiae over the palate, a very significant sign, is not included in the Centor Criteria. Palatal petechiae were present in 8 out of the 100 patients. Six out of these 8 with palatal petechiae had positive throat culture for strep (75%). Only 7 out of 20 with exudates had positive strep culture. Sixteen out of the 100 patients had rapid strep test positive. Those 84/100 who had negative rapid strep also had negative throat culture. Statistics. We used Fisher's exact test, comparing throat culture positive and negative versus presence of exudates and palatal hemorrhages with positive and negative throat cultures and the resultant P value <.0001. Conclusion. Our study concludes that addition of petechiae over the palate to Centor Criteria will increase the possibility of diagnosing acute group A streptococcal pharyngitis in children. PMID- 27493986 TI - A 15-Year-Old Boy With Facial Palsy and Progressive Hearing Loss. PMID- 27493987 TI - Local coverage determination policy and the use of stereotactic body radiation therapy for prostate cancer. AB - INTRODUCTION: Local coverage determinations (LCDs) are local decisions that regulate healthcare coverage. We evaluated the impact of LCDs as well as patient, tumor, and market characteristics on the adoption of stereotactic body radiation therapy (SBRT) for prostate cancer. METHODS: Using Surveillance, Epidemiology, and End Results (SEER)-Medicare, we identified men treated with SBRT, intensity modulated radiotherapy (IMRT), and robotic prostatectomy. We compared demographics, clinical characteristics, and market factors among these three treatments. Our primary exposure was LCD policy; using the Medicare Coverage Database, we categorized LCDs as favorable (SBRT covered), neutral (SBRT covered in the context of a clinical trial or registry), unfavorable (SBRT not covered), or absent (i.e., SBRT not governed by an LCD at the time of treatment). We fit a multivariable multinomial logistic regression model and generated predicted probabilities to examine the relation between LCDs and SBRT. RESULTS: During this early period of SBRT adoption, IMRT was the most common of the three treatments followed by robotic prostatectomy and then SBRT. SBRT use was high when governed by favorable and neutral LCDs and lowest when governed by unfavorable LCDs. Compared with favorable LCDs, areas where LCDs were absent were associated with higher SBRT use compared with IMRT (odds ratio [OR] 1.56; 95%CI, 1.07-2.25) and robotic prostatectomy (OR 1.84; 95%CI, 1.25-2.69). CONCLUSIONS: When present, LCDs appear to regulate early SBRT adoption, but, when absent, are associated with increased SBRT use. Although SBRT use was uncommon, it varied across a wide range of patient, tumor, and market characteristics. PMID- 27493988 TI - Intestinal Parasite Profile in the Stool of HIV Positive Patients in relation to Immune Status and Comparison of Various Diagnostic Techniques with Special Reference to Cryptosporidium at a Tertiary Care Hospital in South India. AB - Acquired immunodeficiency syndrome and related opportunistic infections are a significant cause of morbidity and mortality in susceptible population. This study aims to negate the paucity of data regarding the relation between CD4 levels, prevalence of enteric parasites, and the outcome of treatment with HAART (highly active antiretroviral therapy) and Cotrimoxazole in Kerala, India. Multiple stool samples from 200 patients in a cross-sectional study were subjected to microscopy and Cryptosporidium stool antigen ELISA. Parasites were identified in 18 samples (9%). Cystoisospora and Cryptosporidium spp. were seen in 9 cases (4.5%) and 5 cases (2.5%), respectively. Microsporidium spores and Chilomastix mesnili cysts were identified in 1 case each (0.5% each). Seven cases of Cystoisospora diarrhoea recovered after treatment with Cotrimoxazole. Diarrhoea due to Cryptosporidium spp. in all 5 cases subsided after immune reconstitution with HAART. This study concludes that a positive association was seen between low CD4 count (<200 cells/MUL) and overall parasite positivity (P value < 0.01). ELISA is a more sensitive modality for the diagnosis of Cryptosporidium diarrhoea. Chilomastix mesnili, generally considered a nonpathogen, may be a cause of diarrhoeal disease in AIDS. Immune reconstitution and Cotrimoxazole prophylaxis remain to be the best therapeutic approach in AIDS related diarrhoea. PMID- 27493989 TI - Effect of Aerobic Exercise Training on Blood Pressure in Indians: Systematic Review. AB - Introduction. High blood pressure (BP) is one of the most important modifiable risk factors for cardiovascular diseases, which accounts for one in every eight deaths worldwide. It has been predicted that, by 2020, there would be 111% increase in cardiovascular deaths in India. Aerobic exercise in the form of brisk walking, jogging, running, and cycling would result in reduction in BP. Many meta analytical studies from western world confirm this. However, there is no such review from Indian subcontinent. Objective. Our objective is to systematically review and report the articles from India in aerobic exercise on blood pressure. Methodology. Study was done in March 2016 in Google Scholar using search terms "Aerobic exercise" AND "Training" AND "Blood pressure" AND "India." This search produced 3210 titles. Results. 24 articles were identified for this review based on inclusion and exclusion criteria. Total of 1107 subjects participated with median of 25 subjects. Studies vary in duration from +3 weeks to 12 months with each session lasting 15-60 minutes and frequency varies from 3 to 8 times/week. The results suggest that there was mean reduction of -05.00 mmHg in SBP and 03.09 mmHg in DBP after aerobic training. Conclusion. Aerobic training reduces the blood pressure in Indians. PMID- 27493990 TI - Musculoskeletal Disorders and Perceived Work Demands among Female Nurses at a Tertiary Care Hospital in India. AB - Introduction. Musculoskeletal disorders (MSD) are common among nurses and can affect patient outcomes. There is a dearth of literature on MSD among Indian nurses. The study objective was to measure prevalence of MSD and their association with perceived work demands and sociodemographic variables among female nurses at a tertiary care hospital in rural India. Methods. A cross sectional study was undertaken in 2013 through interviewer administered questionnaires which comprised three parts: sociodemographic data, modified Nordic questionnaire, and perceived physical and psychological work demands. Results. 296 nurses with a mean age of 30.4 years participated. Prevalence of any MSD in the last seven days was 60.5% with low back pain being the most common and elbow pain the least common. Occurrence of any MSD was associated with age, number of children, working hours at home, BMI, and total work experience. High perceived physical demands score was associated with lower back (OR: 3.06) and knee pain (OR: 7.73). Conclusion. Prevalence of MSD was high and occurrence of lower back and knee MSD was associated with perceived physical demands. This information should be used as a benchmark and guiding tool for designing work place interventions to improve working conditions and health of nurses. PMID- 27493991 TI - Microfluidic device for the formation of optically excitable, three-dimensional, compartmentalized motor units. AB - Motor units are the fundamental elements responsible for muscle movement. They are formed by lower motor neurons and their muscle targets, synapsed via neuromuscular junctions (NMJs). The loss of NMJs in neurodegenerative disorders (such as amyotrophic lateral sclerosis or spinal muscle atrophy) or as a result of traumatic injuries affects millions of lives each year. Developing in vitro assays that closely recapitulate the physiology of neuromuscular tissues is crucial to understand the formation and maturation of NMJs, as well as to help unravel the mechanisms leading to their degeneration and repair. We present a microfluidic platform designed to coculture myoblast-derived muscle strips and motor neurons differentiated from mouse embryonic stem cells (ESCs) within a three-dimensional (3D) hydrogel. The device geometry mimics the spinal cord-limb physical separation by compartmentalizing the two cell types, which also facilitates the observation of 3D neurite outgrowth and remote muscle innervation. Moreover, the use of compliant pillars as anchors for muscle strips provides a quantitative functional readout of force generation. Finally, photosensitizing the ESC provides a pool of source cells that can be differentiated into optically excitable motor neurons, allowing for spatiodynamic, versatile, and noninvasive in vitro control of the motor units. PMID- 27493993 TI - Shock compression response of forsterite above 250 GPa. AB - Forsterite (Mg2SiO4) is one of the major planetary materials, and its behavior under extreme conditions is important to understand the interior structure of large planets, such as super-Earths, and large-scale planetary impact events. Previous shock compression measurements of forsterite indicate that it may melt below 200 GPa, but these measurements did not go beyond 200 GPa. We report the shock response of forsterite above ~250 GPa, obtained using the laser shock wave technique. We simultaneously measured the Hugoniot and temperature of shocked forsterite and interpreted the results to suggest the following: (i) incongruent crystallization of MgO at 271 to 285 GPa, (ii) phase transition of MgO at 285 to 344 GPa, and (iii) remelting above ~470 to 500 GPa. These exothermic and endothermic reactions are seen to occur under extreme conditions of pressure and temperature. They indicate complex structural and chemical changes in the system MgO-SiO2 at extreme pressures and temperatures and will affect the way we understand the interior processes of large rocky planets as well as material transformation by impacts in the formation of planetary systems. PMID- 27493995 TI - When lives are put on hold: Lengthy asylum processes decrease employment among refugees. AB - European governments are struggling with the biggest refugee crisis since World War II, but there exists little evidence regarding how the management of the asylum process affects the subsequent integration of refugees in the host country. We provide new causal evidence about how one central policy parameter, the length of time that refugees wait in limbo for a decision on their asylum claim, affects their subsequent economic integration. Exploiting exogenous variation in wait times and registry panel data covering refugees who applied in Switzerland between 1994 and 2004, we find that one additional year of waiting reduces the subsequent employment rate by 4 to 5 percentage points, a 16 to 23% drop compared to the average rate. This deleterious effect is remarkably stable across different subgroups of refugees stratified by gender, origin, age at arrival, and assigned language region, a pattern consistent with the idea that waiting in limbo dampens refugee employment through psychological discouragement, rather than a skill atrophy mechanism. Overall, our results suggest that marginally reducing the asylum waiting period can help reduce public expenditures and unlock the economic potential of refugees by increasing employment among this vulnerable population. PMID- 27493992 TI - Analysis of neural crest-derived clones reveals novel aspects of facial development. AB - Cranial neural crest cells populate the future facial region and produce ectomesenchyme-derived tissues, such as cartilage, bone, dermis, smooth muscle, adipocytes, and many others. However, the contribution of individual neural crest cells to certain facial locations and the general spatial clonal organization of the ectomesenchyme have not been determined. We investigated how neural crest cells give rise to clonally organized ectomesenchyme and how this early ectomesenchyme behaves during the developmental processes that shape the face. Using a combination of mouse and zebrafish models, we analyzed individual migration, cell crowd movement, oriented cell division, clonal spatial overlapping, and multilineage differentiation. The early face appears to be built from multiple spatially defined overlapping ectomesenchymal clones. During early face development, these clones remain oligopotent and generate various tissues in a given location. By combining clonal analysis, computer simulations, mouse mutants, and live imaging, we show that facial shaping results from an array of local cellular activities in the ectomesenchyme. These activities mostly involve oriented divisions and crowd movements of cells during morphogenetic events. Cellular behavior that can be recognized as individual cell migration is very limited and short-ranged and likely results from cellular mixing due to the proliferation activity of the tissue. These cellular mechanisms resemble the strategy behind limb bud morphogenesis, suggesting the possibility of common principles and deep homology between facial and limb outgrowth. PMID- 27493994 TI - Battery-free, stretchable optoelectronic systems for wireless optical characterization of the skin. AB - Recent advances in materials, mechanics, and electronic device design are rapidly establishing the foundations for health monitoring technologies that have "skin like" properties, with options in chronic (weeks) integration with the epidermis. The resulting capabilities in physiological sensing greatly exceed those possible with conventional hard electronic systems, such as those found in wrist-mounted wearables, because of the intimate skin interface. However, most examples of such emerging classes of devices require batteries and/or hard-wired connections to enable operation. The work reported here introduces active optoelectronic systems that function without batteries and in an entirely wireless mode, with examples in thin, stretchable platforms designed for multiwavelength optical characterization of the skin. Magnetic inductive coupling and near-field communication (NFC) schemes deliver power to multicolored light-emitting diodes and extract digital data from integrated photodetectors in ways that are compatible with standard NFC-enabled platforms, such as smartphones and tablet computers. Examples in the monitoring of heart rate and temporal dynamics of arterial blood flow, in quantifying tissue oxygenation and ultraviolet dosimetry, and in performing four-color spectroscopic evaluation of the skin demonstrate the versatility of these concepts. The results have potential relevance in both hospital care and at-home diagnostics. PMID- 27493997 TI - Durable and sustained immune tolerance to ERT in Pompe disease with entrenched immune responses. AB - BACKGROUND: Enzyme replacement therapy (ERT) has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD), a rapidly progressive neuromuscular disorder. Yet marked interindividual variability in response to ERT, primarily attributable to the development of antibodies to ERT, remains an ongoing challenge. Immune tolerance to ongoing ERT has yet to be described in the setting of an entrenched immune response. METHODS: Three infantile Pompe patients who developed high and sustained rhGAA IgG antibody titers (HSAT) and received a bortezomib-based immune tolerance induction (ITI) regimen were included in the study and were followed longitudinally to monitor the long-term safety and efficacy. A trial to taper the ITI protocol was attempted to monitor if true immune tolerance was achieved. RESULTS: Bortezomib based ITI protocol was safely tolerated and led to a significant decline in rhGAA antibody titers with concomitant sustained clinical improvement. Two of the 3 IPD patients were successfully weaned off all ITI protocol medications and continue to maintain low/no antibody titers. ITI protocol was significantly tapered in the third IPD patient. B cell recovery was observed in all 3 IPD patients. CONCLUSION: This is the first report to our knowledge on successful induction of long-term immune tolerance in patients with IPD and HSAT refractory to agents such as cyclophosphamide, rituximab, and methotrexate, based on an approach using the proteasome inhibitor bortezomib. As immune responses limit the efficacy and cost-effectiveness of therapy for many conditions, proteasome inhibitors may have new therapeutic applications. FUNDING: This research was supported by a grant from the Genzyme Corporation, a Sanofi Company (Cambridge, Massachusetts, USA), and in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network (RDCRN). PMID- 27493998 TI - A location-centric network approach to analyzing epidemic dynamics. AB - Recent health threats, such as the SARS, H1N1, and Ebola pandemics, have stimulated great interest in network models to study the transmission of communicable diseases through human interaction and mobility. Most current network models have focused on an individual-centric perspective where individuals are represented as nodes, and the interactions among them as edges. Few of these models are concerned with the discovery of the spatial patterns and dynamics of epidemics. We propose a location-centric, transmission network approach, in which nodes denote locations and edges denote possible disease transmissions between locations. We then identify the dynamics of transmission flows, the dynamics of critical locations, and the spatial-temporal extent of transmission pathways to assess the impact of these spatial dynamics on the evolution of an epidemic. Results show that transmission flows shift from elementary schools to middle schools and finally universities and professional schools at different phases of an epidemic. Critical locations, identified using network analysis, are responsible for the upsurge in transmission flows during the peaks of the epidemic. The length of transmission pathways shows a power law distribution and their spatial extent is rather small. Insights gained from this study will help devise spatially sensitive strategies to control communicable diseases. PMID- 27493996 TI - Mechanized azobenzene-functionalized zirconium metal-organic framework for on command cargo release. AB - Stimuli-responsive metal-organic frameworks (MOFs) have gained increasing attention recently for their potential applications in many areas. We report the design and synthesis of a water-stable zirconium MOF (Zr-MOF) that bears photoresponsive azobenzene groups. This particular MOF can be used as a reservoir for storage of cargo in water, and the cargo-loaded MOF can be further capped to construct a mechanized MOF through the binding of beta-cyclodextrin with the azobenzene stalks on the MOF surface. The resulting mechanized MOF has shown on command cargo release triggered by ultraviolet irradiation or addition of competitive agents without premature release. This study represents a simple approach to the construction of stimuli-responsive mechanized MOFs, and considering mechanized UiO-68-azo made from biocompatible components, this smart system may provide a unique MOF platform for on-command drug delivery in the future. PMID- 27493999 TI - Integration of Multi-Modal Biomedical Data to Predict Cancer Grade and Patient Survival. AB - The Big Data era in Biomedical research has resulted in large-cohort data repositories such as The Cancer Genome Atlas (TCGA). These repositories routinely contain hundreds of matched patient samples for genomic, proteomic, imaging, and clinical data modalities, enabling holistic and multi-modal integrative analysis of human disease. Using TCGA renal and ovarian cancer data, we conducted a novel investigation of multi-modal data integration by combining histopathological image and RNA-seq data. We compared the performances of two integrative prediction methods: majority vote and stacked generalization. Results indicate that integration of multiple data modalities improves prediction of cancer grade and outcome. Specifically, stacked generalization, a method that integrates multiple data modalities to produce a single prediction result, outperforms both single-data-modality prediction and majority vote. Moreover, stacked generalization reveals the contribution of each data modality (and specific features within each data modality) to the final prediction result and may provide biological insights to explain prediction performance. PMID- 27494000 TI - [Perspectives to improve the sexual health of sexual and gender identity minorities in Guatemala]. AB - Sexual and gender identity minorities in Guatemala are disproportionally affected by HIV and other sexually transmitted infections (STI). However, little is known about the health determinants among these minorities that contribute to infection risk. Health researchers from the United States and Guatemala sought to explore sexual health needs and identify characteristics of HIV/STI prevention programs for these minorities.Our partnership conducted 8 focus groups with gay and bisexual men, men who have sex with men, and transgender women; and 10 in-depth interviews with community leaders. We analyzed transcripts of the focus groups and in-depth interviews using constant comparison.We identified 24 factors that influence sexual health which we organized into 5 ecological domains and 16 characteristics of potentially successful programs to reduce HIV/STI risk.The identification of sexual risk factors and characteristics of potentially successful programs offers great potential to develop interventions to help reduce the risk of HIV/STI infection among these minorities in Guatemala. PMID- 27494001 TI - Antifouling membranes for sustainable water purification: strategies and mechanisms. AB - One of the greatest challenges to the sustainability of modern society is an inadequate supply of clean water. Due to its energy-saving and cost-effective features, membrane technology has become an indispensable platform technology for water purification, including seawater and brackish water desalination as well as municipal or industrial wastewater treatment. However, membrane fouling, which arises from the nonspecific interaction between membrane surface and foulants, significantly impedes the efficient application of membrane technology. Preparing antifouling membranes is a fundamental strategy to deal with pervasive fouling problems from a variety of foulants. In recent years, major advancements have been made in membrane preparation techniques and in elucidating the antifouling mechanisms of membrane processes, including ultrafiltration, nanofiltration, reverse osmosis and forward osmosis. This review will first introduce the major foulants and the principal mechanisms of membrane fouling, and then highlight the development, current status and future prospects of antifouling membranes, including antifouling strategies, preparation techniques and practical applications. In particular, the strategies and mechanisms for antifouling membranes, including passive fouling resistance and fouling release, active off surface and on-surface strategies, will be proposed and discussed extensively. PMID- 27494002 TI - Gas-phase microsolvation of ubiquitin: investigation of crown ether complexation sites using ion mobility-mass spectrometry. AB - In this study the gas-phase structure of ubiquitin and its lysine-to-arginine mutants was investigated using ion mobility-mass spectrometry (IM-MS) and electron transfer dissociation-mass spectrometry (ETD-MS). Crown ether molecules were attached to positive charge sites of the proteins and the resulting non covalent complexes were analysed. Collision induced dissociation (CID) experiments revealed relative energy differences between the wild type and the mutant crown-ether complexes. ETD-MS experiments were performed to identify the crown ether binding sites. Although not all of the binding sites could be revealed, the data confirm that the first crown ether is able to bind to the N terminus. IM-MS experiments show a more compact structure for specific charge states of wild type ubiquitin when crown ethers are attached. However, data on ubiquitin mutants reveal that only specific lysine residues contribute to the effect of charge microsolvation. A compaction is only observed for one of the investigated mutants, in which the lysine has no proximate interaction partner. On the other hand when the lysine residues are involved in salt bridges, attachment of crown ethers has little effect on the structure. PMID- 27494003 TI - Kinetic trapping - a strategy for directing the self-assembly of unique functional nanostructures. AB - Supramolecular self-assembly into various nano- or microscopic structures based on non-covalent interactions between molecules has been recognized as a very efficient approach that leads to functional materials. Since most non-covalent interactions are relatively weak and form and break without significant activation barriers, the thermodynamic equilibrium of many supramolecular systems can be easily influenced by processing pathways that allow the system to stay in a kinetically trapped state. Thus far, kinetic traps have been found to be very important in producing more elaborate structural and functional diversity of self assembled systems. In this review, we try to summarize the approaches that can produce kinetically trapped self-assemblies based on examples made by us. We focus on the following subjects: (1) supramolecular pathway dependent self assembly, including kinetically trapped self-assemblies facilitated by host-guest chemistry, coordination chemistry, and electrostatic interactions; (2) physical processing pathway dependent self-assembly, including solvent quality controlled self-assembly, evaporation induced self-assembly and crystallization induced self assembly. PMID- 27494004 TI - Crystallinity-induced shape evolution of Pt-Ag nanosheets from branched nanocrystals. AB - Crystallinity offers countless opportunities for the controlled synthesis of multimetallic 2D and 3D nanomaterials. Herein we have successfully synthesized 2D Pt-Ag ultrathin nanosheets through the oxidative etching of twin seeds and 3D Pt Ag-Cu tetrapods via altering the crystallinity through the incorporation of copper into the Pt-Ag alloy. A better electrocatalytic activity is obtained for the oxidation of formic acid which is 3.8 times higher than that of a commercial platinum catalyst as the stepped surface atom densities are higher on the nanosheets. PMID- 27494005 TI - Studies of Energy-yielding Reactions in Thymus Nuclei : I. COMPARISON OF NUCLEAR AND MITOCHONDRIAL PHOSPHORYLATION. PMID- 27494006 TI - Studies on Energy-yielding Reactions in Thymus Nuclei : II. PATHWAYS OF AEROBIC CARBOHYDRATE CATABOLISM. PMID- 27494007 TI - Studies on Energy-yielding Reactions in Thymus Nuclei : III. PARTICIPATION OF GLYCOLYSIS AND THE CITRIC ACID CYCLE IN NUCLEAR ADENOSINE TRIPHOSPHATE SYNTHESIS. PMID- 27494008 TI - Conference presentations: Lead the poster parade. PMID- 27494009 TI - Planned Home Vaginal Birth After Cesarean. PMID- 27494010 TI - Diet Therapy May Be As Effective As Glyburide For Treatment Of Mild Gestational Diabetes. PMID- 27494011 TI - Early And Exclusive Breastfeeding May Protect Against Neonatal Mortality. PMID- 27494012 TI - Provider Skill Influences Perinatal Outcomes. PMID- 27494013 TI - Parents Desire Parenting Education During Prenatal Care. PMID- 27494014 TI - THE NATURE OF DISCOVERY. PMID- 27494015 TI - DEFINING A DISCOVERY: PRIORITY AND METHODOLOGICAL CONTROVERSY IN EARLY NINETEENTH CENTURY ANATOMY. AB - In the early nineteenth century, Charles Bell and Francois Magendie engaged in a decades-long priority dispute over the discovery of the roots of motor and sensory nerves. The constantly recalibrated arguments of its participants illuminate changes in the life sciences during that period. When Bell first wrote about the nerves in 1811, surgeon-anatomists ran small schools out of their homes, natural theology was in vogue, exchanges between British and French medical practitioners were limited by the Napoleonic Wars, and British practitioners typically rejected experimental physiology and vivisection. By the end of Magendie's career, medical science was produced in the laboratory, taught through artfully produced performances of the sort at which Magendie excelled, and disseminated through journals. It is not entirely clear which historical character, Bell or Magendie, 'won' the dispute, nor that they even had clear and consistent positions in it, but what is clear is that one style of science had won out over the other, and over the course of the dispute, pedagogy lost pride of place in medical science. PMID- 27494016 TI - LEONARDO DA VINCI AND THE ORIGIN OF SEMEN. AB - It is well known that Leonardo da Vinci made several drawings of the human male anatomy. The early drawings (before 1500) were incorrect in identifying the origin of semen, where he followed accepted teaching of his time. It is widely thought that he did not correct this mistake, a view that is reflected in several biographies. In fact, he made a later drawing (after 1500) in which the description of the anatomy is remarkably accurate and must have been based on careful dissection. In addition to highlighting this fact, acknowledged previously in only one other source, this article reviews the background to Leonardo's knowledge of the relevant anatomy. PMID- 27494017 TI - Largest healthcare executive search firms. PMID- 27494018 TI - Defining "intermittent UVR exposure". AB - BACKGROUND: Cutaneous malignant melanoma (CMM) has been associated with "intermittent UVR exposure", which in previous studies has mainly been assessed by retrospective questionnaire data. Further, there is no uniform definition of the term "intermittent UVR exposure". OBJECTIVES: We aimed to define and quantify "intermittent UVR exposure" by an objective measure. METHODS: A broad study population of adults and children had data collected during a summer period. Data were personal UVR dosimetry measurements, from which the number of "intermittent days" was derived, sun behaviour diaries and retrospective questionnaires. Two definitions of intermittent UVR exposure were tested: (1) days when UVR dose exceeded 3 times individual average daily UVR dose, and (2) days when UVR dose exceeded individual constitutive skin type. Measures of nevi and lentigines were used as surrogates for CMM. RESULTS: Using the first definition based solely on UVR dosimetry data we found 1241 "intermittent days" out of a total of 17 277 days (7.2%) among 148 participants. The numbers for nevi and lentigo density were significantly predicted by the number of intermittent days (R(2) = 0.15 and R(2) = 0.40, p < 0.001). The corresponding numbers for prediction of nevi and lentigo density by retrospective questionnaire data was lower (R(2) = 0.11, R(2) = 0.26, p < 0.001). CONCLUSIONS: We introduce a well-defined objective measure of intermittent UVR exposure. This measure may provide a better prediction of solar skin damage and CMM than retrospective questionnaire data. PMID- 27494019 TI - Hydrogen Peroxide Induced Cell Death: The Major Defences Relative Roles and Consequences in E. coli. AB - We recently developed a mathematical model for predicting reactive oxygen species (ROS) concentration and macromolecules oxidation in vivo. We constructed such a model using Escherichia coli as a model organism and a set of ordinary differential equations. In order to evaluate the major defences relative roles against hydrogen peroxide (H2 O2), we investigated the relative contributions of the various reactions to the dynamic system and searched for approximate analytical solutions for the explicit expression of changes in H2 O2 internal or external concentrations. Although the key actors in cell defence are enzymes and membrane, a detailed analysis shows that their involvement depends on the H2 O2 concentration level. Actually, the impact of the membrane upon the H2 O2 stress felt by the cell is greater when micromolar H2 O2 is present (9-fold less H2 O2 in the cell than out of the cell) than when millimolar H2 O2 is present (about 2 fold less H2 O2 in the cell than out of the cell). The ratio between maximal external H2 O2 and internal H2 O2 concentration also changes, reducing from 8 to 2 while external H2 O2 concentration increases from micromolar to millimolar. This non-linear behaviour mainly occurs because of the switch in the predominant scavenger from Ahp (Alkyl Hydroperoxide Reductase) to Cat (catalase). The phenomenon changes the internal H2 O2 maximal concentration, which surprisingly does not depend on cell density. The external H2 O2 half-life and the cumulative internal H2 O2 exposure do depend upon cell density. Based on these analyses and in order to introduce a concept of dose response relationship for H2 O2-induced cell death, we developed the concepts of "maximal internal H2 O2 concentration" and "cumulative internal H2 O2 concentration" (e.g. the total amount of H2 O2). We predict that cumulative internal H2 O2 concentration is responsible for the H2 O2-mediated death of bacterial cells. PMID- 27494020 TI - Reduction in Hospital-Wide Clinical Laboratory Specimen Identification Errors following Process Interventions: A 10-Year Retrospective Observational Study. AB - BACKGROUND: Accurate patient identification and specimen labeling at the time of collection are crucial steps in the prevention of medical errors, thereby improving patient safety. METHODS: All patient specimen identification errors that occurred in the outpatient department (OPD), emergency department (ED), and inpatient department (IPD) of a 3,800-bed academic medical center in Taiwan were documented and analyzed retrospectively from 2005 to 2014. To reduce such errors, the following series of strategies were implemented: a restrictive specimen acceptance policy for the ED and IPD in 2006; a computer-assisted barcode positive patient identification system for the ED and IPD in 2007 and 2010, and automated sample labeling combined with electronic identification systems introduced to the OPD in 2009. RESULTS: Of the 2000345 specimens collected in 2005, 1023 (0.0511%) were identified as having patient identification errors, compared with 58 errors (0.0015%) among 3761238 specimens collected in 2014, after serial interventions; this represents a 97% relative reduction. The total number (rate) of institutional identification errors contributed from the ED, IPD, and OPD over a 10-year period were 423 (0.1058%), 556 (0.0587%), and 44 (0.0067%) errors before the interventions, and 3 (0.0007%), 52 (0.0045%) and 3 (0.0001%) after interventions, representing relative 99%, 92% and 98% reductions, respectively. CONCLUSIONS: Accurate patient identification is a challenge of patient safety in different health settings. The data collected in our study indicate that a restrictive specimen acceptance policy, computer-generated positive identification systems, and interdisciplinary cooperation can significantly reduce patient identification errors. PMID- 27494021 TI - Relationship between Individual External Doses, Ambient Dose Rates and Individuals' Activity-Patterns in Affected Areas in Fukushima following the Fukushima Daiichi Nuclear Power Plant Accident. AB - The accident at Fukushima Daiichi Nuclear Power Plant on March 11, 2011, released radioactive material into the atmosphere and contaminated the land in Fukushima and several neighboring prefectures. Five years after the nuclear disaster, the radiation levels have greatly decreased due to physical decay, weathering, and decontamination operations in Fukushima. The populations of 12 communities were forced to evacuate after the accident; as of March 2016, the evacuation order has been lifted in only a limited area, and permanent habitation is still prohibited in most of the areas. In order for the government to lift the evacuation order and for individuals to return to their original residential areas, it is important to assess current and future realistic individual external doses. Here, we used personal dosimeters along with the Global Positioning System and Geographic Information System to understand realistic individual external doses and to relate individual external doses, ambient doses, and activity-patterns of individuals in the affected areas in Fukushima. The results showed that the additional individual external doses were well correlated to the additional ambient doses based on the airborne monitoring survey. The results of linear regression analysis suggested that the additional individual external doses were on average about one-fifth that of the additional ambient doses. The reduction factors, which are defined as the ratios of the additional individual external doses to the additional ambient doses, were calculated to be on average 0.14 and 0.32 for time spent at home and outdoors, respectively. Analysis of the contribution of various activity patterns to the total individual external dose demonstrated good agreement with the average fraction of time spent daily in each activity, but the contribution due to being outdoors varied widely. These results are a valuable contribution to understanding realistic individual external doses and the corresponding airborne monitoring-based ambient doses and time-activity patterns of individuals. Moreover, the results provide important information for predicting future cumulative doses after the return of residents to evacuation order areas in Fukushima. PMID- 27494022 TI - PI-103 and Quercetin Attenuate PI3K-AKT Signaling Pathway in T- Cell Lymphoma Exposed to Hydrogen Peroxide. AB - Phosphatidylinositol 3 kinase-protein kinase B (PI3K-AKT) pathway has been considered as major drug target site due to its frequent activation in cancer. AKT regulates the activity of various targets to promote tumorigenesis and metastasis. Accumulation of reactive oxygen species (ROS) has been linked to oxidative stress and regulation of signaling pathways for metabolic adaptation of tumor microenvironment. Hydrogen peroxide (H2O2) in this context is used as ROS source for oxidative stress preconditioning. Antioxidants are commonly considered to be beneficial to reduce detrimental effects of ROS and are recommended as dietary supplements. Quercetin, a ubiquitous bioactive flavonoid is a dietary component which has attracted much of interest due to its potential health promoting effects. Present study is aimed to analyze PI3K-AKT signaling pathway in H2O2 exposed Dalton's lymphoma ascite (DLA) cells. Further, regulation of PI3K AKT pathway by quercetin as well as PI-103, an inhibitor of PI3K was analyzed. Exposure of H2O2 (1mM H2O2 for 30min) to DLA cells caused ROS accumulation and resulted in increased phosphorylation of PI3K and downstream proteins PDK1 and AKT (Ser-473 and Thr-308), cell survival factors BAD and ERK1/2, as well as TNFR1. However, level of tumor suppressor PTEN was declined. Both PI-103 & quercetin suppressed the enhanced level of ROS and significantly down-regulated phosphorylation of AKT, PDK1, BAD and level of TNFR1 as well as increased the level of PTEN in H2O2 induced lymphoma cells. The overall result suggests that quercetin and PI3K inhibitor PI-103 attenuate PI3K-AKT pathway in a similar mechanism. PMID- 27494023 TI - Stability of Chloropyromorphite in Ryegrass Rhizosphere as Affected by Root Secreted Low Molecular Weight Organic Acids. AB - Understanding the stability of chloropyromorphite (CPY) is of considerable benefit for improving risk assessment and remediation strategies in contaminated water and soil. The stability of CPY in the rhizosphere of phosphorus-deficient ryegrass was evaluated to elucidate the role of root-secreted low molecular weight organic acids (LMWOAs) on the dissolution of CPY. Results showed that CPY treatments significantly reduced the ryegrass biomass and rhizosphere pH. The presence of calcium nitrate extractable lead (Pb) and phosphorus (P) suggested that CPY in the rhizosphere could be bioavailable, because P and Pb uptake by ryegrass potentially provided a significant concentration gradient that would promote CPY dissolution. Pb accumulation and translocation in ryegrass was found to be significantly higher in P-sufficient conditions than in P-deficient conditions. CPY treatments significantly enhanced root exudation of LMWOAs irrigated with P-nutrient solution or P-free nutrient solution. Oxalic acid was the dominant species in root-secreted LMWOAs of ryegrass under P-free nutrient solution treatments, suggesting that root-secreted oxalic acid may be the driving force of root-induced dissolution of CPY. Hence, our work, provides clarifying hints on the role of LMWOAs in controlling the stability of CPY in the rhizosphere. PMID- 27494024 TI - Revised North Star Ambulatory Assessment for Young Boys with Duchenne Muscular Dystrophy. AB - The advent of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify reliable outcome measures for young boys with DMD. The aim of this study was to develop a revised version of the North Star Ambulatory Assessment (NSAA) suitable for boys between the age of 3 and 5 years by identifying age appropriate items and revising the scoring system accordingly. Using the scale in 171 controls between the age of 2.9 and 4.8 years, we identified items that were appropriate at different age points. An item was defined as age appropriate if it was completed, achieving a full score, by at least 85% of the typically developing boys at that age. At 3 years (+/-3months) there were only 8 items that were age appropriate, at 3 years and 6 months there were 13 items while by the age of 4 years all 17 items were appropriate. A revised version of the scale was developed with items ordered according to the age when they could be reliably performed. The application of the revised version of the scale to data collected in young DMD boys showed that very few of the DMD boys were able to complete with a full score all the age appropriate items. In conclusion, our study suggests that a revised version of the NSAA can be used in boys from the age of 3 years to obtain information on how young DMD boys acquire new abilities and how this correlates with their peers. PMID- 27494025 TI - Strain Mediated Adaptation Is Key for Myosin Mechanochemistry: Discovering General Rules for Motor Activity. AB - A structure-based model of myosin motor is built in the same spirit of our early work for kinesin-1 and Ncd towards physical understanding of its mechanochemical cycle. We find a structural adaptation of the motor head domain in post powerstroke state that signals faster ADP release from it compared to the same from the motor head in the pre-powerstroke state. For dimeric myosin, an additional forward strain on the trailing head, originating from the postponed powerstroke state of the leading head in the waiting state of myosin, further increases the rate of ADP release. This coordination between the two heads is the essence of the processivity of the cycle. Our model provides a structural description of the powerstroke step of the cycle as an allosteric transition of the converter domain in response to the Pi release. Additionally, the variation in structural elements peripheral to catalytic motor domain is the deciding factor behind diverse directionalities of myosin motors (myosin V & VI). Finally, we observe that there are general rules for functional molecular motors across the different families. Allosteric structural adaptation of the catalytic motor head in different nucleotide states is crucial for mechanochemistry. Strain mediated coordination between motor heads is essential for processivity and the variation of peripheral structural elements is essential for their diverse functionalities. PMID- 27494026 TI - Molecular Characterization of the ORF3 and S1 Genes of Porcine Epidemic Diarrhea Virus Non S-INDEL Strains in Seven Regions of China, 2015. AB - In an effort to trace the evolution of porcine epidemic diarrhea virus (PEDV), S1 and ORF3 genes of viruses identified in 41 pig farms from seven regions (North, Northeast, Northwest, Central, East, South West, and South, respectively) of China in 2015 were sequenced and analyzed. Sequence analysis revealed that the 41 ORF3 genes and 29 S1 genes identified in our study exhibited nucleotide homologies of 98.2%-100% and 96.6%-100%, respectively; these two genes exhibited low nucleotide sequence similarities with classical CV777 strain and early Chinese strain LZC. Phylogenetic analysis indicated that the identified PEDV strains belonged to global non S-INDEL strains, and exhibited genetic diversity; S1 gene of the HLJ2015/DP1-1 strain harbored an unique deletion of 12 nucleotides (A1130CAACTCCACTG1141); while the Chinese PEDV S-INDEL reference strains included two types of the "CV777" S-INDEL as well as the "US" S-INDEL, and all co circulated with Chinese non S-INDEL strains. Of 29 identified S1 genes, the SS2 epitope (Y748SNIGVCK755) was highly conserved, while the SS6 epitope (L764QDGQVKI771) and pAPN receptor-binding region (aa 490-615) exhibited amino substitutions. Nine possible recombination events were identified between the 29 identifed S1 genes and the 3 S1 reference genes from early Chinese PEDV strains. The complete S genes of selected Chinese PEDV field strains (2011-2015) showed 5.18%-6.07% nucleotide divergence, which is far higher than the divergence observed in early Chinese PEDV strains (3.1%) (P<0.05). Our data provide evidence that PEDV non S-INDEL strains with genetic diversities and potential recombination circulate in seven regions of China in 2015; Chinese PEDV S-INDEL strains exhibit genetic diversity and co-circulate with non S-INDEL strains. PMID- 27494027 TI - Dual Targeting of Intracellular Pathogenic Bacteria with a Cleavable Conjugate of Kanamycin and an Antibacterial Cell-Penetrating Peptide. AB - Bacterial infection caused by intracellular pathogens, such as Mycobacterium, Salmonella, and Brucella, is a burgeoning global health epidemic that necessitates urgent action. However, the therapeutic value of a number of antibiotics, including aminoglycosides, against intracellular pathogenic bacteria is compromised due to their inability to traverse eukaryotic membranes. For this significant problem to be addressed, a cleavable conjugate of the antibiotic kanamycin and a nonmembrane lytic, broad-spectrum antimicrobial peptide with efficient mammalian cell penetration, P14LRR, was prepared. This approach allows kanamycin to enter mammalian cells as a conjugate linked via a tether that breaks down in the reducing environment within cells. Potent antimicrobial activity of the P14KanS conjugate was demonstrated in vitro, and this reducible conjugate effectively cleared intracellular pathogenic bacteria within macrophages more potently than that of a conjugate lacking the disulfide moiety. Notably, successful clearance of Mycobacterium tuberculosis within macrophages was observed with the dual antibiotic conjugate, and Salmonella levels were significantly reduced in an in vivo Caenorhabditis elegans model. PMID- 27494028 TI - Integrated Monitoring of Mola mola Behaviour in Space and Time. AB - Over the last decade, ocean sunfish movements have been monitored worldwide using various satellite tracking methods. This study reports the near-real time monitoring of fine-scale (< 10 m) behaviour of sunfish. The study was conducted in southern Portugal in May 2014 and involved satellite tags and underwater and surface robotic vehicles to measure both the movements and the contextual environment of the fish. A total of four individuals were tracked using custom made GPS satellite tags providing geolocation estimates of fine-scale resolution. These accurate positions further informed sunfish areas of restricted search (ARS), which were directly correlated to steep thermal frontal zones. Simultaneously, and for two different occasions, an Autonomous Underwater Vehicle (AUV) video-recorded the path of the tracked fish and detected buoyant particles in the water column. Importantly, the densities of these particles were also directly correlated to steep thermal gradients. Thus, both sunfish foraging behaviour (ARS) and possibly prey densities, were found to be influenced by analogous environmental conditions. In addition, the dynamic structure of the water transited by the tracked individuals was described by a Lagrangian modelling approach. The model informed the distribution of zooplankton in the region, both horizontally and in the water column, and the resultant simulated densities positively correlated with sunfish ARS behaviour estimator (rs = 0.184, p<0.001). The model also revealed that tracked fish opportunistically displace with respect to subsurface current flow. Thus, we show how physical forcing and current structure provide a rationale for a predator's fine-scale behaviour observed over a two weeks in May 2014. PMID- 27494029 TI - Whole Exome Sequencing Identifies TSC1/TSC2 Biallelic Loss as the Primary and Sufficient Driver Event for Renal Angiomyolipoma Development. AB - Renal angiomyolipoma is a kidney tumor in the perivascular epithelioid (PEComa) family that is common in patients with Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) but occurs rarely sporadically. Though histologically benign, renal angiomyolipoma can cause life-threatening hemorrhage and kidney failure. Both angiomyolipoma and LAM have mutations in TSC2 or TSC1. However, the frequency and contribution of other somatic events in tumor development is unknown. We performed whole exome sequencing in 32 resected tumor samples (n = 30 angiomyolipoma, n = 2 LAM) from 15 subjects, including three with TSC. Two germline and 22 somatic inactivating mutations in TSC2 were identified, and one germline TSC1 mutation. Twenty of 32 (62%) samples showed copy neutral LOH (CN-LOH) in TSC2 or TSC1 with at least 8 different LOH regions, and 30 of 32 (94%) had biallelic loss of either TSC2 or TSC1. Whole exome sequencing identified a median of 4 somatic non-synonymous coding region mutations (other than in TSC2/TSC1), a mutation rate lower than nearly all other cancer types. Three genes with mutations were known cancer associated genes (BAP1, ARHGAP35 and SPEN), but they were mutated in a single sample each, and were missense variants with uncertain functional effects. Analysis of sixteen angiomyolipomas from a TSC subject showed both second hit point mutations and CN-LOH in TSC2, many of which were distinct, indicating that they were of independent clonal origin. However, three tumors had two shared mutations in addition to private somatic mutations, suggesting a branching evolutionary pattern of tumor development following initiating loss of TSC2. Our results indicate that TSC2 and less commonly TSC1 alterations are the primary essential driver event in angiomyolipoma/LAM, whereas other somatic mutations are rare and likely do not contribute to tumor development. PMID- 27494031 TI - Genomic Inbreeding and Relatedness in Wild Panda Populations. AB - Inbreeding and relatedness in wild panda populations are important parameters for panda conservation. Habitat loss and fragmentation are expected to increase inbreeding but the actual inbreeding levels in natural panda habitats were unknown. Using 150,025 SNPs and 14,926 SNPs selected from published whole-genome sequences, we estimated genomic inbreeding coefficients and relatedness of 49 pandas including 34 wild pandas sampled from six habitats. Qinling and Liangshan pandas had the highest levels of inbreeding and relatedness measured by genomic inbreeding and coancestry coefficients, whereas the inbreeding levels in Qionglai and Minshan were 28-45% of those in Qinling and Liangshan. Genomic coancestry coefficients between pandas from different habitats showed that panda populations from the four largest habitats, Minshan, Qionglai, Qinling and Liangshan, were genetically unrelated. Pandas between these four habitats on average shared 66.0 69.1% common alleles and 45.6-48.6% common genotypes, whereas pandas within each habitat shared 71.8-77.0% common alleles and 51.7-60.4% common genotypes. Pandas in the smaller populations of Qinling and Liangshan were more similarly to each other than pandas in the larger populations of Qionglai and Minshan according to three genomic similarity measures. Panda genetic differentiation between these habitats was positively related to their geographical distances. Most pandas separated by 200 kilometers or more shared no common ancestral alleles. The results provided a genomic quantification of the actual levels of inbreeding and relatedness among pandas in their natural habitats, provided genomic confirmation of the relationship between genetic diversity and geographical distances, and provided genomic evidence to the urgency of habitat protection. PMID- 27494030 TI - Innovative Approaches Using Lichen Enriched Media to Improve Isolation and Culturability of Lichen Associated Bacteria. AB - Lichens, self-supporting mutualistic associations between a fungal partner and one or more photosynthetic partners, also harbor non-photosynthetic bacteria. The diversity and contribution of these bacteria to the functioning of lichen symbiosis have recently begun to be studied, often by culture-independent techniques due to difficulties in their isolation and culture. However, culturing as yet unculturable lichenic bacteria is critical to unravel their potential functional roles in lichen symbiogenesis, to explore and exploit their biotechnological potential and for the description of new taxa. Our objective was to improve the recovery of lichen associated bacteria by developing novel isolation and culture approaches, initially using the lichen Pseudevernia furfuracea. We evaluated the effect of newly developed media enriched with novel lichen extracts, as well as the influence of thalli washing time and different disinfection and processing protocols of thalli. The developed methodology included: i) the use of lichen enriched media to mimic lichen nutrients, supplemented with the fungicide natamycin; ii) an extended washing of thalli to increase the recovery of ectolichenic bacteria, thus allowing the disinfection of thalli to be discarded, hence enhancing endolichenic bacteria recovery; and iii) the use of an antioxidant buffer to prevent or reduce oxidative stress during thalli disruption. The optimized methodology allowed significant increases in the number and diversity of culturable bacteria associated with P. furfuracea, and it was also successfully applied to the lichens Ramalina farinacea and Parmotrema pseudotinctorum. Furthermore, we provide, for the first time, data on the abundance of culturable ecto- and endolichenic bacteria that naturally colonize P. furfuracea, R. farinacea and P. pseudotinctorum, some of which were only able to grow on lichen enriched media. This innovative methodology is also applicable to other microorganisms inhabiting these and other lichen species. PMID- 27494032 TI - Putative Mechanisms of Viral Transmission and Molecular Dysregulation of Mammary Epithelial Cells by Human Papillomavirus: Implications for Breast Cancer. AB - Breast cancer is the most common cancer in women worldwide. Several studies have demonstrated the presence of Human papillomavirus (HPV) DNA in breast cancer samples. However, the role of HPV in breast carcinogenesis is not clear, and the interaction mechanisms between this infectious agent and the breast cancer cell need to be more fully clarified. In this article, we discuss the putative roles of HPV infection in breast carcinogenesis. PMID- 27494033 TI - Inactivation of Pseudomonas aeruginosa by chitosan coated iron oxide nanoparticles. AB - BACKGROUND: Pseudomonas aeruginosa is one of the potent opportunistic pathogens associated with respiratory and urinary tract infection. The bacterium owes its pathogenicity due to the intrinsic resistance to antibiotics and disinfectants. OBJECTIVE: The present study is focused on the synthesis of antibacterial chitosan coated iron oxide nanoparticles for rapid inactivation of Pseudomonas aeruginosa. We have discussed the relevant patents on synthesis and antibacterial potential of metallic nanoparticles and chitosan. METHOD: Chitosan coated iron oxide nanoparticles were synthesized by co-precipitation method at room temperature using non-toxic chitosan and iron salts in alkali media. The particles were characterized and evaluated for antibacterial property against Pseudomonas aeruginosa. RESULTS: The average size of the particles was measured as 52 nm. The surface area of the coated particles was as high as 90 +/-5 m2/g. FTIR spectra confirmed the coating of chitosan on nanoparticles. The coated particles showed excellent antibacterial activity against the bacteria. The minimum inhibitory concentration of the coated particles was 105 ug mol-1. The morphological alteration and cytoplasmic leakage of bacteria were confirmed by SEM image and release of intracellular constituents, respectively. Higher 260 nm absorbance value confirmed stronger antibacterial activity of the coated nanoparticles as compared to pure chitosan and bare iron oxide nanoparticles. CONCLUSION: The study indicated that chitosan coated iron oxide nanoparticles have superior antibacterial property as compared to pure chitosan and iron oxide nanoparticles. PMID- 27494034 TI - The Year's Best: Interpersonal Elements of Bisexual Women's Most Satisfying Sexual Experiences in the Past Year. AB - Sexual satisfaction is commonly defined and discussed in physiological terms of arousal and orgasm. Yet this narrow discourse does not accommodate the complex, multidimensional, and interpersonal aspects of sexual experience. To broaden and deepen our understanding of sexual satisfaction, we employed McClelland's (2014) holistic four-factor framework of sexual satisfaction in a theoretical thematic analysis of 39 behaviorally bisexual women's descriptions of their "best" partnered sexual experiences from the past year. We found women's accounts mapped on to four elements: emotional attunement, emotional gratification, partner gratification, and sensory gratification. Relational and emotional dynamics, including emotional security, quality of interpersonal interaction during and after a sexual encounter, mutuality, intimacy, partner skill, novelty, and communication, were key to participants' best sex experiences. Our findings support a multifaceted model of women's sexual satisfaction that accounts for emotional, relational, and embodied experiences and the diverse relationships and behaviors these might involve. PMID- 27494035 TI - Correction to "What is in a Beer? Proteomic Characterization and Relative Quantification of Hordein (Gluten) in Beer". PMID- 27494036 TI - Long-term update of the 24954 EORTC phase III trial on larynx preservation. AB - The long-term results of the EORTC 24954 trial comparing sequential versus alternating chemotherapy and radiotherapy (RT) for patients with locally advanced laryngeal and hypopharyngeal cancer are reported. From 1996 to 2004, 450 patients were randomly assigned (1-1) to a sequential arm (SA = induction cisplatin 5fluorouracil followed by a 70Gy-RT for the responders or a total laryngectomy and post-operative RT for the non-responders) and an alternating arm (AA = cisplatin-5fluorouracil alternated with three 2-week courses of 20 Gy-RT for a total dose of 60 Gy). Median follow-up was 10.2 years. Ten-year survival with functional larynx (primary end-point) and overall survival were similar in both arms (18.7% and 33.6% in SA versus 18.3% and 31.6% in AA). Late toxicity was also similar; however, a trend for higher larynx preservation and better laryngeal function was observed in AA. PMID- 27494039 TI - Synthesis, Characterization and Biological Activities of Creatinine Amides and Creatinine Schiff Bases. AB - BACKGROUND: In spite of substantial progress in scientific cognizance and medical technology, still infectious diseases are among the leading cause of morbidity and mortality. Creatinine and Schiff bases are well known for their diverse range of biological activities and thought to be emerging and useful therapeutic target for the treatment of several diseases. METHODS: The present work was aimed to illustrate the influence of substitution of amides and Schiff bases on creatinine and their antimicrobial, antioxidant and anti-urease effectiveness was determined. Creatinine substituted amides (1-2) and creatinine Schiff bases (3-7) were synthesized and characterized by NMR and IR spectral data in combination with elemental analysis. All the compounds (1-7) were investigated on Jack bean urease for their urease inhibitory potential. Investigation of antimicrobial activity of the compounds was made by the agar dilution method. Moreover, 1,1 diphenyl-2- picrylhydrazyl (DPPH) method was used to determine their antioxidant potential. Molecular docking studies were also carried out to elucidate their relationship with the binding pockets of the enzyme. RESULTS: The compounds were found to be potent inhibitors of urease. The synthesized derivatives exhibited significant inhibition against Gram-positive and Gram-negative bacterial strains, as compared to standard, ciprofloxacin. Creatinine based derivatives exhibited potential antifungal activity when tested on infectious and pathogenic fungal strains. Similarly, most of the compounds exhibited good antioxidant activity. CONCLUSION: These derivatives may serve as a source of potential antioxidants and also help to retard microbial growth in food industry. Similarly, the studies provide a basis for further research to develop more potent urease inhibitory compounds of medicinal /agricultural interest. PMID- 27494037 TI - Methadone is superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer. AB - BACKGROUND: Cancer pain is still inadequately treated in up to 60% of cancer patients. Based on the additional effect on the N-Methyl-d-Aspartate receptor, we expected that methadone (Met) could provide better pain relief than fentanyl (Fen) in cancer pain with a neuropathic pain component. METHODS: A randomised controlled trial was performed with 52 strong opioids naive patients with head and-neck cancer with substantial pain (pain Numerical Rating Scale [NRS] > 4) and a neuropathic pain component (Douleur Neuropathique [DN4] > 4). Twenty-six patients were treated with Met and 26 with Fen. Patients were evaluated at 1, 3 and 5 weeks. The primary outcomes were reduction in average pain, clinical success (defined as 50% average pain decrease) and reduction in pain interference. Secondary outcomes were global perceived effect (GPE) and side effects. FINDINGS: Reduction in NRS was higher with the use of Met at 1, 3 and 5 weeks (pain change 2.9, 3.1 and 3.1) compared to Fen (1.4, 1.7 and 2.0). This difference was significant at 1 (p = 0.011) and at 3 weeks (p = 0.03). Clinical success (>50% improvement) was higher with Met at 1 week (15% versus 50%, p = 0.012). The change in pain interference, the GPE and side-effect profile were not significantly different between the groups. INTERPRETATION: This is the first study to compare the effects of Met to Fen in cancer patients with a neuropathic pain component. Based on the results of this study, Met should be considered in the treatment of oncological pain with a neuropathic component. PMID- 27494040 TI - Injury pattern in lethal motorbikes-pedestrian collisions, in the area of Barcelona, Spain. AB - INTRODUCTION: There are several studies about M1 type vehicle-pedestrian collision injury pattern, and based on them, there has been several changes in automobiles for pedestrian protection. However, the lack of sufficient studies about injury pattern in motorbikes-pedestrian collisions leads to a lack of optimization design of these vehicles. The objective of this research is to study the injury pattern of pedestrians involved in collisions with motorized two wheeled vehicles. METHODS: A retrospective descriptive study of pedestrian's deaths after collisions with motorcycles in an urban area, like Barcelona was performed. The cases were collected from the Forensic Pathology Service database of the Institute of Legal Medicine of Catalonia. The selected cases were categorized as pedestrian-motorcycle collision, between January 1st, 2005 and December 31st, 2014. Data were collected from the autopsy, medical, and police report. The collected information was then analyzed using Microsoft Excel statistical functions. RESULTS: Traumatic Brain Injury is the main cause of death in pedestrian hit by motorized two-wheeled vehicles (62.85%). The most frequent injury was the subarachnoid hemorrhage, in 71.4% of cases, followed by cerebral contusions and skull base fractures (65.7%). By contrast, pelvic fractures and tibia fractures only appeared in 28.6%. CONCLUSIONS: The study characterizes the injury pattern of pedestrians involved in a collision with motorized two-wheeled vehicles in an urban area, like Barcelona, which has been found to be different from other vehicle-pedestrian collisions, with a higher incidence of brain injuries and minor frequency of lower extremities fractures in pelvis, tibia and fibula. PMID- 27494041 TI - Reducing Phosphorus to Curb Lake Eutrophication is a Success. AB - As human populations increase and land-use intensifies, toxic and unsightly nuisance blooms of algae are becoming larger and more frequent in freshwater lakes. In most cases, the blooms are predominantly blue-green algae (Cyanobacteria), which are favored by low ratios of nitrogen to phosphorus. In the past half century, aquatic scientists have devoted much effort to understanding the causes of such blooms and how they can be prevented or reduced. Here we review the evidence, finding that numerous long-term studies of lake ecosystems in Europe and North America show that controlling algal blooms and other symptoms of eutrophication depends on reducing inputs of a single nutrient: phosphorus. In contrast, small-scale experiments of short duration, where nutrients are added rather than removed, often give spurious and confusing results that bear little relevance to solving the problem of cyanobacteria blooms in lakes. PMID- 27494042 TI - Exercise improves depressive symptoms in older adults: An umbrella review of systematic reviews and meta-analyses. AB - Late-life depression is a growing public health concern. Exercise may be of added value but the literature remains equivocal. We conducted a systematic overview of meta-analyses and an exploratory pooled analysis of previous meta-analyses to determine the effect of exercise on depression in older adults. Two independent researchers searched Pubmed, CINAHL, Cochrane Plus, PsycArticles, and PsycInfo for meta-analyses on exercise in late-life depression. Methodological quality was assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) Instrument. We pooled effect sizes from previous meta-analyses of randomized controlled trials to determine the effect of exercise on depression in older adults. The systematic review yielded 3 meta-analyses. In total, 16 unique cohorts of 1487 participants were included. The quality of the three included meta-analyses was considered as "moderate" according to AMSTAR scores. No serious adverse events were reported. Compared to controls (n=583), those exercising (n=541) significantly reduced depressive symptoms. Our umbrella review indicates that exercise is safe and efficacious in reducing depressive symptoms in older people. Since exercise has many other known health benefits, it should be considered as a core intervention in the multidisciplinary treatment of older adults experiencing depression. PMID- 27494043 TI - Drugs for Hepatitis. PMID- 27494044 TI - "Race for the Surface": Eukaryotic Cells Can Win. AB - With an aging population and the consequent increasing use of medical implants, managing the possible infections arising from implant surgery remains a global challenge. Here, we demonstrate for the first time that a precise nanotopology provides an effective intervention in bacterial cocolonization enabling the proliferation of eukaryotic cells on a substratum surface, preinfected by both live Gram-negative, Pseudomonas aeruginosa, and Gram-positive, Staphylococcus aureus, pathogenic bacteria. The topology of the model black silicon (bSi) substratum not only favors the proliferation of eukaryotic cells but is biocompatible, not triggering an inflammatory response in the host. The attachment behavior and development of filopodia when COS-7 fibroblast cells are placed in contact with the bSi surface are demonstrated in the dynamic study, which is based on the use of real-time sequential confocal imaging. Bactericidal nanotopology may enhance the prospect for further development of inherently responsive antibacterial nanomaterials for bionic applications such as prosthetics and implants. PMID- 27494045 TI - Development and application of dot-enzyme-linked immunosorbent (dot-ELISA) assay for detection of Brucella melitensis and evaluation of the shedding pattern in infected goats. AB - Early and accurate diagnosis of Brucella melitensis is essential for the treatment and control of brucellosis both in animals and humans. The thrust for the development of a rapid diagnostic technique to overcome the limitations of conventional microbiological and serological tests brought about this investigation on the development and application of dot-ELISA for antigen and antibody detection in infected goats. Fifteen apparently healthy Boer aged 2-3 years which tested negative for brucellosis using PCR and ELISA, were grouped into A (10 goats infected intraocularly with 107 CFU of B. melitensis) and B (5 goats) as control. Discharges (ocular, nasal, and vaginal) and blood were collected at days 3, 7, 10, 14, weekly until 42 post-infection (pi) for dot ELISA, PCR, and RBPT. Dot-ELISA detected B. melitensis antigen and antibody in group A at day 3 and 7 pi, respectively with adequate sensitivity and specificity relative to PCR and RBPT. The bacteria shedding detected from discharges at day 3 pi in the nasal and ocular route with dot-ELISA. Group B were consistently negative. Values such as speed, simplicity, field adaptability, high sensitivity, and specificity make dot-ELISA a rapid and adequate technique for diagnosis of brucellosis in B. melitensis infected goats within few hours. PMID- 27494046 TI - Dissecting the Influence of Protein Flexibility on the Location and Thermodynamic Profile of Explicit Water Molecules in Protein-Ligand Binding. AB - Explicit water molecules in the binding site of proteins play a crucial role for protein-ligand association. Recent advances in computer-aided drug discovery methodology allow for an accurate prediction of the localized position and thermodynamic profile of water molecules (i.e., hydration sites) in the binding site. The underlying calculations are based on MD simulations of explicit water molecules in a restrained protein structure. However, the ligand-binding process is typically associated with protein conformational change that influences the position and thermodynamic properties of the hydration site. In this manuscript, we present the developments of two methods to incorporate the influence of protein conformational change on hydration sites either by following the conformational transition step-by-step (method I) or to match the hydration sites of the two transition end states using local coordinate systems (method II). Using these methods, we highlight the difference in the estimated protein desolvation free energy with and without inclusion of protein flexibility. To the best of our knowledge, this is the first study that explicitly studies the influence of protein conformational change on the position and thermodynamic profiles of water molecules and provides methodology to incorporate protein flexibility into the estimation of the desolvation free energy. PMID- 27494048 TI - Examining the durability of incidentally learned trust from gaze cues. AB - In everyday interactions we find our attention follows the eye gaze of faces around us. As this cueing is so powerful and difficult to inhibit, gaze can therefore be used to facilitate or disrupt visual processing of the environment, and when we experience this we infer information about the trustworthiness of the cueing face. However, to date no studies have investigated how long these impressions last. To explore this we used a gaze-cueing paradigm where faces consistently demonstrated either valid or invalid cueing behaviours. Previous experiments show that valid faces are subsequently rated as more trustworthy than invalid faces. We replicate this effect (Experiment 1) and then include a brief interference task in Experiment 2 between gaze cueing and trustworthiness rating, which weakens but does not completely eliminate the effect. In Experiment 3, we explore whether greater familiarity with the faces improves the durability of trust learning and find that the effect is more resilient with familiar faces. Finally, in Experiment 4, we push this further and show that evidence of trust learning can be seen up to an hour after cueing has ended. Taken together, our results suggest that incidentally learned trust can be durable, especially for faces that deceive. PMID- 27494047 TI - Engineering of New Pneumocandin Side-Chain Analogues from Glarea lozoyensis by Mutasynthesis and Evaluation of Their Antifungal Activity. AB - Pneumocandins are lipohexapeptides of the echinocandin family that inhibit fungal 1,3-beta-glucan synthase. Most of the pathway steps have been identified previously. However, the lipoinitiation reaction has not yet been experimentally verified. Herein, we investigate the lipoinitiation step of pneumocandin biosynthesis in Glarea lozoyensis and demonstrate that the gene product, GLligase, catalyzes this step. Disruption of GLHYD, a gene encoding a putative type II thioesterase and sitting upstream of the pneumocandin acyl side chain synthase gene, GLPKS4, revealed that GLHYD was necessary for optimal function of GLPKS4 and to attain normal levels of pneumocandin production. Double disruption of GLHYD and GLPKS4 did not affect residual function of the GLligase or GLNRPS4. Mutasynthesis experiments with a gene disruption mutant of GLPKS4 afforded us an opportunity to test the substrate specificity of GLligase in the absence of its native polyketide side chain to diversify pneumocandins with substituted side chains. Feeding alternative side chain precursors yielded acrophiarin and four new pneumocandin congeners with straight C14, C15, and C16 side chains. A comprehensive biological evaluation showed that one compound, pneumocandin I (5), has elevated antifungal activity and similar hemolytic activity compared to pneumocandin B0, the starting molecule for caspofungin. This study demonstrates that the lipoinitiation mechanism in pneumocandin biosynthesis involves interaction among a highly reducing PKS, a putative type II thioesterase, and an acyl AMP-ligase. A comparison of the SAR among pneumocandins with different length acyl side chains demonstrated the potential for using GLligase for future engineering of new echinocandin analogues. PMID- 27494049 TI - Computational profiling of pore properties of outer membrane proteins. PMID- 27494050 TI - Examination of Pyridazine as a Possible Scaffold for Nucleophilic Catalysis. AB - Pyridazines with amino groups positioned para to each aromatic ring nitrogen and fixed in six-membered rings were prepared. The representative symmetric amino N Et derivative was found to slightly exceed DMAP in catalytic activity in the acetylation reaction of a tertiary alcohol in C6D6. Nucleophilicity eclipsing that of DMAP was established in competitive reactions using phenacyl bromide as the electrophile, and the unsymmetric N-Et derivative was revealed to have even higher nucleophilicity. PMID- 27494051 TI - Co-Occurring Disorders: A Challenge for Mexican Community-Based Residential Care Facilities for Substance Use. AB - OBJECTIVE: In Mexico, specialized treatment services for people with co-occurring disorders are limited within public health services, while private options are deemed too costly. More than 2,000 community-based residential care facilities have risen as an alternative and are the main source of treatment for individuals with substance use disorders; however, suboptimal practices within such facilities are common. Information on the clinical characteristics of patients receiving care in these facilities is scarce and capacity to provide high-quality care for co-occurring disorders is unknown. The aims of this study were to examine the prevalence of co-occurring disorders in patients receiving treatment for substance use in these community-based residential centers and to assess whether the presence of co-occurring disorders is associated with higher severity of substance use, psychiatric symptomatology, and other health risks. METHODS: This study was conducted with 601 patients receiving treatment for substance use disorders at 30 facilities located in five Mexican states, recruited in 2013 and 2014. Patients were assessed with self-report measures on substance use, service utilization, suicidality, HIV risk behaviors, psychiatric symptomatology, and psychiatric disorder diagnostic criteria. RESULTS: The prevalence of any co occurring disorder in this sample was 62.6%. Antisocial personality disorder was the most prevalent (43.8%), followed by major depressive disorder (30.9%). The presence of a co-occurring disorder was associated with higher severity of psychiatric symptoms (aB = .496, SE = .050, p < .05); more days of substance use (aB = .219, SE = .019, p < .05); current suicidal ideation (aOR = 5.07, 95% CI [2.58, 11.17]; p < .05), plans (aOR = 5.17 95% CI [2.44, 12.73]; p < .05), and attempts (aOR = 6.43 95% CI [1.83, 40.78]; p < .05); more sexual risk behaviors; and more contact with professional services (aOR = 1.77, 95% CI [1.26, 2.49], p < .05). CONCLUSIONS: Co-occurring disorders are highly prevalent in community-based residential centers in Mexico and are associated with significantly increased probability of other health risks. This highlights the need to develop care standards for this population and the importance of clinical research in these settings. PMID- 27494052 TI - Effects of Group-Based Exercise on Range of Motion, Muscle Strength, Functional Ability, and Pain During the Acute Phase After Total Knee Arthroplasty: A Controlled Clinical Trial. AB - Study Design Prospective observational study including a historical control group. Background The extent to which group-based exercise (G-EXE) improves knee range of motion (ROM), quadriceps strength, and gait ability is similar to that of individualized exercise (I-EXE) at 6 weeks and 8 months after total knee arthroplasty (TKA). However, the benefits of G-EXE for patients during the acute recovery phase after TKA remain unclear. Objective To determine the effects of G EXE during the acute recovery phase after TKA on knee ROM, quadriceps strength, functional ability, and knee pain. Methods Two hundred thirty-one patients participated in G-EXE in addition to regular ambulation and activities-of-daily living exercises twice daily during the hospital stay. Outcomes were compared to those of a retrospectively identified, historical control group (I-EXE group [n = 206]) that included patients who performed exercises identical to those performed by the G-EXE group. The outcomes included knee ROM, quadriceps strength, pain intensity, and timed up-and-go test score at 1 month before surgery and at discharge. Analyses were adjusted for age, body mass index, sex, length of hospital stay, and preoperative values. Results Changes in ROM of knee flexion and extension (P<.001) and quadriceps strength (P<.001) were significantly better in the G-EXE group than those in the I-EXE group at discharge. The pain intensity improved more in the G-EXE group than in the I-EXE group at discharge (P<.001). However, the changes in the timed up-and-go scores were not significantly different. Conclusion Patients performing G-EXE in addition to regular ambulation and activities-of-daily-living exercises demonstrated greater changes in knee ROM, quadriceps strength, and knee pain than those performing I-EXE in addition to regular ambulation and activities-of-daily-living exercises. The nonrandomized, asynchronous design decreases certainty of these findings. Level of Evidence Therapy, level 2b. J Orthop Sports Phys Ther 2016;46(9):742-748. Epub 5 Aug 2016. doi:10.2519/jospt.2016.6409. PMID- 27494053 TI - Comparison of Electromyographic Activity of the Superior and Inferior Portions of the Gluteus Maximus Muscle During Common Therapeutic Exercises. AB - Study Design Controlled laboratory study, repeated-measures design. Background Previous studies have reported that the superior and inferior portions of the gluteus maximus have different functional roles. Knowledge of how the different portions of the gluteus maximus are activated during therapeutic exercise may lead to more specific exercise prescription. Objective To compare muscle activation of the superior and inferior portions of the gluteus maximus during commonly used therapeutic exercises. Methods Twenty healthy persons participated. Electromyographic (EMG) signals were obtained from the superior and inferior portions of the gluteus maximus using fine-wire electrodes. Normalized EMG signal amplitudes were compared between the superior and inferior gluteus maximus across 11 exercises using a 2-way repeated-measures analysis of variance. Results The superior portion of the gluteus maximus had significantly greater relative EMG activity than the inferior portion of the gluteus maximus during exercises that incorporated elements of hip abduction and/or external rotation (5 of 11 exercises evaluated). There was no significant difference in activation between the superior and inferior portions of the gluteus maximus during the remaining 6 exercises. Conclusion The results of the present study demonstrate preferential activation of the superior portion of the gluteus maximus during exercises that incorporate elements of hip abduction and/or external rotation. In contrast, exercises that primarily involve hip extension target both portions of the gluteus maximus to a similar extent. J Orthop Sports Phys Ther 2016;46(9):794 799. Epub 5 Aug 2016. doi:10.2519/jospt.2016.6493. PMID- 27494054 TI - The Influence of a Prefabricated Foot Orthosis on Lower Extremity Mechanics During Running in Individuals With Varying Dynamic Foot Motion. AB - Study Design Controlled laboratory study, cross-sectional. Background Orthotic prescription is often based on the premise that the mechanical effects will be more prominent in individuals with greater calcaneal eversion. Objective To compare the effects of a prefabricated foot orthosis on lower extremity kinematics and kinetics between recreational athletes with high and low calcaneal eversion during running. Methods Thirty-one recreational athletes were included in this study. Three-dimensional kinematic and kinetic data were collected while running with and without a foot orthosis. Participants were grouped based on the degree of calcaneal eversion during the running trials relative to a standing trial (dynamic foot motion). The effects of the orthosis on the frontal and transverse plane angles and moments of the hip and knee were compared between the 10 participants with the greatest and least amount of dynamic foot motion. Results There were no significant interactions (group by orthotic condition) for any of the kinematic or kinetic variables of interest. Conclusion The effects of an orthosis on the mechanics of the hip and knee do not appear to be dependent on an individual's dynamic foot motion. J Orthop Sports Phys Ther 2016;46(9):749 755. Epub 5 Aug 2016. doi:10.2519/jospt.2016.6253. PMID- 27494055 TI - Sensitivity to Change of a Computer Adaptive Testing Instrument for Outcome Measurement After Hip and Knee Arthroplasty and Periacetabular Osteotomy. AB - Study Design Clinical measurement study. Background Computer adaptive testing (CAT) methods may allow detection of change across the continuum of osteoarthritis (OA) care. Objective To evaluate the sensitivity to change of a self-report OA CAT instrument (OA-CAT) following surgery. Methods Core measures consisted of the 5-item OA-CAT function, pain, and disability scales; the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); the University of California at Los Angeles activity rating scale; and the Medical Outcomes Study 12-Item Short-Form Health Survey (SF-12), which were administered in 3 samples. Fifty-three patients with hip dysplasia completed the core measures, the Hip disability and Osteoarthritis Outcome Score physical function short form (HOOS PS), and the Modified Harris Hip Score (MHHS) before periacetabular osteotomy, and at 6 months, 1 year, and 2 years after periacetabular osteotomy. The hip (n = 62) and knee (n = 66) arthroplasty samples completed core measures and the MHHS or the Knee Society's Knee Scoring System at baseline and at 3-month follow-up. Mean change, floor and ceiling effects (percent), and effect size were calculated. Results For osteotomy, the 6-month physical function effect sizes for the OA-CAT, WOMAC, HOOS-PS, MHHS, and SF-12 physical component summary scores were 0.66 (95% confidence interval [CI]: 0.08, 1.61), 0.78 (95% CI: 0.56, 1.10), 0.91 (95% CI: 0.70, 1.21), 0.64 (95% CI: 0.22, 1.07), and 0.87 (95% CI: 0.53, 1.38), respectively. Effect-size trends were all increased at 1 year, and most were level at 2 years. For hip arthroplasty, the OA-CAT, WOMAC, MHHS, and SF-12 effect sizes were 1.27 (95% CI: 0.88, 1.84), 1.50 (95% CI: 1.20, 1.80), 0.68 (95% CI: 0.35, 1.04), and 0.56 (95% CI: 0.29, 0.88), respectively. For knee arthroplasty, the OA-CAT, WOMAC, Knee Society Knee Scoring System, and SF-12 effect sizes were 0.81 (95% CI: 0.56, 1.14), 0.85 (95% CI: 0.61, 1.10), 0.09 (95% CI: -0.22, 0.40), and -0.01 (95% CI: -0.39, 0.31), respectively. The OA-CAT and SF-12 demonstrated smaller ceiling effects than the HOOS-PS and other instruments, especially at 1 and 2 years. Administration time was less for the OA CAT than for the WOMAC physical function subscale. Conclusion The OA-CAT shows potential for outcome measurement after hip and knee surgery. Larger studies are needed to better understand relative performance. J Orthop Sports Phys Ther 2016;46(9):756-767. Epub 5 Aug 2016. doi:10.2519/jospt.2016.6442. PMID- 27494056 TI - Test-Retest Reliability of Rating of Perceived Exertion and Agreement With 1 Repetition Maximum in Adults. AB - Study Design Clinical measurement. Background It has been suggested that rating of perceived exertion (RPE) may be a useful alternative to 1-repetition maximum (1RM) to determine proper resistance exercise dosage. However, the test-retest reliability of RPE for resistance exercise has not been determined. Additionally, prior research regarding the relationship between 1RM and RPE is conflicting. Objectives The purpose of this study was to (1) determine test-retest reliability of RPE related to resistance exercise and (2) assess agreement between percentages of 1RM and RPE during quadriceps resistance exercise. Methods A sample of participants with and without knee pathology completed a series of knee extension exercises and rated the perceived difficulty of each exercise on a 0-to 10 RPE scale, then repeated the procedure 1 to 2 weeks later for test-retest reliability. To determine agreement between RPE and 1RM, participants completed knee extension exercises at various percentages of their 1RM (10% to 130% of predicted 1RM) and rated the perceived difficulty of each exercise on a 0-to-10 RPE scale. Percent agreement was calculated between the 1RM and RPE at each resistance interval. Results The intraclass correlation coefficient indicated excellent test-retest reliability of RPE for quadriceps resistance exercises (intraclass correlation coefficient = 0.895; 95% confidence interval: 0.866, 0.918). Overall percent agreement between RPE and 1RM was 60%, but agreement was poor within the ranges that would typically be used for training (50% 1RM for muscle endurance, 70% 1RM and greater for strength). Conclusion Test-retest reliability of perceived exertion during quadriceps resistance exercise was excellent. However, agreement between the RPE and 1RM was poor, especially in common training zones for knee extensor strengthening. J Orthop Sports Phys Ther 2016;46(9):768-774. Epub 5 Aug 2016. doi:10.2519/jospt.2016.6498. PMID- 27494057 TI - Feedback and Feedforward Control During Walking in Individuals With Chronic Ankle Instability. AB - Study Design Controlled laboratory study. Background Recurrent ankle sprains associated with chronic ankle instability (CAI) occur not only in challenging sports but also in daily walking. Understanding whether and how CAI alters feedback and feedforward controls during walking may be important for developing interventions for CAI prevention or treatment. Objective To understand whether CAI is associated with changes in feedback and feedforward control when individuals with CAI are subjected to experimental perturbation during walking. Methods Twelve subjects with CAI and 12 control subjects walked on a treadmill while adapting to external loading that generated inversion perturbation at the ankle joint. Ankle kinematics around heel contact during and after the adaptation were compared between the 2 groups. Results Both healthy and CAI groups showed an increase in eversion around heel contact in early adaptation to the external loading. However, the CAI group adapted back toward the baseline, while the healthy controls showed further increase in eversion in late adaptation. When the external loading was removed in the postadaptation period, healthy controls showed an aftereffect consisting of an increase in eversion around heel contact, but the CAI group showed no aftereffect. Conclusion The results provide preliminary evidence that CAI may alter individuals' feedback and feedforward control during walking. J Orthop Sports Phys Ther 2016;46(9):775-783. Epub 5 Aug 2016. doi:10.2519/jospt.2016.6403. PMID- 27494058 TI - Differential Diagnosis and Intervention of Proximal Median Nerve Entrapment: A Resident's Case Problem. AB - Study Design Resident's case problem. Background Entrapment neuropathies represent a diagnostic challenge and require a comprehensive understanding of the nerve's path and the anatomical structures that may cause compression of the nerve. This resident's case problem details the evaluation and differential diagnosis process for median nerve entrapment resulting from forceful and repetitive pronation/supination motions. Diagnosis Median nerve compression syndromes include pronator syndrome, anterior interosseous nerve syndrome, and carpal tunnel syndrome. A cluster of clinical special tests were performed to determine the anatomical site of median nerve entrapment. Based on the patient's history and clinical test results, a diagnosis of pronator syndrome was determined. Provocation testing specific to pronator syndrome assisted with further localizing the site of entrapment to the pronator teres muscle, which guided effective management strategies. Discussion This resident's case problem illustrates the importance of detailed anatomical knowledge and a differential diagnostic process when evaluating a patient with signs and symptoms of an entrapment neuropathy of the median nerve. Electrodiagnostic studies are useful in ruling out carpal tunnel and anterior interosseous nerve syndromes, but are often inconclusive in cases of pronator syndrome. Therefore, a diagnosis of pronator syndrome in this case problem was based on a detailed understanding of median nerve anatomy, potential sites of compression, and unique clinical features associated with this condition. Level of Evidence Differential diagnosis, level 4. J Orthop Sports Phys Ther 2016;46(9):800-808. Epub 5 Aug 2016. doi:10.2519/jospt.2016.6723. PMID- 27494062 TI - Blood-Brain Barrier ABC-transporter P-glycoprotein in Alzheimer's Disease: Still a Suspect? AB - Alzheimer's disease is a neurodegenerative disorder and the most common form of dementia. One of the pathological hallmarks of the disease is amyloid deposition in the brain. The major cause of amyloid deposition in sporadic Alzheimer's disease is thought to be decreased brain clearance of amyloid. There is compelling preclinical evidence that the blood-brain barrier, a structure that maintains homeostasis in the central nervous system and protects the brain from harmful substances, plays an important role in amyloid clearance. Indeed, several dedicated transporter systems are present at the blood-brain barrier which may have a role in brain amyloid clearance, such as P-glycoprotein (P-gp). In vitro experiments and animal studies indicated increased amyloid deposition when P-gp was eliminated by pharmacological blockade or by genetic modification. And as decreased P-gp expression has been found in AD brains, P-gp became more and more a suspect. Using an imaging technique called positron emission tomography, P-gp transporter function was found to be decreased in Alzheimer's disease patients compared to healthy controls, further establishing the important role of P-gp in the pathogenesis of the disease. In this review, we summarize what is now known about P-gp in Alzheimer's disease pathology, as these transporters may provide a novel target for therapeutic strategies. PMID- 27494060 TI - Tuberculosis-induced Fish-Scale Degeneration of the Central Airways. PMID- 27494063 TI - Kinetic Models for Measuring P-glycoprotein Function at the Blood-Brain Barrier with Positron Emission Tomography. AB - P-glycoprotein function is associated with a number of neurodegenerative and psychiatric diseases as well as with pharmacoresistance to for example antiepileptic drugs. The ability to measure P-gp function in vivo would allow for an increased understanding of the mechanisms of disease and treatment. This review assesses the various approaches to in vivo quantification of P-gp function using currently available P-gp tracers and PET in humans. First, the use of compartment models, and their interpretation in terms of P-gp function at the blood-brain barrier, is discussed. Then, the methods that have been used to quantify PET data of the P-gp tracers [11C]verapamil, [11C]N-desmetyl-loperamide (dLop), [11C]laniquidar, [11C]phenytoin, [11C]tariquidar and [11C]elacridar are reviewed. In summary, the extraction of P-gp substrate PET tracers, which is their plasma to tissue rate constant K corrected for variations in regional cerebral blood flow, is generally considered to be the preferred measure of P-gp function. PMID- 27494059 TI - Maternal Calorie Restriction Causing Uteroplacental Insufficiency Differentially Affects Mammalian Placental Glucose and Leucine Transport Molecular Mechanisms. AB - We examined the effect of mild (Mi; ~25%) and moderate (Mo; ~50%) maternal calorie restriction (MCR) vs ad libitum-fed controls on placental glucose and leucine transport impacting fetal growth potential. We observed in MiMCR a compensatory increase in transplacental (TP) glucose transport due to increased placental glucose transporter isoform (GLUT)-3 but no change in GLUT1 protein concentrations. This change was paralleled by increased glut3 mRNA and 5 hydroxymethylated cytosines with enhanced recruitment of histone 3 lysine demethylase to the glut3 gene locus. To assess the biologic relevance of placental GLUT1, we also examined glut1 heterozygous null vs wild-type mice and observed no difference in placental GLUT3 and TP or intraplacental glucose and leucine transport. Both MCR states led to a graded decrease in TP and intraplacental leucine transport, with a decline in placental L amino acid transporter isoform 2 (LAT2) concentrations and increased microRNA-149 (targets LAT2) and microRNA-122 (targets GLUT3) expression in MoMCR alone. These changes were accompanied by a step-wise reduction in uterine and umbilical artery Doppler blood flow with decreased fetal left ventricular ejection fraction and fractional shortening. We conclude that MiMCR transactivates placental GLUT3 toward preserving TP glucose transport in the face of reduced leucine transport. This contrasts MoMCR in which a reduction in placental GLUT3 mediated glucose transport with a reciprocal increase in miR-122 expression was encountered. A posttranscriptional reduction in LAT2-mediated leucine transport also occurred with enhanced miR-149 expression. Both MCR states, although not affecting placental GLUT1, resulted in uteroplacental insufficiency and fetal growth restriction with compromised cardiovascular health. PMID- 27494064 TI - Non-ambient Conditions in the Investigation and Manufacturing of Drug Forms. AB - For the formation of a drug, a pharmacologically active compound must be prepared in a specific form. The drug must be manufactured, packaged, stored, transported, administred and delivered to a target in the body. To successfully prepare a drug form that will be robust through manufacturing, stable before administration and active with high bioavailability after administration, one needs to produce solid forms with controlled crystal structure and particle size and shape - often as multi-component composites. Considering drugs as materials, one can apply the knowledge of solid-state chemistry and materials science and non-ambient conditions to obtain solid forms with optimized properties. These conditions include, among others, different types of mechanical and ultrasonic treatment, hydrostatic compression, high-temperature or cryogenic spray-drying and crystallization from supercritical solvents. Solid-state reactions (e.g. dehydration or clathrate decomposition) can be effective in accessing metastable polymorphs or in micronizing a sample uniformly. To achieve control over the drug forms and the processes used for their robust manufacturing, one needs to take into account both the thermodynamic and kinetic aspects of their transformations. PMID- 27494065 TI - Importance of P-gp PET Imaging in Pharmacology. AB - Capillary endothelial cells in the brain express P-glycoprotein (P-gp), which works as a functional blood-brain barrier (BBB). P-gp pumps out multiple types of molecules from the brain parenchyma into the blood. Therefore, altered P-gp function at the BBB will change the concentrations of therapeutic drugs in the central nervous system (CNS) and hence impact the toxicity and efficacy of CNS drugs. Positron emission tomography (PET) is the only way to non-invasively measure P-gp function in the living human brain. PET imaging of P-gp function was first demonstrated in 1998 with the substrate tracer racemic [11C]verapamil. Since then, several drug interaction studies and proof-of-concept studies regarding drug resistance have been performed with P-gp PET imaging. Although preclinical findings have been very positive regarding the possibilities and importance of P-gp PET imaging, very few studies have shown the clinical relevance of P-gp PET imaging in different disorders of the brain. This review summarizes the pharmacological studies with PET using substrate tracers and emphasizes the importance of PET imaging to understand the mechanism of action of CNS drugs. PMID- 27494066 TI - Experimental-Theoretic Approach to Drug-Lymphocyte Interactome Networks with Flow Cytometry and Spectral Moments Perturbation Theory. AB - We can combine experimental techniques like Flow Cytometry Analysis (FCA) with Chemoinformatics methods to predict the complex networks of interactions between organic compounds and targets in the immune system. In this work, we determined experimentally the values of EC50 = 17.82 MUg/mL and Cytotoxicity = 20.6 % for the anti-microbial / anti-parasite drug Dermofural over Balb/C CD9 lymphocytes using flow cytometry. After that, we developed a new Perturbation-theory model for Drug-Cell Target Interactome in Lymphocytes based on dispersion-polarization moments of drug structure. The models correctly classifies 34591 out of 42715 (Accuracy = 80.9%) cases of perturbations in assay endpoints of 11492 drugs (including both train and validation series). Each endpoint correspond to one out of 2616 assays, 38 molecular and cellular targets, 77 standard type measures, in four possible (human and rodents). PMID- 27494067 TI - Detection of Quinolone Resistance in Salmonella typhimurium Pig Isolates Determined by gyrA Gene Mutation Using PCR- and Sequence-Based Techniques within the gyrA Gene. AB - BACKGROUND: The emergence of reduced susceptibility to fluoroquinolones among Salmonella enterica serotype Typhimurium isolates leading to clinical failure of treatment poses a great therapeutic challenge. METHODS: The current study is focused on the evaluation of the minimum inhibitory concentration (MIC) of quinolones in 29 Salmonella typhimurium of 86 Salmonella spp. strains, obtained from pigs from the State of Mexico. The MIC was performed with the Kirby-Bauer method. On the other hand, the GyrA gene was sequenced. The present study was undertaken to describe the resistance profiles and fluoroquinolone resistance mechanism of Salmonella Typhimurium. RESULTS: The DNA sequence of the gyrA genes from Salmonella enterica serovar typhimurium revealed strong similarity between gyrA and its counterpart in Escherichia coli. The sequencing of quinolone resistance-determining region (QRDR) of the gyrA gene showed the presence of mutation at either S83 or at D87 in almost all the Salmonella typhimurium isolates. CONCLUSION: This mutation, although phenotypically expressed as decreased susceptibility to fluoroquinolones goes undetected by the disk diffusion method using the present method of Kirby-Bauer. Hence, it can increase morbidity and mortality due to delay in appropriate antibiotic treatment. PMID- 27494068 TI - Down-regulation of 21A Alu RNA as a tool to boost proliferation maintaining the tissue regeneration potential of progenitor cells. AB - 21A is an Alu non-coding (nc) RNA transcribed by RNA polymerase (pol) III. While investigating the biological role of 21A ncRNA we documented an inverse correlation between its expression level and the rate of cell proliferation. The downregulation of this ncRNA not only caused a boost in cell proliferation, but was also associated to a transient cell dedifferentiation, suggesting a possible involvement of this RNA in cell dedifferentiation/reprogramming. In this study, we explored the possibility to enhance proliferation and dedifferentiation of cells of interest, by 21A down-regulation, using a mixture of chemically modified Anti-21A RNAs. Our results confirmed the validity of this approach that allows the amplification of specific cell populations, in a controlled manner and without inducing permanent effects. In addition to induce cell proliferation, the procedure did not decrease the tissue regeneration potential of progenitor cells in two different cell systems. PMID- 27494069 TI - In vitro influence of light radiation on hair steroid concentrations. AB - Hair cortisol concentrations (hairF) are considered to be relatively robust to various confounding influences. However, a potentially important covariate factor that has received little attention in this context is hair exposure to ultraviolet/sunlight radiation. We conducted a detailed experimental investigation to examine the effects of light exposure on hair cortisol. In study I, a hydrocortisone-containing solution was subjected to short-term artificial light irradiation for 1, 3, 5, 10, 15, or 30min to evaluate the stability of cortisol molecules due to radiant energy. In study II, hair samples (N=12) were subjected to single short-term artificial light irradiation for 0, 1, or 5h to examine light-induced effects in the hair matrix. In study III, hair samples (N=25) were subjected to long-term naturalistic sunlight radiation over a period of two months (during summer) with daily exposure times of 0, 1, 3, or 6h, respectively. Besides cortisol, studies II & III also examined concentrations of cortisone (hairE), dehydroepiandrosterone (hairDHEA) and progesterone (hairP) in hair, quantified using LC-MS/MS technology. Results across the three studies consistently revealed effects of light irradiation on hair steroid concentrations: Longer light exposure resulted in a decrease of dissolved hydrocortisone (study I) as well as of hairF and hairE (studies II and III). Conversely, hairDHEA and hairP increased with longer natural sunlight exposure times (study III), while this effect was not observed for short-term artificial light irradiation (study II). Combined, our findings imply sunlight exposure as a potential confound in hair steroid research. Given the experimental character of this investigation, the magnitude of this effect under real-life testing conditions is difficult to estimate. To support future investigation into this, we designed a 'sunlight-exposure' questionnaire to share with the research community. The assessment and statistical accounting for sunlight exposure related effects in future hair steroid research (using this or a similar questionnaire) may help to reduce the potential influence of this unwanted error source and could thus lead to more valid and reliable results. In addition, our data strongly suggest that hair samples for steroid analyses need to be stored in a dark environment. PMID- 27494070 TI - Stress-induced release of matrix metalloproteinase-9 in patients with coronary artery disease: The possible influence of cortisol. AB - Stress and inflammation are both important risk factors for coronary artery disease (CAD). However, the susceptibility to stress-induced inflammation and its determinants have been little explored in patients with CAD. Here, our aim was to study the stress-induced inflammatory response, more precisely the early release of matrix metalloproteinase (MMP)-9, and its association with cortisol response in patients with CAD. Sixty-four patients underwent a standardized laboratory stress test. The stress-induced release of MMP-9 was closely associated with the release of other neutrophil-associated proteins, MMP-8 and myeloperoxidase (MPO). It also showed a large variation among patients, as did cortisol. Twenty minutes after stress, a negative association between changes in MMP-9 and cortisol was seen (p<0.01). In vitro, dexamethasone reduced the IL-8-mediated release of MMP-9 from neutrophils, indicating that glucocorticoids may exert rapid effects on neutrophil activation. Further characterization of patients revealed that stress induced release of MMP-9 was related to leukocyte telomere shortening and increased ultrasound-assessed plaque occurrence in the carotid arteries, but not to other characteristics such as age, gender or psychological background factors. The susceptibility to stress-induced release of MMP-9 may thus have impact on disease phenotype. Stress tests can be useful to identify CAD patients in need of novel prevention and treatment strategies. PMID- 27494072 TI - Anti-adipogenic effect of Glycoside St-E2 and Glycoside St-C1 isolated from the leaves of Acanthopanax henryi (Oliv.) Harms in 3T3-L1 cells. AB - Acanthopanax henryi (Oliv.) Harms has been used in the treatment of arthritis, rheumatism, and abdominal pain. This study evaluated whether natural compounds isolated from the leaves of A. henryi (Oliv.) Harms could inhibit adipocyte differentiation by regulating transcriptional factors such as peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha). AMP-activated protein kinase (AMPK) activity was also evaluated. Among the several compounds isolated from the leaves of A. henryi (Oliv.) Harms, Glycoside St-C1 and Glycoside St-E2 significantly decreased lipid accumulation and the expressions of PPARgamma and C/EBPalpha. Glycoside St-C1 and Glycoside St-E2 were found to activate AMPK when they regulated PPARgamma and C/EBPalpha. Results confirmed that Glycoside St-C1 and Glycoside St-E2 isolated from the leaves of A. henryi (Oliv.) Harms can inhibit adipogenesis through the AMPK-PPARgamma-C/EBPalpha mechanism. Thus, this study suggests that Glycoside St C1 and Glycoside St-E2 have a therapeutic effect due to activation of the AMPKalpha. PMID- 27494071 TI - Concurrent and prospective associations between HPA axis activity and depression symptoms in newlywed women. AB - We investigated the extent to which individual differences in activity of the hypothalamic pituitary adrenal axis (HPA) are associated with depressive symptoms among newlywed couples. Participants were 218 couples (M age 28.4 years; 94% White) who provided 5 saliva samples (later assayed for cortisol and DHEA-S) before and after participation in a discussion of a major area of disagreement in their relationship. Depressive symptoms were assessed initially, and approximately 19- and 37-months later. Results revealed an interactive effect suggesting that concordant levels of cortisol and DHEA-S (either both high or both low) were concurrently and prospectively associated with higher depression scores. Interestingly, this interactive effect was observed for wives only - not for husbands. These observations underscore contemporary theoretical assumptions that the expression of the association between HPA activity and depression is dependent on factors related to the interaction between characteristics of the person and features of the social environment, and moderated by co-occurring variation in endocrine milieu. PMID- 27494073 TI - Predicting permeability of regular tissue engineering scaffolds: scaling analysis of pore architecture, scaffold length, and fluid flow rate effects. AB - The main aim of this research is to numerically obtain the permeability coefficient in the cylindrical scaffolds. For this purpose, a mathematical analysis was performed to derive an equation for desired porosity in terms of morphological parameters. Then, the considered cylindrical geometries were modeled and the permeability coefficient was calculated according to the velocity and pressure drop values based on the Darcy's law. In order to validate the accuracy of the present numerical solution, the obtained permeability coefficient was compared with the published experimental data. It was observed that this model can predict permeability with the utmost accuracy. Then, the effect of geometrical parameters including porosity, scaffold pore structure, unit cell size, and length of the scaffolds as well as entrance mass flow rate on the permeability of porous structures was studied. Furthermore, a parametric study with scaling laws analysis of sample length and mass flow rate effects on the permeability showed good fit to the obtained data. It can be concluded that the sensitivity of permeability is more noticeable at higher porosities. The present approach can be used to characterize and optimize the scaffold microstructure due to the necessity of cell growth and transferring considerations. PMID- 27494074 TI - Executive dysfunction and survival in patients with amyotrophic lateral sclerosis: Preliminary report from a Serbian centre for motor neuron disease. AB - Our objective was to determine whether the presence of executive dysfunction in non-demented amyotrophic lateral sclerosis (ALS) patients might affect the longevity of survival. Forty-eight consecutive non-demented ALS patients (mean age = 52.93 +/- 12.37) were followed for five years. All patients underwent clinical and neuropsychological assessments at baseline visit. Further, a yearly follow-up check for associated dementia (ALS-Dem) was completed and the time of death was recorded, when applicable. Executive deficits were shown in 49.5% of ALS patients, with the most striking differences found on the tests of verbal fluency (both phonemic and category, p < 0.01); as well as inefficient strategy on a working memory test (p < 0.05); as on the more demanding levels of the planning and problem solving task (p < 0.01). It appears that the baseline executive status might predict survival in ALS (p = 0.075), and the patients presenting executive dysfunction could have up to three times greater risk of death, after adjustment by several potential confounding factors. In conclusion, this study suggests that executive dysfunction could potentially influence survival in ALS patients. The cognitive testing might give us important clues about the prognosis of the disease. Further studies with larger sample size are necessary. PMID- 27494075 TI - D-dimer test for excluding the diagnosis of pulmonary embolism. AB - BACKGROUND: Pulmonary embolism (PE) can occur when a thrombus (blood clot) travels through the veins and lodges in the arteries of the lungs, producing an obstruction. People who are thought to be at risk include those with cancer, people who have had a recent surgical procedure or have experienced long periods of immobilisation and women who are pregnant. The clinical presentation can vary, but unexplained respiratory symptoms such as difficulty breathing, chest pain and an increased respiratory rate are common.D-dimers are fragments of protein released into the circulation when a blood clot breaks down as a result of normal body processes or with use of prescribed fibrinolytic medication. The D-dimer test is a laboratory assay currently used to rule out the presence of high D dimer plasma levels and, by association, venous thromboembolism (VTE). D-dimer tests are rapid, simple and inexpensive and can prevent the high costs associated with expensive diagnostic tests. OBJECTIVES: To investigate the ability of the D dimer test to rule out a diagnosis of acute PE in patients treated in hospital outpatient and accident and emergency (A&E) settings who have had a pre-test probability (PTP) of PE determined according to a clinical prediction rule (CPR), by estimating the accuracy of the test according to estimates of sensitivity and specificity. The review focuses on those patients who are not already established on anticoagulation at the time of study recruitment. SEARCH METHODS: We searched 13 databases from conception until December 2013. We cross-checked the reference lists of relevant studies. SELECTION CRITERIA: Two review authors independently applied exclusion criteria to full papers and resolved disagreements by discussion.We included cross-sectional studies of D-dimer in which ventilation/perfusion (V/Q) scintigraphy, computerised tomography pulmonary angiography (CTPA), selective pulmonary angiography and magnetic resonance pulmonary angiography (MRPA) were used as the reference standard.* PARTICIPANTS: Adults who were managed in hospital outpatient and A&E settings and were suspected of acute PE were eligible for inclusion in the review if they had received a pre-test probability score based on a CPR.* INDEX TESTS: quantitative, semi quantitative and qualitative D-dimer tests.* Target condition: acute symptomatic PE.* Reference standards: We included studies that used pulmonary angiography, V/Q scintigraphy, CTPA and MRPA as reference standard tests. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed quality using Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). We resolved disagreements by discussion. Review authors extracted patient-level data when available to populate 2 * 2 contingency tables (true positives (TPs), true-negatives (TNs), false-positives (FPs) and false-negatives (FNs)). MAIN RESULTS: We included four studies in the review (n = 1585 patients). None of the studies were at high risk of bias in any of the QUADAS-2 domains, but some uncertainty surrounded the validity of studies in some domains for which the risk of bias was uncertain. D-dimer assays demonstrated high sensitivity in all four studies, but with high levels of false-positive results, especially among those over the age of 65 years. Estimates of sensitivity ranged from 80% to 100%, and estimates of specificity from 23% to 63%. AUTHORS' CONCLUSIONS: A negative D dimer test is valuable in ruling out PE in patients who present to the A&E setting with a low PTP. Evidence from one study suggests that this test may have less utility in older populations, but no empirical evidence was available to support an increase in the diagnostic threshold of interpretation of D-dimer results for those over the age of 65 years. PMID- 27494076 TI - Pro- and anti-angiogenic VEGF mRNAs in autoimmune thyroid diseases. AB - The aim of this study was to assess the relationships between five different splice isoforms of VEGF mRNA and its plasma levels in individuals treated for autoimmune thyroid diseases (AITD); mainly Graves' disease (GD) and Hashimoto's thyroiditis (HT). In a population from Tunisia, levels of thyroid hormones and antibodies were quantified simultaneously with plasma VEGF and VEGF mRNA isoforms after a period of 6 months of patients' treatment. Plasma VEGF was measured in 110 AITD patients (21 GD and 89 HT patients). VEGF isoforms (VEGF121, VEGF165, VEGF145 and VEGF189 pro-angiogenic isoforms and VEGF165b anti-angiogenic isoform) in peripheral blood mononuclear cells were quantified in 71 patients (20 GD and 51 HT patients) and 86 healthy controls. Decreased levels of VEGF189 mRNA were observed in AITD compared to controls. VEGF165 was increased in GD patients compared to controls and the VEGF165b was increased in HT patients compared to GD. We observed increased levels of VEGF165b in hypothyroid AITD patients after treatment. We have also shown that the VEGF145 isoform levels were determined by FT4 in all patients and by the thyroid status after 6 months of treatment only in HT patients. An association was observed for VEGF165 mRNA levels with anti-TPO antibodies in all patients. Finally, FT4 was associated with VEGF plasma levels but only in healthy controls. In conclusion, this descriptive study highlights the specificity of VEGF mRNA isoforms in AITD, a fact underlining the need for novel clinical trials and the development of personalised theranostic approaches. PMID- 27494078 TI - d-Amino Acid Scan of Two Small Proteins. AB - A "D-scan" of two small proteins, the disulfide-rich Ecballium elaterium trypsin inhibitor II (EETI-II) and a minimized Z domain of protein A (Z33), is reported. For each protein, the stereochemistry of one amino acid at a time was inverted to generate a series of diastereomers. In much the same way an alanine scan determines necessary residues for protein function, the D-scan elucidated the critical stereocenters of the 30-residue EETI-II and the 33-residue Z33. The folding properties and activity of each variant were investigated. A total of 24 out of 30 EETI-II D-scan analogues folded to give a three-disulfide product. Of the 24 variants that folded, half were high-affinity trypsin inhibitors, and three were as active as the wild type (WT). Of these 12 active variants, most were substantially less stable to reduction than WT EETI-II (WT first reduction potential -270.0 +/- 1.5 mV, WT second reduction potential -307.2 +/- 1.1 mV). Similarly, ten Z33 analogues retained high binding affinity to IgG (KD < 250 nM, WT: 24 +/- 1 nM) and 12 additional analogues had reduced but appreciable IgG binding affinity (KD between 250 nM and 2.5 MUM). As with EETI-II, most Z33 analogues were substantially less stable than the WT (DeltaG(H2O, 263 K) = 2.4 +/ 1.2 kcal/mol). Collectively, our findings show that the D-scan is powerful new strategy for studying how the stereochemistry of amino acids affects the structure and function of proteins. PMID- 27494077 TI - Subcutaneous anti-TNF alfa induced sustained minimal disease activity and remission in psoriatic arthritis patients: a retrospective study. AB - OBJECTIVE: The aim of the present study was to assess the rate of sustained Minimal Disease Activity (MDA) and remission in a group of psoriatic arthritis (PsA) patients treated with TNFalpha blockers. METHODS: We perform a retrospective study on our database of PsA patients treated with adalimumab, etanercept and golimumab, with a minimum of 12 months of follow up. Patients were considered in sustained MDA when they met at least 5/7 of the criteria previously defined for at least 12 months of follow up. DAS28-CRP < 2.6, DAPSA score <= 4 and patient global assessment (PGA) <= 20 mm were also evaluated as remission criteria. Concordance between the remission criteria and MDA was also performed. RESULTS: Of the 81 patients treated with TNFalpha blockers, at baseline no patients were in MDA or had a DAPSA score <= 4, while 17 (20.9%) had a DAS28-CRP score < 2.6. PGA <= 20 was recorded in 6 patients (7%). Sustained MDA was achieved in 35 (43.2%) patients while sustained DAPSA, DAS28-CRP and PGA remission were obtained respectively in 19.7%, 35.8% and 44.4% of patients. No difference was found between the three anti-TNFalpha in respect to the probability of achieve MDA. CONCLUSIONS: In this retrospective study, sustained MDA was achieved in 43.2% of patients treated with TNFalpha blockers. Moreover, sustained remission was achieved in a consistent number of patients, configuring this as an achievable target for PsA patients. PMID- 27494081 TI - "Make Sure You're Not Getting Yourself in Trouble:" Building Sexual Relationships and Preventing Sexual Violence at the U.S. Military Academy at West Point. AB - Sexual violence continues to present a problem on college campuses nationwide and among members of the U.S. military. This study attended to patterns of response in how students (cadets) at the U.S. Military Academy (West Point) discussed sexual and romantic relationships, both potential and actual, in order to examine how, if at all, they enact their sexuality-related values. Constructivist grounded theory was used to analyze semistructured interviews with three male and three female cadets from each of the 4 years of the undergraduate program, in which they are intended to become "leaders of character" who will serve as Army officers. Findings indicated limitations in cadets' access to developing and implementing sexuality-related skills within this context. Cadets' fear and distrust erected barriers to their pursuing their desires; the ways in which cadets avoided getting in trouble for sexual harassment or sexual assault shifted responsibility from a potential perpetrator onto a potential victim; and cadets were caught in dilemmas regarding romantic relationships as sources of both emotional support and social stigma. These findings have implications for promoting gender equity and for preventing sexual violence at this institution and at others like it, including both university campuses and other military settings. PMID- 27494080 TI - Raynaud's syndrome in children: systematic review and development of recommendations for assessment and monitoring. AB - OBJECTIVES: To develop recommendations for investigation and monitoring of children with Raynaud's syndrome, based on paediatric evidence collated by a systematic review. METHODS: A systematic review was undertaken to establish the paediatric evidence for assessment and monitoring of Raynaud's syndrome. An expert panel including members of the Paediatric Rheumatology European Society (PRES) Scleroderma Working Group, were invited to a consensus meeting where recommendations were developed based on evidence graded by the systematic review and where evidence was lacking, consensus opinion. A nominal technique was used where 75% consensus was taken as agreement. RESULTS: The expert panel recommended testing anti-nuclear antibody (ANA), more specific antibodies associated with connective tissue disease and nail-fold capillaroscopy in all children presenting with Raynaud's syndrome as data suggests these can be risk factors for evolution into a connective tissue disease. The frequency of follow-up recommended depends on presence of these risk factors with the aim to detect evolving connective tissue disease early in high risk individuals. Those with no abnormalities on capillaroscopy and negative autoantibodies were deemed low risk of progression, whereas those with ANA positivity, specific autoantibodies and/or nailfold capillary changes were deemed high risk and more frequent follow-up was recommended. CONCLUSIONS: Recommendations, primarily based on consensus opinion, were agreed regarding investigation and monitoring of children who present with Raynaud's syndrome. Further prospective studies are needed to better define the risk factors for progression to connective tissue disease. PMID- 27494082 TI - The role of colloidal plasmonic nanostructures in organic solar cells. AB - Plasmonic particles can contribute via multiple processes to the light absorption process in solar cells. These particles are commonly introduced into organic solar cells via deposition techniques such as spin-coating or dip-coating. However, such techniques are inherently challenging to achieve homogenous surface coatings as they lack control of inter-particle spacing and particle density on larger areas. Here we introduce interface assisted colloidal self-assembly as a concept for the fabrication of well-defined macroscopic 2-dimensional monolayers of hydrogel encapsulated plasmonic gold nanoparticles. The monolayers showed a pronounced extinction in the visible wavelength range due to localized surface plasmon resonance with excellent optical homogeneity. Moreover this strategy allowed for the investigation of the potential of plasmonic monolayers at different interfaces of P3HT:PCBM based inverted organic solar cells. In general, for monolayers located anywhere underneath the active layer, the solar cell performance decreased due to parasitic absorption. However with thick active layers, where low hole mobility limited the charge transport to the top electrode, the plasmonic monolayer near that electrode spatially redistributed the light and charge generation close to the electrode led to an improved performance. This work systematically highlights the trade-offs that need to be critically considered for designing an efficient plasmonically enhanced organic solar cell. PMID- 27494079 TI - Pre- and perinatal complications in relation to Tourette syndrome and co occurring obsessive-compulsive disorder and attention-deficit/hyperactivity disorder. AB - Pre- and perinatal complications have been implicated in the onset and clinical expression of Tourette syndrome albeit with considerable inconsistencies across studies. Also, little is known about their role in co-occurring obsessive compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in individuals with a tic disorder. Therefore, we aimed to investigate the role of pre- and perinatal complications in relation to the presence and symptom severity of chronic tic disorder and co-occurring OCD and ADHD using data of 1113 participants from the Tourette International Collaborative Genetics study. This study included 586 participants with a chronic tic disorder and 527 unaffected family controls. We controlled for age and sex differences by creating propensity score matched subsamples for both case-control and within-case analyses. We found that premature birth (OR = 1.72) and morning sickness requiring medical attention (OR = 2.57) were associated with the presence of a chronic tic disorder. Also, the total number of pre- and perinatal complications was higher in those with a tic disorder (OR = 1.07). Furthermore, neonatal complications were related to the presence (OR = 1.46) and severity (b = 2.27) of co-occurring OCD and also to ADHD severity (b = 1.09). Delivery complications were only related to co-occurring OCD (OR = 1.49). We conclude that early exposure to adverse situations during pregnancy is related to the presence of chronic tic disorders. Exposure at a later stage, at birth or during the first weeks of life, appears to be associated with co-occurring OCD and ADHD. PMID- 27494083 TI - Comparison of IOL power calculation formulae for pediatric eyes. AB - PurposeTo evaluate and compare the accuracy of modern intraocular lens (IOL) power calculation formulae in pediatric eyes and compare prediction error (PE) obtained with manufacturer's vs personalized lens constant.Patients and methodsAn observational case study was conducted in 117 eyes (117 patients) undergoing pediatric cataract surgery with IOL implantation. PE was calculated as predicted refraction minus actual postoperative refraction, and absolute PE as absolute difference independent of the sign, (APE)=predicted refraction minus actual postoperative refraction. This was done for each formula using manufacturer's and personalized lens constant. Further, PE and APE were evaluated according to axial length (AL).ResultsMean age of children was 2.97 years. About 66/117 eyes (56.4%) were below 2 years of age. Using Holladay 2, Holladay 1, Hoffer Q, and SRK/T formulae with manufacturer's lens constant, mean PE was 0.36, 0.41, 0.69, and 0.28 diopter (D), respectively. With personalized lens constant, it was 0.16, 0.15, 0.50, and -0.12 D, respectively. Difference in mean PE between the formulae was statistically significant (P<0.0001). SRK/T and Holladay 2 formulae had the least PE, both with manufacturer's and personalized constant. For eyes with AL<20 mm, SRK/T and Holladay 2 formulae gave the least PE. Personalizing the lens constant led to a decrease in mean PE in all formulae, except the Hoffer Q formula. However, personalizing the lens constant did not significantly improve the APE. At least 21% eyes had an APE of >2 D with all formulae, even with personalized lens constants.ConclusionIn pediatric eyes, SRK/T and the Holladay 2 formulae had the least PE. Personalizing the lens formula constant did reduce the PE significantly for all formulae except Hoffer Q. In extremely short eyes (AL<20 mm), SRK/T and Holladay 2 formulae gave the best PE. PMID- 27494085 TI - TORCH testing in non-familial paediatric cataract. PMID- 27494084 TI - Preserved functional and structural integrity of the papillomacular area correlates with better visual acuity in retinitis pigmentosa. AB - PurposeLinking multifocal electroretinography (mfERG) and optical coherence tomography (OCT) findings with visual acuity in retinitis pigmentosa (RP) patients.DesignProspective, cross-sectional, nonintervention study.SubjectsPatients with typical RP and age-matched controls, who underwent SD OCT (spectral domain OCT) and mfERG, were included.MethodsMfERG responses were averaged in three zones (zone 1 (0 degrees -3 degrees ), zone 2 (3 degrees -8 degrees ), and zone 3 (8 degrees -15 degrees )). Baseline-to-trough- (N1) and trough-to-peak amplitudes (N1P1) of the mfERG were compared with corresponding areas of the OCT. The papillomacular area (PMA) was analyzed separately. Correlations between best-corrected visual acuity (BCVA, logMAR) and each parameter were determined.Main outcome measuresComparing structural (OCT) and functional (mfERG) measures with the BCVA.ResultsIn RP patients, the N1 and N1P1 responses showed positive association with the central retinal thickness outside zone 1 (P<=0.002), while the central N1 and the N1P1 responses in zones 1, 2, and 3-with the BCVA (P<=0.007). The integrity of the IS/OS line on OCT showed also a positive association with the BCVA (P<0.001). Isolated analysis of the PMA strengthened further the structure-function association with the BCVA (P<=0.037). Interactions between the BCVA and the OCT, respectively, the mfERG parameters were more pronounced in the RP subgroup without macular edema (P<=0.020).ConclusionIn RP patients, preserved structure-function of PMA, measured by mfERG amplitude and OCT retinal thickness, correlated well with the remaining BCVA. The subgroup analyses revealed stronger links between the examined parameters, in the RP subgroup without appearance of macular edema. PMID- 27494086 TI - Molecular genetic approaches for environmental stress tolerant crop plants: Progress and prospects. AB - Global food security is threatened by the severe environmental conditions that have reduced the worldwide crop yield. Plants possess inherent mechanisms to cope with the initial stress phase but to ensure their survival through harsh climate, the intervention of genetic engineering is desirable. Elucidation of genetic loci and deciphering the underlying mechanisms that confer tolerance to plants against stressful conditions followed by its successful introgression into elite, high yielding crop varieties can be an effective way to engineer the crops for increasing productivity. This review provides an overview about the effects of abiotic and biotic stresses on crop plants and the use of genetic engineering approach to cope with these environmental stresses for a sustainable agriculture. Major patents in the field of plant stress tolerance in the last five years have also been summarized. PMID- 27494087 TI - Ligand Symmetry Modulation for Designing Mixed-Ligand Metal-Organic Frameworks: Gas Sorption and Luminescence Sensing Properties. AB - Herein, we report the synthesis of a new mixed-linker Zn(II)-based metal-organic framework (MOF), {[Zn2(atz)2(bpydb)](DMA)8}n (1) (atz = deprotonated 3-amino 1,2,4-triazole, bpydb = deprotonated 4,4'-(4,4'-bipyridine-2,6-diyl) dibenzoic acid, DMA = N,N-dimethylacetamide), through symmetry modulation of a triazole ligand. The desymmetrized triazole linkers not only bond to the Zn(II) ions to result in a new helical Zn-triazolate chain building unit but also lead to the formation of a highly porous framework (N2 uptake: 617 cm(3)/g; BET surface area: 2393 m(2)/g) with 1D helical channels. The adsorption properties of desolved 1 were investigated by H2, C2H2, CO2, and CH4 sorption experiments, which showed that 1 exhibited high uptake capacity for H2 at 77 K and C2H2 around room temperature. More importantly, the high C2H2 uptake capacity but low binding energy makes this MOF a promising candidate for effective C2H2 capture from C2H2/CO2 and C2H2/CH4 mixed gases with low regenerative energy cost. In addition, 1 shows potential application for the luminescence sensing of small aromatic molecules picric acid (PA) and p-xylene (PX). PMID- 27494088 TI - Partial recovery of microbiomes after antibiotic treatment. AB - Antibiotics profoundly affect the gut microbiome and modulate microbial communities. We recently observed that antimicrobial drugs also impact the abundance and distribution of antibiotic resistance genes. In this addendum, we reanalyze our ~1 trillion nucleotide shotgun metagenomic dataset to quantify comprehensive genomic differences at the sequence level before and after antibiotic treatment. We show that 7 day exposure to cefprozil leads to a statistically significant loss of metagenome sequences. Recovery of gut microbiomes 3 months after antibiotherapy was characterized by the emergence of new genome sequences not observed prior to antibiotic exposure. Participants with low initial gut microbiome diversity had an increased amount of sequences related to antibiotic resistance. Therefore, we suggest that while the taxonomical composition of microbiomes is partially affected by the antibiotic, the genomic content and population structure of bacterial communities is noticeably impacted. PMID- 27494089 TI - Health-related quality of life and patient-reported outcomes of ofatumumab plus chlorambucil versus chlorambucil monotherapy in the COMPLEMENT 1 trial of patients with previously untreated CLL. AB - BACKGROUND: Patients diagnosed with chronic lymphocytic leukemia (CLL) are usually elderly and frequently have a number of comorbidities. Health-related quality of life (HRQoL) for these patients is of utmost importance and should be taken into consideration when assessing new treatment options. The combination of ofatumumab with chlorambucil has shown longer progression-free survival compared with chlorambucil alone. In this study, we aim to assess how this treatment combination affects patients' health-related quality of life and patient-reported symptoms. MATERIAL AND METHODS: In this open-label phase III trial, patients with previously untreated CLL for whom fludarabine-based treatment was contra indicated, were randomized 1:1 to receive oral chlorambucil (10 mg/m2) on Days 1 7 of a 28-day treatment cycle or to receive chlorambucil by this schedule plus intravenous ofatumumab (Cycle 1: 300 mg on Day 1 and 1000 mg on Day 8; subsequent cycles: 1000 mg Day 1) for 3-12 cycles. The EORTC QLQ-C30 and QLQ-CLL16 questionnaires were administered to patients before and during treatment, in follow-up and at the time of disease progression. The primary specified patient reported outcomes were HRQoL and fatigue. RESULTS: Patient-reported improvements from baseline in Global Health Status (GHS)/HRQoL scores and fatigue scores were recorded during treatment with both chlorambucil monotherapy and ofatumumab in combination with chlorambucil. There were no significant differences between the two treatment arms for GHS/HRQoL (p = 0.667) or fatigue (p = 0.103). Following treatment, numerical improvements to GHS/HRQoL and fatigue scores were reported, with no significant differences between the two treatment arms. CONCLUSION: Small but detectable improvements in patients' quality of life were reported as a result of treatment. The addition of ofatumumab to chlorambucil did not negatively impact HRQoL. Quality of life was maintained in the months following treatment. PMID- 27494090 TI - Estimation of salient regions related to chronic gastritis using gastric X-ray images. AB - Since technical knowledge and a high degree of experience are necessary for diagnosis of chronic gastritis, computer-aided diagnosis (CAD) systems that analyze gastric X-ray images are desirable in the field of medicine. Therefore, a new method that estimates salient regions related to chronic gastritis/non gastritis for supporting diagnosis is presented in this paper. In order to estimate salient regions related to chronic gastritis/non-gastritis, the proposed method monitors the distance between a target image feature and Support Vector Machine (SVM)-based hyperplane for its classification. Furthermore, our method realizes removal of the influence of regions outside the stomach by using positional relationships between the stomach and other organs. Consequently, since the proposed method successfully estimates salient regions of gastric X-ray images for which chronic gastritis and non-gastritis are unknown, visual support for inexperienced clinicians becomes feasible. PMID- 27494091 TI - CD3D and PRKCQ work together to discriminate between B-cell and T-cell acute lymphoblastic leukemia. AB - Different therapeutic methods have been developed for the B-cell and T-cell subtypes of acute lymphoblastic leukemia (ALL). The identification of molecular biomarkers that can accurately discriminate between B-cell and T-cell ALLs will facilitate the quick determination of therapeutic plans, as well as reveal the intrinsic mechanisms underlining the two different ALL subtypes. This study computationally screened the high-throughput transcriptome dataset for multiple candidate biomarkers and verified their discrimination abilities in an independent sample set using quantitative real-time polymerase chain reaction (PCR) technology. Both technologies suggest that the two genes CD3D and PKRCQ together provided a good model for classification of B-cell and T-cell ALLs, whereas the individual genes did not show consistent discrimination between the two ALL subtypes. Supplementary material is available at http://healthinformaticslab.org/supp/. PMID- 27494092 TI - Comparison of bone-anchored prostheses and socket prostheses for patients with a lower extremity amputation: a systematic review. AB - PURPOSE: This study aimed to provide an overview of a) the used measurement instruments in studies evaluating effects on quality of life (QoL), function, activity and participation level in patients with a lower extremity amputation using bone-anchored prostheses compared to socket prostheses and b) the effects themselves. METHOD: A systematic literature search was conducted in MEDLINE, Cochrane, EMBASE, CINAHL and Web of Science. Included studies compared QoL, function, activity and/or participation level in patients with bone-anchored or socket prostheses. A best-evidence synthesis was performed. RESULTS: Out of 226 studies, five cohort and two cross-sectional studies were eligible for inclusion, all had methodological shortcomings. These studies used 10 different measurement instruments and two separate questions to assess outcome. Bone-anchored prostheses were associated with better condition-specific QoL and better outcomes on several of the physical QoL subscales, outcomes on the physical bodily pain subscale were inconclusive. Outcomes on function and activity level increased, no change was found at participation level. The level of evidence was limited. CONCLUSIONS: There is a need for a standard set of instruments. There was limited evidence that bone-anchored prostheses resulted in higher QoL, function and activity levels than socket prostheses, in patients with socket-related problems. Implications for Rehabilitation Use of bone-anchored prostheses in combination with intensive outpatient rehabilitation may improve QoL, function and activity level compared with socket prosthesis use in patients with a transfemoral amputation and socket-related problems. All clinicians and researchers involved with bone-anchored prostheses should use and publish data on QoL, function, activity and participation level. There needs to be an agreement on a standard set of instruments so that interventions for patients with a lower extremity amputation are assessed consistently. PMID- 27494093 TI - A novel Bayesian approach to acoustic emission data analysis. AB - Acoustic emission (AE) technique is a popular tool for materials characterization and non-destructive testing. Originating from the stochastic motion of defects in solids, AE is a random process by nature. The challenging problem arises whenever an attempt is made to identify specific points corresponding to the changes in the trends in the fluctuating AE time series. A general Bayesian framework is proposed for the analysis of AE time series, aiming at automated finding the breakpoints signaling a crossover in the dynamics of underlying AE sources. PMID- 27494094 TI - Short- and long-term effects of exercise on neck muscle function in cervical radiculopathy: A randomized clinical trial. AB - OBJECTIVE: To compare short- and long-term changes in neck muscle endurance, electromyography measures of neck muscle activation and fatigue and ratings of fatigue and pain after neck-specific training or physical activity in people with cervical radiculopathy. DESIGN: Randomized clinical trial. SUBJECTS/PATIENTS: Seventy-five patients with cervical radiculopathy. METHODS: Patients underwent neck-specific training in combination with a cognitive behavioural approach or prescribed physical activity over a period of 14 weeks. Immediately after the intervention and 12 months later, surface electromyography was recorded from neck flexor and extensor muscles during neck endurance tests. Time to task failure, amplitude and median frequency of the electromyography signal, and subjective fatigue and pain ratings were analysed in 50 patients who completed at least one follow-up. RESULTS: A significant increase in neck flexor endurance time was observed for both groups at 14 weeks compared with baseline and this was maintained at the 12-month follow-up (p < 0.005). No change was identified for the slope of the median frequency. For the neck-specific training group, splenius capitis was less active during neck flexion at both follow-ups (p < 0.01), indicating reduced muscle co-activation. CONCLUSION: Both specific and general exercise increased neck flexor endurance, but neck-specific training only reduced co-activation of antagonist muscles during sustained neck flexion. PMID- 27494095 TI - Applications of large-scale density functional theory in biology. AB - Density functional theory (DFT) has become a routine tool for the computation of electronic structure in the physics, materials and chemistry fields. Yet the application of traditional DFT to problems in the biological sciences is hindered, to a large extent, by the unfavourable scaling of the computational effort with system size. Here, we review some of the major software and functionality advances that enable insightful electronic structure calculations to be performed on systems comprising many thousands of atoms. We describe some of the early applications of large-scale DFT to the computation of the electronic properties and structure of biomolecules, as well as to paradigmatic problems in enzymology, metalloproteins, photosynthesis and computer-aided drug design. With this review, we hope to demonstrate that first principles modelling of biological structure-function relationships are approaching a reality. PMID- 27494096 TI - Passive Dosing in Chronic Toxicity Tests with the Nematode Caenorhabditis elegans. AB - In chronic toxicity tests with Caenorhabditis elegans, it is necessary to feed the nematode with bacteria, which reduces the freely dissolved concentration (Cfree) of hydrophobic organic chemicals (HOCs), leading to poorly defined exposure with conventional dosing procedures. We examined the efficacy of passive dosing of polycyclic aromatic hydrocarbons (PAHs) using silicone O-rings to control exposure during C. elegans toxicity testing and compared the results to those obtained with solvent spiking. Solid-phase microextraction and liquid liquid extraction were used to measure Cfree and the chemicals taken up via ingestion. During toxicity testing, Cfree decreased by up to 89% after solvent spiking but remained constant with passive dosing. This led to a higher apparent toxicity on C. elegans exposed by passive dosing than by solvent spiking. With increasing bacterial cell densities, Cfree of solvent-spiked PAHs decreased while being maintained constant with passive dosing. This resulted in lower apparent toxicity under solvent spiking but an increased apparent toxicity with passive dosing, probably as a result of the higher chemical uptake rate via food (CUfood). Our results demonstrate the utility of passive dosing to control Cfree in routine chronic toxicity testing of HOCs. Moreover, both chemical uptake from water or via food ingestion can be controlled, thus enabling the discrimination of different uptake routes in chronic toxicity studies. PMID- 27494097 TI - Static and dynamic behaviour of responsive graphene oxide-poly(N-isopropyl acrylamide) composite gels. AB - Thermoresponsive hydrogels have enormous potential e.g., as sensors, actuators, and pollution control remedies or in drug delivery systems. Nevertheless, their application is often restricted by physical limitations (poor mechanical strength and uncontrolled thermal response). Composite systems may offer a means of overcoming these limitations. This paper presents a systematic study of the structure and dynamics of graphene oxide-poly-(N-isopropylacrylamide) composite systems, and investigates the effect of the nanoparticle filler content on the mechanical and swelling properties of the systems. A combination of macroscopic (swelling and elastic modulus) and microscopic (differential scanning microcalorimetry, small angle neutron scattering and neutron spin-echo spectroscopy) investigations reveals that the architecture of the polymer network is modified by chain nucleation at the surface of the GO platelets, and these form a percolating network inside the gel. Our results show that the elastic modulus of the gels is reinforced by the filler, but the mobility of the polymer chains in the swollen state is practically unaffected. The macroscopic deswelling of the composites, however, is slowed by the kinetics of ordering in the GO network. PMID- 27494098 TI - Tamoxifen and Fulvestrant Hybrids Showed Potency as Selective Estrogen Receptor Down-Regulators. AB - BACKGROUND: Estrogen receptors (ERs) are an important target for the management of breast cancers. Selective estrogen receptor down-regulators (SERDs) block ER activity, as well as reduce ERalpha protein levels in cells, and therefore are promising therapeutic agents for the treatment of breast cancers. OBJECTIVE: In order to develop potent SERDs, we prepared tamoxifen and fulvestrant hybrids and evaluated their binding activity and down-regulation of ERalpha. METHODS: We designed and synthesized tamoxifen derivatives, which had a 4,4,5,5,5- pentafluoropentyl group on the terminal alkyl chain. The oxidation state of the sulfur atom and alkyl length between the sulfur and nitrogen atoms were varied. Western blotting was performed to determine the ability to down-regulate ERalpha. Binding affinities of synthesized compounds were evaluated by a fluorescence polarization-based competitive binding assay. RESULTS: We successfully prepared nine compounds. Treatment with 11, 14, and 17 effectively reduced ERalpha protein levels in MCF-7 cells in a concentration-dependent manner. This reduction was inhibited by a proteasome inhibitor. The ability of 14 to down-regulate the ERalpha protein level was equal to fulvestrant. All compounds showed a largely equal affinity for ERalpha. CONCLUSION: As indicated by Western blots, the ERalpha degradation activity was observed only in the series of butyl linker derivatives, namely, 11, 14, and 17. These findings suggest that the specific length of the alkyl chain is an important factor in controlling the down regulation of ER. These results provide useful information for designing promising SERD candidates. PMID- 27494099 TI - Fabrication of granular activated carbons derived from spent coffee grounds by entrapment in calcium alginate beads for adsorption of acid orange 7 and methylene blue. AB - Biomass-based granular activated carbon was successfully prepared by entrapping activated carbon powder derived from spent coffee grounds into calcium-alginate beads (SCG-GAC) for the removal of acid orange 7 (AO7) and methylene blue (MB) from aqueous media. The dye adsorption process is highly pH-dependent and essentially independent of ionic effects. The adsorption kinetics was satisfactorily described by the pore diffusion model, which revealed that pore diffusion was the rate-limiting step during the adsorption process. The equilibrium isotherm and isosteric heat of adsorption indicate that SCG-GAC possesses an energetically heterogeneous surface and operates via endothermic process in nature. The maximum adsorption capacities of SCG-GAC for AO7 (pH 3.0) and MB (pH 11.0) adsorption were found to be 665.9 and 986.8mg/g at 30 degrees C, respectively. Lastly, regeneration tests further confirmed that SCG-GAC has promising potential in its reusability, showing removal efficiency of more than 80% even after seven consecutive cycles. PMID- 27494100 TI - Effect of actinobacteria agent inoculation methods on cellulose degradation during composting based on redundancy analysis. AB - In this study, actinobacteria agent including Streptomyces sp. and Micromonospora sp. were inoculated during chicken manure composting by different inoculation methods. The effect of different treatments on cellulose degradation and the relationship between inoculants and indigenous actinobacteria were investigated during composting. The results showed that inoculation in different stages of composting all improved the actinobacteria community diversity particularly in the cooling stage of composting (M3). Moreover, inoculation could distinctly accelerate the degradation of organic matters (OM) especially celluloses. Redundancy analysis indicated that the correlation between indigenous actinobacteria and degradation of OM and cellulose were regulated by inoculants and there were significant differences between different inoculation methods. Furthermore, synergy between indigenous actinobacteria and inoculants for degradation of OM and cellulose in M3 was better than other treatments. Conclusively, we suggested an inoculation method to regulate the indigenous actinobacteria based on the relationship between inoculants and indigenous actinobacteria and degradation content. PMID- 27494102 TI - The role of residual quantities of suspended sludge on nitrogen removal efficiency in a deammonifying moving bed biofilm reactor. AB - In a moving bed biofilm reactor (MBBR) system, the vast majority of biomass is immobilized as biofilm besides small amounts of suspension. In this study, the influence of the individual biomass components of a deammonifying MBBR, the biofilm on carriers (BC), residual suspended biomass (SB) with a volatile suspended solids concentration of 0.09+/-0.03g/L, and its combination (BC+SB) on nitrogen removal efficiency was investigated. While the performance was highest for BC+SB (0.42kgN/(m(3).d)), it was reduced by a factor of 3.5 for BC solely. SB itself was only capable of nitrite accumulation. This suggests a high abundance of AOBs within suspension besides the coexistence of AOBs and anammox bacteria in the biofilm, which could be supported by results using fluorescence in situ hybridization(FISH). Thus, small amounts of suspended microorganisms can positively influence the deammonification's efficiency. If this fraction is partially washed out, the system recovers nevertheless within hours. PMID- 27494101 TI - Successions and diversity of humic-reducing microorganisms and their association with physical-chemical parameters during composting. AB - Humic-reducing microorganisms (HRMs) could utilize humic substances (HS) as terminal electron mediator to promote the biodegradation of recalcitrant pollutants. However, the dynamics of HRMs during composting has not been explored. Here, high throughput sequencing technology was applied to investigate the patterns of HRMs during three composting systems. A total of 30 main genera of HRMs were identified in three composts, with Proteobacteria being the largest phylum. HRMs were detected with increased diversity and abundance and distinct patterns during composting, which were significantly associated with dissolved organic carbon, dissolved organic nitrogen and germination index. Regulating key physical-chemical parameters is a process control of HRMs community composition, thus promoting the redox capability of the compost. The redox capability of HRMs were strengthened during composting, suggesting that HRMs of the compost may play an important role on pollutant degradation of the compost or when they are applied to the contaminated soils. PMID- 27494103 TI - Co-production of carbonic anhydrase and phycobiliproteins by Spirulina sp. and Synechococcus nidulans. AB - The aim of this work was to study the co-production of the carbonic anhydrase, C phycocyanin and allophycocyanin during cyanobacteria growth. Spirulina sp. LEB 18 demonstrated a high potential for simultaneously obtaining the three products, achieving a carbonic anhydrase (CA) productivity of 0.97U/L/d and the highest C phycocyanin (PC, 5.9MUg/mL/d) and allophycocyanin (APC, 4.3MUg/mL/d) productivities. In the extraction study, high extraction yields were obtained from Spirulina using an ultrasonic homogenizer (CA: 25.5U/g; PC: 90mg/g; APC: 70mg/g). From the same biomass, it was possible to obtain three biomolecules that present high industrial value. PMID- 27494105 TI - Production of bioactive protein hydrolysate using the yeasts isolated from soft chhurpi. AB - The aim of this work was to study the production of bioactive protein hydrolysates using yeasts isolated from chhurpi. For this, a total of 125 proteolytic yeasts were isolated and molecular identification was carried out by analysis of the restriction digestion pattern generated by digesting the PCR amplified internal transcribed spacer region and 5.8S rRNA gene (ITS1-5.8S-ITS2) using three endonucleases (HaeIII, CfoI and HinfI). The results obtained showed that different proteolytic yeasts were dominant in marketed products (Kluyveromyces marxianus and Issatchenkia orientalis) and samples from production centers (Trichosporon asahii, Saccharomyces cerevisiae and Exophiala dermatitidis). Proteolytic strains in individual groups showed their ability to hydrolyze milk protein and enhance antioxidant property. Among the isolates, fermentation using K. marxianus YMP45 and S. cerevisiae YAM14 resulted in higher antioxidant activity. This is the first report on application of yeast isolated from fermented food of North-East India for the production of bioactive protein hydrolysate. PMID- 27494104 TI - Biogas production generated through continuous digestion of natural and cultivated seaweeds with dairy slurry. AB - The technical feasibility of long term anaerobic mono-digestion of two brown seaweeds, and co-digestion of both seaweeds with dairy slurry was investigated whilst increasing the organic loading rate (OLR). One seaweed was natural (L. digitata); the second seaweed (S. Latissima) was cultivated. Higher proportions of L. digitata in co-digestion (66.6%) allowed the digester to operate more efficiently (OLR of 5kgVSm(-3)d(-1) achieving a specific methane yield (SMY) of 232LCH4kg(-1)VS) as compared to lower proportions (33.3%). Co-digestion of 66.6% cultivated S. latissima, with dairy slurry allowed a higher SMY of 252LCH4kg( 1)VS but at a lower OLR of 4kgVSm(-3)d(-1). Optimum conditions for mono-digestion of both seaweeds were effected at 4kgVSm(-3)d(-1). Chloride concentrations increased to high levels in the digestion of both seaweeds but were not detrimental to operation. PMID- 27494106 TI - Light intensity impacts the production of biofuel intermediates in Heterosigma akashiwo growing on simulated flue gas containing carbon dioxide and nitric oxide. AB - As a potential biofuel feedstock, the marine microalga, Heterosigma akashiwo, accumulates significant lipids, is capable of long-term growth in outdoor photobioreactors, and is an excellent candidate for the bioremediation of industrial emissions. Here, we evaluated resource partitioning in H. akashiwo growing on a CO2 and NO gas mixture under three light intensities: 160, 560, or 1200MUmolquantam(-2)s(-1). Light levels had no effect on growth; however, cultures in high light accumulated 2.3-fold more carbohydrates and 17% fewer lipids. Light levels did not affect the percentage of saturated fatty acids, but mono-unsaturates increased by 6% and poly-unsaturates decreased by 12% in high light. The fatty acid profiles reported here suggest that H. akashiwo is a good candidate for the production of neutral lipids for biodiesel and also omega-3 fatty acids, and that the quality of biodiesel acquired from feedstocks grown under fluctuating light conditions would be relatively stable. PMID- 27494107 TI - Asthma control and productivity loss in those with work-related asthma: A population-based study. AB - OBJECTIVE: In Canada, asthma is the third leading cause of work loss, yet little is known about the associated productivity loss. The goal of this study was to look at the relationship between asthma control and productivity loss, particularly contrasting those with work-related asthma (WRA) and non-work related asthma (NWRA). METHODS: A population-based random sample of adults with asthma in British Columbia, Canada, was prospectively recruited. Asthma control was graded according to Global Initiative for Asthma classification, while productivity loss and presence of WRA was assessed using questionnaires. Ordinal regression models were then used to associate WRA with asthma control. Generalized linear models were applied to estimate the average productivity loss associated with different levels of asthma control among those with WRA and NWRA. RESULTS: The study included 300 employed adults. Sixty (20%) had WRA. The odds of being controlled were significantly lower in those with WRA (OR = 0.23, 95% CI: 0.09, 0.56; P < 0.01). Those with WRA and uncontrolled asthma had a significant difference in productivity loss due to presenteeism ($659.1 [95% CI: 12.9, 1581.5; P = 0.04]), but not absenteeism ($88.7 [95% CI: -86.5, 279.6; P = 0.35]), when compared to those with NWRA and uncontrolled asthma. There was no significant difference when a similar comparison was made for those with controlled or partially controlled asthma. CONCLUSIONS: WRA is associated with worse asthma control and increased productivity loss. Presenteeism makes a significant contribution to productivity loss and should be considered when evaluating the overall economic burden of asthma, particularly WRA. PMID- 27494108 TI - Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant: A case report and literature review. AB - Ganciclovir-resistant cytomegalovirus infection is sometimes life-threatening for organ transplant recipients. Foscarnet is an alternative, although it may potentially worsen the preexistent impaired renal function. Here we report the case of a successful low-dose leflunomide treatment in a kidney transplant recipient with very high viral replication, who underwent kidney transplantation 10 years before. Administering 10mg leflunomide daily for 5 months without a loading dose completely cleared the ganciclovir-resistant cytomegalovirus strains. PMID- 27494109 TI - Ischemic post-conditioning attenuates renal ischemic reperfusion injury via down regulation of toll-like receptor 4 in diabetic rats. AB - BACKGROUND: Ischemia/reperfusion (I/R) injury, which is commonly seen in the field of renal surgery or transplantation, is a major cause of acute renal failure (ARF). The ischemic ARF in diabetic rats is much more severe than that in the normal rats exposed to as same ischemic time. Ischemic post-conditioning (IPO) is a phenomenon by which intermittent interruptions of blood flow in the early phase of reperfusion can protect organs from I/R injury. To determine whether the renal protection effect of IPO mediates by toll-like receptor 4 (TLR4) signaling pathway in diabetic rats. METHODS: Streptozotocin-induced diabetic rats were randomly divided into three groups: sham operation group, I/R group, and IPO group. Except sham operation group, rats were subjected to 30 min of renal ischemia, both with and without treatment with IPO, then reperfusion 24 h. Light microscope and transmission electronic microscope were used to observe structural changes of renal tubule. RT-PCR was used to measure TLR4 and tumor necrosis factor-alpha (TNF-alpha) mRNA expression level, renal TLR4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) protein expression was detected by Western blot. RESULTS: The results demonstrated that IPO markedly decreased renal ischemic injury caused by I/R and inhibited the proinflammatory expression levels of TLR4, TNF-alpha, and NF-kappaB, all of which up-regulated by I/R in diabetic rats. CONCLUSION: Taken together, our results suggest that proper IPO may have protective effect on the ischemic injury mediated by renal I/R, which might be associated with inhibition of TLR4 signaling pathway in diabetic rats. PMID- 27494110 TI - A Two-Step Absorber Deposition Approach To Overcome Shunt Losses in Thin-Film Solar Cells: Using Tin Sulfide as a Proof-of-Concept Material System. AB - As novel absorber materials are developed and screened for their photovoltaic (PV) properties, the challenge remains to reproducibly test promising candidates for high-performing PV devices. Many early-stage devices are prone to device shunting due to pinholes in the absorber layer, producing "false-negative" results. Here, we demonstrate a device engineering solution toward a robust device architecture, using a two-step absorber deposition approach. We use tin sulfide (SnS) as a test absorber material. The SnS bulk is processed at high temperature (400 degrees C) to stimulate grain growth, followed by a much thinner, low-temperature (200 degrees C) absorber deposition. At a lower process temperature, the thin absorber overlayer contains significantly smaller, densely packed grains, which are likely to provide a continuous coating and fill pinholes in the underlying absorber bulk. We compare this two-step approach to the more standard approach of using a semi-insulating buffer layer directly on top of the annealed absorber bulk, and we demonstrate a more than 3.5* superior shunt resistance Rsh with smaller standard error sigmaRsh. Electron-beam-induced current (EBIC) measurements indicate a lower density of pinholes in the SnS absorber bulk when using the two-step absorber deposition approach. We correlate those findings to improvements in the device performance and device performance reproducibility. PMID- 27494112 TI - Expression profiles of MGMT, p16, and APC genes in tumor and matching surgical margin from patients with oral squamous cell carcinoma. AB - The aim of the study was to assess the expression of MGMT, p16, and APC genes in tumors and matching surgical margin samples from 56 patients with primary OSCC. We also analyzed the association of the clinical variables with the expression of the studied genes. After RNA isolation and cDNA synthesis gene expression levels were assessed by quantitative reverse transcription (qRT)-PCR. Two-sided parametrical Student's t-test for independent groups with equal/unequal variances showed no statistically significant differences in genes' expression in tumor compared to margin samples. No association was found between the genes' expression and clinical parameters, except for MGMT, whose low expression was probably associated with smoking (0.87 vs 1.34, p=0.065). 'Field cancerization' is an area with genetically or epigenetically altered cells and at the same time a risk factor for cancer. Disturbances in gene expression could also be the source of damages leading to cancerization. In conclusion, it is important to mention that the field remaining after a surgery may pose an increased risk of cancer development. It may be suggested that the diagnosis and treatment of cancers should not be concentrated only on the tumor itself, but also on the cancer field effect. Therefore, further molecular analysis on surgical margins and additional research regarding their assessment are required. PMID- 27494113 TI - The perplexities of the ZC3H12A self-mRNA regulation. AB - The mechanisms regulating transcript turnover are key processes in the regulation of gene expression. The list of proteins involved in mRNAs' degradation is still growing, however, the details of RNase-mRNAs interactions are not fully understood. ZC3H12A is a recently discovered inflammation-related RNase engaged in the control of proinflammatory cytokine transcript turnover. ZC3H12A also regulates its own transcript half-live. Here, we studied the details of this regulation. Our results confirm the importance of the 3'UTR in ZC3H12A-dependent ZC3H12A mRNA degradation. We compared the mouse and human stemloop structures present in this region and discovered that the human conserved stem-loop structure is not sufficient for ZC3H12A-dependent degradation. However, this structure is important for the ZC3H12A mRNA post-transcriptional regulation. Our studies emphasize the importance of the neighboring features of the identified stem-loop structure for its biological activity. Removal of this region together with the stem-loop structure greatly inhibits the ZC3H12A regulation of the investigated 3'-untranslated region (3'UTR). PMID- 27494111 TI - Prognostic Impact of Time to Ipsilateral Breast Tumor Recurrence after Breast Conserving Surgery. AB - BACKGROUND: The poor prognosis of patients who experience ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery (BCS) is established. A short time between primary cancer and IBTR is a prognostic factor but no clinically relevant threshold was determined. Classification of IBTR may help tailor treatment strategies. PURPOSE: We determined a specific time frame, which differentiates IBTR into early and late recurrence, and identified prognostic factors for patients with IBTR at time of the recurrence. METHODS: We analyzed 2209 patients with IBTR after BCS. We applied the optimal cut-points method for survival data to determine the cut-off times to IBTR. A subgroup analysis was performed by hormone receptor (HR) status. Survival analyses were performed using a Cox proportional hazard model to determine clinical features associated with distant-disease-free survival (DDFS) after IBTR. We therefor built decision trees. RESULTS: On the 828 metastatic events observed, the majority occurred within the first 3 months after IBTR: 157 in the HR positive group, 98 in the HR negative group. We found different prognostic times to IBTR: 49 months in the HR positive group, 33 in the HR negative group. After multivariate analysis, time to IBTR was the first discriminant prognostic factor in both groups (HR 0.65 CI95% [0.54-0.79] and 0.42 [0.30-0.57] respectively). The other following variables were significantly correlated with the DDFS: the initial number of positive lymph nodes for both groups, the initial tumor size and grade for HR positive tumors. CONCLUSION: A short interval time to IBTR is the strongest factor of poor prognosis and reflects occult distant disease. It would appear that prognosis after IBTR depends more on clinical and histological parameters than on surgical treatment. A prospective trial in a low-risk group of patients to validate the safety of salvage BCS instead of mastectomy in IBTR is needed. PMID- 27494114 TI - Nonparametric Model of Smooth Muscle Force Production During Electrical Stimulation. AB - A nonparametric model of smooth muscle tension response to electrical stimulation was estimated using the Laguerre expansion technique of nonlinear system kernel estimation. The experimental data consisted of force responses of smooth muscle to energy-matched alternating single pulse and burst current stimuli. The burst stimuli led to at least a 10-fold increase in peak force in smooth muscle from Mytilus edulis, despite the constant energy constraint. A linear model did not fit the data. However, a second-order model fit the data accurately, so the higher-order models were not required to fit the data. Results showed that smooth muscle force response is not linearly related to the stimulation power. PMID- 27494115 TI - A review of the relative efficacy of dietary, nutritional supplements, lifestyle, and drug therapies in the management of hypertension. AB - Despite advancements in hypertensive therapies, the prevalence of hypertension and associated morbidities are still immense. Physicians are in great need for updated information on novel and effective antihypertensive therapies. Therefore, the study objective was to provide comprehensive information on the efficacy of available antihypertensive therapies. Antihypertensive therapies were divided into four general approaches: diet, nutritional supplements, lifestyle modification, and conventional antihypertensive medications. A search of PubMed and Google Scholar resulted in an analysis of 30 antihypertensive therapies from meta-analyses and randomized-controlled trials (RCTs). The studies were analyzed using the American Heart Association/American College of Cardiology classification system. Calculated average blood pressure reductions were: (systolic/diastolic) 6/4 mmHg, 4/2 mmHg, 5/3 mmHg, and 9/5 mmHg for dietary, nutritional supplements, lifestyle, and medications, respectively. The results demonstrate that dietary, nutritional supplement and lifestyle strategies have a solid level of evidence to support their efficacy as antihypertensive strategies. These strategies can be as effective as medications and, in some cases, even more effective. Dissemination of this information to physicians/dietitians can help facilitate an important shift in hypertension management. PMID- 27494116 TI - Dual-Mode Luminescent Nanopaper Based on Ultrathin g-C3N4 Nanosheets Grafted with Rare-Earth Upconversion Nanoparticles. AB - Ultrathin graphite-like carbon nitride (g-C3N4) nanosheets have attracted considerable attention due to the enhanced intrinsic photoabsorption and photoresponse with respect to bulk g-C3N4. For the first time, a dual-mode of down- and upconversion luminescent g-C3N4 nanopaper with high optical transparency and mechanical robustness was successfully fabricated through a simple thermal evaporation process using chitosan as a green cross-linking agent. The dual-mode of down- and upconversion fluorescence emission originated from the amino terminated ultrathin g-C3N4 nanosheets functionalized with carboxylic acid modified multicolored rare-earth upconversion nanoparticles (cit-UCNPs) via EDC/NHS coupling chemistry. The homogeneously distributed cit-UCNPs@g-C3N4 nanoconjugates with excellent hydrophilicity displayed good film-forming ability and structural integrity; thus, the photoluminescence of each ingredient was substantially maintained. Results indicated that the freestanding chitosan cross linked cit-UCNPs@g-C3N4 luminescent nanopaper possessed high transmittance, excellent mechanical properties, and remarkable dual-mode emission. The smart design of high performance luminescent nanopaper based on ultrathin g-C3N4 nanosheets grafted with multicolored UCNPs offers a potential strategy to immobilize other multifunctional luminescent materials for easily recognizable and hardly replicable anticounterfeiting fields. PMID- 27494117 TI - Modified AS1411 Aptamer Suppresses Hepatocellular Carcinoma by Up-Regulating Galectin-14. AB - Aptamers are small synthetic oligonucleotides that bind to target proteins with high specificity and affinity. AS1411 is an aptamer that binds to nucleolin, which is overexpressed in the cytoplasm and occurs on the surface of cancer cells. We investigated the therapeutic potential of aptamers in hepatocellular carcinoma (HCC) by evaluating anti-tumor effects and confirming the affinity and specificity of AS1411- and modified AS1411-aptamers in HCC cells. Cell growth was assessed using the MTS assay, and cell death signaling was explored by immunoblot analysis. Fluorescence-activated cell sorting was performed to evaluate the affinity and specificity of AS1411-aptamers in SNU-761 HCC cells. We investigated the in vivo effects of the AS1411-aptamer using BALB/c nude mice in a subcutaneous xenograft model with SNU-761 cells. Treatment with a modified AS1411 aptamer significantly decreased in vitro (under normoxic [P = 0.035] and hypoxic [P = 0.018] conditions) and in vivo (under normoxic conditions, P = 0.041) HCC cell proliferation compared to control aptamers. AS1411- and control aptamers failed to control HCC cell proliferation. However, AS1411- and the modified AS1411-aptamer did not induce caspase activation. Decrease in cell growth by AS1411 or modified AS1411 was not prevented by caspase or necrosis inhibitors. In a microarray, AS1411 significantly enhanced galectin-14 expression. Suppression of HCC cell proliferation by the modified AS1411-aptamer was attenuated by galectin-14 siRNA transfection. Modified AS1411-aptamer suppressed HCC cell growth in vitro and in vivo by up-regulating galectin-14 expressions. Modified AS1411-aptamers may have therapeutic potential as a novel targeted therapy for HCC. PMID- 27494118 TI - Estimating patient specific uncertainty parameters for adaptive treatment re planning in proton therapy using in vivo range measurements and Bayesian inference: application to setup and stopping power errors. AB - In proton therapy, quantification of the proton range uncertainty is important to achieve dose distribution compliance. The promising accuracy of prompt gamma imaging (PGI) suggests the development of a mathematical framework using the range measurements to convert population based estimates of uncertainties into patient specific estimates with the purpose of plan adaptation. We present here such framework using Bayesian inference. The sources of uncertainty were modeled by three parameters: setup bias m, random setup precision r and water equivalent path length bias u. The evolution of the expectation values E(m), E(r) and E(u) during the treatment was simulated. The expectation values converged towards the true simulation parameters after 5 and 10 fractions, for E(m) and E(u), respectively. E(r) settle on a constant value slightly lower than the true value after 10 fractions. In conclusion, the simulation showed that there is enough information in the frequency distribution of the range errors measured by PGI to estimate the expectation values and the confidence interval of the model parameters by Bayesian inference. The updated model parameters were used to compute patient specific lateral and local distal margins for adaptive re planning. PMID- 27494120 TI - The use of neutron scattering to determine the functional structure of glycoside hydrolase. AB - Neutron diffraction provides different information from X-ray diffraction, because neutrons are scattered by atomic nuclei, whereas X-rays are scattered by electrons. One of the key advantages of neutron crystallography is the ability to visualize hydrogen and deuterium atoms, making it possible to observe the protonation state of amino acid residues, hydrogen bonds, networks of water molecules and proton relay pathways in enzymes. But, because of technical difficulties, less than 100 enzyme structures have been evaluated by neutron crystallography to date. In this review, we discuss the advantages and disadvantages of neutron crystallography as a tool to investigate the functional structure of glycoside hydrolases, with some examples. PMID- 27494121 TI - Identification and screening of chemical constituents with hepatoprotective effects from three traditional Chinese medicines for treating jaundice. AB - The constituents with hepatoprotective activity were investigated in three traditional Chinese medicine formulae for treating jaundice, namely, Zhi-Zi-Da Huang-Tang, Yin-Chen-Hao-Tang, and Da-Huang-Xiao-Shi-Tang. By using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry and liquid chromatography coupled with ion trap mass spectrometry, 79 chemical constituents were identified unambiguously or tentatively in three formulae based on the accurate molecular weight, mass spectrometric fragmentation behavior, and comparison with reference standards. Then the hepatoprotective activities of 27 constituents were evaluated on tert-butylhydroperoxide-injured BRL-3A cells. The results indicated that 11 constituents, including protocatechic acid (19), epijasminoside A (56), rutin (71), tetrahydropalmatine (76), rhaponticin (80), 3,4-dicaffeoylquinic acid (82), 3,5-dicaffeoylquinic acid (85), diosmetin-7-O glucoside (90), jatrorrhizine (93), berberine (100), and daidzein (101) exerted hepatoprotective activities. Interestingly, most of the crude drugs in three formulae contained hepatoprotective active constituents, and the combinations of constituents from different crude drugs exhibited greater effects. This result provided evidence to the traditional Chinese medicine theory of combining several drugs together to exert synergistic efficacy. PMID- 27494122 TI - Nonempirical Double-Hybrid Functionals: An Effective Tool for Chemists. AB - Density functional theory (DFT) emerged in the last two decades as the most reliable tool for the description and prediction of properties of molecular systems and extended materials, coupling in an unprecedented way high accuracy and reasonable computational cost. This success rests also on the development of more and more performing density functional approximations (DFAs). Indeed, the Achilles' heel of DFT is represented by the exchange-correlation contribution to the total energy, which, being unknown, must be approximated. Since the beginning of the 1990s, global hybrids (GH) functionals, where an explicit dependence of the exchange-correlation energy on occupied Kohn-Sham orbitals is introduced thanks to a fraction of Hartree-Fock-like exchange, imposed themselves as the most reliable DFAs for chemical applications. However, if these functionals normally provide results of sufficient accuracy for most of the cases analyzed, some properties, such as thermochemistry or dispersive interactions, can still be significantly improved. A possible way out is represented by the inclusion, into the exchange-correlation functional, of an explicit dependence on virtual Kohn Sham orbitals via perturbation theory. This leads to a new class of functionals, called double-hybrids (DHs). In this Account, we describe our nonempirical approach to DHs, which, following the line traced by the Perdew-Burke-Ernzerhof approach, allows for the definition of a GH (PBE0) and a DH (QIDH) model. In such a way, a whole family of nonempirical functionals, spanning on the highest rungs of the Perdew's quality scale, is now available and competitive with other-more empirical-DFAs. Discussion of selected cases, ranging from thermochemistry and reactions to weak interactions and excitation energies, not only show the large range of applicability of nonempirical DFAs, but also underline how increasing the number of theoretical constraints parallels with an improvement of the DFA's numerical performances. This fact further consolidates the strong theoretical framework of nonempirical DFAs. Finally, even if nonempirical DH approaches are still computationally expensive, relying on the fact that they can benefit of all technical enhancements developed for speeding up post-Hartree-Fock methods, there is substantial hope for their near future routine application to the description and prediction of complex chemical systems and reactions. PMID- 27494119 TI - A Comprehensive Evaluation of Steroid Metabolism in Women with Intrahepatic Cholestasis of Pregnancy. AB - Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder, mostly occurring in the third trimester. ICP is defined as an elevation of serum bile acids, typically accompanied by pruritus and elevated activities of liver aminotransferases. ICP is caused by impaired biliary lipid secretion, in which endogenous steroids may play a key role. Although ICP is benign for the pregnant woman, it may be harmful for the fetus. We evaluated the differences between maternal circulating steroids measured by RIA (17-hydroxypregnenolone and its sulfate, 17-hydroxyprogesterone, and cortisol) and GC-MS (additional steroids), hepatic aminotransferases and bilirubin in women with ICP (n = 15, total bile acids (TBA) >8 MUM) and corresponding controls (n = 17). An age-adjusted linear model, receiver-operating characteristics (ROC), and multivariate regression (a method of orthogonal projections to latent structure, OPLS) were used for data evaluation. While aminotransferases, conjugates of pregnanediols, 17 hydroxypregnenolone and 5beta-androstane-3alpha,17beta-diol were higher in ICP patients, 20alpha-dihydropregnenolone, 16alpha-hydroxy-steroids, sulfated 17-oxo C19-steroids, and 5beta-reduced steroids were lower. The OPLS model including steroids measured by GC-MS and RIA showed 93.3% sensitivity and 100% specificity, while the model including steroids measured by GC-MS in a single sample aliquot showed 93.3% sensitivity and 94.1% specificity. A composite index including ratios of sulfated 3alpha/beta-hydroxy-5alpha/beta-androstane-17-ones to conjugated 5alpha/beta-pregnane-3alpha/beta, 20alpha-diols discriminated with 93.3% specificity and 81.3% sensitivity (ROC analysis). These new data demonstrating altered steroidogenesis in ICP patients offer more detailed pathophysiological insights into the role of steroids in the development of ICP. PMID- 27494123 TI - Un/Paid Labor: Medicaid Home and Community Based Services Waivers That Pay Family as Personal Care Providers. AB - The United States long-term services and supports system is built on largely unpaid (informal) labor. There are a number of benefits to allowing family caregivers to serve as paid personal care providers including better health and satisfaction outcomes, expanded workforces, and cost effectiveness. The purpose of this study was to examine how Medicaid HCBS Section 1915(c) waivers for people with intellectual and developmental disabilities allocate personal care services to pay family caregivers. Our analysis revealed about two thirds of waivers in fiscal year (FY) 2014 allowed for family caregivers to potentially be paid for personal care services. This amounted to up to $2.71 billion of projected spending, which is slightly more than half of all personal care service expenditures in FY 2014. PMID- 27494124 TI - Exploring the Self-Disclosure Process in Peer Mentoring Relationships for Transition-Age Youth With Developmental Disabilities. AB - The purpose of this study was to examine the role of the self-disclosure process in regard to connection development and relationship quality in peer mentoring relationships between transition-age youth (ages 15-20) and young adults (ages 18 36) with intellectual and/or developmental disabilities. Self-disclosure is defined as "the disclosure of inner feelings and experiences to another person" that "fosters liking, caring, and trust, thereby facilitating the deepening of close relationships" ( Reis & Shaver, 1988 , p. 372). Nine peer mentoring dyads with varied interpersonal connections were purposefully selected from a larger intervention study. Recorded mentoring conversations were analyzed for self disclosure content and peer mentor response. The findings demonstrated trends related to connection development and differences across degree of connection. In relationships with stronger connections, there was a higher quantity of self disclosure and more frequent disclosure of emotions, and peer mentors responded more frequently with advice and reciprocated self-disclosure. Implications of findings for promoting higher-quality peer mentoring relationships are discussed. PMID- 27494126 TI - Smith-Magenis Syndrome and Social Security Administration's Compassionate Allowances Initiative: An Evaluative Review of the Literature. AB - The Social Security Administration (SSA) launched the Compassionate Allowances List (CAL) in 2008. This created a mechanism for expediting review and delivery of disability benefits, while decreasing application backlog. This study hypothesized that developmental disorders, such as Smith-Magenis syndrome, may meet criterion for inclusion. An evaluative review of the literature was undertaken to determine if the expedited review criterion was met. Ten databases were searched and articles meeting pre-defined criteria were coded according to the SSA definition of disability to determine if severity indices screen in or screen out certain severity levels or exclude Smith-Magenis syndrome entirely in relation to the CAL program. It was strongly recommended that Smith-Magenis syndrome receive consideration for inclusion in the CAL. PMID- 27494125 TI - Parent Involvement in Meaningful Post-School Experiences for Young Adults With IDD and Pervasive Support Needs. AB - Despite initiatives supporting young adults with intellectual and developmental disabilities (IDD) to engage in post-secondary education and integrated employment, those with more intensive support needs are not as easily involved in these post-school experiences. In an effort to learn from positive examples, we examined parent involvement in meaningful post-school experiences by eight young adults with IDD and pervasive support needs. Secondary analysis of data from a prior interview study yielded this smaller sample of eight young adults with meaningful post-school experiences. Their parents were actively involved as fierce advocates and creative problem solvers. The active involvement of parents included: a) attitudinal facilitators, b) advocacy efforts and perceptions, and c) strategic actions. Implications for future research and practice are described. PMID- 27494127 TI - "My Voice Counts, Too": Voting Participation Among Individuals With Intellectual Disability. AB - Despite a strong societal commitment to ensuring that individuals with intellectual disability (ID) fully participate in their communities, few people with ID vote. Little is known about voting experiences from the perspective of people with ID. In-person, semistructured interviews were conducted with 28 adults with ID (Mage = 37 years) to obtain their input on voting. Constant comparison and content analysis methods were used to characterize themes. Results indicated that people with ID are interested in voting and desire to be included in the voting process yet receive little education on political issues or on how to make voting-related decisions. Support from family or service providers and self-advocacy facilitated their ability to vote. Implications of these findings and recommendations for future research are discussed. PMID- 27494130 TI - Detection of Zika virus in Brazilian patients during the first five days of infection - urine versus plasma. AB - Advantages of testing for Zika virus (ZIKV) in urine have been reported, such as the persistence of ZIKV in this type of specimen for up to 20 days after ZIKV disease onset. We investigate 61 patients in the first 5 days post-symptom onset and find more patients testing positive for ZIKV in plasma samples (n=46), than in corresponding urine samples (n=37). For patients respectively testing positive in both plasma and urine (n=28), respective viral loads appeared similar. PMID- 27494131 TI - Fluoride-Assisted Synthesis of 1,4,5,6-Tetrahydropyridazines via [4 + 2] Cyclodimerization of in Situ-Generated Azoalkenes Followed by a C-N Bond Cleavage. AB - An unexpected CsF-assisted C-N bond cleavage was exploited to synthesize highly functionalized and biologically important 1,4,5,6-tetrahydropyridazine derivatives from alpha-halo N-acylhydrazones in excellent yields. The extrusion of nitrogen and the [4 + 2] cycloaddition between in situ-generated azoalkenes is a key reaction in the process. The identified methodology is suitable for synthesizing a wide variety of analogues of tetrahydropyridazines, which are prevalent in many medicinally important small molecules. The reaction conditions are mild, high-yielding, and amenable for the gram scale. PMID- 27494132 TI - Estimating initial contaminant mass based on fitting mass-depletion functions to contaminant mass discharge data: Testing method efficacy with SVE operations data. AB - The mass of contaminant present at a site, particularly in the source zones, is one of the key parameters for assessing the risk posed by contaminated sites, and for setting and evaluating remediation goals and objectives. This quantity is rarely known and is challenging to estimate accurately. This work investigated the efficacy of fitting mass-depletion functions to temporal contaminant mass discharge (CMD) data as a means of estimating initial mass. Two common mass depletion functions, exponential and power functions, were applied to historic soil vapor extraction (SVE) CMD data collected from 11 contaminated sites for which the SVE operations are considered to be at or close to essentially complete mass removal. The functions were applied to the entire available data set for each site, as well as to the early-time data (the initial 1/3 of the data available). Additionally, a complete differential-time analysis was conducted. The latter two analyses were conducted to investigate the impact of limited data on method performance, given that the primary mode of application would be to use the method during the early stages of a remediation effort. The estimated initial masses were compared to the total masses removed for the SVE operations. The mass estimates obtained from application to the full data sets were reasonably similar to the measured masses removed for both functions (13 and 15% mean error). The use of the early-time data resulted in a minimally higher variation for the exponential function (17%) but a much higher error (51%) for the power function. These results suggest that the method can produce reasonable estimates of initial mass useful for planning and assessing remediation efforts. PMID- 27494133 TI - Identification of Cell Type-Specific Differences in Erythropoietin Receptor Signaling in Primary Erythroid and Lung Cancer Cells. AB - Lung cancer, with its most prevalent form non-small-cell lung carcinoma (NSCLC), is one of the leading causes of cancer-related deaths worldwide, and is commonly treated with chemotherapeutic drugs such as cisplatin. Lung cancer patients frequently suffer from chemotherapy-induced anemia, which can be treated with erythropoietin (EPO). However, studies have indicated that EPO not only promotes erythropoiesis in hematopoietic cells, but may also enhance survival of NSCLC cells. Here, we verified that the NSCLC cell line H838 expresses functional erythropoietin receptors (EPOR) and that treatment with EPO reduces cisplatin induced apoptosis. To pinpoint differences in EPO-induced survival signaling in erythroid progenitor cells (CFU-E, colony forming unit-erythroid) and H838 cells, we combined mathematical modeling with a method for feature selection, the L1 regularization. Utilizing an example model and simulated data, we demonstrated that this approach enables the accurate identification and quantification of cell type-specific parameters. We applied our strategy to quantitative time-resolved data of EPO-induced JAK/STAT signaling generated by quantitative immunoblotting, mass spectrometry and quantitative real-time PCR (qRT-PCR) in CFU-E and H838 cells as well as H838 cells overexpressing human EPOR (H838-HA-hEPOR). The established parsimonious mathematical model was able to simultaneously describe the data sets of CFU-E, H838 and H838-HA-hEPOR cells. Seven cell type-specific parameters were identified that included for example parameters for nuclear translocation of STAT5 and target gene induction. Cell type-specific differences in target gene induction were experimentally validated by qRT-PCR experiments. The systematic identification of pathway differences and sensitivities of EPOR signaling in CFU-E and H838 cells revealed potential targets for intervention to selectively inhibit EPO-induced signaling in the tumor cells but leave the responses in erythroid progenitor cells unaffected. Thus, the proposed modeling strategy can be employed as a general procedure to identify cell type-specific parameters and to recommend treatment strategies for the selective targeting of specific cell types. PMID- 27494134 TI - ESBL Detection: Comparison of a Commercially Available Chromogenic Test for Third Generation Cephalosporine Resistance and Automated Susceptibility Testing in Enterobactericeae. AB - Rapid detection and reporting of third generation cephalosporine resistance (3GC R) and of extended spectrum betalactamases in Enterobacteriaceae (ESBL-E) is a diagnostic and therapeutic priority to avoid inefficacy of the initial antibiotic regimen. In this study we evaluated a commercially available chromogenic screen for 3GC-R as a predictive and/or confirmatory test for ESBL and AmpC activity in clinical and veterinary Enterobacteriaceae isolates. The test was highly reliable in the prediction of cefotaxime and cefpodoxime resistance, but there was no correlation with ceftazidime and piperacillin/tazobactam minimal inhibitory concentrations. All human and porcine ESBL-E tested were detected with exception of one genetically positive but phenotypically negative isolate. By contrast, AmpC detection rates lay below 30%. Notably, exclusion of piperacillin/tazobactam resistant, 3GC susceptible K1+ Klebsiella isolates increased the sensitivity and specificity of the test for ESBL detection. Our data further imply that in regions with low prevalence of AmpC and K1 positive E. coli strains chromogenic testing for 3GC-R can substitute for more time consuming ESBL confirmative testing in E. coli isolates tested positive by Phoenix or VITEK2 ESBL screen. We, therefore, suggest a diagnostic algorithm that distinguishes 3GC-R screening from primary culture and species-dependent confirmatory ESBL testing by betaLACTATM and discuss the implications of MIC distribution results on the choice of antibiotic regimen. PMID- 27494135 TI - Truncated Bovine Integrin Alpha-v/Beta-6 as a Universal Capture Ligand for FMD Diagnosis. AB - Foot-and-mouth disease (FMD) is endemic in many regions of the world and is one of the most prevalent epizootic animal diseases. FMD affects livestock, such as cattle, sheep, goats and pigs, and causes enormous economic losses due to reduced productivity and trade restrictions. Preparedness and early diagnosis are essential for effective control of FMD. Many diagnostic assays are dependent on raising high-affinity, anti-FMD virus (FMDV) serotype-specific antibodies in small animals (rabbits and guinea pigs) that give broad virus coverage. Here we show that soluble, truncated forms of bovine alphavbeta6 bind FMDV in an authentic RGD and divalent cation dependent interaction and can be used as the trapping reagent in a FMDV sandwich ELISA. In addition, inclusion of FLAG or His tags facilitates simple purification without the loss of virus binding. We also provide evidence that when combined with a guinea pig polyclonal serum, or serotype-specific monoclonal antibodies, the integrin can be used to detect viruses representative of all FMDV serotypes. We also show that recombinant FMDV empty capsids, with stabilising disulphide bonds, can serve as an antigen in the ELISA and can therefore replace inactivated virus antigen as a positive control for the assay. Our results demonstrate the potential use of bovine alphavbeta6 and FMDV empty capsids in FMD diagnostic assays. PMID- 27494136 TI - Assessing Interventions to Manage West Nile Virus Using Multi-Criteria Decision Analysis with Risk Scenarios. AB - The recent emergence of West Nile virus (WNV) in North America highlights vulnerability to climate sensitive diseases and stresses the importance of preventive efforts to reduce their public health impact. Effective prevention involves reducing environmental risk of exposure and increasing adoption of preventive behaviours, both of which depend on knowledge and acceptance of such measures. When making operational decisions about disease prevention and control, public health must take into account a wide range of operational, environmental, social and economic considerations in addition to intervention effectiveness. The current study aimed to identify, assess and rank possible risk reduction measures taking into account a broad set of criteria and perspectives applicable to the management of WNV in Quebec under increasing transmission risk scenarios, some of which may be related to ongoing warming in higher-latitude regions. A participatory approach was used to collect information on categories of concern to relevant stakeholders with respect to WNV prevention and control. Multi criteria decision analysis was applied to examine stakeholder perspectives and their effect on strategy rankings under increasing transmission risk scenarios. Twenty-three preventive interventions were retained for evaluation using eighteen criteria identified by stakeholders. Combined evaluations revealed that, at an individual-level, inspecting window screen integrity, wearing light colored, long clothing, eliminating peridomestic larval sites and reducing outdoor activities at peak times were top interventions under six WNV transmission scenarios. At a regional-level, the use of larvicides was a preferred strategy in five out of six scenarios, while use of adulticides and dissemination of sterile male mosquitoes were found to be among the least favoured interventions in almost all scenarios. Our findings suggest that continued public health efforts aimed at reinforcing individual-level preventive behaviours combined with the application of larvicides to manage the risk of WNV infection are the interventions most acceptable and effective at reaching current management objectives now and under future theoretical transmission risk. PMID- 27494137 TI - Enantioselective Model Synthesis and Progress toward the Putative Structure of Yuremamine. AB - An enantioselective model synthesis of the 2,3-dihydro-1H-pyrrolo[1,2-a]indole core of the putative structure of yuremamine is reported in 39% overall yield and 96% ee over five steps. The model synthesis leverages enantioselective, rhodium catalyzed hydroacylation of an N-vinylindole-2-carboxaldehyde as the key step in the installation of the stereochemical triad. An enantioselective synthesis of a densely functionalized dihydropyrroloindolone that maps onto the putative structure of yuremamine is demonstrated in 26% yield and 97% ee over eight steps. PMID- 27494138 TI - Extended Thermodynamic Integration: Efficient Prediction of Lambda Derivatives at Nonsimulated Points. AB - Thermodynamic integration (TI) is one of the most commonly used free-energy calculation methods. The derivative of the Hamiltonian with respect to lambda, ??H/?lambda?, is determined at multiple lambda-points. Because a numerical integration step is necessary, high curvature regions require simulations at densely spaced lambda-points. Here, the principle of extended TI is introduced, where ??H/?lambda? values are predicted at nonsimulated lambda-points. On the basis of three model systems, it is shown that extended TI requires significantly fewer lambda-points than regular TI to obtain similar accuracy. PMID- 27494139 TI - Etiology of Pain and Its Association with Quality of Life among Patients with Heart Failure. AB - OBJECTIVE: Describe the etiology of pain among HF patients and examine the relationship between pain and QoL. BACKGROUND: Little is known about the etiology of pain in patients with heart failure (HF) and the impact it has on quality of life (QoL). METHODS: A prospective cohort study of outpatients with NYHA Class II or III HF were surveyed at baseline and at three-month follow-up. The study was conducted in Heart Failure clinics affiliated with a large, urban, academic medical center. RESULTS: Of 104 patients that completed a baseline survey, 73 (70%) completed a follow-up survey. At baseline, 48% of patients reported having pain the previous week. Patients on prescription pain medication (n = 16) had more severe pain (Mean = 4.5 vs. 2.6; p = 0.001). Physician documented pain etiologies included: musculoskeletal (50%, n = 16), cardiac (22%, n = 7), and headache/neurological (22%, n = 7). Linear regression revealed that significant contributions to QoL included HF Class (p = 0.0001), dyspnea (p = 0.0001), and depression (p = 0.01). Pain was not independently associated with QoL (p = 0.17), but moderately correlated with depression (r = 0.49). Although 15% (n = 11) of patients reported a clinically meaningful improvement in pain scores, it was not associated with improvements in QoL (chi2 = 1.6, p = 0.2). DISCUSSION: Pain is prevalent and persistent, due largely to non-cardiac causes. Although pain did not predict QOL, it was associated with depression, which did adversely affect QoL. Clinicians should screen for and treat both symptoms. PMID- 27494140 TI - Platelet Apoptosis in Adult Immune Thrombocytopenia: Insights into the Mechanism of Damage Triggered by Auto-Antibodies. AB - Mechanisms leading to decreased platelet count in immune thrombocytopenia (ITP) are heterogeneous. This study describes increased platelet apoptosis involving loss of mitochondrial membrane potential (DeltaPsim), caspase 3 activation (aCasp3) and phosphatidylserine (PS) externalization in a cohort of adult ITP patients. Apoptosis was not related to platelet activation, as PAC-1 binding, P selectin exposure and GPIb-IX internalization were not increased. Besides, ITP platelets were more sensitive to apoptotic stimulus in terms of aCasp3. Incubation of normal platelets with ITP plasma induced loss of DeltaPsim, while PS exposure and aCasp3 remained unaltered. The increase in PS exposure observed in ITP platelets could be reproduced in normal platelets incubated with ITP plasma by adding normal CD3+ lymphocytes to the system as effector cells. Addition of leupeptin -a cathepsin B inhibitor- to this system protected platelets from apoptosis. Increased PS exposure was also observed when normal platelets and CD3+ lymphocytes were incubated with purified IgG from ITP patients and was absent when ITP plasma was depleted of auto-antibodies, pointing to the latter as responsible for platelet damage. Apoptosis was present in platelets from all patients carrying anti-GPIIb-IIIa and anti-GPIb auto-antibodies but was absent in the patient with anti-GPIa-IIa auto-antibodies. Platelet damage inversely correlated with platelet count and decreased during treatment with a thrombopoietin receptor agonist. These results point to a key role for auto antibodies in platelet apoptosis and suggest that antibody-dependent cell cytotoxicity is the mechanism underlying this phenomenon. PMID- 27494141 TI - Osteopontin Fragments with Intact Thrombin-Sensitive Site Circulate in Cervical Cancer Patients. AB - We investigated whether circulating osteopontin (OPN) could be used as a biomarker for cervical cancer. We employed a monoclonal antibody (mAb 659) specific for the unique and intact thrombin-sensitive site in OPN using an inhibition ELISA. We found significantly higher levels of OPN in 33 cervical cancer patients in both the plasma (mean +/- SD, 612 +/- 106 ng/mL) and serum (424 +/- 121 ng/mL) compared to healthy subjects [409 +/- 56 ng/mL, from 31 plasma samples (P < 0.0001), and 314 +/- 98 ng/mL, from 32 serum samples (P = 0.0002), respectively]. Similar results were obtained when the plasma from a bigger group (147 individuals) of cervical cancer patients (560 +/- 211 ng/mL) were compared with the same plasma samples of the healthy individuals (P = 0.0014). More significantly, the OPN level was highest in stage III-IV disease (614 +/- 210 ng/mL, from 52 individuals; P = 0.0001) and least and non discriminatory in stage I (473 +/- 110 ng/mL, from 40 individuals; P = 0.5318). No such discrimination was found when a mAb of a different specificity (mAb 446) was used in a similar inhibition ELISA to compare the two groups in the first study; a commercial capture ELISA also failed. The possibility that the target epitope recognized by the antibody probe in these assays was absent from the circulating OPN due to protein truncation was supported by gel fractionation of the OPN found in patients' plasma: 60-64 kDa fragments were found instead of the presumably full-length OPN (68 kDa) seen in healthy people. How these fragments are generated and what possible role they play in cancer biology remain interesting questions. PMID- 27494143 TI - Correction: 3'UTR Shortening Potentiates MicroRNA-Based Repression of Pro differentiation Genes in Proliferating Human Cells. AB - [This corrects the article DOI: 10.1371/journal.pgen.1005879.]. PMID- 27494142 TI - The Neural Responses to Social Cooperation in Gain and Loss Context. AB - Cooperation is pervasive and constitutes the core behavioral principle of human social life. Previous studies have revealed that mutual cooperation was reliably correlated with two reward-related brain regions, the ventral striatum and the orbitofrontal cortex. Using functional magnetic resonance imaging (fMRI), this study sought to investigate how the loss and gain contexts modulated the neural responses to mutual cooperation. Twenty-five female participants were scanned when they played a series of one-shot prisoner's dilemma games in the loss and gain contexts. Specifically, participants and partners independently chose to either cooperate with each other or not, and each was awarded or deprived of (in the gain context or the loss context, respectively) a sum of money which depended upon the interaction of their choices. Behavioral results indicated that participants cooperated in nearly half of the experiment trials and reported higher level of positive emotions for mutual cooperation in both contexts, but they cooperated more in the gain than in the loss context. At the neural level, stronger activities in the orbitofrontal cortex were observed for mutual cooperation compared with the other three outcomes in both contexts, while stronger activation in ventral striatum associated with mutual cooperation was observed in the gain context only. Together, our data indicated that, even in the one-shot interaction under loss context, participants still exhibited preference for cooperation and the rewarding experience from a mutually cooperative social interaction activated the ventral striatum and the orbitofrontal cortex, but the loss context weakened the association between the ventral striatum activation and mutual cooperation. PMID- 27494145 TI - Evidence for the contribution of a threshold retrieval process to semantic memory. AB - It is widely held that episodic retrieval can recruit two processes: a threshold context retrieval process (recollection) and a continuous signal strength process (familiarity). Conversely the processes recruited during semantic retrieval are less well specified. We developed a semantic task analogous to single-item episodic recognition to interrogate semantic recognition receiver-operating characteristics (ROCs) for a marker of a threshold retrieval process. We fitted observed ROC points to three signal detection models: two models typically used in episodic recognition (unequal variance and dual-process signal detection models) and a novel dual-process recollect-to-reject (DP-RR) signal detection model that allows a threshold recollection process to aid both target identification and lure rejection. Given the nature of most semantic questions, we anticipated the DP-RR model would best fit the semantic task data. Experiment 1 (506 participants) provided evidence for a threshold retrieval process in semantic memory, with overall best fits to the DP-RR model. Experiment 2 (316 participants) found within-subjects estimates of episodic and semantic threshold retrieval to be uncorrelated. Our findings add weight to the proposal that semantic and episodic memory are served by similar dual-process retrieval systems, though the relationship between the two threshold processes needs to be more fully elucidated. PMID- 27494146 TI - Benefits of subthalamic stimulation for elderly parkinsonian patients aged 70 years or older. AB - OBJECTIVES: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an accepted treatment for advanced Parkinson disease (PD). However, there is general reluctance in considering this therapy for PD patients over age 70 years with limited supporting evidence. Present study investigates age impacts in STN-DBS outcomes, focusing particularly on the elderly patients. PATIENTS AND METHODS: Seventy-two consecutive patients were divided into younger and elderly (n=16, cutoff age=70years) groups. Both groups were comparable in preoperative clinical severity, except the elderly exhibited a levodopa (LD) response (P<0.05) inferior to that of the younger. Improvements in drug-off/DBS-on Unified PD Rating Scale (UPDRS) scores and reduction in daily LD-equivalent dose (LED) after 6 months were evaluated relative to the presurgical drug-off baseline. Preoperative factors predictive of favorable surgical outcomes were analyzed using a multivariate linear regression model. RESULTS: After DBS therapy, elderly patients exhibited clinical improvements particularly in the tremor (56%) and LD induced dyskinesia (78%). Improvement of axial dysfunction (24%) and reduction of daily LED (24%) showed no intergroup difference. Adverse events, particularly dysarthria, occurred frequently in elderly group. The overall improvements in UPDRS scores were suboptimal in elderly group, correlating with their preoperative inferior LD responses. Elderly patients who presented predominantly with akinesia before surgery achieved superior surgical outcomes (adjusted R(2)=0.657, P<0.001). CONCLUSION: STN-DBS therapy is beneficial to some elderly PD patients aged 70 years or older. Tremor, axial dysfunctions and drug-induced dyskinesia are the main indications for the elderly; however, their clinical benefits are inferior to those of younger patients. PMID- 27494144 TI - Dysbiosis of the Fecal Microbiota in Cattle Infected with Mycobacterium avium subsp. paratuberculosis. AB - Johne's disease (JD) is a chronic, intestinal infection of cattle, caused by Mycobacterium avium subsp. paratuberculosis (MAP). It results in granulomatous inflammation of the intestinal lining, leading to malabsorption, diarrhea, and weight loss. Crohn's disease (CD), a chronic, inflammatory gastrointestinal disease of humans, has many clinical and pathologic similarities to JD. Dysbiosis of the enteric microbiota has been demonstrated in CD patients. It is speculated that this dysbiosis may contribute to the intestinal inflammation observed in those patients. The purpose of this study was to investigate the diversity patterns of fecal bacterial populations in cattle infected with MAP, compared to those of uninfected control cattle, using phylogenomic analysis. Fecal samples were selected to include samples from 20 MAP-positive cows; 25 MAP-negative herdmates; and 25 MAP-negative cows from a MAP-free herd. The genomic DNA was extracted; PCR amplified sequenced on a 454 Roche platform, and analyzed using QIIME. Approximately 199,077 reads were analyzed from 70 bacterial communities (average of 2,843 reads/sample). The composition of bacterial communities differed between the 3 treatment groups (P < 0.001; Permanova test). Taxonomic assignment of the operational taxonomic units (OTUs) identified 17 bacterial phyla across all samples. Bacteroidetes and Firmicutes constituted more than 95% of the bacterial population in the negative and exposed groups. In the positive group, lineages of Actinobacteria and Proteobacteria increased and those of Bacteroidetes and Firmicutes decreased (P < 0.001). Actinobacteria was highly abundant (30% of the total bacteria) in the positive group compared to exposed and negative groups (0.1-0.2%). Notably, the genus Arthrobacter was found to predominate Actinobacteria in the positive group. This study indicates that MAP infected cattle have a different composition of their fecal microbiota than MAP negative cattle. PMID- 27494147 TI - Reply to Arguelles. PMID- 27494148 TI - DICERing macrophages for reprogramming TAMs. PMID- 27494150 TI - Interview with Professor Mark Wilcox. AB - Mark Wilcox speaks to Georgia Patey, Commissioning Editor: Professor Mark Wilcox is a Consultant Microbiologist and Head of Microbiology at the Leeds Teaching Hospitals (Leeds, UK), the Professor of Medical Microbiology at the University of Leeds (Leeds, UK), and is the Lead on Clostridium difficile and the Head of the UK C. difficile Reference Laboratory for Public Health England (PHE). He was the Director of Infection Prevention (4 years), Infection Control Doctor (8 years) and Clinical Director of Pathology (6 years) at the Leeds Teaching Hospitals. He is Chair of PHE's Rapid Review Panel (reviews utility of infection prevention and control products for National Health Service), Deputy Chair of the UK Department of Health's Antimicrobial Resistance and Healthcare Associated Infection Committee and a member of PHE's HCAI/AR Programme Board. He is a member of UK/European/US working groups on C. difficile infection. He has provided clinical advice as part of the FDA/EMA submissions for the approval of multiple novel antimicrobial agents. He heads a healthcare-associated infection research team at University of Leeds, comprising approximately 30 doctors, scientists and nurses; projects include multiple aspects of C. difficile infection, diagnostics, antimicrobial resistance and the clinical development of new antimicrobial agents. He has authored more than 400 publications, and is the coeditor of Antimicrobial Chemotherapy (5th/6th/7th Editions, 15 December 2007). PMID- 27494149 TI - Respiratory Muscle Strength as a Predictive Biomarker for Survival in Amyotrophic Lateral Sclerosis. AB - RATIONALE: Biomarkers for survival in amyotrophic lateral sclerosis (ALS) would facilitate the development of novel drugs. Although respiratory muscle weakness is a known predictor of poor prognosis, a comprehensive comparison of different tests is lacking. OBJECTIVES: To compare the predictive power of invasive and noninvasive respiratory muscle strength assessments for survival or ventilator free survival, up to 3 years. METHODS: From a previously published report respiratory muscle strength measurements were available for 78 patients with ALS. Time to death and/or ventilation were ascertained. Receiver operating characteristic analysis was used to determine the cutoff point of each parameter. MEASUREMENTS AND MAIN RESULTS: Each respiratory muscle strength assessment individually achieved statistical significance for prediction of survival or ventilator-free survival. In multivariate analysis sniff trans-diaphragmatic and esophageal pressure, twitch trans-diaphragmatic pressure (Tw Pdi), age, and maximal static expiratory mouth pressure were significant predictors of ventilation-free survival and Tw Pdi and maximal static expiratory mouth pressure for absolute survival. Although all measures had good specificity, there were differing sensitivities. All cutoff points for the VC were greater than 80% of normal, except for prediction of 3-month outcomes. Sequential data showed a linear decline for direct measures of respiratory muscle strength, whereas VC showed little to no decline until 12 months before death/ventilation. CONCLUSIONS: The most powerful biomarker for mortality stratification was Tw Pdi, but the predictive power of sniff nasal inspiratory pressure was also excellent. A VC within normal range suggested a good prognosis at 3 months but was of little other value. PMID- 27494152 TI - Household Food Insecurity Is Associated with Nutritional Status among Iranian Children. AB - This cross-sectional study was conducted to determine household food security status and sociodemographic factors influencing it and to examine whether food insecurity of household is a risk factor for underweight, stunting, and thinness in primary school children of Sistan and Baluchestan Province in southeastern Iran. A sample of 610 students aged 7-11 years was selected by a multistage cluster random sampling method during December 2013-May 2014. Using U.S. Department of Agriculture Food Security questionnaire, 42.3% of households showed some degree of food insecurity. Food insecurity was positively associated with household size (p = .002) and number of children per household (p = .001) and negatively associated with mother's and father's education level (p = .005 and p = .042, respectively), father's occupation status, and household income (p < .0001). Children living in food insecure with severe hunger households were 10.13, 10.07, and 4.54 times as likely to be underweight, stunted, and thin, respectively, as counterparts from food secure households. The findings showed food insecurity was prevalent and associated with sociodemographic factors among households with schoolchildren in southeastern Iran. Nutritional status of children was also associated with food security status of their households. PMID- 27494151 TI - Amyotrophic lateral sclerosis with long lasting disease course and SOD1 and TARDBP mutations: Report of two cases and overview of the literature. PMID- 27494153 TI - Tagging the Untaggable: A Difluoroalkyl-Sulfinate Ketone-Based Reagent for Direct C-H Functionalization of Bioactive Heteroarenes. AB - We have developed a new difluoroalkyl ketal sulfinate salt reagent suitable for direct derivatization of heteroarene C-H bonds. The reagent is capable of introducing a ketone functional group on heteroarene bioactive compounds via a one-pot reaction. Remarkably, in three examples the ketone analog and its parent drug had almost identical cytotoxicity. In a representative example, the ketone analog was bioconjugated with a delivery vehicle via an acid-labile semicarbazone linkage and with a photolabile protecting group to produce the corresponding prodrug. Controlled release of the drug-ketone analog was demonstrated in vitro for both systems. This study provides a general approach to obtain taggable ketone analogs directly from bioactive heteroarene compounds with limited options for conjugation. We anticipate that this sodium ketal-sulfinate reagent will be useful for derivatization of other heteroarene-based drugs to obtain ketone taggable analogs with retained efficacy. PMID- 27494155 TI - Comparative study on the in vitro performance of blister molded and conventional lornoxicam immediate release liquitablets: accelerated stability study and anti inflammatory and ulcerogenic effects. AB - CONTEXT: Lornoxicam is a potent non-steroidal anti-inflammatory drug (NSAID). It shows limited solubility in the gastric pH, delayed bioavailability and pharmacodynamic effects with aggravated gastric side effects (due to longer residence in the stomach wall). OBJECTIVE: To enhance dissolution of lornoxicam in the gastric fluid and expectedly absorption and pharmacological action, with less ulcerogenic effects. MATERIALS AND METHODS: Formulation of immediate release (IR) lornoxicam liquitablets containing both liquid and solid release modulators (wetting agent, solubilizers and microenvironmental pH modifiers). Beside the traditional direct compression technique employed for the preparation of liquitablets a new technique, blister molding, was also used. The effect of the two different manufacturing methods on the fast release characteristics (rapid disintegration and dissolution) was studied. Stability and pharmacological activity of the optimum formula were also explored. RESULTS: Similarity factor pointed out the superiority of molding technique in enhancing dissolution of lornoxicam owing to significant crystallinity reduction (XRD). Optimum formula showed negligible change in drug content and dissolution profiles over 12 weeks, significantly improved anti-inflammatory activity and significantly reduced gastric ulcerative effect over pure lornoxicam and commercial formula. DISCUSSION AND CONCLUSION: Blister molded lornoxicam liquitablet of improved dissolution and pharmacological activity and less gastric erosion was successfully prepared. PMID- 27494156 TI - Clinical features and management of erythromelalgia: long term follow-up of 46 cases. AB - OBJECTIVES: To review our clinical experience of this rare condition and describe the clinical features and response to therapy in a cohort of patients with erythromelalgia (EM), a rare condition, characterised by paroxysmal hyperthermia of the extremities with erythema, pain and intense burning. METHODS: A review was made of the electronic and paper medical records of patients with the diagnosis of EM, with a telephone interview to verify and complete clinical information relating treatment and outcome. RESULTS: 46 patients (41 females) were included in this study. Mean age was 57 years and mean duration of symptoms was 16 years. Raynaud's phenomenon was present in 36 patients (80%) and 4 patients (9%) had systemic sclerosis. Smoking (current or previous) was identified as a possible risk factor in 26 cases and exposure to chronic vibration in 3 cases. Overall, the effect on quality of life was mild in 15% of cases, moderate in 30% and severe in 48%. The most common symptoms were burning (96%), heat (93%), pain (87%), and redness (83%). Symptoms affected the lower limbs in 98% of cases, upper limbs in 76%, face in 20% and trunk in 11%. Triggers included heat (85%), exercise (78%) and time of day (76%). Various medications were tried, showing poor effect in most cases. Intravenous iloprost was given to 27 patients, with benefit in 17 patients (63%). CONCLUSIONS: Erythromelalgia is a rare chronic debilitating condition. Exercise, heat and night time are common triggers. Current medical therapies are seldom effective and further research is sorely needed. PMID- 27494157 TI - Advances and Potential Applications of Chitosan Nanoparticles as a Delivery Carrier for the Mucosal Immunity of Vaccine. AB - BACKGROUND: Drug research and development has entered into the new epoch of innovation formulation, and the drug delivery system has been in the forefront of pharmaceutical innovation. Chitosan, a natural polysaccharide derived from chitin, due to its well-known biocompatibility and biodegradability, it has been widely used in drug delivery, immunostimulation, tissue regeneration, blood coagulation, wound healing, drug delivery and tissue engineering. Chitosan has become a valuable vaccine adjuvant and delivery carrier, which have attracted increasing attention for its applications. In this paper, we reviewed chitosan nanoparticles, which is a promising biomaterial as vaccine adjuvant and delivery carrier, including characteristics, preparation methods and applications, or even its limitations. We also investigated the mucosal immune delivery route for drug loaded chitosan nanoparticles, such as the routes of oral and nasal. Due to the low toxicity, better biodegradability and adhesivity of chitosan nanoparticles, it can be used as the delivery carrier of vaccine antigens and drugs. These promising studies laid a foundation for the applications of chitosan nanoparticles as a delivery carrier in the vaccine or drug. METHODS: We undertook a structured research of biodegradable polymeric nanoparticles of chitosan used as a delivery carrier for the mucosal immunity of vaccine. We have searched the bibliographic databases for peer-reviewed research literature. The outstanding characteristics of the screened papers were described respectively, and a systematic content analysis methodology was used to analyse the findings. RESULTS: Sixty-three papers were included in the review, the majority defined leadership and governance approaches that had impacted upon the polymeric nanoparticles as the delivery carrier for the mucosal immunity of vaccine in therapeutic applications and developments. Thirty-five papers outlined the superiority characteristics of chitosan nanoparticles that applied in the field of vaccine. Twenty-eight papers overviewed the application prospects of chitosan derivatives used as drug delivery systerm. These included current advances in research and clinical applications of chitosan derivatives. This review identified the drug delivery systerm of chitosan or its derivatives, and we described the synthesis methods, applications and challenges of chitosan. CONCLUSION: The findings of this review identified that the chitosan derivatives were used as delivery carrier for vaccines. It also indicates that the chitosan or its derivatives play a vital role in the drug and vaccine delivery systerm. PMID- 27494158 TI - Evaluation of Lipopeptides as Toll-like Receptor 2 Ligands. AB - BACKGROUND: Peptide-based vaccines are considered to be the next generation of modern immunizations, as they are safe, easy to produce and well-defined. However, due to their weak immunogenic effect, it is important to first develop an appropriate adjuvant for peptide-based vaccines. OBJECTIVE: The aim of this work was to synthesize a series of four adjuvanting moieties as alkyne derivatives, incorporating dipalmitoyl serine (DPS), 1,3-diglyceride (DG), two hexadecane lipoamino acids (diLAA), and 2,3-dipalmitoyl-S-glycerylcysteine (Pam2Cys). Next aim was to synthesize and attach the azide derivative of biotinylated J14 peptide (model B-cell epitope) to the alkynes through copper- catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC) reaction. Final aim was to test the ability of the final biotin labeled conjugates to directly interact with in vitro expressed TLR2 and 8 using AlphaScreen proximity assay. METHOD: All of the peptides were synthesized by manual stepwise solid phase peptide synthesis (SPPS) on rink amide MBHA resin using HATU/DIPEA Fmoc-chemistry. The target compounds were synthesized in a solution phase using CuAAC reaction. RESULTS: Pam2Cys analogue bound to TLR2 as expected. Analogues of DPS and C16-LAA showed also affinity to TLR2, while it did not bind to the control protein (TLR8), demonstrating ability of the DPS and C16-LAA to be recognized by TLR2. CONCLUSION: Four alkyne derivatives of lipids were successfully synthesized and coupled to a biotinylated J14 peptide to give a series of self-adjuvanting ligands. These ligands showed different affinity to TLR2 upon testing by AlphaScreen assay. The DPS derivative showed the most promising affinity in comparison to the standard TLR2 agonist, Pam2Cys. PMID- 27494159 TI - Review: The Role of MOP and DOP Receptors in Treatment of Diarrheapredominant Irritable Bowel Syndrome. AB - Diarrhea-predominant irritable bowel syndrome (IBS-D) is a frequent functional disorder of the gastrointestinal (GI) tract affecting nearly one fifth of the worldwide population. IBS-D is associated with numerous symptoms including diarrhea, bloating, abdominal pain and discomfort, which significantly reduce patients' quality of life. Due to a complex and unclear pathogenesis, effective therapy against IBS-D has not been developed yet. Nowadays, treatment is focused on non-pharmacological (e.g. changes in diet and life style) and pharmacological (e.g. loperamide, ramosetron, rifaximin) approaches. The endogenous opioid system is responsible for the maintenance of homeostasis in the GI tract. Activation of the intestinal opioid receptors (ORs), in particular MU (MOP) and delta (DOP) results in reduction of epithelial secretion and increase of water/electrolyte absorption; moreover, opioids are strong analgesic agents. Thus, ligands of ORs are a promising target in IBS-D treatment. In this review, we discuss the role of ORs in the pathogenesis of IBS-D and the use of "classical" and novel, such as P 317, eluxadoline and biphalin MOP and DOP receptor ligands in preclinical and clinical trials. PMID- 27494161 TI - Congenital Cyst of the Umbilical Cord. AB - Umbilical cord cysts warrant evaluation for structural defects and chromosomal anomalies such as trisomy 18, depending on the type of cyst. The appearance of an enlarged or "gigantic" cord has particular association with a patent urachus, often requiring operative exploration to repair the associated urachal remnant. We describe the unusual case of an umbilical cord cyst-measuring 9 cm in maximal diameter and comprising histopathological features of an urachalcyst-presenting in a healthy ex-36 week newborn with no associated anomalies. PMID- 27494164 TI - Transforming Ni9Te6 from Electron Donor to Acceptor via Ligand Exchange. AB - The ability to donate or accept charge is a fundamental property of a chemical species. This property is typically rooted in the valence electron count and may be determined from the ionization potential and electron affinity. First principles theoretical studies have been carried out to show that a cluster may be transformed from a donor to an acceptor by changing only the ligand. Our studies on a chalcogenide Ni9Te6 cluster show that the ionization potential and electron affinity undergo substantial changes as the attachment of phosphine PH3 decreases the ionization potential to be less than that of sodium, whereas the attachment of PCl3 or CO increases the adiabatic electron affinity to be greater than iodine. The ligands change the electronic properties by creating a coulomb well that can shift the electronic spectrum. Studies on Co9Te6(CO)8 clusters show agreement with experiment and demonstrate that the ideas developed here are applicable to a wider group of clusters. PMID- 27494163 TI - Post-marketing safety surveillance conducted in Korea (2008-2013) following the introduction of the rotavirus vaccine, RIX4414 (RotarixTM). AB - PURPOSE: According to regulations from the Ministry of Food and Drug Safety in Korea, additional safety information on the use of RotarixTM vaccine (RIX4414; GSK, Belgium) in >=3000 evaluable Korean infants was required following vaccine registration. In order to comply with these regulations, we conducted a 6-year open, non-comparative, multicenter post-marketing surveillance (NCT00750893). METHODS: During this time, the original lyophilized vaccine formulation of RIX4414 was replaced by a liquid formulation. Healthy infants aged >=6 weeks were enrolled and given 2 doses of the RIX4414 vaccine, separated by an interval of >=4 weeks. The overall incidence of adverse events (AEs) (expected and unexpected) was then assessed for up to 30 days along with the incidence of serious adverse events (SAEs). Adverse drug reactions (ADRs: any AE whose causality to the drug could not be ruled out) were identified. RESULTS: A total of 3040 children (mean age: 9.55 weeks) were analyzed. One or more expected AE was experienced by 30.5% infants and 8.6% had an ADR. The most commonly seen expected AE was irritability (14.0%). One or more unexpected AE was seen in 32.5% infants and 3.1% experienced an ADR. The most commonly seen unexpected AE was upper respiratory tract infection (8.7%). Of 34 SAEs recorded in 24 subjects, none were related to vaccination. CONCLUSIONS: We conclude that this 6-year surveillance showed both formulations of RIX4414 to have acceptable safety profiles when administered to Korean infants according to local prescribing recommendations and current clinical practice. PMID- 27494165 TI - 4, 5-Dihydrooxazole-pyrazoline hybrids: Synthesis and their evaluation as potential antimalarial agents. AB - A new series of oxazoline-pyrazoline hybrids (4a-p) were synthesized by condensation reaction of substituted oxazoline based chalcones (3a-m) and substituted hydrazines in methanol. Some of the compounds exhibited promising in vitro antimalarial activity for chloroquine sensitive CQ(S) (3D7) strain and chloroquine resistant CQ(R) (RKL9) strain. The most potent analogue 4i (IC50 0.322 MUg/ml) exhibited significant in vivo antimalarial potential against Plasmodium berghei mouse model. The stable complex of 4i with hematin (1:1 stoichiometry) suggests that heme may be one possible target for these hybrid compounds. The study has revealed potential of title compounds as lead for the development of antimalarial agents. PMID- 27494162 TI - The PI3K pathway in B cell metabolism. AB - B cell growth and proliferation is tightly regulated by signaling through the B cell receptor and by other membrane bound receptors responding to different cytokines. The PI3K signaling pathway has been shown to play a crucial role in B cell activation, differentiation and survival. Activated B cells undergo metabolic reprograming in response to changing energetic and biosynthetic demands. B cells also need to be able to coordinate metabolic activity and proliferation with nutrient availability. The PI3K signaling network has been implicated in regulating nutrient acquisition, utilization and biosynthesis, thus integrating receptor-mediated signaling with cell metabolism. In this review, we discuss the current knowledge about metabolic changes induced in activated B cells, strategies to adapt to metabolic stress and the role of PI3K signaling in these processes. PMID- 27494166 TI - Biological importance of structurally diversified chromenes. AB - Compounds incorporating the chromene scaffold are largely present in natural products and display a wide variety of biological activities. Their low toxicity combined to the broad pharmacological properties have inspired medicinal chemists in the search for new therapeutic agents. This review covers the literature between 1993 and on the biological activity of 2H- and 4H-chromenes, both from natural and synthetic origin. Includes a section that identifies a selection of chromene-based natural products, followed by recent literature on bioactive natural chromenes and the corresponding source, covering plants and fruits. Synthetic chromenes are equally important and a separate section addresses the use of these derivatives as new leads for drug discovery. Different biological targets were identified, namely those associated with anticancer, antimicrobial, anti-inflammatory, antithrombotic and antipsychotic activities. PMID- 27494167 TI - Synthesis, antimicrobial activity and advances in structure-activity relationships (SARs) of novel tri-substituted thiazole derivatives. AB - Trisubstituted thiazoles were synthesized and studied for their antimicrobial activity and supported by theoretical calculations. In addition, MIC, MBC and MFC were also tested. Moreover, the present study was analyzed to scrutinize comprehensive structure-activity relationships. In fact, LUMO orbital energy and orbital orientation was reliable to explain their antibacterial and antifungal assay. Amongst the tested compounds, tri-methyl-substituted thiazole compound showed higher antimicrobial activity and low MIC value due to highest LUMO energy. PMID- 27494168 TI - Design, synthesis, and structure-activity relationship studies of benzothiazole derivatives as antifungal agents. AB - A series of compounds with benzothiazole and amide-imidazole scaffolds were designed and synthesized to combat the increasing incidence of drug-resistant fungal infections. The antifungal activity of these compounds was evaluated in vitro, and their structure-activity relationships (SARs) were evaluated. The synthesized compounds showed excellent inhibitory activity against Candida albicans and Cryptococcus neoformans. The most potent compounds 14o, 14p, and 14r exhibited potent activity, with minimum inhibitory concentration (MIC) values in the range of 0.125-2 MUg/mL. Preliminary mechanism studies revealed that the compound 14p might act by inhibiting the CYP51 of Candida albicans. The SARs and binding mode established in this study are useful for further lead optimization. PMID- 27494170 TI - Impact of early mobilization and rehabilitation on global functional outcome one year after aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: To assess the impact of early mobilization and rehabilitation on global functional outcome one year after aneurysmal subarachnoid haemorrhage. METHODS: Prospective, controlled, interventional study comprising patients managed in the neuro-intermediate ward following repair of a ruptured intracranial aneurysm. Patients in the Control group (n = 76) received standard treatment, whereas those in the Early Rehab group (n = 92) in addition underwent early mobilization and rehabilitation. Demographic, clinical and intervention data were registered. Global functional outcome was assessed using the modified Rankin Scale and the Glasgow Outcome Scale Extended. RESULTS: The 2 groups were similar in their demographic and clinical characteristics. Early Rehab group patients were mobilized more quickly (p < 0.001), median 1.4 days (range 0-23 days) after aneurysm repair. After 1 year, 47% of the patients had made a good recovery, whereas 6.5% had died. Regression analysis did not reveal any significant effect of early rehabilitation on functional outcome. However, in poor-grade patients, early rehabilitation more than doubled the chance of a favourable outcome (adjusted odds ratio = 2.33; confidence interval 1.04-5.2, p = 0.039). CONCLUSION: Early mobilization and rehabilitation probably increases the chance of a good functional outcome in poor-grade aneurysmal subarachnoid haemorrhage patients. PMID- 27494169 TI - Recovery Estimation of Dried Foodborne Pathogens Is Directly Related to Rehydration Kinetics. AB - Drying is a common process which is used to preserve food products and technological microorganisms, but which is deleterious for the cells. The aim of this study is to differentiate the effects of drying alone from the effects of the successive and necessary rehydration. Rehydration of dried bacteria is a critical step already studied in starter culture but not for different kinetics and not for pathogens. In the present study, the influence of rehydration kinetics was investigated for three foodborne pathogens involved in neonatal diseases caused by the consumption of rehydrated milk powder: Salmonella enterica subsp. enterica serovar Typhimurium, Salmonella enterica subsp. enterica serovar Senftenberg and Cronobacter sakazakii. Bacteria were dried in controlled relative humidity atmospheres and then rehydrated using different methods. Our results showed that the survival of the three pathogens was strongly related to rehydration kinetics. Consequently, rehydration is an important step to consider during food safety assessment or during studies of dried foodborne pathogens. Also, it has to be considered with more attention in consumers' homes during the preparation of food, like powdered infant formula, to avoid pathogens recovery. PMID- 27494171 TI - A Comparison Study of Single-Echo Susceptibility Weighted Imaging and Combined Multi-Echo Susceptibility Weighted Imaging in Visualizing Asymmetric Medullary Veins in Stroke Patients. AB - BACKGROUND: Asymmetric medullary veins (AMV) are frequently observed in stroke patients and single-echo susceptibility weighted imaging (SWIs) is the main technique in detecting AMV. Our study aimed to investigate which echo time (TE) on single-echo susceptibility is the optimal echo for visualizing AMV and to compare the ability in detecting AMV in stroke patients between SWIs and multi echo susceptibility weighted imaging (SWIc). MATERIALS AND METHODS: Twenty patients with middle cerebral artery stroke were included. SWI was acquired by using a multi-echo gradient-echo sequence with six echoes ranging from 5 ms to 35.240 ms. Three different echoes of SWIs including SWIs1 (TE = 23.144 ms), SWIs2 (TE = 29.192 ms) and SWIs3 (TE = 35.240 ms) were reconstructed. SWIc was averaged using the three echoes of SWIs. Image quality and venous contrast of medullary veins were compared between SWIs and SWIc using peak signal-to-noise ratio (PSNR), mean opinion score (MOS), contrast-to-noise ratio (CNR) and signal-to noise ratio (SNR). The presence of AMV was evaluated in each SWIs (1-3) and SWIc. RESULTS: SWIs2 had the highest PSNR, MOS and CNR and SWIs1 had the highest SNR among three different echoes of SWIs. No significant difference was found in SNR between SWIs1 and SWIs2. PSNR, MOS and CNR in SWIc were significantly increased by 27.9%, 28.2% and 17.2% compared with SWIs2 and SNR in SWIc was significantly increased by 32.4% compared with SWIs1. 55% of patients with AMV were detected in SWIs2, SWIs3 and SWIc, while 50% AMV were found in SWIs1. CONCLUSIONS: SWIs using TE around 29ms was optimal in visualizing AMV. SWIc could improve image quality and venous contrast, but was equal to SWIs using a relative long TE in evaluating AMV. These results provide the technique basis for further research of AMV in stroke. PMID- 27494173 TI - Potential Intervention of alpha- Lipoic Acid and Carnitine on Insulin Sensitivity and Anti-Inflammatory Cytokines Levels in Fructose-Fed Rats, a Model of Metabolic Syndrome. AB - The objective of this work was to evaluate the beneficial effect of alpha-lipoic acid (ALA) and L-carnitine (CAR) on insulin sensitivity and anti-inflammatory markers in animal model of metabolic syndrome (MS), high fructose (HF)-fed rats. Forty male rats were randomly divided into four groups (n = 10). Group 1(control rats, G1), animals were allowed to drink 0.2% gum acacia (GA, p.o) and were fed a modified diet containing 65% cornstarch. The remaining rats were induced MS by feeding the same diet + free access to 10% fructose (w/v) in 0.2% GA (HF, MS) for 4 weeks. After 4 weeks of HF feeding, the rats were further divided into three subgroups; G2: HF (MS) in 0.2% GA, G3: HF (MS)+CAR (200 mg/kg/day) in 0.2% GA and G4: HF (MS)+ALA (200 mg/kg/day) in 0.2% GA, respectively. All ingredients were administered orally by guava daily for four weeks. A significant increase in serum glucose, insulin and Homeostasis Model Assessment-Insulin Resistance (HOMA IR) levels was observed after four weeks of HF feeding compared to control rats. Administration of ALA and CAR reversed the increase of the mentioned parameters. In HF rats, the increase of serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels were significantly lowered, while the reduction of the serum high-density lipoprotein cholesterol (HDL-C) was alleviated after administration of CAR and ALA. The reduction of the serum adiponectin level was significantly increased after administration of CAR and ALA. These data suggested that CAR and/or ALA had a beneficial role in the prevention of MS associated with development of type 2 diabetes. PMID- 27494172 TI - Circadian Rhythm Regulates Development of Enamel in Mouse Mandibular First Molar. AB - Rhythmic incremental growth lines and the presence of melatonin receptors were discovered in tooth enamel, suggesting possible role of circadian rhythm. We therefore hypothesized that circadian rhythm may regulate enamel formation through melatonin receptors. To test this hypothesis, we examined expression of melatonin receptors (MTs) and amelogenin (AMELX), a maker of enamel formation, during tooth germ development in mouse. Using qRT-PCR and immunocytochemistry, we found that mRNA and protein levels of both MTs and AMELX in normal mandibular first molar tooth germs increased gradually after birth, peaked at 3 or 4 day postnatal, and then decreased. Expression of MTs and AMELX by immunocytochemistry was significantly delayed in neonatal mice raised in all-dark or all-light environment as well as the enamel development. Furthermore, development of tooth enamel was also delayed showing significant immature histology in those animals, especially for newborn mice raised in all daylight condition. Interestingly, disruption in circadian rhythm in pregnant mice also resulted in delayed enamel development in their babies. Treatment with melatonin receptor antagonist 4P-PDOT in pregnant mice caused underexpression of MTs and AMELX associated with long lasting deficiency in baby enamel tissue. Electromicroscopic evidence demonstrated increased necrosis and poor enamel mineralization in ameloblasts. The above results suggest that circadian rhythm is important for normal enamel development at both pre- and postnatal stages. Melatonin receptors were partly responsible for the regulation. PMID- 27494174 TI - Polyacrylamide-Polydivinylbenzene Decorated Membrane for Sundry Ionic Stabilized Emulsions Separation via a Facile Solvothermal Method. AB - Aiming to solve the worldwide challenge of stabilized oil-in-water emulsion separation, a PAM-PDVB decorated nylon membrane is fabricated via a facile solvothermal route in our group. The main composition is PAM, while the PDVB plays a role as cross-linker in order to improve the interaction between the polymer and the substrate. By the combination of the superhydrophilic and underwater superoleophobic wettability of the PAM polymer with the micropore size of the substrate, the as-prepared material is able to achieve the separation of various stabilized oil-in-water emulsions including cationic type, nonionic type, and anionic type. Compared with previous works, the emulsions used in this case are more stable and can stay for several days. Besides, the solvothermal method is facile, cost saving, and relatively environmentally friendly in this experiment. Moreover, the PAM-PDVB modified membrane exhibits excellent pH stability, recyclability, and high separation efficiency (above 99%), which can be scaled up and used in the practical industrial field. PMID- 27494175 TI - Sulfur and sulfur nanoparticles as potential antimicrobials: from traditional medicine to nanomedicine. AB - INTRODUCTION: The alarming rate of infections caused by various pathogens and development of their resistance towards a large number of antimicrobial agents has generated an essential need to search for novel and effective antimicrobial agents. Metal nanoparticles such as silver have been widely used and accepted as strong antimicrobial agents, but considering the cost effectiveness and significant bioactivities, researchers are looking to utilize sulfur nanoparticles as an effective alternative to silver nanoparticles. AREAS COVERED: This review has been focused on different approaches for the synthesis of sulfur nanoparticles, their broad spectrum bioactivities and possible mechanisms involved in their bioactivities. Expert commentary: Sulfur nanoparticles are reported to possess broad spectrum antimicrobial activity, and hence can be used to treat microbial infections and potentially tackle the problem of antibiotic resistance. Thus, in the future, sulfur nanoparticles can be used as an effective, non-toxic and economically viable alternative to other precious metal nanoparticles. PMID- 27494176 TI - A green tea-containing starch confection increases plasma catechins without protecting against postprandial impairments in vascular function in normoglycemic adults. AB - Postprandial hyperglycemia (PPH) increases cardiovascular disease risk regardless of glucose intolerance by transiently impairing vascular endothelial function (VEF) by limiting nitric oxide bioavailability in an oxidative stress-dependent manner. Preclinical studies show that green tea catechins attenuate PPH by inhibiting starch digestion. We hypothesized that a starch-based confection containing catechin-rich green tea extract (GTE) would limit PPH-mediated impairments in VEF in normoglycemic adults. We formulated a unique GTE confection and then conducted a double-blind, randomized, controlled, crossover study in healthy men (n = 15; 25.3 +/- 1.0 years; 22.4 +/- 1.8 kg m(-2)) in which they ingested starch confections (50 g carbohydrate) formulated with or without GTE (1 g) prior to evaluating sensory characteristics of confections and plasma glucose, biomarkers of lipid peroxidation and nitric oxide homeostasis, and brachial artery flow-mediated dilation (FMD) at 30 min intervals for 3 h. Sensory evaluation of confections indicated acceptable consumer appeal and an inability to distinguish between confections regardless of GTE. Plasma catechins concentrations increased following ingestion of the GTE confection. However, plasma glucose peaked at 60 min (P < 0.05) following confection ingestion and was unaffected throughout the postprandial period by the GTE confection (P > 0.05). FMD was significantly decreased only at 60 min regardless of confections containing GTE. Also at 60 min, both confections similarly increased plasma malondialdehyde while decreasing arginine and increasing asymmetric dimethylarginine/arginine. The successfully formulated GTE-containing confection effectively delivered catechins, but without mitigating PPH-mediated impairments in VEF in association with oxidative stress that likely limits nitric oxide bioavailability. PMID- 27494177 TI - Patient education and basic body awareness therapy in hip osteoarthritis - a qualitative study of patients' movement learning experiences. AB - BACKGROUND: Osteoarthritis (OA) is associated with pain, dysfunction and reduced quality of life. Patient education (PE) followed by 12 weekly sessions of Basic Body Awareness Therapy (BBAT) was offered to patients with hip OA, aiming to strengthen their ability to move and act functionally in daily life. AIM: To explore how patients described their experiences and outcome from participating in PE and BBAT. METHOD: Individual, semi-structured interviews with five patients, aged 52-78 years, were performed after PE and BBAT at four and ten months. Interview data were analyzed by systematic text condensation. RESULTS: Three main themes emerged. "Becoming motivated and involved" reflected experiences of encouragement and support from information given and communication with group members. In "Movement awareness learning" patients described becoming aware of and improving functional movement, alleviating symptoms and increasing daily functioning. "Movement and disease in a long-term perspective" reflected patients experience of increased self-awareness and taking better care of themselves at 10 months after baseline. Practicing basic movement principles, they felt empowered to handle daily life challenges in more functional and energy economical ways. CONCLUSION: PE followed by BBAT in groups may be beneficial to patients with hip OA, and provide lasting benefits regarding daily life function. Implications for Rehabilitation Insight into disease process and relationship to functional movement gained through patient education may empower patients with hip osteoarthritis in management of daily life Movement awareness and exploration of movement quality using principles from Basic Body Awareness Therapy was found to support patients in finding resources for functional movement, implemented in daily actions Movement strategies characterized by adjustment rather than force was experienced by the patients to support their general functioning, despite of prevailing hip pain Implementing group therapeutic factors (Yalom) in physiotherapy was found to strengthen patients' motivation and belief in functional improvement. PMID- 27494178 TI - Flow-Based Network Analysis of the Caenorhabditis elegans Connectome. AB - We exploit flow propagation on the directed neuronal network of the nematode C. elegans to reveal dynamically relevant features of its connectome. We find flow based groupings of neurons at different levels of granularity, which we relate to functional and anatomical constituents of its nervous system. A systematic in silico evaluation of the full set of single and double neuron ablations is used to identify deletions that induce the most severe disruptions of the multi resolution flow structure. Such ablations are linked to functionally relevant neurons, and suggest potential candidates for further in vivo investigation. In addition, we use the directional patterns of incoming and outgoing network flows at all scales to identify flow profiles for the neurons in the connectome, without pre-imposing a priori categories. The four flow roles identified are linked to signal propagation motivated by biological input-response scenarios. PMID- 27494179 TI - Prevalence of High-Risk Human Papillomavirus (HR-HPV) Genotypes and Multiple Infections in Cervical Abnormalities from Northern Xinjiang, China. AB - Multiple human papillomavirus (HPV) genotypes often coexist within the cervical epithelia and are frequently detected together in various grades of the cervical neoplasia. To date, only a few reports exist on multiple HPV infections of HPV in Xinjiang Uygur Autonomous Region (XUAR). In the present study, we investigated the prevalence of High-Risk HPV (HR-HPV) genotypes and multiple infections. Cervical cytology samples were collected from 428 women who presented cervical abnormalities. Genotyping of HPV was performed by polymerase chain reaction sequencing based typing (PCR-SBT) using consensus primers and specific primers. Of them, 166 samples were positive for HPV according to PCR results using the consensus primers. These samples contained cervical abnormalities enriched with inflammation (n = 107), cervical intraepithelial neoplasia (CIN) I (n = 19), CINII-III (n = 9) and cervical cancer (n = 31). Of the 166 HPV positive samples as determined by PCR analysis, 151 were further typed by PCR-SBT using 19 pairs of genotype-specific primers. Using this method, 17 different HR-HPV genotypes were identified. The most frequently observed HPV genotypes were HPV16 (44.0%, 73/166), 53 (28.9%, 48/166), 52 (25.3%, 42/166), 58 (22.3%, 37/166) and 35 (17.5%, 29/166). The proportions of single and multiple infections in the HPV positive specimens were 34.9% and 65.1%, respectively. Multiple HPV types were most prevalent in the inflammatory state (63.0%), followed by cervical cancer (24.1%), CINI (11.1%), and CINII-III (1.9%). The results of our data analyses suggested that i) multiple HPV infection is not necessarily correlated with the severity of cervical abnormalities; and ii) among the multiple HPV infections, double infections combined with HPV16 is the most common. In addition, L1 full length sequences of the top five high-risk HPV genotypes were amplified and sequenced. According to the L1 sequence of the epidemic genotypes that were amplified, we found that these genotypes contained the sequence point mutation, and that some of these genotypes further showed amino acid modifications. These results provide a basis for the construction of a polyvalent vaccine that is suitable for use in the XUAR, even in economically challenged communities located in China. PMID- 27494180 TI - Moderate-Heavy Alcohol Consumption Lifestyle in Older Adults Is Associated with Altered Central Executive Network Community Structure during Cognitive Task. AB - Older adults today consume more alcohol than previous generations, the majority being social drinkers. The effects of heavy alcohol use on brain functioning closely resemble age-related changes, but it is not known if moderate-heavy alcohol consumption intensifies brain aging. Whether a lifestyle of moderate heavy alcohol use in older adults increased age-related brain changes was examined. Forty-one older adults (65-80 years) that consumed light (< 2 drinks/week and >= 1 drink/month, n = 20) or moderate-heavy (7-21 drinks/week, non-bingers, n = 21) amounts of alcohol were enrolled. Twenty-two young adults (24-35 years) were also enrolled (light, n = 11 and moderate-heavy, n = 11). Functional brain networks based on magnetic resonance imaging data were generated for resting state and during a working memory task. Whole-brain, Central Executive Network (CEN), and Default Mode Network (DMN) connectivity were assessed in light and moderate-heavy alcohol consuming older adults with comparisons to young adults. The older adults had significantly lower whole brain connectivity (global efficiency) and lower regional connectivity (community structure) in the CEN during task and in the DMN at rest. Moderate-heavy older drinkers did not exhibit whole brain connectivity differences compared to the low drinkers. However, decreased CEN connectivity was observed during the task. There were no differences in the DMN connectivity between drinking groups. Taken together, a lifestyle including moderate-heavy alcohol consumption may be associated with further decreases in brain network connectivity within task related networks in older adults. Further research is required to determine if this decrease is compensatory or an early sign of decline. PMID- 27494181 TI - Identification of KCa3.1 Channel as a Novel Regulator of Oxidative Phosphorylation in a Subset of Pancreatic Carcinoma Cell Lines. AB - Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries and overall 5 year survival rates of less than 5%. The most frequent mutations in PDAC are gain of-function mutations in KRAS as well as loss-of-function mutations in p53. Both mutations have severe impacts on the metabolism of tumor cells. Many of these metabolic changes are mediated by transporters or channels that regulate the exchange of metabolites and ions between the intracellular compartment and the tumor microenvironment. In the study presented here, our goal was to identify novel transporters or channels that regulate oxidative phosphorylation (OxPhos) in PDAC in order to characterize novel potential drug targets for the treatment of these cancers. We set up a Seahorse Analyzer XF based siRNA screen and identified previously described as well as novel regulators of OxPhos. The siRNA that resulted in the greatest change in cellular oxygen consumption was targeting the KCNN4 gene, which encodes for the Ca2+-sensitive K+ channel KCa3.1. This channel has not previously been reported to regulate OxPhos. Knock-down experiments as well as the use of a small molecule inhibitor confirmed its role in regulating oxygen consumption, ATP production and cellular proliferation. Furthermore, PDAC cell lines sensitive to KCa3.1 inhibition were shown to express the channel protein in the plasma membrane as well as in the mitochondria. These differences in the localization of KCa3.1 channels as well as differences in the regulation of cellular metabolism might offer opportunities for targeted therapy in subsets of PDAC. PMID- 27494182 TI - Diurnal Variations of Human Circulating Cell-Free Micro-RNA. AB - A 24-hour light and dark cycle-dependent rhythmicity pervades physiological processes in virtually all living organisms including humans. These regular oscillations are caused by external cues to endogenous, independent biological time-keeping systems (clocks). The rhythm is reflected by gene expression that varies in a circadian and specific fashion in different organs and tissues and is regulated largely by dynamic epigenetic and post-transcriptional mechanisms. This leads to well-documented oscillations of specific electrolytes, hormones, metabolites, and plasma proteins in blood samples. An emerging, important class of gene regulators is short single-stranded RNA (micro-RNA, miRNA) that interferes post-transcriptionally with gene expression and thus may play a role in the circadian variation of gene expression. MiRNAs are promising biomarkers by virtue of their disease-specific tissue expression and because of their presence as stable entities in the circulation. However, no studies have addressed the putative circadian rhythmicity of circulating, cell-free miRNAs. This question is important both for using miRNAs as biological markers and for clues to miRNA function in the regulation of circadian gene expression. Here, we investigate 92 miRNAs in plasma samples from 24 young male, healthy volunteers repeatedly sampled 9 times during a 24-hour stay in a regulated environment. We demonstrate that a third (26/79) of the measurable plasma miRNAs (using RT-qPCR on a microfluidic system) exhibit a rhythmic behavior and are distributed in two main phase patterns. Some of these miRNAs weakly target known clock genes and many have strong targets in intracellular MAPK signaling pathways. These novel findings highlight the importance of considering bio-oscillations in miRNA biomarker studies and suggest the further study of a set of specific circulating miRNAs in the regulation and functioning of biological clocks. PMID- 27494183 TI - A Secondary Antibody-Detecting Molecular Weight Marker with Mouse and Rabbit IgG Fc Linear Epitopes for Western Blot Analysis. AB - Molecular weight markers that can tolerate denaturing conditions and be auto detected by secondary antibodies offer great efficacy and convenience for Western Blotting. Here, we describe M&R LE protein markers which contain linear epitopes derived from the heavy chain constant regions of mouse and rabbit immunoglobulin G (IgG Fc LE). These markers can be directly recognized and stained by a wide range of anti-mouse and anti-rabbit secondary antibodies. We selected three mouse (M1, M2 and M3) linear IgG1 and three rabbit (R1, R2 and R3) linear IgG heavy chain epitope candidates based on their respective crystal structures. Western blot analysis indicated that M2 and R2 linear epitopes are effectively recognized by anti-mouse and anti-rabbit secondary antibodies, respectively. We fused the M2 and R2 epitopes (M&R LE) and incorporated the polypeptide in a range of 15-120 kDa auto-detecting markers (M&R LE protein marker). The M&R LE protein marker can be auto-detected by anti-mouse and anti-rabbit IgG secondary antibodies in standard immunoblots. Linear regression analysis of the M&R LE protein marker plotted as gel mobility versus the log of the marker molecular weights revealed good linearity with a correlation coefficient R2 value of 0.9965, indicating that the M&R LE protein marker displays high accuracy for determining protein molecular weights. This accurate, regular and auto-detected M&R LE protein marker may provide a simple, efficient and economical tool for protein analysis. PMID- 27494184 TI - Neuronal mechanisms of motor learning are age dependent. AB - There is controversy whether age-related neuroanatomical and neurophysiological changes in the central nervous system affect healthy old adults' abilities to acquire and retain motor skills. We examined the effects of age on motor skill acquisition and retention and potential underlying mechanisms by measuring corticospinal and intracortical excitability, using transcranial magnetic stimulation. Healthy young (n = 24, 22 years) and old (n = 22, 71 years) adults practiced a wrist flexion-extention visuomotor task or only watched the templates as an attentional control for 20 minutes. Old compared with young adults performed less well at baseline. Although the absolute magnitude of skill acquisition and retention was similar in the 2 age groups (age * intervention * time, p = 0.425), a comparison of baseline-similar age sub-groups revealed impaired skill acquisition but not retention in old versus young. Furthermore, the neuronal mechanisms differed as revealed by an opposite direction of associations in the age-groups between relative skill acquisition and intracortical facilitation during the task, and opposite changes during skill retention in corticospinal excitability at rest and during the task and intracortical inhibition during the task. PMID- 27494186 TI - Novel Sequence-Based Mapping of Recently Emerging H5NX Influenza Viruses Reveals Pandemic Vaccine Candidates. AB - Recently, an avian influenza virus, H5NX subclade 2.3.4.4, emerged and spread to North America. This subclade has frequently reassorted, leading to multiple novel viruses capable of human infection. Four cases of human infections, three leading to death, have already occurred. Existing vaccine strains do not protect against these new viruses, raising a need to identify new vaccine candidate strains. We have developed a novel sequence-based mapping (SBM) tool capable of visualizing complex protein sequence data sets using a single intuitive map. We applied SBM on the complete set of avian H5 viruses in order to better understand hemagglutinin protein variance amongst H5 viruses and identify any patterns associated with this variation. The analysis successfully identified the original reassortments that lead to the emergence of this new subclade of H5 viruses, as well as their known unusual ability to re-assort among neuraminidase subtypes. In addition, our analysis revealed distinct clusters of 2.3.4.4 variants that would not be covered by existing strains in the H5 vaccine stockpile. The results suggest that our method may be useful for pandemic candidate vaccine virus selection. PMID- 27494185 TI - MLST and Whole-Genome-Based Population Analysis of Cryptococcus gattii VGIII Links Clinical, Veterinary and Environmental Strains, and Reveals Divergent Serotype Specific Sub-populations and Distant Ancestors. AB - The emerging pathogen Cryptococcus gattii causes life-threatening disease in immunocompetent and immunocompromised hosts. Of the four major molecular types (VGI-VGIV), the molecular type VGIII has recently emerged as cause of disease in otherwise healthy individuals, prompting a need to investigate its population genetic structure to understand if there are potential genotype-dependent characteristics in its epidemiology, environmental niche(s), host range and clinical features of disease. Multilocus sequence typing (MLST) of 122 clinical, environmental and veterinary C. gattii VGIII isolates from Australia, Colombia, Guatemala, Mexico, New Zealand, Paraguay, USA and Venezuela, and whole genome sequencing (WGS) of 60 isolates representing all established MLST types identified four divergent sub-populations. The majority of the isolates belong to two main clades, corresponding either to serotype B or C, indicating an ongoing species evolution. Both major clades included clinical, environmental and veterinary isolates. The C. gattii VGIII population was genetically highly diverse, with minor differences between countries, isolation source, serotype and mating type. Little to no recombination was found between the two major groups, serotype B and C, at the whole and mitochondrial genome level. C. gattii VGIII is widespread in the Americas, with sporadic cases occurring elsewhere, WGS revealed Mexico and USA as a likely origin of the serotype B VGIII population and Colombia as a possible origin of the serotype C VGIII population. Serotype B isolates are more virulent than serotype C isolates in a murine model of infection, causing predominantly pulmonary cryptococcosis. No specific link between genotype and virulence was observed. Antifungal susceptibility testing against six antifungal drugs revealed that serotype B isolates are more susceptible to azoles than serotype C isolates, highlighting the importance of strain typing to guide effective treatment to improve the disease outcome. PMID- 27494187 TI - Differential Expression of FosB Proteins and Potential Target Genes in Select Brain Regions of Addiction and Depression Patients. AB - Chronic exposure to stress or drugs of abuse has been linked to altered gene expression throughout the body, and changes in gene expression in discrete brain regions are thought to underlie many psychiatric diseases, including major depressive disorder and drug addiction. Preclinical models of these disorders have provided evidence for mechanisms of this altered gene expression, including transcription factors, but evidence supporting a role for these factors in human patients has been slow to emerge. The transcription factor DeltaFosB is induced in the prefrontal cortex (PFC) and hippocampus (HPC) of rodents in response to stress or cocaine, and its expression in these regions is thought to regulate their "top down" control of reward circuitry, including the nucleus accumbens (NAc). Here, we use biochemistry to examine the expression of the FosB family of transcription factors and their potential gene targets in PFC and HPC postmortem samples from depressed patients and cocaine addicts. We demonstrate that DeltaFosB and other FosB isoforms are downregulated in the HPC but not the PFC in the brains of both depressed and addicted individuals. Further, we show that potential DeltaFosB transcriptional targets, including GluA2, are also downregulated in the HPC but not PFC of cocaine addicts. Thus, we provide the first evidence of FosB gene expression in human HPC and PFC in these psychiatric disorders, and in light of recent findings demonstrating the critical role of HPC DeltaFosB in rodent models of learning and memory, these data suggest that reduced DeltaFosB in HPC could potentially underlie cognitive deficits accompanying chronic cocaine abuse or depression. PMID- 27494188 TI - Interannual abundance changes of gelatinous carnivore zooplankton unveil climate driven hydrographic variations in the Iberian Peninsula, Portugal. AB - The persistent massive blooms of gelatinous zooplankton recorded during recent decades may be indicative of marine ecosystem changes. In this study, we investigated the potential influence of the North Atlantic climate (NAO) variability on decadal abundance changes of gelatinous carnivore zooplankton in the Mondego estuary, Portugal, over the period 2003-2013. During the 11-year study, the community of gelatinous carnivores encompassed a larger diversity of hydromedusae than siphonophores; the former dominated by Obelia spp., Lizzia blondina, Clythia hemisphaerica, Liriope tetraphylla and Solmaris corona, while the latter dominated by Muggiaea atlantica. Gelatinous carnivore zooplankton displayed marked interannual variability and mounting species richness over the period examined. Their pattern of abundance shifted towards larger abundances ca. 2007 and significant phenological changes. The latter included a shift in the mean annual pattern (from unimodal to bimodal peak, prior and after 2007 respectively) and an earlier timing of the first annual peak concurrent with enhanced temperatures. These changes were concurrent with the climate-driven environmental variability mainly controlled by the NAO, which displayed larger variance after 2007 along with an enhanced upwelling activity. Structural equation modelling allowed depicting cascading effects derived from the NAO influence on regional climate and upwelling variability further shaping water temperature. Such cascading effect percolated the structure and dynamics of the community of gelatinous carnivore zooplankton in the Mondego estuary. PMID- 27494189 TI - Digestive selection underlies differential utilization of phytoplankton and sedimentary organics by infaunal bivalves: Experiments with cockles (Cerastoderma edule) using cross-labelled mixed diets. AB - Differential utilization of phytoplankton and detrital particles present in natural sediments of mud-flats was studied in a series of experiments performed on the infaunal bivalve Cerastoderma edule. In order to assess digestive selection, parameters of food processing (organic ingestion rate: OIR, gross absorption efficiency: GAE and gut passage time: GPT) were recorded for each organic component in different combinations of food particles radio-labelled with (14)C. Experimental design included the use of both labelled diets of a sole organic component and cross-labelled diets; i.e., mixed suspensions presenting alternatively labelled one of the various components tested: phytoplankton cells, sedimentary organic particles and particulate detritus from vascular salt-marsh plants. Preferential absorption of phytoplankton was accounted for by absorption efficiency values that were two-fold those for sedimentary detritus when recorded with mixed diets of both organic components. Two factors contributed to this difference: a) higher digestibility of microalgae, measured as the ratio of GAE to GPT, and b) faster gut passage of detrital particles that results from digestive selection likely involving the preferential incorporation of phytoplankton into the digestive gland. However, when diets based on a sole organic component (either phytoplankton or detritus) were compared, larger GPT were recorded for detrital particles that enabled improving GAE of this rather refractory food. Overall results of these experiments are consistent with most studies in trophic ecology based on stable isotopes enrichment, concerning both the diversity of trophic sources used by marine bivalves and its preferential utilization of phytoplankton over phyto-detritus. PMID- 27494190 TI - Comprehensive Emerging Chemical Discovery: Novel Polyfluorinated Compounds in Lake Michigan Trout. AB - A versatile screening algorithm capable of efficiently searching liquid chromatographic/mass spectrometric data for unknown compounds has been developed using a combination of open source and generic computing software packages. The script was used to search for select novel polyfluorinated contaminants in Great Lakes fish. However, the framework is applicable whenever full-scan, high resolution mass spectral and chromatographic data are collected. Target compound classes are defined and a matrix of candidates is generated that includes mass spectral profiles and likely fragmentation pathways. The initial calibration was performed using a standard solution of known linear perfluoroalkyl acids. Once validated, Lake Michigan trout data files were analyzed for polyfluoroalkyl acids using the algorithm referencing 3570 possible compounds including C4-C10 perfluoro- and polyfluoroalkyl, polyfluorochloroalkyl acids and sulfonates, and potential ether forms. The results suggest the presence of 30 polyfluorinated chemical formulas which have not been previously reported in the literature. The identified candidates included mono- to hexafluoroalkyl carboxylic acids, mono- and trifluoroalkyl carboxylic acid ethers, and novel polyfluoroalkyl sulfonates. Candidate species identified in lake trout were qualified using theoretical isotopic profile matching, characteristic fragmentation patterns based on known linear perfluoroalkyl acid (PFAA) fragmentation, and retention time reproducibility among replicate extractions and injections. In addition, the relative retention times of multiple species within a compound class were compared based on theoretical octanol-water partition coefficients. PMID- 27494191 TI - Local Optima in Mixture Modeling. AB - It is common knowledge that mixture models are prone to arrive at locally optimal solutions. Typically, researchers are directed to utilize several random initializations to ensure that the resulting solution is adequate. However, it is unknown what factors contribute to a large number of local optima and whether these coincide with the factors that reduce the accuracy of a mixture model. A real-data illustration and a series of simulations are presented that examine the effect of a variety of data structures on the propensity of local optima and the classification quality of the resulting solution. We show that there is a moderately strong relationship between a solution that has a high proportion of local optima and one that is poorly classified. PMID- 27494192 TI - Impact of Microarray Preprocessing Techniques in Unraveling Biological Pathways. AB - To better understand the impact of microarray preprocessing normalization techniques on the analysis of biological pathways in the prediction of chronic fatigue (CF) following radiation therapy, this study has compared the list of predictive genes found using the Robust Multiarray Averaging (RMA) and the Affymetrix MAS5 method, with the list that is obtained working with raw data (without any preprocessing). First, we modeled the spiked-in data set where differentially expressed genes were known and spiked-in at different known concentrations, showing that the precisions established by different gene ranking methods were higher than working with raw data. The results obtained from the spiked-in experiment were extrapolated to the CF data set to run learning and blind validation. RMA and MAS5 provided different sets of discriminatory genes that have a higher predictive accuracy in the learning phase, but lower predictive accuracy during the blind validation phase, suggesting that the genetic signatures generated using both preprocessing techniques cannot be generalizable. The pathways found using the raw data set better described what is a priori known for the CF disease. Besides, RMA produced more reliable pathways than MAS5. Understanding the strengths of these two preprocessing techniques in phenotype prediction is critical for precision medicine. Particularly, this article concludes that biological pathways might be better unraveled working with raw expression data. Moreover, the interpretation of the predictive gene profiles generated by RMA and MAS5 should be done with caution. This is an important conclusion with a high translational impact that should be confirmed in other disease data sets. PMID- 27494194 TI - Meta-analysis of the incidence and risk of arterial and venous thromboembolic events associated with anti-EGFR agents in non-small-cell lung cancer patients. AB - BACKGROUND: To determine the risk of arterial and venous thromboembolic events (ATEs and VETs) associated with anti-epidermal growth factor receptor (EGFR) agents in non-small-cell lung cancer (NSCLC) patients. METHODS: Prospective randomized trials evaluating therapy with or without anti-EGFR agents in NSCLC patients. Data on VTEs and ATEs were extracted. RESULTS: A total of 8,410 patients from 12 trials were included for analysis. Anti-EGFR agents significantly increased the risk of all-grade and high-grade VTEs (Peto OR 1.50, 95%CI 1.16-1.95, P = 0.002; Peto OR 1.73, 95%CI: 1.32-2.26, p < 0.001, respectively), but not for all-grade and high-grade ATEs. CONCLUSION: The use of anti-EGFR agents significantly increased the risk of all-grade and high-grade VTEs but not for ATEs in NSCLC patients. PMID- 27494193 TI - Techniques for the interruption of tubal patency for female sterilisation. AB - BACKGROUND: This is an update of a review that was first published in 2002. Female sterilisation is the most popular contraceptive method worldwide. Several techniques exist for interrupting the patency of fallopian tubes, including cutting and tying the tubes, damaging the tube using electric current, applying clips or silicone rubber rings, and blocking the tubes with chemicals or tubal inserts. OBJECTIVES: To compare the different tubal occlusion techniques in terms of major and minor morbidity, failure rates (pregnancies), technical failures and difficulties, and women's and surgeons' satisfaction. SEARCH METHODS: For the original review published in 2002 we searched MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL). For this 2015 update, we searched POPLINE, LILACS, PubMed and CENTRAL on 23 July 2015. We used the related articles feature of PubMed and searched reference lists of newly identified trials. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing different techniques for tubal sterilisation, irrespective of the route of fallopian tube access or the method of anaesthesia. DATA COLLECTION AND ANALYSIS: For the original review, two review authors independently selected studies, extracted data and assessed risk of bias. For this update, data extraction was performed by one author (TL) and checked by another (RK). We grouped trials according to the type of comparison evaluated. Results are reported as odds ratios (OR) or mean differences (MD) using fixed-effect methods, unless heterogeneity was high, in which case we used random-effects methods. MAIN RESULTS: We included 19 RCTs involving 13,209 women. Most studies concerned interval sterilisation; three RCTs involving 1632 women, concerned postpartum sterilisation. Comparisons included tubal rings versus clips (six RCTs, 4232 women); partial salpingectomy versus electrocoagulation (three RCTs, 2019 women); tubal rings versus electrocoagulation (two RCTs, 599 women); partial salpingectomy versus clips (four RCTs, 3627 women); clips versus electrocoagulation (two RCTs, 206 women); and Hulka versus Filshie clips (two RCTs, 2326 women). RCTs of clips versus electrocoagulation contributed no data to the review.One year after sterilisation, failure rates were low (< 5/1000) for all methods.There were no deaths reported with any method, and major morbidity related to the occlusion technique was rare.Minor morbidity was higher with the tubal ring than the clip (Peto OR 2.15, 95% CI 1.22 to 3.78; participants = 842; studies = 2; I2 = 0%; high-quality evidence), as were technical failures (Peto OR 3.93, 95% CI 2.43 to 6.35; participants = 3476; studies = 3; I2 = 0%; high-quality evidence).Major morbidity was significantly higher with the modified Pomeroy technique than electrocoagulation (Peto OR 2.87, 95% CI 1.13 to 7.25; participants = 1905; studies = 2; I2 = 0%; low-quality evidence), as was postoperative pain (Peto OR 3.85, 95% CI 2.91 to 5.10; participants = 1905; studies = 2; I2 = 0%; moderate quality evidence).When tubal rings were compared with electrocoagulation, postoperative pain was reported significantly more frequently for tubal rings (OR 3.40, 95% CI 1.17 to 9.84; participants = 596; studies = 2; I2 = 87%; low-quality evidence).When partial salpingectomy was compared with clips, there were no major morbidity events in either group (participants = 2198, studies = 1). The frequency of minor morbidity was low and not significantly different between groups (Peto OR 7.39, 95% CI 0.46 to 119.01; participants = 193; studies = 1, low quality evidence). Although technical failure occurred more frequently with clips (Peto OR 0.18, 95% CI 0.08 to 0.40; participants = 2198; studies = 1; moderate quality evidence); operative time was shorter with clips than partial salpingectomy (MD 4.26 minutes, 95% CI 3.65 to 4.86; participants = 2223; studies = 2; I2 = 0%; high-quality evidence).We found little evidence concerning women's or surgeon's satisfaction. No RCTs compared tubal microinserts (hysteroscopic sterilisation) or chemical inserts (quinacrine) to other methods. AUTHORS' CONCLUSIONS: Tubal sterilisation by partial salpingectomy, electrocoagulation, or using clips or rings, is a safe and effective method of contraception. Failure rates at 12 months post-sterilisation and major morbidity are rare outcomes with any of these techniques. Minor complications and technical failures appear to be more common with rings than clips. Electrocoagulation may be associated with less postoperative pain than the modified Pomeroy or tubal ring methods. Further research should include RCTs (for effectiveness) and controlled observational studies (for adverse effects) on sterilisation by minimally-invasive methods, i.e. tubal inserts and quinacrine. PMID- 27494195 TI - Growth of transition metals on cerium tungstate model catalyst layers. AB - Two model catalytic metal/oxide systems were investigated by photoelectron spectroscopy and scanning tunneling microscopy. The mixed-oxide support was a cerium tungstate epitaxial thin layer grown in situ on the W(1 1 0) single crystal. Active particles consisted of palladium and platinum 3D islands deposited on the tungstate surface at 300 K. Both metals were found to interact weakly with the oxide support and the original chemical state of both support and metals was mostly preserved. Electronic and morphological changes are discussed during the metal growth and after post-annealing at temperatures up to 700 K. Partial transition-metal coalescence and self-cleaning from the CO and carbon impurities were observed. PMID- 27494196 TI - Cassava traits and end-user preference: Relating traits to consumer liking, sensory perception, and genetics. AB - Breeding efforts have focused on improving agronomic traits of the cassava plant however little research has been done to enhance the crop palatability. This review investigates the links between cassava traits and end-user preference in relation with sensory characteristics. The main trait is starch and its composition related to the textural properties of the food. Pectin degradation during cooking resulted in increased mealiness. Nutritional components such as carotenoids made the cassava yellow but also altered sweetness and softness; however, yellow cassava was more appreciated by consumers than traditional (white) varieties. Components formed during processing such as organic acids gave fermented cassava products an acidic taste that was appreciated but the fermented smell was not always liked. Anti-nutritional compounds such as cyanogenic glucosides were mostly related to bitter taste. Post-harvest Physiological Deterioration (PPD) affected the overall sensory characteristics and acceptability. Genes responsible for some of these traits were also investigated. Diversity in cassava food products can provide a challenge to identifying acceptance criteria. Socio-economic factors such as gender may also be critical. This review leads to questions in relation to the adaptation of cassava breeding to meet consumer needs and preference in order to maximize income, health and food security. PMID- 27494197 TI - Comprehensive Characterization of Minichromosome Maintenance Complex (MCM) Protein Interactions Using Affinity and Proximity Purifications Coupled to Mass Spectrometry. AB - The extensive identification of protein-protein interactions under different conditions is an important challenge to understand the cellular functions of proteins. Here we use and compare different approaches including affinity purification and purification by proximity coupled to mass spectrometry to identify protein complexes. We explore the complete interactome of the minichromosome maintenance (MCM) complex by using both approaches for all of the different MCM proteins. Overall, our analysis identified unique and shared interaction partners and proteins enriched for distinct biological processes including DNA replication, DNA repair, and cell cycle regulation. Furthermore, we mapped the changes in protein interactions of the MCM complex in response to DNA damage, identifying a new role for this complex in DNA repair. In summary, we demonstrate the complementarity of these approaches for the characterization of protein interactions within the MCM complex. PMID- 27494203 TI - Authors' correction for Euro Surveill. 2016;21(29). PMID- 27494204 TI - Mental health status following severe sulfur mustard exposure: a long-term study of Iranian war survivors. AB - INTRODUCTION: This study aimed to describe the mental health status of sulfur mustard-exposed survivors suffering from severe respiratory and ophthalmological problems. METHODS: Out of 450 invited Iran-Iraq War survivors of sulfur mustard exposure with severe symptoms, 350 participated in this cross-sectional study. Mental health status was assessed using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria. Fisher exact test, Pearson chi-square test, and chi-square test were used to assess any relationship, and the independent-sample t test was employed to compare differences between the veterans with ocular and pulmonary injuries. RESULTS: There were 60.9% (n = 213) survivors who suffered from mental disorders. Among them, 39.7% (n = 139) were previously untreated and required the initiation of psychiatric treatment. The prevalence of anxiety and mood disorders among all survivors was 40.6% (n = 142) and 32.0% (n = 112), respectively. The most common anxiety and mood disorders were posttraumatic stress disorder (32.9%, n = 115) and major depressive disorder (22.3%, n = 78), respectively. Psychiatric disorders were more prevalent in cases with severe pulmonary chemical injury than in subjects with severe ophthalmologic chemical injury. Significant relationships were found between the types of psychiatric disorders and age, education, and occupation (P < .05). CONCLUSION: The psychiatric morbidity in the chemically injured populations was remarkable and significantly different between the populations. The prevalence of mental illness in these groups highlights the need for the appropriate provision of mental health services. PMID- 27494205 TI - Amorphous Semiconductor Nanowires Created by Site-Specific Heteroatom Substitution with Significantly Enhanced Photoelectrochemical Performance. AB - Semiconductor nanowires that have been extensively studied are typically in a crystalline phase. Much less studied are amorphous semiconductor nanowires due to the difficulty for their synthesis, despite a set of characteristics desirable for photoelectric devices, such as higher surface area, higher surface activity, and higher light harvesting. In this work of combined experiment and computation, taking Zn2GeO4 (ZGO) as an example, we propose a site-specific heteroatom substitution strategy through a solution-phase ions-alternative-deposition route to prepare amorphous/crystalline Si-incorporated ZGO nanowires with tunable band structures. The substitution of Si atoms for the Zn or Ge atoms distorts the bonding network to a different extent, leading to the formation of amorphous Zn1.7Si0.3GeO4 (ZSGO) or crystalline Zn2(GeO4)0.88(SiO4)0.12 (ZGSO) nanowires, respectively, with different bandgaps. The amorphous ZSGO nanowire arrays exhibit significantly enhanced performance in photoelectrochemical water splitting, such as higher and more stable photocurrent, and faster photoresponse and recovery, relative to crystalline ZGSO and ZGO nanowires in this work, as well as ZGO photocatalysts reported previously. The remarkable performance highlights the advantages of the ZSGO amorphous nanowires for photoelectric devices, such as higher light harvesting capability, faster charge separation, lower charge recombination, and higher surface catalytic activity. PMID- 27494206 TI - Exploiting the Reactivity of Isocyanide: Coupling Reaction between Isocyanide and Toluene Derivatives Using the Isocyano Group as an N1 Synthon. AB - An unusual oxidative coupling reaction of isocyanide and toluene derivatives using tetrabutylammonium iodide (TBAI) as a catalyst is disclosed. The experimental results and mechanistic study show that the isocyano group acts formally as an N1 synthon during the transformation, thus expanding the reactivity profile of isocyanide. PMID- 27494208 TI - Synthesis and Biological Evaluation of Several Bryostatin Analogues Bearing a Diacylglycerol Lactone C-Ring. AB - As an initial step in designing a simplified bryostatin hybrid molecule, three bryostatin analogues bearing a diacylglycerol lactone-based C-ring, which possessed the requisite pharmacophores for binding to protein kinase C (PKC) together with a modified bryostatin-like A- and B-ring region, were synthesized and evaluated. Merle 46 and Merle 47 exhibited binding affinity to PKC alpha with Ki values of 7000 +/- 990 and 4940 +/- 470 nM, respectively. Reinstallation of the trans-olefin and gem-dimethyl group present in bryostatin 1 in Merle 48 resulted in improved binding affinity, 363 +/- 42 nM. While Merle 46 and 47 were only marginally active biologically, Merle 48 showed sufficient activity on the U937 cells to confirm that it was PMA-like for growth and attachment, as predicted by the substitution pattern of its A- and B-rings. PMID- 27494207 TI - A novel EPID design for enhanced contrast and detective quantum efficiency. AB - Beams-eye-view imaging applications such as real-time soft-tissue motion estimation are hindered by the inherently low image contrast of electronic portal imaging devices (EPID) currently available for clinical use. We introduce and characterize a novel EPID design that provides substantially increased detective quantum efficiency (DQE), contrast-to-noise ratio (CNR) and sensitivity without degradation in spatial resolution. The prototype design features a stack of four conventional EPID layers combined with low noise integrated readout electronics. Each layer consists of a copper plate, a scintillator ([Formula: see text]) and a photodiode/TFT-switch (aSi:H). We characterize the prototype's signal response to a 6 MV photon beam in terms of modulation transfer function (MTF), DQE and CNR. The presampled MTF is estimated using a slanted slit technique, the DQE is calculated from measured normalized noise power spectra (nNPS) and the MTF and CNR is estimated using a Las Vegas contrast phantom. The prototype has been designed and built to be interchangeable with the current clinical EPID on the Varian TrueBeam platform (AS-1200) in terms of size and data output specifications. Performance evaluation is conducted in absolute values as well as in relative terms using the Varian AS-1200 EPID as a reference detector. A fivefold increase of DQE(0) to about 6.7% was observed by using the four-layered design versus the AS-1200 reference detector. No substantial differences are observed between each layer's individual MTF and the one for all four layers operating combined indicating that defocusing due to beam divergence is negligible. Also, using four layers instead of one increases the signal to noise ratio by a factor of 1.7. PMID- 27494209 TI - Nonclassical Phosphomolybdates with Different Degrees of Reduction: Syntheses and Structural and Photo/Electrocatalytic Properties. AB - Four nonclassical phosphomolybdates, formulated as (H2pytty)8[{Mn(H2pytty)(H2O)3}{Sr?P6Mo6(V) Mo12(VI)O73}]2.16H2O (1), [{Mn(H3pytty)(H2O)3}2{Sr?P6Mo4(V)Mo14(VI)O73}].18H2O (2), (H3pytp) (H2pytty)2[{Fe(H2O)4}{Sr?P6Mo3(V)Mo15(VI)O73}].5H2O (3), and (H2pytty)2[{Cd(H2O)4}{Cd(H2O)3 (H3pytty)}{Sr?P6Mo5(V)Mo13(VI)O73}].9H2O (4) (pytty = 3-(pyrazin-2-yl)-5-(1H-1,2,4-triazol-3-yl)-1,2,4-triazolyl; pytp = 4' (4"-pyridyl)-2,4':6',4"-terpyridine) were hydrothermally synthesized and fully characterized. The penta- and hexa-reduced basket clusters represent the highest reduced level of basket-based polyoxometalate so far. In addition, transition metal complexes as bridge units were introduced to basket system for the first time to induce rare two-dimensional inorganic-organic hybrid layer. The results indicate that reduced degrees of the basket clusters of compounds 1-4 can be tuned by altering the molar ratio of organic ligand pytty and Na2MoO4. Compounds 1-4 exhibit bifunctional electrocatalytic behaviors for oxidation of dopamine and reduction of H2O2. Electrocatalytic mechanism, chronoamperometric experiments and electrocatalytic stability are studied in detail. In addition, the compounds show highly efficient catalytic ability for the degradation of typical dyes under UV irradiation. PMID- 27494210 TI - Development and targeting of transcriptional regulatory network controlling FLU1 activation in Candida albicans for novel antifungals. AB - Candidiasis caused by primarily Candida albicans poses serious threat due to dry pipeline and ineffective antifungal strategy against resistance. In this study we propose to target genes involved in efflux mediated Multi drug resistance. The main objective of this study was to understand the regulatory interactions responsible for activating a major MFS transporter gene of Candida albicans. Another aim was to identify the docking effect of certain antifungal compounds upon the transcription factor effectively controlling FLU1. The in silico study carried out here aims at control of gene expression at initial levels. This approach helps to understand regulatory control of FLU1 based on which a predictive map was generated. This data focused on factors with major control that could be suitable target for antifungal agents. The docking results confirm the agreeable effect on the target transcription factor. Broadly this sort of study would account for understanding and targeting any significant gene which in turn would help in adjusting therapeutics accordingly. Further in silico ADMET analysis reported positive values that are indicative of a good antifungal compound with respect to pharmacokinetics. These tests are essential in assessment of good drug candidates because they not only help in refining better drug candidates but weeding out the unsuitable ones too. PMID- 27494211 TI - Mechanical Stability of Flexible Graphene-Based Displays. AB - The mechanical behavior of a prototype touch panel display, which consists of two layers of CVD graphene embedded into PET films, is investigated in tension and under contact-stress dynamic loading. In both cases, laser Raman spectroscopy was employed to assess the stress transfer efficiency of the embedded graphene layers. The tensile behavior was found to be governed by the "island-like" microstructure of the CVD graphene, and the stress transfer efficiency was dependent on the size of graphene "islands" but also on the yielding behavior of PET at relatively high strains. Finally, the fatigue tests, which simulate real operation conditions, showed that the maximum temperature gradient developed at the point of "finger" contact after 80 000 cycles does not exceed the glass transition temperature of the PET matrix. The effect of these results on future product development and the design of new graphene-based displays are discussed. PMID- 27494212 TI - Surface Adsorbed Antibody Characterization Using ToF-SIMS with Principal Component Analysis and Artificial Neural Networks. AB - Artificial neural networks (ANNs) form a class of powerful multivariate analysis techniques, yet their routine use in the surface analysis community is limited. Principal component analysis (PCA) is more commonly employed to reduce the dimensionality of large data sets and highlight key characteristics. Herein, we discuss the strengths and weaknesses of PCA and ANNs as methods for investigation and interpretation of a complex multivariate sample set. Using time-of-flight secondary ion mass spectrometry (ToF-SIMS) we acquired spectra from an antibody and its proteolysis fragments with three primary-ion sources to obtain a panel of 72 spectra and a characteristic peak list of 775 fragment ions. We describe the use of ANNs as a means to interpret the ToF-SIMS spectral data, highlight the optimal neural network design and computational parameters, and discuss the technique limitations. Further, employing Bi3(+) as the primary-ion source, ANNs can accurately classify antibody fragments from the parent antibody based on ToF SIMS spectra. PMID- 27494213 TI - Lack of relationship between masticatory performance and nutritional status in adults with natural dentition. AB - OBJECTIVE: This study assessed the relation among several aspects of the masticatory function and the nutritional status in adults with natural dentition. DESIGN: One hundred adults with natural dentition participated in this cross sectional study. They performed one free-style masticatory test consisting of five trials of 20 silicon-chewing cycles. The preferred chewing side was determined by calculating the asymmetry index. Masticatory performance was determined by sieving the silicon particles, and the cycle duration was also recorded. Weight, body water percentage, body fat mass, muscle mass and osseous mass were measured using a portable digital weighing machine. Body mass index (BMI), waist-hip ratio, skinfold thickness and the upper-arm composition were determined. The relation between masticatory function and a nutritional variable were tested using Pearson or Spearman rank correlation coefficients or using analysis of variance or the Kruskal-Wallis H-test and the Mann-Whitney U test, as appropriate. RESULTS: Whereas body fat percentages for women were significantly higher than for men, the body mass index was higher in men than in women. Participants who were underweight chewed more asymmetrically and more slowly than normal weight or obese participants. A negative correlation was observed between body fat percentage and masticatory laterality. No relation between masticatory performance and any nutritional status indicator was detected. CONCLUSION: Being underweight and having a low body fat percentage seem to be related to a masticatory lateral asymmetry and to a large cycle duration in young adults with natural dentition. Masticatory performance does not seem to be related to nutritional status. PMID- 27494218 TI - CORRIGENDUM: Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort. PMID- 27494214 TI - Revisiting the photosystem II repair cycle. AB - The ability of photosystem (PS) II to catalyze the light-driven oxidation of water comes along with its vulnerability to oxidative damage, in particular of the D1 core subunit. Photodamaged PSII undergoes repair in a multi-step process involving (i) reversible phosphorylation of PSII core subunits; (ii) monomerization and lateral migration of the PSII core from grana to stroma thylakoids; (iii) partial disassembly of PSII; (iv) proteolytic degradation of damaged D1; (v) replacement of damaged D1 protein with a new copy; (vi) reassembly of PSII monomers and migration back to grana thylakoids for dimerization and supercomplex assembly. Here we review the current knowledge on the PSII repair cycle. PMID- 27494215 TI - Biological Testing of Organophosphorus-Inactivated Acetylcholinesterase Oxime Reactivators Identified via Virtual Screening. AB - There is a pressing need for new therapeutics to reactivate covalently inactivated acetylcholinesterase (AChE) due to exposure to organophosphorus (OP) compounds. Current reactivation therapeutics (RTs) are not broad-spectrum and suffer from other liabilities, specifically the inability to cross the blood brain-barrier. Additionally, the chemical diversity of available therapeutics is small, limiting opportunities for structure-activity relationship (SAR) studies to aid in the design of more effective compounds. In order to find new starting points for the development of oxime-containing therapeutic reactivators and to increase our base of knowledge, we have employed a combination of computational and experimental procedures to identify additional compounds with the real or potential ability to reactivate AChE while augmenting and complementing current knowledge. Computational methods were used to identify previously uninvestigated oxime-containing molecules. Experimentally, six compounds were found with reactivation capabilities comparable to, or exceeding, those of 2-pralidoxime (2 PAM) against a panel of AChE inactivated by paraoxon, diisopropylfluorophosphate (DFP), fenamiphos, and methamidophos. One compound showed enhanced reactivation ability against DFP and fenamiphos, the least tractable of these OPs to be reactivated. PMID- 27494219 TI - Biophysical influence of coumarin 35 on bovine serum albumin: Spectroscopic study. AB - The binding mechanism and protein-fluorescence probe interactions between bovine serum albumin (BSA) and coumarin 35 (C35) was investigated by using UV-Vis absorption and fluorescence spectroscopies since they remain major research topics in biophysics. The spectroscopic data indicated that a fluorescence quenching process for BSA-C35 system was occurred. The fluorescence quenching processes were analyzed using Stern-Volmer method. In this regard, Stern-Volmer quenching constants (KSV) and binding constants were calculated at different temperatures. The distance r between BSA (donor) and C35 (acceptor) was determined by exploiting fluorescence resonance energy transfer (FRET) method. Synchronous fluorescence spectra were also studied to observe information about conformational changes. Moreover, thermodynamics parameters were calculated for better understanding of interactions and conformational changes of the system. PMID- 27494222 TI - What Makes Us Whole? PMID- 27494220 TI - Quinazolinone derivative: Model compound for determination of dipole moment, solvatochromism and metal ion sensing. AB - A dihydroquinazolinone derivative 2-(2,4-Dimethoxy-phenyl)-2,3-dihydro-1H quinazolin-4-one (1) was synthesized and characterized by 1H NMR, 13C NMR and FT IR and its spectral, photophysical, intramolecular charge transfer characteristics were studied by absorption and emission spectroscopy. The compound exhibits significant changes in their photophysical properties depending on the solvent polarity. The observed bathochromic emission band and difference in Stokes shift on changing the polarity of the solvents clearly demonstrate the highly polar character of the excited state, which is also supported by the enhancement of dipole moment of the molecule upon photoexcitation. Solvatochromic shift methods based on Lippert-Mataga, Bakhshiev-Kawski and Reichardt's correlations were applied to calculate the ground, excited and change in dipole moments. The effect of solute-solvent interactions on compound 1 was studied using multi-parameter solvent polarity scales proposed by Kamlet-Taft and Catalan. The interactions of various metal ions on compound 1 were also studied using steady state fluorescence measurements. The emission profile reveals that it acts as on-off type fluorescent chemosensor for selective and sensitive detection of Hg2+ions. Complexation stoichiometry and mechanism of quenching were determined from Benesi-Hildebrand and Stern-Volmer plot. PMID- 27494223 TI - Prevalence and Implications of Abnormal Laboratory Results in Patients in the Terminal Phase of Life. AB - BACKGROUND: Pathophysiological changes at the end of life may affect pharmacokinetics of drugs. However, caregivers typically do not extensively monitor patients' laboratory parameters at the end of life. OBJECTIVE: Our aim was to describe laboratory parameters of hospice patients in the week before death. METHODS: A cohort study was conducted on available laboratory results in the week before death, including clinical chemistry and hematology tests. RESULTS: Laboratory data of 125 patients in a palliative care center were included, assessed at a median of 3 days before death. Eighty percent of patients had anemia and almost all had hypoalbuminemia (97%). Elevated levels of gamma glutamyl transferase (gGT) were found in 75%, of alkaline phosphatase (ALP) in 60%, of aspartate aminotransferase (ASAT) in 60%, and of calcium (Ca) in 68%. Alanine aminotransferase (ALAT), bilirubin, sodium (Na), and potassium (K) were abnormal in from 8.8% to 36.0% of patients. A previous unknown poor kidney function was found in 60% of patients. Thirteen patients (22%) with a regular morphine prescription and one patient treated with a non-steroidal anti inflammatory drug (NSAID) had severe kidney failure. CONCLUSIONS: Abnormal laboratory results were expected due to the pathophysiological changes that occur during the last phase of life. Remarkably, however, electrolytes (Na and K) were balanced even shortly before death. Estimated glomerular filtration rate (eGFR), reflecting the kidney function, seems the most clinically relevant laboratory parameter, because it may guide drug choice and dosing. PMID- 27494224 TI - Opioids for Chronic Pain in Patients with History of Substance Use Disorders, Part 1: Assessment and Initiation #311. PMID- 27494225 TI - Opioids for Chronic Pain in Patients with History of Substance Use Disorders, Part 2: Management and Monitoring #312. PMID- 27494226 TI - Meaningful Use. PMID- 27494227 TI - Sampling Molecular Conformers in Solution with Quantum Mechanical Accuracy at a Nearly Molecular-Mechanics Cost. AB - We introduce a method to evaluate the relative populations of different conformers of molecular species in solution, aiming at quantum mechanical accuracy, while keeping the computational cost at a nearly molecular-mechanics level. This goal is achieved by combining long classical molecular-dynamics simulations to sample the free-energy landscape of the system, advanced clustering techniques to identify the most relevant conformers, and thermodynamic perturbation theory to correct the resulting populations, using quantum mechanical energies from density functional theory. A quantitative criterion for assessing the accuracy thus achieved is proposed. The resulting methodology is demonstrated in the specific case of cyanin (cyanidin-3-glucoside) in water solution. PMID- 27494228 TI - Binding of estrogen receptors to switch sites and regulatory elements in the immunoglobulin heavy chain locus of activated B cells suggests a direct influence of estrogen on antibody expression. AB - Females and males differ in antibody isotype expression patterns and in immune responses to foreign- and self-antigens. For example, systemic lupus erythematosus is a condition that associates with the production of isotype skewed anti-self antibodies, and exhibits a 9:1 female:male disease ratio. To explain differences between B cell responses in males and females, we sought to identify direct interactions of the estrogen receptor (ER) with the immunoglobulin heavy chain locus. This effort was encouraged by our previous identification of estrogen response elements (ERE) in heavy chain switch (S) regions. We conducted a full-genome chromatin immunoprecipitation analysis (ChIP seq) using DNA from LPS-activated B cells and an ERalpha-specific antibody. Results revealed ER binding to a wide region of DNA, spanning sequences from the JH cluster to Cdelta, with peaks in EMU and SMU sites. Additional peaks of ERalpha binding were coincident with hs1,2 and hs4 sites in the 3' regulatory region (3'RR) of the heavy chain locus. This first demonstration of direct binding of ER to key regulatory elements in the immunoglobulin locus supports our hypothesis that estrogen and other nuclear hormone receptors and ligands may directly influence antibody expression and class switch recombination (CSR). Our hypothesis encourages the conduct of new experiments to evaluate the consequences of ER binding. A better understanding of ER:DNA interactions in the immunoglobulin heavy chain locus, and respective mechanisms, may ultimately translate to better control of antibody expression, better protection against pathogens, and prevention of pathologies caused by auto-immune disease. PMID- 27494229 TI - 2A4 binds soluble and insoluble light chain aggregates from AL amyloidosis patients and promotes clearance of amyloid deposits by phagocytosis ?. AB - Amyloid light chain (AL) amyloidosis is characterized by misfolded light chain (LC) (amyloid) deposition in various peripheral organs, leading to progressive dysfunction and death. There are no regulatory agency-approved treatments for AL amyloidosis, and none of the available standard of care approaches directly targets the LC protein that constitutes the amyloid. NEOD001, currently in late stage clinical trials, is a conformation-specific, anti-LC antibody designed to specifically target misfolded LC aggregates and promote phagocytic clearance of AL amyloid deposits. The present study demonstrated that the monoclonal antibody 2A4, the murine form of NEOD001, binds to patient-derived soluble and insoluble LC aggregates and induces phagocytic clearance of AL amyloid in vitro. 2A4 specifically labeled all 21 fresh-frozen organ samples studied, which were derived from 10 patients representing both kappa and lambda LC amyloidosis subtypes. 2A4 immunoreactivity largely overlapped with thioflavin T-positive labeling, and 2A4 bound both soluble and insoluble LC aggregates extracted from patient tissue. Finally, 2A4 induced macrophage engagement and phagocytic clearance of AL amyloid deposits in vitro. These findings provide further evidence that 2A4/NEOD001 can effectively clear and remove human AL-amyloid from tissue and further support the rationale for the evaluation of NEOD001 in patients with AL amyloidosis. PMID- 27494231 TI - Non-steroidal anti-inflammatories and the development of analgesic nephropathy: a systematic review. AB - BACKGROUND: Analgesic nephropathy (AN) is chronic renal impairment as a direct consequence of chronic heavy analgesia ingestion. An association between non steroidal anti-inflammatory agents and chronic kidney disease (CKD) has long been suspected. Despite ample observational data obtained in recent decades the relationship remains uncertain. This systematic review intends to summarize the available literature and to define the role of non-steroidal anti-inflammatories in the natural history of AN. METHODS: We conducted a systematic literature search for articles describing the association between non-steroidal anti inflammatory abuse and renal insufficiency. No restriction was placed on publication date, but papers were limited to English language, observational design, and human studies. RESULTS: Nine articles met our inclusion criteria and were discussed in this review. This includes 5 cohort studies and 4 case-control trials, with a combined population of 12,418 study subjects and 23,877 controls. Eight of the nine reports failed to identify any increased risk of chronic renal impairment with heavy non-steroidal anti-inflammatory consumption. Study methods were heterogeneous and the overall quality of data was relatively poor. CONCLUSION: A relationship between non-steroidal anti-inflammatory medicines and the development of CKD has never been proven. Based on the available scientific evidence non-steroidal anti-inflammatory agents do not appear to be implicated in the pathogenesis of AN. PMID- 27494230 TI - Preparation of a reproducible long-acting formulation of risperidone-loaded PLGA microspheres using microfluidic method. AB - The aim of the present study is to prepare risperidone-loaded poly lactic-co glycolic acid (PLGA) microspheres within microfluidic system and to achieve a formulation with uniform size and monotonic and reproducible release profile. In comparison to batch method, T-junction and serpentine chips were utilized and optimizing study was carried out at different processing parameters (e.g. PLGA and surfactant concentration and flow rates ratio of outer to inner phase). The computational fluid dynamic (CFD) modeling was performed, and loading and release study were carried out. CFD simulation indicates that increasing the flow rate of aqueous phase cause to decrease the droplet size, while the change in size of microspheres did not follow a specific pattern in the experimental results. The most uniform microspheres and narrowest standard deviation (66.79 MUm +/- 3.32) were achieved using T-junction chip, 1% polyvinylalcohol, 1% PLGA and flow rates ratio of 20. The microfluidic-assisted microspheres were more uniform with narrower size distribution. The release of risperidone from microspheres produced by the microfluidic method was more reproducible and closer to zero-order kinetic model. The release profile of formulation with 2:1 drug-to-polymer ratio was the most favorable release, in which 41.85% release could be achieved during 24 days. PMID- 27494232 TI - Can breast microbiota provide protective effects against cancer? PMID- 27494233 TI - The study of polymorphic states of paradichlorobenzene by means of nuclear quadrupole resonance relaxometry. AB - The article describes the results of the experimental study of the molecular crystal of paradichlorobenzene in alpha- and beta-phases by means of NQR relaxometry with the inversion of Laplace transformation. The anisotropy effect of the pore space of wood on the distribution of times of the spin-lattice relaxation of p-C6H4Cl2 in the pores of pre-impregnated with the molten sample is shown. It was established that the increase in the T1 spin-lattice relaxation time of (35)Cl nucleus in the wood pores (channels) is observed in the case when the radio frequency field B1 is parallel to the tracheid's of wood. The NQR T1rho dispersion analysis of paradichlorobenzene in alpha-phase was carried out for the first time. PMID- 27494235 TI - Combretastatin A-4 Analogue: A Dual-Targeting and Tubulin Inhibitor Containing Antitumor Pt(IV) Moiety with a Unique Mode of Action. AB - Three new Pt(IV) complexes comprising a combretastatin A-4 analogue were designed and synthesized. The resulting antitumor Pt(IV) complexes could significantly improve the antiproliferative activity and overcome the drug resistance of cisplatin in vitro. Interestingly, these novel compounds not only can carry the DNA binding Pt(II) warhead into the cancer cells but also have a small molecule fragment that can inhibit tubulin polymerization. Among them, complex 13, which was attached to an inhibitor of tubulin at one axial position of Pt(IV) octahedral coordination sphere, could effectively enter cancer cells, arrest the cell cycle in HepG-2 cancer cells at G2/M phases, and induce activation of caspases triggering apoptotic signaling via the mitochondrial-dependent apoptosis pathways. Moreover, complex 13 has the ability to effectively inhibit the tumor growth in the HepG-2 xenograft model without causing significant loss of animal body weight in comparison with cisplatin. PMID- 27494234 TI - Inhibition of Prolyl Hydroxylase Attenuates Fas Ligand-Induced Apoptosis and Lung Injury in Mice. AB - Alveolar epithelial injury and increased alveolar permeability are hallmarks of acute respiratory distress syndrome. Apoptosis of lung epithelial cells via the Fas/Fas ligand (FasL) pathway plays a critical role in alveolar epithelial injury. Activation of hypoxia-inducible factor (HIF)-1 by inhibition of prolyl hydroxylase domain proteins (PHDs) is a possible therapeutic approach to attenuate apoptosis and organ injury. Here, we investigated whether treatment with dimethyloxalylglycine (DMOG), an inhibitor of PHDs, could attenuate Fas/FasL dependent apoptosis in lung epithelial cells and lung injury. DMOG increased HIF 1alpha protein expression in vitro in MLE-12 cells, a murine alveolar epithelial cell line. Treatment of MLE-12 cells with DMOG significantly suppressed cell surface expression of Fas and attenuated FasL-induced caspase-3 activation and apoptotic cell death. Inhibition of the HIF-1 pathway by echinomycin or small interfering RNA transfection abolished these antiapoptotic effects of DMOG. Moreover, intraperitoneal injection of DMOG in mice increased HIF-1alpha expression and decreased Fas expression in lung tissues. DMOG treatment significantly attenuated caspase-3 activation, apoptotic cell death in lung tissue, and the increase in alveolar permeability in mice instilled intratracheally with FasL. In addition, inflammatory responses and histopathological changes were also significantly attenuated by DMOG treatment. In conclusion, inhibition of PHDs protects lung epithelial cells from Fas/FasL dependent apoptosis through HIF-1 activation and attenuates lung injury in mice. PMID- 27494236 TI - Nonhuman Animals, Public Health, and Ethics: A First Step, But.... AB - In December 2015, the Johns Hopkins Bloomberg School of Public Health held the first-ever summit on the intersection between nonhuman animal ethics and human health. The conference covered a variety of issues where animal health intersects with human health, including the wildlife trade, animal agriculture, and animal experimentation. This article provides a brief overview and critique of the summit. PMID- 27494237 TI - Two interesting cases of intracranial IgG4-related disease and discussion of therapy options. PMID- 27494239 TI - Spread of health behaviors in young couples: How relationship power shapes relational influence. AB - INTRODUCTION: Romantic relationships provide a context in which partners can influence each other's health behaviors (e.g., weight-related behaviors, substance use). Partner influence may be especially pronounced among newly parenting adolescent and young adult couples because of the desire to maintain relationships (and therefore openness to influence), and because parenting related challenges can pose risk for uptake of unhealthy behaviors. Two understudied factors that might affect partner influence on health behaviors include relative power within the relationship and prior levels of engagement in health behaviors. METHODS: The current study explored longitudinal partner influence effects in a sample of newly parenting adolescent and young adult females and their male partners (Ncouples = 157) recruited from four obstetrics/gynecology clinics in Connecticut between July 2007 and February 2011. Five health behaviors in two domains were explored: weight-related behaviors (unhealthy eating, exercise) and substance use (cigarette, alcohol, and marijuana use). Relationship power and previous levels of health behaviors were examined as moderators. Variations across gender were also examined. RESULTS: Results of dyadic analysis showed partner influences for alcohol use. Partner influence depended on relationship power for eating, alcohol, and marijuana use, and on previous behavior for cigarette use. Results also varied by gender - only female to-male influence was found for unhealthy eating and cigarette use. Higher relationship power was protective against smoking escalation for females. DISCUSSION: These results differ from previous research findings mainly on male to-female influences. Such asymmetries may reflect traditional female dominance in food preparation, as well as shifts in power balances postpartum. Targeting relational power dynamics may buffer the spread and escalation of unhealthy behaviors in young parents, with implications for the health of both members of a couple as well as their children. PMID- 27494241 TI - The Relationship between Metabolically Obese Non-Obese Weight and Stroke: The Korea National Health and Nutrition Examination Survey. AB - OBJECTIVE: Both metabolic syndrome (MetS) and obesity increase the risk of stroke. However, few studies have compared the risks of stroke associated with metabolically obese non-obese weight (MONW) and metabolically healthy obesity (MHO). This study aimed to compare the prevalence of stroke in MONW and MHO individuals. METHODS: A total of 25,744 subjects aged >=40 years were selected from the 2007-2014 Korean National Health and Nutrition Examination Survey. MetS was defined using 2001 National Cholesterol Education Program/Adult Treatment Panel III and 2005 American Heart Association/National Heart, Lung, and Blood Institute criteria. Non-obese weight and obesity were defined as a body mass index (BMI) <25 kg/m2 and >=25 kg/m2, respectively. MONW was defined as meeting the MetS criteria with a BMI <25 kg/m2 and MHO was defined as not meeting the MetS criteria with a BMI >=25 kg/m2. RESULTS: Women with MONW had a higher prevalence of stroke than those with MHO (odds ratio [OR] = 2.27, 95% confidence interval [CI]: 1.45-3.57). The prevalence of stroke increased as the number of MetS components increased. The ORs for MONW with 3, 4, and 5 MetS components were 1.95 (95% CI: 1.19-3.21), 2.49 (95% CI: 1.46-4.24) and 2.74 (95% CI: 1.39-5.40), respectively. CONCLUSIONS: Our study findings may better emphasize the risk of stroke among more lean but unhealthy individuals, who appear healthy but may be suffering from MetS. These findings also highlight the need for stroke risk factor assessment in non-obese weight individuals. PMID- 27494240 TI - The emotional cost of distance: Geographic social network dispersion and post traumatic stress among survivors of Hurricane Katrina. AB - RATIONALE: Social networks offer important emotional and instrumental support following natural disasters. However, displacement may geographically disperse network members, making it difficult to provide and receive support necessary for psychological recovery after trauma. OBJECTIVES: We examine the association between distance to network members and post-traumatic stress using survey data, and identify potential mechanisms underlying this association using in-depth qualitative interviews. METHODS: We use longitudinal, mixed-methods data from the Resilience in Survivors of Katrina (RISK) Project to capture the long-term effects of Hurricane Katrina on low-income mothers from New Orleans. Baseline surveys occurred approximately one year before the storm and follow-up surveys and in-depth interviews were conducted five years later. We use a sequential explanatory analytic design. With logistic regression, we estimate the association of geographic network dispersion with the likelihood of post traumatic stress. With linear regressions, we estimate the association of network dispersion with the three post-traumatic stress sub-scales. Using maximal variation sampling, we use qualitative interview data to elaborate identified statistical associations. RESULTS: We find network dispersion is positively associated with the likelihood of post-traumatic stress, controlling for individual-level socio-demographic characteristics, exposure to hurricane-related trauma, perceived social support, and New Orleans residency. We identify two social-psychological mechanisms present in qualitative data: respondents with distant network members report a lack of deep belonging and a lack of mattering as they are unable to fulfill obligations to important distant ties. CONCLUSION: Results indicate the importance of physical proximity to emotionally-intimate network ties for long-term psychological recovery. PMID- 27494243 TI - Exonuclease 1 and its versatile roles in DNA repair. AB - Exonuclease 1 (EXO1) is a multifunctional 5' -> 3' exonuclease and a DNA structure-specific DNA endonuclease. EXO1 plays roles in DNA replication, DNA mismatch repair (MMR) and DNA double-stranded break repair (DSBR) in lower and higher eukaryotes and contributes to meiosis, immunoglobulin maturation, and micro-mediated end-joining in higher eukaryotes. In human cells, EXO1 is also thought to play a role in telomere maintenance. Mutations in the human EXO1 gene correlate with increased susceptibility to some cancers. This review summarizes recent studies on the enzymatic functions and biological roles of EXO1, its possible protective role against cancer and aging, and regulation of EXO1 by posttranslational modification. PMID- 27494244 TI - Flow Cytometry in Detection of Fetal Red Blood Cells and Maternal F Cells to Identify Fetomaternal Hemorrhage. AB - Accurate detection and quantitation of fetomaternal hemorrhage (FMH) is critical to the obstetric management of rhesus D alloimmunization in Rh-negative pregnant women. The flow cytometry is based on the detection of fetal red blood cells using a monoclonal anti-HbF antibody, and is the method most indicated for this estimation. The objective of this study was to quantify fetal red blood cell levels of pregnant women using flow cytometry. We analyzed 101 peripheral blood samples from Rh-negative and Rh-positive women, whose mean age was 24 years (20 32 years), after vaginal delivery or cesarean section. Our study showed that 53% of pregnant women had fetal red blood cells levels <2.0 mL, 31% between 2.0-3.9 mL, 16% between 4.0-15.0 mL, and 1% >15.0 mL. Accurate quantitation of fetal red blood cells is necessary to determine the appropriate dose of anti-D (RHD) immunoglobulin to be administered to pregnant or postpartum women. PMID- 27494247 TI - Climatic conditions and child height: Sex-specific vulnerability and the protective effects of sanitation and food markets in Nepal. AB - Environmental conditions in early life are known to have impacts on later health outcomes, but causal mechanisms and potential remedies have been difficult to discern. This paper uses the Nepal Demographic and Health Surveys of 2006 and 2011, combined with earlier NASA satellite observations of variation in the Normalized Difference Vegetation Index (NDVI) at each child's location and time of birth to identify the trimesters of gestation and periods of infancy when climate variation is linked to attained height later in life. We find significant differences by sex: males are most affected by conditions in their second trimester of gestation, and females in the first three months after birth. Each 100-point difference in NDVI at those times is associated with a difference in height-for-age z-score (HAZ) measured at age 12-59 months of 0.088 for boys and 0.054 for girls, an effect size similar to that of moving within the distribution of household wealth by close to one quintile for boys and one decile for girls. The entire seasonal change in NDVI from peak to trough is approximately 200-300 points during the 2000-2011 study period, implying a seasonal effect on HAZ similar to one to three quintiles of household wealth. This effect is observed only in households without toilets; in households with toilets, there is no seasonal fluctuation, implying protection against climatic conditions that facilitate disease transmission. We also use data from the Nepal Living Standards Surveys on district-level agricultural production and marketing, and find a climate effect on child growth only in districts where households' food consumption derives primarily from their own production. Robustness tests find no evidence of selection effects, and placebo regression results reveal no significant artefactual correlations. The timing and sex-specificity of climatic effects are consistent with previous studies, while the protective effects of household sanitation and food markets are novel indications of mechanisms by which households can gain resilience against adverse climatic conditions. PMID- 27494248 TI - Overloaded and stressed: whole-cell considerations for bacterial synthetic biology. AB - The predictability and robustness of engineered bacteria depend on the many interactions between synthetic constructs and their host cells. Expression from synthetic constructs is an unnatural load for the host that typically reduces growth, triggers stresses and leads to decrease in performance or failure of engineered cells. Work in systems and synthetic biology has now begun to address this through new tools, methods and strategies that characterise and exploit host construct interactions in bacteria. Focusing on work in E. coli, we review here a selection of the recent developments in this area, highlighting the emerging issues and describing the new solutions that are now making the synthetic biology community consider the cell just as much as they consider the construct. PMID- 27494246 TI - Use of In Vitro Assays to Assess Immunogenicity Risk of Antibody-Based Biotherapeutics. AB - An In Vitro Comparative Immunogenicity Assessment (IVCIA) assay was evaluated as a tool for predicting the potential relative immunogenicity of biotherapeutic attributes. Peripheral blood mononuclear cells from up to 50 healthy naive human donors were monitored up to 8 days for T-cell proliferation, the number of IL-2 or IFN-gamma secreting cells, and the concentration of a panel of secreted cytokines. The response in the assay to 10 monoclonal antibodies was found to be in agreement with the clinical immunogenicity, suggesting that the assay might be applied to immunogenicity risk assessment of antibody biotherapeutic attributes. However, the response in the assay is a measure of T-cell functional activity and the alignment with clinical immunogenicity depends on several other factors. The assay was sensitive to sequence variants and could differentiate single point mutations of the same biotherapeutic. Nine mAbs that were highly aggregated by stirring induced a higher response in the assay than the original mAbs before stirring stress, in a manner that did not match the relative T-cell response of the original mAbs. In contrast, mAbs that were glycated by different sugars (galactose, glucose, and mannose) showed little to no increase in response in the assay above the response to the original mAbs before glycation treatment. The assay was also used successfully to assess similarity between multiple lots of the same mAb, both from the same manufacturer and from different manufacturers (biosimilars). A strategy for using the IVCIA assay for immunogenicity risk assessment during the entire lifespan development of biopharmaceuticals is proposed. PMID- 27494249 TI - Response: letter to the editor. PMID- 27494250 TI - Underreporting and Missed Opportunities for Uptake of Intermittent Preventative Treatment of Malaria in Pregnancy (IPTp) in Mali. AB - OBJECTIVES: To identify factors contributing to low uptake of intermittent preventive treatment of malaria in pregnancy with sulfadoxine-pyrimethamine (IPTp SP) in rural Mali. METHODS: We conducted secondary data analysis on Mali's 2012 2013 Demographic and Health Survey (DHS) to determine the proportion of women who failed to take IPTp-SP due to ineligibility or non-attendance at antenatal care (ANC). We also identified the proportion who reported taking other or unknown medications to prevent malaria in pregnancy and those who did not know if they took any medication to prevent malaria in pregnancy. We conducted qualitative interviews, focus groups and ANC observations in six rural sites in Mali's Sikasso and Koulikoro regions to identify reasons for missed opportunities. RESULTS: Our secondary data analysis found that reported IPTp-SP coverage estimates are misleading due to their dependence on a variable ("source of IPTp") that is missing 62% of its data points. Among all women who gave birth in the two years prior to the survey, 56.2% reported taking at least one dose of IPTp-SP. Another 5.2% reported taking chloroquine, 1.9% taking another drug to prevent malaria in pregnancy, 4.4% not knowing what drug they took to prevent malaria, and 1.1% not knowing if they took any drug to prevent malaria. The majority of women who did not receive IPTp-SP were women who also did not attend ANC. Our qualitative data revealed that many health centers neither administer IPTp-SP by directly observed therapy, nor give IPTp-SP at one month intervals through the second and third trimesters, nor provide IPTp-SP free of charge. Women generally reported IPTp-SP as available and tolerable, but frequently could not identify its name or purpose, potentially affecting accuracy of responses in household surveys. CONCLUSION: We estimate IPTp-SP uptake to be significantly higher than stated in Mali's 2012-13 DHS report. Increasing ANC attendance should be the first priority for increasing IPTp-SP coverage. Reducing cost and access barriers, ensuring that providers follow up-to-date guidelines, and improving patient counseling on IPTp-SP would also facilitate optimal uptake. PMID- 27494251 TI - Failure to Burrow and Tunnel Reveals Roles for jim lovell in the Growth and Endoreplication of the Drosophila Larval Tracheae. AB - The Drosophila protein Jim Lovell (Lov) is a putative transcription factor of the BTB/POZ (Bric- a-Brac/Tramtrack/Broad/ Pox virus and Zinc finger) domain class that is expressed in many elements of the developing larval nervous system. It has roles in innate behaviors such as larval locomotion and adult courtship. In performing tissue-specific knockdown with the Gal4-UAS system we identified a new behavioral phenotype for lov: larvae failed to burrow into their food during their growth phase and then failed to tunnel into an agarose substratum during their wandering phase. We determined that these phenotypes originate in a previously unrecognized role for lov in the tracheae. By using tracheal-specific Gal4 lines, Lov immunolocalization and a lov enhancer trap line, we established that lov is normally expressed in the tracheae from late in embryogenesis through larval life. Using an assay that monitors food burrowing, substrate tunneling and death we showed that lov tracheal knockdown results in tracheal fluid-filling, producing hypoxia that activates the aberrant behaviors and inhibits development. We investigated the role of lov in the tracheae that initiates this sequence of events. We discovered that when lov levels are reduced, the tracheal cells are smaller, more numerous and show lower levels of endopolyploidization. Together our findings indicate that Lov is necessary for tracheal endoreplicative growth and that its loss in this tissue causes loss of tracheal integrity resulting in chronic hypoxia and abnormal burrowing and tunneling behavior. PMID- 27494252 TI - Comparison of Detailed and Simplified Models of Human Atrial Myocytes to Recapitulate Patient Specific Properties. AB - Computer studies are often used to study mechanisms of cardiac arrhythmias, including atrial fibrillation (AF). A crucial component in these studies is the electrophysiological model that describes the membrane potential of myocytes. The models vary from detailed, describing numerous ion channels, to simplified, grouping ionic channels into a minimal set of variables. The parameters of these models, however, are determined across different experiments in varied species. Furthermore, a single set of parameters may not describe variations across patients, and models have rarely been shown to recapitulate critical features of AF in a given patient. In this study we develop physiologically accurate computational human atrial models by fitting parameters of a detailed and of a simplified model to clinical data for five patients undergoing ablation therapy. Parameters were simultaneously fitted to action potential (AP) morphology, action potential duration (APD) restitution and conduction velocity (CV) restitution curves in these patients. For both models, our fitting procedure generated parameter sets that accurately reproduced clinical data, but differed markedly from published sets and between patients, emphasizing the need for patient specific adjustment. Both models produced two-dimensional spiral wave dynamics for that were similar for each patient. These results show that simplified, computationally efficient models are an attractive choice for simulations of human atrial electrophysiology in spatially extended domains. This study motivates the development and validation of patient-specific model-based mechanistic studies to target therapy. PMID- 27494253 TI - Ecosystem Carbon Storage in Alpine Grassland on the Qinghai Plateau. AB - The alpine grassland ecosystem can sequester a large quantity of carbon, yet its significance remains controversial owing to large uncertainties in the relative contributions of climate factors and grazing intensity. In this study we surveyed 115 sites to measure ecosystem carbon storage (both biomass and soil) in alpine grassland over the Qinghai Plateau during the peak growing season in 2011 and 2012. Our results revealed three key findings. (1) Total biomass carbon density ranged from 0.04 for alpine steppe to 2.80 kg C m-2 for alpine meadow. Median soil organic carbon (SOC) density was estimated to be 16.43 kg C m-2 in alpine grassland. Total ecosystem carbon density varied across sites and grassland types, from 1.95 to 28.56 kg C m-2. (2) Based on the median estimate, the total carbon storage of alpine grassland on the Qinghai Plateau was 5.14 Pg, of which 94% (4.85 Pg) was soil organic carbon. (3) Overall, we found that ecosystem carbon density was affected by both climate and grazing, but to different extents. Temperature and precipitation interaction significantly affected AGB carbon density in winter pasture, BGB carbon density in alpine meadow, and SOC density in alpine steppe. On the other hand, grazing intensity affected AGB carbon density in summer pasture, SOC density in alpine meadow and ecosystem carbon density in alpine grassland. Our results indicate that grazing intensity was the primary contributing factor controlling carbon storage at the sites tested and should be the primary consideration when accurately estimating the carbon storage in alpine grassland. PMID- 27494255 TI - Quantification of Hepatic Vascular and Parenchymal Regeneration in Mice. AB - BACKGROUND: Liver regeneration consists of cellular proliferation leading to parenchymal and vascular growth. This study complements previous studies on cellular proliferation and weight recovery by (1) quantitatively describing parenchymal and vascular regeneration, and (2) determining their relationship. Both together are needed to (3) characterize the underlying growth pattern. METHODS: Specimens were created by injecting a polymerizing contrast agent in either portal or hepatic vein in normal or regenerating livers after 70% partial hepatectomy. 3D image data were obtained through micro-CT scanning. Parenchymal growth was assessed by determining weight and volume of the regenerating liver. Vascular growth was described by manually determined circumscribed parameters (maximal vessel length and radius of right inferior portal/hepatic vein), automatically determined cumulative parameters (total edge length and total vascular volume), and parameters describing vascular density (total edge length/volume, vascular volume fraction). The growth pattern was explored by comparing the relative increase of these parameters to the increase expected in case of isotropic expansion. RESULTS: Liver volume recovery paralleled weight recovery and reached 90% of the original liver volume within 7 days. Comparing radius-related vascular parameters immediately after surgical resection and after virtual resection in-silico revealed a slight increase, possibly reflecting the effect of resection-induced portal hyperperfusion. Comparing length-related parameters between post-operative day 7 and after virtual resection showed similar vascular growth in both vascular systems investigated. In contrast, radius-related parameters increased slightly more in the portal vein. Despite the seemingly homogeneous 3D growth, the observed vascular parameters were not compatible with the hypothesis of isotropic expansion of liver parenchyma and vascular structures. CONCLUSION: We present an approach for the quantitative analysis of the vascular systems of regenerating mouse livers. We applied this technique for assessing the hepatic growth pattern. Prospectively, this approach can be used to investigate hepatic vascular regeneration under different conditions. PMID- 27494254 TI - A Primate APOL1 Variant That Kills Trypanosoma brucei gambiense. AB - Humans are protected against infection from most African trypanosomes by lipoprotein complexes present in serum that contain the trypanolytic pore-forming protein, Apolipoprotein L1 (APOL1). The human-infective trypanosomes, Trypanosoma brucei rhodesiense in East Africa and T. b. gambiense in West Africa have separately evolved mechanisms that allow them to resist APOL1-mediated lysis and cause human African trypanosomiasis, or sleeping sickness, in man. Recently, APOL1 variants were identified from a subset of Old World monkeys, that are able to lyse East African T. b. rhodesiense, by virtue of C-terminal polymorphisms in the APOL1 protein that hinder that parasite's resistance mechanism. Such variants have been proposed as candidates for developing therapeutic alternatives to the unsatisfactory anti-trypanosomal drugs currently in use. Here we demonstrate the in vitro lytic ability of serum and purified recombinant protein of an APOL1 ortholog from the West African Guinea baboon (Papio papio), which is able to lyse examples of all sub-species of T. brucei including T. b. gambiense group 1 parasites, the most common agent of human African trypanosomiasis. The identification of a variant of APOL1 with trypanolytic ability for both human infective T. brucei sub-species could be a candidate for universal APOL1-based therapeutic strategies, targeted against all pathogenic African trypanosomes. PMID- 27494256 TI - Is hepatic oxidative stress a main driver of dietary selenium toxicity in white sturgeon (Acipenser transmontanus)? AB - Most species of sturgeon have experienced significant population declines and poor recruitment over the past decades, leading many, including white sturgeon (Acipenser transmontanus), to be listed as endangered. Reasons for these declines are not yet fully understood but benthic lifestyle, longevity, and delayed sexual maturation likely render sturgeon particularly susceptible to factors such as habitat alteration and contaminant exposures. One contaminant of particular concern to white sturgeon is selenium (Se), especially in its more bioavailable form selenomethionine (SeMet), as it is known to efficiently bioaccumulate in prey items of this species. Studies have shown white sturgeon to be among the most sensitive species of fish to dietary SeMet as well as other pollutants such as metals, dioxin-like chemicals and endocrine disrupters. One of the primary hypothesized mechanisms of toxicity of SeMet in fish is oxidative stress; however, little is know about the specific mode by which SeMet affects the health of white sturgeon. Therefore, the aim of this study was to characterize oxidative stress and associated antioxidant responses as a molecular event of toxicity, and to link it with the pathological effects observed previously. Specifically, three year-old white sturgeon were exposed for 72 days via their diet to 1.4, 5.6, 22.4 or 104.4ug Se per g feed (dm). Doses were chosen to range over a necessary Se intake level, current environmentally relevant intakes and an intake representing predicted increases of Se release. Lipid hydroperoxides, which are end products of lipid oxidation, were quantified as a marker of oxidative stress. Changes in gene expression of glutathione peroxidase (GPx), superoxide dismutase, catalase, glutathione S-transferase, apoptosis inducing factor and caspase 3 were quantified as markers of the response to oxidative stress. Concentrations of lipid hydroperoxides were highly variable within dose groups and no dose response was observed. GPx expression was significantly increased in the low dose group indicating an induced antioxidant response. Expression of other genes were not significantly induced or suppressed. Overall, there was very little evidence of oxidative stress, and therefore, in contrast to previous reports on other species of teleost fishes, oxidative stress is not believed to be a main driver of toxicity in white sturgeon exposed to SeMet. PMID- 27494258 TI - NIAS-Server: Neighbors Influence of Amino acids and Secondary Structures in Proteins. AB - The exponential growth in the number of experimentally determined three dimensional protein structures provide a new and relevant knowledge about the conformation of amino acids in proteins. Only a few of probability densities of amino acids are publicly available for use in structure validation and prediction methods. NIAS (Neighbors Influence of Amino acids and Secondary structures) is a web-based tool used to extract information about conformational preferences of amino acid residues and secondary structures in experimental-determined protein templates. This information is useful, for example, to characterize folds and local motifs in proteins, molecular folding, and can help the solution of complex problems such as protein structure prediction, protein design, among others. The NIAS-Server and supplementary data are available at http://sbcb.inf.ufrgs.br/nias . PMID- 27494257 TI - When Does Return of Voluntary Finger Extension Occur Post-Stroke? A Prospective Cohort Study. AB - OBJECTIVES: Patients without voluntary finger extension early post-stroke are suggested to have a poor prognosis for regaining upper limb capacity at 6 months. Despite this poor prognosis, a number of patients do regain upper limb capacity. We aimed to determine the time window for return of voluntary finger extension during motor recovery and identify clinical characteristics of patients who, despite an initially poor prognosis, show upper limb capacity at 6 months post stroke. METHODS: Survival analysis was used to assess the time window for return of voluntary finger extension (Fugl-Meyer Assessment hand sub item finger extension>=1). A cut-off of >=10 points on the Action Research Arm Test was used to define return of some upper limb capacity (i.e. ability to pick up a small object). Probabilities for regaining upper limb capacity at 6 months post-stroke were determined with multivariable logistic regression analysis using patient characteristics. RESULTS: 45 of the 100 patients without voluntary finger extension at 8 +/- 4 days post-stroke achieved an Action Research Arm Test score of >=10 points at 6 months. The median time for regaining voluntary finger extension for these recoverers was 4 weeks (lower and upper percentile respectively 2 and 8 weeks). The median time to return of VFE was not reached for the whole group (N = 100). Patients who had moderate to good lower limb function (Motricity Index leg>=35 points), no visuospatial neglect (single-letter cancellation test asymmetry between the contralesional and ipsilesional sides of <2 omissions) and sufficient somatosensory function (Erasmus MC modified Nottingham Sensory Assessment>=33 points) had a 0.94 probability of regaining upper limb capacity at 6 months post-stroke. CONCLUSIONS: We recommend weekly monitoring of voluntary finger extension within the first 4 weeks post-stroke and preferably up to 8 weeks. Patients with paresis mainly restricted to the upper limb, no visuospatial neglect and sufficient somatosensory function are likely to show at least some return of upper limb capacity at 6 months post-stroke. PMID- 27494259 TI - Fast isotopic separation of 10 B and 11 B boric acid by capillary zone electrophoresis. AB - Fast isotopic separation of 10 B and 11 B boric acid by CZE was demonstrated. The BGE contained 25 mM phenylalanine and 5 mM putrescine (rN 8.95). The running conditions were +25 kV at 20 degrees C with indirect photometric detection at 210 nm. Baseline separation was achieved in less than 9 min. RSD of migration times and corrected peak areas were less than 0.5 and 3%, respectively (n = 5). Linearity was demonstrated in the range 0.2-2 mM for 11 B and 0.2-0.5 mM for 10 B. PMID- 27494260 TI - Comparison of immune persistence among inactivated and live attenuated hepatitis a vaccines 2 years after a single dose. AB - OBJECTIVE: Compare immune persistence from one dose of each of 3 different hepatitis A vaccines when given to school-age children: a domestic, live attenuated hepatitis A vaccine (H2 vaccine); a domestic inactivated hepatitis A vaccine (Healive(r)); and an imported, inactivated hepatitis A vaccine (Havrix(r)),. METHODS: School-age children were randomized into 1 of 4 groups to receive a single dose of a vaccine: H2 vaccine, Healive(r), Havrix(r), or hepatitis B vaccine [control]. Serum samples were collected 12 and 24 months after vaccination for measurement of anti-HAV IgG using microparticle enzyme immunoassay. Seropositivity was defined as >= 20 mUI/ml. We compared groups on seropositivity and geometric mean concentration (GMC). RESULTS: Seropositive rates for the H2, Healive(r), Havrix(r), and control groups were 64%, 94.4%, 73%, and 1.0%, respectively, 12-months post-vaccination; and 63%, 95.6%, 72%, and 1.0%, respectively 24-months post-vaccination. Seropositivity was greater for Healive(r) than for H2 and Havrix(r) at 12 months (p-values < 0.001) and 24 months (p-values < 0.0001). Average GMCs for the H2, Healive(r), Havrix(r), and control groups, in mIU/ml, were 29.7, 81.0, 36.4, and 2.9, respectively at 12 months, and 30.9, 112.2, 44.3, and 2.9, respectively, at 24 months. GMCs were greater for Healive(r) than for H2 and Havrix(r) at 12 months (p-values < 0.0001 and < 0.001, respectively) and 24 months (p-values < 0.001). No statistically significant differences in seropositivity or GMC were found within groups between 12 and 24 months. CONCLUSION: Immunity persisted 24 months after a single dose of inactivated hepatitis A vaccine and live attenuated hepatitis A vaccine. PMID- 27494261 TI - Successful emotion regulation requires both conviction and skill: beliefs about the controllability of emotions, reappraisal, and regulation success. AB - To succeed in self-regulation, people need to believe that it is possible to change behaviour and they also need to use effective means to enable such a change. We propose that this also applies to emotion regulation. In two studies, we found that people were most successful in emotion regulation, the more they believed emotions can be controlled and the more they used an effective emotion regulation strategy - namely, cognitive reappraisal. Cognitive reappraisal moderated the link between beliefs about the controllability of emotion and success in emotion regulation, when reappraisal was measured as a trait (Study 1) or manipulated (Study 2). Such moderation was found when examining the regulation of disgust elicited by emotion-inducing films (Study 1), and the regulation of anger elicited by real political events (Study 2). We discuss the implications of our findings for research and practice in emotion regulation. PMID- 27494262 TI - Vibrational Effects on Electron Momentum Distributions of Outer-Valence Orbitals of Oxetane. AB - Vibrational effects on electron momentum distributions (EMDs) of outer-valence orbitals of oxetane are computed with a comprehensive consideration of all vibrational modes. It is found that vibrational motions influence EMDs of all outer-valence orbitals noticeably. The agreement between theoretical and experimental momentum profiles of the first five orbitals is greatly improved when including molecular vibrations in the calculation. In particular, the large turn-up at low momentum in the experimental momentum profile of the 3b1 orbital is well interpreted by vibrational effects, indicating that, besides the low frequency ring-puckering mode, C-H stretching motion also plays a significant role in affecting EMDs of outer-valence orbitals of oxetane. The case of oxetane exhibits the significance of checking vibrational effects when performing electron momentum spectroscopy measurements. PMID- 27494263 TI - Medical therapy to prevent recurrence of ventricular arrhythmia in normal and structural heart disease patients. AB - INTRODUCTION: Recurrent ventricular arrhythmias (VA) are a source of significant morbidity in patients without structural heart disease (SHD) and also mortality in patients with SHD. The treatment goals for these two patient populations differ greatly. Areas covered: The secondary prevention of recurrent VA in patients without and with SHD will be reviewed, focusing on clinical data (especially randomized, controlled trials) in the literature as determined through searches in PubMed and ClinicalTrials.gov. This will include beta blockers, non-dihydropyridine calcium channel blockers and antiarrhythmic drugs in both subgroups and non-antiarrhythmic medications in SHD. Expert commentary: The available options for medical therapy for VA in both normal hearts and SHD are insufficient, due to substandard efficacy and toxicities. While non pharmacologic therapies may provide an excellent option, further drug development and randomized trials are needed, as is a reappraisal of the current mode of utilization. PMID- 27494265 TI - Erratum. PMID- 27494264 TI - Zirconium-Based Metal-Organic Framework for Removal of Perrhenate from Water. AB - The efficient removal of pertechnetate (TcO4(-)) anions from liquid waste or melter off-gas solution for an alternative treatment is one of the promising options to manage (99)Tc in legacy nuclear waste. Safe immobilization of (99)Tc is of major importance because of its long half-life (t1/2 = 2.13 * 10(5) yrs) and environmental mobility. Different types of inorganic and solid-state ion exchange materials have been shown to absorb TcO4(-) anions from water. However, both high capacity and selectivity have yet to be achieved in a single material. Herein, we show that a protonated version of an ultrastable zirconium-based metal organic framework can adsorb perrhenate (ReO4(-)) anions, a nonradioactive surrogate for TcO4(-), from water even in the presence of other common anions. Synchrotron-based powder X-ray diffraction and molecular simulations were used to identify the position of the adsorbed ReO4(-) (surrogate for TcO4(-)) molecule within the framework. PMID- 27494266 TI - Variation of DNA Methylome of Zebrafish Cells under Cold Pressure. AB - DNA methylation is an essential epigenetic mechanism involved in multiple biological processes. However, the relationship between DNA methylation and cold acclimation remains poorly understood. In this study, Methylated DNA Immunoprecipitation Sequencing (MeDIP-seq) was performed to reveal a genome-wide methylation profile of zebrafish (Danio rerio) embryonic fibroblast cells (ZF4) and its variation under cold pressure. MeDIP-seq assay was conducted with ZF4 cells cultured at appropriate temperature of 28 degrees C and at low temperature of 18 degrees C for 5 (short-term) and 30 (long-term) days, respectively. Our data showed that DNA methylation level of whole genome increased after a short term cold exposure and decreased after a long-term cold exposure. It is interesting that metabolism of folate pathway is significantly hypomethylated after short-term cold exposure, which is consistent with the increased DNA methylation level. 21% of methylation peaks were significantly altered after cold treatment. About 8% of altered DNA methylation peaks are located in promoter regions, while the majority of them are located in non-coding regions. Methylation of genes involved in multiple cold responsive biological processes were significantly affected, such as anti-oxidant system, apoptosis, development, chromatin modifying and immune system suggesting that those processes are responsive to cold stress through regulation of DNA methylation. Our data indicate the involvement of DNA methylation in cellular response to cold pressure, and put a new insight into the genome-wide epigenetic regulation under cold pressure. PMID- 27494267 TI - A shift in coronary care unit patient population: Ten year experience from an urban tertiary care center. AB - The need for cardiovascular expertise in the treatment of advanced heart failure (AHF), malignant arrhythmias, and structural heart disease has shifted the role of the CCU to a more diverse and medically complex patient population. This study's purpose was to analyze the temporal trends in the principal diagnosis leading to admission to the CCU in a tertiary referral hospital. Over the last 15 years, the CCU has evolved from a medical unit strictly focusing on the care of patients with ACS to an advanced cardiac intensive care unit. The trends observed at our center provide further evidence that today's CCU contains a broader, more complex, critically-ill patient population. PMID- 27494268 TI - A new approach for estimating the density of liquids. AB - We propose a novel approach with which to estimate the density of liquids. The approach is based on the assumption that the systems would be structurally similar when viewed at around the length scale (inverse wavenumber) of the first peak of the structure factor, unless their thermodynamic states differ significantly. The assumption was implemented via a similarity transformation to the radial distribution function to extract the density from the structure factor of a reference state with a known density. The method was first tested using two model liquids, and could predict the densities within an error of several percent unless the state in question differed significantly from the reference state. The method was then applied to related real liquids, and satisfactory results were obtained for predicted densities. The possibility of applying the method to amorphous materials is discussed. PMID- 27494269 TI - Correlation between electrical and hemodynamic responses during visual stimulation with graded contrasts. AB - Brain functional activity involves complex cellular, metabolic, and vascular chain reactions, making it difficult to comprehend. Electroencephalography (EEG) and functional near infrared spectroscopy (fNIRS) have been combined into a multimodal neuroimaging method that captures both electrophysiological and hemodynamic information to explore the spatiotemporal characteristics of brain activity. Because of the significance of visually evoked functional activity in clinical applications, numerous studies have explored the amplitude of the visual evoked potential (VEP) to clarify its relationship with the hemodynamic response. However, relatively few studies have investigated the influence of latency, which has been frequently used to diagnose visual diseases, on the hemodynamic response. Moreover, because the latency and the amplitude of VEPs have different roles in coding visual information, investigating the relationship between latency and the hemodynamic response should be helpful. In this study, checkerboard reversal tasks with graded contrasts were used to evoke visual functional activity. Both EEG and fNIRS were employed to investigate the relationship between neuronal electrophysiological activities and the hemodynamic responses. The VEP amplitudes were linearly correlated with the hemodynamic response, but the VEP latency showed a negative linear correlation with the hemodynamic response. PMID- 27494271 TI - High Energy Density All Solid State Asymmetric Pseudocapacitors Based on Free Standing Reduced Graphene Oxide-Co3O4 Composite Aerogel Electrodes. AB - Modern flexible consumer electronics require efficient energy storage devices with flexible free-standing electrodes. We report a simple and cost-effective route to a graphene-based composite aerogel encapsulating metal oxide nanoparticles for high energy density, free-standing, binder-free flexible pseudocapacitive electrodes. Hydrothermally synthesized Co3O4 nanoparticles are successfully housed inside the microporous graphene aerogel network during the room temperature interfacial gelation at the Zn surface. The resultant three dimensional (3D) rGO-Co3O4 composite aerogel shows mesoporous quasiparallel layer stack morphology with a high loading of Co3O4, which offers numerous channels for ion transport and a 3D interconnected network for high electrical conductivity. All solid state asymmetric pseudocapacitors employing the composite aerogel electrodes have demonstrated high areal energy density of 35.92 MUWh/cm(2) and power density of 17.79 mW/cm(2) accompanied by excellent cycle life. PMID- 27494270 TI - A four-week team-rehabilitation programme in a warm climate decreases disability and improves health and body function for up to one year: A prospective study in Swedish patients with inflammatory joint diseases. AB - OBJECTIVE: In the era of biologics, we evaluated the short- and long-term effects of team-rehabilitation in a warm climate in patients with arthritis and an inadequate response to physio-therapy in Sweden. METHODS: A total of 161 patients with peripheral arthritis and spondyloarthritis, 63% treated with biologics, followed team-rehabilitation for a period of 4 weeks. The outcomes assessed pre- and post-rehabilitation and after 3 and 12 months covered the Heath Assessment Questionnaire (HAQ), Bath Ankylosing Spondylitis Functional Index (BASFI), EuroQoL 5-Dimensions (EQ-5D), general health (VAS-GH), pain (VAS-pain) and the International Physical Activity Questionnaire. RESULTS: HAQ, VAS-GH and VAS-pain improved significantly from pre-rehabilitation to all follow-up time-points, and BASFI and EQ-5D up to 3 months. In patients treated with biologics, the results were similar. At 3 and 12 months the proportions of patients reporting improvement above the minimal clinically important difference were HAQ 62% and 35%, BASFI 73% and 61%, EQ-5D 47% and 39%, VAS-GH 68% and 52%, and VAS-pain 68% and 51%, respectively. Physical activity increased significantly from pre rehabilitation to 12 months and this increase correlated with an improvement in EQ-5D (r = 0.20, p = 0.040). CONCLUSION: Team-rehabilitation in a warm climate resulted in clinically meaningful improvements in body function, activities and well-being, and promoted physical activity for up to one year. PMID- 27494272 TI - Efficacy of tip cryotherapy in the treatment of idiopathic guttate hypomelanosis (IGH): a randomized, controlled, evaluator-blinded study. AB - BACKGROUND: Idiopathic guttate hypomelanosis (IGH) is a common hypopigmentation affecting a large amount of older population. However, there is no standard treatment. Cryotherapy has been reported as an alternative therapy for years; nevertheless, there is no randomized controlled study to determine its efficacy. OBJECTIVES: To evaluate the efficacy and side effects of tip cryotherapy in IGH treatment. MATERIAL AND METHODS: Total 101 lesions were included. Forty-three lesions were treated with cryotherapy and 58 lesions were assigned as control. A single session of tip cryotherapy was delivered and remained for 5 s. Colorimeter was used to measure lesional luminosity at baseline and then monthly until 4 months. Digital photographs were evaluated by two blinded dermatologists. In addition, patients' assessments and side effects were assessed. RESULTS: Mean luminosity scale gradually decreased from baseline. Also, the score of the treated lesions has been significantly lower than that of the control lesions since week 8 (p = .005). At the fourth month, dermatologists' assessment revealed that 82.3% of the treated lesions comparing to only 2% of the control showed more than 75% improvement (p < .001). Burning sensation was the most common side effect. CONCLUSION: Tip cryotherapy appears to be an effective therapy with minimal adverse effect for IGH. PMID- 27494273 TI - Nanopillar Arrayed Triboelectric Nanogenerator as a Self-Powered Sensitive Sensor for a Sleep Monitoring System. AB - A flexible and low-cost triboelectric nanogenerator (TENG) based on a patterned aluminum-plastic film and an entrapped cantilever spring leaf is developed as a self-powered sensitive triboelectric sensor for sleep-body movement monitoring. The working mechanism and the impact factors of electric output performance were systematically investigated and elaborated. Due to the patterned nanostructures of the recently designed TENG, both the output voltage and current are greatly enhanced, and thereby the sensitivity of the device is significantly improved. The self-powered and sensitive device has been demonstrated as a smart body motion sensor of sleep monitoring for diagnosis of sleep disorders due to its high sensitivity and excellent stability. This work may promote the application of self-powered TENGs for healthcare and be helpful for the development of real time mobile healthcare services and smart external portable electronics. PMID- 27494276 TI - Finite Systems in a Heat Bath: Spectrum Perturbations and Thermodynamics. AB - When a finite system is at equilibrium with a heat bath, the equilibrium temperature is dictated by the heat bath and not by the intrinsic thermostatistics of the finite system. If not sufficiently large, it may be necessary for the finite system to change its thermostatistics in order to be at equilibrium with the heat bath. We account for this process by invoking Landsberg's notion of temperature-dependent energy levels. We establish that the mismatch between the intrinsic temperature of the excited finite system and that of the heat bath drives a spectrum perturbation which enables thermal equilibrium. We show that the temperature-induced spectrum perturbation is equivalent to Hill's purely thermodynamic subdivision potential. The difference between intrinsic and equilibrium temperature provides us with a measure for how large a system can be before it no longer needs to be regarded as small. The theoretical framework proposed in this paper identifies the role of temperature in a bottom-up thermostatistical description of finite systems. PMID- 27494274 TI - Coupling between the DEAD-box RNA helicases Ded1p and eIF4A. AB - Eukaryotic translation initiation involves two conserved DEAD-box RNA helicases, eIF4A and Ded1p. Here we show that S. cerevisiae eIF4A and Ded1p directly interact with each other and simultaneously with the scaffolding protein eIF4G. We delineate a comprehensive thermodynamic framework for the interactions between Ded1p, eIF4A, eIF4G, RNA and ATP, which indicates that eIF4A, with and without eIF4G, acts as a modulator for activity and substrate preferences of Ded1p, which is the RNA remodeling unit in all complexes. Our results reveal and characterize an unexpected interdependence between the two RNA helicases and eIF4G, and suggest that Ded1p is an integral part of eIF4F, the complex comprising eIF4G, eIF4A, and eIF4E. PMID- 27494277 TI - Monitoring CO2 invasion processes at the pore scale using geological labs on chip. AB - In order to investigate at the pore scale the mechanisms involved during CO2 injection in a water saturated pore network, a series of displacement experiments is reported using high pressure micromodels (geological labs on chip - GLoCs) working under real geological conditions (25 < T ( degrees C) < 75 and 4.5 < p (MPa) < 8). The experiments were focused on the influence of three experimental parameters: (i) the p, T conditions, (ii) the injection flow rates and (iii) the pore network characteristics. By using on-chip optical characterization and imaging approaches, the CO2 saturation curves as a function of either time or the number of pore volume injected were determined. Three main mechanisms were observed during CO2 injection, namely, invasion, percolation and drying, which are discussed in this paper. Interestingly, besides conventional mechanisms, two counterintuitive situations were observed during the invasion and drying processes. PMID- 27494275 TI - Drosophila larval to pupal switch under nutrient stress requires IP3R/Ca(2+) signalling in glutamatergic interneurons. AB - Neuronal circuits are known to integrate nutritional information, but the identity of the circuit components is not completely understood. Amino acids are a class of nutrients that are vital for the growth and function of an organism. Here, we report a neuronal circuit that allows Drosophila larvae to overcome amino acid deprivation and pupariate. We find that nutrient stress is sensed by the class IV multidendritic cholinergic neurons. Through live calcium imaging experiments, we show that these cholinergic stimuli are conveyed to glutamatergic neurons in the ventral ganglion through mAChR. We further show that IP3R dependent calcium transients in the glutamatergic neurons convey this signal to downstream medial neurosecretory cells (mNSCs). The circuit ultimately converges at the ring gland and regulates expression of ecdysteroid biosynthetic genes. Activity in this circuit is thus likely to be an adaptation that provides a layer of regulation to help surpass nutritional stress during development. PMID- 27494278 TI - Dual Emission and Mechanofluorochromism of a V-Shaped pi-System Composed of Disulfonyl-Substituted Dibenzocyclooctatetraenes. AB - A series of dibenzocyclooctatetraenes 6 bearing phenylethynyl and phenylsulfonyl groups were synthesized from bromo-substituted formylbenzyl sulfone 4 via cyclic dimerization of 4 and Sonogashira coupling of the resulting dibromocyclooctatetraene 3 with terminal acetylenes. The diamino derivative 6b exhibited dual emission with emission maxima at 436 and 547 nm. Furthermore, in the fluorescence of 6b, solvatofluorochromism was observed in response to solvent polarity, whereas in the solid states, mechanofluorochromism was observed. PMID- 27494279 TI - Positron range in tissue-equivalent materials: experimental microPET studies. AB - In this work an experimental investigation was carried out to study the effect that positron range has over positron emission tomography (PET) scans through measurements of the line spread function (LSF) in tissue-equivalent materials. Line-sources consisted of thin capillary tubes filled with (18)F, (13)N or (68)Ga water-solution inserted along the axis of symmetry of cylindrical phantoms constructed with the tissue-equivalent materials: lung (inhale and exhale), adipose tissue, solid water, trabecular and cortical bone. PET scans were performed with a commercial small-animal PET scanner and image reconstruction was carried out with filtered-backprojection. Line-source distributions were analyzed using radial profiles taken on axial slices from which the spatial resolution was determined through the full-width at half-maximum, tenth-maximum, twentieth maximum and fiftieth-maximum. A double-Gaussian model of the LSFs was used to fit experimental data which can be incorporated into iterative reconstruction methods. In addition, the maximum activity concentration in the line-sources was determined from reconstructed images and compared to the known values for each case. The experimental data indicates that positron range in different materials has a strong effect on both spatial resolution and activity concentration quantification in PET scans. Consequently, extra care should be taken when computing standard-uptake values in PET scans, in particular when the radiopharmaceutical is taken up by different tissues in the body, and more even so with high-energy positron emitters. PMID- 27494280 TI - Identification and discrimination of three common Aloe species by high performance liquid chromatography-tandem mass spectrometry coupled with multivariate analysis. AB - Aloe arborescens, Aloe barbadensis and Aloe ferox are the most widely cultivated and used among 500 aloe species due to their potent bioactivity. However, the difference of aloe species is neglected and labeled only one name Aloe in the market without specifying aloe species discrimination in general. Furthermore, differences in bioactivity and side effects from different aloe species have not been well investigated. This study develops an effective method for simultaneous qualitative and quantitative determination of three common aloe species using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and high performance liquid chromatography-diode array detection (HPLC-DAD). The extraction conditions were optimized by response surface methodology (RSM) based on methanol concentration, extraction time and solvent-to-material ratio. A partial least squares-discriminant analysis (PLS-DA) was used to identify the three aloe species. The developed HPLC-MS/MS method coupled with multivariate analysis can be applied to discriminate three aloe species successfully. PMID- 27494281 TI - Pharmacokinetic studies of novel berberine derivatives with ultra-performance liquid chromatography-tandem mass spectrometry. AB - An ultra-performance liquid chromatography with tandem mass spectrometric detection method was developed for the detection of berberine and its derivatives (A4, B4) in rat plasma and other organs. This validated method was successfully applied to our pharmacokinetic study of BBR derivatives in rats. At the same dose of administration, the Cmax of B4 was about eight times higher than BBR, and its half-life was approximately two times longer than BBR, according to the bigger areas under plasma concentration curves. Inversely, the pharmacokinetic parameter levels of A4 were all inferior to BBR, suggesting a tight structure-activity relationship of these compounds. Small dose of parenteral administration was used for the study of absolute oral bioavailability of A4, B4, and BBR, and the results calculated were 0.12%, 3.4% and 0.7%, respectively. The accumulations of B4 among all organs were intestine>liver>heart>kidney>lung>spleen>plasma, proving a deeply targeting property of B4, which met our experimental assumption. Together, the experimental results proved that compared with BBR and A4, the derivative B4 had higher absolute oral bioavailability and the ability of deeply targeting so that can be likely used in some organ-targeted diseases. PMID- 27494283 TI - Influence of sp(3)-sp(2) Carbon Nanodomains on Metal/Support Interaction, Catalyst Durability, and Catalytic Activity for the Oxygen Reduction Reaction. AB - In this work, platinum nanoparticles were impregnated by two different techniques, namely the carbonyl chemical route and photodeposition, onto systematically surface-modified multiwalled carbon nanotubes. The different interactions between platinum nanoparticles with sp(2)-sp(3) carbon nanodomains were investigated. The oxidation of an adsorbed monolayer of carbon monoxide, used to probe electronic catalytic modification, suggests a selective nucleation of platinum nanoparticles onto sp(2) carbon nanodomains when photodeposition synthesis is carried out. XPS attests the catalytic center electronic modification obtained by photodeposition. DFT calculations were used to determine the interaction energy of a Pt cluster with sp(2) and sp(3) carbon surfaces as well as with oxidized ones. The interaction energy and electronic structure of the platinum cluster presents dramatic changes as a function of the support surface chemistry, which also modifies its catalytic properties evaluated by the interaction with CO. The interaction energy was calculated to be 8-fold higher on sp(3) and oxidized surfaces in comparison to sp(2) domains. Accelerated Stability Test (AST) was applied only on the electronic-modified materials to evaluate the active phase degradation and their activity toward oxygen reduction reaction (ORR). The stability of photodeposited materials is correlated with the surface chemical nature of supports indicating that platinum nanoparticles supported onto multiwalled carbon nanotubes with the highest sp(2) character show the higher stability and activity toward ORR. PMID- 27494282 TI - Neural Activity during Voluntary Movements in Each Body Representation of the Intracortical Microstimulation-Derived Map in the Macaque Motor Cortex. AB - In order to accurately interpret experimental data using the topographic body map identified by conventional intracortical microstimulation (ICMS), it is important to know how neurons in each division of the map respond during voluntary movements. Here we systematically investigated neuronal responses in each body representation of the ICMS map during a reach-grasp-retrieval task that involves the movements of multiple body parts. The topographic body map in the primary motor cortex (M1) generally corresponds to functional divisions of voluntary movements; neurons at the recording sites in each body representation with movement thresholds of 10 MUA or less were differentially activated during the task, and the timing of responses was consistent with the movements of the body part represented. Moreover, neurons in the digit representation responded differently for the different types of grasping. In addition, the present study showed that neural activity depends on the ICMS current threshold required to elicit body movements and the location of the recording on the cortical surface. In the ventral premotor cortex (PMv), no correlation was found between the response properties of neurons and the body representation in the ICMS map. Neural responses specific to forelimb movements were often observed in the rostral part of PMv, including the lateral bank of the lower arcuate limb, in which ICMS up to 100 MUA evoked no detectable movement. These results indicate that the physiological significance of the ICMS-derived maps is different between, and even within, areas M1 and PMv. PMID- 27494284 TI - Managing Osteoporosis: A Survey of Knowledge, Attitudes and Practices among Primary Care Physicians in Israel. AB - BACKGROUND: Osteoporosis is a systemic skeletal disorder characterized by impaired bone quality and microstructural deterioration leading to an increased propensity to fractures. This is a major health problem for older adults, which comprise an increasingly greater proportion of the general population. Due to a large number of patients and the insufficient availability of specialists in Israel and worldwide, osteoporosis is treated in large part by primary care physicians. We assessed the knowledge of primary care physicians on the diagnosis and treatment of osteoporosis. METHODS: Physician's knowledge, sources of knowledge acquisition and self-evaluation of knowledge were assessed using a multiple choice questionnaire. Professional and demographic characteristics were assessed as well. RESULTS: Of 490 physicians attending a conference, 363 filled the questionnaires (74% response rate). The physicians demonstrated better expertise in diagnosis than in medications (mechanism of action, side effects or contra-indications) but less than for other treatment related decisions. Overall, 50% demonstrated adequate knowledge of calcium and vitamin D supplementation, 51% were aware of the main therapeutic purpose of osteoporosis pharmacotherapy and 3% were aware that bisphosphonates should be avoided in patients with impaired renal function. Respondents stated frontal lectures at meetings as their main source of information on the subject. CONCLUSION: The study indicates the need to intensify efforts to improve the knowledge of primary care physicians regarding osteoporosis, in general; and osteoporosis pharmacotherapy, in particular. PMID- 27494285 TI - Two-Dimensional Inorganic Cationic Network of Thorium Iodate Chloride with Unique Halogen-Halogen Bonds. AB - A unique two-dimensional inorganic cationic network with the formula [Th3O2(IO3)5(OH)2]Cl was synthesized hydrothermally. Its crystal structure can best be described as positively charged slabs built with hexanuclear thorium clusters connected by iodate trigonal pyramids. Additional chloride anions are present in the interlayer spaces but surprisingly are not exchangeable, as demonstrated by a series of CrO4(2-) uptake experiments. This is because all chloride anions are trapped by multiple strong halogen-halogen interactions with short Cl-I bond lengths ranging from 3.134 to 3.333 A, forming a special Cl centered trigonal-pyramidal polyhedron as a newly observed coordination mode for halogen bonds. Density functional theory calculations clarified that electrons transformed from central Cl atoms to I atoms, generating a halogen-halogen interaction energy with a value of about -8.3 kcal mol(-1) per Cl...I pair as well as providing a total value of -57.9 kcal mol(-1) among delocalized halogen halogen bonds, which is a new record value reported for a single halogen atom. Additional hydrogen-bonding interaction is also present between Cl and OH, and the interaction energy is predicted to be -8.1 kcal mol(-1), confirming the strong total interaction to lock the interlayer Cl anions. PMID- 27494287 TI - Assessing for Unilateral Spatial Neglect Using Eye-Tracking Glasses: A Feasibility Study. AB - The aim of this feasibility study was to identify whether eye-tracking glasses could sensitively differentiate unilateral spatial neglect (USN) among a sample of participants who had a stroke, and to determine whether a larger study was viable. A sample of 13 inpatients (N = 7 with neglect, N = 6 without neglect) aged 50-78 years undertook a task while wearing Tobii eye-tracking glasses. The kitchen environment and the task of making a cup of coffee were standardized. Two commonly reported tests for USN, the Bells Test and the Line Crossing Test, were also used as a reference standard for the eye-tracking data. Participants with USN spent significantly more time searching on the right-hand side (p = .006) for items during the task than those without neglect. There was a moderate correlation between eye-tracking data and the Bells Test (r = .622, p = .04). Overall, this study supported the feasibility of using a real-life task with eye tracking to detect neglect. PMID- 27494286 TI - Imaging Evaluation of Malignant Chest Wall Neoplasms. AB - Neoplasms of the chest wall are uncommon lesions that represent approximately 5% of all thoracic malignancies. These tumors comprise a heterogeneous group of neoplasms that may arise from osseous structures or soft tissues, and they may be malignant or benign. More than 50% of chest wall neoplasms are malignancies and include tumors that may arise as primary malignancies or secondarily involve the chest wall by way of direct invasion or metastasis from intrathoracic or extrathoracic neoplasms. Although 20% of chest wall tumors may be detected at chest radiography, chest wall malignancies are best evaluated with cross sectional imaging, principally multidetector computed tomography (CT) and magnetic resonance (MR) imaging, each of which has distinct strengths and limitations. Multidetector CT is optimal for depicting bone, muscle, and vascular structures, whereas MR imaging renders superior soft-tissue contrast and spatial resolution and is better for delineating the full extent of disease. Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT is not routinely performed to evaluate chest wall malignancies. The primary functions of PET/CT in this setting include staging of disease, evaluation of treatment response, and detection of recurrent disease. Ultrasonography has a limited role in the evaluation and characterization of superficial chest wall lesions; however, it can be used to guide biopsy and has been shown to depict chest wall invasion by lung cancer more accurately than CT. It is important that radiologists be able to identify the key multidetector CT and MR imaging features that can be used to differentiate malignant from benign chest lesions, suggest specific histologic tumor types, and ultimately guide patient treatment. ((c))RSNA, 2016. PMID- 27494288 TI - Formation of delta-Lactones by Cerium-Catalyzed, Baeyer-Villiger-Type Coupling of beta-Oxoesters, Enol Acetates, and Dioxygen. AB - Formation of delta-lactones is observed when cyclopentanone-2-carboxylates are converted in a cerium-catalyzed reaction with alpha-aryl vinyl acetates under oxidative conditions. The products of this transformation possess a 1,4 dicarbonyl constitution together with a quaternary carbon center. Atmospheric oxygen is the oxidant in this process, which can be regarded as ideal from economic and ecological points of view. Further advantages of this new C-C coupling and oxidation reaction are its operational simplicity and the application of nontoxic and inexpensive CeCl3.7 H2O as precatalyst. This so far unprecedented reaction is proposed to proceed via 1,2-dioxane derivatives, which decompose under formation of an oxycarbenium cation in a Baeyer-Villiger-type pathway. This mechanistic picture is supported by the observation that electron rich (donor substituted or heteroaromatic) enol esters give higher yields than electron deficient congeners. Apart from 1,4-diketones and alpha-hydroxylated beta-oxoesters formed as byproducts, the yields of delta-lactones range from moderate to good (up to 74%). PMID- 27494289 TI - Investigating the Influence of Polymers on Supersaturated Flufenamic Acid Cocrystal Solutions. AB - The development of enabling formulations is a key stage when demonstrating the effectiveness of pharmaceutical cocrystals to maximize the oral bioavailability for poorly water soluble drugs. Inhibition of drug crystallization from a supersaturated cocrystal solution through a fundamental understanding of the nucleation and crystal growth is important. In this study, the influence of the three polymers of polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and a copolymer of N-vinly-2-pyrrodidone (60%) and vinyl acetate (40%) (PVP-VA) on the flufenamic acid (FFA) crystallization from three different supersaturated solutions of the pure FFA and two cocrystals of FFA-NIC CO and FFA-TP CO has been investigated by measuring nucleation induction times and desupersaturation rates in the presence and absence of seed crystals. It was found that the competition of intermolecular hydrogen bonding among drug/coformer, drug/polymer, and coformer/polymer was a key factor responsible for maintaining supersaturation through nucleation inhibition and crystal growth modification in a cocrystal solution. The supersaturated cocrystal solutions with predissolved PEG demonstrated more effective stabilization in comparison to the pure FFA in the presence of the same polymer. In contrast, neither of the two cocrystal solutions, in the presence of PVP or PVP-VA, exhibited a better performance than the pure FFA with the same predissolved polymer. The study suggests that the selection of a polymeric excipient in a cocrystal formulation should not be solely dependent on the interplay of the parent drug and polymer without considering the coformer effects. PMID- 27494290 TI - Historical record of nuclear activities from 129I in corals from the northern hemisphere (Philippines). AB - Iodine-129 is a long-lived fission product that is majorly released in human nuclear activities (HNA) such as nuclear bomb testing, nuclear fuel reprocessing, and nuclear accidents. It is a good environmental tracer and former measurements of 129I in corals from the southern hemisphere show the increasing trend of 129I concentrations in the marine environment caused by HNA. Here we show time series of 129I/127(stable)I isotopic ratios in two coral cores from the northern hemisphere (Philippines) and how these record 129I released from HNA in even greater, unprecedented detail. Corals were taken from the Pacific Ocean (Baler) and South China Sea (Parola) sides of the Philippines. We observed nearly identical peaks (129I/127I ~ 31.5 * 10-12) in both the Baler and Parola records, each attributed to the year 1962 - the year with the highest recorded amount of 129I release from nuclear bomb testing. This 1962 129I bomb signal offers a new time marker that can be used to establish or confirm age models of corals, comparable to or possibly better than the well-known coral 14C bomb peak. We also observed nuclear fuel reprocessing and Chernobyl accident 129I signals in years 1977, 1980, and 1986, concurrently in Parola and with 9 to 11-year lags in Baler. This discrepancy in timing suggests that 129I was transported to the South China Sea and Pacific Ocean sides of the Philippines directly from the atmosphere and through prevailing ocean currents, respectively. Lastly, we observed surprisingly high 129I/127I isotopic ratios (i.e., 22.8 to 38.9 * 10-12) in the Parola record after the year 1996, which is in contrast to the decreasing trend observed in the Baler record and in published 129I releases of different HNA. These results possibly indicate the presence of unknown sources of 129I in the South China Sea region. PMID- 27494291 TI - Ionizer induced 220Rn decay product removal in confined environment: Continuous vs. instantaneous source. AB - This paper presents an experimental approach to evaluate the effectiveness of unipolar ionizers in indoor environment for the removal of thoron (220Rn) daughter products. Both continuous and instantaneous source conditions were simulated during these experiments. Activity and aerosol related parameters were measured for these experiments and results were interpreted. Activity concentration was found to be reduced by a factor 6.6 and 34 for continuous and instantaneous source conditions, respectively. The particle size dependency of mitigation of particles using ionizer is also discussed. The effect of ionizer on activity size distribution has been directly measured for the first time. The ionizer induced changes in particle size distributions were coupled to Dose Reduction Factor (DRF) model and significant DRF values were obtained for both source conditions. This study discusses open issues which are important for establishing ionizer induced radioactivity mitigation as a technology application. PMID- 27494292 TI - The spatio-temporal specificity of PYR1/PYL/RCAR ABA receptors in response to developmental and environmental cues. AB - From the different functions ABA exerted between the aboveground and belowground, seed and vegetative tissues, primary root and lateral root, stimulating stomatal closure and inhibiting stomatal opening, between young and senescence leaves in stomatal movement, among different cells in plasma membrane water permeability, we addressed the organ-, tissue-, cell-, physiological processes-, and development stage specificities of PYR1/PYL/RCAR ABA receptors. This specificity may reflect the spatio-temporal properties of water potentials as well as the endogenous ABA levels in detail context, which plus the various affinities among this receptor families, resulted in the specificity of the transcripts as well as genes functions. PYR1/PYL/RCAR ABA receptors may integrate the message of ABA resource (local signaling or long distance signaling) and concentration, thus fine-tuning ABA response to environmental- and developmental cues. It also evolutionally affording land plants sophisticated mechanism to survival adverse environments. PMID- 27494293 TI - Effects of dispersal and selection on stochastic assembly in microbial communities. AB - Stochastic processes can play an important role in microbial community assembly. Dispersal limitation is one process that can increase stochasticity and obscure relationships between environmental variables and microbial community composition, but the relationship between dispersal, selection and stochasticity has not been described in a comprehensive way. We examine how dispersal and its interactions with drift and selection alter the consistency with which microbial communities assemble using a realistic, individual-based model of microbial decomposers. Communities were assembled under different environmental conditions and dispersal rates in repeated simulations, and we examined the compositional difference among replicate communities colonizing the same type of leaf litter ('within-group distance'), as well as between-group deterministic selection. Dispersal rates below 25% turnover per year resulted in high within-group distance among communities and no significant environmental effects. As dispersal limitation was alleviated, both within- and between-group distance decreased, but despite this homogenization, deterministic environmental effects remained significant. In addition to direct effects of dispersal rate, stochasticity of community composition was influenced by an interaction between dispersal and selection strength. Specifically, communities experiencing stronger selection (less favorable litter chemistries) were more stochastic, possibly because lower biomass and richness intensified drift or priority effects. Overall, we show that dispersal rate can significantly alter patterns of community composition. Partitioning the effects of dispersal, selection and drift based on static patterns of microbial composition will be difficult, if not impossible. Experiments will be required to tease apart these complex interactions between assembly processes shaping microbial communities. PMID- 27494294 TI - Human Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons: In Vivo Pharmacokinetics of Dibenzo[def,p]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry. AB - Metabolism is a key health risk factor following exposures to pro-carcinogenic polycyclic aromatic hydrocarbons (PAHs) such as dibenzo[def,p]chrysene (DBC), an IARC classified 2A probable human carcinogen. Human exposure to PAHs occurs primarily from the diet in nonsmokers. However, little data is available on the metabolism and pharmacokinetics in humans of high molecular weight PAHs (>=4 aromatic rings), including DBC. We previously determined the pharmacokinetics of DBC in human volunteers orally administered a microdose (29 ng; 5 nCi) of [14C] DBC by accelerator mass spectrometry (AMS) analysis of total [14C] in plasma and urine. In the current study, we utilized a novel "moving wire" interface between ultraperformance liquid chromatography (UPLC) and AMS to detect and quantify parent DBC and its major metabolites. The major [14C] product identified in plasma was unmetabolized [14C]-DBC itself (Cmax = 18.5 +/-15.9 fg/mL, Tmax= 2.1 +/- 1.0 h), whereas the major metabolite was identified as [14C]-(+/-)-DBC-11,12 diol (Cmax= 2.5 +/-1.3 fg/mL, Tmax= 1.8 h). Several minor species of [14C]-DBC metabolites were also detected for which no reference standards were available. Free and conjugated metabolites were detected in urine with [14C]-(+/-)-DBC 11,12,13,14-tetraol isomers identified as the major metabolites, 56.3% of which were conjugated (Cmax= 35.8 +/- 23.0 pg/pool, Tmax = 6-12 h pool). [14C]-DBC 11,12-diol, of which 97.5% was conjugated, was also identified in urine (Cmax = 29.4 +/- 11.6 pg/pool, Tmax = 6-12 h pool). Parent [14C]-DBC was not detected in urine. This is the first data set to assess metabolite profiles and associated pharmacokinetics of a carcinogenic PAH in human volunteers at an environmentally relevant dose, providing the data necessary for translation of high dose animal models to humans for translation of environmental health risk assessment. PMID- 27494295 TI - Time-resolved homo-FRET studies of biotin-streptavidin complexes. AB - Forster resonance energy transfer is a mechanism of fluorescence quenching that is notably useful for characterizing properties of biomolecules and/or their interactions. Here we study water-solutions of Biotin-Streptavidin complexes, in which Biotin is labeled with a rigidly-bound fluorophore that can interact by Forster resonance energy transfer with the fluorophores labeling the other, up to three, Biotins of the same complex. The fluorophore, Atto550, is a Rhodamine analogue. We detect the time-resolved fluorescence decay of the fluorophores with an apparatus endowed with single-photon sensitivity and temporal resolution of ~30ps. The decay profiles we observe for samples containing constant Biotin Atto550 conjugates and varying Streptavidin concentrations are multi-exponential. Each decay component can be associated with the rate of quenching exerted on each donor by each of the acceptors that label the other Biotin molecules, depending on the binding site they occupy. The main features that lead to this result are that (i) the transition dipole moments of the up-to-four Atto550 fluorophores that label the complexes are fixed as to both relative positions and mutual orientations; (ii) the fluorophores are identical and the role of donor in each Biotin-Streptavidin complex is randomly attributed to the one that has absorbed the excitation light (homo-FRET). Obviously the high-temporal resolution of the excitation-detection apparatus is necessary to discriminate among the fluorescence decay components. PMID- 27494296 TI - ClustENM: ENM-Based Sampling of Essential Conformational Space at Full Atomic Resolution. AB - Accurate sampling of conformational space and, in particular, the transitions between functional substates has been a challenge in molecular dynamic (MD) simulations of large biomolecular systems. We developed an Elastic Network Model (ENM)-based computational method, ClustENM, for sampling large conformational changes of biomolecules with various sizes and oligomerization states. ClustENM is an iterative method that combines ENM with energy minimization and clustering steps. It is an unbiased technique, which requires only an initial structure as input, and no information about the target conformation. To test the performance of ClustENM, we applied it to six biomolecular systems: adenylate kinase (AK), calmodulin, p38 MAP kinase, HIV-1 reverse transcriptase (RT), triosephosphate isomerase (TIM), and the 70S ribosomal complex. The generated ensembles of conformers determined at atomic resolution show good agreement with experimental data (979 structures resolved by X-ray and/or NMR) and encompass the subspaces covered in independent MD simulations for TIM, p38, and RT. ClustENM emerges as a computationally efficient tool for characterizing the conformational space of large systems at atomic detail, in addition to generating a representative ensemble of conformers that can be advantageously used in simulating substrate/ligand-binding events. PMID- 27494298 TI - Bioherbicidal activity of a germacranolide sesquiterpene dilactone from Ambrosia artemisiifolia L. AB - Ambrosia artemisiifolia L. (common ragweed) is an invasive plant whose allelopathic properties have been suggested by its field behaviour and demonstrated through phytotoxicity bioassays. However, the nature of the molecules responsible for the allelopathic activity of common ragweed has not been explored. The main objective of this study was to identify the phytotoxic molecules produced by A. artemisiifolia. A preliminary investigation has indicated that a methanol extract of A. artemisiifolia completely inhibited the germination of cress and radish. Semi-preparative fractionation of the methanol extract allowed separating of phytotoxic fraction which contained a single compound. The structure of this compound was elucidated by liquid chromatography mass spectrometry (LC-MS)/MS, high-resolution mass spectral, nuclear magnetic resonance, and Fourier transform infrared spectra as sesquiterpene lactone isabelin (C15H16O4). The effect of pure isabelin was tested on four different weed species, confirming the inhibitory activity of molecule. The results indicate directions for the future studies about herbicidal specific activity of isabelin, as pure molecule or in the crude extract, as a potential candidate for biological weed control. PMID- 27494297 TI - Cell type specific DNA methylation in cord blood: A 450K-reference data set and cell count-based validation of estimated cell type composition. AB - Epigenome-wide association studies of prenatal exposure to different environmental factors are becoming increasingly common. These studies are usually performed in umbilical cord blood. Since blood comprises multiple cell types with specific DNA methylation patterns, confounding caused by cellular heterogeneity is a major concern. This can be adjusted for using reference data consisting of DNA methylation signatures in cell types isolated from blood. However, the most commonly used reference data set is based on blood samples from adult males and is not representative of the cell type composition in neonatal cord blood. The aim of this study was to generate a reference data set from cord blood to enable correct adjustment of the cell type composition in samples collected at birth. The purity of the isolated cell types was very high for all samples (>97.1%), and clustering analyses showed distinct grouping of the cell types according to hematopoietic lineage. We explored whether this cord blood and the adult peripheral blood reference data sets impact the estimation of cell type composition in cord blood samples from an independent birth cohort (MoBa, n = 1092). This revealed significant differences for all cell types. Importantly, comparison of the cell type estimates against matched cell counts both in the cord blood reference samples (n = 11) and in another independent birth cohort (Generation R, n = 195), demonstrated moderate to high correlation of the data. This is the first cord blood reference data set with a comprehensive examination of the downstream application of the data through validation of estimated cell types against matched cell counts. PMID- 27494299 TI - Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy. AB - : Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] <= 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (>=1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and 7.8 (-44.3, 28.8) kg/m2 * g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis. TRIAL REGISTRATION: ClincalTrials.gov Identifier: NCT00409175, NCT00791492, and NCT00925002. PMID- 27494300 TI - Regulation of platelet membrane protein shedding in health and disease. AB - Extracellular proteolysis of platelet plasma membrane proteins is an event that ensues platelet activation. Shedding of surface receptors such as glycoprotein (GP) Ibalpha, GPV and GPVI as well as externalized proteins P-selectin and CD40L releases soluble ectodomain fragments that are subsequently detectable in plasma. This results in the irreversible functional downregulation of platelet receptor mediated adhesive interactions and the generation of biologically active fragments. In this review, we describe molecular insights into the regulation of platelet receptor and ligand shedding in health and disease. The scope of this review is specially focused on GPIbalpha, GPV, GPVI, P-selectin and CD40L where we: (1) describe the basic physiological regulation of expression and shedding of these proteins in hemostasis illustrate alterations in receptor expression during (2) apoptosis and (3) ex vivo storage relevant for blood banking purposes; (4) discuss considerations to be made when analyzing and interpreting shedding of platelet membrane proteins and finally; (5) collate clinical evidence that quantify these platelet proteins during disease. PMID- 27494301 TI - Community-acquired hyperkalemia in elderly patients: risk factors and clinical outcomes. AB - BACKGROUND: Although the risk and related factors of hyperkalemia developed in the hospital are known in elderly, risk and related factors of community-acquired hyperkalemia (CAH) in this population are not well known. This study was performed to investigate the risk of CAH in elderly and evaluate the related factors and clinical outcomes. Study design, setting and participants, intervention: Patients (aged >=65 years) with hyperkalemia were screened. Group 1 (young-old); 65-74 years/old, Group 2 (middle-old); 75-84 years/old, Group 3 (oldest-old); >=85 years/old, and Group 4 (control group); >=65 years/old (normal serum potassium levels). The relation between CAH and hospital expenses (HE), the number of comorbid diseases (NCD), and all-cause of mortality rates (MR) were evaluated. We also investigated whether drugs, sex, and NCD are risk factors for the development of CAH. RESULTS: There was a positive correlation between serum potassium levels and length of hospital stay, MR, HE, and NCD (p < 0.001). Risk factors for CAH were the use of non-steroidal-anti inflammatory drugs (NSAIDs) (Odds Ratio [OR]: 2.679), spironolactone (OR: 2.530), and angiotensin converting enzyme inhibitors (ACEI) (OR: 2.242), angiotensin receptor blockers (ARB) (OR: 2.679), >=2 comorbid diseases (OR: 2.221), female gender (OR: 2.112), and renal injury (OR: 5.55). CAH risk was found to be increased 30.03 times when any of ACEI, ARB, NSAIDs, or spironolactone is given to a patient with a renal injury. CONCLUSION: Use of NSAIDs, ACEI, ARB, spironolactone and increased NCD are all independent risk factors for CAH in the elderly, especially in patients with kidney diseases. PMID- 27494302 TI - Drug repurposing: a new front in the war against Staphylococcus aureus. AB - Staphylococcus aureus continues its domination of worldwide bacterial infection rates, thereby remaining a pathogen of significant public health interest. A major reason for its continued success is its ability to acquire and maintain diverse drug resistance mechanisms, leading to a paucity of antimicrobials active against it, concomitantly leading to a continuous search for new antimicrobial agents. However, with the withdrawal of the major pharmaceutical firms from the anti-infective area, drug repurposing has provided a potential boost to the drug pipeline. In this review, we provide an overview of the currently approved drugs with repurposing potential against Staphylococcus aureus, thus augmenting the classical drug discovery pathway. PMID- 27494304 TI - The effect of dual tasking on foot kinematics in people with functional ankle instability. AB - BACKGROUND: Some cases of repeated inversion ankle sprains are thought to have a neurological basis and are termed functional ankle instability (FAI). In addition to factors local to the ankle, such as loss of proprioception, cognitive demands have the ability to influence motor control and may increase the risk of repetitive lateral sprains. OBJECTIVE: The purpose of this study was to investigate the effect of cognitive demand on foot kinematics in physically active people with functional ankle instability. METHODS: 21 physically active participants with FAI and 19 matched healthy controls completed trials of normal walking (single task) and normal walking while performing a cognitive task (dual task). Foot motion relative to the shank was recorded. Cognitive performance, ankle kinematics and movement variability in single and dual task conditions was characterized. RESULTS: During normal walking, the ankle joint was significantly more inverted in FAI compared to the control group pre and post initial contact. Under dual task conditions, there was a statistically significant increase in frontal plane foot movement variability during the period 200ms pre and post initial contact in people with FAI compared to the control group (p<0.05). Dual task also significantly increased plantar flexion and inversion during the period 200ms pre and post initial contact in the FAI group (p<0.05). CONCLUSION: participants with FAI demonstrated different ankle movement patterns and increased movement variability during a dual task condition. Cognitive load may increase risk of ankle instability in these people. PMID- 27494305 TI - Mobile inertial sensor based gait analysis: Validity and reliability of spatiotemporal gait characteristics in healthy seniors. AB - Gait analysis is commonly used to identify gait changes and fall risk in clinical populations and seniors. Body-worn inertial sensor based gait analyses provide a feasible alternative to optometric and pressure based measurements of spatiotemporal gait characteristics. We assessed validity and relative and absolute reliability of a body-worn inertial sensor system (RehaGait((r))) for measuring spatiotemporal gait characteristics compared to a standard stationary treadmill (Zebris((r))). Spatiotemporal gait parameters (walking speed, stride length, cadence and stride time) were collected for 24 healthy seniors (age: 75.3+/-6.7 years) tested on 2 days (1 week apart) simultaneously using the sensor based system and instrumented treadmill. Each participant completed walking tests (200 strides) at different walking speeds and slopes. The difference between the RehaGait((r)) system and the treadmill was trivial (Cohen's d<0.2) except for speed and stride length at slow speed (Cohen's d, 0.35 and 0.49, respectively). Intraclass correlation coefficients (ICC) were excellent for temporal gait characteristics (cadence and stride time; ICC: 0.99-1.00) and moderate for stride length (ICC: 0.73-0.89). Both devices had excellent day-to-day reliability for all gait parameters (ICC: 0.82-0.99) except for stride length at slow speed (ICC: 0.74). The RehaGait((r)) is a valid and reliable tool for assessing spatiotemporal gait parameters for treadmill walking at different speeds and slopes. PMID- 27494303 TI - Hypoxia-Inducible Factor-1alpha Regulates CD55 in Airway Epithelium. AB - Airway epithelial CD55 down-regulation occurs in several hypoxia-associated pulmonary diseases, but the mechanism is unknown. Using in vivo and in vitro assays of pharmacologic inhibition and gene silencing, the current study investigated the role of hypoxia-inducible factor (HIF)-1alpha in regulating airway epithelial CD55 expression. Hypoxia down-regulated CD55 expression on small-airway epithelial cells in vitro, and in murine lungs in vivo; the latter was associated with local complement activation. Treatment with pharmacologic inhibition or silencing of HIF-1alpha during hypoxia-recovered CD55 expression in small-airway epithelial cells. HIF-1alpha overexpression or blockade, in vitro or in vivo, down-regulated CD55 expression. Collectively, these data show a key role for HIF-1alpha in regulating the expression of CD55 on airway epithelium. PMID- 27494306 TI - Facile Preparation of Stable Antibody-Gold Conjugates and Application to Affinity Capture Self-Interaction Nanoparticle Spectroscopy. AB - Protein-nanoparticle conjugates are widely used for conventional applications such as immunohistochemistry and biomolecular detection as well as emerging applications such as therapeutics and advanced materials. Nevertheless, it remains challenging to reproducibly prepare stable protein-nanoparticle conjugates with highly similar optical properties. Here we report an improved physisorption method for reproducibly preparing stable antibody-gold conjugates at acidic pH using polyclonal antibodies from a wide range of species (human, goat, rabbit, mouse, and rat). We find that gold particles synthesized using citrate alone or in combination with tannic acid are similar in size but display variable colloidal stability when conjugated to polyclonal antibodies. The variability in conjugate stability is due to differences in the pH and composition of the original gold colloid, which prevents reproducible preparation of stable antibody conjugates without additional purification of the particles prior to conjugation. Sedimentation-based purification of gold particles synthesized using different methods enabled reproducible generation of antibody gold conjugates with high stability and similar plasmon wavelengths. We also find that antibody conjugates prepared using our improved procedure display excellent performance when applied to a high-throughput immunogold assay (affinity-capture self-interaction nanoparticle spectroscopy, AC-SINS) for identifying monoclonal antibodies with low self-association, high solubility, and low viscosity. The stable antibody conjugates prepared with various types of gold colloid result in robust and reproducible AC-SINS measurements of antibody self-association using extremely dilute (microgram per mL) and unpurified antibody solutions. We expect that this improved methodology will be useful for reproducibly preparing stable antibody-gold conjugates for diverse applications. PMID- 27494309 TI - An Evaluation Tool for Agricultural Health and Safety Mobile Applications. AB - As the use of mobile devices and their software applications, or apps, becomes ubiquitous, use amongst agricultural working populations is expanding as well. The smart device paired with a well-designed app has potential for improving workplace health and safety in the hands of those who can act upon the information provided. Many apps designed to assess workplace hazards and implementation of worker protections already exist. However, the abundance and diversity of such applications also presents challenges regarding evaluation practices and assignation of value. This is particularly true in the agricultural workspace, as there is currently little information on the value of these apps for agricultural safety and health. This project proposes a framework for developing and evaluating apps that have potential usefulness in agricultural health and safety. The evaluation framework is easily transferable, with little modification for evaluation of apps in several agriculture-specific areas. PMID- 27494310 TI - Significance of Pharmacogenetics and Pharmacogenomics Research in Current Medical Practice. AB - Human genome sequencing highlights the involvement of genetic variation towards differential risk of human diseases, presence of different phenotypes, and response to pharmacological elements. This brings the field of personalized medicine to forefront in the era of modern health care. Numerous recent approaches have shown that how variation in the genome at single nucleotide level can be used in pharmacological research. The two broad aspects that deal with pharmacological research are pharmacogenetics and pharmacogenomics. This review encompasses how these variations have created the basis of pharmacogenetics and pharmacogenomics research and important milestones accomplished in these two fields in different diseases. It further discusses at length their importance in disease diagnosis, response of drugs, and various treatment modalities on the basis of genetic determinants. PMID- 27494308 TI - Examination of the association of sex and race/ethnicity with appearance concerns: a Scleroderma Patient-centered Intervention Network (SPIN) Cohort study. AB - OBJECTIVES: Appearance concerns are common in systemic sclerosis (SSc) and have been linked to younger age and more severe disease. No study has examined their association with sex or race/ethnicity. METHODS: SSc patients were sampled from the Scleroderma Patient-centered Intervention Network Cohort. Presence of appearance concerns was assessed with a single item, and medical and sociodemographic information were collected. RESULTS: Of 644 patients, appearance concerns were present in 72%, including 421 of 565 women (75%), 42 of 79 men (53%), 392 of 550 patients who identified as White (71%), 35 of 41 who identified as Black (85%), and 36 of 53 who identified as another race/ethnicity (68%). In multivariate analysis, women had significantly greater odds of reporting appearance concerns than men (odds ratio (OR)=2.97, 95% confidence interval (CI)=1.78-4.95, p<.001). Black patients had significantly greater odds of appearance concerns than White patients in unadjusted (OR=2.64, 95% CI=1.01-6.34, p=.030), but not multivariate analysis (OR=1.76, 95% CI=0.67-4.60, p=.250). Compared to a general population sample, appearance concerns were substantially more common in SSc, particularly for men across all age groups and for younger women. The most commonly reported features of concern were related to the face and head, followed by the hands and fingers; this did not differ by sex or race/ethnicity. CONCLUSIONS: Appearance concerns were common in SSc. Women were substantially more likely than men to have appearance concerns. Although non significant in multivariate analysis, Black patients were more likely to have concerns than White patients, likely due to more severe changes in appearance. PMID- 27494311 TI - Influence of silver nanoparticles on heavy metals of pore water in contaminated river sediments. AB - Despite the increasing knowledge on the discharge of silver nanoparticles (AgNPs) into the environment and their potential toxicity to microorganisms, the interaction of AgNPs with heavy metals remains poorly understood. This study focused on the effect of AgNPs on heavy metal concentration and form in sediment contaminated with heavy metals from the Xiangjiang River. The results showed that the concentration of Cu, Zn, Pb and Cd decreased and then increased with a change in form. The changes in form and concentrations of heavy metals in pore water suggested that Cu and Zn were more likely to be affected compared to Pb and Cd. The concentrations of Hg in sediment pore water in three AgNPs-dosed containers, increased greatly until they reached their peaks at 4.468 +/- 0.133, 4.589 +/- 0.235, and 5.083 +/- 0.084 MUg L(-1) in Bare AgNPs, Citrate AgNPs and Tween 80 AgNPs, respectively. The measurements of Hg concentrations in the sediment pore water, combined with SEM and EDX analysis, demonstrated that added AgNPs stabilized in pore water and formed an amalgam with Hg(0), which can affect Hg transportation over long distance. PMID- 27494312 TI - Toluene removal by sequential adsorption-plasma catalytic process: Effects of Ag and Mn impregnation sequence on Ag-Mn/gamma-Al2O3. AB - A series of Ag-Mn/gamma-Al2O3 were prepared under different Ag/Mn impregnation sequence and tested in the sequential adsorption-plasma catalytic removal of toluene. When Mn was impregnated first, the resulting catalyst, Ag-Mn(F)/gamma Al2O3, had longer breakthrough time, gave less emission of toluene, had higher CO2 selectivity, and had better carbon balance and COx yield compared to catalysts prepared via other impregnation sequences. After 120 min of NTP treatment, the carbon balance of Ag-Mn(F)/gamma-Al2O3 was 91%, with 87% as COx contributions. A Brunauer-Emmett-Teller (BET) analysis and X-ray photoelectron spectroscopy (XPS) results show that, the impregnation sequence impacts the BET surface area and the ratio and existing state of Ag on the surface of the catalysts. The longer breakthrough time when using Ag-Mn(F)/gamma-Al2O3 as catalyst is attributed to the large amount of Ag(+) on the surface. Ag(+) is a new active site for toluene adsorption. When Ag was impregnated first (Ag(F) Mn/gamma-Al2O3) or Ag and Mn co-impregnated (Ag-Mn-C/gamma-Al2O3), the predominant specie was Ag(+). Both Ag(0) and Ag(+) species were detected on Ag Mn(F)/gamma-Al2O3. Ag(0) cooperation with MnOx may promote the migration of surface active oxygen. This would facilitate the oxidation of adsorbed toluene with CC bond already weakened by Ag(+) and would result in higher CO2 selectivity and better carbon balance as seen in the Ag-Mn(F)/gamma-Al2O3 system. PMID- 27494313 TI - Microbial toxicity of ionic species leached from the II-VI semiconductor materials, cadmium telluride (CdTe) and cadmium selenide (CdSe). AB - This work investigated the microbial toxicity of soluble species that can potentially be leached from the II-VI semiconductor materials, cadmium telluride and cadmium selenide. The soluble ions tested included: cadmium, selenite, selenate, tellurite, and tellurate. Their toxicity towards the acetoclastic and hydrogen-consuming trophic groups in a methanogenic consortium as well as towards a bioluminescent marine bacterium, Aliivibrio fischeri (Microtox((r)) test), was assessed. The acetoclastic methanogenic activity was the most affected as evidenced by the low 50% inhibiting concentrations (IC50) values obtained of 8.6 mg L(-1) for both cadmium and tellurite, 10.2 mg L(-1) for tellurate, and 24.1 mg L(-1) for selenite. Both tellurium oxyanions caused a strong inhibition of acetoclastic methanogenesis at low concentrations, each additional increment in concentration provided progressively less inhibition increase. In the case of the hydrogenotrophic methanogenesis, cadmium followed by selenite caused the greatest inhibition with IC50 values of 2.9 and 18.0 mg L(-1), respectively. Tellurite caused a moderate effect as evidenced by a 36.8% inhibition of the methanogenic activity at the highest concentration tested, and a very mild effect of tellurate was observed. Microtox((r)) analyses showed a noteworthy inhibition of cadmium, selenite, and tellurite with 50% loss in bioluminescence after 30 min of exposure of 5.5, 171.1, and 458.6 mg L(-1), respectively. These results suggest that the leaching of cadmium, tellurium and selenium ions from semiconductor materials can potentially cause microbial toxicity. PMID- 27494314 TI - Enhanced stable long-term operation of biotrickling filters treating VOCs by low dose ozonation and its affecting mechanism on biofilm. AB - For long-term operation of highly loaded biotrickling filters (BTFs), the prevention of excess biomass accumulation was essential for avoiding BTF failure. In this study, we proposed low-dose ozonation as a biomass control strategy to maintain high removal efficiencies of volatile organic compounds (VOCs) over extended operation of BTFs. To obtain an optimized biomass control strategy, the relative performance of five parallel BTFs receiving different ozone doses was determined, and the affecting mechanism of ozonation on biofilm was elucidated. Experimental results showed that the decline in ozone-free BTF performance began from day 150, which was correlated with excess biomass accumulation, abundant excretion of extracellular polymeric substances (EPS) and a decline in metabolic activity of biofilm over extended operation. Ozone of 5-10 mg m(-3) was effective in preventing excessive growth and uneven distribution of biomass, and eventually maintaining long-term stable operations. Ozone of over 20 mg m(-3) possibly inhibited microorganism growth severely, thereby deteriorating the elimination performance instead. Comparison of the biofilm EPS indicated that the presence of ozone reduce EPS contents to different extents, which was possibly beneficial for mass transfer and metabolic activity. Comparative community analysis showed that ozonation resulted in different microbial communities in the BTFs. Dyella was found to be the most abundant bacterial genera in all BTFs regardless of ozonation, indicating strong resistance to ozonation. Chryseobacterium and Burkholderia members were markedly enriched in the ozone-added biofilm, implying good adaptation to ozone presence. These findings provided an improved understanding of low-dose ozonation in maintaining a stable long-term operation of BTF. PMID- 27494315 TI - Studies on organic and in-organic biostimulants in bioremediation of diesel contaminated arable soil. AB - In this study, use of inorganic fertilizer (N.P.K) was compared with organic manure (compost) in the bioremediation of diesel-polluted agricultural soil over a two-month period. Renewal by enhanced natural attenuation was used as control. The results revealed that total petroleum hydrocarbon removal from polluted soil was 71.40 +/- 5.60% and 93.31 +/- 3.60% for N.P.K and compost amended options, respectively. The control (natural attenuation) had 57.90 +/- 3.98% of total petroleum hydrocarbon removed. Experimental data fitted second order kinetic model adequately for compost amended option. The fertilizer amended option was found to be 1.04 times slower (k2 = 4.00 +/- 1.40 * 10(-7)gmg(-1)d(-1), half-life = 28.15 d) than compost amended option (k2 = 1.39 +/- 0.54 * 10(-5) gmg(-1)d(-1), half-life = 8.10 d) but 1.21 times (20.6%) faster than the control (k2 = 2.57 +/- 0.16 * 10(-7) gmg(-1)d(-1), half-life = 43.81 d). The hydrocarbon utilizers isolated from the diesel contaminated soil were: Bacillus nealsoni, Micrococcus luteus, Aspergillus awamori, and Fusarium proliferatum. The phytotoxicity test showed that germination indices for natural attenuation (control), fertilizer (NPK) and compost amended options were 34%, 56%, and 89%, respectively. PMID- 27494316 TI - Degradation mechanisms of geosmin and 2-MIB during UV photolysis and UV/chlorine reactions. AB - We conducted chlorination, UV photolysis, and UV/chlorin reactions to investigate the intermediate formation and degradation mechanisms of geosmin and 2 methylisoborneol (2-MIB) in water. Chlorination hardly removed geosmin and 2-MIB, while the UV/chlorine reaction at 254 nm completely removed geosmin and 2-MIB within 40 min and 1 h, respectively, with lesser removals of both compounds during UV photolysis. The kinetics during both UV photolysis and UV/chlorine reactions followed a pseudo first-order reaction. Chloroform was found as a chlorinated intermediate during the UV/chlorine reaction of both geosmin and 2 MIB. The pH affected both the degradation and chloroform production during the UV/chlorine reaction. The open ring and dehydration intermediates identified during UV/chlorine reactions were 1,4-dimethyl-adamantane, and 1,3-dimethyl adamantane from geosmin, 2-methylenebornane, and 2-methyl-2-bornene from 2-MIB, respectively. Additionally, 2-methyl-3-pentanol, 2,4-dimethyl-1-heptene, 4-methyl 2-heptanone, and 1,1-dichloro-2,4-dimethyl-1-heptane were newly identified intermediates from UV/chlorine reactions of both geosmin and 2-MIB. These intermediates were degraded as the reaction progressed. We proposed possible degradation pathways during the UV photolysis and UV/chlorine reactions of both compounds using the identified intermediates. PMID- 27494317 TI - Sorbent materials for rapid remediation of wash water during radiological event relief. AB - Procedures for removing harmful radiation from interior and exterior surfaces of homes and businesses after a nuclear or radiological disaster may generate large volumes of radiologically contaminated waste water. Rather than releasing this waste water to potentially contaminate surrounding areas, it is preferable to treat it onsite. Retention barrels are a viable option because of their simplicity in preparation and availability of possible sorbent materials. This study investigated the use of aluminosilicate clay minerals as sorbent materials to retain (137)Cs, (85)Sr, and (152)Eu. Vermiculite strongly retained (137)Cs, though other radionuclides displayed diminished affinity for the surface. Montmorillonite exhibited increased affinity to sorb (85)Sr and (152)Eu in the presence of higher concentrations of (137)Cs. To simulate flow within retention barrels, vermiculite was mixed with sand and used in small-scale column experiments. The GoldSim contaminate fate module was used to model breakthrough and assess the feasibility of using clay minerals as sorbent materials in retention barrels. The modeled radionuclide breakthrough profiles suggest that vermiculite-sand and montmorillonite-sand filled barrels could be used for treatment of contaminated water generated from field operations. PMID- 27494319 TI - A Method for Non-Rigid Face Alignment via Combining Local and Holistic Matching. AB - We propose a method for non-rigid face alignment which only needs a single template, such as using a person's smile face to match his surprise face. First, in order to be robust to outliers caused by complex geometric deformations, a new local feature matching method called K Patch Pairs (K-PP) is proposed. Specifically, inspired by the state-of-art similarity measure used in template matching, K-PP is to find the mutual K nearest neighbors between two images. A weight matrix is then presented to balance the similarity and the number of local matching. Second, we proposed a modified Lucas-Kanade algorithm combined with local matching constraint to solve the non-rigid face alignment, so that a holistic face representation and local features can be jointly modeled in the object function. Both the flexible ability of local matching and the robust ability of holistic fitting are included in our method. Furthermore, we show that the optimization problem can be efficiently solved by the inverse compositional algorithm. Comparison results with conventional methods demonstrate our superiority in terms of both accuracy and robustness. PMID- 27494318 TI - Echoic Sensory Substitution Information in a Single Obstacle Circumvention Task. AB - Accurate motor control is required when walking around obstacles in order to avoid collisions. When vision is unavailable, sensory substitution can be used to improve locomotion through the environment. Tactile sensory substitution devices (SSDs) are electronic travel aids, some of which indicate the distance of an obstacle using the rate of vibration of a transducer on the skin. We investigated how accurately such an SSD guided navigation in an obstacle circumvention task. Using an SSD, 12 blindfolded participants navigated around a single flat 0.6 x 2 m obstacle. A 3-dimensional Vicon motion capture system was used to quantify various kinematic indices of human movement. Navigation performance under full vision was used as a baseline for comparison. The obstacle position was varied from trial to trial relative to the participant, being placed at two distances 25 cm to the left, right or directly ahead. Under SSD guidance, participants navigated without collision in 93% of trials. No collisions occurred under visual guidance. Buffer space (clearance between the obstacle and shoulder) was larger by a factor of 2.1 with SSD guidance than with visual guidance, movement times were longer by a factor of 9.4, and numbers of velocity corrections were larger by a factor of 5 (all p<0.05). Participants passed the obstacle on the side affording the most space in the majority of trials for both SSD and visual guidance conditions. The results are consistent with the idea that SSD information can be used to generate a protective envelope during locomotion in order to avoid collisions when navigating around obstacles, and to pass on the side of the obstacle affording the most space in the majority of trials. PMID- 27494320 TI - Population Structure, Genetic Diversity and Molecular Marker-Trait Association Analysis for High Temperature Stress Tolerance in Rice. AB - Rice exhibits enormous genetic diversity, population structure and molecular marker-traits associated with abiotic stress tolerance to high temperature stress. A set of breeding lines and landraces representing 240 germplasm lines were studied. Based on spikelet fertility percent under high temperature, tolerant genotypes were broadly classified into four classes. Genetic diversity indicated a moderate level of genetic base of the population for the trait studied. Wright's F statistic estimates showed a deviation of Hardy-Weinberg expectation in the population. The analysis of molecular variance revealed 25 percent variation between population, 61 percent among individuals and 14 percent within individuals in the set. The STRUCTURE analysis categorized the entire population into three sub-populations and suggested that most of the landraces in each sub-population had a common primary ancestor with few admix individuals. The composition of materials in the panel showed the presence of many QTLs representing the entire genome for the expression of tolerance. The strongly associated marker RM547 tagged with spikelet fertility under stress and the markers like RM228, RM205, RM247, RM242, INDEL3 and RM314 indirectly controlling the high temperature stress tolerance were detected through both mixed linear model and general linear model TASSEL analysis. These markers can be deployed as a resource for marker-assisted breeding program of high temperature stress tolerance. PMID- 27494321 TI - Genome-Wide Association Analyses in 128,266 Individuals Identifies New Morningness and Sleep Duration Loci. AB - Disrupted circadian rhythms and reduced sleep duration are associated with several human diseases, particularly obesity and type 2 diabetes, but until recently, little was known about the genetic factors influencing these heritable traits. We performed genome-wide association studies of self-reported chronotype (morning/evening person) and self-reported sleep duration in 128,266 white British individuals from the UK Biobank study. Sixteen variants were associated with chronotype (P<5x10-8), including variants near the known circadian rhythm genes RGS16 (1.21 odds of morningness, 95% CI [1.15, 1.27], P = 3x10-12) and PER2 (1.09 odds of morningness, 95% CI [1.06, 1.12], P = 4x10-10). The PER2 signal has previously been associated with iris function. We sought replication using self reported data from 89,283 23andMe participants; thirteen of the chronotype signals remained associated at P<5x10-8 on meta-analysis and eleven of these reached P<0.05 in the same direction in the 23andMe study. We also replicated 9 additional variants identified when the 23andMe study was used as a discovery GWAS of chronotype (all P<0.05 and meta-analysis P<5x10-8). For sleep duration, we replicated one known signal in PAX8 (2.6 minutes per allele, 95% CI [1.9, 3.2], P = 5.7x10-16) and identified and replicated two novel associations at VRK2 (2.0 minutes per allele, 95% CI [1.3, 2.7], P = 1.2x10-9; and 1.6 minutes per allele, 95% CI [1.1, 2.2], P = 7.6x10-9). Although we found genetic correlation between chronotype and BMI (rG = 0.056, P = 0.05); undersleeping and BMI (rG = 0.147, P = 1x10-5) and oversleeping and BMI (rG = 0.097, P = 0.04), Mendelian Randomisation analyses, with limited power, provided no consistent evidence of causal associations between BMI or type 2 diabetes and chronotype or sleep duration. Our study brings the total number of loci associated with chronotype to 22 and with sleep duration to three, and provides new insights into the biology of sleep and circadian rhythms in humans. PMID- 27494322 TI - Cost-Effectiveness Analysis of 1-Year Treatment with Golimumab/Standard Care and Standard Care Alone for Ulcerative Colitis in Poland. AB - OBJECTIVE: The objective of this study was to assess the cost-effectiveness of induction and maintenance treatment up to 1 year of ulcerative colitis with golimumab/standard care and standard care alone in Poland. METHODS: A Markov model was used to estimate the expected costs and effects of golimumab/standard care and a standard care alone. For each treatment option the costs and quality adjusted life years were calculated to estimate the incremental cost-utility ratio. The analysis was performed from the perspective of the Polish public payer and society over a 30-years time horizon. The clinical parameters were derived mainly from the PURSUIT-SC and PURSUIT-M clinical trials. Different direct and indirect costs and utility values were assigned to the various model health states. RESULTS: The treatment of ulcerative colitis patients with golimumab/standard care instead of a standard care alone resulted in 0.122 additional years of life with full health. The treatment with golimumab/standard care was found to be more expensive than treatment with the standard care alone from the public payer perspective and from social perspective. The incremental cost-utility ratio of golimumab/standard care compared to the standard care alone is estimated to be 391,252 PLN/QALY gained (93,155 ?/QALYG) from public payer perspective and 374,377 PLN/QALY gained (89,137 ?/QALYG) from social perspective. CONCLUSIONS: The biologic treatment of ulcerative colitis patients with golimumab/standard care is more effective but also more costly compared with standard care alone. PMID- 27494323 TI - Leishmania donovani Utilize Sialic Acids for Binding and Phagocytosis in the Macrophages through Selective Utilization of Siglecs and Impair the Innate Immune Arm. AB - BACKGROUND: Leishmania donovani, belonging to a unicellular protozoan parasite, display the differential level of linkage-specific sialic acids on their surface. Sialic acids binding immunoglobulin-like lectins (siglecs) are a class of membrane-bound receptors present in the haematopoetic cell lineages interact with the linkage-specific sialic acids. Here we aimed to explore the utilization of sialic acids by Leishmania donovani for siglec-mediated binding, phagocytosis, modulation of innate immune response and signaling pathways for establishment of successful infection in the host. METHODOLOGY/PRINCIPLE FINDINGS: We have found enhanced binding of high sialic acids containing virulent strains (AG83+Sias) with siglec-1 and siglec-5 present on macrophages compared to sialidase treated AG83+Sias (AG83-Sias) and low sialic acids-containing avirulent strain (UR6) by flow cytometry. This specific receptor-ligand interaction between sialic acids and siglecs were further confirmed by confocal microscopy. Sialic acids-siglec-1 mediated interaction of AG83+Sias with macrophages induced enhanced phagocytosis. Additionally, sialic acids-siglec-5 interaction demonstrated reduced ROS, NO generation and Th2 dominant cytokine response upon infection with AG83+Sias in contrast to AG83-Sias and UR6. Sialic acids-siglecs binding also facilitated multiplication of intracellular amastigotes. Moreover, AG83+Sias induced sialic acids-siglec-5-mediated upregulation of host phosphatase SHP-1. Such sialic acids siglec interaction was responsible for further downregulation of MAPKs (p38, ERK and JNK) and PI3K/Akt pathways followed by the reduced translocation of p65 subunit of NF-kappabeta to the nucleus from cytosol in the downstream signaling pathways. This sequence of events was reversed in AG83-Sias and UR6-infected macrophages. Besides, siglec-knockdown macrophages also showed the reversal of AG83+Sias infection-induced effector functions and downstream signaling events. CONCLUSIONS/SIGNIFICANCES: Taken together, this study demonstrated that virulent parasite (AG83+Sias) establish a unique sialic acids-mediated binding and subsequent phagocytosis in the host cell through the selective exploitation of siglec-1. Additionally, sialic acids-siglec-5 interaction altered the downstream signaling pathways which contributed impairment of immune effector functions of macrophages. To the best of our knowledge, this is a comprehensive report describing sialic acids-siglec interactions and their role in facilitating uptake of the virulent parasite within the host. PMID- 27494325 TI - Contribution of dot-blot assay to the diagnosis and management of myositis: a three-year practice at a university hospital centre. AB - OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are heterogeneous autoimmune diseases with wide clinical spectrum that may lead to delayed diagnosis. The aim of this study was to examine the impact of IIM-specific dot-blot assay on diagnostic process of patients presenting with muscular or systemic symptoms evocating of IIM. METHODS: We collected all the prescriptions of an IIM specific dot-blot assay (8 autoantigens including Jo-1, PL-7, PL-12, SRP, Mi-2, Ku, PM/Scl and Scl-70) over a 38-month period. RESULTS: 316 myositis dot-blot assays (MSD) were performed in 274 patients (156 women, mean age 53+/-10.6 years) referring for muscular and/or systemic symptoms suggesting IIM. The timing of dot prescription through the diagnostic process was highly variable: without (35%), concomitantly (16%) or after electromyographic studies (35%). Fifty-nine patients (22%) had IIM according to Bohan and Peter's criteria. Among them, 29 (49%) had positive dot (8 Jo-1, 6 PM-Scl, 5 PL-12, 5 SRP, 2 Mi-2, 2 PL-7 and 1 Ku). Various other diagnoses were performed including 35 autoimmune disease or granulomatosis (12%), 19 inflammatory rheumatic disease (7%), 16 non inflammatory muscular disorders (6%), 10 drug-induced myalgia (4%), 11 infectious myositis (4%). Except 11 borderline SRP results and one transient PM-Scl, MSD was positive only in one case of IIM. Dot allowed clinicians to correct diagnosis in 4 cases and improved the diagnosis of IIM subtypes in 4 cases. CONCLUSIONS: This study reflects the interest of myositis dot in the rapid diagnosis process of patients with non specific muscular symptoms leading to various diagnoses including IIM. PMID- 27494324 TI - Prenatal Cocaine Exposure Upregulates BDNF-TrkB Signaling. AB - Prenatal cocaine exposure causes profound changes in neurobehavior as well as synaptic function and structure with compromised glutamatergic transmission. Since synaptic health and glutamatergic activity are tightly regulated by brain derived neurotrophic factor (BDNF) signaling through its cognate tyrosine receptor kinase B (TrkB), we hypothesized that prenatal cocaine exposure alters BDNF-TrkB signaling during brain development. Here we show prenatal cocaine exposure enhances BDNF-TrkB signaling in hippocampus and prefrontal cortex (PFCX) of 21-day-old rats without affecting the expression levels of TrkB, P75NTR, signaling molecules, NMDA receptor-NR1 subunit as well as proBDNF and BDNF. Prenatal cocaine exposure reduces activity-dependent proBDNF and BDNF release and elevates BDNF affinity for TrkB leading to increased tyrosine-phosphorylated TrkB, heightened Phospholipase C-gamma1 and N-Shc/Shc recruitment and higher downstream PI3K and ERK activation in response to ex vivo BDNF. The augmented BDNF-TrkB signaling is accompanied by increases in association between activated TrkB and NMDARs. These data suggest that cocaine exposure during gestation upregulates BDNF-TrkB signaling and its interaction with NMDARs by increasing BDNF affinity, perhaps in an attempt to restore the diminished excitatory neurotransmission. PMID- 27494329 TI - Why Do People Still Text While Driving? PMID- 27494326 TI - Dopamine- and Tyrosine Hydroxylase-Immunoreactive Neurons in the Brain of the American Cockroach, Periplaneta americana. AB - The catecholamine dopamine plays several vital roles in the central nervous system of many species, but its neural mechanisms remain elusive. Detailed neuroanatomical characterization of dopamine neurons is a prerequisite for elucidating dopamine's actions in the brain. In the present study, we investigated the distribution of dopaminergic neurons in the brain of the American cockroach, Periplaneta americana, using two antisera: 1) an antiserum against dopamine, and 2) an antiserum against tyrosine hydroxylase (TH, an enzyme required for dopamine synthesis), and identified about 250 putatively dopaminergic neurons. The patterns of dopamine- and TH-immunoreactive neurons were strikingly similar, suggesting that both antisera recognize the same sets of "dopaminergic" neurons. The dopamine and TH antibodies intensively or moderately immunolabeled prominent brain neuropils, e.g. the mushroom body (memory center), antennal lobe (first-order olfactory center) and central complex (motor coordination center). All subdivisions of the mushroom body exhibit both dopamine and TH immunoreactivity. Comparison of immunolabeled neurons with those filled by dye injection revealed that a group of immunolabeled neurons with cell bodies near the calyx projects into a distal region of the vertical lobe, which is a plausible site for olfactory memory formation in insects. In the antennal lobe, ordinary glomeruli as well as macroglomeruli exhibit both dopamine and TH immunoreactivity. It is noteworthy that the dopamine antiserum labeled tiny granular structures inside the glomeruli whereas the TH antiserum labeled processes in the marginal regions of the glomeruli, suggesting a different origin. In the central complex, all subdivisions excluding part of the noduli and protocerebral bridge exhibit both dopamine and TH immunoreactivity. These anatomical findings will accelerate our understanding of dopaminergic systems, specifically in neural circuits underlying aversive memory formation and arousal, in insects. PMID- 27494330 TI - Insta-Grams: The Effect of Consumer Weight on Reactions to Healthy Food Posts. AB - Each day, social networking sites become increasingly inundated with food imagery. Since many of these images are of fresh, vibrant, and healthy eats, photo sharing of food through social media should have a long-term positive effect on consumption habits. Yet, obesity rates in the United States continue to rise, suggesting that people are spending more time posting images of healthy foods and paying less attention to the actual foods they consume. This confounding relationship could be explained by consumer weight, in that overweight consumers desire to engage with social media maybe for the purpose of expressing, presenting, and identifying with a healthy lifestyle. In the context of food posts, individuals higher in body mass index may be more likely to engage in social media activity (e.g., likes, shares, comments) that validates healthy food choices to others in their online community. A between-subjects experimental design tested this proposed effect using a manipulated Instagram post of a healthy food item (i.e., black bean veggie burger). Results indicate that obese individuals are more likely to engage with healthy food posts compared with their normal weight and overweight counterparts. The effect is even more pronounced when posts are absent of prior social media activity. Based upon these results, obese individuals are encouraged to establish and maintain social network connections with others who routinely post images of healthy food in their social media feeds. Limitations and directions for future research are provided. PMID- 27494328 TI - Cleavage of Model Substrates by Arabidopsis thaliana PRORP1 Reveals New Insights into Its Substrate Requirements. AB - Two broad classes of RNase P trim the 5' leader of precursor tRNAs (pre-tRNAs): ribonucleoprotein (RNP)- and proteinaceous (PRORP)-variants. These two RNase P types, which use different scaffolds for catalysis, reflect independent evolutionary paths. While the catalytic RNA-based RNP form is present in all three domains of life, the PRORP family is restricted to eukaryotes. To obtain insights on substrate recognition by PRORPs, we examined the 5' processing ability of recombinant Arabidopsis thaliana PRORP1 (AtPRORP1) using a panel of pre-tRNASer variants and model hairpin-loop derivatives (pATSer type) that consist of the acceptor-T-stem stack and the T-/D-loop. Our data indicate the importance of the identity of N-1 (the residue immediately 5' to the cleavage site) and the N-1:N+73 base pair for cleavage rate and site selection of pre tRNASer and pATSer. The nucleobase preferences that we observed mirror the frequency of occurrence in the complete suite of organellar pre-tRNAs in eight algae/plants that we analyzed. The importance of the T-/D-loop in pre-tRNASer for tight binding to AtPRORP1 is indicated by the 200-fold weaker binding of pATSer compared to pre-tRNASer, while the essentiality of the T-loop for cleavage is reflected by the near-complete loss of activity when a GAAA-tetraloop replaced the T-loop in pATSer. Substituting the 2'-OH at N-1 with 2'-H also resulted in no detectable cleavage, hinting at the possible role of this 2'-OH in coordinating Mg2+ ions critical for catalysis. Collectively, our results indicate similarities but also key differences in substrate recognition by the bacterial RNase P RNP and AtPRORP1: while both forms exploit the acceptor-T-stem stack and the elbow region in the pre-tRNA, the RNP form appears to require more recognition determinants for cleavage-site selection. PMID- 27494331 TI - Disclosure Pattern of Self-Labeled People Living with HIV/AIDS on Chinese Social Networking Site: An Exploratory Study. AB - HIV/AIDS is an important public health issue in China. The number of people living with HIV/AIDS (PLWHA) has been increasing since the introduction of highly active antiretroviral therapy. PLWHA's life quality is becoming an important issue, with lack of research in China. In this study, a group of PLWHA (n = 663) was identified using HIV/AIDS relevant usernames on a Chinese social networking site (Weibo) to study their daily living situations. We found that more than 99.10% of PLWHA were male, among whom 90.80% turned out to be homosexual. They had significantly more fans and followees, but fewer postings compared to the general population. The mean age of the PLWHA was 28.96 (SD = 5.05) years old, and southwest and northwest China had a high prevalence of HIV/AIDS. In addition, PLWHA's postings were coded and we found that more than half of the postings (n = 769, 51.03%) contained strong emotions. Less than one-fifth of the postings were directly related to HIV/AIDS topics (n = 269, 17.85%), while seeking emotional support, such as looking for stable partnership, was ranked as the first priority of support seeking. In summary, we found that the majority of the self-labeled PLWHA were likely to be men who have sex with men. They used Weibo to share their daily life events and seek emotional support. Implications for promoting HIV/AIDS education and prevention through Chinese social networking sites were also discussed. PMID- 27494334 TI - Critical Factors Influencing Decision to Adopt Human Resource Information System (HRIS) in Hospitals. AB - The aim of this research is to explore factors influencing the management decisions to adopt human resource information system (HRIS) in the hospital industry of Bangladesh-an emerging developing country. To understand this issue, this paper integrates two prominent adoption theories-Human-Organization Technology fit (HOT-fit) model and Technology-Organization-Environment (TOE) framework. Thirteen factors under four dimensions were investigated to explore their influence on HRIS adoption decisions in hospitals. Employing non probability sampling method, a total of 550 copies of structured questionnaires were distributed among HR executives of 92 private hospitals in Bangladesh. Among the respondents, usable questionnaires were 383 that suggesting a valid response rate of 69.63%. We classify the sample into 3 core groups based on the HRIS initial implementation, namely adopters, prospectors, and laggards. The obtained results specify 5 most critical factors i.e. IT infrastructure, top management support, IT capabilities of staff, perceived cost, and competitive pressure. Moreover, the most significant dimension is technological dimension followed by organisational, human, and environmental among the proposed 4 dimensions. Lastly, the study found existence of significant differences in all factors across different adopting groups. The study results also expose constructive proposals to researchers, hospitals, and the government to enhance the likelihood of adopting HRIS. The present study has important implications in understanding HRIS implementation in developing countries. PMID- 27494335 TI - Building a drug development database: challenges in reliable data availability. AB - CONTEXT: Policy and legislative efforts to improve the biomedical innovation process must rely on a detailed and thorough analysis of drug development and industry output. OBJECTIVE: As part of our efforts to build a publicly-available database on the characteristics of drug development, we present work undertaken to test methods for compiling data from public sources. These initial steps are designed to explore challenges in data extraction, completeness and reliability. Specifically, filing dates for Investigational New Drugs (IND) applications with the U.S. Food and Drug Administration (FDA) were chosen as the initial objective data element to be collected. MATERIALS AND METHODS: FDA's Drugs@FDA database and the Federal Register (FR) were used to collect IND dates for the 587 New Molecular Entities (NMEs) approved between 1994 and 2014. When available, the following data were captured: approval date, IND number, IND date and source of information. RESULTS: At least one IND date was available for 445 (75.8%) of the 587 NMEs. The Drugs@FDA database provided IND dates for 303 (51.6%) NMEs and the FR contributed with 297 (50.6%) IND dates. Out of the 445 NMEs for which an IND date was obtained, 274 (61.6%) had more than one date reported. DISCUSSION: Key finding of this paper is a considerable inconsistency in reliably available or reported data elements, in this particular case, IND application filing dates as assembled from publicly-available sources. CONCLUSION: Our team will continue to focus on finding ways to collect relevant information to measure impact of drug innovation. PMID- 27494336 TI - The Activity of Antimicrobial Surfaces Varies by Testing Protocol Utilized. AB - BACKGROUND: Contaminated hospital surfaces are an important source of nosocomial infections. A major obstacle in marketing antimicrobial surfaces is a lack of efficacy data based on standardized testing protocols. AIM: We compared the efficacy of multiple testing protocols against several "antimicrobial" film surfaces. METHODS: Four clinical isolates were used: one Escherichia coli, one Klebsiella pneumoniae, and two Staphylococcus aureus strains. Two industry methods (modified ISO 22196 and ASTM E2149), a "dried droplet", and a "transfer" method were tested against two commercially available antimicrobial films, one film in development, an untreated control, and a positive (silver) control film. At 2 (only ISO) and 24 hours following inoculation, bacteria were collected from film surfaces and enumerated. RESULTS: Compared to untreated films in all protocols, there were no significant differences in recovery on either commercial brand at 2 or 24 hours after inoculation. The silver surface demonstrated significant microbicidal activity (mean loss 4.9 Log10 CFU/ml) in all methods and time points with the exception of 2 hours in the ISO protocol and the transfer method. Using our novel droplet method, no differences between placebo and active surfaces were detected. The surface in development demonstrated variable activity depending on method, organism, and time point. The ISO demonstrated minimal activity at 2 hours but significant activity at 24 hours (mean 4.5 Log10 CFU/ml difference versus placebo). The ASTEM protocol exhibited significant differences in recovery of staphylococci (mean 5 Log10 CFU/ml) but not Gram-negative isolates (10 fold decrease). Minimal activity was observed with this film in the transfer method. CONCLUSIONS: Varying results between protocols suggested that efficacy of antimicrobial surfaces cannot be easily and reproducibly compared. Clinical use should be considered and further development of representative methods is needed. PMID- 27494337 TI - Do Your School Mates Influence How Long You Game? Evidence from the U.S. AB - The goal of this paper is to estimate peer influence in video gaming time among adolescents. Using a nationally representative sample of the U.S. school-aged adolescents in 2009-2010, we estimate a structural model that accounts for the potential biases in the estimate of the peer effect. Our peer group is exogenously assigned and includes one year older adolescents in the same school grade as the respondent. The peer measure is based on peers' own reports of video gaming time. We find that an additional one hour of playing video games per week by older grade-mates results in .47 hours increase in video gaming time by male responders. We do not find significant peer effect among female responders. Effective policies aimed at influencing the time that adolescents spend video gaming should take these findings into account. PMID- 27494338 TI - Chemical Approaches to Addressing the Instability and Toxicity of Lead-Halide Perovskite Absorbers. AB - The impressive rise in efficiencies of solar cells employing the three dimensional (3D) lead-iodide perovskite absorbers APbI3 (A = monovalent cation) has generated intense excitement. Although these perovskites have remarkable properties as solar-cell absorbers, their potential commercialization now requires a greater focus on the materials' inherent shortcomings and environmental impact. This creates a challenge and an opportunity for synthetic chemists to address these issues through the design of new materials. Synthetic chemistry offers powerful tools for manipulating the magnificent flexibility of the perovskite lattice to expand the number of functional analogues to APbI3. To highlight improvements that should be targeted in new materials, here we discuss the intrinsic instability and toxicity of 3D lead-halide perovskites. We consider possible sources of these instabilities and propose methods to overcome them through synthetic design. We also discuss new materials developed for realizing the exceptional photophysical properties of lead-halide perovskites in more environmentally benign materials. In this Forum Article, we provide a brief overview of the field with a focus on our group's contributions to identifying and addressing problems inherent to 3D lead-halide perovskites. PMID- 27494339 TI - N-acetylcysteine with apocynin prevents hyperoxaluria-induced mitochondrial protein perturbations in nephrolithiasis. AB - Diminished mitochondrial activities were deemed to play an imperative role in surged oxidative damage perceived in hyperoxaluric renal tissue. Proteomics is particularly valuable to delineate the damaging effects of oxidative stress on mitochondrial proteins. The present study was designed to apply large-scale proteomics to describe systematically how mitochondrial proteins/pathways govern the renal damage and calcium oxalate crystal adhesion in hyperoxaluria. Furthermore, the potential beneficial effects of combinatorial therapy with N acetylcysteine (NAC) and apocynin were studied to establish its credibility in the modulation of hyperoxaluria-induced alterations in mitochondrial proteins. In an experimental setup with male Wistar rats, five groups were designed for 9 d. At the end of the experiment, 24-h urine was collected and rats were euthanized. Urinary samples were analyzed for kidney injury marker and creatinine clearance. Transmission electron microscopy revealed distorted renal mitochondria in hyperoxaluria but combinatorial therapy restored the normal mitochondrial architecture. Mitochondria were isolated from renal tissue of experimental rats, and mitochondrial membrane potential was analyzed. The two-dimensional electrophoresis (2-DE) based comparative proteomic analysis was performed on proteins isolated from renal mitochondria. The results revealed eight differentially expressed mitochondrial proteins in hyperoxaluric rats, which were identified by Matrix-assisted laser desorption/ionization time of flight/time of flight (MALDI-TOF/TOF) analysis. Identified proteins including those involved in important mitochondrial processes, e.g. antioxidant defense, energy metabolism, and electron transport chain. Therapeutic administration of NAC with apocynin significantly expunged hyperoxaluria-induced discrepancy in the renal mitochondrial proteins, bringing them closer to the controls. The results provide insights to further understand the underlying mechanisms in the development of hyperoxaluria-induced nephrolithiasis and the therapeutic relevance of the combinatorial therapy. PMID- 27494340 TI - Breast adenomyoepithelioma and adenomyoepithelioma with carcinoma (malignant adenomyoepithelioma) with associated breast malignancies: A case series emphasizing histologic, radiologic, and clinical correlation. AB - The 2012 World Health Organization (WHO) classification of breast tumors distinguishes adenomyoepitheliomas (AMEs) as benign tumors composed of a biphasic proliferation of phenotypically variable myoepithelial cells around small epithelial lined spaces. Many AMEs have demonstrated benign behavior and are often cured with excision with negative margins, but some have exhibited malignant transformation of the myoepithelial cells, ductal epithelial cells, or both. When one of the components is histologically malignant, it is termed AME with carcinoma. Due to the rarity, the literature correlating imaging, histology, and clinical outcome is limited. A retrospective review was undertaken. A review of an institutional pathology database identified 14 cases with AME or malignant AME. Most AMEs had nonspecific imaging findings and were categorized as Bi-Rads 4. Histologic features of AME did not correlate with prior or concurrent breast malignancies or any radiographic features. Clinical follow up could be obtained for all but one case (mean follow up time = 75 months). 5 cases had no known treatment post-biopsy and 5 patients received mastectomy. No recurrences were noted. 3/13 cases of benign AME had associated breast malignancies including invasive ductal adenocarcinoma and ductal carcinoma in-situ. 1 case of malignant AME had a synchronous separate malignant phyllodes tumor. Given the unclear and unpredictable propensity for malignant transformation, conservative excision with negative margins currently seems appropriate. PMID- 27494341 TI - The impact of angry rumination on anger-primed cognitive control. AB - BACKGROUND AND OBJECTIVES: Recent research suggests that angry rumination augments aggressive behavior by depleting self-control resources. Yet, few studies have been conducted to empirically support this proposal. In the present study, we therefore sought to investigate the effects of angry rumination, relative to distraction, on self-reported anger and a behavioral indicator of self-control. METHODS: Seventy-two participants recalled and imagined an anger inducing autobiographical memory and were instructed to engage in either angry rumination (n = 37) or distraction (n = 35). Following these emotion regulation instructions, participants performed an affective Go/NoGo task in order to assess behavioral self-control along with several questionnaires to assess anger related constructs. RESULTS: As expected, results revealed that angry rumination augmented anger, whereas anger decreased in the distraction condition. Contrary to predictions, we found no differences between both groups in performance on the affective Go/NoGo task. LIMITATIONS: A potential limitation is we instructed our participants on how to regulate their emotions rather than letting angry rumination occur spontaneously. CONCLUSIONS: The findings indicate that whereas angry rumination results in heightened anger, it does not seem to result in lower self-control as measured with a behavioral task that requires cognitive control. More research is needed to test the boundary conditions regarding the role of self-control in understanding rumination-induced aggression. PMID- 27494342 TI - Upright posture improves affect and fatigue in people with depressive symptoms. AB - BACKGROUND AND OBJECTIVES: Slumped posture is a diagnostic feature of depression. While research shows upright posture improves self-esteem and mood in healthy samples, little research has investigated this in depressed samples. This study aimed to investigate whether changing posture could reduce negative affect and fatigue in people with mild to moderate depression undergoing a stressful task. METHODS: Sixty-one community participants who screened positive for mild to moderate depression were recruited into a study purportedly on the effects of physiotherapy tape on cognitive function. They were randomized to sit with usual posture or upright posture and physiotherapy tape was applied. Participants completed the Trier Social Stress Test speech task. Changes in affect and fatigue were assessed. The words spoken by the participants during their speeches were analysed. RESULTS: At baseline, all participants had significantly more slumped posture than normative data. The postural manipulation significantly improved posture and increased high arousal positive affect and fatigue compared to usual posture. The upright group spoke significantly more words than the usual posture group, used fewer first person singular personal pronouns, but more sadness words. Upright shoulder angle was associated with lower negative affect and lower anxiety across both groups. LIMITATIONS: The experiment was only brief and a non clinical sample was used. CONCLUSIONS: This preliminary study suggests that adopting an upright posture may increase positive affect, reduce fatigue, and decrease self-focus in people with mild-to-moderate depression. Future research should investigate postural manipulations over a longer time period and in samples with clinically diagnosed depression. PMID- 27494344 TI - Role of miR-146a in the Regulation of Inflammation in an In Vitro Model of Graves' Orbitopathy. AB - PURPOSE: To investigate the role of microRNA 146a (miR-146a) in the regulation of inflammation in an in vitro model of Graves' orbitopathy (GO). METHODS: The level of miR-146a expression in orbital adipose tissue was compared between GO and non GO by quantitative real-time PCR (qPCR). The effects of interleukin 1beta (IL 1beta) on miR-146a expression were analyzed in orbital fibroblasts by qPCR. To investigate the molecular mechanism underlying IL-1beta-induced miR-146a expression, the effects of inhibitors of nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB), mitogen-activated protein kinase/extracellular signal-regulated kinases (MEK)-1/2, c-Jun N-terminal kinases (JNK)-1/2, p38 MAP kinase, and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) were analyzed. The effects of miR-146a mimics and inhibitors on IL-1beta induced IL-6 release were examined by ELISA and Western blotting. RESULTS: The level of miR-146a expression was significantly higher in GO orbital adipose tissue than in non-GO (P = 0.032). Interleukin 1beta induced a time- and concentration-dependent increase in miR-146a expression. Interleukin 1beta (10 ng/mL, 16 hours) induced an approximately 17.5-fold increase in miR-146 expression. The increase in miR-146a expression by IL-1beta was significantly inhibited by NF-kappaB, JNK-1/2, and PI3K inhibitors (1.94 +/- 0.25, 5.28 +/- 0.34 and 9.73 +/- 2.32-fold, respectively, P < 0.05 compared with IL-1beta induced miR-146 expression, independent t-test). Interleukin 1beta-induced IL-6 protein production was further decreased by miR-146a mimics, but not by inhibitors of miR-146a. CONCLUSIONS: MicroRNA 146a was upregulated by inflammatory stress in orbital fibroblasts. Our results indicated that miR-146a had a positive effect on the anti-inflammatory process. MicroRNA 146a may play a role in the regulation of inflammation in orbital fibroblasts, and may participate in the pathogenesis of GO. PMID- 27494343 TI - CNTF Attenuates Vasoproliferative Changes Through Upregulation of SOCS3 in a Mouse-Model of Oxygen-Induced Retinopathy. AB - PURPOSE: Retinal vascular disease represents a major cause for vision loss in the Western world. Recent research has shown that neuronal and vascular damage are closely related in retinal disease. Ciliary neurotrophic factor (CNTF) is a well studied neurotrophic factor that is currently being tested in clinical trials for the treatment of retinal degenerative diseases and macular telangiectasia. However, little is known about its effect on retinal vasculature. In this study, we investigate the effects of CNTF in retinal neovascular disease using the mouse model of oxygen-induced retinopathy (OIR). METHODS: Newborn pups were exposed to 75% oxygen from postnatal day (P)7 to P12 and subsequently returned to room air. Ciliary neurotrophic factor was injected intravitreally at OIR P12 and the vaso obliterated and neovascular areas were quantified at OIR P17. Immunohistochemistry, RNA, and protein analysis were used to identify CNTF responsive cells. In vitro experiments were performed to analyze the effect of CNTF on endothelial and astroglial cells. RESULTS: In the OIR model, CNTF facilitated capillary regrowth and attenuated preretinal neovascularization in a dose-dependent manner. The protective effect of CNTF was mediated via activation of the JAK/STAT3/SOCS3 signaling pathway. Immunohistochemical studies identified endothelial cells among others as CNTF-responsive cells in the retina. In vitro studies confirmed the anti-angiogenic effect of CNTF on endothelial cell sprouting. CONCLUSIONS: This study provides evidence for a therapeutic potential of CNTF beyond degenerative retinal disease. Vasoproliferative retinopathies may benefit from a CNTF-dependent and SOCS3-mediated angiomodulatory effect. PMID- 27494345 TI - Peripheral Blood Mitochondrial DNA Damage as a Potential Noninvasive Biomarker of Diabetic Retinopathy. AB - PURPOSE: In the development of diabetic retinopathy, retinal mitochondria become dysfunctional, and mitochondrial DNA (mtDNA) is damaged. Because retinopathy is a progressive disease, and circulating glucose levels are high in diabetes, our aim was to investigate if peripheral blood mtDNA damage can serve as a potential biomarker of diabetic retinopathy. METHODS: Peripheral blood mtDNA damage was investigated by extended-length PCR in rats and mice, diabetic for 10 to 12 months (streptozotocin-induced, type 1 model), and in 12- and 40-week-old Zucker diabetic fatty rats (ZDF, type 2). Mitochondrial copy number (in gDNA) and transcription (in cDNA) were quantified by qPCR. Similar parameters were measured in blood from diabetic patients with/without retinopathy. RESULTS: Peripheral blood from diabetic rodents had significantly increased mtDNA damage and decreased copy numbers and transcription. Lipoic acid administration in diabetic rats, or Sod2 overexpression or MMP-9 knockdown in mice, the therapies that prevent diabetic retinopathy, also ameliorated blood mtDNA damage and restored copy numbers and transcription. Although blood from 40-week-old ZDF rats had significant mtDNA damage, 12-week-old rats had normal mtDNA. Diabetic patients with retinopathy had increased blood mtDNA damage, and decreased transcription and copy numbers compared with diabetic patients without retinopathy and nondiabetic individuals. CONCLUSIONS: Type 1 diabetic rodents with oxidative stress modulated by pharmacologic/genetic means, and type 2 animal model and patients with/without diabetic retinopathy, demonstrate a strong relation between peripheral blood mtDNA damage and diabetic retinopathy, and suggest the possibility of use of peripheral blood mtDNA as a noninvasive biomarker of diabetic retinopathy. PMID- 27494346 TI - Perceived Visual Distortions in Juvenile Amblyopes During/Following Routine Amblyopia Treatment. AB - PURPOSE: To establish the point prevalence of perceived visual distortions (PVDs) in amblyopic children; the association between severity of PVDs and clinical parameters of amblyopia; and the relationship between PVDs and amblyopia treatment outcomes. METHODS: Perceived visual distortions were measured using a 16-point dichoptic alignment paradigm in 148 visually normal children (aged, 9.18 +/- 2.51 years), and 82 amblyopic children (aged, 6.33 +/- 1.48 years) receiving or following amblyopia treatment. Global distortion (GD; vector sum of mean centered individual alignment error between physical and perceived target location) and Global uncertainty (GU; SD of GD over two experiment runs) were compared to age-matched control data, and correlated against clinical parameters of amblyopia (type, monocular visual acuity, pretreatment interocular acuity difference, refractive error, age at diagnosis, motor fusion, stereopsis, near angle of deviation) and amblyopia treatment outcomes (refractive adaption duration, treatment duration, occlusion dosage, posttreatment interocular acuity difference, number of lines improvement). RESULTS: Point prevalence of PVDs in amblyopes was 56.1%. Strabismic amblyopes experienced more severe distortions than anisometropic or microtropic amblyopes (GD Kruskal Wallis H = 16.89, P < 0.001; GU Kruskal Wallis H = 15.31, P < 0.001). Perceived visual distortions severity moderately correlated with the strength of binocular function, (e.g., log stereoacuity [GD rho = 0.419, P < 0.001; GU rho = 0.384, P < 0.001)], and strongly with near angle of deviation (GD rho = 0.578, P < 0.001; GU rho = 0.384, P < 0.001). There was no relationship between severity of PVDs and amblyopia treatment outcomes, or the amblyopic visual acuity deficit. Perceived visual distortions persisted in more than one-half of treated amblyopic cases whose treatment was deemed successful. CONCLUSIONS: Perceived visual distortions are common symptoms of amblyopia and are correlated with binocular (stereoacuity, angle of deviation), but not monocular (visual acuity) clinical outcomes. This adds to evidence demonstrating the role of decorrelated binocular single vision in many aspects of amblyopia, and emphasizes the importance of restoring and improving binocular single vision in amblyopic individuals. PMID- 27494347 TI - Therapeutic Effect of Protocatechuic Aldehyde in an In Vitro Model of Graves' Orbitopathy. AB - PURPOSE: Protocatechuic aldehyde (3,4-dihydroxybenzaldehyde; PCA) is extracted from Salvia miltiorrhiza, and has been reported to possess antiproliferative, antioxidant, and antiadipogenesis properties in various in vivo and in vitro experiments. This study aimed to outline the antioxidant and suppressive effects of PCA on adipogenesis and hyaluronan production in orbital fibroblasts to help with designing therapeutic approaches for Graves' orbitopathy (GO). METHODS: We assessed the in vitro effects of PCA on orbital fibroblasts, which were cultured from orbital fat tissue obtained from patients undergoing orbital decompression for severe GO. Control tissue was obtained from patients undergoing orbital surgery with no history of GO or Graves' hyperthyroidism. RESULTS: The 2,2 diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt assay results confirmed the free radical scavenging effect of PCA after treatment. Protocatechuic aldehyde exhibited a suppressive effect on intracellular reactive oxygen species generation and upregulated heme oxygenase-1 expression in Western blot analysis. Protocatechuic aldehyde attenuated TNF-alpha and IL-1beta-induced hyaluronan production. Oil Red-O staining results revealed a decrease in lipid droplets and suppressed expression of the adipogenesis-related proteins peroxisome proliferator-activated receptor (PPAR)-gamma, CCAAT/enhancer binding protein (c/EBP)-alpha, and c/EBP-beta upon treatment with PCA during adipose differentiation. CONCLUSIONS: In this study, PCA exerted significant antioxidant and antiadipogenic effects and inhibited the production of hyaluronan in GO orbital fibroblasts. Accordingly, PCA potentially could be used as a novel treatment option for GO. PMID- 27494348 TI - A new CE with contactless conductivity detection method for the determination of complex cationic compositions: Application to the analysis of pen inks. AB - A CE with contactless conductivity detection methodology using a novel background electrolyte for the separation and determination of 17 metal cations (Cs+ , Rb+ , K+ , Ca2+ , Na+ , Mg2+ , Mn2+ , Sr2+ , Li+ , Ba2+ , Fe2+ , Pb2+ , Cd2+ , Zn2+ , Co2+ , Cu2+ and Ni2+ ) and ammonium has been investigated. The buffer, based on lactic acid and beta-alanine, was experimentally compared with other two commonly used electrolytes, showing important improvements, such as shorter analysis times (<11 min), better electrophoretic resolutions and higher detectabilities for certain analytes, such as Fe2+ and Pb2+ . The inclusion of other additives such as 18-Crown-6 and alpha-hydroxyisobutyric acid was studied in order to obtain the best separation of the analytes of interest. The optimised method was applied to the analysis of 11 water-based pen inks and the determination of their metal composition. The methodology was demonstrated for the comparison and differentiation of pen inks. PMID- 27494349 TI - The Different Roles of Entropy and Solubility in High Entropy Alloy Stability. AB - Multiprincipal element high entropy alloys stabilized as a single alloy phase represent a new material system with promising properties, such as high corrosion and creep resistance, sluggish diffusion, and high temperature tensile strength. However, the mechanism of stabilization to form single phase alloys is controversial. Early studies hypothesized that a large entropy of mixing was responsible for stabilizing the single phase; more recent work has proposed that the single-phase solid solution is the result of mutual solubility of the principal elements. Here, we demonstrate the first self-consistent study of the relative importance of these two proposed mechanisms. In situ high-throughput synchrotron diffraction studies were used to monitor the stability of the single phase alloy in thin-film (Al1-x-yCuxMoy)FeNiTiVZr composition spread samples. Our results indicate that a metastable solid solution can be captured via the rapid quenching typical of physical vapor deposition processes, but upon annealing the solid-solution phase stability is primarily governed by mutual miscibility. PMID- 27494350 TI - The Impact of Gestational Age at Delivery on Urologic Outcomes for the Fetus with Hydronephrosis. AB - OBJECTIVE: Compare short-term urologic outcomes with delivery timing in fetuses with severe hydronephrosis. METHODS: An ultrasound database was queried for severe hydronephrosis. Cases were categorized into late preterm/early term (36 0/7 - 38 6/7 weeks) and full term (39 0/7 weeks or greater) groups. Baseline characteristics were compared using standard statistical methods. Spearman's correlation analysis was performed for grade and severity of hydronephrosis on first postnatal ultrasound with gestational age at delivery. RESULTS: Of 589 cases, 79 (33 late preterm/early term, 46 full term) met criteria. Baseline characteristics were similar between groups. Spearman's correlation coefficients (rs) indicated that increased postnatal Society for Fetal Urology grade, rs= 0.26 (95% CI [-.48, -.002]), and severity of hydronephrosis, rs= -0.39 (95% CI [ .59, -.14]), both correlated with earlier delivery. CONCLUSION: Late preterm/early term delivery resulted in worse short-term postnatal renal outcomes. Unless otherwise indicated, delivery for fetal hydronephrosis should be deferred until 39 weeks. PMID- 27494351 TI - Insights into the Effects of Zinc Doping on Structural Phase Transition of P2 Type Sodium Nickel Manganese Oxide Cathodes for High-Energy Sodium Ion Batteries. AB - P2-type sodium nickel manganese oxide-based cathode materials with higher energy densities are prime candidates for applications in rechargeable sodium ion batteries. A systematic study combining in situ high energy X-ray diffraction (HEXRD), ex situ X-ray absorption fine spectroscopy (XAFS), transmission electron microscopy (TEM), and solid-state nuclear magnetic resonance (SS-NMR) techniques was carried out to gain a deep insight into the structural evolution of P2 Na0.66Ni0.33-xZnxMn0.67O2 (x = 0, 0.07) during cycling. In situ HEXRD and ex situ TEM measurements indicate that an irreversible phase transition occurs upon sodium insertion-extraction of Na0.66Ni0.33Mn0.67O2. Zinc doping of this system results in a high structural reversibility. XAFS measurements indicate that both materials are almost completely dependent on the Ni(4+)/Ni(3+)/Ni(2+) redox couple to provide charge/discharge capacity. SS-NMR measurements indicate that both reversible and irreversible migration of transition metal ions into the sodium layer occurs in the material at the fully charged state. The irreversible migration of transition metal ions triggers a structural distortion, leading to the observed capacity and voltage fading. Our results allow a new understanding of the importance of improving the stability of transition metal layers. PMID- 27494352 TI - Photoelectrochromism in the Retinal Protonated Schiff Base Chromophore: Photoisomerization Speed and Selectivity under a Homogeneous Electric Field at Different Operational Regimes. AB - The spectral tunability, photoisomerization efficiency and selectivity, of the native all-trans retinal protonated Shiff base (PSB) chromophore driven by a homogeneous electric field is systematically investigated. By analyzing the absorption wavelength dependence, charge distribution, and PES profiles along selected torsional angles, as well as the electronic structure, energetics, and topography of the CI seam in the presence of strong positive and negative electric fields, we recognize the existence of qualitatively/fundamentally different photophysics and photochemistry with respect to the unperturbed (i.e., absence of an electric field) chromophore. We rationalize the findings within the scope of molecular orbital theory and deliver a unified picture of the photophysics of the retinal PSB chromophore over a wide, even beyond the usually observed, spectral regime, ranging from the near-infrared to the ultraviolet absorption energies. This work has a 3-fold impact: a) it accounts for, and extends, previous theoretical studies on the subject; b) it delivers a rationale for the ES lifetimes observed in retinal proteins, both archeal and visual rhodopsins, as well as in solvent; and c) the transferability of the discovered trends on PSB mimics is demonstrated. PMID- 27494353 TI - Revisiting the Male-Produced Aggregation Pheromone of the Lesser Mealworm, Alphitobius diaperinus (Coleoptera, Tenebrionidae): Identification of a Six Component Pheromone from a Brazilian Population. AB - The lesser mealworm, Alphitobius diaperinus Panzer 1797 (Coleoptera: Tenebrionidae), is a cosmopolitan insect pest affecting poultry production. Due to its cryptic behavior, insecticide control is usually not efficient. Thus, sustainable and effective methods would have an enormous and positive impact in poultry production. The aim of this study was to confirm the identity of the male produced aggregation pheromone for a Brazilian population of A. diaperinus and to evaluate its biological activity in behavioral assays. Six male-specific compounds were identified: (R)-limonene (1), (E)-ocimene (2), 2-nonanone (3), (S) linalool (4), (R)-daucene (5), all described before in an American population, and a sixth component, (E,E)-alpha-farnesene (6), which is apparently exclusive to a Brazilian population. Y-Tube bioassays confirmed the presence of a male produced aggregation pheromone and showed that all components need to be present in a similar ratio and concentration as emitted by male A. diaperinus to produce a positive chemotactic response. PMID- 27494354 TI - Risks and benefits of epilepsy surgery in a pediatric population: Consequences for memory and academic skills. AB - We examined benefits and risks for memory and academic functioning associated with epilepsy surgery in a pediatric population. A total of 46 patients with intractable seizures and a single seizure focus were divided into four groups according to focus localization: right temporal, left temporal, frontal, and parietal/occipital region. Pre- and postsurgery performance measures were compared across groups and with a fifth group of patients that had intractable seizures but did not undergo surgery. Both groups with temporal lobe epilepsy showed significant declines in memory test scores, while performance of the group with frontal lobe epilepsy improved. These changes were mirrored in parental reports of everyday memory. Consistent with other pediatric studies, no lateralized material-specific declines in the groups with temporal lobe epilepsy were found. When memory improved, the improvement was associated with decreases in seizure frequency and the number of anticonvulsant medications. Presurgical performance was the best predictor of declines in memory test performance. Deterioration of academic test scores in the group that did not have surgery exemplified a potential risk of living with seizures and antiepilepsy medication. PMID- 27494355 TI - Interictal epileptic discharge correlates with global and frontal cognitive dysfunction in temporal lobe epilepsy. AB - OBJECTIVE: Temporal lobe epilepsy (TLE) with hippocampal sclerosis has widespread effects on structural and functional connectivity and often entails cognitive dysfunction. EEG is mandatory to disentangle interactions in epileptic and physiological networks which underlie these cognitive comorbidities. Here, we examined how interictal epileptic discharges (IEDs) affect cognitive performance. METHODS: Thirty-four patients (right TLE=17, left TLE=17) were examined with 24 hour video-EEG and a battery of neuropsychological tests to measure intelligence quotient and separate frontal and temporal lobe functions. Hippocampal segmentation of high-resolution T1-weighted imaging was performed with FreeSurfer. Partial correlations were used to compare the number and distribution of clinical interictal spikes and sharp waves with data from imagery and psychological tests. RESULTS: The number of IEDs was negatively correlated with executive functions, including verbal fluency and intelligence quotient (IQ). Interictal epileptic discharge affected cognitive function in patients with left and right TLE differentially, with verbal fluency strongly related to temporofrontal spiking. In contrast, IEDs had no clear effects on memory functions after corrections with partial correlations for age, age at disease onset, disease duration, and hippocampal volume. CONCLUSION: In patients with TLE of long duration, IED occurrence was strongly related to cognitive deficits, most pronounced for frontal lobe function. These data suggest that IEDs reflect dysfunctional brain circuitry and may serve as an independent biomarker for cognitive comorbidity. PMID- 27494356 TI - Electroclinical aspects and therapy of Han patients with juvenile myoclonic epilepsy in northern China. AB - OBJECTIVE: The objective of this study was to assess the electroclinical aspects and treatment of Han patients with juvenile myoclonic epilepsy (JME) in northern China. METHODS: One hundred fifty-six outpatients with JME from six epilepsy centers, between January 2011 and June 2012, were followed up for at least two years. They underwent twenty-four-hour video-EEG recording. Brain imaging was performed using magnetic resonance imaging (MRI). Clinical aspects, electroencephalographic (EEG) features, and antiepileptic drugs (AEDs) received were reviewed. RESULTS: Generalized tonic-clonic seizures (GTCS) were found in 150/156 patients. Delay of diagnosis was 4.60+/-9.92years. Photosensitivity was more common in eye closure condition during IPS in patients with JME; in addition, patients with JME with myoclonic seizures (MS) and GTCS as seizure types were likely to present photoparoxysmal responses (PPRs). The 82 nontreated patients showed a median latency to first interictal or ictal generalized spike wave discharge (GSWD) of 50min (IQR: 22-102min). The first GSWDs were recorded in 63%, 76%, 90%, and 98% patients within one, two, three, and 4h, respectively; only 2% of patients had first GSWDs after 4h. One hundred eleven patients (111/156) chose extended-release valproate (VPA) at daily doses <=1000mg. The percentages of seizure-free patients among MS, GTCS, and absence seizure (AS) groups were 88.3%, 99.0%, and 94.9%, respectively. CONCLUSION: Photoparoxysmal responses were more common in patients with JME with MS and GTCS and rare in patients with JME with MS and AS in northern Chinese Han patients. Most patients with JME in northern China chose VPA as first therapeutic choice, and low dose (500 to 1000mg daily) of extended-release VPA may be an optimal choice for them. Video-EEG monitoring for at least 4h may be helpful in detecting the first interictal or ictal GSWD in patients with potential JME. Moreover, video-EEG monitoring performed at about 9 o'clock in the morning with patients in the awake state might be useful to find the first GSWD. For JME diagnosis, Class II criteria are more helpful than Class I counterparts, the latter yielding more missed diagnoses. PMID- 27494357 TI - Vocational factors which predict seizure prognosis in young adults during military service. AB - BACKGROUND: The vocational parameters regarding epilepsy are not well established. Our aim was to assess the risk of seizures as a function of occupational stress and disease severity in military recruits of the IDF (Israel Defense Force) and to examine the effect of new classification criteria (used between the late nineties and early two thousands) in comparison with that of previous criteria (used during the mid-eighties to mid-nineties). METHODS: The medical records of over 150,000 18-year-old men recruited to the IDF between the mid-nineties and the mid-two thousands were used to assemble a cohort, which was followed for a period of 36months. The severity of the disease was determined according to 3 categories, according to the medical history. The recruits were subdivided according to their occupational categories to Combat Units (CUs), Maintenance Units (MUs), and Administrative Units (AUs). We compared the incidence rates of the different groups with the findings from a previous follow up. RESULTS: The annual incidence rates during 36months of follow-up were 0.026%, 4.7%, and 8.8%, in categories 1 to 3, respectively. The relative risk of seizure incidence in CU and MU was lower than in AU (0.42 and 0.81, p<0.0001). Similar findings were found in other disease categories. CONCLUSIONS: Job assignment to CU (less convenient conditions like sleep deprivation and strenuous physical activity) did not increase the incidence of seizures. It was found that EEG examination is an important criterion in the vocational evaluation of subjects that have had one or more seizures. This study supports the establishment of vocational criteria and recommends the integration of people diagnosed with epilepsy in most occupations. PMID- 27494358 TI - Epilepsy or seizure disorder? The effect of cultural and socioeconomic factors on self-reported prevalence. AB - Self-reported epilepsy may be influenced by culture, knowledge, and beliefs. We screened 6420 residents of the District of Columbia (DC) for epilepsy to investigate whether socio-demographics were associated with whether they reported their diagnosis as epilepsy or as seizure disorder. Lifetime and active prevalence rates were 0.54% and 0.21%, respectively for 'epilepsy' and 1.30% and 0.70%, respectively for 'seizure disorder'. Seizure disorder was reported significantly more often than epilepsy among blacks, females, respondents>=50years, those with lower level education, respondents who lived alone and in low income neighborhoods, and those who resided in DC for at least five years. Clinicians should assure that patients and caregivers understand that epilepsy is synonymous with seizure disorder and other culturally appropriate terms, in order to optimize compliance with treatment, disease management instructions, and utilization of other resources targeted at persons with epilepsy. Furthermore, education and awareness campaigns aimed at improving access-to-care, reducing stigma, and increasing awareness of adverse events, such as SUDEP, should include a more diverse definition of epilepsy in their messages. PMID- 27494359 TI - Local brain activity persists during apparently generalized postictal EEG suppression. AB - OBJECTIVES: Postictal generalized EEG suppression (PGES) frequently occurs after generalized convulsive seizures (GCS) and may be involved in the pathophysiology of sudden unexpected death in epilepsy (SUDEP). It is usually determined using conventional scalp EEG which is likely to miss cerebral activity in deeper brain structures. Here, we examined intracranial EEG activity after GCS to unravel the pattern and extent of local brain activity during apparent PGES on scalp EEG (s PGES). METHODS: We retrospectively reviewed electroencephalographic data of people with chronic epilepsy who had GCS during presurgical video-EEG monitoring using simultaneous intracranial and scalp EEG (10-20 system) electrodes. RESULTS: Twenty-five GCS (20 with s-PGES) of 15 patients with an average number of 88+/-42 intracranial electrode contacts were included. The majority of GCS with s-PGES (18 of 20) displayed persisting or reemerging intracranial EEG activity during apparent PGES on scalp EEG. Three patterns were identified: Pattern 1 (11 GCS, 6 patients) consisted of continuous local interictal activity; Pattern 2 (5 GCS, 5 patients) displayed suppressed EEG activity at all intracranial contacts in the early phase of s-PGES, but reemerging local brain activity before s-PGES dissolved; and Pattern 3 (2 GCS, 2 patients) showed persistent local ictal activity during s-PGES. Persisting intracranial EEG activity at PGES onset on scalp EEG was present in 10+/-14% (range: 0 to 42%) of all intracranial contacts and mostly in the temporal lobe. CONCLUSIONS: Our results reveal that, during apparently generalized postictal EEG suppression, local brain activity persists or reemerges in most GCS. Possible implications of this localized neuronal activity in the context of SUDEP are discussed in the paper. PMID- 27494360 TI - Conversation analysis in the differentiation of psychogenic nonepileptic and epileptic seizures in pediatric and adolescent settings. AB - The differential diagnosis of epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) is often difficult, especially in pediatric and adolescent settings. Conversation analysis (CA) can be a worthwhile diagnostic tool in adults. The aim of this study was to assess the diagnostic value of CA in Italian children and adolescents. Ten patients (seven females and three males), diagnosed using video-EEG as having either ES or PNES, underwent a video-recorded interview by a physician from outside the center specifically trained for this purpose. An external linguistic rater then examined the video recordings and transcripts using CA. Diagnoses formulated on the basis of interactional and linguistic features of the patients' speech were compared with diagnoses made by seizure experts on the basis of all available clinical information including the video-EEG findings. Conversation analysis diagnoses corresponded to the video-EEG diagnoses in 8 out of 10 cases. In conclusion, while some conversational adaptation is necessary to enable children and adolescents to share their seizure experiences with an adult health professional, this study indicates the differential diagnostic potential of a CA approach in these young people with PNES or epilepsy. Larger samples are obviously needed to confirm these findings. PMID- 27494361 TI - Biological diversity of Salix taxa in Cu, Pb and Zn phytoextraction from soil. AB - The aim of the study was to estimate the efficiency of copper (Cu), lead (Pb) and zinc (Zn) phytoextraction by 145 Salix taxa cultivated in an area affected by industrial activity. Survivability and biomass of plants were also analyzed. The highest Cu, Pb and Zn content in shoots was 33.38 +/- 2.91 (S. purpurea * viminalis 8), 24.64 +/- 1.97 (S. fragilis 1) and 58.99 +/- 4.30 (S. eriocephala 7) mg kg-1 dry weight, respectively. In the case of unwashed leaves, the highest content of these metals was 135.06 +/- 8.14 (S. purpurea 26), 67.98 +/- 5.27 (S. purpurea 45) and 142.56 +/- 12.69 (S. alba * triandra 2) mg kg-1 dw, while in washed leaves it was 106.02 +/- 11.12 (S. purpurea 45), 55.06 +/- 5.75 (S. purpurea 45) and 122.87 +/- 12.33 (S. alba * triandra 2) mg kg-1 dw, respectively. The differences between the highest and lowest values for Cu, Pb and Zn were 545%, 20500% and 535% in shoots; 2692%, 2560% and 7500% in unwashed leaves; and 3286%, 2221% and 6950% in washed leaves, respectively. S. acutifolia was able to effectively accumulate all three metals jointly, producing shoots that were well developed in both length and diameter when compared with the other tested willows-an ability that would suggest its high suitability for practical application. PMID- 27494362 TI - Where is the future of cardiac lead extraction heading? AB - INTRODUCTION: Transvenous lead extraction (TLE) is the gold standard for lead removal. The increasing rate of cardiac implantable electronic device (CIED) implantations and of CIED related complications highlight the importance of transvenous lead extraction . AREAS COVERED: The TLE scenario is constantly changing. Optimizing lead related technology and improving TLE practice across the world are the cornerstones to improving safety and efficacy. We review the state of the art in TLE, focusing on potential future implications and improvements in terms of skills and technologies. Expert commentary: The increased number of extractions will increase the necessity of safe and effective TLE. New technologies, techniques and appropriate training is warranted across the world. PMID- 27494363 TI - Formation of Ordered Phospholipid Monolayer on a Hydrophilically Modified Au(111) Substrate. AB - The molecular arrangement of phospholipid molecules was investigated on a hydrophilically modified gold surface within an aqueous solution by scanning tunneling microscopy. By suspending phospholipid (1-palmitoyl-2-oleoyl-sn-glycero 3-phosphocholine, POPC) nanoparticles in the aqueous electrolyte surrounding a hydrophilically modified gold (111) substrate with 3-mercaptopropionic acid (SH C2H4-COOH, 3-MPA), well-ordered adlattices of POPC were observed. Traces of particle fusion were visualized before formation of the adlattice. Addition of cholesterol to the suspension seems to facilitate accommodation of POPC on this surface. The observed unit cells of POPC adlattices had dimensions of 0.5 nm * 1.9-2.5 nm. By high-resolution imaging, each unit cell was discerned to be occupied by one upright POPC molecule. The POPC + cholesterol suspension also leads to formation of a flat integrated POPC layer, which may be a lipid bilayer covering the surface. PMID- 27494365 TI - PdCuPt Nanocrystals with Multibranches for Enzyme-Free Glucose Detection. AB - By carefully controlling the synthesis condition, branched PtCu bimetallic templates were synthesized in aqueous solution. After the galvanic replacement reaction between PtCu templates and the Pt precursors, PdCuPt trimetallic nanocrystals with branched structures were obtained. Owing to the open structure and the optimized composition, the electrochemical experimental results reveal that the PdCuPt trimetallic nanocrystals possess high electrocatalytic activity, selectivity and stability for the oxidation of glucose in alkaline solution. In detail, a detection limit of 1.29 MUM and a sensitivity of 378 MUA/mM/cm(2) are achieved. The good electrocatalytic performance should be attributed to the unique branched nanostructure as well as the synergistic effect among metals. The superior catalytic properties suggest that these nanocrystals are promising for enzyme-free detection of glucose. PMID- 27494366 TI - The potential of cystatin-C to evaluate the prognosis of acute heart failure: A comparative study. AB - BACKGROUND: The prognosis of acute heart failure (HF) can be determined by cardio renal function which is assessed by cystatin-C (Cys-C). We evaluated whether Cys C could be a more useful prognostic indicator in acute HF, compared with uric acid (UA) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). METHODS: Two hundred thirty-two HF patients in the emergency room were studied using measurements of Cys-C, UA, and NT-proBNP. During the follow-up, cardiac events, defined as the composites of recurrent HF or cardiac death, were determined. RESULTS: Seventy-seven cardiac events (28 cardiac deaths, 49 recurrent HFs) occurred over two years. The events group revealed higher levels of Cys-C, UA, and NT-proBNP. They showed increased blood urea nitrogen and creatinine, reduced septal tissue Doppler velocity (TVI-Sm), and low frequencies of beta-blockers (BB), diuretics and angiotensin-converting enzyme inhibitors/-receptor blockers. Cys-C (the best cutoff: 1.7 mg/l) had a steady, persistent hazard ratio (HR) over two years. On multivariate analysis, Cys-C, TVI-Sm, and BB were significant predictors for adverse events. Cys-C provided an incremental value for prognosis more than NT-proBNP and UA did over the follow-up period. CONCLUSIONS: Compared with UA and NT-proBNP, Cys-C could be better prognostic biomarker for cardiac events two years after acute HF. PMID- 27494364 TI - Enhanced exercise and regenerative capacity in a mouse model that violates size constraints of oxidative muscle fibres. AB - A central tenet of skeletal muscle biology is the existence of an inverse relationship between the oxidative fibre capacity and its size. However, robustness of this relationship is unknown. We show that superimposition of Estrogen-related receptor gamma (Errgamma) on the myostatin (Mtn) mouse null background (Mtn(-/-)/Errgamma(Tg/+)) results in hypertrophic muscle with a high oxidative capacity thus violating the inverse relationship between fibre size and oxidative capacity. We also examined the canonical view that oxidative muscle phenotype positively correlate with Satellite cell number, the resident stem cells of skeletal muscle. Surprisingly, hypertrophic fibres from Mtn(-/ )/Errgamma(Tg/+) mouse showed satellite cell deficit which unexpectedly did not affect muscle regeneration. These observations 1) challenge the concept of a constraint between fibre size and oxidative capacity and 2) indicate the important role of the microcirculation in the regenerative capacity of a muscle even when satellite cell numbers are reduced. PMID- 27494367 TI - Complete replication-competent adenovirus 11p vectors with E1 or E3 insertions show improved heat stability. AB - Conventional adenovirus vectors harboring E1 or E3 deletions followed by the insertion of an exogenous gene show considerably reduced virion stability. Here, we report strategies to generate complete replication-competent Ad11p(RCAd11p) vectors that overcome the above disadvantage. A GFP cassette was successfully introduced either upstream of E1A or in the E3A region. The resulting vectors showed high expression levels of the hexon and E1genes and also strongly induced the cytopathic effect in targeted cells. When harboring oversized genomes, the RCAd11pE1 and RCAd11pE3 vectors showed significantly improved heat stability in comparison to Ad11pwt;of the three, RCAd11pE3 was the most tolerant to heat treatment. Electron microscopy showed that RCAd11pE3, RCAd11pE1, Ad11pwt, and Ad11pE1 Delmanifested dominant, moderate, minimum, or no full virus particles after heat treatment at 47 degrees C for 5h. Our results demonstrated that both genome size and the insertion site in the viral genome affect virion stability. PMID- 27494368 TI - Use of prasugrel in the setting of clopidogrel hypersensitivity: Case report and systematic review of the literature. AB - Allergic reactions to clopidogrel soon after coronary stent implantation pose an important and challenging clinical problem. We describe a 44-year-old man who developed a diffuse maculopapular rash four days after initiation of clopidogrel with drug-eluting coronary stent placement. An initial treat-through strategy was unsuccessful due to patient intolerance to corticosteroids. Because of persistent hypersensitivity, clopidogrel was substituted with prasugrel which was continued successfully for one year without reaction. A systematic review of the literature was performed which identified 10 prior case reports of patients with clopidogrel hypersensitivity who were subsequently treated with prasugrel. Patient characteristics and clinical outcomes of these patients plus the current case were reviewed. There were 9 men and 2 women with ages from 44 to 76 years. All patients had undergone coronary stent procedures. Prasugrel was successfully used without cross-reactivity in 9 of the 11 patients (82%). Cross-reactivity was reported in two patients who developed hypersensitivity reactions to prasugrel similar to those experienced on clopidogrel. In conclusion, prasugrel can be used successfully in most patients with a history of clopidogrel hypersensitivity. However, potential cross-reactivity between these two thienopyridines may occur in some patients. PMID- 27494369 TI - High negative pressure subcutaneous suction drain for managing debilitating subcutaneous emphysema secondary to tube thoracostomy for an iatrogenic post computed tomography guided transthoracic needle biopsy pneumothorax: Case report and review of literature. AB - INTRODUCTION: Subcutaneous emphysema is a common complication of tube thoracostomy. Though self-limiting, it should be treated when it causes palpebral closure, dyspnea, dysphagia or undue disfigurement resulting in anxiety and distress to the patient. PRESENTATION OF CASE: A 72year old man who was a known case of COPD on bronchodilators developed a large pneumothorax and respiratory distress after a CT guided transthoracic lung biopsy done for a lung opacity (approx. 3*3cm) at the right hilar region on Chest X-ray. Within 24h of an urgent tube thoracostomy, patient developed intractable subcutaneous emphysema with closure of palpebral fissure and dyspnea unresponsive to increasing suction on chest tube. A subcutaneous fenestrated drain was placed mid-way between the nipple and clavicle in the mid-clavicular line bilaterally. Continuous negative suction (-150mmHg) resulted in immediate, sustained relief and complete resolution within 5days. DISCUSSION: Extensive and debilitating SE (subcutaneous emphysema) has to be treated promptly to relieve patient discomfort, dysphagia or imminent respiratory compromise. A variety of treatment have been tried including infraclavicular blow-hole incisions, subcutaneous drains +/- negative pressure suction, fenestrated angiocatheters, Vacuum assisted dressings and increasing suction on a pre-existing chest tube. We describe a high negative pressure subcutaneous suction drain which provides immediate and sustained relief in debilitating SE. CONCLUSION: Debilitating subcutaneous emphysema which causes distress, anxiety, palpebral closure, dyspnoea or dysphagia requires intervention. High negative pressure subcutaneous suction drain provides immediate and sustained relief in extensive and debilitating SE. PMID- 27494370 TI - Laparoscopic cholecystectomy in a 2 year old male child with choleilithiasis and recurrent right hypochondrial pain: Case report and review of literature. AB - INTRODUCTION: Gallstone disease has been considered an uncommon entity in children and infants, but its incidence is reportedly increasing which may be attributed to widespread use of diagnostic imaging (ultrasonography). PRESENTATION OF CASE: An apparently healthy 2 year old male child presented to our Outpatient department with chief complaint of recurrent abdominal pain. The episodes of pain were acute in onset and associated with vomiting. As per the complete examination and findings, a diagnosis of chronic calculous cholecystitis was made. A four port laparoscopic cholecystectomy was done. DISCUSSION: The incidence of gallstones in children in India has not been sufficiently studied. The incidence of gallstone disease in India was found to be 0.3% with the incidence in age group 0-10 being less than 0.1%. In contrast to adult gallstone disease, it has been found that there is no female preponderance in gallstone diseases of infancy. Also, the majority of children having increased haemoglobin turnover develop pigment stones only after 5 years of age. CONCLUSION: The probability of gallstone disease in infants and young children should not be ignored. Gall stones should always be considered as a differential diagnosis when young patients present with complaints of abdominal pain. PMID- 27494371 TI - Dermatofibrosarcoma protuberans post basal cell carcinoma excision: A case report. AB - INTRODUCTION: Dermatofibrosarcoma protuberans (DFSP) is a rare, malignant, soft tissue neoplasm of the dermis. Tumor recurrence is common following resection, and can be locally devastating if not identified in a timely manner. We report a unique case of this rare tumor. This case poses the question of an association between basal cell carcinoma (BCC) and DFSP, and presents the possible need for increased awareness of DFSP for healthcare providers and patients with a history of non-melanoma skin cancers as well as surgical or burn scars. PRESENTATION OF CASE: A 77-year-old male with a history of surgical excision of BCC presented with several palpable lesions in the superficial cutaneous tissue of the right anterior abdominal wall. Most of the lesions were consistent with lipoma; however, one lesion near the excision site of the BCC was more solid in consistency. The mass was removed with wide local excision encompassing all layers down to the abdominal fascia. Subsequent pathology findings included CD34 positive spindle cells in a whorled pattern consistent with DFSP. Resection margins were positive and a wide re-excision was performed with margins being negative. DISCUSSION: DFSP comprises approximately 0.01% of all malignant tumors. There are no known precipitating factors of DFSP, but its presence in surgical and burn scars is not uncommon. An association between DFSP and basal cell carcinoma has been suggested in the literature. Dermatofibroma and rarely DFSP may demonstrate basaloid proliferation of the overlying epidermis with characteristics of BCC. One case reporting coexistent DFSP and BCC located to the ear also suggested an association, but concluded that the finding was likely incidental due to sun exposure. In our case, the lesion's location is less routinely subjected to sun exposure and points more towards a possible association. The mainstay of treatment for local DFSP is wide local excision. Negative margins with the removal of fascia and muscle tissue as necessary is essential and the most significant prognostic factor. Three-dimensional reconstructions of DFSP have shown villous finger like projections of primary tumors, which is believed to be responsible for local recurrence. Recurrence can be devastating, as several cases have demonstrated rapid growth of remaining cells with increased morbidity following further resection. CONCLUSION: Based on this case and those found in the literature, we believe an association may exist between DFSP and BCC and further study of this association is needed. DFSP is a rare malignancy unknown to many healthcare providers, but in the presence of increased awareness and physician vigilance in surgical resection and follow up, the potential morbidity of DFSP may be prevented. PMID- 27494372 TI - Diagnostic and therapeutic dilemmas in intra-abdominal desmoid tumors: A case report and literature review. AB - INTRODUCTION: Intra-abdominal desmoid tumors (DTs) are a rare and anatomically diverse group of locally-aggressive, benign neoplasms. They are often difficult to diagnose, even in patients who possess risk factors for the disease. Even after a diagnosis has been reached, the optimal therapy is often not well defined. PRESENTATION OF CASE: The case discussed of a 33-year old male with a giant intra-abdominal desmoid is an example of both the diagnostic and therapeutic dilemmas that arise when confronted with a patient with a DT. Initial confusion over diagnosis led to ineffective therapy, but once the correct diagnosis was made, the patient went on to definitive surgical resection. DISCUSSION: The differential diagnosis of DTs is broad, and the diagnosis is often delayed due to nonspecific presentations. Immunohistochemistry is crucial in the accurate histological diagnosis, which guides treatment. Chemotherapy and radiation have a role in the management of both primary and recurrent lesions, but surgical resection remains the cornerstone of treatment. CONCLUSION: DTs present a clinical challenge in their diagnosis and management, and despite providing standard medical and surgical treatment, recurrence rates are high and continued surveillance is crucial. PMID- 27494373 TI - Abdominal trauma leading to diagnosis of Crohn's disease. PMID- 27494374 TI - Erratum. PMID- 27494375 TI - Motor versus body awareness: Voxel-based lesion analysis in anosognosia for hemiplegia and somatoparaphrenia following right hemisphere stroke. AB - Anosognosia for hemiplegia (AHP) is informative about the neurocognitive basis of motor awareness. However, it is frequently associated with concomitant symptoms, such as hemispatial neglect and disturbances in the sense of body ownership (DSO). Although double dissociations between these symptoms have been reported, there is ongoing debate about whether they are manifestations of independent abnormalities, or a single neurocognitive deficit. We aimed to investigate the specificity of lesions associated with AHP by surpassing four, existing methodological limitations: (a) recruit a relatively large sample of patients (total N = 70) in a multi-centre study; (b) identify lesions associated with AHP in grey and white matter using voxel-based methods; (c) take into account the duration of AHP and concomitant neglect symptoms; and (d) compare lesions against a control hemiplegic group, patients suffering from AHP and DSO, and a few, rare patients with selective DSO. Results indicated that acute AHP is associated with a wide network, mainly including: (1) the Rolandic operculum, (2) the insula and (3) the superior temporal gyri. Subcortically, damage mainly involved the basal ganglia and white matter, mostly the superior corona radiate, arcuate fasciculus and the part of the ventral, superior longitudinal fasciculus. Persistent symptoms were linked with wider damage involving fronto-temporal cortex and long white matter tracts. A shift in the latero-medial direction (mainly involving the basal ganglia and surrounding white matter) emerged when DSO was taken accounted for. These results suggest that while bodily awareness is processed by areas widely distributed across the brain, intact subcortical structures and white matter tracts may be necessary to support basic feelings of owning and controlling contralateral body parts. An accurate and 'up-to-date' awareness of our motor abilities, however, may rely also on intact processing in cortical areas which presumably allow higher-order inferences about the current state of the body. PMID- 27494376 TI - Temporal subtraction contrast-enhanced dedicated breast CT. AB - The development of a framework of deformable image registration and segmentation for the purpose of temporal subtraction contrast-enhanced breast CT is described. An iterative histogram-based two-means clustering method was used for the segmentation. Dedicated breast CT images were segmented into background (air), adipose, fibroglandular and skin components. Fibroglandular tissue was classified as either normal or contrast-enhanced then divided into tiers for the purpose of categorizing degrees of contrast enhancement. A variant of the Demons deformable registration algorithm, intensity difference adaptive Demons (IDAD), was developed to correct for the large deformation forces that stemmed from contrast enhancement. In this application, the accuracy of the proposed method was evaluated in both mathematically-simulated and physically-acquired phantom images. Clinical usage and accuracy of the temporal subtraction framework was demonstrated using contrast-enhanced breast CT datasets from five patients. Registration performance was quantified using normalized cross correlation (NCC), symmetric uncertainty coefficient, normalized mutual information (NMI), mean square error (MSE) and target registration error (TRE). The proposed method outperformed conventional affine and other Demons variations in contrast enhanced breast CT image registration. In simulation studies, IDAD exhibited improvement in MSE (0-16%), NCC (0-6%), NMI (0-13%) and TRE (0-34%) compared to the conventional Demons approaches, depending on the size and intensity of the enhancing lesion. As lesion size and contrast enhancement levels increased, so did the improvement. The drop in the correlation between the pre- and post contrast images for the largest enhancement levels in phantom studies is less than 1.2% (150 Hounsfield units). Registration error, measured by TRE, shows only submillimeter mismatches between the concordant anatomical target points in all patient studies. The algorithm was implemented using a parallel processing architecture resulting in rapid execution time for the iterative segmentation and intensity-adaptive registration techniques. Characterization of contrast-enhanced lesions is improved using temporal subtraction contrast-enhanced dedicated breast CT. Adaptation of Demons registration forces as a function of contrast enhancement levels provided a means to accurately align breast tissue in pre- and post-contrast image acquisitions, improving subtraction results. Spatial subtraction of the aligned images yields useful diagnostic information with respect to enhanced lesion morphology and uptake. PMID- 27494377 TI - Synthesis and characterization of Cu-Zn/TiO2 for the photocatalytic conversion of CO2 to methane. AB - Different Cu-Zn/TiO2 catalysts were synthesized by using the wet impregnation method. The prepared catalysts were used for the conversion of CO2 into methane by photocatalysis. Various characterization techniques were used to observe the surface morphology, crystalline phase, Brunauer-Emmett-Teller (BET) surface area, presence of impregnated Cu and Zn, and functional group. Scanning electron microscope analysis showed spherical morphology, and slight agglomeration of catalyst particles was observed. BET analysis revealed that the surface area of the catalyst was decreased from 10 to 8.5 m2/g after impregnation of Cu and Zn over TiO2 support. Synergetic effect of Cu and Zn over TiO2 support (Cu2.6/TiO2, Zn0.5/TiO2 and Cu2.6-Zn0.5/TiO2) and the effects of Cu loading (0, 1.8, 2.1, 2.6 and 2.9 wt%) were also investigated at different feed molar ratios of H2/CO2 (2:1 and 4:1). The Cu2.6-Zn0.5/TiO2 catalyst showed a maximum conversion of 14.3% at a feed molar ratio of 4. The addition of Zn over the catalyst surface increased the conversion of CO2 from 10% to 14.3% which might be due to synergy of Cu and Zn over TiO2 support. PMID- 27494378 TI - Influence of Sodium Cationization versus Protonation on the Gas-Phase Conformations and Glycosidic Bond Stabilities of 2'-Deoxyadenosine and Adenosine. AB - The influence of noncovalent interactions with a sodium cation on the gas-phase structures and N-glycosidic bond stabilities of 2'-deoxyadenosine (dAdo) and adenosine (Ado), [dAdo+Na](+) and [Ado+Na](+), are probed via infrared multiple photon dissociation (IRMPD) action spectroscopy and energy-resolved collision induced dissociation (ER-CID) experiments. ER-CID experiments are also performed on the protonated forms of these nucleosides, [dAdo+H](+) and [Ado+H](+), for comparison purposes. Complementary electronic structure calculations are performed to determine the structures and relative stabilities of the stable low energy conformations of the sodium cationized nucleoside complexes and to predict their IR spectra. Comparison between the measured IRMPD action spectra and calculated IR spectra enables the conformations of the sodium cationized nucleosides present in the experiments to be elucidated. The influence of sodium cationization versus protonation on the structures and IR spectra is elucidated by comparison to IRMPD and theoretical results previously reported for the protonated forms of these nucleosides. The influence of sodium cationization versus protonation on the glycosidic bond stability of the adenine nucleosides is determined by comparison of the ER-CID behavior of these systems. All structures present in the experiments are found to involve tridentate binding of Na(+) to the N3, O4', and O5' atoms forming favorable 5- and 6-membered chelation rings, which requires that adenine rotate to a syn configuration. This mode of sodium cation binding results in moderate flexibility of the sugar moiety such that the sugar puckering of the conformations present varies between C2'-endo and O4' endo. Sodium cationization is found to be less effective toward activating the N glycosidic bond than protonation for both dAdo and Ado. Both the IRMPD yields and ER-CID behavior indicate that the 2'-hydroxyl substituent of Ado stabilizes the N glycosidic bond relative to that of dAdo. PMID- 27494379 TI - Dialysis: the best quality at the lowest cost. PMID- 27494380 TI - Whole-Exome-Sequencing Reveals Small Deletions in CASP14 in Patients with Autosomal Recessive Inherited Ichthyosis. PMID- 27494382 TI - Bilateral Outer Retinal Necrosis Following Mumps Infection. PMID- 27494383 TI - A Concise Approach to Site-Specific Topological Protein-Poly(amino acid) Conjugates Enabled by in Situ-Generated Functionalities. AB - Controlling the topology of polymer-modified proteins has attracted growing interest. However, one of the main challenges in this field is the lack of efficient and site-specific methods for installing multiple bioorthogonal functionalities on substrate polymers. We report here an orchestrating strategy that provides easy access to various topological protein-poly(amino acid) (PAA) conjugates in high yields. This method features the in situ installation of two "chemical handles", including a thioester for native chemical ligation and a polyglycine nucleophile for sortase A-mediated ligation, at both ends of substrate PAAs. As a result, neither pre-functionalization of initiator or monomer units, nor post-polymerization modification of the resultant polymers, is necessary. Site-specific topological conjugates, particularly circular conjugates, can be conveniently synthesized under mild conditions from the functionalized PAAs. The biomedical utility of our method is demonstrated by the rapid and efficient generation of several therapeutic interferon-alpha conjugates, which exhibit significantly enhanced protease resistance and thermostability. Given the versatility of both PAAs and proteins, the method offers a convenient approach to producing libraries of conjugates for biological applications. PMID- 27494381 TI - Biology and biogenesis of shed microvesicles. AB - The ability of cells to transmit bioactive molecules to recipient cells and the extracellular environment is a fundamental requirement for both normal physiology and disease pathogenesis. It has traditionally been thought that soluble factors released from cells were responsible for this cellular signaling but recent research has revealed a fundamental role for microvesicles in this process. Microvesicles are heterogeneous membrane-bound sacs that are shed from the surface of cells into the extracellular environment in a highly regulated process. They are shed following the selective incorporation of a host of molecular cargo including multiple types of proteins and nucleic acids. In addition to providing new insight into the etiology of complex human diseases, microvesicles also show great promise as a tool for advanced diagnosis and therapy as we move forward into a new age of personalized medicine. Here we review current status of the rapidly evolving field of microvesicle biology, highlighting critical regulatory roles for several small GTPases in the biology and biogenesis of shed microvesicles. PMID- 27494384 TI - Equation of state and thermodynamic Gruneisen parameter of monoclinic 1,1-diamino 2,2-dinitroethylene. AB - In situ synchrotron x-ray diffraction experiments were conducted on 1,1-diamino 2,2-dinitroethylene (FOX-7) at pressures up to 6.8 GPa and temperatures up to 485 K. Within the resolution of the present diffraction data, our results do not reveal evidence for a pressure-induced structural phase transition near 2 GPa, previously observed in several vibrational spectroscopy experiments. Based on unit-cell volume measurements, the least-squares fit using the third-order Birch Murnaghan equation of state (EOS) yields K 0 = 12.6 +/- 1.4 GPa and [Formula: see text] = 11.3 +/- 2.1 for the alpha-phase of FOX-7, which are in good agreement with recently reported values for the deuterated sample, indicating that the effect of hydrogen-deuterium substitution on the compressibility of FOX 7 is negligibly small. A thermal EOS is also obtained for the alpha-phase of FOX 7, including pressure dependence of thermal expansivity, (?alpha/?P)T = -7.0 +/- 2.0 * 10(-5) K(-1) GPa(-1), and temperature derivative of the bulk modulus, (?K T/?T)P = -1.1 * 10(-2) GPa K(-1). From these EOS parameters, we calculate heat capacity at constant volume (C V) and thermodynamic Gruneisen parameter (gamma TH) as a function of temperature. At ambient conditions, the calculated gamma TH is 1.055, which is in good agreement with the value (1.09) previously obtained from density functional theory (DFT). The obtained C V, however, is 13% larger than that calculated from the first-principles calculations, indicating that the dispersion correction in the DFT calculations may need to be further improved for describing intermolecular interactions of molecular crystals. PMID- 27494385 TI - Biodegradation of 1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane (DDT) by using Serratia marcescens NCIM 2919. AB - A solvent tolerant bacterium Serratia marcescens NCIM 2919 has been evaluated for degradation of DDT (1,1,1-trichloro-2,2-bis (4-chlorophenyl) ethane). The bacterium was able to degrade up to 42% of initial 50 mg L-1 of DDT within 10 days of incubation. The highlight of the work was the elucidation of DDT degradation pathway in S. marcescens. A total of four intermediates metabolites viz. 2,2-bis (chlorophenyl)-1,1-dichloroethane (DDD), 2,2-bis (chlorophenyl)-1,1 dichloroethylene (DDE), 2,2-bis (chlorophenyl)-1-chloroethylene (DDMU), and 4 chlorobenzoic acid (4-CBA) were identified by GC-Mass and FTIR. 4-CBA was found to be the stable product of DDT degradation. Metabolites preceding 4-CBA were not toxic to strain as reveled through luxuriant growth in presence of varying concentrations of exogenous DDD and DDE. However, 4-CBA was observed to inhibit the growth of bacterium. The DDT degrading efficiency of S. marcescens NCIM 2919 hence could be used in combination with 4-CBA utilizing strains either as binary culture or consortia for mineralization of DDT. Application of S. marcescens NCIM 2919 to DDT contaminated soil, showed 74.7% reduction of initial 12.0 mg kg-1 of DDT after 18-days of treatment. PMID- 27494387 TI - Obesity: BMI-increasing variant identified in Samoans. PMID- 27494386 TI - Frostbite: Spectrum of Imaging Findings and Guidelines for Management. AB - Frostbite is a localized cold thermal injury that results from tissue freezing. Frostbite injuries can have a substantial effect on long-term limb function and mobility if not promptly evaluated and treated. Imaging plays a critical role in initial evaluation of frostbite injuries and in monitoring response to treatment. A multimodality approach involving radiography, digital subtraction angiography (DSA), and/or multiphase bone scintigraphy with hybrid single photon emission computed tomography (SPECT)/computed tomography (CT) is often necessary for optimal guidance of frostbite care. Radiographs serve as an initial survey of the affected limb and may demonstrate characteristic findings, depending on the time course and severity of injury. DSA is used to evaluate perfusion of affected soft tissues and identify potential targets for therapeutic intervention. Angiography directed thrombolysis plays an essential role in tissue preservation and salvage in deep frostbite injuries. Multiphase bone scintigraphy with technetium 99m labeled diphosphonate provides valuable information regarding the status of tissue viability after initial treatment. The addition of SPECT/CT to multiphase bone scintigraphy enables precise anatomic localization of the level and depth of tissue necrosis before its appearance at physical examination and can help uncover subtle findings that may remain occult at scintigraphy alone. Multiphase bone scintigraphy with SPECT/CT is the modality of choice for prognostication and planning of definitive surgical care of affected limbs. Appropriate use of imaging to direct frostbite care can help limit the effects that these injuries have on limb function and mobility. (c)RSNA, 2016. PMID- 27494388 TI - Diabetes: Natural autoantibodies protect against T1DM. PMID- 27494389 TI - Parathyroid gland: GNAS defects in a large PHP cohort. PMID- 27494390 TI - Thyroid cancer: Mortality unaffected by rise in use of imaging tests. PMID- 27494391 TI - Vitamin D and falls - the dosage conundrum. AB - Falls are a major health problem in elderly individuals. Although intensive physical therapy and management of hazards in the home can reduce falls by 25%, long-term practicality limits their use. Interest in vitamin D as a medical therapy has led to many trials; however, results using daily oral doses of vitamin D have been inconsistent. In the past 5 years, studies on the effect of bolus doses of vitamin D have produced surprising results. Bolus doses of vitamin D, given annually (at a dose of 300,000 IU or 500,000 IU) or monthly (at a dose of 24,000 IU or 60,000 IU) - equivalent to approximate daily doses of 800 IU, 1400 IU and 2,000 IU - result in a significant increase in the number of falls and fractures associated with serum levels of 25-hydroxyvitamin D greater than 40 45 ng/ml (equivalent to 100-112 nmol/l). These unexpected results show increased falls and fractures are adverse events related to vitamin D administration. Until further safety data is available, bolus dosing or daily doses should not exceed 3,000 IU and serum levels of 25-hydroxyvitamin D should not exceed 40-45 ng/ml (equivalent to 100-112 nmol/l) in elderly individuals. PMID- 27494392 TI - Magnetic Materials for the Selective Analysis of Peptide and Protein Biomarkers. AB - This mini-review article provides an overview on the use of magnetic materials for the analysis of protein biomarkers. In particular, the advantage provided by magnetic solid phase extraction will be discussed with selected examples, considering untargeted analysis for screening new biomarker proteins and targeted investigation on known and suggested new biomarkers. Aspects, such as enrichment efficiency over conventional techniques, ease of use, functionalization versatility and automation will be considered, together with quantification and deeper structure elucidation provided by coupling selective or specific enrichment to powerful characterization techniques, such as mass spectrometry. PMID- 27494393 TI - New therapeutic property of Dimebon as a neuroprotective agent. AB - Dimebon (or Latrepirdine) was initially used as an anti-histamergic drug but later new therapeutic properties were rediscovered, adding to a growing body of "old" agents with prominent neuroprotective effects. In the present manuscript, we are focusing on our latest study on Dimebon with regard to brain"s pathological processes using in vivo proteinopathy models. In the study, neurodegenerative pathology has been attributed to a group of aggregate-prone proteins: hyperphosphorylated tau, fused in sarcoma and gamma-synuclein , which are involved in a number of neurological disorders. We have also presented our in vitro model based on overexpression of an aberrant mutant form of transactive response DNA binding 43 kDa protein in cultured SH-SY5Y neuroblastoma cells. Dimebon treatment followed by the activation of autophagy markers resulted in reduced number of inclusion containing cells. The most significant effects of Dimebon appeared to be on the improving cellular energy balance, mitochondria stability by increasing the threshold for nonselective mitochondrial pore opening as well as on increased calcium retention capacity while reducing lipid peroxidation. The therapeutic potential of Dimebon and newly designed analogs show disease modifying properties and could be used to treat neurodegenerative disorders. In addition, new data hint on a possible anti-aging effect and potential application of Dimebon for treatment of anxiety, ischemia and depression. Overall, our findings suggest that the most pronounced effect of Dimebon was observed when treatment was started at the early stages of disease onset and this factor needs to be taken into account while planning future clinical trials. PMID- 27494394 TI - Clinical Impact Research - how to choose experimental or observational intervention study? AB - BACKGROUND: Interventions directed to individuals by health and social care systems should increase health and welfare of patients and customers. AIMS: This paper aims to present and define a new concept Clinical Impact Research (CIR) and suggest which study design, either randomized controlled trial (RCT) (experimental) or benchmarking controlled trial (BCT) (observational) is recommendable and to consider the feasibility, validity, and generalizability issues in CIR. METHODS: The new concept is based on a narrative review of the literature and on author's idea that in intervention studies, there is a need to cover comprehensively all the main impact categories and their respective outcomes. The considerations on how to choose the most appropriate study design (RCT or BCT) were based on previous methodological studies on RCTs and BCTs and on author's previous work on the concepts benchmarking controlled trial and system impact research (SIR). RESULTS: The CIR covers all studies aiming to assess the impact for health and welfare of any health (and integrated social) care or public health intervention directed to an individual. The impact categories are accessibility, quality, equality, effectiveness, safety, and efficiency. Impact is the main concept, and within each impact category, both generic- and context-specific outcome measures are needed. CIR uses RCTs and BCTs. CONCLUSIONS: CIR should be given a high priority in medical, health care, and health economic research. Clinicians and leaders at all levels of health care can exploit the evidence from CIR. Key messages The new concept of Clinical Impact Research (CIR) is defined as a research field aiming to assess what are the impacts of healthcare and public health interventions targeted to patients or individuals. The term impact refers to all effects caused by the interventions, with particular emphasis on accessibility, quality, equality, effectiveness, safety, and efficiency. CIR uses two study designs: randomized controlled trials (RCTs) (experimental) and benchmarking controlled trials (BCTs) (observational). Suggestions on how to choose between RCT and BCT as the most suitable study design are presented. Simple way of determining the study question in CIR based on the PICO (patient, intervention, control intervention, outcome) framework is presented. CIR creates the scientific basis for clinical decisions. Clinicians and leaders at all levels of health care and those working for public health can use the evidence from CIR for the benefit of patients and the population. PMID- 27494395 TI - (15)N NMR Spectroscopy, X-ray and Neutron Diffraction, Quantum-Chemical Calculations, and UV/vis-Spectrophotometric Titrations as Complementary Techniques for the Analysis of Pyridine-Supported Bicyclic Guanidine Superbases. AB - Pyridine substituted with one and two bicyclic guanidine groups has been studied as a potential source of superbases. 2-{hpp}C5H4N (I) and 2,6-{hpp}2C5H3N (II) (hppH = 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine) were protonated using [HNEt3][BPh4] to afford [I-H][BPh4] (1a), [II-H][BPh4] (2), and [II-H2][BPh4]2 (3). Solution-state (1)H and (15)N NMR spectroscopy shows a symmetrical cation in 2, indicating a facile proton-exchange process in solution. Solid-state (15)N NMR data differentiates between the two groups, indicating a mixed guanidine/guanidinium. X-ray diffraction data are consistent with protonation at the imine nitrogen, confirmed for 1a by single-crystal neutron diffraction. The crystal structure of 1a shows association of two [I-H](+) cations within a cage of [BPh4](-) anions. Computational analysis performed in the gas phase and in MeCN solution shows that the free energy barrier to transfer a proton between imino centers in [II-H](+) is 1 order of magnitude lower in MeCN than in the gas phase. The results provide evidence that linking hpp groups with the pyridyl group stabilizes the protonation center, thereby increasing the intrinsic basicity in the gas phase, while the bulk prevents efficient cation solvation, resulting in diminished pKa(MeCN) values. Spectrophotometrically measured pKa values are in excellent agreement with calculated values and confirm that I and II are superbases in solution. PMID- 27494396 TI - Patient and Family Member-Led Research in the Intensive Care Unit: A Novel Approach to Patient-Centered Research. AB - INTRODUCTION: Engaging patients and family members as partners in research increases the relevance of study results and enhances patient-centered care; how to best engage patients and families in research is unknown. METHODS: We tested a novel research approach that engages and trains patients and family members as researchers to see if we could understand and describe the experiences of patients admitted to the intensive care unit (ICU) and their families. Former patients and family members conducted focus groups and interviews with patients (n = 11) and families of surviving (n = 14) and deceased (n = 7) patients from 13 ICUs in Alberta Canada, and analyzed data using conventional content analysis. Separate blinded qualitative researchers conducted an independent analysis. RESULTS: Participants described three phases in the patient/family "ICU journey"; admission to ICU, daily care in ICU, and post-ICU experience. Admission to ICU was characterized by family shock and disorientation with families needing the presence and support of a provider. Participants described five important elements of daily care: honoring the patient's voice, the need to know, decision making, medical care, and culture in ICU. The post-ICU experience was characterized by the challenges of the transition from ICU to a hospital ward and long-term effects of critical illness. These "ICU journey" experiences were described as integral to appropriate interactions with the care team and comfort and trust in the ICU, which were perceived as essential for a community of caring. Participants provided suggestions for improvement: 1) provide a dedicated family navigator, 2) increase provider awareness of the fragility of family trust, 3) improve provider communication skills, 4) improve the transition from ICU to hospital ward, and 5) inform patients about the long-term effects of critical illness. Analyses by independent qualitative researchers identified similar themes. CONCLUSIONS: Patient and family member-led research is feasible and can identify opportunities for improving care. PMID- 27494397 TI - Genome-Wide Association Study for Indicator Traits of Sexual Precocity in Nellore Cattle. AB - The objective of this study was to perform a genome-wide association study (GWAS) to detect chromosome regions associated with indicator traits of sexual precocity in Nellore cattle. Data from Nellore animals belonging to farms which participate in the DeltaGen(r) and Paint(r) animal breeding programs, were used. The traits used in this study were the occurrence of early pregnancy (EP) and scrotal circumference (SC). Data from 72,675 females and 83,911 males with phenotypes were used; of these, 1,770 females and 1,680 males were genotyped. The SNP effects were estimated with a single-step procedure (WssGBLUP) and the observed phenotypes were used as dependent variables. All animals with available genotypes and phenotypes, in addition to those with only phenotypic information, were used. A single-trait animal model was applied to predict breeding values and the solutions of SNP effects were obtained from these breeding values. The results of GWAS are reported as the proportion of variance explained by windows with 150 adjacent SNPs. The 10 windows that explained the highest proportion of variance were identified. The results of this study indicate the polygenic nature of EP and SC, demonstrating that the indicator traits of sexual precocity studied here are probably controlled by many genes, including some of moderate effect. The 10 windows with large effects obtained for EP are located on chromosomes 5, 6, 7, 14, 18, 21 and 27, and together explained 7.91% of the total genetic variance. For SC, these windows are located on chromosomes 4, 8, 11, 13, 14, 19, 22 and 23, explaining 6.78% of total variance. GWAS permitted to identify chromosome regions associated with EP and SC. The identification of these regions contributes to a better understanding and evaluation of these traits, and permits to indicate candidate genes for future investigation of causal mutations. PMID- 27494398 TI - Trend in and predictors for cardiovascular mortality in patients with rheumatoid arthritis over a period of 15 years: a prospective cohort study. AB - OBJECTIVES: To investigate a) the cardiovascular (CV) mortality in a clinical cohort of patients with established rheumatoid arthritis (RA) in comparison with the general population over 15 years, b) the trend in this CV mortality during the study period, and c) for a broad range of predictors, which baseline variables predict CV mortality. METHODS: In 1997, a sample of 1222 patients was randomly selected from the register of a rheumatology outpatient clinic in Amsterdam. Their CV mortality between 1997 and 2012 was obtained from Statistics Netherlands. The standardised mortality ratio (SMR) for CV mortality was calculated. A linear poisson regression analysis was performed to investigate if there was a trend in SMR over time. A Cox regression analysis was performed to determine which baseline variables predicted CV mortality. RESULTS: Mean age of the population at baseline was 60.4 (SD 15.4) years and 72.6% of the patients were women. Estimated SMR (95% confidence interval) for CV mortality was 1.24 (1.05, 1.43). The SMR decreased with 3% annually (p=0.16). Higher age, higher erythrocyte sedimentation rate, having CV comorbidity and diabetes mellitus (DM) were predictors for CV mortality. CONCLUSIONS: CV mortality among patients with RA in the past 15 years was still higher than in the general population. CV mortality decrease was not statistically significant. As CV mortality in RA is still higher than in the general population, continued attention for CV diseases in RA is important. Both tight control of disease activity and good care for comorbid conditions (CV diseases and DM) are advocated. PMID- 27494400 TI - Following [FeFe] Hydrogenase Active Site Intermediates by Time-Resolved Mid-IR Spectroscopy. AB - Time-resolved nanosecond mid-infrared spectroscopy is for the first time employed to study the [FeFe] hydrogenase from Chlamydomonas reinhardtii and to investigate relevant intermediates of the enzyme active site. An actinic 355 nm, 10 ns laser flash triggered photodissociation of a carbonyl group from the CO-inhibited state Hox-CO to form the state Hox, which is an intermediate of the catalytic proton reduction cycle. Time-resolved infrared spectroscopy allowed us to directly follow the subsequent rebinding of the carbonyl, re-forming Hox-CO, and determine the reaction half-life to be t1/2 ~ 13 +/- 5 ms at room temperature. This gives direct information on the dynamics of CO inhibition of the enzyme. PMID- 27494399 TI - Are short (blue) wavelengths necessary for light treatment of seasonal affective disorder? AB - Despite widely published speculation regarding a potential potency advantage of short-wavelength (blue-appearing) light for Seasonal Affective Disorder (SAD) treatment, there have been few systematic studies. Those comparing short wavelength to broad-wavelength (white) light under actual clinical conditions suggest equivalent effectiveness. This multicenter, parallel-group design trial was undertaken to compare the effects of light therapy on SAD using blue (~465 nm) versus blue-free (595-612 nm) LED lights. Fifty-six medication-free subjects aged 21-64 years who met DSM-IV-TR criteria for recurrent major depression with winter-type seasonal pattern were enrolled in this blinded study at five participating centers between January and March 2012. Thirty-five subjects met the criteria for randomization to 30 min of either blue (~465 nm) or blue-free (595-612 nm) daily morning light therapy. Twenty-nine subjects completed the study; three subjects withdrew due to treatment-related adverse events, including migraines, and three withdrew for non-study-related reasons. The primary effectiveness variable was depression score (SIGH-ADS) after six weeks of daily light treatment. Secondary effectiveness variables included quality-of-life (QoL) and suicidality ratings. Using an intent-to-treat analysis, mean depression scores were different at baseline for the blue group (29 +/- 5 versus 26 +/- 5, p = 0.05 blue versus blue-free, respectively), and the initial score was used as a covariate. Baseline scores were not significantly different between treatment groups among those who completed the study, and no significant differences in depression scores were observed after 6 weeks (mean +/- SD scores at 6 weeks: 5.6 +/- 6.1 versus 4.5 +/- 5.3, p = 0.74, blue versus blue-free, respectively). In addition, the proportion of subjects who met remission criteria, defined as a depression score <=8, was not significantly different between the two groups (p = 0.41); among the 29 subjects who completed the study, 76% of subjects experienced remission by the end of the trial, which coincided with the beginning of spring. The QoL and suicidality ratings were also significantly improved from pre- to post-treatment, with no significant difference between treatments. No subject experienced worsening or non-improved symptoms over the 6-week trial. The main finding of this study is that subjects treated with blue light did not improve more than subjects treated with blue-free light; both showed substantial improvement on multiple measures. Failure to find differences may have resulted from methodological constraints, including a small sample size. Recruitment began mid-winter during an unusually mild season, and the trial was terminated earlier than planned by the study sponsor due to a failure to detect a difference. However, if confirmed in a larger randomized sample, these results suggest that blue wavelengths are not necessary for successful SAD treatment. PMID- 27494401 TI - Identifying the Dominant Personality Profiles in Medical Students: Implications for Their Well-Being and Resilience. AB - PURPOSE: There is a high prevalence of stress, depression, and burn-out in medical students. Medical students differ widely in personality traits, self perceptions, and values that may have an impact on their well-being. This study aimed to investigate variability in their personality profiles in relation to their potential for well-being and resilience. METHOD: Participants were 808 medical students from The University of Queensland. An online questionnaire collected socio-demographics and the Temperament and Character Inventory to assess personality traits. Latent profile analyses identified students' trait profiles. RESULTS: Two distinct personality profiles were identified. Profile 1 ("Resilient") characterized 60% of the sample and was distinguished by low Harm Avoidance combined with very high Persistence, Self-Directedness and Cooperativeness compared to Profile 2 ("Conscientious"). Both Profiles had average levels of Reward Dependence and Novelty Seeking and low levels of Self Transcendence. Profiles did not differ by age, gender, or country of birth, but rural background students were more likely to have Profile 1. While both Profiles indicate mature and healthy personalities, the combination of traits in Profile 1 is more strongly indicative of well-being and resilience. CONCLUSIONS: Finding two distinct profiles of personality highlights the importance of considering combinations of traits and how they may interact with medical students' potential for well-being. Although both profiles of students show healthy personalities, many may lack the resilience to maintain well-being over years of medical training. Programs that develop character and personality self-awareness would enhance their well-being and prepare them to promote the health of their patients. PMID- 27494402 TI - Detection of long non-coding RNAs in human breastmilk extracellular vesicles: Implications for early child development. AB - Breastmilk has many documented beneficial effects on the developing human infant, but the components of breastmilk that influence these developmental pathways have not been fully elucidated. Increasing evidence suggests that non-coding RNAs encapsulated in extracellular vesicles (EVs) represent an important mechanism of communication between the mother and child. Long non-coding RNAs (lncRNAs) are of particular interest given their key role in gene expression and development. However, it is not known whether breastmilk EVs contain lncRNAs. We used qRT-PCR to determine whether EVs isolated from human breastmilk contain lncRNAs previously reported to be important for developmental processes. We detected 55 of the 87 screened lncRNAs in EVs from the 30 analyzed breastmilk samples, and CRNDE, DANCR GAS5, SRA1 and ZFAS1 were detected in >90% of the samples. GAS5, SNHG8 and ZFAS1 levels were highly correlated (Spearman's rho>0.9; P<0.0001), which may indicate that the loading of these lncRNAs into breastmilk EVs is regulated by the same pathways. The detected lncRNAs are important epigenetic regulators involved in processes such as immune cell regulation and metabolism. They may target a repertoire of recipient cells in offspring and could be essential for child development and health. Further experimental and epidemiological studies are warranted to determine the impact of breastmilk EV encapsulated lnRNAs in mother to child signaling. PMID- 27494404 TI - HDAC9 Variant Rs2107595 Modifies Susceptibility to Coronary Artery Disease and the Severity of Coronary Atherosclerosis in a Chinese Han Population. AB - A previous genome-wide association study showed that a single nucleotide polymorphism (SNP) rs2107595 in histone deacetylase 9 (HDAC9) gene was associated with large artery stroke (LAS) in Caucasians. Based on the similar atherosclerotic pathogenesis between LAS and coronary artery disease (CAD), we aimed to evaluate the associations of SNP rs2107595 with CAD risk and the severity of coronary atherosclerosis in a Chinese Han population, and explore the potential gene-environment interactions among SNP rs2107595 and conventional CAD risk factors. In a two-stage case-control study with a total of 2317 CAD patients and 2404 controls, the AG + AA genotypes of SNP rs2107595 were significantly associated with increased CAD risk (Adjusted odds ratio (OR) = 1.23, Padj = 0.001) and higher modified Gensini scores (Adjusted OR = 1.38, Padj < 0.001). These associations remained significant in subtype analyses for unstable angina pectoris (UAP), non-ST-segment elevation myocardial infarction (NSTEMI) and ST segment elevation myocardial infarction (STEMI). Subgroup and multifactor dimensionality reduction analyses (MDR) further found the gene-environment interactions among SNP rs2107595, body mass index, type 2 diabetes and hyperlipidemia in CAD risk and the severity of coronary atherosclerosis. Moreover, patients with CAD had higher levels of HDAC9 mRNA expression and plasma HDAC9 than controls. Subsequent genotype-phenotype analyses observed the significant correlations of SNP rs2107595 with HDAC9 mRNA expression and plasma HDAC9 levels in controls and patients with NSTEMI and STEMI. Taken together, our data suggest that SNP rs2107595 may contribute to coronary atherosclerosis and CAD risk through a possible mechanism of regulating HDAC9 expression and gene environment interactions. PMID- 27494406 TI - FITC Conjugation Markedly Enhances Hepatic Clearance of N-Formyl Peptides. AB - In both septic and aseptic inflammation, N-formyl peptides may enter the circulation and induce a systemic inflammatory response syndrome similar to that observed during septic shock. The inflammatory response is brought about by the binding of N-formyl peptide to formyl peptide receptors (FPRs), specific signaling receptors expressed on myeloid as well as non-myeloid cells involved in the inflammatory process. N-formyl peptides conjugated with fluorochromes, such as fluorescein isothiocyanate (FITC) are increasingly experimentally used to identify tissues involved in inflammation. Hypothesizing that the process of FITC conjugation may transfer formyl peptide to a ligand that is efficiently cleared from the circulation by the natural powerful hepatic scavenging regime we studied the biodistribution of intravenously administered FITC-fNLPNTL (Fluorescein isothiocyanate- N-Formyl-Nle-Leu-Phe-Nle-Tyr-Lys) in mice. Our findings can be summarized as follows: i) In contrast to unconjugated fNLPNTL, FITC-fNLPNTL was rapidly taken up in the liver; ii) Mouse and human liver sinusoidal endothelial cells (LSECs) and hepatocytes express formyl peptide receptor 1 (FRP1) on both mRNA (PCR) and protein (Western blot) levels; iii) Immunohistochemistry showed that mouse and human liver sections expressed FRP1 in LSECs and hepatocytes; and iv) Uptake of FITC-fNLPNTL could be largely blocked in mouse and human hepatocytes by surplus-unconjugated fNLPNTL, thereby suggesting that the hepatocytes in both species recognized FITC-fNLPNTL and fNLPNTL as indistinguishable ligands. This was in contrast to the mouse and human LSECs, in which the uptake of FITC-fNLPNTL was mediated by both FRP1 and a scavenger receptor, specifically expressed on LSECs. Based on these results we conclude that a significant proportion of FITC-fNLPNTL is taken up in LSECs via a scavenger receptor naturally expressed in these cells. This calls for great caution when using FITC-fNLPNTL and other chromogen-conjugated formyl peptides as a probe to identify cells in a liver engaged in inflammation. Moreover, our finding emphasizes the role of the liver as an important neutralizer of otherwise strong inflammatory signals such as formyl peptides. PMID- 27494403 TI - The Hippo Pathway Targets Rae1 to Regulate Mitosis and Organ Size and to Feed Back to Regulate Upstream Components Merlin, Hippo, and Warts. AB - Hippo signaling acts as a master regulatory pathway controlling growth, proliferation, and apoptosis and also ensures that variations in proliferation do not alter organ size. How the pathway coordinates restricting proliferation with organ size control remains a major unanswered question. Here we identify Rae1 as a highly-conserved target of the Hippo Pathway integrating proliferation and organ size. Genetic and biochemical studies in Drosophila cells and tissues and in mammalian cells indicate that Hippo signaling promotes Rae1 degradation downstream of Warts/Lats. In proliferating cells, Rae1 loss restricts cyclin B levels and organ size while Rae1 over-expression increases cyclin B levels and organ size, similar to Hippo Pathway over-activation or loss-of-function, respectively. Importantly, Rae1 regulation by the Hippo Pathway is crucial for its regulation of cyclin B and organ size; reducing Rae1 blocks cyclin B accumulation and suppresses overgrowth caused by Hippo Pathway loss. Surprisingly, in addition to suppressing overgrowth, reducing Rae1 also compromises survival of epithelial tissue overgrowing due to loss of Hippo signaling leading to a tissue "synthetic lethality" phenotype. Excitingly, Rae1 plays a highly conserved role to reduce the levels and activity of the Yki/YAP oncogene. Rae1 increases activation of the core kinases Hippo and Warts and plays a post-transcriptional role to increase the protein levels of the Merlin, Hippo, and Warts components of the pathway; therefore, in addition to Rae1 coordinating organ size regulation with proliferative control, we propose that Rae1 also acts in a feedback circuit to regulate pathway homeostasis. PMID- 27494405 TI - Estimating Geographical Variation in the Risk of Zoonotic Plasmodium knowlesi Infection in Countries Eliminating Malaria. AB - BACKGROUND: Infection by the simian malaria parasite, Plasmodium knowlesi, can lead to severe and fatal disease in humans, and is the most common cause of malaria in parts of Malaysia. Despite being a serious public health concern, the geographical distribution of P. knowlesi malaria risk is poorly understood because the parasite is often misidentified as one of the human malarias. Human cases have been confirmed in at least nine Southeast Asian countries, many of which are making progress towards eliminating the human malarias. Understanding the geographical distribution of P. knowlesi is important for identifying areas where malaria transmission will continue after the human malarias have been eliminated. METHODOLOGY/PRINCIPAL FINDINGS: A total of 439 records of P. knowlesi infections in humans, macaque reservoir and vector species were collated. To predict spatial variation in disease risk, a model was fitted using records from countries where the infection data coverage is high. Predictions were then made throughout Southeast Asia, including regions where infection data are sparse. The resulting map predicts areas of high risk for P. knowlesi infection in a number of countries that are forecast to be malaria-free by 2025 (Malaysia, Cambodia, Thailand and Vietnam) as well as countries projected to be eliminating malaria (Myanmar, Laos, Indonesia and the Philippines). CONCLUSIONS/SIGNIFICANCE: We have produced the first map of P. knowlesi malaria risk, at a fine-scale resolution, to identify priority areas for surveillance based on regions with sparse data and high estimated risk. Our map provides an initial evidence base to better understand the spatial distribution of this disease and its potential wider contribution to malaria incidence. Considering malaria elimination goals, areas for prioritised surveillance are identified. PMID- 27494407 TI - Persistence of focal lymphocytic sialadenitis in patients with primary Sjogren's syndrome treated with rituximab: a possible role for glandular BAFF. PMID- 27494408 TI - DNA Methylation Suppresses Leptin Gene in 3T3-L1 Adipocytes. AB - Leptin is a key regulator of energy intake and expenditure. This peptide hormone is expressed in mouse white adipose tissue, but hardly expressed in 3T3-L1 adipocytes. Using bisulfite sequencing, we found that CpG islands in the leptin promoter are highly methylated in 3T3-L1cells. 5-azacytidine, an inhibitor of DNA methyltransferase, markedly increased leptin expression as pre-adipocytes matured into adipocytes. Remarkably, leptin expression was stimulated by insulin in adipocytes derived from precursor cells exposed to 5-azacytidine, but suppressed by thiazolidinedione and dexamethasone. In contrast, adipocytes derived from untreated precursor cells were unresponsive to both 5-azacytidine and hormonal stimuli, although lipid accumulation was sufficient to boost leptin expression in the absence of demethylation. Taken together, the results suggest that leptin expression in 3T3-L1 cells requires DNA demethylation prior to adipogenesis, transcriptional activation during adipogenesis, and lipid accumulation after adipogenesis. PMID- 27494409 TI - Is the Karyotype of Neotropical Boid Snakes Really Conserved? Cytotaxonomy, Chromosomal Rearrangements and Karyotype Organization in the Boidae Family. AB - Boids are primitive snakes from a basal lineage that is widely distributed in Neotropical region. Many of these species are both morphologically and biogeographically divergent, and the relationship among some species remains uncertain even with evolutionary and phylogenetic studies being proposed for the group. For a better understanding of the evolutionary relationship between these snakes, we cytogenetically analysed 7 species and 3 subspecies of Neotropical snakes from the Boidae family using different chromosomal markers. The karyotypes of Boa constrictor occidentalis, Corallus hortulanus, Eunectes notaeus, Epicrates cenchria and Epicrates assisi are presented here for the first time with the redescriptions of the karyotypes of Boa constrictor constrictor, B. c. amarali, Eunectes murinus and Epicrates crassus. The three subspecies of Boa, two species of Eunectes and three species of Epicrates exhibit 2n = 36 chromosomes. In contrast, C. hortulanus presented a totally different karyotype composition for the Boidae family, showing 2n = 40 chromosomes with a greater number of macrochromosomes. Furthermore, chromosomal mapping of telomeric sequences revealed the presence of interstitial telomeric sites (ITSs) on many chromosomes in addition to the terminal markings on all chromosomes of all taxa analysed, with the exception of E. notaeus. Thus, we demonstrate that the karyotypes of these snakes are not as highly conserved as previously thought. Moreover, we provide an overview of the current cytotaxonomy of the group. PMID- 27494411 TI - Adaptive Suspicious Prevention for Defending DoS Attacks in SDN-Based Convergent Networks. AB - The convergent communication network will play an important role as a single platform to unify heterogeneous networks and integrate emerging technologies and existing legacy networks. Although there have been proposed many feasible solutions, they could not become convergent frameworks since they mainly focused on converting functions between various protocols and interfaces in edge networks, and handling functions for multiple services in core networks, e.g., the Multi-protocol Label Switching (MPLS) technique. Software-defined networking (SDN), on the other hand, is expected to be the ideal future for the convergent network since it can provide a controllable, dynamic, and cost-effective network. However, SDN has an original structural vulnerability behind a lot of advantages, which is the centralized control plane. As the brains of the network, a controller manages the whole network, which is attractive to attackers. In this context, we proposes a novel solution called adaptive suspicious prevention (ASP) mechanism to protect the controller from the Denial of Service (DoS) attacks that could incapacitate an SDN. The ASP is integrated with OpenFlow protocol to detect and prevent DoS attacks effectively. Our comprehensive experimental results show that the ASP enhances the resilience of an SDN network against DoS attacks by up to 38%. PMID- 27494410 TI - Resistance Analyses of HCV NS3/4A Protease and NS5B Polymerase from Clinical Studies of Deleobuvir and Faldaprevir. AB - BACKGROUND & AIM: The resistance profile of anti-hepatitis C virus (HCV) agents used in combination is important to guide optimal treatment regimens. We evaluated baseline and treatment-emergent NS3/4A and NS5B amino-acid variants among HCV genotype (GT)-1a and -1b-infected patients treated with faldaprevir (HCV protease inhibitor), deleobuvir (HCV polymerase non-nucleoside inhibitor), and ribavirin in multiple clinical studies. METHODS: HCV NS3/4A and NS5B population sequencing (Sanger method) was performed on all baseline plasma samples (n = 1425 NS3; n = 1556 NS5B) and on post-baseline plasma samples from patients with virologic failure (n = 113 GT-1a; n = 221 GT-1b). Persistence and time to loss of resistance-associated variants (RAVs) was estimated using Kaplan Meier analysis. RESULTS: Faldaprevir RAVs (NS3 R155 and D168) and deleobuvir RAVs (NS5B 495 and 496) were rare (<1%) at baseline. Virologic response to faldaprevir/deleobuvir/ribavirin was not compromised by common baseline NS3 polymorphisms (e.g. Q80K in 17.5% of GT-1a) or by NS5B A421V, present in 20% of GT-1a. In GT-1b, alanine at NS5B codon 499 (present in 15% of baseline sequences) was associated with reduced response. Treatment-emergent RAVs consolidated previous findings: NS3 R155 and D168 were key faldaprevir RAVs; NS5B A421 and P495 were key deleobuvir RAVs. Among on-treatment virologic breakthroughs, RAVs emerged in both NS3 and NS5B (>90%). Virologic relapse was associated with RAVs in both NS3 and NS5B (53% GT-1b; 52% GT-1b); some virologic relapses had NS3 RAVs only (47% GT-1a; 17% GT-1b). Median time to loss of GT-1b NS5B P495 RAVs post treatment (5 months) was less than that of GT-1b NS3 D168 (8.5 months) and GT-1a R155 RAVs (11.5 months). CONCLUSION: Faldaprevir and deleobuvir RAVs are more prevalent among virologic failures than at baseline. Treatment response was not compromised by common NS3 polymorphisms; however, alanine at NS5B amino acid 499 at baseline (wild-type in GT-1a, polymorphism in GT-1b) may reduce response to this deleobuvir-based regimen. PMID- 27494412 TI - Where Do Female Sex Workers Seek HIV and Reproductive Health Care and What Motivates These Choices? A Survey in 4 Cities in India, Kenya, Mozambique and South Africa. AB - BACKGROUND: A baseline cross-sectional survey among female sex workers (FSWs) was conducted in four cities within the context of an implementation research project aiming to improve FSWs' access to HIV, and sexual and reproductive health (SRH) services. The survey measured where FSWs seek HIV/SRH care and what motivates their choice. METHODS: Using respondent-driven sampling (RDS), FWSs were recruited in Durban, South Africa (n = 400), Tete, Mozambique (n = 308), Mombasa, Kenya (n = 400) and Mysore, India (n = 458) and interviewed. RDS-adjusted proportions were estimated by non-parametric bootstrapping, and compared across cities using post-hoc pairwise comparison tests. RESULTS: Across cities, FSWs most commonly sought care for the majority of HIV/SRH services at public health facilities, most especially in Durban (ranging from 65% for condoms to 97% for HIV care). Services specifically targeting FSWs only had a high coverage in Mysore for STI care (89%) and HIV testing (79%). Private-for-profit clinics were important providers in Mombasa (ranging from 17% for STI care and HIV testing to 43% for HIV care), but not in the other cities. The most important reason for the choice of care provider in Durban and Mombasa was proximity, in Tete 'where they always go', and in Mysore cost of care. Where available, clinics specifically targeting FSWs were more often chosen because of shorter waiting times, perceived higher quality of care, more privacy and friendlier personnel. CONCLUSION: The place where care is sought for HIV/SRH services differs substantially between cities. Targeted services have limited coverage in the African cities compared to Mysore. Convenience appears more important for choosing the place of care than aspects of quality of care. The best model to improve access, linking targeted interventions with general health services, will need to be tailored to the specific context of each city. PMID- 27494413 TI - A dual mechanism of cellulose deficiency in shv3svl1. AB - SHAVEN3 (SHV3) and its homolog SHAVEN3-like 1 (SVL1) encode glycosylphosphatidylinositol (GPI)-anchored proteins (GAPs) that are involved in cellulose biosynthesis and hypocotyl elongation in Arabidopsis thaliana. In a recent report, we showed that the cellulose and hypocotyl elongation defects of the shv3svl1 double mutant are greatly enhanced by exogenous sucrose in the growth medium. Further investigation of this phenomenon showed that shv3svl1 exhibits a hyperpolarized plasma membrane (PM) proton gradient that is coupled with enhanced accumulation of sucrose via the PM sucrose/proton symporter SUC1. The resulting high intracellular sucrose concentration appears to favor starch synthesis at the expense of cellulose synthesis. Here, we describe our interpretation of these results in terms of 2 potential regulators of cellulose synthesis: intracellular sucrose concentration and a putative signaling pathway that involves SHV3-like proteins. PMID- 27494414 TI - Insomnia as a Moderator of Response to Time in Bed Restriction for Augmenting Antidepressant Treatment: A Preliminary Investigation. AB - BACKGROUND: There are complex, bidirectional associations between major depressive disorder and insomnia. In the present study, we evaluated insomnia as a moderator of response to antidepressant therapy in the context of a sleep manipulation (time in bed restriction) for major depressive disorder. METHODS: Fifty-eight adults with major depressive disorder received 8 weeks of fluoxetine 20-40 mgs and were randomized to 8 hr time in bed (8h TIB) or 6 hr time in bed (6h TIB) for the first 2 weeks (participants in the 6h TIB condition were further randomized to a delayed bedtime (Late Bedtime) or advanced rise time (Early Rise Time) group). Insomnia was assessed at baseline using the Insomnia Severity Index. Depression symptom severity was determined by the clinician-rated 17-item Hamilton Rating Scale for Depression (HAMD-17), completed weekly. RESULTS: A group by time interaction was observed whereby HAMD-17 scores were higher for participants assigned to the 6h TIB group (without insomnia, weeks 3 through 7; with insomnia from week 3 through 6, ps < .05) relative to participants without insomnia assigned to the 8h TIB group. There were no differences in HAMD-17 scores for participants with insomnia in the 6h TIB group relative to the 8h TIB group. CONCLUSION: These preliminary findings suggest that response to fluoxetine may be hindered by TIB restriction in individuals without insomnia. Individuals with insomnia respond similarly to fluoxetine regardless of whether their TIB is restricted. Limitations include exclusive use of self-report measures to categorize insomnia, and small sample sizes in several of the subgroups. PMID- 27494415 TI - Simultaneous Identification of 13 Foodborne Pathogens by Using Capillary Electrophoresis-Single Strand Conformation Polymorphism Coupled with Multiplex Ligation-Dependent Probe Amplification and Its Application in Foods. AB - Capillary electrophoresis-single strand conformation polymorphism (CE-SSCP) coupled with stuffer-free multiplex ligation-dependent probe amplification (MLPA) was developed to identify 13 species of foodborne pathogens simultaneously. Species-specific MLPA probes were designed for nine of these species. These probes were targeted to the groEL, glyA, MMS, tuf, inv, ipaH, nuc, vvh, and 16S rRNA genes, which corresponded to Bacillus cereus, Campylobacter coli, Cronobacter sakazakii, Enterococcus spp., Salmonella spp., Shigella spp., Staphylococcus aureus, Vibrio vulnificus, and Yersinia enterocolitica, respectively. MLPA probes that had been previously developed by our laboratory were used for the other four species (Campylobacter jejuni, Clostridium perfringens, Escherichia coli O157:H7, and Listeria monocytogenes). The CE-SSCP method was optimized to identify all 13 foodborne microbes simultaneously in a single electrogram, in which 50-500 pg genomic DNA was detected per microbe. Twelve species were detected from animal-derived food samples (specifically, milk and sliced ham) that had been artificially inoculated with 12 of the foodborne pathogens, excluding V. vulnificus, which is not usually associated with animal foods. The method developed here could be used as an early warning system for outbreaks of foodborne diseases associated with animal-derived foods in the food industry. PMID- 27494416 TI - Structural and Thermal Properties of BaTe2O6: Combined Variable-Temperature Synchrotron X-ray Diffraction, Raman Spectroscopy, and ab Initio Calculations. AB - Variable-temperature Raman spectroscopic and synchrotron X-ray diffraction studies were performed on BaTe2O6 (orthorhombic, space group: Cmcm), a mixed valence tellurium compound with a layered structure, to understand structural stability and anharmonicity of phonons. The structural and vibrational studies indicate no phase transition in it over a wider range of temperature (20 to 853 K). The structure shows anisotropic expansion with coefficients of thermal expansion in the order alphab ? alphaa > alphac, which was attributed to the anisotropy in bonding and structure of BaTe2O6. Temperature evolution of Raman modes of BaTe2O6 indicated a smooth decreasing trend in mode frequencies with increasing temperature, while the full width at half-maximum (fwhm) of all modes systematically increases due to a rise in phonon scattering processes. With the use of our earlier reported isothermal mode Gruneisen parameters, thermal properties such as thermal expansion coefficient and molar specific heat are calculated. The pure anharmonic (explicit) and quasiharmonic (implicit) contribution to the total anharmonicity is delineated and compared. The temperature dependence of phonon mode frequencies and their fwhm values are analyzed by anharmonicity models, and the dominating anharmonic phonon scattering mechanism is concluded in BaTe2O6. In addition to the lattice modes, several external modes of TeOn (n = 5, 6) are found to be strongly anharmonic. The ab initio electronic structure calculations indicated BaTe2O6 is a direct band gap semiconductor with gap energy of ~2.1 eV. Oxygen orbitals, namely, O-2p states in the valence band maximum and the sp-hybridized states in the conduction band minimum, are mainly involved in the electronic transitions. In addition a number of electronic transitions are predicted by the electronic structure calculations. Experimental photoluminescence results are adequately explained by the ab initio calculations. Further details of the structural and vibrational properties are explained in the manuscript. PMID- 27494417 TI - Immunotherapy of advanced renal cell carcinoma: Current and future therapies. AB - Previously a malignancy with few therapeutic options, metastatic renal cell carcinoma (mRCC) treatment is rapidly evolving. Although cytokine therapies (interferon-a, interleukin-2) have been used less frequently over the past decade, recent approval of an immune checkpoint inhibitor, nivolumab, has led to a resurgence in immune therapy for mRCC. With greater understanding of the complex and dynamic interaction between the tumor and the immune system, numerous new immunotherapies are being studied for mRCC. In this article, we review the mechanism of action, clinical outcomes and toxicity profiles of both clinically approved and selected investigational immunotherapies. Either alone or in combination, these novel agents are encouraging for the future of mRCC therapy. PMID- 27494418 TI - Diffusion tensor imaging of the inferior alveolar nerve using 3T MRI: a study for quantitative evaluation and fibre tracking. AB - OBJECTIVES: Diffusion tensor imaging (DTI) can provide structural information and objective values for nerves. The aims of this study were to perform quantitative evaluation and fibre tracking of the normal inferior alveolar nerve (IAN) using DTI on 3.0-T MRI. METHODS: DTI was applied to 92 IANs of 46 healthy volunteers. Circular regions of interest (ROIs) were placed on three different positions at the mandibular foramen, second molar and mental foramen of each nerve on apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps, and the ADC and FA of each ROI were measured. Differences in the values arising from the nerve positions were evaluated. Furthermore, fibre tracking of the IANs was performed by tractography, and the quality of visualization was evaluated. RESULTS: There were no significant differences in the ADC and FA between the right and left sides regardless of the anteroposterior positions. Regarding differences arising from the anteroposterior measurement positions, the ADC and FA showed no significant differences (p > 0.017), except for the ADCs between the positions at the mandibular foramen and mental foramen in the left side (p = 0.0068). Overall, 70 (76%) of the 92 IANs could be visualized fully or partially by tractography. CONCLUSIONS: The ADC and FA of the IAN were successfully obtained from healthy volunteers using DTI and were confirmed to be symmetrical regardless of the measurement positions. DTI is a feasible technique for the quantitative evaluation and visualization of the IAN. PMID- 27494419 TI - The risk of metabolic syndrome in women with previous GDM in a long-term follow up. AB - The aim of this study was to evaluate the incidence of metabolic syndrome (MetS) during long-term follow-up of women with gestational diabetes (GDM). Furthermore, we evaluated the glycemic measures from an oral glucose tolerance test (OGTT) during pregnancy as predictors of incident MetS. Women diagnosed with GDM were divided into two groups according to the results of OGTT: one abnormal value = GDM1 (n = 338) and two abnormal values = GDM2 (n = 151), while women with normal glucose tolerance (n = 385) served as controls. MetS and its components were evaluated in a follow-up study (mean follow-up time 7.3 +/- 5.1 years) according to the International Diabetes Federation (IDF) criteria. Fasting plasma glucose in OGTT was the best predictor of incident MetS in ROC (area under the curve) analysis. The incidence of MetS during a <5-year follow-up was 22.2% in controls, 39.3% in GDM1 and 60.4% in GDM2; and >10-year follow-up 24.2%, 46.2% and 62.5%, respectively. In controls and GDM2, the incidence of MetS remained nearly constant during the follow-up, whereas in GDM1 it increased. In conclusion, already mild gestational glucose intolerance may progress to MetS and therefore merits intervention measures to prevent future cardiovascular disease. PMID- 27494420 TI - In vitro and in vivo investigation of taste-masking effectiveness of Eudragit E PO as drug particle coating agent in orally disintegrating tablets. AB - CONTEXT: Considering that bitter taste of drugs incorporated in orally disintegrating tablets (ODTs) can be the main reason for avoiding drug therapy, it is of the utmost importance to achieve successful taste-masking. The evaluation of taste-masking effectiveness is still a major challenge. OBJECTIVE: The objective of this study was to mask bitter taste of the selected model drugs by drug particle coating with Eudragit(r) E PO, as well as to evaluate taste masking effectiveness of prepared ODTs using compendial dissolution testing, dissolution in the small-volume shake-flask assembly and trained human taste panel. MATERIALS AND METHODS: Model drugs were coated in fluidized bed. DisintequikTM ODT was used as a novel co-processed excipient for ODT preparation. Selected formulations were investigated in vitro and in vivo using techniques for taste-masking assessment. RESULTS AND DISCUSSION: Significantly slower drug dissolution was observed from tablets with coated drug particles during the first 3 min of investigation. Results of in vivo taste-masking assessment demonstrated significant improvement in drug bitterness suppression in formulations with coated drug. Strong correlation between the results of drug dissolution in the small-volume shake-flask assembly and in vivo evaluation data was established (R >= 0.970). CONCLUSION: Drug particle coating with Eudragit(r) E PO can be a suitable approach for bitter taste-masking. Strong correlation between in vivo and in vitro results implicate that small-volume dissolution method may be used as surrogate for human panel taste-masking assessment, in the case of physical taste-masking approach application. PMID- 27494421 TI - The O-antigen of Plesiomonas shigelloides serotype O36 containing pseudaminic acid. AB - The structure of the repeating unit of O-antigen of Plesiomonas shigelloides serotype O36 has been investigated by 1H and 13C NMR spectroscopy, matrix assisted laser-desorption/ionization time-of-flight mass spectrometry and chemical methods. The new structure of trisaccharide has been established: [Formula: see text] These trisaccharide O-antigen units substitute the core undecasaccharide at C-4 of the beta-D-GlcpNAc residue. The core oligosaccharide and lipid A are identical with these of the serotype O17 (PCM 2231) (Maciejewska, A., Lukasiewicz, J., Kaszowska, M., Jachymek, W., Man-Kupisinska, A.; Lugowski, C. Mar. Drugs.2013, 11 (2), 440-454; Lukasiewicz, J., Dzieciatkowska, M., Niedziela, T., Jachymek, W., Augustyniuk, A., Kenne, L., Lugowski, C. Biochemistry, 2006, 45, 10434-10447). PMID- 27494422 TI - Large volume sample stacking of cationic tetracycline antibiotics toward 10 ppb level analysis by capillary electrophoresis with UV detection. AB - This paper aimed to build up a sensitive CE method for the analysis of tetracyclines (TCs) antibiotics (including tetracycline, chlorotetracycline, oxytetracycline, and doxycycline) with conventional UV detection. Here, the large volume sample stacking was applied to achieve in capillary preconcentration of the targets. To achieve large volume sample stacking, the essential step was a large volume of sample (around 83.3% of total capillary length from inlet to detection window) hydrodynamically loaded. Then, the reserved voltage was added in order to push the sample matrix out of the capillary. Due to different pH between sample solution (pH 4.6) and BGE (pH 11.0), the cationic TCs would turn into negatively charged while the sample matrix was removing from the capillary. Finally, the anionic TCs were stacked at the inlet for the subsequent separation. Although the loss of sample existed during their charge transformation, the LODs could be improved around 40 times than that obtained by normal hydrodynamic injection CE method. Here, the LODs were in the range of 8.1-14.5 MUg/L, around 10 ppb that close to the level by electrochemiluminescence or laser-induced fluorescence detection of TCs by CE. The precision was characterized by RSDs of migration times and peak areas, which were in the range of 0.19-0.24% and 0.97 2.54%, respectively. The recoveries of the developed method were in the range of 95-112% by spiking TCs in the tap water. The proposed inline preconcentration CE method could be a simple, speed, and sensitive method for the quantitative analysis of TCs. PMID- 27494423 TI - Self-limiting multiplexed assembly of lipid membranes on large-area graphene sensor arrays. AB - Phospholipid membranes of different functionalities were simultaneously assembled on arrays of graphene surfaces in a parallel manner using multi-pen lipid dip-pen nano-lithography. The graphene patch facilitates and restricts the spreading of lipids within itself, obviating the need to scan the writing probes and reducing writing time. Binding studies establish that the lipids retain the functionality. PMID- 27494424 TI - Effects of Environmental pH on Antioxidant Interactions between Rosmarinic Acid and alpha-Tocopherol in Oil-in-Water (O/W) Emulsions. AB - Antioxidant regeneration could be influenced by various factors such as antioxidant locations and pH conditions. The effects of environmental pH on the antioxidant interaction between rosmarinic acid and alpha-tocopherol in oil-in water (O/W) emulsions were investigated. Results showed that the combined antioxidants at pH 7 exhibited the strongest synergistic antioxidant activity in comparison with the combinations at other pH conditions as indicated by the interaction index. A drop in pH from 7 to 3 resulted in a reduction in the synergistic effect. However, in the case of pH 3, an additive effect was obtained. Moreover, the effect of the pH on the regeneration of alpha-tocopherol by rosmarinic acid in heterogeneous Tween 20 solutions was studied using EPR spectrometer. The same was true for the regeneration efficiency, where the reaction at pH 7 exhibited the highest regeneration efficiency of 0.3 mol of alpha-tocopheroxyl radicals reduced/mol of phenolics. However, the study on depletions of rosmarinic acid and alpha-tocopherol revealed that the formation of caffeic acid, an oxidative degradation product of rosmarinic acid, could be involved in enhancing the antioxidant activity observed at pH 7 rather than the antioxidant regeneration. This study has highlighted that the importance of pH dependent antioxidant interactions does not solely rely on antioxidant regeneration. In addition, the formation of other oxidative products from an antioxidant should be taken into account. PMID- 27494425 TI - La/Sm/Er Cation Doping Induced Thermal Properties of SrTiO3 Perovskite. AB - The La/Sm/Er cations with different radii doping SrTiO3 (STO) as model Sr0.9R0.1TiO3 (R = La, Sm, Er) were designed to investigate structural characteristics and thermal properties by the molecular dynamics simulation with the Green-Kubo relation at 300-2000 K. The structural characteristics were composed of lattice constant, atoms excursion, and pair correlation function (PCF). The thermal properties consisted of heat capacity and thermal conductivity. The lattice constant of R-doped exhibited less than the STO at 300 1100 K and more than STO at 1500-2000 K, which was encouraged by atom excursion and PCF. The thermal properties was compared with literature data at 300-1100 K. In addition, the thermal properties at 1100-2000 K were predicted. It highlights that thermal conductivity tends to decrease at high temperature, due to perturbation of La, Sm, and Er, respectively. PMID- 27494426 TI - High Piezo-photocatalytic Efficiency of CuS/ZnO Nanowires Using Both Solar and Mechanical Energy for Degrading Organic Dye. AB - High piezo-photocatalytic efficiency of degrading organic pollutants has been realized from CuS/ZnO nanowires using both solar and mechanical energy. CuS/ZnO heterostructured nanowire arrays are compactly/vertically aligned on stainless steel mesh by a simple two-step wet-chemical method. The mesh-supported nanocomposites can facilitate an efficient light harvesting due to the large surface area and can also be easily removed from the treated solution. Under both solar and ultrasonic irradiation, CuS/ZnO nanowires can rapidly degrade methylene blue (MB) in aqueous solution, and the recyclability is investigated. In this process, the ultrasonic assistance can greatly enhance the photocatalytic activity. Such a performance can be attributed to the coupling of the built-in electric field of heterostructures and the piezoelectric field of ZnO nanowires. The built-in electric field of the heterostructure can effectively separate the photogenerated electrons/holes and facilitate the carrier transportation. The CuS component can improve the visible light utilization. The piezoelectric field created by ZnO nanowires can further separate the photogenerated electrons/holes through driving them to migrate along opposite directions. The present results demonstrate a new water-pollution solution in green technologies for the environmental remediation at the industrial level. PMID- 27494427 TI - Biopreservation and Biobanking Mid-Year Report. PMID- 27494429 TI - Interventions for compassionate nursing care: A systematic review. AB - BACKGROUND: Compassion has been identified as an essential element of nursing and is increasingly under public scrutiny in the context of demands for high quality health care. While primary research on effectiveness of interventions to support compassionate nursing care has been reported, no rigorous critical overview exists. OBJECTIVES: To systematically identify, describe and analyse research studies that evaluate interventions for compassionate nursing care; assess the descriptions of the interventions for compassionate care, including design and delivery of the intervention and theoretical framework; and to evaluate evidence for the effectiveness of interventions. REVIEW METHODS: Published international literature written in English up to June 2015 was identified from CINAHL, Medline and Cochrane Library databases. Primary research studies comparing outcomes of interventions to promote compassionate nursing care with a control condition were included. Studies were graded according to relative strength of methods and quality of description of intervention. Narrative description and analysis was undertaken supported by tabulation of key study data including study design, outcomes, intervention type and results. RESULTS: 25 interventions reported in 24 studies were included in the review. Intervention types included staff training (n=10), care model (n=9) and staff support (n=6). Intervention description was generally weak, especially in relation to describing participants and facilitators, and the proposed mechanisms for change were often unclear. Most interventions were associated with improvements in patient-based, nurse-based and/or quality of care outcomes. However, overall methodological quality was low with most studies (n=16) conducted as uncontrolled before and after studies. The few higher quality studies were less likely to report positive results. No interventions were tested more than once. CONCLUSIONS: None of the studies reviewed reported intervention description in sufficient detail or presented sufficiently strong evidence of effectiveness to merit routine implementation of any of these interventions into practice. The positive outcomes reported suggest that further investigation of some interventions may be merited, but high caution must be exercised. Preference should be shown for further investigating interventions reported as effective in studies with a stronger design such as randomised controlled trials. PMID- 27494428 TI - Enroling and retaining human immunodeficiency virus (HIV) patients in their care: A metasynthesis of qualitative studies. AB - OBJECTIVES: To report the findings of a metasynthesis review of qualitative studies on patient and provider experiences and perspectives on linkage and retention in HIV care. DESIGN: The review is an extraction, aggregation, interpretation and synthesis of qualitative findings based on the Sandelowski and Barroso method. DATA SOURCES: A search of the literature was conducted in the databases Cumulative Index to Nursing and Allied Health, PubMed and PsycInfo for articles published from 2008 to 2013. Inclusion criteria were qualitative research articles published in English from across the world and in peer-reviewed journals. Literature reviews, conference abstracts and grey literature were excluded from this metasynthesis. REVIEW METHODS: The review consisted of a) comprehensive search, b) study classification, c) abstraction of findings, d) synthesis. Of the 4640 citations screened, 69 articles were included for this metasynthesis. RESULTS: 69 unique articles from 44 countries were included. This metasynthesis takes into account the perspectives of at least 2263 HIV-positive participants (740 men, 1008 women, 78 transgender individuals and 437 unspecified sex) and 994 healthcare providers, family members and community members. The most salient barriers and facilitators to HIV linkage and retention in HIV care affirm ecological factors that are mostly beyond individual patients' control. Triadic streams of influence concurrently affect care engagement that include a person's psychological state upon diagnosis and their informational challenges (intrapersonal stream); one-on-one interactions with providers and their immediate community (social stream); and life demands, overall quality of care experiences and other structural barriers (cultural-attitudinal stream). Each stream's influence on HIV care engagement varies at any given point to reflect an individual's evolving and unique experiences with HIV infection throughout the illness trajectory. CONCLUSION: There is sufficient evidence that detail how to best link and retain patients in HIV care. Themes identified indicate going beyond individual-level factors and towards shifting attention and resources to systems that patients navigate. Forceful structural-level actions are needed to correct these long-identified barriers and enhance care engagement facilitators. PMID- 27494430 TI - Nurse practitioner caseload in primary health care: Scoping review. AB - OBJECTIVES: To identify recommendations for determining patient panel/caseload size for nurse practitioners in community-based primary health care settings. DESIGN: Scoping review of the international published and grey literature. DATA SOURCES: The search included electronic databases, international professional and governmental websites, contact with experts, and hand searches of reference lists. Eligible papers had to (a) address caseload or patient panels for nurse practitioners in community-based primary health care settings serving an all-ages population; and (b) be published in English or French between January 2000 and July 2014. Level one testing included title and abstract screening by two team members. Relevant papers were retained for full text review in level two testing, and reviewed by two team members. A third reviewer acted as a tiebreaker. Data were extracted using a structured extraction form by one team member and verified by a second member. Descriptive statistics were estimated. Content analysis was used for qualitative data. RESULTS: We identified 111 peer-reviewed articles and grey literature documents. Most of the papers were published in Canada and the United States after 2010. Current methods to determine panel/caseload size use large administrative databases, provider work hours and the average number of patient visits. Most of the papers addressing the topic of patient panel/caseload size in community-based primary health care were descriptive. The average number of patients seen by nurse practitioners per day varied considerably within and between countries; an average of 9-15 patients per day was common. Patient characteristics (e.g., age, gender) and health conditions (e.g., multiple chronic conditions) appear to influence patient panel/caseload size. Very few studies used validated tools to classify patient acuity levels or disease burden scores. DISCUSSION: The measurement of productivity and the determination of panel/caseload size is complex. Current metrics may not capture activities relevant to community-based primary health care nurse practitioners. Tools to measure all the components of these role are needed when determining panel/caseload size. Outcomes research is absent in the determination of panel/caseload size. CONCLUSION: There are few systems in place to track and measure community-based primary health care nurse practitioner activities. The development of such mechanisms is an important next step to assess community based primary health care nurse practitioner productivity and determine patient panel/caseload size. Decisions about panel/caseload size must take into account the effects of nurse practitioner activities on outcomes of care. PMID- 27494431 TI - Selectivity Determination of a Small Molecule Chemical Probe Using Protein Microarray and Affinity Capture Techniques. AB - Small molecule selectivity is an essential component of candidate drug selection and target validation. New technologies are required to better understand off target effects, with particular emphasis needed on broad protein profiling. Here, we describe the use of a tritiated chemical probe and a 9000 human protein microarray to discern the binding selectivity of an inhibitor of the mRNA decapping scavenger enzyme DcpS. An immobilized m7GTP resin was also used to assess the selectivity of a DcpS inhibitor against mRNA cap-associated proteins in whole cell extracts. These studies confirm the exquisite selectivity of diaminoquinazoline DcpS inhibitors, and highlight the utility of relatively simple protein microarray and affinity enrichment technologies in drug discovery and chemical biology. PMID- 27494432 TI - Gelatin Methacrylate Hydrogels as Biomimetic Three-Dimensional Matrixes for Modeling Breast Cancer Invasion and Chemoresponse in Vitro. AB - Recent studies have shown that three-dimensional (3D) culture environments allow the study of cellular responses in a setting that more closely resembles the in vivo milieu. In this context, hydrogels have become popular scaffold options for the 3D cell culture. Because the mechanical and biochemical properties of culture matrixes influence crucial cell behavior, selecting a suitable matrix for replicating in vivo cellular phenotype in vitro is essential for understanding disease progression. Gelatin methacrylate (GelMA) hydrogels have been the focus of much attention because of their inherent bioactivity, favorable hydration and diffusion properties, and ease-of-tailoring of their physicochemical characteristics. Therefore, in this study we examined the efficacy of GelMA hydrogels as a suitable platform to model specific attributes of breast cancer. We observed increased invasiveness in vitro and increased tumorigenic ability in vivo in breast cancer cells cultured on GelMA hydrogels. Further, cells cultured on GelMA matrixes were more resistant to paclitaxel treatment, as shown by the results of cell-cycle analysis and gene expression. This study, therefore, validates GelMA hydrogels as inexpensive, cell-responsive 3D platforms for modeling key characteristics associated with breast cancer metastasis, in vitro. PMID- 27494433 TI - Directed Assembly of Nanoparticle Catalysts on Nanowire Photoelectrodes for Photoelectrochemical CO2 Reduction. AB - Reducing carbon dioxide with a multicomponent artificial photosynthetic system, closely mimicking nature, represents a promising approach for energy storage. Previous works have focused on exploiting light-harvesting semiconductor nanowires (NW) for photoelectrochemical water splitting. With the newly developed CO2 reduction nanoparticle (NP) catalysts, direct interfacing of these nanocatalysts with NW light absorbers for photoelectrochemical reduction of CO2 becomes feasible. Here, we demonstrate a directed assembly of NP catalysts on vertical NW substrates for CO2-to-CO conversion under illumination. Guided by the one-dimensional geometry, well-dispersed assembly of Au3Cu NPs on the surface of Si NW arrays was achieved with facile coverage tunability. Such Au3Cu NP decorated Si NW arrays can readily serve as effective CO2 reduction photoelectrodes, exhibiting high CO2-to-CO selectivity close to 80% at -0.20 V vs RHE with suppressed hydrogen evolution. A reduction of 120 mV overpotential compared to the planar (PL) counterpart was observed resulting from the optimized spatial arrangement of NP catalysts on the high surface area NW arrays. In addition, this system showed consistent photoelectrochemical CO2 reduction capability up to 18 h. This simple photoelectrode assembly process will lead to further progress in artificial photosynthesis, by allowing the combination of developments in each subfield to create an efficient light-driven system generating carbon-based fuels. PMID- 27494434 TI - Novel organelles in primate retinal epithelium. AB - We are investigating age-related changes in organelles in monkey retinal epithelium using transmission and analytic electron microscopy. We previously described a circular organelle in retinal epithelium with a diameter of about 0.5MUm. The organelle is unique in containing a single, round vacuole within an otherwise electron dense interior. We suggested that the organelle might be a melanosome with lysosomal properties. We now find that there are two similar organelles with such a single vacuole but which differ in their chemical composition, electron density, cell location and according to age. Epon embedded sections from the macular epithelium of seven monkeys, ranging from 1 to 35 years of age, were examined by transmission electron microscopy. A seven year old monkey was processed for analytic electron microscopy to determine the chemical composition of the organelles. The number and location of the organelles in the retinal epithelium were determined. The chemical composition of these two organelles was different. One of the organelles contained high mole fractions of oxygen and nitrogen and little phosphorous characteristic of melanin; the other had little oxygen and nitrogen and higher mole fractions of phosphorous uncharacteristic of melanin, but more common with lysosomal organelles. The latter had an electron dense rim around the vacuole, a less electron dense interior than the melanin containing organelle and also contained iron. The melanin containing organelle was more common in young monkeys and in the middle third of the cell. The organelle without melanin was more common in old monkeys and localized in the basal third of the cell. Two similarly vacuolated organelles, not identified before in retinal epithelium, differ in their chemical composition. One contains melanin; the other does not. The former is more common in young and the latter more common in old monkeys. This suggests reorganization and or degradation of melanin-containing organelles with age. These changes show how analytic electron microscopy can distinguish major ultra-structural differences in organelles when mere observation fails to do so easily. PMID- 27494435 TI - Adult Intraosseous Access by Advanced EMTs: A Statewide Non-Inferiority Study. AB - OBJECTIVE: Intraosseous (IO) access is increasingly being used as an alternative to peripheral intravenous access, which is often difficult or impossible to establish in critically ill patients in the prehospital setting. Until recently, only Paramedics performed adult IO access. In 2014, Vermont Emergency Medical Services (EMS) expanded the Advanced Emergency Medical Technicians (AEMTs) scope of practice to include IO access in adult patients. This study compares successful IO access in adults performed by AEMTs compared to Paramedics in the prehospital setting. METHODS: All Vermont EMS patient encounters between January 1, 2013 and November 30, 2015 were examined, and 543 adult patients with a documented IO access insertion attempt were identified. The proportion of successful IO insertions was compared between AEMTs and Paramedics using a Chi Squared statistic and a non-inferiority test. RESULTS: There was no significant difference in the percentage of successful IO access between AEMTs and Paramedics [95.2% and 95.6%, respectively; P = 0.84]. The confidence interval around this 0.4% difference (95% confidence interval = -4.2, 3.2) was within a pre-specified delta of +/-10% indicating non-inferiority of AEMTs compared to Paramedics. CONCLUSIONS: This study's finding that successful IO access was not different among AEMTs and Paramedics lends evidence in support of expanding the scope of practice of AEMTs to include establishing IO access in adults. PMID- 27494436 TI - The co-occurrence of nicotine and other substance use and addiction among youth and adults in the United States: implications for research, practice, and policy. AB - BACKGROUND: The increasing popularity of non-cigarette nicotine products, especially among youth, highlights the need for greater attention to their potential risks, including nicotine addiction and other substance use and addiction. OBJECTIVES: To examine the extent to which nicotine product use co occurs with other substance use and addiction among youth and adults, describe the demographic groups and types of nicotine products associated with an increased risk of such co-occurrence, and discuss implications for research, prevention, clinical practice, and policy. METHODS: Analyzing 2014 data from two nationally representative US surveys, the National Survey on Drug Use and Health (NSDUH) and the Monitoring the Future (MTF) study, we examined the co-occurrence between nicotine product use and alcohol and other drug use and addiction. RESULTS: Individuals of all ages who reported using nicotine products of any kind were significantly more likely than nonusers to report alcohol, marijuana, other drug, and poly-substance use and to meet diagnostic criteria for a substance-use disorder. Users of multiple nicotine products generally were the most likely to engage in alcohol and other drug use and to be addicted to these other substances. CONCLUSIONS: The substantial co-occurrence of all forms of nicotine use and other substance use and addiction underscores the need to control the growing use of non-cigarette nicotine products among youth and to incorporate all forms of nicotine product use into substance use and addiction research, prevention, clinical practice, and policy efforts. PMID- 27494437 TI - Antimicrobial Cluster Bombs: Silver Nanoclusters Packed with Daptomycin. AB - Integration of two distinctive bactericides into one entity is a promising platform to improve the efficiency of antimicrobial agents. We report an efficient antimicrobial hybrid formed through conjugating silver nanoclusters (AgNCs) with daptomycin. The as-designed antimicrobial hybrid (D-AgNCs) inherits intrinsic properties of both bactericides with an enhanced synergistic performance. In particular, the chemically integrated D-AgNCs showed improved bacterial killing efficiency over the physically mixed daptomycin and AgNCs (D+AgNCs). More interestingly, the as-designed D-AgNCs could effectively damage the bacterial membrane. Propidium iodide (PI) stain showed bacterial membrane damage in about 85% of the bacteria population after treatment with D-AgNCs through creation of larger pores on the membrane as compared to D+AgNCs, largely due to the localization of daptomycin within the hybrid structure. These larger pores facilitated the entry of the D-AgNCs into the cell and led to more severe DNA damage of the bacterial DNA as compared to D+AgNCs in genomic DNA PAGE analysis. TUNEL assay further depicted more bacterial DNA breaks induced by D AgNCs. The RecA gene expression level was upregulated, suggestive of DNA repair activation. The strong induced DNA damage benefited from the localization of AgNCs in the core of the antimicrobial hybrid structure, which could generate localized high ROS concentration and work as a critical ROS reservoir to continually generate ROS within the bacterium. The continual bombardments by these ROS generators restrict the ability of the bacteria to now develop resistance against this. PMID- 27494438 TI - Pair Potential That Reproduces the Shape of Isochrones in Molecular Liquids. AB - Many liquids have curves (isomorphs) in their phase diagrams along which structure, dynamics, and some thermodynamic quantities are invariant in reduced units. A substantial part of their phase diagrams is thus effectively one dimensional. The shapes of these isomorphs are described by a material-dependent function of density, h(rho), which for real liquids is well approximated by a power law, rho(gamma). However, in simulations, a power law is not adequate when density changes are large; typical models, such as Lennard-Jones liquids, show that gamma(rho) = d ln h(rho)/d ln rho is a decreasing function of density. This article presents results from computer simulations using a new pair potential that diverges at a nonzero distance and can be tuned to give a more realistic shape of gamma(rho). Our results indicate that the finite size of molecules is an important factor to take into account when modeling liquids over a large density range. PMID- 27494439 TI - Mindful Connections: The Role of a Peer Support Group on the Psychosocial Adjustment for Adults Recovering From Brain Injury. AB - How does participating in a peer support group impact an adult's psychosocial adjustment following brain injury? This question was investigated using a qualitative approach, interviewing patients recruited from an ambulatory care program. Data analysis guided by Bury's sociological framework, biographical disruption and biographical repair, revealed participants' pregroup disrupted sense of self, including subthemes related to intrinsic losses and uncertainty. Enhanced psychosocial adjustment including subthemes described participants' reorientation through shared experience. Finally, a postgroup adapted sense of self including subthemes was characterized by heightened purpose, self-awareness, and acceptance. Findings lend weight to using tailored peer interventions to optimize psychosocial adjustment for this population. PMID- 27494440 TI - Microalgae-activated sludge treatment of molasses wastewater in sequencing batch photo-bioreactor. AB - The aim of this work was the examination of the treatment potential of molasses wastewater, by the utilization of activated sludge and microalgae. The systems used included a sequencing batch bioreactor and a similar photo-bioreactor, favoring microalgae growth. The microalgae treatment of molasses wastewater mixture resulted in a considerable reduction in the total nitrogen content. A reduction in the ammonium and nitrate content was observed in the photo bioreactor, while the effluent's total nitrogen consisted mainly of 50% organic nitrogen. The transformation of the nitrogen forms in the photo-bioreactor was attributed to microalgae activity, resulting in the production of a better quality effluent. Lower COD removal was observed for the photo-bioreactor than the control, which however increased, by the replacement of the anoxic phase by a long aeration period. The mechanism of nitrogen removal included both the denitrification process during the anoxic stage and the microalgae activities, as the replacement of the anoxic stage resulted in low total nitrogen removal capacities. A decrease in the photobioreactor performance was observed after 35 days of operation due to biofilm formation on the light tube surface, while the operation at higher temperature accelerated microalgae growth, resulting thus in the early failure of the photoreactor. PMID- 27494441 TI - Sparsity-constrained PET image reconstruction with learned dictionaries. AB - PET imaging plays an important role in scientific and clinical measurement of biochemical and physiological processes. Model-based PET image reconstruction such as the iterative expectation maximization algorithm seeking the maximum likelihood solution leads to increased noise. The maximum a posteriori (MAP) estimate removes divergence at higher iterations. However, a conventional smoothing prior or a total-variation (TV) prior in a MAP reconstruction algorithm causes over smoothing or blocky artifacts in the reconstructed images. We propose to use dictionary learning (DL) based sparse signal representation in the formation of the prior for MAP PET image reconstruction. The dictionary to sparsify the PET images in the reconstruction process is learned from various training images including the corresponding MR structural image and a self created hollow sphere. Using simulated and patient brain PET data with corresponding MR images, we study the performance of the DL-MAP algorithm and compare it quantitatively with a conventional MAP algorithm, a TV-MAP algorithm, and a patch-based algorithm. The DL-MAP algorithm achieves improved bias and contrast (or regional mean values) at comparable noise to what the other MAP algorithms acquire. The dictionary learned from the hollow sphere leads to similar results as the dictionary learned from the corresponding MR image. Achieving robust performance in various noise-level simulation and patient studies, the DL-MAP algorithm with a general dictionary demonstrates its potential in quantitative PET imaging. PMID- 27494443 TI - Letter to the Editor: RNF213 variant and quasimoyamoya disease. PMID- 27494442 TI - Perinatal Exposure to Traffic-Related Air Pollution and Autism Spectrum Disorders. AB - BACKGROUND: Studies from the United States indicate that exposure to air pollution in early life is associated with autism spectrum disorders (ASD) in children, but the evidence is not consistent with European data. OBJECTIVE: We aimed to investigate the association between exposure to air pollution from road traffic and the risk of ASD in children, with careful adjustment for socioeconomic and other confounders. METHOD: Children born and residing in Stockholm, Sweden, during 1993-2007 with an ASD diagnosis were identified through multiple health registers and classified as cases (n = 5,136). A randomly selected sample of 18,237 children from the same study base constituted controls. Levels of nitrogen oxides (NOx) and particulate matter with diameter <= 10 MUm (PM10) from road traffic were estimated at residential addresses during mother's pregnancy and the child's first year of life by dispersion models. Odds ratios (OR) and 95% confidence intervals (CI) for ASD with or without intellectual disability (ID) were estimated using logistic regression models after conditioning on municipality and calendar year of birth as well as adjustment for potential confounders. RESULT: Air pollution exposure during the prenatal period was not associated with ASD overall (OR = 1.00; 95% CI: 0.86, 1.15 per 10-MUg/m3 increase in PM10 and OR = 1.02; 95% CI: 0.94, 1.10 per 20-MUg/m3 increase in NOx during mother's pregnancy). Similar results were seen for exposure during the first year of life, and for ASD in combination with ID. An inverse association between air pollution exposure and ASD risk was observed among children of mothers who moved to a new residence during pregnancy. CONCLUSION: Early-life exposure to low levels of NOx and PM10 from road traffic does not appear to increase the risk of ASD. Citation: Gong T, Dalman C, Wicks S, Dal H, Magnusson C, Lundholm C, Almqvist C, Pershagen G. 2017. Perinatal exposure to traffic related air pollution and autism spectrum disorders. Environ Health Perspect 125:119-126; http://dx.doi.org/10.1289/EHP118. PMID- 27494444 TI - Prevalence of potential familial hypercholesteremia (FH) in 54,811 statin-treated patients in clinical practice. AB - BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a life-threatening disease, characterized by elevated LDL-C levels and a premature, increased risk of coronary heart disease (CHD) that is globally underdiagnosed. The percentage of patients with possible or probable FH in various countries was examined in the Dyslipidemia International Study (DYSIS). METHODS: DYSIS is a multinational, cross-sectional observational study of 54,811 adult outpatients treated with statin therapy. The percentages of patients with high levels of LDL-C, and with possible or probable FH, were assessed using the Dutch scoring method for FH across 29 countries, in age subgroups for the analysis population and among diabetes patients. RESULTS: Despite statin therapy, 16.1% (range 4.4-27.6%) of patients had LDL-C >3.6 mmol/L (140 mg/dL) across countries and the prevalence of possible FH was 15.0% (range 5.5-27.8%) and 1.1% (range 0.0-5.4%) for probable FH. The highest percentages of probable FH occurred in Egypt (5.4%), the Baltic states (4.2%), Russia (3.2%), and Slovenia (3.1%), with the lowest rates in Israel (0.0%), Canada (0.2%), and Sweden (0.3%). Rates of FH were the highest in younger patients (45-54 years) for secondary prevention, regardless of the presence/absence of diabetes. CONCLUSIONS: Despite statin therapy, high LDL-C levels and rates of possible and probable FH were observed in some countries. The prevalence of FH was the highest in younger age patients, and >60% of patients with probable FH displayed CHD. Earlier diagnosis and treatment of patients with FH are needed to reduce CHD risk in these patients. PMID- 27494445 TI - Atherosclerotic plaque behind the stent changes after bare-metal and drug-eluting stent implantation in humans: Implications for late stent failure? AB - BACKGROUND AND AIMS: The natural history and the role of atherosclerotic plaque located behind the stent (PBS) are still poorly understood. We evaluated the serial changes in PBS following bare-metal (BMS) compared to first-generation drug-eluting stent (DES) implantation and the impact of these changes on in-stent neointimal hyperplasia (NIH). METHODS: Three-dimensional coronary reconstruction by angiography and intravascular ultrasound was performed after intervention and at 6-10-month follow-up in 157 patients with 188 lesions treated with BMS (n = 89) and DES (n = 99). RESULTS: There was a significant decrease in PBS area ( 7.2%; p < 0.001) and vessel area (-1.7%; p < 0.001) after BMS and a respective increase in both areas after DES implantation (6.1%; p < 0.001 and 4.1%; p < 0.001, respectively). The decrease in PBS area significantly predicted neointimal area at follow-up after BMS (beta: 0.15; 95% confidence interval [CI]: 0.10-0.20, p < 0.001) and DES (beta: 0.09; 95% CI: 0.07-0.11; p < 0.001) implantation. The decrease in PBS area was the most powerful predictor of significant NIH after BMS implantation (odds ratio: 1.13; 95% CI: 1.02-1.26; p = 0.02). CONCLUSIONS: The decrease in PBS area after stent implantation is significantly associated with the magnitude of NIH development at follow-up. This finding raises the possibility of a communication between the lesion within the stent and the underlying native atherosclerotic plaque, and may have important implications regarding the pathobiology of in-stent restenosis and late/very late stent thrombosis. PMID- 27494446 TI - The relationship between vitamin K and peripheral arterial disease. AB - BACKGROUND AND AIMS: A high dietary intake of vitamin K1 (phylloquinone) and vitamin K2 (menaquinones) is thought to decrease cardiovascular disease risk by reducing vascular calcification. The objective of this study is to explore if there is a relationship between phylloquinone and menaquinones intake and risk of PAD. METHODS: We investigated the association between intake of phylloquinone and menaquinones with PAD in a prospective cohort with 36,629 participants. Occurrence of PAD was obtained by linkage to national registries. Baseline intake of phylloquinone and menaquinones was estimated using a validated food-frequency questionnaire. Multivariate Cox regression was used to estimate adjusted hazard ratio's for the association. RESULTS: During 12.1 years (standard deviation 2.1 years) of follow-up, 489 incident cases of PAD were documented. Menaquinones intake was associated with a reduced risk of PAD with a hazard ratio (HR) of 0.71, 95% CI; 0.53-0.95 for the highest versus lowest quartile. A stronger association was observed (p interaction 0.0001) in participants with hypertension (HRQ4 versus Q1 0.59; 95% CI 0.39-0.87) or diabetes (HRQ4 versus Q1 0.56; 95% CI 0.18-1.91), though confidence intervals were wide in the small (n = 530) diabetes stratum. Phylloquinone intake was not associated with PAD risk. CONCLUSIONS: High intake of menaquinones was associated with a reduced risk of PAD, at least in hypertensive participants. High intake of phylloquinone was not associated with a reduced risk of PAD. PMID- 27494447 TI - Dietary counseling is associated with an improved lipid profile in children with familial hypercholesterolemia. AB - BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Guidelines recommend cholesterol-lowering medication from 8 to 10 years of age and dietary recommendations. Little is known about the diet of FH children and the effect of dietary counseling. The aim of the study was to describe the diet of FH children with respect to fat quality, and to investigate if dietary counseling improved lipid profile. METHODS: Fifty four FH children (5-18 years) were included in the study and dietary intake was recorded with a pre-coded food diary for four days. Information about plasma lipid levels was obtained. RESULTS: Median intake of total fat, monounsaturated fat, polyunsaturated fat (PUFA) and saturated fat (SFA) was 30.8, 10.4, 5.9 and 12.0 E %, respectively. Among non-statin treated FH children, SFA intake was significantly correlated with TC, LDL-C and apolipoprotein (apo) B (rsp = 0.55; p = 0.004, rsp = 0.46; p = 0.02, and rsp = 0.45; p = 0.02, respectively), and PUFA/SFA ratio significantly inversely correlated with TC (rsp = -0.42; p = 0.03). Compared to the first visit, non-statin and non-plant sterol treated FH children (n = 10) had significantly reduced levels of TC (p < 0.01), LDL-C (p = 0.01), high-density lipoprotein cholesterol (p = 0.02), apo B (p = 0.05) and apo A-1 (p = 0.02) levels at a later visit. CONCLUSIONS: FH children had a higher intake of SFA than recommended and the SFA intake was positively correlated with plasma TC, LDL-C and apo B levels in FH children not using statins. Importantly, the plasma lipid profile was improved in FH children after dietary counseling where focus was on reducing intake of SFA and dietary cholesterol. PMID- 27494448 TI - Long-term effects of weight loss with a very-low carbohydrate, low saturated fat diet on flow mediated dilatation in patients with type 2 diabetes: A randomised controlled trial. AB - BACKGROUND AND AIMS: Very-low carbohydrate diets can improve glycaemic control in patients with type 2 diabetes (T2DM). However, compared to traditional higher carbohydrate, low fat (HighCHO) diets, they have been associated with impaired endothelial function (measured by flow mediated dilatation [FMD]) that is possibly related to saturated fat. This study aimed to examine the effects of a 12-month hypocaloric very-low carbohydrate, low saturated fat (LowCHO) diet compared to an isocaloric HighCHO diet. METHODS: One hundred and fifteen obese patients with T2DM (age:58.4 +/- 0.7 [SEM] yr, BMI:34.6 +/- 0.4 kg/m(2), HbA1c:7.33 [56.3 mmol/mol] +/- 0.10%) were randomised to consume an energy restricted LowCHO diet (Carb:Pro:Fat:Sat-Fat 14:28:58: < 10% energy; n = 58) or isocaloric HighCHO diet (53:17:30: < 10%; n = 57) whilst undertaking exercise (60 min, 3/wk). Bodyweight, HbA1c and FMD were assessed. RESULTS: Seventy eight participants completed the intervention (LowCHO = 41, HighCHO = 37). Both groups experienced similar reductions in weight and HbA1c (-10.6 +/- 0.7 kg, -1.05 +/- 0.10%; p < 0.001 time, p >= 0.48 time * diet). FMD did not change (p = 0.11 time, p = 0.20 time * diet). CONCLUSIONS: In patients with obesity and T2DM, HighCHO diet and LowCHO diet have similar effects on endothelial function. PMID- 27494449 TI - Gender and age effects on risk factor-based prediction of coronary artery calcium in symptomatic patients: A Euro-CCAD study. AB - BACKGROUND AND AIMS: The influence of gender and age on risk factor prediction of coronary artery calcification (CAC) in symptomatic patients is unclear. METHODS: From the European Calcific Coronary Artery Disease (EURO-CCAD) cohort, we retrospectively investigated 6309 symptomatic patients, 62% male, from Denmark, France, Germany, Italy, Spain and USA. All of them underwent risk factor assessment and CT scanning for CAC scoring. RESULTS: The prevalence of CAC among females was lower than among males in all age groups. Using multivariate logistic regression, age, dyslipidaemia, hypertension, diabetes and smoking were independently predictive of CAC presence in both genders. In addition to a progressive increase in CAC with age, the most important predictors of CAC presence were dyslipidaemia and diabetes (beta = 0.64 and 0.63, respectively) in males and diabetes (beta = 1.08) followed by smoking (beta = 0.68) in females; these same risk factors were also important in predicting increasing CAC scores. There was no difference in the predictive ability of diabetes, hypertension and dyslipidaemia in either gender for CAC presence in patients aged <50 and 50-70 years. However, in patients aged >70, only dyslipidaemia predicted CAC presence in males and only smoking and diabetes were predictive in females. CONCLUSIONS: In symptomatic patients, there are significant differences in the ability of conventional risk factors to predict CAC presence between genders and between patients aged <70 and >=70, indicating the important role of age in predicting CAC presence. PMID- 27494450 TI - To evaluate the prevalence of symptomatic and non-symptomatic ductus arteriosus and accuracy of physical signs in diagnosing PDA in preterm infants using blinded comparison of clinical and echocardiographic findings during the first week of life: a prospective observational study from Iran. AB - AIMS: To evaluate the prevalence of symptomatic and non-symptomatic ductus arteriosus (PDA) and accuracy of physical signs in diagnosing PDA in preterm infants using blinded comparison of clinical and echocardiographic findings during the first week of life. METHODS AND MATERIAL: This prospective observational cross-sectional study enrolled 200 preterm infants, who underwent echocardiography on 4th-7th postnatal day. The neonates who were diagnosed to have PDA on echo were observed for clinical features of PDA to label it symptomatic PDA. Symptomatic PDA was defined as detecting one or all of these symptoms in a neonate with PDA: bounding pulse, pericardial hyperactivity, systolic or continuous murmur. RESULTS: Forty-five infants had PDA on echocardiography. 66.7% neonates with PDA were symptomatic and the most prevalent symptom in them was heart murmur (100%) either alone or combined with other clinical features. Isolated murmur was seen in 31.2%, murmur and hyperdynamic precordium was seen in 8.8%, murmur and bounding pulses were seen in 6.67% and all three features simultaneously were seen in 20% of infants. The sensitivity of murmur for diagnosing symptomatic PDA was highest. CONCLUSION: Presence of murmur is the most important clinical feature for diagnosis of symptomatic PDA and has good specificity. PMID- 27494451 TI - Elucidating the Mechanism of Zn(2+) Sensing by a Bipyridine Probe Based on Two Photon Absorption. AB - In this work, we examine, by means of computational methods, the mechanism of Zn(2+) sensing by a bipyridine-centered, D-pi-A-pi-D-type ratiometric molecular probe. According to recently published experimental data [Divya, K. P.; Sreejith, S.; Ashokkumar, P.; Yuzhan, K.; Peng, Q.; Maji, S. K.; Tong, Y.; Yu, H.; Zhao, Y.; Ramamurthy, P.; Ajayaghosh, A. A ratiometric fluorescent molecular probe with enhanced two-photon response upon Zn(2+) binding for in vitro and in vivo bioimaging. Chem. Sci. 2014, 5, 3469-3474], after coordination to zinc ions the probe exhibits a large enhancement of the two-photon absorption cross section. The goal of our investigation was to elucidate the mechanism behind this phenomenon. For this purpose, linear and nonlinear optical properties of the unbound (cation-free) and bound probe were calculated, including the influence of solute-solvent interactions, implicitly using a polarizable continuum model and explicitely employing the QM/MM approach. Because the results of the calculations indicate that many conformers of the probe are energetically accessible at room temperature in solution and hence contribute to the signal, structure-property relationships were also taken into account. Results of our simulations demonstrate that the one-photon absorption bands for both the unbound and bound forms correspond to the bright pi -> pi* transition to the first excited state, which, on the other hand, exhibits negligible two-photon activity. On the basis of the results of the quadratic response calculations, we put forward a notion that it is the second excited state that gives the strong signal in the experimental nonlinear spectrum. To explain the differences in the two-photon absorption activity for the two lowest-lying excited states and nonlinear response enhancement upon binding, we employed the generalized few-state model including the ground, first, and second excited states. The analysis of the optical channel suggests that the large two-photon response is due to the coordination-induced increase of the transition moment from the first to the second excited state. PMID- 27494452 TI - Endoscopic suturing for the prevention of stent migration in benign upper gastrointestinal conditions: a comparative multicenter study. PMID- 27494453 TI - Endoscopic treatment of sporadic small duodenal and ampullary neuroendocrine tumors. AB - Background and study aim: As duodenal neuroendocrine tumors (NETs) are rare, their optimal management has not been clearly established. The aim of this study was to evaluate the feasibility and outcome of endoscopic treatment of duodenal NETs. Patients and methods: We reviewed the files of all patients who underwent endoscopic resection of a sporadic duodenal or ampullary NET between 1996 and 2014 at two centers. Results: A total of 29 patients with 32 uT1N0M0 NETs < 20 mm were included. Treatment consisted of endoscopic mucosal resection in 19 cases, and cap aspiration in 13 cases. Prior submucosal saline injection was used in 15 cases. Mortality was 3 % (one severe bleeding). Morbidity was 38 % (11/29). At post-resection analysis, mean tumor size was 8.9 mm (range 3 - 17 mm), 29 lesions were stage pT1, one was pT2, and 2 were pTx because of piecemeal resection. All NETs were well differentiated. A total of 27 lesions were classified as grade 1 and 5 were grade 2. The resection was R0, R1, and Rx for 16, 14, and 2 lesions, respectively. Three R1 patients underwent additional surgical treatment, with no residual tumor on the surgical specimen but with positive metastatic lymph nodes in two cases. One patient was lost to follow-up. Finally, 24 patients were included in the follow-up analysis. The median follow-up period was 56 months (range 6 - 175 months). Two patients presented a tumor recurrence during the follow-up period. Conclusions: Endoscopic treatment of small duodenal NETs was associated with significant morbidity, a difficulty in obtaining an R0 specimen, and the risk of lymph node metastasis. Nevertheless, it represents an interesting alternative in small grade 1 duodenal lesions and in patients at high surgical risk. PMID- 27494454 TI - All-cause mortality after ERCP. AB - Background and study aims: This study aimed to externally validate a recently developed English model for the prediction of 30-day mortality after endoscopic retrograde cholangiopancreatography (ERCP). Real-world mortality data beyond 30 days post-ERCP are scarce; thus, the study also aimed to develop a prediction model for mortality up to 12 months post-ERCP. Patients and methods: All patients who underwent their first ERCP during a 3-year period (n = 16 478), as identified from the Swedish Hospital Discharge Registry, were linked to the Swedish Death Registry. Factors associated with all-cause mortality up to 12 months post-ERCP were identified by Cox proportional hazards analysis. A prediction model was developed. Results: Post-ERCP mortality was 5 % at 30 days and increased to 11.9 % at 3 months. The English model slightly overpredicted 30-day mortality, which was corrected with recalibration. Discriminant validity of the recalibrated model was very good (c-statistic = 0.82). Independent predictors of medium-term mortality were: emergency admission (hazard ratio [HR] 1.48), cancer (HR 3.79), noncancer co-morbidity (1.33), gallstone-related diagnosis (HR 0.21), and age (HR 4.86 for >= 85 years vs. < 55 years). The c-statistic for 3 - 12-month mortality was 0.86 - 0.88. Specific ERCP complication codes were identified in 1.8 % of deaths within 30 days post-ERCP (0.09 % of ERCPs), and 75 % of deaths (18 % of ERCPs) within 1 year post-ERCP were due to cancer. Conclusions: Mortality doubled from 30 days to 3 months post-ERCP, but it was attributed mainly to underlying disease, notably cancer, and infrequently to ERCP-related causes. A previously developed model predicting 30-day mortality was externally validated. A model accurately predicting mortality up to 12 months post-ERCP was developed. PMID- 27494455 TI - Impact of an automated system for endocytoscopic diagnosis of small colorectal lesions: an international web-based study. AB - Background and study aims: Optical diagnosis of colorectal polyps is expected to improve the cost-effectiveness of colonoscopy, but achieving a high accuracy is difficult for trainees. Computer-aided diagnosis (CAD) is therefore receiving attention as an attractive tool. This study aimed to validate the efficacy of the latest CAD model for endocytoscopy (380-fold ultra-magnifying endoscopy). Patients and methods: This international web-based trial was conducted between August and November 2015. A web-based test comprising one white-light and one endocytoscopic image of 205 small colorectal polyps (<= 10 mm) from 123 patients was undertaken by both CAD and by endoscopists (three experts and ten non-experts from three countries). Outcome measures were accuracy in identifying neoplastic change in diminutive (<= 5 mm) and small (<= 10 mm) polyps, and accuracy in predicting post-polypectomy surveillance intervals according to current guidelines for high confidence optical diagnoses of diminutive polyps. Results: Of the 205 small polyps (147 neoplastic and 58 non-neoplastic), 139 were diminutive. CAD was accurate for 89 % (95 % confidence interval [CI] 83 % - 94 %) of diminutive polyps and 89 % (84 % - 93 %) of small polyps, which was significantly greater than results for the non-experts (73 % [71 % - 76 %], P < 0.001; and 76 % [74 % - 78 %], P < 0.001, respectively) and comparable with the experts' results (90 % [87 % - 93 %], P = 0.703; and 91 % [89 % - 93 %], P = 0.106, respectively). The surveillance interval predicted by CAD provided 98 % (93 % - 100 %) and 96 % (91 % - 99 %) agreement with pathology-directed intervals of the European and American guidelines, respectively. Conclusions: The use of CAD in endocytoscopy can be effective in the management of diminutive/small colorectal polyps.UMIN Clinical Trial Registry: UMIN000018185. PMID- 27494456 TI - C9ORF72 is a GDP/GTP exchange factor for Rab8 and Rab39 and regulates autophagy. AB - Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS-FTD) are devastating neurodegenerative disease affecting motoneurons from the spinal chord and neurons from the frontal and temporal cortex, respectively. The most common genetic cause for ALS-FTD is an expansion of GGGGCC repeats within the first intron of the C9ORF72 gene. However, little is known on the function of C9ORF72. Recently, other and we found that C9ORF72 forms a stable complex with the SMCR8 and WDR41 proteins. This complex acts as a GDP/GTP exchange factor for the small RAB GTPases Rab8a and Rab39b. Since Rab8 and Rab39 are involved in macroautophagy, we tested the role of C9ORF72 in this mechanism. Decrease expression of C9ORF72 in neuronal cultures leads to autophagy dysfunction characterized by accumulation of aggregates of p62/SQSTM1. However, loss of C9ORF72 expression does not cause major neuronal cell death, suggesting that a second stress may be required to promote cell toxicity. Intermediate size of polyglutamine repeats within Ataxin-2 (ATXN2) is an important genetic modifier of ALS-FTD. We found that decrease expression of C9ORF72 synergizes the toxicity and aggregation of ATXN2 with intermediate size of polyglutamine (30Q). Overall, our data suggest that reduce expression of C9ORF72 causes suboptimal autophagy that sensitizes neurons to a second stress. These data suggest that reduce expression of C9ORF72 may partly contribute to ALS-FTD pathogenesis. PMID- 27494457 TI - Acute Bilateral Toxic Endotheliitis Following Alcohol Consumption. AB - A 28-year-old male farmer presented to our emergency service with bilateral painful visual loss for the past 7 days that occurred suddenly after alcohol consumption. Examination showed bilateral central corneal epithelial defects, 3+ stromal edema, and cortical cataracts. After treatment with oral and topical corticosteroids for 4 weeks the corneal edema had subsided completely with mild anterior stromal scarring. Rapid progression of cataract to intumescent stage warranted sequential cataract surgeries 1 and 2 months after first presentation. Postoperatively, visual acuity recovered to 20/20 and 20/30 in the right and left eye respectively. This case highlights the extremely rare presentation of bilateral alcohol-induced toxic endothelitis, which recovered after intensive corticosteroid therapy. PMID- 27494458 TI - Toxicity of twenty-two plant essential oils against pathogenic bacteria of vegetables and mushrooms. AB - ASBTRACT Toxicity of twenty-two essential oils to three bacterial pathogens in different horticultural systems: Xanthomonas campestris pv. phaseoli (causing blight of bean), Clavibacter michiganensis subsp. michiganensis (bacterial wilt and canker of tomato), and Pseudomonas tolaasii (causal agent of bacterial brown blotch on cultivated mushrooms) was tested. Control of bacterial diseases is very difficult due to antibiotic resistance and ineffectiveness of chemical products, to that essential oils offer a promising alternative. Minimal inhibitory and bactericidal concentrations are determined by applying a single drop of oil onto the inner side of each plate cover in macrodilution assays. Among all tested substances, the strongest and broadest activity was shown by the oils of wintergreen (Gaultheria procumbens), oregano (Origanum vulgare), and lemongrass (Cymbopogon flexuosus. Carvacrol (64.0-75.8%) was the dominant component of oregano oils, while geranial (40.7%) and neral (26.7%) were the major constituents of lemongrass oil. Xanthomonas campestris pv. phaseoli was the most sensitive to plant essential oils, being susceptible to 19 oils, while 11 oils were bactericidal to the pathogen. Sixteen oils inhibited the growth of Clavibacter michiganensis subsp. michiganensis and seven oils showed bactericidal effects to the pathogen. The least sensitive species was Pseudomonas tolaasii as five oils inhibited bacterial growth and two oils were bactericidal. Wintergreen, oregano, and lemongrass oils should be formulated as potential biochemical bactericides against different horticultural pathogens. PMID- 27494459 TI - Effect of cigarette smoke on monocyte procoagulant activity: Focus on platelet derived brain-derived neurotrophic factor (BDNF). AB - Cigarette smoke (CS) activates platelets, promotes vascular dysfunction, and enhances Tissue Factor (TF) expression in blood monocytes favoring pro-thrombotic states. Brain-derived neurotrophic factor (BDNF), a member of the family of neurotrophins involved in survival, growth, and maturation of neurons, is released by activated platelets (APLTs) and plays a role in the cardiovascular system. The effect of CS on circulating levels of BDNF is controversial and the function of circulating BDNF in atherothrombosis is not fully understood. Here, we have shown that human platelets, treated with an aqueous extract of CS (CSE), released BDNF in a dose-dependent manner. In addition, incubation of human monocytes with BDNF or with the supernatant of platelets activated with CSE increased TF activity by a Tropomyosin receptor kinase B (TrkB)-dependent mechanism. Finally, comparing serum and plasma samples of 12 male never smokers (NS) and 29 male active smokers (AS) we observed a significant increase in microparticle-associated TF activity (MP-TF) as well as BDNF in AS, while in serum, BDNF behaved oppositely. Taken together these findings suggest that platelet-derived BDNF is involved in the regulation of TF activity and that CS plays a role in this pathway by favoring a pro-atherothrombotic state. PMID- 27494461 TI - Rashba Spin-Orbit Coupling, Strong Interactions, and the BCS-BEC Crossover in the Ground State of the Two-Dimensional Fermi Gas. AB - The recent experimental realization of spin-orbit coupled Fermi gases provides a unique opportunity to study the interplay between strong interaction and spin orbit coupling (SOC) in a tunable, disorder-free system. We present here precision ab initio numerical results on the two-dimensional, unpolarized, uniform Fermi gas with attractive interactions and Rashba SOC. Using the auxiliary-field quantum Monte Carlo method and incorporating recent algorithmic advances, we carry out exact calculations on sufficiently large system sizes to provide accurate results systematically as a function of experimental parameters. We obtain the equation of state, the momentum distributions, the pseudospin correlations, and the pair wave functions. Our results help illuminate the rich pairing structure induced by SOC, and provide benchmarks for theory and guidance to future experimental efforts. PMID- 27494462 TI - Experimental Demonstration of Self-Guided Quantum Tomography. AB - Traditional methods of quantum state characterization are impractical for systems of more than a few qubits due to exponentially expensive postprocessing and data storage and lack robustness against errors and noise. Here, we experimentally demonstrate self-guided quantum tomography performed on polarization photonic qubits. The quantum state is iteratively learned by optimizing a projection measurement without any data storage or postprocessing. We experimentally demonstrate robustness against statistical noise and measurement errors on single qubit and entangled two-qubit states. PMID- 27494463 TI - Scalable Dissipative Preparation of Many-Body Entanglement. AB - We present a technique for the dissipative preparation of highly entangled multiparticle states of atoms coupled to common oscillator modes. By combining local spontaneous emission with coherent couplings, we engineer many-body dissipation that drives the system from an arbitrary initial state into a Greenberger-Horne-Zeilinger state. We demonstrate that using our technique highly entangled steady states can be prepared efficiently in a time that scales polynomially with the system size. Our protocol assumes generic couplings and will thus enable the dissipative production of multiparticle entanglement in a wide range of physical systems. As an example, we demonstrate the feasibility of our scheme in state-of-the-art trapped-ion systems. PMID- 27494464 TI - Diffusive and Subdiffusive Spin Transport in the Ergodic Phase of a Many-Body Localizable System. AB - We study high temperature spin transport in a disordered Heisenberg chain in the ergodic regime. By employing a density matrix renormalization group technique for the study of the stationary states of the boundary-driven Lindblad equation we are able to study extremely large systems (400 spins). We find both a diffusive and a subdiffusive phase depending on the strength of the disorder and on the anisotropy parameter of the Heisenberg chain. Studying finite-size effects, we show numerically and theoretically that a very large crossover length exists that controls the passage of a clean-system dominated dynamics to one observed in the thermodynamic limit. Such a large length scale, being larger than the sizes studied before, explains previous conflicting results. We also predict spatial profiles of magnetization in steady states of generic nondiffusive systems. PMID- 27494465 TI - Modular Hamiltonian for Excited States in Conformal Field Theory. AB - We present a novel replica trick that computes the relative entropy of two arbitrary states in conformal field theory. Our replica trick is based on the analytic continuation of partition functions that break the Z_{n} replica symmetry. It provides a method for computing arbitrary matrix elements of the modular Hamiltonian corresponding to excited states in terms of correlation functions. We show that the quantum Fisher information in vacuum can be expressed in terms of two-point functions on the replica geometry. We perform sample calculations in two-dimensional conformal field theories. PMID- 27494466 TI - Precise QCD Predictions for the Production of Dijet Final States in Deep Inelastic Scattering. AB - The production of two-jet final states in deep inelastic scattering is an important QCD precision observable. We compute it for the first time to next-to next-to-leading order (NNLO) in perturbative QCD. Our calculation is fully differential in the lepton and jet variables and allows one to impose cuts on the jets in both the laboratory and the Breit frame. We observe that the NNLO corrections are moderate in size, except at kinematical edges, and that their inclusion leads to a substantial reduction of the scale variation uncertainty on the predictions. Our results will enable the inclusion of deep inelastic dijet data in precision phenomenology studies. PMID- 27494468 TI - Cool Quark Matter. AB - We generalize the state-of-the-art perturbative equation of state of cold quark matter to nonzero temperatures, needed in the description of neutron star mergers and core collapse processes. The new result is accurate to O(g^{5}) in the gauge coupling, and is based on a novel framework for dealing with the infrared sensitive soft field modes of the theory. The zero Matsubara mode sector is treated via a dimensionally reduced effective theory, while the soft nonzero modes are resummed using the hard thermal loop approximation. This combination of known effective descriptions offers unprecedented access to small but nonzero temperatures, both in and out of beta equilibrium. PMID- 27494469 TI - Transmission Microscopy with Nanometer Resolution Using a Deterministic Single Ion Source. AB - We realize a single particle microscope by using deterministically extracted laser-cooled ^{40}Ca^{+} ions from a Paul trap as probe particles for transmission imaging. We demonstrate focusing of the ions to a spot size of 5.8+/ 1.0 nm and a minimum two-sample deviation of the beam position of 1.5 nm in the focal plane. The deterministic source, even when used in combination with an imperfect detector, gives rise to a fivefold increase in the signal-to-noise ratio as compared with conventional Poissonian sources. Gating of the detector signal by the extraction event suppresses dark counts by 6 orders of magnitude. We implement a Bayes experimental design approach to microscopy in order to maximize the gain in spatial information. We demonstrate this method by determining the position of a 1 MUm circular hole structure to a precision of 2.7 nm using only 579 probe particles. PMID- 27494470 TI - Monitoring Nonadiabatic Electron-Nuclear Dynamics in Molecules by Attosecond Streaking of Photoelectrons. AB - Streaking of photoelectrons has long been used for the temporal characterization of attosecond extreme ultraviolet pulses. When the time-resolved photoelectrons originate from a coherent superposition of electronic states, they carry additional phase information, which can be retrieved by the streaking technique. In this contribution we extend the streaking formalism to include coupled electron and nuclear dynamics in molecules as well as initial coherences. We demonstrate how streaked photoelectrons offer a novel tool for monitoring nonadiabatic dynamics as it occurs in the vicinity of conical intersections and avoided crossings. Streaking can provide high time resolution direct signatures of electronic coherences, which affect many primary photochemical and biological events. PMID- 27494471 TI - One Photon Can Simultaneously Excite Two or More Atoms. AB - We consider two separate atoms interacting with a single-mode optical or microwave resonator. When the frequency of the resonator field is twice the atomic transition frequency, we show that there exists a resonant coupling between one photon and two atoms, via intermediate virtual states connected by counterrotating processes. If the resonator is prepared in its one-photon state, the photon can be jointly absorbed by the two atoms in their ground state which will both reach their excited state with a probability close to one. Like ordinary quantum Rabi oscillations, this process is coherent and reversible, so that two atoms in their excited state will undergo a downward transition jointly emitting a single cavity photon. This joint absorption and emission process can also occur with three atoms. The parameters used to investigate this process correspond to experimentally demonstrated values in circuit quantum electrodynamics systems. PMID- 27494473 TI - Accessing Extreme Spatiotemporal Localization of High-Power Laser Radiation through Transformation Optics and Scalar Wave Equations. AB - Although tightly focused intense ultrashort laser pulses are used in many applications from nano-processing to warm dense matter physics, their nonparaxial propagation implies the use of numerical simulations with vectorial wave equations or exact Maxwell solvers that have serious limitations and thus have hindered progress in this important field up to now. Here we present an elegant and robust solution that allows one to map the problem on one that can be addressed by simple scalar wave equations. The solution is based on a transformation optics approach and its validity is demonstrated in both the linear and the nonlinear regime. Our solution allows accessing challenging problems of extreme spatiotemporal localization of high power laser radiation that remain almost unexplored theoretically until now. PMID- 27494472 TI - Solid-State Source of Subcycle Pulses in the Midinfrared. AB - We demonstrate a robust, all-solid-state approach for the generation of microjoule subcycle pulses in the midinfrared through a cascade of carefully optimized parametric-amplification, difference-frequency-generation, spectral broadening, and chirp-compensation stages. This method of subcycle waveform generation becomes possible due to an unusual, ionization-assisted solid-state pulse self-compression dynamics, where highly efficient spectral broadening is enabled by ultrabroadband four-wave parametric amplification phase matched near the zero-group-velocity wavelength of the material. PMID- 27494474 TI - Spectrally Enhancing Near-Field Radiative Transfer between Metallic Gratings by Exciting Magnetic Polaritons in Nanometric Vacuum Gaps. AB - In the present Letter, we theoretically demonstrate that near-field radiative transport between one-dimensional periodic grating microstructures separated by nanometer vacuum gaps can be spectrally enhanced by exciting magnetic polaritons. Fluctuational electrodynamics that incorporates scattering matrix theory with rigorous coupled-wave analysis is employed to exactly calculate the near-field radiative flux between two metallic gratings. In addition to the well-known coupled surface plasmon polaritons, the radiative flux can be also spectrally enhanced due to the magnetic polariton, which is excited in the gap between the grating ridges. The mechanism of magnetic polaritons in the near-field radiative transport are elucidated in detail, while the unusual enhancement cannot be predicted by either Derjaguin's or the effective medium approximations. The effects of the vacuum gap distance and grating geometry parameters between the two gratings are investigated. The findings will open a new way to spectrally control near-field radiative transfer by magnetic polaritons with micro- or nanostructured metamaterials, which holds great potential for improving the performance of energy systems like near-field thermophotovoltaics. PMID- 27494475 TI - Cavitation-Induced Fracture Causes Nanocorrugations in Brittle Metallic Glasses. AB - Brittle metallic glasses exhibit a unique and intriguing fracture morphology of periodic nanocorrugations whose spacing and amplitude are of the order of tens of nanometers. We show through continuum simulations that they fail by spontaneous and simultaneous cavitation within multiple weak zones arising due to intrinsic atomic density fluctuations ahead of a notch tip. Dynamic crack growth would then occur along curved but narrowly confined shear bands that link the growing cavities. This mechanism involves little dissipation and also explains the formation of nanocorrugations. PMID- 27494476 TI - Observation of Double Impurity Critical Gradients for Electromagnetic Turbulence Excitation in Tokamak Plasmas. AB - The impact of impurity ions on a pedestal has been investigated in the HL-2A Tokamak, at the Southwestern Institute of Physics, Chengdu, China. Experimental results have clearly shown that during the H-mode phase, an electromagnetic turbulence was excited in the edge plasma region, where the impurity ions exhibited a peaked profile. It has been found that double impurity critical gradients are responsible for triggering the turbulence. Strong stiffness of the impurity profile has been observed during cyclic transitions between the I-phase and H-mode regime. The results suggest that the underlying physics of the self regulated edge impurity profile offers the possibility for an active control of the pedestal dynamics via pedestal turbulence. PMID- 27494477 TI - Dislocation Structure and Mobility in hcp ^{4}He. AB - Using path-integral Monte Carlo simulations, we assess the core structure and mobility of the screw and edge basal-plane dislocations in hcp ^{4}He. Our findings provide key insights into recent interpretations of giant plasticity and mass flow junction experiments. First, both dislocations are dissociated into nonsuperfluid Shockley partial dislocations separated by ribbons of stacking fault, suggesting that they are unlikely to act as one-dimensional channels that may display Luttinger-liquid-like behavior. Second, the centroid positions of the partial cores are found to fluctuate substantially, even in the absence of applied shear stresses. This implies that the lattice resistance to motion of the partial dislocations is negligible, consistent with the recent experimental observations of giant plasticity. Further results indicate that both the structure of the partial cores and the zero-point fluctuations play a role in this extreme mobility. PMID- 27494478 TI - Topological Instabilities in ac-Driven Bosonic Systems. AB - Under nonequilibrium conditions, bosonic modes can become dynamically unstable with an exponentially growing occupation. On the other hand, topological band structures give rise to symmetry protected midgap states. In this Letter, we investigate the interplay of instability and topology. Thereby, we establish a general relation between topology and instability under ac driving. We apply our findings to create dynamical instabilities which are strongly localized at the boundaries of a finite-size system. As these localized instabilities are protected by symmetry, they can be considered as topological instabilities. PMID- 27494479 TI - Geometric Origin of Superfluidity in the Lieb-Lattice Flat Band. AB - The ground state and transport properties of the Lieb lattice flat band in the presence of an attractive Hubbard interaction are considered. It is shown that the superfluid weight can be large even for an isolated and strictly flat band. Moreover the superfluid weight is proportional to the interaction strength and to the quantum metric, a band structure quantity derived solely from the flat-band Bloch functions. These predictions are amenable to verification with ultracold gases and may explain the anomalous behavior of the superfluid weight of high T_{c} superconductors. PMID- 27494480 TI - Connecting Local Yield Stresses with Plastic Activity in Amorphous Solids. AB - In model amorphous solids produced via differing quench protocols, a strong correlation is established between local yield stress measured by direct local probing of shear stress thresholds and the plastic rearrangements observed during remote loading in shear. This purely local measure shows a higher predictive power for identifying sites of plastic activity when compared with more conventional structural properties. Most importantly, the sites of low local yield stress, thus defined, are shown to be persistent, remaining predictive of deformation events even after fifty or more such plastic rearrangements. This direct and nonperturbative approach gives access to relevant transition pathways that control the stability of amorphous solids. Our results reinforce the relevance of modeling plasticity in amorphous solids based on a gradually evolving population of discrete and local zones preexisting in the structure. PMID- 27494481 TI - Real-Time Examination of Atomistic Mechanisms during Shock-Induced Structural Transformation in Silicon. AB - The experimental determination of atomistic mechanisms linking crystal structures during a compression-driven solid-solid phase transformation is a long-standing and challenging scientific objective. Using new capabilities at the Dynamic Compression Sector at the Advanced Photon Source, the structure of shocked Si at 19 GPa was identified as simple hexagonal, and the lattice orientations between ambient cubic diamond and simple hexagonal structures were related. The approach is general and provides a powerful new method for examining atomistic mechanisms during stress-induced structural changes. PMID- 27494482 TI - Universal Non-Debye Scaling in the Density of States of Amorphous Solids. AB - At the jamming transition, amorphous packings are known to display anomalous vibrational modes with a density of states (DOS) that remains constant at low frequency. The scaling of the DOS at higher packing fractions remains, however, unclear. One might expect to find a simple Debye scaling, but recent results from effective medium theory and the exact solution of mean-field models both predict an anomalous, non-Debye scaling. Being mean-field in nature, however, these solutions are only strictly valid in the limit of infinite spatial dimension, and it is unclear what value they have for finite-dimensional systems. Here, we study packings of soft spheres in dimensions 3 through 7 and find, away from jamming, a universal non-Debye scaling of the DOS that is consistent with the mean-field predictions. We also consider how the soft mode participation ratio evolves as dimension increases. PMID- 27494483 TI - Self-Organized Growth, Structure, and Magnetism of Monatomic Transition-Metal Oxide Chains. AB - We report on the self-organized growth of monatomic transition-metal oxide chains of (3*1) periodicity and unusual MO_{2} stoichiometry (M=Ni, Co, Fe, Mn) on Ir(100). We analyze their structural and magnetic properties by means of quantitative LEED, STM, and density functional theory (DFT) calculations. LEED analyses reveal a fascinating common atomic structure in which the transition metal atoms sit above a missing-row structure of the surface and are coupled to the substrate only via oxygen atoms. This structure is confirmed by DFT calculations with structural parameters deviating by less than 1.7 pm. The DFT calculations predict that the NiO_{2} chains are nonmagnetic, CoO_{2} chains are ferromagnetic, while FeO_{2} and MnO_{2} are antiferromagnetic. All structures show only weak magnetic interchain coupling. Further, we demonstrate the growth of oxide chains of binary alloys of Co and Ni or Fe on Ir(100), which allows us to produce well-controlled ensembles of ferromagnetic chains of different lengths separated by nonmagnetic or antiferromagnetic segments. PMID- 27494484 TI - Long-Term Repellency of Liquids by Superoleophobic Surfaces. AB - Applications of superoleophobic surfaces depend on the stability of the air cushion formed under liquid drops. To analyze the longevity of air cushions we used reflection-interference contrast microscopy (RICM) for drops on a porous fractal-like structure of sintered nanoparticles. RICM permits us to monitor the height of the air cushion with nanometer resolution. Whereas the air cushion under all investigated liquids was stable on a time scale of a few seconds to minutes and liquids rolled off, liquids with low surface tension penetrated the coating on the time scale of hours and longer. The penetration speed showed a power law dependence on time, dz/dt~t^{p}, the exponent p varying from -0.5 to 1.2. Thus, penetration is qualitatively different from the Lucas-Washburn law that governs spontaneous capillary filling of porous structures. PMID- 27494485 TI - Collapse of Ferromagnetism and Fermi Surface Instability near Reentrant Superconductivity of URhGe. AB - We present thermoelectric power and resistivity measurements in the ferromagnetic superconductor URhGe for a magnetic field applied along the hard magnetization b axis of the orthorhombic crystal. Reentrant superconductivity is observed near the spin reorientation transition at H_{R}=12.75 T, where a first order transition from the ferromagnetic to the polarized paramagnetic state occurs. Special focus is given to the longitudinal configuration, where both the electric and heat current are parallel to the applied field. The validity of the Fermi liquid T^{2} dependence of the resistivity through H_{R} demonstrates clearly that no quantum critical point occurs at H_{R}. Thus, the ferromagnetic transition line at H_{R} becomes first order implying the existence of a tricritical point at finite temperature. The enhancement of magnetic fluctuations in the vicinity of the tricritical point stimulates the reentrance of superconductivity. The abrupt sign change observed in the thermoelectric power with the thermal gradient applied along the b axis together with the strong anomalies in the other directions is definitive macroscopic evidence that in addition a significant change of the Fermi surface appears through H_{R}. PMID- 27494486 TI - Pseudogaps and Emergence of Coherence in Two-Dimensional Electron Liquids in SrTiO_{3}. AB - Using tunneling spectroscopy, we show that pseudogaps emerge in strongly correlated, two-dimensional electron liquids in SrTiO_{3} quantum wells that are tuned near a quantum critical point. Coherence peaks emerge at low temperatures in quantum wells embedded in antiferromagnetic SmTiO_{3} that remain itinerant to the lowest thickness. Quantum wells embedded in ferrimagnetic GdTiO_{3} that become ferromagnetic at low temperatures show no indication of quasiparticle coherence. They undergo a symmetry-lowering metal-to-insulator transition at the lowest thicknesses that coincides with a vanishing single-particle density of states (DOS) around the Fermi level. Both types of quantum wells show a power-law depletion of the DOS at high energies. The results show that the different pseudogap behaviors are closely correlated with the type of magnetism in the proximity of the quantum wells and thus provide insights into the microscopic mechanisms. PMID- 27494467 TI - Observation of an Anomalous Line Shape of the eta^{'}pi^{+}pi^{-} Mass Spectrum near the pp[over -] Mass Threshold in J/psi->gammaeta^{'}pi^{+}pi^{-}. AB - Using 1.09*10^{9} J/psi events collected by the BESIII experiment in 2012, we study the J/psi->gammaeta^{'}pi^{+}pi^{-} process and observe a significant abrupt change in the slope of the eta^{'}pi^{+}pi^{-} invariant mass distribution at the proton-antiproton (pp[over -]) mass threshold. We use two models to characterize the eta^{'}pi^{+}pi^{-} line shape around 1.85 GeV/c^{2}: one that explicitly incorporates the opening of a decay threshold in the mass spectrum (Flatte formula), and another that is the coherent sum of two resonant amplitudes. Both fits show almost equally good agreement with data, and suggest the existence of either a broad state around 1.85 GeV/c^{2} with strong couplings to the pp[over -] final states or a narrow state just below the pp[over -] mass threshold. Although we cannot distinguish between the fits, either one supports the existence of a pp[over -] moleculelike state or bound state with greater than 7sigma significance. PMID- 27494487 TI - Anomalous Hall Effect in a 2D Rashba Ferromagnet. AB - Skew scattering on rare impurity configurations is shown to dominate the anomalous Hall effect in a 2D Rashba ferromagnet. The mechanism originates in scattering on rare impurity pairs separated by distances of the order of the Fermi wavelength. The corresponding theoretical description goes beyond the conventional noncrossing approximation. The mechanism provides the only contribution to the anomalous Hall conductivity in the most relevant metallic regime and strongly modifies previously obtained results for lower energies in the leading order with respect to impurity strength. PMID- 27494488 TI - Ultralow Thermal Conductivity in Full Heusler Semiconductors. AB - Semiconducting half and, to a lesser extent, full Heusler compounds are promising thermoelectric materials due to their compelling electronic properties with large power factors. However, intrinsically high thermal conductivity resulting in a limited thermoelectric efficiency has so far impeded their widespread use in practical applications. Here, we report the computational discovery of a class of hitherto unknown stable semiconducting full Heusler compounds with ten valence electrons (X_{2}YZ, X=Ca, Sr, and Ba; Y=Au and Hg; Z=Sn, Pb, As, Sb, and Bi) through high-throughput ab initio screening. These new compounds exhibit ultralow lattice thermal conductivity kappa_{L} close to the theoretical minimum due to strong anharmonic rattling of the heavy noble metals, while preserving high power factors, thus resulting in excellent phonon-glass electron-crystal materials. PMID- 27494490 TI - Fractionally Charged Zero-Energy Single-Particle Excitations in a Driven Fermi Sea. AB - A voltage pulse of a Lorentzian shape carrying half of the flux quantum excites out of a zero-temperature Fermi sea an electron in a mixed state, which looks like a quasiparticle with an effectively fractional charge e/2. A prominent feature of such an excitation is a narrow peak in the energy distribution function lying exactly at the Fermi energy MU. Another spectacular feature is that the distribution function has symmetric tails around MU, which results in a zero-energy excitation. This sounds improbable since at zero temperature all available states below MU are fully occupied. The resolution lies in the fact that such a voltage pulse also excites electron-hole pairs, which free some space below MU and thus allow a zero-energy quasiparticle to exist. I discuss also how to address separately electron-hole pairs and a fractionally charged zero-energy excitation in an experiment. PMID- 27494489 TI - Levy Flights due to Anisotropic Disorder in Graphene. AB - We study transport properties of graphene with anisotropically distributed on site impurities (adatoms) that are randomly placed on every third line drawn along carbon bonds. We show that stripe states characterized by strongly suppressed backscattering are formed in this model in the direction of the lines. The system reveals Levy-flight transport in the stripe direction such that the corresponding conductivity increases as the square root of the system length. Thus, adding this type of disorder to clean graphene near the Dirac point strongly enhances the conductivity, which is in stark contrast with a fully random distribution of on-site impurities, which leads to Anderson localization. The effect is demonstrated both by numerical simulations using the Kwant code and by an analytical theory based on the self-consistent T-matrix approximation. PMID- 27494492 TI - Giant Frictional Drag in Double Bilayer Graphene Heterostructures. AB - We study the frictional drag between carriers in two bilayer graphene flakes separated by a 2-5 nm thick hexagonal boron nitride dielectric. At temperatures (T) lower than ~10 K, we observe a large anomalous negative drag emerging predominantly near the drag layer charge neutrality. The anomalous drag resistivity increases dramatically with reducing T, and becomes comparable to the layer resistivity at the lowest T=1.5 K. At low T the drag resistivity exhibits a breakdown of layer reciprocity. A comparison of the drag resistivity and the drag layer Peltier coefficient suggests a thermoelectric origin of this anomalous drag. PMID- 27494491 TI - Negative Coulomb Drag in Double Bilayer Graphene. AB - We report on an experimental measurement of Coulomb drag in a double quantum well structure consisting of bilayer-bilayer graphene, separated by few layer hexagonal boron nitride. At low temperatures and intermediate densities, a novel negative drag response with an inverse sign is observed, distinct from the momentum and energy drag mechanisms previously reported in double monolayer graphene. By varying the device aspect ratio, the negative drag component is suppressed and a response consistent with pure momentum drag is recovered. In the momentum drag dominated regime, excellent quantitative agreement with the density and temperature dependence predicted for double bilayer graphene is found. PMID- 27494493 TI - Detection of Majorana Kramers Pairs Using a Quantum Point Contact. AB - We propose a setup that integrates a quantum point contact (QPC) and a Josephson junction on a quantum spin Hall sample, experimentally realizable in InAs/GaSb quantum wells. The confinement due to both the QPC and the superconductor results in a Kramers pair of Majorana zero-energy bound states when the superconducting phases in the two arms differ by an odd multiple of pi across the Josephson junction. We investigate the detection of these Majorana pairs with the integrated QPC, and find a robust switching from normal to Andreev scattering across the edges due to the presence of Majorana Kramers pairs. Such a switching of the current represents a qualitative signature where multiterminal differential conductances oscillate with alternating signs when the external magnetic field is tuned. We show that this qualitative signature is also present in current cross-correlations. Thus, the change of the backscattering current nature affects both conductance and shot noise, the measurement of which offers a significant advantage over quantitative signatures such as conductance quantization in realistic measurements. PMID- 27494494 TI - Topological Superconductivity on the Surface of Fe-Based Superconductors. AB - As one of the simplest systems for realizing Majorana fermions, the topological superconductor plays an important role in both condensed matter physics and quantum computations. Based on ab initio calculations and the analysis of an effective 8-band model with superconducting pairing, we demonstrate that the three-dimensional extended s-wave Fe-based superconductors such as Fe_{1+y}Se_{0.5}Te_{0.5} have a metallic topologically nontrivial band structure, and exhibit a normal-topological-normal superconductivity phase transition on the (001) surface by tuning the bulk carrier doping level. In the topological superconductivity (TSC) phase, a Majorana zero mode is trapped at the end of a magnetic vortex line. We further show that the surface TSC phase only exists up to a certain bulk pairing gap, and there is a normal-topological phase transition driven by the temperature, which has not been discussed before. These results pave an effective way to realize the TSC and Majorana fermions in a large class of superconductors. PMID- 27494495 TI - Coherent Excited States in Superconductors due to a Microwave Field. AB - We describe theoretically the depairing effect of a microwave field on diffusive s-wave superconductors. The ground state of the superconductor is altered qualitatively in analogy to the depairing due to a dc current. In contrast to dc depairing, the density of states acquires, for microwaves with frequency omega_{0}, steps at multiples of the photon energy Delta+/-nhomega_{0} and shows an exponential-like tail in the subgap regime. We show that this ac depairing explains the measured frequency shift of a superconducting resonator with microwave power at low temperatures. PMID- 27494496 TI - Magnetic Precursor of the Pressure-Induced Superconductivity in Fe-Ladder Compounds. AB - The pressure effects on the antiferromagentic orders in iron-based ladder compounds CsFe_{2}Se_{3} and BaFe_{2}S_{3} have been studied using neutron diffraction. With identical crystal structure and similar magnetic structures, the two compounds exhibit highly contrasting magnetic behaviors under moderate external pressures. In CsFe_{2}Se_{3} the ladders are brought much closer to each other by pressure, but the stripe-type magnetic order shows no observable change. In contrast, the stripe order in BaFe_{2}S_{3} undergoes a quantum phase transition where an abrupt increase of Neel temperature by more than 50% occurs at about 1 GPa, accompanied by a jump in the ordered moment. With its spin structure unchanged, BaFe_{2}S_{3} enters an enhanced magnetic phase that bears the characteristics of an orbital selective Mott phase, which is the true neighbor of superconductivity emerging at higher pressures. PMID- 27494497 TI - Magnetic Reversal of Electric Polarization with Fixed Chirality of Magnetic Structure in a Chiral-Lattice Helimagnet MnSb_{2}O_{6}. AB - The correlation between magnetic and dielectric properties has been investigated for the single crystal of the chiral triangular-lattice helimagnet MnSb_{2}O_{6}. We found that the spin-spiral plane in the ground state has a considerable tilting from the (110) plane and that the sign of the spin-spiral tilting angle is coupled to the clockwise or counterclockwise manner of spin rotation and accordingly to the sign of magnetically induced electric polarization. This leads to unique magnetoelectric responses such as the magnetic-field-induced selection of a single ferroelectric domain as well as the reversal of electric polarization just by a slight tilting of the magnetic field direction, where the chiral nature of the crystal structure plays a crucial role through the coupling of the chirality between the crystal and magnetic structures. Our results demonstrate that crystallographic chirality can be an abundant source of novel magnetoelectric functions with coupled internal degrees of freedom. PMID- 27494498 TI - Optical Activation of Germanium Plasmonic Antennas in the Mid-Infrared. AB - Impulsive interband excitation with femtosecond near-infrared pulses establishes a plasma response in intrinsic germanium structures fabricated on a silicon substrate. This direct approach activates the plasmonic resonance of the Ge structures and enables their use as optical antennas up to the mid-infrared spectral range. The optical switching lasts for hundreds of picoseconds until charge recombination redshifts the plasma frequency. The full behavior of the structures is modeled by the electrodynamic response established by an electron hole plasma in a regular array of antennas. PMID- 27494499 TI - Water Dielectric Effects in Planar Confinement. AB - We investigate the dielectric profile of water confined between two planar polar walls using atomistic molecular dynamics simulations. For a water slab thickness below 1 nm the dielectric response is highly asymmetric: while the parallel component slightly increases compared to bulk, the perpendicular one decreases drastically due to anticorrelated polarization of neighboring water molecules. We demonstrate the importance of the dielectric contribution due to flexible polar headgroups and derive an effective dielectric tensorial box model suitable for coarse-grained electrostatic modeling. PMID- 27494500 TI - Guiding Catalytically Active Particles with Chemically Patterned Surfaces. AB - Catalytically active Janus particles suspended in solution create gradients in the chemical composition of the solution along their surfaces, as well as along any nearby container walls. The former leads to self-phoresis, while the latter gives rise to chemiosmosis, providing an additional contribution to self motility. Chemiosmosis strongly depends on the molecular interactions between the diffusing chemical species and the wall. We show analytically, using an approximate "point-particle" approach, that by chemically patterning a planar substrate one can direct the motion of Janus particles: the induced chemiosmotic flows can cause particles to either "dock" at the chemical step between the two materials or follow a chemical stripe. These theoretical predictions are confirmed by full numerical calculations. Generically, docking occurs for particles which tend to move away from their catalytic caps, while stripe following occurs in the opposite case. Our analysis reveals the physical mechanisms governing this behavior. PMID- 27494501 TI - Curling Liquid Crystal Microswimmers: A Cascade of Spontaneous Symmetry Breaking. AB - We report curling self-propulsion in aqueous emulsions of common mesogenic compounds. Nematic liquid crystal droplets self-propel in a surfactant solution with concentrations above the critical micelle concentration while undergoing micellar solubilization [Herminghaus et al., Soft Matter 10, 7008 (2014)]. We analyzed trajectories both in a Hele-Shaw geometry and in a 3D setup at variable buoyancy. The coupling between the nematic director field and the convective flow inside the droplet leads to a second symmetry breaking which gives rise to curling motion in 2D. This is demonstrated through a reversible transition to nonhelical persistent swimming by heating to the isotropic phase. Furthermore, autochemotaxis can spontaneously break the inversion symmetry, leading to helical trajectories in 3D. PMID- 27494502 TI - Law of Localization in Chemical Reaction Networks. AB - In living cells, chemical reactions are connected by sharing their products and substrates, and form complex networks, e.g., metabolic pathways. Here we developed a theory to predict the sensitivity, i.e., the responses of concentrations and fluxes to perturbations of enzymes, from network structure alone. Nonzero response patterns turn out to exhibit two characteristic features, localization and hierarchy. We present a general theorem connecting sensitivity with network topology that explains these characteristic patterns. Our results imply that network topology is an origin of biological robustness. Finally, we suggest a strategy to determine real networks from experimental measurements. PMID- 27494503 TI - Defect-Mediated Morphologies in Growing Cell Colonies. AB - Morphological trends in growing colonies of living cells are at the core of physiological and evolutionary processes. Using active gel equations, which include cell division, we show that shape changes during the growth can be regulated by the dynamics of topological defects in the orientation of cells. The friction between the dividing cells and underlying substrate drives anisotropic colony shapes toward more isotropic morphologies, by mediating the number density and velocity of topological defects. We show that the defects interact with the interface at a specific interaction range, set by the vorticity length scale of flows within the colony, and that the cells predominantly reorient parallel to the interface due to division-induced active stresses. PMID- 27494504 TI - Erratum: Implication of the Proton-Deuteron Radiative Capture for Big Bang Nucleosynthesis [Phys. Rev. Lett. 116, 102501 (2016)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.116.102501. PMID- 27494506 TI - Electron-phonon interaction and superconductivity in BaIr2P2. AB - Detailed calculations of the electronic structure, phonons and electron-phonon coupling of the superconducting compound BaIr2P2 were performed from first principles. The electronic structure showed excellent agreement with the available experimental data. The total electron-phonon coupling constant was [Formula: see text] and the logarithmically averaged phonon frequency was [Formula: see text] K. From the Allen-Dynes formula, with [Formula: see text], the superconducting critical temperature was estimated to be [Formula: see text] K, which is in excellent agreement with the experiment. These results indicate that the electron-phonon coupling is of moderate strength and is easily capable of supporting the observed superconductivity. PMID- 27494505 TI - Individualized treatment to optimize eventual cognitive outcome in congenital hypothyroidism. AB - BACKGROUND: In congenital hypothyroidism (CH), age-specific reference ranges (asRR) for fT4 and thyrotropine (TSH) are usually used to signal over/under treatment. We compared the consequences of individual fT4 steady-state concentrations (SSC's) and asRR regarding over-treatment signaling and intelligence quotient at 11 y (IQ11) and the effect of early over-treatment with high L-T4 dosages on IQ11. METHODS: Sixty-one patients (27 severe, 34 mild CH) were psychologically tested at 1.8, 6, and 11 y. Development scores were related to over-treatment in the period 0-24 mo, relative to either individual fT4SSC's or asRR. Three groups were formed, based on severity of over/under-treatment 0-5 mo (severe, mild, and no over/under-treatment). RESULTS: FT4 and TSH asRR missed 41-50% of the over-treatment episodes and consequently 22% of the over-treated patients, classified as such by fT4SSC's. Severe over-treatment 0-5 mo led to lowered IQ11's and to a 5.5-fold higher risk of IQ11 < 85 than other treatment regimes. Under-treatment had no effect on development scores. Initial L-T4 dosages >10 ug/kg resulted in a 3.7-fold higher risk of over-treatment than lower dosages. CONCLUSIONS: Data suggest that asRR, compared to fT4SSC's, signal over treatment insufficiently. Using fT4SSC's and avoiding over-treatment may optimize cognitive outcome. Lowered IQ11's are usually a late complication of severe early over-treatment. PMID- 27494507 TI - How Do Patients and Health Workers Interact around Malaria Rapid Diagnostic Testing, and How Are the Tests Experienced by Patients in Practice? A Qualitative Study in Western Uganda. AB - BACKGROUND: Successful scale-up in the use of malaria rapid diagnostic tests (RDTs) requires that patients accept testing and treatment based on RDT results and that healthcare providers treat according to test results. Patient-provider communication is a key component of quality care, and leads to improved patient satisfaction, higher adherence to treatment and better health outcomes. Voiced or perceived patient expectations are also known to influence treatment decision making among healthcare providers. While there has been a growth in literature on provider practices around rapid testing for malaria, there has been little analysis of inter-personal communication around the testing process. We investigated how healthcare providers and patients interact and engage throughout the diagnostic and treatment process, and how the testing service is experienced by patients in practice. METHODS: This research was conducted alongside a larger study which explored determinants of provider treatment decision-making following negative RDT results in a rural district (Kibaale) in mid-western Uganda, ten months after RDT introduction. Fifty-five patients presenting with fever were observed during routine outpatient visits at 12 low-level public health facilities. Observation captured communication practices relating to test purpose, results, diagnosis and treatment. All observed patients or caregivers were immediately followed up with in-depth interview. Analysis followed the 'framework' approach. A summative approach was also used to analyse observation data. RESULTS: Providers failed to consistently communicate the reasons for carrying out the test, and particularly to RDT-negative patients, a diagnostic outcome or the meaning of test results, also leading to confusion over what the test can detect. Patients appeared to value testing, but were frustrated by the lack of communication on outcomes. RDT-negative patients were dissatisfied by the absence of information on an alternative diagnosis and expressed uncertainty around adequacy of proposed treatment. CONCLUSIONS: Poor provider communication practices around the testing process, as well as limited inter-personal exchange between providers and patients, impacted on patients' perceptions of their proposed treatment. Patients have a right to health information and may be more likely to accept and adhere to treatment when they understand their diagnosis and treatment rationale in relation to their perceived health needs and visit expectations. PMID- 27494508 TI - Evaluating Clonal Expansion of HIV-Infected Cells: Optimization of PCR Strategies to Predict Clonality. AB - In HIV-infected individuals receiving suppressive antiretroviral therapy, the virus persists indefinitely in a reservoir of latently infected cells. The proliferation of these cells may contribute to the stability of the reservoir and thus to the lifelong persistence of HIV-1 in infected individuals. Because the HIV-1 replication process is highly error-prone, the detection of identical viral genomes in distinct host cells provides evidence for the clonal expansion of infected cells. We evaluated alignments of unique, near-full-length HIV-1 sequences to determine the relationship between clonality in a short region and clonality in the full genome. Although it is common to amplify and sequence short, subgenomic regions of the viral genome for phylogenetic analysis, we show that sequence identity of these amplicons does not guarantee clonality across the full viral genome. We show that although longer amplicons capture more diversity, no subgenomic region can recapitulate the diversity of full viral genomes. Consequently, some identical subgenomic amplicons should be expected even from the analysis of completely unique viral genomes, and the presence of identical amplicons alone is not proof of clonally expanded HIV-1. We present a method for evaluating evidence of clonal expansion in the context of these findings. PMID- 27494511 TI - Why do patients with myositis die? A retrospective analysis of a single-centre cohort. AB - OBJECTIVES: Causes of death in inflammatory myopathies have rarely been studied. We have assessed a cohort of myositis patients followed in a single centre over a 37-year period, reviewing the mortality rate, causes of death and predictors of poor prognosis. METHODS: We performed a single-centre, retrospective study on patients aged >=16 years fulfilling 3 or 4 of the Bohan and Peter criteria, noting their demographic data, clinical features, serology, treatment and outcome. RESULTS: Of 97 patients identified, 74.2% were female. The mean age at diagnosis was 40.5 years (SD 13.2). 38.1% had adult-onset dermatomyositis, 36.1% adult-onset polymyositis and 25.8% overlap myositis. 96.9% had upper and lower limb involvement (UL+/LL+) and 62.9% had a highest CK>=10 times the upper limit of normal. 33% had significant infection(s). The disease course was chronic persistent in 29.9%, relapsing and remitting in 34% and monophasic in 36.1%. All received steroids and 92.8% other immunosuppressant(s). The median follow-up was 9 years (IQR 11.5). The estimated cumulative proportion survival at 5, 10, 15 and 20 years were 94.6%, 82.2%, 72,1% and 66.1%, respectively. 24.7% of patients died, mostly due to infection (29.2%). In univariate analysis, lung involvement (HR 1.78, p=0.013), infection (HR 4.18, p=0.003) and UL+/LL+ (HR 0.13, p=0.010) were statistically significantly associated with the risk of death. In the multivariate analysis infection (HR 3.68, p=0.009) and UL+/LL+ (HR 0.16, p=0.027) were statistically significantly associated with survival. CONCLUSIONS: A good long-term survival is reported. Nevertheless, careful follow-up of myositis patients is important. PMID- 27494510 TI - Endoplasmic Reticulum-Localized Iridium(III) Complexes as Efficient Photodynamic Therapy Agents via Protein Modifications. AB - Protein inactivation by reactive oxygen species (ROS) such as singlet oxygen ((1)O2) and superoxide radical (O2(*-)) is considered to trigger cell death pathways associated with protein dysfunction; however, the detailed mechanisms and direct involvement in photodynamic therapy (PDT) have not been revealed. Herein, we report Ir(III) complexes designed for ROS generation through a rational strategy to investigate protein modifications by ROS. The Ir(III) complexes are effective as PDT agents at low concentrations with low-energy irradiation (<= 1 J cm(-2)) because of the relatively high (1)O2 quantum yield (> 0.78), even with two-photon activation. Furthermore, two types of protein modifications (protein oxidation and photo-cross-linking) involved in PDT were characterized by mass spectrometry. These modifications were generated primarily in the endoplasmic reticulum and mitochondria, producing a significant effect for cancer cell death. Consequently, we present a plausible biologically applicable PDT modality that utilizes rationally designed photoactivatable Ir(III) complexes. PMID- 27494512 TI - Clinical Correlates of Computationally Derived Visual Field Defect Archetypes in Patients from a Glaucoma Clinic. AB - PURPOSE: To assess the clinical validity of visual field (VF) archetypal analysis, a previously developed machine learning method for decomposing any Humphrey VF (24-2) into a weighted sum of clinically recognizable VF loss patterns. MATERIALS AND METHODS: For each of 16 previously identified VF loss patterns ("archetypes," denoted AT1 through AT16), we screened 30,995 reliable VFs to select 10-20 representative patients whose VFs had the highest decomposition coefficients for each archetype. VF global indices and patient ocular and demographic features were extracted retrospectively. Based on resemblances between VF archetypes and clinically observed VF patterns, hypotheses were generated for associations between certain VF archetypes and clinical features, such as an association between AT6 (central island, representing severe VF loss) and large cup-to-disk ratio (CDR). Distributions of the selected clinical features were compared between representative eyes of certain archetypes and all other eyes using the two-tailed t-test or Fisher exact test. RESULTS: 243 eyes from 243 patients were included, representative of AT1 through AT16. CDR was more often >= 0.7 among eyes representative of AT6 (central island; p = 0.002), AT10 (inferior arcuate defect; p = 0.048), AT14 (superior paracentral defect; p = 0.016), and AT16 (inferior paracentral defect; p = 0.016) than other eyes. CDR was more often < 0.7 among eyes representative of AT1 (no focal defect; p < 0.001) and AT2 (superior defect; p = 0.027), which was also associated with ptosis (p < 0.001). AT12 (temporal hemianopia) was associated with history of stroke (p = 0.022). AT11 (concentric peripheral defect) trended toward association with trial lens correction > 6D (p = 0.069). CONCLUSIONS: Shared clinical features between computationally derived VF archetypes and clinically observed VF patterns support the clinical validity of VF archetypal analysis. PMID- 27494513 TI - MicroTrout: A comprehensive, genome-wide miRNA target prediction framework for rainbow trout, Oncorhynchus mykiss. AB - Rainbow trout represent an important teleost research model and aquaculture species. As such, rainbow trout are employed in diverse areas of biological research, including basic biological disciplines such as comparative physiology, toxicology, and, since rainbow trout have undergone both teleost- and salmonid specific rounds of genome duplication, molecular evolution. In recent years, microRNAs (miRNAs, small non-protein coding RNAs) have emerged as important posttranscriptional regulators of gene expression in animals. Given the increasingly recognized importance of miRNAs as an additional layer in the regulation of gene expression and hence biological function, recent efforts using RNA- and genome sequencing approaches have resulted in the creation of several resources for the construction of a comprehensive repertoire of rainbow trout miRNAs and isomiRs (variant miRNA sequences that all appear to derive from the same gene but vary in sequence due to post-transcriptional processing). Importantly, through the recent publication of the rainbow trout genome (Berthelot et al., 2014), mRNA 3'UTR information has become available, allowing for the first time the genome-wide prediction of miRNA-target RNA relationships in this species. We here report the creation of the microtrout database, a comprehensive resource for rainbow trout miRNA and annotated 3'UTRs. The comprehensive database was used to implement an algorithm to predict genome-wide rainbow trout-specific miRNA-mRNA target relationships, generating an improved predictive framework over previously published approaches. This work will serve as a useful framework and sequence resource to experimentally address the role of miRNAs in several research areas using the rainbow trout model, examples of which are discussed. PMID- 27494514 TI - The coverage of elective revascularisation procedure codes in the National Finnish Hospital Discharge Register. AB - INTRODUCTION: Administrative registers provide an attractive data source for real life effectiveness studies. The validity of coronary artery disease diagnoses in the Finnish National Hospital Discharge Register (HDR) is high but the validity of revascularization procedure codes (percutaneous coronary intervention; PCI and coronary artery bypass grafting; CABG) are unknown. METHODS: All elective PCIs (n = 1771) and CABGs (n = 1819), performed at the Heart Center, Kuopio University Hospital, Finland between years 2007 and 2014 were identified from the unit's Special Electronic Medical Records (sEMR). Personal identity codes were used to link these data to the HDR. Sensitivity was estimated as proportion of operations recorded in sEMR and HDR. RESULTS: With the strictest assumption of exactly the same intervention day in HDR and sEMR, the sensitivity for procedure codes were 84.6% for PCI and 97.1% for CABG, respectively. When a one-day difference was allowed in the dates, the sensitivity increased to 87.6% for PCI and 98.0% for CABG. Altogether 62.1% of elective PCIs and 69.2% of CABGs were correctly classified as elective procedures in the HDR. CONCLUSION: The potential of the research application of the HDR extends beyond traditionally used diagnostic codes. One feasible application is the assessment of real-life effectiveness of different procedures. KEY MESSAGES The majority of PCIs (87.6%) and CABGs (98.0%), performed in the Heart Center, Kuopio University Hospital responsible for the treatment of approximately one fifth of the Finnish population, were captured by the Finnish National Hospital Discharge Register. However, only 62.1% of elective PCIs and 69.2% of CABGs were correctly classified as elective procedures in the HDR. Electivity data were missing from approximately one third of the procedures. This study produces new information of the potential use of HDR for real-life effectiveness studies to support evidence-based decision making in health care. PMID- 27494515 TI - Size of the Organic Cation Tunes the Band Gap of Colloidal Organolead Bromide Perovskite Nanocrystals. AB - A few approaches have been employed to tune the band gap of colloidal organic inorganic trihalide perovskites (OTPs) nanocrystals by changing the halide anion. However, to date, there is no report of electronic structure tuning of perovskite NCs upon changing the organic cation. We report here, for the first time, the room temperature colloidal synthesis of (EA)x(MA)1-xPbBr3 nanocrystals (NCs) (where, x varies between 0 and 1) to tune the band gap of hybrid organic inorganic lead perovskite NCs from 2.38 to 2.94 eV by varying the ratio of ethylammonium (EA) and methylammonium (MA) cations. The tuning of band gap is confirmed by electronic structure calculations within density functional theory, which explains the increase in the band gap upon going toward larger "A" site cations in APbBr3 NCs. The photoluminescence quantum yield (PLQY) of these NCs lies between 5% to 85% and the average lifetime falls in the range 1.4 to 215 ns. A mixture of MA cations and its higher analog EA cations provide a versatile tool to tune the structural as well as optoelectronic properties of perovskite NCs. PMID- 27494516 TI - Intra-articular glucocorticoid injections should not be neglected in the remission targeted treatment of early rheumatoid arthritis: a post hoc analysis from the NEO-RACo trial. AB - OBJECTIVES: To study the effects of neglecting intra-articular glucocorticoid injections (IAGCIs) into swollen joints in early rheumatoid arthritis (RA). METHODS: Ninety-nine patients with early, DMARD naive RA were treated, aiming at remission, with methotrexate, sulfasalazine, hydroxychloroquine, low-dose oral prednisolone and, when needed, IAGCIs for 2 years, and randomised to receive infliximab or placebo from weeks 4 to 26. During each of the 15 study visits, patients were scored retrospectively 0.2-0.4 points (depending on the number of non-injected joints) if IAGCIs to all swollen joints were not given. Patients were divided into tertiles by their cumulative scores for neglected injections (CSNI) over 24 months. 28-joint disease activity score (DAS28) area under the curve (AUC) between 0-24 months, remission rates, changes in quality of life, and radiological changes during the follow-up were assessed. Trends across tertiles of CSNI were tested with generalised linear models. RESULTS: Higher CSNI was associated with lower strict remission rates (p=0.005), and lower quality of life (p=0.004) at 24 months, and higher DAS28 AUC (p<0.001) during the follow-up. At 24 months, DAS28 remission rates were 90%, 93% and 76% (p=0.081), and strict remission rates were 74%, 77% and 39% by tertiles of CSNI. No significant differences were observed in radiological progression (p=0.089). IAGCIs were well tolerated. CONCLUSIONS: Neglecting IAGCIs into swollen joints is associated with lower remission rates, higher disease activity, and lower quality of life. Hence, IAGCIs should be used as an integral part of the targeted treatment of early RA. PMID- 27494517 TI - Epidemiology, Seasonality and Factors Associated with Rotavirus Infection among Children with Moderate-to-Severe Diarrhea in Rural Western Kenya, 2008-2012: The Global Enteric Multicenter Study (GEMS). AB - OBJECTIVE: To evaluate factors associated with rotavirus diarrhea and to describe severity of illness among children <5 years old with non-dysenteric, moderate-to severe diarrhea (MSD) in rural western Kenya. METHODS: We analyzed data from children <5 years old with non-dysenteric MSD enrolled as cases in the Global Enteric Multicenter Study (GEMS) in Kenya. A non-dysenteric MSD case was defined as a child with >=3 loose stools in 24 hrs. and one or more of the following: sunken eyes, skin tenting, intravenous rehydration, or hospitalization, who sought care at a sentinel health center within 7 days of illness onset. Rotavirus antigens in stool samples were detected by ELISA. Demographic and clinical information was collected at enrollment and during a single follow-up home visit at approximately 60 days. We analyzed diarrhea severity using a GEMS 17 point numerical scoring system adapted from the Vesikari score. We used logistic regression to evaluate factors associated with rotavirus infection. RESULTS: From January 31, 2008 to September 30, 2012, among 1,637 (92%) non-dysenteric MSD cases, rotavirus was detected in stools of 245 (15.0%). Rotavirus-positive compared with negative cases were: younger (median age, 8 vs. 13 months; p<0.0001), had more severe illness (median severity score, 9 vs 8; p<0.0001) and had to be hospitalized more frequently (37/245 [15.1%] vs. 134/1,392 [9.6%]), p <0.013). Independent factors associated with rotavirus infection included age 0 11 months old (aOR = 5.29, 95% CI 3.14-8.89) and presenting with vomiting >=3 times/24hrs (aOR = 2.58, 95% CI [1.91-3.48]). Rotavirus was detected more commonly in warm and dry months than in the cool and rainy months (142/691 [20%] vs 70/673 [10%]) p<0.0001). CONCLUSIONS: Diarrhea caused by rotavirus is associated with severe symptoms leading to hospitalization. Consistent with other settings, infants had the greatest burden of disease. PMID- 27494518 TI - Stereoselective Synthesis of Ezetimibe via Cross-Metathesis of Homoallylalcohols and alpha-Methylidene-beta-Lactams. AB - Ru-catalyzed cross-metathesis (CM) reaction between beta-arylated alpha methylidene-beta-lactams and terminal olefins was developed. The CM reaction is effectively catalyzed with Hoveyda-Grubbs second-generation catalyst affording corresponding alpha-alkylidene-beta-aryl-beta-lactams in good isolated yields (41 83%) with exclusive Z-selectivity. The developed protocol was successfully applied for stereoselective preparation of Ezetimibe, the commercial cholesterol absorption inhibitor. PMID- 27494519 TI - ROOT HAIR DEFECTIVE SIX-LIKE Class I Genes Promote Root Hair Development in the Grass Brachypodium distachyon. AB - Genes encoding ROOT HAIR DEFECTIVE SIX-LIKE (RSL) class I basic helix loop helix proteins are expressed in future root hair cells of the Arabidopsis thaliana root meristem where they positively regulate root hair cell development. Here we show that there are three RSL class I protein coding genes in the Brachypodium distachyon genome, BdRSL1, BdRSL2 and BdRSL3, and each is expressed in developing root hair cells after the asymmetric cell division that forms root hair cells and hairless epidermal cells. Expression of BdRSL class I genes is sufficient for root hair cell development: ectopic overexpression of any of the three RSL class I genes induces the development of root hairs in every cell of the root epidermis. Expression of BdRSL class I genes in root hairless Arabidopsis thaliana root hair defective 6 (Atrhd6) Atrsl1 double mutants, devoid of RSL class I function, restores root hair development indicating that the function of these proteins has been conserved. However, neither AtRSL nor BdRSL class I genes is sufficient for root hair development in A. thaliana. These data demonstrate that the spatial pattern of class I RSL activity can account for the pattern of root hair cell differentiation in B. distachyon. However, the spatial pattern of class I RSL activity cannot account for the spatial pattern of root hair cells in A. thaliana. Taken together these data indicate that that the functions of RSL class I proteins have been conserved among most angiosperms-monocots and eudicots despite the dramatically different patterns of root hair cell development. PMID- 27494520 TI - Dopamine Receptor Gene DRD4 7-Repeat Allele X Maternal Sensitivity Interaction on Child Externalizing Behavior Problems: Independent Replication of Effects at 18 Months. AB - The DRD4 VNTR has been associated with child behavior problems in interaction with maternal insensitivity in European and American cohorts of preschoolers, with the 7-repeat (7R) allele associated with greater problems. We sought to replicate and expand these findings by examining effects on reports of child behavior problems at 18 months. A 63 family sample with data for observed maternal sensitivity ratings, DRD4 VNTR genotype, and maternal report of child behavior problems at 18-months was used in this preliminary analysis. Maternal sensitivity was measured at 6-months of age using laboratory observational measures (free-play and a teaching task). Maternal report of toddler behavior was obtained at 18-months via the standard Child Behavior Checklist, and infant genotype on the DRD4 VNTR was obtained using PCR. Infants carrying the DRD4 7R allele showed greater effects of maternal insensitivity than non-carriers for behavioral problems at 18-months. We replicated previous findings of association of infant DRD4 x maternal sensitivity interactions with child Externalizing problems in the European-ancestry sample (N = 42) in a median split of maternal sensitivity (p = .00011, eta2 = .329) and in regression analyses controlling for maternal age, maternal depression, and child gender in European ancestry (B = 3.4, SE 1.33, p = .01) and the total sample (B = -2.2, SE 1.02, p = .02). Exploratory analyses also found evidence of DRD4 x maternal sensitivity interaction with the CBCL ADHD scale. These findings replicate in an independent cohort DRD4 x maternal insensitivity interaction effect on child externalizing behavior problems at 18 months, further supporting the role of the DRD4 genotype in differential sensitivity to parenting. PMID- 27494521 TI - Characterization of Cells Isolated from Genetic and Trauma-Induced Heterotopic Ossification. AB - Heterotopic ossification (HO) is the pathologic formation of bone separate from the normal skeleton. Although several models exist for studying HO, an understanding of the common in vitro properties of cells isolated from these models is lacking. We studied three separate animal models of HO including two models of trauma-induced HO and one model of genetic HO, and human HO specimens, to characterize the properties of cells derived from tissue containing pre-and mature ectopic bone in relation to analogous mesenchymal cell populations or osteoblasts obtained from normal muscle tissue. We found that when cultured in vitro, cells isolated from the trauma sites in two distinct models exhibited increased osteogenic differentiation when compared to cells isolated from uninjured controls. Furthermore, osteoblasts isolated from heterotopic bone in a genetic model of HO also exhibited increased osteogenic differentiation when compared with normal osteoblasts. Finally, osteoblasts derived from mature heterotopic bone obtained from human patients exhibited increased osteogenic differentiation when compared with normal bone from the same patients. These findings demonstrate that across models, cells derived from tissues forming heterotopic ossification exhibit increased osteogenic differentiation when compared with either normal tissues or osteoblasts. These cell types can be used in the future for in vitro investigations for drug screening purposes. PMID- 27494522 TI - Comparative Analysis of Pain Behaviours in Humanized Mouse Models of Sickle Cell Anemia. AB - Pain is a hallmark feature of sickle cell anemia (SCA) but management of chronic as well as acute pain remains a major challenge. Mouse models of SCA are essential to examine the mechanisms of pain and develop novel therapeutics. To facilitate this effort, we compared humanized homozygous BERK and Townes sickle mice for the effect of gender and age on pain behaviors. Similar to previously characterized BERK sickle mice, Townes sickle mice show more mechanical, thermal, and deep tissue hyperalgesia with increasing age. Female Townes sickle mice demonstrate more hyperalgesia compared to males similar to that reported for BERK mice and patients with SCA. Mechanical, thermal and deep tissue hyperalgesia increased further after hypoxia/reoxygenation (H/R) treatment in Townes sickle mice. Together, these data show BERK sickle mice exhibit a significantly greater degree of hyperalgesia for all behavioral measures as compared to gender- and age matched Townes sickle mice. However, the genetically distinct "knock-in" strategy of human alpha and beta transgene insertion in Townes mice as compared to BERK mice, may provide relative advantage for further genetic manipulations to examine specific mechanisms of pain. PMID- 27494523 TI - Importance of Hypervariable Region 2 for Stability and Affinity of a Shark Single Domain Antibody Specific for Ebola Virus Nucleoprotein. AB - Single-domain antibodies derived from the unique New Antigen Receptor found in sharks have numerous potential applications, ranging from diagnostic reagents to therapeutics. Shark-derived single-domain antibodies possess the same characteristic ability to refold after heat denaturation found in single-domain antibodies derived from camelid heavy-chain-only antibodies. Recently, two shark derived single-domain antibodies specific for the nucleoprotein of Ebola virus were described. Our evaluation confirmed their high affinity for the nucleoprotein, but found their melting temperatures to be low relative to most single-domain antibodies. Our first approach towards improving their stability was grafting antigen-binding regions (complementarity determining regions) of one of these single-domain antibodies onto a high melting temperature shark single domain antibody. This resulted in two variants: one that displayed excellent affinity with a low melting temperature, while the other had poor affinity but a higher melting temperature. These new proteins, however, differed in only 3 amino acids within the complementarity determining region 2 sequence. In shark single domain antibodies, the complementarity determining region 2 is often referred to as hypervariable region 2, as this segment of the antibody domain is truncated compared to the sequence in camelid single-domain antibodies and conventional heavy chain variable domains. To elucidate which of the three amino acids or combinations thereof were responsible for the affinity and stability we made the 6 double and single point mutants that covered the intermediates between these two clones. We found a single amino acid change that achieved a 10 degrees C higher melting temperature while maintaining sub nM affinity. This research gives insights into the impact of the shark sdAb hypervariable 2 region on both stability and affinity. PMID- 27494524 TI - Why Do Drivers Use Mobile Phones While Driving? The Contribution of Compensatory Beliefs. AB - The current study is the first to investigate the contribution of compensatory beliefs (i.e., the belief that the negative effects of an unsafe behavior can be "neutralized" by engaging in another safe behavior; e.g., "I can use a mobile phone now because I will slow down ") on drivers' mobile phone use while driving. The effects of drivers' personal characteristics on compensatory beliefs, mobile phone use and self-regulatory behaviors were also examined. A series of questions were administered to drivers, which included (1) personal measures, (2) scales that measured compensatory beliefs generally in substance use and with regard to driving safety, and (3) questions to measure drivers' previous primary mobile phone usage and corresponding self-regulatory actions. Overall, drivers reported a low likelihood of compensatory beliefs, prior mobile phone use, and a strong frequency of self-regulatory behaviors. Respondents who had a higher tendency toward compensatory beliefs reported more incidents or crash involvement caused by making or answering calls and sending or reading messages. The findings provide strong support for the contribution of compensatory beliefs in predicting mobile phone usage in the context of driving. Compensatory beliefs can explain 41% and 43% of the variance in the active activities of making calls and texting/sending messages compared with 18% and 31% of the variance in the passive activities of answering calls and reading messages. Among the regression models for predicting self-regulatory behaviors at the tactical or operational level, compensatory beliefs emerge as significant predictors only in predicting shorter conversations while on a call. The findings and limitations of the current study are discussed. PMID- 27494525 TI - The plant alkaloid chelerythrine binds to chromatin, alters H3K9Ac and modulates global gene expression. AB - Chelerythrine (CHL), a plant alkaloid, possesses antimicrobial, anti inflammatory, and antitumor properties. Although CHL influences several key signal transduction pathways, its ability to interact directly with nucleoprotein complex chromatin, in eukaryotic cells has so far not been looked into. Here we have demonstrated its association with hierarchically assembled chromatin components, viz. long chromatin, chromatosome, nucleosome, chromosomal DNA, and histone H3 and the consequent effect on chromatin structure. CHL was found to repress acetylation at H3K9. It is more target-specific in terms of gene expression alteration and less cytotoxic compared to its structural analog sanguinarine. PMID- 27494526 TI - Young People Smokers' Reactions on Peer Influence Not to Smoke. AB - BACKGROUND: Peers exert influence not to smoke but little is yet known on how this affects young people's behavior and cognitions. OBJECTIVES: This experimental study investigates the impact of two types of peer influence not to smoke on the verbalized attitudes and responses of daily-smoking young people. METHODS: Two conditions were conducted: 1) a peer confederate stating three times that s/he had quit smoking and was glad to have done so (covert peer influence); 2) a peer confederate making similar statements, but urging to quit smoking (overt peer influence). The participant performed a music task with the peer in order to disguise the true nature of the experiment. Thirty-one daily-smoking young people (16-24 years) participated; 44 responses in the overt and 34 responses in the covert condition were analyzed in a discourse analysis. RESULTS: The participants in the covert condition were more elaborative about smoking, i.e., taking an active role in a dialogue about the experiences of the peer or the participant in quitting smoking while in the overt condition participants showed more passive resistance, i.e., not showing an intention to follow the advice but avoid causing the peer embarrassment or discomfort. Open resistance, i.e., demonstration of being well-informed and indicating the redundancy of the advice, does not significantly differ in these two conditions but occurs, for both, primarily at the third discouragement. CONCLUSIONS: Overt and frequent discouragement seems to be less effective in stimulating young people to take an active role in the dialogue with their peers about smoking. PMID- 27494527 TI - Elevated Fasting Blood Glucose Is Predictive of Poor Outcome in Non-Diabetic Stroke Patients: A Sub-Group Analysis of SMART. AB - BACKGROUND: Although increasing evidence suggests that hyperglycemia following acute stroke adversely affects clinical outcome, whether the association between glycaemia and functional outcome varies between stroke patients with?without pre diagnosed diabetes remains controversial. We aimed to investigate the relationship between the fasting blood glucose (FBG) and the 6-month functional outcome in a subgroup of SMART cohort and further to assess whether this association varied based on the status of pre-diagnosed diabetes. METHODS: Data of 2862 patients with acute ischemic stroke (629 with pre-diagnosed diabetics) enrolled from SMART cohort were analyzed. Functional outcome at 6-month post stroke was measured by modified Rankin Scale (mRS) and categorized as favorable (mRS:0-2) or poor (mRS:3-5). Binary logistic regression model, adjusting for age, gender, educational level, history of hypertension and stroke, baseline NIHSS and treatment group, was used in the whole cohort to evaluate the association between admission FBG and functional outcome. Stratified logistic regression analyses were further performed based on the presence/absence of pre-diabetes history. RESULTS: In the whole cohort, multivariable logistical regression showed that poor functional outcome was associated with elevated FBG (OR1.21 (95%CI 1.07 1.37), p = 0.002), older age (OR1.64 (95% CI1.38-1.94), p<0.001), higher NIHSS (OR2.90 (95%CI 2.52-3.33), p<0.001) and hypertension (OR1.42 (95%CI 1.13-1.98), p = 0.04). Stratified logistical regression analysis showed that the association between FBG and functional outcome remained significant only in patients without pre-diagnosed diabetes (OR1.26 (95%CI 1.03-1.55), p = 0.023), but not in those with premorbid diagnosis of diabetes (p = 0.885). CONCLUSION: The present results demonstrate a significant association between elevated FBG after stroke and poor functional outcome in patients without pre-diagnosed diabetes, but not in diabetics. This finding confirms the importance of glycemic control during acute phase of ischemic stroke especially in patients without pre-diagnosed diabetes. Further investigation for developing optimal strategies to control blood glucose level in hyperglycemic setting is therefore of great importance. TRIAL REGISTRATION: ClinicalTrials.gov NCT00664846. PMID- 27494528 TI - Moderators of Treatment Effects of a Video-Based Cognitive-Behavioral Therapy for Insomnia Comorbid With Cancer. AB - PURPOSE: To assess the moderating role of demographic and clinical variables on the efficacy of a video-based cognitive behavioral therapy for insomnia (VCBT-I) among breast cancer patients. PATIENTS AND METHODS: As part of a randomized controlled trial, 80 women received VCBT-I. RESULTS: Patients with a more advanced breast cancer were less likely to show reductions on the Insomnia Severity Index (ISI) and increased sleep efficiency at posttreatment. Patients using an antidepressant medication showed a larger reduction of ISI scores and a higher rate of insomnia remission. Remission of insomnia was also significantly more likely in individuals with a higher annual income. When using a multivariate binary classification tree analysis, the best and unique predictor of insomnia remission was having a less severe baseline ISI score. CONCLUSION: Although efficacious in general, VCBT-I does not appear to be an optimal format for everybody. PMID- 27494530 TI - Benefits and Limitations of Polymorphic and Amorphous Forms of Active Pharmaceutical Ingredients. AB - Active pharmaceutical ingredients (APIs) can exist in different polymorphic forms as well as in amorphous state. Polymorphic and amorphous forms of APIs can differ in physicochemical properties which in turn can significantly influence their therapeutic safety and effectiveness of the treatment. This review focuses on benefits and limitations of polymorphic and amorphous forms of APIs used in preformulation and formulation studies. Authors present their work on safety precautions for the use of polymorphic and amorphous forms of APIs, analytical techniques used for their identification as well as methods of their preparation especially in regard to limitations of labile APIs. PMID- 27494529 TI - Novel Roles of Epoxyeicosanoids in Regulating Cardiac Mitochondria. AB - Maintenance of a healthy pool of mitochondria is important for the function and survival of terminally differentiated cells such as cardiomyocytes. Epoxyeicosatrienoic acids (EETs) are epoxy lipids derived from metabolism of arachidonic acid by cytochrome P450 epoxygenases. We have previously shown that EETs trigger a protective response limiting mitochondrial dysfunction and reducing cellular death. The aim of this study was to investigate whether EET mediated effects influence mitochondrial quality in HL-1 cardiac cells during starvation. HL-1 cells were subjected to serum- and amino acid free conditions for 24h. We employed a dual-acting synthetic analog UA-8 (13-(3 propylureido)tridec-8-enoic acid), possessing both EET-mimetic and soluble epoxide hydrolase (sEH) inhibitory properties, or 14,15-EET as model EET molecules. We demonstrated that EET-mediated events significantly improved mitochondrial function as assessed by preservation of the ADP/ATP ratio and oxidative respiratory capacity. Starvation induced mitochondrial hyperfusion observed in control cells was attenuated by UA-8. However, EET-mediated events did not affect the expression of mitochondrial dynamic proteins Fis1, DRP-1 or Mfn2. Rather we observed increased levels of OPA-1 oligomers and increased mitochondrial cristae density, which correlated with the preserved mitochondrial function. Increased DNA binding activity of pCREB and Nrf1/2 and increased SIRT1 activity together with elevated mitochondrial proteins suggest EET-mediated events led to preserved mitobiogenesis. Thus, we provide new evidence for EET mediated events that preserve a healthier pool of mitochondria in cardiac cells following starvation-induced stress. PMID- 27494531 TI - Predictors of Diet-Induced Weight Loss in Overweight Adults with Type 2 Diabetes. AB - AIMS: A very low calorie diet improves the metabolic regulation of obesity related type 2 diabetes, but not for all patients, which leads to frustration in patients and professionals alike. The aim of this study was to develop a prediction model of diet-induced weight loss in type 2 diabetes. METHODS: 192 patients with type 2 diabetes and BMI>27 kg/m2 from the outpatient diabetes clinic of the Erasmus Medical Center underwent an 8-week very low calorie diet. Baseline demographic, psychological and physiological parameters were measured and the C-index was calculated of the model with the largest explained variance of relative weight loss using backward linear regression analysis. The model was internally validated using bootstrapping techniques. RESULTS: Weight loss after the diet was 7.8+/-4.6 kg (95%CI 7.2-8.5; p<0.001) and was independently associated with the baseline variables fasting glucose (B = -0.33 (95%CI -0.49, 0.18), p = 0.001), anxiety (HADS; B = -0.22 (95%CI -0.34, -0.11), p = 0.001), numb feeling in extremities (B = 1.86 (95%CI 0.85, 2.87), p = 0.002), insulin dose (B = 0.01 (95%CI 0.00, 0.02), p = 0.014) and waist-to-hip ratio (B = 6.79 (95%CI 2.10, 11.78), p = 0.003). This model explained 25% of the variance in weight loss. The C-index of this model to predict successful (>=5%) weight loss was 0.74 (95%CI 0.67-0.82), with a sensitivity of 0.93 (95% CI 0.89-0.97) and specificity of 0.29 (95% CI 0.16-0.42). When only the obese T2D patients (BMI>=30 kg/m2; n = 181) were considered, age also contributed to the model (B = 0.06 (95%CI 0.02, 0.11), p = 0.008), whereas waist-to-hip ratio did not. CONCLUSIONS: Diet-induced weight loss in overweight adults with T2D was predicted by five baseline parameters, which were predominantly diabetes related. However, failure seems difficult to predict. We propose to test this prediction model in future prospective diet intervention studies in patients with type 2 diabetes. PMID- 27494532 TI - Prospects for subunit vaccines: Technology advances resulting in efficacious antigens requires matching advances in early clinical trial investment. AB - With the continued march of antimicrobial resistance, a renewed impetus for better vaccines has been heralded. Identification of potent subunit vaccines has been greatly facilitated by recent developments in reverse vaccinology and proteomics strategies. There are a range of antimicrobial resistant bacterial pathogens that could be targeted by potent vaccine antigens identified within the coming years. However, cost is a significant hurdle in progressing lead antigen candidates to clinical trials. In order for novel vaccine technologies to realize their clinical potential, there is a requirement to improve investment and incentives to expedite the development of vaccines that are apparently efficacious in preclinical trials. PMID- 27494533 TI - Chronic exposure to endosulfan induces inflammation in murine colon via beta catenin expression and IL-6 production. AB - Endosulfan (ENDO) is a widely used organochlorine (OC) pesticide and persistent organo-pollutant. Epidemiological studies have shown that high levels of OC exposure were related to colorectal cancer (CRC) incidence. The objectives of the present study were to evaluate histological changes in the colon, as well as in in situ expression of beta-catenin and P-selectin, and serum levels of select pro inflammatory cytokines in mice administered ENDO; there is a relationship between increased serum IL-6 and P-selectin levels in CRC patients and aberrant beta catenin signaling is important in initiation/maintenance of most CRCs. Mice were exposed to ENDO (at dose < LD50) orally once a week for up to 24 weeks, and monitored (inclusive) for a total of 42 weeks. The experiment was comprised of three groups, one that did not receive ENDO (olive oil vehicle), one administered 2 mg ENDO/kg/week and a positive control (for induction of CRC) given a weekly 20 mg 1,2-dimethylhydrazine (DMH)/kg injection. The results indicated that oral administration of ENDO provoked moderate inflammation starting at six weeks, and severe colonic inflammation with an appearance of dysplastic formations (aberrant crypts) in mice treated with ENDO (or DMH) for 12 weeks or longer. Serum IL-6 levels significantly increased starting at six weeks and rose to a peak of 15 fold higher than in controls at 42 weeks; TNFalpha levels likewise significantly increased, with a later peak (~four-fold higher than controls) at 30-42 weeks. Immunohistochemical analysis of the colon also showed that expression of beta catenin and P-selectin increased with length of exposure to ENDO. Taken together, the results indicate that continued repeated oral exposure to ENDO induces increased expression of beta-catenin and P-selectin, inflammation in the colon, and, ultimately, local tissue dysplasia. PMID- 27494534 TI - Boswellia serrata Protects Against Glutamate-Induced Oxidative Stress and Apoptosis in PC12 and N2a Cells. AB - This study was designed to investigate whether the extract from Boswellia serrata oleo-gum resin (BSE) can protect against glutamate-induced oxidative damage and cytotoxicity in PC12 and N2a cell lines. Using a simple and reliable reverse phase high-performance liquid chromatography (HPLC), the amount of 3-acetyl-11 keto-beta-boswellic acid (AKBA) in the BSE was found to be 18.5% w/w. The results confirmed that BSE and AKBA, at concentrations as high as 100 MUg/mL or 10 MUM, respectively, caused no significant cytotoxicity or apoptotic cell death. Co- and pretreatment with BSE (25-100 MUg/mL) or AKBA (5 MUM) restored the viability of PC12 and N2a cells under glutamate toxicity (8 mM). Treatment with BSE and AKBA also attenuated the toxic effects of glutamate on intracellular reactive oxygen species, lipid peroxidation, superoxide dismutase activity, and oxidative DNA damage compared with the untreated glutamate-injured cells. Furthermore, BSE and AKBA decreased the apoptotic cell population in the sub-G1 region and the rate of both early and late-stage apoptosis induced by glutamate in the cells. Our data suggest that the protective effects of Boswellia extract and AKBA against glutamate toxicity in PC12 and N2a cells may be mediated through the amelioration of the oxidative stress and the resultant apoptosis. PMID- 27494535 TI - Colloidal preparation and electrocatalytic hydrogen production of MoS2 and WS2 nanosheets with controllable lateral sizes and layer numbers. AB - Although layered transition metal dichalcogenide (TMD) nanosheets have attracted great attention due to their unique properties, it still remains challenge to develop a facile strategy for the precise control of the lateral sizes and layer numbers of TMD nanosheets. In this study, we demonstrate a solution-phase synthetic protocol to prepare colloidal MS2 (M = Mo, W) nanosheets which possess extremely small lateral dimensions from 15 to 40 nm and well-controlled odd numbers of layers, such as 1, 3, and 5 layers, as characterized by transmission electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy. The size- and layer-dependence of the optical properties of colloidal MS2 (M = Mo, W) nanosheets are revealed by Raman and absorption spectra for the first time. These colloidal nanosheets, especially the single-layer ones, possess a large number of edge sites that serve as active sites for the hydrogen evolution reaction (HER). The catalysts exhibit a small HER overpotential and low Tafel slope of approximately 100 mV and 52 mV per decade for MoS2, and 80 mV and 46 mV per decade for WS2, respectively. Importantly, these products show enhanced stability after 500 potential cycles, and the current density remains almost unchanged during the test. PMID- 27494536 TI - Residential greenness and blood lipids in children: A longitudinal analysis in GINIplus and LISAplus. AB - INTRODUCTION: There is some evidence of decreased cardiovascular disease (CVD) mortality and morbidity among adults residing in greener places. Among others, blood lipids are well established risk factors for CVD. In our previous study, we observed the inverse association between greenness and blood pressure in 10-year old children. In the current study, we investigated whether there is also a link between residential greenness and blood lipids in 10- and 15-year-old children. METHODS: Complete data on blood lipids (total cholesterol, HDL, LDL and triglyceride), residential greenness (NDVI in 100-m, 300- and 500-m buffers around residences) and confounders were available for 1,552 participants at 10 and 15 years of age, residing in two study areas of two German birth cohorts - GINIplus and LISAplus. Longitudinal associations between NDVI and blood lipids were assessed by generalized estimation equations. RESULTS: No associations were observed between residential greenness in any of the chosen buffers and blood lipids in children (e.g., change in blood lipids per interquartile increase in NDVI in 100-m buffer for total cholesterol and LDL: means ratio=1.00 (95% confidence interval: 0.99-1.01), for triglyceride: 0.98 (0.96-1.00)). No area- or sex-varying effects were evident. Change of the residence between 10 and 15 years also did not yield any consistent associations. CONCLUSIONS: There is no evidence of an association between greenness and blood lipids in 10- and 15-years old children. PMID- 27494538 TI - Are nails a valuable non-invasive alternative for estimating human exposure to phthalate esters? AB - Most human biomonitoring studies conducted in the past year for assessing the human exposure to phthalate esters (PEs) employed measurements of PE metabolites in urine. Although urine is recognized as a valuable non-invasive matrix, it has also limitations regarding the short time window for exposure. Therefore, in this pilot feasibility study we aimed to assess the human exposure to seven PE metabolites (including mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5 oxohexyl) phthalate (5-oxo-MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (5-OH MEHP), mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), monoethyl phthalate (MEP) and mono-benzyl phthalate (MBzP)) using human nails. Paired nails and urine samples from the same individuals were used for comparison. Median levels of specific PE metabolites measured in nails and in spot urine of twenty Belgian individuals ranged from [Ln(H2O)9]3+ + [An(BTP)3]3+ exchange reaction energies were evaluated, revealing Eu <-> Am and Gd <-> Cm reactions to favor the An species. Detailed QTAIM analysis of Eu, Gd, Am, and Cm complexes revealed increased covalent character in M-O and M-N bonds when M = An, with this increase being more pronounced in the BTP complexes. This therefore implies a small electronic contribution to An-N bond stability and the experimentally observed selectivity of the BTP ligand for Am and Cm over lanthanides. PMID- 27494550 TI - Eu(2+)-Activated Alkaline-Earth Halophosphates, M5(PO4)3X:Eu(2+) (M = Ca, Sr, Ba; X = F, Cl, Br) for NUV-LEDs: Site-Selective Crystal Field Effect. AB - Eu(2+)-activated M5(PO4)3X (M = Ca, Sr, Ba; X = F, Cl, Br) compounds providing different alkaline-earth metal and halide ions were successfully synthesized and characterized. The emission peak maxima of the M5(PO4)3Cl:Eu(2+) (M = Ca, Sr, Ba) compounds were blue-shifted from Ca to Ba (454 nm for Ca, 444 nm for Sr, and 434 nm for Ba), and those of the Sr5(PO4)3X:Eu(2+) (X = F, Cl, Br) compounds were red shifted along the series of halides, F -> Cl -> Br (437 nm for F, 444 nm for Cl, and 448 nm for Br). The site selectivity and occupancy of the activator ions (Eu(2+)) in the M5(PO4)3X:Eu(2+) (M = Ca, Sr, Ba; X = F, Cl, Br) crystal lattices were estimated based on theoretical calculation of the 5d -> 4f transition energies of Eu(2+) using LCAO. In combination with the photoluminescence measurements and theoretical calculation, it was elucidated that the Eu(2+) ions preferably enter the fully oxygen-coordinated sites in the M5(PO4)3X:Eu(2+) (M = Ca, Sr, Ba; X = F, Cl, Br) compounds. This trend can be well explained by "Pauling's rules". These compounds may provide a platform for modeling a new phosphor and application in the solid-state lighting field. PMID- 27494551 TI - Covalent Nitrogen Doping and Compressive Strain in MoS2 by Remote N2 Plasma Exposure. AB - Controllable doping of two-dimensional materials is highly desired for ideal device performance in both hetero- and p-n homojunctions. Herein, we propose an effective strategy for doping of MoS2 with nitrogen through a remote N2 plasma surface treatment. By monitoring the surface chemistry of MoS2 upon N2 plasma exposure using in situ X-ray photoelectron spectroscopy, we identified the presence of covalently bonded nitrogen in MoS2, where substitution of the chalcogen sulfur by nitrogen is determined as the doping mechanism. Furthermore, the electrical characterization demonstrates that p-type doping of MoS2 is achieved by nitrogen doping, which is in agreement with theoretical predictions. Notably, we found that the presence of nitrogen can induce compressive strain in the MoS2 structure, which represents the first evidence of strain induced by substitutional doping in a transition metal dichalcogenide material. Finally, our first principle calculations support the experimental demonstration of such strain, and a correlation between nitrogen doping concentration and compressive strain in MoS2 is elucidated. PMID- 27494552 TI - Support Persons' Perceptions of Giving Vocational Rehabilitation Support to Clients With Acquired Brain Injury in Sweden. AB - The aim of this article is to explore the perception of being a support person for clients with acquired brain injury undergoing vocational rehabilitation. Nine support persons, identified by clients with brain injury, were interviewed. Interviews were analyzed using qualitative content analysis, resulting in 3 themes for assisting the client: commitment, adaptation, and cooperation. Within each theme, multiple dimensions were identified, reflecting the complexity of vocational rehabilitation following acquired brain injury. Commitment built on social relations is linked to sustainability of support. The included support persons' role was especially valuable in contexts where adaptation and cooperation were required. PMID- 27494553 TI - Graphene Quantum Dot-MnO2 Nanosheet Based Optical Sensing Platform: A Sensitive Fluorescence "Turn Off-On" Nanosensor for Glutathione Detection and Intracellular Imaging. AB - Glutathione (GSH) monitoring has attracted extensive attention because it serves a vital role in human pathologies. Herein, a convenient fluorescence "turn off on" nanosensor based on graphene quantum dots (GQDs)-manganese dioxide (MnO2) nanosheet has been designed for selective detection of GSH in living cells. The fluorescence intensity of GQDs can be quenched by MnO2 nanosheets via a fluorescence resonance energy transfer. However, GSH can reduce MnO2 nanosheets to Mn(2+) cations and release GQDs, causing sufficient recovery of fluorescent signal. The MnO2 nanosheets serve as both fluorescence nanoquencher and GSH recognizer in the sensing platform. The sensing platform displayed a sensitive response to GSH in the range of 0.5-10 MUmol L(-1), with a detection limit of 150 nmol L(-1). Furthermore, the chemical response of the GQDs-MnO2 nanoprobe exhibits high selectivity toward GSH over other electrolytes and biomolecules. Most importantly, the promising platform was successfully applied in monitoring the intracellular GSH in living cells, indicating its great potential to be used in disease diagnosis. Meanwhile, this GQDs-MnO2 platform is also generalizable and can be easily expanded to the detection and imaging of other reactive species in living cells. PMID- 27494554 TI - Attaching Accessory Devices to the Replisome. AB - Evidence mounts, via two studies published in Molecular Cell (Villa et al. 2016; Samora et al. 2016), that Ctf4 recruits to the replisome various factors that play diverse roles in chromosome duplication, by acting as an interaction hub. PMID- 27494555 TI - Who Put the "A" in ATP? Generation of ATP from ADP-Ribose in the Nucleus for Hormone-Dependent Gene Regulation. AB - In a recent issue of Science, Wright et al. (2016) describe a pathway for the synthesis of nuclear ATP, leading from NAD(+) to poly(ADP-ribose) to ADP-ribose to ATP, which supports the activity of ATP-dependent chromatin remodeling enzymes during hormone-dependent transcription. PMID- 27494556 TI - Who Is in the Driver's Seat: Tracing Cancer Genes Using CRISPR-Barcoding. AB - Intratumor heterogeneity is thought to be the driving force of tumor evolution and therapy resistance. Yet tools to study these processes are limited. In this issue, Guernet et al. (2016) devised clustered regularly interspaced short palindromic repeats (CRISPR)-barcoding to functionally annotate specific mutations and study clonal evolution in heterogeneous cell populations. PMID- 27494559 TI - K63-Ubiquitylation and TRAF6 Pathways Regulate Mammalian P-Body Formation and mRNA Decapping. PMID- 27494557 TI - Methods for Optimizing CRISPR-Cas9 Genome Editing Specificity. AB - Advances in the development of delivery, repair, and specificity strategies for the CRISPR-Cas9 genome engineering toolbox are helping researchers understand gene function with unprecedented precision and sensitivity. CRISPR-Cas9 also holds enormous therapeutic potential for the treatment of genetic disorders by directly correcting disease-causing mutations. Although the Cas9 protein has been shown to bind and cleave DNA at off-target sites, the field of Cas9 specificity is rapidly progressing, with marked improvements in guide RNA selection, protein and guide engineering, novel enzymes, and off-target detection methods. We review important challenges and breakthroughs in the field as a comprehensive practical guide to interested users of genome editing technologies, highlighting key tools and strategies for optimizing specificity. The genome editing community should now strive to standardize such methods for measuring and reporting off-target activity, while keeping in mind that the goal for specificity should be continued improvement and vigilance. PMID- 27494558 TI - Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-beta Catenin Signaling. AB - The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-beta-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active beta-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymerizing TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochemical studies informed by these structures demonstrate that polymerization is required for Tankyrase to drive beta-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling. PMID- 27494560 TI - Linker-Mediated Self-Assembly Dynamics of Charged Nanoparticles. AB - Using in situ liquid cell transmission electron microscopy (TEM), we visualized a stepwise self-assembly of surfactant-coated and hydrated gold nanoparticles (NPs) into linear chains or branched networks. The NP binding is facilitated by linker molecules, ethylenediammonium, which form hydrogen bonds with surfactant molecules of neighboring NPs. The observed spacing between bound neighboring NPs, ~15 A, matches the combined length of two surfactants and one linker molecule. Molecular dynamics simulations reveal that for lower concentrations of linkers, NPs with charged surfactants cannot be fully neutralized by strongly binding divalent linkers, so that NPs carry higher effective charges and tend to form chains, due to poor screening. The highly polar NP surfaces polarize and partly immobilize nearby water molecules, which promotes NPs binding. The presented experimental and theoretical approach allows for detail observation and explanation of self-assembly processes in colloidal nanosystems. PMID- 27494562 TI - Sphingosine-1-phosphate receptor: a novel therapeutic target in ulcerative colitis. PMID- 27494563 TI - The use of spent mushroom compost to enhance the ability of Atriplex halimus to phytoremediate contaminated mine soils. AB - The mushroom cultivation industry produces a huge amount of spent mushroom compost (SMC), a wide world agricultural organic waste which causes serious environmental problems. However, this cheap organic waste could be useful in the remediation of contaminated soils. The aim of this work was to assess the potential of SMC in combination with the native shrub Atriplex halimus, to phytoremediate two mine soils contaminated with Cd, Pb and Cu. Firstly, to minimize metal availability in the soil, the optimal doses of SMC were determined. Secondly, a phytoremediation assay in greenhouse conditions was carried out to test the effects of A. halimus in combination with SMC at different doses. The results showed the ability of SMC to reduce soil acidity, the mobility of the metals and the enhancement of A. halimus growth. SMC promoted metal immobilization in the root of A. halimus and decreased the translocation from the roots to the shoots. The combination of SMC amendment and A. halimus produced phytostabilization of the metals in the mine soils assayed. In conclusion, SMC represents an adequate organic solid waste which in combination with A. halimus can reduce the adverse impact caused by the high mobility of metals in acid mine soils. PMID- 27494564 TI - Confidence-Competence Mismatch and Reasons for Failure of Non-Medical Tourniquet Users. AB - OBJECTIVE: Tourniquet application is a lifesaving skill taught worldwide in first aid bleeding control courses. We observed performance among non-medical users of tourniquets in their confidence, competence, and reasons for failure. METHODS: 179 Israeli military recruits without prior medical training underwent their standard first aid course where they learned Combat Application Tourniquet (CAT; Composite Resources, Rock Hill, SC, USA) use. After course completion, they self reported confidence in tourniquet use. User performance was assessed 7-14 days later using a HapMedTM mannequin that assessed time, pressure, and blood loss. Competent performance required in aggregate: 1) use with pressure of 200 mmHg or more, 2) hemorrhage volume of less than 638 mL, and 3) correct placement of the tourniquet. For failed performance, a reason for failure was reported independently by both the user and an expert observer. RESULTS: 45 of 179 user performances (25%) were competent. Users who reported high confidence had only a slightly higher chance of achieving competence in tourniquet application (r = 0.17, p = 0.022). The most common reason for failure was excess slack in the CAT's strap (experts 55%, users 39%), and too few turns of the windlass (23% and 31%, respectively) was the second most common reason. Expert and user evaluations had poor agreement (kappa = 0.44, 95% CI 0.32-0.56). CONCLUSION: The most common reason for failed use of tourniquets among non-medical users was excess slack in the tourniquet strap. Users self-evaluated their performance inaccurately and demonstrated a confidence-competence mismatch. These pitfalls in performance may help tourniquet instructors improve training of caregivers. PMID- 27494565 TI - Effects of growth temperature and carbon dioxide enrichment on soybean seed components at different stages of development. AB - Soybean plants were grown to maturity in controlled environment chambers and at the onset of flowering three temperature treatments were imposed that provided optimum [28/24 degrees C], low [22/18 degrees C] or high [36/32 degrees C] chamber air temperatures. In addition, plants were treated continuously with either 400 or 800 MUmol mol-1 CO2. Seeds were harvested at 42, 53, 69 and 95 days after planting (i.e., final maturity). This study quantified 51 metabolites in developing soybean seeds, plus total lipids and proteins were measured at maturity. About 80% of measured soluble carbohydrates, amines and organic acids decreased to low levels in mature seeds, although important exceptions were raffinose, ribose/arabinose, citrate and all eight fatty acids. This suggested that the metabolism of young seeds supported lipid and protein synthesis. A total of 35 and 9 metabolites differed among temperature and CO2 treatments, respectively, and treatment effects were predominately observed on the first and second samplings. However, shikimate, pinitol and oleate were increased by high temperature treatments in mature seeds. The above results indicated that CO2 enrichment primarily altered metabolite levels during the initial stages of seed development and this was likely due to enhanced photosynthate formation in leaves. PMID- 27494566 TI - Dual contribution of surface charge and protein-binding affinity to the cytotoxicity of polystyrene nanoparticles in nonphagocytic A549 cells and phagocytic THP-1 cells. AB - Knowledge that links the physicochemical properties of nanoparticles (NP) to their toxicity is key to evaluating and understanding mechanisms underlying toxicity and developing appropriate testing methods for NP; however, this is currently limited since only a small set of NP have been used, with typically poor control of their physical properties. In this study, eight types of polystyrene NP (PLNP) were synthesized with different functional groups, but all based on an identical core. In vitro cell-based assays were performed to determine the influence of changes in physicochemical properties, such as charge, hydrodynamic size, and protein binding potential, in relation to NP-mediated toxicity. The PLNP were incubated with nonphagocytic A549 cells or phagocytic differentiated THP-1 cells for 4 h with/without fetal bovine serum (FBS), followed by incubation for 20 h in FBS-supplemented medium with/without a washing step, to assess cell-type specificity and impact of protein corona formation. The effect of surface charge on cytotoxicity differed between A549 cells and THP-1 cells. In nonphagocytic A549 cells, the zeta potential of PLNP exhibited a negative correlation with cytotoxicity, partly due to the level of coronated protein that might affect cellular uptake. In phagocytic THP-1 cells, the zeta potential of PLNP showed a positive correlation with cytotoxicity but coronated protein levels displayed no marked association with cytotoxicity, owing to the professional uptake efficacy of phagocytic cells. The consistency of our data with THP-1 cells with the surface charge paradigm in nanotoxicology suggests that phagocytic cells are the predominant targets for lung inflammatory reactions induced by PLNP. PMID- 27494567 TI - Ultrafast Time-Resolved Emission and Absorption Spectra of meso-Pyridyl Porphyrins upon Soret Band Excitation Studied by Fluorescence Up-Conversion and Transient Absorption Spectroscopy. AB - A comprehensive study of ultrafast molecular relaxation processes of isomeric meso-(pyridyl) porphyrins (TpyPs) has been carried out by using femtosecond time resolved emission and absorption spectroscopic techniques upon pumping at 400 nm, Soret band (B band or S2), in 4:1 dichloromethane (DCM) and tetrahydrofuran (THF) solvent mixture. By combined studies of fluorescence up-conversion, time correlated single photon counting, and transient absorption spectroscopic techniques, a complete model with different microscopic rate constants associated with elementary processes involved in electronic manifolds has been reported. Besides, a distinct coherent nuclear wave packet motion in Qy state is observed at low-frequency mode, ca. 26 cm(-1) region. Fluorescence up-conversion studies constitute ultrafast time-resolved emission spectra (TRES) over the whole emission range (430-710 nm) starting from S2 state to Qx state via Qy state. Careful analysis of time profiles of up-converted signals at different emission wavelengths helps to reveal detail molecular dynamics. The observed lifetimes are as indicated: A very fast decay component with 80 +/- 20 fs observed at ~435 nm is assigned to the lifetime of S2 (B) state, whereas being a rise component in the region of between 550 and 710 nm emission wavelength pertaining to Qy and Qx states, it is attributed to very fast internal conversion (IC) occurring from B > Qy and B -> Qx as well. Two distinct components of Qy emission decay with ~200 300 fs and ~1-1.5 ps time constants are due to intramolecular vibrational redistribution (IVR) induced by solute-solvent inelastic collisions and vibrational redistribution induced by solute-solvent elastic collision, respectively. The weighted average of these two decay components is assigned as the characteristic lifetime of Qy, and it ranges between 0.3 and 0.5 ps. An additional ~20 +/- 2 ps rise component is observed in Qx emission, and it is assigned to the formation time of thermally equilibrated Qx state by vibrational cooling/relaxations of excess energy within solvent. This relaxed Qx state decays to ground as well as triplet state by 7-8 ns time scale. The femtosecond transient absorption studies of TpyPs in three different excitations at S2 (400 nm), Qy (515 nm), and Qx (590 nm) along with extensive global and target model analysis of TA data exclusively generate the true spectra of each excited species/state with their respective lifetimes along with microscopic rate constants associated with each state. The following five exponential components with lifetime values of 65-70 fs, ~0.3-0.5 ps, ~20 +/- 2 ps, ~7 +/- 1 ns, and 1-2 MUs are observed which are associated with S2, Qy, hot Qx, thermally relaxed Qx, and lowest triplet (T1) states, respectively, when excited at S2, and four (Qy, hot Qx, thermally relaxed Qx, and lowest triplet (T1) states) and three (hot Qx, thermally relaxed Qx, and lowest triplet (T1) states) states are obtained when excited at 515 nm (Qy) and 590 nm (Qx), respectively, as expected. The TA results parallel the fluorescence up-conversion studies, and both the results not only compliment each other but also unveil the ultrafast internal conversion from S2 to Qy, S2 to Qx, and Qy to Qx for all three isomers in a similar fashion with nearly equal characteristic decay times. PMID- 27494568 TI - Views and experience of communication when receiving a serious mental health diagnosis: satisfaction levels, communication preferences, and acceptability of the SPIKES protocol. AB - BACKGROUND: There is limited research investigating how information about a mental health diagnosis is discussed and received. AIMS: To measure community based service users' satisfaction and preferences toward receiving news of a serious mental health diagnosis and to assess the acceptability of a diagnostic communication protocol (SPIKES: Setting; Perception; Invitation; Knowledge; Empathy; Summarizing). METHOD: A survey was conducted with 101 participants. RESULTS: Participants rated the methods clinicians use to facilitate diagnostic discussions are highly important; however, they were not wholly satisfied with their experience. Higher satisfaction was reported if participants were provided with information in a face-to-face meeting (p < 0.001), and if they received supplementary support at the time of diagnosis from additional health professionals rather than only a sole practitioner (p < 0.001). The SPIKES protocol was rated as highly acceptable, with Empathy being rated as the most important feature. CONCLUSIONS: This research indicates there were specific areas of communication practices which can be improved within mental health service provision, as a gap existed between participants' desire for support and their experience. Strategies outlined in the SPIKES protocol, and others such as addressing stigma concerns, may prove useful in development of clinician training and service improvement. PMID- 27494569 TI - Birth Satisfaction Scale/Birth Satisfaction Scale-Revised (BSS/BSS-R): A large scale United States planned home birth and birth centre survey. AB - OBJECTIVE: to explore the prevalence of birth satisfaction for childbearing women planning to birth in their home or birth centers in the United States. Examining differences in birth satisfaction of the home and birth centers; and those who birthed in a hospital using the 30-item Birth Satisfaction Scale (BSS) and the 10 item Birth Satisfaction Scale-Revised (BSS-R). STUDY DESIGN: a quantitative survey using the BSS and BSS-R were employed. Additional demographic data were collected using electronic linkages (QualtricsTM). PARTICIPANTS: a convenience sample of childbearing women (n=2229) who had planned to birth in their home or birth center from the US (United States) participated. Participants were recruited via professional and personal contacts, primarily their midwives. RESULTS: the total 30-item BSS score mean was 128.98 (SD 16.92) and the 10-item BSS-R mean score was 31.94 (SD 6.75). Sub-scale mean scores quantified the quality of care provision, women's personal attributes, and stress experienced during labour. Satisfaction was higher for women with vaginal births compared with caesareans deliveries. In addition, satisfaction was higher for women who had both planned to deliver in a home or a birth centre, and who had actually delivered in a home or a birth center. KEY CONCLUSIONS: total and subscale birth satisfaction scores were positive and high for the overall sample IMPLICATIONS FOR PRACTICE: the BSS and the BSS-R provide a robust tool to quantify women's experiences of childbirth between variables such as birth types, birth settings and providers. PMID- 27494561 TI - Image-guided ultrasound phased arrays are a disruptive technology for non invasive therapy. AB - Focused ultrasound offers a non-invasive way of depositing acoustic energy deep into the body, which can be harnessed for a broad spectrum of therapeutic purposes, including tissue ablation, the targeting of therapeutic agents, and stem cell delivery. Phased array transducers enable electronic control over the beam geometry and direction, and can be tailored to provide optimal energy deposition patterns for a given therapeutic application. Their use in combination with modern medical imaging for therapy guidance allows precise targeting, online monitoring, and post-treatment evaluation of the ultrasound-mediated bioeffects. In the past there have been some technical obstacles hindering the construction of large aperture, high-power, densely-populated phased arrays and, as a result, they have not been fully exploited for therapy delivery to date. However, recent research has made the construction of such arrays feasible, and it is expected that their continued development will both greatly improve the safety and efficacy of existing ultrasound therapies as well as enable treatments that are not currently possible with existing technology. This review will summarize the basic principles, current statures, and future potential of image-guided ultrasound phased arrays for therapy. PMID- 27494571 TI - The value of mortality risk reductions. Pure altruism - a confounder? AB - This paper examines public valuations of mortality risk reductions. We set up a theoretical framework that allows for altruistic preferences, and subsequently test theoretical predictions through the design of a discrete choice experiment. By varying the tax scenario (uniform versus individual tax), the experimental design allows us to verify whether pure altruistic preferences are present and the underlying causes. We find evidence of negative pure altruism. Under a coercive uniform tax system respondents lower their willingness to pay possibly to ensure that they are not forcing others to pay at a level that corresponds to their own - higher - valuations. This hypothesis is supported by the observation that respondents perceive other individuals' valuations to be lower than their own. Our results suggest that public valuations of mortality risk reductions may underestimate the true societal value because respondents are considering other individuals' welfare, and wrongfully perceive other people's valuations to be low. PMID- 27494570 TI - A multicentre, open-label, randomised phase III study comparing a new levonorgestrel intrauterine contraceptive system (LNG-IUS 8) with combined oral contraception in young women of reproductive age. AB - OBJECTIVES: To compare user satisfaction and adverse events (AEs) with a levonorgestrel intrauterine system (LNG-IUS 8; average levonorgestrel release rate approximately 8 MUg/24 h over the first year [total content 13.5 mg]) and a 30 MUg ethinyl estradiol/3 mg drospirenone (EE/DRSP) combined oral contraceptive (COC) in a population of young women. METHODS: Nulliparous and parous women (aged 18-29 years) with regular menstrual cycles (21-35 days) were randomised to LNG IUS 8 or EE/DRSP for 18 months. The primary endpoint was the overall user satisfaction rate at month 18/end of study visit. RESULTS: Overall, 279 women were randomised to LNG-IUS 8 with attempted placement and 281 women were randomised to EE/DRSP and took >=1 pill; the mean age was 23.7 and 23.9 years, and 77.4% and 73.3% were nulliparous, respectively. At month 18/end of study, 82.1% and 81.9% of women, respectively, reported being 'very satisfied' or 'satisfied' with their treatment; however, significantly more LNG-IUS 8 users reported a preference to continue their treatment post-study (66.2% vs 48.8%; p = 0.0001). There were two pregnancies (one ectopic pregnancy, one spontaneous abortion) reported in the LNG-IUS 8 group and six (three live births, two spontaneous abortions, one induced abortion) in the EE/DRSP group. CONCLUSIONS: LNG-IUS 8 and EE/DRSP were associated with similarly high user satisfaction rates. However, LNG-IUS 8 users were significantly more likely to prefer to continue their contraceptive method post-study, indicating that a levonorgestrel intrauterine system is an appealing contraceptive option for young women. PMID- 27494572 TI - Therapist interventions and client ambivalence in two cases of narrative therapy for depression. AB - AIM: We understand ambivalence as a cycle of opposing expressions by two internal voices. The emergence of a suppressed voice produces an innovative moment (IM), challenging the dominant voice, which represents the client's problematic self narrative. The emergence of the IM is opposed by the dominant voice, leading to a return to the problematic self-narrative. This study analyzed therapist and client responses to each other in episodes of ambivalence. METHOD: The therapeutic collaboration coding system (TCCS) assesses whether and how the therapeutic dyad is working within the therapeutic zone of proximal development (TZPD) by examining client responses to therapist interventions. We applied the TCCS to episodes in which a good- and a poor-outcome client in narrative therapy expressed ambivalence. RESULTS: In both the good- and poor-outcome cases, the therapist responded to the emergence of ambivalence similarly, balancing challenging and supporting. The good-outcome case responded at the developmental level proposed by the therapist when challenged, while the poor-outcome case lagged behind the level proposed. DISCUSSION: This supports the theoretical explanation that the therapist did not match client's developmental level in the poor-outcome case, working beyond the client's current TZPD and contributing to the maintenance of ambivalence. PMID- 27494573 TI - An Exploratory Study Investigating How Adults with Intellectual Disabilities Perform on the Visual Association Test (VAT). AB - BACKGROUND: Neuropsychological tests of memory are believed to offer the greatest sensitivity at identifying people at the risk of developing dementia. There is a paucity of standardized and appropriate neuropsychological assessments of memory for adults with an intellectual disability. This study examines how adults with an intellectual disability perform on the Visual Association Test (VAT). METHODS: Forty participants (18-45 years) with intellectual disability, without a diagnosis of dementia, completed the VAT and subtests of the CAMCOG-DS. Correlational analysis of the test variables was carried out. RESULTS: All participants performed well on the VAT irrespective of age, gender or IQ. No significant correlations were found between the VAT and the subtests of the CAMCOG-DS. CONCLUSIONS: The VAT was found to be an easy and quick test to use with people with intellectual disability and all participants scored above 'floor' level. PMID- 27494575 TI - Challenging Problems in Rhinoplasty. PMID- 27494574 TI - Atypical VZV Retinitis in a Patient with Good Syndrome. AB - PURPOSE: To describe atypical varicella zoster virus (VZV) retinitis in a patient with Good syndrome. METHODS: A 63-year-old patient with Good syndrome presented with bilateral necrotizing retinitis starting from the posterior pole. He had a history of thymoma status post thymectomy 4 years previously, left-sided sinusitis, and recent pulmonary aspergillosis. Qualitative PCR was performed on aqueous fluid. RESULTS: Immunological investigations revealed reduced levels of CD4+ T cells and immunoglobulins. Qualitative PCR was positive for VZV and negative for cytomegalovirus, herpes simplex virus (HSV)-1, and HSV-2. The patient was treated with oral valacyclovir and three courses of immunoglobulin supplementation. The atypical retinitis showed improvement after therapy. CONCLUSION: Good syndrome should be considered in a patient with opportunistic infections and history of thymoma in the absence of human immunodeficiency virus. Atypical retinitis can occur in patients with Good syndrome and quantitative PCR is important for accurate diagnosis. PMID- 27494576 TI - Columellar Aesthetics in Open Rhinoplasty. AB - Detailed descriptions of the ideals of columellar aesthetics and nostril shape are conspicuously lacking from the medical literature. Achieving an aesthetic nasal base is critical to an optimal rhinoplasty result. Deviations in the columella and variations in its width and height lead to distortion of nostril shape and frequently compromise function. Six types of columellar disproportion are presented with detailed explanations of how to treat each. By properly recognizing and addressing columellar deformities, the surgeon can optimize both the aesthetic and functional results that are achieved. PMID- 27494577 TI - Nasal Soft-Tissue Triangle Deformities. AB - The soft-tissue triangle is one of the least areas attended to in rhinoplasty. Any postoperative retraction, notching, or asymmetries of soft triangles can seriously affect the rhinoplasty outcome. A good understanding of the risk factors predisposing to soft triangle deformities is necessary to prevent such problems. The commonest risk factors in our study were the wide vertical domal angle between the lateral and intermediate crura, and the increased length of intermediate crus. Two types of soft triangle grafts were described to prevent and treat soft triangle deformities. The used soft triangle grafts resulted in an excellent long-term aesthetic and functional improvement. PMID- 27494578 TI - Refining the Nasal Dorsum with Free Diced Cartilage. AB - Refining the nasal dorsum has become a major challenge in modern rhinoplasty as irregularities of the nasal dorsum account for a significant number of revision surgeries. In our department, free diced cartilage is now routinely applied for smoothening of the nasal dorsum. In this retrospective study, the outcomes with regard to irregularities or contour deficits of the nasal dorsum of 431 rhinoplasty cases operated by a single surgeon between July 2013 and June 2015, using free diced cartilage, are compared with 327 cases operated by the same surgeon between January 2007 and December 2008, before the introduction of the free diced cartilage technique. A decrease in early revision surgeries (i.e., revision within the 2-year period evaluated) due to dorsal irregularities or contour deficits is seen. Being a quick, easy, and highly cost-effective procedure, we feel that free diced cartilage is currently the ideal technique for refinements of the nasal dorsum. PMID- 27494579 TI - Septal Surgery Challenges in Rhinoplasty. AB - During rhinoplasty, the most stressful areas of the nasal cartilaginous septum are at the key area and anterior nasal spine. A stable fixation of the caudal septum to respond to these stresses is of utmost importance. The prerequisite for a successful fixation is a well-prepared recipient bed for caudal septum and suture fixation. The bed can be opened by using scissors, osteotome, or powered instrumentation. Simple or multiple sutures passing from the bone and/or surrounding soft tissues are used for fixation. At the key area, if a complete separation of the L-strut occurs, it should be sutured to nasal bones and upper lateral cartilages. The septum should be supported by splinting spreader grafts to increase stability. To prevent dorsal irregularities, a dorsal onlay camouflage graft should be used. The best way is to take cautions to prevent such a mishap. That is why a dorsal segment of 12 to 15 mm should be preserved, at least at the key area, and part of the mucoperichondrium should stay attached to the septum. PMID- 27494580 TI - Rhinoplasty: The Asymmetric Crooked Nose-An Overview. AB - There are three reasons why the asymmetric crooked nose is one of the greatest challenges in rhinoplasty surgery. First, the complexity of the problem is not appreciated by the patient nor understood by the surgeon. Patients often see the obvious deviation of the nose, but not the distinct differences between the right and left sides. Surgeons fail to understand and to emphasize to the patient that each component of the nose is asymmetric. Second, these deformities can be improved, but rarely made flawless. For this reason, patients are told that the result will be all "-er words," better, straighter, cuter, but no "t-words," there is no perfect nor straight. Most surgeons fail to realize that these cases represent asymmetric noses on asymmetric faces with the variable of ipsilateral and contralateral deviations. Third, these cases demand a wide range of sophisticated surgical techniques, some of which have a minimal margin of error. This article offers an in-depth look at analysis, preoperative planning, and surgical techniques available for dealing with the asymmetric crooked nose. PMID- 27494581 TI - Options for Middle Vault and Dorsum Restoration after Hump Removal in Primary Rhinoplasty. AB - Prevention of unfavorable sequelae following humpectomy in reduction rhinoplasty by restoration of the middle nasal vault complex today has become imperative in the majority of patients with perhaps the exception of small humps. In general, the techniques used for preservation and reconstruction of these important anatomical structures can be divided into two main categories: spreader graft and spreader flap techniques. Oversimplified spreader graft techniques require donor cartilage, whereas spreader flap techniques use the excess height of the medial portion of the upper lateral cartilages in patients with a cartilaginous hump. In principle, both donor cartilage and preserved upper lateral cartilages usually are positioned along both sides of the dorsal septum to provide natural and harmonious contours as well as to avoid functional impairment (valve collapse). However, the considerable number of publications on this topic attests to existing downsides of both surgical principles. To overcome these shortcomings, we illustrate additional modifications in the application of spreader grafts as well as spreader flaps. However, the main goal of this article is to provide an algorithm helping to decide which technique is best suited to meet the requirements of each individual patient. PMID- 27494582 TI - The Articulated Alar Rim Graft: Reengineering the Conventional Alar Rim Graft for Improved Contour and Support. AB - Surgical refinement of the wide nasal tip is challenging. Achieving an attractive, slender, and functional tip complex without destabilizing the lower nasal sidewall or deforming the contracture-prone alar rim is a formidable task. Excisional refinement techniques that rely upon incremental weakening of wide lower lateral cartilages (LLC) often destabilize the tip complex and distort tip contour. Initial destabilization of the LLC is usually further exacerbated by "shrink-wrap" contracture, which often leads to progressive cephalic retraction of the alar margin. The result is a misshapen tip complex accentuated by a conspicuous and highly objectionable nostril deformity that is often very difficult to treat. The "articulated" alar rim graft (AARG) is a modification of the conventional rim graft that improves treatment of secondary alar rim deformities, including postsurgical alar retraction (PSAR). Unlike the conventional alar rim graft, the AARG is sutured to the underlying tip complex to provide direct stationary support to the alar margin, thereby enhancing graft efficacy. When used in conjunction with a well-designed septal extension graft (SEG) to stabilize the central tip complex, lateral crural tensioning (LCT) to tighten the lower nasal sidewalls and minimize soft-tissue laxity, and lysis of scar adhesions to unfurl the retracted and scarred nasal lining, the AARG can eliminate PSAR in a majority of patients. The AARG is also highly effective for prophylaxis against alar retraction and in the treatment of most other contour abnormalities involving the alar margin. Moreover, the AARG requires comparatively little graft material, and complications are rare. We present a retrospective series of 47 consecutive patients treated with the triad of AARG, SEG, and LCT for prophylaxis and/or treatment of alar rim deformities. Outcomes were favorable in nearly all patients, and no complications were observed. We conclude the AARG is a simple and effective method for avoiding and correcting most alar rim deformities. PMID- 27494583 TI - Pollybeak Deformity in Middle Eastern Rhinoplasty: Prevention and Treatment. AB - The pollybeak deformity is one of the commonest causes of revision rhinoplasty. The Middle Eastern nose has certain criteria that predispose to the development of pollybeak deformity. The aim of this study is to detect the factors contributing to the development of pollybeak deformity in the Middle Eastern nose and methods used to prevent as well as to treat such deformity. Out of the 1,160 revision patients included in this study, 720 (62%) patients had a pollybeak deformity. The commonest contributing factors included underprojected tip with poor support in 490 (68%) patients, excessive supratip scarring in 259 (36%) patients, overresected bony dorsum in 202 (28%) patients, and high anterior septal angle in 173 (24%) patients. The methods used by the authors to treat the pollybeak deformity are described, along with the local steroid injection protocol used to guard against the recurrence of pollybeak deformity. PMID- 27494584 TI - Modern Rhinoplasty: Is There a Place for the Closed Approach? AB - Rhinoplasty is one of the most commonly performed cosmetic surgeries and, in many cases, an elective procedure. Therefore, it is crucial to assess the functional and aesthetic issues of the patient accurately and devise the proper surgical strategy most beneficial to the patient. Modern rhinoplasties can be approached by two distinct techniques: the open technique or the closed, endonasal technique. While most rhinosurgeons today prefer the open procedure due its superior access to the nasal scaffold and overview over the surgical field in particular, we highlight in this article techniques and benefits of endonasal rhinoplasty and critically discuss situations where such an approach yields superior results. Each rhinoplasty procedure, with its inherent strengths and weaknesses, has to be matched with a given nasal condition and the desired results to offer the maximum benefit to the patient. Therefore, each rhinosurgeon should be knowledgeable and trained in the endonasal technique. Open rhinosurgery is not always necessary and may even be disadvantageous in some cases. PMID- 27494585 TI - Revision Rhinoplasty: What Can We Learn from Error Patterns? An Analysis of Revision Surgery. AB - Of the many challenges in rhinoplasty, achieving a satisfactory outcome at the first operation is important. There are multiple reasons for secondary surgery, and generally revisions can be broadly classified into minor (often one area of deficit) or a total redo. Understanding the common technical reasons for failure in primary surgery by analyzing the deformities has resulted in various error patterns emerging. Understanding these patterns means we can modify techniques in primary surgery to reduce the incidence of revision. This article describes our prospective revision rhinoplasty experience over 5 and then 2 years, highlighting the main error patterns encountered. We also describe a stepwise analysis of four frequently encountered key problem areas alongside techniques to address them and offer pearls to help prevent further revision. Comparison of two cohorts of patients from a teaching hospital setting and private practice with the same operating surgeon indicates an increasing tendency to the open approach for revisions. The re-revision rates for these groups are 15.7 and 9%, respectively. Revision rhinoplasty is a difficult operation to perform to the satisfaction of both the surgeon and the patient. Understanding the common technical reasons for failure in primary surgery by fully analyzing the deformities means we can modify techniques in primary surgery to reduce the incidence of revision. PMID- 27494586 TI - The Tongue-in-Groove Technique in Primary and Revision Rhinoplasty. AB - The tongue-in-groove (TIG) is a conservative but powerful surgical suture technique to control tip rotation and projection, to set an appropriate alar columellar relationship, to straighten a caudal septal deviation, and to stabilize the nasal base. TIG is suitable in primary and most revision cases and is easily combined with other surgical techniques. Seventeen years after its popularization, the TIG technique is embedded in modern-day rhinoplasty literature and teaching material. This article describes indications and considerations during external primary and revision rhinoplasty, based on clinical experience and the available literature. PMID- 27494587 TI - Contemporary Issues in the Open Management of Subcondylar Fractures of the Mandible. AB - Subcondylar fractures encompass a large portion of mandible fractures. Owing to their proximity to the temporomandibular joint and difficulty achieving surgical exposure, treatment of these fractures has been challenging and highly debated throughout the literature. While no one modality is the accepted gold standard, there are multiple options for addressing these fractures that can yield satisfying results for both patient and surgeon alike. A thorough literature review was conducted using PubMed, analyzing articles in the past 15 years for relevance to the subject matter. Various search terms were used to glean information regarding closed treatment, open treatment, and the risks and benefits of the different surgical approaches involved. The articles were reviewed by all of the authors for applicability and quality of data provided. A total of 50 articles were selected for inclusion in the current study. The open management of subcondylar fractures encompasses a vast array of techniques. While some surgeons advocate closed treatment in some circumstances, open treatment affords numerous advantages with the advent of multiple access modalities. There is no single superior method, and as such, the craniofacial surgeon should have a comprehensive understanding of options so as to select the appropriate option that is individualized to the patient. A clear understanding of fracture biomechanics balanced with patient expectations and operative safety allows for the surgeon to make a sound decision for treatment. PMID- 27494588 TI - Evaluation of the Effect of Bosentan-Mediated Endothelin Receptor Blockade on Flap Survival in Rats: An Experimental Study. AB - Local skin flaps are important tools for performing plastic surgery. Skin flaps are used for closure of defects after tumor excision or in tissue losses after trauma. However, problems associated with these flaps are commonly encountered, particularly in areas of marginal necrosis. Bosentan is a vasodilator that exerts its effect through endothelin receptor blockade, and has been shown to prevent ischemic tissue damage. However, no reports have addressed the effect of bosentan on skin flaps. The aim of the study was to investigate the effects of bosentan, which may be applied clinically to promote survival of ischemic skin flaps. A modified McFarlane flap was elevated in the dorsum of 20 Albino Wistar rats with a width-to-length ratio of 3 to 10 cm, respectively, with the caudal base. Perioperatively, 0.9% of physiologic NaCl and injectable distilled water of identical volume were injected into rats in Group 1 (n = 10), and 5 mg/kg bosentan was injected intraperitoneally into rats in Group 2 (n = 10). All of the rats were followed up for 7 days postoperatively. The surviving parts of the flaps were measured at the end of day 7. Acute and chronic inflammation, amount of granulation tissue, fibroblast maturation, amount of collagen, and amounts of reepithelialization and neovascularization present in the ischemic zones of the distal parts of the flaps were evaluated histopathologically, and results were compared statistically. The mean flap survivals were 61.1% in Group 1 and 91.1% in Group 2; the percentage of the surviving flap area in Group 2 was higher than that in Group 1 (p < 0.005). In both groups, there was significantly less acute inflammation in the ischemic zones in Group 2 than in Group 1 (p < 0.005). No significant difference was found in the amounts of chronic inflammation and granulation tissue between the two groups (p > 0.005). Fibroblast maturation, amount of collagen, and amounts of reepithelialization and neovascularization investigated in Group 2 were statistically significantly higher than those in Group 1 (p < 0.005). We believe that bosentan may be used prophylactically to increase survival in risky skin flaps because it decreases ischemic necrosis distal to skin flaps, thus exerting favorable effects on flap survival. PMID- 27494589 TI - Effects of Deferoxamine on Fat Graft Survival. AB - The most important problem in fat transplantation is the unpredictable rates of resorption. Deferoxamine (DFO) is an iron-chelating agent with many useful functions including stimulating angiogenesis and antioxidant nature. The purpose of the study is to evaluate the effects of DFO on fat graft viability in rat model. A total of 24 Wistar rats were divided into three groups and 0.5 g of the left inguinal fat pad was extracted. In control group, fat grafts were implanted to the parascapular area without performing any procedure. In sham group, they were implanted in 0.2 mL saline solution followed by serial saline injections for 1 month. In the study group, fat grafts were implanted in 0.2 mL saline solution and 300 mg DFO followed by serial DFO injections for 1 month. At the postoperative second month, fat grafts were taken back and sent for histopathologic examination. The weight measurements of biopsy specimens in the study group demonstrated significantly higher than in the other two groups. Inflammation and fibrosis rates were also found to be significantly higher in the study group compared with the other groups; however, no significant difference in the apoptosis rates was detected between the groups. Fat grafts enriched with DFO showed significant increase in fatty tissue content in the study group compared with the control and sham groups. DFO increases the fat graft survival in rats and it may be a useful addition in autologous fat grafting procedures to increase fat graft viability and obtain maximal long-term durability. PMID- 27494590 TI - Nasofrontal Angle and Nasal Dorsal Aesthetics: A Quantitative Investigation of Idealized and Normative Values. AB - This study is a quantitative evaluation of the influence of the lower component of the nasofrontal angle on perceived attractiveness and threshold values of desire for rhinoplasty. The nasofrontal angle of an idealized silhouette male Caucasian profile image was altered incrementally between 106 and 148 degrees. Images were rated on a Likert scale by pretreatment patients (n = 75), laypeople (n = 75), and clinicians (n = 35). The results demonstrated that a nasofrontal angle of approximately 130 degrees is ideal, corresponding to a lower component of 60 degrees, with a range of 127 to 142 degrees deemed acceptable. Angles above or below this range are perceived as unattractive, and anything outside the range of 118 to 145 degrees is deemed very unattractive. Reduced nasofrontal angles, simulating a nasal hump deformity, of less than 115 degrees were deemed the least attractive. In terms of threshold values of desire for surgery, for all groups a threshold value of 148 degrees indicated a preference for surgery: for patients, the threshold value was 121 degrees or less; for lay people, the threshold value was 124 degrees or less; and similarly for clinicians, the threshold value was 118 degrees or less. Clinicians were the least critical, and patients appeared to be less critical than lay people. This stresses the importance of using patients as observers, as well as laypeople and clinicians, in facial attractiveness research. From the results of this study, it is recommended that in rhinoplasty planning, the range of normal variability of the nasofrontal angle, in terms of observer acceptance, is taken into account as well as the threshold values of desire for surgery. PMID- 27494591 TI - The Pi Graft for Correction of Severe Saddle Nose Deformity. AB - Saddle nose deformity is challenging because there is both aesthetic and functional compromise, and high rates of recurrence have been reported. Autologous costal cartilage is the widely preferred medium for reconstruction, but there may be room for improvement in the configuration of the cartilage struts. The pi graft is stabilized at two points, proximally and distally, distinguishing it from the traditional L-strut. Indications include severe (Types III and IV) saddle nose deformity with collapse of the mid-vault, and recurrence after prior reconstruction. Costal cartilage is harvested and three struts are crafted to make the foundation layer: a dorsal strut, caudal strut, and mid-vault strut. An aesthetic layer is composed of a carefully crafted dorsal graft and tip graft. Three men and 11 women were treated from 2013 to 2015 using this method for severe saddle nose deformity. Aesthetic and functional outcomes were evaluated. Patients were followed up for 12 months (range, 8-14 months). There was no recurrence of deformity or warping of the aesthetic or foundation layers. All patients were guided to anticipate refinement of the tip at 3 months to ease the burden on the skin envelope in stage I, but only five patients (35.7%) opted for it, as the remaining patients were satisfied with their appearance. The pi graft is a composite reconstructive method that is designed to minimize warping and recurrence of the saddle nose deformity. This method was successful in this series, although objective comparisons with traditional methods were not made. PMID- 27494592 TI - A New Perspective for Spreader Graft Use in Severely Deviated Septum: Is Septal Continuity an Obligation for a Stable and Straight Nasal Septum? AB - Severe septal deviation is a challenging deformity usually treated using aggressive surgical methods, and extracorporeal septoplasty (ECS) is a commonly used method for this issue. However, this method has severe risks and complications such as the recurrent deformity or nasal saddling. In this article, we present an alternative solution to ECS procedure for the correction of severe septal deviation. Sixteen patients with severe c- or s-shaped septal deviation with a mean age of 26.5 years were included in the study. The entire deviated part of the septal cartilage was resected as a vertical block creating a full thickness defect between the most cranial and caudal parts of the septal cartilage. After that, two spreader grafts were placed bilaterally facilitating the septal integrity and leaving the full-thickness septal defect unchanged. The surgical results were evaluated using the preoperative and postoperative facial photographs and patient satisfaction was determined using nine relevant questions of DAS-59 scale. The only complication observed in the follow-up period of 19 months was hanging columella deformity which was corrected at the postoperative first year. The mean length of the resected septal segment was 12.4 mm. The mean length of the resultant septal cartilage defect after the vertical resection was 5.9 mm. The mean length of the placed spreader grafts was 25.6 mm. The comparison of the preoperative and postoperative photographs showed significant improvement of the nasal contour and considerable correction of the septal deviation. The statistical evaluation of the answers given to the questions of the DAS-59 scale clearly demonstrates that a significant degree of patient satisfaction was achieved. Severe septal deviation may be successfully corrected by full-thickness resection of the deviated part and reconstruction with bilateral spreader grafts with a low risk of postoperative complications. PMID- 27494593 TI - Successful Nose Replantation Using Leeches for Venous Draining. PMID- 27494594 TI - Risk of Congenital Heart Defects after Ambient Heat Exposure Early in Pregnancy. AB - BACKGROUND: Congenital heart defects may be environmentally related, but the association with elevated ambient temperature has received little attention. OBJECTIVES: We studied the relationship between outdoor heat during the first trimester of pregnancy and risk of congenital heart defects. METHODS: We carried out a retrospective cohort study of 704,209 fetuses between 2 and 8 weeks postconception from April to September in Quebec, Canada, 1988-2012. We calculated the prevalence of congenital heart defects at birth according to the number of days women were exposed to maximum temperature >= 30 degrees C. In log binomial regression models, we estimated prevalence ratios (PR) and 95% confidence intervals (CI) for the relationship of temperature with seven critical and eight noncritical heart defects, adjusted for pregnancy characteristics. RESULTS: Prevalence of congenital heart defects was 979.5 per 100,000 for 10 days or more of temperature >= 30 degrees C compared with 878.9 per 100,000 for 0 days of exposure. Temperature was more precisely associated with noncritical than critical defects, which had lower prevalence. Fetuses exposed to 15 days of temperature >= 30 degrees C between 2 and 8 weeks postconception had 1.06 times the risk of critical defects (95% CI: 0.67, 1.67) and 1.12 times the risk of noncritical defects (95% CI: 0.98, 1.29) relative to 0 days. Associations were higher for atrial septal defects (PR 1.37, 95% CI: 1.10, 1.70) than for other noncritical defects. For atrial septal defects, associations with elevated temperatures began the 3rd week postconception. CONCLUSIONS: Extreme heat exposure during the first trimester may be associated with noncritical heart defects, especially of the atrial septum. Citation: Auger N, Fraser WD, Sauve R, Bilodeau-Bertrand M, Kosatsky T. 2017. Risk of congenital heart defects after ambient heat exposure early in pregnancy. Environ Health Perspect 125:8-14; http://dx.doi.org/10.1289/EHP171. PMID- 27494595 TI - Effect of hand cooling on body temperature, cardiovascular and perceptual responses during recumbent cycling in a hot environment. AB - The purpose of this study was to quantify physiological and perceptual responses to hand immersion in water during recumbent cycling in a hot environment. Seven physically active males (body mass 79.8 +/- 6.3 kg; stature 182 +/- 5 cm; age 23 +/- 3 years) immersed their hands in 8, 14 and 34 degrees C water whilst cycling at an intensity (W) equivalent to 50% [Formula: see text]O2peak for 60 min in an environmental chamber (35 degrees C, 50% relative humidity). 8 and 14 degrees C water attenuated an increase in body temperature, and lowered cardiorespiratory and skin blood flow demands. These effects were considered to be practically beneficial (standardised effect size > 0.20). There was a tendency for 8 and 14 degrees C to extend exercise duration versus 34 degrees C (>7%). Heart rate, intestinal, mean skin and mean body temperature were less in 8 degrees C compared to 14 degrees C; these differences were considered practically beneficial. Augmented heat loss at the palm-water surface might enable cooler blood to return to the body and limit physiological strain. These findings provide a mechanistic basis for continuous hand cooling and indicate that endurance exercise in hot environments could be improved using this method. Future research should investigate its effectiveness during cycling and running performance. PMID- 27494596 TI - Relationship between antibiotic residues and occurrence of resistant bacteria in Nile tilapia (Oreochromisniloticus) cultured in cage-farm. AB - The aim of this study was to investigate the relationship between antibiotic residues found in the muscle of cage-farm-raised Nile tilapia (Oreochromisniloticus), the occurrence of resistant bacteria, and the sanitary practices adopted by farmers in Ilha Solteira reservoir, Brazil. Nine fish (three small fish, 40-200 g; three medium-sized fish, 200-500 g; and three large fish, 500-800 g) were collected from four cage farms every three months from April 2013 to January 2014. Ten antibiotic residues were determined using liquid chromatography-mass spectrometry, and bacteria were isolated and tested for antibiotic resistance to determine the multiple antibiotic resistance (MAR) index. Only three antibiotics (oxytetracycline, tetracycline, and florfenicol) were detected in the muscle of Nile tilapia, and their residues were the highest in small fish; however, the MAR index was higher in large fish. In addition, a direct positive relationship between the MAR index and the concentration of antibiotic residues in Nile tilapia was found. Overall, the adoption of prophylactic management practices improved the sanitary status of cage farms, reducing bacterial infections and hampering the development of antibiotic resistant bacteria. PMID- 27494597 TI - Development of an Age Band on the ManuVis for 3-Year-Old Children with Visual Impairments. AB - AIM: To compare fine motor performance of 3-year-old children with visual impairment with peers having normal vision, to provide reference scores for 3 year-old children with visual impairment on the ManuVis, and to assess inter rater reliability. METHOD: 26 children with visual impairment (mean age: 3 years 7 months (SD 3 months); 17 boys) and 28 children with normal vision (mean age: 3 years 7 months (SD 4 months); 14 boys) participated in the study. The ManuVis age band for 3-year-old children comprised two one-handed tasks, two two-handed tasks, and a pre-writing task. RESULTS: Children with visual impairment needed more time on all tasks (p < .01) and performed the pre-writing task less accurately than children with normal vision (p < .001). Children aged 42-47 months performed significantly faster on two tasks and had better total scores than children aged 36-41 months (p < .05). Inter-rater reliability was excellent (Intra-class Correlation Coefficient = 0.96-0.99). CONCLUSIONS: The ManuVis age band for 3-year-old children is appropriate to assess fine motor skills, and is sensitive to differences between children with visual impairment and normal vision and between half-year age groups. Reference scores are provided for 3-year old children with visual impairment to identify delayed fine motor development. PMID- 27494598 TI - Aurora kinase and RUNX: Reaching beyond transcription. PMID- 27494599 TI - Derivation of a time dependent Schrodinger equation as the quantum mechanical Landau-Lifshitz-Bloch equation. AB - The derivation of the time dependent Schrodinger equation with transversal and longitudinal relaxation, as the quantum mechanical analog of the classical Landau Lifshitz-Bloch equation, has been described. Starting from the classical Landau Lifshitz-Bloch equation the transition to quantum mechanics has been performed and the corresponding von-Neumann equation deduced. In a second step the time Schrodinger equation has been derived. Analytical proofs and computer simulations show the correctness and applicability of the derived Schrodinger equation. PMID- 27494600 TI - Ecological Contexts of Index Cases and Spillover Events of Different Ebolaviruses. AB - Ebola virus disease afflicts both human and animal populations and is caused by four ebolaviruses. These different ebolaviruses may have distinct reservoir hosts and ecological contexts that determine how, where, and when different ebolavirus spillover events occur. Understanding these virus-specific relationships is important for preventing transmission of ebolaviruses from wildlife to humans. We examine the ecological contexts surrounding 34 human index case infections of ebolaviruses from 1976-2014. Determining possible sources of spillover from wildlife, characterizing the environment of each event, and creating ecological niche models to estimate habitats suitable for spillover, we find that index case infections of two ebolaviruses, Ebola virus and Sudan virus, have occurred under different ecological contexts. The index cases of Ebola virus infection are more associated with tropical evergreen broadleaf forests and consuming bushmeat than the cases of Sudan virus. Given these differences, we emphasize caution when generalizing across different ebolaviruses and that location and virus-specific ecological knowledge will be essential to unravelling how human and animal behavior lead to the emergence of Ebola virus disease. PMID- 27494602 TI - Three-Dimensionally Homoconjugated Carbon-Bridged Oligophenylenevinylene for Perovskite Solar Cells. AB - Stabilization of the radical cationic state of a donor molecule by 3-D homoconjugation was probed using a substituted carbon-bridged oligophenylenevinylene backbone (COPV, or 5,5-diarylindeno[2,1-a]indenes). For molecules bearing electron-donating groups as the 5,5-aryl moieties, a one electron oxidation of the COPV backbone results in delocalization of the cationic charge over the whole molecule with a small reorganization energy. The compounds forming a stable radical cation by 3-D homoconjugation produce a uniform amorphous film and show high short-circuit current, high fill factor, and hence high power-conversion efficiency when used as a hole-transporting layer of an organic-inorganic hybrid lead perovskite solar cell. This material thus shows a performance and stability in air comparable to those obtained with the benchmark material, spiro-MeOTAD. PMID- 27494601 TI - The Temporal Signature of Memories: Identification of a General Mechanism for Dynamic Memory Replay in Humans. AB - Reinstatement of dynamic memories requires the replay of neural patterns that unfold over time in a similar manner as during perception. However, little is known about the mechanisms that guide such a temporally structured replay in humans, because previous studies used either unsuitable methods or paradigms to address this question. Here, we overcome these limitations by developing a new analysis method to detect the replay of temporal patterns in a paradigm that requires participants to mentally replay short sound or video clips. We show that memory reinstatement is accompanied by a decrease of low-frequency (8 Hz) power, which carries a temporal phase signature of the replayed stimulus. These replay effects were evident in the visual as well as in the auditory domain and were localized to sensory-specific regions. These results suggest low-frequency phase to be a domain-general mechanism that orchestrates dynamic memory replay in humans. PMID- 27494604 TI - Removal of sulfamethazine antibiotics using CeFe-graphene nanocomposite as catalyst by Fenton-like process. AB - The presence of sulfonamide (SMT) antibiotics in aquatic environments has received increasing attention in recent years, and they are ubiquitous pollutants which cannot be effectively removed by conventional wastewater treatment processes. In this paper, the nanocomposites Ce(0)/Fe(0)-reduced graphene oxide (Ce(0)/Fe(0)-RGO) were synthesized through chemical reduction method, and characterized by Raman and FTIR before and after use. The addition of RGO can prevent the agglomeration of Ce(0) and Fe(0). The elimination of SMT can be divided into adsorption and degradation process. The adsorption of SMT onto the catalyst can enhance its degradation. The effect of pH value, concentration of H2O2, catalyst dosage, temperature and initial SMT concentration on the removal efficiency of SMT was determined. When pH = 7, T = 25 degrees C, H2O2 = 8 mM, Ce(0)/Fe(0)-RGO = 0.5 g/L, SMT = 20 mg/L, the removal efficiency of SMT and TOC was 99% and 73%, respectively. The stability of the catalysts was evaluated with repeated batch experiments using ethanol, water and acid as solvents to wash the used catalysts, respectively. The surface change of the catalysts after each use was characterized by Raman and FTIR analysis. The intermediates were detected by GC-MS and IC, the possible degradation pathway of SMT was tentatively proposed. PMID- 27494605 TI - Alkali modified hydrochar of grape pomace as a perspective adsorbent of Pb(2+) from aqueous solution. AB - Hydrochar produced via hydrothermal carbonization of grape pomace was considered as novel sorbent of Pb(2+) from aqueous solution. In order to enhance the adsorption capacity, hydrochar was chemically modified using 2 M KOH solution. Both materials were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy and X-ray diffraction technique. Batch experiments were performed to examine the effect of sorbent dosage, pH and contact time. Obtained results showed that the KOH treatment increased the sorption capacity of hydrochar from 27.8 mg g(-1) up to 137 mg g(-1) at pH 5. Adsorption of lead on either of the materials was achieved through ion-exchange mechanism, chemisorption and Pb(2+)-pi interaction. The Sips isotherm model gave the best fit with the experimental data obtained for Pb(2+) sorption using activated hydrochar. The adsorption kinetic followed a pseudo second-order model. Thermodynamic parameters implied that the Pb(2+) binding for hydrochar surface was spontaneous and exothermic process. Findings from this work suggest that the hydrothermal carbonization is a promising route for production of efficient Pb (2+) sorbents for wastewater treatment. PMID- 27494603 TI - Requirement of Smad4 from Ocular Surface Ectoderm for Retinal Development. AB - Microphthalmia is characterized by abnormally small eyes and usually retinal dysplasia, accounting for up to 11% of the blindness in children. Right now there is no effective treatment for the disease, and the underlying mechanisms, especially how retinal dysplasia develops from microphthalmia and whether it depends on the signals from lens ectoderm are still unclear. Mutations in genes of the TGF-beta superfamily have been noted in patients with microphthalmia. Using conditional knockout mice, here we address the question that whether ocular surface ectoderm-derived Smad4 modulates retinal development. We found that loss of Smad4 specifically on surface lens ectoderm leads to microphthalmia and dysplasia of retina. Retinal dysplasia in the knockout mice is caused by the delayed or failed differentiation and apoptosis of retinal cells. Microarray analyses revealed that members of Hedgehog and Wnt signaling pathways are affected in the knockout retinas, suggesting that ocular surface ectoderm-derived Smad4 can regulate Hedgehog and Wnt signaling in the retina. Our studies suggest that defective of ocular surface ectoderm may affect retinal development. PMID- 27494606 TI - Influence of exchange group of modified glycidyl methacrylate polymer on phenol removal: A study by batch and continuous flow processes. AB - Contamination of water by phenol is potentially a serious problem due to its high toxicity and its acid character. In this way some treatment process to remove or reduce the phenol concentration before contaminated water disposal on the environment is required. Currently, phenol can be removed by charcoal adsorption, but this process does not allow easy regeneration of the adsorbent. In contrast, polymeric resins are easily regenerated and can be reused in others cycles of adsorption process. In this work, the interaction of phenol with two polymeric resins was investigated, one of them containing a weakly basic anionic exchange group (GD-DEA) and the other, a strongly basic group (GD-QUAT). Both ion exchange resins were obtained through chemical modifications from a base porous resin composed of glycidyl methacrylate (GMA) and divinyl benzene (DVB). Evaluation tests with resins were carried out with 30 mg/L of phenol in water solution, at pH 6 and 10, employing two distinct processes: (i) batch, to evaluate the effect of temperature, and (ii) continuous flow, to assess the breakthrough of the resins. Batch tests revealed that the systems did not follow the model proposed by Langmuir due to the negative values obtained for the constant b and for the maximum adsorption capacity, Q0. However, satisfactory results for the constants KF and n allowed assuming that the behavior of systems followed the Freundlich model, leading to the conclusion that resin GD-DEA had the best interaction with the phenol when in a solution having pH 10 (phenoxide ions). The continuous flow tests corroborated this conclusion since the performance of GD-DEA in removing phenol was also best at pH 10, indicating that the greater availability of the electron pair in the resin with the weakly basic donor group contributed to enhance the resin's interaction with the phenoxide ions. PMID- 27494607 TI - Groundwater level prediction using a SOM-aided stepwise cluster inference model. AB - Accurate groundwater level (GWL) prediction can contribute to sustaining reliable water supply to domestic, agricultural and industrial uses as well as ecological services, especially in arid and semi-arid areas. In this paper, a regional GWL modeling framework was first presented through coupling both spatial and temporal clustering techniques. Specifically, the self-organizing map (SOM) was applied to identify spatially homogeneous clusters of GWL piezometers, while GWL time series forecasting was performed through developing a stepwise cluster multisite inference model with various predictors including climate conditions, well extractions, surface runoffs, reservoir operations and GWL measurements at previous steps. The proposed modeling approach was then demonstrated by a case of an arid irrigation district in the western Hexi Corridor, northwest China. Spatial clustering analysis identified 6 regionally representative central piezometers out of 30, for which sensitivity and uncertainty analysis were carried out regarding GWL predictions. As the stepwise cluster tree provided uncertain predictions, we added an AR(1) error model to the mean prediction to forecast GWL 1 month ahead. Model performance indicators suggest that the modeling system is a useful tool to aid decision-making for informed groundwater resource management in arid areas, and would have a great potential to extend its applications to more areas or regions in the future. PMID- 27494608 TI - High prevalence of anti-hepatitis E virus antibodies among blood donors in central Italy, February to March 2014. AB - Prevalence of anti-hepatitis E virus (HEV) antibodies is highly variable in developed countries, which seems partly due to differences in assay sensitivity. Using validated sensitive assays, we tested 313 blood donors attending a hospital transfusion unit in central Italy in January and February 2014 for anti-HEV IgG and IgM and HEV RNA. Data on HEV exposure were collected from all donors. Overall anti-HEV IgG prevalence was 49% (153/313). Eating raw dried pig-liver sausage was the only independent predictor of HEV infection (adjusted prevalence rate ratio = 2.14; 95% confidence interval: 1.23-3.74). Three donors were positive for either anti-HEV IgM (n = 2; 0.6%) or HEV RNA (n = 2; 0.6%); they were completely asymptomatic, without alanine aminotransferase (ALT) abnormalities. Of the two HEV RNA-positive donors (both harbouring genotype 3), one was anti-HEV IgG- and IgM-positive, the other was anti-HEV IgG- and IgM-negative. The third donor was positive for anti-HEV IgG and IgM but HEV RNA-negative. HEV infection is therefore hyperendemic among blood donors (80% men 18-64 years-old) from central Italy and associated with local dietary habits. Nearly 1% of donors have acute or recent infection, implying potential transmission to blood recipients. Neither ALT nor anti-HEV IgM testing seems useful to prevent transfusion-transmitted HEV infection. PMID- 27494609 TI - Early- or mid-trimester amniocentesis biomarkers for predicting preterm delivery: a meta-analysis. AB - OBJECTIVE: To determine the value of early- or mid-trimester amniotic fluid levels of interleukin-6 (IL-6), matrix metalloproteinase-8 (MMP-8), and glucose for predicting preterm delivery. METHODS: Randomized controlled trials and two arm prospective, retrospective, cohorts, and case-controlled studies in which patients received early- or mid-trimester amniocentesis for karyotyping, and biomarker testing of the amniotic fluid was performed and delivery data were available were included in the analysis. RESULTS: Outcome measures were the associations of amniotic fluid IL-6, MMP-8, and glucose levels with preterm delivery. Differences in means with 95% confidence intervals (CIs) were calculated. Of 288 articles identified, 14 were included in the meta-analysis with a total of 675 patients who had preterm birth and 2518 patients who had term births. The preterm-delivery group had significantly higher amniotic fluid IL-6 and MMP-8 levels, and a significantly lower glucose level than the term delivery group (IL-6: difference in means = 0.32, 95% CI: 0.22-0.43, p < 0.001; MMP-8: difference in means = 4.47, 95% CI: 0.83-8.11), p = 0.016; glucose: difference in means = -5.22, 95% CI: -8.19 to -2.26, p = 0.001) Conclusion: Early- or mid trimester amniotic fluid IL-6, MMP-8, and glucose levels are useful for predicting the risk of preterm delivery. KEY MESSAGES Median amniotic fluid ferritin and IL-6 levels, and mean amniotic fluid ALP levels were higher in the preterm group. The preterm-delivery group had significantly higher amniotic fluid IL-6 and MMP-8 levels, and a significantly lower glucose level than the term delivery group. PMID- 27494610 TI - Magnetic Particle Imaging for High Temporal Resolution Assessment of Aneurysm Hemodynamics. AB - PURPOSE: The purpose of this work was to demonstrate the capability of magnetic particle imaging (MPI) to assess the hemodynamics in a realistic 3D aneurysm model obtained by additive manufacturing. MPI was compared with magnetic resonance imaging (MRI) and dynamic digital subtraction angiography (DSA). MATERIALS AND METHODS: The aneurysm model was of saccular morphology (7 mm dome height, 5 mm cross-section, 3-4 mm neck, 3.5 mm parent artery diameter) and connected to a peristaltic pump delivering a physiological flow (250 mL/min) and pulsation rate (70/min). High-resolution (4 h long) 4D phase contrast flow quantification (4D pc-fq) MRI was used to directly assess the hemodynamics of the model. Dynamic MPI, MRI, and DSA were performed with contrast agent injections (3 mL volume in 3 s) through a proximally placed catheter. RESULTS AND DISCUSSION: 4D pc-fq measurements showed distinct pulsatile flow velocities (20-80 cm/s) as well as lower flow velocities and a vortex inside the aneurysm. All three dynamic methods (MPI, MRI, and DSA) also showed a clear pulsation pattern as well as delayed contrast agent dynamics within the aneurysm, which is most likely caused by the vortex within the aneurysm. Due to the high temporal resolution of MPI and DSA, it was possible to track the contrast agent bolus through the model and to estimate the average flow velocity (about 60 cm/s), which is in accordance with the 4D pc-fq measurements. CONCLUSIONS: The ionizing radiation free, 4D high resolution MPI method is a very promising tool for imaging and characterization of hemodynamics in human. It carries the possibility of overcoming certain disadvantages of other modalities like considerably lower temporal resolution of dynamic MRI and limited 2D characteristics of DSA. Furthermore, additive manufacturing is the key for translating powerful pre-clinical techniques into the clinic. PMID- 27494612 TI - Relationship between Mid-Upper Arm Circumference and Body Mass Index in Inpatients. AB - INTRODUCTION: Nutritional screening is a fundamental aspect of the initial evaluation of the hospitalised patient. Body Mass Index (BMI) in association with other parameters is a good marker of malnutrition (<18.5 kg/m2), but it presents the handicap that the great majority of patients cannot be weighed and measured. For this reason it is necessary to find other indicators that can be measured in these patients. OBJECTIVES: 1) Analyse the relationship between BMI and Mid-Upper Arm Circumference (MUAC); 2) establish a cut-off point of MUAC equivalent to BMI <18.5 kg/m2. MATERIALS AND METHODS: The anthropometric data of patients hospitalised over the period 2004-2013 were retrospectively revised. The following variables were collected: weight, height, BMI, MUAC, sex and age. RESULTS: 1373 patients were evaluated, who presented a mean weight of: 65.04+/ 15.51 kg; height: 1.66+/-0.09 m; BMI: 23.48+/-5.03 kg/m2; MUAC: 26.95+/-4.50 cm; age: 56.24+/-16.77. MUAC correlates suitably to BMI by means of the following equation (simple linear regression): BMI = - 0.042 + 0.873 x MUAC (cm) (R2 = 0.609), with a Pearson r value of 0.78 (p<0.001). The area under the curve of MUAC for the diagnosis of malnutrition was 0.92 (95% CI: 0.90-0.94; p<0.001). The MUAC value <=22.5 cm presented a sensitivity of 67.7%, specificity of 94.5%, and a correct classification of 90%. No significant statistical differences were found in the cut-off point of MUAC for the diagnosis of malnutrition based on sex (p = 0.115) and age (p = 0.694). CONCLUSIONS: 1) MUAC correlates positively and significantly with BMI. 2) MUAC <= 22.5 cm correlates properly with a BMI of <18.5 kg/m2, independent of the age or sex of the patient, although there are other alternatives. MUAC constitutes a useful tool as a marker of malnutrition, fundamentally in patients for whom weight and height cannot be determined. PMID- 27494611 TI - Comprehensive Analysis of the Transcriptional and Mutational Landscape of Follicular and Papillary Thyroid Cancers. AB - Follicular thyroid carcinoma (FTC) and benign follicular adenoma (FA) are indistinguishable by preoperative diagnosis due to their similar histological features. Here we report the first RNA sequencing study of these tumors, with data for 30 minimally invasive FTCs (miFTCs) and 25 FAs. We also compared 77 classical papillary thyroid carcinomas (cPTCs) and 48 follicular variant of PTCs (FVPTCs) to observe the differences in their molecular properties. Mutations in H/K/NRAS, DICER1, EIF1AX, IDH1, PTEN, SOS1, and SPOP were identified in miFTC or FA. We identified a low frequency of fusion genes in miFTC (only one, PAX8 PPARG), but a high frequency of that in PTC (17.60%). The frequencies of BRAFV600E and H/K/NRAS mutations were substantially different in miFTC and cPTC, and those of FVPTC were intermediate between miFTC and cPTC. Gene expression analysis demonstrated three molecular subtypes regardless of their histological features, including Non-BRAF-Non-RAS (NBNR), as well as BRAF-like and RAS-like. The novel molecular subtype, NBNR, was associated with DICER1, EIF1AX, IDH1, PTEN, SOS1, SPOP, and PAX8-PPARG. The transcriptome of miFTC or encapsulated FVPTC was indistinguishable from that of FA, providing a molecular explanation for the similarly indolent behavior of these tumors. We identified upregulation of genes that are related to mitochondrial biogenesis including ESRRA and PPARGC1A in oncocytic follicular thyroid neoplasm. Arm-level copy number variations were correlated to histological and molecular characteristics. These results expanded the current molecular understanding of thyroid cancer and may lead to new diagnostic and therapeutic approaches to the disease. PMID- 27494613 TI - Azine-Hydrazone Tautomerism of Guanylhydrazones: Evidence for the Preference Toward the Azine Tautomer. AB - Guanylhydrazones have been known for a long time and have wide applications in organic synthesis, medicinal chemistry, and material science; however, little attention has been paid toward their electronic and structural properties. Quantum chemical analysis on several therapeutically important guanylhydrazones indicated that all of them prefer the azine tautomeric state (by about 3-12 kcal/mol). A set of simple and conjugated azines were designed using quantum chemical methods, whose tautomeric preference toward the azine tautomer is in the range of 3-8 kcal/mol. Twenty new azines were synthesized and isolated in their neutral state. Variable temperature NMR study suggests existence of the azine tautomer even at higher temperatures with no traces of the hydrazone tautomer. The crystal structures of two representative compounds confirmed that the title compounds prefer to exist in their azine tautomeric form. PMID- 27494615 TI - Sequencing and Characterization of the Invasive Sycamore Lace Bug Corythucha ciliata (Hemiptera: Tingidae) Transcriptome. AB - The sycamore lace bug, Corythucha ciliata (Hemiptera: Tingidae), is an invasive forestry pest rapidly expanding in many countries. This pest poses a considerable threat to the urban forestry ecosystem, especially to Platanus spp. However, its molecular biology and biochemistry are poorly understood. This study reports the first C. ciliata transcriptome, encompassing three different life stages (Nymphs, adults female (AF) and adults male (AM)). In total, 26.53 GB of clean data and 60,879 unigenes were obtained from three RNA-seq libraries. These unigenes were annotated and classified by Nr (NCBI non-redundant protein sequences), Nt (NCBI non-redundant nucleotide sequences), Pfam (Protein family), KOG/COG (Clusters of Orthologous Groups of proteins), Swiss-Prot (A manually annotated and reviewed protein sequence database), and KO (KEGG Ortholog database). After all pairwise comparisons between these three different samples, a large number of differentially expressed genes were revealed. The dramatic differences in global gene expression profiles were found between distinct life stages (nymphs and AF, nymphs and AM) and sex difference (AF and AM), with some of the significantly differentially expressed genes (DEGs) being related to metamorphosis, digestion, immune and sex difference. The different express of unigenes were validated through quantitative Real-Time PCR (qRT-PCR) for 16 randomly selected unigenes. In addition, 17,462 potential simple sequence repeat molecular markers were identified in these transcriptome resources. These comprehensive C. ciliata transcriptomic information can be utilized to promote the development of environmentally friendly methodologies to disrupt the processes of metamorphosis, digestion, immune and sex differences. PMID- 27494614 TI - Predictive Big Data Analytics: A Study of Parkinson's Disease Using Large, Complex, Heterogeneous, Incongruent, Multi-Source and Incomplete Observations. AB - BACKGROUND: A unique archive of Big Data on Parkinson's Disease is collected, managed and disseminated by the Parkinson's Progression Markers Initiative (PPMI). The integration of such complex and heterogeneous Big Data from multiple sources offers unparalleled opportunities to study the early stages of prevalent neurodegenerative processes, track their progression and quickly identify the efficacies of alternative treatments. Many previous human and animal studies have examined the relationship of Parkinson's disease (PD) risk to trauma, genetics, environment, co-morbidities, or life style. The defining characteristics of Big Data-large size, incongruency, incompleteness, complexity, multiplicity of scales, and heterogeneity of information-generating sources-all pose challenges to the classical techniques for data management, processing, visualization and interpretation. We propose, implement, test and validate complementary model based and model-free approaches for PD classification and prediction. To explore PD risk using Big Data methodology, we jointly processed complex PPMI imaging, genetics, clinical and demographic data. METHODS AND FINDINGS: Collective representation of the multi-source data facilitates the aggregation and harmonization of complex data elements. This enables joint modeling of the complete data, leading to the development of Big Data analytics, predictive synthesis, and statistical validation. Using heterogeneous PPMI data, we developed a comprehensive protocol for end-to-end data characterization, manipulation, processing, cleaning, analysis and validation. Specifically, we (i) introduce methods for rebalancing imbalanced cohorts, (ii) utilize a wide spectrum of classification methods to generate consistent and powerful phenotypic predictions, and (iii) generate reproducible machine-learning based classification that enables the reporting of model parameters and diagnostic forecasting based on new data. We evaluated several complementary model-based predictive approaches, which failed to generate accurate and reliable diagnostic predictions. However, the results of several machine-learning based classification methods indicated significant power to predict Parkinson's disease in the PPMI subjects (consistent accuracy, sensitivity, and specificity exceeding 96%, confirmed using statistical n-fold cross-validation). Clinical (e.g., Unified Parkinson's Disease Rating Scale (UPDRS) scores), demographic (e.g., age), genetics (e.g., rs34637584, chr12), and derived neuroimaging biomarker (e.g., cerebellum shape index) data all contributed to the predictive analytics and diagnostic forecasting. CONCLUSIONS: Model-free Big Data machine learning based classification methods (e.g., adaptive boosting, support vector machines) can outperform model-based techniques in terms of predictive precision and reliability (e.g., forecasting patient diagnosis). We observed that statistical rebalancing of cohort sizes yields better discrimination of group differences, specifically for predictive analytics based on heterogeneous and incomplete PPMI data. UPDRS scores play a critical role in predicting diagnosis, which is expected based on the clinical definition of Parkinson's disease. Even without longitudinal UPDRS data, however, the accuracy of model-free machine learning based classification is over 80%. The methods, software and protocols developed here are openly shared and can be employed to study other neurodegenerative disorders (e.g., Alzheimer's, Huntington's, amyotrophic lateral sclerosis), as well as for other predictive Big Data analytics applications. PMID- 27494616 TI - The Emergence of Quinolone Resistant Shigella sonnei, Pondicherry, India. AB - Ciprofloxacin resistant Shigella sonnei across the globe have been increasing alarmingly. In order to understand the emergence of S.sonnei with respect to ciprofloxacin resistance in our patient population, the following study was carried out. Of the 184 Shigella sp. Isolated from 2012 to 2015, 34 S.sonnei which were confirmed by standard methods and subjected to antimicrobial susceptibility testing were selected. The minimum inhibitory concentrations (MICs) of 16/34 quinolone resistant isolates tested ranged from 4micrograms/ml to 16micrograms/ml for ciprofloxacin, from 16 micrograms/ml to 64 micrograms/ml for ofloxacin and from 16micrograms/ml to 64micrograms/ml for levofloxacin. Sequence determination of the quinolone resistance determining regions of gyrA, gyrB, parC, and parE genes showed mutations in GyrA at Gln69/Trp, Phe71/Ser, Ser72/Pro, Met75/Leu, Ser90/Cys, Met94/Leu, His106/Pro, Asn161/His, Thr163/Ala and in ParC at Ala64/Asp. Among the plasmid-mediated quinolone resistance (PMQRs) targets investigated,qnrB was the most (93.7%) prevalent followed by qnrC (18.7%). None hadqnrA, qnrS and qepA. Two (0.1%) of the isolates harboured theaac(6')-lb gene. Drug accumulation assay detected the presence of efflux pump activity in 9/15 (60%) among ciprofloxacin resistant isolates. All isolates harboured the ipaH gene followed by ial (17.6%), sen (11.7%), set1A&set1B (5.8%) genes. None had stx1 element. PCR for Enterobacterial repetitive intergenic consensus (ERIC) sequences resulted in 4 unique clusters, of which Type III was the most (44%) dominant but there was no correlation between the ERIC types and the antibiotic resistance pattern or the virulence profile. A documented increase in S.sonnei harbouring the qnrgenes and some unusual genes like set1Aand indicate an ongoing process of horizontal gene transfer. The accumulation of novel mutations in GyrA and ParC in the presence of efflux pump and PMQR genes contributed to the raised MIC to quinolones. These findings are crucial in our understanding of quinolone resistance in these isolates. PMID- 27494617 TI - Cut-Off Value for Pain Sensitivity Questionnaire in Predicting Surgical Success in Patients with Lumbar Disc Herniation. AB - Various factors related to predict surgical success were studied; however, a standard cut-off point for the Pain Sensitivity Questionnaire (PSQ) measure has not yet been established for a favorable surgical outcome for lumbar disc herniation (LDH). This study was to find the optimal cut-off point on the PSQ to distinguish surgical success in patients with LDH. A total of 154 patients with LDH consecutively referred to our clinic were enrolled into this prospective study between February 2011 and January 2014. All participants completed the PSQ. Patients completed the Oswestry Disability Index (ODI) score before surgery, and at 2 years after surgery. Surgical success was defined as a 13-point improvement from the baseline ODI scores. The cut-off value for PSQ was determined by the receiver-operating characteristic curve (ROC). The mean age of patients was 49.3+/-9.6 years, and there were 80 women. The mean time for follow-up assessment was 31+/-5 months (range 24-35). Post-surgical success was 79.9% (n = 123) at 2 years follow up. The mean score for the total PSQ, PSQ-minor, and PSQ-moderate were 6.0 (SD = 1.6), 5.4 (SD = 1.9) and 6.5 (SD = 1.7), respectively. Total PSQ score was also significantly correlated with the total scores of the ODI. The optimal total PSQ cut-off point was determined as > 5.2 to predict surgical success in LDH patients, with 80.0% sensitivity and 75.6% specificity (AUC-0.814, 95% CI 0.703-0.926). This study showed that the PSQ could be considered a parameter for predicting surgical success in patients with LDH, and can be useful in clinical practice. PMID- 27494618 TI - Effects of levetiracetam monotherapy on sperm parameters and sex hormones: Data from newly diagnosed patients with epilepsy. AB - PURPOSE: Epilepsy has an impact on the reproductive system. Males with epilepsy have lower fertility rates, hypo-sexuality and reduced potency compared with the general population. Anti-epileptic drugs and epilepsy itself are thought to be responsible for this reduced fertility. LEV is a second-generation anti-epileptic agent with low incidences of both adverse effects and drug-drug interactions. In this study, we have investigated the effects of LEV treatment on sex hormones and sperm parameters in newly diagnosed epilepsy patients. METHODS: We recruited 26 males with newly diagnosed epilepsy and introduced LEV monotherapy. Patients were divided into two groups depending on whether they had partial or generalized seizures. We acquired the results of pre- and post-treatment sperm analyses and serum sex hormone levels. We also recorded the maximum dose, daily dose and treatment duration for each individual. Pre- and post-treatment comparisons and correlations between both sperm and sex hormone parameters and both treatment duration and dose were determined. RESULTS: Pre- and post-treatment sex hormone levels were not significantly different. The total sperm count, percentage of normal morphology and functional sperm count tested after treatment were significantly lower in both groups compared with pre-treatment values (p<0.05). There was a moderate correlation between daily dose and reduction in functional sperm count (r: 0.41, p: 0.034). CONCLUSIONS: Our findings confirm that LEV treatment of newly diagnosed epilepsy patients decreases sperm parameters without altering sex hormone levels. Our results may guide the choice of anti-epileptic drug treatment among men with epilepsy. PMID- 27494619 TI - Tools and strategies for scarless allele replacement in Drosophila using CRISPR/Cas9. AB - Genome editing via the CRISPR/Cas9 RNA-guided nuclease system has opened up exciting possibilities for genetic analysis. However, technical challenges associated with homology-directed repair have proven to be roadblocks for producing changes in the absence of unwanted, secondary mutations commonly known as "scars." To address these issues, we developed a 2-stage, marker-assisted strategy to facilitate precise, "scarless" edits in Drosophila with a minimal requirement for molecular screening. Using this method, we modified 2 base pairs in a gene of interest without altering the final sequence of the CRISPR cut sites. We executed this 2-stage allele swap using a novel transformation marker that drives expression in the pupal wings, which can be screened for in the presence of common eye-expressing reporters. The tools we developed can be used to make a single change or a series of allelic substitutions in a region of interest in any D. melanogaster genetic background as well as in other Drosophila species. PMID- 27494620 TI - Microscopic Analyses of Latent and Visible Monilinia fructicola Infections in Nectarines. AB - Little is known about the histologic features of a latent Monilinia fructicola infection and brown rot in infected fruit. This report informs on the results of an investigation whose aim was to analyze the microanatomy of nectarines with a latent and visible M. fructicola infection. Mature nectarines were inoculated with an M. fructicola isolate and incubated at 25 degrees C for 0, 24, 48, 72, or 96 hours in the dark. For investigating the latent infection process, the inoculated nectarines were first incubated at 25 degrees C for 24 hours in the dark and then incubated at 4 degrees C for 72, 144, 216, and 288 hours in the dark. At the end of the incubation, samples of nectarine tissue were excised from the inoculation points and prepared for light and transmission electron microscopic examinations. No signs of disease were seen on the surface of nectarines with a latent infection over the 288-hour incubation period. When the tissue samples were microscopically examined, M. fructicola colonized the stomata and this stomatal colonization progressively increased over time and was associated with gradual collapse of the epidermal cells and colonization of the subepidermis. In nectarines with visible brown rot, the disease usually appeared after 24 hours on the surface and in the uppermost layers of epidermal cells, which began to collapse after 48 hours. Subsequently, the diseased tissues of the nectarines displayed (a) colonization of the epidermis and mesocarp by M. fructicola with thin and thick hyphae, (b) collapse and disruption of epidermal and mesocarpic cells, (c) lysogenic cavities in the subepidermis and mesocarp, (d) degradation of the cuticle and epidermis, and (e) M. fructicola sporulation. M. fructicola is active during latent infections because slow and progressive colonization of nectarine subcuticular cells by the fungus occurs. PMID- 27494622 TI - First thoughts on the effects on the protection of laboratory animals of the UK's departure from the European Union. PMID- 27494621 TI - Intragenic ERG Deletions Do Not Explain the Biology of ERG-Related Acute Lymphoblastic Leukemia. AB - Intragenic ERG deletions occur in 3-5% of B-cell precursor acute lymphoblastic leukemia, specifically in B-other subtype lacking the classifying genetic lesions. They represent the only genetic lesion described so far present in the majority of cases clustering into a subgroup of B-other subtype characterized by a unique gene expression profile, probably sharing a common, however, not yet fully described, biological background. We aimed to elucidate whether ERG deletions could drive the specific biology of this ERG-related leukemia subgroup through expression of aberrant or decreased expression of wild type ERG isoforms. We showed that leukemic cells with endogenous ERG deletion express an aberrant transcript translated into two proteins in transfected cell lines and that one of these proteins colocalizes with wild type ERG. However, we did not confirm expression of the proteins in acute lymphoblastic leukemia cases with endogenous ERG deletion. ERG deletions resulted in significantly lower expression of wild type ERG transcripts compared to B-other cases without ERG deletion. However, cases with subclonal ERG deletion, clustering to the same ERG deletion associated subgroup, presented similar levels of wild type ERG as cases without ERG deletion. In conclusion, our data suggest that neither the expression of aberrant proteins from internally deleted allele nor the reduced expression of wild type ERG seem to provide a plausible explanation of the specific biology of ERG related leukemia subgroup. PMID- 27494623 TI - The use of in vivo, ex vivo, in vitro, computational models and volunteer studies in vision research and therapy, and their contribution to the Three Rs. AB - Much is known about mammalian vision, and considerable progress has been achieved in treating many vision disorders, especially those due to changes in the eye, by using various therapeutic methods, including stem cell and gene therapy. While cells and tissues from the main parts of the eye and the visual cortex (VC) can be maintained in culture, and many computer models exist, the current non-animal approaches are severely limiting in the study of visual perception and retinotopic imaging. Some of the early studies with cats and non-human primates (NHPs) are controversial for animal welfare reasons and are of questionable clinical relevance, particularly with respect to the treatment of amblyopia. More recently, the UK Home Office records have shown that attention is now more focused on rodents, especially the mouse. This is likely to be due to the perceived need for genetically-altered animals, rather than to knowledge of the similarities and differences of vision in cats, NHPs and rodents, and the fact that the same techniques can be used for all of the species. We discuss the advantages and limitations of animal and non-animal methods for vision research, and assess their relative contributions to basic knowledge and clinical practice, as well as outlining the opportunities they offer for implementing the principles of the Three Rs (Replacement, Reduction and Refinement). PMID- 27494624 TI - More than 70 years of pyrogen detection: Current state and future perspectives. AB - In the quality assurance of medical products, tests for sterility are essential. For parenteral pharmaceuticals, avoiding the presence of pyrogens is crucial. These fever-inducing substances (endotoxins and non-endotoxins) are not eliminated by standard sterilisation processes, and are biologically active once in the bloodstream, causing risks to human health, ranging from mild reactions (e.g. fever) to septic shock and death. Therefore, for injectable formulations, pyrogen testing is mandatory. Over the years, various pyrogen testing methods have been introduced, namely: in the 1940s, the rabbit pyrogen test, which is an in vivo test that measures the fever reaction as an endpoint; in the 1970s, the Limulus Amoebocyte Lysate (LAL) test, which is an in vitro test (with the haemolymph of the horseshoe crab) that specifically detects endotoxin; and in 2010, the Monocyte-Activation Test (MAT), which is a non-animal based in vitro pyrogen test that represents a full replacement of the rabbit test. Due to the ubiquity and biological significance of pyrogens, we are currently further developing the MAT so that it can be used for other applications. More specifically, our focus is on the detection of pyrogenic contamination on medical devices, as well as on the measurement of air quality. In addition, further improvements to permit the use of cryopreserved blood in the MAT, to overcome the limitations in the availability of freshly-drawn blood from human donors, are ongoing. PMID- 27494625 TI - Evaluation of non-animal methods for assessing skin sensitisation hazard: A Bayesian Value-of-Information analysis. AB - This paper offers a Bayesian Value-of-Information (VOI) analysis for guiding the development of non-animal testing strategies, balancing information gains from testing with the expected social gains and costs from the adoption of regulatory decisions. Testing is assumed to have value, if, and only if, the information revealed from testing triggers a welfare-improving decision on the use (or non use) of a substance. As an illustration, our VOI model is applied to a set of five individual non-animal prediction methods used for skin sensitisation hazard assessment, seven battery combinations of these methods, and 236 sequential 2 test and 3-test strategies. Their expected values are quantified and compared to the expected value of the local lymph node assay (LLNA) as the animal method. We find that battery and sequential combinations of non-animal prediction methods reveal a significantly higher expected value than the LLNA. This holds for the entire range of prior beliefs. Furthermore, our results illustrate that the testing strategy with the highest expected value does not necessarily have to follow the order of key events in the sensitisation adverse outcome pathway (AOP). PMID- 27494626 TI - Exploring waiving opportunities for mammalian acute systemic toxicity tests. AB - A survey was carried out to explore opportunities for waiving mammalian acute systemic toxicity tests. We were interested in finding out whether data from a sub-acute toxicity test could be used to predict the outcome of an acute systemic toxicity test. The survey was directed at experts in the field of toxicity testing, and was carried out in the context of the upcoming 2018 final registration deadline for chemicals under the EU REACH Regulation. In addition to the survey, a retrospective data analysis of chemicals that had already been registered with the European Chemicals Agency, and for which both acute and sub acute toxicity data were available, was carried out. This data analysis was focused on chemicals that were administered via the oral route. The answers to the questionnaire showed a willingness to adopt waiving opportunities. In addition, the responses showed that data from a sub-acute toxicity test or dose range finding study might be useful for predicting chemicals that do not require classification for acute oral toxicity (LD50 > 2000mg/kg body weight). However, with the exception of substances that fall into the non-classified category, it is difficult to predict current acute oral toxicity categories. PMID- 27494627 TI - Local tolerance testing under REACH: Accepted non-animal methods are not on equal footing with animal tests. AB - In general, no single non-animal method can cover the complexity of any given animal test. Therefore, fixed sets of in vitro (and in chemico) methods have been combined into testing strategies for skin and eye irritation and skin sensitisation testing, with pre-defined prediction models for substance classification. Many of these methods have been adopted as OECD test guidelines. Various testing strategies have been successfully validated in extensive in-house and inter-laboratory studies, but they have not yet received formal acceptance for substance classification. Therefore, under the European REACH Regulation, data from testing strategies can, in general, only be used in so-called weight-of evidence approaches. While animal testing data generated under the specific REACH information requirements are per se sufficient, the sufficiency of weight-of evidence approaches can be questioned under the REACH system, and further animal testing can be required. This constitutes an imbalance between the regulatory acceptance of data from approved non-animal methods and animal tests that is not justified on scientific grounds. To ensure that testing strategies for local tolerance testing truly serve to replace animal testing for the REACH registration 2018 deadline (when the majority of existing chemicals have to be registered), clarity on their regulatory acceptance as complete replacements is urgently required. PMID- 27494628 TI - Fine Mapping of Two Additive Effect Genes for Awn Development in Rice (Oryza sativa L.). AB - Awns, important domestication and agronomic traits in rice (Oryza sativa L.), are conferred by polygenes and the environment. Near isogenic line (NIL) pairs BM33 and BM38 were constructed from crosses between awnless japonica cv Nipponbare as recurrent parent, and lines SLG or Funingxiaohongmang (awned japonica accessions), respectively, as donors. In order to study the genetic and molecular mechanism of awning, two unknown, independent genes with additive effects were identified in a cross between the NILs. To map and clone the two genes, a BC4F4 population of 8,103 individuals and a BC4F6 population of 11,206 individuals were constructed. Awn3-1 was fine mapped to a 101.13 kb genomic region between Indel marker In316 and SNP marker S9-1 on chromosome 3. Nine predicted genes in the interval were annotated in the Rice Annotation Project Database (RAP-DB), and Os03g0418600 was identified as the most likely candidate for Awn3-1 through sequence comparisons and RT-PCR assays. Awn4-2 was fine mapped to a 62.4 kb genomic region flanked by simple sequence repeat (SSR) marker M1126 and Indel maker In73 on chromosome 4L. This region contained the previously reported gene An-1 that regulates awn development. Thus, An-1 may be the candidate gene of Awn4 2. These results will facilitate cloning of the awn genes and thereby provide an understanding of the molecular basis of awn development. PMID- 27494629 TI - Safety and efficacy of extracorporeal shock wave therapy (ESWT) in calcinosis cutis associated with systemic sclerosis. AB - OBJECTIVES: Calcinosis cutis is a frequent, difficult to treat manifestation of systemic sclerosis (SSc) associated with high morbidity. The aim of this prospective, controlled, monocentric study was to assess safety and efficacy of extracorporeal shock wave therapy (ESWT) for calcinosis cutis of the finger in SSc patients. METHODS: A 12-week proof of concept study in which 4 SSc patients with calcinosis cutis were treated at one painful finger with high-energy, focused ESWT, in 3 sessions with one-week interval between each session. A second, untreated finger, served as control. The outcome parameters were: change in pain, change in size of calcification measured by ultrasound (US) and computed tomography (CT) and of the force by pressing the finger against a Dolorimeter. RESULTS: Pain was reduced (by 91% and 60%) in the treated finger in two out of four patients. There was no change in the control fingers. The size of the calcinosis in the treated finger was reduced in three (US) and four patients (CT). Inter-assessor agreement was acceptable for US volume measures (ICC=0.863). CONCLUSIONS: We could show promising evidence for safety and efficacy of ESWT for chronic, treatment resistant calcinosis cutis in SSc patients, thus justifying the initiation of larger multicentre controlled trials. PMID- 27494630 TI - Influenza immunization during pregnancy: Benefits for mother and infant. AB - The serious consequences of influenza infection during pregnancy have been recognized for almost a century. In this article, we reviewed the evidence on the immunogenicity, safety and impact of maternal influenza immunization for both mother and child. After vaccination, pregnant women have similar protective titers of anti-influenza antibodies as non-pregnant women, demonstrating that pregnancy does not alter the trivalent inactivated influenza vaccine immune response. Studies from the United States, Europe and resource-constrained regions demonstrate that maternal vaccination is associated with increased anti-influenza antibody concentrations and protection in the newborn child as well as the immunized mother. Given the acceptable safety profile of influenza vaccines and the World Health Organization's recommendation for its use in pregnant women, maternal vaccination with inactivated influenza vaccine is a cost-effective approach to decrease influenza disease in newborns. However, as seen for influenza immunization in the elderly, the protective efficacy of current inactivated vaccines in protection of newborns is 50% at best, indicating significant room for vaccine improvement, which could potentially be achieved by addition of a safe and effective adjuvant. Thus, global deployment of inactivated influenza immunization during pregnancy would have substantial and measurable health benefits for mothers and their newborns. PMID- 27494632 TI - Rapid electrostatics-assisted layer-by-layer assembly of near-infrared-active colloidal photonic crystals. AB - Here we report a rapid and scalable bottom-up technique for layer-by-layer (LBL) assembling near-infrared-active colloidal photonic crystals consisting of large (?1MUm) silica microspheres. By combining a new electrostatics-assisted colloidal transferring approach with spontaneous colloidal crystallization at an air/water interface, we have demonstrated that the crystal transfer speed of traditional Langmuir-Blodgett-based colloidal assembly technologies can be enhanced by nearly 2 orders of magnitude. Importantly, the crystalline quality of the resultant photonic crystals is not compromised by this rapid colloidal assembly approach. They exhibit thickness-dependent near-infrared stop bands and well-defined Fabry Perot fringes in the specular transmission and reflection spectra, which match well with the theoretical calculations using a scalar-wave approximation model and Fabry-Perot analysis. This simple yet scalable bottom-up technology can significantly improve the throughput in assembling large-area, multilayer colloidal crystals, which are of great technological importance in a variety of optical and non-optical applications ranging from all-optical integrated circuits to tissue engineering. PMID- 27494633 TI - Dissecting Embryonic Stem Cell Self-Renewal and Differentiation Commitment from Quantitative Models. AB - To model quantitatively embryonic stem cell (ESC) self-renewal and differentiation by computational approaches, we developed a unified mathematical model for gene expression involved in cell fate choices. Our quantitative model comprised ESC master regulators and lineage-specific pivotal genes. It took the factors of multiple pathways as input and computed expression as a function of intrinsic transcription factors, extrinsic cues, epigenetic modifications, and antagonism between ESC master regulators and lineage-specific pivotal genes. In the model, the differential equations of expression of genes involved in cell fate choices from regulation relationship were established according to the transcription and degradation rates. We applied this model to the Murine ESC self renewal and differentiation commitment and found that it modeled the expression patterns with good accuracy. Our model analysis revealed that Murine ESC was an attractor state in culture and differentiation was predominantly caused by antagonism between ESC master regulators and lineage-specific pivotal genes. Moreover, antagonism among lineages played a critical role in lineage reprogramming. Our results also uncovered that the ordered expression alteration of ESC master regulators over time had a central role in ESC differentiation fates. Our computational framework was generally applicable to most cell-type maintenance and lineage reprogramming. PMID- 27494634 TI - Development and evaluation of a school-based asthma educational program. AB - OBJECTIVES: To develop, implement, and evaluate the effects of a school-based asthma educational program on Saudi primary school teachers' asthma awareness and competence in delivering asthma-related first aid interventions. METHODS: An asthma educational intervention program entitled "School Asthma Action Program" (SAAP) was designed based on pedagogical principles and implemented among teachers randomly selected from girls' primary schools in Riyadh, Saudi Arabia. This pilot study employed a pre-test/post-test experimental design. A previously tested asthma awareness questionnaire and a custom-designed asthma competence score sheet were used to evaluate the effects of the educational intervention program on teacher's asthma awareness and competence in providing asthma-related first aid interventions at schools. RESULTS: Forty-seven teachers from five different primary schools participated in the program. Of the 47 teachers, 39 completed both the pre- and post-program questionnaires. The SAAP improved teachers' awareness of asthma (teachers' median pre-program score was 11 (range 5 18) and their post-program score was 15 (range 7-18), p < 0.001) and their attitudes toward asthma management at schools (teachers' median pre-program score was 74 (range 15-75) and their post-program score was 75 (range 15-75), p = 0.043). Further, it improved teachers' competence in providing asthma-related first aid interventions (teachers' mean pre-program score was 1.4 +/- 2.3 and their mean post-program score was 9.8 +/- 0.5, p < 0.001). After completing the SAAP, a high proportion of teachers reported increased confidence in providing care to children with asthma at school. CONCLUSION: School-based asthma educational programs can significantly improve teachers' knowledge of asthma and their competence in providing asthma-related first aid interventions during emergencies. PMID- 27494635 TI - Bonding, Luminescence, Metallophilicity in Linear Au3 and Au2Ag Chains Stabilized by Rigid Diphosphanyl NHC Ligands. AB - The heterofunctional and rigid ligand N,N'-diphosphanyl-imidazol-2-ylidene (PCNHCP; P = P(t-Bu)2), through its phosphorus and two N-heterocyclic carbene (NHC) donors, stabilizes trinuclear chain complexes, with either Au3 or AgAu2 cores, and dinuclear Au2 complexes. The two oppositely situated PCNHCP (L) ligands that "sandwich" the metal chain can support linear and rigid structures, as found in the known tricationic Au(I) complex [Au3(MU3 PCNHCP,kappaP,kappaCNHC,kappaP)2](OTf)3 (OTf = CF3SO3; [Au3L2](OTf)3; Chem. Commun. 2014, 50, 103-105) now also obtained by transmetalation from [Ag3(MU3 PCNHCP,kappaP,kappaCNHC,kappaP)2](OTf)3 ([Ag3L2](OTf)3), or in the mixed-metal tricationic [Au2Ag(MU3-PCNHCP,kappaP,kappaCNHC,kappaP)2](OTf)3 ([Au2AgL2](OTf)3). The latter was obtained stepwise by the addition of AgOTf to the digold(I) complex [Au2(MU2-PCNHCP,kappaP,kappaCNHC)2](OTf)2 ([Au2L2](OTf)2). The latter contains two dangling P donors and displays fluxional behavior in solution, and the Au...Au separation of 2.8320(6) A in the solid state is consistent with metallophilic interactions. In the solvento complex [Au3Cl2(tht)(MU3 PCNHCP,kappaP,kappaCNHC,kappaP)](OTf).MeCN ([Au3Cl2(tht)L](OTf).MeCN), which contains only one L and one tht ligand (tht = tetrahydrothiophene), the metal chain is bent (148.94(2) degrees ), and the longer Au...Au separation (2.9710(4) A) is in line with relaxation of the rigidity due to a more "open" structure. Similar features were observed in [Au3Cl2(SMe2)L](OTf).2MeCN. A detailed study of the emission properties of [Au3L2](OTf)3, [Au3Cl2(tht)L](OTf).MeCN, [Au2L2](OTf)2, and [Au2AgL2](OTf)3 was performed by means of steady state and time-resolved photophysical techniques. The complex [Au3L2](OTf)3 displays a bright (photoluminescence quantum yield = 80%) and narrow emission band centered at 446 nm with a relatively small Stokes' shift and long-lived excited-state lifetime on the microsecond timescale, both in solution and in the solid state. In line with the very narrow emission profile centered in the violet-blue region, fabrication of organic light-emitting devices (OLEDs) comprising the [Au3L2](OTf)3 complex demonstrated its usefulness as a deep-blue emitter in solution-processed OLEDs. Electrochemical and Raman spectroscopic studies were also performed on [Au3L2](OTf)3. Experimental results were rationalized by means of Wave-Function Theory (WFT) and Density Functional Theory (DFT). MP2 calculations gave a satisfactory description of the structures of the cationic complexes [Au3L2](3+) and [Au2L2](2+) and pointed to Au...Au interactions having an electrostatic component owing to the dissimilar charge distribution in the chain caused by the heterofunctional ligand. The nature of the emitting states and their geometric distortions relative to the ground states in [Au3L2](3+) and [Au2L2](2+) was studied by DFT, revealing contraction of the Au...Au distances and coordination geometry changes by association of the dangling P donor, respectively. PMID- 27494631 TI - Inducible Nitric Oxide Synthase in the Carcinogenesis of Gastrointestinal Cancers. AB - SIGNIFICANCE: Gastrointestinal (GI) cancer taken together constitutes one of the most common cancers worldwide with a broad range of etiological mechanisms. In this review, we have examined the impact of nitric oxide (NO) on the etiology of colon, colorectal, gastric, esophageal, and liver cancers. Recent Advances: Despite differences in etiology, initiation, and progression, chronic inflammation has been shown to be a common element within these cancers showing interactions of numerous pathways. NO generated at the inflammatory site contributes to the initiation and progression of disease. The amount of NO generated, time, and site vary and are an important determinant of the biological effects initiated. Among the nitric oxide synthase enzymes, the inducible isoform has the most diverse range, participating in numerous carcinogenic processes. There is emerging evidence showing that inducible nitric oxide synthase (NOS2) plays a central role in the process of tumor initiation and/or development. CRITICAL ISSUES: Redox inflammation through NOS2 and cyclooxygenase-2 participates in driving the mechanisms of initiation and progression in GI cancers. FUTURE DIRECTIONS: Understanding the underlying mechanism involved in NOS2 activation can provide new insights into important prevention and treatment strategies. Antioxid. Redox Signal. 26, 1059-1077. PMID- 27494636 TI - Variation in ruminal in situ degradation of crude protein and starch from maize grains compared to in vitro gas production kinetics and physical and chemical characteristics. AB - The objectives of this study were (1) to evaluate in situ ruminal dry matter (DM), crude protein (CP) and starch degradation characteristics and in vitro gas production (GP) kinetics using a set of 20 different maize grain genotypes and (2) to predict the effective degradation (ED) of CP and starch from chemical and physical characteristics alone or in combination with in vitro GP measurements. Maize grains were characterised by different chemical and physical characteristics. Ruminal in situ degradation was measured in three lactating Jersey cows. Ground grains (sieve size: 2 mm) were incubated in bags for 1, 2, 4, 8, 16, 24, 48 and 72 h. Bag residues were analysed for CP and starch content. Degradation kinetics was determined and the ED of DM, CP and starch calculated using a ruminal passage rate of 5%/h and 8%/h. The GP of the grains (sieve size: 1 mm) was recorded after 2, 4, 6, 8, 12, 24, 48 and 72 h incubation in buffered rumen fluid and fitted to an exponential equation to determine GP kinetics. Correlations and stepwise multiple linear regressions were evaluated for the prediction of ED calculated for a passage rate of 5%/h (ED5) for CP (EDCP5) and starch (EDST5). The in situ parameters and ED5 varied widely between genotypes with average values (+/-SD) of 64% +/- 4.2, 62% +/- 4.1 and 65% +/- 5.2 for ED5 of DM, EDCP5 and EDST5 and were on average 10 percentage points lower for a passage rate of 8%/h. Degradation rates varied between 4.8%/h and 7.4%/h, 4.1%/h and 6.5%/h and 5.3%/h and 8.9%/h for DM, CP and starch, respectively. These rates were in the same range as GP rates (6.0-8.3%/h). The EDCP5 and EDST5 were related to CP concentration and could be evaluated in detail using CP fractions and specific amino acids. In vitro GP measurements and GP rates correlated well with EDCP5 and EDST5 and predicted EDCP5 and EDST5 in combination with the chemical characteristics of the samples. Equations can be used to obtain quick and cost effective information on ruminal degradation of CP and starch from maize grains. PMID- 27494637 TI - Nutritional value of raw and micronised field beans (Vicia faba L. var. minor) with and without enzyme supplementation containing tannase for growing chickens. AB - An experiment examined the effects of two field bean cultivar samples with different tannin contents, the effect of heat treatment (micronising) and the effect of dietary supplementation of a proprietary enzyme preparation containing tannase, pectinase, and xylanase activities on metabolisable energy (ME), total tract dry matter digestibility (DMD) and ether extract digestibility (EED), nitrogen retention (NR), tannin degradability, gastrointestinal tract (GIT) development, and endogenous mucin losses excretion in broiler chickens. The Control diet contained per kg 221 g crude protein and 12.83 MJ ME. Four additional diets contained 300 g/kg of each of the two untreated or micronised experimental field bean cultivar samples. Each diet was then split into two batches and one of them was supplemented with 3400 units tannase per kg diet resulting in 10 diets in total. Each diet was fed to seven pens with two randomly selected male broilers each. Birds fed the high tannin bean sample had a lower weight gain (p < 0.001), and a lower determined apparent ME (p < 0.05), and DMD (p < 0.001) but a higher tannin degradability (p < 0.001). Compared to the Control diet, feeding field beans increased (p < 0.001) the weights of the proventriculus and gizzard of the birds, and also increased endogenous mucin losses (p < 0.05). Supplementing diets with the tannase-containing enzyme preparation improved dietary ME (p < 0.001), DMD (p < 0.001), NR (p < 0.001) and DEE (p < 0.05), but did not change tannin degradability. Heat treatment of the beans reduced the degradability of condensed tannins and increased endogenous mucin losses (p < 0.05). The differences in the feeding value of the different field bean samples were not improved by heat treatment, but enzyme supplementation improved the feeding value of all diets regardless of the bean samples or heat treatment. Further research is warranted to study the effectiveness of tannase supplementation in poultry diet formulations by dose response trials with purified tannase preparations. PMID- 27494638 TI - Effect of dietary supplementation of gallic acid on nitrogen balance, nitrogen excretion pattern and urinary nitrogenous constituents in beef cattle. AB - The objective of the trial was to study the effects of dietary supplementation of gallic acid (GA) on nitrogen (N) balance, N excretion pattern and urinary N constituents in beef cattle. In a 4 * 4 Latin square design, four male 30-month old Simmental cattle (443 +/- 22 kg live weight) received four levels of GA (purity >= 98.5%), i.e. 0, 5.3, 10.5, 21.1 g/kg DM, added to a basal ration. Each experimental period lasted 17 d, consisting of 12 d adaptation and 5 d sampling. The results showed that supplementation of GA at 5.3, 10.5 or 21.1 g/kg DM did not affect the N balance but regulated the N excretion pattern by increasing the ratio of faecal N/urinary N and decreasing the ratio of urinary urea N/total urinary N in beef cattle fed at maintenance level. PMID- 27494639 TI - Nonlinear Refractory Plasmonics with Titanium Nitride Nanoantennas. AB - Titanium nitride (TiN) is a novel refractory plasmonic material which can sustain high temperatures and exhibits large optical nonlinearities, potentially opening the door for high-power nonlinear plasmonic applications. We fabricate TiN nanoantenna arrays with plasmonic resonances tunable in the range of about 950 1050 nm by changing the antenna length. We present second-harmonic (SH) spectroscopy of TiN nanoantenna arrays, which is analyzed using a nonlinear oscillator model with a wavelength-dependent second-order response from the material itself. Furthermore, characterization of the robustness upon strong laser illumination confirms that the TiN antennas are able to endure laser irradiation with high peak intensity up to 15 GW/cm(2) without changing their optical properties and their physical appearance. They outperform gold antennas by one order of magnitude regarding laser power sustainability. Thus, TiN nanoantennas could serve as promising candidates for high-power/high-temperature applications such as coherent nonlinear converters and local heat sources on the nanoscale. PMID- 27494640 TI - Electronically Excited States of Borylenes. AB - Borylenes, RB, are elusive reactive intermediates. Still not much is known about their excited states from spectroscopic experiments, and existing knowledge is limited to diatomic borylenes only. The electronic structure and geometry of borylenes with diverse substituents on boron (where R = H, F, Cl, CH3, CF3, tBu, NH2, Ph, and SiMe3) were studied by means of computational chemistry. For this purpose, geometries of borylenes in their lowest singlet and triplet states were optimized at the B3LYP/def2-TZVP level of theory. Additionally, the influence of substitution on the energies of frontier molecular orbitals, HOMO-LUMO energy gaps, singlet-triplet energy splittings, and excitation energies was investigated. Two lowest vertical singlet-singlet excitations were computed using EOM-CCSD and TD-DFT (using hybrid B3LYP, and long-range separated CAM-B3LYP and omegaB97X functionals) in combination with the aug-cc-pVTZ basis set. The electronic transitions involve excitations from nonbonding sp boron orbital (HOMO) mainly to empty p(B) orbitals and partially to the orbitals of the substituent, and are of n -> pi* type. The results can facilitate prospective identification of borylenes, e.g., in UV-vis matrix isolation or time-resolved spectroscopy experiments. PMID- 27494641 TI - The effect of subchronic supplementation with folic acid and l-arginine on homocysteine-induced seizures. AB - The aim of the present study was to examine the effect of subchronic co administration of folic acid (F) and l-arginine (A) on behavioural and electroencephalographic (EEG) characteristics of dl homocysteine thiolactone (H) induced seizures in adult rats. The activity of membrane ATPases in different brain regions were also investigated. Rats were treated with F, A, or vehicle for 15 days (regimen: F 5 mg/kg + A 500 mg/kg (F5A500); F 10 mg/kg + A 300 mg/kg (F10A300)). Seizures were elicited by convulsive dose of H (H, F5A500H, F10A300H) Subchronic supplementation with F and A did not affect seizure incidence, number of seizure episodes, and severity in F5A500H and F10A300H groups vs. H group. However, a tendency to increase latency and decrease the number of seizure episodes was noticed in the F10A300H group. EEG mean spectral power densities during ictal periods were significantly lower in F10A300H vs. H group. The activity of Na+/K+-ATPase and Mg2+-ATPase was significantly increased in almost all examined structures in rats treated with F and A. We can conclude that subchronic supplementation with folic acid and l-arginine has an antiepileptic effect in dl homocysteine thiolactone induced epilepsy. PMID- 27494642 TI - Low-temperature SCR of NOx by NH3 over MnOx/SAPO-34 prepared by two different methods: a comparative study. AB - The low-temperature selective catalytic reduction (SCR) of NOx is a promising technology for removing NOx from flue gases. However, the vulnerability of Mn based catalysts to SO2 and H2O poisoning makes them unsuitable for industrial application. Herein, catalysts based on the MnOx/SAPO-34 catalysts were prepared by conventional impregnation and an improved molecularly designed dispersion method for use in the low-temperature SCR. The improved molecularly designed catalyst containing 20 wt% of MnOx exhibited high low-temperature NH3-SCR activity. Nearly 90% of the NOx was converted exclusively to N2 at 160 degrees C using this catalyst. The structure and morphological analyses of the catalyst showed that the amorphous MnOx was well dispersed on the surface of the support. The reasons for the high performance of the catalysts were ascertained using surface N2 adsorption, XPS, H2-TPR and NH3-TPD. The results of these analyses indicated that high specific surface area and the redox capability, of the abundant Mn4+ and Mn3+ species, coupled with the surface chemisorbed oxygen and strong acid sites had a significant effect on the SCR reaction. In addition, the effects of SO2 and H2O on activity of the catalysts were also investigated and it was found that the highly dispersed 20 wt% MnOx/SAPO-34 catalyst exhibited better SO2 poisoning resistance than the other impregnated catalysts. PMID- 27494643 TI - Perceptions of orthodontic specialist training in the United Kingdom: a national survey of postgraduate orthodontic student opinion. AB - INTRODUCTION: Postgraduate orthodontic education is highly challenging. There is a lack of evidence regarding orthodontic postgraduates' perceptions of their orthodontic education in the United Kingdom. In addition, no study has been conducted to compare the postgraduate orthodontic training experience between UK trainees and international postgraduates. OBJECTIVES: (1) To investigate orthodontic UK trainees' and international postgraduates' perception and satisfaction of their orthodontic education. (2) To compare postgraduate orthodontic training experience between UK trainees and international postgraduates. (3) To compare orthodontic caseload between UK trainees and international postgraduates. METHODS: Utilizing a descriptive, cross-sectional survey, conducted through a web-based self-administered questionnaire, the sample population consisted of all 189 orthodontic postgraduates in the United Kingdom. RESULTS: One hundred and twenty-five questionnaires were completed resulting in a response rate of 66.1%. All three academic years were evenly represented. Ninety five (76%) respondents rated the quality of their postgraduate orthodontic education as excellent. Over 90% of third year postgraduates felt the quality of their education was excellent. The majority of orthodontic trainees (n = 98, 78.4%) were satisfied with the number of cases. Apart from the first year postgraduates, other postgraduates regardless of UK trainee or international postgraduate status reported a high number of cases in treatment, with 45 (36%) respondents treating more patients than the recommended range of 80-120. Postgraduates' responses were less positive regarding their ability to influence the delivery of their programme, whether their programme represented value for money and the fairness of their training. Most of the respondents believed that UK trainees had an advantage in communicating with patients. CONCLUSION: The majority of orthodontic postgraduates rated the quality of their postgraduate education as excellent. Apart from first year postgraduates, other postgraduates irrespective of UK trainee or international postgraduate status reported a high number of cases in treatment. There was no difference in caseload between UK trainee and international postgraduate groups. PMID- 27494644 TI - A pilot study of cardiac electrophysiology catheters to map and pace bladder electrical activity. AB - AIMS: This is a pilot study to evaluate the feasibility of using diagnostic cardiac electrophysiology catheters for recording intrinsic urinary bladder electrical activity and for electrical pacing capture of bladder tissue. METHODS: During cystoscopy, a curved quadripolar catheter was introduced and contact was made with the right and left halves of the dome and trigone in adult female patients undergoing cystoscopy. Electrical activity was recorded, using a commercially available cardiac electrophysiologic recording system, before and during pacing at 0.5-3.0 Hz. RESULTS: Apparent spontaneous electrical depolarizations were detected in both the trigone and the dome. The amplitude of these depolarizations was in the microVolt range. During pacing, local electrical capture was noted in the trigone, but not in the dome. CONCLUSIONS: Spontaneous low-amplitude electrical activity was detected in the bladder through the use of commercially available cardiac electrophysiology equipment. While these low-level signals could represent noise, the voltage, and morphology resemble detrusor muscle action potentials previously seen in animal studies. Pacing induced local electrical capture in the trigone but not the dome. PMID- 27494645 TI - Microwave treatment of dairy manure for resource recovery: Reaction kinetics and energy analysis. AB - A newly designed continuous-flow 915 MHz microwave wastewater treatment system was used to demonstrate the effectiveness of the microwave enhanced advanced oxidation process (MW/H2O2-AOP) for treating dairy manure. After the treatment, about 84% of total phosphorus and 45% of total chemical oxygen demand were solubilized with the highest H2O2 dosage (0.4% H2O2 per %TS). The reaction kinetics of soluble chemical oxygen demand revealed activation energy to be in the range of 5-22 kJ mole-1. The energy required by the processes was approximately 0.16 kWh per liter of dairy manure heated. A higher H2O2 dosage used in the system had a better process performance in terms of solids solubilization, reaction kinetics, and energy consumption. Cost-benefit analysis for a farm-scale MW/H2O2-AOP treatment system was also presented. The results obtained from this study would provide the basic knowledge for designing an effective farm-scale dairy manure treatment system. PMID- 27494646 TI - Motives underlying smoking in college students with ADHD. AB - BACKGROUND: The positive association between attention deficit hyperactivity disorder (ADHD) symptoms and smoking in youth has been well documented. Less research has examined why individuals with ADHD, particularly college students, are at increased risk for smoking. OBJECTIVES: This longitudinal study examined whether smoking motives [cognitive enhancement, tolerance, negative reinforcement (smoking to reduce negative affect or stress), craving, social influences, and weight control] helped to explain the relation between ADHD symptoms (inattention and hyperactivity/impulsivity) and cigarette smoking among college students. METHODS: Participants were 889 undergraduates (21% men) and their parents who completed online surveys at the beginning and end of the Fall semester regarding their smoking behaviors, ADHD symptoms, and smoking motives. Structural equation modeling was used to analyze data and answer research questions. RESULTS: Nineteen percent of students reported smoking, while 20% reported one or more inattentive symptoms, 35% reported one or more hyperactive/impulsive symptoms, and 3.3% met criteria for ADHD. All smoking motives significantly moderated the relation between inattentive symptoms and smoking, while most smoking motives (negative reinforcement, tolerance, craving, cognitive enhancement, and weight control) moderated the link between hyperactive/impulsive symptoms and smoking. Results remained significant after controlling for stimulant medication use and conduct disorder symptoms. Conclusions/Importance. Addressing negative reinforcement, craving, social influences, and tolerance in prevention and intervention efforts on college campuses may reduce smoking. Results also highlight the importance of assessing a range of ADHD symptoms in college students as ADHD symptoms, even at subthreshold levels, were associated with increased smoking rates among college students. PMID- 27494647 TI - Effects of active pause pattern of surface electromyographic activity among subjects performing monotonous tasks: A systematic review. AB - Active pauses have shown potentially beneficial effects to increase the variability of the electrical activation pattern of muscles. However, there is a lack of consensus as to how to design and implement those pauses and the processing methods of surface electromyography (EMG) data when evaluating low level monotonous tasks. The aim of this systematic review was to synthesize the evidences regarding the way which active pauses have been applied, and the methods used to investigate the related EMG changes. PubMed-MEDLINE, Embase, Web of Science, Lilacs, Ebsco, and Scopus databases were searched. Two authors independently extracted data from the primary studies. The methodological quality was assessed using a list from van der Windt et al. (2000), and the level of evidence was synthesized through GRADE. The ISEK guideline for reporting EMG data was also applied as a checklist. Fifteen studies were included - 14 with high methodological quality. In general, active pauses were able to change the level of EMG activity in monotonous tasks. The level of evidence through GRADE was very low for all EMG processing methods, except RMS which was low. A vast heterogeneity concerning the methods applied to analyze EMG data contributed to decrease the quality of evidence synthesis, and the findings need to be carefully considered. The GRADE approach and the ISEK guideline contributed to identify important flaws in the literature. Future studies investigating active pauses in longitudinal studies and following the standard for recording and reporting EMG data care are warranted. PMID- 27494648 TI - BRAF and MEK inhibitors in pediatric glioma: new therapeutic strategies, new toxicities. AB - INTRODUCTION: BRAF mutation was initially reported in metastatic melanomas, and more recently in a variety of human cancers. BRAF acts as a down-stream effector of growth factor signaling leading to cell cycle progression, proliferation and survival. Development of selective inhibitors of BRAF has improved the survival of patients with melanoma and offers potential new therapeutic strategy in children with BRAF-mutant glioma. Areas covered: Mechanisms of resistance to BRAF inhibitors have recently been described as due to the paradoxical activation of the MAPK pathway. Combination therapy with BRAF and MEK inhibition has proved capable of overcoming the resistance with effective results in patients with melanoma. Prospective studies in pediatric glioma are warranted. Combination therapy has a different toxicity profile compared to BRAF inhibitor alone. Herein we review the state-of-the-art of toxicities associated with these agents, with a special focus on children. Expert opinion: Some toxicities appear more specific to adults, due to a combination of factors, such as patient age and predisposing risk factors. Moreover, it is recommended that the co-administration of BRAF inhibitors and drugs metabolized by the cytochrome P450 system in the liver be avoided, as this can lead to significant complications secondary to pharmacological interactions. PMID- 27494649 TI - Behavior of Photocarriers in the Light-Induced Metastable State in the p-n Heterojunction of a Cu(In,Ga)Se2 Solar Cell with CBD-ZnS Buffer Layer. AB - We fabricated Cu(In,Ga)Se2 (CIGS) solar cells with a chemical bath deposition (CBD)-ZnS buffer layer grown with varying ammonia concentrations in aqueous solution. The solar cell performance was degraded with increasing ammonia concentration, due to actively dissolved Zn atoms during CBD-ZnS precipitation. These formed interfacial defect states, such as hydroxide species in the CBD-ZnS film, and interstitial and antisite Zn defects at the p-n heterojunction. After light/UV soaking, the CIGS solar cell performance drastically improved, with a rise in fill factor. With the Zn-based buffer layer, the light soaking treatment containing blue photons induced a metastable state and enhanced the CIGS solar cell performance. To interpret this effect, we suggest a band structure model of the p-n heterojunction to explain the flow of photocarriers under white light at the initial state, and then after light/UV soaking. The determining factor is a p+ defect layer, containing an amount of deep acceptor traps, located near the CIGS surface. The p+ defect layer easily captures photoexcited electrons, and then when it becomes quasi-neutral, attracts photoexcited holes. This alters the barrier height and controls the photocurrent at the p-n junction, and fill factor values, determining the solar cell performance. PMID- 27494650 TI - Formulation and evaluation of novel controlled release of topical pluronic lecithin organogel of mefenamic acid. AB - In the present study, pluronic lecithin based organogels (PLO gels) were formulated as topical carrier for controlled delivery of mefenamic acid. Ten organogel formulations were prepared by a method employing lecithin as lipophilic phase and pluronic F-127 as hydrophilic phase in varying concentrations to study various parameters using in vitro diffusion study and in vivo studies. All formulations were found to be off-white, homogenous, and reluctant to be washed easily and have pH value within the range of 5.56-5.80 which is nonirritant. Polymer concentration increased in formulations of F1 to F5 (lecithin) and F6 to F10 (pluronic) resulted in decrease of the gelation temperature, increase of viscosity and reduction of spreadability of gels having polymer tendency to form rigid 3D network. Organogels with higher viscosity were found to be more stable and retard the drug release from the gel. The formulations of F2 and F3 were selected for kinetic studies and stability studies, as they found to have all physical parameters within acceptable limits, highest percent drug content and exhibited highest drug release in eight hours. The order of drug release from various formulations was found to be F2 > F3 > F10 > F4 > F1 > F9 > F8 > F5 > F7 > F6. The optimized formulation F2 was found to follow zero order rate kinetics showing controlled release of the drug from the formulations. In vivo anti inflammatory activity of optimized mefenamic acid organogel (F2) against a standard marketed preparation (Volini gel) was found satisfactory and significant. PMID- 27494652 TI - Femtomolar Detection of Silver Nanoparticles by Flow-Enhanced Direct-Impact Voltammetry at a Microelectrode Array. AB - We report the femtomolar detection of silver (Ag) nanoparticles by direct-impact voltammetry. This is achieved through the use of a random array of microelectrodes (RAM) integrated into a purpose-built flow cell, allowing combined diffusion and convection to the electrode surface. A coupled RAM-flow cell system is implemented and is shown to give reproducible wall-jet type flow characteristics, using potassium ferrocyanide as a molecular redox species. The calibrated flow system is then used to detect and quantitatively size Ag nanoparticles at femtomolar concentrations. Under flow conditions, it is found the nanoparticle impact frequency increases linearly with the volumetric flow rate. The resulting limit of detection is more than 2 orders of magnitude smaller than the previous detection limit for direct-impact voltammetry (900 fM) [J. Ellison et al. Sens. Actuators, B 2014, 200, 47], and is more than 30 times smaller than the previous detection limit for mediated-impact voltammetry (83 fM) [T. M. Alligrant et al. Langmuir 2014, 30, 13462]. PMID- 27494651 TI - NPR3 protects cardiomyocytes from apoptosis through inhibition of cytosolic BRCA1 and TNF-alpha. AB - Natriuretic peptide receptor 3 (NPR3) is a clearance receptor by binding and internalizing natriuretic peptides (NPs) for ultimate degradation. Patients with cardiac failure show elevated NPs. NPs are linked to poor long-term survival because of their apoptotic effects. However, the underling mechanisms have not been identified yet. Here we report the role of NPR3 in anti-apoptosis via the breast cancer type 1 susceptibility protein (BRCA1) and tumor necrosis factor alpha (TNF-alpha ). To demonstrate a role for NPR3 in apoptosis, stable H9C2 cardiomyocyte cell lines using shRNA to knockdown NPR3 were generated. The activities of caspase-3, 8, and 9 were significantly increased in NPR3 knockdown H9C2 cardiomyocytes. Knockdown of NPR3 increased the expression of BRCA1. Also NPR3 knockdown remarkably increased the activity of cAMP response element-binding protein (CREB), a positive regulatory element for BRCA1 expression. BRCA1 showed dispersed nuclear localization in non-cardiomyocytes while predominantly cytoplasmic localization in H9C2 cells. Meanwhile, NPR3 knockdown significantly increased TNF-alpha gene expression. These data show that NPR3 knockdown in H9C2 cells triggered both extrinsic and intrinsic apoptotic pathways. NPR3 protects cardiomyocytes from apoptosis through inhibition of cytosolic BRCA1 and TNF alpha, which are regulators of apoptosis. Our studies demonstrate anti-apoptosis role of NPR3 in protecting cardiomyocytes and establish the first molecular link between NP system and programmed cell death. PMID- 27494653 TI - Tradeoffs of strategically reconnecting rivers to their floodplains: The case of the Lower Illinois River (USA). AB - During the latter half of the 19th Century and first half of the 20th Century, the Illinois River was heavily altered through leveeing off large portions of its floodplain, draining wetlands, and the construction of dams and river-training structures that facilitated navigation. As a result of these alterations, flood stages continue to rise, increasing flood risk and threatening to overtop levees along the La Grange Segment (LGS) of the Illinois River. Over the last two decades, more emphasis has been placed on reconnecting portions of floodplains to rivers in order to solve the long-term problem of rising flood heights attributed to continual heightening of levees to provide flood protection. Multiple studies have suggested that strategically reconnecting larger portions of the LGS could result in more sustainable floodplain management. However, the true costs and benefits of reconnecting the floodplain are not known. We use a novel hydrodynamic, geospatial, economic, and habitat suitability framework to assess the tradeoffs of strategically reconnecting the Illinois River to its floodplain in order to decrease flood risk, improve floodplain habitats, and limit the costs of reconnection. Costs include building-associated losses, lost agricultural profits, and levee removal and construction costs. Tested scenarios demonstrate that while flood heights and environmental benefits are maximized through the most aggressive levee setbacks and removals, these scenarios also have the highest costs. However, the tradeoff of implementing lower-cost scenarios is that there is less flood-height reduction and less floodplain habitat available. Several individual levee districts have high potential for reconnection based on limiting potential damages as well as providing floodplain habitat. To implement large-scale strategic floodplain reconnection, costs range from $1.2-$4.3 billion. As such, payments for ecosystem services will likely be necessary to compensate landowners for decreased long-term agricultural production and building losses that result in flood-reduction benefits and increased floodplain habitat. PMID- 27494654 TI - Testing approaches for calculating stomatal ozone fluxes from passive samplers. AB - Current ozone (O3) levels are high enough to negatively affect vegetation and may become worse in the future. Ozone risk assessments have recently shifted from exposure-based to flux-based metrics. Modeling stomatal O3 fluxes requires hourly O3 and meteorological data, which are not always available. Large datasets of O3 concentrations measured with passive samplers exist worldwide, and usually provide weekly to monthly means. We tested the suitability of using aggregated data instead of hourly data for O3 flux calculations with 3-year time series of O3 data from 24 Spanish air quality stations. Five different approaches and three different parameterizations were tested. Ozone-averaged values in combination with hourly meteorological data provided the most robust estimates of accumulated O3 fluxes (Phytotoxic Ozone Dose with no threshold, POD0), and the median of the absolute percent error (MAPE) due to aggregation came close to 5%. Aggregations from 1week to 1month yielded similar errors, which is important in the cost efficiency terms of the chosen passive sampler exposure periodicity. One major limitation of these approaches is that they are not suitable for high POD thresholds, and that accuracy of the measurements with passive samplers has to be strictly assured in order to finally obtain acceptable errors. A combination of meteorological data and O3 passive sampler measurements may be used to estimate O3 fluxes at remote forest sites as a valuable risk assessment tool. PMID- 27494655 TI - Temporal variation of sedimentation rates and potential factors influencing those rates over the last 100years in Bohai Bay, China. AB - Fourteen sediment cores were collected from Bohai Bay, China, which is close to the fast-developing megacities such as Beijing and Tianjin, and dated using excess Pb-210 and Cs-137. Using the constant rate of supply model (CRS), the temporal variation of sedimentation rates over the last 100years in Bohai Bay was determined, and its main factors influencing sedimentation rates were discussed. The sedimentation rates before 1980 were relatively stable, ranging from 0.26+/ 0.04g/(cm2.y) in 1920 to 0.39+/-0.08g/(cm2.y) in 1980. A gradual increase in sedimentation rate was found from 0.39+/-0.08g/(cm2.y) in 1980 to 0.84+/ 0.13g/(cm2.y) in 2010. Riverine input was the main factors influencing sedimentation rates in Bohai Bay before 1980. After 1980, the accelerated increase in sedimentation rate may be attributed to the large-scale reclamation along the coastline. It is worth noting that eutrophication caused by an increase in sewage discharge and overuse of chemical fertilizer, also may influence recent acceleration in sedimentation rate. PMID- 27494656 TI - Characterization of brominated flame retardants in construction and demolition waste components: HBCD and PBDEs. AB - The vast majority of construction material is inert and can be managed as nonhazardous. However, structures may have either been built with some environmentally unfriendly substances such as brominated flame retardants (BFRs), or have absorbed harmful elements such as heavy metals. This study focuses on end of-life construction materials, i.e. construction and demolition (C&D) waste components. The aim was to characterize the concentration of extremely harmful substances, primarily BFRs, including hexabromocyclododecane (HBCD) and polybrominateddiphenyl ethers (PBDEs). Results revealed extremely high contents of HBCD and PBDEs in typical C&D waste components, particularly polyurethane foam materials. Policies should therefore be developed for the proper management of C&D waste, with priority for POP-containing debris. The first priority is to develop a classification system and procedures to separate out the harmful materials for more extensive processing. Additionally, identification and quantification of the environmental implications associated with dumping dominated disposal of these wastes are required. Finally, more sustainable materials should be selected for use in the construction industry. PMID- 27494657 TI - Arbuscular mycorrhizal fungi-assisted phytoremediation of a lead-contaminated site. AB - Knowledge of the behavior of plant species associated with arbuscular mycorrhizal fungi (AMF) and the ability of such plants to grow on metal-contaminated soils is important to phytoremediation. Here, we evaluate the occurrence and diversity of AMF and plant species as well as their interactions in soil contaminated with lead (Pb) from the recycling of automotive batteries. The experimental area was divided into three locations: a non-contaminated native area, a coarse rejects deposition area, and an area receiving particulate material from the chimneys during the Pb melting process. Thirty-nine AMF species from six families and 10 genera were identified. The Acaulospora and Glomus genera exhibited the highest occurrences both in the bulk (10 and 6) and in the rhizosphere soils (9 and 6). All of the herbaceous species presented mycorrhizal colonization. The highest Pb concentrations (mgkg-1) in roots and shoots, respectively, were observed in Vetiveria zizanoides (15,433 and 934), Pteris vitata (9343 and 865), Pteridim aquilinun (1433 and 733), and Ricinus communis (1106 and 625). The diversity of AMF seems to be related to the area heterogeneity; the structure communities of AMF are correlated with the soil Pb concentration. We found that plant diversity was significantly correlated with AMF diversity (r=0.645; P>0.05) in areas with high Pb soil concentrations. A better understanding of AMF communities in the presence of Pb stress may shed light on the interactions between fungi and metals taking place in contaminated sites. Such knowledge can aid in developing soil phytoremediation techniques such as phytostabilization. PMID- 27494658 TI - Alpine vegetation phenology dynamic over 16years and its covariation with climate in a semi-arid region of China. AB - Vegetation phenology is a sensitive indicator of ecosystem response to climate change, and plays an important role in the terrestrial biosphere. Improving our understanding of alpine vegetation phenology dynamics and the correlation with climate and grazing is crucial for high mountains in arid areas subject to climatic warming. Using a time series of SPOT Normalized Difference Vegetation Index (NDVI) data from 1998 to 2013, the start of the growing season (SOS), end of the growing season (EOS), growing season length (GSL), and maximum NDVI (MNDVI) were extracted using a threshold-based method for six vegetation groups in the Heihe River headwaters. Spatial and temporal patterns of SOS, EOS, GSL, MNDVI, and correlations with climatic factors and livestock production were analyzed. The MNDVI increased significantly in 58% of the study region, whereas SOS, EOS, and GSL changed significantly in <5% of the region. The MNDVI in five vegetation groups increased significantly by a range from 0.045 to 0.075. No significant correlation between SOS and EOS was observed in any vegetation group. The SOS and GSL were highly correlated with temperature in May and April-May, whereas MNDVI was correlated with temperature in August and July-August. The EOS of different vegetation groups was correlated with different climatic variables. Maximum and minimum temperature, accumulated temperature, and effective accumulated temperature showed stronger correlations with phenological metrics compared with those of mean temperature, and should receive greater attention in phenology modeling in the future. Meat and milk production were significantly correlated with the MNDVI of scrub, steppe, and meadow. Although the MNDVI increased in recent years, ongoing monitoring for rangeland degradation is recommended. PMID- 27494659 TI - Reduced carbon sequestration potential of biochar in acidic soil. AB - Biochar application in soil has been proposed as a promising method for carbon sequestration. While factors affecting its carbon sequestration potential have been widely investigated, the number of studies on the effect of soil pH is limited. To investigate the carbon sequestration potential of biochar across a series of soil pH levels, the total carbon emission, CO2 release from inorganic carbon, and phospholipid fatty acids (PLFAs) of six soils with various pH levels were compared after the addition of straw biochar produced at different pyrolysis temperatures. The results show that the acidic soils released more CO2 (1.5-3.5 times higher than the control) after the application of biochar compared with neutral and alkaline soils. The degradation of both native soil organic carbon (SOC) and biochar were accelerated. More inorganic CO2 release in acidic soil contributed to the increased degradation of biochar. Higher proportion of gram positive bacteria in acidic soil (25%-36%) was responsible for the enhanced biochar degradation and simultaneously co-metabolism of SOC. In addition, lower substrate limitation for bacteria, indicated by higher C-O stretching after the biochar application in the acidic soil, also caused more CO2 release. In addition to the soil pH, other factors such as clay contents and experimental duration also affected the phsico-chemical and biotic processes of SOC dynamics. Gram negative/gram-positive bacteria ratio was found to be negatively related to priming effects, and suggested to serve as an indicator for priming effect. In general, the carbon sequestration potential of rice-straw biochar in soil reduced along with the decrease of soil pH especially in a short-term. Given wide spread of acidic soils in China, carbon sequestration potential of biochar may be overestimated without taking into account the impact of soil pH. PMID- 27494660 TI - A preliminary nationwide survey of the presence of emerging contaminants in drinking and source waters in Brazil. AB - This is the first nationwide survey of emerging contaminants in Brazilian waters. One hundred drinking water samples were investigated in 22 Brazilian state capitals. In addition, seven source water samples from two of the most populous regions of the country were evaluated. Samples were collected from June to September of 2011 and again during the same period in 2012. The study covered emerging contaminants of different classes, including hormones, plasticizers, herbicides, triclosan and caffeine. The analytical method for the determination of the compounds was based on solid-phase extraction followed by analysis via liquid chromatography electrospray triple-quadrupole mass spectrometry (LC MS/MS). Caffeine, triclosan, atrazine, phenolphthalein and bisphenol A were found in at least one of the samples collected in the two sampling campaigns. Caffeine and atrazine were the most frequently detected substances in both drinking and source water. Caffeine concentrations in drinking water ranged from 1.8ngL-1 to values above 2.0MUgL-1 while source-water concentrations varied from 40ngL-1 to about 19MUgL-1. For atrazine, concentrations were found in the range from 2.0 to 6.0ngL-1 in drinking water and at concentrations of up to 15ngL-1 in source water. The widespread presence of caffeine in samples of treated water is an indication of the presence of domestic sewage in the source water, considering that caffeine is a compound of anthropogenic origin. PMID- 27494661 TI - Detecting the impact of heavy metal contaminated sediment on benthic macroinvertebrate communities in tropical streams. AB - The effects of heavy metal pollution on benthic macroinvertebrate communities in tropical streams draining ultramafic systems have not been explored, despite a pressing need for ecological risk assessment to protect and manage aquatic ecosystems in these areas. The objective of this study was to examine benthic macroinvertebrate community composition in relation to metal concentrations in stream sediments and other physico-chemical variables in the Manyame River system, which drains part of the Great Dyke of Zimbabwe. Benthic macroinvertebrate sampling and community composition analysis, sediment collection, processing and metal analysis and assessment of other variables in the water column were done once at 55 sampling sites: 12 urban, 30 communal (i.e. sparsely populated rural areas, with livelihoods centred around subsistence agriculture) and 11 Great Dyke sites. Canonical correspondence analysis and partial canonical correspondence analysis (pCCA) were used to determine the importance of sediment heavy metal concentrations in explaining benthic macroinvertebrate community composition in comparison with other factors. Water quality ranged from very poor for urban locations due to sewage pollution, to good in communal locations. Significantly high concentrations of metals (ANOVA, p<0.05) and high magnesium/calcium (Mg/Ca) ratio were recorded in sediments for the Great Dyke site locations. The Mg/Ca ratio, Ca2+, Cr3+ and K+ were found to be important metals structuring benthic macroinvertebrate communities in the study streams, with metals explaining a larger percentage (58.0%) of the total variation explained compared to other variables (35.9%). However, taxa richness, diversity, evenness, percentage of Ephemeroptera, Plecoptera Trichoptera related metrics were higher at some Great Dyke sites than at communal sites. Thus, measures of taxa richness, diversity and %EPT may provide misleading information when assessing heavy metals in moderately polluted environments as in this study. Assessment of tropical streams draining ultramafic systems that are heavy metal contaminated should also include benthic invertebrate community structure analysis, as it is possible that common endpoints, such as %EPT, may not identify impacts to aquatic communities. PMID- 27494662 TI - The relation between outcome expectation, therapeutic alliance, and outcome among depressed patients in group cognitive-behavioral therapy. AB - OBJECTIVE: Although patients' expectation for improvement correlates with their treatment outcome, there remains limited information regarding the mechanisms through which outcome expectation influences outcome. Although several studies have revealed alliance as a mediator of the expectancy-outcome relation, most have focused on individual psychotherapy only. More research is needed examining mediators, including alliance quality, of the outcome expectation-outcome relation in group therapy. METHOD: This study focused on such associative chains among 91 depressed outpatients who completed 10 weeks of group cognitive behavioral therapy. We conducted simple and multiple mediation analyses, accounting for the nested data structure. RESULTS: As predicted, we found: (i) The relations between baseline outcome expectation and both posttreatment anxiety and depression were mediated by alliance quality; (ii) the early therapy outcome expectation-posttreatment anxiety relation was mediated by mid-treatment alliance; (iii) the relation between early alliance and posttreatment interpersonal problems was mediated by during-therapy outcome expectation; and (iv) the relation between baseline outcome expectation and posttreatment interpersonal problems was mediated by two variables acting in turn, early alliance and during-therapy outcome expectation. All other tested models were not significant. CONCLUSIONS: Results suggest that bidirectional relations between outcome expectation and alliance, with both directions influencing outcome. Clinical and empirical implications are discussed. PMID- 27494663 TI - Discrimination and mental health among Latinos: variation by place of origin. AB - The US Latino population experiences high rates of discrimination, which may contribute to psychiatric disorders. Yet, little is known about the distinctions in this relationship for Latino subgroups. Using data from the National Latino and Asian American study, we examined the association between discrimination and mental health for 2503 Latinos. Logistic regression analyses were used to examine variation in the relationship by place of origin (Cuba, Puerto Rico, Mexico, or Other). Results suggest that perceived discrimination increased the probability of having a psychiatric disorder. The effect of discrimination on having a psychiatric disorder was greater for Mexicans than Puerto Ricans. The findings of this study suggest that variation exists in the relationship between discrimination and mental health by origin. Implications for practice include increasing awareness of place of origin, in addition to discrimination, as a risk factor for mental illness. Future research should examine this relationship longitudinally and consider immigration status. PMID- 27494665 TI - "If You See Something, Say Something". PMID- 27494664 TI - Cytotoxic Tirucallane and Apotirucallane Triterpenoids from the Stems of Picrasma quassioides. AB - Phytochemical investigation on the stems of Picrasma quassioides led to the isolation of a novel compound, picraquassin A (1), with an unprecedented 21,24 cycloapotirucallane skeleton, and four new apotirucallane-type triterpenoids (2 5), together with 15 new tirucallane-type triterpenoids (6-20) and 10 known tirucallane-type triterpenoids (21-30). To our knowledge, this is the first report demonstrating the presence of apotirucallane-type triterpenoids in the genus Picrasma. The structures of the new compounds were determined based on spectroscopic data interpretation. Cytotoxicities of the isolated compounds were evaluated using three human cancer cell lines, MKN-28, A-549, and MCF-7. Compound 2 exhibited the most potent activity against MKN-28 cells with an IC50 value of 2.5 MUM. Flow cytometry and Western blot analysis revealed that 2 induces the apoptosis of MKN-28 cells via activating caspase-3/-9, while increasing Bax and Bad and decreasing Bcl-2 expression levels. PMID- 27494666 TI - ADARs Edit MicroRNAs to Promote Leukemic Stem Cell Activity. AB - Leukemic stem cells (LSCs) drive progression of chronic myeloid leukemia (CML) and tyrosine kinase inhibitor resistance through poorly understood mechanisms. Now in Cell Stem Cell, Zipeto et al. (2016) show targeting the RNA editing enzyme ADAR1 restores expression of let-7 and efficiently kills LSCs, providing an innovative therapeutic target in CML. PMID- 27494667 TI - Stressed-Out HSCs Turn Up p38alpha and Purine to Proliferate. AB - Changes in cellular metabolism drive hematopoietic stem cell (HSC) behavior during homeostasis, although whether they control HSC behavior during stress conditions is unclear. In this issue of Cell Stem Cell, Karigane et al. (2016) identify a p38alpha-dependent pathway that alters purine metabolism in HSCs during stress hematopoiesis, promoting hematopoietic recovery. PMID- 27494668 TI - Neural Differentiation in the Third Dimension: Generating a Human Midbrain. AB - In recent years, technological improvements in three-dimensional (3D) culture systems have enabled the generation of organoids or spheroids representing a variety of tissues, including the brain. In this issue of Cell Stem Cell, Jo et al. (2016) describe a 3D culture model of the human midbrain containing dopaminergic neurons and neuromelanin. PMID- 27494669 TI - Mesoderm, Cooked Up Fast and Served to Order. AB - New sequencing technologies have made it possible to interrogate with unprecedented depth the intrinsic changes experienced by cells as they transit the arena of development. Recently in Cell, Loh, Chen, and colleagues investigated early lineage-restricted human mesoderm cell types and their precursors going back to pluripotency (Loh et al., 2016). PMID- 27494670 TI - Hematopoietic Lineage Diversification, Simplified. AB - Hematopoiesis is a complex process that requires a high degree of transcriptional diversification during lineage commitment and differentiation. de Graaf et al. (2016) have now generated a comprehensive gene expression dataset that allows cell-type-specific genes as well as associated transcription factor expression patterns to be readily identified. PMID- 27494671 TI - Deteriorating Infrastructure in the Aged Muscle Stem Cell Niche. AB - Following an injury, the extracellular matrix (ECM) undergoes dramatic remodeling to facilitate tissue repair. In a new study, Lukjanenko and colleagues show how an age-associated change in this process affects the regenerative ability of muscle stem cells (MuSCs). PMID- 27494672 TI - Current Public Support for Human-Animal Chimera Research in Japan Is Limited, Despite High Levels of Scientific Approval. PMID- 27494673 TI - Global Distribution of Businesses Marketing Stem Cell-Based Interventions. AB - A structured search reveals that online marketing of stem-cell-based interventions is skewed toward developed economies including the United States, Ireland, Australia, and Germany. Websites made broad, imprecise therapeutic claims and frequently failed to detail procedures. Widespread marketing poses challenges to regulators, bioethicists, and those seeking realistic hope from therapies. PMID- 27494675 TI - Environmental factors in the etiology of isolated and nonisolated esophageal atresia in a Chinese population: A case-control study. AB - BACKGROUND: Esophageal atresia (EA) is a common birth defect that occurs with tracheoesophageal fistula (TEF), although etiological studies on EA/TEF have produced inconsistent results. METHODS: The aim of this study was to examine the association between environmental factors during pregnancy and the risk of EA/TEF in a Chinese population. Cases of isolated EA and nonisolated EA and unaffected controls were identified between July 2005 and November 2015, and face-to-face questionnaires concerning exposure to environmental factors were administered to the birth mothers of 130 cases and 400 controls. The adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the association between environmental factors and the risk of EA/TEF. RESULTS: The results of this case control study suggest that lower maternal education (p < 0.0001), maternal binge drinking (OR = 2.63; 95% CI, 1.05-6.6) and pickled food consumption (OR = 2.04; 95% CI, 1.31-3.71) during pregnancy increase the risk of EA in offspring, while maternal folic acid supplementation (OR = 0.45; 95% CI, 0.29-0.71) is significantly associated with a decreased risk of EA. CONCLUSION: These results suggest a role for environmental exposures in the etiology of EA/TEF; however, further studies are needed to replicate the observed associations. Birth Defects Research (Part A) 106:840-846, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27494674 TI - Contributions of Mammalian Chimeras to Pluripotent Stem Cell Research. AB - Chimeras are widely acknowledged as the gold standard for assessing stem cell pluripotency, based on their capacity to test donor cell lineage potential in the context of an organized, normally developing tissue. Experimental chimeras provide key insights into mammalian developmental mechanisms and offer a resource for interrogating the fate potential of various pluripotent stem cell states. We highlight the applications and current limitations presented by intra- and inter species chimeras and consider their future contribution to the stem cell field. Despite the technical and ethical demands of experimental chimeras, including human-interspecies chimeras, they are a provocative resource for achieving regenerative medicine goals. PMID- 27494676 TI - Risk Factors for Glaucoma in a Cohort of Patients with Fuchs Heterochromic Iridocyclitis. AB - PURPOSE: To describe the incidence and risk factors for ocular hypertension and/or glaucoma in patients with Fuchs heterochromic iridocyclitis (FHC). METHODS: Retrospective analysis of 88 patients with FHC. Kaplan-Meier curves estimated the time to develop cataract and ocular hypertension/glaucoma. Possible prognostic factors were investigated in univariate Kaplan-Meier analyses using the Mantel-Cox logrank test. RESULTS: At presentation with FHC, 52% of patients had a cataract and 26% of patients had ocular hypertension/glaucoma. The estimated percentage of patients with a cataract or ocular hypertension/glaucoma by 4 years after presentation was 71% (CI: 58-81%) and 39% (CI: 28-51%), respectively. Patients aged >=50 years had significantly greater risk of developing glaucoma (p = 0.0065). After adjusting for age-group, having a cataract at presentation was associated with increased risk of glaucoma (p = 0.032). CONCLUSIONS: Risk factors for development of ocular hypertension/glaucoma were increasing patient age and having a cataract at presentation with FHC. PMID- 27494677 TI - Finding Peace Beyond the Pain: Sunder's Journey in the Hospice. AB - Dame Cicely Saunders revolutionized the concept of pain by coining the term "total pain", the sum of the physical, psychological, social, spiritual, emotional components that make up the total pain experience. Optimal pain relief may not be possible until all elements of the pain and suffering are addressed. This narrative describes the journey of Sunder in the hospice. A caring husband, and a doting father, he came to the hospice by force, in immense pain and suffering. He stayed on by choice and found the peace he was looking for beyond his pain and sufferings, ably supported by the dedicated hospice team. He was able to live the last few months of his life as comfortably as was possible, and left this world in peace, with dignity. The narrative reiterates the belief that hospice, with its philosophy of active "total care" is an ideal place for addressing the concept of "total pain." PMID- 27494678 TI - Adverse effects of bisphenol A (BPA) on the dopamine system in two distinct cell models and corpus striatum of the Sprague-Dawley rat. AB - The aim of this study was to examine the effects of bisphenol A (BPA) on the brain dopamine (DA) system utilizing both in vitro models (GH3 cells, a rat pituitary cell line, and SH-SY5Y cells, a human neuroblastoma cell line) and an animal model such as Sprague-Dawley (SD) rats. First, cellular DA uptake was measured 2 or 8 h following BPA exposure (0.1-400 MUM) in SH-SY5Y cells, where a significant increase in DA uptake was noted. BPA exerted no marked effect on dopamine active transporter levels in GH3 cells exposed for 8 or 24 h. However, SH-SY5Y cells displayed an increase in dopamine transporter (DAT) levels following 24 h of exposure to BPA. In contrast to DAT levels, BPA exposure produced no marked effect on DA D1 receptor levels in SH-SY5Y cells, yet a significant decrease in GH3 cells following both 8- and 24-h exposure periods was noted, suggesting that BPA exerts differential effects dependent upon cell type. BPA produced no significant effects on prolactin levels at 2 h, but a marked fall occurred at 24 h of exposure in GH3 cells. Finally, to examine the influence of dietary developmental exposure to BPA on brain DA levels in F1 offspring, SD rats were exposed to BPA (0.5-20 mg/kg) through maternal transfer and/or diet and striatal DA levels were measured on postnatal day (PND) 60 using high-performance liquid chromatography (HPLC). Data demonstrated that chronic exposure to BPA did not significantly alter striatal DA levels in the SD rat. PMID- 27494679 TI - [Femtosecond Laser-Assisted Cataract Surgery: Current Status and Outlook]. PMID- 27494680 TI - [Ocular Lymphomas]. PMID- 27494681 TI - [Management of Periocular Soft Tissue Injuries]. PMID- 27494682 TI - [LASIK and Femto-LASIK]. PMID- 27494683 TI - High-fat diet plus carbon tetrachloride-induced liver fibrosis is alleviated by betaine treatment in rats. AB - Steatosis, the first lesion in non-alcoholic fatty liver disease (NAFLD), may progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Steatosis predisposes the liver to oxidative stress, inflammation, and cytokines. Betaine (BET) has antioxidant, antiinflammatory and hepatoprotective effects. However, the effects of BET on liver fibrosis development are unknown. Rats were treated with high-fat diet (60% of total calories from fat) for 14weeks. Carbon tetrachloride (0.2mL/kg; two times per week; i.p.) was administered to rats in the last 6weeks with/without commercial food containing BET (2%; w/w). Serum liver function tests and tumor necrosis factor-alpha, insulin resistance, hepatic triglyceride (TG) and hydroxyproline (HYP) levels and oxidative stress parameters were determined along with histopathologic observations. Alpha-smooth muscle actin (alpha-SMA), transforming growth factor-beta1 (TGF-beta1) and type I collagen (COL1A1) protein expressions and mRNA expressions of matrix metalloproteinase-2 (MMP-2) and its inhibitors (TIMP-1 and TIMP-2) were evaluated. BET decreased TG and HYP levels, prooxidant status and fibrotic changes in the liver. alpha-SMA, COL1A1 and TGF-beta1 protein expressions, MMP-2, TIMP-1, and TIMP-2 mRNA expressions diminished due to BET treatment. BET has an antifibrotic effect and this effect may be related to its antioxidant and antiinflammatory actions together with suppression on HSC activation. PMID- 27494684 TI - Asiatic acid inhibits pulmonary inflammation induced by cigarette smoke. AB - Asiatic acid (AA) is one of the major components of Titrated extract of Centella asiatica (TECA), which has been reported to possess antioxidant and anti inflammatory activities. The purpose of this study was to investigate the protective effect of AA on pulmonary inflammation induced by cigarette smoke (CS). AA significantly attenuated the infiltration of inflammatory cells in bronchoalveolar lavage fluid (BALF) of CS exposure mice. AA also decreased ROS production and NE activity, and inhibited the release of proinflammatory cytokines in BALF. AA reduced the recruitment of inflammatory cells and MCP-1 expression in lung tissue of CS exposure mice. AA also attenuated mucus overproduction, and decreased the activation of MAPKs and NF-kB in lung tissue. Furthermore, AA increased HO-1 expression and inhibited the reduced expression of SOD3 in lung tissue. These findings indicate that AA effectively inhibits pulmonary inflammatory response, which is an important process in the development of chronic obstructive pulmonary disease (COPD) via suppression of inflammatory mediators and induction of HO-1. Therefore, we suggest that AA has the potential to treat inflammatory disease such as COPD. PMID- 27494685 TI - Enhanced effect of kappa-carrageenan on TNBS-induced inflammation in mice. AB - BACKGROUND: As a sulfated polysaccharide, carrageenan has been widely used as common food additive. METHODS: In the present study, we investigated the effects of kappa-carrageenan on TNBS-induced gut inflammation in mice. BALB/c mice were pretreated with kappa-carrageenan for 14days prior to the administration of TNBS. RESULTS: Our results showed that kappa-carrageenan pretreatment aggravated the loss of body weight and further increased the mortality rate. Histological and morphological analyses revealed that the TNBS-induced colonic inflammation was deteriorated by the kappa-carrageenan administration. The ratio of CD4(+)CD25(+)CD127dim/CD4(+) of the kappa-carrageenan+TNBS groups was significantly lower than that of the TNBS group. The expression of IL-2, TNF alpha and IL-6 was significantly increased, whereas the expression of IL-10 was significantly decreased in the kappa-carrageenan+TNBS groups. In addition, kappa carrageenan, together with TNBS, decreased the enzyme activity of SOD and GSH-px and up-regulated the expression of TLR4, NF-kappaB, p-ERK, p-JNK, p-Jun., IL-8 and MDA in the colonic mucosa. CONCLUSIONS: kappa-Carrageenan aggravated the TNBS induced intestinal inflammation, and such an effect could be associated with the oxidative stress and activation of TLR4-NF-kappaB and MAPK/ERK1/2 pathway. PMID- 27494686 TI - Lipoxin A4 protects against lipopolysaccharide-induced sepsis by promoting innate response activator B cells generation. AB - Sepsis is a serious disease that leads to severe inflammation, dysregulation of immune system, multi-organ failure and death. Innate response activator (IRA) B cells, which produce granulocyte-macrophage colony-stimulating factor (GM-CSF), protect against microbial sepsis. Lipid mediator lipoxin A4 (LXA4) exerts anti inflammatory and immunoregulatory effects, and it has been reported that LXA4 receptor ALX/FPR2 is expressed on B cells. Here, we investigated the potential role of LXA4 on IRA B cells in lipopolysaccharide (LPS)-induced sepsis. We found that LXA4 significantly promoted the expansion of splenic IRA B cells and increased GM-CSF expression in splenic B cells with LPS stimulation. After splenectomy, LXA4 treatment did not change the serum or peritoneal IL-1beta, IL-6 and TNF-alpha levels in LPS-induced sepsis. LXA4 accelerated the migration of peritoneal B cells to spleen for their differentiation into IRA B cells, whereas this effect was independent of peritoneal macrophage. Furthermore, LXA4 enhanced the phosphorylation level of signal transducer and activator of transcription 5 (STAT5) in splenic B cells. These results suggest that LXA4 protects against LPS induced sepsis by promoting the generation and migration of splenic IRA B cells, and the underlying molecular mechanism may be related to STAT5 activation. It might provide new insights and therapeutic approaches for treating sepsis. PMID- 27494687 TI - Betahistine attenuates murine collagen-induced arthritis by suppressing both inflammatory and Th17 cell responses. AB - The objective of this study was to evaluate the potential therapeutic effects of betahistine dihydrochloride (betahistine) in a collagen-induced arthritis (CIA) mouse model. CIA was induced in DBA/1 male mice by primary immunization with 100MUl of emulsion containing 2mg/ml chicken type II collagen (CII) mixed with complete Freund's adjuvant (CFA) in an 1:1 ratio, and booster immunization with 100MUl of emulsion containing 2mg/ml CII mixed with incomplete Freund's adjuvant (IFA) in an 1:1 ratio. Immunization was performed subcutaneously at the base of the tail. After being boosted on day 21, betahistine (1 and 5mg/kg) was orally administered daily for 2weeks. The severity of CIA was determined by arthritic scores and assessment of histopathological joint destruction. Expression of cytokines in the paw and anti-CII antibodies in the serum was evaluated by ELISA. The proliferative response against CII in the lymph node cells was measured by (3)H-thymidine incorporation assay. The frequencies of different CII specific CD4(+) T cell subsets in the lymph node were determined by flow-cytometric analysis. Betahistine treatment attenuated the severity of arthritis and reduced the levels of pro-inflammatory cytokines, including TNF-alpha, IL-6, IL-23 and IL 17A, in the paw tissues of CIA mice. Lymph node cells from betahistine-treated mice showed a decrease in proliferation, as well as a lower frequency of Th17 cells. In vitro, betahistine suppressed CD4(+) T cell differentiation into Th17 cells. These results indicate that betahistine is effective in suppressing both inflammatory and Th17 responses in mouse CIA and that it may have therapeutic value as an adjunct treatment for rheumatoid arthritis. PMID- 27494688 TI - Depletion of T lymphocytes ameliorates cardiac fibrosis in streptozotocin-induced diabetic cardiomyopathy. AB - T cell infiltration has been associated with increased coronary heart disease risk in patients with diabetes mellitus. Effect of modulation of T cell trafficking on diabetes-induced cardiac fibrosis has yet to be determined. Therefore, our aim was to investigate the circulatory T cell depletion-mediated cardioprotection in streptozotocin-induced diabetic cardiomyopathy. Fingolimod (FTY720), an immunomodulatory drug, was tested in wild-type (WT) C57BL/6 and recombination activating gene 1 (Rag1) knockout (KO) mice without mature lymphocytes in streptozotocin-induced type 1 diabetic model. FTY720 (0.3mg/kg/day) was administered intraperitoneally daily for the first 4weeks with interim 3weeks then resumed for another 4weeks in 11weeks study period. T lymphocyte counts, cardiac histology, function, and fibrosis were examined in diabetic both WT and KO mice. FTY720 reduced both CD4(+) and CD8(+) T cells in diabetic WT mice. FTY720-treated diabetic WT mouse myocardium showed reduction in CD3 T cell infiltration and decreased expression of S1P1 and TGF-beta1 in cardiac tissue. Fibrosis was reduced after FTY720 treatment in diabetic WT mice. Rag1 KO mice exhibited no CD4(+) and CD8(+) T cells in the blood and CD3 T cells in the heart. Diabetic Rag1 KO mouse hearts appeared no fibrosis and exhibited preserved myocardial contractility. FTY720-induced antifibrosis was abolished in diabetic Rag1 KO mice. These findings demonstrate that chronic administration with FTY720 induces lymphopenia and protects diabetic hearts in WT mice whereas FTY720 increases cardiac fibrosis and myocardial dysfunction in diabetic Rag1 KO mice without mature lymphocytes. PMID- 27494689 TI - Effects of rule changes on physical demands and shot characteristics of elite standard men's squash and implications for training. AB - The physical demands and rally characteristics of elite-standard men's squash have not been well documented since recent rule changes (scoring and tin height). This information is needed to design optimal training drills for physical conditioning provided here based on an analysis of movement and shot information. Matches at the 2010 (n = 14) and 2011 (n = 27) Rowe British Grand Prix were analysed. Rallies were split into four ball-in-play duration categories using the 25th (short), 75th (medium), 95th percentiles (long) and maximum values. Cohen's d and chi-squared tests of independence evaluated effects of rally and rule changes on patterns of play. The proportion of long, middle and short shots was related to the duration of the rally with more shots played in the middle and front of the court in short rallies (phi = 0.12). The frequencies of shots played from different areas of the court have not changed after the adoption of new rules but there is less time available to return shots that reflect the attacking nature of match play for elite-standard men players. Aspiring and current elite standard players need to condition themselves to improve their ability to cope with these demands using the ghosting patterns presented that mimic demands of modern match play. PMID- 27494690 TI - Ab initio study of magnetoelectric coupling in La0.66Sr0.33MnO3 / PbZr0.2Ti0.8O3 multiferroic heterostructures. AB - Multiferroic heterostructures composed of thin layers of ferromagnetic and ferroelectric perovskites have attracted considerable attention in recent years. We apply ab initio computational methods based on density functional theory to study the magnetoelectric coupling at the (0 0 1) interface between [Formula: see text] (LSMO) and [Formula: see text] (PZT). Our study demonstrates that the ferroelectric polarization of PZT has a strong influence on the distribution of magnetization in LSMO. The presence of polarized PZT changes the balance between the ferromagnetic and antiferromagnetic states of LSMO. The observed interfacial magnetoelectric effect can be explained by the variation of the charge density across the LSMO/PZT interface and by the change of the magnetic order in the LSMO layer adjacent to PZT. PMID- 27494691 TI - The Structure of the Carbene Stabilized Si2H2 May Be Equally Well Described with Coordinate Bonds as with Classical Double Bonds. AB - The cyclic alkyl(amino) carbene stabilized Si2H2 has been isolated in the molecular form of composition (Me-cAAC:)2Si2H2 (1) and (Cy-cAAC:)2Si2H2 (2) at room temperature. Compounds 1 and 2 were synthesized from the reduction of HSiCl3 using 3 equiv of KC8 in the presence of 1 equiv of Me-cAAC: and Cy-cAAC:, respectively. These are the first molecular examples of Si2H2 characterized by single crystal X-ray structural analysis. Moreover, electrospray ionization mass spectrometry and (1)H as well as (29)Si NMR data are reported. Furthermore, the structure of compound 1 has been investigated by theoretical methods. The theoretical analysis of 1 explains equally well its structure with coordinate bonds as with classical double bonds of a 2,3-disila-1,3-butadiene. PMID- 27494692 TI - Real world evidence of use of anti-VEGF therapy in Denmark. AB - OBJECTIVE: This study evaluates real-world evidence regarding the frequency of anti-vascular-endothelial-growth-factor (VEGF) injections during the first year of therapy of treatment-naive patients with neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME) and retinal vein occlusion (RVO) from the Danish National Patient Registry. There was a switch in anti-VEGF treatment for naive nAMD patients during the study period, following the introduction of aflibercept, which was expected to reduce the injection frequency relative to ranibizumab due to a perception of prolonged treatment duration of aflibercept. METHODS: All treatment-naive nAMD, DME or RVO patients who received an intravitreal injection in Denmark from 1 January 2012 to 31 July 2015 were eligible for inclusion. Patients were required to have been treated for at least one year and, for nAMD, to have received at least three injections during the first four months of treatment. Patients were allocated to half-year groupings (2012/1 to 2014/1) based on registration of their first intravitreal injection. Injection frequency during the first year of treatment was calculated for each group and t-tests investigated whether injection frequencies changed over time. RESULTS: In treatment naive nAMD patients (n = 500), the mean (SD) number of anti VEGF injections increased significantly from 6.04 (1.71) in 2012/1 to 6.73 (1.62) in 2014/1 (p = .001; 2012/1 and 2012/2 vs. 2014/1) across all treatments. A similar trend was found for DME patients (n = 76) from 2012/1 to 2014/1 and RVO patients (n = 82) from 2012/2 to 2014/1, with mean injection frequencies increasing significantly from 5.14 (2.29) to 5.93 (1.98) (p = .007), and from 4.83 (1.21) to 6.08 (1.55) (p = .024), respectively. Post hoc sensitivity analysis also found a significant increase in injection frequency in nAMD patients who did not receive a loading phase (4.55 in 2012/1 and 5.05 in 2014/1; p = .006; n = 616). CONCLUSIONS: In contrast to the decrease in injection frequency predicted with a switch to aflibercept treatment for nAMD, our study showed that injection frequencies increased significantly from 2012 to 2014 in patients initiating therapy across the three diseases. PMID- 27494693 TI - Effects of apelin on reproductive functions: relationship with feeding behavior and energy metabolism. AB - Apelin is an adipose tissue derived peptidergic hormone. In this study, 40 male Sprague-Dawley rats were used (four groups; n = 10). Apelin-13 at three different dosages (1, 5 and 50 MUg/kg) was given intraperitoneally while the control group received vehicle the same route for a period of 14 days. In results, apelin-13 caused significant decreases in serum testosterone, luteinizing hormone and follicle-stimulating hormone levels (p < 0.05). Administration of apelin-13 significantly increased body weights, food intake, serum low-density lipoprotein and total cholesterol levels (p < 0.05), but caused significant decreases in high density lipoprotein levels (p < 0.05). Serum glucose and triglyceride levels were not significantly altered by apelin-13 administration. Significant decreases in both uncoupling protein (UCP)-1 levels in the white and brown adipose tissues and UCP-3 levels in the biceps muscle (p < 0.05) were noted. The findings of the study suggest that apelin-13 may not only lead to obesity by increasing body weight but also cause infertility by suppressing reproductive hormones. PMID- 27494694 TI - Electron Shuttles Enhance Anaerobic Ammonium Oxidation Coupled to Iron(III) Reduction. AB - Anaerobic ammonium oxidation coupled to iron(III) reduction, termed Feammox, is a newly discovered nitrogen cycling process. However, little is known about the roles of electron shuttles in the Feammox reactions. In this study, two forms of Fe(III) (oxyhydr)oxide ferrihydrite (ex situ ferrihydrite and in situ ferrihydrite) were used in dissimilatory Fe(III) reduction (DIR) enrichments from paddy soil. Evidence for Feammox in DIR enrichments was demonstrated using the (15)N-isotope tracing technique. The extent and rate of both the (30)N2-(29)N2 and Fe(II) formation were enhanced when amended with electron shuttles (either 9,10-anthraquinone-2,6-disulfonate (AQDS) or biochar) and further simulated when these two shuttling compounds were combined. Although the Feammox-associated Fe(III) reduction accounted for only a minor proportion of total Fe(II) formation compared to DIR, it was estimated that the potentially Feammox-mediated N loss (0.13-0.48 mg N L(-1) day(-1)) was increased by 17-340% in the enrichments by the addition of electron shuttles. The addition of electron shuttles led to an increase in the abundance of unclassified Pelobacteraceae, Desulfovibrio, and denitrifiers but a decrease in Geobacter. Overall, we demonstrated a stimulatory effect of electron shuttles on Feammox that led to higher N loss, suggesting that electron shuttles might play a crucial role in Feammox-mediated N loss from soils. PMID- 27494695 TI - Effects of organic matter addition on methylmercury formation in capped and uncapped marine sediments. AB - In situ subaqueous capping (ISC) of contaminated marine sediments is frequently proposed as a feasible and effective mitigation option. However, though effective in isolating mercury species migration into overlying water, capping can also alter the location and extent of biogeochemical zones and potentially enhance methylmercury (MeHg) formation in Hg-contaminated marine sediments. We carried out a boxcosm study to investigate whether the addition of organic carbon (OC) to Hg-contaminated marine sediments beneath an in situ cap would initiate and/or enhance MeHg formation of the inorganic Hg present. The study was motivated by ongoing efforts to remediate ca. 30,000 m(2) of Hg-contaminated seabed sediments from a Hg spill from the U864 WWII submarine wreck. By the time of sinking, the submarine is assumed to have been holding a cargo of ca. 65 tons of liquid Hg. Natural organic matter and petroleum hydrocarbons from fuels and lubricants in the wreck are potential sources of organic carbon that could potentially fuel MeHg formation beneath a future cap. The results of our study clearly demonstrated that introduction of algae OC to Hg-contaminated sediments, triggered high rates of MeHg production as long a there was sufficient OC. Thus, MeHg production was limited by the amount of organic carbon available. The study results also confirmed that, within the six-month duration of the study and in the absence of bioturbating fauna, a 3-cm sediment clay cap could effectively reduce fluxes of Hg species to the overlying water and isolate the Hg contaminated sediments from direct surficial deposition of organic matter that could potentially fuel methylation. PMID- 27494696 TI - Assessment of intermittently loaded woodchip and sand filters to treat dairy soiled water. AB - Land application of dairy soiled water (DSW) is expensive relative to its nutrient replacement value. The use of aerobic filters is an effective alternative method of treatment and potentially allows the final effluent to be reused on the farm. Knowledge gaps exist concerning the optimal design and operation of filters for the treatment of DSW. To address this, 18 laboratory scale filters, with depths of either 0.6 m or 1 m, were intermittently loaded with DSW over periods of up to 220 days to evaluate the impacts of depth (0.6 m versus 1 m), organic loading rates (OLRs) (50 versus 155 g COD m(-2) d(-1)), and media type (woodchip versus sand) on organic, nutrient and suspended solids (SS) removals. The study found that media depth was important in contaminant removal in woodchip filters. Reductions of 78% chemical oxygen demand (COD), 95% SS, 85% total nitrogen (TN), 82% ammonium-nitrogen (NH4N), 50% total phosphorus (TP), and 54% dissolved reactive phosphorus (DRP) were measured in 1 m deep woodchip filters, which was greater than the reductions in 0.6 m deep woodchip filters. Woodchip filters also performed optimally when loaded at a high OLR (155 g COD m( 2) d(-1)), although the removal mechanism was primarily physical (i.e. straining) as opposed to biological. When operated at the same OLR and when of the same depth, the sand filters had better COD removals (96%) than woodchip (74%), but there was no significant difference between them in the removal of SS and NH4N. However, the likelihood of clogging makes sand filters less desirable than woodchip filters. Using the optimal designs of both configurations, the filter area required per cow for a woodchip filter is more than four times less than for a sand filter. Therefore, this study found that woodchip filters are more economically and environmentally effective in the treatment of DSW than sand filters, and optimal performance may be achieved using woodchip filters with a depth of at least 1 m, operated at an OLR of 155 g COD m(-2) d(-1). PMID- 27494697 TI - Transformation of graphene oxide by chlorination and chloramination: Implications for environmental transport and fate. AB - The rapidly increasing and widespread use of graphene oxide (GO) calls for immediate attention on the environmental fate of this material. To date, very little is known about the environmental transformation of GO. This study explored the changes of physicochemical properties of GO from chlorination and chloramination, which simulated the reactions occurring in water and wastewater treatment systems. Significant changes of GO surface O-functionalities occurred and scrolling of graphene sheets (those of very large sizes) were observed upon the treatments. Chloroform, a byproduct from chlorination was also detected, indicating the ring-opening on the edge of GO nanosheets. The changes of GO surface O-functionalities were attributable to the oxidation of quinone groups of GO by chlorine or chloramine. The scrolling of large-sized GO sheets may be attributable to the destruction of benzene rings at the edge of the GO. The results of membrane filtration experiments and column transport experiments indicated that chlorination and chloramination enhanced the mobility and transport of GO, likely by increasing the colloidal stability and inhibiting the agglomeration of GO nanosheets. The findings of this study further underline the significant implications of GO transformation on the fate and transport of this new nanomaterial. PMID- 27494698 TI - Identification of transformation products during advanced oxidation of diatrizoate: Effect of water matrix and oxidation process. AB - Removal of micropollutants from reverse osmosis (RO) brines of wastewater desalination by oxidation processes is influenced by the scavenging capacity of brines components, resulting in the accumulation of transformation products (TPs) rather than complete mineralization. In this work the iodinated contrast media diatrizoate (DTZ) was used as model compound due to its relative resistance to oxidation. Identification of TPs was performed in ultrapure water (UPW) and RO brines applying nonthermal plasma (NTP) and UVA-TiO2 as oxidation techniques. The influence of main RO brines components in the formation and accumulation of TPs, such as chloride, bicarbonate alkalinity and humic acid, was also studied during UVA-TiO2. DTZ oxidation pattern in UPW resulted similar in both UVA-TiO2 and NTP achieving 66 and 61% transformation, respectively. However, DTZ transformation in RO brines was markedly lower in UVA-TiO2 (9%) than in NTP (27%). These differences can be attributed to the synergic effect of RO brines components during NTP. Moreover, reactive species other than hydroxyl radical contributed to DTZ transformation, i.e., direct photolysis in UVA-TiO2 and direct photolysis + O3 in NTP accounted for 16 and 23%, respectively. DTZ transformation led to iodide formation in both oxidation techniques but it further oxidized to iodate by ozone in NTP. In total 14 transformation products were identified in UPW of which 3 were present only in UVA-TiO2 and 2 were present exclusively in NTP; 5 of the 14 TPs were absent in RO brines. Five of them were new and were denoted as TP 474A/B, TP-522, TP-586, TP-602, TP-628. TP-522 (mono-chlorinated) was elucidated only in presence of high chloride titer-synthetic water matrix in NTP, most probably formed by active chlorine species generated in situ. TPs accumulation in RO brines was markedly different in comparison to UPW. This denotes the influence of RO brines components in the formation of reactive species that could further attack DTZ/TPs and/or scavenging performed by these brine components that could limit further TPs degradation. Five plausible degradation pathways are proposed for DTZ transformation in UPW. PMID- 27494701 TI - Synthesis of Isoindolinones by Pd-Catalyzed Coupling between N-Methoxybenzamide and Styrene Derivatives. AB - An atom-economical protocol for a tandem process involving Fujiwara-Moritani-aza Wacker reactions has been developed for the Pd-catalyzed coupling between N methoxy benzamide and styrene derivatives. The generality of the methodology was demonstrated by the synthesis of a library of 25 3-benzylidene isoindolinones in moderate to good yields. A further 40 3-benzyl derivatives were obtained by telescoping the process with a catalytic hydrogenation reaction. PMID- 27494700 TI - Modeling and Simulation of Mucus Flow in Human Bronchial Epithelial Cell Cultures - Part I: Idealized Axisymmetric Swirling Flow. AB - A multi-mode nonlinear constitutive model for mucus is constructed directly from micro- and macro-rheology experimental data on cell culture mucus, and a numerical algorithm is developed for the culture geometry and idealized cilia driving conditions. This study investigates the roles that mucus rheology, wall effects, and HBE culture geometry play in the development of flow profiles and the shape of the air-mucus interface. Simulations show that viscoelasticity captures normal stress generation in shear leading to a peak in the air-mucus interface at the middle of the culture and a depression at the walls. Linear and nonlinear viscoelastic regimes can be observed in cultures by varying the hurricane radius and mean rotational velocity. The advection-diffusion of a drug concentration dropped at the surface of the mucus flow is simulated as a function of Peclet number. PMID- 27494699 TI - Modulatory Effects of Sex Steroids Progesterone and Estradiol on Odorant Evoked Responses in Olfactory Receptor Neurons. AB - The influence of the sex steroid hormones progesterone and estradiol on physiology and behavior during menstrual cycles and pregnancy is well known. Several studies indicate that olfactory performance changes with cyclically fluctuating steroid hormone levels in females. Knowledge of the exact mechanisms behind how female sex steroids modulate olfactory signaling is limited. A number of different known genomic and non-genomic actions that are mediated by progesterone and estradiol via interactions with different receptors may be responsible for this modulation. Next generation sequencing-based RNA-Seq transcriptome data from the murine olfactory epithelium (OE) and olfactory receptor neurons (ORNs) revealed the expression of several membrane progestin receptors and the estradiol receptor Gpr30. These receptors are known to mediate rapid non-genomic effects through interactions with G proteins. RT-PCR and immunohistochemical staining results provide evidence for progestin and estradiol receptors in the ORNs. These data support the hypothesis that steroid hormones are capable of modulating the odorant-evoked activity of ORNs. Here, we validated this hypothesis through the investigation of steroid hormone effects by submerged electro-olfactogram and whole cell patch-clamp recordings of ORNs. For the first time, we demonstrate that the sex steroid hormones progesterone and estradiol decrease odorant-evoked signals in the OE and ORNs of mice at low nanomolar concentrations. Thus, both of these sex steroids can rapidly modulate the odor responsiveness of ORNs through membrane progestin receptors and the estradiol receptor Gpr30. PMID- 27494703 TI - Current progress of Reelin in development, inflammation and tissue remodeling: from nervous to visual systems. AB - Reelin is a matrix glycoprotein that plays a pivotal role for the positioning of neurons throughout brain development. In the early developing cortex Reelin regulates radial migration of cortical neurons while later in development, Reelin promotes maturation of dendrites and dendritic spines. Low Reelin levels characterize healthy adult brain while increased Reelin levels have been associated with cellular events underlying response to injury. Reelin has been detected in structural and immune cells outside brain (liver, gut/colon tracts, kidney, testis, ovary, lung, retina and cornea). In the Visual system, Reelin was first described in the retina and thereafter in the cornea. Increased Reelin levels were observed during retinogenesis, low levels were found in adulthood and a significant increase was detected upon injury. Insult-driven Reelin changes occur after upregulation of adhesion molecules, cytokines, neurotrophins, growth factors, neuropeptides and other mediators as well as their receptors. These soluble factors contribute to the development of nervous and visual system and promote survival/recovery of neurons/accessory cells populating the injured visual system. Likewise, Reelin might modulate these factors by driving different multiple effects on homeostasis/plasticity, inflammation, healing and remodeling at different physiopathological levels. Very low-density lipoprotein receptor, apolipoprotein E receptor 2, integrins and the adaptor molecule Disabled 1 trigger Reelin. Recent advances highlight some Reelin activities during inflammation and tissue remodeling and point out to a crucial Reelin activity in the visual system. A better understanding of Reelin function in retinal development might open to new attractive perspective for counteracting retina degeneration. PMID- 27494702 TI - The Arabidopsis Protein Phosphatase PP2C38 Negatively Regulates the Central Immune Kinase BIK1. AB - Plants recognize pathogen-associated molecular patterns (PAMPs) via cell surface localized pattern recognition receptors (PRRs), leading to PRR-triggered immunity (PTI). The Arabidopsis cytoplasmic kinase BIK1 is a downstream substrate of several PRR complexes. How plant PTI is negatively regulated is not fully understood. Here, we identify the protein phosphatase PP2C38 as a negative regulator of BIK1 activity and BIK1-mediated immunity. PP2C38 dynamically associates with BIK1, as well as with the PRRs FLS2 and EFR, but not with the co receptor BAK1. PP2C38 regulates PAMP-induced BIK1 phosphorylation and impairs the phosphorylation of the NADPH oxidase RBOHD by BIK1, leading to reduced oxidative burst and stomatal immunity. Upon PAMP perception, PP2C38 is phosphorylated on serine 77 and dissociates from the FLS2/EFR-BIK1 complexes, enabling full BIK1 activation. Together with our recent work on the control of BIK1 turnover, this study reveals another important regulatory mechanism of this central immune component. PMID- 27494705 TI - A Preliminary Investigation of Ethnic Differences in Resistance in Multisystemic Therapy. AB - Therapy process research suggests that an inverted U-shaped trajectory of client resistance, referred to as the struggle-and-working-through pattern, predicts positive treatment outcomes. However, this research may lack external validity given the exclusive focus on European Americans. This preliminary study explores differences in resistance patterns in a sample of African American and European American juvenile drug offenders and their families (n = 41) participating in Multisystemic Therapy. Resistance was coded from session recordings at the beginning, middle, and end of treatment. There were significant ethnic differences in (a) mean resistance at midtreatment, (b) resistance trajectories, and (c) predictive relationships between resistance trajectories and criminal desistance. Notably, a negative quadratic (i.e., inverted U-shaped) resistance trajectory was more characteristic of European Americans who desisted from crime, whereas a positive quadratic (U-shaped) resistance pattern was more characteristic of African Americans who desisted. There was no relationship between resistance trajectory and later drug abstinence (i.e., cannabis). Within the context of evidence-based therapies, core treatment processes may vary significantly as a function of client ethnicity. We recommend that clinical scientists make efforts to test for ethnic differences in treatment process so that therapies like Multisystemic Therapy can be understood in a more comprehensive and nuanced manner. PMID- 27494704 TI - Kdm5/Lid Regulates Chromosome Architecture in Meiotic Prophase I Independently of Its Histone Demethylase Activity. AB - During prophase of the first meiotic division (prophase I), chromatin dynamically reorganises to recombine and prepare for chromosome segregation. Histone modifying enzymes are major regulators of chromatin structure, but our knowledge of their roles in prophase I is still limited. Here we report on crucial roles of Kdm5/Lid, one of two histone demethylases in Drosophila that remove one of the trimethyl groups at Lys4 of Histone 3 (H3K4me3). In the absence of Kdm5/Lid, the synaptonemal complex was only partially formed and failed to be maintained along chromosome arms, while localisation of its components at centromeres was unaffected. Kdm5/Lid was also required for karyosome formation and homologous centromere pairing in prophase I. Although loss of Kdm5/Lid dramatically increased the level of H3K4me3 in oocytes, catalytically inactive Kdm5/Lid can rescue the above cytological defects. Therefore Kdm5/Lid controls chromatin architecture in meiotic prophase I oocytes independently of its demethylase activity. PMID- 27494706 TI - Prevalence of Risk Factors for Cardiovascular Diseases in Bangladesh: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Given the rising incidence of cardiovascular diseases (CVDs) in Bangladesh, an improved understanding of the epidemiology of CVD risk factors is needed. Therefore, we reviewed published studies on CVD modifiable risk factors e.g., Type 2 Diabetes Mellitus (T2DM), hypertension (HTN), dyslipidemia and smoking as well as studies on CVDs and conducted a meta-analysis of risk factors and disease prevalence. METHODS: We searched the GLOBAL HEALTH, MEDLINE, EMBASE 'BanglaJol' databases for all studies in English on CVDs and its associated modifiable risk factors. Random effects meta-analysis methods were used to estimate pooled prevalence. RESULTS: There were 74 eligible studies (outcome: T2DM = 32, HTN = 24, dyslipidaemia = 8 and smoking = 25; CVDs = 10). Due to high between study heterogeneity (p<0.001, I2> 95%) in the prevalence of CVD risk factors, we presented median and interquartile range (IQR) instead of the pooled estimates as the summary measures. Median (IQR) prevalence of T2DM, HTN, dyslipidemia and smoking were 5.9% (1.97%-8.25%); 15.1% (10.52%-17.60%); 34.35% (10.66%-48.50%) and 40.56% (0.80%-55.95%), respectively. The prevalence of T2DM and dyslipidemia were significantly higher in urban compared to rural populations (13.5 vs 6%, p<0.001; 41.5 vs 30%, p = 0.007, respectively). CONCLUSIONS: The prevalence of risk factors for CVDs is high in Bangladesh, more so in urban areas. Ageing of the population may be a factor but urbanization seems to have an influence, possibly related to changes in dietary and physical activity patterns. Further research, in particular longitudinal studies, is needed to explore the complex interaction of these factors and to inform policies and programs for the prevention and management of CVDs in Bangladesh. PMID- 27494707 TI - Comparison of Two Commercial Automated Nucleic Acid Extraction and Integrated Quantitation Real-Time PCR Platforms for the Detection of Cytomegalovirus in Plasma. AB - Quantitation of cytomegalovirus (CMV) viral load in the transplant patients has become a standard practice for monitoring the response to antiviral therapy. The cut-off values of CMV viral load assays for preemptive therapy are different due to the various assay designs employed. To establish a sensitive and reliable diagnostic assay for preemptive therapy of CMV infection, two commercial automated platforms including m2000sp extraction system integrated the Abbott RealTime (m2000rt) and the Roche COBAS AmpliPrep for extraction integrated COBAS Taqman (CAP/CTM) were evaluated using WHO international CMV standards and 110 plasma specimens from transplant patients. The performance characteristics, correlation, and workflow of the two platforms were investigated. The Abbott RealTime assay correlated well with the Roche CAP/CTM assay (R2 = 0.9379, P<0.01). The Abbott RealTime assay exhibited higher sensitivity for the detection of CMV viral load, and viral load values measured with Abbott RealTime assay were on average 0.76 log10 IU/mL higher than those measured with the Roche CAP/CTM assay (P<0.0001). Workflow analysis on a small batch size at one time, using the Roche CAP/CTM platform had a shorter hands-on time than the Abbott RealTime platform. In conclusion, these two assays can provide reliable data for different purpose in a clinical virology laboratory setting. PMID- 27494708 TI - Perceived burdensomeness and suicide ideation in adult outpatients receiving exposure therapy for anxiety disorders. AB - Perceived burdensomeness is considered a proximal risk factor for suicide ideation. However, there is a lack of prospective studies. Furthermore, it is unclear in as much psychotherapy for anxiety disorders is associated with a decrease in suicide ideation. A total of 105 adult outpatients suffering from panic disorder, agoraphobia, or specific phobia received manualized exposure therapy. Perceived burdensomeness was considered as predictor of suicide ideation concurrently, after the fourth and the tenth therapy session and posttreatment - controlling for baseline symptom distress, suicide ideation, number of therapy sessions and age. Furthermore, pre-to post-changes in suicide ideation and perceived burdensomeness were assessed. Perceived burdensomeness emerged as a significant predictor of suicidal ideation concurrently and after the fourth and the tenth therapy session, but not at the end of therapy. Treatment had no effect on suicide ideation and only a marginal effect on perceptions of burdensomeness. In conclusion, the current study highlights the importance of perceptions of burdensomeness in understanding suicide ideation. PMID- 27494709 TI - Progress and potential of RAS mutation detection for diagnostics and companion diagnostics. AB - INTRODUCTION: The importance of RAS mutation in carcinogenesis is established, and knowledge of an individual cancer's mutation status is important for optimal treatment. Areas covered: This paper is restricted to RAS testing in cancer, and highlights papers relevant to current practice. Expert commentary: Multiple laboratory methods are available for RAS gene analysis. PCR is commonly used to determine RAS status, providing a robust and inexpensive technology for clinical use. Next generation sequencing (NGS) platforms are changing the way in which mutation status is determined, though they require considerable expertise. Pre analytical issues affect both methods and should be considered. The interpretation and reporting of results is not simple, particularly for NGS. External quality assurance is a pre-requisite for success, and is mandated by most laboratory accreditation schemes. The use of RAS testing is now extending beyond biopsy material to include the detection of mutations in circulating cell free DNA and tumour cells. PMID- 27494710 TI - The translation factors of Drosophila melanogaster. AB - Synthesis of polypeptides from mRNA (translation) is a fundamental cellular process that is coordinated and catalyzed by a set of canonical 'translation factors'. Surprisingly, the translation factors of Drosophila melanogaster have not yet been systematically identified, leading to inconsistencies in their nomenclature and shortcomings in functional (Gene Ontology, GO) annotations. Here, we describe the complete set of translation factors in D. melanogaster, applying nomenclature already in widespread use in other species, and revising their functional annotation. The collection comprises 43 initiation factors, 12 elongation factors, 3 release factors and 6 recycling factors, totaling 64 of which 55 are cytoplasmic and 9 are mitochondrial. We also provide an overview of notable findings and particular insights derived from Drosophila about these factors. This catalog, together with the incorporation of the improved nomenclature and GO annotation into FlyBase, will greatly facilitate access to information about the functional roles of these important proteins. PMID- 27494712 TI - Reactivity and Properties of Metal Complexes Enabled by Flexible and Redox-Active Ligands with a Ferrocene Backbone. AB - Our group has focused on the organometallic chemistry of rare-earth metals and actinides for a decade. By installing ferrocenediamide ligands at electropositive metal centers, we have been able to disclose unprecedented reactivity toward aromatic N-heterocycles, arenes, and other small molecules such as P4. Systematic studies employing X-ray crystallography, spectroscopy, cyclic voltammetry, and density functional theory calculations revealed that the ferrocene backbone could stabilize the electron-deficient metal through a donor-acceptor-type interaction. Most noteworthy is that this interaction can be readily turned on or off by the addition or removal of a Lewis base. In addition to its flexible coordination, the redox-active nature of the ferrocene backbone enabled us to explore redox switchable transformations. The introduction of ferrocene-based ligands into organolanthanide chemistry not only helped us to study intriguing fundamental problems but also led to fruitful chemistry including small-molecule activation and controlled copolymerization reactions. PMID- 27494711 TI - Cilostazol Modulates Autophagic Degradation of beta-Amyloid Peptide via SIRT1 Coupled LKB1/AMPKalpha Signaling in Neuronal Cells. AB - A neuroprotective role of autophagy mediates the degradation of beta-amyloid peptide (Abeta) in Alzheimer's disease (AD). The previous study showed cilostazol modulates autophagy by increasing beclin1, Atg5 and LC3-II expressions, and depletes intracellular Abeta accumulation. This study elucidated the mechanisms through which cilostazol modulates the autophagic degradation of Abeta in neurons. In N2a cells, cilostazol (10-30 MUM), significantly increased the expression of P-AMPKalpha (Thr 172) and downstream P-ACC (acetyl-CoA carboxylase) (Ser 79) as did resveratrol (SIRT1 activator), or AICAR (AMPK activator), which were blocked by KT5720, compound C (AMPK inhibitor), or sirtinol. Furthermore, phosphorylated-mTOR (Ser 2448) and phosphorylated-P70S6K (Thr 389) expressions were suppressed, and LC3-II levels were elevated in association with decreased P62/Sqstm1 by cilostazol. Cilostazol increased cathepsin B activity and decreased p62/SQSTM 1, consequently decreased accumulation of Abeta1-42 in the activated N2aSwe cells, and these results were blocked by sirtinol, compound C and bafilomycin A1 (autophagosome blocker), suggesting enhanced autophagosome formation by cilostazol. In SIRT1 gene-silenced N2a cells, cilostazol failed to increase the expressions of P-LKB1 (Ser 428) and P-AMPKalpha, which contrasted with its effect in negative control cells transfected with scrambled siRNA duplex. Further, N2a cells transfected with expression vectors encoding pcDNA SIRT1 showed increased P-AMPKalpha expression, which mimicked the effect of cilostazol in N2a cells; suggesting cilostazol-stimulated expressions of P-LKB1 and P-AMPKalpha were SIRT1-dependent. Unlike their effects in N2a cells, in HeLa cells, which lack LKB1, cilostazol and resveratrol did not elevate SIRT1 or P AMPKalpha expression, indicating cilostazol and resveratrol-stimulated expressions of SIRT1 and P-AMPKalpha are LKB1-dependent. In conclusion, cilostazol upregulates autophagy by activating SIRT1-coupled P-LKB1/P-AMPKalpha and inhibiting mTOR activation, thereby decreasing Abeta accumulation. PMID- 27494714 TI - Health and social conditions in Norwegian polio survivors: A 20-year follow-up study. AB - OBJECTIVE: To explore the physical and social situation of the Norwegian polio population in 2014, and to compare the status of this population in 2014 with the results of a similar survey carried out 20 years previously, in 1994. DESIGN: The study was based on a questionnaire covering demographics, polio history, and current medical, psychological and social conditions. SUBJECTS: The questionnaire was prepared in cooperation with the National Society of Polio Survivors and others with known polio (n = 1,968). A total of 1,408 persons responded (72%), mean age 70 years (range 28-98 years). RESULTS: The most frequent health problems reported were muscle and joint pain, cold intolerance and insomnia. New muscle weakness and loss of muscle volume were reported more frequently in 2014 than in the 1994 study. The use of orthopaedic aids, assistive devices, ventilators and other respiratory aids had increased significantly, but 83% reported that they still had no home care or nursing services support. The 2014 polio population reported only minor subjective worsening of health and well-being compared with the 1994 cohort. CONCLUSION: The present study indicates that the elderly polio population are experiencing new muscle weakness and increasing health problems, but that the deterioration occurs slowly and with fewer consequences for the subjective experience of general health and well-being, indicating that the patients are adapting to their life situation. However, subgroups of the elderly polio population are in need of special care. PMID- 27494715 TI - Study of Robustness in Functionally Identical Coupled Networks against Cascading Failures. AB - Based on coupled networks, taking node load, capacity and load redistribution between two networks into consideration, we propose functionally identical coupled networks, which consist of two networks connected by interlinks. Functionally identical coupled networks are derived from the power grid of the United States, which consists of many independent grids. Many power transmission lines are planned to interconnect those grids and, therefore, the study of the robustness of functionally identical coupled networks becomes important. In this paper, we find that functionally identical coupled networks are more robust than single networks under random attack. By studying the effect of the broadness and average degree of the degree distribution on the robustness of the network, we find that a broader degree distribution and a higher average degree increase the robustness of functionally identical coupled networks under random failure. And SF-SF (two coupled scale-free networks) is more robust than ER-ER (two coupled random networks) or SF-ER (coupled random network and scale-free network). This research is useful to construct robust functionally identical coupled networks such as two cooperative power grids. PMID- 27494713 TI - Amplification of TGFbeta Induced ITGB6 Gene Transcription May Promote Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a devastating, progressive disease with poor survival rates and limited treatment options. Upregulation of alphavbeta6 integrins within the alveolar epithelial cells is a characteristic feature of IPF and correlates with poor patient survival. The pro-fibrotic cytokine TGFbeta1 can upregulate alphavbeta6 integrin expression but the molecular mechanisms driving this effect have not previously been elucidated. We confirm that stimulation with exogenous TGFbeta1 increases expression of the integrin beta6 subunit gene (ITGB6) and alphavbeta6 integrin cell surface expression in a time- and concentration-dependent manner. TGFbeta1-induced ITGB6 expression occurs via transcriptional activation of the ITGB6 gene, but does not result from effects on ITGB6 mRNA stability. Basal expression of ITGB6 in, and alphavbeta6 integrins on, lung epithelial cells occurs via homeostatic alphavbeta6-mediated TGFbeta1 activation in the absence of exogenous stimulation, and can be amplified by TGFbeta1 activation. Fundamentally, we show for the first time that TGFbeta1 induced ITGB6 expression occurs via canonical Smad signalling since dominant negative constructs directed against Smad3 and 4 inhibit ITGB6 transcriptional activity. Furthermore, disruption of a Smad binding site at -798 in the ITGB6 promoter abolishes TGFbeta1-induced ITGB6 transcriptional activity. Using chromatin immunoprecipitation we demonstrate that TGFbeta1 stimulation of lung epithelial cells results in direct binding of Smad3, and Smad4, to the ITGB6 gene promoter within this region. Finally, using an adenoviral TGFbeta1 over expression model of pulmonary fibrosis we demonstrate that Smad3 is crucial for TGFbeta1-induced alphavbeta6 integrin expression within the alveolar epithelium in vivo. Together, these data confirm that a homeostatic, autocrine loop of alphavbeta6 integrin activated TGFbeta1-induced ITGB6 gene expression regulates epithelial basal alphavbeta6 integrin expression, and demonstrates that this occurs via Smad-dependent transcriptional regulation at a single Smad binding site in the promoter of the beta6 subunit gene. Active TGFbeta1 amplifies this pathway both in vitro and in vivo, which may promote fibrosis. PMID- 27494717 TI - Molecular Cloning and Functional Expression of a Delta9- Fatty Acid Desaturase from an Antarctic Pseudomonas sp. A3. AB - Fatty acid desaturase enzymes play an essential role in the synthesis of unsaturated fatty acids. Pseudomonas sp. A3 was found to produce a large amount of palmitoleic and oleic acids after incubation at low temperatures. Using polymerase Chain Reaction (PCR), a novel Delta9- fatty acid desaturase gene was isolated, cloned, and successfully expressed in Escherichia coli. The gene was designated as PA3FAD9 and has an open reading frame of 1,185 bp which codes for 394 amino acids with a predicted molecular weight of 45 kDa. The activity of the gene product was confirmed via GCMS, which showed a functional putative Delta9 fatty acid desaturase capable of increasing the total amount of cellular unsaturated fatty acids of the E. coli cells expressing the gene. The results demonstrate that the cellular palmitoleic acids have increased two-fold upon expression at 15 degrees C using only 0.1 mM IPTG. Therefore, PA3FAD9 from Pseudomonas sp.A3 codes for a Delta9-fatty acid desaturase-like protein which was actively expressed in E. coli. PMID- 27494716 TI - MicroRNA Profiling in the Medial and Lateral Habenula of Rats Exposed to the Learned Helplessness Paradigm: Candidate Biomarkers for Susceptibility and Resilience to Inescapable Shock. AB - Depression is a highly heterogeneous disorder presumably caused by a combination of several factors ultimately causing the pathological condition. The genetic liability model of depression is likely to be of polygenic heterogeneity. miRNAs can regulate multiple genes simultaneously and therefore are candidates that align with this model. The habenula has been linked to depression in both clinical and animal studies, shifting interest towards this region as a neural substrate in depression. The goal of the present study was to search for alterations in miRNA expression levels in the medial and lateral habenula of rats exposed to the learned helplessness (LH) rat model of depression. Ten miRNAs showed significant alterations associating with their response to the LH paradigm. Of these, six and four miRNAs were significantly regulated in the MHb and LHb, respectively. In the MHb we identified miR-490, miR-291a-3p, MiR-467a, miR-216a, miR-18b, and miR-302a. In the LHb miR-543, miR-367, miR-467c, and miR 760-5p were significantly regulated. A target gene analysis showed that several of the target genes are involved in MAPK signaling, neutrophin signaling, and ErbB signaling, indicating that neurotransmission is affected in the habenula as a consequence of exposure to the LH paradigm. PMID- 27494718 TI - Astroglia in Thick Tissue with Super Resolution and Cellular Reconstruction. AB - We utilized the recently published method of passive CLARITY to explore brain astrocytes for the first time with our optimized method. Astrocytes are the fundamental cells in the brain that act to maintain the synaptic activity of neurons, support metabolism of all neurons, and communicate through extensive networks throughout the CNS. They are the defining cell that differentiates lower organisms from humans. From a disease vantage point they are the principal cause of brain tumors and the propagator of neurodegenerative diseases like amyotrophic lateral sclerosis. New methods to study these cells is paramount. Our modified use of CLARITY provides a new way to study these brain cells. To reduce cost, speed up tissue clearing process, reduce human handling error, and to retrieve quantifiable data from single confocal and pseudo-super resolution microscopy we modified and optimized the original protocol. PMID- 27494719 TI - A Protocolised Once a Day Modified Early Warning Score (MEWS) Measurement Is an Appropriate Screening Tool for Major Adverse Events in a General Hospital Population. AB - BACKGROUND: The Modified Early Warning Score (MEWS) was developed to timely recognise clinically deteriorating hospitalised patients. However, the ability of the MEWS in predicting serious adverse events (SAEs) in a general hospital population has not been examined prospectively. The aims were to (1) analyse protocol adherence to a MEWS protocol in a real-life setting and (2) to determine the predictive value of protocolised daily MEWS measurement on SAEs: death, cardiac arrests, ICU-admissions and readmissions. METHODS: All adult patients admitted to 6 hospital wards in October and November 2015 were included. MEWS were checked each morning by the research team. For each critical score (MEWS >= 3), the clinical staff was inquired about the actions performed. 30-day follow-up for SAEs was performed to compare between patients with and without a critical score. RESULTS: 1053 patients with 3673 vital parameter measurements were included, 200 (19.0%) had a critical score. The protocol adherence was 89.0%. 18.2% of MEWS were calculated wrongly. Patients with critical scores had significant higher rates of unplanned ICU admissions [7.0% vs 1.3%, p < 0.001], in-hospital mortality [6.0% vs 0.8%, p < 0.001], 30-day readmission rates [18.6% vs 10.8%, p < 0.05], and a longer length of stay [15.65 (SD: 15.7 days) vs 6.09 (SD: 6.9), p < 0.001]. Specificity of MEWS related to composite adverse events was 83% with a negative predicting value of 98.1%. CONCLUSIONS: Protocol adherence was high, even though one-third of the critical scores were calculated wrongly. Patients with a MEWS >= 3 experienced significantly more adverse events. The negative predictive value of early morning MEWS < 3 was 98.1%, indicating the reliability of this score as a screening tool. PMID- 27494720 TI - Quantitative image analysis to characterize the dynamics of Listeria monocytogenes biofilms. AB - This work shows that the combination of two-dimensional (2D) and three dimensional (3D) analyses of images acquired by confocal laser scanning microscopy facilitates the quantitative spatiotemporal characterization of architectures formed by Listeria monocytogenes biofilms. In particular, the analysis of structural features such as maximum thickness, biovolume, areal porosity and maximum diffusion distance allowed elucidating differences in biofilm formation of three L. monocytogenes strains (L1A1, CECT5873 and CECT4032). The analysis showed a common sequence for all strains. In the first phase, independent clusters evolve to interconnected clusters and honeycomb-like structures. Flat biofilms characterized the second phase. The structures disappear in the third phase. Nevertheless, the duration of the phases differed from strain to strain. L1A1 strain exhibited the slowest dynamics and the thickest biofilms while the strain CECT4032 presented the faster dynamics and the thinnest biofilms. Also, the number of dead cells varies significantly from strain to strain. From the results of the analysis, it can be concluded that 2D parameters are critical to differentiating morphological features while 3D parameters ease the interpretation and comparative study of the different phases during the life cycle of biofilms. PMID- 27494722 TI - Clinical value of drug-coated balloon angioplasty for de novo lesions in patients with coronary artery disease. AB - BACKGROUND: Despite the low restenosis rates of drug-eluting stents (DES), several problems remain, including stent thrombosis, stent fracture, and neo atherosclerosis. 'Stent-less' (balloon alone) percutaneous coronary intervention (PCI) is still being used, and several clinical trials have supported the efficacy of DCB. The aim of this study was to investigate the efficacy of a drug coated balloon (DCB) in the treatment of de novo coronary artery disease. METHODS: We enrolled 60 consecutive patients who had been given elective PCI between May 2014 and June 2015. They were randomly assigned to a 'stent-less' group (n=30) and a 'stent' group (n=30). Twenty-seven patients were treated with DCB alone and 33 with DES, and then evaluated for target lesion revascularization (TLR) rate and by quantitative coronary angiography (QCA) eight months later. RESULTS: TLR rates were similar in the two groups (DCB; 0.0%, DES; 6.1%, P=0.169). In the QCA analysis, minimal lumen diameter (MLD) and acute gain were significantly smaller in the DCB group than in the DES group immediately after PCI (2.36+/-0.46 vs 2.64+/-0.37, P=0.011, and 1.63+/-0.41 vs 2.08+/-0.37, P<0.0001, respectively). Eight months after PCI, however, there was no significant difference in MLD or late lumen loss between the two groups. CONCLUSIONS: A 'stent-less' PCI using DCB could be useful even in the DES era. After 'stent-less' PCI, antiplatelet agents might be reduced or discontinued more safely than after DES implantation. PMID- 27494721 TI - Differential left-to-right atria gene expression ratio in human sinus rhythm and atrial fibrillation: Implications for arrhythmogenesis and thrombogenesis. AB - BACKGROUND: Atrial fibrillation (AF) causes atrial remodeling, and the left atrium (LA) is the favored substrate for maintaining AF. It remains unclear if AF remodels both atria differently and contributes to LA arrhythmogenesis and thrombogenesis. Therefore, we wished to characterize the transcript profiles in the LA and right atrium (RA) in sinus rhythm (SR) and AF respectively. METHODS: Paired LA and RA appendages acquired from patients receiving cardiac surgery were used for ion-channel- and whole-exome-based transcriptome analysis. The ultrastructure was evaluated by immunohistochemistry. RESULTS: Twenty-two and twenty ion-channels and transporters were differentially expressed between the LA and RA in AF and SR, respectively. Among these, 15 genes were differentially expressed in parallel between AF and SR. AF was associated with increased LA/RA expression ratio in 9 ion channel-related genes, including genes related to calcium handling. In microarray, AF was associated with a differential LA/RA gene expression ratio in 309 genes, and was involved in atherosclerosis-related signaling. AF was associated with the upregulation of thrombogenesis-related genes in the LA appendage, including P2Y12, CD 36 and ApoE. Immunohistochemistry showed higher expressions of collagen-1, oxidative stress and TGF-beta1 in the RA compared to the LA. CONCLUSIONS: AF was associated with differential LA-to-RA gene expression related to specific ion channels and pathways as well as upregulation of thrombogenesis-related genes in the LA appendage. Targeting the molecular mechanisms underlying the LA-to-RA difference and AF-related remodeling in the LA appendage may help provide new therapeutic options in treating AF and preventing thromboembolism in AF. PMID- 27494723 TI - Therapeutic efficacy of PCSK9 monoclonal antibodies in statin-nonresponsive patients with hypercholesterolemia and dyslipidemia: A systematic review and meta analysis. AB - BACKGROUND AND OBJECTIVE: Heterozygous familial hypercholesterolemia and dyslipidemia are the predominant causes for cardiovascular disease (CVD). Clinical guidelines for lowering CVD risk have advocated that low density lipoprotein-cholesterol (LDL-C) must be reduced. The primary choice of therapy for controlling lipidemia has been statins, which are not completely effective. Proprotein convertase subtilisin/kexin type-9 (PCSK9), which interferes with LDL clearance from circulation, inversely relates to the LDL-C levels. The loss of statin efficacy is likely due to increased circulating PCSK9 and antibody therapy against PCSK9 has been found to be efficacious in lowering LDL-C. In this study, we evaluated the efficacy of PCSK9-mAbs for lowering LDL-C, in statin non responsive hypercholesterolemia patients. STUDY DESIGN AND METHODS: PubMed, EMBASE, Scholar, Web of Science and Scopus databases were searched to identify randomized controlled trials of PCSK9 antibody-statin combination vs statin, published till 2015. Two reviewers independently screened the articles, and a collective decision was reached about the included studies in the metaanalysis. Parameters analyzed: change from baseline in LDL-C, high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC); ApoB and ApoA1 levels. RESULTS: A total of 12 studies with 4909 patients were selected. Overall, add-on therapy with PCSK9-mAb to the ongoing statin therapy was found to achieve greater reduction in LDL-C, ApoB, TC, compared to statin therapy. There were no major treatment emergent adverse effects due to PCSK9-mAb therapy. CONCLUSIONS: In adult patients with heterozygous familial hypercholesterolemia and dyslipidemia, PCSK9-mAb therapy in combination with statins was able to achieve the goal of lowering LDL-C. PMID- 27494724 TI - A case of initial rhythm of pulseless electrical activity caused by vasospastic angina. PMID- 27494725 TI - Iron deficiency in heart failure: Impact on response to cardiac resynchronization therapy. PMID- 27494726 TI - Refractory torsade de pointes induced by terlipressin (Glypressin). PMID- 27494727 TI - Guide extension, unmissable tool in the armamentarium of modern interventional cardiology. A comprehensive review. AB - Due to the aging population undergoing percutaneous coronary intervention (PCI), interventional cardiologists are confronted daily with treatment of lesions with complex anatomy. Despite improvements in stent devices and PCI techniques, these lesions remain a challenge in terms of procedural success. Guide-extensions (GE) are coaxial "mother and child" catheters employed to facilitate device delivery but they can be used in many different complex scenarios. A comprehensive review of the possible applications of GE and of the GuideLinerTM (GL), the most widely used GE device, is missing. We therefore aim to provide a comprehensive review of all the potential applications of the GL and other GE devices, describe its limitations as well as tips and tricks for successful usage of this GE catheter. PMID- 27494728 TI - The impact of T786C and G894T polymorphisms of eNOS on vascular endothelial growth factor serum levels in type 2 diabetes patients. PMID- 27494729 TI - An anterior left ventricular lead position is associated with increased mortality and non-response in cardiac resynchronization therapy. AB - BACKGROUND: Non-response to cardiac resynchronization therapy (CRT) might be due to insufficient resynchronization as a result of a sub-optimal left ventricular lead positon (LV-LP). OBJECTIVE: To evaluate the impact of different LV-LPs on mortality and symptomatic improvement in a large cohort of patients treated with CRT. METHODS: We performed a nationwide cohort study on consecutive patients receiving a CRT device from 1997 to 2012 registered in the Danish pacemaker and ICD register. The LV-LP was defined clockwise in a left anterior oblique (LAO) view and categorized as anterior (<=2 o'clock), lateral (2 to 4 o'clock) or posterior (>4 o'clock), and as basal, mid-ventricular, or apical in a right anterior oblique (RAO) view. Outcomes were all cause mortality and clinical response (improvement in NYHA class). Adjusted hazard ratio (aHR) and odds ratio (aOR) with 95% confidence intervals (CI) were calculated using Cox and logistic regression analysis. RESULTS: A total of 2594 patients were included. A lateral LV-LP, (aHR 0.77, 95% CI 0.64-0.92, p=0.004), and a posterior LV-LP, (aHR 0.71 95% CI 0.53-0.97, p=0.029) were associated with lower mortality as compared to an anterior LV-LP. A lateral LV-PV was associated with higher clinical response rate as compared to an anterior LV-LP (aOR 1.37, 1.03-1.83, p=0.032). No statistically significant associations were observed between LV-LP in the RAO view and mortality or clinical response. CONCLUSION: An anterior left ventricular lead position is associated with increased all-cause mortality and lower clinical response rate in patients treated with CRT and should be avoided. PMID- 27494730 TI - Atrial natriuretic peptide therapy and in-hospital mortality in acute myocardial infarction patients undergoing percutaneous coronary intervention. AB - BACKGROUND: Atrial natriuretic peptide (ANP) therapy has been reported to have beneficial effects in patients with acute myocardial infarction (AMI); however, its impact on in-hospital mortality remains unclear. This study aimed to investigate the effects of ANP therapy on in-hospital mortality in AMI patients undergoing percutaneous coronary intervention (PCI). METHODS: This was a retrospective cohort study using the Diagnosis Procedure Combination inpatient database in Japan. We identified AMI patients who underwent PCI with stent implantation on the day of admission, between 2010 and 2014. We compared 30-day in-hospital mortality between patients who started ANP therapy on the day of admission (ANP group) and those who received no ANP therapy during hospitalization (control group), using propensity score and instrumental variable methods. RESULTS: Of 60,592 eligible patients (8189 ANP group, 52,403 control group) from 850 hospitals, 1:1 propensity score matching created 8027 pairs. There was no significant difference in 30-day in-hospital mortality between the ANP and control groups (3.4% vs. 3.8%, respectively; p=0.162; risk difference, 0.42%; 95% confidence interval [CI], -1.00% to 0.15%) in the propensity score matched cohort. Logistic regression analysis with adjustment for propensity score deciles found no significant association between ANP therapy and 30-day in hospital mortality (odds ratio, 0.99; 95% CI, 0.82 to 1.19). Instrumental variable analysis also showed no significant association between ANP therapy and 30-day in-hospital mortality (risk difference, -0.59%; 95% CI, -1.24% to 0.05%). CONCLUSIONS: This study found no significant association between ANP therapy and in-hospital mortality in AMI patients undergoing PCI. PMID- 27494731 TI - No evidence of adverse cardiac remodeling in former elite endurance athletes. AB - BACKGROUND: The impact of high exercise loads on a previously healthy heart remains controversial. We examined the consequences of decades of strenuous endurance exercise at the highest competition level on heart dimensions and volumes as well as on serum biomarkers of cardiac fibrosis/remodeling. METHODS AND RESULTS: We compared echocardiographic measurements and serum biomarkers of cardiac fibrosis/remodeling [troponin I, galectin-3, matrix metallopeptidase-2 and -9, N-terminal pro-brain natriuretic peptide, carboxy-terminal propeptide of type I procollagen, and soluble suppressor of tumorigenicity-2 (sST 2)/interleukin(IL)-1R4] in 53 male athletes [11 former professional ('elite') and 42 amateur-level ('sub-elite') cyclists or runners, aged 40-70years] and 18 aged matched controls. A subset of 15 subjects (5 controls, 3 sub-elite and 7 elite athletes) also underwent cardiac magnetic resonance imaging (cMRI). Elite and sub elite athletes had greater echocardiography-determined left ventricular myocardial mass indexed to body surface area than controls (113+/-22, 115.2+/ 23.1 and 94.8+/-21g/m(2), respectively, p=0.008 for group effect), with similar results for left (50.5+/-4.4, 48.2+/-4.3 and 46.4+/-5.2mm, p=0.008) and right (38.6+/-3.8, 41.1+/-5.5 and 34.7+/-4.3mm, p<0.001) ventricular end-diastolic diameter, and cMRI-determined left atrial volume indexed to body surface area (62.7+/-8.1, 56.4+/-16.0 and 39.0+/-14.1ml/m(2), p=0.026). Two athletes showed a non-coronary pattern of small, fibrotic left ventricular patches detected by late gadolinium enhancement. No group effect was noted for biomarkers. CONCLUSIONS: Regardless of their competition level at a younger age, veteran endurance athletes showed an overall healthy, non-pathological pattern of cardiac remodeling. Nonetheless, the physiopathology of the ventricular fibrotic patches detected warrants further investigation. PMID- 27494732 TI - Improved Accuracy in RNA-Protein Rigid Body Docking by Incorporating Force Field for Molecular Dynamics Simulation into the Scoring Function. AB - RNA-protein interactions play fundamental roles in many biological processes. To understand these interactions, it is necessary to know the three-dimensional structures of RNA-protein complexes. However, determining the tertiary structure of these complexes is often difficult, suggesting that an accurate rigid body docking for RNA-protein complexes is needed. In general, the rigid body docking process is divided into two steps: generating candidate structures from the individual RNA and protein structures and then narrowing down the candidates. In this study, we focus on the former problem to improve the prediction accuracy in RNA-protein docking. Our method is based on the integration of physicochemical information about RNA into ZDOCK, which is known as one of the most successful computer programs for protein-protein docking. Because recent studies showed the current force field for molecular dynamics simulation of protein and nucleic acids is quite accurate, we modeled the physicochemical information about RNA by force fields such as AMBER and CHARMM. A comprehensive benchmark of RNA-protein docking, using three recently developed data sets, reveals the remarkable prediction accuracy of the proposed method compared with existing programs for docking: the highest success rate is 34.7% for the predicted structure of the RNA protein complex with the best score and 79.2% for 3,600 predicted ones. Three full atomistic force fields for RNA (AMBER94, AMBER99, and CHARMM22) produced almost the same accurate result, which showed current force fields for nucleic acids are quite accurate. In addition, we found that the electrostatic interaction and the representation of shape complementary between protein and RNA plays the important roles for accurate prediction of the native structures of RNA protein complexes. PMID- 27494733 TI - Molecular Genetic Approaches for Environmental Stress Tolerant Crop Plants: Progress and Prospects. AB - BACKGROUND: Global food security is threatened by the severe environmental conditions that have reduced the worldwide crop yield. Plants possess inherent mechanisms to cope with the initial stress phase but to ensure their survival through harsh climate, the intervention of genetic engineering is desirable. OBJECTIVE: We present a comprehensive review on the progress made in the field of developing environmental stress tolerant crops and the prospects that can be undertaken for achieving it. METHODS: We review the effects of abiotic and biotic stresses on crop plants, and the use of different molecular genetic approaches to cope with these environmental stresses for establishment of sustainable agriculture. The various strategies employed in different crops have also been discussed. We also summarized the major patents in the field of plant stress tolerance that have been granted in the last five years. RESULTS: On the basis of these analyses, we propose that genetic engineering of crops is the preferred approach over the traditional methods for yielding healthier and viable agriculture in response to the different stressful environments. The wild progenitors of cultivated crop species can prove to be highly potential genetic resources in this regard and can be exploited to produce better crops that are relatively tolerant towards various environmental stresses. CONCLUSION: Thus, elucidation of genetic loci and deciphering the underlying mechanisms that confer tolerance to plants against stressful conditions followed by its successful introgression into elite, high-yielding crop varieties can be an effective way to engineer the crops for sustainable agriculture. PMID- 27494734 TI - Inactivation of Pseudomonas aeruginosa by Chitosan Coated Iron Oxide Nanoparticles. AB - BACKGROUND: Pseudomonas aeruginosa is one of the potent opportunistic pathogens associated with respiratory and urinary tract infection. The bacterium owes its pathogenicity due to the intrinsic resistance to antibiotics and disinfectants. OBJECTIVE: The present study is focused on the synthesis of antibacterial chitosan coated iron oxide nanoparticles for rapid inactivation of Pseudomonas aeruginosa. We have discussed the relevant patents on synthesis and antibacterial potential of metallic nanoparticles and chitosan. METHOD: Chitosan coated iron oxide nanoparticles were synthesized by coprecipitation method at room temperature using non-toxic chitosan and iron salts in alkali media. The particles were characterized and evaluated for antibacterial property against Pseudomonas aeruginosa. RESULTS: The average size of the particles was measured as 52 nm. The surface area of the coated particles was as high as 90 +/-5 m2/g. FTIR spectra confirmed the coating of chitosan on nanoparticles. The coated particles showed excellent antibacterial activity against the bacteria. The minimum inhibitory concentration of the coated particles was 105)ug mol-1. The morphological alteration and cytoplasmic leakage of bacteria were confirmed by SEM image and release of intracellular constituents, respectively. Higher 260 nm absorbance value confirmed stronger antibacterial activity of the coated nanoparticles as compared to pure chitosan and bare iron oxide nanoparticles. CONCLUSION: The study indicated that chitosan coated iron oxide nanoparticles have superior antibacterial property as compared to pure chitosan and iron oxide nanoparticles. PMID- 27494735 TI - Preparation and Biochemical Property of Penicillin G Amidase-Loaded Alginate and Alginate/Chitosan Hydrogel Beads. AB - BACKGROUND: Penicillin G amidase (PGA) (EC 3.5.1.11) are enzymes that are mainly involved in the synthesis of semi-synthetic }-lactam antibiotics. Soluble PGA is costly and lacks long term operational stability. We revised most of the patents related to Penicillin G amidase (PGA) immobilization in the section "Recent Patents on Immobilized Penicillin G Amidase". OBJECTIVE: The aim of this work was to study comparative biochemical property of PGA enzyme immobilized in two hydro gel beads - Ca-alginate and alginate+chitosan hybrid and morphologically characterised by SEM. METHODS: PGA immobilized in alginate+chitosan hybrid bead shows high pH and thermal stability. Km, Vmax and Effectiveness factor (1) value of free PGA were 56.19 mg/ml, 1.786 U/ml and 1, respectively. These parameters for PGA immobilized alginate beads were 64.84 mg/ml, 0.781U/ml and 0.437, respectively and for PGA immobilized alginate+chitosan hybrid beads were 87.08 mg/ml, 0.622 U/ml and 0.348, respectively. RESULTS: Immobilized PGA on alginate+chitosan hybrid beads gave the highest thermal stability, reusability and storage stability than alginate immobilized PGA. CONCLUSION: The entrapment of PGA on alginate+chitosan hybrid beads revealed several advantages and could be used in 6APA (6- aminopenicillanic acid) production. PMID- 27494736 TI - Phenotypic Characterization of Toxic Compound Effects on Liver Spheroids Derived from iPSC Using Confocal Imaging and Three-Dimensional Image Analysis. AB - Cell models are becoming more complex to better mimic the in vivo environment and provide greater predictivity for compound efficacy and toxicity. There is an increasing interest in exploring the use of three-dimensional (3D) spheroids for modeling developmental and tissue biology with the goal of accelerating translational research in these areas. Accordingly, the development of high throughput quantitative assays using 3D cultures is an active area of investigation. In this study, we have developed and optimized methods for the formation of 3D liver spheroids derived from human iPS cells and used those for toxicity assessment. We used confocal imaging and 3D image analysis to characterize cellular information from a 3D matrix to enable a multi-parametric comparison of different spheroid phenotypes. The assay enables characterization of compound toxicities by spheroid size (volume) and shape, cell number and spatial distribution, nuclear characterization, number and distribution of cells expressing viability, apoptosis, mitochondrial potential, and viability marker intensities. In addition, changes in the content of live, dead, and apoptotic cells as a consequence of compound exposure were characterized. We tested 48 compounds and compared induced pluripotent stem cell (iPSC)-derived hepatocytes and HepG2 cells in both two-dimensional (2D) and 3D cultures. We observed significant differences in the pharmacological effects of compounds across the two cell types and between the different culture conditions. Our results indicate that a phenotypic assay using 3D model systems formed with human iPSC-derived hepatocytes is suitable for high-throughput screening and can be used for hepatotoxicity assessment in vitro. PMID- 27494737 TI - The Complexity of Dynamics in Small Neural Circuits. AB - Mean-field approximations are a powerful tool for studying large neural networks. However, they do not describe well the behavior of networks composed of a small number of neurons. In this case, major differences between the mean-field approximation and the real behavior of the network can arise. Yet, many interesting problems in neuroscience involve the study of mesoscopic networks composed of a few tens of neurons. Nonetheless, mathematical methods that correctly describe networks of small size are still rare, and this prevents us to make progress in understanding neural dynamics at these intermediate scales. Here we develop a novel systematic analysis of the dynamics of arbitrarily small networks composed of homogeneous populations of excitatory and inhibitory firing rate neurons. We study the local bifurcations of their neural activity with an approach that is largely analytically tractable, and we numerically determine the global bifurcations. We find that for strong inhibition these networks give rise to very complex dynamics, caused by the formation of multiple branching solutions of the neural dynamics equations that emerge through spontaneous symmetry breaking. This qualitative change of the neural dynamics is a finite-size effect of the network, that reveals qualitative and previously unexplored differences between mesoscopic cortical circuits and their mean-field approximation. The most important consequence of spontaneous symmetry-breaking is the ability of mesoscopic networks to regulate their degree of functional heterogeneity, which is thought to help reducing the detrimental effect of noise correlations on cortical information processing. PMID- 27494738 TI - New insights into Legionella pneumophila biofilm regulation by c-di-GMP signaling. AB - The waterborne pathogen Legionella pneumophila grows as a biofilm, freely or inside amoebae. Cyclic-di-GMP (c-di-GMP), a bacterial second messenger frequently implicated in biofilm formation, is synthesized and degraded by diguanylate cyclases (DGCs) and phosphodiesterases (PDEs), respectively. To characterize the c-di-GMP-metabolizing enzymes involved in L. pneumophila biofilm regulation, the consequences on biofilm formation and the c-di-GMP concentration of each corresponding gene inactivation were assessed in the Lens strain. The results showed that one DGC and two PDEs enhance different aspects of biofilm formation, while two proteins with dual activity (DGC/PDE) inhibit biofilm growth. Surprisingly, only two mutants exhibited a change in global c-di-GMP concentration. This study highlights that specific c-di-GMP pathways control L. pneumophila biofilm formation, most likely via temporary and/or local modulation of c-di-GMP concentration. Furthermore, Lpl1054 DGC is required to enable the formation a dense biofilm in response to nitric oxide, a signal for biofilm dispersion in many other species. PMID- 27494739 TI - The Prosocial Cyberball Game: Compensating for social exclusion and its associations with empathic concern and bullying in adolescents. AB - In this study we examined prosocial compensating behavior towards socially excluded ingroup and outgroup members by using a 'Prosocial Cyberball Game' in 9 17 year old Dutch adolescents (N = 133). Results showed that adolescents compensated for the social exclusion of an unknown peer in a virtual ball tossing game, by tossing the ball more often to that player in compensation conditions compared to the fair play condition. The proportion of tosses towards the excluded player did not significantly differ as a function of the group status of that player. Although compensating behavior towards ingroup versus outgroup members did not differ, the underlying motivation for this behavior may vary. More empathic concern was associated with more prosocial tosses towards an ingroup member, while more self-reported bullying behavior was associated with less compensating behavior in the outgroup condition. These findings may have practical implications for programs intending to change bystander behavior in bullying situations. PMID- 27494740 TI - The effectiveness of the Penn Resiliency Programme (PRP) and its adapted versions in reducing depression and anxiety and improving explanatory style: A systematic review and meta-analysis. AB - Mental health problems in children can be precursors of psychosocial problems in adulthood. The aim of this study is to assess the effectiveness of the universal application of a resilience intervention (PRP and derivatives), which has been proposed for large scale roll-out. Electronic databases were searched for published randomized controlled trials of PRP and derivatives to prevent depression and anxiety and improve explanatory style in students aged 8-17 years. Studies were meta-analysed and effect sizes with confidence intervals were calculated. The Quality Assessment Tool for Quantitative Studies of the Effective Public Health Practice Project was used to determine the confidence in the effect estimates. Nine trials from Australia, the Netherlands and USA met the inclusion criteria. No evidence of PRP in reducing depression or anxiety and improving explanatory style was found. The large scale roll-out of PRP cannot be recommended. The content and structure of universal PRP should be re-considered. PMID- 27494741 TI - Adolescent harm avoidance as a longitudinal predictor of maladaptive cognitive emotion regulation in adulthood: The mediating role of inhibitory control. AB - The current study investigates the effect of adolescent harm avoidance (HA) on maladaptive cognitive emotion regulation strategies (mCER) in early adulthood. The mediating role of inhibitory control and the moderating effect of gender on this link were also examined. Longitudinal data from 261 adolescents (147 female) were collected in three phases (T0, T1 and T2) over approximately 10 years. Results revealed that, after controlling for HA in adulthood (T2), female adolescents' HA (T0) significantly predicted mCER strategies after 10 years (T2), whereas male adolescents' HA only predicted catastrophizing. In addition, attentional impulsivity (T1) significantly mediated the relation between HA and mCER, though only among women. There was no significant indirect effect for emotional interference and stop-signal reaction time. Results revealed gender and measure specific associations between HA and inhibitory control and suggest that HA could induce inhibitory deficits leading to mCER. PMID- 27494742 TI - microRNA-214 Governs Lung Cancer Growth and Metastasis by Targeting Carboxypeptidase-D. AB - Lung cancer is one of the most malignant cancers with a high metastatic potential. The purpose of this study was to study the role and the underlying mechanism of miR-214 in lung cancer progression. The expression of miR-214 in normal lung and lung cancer tissue was analyzed by quantitative real-time PCR analysis. Furthermore, H1299 cells were infected with miR-214 lentivirus, and the effect of infection on cell viability and migration was analyzed. Carboxypeptidase-D (CPD), as a potential target of miR-214, was characterized in either normal lung or lung cancer tissues. The interaction of CPD expression with the tumor suppressing effect of miR-214 was characterized. We demonstrated that low miR-214 expression is a hallmark of lung cancer, especially high-grade and metastatic cancer. In vitro studies in H1299 cells confirmed that low miR-214 expression is associated with enhanced proliferation and migratory abilities. Similarly, CPD overexpression coincides with high-grade lung cancer and the CPD overexpression could reverse the inhibitory effects of miR-214. miR-214 is a tumor suppressor in lung cancer. miR-214 inhibits lung cancer progression by targeting CPD. The miR-214-CPD axis may be a therapeutic axis for lung cancer patients. PMID- 27494744 TI - Systematics of BX3 and BX2(+) Complexes (X = F, Cl, Br, I) with Neutral Diphosphine and Diarsine Ligands. AB - The coordination chemistry of the neutral diphosphines, R2P(CH2)2PR2 (R = Me or Et) and o-C6H4(PR'2)2 (R' = Me or Ph), and the diarsine, o-C6H4(AsMe2)2, toward the Lewis acidic BX3 (X = F, Cl, Br, and I) fragments is reported, including several rare complexes incorporating BF3 and BF2(+). The studies have revealed that the flexible dimethylene linked diphosphines form [(BX3)2{MU-R2P(CH2)2PR2}] exclusively, confirmed by multinuclear NMR ((1)H, (11)B, (19)F{(1)H}, and (31)P{(1)H}) and IR spectroscopy and microanalytical data. Crystallographic determinations of the four BX3 complexes with Et2P(CH2)2PEt2 confirm the 2:1 stoichiometry and, taken together with the spectroscopic data, reveal that the Lewis acid behavior of the BX3 fragment toward phosphine ligands increases in the order F ? Cl ~ Br < I. The first diphosphine- and diarsine-coordinated dihaloboronium cations, [BX2{o-C6H4(EMe2)2}](+) (E = P, As), are obtained using the rigid, preorganized o-phenylene linkages. These complexes are characterized similarly, and the data indicate that the complexes with o-C6H4(AsMe2)2 are much more labile and readily decomposed than the phosphine analogues. X-ray crystallographic studies on [BX2{o-C6H4(PMe2)2}][BX4] (X = Cl, Br), [BI2{o C6H4(PMe2)2}][I3], and [BCl2{o-C6H4(AsMe2)2}][BCl4] confirm the presence of distorted tetrahedral coordination at boron through a chelating diphosphine or diarsine and two X ligands, with d(B-P) revealing a similar increase in Lewis acidity down group 17. Comparison of d(B-P) and d(B-As) reveals an increase of ca. 0.08 A from P to As. Reaction of BCl3 with the diphosphine dioxide Ph2P(O)CH2P(O)Ph2 gives the ligand-bridged dimer [(BCl3)2{Ph2P(O)CH2P(O)Ph2}], while using either BF3 gas or [BF3(SMe2)] gives a mixture containing both [(BF3)2{MU-Ph2P(O)CH2P(O)Ph2}] and the unexpected difluoroboronium salt, [BF2{Ph2P(O)CH2P(O)Ph2}][B2F7] containing a chelating phosphine oxide. The structure of the latter was confirmed crystallographically. PMID- 27494743 TI - Soda consumption and hospital admissions among Californian adults with asthma. AB - INTRODUCTION: Asthma prevalence has been increasing consistently since 1995 in California. Recent studies have found that consuming soda and sugar-containing drinks may pose a risk for asthma. Research that examines the relationship between soda intake and asthma among adult asthmatics is limited. OBJECTIVE: This study investigated the relationship between sugar-sweetened soda consumption and asthma hospitalization among adult asthmatics in California. METHODS: This cross sectional study was based on the 2011-2012 California Health Interview Survey (CHIS) data and included 3,784 adults who were diagnosed with asthma by a doctor and who currently reported either that they still had asthma, or that they had suffered from an asthma attack in the last 12 months. The analysis was survey weighted. The exposure variable was soda intake measured as the number of times soda was consumed in the last week. The health outcome measure was overnight hospital admission due to asthma. Logistic regression was used to examine the association between soda consumption and overnight hospital admission after adjusting for age, education, sex, race/ethnicity, weight status, smoking status, and self-rated health. RESULTS: Adults with asthma who drank soda three or more times per week reported higher odds of overnight hospitalization (adjusted odds ratio = 2.77, 95% CI: 1.51-5.10, p = 0.001). CONCLUSIONS: Our findings suggest that efforts designed to limit soda consumption would benefit asthma suffers by reducing hospital admissions. This, however, needs further research to confirm a direct causal association. PMID- 27494745 TI - Separation of phenol-containing pyrolysis products using comprehensive two dimensional chromatography with columns based on pyridinium ionic liquids. AB - We describe the application of columns with highly polar stationary liquid phases based on pyridinium ionic liquids for the two-dimensional chromatography separation of bio-oil and product of coal pyrolysis. By using inverse combination columns-a first ionic liquid column and a second nonpolar column-good separation results have been obtained. In the analysis of coal pyrolysis products, the suggested approach provides a much better resolution between components in comparison with a less polar first-dimension column (based on polyethylene glycol). A good selectivity for the peaks of phenols is observed, and the group of phenols is well detached and separated from the group of diaromatics. A good separation picture was obtained also for bio-oil, the groups of phenols and guaiacol derivatives are distinguished with good resolution of substances within each group. PMID- 27494746 TI - Access to experimentally infeasible spectra by pure-shift NMR covariance. AB - Covariance processing is a versatile processing tool to generate synthetic NMR spectral representations without the need to acquire time-consuming experimental datasets. Here we show that even experimentally prohibited NMR spectra can be reconstructed by introducing key features of a reference 1D CHn-edited spectrum into standard 2D spectra. This general procedure is illustrated with the calculation of experimentally infeasible multiplicity-edited pure-shift NMR spectra of some very popular homonuclear (ME-psCOSY and ME-psTOCSY) and heteronuclear (ME-psHSQC-TOCSY and ME-psHMBC) experiments. PMID- 27494747 TI - Different blood pressure responses to opioids in 3 rat hypertension models: role of the baseline status of sympathetic and renin-angiotensin systems. AB - Opioids interact with sympathetic and renin-angiotensin systems in control of mean arterial pressure (MAP). Our earlier finding that biphalin, a synthetic enkephalin analogue, decreased MAP in anaesthetized spontaneously hypertensive rats (SHR) prompted us to further explore this action, to get new insights into pathogenesis of various forms of hypertension. Biphalin effects were studied in SHR, uninephrectomized rats on a high-salt diet (HS/UNX), and rats with angiotensin-induced hypertension (Ang-iH). Besides MAP, renal and iliac blood flows (RBF, IBF) and vascular resistances were measured. In anaesthetized and conscious SHR, biphalin (300 MUg.h-1.kg-1 i.v.) decreased MAP by ~10 and ~20 mm Hg, respectively (P < 0.001). In anaesthetized HS/UNX and normotensive rats, MAP increased by ~6-7 mm Hg (P < 0.02); without anaesthesia, only transient decreases occurred. MAP never changed in Ang-iH rats. Morphine (1.5 mg.h-1.kg-1 i.v.) decreased MAP in HS/UNX but only transiently so without anaesthesia; such anaesthesia dependence of response was also seen in normotensive rats. Ang-iH rats never responded to morphine. Hypotensive effect in SHR only depends primarily on the reduction by biphalin of vascular responsiveness to increased sympathetic stimulation; such increase is well documented for SHR. No MAP response to biphalin or morphine in Ang-iH could depend on angiotensin-induced alterations of the vascular wall morphology and function. PMID- 27494748 TI - Invited Commentary. PMID- 27494749 TI - Surgical Approaches to Non-thyrogenic and Non-thymic Mediastinal Tumors of the Thoracic Inlet. AB - BACKGROUND: Non-thyrogenic and non-thymic mediastinal tumors of the thoracic inlet are in close proximity to several important vessels and nerves. The narrow confines of the thoracic inlet make complete excision of these tumors difficult, and selecting the appropriate surgical approach is important to successful resection. METHODS: Records from 57 patients who presented to our department with non-thyrogenic and non-thymogenic tumors of the thoracic inlet from November 2004 to November 2015 were reviewed. All but one of the patients received surgical treatment. Thirty-two tumors were excised via video-assisted thoracic surgery (VATS). Other approaches included thoracotomy, supraclavicular incision, supraclavicular incision plus thoracotomy/VATS, and a posterior midline approach with semi-laminectomy combined with VATS. RESULTS: Tumors were resected completely in 54 cases and partially in one. One procedure (VATS) was aborted. There were no surgical mortalities, but there were some postoperative complications. The majority of the tumors were benign neurogenic tumors. CONCLUSIONS: Most tumors of the thoracic inlet are benign and can be removed via VATS. Thoracotomy is the appropriate approach for large tumors, particularly in cases where the first to second rib cannot be visualized. A supraclavicular approach is recommended for resection of tumors arising from the brachial plexus, and a supraclavicular approach combined with VATS or thoracotomy may be useful for larger masses. A posterior midline approach with semi-laminectomy combined with VATS is appropriate for dumbbell-shaped tumors. PMID- 27494750 TI - Expanding Surgical Opportunities: Endoscopic Harvesting of the Vena Saphena Parva in Supine Position. AB - The small saphenous vein (SSV) has proved to be a valid graft option for coronary artery bypass grafting (CABG), if other grafts are absent or unsuitable. Beside the described open technique we herein present our approach to endoscopic harvesting in supine position in seven patients. Harvesting was successful in six patients. Mean skin-to-skin time was 29.8 minutes. There were no infections or neurological deficits and the intraoperatively measured graft flow was excellent according to mean flow and low pulsatility index. Therefore, endoscopic harvesting of the SSV extends surgical opportunities not only in CABG, but also in surgery of peripheral artery disease. PMID- 27494751 TI - Clinical use of ruxolitinib in an academic medical center in unselected patients with myeloproliferative neoplasms not on clinical study. AB - Ruxolitinib is the only approved therapy for myelofibrosis (MF). However, its use in patients with myeloproliferative neoplasms (MPN) not participating in clinical studies has been poorly described. We reviewed the medical records of 45 patients (35 MF, 10 others) treated with ruxolitinib at our center, off clinical study, during the year after its approval. Patients had advanced features and were refractory to multiple therapies. Ruxolitinib was effective in reducing splenomegaly (51% response rate) and constitutional symptoms (42% response rate). It controlled blood counts in patients with polycythemia and thrombocythemia but was not effective in patients with non-classic MPNs. Ruxolitinib was an active therapy in patients previously treated with a JAK inhibitor and was safely combined with hypomethylating agents in patients with elevated blasts. Median overall survival was 24 months; 10 patients transformed to acute leukemia. Its use in combination with other active agents should be further explored in clinical studies. PMID- 27494752 TI - Synthesis of a novel PEGDGA-coated hPAMAM complex as an efficient and biocompatible gene delivery vector: an in vitro and in vivo study. AB - hPAMAM/DNA polyplexes, compared to viral vectors, display unique characteristics including more safety, less immune response outcomes, a simpler synthesis and an easier process. Given the importance of these polymers, hPAMAM coated with the PEGDGA copolymer was developed as a promising non-viral gene carrier. In the present study, a new complex of hPAMAM, PEGDGA-modified hyperbranched polyamidoamine (hPAMAM), was established as a versatile non-viral gene vector. The hPAMAM polymer was synthesized by using a modified one-pot method. The resulting hPAMAM-PEGDGA polymer was able to efficiently protect encapsulated-DNA against degradation for over 2 h. In addition to low cytotoxicity, the transfection efficiency of hPAMAM-PEGDGA represented much higher (p < 0.05) than that of Lipofectamine 2000 in both MCF7 and MDA-MB231 cells (an approximately 4.5 fold increase). Cellular uptake of hPAMAM-PEGDGA in MDA-MB231 cells, 254.79 +/- 2.1, was significantly higher than that in MCF7 cells, 51.61 +/- 6.1 (p < 0.05). EMA-labeled DNA can be clearly observed in the tumor tissue of mice receiving hPAMAM-PEGDGA/EMA-labeled DNA. However, a significant number of fluorescent spots can be found in the tumor tissue of mice receiving hPAMAM/DNA, when compared to those treated with naked hPAMAM/DNA. It has been observed that GFP is expressed more highly in hPAMAM-PEGDGA/EMA-labeled/DNA than the one in PAMAM/DNA. The results indicated that hPAMAM-PEGDGA-mediated gene delivery to breast cancer cells is a feasible and effective strategy that may offer a new therapeutic avenue as a non-viral gene delivery carrier. Notably, According to these findings, this newly-introduced copolymer, the hPAMAM-PEGDGA complex, has proved to be a promising strategy for drug or gene delivery to tissues or cell types of interest, particularly to triple-negative breast cancer. PMID- 27494753 TI - Trans Bodies, Trans Selves: The Owner's Manual to Life, Health, and Self. AB - In this article, the author reviews Trans Bodies, Trans Selves as an educational and clinical resource from the perspective of an academic physician working with transgender and gender non-conforming patients. PMID- 27494754 TI - Chrysobalanus icaco L. fruits inhibit NADPH oxidase complex and protect DNA against doxorubicin-induced damage in Wistar male rats. AB - Chrysobalanus icaco L. is an underexplored plant found in tropical areas around the globe. Currently, there is no apparent information regarding the effects C. icaco fruits may exert in vivo or potential role in health promotion. This study aimed at providing evidence regarding the in vivo influence of this fruit on antigenotoxicity, antimutagenicity, and oxidative stress in rats. Male Wistar rats were treated with 100, 200, or 400 mg/kg body weight (bw)/d C. icaco fruit for 14 d. Doxorubicin (DXR, 15 mg/kg bw, ip) was used for DNA damaging and as an oxidant to generate reactive oxygen species (ROS). Genomic instability was assessed by the comet assay and micronucleus (MN) test, while antioxidant activity was determined by oxidative burst of neutrophils. Chrysobalanus icaco fruit polyphenols were quantified and characterized by high-performance liquid chromatography coupled to a diode array detector and tandem mass spectrometer (HPLC-DAD-MS/MS). The concentrations of 19 chemical elements were determined by inductively coupled plasma-mass spectroscopy (ICP-MS). Significant amounts of polyphenols, magnesium, and selenium were found in C. icaco fruit. This fruit displayed in vivo antioxidant activity against DXR-induced damage in rat peripheral blood neutrophils, antigenotoxicity in peripheral blood cells, and antimutagenicity in bone-marrow cells and peripheral blood cells. Correlation analyses between endpoints examined indicated that the mechanism underlying chemopreventive actions of C. icaco fruit was attributed to inhibition of NADPH oxidase complex manifested as low levels of DNA damage in animals exposed to DXR. Data indicate that phytochemicals and minerals in C. icaco fruit protect DNA against damage in vivo associated with their antioxidant properties. PMID- 27494755 TI - Size matters: decreased glandular levels of anti-inflammatory short thymic stromal lymphopoietin in primary Sjogren's syndrome. PMID- 27494756 TI - Neurobehavioural assessment and diagnosis in disorders of consciousness: a preliminary study of the Sensory Tool to Assess Responsiveness (STAR). AB - The Sensory Tool to Assess Responsiveness (STAR) is an interdisciplinary neurobehavioural diagnostic tool for individuals with prolonged disorders of consciousness. It utilises current diagnostic criteria and is intended to improve upon the high misdiagnosis rate in this population. This study assesses the inter rater reliability of the STAR and its diagnostic validity in comparison with the Coma Recovery Scale-Revised (CRS-R) and the Wessex Head Injury Matrix (WHIM). Participants were patients with severe acquired brain injury resulting in a disorder of consciousness, who were admitted to the Royal Leamington Spa Rehabilitation Hospital between 1999 and 2009. Patients underwent sensory stimulation sessions during their period of admission, which were recorded on video. Using this footage, patients were re-assessed for this study using the STAR, WHIM and CRS-R criteria. The STAR demonstrated "moderate" inter-rater reliability, "substantial" diagnostic agreement with the CRS-R, and "moderate" agreement with the WHIM. There were no significant differences between diagnoses assigned by the different assessments. The STAR demonstrated a good degree of inter-rater reliability in identification of diagnoses for patients with disorders of consciousness. The diagnostic outcomes of the STAR agreed at a good level with the CRS-R, moderately with the WHIM, and did not significantly differ from either. This demonstrates the reliability and validity of the STAR, showing its appropriateness for clinical use. Future longitudinal studies and research into the STAR's applicability in long-stay rehabilitation are indicated. PMID- 27494757 TI - Characteristics, Properties and Analytical Methods of Cefadroxil: A Review. AB - Infections are the second leading cause of mortality worldwide and there are many reasons justifying the need for further studies of antimicrobial agents. Cefadroxil is a drug that has bactericidal activity and broad spectrum of action. Quantitative analyzes about cefadroxil are essential for the understanding of bioavailability, bioequivalence, and therapeutic control, which will ensure the product's characteristics and patients' safety. Thus, this study highlights a brief literature review about the drug and the existing methods developed for the determination of cefadroxil found in official and scientific papers. According to the methods found in literature, liquid chromatography and spectrophotometry of absorption in the ultraviolet region prevailed over the others. Importantly, most of the solvents used for the development of the described analytical methods are toxic to the environment, making it necessary to educate researchers and pharmaceutical companies to use nontoxic solvents to provide environmental friendly methods and better benefits to equipments and mainly to analysts. PMID- 27494758 TI - Predictors of future exacerbation risk in patients with asthma. AB - OBJECTIVES: Although modern treatment of asthma improves asthma control, some patients still experience exacerbations. The aim of the present study was to detect predictors of asthmatic exacerbations Methods: We included patients with asthma followed up in asthma clinics of 2 tertiary University hospitals. Demographic and functional characteristics, levels of exhaled NO, and inflammatory biomarkers (IL-13, EpsilonCP kappaalphaiota IL-8) and cell counts in induced sputum were recorded at baseline. Measurements were performed with the patients in stability and were considered as their personal best. Patients received optimal treatment with good compliance and were followed up for 1 year for asthma exacerbations occurrence. Evaluation of the effect of recorded parameters on asthma exacerbations was performed with univariate and multivariate Poisson regression analysis. RESULTS: 171 patients (118 female) with bronchial asthma (mean age 51.6 +/- 13.2 years) were included in the study. The mean number of exacerbations in 1 year of follow up was 0.4 +/- 0.8 while the majority of patients (71.9%) did not experience any exacerbation. In multivariate Poisson Regression analysis only 3 characteristics were predictors of future exacerbations: FEV1 [IRR(95% CI)], [0.970(0.954-0.987)], p = 0.001, high BMI [1.078(1.030-1.129)], p = 0.001, and the need for permanent treatment with oral corticosteroids for asthma control maintenance [2.542(1.083-5.964)], p = 0.032 CONCLUSION: Optimal guideline-based asthma management results in minimal occurrence of exacerbations in the majority of patients. Predictors of exacerbations are low FEV1 levels in stability, high BMI and the need for permanent treatment with oral corticosteroids. PMID- 27494759 TI - Photocatalytic Generation of 2-Azolyl Radicals: Intermediates for the Azolylation of Arenes and Heteroarenes via C-H Functionalization. AB - The 2-azolyl radical, generated from 2-bromoazoles via photocatalysis, is a powerful intermediate for the intermolecular arylation of unmodified (hetero)arenes. The reaction is characterized by mild conditions, operational simplicity, tolerance toward functional and sterically demanding groups, broad scope, and anti-Minisci selectivity. A working mechanism is provided, and a low solubility amine is essential for successful coupling. The utility of the reaction is demonstrated via late-stage functionalization of methyl estrone and application toward other bromoarenes. PMID- 27494760 TI - Single-Molecule Analysis of the Supramolecular Organization of the M2 Muscarinic Receptor and the Galphai1 Protein. AB - G protein-coupled receptors constitute the largest family of transmembrane signaling proteins and the largest pool of drug targets, yet their mechanism of action remains obscure. That uncertainty relates to unresolved questions regarding the supramolecular nature of the signaling complex formed by receptor and G protein. We therefore have characterized the oligomeric status of eGFP tagged M2 muscarinic receptor (M2R) and Gi1 by single-particle photobleaching of immobilized complexes. The method was calibrated with multiplexed controls comprising 1-4 copies of fused eGFP. The photobleaching patterns of eGFP-M2R were indicative of a tetramer and unaffected by muscarinic ligands; those of eGFP-Gi1 were indicative of a hexamer and unaffected by GTPgammaS. A complex of M2R and Gi1 was tetrameric in both, and activation by a full agonist plus GTPgammaS reduced the oligomeric size of Gi1 without affecting that of the receptor. A similar reduction was observed upon activation of eGFP-Galphai1 by the receptor mimic mastoparan plus GTPgammaS, and constitutively active eGFP-Galphai1 was predominantly dimeric. The oligomeric nature of Gi1 in live CHO cells was demonstrated by means of Forster resonance energy transfer and dual-color fluorescence correlation spectroscopy in studies with eGFP- and mCherry-labeled Galphai1; stochastic FRET was ruled out by means of non-interacting pairs. These results suggest that the complex between M2R and holo-Gi1 is an octamer comprising four copies of each, and that activation is accompanied by a decrease in the oligomeric size of Gi1. The structural feasibility of such a complex was demonstrated in molecular dynamics simulations. PMID- 27494761 TI - Cu2ZnSnS4 Nanoparticle Sensitized Metal-Organic Framework Derived Mesoporous TiO2 as Photoanodes for High-Performance Dye-Sensitized Solar Cells. AB - We present a facile hot injection and hydrothermal method to synthesize Cu2ZnSnS4 (CZTS) nanoparticles sensitized metal-organic frameworks (MOFs)-derived mesoporous TiO2. The MOFs-derived TiO2 inherits the large specific surface area and abundantly porous structures of the MOFs structure, which is of great benefit to effectively enhance the dye loading capacity, prolong the incident light traveling length by enhancing the multiple interparticle light-scattering process, and therefore improve the light absorption capacity. The sensitization of CZTS nanoparticles effectively enlarges the photoresponse range of TiO2 to the visible light region and facilitates photoinduced carrier transport. The formed heterostructure between CZTS nanoparticles and MOFs-derived TiO2 with matched band gap structure effectively suppresses the recombination rates of photogenerated electron/hole pairs and prolongs the lifespan of the carriers. Photoanodes based upon CZTS/MOFs-derived TiO2 photoanodes can achieve the maximal photocurrent of 17.27 mA cm(-2) and photoelectric conversion performance of 8.10%, nearly 1.93 and 2.21 times higher than those of TiO2-based photoanode. The related mechanism and model are investigated. The strikingly improved photoelectric properties are ascribed to a synergistic action between the MOFs derived TiO2 and the sensitization of CZTS nanoparticles. PMID- 27494762 TI - The Structure of Multidimensional Perfectionism: Support for a Bifactor Model With a Dominant General Factor. AB - Evidence suggests perfectionism is a multidimensional construct composed of 2 higher order factors: perfectionistic strivings and perfectionistic concerns. However, the substantial overlap between perfectionistic strivings and perfectionistic concerns is problematic, as are the unanswered questions regarding the structure of perfectionism following removal of common variance. This research addressed this through bifactor modeling. Three student samples (N = 742) completed Hewitt and Flett's ( 1991 ) Multidimensional Perfectionism Scale, Frost, Marten, Lahart, and Rosenblate's ( 1990 ) Multidimensional Perfectionism Scale, and Slaney, Rice, Mobley, Trippi, and Ashby's ( 2001 ) Almost Perfect Scale-Revised. Greater support was consistently found for the bifactor model, relative to the 2-factor model. Results suggest the bifactor model best represents the structure of perfectionism and provide preliminary support for the use of a general factor score. Researchers are cautioned that removal of general variance may render the reliability of specific factors (i.e., perfectionistic strivings and perfectionistic concerns) suspect. PMID- 27494764 TI - The Effects of Air Flow Rates, Secondary Air Inlet Geometry, Fuel Type, and Operating Mode on the Performance of Gasifier Cookstoves. AB - Development of biomass cookstoves that reduce emissions of CO and PM2.5 by more than 50% and 95%, respectively, compared to a three-stone fire has been promoted as part of efforts to reduce exposure to household air pollution (HAP) among people that cook with solid fuels. Gasifier cookstoves have attracted interest because some have been shown to emit less CO and PM2.5 than other designs. A laboratory test bed and new test procedure were used to investigate the influence of air flow rates, stove geometry, fuel type, and operating mode on gasifier cookstove performance. Power output, CO emissions, PM2.5 emissions, fuel consumption rates, producer gas composition, and fuel bed temperatures were measured. The test bed emitted <41 mg.MJd-1 PM2.5 and <8 g.MJd-1 CO when operating normally with certain prepared fuels, but order of magnitude increases in emission factors were observed for other fuels and during refueling. Changes in operating mode and fuel type also affected the composition of the producer gas entering the secondary combustion zone. Overall, the results suggest that the effects of fuel type and operator behavior on emissions need to be considered, in addition to cookstove design, as part of efforts to reduce exposure to HAP. PMID- 27494763 TI - Structure Prediction of RNA Loops with a Probabilistic Approach. AB - The knowledge of the tertiary structure of RNA loops is important for understanding their functions. In this work we develop an efficient approach named RNApps, specifically designed for predicting the tertiary structure of RNA loops, including hairpin loops, internal loops, and multi-way junction loops. It includes a probabilistic coarse-grained RNA model, an all-atom statistical energy function, a sequential Monte Carlo growth algorithm, and a simulated annealing procedure. The approach is tested with a dataset including nine RNA loops, a 23S ribosomal RNA, and a large dataset containing 876 RNAs. The performance is evaluated and compared with a homology modeling based predictor and an ab initio predictor. It is found that RNApps has comparable performance with the former one and outdoes the latter in terms of structure predictions. The approach holds great promise for accurate and efficient RNA tertiary structure prediction. PMID- 27494765 TI - Statistical thermodynamics of non-stoichiometric ceria and ceria zirconia solid solutions. AB - The thermodynamic redox properties of ceria and ceria zirconia solid solutions are analysed with a new methodology for modelling such systems based on the statistical mechanics of lattice configurations. Experimental thermogravimetric equilibrium data obtained for small non-stoichiometry measurements are combined with literature data to cover a large range of non-stoichiometry (CeO2-delta, delta = 0.001-0.32), temperature (1073-1773 K) and oxygen partial pressure (1-10( 13) bar). A dilute species model of defect clusters , obeying the law of mass action, was sufficient to describe the system over the whole range of conditions, leading to a simple analytical equation of state for the system. This offers new physical insight into the redox properties of ceria based materials, and the theoretical methods developed should also be of great interest for other materials which exhibit continuous oxygen non-stoichiometry similar to ceria, such as perovskite oxides. PMID- 27494766 TI - The attention-weighted sample-size model of visual short-term memory: Attention capture predicts resource allocation and memory load. AB - We investigated the capacity of visual short-term memory (VSTM) in a phase discrimination task that required judgments about the configural relations between pairs of black and white features. Sewell et al. (2014) previously showed that VSTM capacity in an orientation discrimination task was well described by a sample-size model, which views VSTM as a resource comprised of a finite number of noisy stimulus samples. The model predicts the invariance of [Formula: see text] , the sum of squared sensitivities across items, for displays of different sizes. For phase discrimination, the set-size effect significantly exceeded that predicted by the sample-size model for both simultaneously and sequentially presented stimuli. Instead, the set-size effect and the serial position curves with sequential presentation were predicted by an attention-weighted version of the sample-size model, which assumes that one of the items in the display captures attention and receives a disproportionate share of resources. The choice probabilities and response time distributions from the task were well described by a diffusion decision model in which the drift rates embodied the assumptions of the attention-weighted sample-size model. PMID- 27494768 TI - Online Extraction Coupled to Liquid Chromatography Analysis (OLE-LC): Eliminating Traditional Sample Preparation Steps in the Investigation of Solid Complex Matrices. AB - Current methods employed for the analysis of the chemical composition of solid matrices (such as plant, animal, or human tissues; soil; etc.) often require many sample treatment steps, including an extraction step with exclusively dedicated solvents. This work describes an optimized analytical setup in which the extraction of a solid sample is directly coupled to its analysis by high performance liquid chromatography. This approach avoids (i) the use of pumps and valves other than those comprising the HPLC instrument, (ii) the use of solvents other than those of the mobile phase, and (iii) the need to stop the mobile phase flow at any time during the full analytical procedure. The compatibility of this approach with the direct analysis of fresh tissues (leaves, stems, and seeds of four plant species with dissimilar chemical compositions) was successfully demonstrated, leading to the elimination of sample preparation steps such as drying, grinding, concentration, dilution, and filtration, among others. This work describes a new, simple, and efficient green approach to minimize or eliminate sample treatment procedures. It could be easily applied for quality control of plant materials and their derived products through chromatographic fingerprints and for untargeted metabolomic investigations of solid matrices, among other applications. PMID- 27494767 TI - Impact of fibroblast growth factor 21 on the secretome of human perivascular preadipocytes and adipocytes: a targeted proteomics approach. AB - CONTEXT: Perivascular adipose tissue (PVAT) is suggested to impact on vascular cells via humoral factors, possibly contributing to endothelial dysfunction and atherosclerosis. OBJECTIVE: To address whether the hepatokine fibroblast growth factor (FGF) 21 affects the PVAT secretome. METHODS: Human perivascular (pre)adipocytes were subjected to targeted proteomics and whole-genome gene expression analysis. RESULTS: Preadipocytes, as compared to adipocytes, secreted higher amounts of inflammatory cytokines and chemokines. Adipocytes released higher amounts of adipokines [e.g. adipisin, visfatin, dipeptidyl peptidase 4 (DPP4), leptin; p < 0.05, all]. In preadipocytes, omentin 1 release was 1.28-fold increased by FGF-21 (p < 0.05). In adipocytes, FGF-21 reduced chemerin release by 5% and enhanced DPP4 release by 1.15-fold (p < 0.05, both). FGF-21 altered the expression of four secretory genes in preadipocytes and of 18 in adipocytes (p < 0.01, all). CONCLUSION: The hepatokine FGF-21 exerts secretome-modulating effects in human perivascular (pre)adipocytes establishing a new liver-PVAT-blood vessel axis that possibly contributes to vascular inflammation and atherosclerosis. PMID- 27494769 TI - Cylindrospermopsin effects on protein profile of HepG2 cells. AB - Human hepatoma cells (HepG2) were exposed to purified cylindrospermopsin (CYN), a potent toxicant for eukaryotic cells produced by several cyanobacteria. Exposure to 10 MUg l-1 of CYN for 24 h resulted in alteration of expression of 48 proteins, from which 26 were identified through mass spectrometry. Exposure to 100 MUg l-1 of CYN for 24 h affected nuclear area and actin filaments intensity, which can be associated with cell proliferation and toxicity. The proteins are implicated in different biological processes: protein folding, xenobiotic efflux, antioxidant defense, energy metabolism and cell anabolism, cell signaling, tumorigenic potential, and cytoskeleton structure. Protein profile indicates that CYN exposure may lead to alteration of glucose metabolism that can be associated with the supply of useful energy to cells respond to chemical stress and proliferate. Increase of G protein-coupled receptors (GPCRs), heterogeneous nuclear ribonucleoproteins (hnRNP), and reactive oxygen species (ROS) levels observed in HepG2 cells can associate with cell proliferation and resistance. Increase of MRP3 and glutathione peroxidase can protect cells against some chemicals and ROS. CYN exposure also led to alteration of the expression of cytoskeleton proteins, which may be associated with cell proliferation and toxicity. PMID- 27494770 TI - Electronic cigarette initiation among minority youth in the United States. AB - BACKGROUND: Electronic cigarettes (e-cigarette) use among youth is a pressing public health issue, with prevalence of use surpassing that of tobacco cigarettes. While research concerning e-cigarettes has proliferated in recent years, there is a dearth of information regarding those whose first exposure to tobacco products was an e-cigarette. OBJECTIVES: To examine factors associated with e-cigarette initiation among minority youth in the United States. METHODS: Data on minority students in middle and high schools in the United States derived from the 2014 National Youth Tobacco Survey (NYTS) were sampled (weighted N = 27,294,454). We examined e-cigarette initiation among minority youth using logistic regression models to identify related factors. RESULTS: In 2014, 736,158 minority youth were e-cigarette initiators. Odds of e-cigarette initiation was highest among Hispanic youth [adjusted odds ratio (AOR) = 2.70; 95% confidence interval (CI) = 1.60-4.56]. Exposure to e-cigarette advertising (AOR = 1.64; 95% CI = 1.07-2.50), perceptions of little to no harm (AOR = 7.08; 95% CI = 4.03 12.46), and believing e-cigarettes were less addictive than tobacco (AOR = 2.15; 95% CI = 1.52-3.02) were associated with e-cigarette initiation. CONCLUSIONS: Odds of initiating e-cigarette use was highest among Hispanic youth. Among minority youth, e-cigarette initiation was associated with perceptions of harm and addiction potential, as well as exposure to e-cigarette advertising. Therefore, prevention efforts targeting minority youth who are at risk of becoming e-cigarette initiators may benefit by incorporating these factors into prevention campaigns. PMID- 27494771 TI - [Staff Satisfaction within Duty Hour Models: Longitudinal Survey on Suitability and Legal Conformity at a Surgical Maximum Care Department]. AB - Background Between the conflicting requirements of clinic organisation, the European Working Time Directive, patient safety, an increasing lack of junior staff, and competitiveness, the development of ideal duty hour models is vital to ensure maximum quality of care within the legal requirements. To achieve this, it is useful to evaluate the actual effects of duty hour models on staff satisfaction. Materials and Methods After the traditional 24-hour duty shift was given up in a surgical maximum care centre in 2007, an 18-hour duty shift was implemented, followed by a 12-hour shift in 2008, to improve handovers and reduce loss of information. The effects on work organisation, quality of life and salary were analysed in an anonymous survey in 2008. The staff survey was repeated in 2014. Results With a response rate of 95% of questionnaires in 2008 and a 93% response rate in 2014, the 12-hour duty model received negative ratings due to its high duty frequency and subsequent social strain. Also the physical strain and chronic tiredness were rated as most severe in the 12-hour rota. The 18-hour duty shift was the model of choice amongst staff. The 24-hour duty model was rated as the best compromise between the requirements of work organisation and staff satisfaction, and therefore this duty model was adapted accordingly in 2015. Conclusion The essential basis of a surgical department is a duty hour model suited to the requirements of work organisation, the Working Time Directive and the needs of the surgical staff. A 12-hour duty model can be ideal for work organisation, but only if augmented with an adequate number of staff members, the implementation of this model is possible without the frequency of 12-hour shifts being too high associated with strain on surgical staff and a perceived deterioration of quality of life. A staff survey should be performed on a regular basis to assess the actual effects of duty hour models and enable further optimisation. The much criticised 24-hour duty model seems to be much better than its reputation, if augmented by additional staff members in the evening hours. PMID- 27494772 TI - Chitosan/alginate based multilayers to control drug release from ophthalmic lens. AB - In this study we investigated the possibility of using layer-by-layer deposition, based in natural polymers (chitosan and alginate), to control the release of different ophthalmic drugs from three types of lens materials: a silicone-based hydrogel recently proposed by our group as drug releasing soft contact lens (SCL) material and two commercially available materials: CI26Y for intraocular lens (IOLs) and Definitive 50 for SCLs. The optimised coating, consisting in one double layer of (alginate - CaCl2)/(chitosan+glyoxal) topped with a final alginate-CaCl2 layer to avoid chitosan degradation by tear fluid proteins, proved to have excellent features to control the release of the anti-inflammatory, diclofenac, while keeping or improving the physical properties of the lenses. The coating leads to a controlled release of diclofenac from SCL and IOL materials for, at least, one week. Due to its high hydrophilicity (water contact angle~0) and biocompatibility, it should avoid the use of further surface treatments to enhance the users comfort. However, the barrier effect of this coating is specific for diclofenac, giving evidence to the need of optimizing the chemical composition of the layers in view of the desired drug. PMID- 27494773 TI - The tyrosine kinase inhibitor, nilotinib potentiates a prothrombotic state. AB - Tyrosine kinase inhibitors (TKI) such as imatinib, nilotinib and dasatinib are now established as highly effective frontline therapies for chronic myeloid leukaemia (CML). Disease control is achieved in the majority of patients and survival is excellent such that recent focus has been on toxicities of these agents. Cumulative data have reported an excess of serious vascular complications, including arterial thrombosis and peripheral arterial occlusive disease, in patients receiving nilotinib in comparison with other TKIs, with resultant interest in delineating the pathophysiology and implications for rationale cardiovascular risk modification. To address this issue, we studied the effects of imatinib, nilotinib and dasatinib on platelet function and thrombus formation in human and mouse models using in vitro, ex vivo and in vivo approaches. In vitro studies demonstrated that dasatinib and imatinib but not nilotinib inhibited ADP, CRP, and collagen-induced platelet aggregation and moreover, that nilotinib potentiated PAR-1-mediated alpha granule release. Pretreatment of wild-type C57BL/6 mice with nilotinib but not imatinib or dasatinib, significantly increased thrombus growth and stability, on type I collagen under ex vivo arterial flow conditions and increased thrombus growth and stability following FeCl3-induced vascular injury of mesenteric arterioles and carotid artery injury in vivo. Whole blood from nilotinib-treated CML patients, demonstrated increased platelet adhesion ex vivo under flow, increased plasma soluble P- and E-selectin, sICAM-1, sVCAM-1, TNF-alpha, IL-6 levels and endogenous thrombin potential (ETP) levels in vivo, despite being on daily low dose aspirin. These results demonstrate that nilotinib can potentiate platelet and endothelial activation and platelet thrombus formation ex vivo and in vivo. PMID- 27494774 TI - Cost-of-illness models for venous thromboembolism: One size does not fit all. PMID- 27494777 TI - Early remission status predicts long-term outcomes in patients with Crohn's disease treated with certolizumab pegol. AB - BACKGROUND: In Crohn's disease (CD), rapid response to anti-tumor necrosis factor therapy improves short- and medium-term outcomes, but the relationship between early remission (ER) and long-term remission is unclear. AIMS: This exploratory analysis of PRECiSE 3 (NCT00160524) assessed whether ER after initiation of certolizumab pegol predicted long-term remission. METHODS: Patients enrolled in PRECiSE 3 had completed PRECiSE 1 or 2, two randomized placebo-controlled studies for moderate to severe CD, and received open-label certolizumab pegol 400 mg every 4 weeks for a total treatment duration of <=7.5 years. Time to loss of remission between patients with and without ER (Harvey-Bradshaw Index <=4 at or before Week 6 of PRECiSE 1 or 2) was compared by log-rank test of Kaplan-Meier estimates. RESULTS: At baseline, patients with (n = 242) and without (n = 148) ER had mean (standard deviation [SD]) durations of CD of 6.8 (6.6) and 7.4 (7.8) years, mean (SD) CD Activity Index scores of 280.3 (53.4) and 311.1 (55.5), with 45.5% and 41.9% of patients having ileocolonic CD, and median C-reactive protein concentrations of 8.0 and 5.0 mg/L, respectively. Median certolizumab pegol plasma concentrations during the first 6 weeks of therapy were similar in both groups. Mean time to loss of remission was significantly longer in patients with versus without ER (2.77 vs. 1.14 years, p < 0.0001). CONCLUSIONS: In certolizumab pegol-treated patients with CD, ER appears to be an important predictor of long term clinical remission. Prospective trials are needed to determine whether ER improves other long-term outcomes. PMID- 27494776 TI - Down-regulation of miR-20a-5p triggers cell apoptosis to facilitate mycobacterial clearance through targeting JNK2 in human macrophages. AB - Induction of cell apoptosis is one of the major host defense mechanisms through which macrophages control Mycobacterium tuberculosis (Mtb) infection. However, the mechanisms underlying macrophage apoptosis triggered by Mtb infection are still largely unknown. In this study, a microarray profiling survey revealed 14 miRNAs were down-regulated in CD14+ monocytes from active pulmonary tuberculosis patients, and only the reduction of miR-20a-5p could be reversed after successful anti-tuberculosis treatment. Validation of miR-20a-5p expression was confirmed using real time qPCR. Moreover, miR-20a-5p expression also decreased in differentiated THP-1 macrophages after mycobacterial infection in vitro. Functional assays through forced or inhibited expression of miR-20a-5p in THP-1 macrophages demonstrated that miR-20a-5p functioned as a negative regulator of mycobacterial-triggered apoptosis. Importantly, inhibition of miR-20a-5p expression resulted in more efficient mycobacterial clearance from infected THP-1 macrophages while miR-20a-5p overexpression promoted mycobacterial survival. Mechanistically, miR-20a-5p was demonstrated to regulate Bim expression in a JNK2 dependent manner, unlike Bcl2, and luciferase assay showed JNK2 was a novel direct target of miR-20a-5p. Together, our findings indicate that downregulation of miR-20a-5p triggers macrophage apoptosis as a novel mechanism for host defense against mycobacterial infection. PMID- 27494775 TI - Therapeutic targets and new directions for antibodies developed for ovarian cancer. AB - Antibody therapeutics against different target antigens are widely used in the treatment of different malignancies including ovarian carcinomas, but this disease still requires more effective agents. Improved understanding of the biological features, signaling pathways, and immunological escape mechanisms involved in ovarian cancer has emerged in the past few years. These advances, including an appreciation of the cross-talk between cancer cells and the patient's immune system, have led to the identification of new targets. In turn, potential antibody treatments with various mechanisms of action, including immune activation or toxin-delivery, that are directed at these targets have been developed. Here, we identify established as well as novel targets for antibodies in ovarian cancer, and discuss how they may provide fresh opportunities to identify interventions with enhanced therapeutic potential. PMID- 27494778 TI - Surgical Treatment of Subretinal Fibrosis Caused Macular Detachment in Vogt Koyanagi-Harada Disease: A Pioneer Study. AB - PURPOSE: To describe surgical outcomes of macular detachment caused by subretinal fibrosis (SRF) in Vogt-Koyanagi-Harada disease (VKH). METHODS: Retrospective review of VKH patients who underwent SRF removal surgery. RESULTS: Seven eyes of six VKH patients with preoperative BCVA ranging from light perception to 20/250 were included. Six eyes underwent uncomplicated SRF removal with C3F8 or silicone oil (SO) tamponade and the following optional primary or subsequent procedures: intravitreal injection of triamcinolone acetonide, SO removal, lensectomy, or phacoemulsification with intraocular lens (IOL) implantation. All six eyes had attached macula and improved BCVA at the last visit (ranging from 20/2000 to 20/67) compared to baseline; the other eye, however, showed no light perception after surgery due to optic nerve injury. CONCLUSIONS: In VKH patients, macular detachment caused by SRF can be treated with surgery with generally favorable outcomes. Extreme caution should be taken to avoid optic nerve injury. PMID- 27494779 TI - Ligand-Controlled Stereodivergent, Enantioselective Conjugate Addition of 2 Oxazoline- and 2-Thiazoline-4-carboxylate to Nitroalkene Catalyzed by Chiral Copper Complexes. AB - The copper-catalyzed asymmetric conjugate addition of 2-oxazoline- and 2 thiazoline 4-carboxylate to a nitroalkene proceeded to give either the syn or anti adduct selectively in high enantiomeric excess when an appropriate chiral ligand was used. Subsequent reduction of the nitro group followed by hydrolysis of the oxazoline ring yielded an optically active gamma-lactam of protected alpha quaternary serine derivative. PMID- 27494781 TI - Nerve transfers for restoration of finger flexion in patients with tetraplegia. AB - OBJECTIVE The purpose of this paper was to report the authors' results with finger flexion restoration by nerve transfer in patients with tetraplegia. METHODS Surgery was performed for restoration of finger flexion in 17 upper limbs of 9 patients (8 male and 1 female) at a mean of 7.6 months (SD 4 months) after cervical spinal cord injury. The patients' mean age at the time of surgery was 28 years (SD 15 years). The motor level according to the ASIA (American Spinal Injury Association) classification was C-5 in 4 upper limbs, C-6 in 10, and C-7 in 3. In 3 upper limbs, the nerve to the brachialis was transferred to the anterior interosseous nerve (AIN), which was separated from the median nerve from the antecubital fossa to the midarm. In 5 upper limbs, the nerve to the brachialis was transferred to median nerve motor fascicles innervating finger flexion muscles in the midarm. In 4 upper limbs, the nerve to the brachioradialis was transferred to the AIN. In the remaining 5 upper limbs, the nerve to the extensor carpi radialis brevis (ECRB) was transferred to the AIN. Patients were followed for an average of 16 months (SD 6 months). At the final evaluation the range of finger flexion and strength were estimated by manual muscle testing according to the British Medical Research Council scale. RESULTS Restoration of finger flexion was observed in 4 of 8 upper limbs in which the nerve to the brachialis was used as a donor. The range of motion was incomplete in all 5 of these limbs, and the strength was M3 in 3 limbs and M4 in 1 limb. Proximal retrograde dissection of the AIN was associated with better outcomes than transfer of the nerve to the brachialis to median nerve motor fascicles in the arm. After the nerve to the brachioradialis was transferred to the AIN, incomplete finger flexion with M4 strength was restored in 1 limb; the remaining 3 limbs did not show any recovery. Full finger flexion with M4 strength was demonstrated in all 5 upper limbs in which the nerve to the ECRB was transferred to the AIN. No functional downgrading of elbow flexion or wrist extension strength was observed. CONCLUSIONS In patients with tetraplegia, finger flexion can be restored by nerve transfer. Nerve transfer using the nerve to the ECRB as the donor nerve produced better recovery of finger flexion in comparison with nerve transfer using the nerve to the brachialis or brachioradialis. PMID- 27494780 TI - Comparison of laboratory and field testing performance evaluations of siloxane polyurethane fouling-release marine coatings. AB - A series of eight novel siloxane-polyurethane fouling-release (FR) coatings were assessed for their FR performance in both the laboratory and in the field. Laboratory analysis included adhesion assessments of bacteria, microalgae, macroalgal spores, adult barnacles and pseudobarnacles using high-throughput screening techniques, while field evaluations were conducted in accordance with standardized testing methods at three different ocean testing sites over the course of six-months exposure. The data collected were subjected to statistical analysis in order to identify potential correlations. In general, there was good agreement between the laboratory screening assays and the field assessments, with both regimes clearly distinguishing the siloxane-polyurethane compositions comprising monofunctional poly(dimethyl siloxane) (PDMS) (m-PDMS) as possessing superior, broad-spectrum FR properties compared to those prepared with difunctional PDMS (d-PDMS). Of the seven laboratory screening techniques, the Cellulophaga lytica biofilm retraction and reattached barnacle (Amphibalanus amphitrite) adhesion assays were shown to be the most predictive of broad spectrum field performance. PMID- 27494782 TI - Magnetic resonance imaging-based measures predictive of short-term surgical outcome in patients with Chiari malformation Type I: a pilot study. AB - OBJECTIVE This study identifies quantitative imaging-based measures in patients with Chiari malformation Type I (CM-I) that are associated with positive outcomes after suboccipital decompression with duraplasty. METHODS Fifteen patients in whom CM-I was newly diagnosed underwent MRI preoperatively and 3 months postoperatively. More than 20 previously described morphological and physiological parameters were derived to assess quantitatively the impact of surgery. Postsurgical clinical outcomes were assessed in 2 ways, based on resolution of the patient's chief complaint and using a modified Chicago Chiari Outcome Scale (CCOS). Statistical analyses were performed to identify measures that were different between the unfavorable- and favorable-outcome cohorts. Multivariate analysis was used to identify the strongest predictors of outcome. RESULTS The strongest physiological parameter predictive of outcome was the preoperative maximal cord displacement in the upper cervical region during the cardiac cycle, which was significantly larger in the favorable-outcome subcohorts for both outcome types (p < 0.05). Several hydrodynamic measures revealed significantly larger preoperative-to-postoperative changes in the favorable outcome subcohort. Predictor sets for the chief-complaint classification included the cord displacement, percent venous drainage through the jugular veins, and normalized cerebral blood flow with 93.3% accuracy. Maximal cord displacement combined with intracranial volume change predicted outcome based on the modified CCOS classification with similar accuracy. CONCLUSIONS Tested physiological measures were stronger predictors of outcome than the morphological measures in patients with CM-I. Maximal cord displacement and intracranial volume change during the cardiac cycle together with a measure that reflects the cerebral venous drainage pathway emerged as likely predictors of decompression outcome in patients with CM-I. PMID- 27494783 TI - Conflicting calculations of pelvic incidence and pelvic tilt secondary to transitional lumbosacral anatomy (lumbarization of S-1): case report. AB - Advancements in the understanding of adult spinal deformity have led to a greater awareness of the role of the pelvis in maintaining sagittal balance and alignment. Pelvic incidence has emerged as a key radiographic measure and should closely match lumbar lordosis. As proper measurement of the pelvic incidence requires accurate identification of the S-1 endplate, lumbosacral transitional anatomy may lead to errors. The purpose of this study is to demonstrate how lumbosacral transitional anatomy may lead to errors in the measurement of pelvic parameters. The current case highlights one of the potential complications that can be avoided with awareness. The authors report the case of a 61-year-old man who had undergone prior lumbar surgeries and then presented with symptomatic lumbar stenosis and sagittal malalignment. Radiographs showed a lumbarized S-1. Prior numbering of the segments in previous surgical and radiology reports led to a pelvic incidence calculation of 61 degrees . Corrected numbering of the segments using the lumbarized S-1 endplate led to a pelvic incidence calculation of 48 degrees . Without recognition of the lumbosacral anatomy, overcorrection of the lumbar lordosis might have led to negative sagittal balance and the propensity to develop proximal junction failure. This case illustrates that improper identification of lumbosacral transitional anatomy may lead to errors that could affect clinical outcome. Awareness of this potential error may help improve patient outcomes. PMID- 27494784 TI - Contralateral psoas hematoma after minimally invasive, lateral retroperitoneal transpsoas lumbar interbody fusion: a multicenter review of 3950 lumbar levels. AB - OBJECTIVE Minimally invasive lateral lumbar interbody fusion (LLIF) via the retroperitoneal transpsoas approach is a technically demanding procedure with a multitude of potential complications. A relatively unknown complication is the contralateral psoas hematoma. The authors speculate that injury occurs from segmental vessel injury at the time of contralateral annulus release; however, this is not fully understood. In this multicenter retrospective review, the authors report the incidence of this contralateral complication and its neurological sequelae. METHODS This study was a retrospective chart review of all minimally invasive LLIF performed at participating institutions from 2008 to 2014. Exclusion criteria included an underlying diagnosis of trauma or neoplasia as well as lateral corpectomies or anterior column releases. Single-level, multilevel, and stand-alone constructs were included. All patients underwent preoperative MRI. Follow-up was at least 12 months. All complications and clinical outcomes were self-reported by each surgeon. RESULTS There were 3950 lumbar interbody cages placed via the retroperitoneal transpsoas approach, with 7 cases (0.18% incidence) of symptomatic contralateral psoas hematoma, 3 of which required reoperation for hematoma evacuation. Neurological outcome did not improve after reoperation. Reoperation occurred an average of 1 month after the initial operation due to a delay in diagnosis. In 1 case, segmental artery injury was confirmed at the time of surgery; in the others, segmental vessel injury was suspected, although it could not be confirmed. Neurological deficits persisted in 3 patients while the others remained neurologically intact. Two patients were receiving antiplatelet therapy prior to the procedure. CONCLUSIONS The contralateral psoas hematoma is a rare complication suspected to occur from segmental vessel injury during contralateral annulus release. Detailed review of preoperative imaging for aberrant vessel anatomy may prevent injury and subsequent neurological deficit. PMID- 27494785 TI - Factors associated with increased healthcare utilization among adults with asthma. AB - OBJECTIVE: To evaluate determinants of increased emergency room (ER) visit and hospitalization among adults with asthma, with emphasis on the role of psychological distress, self-efficacy, and obesity. METHODS: For analysis 2009, 2011/2012 California Health Interview Survey was used. Adults who reported lifetime asthma were selected. Association between ER and overnight hospital stay with population characteristics were conducted using chi-square analysis. Multivariable binary logistic regression models, taking into account control variables, were utilized to assess the relationship between ER visit or overnight hospital stay with that of psychological distress, self-efficacy, and obesity. RESULTS: Odds of ER visits were higher among those with mild-to-moderate psychological distress (adjusted odds ratio [aOR] = 1.94, 95% CI: 1.28, 2.94), and among those with serious psychological distress (aOR = 2.62, 95% CI: 1.65, 4.16). Mild-to-moderate distress was associated with two-fold increase in hospital overnight stay (aOR = 2.05, 95% CI: 1.29, 3.25). Adults with asthma who reported low self-efficacy had increased ER visits (aOR = 6.21, 95% CI: 3.63, 10.65) and hospitalization (aOR = 4.13, 95% CI: 2.63, 6.49). Finally, adults who had asthma and were obese had higher odds of ER visits (aOR = 1.60, 95% CI: 1.20, 2.13). CONCLUSIONS: Healthcare utilization is higher among asthma patients with psychological distress, low self-efficacy, and obesity. Interventions, such as incorporation of integrated care models, are critical to ensure early screening of mental health status among such patients. In addition, there is a need for patient education and improved weight management among adults with asthma. PMID- 27494786 TI - Investigating a persistent odor at an aircraft seat manufacturer. AB - An aircraft seat manufacturing company requested a NIOSH health hazard evaluation to help identify a strong odor that had persisted throughout the facility for over a year. Employees reported experiencing health effects thought to be related to the odor. We collected and analyzed area air samples for volatile organic compounds, endotoxin, bacterial and fungal metagenome, and metalworking fluid aerosol. Bulk metalworking fluid samples were analyzed for endotoxin, bacterial and fungal metagenome, and viable bacteria and fungus. We also evaluated the building ventilation systems and water diversion systems. Employees underwent confidential medical interviews about work practices, medical history, and health concerns. Based on our analyses, the odor was likely 2-methoxy-3,5 dimethylpyrazine. This pyrazine was found in air samples across the facility and originated from bacteria in the metalworking fluid. We did not identify bacteria known to produce the compound but bacteria from the same Proteobacteria order were found as well as bacteria from orders known to produce other pyrazines. Chemical and biological contaminants and odors could have contributed to health symptoms reported by employees, but it is likely that the symptoms were caused by several factors. We provided several recommendations to eliminate the odor including washing and disinfecting the metalworking machines and metalworking fluid recycling equipment, discarding all used metalworking fluid, instituting a metalworking fluid maintenance program at the site, and physically isolating the metalworking department from other departments. PMID- 27494787 TI - Effect of Chronic Medical Conditions in Veterans with Multiple Sclerosis on Long Term Disability. AB - BACKGROUND The goal of this observational study was to examine the effect of common chronic medical conditions (CMCs) on long-term disability (activity limitation) in veterans already diagnosed with multiple sclerosis (MS). MATERIAL AND METHODS We retrospectively reviewed the electronic charts of 124 veterans with MS who have been regularly followed in our MS clinic for 10 or more years. General linear model analysis examined whether MS-related severity as measured by the Expanded Disability Status Scale (EDSS) and the presence of CMCs affected long-term disability as measured by the total score on the Functional Independence Measure (TFIM). RESULTS Commonly encountered CMCs were increased BMI (61%), hyperlipidemia (78%), hypertension (65%), current smokers (47%), and arthritis/arthralgia (24%). Results suggest that the number of CMCs was not predictive of final TFIM scores; of the variables examined, only initial EDSS score was predictive of final TFIM scores. CONCLUSIONS The presence of CMCs did not affect the long-term disability in veterans diagnosed with MS, this was due mainly to CMCs being closely monitored and co-treated with other medical specialties. PMID- 27494788 TI - Research tasks as part of the general practice clerkship in undergraduate medical education - a pilot project on feasibility and acceptance. AB - OBJECTIVE: To assess the integration of a research task performed by students during their two-week clerkship in general practice. METHODS: Students were assigned to interview five patients with coronary heart disease using a standardised questionnaire focusing on potential interaction of medications with statins. Acceptance and feasibility was assessed by means of a questionnaire survey of teaching physicians (n = 20) and students (n = 20). RESULTS: According to most teaching physicians and students the recruitment of patients during the two-week clerkship was possible, and the practice work flow was not disturbed by the project. Both groups considered the research task on the documentation of potential drug interactions with statins as suitable. According to the teaching physicians the project had a learning effect for the students. In contrast, the students graded their learning effect less highly between 'satisfactory' and 'sufficient'. The overall assessment of the project by the students was on average 'satisfactory' and differed from the assessment by the teaching physicians ('good'). CONCLUSIONS: Adequate informing of students and participating physicians about the nature of the project and presenting preliminary results of the data in a plenary session at the end of the clerkship are essential for the acceptance of such projects. PMID- 27494789 TI - Ab initio molecular dynamics study of an aqueous NaCl solution under an electric field. AB - We report on an ab initio molecular dynamics study of an aqueous NaCl solution under the effect of static electric fields. We found that at low-to-moderate field intensity regimes chlorine ions have a greater mobility than sodium ions which, being a sort of "structure makers", are able to drag their own coordination shells. However, for field strengths exceeding 0.15 V A(-1) the mobility of sodium ions overcomes that of chlorine ions as both types of ions do actually escape from their respective hydration cages. The presence of charged particles lowers the water dissociation threshold (i.e., the minimum field strength which induces a transfer of protons) from 0.35 V A(-1) to 0.25 V A(-1); moreover, a protonic current was also recorded at the estimated dissociation threshold of the solution. The behaviour of the current-voltage diagram of the protonic response to the external electric field is Ohmic as in pure water, with a resulting protonic conductivity of about 2.5 S cm(-1). This value is approximately one third of that estimated in pure water (7.8 S cm(-1)), which shows that the partial breaking of hydrogen bonds induced by the solvated ions hinders the migration of protonic defects. Finally, the conductivity of Na(+) and Cl(-) ions (0.2 S cm(-1)) is in fair agreement with the available experimental data for a solution molarity of 1.7 M. PMID- 27494790 TI - Acceptability of GM foods among Pakistani consumers. AB - In Pakistan majority of the consumers do not have information about genetically modified (GM) foods. In developing countries particularly in Pakistan few studies have focused on consumers' acceptability about GM foods. Using comprehensive primary dataset collected from 320 consumers in 2013 from Pakistan, this study analyzes the determinants of consumers' acceptability of GM foods. The data was analyzed by employing the bivariate probit model and censored least absolute deviation (CLAD) models. The empirical results indicated that urban consumers are more aware of GM foods compared to rural consumers. The acceptance of GM foods was more among females' consumers as compared to male consumers. In addition, the older consumers were more willing to accept GM food compared to young consumers. The acceptability of GM foods was also higher among wealthier households. Low price is the key factor leading to the acceptability of GM foods. The acceptability of the GM foods also reduces the risks among Pakistani consumers. PMID- 27494791 TI - Centennial Celebration: Endocrine Reviews Past Highlights for January and May. PMID- 27494794 TI - Solid-Phase Synthesis of Cyclic Depsipeptides Containing a Tyrosine Phenyl Ester Bond. AB - The first solid-phase strategy for the synthesis of cyclic depsipeptides containing a phenyl ester linkage in their structure is described. The key steps of the synthesis were the formation of the phenyl ester bond and the on-resin head-to-side-chain cyclization. The amino acid configuration significantly influenced the formation and the stability of the cyclic depsipeptides. The presence of a l-Tyr(1) and a d-Tyr(7) led to the most stable sequences. PMID- 27494796 TI - Nanoscale Strategies for Light Harvesting. AB - Recent advances and the current status of challenging light-harvesting nanomaterials, such as semiconducting quantum dots (QDs), metal nanoparticles, semiconductor-metal heterostructures, pi-conjugated semiconductor nanoparticles, organic-inorganic heterostructures, and porphyrin-based nanostructures, have been highlighted in this review. The significance of size-, shape-, and composition dependent exciton decay dynamics and photoinduced energy transfer of QDs is addressed. A fundamental knowledge of these photophysical processes is crucial for the development of efficient light-harvesting systems, like photocatalytic and photovoltaic ones. Again, we have pointed out the impact of the metal nanoparticle-based surface energy transfer process for developing light harvesting systems. On the other hand, metal-semiconductor hybrid nanostructures are found to be very promising for photonic applications due to their exciton plasmon interactions. Potential light-harvesting systems based on dye-doped pi conjugated semiconductor polymer nanoparticles and self-assembled structures of pi-conjugated polymer are highlighted. We also discuss the significance of porphyrin-based nanostructures for potential light-harvesting systems. Finally, the future perspective of this research field is given. PMID- 27494797 TI - Use of panel testing for detection of antinuclear antibody in a resource-limited setting: an appraisal. AB - OBJECTIVES: Despite an increase in the incidence of systemic connective tissue diseases (CTD), panel testing for detection of antinuclear antibodies (ANA) is not a routine practice in many health centers of the Indian subcontinent. Consequently, the data on its significance is scanty. METHODS: To evaluate utility of panel testing, line immunoassay (LIA) and indirect immunofluorescence antinuclear antibody test (IIF-ANA) were performed in 321 cases of CTD. RESULTS: Out of 321 serum samples screened by the above tests, 227 were positive and 18 were negative by both LIA and IIF-ANA. Additional 11/321 (3.4%) cases were picked up by LIA. SSA was most common specificity in these cases followed by SSA/SSB, SSB, Ro-52, Jo-1, dsDNA and nRNP/Sm. CONCLUSION: Use of LIA along with IF-ANA and ELISA improves sensitivity of CTD screening. PMID- 27494795 TI - Preparation and quantification of the total phenolic products in Citrus fruit using solid-phase extraction coupled with high-performance liquid chromatography with diode array and UV detection. AB - Citrus fruit is an important health-promoting food that is rich in dietary phenolic metabolites. Traditional Chinese medicines, such as Zhishi and Zhiqiao, come from young and immature fruits of Citrus cultivars. The preparation of diversified bioactive phenolic products and establishment of the corresponding quality control methodology are challenging and necessary. In the current study, four types of solid-phase extraction sorbents for the enrichment and clean-up of the phenolic matrix were evaluated. A solid-phase extraction column coated with Strata-X was finally used in the procedure. Twenty phenolic compounds were selected to evaluate the extraction performances of the sorbents using high performance liquid chromatography analysis. Under the optimized conditions, good linearities were obtained with R2 more than 0.9996 for all analytes with LODs of 0.04-1.012 MUg/g. Intra- and interday relative standard deviation values were less than 3%, and the recovery was equal to or higher than 90.02%. Compared to non-solid-phase extraction process, the content of total phenolic products was elevated 35.55-68.48% with solid-phase extraction. Finally, the developed and validated method was successfully applied to the discrimination of Zhishi samples from different species as well as Zhishi and Zhiqiao samples in different development stages. PMID- 27494798 TI - Influenza epidemiology, vaccine coverage and vaccine effectiveness in children admitted to sentinel Australian hospitals in 2014: the Influenza Complications Alert Network (FluCAN). AB - The Influenza Complications Alert Network (FluCAN) is a sentinel hospital-based surveillance programme operating in all states and territories in Australia. We summarise the epidemiology of children hospitalised with laboratory-confirmed influenza in 2014 and reports on the effectiveness of inactivated trivalent inactivated vaccine (TIV) in children. In this observational study, cases were defined as children admitted with acute respiratory illness (ARI) with influenza confirmed by PCR. Controls were hospitalised children with ARI testing negative for influenza. Vaccine effectiveness (VE) was estimated as 1 minus the odds ratio of vaccination in influenza positive cases compared with test-negative controls using conditional logistic regression models. From April until October 2014, 402 children were admitted with PCR-confirmed influenza. Of these, 28% were aged < 1 year, 16% were Indigenous, and 39% had underlying conditions predisposing to severe influenza. Influenza A was detected in 90% of cases of influenza; influenza A(H1N1)pdm09 was the most frequent subtype (109/141 of subtyped cases) followed by A(H3N2) (32/141). Only 15% of children with influenza received antiviral therapy. The adjusted VE of one or more doses of TIV for preventing hospitalised influenza was estimated at 55.5% (95% confidence intervals (CI): 11.6-77.6%). Effectiveness against influenza A(H1N1)pdm09 was high (91.6% , 95% CI: 36.0-98.9%) yet appeared poor against H3N2. In summary, the 2014 southern hemisphere TIV was moderately effective against severe influenza in children. Significant VE was observed against influenza A(H1N1)pdm09. PMID- 27494800 TI - The Kondo temperature of a two-dimensional electron gas with Rashba spin-orbit coupling. AB - We use the Hirsch-Fye quantum Monte Carlo method to study the single magnetic impurity problem in a two-dimensional electron gas with Rashba spin-orbit coupling. We calculate the spin susceptibility for various values of spin-orbit coupling, Hubbard interaction, and chemical potential. The Kondo temperatures for different parameters are estimated by fitting the universal curves of spin susceptibility. We find that the Kondo temperature is almost a linear function of Rashba spin-orbit energy when the chemical potential is close to the edge of the conduction band. When the chemical potential is far away from the band edge, the Kondo temperature is independent of the spin-orbit coupling. These results demonstrate that, for single impurity problems in this system, the most important reason to change the Kondo temperature is the divergence of density of states near the band edge, and the divergence is induced by the Rashba spin-orbit coupling. PMID- 27494799 TI - Effectiveness of repetitive trancranial or peripheral magnetic stimulation in neuropathic pain. AB - PURPOSE: Maladaptive plasticity in the sensorimotor system, following neurological lesions or diseases, plays a central role in the generation and maintenance of neuropathic pain. Repetitive magnetic stimulation of the central and peripheral nervous system has gained relevance as noninvasive approach for neuromodulation and pain relief. Systematic reviews that evaluate the effectiveness and specificity of different protocols of repetitive magnetic stimulation to control neuropathic pain in clinical populations have the potential to improve the therapeutic applicability of this technique. METHODS: Studies whose primary goal was to evaluate the effectiveness of repetitive magnetic stimulation for the treatment of various types of neuropathic pain published in PubMed until August 2015 have been included in this systematic review. RESULTS: A total of 39 articles fulfilling the inclusion criteria were analyzed of which 37 studies investigated pain modulation using repetitive magnetic stimulation over the motor or non-motor cortices and two studies evaluated pain modulation using repetitive peripheral magnetic stimulation protocols. CONCLUSIONS: Repetitive transcranial magnetic stimulation of the primary motor cortex using high frequency stimulation protocols can effectively reduce neuropathic pain, particularly in individuals with pain related to non cerebral lesions. The application of multiple sessions can lead to long-lasting pain modulation and cumulative effects. Implications for Rehabilitation Maladaptive plasticity plays a central role in sensitization of nociceptive pathways, generation and maintainance of neuropathic pain; Most neuropathic pain conditions are refractory to pharmacological therapies; Repetitive magnetic stimulation of the central and peripheral nervous system has gained relevance as noninvasive approach for neuromodulation and pain relief. PMID- 27494801 TI - Substrate Engineering Enabling Fluorescence Droplet Entrapment for IVC-FACS-Based Ultrahigh-Throughput Screening. AB - In vitro compartmentalization-based fluorescence-activated cell sorting (IVC FACS) is a powerful screening tool for directed evolution of enzymes. However, the efficiency of IVC-FACS is limited by the tendency of the fluorescent reporter to diffuse out of the droplets, which decouples the genotype and phenotype of the target gene. Herein we present a new strategy called fluorescence droplet entrapment (FDE) to solve this problem. The substrate is designed with a polarity that enables it to pass through the oil phase, react with the enzyme and generate an oil-impermeable and fluorescent product that remains entrapped inside the droplet. Several FDE substrates were designed, using two distinct substrate engineering strategies, for the detection of phosphotriesterases, carboxylesterases, and glycosidases activities. Model screening assays in which rare phosphotriesterase-active cells were enriched from large excesses of inactive cells showed that the enrichment efficiency achievable using an FDE substrate was as high as 900-fold: the highest yet reported in such an IVC-FACS system. Thus, FDE provides a means to tightly control the onset of the enzymatic reaction, minimize droplet cross-talk, and lower the background fluorescence. It therefore may serve as a useful strategy for the IVC-FACS screening of enzymes, antibodies, and other proteins. PMID- 27494803 TI - The synthesis of a pyridine-N-oxide isophthalamide rotaxane utilizing supplementary amide hydrogen bond interactions. AB - The synthesis of a pyridine-N-oxide containing rotaxane, not requiring an additional ionic template, has been achieved in 32% yield. Successful rotaxane formation is dependent upon the structure of the isophthalamide macrocycle used, an observation which has been rationalised by a combination of NMR spectroscopy, X-ray crystallography and computational modelling. PMID- 27494802 TI - Molecular docking and dynamics simulation study of flavonoids as BET bromodomain inhibitors. AB - Bromodomains (BRDs) are the epigenetic proteins responsible for transcriptional regulation through its interaction with methylated or acetylated histone residues. The lysine residues of Bromodomain-1 (BD1) of Brd4 undergo epsilon-N Acetylation posttranslational modifications to control transcription of genes. Due to its role in diverse cellular functions, Brd4 of bromodomain family, was considered as a prominent target for many diseases such as cancer, obesity, kidney disease, lung fibrosis, inflammatory diseases, etc. In this study, an attempt has been made to screen compounds from flavonoids and extended flavonoids libraries targeting acetylated lysine (KAc) binding site of BD1 of Brd4 using docking and molecular dynamics simulations. Two different docking programs AutoDock and Glide were used to compare their suitability for the receptor. Interestingly, in both the docking programs, the screened flavonoids have occupied the same binding pocket confirming the selection of active site. Further the MMGBSA binding free energy calculations and ADME analysis were carried out on screened compounds to establish their anti-cancerous properties. We have identified a flavonoid which shows docking and Glide e-model score comparatively much higher than those of already reported known inhibitors against Brd4. The protein-ligand complex with top-ranked flavonoid was used for dynamics simulation study for 50 ns in order to validate its stability inside the active site of Brd4 receptor. The results provide valuable information for structure-based drug design of Brd4 inhibitors. PMID- 27494804 TI - Trait Variance and Response Style Variance in the Scales of the Personality Inventory for DSM-5 (PID-5). AB - Using self- and observer reports on the Personality Inventory for DSM-5 (PID-5) and the HEXACO Personality Inventory-Revised (HEXACO-PI-R), we identified for each inventory several trait dimensions (each defined by both self- and observer reports on the facet-level scales belonging to the same domain) and 2 source dimensions (each defined by self-reports or by observer reports, respectively, on all facet-level scales). Results (N = 217) showed that the source dimensions of the PID-5 were very large (much larger than those of the HEXACO-PI-R), and suggest that self-report (or observer report) response styles substantially inflate the intercorrelations and the alpha reliabilities of the PID-5 scales. We discuss the meaning and the implications of the large PID-5 source components, and we suggest some methods of controlling their influence. PMID- 27494805 TI - Feature-based multi-resolution registration of immunostained serial sections. AB - The form and exact function of the blood vessel network in some human organs, like spleen and bone marrow, are still open research questions in medicine. In this paper, we propose a method to register the immunohistological stainings of serial sections of spleen and bone marrow specimens to enable the visualization and visual inspection of blood vessels. As these vary much in caliber, from mesoscopic (millimeter-range) to microscopic (few micrometers, comparable to a single erythrocyte), we need to utilize a multi-resolution approach. Our method is fully automatic; it is based on feature detection and sparse matching. We utilize a rigid alignment and then a non-rigid deformation, iteratively dealing with increasingly smaller features. Our tool pipeline can already deal with series of complete scans at extremely high resolution, up to 620 megapixels. The improvement presented increases the range of represented details up to smallest capillaries. This paper provides details on the multi-resolution non-rigid registration approach we use. Our application is novel in the way the alignment and subsequent deformations are computed (using features, i.e. "sparse"). The deformations are based on all images in the stack ("global"). We also present volume renderings and a 3D reconstruction of the vascular network in human spleen and bone marrow on a level not possible before. Our registration makes easy tracking of even smallest blood vessels possible, thus granting experts a better comprehension. A quantitative evaluation of our method and related state of the art approaches with seven different quality measures shows the efficiency of our method. We also provide z-profiles and enlarged volume renderings from three different registrations for visual inspection. PMID- 27494806 TI - A split recognition mode combined with cascade signal amplification strategy for highly specific, sensitive detection of microRNA. AB - MicroRNAs (miRNAs) are vital for many biological processes and have been regarded as cancer biomarkers. Specific and sensitive detection of miRNAs is essential for cancer diagnosis and therapy. Herein, a split recognition mode combined with cascade signal amplification strategy is developed for highly specific and sensitive detection of miRNA. The split recognition mode possesses two specific recognition processes, which are based on toehold-mediated strand displacement reaction (TSDR) and direct hybridization reaction. Two recognition probes, hairpin probe (HP) with overhanging toehold domain and assistant probe (AP), are specially designed. Firstly, the toehold domain of HP and AP recognize part of miRNA simultaneously, accompanied with TSDR to unfold the HP and form the stable DNA Y-shaped junction structure (YJS). Then, the AP in YJS can further act as primer to initiate strand displacement amplification, releasing numerous trigger sequences. Finally, the trigger sequences hybridize with padlock DNA to initiate circular rolling circle amplification and generate enhanced fluorescence responses. In this strategy, the dual recognition effect of split recognition mode guarantees the excellent selectivity to discriminate let-7b from high homology sequences. Furthermore, the high amplification efficiency of cascade signal amplification guarantees a high sensitivity with the detection limit of 3.2 pM and the concentration of let-7b in total RNA sample extracted from Hela cells is determined. These results indicate our strategy will be a promising miRNA detection strategy in clinical diagnosis and disease treatment. PMID- 27494807 TI - Induced nanoparticle aggregation for short nucleic acid quantification by depletion isotachophoresis. AB - A rapid (<20min) gel-membrane biochip platform for the detection and quantification of short nucleic acids is presented based on a sandwich assay with probe-functionalized gold nanoparticles and their separation into concentrated bands by depletion-generated gel isotachophoresis. The platform sequentially exploits the enrichment and depletion phenomena of an ion-selective cation exchange membrane created under an applied electric field. Enrichment is used to concentrate the nanoparticles and targets at a localized position at the gel membrane interface for rapid hybridization. The depletion generates an isotachophoretic zone without the need for different conductivity buffers, and is used to separate linked nanoparticles from isolated ones in the gel medium and then by field-enhanced aggregation of only the linked particles at the depletion front. The selective field-induced aggregation of the linked nanoparticles during the subsequent depletion step produces two lateral-flow like bands within 1cm for easy visualization and quantification as the aggregates have negligible electrophoretic mobility in the gel and the isolated nanoparticles are isotachophoretically packed against the migrating depletion front. The detection limit for 69-base single-stranded DNA targets is 10 pM (about 10 million copies for our sample volume) with high selectivity against nontargets and a three decade linear range for quantification. The selectivity and signal intensity are maintained in heterogeneous mixtures where the nontargets outnumber the targets 10,000 to 1. The selective field-induced aggregation of DNA-linked nanoparticles at the ion depletion front is attributed to their trailing position at the isotachophoretic front with a large field gradient. PMID- 27494808 TI - A G-quadruplex-selective luminescent probe with an anchor tail for the switch-on detection of thymine DNA glycosylase activity. AB - Thymine DNA glycosylase (TDG) performs essential functions in maintaining genetic integrity and epigenetic regulation, which also plays an essential role in DNA demethylation. In this work, the novel iridium(III) complex 1 with an anchor tail was synthesized and employed to construct a G-quadruplex-based assay for detecting TDG activity in aqueous solution by using the mismatched base excising property of TDG with T4 DNA ligase and phi29 DNA polymerase, in concert with the rolling circle amplification (RCA) strategy. The assay achieved a detection limit of 0.048UmL(-)(1) (0.012ngmL(-1)), and showed high selectivity towards TDG even in the presence of other proteins and enzymes. Additionally, the assay could function in diluted cellular debris. PMID- 27494809 TI - Modulating luminescence of Tb(3+) with biomolecules for sensing heparin and its contaminant OSCS. AB - The detection of heparin (Hep) and its contaminant oversulfated chondroitin sulfate (OSCS) is of great importance in clinics but remains challenging. Here, we report a sensitive and selective time-resolved luminescence (TRL) biosensing system for Hep by modulating the photoluminescence of Tb(3+) with guanine-rich ssDNA and Hep-specific AG73 peptide (RKRLQVQLSIRT). With the developed system, Hep including both unfractionated Hep (UFH) and the low molecular weight Hep (LMWH) has been successfully detected with a satisfactory detection limit. Owing to the highly specific interaction between Hep and AG73 peptide, major interfering substances in Hep detection, such as Hep analogs of chondrotin sulfate (Chs) and hyaluronic acid (HA), did not interfere with Hep detection. The established TRL sensing system was then successfully used for monitoring Hep metabolism in living rats by microdialysis. Moreover, the proposed TRL sensing system was further applied to analyze OSCS contaminant in Hep with heparinases treatment by exploring the inhibition effects of OSCS on the activity of heparinases. As low as 0.002% of OSCS in Hep was identified. PMID- 27494810 TI - Magnetic nanowires for rapid and ultrasensitive isolation of DNA from cervical specimens for the detection of multiple human papillomaviruses genotypes. AB - Detecting human papillomavirus (HPV) is central in diagnosing and monitoring HPV related disease. However, limited sensitivity and the wide variability of the HPV genome pose challenges in the identification of HPV genes, particularly high-risk types. This study reports the development of polyethyleneimine-conjugated magnetic nanowires (PEI-MNWs) and their use in the isolation, identification, and analysis of multiple genotypes of HPV DNA from cervical cancer specimens. The nanowires are electrochemically doped with a high density of magnetic nanoparticles and biotin moieties during potentiostatic deposition, thereby allowing conjugating cationic branched polymers to direct the attachment of negatively charged DNA molecules with strong magnetic response. For proof of concept, the rapid and ultrasensitive isolation of HPV DNA is performed at concentrations as low as 10pg/mL with an efficiency of >95%. For clinical optimization, the analytical and clinical sensitivity of PEI-MNWs is compared with that of the Roche Cobas 4800 HPV Test and demonstrates excellent correlation for multiple HPV DNA genotypes with superior threshold cycle values. The high sensitivity, specificity, and good reproducibility of PEI-MNWs are particularly well suited for the recovery of DNA and provide significant and clinically meaningful evidence for the early detection and treatment of HPV-associated cancers. PMID- 27494811 TI - Low potential detection of indole-3-acetic acid based on the peroxidase-like activity of hemin/reduced graphene oxide nanocomposite. AB - An amperometric sensor was firstly established for the detection of indole-3 acetic acid (IAA) at low potential based on the hemin/reduced graphene oxide (hemin/rGO) composite. The hemin/rGO nanocomposite was prepared by a simple and facile hydrothermal method without using any reducing agent. It exhibited peroxidase-like activity for the catalytic oxidation of IAA in the presence of oxygen. The consumption of oxygen has a linear relationship with the concentration of IAA in the range from 0.1 to 43MUM and from 43 to 183MUM. The detection limit was down to 0.074MUM. This sensor was unaffected by many interfering substances and stable over time. Such work broadened the application of hemin/rGO and provided a new method for IAA detection. PMID- 27494812 TI - Simultaneous determination of 6-mercaptopruine, 6-thioguanine and dasatinib as three important anticancer drugs using nanostructure voltammetric sensor employing Pt/MWCNTs and 1-butyl-3-methylimidazolium hexafluoro phosphate. AB - 6-Mercaptopurine, 6-thioguanine and dasatinib are three important anticancer drugs with high adverse effects in human body. In this study, a Pt/MWCNTs-1-butyl 3-methylimidazolium hexafluoro phosphate-modified carbon paste electrode was developed for the simultaneously determination of 6-mercaptopurine, 6-thioguanine and dasatinib for the first time. The Pt/MWCNTs synthesized by polyol method and have been characterized by transmission electron microscopy and X-ray diffraction methods. The obtained data revealed that the electro-oxidation of 6 mercaptopurine, 6-thioguanine and dasatinib is facilitated as a novel voltammetric sensor. After optimization of electrochemical parameters employing this sensor at pH 8.0, the oxidation peak currents for 6-mercaptopurine, 6 thioguanine and dasatinib were found to vary linearly with their concentrations in the range of 0.05-550MUM; 0.1-500MUM and 5.0-500MUM with detection limits of 0.009MUM, 0.05MUM and 1.0MUM respectively using square wave voltammetric method. The modified electrode has been applied for the selective and precise analysis of 6-mercaptopurine, 6-thioguanine and dasatinib in pharmaceutical formulations and urine samples. PMID- 27494814 TI - A novel miniature robotic device for frameless implantation of depth electrodes in refractory epilepsy. AB - OBJECTIVE The authors' group recently published a novel technique for a navigation-guided frameless stereotactic approach for the placement of depth electrodes in epilepsy patients. To improve the accuracy of the trajectory and enhance the procedural workflow, the authors implemented the iSys1 miniature robotic device in the present study into this routine. METHODS As a first step, a preclinical phantom study was performed using a human skull model, and the accuracy and timing between 5 electrodes implanted with the manual technique and 5 with the aid of the robot were compared. After this phantom study showed an increased accuracy with robot-assisted electrode placement and confirmed the robot's ability to maintain stability despite the rotational forces and the leverage effect from drilling and screwing, patients were enrolled and analyzed for robot-assisted depth electrode placement at the authors' institution from January 2014 to December 2015. All procedures were performed with the S7 Surgical Navigation System with Synergy Cranial software and the iSys1 miniature robotic device. RESULTS Ninety-three electrodes were implanted in 16 patients (median age 33 years, range 3-55 years; 9 females, 7 males). The authors saw a significant increase in accuracy compared with their manual technique, with a median deviation from the planned entry and target points of 1.3 mm (range 0.1-3.4 mm) and 1.5 mm (range 0.3-6.7 mm), respectively. For the last 5 patients (31 electrodes) of this series the authors modified their technique in placing a guide for implantation of depth electrodes (GIDE) on the bone and saw a significant further increase in the accuracy at the entry point to 1.18 +/- 0.5 mm (mean +/- SD) compared with 1.54 +/- 0.8 mm for the first 11 patients (p = 0.021). The median length of the trajectories was 45.4 mm (range 19-102.6 mm). The mean duration of depth electrode placement from the start of trajectory alignment to fixation of the electrode was 15.7 minutes (range 8.5-26.6 minutes), which was significantly faster than with the manual technique. In 12 patients, depth electrode placement was combined with subdural electrode placement. The procedure was well tolerated in all patients. The authors did not encounter any case of hemorrhage or neurological deficit related to the electrode placement. In 1 patient with a psoriasis vulgaris, a superficial wound infection was encountered. Adequate physiological recordings were obtained from all electrodes. No additional electrodes had to be implanted because of misplacement. CONCLUSIONS The iSys1 robotic device is a versatile and easy to use tool for frameless implantation of depth electrodes for the treatment of epilepsy. It increased the accuracy of the authors' manual technique by 60% at the entry point and over 30% at the target. It further enhanced and expedited the authors' procedural workflow. PMID- 27494813 TI - A viscosity sensitive fluorescent dye for real-time monitoring of mitochondria transport in neurons. AB - We present here a viscosity sensitive fluorescent dye, namely thiophene dihemicyanine (TDHC), that enables the specific staining of mitochondria. In comparison to the common mitochondria tracker (Mitotracker Deep Red, MTDR), this dye demonstrated its unique ability for robust staining of mitochondria with high photostability and ultrahigh signal-to-noise ratio (SNR). Moreover, TDHC also showed high sensitivity towards mitochondria membrane potential (DeltaPsim) and intramitochondria viscosity change. Consequently, this dye was utilized in real time monitoring of mitochondria transport in primary cortical neurons. Finally, the Two-Photon Microscopy (TPM) imaging ability of TDHC was also demonstrated. PMID- 27494815 TI - Repeat stereotactic radiosurgery as salvage therapy for locally recurrent brain metastases previously treated with radiosurgery. AB - OBJECTIVE There are a variety of salvage options available for patients with brain metastases who experience local failure after stereotactic radiosurgery (SRS). These options include resection, whole-brain radiation therapy, laser thermoablation, and repeat SRS. There is little data on the safety and efficacy of repeat SRS following local failure of a prior radiosurgical procedure. This study evaluates the clinical outcomes and dosimetric characteristics of patients who experienced tumor recurrence and were subsequently treated with repeat SRS. METHODS Between 2002 and 2015, 32 patients were treated with repeat SRS for local recurrence of >= 1 brain metastasis following initial SRS treatment. The Kaplan Meier method was used to estimate time-to-event outcomes including overall survival (OS), local failure, and radiation necrosis. Cox proportional hazards analysis was performed for predictor variables of interest for each outcome. Composite dose-volume histograms were constructed for each reirradiated lesion, and these were then used to develop a predictive dosimetric model for radiation necrosis. RESULTS Forty-six lesions in 32 patients were re-treated with a second course of SRS after local failure. A median dose of 20 Gy (range 14-22 Gy) was delivered to the tumor margin at the time of repeat SRS. Local control at 1 year was 79% (95% CI 67%-94%). Estimated 1-year OS was 70% (95% CI 55%-88%). Twelve patients had died at the most recent follow-up, with 8/12 patients experiencing neurological death (as described in Patchell et al.). Eleven of 46 (24%) lesions in 11 separate patients treated with repeat SRS were associated with symptomatic radiation necrosis. Freedom from radiation necrosis at 1 year was 71% (95% CI 57% 88%). Analysis of dosimetric data revealed that the volume of a lesion receiving 40 Gy (V40Gy) was the most predictive factor for the development of radiation necrosis (p = 0.003). The following V40Gy thresholds were associated with 10%, 20%, and 50% probabilities of radiation necrosis, respectively: 0.28 cm3 (95% CI 3%-28%), 0.76 cm3 (95% CI 9%-39%), 1.60 cm3 (95% CI 26%-74%). CONCLUSIONS Repeat SRS appears to be an effective salvage option for patients with brain metastases experiencing local failure following initial SRS treatment. This series demonstrates durable local control and, although rates of radiation necrosis are significant, repeat SRS may be indicated for select cases of local disease recurrence. Because the V40Gy is predictive of radiation necrosis, limiting this value during treatment planning may allow for a reduction in radiation necrosis rates. PMID- 27494816 TI - Craniopharyngioma recurrence: the impact of tumor topography. PMID- 27494817 TI - Vascular permeability and iron deposition biomarkers in longitudinal follow-up of cerebral cavernous malformations. AB - OBJECTIVE Vascular permeability and iron leakage are central features of cerebral cavernous malformation (CCM) pathogenesis. The authors aimed to correlate prospective clinical behavior of CCM lesions with longitudinal changes in biomarkers of dynamic contrast-enhanced quantitative permeability (DCEQP) and quantitative susceptibility mapping (QSM) assessed by MRI. METHODS Forty-six patients with CCMs underwent 2 or more permeability and/or susceptibility studies in conjunction with baseline and follow-up imaging and clinical surveillance during a mean 12.05 months of follow-up (range 2.4-31.27 months). Based on clinical and imaging features, cases/lesions were classified as stable, unstable, or recovering. Associated and predictive changes in quantitative permeability and susceptibility were investigated. RESULTS Lesional mean permeability and QSM values were not significantly different in stable versus unstable lesions at baseline. Mean lesional permeability in unstable CCMs with lesional bleeding or growth increased significantly (+85.9% change; p = 0.005), while mean permeability in stable and recovering lesions did not significantly change. Mean lesional QSM values significantly increased in unstable lesions (+44.1% change; p = 0.01), decreased slightly with statistical significance in stable lesions ( 3.2% change; p = 0.003), and did not significantly change in recovering lesions. Familial cases developing new lesions during the follow-up period showed a higher background brain permeability at baseline (p = 0.001), as well as higher regional permeability (p = 0.003) in the area that would later develop a new lesion as compared with the homologous contralateral brain region. CONCLUSIONS In vivo assessment of vascular permeability and iron deposition on MRI can serve as objective and quantifiable biomarkers of disease activity in CCMs. This may be applied in natural history studies and may help calibrate clinical trials. The 2 techniques are likely applicable in other disorders of vascular integrity and iron leakage such as aging, hemorrhagic microangiopathy, and traumatic brain injury. PMID- 27494818 TI - Effectiveness of minocycline in acute white matter injury after intracerebral hemorrhage. AB - OBJECTIVE Intracerebral hemorrhage (ICH) is a fatal disease with high morbidity and mortality, which may be followed by white matter injury (WMI) due to the local oxidizing reaction induced by iron (Fe). In this study, the authors examined the effect of the tetracycline antibiotic minocycline on Fe-induced WMI and c-Jun N-terminal kinase (JNK) activation in rats. METHODS Thirty-six male Sprague-Dawley rats underwent an intracaudate injection of saline, Fe, or Fe + minocycline. Another 36 rats had an intracaudate injection of autologous blood and were treated with minocycline or vehicle (saline). Biomarkers of both WMI and JNK activation were examined. RESULTS In the Fe-injection group, minocycline suppressed WMI labeled by beta-amyloid precursor protein (beta-APP) and degraded myelin basic protein (dMBP)/MBP ratio. Protein levels of phosphorylated-JNK were increased after Fe injection, and could be suppressed by minocycline treatment. In the autologous blood-injection group, beta-APP and dMBP/MBP levels increased in the ipsilateral site compared with the contralateral site, which could be suppressed by 7 days of minocycline intervention. CONCLUSIONS Iron plays a critical role in WMI after ICH, which can be suppressed by minocycline through reducing the damage induced by Fe. PMID- 27494819 TI - Preventive effects of cilostazol against the development of shunt-dependent hydrocephalus after subarachnoid hemorrhage. AB - OBJECTIVE Chronic hydrocephalus develops in association with the induction of tenascin-C (TNC), a matricellular protein, after aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to examine if cilostazol, a selective inhibitor of phosphodiesterase Type III, suppresses the development of chronic hydrocephalus by inhibiting TNC induction in aneurysmal SAH patients. METHODS The authors retrospectively reviewed the factors influencing the development of chronic shunt-dependent hydrocephalus in 87 patients with Fisher Grade 3 SAH using multivariate logistic regression analyses. Cilostazol (50 or 100 mg administered 2 or 3 times per day) was administered from the day following aneurysmal obliteration according to the preference of the attending neurosurgeon. As a separate study, the effects of different dosages of cilostazol on the serum TNC levels were chronologically examined from Days 1 to 12 in 38 SAH patients with Fisher Grade 3 SAH. RESULTS Chronic hydrocephalus occurred in 12 of 36 (33.3%), 5 of 39 (12.8%), and 1 of 12 (8.3%) patients in the 0 mg/day, 100 to 200 mg/day, and 300 mg/day cilostazol groups, respectively. The multivariate analyses showed that older age (OR 1.10, 95% CI 1.13-1.24; p = 0.012), acute hydrocephalus (OR 23.28, 95% CI 1.75-729.83; p = 0.016), and cilostazol (OR 0.23, 95% CI 0.05-0.93; p = 0.038) independently affected the development of chronic hydrocephalus. Higher dosages of cilostazol more effectively suppressed the serum TNC levels through Days 1 to 12 post-SAH. CONCLUSIONS Cilostazol may prevent the development of chronic hydrocephalus and reduce shunt surgery, possibly by the inhibition of TNC induction after SAH. PMID- 27494820 TI - Predictors of 30-day readmission after aneurysmal subarachnoid hemorrhage: a case control study. AB - OBJECTIVE Despite persisting questions regarding its appropriateness, 30-day readmission is an increasingly common quality metric used to influence hospital compensation in the United States. However, there is currently insufficient evidence to identify which patients are at highest risk for readmission after aneurysmal subarachnoid hemorrhage (SAH). The objective of this study was to identify predictors of 30-day readmission after SAH, to focus preventative efforts, and to provide guidance to funding agencies seeking to risk-adjust comparisons among hospitals. METHODS The authors performed a case-control study of 30-day readmission among aneurysmal SAH patients treated at a single center between 2003 and 2013. To control for geographic distance from the hospital and year of treatment, the authors randomly matched each case (30-day readmission) with approximately 2 SAH controls (no readmission) based on home ZIP code and treatment year. They evaluated variables related to patient demographics, socioeconomic characteristics, comorbidities, presentation severity (e.g., Hunt and Hess grade), and clinical course (e.g., need for gastrostomy or tracheostomy, length of stay). Conditional logistic regression was used to identify significant predictors, accounting for the matched design of the study. RESULTS Among 82 SAH patients with unplanned 30-day readmission, the authors matched 78 patients with 153 nonreadmitted controls. Age, demographics, and socioeconomic factors were not associated with readmission. In univariate analysis, multiple variables were significantly associated with readmission, including Hunt and Hess grade (OR 3.0 for Grade IV/V vs I/II), need for gastrostomy placement (OR 2.0), length of hospital stay (OR 1.03 per day), discharge disposition (OR 3.2 for skilled nursing vs other disposition), and Charlson Comorbidity Index (OR 2.3 for score >= 2 vs 0). However, the only significant predictor in the multivariate analysis was discharge to a skilled nursing facility (OR 3.2), and the final model was sensitive to criteria used to enter and retain variables. Furthermore, despite the significant association between discharge disposition and readmission, less than 25% of readmitted patients were discharged to a skilled nursing facility. CONCLUSIONS Although discharge disposition remained significant in multivariate analysis, most routinely collected variables appeared to be weak independent predictors of 30-day readmission after SAH. Consequently, hospitals interested in decreasing readmission rates may consider multifaceted, cost-efficient interventions that can be broadly applied to most if not all SAH patients. PMID- 27494821 TI - Contemporary analysis of the intraoperative and perioperative complications of neurosurgical procedures performed in the sitting position. AB - OBJECTIVE Historically, performing neurosurgery with the patient in the sitting position offered advantages such as improved visualization and gravity-assisted retraction. However, this position fell out of favor at many centers due to the perceived risk of venous air embolism (VAE) and other position-related complications. Some neurosurgical centers continue to perform sitting-position cases in select patients, often using modern monitoring techniques that may improve procedural safety. Therefore, this paper reports the risks associated with neurosurgical procedures performed in the sitting position in a modern series. METHODS The authors reviewed the anesthesia records for instances of clinically significant VAE and other complications for all neurosurgical procedures performed in the sitting position between January 1, 2000, and October 8, 2013. In addition, a prospectively maintained morbidity and mortality log of these procedures was reviewed for instances of subdural or intracerebral hemorrhage, tension pneumocephalus, and quadriplegia. Both overall and specific complication rates were calculated in relation to the specific type of procedure. RESULTS In a series of 1792 procedures, the overall complication rate related to the sitting position was 1.45%, which included clinically significant VAE, tension pneumocephalus, and subdural hemorrhage. The rate of any detected VAE was 4.7%, but the rate of VAE requiring clinical intervention was 1.06%. The risk of clinically significant VAE was highest in patients undergoing suboccipital craniotomy/craniectomy with a rate of 2.7% and an odds ratio (OR) of 2.8 relative to deep brain stimulator cases (95% confidence interval [CI] 1.2-70, p = 0.04). Sitting cervical spine cases had a comparatively lower complication rate of 0.7% and an OR of 0.28 as compared with all cranial procedures (95% CI 0.12-0.67, p < 0.01). Sitting cervical cases were further subdivided into extradural and intradural procedures. The rate of complications in intradural cases was significantly higher (OR 7.3, 95% CI 1.4-39, p = 0.02) than for extradural cases. The risk of VAE in intradural spine procedures did not differ significantly from sitting suboccipital craniotomy/craniectomy cases (OR 0.69, 95% CI 0.09-5.4, p = 0.7). Two cases (0.1%) had to be aborted intraoperatively due to complications. There were no instances of intraoperative deaths, although there was a single death within 30 days of surgery. CONCLUSIONS In this large, modern series of cases performed in the sitting position, the complication rate was low. Suboccipital craniotomy/craniectomy was associated with the highest risk of complications. When appropriately used with modern anesthesia techniques, the sitting position provides a safe means of surgical access. PMID- 27494822 TI - Endoscope-assisted transsphenoidal puncture of the cavernous sinus for embolization of carotid-cavernous fistula in a neurosurgical hybrid operating suite. AB - Endovascular embolization is the treatment of choice for carotid-cavernous fistulas (CCFs), but failure to catheterize the cavernous sinus may occur as a result of vessel tortuosity, hypoplasia, or stenosis. In addition to conventional transvenous or transarterial routes, alternative approaches should be considered. The authors present a case in which a straightforward route to the CCF was accessed via transsphenoidal puncture of the cavernous sinus in a neurosurgical hybrid operating suite. This 82-year-old man presented with severe chemosis and proptosis of the right eye. Digital subtraction angiography revealed a Type B CCF with a feeding artery arising from the meningohypophyseal trunk of the right cavernous segment of the internal carotid artery. The CCF drained through a thrombosed right superior ophthalmic vein that ended deep in the orbit; there were no patent sinuses or venous plexuses connecting to the CCF. An endoscope assisted transsphenoidal puncture created direct access to the nidus for embolization. Embolic agents were deployed through the puncture needle to achieve complete obliteration. Endoscope-assisted transsphenoidal puncture of the cavernous sinus is a feasible alternative to treat difficult-to-access CCFs in a neurosurgical hybrid operating suite. PMID- 27494823 TI - Facile Incorporation of Pd(PPh3)2Hal Substituents into Polymethines, Merocyanines, and Perylene Diimides as a Means of Suppressing Intermolecular Interactions. AB - Compounds with polarizable pi systems that are susceptible to attack with nucleophiles at C-Hal (Hal = Cl, Br) bonds react with Pd(PPh3)4 to yield net oxidative addition. X-ray structures show that the resulting Pd(PPh3)2Hal groups greatly reduce intermolecular pi-pi interactions. The Pd-functionalized dyes generally exhibit solution-like absorption spectra in films, whereas their Hal analogues exhibit features attributable to aggregation. PMID- 27494824 TI - A population-based study of large granular lymphocyte leukemia. AB - Large granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder of cytotoxic cells. T-cell LGL (T-LGL) leukemia is characterized by accumulation of cytotoxic T cells in blood and infiltration of the bone marrow, liver or spleen. Population-based studies have not been reported in LGL leukemia. We present clinical characteristics, natural history and risk factors for poor survival in patients with LGL leukemia using the Surveillance, Epidemiology, and End Results Program (SEER) and the United States National Cancer Data Base (NCDB). LGL leukemia is an extremely rare disease with the incidence of 0.2 cases per 1 000 000 individuals. The median age at diagnosis was 66.5 years with females likely to be diagnosed at 3 years earlier compared with males. Analysis of patient-level data using NCDB (n=978) showed that 45% patients with T-LGL leukemia required some form of systemic treatment at the time of diagnosis. T-LGL leukemia patients have reduced survival compared with general population, with a median overall survival of 9 years. Multivariate analysis showed that age >60 years at the time of diagnosis and the presence of significant comorbidities were independent predictors of poor survival. PMID- 27494825 TI - Crizotinib treatment for refractory pediatric acute myeloid leukemia with RAN binding protein 2-anaplastic lymphoma kinase fusion gene. PMID- 27494827 TI - The level of detail required in a deformable phantom to accurately perform quality assurance of deformable image registration. AB - The primary purpose of the study was to determine how detailed deformable image registration (DIR) phantoms need to adequately simulate human anatomy and accurately assess the quality of DIR algorithms. In particular, how many distinct tissues are required in a phantom to simulate complex human anatomy? Pelvis and head-and-neck patient CT images were used for this study as virtual phantoms. Two data sets from each site were analyzed. The virtual phantoms were warped to create two pairs consisting of undeformed and deformed images. Otsu's method was employed to create additional segmented image pairs of n distinct soft tissue CT number ranges (fat, muscle, etc). A realistic noise image was added to each image. Deformations were applied in MIM Software (MIM) and Velocity deformable multi-pass (DMP) and compared with the known warping. Images with more simulated tissue levels exhibit more contrast, enabling more accurate results. Deformation error (magnitude of the vector difference between known and predicted deformation) was used as a metric to evaluate how many CT number gray levels are needed for a phantom to serve as a realistic patient proxy. Stabilization of the mean deformation error was reached by three soft tissue levels for Velocity DMP and MIM, though MIM exhibited a persisting difference in accuracy between the discrete images and the unprocessed image pair. A minimum detail of three levels allows a realistic patient proxy for use with Velocity and MIM deformation algorithms. PMID- 27494829 TI - Editorial: Resurrecting the rubric 'For debate'. PMID- 27494826 TI - Gene Expression Profiling in Blood Provides Reproducible Molecular Insights into Asthma Control. AB - RATIONALE: Maintaining optimal symptom control remains the primary objective of asthma treatment. Better understanding of the biologic underpinnings of asthma control may lead to the development of improved clinical and pharmaceutical approaches. OBJECTIVES: To identify molecular pathways and interrelated genes whose differential expression was associated with asthma control. METHODS: We performed gene set enrichment analyses of asthma control in 1,170 adults with asthma, each with gene expression data derived from either whole blood (WB) or unstimulated CD4+ T lymphocytes (CD4), and a self-reported asthma control score representing either the preceding 6 months (chronic) or 7 days (acute). Our study comprised a discovery WB cohort (n = 245, chronic) and three independent, nonoverlapping replication cohorts: a second WB set (n = 448, acute) and two CD4 sets (n = 300, chronic; n = 77, acute). MEASUREMENTS AND MAIN RESULTS: In the WB discovery cohort, we found significant overrepresentation of genes associated with asthma control in 1,106 gene sets from the Molecular Signatures Database (false discovery rate, <5%). Of these, 583 (53%) replicated in at least one replication cohort (false discovery rate, <25%). Suboptimal control was associated with signatures of eosinophilic and granulocytic inflammatory signals, whereas optimal control signatures were enriched for immature lymphocytic patterns. These signatures included two related biologic processes related to activation by TREM-1 (triggering receptor expressed on myeloid cells 1) and lipopolysaccharide. CONCLUSIONS: Together, these results demonstrate the existence of specific, reproducible transcriptomic components in blood that vary with degree of asthma control and implicate a novel biologic target (TREM-1). PMID- 27494828 TI - Trichostatin A Inhibits Retinal Pigmented Epithelium Activation in an In Vitro Model of Proliferative Vitreoretinopathy. AB - PURPOSE: Proliferative vitreoretinopathy (PVR) is a blinding disorder that develops after a retinal tear or detachment. Activation of the retinal pigmented epithelium (RPE) is implicated in PVR; however, the mechanisms leading to enhanced RPE proliferation, migration, and contraction remain largely unknown. This study utilized an in vitro model of PVR to investigate the role of acetylation in RPE activation and its contribution to the progression of this disease. METHODS: ARPE-19 cells, primary cultures of porcine RPE, and induced pluripotent stem cell-derived RPE (iPS-RPE) were utilized for cellular and molecular analyses. Cells treated with transforming growth factor beta 2 (TGFbeta2; 10 ng/mL) alone or in the presence of the broad-spectrum histone deacetylase (HDAC) inhibitor, trichostatin A (TSA; 0.1 MUM), were assessed for contraction and migration through collagen contraction and scratch assays, respectively. Western blotting and immunofluorescence analysis were performed to assess alpha-smooth muscle actin (alpha-SMA) and beta-catenin expression after TGFbeta2 treatment alone or in combination with TSA. RESULTS: TGFbeta2 significantly increased RPE cell contraction in collagen matrix and this effect was inhibited in the presence of TSA (0.1 MUM). In agreement with these data, immunofluorescence analysis of TSA-treated iPS-RPE wounded monolayers revealed decreased alpha-SMA as compared with control. Scratch assays to assess wound healing revealed TSA inhibited TGFbeta2-mediated iPS-RPE cell migration. CONCLUSIONS: Our findings indicate a role of acetylation in RPE activation. Specifically, the HDAC inhibitor TSA decreased RPE cell proliferation and TGFbeta2-mediated cell contraction and migration. Further investigation of pharmacological compounds that modulate acetylation may hold promise as therapeutic agents for PVR. PMID- 27494830 TI - New therapeutic strategies for invasive aspergillosis in the era of azole resistance: how should the prevalence of azole resistance be defined? AB - Given reports showing a high prevalence of azole resistance in Aspergillus fumigatus, alternatives to azole therapy are discussed when a threshold of 10% of azole-resistant environmental isolates is reached. This raises the issue of calculation of this threshold, either on the prevalence of azole-resistant isolates as a whole or on the prevalence of azole-resistant cases in populations at risk of invasive aspergillosis (IA). For isolate evaluation, there are high disparities in routine microbiological procedures for the isolation of A. fumigatus and azole resistance detection. There are also huge differences between the microbiological work-up for diagnosing IA. Some centres rely on galactomannan detection alone without actively trying to culture appropriate samples, which affects reliability of the figures on the prevalence of resistance and thus the threshold of resistance. Moreover, reports from the laboratory could mix up figures from completely different patient populations: frequent azole-resistant isolates from pneumology patients and rare azole-resistant isolates from haematology patients. Therefore, to sum isolates from different specimens and different wards can lead to erroneous calculations for the restricted populations at risk of developing IA. In conclusion, assessing the incidence of azole resistance in A. fumigatus should be based on harmonized consensual microbiological methods and reports should be restricted to IA episodes in identified populations at risk of IA when the issue is to define an operational threshold for modifying recommendations. PMID- 27494831 TI - Azole resistance surveillance in Aspergillus fumigatus: beneficial or biased? AB - Azole resistance is a growing concern with Aspergillus fumigatus, and may cause increased mortality in patients with azole-resistant invasive aspergillosis (IA). Microbial surveillance has been recognized as a fundamental component of resistance management. Surveillance information may be used to inform decisions regarding health services and research funding allocation, to guide local infection control in hospitals and communities, and to direct local and national drug policies and guidelines. Azole resistance frequencies have been based on screening of unselected A. fumigatus isolates, on the number of azole-resistant cases within a cohort of patients with a specific Aspergillus disease, or on analysis of patients within a specific risk group. The various surveillance approaches differ in their aims, as well as in their associated advantages and drawbacks. Nevertheless, a wide range of azole resistance frequencies has been reported, partly due to the denominator used. As most azole resistance is believed to develop in the environment and, as a consequence, azole-naive patients may present with azole-resistant aspergillosis, experts recommended a 10% resistance frequency threshold above which the standard treatment choice, i.e. voriconazole, should be reconsidered. We believe that local resistance rates based on Aspergillus disease and/or risk group should be leading for decisions regarding empirical antifungal therapy in specific units. In addition, patient factors should be considered, such as admission to the ICU. Collecting valid surveillance data may be challenging in azole resistance due to numerous factors that present potential biases. Surveillance research may benefit from further standardization, which may be facilitated through the recently instituted International Society for Human and Animal Mycology (ISHAM) Aspergillus Resistance Surveillance Working Group. PMID- 27494832 TI - CTX-M-15-H30Rx-ST131 subclone is one of the main causes of healthcare-associated ESBL-producing Escherichia coli bacteraemia of urinary origin in Spain. AB - OBJECTIVES: The objective of this study was to assess the prevalence and molecular epidemiology of ESBL-producing Escherichia coli causing healthcare associated (HCA) and community-associated (CA) bacteraemia of urinary origin (BUO) in Spain. METHODS: An observational cohort study was conducted at eight hospitals from different Spanish geographical areas (2010-11). BUO episodes (n = 425) were classified as HCA (n = 215) and CA (n = 210), and one blood isolate per episode was collected. Susceptibility testing was performed, ESBLs were screened by double-disc diffusion test and ESBL and OXA-1 genes were characterized (PCR and sequencing). Population structure (phylogenetic groups, XbaI-PFGE and MLST) and ST131 subtyping (PCR) were determined. Virulence genes were detected by PCR and virulence score, profiles and extraintestinal pathogenic E. coli (ExPEC) status calculated. RESULTS: ESBL-producing E. coli prevalence was 9.2% (39/425). ESBL-producing E. coli episodes were significantly associated with HCA-BUO episodes [14% (30/215) versus 4.3% (9/210); P = 0.001]. The highest non susceptibility proportions corresponded to ciprofloxacin (97.4%), amoxicillin/clavulanate (74.4%), co-trimoxazole (69.2%) and tobramycin (61.5%). Of the 39 ESBL-producing E. coli isolates, 34 produced CTX-M enzymes (21 CTX-M 15, 11 CTX-M-14 and 2 CTX-M-1). Fifteen STs were identified, the B2-ST131 clone being the most prevalent (54%; 21/39). All ST131 isolates were ExPEC and had the highest virulence scores, but they showed less diversity in virulence profiles than other STs. The H30Rx subclone accounted for most ST131 isolates (20/21), co produced CTX-M-15 (20/20) and OXA-1 (19/20) enzymes and was associated with HCA episodes (16/20). CONCLUSIONS: The CTX-M-15-ST131-H30Rx subclone is a relevant MDR pathogen causing BUO, mainly HCA episodes. The dominance of this subclone with comparatively less diversity of virulence profiles reflects the spread of a successful and MDR ESBL ST131 lineage in Spain. PMID- 27494833 TI - An orientation to wellness for new faculty of medicine members: meeting a need in faculty development. AB - OBJECTIVES: To evaluate the format, content, and effectiveness of a newly developed orientation to wellness workshop, and to explore participants' overall perceptions. METHODS: This was a mixed methods study. Participants consisted of 47 new faculty of medicine members who attended one of the four workshops held between 2011 and 2013. Questionnaires were used to evaluate workshop characteristics (10 survey items; response scale 1=unacceptable to 7=outstanding), intention to change behavior (yes/no), and retrospective pre/post workshop self-efficacy (4 survey items; response scale 1=no confidence to 6=absolute confidence). Mean scores and standard deviations were calculated for the workshop characteristics. Pre/post workshop self-efficacy scores were compared using a Wilcoxon signed-rank test. Participants' written qualitative feedback was coded using an inductive strategy to identify themes. RESULTS: There was strong support for the workshop characteristics with mean scores entirely above 6.00 (N=42). Thirty-one of 34 respondents (91%) expressed intention to change their behavior as a result of participating in the workshop. The post workshop self-efficacy scores (N=38 respondents) increased significantly for all four items (p<0.0001) compared to pre workshop ratings. Participants perceived the key workshop elements as the evidence-based content relevant to academic physicians, incorporation of practical tips and strategies, and an atmosphere conducive to discussion and experience sharing. CONCLUSIONS: Participants welcomed wellness as a focus of faculty development. Enhancing instruction around wellness has the potential to contribute positively to the professional competency and overall functioning of faculty of medicine members. PMID- 27494834 TI - GSK3beta inactivation promotes the oncogenic functions of EZH2 and enhances methylation of H3K27 in human breast cancers. AB - During the process of tumorigenesis, inactivation of tumor suppressors is a critical step. EZH2, a histone methyltransferase, promotes cell growth and migration through catalyzing trimethylation of histone H3 at Lys 27 (H3K27me3) and plays an important role in tumorigenesis. Its expression can be controlled by phosphorylation. However, the regulation of EZH2 activity by tumor suppressor kinase is not well understood. In this study, we show that glycogen synthase kinase 3 beta (GSK3beta) negatively regulates H3K27 trimethylation. We also validate that GSKbeta physically interacts with EZH2, and their interaction occurs in the cytosol. GSK3beta phosphorylates EZH2 at Ser363 and Thr367 in vitro, and activating GSK3beta upregulates Thr367 phosphorylationin vivo. Cells expressing GSK3beta-non-phosphorylatable mutant EZH2 have higher H3K27 trimethylation and enhanced ability of cell migration and anchorage-independent growth. Inactivation of GSK3beta as measured by its phosphorylation at Ser9 is positively correlated with higher level of H3K27 trimethylation in tumor tissues from breast cancer patients. Our study indicated that GSK3beta phosphorylates EZH2 at Ser363 and Thr367, resulting in reduced H3K27 trimethylation and biological activity of EZH2 in breast cancer. PMID- 27494835 TI - DR5 mAb-conjugated, DTIC-loaded immuno-nanoparticles effectively and specifically kill malignant melanoma cells in vivo. AB - We combined chemo- and immunotherapies by constructing dual therapeutic function immuno-nanoparticles (NPs) consisting of death receptor 5 monoclonal antibody (DR5 mAb)-conjugated nanoparticles loaded with dacarbazine (DTIC) (DTIC-NPs-DR5 mAb). We determined the in vivo targeting specificity of DTIC-NPs-DR5 mAb by evaluating distribution in tumor-bearing nude mice using a real-time imaging system. Therapeutic efficacy was assessed in terms of its effect on tumor volume, survival time, histomorphology, microvessel density (MVD), and apoptotic index (AI). Systemic toxicity was evaluated by measuring white blood cells (WBC) counts, alanine aminotransferase (ALT) levels, and creatinine clearance (CR).In vivo and ex vivo imaging indicates that DR5 mAb modification enhanced the accumulation of NPs within the xenograft tumor. DTIC-NPs-DR5 mAb inhibited tumor growth more effectively than DTIC or DR5 mAb alone, indicating that combining DTIC and DR5 mAb through pharmaceutical engineering achieves a better therapeutic effect. Moreover, the toxicity of DTIC-NPs-DR5 mAb was much lower than that of DTIC, implying that DR5 mAb targeting reduces nonspecific uptake of DTIC into normal tissue and thus decreases toxic side effects. These results demonstrate that DTIC-NPs-DR5 mAb is a safe and effective nanoparticle formulation with the potential to improve the efficacy and specificity of melanoma treatment. PMID- 27494836 TI - Novel anti-CD3 chimeric antigen receptor targeting of aggressive T cell malignancies. AB - Peripheral T-cell lymphomas (PTCLS) comprise a diverse group of difficult to treat, very aggressive non-Hodgkin's lymphomas (NHLS) with poor prognoses and dismal patient outlook. Despite the fact that PTCLs comprise the majority of T cell malignancies, the standard of care is poorly established. Chimeric antigen receptor (CAR) immunotherapy has shown in B-cell malignancies to be an effective curative option and this extends promise into treating T-cell malignancies. Because PTCLS frequently develop from mature T-cells, CD3 is similarly strongly and uniformly expressed in many PTCL malignancies, with expression specific to the hematological compartment thus making it an attractive target for CAR design. We engineered a robust 3rd generation anti-CD3 CAR construct (CD3CAR) into an NK cell line (NK-92). We found that CD3CAR NK-92 cells specifically and potently lysed diverse CD3+ human PTCL primary samples as well as T-cell leukemia cells lines ex vivo. Furthermore, CD3CAR NK-92 cells effectively controlled and suppressed Jurkat tumor cell growth in vivo and significantly prolonged survival. In this study, we present the CAR directed targeting of a novel target - CD3 using CAR modified NK-92 cells with an emphasis on efficacy, specificity, and potential for new therapeutic approaches that could improve the current standard of care for PTCLs. PMID- 27494837 TI - Loss of NEDD4 contributes to RTP801 elevation and neuron toxicity: implications for Parkinson's disease. AB - Parkinson's disease (PD) is a disorder characterized by the degeneration of certain neuronal populations in the central and peripheral nervous system. One of the hallmarks of the disease is the toxic accumulation of proteins within susceptible neurons due to major impairment in the degradation/clearance protein systems.RTP801 is a pro-apoptotic protein that is sufficient and necessary to induce neuronal death in cellular and animal models of PD. RTP801 is also upregulated in sporadic and parkin mutant PD brains. Here, we report the role of NEDD4, an E3 ligase involved in alpha-synuclein degradation and PD pathogenesis, in the regulation of RTP801 protein levels and toxicity. NEDD4 polyubiquitinates RTP801 in a cell-free system and in cellular cultures, and they interact physically. NEDD4 conjugates K63-ubiquitin chains to RTP801 and targets it for degradation. NEDD4 regulates RTP801 protein levels in both cultured cells and in the brain tissue. NEDD4 levels are diminished in nigral neurons from human PD brains. Interestingly, neurotoxin 6-OHDA decreases dramatically NEDD4 protein expression but elevates RTP801 protein levels. Moreover, NEDD4 protects neuronal PC12 cells from both 6-OHDA and RTP801-induced toxicity. In primary cortical neurons, NEDD4 knockdown toxicity is mediated by RTP801 since the double knockdown of RTP801 and NEDD4 abrogates the loss of phospho Ser473-Akt and the appearance of caspase-cleaved spectrin fragments.Thus, NEDD4 ligase regulates RTP801 and is sensitive to PD-associated oxidative stress. This suggests that NEDD4 loss of function in PD could contribute importantly into neuronal death by elevating RTP801. PMID- 27494838 TI - EGFR-targeted therapy results in dramatic early lung tumor regression accompanied by imaging response and immune infiltration in EGFR mutant transgenic mouse models. AB - Lung adenocarcinoma patients harboring kinase domain mutations in Epidermal growth factor receptor (EGFR) have significant clinical benefit from EGFR targeted tyrosine kinase inhibitors (TKIs). Although a majority of patients experience clinical symptomatic benefit immediately, an objective response can only be demonstrated after 6-8 weeks of treatment. Evaluation of patient response by imaging shows that 30-40% of patients do not respond due to intrinsic resistance to these TKIs. We investigated immediate-early effects of EGFR-TKI treatment in mutant EGFR-driven transgenic mouse models by FDG-PET and MRI and correlated the effects on the tumor and the tumor microenvironment. Within 24 hours of erlotinib treatment we saw approximately 65% tumor regression in mice with TKI-sensitive EGFRL858R lung adenocarcinoma. However, mice with EGFRL858R/T790M-driven tumors did not respond to either erlotinib or afatinib monotherapy, but did show a significant tumor response to afatinib-cetuximab combination treatment. The imaging responses correlated with the inhibition of downstream EGFR signaling, increased apoptosis, and decreased proliferation in the tumor tissues. In EGFRL858R-driven tumors, we saw a significant increase in CD45+ leukocytes, NK cells, dendritic cells, macrophages and lymphocytes, particularly CD8+ T cells. In response to erlotinib, these dendritic cells and macrophages had significantly higher MHC class II expression, indicating increased antigen-presenting capabilities. Together, results of our study provide novel insight into the immediate-early therapeutic response to EGFR TKIs in vivo. PMID- 27494839 TI - DeltaNp63 drives metastasis in breast cancer cells via PI3K/CD44v6 axis. AB - P63 is a transcription factor belonging to the family of p53, essential for the development and differentiation of epithelia. In recent years, it has become clear that altered expression of the different isoforms of this gene can play an important role in carcinogenesis. The p63 gene encodes for two main isoforms known as TA and DeltaN p63 with different functions. The role of these different isoforms in sustaining tumor progression and metastatic spreading however has not entirely been clarified. Here we show that breast cancer initiating cells express DeltaNp63 isoform that supports a more mesenchymal phenotype associated with a higher tumorigenic and metastatic potential. On the contrary, the majority of cells within the tumor appears to express predominantly TAp63 isoform. While DeltaNp63 exerts its effects by regulating a PI3K/CD44v6 pathway, TAp63 modulates this pathway in an opposite fashion. As a result, tumorigenicity and invasive capacity of breast cancer cells is a balance of the two isoforms. Finally, we found that tumor microenvironmental cytokines significantly contribute to the establishment of breast cancer cell phenotype by positively regulating DeltaNp63 and CD44v6 expression. PMID- 27494840 TI - Impaired 53BP1/RIF1 DSB mediated end-protection stimulates CtIP-dependent end resection and switches the repair to PARP1-dependent end joining in G1. AB - End processing at DNA double strand breaks (DSB) is a decisive step in repair pathway selection. Here, we investigated the role of 53BP1/RIF1 in limiting BRCA1/CtIP-mediated end resection to control DSB repair pathway choice. ATM orchestrates this process through 53BP1 phosphorylation to promote RIF1 recruitment. As cells enter S/G2-phase, end resection is activated, which displaces pATM from DSB sites and diminishes 53BP1 phosphorylation and RIF1 recruitment. Consistently, the kinetics of ATM and 53BP1 phosphorylation in S/G2 phase concur. We show that defective 53BP1/RIF1-mediated DSB end-protection in G1 phase stimulates CtIP/MRE11-dependent end-resection, which requires Polo-like kinase 3. This end resection activity in G1 was shown to produce only short tracks of ssDNA overhangs, as evidenced by the findings that in 53BP1 depleted cells, (i) RPA focus intensity was significantly lower in G1 compared to that in S/G2 phase, and (ii) EXO1 knockdown did not alter either number or intensity of RPA foci in G1 but significantly decreased the RPA focus intensity in S/G2 phase. Importantly, we report that the observed DSB end resection in G1 phase inhibits DNA-PK-dependent nonhomologous end joining but is not sufficient to stimulate HR. Instead, it switches the repair to the alternative PARP1-dependent end joining pathway. PMID- 27494841 TI - Agonistic analogs of growth hormone releasing hormone (GHRH) promote wound healing by stimulating the proliferation and survival of human dermal fibroblasts through ERK and AKT pathways. AB - Decreased or impaired proliferation capability of dermal fibroblasts interferes with successful wound healing. Several growth factors tested failed to fully restore the growth of fibroblasts, possibly due to their rapid degradation by proteases. It is therefore critical to find new agents which have stimulatory effects on fibroblasts while being highly resistant to degradation. In such a scenario, the activities of two agonistic analogs of growth hormone releasing hormone (GHRH), MR-409 and MR-502, were evaluated for their impact on proliferation and survival of primary human dermal fibroblasts. In vitro, both analogs significantly stimulated cell growth by more than 50%. Under serum depletion induced stress, fibroblasts treated with MR-409 or MR-502 demonstrated better survival rates than control. These effects can be inhibited by either PD98059 or wortmannin. Signaling through MEK/ERK1/2 and PI3K/AKT in an IGF-1 receptor-independent manner is required. In vivo, MR-409 promoted wound closure. Animals treated topically with MR-409 healed earlier than controls in a dose dependent manner. Histologic examination revealed better wound contraction and less fibrosis in treated groups. In conclusion, MR-409 is a potent mitogenic and anti-apoptotic factor for primary human dermal fibroblasts. Its beneficial effects on wound healing make it a promising agent for future development. PMID- 27494842 TI - The photosensitizer verteporfin has light-independent anti-leukemic activity for Ph-positive acute lymphoblastic leukemia and synergistically works with dasatinib. AB - Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, particularly from the viewpoints of microenvironmental independence. Patient-derived xenografts (PDX) are established by the transfer of primary tumor cells directly from patients into immunodeficient mice and can provide primary-like tumor cells of the amount needed at the desired time. We developed a high-throughput drug screening system using PDX cells and performed drug screening using the PDX cells of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). We established four Ph+ ALL PDX mice and performed high-throughput screening of 3440 compounds using leukemia cells from the PDX mice (PDX-cell screening). The profiles of drugs selected by PDX-cell screening were markedly different from those by screening using the Ph+ ALL cell line. We found that verteporfin, an FDA-approved drug, exhibited strong PDX cell-specific cytotoxicity. In the validation assay, its GI50 was 228 nM, 395 nM, and 538 nM in three PDX cells and 3.93 uM, 2.11 uM, and 5.61 uM in three cell lines. Although verteporfin is a photosensitizer activated by photoirradiation, its cytotoxic effects were mediated by the light-independent production of reactive oxygen species; therefore, its anti-leukemic effects were also exerted in vivo without photoirradiation. Furthermore, it exhibited synergistic effects with dasatinib, an ABL kinase inhibitor. These results indicated the potential of verteporfin as a new anti-leukemic reagent. PMID- 27494843 TI - Cardiac fibrosis in mouse expressing DsRed tetramers involves chronic autophagy and proteasome degradation insufficiency. AB - Proteinopathy in the heart which often manifests excessive misfolded/aggregated proteins in cardiac myocytes can result in severe fibrosis and heart failure. Here we developed a mouse model, which transgenically express tetrameric DsRed, a red fluorescent protein (RFP), in an attempt to mimic the pathological mechanisms ofcardiac fibrosis. Whilst DsRed is expressed and forms aggregation in most mouse organs, certain pathological defects are specifically recapitulated in cardiac muscle cells including mitochondria damages, aggresome-like residual bodies, excessive ubiquitinated proteins, and the induction of autophagy. The proteinopathy and cellular injuries caused by DsRed aggregates may be due to impaired or overburdened ubiquitin-proteasome system and autophagy-lysosome systems. We further identified that DsRed can be ubiquitinated and associated with MuRF1, a muscle-specific E3 ligase. Concomitantly, an activation of NF kappaB signaling and a strong TIMP1 induction were noted, suggesting that RFP induced fibrosis was augmented by a skewed balance between TIMP1 and MMPs. Taken together, our study highlights the molecular consequences of uncontrolled protein aggregation leading to congestive heart failure, and provides novel insights into fibrosis formation that can be exploited for improved therapy. PMID- 27494844 TI - Dose-dependent genotype effects of BDNF Val66Met polymorphism on default mode network in early stage Alzheimer's disease. AB - In humans, brain-derived neurotrophic factor (BDNF) has been shown to play a pivotal role in neurocognition, and its gene contains a functional polymorphism (Val66Met) that may explain individual differences in brain volume and memory related activity.In this study, we enrolled 186 Alzheimer's disease (AD) patients who underwent 3D T1 magnetic resonance imaging, and explored the gray matter (GM) structural covariance networks (SCN). The patients were divided into three groups according to their genotype: Met/Met (n = 45), Val/Met (n = 86) and Val/Val (n = 55). Seed-based analysis was performed focusing on four SCN networks. Neurobehavioral scores served as the major outcome factor.Only peak cluster volumes of default mode medial temporal lobe network showed significant genotype interactions, of which the interconnected peak clusters showed dose-dependent genotype effects. There were also significant correlations between the cognitive test scores and interconnected-cluster volumes, especially in the orbitofrontal cortex.These findings support the hypothesis that BDNF rs6265 polymorphisms modulate entorhinal cortex-interconnected clusters and the valine allele was associated with stronger structural covariance patterns that determined the cognitive outcomes. PMID- 27494845 TI - Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myeloma. AB - Bcl2 and IAP families are anti-apoptotic proteins deregulated in multiple myeloma (MM) cells. Pharmacological inhibition of each of these families has shown significant activity only in subgroups of MM patients. Here, we have examined a broad-spectrum Bcl2 family inhibitor Obatoclax (OBX) in combination with a Smac mimetic LCL161 in MM cell lines and patient cells. LCL161/OBX combination induced synergistic cytotoxicity and anti-proliferative effects on a broad range of human MM cell lines. The cytotoxicity was mediated through inhibition of the IAPs, activation of caspases and up regulation of the pro-apoptotic proteins Bid, Bim, Puma and Noxa by the drug combination. In addition, we observed that OBX caused ER stress and activated the Unfolded Protein Response (UPR) leading to drug resistance. LCL161, however inhibited spliced Xbp-1, a pro-survival factor. In addition, we observed that OBX increased GRP78 localization to the cell surface, which then induced PI3K dependent Akt activation and resistance to cell death. LCL161 was able to block OBX induced Akt activation contributing to synergistic cell death. Our results support clinical evaluation of this combination strategy in relapsed refractory MM patients. PMID- 27494847 TI - Preoperative neutrophil-to-lymphocyte ratio and tumor-related factors to predict lymph node metastasis in patients with pancreatic ductal adenocarcinoma (PDAC). AB - As a poor prognosis indicator in patients with pancreatic ductal adenocarcinoma (PDCA), lymph node (LN) metastasis is of great importance in treatment. Present study was performed to evaluate the predictive value of preoperative neutrophil to-lymphocyte ratio (NLR), Platelet-to-lymphocyte ratio (PLR) and possible clinical parameters on the LN metastasis in PDCA patients. A total of 159 operable patients with PDCA were enrolled in our study. The clinical utility of NLR and other clinical parameters was evaluated by receiver operating characteristic (ROC) curves. Overall survival analysis indicated that LN metastasis is an independent prognostic factor. The logistic analysis was used to determine the independent parameters associated with LN metastasis. Ideal cutoff values for predicting LN metastasis are 2.12 for NLR and 130.96 for PLR according to the ROC curve. Multivariate analyses indicate that NLR (HR 2.588; 95% CI 1.246 5.376; P = 0.011), CA125 (HR 6.348; 95% CI 2.056-19.594; P = 0.001) and CA19-9 (HR 2.738; 95% CI 1.151-6.515; P = 0.023) are associated significantly with LN metastasis independently. Preoperative NLR, CA125 and CA19-9 are useful biomarkers for the prediction of LN metastasis in PDCA patients. PMID- 27494846 TI - ADAR1 is vital for B cell lineage development in the mouse bone marrow. AB - Adenosine deaminase acting on RNA (ADAR) 1 is the master editor of the transcriptome, catalyzing the conversion of adenosine to inosine (A-to-I). RNA transcripts fold into a variety of secondary structures including long intramolecular RNA duplexes that are the major substrate of ADAR1. Most A-to-I editing sites occur within RNA duplexes formed by complementary pairing of inverted retrotransposable elements interspersed within noncoding regions of transcripts. This catalytic activity of ADAR1 most likely prevents the abnormal activation of cytosolic nucleic acid sensors by self-dsRNAs. Homozygous disruption of mouse Adar is embryonic lethal due to a toxic type-I interferons response and correspondingly biallelic missense mutations in human ADAR1 cause a severe congenital interferonopathy. Here, we report that Cd19-Cre-mediated Adar gene ablation in the mouse causes a significant defect in the final stages of B cell development with an almost complete absence of newly formed immature and CD23+ mature recirculating B cells in the BM. Adar ablation in pre-B cells induced upregulation of typical interferon-stimulated genes (ISGs) and apoptosis upon further maturation. ADAR1 deficiency also inhibited the in vitro, IL-7 mediated, differentiation of BM-derived B cell precursors. In summary, ADAR1 is required, non-redundantly, for normal B lymphopoiesis in the BM and peripheral maintenance. PMID- 27494848 TI - Metformin use improves survival of diabetic liver cancer patients: systematic review and meta-analysis. AB - Metformin has garnered considerable interest as a chemo-preventive and chemo therapeutic agent given the increased risk of liver cancer among diabetic patients. This work was performed to illustrate the association between metformin use and survival of diabetic liver cancer patients. We conducted a comprehensive literature search of PubMed, Web of Science, Embase, BIOSIS Previews, Cochrane Library from inception to 12 May 2016. Meta-analyses were performed using Stata (version 12.0), with hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) as effect measures. Eleven cohort studies involving 3452 liver cancer patients fulfilled the inclusion criteria. Meta-analyses showed that metformin use was associated with better survival (HR = 0.59; 95% CI, 0.42-0.83; p = 0.002) of liver cancer patients, and the beneficial effect persisted (HR = 0.64; 95% CI, 0.42-0.97; p = 0.035) when the population was restricted to diabetic liver cancer patients. After adjusting for age, etiology, index of tumor severity and treatment of liver cancer, the association between metformin use and better survival of liver cancer patients was stable, pooled HR ranged from 0.47 to 0.57. The results indicated that metformin use improved survival of diabetic liver cancer patients. However, the results should be interpreted with caution given the possibility of residual confounding. Further prospective studies are still needed to confirm the prognostic benefit of metformin use. PMID- 27494849 TI - Twist1-induced epithelial-mesenchymal transition according to microsatellite instability status in colon cancer cells. AB - Colorectal cancer (CRC) with microsatellite instability (MSI) may exhibit impaired epithelial-mesenchymal transition (EMT), but little is known about the underlying mechanisms of this phenomenon. In this study, we investigated the role of Twist1 and its downstream signaling cascades in EMT induction according to MSI status. To investigate the effects of Twist1 on EMT induction according to MSI status, MSS LS513 and MSI LoVo colon cancer cell lines, which overexpress human Twist1, were generated. Twist1-induced EMT and its downstream signaling pathways were evaluated via in vitro and in vivo experiments. We found that Twist1 induced EMT markers and stem cell-like characteristics via AKT signaling pathways. Twist1 induced activation of AKT and suppression of glycogen synthase kinase (GSK) 3beta, which resulted in the activation of beta-catenin, increasing CD44 expression. In addition, Twist1 activated the AKT-induced NF-kappaB pathway, increasing CD44 and CD166 expression. Activation of both the AKT/GSK-3beta/beta catenin and AKT/NF-kappaB pathways occurred in MSS LS513 cells, while only the AKT/GSK-3beta/beta-catenin pathway was activated in MSI LoVo cells. In conclusion, Twist1 induces stem cell-like characteristics in colon cancer cell lines related to EMT via AKT signaling pathways, and those pathways depend on MSI status. PMID- 27494850 TI - The 3'UTR signature defines a highly metastatic subgroup of triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a highly heterogeneous disease with an aggressive clinical course. Prognostic models are needed to chart potential patient outcomes. To address this, we used alternative 3'UTR patterns to improve postoperative risk stratification. We collected 327 publicly available microarrays and generated the 3'UTR landscape based on expression ratios of alternative 3'UTR. After initial feature filtering, we built a 17-3'UTR-based classifier using an elastic net model. Time-dependent ROC comparisons and Kaplan Meier analyses confirmed an outstanding discriminating power of our prognostic model for TNBC patients. In the training cohort, 5-year event-free survival (EFS) was 78.6% (95% CI 71.2-86.0) for the low-risk group, and 16.3% (95% CI 2.3-30.4) for the high-risk group (log-rank p<0.0001; hazard ratio [HR] 8.29, 95% CI 4.78 14.4), In the validation set, 5-year EFS was 75.6% (95% CI 68.0-83.2) for the low risk group, and 33.2% (95% CI 17.1-49.3) for the high-risk group (log-rank p<0.0001; HR 3.17, 95% CI 1.66-5.42). In conclusion, the 17-3'UTR-based classifier provides a superior prognostic performance for estimating disease recurrence and metastasis in TNBC patients and it may permit personalized management strategies. PMID- 27494851 TI - Differential expression of cyclooxygenase-2 in metastatic melanoma affects progression free survival. AB - The possible correlation between cyclooxygenase-2 (COX-2) expression and disease progression in melanoma is still a matter of debate. Analysis of COX-2 expression in 45 lymph node melanoma metastases demonstrates a significant correlation between the percent of expression and progression free survival (PFS). A positive COX-2 expression >=10% (COX-2high), as opposite to a positive expression <=9% (COX-2low), translated into a striking significant reduction of PFS of about 3 years. The reduction in PFS correlated neither with BRAFV600E nor with NRASQ61 expression in the analyzed samples. This concept was reinforced by the finding that tumour development in COX-2-/- mice was almost blunted. Similarly, inhibition of COX-2 protein expression in human melanoma cell lines, by using siRNAs technology as well as selective inhibition of COX-2 activity by celecoxib, reduced cellular proliferation and invasiveness. In conclusion we show that COX 2high is a negative prognostic factor in metastatic melanoma. Our study also clarifies that the uncertainty about the role of COX-2 in metastatic malignant melanoma, found in the current relevant literature, is probably due to the fact that a threshold in COX-2 expression has to be reached in order to impact on cancer malignancy. Our findings suggest that COX-2 expression may become an useful diagnostic tool in defining melanoma malignancy as well as argue for a possible therapeutic use of NSAID as add on therapy in selected cases. PMID- 27494852 TI - PATZ1 expression correlates positively with BAX and negatively with BCL6 and survival in human diffuse large B cell lymphomas. AB - Non-Hodgkin lymphomas (NHLs) include a heterogeneous group of diseases, which differ in both cellular origin and clinical behavior. Among the aggressive malignancies of this group, the diffuse large B-cell lymphomas (DLBCLs) are the most frequently observed. They are themselves clinically and molecularly heterogeneous and have been further sub-divided in three sub-types according to different cell of origin, mechanisms of oncogenesis and clinical outcome. Among them, the germinal center B-cell-like (GCB) derives from the germinal center and expresses the BCL6 oncogene. We have previously shown that Patz1-knockout mice develop B-cell neoplasias, suggesting a tumor suppressor role for PATZ1 in human NHLs. Here, by immunohistochemical analysis of a tissue-microarray including 170 NHLs, we found that PATZ1 nuclear expression is down-regulated in follicular lymphomas and DLBCLs. Moreover, consistent with our previous results showing a PATZ1-dependent regulation of BCL6 and BAX transcription, we show that low PATZ1 nuclear expression significantly correlates with high BCL6 expression, mainly in DLBCLs, and with low BAX expression, also considering separately follicular lymphomas and DLBCLs. Finally, by analyzing overall and progression-free survival in DLBCL patients that underwent rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, low levels of PATZ1 were significantly associated to a worst outcome and demonstrated an independent prognostic factor in multivariate analysis, including known prognostic factors of DLBCL, IPI score and cell of origin (GCB/non-GCB). Therefore, we propose PATZ1 as a new prognostic marker of DLBCLs, which may act as a tumor suppressor by enhancing apoptosis through inhibiting and enhancing transcription of BCL6 and BAX, respectively. PMID- 27494853 TI - Met promotes the formation of double minute chromosomes induced by Sei-1 in NIH 3T3 murine fibroblasts. AB - BACKGROUND: Sei-1 is an oncogene capable of inducing double minute chromosomes (DMs) formation. DMs are hallmarks of amplification and contribute to oncogenesis. However, the mechanism of Sei-1 inducing DMs formation remains unelucidated. RESULTS: DMs formation significantly increased during serial passage in vivo and gradually decreased following culture in vitro. micro nuclei (MN) was found to be responsible for the reduction. Of the DMs-carrying genes, Met was found to be markedly amplified, overexpressed and highly correlated with DMs formation. Inhibition of Met signaling decreased the number of DMs and reduced the amplification of the DMs-carrying genes. We identified a 3.57Mb DMs representing the majority population, which consists of the 1.21 Mb AMP1 from locus 6qA2 and the 2.36 Mb AMP2 from locus 6qA2-3. MATERIALS AND METHODS: We employed NIH-3T3 cell line with Sei-1 overexpression to monitor and characterize DMs in vivo and in vitro. Array comparative genome hybridization (aCGH) and fluorescence in situ hybridization (FISH) were performed to reveal amplification regions and DMs-carrying genes. Metaphase spread was prepared to count the DMs. Western blot and Met inhibition rescue experiments were performed to examine for involvement of altered Met signaling in Sei-1 induced DMs. Genomic walking and PCR were adopted to reveal DMs structure. CONCLUSIONS: Met is an important promotor of DMs formation. PMID- 27494855 TI - Next generation multi-scale biophysical characterization of high precision cancer particle radiotherapy using clinical proton, helium-, carbon- and oxygen ion beams. AB - The growing number of particle therapy facilities worldwide landmarks a novel era of precision oncology. Implementation of robust biophysical readouts is urgently needed to assess the efficacy of different radiation qualities. This is the first report on biophysical evaluation of Monte Carlo simulated predictive models of prescribed dose for four particle qualities i.e., proton, helium-, carbon- or oxygen ions using raster-scanning technology and clinical therapy settings at HIT. A high level of agreement was found between the in silico simulations, the physical dosimetry and the clonogenic tumor cell survival. The cell fluorescence ion track hybrid detector (Cell-Fit-HD) technology was employed to detect particle traverse per cell nucleus. Across a panel of radiobiological surrogates studied such as late ROS accumulation and apoptosis (caspase 3/7 activation), the relative biological effectiveness (RBE) chiefly correlated with the radiation species-specific spatio-temporal pattern of DNA double strand break (DSB) formation and repair kinetic. The size and the number of residual nuclear gamma H2AX foci increased as a function of linear energy transfer (LET) and RBE, reminiscent of enhanced DNA-damage complexity and accumulation of non-repairable DSB. These data confirm the high relevance of complex DSB formation as a central determinant of cell fate and reliable biological surrogates for cell survival/ RBE. The multi-scale simulation, physical and radiobiological characterization of novel clinical quality beams presented here constitutes a first step towards development of high precision biologically individualized radiotherapy. PMID- 27494857 TI - Visceral fat adipocytes from obese and colorectal cancer subjects exhibit distinct secretory and omega6 polyunsaturated fatty acid profiles and deliver immunosuppressive signals to innate immunity cells. AB - Obesity is a low-grade chronic inflammatory state representing an important risk factor for colorectal cancer (CRC). Adipocytes strongly contribute to inflammation by producing inflammatory mediators. In this study we investigated the role of human visceral fat adipocytes in regulating the functions of innate immunity cells. Adipocyte-conditioned media (ACM) from obese (n = 14) and CRC (lean, n = 14; obese, n = 13) subjects released higher levels of pro inflammatory/immunoregulatory factors as compared to ACM from healthy lean subjects (n = 13). Dendritic cells (DC), differentiated in the presence of ACM from obese and CRC subjects, expressed elevated levels of the inhibitory molecules PD-L1 and PD-L2, and showed a reduced IL-12/IL-10 ratio in response to both TLR ligand- and gammadelta T lymphocyte-induced maturation. Furthermore, CRC patient-derived ACM inhibited DC-mediated gammadelta T cell activation. The immunosuppressive signals delivered by ACM from obese and CRC individuals were associated with a pro-inflammatory secretory and omega6 polyunsaturated fatty acid profile of adipocytes. Interestingly, STAT3 activation in adipocytes correlated with dihomo-gammalinolenic acid content and was further induced by arachidonic acid, which conversely down-modulated PPARgamma. These results provide novel evidence for a cross-talk between human adipocytes and innate immunity cells whose alteration in obesity and CRC may lead to immune dysfunctions, thus setting the basis for cancer development. PMID- 27494858 TI - Dichloroacetate potentiates tamoxifen-induced cell death in breast cancer cells via downregulation of the epidermal growth factor receptor. AB - Metabolic reprogramming in cancer cells has recently been recognized as an essential hallmark of neoplasia. In this context, metabolic alterations represent an attractive therapeutic target, and encouraging results with drugs targeting various metabolic processes have been obtained in preclinical studies. Recently, several studies have suggested that dichloroacetate (DCA), a specific pyruvate dehydrogenase kinase inhibitor, may be a potential anticancer drug in a large number of diverse tumors. However, the precise mechanism is not fully understood, which is important for the use of DCA in cancer treatment. In the present study, we found that DCA sensitized MCF7 breast cancer cells to tamoxifen-induced cell death by decreasing epidermal growth factor receptor (EGFR) expression. The downregulation of EGFR was caused by degradation of the protein. Furthermore, p38 mitogen-activated protein kinase played an important role in DCA/tamoxifen induced EGFR degradation. Finally, DCA also promoted comparable tamoxifen-induced cell death in tamoxifen-resistant MCF7 cells, which were established by long-term treatment with tamoxifen. In summary, our results suggest that DCA is an attractive potential drug that sensitizes cells to tamoxifen-induced cell death and overcome tamoxifen resistance via downregulation of EGFR expression in breast cancer cells. PMID- 27494859 TI - MiRNA-22 inhibits oncogene galectin-1 in hepatocellular carcinoma. AB - Hepatic stellate cells (HSCs) induce immune privilege and promote hepatocellular carcinoma (HCC) by suppressing the immune system. On the other hand, galectin-1 and miRNA-22 (miR-22) are dysregulated in HCC and serve as prognostic indicators for patients. In this study, therefore, we measured galectin-1 and miR-22 expression in HSCs isolated from HCC tissues (Ca-HSCs), and in normal liver tissues (N-HSCs) as a control. We also investigated the apoptosis rate among T cells and the production of cytokines (IFN-gamma and IL-10) in HSCs co-cultured with T cells. And we used immunohistochemical staining to tested for correlation between galectin-1 expression, CD3 expression and clinicopathological features in 162 HCC patients. Our results showed that galectin-1 expression was much higher in Ca-HSCs than in N-HSCs. Overexpression of galectin-1 promoted HSC-induced T cell apoptosis and cytokine production (IFN-gamma and IL-10), while miR-22 expression inhibited it. Galectin-1 expression correlated negatively with miR-22 expression in HSCs. High galectin-1 and low CD3 expression levels were associated with poor prognosis in HCC patients. These results suggest that the immunosuppressive microenvironment promoted by HSC-derived galectin-1 in HCC can be inhibited by miR-22. Galectin-1 and miR-22 could potentially serve as prognostic markers and therapeutic targets in HCC. PMID- 27494860 TI - Apatinib inhibits cellular invasion and migration by fusion kinase KIF5B-RET via suppressing RET/Src signaling pathway. AB - The Rearranged during transfection (RET) fusion gene is a newly identified oncogenic mutation in non-small cell lung cancer (NSCLC). The aim of this study is to explore the biological functions of the gene in tumorigenesis and metastasis in RET gene fusion-driven preclinical models. We also investigate the anti-tumor activity of Apatinib, a potent inhibitor of VEGFR-2, PDGFR-beta, c-Src and RET, in RET-rearranged lung adenocarcinoma, together with the mechanisms underlying. Our results suggested that KIF5B-RET fusion gene promoted cell invasion and migration, which were probably mediated through Src signaling pathway. Apatinib exerted its anti-cancer effect not only via cytotoxicity, but also via inhibition of migration and invasion by suppressing RET/Src signaling pathway, supporting a potential role for Apatinib in the treatment of KIF5B-RET driven tumors. PMID- 27494861 TI - Decreased fucosylated PSA as a urinary marker for high Gleason score prostate cancer. AB - Fucosylation is an important oligosaccharide modification associated with cancer and inflammation. We investigated whether urinary fucosylated PSA (Fuc-PSA) levels could be used for the detection of high Gleason score prostate cancer. Urine samples were collected from men with abnormal digital rectal examination findings or elevated serum PSA levels, before prostate biopsy. Lectin-antibody ELISA was used to quantify the Lewis-type or core-type fucosylated PSA (PSA-AAL) and core-type fucosylated PSA (PSA-PhoSL) in the urine samples. Both types of urinary Fuc-PSA were significantly decreased in the men with prostate cancer compared with the men whose biopsies were negative for cancer (P = 0.026 and P < 0.001, respectively). Both were also significantly associated with the Gleason scores of the biopsy specimens (P = 0.001 and P < 0.001, respectively). Multivariate analysis showed that PSA density, urinary PSA-AAL, and urinary PSA PhoSL were independent predictors of high Gleason score prostate cancer. The area under the receiver-operator characteristic curve (AUC) value for the prediction of cancers of Gleason score >= 7 was 0.69 for urinary PSA-AAL and 0.72 for urinary PSA-PhoSL. In contrast, the AUC value was 0.59 for serum PSA, 0.63 for PSA density, and 0.58 for urinary PSA. In conclusion, a decreased urinary Fuc-PSA level is a potential marker for the detection of high Gleason score prostate cancer. PMID- 27494862 TI - Destabilisation, aggregation, toxicity and cytosolic mislocalisation of nucleophosmin regions associated with acute myeloid leukemia. AB - Nucleophosmin (NPM1) is a multifunctional protein that is implicated in the pathogenesis of several human malignancies. To gain insight into the role of isolated fragments of NPM1 in its biological activities, we dissected the C terminal domain (CTD) into its helical fragments. Here we focus the attention on the third helix of the NPM1-CTD in its wild-type (H3 wt) and AML-mutated (H3 mutA and H3 mutE) sequences. Conformational studies, by means of CD and NMR spectroscopies, showed that the H3 wt peptide was partially endowed with an alpha helical structure, but the AML-sequences exhibited a lower content of this conformation, particularly the H3 mutA peptide. Thioflavin T assays showed that the H3 mutE and the H3 mutA peptides displayed a significant aggregation propensity that was confirmed by CD and DLS assays. In addition, we found that the H3 mutE and H3 mutA peptides, unlike the H3 wt, were moderately and highly toxic, respectively, when exposed to human neuroblastoma cells. Cellular localization experiments confirmed that the mutated sequences hamper their nucleolar accumulation, and more importantly, that the helical conformation of the H3 region is crucial for such a localization. PMID- 27494863 TI - Guttiferone K suppresses cell motility and metastasis of hepatocellular carcinoma by restoring aberrantly reduced profilin 1. AB - Hepatocellular carcinoma (HCC) is an aggressive malignancy and the 5-year survival rate of advanced HCC is < 10%. Guttiferone K (GUTK) isolated from the Garcinia genus inhibited HCC cells migration and invasion in vitro and metastasis in vivo without apparent toxicity. Proteomic analysis revealed that actin-binding protein profilin 1 (PFN1) was markedly increased in the presence of GUTK. Over expression of PFN1 mimicked the effect of GUTK on HCC cell motility and metastasis. The effect of GUTK on cell motility was diminished when PFN1 was over expressed or silenced. Over-expression of PFN1 or incubation with GUTK decreased F-actin levels and the expression of proteins involved in actin nucleation, branching and polymerization. Moreover, a reduction of PFN1 protein levels was common in advanced human HCC and associated with poor survival rate. In conclusion, GUTK effectively suppresses the motility and metastasis of HCC cells mainly by restoration of aberrantly reduced PFN1 protein expression. PMID- 27494865 TI - Lin28A activates androgen receptor via regulation of c-myc and promotes malignancy of ER-/Her2+ breast cancer. AB - Having previously demonstrated the co-expression status of the Lin28A and androgen receptor (AR) in ER-/Her2+ breast cancer, we tested the hypothesis that Lin28A can activate AR and promotes growth of ER-/Her2+ breast cancer. The expression of Lin28A and AR were examined after Lin28A siRNA and Lin28A plasmid were transfected into ER-/Her2+ breast cancer cells. Chromatin immune precipitation (ChIP) analysis and Luciferase Assays were used to evaluate the effect of Lin28A and c-myc on AR promoter activity. MTT assays, Boyden chamber invasion assays, colony formation assays and flow cytometry analysis were performed. ER-/Her2+ breast cancer cells which transfected with Lin28A siRNAs and Lin28A plasmid were injected into nude mice, and tumorigenesis was monitored. Our data showed that Lin28A can induced AR expression in ER-/Her2+ breast cancer cells. ChIP analysis showed that Lin28A stimulates the recruitment of c-Myc to the promoter of the AR gene. Lin28A enhanced growth ability, colonies ability, cells proliferation activities, invasive ability and inhibited cells apoptosis of ER-/Her2+ breast cancer cells. Lin28A high expression cells exhibited significantly higher tumorigenic ability in vivo. Our study demonstrates that Lin28A can activates androgen receptor via regulation of c-myc and promotes malignancy of ER-/Her2+ breast cancer. Our findings underline a novel role for Lin28A in breast cancer development and activation of the AR axis. PMID- 27494866 TI - Whether regional lymph nodes evaluation should be equally required for both right and left colon cancer. AB - Despite the adequacy of nodal evaluation was gradually improved for colon cancer, the disparity in nodal examination for right colon cancer (RCC) and left colon cancer (LCC) still begs the question of whether 12 nodes is an appropriate threshold for both RCC and LCC. From Surveillance, Epidemiology, and End-Results (SEER) database, we identified 53897 RCC patients and 11822 LCC patients. Compared with LCC patients, RCC patients examined more lymph nodes (18.7 vs 16.3), and more likely to examine >=12 nodes (P<0.001), whereas RCC patients showed lower rates of node positivity (P<0.001). To balance the nodal disparity between RCC and LCC, we revised the 12-node measure based on different tumor locations. With the X-tile, we determined 15 as the optimal node number for RCC and 11 for LCC. To validate the availability of this revised nodal evaluation, the 5-year cancer specific survival (CSS) was calculated according to the optimal node number in RCC and LCC patients, Cox's regression model were used to further assess the prognostic value of this revised nodal evaluation. The results showed that 5-year CSSs were significantly improved for RCC patients with >=15 lymph nodes, and also for LCC patients with >=11 lymph nodes (P<0.001). This revised nodal evaluation could also improve the rate of nodal positivity and long-term survival in both RCC and LCC patients compared with 12-node measure. Therefore, the lymph node examination should be discriminately evaluated for RCC and LCC, instead of using 12-node measure to colon cancer as a whole. PMID- 27494867 TI - Endoplasmic reticulum stress induces secretion of high-mobility group proteins and is associated with tumor-infiltrating lymphocytes in triple-negative breast cancer. AB - BACKGROUND: Although the prognostic and predictive significance of tumor infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC) have been shown, the cause of the TIL influx is unclear. Here, we investigated whether extracellular secretion of HMGN1 is associated with TIL influx, as well as increased endoplasmic reticulum stress (ERS), in human TNBC. METHODS: We reviewed the slides of 767 patients with TNBC and evaluated the TIL levels. We also assessed the expression of HMGs and several ERS-associated molecules using immunohistochemical staining. Western blot analysis of human TNBC cell lines and pharmacological ERS inducers was used to determine if HMGN1 migrates from the nucleus to the extracellular space in response to ERS. RESULTS: On immunohistochemical staining, either higher nuclear or cytoplasmic expression of both HMGB1 and HMGN1 was significantly associated with ERS. TILs showed a positive correlation with the cytoplasmic expression of the HMGs. Western blot analysis of TNBC cell lines showed that ERS induction resulted in the secretion of HMG proteins. CONCLUSIONS: This is the first study to elucidate the associations among ERS, secretion of HMGs, and degree of TILs in TNBCs. Understanding the mechanisms of TIL influx will help in the development of effective immunotherapeutic agents for TNBC. PMID- 27494868 TI - A lupus anti-DNA autoantibody mediates autocatalytic, targeted delivery of nanoparticles to tumors. AB - Strategies to target nanoparticles to tumors that rely on surface modification with ligands that bind molecules overexpressed on cancer cells or the tumor neovasculature suffer from a major limitation: with delivery of toxic agents the amount of molecules available for targeting decreases with time; consequently, the efficiency of nanoparticle delivery is reduced. To overcome this limitation, here we propose an autocatalytic tumor-targeting mechanism based on targeting extracellular DNA (exDNA). exDNA is enriched in the tumor microenviroment and increases with treatment with cytotoxic agents, such as doxorubicin (DOX), due to release of DNA by dying tumor cells. We tested this approach using poly(lactic-co glycolic acid) (PLGA) nanoparticles surface-conjugated with fragments of 3E10 (3E10EN), a lupus anti-DNA autoantibody. We demonstrated that 3E10EN-conjugated nanoparticles bound to DNA and preferentially localized to tumors in vivo. The efficiency of tumor localization of 3E10EN-conjugated, DOX-loaded nanoparticles increased with time and subsequent treatments, demonstrating an autocatalytic effect. 3E10EN-conjugated DOX-loaded nanoparticles exhibited a significant anti tumor effect that was superior to all controls. This work demonstrates the promise of autocatalytic drug delivery mechanisms and establishes proof of concept for a new anti-DNA autoantibody-based approach for enhancing delivery of nanoparticles to tumors. PMID- 27494869 TI - miR-450b-5p induced by oncogenic KRAS is required for colorectal cancer progression. AB - The development and progression of CRC are regarded as a complicated network and progressive event including genetic and/or epigenetic alterations. Recent researches revealed that MicroRNAs are biomarkers and regulators of CRC progression. Analyses of published microarray datasets revealed that miR-450b-5p was highly up-regulated in CRC tissues. In addition, high expression of miR-450b 5p was significantly associated with KRAS mutation. However, the role of miR-450b 5p in the progression of CRC remains unknown. Here, we sought to validate the expression of miR-450b-5p in CRC tissues and investigate the role and underlying mechanism of miR-450b-5p in the progression of CRC. The results revealed that miR 450b-5p was up-regulated in CRC tissues, high expression level of miR-450b-5p was positively associated with poor differentiation, advanced TNM classification and poor prognosis. Moreover, miR-450b-5p was especially high in KRAS-mutated cell lines and could be up-regulated by KRAS/AP-1 signaling. Functional validation revealed that overexpression of miR-450b-5p promoted cell proliferation and tumor growth while inhibited apoptosis of CRC cells. Furthermore, we demonstrated that miR-450b-5p directly bound the 3'-UTRs of SFRP2 and SIAH1, and activated Wnt/beta Catenin signaling. In conclusion, miR-450b-5p induced by oncogenic KRAS is required for colorectal cancer progression. Collectively, our work helped to understand the precise role of miR-450b-5p in the progression of CRC, and might promote the development of new therapeutic strategies against CRC. PMID- 27494870 TI - Novel antibody probes for the characterization of endosialin/TEM-1. AB - Endosialin (Tumor Endothelial Marker-1 (TEM-1), CD248) is primarily expressed on pericytes of tumor-associated microvasculature, tumor-associated stromal cells and directly on tumors of mesenchymal origin, including sarcoma and melanoma. While the function of endosialin/TEM-1 is incompletely understood, studies have suggested a role in supporting tumor growth and invasion thus making it an attractive therapeutic target. In an effort to further understand its role in cancer, we previously developed a humanized anti-endosialin/TEM-1 monoclonal antibody (mAb), called ontuxizumab (MORAb-004) for testing in preclinical and clinical studies. We herein report on the generation of an extensive panel of recombinant endosialin/TEM-1 protein extracellular domain (ECD) fragments and novel mAbs against ECD motifs. The domain-specific epitopes were mapped against ECD sub-domains to identify those that can detect distinct structural motifs and can be potentially formatted as probes suitable for diagnostic and functional studies. A number of mAbS were shown to cross-react with the murine and human protein, potentially allowing their use in human animal models and corresponding clinical trials. In addition, pairing of several mAbs supported their use in immunoassays that can detect soluble endosialin/TEM-1 (sEND) in the serum of healthy subjects and cancer patients. PMID- 27494871 TI - Role of transarterial chemoembolization in relation with sorafenib for patients with advanced hepatocellular carcinoma. AB - BACKGROUND: Although sorafenib is considered standard therapy for advanced hepatocellular carcinoma (HCC), actual treatments vary. We evaluated the effects of different treatment strategies on overall survival. METHODS: A retrospective study of sorafenib-treated patients with advanced HCC was conducted. The primary outcome was overall survival. Prognostic factors were analyzed using multivariate Cox-proportional hazards model. RESULTS: A total of 658 patients (mean age, 54.5 years; 83.3% male) were analyzed; 293, 129, and 236 patients were treated with sorafenib, a combination therapy of sorafenib and transarterial chemoembolization (TACE), and TACE followed by sorafenib, respectively. Overall, 51.2% of patients treated under the combination strategy had portal vein invasion, whereas 89.9% of patients receiving sorafenib monotherapy had distant metastasis. Median overall survival durations were comparable (11.8 months for sorafenib, 16.2 months for the combination therapy, and 13.5 months for TACE followed by sorafenib; P = 0.13). However, among portal vein invasion cases, combination (25.7 months, P = 0.002) and TACE followed by sorafenib (14.0 months, P = 0.030) treatments were associated with longer overall survival duration compared with than sorafenib monotherapy (5.5 months). In a multivariate model, sorafenib duration (hazard ratio [HR], 0.96, P < 0.001) and TACE (HR, 0.24, P < 0.001) along with Child-Pugh stage (HR, 1.83, P = 0.005) were associated with better survival. CONCLUSIONS: In patients with portal vein invasion, TACE performed concurrently with or before sorafenib administration is associated with better survival. PMID- 27494872 TI - Role of micro-RNAs in drug resistance of multiple myeloma. AB - While novel therapeutic approaches have profoundly improved survival of multiple myeloma (MM) patients, drug resistance and treatment refractoriness still persists. This obstacle highly demands thorough investigation into the root and underlying molecular mechanisms to develop more effective strategies. The advent of micro-RNAs (miRNAs) in the study of cancer biology and pathogenesis in recent years has revolutionized therapy in this field and particularly opened new windows to further understanding of tumor drug resistance. However; in spite of the fact that miRNAs involvement in MM pathogenesis and progression has been substantially evidenced, miRNA investigation in MM drug resistance is still in its infancy. Our knowledge of the potential role of miRNAs in MM drug resistance comes from few recent reports confirming that some miRNAs including miR-137/197, miR-21 and miR-221/222 could negatively modulate drug sensitivity of MM cells. Further continuous researches are required to exploit miRNAs to elucidate the critical mechanisms controlling drug resistance in MM. In this review, we will highlight the most recent observations on the role of miRNAs in MM drug resistance. Moreover, approaches and insights into clinical application of miRNAs to overcome MM drug resistance will be discussed. PMID- 27494873 TI - Combinatorial therapeutic targeting of BMP2 and MEK-ERK pathways in NF1 associated malignant peripheral nerve sheath tumors. AB - The clinical management of malignant peripheral nerve sheath tumors (MPNSTs) is challenging not only due to its aggressive and invasive nature, but also limited therapeutic options. Using gene expression profiling, our lab identified BMP2 SMAD1/5/8 pathway as a potential therapeutic target for treating MPNSTs. In this study, we explored the therapeutic impact of targeting BMP2-SMAD1/5/8 pathway in conjunction with RAS-MEK-ERK signaling, which is constitutively activated in MPNSTs. Our results indicated that single agent treatment with LDN-193189, a BMP2 Type I receptor inhibitor, did not affect the growth and survival of MPNST cells at biochemically relevant inhibitory concentrations. However, addition of a MEK1/2 inhibitor, selumetinib, to LDN-193189-treated cells resulted in significant inhibition of cell growth and induction of cell death. LDN-193189 at biochemically effective concentrations significantly inhibited motility and invasiveness of MPNST cells, and these effects were enhanced by the addition of selumetinib. Overall, our results advocate for a combinatorial therapeutic approach for MPNSTs that not only targets the growth and survival via inhibition of MEK1/2, but also its malignant spread by suppressing the activation of BMP2 SMAD1/5/8 pathway. Importantly, these studies were conducted in low-passage patient-derived MPNST cells, allowing for an investigation of the effects of the proposed drug treatments in a biologically-relevant context. PMID- 27494874 TI - Clock gene Per2 as a controller of liver carcinogenesis. AB - Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine (DEN) exposure according to constitutive Per2 mutation. First, we found that Per2m/m liver displayed profound alterations in proliferation gene expression, including c-Myc derepression, phase-advanced Wee1, and arrhythmic Ccnb1 and K-ras mRNA expressions, as well as deregulated inflammation, through arrhythmic liver IL-6 protein concentration, in the absence of any DEN exposure. These changes could then make Per2m/m mice more prone to subsequently develop liver cancers on DEN. Indeed, primary liver cancers were nearly fourfold as frequent in Per2m/m mice as compared to wild-type (WT), 4 months after DEN exposure. The liver molecular clock was severely disrupted throughout the whole carcinogenesis process, including the initiation stage, i.e. within the initial 17 days on DEN. Per2m/m further exhibited increased c-Myc and Ccnb1 mean 24h expressions, lack of P53 response, and arrhythmic ATM, Wee1 and Ccnb1 expressions. DEN-induced tumor related inflammation was further promoted through increased protein concentrations of liver IL-6 and TNF-alpha as compared to WT during carcinogenesis initiation. Per2 mutation severely deregulated liver gene or protein expressions related to three cancer hallmarks, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold. Clock gene Per2 acted here as a liver tumor suppressor from initiation to progression. PMID- 27494875 TI - Spatial distribution of FoxP3+ and CD8+ tumour infiltrating T cells reflects their functional activity. AB - BACKGROUND: Regulatory and cytotoxic T cells are key players in the host's anticancer immune response. We studied the spatial distribution of FoxP+ and CD8+ cells to identify potential interactions. METHODS: In 202 patients 103 pre radiochemotherapy biopsies and 153 post-radiochemotherapy tumour specimens of advanced rectal cancer were available and an immunohistochemical double staining of FoxP3+ and CD8+ tumour-infiltrating lymphocytes was performed to investigate cell density and cell-to-cell distances. RESULTS: FoxP3+ cells decreased after radiochemotherapy by a factor of 3 while CD8+ cells remained nearly unchanged. High epithelial (p=0.033) and stromal (p=0.009) FoxP3+ cell density was associated with an improved overall survival. Cell-to-cell distances of randomly distributed cells were simulated and compared to observed cell-to-cell distances. Observed distances shorter than the simulated, random distances were hypothesized to represent FoxP3+ cells actively interacting with CD8+ cells. Epithelial short distances were associated with a favourable prognosis while the opposite was true for the stromal compartment. CONCLUSION: The analysis of cell-to-cell distances may offer a tool to predict outcome, maybe by identifying functionally active, interacting infiltrating inflammatory cells in different tumour compartments. PMID- 27494876 TI - Xanthine oxidoreductase is required for genotoxic stress-induced NKG2D ligand expression and gemcitabine-mediated antitumor activity. AB - MICA/B (the major histocompatibility antigen-related chain A and B) and Rae I are stress-inducible ligands for the immune-receptor NKG2D. Mechanisms by which genotoxic stress and DNA damage induce the expression of NKG2D ligands remain incompletely understood. Here, we report that inhibition of xanthine oxidoreductase (XOR) activity by allopurinol or inhibition of XOR expression by gene knockdown abrogated genotoxic stress-induced expression of MICA/B and Rae I in three tumor cell lines. XOR knockdown also blocked gemcitabine-mediated antitumor activity in an orthotopic syngeneic mouse model of breast cancer. As a rate-limiting enzyme in the purine catabolic pathway, XOR generates two end products, uric acid and reactive oxygen species (ROS). ROS scavenging had an insignificant effect on genotoxic drug-induced MICA/B expression but modestly inhibited radiation-induced MICA/B expression. Exogenous uric acid (in the form of monosodium urate) induced MICA/B expression by activating the MAP kinase pathway. Allopurinol blocked genotoxic stress-induced MAP kinase activation. Our study provides mechanistic insights into genotoxic stress-induced activation of the MAP kinase pathway and suggests that XOR is required for genotoxic stress induced NKG2D ligand expression and gemcitabine-mediated antitumor activity. PMID- 27494877 TI - FOXM1 confers resistance to gefitinib in lung adenocarcinoma via a MET/AKT dependent positive feedback loop. AB - Gefitinib resistance remains a major problem in the treatment of lung adenocarcinoma. However, the molecular mechanisms of gefitinib resistance are not fully understood. In this study, we characterized the critical role of transcription factor Forkhead box protein M1 (FOXM1) in gefitinib resistance of lung adenocarcinoma cells. In vitro drug sensitivity assays demonstrated that FOXM1 inhibition sensitized PC9/GR and HCC827/GR cells to gefitinib, whereas FOXM1 overexpression enhanced PC9 and HCC827 cell resistance to gefitinib. Increased FOXM1 resulted in the upregulation of hepatocyte growth factor receptor (MET), which led to activation of the protein kinase B (AKT) pathway, whereas knockdown of FOXM1 did the opposite. FOXM1 bound directly to the MET promoter regions and regulated the promoter activities and the expression of MET at the transcriptional level. Moreover, MET/AKT pathway upregulated the expression of FOXM1 in lung adenocarcinoma cells. Inhibition of pAKT by LY294002 or inhibition of pMET by PHA-665752 significantly inhibited the expression of FOXM1 in lung adenocarcinoma cells. Importantly, we further demonstrated that the expression levels of FOXM1, pAKT and MET were significantly increased in lung adenocarcinoma tissues relative to normal lung tissues, and these three biomarkers were concomitantly overexpressed in lung adenocarcinoma tissues. Taken together, our results indicate that FOXM1 promotes acquired resistance to gefitinib of lung adenocarcinoma cells, and FOXM1 crosstalks with MET/AKT signaling to form a positive feedback loop to promote lung adenocarcinoma development. PMID- 27494878 TI - CD24 promoted cancer cell angiogenesis via Hsp90-mediated STAT3/VEGF signaling pathway in colorectal cancer. AB - CD24 is involved in tumor progression of various cancers, but the effects of CD24 on tumor angiogenesis in colorectal cancer are still unknown. We aimed to investigate the underlying mechanism and role of CD24 on colorectal cancer (CRC) angiogenesis. Our data showed that the microvessal density (MVD) was related to the expression of CD24 in primary and metastasis CRC. Silencing of CD24 could dramatically decrease human umbilical vein endothelial cell (HUVEC) migration, invasion and tubule formation, but trivially affected cell proliferation. We also mechanically showed that silencing CD24 could downregulate the expression of VEGF via inhibiting the phosphorylation and translocation of STAT3. Moreover, Hsp90 was identified as the down-interaction protein of CD24 with co immunoprecipitation assay and systematic mass spectrometry. Immunofluorescence results showed Hsp90 partly co-localized with CD24 in CRC cell membrane and there was a positive correlation between CD24 and Hsp90 expression in CRC tissues. We gradually evidenced that Hsp90 modulated the stability and degradation of CD24 in a proteasome-depended manner, and transferred the signal transmission from CD24 to STAT3. 17-AAG, a specific Hsp90, could abrogate the CD24 induce- HUVEC migration, invasion and tubule formation in vitro and in vivo. Collectively, our results suggested that CD24 induced CRC angiogenesis in Hsp90-dependent manner and activated STAT3-mediated transcription of VEGF. We provided a new insight into the regulation mechanism of tumor angiogenesis by exploring the role of CD24 in angiogenesis. PMID- 27494879 TI - Epigenetic activation of LY6K predicts the presence of metastasis and poor prognosis in breast carcinoma. AB - The role of lymphocyte antigen 6 complex, locus K (LY6K) in breast cancer has been studied, whereas the epigenetic control of LY6K transcription is not fully understood. Here, we report that breast cancer patients with increased LY6K expression had shorter disease-free and overall survival than the patients with low levels of LY6K by multivariate analysis. LY6K also was upregulated in breast cancer patients with distant metastases than those without distant metastases, downregulating E-cadherin expression. Furthermore, xenograft tumor volumes from LY6K knockdown nude mice were reduced than those of mice treated with control lentivirus. Interestingly, LY6K has a CpG island (CGI) around the transcription start site and non-CGI in its promoter, called a CGI shore. LY6K expression was inversely correlated with methylation in not only CGI but CGI shore, which are associated with histone modifications. Additionally, LY6K methylation was increased by the PAX3 transcription factor due to the SNP242 mutation in LY6K CGI shore. Taken together, breast cancer risk and metastasis were significantly associated with not only LY6K expression, but also methylation of CGI shore which induced by SNP242 mutation. Our results suggest that an understanding epigenetic mechanism of the LY6K gene may be useful to diagnose carcinogenic risk and predict outcomes of patients with metastatic breast cancer. PMID- 27494880 TI - Predicting the cell death responsiveness and sensitization of glioma cells to TRAIL and temozolomide. AB - Genotoxic chemotherapy with temozolomide (TMZ) is a mainstay of treatment for glioblastoma (GBM); however, at best, TMZ provides only modest survival benefit to a subset of patients. Recent insight into the heterogeneous nature of GBM suggests a more personalized approach to treatment may be necessary to overcome cancer drug resistance and improve patient care. These include novel therapies that can be used both alone and with TMZ to selectively reactivate apoptosis within malignant cells. For this approach to work, reliable molecular signatures that can accurately predict treatment responsiveness need to be identified first. Here, we describe the first proof-of-principle study that merges quantitative protein-based analysis of apoptosis signaling networks with data- and knowledge driven mathematical systems modeling to predict treatment responsiveness of GBM cell lines to various apoptosis-inducing stimuli. These include monotherapies with TMZ and TRAIL, which activate the intrinsic and extrinsic apoptosis pathways, respectively, as well as combination therapies of TMZ+TRAIL. We also successfully employed this approach to predict whether individual GBM cell lines could be sensitized to TMZ or TRAIL via the selective targeting of Bcl-2/Bcl-xL proteins with ABT-737. Our findings suggest that systems biology-based approaches could assist in personalizing treatment decisions in GBM to optimize cell death induction. PMID- 27494881 TI - Expression of the p66Shc protein adaptor is regulated by the activator of transcription STAT4 in normal and chronic lymphocytic leukemia B cells. AB - p66Shc attenuates mitogenic, prosurvival and chemotactic signaling and promotes apoptosis in lymphocytes. Consistently, p66Shc deficiency contributes to the survival and trafficking abnormalities of chronic lymphocytic leukemia (CLL) B cells. The mechanism of p66shc silencing in CLL B cells is methylation independent, at variance with other cancer cell types. Here we identify STAT4 as a novel transcriptional regulator of p66Shc in B cells. Chromatin immunoprecipitation and reporter gene assays showed that STAT4 binds to and activates the p66shc promoter. Silencing or overexpression of STAT4 resulted in a co-modulation of p66Shc. IL-12-dependent STAT4 activation caused a coordinate increase in STAT4 and p66Shc expression, which correlated with enhanced B cell apoptosis. Treatment with the STAT4 inhibitor lisofylline reverted partly this effect, suggesting that STAT4 phosphorylation is not essential for but enhances p66shc transcription. Additionally, we demonstrate that CLL B lymphocytes have a STAT4 expression defect which partly accounts for their p66Shc deficiency, as supported by reconstitution experiments. Finally, we show that p66Shc participates in a positive feedback loop to promote STAT4 expression. These results provide new insights into the mechanism of p66Shc expression in B cells and its defect in CLL, identifying the STAT4/IL-12 pathway as a potential therapeutic target in this neoplasia. PMID- 27494882 TI - Simultaneous targeting of Eph receptors in glioblastoma. AB - Eph tyrosine kinase receptors are frequently overexpressed and functional in many cancers, and they are attractive candidates for targeted therapy. Here, we analyzed the expression of Eph receptor A3, one of the most up-regulated factors in glioblastoma cells cultured under tumorsphere-forming conditions, together with EphA2 and EphB2 receptors. EphA3 was overexpressed in up to 60% of glioblastoma tumors tested, but not in normal brain. EphA3 was localized in scattered areas of the tumor, the invasive ring, and niches near tumor vessels. EphA3 co-localized with macrophage/leukocyte markers, suggesting EphA3 expression on tumor-infiltrating cells of bone marrow origin. We took advantage of the fact that ephrinA5 (eA5) is a ligand that binds EphA3, EphA2 and EphB2 receptors, and used it to construct a novel targeted anti-glioblastoma cytotoxin. The eA5-based cytotoxin potently and specifically killed glioblastoma cells with an IC50 of at least 10-11 M. This and similar cytotoxins will simultaneously target different compartments of glioblastoma tumors while mitigating tumor heterogeneity. PMID- 27494883 TI - Combined cell surface carbonic anhydrase 9 and CD147 antigens enable high efficiency capture of circulating tumor cells in clear cell renal cell carcinoma patients. AB - Circulating tumor cells (CTCs) have emerged as promising tools for noninvasive cancer detection and prognosis. Most conventional approaches for capturing CTCs use an EpCAM-based enrichment strategy, which does not work well in cancers that show low or no expression of EpCAM, such as renal cell carcinoma (RCC). In this study, we developed a new set of cell surface markers including CA9 and CD147 as alternative CTC-capture antigens specifically designed for RCC patients. We showed that the expression of both CA9 and CD147 was prevalent in a RCC patient cohort (n=70) by immunohistochemical analysis, with both molecules in combination covering 97.1% of cases. The NanoVelcro platform combined with CA9-/CD147-capture antibodies demonstrated significantly higher efficiency for capturing both CTC mimicking renal cancer cells and RCC CTCs in peripheral blood, compared to the conventional EpCAM-based method. Using immunofluorescence cytological validation at the single-cell level, we were able to identify bona fide CTCs in RCC patient blood following the well-accepted criteria in our CTC-capture system. We further demonstrated a significant association of CTC numbers as well as the CTC expression status of Vimentin, a mesenchymal marker, with disease progression, including pathologic features and clinical staging. These results provide new insights into developing novel, effective targets/approaches for capturing CTCs, making CTCs a valuable tool for improved cancer detection, prognosis and treatment in RCC. PMID- 27494885 TI - Bromodomain inhibitor OTX015 (MK-8628) combined with targeted agents shows strong in vivo antitumor activity in lymphoma. AB - The bromodomain inhibitor OTX015 (MK-8628) has shown anti-lymphoma activity as a single agent in both the preclinical and clinical settings, as well as in vitro synergism with several anticancer agents. Here, we report in vivo data for OTX015 in combination with the histone deacetylase inhibitor vorinostat, the Bruton's tyrosine kinase inhibitor ibrutinib, the anti-CD20 monoclonal antibody rituximab, and the mTOR inhibitor everolimus in a diffuse large B cell lymphoma model. The antitumor effect of OTX015-containing combinations in SU-DHL-2 xenografts in mice was much stronger than the activity of the corresponding single agents with almost complete tumor eradication for all four combinations. Pharmacokinetic analyses showed similar OTX015 levels in plasma and tumor samples of approximately 1.5 MUM, which is equivalent to the concentration showing strong in vitro activity. For all four combinations, mean terminal levels of the bromodomain inhibitor differed from those in mice exposed to single agent OTX015, indicating a need for thorough pharmacokinetic investigations in phase I combination studies. In conclusion, our results provide a strong rationale to explore OTX015-containing combinations in the clinical lymphoma setting. PMID- 27494886 TI - Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia. AB - An attractive molecular target for novel anti-cancer therapies is the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway which is commonly deregulated in many types of cancer. Nevertheless, the effects of PI3K/Akt/mTOR inhibitors on T lymphocytes, a key component of immune responses, have been seldom explored. In this study we investigated the effects on human CD4+ T-cells of a panel of PI3K/Akt/mTOR inhibitors: BGT226, Torin-2, MK 2206, and ZSTK474. We also assessed their efficacy against two acute leukemia T cell lines. T lymphocytes were stimulated with phytohemagglutinin. Inhibitor effects on cell cycle and apoptosis were analyzed by flow cytometry, while cytotoxicity was assessed by MTT assays. In addition, the activation status of the pathway as well as induction of autophagy were analyzed by Western blotting. Quiescent healthy T lymphocytes were unaffected by the drugs whereas mitogen stimulated lymphocytes as well as leukemic cell lines displayed a cell cycle block, caspase-dependent apoptosis, and dephosphorylation of key components of the signaling pathway. Autophagy was also induced in proliferating lymphocytes and in JURKAT and MOLT-4 cell lines. When autophagy was inhibited by 3 methyladenine or Bafilomycin A1, drug cytotoxicity was increased, indicating that autophagy is a protective mechanism. Therefore, our findings suggest that PI3K/Akt/mTOR inhibitors preserve lymphocyte viability. This is a valuable result to be taken into account when selecting drugs for targeted cancer therapy in order to minimize detrimental effects on immune function. PMID- 27494887 TI - Ablation of human telomerase reverse transcriptase (hTERT) induces cellular senescence in gastric cancer through a galectin-3 dependent mechanism. AB - The human Telomerase Reverse Transcriptase (hTERT) gene encodes a rate-limiting catalytic subunit of telomerase that maintains genomic integrity. Suppression of hTERT expression could induce cellular senescence and is considered a potent approach for gastric cancer therapy. However, control of hTERT expression and function remains poorly understood in gastric cancer. In this study, we demonstrated that high expression levels of hTERT in malignant tissues are correlated with poor survival probability in gastric cancer patients. Knockdown of hTERT expression retarded cell proliferation and cellular senescence, which was confirmed by increased protein expression levels of p21cip1 and p27kip1, and decreased phosphorylation of Rb. In contrast, overexpression of hTERT increased cell proliferation and decreased cellular senescence. Remarkably, the down regulation of hTERT expression was detected in lgals3-/- mouse embryo fibroblasts (MEFs). Knockdown of galectin-3 decreased the expression of hTERT in gastric cancer cells. Galectin-3 ablation-induced cellular senescence was rescued by concomitant overexpression of hTERT. hTERT ablation-induced cellular senescence and p21cip1 and p27kip1 expression was rescued by concomitant overexpression of galectin-3. The size of tumor burdens was increased in hTERT-overexpressed gastric cancer cells xenografted mice, whereas it was repressed by concomitant depletion of galectin-3. Additionally, we determined that the N-terminal domain of galectin-3 directly interacted with hTERT. The telomeric activity of hTERT was also decreased by galectin-3 ablation. Taken together, ablation of hTERT induces cellular senescence and inhibits the growth of gastric cancer cells, suggesting that it could be a potent target in gastric cancer therapy. We also propose that galectin-3 is an important regulator of hTERT expression and telomeric activity in gastric tumorigenesis. PMID- 27494889 TI - Stathmin overexpression is associated with growth, invasion and metastasis of lung adenocarcinoma. AB - Stathmin has been investigated as a tumor biomarker because it appear to be associated with tumorigenesis; however, the effect of stathmin in lung adenocarcinoma (LAC) remains poorly understood. The purpose of this study was to examine the expression of stathmin in lung adenocarcinoma, and to disclose the relationship between them. The expression of stathmin was examined by RT-PCR, IHC and Western blot. Furthermore, small interfering RNA (shRNA)-mediated silencing of stathmin was employed in LAC cells to investigate cell proliferation, invasion and apoptosis. In this study, we showed that overexpression of stathmin was significantly associated with poorly differentiated, lymph node metastasis and advance TNM stages of lung adenocarcinoma. And silencing of stathmin expression inhibited the proliferation, migration and invasion of lung adenocarcinoma PC-9 cells, and retarded the growth of PC-9 cells xenografts in nude mice. Additionally, the anticarcinogenic efficacy of stathmin silencing might be involved in P38 and MMP2 signaling pathways. In conclusion, these results showed that stathmin expression was significantly up-regulated in LAC, which may act as a biomarker for LAC. Furthermore, silence of stathmin inhibiting LAC cell growth indicated that stathmin may be a promising molecular target for LAC therapy. PMID- 27494888 TI - The trans-membrane domain of Bcl-2alpha, but not its hydrophobic cleft, is a critical determinant for efficient IP3 receptor inhibition. AB - The anti-apoptotic Bcl-2 protein is emerging as an efficient inhibitor of IP3R function, contributing to its oncogenic properties. Yet, the underlying molecular mechanisms remain not fully understood. Using mutations or pharmacological inhibition to antagonize Bcl-2's hydrophobic cleft, we excluded this functional domain as responsible for Bcl-2-mediated IP3Rs inhibition. In contrast, the deletion of the C-terminus, containing the trans-membrane domain, which is only present in Bcl-2alpha, but not in Bcl-2beta, led to impaired inhibition of IP3R mediated Ca2+ release and staurosporine-induced apoptosis. Strikingly, the trans membrane domain was sufficient for IP3R binding and inhibition. We therefore propose a novel model, in which the Bcl-2's C-terminus serves as a functional anchor, which beyond mere ER-membrane targeting, underlies efficient IP3R inhibition by (i) positioning the BH4 domain in the close proximity of its binding site on IP3R, thus facilitating their interaction; (ii) inhibiting IP3R channel openings through a direct interaction with the C-terminal region of the channel downstream of the channel-pore. Finally, since the hydrophobic cleft of Bcl-2 was not involved in IP3R suppression, our findings indicate that ABT-199 does not interfere with IP3R regulation by Bcl-2 and its mechanism of action as a cell-death therapeutic in cancer cells likely does not involve Ca2+ signaling. PMID- 27494890 TI - Decreased TCL6 expression is associated with poor prognosis in patients with clear cell renal cell carcinoma. AB - One-third of clear cell renal cell carcinoma (ccRCC) patients present with metastasis at the time of diagnosis. The prognosis of these patients is poor. To identify potential prognostic biomarkers and therapeutic targets for ccRCC, we re evaluated published long non-coding RNA (lncRNA) expression profiling data from the Gene Expression Omnibus and ArrayExpress database. We found that five lncRNAs were differentially expressed in ccRCC and adjacent tissues. These lncRNAs were assessed in an independent cohort of 71 paired patient samples using real-time PCR. Differences in expression of three of the lncRNAs (ENSG00000177133, TCL6, and ENSG00000244020) were validated in this analysis. Kaplan-Meier analysis indicated that low expression of ENSG00000177133 and TCL6 was associated with a poor prognosis. Univariate and multivariate regression analyses demonstrated that TCL6 but not ENSG00000177133 expression was an independent predictor of ccRCC aggressiveness and had hazard ratios predictive of clinical outcome. TCL6 expression was negatively correlated with pTNM stage. Overexpression of TCL6 in 786-O and Caki-1 ccRCC cells decreased proliferation and increased apoptosis compared to controls. Our results indicate that lncRNA expression is altered in ccRCC and that decreased TCL6 expression may be an independent adverse prognostic factor in ccRCC patients. PMID- 27494891 TI - Analysis of the chemotherapeutic effects of a propadiene compound on malignant ovarian cancer cells. AB - Epithelial ovarian cancer is most lethal in female reproductive carcinomas owing to the high chemoresistance and metastasis, so more efficient therapeutic agents are terribly needed. A propadiene compound: 1-phenylpropadienyl phosphine oxide (PHPO), was employed to test the chemotherapeutic efficacy against ovarian cancer cell lines. MTT assay showed that PHPO displayed a much lower IC50 than cisplatin and paclitaxel, while combination treatment of cells with PHPO + cisplatin induced more apoptosis than with PHPO + paclitaxel or with cisplatin + paclitaxel (p < 0.05). Animal assays demonstrated that subcutaneous tumor growth was highly inhibited by PHPO + cisplatin, compared with that inhibited by PHPO or by cisplatin treatment alone, indicating PHPO and cisplatin may have synergistic effects against ovarian cancer growth. We also found that PHPO induced few side effects on animals, compared with cisplatin. Mechanistic studies suggested that treatment of cells with PHPO or with PHPO + cisplatin differentially inhibited the PI3K/Akt, MAPK and ATM/Chk2 pathways, which consequently suppressed the anti apoptotic factors Bcl-xL, Bcl-2 and XIAP, but activated the pro-apoptotic factors Bad, Bax, p53, caspase 9, caspase 8, caspase 7 and PARP. Taken together, PHPO may induce cell apoptosis through multiple signal pathways, especially when used along with cisplatin. Therefore, PHPO may be explored as a prospective agent to effectively treat ovarian cancer. PMID- 27494892 TI - Sirtuin 1 stimulates the proliferation and the expression of glycolysis genes in pancreatic neoplastic lesions. AB - Metabolic reprogramming is a feature of neoplasia and tumor growth. Sirtuin 1 (SIRT1) is a lysine deacetylase of multiple targets including metabolic regulators such as p53. SIRT1 regulates metaplasia in the pancreas. Nevertheless, it is unclear if SIRT1 affects the development of neoplastic lesions and whether metabolic gene expression is altered.To assess neoplastic lesion development, mice with a pancreas-specific loss of Sirt1 (Pdx1-Cre;Sirt1-lox) were bred into a KrasG12D mutant background (KC) that predisposes to the development of pancreatic intra-epithelial neoplasia (PanIN) and ductal adenocarcinoma (PDAC). Similar grade PanIN lesions developed in KC and KC;Sirt1-lox mice but specifically early mucinous PanINs occupied 40% less area in the KC;Sirt1-lox line, attributed to reduced proliferation. This was accompanied by reduced expression of proteins in the glycolysis pathway, such as GLUT1 and GAPDH.The stimulatory effect of SIRT1 on proliferation and glycolysis gene expression was confirmed in a human PDAC cell line. In resected PDAC samples, higher proliferation and expression of glycolysis genes correlated with poor patient survival. SIRT1 expression per se was not prognostic but low expression of Cell Cycle and Apoptosis Regulator 2 (CCAR2), a reported SIRT1 inhibitor, corresponded to poor patient survival.These findings open perspectives for novel targeted therapies in pancreatic cancer. PMID- 27494893 TI - Blood concentration of cyclosporine during early post-transplant period may have influence on the occurrence of chronic graft versus host disease in patients who received allogeneic hematopoietic stem cell transplantation. AB - INTRODUCTION: It has rarely been studied that how the blood level of CsA affect the incidence of chronic GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: A total of 183 patients who underwent allo HSCT from an HLA-matched or haplo matched family donors between 2006 and 2014 were reviewed. RESULTS: The average monthly CsA blood concentration (CsAavr ,ng/ml) was calculated in each patient: 0-1, 1-2, and 2-3 months after allo-HSCT. CsAavr at the first month showed significant association with the occurrence of moderate to severe cGVHD in multivariate analysis adjusted for gender, age, total body irradiation, anti-thymocyte globulin, acute GVHD >= grade 2 and CsAavr levels of other periods. The risk of cGVHD development was lowest in patients with CsAavr of 200-250 ng/ml when compared to those with CsAavr of >= 250 or < 200 ng/ml (p=0.003). CONCLUSIONS: CsA level between 200 and 250 mg/ml during the first month after transplantation was significantly associated with the decreased risk of moderate to severe cGVHD. PMID- 27494894 TI - Advanced interstitial chemotherapy combined with targeted treatment of malignant glioma in rats by using drug-loaded nanofibrous membranes. AB - Glioblastoma multiforme (GBM), the most prevalent and malignant form of a primary brain tumour, is resistant to chemotherapy. In this study, we concurrently loaded three chemotherapeutic agents [bis-chloroethylnitrosourea, irinotecan, and cisplatin; BIC] into 50:50 poly[(d,l)-lactide-co-glycolide] (PLGA) nanofibres and an antiangiogenic agent (combretastatin) into 75:25 PLGA nanofibres [BIC and combretastatin (BICC)/PLGA]. The BICC/PLGA nanofibrous membranes were surgically implanted onto the brain surfaces of healthy rats for conducting pharmacodynamic studies and onto C6 glioma-bearing rats for estimating the therapeutic efficacy.The chemotherapeutic agents were rapidly released from the 50:50 PLGA nanofibres after implantation, followed by the release of combretastatin (approximately 2 weeks later) from the 75:25 PLGA nanofibres. All drug concentrations remained higher in brain tissues than in the blood for more than 8 weeks. The experimental results, including attenuated malignancy, retarded tumour growth, and prolonged survival in tumour-bearing rats, demonstrated the efficacy of the BICC/PLGA nanofibrous membranes. Furthermore, the efficacy of BIC/PLGA and BICC/PLGA nanofibrous membranes was compared. The BICC/PLGA nanofibrous membranes more efficiently retarded the tumour growth and attenuated the malignancy of C6 glioma-bearing rats. Moreover, the addition of combretastatin did not significantly change the drug release behaviour of the BIC/PLGA nanofibrous membranes. The present advanced and novel interstitial chemotherapy and targeted treatment provide a potential strategy and regimen for treating GBM. PMID- 27494895 TI - Hop derived flavonoid xanthohumol inhibits endothelial cell functions via AMPK activation. AB - Angiogenesis, a process characterized by the formation of new blood vessels from pre-existing ones, is a crucial step in tumor growth and dissemination. Recently, increased attention has been addressed to the ability of flavonoids to prevent cancer by suppressing angiogenesis, strategy that we named "angioprevention". Several natural compounds exert their anti-tumor properties by activating 5' adenosine monophosphate-activated protein kinase (AMPK), a key regulator of metabolism in cancer cells. Drugs with angiopreventive activities, in particular metformin, regulate AMPK in endothelial cells. Here we investigated the involvement of AMPK in the anti-angiogenic effects of xanthohumol (XN), the major prenylated flavonoid of the hop plant, and mechanisms of action. The anti angiogenic activity of XN was more potent than epigallocatechin-3-gallate (EGCG). Treatment of endothelial cells with XN led to increased AMPK phosphorylation and activity. Functional studies using biochemical approaches confirmed that AMPK mediates XN anti-angiogenic activity. AMPK activation by XN was mediated by CAMMKbeta, but not LKB1. Analysis of the downstream mechanisms showed that XN induced AMPK activation reduced nitric oxide (NO) levels in endothelial cells by decreasing eNOS phosphorylation. Finally, AKT pathway was inactivated by XN as part of its anti-angiogenic activity, but independently from AMPK, suggesting that these two signaling pathways proceed autonomously. Our study dissects the molecular mechanism by which XN exerts its potent anti-angiogenic activity, pointing out AMPK as a crucial signal transducer. PMID- 27494896 TI - MicroRNA 10b promotes abnormal expression of the proto-oncogene c-Jun in metastatic breast cancer cells. AB - MicroRNAs have been shown to act as oncogenes or tumor suppressers via various cellular pathways. Specifically, in breast cancer, upregulation of miR-10b is positively associated with aggressiveness of tumors. However, the mechanism by which miR-10b contributes to cell malignancy is largely unknown. Here we show that at the receiving end of the miR-10b pathway is the proto-oncogene c-Jun, a transcription factor that plays a critical role in stimulation of cell proliferation and tumor progression. c-Jun is known to be translationally activated by loss of cell contacts or restructuring of the cytoskeleton. A comprehensive analysis of miRNA expression exhibited a significant increase in miR-10b expression. This was supported by analysis of breast cancer cells, which showed that loss of E-cadherin in metastatic cells is accompanied by elevation of miR-10b and interestingly, by a marked increase in accumulation of c-Jun. Silencing miR-10b in metastatic breast cancer cells leads to a decline in c-Jun expression, whereas overexpression of miR-10b in HaCaT cells is sufficient to elevate the accumulation of c-Jun. The increase in c-Jun protein accumulation in metastatic cells is not accompanied by an increase in c-Jun mRNA and is not dependent on MAPK activity. Knockdown and overexpression experiments revealed that the increase is mediated by NF1 and RhoC, downstream targets of miR-10b that affect cytoskeletal dynamics through the ROCK pathway. Overall, we show the ability of miR-10b to activate the expression of c-Jun through RhoC and NF1, which represents a novel pathway for promoting migration and invasion of human cancer cells. PMID- 27494897 TI - MicroRNA-891b is an independent prognostic factor of pancreatic cancer by targeting Cbl-b to suppress the growth of pancreatic cancer cells. AB - Growing evidence has revealed that microRNAs could regulate the proliferation of pancreatic ductal adenocarcinoma (PDAC) cells and predict the prognosis of PDAC. Here the comparative microRNA expression profiles of the good and poor prognosis groups were performed by microRNA microarray. MicroRNA-891b (miR-891b) was screened and validated to be a prognostic predictor of PDAC in the initial group and further evaluated to be an independent predictor for the overall survival of resectable PDACs in an independent cohort. By a series of cellular and animal experiments, as well as clinical specimen analyses, miR-891b was confirmed to target the Cbl-b gene, promot the expression of tumor suppressor p21 protein and inhibit the proliferation of PDAC cells. The results provide a theoretical basis for the study of miR-891b as an independent prognostic predictor of PDAC and the role of miR-891b/Cbl-b pathway in this prediction, as well as the identification of new targets for PDAC. PMID- 27494900 TI - Employing an orthotopic model to study the role of epithelial-mesenchymal transition in bladder cancer metastasis. AB - Epithelial-to-mesenchymal transition (EMT) has been implicated in the progression of bladder cancer. To study its contribution to bladder cancer metastasis, we established new xenograft models derived from human bladder cancer cell lines utilizing an orthotopic "recycling" technique that allowed us to isolate and examine the primary tumor and its corresponding circulating tumor cells (CTC's) and metastatic lesions. Using whole genome mRNA expression profiling, we found that a reversible epithelial-to-mesenchymal transition (EMT) characterized by TGFbeta pathway activation and SNAIL expression was associated with the accumulation of CTCs. Finally, we observed that conditional silencing of SNAIL completely blocked CTC production and regional/distant metastasis. Using this unique bladder cancer xenograft model, we conclude that metastasis is dependent on a reversible EMT mediated by SNAIL. PMID- 27494901 TI - Advanced new strategies for metastatic cancer treatment by therapeutic stem cells and oncolytic virotherapy. AB - The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migratory capacity, which is available for metastatic cancer targeting. Prodrug activating enzyme or anticancer cytokine expressing stem cells successfully inhibited the proliferation of cancer cells. Preclinical models have clearly demonstrated anticancer activity of these two platforms against a number of different cancer types and metastatic cancer. Several systems using therapeutic stem cells or oncolytic virus have entered clinical trials, and promising results have led to late stage clinical development. Consequently, metastatic cancer therapies using stem cells and oncolytic viruses are extremely promising. The following review will focus on the metastatic cancer targeting mechanism of therapeutic stem cells and oncolytic viruses, and potential challenges ahead for advancing the field. PMID- 27494902 TI - MiR-146a-5p inhibits cell proliferation and cell cycle progression in NSCLC cell lines by targeting CCND1 and CCND2. AB - Previous studies have indicated that miR-146a-5p acts as an oncogene in several types of cancer, yet a tumor suppressor gene in others. In non-small cell lung cancer (NSCLC), one report showed that it was downregulated and played the role of tumor suppressor. However, another study showed that miR-146a-5p was overexpressed in the serum of NSCLC patients compared to healthy controls. Therefore, it is obvious that further study of the function of miR-146a-5p in NSCLC is necessary to fully understand its importance. Herein, we have verified that miR- 146a- 5p acts as a tumor suppressor in NSCLC. Our data revealed that the expression level of miR-146a-5p was significantly decreased in several human NSCLC cell lines, and also less abundant in human NSCLC tissues, when compared with controls. Moreover, we observed that miR-146a-5p could suppress cell proliferation, both in vitro and in vivo. Our results also showed that miR-146a 5p directly targeted the 3'-UTR of CCND1 and CCND2 mRNAs as well as decreased their expression at both mRNA and protein levels, causing cell cycle arrest at the G0/G1 phase. Furthermore, siRNA-mediated downregulation of CCND1 or CCND2 yielded the same effects on proliferation and cell cycle arrest as miR-146a-5p upregulation did in the NSCLC cell lines. We confirmed that the expression of miR 146a-5p had negative relationship with CCND1 or CCND2. Besides, we also found that miR-146a-5p could inhibit tumor growth in xengroft mouse models, and CCND1 and CCND2 were downregulated in miR-146a-5p overexpressed xengroft tumor tissues. In summary, our results demonstrated that miR-146a-5p could suppress the proliferation and cell cycle progression in NSCLC cells by inhibiting the expression of CCND1 and CCND2. PMID- 27494904 TI - Amikacin use and therapeutic drug monitoring in adults: do dose regimens and drug exposures affect either outcome or adverse events? A systematic review. AB - OBJECTIVES: The objectives of this study were to identify the amikacin dosage regimens and drug concentrations consistent with good outcomes and to determine the drug exposures related to nephrotoxicity and ototoxicity. METHODS: A literature review was conducted in Medline, EMBASE and the Cochrane Central Register of Controlled Trials. Full journal articles reporting randomized controlled trials, controlled clinical trials, interrupted time series trials, and controlled before and after studies involving amikacin therapeutic drug monitoring (TDM) and dose adjustment were considered for inclusion. RESULTS: Seventeen studies for inclusion were identified, comprising 1677 participants. Amikacin doses ranged from 11 to 15 mg/kg/day with 13 studies using 15 mg/kg/day. Studies were generally designed to compare different aminoglycosides rather than to assess concentration-effect relationships. Only 11 papers presented data on target concentrations, rate of clinical cure and toxicity. Target peak concentrations ranged from 15 to 40 mg/L and target troughs were typically <10 or <5 mg/L. It was not clear whether these targets were achieved. Measured peaks averaged 28 mg/L for twice-daily dosing and 40-45 mg/L for once-daily dosing; troughs averaged 5 and 1-2 mg/L, respectively. Fifteen of the included studies reported rates of nephrotoxicity; auditory and vestibular toxicities were reported in 12 and 8 studies. CONCLUSIONS: This systematic review found little published evidence to support an optimal dosage regimen or TDM targets for amikacin therapy. The use of alternative approaches, such as consensus opinion and a review of current practice, will be required to develop guidelines to maximize therapeutic outcomes and minimize toxicity with amikacin. PMID- 27494903 TI - Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium. AB - BACKGROUND: Exacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy. Inhaled corticosteroids are also readily used in treatment, but may lack specificity. Ideally, new treatment alternatives should suppress unwanted inflammation, but spare beneficial antiviral immunity. METHODS: In the present study, we screened 225 novel macrolides and tested them for enhanced antiviral activity against rhinovirus, as well as anti-inflammatory activity and activity against Gram-positive and Gram negative bacteria. Primary bronchial epithelial cells were grown from 10 asthmatic individuals and the effects of macrolides on rhinovirus replication were also examined. Another 30 structurally similar macrolides were also examined. RESULTS: The oleandomycin derivative Mac5, compared with azithromycin, showed superior induction (up to 5-fold, EC50 = 5-11 MUM) of rhinovirus-induced type I IFNbeta, type III IFNlambda1 and type III IFNlambda2/3 mRNA and the IFN stimulated genes viperin and MxA, yet had no effect on IL-6 and IL-8 mRNA. Mac5 also suppressed rhinovirus replication at 48 h, proving antiviral activity. Mac5 showed antibacterial activity against Gram-positive Streptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negative Escherichia coli (as a model organism) and also the respiratory pathogens Pseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti inflammatory, antiviral and antibacterial activities. CONCLUSIONS: The data support the idea that macrolides have antiviral properties through a mechanism that is yet to be ascertained. We also provide evidence that macrolides can be developed with anti-inflammatory, antibacterial and antiviral activity and show surprising versatility depending on the clinical need. PMID- 27494906 TI - Impact of AAC(6')-Ib-cr in combination with chromosomal-mediated mechanisms on clinical quinolone resistance in Escherichia coli. AB - OBJECTIVES: aac(6')-Ib-cr is the most prevalent plasmid-mediated fluoroquinolone (FQ) resistance mechanism in Enterobacteriaceae. We aimed to analyse the interplay between this plasmid-mediated gene and chromosomal-mediated quinolone resistance mechanisms on both FQ resistance and bacterial fitness in Escherichia coli. METHODS: E. coli ATCC 25922 and derived isogenic strains carrying chromosomal-mediated quinolone resistance modifications (Ser83Leu-Asp87Asn in GyrA, Ser80Arg in ParC and/or a marR gene deletion) were electroporated with a pBK-CMV vector encoding AAC(6')-Ib-cr. The MICs of FQs were determined by microdilution and bactericidal activity was determined using time-kill curves. A peritoneal sepsis murine model was used to evaluate the in vivo impact. Bacterial fitness was analysed using growth curves and competition assays. RESULTS: The presence of the aac(6')-Ib-cr gene increased the MICs of ciprofloxacin and norfloxacin 4-8-fold for all E. coli genotypes, independently of the initial resistance level. Combination of the aac(6')-Ib-cr gene with three or four chromosomal mechanisms was necessary to reach MIC values above the susceptible category. Killing curve assays showed a clear selective advantage for survival in strains harbouring the aac(6')-Ib-cr gene (up to 7 log10 cfu/mL after 24 h). AAC(6')-Ib-cr significantly reduced the ciprofloxacin efficacy in vivo. In terms of bacterial fitness cost, maximal OD was significantly lower for all strains harbouring the aac(6')-Ib-cr gene, independently of chromosomal mutations associated. CONCLUSIONS: The aac(6')-Ib-cr gene, in spite of producing low-level resistance by itself, plays a relevant role in acquisition of a clinical level of ciprofloxacin and norfloxacin resistance, when combined with three or four chromosomal mutations, both in vitro and in vivo. PMID- 27494905 TI - Therapeutic drug monitoring of vancomycin: a guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society. AB - BACKGROUND: Guideline development should be based on the quality of evidence, balance of benefits and harms, economic evaluation and patients' views and preferences. Therefore, these factors were considered in the development of a new guideline for therapeutic drug monitoring (TDM) of vancomycin. OBJECTIVES: To develop an evidence-based guideline for vancomycin TDM and to promote standardized vancomycin TDM in clinical practice in China. METHODS: We referred to the WHO Handbook for Guideline Development and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to rate the quality of evidence and grade the strength of recommendations, according to economic evaluation and patients' views and preferences. We used the GRADE Grid method to formulate the recommendations. RESULTS: The guideline presents recommendations about who should receive vancomycin TDM, how to monitor vancomycin efficacy and renal safety, therapeutic trough concentrations, time to start initial vancomycin TDM, loading dose and how to administer and adjust the vancomycin dose. CONCLUSIONS: We developed an evidence-based guideline for vancomycin TDM, which provides recommendations for clinicians and pharmacists to conduct vancomycin TDM in China. PMID- 27494907 TI - Cluster-dependent colistin hetero-resistance in Enterobacter cloacae complex. AB - OBJECTIVES: Aims of this study were to: (i) evaluate whether the cluster membership could have an impact on hetero-resistance phenotype to colistin in the Enterobacter cloacae complex (ECC); and (ii) determine the genetic mechanism of colistin hetero-resistance in ECC. METHODS: A collection of 124 clinical isolates belonging to 13 clusters were used to analyse the hetero-resistance phenotype (MICs were determined using the broth microdilution method, Etest and population analysis profiling). Different mutants (DeltaphoP, DeltaphoQ, DeltaphoPQ, DeltapmrA, DeltapmrB, DeltapmrAB, DeltaarnE, DeltaarnF and DeltaarnBCADTEF) were constructed and tested for their colistin hetero-resistance phenotype. RESULTS: Based on broth microdilution and Etest results, it was shown that the hetero resistance to colistin depended on the cluster: strains from clusters I, II, IV, VII, IX, X, XI and XII were usually hetero-resistant, whereas those from clusters III, V, VI, VIII and XIII were categorized as susceptible. However, for some cluster V and VIII strains, a small proportion (<10-7) of cells appeared resistant when tested by population analysis profiling. From a mechanistic point of view, analysis of mutants revealed that the mechanism of hetero-resistance was mainly due to the expression of the arn operon and the phoP/phoQ two-component regulatory system. CONCLUSIONS: Because the colistin hetero-resistance appeared cluster-dependent in the ECC, it should be advocated to determine the cluster of the strain associated with the infection in parallel with the MIC of colistin. The resistance mechanism may not be similar to other Enterobacteriaceae since only the two-component regulatory system PhoP/PhoQ (and not PmrA/PmrB) seemed to play a role in resistance regulation. PMID- 27494908 TI - Management of skin and soft-tissue infections at a community teaching hospital using a severity-of-illness tool. AB - OBJECTIVES: Skin and soft-tissue infections (SSTIs) encompass a diverse range of infections of varying severity. The Clinical Resource Efficiency Support Team (CREST) scoring system stratifies patients into four classes (I = least severe to IV = most severe) based on the Standardized Early Warning Score (SEWS). The objective of this study was to apply CREST to hospitalized patients with SSTIs in order to quantify disease severity and evaluate appropriateness of antibiotic management. METHODS: This was a retrospective, hypothesis-generating, single centre evaluation of hospitalized patients with SSTIs admitted in 2011. Based on CREST classification, the empirical antimicrobial choices were categorized as appropriate, over-treatment or under-treatment. RESULTS: A total of 369 patients were screened and 200 met the inclusion criteria. The majority of patients were classified as either CREST class I (n = 68) or class II (n = 102). Over-treatment was more common in the less severe classes (88% and 32% in class I and class II, respectively; P < 0.05). Sixty-three percent of class I (n = 43) were over treated due to both the use of intravenous antibiotics when oral therapy was sufficient and use of unnecessarily broad-spectrum antibiotics. In contrast, 25% (n = 26) of class II were over-treated due to use of unnecessarily broad-spectrum antibiotics. Overall clinical failure rates remained low with only 1%, 4% and 17% of patients unable to achieve initial response in class II, class III and class IV. CONCLUSIONS: Retrospective application of CREST identified opportunities to improve the management of SSTIs. CREST can be of great value in discriminating less-severe SSTIs, which can be treated on an outpatient basis. PMID- 27494909 TI - Levels of bone markers in a population of infants exposed in utero and during breastfeeding to tenofovir within an Option B+ programme in Malawi. AB - OBJECTIVES: No data are available on bone metabolism in infants exposed to tenofovir during breastfeeding. We investigated bone metabolism markers in the first year of life in infants from mothers who received tenofovir, lamivudine and efavirenz during pregnancy and 12 months of breastfeeding in a national Option B+ programme in Malawi. METHODS: Serum samples collected at 6 and 12 months in tenofovir-exposed infants and in a small sample of tenofovir-unexposed infants from the same clinical centre were analysed in batches for levels of bone specific alkaline phosphatase (BAP; marker of bone formation) and of C-terminal telopeptide of type I collagen (CTX; marker of bone resorption). RESULTS: Overall, 136 tenofovir-exposed infants were evaluated. No infant had at either timepoint CTX values above the upper normal limit, while most of them had at 6 and 12 months levels of BAP above the upper normal limit for the age range. Levels of bone markers showed no differences by gender and no association with growth parameters. Tenofovir-unexposed and -exposed children had similar mean levels of bone markers at 6 months (CTX: 0.62 versus 0.55 ng/mL, P = 0.122; BAP: 384 versus 362 U/L, P = 0.631). CONCLUSIONS: No significant association between treatment with tenofovir and CTX or BAP levels was found. The high levels of BAP, coupled to the normal levels observed for CTX, might reflect primarily skeletal growth. Potential negative effects of prolonged exposure to tenofovir through breastfeeding cannot however be excluded and longitudinal studies that evaluate bone mineralization status in children enrolled in Option B+ programmes are warranted. PMID- 27494910 TI - Tissue pharmacokinetics of telavancin in healthy volunteers: a microdialysis study. AB - BACKGROUND: Telavancin is a novel lipoglycoprotein antibiotic with MRSA activity. To date, tissue pharmacokinetics (PK) and plasma protein binding of the drug are insufficiently described. OBJECTIVES: To investigate tissue PK and plasma protein binding of telavancin in healthy volunteers. METHODS: Eight male healthy subjects received a single dose of 10 mg/kg of body weight of telavancin as an intravenous infusion over 1 h. At defined timepoints before and up to 24 h after treatment, total telavancin concentrations were measured in plasma. Additionally, unbound telavancin levels were determined in plasma, muscle and subcutis by means of microdialysis. RESULTS: Key PK parameters of total telavancin in plasma were in good agreement with previously described values. Mean +/- SD Cmax and calculated AUC0-24 of free telavancin in plasma were 13.8 +/- 7.8 mg/L and 82.9 +/- 34.3 mg.h/L, respectively. Unbound drug levels in plasma ranged from 13.2% to 24.8% of corresponding total telavancin. Mean +/- SD Cmax and AUC0-24 of unbound telavancin were 4.3 +/- 1.5 mg/L and 61.5 +/- 27.1 mg.h/L for muscle and 3.4 +/- 1.8 and 50.0 +/- 29.8 mg.h/L for subcutis, respectively. Relevant PK/pharmacodynamic indices were calculated for total and unbound drug. CONCLUSIONS: This study provides important information on soft tissue PK and plasma protein binding of telavancin in healthy volunteers. Unbound plasma concentrations above levels assumed from previously available data and sustained free drug exposure in soft tissues support the current mode of administration. PMID- 27494911 TI - Oral decontamination with aminoglycosides is associated with lower risk of mortality and infections in high-risk patients colonized with colistin-resistant, KPC-producing Klebsiella pneumoniae. AB - OBJECTIVES: Invasive infections caused by KPC-producing Klebsiella pneumoniae (KPCKP) are associated with very high mortality. Because infection is usually preceded by rectal colonization, we investigated if decolonization therapy (DT) with aminoglycosides had a protective effect in selected patients. METHODS: Patients with rectal colonization by colistin-resistant KPCKP who were at high risk of developing infection (because of neutropenia, surgery, previous recurrent KPCKP infections or multiple comorbidities) were followed for 180 days. Cox regression analysis including a propensity score was used to investigate the impact of the use of two intestinal decolonization regimens with oral aminoglycosides (gentamicin and neomycin/streptomycin) on mortality, risk of KPCKP infections and microbiological success. The study was registered with ClinicalTrials.gov (NCT02604849). RESULTS: The study sample comprised 77 colonized patients, of which 44 (57.1%) received DT. At 180 days of follow-up, decolonization was associated with a lower risk of mortality in multivariate analyses (HR 0.18; 95% CI 0.06-0.55) and a lower risk of KPCKP infections (HR 0.14; 95% CI 0.02-0.83) and increased microbiological success (HR 4.06; 95% CI 1.06-15.6). Specifically, gentamicin oral therapy was associated with a lower risk of crude mortality (HR 0.15; 95% CI 0.04-0.54), a lower risk of KPCKP infections (HR 0.86; 95% CI 0.008-0.94) and increased microbiological response at 180 days of follow-up (HR 5.67; 95% CI 1.33-24.1). Neomycin/streptomycin therapy was only associated with a lower risk of crude mortality (HR 0.22; 95% CI 0.06 0.9). CONCLUSIONS: Intestinal decolonization with aminoglycosides is associated with a reduction in crude mortality and KPCKP infections at 180 days after initiating treatment. PMID- 27494912 TI - Dose optimization of voriconazole/anidulafungin combination against Aspergillus fumigatus using an in vitro pharmacokinetic/pharmacodynamic model and response surface analysis: clinical implications for azole-resistant aspergillosis. AB - BACKGROUND: Combination therapy of voriconazole with an echinocandin is often employed in order to increase the efficacy of voriconazole monotherapy. METHODS: Four clinical Aspergillus fumigatus isolates with different in vitro susceptibilities to voriconazole (MIC 0.125-2 mg/L) and anidulafungin (MEC 0.008 0.016 mg/L) were tested in an in vitro pharmacokinetic/pharmacodynamic model simulating human serum concentrations of standard dosages of voriconazole and anidulafungin. Fungal growth was assessed using galactomannan production and quantitative PCR. Drug concentrations were determined with bioassays. Pharmacodynamic interactions were assessed using Bliss independence analysis (BI) and Loewe additivity-based canonical mixture response-surface non-linear regression analysis (LA). Probability of target attainment (PTA) was estimated with Monte Carlo analysis for different doses of anidulafungin (25, 50 and 100 mg) and azole resistance rates (5%-25%). RESULTS: Synergy [BI 51% (8%-80%), LA 0.63 (0.38-0.79)] was found at low anidulafungin (fCmax/MEC <10) and voriconazole (fAUC/MIC <10) exposures, whereas antagonism [BI 12% (5%-18%, LA 1.12 (1.04-4.6)] was found at higher drug exposures. The largest increase in PTA was found with 25 mg of anidulafungin and voriconazole MIC distributions with high (>10%) resistance rates. PTAs for isolates with voriconazole MICs of 1, 2 and 4 mg/L was 78%, 12% and 0% with voriconazole monotherapy and 96%-100%, 68%-82% and 9%-20% with combination therapy, respectively. Optimal activity was associated with a voriconazole tCmin/MIC ratio of 1.5 for monotherapy and 0.75 for combination therapy. CONCLUSIONS: The present study indicated that the combination of voriconazole with low-dose anidulafungin may increase the efficacy and reduce the cost and potential toxicity of antifungal therapy, particularly against azole resistant A. fumigatus isolates and in patients with subtherapeutic serum levels. This hypothesis warrants further in vivo verification. PMID- 27494914 TI - Molecular characterization of blaESBL-producing Escherichia coli cultured from pig farms in Ireland. AB - OBJECTIVES: To characterize ESBL-encoding Escherichia coli cultured from pigs and their plasmids carrying these genes following conjugation into recipient strains. METHODS: Six ESBL-producing E. coli were recovered from faecal samples taken from pigs along with a further isolate from the environment of a farrowing house on three pig farms in Ireland. These isolates were characterized by phylogenetic grouping, MLST and ESBL genotype analyses. Conjugation experiments were carried out in broth mating assays. S1-nuclease PFGE was used to determine the plasmid profiles. Whole-genome sequences of the seven E. coli were determined and subsequently analysed. RESULTS: Phylogenetic groups and the corresponding MLST STs identified among the seven tested E. coli isolates included A/ST10, A/ST34, C/ST23 and C/ST1629. All seven isolates carried one or more high-molecular-weight plasmids and demonstrated the ability to transfer their cefotaxime resistance phenotype at high frequencies. Five transmissible plasmid replicon types were detected, including IncK/B (n = 3), IncI1 (n = 2), IncFIA (n = 1), IncFIB (n = 1) and IncN (n = 1). ESBL-encoding genes, including blaCTX-M-14, blaCTX-M-15 and blaTEM-20, were identified. CONCLUSIONS: As the first report from pig sources in Ireland, characterization of these ESBL-encoding isolates and their transmissible plasmids extends our understanding on these resistance markers from porcine E. coli. PMID- 27494913 TI - Tracking inter-institutional spread of NDM and identification of a novel NDM positive plasmid, pSg1-NDM, using next-generation sequencing approaches. AB - OBJECTIVES: Owing to gene transposition and plasmid conjugation, New Delhi metallo-beta-lactamase (NDM) is typically identified among varied Enterobacteriaceae species and STs. We used WGS to characterize the chromosomal and plasmid molecular epidemiology of NDM transmission involving four institutions in Singapore. METHODS: Thirty-three Enterobacteriaceae isolates (collection years 2010-14) were sequenced using short-read sequencing-by synthesis and analysed. Long-read single molecule, real-time sequencing (SMRTS) was used to characterize genetically a novel plasmid pSg1-NDM carried on Klebsiella pneumoniae ST147. RESULTS: In 20 (61%) isolates, blaNDM was located on the pNDM-ECS01 plasmid in the background of multiple bacterial STs, including eight K. pneumoniae STs and five Escherichia coli STs. In six (18%) isolates, a novel blaNDM-positive plasmid, pSg1-NDM, was found only in K. pneumoniae ST147. The pSg1-NDM-K. pneumoniae ST147 clone (Sg1-NDM) was fully sequenced using SMRTS. pSg1-NDM, a 90 103 bp IncR plasmid, carried genes responsible for resistance to six classes of antimicrobials. A large portion of pSg1-NDM had no significant homology to any known plasmids in GenBank. pSg1-NDM had no conjugative transfer region. Combined chromosomal-plasmid phylogenetic analysis revealed five clusters of clonal bacterial NDM-positive plasmid transmission, of which two were inter institution clusters. The largest inter-institution cluster involved six K. pneumoniae ST147-pSg1-NDM isolates. Fifteen patients were involved in transmission clusters, of which four had ward contact, six had hospital contact and five had an unknown transmission link. CONCLUSIONS: A combined sequencing-by synthesis and SMRTS approach can determine effectively the transmission clusters of blaNDM and genetically characterize novel plasmids. Plasmid molecular epidemiology is important to understanding NDM spread as blaNDM-positive plasmids can conjugate extensively across species and STs. PMID- 27494915 TI - Identification of non-PBP2a resistance mechanisms in Staphylococcus aureus after serial passage with ceftaroline: involvement of other PBPs. AB - OBJECTIVES: Ceftaroline (the active metabolite of ceftaroline fosamil) is a cephalosporin that possesses activity against MRSA due to its differentiating high affinity for PBP2a. It is known that PBP2a sequence variations, including some outside of the transpeptidase-binding pocket, impact ceftaroline susceptibility and recent evidence suggests involvement of non-PBP2a mechanisms in ceftaroline resistance. This study evaluated the potential of ceftaroline to select for resistant Staphylococcus aureus clones during serial passage. METHODS: Selection experiments were performed by up to 20 daily passages of three S. aureus isolates (two MRSA and one MSSA) in broth with increasing selective pressure. Mutants that emerged were tested for changes in ceftaroline susceptibility and genetically characterized. RESULTS: The MSSA isolate developed mutations in PBP2 and PBP3 that increased the ceftaroline MIC by 16-fold and increased the MICs of other beta-lactams. A Glu447Lys substitution in the PBP2a transpeptidase pocket in one MRSA isolate elevated the ceftaroline MIC to 8 mg/L. Selective pressure in a ceftaroline-resistant MRSA isolate generated mutations in LytD, as well as changes in the pbp4 promoter previously shown to result in PBP4 overexpression, the one PBP not inhibited by ceftaroline. Elevated ceftaroline MIC was reversed when tested in combination with extremely low levels of methicillin or meropenem that could inhibit the function of PBP4. CONCLUSIONS: These studies demonstrate that resistance to ceftaroline can be manifested through numerous mechanisms. Further, they support a hypothesis where PBP4 can functionally provide the essential transpeptidase activity required for MRSA cell wall biogenesis when PBP2a is inhibited. PMID- 27494916 TI - HIV pre-exposure prophylaxis for women and infants prevents vaginal and oral HIV transmission in a preclinical model of HIV infection. AB - BACKGROUND: Approximately 1.5 million HIV-positive women become pregnant annually. Without treatment, up to 45% will transmit HIV to their infants, primarily through breastfeeding. These numbers highlight that HIV acquisition is a major health concern for women and children globally. They also emphasize the urgent need for novel approaches to prevent HIV acquisition that are safe, effective and convenient to use by women and children in places where they are most needed. METHODS: 4'-Ethynyl-2-fluoro-2'-deoxyadenosine, a potent NRTI with low cytotoxicity, was administered orally to NOD/SCID/gammac-/- mice and to bone marrow/liver/thymus (BLT) humanized mice, a preclinical model of HIV infection. HIV inhibitory activity in serum, cervicovaginal secretions and saliva was evaluated 4 h after administration. 4'-Ethynyl-2-fluoro-2'-deoxyadenosine's ability to prevent vaginal and oral HIV transmission was evaluated using highly relevant transmitted/founder viruses in BLT mice. RESULTS: Strong HIV inhibitory activity in serum, cervicovaginal secretions and saliva obtained from animals after a single oral dose of 4'-ethynyl-2-fluoro-2'-deoxyadenosine (10 mg/kg) demonstrated efficient drug penetration into relevant mucosal sites. A single daily oral dose of 4'-ethynyl-2-fluoro-2'-deoxyadenosine resulted in efficient prevention of vaginal and oral HIV transmission after multiple high-dose exposures to transmitted/founder viruses in BLT humanized mice. CONCLUSIONS: Our data demonstrated that 4'-ethynyl-2-fluoro-2'-deoxyadenosine efficiently prevents both vaginal and oral HIV transmission. Together with 4'-ethynyl-2-fluoro-2' deoxyadenosine's relatively low toxicity and high potency against drug-resistant HIV strains, these data support further clinical development of 4'-ethynyl-2 fluoro-2'-deoxyadenosine as a potential pre-exposure prophylaxis agent to prevent HIV transmission in women and their infants. PMID- 27494918 TI - Antimicrobial stewardship in wound care: a Position Paper from the British Society for Antimicrobial Chemotherapy and European Wound Management Association. AB - BACKGROUND: With the growing global problem of antibiotic resistance it is crucial that clinicians use antibiotics wisely, which largely means following the principles of antimicrobial stewardship (AMS). Treatment of various types of wounds is one of the more common reasons for prescribing antibiotics. OBJECTIVES: This guidance document is aimed at providing clinicians an understanding of: the basic principles of why AMS is important in caring for patients with infected wounds; who should be involved in AMS; and how to conduct AMS for patients with infected wounds. METHODS: We assembled a group of experts in infectious diseases/clinical microbiology (from the British Society for Antimicrobial Chemotherapy) and wound management (from the European Wound Management Association) who, after thoroughly reviewing the available literature and holding teleconferences, jointly produced this guidance document. RESULTS: All open wounds will be colonized with bacteria, but antibiotic therapy is only required for those that are clinically infected. Therapy is usually empirical to start, but definitive therapy should be based on results of appropriately collected specimens for culture. When prescribed, it should be as narrowly focused, and administered for the shortest duration, as possible. AMS teams should be interdisciplinary, especially including specialists in infection and pharmacy, with input from administrative personnel, the treating clinicians and their patients. CONCLUSIONS: Available evidence is limited, but suggests that applying principles of AMS to the care of patients with wounds should help to reduce the unnecessary use of systemic or topical antibiotic therapy and ensure the safest and most clinically effective therapy for infected wounds. PMID- 27494917 TI - The impact of a multidisciplinary antimicrobial stewardship team on the timeliness of antimicrobial therapy in patients with positive blood cultures: a randomized controlled trial. AB - BACKGROUND: Antimicrobial stewardship teams play an important role in assisting with the optimization of antimicrobial use in acute care settings. We aimed to determine whether a rapid review by a multidisciplinary antimicrobial stewardship team would improve the timeliness of optimal antimicrobial therapy for patients with positive blood cultures. METHODS: This prospective randomized controlled trial was undertaken in two Australian hospitals. Patients received either standard care (a clinical microbiologist, registrar or laboratory scientist communicating the positive blood culture by phone to the treating doctor) or intervention (standard care plus rapid review by a multidisciplinary antimicrobial stewardship team). Outcomes included time to appropriate and/or active antimicrobial therapy and in-hospital mortality. The trial was registered on the Australian New Zealand Clinical Trials Registry (ACTRN12614000258651). RESULTS: A total of 160 patients were enrolled in this study: 81 in the standard care arm and 79 in the intervention arm. Patients in the intervention arm were commenced earlier on active (HR 8.02, 95% CI: 2.15-29.91) and appropriate antimicrobials (HR 1.95, 95% CI: 1.13-3.38), with a higher proportion of patients allocated to the intervention arm receiving active therapy at 48 h (96% versus 82%) and appropriate therapy at 72 h (70% versus 54%). The majority of patients where the blood culture was a contaminant were not started on antimicrobial therapy, and there were no significant differences in time to cessation of antimicrobial therapy. CONCLUSIONS: Antimicrobial stewardship team review of patients with pathogenic positive blood cultures improved the time to both active and appropriate antimicrobial therapy. PMID- 27494919 TI - Use of WGS data for investigation of a long-term NDM-1-producing Citrobacter freundii outbreak and secondary in vivo spread of blaNDM-1 to Escherichia coli, Klebsiella pneumoniae and Klebsiella oxytoca. AB - OBJECTIVES: An outbreak of NDM-1-producing Citrobacter freundii and possible secondary in vivo spread of blaNDM-1 to other Enterobacteriaceae were investigated. METHODS: From October 2012 to March 2015, meropenem-resistant Enterobacteriaceae were detected in 45 samples from seven patients at Aalborg University Hospital, Aalborg, Denmark. In silico resistance genes, Inc plasmid types and STs (MLST) were obtained from WGS data from 24 meropenem-resistant isolates (13 C. freundii, 6 Klebsiella pneumoniae, 4 Escherichia coli and 1 Klebsiella oxytoca) and 1 meropenem-susceptible K. oxytoca. The sequences of the meropenem-resistant C. freundii isolates were compared by phylogenetic analyses. In vitro susceptibility to 21 antimicrobial agents was tested. Furthermore, in vitro conjugation and plasmid characterization was performed. RESULTS: From the seven patients, 13 highly clonal ST18 NDM-1-producing C. freundii were isolated. The ST18 NDM-1-producing C. freundii isolates were only susceptible to tetracycline, tigecycline, colistin and fosfomycin (except for the C. freundii isolates from Patient 2 and Patient 7, which were additionally resistant to tetracycline). The E. coli and K. pneumoniae from different patients belonged to different STs, indicating in vivo transfer of blaNDM-1 in the individual patients. This was further supported by in vitro conjugation and detection of a 154 kb IncA/C2 plasmid with blaNDM-1. Patient screenings failed to reveal any additional cases. None of the patients had a history of recent travel abroad and the source of the blaNDM-1 plasmid was unknown. CONCLUSIONS: To our knowledge, this is the first report of an NDM-1-producing C. freundii outbreak and secondary in vivo spread of an IncA/C2 plasmid with blaNDM-1 to other Enterobacteriaceae. PMID- 27494920 TI - Novel chromosome-encoded erm(47) determinant responsible for constitutive MLSB resistance in Helcococcus kunzii. AB - OBJECTIVES: The aim of the study was to identify the determinant responsible for erythromycin resistance in Helcococcus kunzii clinical isolate UCN99 and to characterize the genetic support and environment of this novel gene. METHODS: MICs were determined using the broth microdilution method according to EUCAST guidelines. The entire genome sequence of H. kunzii UCN99 was determined using a 454/Roche GS Junior sequencer. The fragment encompassing the new resistance gene and its own promoter was cloned into the pAT29 shuttle vector and the recombinant plasmid pAT29Omegaerm(47) was expressed in both Staphylococcus aureus and Streptococcus agalactiae. The transcription start site (TSS) was experimentally determined by 5' RACE-PCR. RESULTS: UCN99 exhibited a constitutive macrolide/lincosamide/streptogramin B (MLSB) resistance phenotype, suggesting the presence of an Erm protein. WGS allowed the identification of a novel gene, named erm(47), encoding a protein sharing 44%-48% amino acid identity with known Erm methylases. In both S. aureus and S. agalactiae, the introduction of pAT29Omegaerm(47) conferred a significant increase (>=16-fold) in MICs of all macrolides and lincosamides tested, as well as a 4-fold increase in MICs of quinupristin (streptogramin B), confirming the MLSB resistance. The TSS identification revealed the presence of a short leader peptide, potentially implicated in a translational attenuation mechanism. It was also demonstrated that erm(47) was harboured by a 81 kb genomic island integrated into a chromosomal gene. CONCLUSIONS: This is the first description of a novel MLSB resistance determinant, named erm(47). The prevalence of this gene among Gram positive cocci must be further investigated to determine its clinical significance. PMID- 27494921 TI - Real-time PCR detection of Neisseria gonorrhoeae susceptibility to penicillin. AB - OBJECTIVES: The objective of this study was to develop a real-time PCR assay targeting the gonococcal porB gene (PorB-PCR) for predicting susceptibility of Neisseria gonorrhoeae to penicillin. This complements a previously described PCR assay for detecting penicillinase-producing N. gonorrhoeae (PPNG) developed by our laboratory (PPNG-PCR). METHODS: The PorB-PCR assay was designed using six probes to characterize various combinations of amino acids at positions 101 and 102 of the PorB1b class protein, including the WT G101/A102 and mutant G101K/A102D, G101K/A102N and G101K/A102G sequences, as well as the PorB1a sequence. The ability of these sequences to predict penicillin susceptibility was initially assessed using 2307 N. gonorrhoeae isolates from throughout Australia for which phenotypic susceptibility data were available. The assay was then applied to N. gonorrhoeae-positive clinical specimens (n = 70). Specificity was assessed by testing commensal Neisseria strains (n = 75) and N. gonorrhoeae negative clinical specimens (n = 171). RESULTS: Testing of the 2307 N. gonorrhoeae isolates using PorB-PCR to detect G101/A102 and PorB1a sequences identified a total of 78.4% (61.2% and 17.2%, respectively) of penicillin susceptible isolates with specificities of 97.4% and 99.3% and positive predictive values of 98.8% and 98.9%, where PPNG strains were simultaneously identified and excluded. Similar performance data were obtained when the PorB-PCR assay was applied to the N. gonorrhoeae-positive clinical specimens. No false positive results were observed for the N. gonorrhoeae-negative samples and no cross-reactions were observed with the non-gonococcal species. CONCLUSIONS: When used in parallel with the previously described PPNG-PCR, the PorB-PCR approach has the potential to facilitate individualized treatment of gonorrhoea using penicillin. PMID- 27494923 TI - Molecular basis of rifampicin resistance in multiresistant porcine livestock associated MRSA. PMID- 27494922 TI - Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii: pharmacodynamics of new dosing strategies. AB - OBJECTIVES: Polymyxin B is being increasingly utilized as a last resort against resistant Gram-negative bacteria. We examined the pharmacodynamics of novel dosing strategies for polymyxin B combinations to maximize efficacy and minimize the emergence of resistance and drug exposure against Acinetobacter baumannii. METHODS: The pharmacodynamics of polymyxin B together with doripenem were evaluated in time-kill experiments over 48 h against 108 cfu/mL of two polymyxin heteroresistant A. baumannii isolates (ATCC 19606 and N16870). Pharmacokinetic/pharmacodynamic relationships were mathematically modelled using S-ADAPT. A hollow-fibre infection model (HFIM) was also used to simulate clinically relevant polymyxin B dosing strategies (traditional, augmented 'front loaded' and 'burst' regimens), together with doripenem, against an initial inoculum of 109 cfu/mL of ATCC 19606. RESULTS: In static time-kill studies, polymyxin B concentrations >4 mg/L in combination with doripenem 25 mg/L resulted in rapid bactericidal activity against both strains with undetectable bacterial counts by 24 h. The mathematical model described the rapid, concentration dependent killing as subpopulation and mechanistic synergy. In the HFIM, the traditional polymyxin B combination regimen was synergistic, with a >7.5 log10 reduction by 48 h. The polymyxin B 'front-loaded' combination resulted in more rapid and extensive initial killing (>8 log10) within 24 h, which was sustained over 10 days. With only 25% of the cumulative drug exposure, the polymyxin B 'burst' combination demonstrated antibacterial activity similar to traditional and 'front-loaded' combination strategies. The polymyxin B 'front-loaded' and 'burst' combination regimens suppressed the emergence of resistance. CONCLUSIONS: Early aggressive dosing regimens for polymyxin combinations demonstrate promise for treatment of heteroresistant A. baumannii infections. PMID- 27494924 TI - Aminoglycoside-associated acute kidney injury in elderly patients with and without shock. AB - OBJECTIVES: Multiresistant Gram-negative pathogens pose major healthcare concerns with a limited therapeutic armamentarium. Aminoglycosides (AG) are under-utilized due to nephrotoxicity. We aimed to evaluate AG-associated acute kidney injury (AG AKI) in elderly inpatients, with and without shock. METHODS: We examined the incidence and predictors of AG-AKI by KDIGO criteria and extended renal dysfunction (ERD) in patients aged >60 years. ERD represented a composite of hospital mortality or absence of renal recovery over 6 months following AG-AKI. RESULTS: Two hundred and seventy-eight patients (aged 74 +/- 8 years) were studied; 43% and 19% received >7 and >10 days of AG therapy, respectively, and 70% gentamicin (versus amikacin). Thirteen per cent had shock and 17% developed AG-AKI. Comparing all patients with shock versus no shock, AG-AKI developed in 33% versus 14%, respectively (P = 0.005); correspondingly among 47 patients with AG-AKI, more with shock had stage 2/3 AKI (92% versus 43%) and dialysis (50% versus 9%) (P < 0.01), but more had other strong AKI confounders than AG therapy alone (83% versus 40%, P = 0.02). Multivariate analyses identified mechanical ventilation, frusemide administration and AG therapy >10 days as predictors of AG AKI (P < 0.05), whereas shock, pneumonia and frusemide administration predicted more severe stage 2/3 AG-AKI (P < 0.05). Hospital mortality was 30% versus 7% with AG-AKI versus none (P < 0.001). Twenty-three of 211 (11%) patients with extended analysis had ERD, with 47% experiencing renal recovery following AG-AKI. Mechanical ventilation and contrast administration during index hospitalization predicted ERD (P < 0.05). CONCLUSIONS: AG-AKI is common in the elderly, with a significant risk of ERD, but the cause and severity are greatly influenced by critical illness and shock, more so than AG therapy alone. PMID- 27494925 TI - Pharmacodynamics for antifungal drug development: an approach for acceleration, risk minimization and demonstration of causality. AB - The treatment of invasive fungal diseases constitutes a significant unmet medical need. There are relatively few antifungal agents in clinical development and a paucity of novel targets. Morbidity and mortality remain high and clinical outcomes are compromised by submaximal efficacy, emergence of drug resistance and drug-related toxicity. Thus, new antifungal agents are urgently required. A deep understanding of exposure-response relationships underpins the development of safe and effective clinical regimens of any therapeutic agent. Pharmacokinetics (PK) and pharmacodynamics (PD) is increasingly recognized as a vital tool in the development of new antimicrobial agents and maximizes the probability that the right dose will be studied the first time. There is currently no information or agreement as to what constitutes an adequate PK/PD package for the development of a new antifungal agent. This review provides a summary of the achievements of antifungal PK/PD for the treatment of invasive candidiasis, invasive aspergillosis and cryptococcal meningoencephalitis, and outlines the necessary components of a PK/PD package for a new antifungal agent. Such information is critical for the accelerated and efficient development of new agents and enables improved clinical outcomes to be secured. PMID- 27494926 TI - 1,3-beta-d-Glucan contamination of common antimicrobials-authors' response. PMID- 27494927 TI - Escherichia coli antimicrobial susceptibility profile and cumulative antibiogram to guide empirical treatment of uncomplicated urinary tract infections in women in the province of Quebec, 2010-15. AB - OBJECTIVES: Empirical treatment of uncomplicated urinary tract infections (UTIs) in women should be based on local susceptibility data. We aimed to generate regional and provincial cumulative antibiograms combining data from different laboratory information systems and determine the impact of basic patient characteristics on susceptibility results. METHODS: All positive urine samples for Escherichia coli obtained from women aged 18-65 years old in outpatient settings between 1 April 2010 and 31 March 2015 from four hospitals in Quebec, Canada, were included. The cumulative antibiogram for ciprofloxacin, nitrofurantoin and trimethoprim/sulfamethoxazole was calculated. A clinically significant difference in susceptibility profile was defined as factor(s) that lowered the susceptibility proportion below 80%. RESULTS: A total of 36 293 positive urine cultures were analysed. In the last year of the study, the proportion of susceptibility for ciprofloxacin, nitrofurantoin and trimethoprim/sulfamethoxazole was 90.3%, 95.4% and 81.9%, respectively. The susceptibility proportion was <80% for trimethoprim/sulfamethoxazole in the Montreal region (73.4%; 95% CI 71.1%-75.9%), whereas it remained >80% for the other regions. A significant decrease in susceptibility with time was identified for ciprofloxacin (92.1%-90.3%, P < 0.001) and nitrofurantoin (97.1%-95.4%, P < 0.001). Increasing age, recent hospitalization and site of collection were associated with an increase in resistance for certain antibiotics. CONCLUSIONS: Overall, all first-line antimicrobials remain acceptable choices for empirical treatment of uncomplicated UTIs in women in Quebec. The regional variability in susceptibility data within a single province emphasizes the importance of local susceptibility data to inform the development of empirical treatment guidelines for UTIs. PMID- 27494928 TI - Mosaic tetracycline resistance genes encoding ribosomal protection proteins. AB - First reported in 2003, mosaic tetracycline resistance genes are a subgroup of the genes encoding ribosomal protection proteins (RPPs). They are formed when two or more RPP-encoding genes recombine resulting in a functional chimera. To date, the majority of mosaic genes are derived from sections of three RPP genes, tet(O), tet(W) and tet(32), with others comprising tet(M) and tet(S). In this first review of mosaic genes, we report on their structure, diversity and prevalence, and suggest that these genes may be responsible for an under-reported contribution to tetracycline resistance in bacteria. PMID- 27494929 TI - Comparative effectiveness of echinocandins versus fluconazole therapy for the treatment of adult candidaemia due to Candida parapsilosis: a retrospective observational cohort study of the Mycoses Study Group (MSG-12). AB - OBJECTIVES: A polymorphism in the gene encoding beta-1,3-glucan synthase, the target of the echinocandin class of antifungals, results in increased in vitro MICs of the echinocandins. This has resulted in controversy surrounding use of the echinocandins for treatment of Candida parapsilosis candidaemia. We aimed to compare 30 day mortality in adults with C. parapsilosis candidaemia treated with echinocandins versus fluconazole. METHODS: This is a retrospective observational cohort study. We used the Premier Perspective Database to identify adult patients with C. parapsilosis candidaemia treated with only fluconazole or only an echinocandin as definitive therapy. The primary outcome was 30 day mortality. Propensity scores were derived to estimate the probability the patient would have received either an echinocandin or fluconazole. Inverse probability of treatment weighting (IPTW) was used in a weighted logistic regression to calculate odds of 30 day mortality. RESULTS: There were 307 unique patients with C. parapsilosis candidaemia. One hundred and twenty-six (41%) received fluconazole and 181 (59%) received an echinocandin. Age, gender, race, year of admission, need for ICU resources in the week prior to candidaemia onset, and receipt of vasopressors on the day of candidaemia onset were included in the propensity score model used to calculate inverse probability of treatment weights. Weighted logistic regression demonstrated no difference in 30 day mortality between patients receiving an echinocandin as compared with fluconazole (OR 0.82, 95% CI 0.33-2.07). CONCLUSIONS: Our result supports the 2016 IDSA invasive candidiasis guidelines, which no longer clearly favour treatment with fluconazole over an echinocandin for C. parapsilosis candidaemia. PMID- 27494930 TI - Impact of 48 weeks of atazanavir/ritonavir plus lamivudine dual therapy on cellular HIV-DNA levels in the AtLaS pilot study. PMID- 27494931 TI - Multiplication of blaOXA-23 is common in clinical Acinetobacter baumannii, but does not enhance carbapenem resistance. AB - OBJECTIVES: To investigate the copy number of blaOXA-23 and its correlation with carbapenem resistance in carbapenem-resistant Acinetobacter baumannii (CRAB). METHODS: A total of 113 blaOXA-23-positive clinical CRAB isolates were collected from two hospitals in Zhejiang province, China. Their genetic relatedness was determined by MLST. The MIC of imipenem was determined using the agar diffusion method and the copy number of blaOXA-23 was measured using quantitative real-time PCR (qRT-PCR). The complete genomes of five clinical CRAB strains were sequenced using PacBio technology to investigate the multiplication mechanism of blaOXA-23. RESULTS: Most of the isolates (100/113) belonged to global clone II and the MIC of imipenem ranged from 16 to 96 mg/L. The gene blaOXA-23 resided exclusively in Tn2006 or Tn2009. Approximately 38% of the isolates carried two or more copies of blaOXA-23. The copy number of blaOXA-23 was not correlated with the MIC of imipenem. Within the five sequenced strains, multiple copies of blaOXA-23 were either tandemly clustered or independently inserted at different genomic sites. CONCLUSIONS: Multiplication of blaOXA-23 is common in CRAB, but does not enhance carbapenem resistance. Multiplication can be present in the form of either tandem amplifications or independent insertions at different sites. PMID- 27494933 TI - Head elevation by 3 vs. 6 cm in ProSeal laryngeal mask airway insertion: a randomized controlled trial. AB - BACKGROUND: The sniffing position (neck flexion by head elevation and head extension) is commonly used for insertion of a laryngeal mask airway. However, the appropriate degrees of head elevation and head extension are unclear. In the present study, the success rate of ProSealTM laryngeal mask airway (LMA ProSeal) insertion using two degrees of head elevation was evaluated. METHODS: This prospective randomized, controlled study included 80 adult patients aged 18 to 90 years. In the 3 cm (n = 40) and 6 cm (n = 40) groups, the LMA ProSeal was inserted while the head was elevated 3 cm and 6 cm, respectively, using a pillow of the corresponding height. The success rate, and incidence of blood staining on cuff, sore throat and hoarseness were assessed. The alignments of laryngeal and oral axes were also evaluated. RESULTS: The first attempt success rate was higher in the 3 cm than the 6 cm group (87 % vs. 60 %, P = 0.014). In 86 % of patients in the 6 cm group and 50 % of patients in the 3 cm group in whom the second attempt failed, the third insertion attempt was successful by using a pillow height of the opposite group. The alignments of the two axes were not different between the two groups (P > 0.05). CONCLUSIONS: The first attempt success rate of ProSeal laryngeal mask insertion was higher with 3 cm than 6 cm head elevation in adult patients. TRIAL REGISTRATION: Identifiers: NCT02058030 (08/05/2015), Unique Protocol ID: phdkim1. PMID- 27494932 TI - Using a gamified monitoring app to change adolescents' snack intake: the development of the REWARD app and evaluation design. AB - BACKGROUND: As the snacking pattern of European adolescents is of great concern, effective interventions are necessary. Till now health promotion efforts in children and adolescents have had only limited success in changing adolescents' eating patterns and anthropometrics. Therefore, the present study proposes an innovative approach to influence dietary behaviors in youth based on new insights on effective behavior change strategies and attractive intervention channels to engage adolescents. This article describes the rationale, the development, and evaluation design of the 'Snack Track School' app. The aim of the app is to improve the snacking patterns of Flemish 14- to 16-year olds. METHODS: The development of the app was informed by the systematic, stepwise, iterative, and collaborative principles of the Intervention Mapping protocol. A four week mHealth intervention was developed based on the dual-system model with behavioral change strategies targeting both the reflective (i.e., active learning, advance organizers, mere exposure, goal-setting, monitoring, and feedback) and automatic processes (i.e., rewards and positive reinforcement). This intervention will be evaluated via a controlled pre-post design in Flemish schools among 1400 adolescents. DISCUSSION: When this intervention including strategies focused on both the reflective and automatic pathway proves to be effective, it will offer a new scientifically-based vision, guidelines and practical tools for public health and health promotion (i.e., incorporation of learning theories in intervention programs). TRIAL REGISTRATION: NCT02622165 registrated November 15, 2015 on clinicaltrials.gov. PMID- 27494934 TI - Onchocerciasis transmission in Ghana: the human blood index of sibling species of the Simulium damnosum complex. AB - BACKGROUND: Vector-biting behaviour is important for vector-borne disease (VBD) epidemiology. The proportion of blood meals taken on humans (the human blood index, HBI), is a component of the biting rate per vector on humans in VBD transmission models. Humans are the definitive host of Onchocerca volvulus, but the simuliid vectors feed on a range of animals and HBI is a key indicator of the potential for human onchocerciasis transmission. Ghana has a diversity of Simulium damnosum complex members, which are likely to vary in their HBIs, an important consideration for parameterization of onchocerciasis control and elimination models. METHODS: Host-seeking and ovipositing S. damnosum (sensu lato) (s.l.) were collected from seven villages in four Ghanaian regions. Taxa were morphologically and molecularly identified. Blood meals from individually stored blackfly abdomens were used for DNA profiling, to identify previous host choice. Household, domestic animal, wild mammal and bird surveys were performed to estimate the density and diversity of potential blood hosts of blackflies. RESULTS: A total of 11,107 abdomens of simuliid females (which would have obtained blood meal(s) previously) were tested, with blood meals successfully amplified in 3,772 (34 %). A single-host species was identified in 2,857 (75.7 %) of the blood meals, of which 2,162 (75.7 %) were human. Simulium soubrense Beffa form, S. squamosum C and S. sanctipauli Pra form were the most anthropophagic (HBI = 0.92, 0.86 and 0.70, respectively); S. squamosum E, S. yahense and S. damnosum (sensu stricto) (s.s.)/S. sirbanum were the most zoophagic (HBI = 0.44, 0.53 and 0.63, respectively). The degree of anthropophagy decreased (but not statistically significantly) with increasing ratio of non-human/human blood hosts. Vector to human ratios ranged from 139 to 1,198 blackflies/person. CONCLUSIONS: DNA profiling can successfully identify blood meals from host seeking and ovipositing blackflies. Host choice varies according to sibling species, season and capture site/method. There was no evidence that HBI is vector and/or host density dependent. Transmission breakpoints will vary among locations due to differing cytospecies compositions and vector abundances. PMID- 27494935 TI - Chicken interferome: avian interferon-stimulated genes identified by microarray and RNA-seq of primary chick embryo fibroblasts treated with a chicken type I interferon (IFN-alpha). AB - Viruses that infect birds pose major threats-to the global supply of chicken, the major, universally-acceptable meat, and as zoonotic agents (e.g. avian influenza viruses H5N1 and H7N9). Controlling these viruses in birds as well as understanding their emergence into, and transmission amongst, humans will require considerable ingenuity and understanding of how different species defend themselves. The type I interferon-coordinated response constitutes the major antiviral innate defence. Although interferon was discovered in chicken cells, details of the response, particularly the identity of hundreds of stimulated genes, are far better described in mammals. Viruses induce interferon-stimulated genes but they also regulate the expression of many hundreds of cellular metabolic and structural genes to facilitate their replication. This study focusses on the potentially anti-viral genes by identifying those induced just by interferon in primary chick embryo fibroblasts. Three transcriptomic technologies were exploited: RNA-seq, a classical 3'-biased chicken microarray and a high density, "sense target", whole transcriptome chicken microarray, with each recognising 120-150 regulated genes (curated for duplication and incorrect assignment of some microarray probesets). Overall, the results are considered robust because 128 of the compiled, curated list of 193 regulated genes were detected by two, or more, of the technologies. PMID- 27494937 TI - John McKessar Duncan. PMID- 27494936 TI - An LPL-specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1. AB - LPL contains two principal domains: an amino-terminal catalytic domain (residues 1-297) and a carboxyl-terminal domain (residues 298-448) that is important for binding lipids and binding glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 (GPIHBP1) (an endothelial cell protein that shuttles LPL to the capillary lumen). The LPL sequences required for GPIHBP1 binding have not been examined in detail, but one study suggested that sequences near LPL's carboxyl terminus (residues ~403-438) were crucial. Here, we tested the ability of LPL-specific monoclonal antibodies (mAbs) to block the binding of LPL to GPIHBP1. One antibody, 88B8, abolished LPL binding to GPIHBP1. Consistent with those results, antibody 88B8 could not bind to GPIHBP1-bound LPL on cultured cells. Antibody 88B8 bound poorly to LPL proteins with amino acid substitutions that interfered with GPIHBP1 binding (e.g., C418Y, E421K). However, the sequences near LPL's carboxyl terminus (residues ~403-438) were not sufficient for 88B8 binding; upstream sequences (residues 298-400) were also required. Additional studies showed that these same sequences are required for LPL binding to GPIHBP1. In conclusion, we identified an LPL mAb that binds to LPL's GPIHBP1-binding domain. The binding of both antibody 88B8 and GPIHBP1 to LPL depends on large segments of LPL's carboxyl-terminal domain. PMID- 27494938 TI - Role of Screening Tests in the Detection and Management of Blood Pressure Abnormalities Among Young Population. AB - The prevalence of hypertension is increasing among young population worldwide. So there is an interest in detecting prehypertension and hypertension in childhood. We determined blood pressure (BP) recorded at a screening test in a young population. We retrospectively evaluated the medical records including systolic blood pressure (SBP), diastolic blood pressure (DBP), weight, height, and body mass index (BMI) of 685 male and 130 female apparently healthy adolescents. We evaluated the prevalence of BP categories: normotension, prehypertension, and hypertension. The prevalence of normotension (n = 369), prehypertension (n = 333), and hypertension (n = 113) was 45.3%, 40.9% and 13.9%, respectively; prehypertension and hypertension were significantly higher among males. The prevalence of prehypertension and hypertension was significantly higher among overweight males and females. The BMI significantly correlated with SBP, DBP, and heart rate among both genders. The prevalence of prehypertension and hypertension is high among Turkish adolescents. Screening tests focused on BP and BMI measurement may help detect the young population at risk of hypertension and cardiovascular disease in the future. PMID- 27494939 TI - Oncocytic Papillary Renal Cell Carcinoma in the Background of Renal Adenomatosis. AB - Renal adenomatosis is a rare disease characterized by numerous adenomas in bilateral kidneys. A literature review shows that malignant tumors can arise in this condition. The present case describes an oncocytic papillary renal cell carcinoma (PRCC) arising in renal adenomatosis. A 70-year-old man presented with incidentally identified, multiple right renal masses on computed tomography. Right nephrectomy was performed, and the resected kidney revealed numerous radiologically undetected small nodules additionally. Microscopically, the nodules were papillary neoplasms of variable sizes and cytological features. The largest nodule measured 1.6 cm and was composed of oncocytic cells, meeting the diagnostic criteria of oncocytic PRCC. The smaller nodules of papillary adenomas and tiny lesions showing a single papillary ingrowth were also seen. This case exhibits a spectrum of renal papillary neoplasms in a resected kidney and can be a valuable case in the understanding of tumorigenesis. PMID- 27494940 TI - Learn from the mistakes of care.data. PMID- 27494941 TI - In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis. AB - Dysfunction of homologous recombination is a common denominator of changes associated with breast cancer-predisposing mutations. In our previous work, we identified a functional signature in peripheral blood lymphocytes from women who were predisposed that indicated a shift from homologous recombination to alternative, error-prone DNA double-strand break (DSB) repair pathways. To capture both hereditary and nonhereditary factors, we newly established a protocol for isolation and ex vivo analysis of epithelial cells, epithelial mesenchymal transition cells (EMTs), and fibroblasts from breast cancer specimens (147 patients). By applying a fluorescence-based test system, we analyzed the error-prone DSB repair pathway microhomology-mediated end joining in these tumor derived cell types and peripheral blood lymphocytes. In parallel, we investigated DNA lesion processing by quantitative immunofluorescence microscopy of histone H2AX phosphorylated on Ser139 focus after radiomimetic treatment. Our study reveals elevated histone H2AX phosphorylated on Ser139 damage removal in epithelial cells, not EMTs, and poly(ADP-ribose)polymerase inhibitor sensitivities, which suggested a DSB repair pathway shift with increasing patient age. Of interest, we found elevated microhomology-mediated end joining in EMTs, not epithelial cells, from patients who received a treatment recommendation of adjuvant chemotherapy, that is, those with high-risk tumors. Our discoveries of altered DSB repair activities in cells may serve as a method to further classify breast cancer to predict responsiveness to adjuvant chemotherapy and/or therapeutics that target DSB repair-dysfunctional tumors.-Deniz, M., Kaufmann, J., Stahl, A., Gundelach, T., Janni, W., Hoffmann, I., Keimling, M., Hampp, S., Ihle, M., Wiesmuller, L. In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis. PMID- 27494942 TI - U.S. Food System Working Conditions as an Issue of Food Safety. AB - Food workers' health and hygiene are common pathways to foodborne disease outbreaks. Improving food system jobs is important to food safety because working conditions impact workers' health, hygiene, and safe food handling. Stakeholders from key industries have advanced working conditions as an issue of public safety in the United States. Yet, for the food industry, stakeholder engagement with this topic is seemingly limited. To understand this lack of action, we interviewed key informants from organizations recognized for their agenda-setting role on food-worker issues. Findings suggest that participants recognize the work standards/food safety connection, yet perceived barriers limit adoption of a food safety frame, including more pressing priorities (e.g., occupational safety); poor fit with organizational strategies and mission; and questionable utility, including potential negative consequences. Using these findings, we consider how public health advocates may connect food working conditions to food and public safety and elevate it to the public policy agenda. PMID- 27494943 TI - Transition of Care From Pediatric to Adult Surgery. PMID- 27494944 TI - Ethics Rounds: In the Eye of a Social Media Storm. AB - Social media, no stranger to health care environments, is increasingly used by patients, families, clinicians, and institutions to interact and engage in new ways. The ethical challenges related to the use of social media in the clinical setting are familiar, yet come with a novel twist, including the possibility of having a conflict "go viral". Health care clinicians and institutions must understand and embrace these technologies, while at the same time promoting policies and practices that ensure the ethically appropriate use of social media and address strategies for preventing and responding to a social media crisis. PMID- 27494946 TI - Population Pharmacokinetics of Cefuroxime in Critically Ill Patients Receiving Continuous Venovenous Hemofiltration With Regional Citrate Anticoagulation and a Phosphate-Containing Replacement Fluid. AB - BACKGROUND: Cefuroxime is frequently prescribed as an antimicrobial therapy in critically ill patients. The aim of this study was to develop a new intravenous dosing strategy for cefuroxime in critically ill patients undergoing continuous venovenous hemofiltration with regional citrate anticoagulation (RCA-CVVH) by analyzing its extracorporeal removal and pharmacokinetic (PK) parameters. METHODS: Nine critically ill patients treated with intravenous cefuroxime and RCA CVVH and a phosphate-containing replacement fluid were investigated. Arterial and effluent samples were obtained from all patients and pre- and postfilter venous blood samples were obtained from a subgroup of 5 patients. Plasma cefuroxime levels were determined by ultraperformance liquid chromatography-mass spectrometry in plasma samples collected before and after intravenous infusion of either 1500 mg cefuroxime every 12 hours or 3000 mg continuously over 24 hours. Population PK analysis and dosing simulations were performed using nonlinear mixed-effects modeling and Monte Carlo simulations. RESULTS: The volume of distribution (VD) of cefuroxime in the central compartment, corrected for lean body mass, was 0.11 +/- 0.056 L/kgLBMc, CVVH-mediated clearance was 49.5-50.6 mL/min, the mean elimination half-life (t1/2) was 90 minutes (77-103), and the mean sieving coefficient was 0.89 +/- 0.01. A 2-compartment model with between subject variability in clearance, VD, and t1/2 described these data adequately. Simulation of a standard dosing regimen (750 mg/12 hours) predicted failure to achieve the international target plasma cefuroxime concentration (32 mg/L). CONCLUSIONS: Cefuroxime clearance by RCA-CVVH was twice the reported clearance during standard CVVH. Our PK data predicted that a maintenance dose of 3000 mg cefuroxime, infused over 24 hours, would provide an optimal steady-state plasma concentration of 38.5 mg/L. The developed population PK model for cefuroxime has the potential to inform new dosing schedules in patients receiving cefuroxime during RCA-CVVH. PMID- 27494945 TI - Metabolic profiling of alcohol consumption in 9778 young adults. AB - BACKGROUND: High alcohol consumption is a major cause of morbidity, yet alcohol is associated with both favourable and adverse effects on cardiometabolic risk markers. We aimed to characterize the associations of usual alcohol consumption with a comprehensive systemic metabolite profile in young adults. METHODS: Cross sectional associations of alcohol intake with 86 metabolic measures were assessed for 9778 individuals from three population-based cohorts from Finland (age 24-45 years, 52% women). Metabolic changes associated with change in alcohol intake during 6-year follow-up were further examined for 1466 individuals. Alcohol intake was assessed by questionnaires. Circulating lipids, fatty acids and metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. RESULTS: Increased alcohol intake was associated with cardiometabolic risk markers across multiple metabolic pathways, including higher lipid concentrations in HDL subclasses and smaller LDL particle size, increased proportions of monounsaturated fatty acids and decreased proportion of omega-6 fatty acids, lower concentrations of glutamine and citrate (P < 0.001 for 56 metabolic measures). Many metabolic biomarkers displayed U shaped associations with alcohol consumption. Results were coherent for men and women, consistent across the three cohorts and similar if adjusting for body mass index, smoking and physical activity. The metabolic changes accompanying change in alcohol intake during follow-up resembled the cross-sectional association pattern (R2 = 0.83, slope = 0.72 +/- 0.04). CONCLUSIONS: Alcohol consumption is associated with a complex metabolic signature, including aberrations in multiple biomarkers for elevated cardiometabolic risk. The metabolic signature tracks with long-term changes in alcohol consumption. These results elucidate the double edged effects of alcohol on cardiovascular risk. PMID- 27494947 TI - Evaluation of the New Siemens Tacrolimus Assay on the Dimension EXL Integrated Chemistry System Analyzer: Comparison With an Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method. AB - BACKGROUND: Many patients are maintained at the lower end of the tacrolimus (TAC) reference range (3-7 ng/mL), requiring the use of analytical methods displaying a very low limit of quantification for their follow-up. Therefore, the new Dimension TAC, based on affinity chrome-mediated immunoassay technology, was evaluated on the Dimension EXL Integrated Chemistry System (Siemens Healthcare Diagnostics Inc). The aims of this study were (1) to evaluate the analytical performances with special emphasis on sensibility at low levels of TAC, (2) to compare the results with an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) method. METHODS: Analytical performance (imprecision, linearity, limit of detection, and limit of quantification) was evaluated. Comparison to UPLC/MS/MS was performed on 106 whole blood samples from 88 transplant recipients using regression analysis and Bland-Altman plot analysis. RESULTS: Repeatability and within-laboratory coefficients of variation were <6% at mean TAC control levels of 3.7, 11.7, and 19.2 ng/mL. Linearity was confirmed between 1.0 and 22 ng/mL. Passing-Bablok regression analysis of Siemens TAC assay in comparison with UPLC/MS/MS values displayed a slope of 1.09 and an intercept of -0.42. Using Bland-Altman analysis, the mean bias was 0.27 ng/mL with 1.96 SD limits of -2.14 and 2.67 ng/mL. CONCLUSIONS: The new Dimension TAC immunoassay on the EXL analyzer demonstrated reliable and reproducible performances allowing routine monitoring in transplant patients, even at TAC concentrations at the lower end of the therapeutic range. PMID- 27494948 TI - Ecological risk assessment for DvSnf7 RNA: A plant-incorporated protectant with targeted activity against western corn rootworm. AB - MON 87411 maize, which expresses DvSnf7 RNA, was developed to provide an additional mode of action to confer protection against corn rootworm (Diabrotica spp.). A critical step in the registration of a genetically engineered crop with an insecticidal trait is performing an ecological risk assessment to evaluate the potential for adverse ecological effects. For MON 87411, an assessment plan was developed that met specific protection goals by characterizing the routes and levels of exposure, and testing representative functional taxa that would be directly or indirectly exposed in the environment. The potential for toxicity of DvSnf7 RNA was evaluated with a harmonized battery of non-target organisms (NTOs) that included invertebrate predators, parasitoids, pollinators, soil biota as well as aquatic and terrestrial vertebrate species. Laboratory tests evaluated ecologically relevant endpoints such as survival, growth, development, and reproduction and were of sufficient duration to assess the potential for adverse effects. No adverse effects were observed with any species tested at, or above, the maximum expected environmental concentration (MEEC). All margins of exposure for NTOs were >10-fold the MEEC. Therefore, it is reasonable to conclude that exposure to DvSnf7 RNA, both directly and indirectly, is safe for NTOs at the expected field exposure levels. PMID- 27494950 TI - The Oxygen-Rich Beryllium Oxides BeO4 and BeO6. AB - Two novel isomers of BeO4 with the structures OBeOOO and OBe(O3 ) in the electronic triplet state have been prepared as well as the known disuperoxide complex Be(O2 )2 in solid noble-gas matrices. We also report the synthesis of the oxygen-rich bis(ozonide) complex Be(O3 )2 in the triplet state which has a D2d equilibrium geometry. The molecular structures were identified by infrared absorption spectroscopy with isotopic substitutions as well as quantum chemical calculations. PMID- 27494949 TI - Slow infusion rate of doxorubicin induces higher pro-inflammatory cytokine production. AB - Different infusion rates of doxorubicin (DOX) have been used for treating human malignancies. Organ toxicity after DOX infusion is a major issue in treatment disruption. However, whether different DOX infusion rates induce different toxicity is still unknown. In this study, we examined the toxicity effects of different DOX infusion rates in the early phase of organ toxicity. Thirty-six rats were randomly divided into 5-, 15-, and 30-min infusion rate groups. A single dose of DOX (8.3 mg/kg, I.V.) was administered at different infusion rates. Blood samples were collected from the femoral artery at 1, 3, 6, 9, 12, 18, 24, 36, and 48 h after DOX administration. The blood cell count and blood biochemistry were analyzed. The liver, kidney, and heart were removed for pathological examinations after the rats were sacrificed. Our findings show that the 30-min group had higher injury markers in the liver (glutamic oxaloacetic transaminase and glutamic pyruvic transaminase), kidneys (blood urea nitrogen and creatinine), and heart (creatine phosphokinase-MB and lactate dehydrogenase), and had higher tumor necrosis factor-alpha and interleukin 6 levels than did the other groups. The 30-min group also had more severe damage according to the pathological examinations. In conclusion, slower infusion of DOX induced a higher inflammatory response and greater organ damage. PMID- 27494951 TI - Assessment of retinal vascular calibres as a biomarker of disease activity in birdshot chorioretinopathy. AB - PURPOSE: Birdshot chorioretinopathy (BCR) is a potentially blinding ocular disorder involving the retinal vasculature and choroid without any systemic manifestations. The objective of the study was to describe vascular calibre changes in BCR and analyse the possibility of this optical biomarker for staging and monitoring disease activity in BCR. METHODS: This retrospective case-control study at a tertiary referral eye centre in the UK included 33 eyes from 21 patients with BCR and equal number of eyes from control subjects. Diagnosis of BCR was confirmed on fundus fluorescein and indocyanine green angiography. Vascular calibres were measured using validated semiautomated software. RESULTS: Patients with BCR had smaller retinal venular calibres central retinal venular equivalent (CRVE) than controls (211.3 versus 227.9 MUm, p = 0.008). After adjusting for variables, the difference between the two groups for CRVE at baseline was statistically significant based on two different analysis methods. Central retinal venular equivalent (CRVE) was lower at the 6-month follow-up visit (206.2 versus 213.8 MUm, p-value = 0.03), and arteriole-to-venule ratio was larger (0.74 versus 0.71, p = 0.04) in subjects with BCR. Arteriolar calibre (CRAE) remained the same. CONCLUSION: This study provides novel insight into the pattern of vascular involvement in BCR. There was significant difference in the CRVE in patients with BCR. More studies are needed to correlate this data with visual function and treatment outcome and to validate the findings. PMID- 27494952 TI - Symptomatic discoid lateral meniscus: a clinical and arthroscopic study in a Chinese population. AB - BACKGROUND: Discoid lateral meniscus (DLM) is relatively common in East Asia..Symptomatic discoid lateral meniscus (SDLM) is an important indication for knee arthroscopic surgery. However, studies investigating SDLM are rare. The purpose of this study was to evaluate the clinical characteristics and intra articular variants of SDLM in a Chinese population. METHODS: We retrospectively reviewed all patients with SDLM from January 2005 to December 2014 in our hospital. Clinical variables included gender, age, duration, age of onset, affected side, symptoms and trauma history as well as arthroscopic findings: DLM types, tear patterns and concomitant medial meniscus tear, which were evaluated and compared statistically. RESULTS: Of the 496 consecutive participants with SDLM, females outnumbered males (69.6 % vs. 30.4 %). The age of onset ranged from 3 to 80 years (median, 31 years), and was significantly higher in females than in males (p < 0.0001). Trauma history in males was significantly higher than in females (45 % vs. 35.1 %, p = 0.0356). Males showed a higher incidence of popping and snapping, while females manifested higher range-of-motion (ROM) limitations (p = 0.0179, and p = 0.0392, respectively). No significant difference in intra articular variants was observed between genders. The complete type was the most frequent (344, 69.4 %), followed by the incomplete type (149, 30 %), and the Wrisberg type (3, 0.6 %). Significant difference in tear patterns was found between complete and incomplete types (p < 0.0001). Few patients showed medial meniscus tear (11, 2.2 %), at a significantly higher age compared with patients without tear (median, 57 years vs. 33 years, p < 0.0001). CONCLUSIONS: The majority of Chinese patients with SDLM are young and middle-aged females. Female patients had an older age of onset, higher incidence of ROM limitation and limited trauma history. The complete type is the most common, with tear patterns varying between complete and incomplete types. The SDLM does not significantly affect the medial meniscus. PMID- 27494954 TI - Cancer Risk Factor Knowledge Among Young Adults. AB - Cancer is the second leading cause of death in the USA. Incidence and mortality rates for cancer have risen steadily and cost the healthcare system over $264 billion annually. Cancer risk can be reduced by restricting alcohol consumption, avoiding tobacco, eating a balanced diet, limiting sun exposure, exercising, and seeking routine cancer screenings. The purpose of this study is to examine cancer risk factor knowledge among college students. Researchers surveyed undergraduate and graduate students (n = 758) at a mid-sized public university in the Southeast about their knowledge regarding cancer risk factors including smoking, alcohol consumption, diet, obesity, hypertension, and human papillomavirus (HPV). Participants were mostly able to identify the association between cancers and health risk behaviors that have received widespread media coverage, are somewhat intuitive, or are salient to their life stage such as drinking, tanning, and smoking. Nearly all participants correctly reported exposure to ultraviolet (UV) rays, and smoking increased risk of developing skin and lung cancer, respectively. Most students correctly identified an increased risk of liver cancer associated with alcohol use but missed head/neck and breast cancer. However, knowledge of less publicized relationships was insufficient. The findings offer encouragement to public health professionals that campaigns have increased awareness of cancer risk. However, there were many relationships that revealed a lack of knowledge, and future campaigns can target lesser-known cancer risk relationships to reduce the personal tragedy and societal burden of cancer. PMID- 27494953 TI - Associations between systemic inflammation, mycobacterial loads in sputum and radiological improvement after treatment initiation in pulmonary TB patients from Brazil: a prospective cohort study. AB - BACKGROUND: Mycobacterium tuberculosis infection is known to cause inflammation and lung tissue damage in high-risk populations. Nevertheless, direct associations between mycobacterial loads, systemic inflammation and pulmonary lesions upon treatment initiation have not been fully characterized. In the present exploratory study, we prospectively depict the immune profile, microbial clearance and evolution of radiographic lesions in a pulmonary tuberculosis (PTB) patient cohort before and 60 days after anti-tuberculous treatment (ATT) initiation. METHODS: Circulating levels of cytokines (IL-2, IL-4, IL-6, IL-10, IFN-gamma, TNF-alpha) and C-reactive protein (CRP), as well as values of erythrocyte sedimentation rate (ESR) were measured in cryopreserved serum samples obtained from 73 PTB patients at pre-ATT and day 60 of treatment. Changes of the immune profile over time were compared with mycobacterial loads in sputum and culture conversion at day 60 of ATT. Additional analyses tested associations between improvement of chest radiographic lesions at day 60 and pre-treatment status of inflammation and mycobacterial loads. RESULTS: Within the inflammatory parameters evaluated, values of CRP, IL-2, IL-4, TNF-alpha and ESR significantly decreased upon treatment initiation. On the converse, IL-10 levels substantially increased at day 60 of ATT, whereas concentrations of IL-6 and IFN-gamma remained unchanged. Multidimensional analyses revealed that ESR, IL-2, IL-4 and CRP were the parameters with the highest power to discriminate individuals before and after treatment initiation. We further demonstrated that higher bacterial loads in sputum at pre-ATT were associated with increased systemic inflammation and higher risk for positive M. tuberculosis sputum cultures at day 60 of treatment. Furthermore, we found that pre-ATT mycobacterial loads in sputum and systemic inflammation synergistically associated with the status of radiographic lesions during treatment (Relative risk for chest X-ray improvement: 10.0, 95 % confidence interval: 2.4-40.0, P = 0.002). CONCLUSIONS: M. tuberculosis loads in sputum are directly associated to the status of systemic inflammation and potentially impact the immune profile, culture conversion and evolution of lung lesions upon ATT initiation. PMID- 27494955 TI - Two-stage Bayesian model to evaluate the effect of air pollution on chronic respiratory diseases using drug prescriptions. AB - Exposure to high levels of air pollutant concentration is known to be associated with respiratory problems which can translate into higher morbidity and mortality rates. The link between air pollution and population health has mainly been assessed considering air quality and hospitalisation or mortality data. However, this approach limits the analysis to individuals characterised by severe conditions. In this paper we evaluate the link between air pollution and respiratory diseases using general practice drug prescriptions for chronic respiratory diseases, which allow to draw conclusions based on the general population. We propose a two-stage statistical approach: in the first stage we specify a space-time model to estimate the monthly NO2 concentration integrating several data sources characterised by different spatio-temporal resolution; in the second stage we link the concentration to the beta2-agonists prescribed monthly by general practices in England and we model the prescription rates through a small area approach. PMID- 27494956 TI - Characterizing the spatial distribution of multiple pollutants and populations at risk in Atlanta, Georgia. AB - BACKGROUND: Exposure metrics that identify spatial contrasts in multipollutant air quality are needed to better understand multipollutant geographies and health effects from air pollution. Our aim is to improve understanding of: (1) long-term spatial distributions of multiple pollutants; and (2) demographic characteristics of populations residing within areas of differing air quality. METHODS: We obtained average concentrations for ten air pollutants (p=10) across a 12 km grid (n=253) covering Atlanta, Georgia for 2002-2008. We apply a self-organizing map (SOM) to our data to derive multipollutant patterns observed across our grid and classify locations under their most similar pattern (i.e, multipollutant spatial type (MST)). Finally, we geographically map classifications to delineate regions of similar multipollutant characteristics and characterize associated demographics. RESULTS: We found six MSTs well describe our data, with profiles highlighting a range of combinations, from locations experiencing generally clean air to locations experiencing conditions that were relatively dirty. Mapping MSTs highlighted that downtown areas were dominated by primary pollution and that suburban areas experienced relatively higher levels of secondary pollution. Demographics show the largest proportion of the overall population resided in downtown locations experiencing higher levels of primary pollution. Moreover, higher proportions of nonwhites and children in poverty reside in these areas when compared to suburban populations that resided in areas exhibiting relatively lower pollution. CONCLUSION: Our approach reveals the nature and spatial distribution of differential pollutant combinations across urban environments and provides helpful insights for identifying spatial exposure and demographic contrasts for future health studies. PMID- 27494957 TI - Non-stationary spatio-temporal modeling of traffic-related pollutants in near road environments. AB - A problem often encountered in environmental epidemiological studies assessing the health effects associated with ambient exposure to air pollution is the spatial misalignment between monitors' locations and subjects' actual residential locations. Several strategies have been adopted to circumvent this problem and estimate pollutants concentrations at unsampled sites, including spatial statistical or geostatistical models that rely on the assumption of stationarity to model the spatial dependence in pollution levels. Although computationally convenient, the assumption of stationarity is often untenable for pollutants concentration, particularly in the near-road environment. Building upon the work of Fuentes (2001) and Schmidt et al. (2011), in this paper we present a non stationary spatio-temporal model for three traffic-related pollutants in a localized near-road environment. Modeling each pollutant separately and independently, we express each pollutant's concentration as a mixture of two independent spatial processes, each equipped with a non-stationary covariance function with covariates driving the non-stationarity and the mixture weights. PMID- 27494958 TI - Acute effects of aircraft noise on cardiovascular admissions - an interrupted time-series analysis of a six-day closure of London Heathrow Airport caused by volcanic ash. AB - Acute noise exposure may acutely increase blood pressure but the hypothesis that acute exposure to aircraft noise may trigger cardiovascular events has not been investigated. This study took advantage of a six-day closure of a major airport in April 2010 caused by volcanic ash to examine if there was a decrease in emergency cardiovascular hospital admissions during or immediately after the closure period, using an interrupted daily time-series study design. The population living within the 55dB(A) noise contour was substantial at 0.7 million. The average daily admission count was 13.9 (SD 4.4). After adjustment for covariates, there was no evidence of a decreased risk of hospital admission from cardiovascular disease during the closure period (relative risk 0.97 (95% CI 0.75-1.26)). Using lags of 1-7 days gave similar results. Further studies are needed to investigate if transient aircraft noise exposure can trigger acute cardiovascular events. PMID- 27494959 TI - Mitigating the effects of preferentially selected monitoring sites for environmental policy and health risk analysis. AB - The potential effects of air pollution are a major concern both in terms of the environment and in relation to human health. In order to support both environmental and health policy there is a need for accurate estimates of the exposures that populations might experience. The information for this typically comes from environmental monitoring networks but often the locations of monitoring sites are preferentially located in order to detect high levels of pollution. Using the information from such networks has the potential to seriously affect the estimates of pollution that are obtained and that might be used in health risk analyses. In this context, we explore the topic of preferential sampling within a long-standing network in the UK that monitored black smoke due to concerns about its effect on public health, the extent of which came to prominence during the famous London fog of 1952. Abatement measures led to a decline in the levels of black smoke and a subsequent reduction in the number of monitoring locations that were thought necessary to provide the information required for policy support. There is evidence of selection bias during this process with sites being kept in the most polluted areas. We assess the potential for this to affect the estimates of risk associated air pollution and show how using Bayesian spatio-temporal exposure models may be used to attempt to mitigate the effects of preferential sampling in this case. PMID- 27494960 TI - How robust are the estimated effects of air pollution on health? Accounting for model uncertainty using Bayesian model averaging. AB - The long-term impact of air pollution on human health can be estimated from small area ecological studies in which the health outcome is regressed against air pollution concentrations and other covariates, such as socio-economic deprivation. Socio-economic deprivation is multi-factorial and difficult to measure, and includes aspects of income, education, and housing as well as others. However, these variables are potentially highly correlated, meaning one can either create an overall deprivation index, or use the individual characteristics, which can result in a variety of pollution-health effects. Other aspects of model choice may affect the pollution-health estimate, such as the estimation of pollution, and spatial autocorrelation model. Therefore, we propose a Bayesian model averaging approach to combine the results from multiple statistical models to produce a more robust representation of the overall pollution-health effect. We investigate the relationship between nitrogen dioxide concentrations and cardio-respiratory mortality in West Central Scotland between 2006 and 2012. PMID- 27494961 TI - Modelling collinear and spatially correlated data. AB - In this work we present a statistical approach to distinguish and interpret the complex relationship between several predictors and a response variable at the small area level, in the presence of (i) high correlation between the predictors and (ii) spatial correlation for the response. Covariates which are highly correlated create collinearity problems when used in a standard multiple regression model. Many methods have been proposed in the literature to address this issue. A very common approach is to create an index which aggregates all the highly correlated variables of interest. For example, it is well known that there is a relationship between social deprivation measured through the Multiple Deprivation Index (IMD) and air pollution; this index is then used as a confounder in assessing the effect of air pollution on health outcomes (e.g. respiratory hospital admissions or mortality). However it would be more informative to look specifically at each domain of the IMD and at its relationship with air pollution to better understand its role as a confounder in the epidemiological analyses. In this paper we illustrate how the complex relationships between the domains of IMD and air pollution can be deconstructed and analysed using profile regression, a Bayesian non-parametric model for clustering responses and covariates simultaneously. Moreover, we include an intrinsic spatial conditional autoregressive (ICAR) term to account for the spatial correlation of the response variable. PMID- 27494962 TI - Air pollution and stroke - an overview of the evidence base. AB - Air pollution is being increasingly recognized as a significant risk factor for stroke. There are numerous sources of air pollution including industry, road transport and domestic use of biomass and solid fuels. Early reports of the association between air pollution and stroke come from studies investigating health effects of severe pollution episodes. Several daily time series and case crossover studies have reported associations with stroke. There is also evidence linking chronic air pollution exposure with stroke and with reduced survival after stroke. A conceptual framework linking air pollution exposure and stroke is proposed. It links acute and chronic exposure to air pollution with pathways to acute and chronic effects on stroke risk. Current evidence regarding potential mechanisms mainly relate to particulate air pollution. Whilst further evidence would be useful, there is already sufficient evidence to support consideration of reduction in air pollution as a preventative measure to reduce the stroke burden globally. PMID- 27494963 TI - Editorial for SSTE special issue on Environment and Health. PMID- 27494964 TI - [Not Available]. PMID- 27494966 TI - [Not Available]. PMID- 27494967 TI - [Not Available]. PMID- 27494965 TI - [Not Available]. AB - REFLEXIONS ABOUT NEW STRATEGIES OF RADIOTHERAPY FOR EARLY BREAST CANCER: Radiotherapy (RT) remains a major treatment element in early breast cancer, with a major impact on local control and survival. For ductal carcinoma in situ (DCIS), RT reduces local recurrence (LR) rates by 50 to 60 % after conservative surgery (both in situ and invasive). This was confirmed by four randomized trials and one meta-analysis. For infiltrating breast cancers (IBC), RT also reduces LR rates by 65 to 75 % after conservative surgery. Boost allows an additional reduction of LR. RT is efficient in all age categories, but hypofractionated schemes are particularly adapted to elderly women. Partial breast irrradiation techniques are very much heterogeneous and lack follow-up. They should be used in LR low-risk patients only and in the frame of controlled studies. Locoregional RT for high-risk patients (especially in pN+) remains essential to reduce the locoregional recurrence rate and to increase survival, as confirmed in several meta-analyses. Four studies showed a survival benefit (2-3 %), thanks to internal mammary chain irradiation in LR high-risk patients. Moreover, axillary RT seems to be a likely valuable alternative to axillary dissection in case of sentinel node invasion. Finally, with the modern techniques and dosimetric optimization, RT toxicity was reduced, or even cancelled, arousing hope for a better increased benefit for the patients in the future. PMID- 27494968 TI - [Not Available]. AB - TREATMENT OF NSCLC WITH NIVOLUMAB: Chemotherapy with docetaxel has remained a cornerstone of second-line treatment for more than 15 years, but it is associated with an unfavorable safety profile. Recently, the results of 2 randomized phase III trials assessing nivolumab in lung cancer, Check-Mate-017 and Check- Mate 057, have deeply changed our current clinical practice and open the debate for further improvements in the clinical care of lung cancer. This paper explores the recent findings about nivolumab in the second-line setting and discusses future directions for nivolumab and other immune Oncology drugs. PMID- 27494970 TI - [Not Available]. AB - THE ROLE OF RUXOLITINIB IN THE TREATMENT OF MYELOPROLIFERATIVE NEOPLASMS: The discovery of the JAK2V617F mutation in 2005, present in 95% of polycythemia vera (PV) and in 55% of myelofibrosis (MF) patients, opened the way for a new era of targeted therapies for myeloproliferative neoplasms. Ruxolitinib was the first-in class Janus Kinase (JAK) inhibitor approved for the management of these diseases. In PV patients, conventional treatment strategies including aspirin, phlebotomy, cytoreductive agents such as hydroxyurea and interferon, clearly provide clinical benefits. However, some patients develop resistance or intolerance to these treatments. Ruxolitinib has been approved for PV patients who are resistant to or intolerant of hydroxyurea, based on the results of the phase 3 RESPONSE study. This study showed that ruxolitinib improves hematocrit control, reduces splenomegaly, and ameliorate disease-related symptoms as compared with best available therapy. In MF patients, the only curative treatment is allogeneic stem cell transplantation, but it remains restricted to a limited group of patients with poor prognosis and who are eligible for such procedure associated with non negligible transplant-related mortality. Other treatments are palliative and unlikely to prolong survival. Ruxolitinib has been approved in the United States for MF patients with intermediate or high-risk disease, and in Europe for disease related splenomegaly or symptoms in adults with MF, based on phase 3 COMFORT-I and COMFORT-II studies. These studies showed that ruxolitinib was able to reduce splenomegaly, ameliorate symptoms, and improve survival. However, the journey is not finished yet since there are still important unmet needs for MF patients, including improvement in cytopenias, and significant modification of disease natural history. PMID- 27494971 TI - [Not Available]. PMID- 27494969 TI - [Not Available]. AB - BIOLOGICAL ASPECTS OF JAK/STAT SIGNALING IN BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: Myeloproliferative disorders more recently named Myeloproliferative neoplasms (MPN) display several clinical entities: chronic myeloid leukemia (CML), the classical MPN including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and atypical and unclassifiable NMP. The term MPN is mostly used for classical BCR-ABL-negative (myeloproliferative disorder) (ET, PV, PMF). These are clonal diseases resulting from the transformation of an hematopoietic stem cell and leading to an abnormal production of myeloid cells. The genetic defects responsible for the myeloproliferative abnormalities are called " driver " mutations and all result in deregulation of the cytokine receptor / JAK2 / STAT axis. Among them, JAK2, the thrombopoietin receptor (MPL) and calreticulin (CALR) mutations are found in around 90% of the cases. These driver MPN mutations can be associated with other driver mutations also found in other hematological malignancies, especially in PMFs. These are chronic diseases with major risks being thrombosis, hemorrhage and cytopenias for PMF and the long-term progression to myelofibrosis and the transformation to leukemia. Most recent therapeutic have focused on targeting the JAK2 signaling pathway directly by inhibitors of JAK2 or indirectly. Interferon a allows in some cases hematologic and molecular remission patients. PMID- 27494972 TI - [Not Available]. AB - FUNDAMENTAL BASIS OF METASTATIC PROCESS: Metastatic process is described as a "dissemination of neoplastic cells in a distant secondary site, in which cells proliferate to develop a mass of cells partially differentiated". The vast majority of death in solid cancers is the consequence of metastasis development which lead to vital organ dysfunction. In the present review, either recent discoveries or controversial subjects associated with metastasis process will be discussed. Indeed epithelia-mesenchymal transition (EMT), circulating tumor cells, tumor dormancy, colonization in distant organ and cancer stem cells are tackled. PMID- 27494973 TI - [Not Available]. AB - ANTI-PD1 ROLE IN TREATMENT OF CUTANEOUS MELANOMA: The treatment of metastatic melanoma dramatically changed over the last years. Two therapeutic revolutions emerged in parallel, targeted anti-BRAF and anti-MEK therapies, for patients BRAFV600 mutated and immunotherapy with immune checkpoint blockers using anti CTLA-4 then anti-PD1 monoclonal antibodies. Indeed, melanoma immunotherapy was a golden objective for many years but in spite of important efforts using cytokines (interferon, interleukin) and different vaccine approaches no objective improvement of patients 'prognosis was obtained. Ipilimumab, authorized in 2011, was the first drug which showed a benefit of overall survival in patients with metastatic melanoma in spite a low response rate (10-15) and the occurrence of about 25% of serious toxicity. Anti-PD1 appear as a new generation of immune checkpoint blockade with response rates between 30 to 40% of the patients, a proven overall survival benefit as compared with chemotherapy or ipilimumab and less toxicity than ipilimumab. Two molecules, pembrolizumab and nivolumab were recently approved in monotherapy, for metastatic melanoma. Several questions remain unresolved: the respective indications of anti-PD1 and targeted therapies in first line therapy in patients with BRAF mutant melanoma, the benefit of combining immunotherapy with radiotherapy or with targeted therapies, the optimal treatment duration, and the benefit of the anti-PD1 in the adjuvant setting. The combination of ipilimumab and nivolumab, recently approved by the FDA but not yet in Europ, shows an improvement of the objective response rates (50-57%) and progression free survival compared with nivolumab but is associated with an higer incidence of serious adverse events (more than 50%). PMID- 27494974 TI - [Not Available]. AB - OLIGOMETASTASIS AND OLIGOPROGRESSION: Oligometastic progression (or solitary metastases) can justify ablative treatment for metastatic treatment. When such a strategy is discussed, it is important to notice that definition of oligometastases is not consensual both in terms of clinical presentation than on the biological basis. Does a specific biological background truly exist and are there markers that could predict for additional occult disease and its oligo or polymetastatic profile in individuals with demonstrated oligometastasis. This article provides a summary of the state of the art in this field and highlights some current areas of controversies. PMID- 27494975 TI - [Not Available]. AB - MOLECULAR EVALUATION OF METASTATIC DISEASE: WHY PATHOLOGY REMAINS (AND WILL REMAIN) MANDATORY?: Numerous techniques are now available for the molecular evaluation of a tissular or cellular sample in the context of metastatic disease. They include in situ molecular techniques, such as immunohistochemistry for the study of proteins and peptides, in situ hybridization for the study of nucleic acids and in situ cytogenetics (FISH and its variants) for the demonstration of chromosome alterations. They also include all the techniques of molecular biology, which can now be applied to frozen as well as fixed tissue samples. The combination of all these techniques makes it possible an integrated and coherent approach, not limited to the description of DNA abnormalities, but able to correlate genomic alterations with functional, and even structural changes. A second major interest of the analysis of tissue samples is that they make it possible to analyzing not only tumor cells, but also their environment, formed by the stroma and its populations. The study of stroma and of stromal cells, in particular of immune cells, is now of paramount importance for providing new prognostic and predictive biomarkers, especially for anti-angiogenic strategies and for cancer immunotherapy. Tissue analysis is therefore the only way to perform a " total ", " phenogenomic " characterization of the tumor as an organ : this is particularly important in the moment in which descriptive genomics is substituted by functional genomics and integrated biology. PMID- 27494976 TI - [Not Available]. AB - HOW A BIOMARKER CAN BECOME AN ACCEPTABLE SUBSTITUTION CRITERIA ?: Numerous biomarkers of the treatment activity are now available as a result of the fascinating progresses in biology and biotechnology. Together with the rapidly growing understanding of the mechanisms of action of new agents, these biomarkers provide promising tools to evaluate early the effect of treatments against cancer. It is tempting to use these new markers of activity as primary endpoints to evaluate new treatments in the context of randomized clinical trials. Nevertheless, a mandatory preliminary step is to demonstrate that the two endpoints carry the same information in order to validate whether the biomarker is a surrogate of the final endpoint. We illustrate on several examples in prostate, gastric and early breast cancer that it is important to distinguish two levels of information: the individual level that allows to monitor a patient to anticipate treatment failure, and the trial level that enables to predict the treatment effect on the final endpoint based on the treatment effect measured on the surrogate endpoint. In several cases, the formal validation turned out to be disappointing despite strong biological rational. PMID- 27494977 TI - [Not Available]. AB - THE BIG NATIONAL DATABASES AND STUDIES ON REAL WORLD DATA: EXAMPLE OF SARCOMAS IN FRANCE: Sarcomas are rare and heterogeneous tumours, and improvement of knowledge and of patient management need to gather and share data and biological material. The French sarcoma database stores in a warehouse clinical, pathological, molecular, therapeutic and follow-up data as well as data on samples and medical practices. This database and the national structured networks constitute major tools for the French Sarcoma Group. PMID- 27494978 TI - [Not Available]. AB - NEOADJUVANT CHEMOTHERAPY IN HER2-POSITIVE AND TRIPLE-NEGATIVE BREAST CANCER: Neoadjuvant chemotherapy is a standard option in the management of operable breast cancer, as effective as adjuvant chemotherapy in term of survival and with the potential to increase the rate of breast conservation. In HER2+ and triple negative breast cancers, neoadjuvant chemotherapy is associated with a high probability of pathological complete response, which strongly predicts survival outcome. In HER2+ breast cancer, trastuzumab, in combination with neoadjuvant chemotherapy, mostly anthracyclines and taxane-based, demonstrated a significant increase in pathological complete response rate. Recently, dual HER2 blockade strategies (lapatinib-trastuzumab or pertuzumab-trastuzumab) demonstrated a significant improvement in terms of pathological complete response over trastuzumab. In triple-negative breast cancer, recent data indicate that incorporating platinum compounds to neoadjuvant chemotherapy also significantly improves this parameter. Yet, in both subtypes, whether these substantial improvements may lead to significant benefits in terms of survival and breast conserving surgery remains to be demonstrated. PMID- 27494979 TI - [Not Available]. PMID- 27494980 TI - [Not Available]. AB - SURGICAL DE-ESCALATION FOR INVASIVE BREAST CANCER TREATMENT: A surgical therapeutic de-escalation is going to continue but necessarily has to design in a progressive careful way and especially arranged with the other practitioners and therapeutic methods. These strategies concern as well the surgery of the breast as that of the axillary basin. PMID- 27494981 TI - [Not Available]. AB - THERAPEUTIC DE-ESCALATION IN BREAST CANCER SURGERY: CONS: Therapeutic de escalation in breast cancer surgery is not recommanded for all patients. Concerning the axillary management, there are still some contraindications for practicing sentinel node, and avoiding axillary dissection is not safe for more than 3 positive sentinel nodes and in the absence of adjuvant treatment. Mastectomy can also be preferred by patients rather than conservative surgery, especially in case of genetic mutation, or for oncological reasons. Larger glandular resections, known as oncoplasties, should also be chosen in case of associated ductal carcinoma in situ and risky subgroups of local recurrence after neoadjuvant therapy. Finally, all patients will not benefit from ambulatory surgery. PMID- 27494982 TI - [Not Available]. AB - DE-ESCALATION OF RADIOTHERAPY OF INFILTRATING BREAST CANCER: WHERE CAN WE GO?: Adjuvant radiotherapy (RT) has an important role in the management of infiltrating breast cancer, not only to improve local control but also overall survival. So, all attempt of de-escalation must be performed in the context of large prospective studies. However, RT could induce some complications and last 5 to 7 weeks. Three ways of RT de-escalation have been studied. PMID- 27494983 TI - Comparison of different regimens of estradiol benzoate treatments followed by long-acting progesterone to prepare noncycling mares as embryo recipients. AB - The present study evaluated the influence of different regimens of estradiol benzoate (EB) treatments followed by a single dose of long-acting progesterone (LA P4) on plasma estrogen and P4 concentrations in noncyclic mares prepared as embryo recipients. Twenty-one anestrous mares were distributed into three groups (n = 7 mares per group), according to the EB dose received (single dose of 2.5 mg, total of 5 mg in decreasing doses, and total of 10 mg in decreasing doses), which was followed by a single administration of 1500 mg of LA P4 in all groups. Mares were reevaluated during the ovulatory phase and seven of them became part of the cyclic nontreated control group. Ultrasonography was performed to monitor endometrial edema, and blood samples were collected to measure estradiol (E2), estrogen conjugate (EC), and P4 by RIA. Maximum uterine edema was achieved 24 hours after administration of EB in all treated groups. Maximum E2 concentrations were observed 24 hours after the first EB injection in treated groups and there were no differences (P > 0.05) among treatments. Maximum EC concentration was observed 24 hours after the single EB injection in the 2.5-mg group, whereas in the 5- and 10-mg groups EC peaks were observed 48 hours after the first EB administration. Maximum P4 concentrations were detected 24 hours after LA P4 injection, although higher P4 concentrations were observed in the group treated with 2.5 mg of EB than in that treated with 10 mg of EB (P < 0.05). Because P4 concentrations were reduced after administration of high doses of EB, we also measured 17alpha-hydroxyprogesterone (17-OH-P) to test the hypothesis that high concentrations of EB would accelerate the conversion of P4 to 17-OH-P. However, 17-OH-P concentrations paralleled P4 profile in all groups, irrespective of EB doses. In summary, the three EB treatment regimens induced similar E2 peaks, although the observation of EC peaks 24 hours after E2 peaks in the 5- and 10-mg groups indicate that an excess of E2 was given, which was converted into EC to be inactivated. Administration of 10 mg of EB reduced P4 concentrations 24 hours after LA P4 was given. We demonstrated that the mechanism by which this reduction occurred was not by an increase in P4 metabolism to 17alpha-OH-P. In conclusion, the use of 2.5 mg of EB followed by 1500 mg of LA P4 appears to be a more appropriate regimen to treat noncyclic mares, although additional studies are needed to verify embryo survival with this treatment dose. PMID- 27494984 TI - Frontal Lobe Epilepsy: A Primer for Psychiatrists and a Systematic Review of Psychiatric Manifestations. AB - BACKGROUND: Frontal lobe epilepsy (FLE) can masquerade as a primary psychiatric condition, be misdiagnosed in-lieu of a true psychiatric disorder, or may be comorbid with psychiatric illness. OBJECTIVES: To (1) qualitatively review psychiatric manifestations of FLE and (2) to systematically review the cases/case series of psychiatric manifestations of FLE presented in the literature to date. METHODS: A systematic review of the literature was performed following the PRISMA guidelines and using PubMed/Medline, PsychInfo, and Cochrane database of systematic reviews to identify cases and case series of psychiatric manifestations of FLE. RESULTS: A total of 35 separate articles were identified. Further, 17 patients primarily presented with psychosis, 33 with affective symptoms, and 16 with personality changes. Also, 62% of cases were males and 38% were females. Ages ranged from 2-83 years with the average age of 32.7. Prior psychiatric history was reported in 27.3% of cases. Causes of seizure were known in 53%, with the most common causes being dysplasia and tumor. Only 6 cases (<10%) did not have electroencephalographic correlations. Psychiatric manifestations were primarily ictal in 74.3% of the cases. Associated manifestations included motor (63.6%), cognitive (34.8%), and medical (9.0%) findings. Surgery was required in 31.8% of the cases, whereas others were treated with medications alone. All, but 3, patients were seizure free and saw an improvement in symptoms with treatment. CONCLUSIONS: Given the complexity and multifunctionality of the frontal lobes, FLE can present with complex, psychiatric manifestations, with associated motor, cognitive, and medical changes; thus, psychiatrists should keep FLE on the differential diagnosis of complex neuropsychiatric cases. PMID- 27494985 TI - The Psychosocial Assessment of Candidates for Transplantation: A Cohort Study of its Association With Survival Among Lung Transplant Recipients. AB - BACKGROUND: The United Network for Organ Sharing mandates a psychosocial assessment of transplant candidates before listing. A quantified measure for determining transplant candidacy is the Psychosocial Assessment of Candidates for Transplant (PACT) scale. This instrument's predictive value for survival has not been rigorously evaluated among lung transplantation recipients. METHODS: We reviewed medical records of all patients who underwent lung transplantation at Mayo Clinic, Rochester from 2000-2012. A transplant psychiatrist had assessed lung transplant candidates for psychosocial risk with the PACT scale. Recipients were divided into high- and low psychosocial risk cohorts using a PACT score cutoff of 2. The main outcome variable was posttransplant survival. Mortality was analyzed using the Kaplan-Meier estimator and Cox proportional hazard models. RESULTS: This study included 110 lung recipients: 57 (51.8%) were females, 101 (91.8%) Whites, mean age: 56.4 years. Further, 7 (6.4%) recipients received an initial PACT score <2 (poor or borderline candidates) and later achieved a higher score, allowing transplant listing; 103 (93.6%) received initial scores >=2 (acceptable, good or great candidates). An initial PACT score < 2 was modestly associated with higher mortality (adjusted hazard ratio = 2.73, p = 0.04). CONCLUSIONS: Lung transplant recipients who initially received a low score on the PACT scale, reflecting poor or borderline psychosocial candidacy, experienced greater likelihood of mortality. This primary finding suggests that the psychosocial assessment, as measured by the PACT scale, may provide additional mortality risk stratification for lung transplant candidates. PMID- 27494986 TI - When Is It Safe for Patients to Drive After Right Total Knee Arthroplasty? AB - BACKGROUND: Advances in surgical technique and pain management have changed total knee arthroplasty (TKA). How soon after TKA are patients able to return to driving is a common question. Most surgeons prescribe 6-8 weeks postoperative based on old literature. Our hypothesis is that patient who undergoes TKA with contemporary techniques will return to their baseline before the 6th postoperative week. METHODS: After institutional review board approval, 50 patients with right TKA were prospectively evaluated. All patients underwent a preoperative brake reaction time (BRT), 2, 4, and 6 weeks postoperative. At each testing, we ask them if they felt that they were ready to drive. RESULTS: Forty seven patients completed the study protocol. Mean preoperative BRT was 0.692 seconds. At 2 weeks postoperative, the BRT was 0.631 seconds. Thirty-nine patients (80%) reached their baseline by 2 weeks, and the remaining 10 (20%) reached it at 4 weeks postoperative. Confounding variables revealed no differences between groups. From the group that returned to baseline at 2 weeks, 67% patients stated they felt they were ready to drive, 21% patients said they were not sure, and 12% patients stated they were not ready to drive. CONCLUSION: BRT returned to baseline in most patients by the 2nd week postoperative and in all patients by the 4th week. Patient perception of driving ability can predict return of BRT. These findings have allowed us to encourage patients to reevaluate their driving ability between the 2nd and 4th postoperative weeks after TKA. PMID- 27494987 TI - Cutaneous manifestations in inflammatory bowel disease: a single institutional study of non-neoplastic biopsies over 13 years. AB - BACKGROUND: Skin is commonly affected by extraintestinal manifestations of inflammatory bowel disease (IBD), but a controlled, systematic histopathologic analysis of cutaneous lesions is lacking. METHODS: A total of 4147 classified IBD [Crohn disease (CD) or ulcerative colitis (UC); 2000-2013] resections were cross referenced with skin biopsies. Associated non-neoplastic skin biopsies were categorized by basic reaction pattern and neutrophilic vs. granulomatous. RESULTS: Of 4147 patients, 133 had non-neoplastic skin biopsies (106/2772, 3.7% CD; 27/1375, 2% UC). Overall, miscellaneous > nodular and diffuse dermal > spongiotic dermatitides were most common (31.6, 21.8 and 15%, respectively). Spongiotic dermatitis, vasculitis, panniculitis and infections showed CD bias. Psoriasiform, perivascular, nodular/diffuse dermal and bullous categories, as well as neutrophilic processes, showed UC bias. Leukocytoclastic vasculitis, panniculitis and pyoderma gangrenosum were exclusive to CD and psoriasis vulgaris to UC. One CD patient had inverse psoriasis. CONCLUSIONS: Our findings show the majority of dermatopathologic manifestations of IBD to have overlapping histology or pathophysiology to intestinal disease; with a wider spectrum of histologic patterns than typically discussed. Diseases 'classically' associated with IBD are relatively rare biopsy specimens. Cutaneous manifestations of IBD are more common in CD than UC and should be considered when reviewing an unexplained skin lesion in an IBD patient. PMID- 27494988 TI - Evaluation of joint type modelling in the human hand. AB - This short communication presents preliminary results from an extensive investigation of joint modelling for the human hand. We use finger and hand movement data recorded from both hands of 110 subjects using passive reflective markers on the skin. Furthermore, we use data which was recorded from a single Thiel-fixated cadaver hand using also passive reflective markers but fixed to the bone. Our data clearly demonstrate that, for wrist and finger joints, hinge joint models are sufficiently accurate to describe their movement in Cartesian space. PMID- 27494989 TI - A system to measure the pupil response to steady lights in freely behaving mice. AB - BACKGROUND: Transgenic mice are widely used for the study of basic visual function and retinal disease, including in psychophysical tests. Mice have a robust pupillary light reflex that controls the amount of light that enters the eye, and the attenuating effects of the pupil must be considered during such tests. Measurement of the size of pupils at various luminance levels requires that mice remain stable over prolonged periods of time; however, sedation of mice with anesthesia and/or manual restraint can influence the size of their pupils. NEW METHOD: We present a system to measure the pupillary light response to steady lights of freely behaving mice using a custom-built, portable device that automatically acquires close-up images of their eyes. The device takes advantage of the intrinsic nature of mice to inspect objects of interest and can be used to measure pupillary responses in optomotor or operant behavior testing chambers. RESULTS: The size of the pupils in freely behaving mice decreased gradually with luminance from a maximal area in the dark of 3.8mm2 down to a minimum 0.14mm2 at 80 scotopic cd/m2. The data was well fit with a Hill equation with Lo equal to 0.21cd/m2 and coefficient h=0.48. COMPARISON WITH EXISTING METHODS: These values agree with prior measurements of the pupillary response of unrestrained mice that use more laborious and time consuming approaches. CONCLUSIONS: Our new method facilitates practical, straightforward and accurate measurements of pupillary responses made under the same experimental conditions as those used during psychophysical testing. PMID- 27494990 TI - Relationships of CD163 and CD169 positive cell numbers in the endometrium and fetal placenta with type 2 PRRSV RNA concentration in fetal thymus. AB - Several routes of porcine reproductive and respiratory virus PRRSV transmission across the porcine diffuse epitheliochorial placentation have been proposed, but none have been proven. The objectives of this study were to investigate associations between numbers of CD163 and CD169 positive macrophages, cathepsin positive areolae, and type 2 PRRSV load at the maternal-fetal interface in order to examine important factors related to transplacental infection. On gestation day 85 +/- 1, naive pregnant gilts were inoculated with PRRSV (n = 114) or were sham inoculated (n = 19). At 21 days post-inoculation (dpi), dams and their litters were humanely euthanized and necropsied. Samples of the maternal-fetal interface (uterus with fully attached placenta) and fetal thymus were collected for analysis by RT-qPCR to quantify PRRSV RNA concentration. The corresponding paraffin-embedded uterine tissue sections were subjected to immunohistochemistry for PRRSV nucleocapsid N protein, CD163, CD169, and cathepsin. Our findings confirm significant increases in the numbers of PRRSV, CD163 and CD169 positive cells at the maternal-fetal interface during type 2 PRRSV infection in pregnant gilts. PRRSV load in fetal thymus was positively related to CD163(+) cell count in endometrium and negatively related to CD163(+) cell count in placenta, but unrelated to CD169 counts or cathepsin positive areolae. The endometrium:placenta ratio of CD163 cells, and to a lesser extent CD169 cells, was significantly associated with an increase fetal viral load in thymus. These findings suggest a more important role for CD163(+) cells following trans-placental PRRSV infection, but dichotomous responses in endometrium and placenta for both CD163 and CD169 cells. PMID- 27494991 TI - A framework to assess patient-reported adverse outcomes arising during hospitalization. AB - BACKGROUND: The assessment of adverse events from a patient-centered view includes patient-reported adverse outcomes. An adverse outcome refers to any suboptimal outcome experienced by the patient; when adverse outcomes are identified through a patient interview these are called patient-reported adverse outcomes. An adverse event is an adverse outcome that is more likely due to the processes of medical care rather than to the mere progression of disease. In the context of a large-scale study assessing post-hospitalization adverse events, we developed a conceptual framework to assess patient-reported adverse outcomes (PRAOs). This methodological manuscript describes this conceptual framework. METHODS: The PRAO framework builds on a validated adverse event ascertainment method including three phases: Phase 1 involves an inquiry to ascertain the occurrence of any patient-reported adverse outcome. It is completed by a structured telephone interview to obtain details - from a patient perspective - on symptoms that developed and/or worsened after hospitalization. Phase 2 involves the classification of PRAOs by physicians not involved in the patient care. Physician-reviewers then rate the PRAOs using well-adopted scales to determine whether the occurrence was the natural progression of the underlying illness or due to medical care. When the PRAO is rated as "due to medical care", it is then classified as an "adverse event". Phase 3 involves the classification of adverse events as preventable or ameliorable. RESULTS: Out of the 1347 patients contacted at 1-month post-discharge, 469 reported AOs and after reviewing 369 cases, 29 were classified as AEs. Observed agreement levels between raters were 87.3, 85.5, and 85.2 % respectively displaying a good agreement (k > 0.60). CONCLUSION: The framework incorporates PRAOs as a way to identify cases that need to be evaluated for adverse events. Further validation of this framework is warrant with the final aim of implementation at larger scale. The implementation of this framework will enable clinicians, researchers and healthcare institutions to compare outcome rates across providers and over time. PMID- 27494992 TI - Timing of obstetrical assistance affects peripartal cardiac autonomic function and early maternal behavior of dairy cows. AB - Peripartal autonomic nervous system function and early maternal behavior were investigated in 79 multiparous Holstein-Friesian cows. Animals were allocated into four groups based on the technology of calving management: 1) unassisted calving in a group pen (UCG; N=19), 2) unassisted calving in an individual pen (UCI; N=21), 3) assisted calving with appropriately timed obstetrical assistance (ACA; N=20), and 4) assisted calving with premature obstetrical assistance (ACP; N=19). Heart rate, the high frequency (HF) component of heart rate variability (HRV) as a measure of vagal activity and the ratio between the low frequency (LF) and HF components (LF/HF ratio) as a parameter of sympathetic nervous system activity were calculated. Heart rate and HRV parameters were presented as areas under the curves (AUC) for the following periods: 1) prepartum period (between 96h before the onset of calving restlessness and the onset of restlessness), 2) parturition (between the onset calving restlessness and delivery), and 3) postpartum period (during a 48-h period after delivery). Pain-related behaviors were recorded during parturition (i.e., the occurrence of vocalization and stretching the neck towards the abdomen) and during a 2-h observation period after calving (i.e., the occurrence of vocalization, stretching the neck towards the abdomen and the duration of standing with an arched back). Early maternal behavior was observed during the first 2h following calving as follows: 1) latency and duration of sniffing calf's head/body, and 2) latency and duration of licking calf's head/body. No difference was found across groups in autonomic function before the onset of calving restlessness. Area under the heart rate curve was higher in ACP cows during parturition (39.6+/-2.5beats/min*h) compared to UCG, UCI and ACA animals (AUC=13.1+/-0.9beats/min*h, AUC=22.3+/-1.4beats/min*h and AUC=25.0+/-2.1beats/min*h, respectively). Area under the heart rate curve did not differ across the UCG, UCI and ACA groups during the postpartum period (AUC=65.2+/-16.7beats/min*h, AUC=58.0+/-14.2beats/min*h and AUC=62.9+/ 12.1beats/min*h, respectively) but it was higher in ACP cows compared to the former groups (AUC=269.1+/-36.3beats/min*h). During parturition, area under the HF curve reflected a lower vagal tone (AUC=-30.5+/-1.6n.u.*h) in cows with premature obstetrical assistance than in animals that calved individually without farmer assistance (AUC=2.7+/-0.4n.u.*h) or with appropriately timed assistance (AUC=3.2+/-1.2n.u.*h). During parturition, LF/HF ratio showed greater sympathetic activity in ACP cows than in animals from any other group. Area under the HF curve was similar across UCG, UCI and ACA cows (AUC=-232.1+/-42.0n.u.*h, AUC= 163.4+/-35.6n.u.*h and AUC=-331.4+/-56.2n.u.*h, respectively) during the postpartum period and was the lowest in ACP cows (AUC=-1025.6+/-44.2n.u.*h) reflecting a long-term stress load in the latter group. During parturition, both vocalization and stretching the neck towards the abdomen occurred more often in UCG cows than in cows from any other groups, and the incidence of both behaviors was statistically higher in ACP cows than in UCI and ACA animals. There were no significant differences across groups in these behaviors during the 2-h postpartum observation. UCG cows had a shorter latency and a longer duration of maternal grooming during the first 2h following delivery compared to any other groups. UCI and ACA dams spent more time with licking the calf within the 2-h period after calving and had a shorter latency to sniff and lick the offspring compared to cows that received premature assistance. Group calving is less stressful for cows than calving in an individual pen either with or without obstetrical assistance. Calving in a group or with appropriately timed farmer assistance supports the expression of early maternal behavior and lead to a rapid postpartum recovery of the autonomic nervous system. Premature obstetrical assistance means stress for cows during parturition, leads to a prolonged postpartum recovery of the autonomic nervous system and inhibits the expression of early maternal behavior. PMID- 27494993 TI - Computational strategies to explore antimalarial thiazine alkaloid lead compounds based on an Australian marine sponge Plakortis Lita. AB - In this work, an attempt was made to propose new leads based on the natural scaffold Thiaplakortone-A active against malaria. The 2D QSAR studies suggested that three descriptors correlate with the anti-malarial activity with an R2 value of 0.814. Robustness, reliability, and predictive power of the model were tested by internal validation, external validation, Y-scrambling, and applicability domain analysis. HQSAR studies were carried out as an additional tool to find the sub-structural fingerprints. The CoMFA and CoMSIA models gave Q2 values of 0.813 and 0.647, and [Formula: see text] values of 0.994 and 0.984, respectively. Using the 2D-QSAR equation, the activity values of the seven modified compounds were calculated and it was found that three molecules showed good anti-malarial activity. Molecular docking of the 42 Thiaplakortone-A derivatives with Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was carried out to find out protein-ligand interactions. Data mining of the bioassay data-set AID: 504850 using the classifier based on Random Forest of Weka suggested that all of the eight molecules selected and three out of the seven virtual molecules were anti-malarial active. Both the virtual molecules and drug molecules were docked with CYP3A4, indicating that the virtual molecules could metabolize easily. Toxicity studies using Osiris shows that three molecules showed no toxic characters. PMID- 27494994 TI - Excessive visceral fat area as a risk factor for early postoperative complications of total gastrectomy for gastric cancer: a retrospective cohort study. AB - BACKGROUND: Obesity is a known risk factor for complications after digestive surgery. Body mass index (BMI) is commonly used as an index of obesity but does not always reflect the degree of obesity. Although some studies have shown that high visceral fat area (VFA) is associated with poor outcomes in digestive surgery, few have examined the relationship between VFA and total gastrectomy. In this study, we demonstrated that VFA is more useful than BMI in predicting complications after total gastrectomy. METHODS: Seventy-five patients who underwent total gastrectomy for gastric cancer were enrolled in this study; they were divided into two groups: a high-VFA group (n = 26, >=100 cm(2)) and a low VFA group (n = 49, <100 cm(2)). We retrospectively evaluated the preoperative characteristics and surgical outcomes of all patients and examined postoperative complications within 30 days of surgery (including cardiac complications, pneumonia, ileus, anastomotic leakage, pancreatic fistula, incisional surgical site infection [SSI], abdominal abscess, and hemorrhage). RESULTS: The incidence of anastomotic leakage (p = 0.03) and incisional SSI (p = 0.001) were higher in the high-VFA group than in the low-VFA group. No significant differences were observed in the other factors. We used univariate analysis to identify risk factors for anastomotic leakage and incisional SSI. Age and VFA were risk factors for anastomotic leakage, and BMI and VFA were risk factors for incisional SSI. A multivariate analysis including these factors found that only VFA was a predictor of anastomotic leakage (hazard ratio [HR] 4.62; 95 % confidence interval [CI] 1.02-21.02; p = 0.048) and incisional SSI (HR 4.32; 95 % CI 1.18-15.80; p = 0.027]. CONCLUSIONS: High VFA is more useful than BMI in predicting anastomotic leakage and SSI after total gastrectomy. Therefore, we should consider the VFA value during surgery. PMID- 27494995 TI - Complete mitochondrial genomes of four entomopathogenic nematode species of the genus Steinernema. AB - BACKGROUND: Nematodes belonging to the genus Steinernema are insect parasites and are used as effective biological agents against soil-dwelling insect pests. Although the full nuclear genomes of multiple Steinernema species have become available recently, mitochondrial genome information for the genus is limited. In this study, we sequenced the complete mitochondrial genomes of four species of Steinernema and analysed their structure, codon usage and phylogenetic relationships. RESULTS: Mitochondrial genomes of Steinernema carpocapsae, S. glaseri, S. kushidai and S. litorale comprised 13,924, 13,851, 15,182 and 21,403 bp, respectively, with highly AT-rich nucleotide contents (AT ratio of 71.05 76.76 %). All the expected genes, including 12 protein-coding genes (encoding ATP6, CYTB, COX1-3, ND1-6 and ND4L), two rRNA genes and 22 tRNA genes were identified in the four genomes. Phylogenetic analyses based on the amino acid sequences of the 12 protein-coding genes identified the Steinernema species as monophyletic, representing a sister clade of Rhabditina and Ascaridida. In addition, they were more closely positioned to other Clade 10 nematodes, including Bursaphelenchus xylophilus, Aphelenchoides besseyi and Panagrellus redivivus, than to Strongyloides species. Gene arrangements and codon usage analyses supported this relationship. Mitochondrial genome comparison of two distinct strains of S. carpocapsae detected high intra-specific diversity. CONCLUSIONS: The mitochondrial genomes of four species of Steinernema determined in this study revealed inter- and intra-species divergences/diversities of mitochondrial genomes in this genus. This information provides useful insights into the phylogenetic position of the genus Steinernema within the Nematoda and represents a useful resource for selecting molecular markers for diagnosis and population studies. These data will increase our understanding of the interesting biology of insect parasites. PMID- 27494996 TI - Intraumbilical versus periumbilical incision in laparoscopic cholecystectomy: A randomized controlled trial. AB - INTRODUCTION: An important issue in laparoscopic surgery is initial peritoneal access. An intraumbilical (IU) incision may be easier and faster to place, but due to concerns about wound complications, the periumbilical (PU) incision is still often used. A prospective randomized controlled study was performed to investigate the outcomes of the IU incision and PU incision in laparoscopic cholecystectomy. METHODS: Study subjects were patients who received laparoscopic cholecystectomy for acute or chronic cholecystitis, gallbladder polyp or adenomyomatosis, or porcelain gallbladder from June 2014 to January 2015. Enrolled subjects were randomly allocated to the IU incision group or the PU incision group. Demographic data, perioperative outcomes, and the results of a cosmetic satisfaction questionnaire were analyzed. RESULTS: A total of 130 subjects were analyzed (64 in the IU group, 66 in the PU group). There were no differences in patient demographics. The operation time was significantly shorter in the IU group (34.2 +/- 14.6 vs 41.7 +/- 21.3, P = 0.020). The cosmetic survey score was significantly higher in the IU group (36.8 +/- 5.2 vs 33.2 +/- 5.2, P < 0.001). There was no difference in the complication rates of the two groups. CONCLUSIONS: The IU incision is a safe, feasible method of initial intraperitoneal access that can reduce the operation time and offer superior cosmetic effects to the patient. PMID- 27494997 TI - Changing paradigms in the management of diverticulitis. AB - The management of diverticular disease has evolved in the last few decades from a structured therapeutic approach including operative management in almost all cases to a variety of medical and surgical approaches leading to a more individualized strategy. There is an ongoing debate among surgeons about the surgical management of diverticular disease, questioning not only the surgical procedure of choice, but also about who should be operated and the timing of surgery, both in complicated and uncomplicated diverticular disease. This article reviews the current treatment of diverticulitis, with a focus on the indications and methods of surgery in both the emergency and elective settings. Further investigation with good clinical data is needed for the establishment of clear guidelines. PMID- 27494998 TI - Laparoscopic insertion of the peritoneal catheter in ventriculoperitoneal shunting. Review of 405 consecutive cases. AB - BACKGROUND: Based upon our excellent previous experience with 151 adult patients and 39 children whom had the peritoneal catheter in ventriculoperitoneal shunting placed laparoscopically, we continued following this technique as a first-line procedure in ventriculoperitoneal shunting. Now we analyzed our experience with additional 405 cases for a better comprehension of the complications, advantages and disadvantages of this procedure on this high number of patients. A strict interdisciplinary setting with the maximum of medical intraoperative competence was our goal and therefore better results. MATERIAL AND METHODS: N = 405 patients with intraperitoneal shunt insertion from the years 2006-2013 (Follow-up period ranges from 2 to 9 years with a 5,9-year mean follow-up period) were retrospectively analyzed with a special focus on the possible peritoneal catheter complications after laparoscopical shunt insertion. In our department all the peritoneal catheters in ventriculoperitoneal shunting are inserted laparoscopically, when there is no contraindication for this technique. RESULTS: We had 0% peritoneal catheter misplacement rate with help of the laparoscopic technique. In two cases (0.49%) injury of the small bowel could be repaired immediately with no further action required. In two cases umbilical hernias have been accidently discovered and the repair of the hernias took place in the same surgical session. As this technique helps us to control the shunt position intraperitoneally by direct laparoscopic vision, the patients spared an extra radiation exposure, to control the position of the peritoneal catheter. A diagnostic laparoscopy is also possible if needed. The time of the operation is shortened in comparison with the needed time, which is mentioned in literature, for the open laparotomy and of course the needed anesthesia and its possible risks and complications decreased. CONCLUSION: No revision surgeries were required because of any misplacement of the peritoneal catheter, no additional technique related risks compared to the open surgical technique, no abdominal x rays were needed, the operation time is shortened and the dose of anesthesia needed is decreased and of course its possible side effects' rate is also decreased. Another great benefit of this technique is the possibility of accidental diagnosis of intra-abdominal pathologies. Also, if a surgical treatment of this accidentally discovered intra-abdominal pathologies is needed, it can take place in the same surgical session. No prolonged surgery time as the laparoscopic technique is much easier, controllable and fast. PMID- 27494999 TI - Prognostic value of presepsin for outcomes and complications in enterocutaneous fistula complicated by abdominal sepsis. AB - BACKGROUND: Enterocutaneous fistula (ECF) poses a supreme challenge for the surgeons associated with abdominal sepsis, fluid electrolyte imbalance and undernutrition. Individual prognostic stratification is pivotal in the clinical management. Presepsin is a novel biomarker showing diagnostic and prognostic value in sepsis. We aimed to evaluate the prognostic value of presepsin in ECF. METHODS: Consecutive patients with ECF were enrolled if diagnosed as abdominal sepsis from June 2014 to June 2015. Serum concentration of presepsin at admission was measured, and medical records including demographics, medical history, treatment modalities, complications and outcomes were collected. Kaplan-Meier curves was drawn to demonstrate the cumulative incidence of source control of infection and fistula closure, and Cox regression analysis was performed to identify independent factors. Association between presepsin and other markers was evaluated by Pearson's correlation coefficient. RESULTS: 71 patients were included with the median presepsin concentration of 726 pg/mL at admission. Baseline presepsin levels showed predictive potential in successful source control of intra-abdominal infection but not in fistula closure. Patients with higher presepsin had more severe intra-abdominal infection as denoted by higher levels of WBC, CRP and PCT, as well as high risks of complications and failure of fistula closure compared with those having lower presepsin (<=726 pg/mL). Presepsin concentration was positively associated with APACHE II score, CRP and PCT. CONCLUSIONS: Presepsin shows prognostic values for source control of abdominal sepsis and clinical courses of ECF. This index may help stratify patients, facilitating the monitoring and adjustment of the therapeutic regimen at an early stage. PMID- 27495000 TI - Nutritional quality of foods and non-alcoholic beverages advertised on Mexican television according to three nutrient profile models. AB - BACKGROUND: Evidence supports that television food advertisements influence children's food preferences and their consumption. However, few studies have examined the extent and nature of food marketing to children in low and middle income countries. This study aims to assess the nutritional quality of foods and beverages advertised on Mexican TV, applying the Mexican, World Health Organization (WHO) European and United Kingdom (UKNPM) nutrient profile models, before the Mexican regulation on food marketing came into effect. METHODS: We recorded 600 h on the four national public and free TV channels with the highest national ratings, from December 2012 to April 2013. Recordings were done for 40 randomly selected (week, weekend, school and vacation) days, from 7 am to 10 pm. Nutritional information per 100 g/ml of product was obtained from the product labels or company websites. RESULTS: A total of 2,544 food and non-alcoholic beverage advertisements were broadcast, for 275 different products. On average, the foods advertised during cartoon programming had the highest energy (367 kcal) and sugar (30.0 g) content, while foods advertised during sport programming had the highest amount of total fat (9.5 g) and sodium (412 mg) content. More than 60 % of the foods advertised did not meet any nutritional quality standards. 64.3 % of the products did not comply with the Mexican nutritional standards, as compared with 83.1 % and 78.7 % with WHO Europe and UKNPM standards, respectively. The food groups most frequently advertised were beverages (24.6 %), followed by chocolate and confectionery sugar (19.7 %), cakes, sweet biscuits and pastries (12.0 %), savory snacks (9.3 %), breakfast cereals (7.1 %), ready-made food (6.4 %) and dairy products (6.0 %). CONCLUSION: The majority of foods and beverages advertised on Mexican TV do not comply with any nutritional quality standards, and thus should not be marketed to children. The nutritional quality standards applied by the Mexican regulation are much weaker than those applied by the WHO Europe and United Kingdom. The Mexican government should improve the nutrition standards in its new regulation, especially the sugar cut off points. PMID- 27495001 TI - 15 Years of penile cancer management in the United States: An analysis of the use of partial penectomy for localized disease and chemotherapy in the metastatic setting. AB - BACKGROUND: Penile cancer remains a rare disease in the United States, and its understanding may be limited by the uncommon nature of the malignancy. We sought to describe recent penile cancer treatment patterns using the National Cancer Data Base. METHODS: A retrospective review of data obtained from the National Cancer Data Base from 1998 to 2012 was performed. We obtained demographic information and therapeutic approaches within the following2 clinical scenarios: performance of partial penectomy for early stage disease (clinical Ta-T2) and the use of chemotherapy for metastatic disease. Multivariate logistic analysis was performed. RESULTS: A total of 2,677 patients presented with early stage penile carcinoma. The proportion receiving partial penectomy increased from 74% in 1998 to 2000 to 80% in 2010 to 2012 (P<0.001). Partial penectomy was more common in the elderly (age>80, odd ratios [OR] = 1.53, 95% CI: 1.05-2.23), young (age<50, OR = 1.46, 95% CI: 1.02-2.07), and in African Americans (OR = 1.45, 95% CI: 1.00 2.12). Increasing tumor size was significantly associated with decreased likelihood of receiving partial penectomy. Of those presenting with metastatic disease (n = 819), use of chemotherapy increased over the time period from 39% receiving chemotherapy in 1998 to 2000 to 49% in 2010 to 2012 (P<0.03). Patients least likely to receive chemotherapy were older and with higher Comorbidity score (both P<0.05), African American (OR = 0.46, 95% CI: 0.30-0.73), and living>=50 miles from the nearest treatment hospital (OR = 0.37, 95% CI: 0.25-0.55). CONCLUSIONS: Penile-sparing surgery for early stage disease and the use of chemotherapy for metastatic disease are becoming more commonly utilized over the past several years. Further work is needed to define clinical and nonclinical factors associated with the treatment. PMID- 27495002 TI - Whole genome sequencing reveals mycobacterial microevolution among concurrent isolates from sputum and blood in HIV infected TB patients. AB - BACKGROUND: In the context of advanced immunosuppression, M. tuberculosis is known to cause detectable mycobacteremia. However, little is known about the intra-patient mycobacterial microevolution and the direction of seeding between the sputum and blood compartments. METHODS: From a diagnostic study of HIV infected TB patients, 51 pairs of concurrent blood and sputum M. tuberculosis isolates from the same patient were available. In a previous analysis, we identified a subset with genotypic concordance, based on spoligotyping and 24 locus MIRU-VNTR. These paired isolates with identical genotypes were analyzed by whole genome sequencing and phylogenetic analysis. RESULTS: Of the 25 concordant pairs (49 % of the 51 paired isolates), 15 (60 %) remained viable for extraction of high quality DNA for whole genome sequencing. Two patient pairs were excluded due to poor quality sequence reads. The median CD4 cell count was 32 (IQR; 16 101)/mm(3) and ten (77 %) patients were on ART. No drug resistance mutations were identified in any of the sequences analyzed. Three (23.1 %) of 13 patients had SNPs separating paired isolates from blood and sputum compartments, indicating evidence of microevolution. Using a phylogenetic approach to identify the ancestral compartment, in two (15 %) patients the blood isolate was ancestral to the sputum isolate, in one (8 %) it was the opposite, and ten (77 %) of the pairs were identical. CONCLUSIONS: Among HIV-infected patients with poor cellular immunity, infection with multiple strains of M. tuberculosis was found in half of the patients. In those patients with identical strains, whole genome sequencing indicated that M. tuberculosis intra-patient microevolution does occur in a few patients, yet did not reveal a consistent direction of spread between sputum and blood. This suggests that these compartments are highly connected and potentially seed each other repeatedly. PMID- 27495004 TI - [Adjusted morbidity groups: A new multiple morbidity measurement of use in Primary Care]. AB - The Adjusted Morbidity Groups (GMA) is a new morbidity measurement developed and adapted to the Spanish healthcare System. It enables the population to be classified into 6 morbidity groups, and in turn divided into 5 levels of complexity, along with one healthy population group. Consequently, the population is divided into 31 mutually exclusive categories. The results of the stratification in Catalonia are presented. GMA is a method for grouping morbidity that is comparable to others in the field, but has been developed with data from the Spanish health system. It can be used to stratify the population and to identify target populations. It has good explanatory and predictive results in the use of health resources indicators. The Spanish Ministry of Health is promoting the introduction of the GMA into the National Health System. PMID- 27495003 TI - No difference in health-related quality of life, after a food challenge with cashew nut in children participating in a clinical trial. AB - BACKGROUND: Previous studies showed that health-related quality of life (HRQL) significantly improved after the food challenge, with greater improvements in HRQL after a negative outcome than after a positive outcome. It is currently unknown whether this also occurs in patients undergoing DBPCFCs with cashew nut in the context of a clinical trial. METHODS: Quality of life was studied in children enrolled in a cashew nut study using Food Allergy Quality of Life Questionnaires (FAQLQs). Children, teenagers and parents of the children completed the questionnaires before the challenge test and 6 months after the DBPCFC with cashew nut. The difference in the change in HRQL between the children with a positive and negative DBPCFC outcome was studied by Mann-Whitney U-test. RESULTS: In total, 112 children (67 boys, median age of 9 years) were included. The children, teenagers and parents of the children completed 143 sets of questionnaires in total. There were no significant differences in baseline total and domain scores compared to the follow-up scores in the FAQLQ-CF, FAQLQ-TF and FAQLQ-PF. In children, the delta FAIM score in the negative DBPCFC tested group was significantly better than the delta FAIM score in the positive challenged group (p = 0.026). There were no significant differences in the changes in the scores of the FAQLQ-CF and FAQLQ-PF in the children with a positive challenge outcome, compared to the children with a negative challenge result. However, there was a significant difference in the change in score between the latter groups in the domain 'accidental exposure' of the FAQLQ-TF (p = 0.049). CONCLUSION: This study showed no difference in the change in HRQL scores after a DBPCFC with cashew nut in children participating in a clinical trial. The utility of HRQL as an outcome for clinical trials in food allergy may be limited if participant baseline HRQL is relatively unimpaired. PMID- 27495005 TI - Severe chronic osteomyelitis caused by Morganella morganii with high population diversity. AB - A case of chronic osteomyelitis probably caused by Morganella morganii, occurring over a period of 30 years, is reported. The organism was identified through a combination of sample culture, direct sequencing, and 16S RNA gene amplicon sequencing. Further whole-genome sequencing and population structure analysis of the isolates from the patient showed the bacterial population to be highly diverse. This case provides a valuable example of a long-term infection caused by an opportunistic pathogen, M. morganii, with high diversity, which might evolve during replication within the host. PMID- 27495006 TI - Infection of human uterine fibroblasts by Zika virus in vitro: implications for viral transmission in women. PMID- 27495007 TI - D-4F, an apolipoprotein A-I mimetic, inhibits TGF-beta1 induced epithelial mesenchymal transition in human alveolar epithelial cell. AB - Emerging evidences support that transforming growth factor beta1 (TGF-beta1) induced epithelial-mesenchymal transition (EMT) participates in the pathogenesis of pulmonary fibrosis and asthmatic airway remodeling. Recent studies demonstrated that apolipoprotein A-I (Apo A-I) is the only known substance that can resolve established pulmonary fibrotic nodules, and Apo A-I mimetic D-4F (a synthetic polypeptide consisting of 18 amino acids) plays an inhibitory role in murine asthmatic model. However, cellular mechanisms for such therapeutic effects of Apo A-I and D-4F remain to be elucidated. This study evaluated the effects of D-4F on TGF-beta1 induced EMT in human type II alveolar epithelial cell line A549. A549 cells treated with 10ng/ml of TGF-beta1 manifested distinct EMT, including fibroblastic morphological changes, down-regulation of epithelial marker E-cadherin and up-regulation of mesenchymal marker vimentin. These EMT related changes were all inhibited by D-4F in a concentration dependent manner. Transcriptional investigation demonstrated clearly that D-4F dose-dependently compensated for the reduced E-cadherin mRNA level and the increased vimentin mRNA level in TGF-beta1 treated A549 cells. Translational analysis revealed that D-4F significantly reversed the TGF-beta1 induced changes of E-cadherin and vimentin levels. These results suggested that D-4F inhibits TGF-beta1 induced EMT in human alveolar epithelial cell. Given the functional similarities between D-4F and Apo A-I, it is speculated that D-4F and Apo A-I are able to exert possible anti fibrotic and anti-asthmatic effects via inhibiting alveolar EMT, and D-4F may possess beneficial clinical potential for patients suffering from pulmonary fibrosis and asthma. PMID- 27495008 TI - Is proteomics still knockin' on the hematological door? PMID- 27495009 TI - Innovative biocatalytic production of soil substrate from green waste compost as a sustainable peat substitute. AB - In the present work, a new simple and quick eco-friendly method is discussed to handle effectively the green wastes and produce a sustainable peat substitute of high quality on the large scale. Principal physicochemical parameters, i.e., temperature, moisture, specific weight, pH, electrical conductivity and, also, microorganisms, organic matter, humic substances, total Kjeldahl nitrogen and total organic carbon, C/N ratio, ash, metal content and phytotoxicity, were monitored systematically. Humic substances content values were interrelated to both C/N ratio and pH values and, similarly, bulk density, TOC, TKN, C/N, GI, ash and organic matter were found interconnected to each other. A novel biocatalyst, extremely rich in soil microorganisms, prepared from compost extracts and peaty lignite, accelerated the biotransformation. Zeolite was also employed. The compost does not demonstrate any phytotoxicity throughout the entire biotransformation process and has increased humic substances content. Both humic substances content and germination index can be employed as maturation indices of the compost. Addition of compost, processed for 60 days only, in cultivations of grass plants led to a significant increase in the stem mass and root size, annotating the significant contribution of the compost to both growth and germination. The product obtained is comparable to peat humus, useful as peat substitute and can be classified as a first class soil conditioner suitable for organic farming. PMID- 27495010 TI - Shoe soles as a potential vector for pathogen transmission: a systematic review. AB - Shoe soles are possible vectors for infectious diseases. Although studies have been performed to assess the prevalence of infectious pathogens on shoe soles and decontamination techniques, no systematic review has ever occurred. The aim of this study was to perform a systematic review of the literature to determine the prevalence of infectious agents on shoe bottoms and possible decontamination strategies. Three electronic bibliographic databases were searched using a predefined search strategy evaluating prevalence of infectious pathogens on shoe bottoms and decontamination strategies. Quality assessment was performed independently by two reviews with disagreements resolved by consensus. Thirteen studies were identified that supported the hypothesis that shoe soles are a vector for infectious pathogens. Methicillin-resistant Staphylococcus aureus, Clostridium difficile and multidrug-resistant Gram-negative species among other pathogens were documented on shoe bottoms in the health care setting, in the community and among food workers. Fifteen studies were identified that investigated decontamination strategies for shoe soles. A number of decontamination strategies have been studied of which none have been shown to be consistently successful at disinfecting shoe soles. In conclusion, a high prevalence of microbiological pathogens was identified from shoe soles studied in the health care, community and animal worker setting. An effective decontamination strategy for shoe soles was not identified. Studies are needed to assess the potential for contaminated shoes to contribute to the transmission of infectious pathogens. PMID- 27495011 TI - NF-YC in glioma cell proliferation and tumor growth and its role as an independent predictor of patient survival. AB - Gliomas are tumors affecting the central nervous system and affecting approximately 7/10,000 people with the median survival of only 14.6 months. As such, there is a need to uncover and explore alternative targets and pathways of gliomagenesis as well as a need to develop early and effective predictive markers of the disease. In this study we utilized a wide range of patient glioma sections to assess the characteristic expression of NF-YC and investigate whether NF-YC could serve as an independent predictor of patient survival. Additionally, an in vitro glioma model of manipulated NF-YC was used to investigate NF-YC's role in the glioma growth process and ultimately validated in an animal model of tumor growth. Here, we present evidence of the NF-YC subunit of the NF-Y transcription factor complex as an independent prognostic maker for glioma patient survival. We also describe that NF-YC is positively correlated with a universal marker of cellular proliferation. Mechanistic investigation into the role of NF-YC in gliomagenesis showed that NF-YC plays a role in cell cycle progression through the inhibition of the cyclin-dependent kinase inhibitor p21. Finally, NF-YC plays a role in the epithelial-mesenchymal transition preceding metastasis. We propose a novel target of glioma cell proliferation, growth and metastasis. Additionally, we identify NF-YC as a novel and independent predictor of patient survival to be subsequently trialed. PMID- 27495012 TI - GABA predicts visual intelligence. AB - Early psychological researchers proposed a link between intelligence and low level perceptual performance. It was recently suggested that this link is driven by individual variations in the ability to suppress irrelevant information, evidenced by the observation of strong correlations between perceptual surround suppression and cognitive performance. However, the neural mechanisms underlying such a link remain unclear. A candidate mechanism is neural inhibition by gamma aminobutyric acid (GABA), but direct experimental support for GABA-mediated inhibition underlying suppression is inconsistent. Here we report evidence consistent with a global suppressive mechanism involving GABA underlying the link between sensory performance and intelligence. We measured visual cortical GABA concentration, visuo-spatial intelligence and visual surround suppression in a group of healthy adults. Levels of GABA were strongly predictive of both intelligence and surround suppression, with higher levels of intelligence associated with higher levels of GABA and stronger surround suppression. These results indicate that GABA-mediated neural inhibition may be a key factor determining cognitive performance and suggests a physiological mechanism linking surround suppression and intelligence. PMID- 27495013 TI - Auditory white noise reduces age-related fluctuations in balance. AB - Fall prevention technologies have the potential to improve the lives of older adults. Because of the multisensory nature of human balance control, sensory therapies, including some involving tactile and auditory noise, are being explored that might reduce increased balance variability due to typical age related sensory declines. Auditory white noise has previously been shown to reduce postural sway variability in healthy young adults. In the present experiment, we examined this treatment in young adults and typically aging older adults. We measured postural sway of healthy young adults and adults over the age of 65 years during silence and auditory white noise, with and without vision. Our results show reduced postural sway variability in young and older adults with auditory noise, even in the absence of vision. We show that vision and noise can reduce sway variability for both feedback-based and exploratory balance processes. In addition, we show changes with auditory noise in nonlinear patterns of sway in older adults that reflect what is more typical of young adults, and these changes did not interfere with the typical random walk behavior of sway. Our results suggest that auditory noise might be valuable for therapeutic and rehabilitative purposes in older adults with typical age-related balance variability. PMID- 27495014 TI - Memantine, an NMDA receptor antagonist, improves working memory deficits in DGKbeta knockout mice. AB - Diacylglycerol kinase (DGK) beta is a type 1 isozyme of the DGK family. We previously reported that DGKbeta was deeply involved in neurite spine formation, and DGKbeta knockout (KO) mice exhibited behavioral abnormalities concerning spine formation, such as cognitive, emotional, and attentional impairment. Moreover, some of these abnormalities were ameliorated by the administration of a mood stabilizer. However, there is no data about how memory-improving drugs used in the treatment of Alzheimer's disease affect DGKbeta KO mice. In the present study, we evaluated the effect of an anti-Alzheimer's drug, memantine on the working memory deficit observed in DGKbeta KO mice. In the Y-maze test, the administration of memantine significantly improved working memory of DGKbeta KO mice. We also found that the expression levels of the NR2A and NR2B N-methyl-d aspartate (NMDA) receptor subunits were increased in the prefrontal cortex, but decreased in the hippocampus of DGKbeta KO mice. These altered expression levels of NR2 subunits might be related to the effect of an NMDA receptor antagonist, memantine. Taken together, these findings may support the hypothesis that DGKbeta has a pivotal role in cognitive function. PMID- 27495015 TI - Effect of vitamin B supplementation on cancer incidence, death due to cancer, and total mortality: A PRISMA-compliant cumulative meta-analysis of randomized controlled trials. AB - BACKGROUND: Observational studies have suggested that vitamin B supplementation is associated with cancer risk, but this association remains controversial. A pooled data-based meta-analysis was conducted to summarize the evidence from randomized controlled trials (RCTs) investigating the effects of vitamin B supplementation on cancer incidence, death due to cancer, and total mortality. METHODS: PubMed, EmBase, and the Cochrane Library databases were searched to identify trials to fit our analysis through August 2015. Relative risk (RR) was used to measure the effect of vitamin B supplementation on the risk of cancer incidence, death due to cancer, and total mortality using a random-effect model. Cumulative meta-analysis, sensitivity analysis, subgroup analysis, heterogeneity tests, and tests for publication bias were also conducted. RESULTS: Eighteen RCTs reporting the data on 74,498 individuals were included in the meta-analysis. Sixteen of these trials included 4103 cases of cancer; in 6 trials, 731 cancer related deaths occurred; and in 15 trials, 7046 deaths occurred. Vitamin B supplementation had little or no effect on the incidence of cancer (RR: 1.04; 95% confidence interval [CI]: 0.98-1.10; P = 0.216), death due to cancer (RR, 1.05; 95% CI: 0.90-1.22; P = 0.521), and total mortality (RR, 1.00; 95% CI: 0.94-1.06; P = 0.952). Upon performing a cumulative meta-analysis for cancer incidence, death due to cancer, and total mortality, the nonsignificance of the effect of vitamin B persisted. With respect to specific types of cancer, vitamin B supplementation significantly reduced the risk of skin melanoma (RR, 0.47; 95% CI: 0.23-0.94; P = 0.032). CONCLUSION: Vitamin B supplementation does not have an effect on cancer incidence, death due to cancer, or total mortality. It is associated with a lower risk of skin melanoma, but has no effect on other cancers. PMID- 27495016 TI - Anatomic Study of Anterior Transdiscal Axial Screw Fixation for Subaxial Cervical Spine Injuries. AB - Anterior transdiscal axial screw (ATAS) fixation is an alternative or supplement to the plate and screw constructs for the upper cervical spine injury. However, no existing literatures clarified the anatomic feasibility of this technique for subaxial cervical spine. Therefore, the objective of this study was to evaluate the anatomical feasibility and to establish guidelines for the use of the ATAS fixation for the subaxial cervical spine injury.Fifty normal cervical spines had radiographs to determine the proposed screw trajectory (the screw length and insertion angle) and the interbody graft-related parameters (the disc height and depth, and the distance between anterior vertebral margin and the screw) for all levels of the subaxial cervical spine. Following screw insertion in 8 preserved human cadaver specimens, surgical simulation and dissection verified the feasibility and safety of the ATAS fixation.Radiographic measurements showed the mean axial screw length and cephalic incline angle of all levels were 41.2 mm and 25.2 degrees , respectively. The suitable depth of the interbody graft was >11.7 mm (the distance between anterior vertebral margin and the screw), but <17.1 mm (disc depth). Except the axial screw length, increase in all the measurements was seen with level up to C5-C6 segment. Simulated procedure in the preserved specimens demonstrated that ATAS fixation could be successfully performed at C2 C3, C3-C4, C4-C5, and C5-C6 levels, but impossible at C6-C7 due to the obstacle of the sternum. All screws were placed accurately. None of the screws penetrated into the spinal canal and caused fractures determined by dissecting the specimens.The anterior transdiscal axial screw fixation, as an alternative or supplementary instrumentation for subaxial cervical spine injuries, is feasible and safe with meticulous surgical planning. PMID- 27495017 TI - Diagnose of occult bronchial foreign body: A rare case report of undetected Chinese medicine aspiration for 10 long years. AB - BACKGROUND: Occult bronchial foreign body can be very difficult to diagnose early in an adult patient without acute symptoms. This report describes a rare case of undetected Chinese medicine "Coptis chinensis" aspiration for 10 long years. METHODS: A case was reported that a female patient complained of a 10-year history of productive cough. A battery of tests were given to confirm the diagnosis. RESULTS: Chest computed tomography (CT) showed extensive bronchiectasis and multiple nodules, along with stenosis of left lower lobar bronchus. An extensive solid lesion with surrounding inflammatory granulation tissue was seen on her first bronchoscopy and biopsy revealed chronic mucosal inflammation. A neglected history of Coptis chinensis regularly kept in-mouth while sleeping for the last 10 years in this patient provided clues for a final diagnosis. Confirmatory diagnosis of bilateral tracheobronchial foreign bodies caused by recurrent inhalation of Coptis chinensis was made by a second bronchoscopy. CONCLUSIONS: This case clearly demonstrates that a precise medical history is often overlooked. A high index of suspicion, a precise medical history, radiographic features of chronic respiratory symptoms not explained by other conditions were keys to diagnosing this case. PMID- 27495018 TI - The adoption of the Reference Framework for diabetes care among primary care physicians in primary care settings: A cross-sectional study. AB - The prevalence of diabetes mellitus has been increasing both globally and locally. Primary care physicians (PCPs) are in a privileged position to provide first contact and continuing care for diabetic patients. A territory-wide Reference Framework for Diabetes Care for Adults has been released by the Hong Kong Primary Care Office in 2010, with the aim to further enhance evidence-based and high quality care for diabetes in the primary care setting through wide adoption of the Reference Framework.A valid questionnaire survey was conducted among PCPs to evaluate the levels of, and the factors associated with, their adoption of the Reference Framework.A total of 414 completed surveys were received with the response rate of 13.0%. The average adoption score was 3.29 (SD 0.51) out of 4. Approximately 70% of PCPs highly adopted the Reference Framework in their routine practice. Binary logistic regression analysis showed that the PCPs perceptions on the inclusion of sufficient local information (adjusted odds ratio [aOR] = 4.748, 95%CI 1.597-14.115, P = 0.005) and reduction of professional autonomy of PCPs (aOR = 1.859, 95%CI 1.013-3.411, P = 0.045) were more likely to influence their adoption level of the Reference Framework for diabetes care in daily practices.The overall level of guideline adoption was found to be relatively high among PCPs for adult diabetes in primary care settings. The adoption barriers identified in this study should be addressed in the continuous updating of the Reference Framework. Strategies need to be considered to enhance the guideline adoption and implementation capacity. PMID- 27495019 TI - Widespread pain and depression are key modifiable risk factors associated with reduced social participation in older adults: A prospective cohort study in primary care. AB - In older adults, reduced social participation increases the risk of poor health related quality of life, increased levels of inflammatory markers and cardiovascular disease, and increased mortality. Older adults frequently present to primary care, which offers the potential to deliver interventions at the point of care to increase social participation. The aim of this prospective study was to identify the key modifiable exposures that were associated with reduced social participation in a primary care population of older adults.The study was a population-based prospective cohort study. Participants (n = 1991) were those aged >=65 years who had completed questionnaires at baseline, and 3 and 6-year follow-ups. Generalized linear mixed modeling framework was used to test for associations between exposures and decreasing social participation over 6 years.At baseline, 44% of participants reported reduced social participation, increasing to 49% and 55% at 3 and 6-year follow-up. Widespread pain and depression had the strongest independent association with reduced social participation over the 6-year follow-up period. The prevalence of reduced social participation for those with widespread pain was 106% (adjusted incidence rate ratio 2.06, 95% confidence interval 1.72, 2.46), higher than for those with no pain. Those with depression had an increased prevalence of 82% (adjusted incidence rate ratio 1.82, 95% confidence interval 1.62, 2.06). These associations persisted in multivariate analysis.Population ageing will be accompanied by increasing numbers of older adults with pain and depression. Future trials should assess whether screening for widespread pain and depression, and targeting appropriate treatment in primary care, increase social participation in older people. PMID- 27495020 TI - Effect of prenatal and postnatal malnutrition on intellectual functioning in early school-aged children in rural western China. AB - The aim of this study was to evaluate the effect of prenatal and postnatal malnutrition on the intellectual functioning of early school-aged children. We followed the offspring of women who had participated in a trial of prenatal supplementation with different combinations of micronutrients and who remained resident in the study field. We measured their intellectual functioning using the Wechsler intelligence scale for children (WISC-IV). Height-for-age, weight-for age, and body mass index (BMI)-for-age were used as anthropometric nutritional status indices. Four of the 5 composite scores derived from the WISC-IV, except for working memory index (WMI), were significantly lower in low birth weight children after adjusting for confounds. All 5 composite scores, including full scale intelligence quotient (FSIQ), verbal comprehension index (VCI), WMI, perceptual reasoning index (PRI), and processing speed index (PSI) were significant lower in stunted and underweight children. The differences in the means of WISC-IV test scores were greatest between stunted and nonstunted children. The means for FSIQ, VCI, WMI, PRI, and PSI were as follows: 5.88 (95% confidence interval [CI]: 2.84-8.92), 5.08 (95% CI: 1.12-8.41), 4.71 (95% CI: 1.78-7.66), 6.13 (95% CI: 2.83-9.44), and 5.81 (95% CI: 2.61-9.00). These means were lower in stunted children after adjusting for confounds. Our results suggest the important influences of low birth weight and postnatal malnutrition (stunting, low body weight) on intellectual functioning in early school-aged children. PMID- 27495021 TI - Optimal tumor shrinkage predicts long-term outcome in advanced nonsmall cell lung cancer (NSCLC) treated with target therapy: Result from 3 clinical trials of advanced NSCLC by 1 institution. AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are used as standard therapies for advanced nonsmall cell lung cancer (NSCLC) patients with EGFR mutation positive. Because these targeted therapies could cause tumor necrosis and shrinkage, the purpose of the study is to search for a value of optimal tumor shrinkage as an appropriate indicator of outcome for advanced NSCLC.A total of 88 NSCLC enrollees of 3 clinical trials (IRESSA registration clinical trial, TRUST study and ZD6474 study), who received Gefitinib (250 mg, QD), Erlotinib (150 mg, QD), and ZD6474 (100 mg, QD), respectively, during December 2003 and October 2007, were retrospectively analyzed. The response evaluation criteria in solid tumors (RECIST) were used to identify responders, who had complete response (CR) or partial responses (PR) and nonresponders who had stable disease (SD) or progressive disease (PD). Receiver operating characteristics (ROC) analysis was used to find the optimal tumor shrinkage as an indicator for tumor therapeutic outcome. Univariate and multivariate Cox regression analyses were performed to compare the progression free survival (PFS) and overall survival (OS) between responders and nonresponders stratified based on radiologic criteria.Among the 88 NSCLC patients, 26 were responders and 62 were nonresponders based on RECIST 1.0. ROC indicated that 8.32% tumor diameter shrinkage in the sum of the longest tumor diameter (SLD) was the cutoff point of tumor shrinkage outcomes, resulting in 46 responders (<=8.32%) and 42 nonresponders (>=8.32%). Univariate and multivariate Cox regression analyses indicated that (1) the responders (<=8.32%) and nonresponders (>= -8.32%) were significantly different in median PFS (13.40 vs 1.17 months, P < 0.001) and OS (19.80 vs 7.90 months, P < 0.001) and (2) -8.32% in SLD could be used as the optimal threshold for PFS (hazard ratio [HR], 8.11, 95% CI, 3.75 to 17.51, P < 0.001) and OS (HR, 2.36, 95% CI, 1.41 to 3.96, P = 0.001).However, 8.32% tumor diameter shrinkage is validated as a reliable outcome predictor of advanced NSCLC patients receiving EGFR-TKIs therapies and may provide a practical measure to guide therapeutic decisions. PMID- 27495022 TI - Prevalence and impact of Clostridium difficile infection in elderly residents of long-term care facilities, 2011: A nationwide study. AB - The elderly population is particularly vulnerable to Clostridium difficile infection (CDI), but the epidemiology of CDI in long-term care facilities (LTCFs) is unknown.We performed a retrospective cohort study and used US 2011 LTCF resident data from the Minimum Data Set 3.0 linked to Medicare claims. We extracted CDI cases based on International Classification of Diseases-9 coding, and compared residents with the diagnosis of CDI to those who did not have a CDI diagnosis during their LTCF stay. We estimated CDI prevalence rates and calculated 3-month mortality rates.The study population consisted of 2,190,613 admissions (median age 82 years; interquartile range 76-88; female to male ratio 2:1; >80% whites), 45,500 of whom had a CDI diagnosis. The nationwide CDI prevalence rate was 1.85 per 100 LTCF admissions (95% confidence interval [CI] 1.83-1.87). The CDI rate was lower in the South (1.54%; 95% CI 1.51-1.57) and higher in the Northeast (2.29%; 95% CI 2.25-2.33). Older age, white race, presence of a feeding tube, unhealed pressure ulcers, end-stage renal disease, cirrhosis, bowel incontinence, prior tracheostomy, chemotherapy, and chronic obstructive pulmonary disease were independently related to "high risk" for CDI. Residents with a CDI diagnosis were more likely to be admitted to an acute care hospital (40% vs 31%, P < 0.001) and less likely to be discharged to the community (46% vs 54%, P < 0.001) than those not reported with CDI during stay. Importantly, CDI was associated with higher mortality (24.7% vs 18.1%, P = 0.001).CDI is common among the elderly residents of LTCFs and is associated with significant increase in 3-month mortality. The prevalence is higher in the Northeast and risk stratification can be used in CDI prevention policies. PMID- 27495023 TI - A telemedicine wound care model using 4G with smart phones or smart glasses: A pilot study. AB - To assess the feasibility of a wound care model using 4th-generation mobile communication technology standards (4G) with smart phones or smart glasses for wound management.This wound care model is an interactive, real-time platform for implementing telemedicine changing wound dressings, or doing operations. It was set up in March 2015 between Jinhua in Zhejiang province and Shanghai, China, which are 328 km apart. It comprised of a video application (APP), 4G net, smart phones or smart glasses, and a central server.This model service has been used in 30 patients with wounds on their lower extremities for 109 times in 1 month. Following a short learning curve, the service worked well and was deemed to be user-friendly. Two (6.7%) patients had wounds healed, while others still required wound dressing changes after the study finished. Both local surgeons and patients showed good acceptance of this model (100% and 83.33%, respectively).This telemedicine model is feasible and valuable because it provides an opportunity of medical service about wound healing in remote areas where specialists are scarce. PMID- 27495024 TI - Variability in the lymph node retrieval after resection of colon cancer: Influence of operative period and process. AB - The purpose of this study was to evaluate variations in the number of retrieved lymph nodes (LNs) over time and to determine the factors that influence the retrieval of <12 LNs during colon cancer resection.Patients with colon cancer who were surgically treated between 1997 and 2013 were identified from our institutional tumor registry. Patient, tumor, and pathologic variables were evaluated. Factors that influenced the retrieval of <12 LNs were evaluated using multivariate logistic regression modeling, including time effects.In total, 6967 patients were identified. The median patient age was 61 years (interquartile range [IQR] = 45-79 years) and 58.4% of these patients were male. The median number of LNs retrieved was 21 (IQR = 14-29), which increased from 14 (IQR = 11 27) in 1997 to 26 (IQR = 19-34) in 2013. The proportion of patients with >=12 retrieved LNs increased from 72% in 1997 to 98.8% in 2013 (P < 0.00001). This corresponded to the more recent emphasis on a multidisciplinary approach to adequate LN evaluation. The number of retrieved LNs was also found to be associated with age, sex, tumor location, T stage, and operative year. Tumor location and T stage influenced the number of retrieved LNs, irrespective of the operative year (P < 0.05). Factors including a tumor location in the sigmoid/left colon, old age, open resection, earlier operative year, and early T stage were more likely to be associated with <12 recovered LNs (P < 0.5; chi-squared test) (P < 0.001).The total number of retrieved LNs may be influenced by tumor location and T stage of a colon cancer, irrespective of the year of surgery. LN retrieval after colon cancer resection has increased in recent years due to a better awareness of its importance and the use of multidisciplinary approaches. PMID- 27495025 TI - Short-term family-centered workshop for children with developmental delays enhances family functioning and satisfaction: A prospective clinical trial. AB - We investigated the clinical efficacy on family functioning and parental satisfaction of a short-term family-centered workshop for children with developmental delays.A total of 32 children with developmental delays and their parents participated in 2-hour weekly group therapy sessions over 6 weeks. The workshop was conducted by rehabilitation professionals and teachers using a family-centered multidisciplinary approach. Both before and after the 6-week workshop, the parents were administered the Pediatric Quality of Life Inventory (PedsQL) Family Impact Module, the PedsQL Healthcare Satisfaction Module, the Hospital Anxiety and Depression Scale, and the World Health Organization Quality of Life brief assessment instrument. Overall satisfaction with the workshop was also evaluated.Significant improvements were noted in physical aspect (P = 0.03), communication (P = 0.002), and daily activities (P = 0.04) in the PedsQL Family Impact Module, and in communication (P = 0.03) and technical skills (P = 0.05) in the PedsQL Healthcare Satisfaction Module. Overall satisfaction with the workshop was rated as very high. There was no significant effect on psychological distress or quality of life.Short-term family-centered workshops for children with developmental delays improved family functioning and the parental perception of satisfaction, including health care satisfaction. PMID- 27495026 TI - HBV is a risk factor for poor patient prognosis after curative resection of hepatocellular carcinoma: A retrospective case-control study. AB - Controversy exists regarding pathological factors affecting the prognosis of hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV-HCC). Their postoperative clinical behaviors and the exact HBV Deoxyribonucleic Acid (DNA) thresholds that distinguish good and poor prognoses are unknown. This study aimed to compare clinicopathological, pre- and postoperative clinical factors and overall and recurrence-free survival (RFS) between HBV-HCC patients and nonhepatitis B and nonhepatitis C HCC (NBC-HCC) patients to determine the optimal prognostic HBV DNA threshold.Data from 1440 patients with HBV-HCC and NBC-HCC who underwent curative hepatectomy were retrospectively analyzed.Liver function in the HBV-HCC group was significantly worse than in the NBC-HCC group. Compared with NBC-HCC patients, HBV-HCC patients had significantly more vascular invasion and advanced HCC. The HBV-HCC patients also had significantly worse liver function and more complications. Further survival analysis showed significantly lower overall and RFS rates and a higher early recurrence rate in the HBV-HCC group. Univariate analysis indicated that HBV was a risk factor for overall and RFS. Finally, X-tile analysis revealed that the optimal HBV DNA cutoff points for predicting RFS and overall survival in HCC patients were 10,100 and 12,800 IU/mL, respectively.After hepatectomy for HCC, HBV-HCC patients had more complications and a worse prognosis than NBC-HCC patients. Antiviral therapy should be considered before hepatectomy in patients with high (more than approximately 10 IU/mL) HBV DNA levels. PMID- 27495027 TI - Polymorphism in the IL4R gene and clinical features are associated with glioma prognosis: Analyses of case-cohort studies. AB - Inflammatory gene polymorphisms may be associated with glioma risk. The purpose of this study was to analyze effects of certain inflammatory gene and some clinical factors on patient survival.The clinical information of 269 glioma patients conceived operation from September 2010 to May 2014 to decide the 1-, 3 year survival rates according to follow-up results and analyze age, gender, the WHO classification, extent of surgical resection, radiotherapy and chemotherapy factors effects on prognosis. Survival distributions were estimated by using the Kaplan-Meier method and difference in the survival was tested using the log-rank test. To estimate the association between the IL4, IL13, IL10, IL4R SNPs, and PFS and OS in glioma, the HR and 95% CI were calculated by univariate Cox proportional hazards model. Multivariate Cox model were performed to compute adjusted HR and 95% CI. All data was analyzed with SPSS17.0 package. Extent of surgical resection, chemotherapy, and age are an important factor in glioma overall survival and progression-free survival overall. Extent of surgery and chemotherapy are important factors in astrocytoma overall survival. Univariate analysis showed that IL4R rs1801275 was significantly associated with overall survival of glioma and astrocytoma patients (P < 0.05). Multivariate Cox regression analysis showed that IL4R rs1801275 GG genotype could increase the death risk of glioma and astrocytoma patients (Glioma: hazard ratio [HR]: 4.897, 95% confidence limits [95% CI]: 1.962-12.222, P = 0.001; Astrocytoma: HR: 15.944, 95% CI: 4.019-63.253, P < 0.05).Our research results showed that extent of surgical resection, age, and chemotherapy affect the prognosis of glioma. The IL4R gene may affect the survival of glioma patients. PMID- 27495028 TI - Small intestine contrast ultrasonography for the detection and assessment of Crohn disease: A meta-analysis. AB - BACKGROUND: Crohn disease (CD) is a chronic relapsing disease. Imaging modalities are essential for the diagnosis and assessment of CD. Small intestine contrast ultrasonography (SICUS) is a well-tolerated, noninvasive and radiation-free modality and has shown potential in CD assessment. We aimed at evaluating the diagnostic accuracy of SICUS in the detection and assessment of small-bowel lesions and complications in CD. METHODS: We searched PubMed database for relevant studies published before April 24, 2016. We integrated the true positive, false positive, false negative, and true negative into the pooled estimates of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio. Forest plots were to represent the pooled results of all studies. RESULTS: Thirteen articles were finally considered eligible. The pooled sensitivity and specificity of SICUS in detecting small bowel lesions were 0.883 (95% confidence interval (CI) 0.847-0.913) and 0.861 (95% CI 0.828-0.890), respectively. The pooled diagnostic odds ratio was 39.123 (95% CI 20.014-76.476) and the area under the curve of summary receiver operating characteristic was 0.9273 (standard error: 0.0152). In subgroup analyses, SICUS represented fine sensitivity and specificity in proximal and distal small intestine lesion, as well as in CD-related complications such as stricture, dilation, abscess, and fistula. CONCLUSION: SICUS is accurate enough to make a complete assessment about the location, extent, number, and almost all kinds of complications in CD small-bowel lesions. PMID- 27495029 TI - Clinical characteristics and prognostic factors of primary gastric lymphoma: A retrospective study with 165 cases. AB - Primary gastric lymphoma (PGL) is the most common extranodal non-Hodgkin lymphoma. This retrospective study aimed to analyze the clinical characteristics, prognostic factors, and roles of different treatment modalities in patients with PGL.From January 2003 to November 2014, 165 patients who were diagnosed with PGL at West China Hospital were enrolled in this study. The clinical features, treatment, and follow-up information were analyzed.In this study, diffuse large B cell lymphoma (DLBCL) (108, 65.5%) and mucosa-associated lymphoid tissue (MALT) lymphoma (52, 31.5%) were two predominant histological subtypes. One-year and 5 year overall survival (OS) rates of all patients were 95.2% and 79.5%, respectively; in whom 110 (66.7%) underwent surgery, 110 (66.7%) received chemotherapy, 12 (7.3%) received radiotherapy, and 10 (6.1%) received Helicobacter pylori eradication. And 75 patients (45.5%) were treated with at least 2 different types of therapies. Elevated lactic dehydrogenase (LDH) levels, poor performance status (PS), advanced stage, International Prognostic Index (IPI) score >=3, conservative treatment, and high-grade histological subtype were associated with worse prognosis in univariate analysis. Cox regression analysis showed that LDH levels, PS, staging, and histological subtype were independent predictors of survival outcomes. In the DLBCL type, 5-year OS was significantly better in the surgically treated group (80.1%) than that of patients conservatively treated (49.8%) (P = 0.001). Surgical treatment had almost no impact on OS in the MALT type than conservative treatment (P = 0.597). The proportion of patients received conservative treatment increased from 4.5% in period 1 to 51.7% in period 4.High LDH levels, poor PS, advanced staging, and malignant pathological type at diagnosis are significantly associated with poor OS. Our data suggest that surgery is superior in prognosis over conservative treatment in the DLBCL type, but not in the MALT type. Recently, conservative treatment is becoming more preferred approach in patients with PGL. PMID- 27495030 TI - Hormone replacement therapy benefits meibomian gland dysfunction in perimenopausal women. AB - Meibomian gland dysfunction (MGD) is believed to be the leading cause of dry eye (DE) disease worldwide. The connection between aging and MGD has long been recognized. However, few studies have addressed the relationship between MGD and hormone replacement therapy (HRT) in perimenopausal women, and not have examined the prevalence of MGD in perimenopausal women. The purpose of this study was to address and evaluate the possible relationship between MGD and HRT in perimenopausal women.The results suggest that perimenopausal women have a high prevalence of DE related to perimenopausal symptoms. The study also shows that perimenopausal women who use HRT can gain benefits for DE as well as for perimenopausal symptoms. Physicians caring for women who are experiencing DE related to perimenopausal symptoms should consider HRT. PMID- 27495031 TI - Evaluation of left and right ventricular myocardial function after lung resection using speckle tracking echocardiography. AB - The impact of major lung resections on myocardial function has not been well investigated. We aimed to identify this impact through the use of speckle tracking echocardiography (STE) to evaluate the right and left ventricular myocardial function in patients who underwent lung resections.Thirty patients who had lung resections were recruited for this study. Ten patients who underwent pneumonectomies were matched by age and sex, with 20 patients who underwent lobectomies. STE was performed on both right and left ventricle (RV and LV). Strain values of pre and postlung resections were compared in both the pneumonectomy group and the lobectomy group. Comparison between the pneumonectomy group and the lobectomy group was also studied.Left ventricular ejection fraction remained normal (>55%), but significantly decreased after lung resection in both the pneumonectomy group and the lobectomy group. An accelerated heart rate was observed in both groups after lung resection, with the pneumonectomy group demonstrating extra rapid heart rate (P < 0.05). Strain values in the RV and LV decreased in both groups after lung resection, with the pneumonectomy group exhibiting a further decrease in longitudinal strain in LV and RV when compared with the lobectomy group (P < 0.05).Right and left ventricular dysfunction can occur after lung resection regardless of pneumonectomy or lobectomy, and lobectomy may have a less significant impact on myocardial functions. This study demonstrated that STE is able to detect acute cardiac dysfunction after lung resection. PMID- 27495032 TI - The link between chronic rhinosinusitis and asthma: A questionnaire-based study. AB - Treatments for chronic rhinosinusitis (CRS) and asthma can affect both conditions, based on the united airway concept. This study aimed to evaluate the link between CRS and asthma, based on disease-specific quality of life measures.We performed a prospective cohort study to investigate the correlations between results from CRS- and asthma-specific questionnaires. Thirty-two patients with asthma and CRS were evaluated before and after undergoing nasal surgery at a tertiary medical center.There were significant correlations between the results from the Asthma Control Test (ACT) and the Sino-Nasal Outcome Test-22, as well as between the results of the ACT and Rhinoconjunctivitis Quality of Life Questionnaire, at both the preoperative and 3-month postoperative evaluations (P < 0.01). Moreover, nasal surgery improved the sinonasal symptoms, asthma control, and pulmonary function (P < 0.01).Increasingly severe sinonasal symptoms of CRS were associated with poor asthma control. Therefore, CRS and asthma should be considered and treated as common airway diseases. PMID- 27495033 TI - A simple prognostic score system predicts the prognosis of solitary large hepatocellular carcinoma following hepatectomy. AB - Solitary large hepatocellular carcinomas (SLHCC) form a heterogeneous group of patients with different survival probabilities. The aim of our study was to develop a simple prognostic index for identifying prognostic subgroups of SLHCC patients.A retrospective analysis of clinical data from 268 patients with operable SLHCC was conducted to investigate prognostic factors and to construct a score system based on risk factors. A Cox proportional hazard regression analysis was used to evaluate the variables associated with prognosis. Survival analyses were performed using Kaplan-Meier survival curves.Three variables remained in the final multivariate model: platelet to lymphocyte ratio (PLR), microvascular invasion (MVI), and tumor size with hazard ratios equal to 1.004 (95% confidence interval: 1.001-1.006), 1.092 (1.044-1.142), and 2.233 (1.125-2.233), respectively. A score of 1 was assigned to each risk factor. Patient scores were determined based on these risk factors; thus, the scores ranged between 0 and 3. Ultimately, three categories (0, 1-2, 3) were defined. Patients with scores of 3 had a 5-year survival rate of 25.4%, whereas patients with a score of 0 had a 5 year survival rate of 52.1%. The prognosis significantly worsened as the score increased. Similar results were found among cirrhotic and noncirrhotic patients.Our simple prognostic index successfully predicts SLHCC survival. PMID- 27495034 TI - Progression-free and overall survival in metastatic castration-resistant prostate cancer treated with abiraterone acetate can be predicted with serial C11-acetate PET/CT. AB - In this retrospective study, we evaluated the benefit of repeated carbon 11 (C11) acetate positron emission tomography/computed tomography (PET/CT) to assess response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA).A total of 30 patients with mCRPC were monitored with C11-acetate PET/CT and PSA levels during their treatment with AA. Retrospective evaluation of their response was made after 102 days (median; range 70-155) of treatment. Statistical analyses were employed to detect predictors of progression-free survival (PFS) and overall survival (OS), and potential correlation between serum levels of PSA, standardized uptake values (SUVpeak), and bone lesion index measured from PET were investigated.At follow-up 10 patients exhibited partial response (PR), 10 progressive disease (PD), and 10 stable disease (SD), as assessed by PET/CT. In survival analysis, both PR and PD were significantly associated with PFS and OS. CT response was also associated with OS, but only 19/30 patients demonstrated a lesion meeting target lesion criteria according to RECIST 1.1. No PET/CT baseline characteristic was significantly associated with PFS or OS. A PSA response (reduction in the level by >50%) could also predict PFS and OS. In the subgroup lacking a PSA response, those with PD had significantly shorter OS than those with PR or SD.PFS and OS in patients with mCRPC treated with AA can be predicted from repeated C11-acetate PET/CT. This may be of particular clinical value in patients who do not exhibit a PSA response to treatment. PMID- 27495035 TI - Risk factors associated with postcraniotomy meningitis: A retrospective study. AB - Postcraniotomy meningitis (PCM) is a major challenge in neurosurgery, and changing patterns of infectious agents in PCM have been noted. The limited epidemiological data and urgent clinical needs motivated this research. We conducted this study to determine a risk assessment for PCM and the current pattern of infectious agents.We performed a retrospective case-control study of significant cases of postcraniotomy meningitis in the Changhua Christian Hospital System between January 1, 2008, and December 31, 2012. Postcraniotomy meningitis was diagnosed in 22 out of 4392 surgical patients; this data was reviewed for risk assessment.This study assessed the risk factors for postcraniotomy meningitis and found that it was more frequently seen in patients who were elderly (OR = 1.57, 95% CI = 1.32-2.98, P = 0.013), underwent emergency procedures (OR = 4.82, 95% CI = 1.50-14.53, P = 0.008), had leak of cerebrospinal fluid (OR = 4.62, 95% CI = 2.03-10.50, P = 0.012), had external ventricular drainage (OR = 4.68, 95% CI = 2.46-8.87, P = 0.006), were admitted to the intensive care unit (OR = 2.41, 95% CI = 1.53-8.08, P = 0.012), had used drain placement >72 hours (OR = 2.66, 95% CI = 1.04-4.29, P = 0.007), had surgery >4.5 hours (OR = 2.38, 95% CI = 1.39-4.05, P = 0.005), had repeat operations (OR = 2.74, 95% CI = 1.31-5.73, P = 0.018), endured trauma (OR = 5.97, 95% CI = 1.57 17.61, P = 0.007), or had 30-days mortality (OR = 5.07, 95% CI = 2.20-11.48, P = 0.001). The predominant pathogens isolated from cerebrospinal fluid were Staphylococcus aureus in 8 patients (36.7%) and Acinetobacter baumannii in 7 patients (31.8%). In our study, the mortality rate was 5.1% among all postcraniotomy patients.Accurate risk assessment, early diagnosis, and choice of appropriate antibiotics in accordance with epidemiologic information are the cornerstones of reducing mortality and morbidity in PCM. The changing pattern of infectious agents in PCM over time suggests the necessity of further studies to provide the most up-to-date insight to physicians. PMID- 27495036 TI - Can eculizumab be discontinued in aHUS?: Case report and review of the literature. AB - BACKGROUND: The management of atypical hemolytic uremic syndrome (aHUS) has evolved into better control of thrombotic microangiopathy (TMA) and recovery of renal functions since the recent introduction of the terminal complement cascade blocker, eculizumab, into clinical use. Better characterization of genotype phenotype relations has become possible with genetic and clinical studies. However, these advances brought up some important issues, such as the possibility and timing of discontinuation of eculizumab and strategy of follow-up that need to be enlightened. CASE SUMMARY: One of our aHUS cases with a novel complement factor H mutation, who developed unusual laboratory findings (thrombocytopenia and mild creatinine elevation without other features of TMA) following discontinuation of eculizumab was presented. Literature and case reports relevant to discontinuation of eculizumab in aHUS patients were reviewed. CONCLUSION: Limited experience suggests that the risk of recurrence of TMA following discontinuation of eculizumab is relatively low for patients with MCP mutations, homozygous CFHR3/R1 deletions, anti-CFH antibodies, CFI mutations, and no identifiable mutations, whereas there is a major risk for patients with CFH mutations. Early detection of TMA recurrence and prompt retreatment with eculizumab seem to be efficient in controlling of TMA and restoration of kidney functions. PMID- 27495037 TI - Radiation-induced nausea and vomiting: Is ABO blood group as important as radiation and patient-related factors? An observational study. AB - Despite the improvements in cancer screening and treatment, it still remains as one of the leading causes of mortality worldwide. Nausea and vomiting as the side effects of different cancer treatment modalities, such as radiotherapy, are multifactorial and could affect the treatment continuation and patient quality of life. Therefore, the aim of this study was to assess the possible linkage between ABO blood groups and radiation-induced nausea and vomiting (RINV), also its incidence and affecting factors.One hundred twenty-eight patients referring to Tohid hospital of Sanandaj, Iran, were selected and the patients and treatment related factors were determined in a cross-sectional study. Patients' nausea and vomiting were recorded from the onset of treatment until 1 week after treatment accomplishment. Also, previous possible nausea and vomiting were recorded. The frequencies of nausea and vomiting and their peak time were examined during the treatment period.The association between ABO blood group and the incidence of radiotherapy-induced nausea and vomiting (RINV) were significant and it seems that A blood group patients are the most vulnerable individuals to these symptoms. The association between Rhesus antigen and the time of maximum severity of RINV may indicate that Rhesus antigen affects the time of maximum severity of RINV. The incidence of RINV was not affected by karnofsky performance status, but it was related to the severity of RINV. Furthermore, among the factors affecting the incidence of nausea and vomiting, nausea and vomiting during patient's previous chemotherapy, radiotherapy region, and background gastrointestinal disease were shown to be three important factors.In addition to familiar RINV affecting factors, ABO blood group may play an important role and these results address the needs for further studies with larger sample size. PMID- 27495038 TI - The relative effect of mammographic screening on breast cancer mortality by socioeconomic status. AB - Breast cancer incidence and mortality are higher in women with a high socioeconomic status (SES). The potential to prevent death from breast cancer is therefore greater in the high SES group. This does, however, require that the effectiveness of screening in the high SES group is equal to or greater than the effectiveness in the low SES group. The aim of this study is to assess the relative effectiveness of mammographic screening on breast cancer mortality by SES.In Nijmegen, the Netherlands, women are invited to participate in biennial mammographic screening since 1975. Postal code is collected at each round and is used to calculate the SES of each woman based on the SES indicator of the Netherlands Institute for Social Research. The Dutch average was used to classify the SES score of each woman as either high or low. We designed a case-control study to investigate the effect of mammographic screening in women aged 50 to 75, 40 to 75, and 50 to 69 years, and calculated the odds ratios (ORs) and 95% confidence intervals (CIs).Among the women invited to the mammographic screening program in Nijmegen, 10% had a high SES. In women aged 50 to 75 years, the breast cancer death rate was 38% lower in screened women than in unscreened women. The ORs for women with high SES (OR 0.82, 95% CI 0.31-2.19) and low SES did not differ significantly (OR 0.61, 95% CI 0.47-0.78).Mammographic screening reduces breast cancer mortality, but we did not observe a significant difference in the relative effectiveness of screening by SES. If the effectiveness of mammographic screening is indeed not dependent on SES status, the absolute number of breast cancer deaths prevented by mammographic screening will be greater in the high SES than low SES group, because women with a high SES have a greater risk of breast cancer death. PMID- 27495039 TI - Metabolic syndrome is associated with increased risk of Barrett esophagus: A meta analysis. AB - BACKGROUND: Barrett esophagus (BE) is considered precursor condition of esophageal adenocarcinoma. Its incidence and prevalence are increasing in general population. Studies reported that metabolic syndrome (MS) or diabetes mellitus (DM) is related to increased risk of BE. Current study was to assess and better understand the relationship between MS /DM and BE. METHODS: Electronic search was conducted in the database Pubmed/Medline (-December, 2015), Embase (-December, 2015), Cochrane Library (-December, 2015), and Web of Knowledge (-December, 2015). Studies included were assessed with summary odds ratios (ORs) with 95% confidence intervals (CIs) and compared exposure group with control group. The heterogeneity was examined by the funnel plot and the Egger's test. Subgroup analyses and sensitive analyses were performed for the detection of possible heterogeneity and impact on stability of analysis results. RESULTS: Twelve publications met the criteria and included 355,311 subjects were analyzed. The pooled results showed MS was closely associated with increased risk of BE (OR = 1.23; 95%CI 1.03-1.47; P = 0.024), and yet DM did not significantly increase the risk of BE (OR = 1.07; 95%CI 0.82-1.38; P = 0.627). Substantial heterogeneities were detected. No significant publication bias was detected by Egger's test (P = 0.23). CONCLUSIONS: Based on the results of current meta-analysis, MS is associated with increased risk of BE. Further long-term follow-up prospective study needs to verify the current results, and definite pathophysiological mechanism needs to be further investigated and clearly elucidated. PMID- 27495040 TI - Therapeutic role of hyperinsulinemia/euglycemia in aluminum phosphide poisoning. AB - BACKGROUND: Different protocols have been suggested to treat aluminum phosphide (ALP) poisoning. We aimed to evaluate the possible therapeutic effect of hyperinsulinemia/euglycemia (HIE) in treatment of ALP poisoning. METHODS: In a prospective interventional study, a total of 88 ALP-poisoned patients were included and assigned into HIE group undergoing glucose/insulin/potassium (GIK) protocol and a control group that was managed by routine conventional treatments. The 2 groups were then compared regarding the signs and symptoms of toxicity and their progression, development of complications, and final outcome to detect the possible effect of GIK protocol on the patients' course of toxicity and outcome. RESULTS: The 2 groups were similar in terms of demographic characteristics and on arrival vital signs and lab tests. Using GIK protocol resulted in significantly longer hospital stays (24 vs 60 hours; P < 0.001) and better outcomes (72.7% vs 50% mortality; P = 0.03). Regression analysis showed that GIK duration was an independent variable that could prognosticate mortality (odds ratio [95% confidence interval] = 1.045 [1.004,1.087]). The risk of mortality decreased by 4.5% each hour after initiation of GIK. CONCLUSION: GIK protocol improves the outcome of ALP poisoning and increases the length of hospital stay. PMID- 27495041 TI - Correlation between ambulatory function and clinical factors in hemiplegic patients with intact single lateral corticospinal tract: A pilot study. AB - To define the relationship between the complete destruction of 1 lateral corticospinal tract (CST), as demonstrated by diffusion tensor imaging (DTI) tractography, and ambulatory function 6 months following stroke.Twenty-six adults (17 male, 9 female) with poststroke hemiplegia who were transferred to the physical medicine and rehabilitation department. Participants underwent DTI tractography, which showed that 1 lateral CST had been clearly destroyed.Functional ambulation classification (FAC) scores at admission, discharge, and 6 months after discharge were used to evaluate the patients' ability to walk. The National Institutes of Health Stroke Scale (NIHSS) and the Korean version of the modified Barthel index (K-MBI) at admission, discharge, and 6 months after discharge were used to evaluate the degree of functional recovery.Of the 26 patients, 18 were nonambulatory (FAC level 1-3), and 8 were able to walk without support (FAC level 4-6). The type of stroke (infarction or hemorrhage), site of the lesion, spasticity of lower extremities, cranioplasty, and the time taken from onset to MRI were not statistically significantly correlated with the ability to walk. However, statistically significant correlations were found in relation to age, K-MBI scores, and initial NIHSS scores.Despite the complete damage to the lesion site and the preservation of 1 unilateral CST, as shown by DTI, good outcomes can be predicted on the basis of younger age, low NIHSS scores, and high MBI scores at onset. PMID- 27495042 TI - Significant partial response of metastatic intra-abdominal and pelvic round cell liposarcoma to a small-molecule VEGFR-2 tyrosine kinase inhibitor apatinib: A case report. AB - INTRODUCTION: Myxoid/round cell liposarcoma is the second most common subtype of liposarcoma. Chemotherapy and radiotherapy have a limited efficacy for treating advanced myxoid/round cell liposarcoma, with relatively serious side effects. CASE PRESENTATION: We herein present a 68-year-old Chinese woman initially diagnosed with advanced multiple intra-abdominal and pelvic round cell liposarcoma.She refused to receive cytotoxic chemotherapy and received apatinib as the first-line therapy, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 that has been used in the treatment of patients with metastatic gastric cancer who progressed with 2 or more chemotherapy regimens. This patient was partially responsive to apatinib with a dose of 500 mg daily. No serious drug-related side effects were observed. CONCLUSION: Our findings indicate that some cases of liposarcoma may be responsive to antiangiogenic agent apatinib. Randomized clinical studies are needed to further confirm the efficacy and safety of apatinib in the clinical treatment of liposarcoma. PMID- 27495043 TI - Does surgery for instability of the shoulder truly stabilize the glenohumeral joint?: A prospective comparative cohort study. AB - Despite the fact that surgery is commonly used to treat glenohumeral instability, there is no evidence that such treatment effectively corrects glenohumeral translation. The purpose of this prospective clinical study was to analyze the effect of surgical stabilization on glenohumeral translation.Glenohumeral translation was assessed in 11 patients preoperatively and 1 year postoperatively following surgical stabilization for anterior shoulder instability. Translation was measured using optical motion capture and computed tomography.Preoperatively, anterior translation of the affected shoulder was bigger in comparison to the normal contralateral side. Differences were significant for flexion and abduction movements (P < 0.001). Postoperatively, no patients demonstrated apprehension and all functional scores were improved. Despite absence of apprehension, postoperative anterior translation for the surgically stabilized shoulders was not significantly different from the preoperative values.While surgical treatment for anterior instability limits the chance of dislocation, it does not seem to restore glenohumeral translation during functional range of motion. Such persistent microinstability may explain residual pain, apprehension, inability to return to activity and even emergence of dislocation arthropathy that is seen in some patients. Further research is necessary to better understand the causes, effects, and treatment of residual microinstability following surgical stabilization of the shoulder. PMID- 27495044 TI - Maternal HIV status affects the infant hemoglobin level: A comparative cross sectional study. AB - Children, especially infants, are highly vulnerable to iron-deficiency anemia because of their rapid growth of the brain and the rest of the body. The objectives of this study were to compare the prevalence of iron-deficiency anemia in infants born from HIV-positive mothers and HIV-negative mothers and to identify the determinants of iron-deficiency anemia in infants.A comparative cross-sectional study was conducted in Bahir Dar city. Simple random sampling technique was used to select the study participants. Mothers were interviewed; blood samples were collected from mothers and infants to measure the hemoglobin level and anthropometric indicators were obtained from the infants using world health organization standards. Descriptive statistics were used to estimate the prevalence of infantile anemia. Binary logistic regression and multiple linear regressions were used to identify the determinants of infant anemia.A total of 1459 infants born from HIV-positive and HIV-negative mothers were included. The prevalence of iron-deficiency anemia in infants born from HIV-positive and HIV negative mothers was 41.9% (95% CI: 39-44). Infantile iron-deficiency anemia was associated with maternal HIV infection (adjusted odds ratio [AOR] 2.54 [95% CI: 1.65-3.9]), stunting (AOR 3.46 [95% CI: 2.41-4.97]), low income (AOR 2.72 [95% CI: 2-3.73]), maternal malaria during pregnancy (AOR 1.81 [95% CI: 1.33-2.47]), use of cow milk before 6 month (AOR 1.82 [95% CI: 1.35-2.45]), residence (AOR 0.09 [95% CI: 0.06-0.13]), history of cough or fever 7 days preceding the survey (AOR 2.71 [95% CI: 1.99-3.69]), maternal hemoglobin (B 0.65 [95% CI: 0.61-0.68]), educational status of mother (B 0.22 [95% CI: 0.2-0.23]), age of the mother (B 0.03 [95% CI: -0.03, -0.02]), and family size (B -0.14 [95% CI: -0.18,-0.11]). PMID- 27495045 TI - Pancreatic panniculitis associated with pancreatic carcinoma: A case report. AB - INTRODUCTION: Pancreatic panniculitis is a very rare complication of pancreatic cancer, most often accompanying rare acinar cell carcinoma. We herein report a case of pancreatic panniculitis that was associated with pancreatic mucinous adenocarcinoma. PATIENT INFORMATION: A 57-year-old male was referred to our hospital for weight loss. A physical examination revealed subcutaneous nodules on his lower extremities. The blood test showed abnormal increases in amylase, lipase, and carbohydrate antigen 19-9 levels. A computed tomography scan detected a hypodense 2 * 1.5 cm solid mass with an unclear margin in the head of the pancreas. The biopsy of subcutaneous nodules on the lower extremities was conducted and revealed lobular panniculitis. Pancreatic cancer and pancreatic panniculitis were strongly suspected. After the administration of octreotide acetate and the Whipple procedure, the serous amylase and lipase levels returned to normal, and the pancreatic panniculitis had almost resolved by 4 weeks later. CONCLUSION: Pancreatic panniculitis is a rare complication of pancreatic cancer. However, in the presence of a pancreatic mass, as in this case, clinicians should be aware that panniculitis may be the sentinel of pancreatic carcinoma. PMID- 27495046 TI - Risk factors for mortality in patients with Stenotrophomonas maltophilia bacteremia. AB - Stenotrophomonas maltophilia is a nosocomial pathogen associated with high morbidity and mortality, particularly in immunocompromised or critically ill patients. In this study, we investigated the risk factors for mortality in patients with S. maltophilia bacteremia.Retrospectively, medical records from all patients with S. maltophilia bacteremia between December 2005 and 2014 at Severance Hospital, a 2000-bed tertiary care hospital in Seoul, Korea, were reviewed. Analysis was performed to identify factors associated with 28-day mortality.In total, 142 bacteremia patients were enrolled in this study. The overall 28-day mortality rate was 36.6%. Based on the univariate analysis, hematologic malignancy (P = 0.015), Sepsis-related Organ Failure Assessment (SOFA) score (P < 0.001) and the removal of a central venous catheter (CVC) (P = 0.040) were significantly related to mortality. In the intensive care unit patients, the Acute Physiology and Chronic Health Evaluation II score (P = 0.001) also had significance. Based on the multivariate analysis, the SOFA score (odds ratio [OR] = 1.323; 95% confidence interval [CI]: 1.159, 1.509; P < 0.001) and removal of the CVC (OR = 0.330; 95% CI: 0.109, 0.996; P = 0.049) were independent factors associated with mortality.Our results suggest that removing a CVC may considerably reduce mortality in patients with S. maltophilia bacteremia. PMID- 27495047 TI - The outcomes of patients with severe dengue admitted to intensive care units. AB - Outcomes of adult patients with dengue infections requiring intensive care unit (ICU) admissions remain unclear. We assessed the clinical manifestations and prognostic factors of patients critically ill with severe dengue.This retrospective study was done in a tertiary referral hospital with 96 adult ICU beds. All of the patients with laboratory-confirmed severe dengue infections and admitted to the ICU were enrolled between July 31 and November 31, 2015, during the large outbreak period. The medical records of all the recruited patients were reviewed for the following information: age, gender, clinical manifestations, disease severity scores, underlying conditions, laboratory examinations, and outcomes. The primary endpoint was to find the predictors of ICU mortality.During the study period, 4787 patients with dengue infections required ICU admission. One hundred forty-three (2.99%) were critically ill (mean age: 69.7 years). Hypertension (n = 90, 62.9%) and diabetes mellitus (n = 70, 49.0%) were the 2 most common underlying diseases. Eighty critically ill patients (55.9%) had cobacterial infections, and 33 had cobacteremia. The hematologic system failed most often, followed by thoracic and cardiovascular systems. Fever was the most common presentation (n = 112; 78.3%), followed by anorexia (n = 47; 32.9%) and abdominal pain (n = 46; 32.2%). Overall, 33 patients died (mortality rate: 23.1%). Multivariate analysis showed that ICU mortality was significantly associated with lower Glasgow Coma Scale (GCS) scores, lower platelet counts before ICU discharge, and more organ failures.The number of severe dengue patients who require ICU admission remains high. The mortality rate was associated with lower GCS scores, lower platelet counts, and more organ failures. In addition, more than half of the critically ill dengue patients had comorbid bacterial infections. PMID- 27495048 TI - A meta-analysis for efficacy and safety evaluation of transcatheter left atrial appendage occlusion in patients with nonvalvular atrial fibrillation. AB - OBJECTIVES: This meta-analysis was conducted to evaluate the efficacy and safety of transcatheter left atrial appendage (LAA) occlusion in patients with nonvalvular atrial fibrillation. METHODS: The randomized controlled trials (RCT) or observational studies with any transcatheter LAA occlusion devices were searched in PubMed, Embase, and Cochrane library from inception to November 2015. The incidence rates from individual studies were combined to evaluate the procedural efficacy and safety, including all-cause death, cardiac/neurological death, stroke, transient ischemic attack (TIA), thrombosis, hemorrhagic complications, and pericardial effusion/tamponade. RESULTS: Thirty-eight studies involving 3585 patients and 6 different occlusion devices were eligible for our inclusion criteria. The procedural failure rate for LAA closure was 0.02 (95% CI: 0.02-0.03). The all-cause mortality was 0.03 (95% CI: 0.02-0.03) and cardiac/neurological mortality was 0 (95% CI: 0.00-0.01). The stroke/TIA rate was estimated only 0.01 (95% CI: 0.01-0.01). The incidence of thrombus on devices was 0.01 (95% CI: 0.01-0.02). The major hemorrhagic complication rate was estimated 0.01 (95% CI: 0.00-0.01). Pericardial effusion/tamponade was estimated 0.02 (95% CI: 0.02-0.03). No heterogeneity was observed for above pooled estimates (I = 0). In devices subgroups analysis, the all-cause mortality and cardiac/neurological mortality of PLAATO group were the highest (P = 0.01 and P < 0.01 respectively), whereas the incidence of thrombus on devices in the ACP group was the highest (P < 0.01). In follow-up period subgroups analysis, there were significant differences in all-cause death, stroke/TIA, major hemorrhage, and pericardial effusion/tamponade events between the shorter and longer follow-up period subgroups (P < 0.05). However, the differences among the subgroups were numerically small. CONCLUSIONS: the pooled data demonstrated that transcatheter LAA occlusion was effective and safe in the patients with nonvalvular atrial fibrillation who were not suitable for lifelong antithrombotic therapy. PMID- 27495050 TI - Early diagnosis and follow-up of chronic active Epstein-Barr-virus-associated cardiovascular complications with cardiovascular magnetic resonance imaging: A case report. AB - INTRODUCTION: Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is characterized as chronic or recurrent mononucleosis-like symptoms and elevated EBV deoxyribonucleic acid (EBV-DNA) copies. Cardiovascular complications have high morbidity and mortality. The treatment regimen for CAEBV has not been established yet, resulting in poor prognoses. Herein, we present a case of cardiovascular magnetic resonance imaging (CMRI) evaluation with a series of sequences for CAEBV-associated cardiovascular involvement, which has never been reported. CASE PRESENTATION: A 16-year-old female (body weight, 55 kg) developed a persistent fever and a positive EBV-DNA level of 28,000 copies/mL. Computed tomography angiography (CTA) showed aneurysms involving the aorta and its major branches, as well as multiple aneurysms and stenoses of the coronary arteries. CMRI of the coronary arteries depicted the dilution and stenosis of the arterial lumen as well as the thickening of the arterial wall. Late gadolinium enhancement (LGE) showed subendocardial and transmural delayed enhancement of the left ventricle, suggesting myocardial infarction.CAEBV and associated cardiovascular complications were diagnosed. After treatment with Medrol and Leflunomide, the clinical manifestation and serological parameters reversed to normal. However, the EBV-DNA level increased again to 13,900 copies/mL 2 months later. A follow-up with aorta CTA showed that the arterial walls of the bilateral common iliac artery aneurysms were thicker with new-onset mural thrombi. The aorta CTA also showed new-onset occlusion of the right coronary artery, but a follow-up of CMRI at the same day did not find new-onset delayed enhancement lesion. CONCLUSION: This case reminds clinicians of the vital importance of early diagnosis and close follow-up of CAEBV-associated cardiovascular complications. With cine imaging, coronary artery imaging, LGE imaging, and other novel techniques, CMRI can effectively and comprehensively reveal the early and dynamic changes, and act as an important tool in the field of cardiovascular diseases. PMID- 27495049 TI - Conditional disease-free survival after liver transplantation for hepatocellular carcinoma: A two-center experience. AB - Traditionally, survival estimates following liver transplantation (LT) of hepatocellular carcinoma (HCC) patients were calculated as survival from the surgery date, but future survival probabilities can change over time and conditional disease-free survival (CDFS) may provide patients and clinicians with more accurate prognostic information. This study aimed to assess CDFS in HCC patients after LT.Three hundred eighty-four HCC patients who underwent LT were included. Disease-free survival (DFS) was calculated using the Kaplan-Meier analysis. The 3-year CDFS, which represents the probability of remaining disease free for an additional 3 years, was calculated.1-, 3-, and 5-year DFS rates after LT were 69.9%, 45.8%, and 39.0 %, respectively. Based on the concept of CDFS, the probability of surviving an additional 3 years given that the patient was disease free at 1 year, 3 years, and 5 years were 58.4%, 76.9%, and 83.1%, respectively. Multivariate analysis indicated that larger tumor size (hazard ratio [HR], 1.509; 95% CI, 1.146-1.985; P = 0.003) was associated with poorer DFS. Patients with worse prognostic features at baseline demonstrated the greater increase in CDFS over time.Survival estimates following liver transplantation of HCC patients change according to survival time accrued since surgery. CDFS estimates improved dramatically over time especially among patients with worse prognostic features at the time of surgery. CDFS may be a useful tool in counseling patients with HCC, as it is a more accurate assessment of future survival for those patients who have already survived a certain amount of time. PMID- 27495051 TI - Is poststroke complex regional pain syndrome the combination of shoulder pain and soft tissue injury of the wrist?: A prospective observational study: STROBE of ultrasonographic findings in complex regional pain syndrome. AB - Patients with poststroke complex regional pain syndrome (CRPS) show different symptoms compared to other types of CRPS, as they usually complain of shoulder and wrist pain with the elbow relatively spared. It is thus also known by the term "shoulder-hand syndrome."The aim of this study is to present a possible pathophysiology of poststroke CRPS through ultrasonographic observation of the affected wrist before and after steroid injection at the extensor digitorum communis (EDC) tendon in patients suspected with poststroke CRPS.Prospective evaluation and observation, the STROBE guideline checklist was used.Twenty-three patients diagnosed as poststroke CRPS in accordance to clinical criteria were enrolled. They had a Three Phase Bone Scan (TPBS) done and the cross-sectional area (CSA) of EDC tendon was measured by using ultrasonography. They were then injected with steroid at the EDC tendon. The CSA of EDC tendon, visual analogue scale (VAS), and degree of swelling of the wrist were followed up 1 week after the injection.TPBS was interpreted as normal for 4 patients, suspected CRPS for 10 patients, and CRPS for 9 patients. Ultrasonographic findings of the affected wrist included swelling of the EDC tendon. After the injection of steroid to the wrist, CSA and swelling of the affected wrist compared to that before the treatment was significantly decreased (P < 0.001). The VAS score declined significantly after the injection (P < 0.001).Our results suggest that the pathophysiology of poststroke CRPS might be the combination of frozen shoulder or rotator cuff tear of shoulder and soft tissue injury of the wrist caused by the hemiplegic nature of patients with stroke. PMID- 27495052 TI - Monotypic plasma cell interstitial nephritis as the only clinical manifestation in a patient with previously undiagnosed indolent multiple myeloma: A case report. AB - INTRODUCTION: Predominantly monotypic plasma cell infiltrates are an uncommon renal finding in patients with malignant lymphoplasmacytic proliferation. CASE PRESENTATION: We report the case of a 52-year-old man with chronic kidney disease and significant proteinuria associated with a monoclonal immunoglobulin spike (IgGkappa). Kidney biopsy revealed the presence of atypical multinucleated CD138 plasma cells with voluminous nuclei stained exclusively with a kappa antibody. Electron microscopy showed mesangial and segmental parietal electron-dense, nonorganized hyaline deposits without immunogold labeling for the kappa light chain. The bone marrow aspirate revealed 6% of apparently mature plasmocytes without dystrophy. We therefore concluded that the patient had an indolent multiple myeloma with specific renal involvement in the form of malignant monotypic interstitial plasmacytic infiltration. We initiated a specific chemotherapy regimen including bortezomib-cyclophosphamide-dexamethasone. After 4 months of follow-up, creatinine levels had improved slightly and free kappa light chain levels had decreased significantly within the normal range. CONCLUSION: This case highlights the need to consider neoplastic interstitial plasma cell infiltration systematically in patients diagnosed with an apparently benign monoclonal gammopathy and to consider adaptation of the chemotherapy regimen, to improve renal function. PMID- 27495053 TI - The interplay between hospital and surgeon factors and the use of sentinel lymph node biopsy for breast cancer. AB - BACKGROUND: Several surgeon characteristics are associated with the use of sentinel lymph node biopsy (SLNB) for breast cancer. No studies have systematically examined the relative contribution of both surgeon and hospital factors on receipt of SLNB. OBJECTIVE: To evaluate the relationship between surgeon and hospital characteristics, including a novel claims-based classification of hospital commitment to cancer care (HC), and receipt of SLNB for breast cancer, a marker of quality care. DATA SOURCES/STUDY DESIGN: Observational prospective survey study was performed in a population-based cohort of Medicare beneficiaries who underwent incident invasive breast cancer surgery, linked to Medicare claims, state tumor registries, American Hospital Association Annual Survey Database, and American Medical Association Physician Masterfile. Multiple logistic regression models determined surgeon and hospital characteristics that were predictors of SLNB. RESULTS: Of the 1703 women treated at 471 different hospitals by 947 different surgeons, 65% underwent an initial SLNB. Eleven percent of hospitals were high-volume and 58% had a high commitment to cancer care. In separate adjusted models, both high HC (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.12-2.10) and high hospital volume (HV, OR 1.90, 95% CI 1.28-2.79) were associated with SLNB. Adding surgeon factors to a model including both HV and HC minimally modified the effect of high HC (OR 1.34, 95% CI 0.95-1.88) but significantly weakened the effect of high HV (OR 1.25, 95% CI 0.82-1.90). Surgeon characteristics (higher volume and percentage of breast cancer cases) remained strong independent predictors of SLNB, even when controlling for various hospital characteristics. CONCLUSIONS: Hospital factors are associated with receipt of SLNB but surgeon factors have a stronger association. Since regionalization of breast cancer care in the U.S. is unlikely to occur, efforts to improve the surgical care and outcomes of breast cancer patients must focus on optimizing patient access to SLNB by ensuring hospitals have the necessary resources and training to perform SLNB, staffing hospitals with surgeons who specialize/focus in breast cancer and referring patients who do not have access to SLNB to an experienced center. PMID- 27495054 TI - Role of gender in types and frequency of coronary artery aneurysm and ectasia. AB - This study aimed to evaluate the role of gender in types and frequency of coronary artery aneurysm and ectasia.We assessed retrospectively the angiography records of 6100 patients. At first, we mainly reviewed angiographic movies for the presence of coronary ectasia and/or aneurysm. Consequently, based on the number of the coronary artery involvement, the coronary ectasia and aneurysm were graded as mild if 1 coronary artery was involved and severe if 2 or more coronary arteries were involved. The location of ectasia and aneurysm was analyzed with respect to their isolated or combined location on various coronary arteries. The patients included in the present study were divided into 2 groups based on their gender as male and female. Then, we evaluated the impact of gender on severity and the location of the ectasia and aneurysm.The incidence of the aneurysm and ectasia was 3.5%. Among the patients with aneurysm and ectasia, 6.9% were male and 4.5% were female. Aneurysm and ectasia were evaluated together; their frequency was significantly higher in the male than female patients (P < 0.01). However, when their incidence was evaluated separately, coronary artery ectasia was markedly greater in male patients with regard to female patients (P < 0.01). Incidence of CAE presence on the RCA was significantly greater in males than females (2.7% vs 1.9%, P < 0.05).This study showed that incidence of CAE is more common in males than females. Particularly, frequency for the involvement of CAE on RCA and concurrently on 3 vessels is greater in male patients than female patients. PMID- 27495055 TI - Delay in cutaneous melanoma diagnosis: Sequence analyses from suspicion to diagnosis in 211 patients. AB - Advanced melanoma is an incurable disease with complex and expensive treatments. The best approach to prevent melanoma at advanced stages is an early diagnosis. A knowledge of factors associated with the process of detecting cutaneous melanomas and the reasons for delays in diagnosis is essential for the improvement of the secondary prevention of the disease.Identify sociodemographic, individual, and medical aspects related to cutaneous melanoma diagnosis delay.Interviews evaluated the knowledge of melanoma, signals, symptoms, persons who were suspected, delays in seeking medical attention, physician's deferrals, and related factors of 211 patients.Melanomas were self-discovered in 41.7% of the patients; healthcare providers detected 29.9% of patients and others detected 27%. The main component in delay was patient-related. Only 31.3% of the patients knew that melanoma was a serious skin cancer, and most thought that the pigmented lesion was not important, causing a delay in seeking medical assistance. Patients (36.4%) reported a wait interval of more than 6 months from the onset of an observed change in a pigmented lesion to the first visit to a physician. The delay interval from the first physician visit to a histopathological diagnosis was shorter (<1 month) in 55.5% of patients. Improper treatments without a histopathological confirmation occurred in 14.7% of patients. A professional delay was related to both inappropriate treatments performed without histopathological confirmation (P = 0.003) and long requirements for medical referrals (P < 0.001).A deficient knowledge in the population regarding melanoma and physicians' misdiagnoses regarding suspicious lesions contributed to delays in diagnosis. PMID- 27495056 TI - Salt intake belief, knowledge, and behavior: a cross-sectional study of older rural Chinese adults. AB - Excess sodium consumption is a major cause of high blood pressure and subsequent vascular disease. However, the factors driving people's salt intake behavior remains largely unknown. This study aims to assess the relationship of salt intake behaviors with knowledge and belief on salt and health among older adults in rural China.A cross-sectional survey was conducted among 4693 older participants (men >=50 and women >=60 years old) randomly selected from 120 rural villages in 5 northern provinces in China. Healthy salt intake behavior was defined as either not eating pickled foods or not adding pickles/soy sauce/salt when food was not salty enough in prior 3 months.There were 81% participants having healthy salt intake behavior. Healthy salt intake behavior was more common among women (P < 0.01) and was positively associated with age (P < 0.01) and poorer health status (P < 0.01), but negatively associated with years in school (P < 0.05). After adjusting for age, sex, years in school, and health status, participants who believed in the harm of high salt intake were more likely to have healthy salt intake behavior, compared with those who did not believe (Odds Ratio = 1.6, P < 0.001). Knowledge of salt intake was not significantly related to healthy salt intake behavior.Our study demonstrated that belief in the harm of high salt intake rather than knowledge about salt and health was associated with healthy salt intake behavior, independent of age, sex, years in school, and health status. Future population salt reduction programs should place more emphasis on establishing health beliefs rather than only delivering salt-related knowledge.Clinical trial registration number of the study is NCT01259700. PMID- 27495057 TI - Hospital mortality of patients aged 80 and older after surgical repair for type A acute aortic dissection in Japan. AB - To evaluate whether patients aged 80 and older have higher risk of hospital mortality after repair of type A acute aortic dissection (TAAAD).Emergency surgery for TAAAD in patients aged 80 and older remains a controversial issue because of its high surgical risk.Data from patients who underwent surgical repair of TAAAD between April 2011 and March 2013 were retrospectively extracted from the Japanese Diagnosis Procedure Combination database. The effect of age on hospital mortality was evaluated using multivariate logistic regression analysis.A total of 5175 patients were enrolled. The mean age of patients was 67.1 +/- 13.0 years, and the male:female ratio was 51:49. Patients aged 80 and older more frequently received tracheostomy than their younger counterparts (9.5% vs 5.4%, P <0.001). Intensive care unit and hospital stays were significantly longer in the elderly cohort versus the younger cohort (7.6 vs 6.7 days, P <0.001, and 42.2 vs 35.8 days, P <0.001, respectively). Logistic regression analysis showed that age >=80 years was significantly associated with a higher risk of hospital mortality (adjusted odds ratio, 1.62; 95% confidence interval, 1.28-2.06; P <0.001). In linear regression analysis, age >=80 years was also significantly associated with longer hospital stay (P = 0.007).In a large, nationwide, Japanese database, patients aged 80 and older were at increased risk of hospital mortality and length of hospital stay. PMID- 27495058 TI - Abnormal increase of intraocular pressure in fellow eye after severe ocular trauma: A case report. AB - BACKGROUND: An ocular injury can lead to secondary glaucoma in the traumatized eye in 3% to 20% of cases. Literature on the risk of developing elevated intraocular pressure in the nontraumatized fellow eye is scant. Clinicians treating ocular traumas should also bear in mind sympathetic ophthalmia, a rare bilateral granulomatous panuveitis following accidental or surgical trauma to 1 eye. CASE REPORT: We report a case of high-pressure glaucoma of the fellow eye without any signs of uveitis. The left eye of a 24-year-old man was injured in an inadvertent movement during a free-time table-tennis match. The eye was severely crushed, leading to blindness. His right eye developed medically uncontrolled high-pressure glaucoma only 1 month after the injury. CONCLUSION: To the best of our knowledge, there are no previous reports of post-traumatic glaucoma in the nontraumatized eye after open-globe injury. PMID- 27495059 TI - Molecular evolution and the global reemergence of enterovirus D68 by genome-wide analysis. AB - Human enterovirus D68 (EV-D68) was first reported in the United States in 1962; thereafter, a few cases were reported from 1970 to 2005, but 2 outbreaks occurred in the Philippines (2008) and the United States (2014). However, little is known regarding the molecular evolution of this globally reemerging virus due to a lack of whole-genome sequences and analyses. Here, all publically available sequences including 147 full and 1248 partial genomes from GenBank were collected and compared at the clade and subclade level; 11 whole genomes isolated in Taiwan (TW) in 2014 were also added to the database. Phylogenetic trees were constructed to identify a new subclade, B3, and represent clade circulations among strains. Nucleotide sequence identities of the VP1 gene were 94% to 95% based on a comparison of subclade B3 to B1 and B2 and 87% to 91% when comparing A, C, and D. The patterns of clade circulation need to be clarified to improve global monitoring of EV-D68, even though this virus showed lower diversity among clades compared with the common enterovirus EV-71. Notably, severe cases isolated from Taiwan and China in 2014 were found in subclade B3. One severe case from Taiwan occurred in a female patient with underlying angioimmunoblastic T-cell lymphoma, from whom a bronchoalveolar lavage specimen was obtained. Although host factors play a key role in disease severity, we cannot exclude the possibility that EV D68 may trigger clinical symptoms or death. To further investigate the genetic diversity of EV-D68, we reported 34 amino acid (aa) polymorphisms identified by comparing subclade B3 to B1 and B2. Clade D strains had a 1-aa deletion and a 2 aa insertion in the VP1 gene, and 1 of our TW/2014 strains had a shorter deletion in the 5' untranslated region than a previously reported deletion. In summary, a new subclade, genetic indels, and polymorphisms in global strains were discovered elucidating evolutionary and epidemiological trends of EV-D68, and 11 genomes were added to the database. Virus variants may contribute to disease severity and clinical manifestations, and further studies are needed to investigate the associations between genetic diversity and clinical outcomes. PMID- 27495060 TI - rs1495741 as a tag single nucleotide polymorphism of N-acetyltransferase 2 acetylator phenotype associates bladder cancer risk and interacts with smoking: A systematic review and meta-analysis. AB - Rs1495741 has been identified to infer N-acetyltransferase 2 (NAT2) acetylator phenotype, and to decrease the risk of bladder cancer. However, a number of studies conducted in various regions showed controversial results. To quantify the association between rs1495741 and the risk of bladder cancer and to estimate the interaction effect of this genetic variant with smoking, we performed a systematic literature review and meta-analysis involving 14,815 cases and 58,282 controls from 29 studies. Our results indicates rs1495741 significantly associated with bladder cancer risk (OR = 0.85, 95% CI = 0.82-0.89, test for heterogeneity P = 0.36, I = 7.0%). And we verified this association in populations from Europe, America, and Asia. Further, our stratified meta-analysis showed rs1495741's role is typically evident only in ever smokers, which suggests its interaction with smoking. This study may provide new insight into gene environment study on bladder cancer. PMID- 27495061 TI - Association of depression and psychotropic medication on cardiac-related outcomes in a nationwide community-dwelling elderly population in Taiwan. AB - The objective of this study was to examine the association of depression, psychotropic medications, and mental illness with cardiovascular disease in a nationwide community-dwelling elderly population in Taiwan. A total of 5664 participants who enrolled in the Healthy Aging Longitudinal Study in Taiwan (HALST) were included in the study. Multiple logistic regression was applied to investigate the association of depression, psychotropic medication use, and mental illness, separately, with cardiovascular disease. The results suggested that cardiovascular disease was significantly associated with various definitions of depression, including: the Center for Epidemiologic Studies-Depression scale (CES-D) >= 16, self-reported, and physician-diagnosed for depression (adjusted odds ratio [AOR] = 1.51; 95% confidence interval (CI): 1.14-2.00 for CES-D; AOR = 3.29; 95% CI: 1.99-5.42 for self-reported; and AOR = 2.45; 95% CI: 1.51-3.97 for physician-diagnosed). Additionally, significant associations of cardiovascular disease with the use of antipsychotics (AOR = 2.04; 95% CI: 1.25-3.34), benzodiazepines (BZDs) (AOR = 1.84; 95% CI: 1.52-2.21), and Z-drugs (AOR = 1.41; 95% CI: 1.03-1.93), respectively, were also observed, but not the use of antidepressants. In addition, a significant association of cardiovascular disease with mental illness was found in this study (AOR = 2.33; 95% CI: 1.68-3.24). In line with previous reports, these findings provided supportive evidence that depression and/or mental illness were significantly associated with cardiovascular disease in a community-dwelling elderly population in Taiwan. Moreover, significant associations of cardiovascular disease with the use of antipsychotics, BZDs, and Z-drugs, individually, were found. Further investigation would be of importance to clarify the causal relationship of depression and/or psychotropic medications with cardiovascular disease, especially among elderly populations. PMID- 27495062 TI - Impact on long-term survival of the number of lymph nodes resected in patients with pT1N0 gastric cancer after R0 resection: A multicenter study in China. AB - Although studies on the association between the number of lymph nodes resected and prognosis in patients with pT2-4N0 stages of gastric cancer have reported consistent results, there is no consensus on the optimal number of lymph nodes to be examined for pT1N0 stage gastric cancer. The aim of this study was to evaluate the long-term effect of the number of lymph nodes removed on the outcomes of patients with pT1N0 stage gastric cancer after R0 resection.From December 2009 to December 2011, 227 patients undergoing R0 resection of pT1N0 stage gastric cancer at 4 Chinese centers were enrolled in this study. Patients were assigned to 2 groups according to the number of lymph nodes dissected (<=15 or > 15). Standard survival methods and restricted multivariable Cox regression models were applied.More women (P = 0.031) were in the <=15 group than in the >15 group. The mean number of lymph nodes removed from women was greater than that from men (P = 0.007). The 5-year survival rate was significantly higher in the >15 lymph nodes resected group than the <=15 group. The number of lymph nodes resected was identified as an independent prognostic factor and was significantly correlated with overall survival (OS).A lymphadenectomy with dissection of more than 15 lymph nodes improved the long-term survival of patients with pT1N0 gastric cancer after R0 resection. Therefore, it is necessary to consider removing more than 15 lymph nodes among such patients. PMID- 27495063 TI - Effectiveness of low-level laser on carpal tunnel syndrome: A meta-analysis of previously reported randomized trials. AB - BACKGROUND: Low-level laser therapy (LLLT) has been applied in the treatment of carpal tunnel syndrome (CTS) for an extended period of time without definitive consensus on its effectiveness. This meta-analysis was conducted to evaluate the effectiveness of low-level laser in the treatment of mild to moderate CTS using a Cochrane systematic review. METHODS: We conducted electronic searches of PubMed (1966-2015.10), Medline (1966-2015.10), Embase (1980-2015.10), and ScienceDirect (1985-2015.10), using the terms "carpal tunnel syndrome" and "laser" according to the Cochrane Collaboration guidelines. Relevant journals or conference proceedings were searched manually to identify studies that might have been missed in the database search. Only randomized clinical trials were included, and the quality assessments were performed according to the Cochrane systematic review method. The data extraction and analyses from the included studies were conducted independently by 2 reviewers. The results were expressed as the mean difference (MD) with 95% confidence intervals (CI) for the continuous outcomes. RESULTS: Seven randomized clinical trials met the inclusion criteria; there were 270 wrists in the laser group and 261 wrists in the control group. High heterogeneity existed when the analysis was conducted. Hand grip (at 12 weeks) was stronger in the LLLT group than in the control group (MD = 2.04; 95% CI: 0.08 3.99; P = 0.04; I = 62%), and there was better improvement in the visual analog scale (VAS) (at 12 weeks) in the LLLT group (MD = 0.97; 95% CI: 0.84-1.11; P < 0.01; I = 0%). The sensory nerve action potential (SNAP) (at 12 weeks) was better in the LLLT group (MD = 1.08; 95% CI: 0.44-1.73; P = 0.001; I = 0%). However, 1 included study was weighted at >95% in the calculation of these 3 parameters. There were no statistically significant differences in the other parameters between the 2 groups. CONCLUSION: This study revealed that low-level laser improve hand grip, VAS, and SNAP after 3 months of follow-up for mild to moderate CTS. More high-quality studies using the same laser intervention protocol are needed to confirm the effects of low-level laser in the treatment of CTS. PMID- 27495064 TI - Impact of surgical correction of tetralogy of fallot on short-term right and left ventricular function as determined by 2-dimensional speckle tracking echocardiography. AB - Right ventricular (RV) and left ventricular (LV) dysfunction is an important determinant of poor clinical status in repaired patients with tetralogy of Fallot (TOF). The purpose of our study is to assess the impact of surgical repair on short-term RV and LV function by 2-dimensional speckle tracking echocardiography (STE).Sixty-seven patients (median age 12 months) with TOF before and 6 months after repair and 35 healthy subjects were studied. The patients were divided into the younger (age at surgery <=12 months) and older (age at surgery >12 months) subgroups. RV and LV global longitudinal systolic strain and strain rate (SR), and LV global circumferential and radial systolic strain and SR were measured by STE. After repair, RV longitudinal strain and SR increased in the younger patients, whereas RV longitudinal SR was decreased in the older patients. LV deformation parameters were unchanged in all patients. In the multivariate analysis, patients with better RV and LV deformation parameters preoperatively were identified to have better RV and LV strain and SR postoperatively (P < 0.05 for all). The surgical approach of the pulmonary valve ring was predictive of RV and LV systolic function postoperatively (P < 0.05 for all).After TOF repair, short-term RV function improvement is identified in the younger but not in the older patients, whereas LV function is unchanged in all patients. The preoperative RV and LV deformational indices are the determinant of postoperative biventricular function improvement. STE appears to be a valuable tool for assessment of biventricular function after congenital heart disease surgery. PMID- 27495065 TI - The association between biliary tract inflammation and risk of digestive system cancers: A population-based cohort study. AB - The relationship between biliary tract inflammation (BTI) and digestive system cancers is unclear. This study aimed to evaluate the association between BTI and the risks of digestive system cancers.Using the Taiwan National Health Insurance claims data, information on a cohort of patients diagnosed with BTI (n = 4398) between 2000 and 2009 was collected. A comparison cohort of sex-, age-, and index year-matched persons without BTI (n = 17,592) was selected from the same database. The disease was defined by the ICD-9-CM. Both cohorts were followed until the end of 2010 and incidences of digestive system cancers were calculated.The results revealed an increase in adjusted hazard ratio (aHR) of biliary tract cancer (24.45; 95% confidence interval [CI]: 9.20-65.02), primary liver cancer (1.53; 95% CI: 1.07-2.18), and pancreatic cancer (3.10; 95% CI: 1.20 8.03) in patients with both gallbladder and BTI. The aHR of stomach cancer was also found to be increased (2.73; 95% CI: 1.28-5.81) in patients with gallbladder inflammation only. There were no differences in esophageal cancer (aHR: 0.82; 95% CI: 0.23-2.87) and colorectal cancer (aHR: 0.92; 95% CI: 0.59-1.45). The aHR for digestive system cancers increased by 3.66 times (95% CI: 2.50-5.35) and 12.20 times (95% CI: 8.66-17.17) in BTI visits frequency averaged 2 to 4 visits per year and frequency averaged >=5 visits per year, respectively.Patients with BTI have significantly higher risk of digestive system cancers, particularly biliary tract, pancreatic, and primary liver cancers, compared with those who are without it. PMID- 27495066 TI - A retrospective observational study of functional outcomes, length of stay, and discharge disposition after an inpatient stroke rehabilitation program in Saudi Arabia. AB - Functional outcomes, length of stay (LOS), and discharge disposition have become frequent outcome measures among stroke patients after rehabilitation programs. To examine the trends of changes in functional outcomes, LOS, and discharge disposition in stroke patients discharged from an inpatient rehabilitation facility.All patients (n = 432) were admitted to a tertiary inpatient rehabilitation hospital in Riyadh, Saudi Arabia with stroke diagnoses from November 2008 to December 2014. The functional independence measure (FIM) instrument used to assess the patient's functional status. The LOS was measured as the number of days the patients spent in the hospital from the day of admission to the day of discharge. The FIM efficiency was used to measure the patient's rehabilitation progress. All of the variables of the prospectively collected data were retrospectively analyzed.There were significant changes by years in the total FIM ranging from 23 to 29 (P < 0.001) and subscores: FIM motor ranging from 20 to 26 (P < 0.001); FIM cognitive ranging from 1.8 to 3 (P < 0.001). The mean LOS remained constant, from 52 days in 2011 to 40 days in 2013. The FIM efficiency was stable between years and ranged from 0.52 to 0.72. The rates of discharge (to home) were significantly unstable and ranged from 100% in 2010 and 2011 to 92% in 2013.Our results suggest that functional outcomes in patients with stroke have improved after an inpatient stroke rehabilitation program between 2008 and 2014 even with a constant LOS. Discharge disposition has remained unstable over this period. To improve the efficiency of the stroke rehabilitation program in Saudi Arabia, there is a need to decrease the LOS and emphasize a comprehensive interdisciplinary approach. PMID- 27495067 TI - Lower liver cancer risk with antiviral therapy in chronic hepatitis B patients with normal to minimally elevated ALT and no cirrhosis. AB - For chronic hepatitis B (CHB), alanine aminotransferase (ALT) >=2 * upper limit of normal (ULN) is often used as a major criteria to initiate treatment in absence of cirrhosis, though patients with lower ALT may not be free from future risk of hepatocellular carcinoma (HCC). We aimed to examine the effect of antiviral therapy on HCC incidence based on ALT levels.We performed a retrospective study on 3665 patients consisting of United States and Taiwanese REVEAL-HBV cohort who were consecutive, treatment-naive, noncirrhotic CHB patients aged >=40 years. Patients were categorized by ALT cutoffs (>=2 * ULN vs <2 * ULN) and subgrouped by treatment status. Kaplan-Meier and Cox proportional hazards models were used to calculate cumulative incidence and hazard ratio (HR) of HCC adjusting for REACH-B scores.A total of 202 patients developed HCC. Antiviral treatment significantly reduced HCC risk: HR 0.24, 95% confidence interval 0.10-0.58; P = 0.001. HCC incidence per 100,000 person-years was significantly higher in untreated versus treated patients, even for those with ALT < 2 * ULN: 314.46 versus 0 per 100,000 person-years, P = 0.0042. For patients with Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) >= 2000 IU/mL, the number-needed-to-treat (NNT) were 15 and 14 to prevent 1 incident HCC at year 10 for patients with ALT < 2 * ULN and >=2 * ULN, respectively.After adjustment by REACH-B score, antiviral treatment significantly decreased HCC incidence even in patients with ALT < 2 * ULN. NNT to prevent 1 incident HCC after 10 years of therapy was low (14-15) in patients with mildly elevated HBV DNA >= 2000 IU/mL regardless of ALT levels. PMID- 27495068 TI - The long noncoding RNAs PVT1 and uc002mbe.2 in sera provide a new supplementary method for hepatocellular carcinoma diagnosis. AB - Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver in adults worldwide. Several studies have demonstrated that long noncoding RNAs (lncRNAs) are involved in the development of various types of cancer, including HCC. These findings prompted us to examine the detectability of lncRNAs in blood samples from patients with HCC. In this study, we explored the expression levels of 31 cancer-related lncRNAs in sera from 71 HCC patients and 64 healthy individuals by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). We found that 25 lncRNAs could be detected in the serum and that 7 had significantly different expression levels. A 2-lncRNA signature (PVT1 and uc002mbe.2) identified by stepwise regression showed potential as a diagnostic marker for HCC. The area under the receiver operating characteristic (ROC) curve was 0.764 (95% CI: 0.684-0.833). The sensitivity and specificity values of this serum 2-lncRNA signature for distinguishing HCC patients from the healthy group were 60.56% and 90.62%, respectively. The diagnostic ability of the combination of the serum 2-lncRNA signature with alpha-fetoprotein (AFP) was much greater than that of AFP alone. The expression levels of the 2 lncRNAs were associated with clinical parameters including tumor size, Barcelona Clinic Liver Cancer (BCLC) stage, and serum bilirubin. PMID- 27495069 TI - Splenectomy and risk of renal and perinephric abscesses: A population-based cohort study in Taiwan. AB - Little epidemiological research is available on the relationship between splenectomy and renal and perinephric abscesses. The purpose of the study was to examine this issue in Taiwan.We conducted a population-based retrospective cohort study using the hospitalization dataset of the Taiwan National Health Insurance Program. A total of 16,426 participants aged 20 and older who were newly diagnosed with splenectomy from 1998 to 2010 were assigned to the splenectomy group, whereas 65,653 sex-matched, age-matched, and comorbidity-matched, randomly selected participants without splenectomy were assigned to the nonsplenectomy group. The incidence of renal and perinephric abscesses at the end of 2011 was measured in both groups. The multivariable Cox proportional hazards regression model was used to measure the hazard ratio (HR) and 95% confidence interval (CI) for risk of renal and perinephric abscesses associated with splenectomy and other comorbidities including cystic kidney disease, diabetes mellitus, urinary tract infection, and urolithiasis.The overall incidence rate of renal and perinephric abscesses was 2.14-fold greater in the splenectomy group than that in the nonsplenectomy group (2.24 per 10,000 person-years vs 1.05 per 10,000 person years, 95% CI 2.02, 2.28). After controlling for sex, age, cystic kidney disease, diabetes mellitus, urinary tract infection, and urolithiasis, the multivariable regression analysis demonstrated that the adjusted HR of renal and perinephric abscesses was 2.24 for the splenectomy group (95 % CI 1.30, 3.88), when compared with the nonsplenectomy group. In further analysis, the adjusted HR markedly increased to 7.69 for those comorbid with splenectomy and diabetes mellitus (95% CI 3.31, 17.9).Splenectomy is associated with renal and perinephric abscesses, particularly comorbid with diabetes mellitus. In view of its potential morbidity and mortality, clinicians should consider the possibility of renal and perinephric abscesses when patients with splenectomy present with fever of unknown origin. PMID- 27495070 TI - The suitability of the GERDyzer instrument in pH-test-proven laryngopharyngeal reflux patients. AB - The use of validated patient-reported outcome (PRO) instruments for the treatment outcome measure of laryngopharyngeal reflux (LPR) is crucial given the lack of objective markers. However, current symptom-based PRO instruments can only partially capture the impact of LPR. The GERD Analyzer (GERDyzer), an existing disease-specific PRO instrument, which measures multidimensional health-related quality of life (HRQL) affected by the illness rather than by any specific symptoms, has been validated in patients with erosive gastroesophageal reflux disease (GERD). Following the U.S. Food and Drug Administration PRO guidance, we cross-culturally adapted the GERDyzer instrument into Chinese, and examined the qualitative and quantitative psychometric properties of the Chinese version GERDyzer in pH-test-proven LPR patients.The GERDyzer comprises 10 dimensions of HRQL, including general well-being, pain/discomfort, physical health, diet, energy, activities, leisure activities, social life, mood, and sleep. To examine the content validity, we recruited 26 pH-test-proven LPR participants to conduct 4 focus group meetings for direct patient input on clinical manifestations and HRQL impacts. We also tested the quantitative psychometric properties, including reliability, validity, and responsiveness in 100 pH-test-proven LPR patients.Saturation of concept elicitation was achieved from the 4 focus groups, and a strong conceptual match was evident between the GERDyzer contents and responses from the focus group participants. Cognitive debriefing assessment showed that the Chinese version GERDyzer was adequate for use by patients as it demonstrated linguistic validation and cultural harmonization. Quantitative psychometric properties showed evidence of high internal consistency (Cronbach alpha: 0.96), good to excellent test-retest reliability (intraclass correlation coefficient: 0.84-0.98). Confirmatory factor analysis supported a 2-factor structure. Convergent validity was confirmed by moderate correlation assessments referencing the Reflux Symptoms Index and the Reflux Questionnaire. The discriminant validity was supported by the ability to discriminate moderate-to severe disease from mild disease. The responsiveness was also high in participants with and without typical GERD symptoms (effect sizes 1.20 and 1.21, respectively).In conclusion, the Chinese version GERDyzer instrument is a reliable, valid, and responsive instrument for assessing HRQL in Taiwanese patients with LPR. PMID- 27495071 TI - Effects of cognitive behavioral coaching on depressive symptoms in a sample of type 2 diabetic inpatients in Nigeria. AB - BACKGROUND: Depression is one of the mental health problems confronting those with diabetes mellitus and may result from self-defeating thoughts and lifestyles. Therefore, the aim of this study was to investigate the effects of cognitive behavioral coaching (CBC) program on depressive symptoms in a sample of the Type 2 diabetic inpatients in Onitsha metropolis of Anambra State, Nigeria. METHODS: The design of the study was pretest-post-test randomized control group design. The participants were 80 Type 2 diabetic inpatients randomly assigned to the treatment and control groups. The primary outcome measures were Beck's Depression Inventory-II and a Diabetic Inpatient's Depressive Symptoms Observation Checklist. Mean, standard deviation, repeated measures analysis of covariance, and partial eta squared were used for data analysis. RESULTS: The results revealed that the baseline of depressive symptoms was similar between the control and treatment groups of the Type 2 diabetic inpatients. But, exposing the Type 2 diabetic inpatients to a cognitive behavioral coaching program significantly reduced the depressive symptoms in the treatment group compared to those in the control group at the end of the intervention. The effects of cognitive behavioral coaching program on the depressive symptoms of those in the treatment group remained consistent at a 6 month follow-up meetings compared to the control group. CONCLUSION: Given the potential benefits of a cognitive behavioral coaching program, clinicians and mental health professionals are urged to support and implement evidence-based cognitive-behavioral coaching interventions aimed at promoting diabetic inpatients' wellbeing in the Nigerian hospitals. PMID- 27495072 TI - Pain related to robotic cholecystectomy with lower abdominal ports: effect of the bilateral ultrasound-guided split injection technique of rectus sheath block in female patients: A prospective randomised trial. AB - BACKGROUND: Robotic cholecystectomy (RC) using port sites in the lower abdominal area (T12-L1) rather than the upper abdomen has recently been introduced as an alternative procedure for laparoscopic cholecystectomy. Therefore, we investigated the time course of different components of pain and the analgesic effect of the bilateral ultrasound-guided split injection technique for rectus sheath block (sRSB) after RC in female patients. METHODS: We randomly assigned 40 patients to undergo ultrasound-guided sRSB (RSB group, n = 20) or to not undergo any block (control group, n = 20). Pain was subdivided into 3 components: superficial wound pain, deep abdominal pain, and referred shoulder pain, which were evaluated with a numeric rating scale (from 0 to 10) at baseline (time of awakening) and at 1, 6, 9, and 24 hours postoperatively. Consumption of fentanyl and general satisfaction were also evaluated 1 hour (before discharge from the postanesthesia care unit) and 24 hours postoperatively (end of study). RESULTS: Superficial wound pain was predominant only at awakening, and after postoperative 1 hour in the control group. Bilateral ultrasound-guided sRSB significantly decreased superficial pain after RC (P < 0.01) and resulted in a better satisfaction score (P < 0.05) 1 hour after RC in the RSB group compared with the control group. The cumulative postoperative consumption of fentanyl at 6, 9, and 24 hours was not significantly different between groups. CONCLUSIONS: After RC with lower abdominal ports, superficial wound pain predominates over deep intra abdominal pain and shoulder pain only at the time of awakening. Afterwards, superficial and deep pain decreased to insignificant levels in 6 hours. Bilateral ultrasound-guided sRSB was effective only during the first hour. This limited benefit should be balanced against the time and risks entailed in performing RSB. PMID- 27495073 TI - Fatty liver index as a simple predictor of incident diabetes from the KoGES ARIRANG study. AB - The fatty liver index (FLI), calculated from serum triglyceride, body mass index, waist circumference, and gamma-glutamyltransferase, is considered a surrogate marker of nonalcoholic fatty liver disease (NAFLD). We investigated whether FLI predicts the development of diabetes mellitus (DM) and assessed the predictive ability of FLI for new onset of DM in a prospective population-based cohort study.We analyzed a total of 2784 adults (944 men and 1840 women) aged 40 to 70 years without DM at baseline. Participants were classified according to FLI values into 3 groups: FLI < 30, no NAFLD; 30 <= FLI <= 59, intermediate NAFLD; and FLI >= 60, participants with NAFLD. The area under the receiver-operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were calculated to determine whether FLI improved DM risk prediction.During a mean of 2.6 years follow-up, 88 (3.16%) participants developed DM. The odds ratio analyzed from multivariable-adjusted models (95% confidence interval [CI]) for new onset of DM increased in a continuous manner with increased FLI (<30 vs 30-59 vs >=60 = 1 vs 1.87 [95% CI 1.05-3.33] vs 2.84 [95% CI 1.4-5.75], respectively). The AUC significantly increased when FLI was added to the conventional DM prediction model (0.835, 95% CI: 0.789-0.881, P = 0.0289 vs traditional DM prediction model). The category free NRI was 0.417 (95% CI: 0.199-0.635) and the IDI was 0.015 (95% CI: 0.003 0.026) for overall study participants.We found that FLI, a surrogate marker of hepatic steatosis, resulted in significant improvement in DM risk prediction. Our finding suggests that FLI may have clinical and prognostic information for incident DM among the Korean adult population. PMID- 27495074 TI - Effectiveness of fine-needle aspiration cytology in the diagnosis of lateral cervical nonthyroid tumors. AB - Given that the clinical and radiological examinations of lateral cervical masses are not always sufficient for deciding on appropriate management, the cytological examination of the material obtained by fine-needle aspiration might be an efficient tool in the preoperative investigation of these lesions.In this prospective cross-sectional study we evaluated the efficacy and diagnostic accuracy of fine-needle aspiration cytology in the assessment of lateral cervical nonthyroid tumors, by comparing its results with those of histopathology.A total of 58 patients with lateral cervical masses were included. Preoperative cytological results were compared with the histopathologic examination of surgical specimens.Both cytology and histology indicated that malignant tumors outnumbered benign lesions (62% vs 38%), with 88.9% of malignancies presenting in patients aged >50 years, but cytology was less effective at differentiating between benign and nontumor lesions. Cytology had 76.5% specificity and 78.1% sensitivity for identifying malignant lateral cervical lesions, and there was a concordance between the two diagnostic tests (McNemar test, P = 0.17, kappa = 0.50, P <0.001).Fine-needle aspiration cytology is a simple, quick, and effective procedure that can aid in the preoperative evaluation of lateral cervical masses by differentiating benign tumors and inflammatory processes from malignancies and thus help in determining a subsequent therapeutic strategy. PMID- 27495075 TI - Body mass index and the risk of incident functional disability in elderly Japanese: The OHSAKI Cohort 2006 Study. AB - The relationship between the body mass index (BMI) and the incidence of cause specific disability remains unclear.We conducted a prospective cohort study of 12,376 Japanese individuals aged >=65 years who were followed up for 5.7 years. Information on BMI and other lifestyle factors was collected via a questionnaire in 2006. Functional disability data were retrieved from the public Long-term Care Insurance database. BMI was divided into 6 groups (<21, 21-<23, 23-<25, 25 <27[reference], 27-<29 and >=29). Hazard ratios and 95% confidence intervals for cause-specific disability were estimated using Cox proportional hazards regression models.A U-shaped relationship between BMI and functional disability was observed, with a nadir at 26. The nadir BMI values with the lowest disability risk were 28 for dementia, 25 for stroke, and 23 for joint disease. A low BMI (<23) was a risk factor for disability due to dementia, the HR values (95% CI) being 2.48 (1.70-3.63) for BMI <21 and 2.25 (1.54-3.27) for BMI 21 to <23; a high BMI (>=29) was a risk factor for disability due to joint disease, the HR value (95% CI) being 2.17 (1.40-3.35). There was no significant relationship between BMI and disability due to stroke.The BMI nadirs for cause-specific disability differed: a low BMI (<23) was a risk factor for disability due to dementia, and a high BMI (>=29) was a risk factor for disability due to joint disease. Because BMI values of 23 to <29 did not pose a significantly higher risk for each cause of disability, this range should be regarded as the optimal one for the elderly population. PMID- 27495076 TI - Seasonal changes of 24-hour intraocular pressure rhythm in healthy Shanghai population. AB - The aim of the present study was to investigate and compare the 24-hour intraocular pressure (IOP) rhythms in winter and summer in the healthy population of Shanghai, China.This is a cross-sectional study in which 24-hour IOP measurements were taken for all eligible healthy volunteers in winter and summer, respectively, and the temperature, hours of sunlight (sunlight time), and circulatory parameters, including heart rate, systolic blood pressure, and diastolic blood pressure, were also recorded. The 24-hour IOP curves and IOP parameters (mean, peak, trough, and fluctuation of IOP together with the diurnal to-nocturnal IOP change) in winter and summer were obtained and compared. The magnitude of IOP changes from summer to winter was also calculated.A total of 29 participants (58 eyes), 14 (48.28%) male and 15 (51.72%) female, aged 43.66 +/- 12.20 (19-61) years, were considered eligible for this study. Generally, IOP decreased progressively before noon, increased notably in the nocturnal period, and peaked at 12:00 AM in winter and at 2:00 AM in summer. The pattern of 24-hour IOP in winter and summer was significantly different (P = 0.002). The average IOPs from 4:00 PM to 8:00 AM, except for 6:00 AM, were significantly higher in winter (P < 0.05). However, no significant differences were shown after adjusting for temperature and/or sunlight time. From summer to winter, the extent of IOP increase was mostly around 0 to 3 mm Hg, and the IOPs increased more significantly in the nocturnal period than in the diurnal period (P = 0.05).The 24-hour IOP rhythms were different in winter and summer, with higher IOP level in winter. Temperature and sunlight time, which are independent of heart rate and blood pressure, affected the 24-hour IOP rhythms in healthy people in Shanghai, China. Further investigations are expected for the rhythm of some endogenous substance secretion and the inner mechanism of regulation of IOP. PMID- 27495077 TI - Long-term effects of pioglitazone on first attack of ischemic cerebrovascular disease in older people with type 2 diabetes: A case-control study in Taiwan. AB - Long-term studies demonstrating the effect of pioglitazone use on primary prevention of ischemic cerebrovascular disease in older people with type 2 diabetes mellitus are lacking. This study investigated the relationship between pioglitazone use and first attack of ischemic cerebrovascular disease in Taiwan.We conducted a case-control study using the database of the Taiwan National Health Insurance Program. There were 2359 type 2 diabetic subjects aged >=65 years with newly diagnosed ischemic cerebrovascular disease from 2005 to 2011 as the case group and 4592 sex- and age-matched, randomly selected type 2 diabetic subjects aged >=65 years without ischemic cerebrovascular disease as the control group. The odds ratio (OR) with 95% confidence interval (CI) of ischemic cerebrovascular disease associated with pioglitazone use was measured by the multivariable unconditional logistic regression model.After adjustment for confounding factors, the multivariable logistic regression analysis disclosed that the adjusted ORs of first attack of ischemic cerebrovascular disease associated with cumulative duration of using pioglitazone were 3.34 for <1 year (95% CI 2.59-4.31), 2.53 for 1 to 2 years (95% CI 1.56-4.10), 2.20 for 2 to 3 years (95% CI 1.05-4.64), and 1.09 for >=3 years (95% CI 0.55-2.15), respectively.Our findings suggest that pioglitazone use does not have a protective effect on primary prevention for ischemic cerebrovascular disease among older people with type 2 diabetes mellitus during the first 3 years of use. Whether using pioglitazone for >3 years would have primary prevention for ischemic cerebrovascular disease needs a long-term research to prove. PMID- 27495079 TI - Pseudoaneurysm of the aortic arch: A rare case report of pulmonary cancer complication. AB - BACKGROUND: Pseudoaneurysm of the aortic arch is uncommonly associated with cancer, and is extremely rare in pulmonary cancer. Here, we report an unusual and successfully treated case of aortic arch pseudoaneurysm in a male patient with lung squamous cell carcinoma. METHODS: A 64-year-old male patient was admitted to the Emergency Department, presenting with massive hemoptysis (>500 mL blood during the 12 hours prior to treatment). The diagnosis of aortic arch pseudoaneurysm was confirmed after inspection of computed tomographic angiography and three-dimensional reconstruction. We processed the immediate endovascular stent-grafting for this patient. RESULTS: This patient recovered with no filling or enlargement of the pseudoaneurysm, no episodes of hemoptysis, and no neurological complications during the 4-week follow-up period. CONCLUSION: Herein, we compare our case with other cancer-related pseudoaneurysms in the medical literature and summarize the clinical features and treatment of this unusual case. PMID- 27495078 TI - Comparison of image quality from filtered back projection, statistical iterative reconstruction, and model-based iterative reconstruction algorithms in abdominal computed tomography. AB - The purpose of this study was to compare the image noise-reducing abilities of iterative model reconstruction (IMR) with those of traditional filtered back projection (FBP) and statistical iterative reconstruction (IR) in abdominal computed tomography (CT) imagesThis institutional review board-approved retrospective study enrolled 103 patients; informed consent was waived. Urinary bladder (n = 83) and renal cysts (n = 44) were used as targets for evaluating imaging quality. Raw data were retrospectively reconstructed using FBP, statistical IR, and IMR. Objective image noise and signal-to-noise ratio (SNR) were calculated and analyzed using one-way analysis of variance. Subjective image quality was evaluated and analyzed using Wilcoxon signed-rank test with Bonferroni correction.Objective analysis revealed a reduction in image noise for statistical IR compared with that for FBP, with no significant differences in SNR. In the urinary bladder group, IMR achieved up to 53.7% noise reduction, demonstrating a superior performance to that of statistical IR. IMR also yielded a significantly superior SNR to that of statistical IR. Similar results were obtained in the cyst group. Subjective analysis revealed reduced image noise for IMR, without inferior margin delineation or diagnostic confidence.IMR reduced noise and increased SNR to greater degrees than did FBP and statistical IR. Applying the IMR technique to abdominal CT imaging has potential for reducing the radiation dose without sacrificing imaging quality. PMID- 27495080 TI - Application of Kinesio Taping method for newborn swallowing difficultly: A case report and literature review. AB - BACKGROUND: Preterm infants are at an increased risk of sucking problems, swallowing difficulty, and poor nourishment. During the neonatal period, the neurobehavioral organization of a preterm baby is poor compared with that of appropriate gestational age infants. Kinesio Taping has been widely used for edema control, joint protection, and proprioception training. With the help of augmentation of the sensory input for muscle facilitation and inhibition through tapping, the coordination of the target muscle groups can be improved. Until now, no research is available on the use of Kinesio Taping for the swallowing difficulty of infant. METHODS: We reported a preterm infant suffering from brain edema at birth and swallowing difficultly until 40 weeks. The swallowing reflex was delayed. Moreover, lip closure and rooting reflex combined with the dysfunction grade of jaw movement were poor. We performed KT methods on the baby under the theory of the direction of the tape for facilitate or inhibit the muscle. RESULT: After the Kinesio Taping treatment, the sucking function was improved with good lip closure.One week later, the baby was discharged without the use of an oral gastric tube. CONCLUSION: Kinesio Taping contributed significantly to the improvement of impaired sucking and swallowing and could be implemented as a regular rehabilitative approach for infants suffering from these difficulties. PMID- 27495081 TI - CT-guided percutaneous transthoracic needle biopsy for paramediastinal and nonparamediastinal lung lesions: Diagnostic yield and complications in 1484 patients. AB - Computed tomography-guided percutaneous transthoracic needle biopsy (PTNB) is used for identifying paramediastinal lung lesions that cannot be diagnosed by bronchoscopy, but the diagnostic performance and complication rate are unreported.This retrospective study was approved by the institutional review board committee. A total of 1484 patients who underwent PTNB between April 2012 and April 2015 were enrolled. The cohort was divided into a paramediastinal (n = 195) and a nonparamediastinal group (n = 1289) based on lesion location. Diagnostic yield for malignancy and complication rates were analyzed in both groups. Univariate and multivariate logistic regression analysis was used to determine independent risk factors for hemoptysis complication in the paramediastinal group.Percutaneous transthoracic needle biopsy showed 95.6% (109/114) sensitivity and 100% (77/77) specificity for the diagnosis of lesions in the paramediastinal group, with similar accuracy (95.4%, 186/195) to that in the nonparamediastinal group (94.7%, 1221/1289; P = 0.699). Compared with PTNB for nonparamediastinal lesions, PTNB for paramediastinal lesions demonstrated a comparable pneumothorax rate (8.21% vs 8.69%; P = 0.823) and hemothorax rate (2.56% vs 1.47%; P = 0.261), and a higher hemoptysis rate (28.2% vs 19.4%; P = 0.005). Among 6 defined paramediastinal regions, the overall complication rate was the highest in the posterior region (42.4%) and the lowest in the paraventricular region (13.6%). Multivariate analysis revealed that lesion size of 2 to 3 cm (odds ratio [OR] 3.22), intrapulmonary length of needle path >2 cm (OR 8.85), and proximal to pulmonary artery (OR 10.33) were independent risk factors for hemoptysis in the paramediastinal group.Computed tomography-guided PTNB can diagnose paramediastinal lesions with high yield and acceptable complication rates. Given higher rate of hemoptysis in PTNB for paramediastinal lesions, more attention should be paid in cases with high risks. PMID- 27495082 TI - Comparative assessment of therapeutic safety of norcantharidin, N-farnesyloxy norcantharimide, and N-farnesyl-norcantharimide against Jurkat T cells relative to human normal lymphoblast: A quantitative pilot study. AB - The therapeutic safety of an anticancer drug is one of the most important concerns of the physician treating the cancer patient. Half maximal inhibitory concentration (IC50) and hillslope are usually used to represent the strength and sensitivity of an anticancer drug on cancer cells. The therapeutic safety of the anticancer drug can be assessed by comparing the IC50 and hillslope of anticancer drugs on cancer cells relative to normal cells. Since there are situations where "more anticancer activity" implies "more toxicity," the safety of an anticancer drug in these situations is hard to evaluate by using IC50 and hillslope alone. In a previous study, the "net effect" index was devised to represent the net therapeutic effects of one anticancer drug relative to the other. However, the therapeutic safety of one specific anticancer drug alone was not defined in the "net effect" index. This study introduced the "safety index (SI)" to quantify the degree of safety of an anticancer drug by using 4-parameter logistic model on cancer cells relative to normal cells. The therapeutic safety of norcantharidin (NCTD), N-farnesyloxy-norcantharimide (NOC15), and N-farnesyl-norcantharimide (NC15) in the treatment of Jurkat T cells relative to human normal lymphoblast was compared using the newly defined SI. We found that the SI of NOC15 and NC15 was significantly higher than that of NCTD, suggesting that both NOC15 and NC15 can damage more cancer cells and less normal cells than NCTD. We conclude that both NOC15 and NC15 are safer anticancer drugs than NCTD in the treatment of Jurkat T cells relative to human normal lymphoblast. The SI can be further applied to the screening, developments, and applications of anticancer drugs in the future. PMID- 27495083 TI - Eight years of follow-up after laminectomy of calcium pyrophosphate crystal deposition in the cervical yellow ligament of patient with Coffin-Lowry syndrome: A case report. AB - BACKGROUND: We report 8 years of follow-up after decompression to treat cervical myelopathy in a patient with Coffin-Lowry syndrome (CLS). CLS is a rare X-linked semidominant syndrome associated with growth and psychomotor retardation, general hypotonia, and skeletal abnormalities. In this patient, the spinal cord was compressed by calcium pyrophosphate crystal deposition in the cervical yellow ligament (YL). To date, only 1 report has described clinical features after surgery for calcified cervical YL in CLS. METHODS: A 15-year-old male with tetraplegia secondary to compression of the cervical spinal cord induced by a hypoplastic posterior arch of C1 and calcification of the YL from C2 to C7 was treated surgically with laminectomy from C1 to C7. The patient's history, clinical examination, imaging findings, and treatment are reported. The patient was incapable of speech because of mental retardation, so he could not describe his symptoms. Gait disturbance worsened over the 2 months before admission to our hospital. At admission, the patient could not move his extremities, and tendon reflexes of the upper and lower extremities were significantly increased. Computed tomography of the cervical spine showed YL calcification from C2 to C7. Magnetic resonance imaging showed consecutive compression of the cervical spinal cord. We diagnosed quadriplegia secondary to cervical cord damage and performed emergency surgery. RESULTS: During C1-C7 laminectomy, YL calcification in C2-C7 was observed. The calcification was confirmed as calcium pyrophosphate by crystal analysis. Quadriplegia gradually resolved, and almost disappeared by 2 weeks after the operation. Cervical hyperlordosis was observed in radiographs starting from 1 month after the operation, but it has not progressed and is not associated with any symptoms. CONCLUSIONS: The efficacy of decompression continued, and no postoperative complications have occurred during at least 8 years of follow-up. PMID- 27495084 TI - Aponeurosis of the levator palpebrae superioris in Chinese subjects: A live gross anatomy and cadaveric histological study. AB - An accurate understanding of the anatomy of the levator palpebrae superioris aponeurosis (LPSA) is critical for successful blepharoplasty of aponeurotic ptosis. We investigated the macroscopic and microscopic anatomy of the LPSA.This prospective live gross anatomy study enrolled 200 adult Chinese patients with bilateral mild ptosis undergoing elective blepharoplasty. Full-thick eyelid tissues and sagittal sections from the eyelid skin to the conjunctiva were examined with Masson trichrome staining or antismooth muscle actin (SMA) immunohistochemistry.Gross anatomy showed that the space between the superficial and deep layers of the LPSA could be accessed after incising the overlying superficial fascia, by retracting the white line. Adipose layers were clearly observed in 195 out of 200 patients with bilateral mild ptosis, among which 180 cases had the superficial layer connected to the uncoated adipose. Fifteen cases had the superficial layer connected to the smoothly coated layer, and 5 cases had the superficial layer directly connected to the deep loose fiber, almost without adipose. In previously untreated patients, the LPSA space was located beneath the intact orbital septum. In those with previous surgeries, it was beneath the superficial layer of the LPSA, underlying the destructed orbital septum. Cadaveric histology showed that the deep layer of the LPSA extended into the anterior layer of the tarsal plate and the superficial layer reflexed upward in continuity with the vertical orbital septum. An occult space existed between the 2 layers of the LPSA, with a smooth lining on the deep layer. The superficial layer of the LPSA was SMA-immunonegative but the deep layer was slightly immunopositive for SMA. An occult anatomic space exists between the superficial and deep layers of the LPSA, in proximity to the superior tarsal plate margin. Recognition of the more anatomically significant LPSA deep layer may help improve the aesthetic outcome of blepharoplasty. PMID- 27495085 TI - CONSORT: Effects of adding adefovirdipivoxil to peginterferon alfa-2a at different time points on HBeAg-positivepatients: A prospective, randomized study. AB - BACKGROUND: The aims of this study were to compare the efficacy and safety of the addition of adefovir dipivoxil (ADV) (started at different time points) to pegylated interferon alpha-2a (PEG-INF-alpha2a) and PEG-INF-alpha2a monotherapy. This prospective, randomized study sought to evaluate the safety and efficacy of the combination of PEG-INF-alpha2a and ADV at different time points.120 patients were randomized into groups that received PEG-INF-alpha2a as monotherapy (group A) or in combination with ADV started at week 0 (group B), 12 (group C), or 24 (group D). All patients were followed for 48 weeks. Efficacy and safety analyses were performed. METHODS: Patients in group a received 135 MUg of PEG-INF-alpha2a by subcutaneous injection once weekly for 48 weeks. Patients in the ADV add-on group received 135 MUg of PEG-INF-alpha2a subcutaneously once weekly and received 10 mg of ADV administered once daily for 48 weeks. HBV DNA, HBsAg, HBeAg, and hepatitis B e antibody levels were determined. Responses were determined at week 12 (ADV add-on), the end of treatment for PEG-INF-alpha2a (48weeks) and ADV (EOT) and at the end of 96 weeks of follow-up (EOF). RESULTS: The rate of HBV DNA loss were higher in the combination groups than group A at the week 12, week 48, the EOT and EOF (P < 0.05). The rates of HBeAg seroconversion and HBsAg loss were similar among the treatment groups (P>0.05). The alanineaminotransferase (ALT) normalization rate was higher in the combination group than group A only at the EOT (P = 0.007). By the EOF, the patients with ADV added at week 12 achieved higher rates of HBV DNA loss (71.9%), HBeAg seroconversion (50.0%), HBsAg loss (15.6%), and ALT normalization (78.1%). CONCLUSIONS: PEG-INF-alpha2a plus ADV combination therapy is safe and superior to PEG-INF-alpha2amonotherapyfor decreasing serum HBV DNA and normalizing the ALT level but has no significant impact on the rate of HBeAg seroconversion and HBsAg loss. Adding ADV at week 12 may be an optimal combination strategy. PMID- 27495086 TI - Genetic signatures of heroin addiction. AB - Heroin addiction is a complex psychiatric disorder with a chronic course and a high relapse rate, which results from the interaction between genetic and environmental factors. Heroin addiction has a substantial heritability in its etiology; hence, identification of individuals with a high genetic propensity to heroin addiction may help prevent the occurrence and relapse of heroin addiction and its complications. The study aimed to identify a small set of genetic signatures that may reliably predict the individuals with a high genetic propensity to heroin addiction. We first measured the transcript level of 13 genes (RASA1, PRKCB, PDK1, JUN, CEBPG, CD74, CEBPB, AUTS2, ENO2, IMPDH2, HAT1, MBD1, and RGS3) in lymphoblastoid cell lines in a sample of 124 male heroin addicts and 124 male control subjects using real-time quantitative PCR. Seven genes (PRKCB, PDK1, JUN, CEBPG, CEBPB, ENO2, and HAT1) showed significant differential expression between the 2 groups. Further analysis using 3 statistical methods including logistic regression analysis, support vector machine learning analysis, and a computer software BIASLESS revealed that a set of 4 genes (JUN, CEBPB, PRKCB, ENO2, or CEBPG) could predict the diagnosis of heroin addiction with the accuracy rate around 85% in our dataset. Our findings support the idea that it is possible to identify genetic signatures of heroin addiction using a small set of expressed genes. However, the study can only be considered as a proof-of-concept study. As the establishment of lymphoblastoid cell line is a laborious and lengthy process, it would be more practical in clinical settings to identify genetic signatures for heroin addiction directly from peripheral blood cells in the future study. PMID- 27495087 TI - Voriconazole treatment of Candida tropicalis meningitis: persistence of (1,3) beta-D-glucan in the cerebrospinal fluid is a marker of clinical and microbiological failure: A case report. AB - INTRODUCTION: Infections are still the most common complications of cerebral shunt procedures. Even though fungal etiologies are considered to be rare, they are associated with significant morbidity and mortality. Due to their uncommonness, diagnostic procedures and optimal therapy are poorly defined. We report a case of Candida tropicalis infection of ventriculo-peritoneal cerebrospinal fluid (CSF) shunt in a 49-year-old immune competent male treated with voriconazole (VOR). METHODS: Microbiological and CSF markers (1,3-b-D-glucan BDG) of fungal infection, biofilm production capacity, sensitivity of serial isolates of the pathogen, and the concentration of the antifungal drug have been monitored and related to the clinical course of this infection. RESULTS: Despite appropriate treatment with VOR, in terms of adequate achieved CSF drug concentrations and initial effective therapeutic response, loss of VOR susceptibility of the C tropicalis and treatment failure were observed. CONCLUSION: Biofilm production of the C. tropicalis isolate might have had a significant role in treatment failure. Of interest, clinical and microbiological unfavorable outcome was anticipated by persistence of BDG in CSF. Rising titers of this marker were associated with relapse of fungal infection. PMID- 27495088 TI - Complementary traditional Chinese medicine therapy improves survival in patients with metastatic prostate cancer. AB - More than 50% of prostate cancer patients have used traditional Chinese medicine (TCM) in Taiwan. However, the long-term clinical efficacy of TCM in prostate cancer patients remains unclear. Here, we investigated the relationship between TCM use and the survival of prostate cancer patients.A retrospective nationwide cohort study of prostate cancer patients was conducted between 1998 and 2003 using the Taiwan National Health Insurance Research Database. Patients were classified as TCM users or nonusers, and monitored from the day of prostate cancer diagnosis to death or end of 2012. The association between death risk and TCM use was determined using Cox proportional-hazards models and Kaplan-Meier curves.Of the 1132 selected prostate cancer patients, 730 (64.5%) and 402 (35.5%) were TCM users and nonusers, respectively. The mean follow-up period was 8.38 years, and 292 (25.8%) deaths were reported. TCM users had a decreased mortality rate (21.9%) compared with nonusers (32.8%). A lower death risk was observed with longer TCM use, especially in patients who used TCM for ?200 days (adjusted hazard ratio [aHR] 0.61, 95% confidence interval [CI] 0.44-0.84). TCM users with metastatic prostate cancer had a significant lower HR than nonusers (aHR 0.70, 95% CI 0.51-0.95). Chai-Hu-Jia-Long-Gu-Mu-Li-Tang was the most significant TCM formulae for improving survival in metastatic prostate cancer (aHR 0.18, 95% CI 0.04-0.94).The result suggested that complementary TCM therapy might be associated with a reduced risk of death in metastatic prostate cancer patients. PMID- 27495089 TI - Hemophagocytic lymphohistiocytosis associated with SFTS virus infection: A case report with literature review. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a new emerging zoonosis. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome caused by hyperinflammation. Here, we report the case of SFTS-associated HLH. CASE SUMMARY: A 62-year-old man was admitted to local hospital with 8 days of fever and chill. He had leukopenia, thrombocytopenia, and developed seizure. An attending physician examined bone marrow to rule out hematologic malignancy. He was transferred to tertiary referral hospital for suspicious HLH. We decided to confirm its histologic feature for sure. Bone marrow and liver biopsy showed hemophagocyotic histiocytes. Serological tests for other infections were all negative except SFTS virus polymerase chain reactions (PCRs) as positive from serum, bone marrow, bronchoalveolar lavage fluid, and liver biopsy specimen. A definitive diagnosis was SFTS-associated HLH. During 2 weeks of conservative treatment, he succeeded in recovery from multiple organ failure. CONCLUSION: SFTS should be considered one of differential diagnosis of HLH. In certain endemic areas, SFTS infection deserves clinicians' attention because it can be presented hematologic diseases as HLH. PMID- 27495090 TI - Genetic polymorphisms in the CD14 gene are associated with monocyte activation and carotid intima-media thickness in HIV-infected patients on antiretroviral therapy. AB - HIV-infected individuals on antiretroviral therapy (ART) are at increased risk of cardiovascular disease (CVD). Given the relationship between innate immune activation and CVD, we investigated the association of single-nucleotide polymorphisms (SNPs) in TLR4 and CD14 and carotid intima-media thickness (cIMT), a surrogate measurement for CVD, in HIV-infected individuals on ART and HIV uninfected controls as a cross-sectional, case-control study. We quantified the frequency of monocyte subsets (CD14, CD16), markers of monocyte activation (CD38, HLA-DR), and endothelial adhesion (CCR2, CX3CR1, CD11b) by flow cytometry. Plasma levels of lipopolysaccharide, sCD163, sCD14, sCX3CL1, and sCCL2, were measured by ELISA. Genotyping of TLR4 and CD14 SNPs was also performed. The TT genotype for CD14/-260SNP but not the CC/CT genotype was associated with elevated plasma sCD14, and increased frequency of CD11b+CD14+ monocytes in HIV-infected individuals. The TT genotype was associated with lower cIMT in HIV-infected patients (n = 47) but not in HIV-uninfected controls (n = 37). The AG genotype for TLR4/+896 was associated with increased CX3CR1 expression on total monocytes among HIV-infected individuals and increased sCCL2 and fibrinogen levels in HIV uninfected controls. SNPs in CD14/-260 and TLR4/+896 were significantly associated with different markers of systemic and monocyte activation and cIMT that differed between HIV-infected participants on ART and HIV-uninfected controls. Further investigation on the relationship of these SNPs with a clinical endpoint of CVD is warranted in HIV-infected patients on ART. PMID- 27495091 TI - Method for discriminating synchronous multiple lung cancers of the same histological type: miRNA expression analysis. AB - With the development of imaging technology, an increasing number of synchronous multiple lung cancers (SMLCs) have been diagnosed in recent years. Patients with >1 tumor are diagnosed with either synchronous multiple primary lung cancers (SMPLCs) or other primary tumors and metastases. Clinical guidelines, histological characteristics, and molecular diagnostics have been used to discriminate SMPLCs from other multiple lung cancers. However, there is still ambiguity in the diagnosis of SMPLCs of the same histological type. We enrolled 24 patients with the same histological type of SMLCs and assessed their status using established clinical guidelines, comprehensive histological subtyping, and molecular analysis. The sum value of the differential microRNA (miRNA) expression profiles (DeltaDeltaCt) with matched tumors was evaluated to discriminate SMPLCs of the same histological type from metastases. Twelve patients with lymph node metastases were included for comparison, and the sum value of the DeltaDeltaCt of 5 miRNAs between primary tumors and lymph node metastases was <9. Patients definitively diagnosed with SMPLCs by integrated analysis were also classified as SMPLCs by miRNA analysis; 6 patients showed conflicting diagnoses by integrated and miRNA analysis and 14 were given the same classification. Analysis of miRNA expression profiles is considered to be a useful tool for discriminating SMPLCs from intrapulmonary metastases. PMID- 27495092 TI - Nutritional status and physical inactivity in moderated asthmatics: A pilot study. AB - Preservation of nutritional status and of fat-free mass (FFM) and/or preventing of fat mass (FM) accumulation have a positive impact on well-being and prognosis in asthma patients. Physical inactivity is identified by World Health Organization as the fourth leading risk factor for global mortality. Physical activity (PA) may contribute to limit FM accumulation, but little information is available on the interactions between habitual PA and body composition and their association with disease severity in asthma severity.Associations between habitual PA, FM, FFM, and pulmonary function were investigated in 42 subjects (24 patients with mild-moderate asthma and 18 matched control subjects). Sensewear Armband was used to measure PA and metabolic equivalent of tasks (METs) continuously over 4 days, while body composition was measured by bioelectrical impedance analysis. Respiratory functions were also assessed in all study participants.FM and FFM were comparable in mild-moderate asthmatics and controls, but PA was lower in asthmatics and it was negatively correlated with FM and positively with the FFM marker body cell mass in all study subjects (P < 0.05). Among asthmatics, treated moderate asthmatics (ICS, n = 12) had higher FM and lower PA, METs, steps number/die, and forced expiratory volume in the 1st second (FEV1)/forced vital capacity (FVC) than in untreated intermittent asthmatics (UA, n = 12).This pilot study assesses that in mild-moderate asthma patients, lower PA is associated with higher FM and higher disease severity. The current results support enhancement of habitual PA as a potential tool to limit FM accumulation and potentially contribute to preserve pulmonary function in moderate asthma, considering the physical inactivity a strong risk factor for asthma worsening. PMID- 27495093 TI - Comparison of a tube-holder (Rescuefix) versus tape-tying for minimizing double lumen tube displacement during lateral positioning in thoracic surgery: A prospective, randomized controlled study. AB - BACKGROUND: Double-lumen endotracheal tubes (DLTs) are often displaced during change from the supine to the lateral decubitus position. The aim of this study was to determine whether Rescuefix, a recently developed tube-holder device, is more effective than the traditional tape-tying method for tube security during lateral positioning. METHODS: Patients were randomly assigned to a Rescuefix (R) group (n = 22) or a tape (T) group (n = 22). After intubation with a left-sided DLT and adjustment of the appropriate DLT position using a fiberoptic bronchoscope, the DLT was fixed firmly at the side of the mouth by either Rescuefix or Durapore tape. "Tracheal depth" (from the tracheal carina to the elbow connector of the DLT) and "bronchial depth" (from the left bronchial carina to the elbow connector of the DLT) were measured in the supine position using the fiberoptic bronchoscope. After positional change, tracheal and bronchial depths were measured as described above. As the primary endpoint, displacement of the DLT during positional change was evaluated by obtaining the difference in depths measured when the patient was in the supine and lateral decubitus positions. In addition, after lateral positioning of the patient, any requirement for repositioning the DLT was recorded. RESULTS: After lateral positioning, there were no significant differences in changes in tracheal and bronchial depths between the groups (tracheal depth 6.1 +/- 4.4 mm [R group] and 9.1 +/- 5.6 mm [T group], P = 0.058; bronchial depth 6.5 +/- 4.4 mm [R group], and 8.5 +/- 4.6 mm [T group], P = 0.132). Although the amount of change in tracheal and bronchial depths was not different between the groups, the need to reposition the DLT was significantly lower in the R group than in the T group (32% vs 68%, P = 0.016). CONCLUSION: This study demonstrated that use of Rescuefix did not reduce the amount of DLT displacement, but it did significantly lower the incidence of DLT repositioning compared with the tape-tying method. Therefore, Rescuefix appears to be an effective alternative to minimizing DLT displacement during lateral positioning in thoracic surgery. TRIAL REGISTRATION: http://cris.nih.go.kr identifier: KCT0001949. PMID- 27495094 TI - Early postoperative albumin level following total knee arthroplasty is associated with acute kidney injury: A retrospective analysis of 1309 consecutive patients based on kidney disease improving global outcomes criteria. AB - Hypoalbuminemia has been reported to be an independent risk factor for acute kidney injury (AKI). However, little is known about the relationship between the albumin level and the incidence of AKI in patients undergoing total knee arthroplasty (TKA). The aim of our study was to assess incidence and risk factors for AKI and to evaluate the relationship between albumin level and AKI following TKA.The study included a retrospective review of medical records of 1309 consecutive patients who underwent TKA between January 2008 and December 2014. The patients were divided into 2 groups according to the lowest serum albumin level within 2 postoperative days (POD2_alb level < 3.0 g/dL vs >=3.0 g/dL). Multivariate logistic regression analysis was used to assess risk factors for AKI. A comparison of incidence of AKI, hospital stay, and overall mortality in the 2 groups was performed using propensity score analysis.Of 1309 patients, 57 (4.4%) developed AKI based on Kidney Disease Improving Global Outcomes criteria. Factors associated with AKI included age (odds ratio [OR] 1.05; 95% confidence interval [CI] 1.01-1.09; P = 0.030), diabetes (OR 3.12; 95% CI 1.65-5.89; P < 0.001), uric acid (OR 1.51; 95% CI 1.26-1.82; P < 0.001), beta blocker use (OR 2.65; 95% CI 1.48-4.73; P = 0.001), diuretics (OR 16.42; 95% CI 3.08-87.68; P = 0.001), and POD2_alb level < 3.0 g/dL (OR 1.92; 95% CI 1.09-3.37; P = 0.023). After propensity score analysis, POD2_alb level<3.0 g/dL was associated with AKI occurrence (OR 1.82; 95% CI 1.03-3.24, P = 0.041) and longer hospital stay (P = 0.001).In this study, we demonstrated that POD2_alb level<3.0 g/dL was an independent risk factor for AKI and lengthened hospital stay in patients undergoing TKA. PMID- 27495095 TI - Washed cell salvage in surgical patients: A review and meta-analysis of prospective randomized trials under PRISMA. AB - BACKGROUND: Cell salvage is commonly used as part of a blood conservation strategy. However concerns among clinicians exist about the efficacy of transfusion of washed cell salvage. METHODS: We performed a meta-analysis of randomized controlled trials in which patients, scheduled for all types of surgery, were randomized to washed cell salvage or to a control group with no cell salvage. Data were independently extracted, risk ratio (RR), and weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Data were pooled using a random effects model. The primary endpoint was the number of patients exposed to allogeneic red blood cell (RBC) transfusion. RESULTS: Out of 1140 search results, a total of 47 trials were included. Overall, the use of washed cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 39% (RR = 0.61; 95% CI 0.57 to 0.65; P < 0.001), resulting in an average saving of 0.20 units of allogeneic RBC per patient (weighted mean differences [WMD] = -0.20; 95% CI -0.22 to -0.18; P < 0.001), reduced risk of infection by 28% (RR = 0.72; 95% CI 0.54 to 0.97; P = 0.03), reduced length of hospital stay by 2.31 days (WMD = -2.31; 95% CI -2.50 to -2.11; P < 0.001), but did not significantly affect risk of mortality (RR = 0.92; 95% CI 0.63 to 1.34; P = 0.66). No statistical difference could be observed in the number of patients exposed to re-operation, plasma, platelets, or rate of myocardial infarction and stroke. CONCLUSIONS: Washed cell salvage is efficacious in reducing the need for allogeneic RBC transfusion and risk of infection in surgery. PMID- 27495096 TI - Vertebroplasty and balloon kyphoplasty versus conservative treatment for osteoporotic vertebral compression fractures: A meta-analysis. AB - OBJECTIVE: Although the majority of available evidence suggests that vertebroplasty and kyphoplasty can relieve pain associated with vertebral compression fractures (VCFs) and improve function, some studies have suggested results are similar to those of placebo. The purpose of this meta-analysis was to compare the outcomes of vertebroplasty and kyphoplasty with conservative treatment in patients with osteoporotic VCFs. METHODS: Medline, Cochrane, and Embase databases were searched until January 31, 2015 using the keywords: vertebroplasty, kyphoplasty, compression fracture, osteoporotic, and osteoporosis. Inclusion criteria were randomized controlled trials (RCTs) in which patients with osteoporosis, and VCFs were treated with vertebroplasty/kyphoplasty or conservative management. Outcome measures were pain, function, and quality of life. Standardized differences in means were calculated as a measure of effect size. MAIN RESULTS: Ten RCTs were included. The total number of patients in the treatment and control groups was 626 and 628, respectively, the mean patient age ranged from 64 to 80 years, and the majority was female. Vertebroplasty/kyphoplasty was associated with greater pain relief (pooled standardized difference in means = 0.82, 95% confidence interval [CI]: 0.374-1.266, P < 0.001) and a significant improvement in daily function (pooled standardized difference in means = 1.273, 95% CI: 1.028-1.518, P < 0.001) as compared with conservative treatment. The pooled estimate indicated vertebroplasty/kyphoplasty was associated with higher quality of life (pooled standardized difference in means = 1.545, 95% CI: 1.293-1.798, P < 0.001). Subgroup analysis of 8 vertebroplasty studies and 2 kyphoplasty studies that reported pain data, however, indicated that vertebroplasty provided greater pain relief than conservative treatment but kyphoplasty did not. CONCLUSION: Vertebroplasty may provide better pain relief than balloon kyphoplasty in patients with osteoporotic VCFs, both may improve function, and their effect on quality of life is less clear. PMID- 27495097 TI - Safety and efficacy of a 6-month home-based exercise program in patients with facioscapulohumeral muscular dystrophy: A randomized controlled trial. AB - BACKGROUND: Previous randomized controlled trials investigating exercise training programs in facioscapulohumeral muscular dystrophy (FSHD) patients are scarce and of short duration only. This study assessed the safety and efficacy of a 6-month home-based exercise training program on fitness, muscle, and motor function in FSHD patients. METHODS: Sixteen FSHD patients were randomly assigned to training (TG) and control (CG) groups (both n = 8) in a home-based exercise intervention. Training consisted of cycling 3 times weekly for 35 minutes (combination of strength, high-intensity interval, and low-intensity aerobic) at home for 24 weeks. Patients in CG also performed an identical training program (CTG) after 24 weeks. The primary outcome was change in peak oxygen uptake (VO2 peak) measured every 6 weeks. The principal secondary outcomes were maximal quadriceps strength (MVC) and local quadriceps endurance every 12 weeks. Other outcome measures included maximal aerobic power (MAP) and experienced fatigue every 6 weeks, 6 minute walking distance every 12 weeks, and muscle characteristics from vastus lateralis biopsies taken pre- and postintervention. RESULTS: The compliance rate was 91% in TG. Significant improvements with training were observed in the VO2 peak (+19%, P = 0.002) and MAP by week 6 and further to week 24. Muscle endurance, MVC, and 6-minute walking distance increased and experienced fatigue decreased. Muscle fiber cross-sectional area and citrate synthase activity increased by 34% (P = 0.008) and 46% (P = 0.003), respectively. Dystrophic pathophysiologic patterns were not exacerbated. Similar improvements were experienced by TG and CTG. CONCLUSIONS: A combined strength and interval cycling exercise-training program compatible with patients' daily professional and social activities leads to significant functional benefits without compromising muscle tissue. PMID- 27495098 TI - Effect of perioperative crystalloid or colloid fluid therapy on hemorrhage, coagulation competence, and outcome: A systematic review and stratified meta analysis. AB - BACKGROUND: A meta-analysis concerning perioperative coagulation competence, hemorrhage, and outcome was conducted including the use of hydroxyethyl starches (HESs), dextran, or albumin versus administration of a crystalloid as control to assess the efficacy and safety of colloids and crystalloids for fluid administration during major elective surgery. Surgery was restricted to cardiovascular and noncardiovascular surgery, and HESs were stratified to HES 130/0.4 and HES 200/0.5. METHODS: We searched Cochrane Central Register of Controlled Trials, MEDLINE, ISI Web of Science, EMBASE, conference proceedings, reference lists, and databases of ongoing trials. RESULTS: Thirty one primary clinical randomized controlled trials included 2287 patients undergoing major surgery from January 2000 to August 2015. The perioperative changes in coagulation competence were measured by thromboelastography (TEG) maximum amplitude (MA) in 9 studies administering crystalloids versus HES and in 4 studies administering albumin versus HES. All studies but 1 disclosed increased reduction in TEG-MA following HES administration (P = 0.0001 and 0.0002). The total loss of blood was reported in 17 studies in which crystalloids were compared to HES and 12 studies reported increased blood loss after administration of HES (P < 0.003). When administering albumin versus HES, 6 studies reported reduced hemorrhage associated with albumin administration (P = 0.005). Reoperation was not significantly reduced by the use of crystalloids, but may be more frequent after HESs compared to albumin (P < 0.03). In this analysis, more patients admitted to administration of HESs were exposed to decrease coagulation competence, compared to perioperative crystalloids and albumin administration. CONCLUSION: This stratified meta-analysis showed that increased blood loss was found in noncardiovascular surgery among patients receiving HES compared with crystalloids, followed by a marked reduction in TEG-MA, and infusion of 3rd generation HES products did not influence the results significantly. PMID- 27495099 TI - Comparison between whole mount tissue preparations and virtual tissue microarray samples for measuring Ki-67 and apoptosis indices in human bladder cancer: A cross-sectional study. AB - Recent tissue microarray (TMA)-based studies have shown that cell proliferation- and apoptosis-related biomarkers are associated with clinical outcomes in patients with bladder urothelial carcinoma. However, little is known about the differences in these biomarker measurements between whole mount tissue preparations and TMAs. This study aimed to elucidate the discrepancy in the measurements of Ki-67 indices (KIs) and apoptosis indices (AIs) between whole mount tissue preparations and TMAs of bladder urothelial carcinoma samples.Whole mount tissue preparations for Ki-67 immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling were made from 30 patients who underwent transurethral resection of bladder urothelial carcinoma. Digital microscopy-assisted virtual TMAs, consisting of 3 small round areas (1 or 0.6 mm in diameter), were generated from the same whole mount tissue preparations. The measurement results in highly reactive areas of biomarkers were compared between the whole mount tissue preparation- and the TMA-based methods. Bland-Altman plot analysis, regression analysis, and Kendall tau were performed to investigate differences in the measurement results, systematic biases, and correlations between biomarkers.Although the Bland-Altman plot analysis demonstrated that almost all the plots were within the limits of agreement, fixed biases were detected in the 1- and 0.6-mm TMAs for the KI (0.181 and 0.222, respectively) and the AI (0.055 and 0.063, respectively). Proportional biases were also detected in the 1- and 0.6-mm TMAs for the AI (P < 0.001 and P < 0.001, respectively). Furthermore, positive correlations between KIs and AIs were observed in whole mount tissue preparations (r = 0.260, P = 0.044) and in the 1 mm TMAs (r = 0.375, P = 0.004); however, no such correlation was observed in the 0.6 mm TMAs.Our study suggests that the measurement results for certain biomarkers of bladder urothelial carcinoma obtained from TMA-based samples can be susceptible to systematic bias, and the lack of correlation between biomarkers cannot be avoided as it is in whole mount tissue preparations. Virtual TMAs can help identify systematic bias and establish a better sampling strategy prior to performing high throughput TMAs for biomarker studies. PMID- 27495100 TI - High plasma coenzyme Q10 concentration is correlated with good left ventricular performance after primary angioplasty in patients with acute myocardial infarction. AB - Exogenous administration of coenzyme Q10 (CoQ10) has been shown in experimental models to have a protective effect against ischemia-reperfusion injury. However, it is unclear whether follow-up plasma CoQ10 concentration is prognostic of left ventricular (LV) performance after primary balloon angioplasty in patients with acute ST segment elevation myocardial infarction (STEMI).We prospectively recruited 55 patients with STEMI who were treated with primary coronary balloon angioplasty. Plasma CoQ10 concentrations were measured before primary angioplasty (baseline) and 3 days, 7 days, and 1 month after STEMI using high-performance liquid chromatography. Echocardiography was performed at baseline and at 6-month follow-up. The control group comprised 54 healthy age- and sex-matched volunteers.Serial circulating CoQ10 concentrations significantly decreased with time in the STEMI group. The LV ejection fraction at 6-month follow-up positively correlated with the 1-month plasma CoQ10 tertile. Higher plasma CoQ10 concentrations at 1 month were associated with favorable LV remodeling and systolic function 6 months after STEMI. Multiple linear regression analysis showed that changes in CoQ10 concentrations at 1-month follow-up were predictive of LV systolic function 6 months after STEMI. Changes in CoQ10 concentrations correlated negatively with baseline oxidized low-density lipoprotein and fibrinogen concentrations and correlated positively with leukocyte mitochondrial copy number at baseline.Patients with STEMI who had higher plasma CoQ10 concentrations 1 month after primary angioplasty had better LV performance at 6 month follow-up. In addition, higher plasma CoQ10 concentration was associated with lower grade inflammatory and oxidative stress status. Therefore, plasma CoQ10 concentration may serve as a novel prognostic biomarker of LV systolic function after revascularization therapy for acute myocardial infarction. PMID- 27495101 TI - The clinical application of "jetting suture" technique in annular repair under microendoscopic discectomy: A prospective single-cohort observational study. AB - To introduce a new designed suture technique in annular repair under the microendoscopic discectomy (MED) surgery and to evaluate the clinical application of the technique in annular repair under MED with at least 2-year follow-up period.A new method of annular repair was designed and named "jetting suture" technique. Thirty consecutive patients with lumbar disc herniation were enrolled in the prospective single-cohort observational study. Patients were followed up at intervals of preoperative, postoperative 1 week, 3 months, 6 months, 1 year, and last follow-up. The clinical outcomes were evaluated by using Japanese Orthopaedic Association (JOA) score, Oswestry Disability Index, and modified Mcnab criteria.The procedure was successfully performed in all cases. No case required conversion to an open procedure. The mean age of patients was 36.6 years. Average blood loss was 45.8 +/- 10.2 mL. The preoperative symptoms were alleviated significantly after surgery. All the standardized measures improved significantly at the last follow-up, including JOA score (10.1 to 26.6; P < 0.05) and Oswestry Disability Index (75.3 to 9.6; P < 0.05). Improvement rate of JOA score was 86.4%. Approximately 83.4% of patients reported good or excellent outcomes based on modified Mcnab criteria. No postoperative complication and recurrence of disc herniation was reported.The designed "jetting suture" technique in annular repair under MED can be performed safely and effectively. It could be a viable alternative to annular repair under lumbar discectomy. PMID- 27495102 TI - Osteogenesis imperfecta and clubfoot-a rare combination: Case report and review of the literature. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a rare congenital genetic osteodystrophy, which has a prevalence of 1:20,000. OI is caused by the mutation of the COL1A1/COL1A2 genes, leading to a deficit of quality and/or quantity in the synthesis of procollagen-alpha type 1. Seven different forms of diverse clinical entity have been classified by Sillence and Glorieux, although, recently, up to 11 forms characterized by different genetic mutations have been recognized. Patients with OI suffer from extreme bone fragility and osteoporosis, which often predisposes them to frequent fractures. This paper presents the case of a child with OI type IV who, at birth, was also diagnosed with a severe clubfoot (congenital talipes equinovarus) grade III. Patient's mother also suffers from OI type IV. METHODS: The treatment was started by placing femoro podalic corrective casts, according to the Ponseti method, but some unexpected problems occurred during this treatment. When the patient was 3 months of age, we decided to correct the clubfoot before the time limit planned, performing a bilateral posteromedial surgical release. RESULTS: Three weeks after surgery the casts were removed and replaced with bilateral Spica cast-like braces. On the 6th postoperative week, the patient began wearing Bebax corrective shoes, after 1 year ambidextrous orthopedic shoes. Now, he is 2 years old and has started to walk properly without any orthesis. CONCLUSION: In the presence of an orthopedic pathology associated with OI, it is recommended to manage the patient according to the underlying pathology, always considering the bone fragility associated with OI. The final surgical treatment to correct the clubfoot can be done earlier, if necessary. In our opinion, this uncommon association between OI and clubfoot is non-syndromic. This means that the two congenital diseases are not necessarily included in a singular uncommon genetic syndrome, but the clubfoot was caused by multifactorial causes, especially by both the mother's bisphosphonate drug therapy and the amniocentesis performed during her pregnancy to drain polyhydramnios. In our analysis, those environmental factors could have interacted with an already altered genetic substratum, contributing to develop this rare combination of congenital disorders. PMID- 27495103 TI - Improving the utility of the Brunnstrom recovery stages in patients with stroke: Validation and quantification. AB - The Brunnstrom recovery stages (the BRS) consists of 2 items assessing the poststroke motor function of the upper extremities and 1 assessing the lower extremities. The 3 items together represent overall motor function. Although the BRS efficiently assesses poststroke motor functions, a lack of rigorous examination of the psychometric properties restricts its utility. We aimed to examine the unidimensionality, Rasch reliability, and responsiveness of the BRS, and transform the raw sum scores of the BRS into Rasch logit scores once the 3 items fitted the assumptions of the Rasch model.We retrieved medical records of the BRS (N = 1180) from a medical center. We used Rasch analysis to examine the unidimensionality and Rasch reliability of both upper-extremity items and the 3 overall motor items of the BRS. In addition, to compare their responsiveness for patients (n = 41) assessed with the BRS and the Stroke Rehabilitation Assessment of Movement (STREAM) on admission and at discharge, we calculated the effect size (ES) and standardized response mean (SRM).The upper-extremity items and overall motor items fitted the assumptions of the Rasch model (infit/outfit mean square = 0.57-1.40). The Rasch reliabilities of the upper-extremity items and overall motor items were high (0.91-0.92). The upper-extremity items and overall motor items had adequate responsiveness (ES = 0.35-0.41, SRM = 0.85-0.99), which was comparable to that of the STREAM (ES = 0.43-0.44, SRM = 1.00-1.13).The results of our study support the unidimensionality, Rasch reliability, and responsiveness of the BRS. Moreover, the BRS can be transformed into an interval-level measure, which would be useful to quantify the extent of poststroke motor function, the changes of motor function, and the differences of motor functions in patients with stroke. PMID- 27495104 TI - Probiotics for prevention and treatment of respiratory tract infections in children: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Respiratory tract infections (RTIs) represent one of the main health problems in children. Probiotics are viable bacteria that colonize the intestine and affect the host intestinal microbial balance. Accumulating evidence suggests that probiotic consumption may decrease the incidence of or modify RTIs. The authors systematically reviewed data from randomized controlled trials (RCTs) to investigate the effect of probiotic consumption on RTIs in children. METHODS: MEDLINE/PubMed, Embase, Cochrane Library, and Web of Science were systematically searched for RCTs regarding the effect of probiotics on RTIs in children. The outcomes included number of children experienced with at least 1 RTI episode, duration of illness episodes, days of illness per subject, and school/day care absenteeism due to infection. A random-effects model was used to calculate pooled relative risks, or mean difference (MD) with the corresponding 95% confidence interval (CI). RESULTS: A total of 23 trials involving 6269 children were eligible for inclusion in the systematic review. None of the trials showed a high risk of bias. The quality of the evidence of outcomes was moderate. The age range of subjects was from newborn to 18 years. The results of meta-analysis showed that probiotic consumption significantly decreased the number of subjects having at least 1 RTI episode (17 RCTs, 4513 children, relative risk 0.89, 95% CI 0.82 0.96, P = 0.004). Children supplemented with probiotics had fewer numbers of days of RTIs per person compared with children who had taken a placebo (6 RCTs, 2067 children, MD -0.16, 95% CI -0.29 to 0.02, P = 0.03), and had fewer numbers of days absent from day care/school (8 RCTs, 1499 children, MD -0.94, 95% CI -1.72 to -0.15, P = 0.02). However, there was no statistically significant difference of illness episode duration between probiotic intervention group and placebo group (9 RCTs, 2817 children, MD -0.60, 95% CI -1.49 to 0.30, P = 0.19). CONCLUSION: Based on the available data and taking into account the safety profile of RCTs, probiotic consumption appears to be a feasible way to decrease the incidence of RTIs in children. PMID- 27495105 TI - Carotid plaque is a new risk factor for peripheral vestibular disorder: a retrospective cohort study. AB - Many chronic diseases are associated with dizziness or vertigo, as is peripheral vestibular disorder (PVD). Although carotid plaque development is linked to atherosclerosis, it is unclear whether such plaques can lead to the development of PVD. We therefore conducted this study to investigate the presence of an association between carotid plaque and new PVD events.In this retrospective study, we consecutively enrolled 393 patients >=20 years old who had been treated for chronic diseases such as hypertension, dyslipidemia, and diabetes mellitus for >=6 months at a primary care clinic (Oki Clinic, Japan) between November 2011 and March 2013. Carotid plaque presence was measured with high-resolution ultrasonography for all patients. During a 1-year follow-up period, an otorhinolaryngologist diagnosed and reported any new PVD events (the main end point). Hazard ratios (HRs) and 95% confidence intervals (CIs) for new PVD occurrence were estimated using the Cox proportional hazard regression model.The mean age of the participants was 65.5 years; 33.8% were men, and 12.7%, 82.4%, and 93.1% had diabetes mellitus, hypertension, and dyslipidemia, respectively. There were 76 new PVD events; patients with carotid plaque had a greater risk of such events (crude HR: 3.25; 95% CI: 1.62-6.52) compared to those without carotid plaque. This risk was even higher after adjusting for traditional risk factors for atherosclerosis (adjusted HR: 4.41; 95% CI: 1.75-11.14).Carotid plaques are associated with an increased risk of new PVD events. PMID- 27495106 TI - The thromboelastometric discrepancy between septic and trauma induced disseminated intravascular coagulation diagnosed by the scoring system from the Japanese association for acute medicine. AB - The aim of this study is to evaluate the hematological differences between septic and traumatic disseminated intravascular coagulation (DIC) using the rotational thromboelastometry (ROTEM).This retrospective study includes all sepsis or severe trauma patients transported to our emergency department who underwent ROTEM from 2013 to 2014. All patients were divided into 2 groups based on the presence of DIC diagnosed by the Japanese Association for Acute Medicine (JAAM) DIC score. We statistically analyzed the demographics, clinical characteristics, laboratory data, ROTEM findings (EXTEM and FIBTEM), and outcome.Fifty-seven patients (30 sepsis and 27 severe trauma) were included in primary analysis. Sepsis cases were significantly older and had higher systemic inflammatory response syndrome (SIRS) scores, whereas there were no significant differences in other parameters including Acute Physiology and Chronic Health Evaluation (APACHE) II score, sequential organ failure assessment (SOFA) score. Twenty-six patients (14 sepsis and 12 severe trauma) were diagnosed with DIC. The Septic DIC (S-DIC) group was significantly older and had higher DIC scores than the traumatic DIC (T-DIC) group. Hematologic examination revealed significantly higher CRP, fibrinogen, lower FDP, DD, and higher FDP/DD ratio were found in the S-DIC group in comparison with the T-DIC group. ROTEM findings showed that the A10, A20, and MCF in the FIBTEM test were significantly higher in the S-DIC group. However, no statistical differences were confirmed in the LI30, LI45, and ML in EXTEM test.The plasma fibrinogen level and fibrinogen based clot firmness in whole blood test revealed statistical significance between septic and traumatic DIC patients. PMID- 27495107 TI - A negative nontreponemal and/or specific antitreponemal IgM test does not exclude active infectious syphilis: evidence from a rabbit infectivity test: A case report. AB - BACKGROUND: The diagnostic criteria for active infectious syphilis in the clinic are important matter of controversy and debate. So far, clinicians habitually do use the negative results of the nontreponemal and/or the specific antitreponemal IgM as the evidences of disease-free or active infection-free status. METHOD: We present a case study involving a patient who was admitted to Zhongshan Hospital because of cerebral infarct. Clinical examination indicated he had a history of latent syphilis with negative nontreponemal and specific antitreponemal IgM tests. The cerebrospinal fluid sample from the patient was inoculated into seronegative New Zealand rabbit. RESULTS: Motile Treponema pallidum was detected by a rabbit infectivity test in the patient's cerebrospinal fluid. This syphilis strain was confirmed by DNA subtyping form of "centers for disease control subtype/tp0548 sequence type", and the strain type was 14d/f. Treatment with benzathine penicillin provided no apparent benefit, but treatment with aqueous crystalline penicillin G, especially recommended for neurosyphilis, led to disease regression. No evidence of cerebral infarct was observed during a 2-year follow-up period. CONCLUSION: The definitive differential diagnosis of active infectious syphilis should be reconsidered. Moreover, selecting the appropriate penicillin preparation is important because T pallidum can reside in sequestered sites. It is necessary to treat a patient with known invasion of the central nervous system with aqueous crystalline penicillin G, if previous treatment for syphilis failed and patients had some clinical neurological presentation that is otherwise unexplained, but that could represent neurosyphilis. Additional studies are needed to confirm the results in other syphilis patients. PMID- 27495108 TI - ITRAQ-based quantitative proteomics reveals apolipoprotein A-I and transferrin as potential serum markers in CA19-9 negative pancreatic ductal adenocarcinoma. AB - Currently the diagnosis of pancreatic ductal adenocarcinoma (PDAC) relies on CA19 9 and radiological means, whereas some patients do not have elevated levels of CA19-9 secondary to pancreatic cancer. The purpose of this study was to identify potential serum biomarkers for CA19-9 negative PDAC.A total of 114 serum samples were collected from 3 groups: CA19-9 negative PDAC patients (n = 34), CA19-9 positive PDAC patients (n = 44), and healthy volunteers (n = 36), whereas the first 12 samples from each group were used for isobaric tags for relative and absolute quantitation (iTRAQ) analysis. Thereafter, candidate biomarkers were selected for validation by enzyme-linked immunosorbent assay (ELISA) with the rest specimens.Using the iTRAQ approach, a total of 5 proteins were identified as significantly different between CA19-9 negative PDAC patients and healthy subjects according to our defined criteria. Apolipoprotein A-I (APOA-I) and transferrin (TF) were selected to validate the proteomic results by ELISA in a further 78 serum specimens. It revealed that TF significantly correlated with the degree of histological differentiation (P = 0.042), and univariate and multivariate analyses indicated that TF is an independent prognostic factor for survival (hazard ratio, 0.302; 95% confidence interval, 0.118-0.774; P = 0.013) of patients with PDAC after curative surgery.ITRAQ-based quantitative proteomics revealed that APOA-I and TF may be potential CA19-9 negative PDAC serum markers. PMID- 27495109 TI - Altered structural and functional connectivity between the bilateral primary motor cortex in unilateral subcortical stroke: A multimodal magnetic resonance imaging study. AB - A large number of functional imaging studies have focused on the understanding of motor-related neural activities after ischemic stroke. However, the knowledge is still limited in the structural and functional changes of the interhemispheric connections of the bilateral primary motor cortices (M1s) and their potential influence on motor function recovery following stroke.Twenty-four stroke patients with right hemispheric subcortical infarcts and 25 control subjects were recruited to undergo multimodal magnetic resonance imaging examinations. Structural impairments between the bilateral M1s were measured by fractional anisotropy. Functional changes of the bilateral M1s were assessed via M1-M1 resting-state functional connectivity. Task-evoked activation analysis was applied to identify the roles of the bilateral hemispheres in motor function recovery. Compared with control subjects, unilateral subcortical stroke patients revealed significantly decreased fractional anisotropy and functional connectivity between the bilateral M1s. Stroke patients also revealed higher activations in multiple brain regions in both hemispheres and that more regions were located in the contralesional hemisphere.This study increased our understanding of the structural and functional alterations between the bilateral M1s that occur in unilateral subcortical stroke and provided further evidence for the compensatory role played by the contralesional hemisphere for these alterations during motor function recovery. PMID- 27495110 TI - Association between comorbid conditions and BADL/IADL disability in hypertension patients over age 45: Based on the China health and retirement longitudinal study (CHARLS). AB - Hypertension usually coexists with other chronic conditions and can cause disability in relation to activities of daily living. We examined the association between the number and categories of comorbid conditions and disability affecting activities of daily living in hypertension patients.The data were collected from the 2013 follow-up survey of the China Health and Retirement Longitudinal Study (CHARLS), which contains information about chronic conditions and disability. Additionally, socio-demographic characteristics of 3754 hypertension patients aged 45 and older were included in this study. Comorbid conditions included dyslipidemia, stroke, and 12 other chronic conditions. Disability in relation to activities of daily living was assessed using the basic activities of daily living (BADL) and the instrumental activities of daily living (IADL) instruments. Differences in BADL/IADL disability among patients with different comorbid conditions were compared using the chi-square test, and the influence of chronic conditions and socio-demographic characteristics on BADL/IADL disability was analyzed using logistic models.Without considering the influence of specific chronic conditions on BADL/IADL, hypertension patients with additional comorbid conditions were more likely to suffer from BADL/IADL disability. When considering the effect of specific chronic conditions, the number of comorbid conditions did not significantly influence BADL/IADL disability. Dyslipidemia, chronic lung disease, stroke, memory-related diseases, and arthritis/rheumatism were associated with BADL disability. Chronic lung diseases, heart diseases, stroke, stomach/digestive system diseases, emotional/nervous/psychiatric problems, memory related diseases, arthritis/rheumatism, and asthma were associated with IADL disability. Additionally, female, people with lower education level, people living in village, and people living in middle and western China were more likely suffer from BADL/IADL disability.Comorbid conditions were associated with disability in activities of daily living in hypertension patients aged 45 and older. The specific comorbid conditions had a stronger effect on disability in activities of daily living than the number of comorbid conditions. In addition, we should pay attention to socioeconomic factors related to disability. PMID- 27495112 TI - Zebrafish Danio rerio as a model to study the immune response against infection with Ichthyophthirius multifiliis. PMID- 27495113 TI - Making Judgments: How Blame Mediates the Influence of Rape Myth Acceptance in Police Response to Sexual Assault. AB - As research continues to describe negative experiences and high case attrition within sexual assault cases reported to the police, it is important to better understand the role of first-responding police officers. This study surveyed a sample of sworn police officers ( N = 174) from one department in a midsized city in the Great Lakes region to examine the effect of individual police officer characteristics, rape myth acceptance (RMA), attributions of blame, and case characteristics from a hypothetical vignette, on officer perceptions of a "good" case and behavioral intentions. Results found that although RMA predicts both perceptions of the case and behavioral intentions to respond in ways indicative of perceived seriousness, RMA is mediated by attributions of suspect blame. Victim alcohol use was found to decrease an officer's likelihood of responding more vigorously, showing less likelihood of calling a detective or arresting the suspect, if identified. Future research should begin to connect not only case characteristics but also individual police officer characteristics, attitudes, and attributions of blame, with real case outcomes, in addition to hypothetical scenarios. PMID- 27495114 TI - The Nonlinear Effect of Informal Social Control on Repeat Intimate Partner Violence Victimization. AB - Prior research has examined the effects of neighborhood context on intimate partner violence (IPV) with mixed results. While most studies find that neighborhood disadvantage is positively associated with risk of IPV, the effects are less consistent for characteristics such as social ties and informal social control. One possible explanation for these mixed findings draws from theoretical and empirical literature arguing that a high level of collective efficacy can aid in the control of criminal behavior, but it can also deter residents from acting against crime committed by neighbors. This suggests the possibility of a nonlinear effect of collective efficacy where the risk of IPV may be high in areas with very low levels of collective efficacy because of the inability of neighborhoods to collectively control residents, but it may also be high in areas with very high levels of collective efficacy where residents are less willing to report on the criminal behavior of fellow residents. We test this possibility using survey data for female victims of IPV in Chicago merged with neighborhood characteristics. Findings suggest that the risk of repeat victimization is highest in areas with either very high or very low levels of informal social control. PMID- 27495111 TI - Clinical significance of smear positivity for acid-fast bacilli after >=5 months of treatment in patients with drug-susceptible pulmonary tuberculosis. AB - Patients with pulmonary tuberculosis (TB) with acid-fast bacilli (AFB)-positive sputum smear at 5 months or later during treatment are considered to be cases of treatment failure according to World Health Organization guidelines. This study evaluated the proportion, clinical characteristics, and significance of positive sputum smears after >=5 months of standard treatment in patients with drug susceptible pulmonary TB.This was a retrospective cohort study of 1611 patients with culture-confirmed drug-susceptible pulmonary TB who received standard anti TB treatment from January 2009 to February 2014. Forty-one patients (2.5%) who were smear-positive after >=5 months of treatment and 123 age- and sex-matched control patients were evaluated.Among the 41 smear-positive patients, culture of the sputum specimens yielded Mycobacterium tuberculosis (MTB) in 1 patient (2.4%), nontuberculous mycobacteria (NTM) in 7 (17.1%), and no growth in the remaining 33 patients (80.5%). Treatment was successfully completed in 40 patients (97.6%) with prolongation of the continuation phase regimens without change to second-line anti-TB treatment. In patients with smear positivity after >=5 months of treatment compared with controls, cavitation on chest radiographs (53.7% vs. 25.2%, P = 0.001), bilateral involvement (51.2% vs. 30.1%, P = 0.01) and combined pleural effusion (26.8% vs. 10.6%, P = 0.01) were found more frequently at the time of treatment initiation, and paradoxical response occurred more commonly (19.5% vs. 3.3%, P = 0.002) during treatment.Smear-positive sputum after >=5 months of standard anti-TB treatment was mainly because of nonviable MTB bacilli or NTM in patients with drug-susceptible pulmonary TB. AFB smear alone should not be used to assess treatment failure and careful examination of microbiologic status, including culture and drug susceptibility testing, is needed before making changes to retreatment regimens or empirical second-line anti-TB regimens in these patients. PMID- 27495115 TI - Gestational weight gain and fetal growth in underweight women. AB - BACKGROUND: Despite the current obesity epidemic, maternal underweight remains a common occurrence with potential adverse perinatal outcomes. METHODS: We aimed to investigate the relationship between weight gain during pregnancy, and fetal growth in underweight women with low and late fertility. Women body mass index (BMI), defined according to the World Health Organization's definition, gestational weight gain (GWG), defined by the Institute of Medicine and National Research Council and neonatal birth weight were prospectively collected at maternity ward of Policlinico Abano Terme (Italy) in 793 consecutive at term, uncomplicated deliveries. RESULTS: Among those, 96 (12.1 %) were categorized as underweight (BMI < 18.5 kg/m(2)), 551 (69.5 %) as normal weight, 107 (13.4 %) as overweight, and 39 (4.9 %) as obese, respectively. In all mother groups, GWG was within the range recommended by IOM 2009 guidelines. However, underweight women gained more weight in pregnancy (12.8 +/- 3.9 kg) in comparison to normal weight (12.3 +/- 6.7 kg) and overweight (11.0 +/- 4.7 kg) women and their GWG was significantly higher (p < 0.001) with respect to obese women 5.8 +/- 6.1 kg). In addition, offspring of underweight women were comparable in size at birth to offspring of normal weight women, whereas they were significantly lighter to offspring of both overweight and obese women. CONCLUSIONS: Pre-pregnancy underweight does not impact birth weight of healthy, term neonates in presence of normal GWG. Presumably, medical or personal efforts to reach 'optimal' GWG could be a leading choice for many women living in industrialized and in low-income countries. PMID- 27495116 TI - Upregulated expression of CCR3 in rheumatoid arthritis and CCR3-dependent activation of fibroblast-like synoviocytes. AB - It is recognized that CC chemokine receptor 3 (CCR3) is associated with numerous inflammatory conditions and fibroblast-like synoviocyte (FLS) invasiveness correlates with articular damage in rheumatoid arthritis (RA). However, little is known of the expression and action of CCR3 on FLS in RA. In the present study, we investigated the expression of CCR3 on dispersed synovial tissue and peripheral blood cells in RA and influence of eotaxin-1 on FLS functions by using flow cytometry analysis, FLS challenge, and real-time PCR techniques. The results showed that approximately 7.0 % dispersed synovial cells are CCR3+ cells. Among those CCR3+ cells, 38.1, 23.8, and 20.6 % cells are CD90+CD14-CD3- (representing FLS), CD14+, and CD8+ cells, respectively, indicating that FLS is one of the major populations of CCR3+ cells in the synovial tissue of RA. In peripheral blood, CD14+ CCR3+ cells are elevated, but CD8+CCR3+ cells are reduced in RA. It was found that eotaxin-1 induced upregulated expression of CCR3 and matrix metalloproteinase (MMP)-9 messenger RNAs (mRNAs) in FLS. Since an antagonist of CCR3 suppressed the action of eotaxin-1, the event appeared CCR3 dependent. Moreover, we observed that interleukin (IL)-1beta induced markedly enhanced eotaxin-1 release from FLS, but TNF-alpha reduced eotaxin-1 release at 12 and 24 h following incubation. In conclusion, enhanced expression of CCR3 on synovial cells and increased levels of eotaxin-1 in plasma and synovial fluid (SF) of RA indicate that CCR3-mediated mechanisms may play an important role in RA. Blockage of eotaxin-1 provoked CCR3 and MMP-9 expression in FLS by antagonist of CCR3, implicating that anti-CCR3 agents may have therapeutic use for RA. PMID- 27495118 TI - Metabolism of Carfentanil, an Ultra-Potent Opioid, in Human Liver Microsomes and Human Hepatocytes by High-Resolution Mass Spectrometry. AB - Carfentanil is an ultra-potent synthetic opioid. No human carfentanil metabolism data are available. Reportedly, Russian police forces used carfentanil and remifentanil to resolve a hostage situation in Moscow in 2002. This alleged use prompted interest in the pharmacology and toxicology of carfentanil in humans. Our study was conducted to identify human carfentanil metabolites and to assess carfentanil's metabolic clearance, which could contribute to its acute toxicity in humans. We used Simulations Plus's ADMET PredictorTM and Molecular Discovery's MetaSiteTM to predict possible metabolite formation. Both programs gave similar results that were generally good but did not capture all metabolites seen in vitro. We incubated carfentanil with human hepatocytes for up to 1 h and analyzed samples on a Sciex 3200 QTRAP mass spectrometer to measure parent compound depletion and extrapolated that to represent intrinsic clearance. Pooled primary human hepatocytes were then incubated with carfentanil up to 6 h and analyzed for metabolite identification on a Sciex 5600+ TripleTOF (QTOF) high-resolution mass spectrometer. MS and MS/MS analyses elucidated the structures of the most abundant metabolites. Twelve metabolites were identified in total. N-Dealkylation and monohydroxylation of the piperidine ring were the dominant metabolic pathways. Two N-oxide metabolites and one glucuronide metabolite were observed. Surprisingly, ester hydrolysis was not a major metabolic pathway for carfentanil. While the human liver microsomal system demonstrated rapid clearance by CYP enzymes, the hepatocyte incubations showed much slower clearance, possibly providing some insight into the long duration of carfentanil's effects. PMID- 27495119 TI - Strategies to Determine Assay Format for the Assessment of Neutralizing Antibody Responses to Biotherapeutics. AB - Most biotherapeutics can elicit immune responses in dosed recipients generating anti-drug antibodies (ADAs). Neutralizing antibodies (NAbs) are a subpopulation of ADAs that can potentially impact patient safety and directly mediate loss of drug efficacy by blocking the biological activity of a therapeutic product. Therefore, NAb detection is an important aspect of immunogenicity assessment, requiring sensitive and reliable methods reflective of the therapeutic mechanism of action (MoA). Both cell-based and non cell-based assays are viable options for NAb assessment. However, the scientific approach for the selection of a suitable assay format (cell-based or non cell-based) for NAb assessment is not currently well defined. In this manuscript, the authors summarize the design and utility of cell-based and non cell-based NAb assays and recommend a NAb assay format selection approach that relies on a combination of three factors. These include (i) the therapeutic MoA, (ii) the evidence of desirable assay performance characteristics, and (iii) risk of immunogenicity. The utility of correlating NAb response with pharmacodynamic data is also discussed. The aim of this paper is to provide a consistent strategy that will guide the selection of scientifically justified assay formats capable of detecting clinically relevant NAbs for biotherapeutics with varying MoAs and diverse complexity. PMID- 27495117 TI - Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance. AB - Over the years, significant progress has been made in reducing metabolic instability due to cytochrome P450-mediated oxidation. High-throughput metabolic stability screening has enabled the advancement of compounds with little to no oxidative metabolism. Furthermore, high lipophilicity and low aqueous solubility of presently pursued chemotypes reduces the probability of renal excretion. As such, these low microsomal turnover compounds are often substrates for non-CYP mediated metabolism. UGTs, esterases, and aldehyde oxidase are major enzymes involved in catalyzing such metabolism. Hepatocytes provide an excellent tool to identify such pathways including elucidation of major metabolites. To predict human PK parameters for P450-mediated metabolism, in vitro-in vivo extrapolation using hepatic microsomes, hepatocytes, and intestinal microsomes has been actively investigated. However, such methods have not been sufficiently evaluated for non-P450 enzymes. In addition to the involvement of the liver, extrahepatic enzymes (intestine, kidney, lung) are also likely to contribute to these pathways. While there has been considerable progress in predicting metabolic pathways and clearance primarily mediated by the liver, progress in characterizing extrahepatic metabolism and prediction of clearance has been slow. Well-characterized in vitro systems or in vivo animal models to assess drug-drug interaction potential and intersubject variability due to polymorphism are not available. Here we focus on the utility of appropriate in vitro studies to characterize non-CYP-mediated metabolism and to understand the enzymes involved followed by pharmacokinetic studies in the appropriately characterized surrogate species. The review will highlight progress made in establishing in vitro-in vivo correlation, predicting human clearance and avoiding costly clinical failures when non-CYP-mediated metabolic pathways are predominant. PMID- 27495120 TI - A Quantitative Review and Meta-Models of the Variability and Factors Affecting Oral Drug Absorption-Part I: Gastrointestinal pH. AB - This study aimed to conduct a quantitative meta-analysis for the values of, and variability in, gastrointestinal (GI) pH in the different GI segments; characterize the effect of food on the values and variability in these parameters; and present quantitative meta-models of distributions of GI pH to help inform models of oral drug absorption. The literature was systemically reviewed for the values of, and the variability in, GI pH under fed and fasted conditions. The GI tract was categorized into the following 10 distinct regions: stomach (proximal, mid-distal), duodenum (proximal, mid-distal), jejunum and ileum (proximal, mid, and distal small intestine), and colon (ascending, transverse, and descending colon). Meta-analysis used the "metafor" package of the R language. The time course of postprandial stomach pH was modeled using NONMEM. Food significantly influenced the estimated meta-mean stomach and duodenal pH but had no significant influence on small intestinal and colonic pH. The time course of postprandial pH was described using an exponential model. Increased meal caloric content increased the extent and duration of postprandial gastric pH buffering. The different parts of the small intestine had significantly different pH. Colonic pH was significantly different for descending but not for ascending and transverse colon. Knowledge of GI pH is important for the formulation design of the pH-dependent dosage forms and in understanding the dissolution and absorption of orally administered drugs. The meta-models of GI pH may also be used as part of semi-physiological pharmacokinetic models to characterize the effect of GI pH on the in vivo drug release and pharmacokinetics. PMID- 27495121 TI - Internal carotid artery dissection coincides with celiac artery dissection. PMID- 27495122 TI - Targeting bactoprenol-coupled cell envelope precursors. AB - Targeting the bactoprenol-coupled cell wall precursor lipid II is a validated antibacterial strategy. In this review, selected prototype lipid II-binding antibiotics of different chemical classes are discussed. Although these compounds attack the same molecular target, they trigger nuanced and diverse cellular effects. Consequently, the mechanisms of antibacterial resistance and the likelihood of resistance development may vary substantially. PMID- 27495123 TI - Erratum to: The Simultaneous Occurrence of Histoplasmosis and Cryptococcal Fungemia: A Case Report and Review of the Literature. PMID- 27495124 TI - Passive protection effect of anti-Vibrio anguillarum IgY-encapsulated feed on half-smooth tongue sole (Cynoglossus semilaevi) against V. anguillarum. AB - Vibrio anguillarum is one of the most harmful pathogens associated with hemorrhage septicemia syndrome in the half-smooth tongue sole (C. semilaevis) due to its high virulence. In this study, we attempted to treat half-smooth tongue sole with anti-V. anguillarum egg yolk powder to elicit a passive immunity directly against V. anguillarum infection. Anti-V. anguillarum IgY was beta cyclodextrin encapsulated in egg yolk powders as feed, which could avoid antibody inactivation in the gastrointestinal tract of half-smooth tongue sole. The IgY had an inhibiting effect on the infection of V. anguillarum in vitro. The survival rate of half-smooth tongue sole fed with basal diet containing 15% anti V. anguillarum egg yolk powder was 70% after 7 days post-V. anguillarum challenge (10(7) CFU), which was significantly higher than those fed without anti-V. anguillarum egg yolk powder. As well, the bacterial burden in blood, liver, spleen and kidney was significantly lower in half-smooth tongue sole fed with specific IgY than those fed with non-specific IgY. These results suggested that pathogen-specific IgY may provide a valuable treatment for vibriosis infection and can be a promising food additive. PMID- 27495125 TI - A survey of flood disaster preparedness among hospitals in the central region of Thailand. AB - BACKGROUND: In 2011, Thailand was affected by the one of the worst flood disasters in recent times. Hospitals in Thailand were faced with the challenge of managing the health impacts from this natural disaster. The purpose of this study was to assess flood disaster preparedness among hospitals in the central region of Thailand. METHODS: A survey questionnaire was given to twenty-seven key people responsible for hospital disaster preparedness that experienced disruptions to health services (severely, moderately and slightly) during the flood disaster in 2011 in the central region of Thailand. RESULTS: Of the twenty-four participating hospitals, not one had satisfied the standards in all the dimensions of flood disaster preparedness. All respondent hospitals were deficiently prepared with regard to surge capacity, the management of healthcare services and the management of the supporting systems. The availability of supplies and equipment were found to be in place but preparations were found to be inadequate in organizing staff at all participating hospitals. Trained staff members regarding disaster response were reported to be present in all respondent hospitals. Hospitals that experienced slightly disruptions to their health services did not elect to do any exercises to meet the set standards. None of the hospitals that experienced slightly disruptions to their health services performed any evaluation and improvement in terms of disaster preparedness. CONCLUSIONS: Many hospitals were not up to standard in terms of disaster preparedness. Hospitals should prioritize disaster preparedness to fulfill their responsibility during crisis situations and improve their flood disaster preparedness. PMID- 27495126 TI - Comparing patient outcomes for care delivered by advanced musculoskeletal physiotherapists with other health professionals in the emergency department-A pilot study. AB - BACKGROUND: To compare advanced musculoskeletal physiotherapists with other health professionals by measuring outcomes for patients presenting to the emergency department with lower limb soft tissue injuries or acute low back pain. METHODS: A prospective study was conducted (Lower limb soft tissue injury cohort, n=88), (Acute low back pain cohort, n=29) at the emergency departments of two urban hospitals. A univariate analysis was completed for a number of outcome measures: Lower Extremity Functional Scale, Roland Morris Disability Questionnaire, imaging requirements, Patient Satisfaction Questionnaire, Numerical Pain Rating Scale and medication use. Data was obtained at discharge, two weeks and six weeks post-discharge. RESULTS: Advanced musculoskeletal physiotherapists ordered less imaging, had less opioids (lower limb soft tissue injury) administered to patients, and patients' described equal or more satisfaction when compared to another health professional (p<0.05). No significant differences were found between groups for functional or pain related outcomes in both cohorts (p>0.05). CONCLUSION: Advanced musculoskeletal physiotherapists are less likely to order imaging, obtain similar outcomes regarding pain medications and display equal or more patient satisfaction when compared to other health professionals for patients presenting to the emergency department with lower limb soft tissue injuries or acute low back pain. PMID- 27495127 TI - Interspecific interference competition at the resource patch scale: do large herbivores spatially avoid elephants while accessing water? AB - Animals may anticipate and try to avoid, at some costs, physical encounters with other competitors. This may ultimately impact their foraging distribution and intake rates. Such cryptic interference competition is difficult to measure in the field, and extremely little is known at the interspecific level. We tested the hypothesis that smaller species avoid larger ones because of potential costs of interference competition and hence expected them to segregate from larger competitors at the scale of a resource patch. We assessed fine-scale spatial segregation patterns between three African herbivore species (zebra Equus quagga, kudu Tragelaphus strepsiceros and giraffe Giraffa camelopardalis) and a megaherbivore, the African elephant Loxodonta africana, at the scale of water resource patches in the semi-arid ecosystem of Hwange National Park, Zimbabwe. Nine waterholes were monitored every two weeks during the dry season of a drought year, and observational scans of the spatial distribution of all herbivores were performed every 15 min. We developed a methodological approach to analyse such fine-scale spatial data. Elephants increasingly used waterholes as the dry season progressed, as did the probability of co-occurrence and agonistic interaction with elephants for the three study species. All three species segregated from elephants at the beginning of the dry season, suggesting a spatial avoidance of elephants and the existence of costs of being close to them. However, contrarily to our expectations, herbivores did not segregate from elephants the rest of the dry season but tended to increasingly aggregate with elephants as the dry season progressed. We discuss these surprising results and the existence of a trade-off between avoidance of interspecific interference competition and other potential factors such as access to quality water, which may have relative associated costs that change with the time of the year. PMID- 27495128 TI - Wound healing efficacy of a 660-nm diode laser in a rat incisional wound model. AB - This study aimed to elucidate the optimum usage parameters of low reactive-level laser therapy (LLLT) in a rat incisional wound model. In Sprague-Dawley rats, surgical wounds of 15-mm length were made in the dorsal thoracic region. They were divided into groups to receive 660-nm diode laser irradiation 24 h after surgery at an energy density of 0 (control), 1, 5, or 10 J/cm2. Tissue sections collected on postoperative day 3 were stained with hematoxylin-eosin and an antibody for ED1 to determine the number of macrophages around the wound. Samples collected on day 7 were stained with hematoxylin-eosin and observed via polarized light microscopy to measure the area occupied by collagen fibers around the wound; day 7 skin specimens were also subjected to mechanical testing to evaluate tensile strength. On postoperative day 3, the numbers of macrophages around the wound were significantly lower in the groups receiving 1 and 5 J/cm2 irradiation, compared to the control and 10 J/cm2 irradiation groups (p < 0.01). The area occupied by collagen fibers in day 7 was largest in 5 J/cm2 group, followed by 1 J/cm2 group, although this difference was not significant. The day 7 tensile test demonstrated significantly greater rupture strength in healing tissues from 1 and 5 J/cm2 irradiation groups, compared to the control group (p < 0.05). Thus, LLLT with a 660-nm diode laser with energy density of 1 and 5 J/cm2 enhanced wound healing in a rat incisional wound model. However, a higher radiation energy density yielded no significant enhancement. PMID- 27495129 TI - Laser acupuncture causes thermal changes in small intestine meridian pathway. AB - The acupuncture meridians represent the flow of corporal energy which contains the acupuncture points. Laser acupuncture is a form of acupuncture stimulation by the use of laser. Thermographic images represent the propagation of heat in micro environmental systems. The objective of this study was to investigate the use of thermographic images to document the changes on the small intestine meridian (S.I.M.) when submitted to laser acupuncture. Another important issue regards to the analysis of the flow direction if it is upward when stimulated by acupuncture points. For the execution of this work, a laser acupuncture pen was used in points of the meridian in the S.I.M. Two healthy male volunteers were selected (18 and 60 years old, respectively), and doses of 576,92 J/cm2 with low-power infrared laser equipment with a wavelength of 780 nm in the SI.3 and SI.19 points were applied. An infrared thermal camera was used to measure the temperature of the S.I.M. during the 6 min laser acupuncture pen stimulus. When the laser acupuncture of both volunteers was conducted in the SI.3 point, it presented hyper-radiation of the hemi face in the same side, far from the application site. When this was applied in the SI.19 point, hyper-radiation in the same point and temperature lowering at the end of the meridian were observed. The laser energy caused thermal changes along the path of the S.I.M., distal, and proximal at the same time, proving the existence of the S.I.M. PMID- 27495130 TI - Photo-biomodulatory response of low-power laser irradiation on burn tissue repair in mice. AB - The present work reports the photo-biomodulatory effect of red (632.8 nm) and near infrared (785 and 830 nm) lasers on burn injury in Swiss albino mice. Animals were induced with a 15-mm full thickness burn injury and irradiated with various fluences (1, 2, 3, 4, and 6 J/cm2) of each laser wavelength under study having a constant fluence rate (8.49 mW/cm2). The size of the injury following treatment was monitored by capturing the wound images at regular time intervals until complete healing. Morphometric assessment indicated that the group treated with 3-J/cm2 fluence of 830 nm had a profound effect on healing as compared to untreated controls and various fluences of other wavelengths under study. Histopathological assessment of wound repair on treatment with an optimum fluence (3 J/cm2) of 830 nm performed on days 2, 6, 12, and 18 post-wounding resulted in enhanced wound repair with migration of fibroblasts, deposition of collagen, and neovascularization as compared to untreated controls. The findings of the present study have clearly demonstrated that a single exposure of 3-J/cm2 fluence at 830 nm enhanced burn wound healing progression in mice, which is equivalent to 5 % povidone iodine treatment (reference standard), applied on a daily basis till complete healing. PMID- 27495131 TI - Measuring inter-rater reliability for nominal data - which coefficients and confidence intervals are appropriate? AB - BACKGROUND: Reliability of measurements is a prerequisite of medical research. For nominal data, Fleiss' kappa (in the following labelled as Fleiss' K) and Krippendorff's alpha provide the highest flexibility of the available reliability measures with respect to number of raters and categories. Our aim was to investigate which measures and which confidence intervals provide the best statistical properties for the assessment of inter-rater reliability in different situations. METHODS: We performed a large simulation study to investigate the precision of the estimates for Fleiss' K and Krippendorff's alpha and to determine the empirical coverage probability of the corresponding confidence intervals (asymptotic for Fleiss' K and bootstrap for both measures). Furthermore, we compared measures and confidence intervals in a real world case study. RESULTS: Point estimates of Fleiss' K and Krippendorff's alpha did not differ from each other in all scenarios. In the case of missing data (completely at random), Krippendorff's alpha provided stable estimates, while the complete case analysis approach for Fleiss' K led to biased estimates. For shifted null hypotheses, the coverage probability of the asymptotic confidence interval for Fleiss' K was low, while the bootstrap confidence intervals for both measures provided a coverage probability close to the theoretical one. CONCLUSIONS: Fleiss' K and Krippendorff's alpha with bootstrap confidence intervals are equally suitable for the analysis of reliability of complete nominal data. The asymptotic confidence interval for Fleiss' K should not be used. In the case of missing data or data or higher than nominal order, Krippendorff's alpha is recommended. Together with this article, we provide an R-script for calculating Fleiss' K and Krippendorff's alpha and their corresponding bootstrap confidence intervals. PMID- 27495132 TI - Development and validation of a loop mediated isothermal amplification (LAMP) assay for the detection of Staphylococcus aureus in bovine mastitis milk samples. AB - Staphylococcus (S.) aureus is one of the most important animal pathogens causing bovine mastitis. Also, it is a major human pathogen that may produce a variety of toxins which cause staphylococcal food poisoning. In the present study a LAMP assay based on gene nuc to identify S. aureus was developed and validated. The specificity of the LAMP assay was confirmed by using 70 S. aureus isolates and 21 non-S. aureus strains. The optimal temperature-time combination to amplify gene nuc successfully was 65 degrees C and 30 min. The analytical sensitivity of the developed LAMP assay was 0.26 pg of S. aureus DNA per reaction. The limit of detection evaluated with milk spiked with S. aureus was 9 * 102 CFU mL-1. The final results of this assay were available within less than 2 h. The present study showed that the LAMP assay based on gene nuc appeared to be rapid and simple, and could also be used to identify S. aureus isolates from mastitis milk of dairy cows. PMID- 27495133 TI - Trigeminal autonomic cephalgia caused by recurrent posterior scleritis. AB - A 40-year-old woman presented with a side-locked headache with autonomic features, which then switched sides before reverting to the original side. The atypical features of side swapping, partial response to indometacin and abnormal optic disc appearances ultimately led to a diagnosis of recurrent posterior scleritis. We discuss the differential diagnosis of trigeminal autonomic cephalgias and its secondary causes, and provide practical pointers for its investigation and management. PMID- 27495134 TI - Effect of inflammation on HDL structure and function. AB - PURPOSE OF REVIEW: Studies have shown that chronic inflammatory disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis are associated with an increased risk of atherosclerotic cardiovascular disease. The mechanism by which inflammation increases cardiovascular disease is likely multifactorial but changes in HDL structure and function that occur during inflammation could play a role. RECENT FINDINGS: HDL levels decrease with inflammation and there are marked changes in HDL-associated proteins. Serum amyloid A markedly increases whereas apolipoprotein A-I, lecithin:cholesterol acyltransferase, cholesterol ester transfer protein, paraoxonase 1, and apolipoprotein M decrease. The exact mechanism by which inflammation decreases HDL levels is not defined but decreases in apolipoprotein A-I production, increases in serum amyloid A, increases in endothelial lipase and secretory phospholipase A2 activity, and decreases in lecithin:cholesterol acyltransferase activity could all contribute. The changes in HDL induced by inflammation reduce the ability of HDL to participate in reverse cholesterol transport and protect LDL from oxidation. SUMMARY: During inflammation multiple changes in HDL structure occur leading to alterations in HDL function. In the short term, these changes may be beneficial resulting in an increase in cholesterol in peripheral cells to improve host defense and repair but over the long term these changes may increase the risk of atherosclerosis. PMID- 27495135 TI - Early nutrition, epigenetics, and cardiovascular disease. AB - PURPOSE OF REVIEW: Here, we provide a summary of the current knowledge on the impact of early life nutrition on cardiovascular diseases that have emerged from studies in humans and experimental animal models. The involvement of epigenetic mechanisms in the Developmental Origins of Health and Disease will be discussed in relation to the implications for the heart and the cardiovascular system. RECENT FINDINGS: Environmental cues, such as parental diet and a suboptimal in utero environment can shape growth and development, causing long-lasting cardiometabolic perturbations. Increasing evidence suggest that these effects are mediated at the epigenomic level, and can be passed onto future generations. In the last decade, epigenetic mechanisms (DNA methylation, histone modifications) and RNA-based mechanisms (microRNAs, piRNAs, and tRNAs) have therefore emerged as potential candidates for mediating inheritance of cardiometabolic diseases. SUMMARY: The burden of obesity and associated cardiometabolic diseases is believed to arise through interaction between an individual's genetics and the environment. Moreover, the risk of developing poor cardiometabolic health in adulthood is defined by early life exposure to pathological cues and can be inherited by future generations, initiating a vicious cycle of transmission of disease. Elucidating the molecular triggers of such a process will help tackle and prevent the uncontrolled rise in obesity and cardiometabolic disease. PMID- 27495136 TI - Biomarker-guided antibiotic use in primary care in resource-constrained environments. PMID- 27495138 TI - Response to Black R and Chin R's letter on our article "Epilepsy in children and adolescents: Disease concepts, practical knowledge, and coping". PMID- 27495139 TI - Fitness to drive - When all may not be as it seems. PMID- 27495137 TI - Point-of-care C-reactive protein testing to reduce inappropriate use of antibiotics for non-severe acute respiratory infections in Vietnamese primary health care: a randomised controlled trial. AB - BACKGROUND: Inappropriate antibiotic use for acute respiratory tract infections is common in primary health care, but distinguishing serious from self-limiting infections is difficult, particularly in low-resource settings. We assessed whether C-reactive protein point-of-care testing can safely reduce antibiotic use in patients with non-severe acute respiratory tract infections in Vietnam. METHOD: We did a multicentre open-label randomised controlled trial in ten primary health-care centres in northern Vietnam. Patients aged 1-65 years with at least one focal and one systemic symptom of acute respiratory tract infection were assigned 1:1 to receive either C-reactive protein point-of-care testing or routine care, following which antibiotic prescribing decisions were made. Patients with severe acute respiratory tract infection were excluded. Enrolled patients were reassessed on day 3, 4, or 5, and on day 14 a structured telephone interview was done blind to the intervention. Randomised assignments were concealed from prescribers and patients but not masked as the test result was used to assist treatment decisions. The primary outcome was antibiotic use within 14 days of follow-up. All analyses were prespecified in the protocol and the statistical analysis plan. All analyses were done on the intention-to-treat population and the analysis of the primary endpoint was repeated in the per protocol population. This trial is registered under number NCT01918579. FINDINGS: Between March 17, 2014, and July 3, 2015, 2037 patients (1028 children and 1009 adults) were enrolled and randomised. One adult patient withdrew immediately after randomisation. 1017 patients were assigned to receive C-reactive protein point-of-care testing, and 1019 patients were assigned to receive routine care. 115 patients in the C-reactive protein point-of-care group and 72 patients in the routine care group were excluded in the intention-to-treat analysis due to missing primary endpoint. The number of patients who used antibiotics within 14 days was 581 (64%) of 902 patients in the C-reactive protein group versus 738 (78%) of 947 patients in the control group (odds ratio [OR] 0.49, 95% CI 0.40 0.61; p<0.0001). Highly significant differences were seen in both children and adults, with substantial heterogeneity of the intervention effect across the 10 sites (I(2)=84%, 95% CI 66-96). 140 patients in the C-reactive protein group and 137 patients in the routine care group missed the urine test on day 3, 4, or 5. Antibiotic activity in urine on day 3, 4, or 5 was found in 267 (30%) of 877 patients in the C-reactive protein group versus 314 (36%) of 882 patients in the routine treatment group (OR 0.78, 95% CI 0.63-0.95; p=0.015). Time to resolution of symptoms was similar in both groups. Adverse events were rare, with no deaths and a total of 14 hospital admissions (six in the C-reactive protein group and eight in the control group). INTERPRETATION: C-reactive protein point-of-care testing reduced antibiotic use for non-severe acute respiratory tract infection without compromising patients' recovery in primary health care in Vietnam. Health care providers might have become familiar with the clinical picture of low C reactive protein, leading to reduction in antibiotic prescribing in both groups, but this would have led to a reduction in observed effect, rather than overestimation. Qualitative analysis is needed to address differences in context in order to implement this strategy to improve rational antibiotic use for patients with acute respiratory infection in low-income and middle-income countries. FUNDING: Wellcome Trust, UK, and Global Antibiotic Resistance Partnership, USA. PMID- 27495140 TI - Posttransplantation cyclophosphamide and sirolimus for prevention of GVHD after HLA-matched PBSC transplantation. PMID- 27495141 TI - RNASwift: A rapid, versatile RNA extraction method free from phenol and chloroform. AB - RNASwift is an inexpensive, versatile method for the rapid extraction of RNA. Existing RNA extraction methods typically use hazardous chemicals including phenol, chloroform and formamide which are often difficult to completely remove from the extracted RNA. RNASwift uses sodium chloride and sodium dodecyl sulphate to lyse the cells and isolate the RNA from the abundant cellular components in conjunction with solid phase extraction or isopropanol precipitation to rapidly purify the RNA. Moreover, the purified RNA is directly compatible with downstream analysis. Using spectrophotometry in conjunction with ion pair reverse phase chromatography to analyse the extracted RNA, we show that RNASwift extracts and purifies RNA of higher quality and purity in comparison to alternative RNA extraction methods. The RNASwift method yields approximately 25 MUg of RNA from only 10(8)Escherichia coli cells. Furthermore, RNASwift is versatile; the same simple reagents can be used to rapidly extract RNA from a variety of different cells including bacterial, yeast and mammalian cells. In addition to the extraction of total RNA, the RNASwift method can also be used to extract double stranded RNA from genetically modified E. coli in higher yields compared to alternative methods. PMID- 27495142 TI - Rapid agarose gel electrophoretic mobility shift assay for quantitating protein: RNA interactions. AB - Interactions between proteins and nucleic acids are frequently analyzed using electrophoretic mobility shift assays (EMSAs). This technique separates bound protein:nucleic acid complexes from free nucleic acids by electrophoresis, most commonly using polyacrylamide gels. The current study utilizes recent advances in agarose gel electrophoresis technology to develop a new EMSA protocol that is simpler and faster than traditional polyacrylamide methods. Agarose gels are normally run at low voltages (~10 V/cm) to minimize heating and gel artifacts. In this study we demonstrate that EMSAs performed using agarose gels can be run at high voltages (>=20 V/cm) with 0.5 * TB (Tris-borate) buffer, allowing for short run times while simultaneously yielding high band resolution. Several parameters affecting band and image quality were optimized for the procedure, including gel thickness, agarose percentage, and applied voltage. Association of the siRNA binding protein p19 with its target RNA was investigated using the new system. The agarose gel and conventional polyacrylamide gel methods generated similar apparent binding constants in side-by-side experiments. A particular advantage of the new approach described here is that the short run times (5-10 min) reduce opportunities for dissociation of bound complexes, an important concern in non equilibrium nucleic acid binding experiments. PMID- 27495143 TI - Comorbidities, treatment, and outcome in severe anogenital inverse acne (hidradenitis suppurativa): a 15-year single center report. AB - BACKGROUND: Acne inversa (hidradentitis suppurativa; AI) is a severe chronic relapsing inflammatory skin disease of unknown cause. Anogenital AI has the strongest negative impact on quality of life and causes great disability. OBJECTIVES: We analyzed patients, comorbities, outcome of extensive surgery, and possible adverse effects. PATIENTS AND METHODS: We included patients from January 2000 to March 2015 with anogenital AI Hurley grade III. They were further characterized by modified Sartorius scale, gender and age, comorbidities, pretreatments, and type of surgery (open or closed), and complications. Pain was measured by visual analogue scale (VAS). Treatment was performed by wide excision surgery. RESULTS: A total of 117 patients were identified; mean age was 40.6 +/- 12.6 years. The mean modified Sartorius score was 30.4 +/- 8.4. Risk factors of obesity and active smoking were seen in 31.6% and 14.5%, respectively. Colostomy was needed in a single patient only. Pain was reduced significantly. Intra- and postoperative complications were seen in 20.5% (24/117). CONCLUSIONS: Anogenital AI is a severe and potentially life threatening disease. Severe anogenital AI can be effectively treated by aggressive surgery. Outcome depends also on comorbidities. PMID- 27495144 TI - In vivo imaging of cancer cell size and cellularity using temporal diffusion spectroscopy. AB - PURPOSE: A temporal diffusion MRI spectroscopy based approach has been developed to quantify cancer cell size and density in vivo. METHODS: A novel imaging microstructural parameters using limited spectrally edited diffusion (IMPULSED) method selects a specific limited diffusion spectral window for an accurate quantification of cell sizes ranging from 10 to 20 MUm in common solid tumors. In practice, it is achieved by a combination of a single long diffusion time pulsed gradient spin echo (PGSE) and three low-frequency oscillating gradient spin echo (OGSE) acquisitions. To validate our approach, hematoxylin and eosin staining and immunostaining of cell membranes, in concert with whole slide imaging, were used to visualize nuclei and cell boundaries, and hence, enabled accurate estimates of cell size and cellularity. RESULTS: Based on a two compartment model (incorporating intra- and extracellular spaces), accurate estimates of cell sizes were obtained in vivo for three types of human colon cancers. The IMPULSED derived apparent cellularities showed a stronger correlation (r = 0.81; P < 0.0001) with histology-derived cellularities than conventional ADCs (r = -0.69; P < 0.03). CONCLUSION: The IMPULSED approach samples a specific region of temporal diffusion spectra with enhanced sensitivity to length scales of 10-20 MUm, and enables measurements of cell sizes and cellularities in solid tumors in vivo. Magn Reson Med 78:156-164, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27495145 TI - Immune modulation by hypofractionated stereotactic radiation therapy: Therapeutic implications. AB - Stereotactic body radiation therapy (SBRT) has become an attractive treatment modality and a safe, non-invasive alternative to surgery to control primary or secondary malignant tumors. While emphasis has been on the local tumor control as a treatment objective for SBRT, the rare but intriguing observations of abscopal (or out-of-field) effects have pointed to the exciting possibility of activating anti-tumor immunity by using high-dose radiation. This review summarizes the available evidence supporting immune modulation by SBRT alone, as well as its potential combination with immunotherapy. Promising preclinical research has revealed an array of immune changes following SBRT, which could affect the balance between anti-tumor immunity and tumor-promoting immunosuppression. However, shifting this balance in the clinical setting to obtain survival benefits has rarely been achieved so far, emphasizing the need for a better understanding of the interactions between high-dose radiotherapy and immunity or immunotherapy. Nevertheless, the combination of SBRT with immunotherapy, particularly with immune checkpoint blockers, has the clear potential to substantially increase the rate of abscopal effects. This warrants further research in this area, both in mechanistic preclinical studies and in clinical trials incorporating correlative studies. PMID- 27495146 TI - Evaluating the utility of provider-recorded clinical status in the medical records of HIV-positive adults in a limited-resource setting. AB - Provider-reported summaries of clinical status may assist with clinical management of HIV in resource poor settings if they reflect underlying biological processes associated with HIV disease progression. However, their ability to do so is rarely evaluated. Therefore, we aimed to assess the relationship between a provider-recorded summary of clinical status and indicators of HIV progression. Data were abstracted from 201 randomly selected medical records at a large HIV clinic in the Dominican Republic. Multivariable logistic regressions were used to examine the relationship between provider-assigned clinical status and demographic (gender, age, nationality, education) and clinical factors (reported medication adherence, CD4 cell count, viral load). The mean age of patients was 41.2 (SD = +/-10.9) years and most were female (n = 115, 57%). None of the examined characteristics were significantly associated with provider-recorded clinical status. Higher CD4 cell counts were more likely for females (OR = 2.2 CI: 1.12-4.31) and less likely for those with higher viral loads (OR = 0.33 CI: 0.15-0.72). Poorer adherence and lower CD4 cell counts were significantly associated with higher viral loads (OR = 4.46 CI: 1.11-20.29 and 6.84 CI: 1.47 37.23, respectively). Clinics using provider-reported summaries of clinical status should evaluate the performance of these assessments to ensure they are associated with biologic indicators of disease progression. PMID- 27495147 TI - Factors associated with non-retention in HIV care in an era of widespread antiretroviral therapy. AB - In an era of antiretroviral therapy (ART) for all HIV-1-infected patients, our primary aim was to describe prevalence and characteristics of patients disengaged from care at an urban ambulatory HIV clinic. We conducted a nested case-control study. All patients who disengaged from care (defined as being lost to follow-up for at least one year) from 2007 to 2014 inclusive were identified. Cases were matched to controls in a 1:4 ratio. A total of 1250 cases were included; 250/2289 (10.9%) of patients attending our HIV clinic disengaged from 2007 to 2014. One hundred and twenty-six (50.4%) were heterosexual, 81 (32.4%) were men who have sex with men and 40 (16%) were intravenous drug users. On univariate analysis only, patients with heterosexual risk were more likely to disengage from care (50.4% vs. 33.7%, p: <0.001). Those who disengaged were younger, mean age of 39 (p: <0.001). A higher proportion of patients who disengaged from care was not receiving ART and did not have a suppressed HIV-1 viral load (p: <0.001). On multivariable analysis, Irish patients were less likely to disengage from HIV care (odds ratio: 0.567, p: 0.002). Factors associated with non-retention in HIV care have been identified. A semi-structured interview of those patients who re engaged will take place to further examine reasons for disengagement from care. PMID- 27495148 TI - Improving childhood nutrition and wellness in South Africa: involving mothers/caregivers of malnourished or HIV positive children and health care workers as co-designers to enhance a local quality improvement intervention. AB - BACKGROUND: A significant proportion of children admitted to a hospital in a South African sub-district in 2010 were severely malnourished and - when concurrently HIV positive - were not correctly initiated on antiretroviral therapy. Audit data over a subsequent four year period revealed that 60 % of malnourished children admitted to the hospital were HIV positive. To supplement an ongoing local quality improvement (QI) intervention addressing poor nutritional outcomes in children in this setting, Experience-based Co-design (EBCD) was used to enhance previously low levels of mother, carer and staff engagement. METHODS: EBCD was implemented over an 8 month period. Non-participant observation was conducted comprising a total of 10 h in 5 different clinical locations. Semi-structured interviews were undertaken with 14 purposively selected staff members as well as 10 mothers/caregivers. The staff interviews were audio-taped whilst the mothers/caregiver interviews were filmed; both sets of experiences were analysed for key 'touchpoints'. Mothers/caregivers and staff participated in separate feedback events and then came together to identify their shared priorities for improving the service. Participants worked together in 3 smaller co-design teams to implement improvements. RESULTS: There was overlap in staff and mother/carer views as to their priorities for QI. However, whilst staff typically highlighted pragmatic issues, mothers/caregivers were more likely to identify experiential and relational issues. A total of 38 QI interventions were proposed after the priorities had been discussed and delegated to the 3 co-design teams; 25 of these changes had been implemented or were being planned for by the end of the study period. Examples included: a point of care blood machine being bought to shorten the time in the emergency department whilst waiting for laboratory results; a play area being organised for children attending the HIV clinic; the development of three standard operating procedures to improve clinical handover and waiting times; and privacy screens installed to improve privacy in reception. CONCLUSIONS: The impact of EBCD was noted both in practical improvements focused on a better experience for mothers/caregivers and children within the system and in reflections from stakeholders as to the value added to the ongoing QI intervention by the co-design process. PMID- 27495149 TI - Using multivariate cross correlations, Granger causality and graphical models to quantify spatiotemporal synchronization and causality between pest populations. AB - BACKGROUND: This work combines multivariate time series analysis and graph theory to detect synchronization and causality among certain ecological variables and to represent significant correlations via network projections. Four different statistical tools (cross-correlations, partial cross-correlations, Granger causality and partial Granger causality) utilized to quantify correlation strength and causality among biological entities. These indices correspond to different ways to estimate the relationships between different variables and to construct ecological networks using the variables as nodes and the indices as edges. Specifically, correlations and Granger causality indices introduce rules that define the associations (links) between the ecological variables (nodes). This approach is used for the first time to analyze time series of moth populations as well as temperature and relative humidity in order to detect spatiotemporal synchronization over an agricultural study area and to illustrate significant correlations and causality interactions via graphical models. RESULTS: The networks resulting from the different approaches are trimmed and show how the network configurations are affected by each construction technique. The Granger statistical rules provide a simple test to determine whether one series (population) is caused by another series (i.e. environmental variable or other population) even when they are not correlated. In most cases, the statistical analysis and the related graphical models, revealed intra-specific links, a fact that may be linked to similarities in pest population life cycles and synchronizations. Graph theoretic landscape projections reveal that significant associations in the populations are not subject to landscape characteristics. Populations may be linked over great distances through physical features such as rivers and not only at adjacent locations in which significant interactions are more likely to appear. In some cases, incidental connections, with no ecological explanation, were also observed; however, this was expected because some of the statistical methods used to define non trivial associations show connections that cannot be interpreted phenomenologically. CONCLUSIONS: Incorporating multivariate causal interactions in a probabilistic sense comes closer to reality than doing per se binary theoretic constructs because the former conceptually incorporate the dynamics of all kinds of ecological variables within the network. The advantage of Granger rules over correlations is that Granger rules have dynamic features and provide an easy way to examine the dynamic causal relations of multiple time-series variables. The constructed networks may provide an intuitive, advantageous representation of multiple populations' associations that can be realized within an agro-ecosystem. These relationships may be due to life cycle synchronizations, exposure to a shared climate or even more complicated ecological interactions such as moving behavior, dispersal patterns and host allocation. Moreover, they are useful for drawing inferences regarding pest population dynamics and their spatial management. Extending these models by including more variables should allow the exploration of intra and interspecies relationships in larger ecological systems, and the identification of specific population traits that might constrain their structures in larger areas. PMID- 27495150 TI - Robot-assisted laparoscopic pyeloplasty for ureteropelvic junction obstruction: comparison between pediatric and adult patients-Japanese series. AB - Robotic-assisted procedures are gaining traction as a viable form of minimally invasive surgery in the field of reconstructive surgery. In this article, the aim is to present our initial experience and clinical outcomes of robot-assisted laparoscopic pyeloplasty (RAL-P). We performed RAL-P in 22 patients for the management of ureteropelvic junction obstruction between December 2012 and August 2015. The da Vinci(r) S surgical system was utilized for all cases. All procedures were performed via a transperitoneal approach. We assessed perioperative outcomes, and furthermore, compared between pediatric and adult patients undergoing this procedure. Dismembered procedures were performed in 19 patients. Three patients underwent Y-V plasty, and two patients who experienced failure during the primary pyeloplasty had to undergo reoperation. Although the console time for pediatric patients was significantly shorter than that of adults (123.1 +/- 18.3, 162.4 +/- 23.9 min, respectively, p < 0.001), success rate was not significantly different between pediatric and adults (100 vs 90 %, p = 0.512). According to a comparison of surgical outcomes by age, the console time was significantly shorter in pediatric than in adult patients. This finding may be attributable to the differences in intraabdominal fatty tissues. Besides, RAL P with Y-V plasty was applicable even for cases of failed pyeloplasty. In conclusion, the surgical outcomes of RAL-P were favorable and safe for both pediatric and adult patients, and comparable to findings of previous reports. To our knowledge, this is the first report of a case series of RAL-P in Japan. PMID- 27495152 TI - Neelika Karunaratne. PMID- 27495151 TI - Potential health gains and health losses in eleven EU countries attainable through feasible prevalences of the life-style related risk factors alcohol, BMI, and smoking: a quantitative health impact assessment. AB - BACKGROUND: Influencing the life-style risk-factors alcohol, body mass index (BMI), and smoking is an European Union (EU) wide objective of public health policy. The population-level health effects of these risk-factors depend on population specific characteristics and are difficult to quantify without dynamic population health models. METHODS: For eleven countries-approx. 80 % of the EU-27 population-we used evidence from the publicly available DYNAMO-HIA data-set. For each country the age- and sex-specific risk-factor prevalence and the incidence, prevalence, and excess mortality of nine chronic diseases are utilized; including the corresponding relative risks linking risk-factor exposure causally to disease incidence and all-cause mortality. Applying the DYNAMO-HIA tool, we dynamically project the country-wise potential health gains and losses using feasible, i.e. observed elsewhere, risk-factor prevalence rates as benchmarks. The effects of the "worst practice", "best practice", and the currently observed risk-factor prevalence on population health are quantified and expected changes in life expectancy, morbidity-free life years, disease cases, and cumulative mortality are reported. RESULTS: Applying the best practice smoking prevalence yields the largest gains in life expectancy with 0.4 years for males and 0.3 year for females (approx. 332,950 and 274,200 deaths postponed, respectively) while the worst practice smoking prevalence also leads to the largest losses with 0.7 years for males and 0.9 year for females (approx. 609,400 and 710,550 lives lost, respectively). Comparing morbidity-free life years, the best practice smoking prevalence shows the highest gains for males with 0.4 years (342,800 less disease cases), whereas for females the best practice BMI prevalence yields the largest gains with 0.7 years (1,075,200 less disease cases). CONCLUSION: Smoking is still the risk-factor with the largest potential health gains. BMI, however, has comparatively large effects on morbidity. Future research should aim to improve knowledge of how policies can influence and shape individual and aggregated life style-related risk-factor behavior. PMID- 27495153 TI - W44X mutation in the WWOX gene causes intractable seizures and developmental delay: a case report. AB - BACKGROUND: WW domain containing oxidoreductase (WWOX) gene was cloned in 2000; alteration has been seen in many cancer cells. It acts as a tumor suppresser by blocking cell growth and causing apoptosis. WWOX protein showed different expression of mice brain and spinal cord, for which deletion causes seizure and early death. CASE PRESENTATION: Clinical and molecular characteristics of a consanguineous family show a homozygous mutation of WWOX gene at specific bases, causing a debilitating syndrome characterized by growth retardation, intractable epilepsy, intellectual disability, and early death. Using Whole Exome Sequencing (WES), a novel homozygous mutation in the WWOX gene is identified in a consanguineous Arab family from Qatar with two daughters who presented with intractable seizure and developmental delay. CONCLUSION: The study presents the importance of human WWOX gene for brain development and the association between gene mutation and epileptic encephalopathy. It also highlights the power of WES particularly in clinically challenging cases. PMID- 27495154 TI - Smaller employers are less likely to provide occupational health support. PMID- 27495155 TI - Hydroxylation of diverse flavonoids by CYP450 BM3 variants: biosynthesis of eriodictyol from naringenin in whole cells and its biological activities. AB - BACKGROUND: Cytochrome P450 monooxygenase constitutes a significant group of oxidative enzymes that can introduce an oxygen atom in a high regio- and stereo selectivity mode. We used the Bacillus megaterium cytochrome P450 BM3 (CYP450 BM3) and its variants namely mutant 13 (M13) and mutant 15 (M15) for the hydroxylation of diverse class of flavonoids. RESULTS: Among 20 flavonoids, maximum seven flavonoids were hydroxylated by the variants while none of these molecules were accepted by CYP450 BM3 in in vitro reaction. Moreover, M13 exhibited higher conversion of substrates than M15 and CYP450 BM3 enzymes. We found that M13 carried out regiospecific 3'-hydroxylation reaction of naringenin with the highest conversion among all the tested flavonoids. The apparent K m and k cat values of M13 for naringenin were 446 uM and 1.955 s(-1), respectively. In whole-cell biotransformation experiment with 100 uM of naringenin in M9 minimal medium with 2 % glucose in shake flask culture, M13 showed 2.14- and 13.96-folds higher conversion yield in comparison with M15 (16.11 %) and wild type (2.47 %). The yield of eriodictyol was 46.95 uM [~40.7 mg (13.5 mg/L)] in a 3-L volume lab scale fermentor at 48 h in the same medium exhibiting approximately 49.81 % conversion of the substrate. In addition, eriodictyol exhibited higher antibacterial and anticancer potential than naringenin, flavanone and hesperetin. CONCLUSIONS: We elucidated that eriodictyol being produced from naringenin using recombinant CYP450 BM3 and its variants from B. megaterium, which shows an approach for the production of important hydroxylated compounds of various polyphenols that may span pharmaceutical industries. PMID- 27495156 TI - Impact of disease activity and treatment of comorbidities on the risk of myocardial infarction in rheumatoid arthritis. AB - BACKGROUND: The aim was to estimate the impact of individual risk factors and treatment with various disease-modifying antirheumatic drugs (DMARDs) on the incidence of myocardial infarction (MI) in patients with rheumatoid arthritis (RA). METHODS: We analysed data from 11,285 patients with RA, enrolled in the prospective cohort study RABBIT, at the start of biologic (b) or conventional synthetic (cs) DMARDs. A nested case-control study was conducted, defining patients with MI during follow-up as cases. Cases were matched 1:1 to control patients based on age, sex, year of enrolment and five cardiovascular (CV) comorbidities. Generalized linear models were applied (Poisson regression with a random component, conditional logistic regression). RESULTS: In total, 112 patients developed an MI during follow-up. At baseline, during the first 6 months of follow-up and prior to the MI, inflammation markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) but not 28-joint-count disease activity score (DAS28) were significantly higher in MI cases compared to matched controls and the remaining cohort. Baseline treatment with DMARDs was similar across all groups. During follow-up bDMARD treatment was significantly more often discontinued or switched in MI cases. CV comorbidities were significantly less often treated in MI cases vs. matched controls (36 % vs. 17 %, p < 0.01). In the adjusted regression model, we found a strong association between higher CRP and MI (OR for log-transformed CRP at follow-up: 1.47, 95 % CI 1.00; 2.16). Furthermore, treatment with prednisone >=10 mg/day (OR 1.93, 95 % CI 0.57; 5.85), TNF inhibitors (OR 0.91, 95 % CI 0.40; 2.10) or other bDMARDs (OR 0.85, 95 % CI 0.27; 2.72) was not associated with higher MI risk. CONCLUSIONS: CRP was associated with risk of MI. Our results underline the importance of tight disease control taking not only global disease activity, but also CRP as an individual marker into account. It seems irrelevant with which class of (biologic or conventional) DMARD effective control of disease activity is achieved. However, in some patients the available treatment options were insufficient or insufficiently used - regarding DMARDs to treat RA as well as regarding the treatment of CV comorbidities. PMID- 27495157 TI - Circadian variation of the pancreatic islet transcriptome. AB - Pancreatic islet failure is a characteristic feature of impaired glucose control in diabetes mellitus. Circadian control of islet function is essential for maintaining proper glucose homeostasis. Circadian variations in transcriptional pathways have been described in diverse cell types and shown to be critical for optimization of cellular function in vivo. In the current study, we utilized Short Time Series Expression Miner (STEM) analysis to identify diurnally expressed transcripts and biological pathways from mouse islets isolated at 4 h intervals throughout the 24 h light-dark cycle. STEM analysis identified 19 distinct chronological model profiles, and genes belonging to each profile were subsequently annotated to significantly enriched Kyoto Encyclopedia of Genes and Genomes biological pathways. Several transcriptional pathways essential for proper islet function (e.g., insulin secretion, oxidative phosphorylation), cell survival (e.g., insulin signaling, apoptosis) and cell proliferation (DNA replication, homologous recombination) demonstrated significant time-dependent variations. Notably, KEGG pathway analysis revealed "protein processing in endoplasmic reticulum - mmu04141" as one of the most enriched time-dependent pathways in islets. This study provides unique data set on time-dependent diurnal profiles of islet gene expression and biological pathways, and suggests that diurnal variation of the islet transcriptome is an important feature of islet homeostasis, which should be taken into consideration for optimal experimental design and interpretation of future islet studies. PMID- 27495159 TI - When to start renal replacement therapy in critically ill patients with acute kidney injury: comment on AKIKI and ELAIN. AB - The dilemma of whether and when to start renal replacement therapy among critically ill patients with acute kidney injury in the absence of conventional indications has long been a vexing challenge for clinicians. The lack of high quality evidence has undoubtedly contributed decisional uncertainty and unnecessary practice variation. Recently, two randomized trials (ELAIN and AKIKI) reported specifically on the issue of the timing of initiation of renal replacement therapy in critically ill patients with acute kidney injury. In this commentary, their fundamental differences in trial design, sample size, and widely discrepant findings are considered in context. While both trials are important contributions towards informing practice on this issue, additional evidence from large multicenter randomized trials is needed. PMID- 27495158 TI - RNA expression profile of calcified bicuspid, tricuspid, and normal human aortic valves by RNA sequencing. AB - The molecular mechanisms leading to premature development of aortic valve stenosis (AS) in individuals with a bicuspid aortic valve are unknown. The objective of this study was to identify genes differentially expressed between calcified bicuspid aortic valves (BAVc) and tricuspid valves with (TAVc) and without (TAVn) AS using RNA sequencing (RNA-Seq). We collected 10 human BAVc and nine TAVc from men who underwent primary aortic valve replacement. Eight TAVn were obtained from men who underwent heart transplantation. mRNA levels were measured by RNA-Seq and compared between valve groups. Two genes were upregulated, and none were downregulated in BAVc compared with TAVc, suggesting a similar gene expression response to AS in individuals with bicuspid and tricuspid valves. There were 462 genes upregulated and 282 downregulated in BAVc compared with TAVn. In TAVc compared with TAVn, 329 genes were up- and 170 were downregulated. A total of 273 upregulated and 147 downregulated genes were concordantly altered between BAVc vs. TAVn and TAVc vs. TAVn, which represent 56 and 84% of significant genes in the first and second comparisons, respectively. This indicates that extra genes and pathways were altered in BAVc. Shared pathways between calcified (BAVc and TAVc) and normal (TAVn) aortic valves were also more extensively altered in BAVc. The top pathway enriched for genes differentially expressed in calcified compared with normal valves was fibrosis, which support the remodeling process as a therapeutic target. These findings are relevant to understand the molecular basis of AS in patients with bicuspid and tricuspid valves. PMID- 27495160 TI - 'How families live ...' - the views and experiences of parent-carers who provide family placements to intellectual disability nursing students. AB - AIM: We aimed to learn about the value of family placements from the perspective of parent-carers who provide them to nurse students via a Scottish university Family Placement Scheme. METHOD: Qualitative interviews were conducted with seven parent-carers who provided a family placement over two academic years. Descriptive data was analysed, organized into themes and subject to content analysis: parents' descriptions of caring; their perceived value of family placements; and their views and experiences of participation in intellectual disability nurse education. RESULTS: Family placements are beneficial to nurse students and families with children with an intellectual disability. Description of wider aspects of caring was provided, offering insight into learning experiences of students on placement. CONCLUSION: This model of learning provides opportunities for students to appreciate the reality of caring for a relative with an intellectual disability at home. Students develop their practice skills for working in partnership with family carers. PMID- 27495161 TI - Nitric Oxide Upregulates Proteasomal Protein Degradation in Neurons. AB - Nitric oxide (NO) is involved in many neuronal functions such as neuromodulation and intracellular signaling. Recent studies have demonstrated that nitric oxide is involved in regulation of proteasomal protein degradation. However, its role in neuronal protein degradation still remains unclear. In our study, we investigated the influence of endogenous nitric oxide production in this process. We have shown that nitric oxide synthase blockade prevents decline of the UbG76V GFP fluorescence (GFP-based proteasomal protein degradation reporter) in neuronal processes of the cultured hippocampal neurons. It suggests that nitric oxide may regulate ubiquitin-dependent proteasomal protein degradation in neurons. Also, we have confirmed that the NO synthesis blockade alone significantly impairs long term potentiation, and demonstrated for the first time that simultaneous blockade of the NO and proteins synthesis leads to the long-term potentiation amplitude rescue to the control values. Obtained results suggest that nitric oxide is involved in the protein degradation in proteasomes in physiological conditions. PMID- 27495162 TI - Physicochemical Properties of Bosentan and Selected PDE-5 Inhibitors in the Design of Drugs for Rare Diseases. AB - The study provides the physicochemical characteristic of bosentan (BOS) in comparison to tadalafil (TA) and sildenafil citrate (SIL). Despite some reports dealing with thermal characteristic of SIL and TA, physicochemical properties of BOS have not been investigated so far. Recent clinical reports have indicated that the combination of bosentan and PDE-5 inhibitor can improve the effectiveness of pharmacotherapy of pulmonary arterial hypertension (PAH). However, in order to design personalized medicines for therapy of chronic rare diseases, detailed information on the thermal behaviour and solubility of each drug is indispensable. Thus, XRD, DSC and TGA-QMS analyses were applied to compare the properties of the drugs, their thermal stability as well as to identify the products of thermal degradation. The dehydration of BOS started at 70 degrees C and was followed by the chemical degradation with the onset at 290 degrees C. The highest thermal stability was stated for TA, which decomposed at ca. 320 degrees C, whereas the lowest onset of the thermal decomposition process was stated for SIL, i.e. 190 degrees C. The products of the drug decomposition were identified. FT-FIR was applied to study intra- and intermolecular interactions between the drug molecules. FT-MIR and Raman spectroscopy were used to examine the chemical structure of the drugs. Chemoinformatic tools were used to predict the polar surface area, pKa, or logP of the drugs. Their results were in line with solubility and dissolution studies. PMID- 27495163 TI - Rapid Analysis of the Quality of Amoxicillin and Clavulanate Potassium Tablets Using Diffuse Reflectance Near-Infrared Spectroscopy. AB - The cycle-closed dimer of amoxicillin influences its critical quality and is an important impurity in amoxicillin and clavulanate potassium tablets. The quality of the tablets could be rapidly evaluated using the impurity as an indicator. Here, we report a quantitative model to determine the cycle-closed dimer in samples from different manufacturers using diffuse reflectance near-infrared (NIR) spectroscopy by partial least squares regression for one y variable (PLS1) and hierarchical cluster analysis. Because the contents of the (active pharmaceutical ingredients) APIs (amoxicillin and clavulanate potassium) and water are also the important indexes of the tablet quality, three other quantitative models were used to confirm the API data and water content. All of the four models facilitate rapid and complete control of the tablet quality. In addition, quantitative models were validated in terms of specificity, linearity, accuracy, repeatability, and intermediate precision according to the International Conference on Harmonisation guidelines by evaluating the characteristics of the NIR spectra. These results confirmed that the models were satisfactory. PMID- 27495164 TI - [Do we need to relearn abdominal wall closure? : Small stitches]. AB - The 1-year incisional hernia rate of 9-30 % has been tolerated for decades. Even in the 1970s and 1980s there was evidence that supported reducing suture tension. Recently, the traditional 4:1 relationship between suture and wound length, which has been passed on for years, has been questioned. After first experimental and clinical data suggested an advantage by reducing the width and interval of stitches by 50 %, the prospective randomized STITCH study has now provided evidence by significantly lowering the 1-year hernia rate from 21 % to 13 %. For surgeons this means less of a revolution and more of an innovative evolution of a long-established technique. Before introduction of the technique quality assurance must be carried out with documentation of performance indicators (e.g. number of stitches, length of thread incorporated and wound length). PMID- 27495165 TI - [Surgical anatomy of the abdominal wall]. AB - Knowledge of the anterolateral abdominal wall anatomy is crucial for a surgical approach to the abdominal cavity and for reconstructive surgery of abdominal wall defects. Furthermore it can help the surgeon ensure optimal surgical results by avoiding anatomical complications. This overview presents the surgical relevant anatomy and emphasizes surgical principles and pitfalls in abdominal wall surgery. PMID- 27495166 TI - Health-related quality of life and associated factors in people with HIV: an Irish cohort study. AB - BACKGROUND: Considering the chronic and debilitating nature of HIV infection, health-related quality of life (HRQoL) is an important patient-reported clinical outcome to better understand the effects of this infection and its treatment on patients' lives. The purpose of this study was to assess the HRQoL and its association with sociodemographic, behavioural, clinical, nutrition-related factors and social support in an Irish HIV cohort. METHODS: A cross-sectional, prospective study using the Medical Outcomes Study HIV Health survey assessed the 10 dimensions of HRQoL and summarised as Physical Health Summary (PHS) and Mental Health Summary (MHS) scores. Participants were categorised as having good or poor PHS and MHS using the standardised mean score of 50. The variables independently associated with PHS and MHS were identified using multivariable logistic regression models. RESULTS: Overall, 521 participants completed the HRQoL questionnaire. The median (IQR) PHS and MHS scores were 56 (47-60) and 51 (41-58) respectively. All the covariate groups had lower MHS than PHS. Participants with symptoms of HIV reported the lowest median (IQR) PHS score 44.7 (32.-54.5) and MHS score 36.1 (28.6-48.4). Of the 10 dimensions of HRQoL, the lowest scores were for the energy level and general health. Symptoms of HIV, co-morbidities, social support, employment and ethnicity had independent association with both PHS and MHS. Gender, education, alcohol intake and HIV-complications were associated with PHS. Age, illicit drugs, BMI and malnutrition were associated with MHS. However, CD4 count and viral load were not independently associated with PHS and MHS in multivariable regression models. CONCLUSION: Overall, HIV-infected people in this cohort had an average level of HRQoL. However, it is impaired in people with symptoms and co-morbidities, and not independently associated with CD4 and viral load. Alleviating HIV symptoms and preventing co-morbidities are important in managing HIV. Providing psychosocial supports for behaviour modification and return to work or exploring new opportunities will help to improve HRQoL. Healthcare providers and policy makers need to plan and implement programs to routinely assess the HRQoL in a systematic method to facilitate a holistic management of HIV. PMID- 27495167 TI - Evaluation of the vaginal flora in pregnant women receiving opioid maintenance therapy: a matched case-control study. AB - BACKGROUND: Vaginal infections are a risk factor for preterm delivery. In this study, we sought to evaluate the vaginal flora of pregnant women receiving opioid maintenance therapy (OMT) in comparison to non-dependent, non-maintained controls. METHODS: A total of 3763 women with singleton pregnancies who underwent routine screening for asymptomatic vaginal infections between 10 + 0 and 16 + 0 gestational weeks were examined. Vaginal smears were Gram-stained, and microscopically evaluated for bacterial vaginosis, candidiasis, and trichomoniasis. In a retrospective manner, data of 132 women receiving OMT (cases) were matched for age, ethnicity, parity, education, previous preterm delivery, and smoking status to the data of 3631 controls. The vaginal flora at antenatal screening served as the primary outcome measure. Secondary outcome measures were gestational age and birth weight. RESULTS: In the OMT group, 62/132 (47 %) pregnant women received methadone, 39/132 (29.5 %) buprenorphine, and 31/132 (23.5 %) slow-release oral morphine. Normal or intermediate flora was found in 72/132 OMT women (54.5 %) and 2865/3631 controls [78.9 %; OR 0.49 (95 % CI, 0.33-0.71); p < 0.001]. Candidiasis occurred more frequently in OMT women than in controls [OR 2.11 (95 % CI, 1.26-3.27); p < 0.001]. Findings were inconclusive regarding bacterial vaginosis (+/- candidiasis) and trichomoniasis. Compared to infants of the control group, those of women with OMT had a lower mean birth weight [MD -165.3 g (95 % CI, -283.6 to -46.9); p = 0.006]. CONCLUSIONS: Pregnant women with OMT are at risk for asymptomatic vaginal infections. As recurrent candidiasis is associated with preterm delivery, the vulnerability of this patient population should lead to consequent antenatal infection screening at early gestation. PMID- 27495168 TI - Unravelling the effect of the Dutch school-based nutrition programme Taste Lessons: the role of dose, appreciation and interpersonal communication. AB - BACKGROUND: To unravel the effect of school-based nutrition education, insight into the implementation process is needed. In this study, process indicators of Taste Lessons (a nutrition education programme for Dutch elementary schools) and their association with changes in behavioural determinants relevant to healthy eating behaviour are studied. METHODS: The study sample consisted of 392 Dutch primary school children from 12 schools. Data were collected using teacher and child questionnaires at baseline, and at one and six months after the intervention. Multilevel regression analyses were conducted to study the association between dose, appreciation and children's engagement in interpersonal communication (talking about Taste Lessons with others after the lessons), and change in knowledge, awareness, skills, attitude, emotion, subjective norm and intention towards two target behaviours. RESULTS: With an average implementation of a third of the programme activities, dose positively predicted change in children's subjective norm of the teacher after one month. Teachers and children highly appreciated Taste Lessons. Whereas teacher appreciation was inversely associated, child appreciation was positively associated with children's change in awareness, emotion and subjective norm of teachers after one month and in attitude and subjective norm of parents after six months. Interpersonal communication was positively associated with children's change in five determinants after one month and in attitude and intention after six months. CONCLUSIONS: The implementation process is related to the programme outcomes of Taste Lessons. Process data provide valuable insights into factors that contribute to the effect of interventions in real-life settings. PMID- 27495169 TI - Functional characterization of the Mycobacterium abscessus genome coupled with condition specific transcriptomics reveals conserved molecular strategies for host adaptation and persistence. AB - BACKGROUND: Mycobacterium abscessus subsp. abscessus (MAB) is a highly drug resistant mycobacterium and the most common respiratory pathogen among the rapidly growing non-tuberculous mycobacteria. MAB is also one of the most deadly of the emerging cystic fibrosis (CF) pathogens requiring prolonged treatment with multiple antibiotics. In addition to its "mycobacterial" virulence genes, the genome of MAB harbours a large accessory genome, presumably acquired via lateral gene transfer including homologs shared with the CF pathogens Pseudomonas aeruginosa and Burkholderia cepacia. While multiple genome sequences are available there is little functional genomics data available for this important pathogen. RESULTS: We report here the first multi-omics approach to characterize the primary transcriptome, coding potential and potential regulatory regions of the MAB genome utilizing differential RNA sequencing (dRNA-seq), RNA-seq, Ribosome profiling and LC-MS proteomics. In addition we attempt to address the genomes contribution to the molecular systems that underlie MAB's adaptation and persistence in the human host through an examination of MABs transcriptional response to a number of clinically relevant conditions. These include hypoxia, exposure to sub-inhibitory concentrations of antibiotics and growth in an artificial sputum designed to mimic the conditions within the cystic fibrosis lung. CONCLUSIONS: Our integrated map provides the first comprehensive view of the primary transcriptome of MAB and evidence for the translation of over one hundred new short open reading frames (sORFs). Our map will act as a resource for ongoing functional genomics characterization of MAB and our transcriptome data from clinically relevant stresses informs our understanding of MAB's adaptation to life in the CF lung. MAB's adaptation to growth in artificial CF sputum highlights shared metabolic strategies with other CF pathogens including P. aeruginosa and mirrors the transcriptional responses that lead to persistence in mycobacteria. These strategies include an increased reliance on amino acid metabolism, and fatty acid catabolism and highlights the relevance of the glyoxylate shunt to growth in the CF lung. Our data suggests that, similar to what is seen in chronically persisting P. aeruginosa, progression towards a biofilm mode of growth would play a more prominent role in a longer-term MAB infection. Finally, MAB's transcriptional response to antibiotics highlights the role of antibiotic modifications enzymes, active transport and the evolutionarily conserved WhiB7 driven antibiotic resistance regulon. PMID- 27495170 TI - Smooth muscle cell sheet transplantation preserve cardiac function and minimize cardiac remodeling in a rat myocardial infarction model. AB - BACKGROUND: We examined whether a vascular smooth muscle cell (SMC) sheet is effective in the treatment of a rat myocardial infarction (MI) model. METHODS: We examined the effect of SMC sheet on the cardiac function and cardiac remodeling in a rat MI model in comparison with their effect of dermal fibroblast (DFB) sheet in vivo. Furthermore, we estimated the apoptosis and secretion of angiogenic factor of SMC under hypoxic condition in comparison with DFB. Seven days after MI, monolayer cell sheets were transplanted on the infarcted area (SMC transplantation group, SMC-Tx; DFB transplantation group, DFB-Tx; no cell sheet transplantation group, Untreated; neither MI nor cell sheet transplantation group, Sham). We evaluated cardiac function by echocardiogram, degree of cardiac remodeling by histological examination, and secretion of angiogenic growth factor by enzyme immunoassay. RESULTS: Twenty-eight days after transplantation, SMC-Tx showed the following characteristics compared with the other groups: 1) significantly greater fractional area shortening (SMC-Tx, 32.3 +/- 2.1 %; DFB-Tx, 23.3 +/- 2.1 %; untreated, 25.1 +/- 2.6 %), 2) suppressed left ventricular dilation, smaller scar expansion, and preserved wall thickness of the area at risk and the posterior wall, 3) decreased fibrosis, preserved myocardium in the scar area, and greater number of arterioles in border-zone, 4) tight attachment of SMC sheets on the scarred myocardium, and less apoptotic cell death. In in vitro experiments, SMCs secreted higher amounts of basic fibroblast growth factor (SMC, 157.7 +/- 6.4 pg/ml; DFB, 3.1 +/- 1.0 pg/ml), and showed less apoptotic cell death under hypoxia. CONCLUSIONS: Our results illustrate that transplantation of SMC sheets inhibited the progression of cardiac remodeling and improve cardiac function. These beneficial effects may be due to superior SMC survival. PMID- 27495171 TI - Patient-Centered Outcome Measures to Assess Functioning in Randomized Controlled Trials of Low-Vision Rehabilitation: A Review. AB - Low-vision rehabilitation (LVR) aims to improve the functioning of patients with chronic uncorrectable visual impairment. LVR is inherently a patient-centered intervention since its approach and goals are dictated by the needs and abilities of each individual patient. Accordingly, it is essential to have patient-centered outcome (PCO) measures to assess and compare the efficacy and effectiveness of low-vision interventions; however, there is a lack of evidence on the effectiveness of LVR interventions. We reviewed the literature in order to identify randomized controlled trials (RCTs) in the field of LVR and the outcome measures used to assess patient functioning in these trials. We identified 15 RCTs of LVR that employed nine unique patient-reported, five unique performance based, and one hybrid (combined patient-reported and performance) outcome measures. Since these trials used distinct tools to assess patient functioning, it is difficult to compare the effectiveness of competing rehabilitation interventions across studies. Selecting valid outcome measures that are both relevant to LVR goals of specific patient populations and that measure functioning across a range of visually demanding tasks could improve the ability to detect the effect of LVR and to compare rehabilitation strategies. There are advantages and limitations to the use of both patient-reported and performance based outcome measures, and additional work should be undertaken to explore the relationship between these modes of assessment, as well as strategies for optimally integrating these approaches. Careful selection of outcome measures in the design of future RCTs in LVR may lead to improved understanding of the effectiveness of LVR and, ultimately, to improved functioning of patients with low vision. PMID- 27495172 TI - Inhibition of mouse breast adenocarcinoma growth by ablation with intratumoral alpha-irradiation combined with inhibitors of immunosuppression and CpG. AB - It has been demonstrated that aggressive in situ tumor destruction (ablation) could lead to the release of tumor antigens, which can stimulate anti-tumor immune responses. We developed an innovative method of tumor ablation based on intratumoral alpha-irradiation, diffusing alpha-emitters radiation therapy (DaRT), which efficiently ablates local tumors and enhances anti-tumor immunity. In this study, we investigated the anti-tumor potency of a treatment strategy, which combines DaRT tumor ablation with two approaches for the enhancement of anti-tumor reactivity: (1) neutralization of immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and (2) boost the immune response by the immunoadjuvant CpG. Mice bearing DA3 mammary adenocarcinoma with metastases were treated with DaRT wires in combination with a MDSC inhibitor (sildenafil), Treg inhibitor (cyclophosphamide at low dose), and the immunostimulant, CpG. Combination of all four therapies led to a complete rejection of primary tumors (in 3 out of 20 tumor-bearing mice) and to the elimination of lung metastases. The treatment with DaRT and Treg or MDSC inhibitors (without CpG) also resulted in a significant reduction in tumor size, reduced the lung metastatic burden, and extended survival compared to the corresponding controls. We suggest that the therapy with DaRT combined with the inhibition of immunosuppressive cells and CpG reinforced both local and systemic anti-tumor immune responses and displayed a significant anti-tumor effect in tumor-bearing mice. PMID- 27495173 TI - Orbital myiasis in eviscerated socket and review of literature. AB - Orbital myiasis is a potentially destructive infestation of the orbital tissues. It is uncommon in clinical practice and is seen in patients with poor hygiene with debilitated or immunocompromised state. We report a case of orbital myiasis in an empty socket of an immunocompetent individual. A 65-year-old immunocompetent patient was found to have orbital myiasis in an empty socket status postevisceration, for which he underwent treatment by manual removal of the larvae after application of a suffocating agent, turpentine oil. A total of 12 larvae were removed over the ensuing week. The tissues healed with secondary intention leaving an irregular healthy scar. It was noteworthy that once eviscerated the eye was neglected by the patient. Empty orbital sockets are potential sites for infestations. PMID- 27495174 TI - Non-invasive ventilation for sleep-disordered breathing in Smith-Magenis syndrome. AB - Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterised by behavioural disturbances, intellectual disability and early onset obesity. The physical features of this syndrome are well characterised; however, behavioural features, such as sleep disturbance, are less well understood and difficult to manage. Sleep issues in SMS are likely due to a combination of disturbed melatonin cycle, facial anatomy and obesity-related ventilatory problems. Sleep disorders can be very distressing to patients and their families, as exemplified by our patient's experience, and can worsen behavioural issues as well as general health. This case demonstrates the successful use of non-invasive ventilation in treating underlying obesity hypoventilation syndrome and obstructive sleep apnoea. As a consequence of addressing abnormalities in sleep patterns, some behavioural problems improved. PMID- 27495175 TI - Cor triatriatum sinister with severe obstruction: a rare presentation in an adult. AB - Cor triatriatum sinister is a rare congenital anomaly usually presenting in infancy or childhood. Most cases reported in adulthood have minimal obstruction. A case of critically obstructed cor triatriatum sinister presenting for the first time in adulthood is described here. The characteristic ECG, radiological and echocardiographic findings of this rare anomaly are demonstrated in this case report. The clinical features closely mimic mitral stenosis. The clues to differentiate cor triatriatum from other causes of left ventricular inflow obstruction are described. PMID- 27495176 TI - Transanal endoscopic microsurgery in the management of rectal wall endometriosis. AB - A 29-year-old woman with known history of endometriosis was referred to colorectal outpatient clinic from gynaecology with a history of intermittent rectal bleeding and no associated bowel symptoms. Flexible sigmoidoscopy in concordance with pelvic MRI revealed a 3*2*2 cm sessile lesion in the anterior rectal wall. The lesion was also palpable as a firm mass on digital rectal examination. From the gynaecological point of view no intra-abdominal exploration was required; the sole rectal wall lesion was removed with the minimally invasive surgical technique of transanal endoscopic microsurgery. Full thickness rectal wall excision sample was reported to be histologically complete and confirmed endometriosis. No recurrence was detected at endoscopic follow-up at 6 months. The patient remained symptom free. Therefore, we demonstrated a case of minimally invasive removal of a rectal wall large endometriosis nodule in a fertile woman with a complete, symptomatic, uneventful recovery. PMID- 27495177 TI - Re-emergent tremor in a patient with Parkinson's disease. PMID- 27495178 TI - Systemic sarcoidosis with hypercalcaemia, hypothalamic-pituitary dysfunction and thyroid involvement. AB - Sarcoidosis is a multisystem granulomatous disorder. The lungs are the principal organs affected, however, extrapulmonary involvement including disorders of the pituitary and thyroid glands has been reported but presentation with multiple endocrine manifestations is rare. We report the case of a 36-year-old African American woman who presented with hypercalcaemia, abnormal thyroid function studies and secondary amenorrhoea. On workup including laboratory, radiological testing and biopsy she was diagnosed with sarcoidosis with multi-organ involvement. Endocrine manifestations included non-parathyroid hormone mediated hypercalcaemia related to sarcoidosis, thyroid involvement with sarcoidosis and hypothalamic-pituitary involvement with a sellar and suprasellar mass associated with secondary adrenal insufficiency, secondary hypogonadism, growth hormone deficiency and secondary hypothyroidism. We report to the best of our knowledge the first case of simultaneous multiple endocrine manifestations of sarcoidosis that included hypercalcaemia, hypopituitarism and sarcoidosis of the thyroid gland. PMID- 27495179 TI - The starch-bound alpha-amylase/trypsin-inhibitors in Avena. AB - Oat kernels exhibit an extra-soft texture, a trait recently demonstrated to be largely modulated by starch-bound tryptophan-rich 2S proteins, the vromindolines. In this study, fractionation by two-dimensional electrophoresis of starch-bound proteins in 25 oat (Avena sativa) cultivars and 11 diploid or tetraploid Avena species revealed novel 2S proteins called Avena alpha-amylase/trypsin-inhibitors (AATI) because of their sequence similarity with wheat alpha-amylase/trypsin inhibitors. Thirty-seven AATI polypeptides, about 14 kDa in size, were split into three families named AATI-1, AATI-2, and AATI-3 with different primary structures and isoelectric points. AATI-1 and AATI-2 proteins showed 55.5-60.0 % sequence similarity with wheat alpha-amylase inhibitors CM1, CM2, and CM16, which have been found to cause innate immunity responses in celiac disease and non-celiac gluten sensitivity. Diploid A-genome and tetraploid AC-genome oat species possess three and five genes encoding for the AATI proteins, respectively, whereas hexaploid A. sativa exhibits 12 genes dispersed over the A-, C-, and D-genomes. Some AATI proteins expressed in hexaploid oats were assigned to the A-genome based on similarity to their counterparts in diploid species, contributing to further clarify the genetic origin of hexaploid oats. Moreover, AATI may interact with starch-bound vromindolines in determining the extra-soft texture of oat kernels and, due to their balanced amino acid compositions, may contribute to the biological value of oat proteins in a positive manner. PMID- 27495181 TI - Male-specific risk of first and recurrent venous thrombosis: a phylogenetic analysis of the Y chromosome. AB - : Essentials Men have an unexplained higher risk of a first and recurrent venous thrombosis (VT) than women. We studied the role of the major European Y chromosome haplogroups in first and recurrent VT. In contrast to a study on coronary artery disease, haplogroup I was not linked to VT risk. Haplogroup E carriers may have an increased risk of recurrent VT, but a larger study is needed. SUMMARY: Background The risk of venous thrombosis (VT) recurrence is higher in men than in women. When reproductive risk factors are excluded, this sex difference is also apparent for a first VT. The current explanations for this difference are insufficient. Objectives To study the association between chromosome Y haplogroups and the risks of a first and recurrent VT. Methods Y chromosomes of 3742 men (1729 patients; 2013 controls) from the MEGA case-control study were tracked into haplogroups according to the phylogenetic tree. We calculated the risk of a first VT by comparing the major haplogroups with the most frequent haplogroup. For recurrence risk, 1645 patients were followed for a mean of 5 years, during which 350 developed a recurrence (21%; MEGA follow-up study). We calculated recurrence rates for the major haplogroups, and compared groups by calculating hazard ratios. Results We observed 13 haplogroups, of which R1b was the most frequent (59%). The major haplogroups were not associated with a first VT, with odds ratios ranging from 1.01 to 1.15. Haplogroup E carriers had the highest recurrence rate (53.5 per 1000 person-years, 95% confidence interval [CI] 33.3-86.1), whereas haplogroup R1a carriers had the lowest recurrence rate (24.3 per 1000 person-years, 95% CI 12.6-46.6). As compared with haplogroup R1b carriers, both haplogroups were not significantly associated with recurrence risk. Conclusions In contrast to a study on coronary artery disease, our results do not show a clear predisposing effect of Y haplogroups on first and recurrent VT risk in men. It is therefore unlikely that Y variation can explain the sex difference in VT risk. PMID- 27495184 TI - The Spatial Representation of Angles. AB - We investigated whether angle magnitude, similarly to numerical quantities (i.e., the spatial-numerical association of response codes effect), is associated to the side of response execution. In addition, we investigated whether this association has the properties of a spatially oriented mental line, since angles are taught in a right-to-left progression. We tested two groups of participants: civil engineering students (high familiarity with angles) and psychology students (low familiarity with angles). In Experiment 1, participants were asked to judge the continuity of the angles' arms (continuous vs. dashed). Magnitude of the angles was task-irrelevant. In Experiment 2, they were asked to judge whether the presented angles were smaller or larger than a right angle (90 degrees ). Therefore, the angle magnitude was relevant for performing the task. Overall, engineering students responded faster with their left hand to large angles and with their right hand to small angles. Conversely, psychology students did not show any reliable differences between left- and right-hand responses. In the case of engineering students, the spatial association has a right-to-left (counter clockwise) direction, suggesting the influence of education and practice on the mental representation of angle magnitude. PMID- 27495180 TI - Injectable SN-38-loaded Polymeric Depots for Cancer Chemotherapy of Glioblastoma Multiforme. AB - PURPOSE: SN-38, a potent chemotherapeutic drug, has not been used clinically because of its severe side effects and poor solubility. In this work, we aimed to evaluate the effect of dose and multiple injections of SN-38-loaded polymeric depots on antitumor efficacy and toxicity in vivo. METHODS: Preparation and characterization of SN-38-loaded depots were performed and evaluated in vitro using human glioblastoma cell line, U-87MG. Antitumor efficacy with different depot administrations including dose, position of depot injection and number of injections were evaluated in tumor model in nude mice. RESULTS: Depots encapsulated SN-38 with high encapsulation efficiency (~98.3%). High amount of SN 38 (3.0 +/- 0.1 mg) was prolonged and controlled release over time and showed anticancer activity against U-87MG cell line in vitro. For one course administration, depots exhibited better antitumor efficacy and reduced toxicity compared to free SN-38. Elevated doses and multiple injections of SN-38-loaded depots and free SN-38 provided greater tumor growth inhibition and animal survival. All animals received SN-38-loaded depots were well tolerated and survived while most of those received free SN-38 died at day 30. Free SN-38 showed severe toxic effect compared to minimal toxicity from SN-38-loaded depots which was due to lower SN-38 level in systemic circulation. Fluorescence imaging and histopathology confirmed that SN-38 released from depots was detected throughout tumors 35 days post administration. CONCLUSIONS: SN-38-loaded depots were proved as a promising new treatment for highly invasive glioblastoma multiforme with low acute toxicity due to controlled release of SN-38. PMID- 27495185 TI - Action Video Games Improve Direction Discrimination of Parafoveal Translational Global Motion but Not Reaction Times. AB - Playing action video games enhances visual motion perception. However, there is psychophysical evidence that action video games do not improve motion sensitivity for translational global moving patterns presented in fovea. This study investigates global motion perception in action video game players and compares their performance to that of non-action video game players and non-video game players. Stimuli were random dot kinematograms presented in the parafovea. Observers discriminated the motion direction of a target random dot kinematogram presented in one of the four visual quadrants. Action video game players showed lower motion coherence thresholds than the other groups. However, when the task was performed at threshold, we did not find differences between groups in terms of distributions of reaction times. These results suggest that action video games improve visual motion sensitivity in the near periphery of the visual field, rather than speed response. PMID- 27495186 TI - The effect of a monetary incentive for administrative assistants on the survey response rate: a randomized controlled trial. AB - BACKGROUND: There is sufficient evidence that monetary incentives are effective in increasing survey response rates in the general population as well as with physicians. The objective of this study was to assess the impact of a monetary incentive intended for administrative assistants on the survey response rate of physicians in leadership positions. METHODS: This was an ancillary study to a national survey of chairs of academic Departments of Medicine in the United States about measuring faculty productivity. We randomized survey participants to receive or not receive a $5 gift card enclosed in the survey package. The cover letter explained that the gift card was intended for the administrative assistants as a "thank you for their time." We compared the response rates between the 2 study arms using the Chi-square test. RESULTS: Out of 152 participants to whom survey packages were mailed to, a total of 78 responses were received (51 % response rate). The response rates were 59 % in the incentive arm and 46 % in the no incentive arm. The relative effect of the incentive compared to no monetary incentive was borderline statistically significant (relative risk (RR) = 1.36, 95 % confidence interval (CI) 0.99 to 1.87; p = 0.055). CONCLUSION: Monetary incentives intended for administrative assistants likely increase the response rate of physicians in leadership positions. PMID- 27495187 TI - Intraindividual Analysis of Signal Intensity Changes in the Dentate Nucleus After Consecutive Serial Applications of Linear and Macrocyclic Gadolinium-Based Contrast Agents. AB - PURPOSE: Recent studies reported an increase in the dentate nucleus (DN)-to-pons signal intensity (SI) ratio (DN-pons SI ratio) on unenhanced T1-weighted images in patients who received consecutive serial injections of linear gadolinium-based contrast agents (GBCAs). In contrast, most studies found no increase in the DN pons SI ratio when patients were treated with consecutive serial injections of macrocyclic GBCAs. However, the potential difference between macrocyclic and linear GBCAs has never been assessed in individuals who received subsequent applications of both contrast agents. In this retrospective study, we assessed the evolution of the DN-pons SI ratio change in patients that were treated with a comparable number of serial consecutive injections of the linear GBCA gadopentetate dimeglumine and subsequent serial injections of the macrocyclic GBCAs gadobutrol and gadoterate meglumine. MATERIALS AND METHODS: Data of 36 patients was analyzed. All patients underwent at least 5 consecutive administrations of the linear GBCA gadopentetate dimeglumine followed by an equal number of consecutive administrations of the macrocyclic GBCA gadobutrol. In 12 of the 36 patients, 5 or more final consecutive injections of the macrocyclic GBCA gadoterate meglumine were analyzed additionally. The difference of DN-pons SI ratios on unenhanced T1-weighted images was calculated by subtracting the ratio at the first examination from the ratio at the last examination in each of the 3 periods. RESULTS: The mean DN-pons SI ratio difference in the gadopentetate dimeglumine period was significantly greater than 0 (mean +/- SD, 0.0448 +/- 0.0345; P < 0.001), whereas the mean DN-pons SI ratio difference in the subsequent gadobutrol and gadoterate meglumine period was significantly smaller than 0 (gadobutrol: -0.0178 +/- 0.0459, P = 0.026; gadoterate meglumine: -0.0250 +/- 0.0284, P = 0.011). CONCLUSIONS: In this observational study, the application of the linear GBCA gadopentetate dimeglumine was associated with a DN-pons SI ratio increase, whereas subsequent applications of the macrocyclic GBCAs gadobutrol or gadoterate meglumine in the same patients were not. Rather, the current data tentatively suggest a decrease in preexisting hyperintensities over time when linear GBCAs are changed to macrocyclic GBCAs, potentially indicating a washout effect or precipitation of gadolinium. Future patient studies need to include control groups to replicate the present results, and additional animal studies should be conducted to clarify the underlying mechanism of the proposed SI decrease. PMID- 27495189 TI - High salt intake is associated with a higher risk of cardiovascular events: a 7.2 year evaluation of a cohort of hypertensive patients. AB - BACKGROUND: It is controversial whether high salt intake is directly associated with cardiovascular (CV) events and how far this relation is independent of blood pressure (BP). As Portugal has higher salt consumption and higher mortality by stroke than other European countries, we examined whether salt intake could predict the development of stroke and CV events in a hypertensive population. METHODS: In a longitudinal retrospective study of a cohort of 608 adult treated hypertensive patients 54.1+/-14.3 years of age, BMI 29.3+/-8.3 kg/m, 56.3% women and 17.1% diabetics, we evaluate the long-term prognostic significance of urinary sodium (UNa) excretion measured in 24 h valid samples within the first 3 months after admission along with 24 h ambulatory blood pressure monitoring and pulse wave velocity [(PWV), complior)] measurements. RESULTS: The mean follow-up duration was 7.2 years (0.5-11.1 years), during which 122 CV events occurred including 80 strokes and 36 coronary events. In 608 patients (group A=507 without events and group B=101 with events: 69 strokes, 26 coronary events, six others), the mean 24 h UNa was 208+/-79 mmol/day, corresponding to a salt intake of 12.1+/ 4.6 g/day. Twenty-four hours UNa correlated positively with BMI, PWV and systolic blood pressure (SBP) particularly with night-time SBP. Group B versus A showed higher UNa (260+98 vs. 198+71 mmol/day, P<0.001) and higher PWV, BP office, 24 h, daytime and night-time SBP. Logistic regression analysis identified age, night time SBP and 24 h UNa+ [HR=1.09 (95% CI, 1.06-1.12, P<0.001)] for each 10 mmol increase of UNa+ as the only independent predictors of CV events. UNa+ above the median (189 mmol sodium/day) predicted CV events with HR=2.99 (95% CI, 1.75-5.13, P<0.001) with worse CV event-free survival rates (log rank statistics of 17.44, P<0.001). CONCLUSION: In a cohort of hypertensive patients, high salt intake independently predicts the occurrence of CV events, particularly of stroke. PMID- 27495188 TI - The Use of Acoustic Radiation Force Decorrelation-Weighted Pulse Inversion for Enhanced Ultrasound Contrast Imaging. AB - OBJECTIVES: The use of ultrasound imaging for cancer diagnosis and screening can be enhanced with the use of molecularly targeted microbubbles. Nonlinear imaging strategies such as pulse inversion (PI) and "contrast pulse sequences" (CPS) can be used to differentiate microbubble signal, but often fail to suppress highly echogenic tissue interfaces. This failure results in false-positive detection and potential misdiagnosis. In this study, a novel acoustic radiation force (ARF) based approach was developed for superior microbubble signal detection. The feasibility of this technique, termed ARF decorrelation-weighted PI (ADW-PI), was demonstrated in vivo using a subcutaneous mouse tumor model. MATERIALS AND METHODS: Tumors were implanted in the hindlimb of C57BL/6 mice by subcutaneous injection of MC38 cells. Lipid-shelled microbubbles were conjugated to anti VEGFR2 antibody and administered via bolus injection. An image sequence using ARF pulses to generate microbubble motion was combined with PI imaging on a Verasonics Vantage programmable scanner. ADW-PI images were generated by combining PI images with interframe signal decorrelation data. For comparison, CPS images of the same mouse tumor were acquired using a Siemens Sequoia clinical scanner. RESULTS: Microbubble-bound regions in the tumor interior exhibited significantly higher signal decorrelation than static tissue (n = 9, P < 0.001). The application of ARF significantly increased microbubble signal decorrelation (n = 9, P < 0.01). Using these decorrelation measurements, ADW-PI imaging demonstrated significantly improved microbubble contrast-to-tissue ratio when compared with corresponding CPS or PI images (n = 9, P < 0.001). Contrast-to tissue ratio improved with ADW-PI by approximately 3 dB compared with PI images and 2 dB compared with CPS images. CONCLUSIONS: Acoustic radiation force can be used to generate adherent microbubble signal decorrelation without microbubble bursting. When combined with PI, measurements of the resulting microbubble signal decorrelation can be used to reconstruct images that exhibit superior suppression of highly echogenic tissue interfaces when compared with PI or CPS alone. PMID- 27495190 TI - Blood pressure cuff comparability study. AB - BACKGROUND: Manufacturer-supplied blood pressure (BP) cuffs are part of the automatic oscillometric BP devices algorithm. MATERIALS AND METHODS: This study assessed the differences in BP values using the Omron HEM 907-XL (Omron) device with two types of cuffs: the Baum cuff (BC) and the supplied Omron cuff (OC). A sample of 102 adults participated in the study, 34 per cuff size (adult, large, and extra-large). After a 5-min resting period, three pairs of BP determinations (systolic and diastolic) were taken simultaneously on both arms. One arm was cuffed with a BC and the other arm was cuffed with an OC. The cuffs were switched to opposite arms after 5 min of rest. The order was decided randomly as to which cuff was applied to which arm first. RESULTS: The BP readings were highly correlated between the cuffs (systolic BP, r=0.98; diastolic BP, r=0.98). The overall mean differences (BC-OC) were 2.66 mmHg (SD=3.9 mmHg) for systolic BP (P<0.05) and 0.33 mmHg (SD=2.03 mmHg) for diastolic BP (P>0.05). Increased cuff size corresponded to increased differences in systolic BP values (adult: 1.51 mmHg; large: 2.56 mmHg; and extra-large: 3.9 mmHg; P<0.05). For diastolic BP values, a statistically significant difference was observed only for adult cuff size (difference=1.31 mmHg, SD=1.34 mmHg, P<0.05). CONCLUSION: Using a BC with the Omron could result in higher systolic BP readings and higher diastolic BP readings with the adult cuff size. PMID- 27495191 TI - Hidradenitis suppurativa associated with squamous cell carcinoma: an example of an isoscartopic response. PMID- 27495196 TI - A Kinetic and Nonrigid Approach to Movement Disorders. PMID- 27495197 TI - Diagnosing Parkinson Disease. AB - PURPOSE OF REVIEW: While establishing the diagnosis of Parkinson disease (PD) can be straightforward, it can be challenging in some patients, even for the experienced neurologist. The misdiagnosis rate ranges from 10% to 20% or greater depending on clinician experience. RECENT FINDINGS: Despite promise in the search for a biomarker that can establish the presence of PD and act as a marker of its progression, the diagnosis of PD continues to be based on clinical examination. Core criteria, exclusion criteria, and supportive criteria have been developed to aid the clinician in establishing the diagnosis. Nonmotor symptoms of PD are usually present at the time of diagnosis, may precede motor symptoms, and should be specifically sought during evaluation. Ancillary testing can be appropriate, but its indications and utility must be clearly understood. SUMMARY: The diagnosis of PD requires the recognition of the core features of PD and the differentiation of its clinical presentation from other entities with similar and potentially overlapping symptoms. A careful history and examination guided by clinical diagnostic criteria will usually establish the diagnosis of PD or uncover red flags for the possibilities of other diagnoses. Appropriate selection and interpretation of ancillary testing is critical to avoid misdiagnosis and unnecessary tests. PMID- 27495198 TI - Treating the Motor Symptoms of Parkinson Disease. AB - PURPOSE OF REVIEW: After a patient is diagnosed with Parkinson disease (PD), there are many therapeutic options available. This article provides examples of prototypical patients encountered in clinical practice and illustrates the various pharmacologic and nonpharmacologic treatment options for the motor symptoms of PD. RECENT FINDINGS: Levodopa became available in the late 1960s and remains the gold standard for the treatment of PD even today. Since that time, amantadine, monoamine oxidase type B inhibitors, dopamine agonists, and catechol O-methyltransferase inhibitors have emerged as monotherapy, add-on therapies, or both, in the armamentarium against PD. The most appropriate time to start such drugs remains a clinical decision according to patient symptoms. However, earlier use of levodopa is the more common practice due to its superior benefit and the side effects of dopamine agonists. Deep brain stimulation continues to be the most effective treatment for motor symptoms in appropriate patients, and advances in technology may improve efficacy. New ways to deliver levodopa have emerged (effective extended-release oral preparations and levodopa/carbidopa intestinal gel), and these medications provide additional options for certain patients. Exercise and neurorehabilitation are increasingly recognized as important tools to combat the motor symptoms of PD. Nondopaminergic drugs may help non-levodopa responsive motor symptoms. SUMMARY: Treatment of PD is multifaceted and requires a tailored pharmacotherapeutic and nonpharmacologic approach for a given patient. Patients should be at the center of care, and clinicians should try to provide optimum benefit through the many treatment options available. PMID- 27495192 TI - The inhibitor of semicarbazide-sensitive amine oxidase, PXS-4728A, ameliorates key features of chronic obstructive pulmonary disease in a mouse model. AB - BACKGROUND AND PURPOSE: Chronic obstructive pulmonary disease (COPD) is a major cause of illness and death, often induced by cigarette smoking (CS). It is characterized by pulmonary inflammation and fibrosis that impairs lung function. Existing treatments aim to control symptoms but have low efficacy, and there are no broadly effective treatments. A new potential target is the ectoenzyme, semicarbazide-sensitive mono-amine oxidase (SSAO; also known as vascular adhesion protein-1). SSAO is elevated in smokers' serum and is a pro-inflammatory enzyme facilitating adhesion and transmigration of leukocytes from the vasculature to sites of inflammation. EXPERIMENTAL APPROACH: PXS-4728A was developed as a low MW inhibitor of SSAO. A model of COPD induced by CS in mice reproduces key aspects of human COPD, including chronic airway inflammation, fibrosis and impaired lung function. This model was used to assess suppression of SSAO activity and amelioration of inflammation and other characteristic features of COPD. KEY RESULTS: Treatment with PXS-4728A completely inhibited lung and systemic SSAO activity induced by acute and chronic CS-exposure. Daily oral treatment inhibited airway inflammation (immune cell influx and inflammatory factors) induced by acute CS-exposure. Therapeutic treatment during chronic CS-exposure, when the key features of experimental COPD develop and progress, substantially suppressed inflammatory cell influx and fibrosis in the airways and improved lung function. CONCLUSIONS AND IMPLICATIONS: Treatment with a low MW inhibitor of SSAO, PXS 4728A, suppressed airway inflammation and fibrosis and improved lung function in experimental COPD, demonstrating the therapeutic potential of PXS-4728A for this debilitating disease. PMID- 27495199 TI - Neuropsychiatric Issues in Parkinson Disease. AB - PURPOSE OF REVIEW: This article reviews the recognition and management of neuropsychiatric issues in Parkinson disease (PD), including mood disorders, cognitive impairment, and behavioral disturbances. RECENT FINDINGS: Patients with PD frequently develop neuropsychiatric issues, and these issues can greatly affect their quality of life. In recent years, mood, cognitive, and behavioral issues in PD have received greater recognition, with increasing attention directed toward improved screening and therapeutic interventions for symptomatic treatment. Taken together as a group, neuropsychiatric issues can be found throughout the whole course of PD, from early in the disease, potentially even in a premotor stage, to the time of diagnosis and later in the course with more advanced disease. SUMMARY: In the comprehensive care of patients with PD, recognition of neuropsychiatric issues is critical. Advances in therapeutics for the different neuropsychiatric symptoms are still needed, although several pharmacologic and nonpharmacologic options are available. Patient management frequently requires a multidisciplinary approach, with collaboration of neurologists with neuropsychologists, psychologists, psychiatrists, and other health professionals. PMID- 27495200 TI - Treatment of Advanced Parkinson Disease and Related Disorders. AB - PURPOSE OF REVIEW: Parkinson disease often spans decades of a patient's lifetime. Over time, nonmotor symptoms predominate and may limit dopaminergic therapy. Neurologists continue to play a vital role in treatment. In addition to balancing neurobehavioral complications of Parkinson disease with motor benefit, addressing nonmotor symptoms common in the advanced stage may improve quality of life and reduce symptom burden. Symptoms such as dysphagia, constipation, urinary dysfunction, orthostatic hypotension, and pain respond to nonpharmacologic and pharmacologic therapies. RECENT FINDINGS: Evidence for treatment of many nonmotor symptoms is weak or lacking. The evidence for treatment of the atypical parkinsonian syndromes (progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration) in advanced stages is even more scant. SUMMARY: Engaging palliative care physicians in the joint care of patients can provide patients with access to expertise in end-of-life issues. Neurologic illnesses have specific hospice criteria to guide clinicians for referrals. Evidence supports that assisting patients with advance directives can result in improved satisfaction with care and improved quality of life in the last weeks of life. Neurologists can remain engaged in their patients' care throughout the course of illness. PMID- 27495202 TI - Diagnosis and Management of Tremor. AB - PURPOSE OF REVIEW: Tremor, which is a rhythmic oscillation of a body part, is among the most common involuntary movements. Rhythmic oscillations may manifest in a variety of ways; as a result, a rich clinical phenomenology surrounds tremor. For this reason, diagnosing tremor disorders can be particularly challenging. The aim of this article is to provide the reader with a straightforward approach to the diagnosis and management of patients with tremor. RECENT FINDINGS: Scientific understanding of the pathophysiologic basis of tremor disorders has grown considerably in recent years with the use of a broad range of neuroimaging approaches and rigorous, controlled postmortem studies. The basal ganglia and cerebellum are structures that seem to play a prominent role. SUMMARY: The diagnosis of tremor disorders is challenging. The approach to tremor involves a history and a neurologic examination that is focused on the nuances of tremor phenomenology, of which there are many. The evaluation should begin with a tremor history and a focused neurologic examination. The examination should attend to the many subtleties of tremor phenomenology. Among other things, the history and examination are used to establish whether the main type of tremor is an action tremor (ie, postural, kinetic, or intention tremor) or a resting tremor. The clinician should then formulate two sets of differential diagnoses: disorders in which action tremor is the predominant tremor versus those in which resting tremor is the main tremor. Among the most common of the former type are essential tremor, enhanced physiologic tremor, drug-induced tremor, dystonic tremor, orthostatic tremor, and cerebellar tremor. Parkinson disease is the most common form of resting tremor, along with drug-induced resting tremor. This article details the clinical features of each of these as well as other tremor disorders. PMID- 27495201 TI - Diagnostic Approach to Atypical Parkinsonian Syndromes. AB - PURPOSE OF REVIEW: Although increasingly recognized, atypical parkinsonian syndromes remain challenging to diagnose and are underrecognized due to overlap with other parkinsonisms. This article provides a diagnostic approach to atypical parkinsonian syndromes, including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and dementia with Lewy bodies. The goal of this review is to aid the clinician in recognizing key clinical and pathologic features and to raise awareness of recent advances in diagnostics and treatment. RECENT FINDINGS: Diagnostic criteria for atypical parkinsonian syndromes are evolving to encompass increasingly recognized heterogeneity in the presentation of these disorders and information gleamed from clinicopathologic correlations. PSP and CBD in particular now share similar pathologic clinical features and include a number of phenotypic variants. Pathologic diagnoses are increasingly used in clinical practice, and there is frequent reference now by clinicians to tauopathies, including PSP and CBD, and the synucleinopathies, which include MSA and dementia with Lewy bodies (as well as Parkinson disease). Research into biomarkers, including both tissue and imaging modalities and genetics, has the potential to increase disease recognition and make earlier diagnosis and treatment possible. Although novel therapeutics are being studied for atypical parkinsonian syndromes such as PSP, no new breakthrough interventions have emerged for the treatment of PSP, CBD, and MSA. Current therapeutic management for these disorders frequently uses a multidisciplinary team approach. SUMMARY: The approach to atypical parkinsonian syndromes requires recognition of a constellation of overlapping but distinct clinical features that help with identifying and distinguishing them from Parkinson disease and other similar disorders. PMID- 27495203 TI - Movement Disorders Presenting in Childhood. AB - PURPOSE OF REVIEW: This article provides an overview of movement disorders that present in childhood. Key clinical features are discussed, and a brief guide to management strategies is provided. Recent advances in the field of pediatric movement disorders are also a focus of the article. RECENT FINDINGS: Advances in genetic technologies and cell biology have contributed greatly to the elucidation of underlying disease mechanisms in childhood movement disorders. This article discusses the expanding spectrum of both genetic and acquired movement disorders that present in childhood, including benign, acquired, genetic, and psychogenic movement disorders. SUMMARY: Movement disorders in childhood comprise a wide spectrum of both genetic and acquired diseases, ranging from benign self-limiting conditions to more progressive phenotypes associated with significant morbidity and mortality. Elucidation of the underlying cause is achieved through accurate history, detailed clinical examination, review of video footage (including home videos), and, where appropriate, neuroimaging and laboratory investigations. Early accurate diagnosis will facilitate the instigation of appropriate management strategies. PMID- 27495204 TI - Chorea. AB - PURPOSE OF REVIEW: This article reviews the clinical approach to the diagnosis of adult patients presenting with chorea, using Huntington disease (HD) as a point of reference, and presents the clinical elements that help in the diagnostic workup. Principles of management for chorea and some of the associated features of other choreic syndromes are also described. RECENT FINDINGS: Mutations in the C9orf72 gene, previously identified in families with a history of frontotemporal dementia, amyotrophic lateral sclerosis, or both, have been recognized as one of the most prevalent causes of HD phenocopies in the white population. SUMMARY: The diagnosis of chorea in adult patients is challenging. A varied number of associated causes require a physician to prioritize the investigations, and a detailed history of chorea and associated findings will help. For chorea presenting as part of a neurodegenerative syndrome, the consideration of a mutation in the C9orf72 gene is a new recommendation after excluding HD. There are no new treatment options for chorea, aside from dopamine blockers and tetrabenazine. There are no disease-modifying treatments for HD or other neurodegenerative choreic syndromes. PMID- 27495205 TI - Ataxia. AB - PURPOSE OF REVIEW: This article introduces the background and common etiologies of ataxia and provides a general approach to assessing and managing the patient with ataxia. RECENT FINDINGS: Ataxia is a manifestation of a variety of disease processes, and an underlying etiology needs to be investigated. Pure ataxia is rare in acquired ataxia disorders, and associated symptoms and signs almost always exist to suggest an underlying cause. While the spectrum of hereditary degenerative ataxias is expanding, special attention should be addressed to those treatable and reversible etiologies, especially potentially life-threatening causes. This article summarizes the diseases that can present with ataxia, with special attention given to diagnostically useful features. While emerging genetic tests are becoming increasingly available for hereditary ataxia, they cannot replace conventional diagnostic procedures in most patients with ataxia. Special consideration should be focused on clinical features when selecting a cost effective diagnostic test. SUMMARY: Clinicians who evaluate patients with ataxia should be familiar with the disease spectrum that can present with ataxia. Following a detailed history and neurologic examination, proper diagnostic tests can be designed to confirm the clinical working diagnosis. PMID- 27495206 TI - Diagnosis and Management of Dystonia. AB - PURPOSE OF REVIEW: This article highlights the clinical and diagnostic tools used to assess and classify dystonia and provides an overview of the treatment approach. RECENT FINDINGS: In the past 4 years, the definition and classification of dystonia have been revised, and new genes have been identified in patients with isolated hereditary dystonia (DYT23, DYT24, and DYT25). Expanded phenotypes were reported in patients with combined dystonia, such as those with mutations in ATP1A3. Treatment offerings have expanded as there are more neurotoxins, and deep brain stimulation has been employed successfully in diverse populations of patients with dystonia. SUMMARY: Diagnosis of dystonia rests upon a clinical assessment that requires the examiner to understand the characteristic disease features that are elicited through a careful history and physical examination. The revised classification system uses two distinct nonoverlapping axes: clinical features and etiology. A growing understanding exists of both isolated and combined dystonia as new genes are identified and our knowledge of the phenotypic presentation of previously reported genes has expanded. Genetic testing is commercially available for some of these conditions. Treatment options for dystonia include pharmacologic therapy, chemodenervation, and surgical intervention. Deep brain stimulation benefits many patients with various types of dystonia. PMID- 27495207 TI - Wilson Disease. AB - PURPOSE OF REVIEW: This article reviews the clinical features of Wilson disease, focusing on the neurologic and psychiatric abnormalities, and addresses the diagnostic workup and treatment approaches to managing the disease. RECENT FINDINGS: The list of known mutations causing Wilson disease continues to grow, but advances in genetic testing may soon make it feasible to routinely perform genetic testing on individuals suspected of having Wilson disease. SUMMARY: Wilson disease is a rare genetic disorder with protean manifestations that should be considered in the differential diagnosis of any individual presenting with unexplained neurologic, psychiatric, or hepatic dysfunction. Appropriate diagnostic testing should be expeditiously performed and treatment promptly initiated and maintained since failure to diagnose and treat Wilson disease will result in progressive and ultimately irreversible damage to the neurologic and other systems. PMID- 27495208 TI - Ethics of Preclinical Dopamine Transporter Imaging. AB - While dopamine transporter single-photon emission computed tomography (DAT-SPECT) imaging is sensitive and specific when performed in patients with signs or symptoms of parkinsonism, its predictive value is uncertain in healthy subjects, even with patients who have first-degree relatives affected by Parkinson disease. In deciding whether to honor a patient's request for a DAT-SPECT, neurologists must balance a patient's autonomy rights with beneficence and nonmaleficence and also consider the distributive justice implications of ordering the test. Generally speaking, the benefits of a DAT-SPECT will be too small to justify its use in an asymptomatic patient concerned about developing Parkinson disease. PMID- 27495209 TI - Chemodenervation Coding for Neurologists. PMID- 27495213 TI - Patient Management Problem. PMID- 27495214 TI - Patient Management Problem-Preferred Responses. PMID- 27495216 TI - NICE calls for wider supply of condoms to reduce STIs. PMID- 27495217 TI - Diagnostic hepatic haemodynamic techniques: safety and radiation exposure. AB - BACKGROUND & AIMS: Hepatic venous pressure gradient (HVPG) and transjugular liver biopsy (TJLB) are increasingly used in the management of patients with liver disease. We aimed to describe the safety profile of these procedures, providing data on the intra- and periprocedure complications, radiation exposure and amount of iodinated contrast material used. METHODS: In 106 consecutive patients undergoing HVPG and TJLB data on fluoroscopy time (FT), absorbed radiation dose, equivalent effective dose (mSv) and volume of iodinated contrast material (ICM) were prospectively collected and reviewed, together with clinical and laboratory data. Incidence and severity of procedure-related complications were assessed. In 28 hospitalised patients, creatinine values after 72 hours of the procedure were reviewed to identify contrast-induced nephropathy (CIN). RESULTS: Median effective radiation dose was 5.4 mSv (IQR 10 mSv). A total 28.3% of patients exceeded an effective exposure of 10 mSv and 9.4% exceeded 20 mSv. Only age and BMI correlated with radiation dose (R = .327, P=.001 and R = .410, P<.0001 respectively), and only BMI remained independently associated with an exposure over 20 mSv. Procedure-related complications occurred in eight patients (7.5%), and were minor in six cases. Median ICM volume was 12.5 mL. 6/28 patients met the diagnostic criteria for CIN. CONCLUSIONS: Hepatic venous pressure gradient and Transjugular liver biopsy show a good safety profile and radiation exposure associated with these procedures is in most of the cases low. In hepatic haemodynamic procedures, efforts should be made to reduce the radiation dose in patients with overweight/obesity and to use the minimal possible ICM volume in patients with acute-on-chronic liver failure. PMID- 27495218 TI - Status epilepticus alters hippocampal long-term synaptic potentiation in a rat lithium-pilocarpine model. AB - Seizure-induced memory deficits are frequent in patients with temporal lobe epilepsy. However, the neural mechanisms responsible for this memory impairment are not entirely clear. Persistent changes in synaptic efficacy, long-term potentiation (LTP), and depression are considered a cellular substrate underlying the learning and memory processes. Using a lithium-pilocarpine model to induce status epilepticus (SE) in rats, the present study investigated whether the induction of LTP was altered in hippocampal slices obtained 3 h, 1, 3, and 7 days after SE. One week after SE, LTP induction was decreased in hippocampal slices. The reduced plasticity in post-SE tissue was attributable to N-methyl-D-aspartate receptor-dependent LTP. In contrast to control tissue, ifenprodil, a GluN2B selective antagonist, did not reduce the LTP level in post-SE tissue, suggesting that SE disturbs the functional properties of GluN2B-containing N-methyl-D aspartate receptors. These changes in synaptic transmission may contribute toward the genesis of epilepsy and seizure-associated memory deficits. PMID- 27495219 TI - Cathodal transcranial direct current stimulation of the posterior parietal cortex reduces steady-state postural stability during the effect of light touch. AB - Touching a stable object with a fingertip using slight force (<1 N) stabilizes standing posture independent of mechanical support, which is referred to as the effect of light touch (LT). In the neural mechanism of the effect of LT, the specific contribution of the cortical brain activity toward the effect of LT remains undefined, particularly the contribution toward steady-state postural sway. The aim of the present study was to investigate the cortical region responsible for the reduction of postural sway in response to the effect of LT. Active LT was applied with the right fingertip and transcranial direct current stimulation (sham or cathodal) was applied to the left primary sensorimotor cortex or the left posterior parietal cortex in the two groups. The experiments were conducted using a single-blind sham-controlled crossover design. Steady state postural sway was compared with the factors of transcranial direct current stimulation (sham or cathodal) and time (pre or post). In the results, the effect of LT reduced postural stability in the mediolateral direction after cathodal transcranial direct current stimulation of the left posterior parietal cortex. No effect was observed after stimulation of the left primary sensorimotor cortex. This indicates that the left posterior parietal cortex is partly responsible for the effect of LT when touching a fixed point with the right fingertip during suprapostural tasks, where posture is adjusted according to the precision requirements. Cortical processing of sensory integration for voluntary postural orientation in response to touch occurs in the posterior parietal cortex. PMID- 27495220 TI - Renal Denervation Reverses Hepatic Insulin Resistance Induced by High-Fat Diet. AB - Activation of the sympathetic nervous system (SNS) constitutes a putative mechanism of obesity-induced insulin resistance. Thus, we hypothesized that inhibiting the SNS by using renal denervation (RDN) will improve insulin sensitivity (SI) in a nonhypertensive obese canine model. SI was measured using euglycemic-hyperinsulinemic clamp (EGC), before (week 0 [w0]) and after 6 weeks of high-fat diet (w6-HFD) feeding and after either RDN (HFD + RDN) or sham surgery (HFD + sham). As expected, HFD induced insulin resistance in the liver (sham 2.5 +/- 0.6 vs. 0.7 +/- 0.6 * 10-4 dL ? kg-1 ? min-1 ? pmol/L-1 at w0 vs. w6-HFD [P < 0.05], respectively; HFD + RDN 1.6 +/- 0.3 vs. 0.5 +/- 0.3 * 10-4 dL ? kg-1 ? min-1 ? pmol/L-1 at w0 vs. w6-HFD [P < 0.001], respectively). In sham animals, this insulin resistance persisted, yet RDN completely normalized hepatic SI in HFD-fed animals (1.8 +/- 0.3 * 10-4 dL ? kg-1 ? min-1 ? pmol/L-1 at HFD + RDN [P < 0.001] vs. w6-HFD, [P not significant] vs. w0) by reducing hepatic gluconeogenic genes, including G6Pase, PEPCK, and FOXO1. The data suggest that RDN downregulated hepatic gluconeogenesis primarily by upregulating liver X receptor alpha through the natriuretic peptide pathway. In conclusion, bilateral RDN completely normalizes hepatic SI in obese canines. These preclinical data implicate a novel mechanistic role for the renal nerves in the regulation of insulin action specifically at the level of the liver and show that the renal nerves constitute a new therapeutic target to counteract insulin resistance. PMID- 27495222 TI - Impaired Cardiolipin Biosynthesis Prevents Hepatic Steatosis and Diet-Induced Obesity. AB - Mitochondria are the nexus of energy metabolism, and consequently their dysfunction has been implicated in the development of metabolic complications and progression to insulin resistance and type 2 diabetes. The unique tetra-acyl phospholipid cardiolipin (CL) is located in the inner mitochondrial membrane, where it maintains mitochondrial integrity. Here we show that knockdown of Tafazzin (TAZ kd), a CL transacylase, in mice results in protection against the development of obesity, insulin resistance, and hepatic steatosis. We determined that hypermetabolism protected TAZ kd mice from weight gain. Unexpectedly, the large reduction of CL in the heart and skeletal muscle of TAZ kd mice was not mirrored in the liver. As a result, TAZ kd mice exhibited normal hepatic mitochondrial supercomplex formation and elevated hepatic fatty acid oxidation. Collectively, these studies identify a key role for hepatic CL remodeling in regulating susceptibility to insulin resistance and as a novel therapeutic target for diet-induced obesity. PMID- 27495221 TI - Enhanced Integrin alpha4beta1-Mediated Adhesion Contributes to a Mobilization Defect of Endothelial Progenitor Cells in Diabetes. AB - Diabetes is associated with a deficit of circulating endothelial progenitor cells (EPCs), which has been attributed to their defective mobilization from the bone marrow. The basis for this mobilization defect is not completely understood, and we sought to determine if hyperglycemic conditions enhanced EPC adhesion. We found that culturing EPCs in high glucose media increased adhesion to bone marrow stromal cells. This enhanced adhesion was associated with decreased expression of protein kinase A regulatory subunit 1beta (PRKAR1beta), activation of protein kinase A (PKA), and phosphorylation of alpha4-integrin on serine 988. This potentiated adhesion was reversed by treatment with a PKA inhibitor, overexpression of PRKAR1beta, or expression of a phosphorylation-defective alpha4 integrin variant (alpha4[S988A]). Using a model of type 1 diabetes, we showed that alpha4(S988A)-expressing mice have more circulating EPCs than their wild type counterparts. Moreover, diabetic alpha4(S988A) mice demonstrate enhanced revascularization after hind limb ischemia. Thus, we have identified a novel signaling mechanism activating PKA in diabetes (downregulation of an inhibitory regulatory subunit) that leads to deficits of circulating EPCs and impaired vascular repair, which could be reversed by alpha4-integrin mutation. PMID- 27495223 TI - MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase-Mediated Gluconeogenesis. AB - MicroRNAs (miRNAs) are a new class of regulatory molecules implicated in type 2 diabetes, which is characterized by insulin resistance and hepatic glucose overproduction. We show that miRNA-451 (miR-451) is elevated in the liver tissues of dietary and genetic mouse models of diabetes. Through an adenovirus-mediated gain- and loss-of-function study, we found that miR-451 negatively regulates hepatic gluconeogenesis and blood glucose levels in normal mice and identified glycerol kinase (Gyk) as a direct target of miR-451. We demonstrate that miR-451 and Gyk regulate hepatic glucose production, the glycerol gluconeogenesis axis, and the AKT-FOXO1-PEPCK/G6Pase pathway in an opposite manner; Gyk could reverse the effect of miR-451 on hepatic gluconeogenesis and AKT-FOXO1-PEPCK/G6Pase pathway. Moreover, overexpression of miR-451 or knockdown of Gyk in diabetic mice significantly inhibited hepatic gluconeogenesis, alleviated hyperglycemia, and improved glucose tolerance. Further studies showed that miR-451 is upregulated by glucose and insulin in hepatocytes; the elevation of hepatic miR-451 in diabetic mice may contribute to inhibiting Gyk expression. This study provides the first evidence that miR-451 and Gyk regulate the AKT-FOXO1-PEPCK/G6Pase pathway and play critical roles in hepatic gluconeogenesis and glucose homeostasis and identifies miR-451 and Gyk as potential therapeutic targets against hyperglycemia in diabetes. PMID- 27495224 TI - Peripheral Proinsulin Expression Controls Low-Avidity Proinsulin-Reactive CD8 T Cells in Type 1 Diabetes. AB - Low-avidity autoreactive CD8 T cells (CTLs) escape from thymic negative selection, and peripheral tolerance mechanisms are essential for their regulation. We report the role of proinsulin (PI) expression on the development and activation of insulin-specific CTLs in the NOD mouse model of type 1 diabetes. We studied insulin B-chain-specific CTL from different T-cell receptor transgenic mice (G9Calpha-/-) expressing normal PI1 and PI2 or altered PI expression levels. In the absence of PI2 (Ins2-/-), CTL in pancreatic lymph nodes (PLNs) were more activated, and male G9Calpha-/- mice developed T1D. Furthermore, when the insulin-specific CTLs developed in transgenic mice lacking their specific PI epitope, the CTLs demonstrated increased cytotoxicity and proliferation in vitro and in vivo in the PLNs after adoptive transfer into NOD recipients. Dendritic cell-stimulated proliferation of insulin-specific T cells was reduced in the presence of lymph node stromal cells (LNSCs) from NOD mice but not from mice lacking the PI epitope. Our study shows that LNSCs regulate CTL activation and suggests that exposure to PI in the periphery is very important in maintenance of tolerance of autoreactive T cells. This is relevant for human type 1 diabetes and has implications for the use of antigen-specific therapy in tolerance induction. PMID- 27495225 TI - Reduced beta-Cell Secretory Capacity in Pancreatic-Insufficient, but Not Pancreatic-Sufficient, Cystic Fibrosis Despite Normal Glucose Tolerance. AB - Patients with pancreatic-insufficient cystic fibrosis (PI-CF) are at increased risk for developing diabetes. We determined beta-cell secretory capacity and insulin secretory rates from glucose-potentiated arginine and mixed-meal tolerance tests (MMTTs), respectively, in pancreatic-sufficient cystic fibrosis (PS-CF), PI-CF, and normal control subjects, all with normal glucose tolerance, in order to identify early pathophysiologic defects. Acute islet cell secretory responses were determined under fasting, 230 mg/dL, and 340 mg/dL hyperglycemia clamp conditions. PI-CF subjects had lower acute insulin, C-peptide, and glucagon responses compared with PS-CF and normal control subjects, indicating reduced beta-cell secretory capacity and alpha-cell function. Fasting proinsulin-to-C peptide and proinsulin secretory ratios during glucose potentiation were higher in PI-CF, suggesting impaired proinsulin processing. In the first 30 min of the MMTT, insulin secretion was lower in PI-CF compared with PS-CF and normal control subjects, and glucagon-like peptide 1 and gastric inhibitory polypeptide were lower compared with PS-CF, and after 180 min, glucose was higher in PI-CF compared with normal control subjects. These findings indicate that despite "normal" glucose tolerance, adolescents and adults with PI-CF have impairments in functional islet mass and associated early-phase insulin secretion, which with decreased incretin responses likely leads to the early development of postprandial hyperglycemia in CF. PMID- 27495226 TI - A Direct Comparison of Metabolic Responses to High-Fat Diet in C57BL/6J and C57BL/6NJ Mice. AB - Although nicotinamide nucleotide transhydrogenase (NNT)-deficient C57BL/6J (6J) mice are known to be highly susceptible to diet-induced metabolic disease, this notion stems primarily from comparisons of 6J mice to other inbred strains. To date, very few studies have directly compared metabolic disease susceptibility between NNT-deficient 6J mice and NNT-competent C57BL/6 substrains. In this study, comprehensive profiling of the metabolic response to a high-fat/high sucrose diet (HFD) were compared across time in 6J and C57BL/6NJ (6N) mice. Given that increased peroxide exposure drives insulin resistance, coupled with the fact that NNT regulates peroxide detoxification, it was hypothesized that 6J mice would experience greater derangements in redox homeostasis/metabolic disease upon HFD exposure. Contrary to this, both lines were found to be highly susceptible to diet-induced metabolic disease, as evidenced by impairments in glucose tolerance as early as 24 h into the HFD. Moreover, various markers of the metabolic syndrome, as well as peroxide stress, were actually blunted, rather than exacerbated, in the 6J mice, likely reflecting compensatory increases in alterative redox-buffering pathways. Together, these data provide evidence that the susceptibility to HFD-induced metabolic disease is similar in the 6J and 6N substrains. Given the numerous genetic variances in the 6J stain, including loss of NNT function, these findings suggest that the 6N substrain is the more logical and representative genetic background model for metabolic studies. PMID- 27495227 TI - Chemical disguise of myrmecophilous cockroaches and its implications for understanding nestmate recognition mechanisms in leaf-cutting ants. AB - BACKGROUND: Cockroaches of the genus Attaphila regularly occur in leaf-cutting ant colonies. The ants farm a fungus that the cockroaches also appear to feed on. Cockroaches disperse between colonies horizontally (via foraging trails) and vertically (attached to queens on their mating flights). We analysed the chemical strategies used by the cockroaches to integrate into colonies of Atta colombica and Acromyrmex octospinosus. Analysing cockroaches from nests of two host species further allowed us to test the hypothesis that nestmate recognition is based on an asymmetric mechanism. Specifically, we test the U-present nestmate recognition model, which assumes that detection of undesirable cues (non-nestmate specific substances) leads to strong rejection of the cue-bearers, while absence of desirable cues (nestmate-specific substances) does not necessarily trigger aggression. RESULTS: We found that nests of Atta and Acromyrmex contained cockroaches of two different and not yet described Attaphila species. The cockroaches share the cuticular chemical substances of their specific host species and copy their host nest's colony-specific cuticular profile. Indeed, the cockroaches are accepted by nestmate but attacked by non-nestmate ant workers. Cockroaches from Acromyrmex colonies bear a lower concentration of cuticular substances and are less likely to be attacked by non-nestmate ants than cockroaches from Atta colonies. CONCLUSIONS: Nest-specific recognition of Attaphila cockroaches by host workers in combination with nest-specific cuticular chemical profiles suggest that the cockroaches mimic their host's recognition labels, either by synthesizing nest-specific substances or by substance transfer from ants. Our finding that the cockroach species with lower concentration of cuticular substances receives less aggression by both host species fully supports the U-present nestmate recognition model. Leaf-cutting ant nestmate recognition is thus asymmetric, responding more strongly to differences than to similarities. PMID- 27495228 TI - Unsuspected pulmonary embolism: a diagnostic dilemma. PMID- 27495229 TI - The role and impact of research positions within health care settings in allied health: a systematic review. AB - BACKGROUND: Embedding dedicated research positions within healthcare settings is a potential strategy to build allied health research capacity, with different health care organisations investing in such positions. The aim of this review was to gather evidence regarding the nature of the role of the research position in allied health professional (AHP) healthcare settings and the impact that these positions have on building research capacity. METHODS: A systematic review was undertaken searching eight databases (Medline CINAHL, Cochrane, OTSeeker, Speechbite, PEDro, Web of Science, and Proquest) using English language restrictions. Both authors independently screened abstracts, reviewed full-text articles, extracted data and performed quality assessments using the Mixed Methods Appraisal Tool. Studies were included that reported the evaluation and/or components of the role of a dedicated research position with AHPs in any healthcare setting. A thematic analysis approach was used to synthesise findings. RESULTS: A total of 360 abstracts were initially screened, with 58 full text articles being reviewed. Eight unique studies were included in the thematic analysis clarifying either the nature of role of the research position (n = 7) or impact of the position (n = 4). Studies included mixed methods (n = 3), descriptive case study (n = 4), and observational (n = 1) designs. The majority of studies reported the research positions to provide academic support to individual clinicians and their teams, while developing their own research projects. Other studies reported support for research capacity building at a service and organisational level. Positive changes from these research positions was reported via increased individual research skills and participation and research outputs, improvements in research culture, attitudes and team and organisational level skills. CONCLUSION: Emerging evidence suggests that research positions embedded within healthcare settings can influence individual and team based research skills and research participation of AHPs. Future research is needed to further investigate the sustainability of changes arisen from research positions and what mechanisms of the positions have the greatest impact. Healthcare managers should consider how to support potential components of the research position roles identified in the literature, as well consider evaluating their impact on research capacity, cultural and attitudinal changes of AHP staff in addition to traditional research metrics. PMID- 27495231 TI - FGF9, activin and TGFbeta promote testicular characteristics in an XX gonad organ culture model. AB - Testis development is dependent on the key sex-determining factors SRY and SOX9, which activate the essential ligand FGF9. Although FGF9 plays a central role in testis development, it is unable to induce testis formation on its own. However, other growth factors, including activins and TGFbetas, also present testis during testis formation. In this study, we investigated the potential of FGF9 combined with activin and TGFbeta to induce testis development in cultured XX gonads. Our data demonstrated differing individual and combined abilities of FGF9, activin and TGFbeta to promote supporting cell proliferation, Sertoli cell development and male germ line differentiation in cultured XX gonads. FGF9 promoted proliferation of supporting cells in XX foetal gonads at rates similar to those observed in vivo during testis cord formation in XY gonads but was insufficient to initiate testis development. However, when FGF9, activin and TGFbeta were combined, aspects of testicular development were induced, including the expression of Sox9, morphological reorganisation of the gonad and deposition of laminin around germ cells. Enhancing beta-catenin activity diminished the testis promoting activities of the combined growth factors. The male promoting activity of FGF9 and the combined growth factors directly or indirectly extended to the germ line, in which a mixed phenotype was observed. FGF9 and the combined growth factors promoted male germ line development, including mitotic arrest, but expression of pluripotency genes was maintained, rather than being repressed. Together, our data provide evidence that combined signalling by FGF9, activin and TGFbeta can induce testicular characteristics in XX gonads. PMID- 27495230 TI - Spatiotemporal dynamics of OCT4 protein localization during preimplantation development in mice. AB - Spatiotemporal expression of transcription factors is crucial for genomic reprogramming. Pou5f1 (Oct4) is an essential transcription factor for reprogramming. A recent study reported that OCT4A, which is crucial for establishment and maintenance of pluripotent cells, is expressed in oocytes, but maternal OCT4A is dispensable for totipotency induction. Whereas another study reported that OCT4B, which is not related to pluripotency, is predominantly expressed instead of OCT4A during early preimplantation phases in mice. To determine the expression states of OCT4 in murine preimplantation embryos, we conducted in-depth expression and functional analyses. We found that pluripotency related OCT4 mainly localizes to the cytoplasm in early preimplantation phases, with no major nuclear localization until the 8-16-cell stage despite high expression in both oocytes and early embryos. RNA-sequencing analysis using oocytes and early preimplantation embryos could not identify the splice variants creating alternative forms of OCT4 protein. Forced expression of OCT4 in zygotes by the injection of polyadenylated mRNA clearly showed nuclear localization of OCT4 protein around 3-5-fold greater than physiological levels and impaired developmental competency in a dose-dependent manner. Embryos with modest overexpression of OCT4 could develop to the 16-cell stage; however, more than 50% of the embryos were arrested at this stage, similar to the results for OCT4 depletion. In contrast, extensive overexpression of OCT4 resulted in complete arrest at the 2-cell stage accompanied by downregulation of zygotically activated genes and repetitive elements related to the totipotent state. These results demonstrated that OCT4 protein localization was spatiotemporally altered during preimplantation development, and strict control of Oct4 protein levels was essential for proper totipotential reprogramming. PMID- 27495232 TI - Quercetin modulates Wnt signaling components in prostate cancer cell line by inhibiting cell viability, migration, and metastases. AB - Epithelial-mesenchymal transition (EMT) is a plastic transition in tumor progression during which cancer cells undergo dramatic changes acquiring highly invasive properties. Transforming growth factor-beta (TGF-beta) is an inducer of EMT in epithelial cells and is obligatory for acquiring invasive phenotype in carcinoma. TGF-beta plays a vital role in metastasis and tumorigenesis in prostate cancer, and mutations in the components of Wnt signaling pathways are associated with various kinds of cancers including prostate cancer. The purpose of this study was to identify alterations in Wnt signaling pathway components involved during prostate cancer progression and to determine the effect of quercetin on TGF-beta-induced EMT in prostate cancer (PC-3) cell line. The expression of epithelial and mesenchymal markers and the components of Wnt signaling pathway were evaluated by real-time polymerase chain reaction. It was observed that quercetin prevented TGF-beta-induced expression of vimentin and N cadherin and increased the expression of E-cadherin in PC-3 cells, thus preventing TGF-beta-induced EMT. Furthermore, the relative expression of Twist, Snail, and Slug showed that quercetin significantly decreased TGF-beta-induced expression of Twist, Snail, and Slug. In the present study, the expression of epithelial markers were found to be upregulated in naive state and downregulated in induced state whereas the mesenchymal markers were found to be downregulated in naive state and upregulated in induced state. Thus, our study concludes that quercetin may prevent prostate cancer metastasis by regulating the components of Wnt pathway. PMID- 27495234 TI - Developments in the practice of physician-assisted dying: perceptions of physicians who had experience with complex cases. AB - BACKGROUND: Since the enactment of the euthanasia law in the Netherlands, there has been a lively public debate on assisted dying that may influence the way patients talk about euthanasia and physician-assisted suicide (EAS) with their physicians and the way physicians experience the practice of EAS. AIM: To show what developments physicians see in practice and how they perceive the influence of the public debate on the practice of EAS. METHODS: We conducted a secondary analysis of in-depth interviews with 28 Dutch physicians who had experience with a complex case of EAS. Respondents were recruited both by the network of physicians working for SCEN (Support and Consultation for Euthanasia in the Netherlands) as well as via a national questionnaire, wherein participating physicians could indicate their willingness to be interviewed. RESULTS: Three themes came up in analysing the interviews. First, the interviewed physicians experienced a change in what (family of) patients would expect from them: from a role as an involved caregiver to being the mere performer of EAS. Second, interviewees said that requests for EAS based on non-medical reasons came up more frequently and wondered if EAS was the right solution for these requests. Last, respondents had the impression that the standards of EAS are shifting and that the boundaries of the EAS regulation were stretched. CONCLUSIONS: The perceived developments could make physicians less willing to consider a request for EAS. Our results also raise questions about the role of physicians and of EAS in society. PMID- 27495235 TI - Individual responsibility as ground for priority setting in shared decision making. AB - INTRODUCTION: Given healthcare resource constraints, voices are being raised to hold patients responsible for their health choices. In parallel, there is a growing trend towards shared decision-making, aiming to empower patients and give them more control over healthcare decisions. More power and control over decisions is usually taken to mean more responsibility for them. The trend of shared decision-making would therefore seem to strengthen the case for invoking individual responsibility in the healthcare priority setting. OBJECTIVE: To analyse whether the implementation of shared decision-making would strengthen the argument for invoking individual responsibility in the healthcare priority setting using normative analysis. RESULTS AND CONCLUSIONS: Shared decision-making does not constitute an independent argument in favour of employing individual responsibility since these notions rest on different underlying values. However, if a health system employs shared decision-making, individual responsibility may be used to limit resource implications of accommodating patient preferences outside professional standards and goals. If a healthcare system employs individual responsibility, high level dynamic shared decision-making implying a joint deliberation resulting in a decision where both parties are willing to revise initial standpoints may disarm common objections to the applicability of individual responsibility by virtue of making patients more likely to exercise adequate control of their own actions. However, if communication strategies applied in the shared decision-making are misaligned to the patient's initial capacities, arguments against individual responsibility might, on the other hand, gain strength. PMID- 27495233 TI - MiRNA expression profiling in human gliomas: upregulated miR-363 increases cell survival and proliferation. AB - The role of microRNAs (miRNAs) in glioma biology is increasingly recognized. To investigate the regulatory mechanisms governing the malignant signature of gliomas with different grades of malignancy, we analyzed miRNA expression profiles in human grade I-IV tumor samples and primary glioma cell cultures. Multiplex real-time PCR was used to profile miRNA expression in a set of World Health Organization (WHO) grade I (pilocytic astrocytoma), II (diffuse fibrillary astrocytoma), and IV (glioblastoma multiforme) astrocytic tumors and primary glioma cell cultures. Primary glioma cell cultures were used to evaluate the effect of transfection of specific miRNAs and miRNA inhibitors. miRNA microarray showed that a set of miRNAs was consistently upregulated in all glioma samples. miR-363 was upregulated in all tumor specimens and cell lines, and its expression correlated with tumor grading. The transfection of glioma cells with the specific inhibitor of miR-363 increased the expression level of tumor suppressor growth associated protein 43 (GAP-43). Transfection of miR-363 induced cell survival, while inhibition of miR-363 significantly reduced glioma cell viability. Furthermore, miRNA-363 inhibition induced the downregulation of AKT, cyclin-D1, matrix metalloproteinase (MMP)-2, MMP-9, and Bcl-2 and upregulation of caspase 3. Together, these data suggest that the upregulation of miR-363 may play a role in malignant glioma signature. PMID- 27495236 TI - Are the current notification criteria for Lyme borreliosis in Norway suitable? Results of an evaluation of Lyme borreliosis surveillance in Norway, 1995-2013. AB - BACKGROUND: The approach to surveillance of Lyme borreliosis varies between countries, depending on the purpose of the surveillance system and the notification criteria used, which prevents direct comparison of national data. In Norway, Lyme borreliosis is notifiable to the Surveillance System for Communicable Diseases (MSIS). The current notification criteria include a combination of clinical and laboratory results for borrelia infection (excluding Erythema migrans) but there are indications that these criteria are not followed consistently by clinicians and by laboratories. Therefore, an evaluation of Lyme borreliosis surveillance in Norway was conducted to describe the purpose of the system and to assess the suitability of the current notification criteria in order to identify areas for improvement. METHODS: The CDC Guidelines for Evaluation of Surveillance Systems were used to develop the assessment of the data quality, representativeness and acceptability of MSIS for surveillance of Lyme borreliosis. Data quality was assessed through a review of data from 1996 to 2013 in MSIS and a linkage of MSIS data from 2008 to 2012 with data from the Norwegian Patient Registry (NPR). Representativeness and acceptability were assessed through a survey sent to 23 diagnostic laboratories. RESULTS: Completeness of key variables for cases reported to MSIS was high, except for geographical location of exposureThe NPR-MSIS linkage identified 1047 cases in both registries, while 363 were only reported to MSIS and 3914 were only recorded in NPR. A higher proportion of cases found in both registries were recorded as neuroborreliosis in MSIS (84.4 %) than those cases found only in MSIS (20.1 %). The trend (average yearly increase or decrease in reported cases) of neuroborreliosis in MSIS was not significantly different from the trend for all other clinical manifestations recorded in MSIS in negative binomial regression (p = 0.3). The 16 surveyed laboratories (response proportion 70 %) indicated differences in testing practices and low acceptability of the notification criteria. CONCLUSIONS: Given the challenges associated with diagnosing Lyme borreliosis, the selected notification criteria should be closely linked with the purpose of the surveillance system. Restricting reportable Lyme borreliosis to neuroborreliosis may increase validity, while a more sensitive case definition (potentially including erythema migrans) may better reflect the true burden of disease. We recommend revising the current notification criteria in Norway to ensure that they are unambiguous for clinicians and laboratories. PMID- 27495237 TI - Clinical outcomes associated with albuminuria in central Australia: a cohort study. AB - BACKGROUND: Chronic kidney disease (CKD) and end-stage-kidney disease (ESKD) continue to be under-diagnosed and a major burden for Aboriginal communities in central Australia. The aim of this study was to examine the risk of poor clinical outcomes associated with elevated albumin-to-creatinine ratio (ACR) among Aboriginal people in central Australia. METHODS: Cox proportional hazards models were used to estimate the risk of end stage kidney disease (ESKD), dialysis, CVD (cardiovascular disease) and mortality associated with participants' baseline albuminuria reading from a 10-year cohort study of Aboriginal people (n = 623) from three communities in central Australia. Predictors of progression of albuminuria were also examined in the context of the Kidney Health Australia (KHA) Risk Matrix. RESULTS: A baseline ACR level of >=3.5 mg/mmol was associated with an almost 10-fold increased risk of ESKD (95%CI 2.07-43.8) and a 15-fold risk of dialysis (95%CI 1.89-121). Albuminuria >=3.5 mg/mmol was also associated with a borderline 63 % increased risk of CVD (95%CI 0.98-2.71). No significant association was observed with mortality from all-causes or chronic disease. Diabetes and a waist-to-hip ratio >=0.90 independently predicted a two-fold increased risk of a progression to higher ACR levels. CONCLUSIONS: A single measure of moderately increased albuminuria was a strong predictor of renal failure in this population. A single spot urine ACR analysis in conjunction with the KHA Risk Matrix may be a useful and efficient strategy to screen for risk of CKD and progression to dialysis in remote communities. A focus on individuals with diabetes and/or central obesity for strategies to avoid increases in albuminuria may also prevent future CKD and CVD complications. PMID- 27495239 TI - Geoffrey James Roberts. PMID- 27495238 TI - Recombinant production of medium- to large-sized peptides in Escherichia coli using a cleavable self-aggregating tag. AB - BACKGROUND: Peptides have recently become attractive for therapeutic applications. However, efficient production of medium- to large-sized peptides (30-100 amino acids [aa]) remains challenging both by recombinant and chemical synthesis. We previously reported the formation of active enzyme aggregates in Escherichia coli cells induced by the short beta-structured peptide ELK16 (LELELKLKLELELKLK) and developed a streamlined protein expression and purification approach. In this approach, a cleavable self-aggregating tag (cSAT) consisting of an intein molecule and ELK16 was used to release the recombinant peptides with reasonable purity from active aggregates. RESULTS: In this work, we extended the cSAT approach to a generalized expression and purification solution for a set of medium- to large-sized peptides with important therapeutic uses, including human glucagon-like peptide 1 (31 aa), B-type natriuretic peptide (32 aa), exendin 4 (39 aa), chemokine (C-C motif) ligand 5 (also known as RANTES, 66 aa), stromal cell-derived factor 1alpha (67 aa), insulin-like growth factor 1 (70 aa), and leptin (146 aa). After intein-mediated cleavage, the soluble peptides were released directly into the supernatant while insoluble peptides could be refolded and purified by reverse phase high-performance liquid chromatography. Additionally, an N-terminal thioredoxin tag was added upstream of the target peptides, which can be removed by enterokinase cleavage, generating native N terminus for target peptides. Final yields of the peptides ranged from 0.1 to 1.8 MUg/mg wet cell weight at laboratory scale. CONCLUSIONS: The approach described in this study provides a fast and efficient route to express and purify peptides that are difficult or expensive to produce by chemical synthesis or by ordinary recombinant methods. It is particularly well suited for large peptides, peptides likely to be degraded, and peptides that have toxic effects on the host. It can greatly reduce the cost and time of downstream processing, and thus may be useful for both industrial manufacture and laboratory applications. PMID- 27495240 TI - Long-term antibiotic exposure in soil is associated with changes in microbial community structure and prevalence of class 1 integrons. AB - Antimicrobial resistance is one of the most significant challenges facing the global medical community and can be attributed to the use and misuse of antibiotics. This includes use as growth promoters or for prophylaxis and treatment of bacterial infection in intensively farmed livestock from where antibiotics can enter the environment as residues in manure. We characterised the impact of the long-term application of a mixture of veterinary antibiotics alone (tylosin, sulfamethazine and chlortetracycline) on class 1 integron prevalence and soil microbiota composition. Class 1 integron prevalence increased significantly (P < 0.005) from 0.006% in control samples to 0.064% in the treated plots. Soil microbiota was analysed using 16S rRNA gene sequencing and revealed significant alterations in composition. Of the 19 significantly different (P < 0.05) OTUs identified, 16 were of the Class Proteobacteria and these decreased in abundance relative to the control plots. Only one OTU, of the Class Cyanobacteria, was shown to increase in abundance significantly; a curiosity given the established sensitivity of this class to antibiotics. We hypothesise that the overrepresentation of Proteobacteria as OTUs that decreased significantly in relative abundance, coupled with the observations of an increase in integron prevalence, may represent a strong selective pressure on these taxa. PMID- 27495241 TI - Patterns of bacterial biodiversity in the glacial meltwater streams of the McMurdo Dry Valleys, Antarctica. AB - Microbial consortia dominate glacial meltwater streams from polar regions, including the McMurdo Dry Valleys (MDV), where they thrive under physiologically stressful conditions. In this study, we examined microbial mat types and sediments found in 12 hydrologically diverse streams to describe the community diversity and composition within and across sites. Sequencing of the 16S rRNA gene from 129 samples revealed ~24 000 operational taxonomic units (<97% DNA similarity), making streams the most biodiverse habitat in the MDV. Principal coordinate analyses revealed significant but weak clustering by mat type across all streams (ANOSIM R-statistic = 0.28) but stronger clustering within streams (ANOSIM R-statistic from 0.28 to 0.94). Significant relationships (P < 0.05) were found between bacterial diversity and mat ash-free dry mass, suggesting that diversity is related to the hydrologic regimes of the various streams, which are predictive of mat biomass. However, correlations between stream chemistry and community members were weak, possibly reflecting the importance of internal processes and hydrologic conditions. Collectively, these results suggest that localized conditions dictate bacterial community composition of the same mat types and sediments from different streams, and while MDV streams are hotspots of biodiversity in an otherwise depauperate landscape, controls on community structure are complex and site specific. PMID- 27495242 TI - Genetic and ecophysiological traits of Synechococcus strains isolated from coastal and open ocean waters of the Arabian Sea. AB - The picocyanobacterium Synechococcus is a prominent primary producer in the marine environment. The marine Synechococcus strains are clustered into different clades representing ecologically distinct genotypes. In this study, we compared phylogeny, photophysiology and cell cycles of four novel phycoerythrin-containing Synechococcus strains (clade II of subcluster 5.1) isolated from different depths of the water column (surface and subsurface waters) in coastal and offshore regions of the eastern Arabian Sea. The surface water strains possessed a lesser number of thylakoid layers and had a higher zeaxanthin to chlorophyll a ratio than subsurface strains indicating possible influence of light intensity available at their niche. The DNA distribution pattern of the four strains was bimodal in optimal cellular physiology conditions with cell division restricted to the light period and synchronized with the light-dark cycle. The presence of phycourobilin or phycoerythrobilin and the ratio between these two chromophores in all four strains varied according to available spectral wavelength in situ This study indicates that the timing of cell division is conserved within these genotypically identical Synechococcus strains, despite their having different chromophore ratios. We conclude that the timing of cell division of the Synechococcus strains has a genetic basis rather than being determined by phenotypic characters, such as chromophore content and ratio. PMID- 27495243 TI - Editorial: Special thematic issue on microbe-assisted crop production. PMID- 27495244 TI - Chemotaxis and adherence to fungal surfaces are key components of the behavioral response of Burkholderia terrae BS001 to two selected soil fungi. AB - Burkholderia terrae BS001 has previously been proposed to be a 'generalist' associate of soil fungi, but its strategies of interaction have been largely ignored. Here, we studied the chemotactic behavior of B. terrae BS001 towards Lyophyllum sp. strain Karsten and Trichoderma asperellum 302 and the role of fungal surface molecules in their physical interaction with the bacteria. To assess the involvement of the type 3 secretion system (T3SS), wild-type strain BS001 and T3SS mutant strain BS001-DeltasctD were used in the experiments. First, the two fungi showed divergent behavior when confronted with B. terrae BS001 on soil extract agar medium. Lyophyllum sp. strain Karsten revealed slow growth towards the bacterium, whereas T. asperellum 302 grew avidly over it. Both on soil extract and M9 agar, B. terrae BS001 and BS001-DeltasctD moved chemotactically towards the hyphae of both fungi, with a stronger response to Lyophyllum sp. strain Karsten than to T. asperellum 302. The presence of a progressively increasing glycerol level in the M9 agar enhanced the level of movement. Different oxalic acid concentrations exerted varied effects, with a significantly raised chemotactic response at lower, and a subdued response at higher concentrations. Testing of the adherence of B. terrae BS001 and BS001 DeltasctD to Lyophyllum sp. strain Karsten and to cell envelope-extracted ceramide monohexosides (CMHs) revealed that CMHs in both conidia and hyphae could bind strain BS001 cells. As BS001-DeltasctD adhered significantly less to the CMHs than BS001, the T3SS was presumed to have a role in the interaction. In contrast, such avid adherence was not detected with T. asperellum 302. Thus, B. terrae BS001 shows a behavior characterized by swimming towards Lyophyllum sp. strain Karsten and T. asperellum 302 and attachment to the CMH moiety in the cell envelope, in particular of the former. PMID- 27495245 TI - Warfarin with sulfonylureas and hypoglycemic events: consider dose, length of treatment, and all sulfonylureas. PMID- 27495246 TI - Heart failure due to cytomegalovirus myocarditis in immunocompetent young adults: a case report. AB - BACKGROUND: Cardiac complications constitute a rare clinical manifestation of cytomegalovirus (CMV) infection. This virus is usually asymptomatic in immunocompetent individuals. We report a case of myocarditis and cardiac insufficiency due to primary CMV infection. Serological tests by using ELISA method showed positive results for the virus. CASE PRESENTATION: A 41-year-old man with no prior comorbidities presenting with dyspnoea, fever, and oedema was admitted to the cardiac emergency service. He had fever and dry cough, which aggravated into progressive respiratory distress, lower limb oedema, and orthopnoea 30 days prior to hospitalisation. The electrocardiogram revealed sinus tachycardia, first-degree right bundle branch block, and ventricular and left atrial overload as well as diffuse and nonspecific disturbances of ventricular repolarization. Serological tests were conducted, and IgM (1.54 UI/mL) and IgG (2.5 UI/mL) were found positive only for CMV by using ELISA. The patient was diagnosed with cardiac insufficiency due to CMV myocarditis. He was treated with ganciclovir for 10 days and received supportive medication. CONCLUSION: This case reaffirms the possibility of cardiac involvement in CMV infection and emphasises the importance of viral aetiologies as differential diagnoses for acute myocarditis. PMID- 27495248 TI - Carbon monoxide poisoning cases presenting with non-specific symptoms. AB - Carbon monoxide (CO) is a colourless and odourless gas appearing as a result of incomplete combustion of carbon-containing fuels. Many domestic or occupational poisonings are caused by CO exposure. Malfunctioning heating systems, improperly ventilated motor vehicles, generators, grills, stoves and residential fires may be listed in the common sources of CO exposure. The aim of this study was to emphasize the significance of early diagnosis of CO poisoning with non-invasive measurement of CO levels of the patients with non-specific symptoms using a pulse oximeter device in the triage. Our study was a cross-sectional study. Patients who presented to the emergency department (ED) due to non-specific symptoms and had a Canadian Triage and Acuity scale level of 4 or 5 were included in the study; 106 (5.9%) of 1788 patients admitted during the study period were diagnosed with CO poisoning. Patients with CO poisoning and the other patients had statistically significant differences in terms of presenting symptoms, namely, headache, dizziness, nausea, and vomiting. More CO poisoning cases were admitted in the fall and winter compared to the spring and summer. The number of CO poisoning victims can be decreased if preventive measures like CO monitoring systems and well-designed ventilation systems are generalized at homes and workplaces. Measurement of carboxyhaemoglobin levels of patients presenting to ED due to non-specific symptoms like headache and dizziness during cold seasons and winter months using a pulse CO-oximeter should be a part of the routine of emergency medicine triage. PMID- 27495247 TI - Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients. AB - BACKGROUND: Diabetes is associated with chronic inflammation and activation of the vascular endothelium and the coagulation system, which in a more acute manner are also observed in sepsis. Insulin and metformin exert immune modulatory effects. In this study, we aimed to determine the association of diabetes and preadmission insulin and metformin use with sepsis outcome and host response. METHODS: We evaluated 1104 patients with sepsis, admitted to the intensive care unit and stratified according to the presence or absence of diabetes mellitus. The host response was examined by a targeted approach (by measuring 15 plasma biomarkers reflective of pathways implicated in sepsis pathogenesis) and an unbiased approach (by analyzing whole genome expression profiles in blood leukocytes). RESULTS: Diabetes mellitus was not associated with differences in sepsis presentation or mortality up to 90 days after admission. Plasma biomarker measurements revealed signs of systemic inflammation, and strong endothelial and coagulation activation in patients with sepsis, none of which were altered in those with diabetes. Patients with and without diabetes mellitus, who had sepsis demonstrated similar transcriptional alterations, comprising 74 % of the expressed gene content and involving over-expression of genes associated with pro inflammatory, anti-inflammatory, Toll-like receptor and metabolic signaling pathways and under-expression of genes associated with T cell signaling pathways. Amongst patients with diabetes mellitus and sepsis, preadmission treatment with insulin or metformin was not associated with an altered sepsis outcome or host response. CONCLUSIONS: Neither diabetes mellitus nor preadmission insulin or metformin use are associated with altered disease presentation, outcome or host response in patients with sepsis requiring intensive care. PMID- 27495249 TI - Carbon monoxide exposure among police officers working in a traffic dense region of Southern India. AB - Currently, in India, air pollution is widespread in urban areas where vehicles are major contributors. The aim of this study was to investigate the level of exposure in traffic police officers exposed to vehicle exhaust for less than 8 h/day. The specific objective of the study was to determine the levels of carboxyhaemoglobin (COHb) in these officers. The effect of exposure for 8 h/day is known, but shorter durations of chronic exposure need to be investigated, and there is a need to explore the policy options in this exposed population. This cross-sectional study, included non-smoking traffic police officers between 30 and 50 years of age working for more than 2 years in busy traffic junctions. The cases were sex matched with controls of same age group, working in offices at a teaching hospital. Venous blood was collected at the end of 3 h of duty for estimation of COHb among both the groups. The COHb levels were expressed as percentage values. Differences between the COHb levels among the traffic police officers and office workers were analysed using the Mann-Whitney U test and considered significant at p < 0.05. Traffic police officers had significantly elevated COHb levels compared with the controls; 76.5% of traffic police officers had COHb >2.5% compared with no office workers at this level and 41.2% of the police officers had COHb levels >4%. Overall, 53.8% of officers with COHb >2.5% reported headaches compared with 15.8% of officers with COHb <2.5%. PMID- 27495250 TI - MicroRNA-21 promotes proliferation, migration, and invasion of colorectal cancer, and tumor growth associated with down-regulation of sec23a expression. AB - BACKGROUND: MicroRNA-21 (miR-21) is up-regulated in many cancers, including colorectal cancer (CRC). Nevertheless, the function of miR-21 in CRC and the mechanism underlying that function is still unclear. METHODS: After analyzing the expression of miR-21 and Sec23A in CRC cell lines, we transfected the highest miR 21 expressing cell line, SW-480, with a plasmid containing an miR-21 inhibitor and the lowest miR-21 expressing cell line, DLD-1, with a plasmid containing an miR-21 mimic and measured the effects on the expression of Sec23A and on cell proliferation, migration, and invasion. We also evaluated the effect of knocking down Sec23A on miR-21 expression and its effects on cell proliferation, migration, and invasion. Finally, we assessed the effect of miR-21 in a xenograft tumor model in mice. Tumor tissues from these mice were subjected to immunohistochemical staining to detect the expression of Sec23A. RESULTS: Genetic deletion of miR-21 suppressed the proliferation, migration, and invasion of SW 480 cells, while over-expression of miR-21 promoted proliferation, migration, and invasion of DLD-1 cells. Inhibition of miR-21 increased the expression of Sec23A protein in SW-480 cells while over-expression of miR-21 significantly suppressed the expression of Sec23A protein and Sec23A mRNA in DLD-1 cells. Knockdown of Sec23A increased the expression of miR-21 in SW480 and DLD-1 cells and their proliferation (DLD-1 only), migration, and invasion. Over-expression of miR-21 promoted tumor growth in BALB/c nude mice and suppressed tumor expression of Sec23A. CONCLUSION: These findings provide novel insight into the molecular functions of miR-21 in CRC, which may serve as a potential interesting target. PMID- 27495251 TI - Annual ambient atmospheric mercury speciation measurement from Longjing, a rural site in Taiwan. AB - The main purpose of this study was to monitor ambient air particulates and mercury species [RGM, Hg(p), GEM and total mercury] concentrations and dry depositions over rural area at Longjing in central Taiwan during October 2014 to September 2015. In addition, passive air sampler and knife-edge surrogate surface samplers were used to collect the ambient air mercury species concentrations and dry depositions, respectively, in this study. Moreover, direct mercury analyzer was directly used to detect the mercury Hg(p) and RGM concentrations. The result indicated that: (1) The average highest RGM, Hg(p), GEM and total mercury concentrations, and dry depositions were observed in January, prevailing dust storm occurred in winter season was the possible major reason responsible for the above findings. (2) The highest average RGM, Hg(p), GEM and total mercury concentrations, dry depositions and velocities were occurred in winter. This is because that China is the largest atmospheric mercury (Hg) emitter in the world. Its Hg emissions and environmental impacts need to be evaluated. (3) The results indicated that the total mercury ratios of Kaohsiung to that of this study were 5.61. This is because that Kaohsiung has the largest industry density (~60 %) in Taiwan. (4) the USA showed average lower mercury species concentrations when compared to those of the other world countries. The average ratios of China/USA values were 89, 76 and 160 for total mercury, RGM and Hg(p), respectively, during the years of 2000-2012. PMID- 27495252 TI - Cultural events - does attendance improve health? Evidence from a Polish longitudinal study. AB - BACKGROUND: Although there is strong advocacy for uptake of both the arts and creative activities as determinants of individual health conditions, studies evaluating causal influence of attendance at cultural events on population health using individual population data on health are scarce. If available, results are often only of an associative nature. In this light, this study investigated causative impact of attendance at cultural events on self-reported and physical health in the Polish population. METHODS: Four recent waves (2009, 2011, 2013 and 2015) of the biennial longitudinal Polish household panel study, Social Diagnosis, were analysed. The data, representative for the Polish population aged over 16, with respect to age, gender, classes of place of residence and NUTS 2 regions, were collected from self-report questionnaires. Causative influence of cultural attendance on population health was established using longitudinal population representative data. To account for unobserved heterogeneity of individuals and to mitigate issues caused by omitted variables, a panel data model with a fixed effects estimator was applied. The endogeneity problem (those who enjoy good health are more likely to participate in cultural activities more frequently) was circumvented by application of instrumental variables. RESULTS: Results confirmed positive association between cultural attendance and self reported health. However, in contrast to the often suggested positive causative relationship, such a link was not confirmed by the study. Additionally, no evidence was found to corroborate a positive impact from cultural attendance on physical health. Both findings were substantiated by augmentation in the longitudinal perspective and causal link. CONCLUSIONS: We showed the relation between attendance at cultural events and self-reported health could only be confirmed as associational. Therefore, this study provided little justification to encourage use of passive cultural participation as a measure of health promotion (improvement). Our study did not confirm any identifiable benefit to physical health from passive participation in culture. Future research should investigate the causative influence of active participation in creative activities on health outcomes as, in contrast to passive attendance, it may be influential. PMID- 27495253 TI - An assessment of outcomes with intramedullary fixation of fractured ribs. AB - BACKGROUND: Surgical management of fractured ribs with internal fixation is an increasingly accepted therapy. Concurrently, specific rib fixation prostheses are being developed which should improve results and minimise hardware and rib/splint construct failures. The Synthes titanium intramedullary splint lends itself to difficult to access areas such as posterior rib fractures and fractures under the scapula. We analyse a case series of patients in whom this rib fixation prosthesis has been used. METHODS: Fifteen patients received 35 intramedullary splints. Follow up at 3 and 6 months was performed with three dimensional computed tomography scanning to assess for bone alignment, callus formation and healing, residual deformity, hardware failure or cut through. Computerized finite element analysis (FEA) was used to model forces acting on a posterior fracture with and without an intramedullary fixation splint in situ. RESULTS: Complete healing (bony union) was noted in only 3 (9 %) of the fractures fixed with splints by 3 months. Partial healing (cartilaginous union) was noted in 28 of the 33 fractures (85 %), and non healing was noted in only 2 (6 %). In both those two patients, failure at the rib / splint interface was noted after both patients reported sneezing. No hardware failures were noted. By 6 months the fractures which had shown partial healing, had all completely healed. There were no late failures (between 3 and 6 months) of either hardware or rib/splint interfaces. FEA modelling identified sites of increased stress in the rib at the rib / splint interface and in a modelled intramedullary splint where it spans the fracture. CONCLUSIONS: Further analysis of outcomes with intramedullary splints is warranted as well as further development of intramedullary rib fixation solutions. PMID- 27495254 TI - Genome wide characterization of simple sequence repeats in watermelon genome and their application in comparative mapping and genetic diversity analysis. AB - BACKGROUND: Microsatellite markers are one of the most informative and versatile DNA-based markers used in plant genetic research, but their development has traditionally been difficult and costly. The whole genome sequencing with next generation sequencing (NGS) technologies provides large amounts of sequence data to develop numerous microsatellite markers at whole genome scale. SSR markers have great advantage in cross-species comparisons and allow investigation of karyotype and genome evolution through highly efficient computation approaches such as in silico PCR. Here we described genome wide development and characterization of SSR markers in the watermelon (Citrullus lanatus) genome, which were then use in comparative analysis with two other important crop species in the Cucurbitaceae family: cucumber (Cucumis sativus L.) and melon (Cucumis melo L.). We further applied these markers in evaluating the genetic diversity and population structure in watermelon germplasm collections. RESULTS: A total of 39,523 microsatellite loci were identified from the watermelon draft genome with an overall density of 111 SSRs/Mbp, and 32,869 SSR primers were designed with suitable flanking sequences. The dinucleotide SSRs were the most common type representing 34.09 % of the total SSR loci and the AT-rich motifs were the most abundant in all nucleotide repeat types. In silico PCR analysis identified 832 and 925 SSR markers with each having a single amplicon in the cucumber and melon draft genome, respectively. Comparative analysis with these cross-species SSR markers revealed complicated mosaic patterns of syntenic blocks among the genomes of three species. In addition, genetic diversity analysis of 134 watermelon accessions with 32 highly informative SSR loci placed these lines into two groups with all accessions of C.lanatus var. citorides and three accessions of C. colocynthis clustered in one group and all accessions of C. lanatus var. lanatus and the remaining accessions of C. colocynthis clustered in another group. Furthermore, structure analysis was consistent with the dendrogram indicating the 134 watermelon accessions were classified into two populations. CONCLUSION: The large number of genome wide SSR markers developed herein from the watermelon genome provides a valuable resource for genetic map construction, QTL exploration, map-based gene cloning and marker-assisted selection in watermelon which has a very narrow genetic base and extremely low polymorphism among cultivated lines. Furthermore, the cross-species transferable SSR markers identified herein should also have practical uses in many applications in species of Cucurbitaceae family whose whole genome sequences are not yet available. PMID- 27495256 TI - Pneumatosis intestinalis after gefitinib therapy for pulmonary adenocarcinoma: a case report. AB - BACKGROUND: Pneumatosis intestinalis (PI) is defined as the presence of gas in the bowel wall and is a relatively rare finding. PI has been associated with various pathological conditions and medications. Although several chemotherapeutic agents and molecular targeted therapy agents are reported to be associated with PI, there have been few reports describing the association between the anti-epidermal growth factor receptor agent gefitinib, a tyrosine kinase inhibitor (TKI), and PI. The present report describes a case of PI secondary to gefitinib therapy. CASE PRESENTATION: An 80-year-old woman who had been diagnosed with recurrent lung adenocarcinoma presented with remarkable appetite loss, abdominal distension, and constipation after starting gefitinib therapy. A computed tomography (CT) scan of the abdomen revealed PI extending from the small intestine to the rectum. The patient was managed conservatively, and gefitinib therapy was discontinued. Subsequently, the symptoms improved and a follow-up abdominal X-ray showed a reduction in intramural air. After gefitinib was restarted, PI occurred three more times. CONCLUSIONS: Although PI is extremely rare, physicians should be aware of the risk of PI in patients undergoing gefitinib therapy. PMID- 27495255 TI - Response of Hepatic Stellate Cells to TGFB1 Differs from the Response of Myofibroblasts. Decorin Protects against the Action of Growth Factor. AB - Regardless to the exact nature of damage, hepatic stellate cells (HSCs) and other non-parenchymal liver cells transform to activated myofibroblasts, synthesizing the accumulating extracellular matrix (ECM) proteins, and transforming growth factor-beta1 (TGF-beta1) plays a crucial role in this process. Later it was discovered that decorin, member of the small leucin rich proteoglycan family is able to inhibit this action of TGF-beta1. The aim of our present study was to clarify whether HSCs and activated myofibroblasts of portal region exert identical or different response to TGF-beta1 exposure, and the inhibitory action of decorin against the growth factor is a generalized phenomenon on myofibroblast of different origin? To this end we measured mRNA expression and production of major collagen components (collagen type I, III and IV) of the liver after stimulation and co-stimulation with TGF-beta1 and decorin in primary cell cultures of HSCs and myofibroblasts (MFs). Production of matrix proteins, decorin and members of the TGF-beta1 signaling pathways were assessed on Western blots. Messenger RNA expression of collagens and TIEG was quantified by real-time RT PCR. HSCs and MFs responded differently to TGF-beta1 exposure. In contrast to HSCs in which TGF-beta1 stimulated the synthesis of collagen type I, type III, and type IV, only the increase of collagen type IV was detected in portal MFs. However, in a combined treatment, decorin seemed to interfere with TGF-beta1 and its stimulatory effect was abolished. The different mode of TGF-beta1 action is mirrored by the different activation of signaling pathways in activated HSCs and portal fibroblasts. In HSCs the activation of pSMAD2 whereas in myofibroblasts the activation of MAPK pathway was detected. The inhibitory effect of decorin was neither related to the Smad-dependent nor to the Smad-independent signaling pathways. PMID- 27495257 TI - Relationship between frailty, physical performance and quality of life among nursing home residents: the SENIOR cohort. AB - BACKGROUND: The aim of this study was to assess the relationship between frailty and a large number of indicators related to physical and muscular performance as well as quality of life. METHODS: This is an analysis of data collected at baseline in the Sample of Elderly Nursing home Individuals: an Observational Research (SENIOR) cohort including nursing home residents. Subjects are volunteer, oriented and able to walk (walking assistance allowed) nursing home residents in Belgium. A large number of demographic and clinical characteristics, including physical and muscular performance, were collected from each patient. The prevalence of frailty in this population was assessed using Fried's definition. RESULTS: In total, 662 subjects are included in this analysis. The mean age of the sample is 83.2 +/- 8.99 years, and 484 (73.1 %) are women. In this population of nursing home residents, the prevalence of frailty is 25.1 %, pre-frailty, 59.8 % and robustness, 15.1 %. Compared to non-frail subjects, frail subjects have lower physical and muscular performances and a lower quality of life. CONCLUSION: Frailty, according to Fried's definition, seems to be associated with several clinical indicators suggesting a higher level of disability and an increased propensity to develop major clinical consequences. Follow-up data of the SENIOR cohort will be helpful in confirming these findings, establishing cause-effect relationships and identifying the most predictive components of physical frailty for adverse outcomes in nursing homes. PMID- 27495258 TI - Utilization of long-term care after decompressive hemicraniectomy for severe stroke among older patients. AB - BACKGROUND: While clinical trial data support decompressive hemicraniectomy (DHC) as improving survival among patients with severe ischemic stroke, quality of life outcomes among older persons remain controversial. AIMS: To aid decision-making and understand practice variation, we measured long-term outcomes and patterns of regional variation for a nationwide cohort of ischemic stroke patients after DHC. METHODS: Medicare fee-for-service ischemic stroke cases over age 65 during the year 2008 were used to create a cohort followed for 2 years (2009-2010) after stroke and DHC procedure. Rates of mortality, acute hospital readmission, and long-term care (LTC) utilization were calculated. Multiple logistic regression was used to identify individual predictors of institutional LTC. Regional variation in DHC was calculated through aggregation and merging with the state level data. RESULTS: Among 397,503 acute ischemic stroke patients, 130 (0.03 %) underwent DHC. Mean age was 72 years, and 75 % were between the ages of 65 and 74. Mortality was highest (38 %) within the first 30 days. At 2 years, 59 % of the original cohort had died. The 30-day rate of acute hospital readmission was 25 %. Among survivors, 75 % returned home 1 year after index stroke admission. States with higher per capita health expenditures were associated with wider variation in utilization of DHC. CONCLUSIONS: There is a high rate of mortality among older stroke patients undergoing DHC. Although most survivors of DHC are not permanently institutionalized, there is wide variation in utilization of DHC across the USA. PMID- 27495259 TI - Aesthetic Plastic Surgery Checklist: A Safety Tool. AB - INTRODUCTION: About one in ten patients experiences iatrogenic events, and more than half of these occur in the perioperative environment. The objective of this study was to develop a complete and functional checklist for aesthetic plastic surgery and test it in patients who would undergo elective plastic surgeries. METHODS: Patient data were collected from a general hospital and the particular clinic between October 2013 and October 2015, through history, physical examination, diagnosis, laboratory tests, pre-, during, and postoperatively, and complications. An expanded safety checklist was developed and optimized for aesthetic plastic surgery based on the model presented by the WHO in 2009 with reference to the information related to the prevention of more frequent complications in this specialty. RESULTS: The tool was applied to 486 patients, of whom 430 (88 %) were women and 56 (12 %) were men. The most frequently performed procedure was liposuction with 30 % of cases, and the most widely used type of anesthesia (39 %) was local anesthesia + sedation. The greater adherence of professionals to the checklist was the group of residents (98 %). The observed complications were seromas (7 %), other complications unrelated to the wound (3 %), and hematoma (0.2 %) in only one patient who underwent facelift. CONCLUSION: The use of the checklist in addition to allowing data collection and the identification of potential risks promoted favorable changes in the attitudes of some professionals and generated interest in patient safety and teamwork. LEVEL OF EVIDENCE IV: This journal requires that the authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27495260 TI - Adverse Events of Botulinum Toxin Type A in Facial Rejuvenation: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Botulinum toxin A (BTX-A) is a medical product that is used widely in cosmetics, and concern over the safety profile has increased among injectors and patients. OBJECTIVE: The purpose was to enhance the statistical effect size using a meta-analysis to detect the incidence rate of adverse events (AEs) in the treatment of facial wrinkles. METHODS: A systematic search was performed for randomized, double-blind, placebo-controlled trials published through July 2015. RESULTS: We searched 16 trials, including 42,405 individual participants, and found that in all enrolled facial rejuvenation studies, patients in the BTX-A group had significantly more AEs than those patients in the placebo group (RR = 1.24; 95 % CI 1.07-1.43; p = 0.003). For crow's feet lines injection analysis, the BTX-A group did not exhibit any significant increase in AEs compared with the control group (RR = 1.19; 95 % CI 0.96-1.48; p = 0.12), except in injection site hematoma (RR = 2.14; 95 % CI 1.13-4.07; p = 0.02) in the treatment group. For frown wrinkle injection analysis, AEs were significantly observed in the BTX-A group (RR = 1.47; 95 % CI 1.23-1.77; p < 0.0001), particularly headaches (RR = 1.53; 95 % CI 1.15-2.03; p = 0.003), eyelid ptosis (RR = 5.56; 95 % CI 1.68 18.38; p = 0.005), and heavy eyelids (RR = 6.94; 95 % CI 1.27-37.93; p = 0.03). CONCLUSION: This meta-analysis confirmed the safety profile of BTX-A for glabellar and crow's feet lines, and BTX-A usage for the removal of upper facial wrinkles, which have some significant mild-to-moderate adverse profiles, including headache, eye disorder, eyelid ptosis, and heavy eyelids. Facial injectors should abide by the technical standards of neurotoxic drugs and be familiar with the local pharmacological effects to lessen the severe side effects. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the A5 online Instructions to Authors www.springer.com/00266 . PMID- 27495261 TI - The Aesthetically Ideal Position of the Nipple-Areola Complex on the Breast. AB - BACKGROUND: Several studies have attempted to identify an objective description of the aesthetically ideal breast, but they have all suffered in their reliability because of having several intrinsic limitations. It is therefore essential to design a template of ideal breast features in order to predict and evaluate aesthetic outcomes in both reconstructive and cosmetic breast surgery. The aim of this study was to determine the aesthetically preferred position of the nipple-areola complex on the breast. METHODS: A questionnaire was sent by regular mail to 1000 men and 1000 women aged between 16 and 74 years. They were asked to rank the attractiveness of a series of breasts of women in images with different NAC positions. The images showed breasts from two different angles: 12 frontal-view images with both breasts shown, and five side-view images with only one breast shown. All of the breasts had equal dimensions and proportions, with the same areola size but different NAC positions. Statistical analysis of data was carried out. RESULTS: Eight hundred and thirteen of 2000 participants completed the questionnaire. The NAC placement preferred by both genders had a ratio of 40:60 x and 50:50 y, which means that it was best situated in the middle of the breast gland vertically and slightly lateral to the midpoint horizontally. Significant differences were found between the age and gender subgroup preferences. CONCLUSIONS: This study identified the preferred position of the nipple-areola complex on the female breast in the general population. This is an important information when planning breast reconstructive and cosmetic surgery. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27495262 TI - Performance of real-world functional vision tasks by blind subjects improves after implantation with the Argus(r) II retinal prosthesis system. AB - BACKGROUND: The main objective of this study was to test Argus II subjects on three real-world functional vision tasks. DESIGN: The study was designed to be randomized and prospective. Testing was conducted in a hospital/research laboratory setting at the various participating centres. PARTICIPANTS: Twenty eight Argus II subjects, all profoundly blind, participated in this study. METHODS: Subjects were tested on the three real-world functional vision tasks: Sock Sorting, Sidewalk Tracking and Walking Direction Discrimination task MAIN OUTCOME MEASURES: For the Sock Sorting task, percentage correct was computed based on how accurately subjects sorted the piles on a cloth-covered table and on a bare table. In the Sidewalk Tracking task, an 'out of bounds' count was recorded, signifying how often the subject veered away from the test course. During the Walking Direction Discrimination task, subjects were tested on the number of times they correctly identified the direction of testers walking across their field of view. RESULTS: The mean percentage correct OFF versus ON for the Sock Sorting task was found to be significantly different for both testing conditions (t-test, P < 0.01). On the Sidewalk Tracking task, subjects performed significantly better with the system ON than they did with the system OFF (t test, P < 0.05). Eighteen (18) of 27 subjects (67%) performed above chance with the system ON, and 6 (22%) did so with system OFF on the Walking Direction Discrimination task. CONCLUSIONS: Argus II subjects performed better on all three tasks with their systems ON than they did with their systems OFF. PMID- 27495263 TI - Antibacterial, anti-biofilm and anticancer potentials of green synthesized silver nanoparticles using benzoin gum (Styrax benzoin) extract. AB - This study described a simple and green approach for the synthesis of silver nanoparticles (AgNPs) employing benzoin gum water extract as a reducing and capping agent and their applications. The AgNPs were characterized by ultraviolet visible spectrophotometer, X-ray diffraction pattern, field emission transmission electron microscopy, dynamic light scattering, zeta potential and fourier transform infrared spectroscopy. The AgNPs showed promising antimicrobial activity against various pathogens (Gram-negative, Gram-positive and fungus) and possessed high free radical scavenging activity (104.5 +/- 7.21 % at 1 mg/ml). In addition, the AgNPs exhibited strong cytotoxicity towards human cervical cancer and human lung cancer cells as compared to the normal mouse macrophage cells. Moreover, the AgNPs possessed anti-biofilm activity against Escherichia coli, and compatibility to human keratinocyte HaCaT cells, which suggests the use of dressing with the AgNPs in chronic wound treatment. Therefore, AgNPs synthesized by benzoin gum extract are comparatively green and may have broad spectrum potential application in biomedicine. PMID- 27495264 TI - Corneal endothelial cell loss after Baerveldt glaucoma drainage device implantation in the anterior chamber. AB - PURPOSE: To investigate central and peripheral corneal endothelial cell density (ECD) in relation to Baerveldt (BV) glaucoma drainage device (GDD) tube corneal (TC) distance. METHODS: Prospective study of all patients scheduled for glaucoma tube surgery with 36 months follow-up. A BV GDD was inserted into the anterior chamber (AC). Anterior segment optical coherence tomography (AS-OCT) scans were made to determine the TC distance. Central and peripheral ECD was measured, preoperatively and at 3, 6, 12, 24 and 36 months postoperatively. RESULTS: Fifty three eyes were included [primary open-angle glaucoma, (n = 13); secondary glaucoma, (n = 30); and primary angle-closure glaucoma, (n = 10)]. Central ECD significantly decreased during follow-up, with a mean decrease of 4.54% per year (p < 0.001), and 6.57% in the peripheral quadrant closest to the BV GDD tube (PQC, p < 0.001). In the PQC, a yearly decrease of 1.57% was shown after transiridial tube placement versus 7.43% after placement 'free' into the AC (p = 0.006). Endothelial cell (EC) loss was related to TC distance (mean 1.69 mm), with a central loss of 6.20% and 7.25% in the PQC per year with shorter TC distances, versus a central loss of 4.11% and 5.77% in the PQC per year with longer TC distances (outside mean +/- 2SD, p < 0.001). A difference in EC loss by glaucoma subtype was not identified. CONCLUSION: The TC distance is of significant influence on corneal ECD, a shorter TC distance causing more severe EC loss, especially in the PQC. Transiridial placement of the BV GDD tube seems safer than placement 'free' into the AC. PMID- 27495265 TI - Paronychia-like digital metastases of osteosarcoma. PMID- 27495266 TI - Imaging and quantification of iron-oxide nanoparticles (IONP) using MP-RAGE and UTE based sequences. AB - PURPOSE: To investigate two-dimensional (2D) and three-dimensional (3D) ultrashort echo time (UTE) and 3D magnetization-prepared rapid gradient-echo (MP RAGE) sequences for the imaging of iron-oxide nanoparticles (IONP). METHODS: The phantoms were composed of tubes filled with different IONP concentrations ranging from 2 to 45 mM. The tubes were fixed in an agarose gel phantom (0.9% by weight). Morphological imaging was performed with 3D MP-RAGE, 2D UTE, 2D adiabatic inversion recovery-prepared UTE (2D IR-UTE), 3D UTE with Cones trajectory (3D Cones), and 3D IR-Cones sequences. Quantitative assessment of IONP concentration was performed using R2*(1/T2*) and R1 (1/T1 ) measurements using a 3 Tesla (T) scanner. RESULTS: The 3D MP-RAGE sequence provides high-contrast images of IONP with concentration up to 7.5 mM. Higher IONP concentration up to 37.5 mM can be detected with the UTE sequences, with the highest IONP contrast provided by the 3D IR-Cones sequence. A linear relationship was observed between R2* and IONP concentration up to ~45 mM, and between R1 and IONP concentration up to ~30 mM. CONCLUSION: The clinical 3D MP-RAGE sequence can be used to assess lower IONP concentration up to 7.5 mM. The UTE sequences can be used to assess higher IONP concentration up to 45 mM. Magn Reson Med 78:226-232, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27495268 TI - Clinically atypical nevi following diode laser therapy. PMID- 27495267 TI - TDP-43 pathology in Alzheimer's disease, dementia with Lewy bodies and ageing. AB - Intracellular inclusions consisting of TAR DNA binding protein-43 (TDP-43 pathology) are present in up to 57% of Alzheimer's disease (AD) cases and follow a distinct topographical pattern of progression described in the TDP-43 in AD staging scheme. This scheme has not been applied to the assessment of TDP-43 pathology in dementia with Lewy bodies (DLB) and aged controls. We investigated TDP-43 pathology prevalence and severity in AD, DLB, mixed AD/DLB (Mx AD/DLB) and aged controls. One hundred and nineteen human post-mortem brains were included, neuropathologically diagnosed as AD: 46, DLB: 15, Mx AD/DLB: 19 and aged controls: 39. Paraffin sections inclusive of the amygdala, hippocampus, striatum and neocortex were immunohistochemically stained with antibodies against phosphorylated TDP-43 and staged according to the TDP-43 in AD staging scheme. TDP-43 pathology was present in all groups: AD: 73.9%, DLB: 33.3%, Mx AD/DLB: 52.6% and controls: 17.9%. Prevalence of TDP-43 pathology was significantly higher in AD and Mx AD/DLB compared to controls. In controls, higher age at death was associated with prevalence of TDP-43 pathology and higher TDP-43 in AD stage, suggesting that this type of TDP-43 pathology may partly be an age-associated phenomenon. Significantly higher prevalence of TDP-43 pathology in the AD group indicates that AD pathology possibly triggers and aggravates TDP-43 pathology. The validity of the TDP-43 in AD staging scheme is not limited to AD and should be applied to assess TDP-43 pathology in post mortem brains of aged individuals to further elucidate the role of TDP-43 pathology in age associated neurodegeneration. PMID- 27495270 TI - Students' perceptions of pre-clinical endodontic training with artificial teeth compared to extracted human teeth. AB - PURPOSE: Artificial teeth have several advantages in pre-clinical endodontics training. This study aimed to compare artificial resin teeth with extracted human teeth, from a student's perspective, during a pre-clinical undergraduate endodontic course for three consecutive academic years (2011-2014). METHODS: At the end of the course, students completed a questionnaire that included questions about their perceptions of the difficulty of artificial teeth vs. natural teeth and ranked the perceived advantages of artificial teeth. RESULTS: Participants expressed that all procedures, except obturation, were more difficult to perform on artificial teeth than on natural teeth, a result that was due to the hardness of the resin. They ranked the fairness and availability as the best advantages. CONCLUSION: Artificial teeth have multiple advantages but cannot replace natural teeth. The physical characteristics through the manufacturing material of artificial teeth should be enhanced to increase wider use and acceptance. PMID- 27495269 TI - Effects of infrared laser moxibustion on cancer-related fatigue: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Fatigue is the most common symptom negatively affecting the quality of life of patients with cancer. The objective of the current study was to evaluate the preliminary efficacy and safety of 10.6-MUm infrared laser moxibustion for cancer-related fatigue (CRF). METHODS: The authors conducted a randomized, placebo-controlled trial among 78 patients with cancer who were diagnosed with CRF. The group treated with infrared laser moxibustion received 10.6 MUm of infrared laser moxibustion on the ST36 (bilateral), CV4, and CV6 acupoints. Each participant received a 20-minute treatment session 3 times per week for 4 weeks. The sham group received the same treatment duration on the same acupoints, but without infrared laser output. The outcome was change in fatigue as measured by the Chinese version of the Brief Fatigue Inventory between groups at week 4 with additional evaluation at week 8 for durability of treatment effects. A mixed effects model was used to evaluate the difference in treatment effect over time. RESULTS: Among those randomized, 61 patients (78%) completed the entire study. At the end of the intervention, the individuals in the group treated with the laser were found to have significantly less fatigue than those in the sham group (3.01 vs 4.40; P = .002). The improvement in fatigue persisted to week 8, favoring the group treated with laser moxibustion (3.03 vs 4.26; P = .006). Laser moxibustion was safe, with 3 cases of mild local erythema that resolved without medical intervention reported. CONCLUSIONS: Infrared laser moxibustion appeared to be safe and efficacious for improving CRF in a Chinese patient population. Larger studies in more racial/ethnically diverse populations are needed to confirm the benefit of this technique for fatigue in patients with cancer. Cancer 2016;122:3667-72. (c) 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 27495271 TI - In vivo periodontal tissue regeneration by periodontal ligament stem cells and endothelial cells in three-dimensional cell sheet constructs. AB - BACKGROUND AND OBJECTIVE: Chronic periodontitis causes damage to tooth-supporting tissues, resulting in tooth loss in adults. Recently, cell-sheet-based approaches have been studied to overcome the limitations of conventional cytotherapeutic procedures for periodontal regeneration. The purpose of the present study was to investigate the regenerative potential of periodontal ligament stem cells (PDLSCs) and human umbilical vein endothelial cells (HUVECs) in three-dimensional (3D) cell sheet constructs for periodontal regeneration in vivo. MATERIAL AND METHODS: PDLSCs, HUVECs or co-cultures of both cells were seeded onto temperature responsive culture dishes, and intact cell sheets were fabricated. Cell sheets were wrapped around the prepared human roots in three different combinations and implanted subcutaneously into immunodeficient mice. RESULTS: Histological evaluation revealed that after 2, 4 and 8 wk of implantation, periodontal ligament-like tissue arrangements were observed around the implanted roots in experimental groups compared with controls. Vascular lumens were also observed in periodontal compartments of HUVEC-containing groups. Periodontal ligament regeneration, cementogenesis and osteogenesis were evident in the experimental groups at both weeks 4 and 8, as shown by immunostaining for periostin and bone sialoprotein. Human cells in the transplanted cell sheets were stained by immunohistochemistry for the presence of human mitochondria. CONCLUSIONS: The 3D cell sheet-based approach may be potentially beneficial and is thus encouraged for future regenerative periodontal therapy. PMID- 27495272 TI - Monitoring children's health and well-being by indicators and index: apples and oranges or fruit salad? AB - The use of indicators is a fast and widely spread way to monitor groups of children's health and well-being. Indicators are useful in research; but they are also important tools for planners and politicians. Although they are constructed to simplify reality, in many reports they still offer a complex and confusing picture, not least by their sheer numbers. Although they are constructed to simplify reality, in many reports, they still offer a complex and confusing picture, not least by their sheer numbers. Therefore, there is an increasing demand for even further simplifications, where the indicators are combined into single summary numbers, composite indices. At the same time, as a composite index summarizes a complex and sometimes elusive process, making it more accessible for advocacy and political interventions, the combining of very dissimilar components makes the results difficult to interpret and use. There is an obvious dilemma between the need for rigour and evidence, the research orientation, and the wish for a simple and summarizing overview of the findings, the policy orientation. Models have been created to form indicator sets, either by combining them by simple addition or by weighting them or by just leaving them as separate indicators. Most index systems in operation use an equal weighting system after standardization, once the components have been selected. Examples of these models are described as well as their pros and cons, and a summary of suitable ways of handling the problems of indicators and composite indices is offered. Some surveys have taken the best from different approaches, presenting the results as a summary index for the great picture, as subindices for the various domains of child health and as separate indicators for the detailed study of the basic components. A Swedish Child Health Index is presented as an example of such a solution. PMID- 27495273 TI - Latin American protected areas: Protected from chemical pollution? AB - Protected areas (PAs) are critically important means to preserve species and maintain natural ecosystems. However, the potential impacts of chemical pollution on PAs are seldom mentioned in the scientific literature. Research on the extent of the occurrence of chemical pollution inside PAs and in-depth assessments of how chemical contaminants may adversely affect the maintenance of species abundance, species survival, and ecosystem functions are scarce to nonexistent. We investigated 1) the occurrence of chemical contaminants inside 119 PAs in Latin America from publically available databases, and 2) reviewed case studies of chemical contaminants and pollution in 4 Latin American PAs. Cases of chemical pollution and contamination inside Latin American PAs mostly originated from sources such as mining, oil, and gas extraction. To date, the focus of the research on chemical pollution research inside Latin American PAs has been primarily on the detection of contamination, typically limited to trace metals. Where management actions have occurred, they have been reactive rather than proactive. Protected areas established in wetlands are the most affected by chemical pollution. Based on the information from the pollution and/or contamination occurrence and the case studies analyzed, Latin American PAs are not well safeguarded from chemical pollution, resulting in both challenges and opportunities to conserve biodiversity and ecosystems. Integr Environ Assess Manag 2017;13:360-370. (c) 2016 SETAC. PMID- 27495274 TI - Measurement equivalence of the Consumer Assessment of Healthcare Providers and Systems (CAHPS(r)) Medicare survey items between Whites and Asians. AB - PURPOSE: Asians report worse experiences with care than Whites. This could be due to true differences in care received, expectations about care, or survey response styles. We examined responses to the Consumer Assessment of Healthcare Providers and Systems (CAHPS(r)) Medicare survey items by Whites and Asians, controlling for underlying level on the CAHPS constructs. METHODS: We conducted multiple group analyses to evaluate measurement equivalence of CAHPS Medicare survey data between White and Asian Medicare beneficiaries for CAHPS reporting composites (communication with personal doctor, access to care, plan customer service) and global ratings of care using pooled data from 2007 to 2011. Responses were obtained from 1,326,410 non-Hispanic Whites and 40,672 non-Hispanic Asians (hereafter referred to as Whites and Asians). The median age for Whites was 70, with 24 % 80 or older, and 70 for Asians, with 23 % 80 or older. Fifty-eight percent of Whites and 56 % of Asians were female. RESULTS: A model without group specific estimates fit the data as well as a model that included 12 group specific estimates (7 factor loadings, 3 measured variable errors, and 2 item intercepts): Comparative Fit Index = 0.947 and 0.948; root-mean-square error of approximation = 0.052 and 0.052, respectively). Differences in latent CAHPS score means between Whites and Hispanics estimated from the two models were similar, differing by 0.053 SD or less. CONCLUSIONS: This study provides support for measurement equivalence of the CAHPS Medicare survey composites (communication, access, customer service) and global ratings between White and Asian respondents, supporting comparisons of care experiences between the two groups. PMID- 27495275 TI - Mortality risk and perceived quality of life as a function of waking time in discretionary movement-based behaviors: isotemporal substitution effects. AB - OBJECTIVE: Previous research has examined associations of sedentary behavior (SB), light-intensity physical activity (LIPA) and moderate-to-vigorous physical activity (MVPA) with health-related quality of life (HRQOL) and mortality. However, most of these studies have been limited to examining their potential "independent" effects, as opposed to whether mortality risk and HRQOL vary as a function of waking time in these discretionary movement-related behaviors, which was this study's purpose. METHODS: Data from the 2003-2006 NHANES were employed, with follow-up mortality assessed through 2011 (5377 adults 20-85 years). HRQOL was assessed via survey, with physical activity assessed using an accelerometer over a 7-day monitoring period. Isotemporal substitution analyses were employed. RESULTS: Participants engaged in little MVPA during their monitored waking time and higher mortality risk appeared to cluster more so among those spending a greater proportion of their day in SB with less LIPA engagement. Substituting 30 min/day of SB with MVPA would be expected to reduce mortality risk by 81 % (HRadjusted = 0.19; 95 % CI: 0.06-0.60; P = 0.006) and reduce worse HRQOL by 72 % (OR = 0.28; 95 % CI: 0.13-0.58; P = 0.001). CONCLUSIONS: Allocation of waking time in movement-based behaviors is associated with all-cause mortality and HRQOL. Thus, clinicians should encourage their patients to substitute SB with reasonable amounts of LIPA and MVPA. PMID- 27495276 TI - Predicting urinary incontinence after surgery for pelvic organ prolapse. AB - PURPOSE OF REVIEW: Many women choosing to have surgery for pelvic organ prolapse also choose to undergo continence surgery. This review focuses on available evidence that clinicians may use to counsel patients when choosing whether to perform continence surgery and how predictive analytic tools improve this decision-making process. RECENT FINDINGS: Midurethral sling, Burch cystourethropexy and bladder neck sling are highly effective for the surgical treatment of stress urinary incontinence. Trials demonstrate that continence surgery may be routinely performed to reduce the risk of postoperative incontinence in women undergoing surgery for pelvic organ prolapse with or without preoperative stress urinary incontinence. Although these procedures are effective and well tolerated on average, media concerns, regulatory warnings and litigation reinforce the need for a balanced discussion regarding efficacy and potential adverse events directed at the individual patient during the preoperative visit. Advances in predictive analytics allow surgeons to quantitate individual risk using algorithms that tailor estimates for the individual patient and facilitate shared understanding of risks and benefits. These models are less prone to cognitive biases and frequently outperform experienced clinicians. SUMMARY: This review discusses how predictive analytic tools can be used to improve decisions about continence surgery in the woman planning to undergo prolapse surgery. PMID- 27495277 TI - Erratum to: Sex Disparity in Gastric Cancer: Female Sex is a Poor Prognostic Factor for Advanced Gastric Cancer. PMID- 27495278 TI - Lymph Node Ratio Is Less Prognostic in Melanoma When Minimum Node Retrieval Thresholds Are Not Met. AB - BACKGROUND: Lymph node ratio (LNR), positive nodes divided by nodes examined, has been proposed for prognostication in melanoma to mitigate problems with low node counts. However, it is unclear if LNR offers superior prognostication over total counts of positive nodes and nodes examined. Additionally, the prognostic value of LNR may change if a threshold number of nodes are examined. We evaluated whether LNR is more prognostic than positive nodes and nodes examined, and whether the prognostic value of LNR changes with minimum thresholds. METHODS: Using the National Cancer Data Base Participant User File, we identified 74,692 incident cases with nodal dissection during 2000-2006. We compared LNR versus counts of examined and positive nodes based on Harrell's C, a measure of predictive ability. We then stratified by total nodes examined: greater versus fewer than ten for axillary lymph node dissection (ALND) and greater versus fewer than five for inguinal lymph node dissection (ILND). RESULTS: Overall, LNR had a Harrell's C of 0.628 (95 % confidence interval [CI] 0.625-0.631). Examined and positive nodes were not significantly different from this, with a Harrell's C of 0.625 (95 % CI 0.621-0.630). In ALND, LNR had a Harrell's C of 0.626 (95 % CI 0.610-0.643) with >=10 nodes versus 0.554 (95 % CI 0.551-0.558) < 10 nodes. In ILND, LNR had a Harrell's C of 0.679 (95 % CI 0.664-0.694) with >=5 nodes versus C of 0.601 (95 % CI 0.595-0.606) < 5 nodes. CONCLUSIONS: LNR provides no prognostic superiority versus counts of examined and positive nodes. Moreover, the prognostic value of LNR diminishes when minimum node retrieval thresholds are not met. PMID- 27495280 TI - Robotic-Assisted Placement of an Hepatic Artery Infusion Pump and Catheter for Regional Chemotherapy of the Liver. AB - BACKGROUND: Hepatic artery infusion (HAI) chemotherapy is an effective regional therapy for unresectable colorectal liver metastases (U-CRLM).1 , 2 One of its limitations is the need for a laparotomy, which can delay the use of systemic therapy.3 Here, we describe a purely robotic technique for placement of an HAI pump (Fig 1). PATIENT: A 62-year-old male presented with a symptomatic ascending colon cancer and multiple bilobar unresectable liver metastases. He underwent laparoscopic right colectomy followed by six cycles of FOLFOXIRI and bevacizumab with stable disease by RECIST (Response Evaluation Criteria in Solid Tumors) criteria, and also underwent robotic HAI pump placement. TECHNIQUE: The patient was placed supine on a split-leg table, and four robotic and two laparoscopic assistant ports were placed as shown. Use of the robot allowed for precise dissection of the common hepatic artery (CHA) and gastroduodenal artery (GDA), as well as a portal lymphadenectomy. A standard cholecystectomy was performed and the GDA was dissected for a distance of 2-3 cm from its takeoff from the CHA. The robotic scissors were used to create a precise transverse GDA arteriotomy, and the HAI pump catheter tip was advanced to the CHA/GDA junction and secured with two silk ties. Finally, a methylene blue dye injection test was performed to ensure uniform distribution within the liver. Operative time was 147 min, estimated blood loss was 20 ml, and the postoperative course was uneventful. The first dose of HAI with floxuridine was administered on postoperative day 4 (day of discharge) and systemic chemotherapy was administered 2 weeks later. CONCLUSION: The robotic platform allows for minimally invasive HAI pump placement. Fig. 1 Port placement for robotic-assisted hepatic artery infusion pump placement using the DaVinci Si platform. Illustration depicts a 12 mm periumbilical port for the robotic camera (upper green port), three 8 mm (purple) robotic working ports (the left MCL, right MCL, and right AAL for robotic arms R1, R2, and R3, respectively), and 12 mm (lower green) and 5 mm (red) laparoscopic assistant ports in the right and left lower quadrants, respectively. The pump pocket is created in the left lower quadrant just below the 5 mm (red) port site. PMID- 27495279 TI - Changing Odds of Survival Over Time among Patients Undergoing Surgical Resection of Gallbladder Carcinoma. AB - BACKGROUND: While survival after malignancies is traditionally reported as actuarial survival, conditional survival (CS) may be more clinically relevant by accounting for "accrued" survival time as time progresses. We sought to compare actuarial and CS among patients with gallbladder carcinoma (GBC) . METHODS: A total of 312 patients who underwent curative intent surgery for GBC between 2000 and 2014 were identified using a multi-institutional database. Overall survival (OS) was estimated using the Kaplan-Meier method. CS was calculated as the probability of surviving an additional 3 years at year "x" after surgery using the formula CS3 = S(x+3)/Sx. RESULTS: Among all patients, the median actuarial OS was 24.8 months (IQR 13.3-88.9). While actuarial survival decreased over time, 3 year CS (CS3) increased, with CS3 at 2 years after surgery noted to be 61.8 % compared with the 5-year actuarial OS of 31.6 %. Factors associated with reduced actuarial OS were positive margin status (HR 3.61, 95 % CI 2.47-5.26), increasing tumor size (HR = 1.02, 95 % CI 1.01-1.02), higher tumor grade (HR 2.98, 95 % CI 1.47-6.04), residual disease at repeat resection (HR = 2.78, 95 % CI 1.49-3.49, p < 0.001), and lymph node metastasis (HR = 1.95, 95 % CI 1.39-2.75, all p < 0.001). The calculated CS3 exceeded the actuarial survival within each high-risk patient subgroup. For example, patients with residual disease at repeat resection had an actuarial survival 23.1 % at 5 years versus a CS3 of 56.3 % in patients alive at 2 years (Delta = 33.2 %). CONCLUSIONS: CS provides a more accurate, dynamic estimate for survival, especially among high-risk patients. CS estimates can be used to accurately predict survival and guide clinical decision making. PMID- 27495281 TI - Laparoscopic Anterior Resection with Transvaginal Specimen Extraction (TVSE) for Colorectal Cancer and Concomitant Total Hysterectomy and Bilateral Salpingo Oophrectomy (THBSO): A Technical Description. AB - BACKGROUND: Natural orifice specimen extraction (NOSE) has evolved to circumvent the need for a specimen extraction site. Transvaginal specimen extraction (TVSE) for colorectal disease has been shown to be safe and feasible in selected cases.1 , 2 We describe our technique of TVSE in a case of laparoscopic ultra-low anterior resection (ULAR) with defunctioning ileostomy (DI) with a concomitant total hysterectomy and bilateral salpingo-oophrectomy (THBSO). METHODS AND RESULTS: A 74-year-old Chinese female was diagnosed with a mid-rectal cancer following colonoscopic evaluation for a change in bowel habits. Preoperative magnetic resonance imaging (MRI) suggested T2N0 disease and the patient was recommended for upfront surgery following multidisciplinary discussion. Computed tomography (CT) scan confirmed a 4.3 * 3.4 cm right adnexal cystic lesion, without enhancing septations or soft tissue component. No metastatic disease was identified. The patient underwent a laparoscopic ULAR with DI and THBSO with TVSE; operative time was 469 min. The specimen showed a 2.5 cm mid-rectal tumour. Histology revealed a pT3N1a moderately differentiated adenocarcinoma of the mid rectum, with 1 of 20 lymph nodes involved by metastatic carcinoma. The quality of the total mesorectal excision (TME) was good, with no breach in the mesorectal fascia. The distal and radial margins were 1.5 and 3.0 cm, respectively. The patient recovered well postoperatively, with minimal wound site pain, and was discharged well on postoperative day 5. CONCLUSION: TVSE is oncologically safe and feasible in certain malignant colorectal pathologies. It is an option to consider in selected cases that require a concomitant gynecological procedure. PMID- 27495282 TI - Distal Pancreatectomy with en Bloc Celiac Axis Resection (Modified Appleby Procedure) for Locally Advanced Pancreatic Body Cancer: A Single-Center Review of 80 Consecutive Patients. AB - BACKGROUND: Recently, distal pancreatectomy with en bloc celiac axis resection (DP-CAR) or modified Appleby procedure for locally advanced pancreatic body cancer is increasingly reported. However, actual long-term survival data are still unknown. METHODS: This study retrospectively reviewed 80 consecutive patients with pancreatic body cancer who underwent DP-CAR at a single institution. RESULTS: The study included 40 men and 40 women with a median age of 65 years (range, 44-85 years). A pancreatic fistula was the most common complication, occurring in 47 patients (57.5 %). Other complications with a high incidence were ischemic gastropathy (23 patients, 28.8 %) and delayed gastric emptying (20 patients, 25 %). According to the Clavien-Dindo classification, the major complications, defined as complications of grade 3 or higher, were observed in 33 patients (41.3 %), and the in-hospital mortality involved four patients (5 %). For all 80 patients, the 1-, 2-, and 5-year overall survivals (OSs) were respectively 81.1, 56.9, and 32.7 %, and the median survival time was 30.9 months. The actual 5-year survival for the 61 patients whose surgery was performed five or more years earlier was 27.9 % (17 of 61). The 1-, 2-, and 5 year OSs for the patients who underwent preoperative therapy (100, 90, and 78.8 %) were significantly better than for those who underwent upfront surgery (77.9, 51.5, and 26.7 %; P < 0.0001). CONCLUSIONS: The findings show DP-CAR to be a valid procedure for treating locally advanced pancreatic body cancer, which might contribute more to patients' survival when performed as part of multidisciplinary treatment. PMID- 27495283 TI - Evaluation and treatment of insomnia in adult cancer survivorship programs. AB - PURPOSE: Insomnia is commonly experienced by cancer survivors. Chronic insomnia is associated with significant physical and psychosocial consequences if not properly treated. Both the National Cancer Institute (NCI) and the National Comprehensive Cancer Network (NCCN) recommend the evaluation of sleep disturbances and evidence-based treatment of insomnia during routine survivorship care. To better understand current clinical practices, we conducted a survey of major cancer centers across the United States (US). METHODS: Adult survivorship programs at the 25 US cancer centers that are both NCI-designated comprehensive cancer centers and NCCN member institutions were surveyed about the evaluation and treatment of insomnia in their hospital. RESULTS: All institutions responded to the survey. Thirteen centers (56 %) reported screening <25 % of survivors for sleep disorders, and few clinicians providing survivorship care were well prepared to conduct a proper sleep evaluation. Insomnia was most commonly treated with sleep hygiene, or pharmacotherapy, rather than cognitive-behavioral therapy. No program reported that >50 % of their survivors were receiving optimal insomnia related care. A variety of methods to improve insomnia care were endorsed by respondents. CONCLUSIONS: There is a clear need to improve the evaluation and treatment of insomnia for cancer survivors at institutions across the country. Cancer centers deemed a number of modalities relevant for improving provider confidence in addressing sleep challenges. IMPLICATIONS FOR CANCER SURVIVORS: To improve the quality of insomnia care for survivors, systematic interventions to increase standardized screening for sleep disorders, providing additional sleep medicine training for survivorship clinicians, and optimizing the role of sleep medicine specialists in the oncology setting should be considered. PMID- 27495284 TI - Suicide risk in primary care patients diagnosed with a personality disorder: a nested case control study. AB - BACKGROUND: Personality disorder (PD) is associated with elevated suicide risk, but the level of risk in primary care settings is unknown. We assessed whether PD among primary care patients is linked with a greater elevation in risk as compared with other psychiatric diagnoses, and whether the association is modified by gender, age, type of PD, and comorbid alcohol misuse. METHODS: Using data from the UK Clinical Practice Research Datalink, 2384 suicides were matched to 46,899 living controls by gender, age, and registered practice. Prevalence of PD, other mental disorders, and alcohol misuse was calculated for cases and controls separately and conditional logistic regression models were used to estimate exposure odds ratios. We also fitted gender interaction terms and formally tested their significance, and estimated gender age-specific effects. RESULTS: We found a 20-fold increase in suicide risk for patients with PD versus no recorded psychiatric disorder, and a four-fold increase versus all other psychiatric illnesses combined. Borderline PD and PD with comorbid alcohol misuse were associated with a 37- and 45-fold increased risk, respectively, compared with those with no psychiatric disorders. Relative risks were higher for female than for male patients with PD. Significant risks associated with PD diagnosis were identified across all age ranges, although the greatest elevations were in the younger age ranges, 16-39 years. CONCLUSIONS: The large elevation in suicide risk among patients diagnosed with PD and comorbid alcohol misuse is a particular concern. GPs have a potentially key role to play in intervening with patients diagnosed with PD, particularly in the presence of comorbid alcohol misuse, which may help reduce suicide risk. This would mean working with specialist care, agreed clinical pathways and availability of services for comorbidities such as alcohol misuse, as well as opportunities for GPs to develop specific clinical skills. PMID- 27495285 TI - Conformational Space and Stability of ETD Charge Reduction Products of Ubiquitin. AB - Owing to its versatility, electron transfer dissociation (ETD) has become one of the most commonly utilized fragmentation techniques in both native and non-native top-down mass spectrometry. However, several competing reactions-primarily different forms of charge reduction-occur under ETD conditions, as evidenced by the distorted isotope patterns usually observed. In this work, we analyze these isotope patterns to compare the stability of nondissociative electron transfer (ETnoD) products, specifically noncovalent c/z fragment complexes, across a range of ubiquitin conformational states. Using ion mobility, we find that more extended states are more prone to fragment release. We obtain evidence that for a given charge state, populations of ubiquitin ions formed either directly by electrospray ionization or through collapse of more extended states upon charge reduction, span a similar range of collision cross-sections. Products of gas phase collapse are, however, less stabilized towards unfolding than the native conformation, indicating that the ions retain a memory of previous conformational states. Furthermore, this collapse of charge-reduced ions is promoted if the ions are 'preheated' using collisional activation, with possible implications for the kinetics of gas-phase compaction. Graphical Abstract ?. PMID- 27495286 TI - Lipid Emulsion Formulation of Parenteral Nutrition Affects Intestinal Microbiota and Host Responses in Neonatal Piglets. AB - BACKGROUND: Total parenteral nutrition (TPN) is a cause of intestinal microbial dysbiosis and impaired gut barrier function. This may contribute to life threatening parenteral nutrition-associated liver disease and sepsis in infants. We compared the effects of a lipid emulsion containing long-chain omega-3 polyunsaturated fatty acids (PUFAs; SMOFlipid) and a predominantly omega-6 PUFA emulsion (Intralipid) on microbial composition and host response at the mucosal surface. MATERIALS AND METHODS: Neonatal piglets were provided isocaloric, isonitrogenous TPN for 14 days versus sow-fed (SF) controls. Equivalent lipid doses (10 g/kg/d) were given of either SMOFlipid (ML; n = 10) or Intralipid (SO; n = 9). Ileal segments and mucosal scrapings were used to characterize microbial composition by 16S rRNA gene sequencing and quantitative gene expression of tight junction proteins, mucins, antimicrobial peptides, and inflammatory cytokines. RESULTS: The microbial composition of TPN piglets differed from SF, while ML and SO differed from each other (analysis of molecular variance; P < .05); ML piglets were more similar to SF, as indicated by UniFrac distance ( P < .05). SO piglets showed a specific and dramatic increase in Parabacteroides ( P < .05), while ML showed an increase in Enterobacteriaceae ( P < .05). Gene expression of mucin, claudin 1, beta-defensin 2, and interleukin 8 were higher in TPN; overall increases were significantly less in ML versus SO ( P < .05). CONCLUSION: The formulation of parenteral lipid is associated with differences in the gut microbiota and host response of TPN-fed neonatal piglets. Inclusion of omega-3 long-chain PUFAs appears to improve host-microbial interactions at the mucosal surface, although mechanisms are yet to be defined. PMID- 27495288 TI - Liquid biopsies will be routine NHS test for cancer "in under five years". PMID- 27495287 TI - Effect of oral sodium bicarbonate on fibroblast growth factor-23 in patients with chronic kidney disease: a pilot study. AB - BACKGROUND: The regulation of fibroblast growth factor-23 (FGF23) secretion in patients with chronic kidney disease (CKD) is incompletely understood. An in vitro study showed that metabolic acidosis increased FGF23 in mouse bone. The objective of this study is to evaluate the effect of oral sodium bicarbonate on circulating FGF23 levels in patients with CKD. METHODS: This was a single-blind pilot study. Twenty adults with estimated glomerular filtration rate between 15 45 mL/min/1.73 m(2) and serum bicarbonate between 20-24 mEq/L were treated with placebo for 2 weeks, followed by increasing doses of oral sodium bicarbonate (0.3, 0.6 and 1.0 mEq/kg/day) in 2 week intervals for a total of 6 weeks. C terminal FGF23 levels were measured at the initial visit, after 2 weeks of placebo and after 6 weeks of bicarbonate therapy. Wilcoxon matched-pairs signed rank test was used to compare FGF23 before and after sodium bicarbonate. RESULTS: After 6 weeks of oral sodium bicarbonate, the median FGF23 increased significantly from 150.9 RU/mL (IQR 107.7-267.43) to 191.4 RU/mL (IQR 132.6 316.9) (p = 0.048) and this persisted after excluding participants who received activated vitamin D. CONCLUSIONS: FGF23 increased after short-term oral sodium bicarbonate therapy in patients with CKD and mild metabolic acidosis. It is unclear whether this was due to the alkalinizing effect of sodium bicarbonate or other factors. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( NCT00888290 ) on April 23, 2009. PMID- 27495289 TI - In-Vitro dual inhibition of protein glycation, and oxidation by some Arabian plants. AB - BACKGROUND: Diabetes mellitus is a metabolic disorder of epidemic proportion, projected to become the major cause of morbidity and mortality in the world in future. Despite extensive research in understanding this disease at molecular level, and the discovery of new drugs, diabetes and its complications remain largely untreated. Many of the late diabetic complications are associated with the glycation of proteins in the body. Natural flora has long been a rich source for therapeutic agents, especially against diabetes. The present study deals with the anti-glycation properties of some medicinally important plants of Arabian region. METHODS: Twenty-six medicinal plants, commonly found in different regions of Arabian Peninsula, were evaluated for their protein anti-glycation activity by using BSA-MG glycation assay in-vitro. The extracts were incubated with BSA and MG at 37 degrees C for 9 days, each sample was then examined for the presence of fluorescence (lambdaex 330 nm, and lambdaem 420 nm), which represent the extent of protein glycation. Antioxidant activity was evaluated by using 1,1-diphenyl- 2 picrylhydrazyl (DPPH), iron chelation, and superoxide radical scavenging asaays. RESULTS: The data revealed that out of 26 medicinal plants, five plants viz. Sida cordifolia, Plumbago zeylanica, Tribulus terrestris, Glycyrrhiza glabra, and Rosa indica were active against the in-vitro protein glycation with IC50 values between 0.408- 1.690 mg/mL. Among the active plants, Glycyrrhiza glabra L. was found to be the most potent (IC50 = 0.408 +/- 0.027 mg/mL), followed by Rosa indica (IC50 = 0.596 +/- 0.0179 mg/mL), and Sida cordifolia L. (IC50 = 0.63 +/- 0.009 mg/mL). The antioxidant potential of these plant extracts were also determined by using DPPH (2,2-diphenyl-1-picrylhydrazyl), iron chelation, and superoxide anion radical scavenging assays. Among five plants, Sida cordifolia exhibited a potent anti-oxidant activity in both DPPH and superoxide anion radical scavenging assays (IC50 = 0.005 +/- 0.0004, and 0.078 +/- 0.002 mg/mL, respectively), followed by Rosa indica (IC50 = 0.023 +/- 0.0005 and 0.141 +/- 0.003 mg/mL, respectively). CONCLUSIONS: Protein glycation in hyperglycemic conditions involve oxidative changes. Therefore dual inhibition of protein glycation and oxidation are desirable properties in any test substance investigated for therapeutic purposes. PMID- 27495290 TI - Subjective evaluation of the frequency of coffee intake and relationship to osteoporosis in Chinese men. AB - BACKGROUND: The main purpose of this study was to evaluate the associations between frequency of coffee intake and osteoporosis (OP) in a general Chinese male sample. METHODS: We conducted a large-scale, community-based, cross sectional study to investigate the associations by using a self-report questionnaire to estimate the frequency of coffee intake. A total of 992 men were available for data analysis in this study. Multiple regression models controlling for confounding factors to include frequency of coffee intake variable were performed to investigate the relationships for OP. RESULTS: Positive correlations between frequency of coffee intake and T-score were reported (beta = 0.211, P = 0.024). Multiple regression analysis indicated that the frequency of coffee intake was significantly associated with OP (P < 0.05 for model 1 and model 2). The men with moderate frequency of coffee intake had a lower prevalence of OP. CONCLUSIONS: The findings indicated that consumption of coffee was independently and significantly associated with OP. The prevalence of OP was less frequent in Chinese men with moderate coffee intake. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02451397. PMID- 27495291 TI - A post-hoc analysis of the comparative efficacy of canagliflozin and glimepiride in the attainment of type 2 diabetes-related quality measures. AB - BACKGROUND: The randomized, double-blind CANTATA-SU (CANagliflozin Treatment And Trial Analysis Sulfonyl Urea) clinical trial compared the use of canagliflozin (100 mg or 300 mg) and maximally tolerated glimepiride (6-8 mg) over 104 weeks as add-on therapy for patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin. Compared with glimepiride, canagliflozin use was associated with durable reductions in glycated hemoglobin (A1C), blood pressure (BP), and body weight. The aim of this post-hoc analysis of the CANTATA-SU trial was to assess the comparative efficacy of canagliflozin and glimepiride in the attainment of recently updated diabetes-related quality measures (QMs) for up to 104 weeks of treatment. METHODS: This post-hoc analysis evaluated the proportions of patients achieving individual diabetes-related QMs using data from the randomized, double-blind, Phase 3 CANTATA-SU trial. Change in A1C from baseline, and proportions of the study population achieving QMs: A1C <7.0 %, <8.0 %, and >9.0 % were assessed. Secondary endpoints included change in BP from baseline, and the proportions of the study population achieving QMs related to BP and body weight. RESULTS: The proportions of patients in the canagliflozin 100 mg, canagliflozin 300 mg, and glimepiride groups meeting criteria for all QMs were similar at baseline. At 52 and 104 weeks of treatment, canagliflozin 100 mg and canagliflozin 300 mg provided better or similar reductions in A1C from baseline and achievement of glycemic control QMs compared with glimepiride. At 52 and 104 weeks of treatment, the attainment of QMs related to reductions in body weight and BP all favored canagliflozin compared with glimepiride. Canagliflozin was associated with lower incidence of documented hypoglycemia and severe hypoglycemia compared with glimepiride. CONCLUSIONS: Using the recently adjusted and currently accepted diabetes-related QMs, this analysis observed superior glycemic control with canagliflozin compared with maximally tolerated glimepiride in patients with T2DM who were previously poorly controlled on metformin monotherapy. Compared with maximally tolerated glimepiride, canagliflozin resulted in better achievement of diabetes-related QMs related to weight loss and BP, and was associated with lower incidences of hypoglycemic events. TRIAL REGISTRATION: Clinical trial registry name: CANagliflozin Treatment And Trial Analysis-Sulfonylurea (CANTATA-SU) SGLT2 Add-on to Metformin Versus Glimepiride. CLINICAL TRIAL REGISTRATION NUMBER: NCT00968812 , registered August 28, 2009. PMID- 27495292 TI - Stereoselective Metabolism of Bupropion to OH-bupropion, Threohydrobupropion, Erythrohydrobupropion, and 4'-OH-bupropion in vitro. AB - Bupropion is a widely used antidepressant, smoking cessation aid, and weight-loss therapy. It is administered as a racemic mixture, but the pharmacokinetics and activity of bupropion are stereoselective. The activity and side effects of bupropion are attributed to bupropion and its metabolites S,S- and R,R-OH bupropion, threohydrobupropion, and erythrohydrobupropion. Yet the stereoselective metabolism in vitro and the enzymes contributing to the stereoselective disposition of bupropion have not been characterized. In humans, the fraction of bupropion metabolized (fm) to the CYP2B6 probe metabolite OH bupropion is 5-16%, but ticlopidine increases bupropion exposure by 61%, suggesting a 40% CYP2B6 and/or CYP2C19 fm for bupropion. Yet, the CYP2C19 contribution to bupropion clearance has not been defined, and the enzymes contributing to overall bupropion metabolite formation have not been fully characterized. The aim of this study was to characterize the stereoselective metabolism of bupropion in vitro to explain the stereoselective pharmacokinetics and the effect of drug-drug interactions (DDIs) and CYP2C19 pharmacogenetics on bupropion exposure. The data predict that threohydrobupropion accounts for 50 and 82%, OH-bupropion for 34 and 12%, erythrohydrobupropion for 8 and 4%, and 4'-OH bupropion for 8 and 2% of overall R- and S-bupropion clearance, respectively. The fm,CYP2B6 was predicted to be 21%, and the fm,CYP2C19, 6% for racemic bupropion. Importantly, ticlopidine was found to inhibit all metabolic pathways of bupropion in vitro, including threohydrobupropion, erythrohydrobupropion, and 4'OH bupropion formation, explaining the in vivo DDI. The stereoselective pharmacokinetics of bupropion were quantitatively explained by the in vitro metabolic clearances and in vivo interconversion between bupropion stereoisomers. PMID- 27495293 TI - Absence of association between whole blood viscosity and delirium after cardiac surgery: a case-controlled study. AB - BACKGROUND: Delirium after cardiothoracic surgery is common and associated with impaired outcomes. Although several mechanisms have been proposed (including changes in cerebral perfusion), the pathophysiology of postoperative delirium remains unclear. Blood viscosity is related to cerebral perfusion and thereby might contribute to the development of delirium after cardiothoracic surgery. The aim of this study was to investigate whether whole blood viscosity differs between cardiothoracic surgery patients with and without delirium. METHODS: In this observational study postoperative whole blood viscosity of patients that developed delirium (cases) were compared with non-delirious cardiothoracic surgery patients (controls). Cases were matched with the controls, yielding a 1:4 case-control study. Serial hematocrit, fibrinogen, and whole blood viscosity were determined pre-operatively and at each postoperative day. Delirium was assessed using the validated Confusion Assessment Method for the Intensive Care Unit or Delirium Screening Observation scale. RESULTS: In total 80 cardiothoracic surgery patients were screened of whom 12 delirious and 48 matched non-delirious patients were included. No significant difference was found between both groups in fibrinogen (p = 0.36), hematocrit (p = 0.23) and the area under curve of the whole blood viscosity between shear rates 0.02 and 50 s(-1) (p = 0.80) or between shear rates 0.02 and 5 s(-1) (p = 0.78). CONCLUSION: In this case control study in cardiothoracic surgery patients changes in whole blood viscosity were not associated with the development of delirium. PMID- 27495294 TI - Outcomes of abdominoperineal resection for management of anal cancer in HIV positive patients: a national case review. AB - BACKGROUND: The incidence of anal cancer in human immunodeficiency virus (HIV) positive individuals is increasing, and how co-infection affects outcomes is not fully understood. This study sought to describe the current outcome disparities between anal cancer patients with and without HIV undergoing abdominoperineal resection (APR). METHODS: A retrospective review of all US patients diagnosed with anal squamous cell carcinoma, undergoing an APR, was performed. Cases were identified using a weighted derivative of the Healthcare Utilization Project's National Inpatient Sample (2000-2011). Patients greater than 60 years old were excluded after finding a skewed population distribution between those with and without HIV infection. Multivariable logistic regression and generalized linear modeling analysis examined factors associated with postoperative outcomes and cost. Perioperative complications, in-hospital mortality, length of hospital stay, and hospital costs were compared for those undergoing APR with and without HIV infection. RESULTS: A total of 1725 patients diagnosed with anal squamous cell cancer undergoing APR were identified, of whom 308 (17.9 %) were HIV positive. HIV-positive patients were younger than HIV-negative patients undergoing APR for anal cancer (median age 47 years old versus 51 years old, p < 0.001) and were more likely to be male (95.1 versus 30.6 %, p < 0.001). Postoperative hemorrhage was more frequent in the HIV-positive group (5.1 versus 1.5 %, p = 0.05). Mortality was low in both groups (0 % in HIV-positive versus 1.49 % in HIV-negative, p = 0.355), and length of stay (LOS) (10+ days; 75th percentile of patient data) was similar (36.9 % with HIV versus 29.8 % without HIV, p = 0.262). Greater hospitalization costs were associated with patients who experienced a complication. However, there was no difference in hospitalization costs seen between HIV-positive and HIV-negative patients (p = 0.66). CONCLUSIONS: HIV status is not associated with worse postoperative recovery after APR for anal cancer as measured by length of stay or hospitalization cost. Further study may support APRs to be used more aggressively in HIV-positive patients with anal cancer. PMID- 27495296 TI - Diagnosis and treatment based on quantitative PCR after controlled human malaria infection. AB - BACKGROUND: Controlled human malaria infection (CHMI) has become well-established in the evaluation of drugs and vaccines. Anti-malarial treatment is usually initiated when thick blood smears are positive by microscopy. This study explores the effects of using the more sensitive qPCR as the primary diagnostic test. METHODS: 1691 diagnostic blood samples were analysed by microscopy and qPCR from 115 volunteers (55 malaria naive and 60 having received chemoprophylaxis and sporozoite immunization) who were challenged by five mosquitoes infected with Plasmodium falciparum sporozoites of the NF54 strain. RESULTS: Retrospective analysis of different qPCR criteria for diagnosis and treatment, showed that once daily qPCR (threshold 100 parasites/ml) had 99 % sensitivity and 100 % specificity, and shortened the median prepatent period from 10.5 to 7.0 days after CHMI when compared to twice daily measurement of thick blood smears (threshold 4000 parasites/ml). This is expected to result in a 78 % decrease of adverse events before initiation of treatment in future studies. Trial outcome related to infection and protective efficacy remained unchanged. CONCLUSION: The use of qPCR as the primary diagnostic test in CHMI decreases symptoms as well as parasitaemia while obviating the need for twice daily follow-up. The implementation improves safety while reducing the clinical burden and costs without compromising the evaluation of protective efficacy. PMID- 27495295 TI - A community-based lifestyle and weight loss intervention promoting a Mediterranean-style diet pattern evaluated in the stroke belt of North Carolina: the Heart Healthy Lenoir Project. AB - BACKGROUND: Because residents of the southeastern United States experience disproportionally high rates of cardiovascular disease (CVD), it is important to develop effective lifestyle interventions for this population. METHODS: The primary objective was to develop and evaluate a dietary, physical activity (PA) and weight loss intervention for residents of the southeastern US. The intervention, given in eastern North Carolina, was evaluated in a 2 year prospective cohort study with an embedded randomized controlled trial (RCT) of a weight loss maintenance intervention. The intervention included: Phase I (months 1-6), individually-tailored intervention promoting a Mediterranean-style dietary pattern and increased walking; Phase II (months 7-12), option of a 16-week weight loss intervention for those with BMI >= 25 kg/m(2) offered in 2 formats (16 weekly group sessions or 5 group sessions and 10 phone calls) or a lifestyle maintenance intervention; and Phase III (months 13-24), weight loss maintenance RCT for those losing >= 8 lb with all other participants receiving a lifestyle maintenance intervention. Change in diet and PA behaviors, CVD risk factors, and weight were assessed at 6, 12, and 24 month follow-up. RESULTS: Baseline characteristics (N = 339) were: 260 (77 %) females, 219 (65 %) African Americans, mean age 56 years, and mean body mass index 36 kg/m(2). In Phase I, among 251 (74 %) that returned for 6 month follow-up, there were substantial improvements in diet score (4.3 units [95 % CI 3.7 to 5.0]), walking (64 min/week [19 to 109]), and systolic blood pressure (-6.4 mmHg [-8.7 to -4.1]) that were generally maintained through 24 month follow-up. In Phase II, 138 (57 group only, 81 group/phone) chose the weight loss intervention and at 12 months, weight change was: -3.1 kg (-4.9 to -1.3) for group (N = 50) and -2.1 kg (-3.2 to -1.0) for group/phone combination (N = 75). In Phase III, 27 participants took part in the RCT. At 24 months, weight loss was -2.1 kg (-4.3 to 0.0) for group (N = 51) and 1.1 kg (-2.7 to 0.4) for combination (N = 72). Outcomes for African American and whites were similar. CONCLUSIONS: The intervention yielded substantial improvement in diet, PA, and blood pressure, but weight loss was modest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01433484. PMID- 27495297 TI - Acute arterial baroreflex-mediated changes in plasma catecholamine concentrations in a chronic rat model of myocardial infarction. AB - While it may be predictable that plasma norepinephrine (NE) concentration changes with efferent sympathetic nerve activity (SNA) in response to baroreceptor pressure inputs, an exact relationship between SNA and plasma NE concentration remains to be quantified in heart failure. We examined acute baroreflex-mediated changes in plasma NE and epinephrine (Epi) concentrations in normal control (NC) rats and rats with myocardial infarction (MI) (n = 6 each). Plasma NE concentration correlated linearly with SNA in the NC group (slope: 2.17 +/- 0.26 pg mL(-1) %(-1), intercept: 20.0 +/- 18.2 pg mL(-1)) and also in the MI group (slope: 19.20 +/- 6.45 pg mL(-1) %(-1), intercept: -239.6 +/- 200.0 pg mL(-1)). The slope was approximately nine times higher in the MI than in the NC group (P < 0.01). Plasma Epi concentration positively correlated with SNA in the NC group (slope: 1.65 +/- 0.79 pg mL(-1) %(-1), intercept: 115.0 +/- 69.5 pg mL(-1)) and also in the MI group (slope: 7.74 +/- 2.20 pg mL(-1) %(-1), intercept: 24.7 +/- 120.1 pg mL(-1)). The slope was approximately 4.5 times higher in the MI than in the NC group (P < 0.05). Intravenous administration of desipramine (1 mg kg(-1)) significantly increased plasma NE concentration but decreased plasma Epi concentration in both groups, suggesting that neuronal NE uptake had contributed to the reduction in plasma NE concentration. These results indicate that high levels of plasma catecholamine in MI rats were still under the influence of baroreflex-mediated changes in SNA, and may provide additional rationale for applying baroreflex activation therapy in patients with chronic heart failure. PMID- 27495298 TI - Bidirectional variability in motor cortex excitability modulation following 1 mA transcranial direct current stimulation in healthy participants. AB - Due to the high interindividual response variability following transcranial direct current stimulation (tDCS), it is apparent that further research of the long-lasting effects of the stimulation technique is required. We aimed to investigate interindividual variability following anodal tDCS and cathodal tDCS in a large-scale prospective cross-over study. Motor cortex physiology measurements were obtained using transcranial magnetic stimulation (TMS) in 59 healthy participants comparing motor-evoked potential (MEP) magnitudes following two tDCS paradigms: 1 mA anodal tDCS for 13 min and 1 mA cathodal tDCS for 9 min. Analysis compared MEP changes over time for both polarities. Additionally, we applied hierarchical cluster analysis to assess the dynamics of poststimulation changes. Overall, anodal tDCS resulted in a significant increase in corticospinal excitability lasting for 40 min poststimulation, whereas cathodal tDCS did not alter corticospinal excitability. Cluster analysis revealed for cathodal tDCS both a cluster showing significant stable MEP reduction and a second cluster displaying MEP increase over time. Two diametrical clusters were also found for anodal tDCS Regardless of polarity, individuals with MEP increase following stimulation showed steeper cortical recruitment curves compared to the clusters with decreased MEP magnitudes. The observed findings confirm a bidirectional modulation of corticospinal excitability following 1 mA tDCS in separate subgroups and the relationship to cortical recruitment. PMID- 27495300 TI - Retinal vein occlusion and the use of a dexamethasone intravitreal implant (Ozurdex) in its treatment. PMID- 27495299 TI - Treadmill exercise within lower body negative pressure protects leg lean tissue mass and extensor strength and endurance during bed rest. AB - Leg muscle mass and strength are decreased during reduced activity and non-weight bearing conditions such as bed rest (BR) and spaceflight. Supine treadmill exercise within lower body negative pressure (LBNPEX) provides full-body weight loading during BR and may prevent muscle deconditioning. We hypothesized that a 40-min interval exercise protocol performed against LBNPEX 6 days week(-1) would attenuate losses in leg lean mass (LLM), strength, and endurance during 6 degrees head-down tilt BR, with similar benefits for men and women. Fifteen pairs of healthy monozygous twins (8 male and 7 female pairs) completed 30 days of BR with one sibling of each twin pair assigned randomly as the non-exercise control (CON) and the other twin as the exercise subject (EX). Before and after BR, LLM and isokinetic leg strength and endurance were measured. Mean knee and ankle extensor and flexor strength and endurance and LLM decreased from pre- to post-BR in the male CON subjects (P < 0.01), but knee extensor strength and endurance, ankle extensor strength, and LLM were maintained in the male EX subjects. In contrast, no pre- to post-BR changes were significant in the female subjects, either CON or EX, likely due to their lower pre-BR values. Importantly, the LBNPEX countermeasure prevents or attenuates declines in LLM as well as extensor leg strength and endurance. Individuals who are stronger, have higher levels of muscular endurance, and/or have greater LLM are likely to experience greater losses during BR than those who are less fit. PMID- 27495302 TI - Treatment for stage 4A retinopathy of prematurity: laser and/or ranibizumab. AB - PURPOSE: Stage 4A retinopathy of prematurity (ROP) is a critical phase where retinal detachment develops, but fovea is preserved. The present study aims to evaluate the effect of the first treatment choice (laser photocoagulation (LPC) or intravitreal ranibizumab (IVR)) applied in this critical phase on the prognosis of the disease. METHODS: Records of patients diagnosed with stage 4A ROP and whose first treatment was applied in our clinic were evaluated retrospectively. All patients were referred to our clinic for the treatment of advanced ROP . While group 1 was composed of the patients who were administered LPC as first treatment, group 2 included patients where IVR was applied as first treatment. The patients in both groups were referred to surgical treatment in the presence of progression. RESULTS: The present study included a total of 31 eyes in 16 patients with stage 4A ROP. Eighteen eyes of nine patients in group 1 were first applied LPC, and 13 eyes of seven patients in group 2 were first applied intravitreal ranibizumab. While anatomic outcomes of ten eyes in both groups were favorable, eight eyes in group 1 and three eyes in group 2 displayed progression and were referred to vitreoretinal surgery. CONCLUSIONS: Laser and/or IVR treatment may be effective as a non-surgical treatment for stage 4A ROP. Especially stage 4A ROP until 6 clock hours can regress without surgical treatment. However, in stage 4A with involvement wider than 6 clock hours, non surgical regression is difficult. Prospective controlled large series studies are necessary. PMID- 27495304 TI - A case of systemic lupus erythematosus presenting as bilateral avascular necrosis of femur. AB - BACKGROUND: Avascular necrosis occur as a result of diverse etiology. Chronic inflammatory conditions such as systemic lupus erythematosus considered as a recognize cause. Many cases were reported in systemic lupus erythematosus after treating with corticosteroids. We report a case of a corticosteroid naive patient presented as bilateral avascular necrosis of femoral head and later progressed to a case of systemic lupus erythematosus. CASE PRESENTATION: A 26 year old lady presented with right sided hip pain and diagnosed as avascular necrosis of the femoral head. After 6 months she presented a similar pain in left hip, which revealed avascular necrosis of left femoral head as well. A probable cause for her clinical presentation could not be found after extensive clinical and laboratory evaluation. Patient reported high erythrocyte sedimentation rate persistently, and over the next few years progressed as a case of systemic lupus erythematosus. CONCLUSION: Above case illustrated avascular necrosis could be an early musculoskeletal manifestation of systemic lupus erythematosus even in the absence of corticosteroid administration. PMID- 27495305 TI - The Brexit broadcast that stoked fears over the NHS's future. PMID- 27495303 TI - Difference in glaucoma progression between the first and second eye after consecutive bilateral glaucoma surgery in patients with bilateral uveitic glaucoma. AB - PURPOSE: To determine whether the second eyes (SE) of patients with bilateral uveitic glaucoma undergoing filtration surgery have more glaucomatous progression in terms of visual acuity, visual field (VF) and optic nerve changes compared to the first eyes (FE). METHODS: This retrospective study analysed data of 60 eyes from 30 patients with bilateral uveitic glaucoma who had undergone glaucoma surgery in both eyes on separate occasions. Humphrey VF progression was assessed using the Progressor software. RESULTS: The pre-operative IOP between the FE (43.1 +/- 7.7 mmHg) and SE (40 +/- 8.7 mmHg) was not statistically significant (p = 0.15). IOP reduction was greater in the FE (64 %) than SE (59.7 %) post operatively, but the mean IOP at the final visit in the FE (12.3 +/- 3.9 mmHg) and SE (14.5 +/- 7 mmHg) was not statistically different (p = 0.2). There was no significant change in mean logMAR readings pre and post-operatively (0.45 +/- 0.6 vs 0.37 +/- 0.6, p = 0.4) or between the FE and SE. The number of SE with CDR > 0.7 increased by 23 % compared to the FE. From 23 available VFs, five SE (21.7 %) progressed at a median of five locations (range 1-11 points) with a mean local slope reduction of 1.74 +/- 0.45 dB/year (range -2.39 to -1.26), whereas only one FE progressed. However, there was no significant difference between mean global rate of progression between the FE (-0.9 +/- 1.6 dB/year) and SE (-0.76 +/- 2.1 dB/year, p = 0.17) in the Humphrey VF. CONCLUSION: In eyes with bilateral uveitic glaucoma requiring glaucoma surgery, the SEs had more progressed points on VF and glaucomatous disc progression compared to FEs at the final visit. PMID- 27495301 TI - Giant cell arteritis: ophthalmic manifestations of a systemic disease. AB - BACKGROUND: Giant cell arteritis (GCA) is a systemic granulomatous vasculitis, primarily affecting medium-large arteries. It has a predilection for the aorta and its major branches, including the carotid and vertebral arteries. Ophthalmic artery involvement frequently leads to irreversible visual loss, and therefore GCA is one of the few true ophthalmic emergencies. GCA, although classified as a large vessel vasculitis, is known to affect smaller-sized vessels, resulting in a multiplicity of signs in the eye, some of which are often missed. PURPOSE: We set out to highlight some of the less frequently observed clinical signs, which may provide clues to clinically diagnosing GCA in patients presenting with non classical features and inconclusive inflammatory markers. METHODS: We review the literature and describe the diverse ocular features and some of the systemic findings that can be associated with GCA. RESULTS: Although the most common ocular manifestation of GCA is anterior ischaemic optic neuropathy, the clinical presentation of GCA can vary dramatically. In the absence of obvious ocular involvement, more subtle ophthalmic signs of anterior segment ischaemia, such as hypotony and anisocoria, may be present at the time of initial clinical examination. CONCLUSION: There are no specific biomarkers for disease to date; therefore, pertinent history and clinical examination can guide towards diagnosis in the acute setting. The diagnostic process is not always straightforward, yet appropriate and prompt diagnosis is critical to enable timely intervention and prevent significant morbidity. PMID- 27495306 TI - Author's reply to Mathioudakis and colleagues. PMID- 27495307 TI - Rainfall variation and child health: effect of rainfall on diarrhea among under 5 children in Rwanda, 2010. AB - BACKGROUND: Diarrhea among children under 5 years of age has long been a major public health concern. Previous studies have suggested an association between rainfall and diarrhea. Here, we examined the association between Rwandan rainfall patterns and childhood diarrhea and the impact of household sanitation variables on this relationship. METHODS: We derived a series of rain-related variables in Rwanda based on daily rainfall measurements and hydrological models built from daily precipitation measurements collected between 2009 and 2011. Using these data and the 2010 Rwanda Demographic and Health Survey database, we measured the association between total monthly rainfall, monthly rainfall intensity, runoff water and anomalous rainfall and the occurrence of diarrhea in children under 5 years of age. RESULTS: Among the 8601 children under 5 years of age included in the survey, 13.2 % reported having diarrhea within the 2 weeks prior to the survey. We found that higher levels of runoff were protective against diarrhea compared to low levels among children who lived in households with unimproved toilet facilities (OR = 0.54, 95 % CI: [0.34, 0.87] for moderate runoff and OR = 0.50, 95 % CI: [0.29, 0.86] for high runoff) but had no impact among children in household with improved toilets. CONCLUSION: Our finding that children in households with unimproved toilets were less likely to report diarrhea during periods of high runoff highlights the vulnerabilities of those living without adequate sanitation to the negative health impacts of environmental events. PMID- 27495308 TI - SMARCE1 regulates metastatic potential of breast cancer cells through the HIF1A/PTK2 pathway. AB - BACKGROUND: While aberrant activation of the chromatin-remodeling SWI/SNF complexes has been associated with cancer development and progression, the role of each subunit in tumor cells is poorly defined. This study is aimed to characterize the role of SMARCE1/BAF57 in regulating metastasis of breast cancer cells. METHODS: Genetic approaches and chemical inhibitors were used to manipulate the activities of SMARCE1 and its downstream targets in multiple breast cancer cell lines. Xenograft mouse models were used to analyze the role of SMARCE1 in lung metastasis in vivo. Nonadherent culture conditions were used to elucidate the role of SMARCE1 in regulating anoikis. Chromatin immunoprecipitation (ChIP), immunoprecipitation, and immunoblotting assays were designed to dissect the mechanism of action of SMARCE1. Public databases were used to investigate the relationship between SMARCE1 deregulation and breast cancer prognosis. RESULTS: SMARCE1 knockdown reduced lung metastasis of breast cancer cells and sensitized tumor cells to anoikis. In response to loss of attachment, SMARCE1 interacted with and potentiated transcriptional activity of HIF1A, resulting in rapid PTK2 activation. Both HIF1A and PTK2 were indispensable for SMARCE1-mediated protection against anoikis by promoting activation of ERK and AKT pathways while suppressing the expression of pro-apoptotic BIM protein. Expression data analysis of a large cohort of human breast tumors revealed that high expression of SMARCE1 or PTK2 is associated with poor prognosis and tumor relapse, and PTK2 expression is positively correlated with SMARCE1 expression in basal-like and luminal B subtypes of breast tumors. CONCLUSIONS: SMARCE1 plays an essential role in breast cancer metastasis by protecting cells against anoikis through the HIF1A/PTK2 pathway. SMARCE1-mediated PTK2 activation likely plays a key role in promoting metastasis of basal-like and luminal B subtype of breast tumors. PMID- 27495309 TI - No inequalities in survival from colorectal cancer by education and socioeconomic deprivation - a population-based study in the North Region of Portugal, 2000 2002. AB - BACKGROUND: Association between cancer survival and socioeconomic status has been reported in various countries but it has never been studied in Portugal. We aimed here to study the role of education and socioeconomic deprivation level on survival from colorectal cancer in the North Region of Portugal using a population-based cancer registry dataset. METHODS: We analysed a cohort of patients aged 15-84 years, diagnosed with a colorectal cancer in the North Region of Portugal between 2000 and 2002. Education and socioeconomic deprivation level was assigned to each patient based on their area of residence. We measured socioeconomic deprivation using the recently developed European Deprivation Index. Net survival was estimated using Pohar-Perme estimator and age-adjusted excess hazard ratios were estimated using parametric flexible models. Since no deprivation-specific life tables were available, we performed a sensitivity analysis to test the robustness of the results to life tables adjusted for education and socioeconomic deprivation level. RESULTS: A total of 4,105 cases were included in the analysis. In male patients (56.3 %), a pattern of worse 5- and 10-year net survival in the less educated (survival gap between extreme education groups: -7 % and -10 % at 5 and 10 years, respectively) and more deprived groups (survival gap between extreme EDI groups: -5 % both at 5 and 10 years) was observed when using general life tables. No such clear pattern was found among female patients. In both sexes, when likely differences in background mortality by education or deprivation were accounted for in the sensitivity analysis, any differences in net survival between education or deprivation groups vanished. CONCLUSIONS: Our study shows that observed differences in survival by education and EDI level are most likely attributable to inequalities in background survival. Also, it confirms the importance of using the relevant life tables and of performing sensitivity analysis when evaluating socioeconomic inequalities in cancer survival. Comparison studies of different healthcare systems organization should be performed to better understand its influence on cancer survival inequalities. PMID- 27495310 TI - Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort. AB - Germline mutations in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. Molecular screening of these two genes in patients with a family history of breast or ovarian cancer has revealed pathogenic variants as well as genetic variants of unknown significance (VUS). These VUS may cause a challenge in the genetic counseling process regarding clinical management of the patient and the family. We investigated 32 variants previously detected in 33 samples from patients with a family history of breast or ovarian cancer. cDNA was analyzed for alternative transcripts and selected missense variants located in the BRCT domains of BRCA1 were assessed for their trans-activation ability. Although an extensive cDNA analysis was done, only three of the 32 variants appeared to affect the splice-process (BRCA1 c.213-5T>A, BRCA1 c.5434C>G and BRCA2 c.68 7T>A). In addition, two variants located in the BRCT domains of BRCA1 (c.5075A>C p.Asp1692Ala and c.5513T>G p.Val1838Gly) were shown to abolish the BRCT domain trans-activation ability, whereas BRCA1 c.5125G>A p.Gly1709Arg exhibited equal trans-activation capability as the WT domain. These functional studies may offer further insights into the pathogenicity of certain identified variants; however, this assay is only applicable for a subset of missense variants. PMID- 27495312 TI - God in the brain: Experiencing psychosis in the postsecular United States. AB - There is a growing literature on what contemporary cultural theorists have broadly termed the "postsecular": the abandonment of clear-cut boundaries between the secular and nonsecular in the industrialized West and an embrace of a complex understanding of what is real that neither accepts nor rejects the supernatural. These new cultural currents may affect not only philosophers and theologians, but also the ways in which individuals with psychosis make sense of their experiences. This paper reports on the key findings of an in-depth qualitative analysis of 19 interviews of individuals diagnosed with psychotic disorders. The majority of participants described ongoing and self-conscious struggles to demarcate their experiences as the products of the real world or a "crazy" mind. With equal frequency, participants weighed and debated competing secular and supernatural explanations, often juxtaposing and blending different explanatory frameworks. We found that this syncretic process affected not only the content of psychotic experiences-what delusions or hallucinations are about-but also the type of arguments or logics used to justify particular interpretations. We discuss the implications of these observations with respect to clinical practice and the broader phenomenology of psychosis, challenging often oversimplified discourse on "insight" and suggesting that polarization(s) between "biomedical" and "psychosocial" explanations may be of less relevance to patients' real-world experiences than is often assumed. PMID- 27495311 TI - Comparative genomics and transcriptomics of Pichia pastoris. AB - BACKGROUND: Pichia pastoris has emerged as an important alternative host for producing recombinant biopharmaceuticals, owing to its high cultivation density, low host cell protein burden, and the development of strains with humanized glycosylation. Despite its demonstrated utility, relatively little strain engineering has been performed to improve Pichia, due in part to the limited number and inconsistent frameworks of reported genomes and transcriptomes. Furthermore, the co-mingling of genomic, transcriptomic and fermentation data collected about Komagataella pastoris and Komagataella phaffii, the two strains co-branded as Pichia, has generated confusion about host performance for these genetically distinct species. Generation of comparative high-quality genomes and transcriptomes will enable meaningful comparisons between the organisms, and potentially inform distinct biotechnological utilies for each species. RESULTS: Here, we present a comprehensive and standardized comparative analysis of the genomic features of the three most commonly used strains comprising the tradename Pichia: K. pastoris wild-type, K. phaffii wild-type, and K. phaffii GS115. We used a combination of long-read (PacBio) and short-read (Illumina) sequencing technologies to achieve over 1000X coverage of each genome. Construction of individual genomes was then performed using as few as seven individual contigs to create gap-free assemblies. We found substantial syntenic rearrangements between the species and characterized a linear plasmid present in K. phaffii. Comparative analyses between K. phaffii genomes enabled the characterization of the mutational landscape of the GS115 strain. We identified and examined 35 non synonomous coding mutations present in GS115, many of which are likely to impact strain performance. Additionally, we investigated transcriptomic profiles of gene expression for both species during cultivation on various carbon sources. We observed that the most highly transcribed genes in both organisms were consistently highly expressed in all three carbon sources examined. We also observed selective expression of certain genes in each carbon source, including many sequences not previously reported as promoters for expression of heterologous proteins in yeasts. CONCLUSIONS: Our studies establish a foundation for understanding critical relationships between genome structure, cultivation conditions and gene expression. The resources we report here will inform and facilitate rational, organism-wide strain engineering for improved utility as a host for protein production. PMID- 27495313 TI - Aroma volatile analyses and 2AP characterization at various developmental stages in Basmati and Non-Basmati scented rice (Oryza sativa L.) cultivars. AB - BACKGROUND: Rice plant growth is comprised of distinct phases, such as vegetative, reproductive, grain filling and maturity phases. In these phases synthesis and availability of primary and secondary metabolites including volatile organic compounds (VOC's) is highly variable. In scented rice, aroma volatiles are synthesized in aerial plant parts and deposited in mature grains. There are more than 100 VOCs reported to be responsible for flavor in basmati rice. It will be interesting to keep track of aroma volatiles across the developmental stages in scented rice. Therefore, the aroma volatiles contributing in aroma with special reference to the major compound 2 acetyl-1-pyrroline (2AP) were screened at seven developmental stages in scented rice cultivars Basmati-370 and Ambemohar-157 along with non-scented rice cultivar IR-64 as a control following HS-SPME-GC-MS method. In addition, the expression levels of key genes and precursor levels involved in 2AP biosynthesis were studied. RESULTS: The study indicated that volatilome of scented rice cultivars is more complex than non-scented rice cultivar. N-heterocyclic class was the major distinguishing class between scented from non-scented rice. A total of 14 compounds including, 2AP were detected specifically in scented rice cultivars. Maximum number of compounds were synthesized at seedling stage and decreased gradually at reproductive and maturity. The seedling stage is an active phase of development where maximum number green leaf volatiles were synthesized which are known to act as defense molecules for protection of young plant parts. Among the 14 odor active compounds (OACs), 10 OACs were accumulated at higher concentrations significantly in scented rice cultivars and contribute in the aroma. 2AP content was highest in mature grains followed by at booting stage. Gene expression analysis revealed that reduced expression of betaine aldehyde dehydrogenase 2 (badh2) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and elevated level of triose phosphate isomerase (TPI) and Delta1-Pyrolline-5-carboxylic acid synthetase (P5CS) transcript enhances 2AP accumulation. CONCLUSIONS: Most diverse compounds were synthesized at seedling stage and OACs were accumulated more at flowering followed by seedling stage. Distinct accumulation pattern exists for 2AP and other aroma volatiles at various developmental stages. The study revealed the mechanism of 2AP accumulation such that 2AP in mature grains might be transported from leaves and stem sheath and accumulation takes place in grains. PMID- 27495314 TI - [Phoneme discrimination training with experienced cochlear implant listeners]. AB - BACKGROUND: Computer-based auditory training programmes seem to be a useful tool in the process of auditory rehabilitation after cochlear implantation (CI). Currently, little is known about the learning mechanism and efficiency of such programs. The aim of the study was to evaluate a specific auditory training programme for phoneme discrimination in experienced CI listeners. MATERIALS AND METHODS: A total of 15 CI adult listeners with more than 2 years' CI experience participated in the auditory training. Over a period of 3 weeks they were instructed to train their phoneme discrimination via computer twice a week. Training material consisted of special syllables for consonants (vCv) and vowels (cVc) discrimination. RESULTS: The discrimination abilities for consonants and vowels improved significantly over the training period for training group participants, whereas the changes for the consonants were higher. In addition, the improvement for voiced and unvoiced consonants was significant. CONCLUSION: Computerised auditory training with phonemes improves CI listeners' discrimination abilities for consonants and vowels. PMID- 27495315 TI - The Effect of Unenhanced MRI on the Surgeons' Decision-Making Process in Females with Suspected Appendicitis. AB - BACKGROUND: This prospective study evaluated the impact of the results of unenhanced magnetic resonance imaging (MRI) on the surgeon's diagnosis of acute appendicitis in potentially fertile females. METHODS: 112 female patients, aged 12-55, with suspected appendicitis underwent MRI of the abdomen. At three defined intervals; admission and clinical re-evaluation before and after revealing the MRI results, the surgeon recorded the attendance of each patient in operative treatment, observation or discharge. Appendicitis was confirmed or declined by pathology or by telephone follow-up in case of non-intervention. FINDINGS: Appendicitis was confirmed in 29 of 112 patients. At admission the surgeon's disposition had a sensitivity of 97 % and specificity of 29 %. After knowing the MRI results, sensitivity was 97 % and specificity 64 %. The sensitivity and specificity of MRI alone were 89 and 100 %, with a negative and positive predictive value of 96 and 100 %, respectively. CONCLUSION: We believe that MRI should perhaps be standard in all female patients during their reproductive years with suspected appendicitis. It avoids an operation in 32 % of cases and allows earlier planning for patients with an equivocal clinical picture. Trial number: OND1292733 (Narcis.nl). PMID- 27495317 TI - Mentored Writing: An Arts-Based Curriculum for First-Year Psychiatry Residents. PMID- 27495316 TI - Yttrium-90 Radioembolization for Hepatocellular Carcinoma Prior to Liver Transplantation. AB - BACKGROUND: Liver transplantation (LT) is a well-established procedure for hepatocellular carcinoma (HCC) within the Milan criteria. Yttrium-90 microspheres radioembolization (Y90-RE) has shown to be an effective and safe treatment of primary liver tumors. We retrospectively evaluate the efficacy of the Y90-RE in patients with HCC prior to LT. METHODS: From January 2002 to December 2015, 365 patients were transplanted at the San Camillo Hospital Center. One hundred forty three patients were transplanted for HCC, and in 22 cases the patients were treated with Y90-RE before LT. RESULTS: Three patients were treated with Y90-RE within the Milan criteria, and 19 patients were out of criteria before Y90-RE. Four patients had an increasing MELD score between Y90-RE and LT. On the other hand, alpha-fetoprotein decreases after Y90-RE treatment in all cases. No patient death was observed in Y90-RE procedure or at LT. In 78.9 % of cases, a successful downstaging was observed, and in 100 % of cases bridging was achieved. From Y90 RE treatment overall survival was 43.9 months. From LT, overall mean survival was 30.2 months with a free survival of 29.6 months. The overall survival after LT analysis between the patients treated with Y90-RE and patients without was not significant (p = 0.113). Free survival analysis was not significant (p = 0.897) between the two populations. CONCLUSIONS: We successfully performed LT in patients after Y90-RE treatment both as bridging and downstaging for HCC and obtained a similar overall and free survival of LT for HCC within Milan criteria. Y90-RE becomes a real option to provide curative therapy for patients who traditionally are not considered eligible for surgery. PMID- 27495318 TI - The small RNA SraG participates in PNPase homeostasis. AB - The rpsO-pnp operon encodes ribosomal protein S15 and polynucleotide phosphorylase, a major 3'-5' exoribonuclease involved in mRNA decay in Escherichia coli The gene for the SraG small RNA is located between the coding regions of the rpsO and pnp genes, and it is transcribed in the opposite direction relative to the two genes. No function has been assigned to SraG. Multiple levels of post-transcriptional regulation have been demonstrated for the rpsO-pnp operon. Here we show that SraG is a new factor affecting pnp expression. SraG overexpression results in a reduction of pnp expression and a destabilization of pnp mRNA; in contrast, inhibition of SraG transcription results in a higher level of the pnp transcript. Furthermore, in vitro experiments indicate that SraG inhibits translation initiation of pnp Together, these observations demonstrate that SraG participates in the post-transcriptional control of pnp by a direct antisense interaction between SraG and PNPase RNAs. Our data reveal a new level of regulation in the expression of this major exoribonuclease. PMID- 27495319 TI - Gld2-catalyzed 3' monoadenylation of miRNAs in the hippocampus has no detectable effect on their stability or on animal behavior. AB - Gld2, a noncanonical cytoplasmic poly(A) polymerase, interacts with the RNA binding protein CPEB1 to mediate polyadenylation-induced translation in dendrites of cultured hippocampal neurons. Depletion of Gld2 from the hippocampus leads to a deficit in long-term potentiation evoked by theta burst stimulation. At least in mouse liver and human primary fibroblasts, Gld2 also 3' monoadenylates and thereby stabilizes specific miRNAs, which enhance mRNA translational silencing and eventual destruction. These results suggest that Gld2 would be likely to monoadenylate and stabilize miRNAs in the hippocampus, which would produce measurable changes in animal behavior. We now report that using Gld2 knockout mice, there are detectable alterations in specific miRNA monoadenylation in the hippocampus when compared to wild type, but that these modifications produce no detectable effect on miRNA stability. Moreover, we surprisingly find no overt change in animal behavior when comparing Gld2 knockout to wild-type mice. These data indicate that miRNA monoadenylation-mediated stability is cell type-specific and that monoadenylation has no measurable effect on higher cognitive function. PMID- 27495320 TI - Chitosan silver nanocomposite (CAgNC) as an antifungal agent against Candida albicans. AB - Due to limited numbers of antifungal drugs and emergence of drug resistance have directed to develop nonconventional therapeutic agents against fungal pathogen Candida albicans. In this study, anticandidal activity of chitosan silver nanocomposite (CAgNC) was tested against C. albicans Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of CAgNC were determined as 25 and 100 MUg/ml, respectively. Electron microscopic image results confirmed the ultrastructural cell wall deformities and injuries caused by CAgNC. Propidium iodide (PI) penetration into the CAgNC treated cells could be considered as an evidence for loss of cell membrane integrity and cell death at MFC. Level of intracellular reactive oxygen species (ROS) was increased, while cell viability was decreased with the increased of CAgNC concentrations. In our protein profile results, several induced proteins were observed under CAgNC treatment, and they could be related to multidrug and stress resistant proteins such as CDR1 (55 kDa) and CaHSP70 based on the protein band size. CAgNC mediated cell wall damage, loss of cell membrane integrity, elevated ROS level, and associated oxidative stress have been identified as the main causative factors for the anticandidal activity. Overall results from our study indicated that CAgNC could affect negatively on physiological and biochemical functions of C. albicans suggesting CAgNC as a potential alternative for antifungal chemotherapy. PMID- 27495321 TI - Fungemia due to rare opportunistic yeasts: data from a population-based surveillance in Spain. AB - Fungemia due to rare yeasts constitutes an emerging but poorly investigated condition. Data on risk factors, clinical features, therapy, and outcome of episodes of fungemia due to rare (non-Candida, non-Cryptococcus) yeasts were analyzed in a population-based surveillance program conducted in 29 Spanish hospitals between May 2010 and April 2011. Species identification (DNA sequencing) and antifungal susceptibility testing (EUCAST and CLSI methods) were centrally performed. Fourteen out of 767 episodes of fungemia (1.8%) were due to rare yeasts: Trichosporon asahii, Magnusiomyces capitatus (three cases each), Rhodotorula mucilaginosa, Wickerhamomyces anomalus (two cases each), and Pichia kudriavzevii, Cyberlindnera fabianii, Kodamaea ohmeri, and Lodderomyces elongisporus (one case each). Misidentification by local laboratories was observed in two isolates. Breakthrough fungemia occurred in two episodes due to M. capitatus MIC values for echinocandins were generally high (particularly for M. capitatus, T. asahii, and R. mucilaginosa isolates [>=2 mg/l]), whereas T. asahii isolates showed MICs >=1 mg/l to amphotericin B. Patients with fungemia due to rare yeasts were more likely to have hematological malignancies (28.6% vs. 7.8%; P-value = .021), chronic lung disease (50.0% vs. 22.3%; P-value = .023), and prior immunosuppression (57.1% vs. 22.2%; P-value = .005) compared to those with candidemia. The rate of clinical failure (persistent fungemia and/or 30-day mortality) was 46.2% and did not significantly differ from that observed in episodes of candidemia. In conclusion, non-Candida, non-Cryptococcus yeasts are uncommon causes of fungemia, with immunosuppression and chronic lung disease as predisposing factors. Outcome does not appear to be worse than that of candidemia. PMID- 27495322 TI - Risk factors for drainage-requiring ascites after refractory peritonitis in peritoneal dialysis patients. AB - PURPOSE: Refractory peritonitis remains a thorny issue for patients with chronic peritoneal dialysis (PD). Shortly after catheter removal, some patients develop persistent peritoneal inflammation and ascites formation, which require percutaneous drainage for symptom relief. Our study aimed at finding the risk factors for this kind of event. METHODS: A total of 47 PD patients complicated with refractory peritonitis who underwent catheter removal between January 2009 and December 2011 were enrolled in this study. Data were compared between patients with and without the development of symptomatic ascites requiring drainage during hospitalization. RESULTS: Among the 47 refractory peritonitis patients, 15 patients developed symptomatic ascites that needed further drainage shortly after catheter removal during hospitalization. The following factors were associated with an increased risk: longer dialysis duration, higher peritoneal Kt/V urea, and a significant rise in serum C-reactive protein (CRP) level after catheter removal. These patients had a prolonged hospital stay (62 vs 21 days, P < 0.001) and a significantly higher risk of recurrent loculated ascites during subsequent 6 months of follow-up (33.3 vs 6.2 %, P = 0.022) compared with patients who did not develop ascites requiring drainage during hospitalization. CONCLUSION: A significant portion of patients with refractory PD peritonitis experienced ascites requiring drainage shortly after catheter removal, which led to a prolonged hospitalization. Whether routine drain placement at the time of catheter removal for this high-risk group would be of benefit warrants further prospective studies. PMID- 27495323 TI - Does a history of bullying and abuse predict lower urinary tract symptoms, chronic pain, and sexual dysfunction? AB - PURPOSE: To investigate associations of bullying and abuse with pelvic floor symptoms, urogenital pain, and sexual health characteristics of women presenting to a multidisciplinary women's urology center. METHODS: Retrospective review of a prospective database. Patients completed questions about bullying, abuse, sexual health and validated questionnaires including the Pelvic Floor Dysfunction Inventory (PFDI-20), Overactive Bladder Questionnaire (OAB-q), and visual analog scale (VAS 0-10) for genitourinary pain. Statistical analyses included Chi squared and t tests, which compared victims of bullying and/or abuse to non victims. RESULTS: Three hundred and eighty patients were reviewed. Three hundred and thirty-eight had data on bullying and abuse history. Out of 380, 94 (24.7 %) reported that they were victims of bullying. Out of 380, 104 (27.4 %) reported that they were victims of abuse. Women with a history of bullying and abuse had increased overall pain scores compared to those without a history of either. Women with a history of abuse and bullying had increased PFDI-20, POPDI, and UDI 6 scores compared to women who were not bullied or abused. There was no difference in being sexually active or in sexual satisfaction between the groups. Patients with a history of abuse and bullying had the greatest percentage of dyspareunia (p = 0.009). CONCLUSIONS: Women with a history of bullying, abuse, or both predict increased pelvic floor distress, urological symptoms, increased urogenital pain, and increased dyspareunia. Clinicians should screen for exposure to bullying or abuse in order to provide comprehensive resources to address these psychosocial issues. PMID- 27495324 TI - Povidone-iodine rectal cleansing and targeted antimicrobial prophylaxis using rectal swab cultures in men undergoing transrectal ultrasound-guided prostate biopsy are associated with reduced incidence of postoperative infectious complications. AB - PURPOSE: The aim of this study was to evaluate the effect of povidone-iodine rectal disinfection and targeted antimicrobial prophylaxis in men undergoing transrectal ultrasound-guided prostate biopsy based on rectal swab culture results. METHODS: From January 2011 to December 2015, we studied differences in infectious complications in men who received povidone-iodine rectal disinfection with targeted antimicrobial prophylaxis and those who received empirical prophylaxis before transrectal ultrasound-guided prostate biopsy. Clinical variables including demographics, prior antibiotic, rectal swab culture results, povidone-iodine rectal cleansing, antibiotic prophylaxis, and infectious complications were evaluated. Patients were divided into three groups as follows: Group A received no povidone-iodine rectal cleansing but received empirical antimicrobial prophylaxis; group B received povidone-iodine rectal cleansing and empirical antimicrobial prophylaxis; and group C received povidone-iodine rectal cleansing and targeted antimicrobial prophylaxis. RESULTS: Patients were divided into group A (n = 192; 13.2 %), group B (n = 579; 39.9 %), or group C (n = 679; 46.8 %). In groups A and B, all patients received fluoroquinolone antimicrobial prophylaxis. Group C patients received targeted antimicrobial prophylaxis according to antibiotic resistance of rectal flora, and 71.1 % of these received fluoroquinolone antimicrobial prophylaxis. Infectious complication rates were 3.6, 2.9, and 1.3 % in group A, group B, and group C, respectively. Incidences of acute prostatitis and bacteremia were significantly lower in group C (p = 0.041 and p = 0.049, respectively) than in the other groups. CONCLUSIONS: In the era of quinolone resistance, the combination of povidone-iodine rectal cleansing and targeted antibiotic prophylaxis may reduce the rate of infectious complications. PMID- 27495326 TI - Detection of object onsets and offsets: Does the primacy of onset persist even with bias for detecting offset? AB - Onset primacy is a robust visual phenomenon in which appearance of new objects (onsets) in a scene more effectively captures observers' attention compared with disappearance of previously viewed objects (offsets). We hypothesized that the human attentional system is programmed by default to prioritize the processing of onsets, because quick detection of them is advantageous in most situations. However, the attentional priority may be able to flexibly adapt to the detection of object offsets depending on observers' behavioral goals. To test these hypotheses, two experiments were conducted in which participants were biased toward finding offset of an existing object through top-down and bottom-up manipulations. Results showed that although onset primacy was reduced to some degree under strong offset bias, in general participants continued to detect onsets efficiently. These findings did not eliminate the possibility of attentional flexibility, but they do demonstrate the robustness of onset primacy, suggesting that environmental demands or motivational factors would need to be sufficiently strong for people to switch to an adaptive attentional mode. PMID- 27495325 TI - Factors influencing general practitioners' decisions about cardiovascular disease risk reassessment: findings from experimental and interview studies. AB - BACKGROUND: Guidelines on cardiovascular disease (CVD) risk reassessment intervals are unclear, potentially leading to detrimental practice variation: too frequent can result in overtreatment and greater strain on the healthcare system; too infrequent could result in the neglect of high risk patients who require medication. This study aimed to understand the different factors that general practitioners (GPs) consider when deciding on the reassessment interval for patients previously assessed for primary CVD risk. METHODS: This paper combines quantitative and qualitative data regarding reassessment intervals from two separate studies of CVD risk management. Experimental study: 144 Australian GPs viewed a random selection of hypothetical cases via a paper-based questionnaire, in which blood pressure, cholesterol and 5-year absolute risk (AR) were systematically varied to appear lower or higher. GPs were asked how they would manage each case, including an open-ended response for when they would reassess the patient. Interview study: Semi-structured interviews were conducted with a purposive sample of 25 Australian GPs, recruited separately from the GPs in the experimental study. Transcribed audio-recordings were thematically coded, using the Framework Analysis method. RESULTS: EXPERIMENT: GPs stated that they would reassess the majority of patients across all absolute risk categories in 6 months or less (low AR = 52 % [CI95% = 47-57 %], moderate AR = 82 % [CI95% = 76-86 %], high AR = 87 % [CI95% = 82-90 %], total = 71 % [CI95% = 67-75 %]), with 48 % (CI95% = 43-53 %) of patients reassessed in under 3 months. The majority (75 % [CI95% = 70-79 %]) of patients with low-moderate AR (<=15 %) and an elevated risk factor would be reassessed in under 6 months. Interviews: GPs identified different functions for reassessment and risk factor monitoring, which affected recommended intervals. These included perceived psychosocial benefits to patients, preparing the patient for medication, and identifying barriers to lifestyle change and medication adherence. Reassessment and monitoring intervals were driven by patient motivation to change lifestyle, patient demand, individual risk factors, and GP attitudes. CONCLUSIONS: There is substantial variation in reassessment intervals for patients with the same risk profile. This suggests that GPs are not following reassessment recommendations in the Australian guidelines. The use of shorter intervals for low-moderate AR contradicts research on optimal monitoring intervals, and may result in unnecessary costs and over treatment. PMID- 27495327 TI - Concern for Lost Income Following Donation Deters Some Patients From Talking to Potential Living Donors. AB - CONTEXT: Some living kidney donors report lost income during recovery from surgery. Little is known about whether concern for living donor's lost income affects the decision to undergo donation evaluation and the willingness of transplant candidates to discuss living kidney donation (LKD) with others. OBJECTIVE: To examine whether transplant patients were told by potential donors about lost income concerns and whether patients chose not to discuss LKD with others due to lost income concerns. DESIGN, SETTING, AND PATIENTS: Kidney transplant patients (185 wait-listed candidates, 171 deceased donor recipients, and 100 live donor recipients) at 2 centers completed a questionnaire to assess whether concern about donor's lost income was a consideration in discussion about LKD with others. RESULTS: One-third (32%) were told by a family member/friend that they were willing to donate but were concerned about potential lost income. The majority of those who expressed financial concern (64%) did not initiate donation evaluation. Many patients (42%) chose not to discuss living donation with a family member/friend due to concern about the impact of lost income on the donor. In the multivariable model, lower annual household income was the only statistically significant predictor of both having a potential donor expressing lost income concern and choosing not to talk to someone because of lost income concern. CONCLUSION: Findings from the current study underscore how concern about income loss for living donors may affect decision-making by both transplant candidates and potential donors. PMID- 27495328 TI - MovingU: A prospective cohort study to understand behavioural and environmental contexts influencing physical activity during the transition into emerging adulthood. AB - BACKGROUND: Children and youth are often considered the most active segment of the population, however, research indicates that physical activity (PA) tends to peak during the adolescent years, declining thereafter with age. In particular, the acute transition out of high school is a period for which individuals appear to be at high-risk for becoming less active. Relatively few studies have investigated the factors influencing the changes in PA during this transition period. Therefore the purpose of the MovingU study is to gain a comprehensive understanding of the behavioural patterns and the socio-ecological factors related to the changes in PA during the transition out of high school. METHODS/DESIGN: MovingU is comprised of two phases. Phase I is a prospective cohort design and aims to follow 120 students in their last year of high school through to their first year out of high school. Students will be asked to complete questionnaires measuring various psychosocial and socio-environmental variables (e.g., self-efficacy and distress) four times throughout this transition period. Students will also be given a wrist-worn accelerometer to wear for 7-days at each of the four assessments. Phase II is a cross-sectional study involving 100 first-year university students. Students will be asked to complete the same questionnaire from phase I, wear a wrist-worn accelerometer for 5-days, and complete ecological momentary assessments (EMA) using their smartphones at randomly selected times throughout the day for 5-days. EMA items will capture information regarding contextual and momentary correlates of PA. DISCUSSION: The MovingU study represents the first to evaluate the social and environmental influences of PA behaviour changes, including the use of intensive real-time data capture strategies during the transition out of high school. This information will be critical in the development of interventions aimed to prevent or attenuate such drastic declines in PA during emerging adulthood period. PMID- 27495329 TI - Direct transfer of HRPII-magnetic bead complexes to malaria rapid diagnostic tests significantly improves test sensitivity. AB - BACKGROUND: The characteristic ease of use, rapid time to result, and low cost of malaria rapid diagnostic tests (RDTs) promote their widespread use at the point of-care for malaria detection and surveillance. However, in many settings, the success of malaria elimination campaigns depends on point-of-care diagnostics with greater sensitivity than currently available RDTs. To address this need, a sample preparation method was developed to deliver more biomarkers onto a malaria RDT by concentrating the biomarker from blood sample volumes that are too large to be directly applied to a lateral flow strip. METHODS: In this design, Ni-NTA functionalized magnetic beads captured the Plasmodium falciparum biomarker HRPII from a P. falciparum D6 culture spiked blood sample. This transfer of magnetic beads to the RDT was facilitated by an inexpensive 3D-printed apparatus that aligned the sample tube with the sample deposition pad and a magnet beneath the RDT. Biomarkers were released from the bead surface onto the lateral flow strip using imidazole-spiked running buffer. Kinetics of HRPII binding to the Ni-NTA beads as a function of blood sample volume were explored prior to determining the effect of the proposed method on the limit of detection of Paracheck RDTs. RESULTS: More than 80 % of HRPII biomarkers were extracted from blood sample volumes ranging from 25 to 250 uL. The time required to reach 80 % binding ranged from 5 to 60 min, depending on sample volume. Using 250 MUL of blood and a 30-min biomarker binding time, the limit of detection of the Paracheck Pf RDT brand was improved by 21-fold, resulting in a limit of detection below 1 parasite/MUL. CONCLUSIONS: This approach has the sensitivity and simplicity required to assist in malaria elimination campaigns in settings with limited access to clinical and laboratory resources. PMID- 27495330 TI - Intraoperative workload in robotic surgery assessed by wearable motion tracking sensors and questionnaires. AB - BACKGROUND: The introduction of robotic technology has revolutionized radical prostatectomy surgery. However, the potential benefits of robotic techniques may have trade-offs in increased mental demand for the surgeon and the physical demand for the assisting surgeon. This study employed an innovative motion tracking tool along with validated workload questionnaire to assess the ergonomics and workload for both assisting and console surgeons intraoperatively. METHODS: Fifteen RARP cases were collected in this study. Cases were performed by 10 different participants, six primarily performed console tasks and four primarily performed assisting tasks. Participants had a median 12 (min-3, max-25) years of surgical experience. Both console and assisting surgeons performed robotic prostatectomy cases while wearing inertial measurement units (IMUs) that continuously track neck, shoulder, and torso motion without interfering with the sterile environment. Postoperatively, participants completed a workload questionnaire (SURG-TLX) and a body part discomfort questionnaire. RESULTS: Twenty-six questionnaires were completed from 13 assisting and 13 console surgeons over the 15 cases. Postoperative pain was reported highest for the right shoulder and neck. Mental demands were 41 % higher for surgeons at the console than assisting (p < 0.05), while physical demands were not significantly different. Assisting surgeons worked in demanding neck postures for 58 % of the procedure compared to 24 % for the console surgeon (p < 0.01). Surgeons at the console were primarily static and showed 2-5 times fewer movements than assisting surgeons (p < 0.01). CONCLUSIONS: Postures were more ergonomic during console tasks than when assisting by the bedside; however, the console may constrain postures leading to static loads that have been associated with musculoskeletal symptoms for the neck, torso, and shoulders. The IMU sensors were effective at quantifying ergonomics in robotic prostatectomies, and these methods and findings have broad applications to other robotic procedures. PMID- 27495331 TI - Esophageal stent fixation with endoscopic suturing device improves clinical outcomes and reduces complications in patients with locally advanced esophageal cancer prior to neoadjuvant therapy: a large multicenter experience. AB - BACKGROUND: Endoscopic placement of fully covered self-expanding metal stents (FCSEMS) to treat malignant dysphagia in patients with esophageal cancer significantly improves dysphagia; however, these stents have a high migration rate. AIM: To determine whether FCSEMS fixation using an endoscopic suturing device treated malignant dysphagia and prevented stent migration in patients with locally advanced esophageal cancer receiving neoadjuvant therapy when compared to patients with FCSEMS placement alone. METHOD: A review of patients with locally advanced esophageal cancer who underwent FCSEMS placement at 3 centers was performed. Patients were divided into two groups: Group A (n = 26) was composed of patients who underwent FCSEMS placement with suture placement, and Group B (n = 67) was composed of patients with FCSEMS placement alone. RESULTS: There were no significant differences between Groups A and B in demographics, and tumor characteristics. The technical success rate for stent placement was 100 %. There was no difference between Groups A and B in the median stent diameter and stent lengths. Mean dysphagia score obtained at 1 week after stent placement had improved significantly from baseline (2.4 and 1, respectively, p < 0.001). Patients had a median follow-up of 4 months. Immediate adverse events were mild chest discomfort in 4 patients in Group A and 2 patients in Group B (p = 0.05), and significant acid reflux in 3 patient in Group A compared to 2 patients in Group B (p = 0.1). The stent migration rate was significantly lower in Group A compared to compared to Group B (7.7 vs 26.9 %, respectively, p = 0.004). There was a delayed perforation in 1 patient and 1 death due to aspiration pneumonia in Group B. CONCLUSION: Fixation of esophageal FCSEMSs by using an endoscopic suturing device in patients receiving neoadjuvant therapy was shown to be feasible, safe, and relatively effective at preventing stent migration compared to those who had stent placed alone. PMID- 27495333 TI - Learning curves and surgical outcomes for proctored adoption of laparoscopic ventral mesh rectopexy: cumulative sum curve analysis. AB - BACKGROUND: Laparoscopic ventral mesh rectopexy (VMR) is an effective and well recognised treatment for symptoms of obstructive defecation in the context of rectal prolapse and recto-rectal intussusception. However, due to the technical complexity of VMR, a significant learning curve has been previously described. This paper examines the effect of proctored adoption of VMR on learning curves, operative times, and outcomes. METHODS: A retrospective database analysis of two district general hospitals was conducted, with inclusion of all cases performed by two surgeons since first adoption of the procedure in 2007-2015. Operative time, length of stay, and in-hospital complications were evaluated, with learning curves assessed using cumulative sum curves. RESULTS: Three hundred and eleven patients underwent VMR during the study period and were included for analysis. Patients were near-equally distributed between surgeons (surgeon A: n = 151, surgeon B, n = 160) with no significant differences between gender, age, or ASA grade. In-hospital morbidity was 3.2 %, with 0 % mortality. Cumulative sum curve analysis suggested a change point of between 25 and 30 cases based on operative times and length of stay and was similar between both surgeons. No significant change point was seen for morbidity or mortality. CONCLUSION: VMR is an effective and safe treatment for rectal prolapse. Surgeons in this study were proctored during the adoption process by another surgeon experienced in VMR; this may contribute to increased safety and abbreviated learning curve. In the context of proctored adoption, this study estimates a learning curve of 25-30 cases, without detrimental impact on patient outcomes. PMID- 27495332 TI - Efficacy of transoral incisionless fundoplication (TIF) for the treatment of GERD: a systematic review with meta-analysis. AB - BACKGROUND: The efficacy of transoral incisionless fundoplication (TIF) performed with the EsophyX device (Redmond, Washington, USA) and its long-term outcomes in gastresophageal reflux disease (GERD) are debated. We, therefore, performed a systematic review with meta-analysis of studies evaluating the role of TIF in GERD. METHODS: A systematic search of EMBASE, SCOPUS, PubMed, and the Cochrane Library Central was performed. All original studies reporting outcomes in GERD patients who underwent TIF were identified. Only randomized controlled trials (RCTs) evaluating the efficacy of TIF, and prospective observational studies reporting outcomes after TIF were included. RESULTS: A total of 18 studies (963 patients) published between 2007 and 2015 were identified, including five RCTs and 13 prospective observational studies. The pooled relative risk of response rate to TIF versus PPIs/sham was 2.44 (95 % CI 1.25-4.79, p = 0.0009) in RCTs in the intention-to-treat analysis. The total number of refluxes was reduced after TIF compared with the PPIs/sham group. The esophageal acid exposure time and acid reflux episodes after TIF were not significantly improved. Proton-pump inhibitors (PPIs) usage increased with time and most of the patients resumed PPIs treatment at reduced dosage during the long-term follow-up. The total satisfaction rate after TIF was about 69.15 % in 6 months. The incidence of severe adverse events consisting of gastrointestinal perforation and bleeding was 2.4 %. CONCLUSIONS: TIF is an alternative intervention in controlling GERD-related symptoms with comparable short-term patient satisfaction. Long-term results showed decreased efficacy with time. Patients often resume PPIs at reduced doses in the near future. PMID- 27495334 TI - Biomarkers of acute appendicitis: systematic review and cost-benefit trade-off analysis. AB - BACKGROUND: Acute appendicitis is the most common surgical emergency and can represent a challenging diagnosis, with a negative appendectomy rate as high as 20 %. This review aimed to evaluate the clinical utility of individual biomarkers in the diagnosis of appendicitis and appraise the quality of these studies. METHODS: A systematic review of the literature between January 2000 and September 2015 using of PubMed, OvidMedline, EMBASE and Google Scholar was conducted. Studies in which the diagnostic accuracy, statistical heterogeneity and predictive ability for severity of several biomarkers could be elicited were included. Information regarding costs and process times was retrieved from the regional laboratory. European surgeons blinded to these reviews were independently asked to rank which characteristics of biomarkers were most important in acute appendicitis to inform a cost-benefit trade-off. Sensitivity testing and the QUADAS-2 tool were used to assess the robustness of the analysis and study quality, respectively. RESULTS: Sixty-two studies met the inclusion criteria and were assessed. Traditional biomarkers (such as white cell count) were found to have a moderate diagnostic accuracy (0.75) but lower costs in the diagnosis of acute appendicitis. Conversely, novel markers (pro-calcitonin, IL 6 and urinary 5-HIAA) were found to have high process-related costs including analytical times, but improved diagnostic accuracy. QUADAS-2 analysis revealed significant potential biases in the literature. CONCLUSION: When assessing biomarkers, an appreciation of the trade-offs between the costs and benefits of individual biomarkers is needed. Further studies should seek to investigate new biomarkers and address concerns over bias, in order to improve the diagnosis of acute appendicitis. PMID- 27495335 TI - Clinical impact of laparoscopic hepatectomy: technical and oncological viewpoints. AB - The objective of this study was to assess the clinical impact of laparoscopic hepatectomy from technical and oncological viewpoints through the consecutive 5 year experience of an expert team. The subjects consisted of 491 consecutive hepatectomies performed over the course of 5 years. A total of 190 hepatectomies (38.6 %) were performed laparoscopically, and the remaining 301 (61.4 %) were open hepatectomies. Chronological trends of operative procedures and their indications were evaluated, and patients with hepatocellular carcinoma (HCC) were analyzed from an oncological viewpoint. The proportion of laparoscopic hepatectomies performed increased significantly during the study period (from 17.6 to 49.5 %). According to chronological trends, right hepatectomy was standardized using consecutive steps after minor hepatectomy, left lateral sectionectomy, and left hepatectomy were standardized. The proportion of laparoscopic hepatectomies performed for HCC increased from 21.4 to 71.0 %. No significant difference was observed in the proportion of major hepatectomies performed for HCC between the open and laparoscopy groups (50.6 vs. 48.6 %, p = 0.8053), whereas that of anatomical segmentectomy for HCC was significantly lower in the laparoscopy group (28.7 vs. 11.1 %, p = 0.0064). All laparoscopic anatomical segmentectomies were of segments 5 and 6, and there was no segmentectomy of posterosuperior lesions. The present study shows the consecutive technical developmental processes for minor hepatectomy, left lateral sectionectomy, left hepatectomy, and right hepatectomy without compromising oncological principles. Laparoscopic anatomical segmentectomy for posterosuperior lesions may be the most technically demanding procedure, requiring individualized standardization. PMID- 27495336 TI - Postoperative complications as an independent risk factor for recurrence after laparoscopic ventral hernia repair: a prospective study of 417 patients with long term follow-up. AB - BACKGROUND: Laparoscopic ventral hernia repair (LVHR) has become widely used. This study evaluates outcomes of LVHR, with particular reference to complications, seromas, and long-term recurrence. METHODS: A review of a prospective database of consecutive patients undergoing LVHR with intraperitoneal onlay mesh (IPOM) was performed at a single institution. Patient's characteristics, surgical procedures, and postoperative outcomes were analyzed and related to long-term recurrence. RESULTS: From 2005 to 2014, 417 patients underwent LVHR. Mean age and body mass index (BMI) were 54 years and 31 kg/m2. Mesh fixation was carried out with transfascial sutures, completed with absorbable tacks (72 %), metal tacks (24 %), or intraperitoneal sutures (4 %). Intraoperative complications occurred in three patients. Overall morbidity included 8.25 % of minor complications and 2.5 % of major complications without mortality. The overall recurrence rate was 9.8 %. Median time for recurrence was 15.3 months (3-72) and median follow-up was 31.6 months (8-119). In a multivariate analysis, previous interventions (OR 1.44; CI 1.15-1.79; p = 0.01), postoperative complications (OR 2.57; CI 1.09-6.03; p = 0.03), and Clavien-Dindo score >2 (OR 1.43; CI 1.031-1.876; p = 0.02) appeared as independent prognostic factors of recurrence. Minor complications were associated with 14.7 % of recurrence and major complications with 30 % of recurrence. Emergency LVHR (6 %) did not increase the rate of complications. Overall seroma rate was 18.7 %, with 1.4 % of persisting or complicated seroma. BMI (OR 1.05; CI 1.01-1.08; p = 0.026) and vascular surgery history (OR 5.74; CI 2.11-15.58; p < 0.001) were independent predictive factors for seroma. Recurrence did not appear to be related to seroma. CONCLUSION: LVHR combines the benefits of laparoscopy with those of mesh repair. Seroma formation should no longer be considered as a complication. It is spontaneously regressive in most cases. Postoperative complications and their degree of severity appear to be independent prognostic factors for recurrence, which can be limited with a standardized technique and may make IPOM-LVHR a reference procedure. PMID- 27495337 TI - Robotic partial nephrectomy performed with Airseal versus a standard CO2 pressure pneumoperitoneum insufflator: a prospective comparative study. AB - BACKGROUND: Airseal represents a new generation of valveless and barrier-free surgical trocars that enable a stable pneumoperitoneum with continuous smoke evacuation and carbon dioxide (CO2) recirculation during surgery. The aim of the current study was to evaluate the potential advantages of the Airseal compared to a standard CO2 insufflator in the field of robotic partial nephrectomy (RPN). METHODS: Between October 2012 and April 2015, two cohorts of 122 consecutive patients with clinically localized renal cell carcinoma underwent RPN by a single surgeon, with the use of a standard CO2 pressure insufflator (Group A, 55 patients) or Airseal (Group B, 67 patients) and were prospectively compared. RESULTS: The two groups were similar in baseline, preoperative characteristics. The mean dimension of the lesion, as evaluated by contrast-enhanced CT scan, was 30 (median 28; IQR 2) and 39 mm (median 40; IQR 2) for Groups A and B, respectively (p < 0.05). The complexity of the treated tumors was similar, as indicated by the mean RENAL nephrometry score. Positive surgical margins rate was similar in both groups (3.6 vs 4.5 %, p = 0.8) as well as the need for postoperative blood transfusion (9.1 vs 4.5 %, p = 0.3) and the development of postoperative acute kidney injury (16.4 vs 10.4 %, p = 0.3). Mean operative time and warm ischemia time were significantly shorter in Group B. Moreover, a significant increase in the cases performed as "zero ischemia" was observed in Group B (7.3 vs 30 %, p < 0.01). CONCLUSIONS: This is the first study comparing the Airseal with a standard CO2 insufflator system in the field of the RPN. The preliminary outcomes in terms of overall operative time, warm ischemia time and cases performed as "zero ischemia" are better with respect to standard insufflators. The feasibility, safety and efficacy of combining laser tumor enucleation with the valve-free insufflation systems should be evaluated. PMID- 27495338 TI - Risk factors for lymph node metastasis and long-term outcomes of patients with early gastric cancer after non-curative endoscopic submucosal dissection. AB - BACKGROUND: The long-term outcomes after non-curative gastric endoscopic submucosal dissection (ESD) are still unknown. We aimed to clarify the pathological risk factors for lymph node metastasis (LNM) of early gastric cancer (EGC) and the long-term outcomes among patients who were judged to have had non curative ESD. METHODS: From September 2002 to December 2012, 506 patients who were judged to have had non-curative gastric ESD were enrolled and classified into two groups: (1) those who subsequently underwent additional surgical resection (surgical group, n = 323) and (2) those followed up without additional surgical resection (nonsurgical group, n = 183). We analyzed pathological risk factors for LNM of EGC in the surgical group. Additionally, we compared long-term outcomes in the two groups. RESULTS: LNM was found pathologically in 9.3 % of the surgical group (30/323) at the additional surgical resection after non-curative ESD. In the multivariate logistic regression analysis, lymphovascular invasion (LVI) was an independent risk factor for LNM in the surgical group (odds ratio 8.57, 95 % confidence interval 2.76-38.14, P < 0.0001). The 5-year cause-specific survival rate was similar in the surgical and nonsurgical groups (98.7 and 96.5 %, respectively; log-rank test, P = 0.07). In contrast, the 5-year cause-specific survival rate of patients with LVI in the surgical group was better than that in the nonsurgical group (98.2 and 79.1 %, respectively; log-rank test, P < 0.0001). CONCLUSIONS: A detailed assessment of LVI is essential to the pathological evaluation of endoscopically resected specimens. An additional surgical resection should be strongly recommended for patients with LVI. PMID- 27495339 TI - Preventing anastomotic complications: early results of laparoscopic gastric devascularization two weeks prior to minimally invasive esophagectomy. AB - BACKGROUND: Laparoscopic gastric devascularization (LGD) is an innovative method to improve gastric conduit perfusion and improve anastomotic healing following esophagectomy. This study reports our early experience with LGD performed two weeks prior to minimally invasive esophagectomy (MIE) with intrathoracic anastomosis. METHODS: We performed a retrospective review of all patients who underwent LGD prior to minimally invasive Ivor Lewis esophagectomy between August 2014 and July 2015 at a large academic medical center. LGD included staging laparoscopy with division of the short gastric vessels, left gastric artery and coronary vein, and posterior gastric attachments. Patient demographics, comorbid conditions, clinical stage, use of neoadjuvant chemoradiation, perioperative events, length of hospital stay, 60-day readmission, and complications were collected and analyzed. RESULTS: Thirty patients underwent LGD prior to minimally invasive Ivor Lewis esophagectomy, and 21 (70 %) received neoadjuvant chemoradiation. LGD was performed a median of 14.5 (9-42) days prior to esophagectomy. Median operative time was 39 (18-56) minutes, and median length of stay was 0 (0-1) days. There were no complications or readmissions following LGD. MIE was completed laparoscopically in 93 % of patients; two patients required conversion to an open procedure due to mediastinal inflammation following neoadjuvant chemoradiation. Five patients (17 %) were readmitted within 60 days of surgery: one (3 %) patient with an anastomotic leak, two (7 %) with pneumonia, and two (7 %) with post-operative nausea and vomiting. One patient (3 %) expired following an anastomotic leak that required reoperation, and no patients developed an anastomotic stricture during the study period. CONCLUSIONS: LGD with delayed esophageal resection and reconstruction can be safely performed two weeks prior to MIE with minimal morbidity. The low rate of anastomotic leak (3 %) and absence of anastomotic strictures in this series suggest that this approach may successfully improve gastroesophageal anastomotic healing and reduce the rate of anastomotic complications reported with single-stage approaches. PMID- 27495340 TI - A new experimental model of calculous cholecystitis suitable for the evaluation and training of minimally invasive approaches to cholecystectomy. AB - BACKGROUND: Novel, less invasive approaches such as single-incision laparoscopic cholecystectomy or natural orifice transluminal endoscopic surgery require preclinical evaluation and training. Therefore, there is a need for an experimental model closely mimicking the clinical situation. The aim of our study was to create an experimental model of calculous cholecystitis in a large laboratory animal and test its feasibility for the evaluation of different techniques of cholecystectomy. METHODS: In 11 laboratory pigs, gallstones were placed inside the gallbladder laparoscopically. Levels of inflammatory markers leucocytes (WBC), C-reactive protein (CRP) and interleukin 6 (IL-6)-were monitored on the postoperative days (POD) 1, 2, 3, 7 and 30. Abdominal ultrasound was performed 2 and 4 weeks after the operation. Four weeks after the lithiasis induction, laparoscopic cholecystectomy was performed. The control group consisted of ten healthy animals in which a cholecystectomy was performed. The pigs were monitored for 30 days after surgery. All removed gallbladders were assessed histologically. RESULTS: The induction of lithiasis took 42 (35-52) min with no morbidity and mortality. The values of WBC, CRP and IL-6 increased significantly (vs. baseline) on POD 1, 2 and 3 (p < 0.05) and then normalised. Ultrasonography confirmed the presence of chronic calculous cholecystitis in all cases after 4 weeks. Laparoscopic cholecystectomy was significantly longer in animals with lithiasis, 63 (42-91) versus 46 (31-62) min (p = 0.018). Perioperative gallbladder wall perforation was significantly more frequent in the model group (8/11 vs. 1/10; p = 0.04). In contrast to healthy animals, all gallbladders with stones showed histological signs of chronic inflammation. CONCLUSIONS: A new animal model of calculous cholecystitis was created. Laparoscopic cholecystectomy was more technically difficult compared to operating on a healthy gallbladder. This model may be a suitable tool for effective preclinical training and also for the evaluation of different techniques of cholecystectomy. PMID- 27495341 TI - Superselective intra-arterial hepatic injection of indocyanine green (ICG) for fluorescence image-guided segmental positive staining: experimental proof of the concept. AB - BACKGROUND: Intraoperative liver segmentation can be obtained by means of percutaneous intra-portal injection of a fluorophore and illumination with a near infrared light source. However, the percutaneous approach is challenging in the minimally invasive setting. We aimed to evaluate the feasibility of fluorescence liver segmentation by superselective intra-hepatic arterial injection of indocyanine green (ICG). MATERIALS AND METHODS: Eight pigs (mean weight: 26.01 +/ 5.21 kg) were involved. Procedures were performed in a hybrid experimental operative suite equipped with the Artis Zeego(r), multiaxis robotic angiography system. A pneumoperitoneum was established and four laparoscopic ports were introduced. The celiac trunk was catheterized, and a microcatheter was advanced into different segmental hepatic artery branches. A near-infrared laparoscope (D Light P, Karl Storz) was used to detect the fluorescent signal. To assess the correspondence between arterial-based fluorescence demarcation and liver volume, metallic markers were placed along the fluorescent border, followed by a 3D CT scanning, after injecting intra-arterial radiological contrast (n = 3). To assess the correspondence between arterial and portal supplies, percutaneous intra portal angiography and intra-arterial angiography were performed simultaneously (n = 1). RESULTS: Bright fluorescence signal enhancing the demarcation of target segments was obtained from 0.1 mg/mL, in matter of seconds. Correspondence between the volume of hepatic segments and arterial territories was confirmed by CT angiography. Higher background fluorescence noise was found after positive staining by intra-portal ICG injection, due to parenchymal accumulation and porto systemic shunting. CONCLUSIONS: Intra-hepatic arterial ICG injection, rapidly highlights hepatic target segment borders, with a better signal-to-background ratio as compared to portal vein injection, in the experimental setting. PMID- 27495342 TI - Twenty-year experience with laparoscopic inguinal hernia repair in infants and children: considerations and results on 1833 hernia repairs. AB - BACKGROUND: The role of laparoscopy in pediatric inguinal hernia (IH) is still controversial. The authors reported their twenty-year experience in laparoscopic IH repair in children. METHODS: In a twenty-year period (1995-2015), we operated 1300 infants and children (935 boys-365 girls) with IH using laparoscopy. The average age at surgery was 18 months (range 7 days-14 years). Body weight ranged between 1.9 and 50 kg (average 9.3). Preoperatively all patients presented a monolateral IH, right-sided in 781 cases (60.1 %) and left-sided in 519 (39.9 %). We excluded patients with bilateral IH and unstable patients in which laparoscopy was contraindicated. If the inguinal orifice diameter was >=10 mm, we performed a modified purse string suture on peri-orificial peritoneum, in orifices <=5 mm, we performed a N-shaped suture. RESULTS: No conversion to open surgery was reported. In 533 cases (41 %), we found a contralateral patency of internal inguinal ring that was always closed in laparoscopy. In 1273 cases (97.9 %), we found an oblique external hernia; in 21 cases (1.6 %), a direct hernia; and in 6 cases (0.5 %), a double hernia on the same side (hernia en pantaloon). We found an incarcerated hernia in 27 patients (2 %). Average operative time was 18 min (range 7-65). We recorded 5/1300 recurrences (0.3 %), but in the last 950 patients, we had no recurrence (0 %). We recorded 20 complications (1.5 %): 18 umbilical granulomas and two trocars scar infections, treated in outpatient setting. CONCLUSIONS: On the basis of our twenty-year experience, we prefer to perform IH repair in children using laparoscopy rather than inguinal approach. Laparoscopy is as fast as inguinal approach, and it has the advantage to treat during the same anesthesia a contralateral patency occured in about 40 % of our cases and to treat also rare hernias in about 3 % of cases. PMID- 27495343 TI - Risk factors associated with difficult gastric endoscopic submucosal dissection: predicting difficult ESD. AB - BACKGROUND AND STUDY AIM: Endoscopic submucosal dissection (ESD) is a widely accepted treatment for superficial gastric neoplasms. Difficult ESD can lead to complications, such as bleeding and perforation. To predict difficult ESD procedures, we analyzed the factors associated with difficult ESD. PATIENTS AND METHODS: The medical records of 1052 ESD procedures were retrospectively reviewed. Difficult ESD was defined by any one of three end points: longer procedure time (>=60 min), piecemeal resection, incomplete (R1) resection, or gastric wall perforation. To determine the factors associated with difficult ESD, clinical and pathologic features and endoscopic findings were analyzed. RESULTS: The rates of en bloc resection and curative (R0) resection were 93.3 and 92.4 %, respectively. The mean procedure time was 27.7 +/- 16.7 min. After multivariate analysis, larger tumor size (>=20 mm) was an independent risk factor for longer procedure time (OR 4.1, P < 0.001), for piecemeal resection (OR 2.3, P = 0.003) and incomplete (R1) resection (OR 2.1, P = 0.005). Location of the lesion (upper third) was an independent risk factor for longer procedure time (OR 5.8, P < 0.001), for piecemeal resection (OR 4.1, P < 0.001) and incomplete (R1) resection (OR 4.5, P < 0.001). Submucosal fibrosis was an independent risk factor for longer procedure time (OR 9.7, P < 0.001), for piecemeal resection (OR 2.4, P < 0.001) and incomplete (R1) resection (OR 2.6, P < 0.001). Finally, submucosal invasive gastric cancer was an independent risk factor for piecemeal resection (OR 2.6, P = 0.008), for perforation (OR 19.3, P = 0.001) and for incomplete (R1) resection (OR 2.7, P = 0.001). CONCLUSIONS: Difficult ESD procedures are a function of the lesion size and location, submucosal fibrosis, and submucosal invasive cancer. When a difficult ESD procedure is expected, appropriate preparations should be considered, including consultation with more experienced endoscopists. PMID- 27495344 TI - A prospective randomized comparison of testicular functions, sexual functions and quality of life following laparoscopic totally extra-peritoneal (TEP) and trans abdominal pre-peritoneal (TAPP) inguinal hernia repairs. AB - BACKGROUND: There is very scant literature on the impact of inguinal hernia mesh repair on testicular functions and sexual functions following open and laparoscopic repair. The present randomized study compares TAPP and TEP repairs in terms of testicular functions, sexual functions, quality of life and chronic groin pain. METHODS: This study was conducted from April 2012 to October 2014. A total of 160 patients with uncomplicated groin hernia were randomized to either trans-abdominal pre-peritoneal (TAPP) repair or totally extra-peritoneal (TEP) repair. Testicular functions were assessed by measuring testicular volume, testicular hormone levels preoperatively and at 3 months postoperatively. Sexual functions were assessed using BMSFI, and quality of life was assessed using WHO QOL BREF scale preoperatively and at 3 and 6 months postoperatively. Chronic groin pain was evaluated using the VAS scale at 3 months, 6 months and at 1 year. RESULTS: The median duration of follow-up was 13 months (range 6-18 months). The mean preoperative pain scores (p value 0.35) as well as the chronic groin pain were similar between TEP and TAPP repairs at 3 months (p value 0.06) and 6 months (p value 0.86). The testicular resistive index and testicular volume did not show any significant change at follow-up of 3 months (p value 0.9) in the study population. No significant difference was observed in testicular resistive index and testicular volume when comparing TEP and TAPP groups at at follow-up of 3 months (p value >0.05). There was a statistically significant improvement in the sexual drive score, erectile function and overall satisfaction over the follow-up period following laparoscopic inguinal hernia repair. However, sexual function improvement was similar in patients undergoing both TEP and TAPP repairs. All the domains of quality of life in the study population showed a significant improvement at a follow-up of 3 and 6 months. Subgroup analysis of all the domains of quality of life in both TAPP and TEP groups showed a similar increment as in the study population (p value <0.001); however, the mean scores of all the domains were comparable between the two subgroups (p value >0.05), preoperatively and 3 and 6 months follow-up. CONCLUSIONS: Laparoscopic groin hernia repair improves the testicular functions, sexual functions and quality of life, but TEP and TAPP repairs are comparable in terms of these long-term outcomes. PMID- 27495345 TI - Outcomes of concomitant ventral hernia repair performed during bariatric surgery. AB - BACKGROUND: Currently there is no consensus on management of ventral hernias encountered during bariatric surgery (BS). This study aims to evaluate the incidence and outcomes of concomitant ventral hernia repair (VHR) during BS at our institution. METHODS: Patients who had concomitant VHR during BS from 2004 to 2015 were identified. Data collected included baseline demographics, comorbidities, perioperative parameters, surgical approach and postoperative outcomes. RESULTS: A total of 159 patients underwent concomitant VHR during the study period at the time of BS. One hundred and one (64 %) patients were female; median age was 53 years (IQR 45.0-60.3) and median BMI was 48.2 kg/m2 (IQR 41.6 54.1). Comorbidities included: hypertension (n = 124, 78 %), type 2 diabetes (n = 103, 65 %), hyperlipidemia (n = 100, 63 %), obstructive sleep apnea (n = 98, 62 %) and reflux disease (n = 54, 34 %). Out of 159 patients, 41 patients (26 %) had a prior VHR. Out of 103 patients, 69 patients (67 %) had a previous abdominal surgery. Of the concomitant VHR, 144 (91 %) were completed laparoscopically, 12 (7 %) patients were converted to open surgery and 3 (2 %) patients underwent primary open procedures. Technique included primary suture closure in 115 (72 %) and mesh repair in 44. Early postoperative complications (<30 days) were reported in 16 (10 %) patients, with superficial wound infection (n = 9), bowel obstruction (n = 2), marginal ulcer (n = 2), DVT (n = 1) and pneumonia (n = 1). Hernia recurrence was reported in 3 patients (2 %) in the early post-op period and in 40 patients (25 %) as a late (>30 days) complication. Surgery for recurrent hernia was performed in 31/42 patients during follow-up. At 12-month follow-up, median BMI and % excess weight loss were 34.2 kg/m2 (IQR 29.5-40.9) and 59.6 % (IQR 44.9-74.8 %), respectively. CONCLUSION: Ventral hernia is a common finding in patients undergoing BS. Both primary suture repair and mesh repair result in acceptable results, both in terms of recurrence and perioperative complications. PMID- 27495346 TI - A retrospective comparison of robotic cholecystectomy versus laparoscopic cholecystectomy: operative outcomes and cost analysis. AB - INTRODUCTION: Robotic-assisted surgery is gaining popularity in general surgery. Our objective was to evaluate and compare operative outcomes and total costs for robotic cholecystectomy (RC) and laparoscopic cholecystectomy (LC). METHODS AND PROCEDURES: A retrospective review was performed for all patients who underwent single-procedure RC and LC from January 2011 to July 2015 by a single surgeon at a large academic medical center. Demographics, diagnosis, perioperative variables, postoperative complications, 30-day readmissions, and operative and hospital costs were collected and analyzed between those patient groups. RESULTS: A total of 237 patients underwent RC or LC, and comprised the study population. Ninety-seven patients (40.9 %) underwent LC, and 140 patients (50.1 %) underwent RC. Patients who underwent RC had a higher body mass index (p = 0.03), lower rates of coronary artery disease (p < 0.01), and higher rates of chronic cholecystitis (p < 0.01). There were lower rates of intraoperative cholangiography (p < 0.01) and conversion to an open procedure (p < 0.01), however longer operative times (p < 0.01) for patients in the RC group. There were no bile duct injuries in either group, no difference in bile leak rates (p = 0.65), or need for reoperation (p = 1.000). Cost analysis of outpatient-only procedures, excluding cases with conversion to open or use of intraoperative cholangiography, demonstrated higher total charges (p < 0.01) and cost (p < 0.01) and lower revenue (p < 0.01) for RC compared to LC, with no difference in total payments (p = 0.34). CONCLUSIONS: Robotic cholecystectomy appears to be safe although costlier in comparison with laparoscopic cholecystectomy. Further studies are needed to understand the long-term implications of robotic technology, the cost to the health care system, and its role in minimally invasive surgery. PMID- 27495349 TI - Letter: The History of the Kernohan Notch Revisited. PMID- 27495347 TI - Robotic-assisted ventral hernia repair: a multicenter evaluation of clinical outcomes. AB - BACKGROUND: The open approach continues to be widely performed for ventral hernia repair, while the minimally invasive laparoscopic approach has grown adoption over the last decade. Recently, robotic operation was described as a new modality due to the ease for performing intracorporeal closure of the hernia defect. This study is one of the first multi-institutional case series evaluating robotic assisted laparoscopic ventral hernia repairs, with the goal of describing robotic assisted surgical techniques for ventral and incisional hernia repair and the outcomes in teaching and community hospital settings. METHODS: Medical records of consecutive patients (including surgeon's learning curve cases) who underwent ventral or incisional hernia repair utilizing the da Vinci Surgical System (Intuitive Surgical Inc, Sunnyvale CA) were retrospectively reviewed. Data collected included preoperative history and perioperative outcomes. RESULTS: Data for a total of 368 patients from four institutions involving five surgeons were analyzed. They were predominantly females (60.3 %), and the mean age was 51 years. The majority of the patients were obese or morbidly obese (47.8 and 20.9 %), and 83.2 % of the patients had a history of prior abdominal operation. Conversion rate was 0.8 %, and mean length of stay was 1 day. Total postoperative complications rate up to 30 days was 8.4 %, of which incidence of paralytic ileus was 2.4 %. CONCLUSION: This large case series of 368 patients demonstrates reproducibility of safety and performance associated with robotic-assisted ventral hernia repairs performed by five surgeons at four institutions. In addition, the results of short term perioperative outcomes for surgeons during their early experience for robotic-assisted cases are in the range of what is reported in the existing published data on laparoscopic and open ventral hernia repairs. Further comparative evidence initiatives are being pursued to determine the benefits of robotic-assisted technique and technology for long-term and patient-reported outcomes. PMID- 27495348 TI - Increasing resident utilization and recognition of the critical view of safety during laparoscopic cholecystectomy: a pilot study from an academic medical center. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is a commonly performed surgical procedure; however, it is associated with an increased rate of bile duct injury (BDI) when compared to the open approach. The critical view of safety (CVS) provides a secure method of ductal identification to help avoid BDI. CVS is not universally utilized by practicing surgeons and/or taught to surgical residents. We aimed to pilot a safe cholecystectomy curriculum to demonstrate that educational interventions could improve resident adherence to and recognition of the CVS during LC. METHODS: Forty-three general surgery residents at Thomas Jefferson University Hospital were prospectively studied. Fifty-one consecutive LC cases were recorded during the pre-intervention period, while the residents were blinded to the outcome measured (CVS score). As an intervention, a comprehensive lecture on safe cholecystectomy was given to all residents. Fifty consecutive LC cases were recorded post-intervention, while the residents were empowered to "time-out" and document the CVS with a doublet photograph. Two independent surgeons scored the videos and photographs using a 6-point scale. Residents were surveyed pre- and post-intervention to determine objective knowledge and self-reported comfort using a 5-point Likert scale. RESULTS: In the 18-week study period, 101 consecutive LCs were adequately captured and included (51 pre-intervention, 50 post-intervention). Patient demographics and clinical data were similar. The mean CVS score improved from 2.3 to 4.3 (p < 0.001). The number of videos with CVS score >4 increased from 15.7 to 52 % (p < 0.001). There was strong inter-observer agreement between reviewers. The pre- and post intervention questionnaire response rates were 90.7 and 83.7 %, respectively. A greater number of residents correctly identified all criteria of the CVS post intervention (41-93 %, p < 0.001) and offered appropriate bailout techniques (77 94 %, p < 0.001). Residents strongly agreed that the CVS education should be included in general surgery residency curriculum (mean Likert score = 4.71, SD = 0.54). Residents also agreed that they are more comfortable with their LC skills after the intervention (4.27, sigma = 0.83). CONCLUSION: The combination of focused education along with intraoperative time-out significantly improved CVS scores and knowledge during LC in our institution. PMID- 27495350 TI - Design Considerations of a Fiber Optic Pressure Sensor Protective Housing for Intramuscular Pressure Measurements. AB - Intramuscular pressure (IMP), defined as skeletal muscle interstitial fluid pressure, reflects changes in individual muscle tension and may provide crucial insight into musculoskeletal biomechanics and pathologies. IMP may be measured using fiber-optic fluid pressure sensors, provided the sensor is adequately anchored to and shielded from surrounding muscle tissue. Ineffective anchoring enables sensor motion and inadequate shielding facilitates direct sensor-tissue interaction, which result in measurement artifacts and force-IMP dissociation. The purpose of this study was to compare the effectiveness of polyimide and nitinol protective housing designs to anchor pressure sensors to muscle tissue, prevent IMP measurement artifacts, and optimize the force-IMP correlation. Anchoring capacity was quantified as force required to dislodge sensors from muscle tissue. Force-IMP correlations and non-physiological measurement artifacts were quantified during isometric muscle activations of the rabbit tibialis anterior. Housing structural integrity was assessed after both anchoring and activation testing. Although there was no statistically significant difference in anchoring capacity, nitinol housings demonstrated greater structural integrity and superior force-IMP correlations. Further design improvements are needed to prevent tissue accumulation in the housing recess associated with artificially high IMP measurements. These findings emphasize fundamental protective housing design elements crucial for achieving reliable IMP measurements. PMID- 27495351 TI - Do Selective Serotonin Reuptake Inhibitors (SSRIs) Cause Fractures? AB - Recent meta-analyses report a 70 % increase in fracture risk in selective serotonin reuptake inhibitor (SSRI) users compared to non-users; however, included studies were observational and limited in their ability to establish causality. Here, we use the Bradford Hill criteria to explore causality between SSRIs and fractures. We found a strong, consistent, and temporal relationship between SSRIs and fractures, which appears to follow a biological gradient. However, specificity and biological plausibility remain concerns. In terms of specificity, the majority of available data have limitations due to either confounding by indication or channeling bias. Self-controlled case series address some of these limitations and provide relatively strong observational evidence for a causal relationship between SSRIs and fracture. In doing so, they suggest that falls contribute to fractures in SSRI users. Whether there are also underlying changes in skeletal properties remains unresolved. Initial studies provide some evidence for skeletal effects of SSRIs; however, the pathways involved need to be established before biological plausibility can be accepted. As the link between SSRIs and fractures is based on observational data and not evidence from prospective trials, there is insufficient evidence to definitively determine a causal relationship and it appears premature to label SSRIs as a secondary cause of osteoporosis. SSRIs appear to contribute to fracture-inducing falls, and addressing any fall risk associated with SSRIs may be an efficient approach to reducing SSRI-related fractures. As fractures stemming from SSRI induced falls are more likely in individuals with compromised bone health, it is worth considering bone density testing and intervention for those presenting with risk factors for osteoporosis. PMID- 27495352 TI - Characteristics and Methodological Quality of Meta-Analyses on Hypertension Treatments-A Cross-Sectional Study. AB - Methodological quality of meta-analyses on hypertension treatments can affect treatment decision-making. The authors conducted a cross-sectional study to investigate the methodological quality of meta-analyses on hypertension treatments. One hundred and fifty-eight meta-analyses were identified. Overall, methodological quality was unsatisfactory in the following aspects: comprehensive reporting of financial support (1.9%), provision of included and excluded lists of studies (22.8%), inclusion of grey literature (27.2%), and inclusion of protocols (32.9%). The 126 non-Cochrane meta-analyses had poor performance on almost all the methodological items. Non-Cochrane meta-analyses focused on nonpharmacologic treatments were more likely to consider scientific quality of included studies when making conclusions. The 32 Cochrane meta-analyses generally had good methodological quality except for comprehensive reporting of the sources of support. These results highlight the need for cautious interpretation of these meta-analyses, especially among physicians and policy makers when guidelines are formulated. Future meta-analyses should pay attention to improving these methodological aspects. PMID- 27495353 TI - No more neglect of helminths and HIV. PMID- 27495354 TI - Effect of Wuchereria bancrofti infection on HIV incidence in southwest Tanzania: a prospective cohort study. AB - BACKGROUND: The past decades have seen an ongoing controversial debate about whether the immune activation induced by helminths has an effect on the susceptibility of individuals to HIV. In view of this, we assessed the effect of lymphatic filariasis, a chronic helminth disease elicited by Wuchereria bancrofti, on HIV incidence in southwest Tanzania. METHODS: In this population based cohort study, we enrolled a geographically stratified randomly chosen sample of about 10% of the households in nine distinct sites in southwest Tanzania. All household members present were followed up and tested for HIV and circulating filarial antigen, an indicator of W bancrofti adult worm burden. Our main outcome of interest was HIV incidence in participants with or without lymphatic filariasis. FINDINGS: Between May 29, 2006, and June 16, 2011, we enrolled 4283 households with roughly 18 000 participants. Of these, 2699 individuals from Kyela district participated in at least one round of the EMINI study. In the 1055 initially HIV-negative adolescents and adults with clearly defined lymphatic filariasis status, 32 new HIV infections were observed in 2626 person-years. HIV incidence in lymphatic filariasis-positive participants (1.91 cases per 100 person-years) was significantly higher than the incidence in lymphatic filariasis-negative participants (0.80 cases per 100 person-years). The age-adjusted and sex-adjusted incidence rate ratio was 2.17 (95% CI 1.08-4.37, p=0.0300). Lymphatic filariasis status remained an independent and significantly relevant risk factor for HIV infection when controlled for other known risk factors such as sexual behaviour and socioeconomic factors. INTERPRETATION: To our knowledge, this is the first prospective study demonstrating a significantly increased risk of acquiring HIV for lymphatic filariasis-infected individuals. Immunological studies and interventional treatment studies that eliminate the adult worms and not only the microfilariae are needed to follow up on the results presented. FUNDING: European Union as part of EuropAid; German Federal Ministry of Education and Research; German Center for Infection Research. PMID- 27495355 TI - Neoechinulin A induced memory improvements and antidepressant-like effects in mice. AB - Neoechinulin A is an isoprenyl indole alkaloid that exhibits scavenging, neurotrophic factor-like, and anti-apoptotic activities. However, the effectiveness of neoechinulin A in animal models of disease has not yet been explored. In the present study, we investigated the effects of neoechinulin A on memory impairment in lipopolysaccharide (LPS)-treated mice and its antidepressant like effects in mice. In the Y-maze test, the intracerebroventicular (i.c.v.) administration of LPS (10MUg/mouse) significantly decreased spontaneous alternation behavior, which was prevented by the prior administration of neoechinulin A (300ng/mouse, i.c.v.). None of the treatments altered the locomotor activity of mice. Moreover, the administration of neoechinulin A decreased the immobility time in the forced-swim test or tail suspension test, which was prevented by the prior administration of WAY100635 (an antagonist of 5 HT1A receptors) and parachlorophenylalanine (an inhibitor of tryptophan hydroxylase). These results suggest that neoechinulin A improves memory functions in LPS-treated mice, and also exerts antidepressant-like effects through changes in the 5-HT system. PMID- 27495356 TI - Error-related brain activity in youth and young adults before and after treatment for generalized or social anxiety disorder. AB - Increased error monitoring, as measured by the error-related negativity (ERN), has been shown to persist after treatment for obsessive-compulsive disorder in youth and adults; however, no previous studies have examined the ERN following treatment for related anxiety disorders. We used a flanker task to elicit the ERN in 28 youth and young adults (8-26years old) with primary diagnoses of generalized anxiety disorder (GAD) or social anxiety disorder (SAD) and 35 healthy controls. Patients were assessed before and after treatment with cognitive-behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRI), and healthy controls were assessed at a comparable interval. The ERN increased across assessments in the combined sample. Patients with SAD exhibited an enhanced ERN relative to healthy controls prior to and following treatment, even when analyses were limited to SAD patients who responded to treatment. Patients with GAD did not significantly differ from healthy controls at either assessment. Results provide preliminary evidence that enhanced error monitoring persists following treatment for SAD in youth and young adults, and support conceptualizations of increased error monitoring as a trait-like vulnerability that may contribute to risk for recurrence and impaired functioning later in life. Future work is needed to further evaluate the ERN in GAD across development, including whether an enhanced ERN develops in adulthood or is most apparent when worries focus on internal sources of threat. PMID- 27495357 TI - To what extent is it possible to dissociate the anxiolytic and sedative/hypnotic properties of GABAA receptors modulators? AB - The relatively common view indicates a possible dissociation between the anxiolytic and sedative/hypnotic properties of benzodiazepines (BZs). Indeed, GABAA receptor (GABAAR) subtypes have specific cerebral distribution in distinct neural circuits. Thus, GABAAR subtype-selective drugs may be expected to perform distinct functions. However, standard behavioral test assays provide limited direction towards highlighting new action mechanisms of ligands targeting GABAARs. Automated behavioral tests, lack sensitivity as some behavioral characteristics or subtle behavioral changes of drug effects or that are not considered in the overall analysis (Ohl et al., 2001) and observation-based analyses are not always performed. In addition, despite the use of genetically engineered mice, any possible dissociation between the anxiolytic and sedative properties of BZs remains controversial. Moreover, the involvement the different subtypes of GABAAR subtypes in the anxious behavior and the mechanism of action of anxiolytic agents remains unclear since there has been little success in the pharmacological investigations so far. This raises the question of the involvement of the different subunits in anxiolytic-like and/or sedative effects; and the actual implication of these subunits, particularly, alpha-subunits in the modulation of sedation and/or anxiety-related disorders. This present review was prompted by several conflicting studies on the degree of involvement of these subunits in anxiolytic-like and/or sedative effects. To this end, we explored the GABAergic system, particularly, the role of different subunits containing synaptic GABAARs. We report herein the targeting gene encoding the different subunits and their contribution in anxiolytic-like and/or sedative actions, as well as, the mechanism underlying tolerance to BZs. PMID- 27495358 TI - Mean kurtosis alterations of cerebral white matter in patients with schizophrenia revealed by diffusion kurtosis imaging. AB - INTRODUCTION: Diffusion kurtosis imaging can provide a better understanding of microstructural white matter (WM) changes where crossing fibers exist, compared with conventional diffusion tensor imaging. Here, we aimed to examine the differences of mean kurtosis (MK) and fractional anisotropy (FA) values between patients with schizophrenia and control subjects using voxel-based analysis (VBA). Additionally, we examined the correlation between these values and severity of clinical symptoms in patients with schizophrenia. METHODS: MK and FA values were acquired with a 3.0T scanner from 31 patients with schizophrenia and 31 age-, handedness-, and sex-matched healthy controls. VBA was used to compare the MK and FA maps of the patients with schizophrenia and healthy controls. We also performed a correlation analysis between the MK and FA values of the regions with significant differences and the positive and negative syndrome scale scores in patients with schizophrenia. RESULTS: Compared to FA values, voxels with MK decrease were more widespread across bilateral cerebral the WM of patients with schizophrenia. The MK values of left superior longitudinal fasciculus were significantly negatively correlated with the severity of positive symptoms (r= 0.451, P=0.011). There was no significant correlation between MK and FA values and other clinical variables. CONCLUSION: The diffusion kurtosis indices are suitable for evaluating altered WM structures in the human brain as they may detect white matter alterations of crossing fibers alterations of WM in schizophrenia and assess the clinical state of patients. PMID- 27495359 TI - Reply: Evolution and vascular calcification. PMID- 27495360 TI - The progression of electrophysiologic abnormalities during epileptogenesis after experimental traumatic brain injury. AB - OBJECTIVE: Posttraumatic epilepsy (PTE) accounts for 20% of acquired epilepsies. Experimental models are important for studying epileptogenesis. We previously reported that repetitive high-frequency oscillations with spikes (rHFOSs) occur early after lateral fluid percussion injury (FPI) and may be a biomarker for PTE. The objective of this study was to use multiple electrodes in rat hippocampal and neocortical regions to describe the long-term electroencephalographic and behavioral evolution of rHFOSs and epileptic seizures after traumatic brain injury (TBI). METHODS: Adult male rats underwent mild, moderate, or severe FPI or sham injury followed by video-electroencephalography (EEG) recordings with a combination of 16 neocortical and hippocampal electrodes at an early, intermediate, or late time-point after injury, up to 52 weeks. Recordings were analyzed for the presence of rHFOSs and seizures. RESULTS: Analysis was done on 28 rats with FPI and 7 shams. Perilesional rHFOSs were recorded in significantly more rats after severe (70.3%) than mild (20%) injury or shams (14.3%). Frequency of occurrence was significantly highest in the early (10.8/h) versus late group (3.2/h). Late focal seizures originating from the same electrodes were recorded in significantly more rats in the late (87.5%) versus early period (22.2%), occurring almost exclusively in injured rats. Seizure duration increased significantly over time, averaging 19 s at the beginning of the early period and 27 s at the end of the late period. Seizure frequency also increased significantly over time, from 4.4 per week in the early group to 26.4 per week in the late group. Rarely, rats displayed early seizures or generalized seizures. SIGNIFICANCE: FPI results in early rHFOSs and later spontaneous focal seizures arising from peri-lesional neocortex, supporting its use as a model for PTE. Epilepsy severity increased over time and was related to injury severity. The association between early rHFOSs and later focal seizures suggests that rHFOSs may be a potential noninvasive biomarker of PTE. PMID- 27495361 TI - Candida virulence and ethanol-derived acetaldehyde production in oral cancer and non-cancer subjects. AB - OBJECTIVES: To compare biofilm-forming ability, hydrolytic enzymes and ethanol derived acetaldehyde production of oral Candida isolated from the patients with oral cancer and matched non-oral cancer. MATERIAL AND METHODS: Fungal biofilms were grown in RPMI-1640 medium, and biofilm mass and biofilm activity were assessed using crystal violet staining and XTT salt reduction assays, respectively. Phospholipase, proteinase, and esterase production were measured using agar plate method, while fungal acetaldehyde production was assessed via gas chromatography. RESULTS: Candida isolated from patients with oral cancer demonstrated significantly higher biofilm mass (P = 0.031), biofilm metabolic activity (P < 0.001), phospholipase (P = 0.002), and proteinase (P = 0.0159) activity than isolates from patients with non-oral cancer. High ethanol-derived acetaldehyde-producing Candida were more prevalent in patients with oral cancer than non-oral cancer (P = 0.01). In univariate regression analysis, high biofilm mass (P = 0.03) and biofilm metabolic activity (P < 0.001), high phospholipase (P = 0.003), and acetaldehyde production ability (0.01) were significant risk factors for oral cancer; while in the multivariate regression analysis, high biofilm activity (0.01) and phospholipase (P = 0.01) were significantly positive influencing factors on oral cancer. CONCLUSION: These data suggest a significant positive association between the ability of Candida isolates to form biofilms, to produce hydrolytic enzymes, and to metabolize alcohol to acetaldehyde with their ability to promote oral cancer development. PMID- 27495362 TI - Perspectives on hyperpolarised solution-state magnetic resonance in chemistry. AB - This perspective article reviews some of the recent developments in the field of hyperpolarisation, with a focus on solution-state NMR spectroscopy of small molecules. Two techniques are considered in more detail, dissolution dynamic nuclear polarisation (D-DNP) and signal amplification by reversible exchange (SABRE). Some of the opportunities and challenges for applications of hyperpolarised solution-state magnetic resonance in chemistry are discussed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27495364 TI - Corrigendum to "Multiple forms of metaplasticity at a single hippocampal synapse during late postnatal development" [Dev. Cogn. Sci. 12C (2015) 145-154]. PMID- 27495363 TI - A case-control study of innate immunity pathway gene polymorphisms in Puerto Ricans reveals association of toll-like receptor 2 +596 variant with asthma. AB - BACKGROUND: For many years, African Dust Storms (ADE) has been thought to be associated with high prevalence of asthma in Puerto Rico (PR). Endotoxins (ENX) have been associated with ADE particulate matter (PM) and are known to promote pro-inflammatory responses in lung cells of susceptible individuals through the Toll-like receptor (TLR2/4) signaling pathways. Genetic variants are plausible contributors to such susceptibility. Therefore, we have evaluated a series of nine single nucleotide polymorphisms (SNPs) in TLR genes, which have been correlated positive and negatively to asthma prevalence and/or risk, in the Puerto Rican asthmatic population. METHODS: The following SNPs were evaluated in 62 asthmatics and 61 controls through Taqman(r) Real Time PCR Assay: TLR4 (+896A/G, +1196C/T, -6687A/G); TLR2 (+596C/T, -16934 T/A, +399A/G, +1349C/T) and CD14 (-159C/T, +1188C/G). Genotypes were assessed for asthma association employing an odds ratio (OR) analysis. RESULTS: Minor allele frequencies (n = 123) were determined for those variants as 0.07, 0.06, 0.35, 0.35, 0.37, 0.29, 0.04, 0.35 and 0.11, respectively. Two (+596C/T, +399A/G) TLR2 SNPs showed to be more represented in the asthmatic group by 89 % and 65 %, respectively. TLR4 SNP +896A/G analysis revealed only 1 G/G genotype (2 %) on the asthmatic group. The CD14 SNPs were similarly represented in the Puerto Rican population. Only the TLR2 +596 SNP was found to be significantly associated to asthma (OR = 3.24 for CT, 2.71 for TT) and particularly to females. CONCLUSIONS: The identification of TLR SNPs will reveal potential candidates for gene-environment interactions in Puerto Ricans. As far as we know this is the first study to evaluate this type of TLR gene polymorphisms in Puerto Rican asthmatics, contributing to the current knowledge in the Hispanic population. PMID- 27495365 TI - Corrigendum to "Investigation into omocysteine, vitamin E and malondialdehyde as indicators of successful artificial insemination in synchronized buffalo cows (Bubalus bubalis)" [Res. Vet. Sci. Volume 104, February 2016, Pages 100-105]. PMID- 27495366 TI - Solvent-assisted dispersive solid-phase extraction: A sample preparation method for trace detection of diazinon in urine and environmental water samples. AB - In this research, a sample preparation method termed solvent-assisted dispersive solid-phase extraction (SA-DSPE) was applied. The used sample preparation method was based on the dispersion of the sorbent into the aqueous sample to maximize the interaction surface. In this approach, the dispersion of the sorbent at a very low milligram level was received by inserting a solution of the sorbent and disperser solvent into the aqueous sample. The cloudy solution created from the dispersion of the sorbent in the bulk aqueous sample. After pre-concentration of the diazinon, the cloudy solution was centrifuged and diazinon in the sediment phase dissolved in ethanol and determined by gas chromatography-flame ionization detector. Under the optimized conditions (pH of solution=7.0, Sorbent: benzophenone, 2%, Disperser solvent: ethanol, 500MUL, Centrifuge: centrifuged at 4000rpm for 3min), the method detection limit for diazinon was 0.2, 0.3, 0.3 and 0.3MUgL(-1) for distilled water, lake water, waste water and urine sample, respectively. Furthermore, the pre-concentration factor was 363.8, 356.1, 360.7 and 353.38 in distilled water, waste water, lake water and urine sample, respectively. SA-DSPE was successfully used for trace monitoring of diazinon in urine, lake and waste water samples. PMID- 27495367 TI - Separation of parent homopolymers from polystyrene and poly(ethylene oxide) based block copolymers by liquid chromatography under limiting conditions of desorption 3. Study of barrier efficiency according to block copolymers' chemical composition. AB - Liquid Chromatography under Limiting Conditions of Desorption (LC LCD) is a powerful separation tool for multicomponent polymer systems. This technique is based on a barrier effect of an appropriate solvent, which is injected in front of the sample, and which decelerates the elution of selected macromolecules. In this study, the barrier effects have been evaluated for triblock copolymers polystyrene-b-poly(ethylene oxide)-b-polystyrene (PS-b-PEO-b-PS) according to the content of polystyrene (wt% PS) and PEO-block molar mass. PS-b-PEO-b-PS samples were prepared by Atom Transfer Radical Polymerization (ATRP). The presence of respective parent homopolymers was investigated by applying optimized LC LCD conditions. It was found that the barrier composition largely affects the efficiency of separation and it ought to be adjusted for particular composition range of block copolymers. PMID- 27495368 TI - A comparative evaluation of different ionic liquids for arsenic species separation and determination in wine varietals by liquid chromatography - hydride generation atomic fluorescence spectrometry. AB - The application of different ionic liquids (ILs) as modifiers for chromatographic separation and determination of arsenite [As(III)], arsenate [As(V)], dimethylarsonic acid (DMA) and monomethylarsonic acid (MMA) species in wine samples, by reversed-phase high performance liquid chromatography coupled to hydride generation atomic fluorescence spectrometry detection (RP-HPLC-HG-AFS) was studied in this work. Several factors influencing the chromatographic separation of the As species, such as pH of the mobile phase, buffer solution concentration, buffer type, IL concentration and length of alkyl groups in ILs were evaluated. The complete separation of As species was achieved using a C18 column in isocratic mode with a mobile phase composed of 0.5% (v/v) 1-octyl-3 methylimidazolium chloride ([C8mim]Cl) and 5% (v/v) methanol at pH 8.5. A multivariate methodology was used to optimize the variables involved in AFS detection of As species after they were separated by HPLC. The ILs showed remarkable performance for the separation of As species, which was obtained within 18min with a resolution higher than 0.83. The limits of detection for As(III), As(V), MMA and DMA were 0.81, 0.89, 0.62 and 1.00MUg As L(-1). The proposed method was applied for As speciation analysis in white and red wine samples originated from different grape varieties. PMID- 27495369 TI - Comprehensive profiling of ribonucleosides modification by affinity zirconium oxide-silica composite monolithic column online solid-phase microextraction - Mass spectrometry analysis. AB - More than 140 modified ribonucleosides have been identified in RNA. Determination of endogenous modified ribonucleosides in biological fluids may serve as non invasive disease diagnostic strategy. However, detection of the modified ribonucleosides in biological fluids is challenging, especially for the low abundant modified ribonucleosides due to the serious matrix interferences of biological fluids. Here, we developed a facile preparation strategy and successfully synthesized zirconium oxide-silica (ZrO2/SiO2) composite capillary monolithic column that exhibited excellent performance for the selective enrichment of cis-diol-containing compounds. Compared with the boronate-based affinity monolith, the ZrO2/SiO2 monolith showed ~2 orders of magnitude higher extraction capacity and can be used under physiological pH (pH 6.5-7.5). Using the prepared ZrO2/SiO2 composite monolith as the trapping column and reversed phase C18 column as the analytical column, we further established an online solid phase microextraction (SPME) in combination with liquid chromatography-mass spectrometry (online SPME-LC-MS/MS) analysis for the comprehensive profiling of ribonucleosides modification in human urine. Our results showed that 68 cis-diol containing ribosylated compounds were identified in human urine, which is, to the best of our knowledge, the highest numbers of cis-diol-containing compounds were determined in a single analysis. It is worth noting that four modified ribonucleosides were discovered in the human urine for the first time. In addition, the quantification results from the pooled urine samples showed that compared to healthy controls, the contents of sixteen ribose conjugates in the urine of gastric cancer, eleven in esophagus cancer and seven in lymphoma increased more than two folds. Among these ribose conjugates, four ribose conjugates increased more than two folds in both gastric cancer and esophagus cancer; three ribose conjugates increased more than two folds in both gastric cancer and lymphoma; one ribose conjugate increased more than two folds in both esophagus cancer and lymphoma. The developed analytical method provides a good platform to study the modified ribonucleosides in human body fluids. PMID- 27495370 TI - Separation of pigment formulations by high-performance thin-layer chromatography with automated multiple development. AB - Food packaging is designed to provide sufficient protection for the respective filling, legally binding information for the consumers like nutritional facts or filling information, and an attractive appearance to promote the sale. For quality and safety of the package, a regular quality control of the used printing materials is necessary to get consistently good print results, to avoid migration of undesired ink components into the food and to identify potentially faulty ink batches. Analytical approaches, however, have hardly been considered for quality assurance so far due to the lack of robust, suitable methods for the analysis of rarely soluble pigment formulations. Thus, a simple and generic high-performance thin-layer chromatography (HPTLC) method for the separation of different colored pigment formulations was developed on HPTLC plates silica gel 60 by automated multiple development. The gradient system provided a sharp resolution for differently soluble pigment constituents like additives and coating materials. The results of multi-detection allowed a first assignment of the differently detectable bands to particular chemical substance classes (e.g., lipophilic components), enabled the comparison of different commercially available pigment batches and revealed substantial variations in the composition of the batches. Hyphenation of HPTLC with high resolution mass spectrometry and infrared spectroscopy allowed the characterization of single unknown pigment constituents, which may partly be responsible for known quality problems during printing. The newly developed, precise and selective HPTLC method can be used as part of routine quality control for both, incoming pigment batches and monitoring of internal pigment production processes, to secure a consistent pigment composition resulting in consistent ink quality, a faultless print image and safe products. Hyphenation of HPTLC with the A. fischeri bioassay gave first information on the bioactivity or rather on the toxicological potential of different compounds of the pigment formulations. The results of the bioassay might be helpful to choose pigment compositions that provide both, a high printing quality but at the same time guarantee a high consumer safety, especially in regard to smaller pigment components, which tend to migrate through the packaging. PMID- 27495371 TI - Simultaneous quantitation of trace level hydrazine and acetohydrazide in pharmaceuticals by benzaldehyde derivatization with sample 'matrix matching' followed by liquid chromatography-mass spectrometry. AB - Hydrazine and acetohydrazide are potential genotoxins and therefore need to be controlled in APIs and drug products to ppm levels for patient safety in cases where there is a reasonable probability of either of them being present. They are structurally related and could both be formed in the same chemical process under certain circumstances. However, no previous studies have reported simultaneous trace level quantification of these two compounds. Herein, a chemical derivatization scheme using benzaldehyde followed by LC-MS analysis is presented to address that need. During method development, unexpectedly high recoveries were encountered and presented a major challenge. A systematic investigation was undertaken to understand the benzaldehyde derivatization reaction and determine the underlying causes of the unacceptable recovery. It was found that this was due to the presence of the counter ion of the API in the sample matrix. Employing a 'matrix matching' sample preparation strategy, which involved acidifying the derivatization reaction medium with benzoic acid, gave similar reaction rates for the chemical derivatization in the presence and absence of the API salt and accordingly more consistent recoveries. Resultantly, a robust method for simultaneous quantification of hydrazine and acetohydrazide (1-100ppm) was successfully developed and validated. PMID- 27495372 TI - Expression of switch-associated protein 70 is associated with lymphocyte activation and reduced disability in multiple sclerosis. PMID- 27495373 TI - Development and Pilot Testing of Caregiver-Reported Pediatric Quality Measures for Transitions Between Sites of Care. AB - BACKGROUND: Few measures exist to assess pediatric transition quality between care settings. The study objective was to develop and pilot test caregiver reported quality measures for pediatric hospital and emergency department (ED) to home transitions. METHODS: On the basis of an evidence review, we developed draft caregiver-reported quality measures for transitions between sites of care. Using the RAND-UCLA Modified Delphi method, a multistakeholder panel endorsed measures for further development. Measures were operationalized into 2 surveys, which were administered to caregivers of patients (n = 2839) discharged from Seattle Children's Hospital between July 1 and September 1, 2014. Caregivers were randomized to mail or telephone survey mode. Measure scores were computed as a percentage of eligible caregivers who endorsed receiving the indicated care. Differences in scores were examined according to survey mode and caregiver characteristics. RESULTS: The Delphi panel endorsed 6 of 8 hospital to home transition measures and 2 of 3 ED to home transitions measures. Scores differed significantly according to mode for 1 measure. Caregivers with lower levels of educational attainment and/or Spanish-speaking caregivers reported significantly higher scores on 3 of the measures. The largest difference was reported for the measure that assessed whether caregivers received assistance with scheduling follow-up appointments; 92% score for caregivers with lower educational attainment versus 79% for caregivers with higher educational attainment (P < .001). CONCLUSIONS: We developed 8 new, evidence-based quality measures to assess transition quality from the perspective of caregivers. Pilot testing of these measures in a single institution yielded valuable insights for future testing and implementation of these measures. PMID- 27495375 TI - Deciphering the protein translation inhibition and coping mechanism of trichothecene toxin in resistant fungi. AB - In modern times for combating the deleterious soil microbes for improved sustainable agricultural practices, there is a need to have a proper understanding of the plant-microbe interactions present in the rhizospheric microbiome of the plant roots. In the present study, the interactions of trichodermin with petidyltransferase centre of ribosomal complex was studied by molecular dynamics and in silico interaction methods to demonstrate its mechanism of action and to decipher the possible reason how it may inhibit protein synthesis at the ribosomal complex. Further we have illustrated how trichodermin resistance protein (60S ribosomal protein L3) helps to overcome the deleterious effects of trichothecene compounds like trichodermin. Normal mode analysis of trichodermin resistance protein and 25S rRNA that constitutes the petidyltransferase centre showed that the W-finger region of the protein moved towards 25S rRNA. Further analysis of molecular dynamics simulation time frames showed that several intermediate states of large motions of the protein molecules towards the 25S rRNA which finally blocks the binding pocket of the trichodermin. It indicated that this protein not only changes the local environment and conformation of the petidyltransferase centre but also restrain trichodermin from binding to the 25S rRNA at the petidyltransferase centre. PMID- 27495374 TI - CUB domain-containing protein 1 and the epidermal growth factor receptor cooperate to induce cell detachment. AB - BACKGROUND: While localized malignancies often respond to available therapies, most disseminated cancers are refractory. Novel approaches, therefore, are needed for the treatment of metastatic disease. CUB domain-containing protein1 (CDCP1) plays an important role in metastasis and drug resistance; the mechanism however, is poorly understood. METHODS: Breast cancer cell lines were engineered to stably express EGFR, CDCP1 or phosphorylation site mutants of CDCP1. These cell lines were used for immunoblot analysis or affinity purification followed by immunoblot analysis to assess protein phosphorylation and/or protein complex formation with CDCP1. Kinase activity was evaluated using phosphorylation site-specific antibodies and immunoblot analysis in in vitro kinase assays. Protein band excision and mass spectrometry was utilized to further identify proteins complexed with CDCP1 or DeltaCDCP1, which is a mimetic of the cleaved form of CDCP1. Cell detachment was assessed using cell counting. RESULTS: This paper reports that CDCP1 forms ternary protein complexes with Src and EGFR, facilitating Src activation and Src-dependent EGFR transactivation. Importantly, we have discovered that a class of compounds termed Disulfide bond Disrupting Agents (DDAs) blocks CDCP1/EGFR/Src ternary complex formation and downstream signaling. CDCP1 and EGFR cooperate to induce detachment of breast cancer cells from the substratum and to disrupt adherens junctions. Analysis of CDCP1 containing complexes using proteomics techniques reveals that CDCP1 associates with several proteins involved in cell adhesion, including adherens junction and desmosomal cadherins, and cytoskeletal elements. CONCLUSIONS: Together, these results suggest that CDCP1 may facilitate loss of adhesion by promoting activation of EGFR and Src at sites of cell-cell and cell-substratum contact. PMID- 27495376 TI - Proteomic analysis of 4-hydroxynonenal and nitrotyrosine modified proteins in RTT fibroblasts. AB - Rett syndrome (RTT) is a pervasive developmental disorder, primarily affecting girls with a prevalence of 1 in every 10,000 births. A clear etiological factor present in more than 90% of classical RTT cases is the mutation of the gene encoding methyl-CpG-binding protein 2 (MECP2). Recent work from our group was able to shown a systemic oxidative stress (OxS) in these patients that correlates with the gravity of the clinical features. Using freshly isolated skin fibroblasts from RTT patients and healthy subjects, we have performed a two dimensional gel electrophoresis in order to evidence the oxidative modifications of proteins with special focus on the formation of protein adducts with 4 hydroxynonenal (4-HNE PAs)-a major secondary product of lipid peroxidation- and Nitrotyrosine, a marker derived from the biochemical interaction of nitric oxide (NO) or nitric oxide-derived secondary products with reactive oxygen species (ROS). Then, oxidatively modified spots were identified by mass spectrometry, LC ESI-CID-MS/MS. Our results showed that 15 protein spots presented 4-HNE PAs and/or nitrotyrosine adducts in fibroblasts proteome from RTT patients compared to healthy control cells. Post-translationally modified proteins were related to several functional categories, in particular to cytoskeleton structure and protein folding. In addition, clear upregulated expression of the inducible NO synthase (iNOS) with high nitrite levels were observed in RTT fibroblasts, justifying the increased nitrotyrosine protein modifications. The present work describes not only the proteomic profile in RTT fibroblasts, but also identifies the modified proteins by 4-HNE and nitrotyrosine. Of note, for the first time, it appears that a dysregulation of NO pathway can be associated to RTT pathophysiology. In conclusion, the evidence of a wide range of proteins able to forms adducts with 4-HNE, Nitrotyrosine or with both confirms the possible alteration of several aspects of cellular functions that well correlates to the complex clinical features of RTT patients. PMID- 27495377 TI - Prevalence and predictors of drinking, binge drinking, and related health and social problems in Puerto Rico. AB - BACKGROUND: This paper examines prevalence and predictors of drinking, binge drinking, and alcohol-related social and health problems in Puerto Rico. METHODS: Respondents constitute a multi-stage household probability sample (N = 1,510) from San Juan, Puerto Rico. The response rate was 83%. RESULTS: Men compared to women (Coeff: .34; 95 CI = .19-.50; p < .001), those with more liberal norms (Coeff: 1.05; 95 CI = .87-1.23; p < .001) and those with more positive attitudes about drinking (Coeff: 1.06; 95 CI= .63-1.49; p < .001) have a higher average number of weekly drinks. Those in the 40-49 age group have a lower mean number of weekly drinks than those in the 18-29 age group (Coeff.: -.23; 95 CI = -.42-.03; p < .02). Those with income between $30,001 and $40,000 a year compared to those with less than $10,000, (OR: .28; 95 CI = .08-1.93; p < .039) report fewer social/health problems. Protestants compared to Catholics (AOR: 1.94; 95 CI = 1.08-3.47; p < .026), those with more liberal drinking norms (AOR: 3.62; 95 CI = 1.87-6.99; p < .001) and more positive attitudes about drinking (AOR: 3.41; 95 CI = 1.04-11.09; p < .001), and those who consume a higher number of drink per week (AOR: 1.03; 95 CI = 1.01-1.05; p < .001) and binge (AOR: 3.52; 95 CI = 2.14-5.80; p < .001) are more likely to report social and health problems associated with alcohol use. DISCUSSION AND CONCLUSIONS: The finding that male gender is not associated with binge drinking and social and health problems was not expected. Puerto Ricans appear to drink less than the general population and Hispanics and Puerto Ricans on the U.S. mainland. SCIENTIFIC SIGNIFICANCE: Up to date epidemiological findings provide information about high risk groups and correlates of alcohol problems in the population. These are now available for Puerto Rico and can be used in the design of prevention interventions. (Am J Addict 2016;25:478-485). PMID- 27495378 TI - Vocal sac development and accelerated sexual maturity in the lesser swimming frog, Pseudis minuta (Anura, Hylidae). AB - Sexual maturity involves the differentiation of the reproductive system, the maturation of germ cells, and the development of secondary sexual characteristics. Even though this topic has received much attention, little is known about the sequence of events that encompass reproductive maturation in anurans and what it could reveal about the developmental basis of life cycle evolution. The discovery of froglets of Pseudis minuta with incipient vocal sacs calling in breeding pools alongside several larger adult specimens with fully developed vocal sacs raised the question of the timing of sexual maturity in this species. Here we describe the sequence and timing of differentiation, development and maturation of the vocal sac apparatus and the testes in P. minuta (Anura, Hylidae), in order to establish a timeline of events leading to sexual maturity. Differentiation of the vocal sac apparatus begins at the final metamorphic stages, earlier than reported for other species, and the vocal sac acquires its final shape during the early postmetamorphic period. These modifications occur after gonadal differentiation, which begins early during the larval period and proceeds with a highly accelerated rate of development (e.g., secondary spermatids appear well before metamorphic climax), a situation reported previously for other anuran species only in the genus Pseudis. These results, together with a skeletochronological analysis showing that some calling specimens presented no lines of arrested growth, indicate acceleration in the timing of sexual maturity in Pseudis, and raise questions about the interdependence/decoupling during the development of the different components involved in reaching the adult stage. PMID- 27495379 TI - An approximate stationary solution for multi-allele neutral diffusion with low mutation rates. AB - We address the problem of determining the stationary distribution of the multi allelic, neutral-evolution Wright-Fisher model in the diffusion limit. A full solution to this problem for an arbitrary K*K mutation rate matrix involves solving for the stationary solution of a forward Kolmogorov equation over a (K-1) dimensional simplex, and remains intractable. In most practical situations mutations rates are slow on the scale of the diffusion limit and the solution is heavily concentrated on the corners and edges of the simplex. In this paper we present a practical approximate solution for slow mutation rates in the form of a set of line densities along the edges of the simplex. The method of solution relies on parameterising the general non-reversible rate matrix as the sum of a reversible part and a set of (K-1)(K-2)/2 independent terms corresponding to fluxes of probability along closed paths around faces of the simplex. The solution is potentially a first step in estimating non-reversible evolutionary rate matrices from observed allele frequency spectra. PMID- 27495380 TI - Coronary CTA and percutaneous coronary intervention - A symbiosis waiting to happen. PMID- 27495381 TI - Recognizing and managing common foot injuries. AB - Subtle signs of foot and ankle fractures are often overlooked on initial radiographs. This article describes several commonly missed foot and ankle injuries and provides help in reviewing radiographs and identifying foot and ankle fractures. PMID- 27495382 TI - Serratia marcescens outbreak due to contaminated 2% aqueous chlorhexidine. AB - INTRODUCTION AND OBJECTIVE: An outbreak of Serratia marcescens infections outbreak is described, as well as the epidemiological study that linked the outbreak to the use of 2% aqueous chlorhexidine antiseptic. METHOD: In late November 2014 an increasing incidence of S. marcescens isolates was detected in patients treated in the emergency department. It was considered a possible outbreak, and an epidemiological investigation was started. RESULT: S. marcescens was isolated in 23 samples from 16 patients and in all new bottles of two lots of 2% aqueous chlorhexidine. The contaminated disinfectant was withdrawn, and the Spanish Drugs Agency was alerted (COS 2/2014). The epidemiological study showed that strains isolated from clinical samples and from chlorhexidine belonged to the same clone. No further isolates were obtained once the disinfectant was withdrawn. CONCLUSION: The suspicion of an outbreak and the epidemiological study were essential to control the incidence. PMID- 27495383 TI - Gray matter segmentation of the spinal cord with active contours in MR images. AB - OBJECTIVE: Fully or partially automated spinal cord gray matter segmentation techniques for spinal cord gray matter segmentation will allow for pivotal spinal cord gray matter measurements in the study of various neurological disorders. The objective of this work was multi-fold: (1) to develop a gray matter segmentation technique that uses registration methods with an existing delineation of the cord edge along with Morphological Geodesic Active Contour (MGAC) models; (2) to assess the accuracy and reproducibility of the newly developed technique on 2D PSIR T1 weighted images; (3) to test how the algorithm performs on different resolutions and other contrasts; (4) to demonstrate how the algorithm can be extended to 3D scans; and (5) to show the clinical potential for multiple sclerosis patients. METHODS: The MGAC algorithm was developed using a publicly available implementation of a morphological geodesic active contour model and the spinal cord segmentation tool of the software Jim (Xinapse Systems) for initial estimate of the cord boundary. The MGAC algorithm was demonstrated on 2D PSIR images of the C2/C3 level with two different resolutions, 2D T2* weighted images of the C2/C3 level, and a 3D PSIR image. These images were acquired from 45 healthy controls and 58 multiple sclerosis patients selected for the absence of evident lesions at the C2/C3 level. Accuracy was assessed though visual assessment, Hausdorff distances, and Dice similarity coefficients. Reproducibility was assessed through interclass correlation coefficients. Validity was assessed through comparison of segmented gray matter areas in images with different resolution for both manual and MGAC segmentations. RESULTS: Between MGAC and manual segmentations in healthy controls, the mean Dice similarity coefficient was 0.88 (0.82-0.93) and the mean Hausdorff distance was 0.61 (0.46-0.76) mm. The interclass correlation coefficient from test and retest scans of healthy controls was 0.88. The percent change between the manual segmentations from high and low-resolution images was 25%, while the percent change between the MGAC segmentations from high and low resolution images was 13%. Between MGAC and manual segmentations in MS patients, the average Dice similarity coefficient was 0.86 (0.8-0.92) and the average Hausdorff distance was 0.83 (0.29-1.37) mm. CONCLUSION: We demonstrate that an automatic segmentation technique, based on a morphometric geodesic active contours algorithm, can provide accurate and precise spinal cord gray matter segmentations on 2D PSIR images. We have also shown how this automated technique can potentially be extended to other imaging protocols. PMID- 27495384 TI - Contrast-Enhanced Ultrasound in the Assessment of Patients with Indeterminate Abdominal Findings at Positron Emission Tomography Imaging. AB - Widespread use of fluorodeoxyglucose-positron emission tomography (PET) in cancer imaging may result in a number of indeterminate and false-positive findings. We investigated the role of contrast-enhanced ultrasound (CEUS) as a second-level option after inconclusive PET. We reviewed CEUS images acquired over 4 y, selecting the examinations performed specifically to better assess an unclear PET image. Final diagnosis was confirmed by biopsy, surgery, further imaging or follow-up. Seventy CEUS examinations were performed after a PET scan (44 PET examinations, 19 PET-computer tomography [CT] examinations and 7 PET-CECT examinations). The target organ was the liver in 54 cases, spleen in 12, gallbladder in 2 and pancreas and kidney in one each. In 6 of 70 cases, CEUS was performed because of a negative PET (no uptake) despite an abnormal finding on the CT images of the PET-CT study; CEUS allowed a correct diagnosis in all of these. In 20 of 70 cases, the PET findings were categorized as indeterminate and non-specific (non-specific fluorodeoxyglucose uptake in PET report with no standardized uptake value given); CEUS reached a correct diagnosis in 19 of the 20 cases with one false negative. In 34 of 70 cases, PET was indeterminate, but specific (fluorodeoxyglucose uptake with a standardized uptake value provided); CEUS reached a correct diagnosis in 30 of these 34 cases. In 10 of 70 cases, PET was categorized as determinate but to be investigated because of discrepancy with clinical or imaging findings; CEUS a definitive diagnosis in 9 of 10 cases. CEUS proved to be effective option in the assessment of cancer patients with indeterminate PET findings. PMID- 27495386 TI - [EuroSCORE underestimate the mortality risk in cardiac valve surgery of Mexican population]. AB - OBJECTIVE: The EuroSCORE (European System for cardiac operative risk evaluation) stratifies cardiac risk surgery in easy and accessible manner; it was validated in North America with good results but in many countries of Latin America is used routinely without prior validation. Our objective was to validate the EuroSCORE in patients with cardiac valve surgery at the Instituto Nacional de Cardiologia Ignacio Chavez (INCICh) in Mexico. METHODS: EuroSCORE additive and logistic models were used to predict mortality in adults undergoing cardiac valve surgery from march 2004 to march 2008. The goodness of fit test of Hosmer-Lemeshow was used to evaluate the calibration. The area under the ROC curve was calculated to determinate discrimination. RESULTS: We included 1188 patients with ages of 51.3+/-14.5 years, 52% women. There were significant differences in the prevalence of risk factors among the INCICh and the EuroSCORE populations. Total mortality was 9.68% versus 5% and 5.6% predicted by additive and logistic EuroSCORE. According to additive EuroSCORE the risk was low in 11.3%, intermediate in 52.9% and high in 35.9%; for these groups the mortality was .7%, 6.34% and 17.4% against those predicted of 2%, 3.9% and 7.64%. Hosmer-Lemeshow test had a P<.001 for both models and the area under the ROC curve was .707 and .694 for additive and logistic EuroSCORE. CONCLUSION: In the INCICh 88.7% of patients with cardiac valve surgery had intermediate to high risk and EuroSCORE underestimated the risk of mortality. PMID- 27495385 TI - Prognostic Significance of FDG Uptake of Bone Marrow on PET/CT in Patients With Non-Small-Cell Lung Cancer After Curative Surgical Resection. AB - BACKGROUND: This study evaluated the relationship between 18F-fluorodeoxyglucose (FDG) uptake in bone marrow (BM) on positron emission tomography (PET)/computed tomography (CT) imaging and serum inflammatory markers and assessed the prognostic value of FDG uptake of BM in patients with non-small-cell lung cancer (NSCLC) who underwent curative surgical resection. PATIENTS AND METHODS: We retrospectively enrolled 110 NSCLC patients who underwent FDG PET/CT imaging and subsequent curative surgical resection. The maximum standardized uptake value of NSCLC (Tmax), mean FDG uptake of BM (BM SUV), and BM to liver uptake ratio (BLR) were measured. The relationships between BM SUV, BLR, and serum inflammatory markers were evaluated and the prognostic significance of PET/CT parameters for predicting recurrence-free survival (RFS) and overall survival (OS) were assessed. RESULTS: BM SUV and BLR were significantly associated with serum C reactive protein (CRP) level, white blood cell count, and the neutrophil to lymphocyte ratio (NLR). BLR was also significantly correlated with serum albumin and the platelet to lymphocyte ratio. In univariate analysis, tumor, node, metastases (TNM) stage, serum CRP level, NLR, Tmax, and BLR were significant prognostic factors for RFS and OS, whereas histopathology and tumor size were significant prognostic factors for RFS. In multivariate analysis, BLR, histopathology, TNM stage, and Tmax were independent prognostic factors for RFS and TNM stage and Tmax were independent prognostic factors for OS. CONCLUSION: FDG uptake of BM on PET/CT imaging was correlated with serum inflammatory markers and was an independent predictor for RFS, along with FDG uptake of NSCLC. PMID- 27495387 TI - Triumph and adversity: Exploring the complexities of consumer storytelling in mental health nursing education. AB - Consumer participation in the education of health professionals is increasing, particularly in mental health nursing education and storytelling remains the most frequent approach to consumer involvement. The use of story has tended to be accepted as a legitimate educational tool with limited critique or consideration of its potential consequences presented within the academic literature. A qualitative exploratory research study was undertaken with mental health nurse academics (n = 34) and consumer educators and academics (n = 12), to investigate the perceptions and experiences of mental health nurses and consumers regarding the involvement of consumers in mental health nursing education. Data were analysed thematically. Story was a major theme to emerge from consumer participants and received some attention from nurse academics. Consumers and nurses both referred to the power of story to convey the human experience of mental illness diagnosis and service use; and the vulnerability that can result from storytelling. Consumers also described: story as expectation; preparation and support; and the politics of story. All participants supported the value of storytelling in mental health nursing education. Consumers had considered the complexities in far greater detail. The ongoing value of story as an educational technique requires further research. Equally important is considering a broader range of educational roles for mental health consumers. PMID- 27495388 TI - A comprehensive evaluation of the [2-14C](-)-epicatechin metabolome in rats. AB - Following ingestion of [2-14C](-)-epicatechin by rats, radioactivity in urine, feces, body fluids and tissues collected over a 72h period, was measured and 14C metabolites were analyzed by HPLC-MS2 with a radioactivity monitor. In total 78% of the ingested radioactivity was absorbed from the gastrointestinal tract (GIT), and then rapidly eliminated from the circulatory system via renal excretion. A peak plasma concentration occurred 1h after intake corresponding to ~0.7% of intake. Low amounts of radioactivity, <2% of intake, appeared transiently in body tissues. Glucuronidation and methylation of (-)-epicatechin began in the duodenum but occurred more extensively in the jejunum/ileum. Radioactivity reaching the cecum after 6-12h was predominantly in the form of the ring fission metabolites 5 (3',4'-dihydroxyphenyl)-gamma-valerolactone and 5-(3',4'-dihydroxyphenyl)-gamma hydroxyvaleric acid along with smaller amounts of their phase II metabolites. Low levels of metabolites were detected in the colon. Of the ingested radioactivity, 19% was voided in feces principally as ring-fission metabolites. The main components in plasma were (-)-epicatechin-5-O-glucuronide and 3'-O-methyl-(-) epicatechin-5-O-glucuronide with small amounts of (-)-epicatechin, 3'-O-methyl-( )-epicatechin, 5-(3'-hydroxyphenyl)-gamma-hydroxyvaleric acid-4'-glucuronide and hippuric acid also being detected. No oxidized products of (-)-epicatechin were detected. No compelling evidence was obtained for biliary recycling of metabolites. The findings demonstrate substantial differences in the metabolism of (-)-epicatechin by rats and humans. Caution should, therefore, be exercised when using animal models to draw conclusions about effects induced by (-) epicatechin intake in humans. PMID- 27495389 TI - Hsp90 directly interacts, in vitro, with amyloid structures and modulates their assembly and disassembly. AB - BACKGROUND: The 90kDa heat shock protein (Hsp90) participates in regulating the homeostasis of cellular proteins and was considered one of the key chaperones involved in the control and regulation of amyloid deposits. Hsp90 interacts with the amyloid protein tau through tau aggregation-prone regions, including the VQIVYK hexapeptide motif. This hexapeptide, which self-aggregates, forming amyloid fibrils, is widely used to model amyloid formation mechanisms. Despite evidence showing that Hsp90 interacts directly with Ac-VQIVYK-NH2, its role in the hexapeptide fibrillation process and its binding to peptide structures have not yet been determined. METHODS: Various biochemical and biophysical techniques, including ultracentrifugation, spectrophotometry, spectrofluorimetry, and electron microscopy, were employed to assess the effects of Hsp90 on Ac-VQIVYK NH2 assembly and disassembly processes. RESULTS: At sub-stoichiometric concentrations, Hsp90 bound directly to Ac-VQIVYK-NH2 amyloid structures in vitro, with each Hsp90 dimer interacting with an amyloid structure made of around 50 hexapeptide subunits. Hsp90 inhibited Ac-VQIVYK-NH2 assembly by increasing the critical concentrations of Ac-VQIVYK-NH2 required for assembly. Hsp90 also inhibited the disassembly of Ac-VQIVYK-NH2 amyloid fibrils and promoted their rescue. CONCLUSIONS: A model explaining the dual effect of Hsp90 on the Ac-VQIVYK NH2 amyloid fibrillation process has been proposed. GENERAL SIGNIFICANCE: These in vitro results provide new insights into the possible roles of molecular chaperones in modulating amyloid structures by limiting the spread of toxic species. PMID- 27495390 TI - Methods for the physical characterization and quantification of extracellular vesicles in biological samples. AB - BACKGROUND: Our body fluids contain a multitude of cell-derived vesicles, secreted by most cell types, commonly referred to as extracellular vesicles. They have attracted considerable attention for their function as intercellular communication vehicles in a broad range of physiological processes and pathological conditions. Extracellular vesicles and especially the smallest type, exosomes, have also generated a lot of excitement in view of their potential as disease biomarkers or as carriers for drug delivery. In this context, state-of the-art techniques capable of comprehensively characterizing vesicles in biological fluids are urgently needed. SCOPE OF REVIEW: This review presents the arsenal of techniques available for quantification and characterization of physical properties of extracellular vesicles, summarizes their working principles, discusses their advantages and limitations and further illustrates their implementation in extracellular vesicle research. MAJOR CONCLUSIONS: The small size and physicochemical heterogeneity of extracellular vesicles make their physical characterization and quantification an extremely challenging task. Currently, structure, size, buoyant density, optical properties and zeta potential have most commonly been studied. The concentration of vesicles in suspension can be expressed in terms of biomolecular or particle content depending on the method at hand. In addition, common quantification methods may either provide a direct quantitative measurement of vesicle concentration or solely allow for relative comparison between samples. GENERAL SIGNIFICANCE: The combination of complementary methods capable of detecting, characterizing and quantifying extracellular vesicles at a single particle level promises to provide new exciting insights into their modes of action and to reveal the existence of vesicle subpopulations fulfilling key biological tasks. PMID- 27495391 TI - GRIND2-based 3D-QSAR and prediction of activity spectra for symmetrical bis pyridinium salts with promastigote antileishmanial activity. AB - Leishmaniasis is a major group of neglected tropical diseases caused by the protozoan parasite Leishmania. About 12 million people are affected in 98 countries and 350 million people worldwide are at risk of infection. Current leishmaniasis treatments rely on a relatively small arsenal of drugs, including amphotericin B, pentamidine and others, which in general have some type of inconvenience. Recently, we have synthesized antileishmanial bis-pyridinium derivatives and symmetrical bis-pyridinium cyclophanes. These compounds are considered structural analogues of pentamidine, where the amidino moiety, protonated at physiological pH, is replaced by a positively charged nitrogen atom as a pyridinium ring. In this work, a statistically significant GRIND2-based 3D QSAR model was built and biological activity predictions were in silico carried out allowing rationalization of the different activities recently obtained against Leishmania donovani (in L. donovani promastigotes) for a data set of 19 bis-pyridinium compounds. We will emphasize the most important structural requirements to improve the biological activity and probable interactions with the biological receptor as a guide for lead and prototype optimization. In addition, since no information about the actual biological target for this series of active compounds is provided, we have used Prediction of Activity Spectra for Biologically Active Substances to propose our compounds as potential nicotinic alpha6beta3beta4alpha5 receptor antagonists. This proposal is reinforced by the high structural similarity observed between our compounds and several anthelmintic drugs in current clinical use, which have the same drug action mechanism here predicted. Such new findings would be confirmed with further and additional experimental assays. PMID- 27495734 TI - Effect of a cheese rich in angiotensin-converting enzyme-inhibiting peptides (Gamalost((r))) and a Gouda-type cheese on blood pressure: results of a randomised trial. AB - BACKGROUND: High blood pressure (BP) is the leading risk factor for global disease burden, contributing to 7% of global disability adjusted life years. Angiotensin converting enzyme (ACE)-inhibiting bioactive peptides have the potential to reduce BP in humans. These peptides have been identified in many dairy products and have been associated with significant reductions in BP. OBJECTIVE: The objective of this trial was to examine whether a cheese rich in ACE-inhibiting peptides (Gamalost((r))), or a standard Gouda-type cheese could lower BP. DESIGN: A total of 153 healthy participants were randomised to one of three parallel arms: Gamalost((r)) (n=53, 50 g/day for 8 weeks), Gouda-type cheese (n=50, 80 g/day for 8 weeks), and control (n=50). BP and anthropometric measurements were taken at the baseline and at the end, with an additional BP measurement midway. Based on BP at baseline, participants were categorised as having optimal BP (<120/<80 mmHg), normal-high BP (120-139/80-89 mmHg), or being hypertensive (>140/>90 mmHg). Questionnaires about lifestyle, health, and dietary habits were completed at baseline, midway and end. RESULTS: In total, 148 participants (mean age 43, 52% female) completed the intervention. There were no differences among the three groups in relevant baseline characteristics. BP was reduced in the entire study population, but the cheese groups did not differ from control. However, in a subgroup of participants with slightly elevated BP, BP at 4 weeks of intervention seemed to be borderline significantly more reduced in the Gamalost((r)) group compared with the control group (Dunnett test: diastolic BP 3.5 mmHg, 95% confidence interval (CI) -7.3, 0.4, systolic BP: -4.3 mmHg, 95% CI 9.8, 1.1). CONCLUSION: An intention-to-treat analysis of the data showed no cheese effect upon BP compared to control, but Gamalost((r)) seemed to have a small, non-significant lowering effect on diastolic BP after 4 weeks in people with a normal-high BP. PMID- 27495735 TI - Influence of different anaesthetic protocols over the sperm quality on the fresh, chilled (4 degrees C) and frozen-thawed epididymal sperm samples in domestic dogs. AB - This study assessed the influence of three different anaesthetic protocols on semen quality obtained from the epididymis. Sixty male dogs undergoing to routine sterilization were assigned to three anaesthetic protocols: thiopental group (TG, n = 20), propofol group (PG, n = 20) and ketamine-dexmedetomidine group (KDG, n = 20). Immediately after orchidectomy, the cauda epididymides and vas deferent ducts were isolated and then a retrograde flushing was performed to collect spermatozoa. In experiment 1, after the initial evaluation of the semen (sperm concentration, sperm motility and the percentages of live spermatozoa, abnormal spermatozoa and acrosome membrane integrity), semen samples were diluted in Tris glucose-egg yolk extender and chilled for 48 hr, and the sperm motility was assessed at 6, 24 and 48 hr. In experiment 2, semen samples were diluted in Tris glucose-egg yolk extender and chilled for 24 hr, and then samples were frozen in two extenders with different glycerol concentrations, to reach a final concentration of 50-100 * 10(6) spermatozoa ml(-1) , 20% egg yolk, 0.5% Equex and 4% and 5% glycerol, respectively. Mean values of total sperm concentration, sperm viability and the percentages of intact acrosome and abnormal spermatozoa were not significantly different between experimental groups, and therefore, the anaesthetic protocols assessed did not affect sperm parameters mentioned above. However, our study confirmed a detrimental effect of the use of thiopental (TG) over the total sperm motility (p < 0.05) and progressive sperm motility (p < 0.05) of the fresh and chilled epididymal sperm samples. The anaesthetic protocols including the application of propofol or ketamine-dexmedetomidine can be used to recover sperm in domestic canids without significant changes in sperm quality compared when semen is collected routinely and these techniques could be applicable to endangered wild canids. PMID- 27495736 TI - Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer. AB - BACKGROUND: Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data. METHODS: ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients. RESULTS: ALK rearrangements were detected in 1.7 % in the complete cohort and 2.0 % in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.8 and 1.4 % when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (> 98 %), while the sensitivity was between 69 % (Ventana) and 62 % (in house Dako protocol). Furthermore, only 67 % of the ALK IHC positive cases were positive with both IHC assays. Gene expression analysis revealed that 6/194 (3 %) tumors showed high ALK gene expression (>= 6 AU) and of them only three were positive by either FISH or IHC. CONCLUSION: The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC. PMID- 27495738 TI - I86A/C295A mutant secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus has broadened substrate specificity for aryl ketones. AB - Thermoanaerobacter ethanolicus secondary alcohol dehydrogenase (SADH) reduces aliphatic ketones according to Prelog's Rule, with binding pockets for small and large substituents. It was shown previously that the I86A mutant SADH reduces acetophenone, which is not a substrate of wild-type SADH, to give the anti-Prelog R-product (Musa, M. M.; Lott, N.; Laivenieks, M.; Watanabe, L.; Vieille, C.; Phillips, R. S. ChemCatChem2009, 1, 89-93.). However, I86A SADH did not reduce aryl ketones with substituents larger than fluorine. We have now expanded the small pocket of the active site of I86A SADH by mutation of Cys-295 to alanine to allow reaction of substituted acetophenones. As predicted, the double mutant I86A/C295A SADH has broadened substrate specificity for meta-substituted, but not para-substituted, acetophenones. However, the increase of the substrate specificity of I86A/C295A SADH is accompanied by a decrease in the kcat/Km values of acetophenones, possibly due to the substrates fitting loosely inside the more open active site. Nevertheless, I86A/C295A SADH gives high conversions and very high enantiomeric excess of the anti-Prelog R-alcohols from the tested substrates. PMID- 27495737 TI - Molecular cloning of glucose transporter 1 in grouper Epinephelus coioides and effects of an acute hyperglycemia stress on its expression and glucose tolerance. AB - The glucose transporter family proteins play pivotal roles in glucose metabolism. In this study, we successfully cloned the orange spotted grouper (Epinephelus coioides) glucose transporter 1 (EcGlut1) gene (GenBank accession: JQ623903). The full-length EcGlut1 cDNA was 2126 bp with a 1476 bp ORF, a 437bp5'-UTR and 223bp3'-UTR. EcGlut1 is predicted to encode a 491 amino acid protein with a MW of 53.9 kDa, a pI of 8.66 and a Pfam domain. Bioinformatics analysis revealed that EcGlut1 was evolutionally conserved between fishes with 80-89 % amino acid identities. EcGlut1 was expressed predominantly in heart and liver and at lower levels in muscle, intestine, stomach and brain. We also investigated the effect of acute hyperglycemia stress on EcGlut1 expression. In glucose tolerance test, changes in EcGlut1 mRNA expression in response to glucose injection and glucose metabolism-related indictors were assessed at the same time. Glucose injection significantly suppressed EcGlut1 mRNA expression in liver at 12 h and in brain at 24 h postinjection (P < 0.05). EcGlut1 mRNA levels in heart were increased at 6 h (P < 0.05). Plasma glucose level increased significantly and reached its maximum at 3 h postinjection (P < 0.05). The spatiotemporal expression of EcGlut1 and glucose metabolism suggested that orange spotted grouper might rely on fat anabolism to reduce acute hyperglycemia stress and the delayed transcription of EcGlut1 gene might be one reason for glucose intolerance in E. coioides. PMID- 27495739 TI - Processing of A-form ssDNA by cryptic RNase H fold exonuclease PF2046. AB - RNase H fold protein PF2046 of Pyrococcus furiosus is a 3'-5' ssDNA exonuclease that cleaves after the second nucleotide from the 3' end of ssDNA and prefers poly-dT over poly-dA as a substrate. In our crystal structure of PF2046 complexed with an oligonucleotide of four thymidine nucleotides (dT4), PF2046 accommodates dT4 tightly in a groove and imposes steric hindrance on dT4 mainly by Phe220 such that dT4 assumes the A-form. As poly-dA prefer B-form due to the stereochemical restrictions, the A-form ssDNA binding by PF2046 should disfavor the processing of poly-dA. Phe220 variants display reduced activity toward poly-dA and the A form appears to be a prerequisite for the processing by PF2046. PMID- 27495740 TI - Selenium and redox signaling. AB - Selenium compounds that contain selenol functions or can be metabolized to selenols are toxic via superoxide and H2O2 generation, when ingested at dosages beyond requirement. At supra-nutritional dosages various forms of programmed cell death are observed. At physiological intakes, selenium exerts its function as constituent of selenoproteins, which overwhelmingly are oxidoreductases. Out of those, the glutathione peroxidases counteract hydroperoxide-stimulated signaling cascades comprising inflammation triggered by cytokines or lipid mediators, insulin signaling and different forms of programmed cell death. Similar events are exerted by peroxiredoxins, which functionally depend on the selenoproteins of the thioredoxin reductase family. The thiol peroxidases of both families can, however, also act as sensors for hydroperoxides, thereby initiating signaling cascades. Although the interaction of selenoproteins with signaling events has been established by genetic techniques, the in vivo relevance of these findings is still hard to delineate for several reasons: The biosynthesis of individual selenoproteins responds differently to variations of selenium intakes; selenium is preferentially delivered to privileged tissues via inter-organ trafficking and receptor-mediated uptake, and only half of the selenoproteins known by sequence have been functionally characterized. The fragmentary insights do not allow any uncritical use of selenium for optimizing human health. PMID- 27495741 TI - A review of teaching ethics in the dental curriculum: challenges and future developments. AB - This study considers the role and status of the teaching of ethics on the dental undergraduate curriculum. The study reviews current developments in the delivery of dental ethics education and in particular focuses on the development of new pedagogies and curricula content. The study then critically considers the consequences of a squeezed curricula and the consequent reliance on professional regulation as shorthand for the ethical development of students. The study concludes that, although great strides have been made in improving the teaching of ethics in dental education, further dialogue is needed to better include patient views and develop a more theoretically robust approach to self reflection. PMID- 27495742 TI - The early events underlying genome evolution in a localized Sinorhizobium meliloti population. AB - BACKGROUND: Population genetic analyses based on genome-wide sequencing data have been carried out for Sinorhizobium medicae and S. meliloti, two closely related bacterial species forming nitrogen-fixing symbioses with plants of the genus Medicago. However, genome coverage was low or the isolates had a broad geographic distribution, making it difficult to interpret the estimated diversity and to unravel the early events underlying population genetic variations and ecological differentiation. RESULTS: Here, to gain insight into the early genome level variation and diversification within S. meliloti populations, we first used Illumina paired-end reads technology to sequence a new clone of S. meliloti strain GR4, a highly competitive strain for alfalfa nodulation. The Illumina data and the GR4 genome sequence previously obtained with 454 technology were used to generate a high-quality reference genome sequence. We then used Illumina technology to sequence the genomes of 13 S. meliloti isolates representative of the genomic variation within the GR4-type population, obtained from a single field site with a high degree of coverage. The genome sequences obtained were analyzed to determine nucleotide diversity, divergence times, polymorphism and genomic variation. Similar low levels of nucleotide diversity were observed for the chromosome, pSymB and pSymA replicons. The isolates displayed other types of variation, such as indels, recombination events, genomic island excision and the transposition of mobile elements. CONCLUSIONS: Our results suggest that the GR4 type population has experienced a process of demographic expansion and behaves as a stable genotypic cluster of genome-wide similarity, with most of the genome following a clonal pattern of evolution. Although some of genetic variation detected within the GR4-type population is probably due to genetic drift, others might be important in diversification and environmental adaptation. PMID- 27495743 TI - Short-term test-retest-reliability of conditioned pain modulation using the cold heat-pain method in healthy subjects and its correlation to parameters of standardized quantitative sensory testing. AB - BACKGROUND: Conditioned Pain Modulation (CPM) is often used to assess human descending pain inhibition. Nine different studies on the test-retest-reliability of different CPM paradigms have been published, but none of them has investigated the commonly used heat-cold-pain method. The results vary widely and therefore, reliability measures cannot be extrapolated from one CPM paradigm to another. Aim of the present study was to analyse the test-retest-reliability of the common heat-cold-pain method and its correlation to pain thresholds. METHODS: We tested the short-term test-retest-reliability within 40 +/- 19.9 h using a cold-water immersion (10 degrees C, left hand) as conditioning stimulus (CS) and heat pain (43-49 degrees C, pain intensity 60 +/- 5 on the 101-point numeric rating scale, right forearm) as test stimulus (TS) in 25 healthy right-handed subjects (12females, 31.6 +/- 14.1 years). The TS was applied 30s before (TSbefore), during (TSduring) and after (TSafter) the 60s CS. The difference between the pain ratings for TSbefore and TSduring represents the early CPM-effect, between TSbefore and TSafter the late CPM-effect. Quantitative sensory testing (QST, DFNS protocol) was performed on both sessions before the CPM assessment. STATISTICS: paired t-tests, Intraclass correlation coefficient (ICC), standard error of measurement (SEM), smallest real difference (SRD), Pearson's correlation, Bland Altman analysis, significance level p < 0.05 with Bonferroni correction for multiple comparisons, when necessary. RESULTS: Pain ratings during CPM correlated significantly (ICC: 0.411...0.962) between both days, though ratings for TSafter were lower on day 2 (p < 0.005). The early (day 1: 16.7 +/- 11.7; day 2: 19.5 +/- 11.9; ICC: 0.618, SRD: 20.2) and late (day 1: 1.7 +/- 9.2; day 2: 7.6 +/- 11.5; ICC: 0.178, SRD: 27.0) CPM effect did not differ significantly between both days. Both early and late CPM-effects did not correlate with the pain thresholds. CONCLUSIONS: The short-term test-retest-reliability of the early CPM-effect using the heat-cold-pain method in healthy subjects achieved satisfying results in terms of the ICC. The SRD of the early CPM effect showed that an individual change of > 20 NRS can be attributed to a real change rather than chance. The late CPM-effect was weaker and not reliable. PMID- 27495744 TI - TiO2 microspheres containing magnetic nanoparticles for intra-arterial hyperthermia. AB - Magnetic microspheres measuring 15-35 um in diameter are believed to be useful for intra-arterial hyperthermia. In this study, we attempted to prepare titanium dioxide (TiO2 ) microspheres containing magnetic nanoparticles (MNPs). MNP containing TiO2 microspheres with diameters of approximately 30 um were successfully obtained by sol-gel reaction of titanium tetraisopropoxide in a water-in-oil emulsion with added cosurfactant of 1-butanol and subsequent heat treatment at 200 degrees C. The microspheres showed ferrimagnetism owing to high content of MNPs in approximately 60 wt % and had a low-crystalline TiO2 matrix. Furthermore, the agar phantom was heated to above 43 degrees C after approximately 1 min under an alternating magnetic field of 100 kHz and 300 Oe and showed in vitro biocompatibility similar to that of MNP-free TiO2 microspheres. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2308-2314, 2017. PMID- 27495745 TI - Clinical Application of Pluripotent Stem Cells: An Alternative Cell-Based Therapy for Treating Liver Diseases? AB - The worldwide shortage of donor livers for organ and hepatocyte transplantation has prompted the search for alternative therapies for intractable liver diseases. Cell-based therapy is envisaged as a useful therapeutic option to recover and stabilize the lost metabolic function for acute liver failure, end-stage and congenital liver diseases, or for those patients who are not considered eligible for organ transplantation. In recent years, research to identify alternative and reliable cell sources for transplantation that can be derived by reproducible methods has been encouraged. Human pluripotent stem cells (PSCs), which comprise both embryonic and induced PSCs, may offer many advantages as an alternative to hepatocytes for liver cell therapy. Their capacity for expansion, hepatic differentiation and self-renewal make them a promising source of unlimited numbers of hepatocyte-like cells for treating and repairing damaged livers. Immunogenicity and tumorigenicity of human PSCs remain the bottleneck for successful clinical application. However, recent advances made to develop disease corrected hepatocyte-like cells from patients' human-induced PSCs by gene editing have opened up many potential gateways for the autologous treatment of hereditary liver diseases, which may likely reduce the risk of rejection and the need for lifelong immunosuppression. Well-defined methods to reduce the expression of oncogenic genes in induced PSCs, including protocols for their complete and safe hepatic differentiation, should be established to minimize the tumorigenicity of transplanted cells. On top of this, such new strategies are currently being rigorously tested and validated in preclinical studies before they can be safely transferred to clinical practice with patients. PMID- 27495747 TI - Recent Advances in Mammalian Target of Rapamycin Inhibitor Use in Heart and Lung Transplantation. AB - The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus are increasingly used in cardiothoracic transplantation. Several recent clinical trials have demonstrated their efficacy in combination with reduced cyclosporine dosing in de novo heart transplant recipients, in particular with everolimus. A number of other studies have demonstrated their efficacy for improving renal function and reducing calcineurin inhibitor use, attenuating cardiac allograft vasculopathy progression and reducing cytomegalovirus infections in maintenance heart transplant populations. A growing body of literature, including a small number of clinical trials, now describes the use mTOR inhibitors in lung transplant recipients. The benefits in this population include improved lung and renal function in limited studies. Considerably less evidence is available in pediatric heart transplantation, though similar indications in the maintenance therapy population have been described. The benefits of mTOR inhibitors must be weighed against the increased risk of adverse events and drug intolerance compared with other primary immunosuppressants, and discontinuation rates are particularly high in lung transplant recipients. The risks of surgical wound healing complications in transplant recipients receiving mTOR inhibitors previously or actively supported by mechanical circulatory support devices remains poorly described in the current literature. The current role and recent evidence for mTOR inhibitor use in heart and lung transplantation is examined in this review. PMID- 27495748 TI - Unraveling the Process of the Dying Heart: Do Not Leave Science Alone for the Heart to Live Again. PMID- 27495749 TI - Performance-Based Measures Associate With Frailty in Patients With End-Stage Liver Disease. AB - BACKGROUND: Physical frailty, as measured by the Fried Frailty Index, is increasingly recognized as a critical determinant of outcomes in patients with cirrhosis. However, its utility is limited by the inclusion of self-reported components. We aimed to identify performance-based measures associated with frailty in patients with cirrhosis. METHODS: Patients with cirrhosis, aged 50 years or older, underwent: 6-minute walk test (cardiopulmonary endurance), chair stands in 30 seconds (muscle endurance), isometric knee extension (lower extremity strength), unipedal stance time (static balance), and maximal step length (dynamic balance/coordination). Linear regression associated each physical performance test with frailty. Principal components exploratory factor analysis evaluated the interrelatedness of frailty and the 5 physical performance tests. RESULTS: Of 40 patients with cirrhosis, with a median age of 64 years and Model for End-stage Liver Disease (MELD) MELD of 12.10 (25%) were frail by Fried Frailty Index >=3. Frail patients with cirrhosis had poorer performance in 6 minute walk test distance (231 vs 338 m), 30-second chair stands (7 vs 10), isometric knee extension (86 vs 122 Newton meters), and maximal step length (22 vs 27 in. (P <= 0.02 for each). Each physical performance test was significantly associated with frailty (P < 0.01), even after adjustment for MELD or hepatic encephalopathy. Principal component factor analysis demonstrated substantial, but unique, clustering of each physical performance test to a single factor-frailty. CONCLUSIONS: Frailty in cirrhosis is a multidimensional construct that is distinct from liver dysfunction and incorporates endurance, strength, and balance. Our data provide specific targets for prehabilitation interventions aimed at reducing frailty in patients with cirrhosis in preparation for liver transplantation. PMID- 27495751 TI - Activated Renal Dendritic Cells Cross Present Intrarenal Antigens After Ischemia Reperfusion Injury. AB - BACKGROUND: The healthy kidney contains an extensive population of renal mononuclear phagocytes (RMPs), with substantial phenotypic and functional diversity. However, how this diverse population is affected by ischemia reperfusion injury (IRI), an obligate part of renal transplantation, is not yet well understood. The aim of this study was to characterize the phenotypic and functional alterations in RMPs induced by IRI. METHODS: Renal mononuclear phagocytes were studied 24 and 72 hours after 30 minutes of renal ischemia or sham operation. Kidneys were digested and the phenotypes of renal leukocyte populations were analyzed via flow cytometry. Multiphoton microscopy was used to image renal dendritic cells (DCs) in vivo using CD11c reporter mice. The capacity of renal DCs to present antigen was examined by assessment of proliferation of ovalbumin-specific T cells in rat insulin promoter-membrane-bound ovalbumin transgenic mice after sham or IRI procedures. RESULTS: Ischemia-reperfusion injury induced influx of monocytes, DCs, macrophages, and neutrophils into the kidney. Classification of RMP subpopulations based on CD11b/CD11c expression demonstrated that the RMPs that increased in response to IRI were predominantly newly recruited monocyte-derived inflammatory DCs. In vivo multiphoton imaging of CD11c-EYFP mice revealed that intrarenal DCs exhibited increased number and activity of dendrites in the postischemic period. Ischemia-reperfusion injury also promoted DC-dependent cross-presentation of renal antigens to CD8 T cells in the draining lymph node. CONCLUSIONS: In response to renal IRI, RMP populations are skewed toward those derived from inflammatory monocyte precursors. In addition, renal DCs undergo functional activation, increasing their capacity to activate antigen-specific CD8 T cells in renal draining lymph nodes. PMID- 27495753 TI - Fulminant Hepatic Failure as a Risk Factor for Cytomegalovirus Infection in Children Receiving Preemptive Therapy After Living Donor Liver Transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) is one of the most common causes of infection after solid organ transplantation with symptomatic disease occurring at an incidence of 20% to 40% without preventative measures. Although CMV donor+/recipient - serostatus is well known to be a risk factor, there is little data about other risk factors for CMV infection in the setting of pediatric liver transplantation (LT). We hypothesized that fulminant hepatic failure (FHF) may be a risk factor for CMV infection given anecdotal reports of complications associated with FHF. METHODS: We conducted medical chart review of children who underwent LT at a tertiary children's hospital in Tokyo between November 2005 and October 2015. We evaluated the risk factors, especially FHF, and prognosis for CMV infection under preemptive therapy. RESULTS: Three hundred thirty-seven living donor LT were analyzed. Underlying diseases were cholestatic liver disease (n = 172, 51%), metabolic disease (n = 59, 18%), and FHF (n = 51, 15%). Among 337 LT, 147 (44%) recipients developed CMV antigenemia. In multivariate analysis, FHF (odds ratio, 4.99; 95% confidence interval, 1.86-13.40; P = 0.001) and CMV serostatus were independent risk factors for developing CMV antigenemia. Positive donor serostatus was significantly associated with development of antigenemia within 1-year post-LT regardless of recipient serostatus (P <0.001). On the other hand, positive recipient status was associated with CMV antigenemia in the first 21 days (P <0.001). Only 12 (3.6%) of 337 children developed CMV disease. CONCLUSIONS: Fulminant hepatic failure was found to be a risk factor for CMV infection independent of CMV serostatus. PMID- 27495752 TI - Increased Extravascular Lung Water and Plasma Biomarkers of Acute Lung Injury Precede Oxygenation Impairment in Primary Graft Dysfunction After Lung Transplantation. AB - BACKGROUND: After lung transplantation (LT), early prediction of grade 3 pulmonary graft dysfunction (PGD) remains a research gap for clinicians. We hypothesized that it could be improved using extravascular lung water (EVLWi) and plasma biomarkers of acute lung injury. METHODS: After institutional review board approval and informed consent, consecutive LT recipients were included. Transpulmonary thermodilution-based EVLWi, plasma concentrations of epithelial (soluble receptor for advanced glycation endproducts [sRAGE]) and endothelial biomarkers (soluble intercellular adhesion molecule-1 and endocan [full-length and cleaved p14 fragment]) were obtained before and after LT (0 [H0], 6, 12, 24, 48 and 72 hours after pulmonary artery unclamping). Grade 3 PGD was defined according to the International Society for Lung and Heart Transplantation definition, combining arterial oxygen partial pressure (PaO2)/inspired fraction of oxygen (FiO2) ratio and chest X-rays. Association of clinical risk factors, EVLWi and biomarkers with grade 3 PGD was analyzed under the Bayesian paradigm, using logistic model and areas under the receiver operating characteristic curves (AUCs). RESULTS: In 47 LT recipients, 10 developed grade 3 PGD, which was obvious at H6 in 8 cases. Clinical risk factors, soluble intercellular adhesion molecule 1 and endocan (both forms) were not associated with grade 3 PGD. Significant predictors of grade 3 PGD included (1) EVLWi (optimal cutoff, 13.7 mL/kg; AUC, 0.74; 95% confidence interval [CI], 0.48-0.99), (2) PaO2/FiO2 ratio (optimal cutoff, 236; AUC, 0.68; 95% CI, 0.52-0.84), and (3) sRAGE (optimal cutoff, 11 760 pg/mL; AUC, 0.66; 95% CI, 0.41-0.91) measured at H0. CONCLUSIONS: Immediate postreperfusion increases in EVLWi and sRAGE along with impaired PaO2/FiO2 ratios were early predictors of grade 3 PGD at or beyond 6 hours and may trigger early therapeutic interventions. PMID- 27495755 TI - The Optimal Timing of Hepatitis C Therapy in Transplant Eligible Patients With Child B and C Cirrhosis: A Cost-Effectiveness Analysis. AB - BACKGROUND: Ledipasvir (LDV)/sofosbuvir (SOF) has demonstrated high efficacy, safety, and tolerability in hepatitis C virus (HCV)-infected patients. There is limited data, however, regarding the optimal timing of therapy in the context of possible liver transplantation (LT). METHODS: We compared the cost-effectiveness of 12 weeks of HCV therapy before or after LT or nontreatment using a decision analytical microsimulation state-transition model for a simulated cohort of 10 000 patients with HCV Genotype 1 or 4 with Child B or C cirrhosis. All model parameters regarding the efficacy of therapy, adverse events and the effect of therapy on changes in model for end-stage liver disease (MELD) scores were derived from the SOLAR-1 and 2 trials. The simulations were repeated with 10 000 samples from the parameter distributions. The primary outcome was cost (2014 US dollars) per quality adjusted life year. RESULTS: Treatment before LT yielded more quality-adjusted life year for less money than treatment after LT or nontreatment. Treatment before LT was cost-effective in 100% of samples at a willingness-to-pay threshold of US $100 000 in the base-case and when the analysis was restricted to Child B alone, Child C, or MELD > 15. Treatment before transplant was not cost-effective when MELD was 6-10. In sensitivity analyses, the MELD after which treatment before transplant was cost-effective was 13 and the maximum cost of LDV/SOF therapy at which treatment before LT is cost effective is US $177 381. CONCLUSIONS: From a societal perspective, HCV therapy using LDV/SOF with ribavirin before LT is the most cost-effective strategy for patients with decompensated cirrhosis and MELD score greater than 13. PMID- 27495756 TI - Evaluation of Microvascular Inflammation in ABO-Incompatible Kidney Transplantation. AB - BACKGROUND: In ABO-incompatible kidney transplantation, the diagnostic criteria for antibody-mediated rejection remain controversial because C4d deposition is commonly observed. Thus, we investigated microvascular inflammation (MVI score >= 2) within 1 year as a predictor of graft outcome. METHODS: A total of 148 recipients without preformed or de novo donor-specific anti-HLA antibody were stratified based on MVI score less than 2 (n = 117) and MVI score of 2 or greater (n = 31). RESULTS: We found that 5-year graft survival was significantly lower (P = 0.0129) in patients with MVI (89.8%) than in patients without MVI (97.0%). Graft function, as characterized by serum estimated glomerular filtration rate, was also significantly worse for patients with MVI than it was for patients without MVI, between 3 months and 10 years after transplantation (P = 0.048). Multivariate analysis indicated that HLA class II mismatch (P = 0.0085) was an independent marker of MVI. CONCLUSIONS: Microvascular inflammation score of 2 or greater is significantly associated with poor graft outcome after ABO incompatible kidney transplantation. We suggest that MVI score of 2 or greater in ABOi transplantation be used as a basis to diagnose antibody-mediated rejection. PMID- 27495757 TI - Organ Transplantation in Mexico. PMID- 27495758 TI - Survival Benefit in Older Patients Associated With Earlier Transplant With High KDPI Kidneys. AB - BACKGROUND: Given high dialysis mortality rates for patients older than 60 years, accepting a kidney with a high Kidney Donor Profile Index (KDPI) score could enable earlier and potentially preemptive transplantation (preKT). However, evidence regarding the risks of high KDPI allografts in older patients is limited. Our objective was to determine the relative benefit for older patients of KDPI greater than 85% transplant either preemptively or not compared with remaining on the waitlist. METHODS: United Network of Organ Sharing data from 2003 to 2012 for adult deceased donor kidney transplant candidates was analyzed to evaluate patient survival in patients older than 60 years for preKT and non preKT KDPI greater than 85% transplants compared with candidates remaining on the waitlist including patients who received KDPI 0% to 85% transplants according to multivariate Cox regression models. RESULTS: In the first year posttransplant for KDPI greater than 85% of transplants in recipients older than 60 years, preKT had a reduced mortality hazard (hazards ratio [HR], 0.61; 95% confidence interval [95% CI], 0.41-0.90) and non-preKT an increased mortality hazard (HR, 1.15; 95% CI, 1.03-1.27) compared with the waitlist including KDPI 0% to 85% transplant recipients. At 1 to 2 years and after 2 years, both KDPI greater than 85% groups had significant reductions in mortality (1-2 years: preKT HR, 0.38; 95% CI, [0.23 0.60] and non-preKT HR, 0.52; 95% CI, 0.45-0.61; and 2+ years: preKT HR, 0.50; 95% CI, 0.38-0.66 and non-preKT HR, 0.64; 95% CI, 0.58-0.70, respectively). CONCLUSIONS: PreKT and non-preKT KDPI greater than 85% transplant was associated with lower mortality hazard after the first year compared with the waitlist including KDPI 0% to 85% transplants in patients older than 60 years. Further consideration should be given to increased utilization of high KDPI grafts in older patients with the goal of avoiding or limiting time on dialysis. PMID- 27495759 TI - Use of HCV+ Donors Does Not Affect HCV Clearance With Directly Acting Antiviral Therapy But Shortens the Wait Time to Kidney Transplantation. AB - BACKGROUND: Hepatitis C virus (HCV) infection is prevalent in the renal transplant population but direct acting antiviral agents (DAA) provide an effective cure of HCV infection without risk of allograft rejection. METHODS: We report our experience treating 43 renal transplant recipients with 4 different DAA regimens. RESULTS: One hundred percent achieved a sustained viral response by 12 weeks after therapy, and DAA regimens were well tolerated. Recipients transplanted with a HCV+ donor responded equally well to DAA therapy those transplanted with a kidney from an HCV- donor, but recipients of HCV+ organs experienced significantly shorter wait times to transplantation, 485 days (interquartile range, 228-783) versus 969 days (interquartile range, 452-2008; P = 0.02). CONCLUSIONS: On this basis, we advocate for a strategy of early posttransplant HCV eradication to facilitate use of HCV+ organs whenever possible. Additional studies are needed to identify the optimal DAA regimen for kidney transplant recipients, accounting for efficacy, timing relative to transplant, posttransplant clinical outcomes, and cost. PMID- 27495760 TI - A Call for Research on Individuals Who Opt Out of Living Kidney Donation: Challenges and Opportunities. AB - In light of the transplant community's efforts to increase living donation, preserving donor autonomy is essential. Understanding how often and the reasons why potential living kidney donors opt out of the donor evaluation process for nonmedical reasons is important for assessing donor voluntariness. The experiences of individuals who opt out of donation may reveal avenues for enhancing donor protections and identify modifiable deterrents to donation. A limited number of centers have reported rates of opting out between 0.2% and 22%; the reasons for declining to donate are not well studied. This article calls for further research on potential living donors who opt out of donation. We describe challenges to studying this population and offer a roadmap for an ethical approach to conducting research on individuals who withdraw from living kidney donor evaluation. PMID- 27495761 TI - Delayed Graft Function Phenotypes and 12-Month Kidney Transplant Outcomes. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) leading to delayed graft function (DGF), defined by the United Network for Organ Sharing as dialysis in the first week (UNOS-DGF), associates with poor kidney transplant outcomes. Controversies remain, however, about dialysis initiation thresholds and the utility for other criteria to denote less severe IRI, or slow graft function (SGF). METHODS: Multicenter, prospective study of deceased-donor kidney recipients to compare UNOS-DGF to a definition that combines impaired creatinine reduction in the first 48 hours or greater than 1 dialysis session for predicting 12-month estimated glomerular filtration rate (eGFR). We also assessed 10 creatinine and urine output-based SGF definitions relative to 12-month eGFR. RESULTS: In 560 recipients, 215 (38%) had UNOS-DGF, 330 (59%) met the combined definition, 14 (3%) died, and 23 (4%) had death-censored graft failure by 12 months. Both DGF definitions were associated with lower adjusted 12-month eGFR (95% confidence interval)-by 7.3 (3.6-10.9) and 7.4 (3.8-11.0) mL/min per 1.73 m, respectively. Adjusted relative risks for 12-month eGFR less than 30 mL/min per 1.73 m were 1.9 (1.2-3.1) and 2.1 (1.1-3.7), with unadjusted areas under the curve of 0.618 and 0.627, respectively. For SGF definitions, postoperative day (POD) 7 creatinine had the strongest association with 12-month eGFR, and POD5 creatinine and creatinine reduction between POD1 and POD2 demonstrated modest separations in 12 month eGFR. CONCLUSIONS: Although UNOS-DGF does not adequately predict 12-month function on its own, our findings do not support changing the definition. Postoperative day 7 creatinine is correlated with 12-month eGFR, but large translational studies are needed to understand the biological link between IRI severity at transplant and longer-term outcomes. PMID- 27495762 TI - Graft Versus Host Disease After Liver Transplantation in Adults: A Case series, Review of Literature, and an Approach to Management. AB - BACKGROUND: Graft-versus-host-disease (GVHD) after liver transplantation (LT) is a deadly complication with very limited data on risk factors, diagnosis and management. We report a case series and a comprehensive review of the literature. METHODS: Data were systematically extracted from reports of GVHD after LT, and from the United Network for Organ Sharing database. Group comparisons were performed. RESULTS: One hundred fifty-six adult patients with GVHD after LT have been reported. Median time to GVHD onset was 28 days. Clinical features were skin rash (92%), pancytopenia (78%), and diarrhea (65%). Six-month mortality with GVHD after LT was 73%. Sepsis was the most common cause of death (60%). Enterobacter bacteremia, invasive aspergillosis, and disseminated Candida infections were frequently reported. Recipient age over 50 years is a risk factor for GVHD after LT. Hepatocellular carcinoma was overrepresented, whereas chronic hepatitis C was underrepresented, in reported United States GVHD cases relative to all United Network for Organ Sharing database LT cases. Mortality rate with treatment of GVHD after LT was 84% with high-dose steroids alone, 75% to 100% with regimens using dose increases of calcineurin inhibitors, and 55% with IL-2 antagonists. Mortality was 25% in small case series using the CD2-blocker alefacept or TNF alpha antagonists. CONCLUSIONS: Age older than 50 years and hepatocellular carcinoma appear to be risk factors for GVHD. Hepatitis C may be protective. High dose steroids and calcineurin inhibitors are ineffective in the treatment of GVHD after LT. CD2-blockers and TNF-alpha antagonists appear promising. We propose a diagnostic algorithm to assist clinicians in managing adults with GVHD after LT. PMID- 27495764 TI - How to Perform Selective Liver Biopsy in Living Liver Donors Using Plain Computed Tomography. AB - BACKGROUND: Preoperative donor liver biopsy is the criterion standard to verify the quality of a liver. However, it can cause some complications, thus this study was designed to know whether selective liver biopsy is possible or not, and to find a subgroup that does not require preoperative biopsy. METHODS: We reviewed preoperative images and postoperative outcome in 118 donors from September 2013 to January 2014. Visual grading of steatosis on plain computed tomography (CT) was performed and compared steatosis on preoperative liver biopsy was done within 7 days from the CT scan. RESULTS: Visual grades of plain CT were 1 (n = 50, 42.4%), 2 (n = 47, 39.8%), 3 (n = 13, 11.0%), 4 (n = 7, 5.9%), and 1 (n = 1, 0.8%). Macrovesicular steatosis on liver biopsy according to visual grades were 1 (0.67 +/- 1.3%), 2 (1.67 +/- 1.8%), 3 (6.23 +/- 6.4%), 4 (14.7 +/- 16.6), and 5 (30%). Right liver grafts including right lobe, modified right lobe, and extended right lobe were procured in 106 (89.9%) donors, and 16% (17/106) of the donors were visual grades 3, 4, and 5. Eleven donors (64.7%) were accepted for right liver donation after liver biopsy, whereas 6 (35.3%) donors were deemed possible to donate right liver after weight reduction and reevaluation of steatosis. Transient hepatic dysfunction after right hepatectomy was significantly increased according to the increment of visual grade. CONCLUSIONS: Preoperative liver biopsy may not be necessary in visual grade 1 or 2 donors, but should be performed for grade 3 and 4 donors based on recipient's urgency so as to decide whether to proceed with right hepatectomy or not. PMID- 27495765 TI - Proposal of Muscle-MELD Score, Including Muscularity, for Prediction of Mortality After Living Donor Liver Transplantation. AB - BACKGROUND: The Model for End-stage Liver Diseases (MELD) is currently the most widely accepted scoring system for predicting prognosis and for allocation of liver grafts in patients awaiting liver transplantation (LT). However, this system is independent of the severity of recipient nutritional and functional status. METHODS: The present study retrospectively evaluated the preoperative quality and quantity of skeletal muscle in 231 adult patients undergoing living donor LT (LDLT) between January 2008 and December 2014. Using plain computed tomography imaging at the third lumbar vertebral level, the preoperative muscularity (quantity and quality of skeletal muscle) was evaluated. We included muscularity with the MELD score (Muscle-MELD) and investigated its ability to predict posttransplant mortality. RESULTS: Cox regression analysis provided the following equation for Muscle-MELD: Muscle-MELD = MELD score + 27.0 * low muscle quality + 25.2 * low muscle mass. The overall survival rate after LDLT was significantly lower in patients with high Muscle-MELD than in patients with low Muscle-MELD scores (P < 0.001). Muscle-MELD scores more accurately predicted posttransplant mortality than conventional MELD scores (P = 0.038 for 3 months, P = 0.002 for 6 months, P < 0.001 for 12 months, and P = 0.001 for overall mortality). With multivariate analysis, high Muscle-MELD score was an independent predictor of 6-month mortality after LDLT (odds ratio, 6.715; 95% confidence interval, 3.305-14.653; P < 0.001). CONCLUSIONS: Muscle-MELD score closely correlates with posttransplant mortality. Our results suggest that perioperative nutritional intervention and rehabilitation would affect posttransplant outcomes with improving pretransplant low muscularity. PMID- 27495763 TI - A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts: Implications for Clinical Transplantation. AB - BACKGROUND: Inflammation is central to the pathogenesis of transplant arteriosclerosis (TA). We questioned whether physiologic levels of anti inflammatory A20 influence TA severity. METHODS: We performed major histocompatibility complex mismatched aorta to carotid artery interposition grafts, using wild type (WT) or A20 heterozygote (HET) C57BL/6 (H-2) donors and BALB/c (H-2) recipients, and conversely BALB/c donors and WT/HET recipients. We analyzed aortic allografts by histology, immunohistochemistry, immunofluorescence, and gene profiling (quantitative real-time reverse transcriptase polymerase chain reaction). We validated select in vivo A20 targets in human and mouse smooth muscle cell (SMC) cultures. RESULTS: We noted significantly greater intimal hyperplasia in HET versus WT allografts, indicating aggravated TA. Inadequate upregulation of A20 in HET allografts after transplantation was associated with excessive NF-kB activation, gauged by higher levels of IkBalpha, p65, VCAM-1, ICAM-1, CXCL10, CCL2, TNF, and IL-6 (mostly localized to SMC). Correspondingly, cytokine-induced upregulation of TNF and IL-6 in human and mouse SMC cultures inversely correlated with A20 expression. Aggravated TA in HET versus WT allografts correlated with increased intimal SMC proliferation, and a higher number of infiltrating IFNgamma and Granzyme B CD4 T cells and natural killer cells, and lower number of FoxP3 regulatory T cells. A20 haploinsufficiency in allograft recipients did not influence TA. CONCLUSIONS: A20 haploinsufficiency in vascular allografts aggravates lesions of TA by exacerbating inflammation, SMC proliferation, and infiltration of pathogenic T cells. A20 single nucleotide polymorphisms associating with lower A20 expression or function in donors of vascularized allografts may inform risk and severity of TA, highlighting the clinical implications of our findings. PMID- 27495766 TI - Non-HLA Antibodies May Accelerate Immune Responses After Intestinal and Multivisceral Transplantation. AB - BACKGROUND: Non-HLA alloantibodies and autoantibodies are involved in allograft rejection in kidney and heart transplantation. Their role in intestinal transplantation has not yet been described. We examined the development of antiangiotensin II type I receptor antibodies (anti-AT1R) and antiendothelin type A receptor antibodies associated with the clinical course and histopathological findings of intestinal transplantation recipients. METHODS: Thirty-seven patients underwent intestinal or multivisceral transplantation. Non-HLA antibodies (non HLAabs) were screened in 29 transplant recipients. Antibody-levels greater than 12 U/L were considered positive and were evaluated retrospectively regarding rejection episodes. RESULTS: Twenty patients developed anti-AT1R and/or antiendothelin type A receptor antibodies (non-HLAabs group), 9 did not (control group). The non-HLAabs group had a higher rate of allograft rejection than controls (80% vs 55%), especially a higher rate of antibody-mediated rejections (55% vs 11%, P < 0.01) with detection of donor-specific anti-HLAabs. All rejection episodes in the non-HLAabs group appeared around the time of positive non-HLAabs detection. Five patients had acute cellular rejections at the time of non-HLAabs development, 4 had viral infections. CONCLUSIONS: Our data suggest that antibody-mediated mechanisms targeting antigens beyond HLA may trigger and accelerate immune responses. Given the possibility of pharmacologic targeting of non-HLA receptors, future studies will focus on the explanation of mechanisms how non-HLAabs may enhance rejection and affect long-term allograft survival. PMID- 27495767 TI - Transplant Arteriosclerosis. PMID- 27495770 TI - Successful Treatment of Chronic Hepatitis C Virus Infection With Sofosbuvir and Ledipasvir in Renal Transplant Recipients. AB - BACKGROUND: Treatment of chronic hepatitis C virus (HCV) infection after renal allograft transplantation has been an obstacle because of contraindications associated with IFN-based therapies. Direct-acting antiviral agents are highly efficient treatment options that do not require IFN and may not require ribavirin. Therefore, we assessed the efficacy and safety of sofosbuvir and ledipasvir in renal transplant patients with chronic HCV infection. METHODS: Fifteen renal allograft recipients with therapy-naive HCV genotype (GT) 1a, 1b, or 4 were treated with the combination of sofosbuvir and ledipasvir without ribavirin for 8 or 12 weeks. Clinical data were retrospectively analyzed for viral kinetics and for renal and liver function parameters. Patients were closely monitored for trough levels of immunosuppressive agents, laboratory values, and potential adverse effects. RESULTS: Ten patients (66%) exhibited a rapid virologic response within 4 weeks (HCV GT1a, n = 4; HCV GT1b, n = 6). The other 5 patients exhibited a virologic response within 8 (HCV GT 1b, n = 4) or 12 weeks (HCV GT4, n = 1). One hundred percent of patients exhibited sustained virologic response at week 12 after the end of treatment. Clinical measures of liver function improved substantially for all patients. Adverse events were scarce; renal transplant function and proteinuria remained stable. Importantly, dose adjustments for tacrolimus were necessary for maintaining sufficient trough levels. CONCLUSIONS: The described regimen appears to be safe and effective for patients after renal transplant and is a promising treatment regimen for eradicating HCV in this patient population. PMID- 27495768 TI - Use of Everolimus in Liver Transplantation: Recommendations From a Working Group. AB - Immunosuppression after liver transplantation (LT) is presently based on use of calcineurin inhibitors (CNI), although they are associated with an increased incidence of renal dysfunction, cardiovascular complications, and de novo and recurrent malignancies. Over the past decade, mammalian target of rapamycin inhibitors have received considerable attention as immunosuppressants because they are associated with a more favorable renal profile versus CNI, as well as antiproliferative activity in clinical studies. Comprehensive guidelines on use of everolimus (EVR) in LT are still lacking. In Italy, a project, named Everolimus: the road to long-term functioning, was initiated to collect the experience on EVR after LT with the aim of providing guidance for transplant clinicians. Herein, recommendations by this national consensus group, based on Delphi methodology, are presented. Consensus was reached on 20 of the 23 statements proposed, and their level of evidence, grade of recommendation, and percent of agreement are reported. Statements are grouped into 4 areas: (A) renal function; (B) time of EVR introduction, CNI reduction and elimination, and risk for graft rejection; (C) antiproliferative effects of EVR; and (D) management of EVR-related adverse events. The high level of consensus shows that there is good agreement on the routine use of EVR in predefined clinical scenarios, especially in light of posttransplant nephrotoxicity and other adverse events associated with long-term administration of CNIs. PMID- 27495772 TI - Histological and Extended Clinical Outcomes After ABO-Incompatible Renal Transplantation Without Splenectomy or Rituximab. AB - BACKGROUND: Excellent short-term results have been reported in ABO-incompatible (ABOi) renal transplant recipients managed solely with antibody removal and conventional immunosuppression. However, long-term clinical outcomes with this regimen and predictive information from protocol biopsies are lacking. METHODS: We compared outcome data in ABOi and ABO-compatible (ABOc) recipients receiving this regimen approximately 4 years posttransplant, and histology from biopsies approximately 12 months posttransplant. RESULTS: Patient and graft survivals among 54 ABOi recipients were 98.1% and 90.7%, respectively, at 4 years. Graft function was similar between ABOi (creatinine, 140.3 MUmol/L) and ABOc recipients (creatinine, 140.2 MUmol/L) (P = 0.99), with no significant change over the study period in either group (Deltacreatinine, -0.83 vs 6.6 MUmol/L) (P = 0.59). There was no transplant glomerulopathy in biopsies from either group. Interstitial fibrosis (IF) and tubular atrophy (TA) was present in 7 (28%) of 25 ABOi compared with 7 (20.6%) of 34 ABOc (P = 0.52). Progression of IF/TA from implantation was noted in 6 (24%) of 25 ABOi and 6 (17.6%) of 34 ABOc, respectively. C4d staining without antibody-mediated rejection was present in 13 (52%) 25 early posttransplant biopsies from ABOi recipients by immunohistochemistry, but in only 4 (16%) of 25 at 12 months. CONCLUSIONS: ABO-incompatible renal transplant performed with antibody removal and conventional immunosuppression continues to provide excellent patient and graft survival, and stable renal function over 4 years. Coupled with absent transplant glomerulopathy and low rates of progressive IF/TA on earlier biopsies, this suggests that ABOi with conventional immunosuppression and antibody removal, without rituximab or splenectomy, can achieve long-term outcomes comparable to ABO-compatible transplantation. PMID- 27495773 TI - Safety and Efficacy of Alemtuzumab Induction in Highly Sensitized Pediatric Renal Transplant Recipients. AB - BACKGROUND: Studies show that alemtuzumab, a potent lymphocyte-depleting agent, is well tolerated in pediatric renal transplantation. We report on the use of alemtuzumab induction in highly HLA sensitized (HS) pediatric kidney transplant patients. METHODS: Fifty pediatric renal transplants were performed from 1/2009 12/2014. 15 HS patients received IVIG (2 g/kg *2 doses)/rituximab (375 mg/m *1) for desensitization with alemtuzumab induction (15-30 mg, 1 dose, subcutaneous), whereas 35 nonsensitized patients received anti-IL-2R. Graft survival and infections were compared between 2 groups. RESULTS: All HS patients had received a prior transplant and were older with lower risk for viral infections due to serostatus. Patient survival was 100%, and graft outcomes were similar with mean 1-year creatinine of 1.03 +/- 0.45 versus 0.99 +/- 0.6 (P = 0.48). Although a higher incidence of acute cellular rejection was seen in HS patients receiving alemtuzumab (P = 0.001), there was a nonsignificant difference in antibody mediated rejection. White blood cell and absolute lymphocyte count were significantly lower in alemtuzumab group at 30 days (P < 0.0001) and at 1 year (P = 0.026 and P = 0.001), respectively. There was no significant difference in bacterial, viral, or fungal infections after transplant. CONCLUSIONS: Alemtuzumab induction with desensitization led to nearly equivalent graft survival and functional outcomes in HS pediatric patients as nonsensitized patients receiving anti-IL-2R induction. With this small sample size, we observed significant reduction of white blood cell and absolute lymphocyte count up to 1 year posttransplant. The risk of infection was comparable between the 2 groups; however, patients who received alemtuzumab were older and at lower risk of viral infection due to serostatus. PMID- 27495774 TI - Sequential Use of Normothermic Regional Perfusion and Hypothermic Machine Perfusion in Donation After Cardiac Death Liver Transplantation With Extended Warm Ischemia Time. PMID- 27495776 TI - Conformational Variants of the Individual HLA-I Antigens on Luminex Single Antigen Beads Used in Monitoring HLA Antibodies: Problems and Solutions. AB - BACKGROUND: Single antigen beads (SAB) are used for monitoring HLA antibodies in pretransplant and posttransplant patients despite the discrepancy between virtual and actual crossmatch results and transplant outcomes. This discrepancy can be attributed to the presence of conformational variants of HLA-I on SAB, assessment of which would increase the concordance between SAB and flow cytometry crossmatch (FCXM) results, thus enabling improved organ accessibility for the waiting list patients and a better prediction of antibody-mediated rejection. METHODS: The conformational variants were examined on HLA-I beads, iBeads, acid-/alkali treated beads, and T cells using HLA-I monoclonal antibodies (W6/32, TFL-006, and heavy chain (HC)-10). RESULTS: The affinity of the monoclonal antibodies against HLA-I beads confirmed the presence and heterogeneous density of peptide associated beta2-microglobulin-associated HLA HC (pepA-beta2aHC), peptide-free beta2aHC (pepF-beta2aHC), and beta2-free HC (beta2fHC) on every single antigen coated bead. In contrast, iBeads harbor a high density of pepA-beta2aHC, low density of pepF-beta2aHC, and are lacking beta2fHC. The FCXM analyses confirmed the prevalence of pepA-beta2aHC, but not pepF-beta2aHC or beta2fHC on resting T cells. CONCLUSIONS: The strength of a donor-specific antibody should be assessed with a bead-specific mean fluorescence intensity cutoff based on TFL-006 reactivity against HLA-I beads, and HC-10 against iBeads, where the beta2fHC or pepF-beta2aHC normalized donor-specific antibody level would reveal the true anti pepA-beta2aHC reactivity associated with positive FCXM. PMID- 27495775 TI - Outcomes in Transplant Recipients Treated With Foscarnet for Ganciclovir Resistant or Refractory Cytomegalovirus Infection. AB - BACKGROUND: Antiviral-resistant or refractory cytomegalovirus (CMV) infection is challenging, and salvage therapies, foscarnet, and cidofovir, have significant toxicities. Several investigational anti-CMV agents are under development, but more information is needed on outcomes of current treatments to facilitate clinical trial design for new drugs. METHODS: Records of solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients at a single center over a 10-year period were reviewed retrospectively to characterize those who had received foscarnet treatment for ganciclovir-resistant or refractory CMV infection. Data were collected on virologic responses, mortality, and nephrotoxicity. RESULTS: Of 39 patients (22 SOT, 17 HCT), 15 had documented ganciclovir resistance mutations and 11 (28%) of 39 had tissue-invasive CMV. Median duration of foscarnet was 32 days. Virologic failure occurred in 13 (33%) of 39 and relapses of viremia occurred in 31%. Mortality was 12 (31%) of 39 and was higher in HCT than SOT (P = 0.001), although ganciclovir resistance was more common in SOT (P = 0.003). Doses of ganciclovir or valganciclovir were low in 10 (26%) of 39 at some time before switching to foscarnet. Renal dysfunction occurred in 20 (51%) of 39 by end of treatment and in 7 (28%) of 25 after 6 months. CONCLUSIONS: Outcomes of existing treatment for ganciclovir-resistant or refractory CMV are suboptimal, in terms of virologic clearance, renal dysfunction, and mortality. These data should provide background information for future clinical trials of newer antiviral agents. PMID- 27495778 TI - The Authors' Reply. PMID- 27495779 TI - Radiofrequency ablation for HCC patients with multifocal tumours meeting the Milan criteria: A single-centre experience. AB - BACKGROUND: Radiofrequency ablation (RFA) has been recommended as a curative treatment for patients with single early-stage unifocal hepatocellular carcinomas (HCCs) for years; however, the effect of this treatment on multifocal tumours has remained uncertain. AIMS: We conducted a retrospective study to evaluate the overall survival (OS) and recurrence-free survival (RFS) rates of early HCC patients with multiple tumours subjected to different RFA modalities. METHODS: One hundred fifty-four HCC patients with multifocal tumours who met the Milan criteria and underwent RFA were enrolled in this study. We divided the patients into 3 groups according to the surgical approach utilised (percutaneous, laparoscopic and open RFA; selection was based on the locations of the tumours for whether they were adhered to the subhepatic inferior vena cava or the gastrointestinal tract) and into 2 subgroups according to the tumour numbers and locations. RESULTS: No deaths occurred in the 30-day post-operation period, and there were no significant differences in the complication, OS or RFS rates between the 3 groups. The 1-, 3- and 5-year OS rates were 88.9%, 75.5% and 50.9% in the subgroup with 2 tumours, respectively, versus 91.3%, 56.3% and 17.5% in the subgroup with 3 tumours, respectively (P=0.001). The corresponding values were 93.2%, 77.4% and 50.8% in the subgroup with tumours in the same segment and 82.4%, 54.8% and 23.0% in the subgroup with tumours in different segments (P=0.001). CONCLUSION: RFA was proven to be an effective and safe method for the treatment of multifocal HCCs. Among the patients with 2 tumours within the same segment, RFA achieved better long-term outcomes in terms of both overall and recurrence-free survival. PMID- 27495780 TI - A quick glance at selected topics in this issue. AB - A quick glance at selected topics in this issue aims to highlight selected articles and provide a quick review to the reader. PMID- 27495781 TI - Detecting papillary neovascularization in proliferative diabetic retinopathy using optical coherence tomography angiography. PMID- 27495782 TI - Integrative analysis of metabolome and gut microbiota in diet-induced hyperlipidemic rats treated with berberine compounds. AB - BACKGROUND: Hyperlipidemia is a major component of metabolic syndrome, and often predicts cardiovascular diseases. We developed a new therapeutic agent berberine compounds (BC), consisting of berberine, oryzanol and vitamin B6, and determined their anti-hyperlipidemia activity and underlying mechanisms. METHODS: Male Wistar rats were fed a high fat diet (HFD) to induce hyperlipidemia, and then given BC orally for 4 weeks. Body weight and food intake were recorded weekly, and lipid profiles in serum were determined biochemically. Metabolites in serum, urine, liver and feces were analyzed by GC-MS, and the structure of microbiota was determined by 16S rDNA sequencing. RESULTS: Lipid lowering was observed in the hyperlipidemic rats upon BC treatment without apparent adverse side effects. Metabolomics analysis indicated that the BC treatment resulted in increased pyruvic acid, serotonin, and ketogenic and glycogenic amino acid levels in the serum, increased pyridoxine and 4-pyridoxic acid in the urine, decreased hypotaurine and methionine in the liver, and increased putrescine and decreased deoxycholate and lithocholate in feces. The BC treatment also resulted in an enrichment of beneficial bacteria (e.g. Bacteroides, Blautia) and a decrease in Escherichia. CONCLUSIONS: The lipid lowering effect of BC treatment in hyperlipidemic rats is associated with a global change in the metabolism of lipids, carbohydrates and amino acids, as well as the structure of microbiota. PMID- 27495783 TI - Risk Factors of Physical and Sexual Abuse for Women in Mali: Findings From a Nationally Representative Sample. AB - Mali is a developing country that has marked inequalities between genders. Using the 2012-2013 Mali Demographic and Health Survey, a nationally representative sample of Malian women ( N = 2,527), the study examined the effect of controlling behaviors, childhood exposure to and experience of violence, husband's alcohol use, woman's use of violence, and sociocultural factors on the likelihood of experiencing physical and sexual abuse. Findings indicated that controlling behavior, childhood exposure to violence, and husband's use of alcohol were predictors of physical and sexual abuse. Respondent's use of violence increased risk of physical abuse. Implications for programming in Mali are discussed. PMID- 27495784 TI - [Pathology of lung cancer]. AB - Lung cancer is the leading cause of cancer death in men and the second most frequent cause in women. The pathology of lung tumors is of special relevance concerning therapy and prognosis and current classification systems have to be taken into consideration. The results of molecular tissue subtyping allow further classification and therapeutic options. The histological entities are mainly associated with typical X-ray morphological features. PMID- 27495785 TI - [Radiological knowledge management with the help of departmental wikis]. AB - In times of RIS (radiology information system) and KIS (hospital information system) systems, patient-related data are at the radiologist's disposal at the push of a button. However, this is not the case for other important data. The increasing complexity of modern medicine demands that up-to-date information like protocols, SOPs (Standards of Practice), news and modifications are constantly accessible to all employees. This aspect of quality assurance becomes increasingly important in the context of certification. For such knowledge management purposes we have built a wiki in our department. Here we report our positive experiences with this technology. PMID- 27495786 TI - [Lung cancer screening - risk stratification : Who should undergo screening?]. AB - Lung cancer is one of the leading causes of deaths in Europa and the USA. In approximately 75 % of lung cancer patients, bronchogenic carcinoma is detected at an advanced tumor stage; therefore, therapeutic options which aim at curing the disease in these patients are limited and treatment is mostly palliative. A relatively good prognosis is reserved for the minority of patients where the tumor is detected at an early stage and treatment is potentially curative. For this reason, early diagnosis of lung cancer could save lives. Retrospective analyses of the US national lung screening trial (NLST) showed that especially high-risk populations (e. g. higher age, positive smoking history, overweight and a positive family history for lung cancer) benefit most from lung cancer screening. Thus, the effectiveness of computed tomography (CT) screening can be improved by focusing on high-risk populations. This review article summarizes the risk stratification models of the large European and American screening studies and discusses possible future biomarkers for risk stratification. PMID- 27495787 TI - [Diagnostic work-up of pulmonary nodules : Management of pulmonary nodules detected with low-dose CT screening]. AB - Pulmonary nodules are the most frequent pathological finding in low-dose computed tomography (CT) scanning for early detection of lung cancer. Early stages of lung cancer are often manifested as pulmonary nodules; however, the very commonly occurring small nodules are predominantly benign. These benign nodules are responsible for the high percentage of false positive test results in screening studies. Appropriate diagnostic algorithms are necessary to reduce false positive screening results and to improve the specificity of lung cancer screening. Such algorithms are based on some of the basic principles comprehensively described in this article. Firstly, the diameter of nodules allows a differentiation between large (>8 mm) probably malignant and small (<8 mm) probably benign nodules. Secondly, some morphological features of pulmonary nodules in CT can prove their benign nature. Thirdly, growth of small nodules is the best non-invasive predictor of malignancy and is utilized as a trigger for further diagnostic work up. Non-invasive testing using positron emission tomography (PET) and contrast enhancement as well as invasive diagnostic tests (e.g. various procedures for cytological and histological diagnostics) are briefly described in this article. Different nodule morphology using CT (e.g. solid and semisolid nodules) is associated with different biological behavior and different algorithms for follow up are required. Currently, no obligatory algorithm is available in German speaking countries for the management of pulmonary nodules, which reflects the current state of knowledge. The main features of some international and American recommendations are briefly presented in this article from which conclusions for the daily clinical use are derived. PMID- 27495788 TI - Sunitinib DDI with paracetamol, diclofenac, mefenamic acid and ibuprofen shows sex-divergent effects on the tissue uptake and distribution pattern of sunitinib in mice. AB - PURPOSE: Pharmacokinetic interaction of sunitinib with diclofenac, paracetamol, mefenamic acid and ibuprofen was evaluated due to their P450 mediated metabolism and OATP1B1, OATP1B3, ABCB1, ABCG2 transporters overlapping features. METHODS: Male and female mice were administered 6 sunitinib doses (60 mg/kg) PO every 12 h and 30 min before the last dose were administered vehicle (control groups), 250 mg/kg paracetamol, 30 mg/kg diclofenac, 50 mg/kg mefenamic acid or 30 mg/kg ibuprofen (study groups), euthanized 6 h post last administration and sunitinib plasma, liver, kidney, brain concentrations analyzed. RESULTS: Ibuprofen halved sunitinib plasma concentration in female mice (p < 0.01) and showed 59 % lower concentration than male mice (p < 0.05). Diclofenac and paracetamol female mice showed 45 and 25 % higher plasma concentrations than male mice which were 27 % lower in mefenamic acid female mice. Paracetamol increased 2.2 (p < 0.05) liver and 1.4-fold (p < 0.05) kidney sunitinib concentrations in male mice that were lower in female mice (p < 0.01, p < 0.001, respectively). Ibuprofen increased 2.9 fold (p < 0.01) liver concentration in male mice that were higher than in female mice (p < 0.001). Female control mice had 35 % higher sunitinib brain concentration than male mice but the concentration decreased 37, 33, 10 and 57 % in the diclofenac, paracetamol, mefenamic acid and ibuprofen (p < 0.001), respectively. Tissue-plasma concentrations correlations were nonsignificant in control, paracetamol, mefenamic acid and ibuprofen groups but was significant in the diclofenac group in male mice (liver, brain) and female mice (liver, kidney). CONCLUSIONS: These results portray gender-based sunitinib pharmacokinetic differences and NSAIDs selective effects on male or female mice, with potential clinical translatability. PMID- 27495789 TI - Reply to timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. PMID- 27495790 TI - A single mechanism driving both inactivation and adaptation in rapidly adapting currents of DRG neurons? AB - Rapidly adapting (RA) currents expressed in dorsal root ganglia somatosensory neurons reduce their amplitude in response to prolonged and/or repeated mechanical stimulation. Both inactivation of mechanotransducer channels and adaptation of the force acting on the channels have been suggested to independently decrease RA currents. However, these two mechanisms have similar kinetics and dependence on calcium and voltage. These experimental findings suggest that a single mechanism might underlie both. We constructed a simple Hodgkin-Huxley-type model with a single gating variable driving both inactivation and adaptation to test this hypothesis. Predictions of the model successfully describe key features of mechanical activation as well as inactivation, adaptation, and recovery. The model thus supports the possibility of a single mechanism driving inactivation and adaptation in RA currents. On its own, the model can be integrated into higher-order models of touch receptors because of its accurate simulation of RA currents. PMID- 27495791 TI - Environmental Enteropathy: Elusive but Significant Subclinical Abnormalities in Developing Countries. AB - Environmental enteropathy/Environmental enteric dysfunction (EE/EED) is a chronic disease of small intestine characterized by gut inflammation and barrier disruption, malabsorption and systemic inflammation in the absence of diarrhea. It is predominantly diseases of children in low income countries and is hypothesized to be caused by continuous exposure to fecally contaminated food, water and fomites. It had not been recognized as a priority health issue because it does not cause overt symptoms and was seen in apparently healthy individuals. However, there is a growing concern of EE/EED because of its impact on longitudinal public health issues, such as growth faltering, oral vaccine low efficacy and poor neurocognitive development. Recent works have provided important clues to unravel its complex pathogenesis, and suggest possible strategies for controlling EE/EED. However, effective diagnostic methods and interventions remain unsettled. Here, we review the existing literature, especially about its pathogenesis, and discuss a solution for children living in the developing world. PMID- 27495792 TI - Clevidipine-induced Dyspnea Relief in Acute Heart Failure Patients. PMID- 27495794 TI - Copy number variations and cancer susceptibility: Retraction. PMID- 27495793 TI - Prognostic Impact of Circulating Tumor Cell Detected Using a Novel Fluidic Cell Microarray Chip System in Patients with Breast Cancer. AB - Various types of circulating tumor cell (CTC) detection systems have recently been developed that show a high CTC detection rate. However, it is a big challenge to find a system that can provide better prognostic value than CellSearch in head-to-head comparison. We have developed a novel semi-automated CTC enumeration system (fluidic cell microarray chip system, FCMC) that captures CTC independently of tumor-specific markers or physical properties. Here, we compared the CTC detection sensitivity and the prognostic value of FCMC with CellSearch in breast cancer patients. FCMC was validated in preclinical studies using spike-in samples and in blood samples from 20 healthy donors and 22 breast cancer patients in this study. Using spike-in samples, a statistically higher detection rate (p=0.010) of MDA-MB-231 cells and an equivalent detection rate (p=0.497) of MCF-7 cells were obtained with FCMC in comparison with CellSearch. The number of CTC detected in samples from patients that was above a threshold value as determined from healthy donors was evaluated. The CTC number detected using FCMC was significantly higher than that using CellSearch (p=0.00037). CTC numbers obtained using either FCMC or CellSearch had prognostic value, as assessed by progression free survival. The hazard ratio between CTC+ and CTC- was 4.229 in CellSearch (95% CI, 1.31 to 13.66; p=0.01591); in contrast, it was 11.31 in FCMC (95% CI, 2.245 to 57.0; p=0.000244). CTC detected using FCMC, like the CTC detected using CellSearch, have the potential to be a strong prognostic factor for cancer patients. PMID- 27495796 TI - Serum procalcitonin can guide antibiotic administration for respiratory tract infections in primary care. PMID- 27495797 TI - Sleep apnea is associated with an increased risk of mood disorders: a population based cohort study. AB - PURPOSE: The symptoms of sleep apnea, such as sleep fragmentation and oxygen desaturation, might be risk factors for subsequent mood disorder (MD), but associations between sleep apnea and MD remain unclear. This nationwide population-based study thus aimed to identify the risk of MD in patients with vs. without sleep apnea. METHODS: This cohort study used data from the National Health Insurance database. In total, 5415 patients diagnosed with sleep apnea between 2000 and 2010 were evaluated, and 27,075 matched non-sleep apnea enrollees were included as a comparison cohort. All subjects were followed until 2011. The Cox proportional hazard ratio (HR) was used to investigate the relationship between MD and sleep apnea while controlling covariates and comorbidities of sleep apnea. RESULTS: Of 5415, 154 patients with sleep apnea (2.84 %) were diagnosed with MD during the follow-up period in comparison with 306 of 27,075 individuals (1.13 %) without antecedent sleep apnea. After adjusting for the selected factors and comorbidities, we found that patients with sleep apnea were from 1.82- to 2.07-fold greater risk of MD than the comparisons. Of the three subcategories of MD (major depressive disorder, bipolar disorder, and unspecified MD), sleep apnea had the highest predisposing risk with respect to major depressive disorder (adjusted HR from 1.82 to 2.07) and bipolar disorder (adjusted HR from 2.15 to 3.24). CONCLUSIONS: There is a greater likelihood of MD manifesting in patients with a history of sleep apnea. Health professionals are thus advised to carefully monitor the psychological impacts of sleep apnea. PMID- 27495799 TI - Another Form of Focal Choroidal Excavation Based on Multimodality Imaging. AB - PURPOSE: To describe a peculiar choroidal entity using multimodality imaging and to further understand the relationship between focal choroidal excavation and central serous chorioretinopathy. CASE REPORT: A peculiar entity was detected in both eyes of a 20-year-old male patient who was followed for more than 4 years; one perifoveal focal choroidal excavation and two extrafoveal focal choroidal excavations were noted in each eye. The bilateral perifoveal focal choroidal excavations exhibited progressive development with repeated interconversion between the nonconforming and conforming types. Dilated choroid blood vessels were detected by en face spectral-domain optical coherence tomography (SD-OCT). Although the ellipsoid zone and retinal pigment epithelium layer defect also involved the fovea, a visual acuity of 20/20 was maintained in both eyes, with neither metamorphopsia by Amsler grid nor abnormalities noted by multifocal electroretinogram. However, pigment epithelium detachment finally appeared in the right eye. The microperimetry test revealed reduced threshold sensitivity corresponding to the lesions, and near-infrared autofluorescence revealed increased hyperfluorescence at the latest visit. CONCLUSIONS: Idiopathic focal choroidal excavation may convert to the structure of central serous chorioretinopathy alike, which likely indicates another rare condition of focal choroidal excavation or central serous chorioretinopathy. Wide- and deep-scanning modes should be routinely applied in OCT imaging to detect choroidal disorders. PMID- 27495800 TI - Low predictive value of sentinel lymph node biopsy in patients with thin melanoma. PMID- 27495798 TI - Breakthrough viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients receiving levofloxacin prophylaxis in a Japanese hospital. AB - BACKGROUND: Breakthrough viridans streptococcal bacteremia (VSB) in patients with hematological malignancy receiving levofloxacin prophylaxis is a major blood stream infection (BSI) occurring during febrile neutropenia. However, clinical data focused on VSB in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are lacking. METHODS: The medical records of allo-HSCT recipients who received oral levofloxacin prophylaxis between January 2011 and August 2013 at Toranomon Hospital were reviewed to evaluate breakthrough VSB. Stored viridans streptococcal (VGS) species were identified by using sodA gene sequencing, and were assessed for drug susceptibility. RESULTS: Among the 184 allo-HSCT recipients on levofloxacin prophylaxis, 28 (15.2 %) experienced breakthrough VSB. All of the 28 recipients with VSB were treated with a cefepime-based or piperacillin/tazobactam-based regimen. The susceptibility rates of the VGS strains for levofloxacin, cefepime, piperacillin/tazobactam, meropenem, and vancomycin were 0 %, 95 %, 100 %, 100 %, and 100 %, respectively. Both the MIC50 (minimum inhibitory concentration) and the MIC90 of ceftazidim (0.5 MUg/mL and 2 MUg/mL, respectively) were higher than the MIC90 of all the other anti pseudomonal beta-lactams (APBLs). Only 1 VGS strain had a penicillin MIC >= 2 MUg/mL by the Etest (3.6 %). There were no cases with acute respiratory distress syndrome (ARDS) that was associated with VSB, although the rate of viridans group streptococcal shock syndrome was high (26 %). The crude 30-day mortality rate in the VSB group (10.7 %) did not differ significantly from that in the BSI without VSB group (9.3 %) or non-BSI group (7.0 %) (P = 0.77). Also, VSB was not a risk factor for all-cause mortality up to 60 days following allo-HSCT (P = 0.43). CONCLUSIONS: APBL with increased anti-VGS activity (APBL-VA) monotherapy would typically be optimal for treating the VGS strains in this setting. Indication of adding an empiric anti-gram-positive agent to APBL-VA for treating VSB should depend on local factors, such as the susceptibility results. In addition, breakthrough VSB is probably not a major cause of death in allo-HSCT settings, where beta-lactam non-susceptible VGS and the ARDS are rare. PMID- 27495801 TI - Pharmacological screening of Monotheca buxifolia (Falc.) A. DC. for antinociceptive, anti-inflammatory and antipyretic activities. AB - BACKGROUND: Medicinal plants have proven their importance as a valuable source of molecules with therapeutic potential. Monotheca buxifolia (Falc.) A. DC. (family: Sapotaceae) is traditionally used as a hematinic, laxative, digestive, anthelmintic, antipyretic, and in the treatment of gastro-urinary disorders. To provide scientific evidence for its folkloric use, the present study investigated Monotheca buxifolia fruit hydro-ethanolic extract (MBHE) for its prospective antinociceptive, anti-inflammatory and antipyretic activities. MBHE was eluted through column chromatography to isolate the bioactive secondary metabolites which may probably involve in its beneficial properties. METHODS: The phytochemical constituents in MBHE was elucidated using UV, IR, (1)H-NMR, (13)C NMR, 2D-NMR spectra in combination with EIMS and FAB-MS spectrometric techniques and comparison with literature data of related compounds. The antinociceptive activity of MBHE was evaluated in the acetic acid induced abdominal constriction assay; the anti-inflammatory potential was assessed in the carrageenan induced paw edema, while the antipyretic effect was tested against brewer's yeast induced pyrexia in BALB/c mice at doses of 50, 100 and 150 mg/kg. RESULTS: Elution of MBHE along with various characterization techniques led to the isolation of oleanolic acid and isoquercetin. Significant attenuation of chemical induced nociception was observed with MBHE at tested doses of 50 mg/kg (P < 0.01, 68.87 %), 100 mg/kg (P < 0.01, 68.87 %) and 150 mg/kg (P < 0.001, 83.02 %). During a duration of 1-5 h in the carrageenan induced paw edema assay, significant ameliorative effect (P < 0.01, P < 0.001) was demonstrated by MBHE at 50 mg/kg (22.94-20 %), 100 mg/kg (33.23-21.13 %) and 150 mg/kg (38.23-25 %). MBHE also significantly alleviated the brewer's yeast induced pyrexic response when tested at doses of 50 mg/kg (P < 0.05 in 2nd h), 100 mg/kg (P < 0.05, P < 0.01 and P < 0.001 in 1-5 h) and 150 mg/kg (P < 0.01 and P < 0.001 in 1-5 h). CONCLUSION: These findings suggest that Monotheca buxifolia possess pain, inflammation and pyrexia ameliorating properties, probably mediated by the presence of oleanolic acid and isoquercetin contents, though the involvement of other important phytochemicals constituents cannot be ignored. PMID- 27495802 TI - Food for thought? Potential conflicts of interest in academic experts advising government and charities on dietary policies. AB - BACKGROUND: A conflict of interest (CoI) can occur between public duty and private interest, in which a public official's private-capacity interest could improperly influence the performance of their official duties and responsibilities. The most tangible and commonly considered CoI are financial. However, CoI can also arise due to other types of influence including interpersonal relationships, career progression, or ideology. CoI thus exist in academia, business, government and non-governmental organisations. However, public knowledge of CoI is currently limited due to a lack of information. The mechanisms of managing potential conflicts of interest also remain unclear due to a lack of guidelines. We therefore examined the independence of academic experts and how well potential CoI are identified and addressed in four government and non-governmental organisations in the UK responsible for the development of food policy. METHODS: Policy analysis. We developed an analytical framework to explore CoI in high-level UK food policy advice, using four case studies. Two government policy-making bodies: Department of Health 'Obesity Review Group' (ORG), 'Scientific Advisory Committee on Nutrition' (SACN) and two charities: 'Action on Sugar' (AoS), & 'Heart of Mersey' (HoM). Information was obtained from publicly available sources and declarations. We developed a five point ordinal scale based upon the ideology of the Nolan Principles of Public Life. Group members were individually categorised on the ordinal ConScale from "0", (complete independence from the food and drink industry) to "4", (employed by the food and drink industry or a representative organisation). RESULTS: CoI involving various industries have long been evident in policy making, academia and clinical practice. Suggested approaches for managing CoI could be categorised as "deny", "describe", or "diminish". Declared CoI were common in the ORG and SACN. 4 out of 28 ORG members were direct industry employees. In SACN 11 out of 17 members declared industry advisory roles or industry research funding. The two charities appeared to have equally strong academic expertise but fewer conflicts. No HoM members declared CoI. 5 out of 21 AoS members declared links with industry, mainly pharmaceutical companies. We were unable to obtain information on conflicts for some individuals. CONCLUSIONS: Conflicts of interest are unavoidable but potentially manageable. Government organisations responsible for policy development and implementation must institutionalize an approach to identify (disclose) and manage (mitigate or eliminate) perceived and actual CoI to improve public confidence in government decision-making relevant to food policy. PMID- 27495803 TI - Assessment of the need for psychosomatic care in patients with suspected cardiac disease. AB - OBJECTIVE: The study aimed to assess the subjectively perceived need for additional general disease-oriented and psychotherapeutic care in patients with suspected cardiac disease and to investigate if the request for additional care is consistent with impairment of generic quality of life and the presence of psychosomatic risk factors. MATERIAL AND METHODS: Patients referred for cardiac stress testing because of suspected cardiac disease completed the assessment of the demand for additional psychological treatment (ADAPT) questionnaire, an assessment tool for counselling demand in patients with chronic illness, the SF 36 quality of life and the hospital anxiety and depression scale (HADS) questionnaires. RESULTS: The questionnaires were administered to 233 patients (age: 54.5 +/- 13.4, 57.5 % male). Exclusive demand for disease-oriented counselling was indicated by 45.1 %, demand for psychotherapeutic counselling (exclusive or combined with disease-oriented demand) by 33.9 %. Almost all patients with psychotherapeutic demand (96.3 %) expressed also request for disease-oriented counselling. Patients with exclusive demand for disease-oriented counselling showed significantly lower scores in the emotional and physical functioning and role domains of the SF-36 than the norm population. Patients demanding psychotherapeutic counselling reported significantly lower scores in all SF-36 domains than the norm population. Psychotherapeutic demand was strongly associated with positive indicators for mental distress: SF-36 MH (OR: 4.1), SF 36 MCS (OR: 5.9), HADS anxiety (OR: 3.9), and HADS depression (OR: 3.0). CONCLUSIONS: Our study shows that the patients' request for additional care reflects impairment of generic health status and psychological risk load. This indicates that the assessment of subjectively perceived demand allows to screen for patients who are in need of psychosomatic care and motivated to participate in additional counselling and therapy. PMID- 27495804 TI - Coronary fractional flow reserve measurements of a stenosed side branch: a computational study investigating the influence of the bifurcation angle. AB - BACKGROUND: Coronary hemodynamics and physiology specific for bifurcation lesions was not well understood. To investigate the influence of the bifurcation angle on the intracoronary hemodynamics of side branch (SB) lesions computational fluid dynamics simulations were performed. METHODS: A parametric model representing a left anterior descending-first diagonal coronary bifurcation lesion was created according to the literature. Diameters obeyed fractal branching laws. Proximal and distal main branch (DMB) stenoses were both set at 60 %. We varied the distal bifurcation angles (40 degrees , 55 degrees , and 70 degrees ), the flow splits to the DMB and SB (55 %:45 %, 65 %:35 %, and 75 %:25 %), and the SB stenoses (40, 60, and 80 %), resulting in 27 simulations. Fractional flow reserve, defined as the ratio between the mean distal stenosis and mean aortic pressure during maximal hyperemia, was calculated for the DMB and SB (FFRSB) for all simulations. RESULTS: The largest differences in FFRSB comparing the largest and smallest bifurcation angles were 0.02 (in cases with 40 % SB stenosis, irrespective of the assumed flow split) and 0.05 (in cases with 60 % SB stenosis, flow split 55 %:45 %). When the SB stenosis was 80 %, the difference in FFRSB between the largest and smallest bifurcation angle was 0.33 (flow split 55 %:45 %). By describing the DeltaPSB-QSB relationship using a quadratic curve for cases with 80 % SB stenosis, we found that the curve was steeper (i.e. higher flow resistance) when bifurcation angle increases (DeltaP = 0.451*Q + 0.010*Q (2) and DeltaP = 0.687*Q + 0.017*Q (2) for 40 degrees and 70 degrees bifurcation angle, respectively). Our analyses revealed complex hemodynamics in all cases with evident counter rotating helical flow structures. Larger bifurcation angles resulted in more pronounced helical flow structures (i.e. higher helicity intensity), when 60 or 80 % SB stenoses were present. A good correlation (R(2) = 0.80) between the SB pressure drop and helicity intensity was also found. CONCLUSIONS: Our analyses showed that, in bifurcation lesions with 60 % MB stenosis and 80 % SB stenosis, SB pressure drop is higher for larger bifurcation angles suggesting higher flow resistance (i.e. curves describing the DeltaPSB-QSB relationship being steeper). When the SB stenosis is mild (40 %) or moderate (60 %), SB resistance is minimally influenced by the bifurcation angle, with differences not being clinically meaningful. Our findings also highlighted the complex interplay between anatomy, pressure drops, and blood flow helicity in bifurcations. PMID- 27495806 TI - David Oliver: NHS continuing care is a mess. PMID- 27495805 TI - Effects of tDCS over the right DLPFC on attentional disengagement from positive and negative faces: An eye-tracking study. AB - The aim of this study was to increase insight in the neural substrates of attention processes involved in emotion regulation. The effects of right dorsolateral prefrontal cortex (i.e., DLPFC) stimulation on attentional processing of emotional information were evaluated. A novel attention task allowing a straightforward measurement of attentional engagement toward, and attentional disengagement away from emotional faces was used. A sample of healthy participants received 20 minutes of active and sham anodal transcranial direct current stimulation (i.e., tDCS) applied over the right DLPFC on 2 separate days and completed the attention task after receiving real or sham stimulation. Compared to sham stimulation, tDCS over the right DLPFC led to impairments in attentional disengagement from both positive and negative faces. Findings demonstrate a causal role of right DLPFC activity in the generation of attentional impairments that are implicated in emotional disturbances such as depression and anxiety. PMID- 27495807 TI - Spindle cell sarcomatoid carcinoma of the trachea: first case report of surgical resection. AB - BACKGROUND: Primary malignant tracheal tumors are rare, accounting for approximately 0.2 % of respiratory tract tumors yearly, with squamous cell carcinomas and adenoid cystic carcinomas accounting for two-thirds of these cases. Sarcomatoid carcinomas are a group of poorly differentiated non-small cell lung carcinomas containing a component of sarcoma or sarcoma-like (spindle and/or giant cell) differentiation, categorized into five morphologic subgroups. Spindle cell sarcomatoid carcinoma is a rare variant of sarcomatoid carcinomas, consisting of only spindle-shaped tumor cells. Only one other case has been reported as a primary tracheal tumor. CASE PRESENTATION: We present a 75-year-old male, having progressive dyspnea and cough, with a spindle cell sarcomatoid carcinoma tumor visualized on chest computed tomography scan and confirmed with biopsy. CONCLUSIONS: Due to its low incidence, knowledge of treatment methods, prognostic factors, and etiology is limited thus approaches to eradication have widely varied. We are reporting the second published case of spindle cell sarcomatoid carcinoma of the trachea and the first reported successful outcome of definitive treatment with tracheal resection. PMID- 27495808 TI - Population-level effects of abamectin, azadirachtin and fenpyroximate on the predatory mite Neoseiulus baraki. AB - The coconut production system, in which the coconut mite Aceria guerreronis is considered a key pest, provides an interesting model for integration of biological and chemical control. In Brazil, the most promising biological control agent for the coconut mite is the phytoseiid predator Neoseiulus baraki. However, acaricides are widely used to control the coconut mite, although they frequently produce unsatisfactory results. In this study, we evaluated the simultaneous direct effect of dry residue contact and contaminated prey ingestion of the main acaricides used on coconut palms (i.e., abamectin, azadirachtin and fenpyroximate) on life-history traits of N. baraki and their offspring. These acaricides are registered, recommended and widely used against A. guerreronis in Brazil, and they were tested at their label rates. The offspring of the exposed predators was also evaluated by estimating the instantaneous rate of population increase (r i ). Abamectin compromised female performance, whereas fenpyroximate did not affect the exposed females (F0). Nonetheless, fenpyroximate strongly compromised the offspring (F1) net reproductive rate (R0), intrinsic rate of population growth (r i ), and doubling time (DT). In contrast, fenpyroximate did not have such effects on the 2nd generation (F2) of predators with acaricide exposed grandparents. Azadirachtin did not affect the predators, suggesting that this acaricide can be used in association with biological control by this predatory species. In contrast, the use of abamectin and fenpyroximate is likely to lead to adverse consequences in the biological control of A. guerreronis using N. baraki. PMID- 27495809 TI - Does Surgeon Experience Impact the Risk of Complications After Bernese Periacetabular Osteotomy? AB - BACKGROUND: Bernese periacetabular osteotomy (PAO) is a technically challenging procedure with potential risk for major complications and a previously reported steep learning curve. However, the impact of contemporary hip preservation fellowships on the learning curve of PAO has not been established. QUESTIONS/PURPOSES: (1) What was the frequency of major complications during the PAO learning curve of two surgeons who recently graduated from hip preservation fellowships? (2) Is increasing level of experience associated with the risk of a complication and with operative time, a possible surrogate measure of surgical performance? METHODS: We retrospectively studied 81 PAOs performed by one of two surgeons who recently graduated from a hip preservation fellowship during their first 4 years of practice in two institutions. One of the surgeons participated as a fellow in 78 PAOs with an increasing level of responsibility during the course of 1 full year. The other surgeon performed 41 PAOs as a fellow during 6 months, also with an increasing level of responsibility during that time. There were 68 (84%) female and 13 (16%) male patients (mean age, 18 years; range, 10-36 years). The frequency of complications was recorded early and at 1 year after surgery and graded according to a validated classification system describing five grades of complications. Complications that required surgical intervention (Grade III) and life-threatening complications (Grade IV) were considered major complications. Persistent pain after surgery, although considered a failure of PAO, was not considered a surgical complication as a result of the multifactorial etiology of pain after hip-preserving surgery. However, early reoperation and revision surgery were counted as complications. To evaluate the association between increasing level of experience and the occurrence of complications, we divided each surgeon's experience into his first 20 procedures (initial interval) and his second 20 (experienced interval) to test whether the incidence of complications or operative time was different between the two intervals. Because the association between experience and the likelihood of a complication was estimated to be consistent between the two surgeons, the analysis was performed with data pooled from the two surgeons. To test whether there was a difference in the likelihood of a complication in the initial and the experienced intervals, a multivariate logistic regression analysis was performed and the adjusted risk of a complication between the two intervals was calculated. Linear regression analyses were used to test the association between surgeon level of experience and operative time. RESULTS: The overall incidence of major (Grade III or Grade IV) complications was 6% (95% confidence interval [CI], 2%-14%). These included deep infection (3% [three of 81]), intraoperative posterior column fracture (1% [one of 81]), and pulmonary embolism (1% [one of 81]). With the numbers available, the risk of a complication did not decrease with increasing surgeon experience. After controlling for body mass index and surgeon, the frequency of a complication did not decrease in the experienced interval relative to the initial interval (odds ratio, 0.78; 95% CI, 0.25-2.4; p = 0.6623). The adjusted risk difference between the experienced interval relative and the initial interval was 6% (95% CI, -11% to 23%). When experience was modeled as a continuous variable (number of PAOs performed), increasing experience was not associated with a lower likelihood of a complication (odds ratio per one PAO increase in experience, 0.99; 95% CI, 0.94-1.04; p = 0.5478). However, after adjusting for body mass index and surgeon, increased experience was associated with a reduction in operative time (slope [change in log operative time per one procedure increase in experience], -0.005; 95% CI, -0.009 to -0.0005; p = 0.0292). For every one additional PAO increase in experience, there was a 0.45% decrease in operative time (95% CI, 0.05%-0.86% decrease]. CONCLUSIONS: With a case exposure greater than 40 PAOs and progressive surgical responsibility during contemporary structured training, two young surgeons were able to perform PAO with a low risk of complications. However, even with that surgical experience before independent practice, surgical time decreased over the first 40 PAOs they performed independently. Our data may help guide orthopaedic residency and hip preservation fellowship programs in establishing training requirements and assessing competency in PAO. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 27495810 TI - Syndromic anorectal malformation associated with Holt-Oram syndrome, microcephaly, and bilateral corneal opacity: a case report. AB - BACKGROUND: The occurrence of an anorectal malformation with Holt-Oram syndrome, microcephaly, and bilateral corneal opacity is rare and to the best of our knowledge has not previously been reported in the literature. Hence, there is a need to document our experience in this case and learn as much as possible from it. CASE PRESENTATION: We present the case of a Nigerian female neonate with a postnatal diagnosis of syndromic anorectal malformation associated with Holt-Oram syndrome, microcephaly, and bilateral corneal opacity. The infant had successful staged correction of her anorectal malformation but developed a metastatic Wilms' tumor and died before other corrective procedures could be instituted. CONCLUSIONS: An anorectal malformation is here reported to occur with Holt-Oram syndrome, an association that has not been reported previously. To enhance the prognosis and quality of life of children with syndromic anorectal malformation, prenatal ultrasound monitoring of high-risk pregnancies and expertise in prenatal detection of congenital anomalies are invaluable in antenatal care. PMID- 27495811 TI - The Arabidopsis hnRNP-Q Protein LIF2 and the PRC1 Subunit LHP1 Function in Concert to Regulate the Transcription of Stress-Responsive Genes. AB - LHP1-INTERACTING FACTOR2 (LIF2), a heterogeneous nuclear ribonucleoprotein involved in Arabidopsis thaliana cell fate and stress responses, interacts with LIKE HETEROCHROMATIN PROTEIN1 (LHP1), a Polycomb Repressive Complex1 subunit. To investigate LIF2-LHP1 functional interplay, we mapped their genome-wide distributions in wild-type, lif2, and lhp1 backgrounds, under standard and stress conditions. Interestingly, LHP1-targeted regions form local clusters, suggesting an underlying functional organization of the plant genome. Regions targeted by both LIF2 and LHP1 were enriched in stress-responsive genes, the H2A.Z histone variant, and antagonistic histone marks. We identified specific motifs within the targeted regions, including a G-box-like motif, a GAGA motif, and a telo-box. LIF2 and LHP1 can operate both antagonistically and synergistically. In response to methyl jasmonate treatment, LIF2 was rapidly recruited to chromatin, where it mediated transcriptional gene activation. Thus, LIF2 and LHP1 participate in transcriptional switches in stress-response pathways. PMID- 27495813 TI - Understanding patterns and factors associated with place of death in patients with end-stage kidney disease: A retrospective cohort study. AB - BACKGROUND: Meeting place-of-death preferences is an important measure of the quality of end-of-life care. Systematic review shows that 42% of end-stage kidney disease patients prefer home death. Little research has been undertaken on place of death. AIM: To understand patterns of place of death in patients with end stage kidney disease known in one UK renal unit. DESIGN: A retrospective cohort study of all patients with chronic kidney disease stage 4-5, age ?75 and known to one UK renal unit, who died between 2006 and 2012. Patients were categorised into three management pathways: haemodialysis, conservative and pre-dialysis. RESULTS: A total of 321 patients (mean age, 82.7; standard deviation, 5.21) died (61.7% male). In all, 62.9% died in hospital (95% confidence interval, 57.5%-68.1%), 21.8% died in their usual place of residence (95% confidence interval, 17.5% 26.6%) and 15.3% died in an inpatient palliative care unit (95% confidence interval, 11.6%-19.5%). Management pathway and living circumstances were most strongly associated with place of death. Patients on the conservative pathway had four times the odds of dying out of hospital (odds ratio, 4.0; 95% confidence interval, 2.1-7.5; p < 0.01). Patients living alone were less likely to die out of hospital (odds ratio, 0.3; 95% confidence interval, 0.1-0.6; p < 0.01). There were also changes in place of death over time, with more patients dying out of hospital in 2012 compared to 2006 (odds ratio, 3.1; 95% confidence interval, 1.0 9.7; p < 0.05). CONCLUSION: Most patients with end-stage kidney disease die in hospital, but patients managed without dialysis are significantly more likely to die outside of hospital. Planning ahead is key to be able to meet preference for place of death. PMID- 27495812 TI - FYVE1/FREE1 Interacts with the PYL4 ABA Receptor and Mediates Its Delivery to the Vacuolar Degradation Pathway. AB - Recently, we described the ubiquitylation of PYL4 and PYR1 by the RING E3 ubiquitin ligase RSL1 at the plasma membrane of Arabidopsis thaliana This suggested that ubiquitylated abscisic acid (ABA) receptors might be targeted to the vacuolar degradation pathway because such ubiquitylation is usually an internalization signal for the endocytic route. Here, we show that FYVE1 (previously termed FREE1), a recently described component of the endosomal sorting complex required for transport (ESCRT) machinery, interacted with RSL1 receptor complexes and recruited PYL4 to endosomal compartments. Although the ESCRT pathway has been assumed to be reserved for integral membrane proteins, we show the involvement of this pathway in the degradation of ABA receptors, which can be associated with membranes but are not integral membrane proteins. Knockdown fyve1 alleles are hypersensitive to ABA, illustrating the biological relevance of the ESCRT pathway for the modulation of ABA signaling. In addition, fyve1 mutants are impaired in the targeting of ABA receptors for vacuolar degradation, leading to increased accumulation of PYL4 and an enhanced response to ABA Pharmacological and genetic approaches revealed a dynamic turnover of ABA receptors from the plasma membrane to the endosomal/vacuolar degradation pathway, which was mediated by FYVE1 and was dependent on RSL1. This process involves clathrin-mediated endocytosis and trafficking of PYL4 through the ESCRT pathway, which helps to regulate the turnover of ABA receptors and attenuate ABA signaling. PMID- 27495814 TI - Experiences of patients and caregivers with early palliative care: A qualitative study. AB - BACKGROUND: Early palliative care improves quality of life and satisfaction with care and is increasingly endorsed for patients with advanced cancer. However, little is known about the experience of receiving early palliative care from a patient and caregiver perspective. AIM: The aim of this qualitative study was to determine, from a participant perspective, the experience of receiving early palliative care and elements of that care. DESIGN: Qualitative grounded theory study using individual interviews. SETTING/PARTICIPANTS: The study took place at a comprehensive cancer centre. Patients ( n = 26) and caregivers ( n = 14) from the intervention arm of a cluster-randomised controlled trial of early palliative care versus standard oncology care participated in qualitative interviews. Participants were asked to comment on their quality of life, the quality of care provided over the intervention period and their experiences with the palliative care team. RESULTS: Participants described feeling supported and guided in their illness experience and in their navigation of the healthcare system. Specific elements of early palliative care included prompt, personalised symptom management; holistic support for patients and caregivers; guidance in decision making; and preparation for the future. Patients with symptoms particularly valued prompt attention to their physical concerns, while those without symptoms valued other elements of care. Although three patients were ambivalent about their current need for palliative care, no distress was reported as a consequence of the intervention. CONCLUSION: The elements of care described by participants may be used to develop, support and refine models of early palliative care for patients with cancer. PMID- 27495815 TI - Survival is associated with complete response on MRI after neoadjuvant chemotherapy in ER-positive HER2-negative breast cancer. AB - BACKGROUND: Pathological complete remission (pCR) of estrogen receptor (ER) positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer is rarely achieved after neoadjuvant chemotherapy (NAC). In addition, the prognostic value of pCR for this breast cancer subtype is limited. We explored whether response evaluation by magnetic resonance imaging (MRI) is associated with recurrence-free survival after NAC in ER-positive/HER2-negative breast cancer. METHODS: MRI examinations were performed in 272 women with ER positive/HER2-negative breast cancer before, during and after NAC. MRI interpretation included lesion morphology at baseline, changes in morphology and size, and contrast uptake kinetics. These MRI features, clinical characteristics and final pathology were correlated with recurrence-free survival. RESULTS: The median follow up time was 41 months. There were 35 women with events, including 19 breast-cancer-related deaths. On multivariable analysis, age younger than 50 years (hazard ratio (HR) = 2.55, 95 % confidence interval (CI) 1.3, 5.02, p = 0.007), radiological complete response after NAC (HR = 14.11, CI 1.81, 1818; p = 0.006) and smaller diameters of washout/plateau enhancement at MRI after NAC (HR = 1.02, CI 1.00, 1.04, p = 0.036) were independently associated with best recurrence-free survival. Pathological response was not significant; HR = 2.12, CI 0.86, 4.64, p = 0.096. CONCLUSIONS: MRI after NAC in ER-positive/HER2-negative tumors may be predictive of recurrence-free survival. A radiological complete response at MRI after NAC is associated with an excellent prognosis. PMID- 27495816 TI - Functional Neurologic Outcomes Change Over the First 6 Months After Cardiac Arrest. AB - OBJECTIVES: To determine the longitudinal changes in functional outcome and compare ordinal outcome scale assessments in comatose cardiac arrest survivors. DESIGN: Prospective observational study of comatose cardiac arrest survivors. Subjects who survived to 1 month were included. SETTING: Academic medical center ICU. PATIENTS: Ninety-eight consecutive patients who remained comatose after resuscitation from cardiac arrest; 45 patients survived to 1 month. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients' functional neurologic outcomes were assessed by phone call or in-person clinic visit at 1, 3, 6, and 12 months postcardiac arrest using the modified Rankin Scale, Glasgow Outcome Scale, and Barthel Index. A "good" outcome was defined as modified Rankin Scale 0-3, Barthel Index 70-100, and Glasgow Outcome Scale 4-5. Changes in dichotomized outcomes and shifts on each outcome scale were analyzed. The mean age of survivors was 51 +/- 19 years and 18 (40%) were women. Five (19%) out of 26 patients with data available at all timepoints improved to good modified Rankin Scale outcome and none worsened to poor outcome between postarrest months 1 and 6 (p = 0.06). Thirteen patients (50%) improved on the modified Rankin Scale by 1-3 points and four (15%) worsened by 1-2 points between months 1 and 6 (overall improvement by 0.5 points; 95% CI, 0-1; p = 0.04). From postarrest months 6 to 12, there was no change in the number of patients with good versus poor outcomes. The modified Rankin Scale and Barthel Index were more sensitive to detecting changes in outcome than the Glasgow Outcome Scale. CONCLUSIONS: In initially comatose cardiac arrest survivors, improvements in functional status occur over the first 6 months after the event. There was no significant change in outcome between postarrest months 6 and 12. The modified Rankin Scale is a sensitive outcome scale in this population. PMID- 27495817 TI - Academic Productivity of Accreditation Council for Graduate Medical Education Accredited Critical Care Fellowship Program Directors. AB - OBJECTIVES: Academic productivity is an expectation for program directors of Accreditation Council for Graduate Medical Education-accredited subspecialty programs in critical care medicine. Within the adult critical care Accreditation Council for Graduate Medical Education-accredited programs, we hypothesized that program director length of time from subspecialty critical care certification would correlate positively with academic productivity, and primary field would impact academic productivity. DESIGN: This study received Institutional Review Board exemption from the University of Florida. Data were obtained from public websites on program directors from all institutions that had surgery, anesthesiology, and pulmonary Accreditation Council for Graduate Medical Education-accredited subspecialty critical care training programs during calendar year 2012. Information gathered included year of board certification and appointment to program director, academic rank, National Institutes of Health funding history, and PubMed citations. RESULTS: Specialty area was significantly associated with total (all types of publications) (p = 0.0002), recent (p < 0.0001), last author (p = 0.008), and original research publications (p < 0.0001), even after accounting for academic rank, years certified, and as a program director. These differences were most prominent in full professors, with surgery full professors having more total, recent, last author, and original research publications than full professors in the other critical care specialties. CONCLUSIONS: This study demonstrates that one's specialty area in critical care is an independent predictor of academic productivity, with surgery having the highest productivity. For some metrics, such as total and last author publications, surgery had more publications than both anesthesiology and pulmonary, whereas there was no difference between the latter groups. This suggests that observed differences in academic productivity vary by specialty. PMID- 27495818 TI - Prognostic Impact of Persistent Thrombocytopenia During Extracorporeal Membrane Oxygenation: A Retrospective Analysis of Prospectively Collected Data From a Cohort of Patients With Left Ventricular Dysfunction After Cardiac Surgery. AB - OBJECTIVE: The prognostic impact of thrombocytopenia in patients supported by extracorporeal membrane oxygenation after cardiac surgery is uncertain. We investigated whether thrombocytopenia is independently predictive of poor outcome and describe the incidence and time course of thrombocytopenia in extracorporeal membrane oxygenation patients. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Cardiosurgical ICU at a tertiary referral center. PATIENTS: Three hundred adult patients supported with venoarterial extracorporeal membrane oxygenation for more than 24 hours because of refractory cardiogenic shock after heart surgery between January 2001 and December 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-way analysis of variance was used to compare the time course of platelet count changes between survivors and nonsurvivors. Using multiple Cox regression with time-dependent covariates, we investigated the impact of platelet count on 90-day mortality. In nonsurvivors, the daily incidence of moderate (< 100 - 50 * 10/L), severe (49 - 20 * 10/L), and very severe (< 20 * 10/L) thrombocytopenia was 50%, 54%, and 7%, respectively. Platelet count had a biphasic temporal pattern with an initial decrease until day 4-5 after the initiation of extracorporeal membrane oxygenation. Although a significant recovery of the platelet count was observed in survivors, a recovery did not occur in nonsurvivors (p = 0.0001). After adjusting for suspected confounders, moderate, severe, and very severe thrombocytopenia were independently associated with 90-day mortality. The highest risk was associated with severe (hazard ratio, 5.9 [2.7-12.6]; p < 0.0001) and very severe thrombocytopenia (hazard ratio, 25.9 [10.7-62.9], p < 0.0001). CONCLUSION: Thrombocytopenia is an independent risk factor for poor outcome in extracorporeal membrane oxygenation patients after cardiac surgery, with persistent severe thrombocytopenia likely reflecting a high degree of physiologic imbalance. PMID- 27495819 TI - Visual Fixation in the ICU: A Strong Predictor of Long-Term Recovery After Moderate-to-Severe Traumatic Brain Injury. AB - OBJECTIVE: Posttraumatic amnesia is superior to the initial Glasgow Coma Scale score for predicting traumatic brain injury recovery, but it takes days/weeks to assess. Here, we examined whether return of visual fixation-a potential marker of higher cognitive function-within 24 hours of ICU admission could be used as an early predictor of traumatic brain injury recovery. DESIGN: Two-phase cohort study. SETTING: Level-I trauma ICU. PATIENTS: Moderate-to-severe traumatic brain injury discharged alive between 2010 and 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Return of visual fixation was assessed through standard behavioral assessments in 181 traumatic brain injury patients who had lost the ability to fixate at ICU admission (phase 1) and compared with posttraumatic amnesia duration and the initial Glasgow Coma Scale score to predict performance on the Glasgow Outcome Scale-Extended 10-40 months after injury (n = 144; phase 2a). A subgroup also completed a visual attention task (n = 35; phase 2b) and a brain MRI after traumatic brain injury (n = 23; phase 2c). With an area under the curve equal to 0.85, presence/absence of visual fixation at 24 hours of ICU admission was found as performant as posttraumatic amnesia (area under the curve, 0.81; difference between area under the curve, 0.04; p = 0.28) for predicting patients' Glasgow Outcome Scale-Extended score. Conversely, the initial Glasgow Coma Scale score was not (area under the curve, 0.63). Even when controlling for age/medication/CT scan findings, fixation remained a significant predictor of Glasgow Outcome Scale-Extended scores (beta, -0.29; p < 0.05). Poorer attention performances and greater regional brain volume deficits were also observed in patients who could not fixate at 24 hours of ICU admission versus those who could. CONCLUSIONS: Visual fixation within 24 hours of ICU admission could be as performant as posttraumatic amnesia for predicting traumatic brain injury recovery, introducing a new variable of interest in traumatic brain injury outcome research. PMID- 27495820 TI - Lactated Ringer Is Associated With Reduced Mortality and Less Acute Kidney Injury in Critically Ill Patients: A Retrospective Cohort Analysis. AB - OBJECTIVES: To assess the impact of the percentage of fluid infused as Lactated Ringer (%LR) during the first 2 days of ICU admission in hospital mortality and occurrence of acute kidney injury. DESIGN: Retrospective cohort. SETTING: Analysis of a large public database (Multiparameter Intelligent Monitoring in Intensive Care-II). PATIENTS: Adult patients with at least 2 days of ICU stay, admission creatinine lower than 5 mg/dL, and that received at least 500 mL of fluid in the first 48 hours. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: 10,249 patients were included in mortality analysis and 8,085 were included in the acute kidney injury analysis. For acute kidney injury analysis, we excluded patients achieving acute kidney injury criteria in the first 2 days of ICU stay. Acute kidney injury was defined as stage 2/3 Kidney Disease: Improving Global Outcomes creatinine criteria and was assessed from days 3-7. The effects of %LR in both outcomes were assessed through logistic regression controlling for confounders. Principal component analysis was applied to assess the effect of volume of each fluid type on mortality. Higher %LR was associated with lower mortality and less acute kidney injury. %LR effect increased with total volume of fluid infused. For patients in the fourth quartile of fluid volume (> 7 L), the odds ratio for mortality for %LR equal to 75% versus %LR equal to 25% was 0.50 (95% CI, 0.32-0.79; p < 0.001). Principal component analysis suggested that volume of Lactated Ringer and 0.9% saline infused had opposite effects in outcome, favoring Lactated Ringer. CONCLUSIONS: Higher %LR was associated with reduced hospital mortality and with less acute kidney injury from days 3-7 after ICU admission. The association between %LR and mortality was influenced by the total volume of fluids infused. PMID- 27495821 TI - The Role of kappa Opioid Receptor in Brain Ischemia. AB - OBJECTIVES: Our previous studies indicated that highly selective kappa opioid receptor agonists could protect the brain, indicating an important role of kappa opioid receptor agonist in brain ischemia. In this study, we investigated the role and related mechanisms of kappa opioid receptor agonists in brain ischemia in a middle cerebral artery occlusion mouse model. DESIGN: Animal model. SETTING: Laboratory. SUBJECTS: The middle cerebral artery occlusion model was established by 120 minutes of ischemia followed by 24-hour reperfusion in male adult mice. INTERVENTIONS: Various doses of salvinorin A, a highly selective and potent kappa opioid receptor agonist, were administered intranasally 10 minutes after initiation of reperfusion. Norbinaltorphimine (2.5 mg/kg, IP) as a kappa opioid receptor antagonist was administered in one group before administration of salvinorin A (50MUg/kg) to investigate the specific role of kappa opioid receptor. MEASUREMENTS AND MAIN RESULTS: Infarct volume, kappa opioid receptor expression, and Evans blue extravasation in the brain, and neurobehavioral outcome were determined. Immunohistochemistry and western blot were performed to detect the activated caspase-3, interleukin-10, and tumor necrosis factor-alpha levels to investigate the role of apoptosis and inflammation. kappa opioid receptor expression was elevated significantly in the ischemic penumbral area compared with that in the nonischemic area. Salvinorin A reduced infarct volume and improved neurologic deficits dose-dependently. Salvinorin A at the dose of 50 MUg/kg reduced Evans blue extravasation, suggesting reduced impairment of the blood-brain barrier and decreased the expression of cleaved caspase-3, interleukin-10, and tumor necrosis factor-alpha in the penumbral areas. All these changes were blocked or alleviated by norbinaltorphimine. CONCLUSIONS: kappa opioid receptors were up-regulated and played a critical role in brain ischemia and reperfusion. kappa opioid receptor activation could potentially protect the brain and improve neurologic outcome via blood-brain barrier protection, apoptosis reduction, and inflammation inhibition. PMID- 27495822 TI - Visual system for communicating quality of evidence and strength of recommendations. PMID- 27495823 TI - Prospective cohort study of pregnant Brazilian women elucidates link between Zika virus infection and fetal abnormalities. PMID- 27495824 TI - Sedation during bronchoscopy: data from a nationwide sedation and monitoring survey. AB - BACKGROUND: There is limited knowledge on practice patterns in procedural sedation and analgesia (PSA), the use of propofol, and monitoring during flexible bronchoscopy (FB). The purpose of this study was to assess the current practice patterns of FBs and to focus on the use of propofol, the education of the proceduralist, and the involvement of anaesthesiologists during FB. METHODS: An anonymous questionnaire was sent to 299 pulmonologists. Only respondents who were active physicians in adult respiratory medicine performing FB were subsequently analysed. RESULTS: The response rate was 78 % and 27,149 FB in the previous 12 months were analysed. The overall sedation-related morbidity rate was 0.02 % and mortality was 7/100'000 FB. Sedation was used in 95 % of bronchoscopies. The main drugs used for PSA were propofol (77 %) and midazolam (46 %). In 84 % of PSAs propofol was used without the attendance of an anaesthesiologist. The use of propofol was associated with high volume bronchoscopists (p < 0.010) and career young pulmonologists (p < 0.001). While monitoring vital parameters has become standard practice, pulmonologists reported a very low rate of systematic basic education and training in the field of PSA (50 %). CONCLUSIONS: In Switzerland, PSA during FB is mostly performed with propofol without the attendance of an anaesthesiologist and the use of this drug is expected to increase in the future. While monitoring standards are very high there is need for policies to improve education, systematic training, and support for pulmonologists for PSA during FB. PMID- 27495825 TI - RIFM fragrance ingredient safety assessment, Isopulegol, CAS Registry Number 89 79-2. AB - This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data show that this material is not genotoxic nor does it have skin sensitization potential. The repeated dose, developmental and reproductive, and local respiratory toxicity endpoints were completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (0.03, 0.03 mg/kg/day and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework. PMID- 27495826 TI - In vitro toxicity of reuterin, a potential food biopreservative. AB - Reuterin has a high potential as a food preservative due to both its chemical characteristics and its antimicrobial activity against food-borne pathogens and spoilage bacteria. However, there is a lack of information about its toxicity and its capacity to interfere with the metabolism of drugs by inhibiting cytochrome P450 (CYP) activity. The results of this study indicated that reuterin exhibited a moderate cytotoxicity in the human hepatoma cell line HepG2 according to assays measuring three different endpoints in the same set of cells. Reuterin was much less toxic than acrolein and only four times more toxic than diacetyl, a generally recognized as safe flavoring compound. In vitro experiments utilizing human liver microsomes showed that reuterin presents low possibility of displaying in vivo drug interactions by inhibition of CYP3A4, CYP2D6, and CYP2C9. Therefore, reuterin can be considered a promising food biopreservative, although additional toxicology research is needed before permission for use can be granted. PMID- 27495827 TI - Parsing polyphyletic Pueraria: Delimiting distinct evolutionary lineages through phylogeny. AB - Several taxonomic and phylogenetic studies have hypothesized polyphyly within Pueraria DC., a genus comprising 19 species (24 with varieties) including the highly invasive Pueraria montana var. lobata (Kudzu) introduced to the U.S.A. about 150years ago. Previous efforts to investigate monophyly of the genus have been hampered by limited taxon sampling or a lack of comprehensive evolutionary context that would enable definitive taxonomic associations. This work presents a comprehensive phylogenetic investigation of Pueraria within the context of tribe Phaseoleae (Leguminosae). Polyphyly was found to be more extensive than previously thought, with five distinct lineages spread across the tribe and spanning over 25mya of divergence strongly supported by two chloroplast and one nuclear marker, AS2, presented here as a phylogenetic marker for the first time. Our phylogenies support taxonomic revisions to rectify polyphyly within Pueraria, including the resurrection of Neustanthus, moving one species to Teyleria, and the creation of two new genera, Haymondia and Toxicopueraria (taxonomic revisions published elsewhere). PMID- 27495828 TI - Subjective sleep measures for adolescents: a systematic review. AB - BACKGROUND: Sleep disturbances in adolescents have received significant attention because of their high prevalence and the negative health outcomes. Relative to objective measures, subjective sleep instruments have been the most practical tools used to identify sleep problems and assess responses to interventions in research and clinical settings. This systematic review aims to examine the psychometric properties of subjective measures that are used to assess sleep quality and disturbances among adolescents, identify the strength and limitation of each measurement and inform recommendations for practice. METHODS: PubMed, Embase and PsycInfo were searched from 2000 through May 2016. The reference lists of important articles were included if they met the inclusion criteria. The available measures were evaluated and classified as positive, intermediate or poor according to the quality criteria for health status questionnaires. RESULTS: Thirteen self-reported or parent-reported sleep measures met the inclusion criteria. Of the measurements reviewed, six were generic instruments assessing overall sleep quality and disturbances; five were dimension-specific instruments measuring daytime sleepiness, sleep insufficiency and sleep hygiene; and two were condition-specific instruments for insomnia. None of the subjective sleep measures for adolescents has a psychometric profile with all essential measurement properties. Specifically, the generic sleep measurements capture multiple dimensions but face issues of participant burden and compatibility. Among the domain-specific tools, the Cleveland Adolescent Sleepiness Questionnaire and the Chronic Sleep Reduction Questionnaire have achieved good psychometric merits but need further evaluation for responsiveness. Likewise, essential measurement properties of condition-specific tools for insomnia have yet to be established. CONCLUSIONS: Because of the limited evidence, no definite recommendations can be made at this point. However, each available measurement has its own uniqueness and strength despite the limitations. Future research on measurement development and evaluation for adolescent sleep is needed to ensure the relevance and suitability to different stages of adolescence and social contexts. PMID- 27495829 TI - Atherosclerotic Surrogate Markers in Adults With Down Syndrome: A Case-Control Study. AB - The authors aimed to compare surrogate markers of atherosclerosis (pulse wave velocity, intima-media thickness) between adults with and without Down syndrome (DS) and to assess the impact of parathyroid hormone levels and classic cardiovascular risk factors on arterial stiffness. After comparing 51 adults with DS and 51 healthy adults (siblings of DS individuals), the authors found that adults with DS seem to have lower arterial stiffness, as a result of chronic hypotension. Subclinical atherosclerosis parameters do not correlate with traditional cardiovascular risk factors in adults with DS, thus raising the hypothesis that classic predictive models for cardiovascular disease are not valid in this population. Hyperparathyroidism could play an important role in arterial damage in these individuals. The lower than expected prevalence of obesity and dyslipidemia could be explained by better eating habits, with this study being the first to address the anthropometric and clinical profile of a Mediterranean cohort of adults with DS. PMID- 27495830 TI - [Direct service costs of diabetes mellitus hospitalisations in the Mexican Institute of Social Security]. AB - OBJECTIVE: To estimate the direct costs related to hospitalizations for diabetes mellitus and its complications in the Mexican Institute of Social Security METHODS: The hospital care costs of patients with diabetes mellitus using diagnosis-related groups in the IMSS (Mexican Institute of Social Security) and the hospital discharges from the corresponding E10-E14 codes for diabetes mellitus were estimated between 2008-2013. Costs were grouped according to demographic characteristics and main condition, and were estimated in US dollars in 2013. RESULTS: 411,302 diabetes mellitus discharges were recorded, representing a cost of $1,563 million. 52.44% of hospital discharges were men and 77.26% were for type 2 diabetes mellitus. The biggest cost was attributed to peripheral circulatory complications (34.84%) and people from 45-64 years of age (47.1%). Discharges decreased by 3.84% and total costs by 1.75% in the period analysed. The complications that caused the biggest cost variations were ketoacidosis (50.7%), ophthalmic (22.6%) and circulatory (18.81%). CONCLUSIONS: Hospital care for diabetes mellitus represents an important financial challenge for the IMSS. The increase in the frequency of hospitalisations in the productive age group, which affects society as a whole, is an even bigger challenge, and suggests the need to strengthen monitoring of diabetics in order to prevent complications that require hospital care. PMID- 27495831 TI - Predictors of Occult Atrial Fibrillation in One Hundred Seventy-One Patients with Cryptogenic Transient Ischemic Attack and Minor Stroke. AB - BACKGROUND AND OBJECTIVE: Recent randomized studies have shown the potential of prolonged cardiac rhythm monitoring to detect silent paroxysmal atrial fibrillation (PAF) in patients with cryptogenic stroke. Our aim was to identify clinical and magnetic resonance imaging (MRI) factors that predict the detection of PAF during long-duration rhythm cardiac Holter (LDRCH) monitoring. METHODS: A retrospective analysis was performed using data from 171 patients with cryptogenic stroke or transient ischemic attack who underwent LDRCH monitoring (i.e., 21 days) from 2009 to 2013. Clinical, echocardiographic, and imaging predictors of atrial fibrillation (AF) were determined by multivariable analysis. RESULTS: PAF lasting more than or equal to 30 seconds was diagnosed in 26 of 171 (15%) patients. Median delay to first detected AF episode was 7 (interquartile range: 2-13) days. Four factors were independently predictive of PAF detection on LDRCH: age more than 70 years (odds ratio [OR], 4.6; 95% confidence interval [CI], 1.5-13.8); premature atrial complex on electrocardiogram (OR, 4.6; 95% CI, 1.1-19.6); left ventricular hypertrophy on transthoracic echocardiography (OR, 6.4, 95% CI, 1.6-26.4); and previous white matter lesions on brain MRI (OR, 4.2; 95% CI, 1.2-15.6). Recent brain infarction pattern on diffusion-weighted imaging was not associated with PAF detection on LDRCH. CONCLUSION: LDRCH is a noninvasive and inexpensive test with a high rate of AF detection in patients with cryptogenic stroke or transient ischemic attack. Occult PAF was more commonly diagnosed in older patients with premature atrial complex on the baseline electrocardiogram, left ventricular hypertrophy on echocardiography, and with previous white matter lesions on brain MRI. PMID- 27495832 TI - COA-Cl, a Novel Synthesized Nucleoside Analog, Exerts Neuroprotective Effects in the Acute Phase of Intracerebral Hemorrhage. AB - BACKGROUND: A previous study in our laboratory showed the neuroprotective effects of COA-Cl, a novel synthesized adenosine analog, in a rat cerebral ischemia model. The purpose of the present study was to evaluate the neuroprotective effects of COA-Cl in intracerebral hemorrhage (ICH), another common type of stroke, and investigate potential mechanisms of action. METHODS: Adult Sprague Dawley rats received an injection of 100 ul autologous whole blood into the right basal ganglia. COA-Cl (30 ug/kg) was injected intracerebroventricularly 10 minutes after ICH. A battery of motor deficit tests were performed at 1 day, 3 days, 5 days, and 7 days after ICH. To investigate the mechanism of action, brain water content, TUNEL staining and 8-OHdG immunostaining, and ELISA (to assess oxidative stress) were used. RESULTS: COA-Cl treatment significantly attenuated sensorimotor deficits and reduced brain edema 1 day after ICH. Furthermore, the numbers of perihematomal TUNEL- and 8-OHdG-positive cells were significantly decreased in COA-Cl treated ICH rats. CONCLUSIONS: These results indicate that COA-Cl has neuroprotective effects in ICH. Furthermore, our study provides evidence that COA-Cl may reduce oxidative stress, which may be one mechanism underlying its neuroprotective effects. PMID- 27495833 TI - Intravenous Thrombolysis and Passes of Thrombectomy as Predictors for Endovascular Revascularization in Ischemic Stroke. AB - BACKGROUND: Patient selection for endovascular revascularization treatment (ERT) in acute ischemic stroke depends on the expected benefit-risk ratio. As rapid revascularization is a major determinant of good functional outcome, we aimed to identify its predictors after ERT. METHODS: Consecutive stroke patients from a single stroke center with distal internal carotid artery-, proximal middle cerebral artery- or T-occlusions treated with ERT were retrospectively selected. We assessed admission noncontrast computed tomography and computed tomography angiography for thrombus location, thrombus load (clot burden score), and collateral status. Clinical data were extracted from medical charts. Univariate and multivariate regression analyses were performed to identify predictors of revascularization (thrombolysis in cerebral infarction >=2b) after ERT. RESULTS: A total of 63 patients were identified (median age, 73 years; interquartile range: 62-77; 40 females). Sixteen patients (25.4%) underwent intravenous thrombolysis (ivT) before ERT. Twenty-two patients (34.9%) had additional intra arterial application of recombinant tissue plasminogen activator. The overall recanalization rate was 66.7%, and 9.5% had symptomatic intracranial bleeding. In hospital mortality was 15%, and 30% reached good functional outcome at discharge. In the univariate analysis, preceding ivT and the number of passes for thrombectomy (dichotomized <=2 versus >2) were associated with recanalization. There was a trend for number of thrombectomy passes (as continuous variable) and multimodal ERT. In the multivariate regression analysis, ivT prior to ERT and passes of thrombectomy were identified as independent predictors for recanalization. CONCLUSION: ivT and lower passes of thrombectomy are associated with recanalization after ERT for ischemic stroke with proximal vessel occlusions. PMID- 27495834 TI - How Commonly Is Stroke Found in Patients with Isolated Vertigo or Dizziness Attack? AB - BACKGROUND: The sudden development of vertigo or dizziness without focal neurological symptoms is generally attributable to vestibular diseases such as benign paroxysmal positional vertigo. Isolated vertigo or dizziness attack needs more attention than vestibular diseases. This retrospective study was performed to elucidate the frequency of strokes in patients with isolated vertigo or dizziness attack. SUBJECTS AND METHODS: We enrolled 221 patients (men, 119; women, 102; mean age, 68.4 +/- 10.3 years) who were admitted to our hospital over the last 10 years because of sudden isolated vertigo or dizziness attack without other neurological symptoms except for nystagmus, deafness, or tinnitus. We investigated the clinical features, final diagnosis, neuroimaging findings, and short- or long-term outcome of these patients. RESULTS: One hundred eighteen patients had vertigo whereas the other 103 had dizziness. Brain computed tomography or magnetic resonance imaging revealed recent stroke lesions in 25 patients (11.3%) (ischemic, 21; hemorrhagic, 4).The lesions were generally small and localized in the cerebellum (n = 21), pons (n = 1), medulla oblongata (n = 1), or corona radiata (n = 1). Of the 25 patients, 19 (76%) had dizzy-type spells; none had neurological dysfunction at the time of discharge. In the remaining 196 patients, no stroke was detected on computed tomography or magnetic resonance imaging. CONCLUSIONS: Stroke was found in 11% of patients with isolated vertigo or dizziness attack. The posterior inferior cerebellar artery area was the most frequently implicated for isolated vertigo or dizziness. PMID- 27495835 TI - Anticancer activity of gallic acid template-based benzylidene indanone derivative as microtubule destabilizer. AB - Benzylidene indanones have been designed and synthesized from gallic acid, a plant phenolic acid as possible anticancer agent. The best analogue of the series, that is, 3-(3',4',5'-trimethoxyphenyl)-4,5,6-trimethoxy-2-(4" nitrobenzylidene)-indan-1-one (8) exhibited potent cytotoxicity (IC50 =3-10 MUm) against several human cancer cell lines through microtubule destabilization (IC50 =1.54 MUm) after occupying colchicine-binding site of beta-tubulin. In cell cycle analysis, compound 8 exerted G2/M phase arrest in both MCF-7 and MDA-MB-231 cells and induced apoptosis. It reduced 34.8% solid tumor in in vivo Ehrlich ascite carcinoma in Swiss albino mice at 30 mg/kg dose. In acute oral toxicity experiment, it was tolerable up to 300 mg/kg doses in Swiss albino mice. The lead compound 8 needs to be optimized for better activity. PMID- 27495836 TI - A radiosensitizing effect of RAD51 inhibition in glioblastoma stem-like cells. AB - BACKGROUND: Radioresistant glioblastoma stem cells (GSCs) contribute to tumor recurrence and identification of the molecular targets involved in radioresistance mechanisms is likely to enhance therapeutic efficacy. This study analyzed the DNA damage response following ionizing radiation (IR) in 10 GSC lines derived from patients. METHODS: DNA damage was quantified by Comet assay and DNA repair effectors were assessed by Low Density Array. The effect of RAD51 inhibitor, RI-1, was evaluated by comet and annexin V assays. RESULTS: While all GSC lines displayed efficient DNA repair machinery following ionizing radiation, our results demonstrated heterogeneous responses within two distinct groups showing different intrinsic radioresistance, up to 4Gy for group 1 and up to 8Gy for group 2. Radioresistant cell group 2 (comprising 5 out of 10 GSCs) showed significantly higher RAD51 expression after IR. In these cells, inhibition of RAD51 prevented DNA repair up to 180 min after IR and induced apoptosis. In addition, RAD51 protein expression in glioblastoma seems to be associated with poor progression-free survival. CONCLUSION: These results underscore the importance of RAD51 in radioresistance of GSCs. RAD51 inhibition could be a therapeutic strategy helping to treat a significant number of glioblastoma, in combination with radiotherapy. PMID- 27495837 TI - Gender Differences in Mobility Device Use Among U.S. Older Adults. AB - Objectives: Research has shown greater mobility limitations among women than men. We aimed to examine (a) gender differences in the use of canes for mobility and (b) what factors contribute to these differences under the frameworks of the disablement model and the Theory of Planned Behavior. Method: Using National Health and Aging Trends Study data, we estimated hierarchical logistic regression models to predict the likelihood of cane use among older adults who completed performance-based measures (n = 5,503). We tested the interactions between gender and selected variables to further understand gender difference. Results: In unadjusted analysis, 22% of women and 16% of men used canes. In models adjusted in steps for sociodemographics, health, physical impairments, capacity, psychosocial, and social environment factors, women were progressively less likely to use canes, significantly so at the last step. Suppression effect analyses showed the influence of living alone and receiving mobility help variables. Interaction analyses showed that women reporting poor health or balance were less likely to use canes; obese women were more likely. Discussion: Significant gender differences exist in cane use among older community-living adults. Findings suggest that health and function partly account for these differences. Future research is needed to understand social/cultural factors involved. PMID- 27495838 TI - Rapid detection of G6PD mutations by multicolor melting curve analysis. AB - The MeltPro G6PD assay is the first commercial genetic test for glucose-6 phosphate dehydrogenase (G6PD) deficiency. This multicolor melting curve analysis based real-time PCR assay is designed to genotype 16 G6PD mutations prevalent in the Chinese population. We comprehensively evaluated both the analytical and clinical performances of this assay. All 16 mutations were accurately genotyped, and the standard deviation of the measured Tm was <0.3 degrees C. The limit of detection was 1.0ng/MUL human genomic DNA. The assay could be run on four mainstream models of real-time PCR machines. The shortest running time (150min) was obtained with LightCycler 480 II. A clinical study using 763 samples collected from three hospitals indicated that, of 433 samples with reduced G6PD activity, the MeltPro assay identified 423 samples as mutant, yielding a clinical sensitivity of 97.7% (423/433). Of the 117 male samples with normal G6PD activity, the MeltPro assay confirmed that 116 samples were wild type, yielding a clinical specificity of 99.1% (116/117). Moreover, the MeltPro assay demonstrated 100% concordance with DNA sequencing for all targeted mutations. We concluded that the MeltPro G6PD assay is useful as a diagnostic or screening tool for G6PD deficiency in clinical settings. PMID- 27495839 TI - Practical methods for collecting Trichinella parasites and their excretory secretory products. AB - Trichinella is a unique nematode. Its developmental stages include adult worms, newborn larvae, and muscle larvae. Besides humans, the parasite also infects many kinds of animals, including mice. Mice are widely used as an animal model in the research fields of immunology, cell biology, and host-parasite relationships of trichinellosis. The different developmental stages of Trichinella share similar, but unique characteristics. Therefore, it is important to collect different sources of Trichinella-derived materials for research with appropriate methods. In the present study, we introduce methods to collect Trichinella at different stages as well as their ES products. By optimizing the concentration of artificial gastric juice, volume of medium, and time of incubation for ES collection in vitro, muscle larvae, adult worms, and newborn larvae were collected with less contamination by host materials, and the ES products collected were confirmed to be originally antigenic and biologically active. The DNA, RNA, and proteins isolated from the parasites collected were confirmed to be applicable to analyses, including PCR, real-time PCR, Western blotting, and stimulators of cell cultures (macrophages, splenocytes, and tumor cells). The present study compiled protocols to collect materials from Trichinella and provides a reference for research on Trichinella. PMID- 27495840 TI - When Does Hearing Loss Occur in Vestibular Schwannoma Surgery? Importance of Auditory Brainstem Response Changes in Early Postoperative Phase. AB - OBJECTIVE: Some patients suffer postoperative hearing loss even when the intraoperative auditory brainstem response (ABR) is preserved during vestibular schwannomas surgery. This study was conducted to evaluate whether there are dynamic changes of the ABR after surgery. PATIENTS AND METHODS: In a prospective study from 2010-2012, 46 patients (24 female and 22 male) with vestibular schwannomas were investigated by intraoperative and postoperative ABR monitoring. Development of ABR quality during and after surgery (Class 1 normal, Class 5 complete loss) was correlated to auditory outcome. RESULTS: At the end of surgery, 17 patients had an ABR Class 1-4 and 29 had Class 5. Four hours after surgery, 9 of 23 (39%) patients showed an ABR quality change, and 24 hours after surgery, 15 of 30 (50%) had undergone ABR quality changes. Four different types of postoperative ABR courses could be distinguished-Course 1: stable with reproducible ABR, Course 2: unstable with reproducible ABR, Course 3: unstable with ABR loss, and Course 4: stable with ABR loss. These courses correlated highly significantly with the intraoperative development (P < 0.001) and with hearing outcome (P = 0.003). CONCLUSION: The study identifies ongoing changes of ABR quality and hearing function after the end of vestibular schwannoma surgery. Therefore it seems worthwhile to continue ABR monitoring in the postoperative phase in order to identify patients who are at risk of a secondary hearing deterioration and start therapeutic interventions in a timely manner. PMID- 27495841 TI - Complications in Endovascular Neurosurgery: Critical Analysis and Classification. AB - BACKGROUND: Precisely defining complications, which are used to measure overall quality, is necessary for critical review of delivery of care and quality improvement in endovascular neurosurgery, which lacks common definitions for complications. Furthermore, in endovascular interventions, events that may be labeled complications may not always negatively affect outcome. Our objective is to provide precise definitions for quality evaluation within endovascular neurosurgery. Thus, we propose an endovascular-specific classification system of complications based on our own patient series. METHODS: This single-center review included all patients who had endovascular interventions from September 2013 to August 2015. Complication types were analyzed, and a descriptive analysis was undertaken to calculate the incidence of complications overall and in each category. RESULTS: Two hundred and seventy-five endovascular interventions were performed in 245 patients (65% female; mean age, 55 years). Forty complications occurred in 39 patients (15%), most commonly during treatment of intracranial aneurysms (24/40). Mechanical complications (eg, device deployment, catheter, or closure device failure) occurred in 8/40, technical complications (eg, failure to deploy flow diverter, unintended embolization, air emboli, retroperitoneal hemorrhage, dissection) in 11/40, judgment errors (eg, patient or equipment selection) in 9/40, and critical events (eg, groin hematoma, hemorrhagic or thromboembolic complications) in 12/40 patients. Only 12/40 complications (30%) resulted in new neurologic deficits, vessel injury requiring surgery, or blood transfusion. CONCLUSIONS: We propose an endovascular-specific classification system of complications with 4 categories: mechanical, technical, judgment errors, and critical events. This system provides a framework for future studies and quality control in endovascular neurosurgery. PMID- 27495842 TI - Full-Endoscopic Transforaminal Approach for Removal of a Spontaneous Spinal Epidural Hematoma. AB - BACKGROUND: The incidence of spinal epidural hematoma (SEH) is estimated to be 1 per 1,000,000 patients per year; SEH can be classified as idiopathic, spontaneous, and secondary. The cause of spontaneous SEH is uncertain but it may be associated with minor trauma. SEH can compress surrounding structures, shown by clinical symptoms and signs that affect the spinal cord or nerve roots. Surgical treatment may be considered if medical treatment fails. CASE DESCRIPTION: A 26-year-old man presented with lower back pain and significant radicular symptoms on the left side for a week. He denied previous lumbar trauma or the use of anticoagulation drugs. We used the full-endoscopic transforaminal approach (extraforaminal technique) to remove the SEH under local anesthesia. The patient was discharged home 2 days after surgery and the radicular pain disappeared completely. Three months later, follow-up magnetic resonance imaging showed that the dark-brown lesion had been totally removed. CONCLUSIONS: Spontaneous SEHs are uncommon. Although lumbar laminectomy is the mainstream treatment in those with neurologic deficits caused by epidural hematomas, the percutaneous full-endoscopic transforaminal approach may be an option for certain SEHs. PMID- 27495843 TI - Indirect Bypass Surgery May Be More Beneficial for Symptomatic Patients with Moyamoya Disease at Early Suzuki Stage. AB - OBJECTIVE: Moyamoya disease is a progressive stenosis or occlusion of the internal carotid artery. Revascularization surgery is considered the standard treatment. We conducted a retrospective study in hopes of finding indications for electing different surgical methods. METHODS: A total of 55 hemispheres in 49 patients who received revascularization surgery between January 2013 and December 2015 were included. Medical data such as age and sex were extracted and risk factor analysis for vascular anastomosis patency was conducted with multivariable logistic regression. RESULTS: In this study, direct or combined bypass surgery had a higher incidence of perioperative neurologic defects than did indirect surgery (30.3% vs. 4.5%; P = 0.046). The rates of postsurgery stroke (6.2% vs. 18.2%) and modified Rankin Scale improvement (39.4% vs. 18.2%) were better in the direct or combined bypass surgery group, but no significant difference was found. Moreover, longer operative time (209 +/- 29.4 minutes vs. 101 +/- 16.5 minutes; P < 0.01) and longer hospital stay (9.0 +/- 3.11 days vs. 5.3 +/- 2.03 days; P < 0.01) made direct or combined bypass surgery less advantageous. Multivariable binary logistic regression showed that the late Suzuki stage is a more favorable factor than the early Suzuki stage (odd ratio, 7.78; confidence interval, 1.059 57.155; P = 0.044). CONCLUSIONS: Because vascular anastomosis patency in symptomatic patients with moyamoya disease at early Suzuki stage is relatively lower, indirect bypass surgery may be more beneficial for these patients in view of shorter operative time and hospital stay. PMID- 27495844 TI - Epidemiologic and Demographic Attributes of Primary Spondylodiscitis in a Middle Eastern Population Sample. AB - BACKGROUND: The prevalence and characteristics of spontaneous spondylodiscitis in the Middle East are unknown. There seems to be an emerging dominance of pyogenic infections over tuberculosis and brucellosis. METHODS: We conducted a retrospective observational study based on electronic case records of 4 years from a tertiary reference facility in Oman. Case records, microbiology reports, blood reports, imaging studies, and histopathology, and surgical reports of all spinal infection cases were studied. Patients with secondary infections after invasive spinal interventions and expatriate patients were excluded. Risk factors and comorbidities were also analyzed. RESULTS: Sixty-two cases of primary spondylodiscitis of the spine were identified in this cohort, including 10 cases of tuberculosis, 1 of brucellosis, and 1 of tuberculosis with pyogenic infection. Of the 50 pyogenic infections, 4 were in children; among the adults, the mean age was 49.5 years and 63.8% were male. Thirty-three patients had no medical comorbidities. Common ailments associated were 18 patients with diabetes mellitus, 13 hypertensives, 6 with renal insufficiency, 2 with liver cirrhosis, 3 with alcoholism, 5 with hepatitis C virus, and 2 with immunosuppression. More than 69% involvement was in the lumbar spine. Fourteen patients were infected with Staphylococcus aureus and 9 with Pseudomonas aeruginosa, whereas 35.4% were culture negative. CONCLUSIONS: Spontaneous infective spondylodiscitis affects older men with and without medical comorbidities equally. It often involves the lumbar spine and a third of patients are culture negative. Tuberculosis constitutes only about 17% of primary infections in the spine in this population sample. PMID- 27495845 TI - Serum Levels of MicroRNA miR-371a-3p: A Sensitive and Specific New Biomarker for Germ Cell Tumours. AB - BACKGROUND: Clinical management of germ cell tumours (GCTs) relies on monitoring of serum tumour markers. However, the markers alpha-fetoprotein (AFP), the beta subunit of human chorionic gonadotropin (bHCG), and lactate dehydrogenase (LDH) are expressed in <60% of GCT cases. OBJECTIVE: To test the utility of the microRNAs (miRNAs) miR-371a-3p, miR-372-3p, miR-373-3p, and miR-367-3p as sensitive and specific GCT serum biomarkers. DESIGN, SETTING, AND PARTICIPANTS: Serum levels of miRNAs were measured in 166 consecutive patients with GCT before and after treatment and in 106 male controls. In the first 50 consecutive patients, all four miRNAs were measured. In the main study, only the most sensitive miRNA was further analysed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The specificity and sensitivity of the four miRNAs were studied using receiver operating characteristic curves. miRNA sensitivities were compared to those of classical markers. Statistical cross-comparisons of miRNA levels for GCT subgroups and controls were performed at various time points during treatment. RESULTS AND LIMITATIONS: Overall, miR-371a-3p performed best, with 88.7% sensitivity (95% confidence interval [CI] 82.5-93.3%) and 93.4% specificity (95% CI 86.9-97.3%) and an area under the curve of 0.94, outperforming AFP, bHCG, and LDH (combined sensitivity 50%). According to Kernel density estimation, the sensitivity and specificity were 86.3% and 92.5%, respectively. miR-371a-3p levels dropped to normal after completion of treatment. The miRNA levels correlated with treatment failure and relapse. Teratoma did not express miR-371a 3p. CONCLUSIONS: The miRNA miR-371a-3p is a specific and sensitive novel serum GCT biomarker that accurately correlates with disease activity. Validation of this test in a large-scale prospective study is needed. PATIENT SUMMARY: miR-371a 3p is a novel serum marker for germ cell tumours that is expressed by 88.7% of patients and thus is far more sensitive and specific than classical serum markers. It correlates with tumour burden and treatment results. Validation in a large patient cohort is needed. PMID- 27495846 TI - Re: More Favorable Pathological Outcomes in Men with Low Risk Prostate Cancer Diagnosed on Repeat Versus Initial Transrectal Ultrasound Guided Prostate Biopsy. PMID- 27495847 TI - Re: Re-evaluating PSA Testing Rates in the PLCO Trial. PMID- 27495849 TI - Abdominal rectus diastasis: Questions of wellness and biology. PMID- 27495848 TI - Bile deficiency induces changes in intestinal glucose absorption in mice. AB - BACKGROUND: Biliary tract obstruction is a common clinical problem. In this study, we attempted to understand the change in intestinal glucose absorption after biliary tract obstruction. METHODS: Experimental models of murine biliary duct ligation and external biliary drainage were established. Murine intestinal mucosal glucose absorption was examined with Ussing chambers according to the increase in the short-circuit current in vitro and blood glucose measurement after oral glucose in vivo. The protein expression of the sodium-glucose cotransporter (SGLT1) and the facilitated glucose transporter, member 2 (GLUT2) was analyzed by Western blot and immunohistochemistry. RESULTS: The results from Ussing chamber experiments showed that duodenal mucosal glucose absorption levels were significantly higher in biliary duct ligation and biliary drainage mice than those in normal control mice at 1 and 2 weeks after the operation. Gastrointestinal bile acid administration almost reversed the elevated duodenal mucosal glucose absorption to the normal level in biliary drainage mice. The results from the experiments in vivo further confirmed that the glucose absorption increased in biliary duct ligation and biliary drainage mice. The protein expression levels of SGLT1 in the duodenal mucosae of both biliary duct ligation and biliary drainage mice were markedly higher than those in control mice, and the protein expression of GLUT2 was not significantly altered, compared with control mice. CONCLUSION: Bile deficiency in the intestine upregulates the expression of intestinal mucosal SGLT1 and enhances intestinal mucosal glucose absorption capacity, which contributes to the understanding of intestinal physiologic function for patients with biliary duct obstruction and external biliary drainage. PMID- 27495850 TI - Predictors of improved survival for patients with retroperitoneal sarcoma. AB - BACKGROUND: Retroperitoneal sarcomas are rare tumors that can be locally aggressive with high rates of recurrence. Given that data on survival in patients with retroperitoneal sarcomas are conflicting, we sought to use a nationwide cancer database to identify factors associated with survival in patients with retroperitoneal sarcomas. METHODS: The Surveillance, Epidemiology, and End Results database was utilized to identify patients with retroperitoneal sarcomas from 2002 to 2012. Univariable and multivariable survival analysis was performed using a generalized gamma parametric survival function. RESULTS: A total of 2,920 patients were included; overall 5- and 10-year survivals were 58.4% and 45.3%, respectively. On multivariable survival analysis, age, histologic type, grade, size, local extension, lymph node, and distant metastasis were associated with decreased survival (all P < .05). Patients undergoing operative resection survived 2.5 times longer (95% confidence interval: 2.0-3.0, P < .001) and those receiving radiation therapy 1.3 times longer (95% confidence interval: 1.1-1.6, P = .001), respectively. CONCLUSION: During the past decade, retroperitoneal sarcoma patients treated with radiation demonstrate longer survival compared with patients who did not receive radiation. Further study is needed to fully elucidate the mechanisms that underlie the radiation-related survival benefit observed in this study. PMID- 27495851 TI - Mapping insulin non-covalent interactions with natural polysaccharides by hydrogen/deuterium exchange mass spectrometry. AB - RATIONALE: Drug development efforts involving therapeutic peptides or proteins strongly lead optimization of drug delivery, drug stability, solubility and functionality. The key feature of controlled drug delivery is the use of biocompatible polymers able to interact via non-covalent bonds with an active principle through multiple functional groups. Here amide hydrogen/deuterium exchange (HDX) mass spectrometry was employed to localize insulin dynamics induced by interactions with three natural polysaccharides, i.e. chitosan (CH), sodium alginate (ALG) and chondroitin sulfate (CS). METHODS: LTQ-Orbitap continuous-labelling mass spectra were collected by diluting insulin stock solution (10 mM in 0.1% formic acid) to a final concentration of 0.1 mM in D2 O containing 1 mM deuterated ammonium acetate (final pH .6) (insulin:polysaccharide ratio 1:2, w/w). For peptide mapping, deuterated samples were quenched after 0.5, 30, 60, 120 minutes exchange by adding HCl (pH ) and digested with pepsin before LC-MS/MS analysis. RESULTS: Differences in the insulin backbone dynamics in the presence of the three polysaccharides were highlighted by monitoring peptic peptides at different time points. No significant differences were observed in the presence of CH, whereas the negatively charged ALG and CS were able to induce significant conformational variations at the B-chain level resulting in more protection against H/D exchange. The A-chain interacted only with CS reducing the protein mobility on a long time scale (120 min). HDX data evidenced heterogeneous insulin dynamics in the presence of ALG and CS. CONCLUSIONS: The studies reported here demonstrated the capabilities of mass spectrometry techniques and HDX methods to obtain useful information toward the flexibility and the behavior of native insulin in the presence of natural polysaccharides, and could provide insights to study the behavior of pharmaceutical formulations. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27495852 TI - Arthroscopy Authors Seek Innovative International Readers. AB - Arthroscopy and Arthroscopy Techniques attract authors as a result of our large, innovative, and global audience. In addition, the journals attract authors because of our robust and rapid review process, our wide indexing and search availability, and our openness to diverse article types including Technical Notes with video. PMID- 27495853 TI - Mark P. Cote, P.T., D.P.T., M.S.C.T.R., Associate Editor. PMID- 27495854 TI - Authors' Reply. PMID- 27495855 TI - Regarding "Autologous Osteochondral Transplantation for Osteochondral Lesions of the Talus: Does Previous Bone Marrow Stimulation Negatively Affect Clinical Outcome?". PMID- 27495856 TI - Authors' Reply. PMID- 27495857 TI - Regarding "Use of Hip Arthroscopy and Risk of Conversion to Total Hip Arthroplasty: A Population-Based Analysis". PMID- 27495858 TI - Editorial Commentary: Call for Evidence: How and When to Treat a Stiff Shoulder in Diabetics Requires Clarification. AB - The present study found a slower functional recovery after arthroscopic capsular release in patients with refractory frozen shoulder and diabetes. However, the study has some limitations: retrospective design, small study groups, and incomplete assessments. To better understand the disease and its proper treatment, one has to distinguish between idiopathic and secondary frozen shoulder. At present, little is known about both types of frozen shoulder, and randomized controlled trials are needed to compare surgical intervention with a conservative treatment at different stages of the disease. PMID- 27495859 TI - Editorial Commentary: Your Surgical "Tool Box" Just Got a Little Bit Bigger. AB - There is currently no "gold standard" for the surgical repair of a partial thickness rotator cuff tear. Ranalletta et al. have made a meaningful contribution to the orthopaedic literature with this study that reports the clinical outcomes of 80 patients who underwent arthroscopic transtendon repair of high-grade, articular-sided partial-thickness rotator cuff tears. At a mean follow-up of 62 months, they noted significant improvement in pain, range of motion, and a number of objective shoulder outcome measures. Perhaps most importantly, 92.5% rated their shoulder as "good" or "excellent." Unfortunately, we cannot definitively state whether or not these repairs actually healed given the lack of postoperative imaging, nor do we know the actual depth of these partial tears that can be difficult to objectively quantify. Despite these shortcomings, arthroscopic surgeons who treat rotator cuff disorders will be able to use this information in treating their patients irrespective of their preferred surgical technique. Future studies are needed to definitively determine which repair method, if any, is better. PMID- 27495860 TI - Editorial Commentary: Low Reoperation Rates for Outpatient Rotator Cuff Repairs: Proof of Efficacy? AB - The reoperation rate for people younger than 65 years is approximately 8% at a minimum 2-year follow-up. The low rate is another indicator that outpatient rotator cuff repair is a good operation with acceptable failure risks. PMID- 27495861 TI - Editorial Commentary: Are Larger Screws the Answer When Anatomic Reconstruction of an Acromioclavicular Separation Fails? AB - Although fixation methods have improved, failure after fixation of an acromioclavicular joint separation is not uncommon. This biomechanical study shows that in the setting of graft slippage through previously well-placed clavicular tunnels, a revision anatomic reconstruction is feasible with larger tenodesis screws. Although the risk of clavicular fracture increases with larger tunnels, anatomic revision with larger screws is an option in select cases. PMID- 27495862 TI - Editorial Commentary: Pitching Should Come With a Warning Label. AB - Pitching is not without risk of overuse injuries. Pitch counts have been instituted to reduce the risk, but Riff et al.'s article clearly demonstrates that as pitchers get older they do not adhere to these counts, which increases the risk of injury. PMID- 27495863 TI - Editorial Commentary: Risk Factors for Chondral Lesions in the Hip-There Is More to It Than Cam and Pincer. AB - Age has been cited in a recent article as the largest predictor of both chondral and labral lesions in patients with hip dysplasia. But it was not surprising that there is also a direct relation between a small lateral center-edge angle, acetabular head index, and cartilage degeneration and an increased acetabular index and labral tears in patients with hip dysplasia. The severity of the congenital disease determines the severity of the intra-articular lesions. PMID- 27495865 TI - Editorial Commentary: Outcomes After Patch Use in Rotator Cuff Surgery: Searching for the "Holy Grail". AB - Rotator cuff integrity after repair is the basis for a better patient outcome, and the use of adjunctive graft material may result in a demonstrable benefit toward achieving that end. PMID- 27495864 TI - Editorial Commentary: Postoperative Anterior Cruciate Ligament Reconstruction Protocols Are Like Snowflakes; No 2 Are Alike. AB - Postoperative rehabilitation after arthroscopic and related surgery should follow guidelines that emphasize time (tissue healing) and performance (motion and strength) milestones. These guidelines are often missing in traditional protocols, which assume that all patients arrive in the same condition at the same point in time. The real challenge for the allied health professional will be demonstrating that milestone-based protocols that use the best available evidence are effective, and as a start, we need to eliminate treatments proven ineffective. PMID- 27495866 TI - Editorial Commentary: Love My Surgeon, Love My Surgery: Patient Satisfaction Matters After Hip Arthroscopy. AB - Patient satisfaction following hip arthroscopy is currently underreported and lacks uniformity when published. While current patient reported outcomes are important, they may not reflect overall patient satisfaction because it is complex and multifactorial. However, assessment and documentation of patient satisfaction following hip arthroscopy is critical to demonstrating value and quality. Therefore, it is of pressing importance that the hip arthroscopy community develops an accurate score that is consistent, valid, and reliable. PMID- 27495868 TI - Erratum. PMID- 27495867 TI - Editorial Commentary: The Importance of Developing an Algorithm When Diagnosing Hip Pain. AB - The differential diagnosis of groin pain is broad and complex. Therefore, it is essential to develop an algorithm when differentiating the hip as a cause of groin pain from other sources. Selective injections in and around the hip can be helpful when making the diagnosis but are only one part of the algorithm. PMID- 27495869 TI - Phase 3 evaluation of HP802-247 in the treatment of chronic venous leg ulcers. AB - In 2012 we reported promising results from a phase 2 clinical trial of HP802-247, a novel spray-applied investigational treatment for chronic venous leg ulcers consisting of human, allogeneic fibroblasts and keratinocytes. We now describe phase 3 clinical testing of HP802-247, its failure to detect efficacy, and subsequent investigation into the root causes of the failure. Two randomized, controlled trials enrolled a total of 673 adult outpatients at 96 centers in North America and Europe. The primary endpoint was the proportion of ulcers with confirmed closure at the end of 12 weeks of treatment. An investigation into the root cause for the failure of HP802-247 to show efficacy in these two phase 3 trials was initiated immediately following the initial review of the North American trial results. Four hundred twenty-one patients were enrolled in the North American (HP802-247, 211; Vehicle 210) and 252 in the European (HP802-247, 131; Vehicle 121) trials. No difference in proportion of closed ulcers at week 12 was observed between treatment groups for either the North American (HP802-247, 61.1%; Vehicle 60.0%; p = 0.5896) or the European (HP802-247, 47.0%; Vehicle 50.0%; p = 0.5348) trials. Thorough investigation found no likelihood that design or execution of the trials contributed to the failure. Variability over time during the trials in the clinical response implicated the quality of the cells comprising HP802-247. Concordance between the two separate, randomized, controlled trials with distinct, nonoverlapping investigative sites and independent monitoring teams renders the possibility of a Type II error vanishingly small and provides strong credibility for the unexpected lack of efficacy observed. The most likely causative factors for the efficacy failure in phase 3 was phenotypic change in the cells (primarily keratinocytes) leading to batch to batch variability due to the age of the cell banks. PMID- 27495870 TI - Sortilin facilitates VLDL-B100 secretion by insulin sensitive McArdle RH7777 cells. AB - Studies examining the relationship between cellular sortilin and VLDL-B100 secretion demonstrate inconsistent results. Current studies explore the possibility that discrepancies may be related to insulin sensitivity. McArdle RH7777 cells (McA cells) cultured under serum enriched conditions lose sensitivity to insulin. Following incubation in serum-free DMEM containing 1% BSA, McA cells become insulin responsive and demonstrate reduced apo B secretion. Current studies indicate that insulin sensitive McA cells express lower cellular sortilin that corresponds with reduction in VLDL-B100 secretion without changes in mRNA of either sortilin or apo B. When sortilin expression is further reduced by siRNA knockdown (KD), there are additional decreases in VLDL-B100 secretion. A crystal structure of human sortilin (hsortilin) identifies two binding sites on the luminal domain for the N- and C-termini of neurotensin (NT). A small organic compound (cpd984) was identified that has strong theoretical binding to the N terminal site. Both cpd984 and NT bind hsortilin by surface plasmon resonance. In incubations with insulin sensitive McA cells, cpd984 was shown to enhance VLDL B100 secretion at each level of sortilin KD suggesting cpd984 acted through sortilin in mediating its effect. Current results support a role for sortilin to facilitate VLDL-B100 secretion which is limited to insulin sensitive McA cells. Inconsistent reports of the relationship between VLDL-B100 secretion and sortilin in previous studies may relate to differing functions of sortilin in VLDL-B100 secretion depending upon insulin sensitivity. PMID- 27495871 TI - Proximity mapping of human separase by the BioID approach. AB - Separase is a caspase-like cysteine protease that is best known for its essential role during the metaphase-to-anaphase transition when it cleaves the cohesin ring complex that keeps the sister chromatids together. Another important function of separase is to regulate the process of centriole separation, known as centriole disengagement, at the end of mitosis. We used proximity-dependent biotin identification (BioID) to expand our knowledge on the identity of separase's proximity interactors. We show that separase BioID labeled two domains at the mother centriole: an area underneath the centriolar appendages and another at the proximal end of the mother centriole. BioID analysis identified more than 200 proximity interactors of separase, one being the Alstrom Syndrome Protein 1 (ALMS1) at the base of centrioles. Other proximity interactors are the histone chaperons NAP1L1 and NAP1L4, which localize to the spindle poles during mitosis and the spindle assembly checkpoint proteins BUBR1, SKA1 and SKA3 that reside at kinetochores in early mitosis. Finally, we show that depletion of BUBR1 homolog from Caenorhabditis elegans delayed the recruitment of separase to mitotic chromosomes, and eventually anaphase onset. PMID- 27495872 TI - MicroRNA-187-5p suppresses cancer cell progression in non-small cell lung cancer (NSCLC) through down-regulation of CYP1B1. AB - Lung cancer remains a leading cause of cancer-associated mortality worldwide and non-small lung cancer (NSCLC) is responsible for over 80% of lung cancer-related deaths. Identifying novel molecular biomarker that can inhibit the progression of lung cancer will facilitate the development of new treatment strategies. Herein, we demonstrated that miR-187-5p is a tumor-suppressor miRNA in NSCLC progression. We found that expression of miR-187-5p was decreased obviously in NSCLC tissues. Down-regulation of miR-187-5p was associated with TNM stage and postoperative survival. Overexpression of miR-187-5p inhibited the growth and metastasis of NSCLC cells. The CYP1B1 was a direct target of miR-187-5p and promoted the growth and metastasis of NSCLC cells. Further study showed that CYP1B1 could reverse the inhibitory effect of miR-187-5p on growth and metastasis of NSCLC cells. Taken together, our data highlight the pivotal role of miR-187-5p in the progression of NSCLC. Thus, miR-187-5p may be a potential prognostic marker and of treatment relevance for NSCLC progression intervention. PMID- 27495874 TI - Fear of Dementia. PMID- 27495873 TI - Silencing Drp1 inhibits glioma cells proliferation and invasion by RHOA/ ROCK1 pathway. AB - BACKGROUNDS: Dynamin-related protein 1 (Drp1) is a newly discovered therapeutic target for tumor initiation, migration, proliferation, and chemosensitivity. In the present study, we aimed to examine the level of expression and distribution of DRP1 in glioma tissues and explore the concrete mechanism of DRP1 played in glioma. METHODS: Expression of DRP1 in glioma tissues was determined by immunohistochemistry staining. The DRP1 gene was knocked down using small interfering RNA, and was overexpressed using plasmids in glioma cells. To assess changes in cell function, in vitro assays for invasion and growth were applied. Protein expression was tested by using Western-blot method. Variation of F-actin in cells was analyzed using immunofluorescence staining. Interactions between proteins were determined by co-immunoprecipitation. RESULTS: The protein expression levels of DRP1 were significantly increased in glioma tissues compared to the normal brain tissues. Down-regulation of DRP1 decreased cell proliferation and invasion, and inhibited the formation of pseudopodias and microvillis. Moreover, a possible link between DRP1 and RHOA was confirmed when interactions between these two proteins were observed in the cells. CONCLUSIONS: Our results demonstrated that silencing DRP1 regulated the cytoskeleton remodeling through inhibiting RHOA/ROCK1 pathway, and thus decreased the proliferation and invasion of glioma cells. PMID- 27495875 TI - Regulator of G protein signaling 20 enhances cancer cell aggregation, migration, invasion and adhesion. AB - Several RGS (regulator of G protein signaling) proteins are known to be upregulated in a variety of tumors but their roles in modulating tumorigenesis remain undefined. Since the expression of RGS20 is elevated in metastatic melanoma and breast tumors, we examined the effects of RGS20 overexpression and knockdown on the cell mobility and adhesive properties of different human cancer cell lines, including cervical cancer HeLa, breast adenocarcinoma MDA-MB-231, and non-small cell lung carcinoma H1299 and A549 cells. Expression of RGS20 enhanced cell aggregation, migration, invasion and adhesion as determined by hanging drop aggregation, wound healing, transwell chamber migration and invasion assays. Conversely, shRNA-mediated knockdown of endogenous RGS20 impaired these responses. In addition, RGS20 elevated the expression of vimentin (a mesenchymal cell marker) but down-regulated the expression of E-cadherin, two indicators commonly associated with metastasis. These results suggest that the expression of RGS20 may promote metastasis of tumor cells. PMID- 27495876 TI - Determination of nicotine, glycerol, propylene glycol and water in electronic cigarette fluids using quantitative 1 H NMR. PMID- 27495877 TI - The light switch-off response as a putative rodent test of innate fear. AB - Recent discussions on the ethics in animal experimentation instigate the refinement of methods used in Behavioral Neuroscience, particularly regarding fear/anxiety paradigms. We propose the Light Switch-Off Test (LSOT), based on the innate motivation to cease an aversive stimulus (bright light), displayed naturally by rodents in their habitat. Forty-six male adult Wistar rats were allocated into independent groups: control, diazepam at 1 or 2mg/kg, and meta Chlorophenylpiperazine (mCPP) at 0.5 or 1mg/kg. The experimental box has two square compartments, separated by an acrylic portal. In each side of the box, there is a 40-W incandescent light bulb. After a habituation period in the box, 40 light stimuli (trials lasting up to 20s each) are emitted at random intervals. By crossing compartments during the lighted period, the rat could switch-off the stimulus. Parameters observed are the number of switch-off responses (SORs), latency of SOR and intertrial locomotion. The SOR frequency was higher in rats treated with mCPP at 1mg/kg, an anxiogenic drug, while diazepam at the doses used in this study did not produce effects. Animals exposed solely to the box for the length of the test did not respond in a false positive way. Therefore, the SOR represents a good index to measure the innate rodent fear of bright-lighten areas, once they react quickly in order to turn off the stimulus. Among its many advantages, the LSOT is a simple, replicable, non-invasive and minimally stressful procedure, since it does not expose animals to excessively aversive stimulus. PMID- 27495878 TI - Mild, moderate, and severe intensity cut-points for the Respiratory Distress Observation Scale. AB - BACKGROUND: The Respiratory Distress Observation Scale(c) (RDOS) is a means for assessing respiratory distress when a patient is unable to give a dyspnea self report. Cut-point determination was needed to guide clinical application. METHOD: A Receiver Operating Characteristic (ROC) curve analysis was conducted in a prospective, observation study with inpatients ranked by nurse practitioners (NP) into levels of respiratory distress. A research assistant simultaneously measured RDOS blinded to NP ranking. RESULTS: Participants were 84 adults: mean age of 72.6 (SD = 15.2) years, 53.6% male, 77.4% African-American. NP ranking was distributed: none (30%), mild (26%), moderate (31%), and severe (13%) distress. RDOS scores ranged 0-13 (M = 4.8, SD = 3). NP ranking was significantly correlated with RDOS (rho = .91, p < .01). ROC curve analyses yielded cut-points: none = 0-2, any = 3, mild-moderate = 4-6, and severe >=7 (p < .01). CONCLUSIONS: Intensity cut-point enhances the clinical utility of the RDOS. PMID- 27495879 TI - Anuria since birth: does it impact outcome of kidney transplant in infants? AB - Kidney transplantation (txp) in infants has recently made much progress but provides a unique challenge in infants anuric since birth. Little data exists on outcome of renal txp recipients with anuria since birth. Retrospective chart review was done for outcome of 27 children with wt <=15 kg and they were divided into two groups: Group A (N=21) with urine output and Group B (N=6) anuric since birth had their urological complications and long-term outcome compared. Median age at the time of txp 18 vs 23 months, mean wt 10.8 vs 11.8 kg, and mean ht 77 cm in both, mean follow-up post-txp: 9.4 vs 5.6 years, and neurological problems were noted in 48% and 33% in Group A and Group B. There was no graft thrombosis or post-transplant lymphoproliferative disease and only two rejections. Anuric Group B were older, had more post-txp urological surgeries (66% vs 19%) and UTIs (66% vs 38%) compared to Group A. The overall graft survival at 1, 5, and 10 years was 96%, 86%, and 70%; patient survival at 1, 5, and 10 years was 96%, 85%, and 85%. Long-term graft outcomes in small children, anuric prior to txp, were excellent despite higher rates for UTIs and urological complications. PMID- 27495880 TI - Effects of multifocal soft contact lenses used to slow myopia progression on quality of vision in young adults. AB - PURPOSE: To assess the effects of multifocal soft contact lenses (MF SCLs) used for myopia control on visual acuity (VA) and subjective quality of vision. METHODS: Twenty-four young adult myopes had baseline high and low-contrast VAs and refractions measured and quality of vision assessed by the Quality of Vision (QoV) questionnaire with single vision SCLs. Additional VA and QoV questionnaire data were collected immediately after subjects were fitted with Proclear MF SCLs and again after a 2-week adaptation period of daily lens wear. Data were collected for two MF SCL designs, incorporating +1.50 and +3.00 D peripheral near additions, with a week washout period allowed between the two lens trials. RESULTS: High- and low-contrast VAs were initially reduced with both MF SCL designs, but subsequently improved to be not significantly reduced in the case of high-contrast VA by the end of the 2-week adaptation period. The quality of vision was also reduced, more so with the +3.00 D MF SCL. Quality of Vision (QoV) scores describing frequency, severity and bothersome nature of visual symptoms indicated symptoms worsening rather than resolving over the 2-week period, particularly so with the +3.00 D MF SCL. CONCLUSION: Low and high add MF SCLs adversely affected vision on initial insertion, with sustained effects on low contrast VA and QoV scores but not high-contrast VA. Thus, high-contrast VA is not a suitable surrogate for quality of vision. In prescribing MF SCLs for myopia control, clinicians should educate patients about these effects on vision. PMID- 27495881 TI - Cross-sectional study on knowledge of chronic kidney disease among medical outpatient clinic patients. AB - BACKGROUND: Chronic kidney disease (CKD) is a major health concern worldwide. There are limited studies which look into the actual knowledge level of CKD among the general population both locally and internationally. This study aims to assess the knowledge level of CKD among patients in a secondary hospital in Malaysia. METHODS: Consecutive sampling of patients attending the Medical Outpatient Clinic was performed in this crosssectional study. Respondents were given self-administered questionnaires which contain questions on demographic characteristics and knowledge on CKD. RESULTS: Out of 300 respondents, 78.6% (n=236) of the respondents completed the questionnaire. Majority of respondents (73.7%, n=174) scored less than 4 out of 7 marks on knowledge on CKD. Respondents who were younger, males, having higher education status, professionals/executives and earned higher monthly income were more likely to have a higher mean knowledge score of CKD. Respondents who have heard of CKD were also significantly associated with higher mean knowledge score of CKD. CONCLUSION: The study findings suggest that our Malaysian population is still inadequately informed on CKD, especially those who are at risk of developing CKD and its complications, and also among those of the lower socioeconomic group. In order for successful primary and secondary prevention of CKD, more importance should be placed on increasing awareness on CKD among these atrisk groups. PMID- 27495882 TI - Generation and characterisation of human umbilical cord derived mesenchymal stem cells by explant method. AB - Mesenchymal stem cells (MSCs) derived from human umbilical cord (UC) have been considered as an important tool for treating various malignancies, tissue repair and organ regeneration. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) are better alternative to MSCs that derived from bone marrow (BM-MSCs) as they are regarded as medical waste with little ethical concern for research and easily culture-expanded. In this present study, the foetal distal end of human UC was utilised to generate MSC by explant method. Upon in vitro culture, adherent cells with fibroblastic morphology were generated with rapid growth kinetics. Under the respective inductive conditions, these cells were capable of differentiating into adipocytes and osteocytes; express an array of standard MSC's surface markers CD29, CD73, CD90, CD106 and MHC-class I. Further assessment of immunosuppression activity revealed that MSCs generated from UC had profoundly inhibited the proliferation of mitogen-activated T lymphocytes in a dosedependent manner. The current laboratory findings have reinforced the application of explant method to generate UCMSCs thus, exploring an ideal platform to fulfil the increasing demand of MSCs for research and potential clinical use. PMID- 27495883 TI - Prophylactic bilateral internal iliac artery balloon occlusion in the management of placenta accreta: A 36-month review. AB - BACKGROUND: The contemporary obstetrician is increasingly put to the test by rising numbers of pregnancies with morbidly adherent placenta. This study illustrates our experience with prophylactic bilateral internal iliac artery occlusion as part of its management. METHODS: Between January 2011 to January 2014, 13 consecutive patients received the intervention prior to scheduled caesarean delivery for placenta accreta. All cases were diagnosed by ultrasonography, color Doppler imaging and supplemented with MRI where necessary. The Wanda balloon(TM) catheter (Boston Scientific, Natick, MA, U.S.A) were placed in the proximal segment of the internal iliac arteries preceding surgery. This was followed by a midline laparotomy and classical caesarean section, avoiding the placenta. Both internal iliac balloons were inflated just before the delivery of fetus and deflated once haemostasis was secured. Primary outcomes measured were perioperative blood loss, blood transfusion requirement and the need for ICU admission. RESULTS: The mean and median intraoperative blood loss were 1076mls+/ 707 and 800mls (300-2500) respectively while mean perioperative blood loss was 1261mls+/-946. Just over half of the patients in our series required blood and/or blood products transfusion. Two patients (15.4%) required ICU admission. CONCLUSION: Our study suggests that preoperative prophylactic balloon occlusion of bilateral internal iliac arteries reduces both blood loss and transfusion requirement in patients with placenta accreta, scheduled to undergo elective caesarean hysterectomy. It is an adjunct to be considered in the management of a modern day obstetric problem, although the authors are cautious about generalizing its benefit without larger, randomized trials. PMID- 27495884 TI - Community-acquired bacteremia in Paediatrics: Epidemiology, aetiology and patterns of antimicrobial resistance in a tertiary care centre, Malaysia. AB - INTRODUCTION: bacteremia continues to be one of the major causes of morbidity and mortality despite the existence of numerous antimicrobial agents. this study aimed to provide a Malaysian perspective on paediatric community-acquired bacteraemia based on the documentation of epidemiology and antimicrobial profile of the isolated pathogens. METHOD: A retrospective study was conducted by analysing clinical details, blood cultures and antimicrobial susceptibility testing results in children between the ages of 0 to 13 years old, who were admitted to selayang Hospital over an 11-year period from 2001 until 2011. there were 222 bacteraemia cases and the median age was 11.7 months. the highest number (39%) of bacteraemia cases occurred between ages one month to one year. the three most commonly isolated aetiological agents were Staphylococcus aureus (17.1%), nontyphoidal Salmonella (16.2%), and Streptococcus pneumoniae (12.6%). Almost 8% of the Staphylococcus aureus isolates were methicillin resistant, while nontyphoidal Salmonella (Nts) isolates demonstrated 18.4%, 10.5% and 2.6% resistance towards ampicillin, trimethoprim-sulfamethoxazole and ciprofloxacin respectively. All Nts isolates were sensitive to ceftriaxone. Streptococcus pneumoniae isolates showed 17.9% resistance to penicillin. skin and soft tissue infections as well as lower respiratory tract infections (63.2%) were the main foci of infections in Staphylococcus aureus bacteraemia. Acute gastroenteritis (80.0%) and pneumonia (60.8%) were the main presentations of Nts and Streptococcus pneumoniae bacteraemia respectively. Overall mortality rate was 8.1%. CONCLUSION: Knowledge on the local epidemiology and antibiotic resistance pattern serves as a significant platform in improving the empiric antibiotic therapy for patients with community acquired bacteraemia. PMID- 27495885 TI - Association of Cobb angle progression and neuraxial abnormality on MRI in asymptomatic Adolescent Idiopathic Scoliosis. AB - BACKGROUND: Detection of neuraxial abnormality in neurologically asymptomatic adolescent idiopathic scoliosis (AIS) is crucial prior to surgery. It can only be detected on magnetic resonance imaging (MRI), which was not routinely done in this group of patient. On the other hand, whole spine radiographs for measurement of Cobb angle have been routinely included during clinic follow-up. This study aimed to determine the correlation between Cobb angle progression and neuraxial abnormality finding on MRI in asymptomatic AIS. METHODS: A retrospective study was conducted in the Orthopaedic department of a tertiary hospital. Patients with asymptomatic AIS aged 10-20 years who attended scoliosis clinic from year 2007 to 2010 was reviewed. Patients who had whole spine MRI and two vertebral radiographs at least one year apart were further selected. Statistical analysis was done to see the association between Cobb angle progression and neuraxial abnormality on MRI. RESULTS: The mean age at first presentation was 14.4 years old. Female (n=249) to male (n=50) ratio was 5:1. Only 19 patients fulfilled the selection criteria. There were 5 patients (26.3%) who had neuraxial abnormalities. The mean curve progression was 7.05 degrees (range from -5 degrees to 28 degrees ). Patients with and without neuroaxial abnormality showed mean curve progression of 0.6 degrees and 9.36 degrees respectively. There was no significant association between Cobb angle progression and neuroaxial abnormality (p=1.000). CONCLUSION: Cobb angle progression is not a reliable indicator for predicting neuroaxial abnormality in patients with asymptomatic AIS. However, this study stressed the need to perform MRI prior to operation to document any associated neuraxial abnormality in clinically asymptomatic AIS patients. PMID- 27495886 TI - Acute kidney injury following coronary artery bypass graft surgery in a tertiary public hospital in Malaysia: an analysis of 1228 consecutive cases. AB - BACKGROUND: Acute kidney injury (AKI) following cardiac surgery is well established but the reported incidence is variable due to varying definitions and criteria. Furthermore there is a paucity of such data from Southeast Asia. OBJECTIVES: To determine the incidence of AKI, the associated risk factors, and its impact on early mortality and intensive care unit/hospital stay. METHOD: This is a single centre retrospective observational study to evaluate outcomes on 1260 consecutive patients from a multi-ethnic Southeast Asian population who underwent a primary isolated coronary artery bypass graft (CABG) operation. Data was collected from the hospital's electronic database and analysed using basic descriptive statistics and logistic regression. RESULTS: Overall incidence was 36.2% including 5.5% of patients who required renal replacement therapy (RRT). Multivariate analysis identified age, insulin-dependent diabetes mellitus (IDDM), baseline serum creatinine level (SCr), recent myocardial infarction (MI), cardiopulmonary bypass (CPB) time and intra-aortic balloon pump (IABP) use as independent risk factors for AKI. For patients who required RRT, the SCr and IDDM remained independent predictors. Early 30-day mortality (11.5% vs 0.9%) was significantly higher in patients who developed AKI following CABG. Similarly, AKI was associated with a slight but statistically significant increase in intensive care unit (ICU) and hospital stay. CONCLUSION: Better prognostication and preventative strategies are required to better risk stratify patients undergoing CABG and optimise utilisation of limited healthcare resources. PMID- 27495887 TI - Routine measurements of cord arterial blood lactate levels in infants delivering at term and prediction of neonatal outcome. AB - OBJECTIVE: Our purpose was to evaluate the relationship between umbilical cord arterial blood lactate levels with acid base balance to the mode of delivery and short-term neonatal outcome in a large multiracial population delivering at term in University of Malaya Medical Centre. MATERIALS AND METHODS: Two thousand two hundred and twelve patients of more than 37 weeks of gestation with singleton, liveborn infants with no major anomalies delivering between January 2013 to December 2013 were analysed. Lactate was measured by using portable Lactate analyzer that requires 5 MUml of blood and provides the result within 1 minute. The deliveries took place at the Department of Obstetrics and Gynaecology, University Malaya Medical Centre, Malaysia where umbilical cord blood sampling and blood gas analysis is a part of the routine assessment of all newborn. RESULTS: Gestational age ranged from 37 to 43 weeks (mean 39.05 weeks). The highest mean arterial cord lactate values were noted among babies delivered instrumentally (4.87 mmol/L). Infants who had a normal vaginal delivery had the second highest levels (3.36 mmol/L), followed by infants delivered by emergency caesarean section (3.30mmol/L). The lowest lactate values were noted in deliveries by elective caesarean section (3.0mmol/L). Cord arterial lactate levels were significantly higher among infants born with low Apgar scores (7.02 mmol/L vs 4.6mmol/L, P < 0.001). High arterial cord lactate was a significant predictor of admission to Neonatal intensive care unit (NICU) was 6.0mmol/L. Receiver operator curve (ROC) analysis suggests that lactate and pH are virtually equivalent in their correlation with adverse neonatal outcome. CONCLUSION: Cord lactate levels are significantly related to the mode of delivery and is equivalent to cord arterial pH in predicting adverse neonatal outcomes, with similar efficacies; however, its simplicity, less sampling failure and low cost makes lactate analysis an interesting alternative in obstetric care. PMID- 27495888 TI - Serotype prevalence of Streptococcus pneumoniae in Malaysia - the need for carriage studies. AB - Pneumococcal disease, caused by the bacterium Streptococcus pneumoniae, is a major burden to global health. Although the World Health Organisation (WHO) strongly recommends the inclusion of pneumococcal conjugate vaccines in national immunisation programmes (NIP's) worldwide, this has not occurred in many countries in the WHO South East Asia and Western Pacific regions - particularly longstanding middle-income countries. It is widely accepted that carriage of S. pneumoniae is a precursor to developing any pneumococcal disease. The reduction in pneumococcal disease from vaccine serotypes (VT) following widespread implementation of the pneumococcal conjugate vaccine (PCV) is believed to be through the direct immunogenic protective effect of immunised individuals as well as indirectly through herd immunity diminishing the incidence of disease in nonimmunised individuals. In Malaysia, pneumococcal disease is not included in national surveillance programmes and although PCVs have been licensed, they have not been included in the NIP. Hence, the vaccine is only available privately and the majority of the population is not able to afford it. There is an urgent need to develop surveillance programmes in Malaysia to include pneumococcal serotype data from carriage and invasive disease so that it may help guide national vaccine policy prior to a decision being taken on the inclusion of PCVs in the NIP. PMID- 27495889 TI - Thoracic Aortic Aneurysm as A Cause of Ortner's Syndrome - A Case Series. AB - Hoarseness due to left recurrent laryngeal nerve paralysis was first described in 1897 by Norbert Ortner. Various cardiopulmonary and thoracic arch aorta pathologies associated with left recurrent laryngeal nerve palsy have been described over the last 100 years and is also known as cardio-vocal syndrome. We report our experience with seven cases of Ortners syndrome due to thoracic aortic aneurysm with compression of the left recurrent laryngeal nerve and resultant hoarseness. PMID- 27495890 TI - Allergic reaction to stainless steel sternotomy wires requiring removal: A case report and literature review. AB - Hypersensitivity to stainless steel sternal sutures are an uncommon occurrence. We present a case of such a patient who developed chronic tissue overgranulation over a sternotomy wound eight weeks post-operatively. Primary suspicion was infection, a more common complication however radiological and laboratory investigation showed otherwise. Conservative management provided limited ephemeral success. After ensuring adequate sternal bone healing, the sutures and granulation tissue were eventually surgically removed without complication and the reoperated wound healed well. PMID- 27495891 TI - Polypoid endometriosis of post vaginal fornix: utility of MRI imaging of pelvis with diffusion weighted imaging for diagnosis. AB - Polypoid endometriosis is an uncommon variant of endometriosis which can mimic malignancy due to its presentation as masses. We present a case of polypoid endometriosis which simulated cervical malignancy both on clinical examination and on computed tomography (CT) scanning and discuss how magnetic resonance (MR) imaging, in particular Diffusion Weighted Imaging (DWI), can help to distinguish this condition from true malignancy and avoid invasive surgery. PMID- 27495892 TI - Cardiac tamponade: a rare but preventable complication of central venous catheter in neonates. AB - Pericardial effusion with cardiac tamponade is a rare and life-threatening complication of peripherally inserted central catheter (PICC) in a neonate. We report a 33-week preterm neonate who had sudden clinical deterioration at day seven of total parenteral nutrition regime via PICC. Recognition of pericardial effusion with cardiac tamponade in neonates with a PICC requires a high index of suspicion and steps in prevention include proper catheter tip placement and continuous monitoring of line position and function. PMID- 27495893 TI - Primary breast tuberculosis (TB) in a patient with known invasive breast carcinoma: A case report. AB - Breast tuberculosis (TB) is rare even in endemic countries. Most of these cases occur as secondary TB due to a concurrent infection. Primary breast TB is diagnosed when it is the only site of disease without other foci of infection. The presentation of primary breast TB may often mimic carcinoma of the breast. While imaging is not specific, histopathology provides a definitive diagnosis. Here, we present a case of primary breast TB in a breast cancer patient and review the literature. PMID- 27495894 TI - Gram-negative infection as an unusual cause of endocarditis in a hemodialysis patient. AB - Gram-negative endocarditis is rare and it has high mortality if there is a delay in diagnosis and treatment. Gram-negative organisms should be considered in the differential diagnosis of IE in hemodialysis patients. Central lineassociated bloodstream infections (CLABSIs) can be prevented by following sterile measures during catheter insertion and proper management of catheter site. PMID- 27495895 TI - Sinonasal angioleiomyoma. AB - BACKGROUND: Angioleiomyoma of the nasal cavity is an extremely rare benign neoplasm. It usually occurs in the lower extremities. Up to date, only few cases of angioleiomyoma have been reported. First case of angioleiomyoma of nasal cavity was reported in 1966. We report a rare case of angioleiomyoma arising from the right maxillary sinus. CASE REPORT: A 43-year-old lady presented with recurrent epistaxis and right nasal obstruction for two months duration. Clinical examination revealed a huge right nasal mass obstructing the right nasal cavity. The tumour was excised completely via endoscopic endonasal surgical approach. Histopathological examination confirmed the tumour is sinonasal angioleiomyoma. Postoperatively, she recovered well without any recurrence after a year of followup. CONCLUSION: This tumour has an excellent prognosis and recurrence is extremely rare if excised completely. PMID- 27495896 TI - DEHP exposure in utero disturbs sex determination and is potentially linked with precocious puberty in female mice. AB - Human's ubiquitous exposure to di (2-ethylhexyl) phthalate (DEHP) is thought to be associated with female reproductive toxicity. Previous studies found that DEHP inhibited follicle growth and decreased estradiol levels in adult female mice. However, limited information is available on the link between in utero DEHP exposure and ovarian development in female mouse offspring. The present study evaluates the disturbances in regulatory genes involved in female sex determination and the ovarian outcomes in fetal and postnatal female mice treated with in utero DEHP exposure. Pregnant mice were exposed to DEHP by gavage, with the dosage regime beginning at human relevant exposure levels. After in utero DEHP exposure, increased follicular atresia was observed in the female pups at postnatal days (PND) 21. Foxl2 expression was significantly upregulated, and Fst was significantly downregulated by DEHP above 2mg/kg/d at PND 1 and 21. This suggests that lesion of granulosa cell differentiation and disturbance of follicle development in postnatal female mice. The expression of Cyp11a1 and Star were significantly downregulated by in utero DEHP exposure, indicating effects on estradiol biosynthesis. The female sex determination pathway was disturbed in fetus by DEHP at 2mg/kg/d and above during the critical time window of sex determination causing significant upregulation of Foxl2, Wnt4, beta-catenin and Fst. Furthermore, the increased expression of Wnt4 was supported by whole-mount in situ hybridization (WISH). These results suggest a possible association between in utero DEHP exposure and precocious puberty in the postnatal life of mice offspring, where disturbance of the sex determination regulating pathway acted as an important mechanism. PMID- 27495897 TI - Disruption of motor behavior and injury to the CNS induced by 3-thienylboronic acid in mice. AB - The scarcity of studies on boron containing compounds (BCC) in the medicinal field is gradually being remedied. Efforts have been made to explore the effects of BCCs due to the properties that boron confers to molecules. Research has shown that the safety of some BCCs is similar to that found for boron-free compounds (judging from the acute toxicological evaluation). However, it has been observed that the administration of 3-thienylboronic acid (3TB) induced motor disruption in CD1 mice. In the current contribution we studied in deeper form the disruption of motor performance produced by the intraperitoneal administration of 3TB in mice from two strains (CD1 and C57BL6). Disruption of motor activity was dependent not only on the dose of 3TB administered, but also on the DMSO concentration in the vehicle. The ability of 3TB to enter the Central Nervous System (CNS) was evidenced by Raman spectroscopy as well as morphological effects on the CNS, such as loss of neurons yielding biased injury to the substantia nigra and striatum at doses >=200mg/kg, and involving granular cell damage at doses of 400mg/kg but less injury in the motor cortex. Our work acquaints about the use of this compound in drug design, but the interesting profile as neurotoxic agent invite us to study it regarding the damage on the motor system. PMID- 27495898 TI - Continuous Acquisition of MHC:Peptide Complexes by Recipient Cells Contributes to the Generation of Anti-Graft CD8+ T Cell Immunity. AB - Understanding the evolution of the direct and indirect pathways of allorecognition following tissue transplantation is essential in the design of tolerance-promoting protocols. On the basis that donor bone marrow-derived antigen-presenting cells are eliminated within days of transplantation, it has been argued that the indirect response represents the major threat to long-term transplant survival, and is consequently the key target for regulation. However, the detection of MHC transfer between cells, and particularly the capture of MHC:peptide complexes by dendritic cells (DCs), led us to propose a third, semidirect, pathway of MHC allorecognition. Persistence of this pathway would lead to sustained activation of direct-pathway T cells, arguably persisting for the life of the transplant. In this study, we focused on the contribution of acquired MHC-class I on recipient DCs during the life span of a skin graft. We observed that MHC-class I acquisition by recipient DCs occurs for at least 1 month following transplantation and may be the main source of alloantigen that drives CD8+ cytotoxic T cell responses. In addition, acquired MHC-class I:peptide complexes stimulate T cell responses in vivo, further emphasizing the need to regulate both pathways to induce indefinite survival of the graft. PMID- 27495900 TI - Enteric fever in India: current scenario and future directions. AB - Enteric fever is a major cause of morbidity and mortality in tropical areas worldwide. The Indian subcontinent bears the brunt of the disease, both in terms of absolute case numbers and drug-resistant strains. Recent phylogenetic studies suggest that the multidrug-resistant clade H58 originated in India and subsequently expanded through Asia and Africa. In Africa, it caused unrecognised outbreaks in areas previously considered free of the disease. In this study, we discuss the current status of enteric fever in India, the factors preventing its control and its future directions in this rapidly developing nation. PMID- 27495901 TI - Exploring and Expanding the Fatty-Acid-Binding Protein Superfamily in Fasciola Species. AB - The liver flukes Fasciola hepatica and F. gigantica infect livestock worldwide and threaten food security with climate change and problematic control measures spreading disease. Fascioliasis is also a foodborne disease with up to 17 million humans infected. In the absence of vaccines, treatment depends on triclabendazole (TCBZ), and overuse has led to widespread resistance, compromising future TCBZ control. Reductionist biology from many laboratories has predicted new therapeutic targets. To this end, the fatty-acid-binding protein (FABP) superfamily has proposed multifunctional roles, including functions intersecting vaccine and drug therapy, such as immune modulation and anthelmintic sequestration. Research is hindered by a lack of understanding of the full FABP superfamily complement. Although discovery studies predicted FABPs as promising vaccine candidates, it is unclear if uncharacterized FABPs are more relevant for vaccine formulations. We have coupled genome, transcriptome, and EST data mining with proteomics and phylogenetics to reveal a liver fluke FABP superfamily of seven clades: previously identified clades I-III and newly identified clades IV VII. All new clade FABPs were analyzed using bioinformatics and cloned from both liver flukes. The extended FABP data set will provide new study tools to research the role of FABPs in parasite biology and as therapy targets. PMID- 27495899 TI - CAT3, a novel agent for medulloblastoma and glioblastoma treatment, inhibits tumor growth by disrupting the Hedgehog signaling pathway. AB - Medulloblastoma (MB) and glioblastoma (GBM) are the most prevalent malignant brain tumors. The identification of novel therapeutic strategies is urgent for MB and GBM patients. Herein, we discovered 13a-(S)-3-Hydroxyl-6,7 dimethoxyphenanthro[9,10-b]-indolizidine (PF403) strongly exhibited inhibitory activity against Hedgehog (Hh) pathway-hyperactivated MB and GBM cells with a 50% inhibitory concentration (IC50) of 0.01 nM. CAT3 was designed and synthesized as the prodrug of PF403 and displayed significant in vivo efficacy against MB and GBM. Mechanistic study revealed that CAT3 inhibited MB and GBM primarily by interrupting the Hh signaling pathway. At the molecular level, PF403 inhibited the cell surface accumulation of the Smoothened (Smo) receptor by directly binding or enhancing the interaction of Smo with the repressor Ptch1. Furthermore, PF403 significantly repressed Gli1 nuclear accumulation and transcription by promoting Sufu-Gli1 and PKA-Gli1 interactions. Collectively, our studies support the hypothesis that CAT3 is a promising therapeutic agent for the treatment of Hh-driven MB and GBM. PMID- 27495903 TI - Fatty acid composition of birds and game hunted by the Eastern James Bay Cree people of Quebec. AB - BACKGROUND: Indigenous peoples have traditionally relied on foods hunted and gathered from their immediate environment. The Eastern James Bay Cree people consume wild game and birds, and these are believed to provide health as well as cultural benefits. OBJECTIVE: To determine the fatty acid (FA) composition of traditional game and bird meats hunted in the Eastern James Bay area. DESIGN: Harvested traditional game and birds were analysed for FA composition. A total of 52 samples from six wildlife species were collected in the areas of Chisasibi, Waswanipi and Mistissini, of which 35 were from birds (white partridge and Canada goose) and 17 were from land animals (beaver, moose, caribou and black bear). RESULTS: Alpha-linolenic acid (ALA) was the most common n-3 polyunsaturated fatty acid (PUFA) in all samples except for the black bear flesh, in which it was docosapentaenoic acid (DPAn-3). In white partridge, beaver and caribou flesh, PUFAs (mainly n-6) were the most common category of fats while in goose, moose and black bear flesh, monounsaturated fatty acids (MUFAs) predominated. In all species, saturated fatty acids (SFAs) were the second most important FAs. It would appear that in the land animals and birds that were analysed, the SFA content was lower and the PUFA content was higher than store-bought meats giving them a more heart-healthy profile. CONCLUSIONS: These results showed that the FA composition of game species consumed by the James Bay Cree population is consistent with a beneficial diet and that traditional foods should continue to be promoted among the Cree people to provide better physical health as well as social and spiritual benefits. PMID- 27495902 TI - Oral microbial community typing of caries and pigment in primary dentition. AB - BACKGROUND: Black extrinsic discoloration in primary dentition is a common clinical and aesthetic problem that can co-occur with dental caries, the most common oral diseases in childhood. Although the role of bacteria in the formation of pigment and caries in primary dentition is important, their basic features still remain a further mystery. METHODS: Using targeted sequencing of the V1-V3 hypervariable regions of bacterial 16S ribosomal RNA (rRNA) genes, we obtained a dataset consisting of 831,381 sequences from 111 saliva samples and 110 supragingival plaque samples from 40 patients with pigment (black extrinsic stain), 20 with caries (obvious decay), and 25 with both pigment and caries and from 26 healthy individuals. We applied a Dirichlet multinomial mixture (DMM) based community typing approach to investigate oral microbial community types. RESULTS: Our results revealed significant structural segregation of microbial communities, as indicated by the identification of two plaque community types (A and B) and three saliva community types (C-E). We found that the independent occurrence of the two plaque community types, A and B, was potentially associated with our oral diseases of interest. For type A, three co-occurring bacterial genus pairs could separately play a potential role in the formation of pigment (Leptotrichia and Fusobacterium), caries (unclassified Gemellales and Granulicatella), and mixed caries and pigment (Streptococcus and Mogibacterium). For type B, three co-occurring bacterial genera (unclassified Clostridiaceae, Peptostreptococcus, and Clostridium) were related to mixed pigment and caries. Three dominant bacterial genera (Selenomonas, Gemella, and Streptobacillus) were linked to the presence of caries. CONCLUSIONS: Our study demonstrates that plaque associated oral microbial communities could majorly contribute to the formation of pigment and caries in primary dentition and suggests potential clinical applications of monitoring oral microbiota as an indicator for disease diagnosis and prognosis. PMID- 27495904 TI - Puerperal sepsis, the leading cause of maternal deaths at a Tertiary University Teaching Hospital in Uganda. AB - BACKGROUND: Maternal mortality is highest in sub-Saharan Africa. In Uganda, the WHO- MDG 5 (aimed at reducing maternal mortality by 75 % between 1990 and 2015) has not been attained. The current maternal mortality ratio (MMR) in Uganda is 438 per 100,000 live births coming from 550 per 100,000 in 1990. This study sets out to find causes and predictors of maternal deaths in a tertiary University teaching Hospital in Uganda. METHODS: The study was a retrospective unmatched case control study which was carried out at the maternity unit of Mbarara Regional Referral Hospital (MRRH). The sample included pregnant women aged 15-49 years admitted to the Maternity unit between January 2011 and November 2014. Data from patient charts of 139 maternal deaths (cases) and 417 controls was collected using a standard audit/data extraction form. Multivariable logistic regression analysis was used to assess for the factors associated with maternal mortality. RESULTS: Direct causes of mortality accounted for 77.7 % while indirect causes contributed 22.3 %. The most frequent cause of maternal mortality was puerperal sepsis (30.9 %), followed by obstetric hemorrhage (21.6 %), hypertensive disorders in pregnancy (14.4 %), abortion complications (10.8 %). Malaria was the commonest indirect cause of mortality accounting for 8.92 %. On multivariable logistic regression analysis, the factors associated with maternal mortality were: primary or no education (OR 1.9; 95 % CI, 1.0-3.3); HIV positive sero status (OR, 3.6; 95 % CI, 1.9-7.0); no antenatal care attendance (OR 3.6; 95 % CI, 1.8-7.0); rural dwellers (OR, 4.5; 95 % CI, 2.5-8.3); having been referred from another health facility (OR 5.0; 95 % CI, 2.9-10.0); delay to seek health care (delay-1) (OR 36.9; 95 % CI, 16.2-84.4). CONCLUSIONS: Most maternal deaths occur among mothers from rural areas, uneducated, HIV positive, unbooked mothers (lack of antenatal care), referred mothers in critical conditions and mothers delaying to seek health care. Puerperal sepsis is the leading cause of maternal deaths at Mbarara Regional Referral Hospital. Therefore more research into puerperal sepsis to describe the microbiology and epidemiology of sepsis is recommended. PMID- 27495905 TI - Quality of Life in Portuguese Patients with Diabetic Foot Ulcer Before and After an Amputation Surgery. AB - PURPOSE: Diabetic foot ulcer (DFU) including amputation surgery has serious consequences for patients, the family and healthcare services. DFU affects not only the physical health-related quality of life (HRQoL) of patients but also their mental well-being. The aims of this study were to find the predictors of HRQoL after surgery, to analyse differences in HRQoL, before and after surgery, and to explore the moderating role of a first versus previous amputation(s) in the relationship between physical and mental HRQoL, before and after surgery, in patients with DFU. METHOD: A longitudinal study comprising 108 Portuguese patients was conducted during the period of hospitalization before the surgery and at a follow-up consultation. Participants completed a socio-demographic questionnaire and the SF-36 to assess HRQoL. RESULTS: Physical and mental HRQoL before surgery predicted HRQoL after surgery, as well as the number of diabetes complications and having received a re-amputation. Physical HRQoL decreased after surgery, but there were no differences on mental HRQoL. Having a previous amputation was a moderator between physical and mental HRQoL before and after surgery. CONCLUSION: The results help to identify the most vulnerable patients at risk of having lower HRQoL after surgery, allowing interventions to be tailored to patients' needs in order to promote their quality of life. PMID- 27495907 TI - Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery. PMID- 27495906 TI - Percutaneous irreversible electroporation for breast tissue and breast cancer: safety, feasibility, skin effects and radiologic-pathologic correlation in an animal study. AB - BACKGROUND: To study the safety, feasibility and skin effects of irreversible electroporation (IRE) for breast tissue and breast cancer in animal models. METHODS: Eight pigs were used in this study. IRE was performed on the left breasts of the pigs with different skin-electrode distances, and the right breasts were used as controls. The electrodes were placed 1-8 mm away from the skin, with an electrode spacing of 1.5-2 cm. Imaging and pathological examinations were performed at specific time points for follow-up evaluation. Vital signs, skin damage, breast tissue changes and ablation efficacy were also closely observed. Eight rabbit models with or without VX2 breast tumor implantations were used to further assess the damage caused by and the repair of thin skin after IRE treatment for breast cancer. Contrast-enhanced ultrasound and elastosonography were used to investigate ablation efficacy and safety. RESULTS: During IRE, the color of the pig breast skin reversibly changed. When the skin electrode distance was 3 mm, the breast skin clearly changed, becoming white in the center and purple in the surrounding region during IRE. One small purulent skin lesion was detected several days after IRE. When the skin-electrode distance was 5-8 mm, the breast skin became red during IRE. However, the skin architecture was normal when evaluated using gross pathology and hematoxylin-eosin staining. When the skin-electrode distance was 1 mm, skin atrophy and yellow glabrescence occurred in the rabbit breasts after IRE. When the skin-electrode distance was >=5 mm, there was no skin damage in the rabbit model regardless of breast cancer implantation. After IRE, complete ablation of the targeted breast tissue or cancer was confirmed, and apoptosis was detected in the target tissue and outermost epidermal layer. In the ablated breasts of the surviving animals, complete mammary regeneration with normal skin and hair was observed. Furthermore, no massive fibrosis or mass formation were detected on ultrasound or through hematoxylin-eosin staining. CONCLUSIONS: After IRE, the skin architecture was well preserved when the skin-electrode distance was >=5 mm. Moreover, breast regeneration occurred without mass formation or obvious fibrosis. PMID- 27495908 TI - The River Ruhr - an urban river under particular interest for recreational use and as a raw water source for drinking water: The collaborative research project "Safe Ruhr" - microbiological aspects. AB - Along the intense industrialization of the Ruhr valley (Germany), the River Ruhr became increasingly polluted. Over time, using it for recreational purposes became a serious health hazard and bathing was banned due to chemical and microbiological risks. The purpose of the collaborative project "Safe Ruhr" was to verify the current status and to provide a scientific basis for lifting the bathing ban. As the river also provides a raw water source for drinking water production, it was investigated how well the treatment procedures control possible hygienic risks. As study area, the barrier Lake Baldeney was chosen as it embraces earlier bathing sites and tributes to river bank filtration water for drinking water treatment plants. The hygienic condition of the river water was determined over 18 months by measuring general physical, chemical and microbiological water quality parameters including fecal indicators, bacterial obligate and facultative pathogens, parasitic protozoa, enteric viruses and schistosome parasites (Trichobilharzia). Samples were taken at eight locations including sites before and after receiving the discharge of stormwater and treated wastewater, potential future bathing sites and a raw water abstraction point for potable water production. In summary, for all investigated physico chemical parameters no significant difference between the eight investigated sampling locations on a distinct sampling date were observed. This study focused on hygienically relevant bacteria and parasitic protozoa. Fecal indicators, Escherichia coli, intestinal enterococci and Clostridium perfringens as well as coliform bacteria were detected in 94-100% of the water samples. Enteric pathogens, including Campylobacter spp. and Salmonella enterica, were isolated from 33% and 28% of the samples, respectively, in relatively low concentrations. Among the environmental facultative pathogens, P. aeruginosa was detected at a high frequency of 82% of all samples, but in low numbers, while Aeromonas spp. were found in all water samples in relative high concentrations. The levels of all target organisms were not clearly associated with sources of pollution, with the exception of slightly enhanced numbers of coliform bacteria and E. coli downstream of a sewage discharge point from a wastewater treatment plant. Seasonal variations were observed with higher detection rates of Campylobacter spp. in winter and S. enterica in autumn and winter in contrast to the other bacterial groups, which showed no significant fluctuations throughout the year. Precipitation within two days prior to sampling resulted in a trend of enhanced numbers of coliform bacteria, E. coli, intestinal enterococci and Aeromonas. Sampling and analysis of parasitic protozoa was carried out in accordance to the European bathing water guideline and the ISO 15553 method. Characteristics of the river (flow, vegetation, birds protection zone, bathing of people, sewage etc.) were compared to the number of organisms detected. All in all 184 samples were investigated for Cryptosporidium spp. and Giardia spp. 80% of the samples were positive for Giardia spp. with a mean of 5cysts/100l (0.1-157.9). Highest values were achieved in autumn and winter, lowest values during the assumed bathing season. There seemed to be a trend to lower values in and after a reservoir in the river course, but with no statistical significance. A statistical significance could be shown for higher concentrations after heavy rainfall that led to discharge of combined sewage overflows in the city of Essen. Only 29% of the samples were positive for Cryptosporidium spp. with a single maximum value of 27.7 and all other concentrations below 5 oocysts/100l. On a low level there seemed to be slightly higher findings during summer and bathing season than in autumn and winter. No correlation to heavy rainfall could be found. The findings correspond to earlier results from the River Rhine (Germany). The influence of sewage on the water quality of the Ruhr could be shown from the correlation of Giardia load and activity of combined sewage overflows after heavy rainfall. The rare and low findings of Cryptosporidium spp. lead to the same conclusion, that microbial water quality in the investigation area is rather influenced from sewage water than from diffuse water sources into the River Ruhr. PMID- 27495909 TI - [Editorial]. PMID- 27495910 TI - [Short version of the German S3 guideline for bladder cancer]. AB - Urinary bladder cancer is the second most common cancer of the urogenital system. The Guideline Program in Oncology (Leitlinienprogramm Onkologie) of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF), the German Cancer Society (Deutsche Krebsgesellschaft) and the German Cancer Aid (Deutsche Krebshilfe) as well as 31 different medical societies have developed the first interdisciplinary, evidence-based German guideline for bladder cancer. This short version presents the resulting series of diagnostic and therapeutic recommendations which were based on a systematic literature search and approved by a team of bladder cancer experts. The full version is available under http://leitlinienprogramm-onkologie.de/ . PMID- 27495911 TI - Practical achievements on biomass steam gasification in a rotary tubular coiled downdraft reactor. AB - Today, the impending stringent environmental norms and concerns about the depletion of fossil fuel reserves have added impetus on development of cutting edge technologies for production of alternative fuels from renewable sources, like biomass. The concept of biomass pyro-gasification offers a platform for production of (a) hydrogen, (b) hydrocarbons and (c) value added chemicals, etc. In this context, there exists potential for hydrogen production from biomass by superheated steam gasification. Apart from H2, gaseous products of biomass steam gasification contain CO, CH4 and other hydrocarbons that can be converted to hydrogen through cracking, steam reforming and water gas shift reactions. In the present work, the characteristics of biomass steam gasification in an indigenously designed rotary tubular coiled-downdraft reactor for high value gaseous fuel production from rice husk was studied through a series of experiments. The robust reactor system enhances biomass conversion to gaseous products by improved mass and heat transfer within the system induced by a coiled flow pattern with increased heat transfer area. Also, the system has improved upon the reliability of operation and offered greater continuity of the process and easier control in comparison with a conventional process by making use of an innovative gas cooler assembly and efficient venturi-mixing system for biomass and steam. Subsequently, the effects of reactor temperature, steam-to-biomass ratio and residence time on overall product gas yield and hydrogen yield were investigated. From the experimental results, it can be deduced that an optimum reactor temperature of 750 degrees C, steam-to-biomass ratio of 2.0 and a residence time of 3.0 min contributed highest gas yield (1.252 Nm3 kg-1 moisture free biomass). Based on the obtained experimental results, a projected potential hydrogen yield of 8.6 wt% of the moisture-free biomass could be achieved, and is also practical for production of pure hydrogen. PMID- 27495912 TI - Surgical control and margin status after robotic and open cystectomy in high-risk cases: Caution or equivalence? AB - PURPOSE: The benefits of robotic-assisted radical cystectomy (RARC) are unclear, especially in patients with high-risk disease (pT3/T4). We evaluated pathological and postoperative outcomes of RARC versus open radical cystectomy (ORC) in these patients. METHODS: We identified bladder cancer patients treated with RARC or ORC from January 2010-August 2014. Clinicodemographic factors were examined for potential confounding. Our primary outcome of interest was positive soft-tissue surgical margins (STSMs). Secondary outcomes included post-operative complications and length of stay (LOS). We used logistic regression to define the association between clinical factors with outcomes of interest, focusing on patients with locally advanced disease. RESULTS: We identified 472 patients treated with ORC (407, 86.2 %) or RARC (65, 13.8 %) of which 215 (45.6 %) were high-risk cases based on advanced pathologic stage (pT3/4). RARC patients were more commonly men (96.9 vs. 73.2 %, p < 0.01), had better performance status (ECOG 0, 78.5 vs. 59.7 %, p = 0.031), and received less neoadjuvant chemotherapy (21.5 vs. 39.3 %, p = 0.006). Total (52.3 vs. 59.7 %, p = 0.26) and high-grade complication rates (13.8 vs. 19.7 %, p = 0.27) were similar, but median LOS was shorter after RARC (6 vs. 7 days, p < 0.01). On multivariate analysis, prior pelvic radiation (OR: 4.78, 95 % CI: 2.16-10.57), and advanced tumor stage (OR: 3.06, 95 % CI: 1.56-6.03) were independently associated with positive STSMs in high-risk patients but robotic surgical approach was not (OR: 0.81, 95 % CI: 0.29 2.30; p = 0.69). CONCLUSION: RARC had similar short-term postoperative outcomes compared to ORC and did not compromise oncological control in patients with extravesical disease. PMID- 27495913 TI - Effect of dosimeter's position on occupational radiation extremity dose measurement for nuclear medicine workers during (18)F-FDG preparation for PET/CT. AB - BACKGROUND: The recent spread of positron emission tomography-computed tomography (PET/CT) poses extremity dosimetry challenges. The question arose whether the radiation dose measured by the ring thermoluminescent dosimeter usually worn on the proximal phalanx (P1) of the index finger measures doses that are representative of the true doses received by the upper extremities of the operators. A prospective individual dosimetry study was performed in which the personal equivalent dose Hp (0.07) received during a specific 2-[(18)F]fluoro-2 deoxy-D-glucose ((18)F-FDG) manual dose-dispensing procedure was measured in a paired design by two operational personal electronic dosimeters fitted on the palm side of the index finger, namely in the P1 and distal phalanx (P3) positions. The study participants were ten nuclear medicine technologists working in two nuclear medicine departments. The personal equivalent radiation doses received by the palm side of the proximal phalanx of the index finger [Hp (0.07)P1] and that received by the distal phalanx [Hp (0.07)P3] were compared. RESULTS: The median Hp (0.07)P3/Hp (0.07)P1 ratio per participant varied between 1.0 and 2.5 (based on 23 to 31 measurements per participant). The 271 paired measurements revealed a crude Hp (0.07)P3/Hp (0.07)P1 ratio of 1.67, significantly different from 1 (p = 0.0004, 95 % CI [1.35-2.07]). When adjusted on participant's gender and mother vial activity, the ratio was similar (1.53, p = 0.003, 95 % CI [1.22-1.92]). CONCLUSIONS: The study demonstrated a significant disparity that may exist between the radiation doses measured in the P1 and P3 positions of operators during (18)F-FDG manipulation. These findings emphasize the importance of performing workplace dosimetry studies adapted to each radiopharmaceutical and manipulation thereof, aiming to guarantee optimal workers' dosimetry monitoring schemes. TRIAL REGISTRATION: Hospital Nursing and Paramedical Research Program (PHRIP, 2011-2013) from the French Ministry of Health (DGOS), http://social-sante.gouv.fr/IMG/pdf/Resultats_PHRIP_2011.pdf. PMID- 27495914 TI - Abdo-Man: a 3D-printed anthropomorphic phantom for validating quantitative SIRT. AB - BACKGROUND: The use of selective internal radiation therapy (SIRT) is rapidly increasing, and the need for quantification and dosimetry is becoming more widespread to facilitate treatment planning and verification. The aim of this project was to develop an anthropomorphic phantom that can be used as a validation tool for post-SIRT imaging and its application to dosimetry. METHOD: The phantom design was based on anatomical data obtained from a T1-weighted volume-interpolated breath-hold examination (VIBE) on a Siemens Aera 1.5 T MRI scanner. The liver, lungs and abdominal trunk were segmented using the Hermes image processing workstation. Organ volumes were then uploaded to the Delft Visualization and Image processing Development Environment for smoothing and surface rendering. Triangular meshes defining the iso-surfaces were saved as stereo lithography (STL) files and imported into the Autodesk(r) Meshmixer software. Organ volumes were subtracted from the abdomen and a removable base designed to allow access to the liver cavity. Connection points for placing lesion inserts and filling holes were also included. The phantom was manufactured using a Stratasys Connex3 PolyJet 3D printer. The printer uses stereolithography technology combined with ink jet printing. Print material is a solid acrylic plastic, with similar properties to polymethylmethacrylate (PMMA). RESULTS: Measured Hounsfield units and calculated attenuation coefficients of the material were shown to also be similar to PMMA. Total print time for the phantom was approximately 5 days. Initial scans of the phantom have been performed with Y-90 bremsstrahlung SPECT/CT, Y-90 PET/CT and Tc-99m SPECT/CT. The CT component of these images compared well with the original anatomical reference, and measurements of volume agreed to within 9 %. Quantitative analysis of the phantom was performed using all three imaging techniques. Lesion and normal liver absorbed doses were calculated from the quantitative images in three dimensions using the local deposition method. CONCLUSIONS: 3D printing is a flexible and cost-efficient technology for manufacture of anthropomorphic phantom. Application of such phantoms will enable quantitative imaging and dosimetry methodologies to be evaluated, which with optimisation could help improve outcome for patients. PMID- 27495915 TI - Ischemia/reperfusion injury in vascularized tissue allotransplantation: tissue damage and clinical relevance. AB - PURPOSE OF REVIEW: Ischemia and reperfusion injury (IRI) in vascularized tissue allotransplantation (VCA) remain largely undefined. Because VCA is comprised of different tissues, the sensitivity towards IRI may not be uniform. We, herein, attempt to address mechanistic aspects of IRI in VCA and provide a summary on potential technologies and targets for amelioration or treatment of IRI in this novel field. RECENT FINDINGS: IRI results in a loosened architecture of musculature, hypertrophic, centrally located cell nuclei as well as a high degree of neovascularization. Mitochondria in muscle tissue show a high degree of degeneration after prolonged ischemia whereas the ultrastructure remains normal after short cold ischemia time (CIT). Muscle cell necrosis accompanied by a diffuse inflammatory infiltrate and vasculopathy of small vessels is observed after 30 h of CIT. Nerves revealed a high degree of separation and vacuolization of myelin lamellae because of Wallerian degeneration. Approaches to minimize IRI include use of novel preservation solutions, administration of antioxidative and anti-inflammatory molecules/drugs as well as the implementation of machine perfusion in the setting of VCA. SUMMARY: Hand and face transplantations are logistically challenging procedures. Optimal planning and a highly congruent and motivated team are key to keep ischemia times to a minimum. In addition to pharmacological approaches, machine perfusion seems promising to help circumvent logistic problems and expand the donor pool in VCA. PMID- 27495916 TI - The abdominal wall transplant as a sentinel skin graft. AB - PURPOSE OF REVIEW: Abdominal wall transplantation is a technique used to achieve abdominal closure after intestinal and multivisceral transplantation. This review focuses on whether there are additional benefits for the skin component as an immune-monitoring tool. RECENT FINDINGS: The largest series of abdominal wall transplants has recently been published. Alongside the physiological advantage gained in abdominal closure, the authors describe the immunological insight that the skin component can provide and how this contributes to the management of patients. The skin appears to develop a rash with early rejection, which facilitates early systemic treatment before significant visceral rejection occurs. It can also help in cases in which there is diagnostic doubt regarding the cause of bowel dysfunction such as in instances of intestinal infection. Despite the additional immunological burden of donor tissue, there appears to be no requirement for increased immunosuppressive therapy. SUMMARY: The technical and immunological feasibility of abdominal wall transplantation has now been demonstrated by several centres. Skin transplanted as part of the abdominal wall or as a separate vascularized sentinel skin flap may aid in the diagnosis of rejection. This has the potential to improve graft survival and reduce immunosuppressive morbidity. PMID- 27495918 TI - Insurance claims related to opioid dependence have risen by 3200%, US study finds. PMID- 27495917 TI - Behavioral interventions to reduce inappropriate antibiotic prescribing: a randomized pilot trial. AB - BACKGROUND: Clinicians frequently prescribe antibiotics inappropriately for acute respiratory infections (ARIs). Our objective was to test information technology enabled behavioral interventions to reduce inappropriate antibiotic prescribing for ARIs in a randomized controlled pilot test trial. METHODS: Primary care clinicians were randomized in a 2 * 2 * 2 factorial experiment with 3 interventions: 1) Accountable Justifications; 2) Suggested Alternatives; and 3) Peer Comparison. Beforehand, participants completed an educational module. Measures included: rates of antibiotic prescribing for: non-antibiotic appropriate ARI diagnoses, acute sinusitis/pharyngitis, all other diagnoses/symptoms of respiratory infection, and all three ARI categories combined. RESULTS: We examined 3,276 visits in the pre-intervention year and 3,099 in the intervention year. The antibiotic prescribing rate fell for non antibiotic-appropriate ARIs (24.7 % in the pre-intervention year to 5.2 % in the intervention year); sinusitis/pharyngitis (50.3 to 44.7 %); all other diagnoses/symptoms of respiratory infection (40.2 to 25.3 %); and all categories combined (38.7 to 24.2 %; all p < 0.001). There were no significant relationships between any intervention and antibiotic prescribing for non-antibiotic appropriate ARI diagnoses or sinusitis/pharyngitis. Suggested Alternatives was associated with reduced antibiotic prescribing for other diagnoses or symptoms of respiratory infection (odds ratio [OR], 0.62; 95 % confidence interval [CI], 0.44 0.89) and for all ARI categories combined (OR, 0.72; 95 % CI, 0.54-0.96). Peer Comparison was associated with reduced prescribing for all ARI categories combined (OR, 0.73; 95 % CI, 0.53-0.995). CONCLUSIONS: We observed large reductions in antibiotic prescribing regardless of whether or not study participants received an intervention, suggesting an overriding Hawthorne effect or possibly clinician-to-clinician contamination. Low baseline inappropriate prescribing may have led to floor effects. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01454960 . PMID- 27495919 TI - Inactivation, lysis and degradation by-products of Saccharomyces cerevisiae by electrooxidation using DSA. AB - The yeast Saccharomyces cerevisiae, a microorganism with cell walls resistant to many types of treatments, was chosen as a model to study electrochemical disinfection process using dimensionally stable anodes (DSA). DSA electrodes with nominal composition of Ti/RuO2TiO2 and Ti/RuO2TiO2IrO2 were evaluated in 0.05 mol L-1 Na2SO4 containing yeast. The results showed inactivation about of 100 % of the microorganisms at Ti/RuO2TiO2 by applying 20 and 60 mA cm-2 after 120 min of electrolysis, while a complete inactivation at Ti/RuO2IrO2TiO2 electrode was achieved after 180 min at 60 mA cm-2. When chloride ions were added in the electrolyte solution, 100 % of the yeast was inactivated at 20 mA cm-2 after 120 min of electrolysis, independent of the anode used. In the absence of chloride, the energy consumption (EC) was of 34.80 kWh m-3, at 20 mA cm-2 by using Ti/RuO2TiO2 anode. Meanwhile, in the presence of chloride, EC was reduced, requiring 30.24 and 30.99 kWh m-3 at 20 mA cm-2, for Ti/RuO2TiO2 and Ti/RuO2IrO2TiO2 electrodes, respectively, The best performance for cell lysis was obtained in the presence of chloride with EC of 88.80 kWh m-3 (Ti/RuO2TiO2) and 91.85 kWh m-3 (Ti/RuO2IrO2TiO2) to remove, respectively, 92 and 95 % of density yeast. The results clearly showed that yeast, as a model adopted, was efficiently inactivated and lysed by electrolysis disinfection using DSA-type electrodes. PMID- 27495920 TI - Acute, chronic and biochemical effects of chlorothalonil on Agalychnis callidryas, Isthmohyla pseudopuma and Smilisca baudinii tadpoles. AB - Declines of amphibian populations have been a worldwide issue of concern for the scientific community during the last several decades. Efforts are being carried out to elucidate factors related to this phenomenon. Among these factors, pathogens, climate change, and environmental pollution have been suggested as possible causes. Regarding environmental pollutants, some pesticides are persistent in the environment and capable of being transported long distances from their release point. In Costa Rica, some pesticides have been detected in protected areas, at locations where amphibian populations have declined. Information about toxicity of pesticides used in Costa Rican agriculture to amphibians is still scarce, particularly for native species.Toxicity tests with chlorothalonil, a fungicide intensively used in Costa Rica, were carried out exposing tadpoles of three Costa Rican native species: Agalychnis callidryas, Isthmohyla pseudopuma, and Smilisca baudinii in order to evaluate acute and chronic toxicity as well as the biomarkers cholinesterase activity (ChE), glutathione-S transferase activity (GST), and lipid peroxidation (LPO).96-h LC50: 26.6 (18.9-35.8) MUg/L to A. callidryas, 25.5 (21.3-29.7) MUg/L to I pseudopuma and 32.3 (26.3-39.7) MUg/L to S. baudinii were determined for chlorothalonil. These three species of anurans are among the most sensitive to chlorothalonil according to the literature. Besides, GST was induced in S. baudinii after exposure to sub-lethal concentrations of chlorothalonil while evisceration occurred in S. baudinii and A. callidryas tadpoles exposed to lethal concentrations of the fungicide. Chronic exposure to sub-lethal concentrations accelerated development in S. baudinii and caused lesions in tail of S. baudinii and I. pseudopuma tadpoles. Our results demonstrate that chlorothalonil is highly toxic to native amphibian species and that low concentrations can cause biochemical responses related to phase II of biotransformation and effects on development. PMID- 27495921 TI - Properties of biochars from conventional and alternative feedstocks and their suitability for metal immobilization in industrial soil. AB - In contaminated soils, excessive concentrations of metals and their high mobility pose a serious environmental risk. A suitable soil amendment can minimize the negative effect of metals in soil. This study investigated the effect of different biochars on metal (Cu, Pb, Zn) immobilization in industrial soil. Biochars produced at 300 and 600 degrees C from conventional (MS, maize silage; WP, wooden pellets) and alternative (SC, sewage sludge compost; DR, digestate residue) feedstocks were used as soil amendments at a dosage of 10 % (w/w). The type of feedstock and pyrolysis temperature affected the properties of the biochars and their ability to immobilize metal in soil. Compared to production at 300 degrees C, all biochars produced at 600 degrees C had higher pH (6.2-10.7), content of ash (7.2-69.0 %) and fixed carbon (21.1-56.7 %), but lower content of volatile matter (9.7-37.2 %). All biochars except DR biochar had lower dissolved organic carbon (DOC) content (1.4-2.3 g C/L) when made at 600 degrees C. Only MS and SC biochars had higher cation exchange capacity (25.2 and 44.7 cmol/kg, respectively) after charring at 600 degrees C. All biochars contained low concentrations of Cd, Cu, Ni, Pb and Zn; Cd was volatilized to the greatest extent during pyrolysis. Based on FTIR analysis and molar ratios of H/C and O/C, biochars had a greater degree of carbonization and aromaticity after charring at 600 degrees C. The efficiency of the biochars in metal immobilization depended mainly on their pH, ash content, and concentration of DOC. SC and DR biochars were more effective for Cu and Zn immobilization than MS and WP biochars, which makes them attractive options for large-scale soil amendment. PMID- 27495923 TI - Erratum to: Geophysical, isotopic, and hydrogeochemical tools to identify potential impacts on coastal groundwater resources from Urmia hypersaline Lake, NW Iran. PMID- 27495924 TI - Hypopigmented macules and papules following the lines of Blaschko: a novel variant of Darier's disease. PMID- 27495922 TI - Recovery of Lemna minor after exposure to sulfadimethoxine irradiated and non irradiated in a solar simulator. AB - Sulfonamides are the second most widely used group of veterinary antibiotics which are often detected in the environment. They are eliminated from freshwaters mainly through photochemical degradation. The toxicity of sulfadimethoxine (SDM) was evaluated with the use of Lemna minor before and after 1- and 4-h irradiation in a SunTest CPS+ solar simulator. Eight endpoints consisting of: number and total area of fronds, fresh weight, chlorophylls a and b, carotenoids, activity of catalase and guaiacol peroxidase, and protein content were determined. The total frond area and chlorophyll b content were the most sensitive endpoints with EC50 of 478 and 554 MUg L-1, respectively. The activity of guaiacol peroxidase and catalase increased at SDM concentrations higher than 125 and 500 MUg L-1, respectively. The SDM photodegradation rate for first order kinetics and the half life were 0.259 h-1 and 2.67 h, respectively. The results show that the toxicity of irradiated solutions was caused by SDM only, and the photoproducts appeared to be either non-toxic or much less toxic to L. minor than the parent compound. To study the recovery potential of L. minor, after 7 days exposure in SDM solutions, the plants were transferred to fresh medium and incubated for the next 7 days. L. minor has the ability to regenerate, but a 7-day recovery phase is not sufficient for it to return to an optimal physiological state. PMID- 27495925 TI - Biomechanism of chlorogenic acid complex mediated plasma free fatty acid metabolism in rat liver. AB - BACKGROUND: Plasma free fatty acids (FFA) are involved in blood lipid metabolism as well as many health complications. The present study was conducted to evaluate the potential role of chlorogenic acid complex from green coffee bean (CGA7) on FFA metabolism in high fat diet fed rats. METHODS: Hyperlipidemia was induced in Wistar rats using high-fat diet. The animals were given CGA7/orlistat concurrently for 42 days. The parameters analysed during the study include plasma and liver total cholesterol (TC), Triglycerides (TG) and FFA. AMPK activation in the liver was analysed through ELISA. The multiple factors involved in AMPK mediated FFA metabolism were analysed using western blotting. RESULTS: CGA7 (50, 100, 150 mg/kg BW) decreased triglycerides (TG) and FFA levels in plasma and liver. CGA7 administration led to the activation of AMP-activated protein kinase (AMPK) and a subsequent increase in the levels of carnitine palmitoyltransferase 1 (CPT-1). There was a decrease in acetyl-CoA carboxylase (ACC) activity as evident by the increase in its phosphorylation level. CONCLUSION: Chlorogenic acids improved the blood lipid metabolism in rats by alleviating the levels of FFA and TG, modulating the multiple factors in liver through AMPK pathway. The study concludes that CGA7 complex can be promoted as an active ingredient in nutrition for obesity management. PMID- 27495926 TI - Antimicrobial agents - optimising the ecological balance. AB - BACKGROUND: There is no more challenging a group of pharmaceuticals than antimicrobials. With the antibiotic era came great optimism as countless deaths were prevented from what were previously fatal conditions. Although antimicrobial resistance was quickly identified, the abundance of antibiotics entering the market helped cement attitudes of arrogance as the "battle against pestilence appeared won". Opposite emotions soon followed as many heralded the return of the pre-antibiotic era, suggesting that the "antibiotic pipeline had dried up" and that our existing armament would soon be rendered worthless. DISCUSSION: In reality, humans overrate their ecological importance. For millions of years there has been a balance between factors promoting bacterial survival and those disturbing it. The first half century of the "antibiotic era" was characterised by a cavalier attitude disturbing the natural balance; however, recent efforts have been made through several mechanisms to respond and re-strengthen the antimicrobial armament. Such mechanisms include a variety of incentives, educational efforts and negotiations. Today, there are many more "man-made" factors that will determine a new balance or state of ecological harmony. CONCLUSION: Antibiotics are not a panacea nor will they ever be inutile. New resistance mechanisms will be identified and new antibiotics will be discovered, but most importantly, we must optimise our application of these extraordinary "biological tools"; therein lays our greatest challenge - creating a society that understands and respects the determinants of the effectiveness of antibiotics. PMID- 27495928 TI - Evaluation of the perceptions and cosmetic satisfaction of breast cancer patients undergoing totally implantable vascular access device (TIVAD) placement. AB - PURPOSE: Totally implantable vascular access devices (TIVADs) are widely used to administer chemotherapy to cancer patients. While great progress has been made with respect to breast surgical reconstruction to take into account both aesthetics and patients' perceptions of body integrity, these aspects have not been considered with regard to the impact of TIVAD. In order to address this practice gap, we have adapted our TIVAD implantation technique to improve cosmetic results. The aim of this study was to assess breast cancer patients' comfort level and aesthetic satisfaction with regard to TIVAD insertion. METHODS: Patients with breast cancer admitted for chemotherapy at an outpatient clinic completed a previously validated survey evaluating three main domains: symptoms (pain, discomfort) related to the TIVAD itself in daily activity, information received before and during the surgical procedure, and cosmetic aspects regarding the port insertion site (scar, port, and catheter location). RESULTS: Between September 2010 and June 2011, 232 patients were evaluated. Cosmetic satisfaction with scar location was high (93.3 %). Information given to patients before and during the procedure had a major impact on both symptom perception in daily activity and on cosmetic satisfaction. CONCLUSIONS: Obtaining a more aesthetic scar by placing the TIVAD in the deltopectoral groove contributed to a high rate of cosmetic satisfaction. Furthermore, the relevance of information given to patients before and/or during surgery had a major impact on symptom perception. Therefore, we suggest including a pre-operative information session in the care pathway. PMID- 27495927 TI - It's not only what you say, it's also how you say it: communicating nipah virus prevention messages during an outbreak in Bangladesh. AB - BACKGROUND: During a fatal Nipah virus (NiV) outbreak in Bangladesh, residents rejected biomedical explanations of NiV transmission and treatment and lost trust in the public healthcare system. Field anthropologists developed and communicated a prevention strategy to bridge the gap between the biomedical and local explanation of the outbreak. METHODS: We explored residents' beliefs and perceptions about the illness and care-seeking practices and explained prevention messages following an interactive strategy with the aid of photos showed the types of contact that can lead to NiV transmission from bats to humans by drinking raw date palm sap and from person-to-person. RESULTS: The residents initially believed that the outbreak was caused by supernatural forces and continued drinking raw date palm sap despite messages from local health authorities to stop. Participants in community meetings stated that the initial messages did not explain that bats were the source of this virus. After our intervention, participants responded that they now understood how NiV could be transmitted and would abstain from raw sap consumption and maintain safer behaviours while caring for patients. CONCLUSIONS: During outbreaks, one-way behaviour change communication without meaningful causal explanations is unlikely to be effective. Based on the cultural context, interactive communication strategies in lay language with supporting evidence can make biomedical prevention messages credible in affected communities, even among those who initially invoke supernatural causal explanations. PMID- 27495929 TI - Quantitative analysis of local-level resurgence. AB - Resurgence is the recurrence of a previously reinforced and then extinguished behavior induced by the extinction of another more recently reinforced behavior. Resurgence provides insight into behavioral processes relevant to treatment relapse of a range of problem behaviors. Resurgence is typically studied across three phases: (1) reinforcement of a target response, (2) extinction of the target and concurrent reinforcement of an alternative response, and (3) extinction of the alternative response, resulting in the recurrence of target responding. Because each phase typically occurs successively and spans multiple sessions, extended time frames separate the training and resurgence of target responding. This study assessed resurgence more dynamically and throughout ongoing training in 6 pigeons. Baseline entailed 50-s trials of a free-operant psychophysical procedure, resembling Phases 1 and 2 of typical resurgence procedures. During the first 25 s, we reinforced target (left-key) responding but not alternative (right-key) responding; contingencies reversed during the second 25 s. Target and alternative responding followed the baseline reinforcement contingencies, with alternative responding replacing target responding across the 50 s. We observed resurgence of target responding during signaled and unsignaled probes that extended trial durations an additional 100 s in extinction. Furthermore, resurgence was greater and/or sooner when probes were signaled, suggesting an important role of discriminating transitions to extinction in resurgence. The data were well described by an extension of a stimulus-control model of discrimination that assumes resurgence is the result of generalization of obtained reinforcers across space and time. Therefore, the present findings introduce novel methods and quantitative analyses for assessing behavioral processes underlying resurgence. PMID- 27495930 TI - Ultimate and proximate mechanisms of reciprocal altruism in rats. AB - The reciprocal exchange of goods and services among social partners is a conundrum in evolutionary biology because of its proneness to cheating, but also the behavioral and cognitive mechanisms involved in such mutual cooperation are hotly debated. Extreme viewpoints range from the assumption that, at the proximate level, observed cases of "direct reciprocity" can be merely explained by basic instrumental and Pavlovian association processes, to the other extreme implying that "cultural factors" must be involved, as is often attributed to reciprocal cooperation among humans. Here we argue that neither one nor the other extreme conception is likely to explain proximate mechanisms underlying reciprocal altruism in animals. In particular, we outline that Pavlovian association processes are not sufficient to explain the documented reciprocal cooperation among Norway rats, as has been recently argued. PMID- 27495931 TI - Perceptual learning transfer in an appetitive Pavlovian task. AB - In two experiments, rats were given intermixed or blocked preexposure to two similar compound stimuli, AX and BX. Following preexposure, conditioning trials took place in which AX (Experiment 1) or a novel compound stimulus NX (Experiment 2) was paired with a food-unconditioned stimulus in an appetitive Pavlovian preparation. Animals that were given alternated preexposure showed lower generalization from AX to BX (Experiment 1) and from NX to a new compound, ZX (Experiment 2), than animals that were given blocked preexposure, a perceptual learning and a perceptual learning transfer effect, respectively. PMID- 27495932 TI - Intertrial unconditioned stimuli differentially impact trace conditioning. AB - Three experiments assessed how appetitive conditioning in rats changes over the duration of a trace conditioned stimulus (CS) when unsignaled unconditioned stimuli (USs) are introduced into the intertrial interval. In Experiment 1, a target US occurred at a fixed time either shortly before (embedded), shortly after (trace), or at the same time (delay) as the offset of a 120-s CS. During the CS, responding was most suppressed by intertrial USs in the trace group, less so in the delay group, and least in the embedded group. Unreinforced probe trials revealed a bell-shaped curve centered on the normal US arrival time during the trace interval, suggesting that temporally specific learning occurred both with and without intertrial USs. Experiments 2a and 2b confirmed that the bulk of the trace CS became inhibitory when intertrial USs were scheduled, as measured by summation and retardation tests, even though CS offset evoked a temporally precise conditioned response. Thus, an inhibitory CS may give rise to new stimuli specifically linked to its termination, which are excitatory. A modification to the microstimulus temporal difference model is offered to account for the data. PMID- 27495933 TI - Validity and reliability of ankle morphological measurements on computerized tomography-synthesized planar radiographs. AB - BACKGROUND: Clinical success of total ankle arthroplasty depends heavily on the available information on the morphology of the bones, often obtained from measurements on planar radiographs. The current study aimed to evaluate the intra rater, inter-rater and inter-session reliability and the validity of radiograph based measurements of ankle morphology, and to quantify the effects of examiner experience on these measurements. METHODS: Twenty-four fresh frozen ankle specimens were CT scanned, data of which were used to reconstruct 3D volumetric bone models for synthesizing 2D radiographs. Two orthopaedic surgeons with different levels of clinical experience identified twenty landmarks five times on each of the synthesized sagittal and coronal radiographs and repeated the test on a subsequent day within 5 days. The landmarks were used to calculate fourteen morphological parameters. The two-way mixed-effects (ICC3,1), two-way random effects (ICC2,k) and two-way random-effects (ICC3,k) models were used, respectively, to assess the intra-rater, inter-rater and inter-session reliability of measurements. The validity of the measurements for each examiner was assessed by comparing them with gold standard values obtained from the 2D radiographs projected from the 3D volumetric models using Pearson's correlation analysis and Bland and Altman plots, and the differences were defined as the measurement errors. RESULTS: Most of the morphological parameters were of good to very good intra-rater, inter-session and inter-rater reliability for both examiners (ICC > 0.61). Experience appeared to affect the inter-rater and inter session reliability, the senior examiner showing greater inter-session ICC values than the junior examiner. Most of the tibial parameters had moderate to excellent correlations with the corresponding gold standard values but were underestimated by both examiners, in contrast to most of the talar parameters that were overestimated and had only poor to fair correlations. CONCLUSIONS: Most of the morphological parameters of the ankle can be estimated from radiographs with good to very good intra-rater, inter-session and inter-rater reliability, for both clinically experienced and less experienced examiners. Clinical experience helped increase the reliability of repeated evaluations after a longer interval, such as in a follow-up assessment. It is suggested that critical clinical decisions based on repeated morphology measurements should be made by more experienced surgeons or after appropriate training. PMID- 27495934 TI - Therapeutic evaluation of video-assisted thoracoscopic surgery versus open thoracotomy for pediatric pulmonary hydatid disease. AB - BACKGROUND: Hydatid disease is a severe and widespread human cestode infection, and in children, the lung is the most commonly infected organ. In current practice, the standard surgical procedure for the removal of pulmonary hydatid cysts is thoracotomy; therefore, we evaluated the efficacy and safety of video assisted thoracoscopic surgery (VATS) to treat pediatric pulmonary hydatid disease. To our knowledge, this is the first and large sample comparative study of VATS and thoracotomy for pediatric pulmonary hydatid disease. METHODS: In this study, we retrospectively reviewed 44 (61.1 %) pediatric patients who underwent VATS, and 28 (38.9 %) pediatric patients who underwent conventional thoracotomy from January 2005 to June 2012. Perioperative data, including basic characteristics of patients, the length of hospital stay, intraoperative blood loss, thoracic intubation indwelling time, and complications were compared between VATS and thoracotomy in 72 children with pulmonary hydatid disease. RESULTS: VATS was found to be a safe technique for the treatment of pediatric pulmonary hydatid disease, with zero intraoperative deaths. In the VATS and thoracotomy groups, the hospital stay durations were 10.50 +/- 1.20 days and 17.30 +/- 2.75 days, respectively, and occurrence rates of complications were 9.1 % (4/44) and 17.9 % (5/28), respectively. The hospital stays were shorter and the hospitalization costs was reduced for the patients who underwent VATS compared with conventional thoracotomy (P = 0.001). Although no statistically significant difference in the recurrence rates (P = 0.958) and complication incidence (P = 0.273) between the two surgical groups was observed, less intraoperative bleeding, shorter thoracic intubation indwelling time and reduced postoperative pain were observed in the patients who underwent VATS (P = 0.001). CONCLUSION: Our study demonstrates the feasibility and safety of VATS for pediatric pulmonary hydatid disease treatment, providing a practice-changing concept for the treatment of this disease in the community. VATS can be a promising therapeutic tool, by overcoming many of the drawbacks of thoracotomy, and can be used as an alternative to thoracotomy for selected pediatric patients. PMID- 27495935 TI - Social Modulation or Hormonal Causation? Linkages of Testosterone with Sexual Activity and Relationship Quality in a Nationally Representative Longitudinal Sample of Older Adults. AB - This study used population-representative longitudinal data from the 2005-2006 and 2010-2011 waves of the National Social Life, Health and Aging Project-a probability sample of US adults aged 57-85 at baseline (N = 650 women and 620 men)-to examine the causal direction in linkages of endogenous testosterone (T) with sexual activity and relationship quality. For both genders, our autoregressive effects indicated a large amount of temporal stability, not just in individual-level attributes (T, masturbation) but also dyadic ones (partnered sex, relationship quality)-indicating that a need for more nuanced theories of relational processes. Cross-lagged results suggested gender-specific effects generally more consistent with sexual or relational modulation of T than with hormonal causation. Specifically, men's findings indicated their T might be elevated by their sexual (masturbatory) activity but not vice versa, although androgen levels did lower men's subsequent relationship quality. Women's T, in contrast, was negatively influenced not just by their higher relationship quality but also by their more frequent partnered sex-perhaps reflecting a changing function of sexual activity in late life. PMID- 27495936 TI - Opt-in method is vital for data sharing. PMID- 27495937 TI - Rapid generation of functional hepatocyte-like cells from human adipose-derived stem cells. AB - BACKGROUND: Liver disease is a major cause of death worldwide. Orthotropic liver transplantation (OLT) represents the only effective treatment for patients with liver failure, but the increasing demand for organs is unfortunately so great that its application is limited. Hepatocyte transplantation is a promising alternative to OLT for the treatment of some liver-based metabolic disorders or acute liver failure. Unfortunately, the lack of donor livers also makes it difficult to obtain enough viable hepatocytes for hepatocyte-based therapies. Currently, a fundamental solution to this key problem is still lacking. Here we show a novel non-transgenic protocol that facilitates the rapid generation of functional induced hepatocytes (iHeps) from human adipose-derived stem cells (hADSCs), providing a source of available cells for autologous hepatocytes to treat liver disease. METHODS: We used collagenase digestion to isolate hADSCs. The surface marker was detected by flow cytometry. The multipotential differentiation potency was detected by induction into adipocytes, osteocytes, and chondrocytes. Passage 3-7 hADSCs were induced into iHeps using an induction culture system composed of small molecule compounds and cell factors. RESULTS: Primary cultured hADSCs presented a fusiform or polygon appearance that became fibroblast-like after passage 3. More than 95 % of the cells expressed the mesenchymal cell markers CD29, CD44, CD166, CD105, and CD90. hADSCs possessed multipotential differentiation towards adipocytes, osteocytes, and chondrocytes. We rapidly induced hADSCs into iHeps within 10 days in vitro; the cellular morphology changed from fusiform to close-connected cubiform, which was similar to hepatocytes. After induction, most of the iHeps co-expressed albumin and alpha 1 antitrypsin; they also expressed mature hepatocyte special genes and achieved the basic functions of hepatocyte. Moreover, iHep transplantation could improve the liver function of acute liver-injured NPG mice and prolong life. CONCLUSIONS: We isolated highly purified hADSCs and rapidly induced them into functional hepatocyte-like cells within 10 days. These results provide a source of available cells for autologous hepatocytes to treat liver disease. PMID- 27495939 TI - Intimacy and Smartphone Multitasking-A New Oxymoron? AB - This study investigated the relationship between smartphone multitasking and romantic intimacy. Participants currently in a romantic relationship (N = 128; 98 women; M age = 26.7 years, SD = 4.3) filled out two sets of questionnaires: The Emotional Intimacy Scale, measuring romantic intimacy, and the mobile phone interference in life scale, measuring multitasking on a smartphone. Participants filled out each questionnaire twice, once in relation to themselves and once in relation to their partner (for the partner questionnaire, statements were altered from the first person to the third person singular, he/she instead of I). Results suggested that only the partners' smartphone multitasking scores were negatively related to ratings of romantic intimacy, whereas participants' own smartphone multitasking scores were not related to ratings of romantic intimacy. These results can be explained by the actor-observer asymmetry, suggesting that participants attributed their multitasking behaviors to situations, but attributed their partners multitasking behaviors to behavior patterns or intentionality. This research suggests that smartphone multitasking has a negative association with face-to-face interactions. People should attend to the costs of smartphone use during face-to-face interactions. PMID- 27495938 TI - Tandem Delivery of Multiple Therapeutic Genes Using Umbilical Cord Blood Cells Improves Symptomatic Outcomes in ALS. AB - Current treatment options of chronic, progressive degenerative neuropsychiatric conditions offer only marginal efficacy, and there is no therapy which arrests or even reverses these diseases. Interest in genetic engineering and cell-based approaches have constantly been increasing, although most of them so far proved to be fruitless or at best provided very slight clinical benefit. In the light of the highly complex patho-mechanisms of these maladies, the failure of drugs aimed at targeting single molecules is not surprising. In order to improve their effectiveness, the role of a unique triple-combination gene therapy was investigated in this study. Intravenous injection of human umbilical cord blood mononuclear cell (hUCBMC) cotransduced with adenoviral vectors expressing vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) resulted in prominent increase of life span and performance in behavioral tests in amyotrophic lateral sclerosis (ALS). Expression of the recombinant genes in hUCBMCs was confirmed as soon as 5 days after transduction by RT-PCR, and cells were detectable for as long as 1 month after grafting in lumbar spinal cord by immunofluorescent staining. Xenotransplantation of cells into mice blood without any immunosuppression demonstrated a high level of hUCBMCs homing and survivability in the central nervous system (CNS), most conspicuously in the spinal cord, but not in the spleen or liver. This study confirms an increased addressed homing and notable survivability of triple-transfected cells in lumbar spinal cord, yielding a remarkably enhanced therapeutic potential of hUCBMCs overexpressing neurotrophic factors. PMID- 27495940 TI - Detecting a novel Eriocheir sinensis reovirus by reverse transcription loop mediated isothermal amplification assay. AB - : The novel Eriocheir sinensis reovirus (EsRV) is a pathogen that causes severe disease and high mortality rates in cultivated crabs. Here, we established a highly sensitive and specific rapid reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay that was cheaper and more suitable for field applications in crab aquaculture than those of traditional reverse transcription-polymerase chain reaction (RT-PCR) analysis. The amplification was completed within 45 min under isothermal conditions at 65 degrees C. The RT-LAMP test for EsRV had a detection limit of 15 pg, and sensitivity was 100 times greater than that of conventional RT-PCR. The LAMP primers for EsRV were not amplified by other pathogen strains, indicating good specificity. In addition to detection by electrophoresis, RT-LAMP results were detectable by visual observations of reaction tube turbidity, and calcein was added to visually detect the amplification products. These results indicate that this highly convenient, rapid and sensitive RT-LAMP assay can be used to detect EsRV-infected aquatic organisms. SIGNIFICANCE AND IMPACT OF THE STUDY: Tremor disease (TD) is one of the most serious diseases of Eriocheir sinensis. A novel E. sinensis reovirus (EsRV) was identified from E. sinensis afflicted with TD and caused high mortality. We developed a reverse transcription loop-mediated isothermal amplification assay with high specificity, sensitivity and rapidity to detect EsRV, which can be used to diagnose aquatic animal diseases, particularly where expensive diagnostic instruments are not available. PMID- 27495941 TI - Role of Glycosyltransferases in Pollen Wall Primexine Formation and Exine Patterning. AB - The pollen cell wall is important for protection of male sperm from physical stresses and consists of an inner gametophyte-derived intine layer and a sporophyte-derived exine layer. The polymeric constituents of the robust exine are termed sporopollenin. The mechanisms by which sporopollenin is anchored onto microspores and polymerized in specific patterns are unknown, but the primexine, a transient cell wall matrix formed on the surface of microspores at the late tetrad stage, is hypothesized to play a key role. Arabidopsis (Arabidopsis thaliana) spongy (spg) and uneven pattern of exine (upex) mutants exhibit defective and irregular exine patterns. SPG2 (synonymous with IRREGULAR XYLEM9 LIKE [IRX9L]) encodes a family GT43 glycosyltransferase involved in xylan backbone biosynthesis, while UPEX1 encodes a family GT31 glycosyltransferase likely involved in galactosylation of arabinogalactan proteins. Imaging of developing irx9l microspores showed that the earliest detectable defect was in primexine formation. Furthermore, wild-type microspores contained primexine localized epitopes indicative of the presence of xylan, but these were absent in irx9l These data, together with the spg phenotype of a mutant in IRX14L, which also plays a role in xylan backbone elongation, indicate the presence of xylan in pollen wall primexine, which plays a role in exine patterning on the microspore surface. We observed an aberrant primexine and irregular patterns of incipient sporopollenin deposition in upex1, suggesting that primexine-localized arabinogalactan proteins could play roles in sporopollenin adhesion and patterning early in microspore wall development. Our data provide new insights into the biochemical and functional properties of the primexine component of the microspore cell wall. PMID- 27495942 TI - Differences in calcification and osteogenic potential of herniated discs according to the severity of degeneration based on Pfirrmann grade: a cross sectional study. AB - BACKGROUND: Herniated discs may exhibit calcification, and calcified discs may complicate surgical treatment. However, the osteogenic potential and expression of osteogenic markers in degenerative discs of different degenerative grades are still unclear. Our purposes are to study the differences in calcification rate and osteogenic potential of herniated discs according to different degenerative grades. METHODS: Fifty-eight lumbar intervertebral discs were removed from 41 patients. After grading according to the Pfirrmann scale, calcification was analyzed by micro computed tomography (MU-CT), and expression of osteogenic markers was analyzed by immunohistochemistry and real-time quantitative polymerase chain reaction (qPCR). Data from MU-CT scans were compared with the Kruskal-Wallis test. The Mann-Whitney test was applied to compare data between any two groups. Differences in osteogenic mRNA expression in different regions of the removed discs (posterior vs. anterior) were analyzed by paired t tests. Differences in the posterior portion of removed discs of different Pfirrmann grades were analyzed by one-way analysis of variance (ANOVA), and comparisons of data between discs of any two grades were completed with least significant difference (LSD) tests. RESULTS: Significant differences in calcification according to MU-CT scanning were observed between discs of different degenerative grades. Nearly half of the discs of Pfirrmann grade V showed the highest degree of calcification compared to Pfirrman grade II discs. Bone morphogenetic protein (BMP)-2, Osterix, and Osteocalcin were detected histologically in discs of Pfirrmann grades III-V. Alkaline phosphatase (ALP) expression was observed in discs showing evidence of calcification. The qPCR analysis showed that BMP-2, Osterix, and Osteocalcin were expressed in most degenerated discs. We also observed greater expression of these osteogenic markers in the posterior portion of removed discs than in the anterior portion. CONCLUSIONS: The osteogenic potential of degenerated intervertebral discs appears to increase with the severity of degeneration and to be greater in the tissue near the spinal canal than in tissue in the inner portion of the disc. PMID- 27495943 TI - Projectile propagation of dexamethasone implant in air- and balanced salt solution-filled vitrectomized eyes. PMID- 27495944 TI - Correlation of Adrenomedullin Concentrations with Knee Osteoarthritis Grade. AB - BACKGROUND Adrenomedullin, a recently identified myokine, has an anti inflammatory effect. Therefore, we aimed to assess the correlation of adrenomedullin concentrations with the presence and grade of severity of knee osteoarthritis (OA). MATERIAL AND METHODS We recruited 187 knee OA patients and 109 healthy subjects. The severity of OA was evaluated using the Kellgren Lawrence grading system. RESULTS Compared with the control group, the knee OA group revealed markedly higher adrenomedullin concentrations. Serum and synovial fluid (SF) adrenomedullin concentrations increased with increased KL grades. CONCLUSIONS Serum and SF adrenomedullin concentrations show a correlation with the severity of knee OA. PMID- 27495945 TI - Bone shape difference between control and osteochondral defect groups of the ankle joint. AB - OBJECTIVE: The etiology of osteochondral defects (OCDs), for which the ankle (talocrural) joint is one of the common sites, is not yet fully understood. In this study, we hypothesized that bone shape plays a role in development of OCDs. Therefore, we quantitatively compared the morphology of the talus and the distal tibia between an OCD group and a control group. METHODS: The shape variations of the talus and distal tibia were described separately by constructing two statistical shape models (SSMs) based on the segmentation of the bones from ankle computed tomography (CT) scans obtained from control (i.e., 35 CT scans) and OCD (i.e., 37 CT scans) groups. The first five modes of shape variation for the SSM corresponding to each bone were statistically compared between control and OCD groups using an analysis of variance (ANOVA) corrected with the Bonferroni for multiple comparisons. RESULTS: The first five modes of variation in the SSMs respectively represented 49% and 40% of the total variance of talus and tibia. Less than 5% of the variance per mode was described by the higher modes. Mode 5 of the talus (P = 0.004) primarily describing changes in the vertical neck angle and Mode 1 of the tibia (P < 0.0001) representing variations at the medial malleolus, showed statistically significant difference between the control and OCD groups. CONCLUSION: Shape differences exist between control and OCD groups. This indicates that a geometry modulated biomechanical behavior of the talocrural joint may be a risk factor for OCD. PMID- 27495946 TI - Effect of sample treatment on biomechanical properties of insect cuticle. AB - Experimental limitations often prevent to perform biomechanical measurements on fresh arthropod cuticle samples. Hence, in many cases short- or long-term storage of samples is required. So far, it is not known whether any of the standard lab techniques commonly used to fix or store insect cuticle samples in any way affects the biomechanical properties of the respective samples. In this paper we systematically address this question for the first time, with a focus on practical, easily accessible and common lab-methods including storage in water, ethanol, glutaraldehyde, freezing and desiccation. We performed a comprehensive and sensitive non-destructive Dynamic Mechanical Analysis (DMA) on locust hind leg tibiae using a three-point-bending setup. Our results show that from all tested treatments, freezing samples at -20 degrees C was the best option to maintain the original values for Young's modulus and damping properties of insect cuticle. In addition, our results indicate that the damping properties of locust hind legs might be mechanically optimized in respect to the jumping and kicking direction. PMID- 27495947 TI - Venous thromboembolism in centenarians: Findings from the RIETE registry. AB - BACKGROUND: The balance between the efficacy and safety of anticoagulant therapy in patients aged >=100years receiving anticoagulant therapy for venous thromboembolism (VTE) is uncertain. METHODS: We used data from the RIETE (Registro Informatizado Enfermedad TromboEmbolica) database to assess the rate of VTE recurrences, bleeding events, and mortality appearing during the course of anticoagulant therapy in VTE patients aged >=100years. RESULTS: Of 61,173 patients enrolled in RIETE as of January 2016, 47 (0.08%) were aged >=100years. Of these, 10 (21%) were men, 21 (45%) presented with pulmonary embolism (PE), and 26 with deep vein thrombosis alone. Overall, 35 patients (74%) had severe renal insufficiency, 14 (30%) chronic heart failure, 30 (64%) anemia, 16 (34%) were taking antiplatelets, and 6 (13%) corticosteroids or non-steroidal anti inflammatory drugs. Most patients (95%) were treated initially with low-molecular weight heparin (LMWH) (mean daily dose, 168+/-42IU/kg). Then, 14 (30%) switched to vitamin K antagonists and 29 (62%) kept receiving long-term LMWH therapy (mean, 148+/-51IU/kg/day). During the course of anticoagulant therapy (mean duration, 139days), mortality was high (15/47; 32%). Two patients died of PE (initial PE one, recurrent PE one) and 5 (11%) had minor bleeding, but no major bleeding was reported. CONCLUSIONS: Among patients with acute VTE aged >=100years, the risk of VTE recurrences during the course of anticoagulation outweighed the risk of bleeding. Our data suggest the use of standard anticoagulant therapy in this patient population, even if they have severe renal insufficiency. PMID- 27495948 TI - Chronic pruritic, hyperkeratotic eruption on the feet of a patient with end-stage renal disease. PMID- 27495949 TI - MEDical wards Invasive Candidiasis ALgorithms (MEDICAL):Consensus proposal for management. AB - INTRODUCTION: A majority of invasive Candida infections occur in medical wards; however, evidence for management in this setting is scarce and based primarily on the intensive care or surgical setting. On behalf of the Italian Society for Anti Infective Therapy (SITA) and the Italian Federation of Associations of Hospital Doctors on Internal Medicine (FADOI), the MEDICAL group produced practical management algorithms for patients in internal medicine wards. METHODS: The MEDICAL group panel, composed of 30 members from internal medicine, infectious disease, clinical pharmacology, clinical microbiology and clinical epidemiology, provided expert opinion through the RAND/UCLA method. RESULTS: Seven clinical scenarios were constructed based on clinical severity and probability of invasive candidiasis. For each scenario, the appropriateness of 63 different diagnostic, imaging, management, or therapeutic procedures was determined in two Delphi rounds. The necessity for performing each appropriate procedure, was then determined in a third Delphi round. Results were summarized in algorithms. DISCUSSION: The proposed algorithms provide internal medicine physicians and managers with an easy to interpret tool that is exhaustive, clear and suitable for adaption to individual local settings. Attention was paid to individual patient management and resource allocation. PMID- 27495950 TI - Visual consequences of electronic reader use: a pilot study. AB - BACKGROUND: With the increasing prevalence of electronic readers (e-readers) for vocational and professional uses, it is important to discover if there are visual consequences in the use of these products. There are no studies in the literature quantifying the incidence or severity of eyestrain, nor are there clinical characteristics that may predispose to these symptoms with e-reader use. PURPOSE: The primary objective of this pilot study was to assess the degree of eyestrain associated with e-reader use compared to traditional paper format. The secondary outcomes of this study were to assess the rate of eyestrain associated with e reader use and identify any clinical characteristics that may be associated with the development of eyestrain. METHODS: Forty-four students were randomly assigned to study (e-reader iPAD) and control (print) groups. Participant posture, luminosity of the room, and reading distance from reading device were measured during a 1-h session for both groups. At the end of the session, questionnaires were administered to determine symptoms. RESULTS: Significantly higher rates of eyestrain (p = 0.008) and irritation (p = 0.011) were found among the iPAD study group as compared to the print 'control' group. The study group was also 4.9 times more likely to report severe eyestrain (95 % CI [1.4, 16.9]). No clinical characteristics predisposing to eyestrain could be identified. CONCLUSIONS: These findings conclude that reading on e-readers may induce increased levels of irritation and eyestrain. Predisposing factors, etiology, and potential remedial interventions remain to be determined. PMID- 27495951 TI - Histopathological and ophthalmoscopic evaluation of apocynin on experimental proliferative vitreoretinopathy in rabbit eyes. AB - The aim of the current study was to evaluate the effect of apocynin (APO) on the development of proliferative vitreoretinopathy (PVR). New Zealand-type male rabbits were randomly grouped into three as follows: (1) Sham group rabbits which were applied intraperitoneal (i.p.) vehicle without PVR; (2) PVR group rabbits where PVR was created and an i.p. vehicle was administered for 21 successive days; (3) PVR + APO group rabbits where PVR was created and i.p. APO was administered for 21 successive days. Fundus examination was conducted with an indirect ophthalmoscope before starting the experiments and at each visit afterwards. At the end of the work, the rabbits were sacrificed under high-dose anesthesia and then eye tissues were taken for histopathological analyses. In the PVR + APO group, histopathologic and ophthalmoscopic examination revealed significant decrease in PVR formation. As the result, it has been observed that APO at least partially inhibits PVR formation. PMID- 27495952 TI - Surgical outcomes of patients with iridocorneal endothelial syndrome: a case series. AB - The purpose of this study is to report the intermediate-term surgical outcomes of patients with iridocorneal endothelial syndrome-related glaucoma. The medical records of four patients (five eyes) surgery (Ahmed glaucoma valve implantation surgery and EX-PRESS mini shunt) were retrospectively reviewed. Median follow-up after glaucoma surgery was 24 (15-36) months. The preoperative intraocular pressure was significantly reduced from a median of 33 (22.5-36) mmHg on a median of 4 (4-5) glaucoma medications to a median of 12 (10.5-14.5) mmHg on a median of 2 (0-2) medications at last follow-up after surgery (p = 0.043 for IOP and p = 0.042 for glaucoma medications). Median preoperative visual acuity [0.016 (0.008 0.1)] did not change significantly when compared to median visual acuity at last follow-up [0.016 (0.004-0.5)] (p = 0.59). Intraocular pressure control in patients with iridocorneal endothelial syndrome is challenging and may require multiple operations and revisions. Some modifications during glaucoma drainage implant surgery and use of EX-PRESS mini shunt in certain cases could offer an advantage in these patients. PMID- 27495953 TI - Atrazine alters expression of reproductive and stress genes in the developing hypothalamus of the snapping turtle, Chelydra serpentina. AB - Atrazine is an herbicide used to control broadleaf grasses and a suspected endocrine disrupting chemical. Snapping turtles lay eggs between late May and early June, which could lead to atrazine exposure via field runoff. Our goal was to determine whether a single exposure to 2ppb or 40ppb atrazine during embryogenesis could induce short- and long-term changes in gene expression within the hypothalamus of snapping turtles. We treated eggs with atrazine following sex determination and measured gene expression within the hypothalamus. We selected genes a priori for their role in the hypothalamus-pituitary-gonad or the hypothalamus-pituitary-adrenal axes of the endocrine system. We did not identify any changes in gene expression 24-h after treatment. However, at hatching AR, Kiss1R, and POMC expression was upregulated in both sexes, while expression of CYP19A1 and PDYN was increased in females. Six months after hatching, CYP19A1 and PRLH expression was increased in animals treated with 2ppb atrazine. Our study shows persistent changes in hypothalamic gene expression due to low-dose embryonic exposure to the herbicide atrazine with significant effects in both the HPG and HPA axes. Effects reported here appear to be conserved among vertebrates. PMID- 27495954 TI - Propofol reduced myocardial contraction of vertebrates partly by mediating the cyclic AMP-dependent protein kinase phosphorylation pathway. AB - Propofol inhibits myocardial contraction in a dose dependent manner. The present study is designed to examine the effect of propofol on PKA mediated myocardial contraction in the absence of adrenoreceptor agonist. The contraction of isolated rat heart was measured in the presence or absence of PKA inhibitor H89 or propofol, using a pressure transducer. The levels of cAMP and PKA kinase activity were detected by ELISA. The mRNA and total protein or phosphorylation level of PKA and downstream proteins were tested in the presence or absence of PKA inhibitor H89 or propofol, using RT-PCR, QPCR and western blotting. The phosphorylation level of PKA was examined thoroughly using immunofluorescence and PKA activity non-radioactive detection kit. Propofol induced a dose-dependent negative contractile response on the rat heart. The inhibitory effect of high concentration propofol (50MUM) with 45% decease of control could be partly reversed by the PKA inhibitor H89 (10MUM) and the depressant effect of propofol decreased from 45% to 10%. PKA kinase activity was inhibited by propofol in a dose-dependent manner. Propofol also induced a decrease in phosphorylation of PKA, which was also inhibited by H89, but did not alter the production of cAMP and the mRNA levels of PKA. The downstream proteins of PKA, PLN and RyR2 were phosphorylated to a lesser extent with propofol or H89 than control. These results demonstrated that propofol induced a negative myocardial contractile response partly by mediating the PKA phosphorylation pathway. PMID- 27495955 TI - Effect of fermented red ginseng on cytochrome P450 and P-glycoprotein activity in healthy subjects, as evaluated using the cocktail approach. AB - AIMS: We assessed the drug interaction profile of fermented red ginseng with respect to the activity of major cytochrome (CYP) P450 enzymes and of a drug transporter protein, P-glycoprotein (P-gp), in healthy volunteers. METHODS: This study was an open-label crossover study. The CYP probe cocktail drugs caffeine, losartan, dextromethorphan, omeprazole, midazolam and fexofenadine were administered before and after 2 weeks of fermented red ginseng administration. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data. Values were compared between before and after fermented red ginseng administration using analysis of variance (anova). RESULTS: Fifteen healthy male subjects were evaluated, none of whom were genetically defined as a poor CYP2C9, CYP2C19 or CYP2D6 metabolizer based on genotyping. Before and after fermented red ginseng administration, the geometric least-square mean metabolic ratio (90% CI) was 0.901 (0.830-0.979) for caffeine (CYP1A2) to paraxanthine, 0.774 (0.720-0.831) for losartan (CYP2C9) to EXP3174, 1.052 (0.925-1.197) for omeprazole (CYP2C19) to 5-hydroxyomeprazole, 1.150 (0.860-1.538) for dextromethorphan (CYP2D6) to dextrorphan, and 0.816 (0.673-0.990) for midazolam (CYP3A4) to 1-hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time (AUClast ) for fexofenadine (P-gp) was 1.322 (1.112-1.571). CONCLUSION: No significantly different drug interactions were observed between fermented red ginseng and the CYP probe substrates following the two-week administration of concentrated fermented red ginseng. However, the inhibition of P-gp was significantly different between fermented red ginseng and the CYP probe substrates. The use of fermented red ginseng requires close attention due to the potential for increased systemic exposure when it is used in combination with P-gp substrate drugs. PMID- 27495957 TI - Musculoskeletal imaging: What's new in 2016? PMID- 27495956 TI - Towards Improving the Transfer of Care of Kidney Transplant Recipients. AB - Kidney transplant recipients require specialized medical care and may be at risk for adverse health outcomes when their care is transferred. This document provides opinion-based recommendations to facilitate safe and efficient transfers of care for kidney transplant recipients including minimizing the risk of rejection, avoidance of medication errors, ensuring patient access to immunosuppressant medications, avoidance of lapses in health insurance coverage, and communication of risks of donor disease transmission. The document summarizes information to be included in a medical transfer document and includes suggestions to help the patient establish an optimal therapeutic relationship with their new transplant care team. The document is intended as a starting point towards standardization of transfers of care involving kidney transplant recipients. PMID- 27495958 TI - Out-of-hospital unexpected delivery. PMID- 27495959 TI - Comparison of the visualisation of the subclavian and axillary veins: An ultrasound study in healthy volunteers. AB - OBJECTIVE: To compare the area of the lumen of the axillary and subclavian veins using ultrasound (US) in 50 healthy volunteers. METHODS: Using an ultrasound device, depth, area, short axis vein length and long axis vein, vein-artery and vein-pleura distances were measured for axillary and subclavian approaches. RESULTS: The mean cross-sectional area of the axillary vein was greater than the mean cross-sectional area of the subclavian vein (327+/-89 mm2 versus 124+/-46 mm2, P<0.001). Both the mean transverse (10+/-2mm versus 9+/-2mm) and longitudinal axes (39+/-8mm versus 17+/-7mm) of the axillary vein were greater than those of subclavian vein (P<0.01, P<0.001, respectively). The depths of the axillary and subclavian veins were similar (21+/-6mm versus 20+/-6mm, P=0.43). The axillary and subclavian arteries were visualised in 3 and 45 volunteers, respectively (P<0.001). The pleura was seen in 25 and 37 volunteers with the axillary and subclavian approaches, respectively (P=0.01). The distance between the pleura and the subclavian vein was smaller (6+/-2mm versus 8+/-3mm, P<0.04). CONCLUSION: The present US study shows that visualisation of the axillary vein under US is greater than that for the subclavian vein, mainly due to a better alignment with the long axis of the axillary vein leading to a greater cross sectional area of the axillary vein. TRIAL REGISTER NUMBER: NCT01647815. PMID- 27495960 TI - Optimal Head Rotation for IJV Cannulation: One Size Does Not Fit All. PMID- 27495961 TI - Outcome After General Anesthesia Versus Monitored Anesthesia Care in Transfemoral Transcatheter Aortic Valve Replacement. AB - OBJECTIVE: To evaluate outcomes of monitored anesthesia care (MAC) compared with general anesthesia (GA) in patients undergoing transfemoral transcatheter aortic valve replacement (TAVR). DESIGN: Secondary analysis from the observational and prospective OBSERVANT (OBservational Study of Effectiveness of avR-taVi procedures for severe Aortic steNosis Treatment) study. SETTING: Multicenter study, including Italian hospitals performing TAVR interventions. PARTICIPANTS: One thousand four hundred ninety-four patients with severe and symptomatic aortic stenosis. INTERVENTIONS: Transfemoral TAVR under general or local anesthesia. MEASUREMENTS AND MAIN RESULTS: A propensity score procedure was applied, and 310 pairs were matched with similar baseline characteristics (EuroSCORE II: local anesthesia 6.6+/-5.9% v general anesthesia 7.0+/-7.7%, p = 0.430). MAC was associated with similar 30-day mortality compared with GA (3.9% v 4.8%, p = 0.564). TAVR was performed under MAC without any increased risk of other adverse events. The risk of paravalvular regurgitation>=mild was similar between the study groups (MAC 49.5% v general anesthesia 57.0%, p = 0.858). Two patients receiving on MAC had severe paravalvular regurgitation, whereas this complication was not observed after GA. Permanent pacemaker implantation was 19.1% in the MAC group v 14.8% in the GA group (p = 0.168). Mean intensive care unit stay was 3.5 days for the GA group v 2.9 days for the MAC group (p = 0.086). A similar 3-year survival rate was observed (MAC 69.4% v GA 69.9%, p = 0.966). CONCLUSIONS: Transfemoral TAVR can be performed under MAC with similar immediate and late outcomes as compared with GA. A possible risk of severe paravalvular regurgitation and pacemaker implantation with TAVR under MAC requires further investigation. PMID- 27495962 TI - Grading Aortic Stenosis With Mean Gradient and Aortic Valve Area: A Comparison Between Preoperative Transthoracic and Precardiopulmonary Bypass Transesophageal Echocardiography. AB - OBJECTIVE: The authors hypothesized that average precardiopulmonary bypass (pre CPB) transesophageal echocardiographic (TEE) mean gradient (PGm) and aortic valve area (AVA) values would be significantly different from preoperative transthoracic (TTE) values in the same patients and that these changes would affect pre-CPB TEE grading of aortic stenosis (AS). DESIGN: Retrospective, observational design. SETTING: Single university hospital. PARTICIPANTS: The study comprised 92 patients who underwent aortic valve replacement with or without coronary artery bypass grafting between 2000 and 2012 at Duke University Hospital and who had PGm and AVA values recorded in both pre-CPB TEE and preoperative TTE reporting databases. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PGm with pre-CPB TEE was lower by 6.6 mmHg (95% confidence interval, 4.0 to -9.3 mmHg; p<0.001), whereas AVA was higher by 0.10 cm(2) (95% confidence interval, 0.04 to 0.15 cm(2); p<0.001), compared with preoperative TTE values. When using PGm, pre-CPB TEE generated an AS severity 1 grade lower 39.1% of the time and revealed no difference 55.4% of the time compared to preoperative TTE. When using AVA by continuity, pre-CPB TEE generated an AS severity 1 grade lower 14.1% of the time and revealed no difference 81.5% of the time compared to preoperative TTE. When using either PGm or AVA, preoperative TTE exhibited moderate or severe AS for all study patients, whereas, pre-CPB TEE demonstrated mild AS in 5.4% (n = 92) of patients. CONCLUSIONS: The authors confirmed their hypothesis that pre-CPB TEE generates different PGm and AVA values compared with preoperative TTE. These differences often underestimate AS severity. Hemodynamic standardizations or adjustments of pre-CPB TEE PGm and AVA values may be necessary in anesthetized patients before assigning an AS grade using these parameters. PMID- 27495964 TI - Response to Letter to the Editor Concerning "The Optimal Angle of Head Rotation for Internal Jugular Cannulation as Determined by Ultrasound Evaluation". PMID- 27495963 TI - Noninvasive Positive-Pressure Ventilation in Treatment of Hypoxemia After Extubation Following Type-A Aortic Dissection. AB - OBJECTIVES: To assess the efficacy of noninvasive positive-pressure ventilation (NPPV) in improving hypoxemia after extubation for Stanford type-A aortic dissection and to compare NPPV using a mask or a helmet. DESIGN: Prospective, interventional study. SETTING: Department of Cardiac Surgery of the Beijing Anzhen Hospital, a tertiary university hospital. PARTICIPANTS: Patients experiencing hypoxemia within 24 hours after extubation for Stanford type-A aortic dissection. INTERVENTIONS: The patients were divided into the following 3 groups: high-flux inhalation of oxygen with a Venturi mask (control patients), NPPV with a mask (mask group), and NPPV with a helmet (helmet group) (n = 25/group). MEASUREMENTS AND MAIN RESULTS: Data for blood gas analysis, vital signs, heart function, and complications were collected before the treatment, after 1 and 6 hours of treatment, and at the end of treatment. The oxygen partial pressure/fraction of inspired oxygenation index or PaO2/FIO2 ratio and the oxygen partial pressure were higher and carbon dioxide partial pressure was lower in the mask and helmet groups compared with that of control patients. Compared with control patients and the mask group, the helmet group showed a slower heart rate, lower average arterial pressure, and improved left ventricular ejection fraction, leading to a lower incidence of reintubation and a shorter hospital stay. CONCLUSIONS: NPPV with a helmet may quickly improve oxygen partial pressure, decrease carbon dioxide partial pressure, decrease the reintubation rate, and effectively shorten the hospital stay after extubation for Stanford type-A aortic dissection. PMID- 27495966 TI - Effects of Levosimendan on Endothelial Function and Hemodynamics During Weaning From Veno-Arterial Extracorporeal Life Support. AB - OBJECTIVE: Weaning from veno-arterial extracorporeal life support is challenging. The objective of this trial was to investigate the endothelial and hemodynamic effects of levosimendan in cardiogenic shock patients supported with veno arterial extracorporeal life support. DESIGN: This was a prospective observational trial. SETTING: Cardiovascular intensive care unit of a large tertiary care university hospital in Monza, Italy. PARTICIPANTS AND INTERVENTIONS: Flow-mediated dilatation of the brachial artery and hemodynamic parameters were assessed in 10 cardiogenic shock patients supported with veno arterial extracorporeal life support, before and after the infusion of levosimendan. MEASUREMENTS AND RESULTS: Flow-mediated dilatation increased both as absolute value and as a percentage after levosimendan, from 0.10+/-0.12 to 0.61+/-0.21 mm (p<0.001) and from 3.2+/-4.2% to 17.8+/-10.4% (p<0.001), respectively. Cardiac index increased from 1.93+/-0.83 to 2.64+/-0.97 L/min/m2 (p = 0.008) while mixed venous oxygen saturation increased from 66.0% to 71.5% (p = 0.006) and arterial lactate levels decreased from 1.25 to 1.05 mmol/L (p = 0.004) without significant variations in arterial oxygen saturation or hemoglobin levels. This made it possible for clinicians to reduce extracorporeal membrane oxygenation blood flow from 1.92+/-0.65 to 1.12+/-0.49 L/min/m2 (p<0.001). CONCLUSION: In conclusion, in the authors' study population of adult cardiogenic shock patients supported with veno-arterial extracorporeal life support, their observations supported the use of levosimendan to improve endothelial function and hemodynamics and facilitate weaning from the extracorporeal support. PMID- 27495965 TI - Surgical Repair of Mitral Valve Disease in Children: Perioperative Changes in Respiratory Function. AB - OBJECTIVE: To assess the profile of changes in airway and respiratory tissue mechanics within a follow-up study performed in children with mitral valve disease, before and after surgical valve repair. DESIGN: Perioperative measurements in a prospective, consecutive cross-sectional study. SETTING: University hospital, tertiary care teaching hospital PARTICIPANTS: The study comprised 24 children with congenital or post-rheumatic mitral valve insufficiency. INTERVENTIONS: Input impedance of the respiratory system during spontaneous breathing was measured before and 5 days and 3 weeks after mitral valve surgery. In addition, airway and respiratory tissue mechanics and pulmonary arterial pressure were assessed with the patient under general anesthesia preoperatively and immediately postoperatively. Respiratory tissue elastance and changes in airway measurements were estimated from forced oscillatory impedance data by fitting an appropriate model. MEASUREMENT AND MAIN RESULTS: Relating airway and respiratory tissue mechanics to previously established reference values obtained in age-matched healthy control patients revealed abnormal respiratory function (135+/-6.2% and 148+/-13% in respiratory elastance and resistance, respectively; p<0.001). Improvement in the airway properties was observed immediately after surgery (-15.2+/-3.4%; p<0.005) and lasted for the study period (-19+/-4.1%; p<0.001). Respiratory tissue elastance, which correlated preoperatively to the diastolic pulmonary arterial pressure, decreased only 5 days postoperatively (-20.6+/-4.1%; p<0.005). However, there was no evidence of a clear, immediate effect of surgery on the tissue mechanical parameters measured intraoperatively despite a decrease in diastolic pulmonary pressure. CONCLUSIONS: Mitral valve disease in children leads to abnormal airway and respiratory tissue mechanics. Even though surgical repair of mitral insufficiency alleviates abnormal airway function, residual lung tissue stiffening may persist even weeks after the surgery, contributing to a sustained impairment in lung function. PMID- 27495969 TI - Voice Quality in Native and Foreign Languages Investigated by Inverse Filtering and Perceptual Analyses. AB - OBJECTIVES: Language shift from native (L1) to foreign language (L2) may affect speaker's voice production and induce vocal fatigue. This study investigates the effects of language shift on voice source and perceptual voice quality. STUDY DESIGN: This is a comparative experimental study. SUBJECTS AND METHODS: Twenty four subjects were recorded in L1 and L2. Twelve of the subjects were native Finnish speakers and 12 were native English speakers, and the foreign languages were English and Finnish. Two groups were created based on reports of fatigability. Group 1 had the subjects who did not report more vocal fatigue in L2 than in L1, and in group 2 those who reported more vocal fatigue in L2 than in L1. Acoustic analyses by inverse filtering were conducted in L1 and L2. Also, the subjects' voices were perceptually evaluated in both languages. RESULTS: Results show that language shift from L1 to L2 increased perceived pressedness of voice. Acoustic analyses correlated with the perceptual evaluations. Also, the subjects who reported more vocal loading had poorer voice quality, more strenuous voice production, more pressed phonation, and a higher pitch. CONCLUSIONS: Voice production was less optimal in L2 than in L1. Speech training given in L2 could be beneficial for people who need to use L2 extensively. PMID- 27495967 TI - A nomogram for predicting pathological complete response in patients with human epidermal growth factor receptor 2 negative breast cancer. AB - BACKGROUND: The response to neoadjuvant chemotherapy has been proven to predict long-term clinical benefits for patients. Our research is to construct a nomogram to predict pathological complete response of human epidermal growth factor receptor 2 negative breast cancer patients. METHODS: We enrolled 815 patients who received neoadjuvant chemotherapy from 2003 to 2015 and divided them into a training set and a validation set. Univariate logistic regression was performed to screen for predictors and construct the nomogram; multivariate logistic regression was performed to identify independent predictors. RESULTS: After performing the univariate logistic regression analysis in the training set, tumor size, hormone receptor status, regimens of neoadjuvant chemotherapy and cycles of neoadjuvant chemotherapy were the final predictors for the construction of the nomogram. The multivariate logistic regression analysis demonstrated that T4 status, hormone receptor status and receiving regimen of paclitaxel and carboplatin were independent predictors of pathological complete response. The area under the receiver operating characteristic curve of the training set and the validation set was 0.779 and 0.701, respectively. CONCLUSIONS: We constructed and validated a nomogram to predict pathological complete response in human epidermal growth factor receptor 2 negative breast cancer patients. We also identified tumor size, hormone receptor status and paclitaxel and carboplatin regimen as independent predictors of pathological complete response. PMID- 27495968 TI - Surgery or Rehabilitation: A Randomized Clinical Trial Comparing the Treatment of Vocal Fold Polyps via Phonosurgery and Traditional Voice Therapy with "Voice Therapy Expulsion" Training. AB - OBJECTIVE: Phonomicrosurgery is generally considered to be the treatment of choice for removing vocal fold polyps. However, specific techniques of voice therapy may represent, in selected cases and under certain conditions, a noninvasive therapeutic option for the treatment of such laryngeal lesions. The aim of the present study is to longitudinally assess, in terms of clinical outcomes and quality of life, two groups of patients with cordal polyps, treated either with standard surgery plus standard voice therapy or with a specific training of voice therapy alone, which we have called "Voice Therapy Expulsion." STUDY DESIGN: This study is a randomized controlled trial. METHODS: A total of 150 patients with vocal fold polyps were randomly assigned to either standard surgery or "voice therapy expulsion" protocol. The trial was carried out at the Division of Phoniatrics and Audiology of the Second University of Naples and at the Division of Communication Disorders of Local Health Unit (3 Naples South) from January 2010 to December 2013. A thorough phoniatric evaluation, including laryngostroboscopy, acoustic voice analysis, global grade of dysphonia, instability, roughness, breathiness, asthenia, and strain scale, Voice Handicap Index, and Voice-Related Quality of Life, was performed by using standardized tools, at baseline, at the end of the treatment, and up to 1 year after treatment. RESULTS: We found no significant differences between the two experimental groups in terms of clinical outcomes and personal satisfaction. However, "Voice Therapy Expulsion" was associated with higher scores for quality of life at endpoint evaluation. CONCLUSIONS: Besides phonosurgery, this specific "Voice Therapy Expulsion" technique should be considered as a valid, noninvasive, and well-tolerated therapeutic option for the treatment of selected patients with vocal fold polyps. PMID- 27495970 TI - Esophageal Mucosal Impedance Pattern is Distinct in Patients With Extraesophageal Reflux Symptoms and Pathologic Acid Reflux. AB - OBJECTIVES/STUDY DESIGN: Current diagnostic tests for gastroesophageal reflux disease (GERD) do not consistently measure chronicity of reflux. Mucosal impedance (MI) is a minimally invasive measurement to assess esophageal conductivity changes due to GERD. We aimed to investigate MI pattern in patients with symptoms of extraesophageal reflux (EER) in a prospective longitudinal cohort study. METHODS: Patients with potential symptoms of EER undergoing esophagogastroduodenoscopy (EGD) with wireless pH monitoring were studied. Participants included those with erosive esophagitis (E+), normal EGD/abnormal pH (E-/pH+), and normal EGD/normal pH (E-/pH-). MI was measured from the site of injury in patients with E+, as well as at 2, 5, and 10 cm above the squamocolumnar junction (SCJ) in all participants. RESULTS: Forty-one patients with symptoms of EER were studied. MI measurements at 2 cm above the SCJ were significantly (P = 0.04) different among the three groups, with MI lowest for E+ and greatest for E-/pH- patients. Although not statistically significant, there is a graded increase in median (interquartile range) MI axially along the esophagus at 5 cm (P = 0.20) and at 10 cm (P = 0.27) above the SCJ, with those with reflux (E+ and E-/pH+) having a lower MI than those without. CONCLUSIONS: Patients with symptoms of EER and evidence of acid reflux have an MI lower than those without at 2 cm above the SCJ, with a trend at 5 cm and 10 cm as well. MI may be a tool to assess presence of GERD in patients presenting with EER symptoms. PMID- 27495972 TI - Divergent Successes: What the Abortion Rights Movement Can Learn from Marriage Equality's Success. PMID- 27495971 TI - Risk of self-reported symptoms or diagnosis of active tuberculosis in relationship to low body mass index, diabetes and their co-occurrence. AB - OBJECTIVE: Globally, tuberculosis prevalence has declined, but its risk factors have varied across place and time - low body mass index (BMI) has persisted while diabetes has increased. Using India's National Family Health Survey (NFHS), wave 3 and World Health Survey (WHS) data, we examined their relationships to support projection of future trends and targeted control efforts. METHODS: Multivariate logistic regressions at the individual level with and without diabetes/BMI interactions assessed the relationship between tuberculosis, diabetes and low BMI and the importance of risk factor co-occurrence. Population-level analyses examined how tuberculosis incidence and prevalence varied with diabetes/low BMI co-occurrence. RESULTS: In NFHS, diabetic individuals had higher predicted tuberculosis risks (diabetic vs. non-diabetic: 2.50% vs. 0.63% at low BMI; 0.81% vs. 0.20% at normal BMI; 0.37% vs. 0.09% at high BMI), which were not significantly different when modelled independently or allowing for risk modification with diabetes/low BMI co-occurrence. WHS findings were generally consistent. Population-level analysis found that diabetes/low BMI co-occurrence may be associated with elevated tuberculosis risk, although its predicted effect on tuberculosis incidence/prevalence was generally <=0.2 percentage points and not robustly statistically significant. CONCLUSIONS: Concerns about the additional elevation of tuberculosis risk from diabetes/low BMI co-occurrence and hence the need to coordinate tuberculosis control efforts around the nexus of co occurring diabetes and low BMI may be premature. However, study findings robustly support the importance of individually targeting low BMI and diabetes as part of ongoing tuberculosis control efforts. PMID- 27495973 TI - Bacterial Ice Nucleation in Monodisperse D2O and H2O-in-Oil Emulsions. AB - Ice nucleation is of fundamental significance in many areas, including atmospheric science, food technology, and cryobiology. In this study, we investigated the ice-nucleation characteristics of picoliter-sized drops consisting of different D2O and H2O mixtures with and without the ice-nucleating bacteria Pseudomonas syringae. We also studied the effects of commonly used cryoprotectants such as ethylene glycol, propylene glycol, and trehalose on the nucleation characteristics of D2O and H2O mixtures. The results show that the median freezing temperature of the suspension containing 1 mg/mL of a lyophilized preparation of P. syringae is as high as -4.6 degrees C for 100% D2O, compared to -8.9 degrees C for 100% H2O. As the D2O concentration increases every 25% (v/v), the profile of the ice-nucleation kinetics of D2O + H2O mixtures containing 1 mg/mL Snomax shifts by about 1 degrees C, suggesting an ideal mixing behavior of D2O and H2O. Furthermore, all of the cryoprotectants investigated in this study are found to depress the freezing phenomenon. Both the homogeneous and heterogeneous freezing temperatures of these aqueous solutions depend on the water activity and are independent of the nature of the solute. These findings enrich our fundamental knowledge of D2O-related ice nucleation and suggest that the combination of D2O and ice-nucleating agents could be a potential self-ice-nucleating formulation. The implications of self-nucleation include a higher, precisely controlled ice seeding temperature for slow freezing that would significantly improve the viability of many ice-assisted cryopreservation protocols. PMID- 27495974 TI - Insight into the mechanism of chemical modification of antibacterial agents by antibiotic resistance enzyme O-phosphotransferase-IIIA. AB - In the present work, the mechanism of resistance to aminoglycoside antibiotics was investigated. We examined the conformational changes of the O phosphotransferase-IIIa enzyme, complexed with the antibiotics using MD simulations. The inhibitory effects of a group of antibacterial peptides against the enzyme were also examined, among which CP10A showed the highest affinity and the results correlated with the measured IC50 values. The regioselectivity of the phosphorylation reaction was shown to be in favor of the OH at the 5" position versus the 3' of the antibiotic. The binding mode of CP10A was evaluated by means of MD simulation that resulted in recognizing its Trp8 and Arg13 residues binding near to where residues at the 3' and 5" positions of the antibiotic would bind; thus, they are essential for the peptide inhibitory effect. The major open, semi open, and closed conformations of the binding sites were identified throughout the MD trajectory, which enable the enzyme to regulate the influx of molecules into these sites. Based on the enzyme crystal structure, it was assumed that the 'antibiotic loop' of the enzyme is stable in its liganded mode; however, MD results revealed that the loop is highly flexible in both liganded and ligand free modes. PMID- 27495976 TI - Diabetes-induced mechanophysiological changes in the esophagus. AB - Esophageal disorders are common in diabetes mellitus (DM) patients. DM induces mechanostructural remodeling in the esophagus of humans and animal models. The remodeling is related to esophageal sensorimotor abnormalities and to symptoms frequently encountered by DM patients. For example, gastroesophageal reflux disease (GERD) is a common disorder associated with DM. This review addresses diabetic remodeling of esophageal properties and function in light of the Esophagiome, a scientifically based modeling effort to describe the physiological dynamics of the normal, intact esophagus built upon interdisciplinary approaches with applications for esophageal disease. Unraveling the structural, biomechanical, and sensory remodeling of the esophagus in DM must be based on a multidisciplinary approach that can bridge the knowledge from a variety of scientific disciplines. The first focus of this review is DM-induced morphodynamic and biomechanical remodeling in the esophagus. Second, we review the sensorimotor dysfunction in DM and how it relates to esophageal remodeling. Finally, we discuss the clinical consequences of DM-induced esophageal remodeling, especially in relation to GERD. The ultimate aim is to increase the understanding of DM-induced remodeling of esophageal structure and sensorimotor function in order to assist clinicians to better understand the esophageal disorders induced by DM and to develop better treatments for those patients. PMID- 27495975 TI - Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation. AB - Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans. PMID- 27495977 TI - Target-site and non-target-site based resistance to the herbicide tribenuron methyl in flixweed (Descurainia sophia L.). AB - BACKGROUND: Flixweed (Descurainia sophia L.) is a troublesome and widespread broadleaf weed in winter fields in China, and has evolved high level resistance to acetolactate synthase (ALS)-inhibiting sulfonylurea herbicide tribenuron methyl. RESULTS: We identified a resistant flixweed population (N11) exhibiting 116.3-fold resistance to tribenuron-methyl relative to the susceptible population (SD8). Target-site ALS gene mutation Pro-197-Thr was identified in resistant plants. Moreover, the resistance can be reversed to 28.7-fold by the cytochrome P450 inhibitor malathion. The RNA-Sequencing was employed to identify candidate genes involved in non-target-site metabolic resistance in this population. Total 26 differentially expressed contigs were identified and eight of them (four P450s, one ABC transporter, three glycosyltransferase) verified by qRT-PCR. Consistent over-expression of the two contigs homology to CYP96A13 and ABCC1 transporter, respectively, were further qRT-PCR validated using additional plants from the resistant and susceptible populations. CONCLUSIONS: Tribenuron-methyl resistance in flixweed is controlled by target-site ALS mutation and non-target site based mechanisms. Two genes, CYP96A13 and ABCC1 transporter, could play an important role in metabolic resistance to tribenuron-methyl in the resistant flixweed population and justify further functional studies. PMID- 27495978 TI - Use of a web-based educational intervention to improve knowledge of healthy diet and lifestyle in women with Gestational Diabetes Mellitus compared to standard clinic-based education. AB - BACKGROUND: This study introduced a web-based educational intervention for Australian women with gestational diabetes mellitus (GDM). The aim was to improve knowledge on healthy diet and lifestyle in GDM. Evaluation of the intervention explored women's knowledge and understanding of GDM, healthy diet, healthy food, and healthy lifestyle, after using the web-based program compared to women receiving standard clinic-based GDM education. METHODS: A total of 116 women, aged 18-45 years old, newly diagnosed with GDM, participated (Intervention (n) = 56 and control (n) = 60). Women were randomly allocated to the intervention or control groups and both groups attended a standard GDM education class. Group 1(Intervention) additionally used an online touch screen/computer program. All women completed a questionnaire following the computer program and/or the education class. All questions evaluating levels of knowledge had more than one correct answer and scores were graded from 0 to 1, with each correct component receiving a score, eg. 0.25 per each correct answer in a 4 answer question. Chi square test was performed to compare the two groups regarding knowledge of GDM. RESULTS: Findings indicated that the majority of women in the intervention group reported correct answers for "types of carbohydrate foods" for pregnant women with GDM, compared to the control group (62.5 % vs 58.3 %, respectively). Most women in both groups had an excellent understanding of "fruits and vegetables" (98.2 % vs 98.3 %), and the majority of women in the intervention group understood that they should exercise daily for 30 min, compared to the control group (92.9 % vs 91.7 %). Both groups had a good understanding across all categories, however, the majority of women in the intervention group scored all correct answers (score = 1) in term of foetal effects (17.9 % vs 13.3 %, respectively), maternal predictors (5.4 % vs 5 %), care requirements (39.3 % vs 23.3 %), GDM perceptions (48.2 % vs 46.7 %) and GDM treatment (67.9 % vs 61.7 %), compared to women in the control group. CONCLUSION: The study suggested that both approaches, standard education and standard education plus web-based program, resulted in excellent knowledge scores, but not statistically significant difference between groups. Multiple and immediate access to the web-based education program at home may prove useful as a source of reference for women with GDM. Future study comparing results pre and post intervention is needed. TRIAL REGISTRATION: ACTRN12615000697583 ; Date registered: 03/07/2015; Retrospectively registered. PMID- 27495979 TI - Contamination with ergot bodies (Claviceps purpurea sensu lato) of two horse pastures in Northern Germany. AB - Because the occurrence of Claviceps in European pastures may have been overlooked to cause serious health problem for grazing animals, we documented the degree of Claviceps contamination in two horse pastures and estimated whether the horses could have ingested a critical quantity of alkaloids. We counted the Claviceps sclerotia and determined alkaloid levels using high performance liquid chromatography with fluorescence detection. Depending on the location, the number of sclerotia varied from 0.09 to 0.19 per square meter (central area) and from 0.23 to 55.8 per square meter (border strips). Alkaloid levels in individual sclerotia also varied in different genera of grasses, ranging from 0.98 +/- 0.17 MUg/kg in Agrostis sp. to 25.82 +/- 9.73 MUg/kg in Dactylis sp., equivalent to 0.98 MUg/kg and 7.26 mg/kg. Sclerotia from Dactylis contained high levels of ergosine (0.209 % +/- 0.100 %) and ergocristine (0.374 % +/- 0.070 %). Depending on the localization in pastures, alkaloid levels in forage (dry matter, DM) ranged from 16.1 to 45.4 MUg/kg in central areas and from 23.9 to 722 MUg/kg in border strips. The amount of alkaloids that a horse could have ingested depended on its daily DM uptake, which was higher in the central areas (5.85 kg/day) than in the border strips (2.73 or 0.78 kg/day). In the central areas, this amount of alkaloids ranged from 94.2 to 265.9 MUg/day; and in the border strips, from 65.3 (in 2.73 kg DM/day) to as much as 563.8 MUg/day (in 0.78 kg DM/day). All these amounts are higher than the European averages for alkaloids ingested by horses via feedstuffs. PMID- 27495982 TI - Correction for Hesse et al., Serological Responses to a Norovirus Nonstructural Fusion Protein after Vaccination and Infection. PMID- 27495980 TI - Strong predictive value of mannose-binding lectin levels for cardiovascular risk of hemodialysis patients. AB - BACKGROUND: Hemodialysis patients have higher rates of cardiovascular morbidity and mortality compared to the general population. Mannose-binding lectin (MBL) plays an important role in the development of cardiovascular disease. In addition, hemodialysis alters MBL concentration and functional activity. The present study determines the predictive value of MBL levels for future cardiac events (C-event), cardiovascular events (CV-event) and all-cause mortality in HD patients. METHODS: We conducted a prospective study of 107 patients on maintenance hemodialysis. Plasma MBL, properdin, C3d and sC5b-9 was measured before and after one dialysis session. The association with future C-events, CV events, and all-cause mortality was evaluated using Cox regression models. RESULTS: During median follow-up of 27 months, 36 participants developed 21 C events and 36 CV-events, whereas 37 patients died. The incidence of C-events and CV-events was significantly higher in patients with low MBL levels (<319 ng/mL, lower quartile). In fully adjusted models, low MBL level was independently associated with increased CV-events (hazard ratio 3.98; 95 % CI 1.88-8.24; P < 0.001) and C-events (hazard ratio 3.96; 95 % CI 1.49-10.54; P = 0.006). No association was found between low MBL levels and all-cause mortality. Furthermore, MBL substantially improved risk prediction for CV-events beyond currently used clinical markers. CONCLUSIONS: Low MBL levels are associated with a higher risk for future C-events and CV-events. Therefore, MBL levels may help to identify hemodialysis patients who are at risk to develop cardiovascular disease. PMID- 27495984 TI - Remote ischemic preconditioning improves post resuscitation cerebral function via overexpressing neuroglobin after cardiac arrest in rats. AB - In this study, we investigated the effects of remote ischemic preconditioning on post resuscitation cerebral function in a rat model of cardiac arrest and resuscitation. The animals were randomized into six groups: 1) sham operation, 2) lateral ventricle injection and sham operation, 3) cardiac arrest induced by ventricular fibrillation, 4) lateral ventricle injection and cardiac arrest, 5) remote ischemic preconditioning initiated 90min before induction of ventricular fibrillation, and 6) lateral ventricle injection and remote ischemic preconditioning before cardiac arrest. Reagent of Lateral ventricle injection is neuroglobin antisense oligodeoxynucleotides which initiated 24h before sham operation, cardiac arrest or remote ischemic preconditioning. Remote ischemic preconditioning was induced by four cycles of 5min of limb ischemia, followed by 5min of reperfusion. Ventricular fibrillation was induced by current and lasted for 6min. Defibrillation was attempted after 6min of cardiopulmonary resuscitation. The animals were then monitored for 2h and observed for an additionally maximum 70h. Post resuscitation cerebral function was evaluated by neurologic deficit score at 72h after return of spontaneous circulation. Results showed that remote ischemic preconditioning increased neurologic deficit scores. To investigate the neuroprotective effects of remote ischemic preconditioning, we observed neuronal injury at 48 and 72h after return of spontaneous circulation and found that remote ischemic preconditioning significantly decreased the occurrence of neuronal apoptosis and necrosis. To further comprehend mechanism of neuroprotection induced by remote ischemic preconditioning, we found expression of neuroglobin at 24h after return of spontaneous circulation was enhanced. Furthermore, administration of neuroglobin antisense oligodeoxynucleotides before induction of remote ischemic preconditioning showed that the level of neuroglobin was decreased then partly abrogated neuroprotection of remote ischemic preconditioning. These date suggested that neuroglobin involved in neuroprotective effect of remote ischemic preconditioning. In conclusion, remote ischemic preconditioning attenuated post resuscitation cerebral dysfunction and the neuroprotection was mediated partly by high level of neuroglobin in a rat model of cardiac arrest and resuscitation. PMID- 27495985 TI - Can an auditory multi-feature optimal paradigm be used for the study of processes associated with attention capture in passive listeners? AB - OBJECTIVE: A rarely occurring and highly relevant auditory stimulus occurring outside of the current focus of attention can cause a switching of attention. Such attention capture is often studied in oddball paradigms consisting of a frequently occurring "standard" stimulus which is changed at odd times to form a "deviant". The deviant may result in the capturing of attention. An auditory ERP, the P3a, is often associated with this process. To collect a sufficient amount of data is however very time-consuming. A more multi-feature "optimal" paradigm has been proposed but it is not known if it is appropriate for the study of attention capture. METHODS: An optimal paradigm was run in which 6 different rare deviants (p=.08) were separated by a standard stimulus (p=.50) and compared to results when 4 oddball paradigms were also run. RESULTS: A large P3a was elicited by some of the deviants in the optimal paradigm but not by others. However, very similar results were observed when separate oddball paradigms were run. CONCLUSIONS & SIGNIFICANCE: The present study indicates that the optimal paradigm provides a very time-saving method to study attention capture and the P3a. PMID- 27495986 TI - Early rehabilitation aggravates brain damage after stroke via enhanced activation of nicotinamide adenine dinucleotide phosphate oxidase (NOX). AB - INTRODUCTION: Although physical exercise has emerged as a potential therapeutic modality for functional deficits following ischemic stroke, the extent of this effect appears to be contingent upon the time of exercise initiation. In the present study, we assessed how exercise timing affected brain damage through hyperglycolysis-associated NADPH oxidase (NOX) activation. METHODS: Using an intraluminal filament, adult male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2h and assigned to one non-exercise and three exercise groups. Exercise on Rota-rod was initiated for 30min at 6h (considered very early), at 24h (early), and at day 3 (relatively late) after reperfusion. Lactate production was measured 30min after exercise completion, and NOX activity and protein expression of NOX subunits (p47(phox), gp91(phox), p22(phox) and p67(phox)) and glucose transporter 1 and 3 (Glut-1 and -3) were measured at 3 and 24h after exercise. Apoptotic cell death was determined at 24h after exercise. RESULTS: Lactate production and Glut-1 and Glut-3 expression were increased after very early exercise (6h), but not after late exercise (3 days), suggesting hyperglycolysis. NOX activity was increased with the initiation of exercise at 6h (P<0.05), but not 24h or 3 days, following stroke. Early (6 and 24h), but not late (3 days), post-stroke exercise was associated with increased (P<0.05) expression of the NOX protein subunit p47(phox), gp91(phox)and p67(phox). This may have led to the enhanced apoptosis observed after early exercise in ischemic rats. CONCLUSION: Hyperglycolysis and NOX activation was associated with an elevation in apoptotic cell death after very early exercise, and the detrimental effect of exercise on stroke recovery began to decrease when exercise was initiated 24h after reperfusion. PMID- 27495987 TI - Visceral leishmaniasis in a lung transplant recipient: usefulness of highly sensitive real-time polymerase chain reaction for preemptive diagnosis. AB - We report the case of a lung transplant recipient in whom the diagnosis of visceral leishmaniasis (VL) was made by detection of parasites in a peripheral blood smear when the parasite load already reached 8.9 * 103 parasites/mL. We demonstrated that the VL diagnosis could have been done months before the development of symptoms by the use of Leishmania-specific real-time polymerase chain reaction (PCR), suggesting the role of preemptive PCR-based diagnosis in transplant recipients at risk for VL. PMID- 27495988 TI - Next-generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance. AB - BACKGROUND: Biliary tract cancers (BTCs) are uncommon and are associated with a dismal prognosis. Combinations of gemcitabine and platinum chemotherapy (gemcitabine and platinum-based therapy [GP]) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for a GP response in BTC, this study evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. METHODS: Pretreatment, formalin-fixed, paraffin-embedded samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression-free survival (PFS), and overall survival (OS). RESULTS: When genes with an incidence > 10% were considered, no individual gene was independently predictive of a GP response. In patients with unresectable BTC who received GP as their first-line therapy, the joint status of cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein 53 (TP53), and AT-rich interaction domain 1A (ARID1A) was associated with PFS (P = .0004) and OS (P <= .0001). Patients with mutations in CDKN2A and TP53 were identified as a poor-prognosis cohort with a median PFS of 2.63 months and a median OS of 5.22 months. Patients with mutant ARID1A, regardless of the single mutation status of TP53 or CDKN2A, had similar outcomes. A patient who exhibited mutations in all 3 genes had a median PFS of 20.37 months, and OS was not reached. CONCLUSIONS: In the largest exploratory analysis of this kind for BTC, 3 prevalent, mutually exclusive mutations represent distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker for a GP response. Prospective studies to validate these findings are needed, and they should include the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC. Cancer 2016;122:3657-66. (c) 2016 American Cancer Society. PMID- 27495990 TI - Body size limits dim-light foraging activity in stingless bees (Apidae: Meliponini). AB - Stingless bees constitute a species-rich tribe of tropical and subtropical eusocial Apidae that act as important pollinators for flowering plants. Many foraging tasks rely on vision, e.g. spatial orientation and detection of food sources and nest entrances. Meliponini workers are usually small, which sets limits on eye morphology and thus quality of vision. Limitations are expected both on acuity, and thus on the ability to detect objects from a distance, as well as on sensitivity, and thus on the foraging time window at dusk and dawn. In this study, we determined light intensity thresholds for flight under dim light conditions in eight stingless bee species in relation to body size in a Neotropical lowland rainforest. Species varied in body size (0.8-1.7 mm thorax width), and we found a strong negative correlation with light intensity thresholds (0.1-79 lx). Further, we measured eye size, ocelli diameter, ommatidia number, and facet diameter. All parameters significantly correlated with body size. A disproportionately low light intensity threshold in the minute Trigonisca pipioli, together with a large eye parameter P eye suggests specific adaptations to circumvent the optical constraints imposed by the small body size. We discuss the implications of body size in bees on foraging behavior. PMID- 27495989 TI - Knockout maternal adiponectin increases fetal growth in mice: potential role for trophoblast IGFBP-1. AB - AIMS/HYPOTHESIS: The main objective of this study was to investigate whether maternal adiponectin regulates fetal growth through the endocrine system in the fetal compartment. METHODS: Adiponectin knockout (Adipoq (-/-) ) mice and in vivo adenovirus-mediated reconstitution were used to study the regulatory effect of maternal adiponectin on fetal growth. Primary human trophoblast cells were treated with adiponectin and a specific peroxisome proliferator-activated receptor alpha (PPARalpha) agonist or antagonist to study the underlying mechanism through which adiponectin regulates fetal growth. RESULTS: The body weight of fetuses from Adipoq (-/-) dams was significantly greater than that of wild-type dams at both embryonic day (E)14.5 and E18.5. Adenoviral vector mediated maternal adiponectin reconstitution attenuated the increased fetal body weight induced by maternal adiponectin deficiency. Significantly increased blood glucose, triacylglycerol and NEFA levels were observed in Adipoq (-/-) dams, suggesting that nutrient supply contributes to maternal adiponectin-regulated fetal growth. Although fetal blood IGF-1 concentrations were comparable in fetuses from Adipoq (-/-) and wild-type dams, remarkably low levels of IGF binding protein 1 (IGFBP-1) were observed in the serum of fetuses from Adipoq (-/ ) dams. IGFBP-1 was identified in the trophoblast cells of human and mouse placentas. Maternal fasting robustly increased IGFBP-1 levels in mouse placentas, while reducing fetal weight. Significantly low IGFBP-1 levels were found in placentas of Adipoq (-/-) dams. Adiponectin treatment increased IGFBP-1 levels in primary cultured human trophoblast cells, while the PPARalpha antagonist, MK886, abolished this stimulatory effect. CONCLUSIONS/INTERPRETATION: These results indicate that, in addition to nutrient supply, maternal adiponectin inhibits fetal growth by increasing IGFBP-1 expression in trophoblast cells. PMID- 27495991 TI - Triple bypass for advanced pancreatic head cancer associated with biliary stricture, duodenal stenosis, and recurrent obstructive pancreatitis. AB - Bypass surgery for cancer of the pancreatic head is usually done to palliate the obstructive symptoms in the biliary and/or digestive system. However, it is uncommon for patients to require pancreatic duct drainage for recurrent obstructive pancreatitis. In this article, we report a surgical technique of triple bypass consisting of Roux-en-Y hepaticojejunostomy, gastrojejunostomy, and pancreaticojejunostomy for advanced pancreatic cancer. A 76-year-old male patient with locally advanced and metastatic pancreatic head cancer was referred to our department for biliary stricture, duodenal stenosis, and recurrent obstructive pancreatitis associated with persistent pancreatic pseudocyst. In an attempt to resolve all these problems simultaneously, a triple bypass was performed. The patient survived and continued to receive chemotherapy for almost 1 year after surgery without any serious complications. Thus, triple bypass is a useful surgical technique that could relief symptoms and offer better quality of life to patients with advanced pancreatic cancer presenting with biliary stricture, duodenal stenosis, and severe obstructive pancreatitis difficult to treat by medication or endoscopic procedures. PMID- 27495992 TI - Wandering liver and intestinal malrotation: first report. AB - A wandering liver is a rare development in both the adult and pediatric population where the liver is freely displaced along a transverse axis. We describe the first known occurrence in published literature of a wandering liver in an adult individual who also had an intestinal malrotation complicated by a midgut volvulus. The abnormal ability for a liver to wander presents a highly unusual anatomy that can be disorienting. Laparoscopic surgery is a viable option in reducing a midgut volvulus and addressing an intestinal malrotation in the presence of a wandering liver. This unusual presentation educates clinicians to avoid potential misdiagnosis given the abnormal location of the duodenum, appendix, liver, and gallbladder. PMID- 27495993 TI - Efficacy of recombinant thrombomodulin for DIC after deceased donor liver transplantation: a case report. AB - BACKGROUND: Disseminated intravascular coagulation (DIC) after liver transplantation (LT) is a difficult complication. We report a case of disseminated intravascular coagulation after deceased donor liver transplantation (DDLT) treated with recombinant thrombomodulin (rTM). CASE PRESENTATION: A 30 year-old woman underwent right tri-segment split graft DDLT for acute liver failure. She developed disseminated intravascular coagulation on post-operative day 5 with fever. Computed tomography revealed necrosis of hepatic segment IV, and her acute-phase disseminated intravascular coagulation score was seven points. She was given rTM, and the inflammation, liver function, and coagulation disorders immediately improved. However, pleural effusion drainage from the chest tube became bloody on post-operative day 11, and rTM was discontinued. She progressed well and was discharged from the hospital on post-operative day 28. rTM is an effective treatment for disseminated intravascular coagulation; however, rTM for cases with coagulation disorders, which can occur after liver transplantation, has both risks and benefits. CONCLUSIONS: We report a case of DIC after LT, in which rTM was potentially effective. Further studies are needed to determine the appropriate dosages, duration, and additional considerations for rTM therapy in liver transplantation patients. PMID- 27495994 TI - Diastology: What Does the New Updated Guideline Do for You? PMID- 27495995 TI - Renovascular Duplex Ultrasound in Children: A Lost Cause? PMID- 27495997 TI - Feasibility and Prognostic Effect of Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy in Cytology-Proven, Node-Positive Breast Cancer. AB - BACKGROUND: We evaluated the feasibility and prognostic effect in axillary recurrence or survival of sentinel lymph node biopsy (SLNB) in patients with cytology-proven, node-positive breast cancer after neoadjuvant chemotherapy (NAC). METHODS: This is a retrospective study of 329 patients who were diagnosed with invasive breast cancer and axillary lymph nodes (ALN) metastasis and treated with NAC followed by curative surgery at Samsung Medical Center between January 2007 and December 2013. We analyzed and compared outcomes including prognoses and survival rates among all groups. RESULTS: The median age at the time of surgery was 44.4 years. The median follow-up time was 37 months (range, 1-91 months). The sentinel lymph node (SLN) identification rate was 96.7% (117 of 121 patients). The median number of retrieved SLNs was 4.0 (range, 1-7), and 57 patients had negative SLNs on frozen-section analysis. The false negative rate of SLNB after NAC was 7.8% (5 of 64 patients). In survival analysis, there was no difference in the overall survival (P = .2) and the regional recurrence-free survival (P = .297) among Groups 1, 2, and 4. CONCLUSION: SLNB may be feasible after NAC for node-positive breast cancer and may help reduce surgical morbidity by avoiding the need for standard axillary lymph node dissection in some patients. We suggest that future studies with a large number of patients and a longer follow-up period are necessary to support the use of SLN surgery as an alternative to axillary lymph node dissection in this patient population. PMID- 27495996 TI - Comparing Coordinated Versus Sequential Salpingo-Oophorectomy for BRCA1 and BRCA2 Mutation Carriers With Breast Cancer. AB - BACKGROUND: Women with breast cancer who carry BRCA1 or BRCA2 mutations must also consider risk-reducing salpingo-oophorectomy (RRSO) and how to coordinate this procedure with their breast surgery. We report the factors associated with coordinated versus sequential surgery and compare the outcomes of each. PATIENTS AND METHODS: Patients in our cancer risk database who had breast cancer and a known deleterious BRCA1/2 mutation before undergoing breast surgery were included. Women who chose concurrent RRSO at the time of breast surgery were compared to those who did not. RESULTS: Sixty-two patients knew their mutation carrier status before undergoing breast cancer surgery. Forty-three patients (69%) opted for coordinated surgeries, and 19 (31%) underwent sequential surgeries at a median follow-up of 4.4 years. Women who underwent coordinated surgery were significantly older than those who chose sequential surgery (median age of 45 vs. 39 years; P = .025). There were no differences in comorbidities between groups. Patients who received neoadjuvant chemotherapy were more likely to undergo coordinated surgery (65% vs. 37%; P = .038). Sequential surgery patients had longer hospital stays (4.79 vs. 3.44 days, P = .01) and longer operating times (8.25 vs. 6.38 hours, P = .006) than patients who elected combined surgery. Postoperative complications were minor and were no more likely in either group (odds ratio, 4.76; 95% confidence interval, 0.56-40.6). CONCLUSION: Coordinating RRSO with breast surgery is associated with receipt of neoadjuvant chemotherapy, longer operating times, and hospital stays without an observed increase in complications. In the absence of risk, surgical options can be personalized. PMID- 27495999 TI - Smoking rates vary widely in US racial and ethnic groups. PMID- 27495998 TI - Design and evaluation of a portable intra-operative unified-planning-and-guidance framework applied to distal radius fracture surgery. AB - PURPOSE: During a standard fracture reduction and fixation procedure of the distal radius, only fluoroscopic images are available for planning of the screw placement and monitoring of the drill bit trajectory. Our prototype intra operative framework integrates planning and drill guidance for a simplified and improved planning transfer. METHODS: Guidance information is extracted using a video camera mounted onto a surgical drill. Real-time feedback of the drill bit position is provided using an augmented view of the planning X-rays. We evaluate the accuracy of the placed screws on plastic bones and on healthy and fractured forearm specimens. We also investigate the difference in accuracy between guided screw placement versus freehand. Moreover, the accuracy of the real-time position feedback of the drill bit is evaluated. RESULTS: A total of 166 screws were placed. On 37 plastic bones, our obtained accuracy was [Formula: see text] mm, [Formula: see text] and [Formula: see text] in tip position and orientation (azimuth and elevation), respectively. On the three healthy forearm specimens, our obtained accuracy was [Formula: see text] mm, [Formula: see text] and [Formula: see text]. On the two fractured specimens, we attained: [Formula: see text] mm, [Formula: see text] and [Formula: see text]. When screw plans were applied freehand (without our guidance system), the achieved accuracy was [Formula: see text] mm, [Formula: see text], while when they were transferred under guidance, we obtained [Formula: see text] mm, [Formula: see text]. CONCLUSIONS: Our results show that our framework is expected to increase the accuracy in screw positioning and to improve robustness w.r.t. freehand placement. PMID- 27496000 TI - Editorial overview: New technologies: GPCR drug design and function-exploiting the current (of) structures. PMID- 27496001 TI - Management of Simple Clavicle Fractures by Primary Care Physicians. AB - The clavicle is the most commonly fractured bone. Children with simple fractures are often referred to orthopedic surgeons by primary care physician to ensure adequate care. The objective of this study was to show that simple clavicle fractures have excellent outcomes and are within the scope of primary care physician's practice. We performed a retrospective chart review of 16 adolescents with simple clavicle fractures treated with a sling. Primary outcomes were bony union, pain, and function. The patients with simple clavicle fractures had excellent outcomes with no complications or complaints of pain or restriction of their activities of daily living. The outcomes are similar whether treated by an orthopedic surgeon or a primary care physician. The cost to society and the patient is less when the primary care physician manages the fracture. Therefore, primary care physicians should manage simple clavicle fractures. PMID- 27496003 TI - Exposure to zidovudine adversely affects mitochondrial turnover in primary T cells. AB - Zidovudine (ZDV) is a widely used component of antiretroviral therapy (ART) in resource-limited settings, despite its known adverse effects, which include mitochondrial toxicity in muscle, liver and adipose tissue. It has also been associated with impaired immunological recovery. We hypothesised that ZDV might impair mitochondrial health and survival of primary T cells. We performed a cross sectional analysis of mitochondrial function, mitophagy and susceptibility to apoptosis in healthy donor primary T cells after exposure to ZDV in vitro, together with T cells from patients who were virologically suppressed on ZDV containing ART regimens for >=1 year and age-matched subjects receiving non-ZDV ART regimens. The proportion of T cells expressing mitochondrial reactive oxygen species (mtROS) was significantly higher after in vitro (CD4(+) T cells and CD8(+) T cells) and in vivo (CD4(+) T cells) exposure to ZDV than other antiretroviral agents. We did not detect any effect of ZDV on mitophagy, as indicated by change in autophagic flux. However, spontaneous apoptosis, indicated by upregulation of caspase-3 was greater in ZDV-exposed T cells. In conclusion, ZDV exposure was associated with impaired mitochondrial turnover and increased susceptibility to apoptosis in T cells. These mechanisms could contribute to sub optimal immune reconstitution. PMID- 27496002 TI - Optogenetic Approaches for Controlling Seizure Activity. AB - Optogenetics, a technique that utilizes light-sensitive ion channels or pumps to activate or inhibit neurons, has allowed scientists unprecedented precision and control for manipulating neuronal activity. With the clinical need to develop more precise and effective therapies for patients with drug-resistant epilepsy, these tools have recently been explored as a novel treatment for halting seizure activity in various animal models. In this review, we provide a detailed and current summary of these optogenetic approaches and provide a perspective on their future clinical application as a potential neuromodulatory therapy. PMID- 27496006 TI - Endoscopic-modified medial maxillectomy and its limitation for a solitary fibrous tumor of the lacrimal sac and nasolacrimal duct. AB - Solitary fibrous tumor (SFT) is an uncommon neoplasm that usually arises from the pleura. Recently, SFTs have been reported in the head and neck region located in subsites such as the orbit. SFTs of the lacrimal sac are extremely rare, with only six cases reported in the English literature. We describe a SFT arising from the right lacrimal sac and extending along the nasolacrimal duct into the nasal cavity. Although, the tumor could not be removed by endoscopic-modified medial maxillectomy (EMMM) alone, combined approach with EMMM and a small external incision achieved the complete removal of the tumor. The patient has remained disease-free 24 months after surgery. PMID- 27496004 TI - Exosomes contribute to the transmission of anti-HIV activity from TLR3-activated brain microvascular endothelial cells to macrophages. AB - Human brain microvascular endothelial cells (HBMECs), the major cell type in the blood-brain barrier (BBB), play a key role in maintaining brain homeostasis. However, their role in the BBB innate immunity against HIV invasion of the central nervous system (CNS) remains to be determined. Our early work showed that TLR3 signaling of HBMECs could produce the antiviral factors that inhibit HIV replication in macrophages. The present study examined whether exosomes from TLR3 activated HBMECs mediate the intercellular transfer of antiviral factors to macrophages. Primary human macrophages could take up exosomes from TLR3-activated HBMECs. HBMECs-derived exosomes contained multiple antiviral factors, including several key IFN-stimulated genes (ISGs; ISG15, ISG56, and Mx2) at mRNA and protein levels. The depletion of exosomes from TLR3-activated HBMECs culture supernatant diminished HBMECs-mediated anti-HIV activity in macrophages. In conclusion, we demonstrate that exosomes shed by HBMECs are able to transport the antiviral molecules to macrophages. This finding suggests the possibility that HIV nonpermissive BBB cells (HBMECs) can help to restore the antiviral state in HIV-infected macrophages, which may be a defense mechanism against HIV neuroinvasion. PMID- 27496007 TI - A case of vertebral artery aneurysm presenting with dysphagia. AB - Here, we report a case of vertebral artery aneurysm causing dysphagia in a 56 year-old man who had no remarkable past history. Two months before the first visit, he developed posterior neck pain followed by difficulty swallowing 1 month later. He was referred to our clinic because of gradually worsening dysphagia. Physical examination showed paralysis of cranial nerves IX, X, and XII; therefore, he was hospitalized. Because enhanced CT and MRI showed a partially thrombosed right vertebral artery aneurysm, he was transferred to the care of the Department of Neurosurgery. Parent artery occlusion of the right vertebral artery aneurysm was performed and it improved his symptoms. After regaining his ability to take in liquid food, he was transferred to another hospital for further rehabilitation. In this case, we attributed the dysphagia to aneurysmal compression of the roots of cranial nerves IX, X, and XII. A partially thrombosed cerebral artery aneurysm may often rupture and cause worsening of neurologic symptoms. The prognosis is generally poor because the rupture rate is extremely high especially with large or giant aneurysms. However, this case had a good clinical course owing to treatment by parent artery occlusion. PMID- 27496008 TI - Sentinel node biopsy for oral cancer: A prospective multicenter Phase II trial. AB - OBJECTIVE: A recent study identified a survival benefit with prophylactic neck dissection (ND) at the time of primary surgery as compared with watchful waiting followed by therapeutic neck dissection for nodal relapse, in patients with cN0 oral squamous cell carcinoma (OSCC). Alternative management of cN0 neck cancer is recommended to minimize the adverse effects of ND, indicating the need for sentinel node biopsy (SNB) and limited neck dissection. We conducted a multicenter Phase II study to examine the feasibility of SNB for clinically N0 OSCC. METHODS: Previously untreated N0 OSCC patients (n=57) with clinical late-T2 or T3 tumors were enrolled across 10 institutions. SNB navigated with multislice frozen section analysis of sentinel nodes (SNs) and SNB supported sentinel node lymphatic basin dissection (SN basin dissection) were performed in a one-stage procedure. The endpoint was to investigate the rate of false-negative metastases after SN basin dissection and SNB alone. RESULTS: Most tumors were late-T2 lesions (n=50; 87.7%). SNs were identified in all patients. A total of 196 SNs were detected. Among these SNs, 35 (17.8%) were positive for metastasis (9 in level I, 12 in level II, 12 in level III, 1 in level V and 2 in the contralateral region of the neck). The false-negative rate of SNB supported by SN basin dissection and SNB alone was 4.5% and 9.1%, respectively. The concordance of the SN status in intraoperative frozen sections with the permanent histopathology was 97.4% (191/196). The sensitivity and specificity of intraoperative pathological evaluation were 85.7% (30/35) and 100% (30/30), respectively. The 3-year overall survival (OS) and disease-free survival was 89.5% and 82.5%, respectively. The OS of SN-negative patients was significantly longer than that of SN-positive patients (P=0.047). CONCLUSION: The current study verified that SN basin dissection was a useful back-up procedure for SNB performed as a one-stage procedure, showing a low false-negative rate. SNB alone is an appropriate staging method for patients with clinical N0 staging, and a reliable procedure to determine the appropriate levels for neck dissection. PMID- 27496009 TI - Primary combined small cell carcinoma and squamous cell carcinoma of the oropharynx with special reference to EGFR status of small cell carcinoma component: Case report and review of the literature. AB - Combined small cell carcinoma (SCC) and squamous cell carcinoma (SqCC) of the oropharynx is extremely rare and shows an aggressive clinical course. There are only 5 reported cases of combined SCC and SqCC in the English language literature. Here, we report a 59-year-old male presenting with a right tonsillar mass. The mass was biopsied, and the histological findings showed a proliferation of small-sized tumor cells with scant cytoplasm. Immunohistochemically, the tumor cells were positive for neuroendocrine markers (synaptophysin, chromogranin A, and CD56). Our first diagnosis was tonsillar small cell carcinoma. We treated the patient with concurrent chemoradiotherapy together with cisplatin followed by surgery. The resected tonsillar specimen showed a residual tumor composed of SCC and SqCC, and lymph nodes showed metastatic tumor cells of the SCC component. Immunohistochemically, the SCC component was positive for all neuroendocrine markers and p16; on the other hand, the SqCC component was positive for p40, p63, p16, and EGFR. Fluorescence in situ hybridization revealed that neither component showed any EGFR gene copy number gain. The patient was treated with adjuvant chemotherapy consisting of irinotecan and cisplatin. Liver and bone metastases developed, resulting in the death of the patient. We discuss the present case and review similar cases. Most cases of combined SCC and SqCC occur regardless of p16 status, and a therapeutic strategy has yet to be determined. Further examination of this kind of combined tumor is necessary. PMID- 27496010 TI - Stress hormonal changes in the brain and plasma after acute noise exposure in mice. AB - OBJECTIVE: To investigate the effects of acute noise stress on two amine stress hormones, norepinephrine (NE) and 5-hydroxyindoleacetic acid (5-HIAA) in the brain and plasma of mice after noise exposure. METHODS: Mice were grouped into the control and noise groups. Mice in the noise group were exposed to white noise of 110dB sound pressure level for 60min. Auditory brainstem response thresholds, distortion product otoacoustic emissions, the organ of Corti grading scores, western blots of NE/5-HIAA in the whole brain and hippocampus, and the plasma levels of NE/5-HIAA were compared between the two groups. RESULTS: Significant hearing loss and cochlear damage were demonstrated in the noise group. NE and 5 HIAA in the hippocampus were elevated in the noise group (p=0.019/0.022 for NE/5 HIAA vs. the control). Plasma levels of NE and 5-HIAA were not statistically different between the groups (p=0.052/0.671 for NE/5-HIAA). CONCLUSION: Hearing loss with outer hair cell dysfunction and morphological changes of the organ of Corti after noise exposure in C57BL/6 mice proved the reliability of our animal model as an acute noise stress model. NE and 5-HIAA are suggested to be the potential biomarkers for acute noise stress in the hippocampus. PMID- 27496011 TI - Palpebral sporotrichosis in a 6-year-old child. PMID- 27496012 TI - A GIS Approach to Identifying Socially and Medically Vulnerable Older Adult Populations in South Florida. AB - Purpose of the Study: We define, map, and analyze geodemographic patterns of socially and medically vulnerable older adults within the tri-county region of South Florida. Design and Methods: We apply principal components analysis (PCA) to a set of previously identified indicators of social and medical vulnerability at the census tract level. We create and map age-stratified vulnerability scores using a geographic information system (GIS), and use spatial analysis techniques to identify patterns and interactions between social and medical vulnerability. Results: Key factors contributing to social vulnerability in areas with higher numbers of older adults include age, large household size, and Hispanic ethnicity. Medical vulnerability in these same areas is driven by disease burden, access to emergency cardiac services, availability of nursing home and hospice beds, access to home health care, and available mental health services. Age dependent areas of social vulnerability emerge in Broward County, whereas age dependent areas of medical vulnerability emerge in Palm Beach County. Older-adult social and medical vulnerability interact differently throughout the study area. Implications: Spatial analysis of older adult social and medical vulnerability using PCA and GIS can help identify age-dependent pockets of vulnerability that are not easily identifiable in a populationwide analysis; improve our understanding of the dynamic spatial organization of health care, health care needs, access to care, and outcomes; and ultimately serve as a tool for health care planning. PMID- 27496013 TI - Culture and Language Discordance in the Workplace: Evidence From the National Home Health Aide Survey. AB - Purpose of the study: Home health aides (HHAs) provide valuable resources to address existing and predicted needs for taking care of the aging population. Both the older adult and healthcare provider populations in the United States are becoming increasingly diverse. The study examined the effect of culture and language discordance between HHAs and their patients or coworkers on worker outcomes. Design and methods: Data from this study were from the 2007 National Home Health Aide Survey. T Tests and ordinary least squares regression were used to analyze the relationships between cultural discordance and worker outcomes. Results: Cultural discordance with patients was associated with lower levels of job satisfaction among HHAs. Cultural discordance with coworkers was associated with lower levels of job satisfaction and, increased intent to leave one's job. Implications: The current study suggests that cultural discordance does affect worker outcomes. However, home healthcare workers appear to differentiate between cultural discordance with patients and with coworkers. This article concludes with strategies for all involved in the care of older adults to improve the experience of HHAs and to ensure patients receive the best possible care. PMID- 27496014 TI - Fitness-to-drive Disagreements in Individuals With Dementia. AB - Purpose of the Study: We sought to investigate the agreement between medical and practical fitness-to-drive recommendations in active drivers with dementia. Design and Methods: In this retrospective study, 68 patients underwent medical, visual, and road tests at an official center of the Belgian Road Safety Institute. Physicians provided medical fitness-to-drive recommendations using 1 of 3 categories (favorable, reserved, or unfavorable). On-road assessors used the same 3 categories to make practical fitness-to-drive recommendations. Agreement between the medical and practical fitness-to-drive recommendations was calculated using the percentage of agreement (p0) and weighted kappa (kw). Results: Low agreement was found between physicians and on-road assessors regarding their fitness-to-drive recommendations (p0 = 43%, kw = 0.11, p = .20). Compared with the on-road assessors, the physicians overestimated the fitness to drive of 24 (35%) patients and underestimated the fitness to drive of 15 (22%) patients. Patients who incurred more traffic violations were more likely to be overestimated than underestimated by the physician (p = .03). Implications: This study showed disagreements between the fitness-to-drive recommendations made by the physicians and the on-road assessors in more than half of drivers with dementia. Efforts need to be made to improve the communication between physicians and on-road assessors for joint decision making of fitness to drive in dementia. PMID- 27496015 TI - Anti-inflammatory activity of aqueous extract and bioactive compounds identified from the fruits of Hancornia speciosa Gomes (Apocynaceae). AB - BACKGROUND: Hancornia speciosa Gomes (Apocynaceae), popularly known as "mangabeira," has been used in folk medicine to treat inflammatory disorders, hypertension, dermatitis, diabetes, liver diseases and gastric disorders. Although the ethnobotany indicates that its fruits can be used for the treatment of ulcers and inflammatory disorders, only few studies have been conducted to prove such biological activities. This study investigated the anti-inflammatory properties of the aqueous extract of the fruits of H. speciosa Gomes as well as its bioactive compounds using in vivo experimental models. METHODS: The bioactive compounds were identified by High Performance Liquid Chromatography coupled with diode array detector (HPLC-DAD) and Liquid Chromatography coupled with Mass Spectrometry (LC-MS). The anti-inflammatory properties were investigated through in vivo tests, which comprised xylene-induced ear edema, carrageenan-induced peritonitis and zymosan-induced air pouch. The levels of IL-1beta, IL-6, IL-12 and TNF-alpha were determined using ELISA. RESULTS: Rutin and chlorogenic acid were identified in the extract as the main secondary metabolites. In addition, the extract as well as rutin and chlorogenic acid significantly inhibited the xilol-induced ear edema and also reduced the cell migration in both carrageenan induced peritonitis and zymosan-induced air pouch models. Reduced levels of cytokines were also observed. CONCLUSION: This is the first study that demonstrated the anti-inflammatory activity of the extract of H. speciosa fruits against different inflammatory agents in animal models, suggesting that its bioactive molecules, especially rutin and chlorogenic acid are, at least in part, responsible for such activity. These findings support the widespread use of Hancornia speciosa in popular medicine and demonstrate that its aqueous extract has therapeutical potential for the development of herbal drugs with anti inflammatory properties. PMID- 27496017 TI - Reply to "Comment on: MALDI ionization mechanisms investigated by comparison of isomers of dihydroxybenzoic acid". PMID- 27496016 TI - Effects of dietary postbiotic and inulin on growth performance, IGF1 and GHR mRNA expression, faecal microbiota and volatile fatty acids in broilers. AB - BACKGROUND: Postbiotics (metabolic products by lactic acid bacteria) and prebiotics have been established as substitute to antibiotics in order to enhance immunity and growth performance in broiler chickens. Nonetheless, insufficient information is available on the effects of postbiotics and prebiotics combination on growth performance, faecal microbiota, pH and volatile fatty acids (VFA), as well as liver insulin like growth factor 1 (IGF1) and growth hormone receptor (GHR) mRNA expressions in broiler chickens. The aim of this experiment was to evaluate the effects of different types of postbiotics with different levels of prebiotic (inulin) on broiler for those parameters. RESULTS: The results showed that birds fed T3: (0.3 % RI11 + 0.8 % Inulin), T4: (0.3 % RI11 + 1.0 % Inulin), and T6: (0.3 % RG14+ 1.0 % Inulin) had higher (p < 0.05) final body weight (BW) and total weight gain (WG) than other treatments. Birds fed T3 had lower feed conversion ratio (FCR) which was significantly different from those fed with negative control diet but was similar to other treatments. Postbiotic and inulin increased (p < 0.05) faecal lactic acid bacteria (LAB) and reduced (p < 0.05) Enterobacteriaceae count. Birds fed T4 and T6 had higher faecal acetic acid and propionic acid respectively, and both had higher total VFA and lactic acid bacteria but lower pH and Enterobacteriaceae (ENT) counts compared to other treatments. The liver of birds fed T4 and T6 had higher IGF1 expression compared to other treatments while T6 had higher GHR mRNA expression compared to other treatments. CONCLUSIONS: Results indicate that the addition of postbiotics and inulin combinations had beneficial effects on total BW, feed efficiency, mucosa architecture and IGF1 and GHR mRNA expression in broiler chickens. PMID- 27496018 TI - Tigecycline-based versus sulbactam-based treatment for pneumonia involving multidrug-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex. AB - BACKGROUND: The treatment options for pneumonia involving multidrug-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii (MDR Acb) complex are limited, and the optimal treatment has not been established. METHODS: To compare the efficacy of tigecycline-based with sulbactam (or ampicillin/sulbactam)-based therapy for pneumonia involving MDR Acb complex, we conducted a retrospective study comparing 84 tigecycline-treated adult patients during the period August 2007 to March 2010 with 84 sulbactam or ampicillin/sulbactam-treated adult patients during the period September 2004 to July 2007. Both groups had the matched Acute Physiology and Chronic Health Evaluation (APACHE) II score and received treatment for at least 7 days. RESULTS: The mean APACHE II score was 20.1 for both groups. More patients in sulbactam group had ventilator use (89.3 % versus 69.0 %), bilateral pneumonia (79.8 % versus 60.7 %) and combination therapy (84.5 % versus 53.6 %), particularly with carbapenems (71.4 % versus 6.0 %), while more patients in tigecycline group had delayed treatment (41.7 % versus 26.2 %) (P <0.05). At the end of treatment, more patients in sulbactam group had airway MDR Acb complex eradication (63.5 % versus 33.3 %, P <0.05). The clinical resolution rate was 66.7 % for both groups. The mortality rate during treatment was 17.9 % in sulbactam group, and 25.0 % in tigecycline group (P = 0.259). The multivariate analysis showed that bilateral pneumonia was the only independent predictor for mortality during treatment (adjusted odds ratio, 2.717; 95 % confidence interval, 1.015 to 7.272). CONCLUSIONS: Patients treated with either tigecycline-based or sulbactam-based therapy had a similar clinical outcome, but tigecycline group had a lower microbiological eradiation rate. PMID- 27496019 TI - Elucidating Combinatorial Chromatin States at Single-Nucleosome Resolution. AB - Chromatin immunoprecipitation followed by sequencing (ChIP-seq) has been instrumental to our current view of chromatin structure and function. It allows genome-wide mapping of histone marks, which demarcate biologically relevant domains. However, ChIP-seq is an ensemble measurement reporting the average occupancy of individual marks in a cell population. Consequently, our understanding of the combinatorial nature of chromatin states relies almost exclusively on correlation between the genomic distributions of individual marks. Here, we report the development of combinatorial-iChIP to determine the genome wide co-occurrence of histone marks at single-nucleosome resolution. By comparing to a null model, we show that certain combinations of overlapping marks (H3K36me3 and H3K79me3) co-occur more frequently than would be expected by chance, while others (H3K4me3 and H3K36me3) do not, reflecting differences in the underlying chromatin pathways. We further use combinatorial-iChIP to illuminate aspects of the Set2-RPD3S pathway. This approach promises to improve our understanding of the combinatorial complexity of chromatin. PMID- 27496021 TI - Selective 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in Gliomas. AB - Malignant gliomas are locally invasive tumors that offer a poor prognosis. Evidence shows that complete resection of the tumor at the time of surgery confers a significant improvement in overall survival. In recent years, 5- aminolevulinic acid (ALA)-induced fluorescence has been used by neurosurgeons to good effect in increasing the rate of complete resection. Despite the considerable interest in the use of 5-ALA in fluorescence-guided neurosurgery, the mechanisms behind the accumulation of Protoporphyrin IX (PpIX) in neoplastic tissue are unclear. In this review, we summarize the evidence in the literature on the mechanisms underlying the selective production of PpIX with a specific focus on gliomas. PMID- 27496020 TI - Does home equipment contribute to socioeconomic gradients in Australian children's physical activity, sedentary time and screen time? AB - BACKGROUND: Activity behaviours (physical activity, sedentary time and screen time) have been linked to health outcomes in childhood. Furthermore, socioeconomic disparities have been observed in both children's activity behaviours and health outcomes. Children's physical home environments may play a role in these relationships. This study aimed to examine the associations and interactions between children's physical home environment, socioeconomic status and moderate-to-vigorous physical activity, sedentary time and screen time. METHODS: Australian children (n = 528) aged 9-11 years from randomly selected schools participated in the cross-sectional International Study of Childhood Obesity, Lifestyle and the Environment. Children's physical home environment (access to equipment), socioeconomic status (household income and parental education) and demographic variables (gender and family structure) were determined by parental questionnaire. Moderate-to-vigorous physical activity and sedentary time were measured objectively by 7-day 24-h accelerometry. Screen time was obtained from child survey. The associations between the physical home environment, socioeconomic status and moderate-to-vigorous physical activity, sedentary time and screen time were examined for 427 children, using analysis of covariance, and linear and logistic regression, with adjustment for gender and family structure. RESULTS: The presence of TVs (p < 0.01) and video game consoles (p < 0.01) in children's bedrooms, and child possession of handheld video games (p = 0.04), cell phones (p < 0.01) and music devices (p = 0.04) was significantly and positively associated with screen time. Ownership of these devices (with the exception of music devices) was inversely related to socioeconomic status (parental education). Children's moderate-to-vigorous intensity physical activity (p = 0.04) and possession of active play equipment (p = 0.04) were both positively associated with socioeconomic status (household income), but were not related to each other (with the exception of bicycle ownership). CONCLUSIONS: Children with less electronic devices, particularly in their bedrooms, participated in less screen time, regardless of socioeconomic status. Socioeconomic disparities were identified in children's moderate-to-vigorous physical activity, however socioeconomic status was inconsistently related to possession of active play equipment. Home active play equipment was therefore not a clear contributor to the socioeconomic gradients in Australian children's moderate-to-vigorous physical activity. PMID- 27496022 TI - Development of a video-assisted thoracoscopic lobectomy program in a single institution: results before and after completion of the learning curve. AB - BACKGROUND: The development of a video assisted thoracic surgery lobectomy (VATS L) program provides a dedicated surgical team with a recognized learning curve (LC) of 50 procedures. We analyse the results of our program, comparing the LC with subsequent cases. METHODS: From June 2012 to March 2015, we performed n = 146 VATS major pulmonary resections: n = 50 (Group A: LC); n = 96 (Group B). Pre operative mediastinal staging followed the National Comprehensive Cancer Network guidelines. All procedures were performed using a standard anterior approach to the hilum; lymphadenectomy followed the NCCN recommendations. During the LC, VATS L indication was reserved to clinical stages I, therefore evaluated case by case. RESULTS: Mean operative time was 191 min (120-290) in Group A and 162 min (85 360) in Group B (p <0,01). Pathological T status was similar between two Groups. Lymphadenectomy included a mean of 5.8 stations in Group A and 6.6 in Group B resulting in: pN0 disease: Group A n = 44 (88 %), Group B n = 80 (83.4 %); pN1: Group A n = 3 (6 %), Group B n = 8 (8.3 %); pN2: Group A n = 3 (6 %), Group B n = 8 (8.3 %). Conversion rate was: 8 % in group A (n = 4 vascular injuries); 1.1 % in Group B (n = 1 hilar lymph node disease). We registered n = 6 (12 %) complications in Group A, n = 10 (10.6 %) in Group B. One case (1.1 %) of late post-operative mortality (90 days) was registered in Group B for liver failure. Mean hospital stay was 6.5 days in Group A and 5.9 days in Group B. CONCLUSIONS: We confirm the effectiveness of a VATS-L program with a learning curve of 50 cases performed by a dedicated surgical team. Besides the LC, conversion rate falls down, lymphadenectomy become more efficient, indications can be extended to upper stages. PMID- 27496023 TI - Mid-term oncologic outcome of a novel approach for locally advanced colon cancer with neoadjuvant chemotherapy and surgery. AB - PURPOSE: Neoadjuvant chemotherapy is being actively tested as an emerging alternative for the treatment of locally advanced colon cancer (LACC) patients, resembling its use in other gastrointestinal tumors. This study assesses the mid term oncologic outcome of LACC patients treated with oxaliplatin and fluoropyrimidines-based preoperative chemotherapy followed by surgery. METHODS AND PATIENTS: Patients with radiologically resectable LACC treated with neoadjuvant therapy between 2009 and 2014 were retrospectively analyzed. Radiological, metabolic, and pathological tumor response was assessed. Both postoperative complications, relapse-free survival (RFS), and overall survival (OS) were studied. RESULTS: Sixty-five LACC patients who received treatment were included. Planned treatment was completed by 93.8 % of patients. All patients underwent surgery without delay. The median time between the start of chemotherapy and surgery was 71 days (65-82). No progressive disease was observed during preoperative treatment. A statistically significant tumor volume reduction of 62.5 % was achieved by CT scan (39.8-79.8) (p < 0.001). It was also observed a median reduction of 40.5 % (24.2-63.7 %) (p < 0.005) of SUVmax (Standard Uptake Value) by PET-CT scan. Complete pathologic response was achieved in 4.6 % of patients. Postoperative complications were observed in 15.4 % of patients, with no cases of mortality. After a median follow-up of 40.1 months, (p 25-p 75: 27.3 57.8) 3-5 year actuarial RFS was 88.9-85.6 %, respectively. Five-year actuarial OS was 95.3 %. CONCLUSION: Preoperative chemotherapy in LACC patients is safe and able to induce major tumor regression. Survival times are encouraging, and further research seems warranted. PMID- 27496025 TI - Two scenes or not two scenes: The effects of stimulus repetition and view similarity on scene categorization from brief displays. AB - Previous research suggests that understanding the gist of a scene relies on global structural cues that enable rapid scene categorization. This study used a repetition blindness (RB) paradigm to interrogate the nature of the scene representations used in such rapid categorization. When stimuli are repeated in a rapid serial visual presentation (RSVP) sequence (~10 items/sec), the second occurrence of the repeated item frequently goes unnoticed, a phenomenon that is attributed to a failure to consolidate two conscious episodes (tokens) for a repeatedly activated type. We tested whether RB occurs for different exemplars of the same scene category, which share conceptual and broad structural properties, as well as for identical and mirror-reflected repetitions of the same scene, which additionally share the same local visual details. Across 2 experiments, identical and mirror-image scenes consistently produced a repetition facilitation, rather than RB. There was no convincing evidence of either RB or repetition facilitation for different members of a scene category. These findings indicate that in the first 100-150 ms of processing scenes are represented in terms of local visual features, rather than more abstract category-general features, and that, unlike other kinds of stimuli (words or objects), scenes are not susceptible to token individuation failure. PMID- 27496024 TI - Tracking the emergence of memories: A category-learning paradigm to explore schema-driven recognition. AB - Previous research has shown that prior knowledge structures or schemas affect recognition memory. However, since the acquisition of schemas occurs over prolonged periods of time, few paradigms allow the direct manipulation of schema acquisition to study their effect on memory performance. Recently, a number of parallelisms in recognition memory between studies involving schemas and studies involving category learning have been identified. The current paper capitalizes on these findings and offers a novel experimental paradigm that allows manipulation of category learning between individuals to study the effects of schema acquisition on recognition. First, participants learn to categorize computer-generated items whose category-inclusion criteria differ between participants. Next, participants study items that belong to either the learned category, the non-learned category, both, or neither. Finally, participants receive a recognition test that includes old and new items, either from the learned, the non-learned, or neither category. Using variations on this paradigm, four experiments were conducted. The results from the first three studies suggest that learning a category increases hit rates for old category-consistent items and false alarm rates for new category-consistent lures. Absent the category learning, no such effects are evident, even when participants are exposed to the same learning trials as those who learned the categories. The results from the fourth experiment suggest that, at least for false alarm rates, the effects of category learning are not solely attributable to frequency of occurrence of category-consistent items during learning. Implications for recognition memory as well as advantages of the proposed paradigm are discussed. PMID- 27496026 TI - Authors' reply to Bosco-Levy and Salvo. PMID- 27496027 TI - The role of primary care in improving health equity: report of a workshop held by the WONCA Health Equity Special Interest Group at the 2015 WONCA Europe Conference in Istanbul, Turkey. AB - The WONCA Special Interest Group on Health Equity was established in 2014 to provide a focus of support, education, research and policy on issues relating to promotion of health equity in primary care settings. In keeping with this remit, the group hosted a workshop at the WONCA Europe conference held in Istanbul in October 2015. The aim of the session was to engage practitioners from across Europe in discussion of the barriers and facilitators to addressing the social determinants of health at practice level and in the training of doctors. This commentary reflects on the main findings from this workshop and how these compare with existing work in this field. PMID- 27496028 TI - Antiproliferative Effects of Modified Bioflavonoid in Ex Vivo Model. AB - We studied the effect of modified bioflavonoid and reference drug quercetin dihydrate on proliferation of mononuclears triggered by T- and B-cell mitogens. Lymphocytes were in vivo pretreated with the examined agents followed by their explantation and in vitro activation with T- and B-cell mitogens in cell culture. Intraperitoneal injection of modified bioflavonoid and quercetin dihydrate produced a dose-dependent inhibition of proliferation of the in vitroactivated splenocytes; modified bioflavonoid demonstrated higher antiproliferative activity. PMID- 27496029 TI - Serological Analysis of Immunogenic Properties of Recombinant Meningococcus IgA1 Protease-Based Proteins. AB - Using the genome sequence of IgA1 protease of N. meningitidis of serogroup B, four recombinant proteins of different structure and molecular weight were constructed. These proteins were equal in inducing the formation of specific antibodies to IgA1 protease and had protective properties against meningococci. In the sera of immunized mice, anti-IgA1 protease antibodies were detected by whole-cell ELISA, which indicated the presence of IgA1 protease on the surface of these bacteria. We hypothesized that the protective properties of IgA1 protease based antigens and IgA1 protease analogs could be realized not only via impairment of bacterium adhesion to the mucosa, but also via suppression of this pathogen in the organism. The presented findings seem promising for using these proteins as the basis for anti-meningococcus vaccine. PMID- 27496030 TI - Effect of Fluoxetine on Neurogenesis in Hippocampal Dentate Gyrus after Global Transient Cerebral Ischemia in Rats. AB - Changes in cerebral neurogenesis provoked by ischemia and the effect of fluoxetine on this process were studied using a three-vessel occlusion model of global transient cerebral ischemia. The global transient cerebral ischemia was modeled on male Wistar rats by transient occlusion of three major vessels originating from the aortic arch and supplying the brain (brachiocephalic trunk, left subclavian artery, and left common carotid artery). The cells expressing doublecortin (DCX, a marker of young neurons) were counted in the hippocampal dentate gyrus on day 31 after ischemia modeling. It was found that ischemia inhibited neurogenesis in the dentate gyrus in comparison with sham-operated controls (p<0.05), while fluoxetine (20 mg/kg/day) injected over 10 days after surgery restored neurogenesis to the control level (p<0.001). PMID- 27496031 TI - Physiological Features of Perigonadal Adipose Tissue Containing Uncoupling Protein UCP1 in ICR Mice. AB - Immunoreactive uncoupling protein UCP1 was found in the perigonadal fat of only twothirds of 14-week-old male ICR mice. The presence of UCP1 had no effect on the rate of O2 consumption by the adipose tissue. The cellularity of perigonadal fat estimated by the DNA content was significantly higher in tissue containing UCP1 than in samples without this protein. This regularity was also observed after adaptation of mice to moderate cold (10oC) over 8 weeks. PMID- 27496032 TI - Expression of Cytokine Genes and Growth Factors in Rat Lungs and Kidneys after Subtotal Hepatectomy. AB - Expression of il1b, il6, il10, tnfa, hgf, tgfb, vegf, and fgf2 genes in the lungs and kidneys was examined on rat model of liver regeneration after subtotal hepatectomy. Enhanced expression of il6, il10, tnfa, hgf, and fgf2 genes was detected at the early terms after 80% liver resection. PMID- 27496033 TI - Oxidative Stress and Catalase Gene. AB - We studied the frequency of alleles and genotypes of CAT gene -262C>T polymorphism (rs1001179) in Russian and Buryat adolescents. The frequency of 262T allele was 28.31% in Russians and 16.84% in Buryats (p<0.01). In both ethnic groups, a correlation between the study polymorphism and concentration of diene conjugates was observed. Carriers of TT-genotype of CAT gene-262C>T polymorphism had lower level of diene conjugates than carriers of CT- and CC-genotypes. PMID- 27496034 TI - Clinical Morphological Studies of Myelofibrosis with Different Types of Bone Marrow Involvement in Patients with Chronic Lymphocytic Leukemia. AB - Clinical-morphological study of myelofibrosis was carried out in patients with chronic lymphocytic leukemia at the debut of the disease. Trephinobiopsy specimens of the ileac bone, aspirated specimens of the bone marrow, and peripheral blood smears were studied in 80 patients. Chronic lymphocytic leukemia was associated with myelofibrosis of different severity in 22.5% cases. Morphometric analysis of trephinobiopsy specimens showed that the severity (histology and dissemination) of myelofibrosis correlated with the type of tumor involvement of the bone marrow. Focal tumor involvement of the bone marrow predominated in trephinobiopsy specimens from patients without myelofibrosis, while patients with myelofibrosis developed mainly diffuse tumor infiltration, associated with the greatest dissemination of the initial and manifest myelofibrosis. No myelofibrosis was found in patients with interstitial tumor involvement of the bone marrow. The severity of the initial and manifest myelofibrosis directly correlated with the tumor involvement of the bone marrow and peripheral blood. Evaluation of the prognosis showed that initial myelofibrosis was associated with disease standing of 5.5 months, while manifest condition with a disease of 8.5 months and longer. PMID- 27496035 TI - Relationship between Morphofunctional Changes in Open Traumatic Brain Injury and the Severity of Brain Damage in Rats. AB - A correlation between the severity of morphofunctional disturbances and the volume of brain tissue injury determined by MRT was demonstrated on the model of open traumatic brain injury in rats. A relationship between the studied parameters (limb placing and beam walking tests and histological changes) and impact force (the height of load fell onto exposed brain surface) was revealed. PMID- 27496036 TI - Experimental Evaluation of Biodegradable Film Compositions Based on Gelatin with Colchicine. AB - Biodegradable film compositions based on natural biopolymer gelatin with immobilized colchicine were prepared and their efficiency in prevention of the adhesion process in the pericardium was evaluated on rabbit model of postoperative pericarditis. The use of gelatin-based biodegradable film compositions significantly reduced the intensity of adhesion formation in the pericardial cavity, while immobilization of anti-inflammatory drug colchicine amplified their anti-adhesion activity. PMID- 27496037 TI - Effect of Circulation Parameters on Functional Status of HepaRG Spheroids Cultured in Microbioreactor. AB - We studied the relationship between microcirculation parameters and functional status of HepaRG cells in spheroids and chose an optimal regimen within the physiologically permissible limits of mechanical impact for the cells that maintains the expression of functional genes of the liver. PMID- 27496038 TI - Involvement of Protein Kinase C-delta in the Realization of Cardioprotective Effect of Ischemic Postconditioning. AB - Experiments on isolated perfused rat heart modeled 45-min global ischemia followed by 30-min reperfusion. Ischemic postconditioning was modeled by 3 cycles of reperfusion (30 sec) and ischemia (30 sec). Cardiomyocyte necrosis was assessed by the level of creatine phosphokinase in the perfusate. Postconditioning reduced the release of creatine phosphokinase from the heart by 30%. The cardioprotective effect of ischemic postconditioning was eliminated after inhibition of protein kinase C with cheleritrin or after blockade of delta isoform of protein kinase C with rottlerin. These findings attest to participation of protein kinase C-delta in the realization of the cardioprotective effect of postconditioning. PMID- 27496040 TI - Prognostic Value of the Cumulative Cisplatin Dose During Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A Secondary Analysis of a Prospective Phase III Clinical Trial. AB - BACKGROUND: The objective of this study was to evaluate the prognostic value of the cumulative cisplatin dose (CCD) for long-term survival outcomes after concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC). METHODS: Patients were included in an open-label phase III multicenter randomized controlled trial performed at seven institutions in China, and the 298 patients receiving CCRT only were assessed. Patient survival between different CCD groups were compared. RESULTS: Median CCD for the 298 patients was 240 mg/m2 (range, 40-320 mg/m2); 113 (37.9%) patients received a CCD of <240 (<=200) mg/m2, and 185 (62.1%) received a CCD of >=240 mg/m2. For CCD of >=240 mg/m2 vs. <240 mg/m2, the estimated 5-year overall survival, disease-free survival, locoregional relapse-free survival, and distant metastasis-free survival rates were 83.2% vs. 76.2% (p = .403), 73.5% vs. 67.8% (p = .461), 90.4% vs. 86.8% (p = .551), and 82.6% vs. 79.7% (p = .632), respectively. Multivariate analysis demonstrated that CCD (240 mg/m2) was not an independent prognostic factor in either the entire cohort or stage III/IV subgroup. CONCLUSION: A CCD of >=240 mg/m2 was not an independent prognostic factor in patients with locoregionally advanced NPC at high risk of distant metastasis, and 200 mg/m2 cisplatin may be adequate to achieve a survival benefit. IMPLICATIONS FOR PRACTICE: The current standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) is cisplatin-based concurrent chemoradiotherapy (CCRT), and the cisplatin is delivered every 3 weeks (100 mg/m2) for three cycles. However, the prognostic value of cumulative cisplatin dose (CCD) delivered during CCRT is controversial. The present study investigated the prognostic value of CCD and demonstrated that a CCD of 200 mg/m2 during CCRT is adequate to achieve satisfactory survival outcomes for patients with locoregionally advanced NPC. This finding is of great importance to clinicians because it could allow patients to avoid excessive treatment and toxicities. PMID- 27496039 TI - Preventing and Managing Toxicities of High-Dose Methotrexate. AB - : : High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated. IMPLICATIONS FOR PRACTICE: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity. PMID- 27496041 TI - The Association Between Body Size and Breast Cancer in Han Women in Northern and Eastern China. AB - INTRODUCTION: Although obesity has been reported worldwide as a risk factor for breast cancer, there are still some inconsistencies regarding the association between obesity and breast cancer. Body mass index (BMI) is used most to assess the extent of obesity; however, the association of other body size characteristics, such as waist and hip circumference, with susceptibility to breast cancer in Chinese Han women needs to be better assessed. PATIENTS AND METHODS: Female Chinese Han patients (N = 2,800) were recruited from 21 hospitals in northern and eastern China from April 2012 to April 2013 for a case-control study. The significant differences of factors related to body size between the breast-cancer case and control groups were determined by Student's t test and chi square tests. RESULTS: Premenopausal women with breast cancer had higher BMI and larger waist and hip circumferences (p = 2 * 10-4, <1 * 10-6, and 2 * 10-5, respectively). However, these body-size factors were not associated with postmenopausal breast cancer (p = .45, 0.32, and 0.12, respectively). BMI between 28 and 30 kg/m2 or greater than 32 kg/m2 was related to breast cancer incidence in the overall study population and in premenopausal women but not in the postmenopausal group. CONCLUSION: Obesity is significantly associated with breast cancer in Chinese Han premenopausal women but not in postmenopausal women. Thus, it is important to realize that weight control, as well as avoiding abdominal obesity, should be considered as one of the most effective methods of reducing breast cancer risk. IMPLICATIONS FOR PRACTICE: To better understand the characteristics and risk factors for breast cancer in Han women in northern and eastern China, a case-control study of 2,800 Chinese Han women was conducted. Obesity was significantly associated with breast cancer in Chinese Han premenopausal women but not in postmenopausal women. Consequently, controlling body weight and avoiding abdominal obesity should be considered as one of the most effective methods of reducing breast cancer susceptibility. However, the diversity between this study's finding among Chinese Han women and other data previously reported among European and American populations still needs further investigation. PMID- 27496042 TI - The Neurotoxic TAU45-230 Fragment Accumulates in Upper and Lower Motor Neurons in Amyotrophic Lateral Sclerosis Subjects. AB - Amyotrophic lateral sclerosis (ALS) is a progressive and lethal neurodegenerative disease characterized by the loss of upper and lower motor neurons leading to muscle paralysis in affected individuals. Numerous mechanisms have been implicated in the death of these neurons. However, the pathobiology of this disease has not been completely elucidated. In the present study, we investigated to what extent tau cleavage and the generation of the neurotoxic tau45-230 fragment is associated with ALS. Quantitative Western blot analysis indicated that high levels of tau45-230 accumulated in lumbar and cervical spinal cord specimens obtained from ALS subjects. This neurotoxic tau fragment was also detected in ALS upper motor neurons located in the precentral gyrus. Our results also showed that tau45-230 aggregates were present in the spinal cord of ALS patients. On the other hand, this neurotoxic fragment was not generated in a mouse model of a familial form of this disease. Together, these results suggest a potential role for this neurotoxic tau fragment in the mechanisms leading to the degeneration of motor neurons in the context of sporadic ALS. PMID- 27496044 TI - The autosomal genetic control of sexually dimorphic traits in humans is largely the same across the sexes. AB - There are substantial phenotypic differences between the male and female human. Several complex traits have recently been tested to see whether these phenotypic differences are explained by differences in genetic control between males and females. While some differences in genetic control between males and females are detected, overall the results demonstrate that the genetic control of complex traits in humans is largely the same across the sexes.Please see related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1025 x. PMID- 27496043 TI - Vaccination sequence effects on immunological response and tissue bacterial burden in paratuberculosis infection in a rabbit model. AB - Paratuberculosis (PTB), a chronic granulomatous enteritis produced by Mycobacterium avium subspecies paratuberculosis (MAP), is considered as one of the diseases with the highest economic impact in the ruminant industry. Vaccination against MAP is recommended during the first months after birth on the basis that protection would be conferred before the first contact with mycobacteria. However, little is known about the therapeutic effect of MAP vaccination in controlled experimental conditions. The current study was designed to evaluate the efficacy of vaccination before and after challenge with MAP in a rabbit infection model. The rabbits were divided into four groups: non-infected control (NIC, n = 4), infected control challenged with MAP (IC, n = 5), vaccinated and challenged 1 month after with MAP (VSI, n = 5) and challenged with MAP and vaccinated 2 months later (IVS, n = 5). The results from this study show a quick increase in IFN-gamma release upon stimulation with bovine, avian and johnin PPD in animals vaccinated before MAP challenge. All vaccinated animals show an increased humoral response as seen by western blot and ELISA. The final bacteriology index (considering tissue culture and qPCR) shows that the IC group was the most affected. Vaccination after infection (IVS) produced the lowest bacteriology index showing significant differences with the IC group (p = 0.034). In conclusion, vaccination against MAP shows positive effects in a rabbit model. However, vaccination after infection shows a slightly stronger protective effect compared to vaccination before infection, suggesting a therapeutic effect. This feature could be applied to previously infected adult animals under field conditions. PMID- 27496045 TI - Connecting Professional Practice and Technology at the Bedside: Nurses' Beliefs about Using an Electronic Health Record and Their Ability to Incorporate Professional and Patient-Centered Nursing Activities in Patient Care. AB - The purpose of this research is to determine the effects of implementing an electronic health record on medical-surgical registered nurses' time spent in direct professional patient-centered nursing activities, attitudes and beliefs related to implementation, and changes in level of nursing engagement after deployment of the electronic health record. Patient-centered activities were categorized using Watson's Caritas Processes and the Relationship-Based Care Delivery System. Methods included use of an Attitudes and Beliefs Assessment Questionnaire, Nursing Engagement Questionnaire, and Rapid Modeling Corporation's personal digital assistants for time and motion data collection. There was a significant difference in normative belief between nurses with less than 15 years' experience and nurses with more than 15 years' experience (t21 = 2.7, P = .01). While nurses spent less time at the nurses' station, less time charting, significantly more time in patients' rooms and in purposeful interactions, time spent in relationship-based caring behavior categories actually decreased in most categories. Nurses' engagement scores did not significantly increase. These results serve to inform healthcare organizations about potential factors related to electronic health record deployment which create shifts in nursing time spent across care categories and can be used to explore further patient centered care practices. PMID- 27496046 TI - Study protocol for Norwegian Psychomotor Physiotherapy versus Cognitive Patient Education in combination with active individualized physiotherapy in patients with long-lasting musculoskeletal pain - a randomized controlled trial. AB - BACKGROUND: Norwegian Psychomotor Physiotherapy (NPMP) has been an established treatment approach for more than 50 years, although mostly in the Scandinavian countries, and is usually applied to patients with widespread and long-lasting musculoskeletal pain and/or psychosomatic disorders. Few studies have been investigating outcome of NPMP and no randomized clinical trials (RCT) have been systematically tried out on individuals. METHODS/DESIGN: This is a study protocol for a pragmatic, single blinded RCT, which will take place in a city of Norway. The participants will be block randomized either to receive NPMP or Cognitive Patient Education in combination with active individualized physiotherapy (COPE PT). The intervention will reflect usual care and will be conducted in physiotherapy clinics by five experienced physiotherapists in each of the two treatment approaches. DISCUSSION: The findings of the present study may give an important contribution to our knowledge of the outcome of NPMP, on patients with long-lasting widespread musculoskeletal pain and/or pain located to the neck and shoulder region. TRIAL REGISTRATION: The study has been registered with ClinicalTrials.gov (June 9 th 2015, NCT02482792). PMID- 27496047 TI - Investigation of recrystallization of amorphous trehalose through hot-humidity stage X-ray powder diffraction. AB - The aim of this work was an investigation of the physical changes of the amorphous model material spray-dried trehalose through the use of various analytical techniques and to identify a suitable, rapid method able to quantify the changes. The crystallinity changes and recrystallization process of amorphous samples were investigated by hot-humidity stage X-ray powder diffractometry (HH XRPD) with fresh samples, conventional X-ray powder diffractometry (XRPD) used stored samples and by differential scanning calorimetry (DSC). The data from the three methods were compared and the various forms of trehalose were analysed. HH XRPD demonstrated that the recrystallization began at 40 and 60 degrees C up to 45% RH and at 70 degrees C up to 30% RH into dihydrate form. At 70 degrees C up to 60% RH the anhydrous form of trehalose appeared too. Conventional XRPD results showed, that in the 28days stored samples the dihydrate form was detected at 40 degrees C, 50% RH. Storage at 60 degrees C, 40% RH resulted in the appearance of the anhydrous form and at 60 degrees C, 50% RH both polymorphic forms were detected. By carrying out the DSC measurements at different temperatures the fraction of recrystallized trehalose dihydrate was detected. The recrystallization investigated by HH-XRPD and DSC followed Avrami kinetics, the calculated rate constants of isothermal crystallization (K) were same. Both HH XRPD and conventional XRPD was suitable for the detection of the physical changes of the amorphous model material. DSC measurements showed similar results as HH XRPD. Primarily HH-XRPD could be suggested for prediction, because the method is fast and every changes could be studied on one sample. PMID- 27496048 TI - Biopharmaceutic classification of drugs revisited. AB - The biopharmaceutics classification system (BCS) was based on the tube model of the intestinal lumen. This model considers constant drug permeability along the intestines, a plug flow fluid with the suspended drug particles moving with the fluid, and dissolution in the small particle limit. Since then the research work focusing on drug gastrointestinal (GI) absorption phenomena and processes rely on the classical laws of transport, diffusion and kinetics; however, the homogeneous assumptions associated with the well-stirred Euclidean media, where the classical laws of diffusion and kinetics apply, have been questioned in the past. In this work we explore the biopharmaceutic classification of drugs using a heterogeneous pseudo steady-state model of oral drug absorption. The fraction of dose absorbed (Fabs) was expressed as a function of two time-dependent processes where time dependent coefficients govern drug absorption and non-absorption processes. Fundamental drug properties like the absorption potential are correlated with Fabs and allow the biopharmaceutic classification of drugs taking into account the heterogeneous aspects of oral drug absorption. This analysis reveals that for Class I drugs no time dependency is expected for both absorption and non absorption processes since the gastric emptying is controlling the absorption of Class I drugs while the completion of absorption (Fabs>90%) is terminated along the first part of the jejunum. Due to the biopharmaceutical properties of Class II, III and IV drugs, these drugs travel throughout the GI tract and therefore both absorption and non absorption processes will exhibit time dependency. Thus, the calculation of Fabs (<90%) for Class II, III and IV is dependent on the estimates of the time exponents of time dependent coefficients controlling drug absorption e.g. dissolution, uptake or non absorption e.g. precipitation. PMID- 27496049 TI - Formulation and dissolution kinetics study of hydrophilic matrix tablets with tramadol hydrochloride and different co-processed dry binders. AB - The aim of this study is to present the possibility of using of co-processed dry binders for formulation of matrix tablets with drug controlled release. Hydrophilic matrix tablets with tramadol hydrochloride, hypromellose and different co-processed dry binders were prepared by direct compression method. Hypromelloses MethocelTM K4M Premium CR or MethocelTM K100M Premium CR were used as controlled release agents and Prosolv(r) SMCC 90 or DisintequikTM MCC 25 were used as co-processed dry binders. Homogeneity of the tablets was evaluated using scanning electron microscopy and energy dispersive X-ray microanalysis. The release of tramadol hydrochloride from prepared formulations was studied by dissolution test method. The dissolution profiles obtained were evaluated by non linear regression analysis, release rate constants and other kinetic parameters were determined. It was found that matrix tablets based on Prosolv(r) SMCC 90 and MethocelTM Premium CR cannot control the tramadol release effectively for >12h and tablets containing DisintequikTM MCC 25 and MethocelTM Premium CR >8h. PMID- 27496050 TI - Advances of blood cell-based drug delivery systems. AB - Blood cells, including erythrocytes, leukocytes and platelets are used as drug carriers in a wide range of applications. They have many unique advantages such as long life-span in circulation (especially erythrocytes), target release capacities (especially platelets), and natural adhesive properties (leukocytes and platelets). These properties make blood cell based delivery systems, as well as their membrane-derived carriers, far superior to other drug delivery systems. Despite the advantages, the further development of blood cell-based delivery systems was hindered by limitations in the source, storage, and mass production. To overcome these problems, synthetic biomaterials that mimic blood cell and nanocrystallization of blood cells have been developed and may represent the future direction for blood cell membrane-based delivery systems. In this paper, we review recent progress of the rising blood cell-based drug delivery systems, and also discuss their challenges and future tendency of development. PMID- 27496051 TI - Gradient adjustment method for better discriminating correlating and non correlating regions of physiological signals: application to the partitioning of impaired and intact zones of cerebral autoregulation. AB - Cerebral blood flow (CBF) is regulated over a range of systemic blood pressures by the cerebral autoregulation (CA) control mechanism. This range lies within the lower and upper limits of autoregulation (LLA, ULA), beyond which blood pressure drives CBF, and CA function is considered impaired. A standard method to determine autoregulation limits noninvasively using NIRS technology is via the COx measure: a moving correlation index between mean arterial pressure and regional oxygen saturation. In the intact region, there should be no correlation between these variables whereas in the impaired region, the correlation index should approximate unity. In practice, however, the data may be noisy and/or the intact region may often exhibit a slightly positive relationship. This positive relationship may render traditional autoregulation limit calculations difficult to perform, resulting in the need for manual interpretation of the data using arbitrary thresholds. Further, the underlying mathematics of the technique are asymmetric in terms of the results produced for impaired and intact regions and are, in fact, not computable for the ideal case within the intact region. In this work, we propose a novel gradient adjustment method (GACOx) to enhance the differences in COx values observed in the intact and impaired regions. Results from a porcine model (N = 8) are used to demonstrate that GACOx is successful in determining LLA values where traditional methods fail. It is shown that the derived GACOx indices exhibit a mean difference between the intact/impaired regions of 1.54 +/- 0.26 (mean +/- SD), compared to 0.14 +/- 0.10 for the traditional COx method. The GACOx effectively polarizes the COx data in order to better differentiate the intact and impaired zones and, in doing so, makes the determination of the LLA and ULA points a simpler and more consistent task. The method lends itself to the automation of the robust determination of autoregulation zone limits. PMID- 27496052 TI - Aneuploidy screening of embryonic stem cell clones by metaphase karyotyping and droplet digital polymerase chain reaction. AB - BACKGROUND: Karyotypic integrity is essential for the successful germline transmission of alleles mutated in embryonic stem (ES) cells. Classical methods for the identification of aneuploidy involve cytological analyses that are both time consuming and require rare expertise to identify mouse chromosomes. RESULTS: As part of the International Mouse Phenotyping Consortium, we gathered data from over 1,500 ES cell clones and found that the germline transmission (GLT) efficiency of clones is compromised when over 50 % of cells harbour chromosome number abnormalities. In JM8 cells, chromosomes 1, 8, 11 or Y displayed copy number variation most frequently, whilst the remainder generally remain unchanged. We developed protocols employing droplet digital polymerase chain reaction (ddPCR) to accurately quantify the copy number of these four chromosomes, allowing efficient triage of ES clones prior to microinjection. We verified that assessments of aneuploidy, and thus decisions regarding the suitability of clones for microinjection, were concordant between classical cytological and ddPCR-based methods. Finally, we improved the method to include assay multiplexing so that two unstable chromosomes are counted simultaneously (and independently) in one reaction, to enhance throughput and further reduce the cost. CONCLUSION: We validated a PCR-based method as an alternative to classical karyotype analysis. This technique enables laboratories that are non-specialist, or work with large numbers of clones, to precisely screen ES cells for the most common aneuploidies prior to microinjection to ensure the highest level of germline transmission potential. The application of this method allows early exclusion of aneuploid ES cell clones in the ES cell to mouse conversion process, thus improving the chances of obtaining germline transmission and reducing the number of animals used in failed microinjection attempts. This method can be applied to any other experiments that require accurate analysis of the genome for copy number variation (CNV). PMID- 27496053 TI - Tobacco smoking is associated with decreased semen quality. AB - BACKGROUND: Tobacco smoking is a public health issue and has been implicated in adverse reproductive outcomes including semen quality. Available data however provides conflicting findings. The objective of this study was to evaluate the effect of tobacco smoking on semen quality among men in Ghana. METHODS: In this study, a total of 140 subjects were recruited, comprising 95 smokers and 45 non smokers. Smokers were further categorized into mild, moderate and heavy smokers. Semen parameters such as sperm concentration, motility, viability and normal morphology were measured according to the World Health Organisation criteria. RESULTS: The study showed that smokers had significantly lower semen volume, sperm concentration, sperm motility, total sperm count, sperm morphology, free testosterone and follicle stimulating hormone (p <0.05 respectively), compared with non-smokers. Smokers were at a higher risk of developing oligospermia, asthenozoospermia and teratozoospermia (OR = 3.1, 4.2 and, 4.7; p <0.05) than non smokers. CONCLUSION: Results demonstrated a decline in semen quality in a dose dependent tobacco smoking manner. PMID- 27496054 TI - Curcumin-Mediated Photodynamic Inactivation of Norovirus Surrogates. AB - Photodynamic inactivation (PDI) is extensively used to inactivate different type of pathogens through the use of photosensitizers (PS). Curcumin has been identified as an excellent natural photosensitizer with some potential applications in the food industry. The aim of this study was to assess the antiviral activity of photoactivated curcumin on norovirus surrogates, feline calicivirus (FCV), and murine norovirus (MNV). Initially, different concentrations of curcumin (13.5-1358 uM) were individually mixed with each virus at titers of ca. 6-7 log TCID50/ml and photoactivated by LED blue light with light dose of 3 J/cm2. Results showed that photoactivated curcumin at 50 ug/mL reduced FCV titers by almost 5 log after incubation at 37 degrees C for 30 min. Lower antiviral activity (0.73 log TCID50/mL reduction) was reported for MNV. At room temperature, curcumin at 5 ug/mL reduced FCV titers by 1.75 log TCID50/mL. These results represent a step forward in improving food safety using photoactivated curcumin as an alternative natural additive to reduce viral contamination. PMID- 27496056 TI - Cooperation of Amphiphilicity and Crystallization for Regulating the Self Assembly of Poly(ethylene glycol)-block-poly(lactic acid) Copolymers. AB - Tuning the amphiphilicity of block copolymers has been extensively exploited to manipulate the morphological transition of aggregates. The introduction of crystallizable moieties into the amphiphilic copolymers also offers increasing possibilities for regulating self-assembled structures. In this work, we demonstrate a detailed investigation of the self-assembly behavior of amphiphilic poly(ethylene glycol)-block-poly(l-lactic acid) (PEG-b-PLLA) diblock copolymers with the assistance of a common solvent in aqueous solution. With a given length of the PEG block, the molecular weight of the PLA block has great effect on the morphologies of self-assembled nanoaggregates as a result of varying molecular amphiphilicity and polymer crystallization. Common solvents including N,N dimethylformamide, dioxane, and tetrahydrofuran involved in the early stage of self-assembly led to the change in chain configuration, which further influences the self-assembly of block copolymers. This study expanded the scope of PLA-based copolymers and proposed a possible mechanism of the sphere-to-lozenge and platelet-to-cylinder morphological transitions. PMID- 27496055 TI - A retrospective analysis of Victorian and South Australian clinical registries for prostate cancer: trends in clinical presentation and management of the disease. AB - BACKGROUND: Prostate cancer (PCa) is the most commonly diagnosed malignancy reported to Australian cancer registries with numerous studies from individual registries summarizing diagnostic and treatment characteristics. The aim of this study was to describe annual trends in clinical and treatment characteristics, and changes in surveillance practice within a large combined cohort of men with PCa in South Australia (SA) and Victoria, Australia in 2008-2013. METHODS: Common data items from clinical registries in SA and Victoria were merged to develop a cross-jurisdictional dataset consisting of 13,598 men with PCa. Frequencies were used to describe these variables using the National Comprehensive Cancer Network risk of disease progression categories in 10 year age groups. A logistic regression analysis was performed to assess the impact of a number of factors (both individually and together) on the likelihood of men receiving no active treatment within twelve months of the diagnosis (i.e. managed with active surveillance/watchful waiting). RESULTS: Trend analysis showed that over time: (1) men in SA and Victoria are being diagnosed at older age in 2013, 66.1 (SD = 9.7) years compared to 2009 (64.5 (SD = 9.7)); (2) diagnostic methods and characteristics have changed with time; and (3) types of the treatments have changed, with more men having no active treatment. The majority of men were diagnosed with Prostate-Specific Antigen (PSA) <10 ng/mL (66 %) and Grade Group < 4 (65 %). Nearly seventy percent received radical treatment within 12 months of diagnosis, while ~20 % had no active treatment. In 14 % of cases treatment was not recorded or had not commenced. Having no active treatment was strongly associated older age, lower PSA and lower Grade Group at diagnosis, and in 2013 it was offered more frequently (more than 3 times) than in 2009 (OR = 2.63, 95 % CI: 2.16-3.22). CONCLUSIONS: Findings of this study provide the first cross jurisdictional description of PCa characteristics and management in Australia. These findings will provide benchmarking for ongoing monitoring and feedback of disease management and outcomes of PCa through the Prostate Cancer Outcomes Registry-Australia New Zealand to improve evidence-based practice. PMID- 27496057 TI - Lost in translation: impact of language barriers on children's healthcare. AB - PURPOSE OF REVIEW: As the cultural and linguistic diversity of the United States grows, a greater number of patients with limited English proficiency will enter the healthcare system. Best practices for the care of these individuals include identification of their language assistance needs and prompt provision of interpreter services. This review will summarize the legal basis for providing language access in the healthcare setting, discuss the impact of interpretation services on clinical care, and explore the effects of language barriers on health outcomes. RECENT FINDINGS: There has been greater awareness of language as an important and independent determinant in the racial and ethnic disparities that exist in healthcare. Studies have shown that there is suboptimal identification of patients who require linguistic assistance and, as such, there are missed opportunities to bridge language gaps with many of our patients. The lack of interpretation, or use of informal, untrained interpreters, has significant effects on patient safety, quality of care, and patient satisfaction. SUMMARY: Though federal and regulatory guidelines mandate meaningful access to language services, such processes are still a work in progress in many healthcare settings. Further research and quality improvement initiatives are needed to provide clinicians the knowledge and skills needed to effectively communicate with their limited English proficient patients. PMID- 27496058 TI - The development of moral sense and moral thinking. AB - PURPOSE OF REVIEW: The review critically evaluates recent claims that infants have innate knowledge of morality and examines the sources of moral norms. RECENT FINDINGS: Many studies show that toddlers readily help adults with daily tasks. A more contentious set of studies suggests that young infants prefer actors who help others to those who hinder them. Some researchers have interpreted these findings as indicating that morality is innately present in humans. Others look to alternative explanations in developmental systems theory. SUMMARY: Explaining the emergence of morality as innate, or wholly socialized, is problematic; instead morality could emerge in a developmental system in which children's early capacities are shaped by interpersonal engagement. Children's improving ability to coordinate with others at a practical level is later transformed through language and reflective thought, as children gain the ability to talk about what was previously implicit in interaction. Throughout, parents and caregivers have many opportunities to foster children's moral development in daily interactions. PMID- 27496059 TI - Reading disorders and dyslexia. AB - PURPOSE OF REVIEW: We review current knowledge about the nature of reading development and disorders, distinguishing between the processes involved in learning to decode print, and the processes involved in reading comprehension. RECENT FINDINGS: Children with decoding difficulties/dyslexia experience deficits in phoneme awareness, letter-sound knowledge and rapid automatized naming in the preschool years and beyond. These phonological/language difficulties appear to be proximal causes of the problems in learning to decode print in dyslexia. We review data from a prospective study of children at high risk of dyslexia to show that being at family risk of dyslexia is a primary risk factor for poor reading and children with persistent language difficulties at school entry are more likely to develop reading problems. Early oral language difficulties are strong predictors of later difficulties in reading comprehension. SUMMARY: There are two distinct forms of reading disorder in children: dyslexia (a difficulty in learning to translate print into speech) and reading comprehension impairment. Both forms of reading problem appear to be predominantly caused by deficits in underlying oral language skills. Implications for screening and for the delivery of robust interventions for language and reading are discussed. PMID- 27496060 TI - The effects of hybridization on divergent venom phenotypes: Characterization of venom from Crotalus scutulatus scutulatus * Crotalus oreganus helleri hybrids. AB - Hybridization between divergent species can be analyzed to elucidate expression patterns of distinct parental characteristics, as well as to provide information about the extent of reproductive isolation between species. A known hybrid cross between two rattlesnakes with highly divergent venom phenotypes provided the opportunity to examine occurrence of parental venom characteristics in the F1 hybrids as well as ontogenetic shifts in the expression of these characters as the hybrids aged. Although venom phenotypes of adult rattlesnake venoms are known for many species, the effect of hybridization on phenotype inheritance is not well understood, and effects of hybridization on venom ontogeny have not yet been investigated. The current study investigates both phenomena resulting from the hybridization of a male snake with type I degradative venom, Crotalus oreganus helleri (Southern Pacific Rattlesnake), and a female snake with type II highly toxic venom, Crotalus scutulatus scutulatus (Mojave Rattlesnake). SDS-PAGE, enzymology, Western blot and reversed phase HPLC (RP-HPLC) were used to characterize the venom of the C. o. helleri male, the C. s. scutulatus female and their two hybrid offspring as they aged. In general, Crotalus o. helleri * C. s. scutulatus hybrid venoms appeared to exhibit overlapping parental venom profiles, and several different enzyme activity patterns. Both hybrids expressed C. o. helleri father-specific myotoxins as well as C. s. scutulatus mother-specific Mojave toxin. Snake venom metalloprotease activity displayed apparent sex influenced expression patterns, while hybrid serine protease activities were intermediate to parental activities. The C. s. scutulatus * C. o. helleri hybrid male's venom profile provided the strongest evidence that type I and type II venom characteristics are expressed simultaneously in hybrid venoms, as this snake contained distinctive characteristics of both parental species. However, the possibility of sex-influenced development of metalloprotease activity, as seen in the ontogenetic shifts of the hybrid female, may influence the levels of expression of both type I and type II characteristics in hybrid venoms. Ultimately, the chronological analysis of this known hybrid system reveals the most distinct characteristics that can be used in determining successful hybridization between snakes that follow the type I-type II trend in rattlesnake venom composition, namely the presence of metalloprotease activity and Mojave toxin. PMID- 27496061 TI - Description of Loxtox protein family and identification of a new group of Phospholipases D from Loxosceles similis venom gland. AB - Envenoming resulting from Loxosceles spider bites (loxoscelism) is a recognized public health problem in Brazil. However, the pathophysiology of loxoscelism caused by L. similis bites, which is widespread in Brazil, remains poorly understood. In the present work, the RNA sequencing (RNA-Seq - Next Generation sequencing - NGS) of the L. similis venom gland was performed to identify and analyze the sequences of the key component phospholipase D. The sequences were aligned based on their classical domains, and a phylogenetic tree was constructed. In the bioinformatics analysis, 23 complete sequences of phospholipase D proteins were found and classified as Loxtox proteins, as they contained the characteristic domains of phospholipase D: the active site, the Mg(2+)-binding domain, and the catalytic loop. Three phospholipase D sequences with non-canonical domains were also found in this work. They were analyzed separately and named PLDs from L. similis (PLD-Ls). This study is the first to characterize phospholipase D sequences from Loxosceles spiders by RNA-Seq. These results contribute new knowledge about the composition of L. similis venom, revealing novel tools that could be used for pharmacological, immunological, and biotechnological applications. PMID- 27496062 TI - Effective management of cricopharyngeal achalasia in infants and children with dilatation alone. AB - AIM: Cricopharyngeal achalasia (CPA) is a rare clinical condition that is characterized by aspiration, choking, and nasopharyngeal regurgitation. The aim of this study is to introduce the outcomes of dilatation alone in children with CPA. PATIENTS AND METHOD: After the evaluation of upper esophageal sphincter with endoscopy, dilatation was performed. All patients underwent videofluoroscopic evaluation and swallowing therapy after the surgical procedure. A retrospective chart review was performed in children with CPA. RESULTS: Thirty children who were videofluoroscopically proven to have CPA were included in the study. Their age range was 15days-7years (median 11months). Twenty-one of them were neurologically impaired. Two children were lost to follow-up. Nineteen patients (68%) had a total resolution of CPA and were symptom-free with 1-6 dilatations (median 2). Three of the children (11%) who were severely neurologically impaired had resistant CPA. Three children (11%) treated recently with short follow-up were added to the group. Their VFS evaluations demonstrated improvement, thus we accepted their result as successful. There were two perforations in the series. Three patients died; one 2-month-old (2500g) baby who was accepted from the intensive care unit passed away on postoperative on the 7th day. Two other babies who were unresponsive to dilatation therapy died on follow-up. CONCLUSION: Dilatation can be a safe and effective method on children who are correctly diagnosed to have CPA. PMID- 27496063 TI - Economic and operational burden associated with malnutrition in chronic obstructive pulmonary disease. AB - BACKGROUND: Malnutrition is common in patients with chronic obstructive pulmonary disease (COPD). This study aimed to explore its association with all-cause mortality, emergency hospitalisation and subsequently healthcare costs. METHODS: A prospective cohort observational pilot study was carried out in outpatients with COPD that attended routine respiratory clinics at a large tertiary Australian hospital during 2011. Electronic hospital records and hospital coding was used to determine nutritional status and whether a patient was coded as nourished or malnourished and information on healthcare use and 1-year mortality was recorded. RESULTS: Eight hundred and thirty four patients with COPD attended clinics during 2011, of those 286 went on to be hospitalised during the 12 month follow-up period. Malnourished patients had a significantly higher 1-year mortality (27.7% vs. 12.1%; p = 0.001) and were hospitalised more frequently (1.11 SD 1.24 vs. 1.51 SD 1.43; p = 0.051). Only malnutrition (OR 0.36 95% CI 0.14-0.91; p = 0.032) and emergency hospitalisation rate (OR 1.58 95% CI 1.2-2.1; p = 0.001) were independently associated with 1-year mortality. Length of hospital stay was almost twice the duration in those coded for malnutrition (11.57 SD 10.93 days vs. 6.67 SD 10.2 days; p = 0.003) and at almost double the cost (AUD $23,652 SD $26,472 vs. $12,362 SD $21,865; p = 0.002) than those who were well-nourished. CONCLUSION: Malnutrition is an independent predictor of 1 year mortality and healthcare use in patients with COPD. Malnourished patients with COPD present both an economic and operational burden. PMID- 27496064 TI - Performance assessment of a portable mass spectrometer using a linear ion trap operated in non-scanning mode. AB - RATIONALE: The desire for mass spectrometer portability provides the motivation for simpler, lighter electronics to deliver switched potentials applied to the electrodes of the linear ion trap operated in non-scanning mode. Using a novel method of modelling and theoretical analysis, we simulate the mass analyser performance under these unfavourable operating conditions. METHODS: The electrical fields are simulated using the Charge Particle Optics software which employs the boundary element method. The ion trajectories are computed from the ion cage of the EI source to the interior of the trap where the ions are confined. The spatial/temporal ion distributions during injection are calculated from the individual ion trajectories computed with constant time-steps. Due to geometric non-linearities, betay = 0 lines close to the apex of the stability diagram have been computed for different initial positions with zero initial velocities in order to define the acceptable maximum axial extension. RESULTS: The DC potential well depth has been estimated at about 15 eV from the axial velocity distribution, and the minimum time of ion injection at 120 MUs from the temporal ion distribution. To ensure a mass separation of one unit and the confinement of the whole of the injected ions, buffer gas cooling is necessary to reduce the trajectory excursion amplitudes to 0.1 and 15 mm in the radial and axial directions, respectively. CONCLUSIONS: The portable mass spectrometer is predicted to achieve a mass resolution of better than one mass unit providing that helium buffer gas is used. An additional cooling sequence has to be added prior to moving the operating point toward the apex. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27496065 TI - Increasing the availability of l-arginine and nitric oxide increases sensitivity of nitrous oxide (N2O)-insensitive inbred mice to N2O-induced antinociception. AB - Nitrous oxide (N2O)-induced antinociception in mice is dependent on the neuromodulator nitric oxide (NO). In contrast to C57BL/6J (B6) mice, DBA/2J (D2) mice fail to respond to N2O with a robust antinociceptive response or with an increase in brain nitric oxide synthase (NOS) enzyme activity, suggesting that failure of D2 mice to respond to N2O might result from a deficit of NO function. Therefore, it was of interest to determine whether increasing the availability of NO might increase sensitivity of D2 mice to N2O. Male D2 mice were pretreated with sub-antinociceptive intracerebroventricular doses of the NO donor 3 morpholinosydnoimine or the NO precursor l-arginine then assessed for responsiveness to N2O-induced antinociception using the acetic acid abdominal constriction test. Both pretreatments increased the antinociceptive responsiveness of D2 mice to N2O. These results indicate that the NOS enzyme in D2 mice is functional and that the deficit in NO function that obstructs sensitivity to N2O-induced antinociception may lie in availability or utilization of l-arginine. PMID- 27496066 TI - Large animal canine endovascular ischemic stroke models: A review. AB - BACKGROUND: Stroke is one of the leading causes of death and long-term disability worldwide. Recent exciting developments in the field with endovascular treatments have shown excellent outcomes in acute ischemic stroke. Prior to translating these treatments to human populations, a large-animal ischemic stroke model is needed. With the advent of new technologies in digital subtraction angiography, less invasive endovascular stroke models have been developed. Canines have gyrencephalic brain similar to human brain and accessible neurovascular anatomy for stroke model creation. Canine stroke model can be widely utilized to understand the disease process of stroke and to develop novel treatment. Less invasive endovascular internal carotid emboli injection and coil embolization methods can be used to simulate transient or permanent middle cerebral artery occlusion. Major restriction includes the extensive collateral circulation of canine cerebral arteries that can limit the stroke size. Transient internal carotid artery occlusion can decrease collateral circulation and increase stroke size to some degree. Additional method of manipulating the extent of collateral circulation needs to be studied. Other types of canine stroke models, including vertebral artery occlusion and basilar artery occlusion, can also be accomplished by endovascular thrombi injection. CONCLUSIONS: We extensively review the literature on endovascular technique of creating canine ischemic stroke models and their application in finding new therapies for ischemic stroke. PMID- 27496067 TI - Safety, adherence and efficacy of exercise training in solid-organ transplant candidates: A systematic review. AB - BACKGROUND: Patients awaiting solid-organ transplantation may be encouraged to undertake exercise training to improve pre- and post-transplant outcomes. However, the safety, adherence and efficacy of exercise training in this population remain unclear. METHODS: All randomized, non-randomized and non controlled trials of exercise training interventions in solid-organ transplant candidates were included. The Cochrane risk of bias tool and a modified Newcastle Ottawa scale were used to assess procedural quality. Safety was defined as the number of reported adverse events during exercise training. Adherence was evaluated from session attendance, and efficacy as changes in cardiorespiratory fitness (CRF), exercise capacity, muscular strength, health-related quality of life (HR-QoL) and lung function. RESULTS: Eleven studies involving 874 patients were included: four randomized controlled, one non-randomized controlled and six non-controlled trials. Six studies included heart transplant candidates and five involved patients awaiting lung transplantation. Three trials included aerobic only training, one incorporated resistance-only exercise and seven combined modalities. Twelve adverse events were reported with four due to exercise, although methods to collect these data were often omitted. Exercise adherence ranged from 82.5% to 100%, but was poorly described. No significant between-group changes attributable to exercise training were demonstrated. However, significant within-group improvements in CRF, exercise capacity, muscular strength, lung function and HR-QoL were observed. CONCLUSIONS: Patients awaiting heart or lung transplant appear to tolerate exercise training despite the larger number of adverse events compared to other high-risk populations. Exercise training demonstrated within-group benefits for several outcomes, with no significant between-group differences. Randomized controlled trials with sufficient statistical power are required for all solid-organ transplant candidates. PMID- 27496068 TI - Pharmaceutical and clinical development of phosphonate-based radiopharmaceuticals for the targeted treatment of bone metastases. AB - Therapeutic phosphonate-based radiopharmaceuticals radiolabeled with beta, alpha and conversion electron emitting radioisotopes have been investigated for the targeted treatment of painful bone metastases for >35years. We performed a systematic literature search and focused on the pharmaceutical development, preclinical research and early human studies of these radiopharmaceuticals. The characteristics of an ideal bone-targeting therapeutic radiopharmaceutical are presented and compliance with these criteria by the compounds discussed is verified. The importance of both composition and preparation conditions for the stability and biodistribution of several agents is discussed. Very few studies have described the characterization of these products, although knowledge on the molecular structure is important with respect to in vivo behavior. This review discusses a total of 91 phosphonate-based therapeutic radiopharmaceuticals, of which only six agents have progressed to clinical use. Extensive clinical studies have only been described for (186)Re-HEDP, (188)Re-HEDP and (153)Sm-EDTMP. Of these, (153)Sm-EDTMP represents the only compound with worldwide marketing authorization. (177)Lu-EDTMP has recently received approval for clinical use in India. This review illustrates that a thorough understanding of the radiochemistry of these agents is required to design simple and robust preparation and quality control methods, which are needed to fully exploit the potential benefits of these theranostic radiopharmaceuticals. Extensive biodistribution and dosimetry studies are indispensable to provide the portfolios that are required for assessment before human administration is possible. Use of the existing knowledge collected in this review should guide future research efforts and may lead to the approval of new promising agents. PMID- 27496069 TI - Comment on: Inflammatory mediators in osteoarthritis: A critical review of the state-of-the art, prospects, and future challenges. PMID- 27496070 TI - Optical coherence tomography angiography in treated type 2 neovascularization undergoing monthly anti-VEGF treatment. PMID- 27496071 TI - Design and synthesis of new 2-anilinoquinolines bearing N-methylpicolinamide moiety as potential antiproliferative agents. AB - A series of new 2-anilinoquinolines 6a-o possessing the substantial N methylpicolinamide motif at C5 has been designed and synthesized as sorafenib analogs. The antiproliferative activities of the target compounds were preliminarily appraised against a panel of three human cancer cell lines (MCF-7, SK-BR3, and HCT116), and a selected array was further tested over a panel of approximately 60 cancer cell lines at NCI at 10 MUM concentration. Interestingly, compounds 6c, 6d, 6j, 6k, and 6l showed promising selective anticancer activities (growth inhibition >80%) toward certain cancer cells at 10 MUM testing dose. Compounds 6d and 6j were advanced to five-dose testing mode to determine their GI50 values and compared with our previously reported ureidoquinoline B and sorafenib as reference compounds. The 4-chloro-3-trifluoromethylaniline derivative 6j manifested superior potency than both compound B and sorafenib over eleven and eight cell lines, respectively. It showed GI50 values of 0.36, 0.66, 0.68, and 0.60 MUM against the breast MDA-MB-468, renal A498, and melanoma SK-MEL 5 and UACC-62 cell lines, respectively. Moreover, both 6d and 6j exerted low cytotoxic effects against HFF-1 normal cell line. Furthermore, compounds 6d and 6j were tested against both B-RafV600E and C-Raf kinases and displayed modest inhibitory activities, which were justified by molecular docking study. Compound 6j could serve as a promising candidate for further development of potent anticancer chemotherapeutics. PMID- 27496072 TI - Is Assisted Dying the Baby Boomers' Last Frontier? PMID- 27496073 TI - A profile of Emanuel A. Friedman, MD, DMedSci. PMID- 27496074 TI - Risk Factors for Priapism Readmission. AB - INTRODUCTION: Priapism is a urologic emergency with a tendency to recur in some patients. The frequency of, time to, and risk factors for priapism recurrence have not been well characterized. AIM: To identify predictors of priapism readmission. METHODS: We used the New York Statewide Planning and Research Cooperative System database to identify patients presenting to emergency departments with priapism from 2005 through 2014. Patients were tracked up to 12 months after initial presentation. Proportional hazards regression was used to identify risk factors for priapism readmission. MAIN OUTCOME MEASURES: Readmissions for priapism. RESULTS: The analytic cohort included 3,372 men with a diagnosis of priapism. The average age at first presentation was 39 +/- 18 years and 40% were black. Within 1 year, 24% of patients were readmitted for recurrent priapism, 68% of whom were readmitted within 60 days. On multivariate analysis, sickle cell disease (hazard ratio [HR] = 2.5, 95% CI = 2.0-3.0), drug abuse or psychiatric disease (HR = 1.9, 95% CI = 1.6-2.2), erectile dysfunction history (HR = 1.9, 95% CI = 1.5-2.3), other than commercial medical insurance (HR = 1.2, 95% CI = 1.0-1.4), and inpatient admission for initial priapism event (HR = 0.5, 95% CI = 0.4-0.6) were significant risk factors for readmission. CONCLUSION: Nearly one fourth of patients with priapism were readmitted for recurrent priapism within 1 year of initial presentation. Most readmissions were within 60 days. Future research should focus on strategies to decrease recurrences in high risk patients. PMID- 27496075 TI - Improvement of the soil nitrogen content and maize growth by earthworms and arbuscular mycorrhizal fungi in soils polluted by oxytetracycline. AB - Interactions between earthworms (Eisenia fetida) and arbuscular mycorrhizal fungi (Rhizophagus intraradices, AM fungi) have been suggested to improve the maize nitrogen (N) content and biomass and were studied in soils polluted by oxytetracycline (OTC). Maize was planted and amended with AMF and/or earthworms (E) in the soil with low (1mgkg(-1) soil DM) or high (100mgkg(-1) soil DM) amounts of OTC pollution in comparison to soil without OTC. The root colonization, shoot and root biomass, shoot and root N contents, soil nitrogen forms, ammonia-oxidizing bacteria (AOB) and archaea (AOA) were measured at harvest. The results indicated that OTC decreased maize shoot and root biomass (p<0.05) by mediating the soil urease activity and AOB and AOA abundance, which resulted in a lower N availability for maize roots and shoots. There was a significant interaction between earthworms and AM fungi on the urease activity in soil polluted by OTC (p<0.05). Adding earthworms or AM fungi could increase the maize biomass and N content (p<0.05) in OTC polluted soil by increasing the urease activity and relieving the stress from OTC on the soil N cycle. AM fungi and earthworms interactively increased maize shoot and root biomass (p<0.05) in the OTC polluted soils through their regulation of the urease activity and the abundance of ammonia oxidizers, resulting in different soil NH4(+)-N and NO3(-)-N contents, which may contribute to the N content of maize shoots and roots. Earthworms and AM fungi could be used as an efficient method to relieve the OTC stress in agro-ecosystems. PMID- 27496076 TI - Major geogenic factors controlling geographical clustering of urolithiasis in China. AB - The prevalence of urolithiasis is increasing across the world and exhibits a distinctive characteristic of geographical distribution. Geographical clustering and major geogenic factors for urolithiasis prevalence in China were investigated. High risks of urolithiasis are found in southern China clustered in coastal provinces such as Fujian and Zhejiang and karst regions such as Sichuan, Chongqing, Guizhou, Guangxi, Guangdong, Hunan, and Hubei. The predominant urinary stone composition is a mixture of calcium oxalate and phosphate. We found that the spatial distribution of phosphate-type stones is closely related to that of phosphate ore deposits and carbonate rocks. Hot or warm climate and seasons increase the risk of lithogenesis through high average air temperature. Water and soil environment influence the quality and composition of drinking water and food, thus affecting stone formation in the urinary system. In particular, the increase of Ca(2+)/Mg(2+) ratio (in meq) in drinking water might be the main factor. Besides, the high content of calcium in local plants grown on karst soils and the intake of high oxalate food might contribute to the high prevalence in South China. This study indicates that urolithiasis could be endemic, with geogenic factors playing critical roles in urolithiasis etiology. PMID- 27496077 TI - Fate of mixed pesticides in an integrated recirculating constructed wetland (IRCW). AB - In this study, three model integrated recirculating constructed wetlands (IRCWs) planted with and without Cyperus alternifolius were used to investigate their ability to remove four pesticides (chlorpyrifos, endosulfan, fenvalerate, diuron). Iron (Fe)-impregnated biochar produced by Cyperus alternifolius was added as a primary substrate. Results showed that all four pesticides were efficiently removed in the three IRCWs. The highest pesticide removals were achieved when Fe-impregnated biochar was added to the IRCW (99%), followed by the planted (64-99%) and plant-free IRCW (45-99%). The removal of pesticides in IRCWs followed first-order kinetics, with half-lives of 1.5-11.6h. A mass balance study revealed that sorption (32.2-98.6%) and microbial degradation (1.3-52.8%) were the main removal processes in all IRCWs. This study suggests that the IRCW is a promising system to treat pesticide-contaminated water, and plant and Fe impregnated biochar can enhance pesticide removal. PMID- 27496079 TI - Fulminant Epstein-Barr virus-associated hemophagocytic syndrome in a renal transplant patient and review of the literature. AB - We describe a rare fulminant case of Epstein-Barr virus-associated hemophagocytic syndrome (HPS) in a 37-year-old female renal transplant patient, indistinguishable from severe sepsis clinically and in the laboratory. HPS involves rapidly escalating immune system activation, resulting in a cytokine cascade, which can, especially in immunocompromised patients, lead to multi-organ failure, and even death. Thirty-two Herpesviridae-associated HPS cases in renal transplant patients have been reported and are reviewed. Overall mortality is 47% (15/32 cases). PMID- 27496078 TI - Sexual Function in 16- to 21-Year-Olds in Britain. AB - PURPOSE: Concern about young people's sexuality is focused on the need to prevent harmful outcomes such as sexually transmitted infections and unplanned pregnancy. Although the benefit of a broader perspective is recognized, data on other aspects of sexuality, particularly sexual function, are scant. We sought to address this gap by measuring the population prevalence of sexual function problems, help seeking, and avoidance of sex in young people. METHODS: A cross sectional stratified probability sample survey (Natsal-3) of 15,162 women and men in Britain (response rate: 57.7%), using computer-assisted self-interviews. Data come from 1875 (71.9%) sexually active, and 517 sexually inactive (18.7%), participants aged 16-21 years. Measures were single items from a validated measure of sexual function (the Natsal-SF). RESULTS: Among sexually active 16- to 21-year-old participants, 9.1% of men and 13.4% of women reported a distressing sexual problem lasting 3 months or more in the last year. Most common among men was reaching a climax too quickly (4.5%), and among women was difficulty in reaching climax (6.3%). Just over a third (35.5%) of men and 42.3% of women reporting a problem had sought help, but rarely from professional sources. Among those who had not had sex in the last year, just >10% of young men and women said they had avoided sex because of sexual difficulties. CONCLUSIONS: Distressing sexual function problems are reported by a sizeable minority of sexually active young people. Education is required, and counseling should be available, to prevent lack of knowledge, anxiety, and shame progressing into lifelong sexual difficulties. PMID- 27496080 TI - The prognostic value of serum signal peptide-Cub-Egf domain-containing protein-1 concentrations in acute intracerebral hemorrhage. AB - BACKGROUND: Signal peptide-Cub-Epidermal growth factor domain-containing protein 1 (SCUBE1) in peripheral blood, which is identified as a marker for coagulation, was reported to be an independent predictor of poor outcome in some illnesses. We investigated the clinical utility of serum SCUBE1 in the prognosis of intracerebral hemorrhage (ICH). METHODS: A total of 128 consecutive patients, admitted to emergency service due to acute ICH, and 128 healthy individuals were included in this prospective study. The patients were followed up until 6months or death. An unfavorable outcome was defined as modified Rankin Scale score>2. RESULTS: Serum SCUBE1 concentration was markedly higher in patients than in controls and was associated with hematoma volume, National Institutes of Health Stroke Scale (NIHSS) score and blood platelet count. After adjustment for hematoma volume and NIHSS score, it was still related to early neurological deterioration, hematoma growth, 1-week mortality, 6-month mortality, 6-month unfavorable outcome and 6-month overall survival. Additionally, serum SCUBE1 significantly improved areas under receiver operating characteristic curve of hematoma volume and NIHSS score to predict 6-month unfavorable outcome. CONCLUSIONS: Increased serum SCUBE1 concentrations have close relation to increasing severity and poor prognosis of ICH. PMID- 27496081 TI - Reduced levels of potential circulating biomarkers of cardiovascular diseases in apparently healthy vegetarian men. AB - BACKGROUND: Several evidences report that a vegetarian diet is protector against cardiovascular diseases. Few studies have demonstrated the circulating profile of cardiovascular biomarkers in vegetarians. Therefore, the aims of the current study were compared the plasma concentrations of myeloperoxidase (MPO), metalloproteinase (MMP)-9, MMP-2, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 between healthy vegetarian (Veg) and healthy omnivorous (Omn). METHODS: Using ELISA and multiplexed bead immunoassay, we measured in plasma from 43 Veg and 41 Omn the cardiovascular biomarkers concentrations cited above. RESULTS: We found significant lower concentrations of MPO, MMP-9, MMP-2 and MMP-9/TIMP-1 ratio in Veg compared to Omn (all P<0.05). Moreover, MMP-9 concentrations were correlated positively with leukocytes and neutrophils count in both groups (all P<0.05). CONCLUSION: A vegetarian diet is associated with a healthier profile of cardiovascular biomarkers compared to omnivorous. PMID- 27496082 TI - Early Macrophage Infiltration and Sustained Inflammation in Kidneys From Deceased Donors Are Associated With Long-Term Renal Function. AB - Kidney transplants from living donors (LDs) have a better outcome than those from deceased donors (DDs). Different factors have been suggested to justify the different outcome. In this study, we analyzed the infiltration and phenotype of monocytes/macrophages and the expression of inflammatory and fibrotic markers in renal biopsy specimens from 94 kidney recipients (60 DDs and 34 LDs) at baseline and 4 months after transplantation. We evaluated their association with medium- and long-term renal function. At baseline, inflammatory gene expression was higher in DDs than in LDs. These results were confirmed by the high number of CD68-positive cells in DD kidneys, which correlated negatively with long-term renal function. Expression of the fibrotic markers vimentin, fibronectin, and alpha-smooth muscle actin was more elevated in biopsy specimens from DDs at 4 months than in those from LDs. Gene expression of inflammatory and fibrotic markers at 4 months and difference between 4 months and baseline correlated negatively with medium- and long-term renal function in DDs. Multivariate analysis point to transforming growth factor-beta1 as the best predictor of long term renal function in DDs. We conclude that early macrophage infiltration, sustained inflammation, and transforming growth factor-beta1 expression, at least for the first 4 months, contribute significantly to the difference in DD and LD transplant outcome. PMID- 27496083 TI - Disparities in Unmet Service Needs Among Adults with Intellectual and Other Developmental Disabilities. AB - BACKGROUND: Due to long waiting lists for services, many adults with intellectual and developmental disabilities in the United States have unmet service needs. Little research, however, has identified the characteristics of caregivers and individuals with intellectual and developmental disabilities that relate to the unmet service needs among individuals who are waiting for services. METHOD: The present authors conducted a statewide mail survey of 234 caregivers of individuals with intellectual and developmental disabilities who were waiting for services. The present authors identified which parent and individual with intellectual and developmental disability characteristics were significantly associated with the number of unmet service needs. RESULTS: Individuals with intellectual and developmental disabilities who were in poor health, from minority backgrounds and non-verbal were significantly more likely to have a greater number of unmet service needs. Additionally, individuals with younger caregivers and individuals with caregivers from low-income backgrounds were significantly more likely to report a greater number of unmet service needs. DISCUSSION: Implications for research and policy are discussed. PMID- 27496084 TI - Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. AB - BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by a very high lifetime cancer risk and an early age at diagnosis of a wide cancer spectrum. Precise estimates for the risk of first and subsequent cancers are lacking. METHODS: The National Cancer Institute's Li-Fraumeni Syndrome Study includes families meeting the diagnostic criteria for LFS or Li-Fraumeni-like syndrome, and individuals with a germline TP53 mutation, choroid plexus carcinoma, adrenocortical carcinoma, or >=3 cancers. Herein, we estimated the cumulative risk and annual hazards for first and second cancers among TP53 mutation carriers (TP53 positive [TP53+]) using MATLAB statistical software. RESULTS: This study evaluated 286 TP53+ individuals from 107 families. The cumulative cancer incidence was 50% by age 31 years among TP53+ females and 46 years among males, and nearly 100% by age 70 years for both sexes. Cancer risk was highest after age 20 years for females, mostly due to breast cancer, whereas among males the risk was higher in childhood and later adulthood. Among females, the cumulative incidence rates by age 70 years for breast cancer, soft tissue sarcoma, brain cancer, and osteosarcoma were 54%, 15%, 6%, and 5%, respectively. Among males, the incidence rates were 22%, 19%, and 11%, respectively, for soft tissue sarcoma, brain cancer, and osteosarcoma. Approximately 49% of those with 1 cancer developed at least another cancer after a median of 10 years. The average age-specific risk of developing a second cancer was comparable to that of developing a first cancer. CONCLUSIONS: The cumulative cancer risk in TP53 + individuals was very high and varied by sex, age, and cancer type. Additional work, including prospective risk estimates, is needed to better inform personalized risk management. Cancer 2016;122:3673-81. (c) 2016 American Cancer Society. PMID- 27496086 TI - "The only sure foundations of medicine are, an intimate knowledge of the human body, and observation on the effects of medicinal substances on that". PMID- 27496085 TI - Mechanisms of DHA transport to the brain and potential therapy to neurodegenerative diseases. AB - Docosahexaenoic acid (DHA; 22:6 omega-3) is highly enriched in the brain and is required for proper brain development and function. Its deficiency has been shown to be linked with the emergence of neurological diseases. Dietary omega-3 fatty acid supplements including DHA have been suggested to improve neuronal development and enhance cognitive functions. However, mechanisms of DHA incorporation in the brain remain to be fully understood. Findings suggested that DHA is better incorporated when esterified within lysophospholipid rather than under its non-esterified form. Furthermore, DHA has the potential to be converted into diverse oxylipins with potential neuroprotective effects. Since DHA is poorly synthesized de novo, targeting the brain with specific carriers of DHA might provide novel therapeutic approaches to neurodegenerative diseases. PMID- 27496088 TI - Prevalence and factors associated with cracked nipples in the first month postpartum. AB - BACKGROUND: To assess the prevalence and factors associated with the occurrence of cracked nipples in the first month postpartum. METHODS: This was a cross sectional study nested in a cohort of mothers living in Feira de Santana, state of Bahia, northeastern Brazil. Data from 1,243 mother-child dyads assessed both at the maternity ward and 30 days after delivery were analyzed. The association between cracked nipples as reported by mothers and their possible determinants was analyzed using Poisson regression in a model where the variables were hierarchically organized into four levels: distal (individual characteristics), distal intermediate (prenatal characteristics), proximal intermediate (delivery characteristics), and proximal (postnatal characteristics). RESULTS: The prevalence of cracked nipples was 32 % (95 % confidence interval [95 % CI] 29.4 34.7) in the first 30 days postpartum. The following factors showed significant association with the outcome: poor breastfeeding technique (prevalence ratio [PR] = 3.18, 95 % CI 2.72-3.72); breast engorgement (PR = 1.70, 95 % CI 1.46-1.99); birth in a maternity ward not accredited by the Baby-Friendly Hospital Initiative (PR = 1.51, 95 % CI 1.15-1.99); cesarean section (PR = 1.33, 95 % CI 1.13-1.57); use of a feeding bottle (PR = 1.29, 95 % CI 1.06-1.55); and higher maternal education level (PR = 1.23, 95 % CI 1.04-1.47). CONCLUSIONS: The prevalence of cracked nipples was high in our sample. Most of the factors associated with cracked nipples were related to postnatal characteristics, especially poor breastfeeding technique, which could be improved to help prevent the condition. PMID- 27496087 TI - Gene family expansions and contractions are associated with host range in plant pathogens of the genus Colletotrichum. AB - BACKGROUND: Many species belonging to the genus Colletotrichum cause anthracnose disease on a wide range of plant species. In addition to their economic impact, the genus Colletotrichum is a useful model for the study of the evolution of host specificity, speciation and reproductive behaviors. Genome projects of Colletotrichum species have already opened a new era for studying the evolution of pathogenesis in fungi. RESULTS: We sequenced and annotated the genomes of four strains in the Colletotrichum acutatum species complex (CAsc), a clade of broad host range pathogens within the genus. The four CAsc proteomes and secretomes along with those representing an additional 13 species (six Colletotrichum spp. and seven other Sordariomycetes) were classified into protein families using a variety of tools. Hierarchical clustering of gene family and functional domain assignments, and phylogenetic analyses revealed lineage specific losses of carbohydrate-active enzymes (CAZymes) and proteases encoding genes in Colletotrichum species that have narrow host range as well as duplications of these families in the CAsc. We also found a lineage specific expansion of necrosis and ethylene-inducing peptide 1 (Nep1)-like protein (NLPs) families within the CAsc. CONCLUSIONS: This study illustrates the plasticity of Colletotrichum genomes, and shows that major changes in host range are associated with relatively recent changes in gene content. PMID- 27496090 TI - Leukocyte adhesion molecule dynamics after Natalizumab withdrawal in Multiple Sclerosis. AB - Cell-adhesion molecules (CAMs) dynamics in Multiple Sclerosis (MS) patients have been widely studied after Natalizumab (NTZ) introduction. However, their temporal dynamics after NTZ withdrawal (NTZ-W) has not been described. We prospectively evaluate changes in the expression levels of CAMs (CD49d, CD29, L-Selectin and CD11a) involved in T cell migration of 22 MS patients after NTZ-W. CD49d, CD29 and CD11a expression experienced a continuous increase expression two months after NTZ-W and Cd49d expression at month six after NTZ-W correlated to NTZ treatment duration, both in CD45+CD4+ and CD45+CD8+. CD49d expression up to month three after NTZ-W was related to MS activity in CD45+CD8+ at the end of the study. Results from this study suggest that patients with a longer NTZ treatment are more susceptible to present a "molecular rebound" after NTZ-W. CD49d determination may be a useful tool to closely monitor MS activity in patients who interrupt NTZ. PMID- 27496089 TI - Oral citrulline supplementation protects female mice from the development of non alcoholic fatty liver disease (NAFLD). AB - PURPOSE: Impairments of intestinal barrier function are discussed as risk factors for the development and progression of non-alcoholic fatty liver disease (NAFLD). Studies suggest an association between arginine/citrulline homeostasis and the development of liver damages. Here, the effect of an oral L-citrulline (Cit) supplement on the development of a Western-style diet (WSD)-induced NAFLD was determined in mice. METHODS: Female 6- to 8-week-old C57BL/6J mice were either pair-fed a liquid Western-style or control diet (C) +/- 2.5 g/kg bodyweight Cit for 6 weeks (C + Cit or WSD + Cit). Indices of liver damage, glucose metabolism, intestinal barrier function and NO synthesis were measured. RESULTS: While bodyweight gain was similar between groups, markers of glucose metabolism like fasting blood glucose and HOMA index and markers of liver damage like hepatic triglyceride levels, number of neutrophils and plasminogen activator inhibitor-1 protein levels were significantly lower in WSD + Cit-fed mice when compared to WSD-fed mice only. Protein levels of the tight junction proteins occludin and zonula occludens-1 in duodenum were significantly lower in mice fed a WSD when compared to those fed a WSD + Cit (-~70 and -~60 %, respectively, P < 0.05), whereas portal endotoxin levels, concentration of 3-nitrotyrosine protein adducts in duodenum and toll-like receptor-4 mRNA expression in livers of WSD + Cit-fed mice were markedly lower than in WSD-fed mice (-~43 %, P = 0.056; -~80 and -~48 %, respectively, P < 0.05). CONCLUSION: Our data suggest that the protective effects of supplementing Cit on the development of NAFLD in mice are associated with a decreased translocation of endotoxin into the portal vein. PMID- 27496091 TI - Local cholinergic-GABAergic circuitry within the basal forebrain is modulated by galanin. AB - The basal forebrain (BF) is an important regulator of hippocampal and cortical activity. In Alzheimer's disease (AD), there is a significant loss and dysfunction of cholinergic neurons within the BF, and also a hypertrophy of fibers containing the neuropeptide galanin. Understanding how galanin interacts with BF circuitry is critical in determining what role galanin overexpression plays in the progression of AD. Here, we examined the location and function of galanin in the medial septum/diagonal band (MS/DBB) region of the BF. We show that galanin fibers are located throughout the MS/DBB and intermingled with both cholinergic and GABAergic neurons. Whole-cell patch clamp recordings from MS/DBB neurons in acute slices reveal that galanin decreases tetrodotoxin-sensitive spontaneous GABA release and dampens muscarinic receptor-mediated increases in GABA release in the MS/DBB. These effects are not blocked by pre-exposure to beta amyloid peptide (Abeta1-42). Optogenetic activation of cholinergic neurons in the MS/DBB increases GABA release back onto cholinergic neurons, forming a functional circuit within the MS/DBB. Galanin disrupts this cholinergic-GABAergic circuit by blocking the cholinergic-induced increase in GABA release. These data suggest that galanin works in the BF to reduce inhibitory input onto cholinergic neurons and to prevent cholinergic-induced increase in inhibitory tone. This disinhibition of cholinergic neurons could serve as a compensatory mechanism to counteract the loss of cholinergic signaling that occurs during the progression of AD. PMID- 27496092 TI - Rate of Organ Space Infection Is Reduced with the Use of an Air Leak Test During Major Hepatectomies. AB - BACKGROUND: Organ/space surgical site infections (OSIs) constitute an important postoperative metric. We sought to assess the impact of a previously described air leak test (ALT) on the incidence of OSI following major hepatectomies. METHODS: A single-institution hepatobiliary database was queried for patients who underwent a major hepatectomy without biliary-enteric anastomosis between January 2009 and June 2015. Demographic, clinicopathologic, and intraoperative data including application of ALT-were analyzed for associations with postoperative outcomes, including OSI, hospital length of stay (LOS), morbidity and mortality rates, and readmission rates. RESULTS: Three hundred eighteen patients were identified who met inclusion criteria, of whom 210 had an ALT. ALT and non-ALT patients did not differ in most disease and treatment characteristics, except for higher rates of trisegmentectomy among ALT patients (53 vs. 34 %, p = 0.002). ALT patients experienced lower rates of OSI and 90-day morbidity than non-ALT patients (5.2 vs. 13.0 %, p = 0.015 and 24.8 vs. 40.7 %, p = 0.003, respectively). In turn, OSI was the strongest independent predictor of longer LOS (OR = 4.89; 95 % CI, 2.80-6.97) and higher rates of 30- (OR = 32.0; 95 % CI, 10.9 93.8) and 45-day readmissions (OR = 29.4; 95 % CI, 10.2-84.6). CONCLUSIONS: The use of an intraoperative ALT significantly reduces the rate of OSI following major hepatectomy and may contribute to lower post-discharge readmission rates. PMID- 27496093 TI - A BRCA1/2 Mutational Signature and Survival in Ovarian High-Grade Serous Carcinoma. AB - BACKGROUND: Mutational signatures have been identified by the broad sequencing of cancer genomes and reflect underlying processes of mutagenesis. The clinical application of mutational signatures is not well defined. Here we aim to assess the prognostic utility of mutational signatures in ovarian high-grade serous carcinoma. METHODS: Open access data of 15,439 somatic mutations of 310 ovarian high-grade serous carcinomas from The Cancer Genome Atlas (TCGA) are used to construct a Bayesian model to classify each cancer as either having or lacking a BRCA1/2 mutational signature. We evaluate the association of the BRCA1/2 signature with overall survival on the TCGA dataset and on an independent cohort of 92 ovarian high-grade serous carcinomas from the Australian Ovarian Cancer Study (AOCS). RESULTS: Patients from TCGA with tumors harboring the BRCA1/2 mutational signature have improved survival (55.2 months vs. 38.0 months), which is independent of BRCA1/2 gene mutation status, age, stage, and grade (HR = 0.64; P = 0.02). In the AOCS dataset, the BRCA1/2 mutational signature is also associated with improved overall survival (46.3 months vs. 23.6 months) independent of age and stage (HR = 0.52; P = 0.007). CONCLUSIONS: A BRCA1/2 mutational signature is a prognostic marker in ovarian high-grade serous carcinoma. Mutational signature analysis of ovarian cancer genomes may be useful in addition to testing for BRCA1/2 mutations. IMPACT: This study identifies the use of mutational signatures as a biomarker for survival outcome in ovarian high grade serous carcinoma. Cancer Epidemiol Biomarkers Prev; 25(11); 1511-6. (c)2016 AACR. PMID- 27496095 TI - An audit of residual cancer burden reproducibility in a UK context. AB - AIMS: The residual cancer burden score (RCB) is currently the preferred quantification tool for assessing residual disease following neoadjuvant chemotherapy (NACT) in breast cancer clinical trials. This has been shown to be highly reproducible at the MD Anderson Cancer Centre, where it was developed originally. We wanted to evaluate RCB in a UK context, where macroscopic handling of tissue may differ between sites. METHODS AND RESULTS: The pathology slides from 90 post-NACT patients from Guy's and St Thomas' NHS Foundation Trust and the Royal Bournemouth Hospital were reviewed independently by two specialist breast histopathologists who recalculated the RCB for each case. Data were collated and analysed statistically for interobserver reproducibility, for both numerical and categorical RCB. Overall, agreement between pathologists was 'good' [kappa = 0.775; 95% confidence interval (CI) = 0.668-0.882]. The overall concordance for continuous RCB score and for categorical RCB group was statistically significant (Spearman's correlation coefficient = 0.9497; 95% CI = 0.9235-0.9671; P < 0.0001 and Spearman's correlation coefficient = 0.9145; 95% CI = 0.8712-0.9437; P < 0.0001, respectively). Discordance could not be attributed to any one component of the RCB calculation. CONCLUSIONS: These data suggest that the RCB score is reproducible in a UK context. Further data comparing it to other quantification systems is required, however, before any superiority can be established. PMID- 27496094 TI - Metformin, Diabetes, and Survival among U.S. Veterans with Colorectal Cancer. AB - BACKGROUND: Metformin has been associated with improved colorectal cancer survival, but investigations are limited by small numbers of patients and confounding by diabetic severity. We examined the association between metformin use and overall survival (OS) in patients with diabetes and colorectal cancer in a large population of U.S. veterans, while adjusting for measures of diabetic severity. METHODS: Patients diagnosed with colorectal cancer from January 2001 to December 2008 were identified from the Veterans Affairs Central Cancer Registry. Multivariable models were used to examine the adjusted association of OS with diabetes and use of antidiabetic medications. RESULTS: There were 21,352 patients diagnosed with colorectal cancer identified (n = 16,355 nondiabetic patients, n = 2,038 diabetic patients on metformin, n = 2,136 diabetic patients on medications other than metformin, n = 823 diabetic patients not on antidiabetic medication). Diabetic patients had a significantly worse OS than nondiabetic patients, but metformin users had only a 10% increase in death (HRadj 1.10; 95% CI, 1.03-1.17, P = 0.004), as compared with 22% for users of other antidiabetic medications (HRadj 1.22; 95% CI, 1.15-1.29, P < 0.0001). Among colorectal cancer patients with diabetes, metformin users had a 13% improved OS versus patients taking other antidiabetic medications (HRadj 0.87; 95% CI, 0.79-0.95, P = 0.003), while diabetic patients not on any antidiabetic medications did not differ with respect to OS (HRadj 1.02; 95% CI, 0.90-1.15, P = 0.76). CONCLUSIONS: Among diabetics with colorectal cancer, metformin use is associated with improved survival, despite adjustments for diabetes severity and other risk factors. IMPACT: These data lend further support to the conduct of randomized studies of possible anticancer effects of metformin among patients with colorectal cancer. Cancer Epidemiol Biomarkers Prev; 25(10); 1418-25. (c)2016 AACR. PMID- 27496097 TI - Council of Europe dismisses claim that abortion in Italy is harder because more doctors are objecting. PMID- 27496096 TI - A randomized controlled trial of smoking cessation methods in patients newly diagnosed with pulmonary tuberculosis. AB - BACKGROUND: Tuberculosis (TB) and tobacco use are two major alarming global health issues that tend to be co-prevalent in many developing countries and various surveys have provided evidence on their entangled associations. Accordingly, it is strongly suggested that smoking cessation be incorporated in TB control programs. Therefore, we aimed to evaluate the effectiveness of two smoking cessation methods among newly-diagnosed pulmonary TB patients. METHODS: A total of 210 newly-diagnosed pulmonary TB patients from Tehran, Iran with smoking habits were included in this randomized clinical trial during 2012-2013. Patients were assigned to three groups of control (just TB medical treatment), brief advice (TB medical treatment plus individualized counseling sessions of quitting behavioral therapy) and combined intervention (TB medical treatment plus individualized counseling sessions of quitting behavioral therapy plus medical treatment with slow release bupropion). Patients' abstinence was followed at six time point during six months. Data were analyzed by SPSS v.22 using Generalized Estimating Equations (GEE) model. RESULTS: Abstinance rate at the end of six months were 71.7 % for combined intervention group, 33.9 % for brief advice group and 9.8 % for the control group (p < 0.001). Combined intervention group and brief advice group respectively had 35 times (p < 0.001, OR = 35.26, 95 % CI = 13.77-90.32) and 7 times (p < 0.001, OR = 7.14, 95 % CI = 2.72-18.72) more odds of not being an active smoker at each time point, compared to the control group. CONCLUSION: Considering the prevalence and importance of TB and the substantial influence of these preventive measures on controlling tobacco use, application of such programs is recommended. TRIAL REGISTRATION: The survey was registered in the Iranian registry of clinical trials website (irct.ir) in August 31, 2013 with IRCT ID: IRCT2013062613783N1 . PMID- 27496098 TI - To belong or not to belong: nursing students' interactions with clinical learning environments - an observational study. AB - BACKGROUND: Belongingness has been argued to be a prerequisite for students' learning in the clinical setting but making students feel like they belong to the workplace is a challenge. From a sociocultural perspective, workplace participatory practices is a framework that views clinical learning environments to be created in interaction between students and the workplace and hence, are dependent on them both. The aim of this study was to explore the interdependence between affordances and engagement in clinical learning environments. The research question was: How are nursing students influenced in their interactions with clinical learning environments? METHODS: An observational study with field observations and follow-up interviews was performed. The study setting comprised three academic teaching hospitals. Field observations included shadowing undergraduate nursing students during entire shifts. Fifty-five hours of field observations and ten follow-up interviews with students, supervisors and clinical managers formed the study data. A thematic approach to the analysis was taken and performed iteratively with the data collection. RESULTS: The results revealed that students strived to fill out the role they were offered in an aspirational way but that they became overwhelmed when given the responsibility of care. When students' basic values did not align with those enacted by the workplace, they were not willing to compromise their own values. Workplaces succeeded in inviting students into the community of nurses and the practice of care. Students demonstrated hesitance regarding their desire to belong to the workplace community. CONCLUSION: The results imply that the challenge for clinical education is not to increase the experience of belongingness but to maintain students' critical and reflective approach to health care practice. Additionally, results suggest students to be included as an important stakeholder in creating clinical learning environments rather than being viewed as consumer of clinical education. PMID- 27496102 TI - Chilo iridescent virus (CIV) ORF 012L encodes a protein with both exonuclease and endonuclease functions. AB - Chilo iridescent virus (CIV) is the type member of the genus Iridovirus within the family Iridoviridae. The virions of CIV contain a single linear dsDNA molecule that is circularly permuted and terminally redundant. The genome of CIV contains an open reading frame (ORF 012L) encoding a protein homologous to exonuclease II of Schizosaccharomyces pombe. In this study, we focused on the characterization of CIV ORF 012L. The target ORF was cloned into the pET28a vector, expressed in E. coli strain BL21 (DE3) pLysS with an N-terminal His tag and purified to homogeneity by using Ni-NTA affinity chromatography. Biochemical characterization of the purified CIV 012L confirmed that this viral protein is a functional 5'-3' exonuclease that digests 3'-biotin-labelled oligonucleotides and linear double-stranded DNA (dsDNA) molecules from their 5' termini in a highly processive manner. CIV 012L also has a potent endonuclease activity on dsDNA in vitro. In addition, CIV 012L converted supercoiled plasmid DNA (replicative form I, RFI) into the open circular form (RFII) and then open circular form into linear form (RFIII). Endonuclease activity of CIV 012L was optimal in the presence of 10 mM Mg(2+) or 30 mM Mn(2+) ions and at 150 mM NaCl or KCl salt concentrations. The highest endonuclease activity was obtained at pH 8, and it reached a maximum at 55 degrees C. The CIV 012L protein showed deficiencies for both double- and single-stranded RNAs. PMID- 27496101 TI - Evidence for chemokine synergy during neutrophil migration in ARDS. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterised by pulmonary oedema, respiratory failure and severe inflammation. ARDS is further characterised by the recruitment of neutrophils into the lung interstitium and alveolar space. OBJECTIVES: The factors that regulate neutrophil infiltration into the inflamed lung and our understanding of the pathomechanisms in ARDS remain incomplete. This study aimed at determining the role of the chemokine (C-C motif) ligand (CCL)2 and CCL7 in ARDS. METHODS: CCL2 and CCL7 protein levels were measured in bronchoalveolar lavage (BAL) fluid obtained from lipopolysaccharide(LPS)-challenged human volunteers and two separate cohorts of patients with ARDS. Neutrophil chemotaxis to ARDS BAL fluid was evaluated and the contribution of each was assessed and compared with chemokine (C-X-C motif) ligand 8 (CXCL8). Chemokine receptor expression on neutrophils from blood or BAL fluid of patients with ARDS was analysed by flow cytometry. RESULTS: CCL2 and CCL7 were significantly elevated in BAL fluid recovered from LPS-challenged volunteers and patients with ARDS. BAL fluid from patients with ARDS was highly chemotactic for human neutrophils and neutralising either CCL2 or CCL7 attenuated the neutrophil chemotactic response. Moreover, CCL2 and CCL7 synergised with CXCL8 to promote neutrophil migration. Furthermore, neutrophils isolated from the blood or BAL fluid differentially regulated the cell surface expression of chemokine (C-X-C motif) receptor 1 and C-C chemokine receptor type 2 during ARDS. CONCLUSION: This study highlights important inflammatory chemokines involved in regulating neutrophil migration, which may have potential value as therapeutic targets for the treatment of ARDS. PMID- 27496100 TI - Transcriptomic alterations in the heart of non-obese type 2 diabetic Goto Kakizaki rats. AB - BACKGROUND: There is a spectacular rise in the global prevalence of type 2 diabetes mellitus (T2DM) due to the worldwide obesity epidemic. However, a significant proportion of T2DM patients are non-obese and they also have an increased risk of cardiovascular diseases. As the Goto-Kakizaki (GK) rat is a well-known model of non-obese T2DM, the goal of this study was to investigate the effect of non-obese T2DM on cardiac alterations of the transcriptome in GK rats. METHODS: Fasting blood glucose, serum insulin and cholesterol levels were measured at 7, 11, and 15 weeks of age in male GK and control rats. Oral glucose tolerance test and pancreatic insulin level measurements were performed at 11 weeks of age. At week 15, total RNA was isolated from the myocardium and assayed by rat oligonucleotide microarray for 41,012 genes, and then expression of selected genes was confirmed by qRT-PCR. Gene ontology and protein-protein network analyses were performed to demonstrate potentially characteristic gene alterations and key genes in non-obese T2DM. RESULTS: Fasting blood glucose, serum insulin and cholesterol levels were significantly increased, glucose tolerance and insulin sensitivity were significantly impaired in GK rats as compared to controls. In hearts of GK rats, 204 genes showed significant up regulation and 303 genes showed down-regulation as compared to controls according to microarray analysis. Genes with significantly altered expression in the heart due to non-obese T2DM includes functional clusters of metabolism (e.g. Cyp2e1, Akr1b10), signal transduction (e.g. Dpp4, Stat3), receptors and ion channels (e.g. Sln, Chrng), membrane and structural proteins (e.g. Tnni1, Mylk2, Col8a1, Adam33), cell growth and differentiation (e.g. Gpc3, Jund), immune response (e.g. C3, C4a), and others (e.g. Lrp8, Msln, Klkc1, Epn3). Gene ontology analysis revealed several significantly enriched functional inter-relationships between genes influenced by non-obese T2DM. Protein-protein interaction analysis demonstrated that Stat is a potential key gene influenced by non-obese T2DM. CONCLUSIONS: Non-obese T2DM alters cardiac gene expression profile. The altered genes may be involved in the development of cardiac pathologies and could be potential therapeutic targets in non-obese T2DM. PMID- 27496103 TI - The Effect of Energy Labelling on Menus and a Social Marketing Campaign on Food Purchasing Behaviours of University Students. AB - BACKGROUND: This study assessed the impact of kilojoule (kJ) labelling alone or accompanied by a social marketing campaign on food sales and selection of less energy-dense meals by young adults from a university food outlet. METHODS: There were two kJ labelling intervention phases each of five weeks: (1) kJ labelling alone (2) kJ labels with marketing materials ("8700 kJ campaign"). Food sales of labelled items were tracked during each intervention and five weeks after. Food sales during interventions were also compared with historical sales of foods in the same 10-week period in the previous year. A sub sample of young adults (n = 713; aged 19-24) were surveyed during both the interventions to assess awareness, influence, sentiment and anticipated future impact of kJ labels and the social marketing campaign respectively. RESULTS: There were no differences in sales between the kJ labelling with social marketing and the 5-weeks of labelling before and after. The percentage sale of chicken Caesar burger (3580 kJ, P = 0.01), steak and chips (4000 kJ, P = 0.02) and the grill burger (5500 kJ, P = 0.00) were lower in the year with menu labelling and social marketing campaign. Only 30 % students were initially aware of the kJ labels on the menu but 75 % of students were accepting of kJ labelling, after they were made aware. Respondents viewing the marketing campaign elements and then using kJ values on the menu selected meals with a lower mean energy content; constituting a reduction of 978 kJ (p < 0.01) even though the majority claimed that the 8700 kJ campaign would not impact their food choices. CONCLUSIONS: Point-of-purchase energy labelling may be an effective method to encourage better food choices when eating out among young adults. However, further efforts to increase awareness and provide education about energy requirements to prevent weight gain will be needed. PMID- 27496104 TI - A gain-of-function mutation in Nav1.6 in a case of trigeminal neuralgia. AB - Idiopathic trigeminal neuralgia (TN) is a debilitating pain disorder characterized by episodic unilateral facial pain along the territory of branches of the trigeminal nerve. Human painful disorders, but not TN, have been linked to gain-of-function mutations in peripheral voltage-gated sodium channels (NaV1.7, NaV1.8 and NaV1.9). Gain-of-function mutations in NaV1.6, which is expressed in myelinated and unmyelinated CNS and peripheral nervous system neurons and supports neuronal high-frequency firing, have been linked to epilepsy but not to pain. Here, we describe an individual who presented with evoked and spontaneous paroxysmal unilateral facial pain, and carried a diagnosis of TN. Magnetic resonance imaging showed unilateral neurovascular compression, consistent with pain in areas innervated by the second branch of the trigeminal nerve. Genetic analysis as part of a phase 2 clinical study in patients with TN conducted by Convergence Pharmaceuticals Ltd revealed a previously undescribed de novo missense mutation in NaV1.6 (c.A406G; p.Met136Val). Whole-cell voltage-clamp recordings show that the Met136Val mutation significantly increases peak current density (1.5-fold) and resurgent current (1.6-fold) without altering gating properties. Current-clamp studies in trigeminal ganglion (TRG) neurons showed that Met136Val increased the fraction of high-firing neurons, lowered the current threshold and increased the frequency of evoked action potentials in response to graded stimuli. Our results demonstrate a novel NaV1.6 mutation in TN, and show that this mutation potentiates transient and resurgent sodium currents and leads to increased excitability in TRG neurons. We suggest that this gain-of-function NaV1.6 mutation may exacerbate the pathophysiology of vascular compression and contribute to TN. PMID- 27496106 TI - Genetically Confirmed Neonatal Diabetes: A Single Centre Experience. PMID- 27496105 TI - Rationale and design of the multicenter randomized trial investigating the effects of levosimendan pretreatment in patients with low ejection fraction (<=40 %) undergoing CABG with cardiopulmonary bypass (LICORN study). AB - BACKGROUND: Patients with a left ventricular ejection fraction (LVEF) of less than 40 % are at high risk of developing postoperative low cardiac output syndrome (LCOS). Despite actual treatments (inotropic agents and/or mechanical assist devices), the mortality rate of such patients remains very high (13 to 24 %). The LICORN trial aims at assessing the efficacy of a preoperative infusion of levosimendan in reducing postoperative LCOS in patients with poor LVEF undergoing coronary artery bypass grafting (CABG). METHODS/DESIGN: LICORN study is a multicenter, randomized double-blind, placebo-controlled trial in parallel groups. 340 patients with LVEF <=40 %, undergoing CABG will be recruited from 13 French hospitals. The study drug will be started after anaesthesia induction and infused over 24 h (0.1 MUg/kg/min). The primary outcome (postoperative LCOS) is evaluated using a composite criterion composed of: 1) need for inotropic agents beyond 24 h following discontinuation of the study drug; 2) need for post operative mechanical assist devices or failure to wean from these techniques when inserted pre-operatively; 3) need for renal replacement therapy. Secondary outcomes include: 1) mortality at Day 28 and Day 180; 2) each item of the composite criterion of the primary outcome; 3) the number of "ventilator-free" days and "out of intensive care unit" days at Day 28. DISCUSSION: The usefulness of levosimendan in the perioperative period has not yet been documented with a high level of evidence. The LICORN study is the first randomized controlled trial evaluating the clinical value of preoperative levosimendan in high risk cardiac surgical patients undergoing CABG. TRIAL REGISTRATION NUMBER: NCT02184819 (ClinicalTrials.gov). PMID- 27496107 TI - I'll Have Another Shot, Please! PMID- 27496108 TI - Immunotherapy for Lung Cancer: Many Questions Yet to Be Answered. PMID- 27496109 TI - Donor-Derived T-Cell Large Granular Lymphocytic Leukemia in a Patient With Peripheral T-Cell Lymphoma. AB - T-cell large granular lymphocytic (T-LGL) leukemia after hematopoietic stem cell transplantation (SCT) is rare and its natural history and clinical outcome have not been well described. We report the clinical, morphologic, immunophenotypic, and molecular features of a case of donor-derived T-LGL leukemia in a 16-year-old man who received allogeneic SCT for peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). The patient presented with persistent neutropenia and splenomegaly 9 months after SCT when the chimerism study showed a 100% donor pattern. A splenectomy revealed T-LGL leukemia. Flow cytometric analysis showed an aberrant T-cell population positive for CD3, CD5 (dim, subset), CD7, CD8, CD16 (subset), CD57, CD94 (dim, partial), and T-cell receptor (TCR) alphabeta, and negative for CD4, CD26, CD56, and TCRgammadelta. Molecular studies showed monoclonal TCRbeta and TCRgamma gene rearrangements. Both the immunophenotype and molecular profile of the T-LGL leukemia were different from the pre-SCT PTCL. Sequencing analysis for STAT3 exon 21 did not reveal any mutation in both pre-SCT and post-SCT specimens. The patient did not receive any treatment for T-LGL leukemia; however, his count progressively increased after splenectomy, despite the presence of persistent T-LGL leukemia in the bone marrow. There was no evidence of recurrent PTCL. We propose an algorithm to diagnose this rare post SCT neoplasm. PMID- 27496110 TI - NCCN Guidelines Insights: Melanoma, Version 3.2016. AB - The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma. PMID- 27496111 TI - NCCN's Commitment to Medication Safety: The Vincristine Initiative. AB - The mission of NCCN is to improve the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Improving medication safety is an important aspect of fulfilling this mission. In September 2014, the NCCN Best Practices Committee began a medication safety initiative to improve the safe use of vincristine. This article describes and discusses this initiative. PMID- 27496112 TI - NCCN Framework for Resource Stratification: A Framework for Providing and Improving Global Quality Oncology Care. AB - More than 14 million new cancer cases and 8.2 million cancer deaths are estimated to occur worldwide on an annual basis. Of these, 57% of new cancer cases and 65% of cancer deaths occur in low- and middle-income countries. Disparities in available resources for health care are enormous and staggering. The WHO estimates that the United States and Canada have 10% of the global burden of disease, 37% of the world's health workers, and more than 50% of the world's financial resources for health; by contrast, the African region has 24% of the global burden of disease, 3% of health workers, and less than 1% of the world's financial resources for health. This disparity is even more extreme with cancer. NCCN has developed a framework for stratifying the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to help health care systems in providing optimal care for patients with cancer with varying available resources. This framework is modified from a method developed by the Breast Health Global Initiative. The NCCN Framework for Resource Stratification (NCCN Framework) identifies 4 resource environments: basic resources, core resources, enhanced resources, and NCCN Guidelines, and presents the recommendations in a graphic format that always maintains the context of the NCCN Guidelines. This article describes the rationale for resource-stratified guidelines and the methodology for developing the NCCN Framework, using a portion of the NCCN Cervical Cancer Guideline as an example. PMID- 27496113 TI - Wealth, Health Expenditure, and Cancer: A National Perspective. AB - BACKGROUND: The US health care system is characterized by high health expenditures with penultimate outcomes. This ecological study evaluates the associations between wealth, health expenditure, and cancer outcomes at the state level. METHODS: We extracted gross domestic product (GDP) and health expenditure per capita from the 2009 Bureau of Economic Analysis and the Centers for Medicare & Medicaid Services, respectively. Using data from the NCI, we retrieved colorectal cancer (CRC), breast cancer, and all-cancer age-adjusted rates and computed mortality/incidence (M/I) ratios. We used the Spearman's rank correlation to determine the association between the financial indicators and cancer outcomes, and we constructed geographic distribution maps to describe these associations. RESULTS: GDP per capita significantly correlated with lower M/I ratios for all cancers, breast cancer, and CRC. As for health expenditure per capita, preliminary analysis highlighted a rift between the Northeastern and Southern states, which translated into worse breast and all-cancer outcomes in Southern states. Further analysis showed that higher health expenditure significantly correlated with decreased breast cancer M/I ratio. However, CRC outcomes were not significantly affected by health expenditure, nor were all cancer outcomes. CONCLUSIONS: All cancers, breast cancer, and CRC outcomes significantly correlated with wealth, whereas only breast cancer correlated with higher health expenditure. Future research is needed to evaluate the potential role of policies in optimizing resource allocation in the states' efforts against CRC and minimizing disparities in interstate cancer outcomes. PMID- 27496114 TI - Predictors of In-Hospital Mortality in Patients With Metastatic Cancer Receiving Specific Critical Care Therapies. AB - BACKGROUND: In-hospital mortality is high for critically ill patients with metastatic cancer. To help patients, families, and clinicians make an informed decision about invasive medical treatments, we examined predictors of in-hospital mortality among patients with metastatic cancer who received critical care therapies (CCTs). PATIENTS AND METHODS: We used the 2010 California Healthcare Cost and Utilization Project: State Inpatient Databases to identify admissions of patients with metastatic cancer (age >=18 years) who received CCTs, including invasive mechanical ventilation (IMV), tracheostomy, percutaneous endoscopic gastrostomy (PEG) tube, acute use of dialysis, and total parenteral nutrition (TPN). We first described the characteristics and outcomes of patients who received any CCTs. We then used multivariable logistic regression models with generalized estimating equations (to account for clustering within hospitals) to identify predictors of in-hospital mortality among patients who received any CCTs. RESULTS: For 2010, we identified 99,085 admissions among patients with metastatic cancer. Of these, 9,348 (9.4%) received any CCT during hospitalization; 50% received IMV, 15% PEG tube, 8% tracheostomy, 40% TPN, and 8% acute dialysis. Inpatient mortality was 30%. Of patients who received any CCT and survived to discharge, 27% were discharged to a skilled nursing facility. Compared with patients who died, costs of care were $3,019 higher for admissions in which patients survived the hospitalization. Predictors of in-hospital mortality included non-white race (vs whites), lack of insurance (vs Medicare), unscheduled admissions, principal diagnosis of infections (vs cancer-related), greater burden of comorbidities, end-stage renal disease, liver disease and lung cancer (vs other cancers). CONCLUSIONS: Although more studies are needed to better understand risks and benefits of specific treatments in the setting of specific cancer types, these data will help to inform decision-making for patients with metastatic cancer who become critically ill. PMID- 27496115 TI - Is Advanced Imaging in Early-Stage Breast Cancer Ever Warranted? Reconciling Clinical Judgment With Common Quality Measures. AB - BACKGROUND: The American Board of Internal Medicine Foundation's Choosing Wisely initiative aims to reduce unnecessary advanced imaging for early-stage breast cancer (ESBC). Additionally, NCCN Clinical Practice Guidelines in Oncology for Breast Cancer permit such images when oncologists perceive clinical clues of advanced disease. The utility of advanced imaging in ESBC is not known. PATIENTS AND METHODS: We analyzed all patients with ESBC from January 2010 to June 2012 at a large tertiary cancer center. Early-stage was defined as stage IIb or less. We included advanced imaging within 60 days after diagnosis. Three independent reviewers manually abstracted a sample of charts to determine reason for ordering. RESULTS: A total of 1,143 ESBC cases were identified; 21.8% of which had at least one advanced imaging procedure performed. Imaging modalities varied widely (38% CT, 21% PET, 34% bone scans, and 6% MRI). Patients who underwent advanced imaging were more likely to have triple-negative disease, be younger (age <50 years), and have higher stage disease (stage IIb vs <= stage IIa; all P<.001). A total of 100 cases (40%) were abstracted; 5 were excluded due to bilateral disease. Of the 95 cases remaining, 62% of the imaging studies were performed for staging, 17% for significant concurrent disease, and 22% for findings atypical of ESBC. Of the studies performed for staging, 15% produced clinically meaningful findings. Overall, 45% of studies were ordered for suspicious findings, complex history, or produced a meaningful result. CONCLUSIONS: Of patients with ESBC, 21.8% had at least one advanced imaging procedure within 60 days of diagnosis; almost half were clinically useful. Chart abstraction helped clarify intent. Conversations between clinicians and patients are needed to balance patient preferences and clinician judgment. PMID- 27496117 TI - Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. AB - This is a focused update highlighting the most current NCCN Guidelines for diagnosis and management of Lynch syndrome. Lynch syndrome is the most common cause of hereditary colorectal cancer, usually resulting from a germline mutation in 1 of 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2), or deletions in the EPCAM promoter. Patients with Lynch syndrome are at an increased lifetime risk, compared with the general population, for colorectal cancer, endometrial cancer, and other cancers, including of the stomach and ovary. As of 2016, the panel recommends screening all patients with colorectal cancer for Lynch syndrome and provides recommendations for surveillance for early detection and prevention of Lynch syndrome-associated cancers. PMID- 27496118 TI - Biomarkers in Colorectal Cancer Screening. AB - Colorectal cancer (CRC) is the third most common cause of cancer death in men and women in the United States. The main goals of screening are to prevent carcinogenesis (via adenoma detection and removal) and detect cancer at an early, curable stage. CRC mortality is steadily dropping in the United States, partly because of greater screening utilization. However, nearly 1 in 3 average-risk people are not up to date with standard CRC screening recommendations. This review surveys a wide range of CRC biomarkers in various stages of development, which may offer attractive risk stratification tools; a few have reached the commercial stage. If widely accepted, these tools may contribute to shift CRC screening practices away from 1-step colonoscopy to a 2-step risk stratification process of predictive biomarker measurements followed by colonoscopy for lower risk patients with a positive result. Such strategies could potentially increase the rate of CRC screening. PMID- 27496116 TI - Associations Between End-of-Life Cancer Care Patterns and Medicare Expenditures. AB - BACKGROUND: The purpose of this study was to examine the extent to which patterns of intensive end-of-life care explain geographic variation in end-of-life care expenditures among cancer decedents. METHODS: Using the SEER-Medicare database, we identified 90,465 decedents who were diagnosed with cancer in 2004-2011. Measures of intensive end-of-life care included chemotherapy received within 14 days of death; more than 1 emergency department visit, more than 1 hospitalization, or 1 or more intensive care unit (ICU) admissions within 30 days of death; in-hospital death; and hospice enrollment less than 3 days before death. Using hierarchical generalized linear models, we estimated risk-adjusted expenditures in the last month of life for each hospital referral region and identified key contributors to variation in expenditures. RESULTS: The mean expenditure per cancer decedent in the last month of life was $10,800, ranging from $8,300 to $15,400 in the lowest and highest expenditure quintile areas, respectively. There was considerable variation in the percentage of decedents receiving intensive end-of-life care intervention, with 41.7% of decedents receiving intensive care in the lowest quintile of expenditures versus 57.9% in the highest quintile. Regional patterns of late chemotherapy or late hospice use explained only approximately 1% of the expenditure difference between the highest and lowest quintile areas. In contrast, the proportion of decedents who had ICU admissions within 30 days of death was a major driver of variation, explaining 37.6% of the expenditure difference. CONCLUSIONS: Promoting appropriate end-of life care has the potential to reduce geographic variation in end-of-life care expenditures. PMID- 27496119 TI - Point: The Power of Data to (Mis)Guide Policy to Improve Cancer Health Equity. PMID- 27496120 TI - Counterpoint: Wealth, Health Expenditure, and Cancer-Translating Research Into Efficient Policies. PMID- 27496123 TI - Taq1B Polymorphism of Cholesteryl Ester Transfer Protein (CETP) and Its Effects on the Serum Lipid Levels in Metabolic Syndrome Patients. AB - The metabolic syndrome (MetS) is one of the most important risk factors for type 2 diabetes and cardiovascular disease. This syndrome is characterized by abdominal obesity, hypertension, insulin resistance, and dyslipidemia. The plasma origin of Cholesteryl ester transfer protein (CETP) is responsible for transferring cholesterol esters from high-density lipoprotein particles to apolipoprotein B containing lipoproteins compartment. We conducted this study to investigate the association between CETP gene Taq1B (rs708272) polymorphism in the metabolic syndrome among Iranian subjects. A sample size of 200 patients diagnosed with MetS together with 200 healthy donors as control were enrolled in this study. The investigation of polymorphism was performed by the use of polymerase chain reaction and restriction fragment length polymorphism analysis. To determine the relationship between polymorphism and lipid profile, we measured lipids and CETP concentration in metabolic syndrome and control subjects. Genotype distribution and allelic frequencies of polymorphism were determined and compared in both groups. Our findings showed that all clinical and biochemical characteristics in patients differed from the control group. The results showed that genotype and allele frequency of the Taq1B polymorphism was not significantly different between two groups. Instinctively, CETP was significantly higher in metabolic syndrome (1.64 +/- 0.32 ug/ml) than in control (1.53 +/- 0.34 ug/ml). A low level of CETP was found in blood of B2B2 typified genotype. In spite of Taq1B polymorphism on ester transfer protein concentration, no direct correlation was found between this polymorphism and metabolic syndrome. PMID- 27496122 TI - Factors Associated with Interest in Gene-Panel Testing and Risk Communication Preferences in Women from BRCA1/2 Negative Families. AB - Scientific advances have allowed the development of multiplex gene-panels to assess many genes simultaneously in women who have tested negative for BRCA1/2. We examined correlates of interest in testing for genes that confer modest and moderate breast cancer risk and risk communication preferences for women from BRCA negative families. Female first-degree relatives of breast cancer patients who tested negative for BRCA1/2 mutations (N = 149) completed a survey assessing multiplex genetic testing interest and risk communication preferences. Interest in testing was high (70 %) and even higher if results could guide risk-reducing behavior changes such as taking medications (79 %). Participants preferred to receive genomic risk communications from a variety of sources including: primary care physicians (83 %), genetic counselors (78 %), printed materials (71 %) and the web (60 %). Factors that were independently associated with testing interest were: perceived lifetime risk of developing cancer (odds ratio (OR) = 1.67: 95 % confidence interval (CI) 1.06-2.65) and high cancer worry (OR = 3.12: CI 1.28 7.60). Findings suggest that women from BRCA1/2 negative families are a unique population and may be primed for behavior change. Findings also provide guidance for clinicians who can help develop genomic risk communications, promote informed decision making and customize behavioral interventions. PMID- 27496124 TI - Passive immunization does not provide protection against experimental infection with Mycoplasma haemofelis. AB - Mycoplasma haemofelis (Mhf) is the most pathogenic feline hemotropic mycoplasma. Cats infected with Mhf that clear bacteremia are protected from Mhf reinfection, but the mechanisms of protective immunity are unresolved. In the present study we investigated whether the passive transfer of antibodies from Mhf-recovered cats to naive recipient cats provided protection against bacteremia and clinical disease following homologous challenge with Mhf; moreover, we characterized the immune response in the recipient cats. Ten specified pathogen-free (SPF) cats were transfused with pooled plasma from cats that had cleared Mhf bacteremia; five control cats received plasma from naive SPF cats. After homologous challenge with Mhf, cats were monitored for 100 days using quantitative PCR, hematology, blood biochemistry, Coombs testing, flow cytometry, DnaK ELISA, and red blood cell (RBC) osmotic fragility (OF) measurement. Passively immunized cats were not protected against Mhf infection but, compared to control cats, showed significantly higher RBC OF and B lymphocyte (CD45R/B220(+)) counts and occasionally higher lymphocyte, monocyte and activated CD4(+) T lymphocyte (CD4(+)CD25(+)) counts; they also showed higher bilirubin, total protein and globulin levels compared to those of control cats. At times of peak bacteremia, a decrease in eosinophils and lymphocytes, as well as subsets thereof (B lymphocytes and CD5(+), CD4(+) and CD8(+) T lymphocytes), and an increase in monocytes were particularly significant in the passively immunized cats. In conclusion, passive immunization does not prevent bacteremia and clinical disease following homologous challenge with Mhf, but enhances RBC osmotic fragility and induces a pronounced immune response. PMID- 27496125 TI - Comparison of methods for the identification of microorganisms isolated from blood cultures. AB - BACKGROUND: Bloodstream infections are responsible for thousands of deaths each year. The rapid identification of the microorganisms causing these infections permits correct therapeutic management that will improve the prognosis of the patient. In an attempt to reduce the time spent on this step, microorganism identification devices have been developed, including the VITEK((r)) 2 system, which is currently used in routine clinical microbiology laboratories. METHODS: This study evaluated the accuracy of the VITEK((r)) 2 system in the identification of 400 microorganisms isolated from blood cultures and compared the results to those obtained with conventional phenotypic and genotypic methods. In parallel to the phenotypic identification methods, the DNA of these microorganisms was extracted directly from the blood culture bottles for genotypic identification by the polymerase chain reaction (PCR) and DNA sequencing. RESULTS: The automated VITEK((r)) 2 system correctly identified 94.7 % (379/400) of the isolates. The YST and GN cards resulted in 100 % correct identifications of yeasts (15/15) and Gram-negative bacilli (165/165), respectively. The GP card correctly identified 92.6 % (199/215) of Gram-positive cocci, while the ANC card was unable to correctly identify any Gram-positive bacilli (0/5). CONCLUSIONS: The performance of the VITEK((r)) 2 system was considered acceptable and statistical analysis showed that the system is a suitable option for routine clinical microbiology laboratories to identify different microorganisms. PMID- 27496127 TI - Ultrasonography for the assessment of lung recruitment maneuvers. AB - Lung collapse is a known complication that affects most of the patients undergoing positive pressure mechanical ventilation. Such atelectasis and airways closure lead to gas exchange and lung mechanics impairment and has the potential to develop an inflammatory response in the lungs. These negative effects of lung collapse can be reverted by a lung recruitment maneuver (RM) i.e. a ventilatory strategy that resolves lung collapse by a brief and controlled increment in airway pressures. However, an unsolved question is how to assess such RM at the bedside. The aim of this paper is to describe the usefulness of lung sonography (LUS) to conduct and personalize RM in a real-time way at the bedside. LUS has favorable features to assess lung recruitment due to its high specificity and sensitivity to detect lung collapse together with its non-invasiveness, availability and simple use. PMID- 27496126 TI - The efficacy of Cognitive training in patients with VAsCular Cognitive Impairment, No dEmentia (the Cog-VACCINE study): study protocol for a randomized controlled trial. AB - BACKGROUND: Vascular cognitive impairment, no dementia (VCIND) refers to cognitive deficits associated with underlying vascular causes that fall short of a dementia diagnosis. There is currently no treatment for VCIND. Computerized cognitive training, which has significantly improved cognitive function in healthy older adults and patients with cognitive impairment has not yet been applied to VCIND. METHODS/DESIGN: The proposed study is a three-center, double blinded, randomized controlled trial that will include 60 patients with VCIND. The patients will be randomized to either a training or a control group. The intervention is internet-based cognitive training performed for 30 min over 35 sessions. Neuropsychological assessment and functional and structural MRI will be performed before and after 7 weeks training. Primary outcomes are global cognitive function and executive function. Secondary outcome measures are neuroplasticity changes measured by functional and structural MRI. DISCUSSION: Applying an internet-based, multi-domain, adaptive program, this study aims to assess whether cognitive training improves cognitive abilities and neural plasticity in patients with subcortical VCIND. In addition to the comprehensive assessment of the participants by neuropsychological tests, cerebrovascular risk factors and apolipoprotein E genotyping, neuroplasticity will be used as an evaluation outcome in this study for, to our knowledge, the first time. The combination of functional and structural MRI and neuropsychological tests will have strong sensitivity in evaluating the effects of cognitive training and will also reveal the underlying mechanisms at work. TRIAL REGISTRATION: ClinicalTrials.gov NCT02640716 . Retrospectively registered on 21 December 2015. PMID- 27496128 TI - Genome-wide association study revealed genomic regions related to white/red earlobe color trait in the Rhode Island Red chickens. AB - BACKGROUND: Earlobe color is a naturally and artificially selected trait in chicken. As a head furnishing trait, it has been selected as a breed characteristic. Research has demonstrated that white/red earlobe color was related to at least three loci and sex-linked. However, there has been little work to date to identify the specific genomic regions and genes response to earlobe color in Rhode Island Red chickens. Currently, it is possible to identify the genomic regions responsible for white/red earlobe in Rhode Island Red chicken to eliminate this gap in knowledge by using genome-wide association (GWA) analysis. RESULTS: In the present study, genome-wide association (GWA) analysis was conducted to explore the candidate genomic regions response to chicken earlobe color phenotype. Hens with red dominant and white dominant earlobe was used for case-control analysis by Illumina 600 K SNP arrays. The GWA results showed that 2.38 Mb genomic region (50.13 to 52.51 Mb) with 282 SNPs on chromosome Z were significantly correlated to earlobe color, including sixteen known genes and seven anonymous genes. The sixteen genes were PAM, SLCO4C1, ST8SIA4, FAM174A, CHD1, RGMB, RIOK2, LIX1, LNPEP, SHB, RNF38, TRIM14, NANS, CLTA, GNE, and CPLX1. CONCLUSIONS: The study has revealed the white/red earlobe trait is polygenic and sex-linked in Rhode Island Red chickens. In the genome significant ~2.38 Mb region, twenty-three genes were found and some of them could play critical roles in the formation of white/red earlobe color, especially gene SLCO4C1. Taken together, the candidate genes findings herein can help elucidate the genomic architecture of response to white/red earlobe and provide a new insight on mechanisms underlying earlobe color in Rhode Island Red chickens and other breeds. PMID- 27496129 TI - Five minutes with . . . Jenny Higham, chair of the Medical Schools Council. PMID- 27496130 TI - Incidence and excess mortality of hip fracture in young adults: a nationwide population-based cohort study. AB - BACKGROUND: This study assessed the incidence and excess mortality of hip fractures among inpatients aged 20-40 years in a nationwide population database in Taiwan. METHODS: Subjects were selected from Taiwan's National Health Insurance Research Database for the period 2001-2008 and were followed up until the end of 2010. A total of 4,523 subjects were admitted for the first time with primary diagnosis of hip fracture and treated with operation. RESULTS: The overall annual incidence, mortality, and standardized mortality ratio (SMR) decreased from 7.68 to 7.23 per 100,000, from 1.37 % to 0.94 %, and from 9.06 to 6.71, respectively, from 2001 to 2008. The 1-year, 2-year, 3-year, 5-year, and 10 year mortality rates were 1.28 %, 2.44 %, 3.54 %, 5.32 %, and 10.50 %, respectively for the whole cohort. The 1-year, 2-year, 3-year, 5-year, and 10 year SMRs were 8.33, 7.59, 7.28, 6.39, and 5.82, respectively, for the whole cohort. Risk factors for overall death were male gender, trochanteric fracture, hemiarthroplasty, and higher Charlson comorbidity index (CCI) scores. CONCLUSIONS: The high SMRs found in the present study suggest that young adults with former hip fracture should be closely followed up to prevent early mortality. PMID- 27496131 TI - Occurrence and sequence analysis of porcine deltacoronaviruses in southern China. AB - BACKGROUND: Following the initial isolation of porcine deltacoronavirus (PDCoV) from pigs with diarrheal disease in the United States in 2014, the virus has been detected on swine farms in some provinces of China. To date, little is known about the molecular epidemiology of PDCoV in southern China where major swine production is operated. RESULTS: To investigate the prevalence of PDCoV in this region and compare its activity to other enteric disease of swine caused by porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis coronavirus (TGEV), and porcine rotavirus group C (Rota C), 390 fecal samples were collected from swine of various ages from 15 swine farms with reported diarrhea. Fecal samples were tested by reverse transcription-PCR (RT-PCR) that targeted PDCoV, PEDV, TGEV, and Rota C, respectively. PDCoV was detected exclusively from nursing piglets with an overall prevalence of approximate 1.28 % (5/390), not in suckling and fattening piglets. Interestingly, all of PDCoV-positive samples were from 2015 rather than 2012-2014. Despite a low detection rate, PDCoV emerged in each province/region of southern China. In addition, compared to TGEV (1.54 %, 5/390) or Rota C (1.28 %, 6/390), there were highly detection rates of PEDV (22.6 %, 88/390) in those samples. Notably, all five PDCoV-positive piglets were co infected by PEDV. Furthermore, phylogenetic analysis of spike (S) and nucleocapsid (N) gene sequences of PDCoVs revealed that currently circulating PDCoVs in southern China were more closely related to other Chinese strains of PDCoVs than to those reported in United States, South Korea and Thailand. CONCLUSIONS: This study demonstrated that PDCoV was present in southern China despite the low prevalence, and supported an evolutionary theory of geographical clustering of PDCoVs. PMID- 27496132 TI - Macular choroidal thickness in normal Egyptians measured by swept source optical coherence tomography. AB - BACKGROUND: To provide a normal database of choroidal thickness (CT) in nine Early Treatment Diabetes Retinopathy Study (ETDRS) subfields in Egypt using deep range imaging swept source optical coherence tomography (DRI SS OCT). METHODS: This study included a total of 129 eyes of 71 normal Egyptian subjects, comprising 63 males and 66 females. The mean age was 36.85 +/- 14.22 years (range, 16-67 years). The mean axial length was 23.84 +/- 0.78 mm. CT was measured in nine subfields as defined by the ETDRS-style grid using a DRI SS OCT, and line measurements of subfoveal choroidal thicknesses (SFCT) were also performed. RESULTS: Mean SFCT was 300.87 +/- 72.256 MUm for ring measurements and 319.72 +/- 76.45 MUm for line measurements (P = 0.04). CT was higher in the superior and temporal quadrants than the inferior and nasal quadrants. A negative correlation between subfoveal choroidal thickness and age was detected in all regions (P < 0.001) except the nasal quadrant. A negative correlation between the SFCT and axial length was also detected (P < 0.001). Males tended to have a thicker choroid than females; however, the difference was not significant. CONCLUSIONS: DRI SS OCT provides a topographic map of choroidal thickness with an ETDRS layout. This study establishes, for the first time, a normal database for CT in the Egyptian population. Age and axial length were associated with choroidal parameters in healthy subjects. Line measurements of the SFCT differed significantly from SFCT ring measurements, so it is recommended that each method be compared independently. PMID- 27496133 TI - Barasertib (AZD1152), a Small Molecule Aurora B Inhibitor, Inhibits the Growth of SCLC Cell Lines In Vitro and In Vivo. AB - Small-cell lung cancer (SCLC) cells have rapid proliferation, universal Rb inactivation, and high rates of MYC family amplification, making aurora kinase inhibition a natural target. Preclinical studies have demonstrated activity for Aurora A and pan-Aurora inhibitors with some relationship to MYC family expression. A clinical trial showed activity for an Aurora kinase A inhibitor, but no biomarkers were evaluated. We screened a panel of 23 SCLC lines with and without MYC family gene amplification or high MYC family gene expression for growth inhibition by the highly potent, selective aurora kinase B inhibitor barasertib. Nine of the SCLC lines were very sensitive to growth inhibition by barasertib, with IC50 values of <50 nmol/L and >75% growth inhibition at 100 nmol/L. Growth inhibition correlated with cMYC amplification (P = 0.018) and cMYC gene expression (P = 0.026). Sensitive cell lines were also enriched in a published MYC gene signature (P = 0.042). In vivo, barasertib inhibited the growth of xenografts established from an SCLC line that had high cMYC gene expression, no cMYC amplification, and was positive for the core MYC gene signature. Our studies suggest that SCLC tumors with cMYC amplification/high gene expression will frequently respond to Aurora B inhibitors and that clinical studies coupled with predictive biomarkers are indicated. Mol Cancer Ther; 15(10); 2314-22. (c)2016 AACR. PMID- 27496134 TI - Preclinical Modeling of KIF5B-RET Fusion Lung Adenocarcinoma. AB - RET fusions have been found in lung adenocarcinoma, of which KIF5B-RET is the most prevalent. We established inducible KIF5B-RET transgenic mice and KIF5B-RET dependent cell lines for preclinical modeling of KIF5B-RET-associated lung adenocarcinoma. Doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET transgenic mice developed invasive lung adenocarcinoma with desmoplastic reaction. Tumors regressed upon suppression of KIF5B-RET expression. By culturing KIF5B-RET dependent BaF3 (B/KR) cells with increasing concentrations of cabozantinib or vandetanib, we identified cabozantinib-resistant RETV804L mutation and vandetanib resistant-RETG810A mutation. Among cabozantinib, lenvatinib, ponatinib, and vandetanib, ponatinib was identified as the most potent inhibitor against KIF5B RET and its drug-resistant mutants. Interestingly, the vandetanib-resistant KIF5B RETG810A mutant displayed gain-of-sensitivity (GOS) to ponatinib and lenvatinib. Treatment of doxycycline-induced CCSP-rtTA/tetO-KIF5B-RET bitransgenic mice with ponatinib effectively induced tumor regression. These results indicate that KIF5B RET-associated lung tumors are addicted to the fusion oncogene and ponatinib is the most effective inhibitor for targeting KIF5B-RET in lung adenocarcinoma. Moreover, this study finds a novel vandetanib-resistant RETG810A mutation and identifies lenvatinib and ponatinib as the secondary drugs to overcome this vandetanib resistance mechanism. Mol Cancer Ther; 15(10); 2521-9. (c)2016 AACR. PMID- 27496135 TI - Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance. AB - Therapeutically targeting aberrant intracellular kinase signaling is attractive from a biological perspective but drug development is often hindered by toxicities and inadequate efficacy. Predicting drug behaviors using cellular and animal models is confounded by redundant kinase activities, a lack of unique substrates, and cell-specific signaling networks. Cyclin-dependent kinase (CDK) drugs exemplify this phenomenon because they are reported to target common processes yet have distinct clinical activities. Tumor cell studies of ATP competitive CDK drugs (dinaciclib, AG-024322, abemaciclib, palbociclib, ribociclib) indicate similar pharmacology while analyses in untransformed cells illuminates significant differences. To resolve this apparent disconnect, drug behaviors are described at the molecular level. Nonkinase binding studies and kinome interaction analysis (recombinant and endogenous kinases) reveal that proteins outside of the CDK family appear to have little role in dinaciclib/palbociclib/ribociclib pharmacology, may contribute for abemaciclib, and confounds AG-024322 analysis. CDK2 and CDK6 cocrystal structures with the drugs identify the molecular interactions responsible for potency and kinase selectivity. Efficient drug binding to the unique hinge architecture of CDKs enables selectivity toward most of the human kinome. Selectivity between CDK family members is achieved through interactions with nonconserved elements of the ATP-binding pocket. Integrating clinical drug exposures into the analysis predicts that both palbociclib and ribociclib are CDK4/6 inhibitors, abemaciclib inhibits CDK4/6/9, and dinaciclib is a broad-spectrum CDK inhibitor (CDK2/3/4/6/9). Understanding the molecular components of potency and selectivity also facilitates rational design of future generations of kinase-directed drugs. Mol Cancer Ther; 15(10); 2273-81. (c)2016 AACR. PMID- 27496137 TI - Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases. AB - Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell-cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases. Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays. Equipotent effects were observed in BRAF-mutant cells, whereas in KRAS-mutant cells, MEK inhibition required higher concentrations than Aurora kinase inhibition. Daily oral administration of BI 847325 at 10 mg/kg showed efficacy in both BRAF- and KRAS-mutant xenograft models. Biomarker analysis suggested that this effect was primarily due to inhibition of MEK in BRAF-mutant models but of Aurora kinase in KRAS-mutant models. Inhibition of both MEK and Aurora kinase in KRAS-mutant tumors was observed when BI 847325 was administered once weekly at 70 mg/kg. Our studies indicate that BI 847325 is effective in in vitro and in vivo models of cancers with BRAF and KRAS mutation. These preclinical data are discussed in the light of the results of a recently completed clinical phase I trial assessing safety, tolerability, pharmacokinetics, and efficacy of BI 847325 in patients with cancer. Mol Cancer Ther; 15(10); 2388-98. (c)2016 AACR. PMID- 27496136 TI - Single Agent and Synergistic Activity of the "First-in-Class" Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma. AB - Deregulated PI3K/AKT/mTOR, Ras/Raf/MAPK, and c-Myc signaling pathways are of prognostic significance in hepatocellular carcinoma (HCC). Sorafenib, the only drug clinically approved for patients with advanced HCC, blocks the Ras/Raf/MAPK pathway but it does not inhibit the PI3K/AKT/mTOR pathway or c-Myc activation. Hence, there is an unmet medical need to identify potent PI3K/BRD4 inhibitors, which can be used either alone or in combination with sorafenib to treat patients with advanced HCC. Herein, we show that SF1126 (pan PI3K/BRD4 inhibitor) as single agent or in combination with sorafenib inhibited proliferation, cell cycle, apoptosis, and multiple key enzymes in PI3K/AKT/mTOR and Ras/Raf/MAPK pathway in Hep3B, HepG2, SK-Hep1, and Huh7 HCC cell lines. We demonstrate that the active moiety of the SF1126 prodrug LY294002 binds to and blocks BRD4 interaction with the acetylated histone-H4 chromatin mark protein and displaced BRD4 coactivator protein from the transcriptional start site of MYC in Huh7 and SK-Hep1 HCC cell lines. Moreover, SF1126 blocked expression levels of c-Myc in HCC cells. Treatment of SF1126 either alone or in combination with sorafenib showed significant antitumor activity in vivo Our results establish that SF1126 is a dual PI3K/BRD4 inhibitor. This agent has completed a phase I clinical trial in humans with good safety profile. Our data support the potential future consideration of a phase II clinical trial of SF1126, a clinically relevant dual "first-in-class" PI3K/BRD4 inhibitor in advanced HCC, and a potential combination with sorafenib. Mol Cancer Ther; 15(11); 2553-62. (c)2016 AACR. PMID- 27496140 TI - The Impact of Community-Based Supports and Services on Quality of Life Among the Elderly in China: A Longitudinal Study. AB - Community-based supports and services (CBSS) have been developing rapidly in China as a new way of satisfying the needs of elderly people. However, it is not clear how pervasive these services are or whether the availability of CBSS impacts quality of life. This study examines trends in CBSS and the impact of the perceived CBSS availability on self-reported quality of life among the elderly in China. We found a significant increase in perceived CBSS availability from 2005 to 2011, but the perceived availability of CBSS varies by the type of CBSS. Multivariate analyses show that home medical visits (beta = .181, p = .03), psychological support (beta = .332, p = .02), social and recreation activities (beta = .231, p = .02), and legal consulting services (beta = .271, p = .02) were each significantly associated with a good quality of life. Results from this study provide insight that can inform CBSS strategies and the development of new services for the elderly in China. PMID- 27496138 TI - Alterative Expression and Localization of Profilin 1/VASPpS157 and Cofilin 1/VASPpS239 Regulates Metastatic Growth and Is Modified by DHA Supplementation. AB - Profilin 1, cofilin 1, and vasodialator-stimulated phosphoprotein (VASP) are actin-binding proteins (ABP) that regulate actin remodeling and facilitate cancer cell metastases. miR-17-92 is highly expressed in metastatic tumors and profilin1 and cofilin1 are predicted targets. Docosahexaenoic acid (DHA) inhibits cancer cell proliferation and adhesion. These studies tested the hypothesis that the metastatic phenotype is driven by changes in ABPs including alternative phosphorylation and/or changes in subcellular localization. In addition, we tested the efficacy of DHA supplementation to attenuate or inhibit these changes. Human lung cancer tissue sections were analyzed for F-actin content and expression and cellular localization of profilin1, cofilin1, and VASP (S157 or S239 phosphorylation). The metastatic phenotype was investigated in A549 and MLE12 cells lines using 8 Br-cAMP as a metastasis inducer and DHA as a therapeutic agent. Migration was assessed by wound assay and expression measured by Western blot and confocal analysis. miR-17-92 expression was measured by qRT PCR. Results indicated increased expression and altered cellular distribution of profilin1/VASP(pS157), but no changes in cofilin1/VASP(pS239) in the human malignant tissues compared with normal tissues. In A549 and MLE12 cells, the expression patterns of profilin1/VASP(pS157) or cofilin1/VASP(pS239) suggested an interaction in regulation of actin dynamics. Furthermore, DHA inhibited cancer cell migration and viability, ABP expression and cellular localization, and modulated expression of miR-17-92 in A549 cells with minimal effects in MLE12 cells. Further investigations are warranted to understand ABP interactions, changes in cellular localization, regulation by miR-17-92, and DHA as a novel therapeutic. Mol Cancer Ther; 15(9); 2220-31. (c)2016 AACR. PMID- 27496139 TI - Pre-pregnancy obesity and non-adherence to multivitamin use: findings from the National Pregnancy Risk Assessment Monitoring System (2009-2011). AB - BACKGROUND: Although adequate folic acid or multivitamins can prevent up to 70 % of neural tube defects, the majority of U.S. non-pregnant women of childbearing age do not use multivitamins every day. Factors influencing consistent multivitamin use are not fully explored. This study aims to investigate the association between pre-pregnancy body mass index (BMI) and multivitamin use before pregnancy using a large, nationally representative sample of women with recent live births. METHODS: The national 2009-2011 Pregnancy Risk Assessment Monitoring System data were analyzed. The sample included women with recent singleton live births (N = 104,211). The outcome of interest was multivitamin use which was categorized as no multivitamin use, 1-3 times/week, 4-6 times/week, and daily use. Maternal BMI was examined as underweight (<18.50 kg/m(2)), normal weight (18.50-24.99 kg/m(2)), overweight (25.00-29.99 kg/m(2)), and obese (>=30.00 kg/m(2)). Multinomial logistic regression was conducted, and adjusted odds ratios and 95 % confidence intervals were calculated. RESULTS: Compared to women with normal weight, overweight and obese women had significantly increased odds of not taking multivitamins after adjusting for confounding factors. Further, the lack of multivitamin use increased in magnitude with the level of BMI (ORoverweight = 1.2, 95 % CI = 1.1-1.3; ORobese = 1.4, 95 % CI = 1.2-1.5). CONCLUSIONS: Obese and overweight women were less likely to follow the recommendation for preconception multivitamin use compared to normal weight women. All health care professionals must enhance preconception care with particular attention to overweight and obese women. Preconception counseling may be an opportunity to discuss healthy eating and benefits of daily multivitamin intake before pregnancy. PMID- 27496141 TI - Involving Caregivers of People With Dementia to Validate Booklets on Food-Related Activities: A Qualitative Think-Aloud Study. AB - This study is the first to explore informal dementia caregivers' perceptions and outlook on written materials about all food-related processes: shopping, food preparation, and eating. The aim of the study was to develop and evaluate the content, format, and usefulness of two separate booklets (one newly developed and one existing) on food-related processes. Twenty dementia caregivers were provided with one of the two booklets, and a Think-Aloud method was used to gather information about their views on the booklets. The findings indicated that incorporating all three food processes in a new booklet could be beneficial for the participant. Shopping, purchasing food, driving, and dangers in the kitchen were addressed only in the developed booklet, and participants regarded them as important and useful areas to address. Therefore, this study has shown that tailored information may enhance caregivers' confidence and support them in making decisions to help them adapt to food-related changes. PMID- 27496142 TI - The effect of age on relational encoding as revealed by hippocampal functional connectivity. AB - The neural processes mediating cognition occur in networks distributed throughout the brain. The encoding and retrieval of relational memories, memories for multiple items or multifeatural events, is supported by a network of brain regions, particularly the hippocampus. The hippocampal coupling hypothesis suggests that the hippocampus is functionally connected with the default mode network (DMN) during retrieval, but during encoding, decouples from the DMN. Based on prior research suggesting that older adults are less able to modulate between brain network states, we tested the hypothesis that older adults' hippocampus would show functional connectivity with the DMN during relational encoding. The results suggest that, while the hippocampus is functionally connected to some regions of the DMN during relational encoding in both younger and older adults, older adults show additional DMN connectivity. Such age-related changes in network modulation appear not to be mediated by compensatory processes, but rather to reflect a form of neural inefficiency, most likely due to reduced inhibition. PMID- 27496143 TI - A decade of intestinal protozoan epidemiology among settled immigrants in Qatar. AB - BACKGROUND: The World Health Organization estimates that about 3.5 billion people worldwide are affected by intestinal parasitic infections. Reports have already emphasized the role of immigrants in outbreaks of parasitic diseases in industrialized countries. With the mass influx of immigrants to Qatar, patent intestinal parasitic infections have been observed. Herein, the prevalence of intestinal protozoan infections was analysed in 29,286 records of subjects referred for stool examination at the Hamad Medical Corporation over the course of a decade (2005 to 2014, inclusive). RESULTS: Overall prevalence of combined protozoan infections was 5.93 % but there were significant temporal trends, age and sex effects and those arising from the region of origin of the subjects. The most common protozoan was Blastocystis hominis (overall prevalence 3.45 %). Giardia duodenalis, Chilomastix mesnili, Entamoeba coli, Entamoeba hartmanni, Endolimax nana, Iodamoeba butschlii, Entamoeba histolytica/dispar, Cryptosporidium sp. and a single case of Isospora were also detected. The prevalence of combined protozoan infections, G. duodenalis and the non-pathogenic amoebae all declined significantly across the decade. That of B. hominis varied between years but showed no directional trend across years and there was no evidence that prevalence of E. histolyitica/dispar changed significantly. Protozoan infections were observed among all regional groups, but prevalence was higher among subjects from the Arabian Peninsula, Africa and Asia compared to those from the Eastern Mediterranean and Qatar. Prevalence was higher among male subjects in all cases, but age-prevalence profiles differed between the taxa. CONCLUSION: These results offer optimism that prevalence will continue to decline in the years ahead. PMID- 27496144 TI - How old are you, really? Communicating chronic risk through 'effective age' of your body and organs. AB - In communicating chronic risks, there is increasing use of a metaphor that can be termed 'effective-age': the age of a 'healthy' person who has the same risk profile as the individual in question. Popular measures include 'real-age', 'heart-age', 'lung-age' and so on.Here we formally define this concept, and illustrate its use in a variety of areas. We explore conditions under which the years lost or gained that are associated with exposure to risk factors depends neither on current chronological age, nor the period over which the risk is defined. These conditions generally hold for all-cause adult mortality, which enables a simple and vivid translation from hazard-ratios to years lost or gained off chronological age. Finally we consider the attractiveness and impact of this concept.Under reasonable assumptions, the risks associated with specific behaviours can be expressed in terms of years gained or lost off your effective age. The idea of effective age appears a useful and attractive metaphor to vividly communicate risks to individuals. PMID- 27496145 TI - Capsule Commentary on Bodenmann et al., Case Management May Reduce Emergency Department Frequent Use in a Universal Health Coverage System: a Randomized Controlled Trial. PMID- 27496146 TI - Early severe anemia as the first sign of cystic fibrosis. AB - Severe anemia is reported to occur rarely in patients with cystic fibrosis (CF). This study aimed to determine the factors associated with early severe anemia in infants with CF. This study included 231 infants with CF from 3 pediatric CF centers ten year period that were retrospectively reviewed in terms of severe anemia as the first sign of CF. Factors that could affect anemia, such as age, pancreatic insufficiency, mutations, vitamin A and E, and albumin level were evaluated. Clinical and laboratory findings in CF patients that presented with severe anemia and no respiratory symptoms were compared to those in CF patients that did not present with severe anemia. Severe anemia as the first sign of CF was noted in 17 of 231 patients. Patient age, prolonged PT/INR and the albumin level differed significantly between the 2 groups of patients (P < 0.001). Feeding pattern, pancreatic insufficiency, vitamin E and A levels, and the types of genetic mutations did not differ between the 2 groups. The mean hemoglobin level was 5.59 +/- 0.21 g/dL and respiratory symptoms began a mean 6.3 months after diagnosis of CF in the anemia group. CONCLUSION: In early infancy severe anemia in the absence of respiratory symptoms can be the first sign of CF. CF should be considered in the differential diagnosis of severe anemia in infants. Anemia can occur several months before respiratory symptoms in patients with CF and may be caused due to several reasons. WHAT IS KNOWN: * Severe anemia as a first sign is reported to occur rarely in patients with cystic fibrosis. * Although anemia is well known in cystic fibrosis, factors that cause severe anemia are not known clearly. What is New: * This study shows the importance of severe anemia as the first sign of cystic fibrosis. * Anemia can occur several months before respiratory symptoms in patients with CF. PMID- 27496147 TI - Phenylketonuria screening in the Republic of Macedonia. AB - Phenylketonuria is an autosomal recessive inborn error of metabolism which can be prevented by early and continuous treatment. Therefore newborn screening for phenylketonuria has been introduced in many countries. We present here the results of the selective newborn screening for inborn errors of metabolism, including PKU, performed by tandem mass spectrometry which has been introduced in Macedonia since 2011. PMID- 27496148 TI - Cumulative risk of false positive test in relation to breast symptoms in mammography screening: a historical prospective cohort study. AB - Mammography has been found effective as the primary screening test for breast cancer. We estimated the cumulative probability of false positive screening test results with respect to symptom history reported at screen. A historical prospective cohort study was done using individual screening data from 413,611 women aged 50-69 years with 2,627,256 invitations for mammography screening between 1992 and 2012 in Finland. Symptoms (lump, retraction, and secretion) were reported at 56,805 visits, and 48,873 visits resulted in a false positive mammography result. Generalized linear models were used to estimate the probability of at least one false positive test and true positive at screening visits. The estimates were compared among women with and without symptoms history. The estimated cumulative probabilities were 18 and 6 % for false positive and true positive results, respectively. In women with a history of a lump, the cumulative probabilities of false positive test and true positive were 45 and 16 %, respectively, compared to 17 and 5 % with no reported lump. In women with a history of any given symptom, the cumulative probabilities of false positive test and true positive were 38 and 13 %, respectively. Likewise, women with a history of a 'lump and retraction' had the cumulative false positive probability of 56 %. The study showed higher cumulative risk of false positive tests and more cancers detected in women who reported symptoms compared to women who did not report symptoms at screen. The risk varies substantially, depending on symptom types and characteristics. Information on breast symptoms influences the balance of absolute benefits and harms of screening. PMID- 27496149 TI - Randomised, waiting list controlled trial of cognitive-behavioural therapy for persistent postconcussional symptoms after predominantly mild-moderate traumatic brain injury. AB - BACKGROUND: Persistent postconcussional symptoms (PCS) can be a source of distress and disability following traumatic brain injury (TBI). Such symptoms have been viewed as difficult to treat but may be amenable to psychological approaches such as cognitive-behavioural therapy (CBT). OBJECTIVES: To evaluate the effectiveness of a 12-session individualised, formulation-based CBT programme. METHOD: Two-centre randomised waiting list controlled trial with 46 adults with persistent PCS after predominantly mild-to-moderate TBI (52% with post-traumatic amnesia (PTA)<=24 hours), but including some with severe TBIs (20% with PTA>7 days). RESULTS: Improvements associated with CBT were found on the primary outcome measures relating to quality of life (using the Quality of Life Assessment Schedule and the Brain Injury Community Rehabilitation Outcome Scale). Treatment effects after covarying for treatment duration were also found for PCS and several secondary outcomes, including measures of anxiety and fatigue (but not depression or post-traumatic stress disorder (PTSD)). Improvements were more apparent for those completing CBT sessions over a shorter period of time, but were unrelated to medicolegal status, injury severity or length of time since injury. CONCLUSIONS: This study suggests that CBT can improve quality of life for adults with persistent PCS and potentially reduce symptoms for some, in the context of outpatient brain injury rehabilitation services. TRIAL REGISTRATION NUMBER: ISRCTN49540320. PMID- 27496150 TI - Acute blood glucose fluctuation enhances rat aorta endothelial cell apoptosis, oxidative stress and pro-inflammatory cytokine expression in vivo. AB - BACKGROUND: Complications of diabetes mellitus (DM) are related not only to elevated plasma glucose, but also plasma glucose fluctuations. However, the specific mechanism underlying the role of plasma glucose fluctuation in the pathogenesis of DM complications remains poorly understood. In the present study, the influence of acute fluctuant hyperglycemia and persistent hyperglycemia on vascular endothelial cell apoptosis, function, oxidative stress and inflammation was examined in vivo. METHODS: Rats were assigned to three different groups (n = 10/group) that received 48-h infusions of saline (SAL group), continuous 50 % glucose (constant high glucose group [CHG]), or intermittent 50 % glucose (acute blood glucose fluctuation group [AFG]). Plasma 8-isoprostaglandin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) levels were quantified by using enzyme-linked immunosorbent assay (ELISA) commercial kits. Plasma insulin levels were measured by radioimmunoassays (RIAs) using kits. The aortic segment was collected. The levels of malondialdehyde (MDA) and activity of glutathione peroxidase (GSH-PX) were measured in endothelial homogenates prepared from endothelial cells harvested from the aorta using colorimetric kits. Apoptosis of vascular endothelial cells was determined with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Endothelial dysfunction was assessed by isometric tension recording to evaluate the endothelial function. The expression of B cell lymphoma-2 (Bcl-2), Bcl-2 Associated X protein (Bax), pro caspase-3, caspase-3 p17, 3-nitrotyrosine (3-NT) and p47phox protein in rat aortic endothelial cells were tested with Western blot analysis. Endothelial cells reactive oxygen species (ROS) formation was determined using dihydroethidium-dependent fluorescence microtopography in aortic cryo-sections. Expression of IL-6, TNF-alpha and ICAM-1 mRNAs in vascular endothelial cells were determined by real-time quantitative PCR. RESULTS: Endothelial cells apoptosis and dysfunction were observed significantly in the aortas of the AFG group (P < 0.05). The AFG had reduced Bcl-2 and pro caspase-3 levels and enhanced Bax mitochondrial translocation and caspase-3 p17 protein levels in comparison with the CHG group (P < 0.05). Both AFG and CHG induced beta cell dysfunction and insulin resistance (P < 0.05). AFG increased MDA and 8 isoprostaglandin levels in plasma, oxidative stress in vascular endothelial cells, and inflammatory cytokines in plasma and vascular endothelial cells (P < 0.05). CONCLUSION: Acute glucose fluctuation may cause significant oxidative stress and inflammation in endothelial cells, increase the adhesion of monocytes to endothelial cells, and elevate endothelial cell apoptosis, resulting in severe cardiovascular injury. PMID- 27496151 TI - Fetal outcome and recommendations of pregnancies in lupus nephritis in the 21st century. A prospective multicenter study. AB - The aim of this multicenter study was to assess the present risk of fetal complications and the inherent risk factors in pregnant women with lupus nephritis. Seventy-one pregnancies in 61women (59 Caucasians and 2 Asians) with lupus nephritis were prospectively followed between October 2006 and December 2013. All patients received a counselling visit within 3 months before the beginning of pregnancy and were followed by a multidisciplinary team. At baseline mild active nephritis was present in 15 cases (21.1%). Six pregnancies (8.4%) resulted in fetal loss. Arterial hypertension at baseline (P = 0.003), positivity for lupus anticoagulant (P = 0.001), anticardiolipin IgG antibodies (P = 0.007), antibeta2 IgG (P = 0.018) and the triple positivity for antiphospholipid antibodies (P = 0.004) predicted fetal loss. Twenty pregnancies (28.2%) ended pre term and 12 newborns (16.4%) were small for gestational age. Among the characteristics at baseline, high SLE disease activity index (SLEDAI) score (P = 0.027), proteinuria (P = 0.045), history of renal flares (P = 0.004), arterial hypertension (P = 0.009) and active lupus nephritis (P = 0.000) increased the probability of preterm delivery. Odds for preterm delivery increased by 60% for each quarterly unit increase in SLEDAI and by 15% for each quarterly increase in proteinuria by 1 g per day. The probability of having a small for gestational age baby was reduced by 85% in women who received hydroxychloroquine therapy (P = 0.023). In this study, the rate of fetal loss was low and mainly associated with the presence of antiphospholipid antibodies. Preterm delivery remains a frequent complication of pregnancies in lupus. SLE and lupus nephritis activity are the main risk factors for premature birth. Arterial hypertension predicted both fetal loss and preterm delivery. Based on our results the key for a successful pregnancy in lupus nephritis is a multidisciplinary approach with close medical, obstetric and neonatal monitoring. This entails: a) a preconception evaluation to establish and inform women about pregnancy risks; b) planning pregnancy during inactive lupus nephritis, maintained inactive with the lowest possible dosage of allowed drugs; c) adequate treatment of known risk factors (arterial hypertension, antiphospholipid and antibodies); d) close monitoring during and after pregnancy to rapidly identify and treat SLE flares and obstetric complications. PMID- 27496152 TI - Prevention & treatment of obstetrical complications in APS: Is hydroxychloroquine the Holy Grail we are looking for? AB - Pregnancy morbidity is part of the clinical spectrum of the anti-phospholipid syndrome (APS), with an important social and economical cost. Antiplatelet and anticoagulant agents are effective in preventing the clinical manifestations in the majority of the patients. However, a consistent proportion of the pregnant women present recurrences in spite of the standard therapy. Observational studies and anecdotal reports raised the issue of additional therapeutic strategies in these refractory cases. Among these, anti-malarials (AMs) and in particular hydroxychloroquine (HCQ) are becoming more and more popular in APS as well as in other systemic autoimmune rheumatic conditions. AMs display a pleiotropic activity spanning from immunomodulation effect to anti-inflammatory and anti thrombotic activities, all of which potentially useful in APS. The well-known safety of HCQ in pregnancy encouraged its use in pregnant women with autoimmune rheumatic disorders including APS and observational reports suggested a protective effect on obstetrical recurrences. Since thrombosis does not seem to be the main pathogenic mechanism in obstetric APS, effectiveness of the treatment with HCQ should be related to other pharmacological effects rather than to the anti-platelet or anti-thrombotic activity of the molecule. Experimental models showed that HCQ may restore some defective biological functions induced by anti phospholipid antibodies (aPL) on trophoblasts and a recent study reported a protective effect on in vivo aPL-mediated placental and foetal neurodevelopmental abnormalities. Although the rational behind the use of HCQ in obstetric APS is sound, the evidence from the real life is not conclusive and a critical appraisal through clinical trials is mandatory. PMID- 27496153 TI - The 2014 primary health care reform in Poland: Short-term fixes instead of a long term strategy. AB - At the end of 2013, the Minister of Health started legislative changes directly and indirectly affecting primary health care (PHC). The reforms were widely criticised among certain groups of medical professionals, including family medicine physicians. The latter mainly criticised the formal inclusion of specialists in internal diseases and paediatrics into PHC within the statutory health care system, which in practice meant that these two groups of specialists were no longer required to specialize in family medicine from 2017 in order to enter into contracts with the public payer and would be able to set up solo PHC practices-something over which family medicine physicians used to have a monopoly. They argued that paediatricians and internists did not have the necessary professional competencies to work as PHC physicians and thus assure provision of a comprehensive and coordinated PHC. The government's stance was that the proposed measure was necessary to assure the future provision of PHC, given the shortage of specialists in family medicine. Certain groups of medical professionals were also supportive of the proposed change. The key argument in favour was that it could improve access to PHC, especially for children. However, while this was not the subject of the critique or even a policy debate, the proposal ignored the increasing health care needs of older patients-the key recipients of PHC services. The policy was passed in the Parliament in March April 2014 without a dialogue with the key stakeholders, which is typical of health care (and other) reforms in Poland. The strong opposition against the reform from the family medicine specialists, represented by two strong organisations, may jeopardise the policy implementation in the future. PMID- 27496154 TI - Physician density planning in a public healthcare system: Complexities, threats and opportunities-The case of the Israeli healthcare system. AB - Human-resource planning in healthcare is one of the most significant challenges that healthcare systems worldwide face. Among all healthcare professions, the planning of physician supply is the most complex of all due to physicians' lengthy training and many specialties. Forecasts showing a disturbing downward trend in the ratio of physicians to population in Israel prompted the Israeli Government in 2010 to establish a committee mandated to predict demand for physicians and recommend steps to adjust supply to it. The committee analyzed numerous variables that affect physician supply and demand and recommended measures that in greater part were implemented. The article discusses the methodology of the committee, its recommendations, and their implementation such as a 52% increase in the number of first-year medical students between 2010 and 2012. Its analysis of the current situation shows that the implementation of the recommendations successfully stemmed the decrease in physician density and attained the committee's other long-term objectives: physician density of 2.9 per 1000 of population and an increase (32.5%) in the number of physicians who began training in targeted specialties. PMID- 27496155 TI - What drives public health care expenditure growth? Evidence from Swiss cantons, 1970-2012. AB - A better understanding of the determinants of public health care expenditures is key to designing effective health policies. We integrate demand and supply-side determinants and factors from political economy into an empirical analysis of the highly decentralized Swiss health care system and control for major health care finance reforms. We compile a novel data set of the cantonal health care expenditure in Switzerland, which currently amounts to about one fifth of total health care expenditure. We analyze the period 1970-2012 and use dynamic panel estimation methods. We find that per capita income, the unemployment rate and the share of foreigners are positively related to public health care expenditure growth. With regard to political economy aspects, public health care expenditures increase with the share of women elected to parliament. However, institutional restrictions for politicians, such as fiscal rules, do not appear to limit public health care expenditure growth. PMID- 27496156 TI - Introducing Diagnosis-Related Groups in Kazakhstan: Evolution, achievements, and challenges. AB - In 2012, Kazakhstan introduced Diagnosis-Related Groups (DRGs), as part of a package of reforms which sought to contain costs and to improve efficiency and transparency in the health system; but the main challenge was to design and implement a DRG system in just one year. In 2011-2012, Kazakhstan developed its own DRG system. Initially 180 DRGs were defined to group inpatient cases but this number was subsequently expanded to more than 400. Because of time limits, the cost weights had to be derived in the absence of existing standard hospital cost accounting systems, and a national patient data transfer system also needed developing. Most importantly, huge efforts were needed to develop a regulatory framework and build up DRG capabilities at a national level. The implementation of DRGs was facilitated by strong political will for their introduction as part of a coherent package of health reforms, and consolidated efforts to build capacity. DRGs are now the key payment mechanism for hospitals. However the reforms are not fully institutionalized: the DRG structure is continuously being refined in a context of data limitations, and the revision of cost weights is most affected by insufficient data and the lack of standardized reporting mechanisms. Capacity around DRG coding is also still being developed. Countries planning to introduce DRG systems should be aware of the challenges in moving too quickly to implement DRGs as the main hospital reimbursement mechanism. PMID- 27496157 TI - Learning game for training child bicyclists' situation awareness. AB - Encouraging more children to bicycle would produce both environmental and health benefits, but bicycling accidents are a major source of injuries and fatalities among children. One reason for this may be children's less developed hazard perception skills. We assume that children's situation awareness could be trained with a computer based learning game, which should also improve their hazard perception skills. In this paper, we present a prototype for such a game and pilot it with 8-9year old children. The game consisted of videos filmed from a bicyclist's perspective. Using a touchscreen, the player's task was to point out targets early enough to gain points. The targets were either overt (other visible road users on a potentially conflicting course) or covert (occlusions, i.e. locations where other road users could suddenly emerge). If a target was missed or identified too late, the video was paused and feedback was given. The game was tested with 49 children from the 2nd grade of primary school (aged 8-9). 31 young adults (aged 22-34) played the game for comparison. The effect of the game on situation awareness was assessed with situation awareness tests in a crossover design. Similar videos were used in the tests as in the game, but instead of pointing out the targets while watching, the video was suddenly masked and participants were asked to locate all targets which had been present just before the masking, choosing among several possible locations. Their performance was analyzed using Signal Detection Theory and answer latencies. The game decreased answer latency and marginally changed response bias in a less conservative direction for both children and adults, but it did not significantly increase sensitivity for targets. Adults performed better in the tests and in the game, and it was possible to satisfactorily predict group membership based on the scores. Children found it especially difficult to find covert targets. Overall, the described version of the learning game cannot be regarded as an effective tool for situation awareness/hazard perception training, but ways to improve the game are discussed. PMID- 27496158 TI - Attenuation and quantitation of virulence gene expression in quorum-quenched Dickeya chrysanthemi. AB - N-Acyl-homoserine lactones (AHLs)-dependent quorum sensing (QS) system(s) is recruited by the soft rot bacterium Dickeya chrysanthemi for coordinating its social activities such as secretion of plant cell wall-degrading enzymes, while the main signal molecule and quantity dependence of virulence to QS in this bacterium have not been clarified. To do this end, the involvement of AHLs in African violet leaves and potato tuber maceration; swarming motility; pectate lyase and polygalacturonase enzymes production and in planta expression of virulence genes including pelE, pehX and pemA by electroporating two quorum quenching vectors. The expression of two types of AHL-lactonase expressing vector caused dramatic decrease in swarming motility, production of pectinolytic enzymes and macerating of plant tissues. The maximum ability of quenching of QS in repression of D. chrysanthemi virulence was assessed quantitatively by q-RT-PCR, as expression of pelE, pehX and pemA genes were decreased 90.5-92.18 % in quenched cells. We also showed that virulence and pathogenicity of this bacterium was under the control of DHL-dependent QS system and that the existence of second DHL operating system is probable for this bacterium. Thus, this signal molecule would be the key point for future research to design DHL-specific lactonase enzymes using bioinformatics methods. PMID- 27496159 TI - Critical contribution of KV1 channels to the regulation of coronary blood flow. AB - Ion channels in smooth muscle control coronary vascular tone, but the identity of the potassium channels involved requires further investigation. The purpose of this study was to evaluate the functional role of KV1 channels on porcine coronary blood flow using the selective antagonist correolide. KV1 channel gene transcripts were found in porcine coronary arteries, with KCNA5 (encoding KV1.5) being most abundant (P < 0.001). Immunohistochemical staining demonstrated KV1.5 protein in the vascular smooth muscle layer of both porcine and human coronary arteries, including microvessels. Whole-cell patch-clamp experiments demonstrated significant correolide-sensitive (1-10 uM) current in coronary smooth muscle. In vivo studies included direct intracoronary infusion of vehicle or correolide into a pressure-clamped left anterior descending artery of healthy swine (n = 5 in each group) with simultaneous measurement of coronary blood flow. Intracoronary correolide (~0.3-3 uM targeted plasma concentration) had no effect on heart rate or systemic pressure, but reduced coronary blood flow in a dose-dependent manner (P < 0.05). Dobutamine (0.3-10 ug/kg/min) elicited coronary metabolic vasodilation and intracoronary correolide (3 uM) significantly reduced coronary blood flow at any given level of myocardial oxygen consumption (P < 0.001). Coronary artery occlusions (15 s) elicited reactive hyperemia and correolide (3 uM) reduced the flow volume repayment by approximately 30 % (P < 0.05). Taken together, these data support a major role for KV1 channels in modulating baseline coronary vascular tone and, perhaps, vasodilation in response to increased metabolism and transient ischemia. PMID- 27496160 TI - Recommendations for authors of manuscripts reporting inhibitor cases developed in previously treated patients with hemophilia: communication from the SSC of the ISTH. AB - Aim The scope of this recommendation is to provide guidance for reporting of inhibitor cases in previously treated patients (PTPs) with hemophilia A. This guidance is intended to improve transparency and completeness of reporting of observed events; it does not cover planning, executing or analyzing original studies aimed at the assessment of inhibitor rates. Recommendation We recommend that for each case of inhibitor development reported in a published paper, a paragraph or a table is included in the main publication reporting as a minimum the underlined data fields in Table . We recommend transparent reporting when any of the suggested information is not available. We recommend that particular care is used in reporting the timeline of events by clearly identifying a reference time-point. We suggest that journals in the field adopt this guidance as instructions for the authors and as a guide for reviewers. Conclusion Development of inhibitors in PTPs is a very rare event. Standardized reporting of inhibitor characteristics will contribute to generating a body of evidence otherwise not available. Case by case reporting of the recommended data elements may shed light on the natural history and risk factors of inhibitor development in PTPs and be useful for tailoring care in similar future cases. PMID- 27496162 TI - Support for indoor tanning policies among young adult women who indoor tan. AB - The purpose of this study to examine support for indoor tanning policies and correlates of policy support among young adult women who indoor tan. Non-Hispanic white women ages 18-30 who indoor tanned in the past year (n = 356, M 23.3 age, SD 3.1) recruited in the Washington, DC area from 2013 to 2016 completed measures of indoor tanning behaviors, attitudes, perceptions, beliefs, and policy support. Most women in the sample supported policies to prevent children under the age of 18 from indoor tanning (74.0 %) and stronger warnings about the risks of indoor tanning on tanning devices (77.6 %); only 10.1 % supported a total ban. In multivariable analyses, support for individual indoor tanning policies varied by demographics (e.g., age), frequent indoor tanning behavior, indoor tanning beliefs, and risk perceptions. Non-Hispanic white young adult women who indoor tan, the primary consumers of indoor tanning, and a high-risk population, largely support indoor tanning prevention policies implemented by many state governments and those currently under review for national enactment. Given low levels of support for a total indoor tanning ban, support for other potential policies (e.g., increasing the minimum age to 21) should be investigated to inform future steps to reduce indoor tanning and the associated health risks. PMID- 27496163 TI - PHE guidance does warn about PSA testing. PMID- 27496161 TI - The relative contribution of climate variability and vector control coverage to changes in malaria parasite prevalence in Zambia 2006-2012. AB - BACKGROUND: Four malaria indicator surveys (MIS) were conducted in Zambia between 2006 and 2012 to evaluate malaria control scale-up. Nationally, coverage of insecticide-treated nets (ITNs) and indoor residual spraying (IRS) increased over this period, while parasite prevalence in children 1-59 months decreased dramatically between 2006 and 2008, but then increased from 2008 to 2010. We assessed the relative effects of vector control coverage and climate variability on malaria parasite prevalence over this period. METHODS: Nationally representative MISs were conducted in April-June of 2006, 2008, 2010 and 2012 to collect household-level information on malaria control interventions such as IRS, ITN ownership and use, and child parasite prevalence by microscopic examination of blood smears. We fitted Bayesian geostatistical models to assess the association between IRS and ITN coverage and climate variability and malaria parasite prevalence. We created predictions of the spatial distribution of malaria prevalence at each time point and compared results of varying IRS, ITN, and climate inputs to assess their relative contributions to changes in prevalence. RESULTS: Nationally, the proportion of households owning an ITN increased from 37.8 % in 2006 to 64.3 % in 2010 and 68.1 % in 2012, with substantial heterogeneity sub-nationally. The population-adjusted predicted child malaria parasite prevalence decreased from 19.6 % in 2006 to 10.4 % in 2008, but rose to 15.3 % in 2010 and 13.5 % in 2012. We estimated that the majority of this prevalence increase at the national level between 2008 and 2010 was due to climate effects on transmission, although there was substantial heterogeneity at the provincial level in the relative contribution of changing climate and ITN availability. We predict that if climate factors preceding the 2010 survey were the same as in 2008, the population-adjusted prevalence would have fallen to 9.9 % nationally. CONCLUSIONS: These results suggest that a combination of climate factors and reduced intervention coverage in parts of the country contributed to both the reduction and rebound in malaria parasite prevalence. Unusual rainfall patterns, perhaps related to moderate El Nino conditions, may have contributed to this variation. Zambia has demonstrated considerable success in scaling up vector control. This analysis highlights the importance of accounting for climate variability when using cross-sectional data for evaluation of malaria control efforts. PMID- 27496164 TI - Stress and Coping Predicts Adjustment and Glycemic Control in Adolescents with Type 1 Diabetes. AB - BACKGROUND: Adolescents with type 1 diabetes are at increased risk for deteriorating glycemic control, poor quality of life, and depressive symptoms. Stress and coping are related to these outcomes in adolescents with diabetes, yet few studies have examined these constructs longitudinally. PURPOSE: This study aimed to describe stress and coping in adolescents with type 1 diabetes and to examine coping strategies as predictors of adolescent adjustment (i.e., depressive symptoms, quality of life) and glycemic control. METHODS: Adolescents with type 1 diabetes completed measures of diabetes-related stress, coping, symptoms of depression, and quality of life at baseline, 6 months, and 12 months. Data on glycemic control were collected from the adolescents' medical charts. RESULTS: The adolescents' use of primary control coping (e.g., problem solving) and secondary control engagement coping (e.g., positive thinking) strategies predicted significantly fewer problems with quality of life and fewer depressive symptoms over time. In contrast, the use of disengagement coping strategies (e.g., avoidance) predicted more problems with quality of life and depressive symptoms. Coping was not a significant predictor of glycemic control. Coping mediated the effects of diabetes-related stress on depressive symptoms and quality of life. CONCLUSIONS: The ways in which adolescents with type 1 diabetes cope with diabetes-related stress predict quality of life and symptoms of depression but not glycemic control. Through the use of screening to identify adolescent's diabetes-related stress and targeted interventions to improve coping strategies, there is potential to improve outcomes. PMID- 27496165 TI - What is the role of radiological testing of lower esophageal sphincter function? AB - Radiological fluoroscopic evaluation remains the primary imaging modality of choice to evaluate patients with swallowing disorders, despite the increasing availability and technical advantages of nonradiological techniques and the current radiological focus on cross-sectional imaging studies, such as computed tomography and magnetic resonance imaging. The radiological swallowing evaluation should be tailored to assess the entire upper gastrointestinal tract, including the lower esophageal sphincter. Fluoroscopy enables the simultaneous assessment of esophageal motility disorders, as well as structural pathologies, including strictures, webs, rings, diverticula, and tumors. Mono- and double-contrast esophagrams and solid bolus tests together allow assessment of lower esophageal sphincter function and complement other methods, such as endoscopy, manometry, or impedance planimetry. Here we review the role of radiological studies for correct assessment of structural and functional pathologies at the level of the lower esophageal sphincter. PMID- 27496167 TI - Standardization of Arterial Stiffness Measurements Make Them Ready for Use in Clinical Practice. PMID- 27496166 TI - The genome-wide role of HSF-1 in the regulation of gene expression in Caenorhabditis elegans. AB - BACKGROUND: The heat shock response, induced by cytoplasmic proteotoxic stress, is one of the most highly conserved transcriptional responses. This response, driven by the heat shock transcription factor HSF1, restores proteostasis through the induction of molecular chaperones and other genes. In addition to stress dependent functions, HSF1 has also been implicated in various stress-independent functions. In C. elegans, the HSF1 homolog HSF-1 is an essential protein that is required to mount a stress-dependent response, as well as to coordinate various stress-independent processes including development, metabolism, and the regulation of lifespan. In this work, we have performed RNA-sequencing for C. elegans cultured in the presence and absence of hsf-1 RNAi followed by treatment with or without heat shock. This experimental design thus allows for the determination of both heat shock-dependent and -independent biological targets of HSF-1 on a genome-wide level. RESULTS: Our results confirm that C. elegans HSF-1 can regulate gene expression in both a stress-dependent and -independent fashion. Almost all genes regulated by HS require HSF-1, reinforcing the central role of this transcription factor in the response to heat stress. As expected, major categories of HSF-1-regulated genes include cytoprotection, development, metabolism, and aging. Within both the heat stress-dependent and -independent gene groups, significant numbers of genes are upregulated as well as downregulated, demonstrating that HSF-1 can both activate and repress gene expression either directly or indirectly. Surprisingly, the cellular process most highly regulated by HSF-1, both with and without heat stress, is cuticle structure. Via network analyses, we identify a nuclear hormone receptor as a common link between genes that are regulated by HSF-1 in a HS-dependent manner, and an epidermal growth factor receptor as a common link between genes that are regulated by HSF-1 in a HS-independent manner. HSF-1 therefore coordinates various physiological processes in C. elegans, and HSF-1 activity may be coordinated across tissues by nuclear hormone receptor and epidermal growth factor receptor signaling. CONCLUSION: This work provides genome-wide HSF-1 regulatory networks in C. elegans that are both heat stress-dependent and independent. We show that HSF-1 is responsible for regulating many genes outside of classical heat stress-responsive genes, including genes involved in development, metabolism, and aging. The findings that a nuclear hormone receptor may coordinate the HS-induced HSF-1 transcriptional response, while an epidermal growth factor receptor may coordinate the HS-independent response, indicate that these factors could promote cell non-autonomous signaling that occurs through HSF 1. Finally, this work highlights the genes involved in cuticle structure as important HSF-1 targets that may play roles in promoting both cytoprotection as well as longevity. PMID- 27496168 TI - Arterial Path Length for Arterial Stiffness: Methodological Consideration. AB - BACKGROUND: Carotid-femoral pulse wave velocity (cfPWV) is the most established measure of central arterial stiffness and is calculated by dividing the distance travelled by the pulse wave by the pulse transit time. However, there is no universally accepted standardized measurement of pulse travel distance for cfPWV. This study sought to assess validity and convertibility of 2 most frequently used travel distance estimations, and create the simple and useful conversion equation to unify cfPWV values obtained with different methodologies for pulse travel distance. METHODS: In a total of 227 adults, cfPWV was calculated using 2 different pulse travel distances: suprasternum-femoral distance minus suprasternum-carotid distance (the subtraction method) and carotid-femoral straight distance * 0.8 (the 80% method). They were compared against 3D arterial tracing via magnetic resonance imaging (MRI). RESULTS: The subtraction method underestimated travel distance and cfPWV by 8.7% although correlations with the MRI reference values were significant. The 80% method provided more reliable cfPWV, showing a stronger linearity (r = 0.96, P < 0.0001) and a better agreement with the MRI-based reference value (+0.02+/-0.54 m/s). Values of cfPWV were influenced primarily by pulse transit time, explaining ~80% of the variation in cfPWV, and the contribution of pulse travel distance was relatively small irrespective of how the travel distance was measured. After the application of the conversion factor (the 80% method = the subtraction method * 1.1), cfPWV values obtained with both methods were strongly correlated and estimation errors were comparable (+0.03+/-0.75 m/s). CONCLUSION: Our findings indicate that the subtraction method and the 80% method can provide equivalent cfPWV values by the application of a simple conversion factor. PMID- 27496169 TI - Modified posteromedial approach for treatment of posterior pilon variant fracture. AB - BACKGROUND: Posterior pilon variant fracture is a recently described posterior malleolus fracture characterized by the involvement of both posterolateral and posteromedial malleolar fragment. The associated surgical approach remains controversial. The aim of this study was to present the application of modified posteromedial approach in the treatment for posterior pilon variant fracture. METHODS: Sixteen patients were identified with posterior pilon variant fractures. All fractures were operated via modified posteromedial approach. Fragment length ratio, area ratio and height were measured as morphologic assessments. The clinical outcome was evaluated with American Orthopaedic Foot & Ankle Society ankle-hind foot score and visual analogue scale. Radiological images were evaluated using osteoarthritis-score. RESULTS: According to the radiological measurements, the average fragment length ratio of posteromedial and posterolateral fragment was 25.3 and 31.5 % respectively. All fractures healed within a mean period of 13.1 weeks without malalignment or articular step-off. Fourteen patients were followed up, and all achieved good or excellent ankle function. The average score of American Orthopaedic Foot & Ankle Society and visual analogue scale at rest, motion and weight bearing walking was 85.6 and 0.25, 0.81, 1.31 respectively. CONCLUSION: Modified posteromedial approach provides an alternative surgical treatment for posterior pilon variant fractures, and the short-term outcome was good. PMID- 27496170 TI - Vaccination against pancreas disease in Atlantic salmon, Salmo salar L., reduces shedding of salmonid alphavirus. AB - Salmon pancreas disease virus, often referred to as salmonid alphavirus (SAV), causes pancreas disease (PD) in European salmonids. SAV transmits horizontally from fish shedding virus into the water and ocean currents are believed to be a main contributor of viral spread between marine farms. Vaccination against PD is previously shown to reduce mortality and severity of clinical PD. In this study, we demonstrate that vaccination against PD significantly reduces viral shedding from infected individuals. The results suggest that PD vaccination can be an important tool to reduce the infection pressure, a known key risk for PD outbreaks at neighbouring farms. PMID- 27496171 TI - Online psychophysics: reaction time effects in cognitive experiments. AB - Using the Internet to acquire behavioral data is currently on the rise. However, very basic questions regarding the feasibility of online psychophysics are still open. Here, we aimed to replicate five well-known paradigms in experimental psychology (Stroop, Flanker, visual search, masked priming, attentional blink) in three settings (classical "lab", "web-in-lab", "web") to account for possible changes in technology and environment. Lab and web-in-lab data were both acquired in an in-lab setting with lab using "Gold Standard" methods, while web-in-lab used web technology. This allowed for a direct comparison of potential differences in acquisition software. To account for additional environmental differences, the web technology experiments were published online to participate from home (setting web), thereby keeping the software and experimental design identical and only changing the environmental setting. Our main results are: First, we found an expected fixed additive timing offset when using web technology (M = 37 ms, SD = 8.14) and recording online (M = 87 ms, SD = 16.04) in comparison to lab data. Second, all task-specific effects were reproduced except for the priming paradigm, which couldn't be replicated in any setting. Third, there were no differences in error rates, which are independent of the timing offset. This finding further supports the assumption of data equality over all settings. Fourth, we found that browser type might be influencing absolute reaction times. Together, these results contribute to the slowly but steadily growing literature that online psychophysics is a suitable complement - or even substitute - to lab data acquisition. PMID- 27496172 TI - "Going to town": Large-scale norming and statistical analysis of 870 American English idioms. AB - An idiom is classically defined as a formulaic sequence whose meaning is comprised of more than the sum of its parts. For this reason, idioms pose a unique problem for models of sentence processing, as researchers must take into account how idioms vary and along what dimensions, as these factors can modulate the ease with which an idiomatic interpretation can be activated. In order to help ensure external validity and comparability across studies, idiom research benefits from the availability of publicly available resources reporting ratings from a large number of native speakers. Resources such as the one outlined in the current paper facilitate opportunities for consensus across studies on idiom processing and help to further our goals as a research community. To this end, descriptive norms were obtained for 870 American English idioms from 2,100 participants along five dimensions: familiarity, meaningfulness, literal plausibility, global decomposability, and predictability. Idiom familiarity and meaningfulness strongly correlated with one another, whereas familiarity and meaningfulness were positively correlated with both global decomposability and predictability. Correlations with previous norming studies are also discussed. PMID- 27496173 TI - Efficient n-gram analysis in R with cmscu. AB - We present a new R package, cmscu, which implements a Count-Min-Sketch with conservative updating (Cormode and Muthukrishnan Journal of Algorithms, 55(1), 58 75, 2005), and its application to n-gram analyses (Goyal et al. 2012). By writing the core implementation in C++ and exposing it to R via Rcpp, we are able to provide a memory-efficient, high-throughput, and easy-to-use library. As a proof of concept, we implemented the computationally challenging (Heafield et al. 2013) modified Kneser-Ney n-gram smoothing algorithm using cmscu as the querying engine. We then explore information density measures (Jaeger Cognitive Psychology, 61(1), 23-62, 2010) from n-gram frequencies (for n=2,3) derived from a corpus of over 2.2 million reviews provided by a Yelp, Inc. dataset. We demonstrate that these text data are at a scale beyond the reach of other more common, more general-purpose libraries available through CRAN. Using the cmscu library and the smoothing implementation, we find a positive relationship between review information density and reader review ratings. We end by highlighting the important use of new efficient tools to explore behavioral phenomena in large, relatively noisy data sets. PMID- 27496174 TI - Trial-by-trial identification of categorization strategy using iterative decision bound modeling. AB - Identifying the strategy that participants use in laboratory experiments is crucial in interpreting the results of behavioral experiments. This article introduces a new modeling procedure called iterative decision-bound modeling (iDBM), which iteratively fits decision-bound models to the trial-by-trial responses generated from single participants in perceptual categorization experiments. The goals of iDBM are to identify: (1) all response strategies used by a participant, (2) changes in response strategy, and (3) the trial number at which each change occurs. The new method is validated by testing its ability to identify the response strategies used in noisy simulated data. The benchmark simulation results show that iDBM is able to detect and identify strategy switches during an experiment and accurately estimate the trial number at which the strategy change occurs in low to moderate noise conditions. The new method is then used to reanalyze data from Ell and Ashby (2006). Applying iDBM revealed that increasing category overlap in an information-integration category learning task increased the proportion of participants who abandoned explicit rules, and reduced the number of training trials needed to abandon rules in favor of a procedural strategy. Finally, we discuss new research questions made possible through iDBM. PMID- 27496176 TI - Factors Associated with Self-Reported Cervical Cancer Screening Among Women Aged 18 Years and Older in the United States. AB - In 2016, an estimated 4120 women will die as a result of cervical cancer. The objective of this study was to examine the factors associated with cervical cancer screening among women 18 years of age and older in the United States (U.S.). Using the 2012 Behavioral Risk Factor Surveillance System survey, women over the age of 18 in the U.S. were examined to assess factors associated with cervical cancer screening. Analyses were conducted using SAS 9.2. Of the 272,692 study participants, 258,496 (95 %) had obtained cervical cancer screening. After adjusting for demographic and socioeconomic factors, being non-Hispanic White, Hispanic or Latino, Asian, Native Hawaiian or Other Pacific Islander, in the age group 18-44 years and 75 years and above, having less than a high school education and an annual household income of less than a $25,000, having never married, and residing in the West region of the U.S. reduced the likelihood of participation in cervical cancer screening. Also, after adjusting for demographic and socioeconomic factors, being between the ages of 45-74 years of age, having more than a high school education, having a higher income, and residing in the South region of the U.S. increased the likelihood of participation in cervical cancer screening. The results of this study suggest that socio-demographic factors and region of residence are predictors of cervical cancer screening. These findings highlight the need to identify potential prevention strategies to promote cervical cancer screening among at-risk populations and groups. PMID- 27496175 TI - Functional prediction of differentially expressed lncRNAs in HSV-1 infected human foreskin fibroblasts. AB - BACKGROUND: One of the most important functions of long noncoding RNAs (lncRNAs) is to control protein coding gene transcription by acting locally in cis, or remotely in trans. Herpes Simplex Virus type I (HSV-1) latently infects over 80 % of the population, its reactivation from latency usually results in productive infections in human epithelial cells, and is responsible for the common cold sores and genital Herpes. HSV-1 productive infection leads to profound changes in the host cells, including the host transcriptome. However, how genome wide lncRNAs expressions are affected by the infection and how lncRNAs expression relates to protein coding gene expression have not been analyzed. METHODS: We analyzed differentially expressed lncRNAs and their potential targets from RNA seq data in HSV-1 infected human foreskin fibroblast (HFF) cells. Based on correlations of expression patterns of differentially expressed protein-coding genes and lncRNAs, we predicted that these lncRNAs may regulate, either in cis or in trans, the expression of many cellular protein-coding genes. RESULTS: Here we analyzed HSV-1 infection induced, differentially expressed lncRNAs and predicted their target genes. We detected 208 annotated and 206 novel differentially expressed lncRNAs. Gene Ontology and Pathway enrichment analyses revealed potential lncRNA targets, including genes in chromatin assembly, genes in neuronal development and neurodegenerative diseases and genes in the immune response, such as Toll-like receptor signaling and RIG-I-like receptor signaling pathways. CONCLUSIONS: We found that differentially expressed lncRNAs may regulate the expression of many cellular protein-coding genes involved in pathways from native immunity to neuronal development, thus revealing important roles of lncRNAs in the regulation of host transcriptional programs in HSV-1 infected human cells. PMID- 27496177 TI - Pregnancy complications in singleton pregnancies with isolated fetal heart defects. AB - INTRODUCTION: As the prenatal detection rates of congenital heart defects (CHDs) increase, obstetricians are more frequently faced with pregnancies complicated by a fetal CHD. Congenital anomalies in general are associated with preterm birth and fetal demise. The aim of this study was to gain insight into the prevalence of preterm birth and fetal demise in singleton pregnancies with fetuses with isolated CHDs. MATERIAL AND METHODS: A geographical cohort study was performed in a large region in the Netherlands. Fetuses and infants from singleton pregnancies diagnosed with severe isolated CHD, born between 1 January 2002 and 1 January 2012, were included. All cases in the CHD cohort were assessed for preterm birth or fetal demise. The proportions of preterm birth and fetal demise were compared with those in a control group and odds ratios were calculated. RESULTS: The proportion of preterm births in the CHD cohort (n = 1013) was 9.1% (95% CI 7.3 10.9) compared with 5.6% (95% CI 5.4-5.8) in the control group, with an odds ratio of 1.7 (95% CI 1.4-2.1). The preterm birth started spontaneously in 49.5% and 38.4% were induced. In 15 cases fetal demise occurred (1.5%; 95% CI 0.8-2.2), compared with 0.7% (95% CI 0.6-0.8) in the control group, odds ratio 2.0 (95% CI 1.2-3.4). CONCLUSIONS: Higher rates of preterm birth and fetal demise occur in fetuses with isolated CHD compared with the general population. Prenatal specialists should be vigilant for signs of heart failure, premature closure of the foramen ovale or fetal distress in fetuses with isolated CHDs. PMID- 27496179 TI - Using Genetically Encodable Self-Assembling Gd(III) Spin Labels To Make In-Cell Nanometric Distance Measurements. AB - Double electron-electron resonance (DEER) can be used to study the structure of a protein in its native cellular environment. Until now, this has required isolation, in vitro labeling, and reintroduction of the protein back into the cells. We describe a completely biosynthetic approach that avoids these steps. It exploits genetically encodable lanthanide-binding tags (LBT) to form self assembling Gd(III) metal-based spin labels and enables direct in-cell measurements. This approach is demonstrated using a pair of LBTs encoded one at each end of a 3-helix bundle expressed in E. coli grown on Gd(III) -supplemented medium. DEER measurements directly on these cells produced readily detectable time traces from which the distance between the Gd(III) labels could be determined. This work is the first to use biosynthetically produced self assembling metal-containing spin labels for non-disruptive in-cell structural measurements. PMID- 27496178 TI - A unified approach towards Trypanosoma brucei functional genomics using Gibson assembly. AB - Trypanosoma brucei is the causative agent of human African trypanosomiasis and nagana in cattle. Recent advances in high throughput phenotypic and interaction screens have identified a wealth of novel candidate proteins for diverse functions such as drug resistance, life cycle progression, and cytoskeletal biogenesis. Characterization of these proteins will allow a more mechanistic understanding of the biology of this important pathogen and could identify novel drug targets. However, methods for rapidly validating and prioritizing these potential targets are still being developed. While gene tagging via homologous recombination and RNA interference are available in T. brucei, a general strategy for creating the most effective constructs for these approaches is lacking. Here, we adapt Gibson assembly, a one-step isothermal process that rapidly assembles multiple DNA segments in a single reaction, to create endogenous tagging, overexpression, and long hairpin RNAi constructs that are compatible with well established T. brucei vectors. The generality of the Gibson approach has several advantages over current methodologies and substantially increases the speed and ease with which these constructs can be assembled. PMID- 27496181 TI - Myeloma bone disease: Progress in pathogenesis. AB - Myeloma bone disease (MBD) is one of the most serious complications of multiple myeloma (MM) and the most severe cause of MM morbidity. Dysregulation of osteoblast and osteoclast cells plays key roles in MBD. In the bone marrow microenvironment, myeloma cells, osteoblasts, osteoclasts and bone marrow stromal cells can secrete multiple cytokines, categorized as osteoclast cell activating factors (OAFs) and osteoblast cell inactivating factors, which have been discovered to participate in bone metabolism and contribute to the pathogenesis of MBD. Several signaling pathways related to these cytokines were also revealed in the MBD pathogenesis. To better understand the pathogenesis of MBD and therefore the potential therapeutic targets of this disease, we will summarize recent study progress in the factors and underlying signaling pathways involved in the occurrence and development of MBD. PMID- 27496182 TI - Iris Krass. PMID- 27496180 TI - Design and protocol for the Focusing on Clozapine Unresponsive Symptoms (FOCUS) trial: a randomised controlled trial. AB - BACKGROUND: For around a third of people with a diagnosis of schizophrenia, the condition proves to respond poorly to treatment with many typical and atypical antipsychotics. This is commonly referred to as treatment-resistant schizophrenia. Clozapine is the only antipsychotic with convincing efficacy for people whose symptoms are considered treatment-resistant to antipsychotic medication. However, 30-40 % of such conditions will have an insufficient response to the drug. Cognitive behavioural therapy has been shown to be an effective treatment for schizophrenia when delivered in combination with antipsychotic medication, with several meta-analyses showing robust support for this approach. However, the evidence for the effectiveness of cognitive behavioural therapy for people with a schizophrenia diagnosis whose symptoms are treatment-resistant to antipsychotic medication is limited. There is a clinical and economic need to evaluate treatments to improve outcomes for people with such conditions. METHODS/DESIGN: A parallel group, prospective randomised, open, blinded evaluation of outcomes design will be used to compare a standardised cognitive behavioural therapy intervention added to treatment as usual versus treatment as usual alone (the comparator group) for individuals with a diagnosis of schizophrenia for whom an adequate trial of clozapine has either not been possible due to tolerability problems or was not associated with a sufficient therapeutic response. The trial will be conducted across five sites in the United Kingdom. DISCUSSION: The recruitment target of 485 was achieved, with a final recruitment total of 487. This trial is the largest definitive, pragmatic clinical and cost-effectiveness trial of cognitive behavioural therapy for people with schizophrenia whose symptoms have failed to show an adequate response to clozapine treatment. Using a prognostic risk model, baseline information will be used to explore whether there are identifiable subgroups for which the treatment effect is greatest. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99672552 . Registered 29(th) November 2012. PMID- 27496183 TI - The importance of n-6/n-3 fatty acids ratio in the major depressive disorder. AB - This review aims to clarify the relation between the ratio of omega-6 to omega-3 fatty acids and the development of depression. It is explained how these fatty acids are involved in the production of eicosanoids and how these fatty acids can affect the membrane fluidity, by their incorporation into membrane phospholipids. In addition, it is described how omega-3 derivatives are shown to regulate gene transcription. In view of the pathophysiology of depression, the mechanisms of how an altered ratio of omega-6 to omega-3 could be involved in depression are discussed. Possible mechanisms could include an increased production of pro inflammatory cytokines, which can activate the HPA axis and a changed membrane fluidity, which potentially affects membrane bound enzymes, ion channels, receptor activity and neurotransmitter binding. In view of clinical trials, it is also discussed whether omega-3 supplementation could have a beneficial effect in the treatment of depressive patient. There are strong indications that an increased ratio of membrane omega-6 to omega-3 is involved in the pathogenesis of depression and so far, omega-3 supplementation has shown positive effects in clinical trials. PMID- 27496184 TI - Multiplicity of effects and health benefits of resveratrol. AB - Resveratrol is mainly found in grapes and red wine, also in some plants and fruits, such as peanuts, cranberries, pistachios, blueberries and bilberries. Moreover, nowadays this compound is available as purified preparation and dietary supplement. Resveratrol provides a wide range of benefits, including cardiovascular protective, antiplatelet, antioxidant, anti-inflammatory, blood glucose-lowering and anticancer activities, hence it exhibits a complex mode of action. During the recent years, these properties have been widely studied in animal and human models, both in vitro and in vivo. This paper is intended to present information published during the recent years on the biological activities and multiple effects of resveratrol. PMID- 27496185 TI - Association between clinical parameters and ST-segment resolution after primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate and compare various parameters between complete and incomplete ST-segment resolution (STR) patients' groups and to identify associates of STR in patients with acute ST segment elevation myocardial infarction (STEMI) after primary percutaneous coronary intervention (PPCI) (primary outcome). MATERIALS AND METHODS: A total of 203 consecutive patients were divided into two groups according to the degree of STR: <70% (incomplete) and >=70% (complete resolution) 5-15min after the PPCI. The cardiovascular risk factors, sex, Killip class, Thrombolysis in Myocardial Infarction (TIMI) flow, symptom-onset-to-balloon time and door-to-balloon time, and adverse cardiovascular events (secondary outcome) were assessed and compared between two groups. RESULTS: There were 147 patients with incomplete STR and 56 patients with complete STR. Patients with complete STR were younger, had lower Killip class, shorter duration of the chest pain and were less likely to have anterior myocardial infarction (AMI). Patients in the incomplete STR group had longer symptom-onset-to-balloon and door-to-balloon intervals. TIMI3 flow after PPCI was more common in the complete STR group. TIMI flow <=2 after PCI, AMI and symptom onset-to-balloon time were inversely associated with STR (beta coefficients -28.635, -28.611, and -0.917, respectively). AMI (OR=29.9), symptom onset-to-balloon time (OR=1.7) and patient's age (OR=1.1) were associated with an increased likelihood of having incomplete STR. CONCLUSIONS: Patients with complete STR were younger, had lower Killip class, shorter duration of STEMI, were less likely to have AMI, were more likely to recover TIMI3 flow. Age, TIMI flow grade 2 or less after PPCI, AMI and symptom-onset-to-balloon time were associated with STR. PMID- 27496186 TI - Comparison of the Ponseti method versus early tibialis anterior tendon transfer for idiopathic clubfoot: A prospective randomized study. AB - OBJECTIVE: The aim of the study was to compare functional and radiological outcomes in clubfoot patients treated by early Tibialis anterior tendon transfer and Ponseti method. MATERIALS AND METHODS: A prospective, randomized study was conducted. A total of 39 children with a mean age of 17.05 days (55 clubfeet) were randomly allocated into one of two groups: first (conservative Ponseti method) group (n=28) or second (early tibialis anterior tendon transfer [TATT]) group (n=27). Foot function and radiographic measurements were evaluated. The condition of the subjects was observed until they reached the age of 2 years. RESULTS: The clinical and radiological data did not differ between groups at the age of 6 months. No statistically significant difference regarding Pirani and Dimeglio scale among the groups was observed at the last follow-up. A statistically significant difference was observed in the foot dorsal flexion; it was lower in the second group (P=0.03). Other clinical parameters did not differ between groups. According radiographic data, only the talocalcaneal angle (TCA) was significantly higher in the second group (P=0.003). Children who underwent TATT were 5.00-fold (P=0.002) and 1.67-fold (P=0.017) more likely to have TCA larger than 30 degrees (which reflects the normal range of the TCA) in DP and lateral views, respectively, and 3.40-fold (P=0.019) more likely to have foot dorsal flexion of less than 15 degrees than their counterparts undergoing the conservative Ponseti treatment. CONCLUSIONS: Early TATT allowed a significant reduction in the brace wear duration and resulted in the same outcomes as using the Ponseti method. Additionally, TATT can provide some improvement of hindfoot varus. However, a possible weakening of dorsiflexion should be also taken into account. Our experience has shown the need for a larger sample and longer term studies. PMID- 27496188 TI - Genetic linkage studies of a North Carolina macular dystrophy family. AB - BACKGROUND AND OBJECTIVE: North Carolina macular dystrophy (NCMD) is a very rare autosomal dominant hereditary disease. Up to date there are three types of NCMD described and consequently named macular dystrophy, retinal: MCDR1, MCDR2 and MCDR3. The aim of this study was to perform linkage and copy number variation analysis for the family affected by NCMD followed by the selected candidate gene sequencing. MATERIALS AND METHODS: This study concerned a 3-generation, non consanguineous Latvian family with NCMD. Genome-wide scan, copy number variation and non-parametric linkage analysis was performed. Analysis resolved the locus of interest to the 5p15.33 region. Two of the genes, iroquois homeobox 2 (IRX2) and iroquois homeobox 4 (IRX4), were selected and sanger sequencing was performed. RESULTS: Linkage analysis indicated a region on chromosome 5 for the analyzed family, corresponding to a genetic locus previously described for MCDR3 (5p15 p13). Chromosomal aberrations were not identified in the affected family members. An upstream intron variant (NM_001278634: c.-139G > A (rs6876836)) in IRX4 gene segregated with NCMD phenotype in the analyzed family. CONCLUSIONS: It is unlikely to be the causative mutation of NCMD due to its high minor allele frequency 0.3532. Therefore, the role of IRX2 and IRX4 genes in the pathogenesis of NCMD has not been proved. Considerable variability in visual acuity between individuals of the same age group in all the families examined was noted. No overlap between NCMD grade and family generation was seen in the family described in the present study. PMID- 27496187 TI - Pilot study of safety and efficacy of polyprenols in combination with coenzyme Q10 in patients with statin-induced myopathy. AB - BACKGROUND AND OBJECTIVE: Statin-induced myopathy (SIM) has been partially attributed to deficiency of dolichol and coenzyme Q10 (CoQ10). We aimed to test the safety and efficacy of plant polyprenols in combination with CoQ10 for alleviation of SIM. MATERIALS AND METHODS: In an open-label, one-center prospective pilot study patients with SIM received conifer-tree needle polyprenols (4mg/day) and CoQ10 (100mg/day) for 8 weeks. Symptoms and safety were evaluated according to symptom severity score (0-10), creatine kinase (CK) levels, exercise test, dynamometry, complete blood count, clinical biochemistry and electrocardiography. RESULTS: Of the 14 patients, 11 completed the study per protocol. Two patients withdrew consent due to travels abroad, and it was discontinued for one patient with stage 3 chronic kidney disease due to asymptomatic elevations of liver enzymes at week 4. No safety parameters changed significantly in per protocol group. Non-significant increase of CK levels was observed (P=0.231). Muscle pain (n=10) and weakness (n=7) scores improved significantly (P<0.001 and P=0.018, respectively). Muscle pain completely disappeared in 2 patients, weakness resolved in 3 patients and cramps disappeared in two patients. Four patients assessed improvement strong enough to consider increase of statin dose. No changes were observed in exercise test or dynamometry. CONCLUSIONS: Conifer-tree polyprenols in combination with CoQ10 may be generally safe in patients with SIM, but caution should be exercised in patients with glomerular filtration rate <60mL/min and routine monitoring of the liver enzymes and CK is advocated in all patients. The observed efficacy provides the rationale for a larger, double-blind controlled study with polyprenols. PMID- 27496189 TI - BCG-SSI((r)) vaccine-associated lymphadenitis: Incidence and management. AB - BACKGROUND AND OBJECTIVE: There is a high incidence of childhood tuberculosis in Latvia, including children aged less than 1 year, while BCG-associated lymphadenitis is one of the most frequent adverse events requiring surgical treatment. The aim of this study was to analyze the incidence of purulent BCG adenitis through-out the population of Latvia after the introduction of BCG SSI((r)) vaccine and to evaluate the treatment results. MATERIAL AND METHODS: The study included 194 patients. All patients had received the BCG-SSI((r)) vaccine during the first week of life routinely or at a later time according to the indications. The indications for surgical treatment were lymph node destruction also affecting the skin. All patients in this study received surgical treatment - the affected lymph node extirpation. RESULTS: The mean age of the patients was 5.12+/-0.96 months. A total of 172 patients had purulent axillar lymphadenitis, 14 had purulent supraclavicular lymphadenitis, 8 patients had lymphadenitis at both localizations. During the whole study period the incidence of BCG adenitis varied from 0.02% to 0.36%, while the mean rate was 0.11%+/-0.08% from 184,068 vaccinated children during the study period. We observed an increasing trend in the incidence of BCG lymphadenitis during the study period. The primary and complete healing rate at the end of period was 99.5% (n=193) following an affected lymph node extirpation. The mean hospitalization time after the operation was 3.71+/-0.18 days. CONCLUSIONS: The incidence of BCG-SSI((r)) vaccine associated purulent lymphadenitis varied widely with an increasing trend, followed by the return to the product characteristic limits. Indications for the surgical treatment should not be changed. Extirpation of the purulent BCG adenitis is a safe treatment method and leads to the primary wound healing in the majority of cases. PMID- 27496190 TI - Pay for performance of Estonian family doctors and impact of different practice- and patient-related characteristics on a good outcome: A quantitative assessment. AB - BACKGROUND AND OBJECTIVE: Several practice- and patient-related characteristics are reported to have an influence on a good quality outcome. Estonia started the pay-for-performance (P4P) system for family doctors (FDs) in 2006. Every year the number of FDs participating in P4P has increased, but only half of the FDs achieved good outcome. The aim of this study was to find out which practice- and patient-related characteristics could have an impact on a good outcome. MATERIALS AND METHODS: The study was conducted using the database from the Estonian Health Insurance Fund. All working FDs were divided into two groups (with "good" and "poor" outcomes) according their achievements in P4P. We chose characteristics which described structure (practice list size, number of doctors, composition of FDs list: age, number of chronically ill patients) during the observation period 2006-2012. RESULTS: During the observation period 2006-2012, the number of FDs with a good outcome in P4P increased from 6% (2006) to 53% (2012). The high number of FDs in primary care teams, longer experience of participation in P4P and the smaller number of patients on FDs' lists all have an impact on a good outcome. The number of chronically ill patients in FDs lists has no significant effect on an outcome, but P4P increases the number of disease-diagnosed patients. CONCLUSIONS: Different practice and patient-related characteristics have an impact on a good outcome. As workload increases, smaller lists of FDs patients or increased staff levels are needed in order to maintain a good outcome. PMID- 27496191 TI - Problematic computer game use as expression of Internet addiction and its association with self-rated health in the Lithuanian adolescent population. AB - BACKGROUND AND OBJECTIVE: Computers and the Internet have become an integral part of today's life. Problematic gaming is related to adolescent's health. The aim of our study was to evaluate the prevalence of Internet addiction among 13-18-year old schoolchildren and its relation to sex, age, and time spent playing computer games, game type, and subjective health evaluation. MATERIALS AND METHODS: A total of 1806 schoolchildren aged 13-18 years were interviewed. The evaluation of Internet addiction was conducted by the Diagnostic Questionnaire according to Young's methodology. The relation between the choice of computer games type, time spent while playing computer games and respondents' Internet addiction were assessed by using multivariate logistic regression analysis. RESULTS: One-tenth (10.6%) of the boys and 7.7% of the girls aged 13-18 years were Internet addicted. Internet addiction was associated with the type of computer game (action or combat vs. logic) among boys (OR=2.42; 95% CI, 1.03-5.67) and with the amount of time spent playing computer games per day during the last month (>=5 vs. <5h) among girls (OR=2.10; 95% CI, 1.19-3.70). The boys who were addicted to the Internet were more likely to rate their health poorer in comparison to their peers who were not addicted to the Internet (OR=2.48; 95% CI, 1.33-4.62). CONCLUSIONS: Internet addiction was significantly associated with poorer self rated health among boys. PMID- 27496192 TI - Dimethylfumarate induces cell cycle arrest and apoptosis via regulating intracellular redox systems in HeLa cells. AB - Dimethylfumarate (DMF) is cytotoxic to several kinds of cells and serves as an anti-tumor drug. This study was designed to investigate the effects and underlying mechanism of DMF on cervical cancer cells. HeLa cells were cultured and treated with 0, 50, 100, 150, and 200 MUM DMF, respectively. After 24 h, cell growth was evaluated using Cell Counting Kit-8 (CCK-8) assay and the cell cycle was examined using flow cytometry. In addition, cell apoptosis was detected by Annexin V/propidium iodide (PI) staining and the expressions of caspase-3 and poly-ADP-ribose polymerase (PARP) were detected using western blotting. The redox related factors were then assessed. Furthermore, all of the indicators were detected in HeLa cells after combined treatment of DMF and N-acetyl-L-cysteine (NAC, an oxygen-free radical scavenger). The cell number and cell growth of HeLa were obviously inhibited by DMF in a dose-dependent manner, as the cell cycle was arrested at G0/G1 phase (P < 0.05). The apoptotic HeLa cells were markedly increased, and the expression levels of caspase-3 and PARP were significantly increased in a DMF concentration-dependent way (P < 0.05). Meanwhile, loss of ?Psim, increase in reactive oxygen species and O2.-, and the decrease in catalase activity and glutathione (GSH) level were found after DMF treatment (P < 0.05). All these changes were significantly attenuated and even completely disappeared by adding NAC (P < 0.05). In conclusion, the cytotoxicity of DMF on cell proliferation and apoptosis of HeLa cells was mainly related to the intracellular redox systems by depletion of intracellular GSH. PMID- 27496193 TI - Directed differentiation of human embryonic stem cells into keratinocyte progenitors in vitro: an attempt with promise of clinical use. AB - Human embryonic stem cells (hESCs) can differentiate into all somatic lineages including stratified squamous epithelia. Thus, efficient methods are required to direct hESC differentiation to obtain a pure subpopulation for tissue engineering. The study aimed to assess the effects of retinoic acid (RA), bone morphogenetic protein-4 (BMP4), and ascorbic acid (AA) on the differentiation of hESCs into keratinocyte progenitors in vitro. The first media contained AA and BMP4; the second contained RA, AA, and BMP4; the third was commercial-defined keratinocyte serum-free medium, which was used to differentiate H9 hESCs (direct approach) or embryoid bodies (EBs) (indirect approach) into keratinocyte progenitors. Real-time RT-PCR, immunofluorescence, and flow-cytometry were used to characterize the differentiated cells. Cells induced by AA + BMP4 + RA showed the typical epithelial morphology, while cells induced by AA + BMP4 showed multiple appearances. CK14 and p63 messenger RNA (mRNA) expressions in the AA + BMP4 + RA-treated cells were higher than those of the AA + BMP4-treated cells (CK14: 22.4-fold; p63: 84.7-fold). Epithelial marker CK18 mRNA expressions at 14 d of differentiation and keratinocyte marker CK14 and transcription factor p63 mRNA expressions at 35 d of differentiation were higher in cells differentiated from hESCs compared with those differentiated from EBs (CK18 10.51 +/- 3.26 vs. 6.67 +/- 1.28; CK14 9.27 +/- 3.61 vs. 5.32 +/- 1.86; p63 0.73 +/- 0.06 vs. 0.44 +/- 0.12, all P < 0.05) After hESC induction by AA+BMP4+RA, CK14 mRNA expression was upregulated after day 21, peaking by 35 d of differentiation. Combined RA, BMP4, and AA could effectively induce differentiation of hESCs into keratinocyte progenitors in vitro. These keratinocytes could be used for oral mucosa and skin tissue engineering. PMID- 27496194 TI - Murine Flt3 ligand-generated plasmacytoid and conventional dendritic cells display functional differentiation in activation, inflammation, and antigen presentation during BCG infection in vitro. AB - Dendritic cells (DCs) are composed of distinct subsets. Their immunologic functions (especially in pathogenic infection, such as with mycobacteria) are poorly understood, largely because of their rarity and difficulty of preparation. We used the murine Fms-like tyrosine kinase 3 (Flt3) ligand to generate conventional DCs (FL-cDCs) and plasmacytoid DCs (FL-pDCs) and further evaluated their immunological responses to bacillus Calmette-Guerin (BCG) infection in vitro. BCG cells were observed inside both FL-cDCs and FL-pDCs by confocal microscopy, as confirmed by flow cytometric analysis showing a low infection rate of approximately 6 %, which was similar to in vivo results. The CD40, CD80, CD86, and MHC-II proteins were significantly upregulated in both FL-cDCs and -pDCs beginning at 4 h post-BCG exposure. FL-pDCs secreted TNF-alpha and IL-6 earlier and at significantly higher levels in the first 12 h following infection, but demonstrated delayed and weak activation and maturation compared to FL-cDCs. Although both subsets proved capable of presenting a mycobacterial antigen, FL pDCs exhibited weaker activity in this respect than did FL-cDCs. In summary, the existence of FL-generated cDCs and pDCs imply functional differentiation in activation, inflammation, and antigen presentation, although both cells types participated extensively in the immune response to BCG infection. PMID- 27496195 TI - Systematic review and critical appraisal of transitional care programmes in rheumatology. AB - OBJECTIVES: Identify existing models of transitional care in rheumatic and musculoskeletal diseases (RMD), describe their strengths and weaknesses, and provide support to a consensus initiative to develop recommendations for transitional care. METHODS: A systematic review was conducted to identify publications describing transition programmes in RMD. Eligibility for inclusion required detailed description of the programme. Descriptive information was collected, including country of the programme, target diseases and ages of the patients, resources, elements of the transition process and, when described, outcomes and quality indicators. Quality assessment of the programmes included: level of definition and the evidence base for the programme, availability of quality indicators and evidence of effectiveness. RESULTS: Overall, 27 articles were identified and evaluated, related to 8 programmes in 6 countries: 4 covered all RMDs, 3 specific for patients with juvenile idiopathic arthritis (JIA) and 1 programme generic for chronic diseases and adapted for RMD. Core elements of these transition programmes included the following: a written transition policy; patient individualised planning and flexibility of transitional care; designation of transition coordinator role; acquisition of knowledge and skills in self management of care; decision making, shared care and communication between paediatric and adult health care provider teams and a planned transfer to adult rheumatology. Only 2 provided evidence of effectiveness according to previously specified outcome measures. CONCLUSIONS: Transitional care programmes in RMDs are variable in their structures, staffing and processes. There are no standardised measures of outcome or effectiveness. This information provides important valuable insights and strategies to develop transitional care in RMD. PMID- 27496196 TI - Lung adenocarcinoma harboring concomitant SPTBN1-ALK fusion, c-Met overexpression, and HER-2 amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy. AB - Crizotinib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity against mesenchymal-epithelial transition factor (MET) and anaplastic lymphoma kinase (ALK). However, the concomitant oncogenic drivers may affect the sensitivity of crizotinib. Herein, we present a 69-year-old never-smoker Chinese male with advanced lung adenocarcinoma harboring concomitant spectrin beta non erythrocytic 1 (SPTBN1)-ALK fusion, c-Met overexpression, and human epidermal growth factor receptor-2 (HER-2) amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy. Although the patient received timely and comprehensive treatment, the overall survival was only 8 months. Therefore, c Met overexpression, HER-2 gene amplification, and SPTBN1-ALK gene fusion can coexist in lung adenocarcinoma and may become a potential biomarker of cancer refractory to crizotinib, chemotherapy, and radiotherapy as well as of a relatively poor prognosis. In addition, the novel SPTBN1-ALK fusion gene may become a potential target for anti-tumor therapy. PMID- 27496197 TI - Spectrum optimization for computed radiography mammography systems. AB - PURPOSE: Technical quality assurance is a key issue in breast screening protocols. While full-field digital mammography systems produce excellent image quality at low dose, it appears difficult with computed radiography (CR) systems to fulfill the requirements for image quality, and to keep the dose below the limits. However, powder plate CR systems are still widely used, e.g., they represent ~30% of the devices in the Austrian breast cancer screening program. For these systems the selection of an optimal spectrum is a key issue. METHODS: We investigated different anode/filter (A/F) combinations over the clinical range of tube voltages. The figure-of-merit (FOM) to be optimized was squared signal difference-to-noise ratio divided by glandular dose. Measurements were performed on a Siemens Mammomat 3000 with a Fuji Profect reader (SiFu) and on a GE Senograph DMR with a Carestream reader (GECa). RESULTS: For 50mm PMMA the maximum FOM was found with a Mo/Rh spectrum between 27kVp and 29kVp, while with 60mm Mo/Rh at 28kVp (GECa) and W/Rh 25kVp (SiFu) were superior. For 70mm PMMA the Rh/Rh spectrum had a peak at about 31kVp (GECa). FOM increases from 10% to >100% are demonstrated. CONCLUSION: Optimization as proposed in this paper can either lead to dose reduction with comparable image quality or image quality improvement if necessary. For systems with limited A/F combinations the choice of tube voltage is of considerable importance. In this work, optimization of AEC parameters such as anode-filter combination and tube potential was demonstrated for mammographic CR systems. PMID- 27496198 TI - Hepatitis E virus in acute liver failure: An unusual suspect? PMID- 27496199 TI - Foot contact dermatitis: nitrofurazone as the main cause in a retrospective, cross-sectional study over a 16-year period from Turkey. AB - BACKGROUND: The major causative agents in allergic contact dermatitis of the foot may differ from country to country. Sufficient data on foot eczema in patients from Turkey are lacking. OBJECTIVE: To identify the clinically relevant contact allergens in foot eczema and determine the role of patch test series and patients' own materials in the detection of the responsible allergens. METHODS: Among 1753 patients patch tested between 1996 and 2012 in our clinic, 53 with suspected allergic foot eczema were enrolled in this retrospective, cross sectional study. Forty nine patients were patch tested with the extended European baseline series, 49 with supplemental series including rubber, leather, topical drugs, textile, cosmetic series containing preservatives and emulgators and varnish/plastic/glue series, and 37 with their own substances. RESULTS: Thirty of the 53 patch tested patients showing sensitization to at least one clinically relevant allergen were diagnosed with allergic foot eczema. The main eliciting agent was nitrofurazone (n = 8), followed by leather shoe allergens, ie, potassium dichromate (n = 6), p-tert-butylphenol formaldehyde resin and formaldehyde, in the second range. Rubber shoe allergens were less frequently observed (n = 3). In more than 1/3 of the patients, the causative agent could only be identified by testing the patient's own substances and/or supplemental series. CONCLUSION: Nitrofurazone was the leading causative agent followed by leather shoe allergens. Pediatric patients were frequently sensitized with shoe allergens. Patch testing with patient's own substances had a critical value in the detection of the causative agent in a significant number of patients. PMID- 27496200 TI - Occurrence and outcome of de novo metastatic breast cancer by subtype in a large, diverse population. AB - PURPOSE: To examine the occurrence and outcomes of de novo metastatic (Stage IV) breast cancer, particularly with respect to tumor HER2 expression. METHODS: We studied all 6,268 de novo metastatic breast cancer cases diagnosed from 1 January 2005 to 31 December 2011 and reported to the California Cancer Registry. Molecular subtypes were classified according to HER2 and hormone receptor (HR, including estrogen and/or progesterone receptor) expression. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) of Stage IV versus Stage I-III breast cancer; Cox proportional hazards regression was used to assess relative hazard (RH) of mortality. RESULTS: Five percent of invasive breast cancer was metastatic at diagnosis. Compared to patients with earlier stage disease, patients with de novo metastatic disease were significantly more likely to have HER2+ tumors (HR+/HER2+: OR 1.29, 95 % CI 1.17-1.42; HR-/HER2+: OR 1.40, 95 %CI 1.25-1.57, vs. HR+/HER2-). Median survival improved over time, but varied substantially across race/ethnicity (Asians: 34 months; African Americans: 6 months), neighborhood socioeconomic status (SES) (highest: 34 months, lowest: 20 months), and molecular subtype (HR+/HER2+: 45 months; triple negative: 12 months). In a multivariable model, triple negative (RH 2.85, 95 % CI 2.50-3.24) and HR-/HER2+ (RH 1.60, 95 % CI 1.37-1.87) had worse, while HR+/HER2+ had similar, risk of all-cause death compared to HR+/HER2- breast cancer. CONCLUSIONS: De novo metastatic breast cancer was more likely to be HER2+. Among metastatic tumors, those that were HER2+ had better survival than other subtypes. PMID- 27496202 TI - Simple Preparation of Rhodococcus erythropolis DSM 44534 as Biocatalyst to Oxidize Diols into the Optically Active Lactones. AB - In the current study, we present a green toolbox to produce ecological compounds like lactone moiety. Rhodococcus erythropolis DSM 44534 cells have been used to oxidize both decane-1,4-diol () and decane-1,5-diol () into the corresponding gamma- () and delta-decalactones () with yield of 80% and enantiomeric excess (ee) = 75% and ee = 90%, respectively. Among oxidation of meso diols, (-)-(1S,5R) cis-3-oxabicyclo[4.3.0]non-7-en-2-one (5a) with 56% yield and ee = 76% as well as (-)-(2R,3S)-cis-endo-3-oxabicyclo[2.2.1]dec-7-en-2-one (6a) with 100% yield and ee = 90% were formed. It is worth mentioning that R. erythropolis DSM 44534 grew in a mineral medium containing ethanol as the sole source of energy and carbon Chirality 28:623-627, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27496201 TI - Prevalence of adhesin and toxin genes in E. coli strains isolated from diarrheic and non-diarrheic pigs from smallholder herds in northern and eastern Uganda. AB - BACKGROUND: Enterotoxigenic E. coli (ETEC) significantly contribute to diarrhea in piglets and weaners. The smallholder pig producers in Uganda identified diarrhea as one of the major problems especially in piglets. The aim of this study was to; i) characterize the virulence factors of E. coli strains isolated from diarrheic and non-diarrheic suckling piglets and weaners from smallholder herds in northern and eastern Uganda and ii) identify and describe the post mortem picture of ETEC infection in severely diarrheic piglets. Rectal swab samples were collected from 83 piglets and weaners in 20 herds and isolated E. coli were characterized by PCR, serotyping and hemolysis. RESULTS: The E. coli strains carried genes for the heat stable toxins STa, STb and EAST1 and adhesins F4 and AIDA-I. The genes for the heat labile toxin LT and adhesins F5, F6, F18 and F41 were not detected in any of the E. coli isolates. Where the serogroup could be identified, E. coli isolates from the same diarrheic pig belonged to the same serogroup. The prevalence of EAST1, STb, Stx2e, STa, AIDA-I, and F4 in the E. coli isolates from suckling piglets and weaners (diarrheic and non-diarrheic combined) was 29, 26.5, 2.4, 1.2, 16, and 8.4 %, respectively. However the prevalence of F4 and AIDA-I in E. coli from diarrheic suckling piglets alone was 22.2 and 20 %, respectively. There was no significant difference in the prevalence of the individual virulence factors in E. coli from the diarrheic and non-diarrheic pigs (p > 0.05). The main ETEC strains isolated from diarrheic and non-diarrheic pigs included F4/STb/EAST1 (7.2 %), F4/STb (1.2 %), AIDA/STb/EAST1 (8 %) and AIDA/STb (8 %). At post-mortem, two diarrheic suckling piglets carrying ETEC showed intact intestinal villi, enterocytes and brush border but with a layer of cells attached to the brush border, suggestive of ETEC infections. CONCLUSION: This study has shown that the F4 fimbriae is the most predominant in E. coli from diarrheic piglets in the study area and therefore an F4-based vaccine should be considered one of the preventive measures for controlling ETEC infections in the piglets in northern and eastern Uganda. PMID- 27496204 TI - Risk-induced neophobia: does sensory modality matter? AB - Recent studies have documented that exposure to high levels of background risk can induce neophobic predator avoidance in prey animals, whereby they respond to any novel cue with an anti-predator response. Such phenotypically plastic predator avoidance may allow prey to maximize anti-predator benefits in variable risk environments. It remains poorly understood whether risk assessment information from different sensory modalities can be integrated to induce generalized, cross-sensory system neophobic responses. Here, we directly test this hypothesis by exposing juvenile convict cichlids (Amatitlania nigrofasciata) to high- versus low-risk environments using either conspecific alarm cue (chemosensory risk) or a model avian predator (visual/mechanical risk) and testing their response to a novel chemosensory cue (Experiment 1) or visual cue (Experiment 2). Our results suggest that regardless of the sensory modality used to increased perceived risk, cichlids pre-exposed to high-risk conditions exhibited increased predator avoidance in response to any novel visual or chemical cue. As expected, cichlids pre-exposed to low-risk conditions did not display any neophobic responses. Our results suggest that induced neophobia is not cue specific; rather, it may function as a generalized response to perceived predation risk. PMID- 27496203 TI - Hypoxia exposure and B-type natriuretic peptide release from Langendorff heart of rats. AB - AIM: We studied whether available oxygen without induced mechanical stretch regulates the release of the biologically active B-type natriuretic peptide (BNP) from Langendorff heart. METHODS: Rat hearts were isolated and perfused with a physiological Krebs-Henseleit solution at a constant hydrostatic pressure in Langendorff set-up. The basal O2 level of perfusate (24.4 +/- 0.04 mg L-1 ) was gradually lowered to 3.0 +/- 0.01 mg L-1 over 20 min using N2 gas (n = 7). BNP and O2 level were measured from coronary flow. During control perfusions (n = 5), the O2 concentration was kept at 26.6 +/- 0.3 mg L-1 . RESULTS: A low oxygen concentration in the perfusate was associated with a significant increase in BNP release (F = 40.4, P < 0.001). Heart rate decreased when the oxygen concentration in the perfusate reached 9.1 +/- 0.02 mg L-1 and continued to fall in lower oxygen concentrations (F = 14.8, P < 0.001). There was also a significant but inverse correlation between BNP and oxygen in the coronary flow (R2 = 0.27, P < 0.001). CONCLUSION: In the spontaneously beating Langendorff rat heart, a decreasing concentration of oxygen in the ingoing perfusion increased the secretion of BNP. The effect of oxygen was independent of mechanical stretch of the heart as it occurred even when the heart rate decreased but the pressure conditions remained constant. The difference in the oxygen capacitance of blood and Krebs-Henseleit solution appears to be a major factor affecting secretion of BNP, which is correlated with the oxygen tension of myocardial cells and affected both by the oxygen concentration and capacitance of solution perfusing the heart and by the coronary flow. PMID- 27496205 TI - Harbour seals (Phoca vitulina) are able to time precisely. AB - Time along with space is one of the two fundamental dimensions of life. Whereas spatial aspects have been considered in experiments with marine mammals, research has so far not focused on timing per se although it is most likely involved in many behaviours such as foraging or navigation. This study investigated whether harbour seals possess a sense of time and how precisely they are able to discriminate time intervals. Experiments took place in a chamber that allowed keeping ambient illumination constant at 40 lx. The animal was presented with a white circle on a black background on a monitor displayed for a preset time interval. In a two-alternative forced-choice experiment, the animal had to indicate the presence of the standard or a longer comparison time interval by moving its head to one out of two response targets. Time difference thresholds were assessed for various standard intervals between 3 to 30 s adopting a staircase procedure. The experimental animal found access to the task easily and discriminated time intervals with difference thresholds partly in the millisecond range. Thus our study revealed a well-developed sense of time in a pinniped species. Time, besides information provided by the classical senses, is thus most likely an important parameter seals can rely on for various tasks including navigation and foraging. PMID- 27496206 TI - An in silico study of the effect of SOD1 electrostatic loop dynamics on amyloid like filament formation. AB - Superoxide dismutase [Cu-Zn], or SOD1, is a homo-dimeric protein that functions as an antioxidant by scavenging for superoxides. A wide range of SOD1 variants are linked to inherited, or familial, amyotrophic lateral sclerosis, a progressive and fatal neurodegenerative disease. Aberrant SOD1 oligomerization has been strongly implicated in disease causation, even for sporadic ALS, or SALS, which accounts for ~90 % of ALS cases. Small heat shock proteins (sHSP) have been shown to protect against amyloid fibril formation in vitro, and the sHSP alphaB-crystallin suppresses in vitro aggregation of SOD1. We are seeking to elucidate the structural features of both SOD1 amyloid formation and alphaB crystallin amyloid suppression. Specifically, we have used a flexible docking protocol to refine our model of a SOD1 non-obligate tetramer, postulated to function as a transient desolvating complex. Homology modeling and molecular dynamics (MD) are used to supply the missing structural elements of a previously characterized SOD1 amyloid filament, thereby providing a structural analysis for the observed gain of interaction. This completed filament is then further modified using MD to provide a structural model for protofibril capping of SOD1 filaments by alphaB-crystallin. PMID- 27496207 TI - Extended lateral thoracic fasciocutaneous biosynthetic flap for reconstruction of full-thickness partial external ear defects: an experimental study. AB - External ear reconstruction is a controversial topic in reconstructive plastic surgery. Here, we prepared a pedicled biosynthetic flap for full-thickness, partial ear defects in rabbits. We operated on six adult female New Zealand rabbits weighing 3-4 kg. The dimensions of the lateral thoracic fasciocutaneous flap were 7 * 6 cm. The flap was elevated based on one of the bilaterally located internal thoracic arteries, which were dissected proximally. The pedicled flap was folded in two, and polypropylene mesh was sandwiched in the middle. The flap was adapted to a defect of 3.5 * 3 cm in diameter. In fact, the defect was created before elevation of the flap. Rabbits were followed up for 4 weeks, at the end of which they were killed and their ears were evaluated histopathologically. The survival rate of the rabbits was 100 %. All pedicled biosynthetic flaps were viable, but one showed partial (20 %) necrosis (1/6) and one was partially detached (1/6). Macroscopic (color, thickness, texture) and histological (polymorphonuclear leukocyte invasion in the skin, subcutaneous tissue, and at the junction between the polypropylene mesh and the flap) features of the flap were compared to the ipsilateral ear. A new technique was developed for partial external ear reconstruction with sufficient inner skeletal support and outer skin lining. Level of evidence Level NA. PMID- 27496208 TI - Polypropylene mesh for nasal septal perforation repair: an experimental study. AB - The aim of this study is to determine the effectiveness and biocompatibility of polypropylene mesh for the repair of nasal septal perforations in an animal model on rabbits. A full-thickness nasal septal perforation with a diameter of nearly 10 * 10 mm was created on 12 rabbits, and then the perforation was reconstructed with two different methods. We used mucosal flaps and polypropylene mesh as an interpositional graft in group 1. Only mucosal flaps were used for reconstruction and are identified as group 2. After 4 weeks, we removed the nasal septum of the rabbits and performed histopathological examinations for acute rejection, infection, inflammatory response, fibrosis, and granuloma formation. We found perforation closure rates of 75 and 25 % in groups 1 and 2, respectively. Inflammatory response was seen in all specimens of group 1 (100 %). The inflammatory response was +1 in five of the specimens (62.5 %), +2 in one specimen (12.5 %), and +3 in two specimens (25 %). Mild fibrosis around the mesh was detected in four specimens (50 %), medium-level fibrosis was detected in one (12.5 %), and no fibrosis was detected in three (37.5 %). Severe fibrosis was not seen in any specimens. The foreign-body reaction was limited to a few giant cells, and granuloma formation was seen in two specimens (25 %). The propylene mesh showed excellent biocompatibility with the septal mucosa, and it can, therefore, be used for the repair of septal perforation as an interpositional graft safely. PMID- 27496209 TI - Transaxillary gasless endoscopic thyroidectomy versus conventional open thyroidectomy: a randomized study. AB - The objective of this study is to compare the outcomes of transaxillary gasless endoscopic thyroidectomy (TGET) and conventional open thyroidectomy (COT). Thirty three patients with thyroid nodule were enrolled. All patients were randomized into two different groups. Sixteen patients underwent TGET and 17 patients underwent COT. We analyzed the patients' characteristics, wound satisfaction, the intraoperative phase, hospitalization, pain, and costs. The operative time for the TGET group was significantly longer than in the COT group. The estimated blood loss, the hospitalized days, and pain between the two groups were not significantly different. The drainage content was significantly more in the TGET group. The patients' wound satisfaction and mean total cost per case were significantly greater in the TGET group. The TGET provided better cosmetic outcomes and was comparable regarding the estimated blood loss, pain, complication, and hospitalization. However, the TGET required a longer operative time which determines the higher costs. PMID- 27496210 TI - MicroRNA Regulators of Anxiety and Metabolic Disorders. AB - Anxiety-related and metabolic disorders are under intense research focus. Anxiety induced microRNAs (miRNAs) are emerging as regulators that are not only capable of suppressing inflammation but can also induce metabolic syndrome-related processes. We summarize here evidence linking miRNA pathways which share regulatory networks in metabolic and anxiety-related conditions. In particular, miRNAs involved in these disorders include regulators of acetylcholine signaling in the nervous system and their accompanying molecular machinery. These have been associated with anxiety-prone states in individuals, while also acting as inflammatory suppressors. In peripheral tissues, altered miRNA pathways can lead to dysregulated metabolism. Common pathways in metabolic and anxiety-related phenomena might offer an opportunity to reclassify 'healthy' and 'unhealthy', as well as metabolic and anxiety-prone biological states, and inform putative strategies to treat these disorders. PMID- 27496211 TI - Oxazolidinone-based allosteric modulators of mGluR5: Defining molecular switches to create a pharmacological tool box. AB - Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity. This work resulted in the identification of dipyridyl 22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse. PMID- 27496212 TI - Synthesis and biological evaluation of some novel triazole hybrids of curcumin mimics and their selective anticancer activity against breast and prostate cancer cell lines. AB - The anti-cancer property of curcumin, an active component of turmeric, is limited due to its poor solubility, stability and bioavailability. To enhance its efficacy, we designed a novel series of twenty-four monocarbonyl curcumin analogue-1,2,3-triazole conjugates and evaluated their anti-cancer activity towards endocrine related cancers. The new compounds (17-40) were synthesized through CuAAC click reaction and SAR analysis carried out. Out of these all, compound 17 showed most significant anti-cancer activity against prostate cancer cells with IC50 values of 8.8MUM and 9.5MUM in PC-3 and DU-145 cells, respectively. Another compound 26 showed significant anti-cancer activity against breast cancer cells with IC50 of 6MUM, 10MUM and 6.4MUM in MCF-7, MDA-MB-231 and 4T1 cells, respectively while maintaining low toxicity towards non-cancer originated cell line, HEK-293. Compounds 17 and 26 arrested cell cycle and induced mitochondria-mediated apoptosis in cancer cells. Further, both of these compounds significantly down-regulated cell proliferation marker (PCNA), inhibited activation of cell survival protein (Akt phosphorylation), upregulated pro-apoptotic protein (Bax) and down-regulated anti-apoptotic protein (Bcl-2) in their respective cell lines. In addition, in vitro stability, solubility and plasma binding studies of the compounds 17 and 26 showed them to be metabolically stable. Thus, this study identified two new curcumin monocarbonyl-1,2,3-triazole conjugate compounds with more potent activity than curcumin against breast and prostate cancers. PMID- 27496213 TI - Charting the chemical space around the (iso)indoline scaffold, a comprehensive approach towards multitarget directed ligands. AB - Within the framework of orthosteric G protein coupled receptor (GPCR) polypharmacology herein we report the systematic elaboration and thorough evaluation of a data matrix generated by sampling the chemical space around a common 5,6-fused bicyclic heteroaromatic template applying characteristic pharmacophore elements of central nervous system (CNS) relevant aminergic GPCR ligands. PMID- 27496214 TI - Quantitation of Human Cells that Produce Neutrophils and Platelets in Vivo Obtained from Normal Donors Treated with Granulocyte Colony-Stimulating Factor and/or Plerixafor. AB - Plerixafor (P) together with granulocyte colony-stimulating factor (G) is now recognized as an important strategy for mobilizing hematopoietic cells for use in patients given myelosuppressive therapies. However, quantitative comparisons of their ability to mobilize human cells with different hematopoietic activities in vitro or in vivo (in immunodeficient mice) and their interrelationships have not been investigated. To address these questions, we collected samples from 5 normal adult volunteers before and after administering P alone and from another 5 before and after a 4-day course of G and again after a subsequent injection of P. Measurements of their blood content of CD34+ cells, in vitro myeloid colony forming cells, 3- and 6-week long-term culture (LTC) cell outputs, and levels of circulating human platelets, as well as myeloid and lymphoid cells obtained in immunodeficient mice that received transplants, showed all activities were maximal 4 hours after P preceded by G, and 3-week LTC outputs showed the highest concordance with the 3-week circulating human neutrophil levels obtained in mice that received transplants. Thus, human cells capable of producing neutrophils rapidly in vivo were optimally mobilized by the G + P protocol, and the 3-week LTC assay appears to offer a more specific predictor of their levels than conventional CD34+ cell or colony-forming cell counts. PMID- 27496216 TI - HapLogic: A Predictive Human Leukocyte Antigen-Matching Algorithm to Enhance Rapid Identification of the Optimal Unrelated Hematopoietic Stem Cell Sources for Transplantation. AB - The search for a suitable human leukocyte antigen (HLA)-matched unrelated adult stem cell donor (URD) or umbilical cord blood unit (UCB) is a complex process. The National Marrow Donor Program (NMDP) developed a search algorithm known as HapLogic, which is currently provided within the NMDP Traxis application. The HapLogic algorithm has been in use since 2006 and has advanced URD/UCB HLA matching technology. The algorithm has been shown to have high predictive accuracy, which can streamline URD/UCB selection and drive efficiencies in the search process to the benefit of the stem cell transplantation community. Here, we describe the fundamental components of the NMDP matching algorithm, output, validation, and future directions. PMID- 27496217 TI - Impact of Graft-Recipient ABO Compatibility on Outcomes after Umbilical Cord Blood Transplant for Nonmalignant Disease. AB - Existing literature shows mixed conclusions regarding the impact of ABO incompatibility on outcomes after hematopoietic stem cell transplantation. Because the future for umbilical cord blood (UCB) expansion technologies is bright, we assessed whether this typically overlooked graft characteristic impacted various outcomes after UCB transplantation (UCBT) for nonmalignant disorders (NMDs). A prospectively maintained institutional blood and marrow transplant program database was queried for all patients undergoing first UCBT for NMDs. UCB and recipient ABO compatibility was considered as matched, major mismatched, minor mismatched, or bidirectional mismatched. The impact of ABO incompatibility was assessed on overall survival, graft failure, acute and chronic graft-versus-host disease (GVHD), time to neutrophil and platelet recovery, day 0 to day 100 RBC transfusion burden, and donor hematopoietic chimerism. Through December 2014, 270 patients have undergone first UCBT for various NMDs. In both univariable and multivariable analyses, ABO compatibility status did not appear to impact any outcomes assessed, although a trend toward increased grades III to IV acute GVHD was seen in recipients of major mismatched units. When considering UCBT for treatment of NMDs, ABO compatibility between the donor unit and intended recipient does not appear to be an important consideration in the UCB unit choice. PMID- 27496215 TI - Post-Transplant Outcomes in High-Risk Compared with Non-High-Risk Multiple Myeloma: A CIBMTR Analysis. AB - Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (<45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P < .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P < .001) and 72% versus 85% (P < .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM. PMID- 27496218 TI - High Variability in the Reported Management of Hepatic Veno-Occlusive Disease in Children after Hematopoietic Stem Cell Transplantation. AB - Veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). Patients with VOD are often critically ill and require close collaboration between transplant physicians and intensivists. We surveyed members of a consortium of pediatric intensive care unit (PICU) and transplant physicians to assess variability in the self-reported approach to the diagnosis and management of VOD. An internet-based self-administered survey was sent to pediatric HSCT and PICU providers from September 2014 to February 2015. The survey contained questions relating to the diagnosis and treatment of VOD. The response rate was 41% of 382 providers surveyed. We found significant variability in the diagnostic and management approaches to VOD in children. Even though ultrasound is not part of the diagnostic criteria, providers reported using reversal of portal venous flow seen on abdominal ultrasound in addition to Seattle criteria (70%) or Baltimore criteria to make the diagnosis of VOD. Almost 40% of respondents did not diagnose VOD in anicteric patients (bilirubin < 2 mg/dL). Most providers (75%) initiated treatment with defibrotide at the time of diagnosis, but 14%, 7%, and 6% of the providers waited for reversal of portal venous flow, renal dysfunction, or pulmonary dysfunction, respectively, to develop before initiating therapy. Only 50% of the providers restricted fluids to 75% of the daily maintenance, whereas 21% did not restrict fluids at all. Albumin with diuretics was used by 95% of respondents. Platelets counts were maintained at 20,000 to 50,000/mm(3) and 10,000 to 20,000/mm(3) by 64% and 20% of the respondents, respectively. Paracentesis was generally initiated in the setting of oliguria or hypoxia, and nearly 50% of the providers used continuous drainage to gravity, whereas the remainder used an intermittent drainage approach. Nearly 73% of the transplant providers used VOD prophylaxis, whereas the remainder did not use any medications for VOD prophylaxis. There was also considerable variation in the management strategies among the transplant and critical care providers. We conclude that there is considerable self-reported variability in the diagnosis and management of VOD in children. The practice variations reported in this study should encourage the development of standard practice guidelines, which will be helpful in improving the outcome of this potentially fatal complication. PMID- 27496219 TI - Meta-analysis looks at effectiveness of MoodGYM programme in computerised cognitive behavioural therapy. PMID- 27496220 TI - Linear mass scans in quadrupole ion traps using the inverse Mathieu q scan. AB - RATIONALE: Secular frequency scanning is a method of mass selectively scanning ions out of a quadrupole ion trap by linearly ramping the frequency of the resonance ejection signal through ion secular frequencies at constant rf amplitude and frequency. The method is electronically much simpler than resonance ejection but it requires a complex nonlinear calibration procedure to correlate mass-to-charge with time. METHODS: A method of secular frequency scanning in quadrupole ion traps is described in which mass-to-charge is linear with time. This method, termed an "inverse Mathieu q scan", contrasts with linear frequency sweeping which requires a complex nonlinear mass calibration procedure. In the current method, mass scans are forced to be linear with time by scanning the frequency of the supplementary ac so that there is an inverse relationship between the ejected ion's Mathieu q parameter and time. RESULTS: In all cases, excellent mass spectral linearity is observed. The rf amplitude is shown to control both the scan range and the scan rate, whereas the ac amplitude and scan rate influence the mass resolution. The scan rate depends linearly on the rf amplitude, a unique feature of this scan. Although changes in either rf or ac amplitude affect the positions of peaks in time, they do not change the mass calibration procedure since this only requires a simple linear fit of m/z vs time. Space charge effects are shown to give rise to significant changes in resolution as well as to mass shifts. CONCLUSIONS: A method of secular frequency scanning which provides a linear mass scale has been demonstrated. The inverse Mathieu q scan offers a significant increase in mass range and power savings while maintaining access to linearity, paving the way for a mass spectrometer based completely on ac waveforms for ion isolation, ion activation, and ion ejection. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27496221 TI - Albuminuria is not associated with elevated urinary vesicle concentration but can confound nanoparticle tracking analysis. AB - AIM: Extracellular vesicles, such as exosomes, are present in urine with reports of roles in intercellular signalling and diagnostic utility. However, the extent to which the concentration and characteristics of urinary vesicles are altered in albuminuric renal disease has not been well characterized. In this study, we examined the number and characteristics of extracellular vesicles in albuminuric urine. METHODS: Vesicles were isolated from the urine of 32 patients with varying levels of albuminuria using ultracentrifugation and density gradient purification and were examined using nanoparticle tracking analysis, immunoblotting and transmission electron microscopy. The size profile of particles in these urine preparations was compared with albumin-containing solutions. RESULTS: Overall, there were no substantial differences in the number, or characteristics, of vesicles released into proteinuric urine. Analysis of albumin-containing solutions showed particles of exosome-like size, suggesting that such particles can mimic exosomes in standard nanoparticle tracking analysis. Albumin and IgG depletion of proteinuric urine resulted in a substantial reduction in the concentration of particles detected by nanoparticle tracking analysis. CONCLUSION: There was no increase in urinary vesicle concentration in patients with albuminuria. Furthermore, these results demonstrate the need for cautious interpretation of nanoparticle tracking analysis of vesicle concentration in biological fluids containing protein and for sophisticated preparative methods in vesicle purification from urine. PMID- 27496223 TI - Impact of orthognathic surgery on oral health-related quality of life in patients with jaw deformities. AB - The purpose of this study was to clarify the impact of orthognathic surgery on oral health-related quality of life (OHRQOL) in patients with jaw deformities. The subjects were 65 patients (21 males and 44 females) who underwent orthognathic surgery. The mean age of the patients was 23.6 years. Forty-seven patients had skeletal class III malocclusions, eight patients had skeletal class II, and 10 patients had skeletal class I with facial asymmetry and/or open bite. OHRQOL was assessed using the Japanese version of the Oral Health Impact Profile (OHIP-J54) before and 6 months after surgery. While OHIP-J54 scores in the patients before surgery were significantly higher than those in the control subjects, OHIP-J54 scores after surgery were significantly lower than those before surgery. OHIP-J54 scores in older patients were significantly higher than those in younger patients. In conclusion, most patients with jaw deformities have lower OHRQOL than individuals with normal occlusion, and orthognathic surgery has a positive impact on OHRQOL. The determination of OHRQOL in patients with jaw deformities seems to be very useful for understanding the patients' problems and for assessing the extent of changes in terms of patient well-being. PMID- 27496222 TI - Disrupted cooperation between transcription factors across diverse cancer types. AB - BACKGROUND: Transcription Factors (TFs), essential for many cellular processes, generally work coordinately to induce transcriptional change in response to internal and external signals. Disrupted cooperation between TFs, leading to dysregulation of target genes, contributes to the pathogenesis of many diseases, including cancer. Although the aberrant activation of individual TFs and the functional effects have been widely studied, the perturbation of TF cooperativity in cancer has rarely been explored. RESULTS: We used TF co-expression as proxy as cooperativity and performed a large-scale study on disrupted TF cooperation across seven cancer types. While the connectivity of downstream effectors, like metabolic genes and TF targets, were more or similarly disrupted than/with non TFs, the cooperativity of TFs (upstream regulators) were consistently less disturbed in all studied cancer types. Highly coordinated TFs in normal, however, generally lost that cooperation in cancer. Although different types of cancer shared very few TF pairs with highly disrupted cooperation, the cooperativity of interferon regulatory factors (IRF) was highly disrupted in six cancer types. Specifically, the cooperativity of IRF8 was highly perturbed in lung cancer, which was further validated by two independent lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) datasets. More interestingly, the cooperativity of IRF8 was markedly associated with tumor progression and even contributed to the patient survival independent of tumor stage. CONCLUSIONS: Our findings underscore the far more important role of TF cooperativity in tumorigenesis than previously appreciated. Disrupted cooperation of TFs provides potential clinical utility as prognostic markers for predicting the patient survival. PMID- 27496224 TI - Decreased basal insulin secretion from pancreatic islets of pups in a rat model of maternal obesity. AB - Maternal obesity (MO) is a deleterious condition that enhances susceptibility of adult offspring to metabolic diseases such as type 2 diabetes. The objective is to study the effect of MO on in vitro insulin secretion and pancreatic cellular population in offspring. We hypothesize that a harmful antenatal metabolic environment due to MO diminishes the basal glucose-responsive secretory function of pancreatic beta cells in offspring. Mothers were fed a control (C) or high-fat diet from weaning through pregnancy (120 days) and lactation. At postnatal days (PNDs) 36 and 110, pups were killed, peripheral blood was collected and pancreatic islets were isolated. Basal insulin secretion was measured in vitro in islets for 60 min. It was found that blood insulin, glucose and homeostasis model assessment (HOMA) index were unaffected by maternal diet and age in females. However, male MO offspring at PND 110 showed hyperinsulinemia and insulin resistance compared with C. Body weight was not modified by MO, but fat content was higher in MO pups compared with C pups. Triglycerides and leptin concentrations were higher in MO than in C offspring in all groups except in females at PND 36. Pancreatic islet cytoarchitecture was unaffected by MO. At PND 36, islets of male and female C and MO offspring responded similarly to glucose, but at PND 110, male and female MO offspring islets showed a 50% decrease in insulin secretion. It was concluded that MO impairs basal insulin secretion of offspring with a greater impact on males than females, and this effect mainly manifests in adulthood. PMID- 27496225 TI - Disparity in maternal, newborn and child health services in high focus states in India: a district-level cross-sectional analysis. AB - OBJECTIVES: To examine the level and trend in the coverage gap of a set of interventions of maternal and child health services using a summary index and to assess the disparity in usage of maternal and child health services in the districts of high focus states of India. DESIGN: Data for the present study are taken from the Annual Health Survey (AHS), 2010-2013 and Census of India, 2011. SETTINGS: This study used secondary data from states having higher mortality and fertility rates, termed as high focus states in India. PARTICIPANTS: District level information regarding children aged 12-23 months and ever married women aged 15-49 years has been extracted from the AHS (2010-2013), and household amenities, female literacy and main workforce information has been obtained from the Census of India 2011. MEASURES: 2 summary indexes were calculated first for maternal and child health services and another for socioeconomic and development status, using data from AHS and Census. Cronbach's alpha was used to assess the internal consistency of the items used in the index. RESULTS: The result shows that the coverage gap is highest in Uttar Pradesh (37%) and lowest in Madhya Pradesh (21%). Converge gap and socioeconomic development are negatively correlated (r=-0.49, p=0.01). The average coverage gap was highest in the lowest quintile of socioeconomic development. There was an absolute change of 1.5% per year in coverage gap during 2009-2013. In regression analysis, the coefficient of determination was 0.24, beta=-30.05, p=0.01 for a negative relationship between socioeconomic development and coverage gap. CONCLUSIONS: There is a significant disparity in the usage of maternal and child healthcare services in the districts of India. Resource-rich people (urban residents and richest quintile) are way ahead of marginalised people (rural residents and poorest quintile) in the usage of healthcare services. PMID- 27496226 TI - Systematic review of validated case definitions for diabetes in ICD-9-coded and ICD-10-coded data in adult populations. AB - OBJECTIVES: With steady increases in 'big data' and data analytics over the past two decades, administrative health databases have become more accessible and are now used regularly for diabetes surveillance. The objective of this study is to systematically review validated International Classification of Diseases (ICD) based case definitions for diabetes in the adult population. SETTING, PARTICIPANTS AND OUTCOME MEASURES: Electronic databases, MEDLINE and Embase, were searched for validation studies where an administrative case definition (using ICD codes) for diabetes in adults was validated against a reference and statistical measures of the performance reported. RESULTS: The search yielded 2895 abstracts, and of the 193 potentially relevant studies, 16 met criteria. Diabetes definition for adults varied by data source, including physician claims (sensitivity ranged from 26.9% to 97%, specificity ranged from 94.3% to 99.4%, positive predictive value (PPV) ranged from 71.4% to 96.2%, negative predictive value (NPV) ranged from 95% to 99.6% and kappa ranged from 0.8 to 0.9), hospital discharge data (sensitivity ranged from 59.1% to 92.6%, specificity ranged from 95.5% to 99%, PPV ranged from 62.5% to 96%, NPV ranged from 90.8% to 99% and kappa ranged from 0.6 to 0.9) and a combination of both (sensitivity ranged from 57% to 95.6%, specificity ranged from 88% to 98.5%, PPV ranged from 54% to 80%, NPV ranged from 98% to 99.6% and kappa ranged from 0.7 to 0.8). CONCLUSIONS: Overall, administrative health databases are useful for undertaking diabetes surveillance, but an awareness of the variation in performance being affected by case definition is essential. The performance characteristics of these case definitions depend on the variations in the definition of primary diagnosis in ICD-coded discharge data and/or the methodology adopted by the healthcare facility to extract information from patient records. PMID- 27496227 TI - Usage, adherence and attrition: how new mothers engage with a nurse-moderated web based intervention to support maternal and infant health. A 9-month observational study. AB - OBJECTIVES: To identify factors predicting use, adherence and attrition with a nurse-moderated web-based group intervention designed to support mothers of infants aged 0-6 months. DESIGN: 9-Month observational study. SETTING: Community maternal and child health service. PARTICIPANTS: 240 mothers attending initial postnatal health checks at community clinics who were randomly assigned to the intervention arm of a pragmatic preference randomised trial (total randomised controlled trial, n=819; response rate=45%). INTERVENTION: In the first week (phase I), mothers were assisted with their first website login by a research assistant. In weeks 2-7 (phase II), mothers participated in the web-based intervention with an expectation of weekly logins. The web-based intervention was comparable to traditional face-to-face new mothers' groups. During weeks 8-26 (phase III), mothers participated in an extended programme at a frequency of their choosing. PRIMARY OUTCOME MEASURES: Number of logins and posted messages. Standard self-report measures assessed maternal demographic and psychosocial characteristics. RESULTS: In phase II, the median number of logins was 9 logins (IQR=1-25), and in phase III, it was 10 logins (IQR=0-39). Incident risk ratios from multivariable analyses indicated that compared to mothers with the lowest third of logins in phase I, those with the highest third had 6.43 times as many logins in phase II and 7.14 times in phase III. Fifty per cent of mothers logged in at least once every 30 days for 147 days after phase I and 44% logged-in at least once in the last 30 days of the intervention. Frequency of logins during phase I was a stronger predictor of mothers' level of engagement with the intervention than their demographic and psychosocial characteristics. CONCLUSIONS: Mothers' early use of web-based interventions could be employed to customise engagement protocols to the circumstances of individual mothers with the aim of improving adherence and reducing attrition with web-based interventions. TRIAL REGISTRATION NUMBER: ACTRN12613000204741; Results. PMID- 27496228 TI - Exploring unintended consequences of policy initiatives in mental health: the example of Child and Adolescent Mental Health Services (CAMHS) in England. AB - OBJECTIVES: The impact of policy and funding on Child and Adolescent Mental Health Service (CAMHS) activity and capacity, from 2003 to 2012, was assessed. The focus was on preschool children (aged 0-4 years), as current and 2003 policy initiatives stressed the importance of 'early intervention'. SETTINGS: National service capacity from English CAMHS mapping was obtained from 2003 to 2008 inclusive. English Hospital Episode Statistics (HES) for English CAMHS was obtained from 2003 to 2012. The Child and Adolescent Faculty of the Royal College of Psychiatrists surveyed its members about comparative 0-4-year service activity and attitudes in 2012. PARTICIPANTS: CAMHS services in England provided HES and CAMHS mapping data. The Child and Adolescent Faculty of the Royal College of Psychiatrists are child psychiatrists, including trainees. OUTCOME MEASURES: CAMHS mapping data provided national estimates of total numbers of CAMHS patients, whereas HES data counted appointments or episodes of inpatient care. The survey reported on Child Psychiatrists' informal estimates of service activity and attitudes towards children aged 0-4 years. RESULTS: The association between service capacity and service activity was moderated by an interaction between specified funding and age, the youngest children benefiting least from specified funding and suffering most when it was withdrawn (Pr=0.005). Policy review and significant differences between age-specific HES trends (Pr<0.001) suggested this reflected prioritisation of older children. Clinicians were unaware of this effect at local level, though it significantly influenced their attitudes to prioritising this group (Pr=0.02). CONCLUSIONS: If the new policy initiative for CAMHS is to succeed, it will need to have time-limited priorities attached to sustained, specified funding, with planning for limits as well as expansion. Data collection for policy evaluation should include measures of capacity and activity. PMID- 27496229 TI - Semi-individualised Chinese medicine treatment as an adjuvant management for diabetic nephropathy: a pilot add-on, randomised, controlled, multicentre, open label pragmatic clinical trial. AB - INTRODUCTION: Diabetes mellitus and diabetic nephropathy (DN) are prevalent and costly to manage. DN is the leading cause of end-stage kidney disease. Conventional therapy blocking the renin-angiotensin system has only achieved limited effect in preserving renal function. Recent observational data show that the use of Chinese medicine (CM), a major form of traditional medicine used extensively in Asia, could reduce the risk of end-stage kidney disease. However, existing clinical practice guidelines are weakly evidence-based and the effect of CM remains unclear. This trial explores the effect of an existing integrative Chinese-Western medicine protocol for the management of DN. OBJECTIVE: To optimise parameters and assess the feasibility for a subsequent phase III randomised controlled trial through preliminary evaluation on the effect of an adjuvant semi-individualised CM treatment protocol on patients with type 2 diabetes with stages 2-3 chronic kidney disease and macroalbuminuria. METHODS AND ANALYSIS: This is an assessor-blind, add-on, randomised, controlled, parallel, multicentre, open-label pilot pragmatic clinical trial. 148 patients diagnosed with DN will be recruited and randomised 1:1 to a 48-week additional semi individualised CM treatment programme or standard medical care. Primary end points are the changes in estimated glomerular filtration rate and spot urine albumin-to-creatinine ratio between baseline and treatment end point. Secondary end points include fasting blood glucose, glycated haemoglobin, brain natriuretic peptide, fasting insulin, C peptide, fibroblast growth factor 23, urinary monocyte chemotactic protein-1, cystatin C, nephrin, transforming growth factor beta1 and vascular endothelial growth factor. Adverse events are monitored through self-completed questionnaire and clinical visits. Outcomes will be analysed by regression models. Enrolment started in July 2015. ETHICS AND REGISTRATION: This protocol is approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (reference number UW 14-301). TRIAL REGISTRATION NUMBER: NCT02488252. PMID- 27496230 TI - Hypertensive disorders of pregnancy and risk of diabetes in Indian women: a cross sectional study. AB - BACKGROUND: Epidemiological data from high-income countries suggest that women with hypertensive disorders of pregnancy (HDP) are more likely to develop diabetes later in life. OBJECTIVE: We investigated the association between pre eclampsia and eclampsia (PE&E) during pregnancy and the risk of diabetes in Indian women. DESIGN: Cross-sectional study. SETTING: India. METHODS: Data from India's third National Family Health Survey (NFHS-3, 2005-2006), a cross sectional survey of women aged 15-49 years, are used. Self-reported symptoms suggestive of PE&E were obtained from 39 657 women who had a live birth in the 5 years preceding the survey. The association between PE&E and self-reported diabetes status was assessed using multivariable logistic regression models adjusting for dietary intake, body mass index (BMI), tobacco smoking, alcohol drinking, frequency of TV watching, sociodemographic characteristics and geographic region. RESULTS: The prevalence of symptoms suggestive of PE&E in women with diabetes was 1.8% (n=207; 95% CI 1.5 to 2.0; p<0.0001) and 2.1% (n=85; 95% CI 1.8 to 2.3; p<0.0001), respectively, compared with 1.1% (n=304; 95% CI 1.0 to 1.4) and 1.2% (n=426; 95% CI 1.1 to 1.5) in women who did not report any PE&E symptoms. In the multivariable analysis, PE&E was associated with 1.6 times (OR=1.59; 95% CI 1.31 to 1.94; p<0.0001) and 1.4 times (OR=1.36; 95% CI 1.05 to 1.77; p=0.001) higher risk for self-reported diabetes even after controlling for dietary intake, BMI and sociodemographic characteristics. CONCLUSIONS: HDP is strongly associated with the risk of diabetes in a large nationally representative sample of Indian women. These findings are important for a country which is already tackling the burden of young onset of diabetes in the population. However, longitudinal medical histories and a clinical measurement of diabetes are needed in this low-resource setting. PMID- 27496231 TI - Identification of adults with sepsis in the prehospital environment: a systematic review. AB - OBJECTIVE: Early identification of sepsis could enable prompt delivery of key interventions such as fluid resuscitation and antibiotic administration which, in turn, may lead to improved patient outcomes. Limited data indicate that recognition of sepsis by paramedics is often poor. We systematically reviewed the literature on prehospital sepsis screening tools to determine whether they improved sepsis recognition. DESIGN: Systematic review. The electronic databases MEDLINE, EMBASE, CINAHL, the Cochrane Library and PubMed were systematically searched up to June 2015. In addition, subject experts were contacted. SETTING: Prehospital/emergency medical services (EMS). STUDY SELECTION: All studies addressing identification of sepsis (including severe sepsis and septic shock) among adult patients managed by EMS. OUTCOME MEASURES: Recognition of sepsis by EMS clinicians. RESULTS: Owing to considerable variation in the methodological approach adopted and outcome measures reported, a narrative approach to data synthesis was adopted. Three studies addressed development of prehospital sepsis screening tools. Six studies addressed paramedic diagnosis of sepsis with or without use of a prehospital sepsis screening tool. CONCLUSIONS: Recognition of sepsis by ambulance clinicians is poor. The use of screening tools, based on the Surviving Sepsis Campaign diagnostic criteria, improves prehospital sepsis recognition. Screening tools derived from EMS data have been developed, but they have not yet been validated in clinical practice. There is a need to undertake validation studies to determine whether prehospital sepsis screening tools confer any clinical benefit. PMID- 27496233 TI - Patient safety priorities in mental healthcare in Switzerland: a modified Delphi study. AB - OBJECTIVE: Identifying patient safety priorities in mental healthcare is an emerging issue. A variety of aspects of patient safety in medical care apply for patient safety in mental care as well. However, specific aspects may be different as a consequence of special characteristics of patients, setting and treatment. The aim of the present study was to combine knowledge from the field and research and bundle existing initiatives and projects to define patient safety priorities in mental healthcare in Switzerland. The present study draws on national expert panels, namely, round-table discussion and modified Delphi consensus method. DESIGN: As preparation for the modified Delphi questionnaire, two round-table discussions and one semistructured questionnaire were conducted. Preparative work was conducted between May 2015 and October 2015. The modified Delphi was conducted to gauge experts' opinion on priorities in patient safety in mental healthcare in Switzerland. In two independent rating rounds, experts made private ratings. The modified Delphi was conducted in winter 2015. RESULTS: Nine topics were defined along the treatment pathway: diagnostic errors, non-drug treatment errors, medication errors, errors related to coercive measures, errors related to aggression management against self and others, errors in treatment of suicidal patients, communication errors, errors at interfaces of care and structural errors. CONCLUSIONS: Patient safety is considered as an important topic of quality in mental healthcare among experts, but it has been seriously neglected up until now. Activities in research and in practice are needed. Structural errors and diagnostics were given highest priority. From the topics identified, some are overlapping with important aspects of patient safety in medical care; however, some core aspects are unique. PMID- 27496232 TI - Design and rationale of a multicentre, randomised, double-blind, placebo controlled clinical trial to evaluate the effect of vitamin D on ventricular remodelling in patients with anterior myocardial infarction: the VITamin D in Acute Myocardial Infarction (VITDAMI) trial. AB - INTRODUCTION: Decreased plasma vitamin D (VD) levels are linked to cardiovascular damage. However, clinical trials have not demonstrated a benefit of VD supplements on left ventricular (LV) remodelling. Anterior ST-elevation acute myocardial infarction (STEMI) is the best human model to study the effect of treatments on LV remodelling. We present a proof-of-concept study that aims to investigate whether VD improves LV remodelling in patients with anterior STEMI. METHODS AND ANALYSIS: The VITamin D in Acute Myocardial Infarction (VITDAMI) trial is a multicentre, randomised, double-blind, placebo-controlled trial. 144 patients with anterior STEMI will be assigned to receive calcifediol 0.266 mg capsules (Hidroferol SGC)/15 days or placebo on a 2:1 basis during 12 months. PRIMARY OBJECTIVE: to evaluate the effect of calcifediol on LV remodelling defined as an increase in LV end-diastolic volume >=10% (MRI). SECONDARY OBJECTIVES: change in LV end-diastolic and end-systolic volumes, ejection fraction, LV mass, diastolic function, sphericity index and size of fibrotic area; endothelial function; plasma levels of aminoterminal fragment of B-type natriuretic peptide, galectin-3 and monocyte chemoattractant protein-1; levels of calcidiol (VD metabolite) and other components of mineral metabolism (fibroblast growth factor-23 (FGF-23), the soluble form of its receptor klotho, parathormone and phosphate). Differences in the effect of VD will be investigated according to the plasma levels of FGF-23 and klotho. Treatment safety and tolerability will be assessed. This is the first study to evaluate the effect of VD on cardiac remodelling in patients with STEMI. ETHICS AND DISSEMINATION: This trial has been approved by the corresponding Institutional Review Board (IRB) and National Competent Authority (Agencia Espanola de Medicamentos y Productos Sanitarios (AEMPS)). It will be conducted in accordance with good clinical practice (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical Practice (ICH-GCP)) requirements, ethical principles of the Declaration of Helsinki and national laws. The results will be submitted to indexed medical journals and national and international meetings. TRIAL REGISTRATION NUMBER: NCT02548364; Pre-results. PMID- 27496234 TI - Combined cognitive-behavioural and mindfulness programme for people living with dystonia: a proof-of-concept study. AB - OBJECTIVES: To design and test the delivery of an intervention targeting the non motor symptoms of dystonia and pilot key health and well-being questionnaires in this population. DESIGN: A proof-of-concept study to test the delivery, acceptability, relevance, structure and content for a 3-day group residential programme for the management of dystonia. SETTING: Participants were recruited from a single botulinum toxin clinic. The intervention was delivered in the community. PARTICIPANTS: 14 participants consented to take part (2 withdrew prior to the starting of intervention). The average age was 60 years (range 44-77), 8 of whom were female. After drop-out, 9 participants completed the 3-day programme. INTERVENTION: A 3-day group residential programme. PRIMARY AND SECONDARY OUTCOME MEASURES: Process evaluation and interviews were carried out before and after the intervention to explore participant's views and expectations, as well as experiences of the intervention. Select questionnaires were completed at baseline, 1-month and 3-month follow-up. RESULTS: Although participants were not sure what to expect from the programme, they found it informative and for many this together with being in a group with other people with dystonia legitimised their condition. Mindfulness was accepted and adopted as a coping strategy. This was reflected in the 1-month follow-up. CONCLUSIONS: We successfully delivered a 3-day residential programme to help those living with dystonia manage their condition. Further improvements are suggested. The quantitative outcome measures were acceptable to this group of patients with dystonia. PMID- 27496235 TI - Feasibility of repeated self-measurements of maximum step length and gait speed by community-dwelling older persons. AB - OBJECTIVES: Self-management of mobility and fall risk can be important in fall prevention; however, it remains unstudied. Therefore, the current study assessed whether community-dwelling older persons were able to repeatedly self-assess maximum step length (MSL) and gait speed (GS) in their own home for a 6-month period, how these tests changed during this period and if these changes were related to falling. DESIGN: This is a prospective study. SETTING: This study was conducted at home. PARTICIPANTS: A total of 56 community-dwelling older adults (24 women (43%), mean age 76.2 (SD 3.9) years) entered the study; of which, 45 completed the study. METHODS: Participants performed MSL and GS once a week in their own home during a 6-month period. PRIMARY AND SECONDARY OUTCOMES: Repeated MSL and GS measurements were the primary outcomes. Falls, self-management and mobility were the secondary outcomes. RESULTS: Self-assessment of MSL and GS by older persons is feasible. Compliance of repeatedly self-measuring MSL and GS was good; the median number of weekly measurements was 23.0 (88%) and 21.0 (81%) for MSL and GS, respectively. Drop-outs showed less self-management abilities compared to the participants who completed the study (p=0.049). Linear mixed models showed a small significant improvement in MSL and GS over time (p<0.001), without an influence on falling. CONCLUSIONS: Most community-dwelling older persons are able and willing to repeatedly assess their MSL and GS. Self-managing mobility and fall risk did not increase fall occurrence. The fact that older persons can be actively involved in their own healthcare is clinically relevant. Further studies are needed to examine the (cost-)effectiveness of self-management in fall prevention interventions. PMID- 27496236 TI - Comparing the accuracy of quantitative versus qualitative analyses of interim PET to prognosticate Hodgkin lymphoma: a systematic review protocol of diagnostic test accuracy. AB - INTRODUCTION: Hodgkin lymphoma is an effectively treated malignancy, yet 20% of patients relapse or are refractory to front-line treatments with potentially fatal outcomes. Early detection of poor treatment responders is crucial for appropriate application of tailored treatment strategies. Tumour metabolic imaging of Hodgkin lymphoma using visual (qualitative) 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is a gold standard for staging and final outcome assessment, but results gathered during the interim period are less accurate. Analysis of continuous metabolic-morphological data (quantitative) FDG PET may enhance the robustness of interim disease monitoring, and help to improve treatment decision-making processes. The objective of this review is to compare diagnostic test accuracy of quantitative versus qualitative interim FDG-PET in the prognostication of patients with Hodgkin lymphoma. METHODS: The literature on this topic will be reviewed in a 3-step strategy that follows methods described by the Joanna Briggs Institute (JBI). First, MEDLINE and EMBASE databases will be searched. Second, listed databases for published literature (MEDLINE, Tripdatabase, Pedro, EMBASE, the Cochrane Central Register of Controlled Trials and WoS) and unpublished literature (Open Grey, Current Controlled Trials, MedNar, ClinicalTrials.gov, Cos Conference Papers Index and International Clinical Trials Registry Platform of the WHO) will be queried. Third, 2 independent reviewers will analyse titles, abstracts and full texts, and perform hand search of relevant studies, and then perform critical appraisal and data extraction from selected studies using the DATARI tool (JBI). If possible, a statistical meta-analysis will be performed on pooled sensitivity and specificity data gathered from the selected studies. Statistical heterogeneity will be assessed. Funnel plots, Begg's rank correlations and Egger's regression tests will be used to detect and/or correct publication bias. ETHICS AND DISSEMINATION: The results will be disseminated by publishing in a peer-reviewed journal. Ethical assessment will not be needed; only existing sources of literature will be searched. TRIAL REGISTRATION NUMBER: CRD42016027953. PMID- 27496237 TI - Estimating the economic burden of cardiovascular events in patients receiving lipid-modifying therapy in the UK. AB - OBJECTIVES: To characterise the costs to the UK National Health Service of cardiovascular (CV) events among individuals receiving lipid-modifying therapy. DESIGN: Retrospective cohort study using Clinical Practice Research Datalink records from 2006 to 2012 to identify individuals with their first and second CV related hospitalisations (first event and second event cohorts). Within-person differences were used to estimate CV-related outcomes. SETTING: Patients in the UK who had their first CV event between January 2006 and March 2012. PARTICIPANTS: Patients >=18 years who had a CV event and received at least 2 lipid-modifying therapy prescriptions within 180 days beforehand. PRIMARY AND SECONDARY OUTCOME MEASURES: Direct medical costs (2014 L) were estimated in 3 periods: baseline (pre-event), acute (6 months afterwards) and long-term (subsequent 30 months). Primary outcomes included incremental costs, resource usage and total costs per period. RESULTS: There were 24 093 patients in the first event cohort of whom 5274 were included in the second event cohort. The mean incremental acute CV event costs for the first event and second event cohorts were: coronary artery bypass graft/percutaneous transluminal coronary angioplasty (CABG/PTCA) L5635 and L5823, myocardial infarction L4275 and L4301, ischaemic stroke L3512 and L4572, heart failure L2444 and L3461, unstable angina L2179 and L2489 and transient ischaemic attack L1537 and L1814. The mean incremental long-term costs were: heart failure L848 and L2829, myocardial infarction L922 and L1385, ischaemic stroke L973 and L682, transient ischaemic attack L705 and L1692, unstable angina L328 and L677, and CABG/PTCA L-368 and L599. Hospitalisation accounted for 95% of acute and 61% of long-term incremental costs. Higher comorbidity was associated with higher long-term costs. CONCLUSIONS: Revascularisation and myocardial infarction were associated with the highest incremental costs following a CV event. On the basis of real-world data, the economic burden of CV events in the UK is substantial, particularly among those with greater comorbidity burden. PMID- 27496238 TI - Understanding and reducing the prescription of hypnotics and sedatives at the interface of hospital care and general practice: a protocol for a mixed-methods study. AB - INTRODUCTION: Hypnotics and sedatives, especially benzodiazepines and Z-drugs, are frequently prescribed for longer periods than recommended-in spite of potential risks for patients. Any intervention to improve this situation has to take into account the interplay between different actors, interests and needs. The ultimate goal of this study is to develop-together with the professionals involved-ideas for reducing the use of hypnotics and sedatives and then to implement and evaluate adequate interventions in the hospital and at the primary and secondary care interface. METHODS AND ANALYSIS: The study will take place in a regional hospital in northern Germany and in some general practices in this region. We will collect data from doctors, nurses, patients and a major social health insurer to define the problem from multiple perspectives. These data will be explored and discussed with relevant stakeholders to develop interventions. The interventions will be implemented and, in a final step, evaluated. Both quantitative and qualitative data, including surveys, interviews, chart reviews and secondary analysis of social health insurance data, will be collected to obtain a full understanding of the frequency and the reasons for using hypnotics and sedatives. ETHICS AND DISSEMINATION: Approval has been granted from the ethics review committee of the University Medical Center Gottingen, Germany. Results will be disseminated to researchers, clinicians and policy makers in peer reviewed journal articles and conference publications. One or more dissemination events will be held locally during continuous professional development events for local professionals, including (but not confined to) the study participants. PMID- 27496239 TI - Nutritional route in oesophageal resection trial II (NUTRIENT II): study protocol for a multicentre open-label randomised controlled trial. AB - INTRODUCTION: Early start of an oral diet is safe and beneficial in most types of gastrointestinal surgery and is a crucial part of fast track or enhanced recovery protocols. However, the feasibility and safety of oral intake directly following oesophagectomy remain unclear. The aim of this study is to investigate the effects of early versus delayed start of oral intake on postoperative recovery following oesophagectomy. METHODS AND ANALYSIS: This is an open-label multicentre randomised controlled trial. Patients undergoing elective minimally invasive or hybrid oesophagectomy for cancer are eligible. Further inclusion criteria are intrathoracic anastomosis, written informed consent and age 18 years or older. Inability for oral intake, inability to place a feeding jejunostomy, inability to provide written consent, swallowing disorder, achalasia, Karnofsky Performance Status <80 and malnutrition are exclusion criteria. Patients will be randomised using online randomisation software. The intervention group (direct oral feeding) will receive a liquid oral diet for 2 weeks with gradually expanding daily maximums. The control group (delayed oral feeding) will receive enteral feeding via a jejunostomy during 5 days and then start the same liquid oral diet. The primary outcome measure is functional recovery. Secondary outcome measures are 30 day surgical complications; nutritional status; need for artificial nutrition; need for additional interventions; health-related quality of life. We aim to recruit 148 patients. Statistical analysis will be performed according to an intention to treat principle. Results are presented as risk ratios with corresponding 95% CIs. A two-tailed p<0.05 is considered statistically significant. ETHICS AND DISSEMINATION: Our study protocol has received ethical approval from the Medical research Ethics Committees United (MEC-U). This study is conducted according to the principles of Good Clinical Practice. Verbal and written informed consent is required before randomisation. All data will be collected using an online database with adequate security measures. TRIAL REGISTRATION NUMBERS: NCT02378948 and Dutch trial registry: NTR4972; Pre-results. PMID- 27496240 TI - Study on the development of an infectious disease-specific health literacy scale in the Chinese population. AB - OBJECTIVES: To develop a scale to assess infectious disease-specific health literacy (IDSHL) in China and test its initial psychometric properties. METHODS: Item pooling, reduction and assessment of psychometric properties were conducted. The scale was divided into 2 subscales; subscale 1 assessed an individual's skills to prevent/treat infectious diseases and subscale 2 assessed cognitive ability. In 2014, 9000 people aged 15-69 years were randomly sampled from 3 provinces and asked to complete the IDSHL questionnaire. Cronbach's alpha was calculated to assess reliability. Exploratory factor analysis, t-test, correlations, receiver operating characteristic (ROC) curve and logistic regression were used to examine validity. RESULTS: Each of the 22 items in subscale 1 had a content validity index >0.8. In total, 8858 people completed the scale. The principal components factor analysis suggested a 5-factor solution. All factor loadings were >0.40 (p<0.05). The IDSHL score was 22.07+/-7.91 (mean+/ SD; total score=38.62). Significant differences were observed across age (r= 0.276), sex (males: 21.65+/-8.03; females: 22.47+/-7.78), education (14.16+/-8.19 to 26.55+/-6.26), 2-week morbidity (present: 20.62+/-8.17, absent: 22.35+/-7.83; p<0.001) and health literacy of the highest and lowest 27% score groups (all p<0.05). The ROC curve indicated that 76.2% of respondents were adequate in IDSHL. Binary logistic regression analysis revealed 12 predictors of IDSHL adequacy (p<0.05). Among the 22 remaining items, Corrected Item-Total Correlation ranged from 0.316 to 0.504 and Cronbach's alpha values ranged from 0.754 to 0.810 if the items were deleted. The overall alpha value was 0.839 and the difficulty coefficient ranged from 1.19 to 4.08. For subscale 2, there were statistically significant differences between the mean scores of those with a correct/incorrect answer (all p<0.001). CONCLUSIONS: The newly developed 28-item scale provides an efficient, psychometrically sound and user-friendly measure of IDSHL in the Chinese population. PMID- 27496241 TI - Nurses' sleep quality, work environment and quality of care in the Spanish National Health System: observational study among different shifts. AB - OBJECTIVE: The main objective of this study was to determine the relationship between the characteristics of nurses' work environments in hospitals in the Spanish National Health System (SNHS) with nurse reported quality of care, and how care was provided by using different shifts schemes. The study also examined the relationship between job satisfaction, burnout, sleep quality and daytime drowsiness of nurses and shift work. METHODS: This was a multicentre, observational, descriptive, cross-sectional study, centred on a self-administered questionnaire. The study was conducted in seven SNHS hospitals of different sizes. We recruited 635 registered nurses who worked on day, night and rotational shifts on surgical, medical and critical care units. Their average age was 41.1 years, their average work experience was 16.4 years and 90% worked full time. A descriptive and bivariate analysis was carried out to study the relationship between work environment, quality and safety care, and sleep quality of nurses working different shift patterns. RESULTS: 65.4% (410) of nurses worked on a rotating shift. The Practice Environment Scale of the Nursing Work Index classification ranked 20% (95) as favourable, showing differences in nurse manager ability, leadership and support between shifts (p=0.003). 46.6% (286) were sure that patients could manage their self-care after discharge, but there were differences between shifts (p=0.035). 33.1% (201) agreed with information being lost in the shift change, showing differences between shifts (p=0.002). The Pittsburgh Sleep Quality Index reflected an average of 6.8 (SD 3.39), with differences between shifts (p=0.017). CONCLUSIONS: Nursing requires shift work, and the results showed that the rotating shift was the most common. Rotating shift nurses reported worse perception in organisational and work environmental factors. Rotating and night shift nurses were less confident about patients' competence of self-care after discharge. The most common nursing care omissions reported were related to nursing care plans. For the Global Sleep Quality score, difference were found between day and night shift workers. PMID- 27496242 TI - Effect of warning symbols in combination with education on the frequency of erroneously crushing medication in nursing homes: an uncontrolled before and after study. AB - OBJECTIVES: Residents of nursing homes often have difficulty swallowing (dysphagia), which complicates the administration of solid oral dosage formulations. Erroneously crushing medication is common, but few interventions have been tested to improve medication safety. Therefore, we evaluated the effect of warning symbols in combination with education on the frequency of erroneously crushing medication in nursing homes. SETTING: This was a prospective uncontrolled intervention study with a preintervention and postintervention measurement. The study was conducted on 18 wards (total of 200 beds) in 3 nursing homes in the North of the Netherlands. PARTICIPANTS: We observed 36 nurses/nursing assistants (92% female; 92% nursing assistants) administering medication to 197 patients (62.9% female; mean age 81.6). INTERVENTION: The intervention consisted of a set of warning symbols printed on each patient's unit dose packaging indicating whether or not a medication could be crushed as well as education of ward staff (lectures, newsletter and poster). PRIMARY OUTCOME MEASURE: The relative risk (RR) of a crushing error occurring in the postintervention period compared to the preintervention period. A crushing error was defined as the crushing of a medication considered unsuitable to be crushed based on standard reference sources. Data were collected using direct (disguised) observation of nurses during drug administration. RESULTS: The crushing error rate decreased from 3.1% (21 wrongly crushed medicines out of 681 administrations) to 0.5% (3/636), RR=0.15 (95% CI 0.05 to 0.51). Likewise, there was a significant reduction using data from patients with swallowing difficulties only, 87.5% (21 errors/24 medications) to 30.0% (3/10) (RR 0.34, 95% CI 0.13 to 0.89). Medications which were erroneously crushed included enteric-coated formulations (eg, omeprazole), medication with regulated release systems (eg, Persantin; dipyridamol) and toxic substances (eg, finasteride). CONCLUSIONS: Warning symbols combined with education reduced erroneous crushing of medication, a well-known and common problem in nursing homes. PMID- 27496244 TI - Eccentric small-zone ray tracing wavefront aberrometry for refraction in keratoconus. AB - PURPOSE: To compare objective refraction using small-zone eccentric laser ray tracing (LRT) wavefront aberrometry to standard autorefraction in keratoconus (KC), and whether the visual acuities achieved with these refractions differ from corresponding values in healthy eyes. METHODS: Twenty-nine eyes of 29 patients with KC and 29 eyes of 29 healthy controls were included in this prospective unmasked case-control study. The uncorrected (UCVA) and spectacle-corrected (SCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuities based on refractions derived from LRT in central and four eccentric zones were compared to those achieved with standard autorefraction. The spherical equivalent (M) and two astigmatic power vectors (C0 and C45) were calculated for all refractions. Pentacam HR(r) was used to generate keratometry readings of the corresponding zones. RESULTS: In KC, the refraction from the upper nasal zone rendered a higher SCVA than the standard autorefraction more often than in the controls (p < 0.001). There were no significant variation in M between the different LRT measurement points in the control group, but central data provided the best SCVA. The UCVA:s and SCVA:s were worse in KC, and the KC eyes showed inferior myopia and superior hyperopia. Multiple refractions rendered similar SCVA:s in KC. Pentacam HR(r) showed higher keratometry readings infero-temporally, but also lower readings supero-nasally, compared to controls. CONCLUSION: In KC, eccentric LRT measurements gave better SCVA than standard autorefraction more often than in healthy eyes. Eccentric LRT may become a valuable tool in the demanding task of subjective refraction in KC. PMID- 27496243 TI - Development and initial cohort validation of the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ) for use across musculoskeletal care pathways. AB - OBJECTIVES: Current musculoskeletal outcome tools are fragmented across different healthcare settings and conditions. Our objectives were to develop and validate a single musculoskeletal outcome measure for use throughout the pathway and patients with different musculoskeletal conditions: the Arthritis Research UK Musculoskeletal Health Questionnaire (MSK-HQ). SETTING: A consensus workshop with stakeholders from across the musculoskeletal community, workshops and individual interviews with a broad mix of musculoskeletal patients identified and prioritised outcomes for MSK-HQ inclusion. Initial psychometric validation was conducted in four cohorts from community physiotherapy, and secondary care orthopaedic hip, knee and shoulder clinics. PARTICIPANTS: Stakeholders (n=29) included primary care, physiotherapy, orthopaedic and rheumatology patients (n=8); general practitioners, physiotherapists, orthopaedists, rheumatologists and pain specialists (n=7), patient and professional national body representatives (n=10), and researchers (n=4). The four validation cohorts included 570 participants (n=210 physiotherapy, n=150 hip, n=150 knee, n=60 shoulder patients). OUTCOME MEASURES: Outcomes included the MSK-HQ's acceptability, feasibility, comprehension, readability and responder burden. The validation cohort outcomes were the MSK-HQ's completion rate, test-retest reliability and convergent validity with reference standards (EQ-5D-5L, Oxford Hip, Knee, Shoulder Scores, and the Keele MSK-PROM). RESULTS: Musculoskeletal domains prioritised were pain severity, physical function, work interference, social interference, sleep, fatigue, emotional health, physical activity, independence, understanding, confidence to self-manage and overall impact. Patients reported MSK-HQ items to be 'highly relevant' and 'easy to understand'. Completion rates were high (94.2%), with scores normally distributed, and no floor/ceiling effects. Test-retest reliability was excellent, and convergent validity was strong (correlations 0.81-0.88). CONCLUSIONS: A new musculoskeletal outcome measure has been developed through a coproduction process with patients to capture prioritised outcomes for use throughout the pathway and with different musculoskeletal conditions. Four validation cohorts found that the MSK-HQ had high completion rates, excellent test-retest reliability and strong convergent validity with reference standards. Further validation studies are ongoing, including a cohort with rheumatoid/inflammatory arthritis. PMID- 27496245 TI - Combined unicompartmental knee arthroplasty and anterior cruciate ligament reconstruction in knees with osteoarthritis and deficient anterior cruciate ligament. AB - BACKGROUND: Relative young and more active patients with osteoarthritis (OA) of the isolated medial femorotibial compartment in conjunction with anterior cruciate ligament (ACL) deficiency are difficult to treat. The aim of this study was to explore the early clinical outcomes of combined Oxford unicompartmental knee arthroplasty (UKA) and ACL reconstruction for the patients presenting ACL deficiency and isolated OA of the medial compartment. METHODS: Twenty-eight patients were included into the study. All patients were treated by combined Oxford UKA and ACL reconstruction. Plain radiographs in the antero-posterior and lateral view and long-leg standing radiographs were routinely performed prior to and after surgery. Stress radiographs in valgus were additionally available in order to verify the well-preserved lateral compartment. The varus deformity of the knee prior to surgery and the valgus degree after surgery, the posterior slope of the tibial component and the range of motion (ROM) of the knee after surgery were measured and recorded. Clinical evaluations include Oxford Knee Score (OKS), Knee Society Score (KSS-clinical score; KSS-function score) and Tegner activity score. RESULTS: All the patients were followed up for 52 +/- 8 months. The leg alignment showed 3.1 +/- 0.6 degrees of varus deformity prior to surgery and 4.0 +/- 0.7 degrees of valgus after surgery. The OKS, KSS and Tegner activity score improved significantly after surgery (P < 0.05). The mean ROM of the operated knee was 123.5 +/- 2.8 degrees at the last follow-up. The posterior slope of the tibial component was 3.9 +/- 1.2 degrees . A significant correlation was found between them according to the Pearson's correlation (r = 0.39, P = 0.03). There were 2 patients (7 %) with the complication of mobile bearing dislocation, and a second operation of replacing a thicker mobile bearing was performed for them. CONCLUSION: The early clinical data have shown that combined surgery of UKA and ACL reconstruction has revealed promising results. However, long-term follow-up studies should be done in these patients. TRIAL REGISTRATION: Current trial ISRCTN24663935 (Retrospectively registered on 21 July 2016). PMID- 27496246 TI - Restorative proctocolectomy with two different pouch designs: few complications with good function. AB - AIM: The object of this study was to compare function and quality of life after restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis (IPAA) surgery having two different pouch designs. METHOD: Patients having RPC in an academic unit from 2000 who had had the loop-ileostomy closed by June 2013 were identified from the hospital medical records. They were sent a questionnaire regarding quality of life and interviewed using a pouch function score (PFS) described by Oresland (score 0-16, higher scores denote worse function). RESULTS: One hundred and three patients underwent surgery, of whom 56 had a J-pouch design and 47 a K-pouch design, this being a double-folded Kock pouch without the nipple valve. No patients have had the pouch removed or defunctioned due to failure at a mean of 8 years. The reoperation rate was 11.6%. The mean PFS was 5.43 and 5.27 for J- and K-pouches, respectively (P = 0.766). More patients with a J-pouch reported a social handicap due to poor bowel function (P = 0.041). Patients with a PFS >= 8 had a poorer quality of life. A score of >= 8 was reported by 16% of K pouch and 25% of J-pouch patients (P = 0.29). CONCLUSION: RPC is a safe procedure with a low complication rate and good functional outcome. Small improvements in function have an impact on a patient's quality of life. Although the J-pouch is the most commonly used, the K-pouch has some advantages. Other pouch designs deserve further evaluation. PMID- 27496247 TI - Flavonoids stimulate cholecystokinin peptide secretion from the enteroendocrine STC-1 cells. AB - Animal experiments showed that flavonoids might have the potential for an anti obesity effect by reducing weight and food intake. However, the exact mechanisms that could be involved in these proposed effects are still under investigation. The complex process of food intake is partially regulated by gastrointestinal hormones. Cholecystokinin (CCK) is the best known gastrointestinal hormone to induce satiety signal that plays a key role in food intake regulation. It is released from the endocrine cells (I cell) in response to the ingestion of nutrients into the small intestine. In this study, we investigated the possible effects of flavonoids (quercetin, kaempferol, apigenin, rutin and baicalein) on stimulation of CCK release in vitro using enteroendocrine STC-1 cells. In comparison with the control, quercetin, kaempferol and apigenin resulted in a significant increase in CCK secretion with quercetin showing the highest activity. On the other hand, no significant effect was seen by rutin and baicalein. To our knowledge, this is the first report to study the stimulation of CCK peptide hormone secretion from STC-1 cells by quercetin and kaempferol, rutin, apigenin and baicalein. Based on the cell-based results in this work, it can be suggested that the reported activity of flavonoids against food intake and weight could be mediated by stimulation of CCK signal which in turn is responsible for food intake reduction, but future animal and human studies are needed to confirm this conclusion at organism level. PMID- 27496248 TI - An Evaluation of FrancoForme: A CASE-MANAGED HOME-BASED PRIMARY AND SECONDARY CARDIOVASCULAR DISEASE PREVENTION PROGRAM FOR FRENCH-SPEAKING CANADIANS. AB - PURPOSE: Cardiovascular disease (CVD) is the leading cause of mortality globally. Telephone-delivered interventions targeting cardiovascular risk factors are gaining popularity. This study is an evaluation of FrancoForme, a cardiovascular risk factor reduction program for the primary and secondary prevention of CVD among French-speaking patients of Eastern Ontario. METHODS: This study reports on changes in cardiovascular risk factors, weekly exercise levels, and psychosocial characteristics including anxiety, depression, and quality of life upon program completion (3 months) and at 1 year after the start of the program. Repeated measures analysis of variance was used to compare changes in outcomes between primary prevention risk groups (low, moderate, and high risk for CVD) and the secondary prevention group (ie, cardiac rehabilitation) at baseline, 3 months and 12 months. RESULTS: A total of 762 patients enrolled in FrancoForme between 2008 and 2015. At 3 months, all program completers (n = 507) experienced significant reductions for all cardiovascular risk factors except diastolic blood pressure. Minutes of self-reported exercise increased significantly by an average 90 minutes per week and all psychosocial variables improved. Significant group effects were observed across several risk factors. Among 12-month responders (n = 240), exercise, high-density lipoproteins, triglycerides, cholesterol, and all psychosocial variables were improved over baseline results. CONCLUSIONS: FrancoForme is unique in targeting both the primary and secondary prevention of CVD and removes several of the barriers to participating in a conventional CVD prevention program for French-speaking patients. FrancoForme is successful, receiving high satisfaction rates and resulting in significant improvements in cardiovascular risk factors, exercise, anxiety, and depression, as well as quality of life. PMID- 27496250 TI - Biopsychosocial-Spiritual Factors Impacting Referral to and Participation in Cardiac Rehabilitation for African American Patients: A SYSTEMATIC REVIEW. AB - PURPOSE: The purposes of this systematic review were to (1) review the literature related to the demographic and biopsychosocial-spiritual factors impacting cardiac rehabilitation (CR) referral and participation of African American patients with cardiovascular disease (CVD); (2) identify barriers and facilitators to CR referral and participation for this population; (3) identify gaps in the literature; and (4) make recommendations for future research studies and interventions. METHODS: The Cooper 7-step protocol for research synthesis was followed to formulate a research question and search MEDLINE via PubMed, PsycINFO via EBSCO, and CINAHL via EBSCO. A second reviewer repeated the searches performed by the first author in the initial review. RESULTS: A total of 1640 articles identified using the search strategy yielded 7 articles that fit the search criteria. Most studies measured demographic or social factors. Two studies measured biological factors, 1 study measured psychological factors, and no study measured spiritual factors. CONCLUSIONS: According to the studies reviewed, African American patients with CVD were less likely to receive a CR referral, more likely to enroll in CR with more cardiovascular risk factors, and less likely to participate in and complete CR due to factors related to low socioeconomic status (eg, lack of insurance, work conflicts, lower level of education) than non-Hispanic white patients. Further research is needed on the interaction between demographic/biopsychosocial-spiritual factors and referral to and participation of African Americans in CR in order to ensure that interventions fit the needs of this particular population. PMID- 27496249 TI - Effect of Chronic Kidney Disease and Supplemental Polyunsaturated Fatty Acid Use on Exercise Levels During Cardiac Rehabilitation in Patients With Coronary Artery Disease. AB - PURPOSE: The correlation between chronic kidney disease (CKD) and increased cardiovascular disease-related mortality is well established. Cardiac rehabilitation (CR) improves exercise capacity, quality of life, and risk factors in patients with coronary artery disease (CAD). Data on the benefits of CR in patients with CKD are sparse. The purpose of this study was to compare outcomes after CR in patients with CAD but normal renal function, versus those with CAD and CKD. METHODS: We studied 804 patients with CAD entering an exercise-based CR program. Demographics, risk factors, exercise capacity in metabolic equivalent levels (METs), and estimated glomerular filtration rate (GFR) were recorded before and after the 3-month CR program. Use of polyunsaturated fatty acid (PUFA) was determined by medical records review. Stage III-V CKD (GFR <60 mL/min/1.73 m) was present in 170 patients at baseline. RESULTS: After CR, METs improved in all patients, although increases in patients with a GFR 30 to 59 mL/min/1.73 m (Delta1.6) and a GFR <30 (Delta1.2) were smaller than those in patients with a GFR >=60 (Delta2.6, P < .05 vs GFR 30-59 and GFR <30). In patients with a GFR >=60 mL/min/1.73 m, PUFA use was associated with a 20% greater increase in MET levels compared with nonusers (Delta3.0 vs Delta2.5, P = .02); and in patients with a GFR 30 to 59, PUFA use was associated with 30% increase in MET level compared with nonusers (Delta2.0 vs Delta1.4, P = .03). These observations persisted after multivariable adjustment for baseline MET level, demographics, and risk factors. CONCLUSIONS: Potential mitigation by PUFA of the smaller improvement in exercise capacity with decreasing GFR requires confirmation in prospective randomized trials. PMID- 27496251 TI - Relevance and attitudes toward histology and embryology course through the eyes of freshmen and senior medical students: Experience from Serbia. AB - Histology and embryology are prerequisite for understanding the complexity of cell and tissue organization, function and development. The aim of this study was to examine the attitudes of medical students toward relevance of histology and embryology in their pre-clinical and clinical medical practice. The study sample consisted of 900 undergraduate students of 1st and 6th study year at the School of Medicine in Belgrade, Serbia. Data were collected using an anonymous questionnaire. Senior students reported the relevance of histology and embryology knowledge for learning pathology, dermatology, physiology, gynecology and obstetrics, pathophysiology and pediatrics. Examination of students' attitudes revealed that 1st year participants more often acknowledged histology and embryology as being of great importance for their professional career. Analysis according to gender indicated that female students consider embryology as of greater importance for further medical education and future clinical practice than male students. Overall, study results suggest that medical students have a positive attitude toward histology and embryology undergraduate course. This evidence could be used as an additional motive for the development of histology and embryology courses, with special emphasis on practical application of knowledge in clinically-oriented setting. PMID- 27496252 TI - Changes in biting forces with implant-supported overdenture in the lower jaw: A comparison between conventional and mini implants in a pilot study. AB - The biting ability of patients improves noticeably after receiving implant supported overdentures in comparison to conventional complete dentures. However, the change of biting with such treatment concepts has been quantitatively investigated in only a limited number of studies. The aim of the present study has been to measure the biting forces of edentulous patients with complete dentures and after receiving implant-supported overdentures. A total of 26 edentulous patients were included. Ten patients received two to four conventional implants (control group, O3.3-3.7mm, L11-13mm) and 16 patients received four to five mini implants (study group, O1.8-2.4mm, L13-15mm) inserted in the mandibular interforaminal region. All patients received a lower overdenture with ball/rubber ring attachments and a complete denture for the maxilla. The biting forces were measured using Prescale pressure sheets type low before the insertion of implants and after receiving implant-supported overdenture. The measured sheets were later scanned and analysed using FPD-8010E software. The range of biting forces before the insertion of implants was 80N-122N for the control group and 66-88N for the study group. After the insertion of implants, the range of biting forces increased to 167N-235N for the control group and to 81N-138N for the study group. However, the increase in biting forces after the insertion of implants was not significant for either group. No significant difference was obtained between the two implant systems. The biting forces improved after insertion of implants regardless of which implant system was used. However, the degree of improvement is noticeably related to the original bone quality of the mandible at the insertion regions of implants. PMID- 27496254 TI - Acral syringotropic melanomas with florid eccrine duct hyperplasia, a report of two cases. PMID- 27496253 TI - Glycated albumin is superior to glycated hemoglobin for glycemic control assessment at an early stage of diabetes treatment: A multicenter, prospective study. AB - AIMS: This study was to determine whether serum glycated albumin (GA) was a better indicator of glycemic control than hemoglobin A1c (HbA1c) when starting a new treatment regimen for type 2 diabetes. METHODS: Newly diagnosed type 2 diabetes patients, or patients who had poor glycemic control with oral hypoglycemic agents, were enrolled at 10 hospitals in Beijing. Serum GA, HbA1c, fasting blood glucose (FBG), and C-peptide were assayed on Days 0, 14, 28, and 91 after treatment. RESULTS: Four hundred ninety-nine patients were enrolled. Mean FBG, GA and HbA1c decreased significantly in patients at Days 14, 28, and 91. In patients with improved glycemic control, the reduction of GA and HbA1c levels was 10.5+/-13.3% vs. 5.1+/-5.4% on Day 14, 16.0+/-13.4% vs. 9.0+/-7.0% on Day 28, and 18.0+/-16.7% vs. 18.3+/-9.4% on Day 91, respectively, compared with baseline values. Changes in GA on Day 14, 28 and 91 were all closely correlated with changes in HbA1c on Day 91. Change in GA on Day 14 was correlated with treatment effectiveness evaluated by HbA1c on Day 91. CONCLUSIONS: GA may be a useful marker for assessing glycemic control at an early stage of new diabetes treatment and assist in guiding adjustments to treatment and therapy. PMID- 27496255 TI - Is employment-focused case management effective for patients with substance use disorders? Results from a controlled multi-site trial in Germany covering a 2 years-period after inpatient rehabilitation. AB - BACKGROUND: Substance use disorders are associated with unemployment. An employment-focused case management (CMRE) has been conceptualised as a specific intervention to help substance use disorder patients return to competitive employment immediately after inpatient rehabilitation. This study investigated the effect of the intervention on return to work of persons with substance use disorders. METHOD: The study was conducted in four German inpatient rehabilitation departments, and included unemployed patients (aged between 18 and 63 years) with a main clinical diagnosis of ICD-10 F10-19 disorders. Six weeks before discharge, patients were randomly allocated to CMRE or standard care (SC) using a quasi-randomised approach. The primary outcome measure was integration into competitive employment 24 months after discharge from rehabilitation. Secondary outcome domains were abstinence, duration of employment, proportion of publicly funded employment, satisfaction with life, precarious housing situation and precarious financial situation, and use of follow-up services. Outcome measures were assessed 6 weeks and 1-2 days prior to discharge, and 12 and 24 months after discharge from rehabilitation. RESULTS: One hundred sixty patients were allocated into the CMRE group and 160 patients into the control group. 267 resp. 179 participants could be included in the analyses performed for the 12-, and the 24-months follow-up assessments. At the study endpoint the rate of integration into the primary labour market was 35.6 % in the CMRE group and 41.2 % in the control group, respectively (Relative Risk 0.92, 95 % CI, 0.47; 1.79). There was a significantly higher proportion in the CMRE group, however, which immediately after discharge linked with services of the Federal Employment Agency or Job Centres. There were no statistically significant differences in other outcomes between the groups. CONCLUSIONS: Compared to SC, the additional specific CMRE intervention did not result in superior effects on return to work rates, abstinence, satisfaction with life, and housing and precarious financial situation. But CMRE was more effective on linking substance use disorder patients with services of the Federal Employment Agency or Job Centres. Reasons for the finding that such close linking does not have an impact on return to work rates are discussed in detail. TRIAL REGISTRATION: Identifier: DRKS00003574 ; March 12, 2012. The trial was retrospectively registered. PMID- 27496256 TI - Drug discovery for hearing loss: Phenotypic screening of chemical compounds on primary cultures of the spiral ganglion. AB - In the United States there are, at present, no drugs that are specifically FDA approved to treat hearing loss. Although several clinical trials are ongoing, including one testing D-methionine that is supported by the US Army, none of these trials directly address the effect of noise exposure on cochlear spiral ganglion neurons. We recently published the first report of a systematic chemical compound screen using primary, mammalian spiral ganglion cultures in which we were able to detect a compound and others in its class that increased neurite elongation, a critical step in restoring cochlear synapses after noise induced hearing loss. Here we discuss the issues, both pro and con, that influenced the development of our approach. These considerations may be useful for future compound screens that target the same or other attributes of cochlear spiral ganglion neurons. PMID- 27496257 TI - Improving dispatcher-assisted public access defibrillation use. PMID- 27496258 TI - Getting the right bystander to the right place at the right time. PMID- 27496259 TI - Systematic review of paediatric track and trigger systems for hospitalised children. AB - CONTEXT: Early and accurate recognition of the deteriorating hospitalised child is complex. Paediatric track and trigger systems (PTTS) support clinical decision making by 'tracking' the child's condition through monitoring of clinical signs and 'triggering' a request for an appropriate review when pre-determined criteria are breeched. OBJECTIVE: To describe the number and nature of published PTTS and appraise the evidence on their validity, calibration, and effect on important patient outcomes (death, cardiac and/or respiratory arrest, unplanned transfer to intensive/high dependency care, immediate/urgent request for review, rapid response system activation). METHOD: GRADE methodology. Papers identified through electronic database and citation searching. RESULTS: Thirty-three PTTS were identified from 55 studies. There was considerable variety in the number and type of parameters, although all contained one or more vital signs. The evidence to support PTTS implementation was very low and the majority of outcomes did not achieve statistical significance. When PTTS was implemented as part of a rapid response system, the evidence was moderate to low but there was some evidence of a statistically significant improvement in outcome. CONCLUSION: There is now some limited evidence for the validity and clinical utility of PTTS scores. The high (and increasing) number of systems is a significant confounder. Further research is needed particularly around the thresholds for the vital signs and the reliability, accuracy and calibration of PTTS in different settings. PMID- 27496260 TI - Ventilation fraction during the first 30s of neonatal resuscitation. AB - AIM: Approximately 5% of newborns receive positive pressure ventilation (PPV) for successful transition. Guidelines urge providers to ensure effective PPV for 30 60s before considering chest compressions and intravenous therapy. Pauses in this initial PPV may delay recovery of spontaneous respiration. The aim was to find the ventilation fraction during the first 30s of PPV in non-breathing babies. METHODS: Prospective observational study in two hospitals in Norway. All newborns receiving PPV immediately after delivery were included. Cameras with motion detectors were installed at every resuscitation bay capturing both expected and unexpected compromised newborns. We determined the cumulative number of seconds with PPV efforts excluding pauses in infants without spontaneous breathing and reported ventilation fraction during the first minute. Data are presented as median (IQR). RESULTS: 110 of 3508 (3%) newborns received PPV and were filmed in the resuscitation bays. PPV started 42 (18-78)s after arrival at the resuscitation bay and median duration was 100 (35-225)s. Forty-eight infants (44%) were ventilated continuously, or with minimal pause (ventilation fraction >90%) during the first 30s of PPV. For the remaining 62 infants ventilation fraction was 60% (39-75). PPV was interrupted due to adjustments, checking heart rate, stimulation, administration of CPAP and suctioning. CONCLUSION: In 56% of the neonatal resuscitations interruptions in ventilation are frequent with 60% ventilation fraction during the first 30s of PPV. Eliminating disruption for improved quality of PPV delivery should be emphasized when training newborn resuscitation providers. PMID- 27496261 TI - Reply to Letter: Could one degree in temperature change the world? Maybe for targeted temperature management! PMID- 27496262 TI - Amiodarone or lidocaine for cardiac arrest: A systematic review and meta analysis. AB - BACKGROUND: Guidelines for treatment of out-of-hospital cardiac arrest (OOH-CA) with shockable rhythm recommend amiodarone, while lidocaine may be used if amiodarone is not available. Recent underpowered evidence suggests that amiodarone, lidocaine or placebo are equivalent with respect to survival at hospital discharge, but amiodarone and lidocaine showed higher hospital admission rates. We undertook a systematic review and meta-analysis to assess efficacy of amiodarone vs lidocaine vs placebo. METHODS: We included studies published in PubMed and EMBASE databases from inception until May 15th, 2016. The primary outcomes were survival at hospital admission and discharge in OOH-CA patients enrolled in randomized clinical trials (RCT) according to resuscitation with amiodarone vs lidocaine vs placebo. If feasible, secondary analysis was performed including in the analysis also patients with in-hospital CA and data from non RCT. RESULTS: A total of seven findings were included in the metanalysis (three RCTs, 4 non-RCTs). Amiodarone was as beneficial as lidocaine for survival at hospital admission (primary analysis odds ratio-OR 0.86-1.23, p=0.40) and discharge (primary analysis OR 0.87-1.30, p=0.56; secondary analysis OR 0.86 1.27, p=0.67). As compared with placebo, survival at hospital admission was higher both for amiodarone (primary analysis OR 1.12-1.54, p<0.0001; secondary analysis OR 1.07-1.45, p<0.005) and lidocaine (secondary analysis only OR 1.14 1.58, p=0.0005). With regards to hospital discharge there were no differences between placebo and amiodarone (primary outcome OR 0.98-1.44, p=0.08; secondary outcome OR 0.92-1.33, p=0.28) or lidocaine (secondary outcome only OR 0.97-1.45, p=0.10). CONCLUSIONS: Amiodarone and lidocaine equally improve survival at hospital admission as compared with placebo. However, neither amiodarone nor lidocaine improve long-term outcome. PMID- 27496263 TI - Are the literacy difficulties that characterize developmental dyslexia associated with a failure to integrate letters and speech sounds? AB - The 'automatic letter-sound integration hypothesis' (Blomert, ) proposes that dyslexia results from a failure to fully integrate letters and speech sounds into automated audio-visual objects. We tested this hypothesis in a sample of English speaking children with dyslexic difficulties (N = 13) and samples of chronological-age-matched (CA; N = 17) and reading-age-matched controls (RA; N = 17) aged 7-13 years. Each child took part in two priming experiments in which speech sounds were preceded by congruent visual letters (congruent condition) or Greek letters (baseline). In a behavioural experiment, responses to speech sounds in the two conditions were compared using reaction times. These data revealed faster reaction times in the congruent condition in all three groups. In a second electrophysiological experiment, responses to speech sounds in the two conditions were compared using event-related potentials (ERPs). These data revealed a significant effect of congruency on (1) the P1 ERP over left frontal electrodes in the CA group and over fronto-central electrodes in the dyslexic group and (2) the P2 ERP in the dyslexic and RA control groups. These findings suggest that our sample of English-speaking children with dyslexic difficulties demonstrate a degree of letter-sound integration that is appropriate for their reading level, which challenges the letter-sound integration hypothesis. PMID- 27496264 TI - Coagulation Profile Dynamics in Pediatric Patients with Cushing Syndrome: A Prospective, Observational Comparative Study. AB - OBJECTIVE: To evaluate the association between Cushing syndrome and hypercoagulability in children. STUDY DESIGN: A prospective, observational study was performed of 54 patients with Cushing syndrome, 15.1 +/- 3.9 years, treated at the National Institutes of Health Clinical Center. Coagulation profiles were taken before and 6-12 months after surgery and compared with18 normocortisolemic children, 13.7 +/- 3.6 years. RESULTS: At baseline, patients with Cushing syndrome had greater levels of the procoagulant factor VIII (FVIII) vs controls (145 IU/dL +/- 84 vs 99 +/- 47, P = .04); 6-12 months after surgery, FVIII levels decreased to 111 +/- 47, P = .05. Patients with Cushing syndrome had greater levels of the antifibrinolytic alpha2-antiplasmin, 96 +/- 17% vs 82 +/- 26%, P = .015. After surgery, antifibrinolytic alpha2-antiplasmin levels decreased to 82 +/- 24%, P < .001. Anticoagulants were greater in patients with Cushing syndrome vs controls at baseline, including protein C (138 +/- 41% vs 84 +/- 25%, P < .001), protein S (94 +/- 19% vs 74 +/- 19%, P = .001), and antithrombin III (96 +/- 18% vs 77 +/- 13%, P < .0001). The 24-hour urinary free cortisol levels correlated positively with FVIII levels, r = 0.43, P = .004. CONCLUSION: Children with Cushing syndrome had elevated procoagulants, antifibrinolytics, and anticoagulants at baseline compared with controls; normalization of coagulation measures was seen after surgical cure. Despite the increase in anticoagulants, hypercortisolemia is associated with a hypercoagulable state in children, as is the case in adults. This finding has potential implications for prevention of venous thromboembolism in children with Cushing syndrome. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00001595. PMID- 27496265 TI - Benign Joint Hypermobility Minimally Impacts Autonomic Abnormalities in Pediatric Subjects with Chronic Functional Pain Disorders. AB - OBJECTIVE: To determine if children with benign joint hypermobility (BJH) syndrome and chronic functional pain disorders have more autonomic dysfunction. STUDY DESIGN: Retrospective chart review study of pediatric patients seen in the pediatric neurogastroenterology and autonomic clinic who underwent autonomic testing and had either a Beighton score of >=6 and met Brighton criteria for BJH (with BJH) or a score of <=2 (no BJH). RESULTS: Twenty-one female subjects (10 without BJH) met inclusion criteria; 64% of BJH had diagnosis confirmed by genetics consultation. We evaluated for postural tachycardia syndrome, syncope, orthostatic intolerance, and orthostatic hypotension. None of these diagnoses, as well as baseline heart rate, peak heart rate in first 10 minutes of head up tilt (P = .35 and P = .61, respectively), and sudomotor index (suggestive of autonomic neuropathy) (P = .58), showed differences between the groups. Age of onset of symptoms was also similar (P = .61) (BJH vs without BJH: median [range]:15.6 years [12.9-17.5] vs 15.4 years [11.1-18.2]). There was no difference between groups in complaints of migraine, chronic nausea, chronic fatigue, lightheadedness, dizziness, fainting >3 times/lifetime, delayed onset of sleep, irritable bowel syndrome, dyspepsia, abdominal migraine, functional abdominal pain, constipation, or fibromyalgia. CONCLUSIONS: Children with chronic functional pain disorders and BJH have autonomic testing findings and comorbid features compared with a similar cohort of subjects without BJH, suggesting that BJH is not the driver of the autonomic and comorbid disorders. PMID- 27496266 TI - Kawasaki Disease and Exposure to Fine Particulate Air Pollution. AB - OBJECTIVE: To analyze associations of short-term exposure to fine particulate matter (diameter <= 2.5 um [PM2.5]), a measurable component of urban pollution, with the event date of fever onset for patients with Kawasaki disease (KD) residing in 7 metropolitan regions. STUDY DESIGN: A case-crossover study design was used. Time trends, seasonality, month, and weekday were controlled for by matching. We assembled PM2.5 exposure measurements from urban monitors and imputed PM2.5 to provide day-to-day temporal variability and resolution for time series indexes of exposures. Selected exposure windows (to 14 days) of PM2.5 were examined. RESULTS: A total of 3009 KD events were included for which the subject resided within a study metropolitan area and the event date occurred during years with available PM2.5. The estimated ORs (with 95% CIs) of an event of KD associated with a 10 ug/m(3) PM2.5 lagged moving average concentration of lagged exposure period (ie, concurrent, preceding day[s]) revealed no evidence of a consistent, statistically significant, positive association between elevated PM2.5 exposure and increased risk of KD. Extended analysis with stratification by city, sex, age, ethnic origin, incomplete or complete clinical manifestations, the presence of coronary aneurysm, and intravenous immunoglobulin resistance did not provide evidence of a consistent, statistically significant, positive association between elevated exposure to PM2.5 and increased risk of KD for any of the strata studied. CONCLUSIONS: This multicity study failed to establish a risk of the event of KD with short-term fine particulate exposure. Our negative findings add to the growing field of environmental epidemiology research of KD. PMID- 27496267 TI - Geophagy Is Associated with Growth Faltering in Children in Rural Bangladesh. AB - OBJECTIVE: To determine the relationship between geophagy (mouthing of dirt, sand, clay, or mud) and growth faltering in young children. STUDY DESIGN: We examined linear growth as height and weight standardized by age and sex, and weight standardized by height, in a cohort of children aged 6-36 months in rural Mirzapur, Bangladesh. We determined geophagy behavior at baseline through caregiver report. Anthropometric measurements were assessed at baseline and at a 1-year follow-up. RESULTS: We found that among children not stunted at baseline, those with caregiver-reported geophagy at baseline grew less over 1 year compared with their peers, with a difference in the change of standardized height for age and sex of -0.31 (95% CI, -0.61 to -0.01). CONCLUSION: These findings show that caregiver-reported geophagy was associated with growth faltering in a pediatric population in rural Bangladesh. Future studies are needed to learn more about this exposure pathway and its relevance to child growth. PMID- 27496268 TI - The Imperative Nature of Physical Exam in Identifying Pediatric Scaphoid Fractures. PMID- 27496269 TI - Cutaneous Nocardiosis: A Conspicuous Eyelid Eschar. PMID- 27496270 TI - Utility of Body Mass Index in Identifying Excess Adiposity in Youth Across the Obesity Spectrum. AB - OBJECTIVES: To determine the proportion of youth within a given body mass index (BMI) obesity category with excess adiposity using dual energy x-ray absorptiometry (DXA). Furthermore, to examine whether mean differences in cardiometabolic risk factors based upon various excess adiposity cutpoints were present. STUDY DESIGN: DXA data from the National Health and Nutrition Examination Survey 1999-2006 (n = 10 465; 8-20 years of age) were used for this analysis. Obesity categories were defined using Centers for Disease Control and prevention definitions for age and sex. Excess adiposity was defined using cohort specific cutpoints at 75th, 85th, and 90th percentiles of DXA body fat (%) by age and sex using quantile regression models. Additionally, we examined differences in cardiometabolic risk factors among youth (BMI percentile >85th) above and below various excess adiposity cutpoints. RESULTS: Nearly all youth with class 3 obesity (100% male, 100% female; 97% male, 99% female; and 95% male, 96% female; using the 75th, 85th, and 90th DXA percentiles, respectively) and a high proportion of those with class 2 obesity (98% male, 99% female; 92% male, 91% female; and 76% male, 76% female) had excess adiposity. Significant discordance was observed between BMI categorization and DXA-derived excess adiposity among youth with class 1 obesity or overweight. Elevated cardiometabolic risk factors were present in youth with excess adiposity, regardless of the cutpoint used. CONCLUSIONS: BMI correctly identifies excess adiposity in most youth with class 2 and 3 obesity but a relatively high degree of discordance was observed in youth with obesity and overweight. Cardiometabolic risk factors are increased in the presence of excess adiposity, regardless of the cutpoint used. PMID- 27496271 TI - mHealth Intervention to Improve Diabetes Risk Behaviors in India: A Prospective, Parallel Group Cohort Study. AB - BACKGROUND: In low/middle income countries like India, diabetes is prevalent and health care access limited. Most adults have a mobile phone, creating potential for mHealth interventions to improve public health. To examine the feasibility and initial evidence of effectiveness of mDiabetes, a text messaging program to improve diabetes risk behaviors, a global nonprofit organization (Arogya World) implemented mDiabetes among one million Indian adults. OBJECTIVE: A prospective, parallel cohort design was applied to examine whether mDiabetes improved fruit, vegetable, and fat intakes and exercise. METHODS: Intervention participants were randomly selected from the one million Nokia subscribers who elected to opt in to mDiabetes. Control group participants were randomly selected from non-Nokia mobile phone subscribers. mDiabetes participants received 56 text messages in their choice of 12 languages over 6 months; control participants received no contact. Messages were designed to motivate improvement in diabetes risk behaviors and increase awareness about the causes and complications of diabetes. Participant health behaviors (exercise and fruit, vegetable, and fat intake) were assessed between 2012 and 2013 via telephone surveys by blinded assessors at baseline and 6 months later. Data were cleaned and analyzed in 2014 and 2015. RESULTS: 982 participants in the intervention group and 943 in the control group consented to take the phone survey at baselne. At the end of the 6-month period, 611 (62.22%) in the intervention and 632 (67.02%) in the control group completed the follow-up telephone survey. Participants receiving texts demonstrated greater improvement in a health behavior composite score over 6 months, compared with those who received no messages F(1, 1238) = 30.181, P<.001, 95% CI, 0.251-0.531. Fewer intervention participants demonstrated health behavior decline compared with controls. Improved fruit, vegetable, and fat consumption (P<.01) but not exercise were observed in those receiving messages, as compared with controls. CONCLUSIONS: A text messaging intervention was feasible and showed initial evidence of effectiveness in improving diabetes-related health behaviors, demonstrating the potential to facilitate population-level behavior change in a low/middle income country. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN): 12615000423516; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367946&isReview= rue (Archived by WebCite at http://www.webcitation.org/6j5ptaJgF). PMID- 27496274 TI - [Pansclerotic morphea with a rapidly fatal outcome in an 11-year-old girl]. AB - BACKGROUND: Pansclerotic morphea is a poorly described but extremely debilitating variant of localized scleroderma. We report a case with a rapidly fatal outcome in an 11-year-old girl. PATIENTS AND METHODS: An 11-year-old girl with a 2-year history of morphea presented at our institution in April 2012. The sclerosis had started on her trunk and progressed rapidly to involve her entire skin. Initial treatment with corticosteroids was ineffective and she presented extremely painful ulcerations of the lower limbs. The outcome was rapidly fatal, in early 2014, due to cachexia and sepsis after two amputations and several failed treatments including methotrexate. DISCUSSION: Pansclerotic morphea is characterized by rapidly progressing sclerosis involving the entire skin, trophic cutaneous ulcers, painful contraction and limited joint mobility. The prognosis is poor since the disease has an incapacitating and potentially fatal outcome. No reliably effective treatment has yet been established. CONCLUSION: Our case highlights the clinical characteristics of this uncommon form of localized scleroderma, the extremely severe prognosis, and the therapeutic challenge involved. PMID- 27496272 TI - Low dose ouabain stimulates NaK ATPase alpha1 subunit association with angiotensin II type 1 receptor in renal proximal tubule cells. AB - Our laboratory has recently demonstrated that low concentrations of ouabain increase blood pressure in rats associated with stimulation of NaK ATPase activity and activation of the Src signaling cascade in NHE1-dependent manner. Proteomic analysis of human kidney proximal tubule cells (HKC11) suggested that the Angiotensin II type 1 receptor (AT1R) as an ouabain-associating protein. We hypothesize that ouabain-induced stimulation of NaK ATPase activity is mediated through AT1R. To test this hypothesis, we examined the effect of ouabain on renal cell angiotensin II production, the effect of AT1R inhibition on ouabain stimulated NKA activity, and the effect of ouabain on NKA-AT1R association. Ouabain increased plasma angiotensin II levels in rats treated with ouabain (1MUg/kg body wt./day) for 9days and increased angiotensin II levels in cell culture media after 24h treatment with ouabain in human (HKC11), mouse (MRPT), and human adrenal cells. Ouabain 10pM stimulated NKA-mediated 86Rb uptake and phosphorylation of EGFR, Src, and ERK1/2. These effects were prevented by the AT1R receptor blocker candesartan. FRET and TIRF microscopy using Bodipy-labeled ouabain and mCherry-NKA or mCherry-AT1R demonstrated association of ouabain with AT1R and NKA. Further our FRET and TIRF studies demonstrated increased association between AT1R and NKA upon treatment with low dose ouabain. We conclude that ouabain stimulates NKA in renal proximal tubule cells through an angiotensin/AT1R-dependent mechanism and that this pathway contributes to cardiac glycoside associated hypertension. PMID- 27496275 TI - Are state laws granting pharmacists authority to vaccinate associated with HPV vaccination rates among adolescents? AB - OBJECTIVES: We explored whether state laws allowing pharmacists to administer human papillomavirus (HPV) vaccinations to adolescents are associated with a higher likelihood of HPV vaccine uptake. METHODS: We examined provider-reported HPV vaccination among 13-17year olds in the National Immunization Survey-Teen: 2008-2014 for girls (N=48,754) and 2010-2014 for boys (N=31,802). Outcome variables were HPV vaccine initiation (?1 dose) and completion (?3 doses). The explanatory variable of interest was a categorical variable for the type of pharmacist authority regarding HPV vaccination for adolescents (<18years) in the state: not permitted (reference), by prescription, by collaborative practice protocol, or independent authority. We ran separate difference-in-difference regression models by sex. RESULTS: During 2008-2014, 15 states passed laws allowing pharmacists to administer HPV vaccine to adolescents. Pharmacist authority laws were not statistically significantly associated with increased HPV vaccine initiation or completion. CONCLUSIONS: As currently implemented, state laws allowing pharmacists to administer HPV vaccine to adolescents were not associated with uptake. Possible explanations that need further research include restrictions on pharmacists' third-party billing ability and the lack of promotion of pharmacy vaccination services to age-eligible adolescents. PMID- 27496276 TI - High frequency ultrasound to assess skin thickness in healthy adults. AB - BACKGROUND: Intradermal immunization is gaining increased attention due to multiple factors: (1) intradermal (ID) vaccination has been shown to induce improved immunogenicity compared to intramuscular (IM) vaccination; (2) ID vaccination has been shown to have a dose-sparing potential over IM leading to a reduced vaccine cost and an increased availability of vaccines worldwide. However, the currently used Mantoux technique for ID injection is difficult to standardize and requires training. The aim of the study was (1) to assess the epidermal and dermal thickness at the proximal ventral and dorsal forearm (PVF & PDF) and deltoid in adults aged 18-65years (2) to determine the maximum penetration depth and needle characteristics for the development of a platform of medical devices suited for intradermal injection, VAX-IDTM. MATERIALS AND METHODS: Mean thickness of the PVF, PDF and deltoid were measured using high frequency ultrasound of healthy adults aged 18-65years. Correlation with gender, age and BMI was assessed using Mann-Whitney U Test, Spearman correlation and Wilcoxon Signed Ranks Test, respectively. RESULTS: Results showed an overall mean skin thickness of 1.19mm (0.65-1.55mm) at the PVF, 1.44mm (0.78-1.84mm) at the PDF, and 2.12mm (1,16-3.19mm) at the deltoid. Thickness of PVF & PDF and deltoid were significantly different for men vs women (pmean<0.001, <0.001, <0.001, and pmin<0.001, 0.012, <0.001, respectively). A significant association was found for age at the deltoid region (p<0.001). Skin thickness for PVF, PDF & deltoid was significantly associated to BMI (p<0.001). CONCLUSION: Significant differences in skin thickness were seen for the PVF, PDF and deltoid region for gender, and BMI. Age only influenced the skin thickness at deltoid region. A needle length of 1.0mm is best option for intradermal injection at the dorsal forearm (NCT02363465). PMID- 27496277 TI - Usability evaluation of intradermal adapters (IDA). AB - Intradermal adapter device technology minimizes the complexity of the Mantoux technique, thereby providing predictable, reproducible intradermal (ID) injections and removing the concerns regarding the ease and reliability of Mantoux technique when using conventional needle and syringe. The technology employs a simple device with geometry designed to gently deform the skin surface and the subcutaneous tissue, providing the ideal angle and depth of needle insertion for consistently successful intradermal injections. The results of this development were presented at the First, Second and Third Skin Vaccination Summits in 2011, 2013 and 2015 respectively [1,2,3]. The current publication addresses the performance of intradermal adapters (IDA) evaluated in three preclinical studies. The evaluations were based on the assessment of bleb formation in a skin model, an accepted indicator of ID injection success. All evaluated devices share the same proprietary dermal interface technology. Devices instituting this design are easy to use, require minimal training, and employ conventionally molded parts and cannula. These studies evaluated IDAs of initial design integral with luer lock needles, IDAs for use with conventional syringes, and intradermal adapters for use with auto disable syringes (ADID adapters). The evaluated ID adapters were intended to consistently place the lancet of the needle at a depth of 0.75mm from the skin's surface. This placement depth addresses the variation in the skin thickness at immunization sites for the majority of patients independent of many other variables. Most participants preferred the intradermal adapter method over the traditional Mantoux and identified a need for the adapter at their workplace. Evaluation of IDAs by registered nurses indicated these devices increase success of bleb formation. The use of IDA increased the success of forming blebs by about 30%. Nurses felt the injections were much easier to perform, in particular by novices. PMID- 27496278 TI - Proteome-wide antigen discovery of novel protective vaccine candidates against Staphylococcus aureus infection. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a rapidly growing problem, especially in hospitals where MRSA cause increased morbidity and mortality and a significant rise in health expenditures. As many strains of MRSA are resistant to other antimicrobials in addition to methicillin, there is an urgent need to institute non-antimicrobial measures, such as vaccination, against the spread of MRSA. With the aim of finding new protective antigens for vaccine development, this study used a proteome-wide in silico antigen prediction platform to screen the proteome of S. aureus strain MRSA252. Thirty-five different S. aureus proteins were identified, recombinantly expressed, and tested for protection in a lethal sepsis mouse model using S. aureus strain MRSA252 as the challenge organism. We found that 13 of the 35 recombinant peptides yielded significant protection and that 12 of these antigens were highly conserved across 70 completely sequenced S. aureus strains. Thus, this in silico platform was capable of identifying novel candidates for inclusion in future vaccines against MRSA. PMID- 27496279 TI - Viscoelasticity of Tendons Under Transverse Compression. AB - Tendons are highly anisotropic and also viscoelastic. For understanding and modeling their 3D deformation, information is needed on their viscoelastic response under off-axis loading. A study was made, therefore, of creep and recovery of bovine digital extensor tendons when subjected to transverse compressive stress of up to ca. 100 kPa. Preconditioned tendons were compression tested between glass plates at increasing creep loads. The creep response was anomalous: the relative rate of creep reduced with the increasing stress. Over each ca. 100 s creep period, the transverse creep deformation of each tendon obeyed a power law dependence on time, with the power law exponent falling from ca. 0.18 to an asymptote of ca. 0.058 with the increasing stress. A possible explanation is stress-driven dehydration, as suggested previously for the similar anomalous behavior of ligaments. Recovery after removal of each creep load was also anomalous. Relative residual strain reduced with the increasing creep stress, but this is explicable in terms of the reducing relative rate of creep. When allowance was made for some adhesion occurring naturally between tendon and the glass plates, the results for a given load were consistent with creep and recovery being related through the Boltzmann superposition principle (BSP). The tendon tissue acted as a pressure-sensitive adhesive (PSA) in contact with the glass plates: explicable in terms of the low transverse shear modulus of the tendons. PMID- 27496280 TI - Long-term (5 years) cryopreserved spermatogonia have high capacity to generate functional gametes via interspecies transplantation in salmonids. AB - Although sperm cryopreservation is a powerful tool widely applicable in biodiversity conservation and broodstock management, cryopreservation of teleost eggs and embryos remains challenging. In the present study, we demonstrated that spermatogonia of rainbow trout (Oncorhynchus mykiss) cryopreserved for 5 years possessed the ability to differentiate into functional eggs or sperm in the gonads of triploid recipient masu salmon (Oncorhynchus masou). After cryopreservation for 5 years in liquid nitrogen, intraperitoneally transplanted spermatogonia migrated toward, and incorporated into, the gonads of xenogeneic recipients. The transplanted spermatogonia resumed spermatogenesis and oogenesis in male and female recipients, respectively, and differentiated into sperm or eggs within the gonads of male and female recipients at 2 years posttransplantation. The differentiated sperm and eggs generated normal rainbow trout representative of donor phenotypes. Thus, cryopreservation of spermatogonia is a powerful and reliable method for long-term preservation of fish genetic resources. PMID- 27496281 TI - Antibiotic resistance evolved via inactivation of a ribosomal RNA methylating enzyme. AB - Modifications of the bacterial ribosome regulate the function of the ribosome and modulate its susceptibility to antibiotics. By modifying a highly conserved adenosine A2503 in 23S rRNA, methylating enzyme Cfr confers resistance to a range of ribosome-targeting antibiotics. The same adenosine is also methylated by RlmN, an enzyme widely distributed among bacteria. While RlmN modifies C2, Cfr modifies the C8 position of A2503. Shared nucleotide substrate and phylogenetic relationship between RlmN and Cfr prompted us to investigate evolutionary origin of antibiotic resistance in this enzyme family. Using directed evolution of RlmN under antibiotic selection, we obtained RlmN variants that mediate low-level resistance. Surprisingly, these variants confer resistance not through the Cfr like C8 methylation, but via inhibition of the endogenous RlmN C2 methylation of A2503. Detection of RlmN inactivating mutations in clinical resistance isolates suggests that the mechanism used by the in vitro evolved variants is also relevant in a clinical setting. Additionally, as indicated by a phylogenetic analysis, it appears that Cfr did not diverge from the RlmN family but from another distinct family of predicted radical SAM methylating enzymes whose function remains unknown. PMID- 27496282 TI - tRNA anticodon loop modifications ensure protein homeostasis and cell morphogenesis in yeast. AB - Using budding yeast, we investigated a negative interaction network among genes for tRNA modifications previously implicated in anticodon-codon interaction: 5 methoxy-carbonyl-methyl-2-thio-uridine (mcm5s2U34: ELP3, URM1), pseudouridine (Psi38/39: DEG1) and cyclic N6-threonyl-carbamoyl-adenosine (ct6A37: TCD1). In line with functional cross talk between these modifications, we find that combined removal of either ct6A37 or Psi38/39 and mcm5U34 or s2U34 results in morphologically altered cells with synthetic growth defects. Phenotypic suppression by tRNA overexpression suggests that these defects are caused by malfunction of tRNALysUUU or tRNAGlnUUG, respectively. Indeed, mRNA translation and synthesis of the Gln-rich prion Rnq1 are severely impaired in the absence of Psi38/39 and mcm5U34 or s2U34, and this defect can be rescued by overexpression of tRNAGlnUUG Surprisingly, we find that combined modification defects in the anticodon loops of different tRNAs induce similar cell polarity- and nuclear segregation defects that are accompanied by increased aggregation of cellular proteins. Since conditional expression of an artificial aggregation-prone protein triggered similar cytological aberrancies, protein aggregation is likely responsible for loss of morphogenesis and cytokinesis control in mutants with inappropriate tRNA anticodon loop modifications. PMID- 27496284 TI - James Riddick Heron. PMID- 27496283 TI - Efficiency of integron cassette insertion in correct orientation is ensured by the interplay of the three unpaired features of attC recombination sites. AB - The integron is a bacterial recombination system that allows acquisition, stockpiling and expression of cassettes carrying protein-coding sequences, and is responsible for the emergence and rise of multiresistance in Gram-negative bacteria. The functionality of this system depends on the insertion of promoterless cassettes in correct orientation, allowing their expression from the promoter located upstream of the cassette array. Correct orientation is ensured by strand selectivity of integron integrases for the bottom strand of cassette recombination sites (attC), recombined in form of folded single-stranded hairpins. Here, we investigated the basis of such strand selectivity by comparing recombination of wild-type and mutated attC sites with different lengths, sequences and structures. We show that all three unpaired structural features that distinguish the bottom and top strands contribute to strand selectivity. The localization of Extra-Helical Bases (EHBs) directly favors integrase binding to the bottom strand. The Unpaired Central Spacer (UCS) and the Variable Terminal Structure (VTS) influence strand selectivity indirectly, probably through the stabilization of the bottom strand and the resulting synapse due to the nucleotide skew between the two strands. These results underscore the importance of the single-stranded nature of the attC site that allows such tight control over integron cassette orientation. PMID- 27496285 TI - Decreased extrusion of calcium phosphate cement versus high viscosity PMMA cement into spongious bone marrow-an ex vivo and in vivo study in sheep vertebrae. AB - BACKGROUND CONTEXT: Vertebroplasty or kyphoplasty of osteoporotic vertebral fractures bears the risk of pulmonary cement embolism (3.5%-23%) caused by leakage of commonly applied acrylic polymethylmethacrylate (PMMA) cement to spongious bone marrow or outside of the vertebrae. Ultraviscous cement and specific augmentation systems have been developed to reduce such adverse effects. Rapidly setting, resorbable, physiological calcium phosphate cement (CPC) may also represent a suitable alternative. PURPOSE: This study aimed to compare the intravertebral extrusion of CPC and PMMA cement in an ex vivo and in vivo study in sheep. STUDY DESIGN/SETTING: A prospective experimental animal study was carried out. METHODS: Defects (diameter 5 mm; 15 mm depth) were created by a ventrolateral percutaneous approach in lumbar vertebrae of female Merino sheep (2 4 years) either ex vivo (n=17) or in vivo (n=6), and injected with: (1) CPC (L3); (2) CPC reinforced with 10% poly(l-lactide-co-glycolide) (PLGA) fibers (L4); or (3) PMMA cement (L5; Kyphon HV-R). Controls were untouched (L1) or empty defects (L2). The effects of the cement injections were assessed in vivo by blood gas analysis and ex vivo by computed tomography (CT), micro-CT (voxel size: 67 um), histology, and biomechanical testing. RESULTS: Following ex vivo injection, micro CT documented significantly increased extrusion of PMMA cement in comparison to CPC (+/- fibers) starting at a distance of 1 mm from the edge of the defect (confirmed by histology); this was also demonstrated by micro-CT following in vivo cement injection. In addition, blood gas analysis showed consistently significantly lower values for the fraction of oxygenized hemoglobin/total hemoglobin (FO2Hb) in the arterial blood until 25 minutes following injection of the PMMA cement (p <= .05 vs. CPC; 7, 15 minutes). Biomechanical testing following ex vivo injection showed significantly lower compressive strength and Young modulus than untouched controls for the empty defect (40% and 34% reduction, respectively) and all three cement-injected defects (21%-27% and 29% 32% reduction, respectively), without significant differences among the cements. CONCLUSIONS: Because of comparable compressive strength, but significantly lower cement extrusion into spongious bone marrow than PMMA cement, physiological CPC (+/- PLGA fibers) may represent an attractive alternative to PMMA for vertebroplasty or kyphoplasty of osteoporotic vertebral fractures to reduce the frequency or severity of adverse effects. PMID- 27496287 TI - Storytelling and Consumerism. PMID- 27496286 TI - Quality of life outcomes following cervical decompression for coexisting Parkinson's disease and cervical spondylotic myelopathy. AB - BACKGROUND CONTEXT: Coexisting Parkinson's disease (PD) and cervical spondylotic myelopathy (CSM) presents a diagnostic and therapeutic challenge due to symptomatic similarities between the diseases. Whereas CSM patients are routinely treated with surgery, PD patients face poorer outcomes following spine surgery. No studies have investigated the quality of life (QOL) outcomes following decompression in coexisting PD and CSM. PURPOSE: The purpose of the present study was to characterize QOL outcomes for patients with coexisting PD and CSM following cervical decompression. STUDY DESIGN/SETTING: This is a matched cohort study at a single tertiary-care center. PATIENT SAMPLE: Patients with coexisting PD and CSM undergoing cervical decompression between June 2009 and December 2014 were included. These patients were matched to controls with CSM alone by age, gender, American Society of Anesthesiologists classification, Modified Japanese Orthopaedic Association scores, and operative parameters. OUTCOME MEASURES: The primary outcome measure was QOL outcomes assessed by change in the EuroQol 5 Dimensions (EQ-5D), Pain Disability Questionnaire (PDQ), and Patient Health Questionnaire-9 (PHQ-9) at last follow-up (LFU). Change in QOL exceeding the minimal clinically important difference (MCID) was secondary. METHODS: QOL data were collected using the institutional prospectively collected database of patient-reported health status measures. Simple and multivariable regressions were used to assess the impact of PD upon change in QOL. RESULTS: Eleven PD patients were matched to 44 controls. Control patients experienced QOL improvement across all three measures, whereas PD patients only improved with respect to PDQ(89.9-80.7, p=.03). Despite no significant differences in preoperative QOL, PD patients experienced poorer QOL at LFU in EQ-5D (0.526 vs. 0.707, p=.01) and PDQ (80.7 vs. 51.4, p=.03), and less frequently achieved an EQ 5D MCID (18% vs. 57%, p=.04). However, no differences in the achievement of an MCID in PDQ or PHQ-9 were observed between cohorts. Multivariable regression identified PD as a significant independent predictor of poorer improvement in EQ 5D (beta=-0.09, p<.01) and failure to achieve an EQ-5D MCID (odds ratio: 0.08, p<.01). CONCLUSIONS: This is the first study to characterize QOL outcomes following cervical decompression for patients with coexisting PD and CSM. Although myelopathy may have been less severe among PD patients, a significant reduction in pain-related disability was observed following decompression. However, PD predicted diminished improvement in overall QOL measured by the EQ 5D. PMID- 27496288 TI - ACR Appropriateness Criteria Low Back Pain. AB - Most patients presenting with uncomplicated acute low back pain (LBP) and/or radiculopathy do not require imaging. Imaging is considered in those patients who have had up to 6 weeks of medical management and physical therapy that resulted in little or no improvement in their back pain. It is also considered for those patients presenting with red flags raising suspicion for serious underlying conditions, such as cauda equina syndrome, malignancy, fracture, and infection. Many imaging modalities are available to clinicians and radiologists for evaluating LBP. Application of these modalities depends largely on the working diagnosis, the urgency of the clinical problem, and comorbidities of the patient. When there is concern for fracture of the lumbar spine, multidetector CT is recommended. Those deemed to be interventional candidates, with LBP lasting for > 6 weeks having completed conservative management with persistent radiculopathic symptoms, may seek MRI. Patients with severe or progressive neurologic deficit on presentation and red flags should be evaluated with MRI. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (the RAND/UCLA Appropriateness Method and the Grading of Recommendations Assessment, Development, and Evaluation) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. PMID- 27496289 TI - Esophageal hypersensitivity in noncardiac chest pain. AB - Noncardiac chest pain (NCCP) is an often-encountered clinical problem. Although many patients suffer from persistent or recurrent chest pain, treatment remains a challenge owing to its various possible etiologies. Gastroesophageal reflux disease (GERD) is the most common cause of NCCP. In GERD-related NCCP, proton pump inhibitor treatment appears to be effective. However, the pathophysiology remains to be fully elucidated in NCCP patients without GERD. Treatment for non GERD-related NCCP has been aimed at esophageal motility disorders and visceral hypersensitivity. As there is growing evidence that esophageal visceral hypersensitivity plays a role in NCCP, pain modulators have become the mainstay of therapy in patients with non-GERD-related NCCP. However, there is an unmet need for the treatment of esophageal hypersensitivity in NCCP due to modest evidence for the benefit of pain modulators, including antidepressants, in non GERD-related NCCP. Recent studies have demonstrated that esophageal mast cell infiltration and impaired mucosal integrity are related to visceral hypersensitivity in patients with NCCP. Thus, esophageal mast cell stabilization and restoration of esophageal mucosal integrity could be considered potential therapeutic targets in selected NCCP patients with hypersensitivity. However, further observations are necessary to shed light on esophageal hypersensitivity in NCCP. PMID- 27496290 TI - Three-dimensional autologous cartilage framework fabrication assisted by new additive manufactured ear-shaped templates for microtia reconstruction. AB - BACKGROUND: During microtia reconstruction, the intraoperative design of the cartilage framework is important for the appearance and symmetry of the bilateral auricles. Templates (traditionally, the X-ray film template) are usually utilized to complete the task, which can provide cues regarding size, cranioauricular angle and positioning to the surgeons. With a combination of three-dimensional (3D) scanning and additive manufacturing (AM) techniques, we utilized two different ear-shaped templates (sheet moulding and 3D templates) during the fabrication of 3D-customized autologous cartilage frameworks for auricle reconstruction. METHODS: Forty unilateral microtia patients were included in the study. All the patients underwent auricle reconstruction using the tissue expanding technique assisted by the new AM templates. Images were processed using computer-aided design software and exported to print two different AM ear-shaped templates: sheet moulding and 3D. Both templates were assisted by the 3D framework fabrication. The 3D images of each patient's head were captured preoperatively using a 3D scanner. X-ray film templates were also made for the patients. The lengths and widths of the contralateral auricles, X-ray film and sheet moulding templates were measured in triplicate. The error of the template and the contralateral auricle were used to compare the accuracy between the two templates. RESULTS: Between January and May 2014, 40 unilateral microtia patients aged 6-29 years were included in this study. All patients underwent auricle reconstruction using autogenous costal cartilage. The sterilized AM templates were used to assist in the framework fabrication. The operative time was decreased by an average of 15 min compared with the method assisted by the X-ray film template. Postoperative appearance evaluation (based on five indexes: symmetry, length, width, cranioauricular angle and the substructure of the reconstructed ear) was performed by both the doctors and the patients (or their parents). Follow-up (ranging from 9 to 18 months) showed that all of the patients obtained satisfactory results with life-like 3D configuration and symmetric cranioauricular angle. The follow-up showed that no surgery-related complications occurred. Comparing the accuracy of the X-ray film and sheet moulding templates, the average errors of length were 1.8 mm +/- 1.44 mm and 0.39 mm +/- 0.35 mm, respectively, and the average width errors were 1.32 mm +/- 0.88 mm and 0.3 mm +/ 0.47 mm, respectively. The new sheet moulding template was more accurate than the X-ray template. CONCLUSIONS: The new sheet-moulding template is much more accurate than the traditional X-ray film template. Framework fabrication assisted by accurate 3D and informative AM templates contributed to individualized cartilage framework fabrication and satisfactory results. PMID- 27496291 TI - A systematic review of the use of lasers for the treatment of hidradenitis suppurativa. AB - AIM: To conduct a systematic review of the effectiveness of various types of lasers (and light based therapies) for the treatment of hidradenitis suppurativa (HS) and to establish recommendations based on our findings. DATA SOURCES: MEDLINE, Cochrane and PubMed databases. STUDY SELECTION: English language studies describing the use of laser for the treatment of HS. DATA EXTRACTION: Multiple reviewers performed independent extraction and identified 22 studies that met the inclusion and exclusion criteria. DATA SYNTHESIS: Studies were categorised according to grading recommendations based on evidence quality guidelines for systematic reviews. Only 2 studies met criteria to be assigned the highest grade. CONCLUSION: Nd:YAG laser has been shown to be effective for the treatment of HS, as is intense pulsed light therapy (IPL) using the same principles of laser hair removal. There is weak evidence to recommend the use of carbon dioxide, diode or alexandrite lasers. The need for larger randomized controlled trials is highlighted. PMID- 27496292 TI - Absence of a conventional spindle mitotic checkpoint in the binucleated single celled parasite Giardia intestinalis. AB - The spindle assembly checkpoint (SAC) joins the machinery of chromosome-to spindle microtubule attachment with that of the cell cycle to prevent missegregation of chromosomes during mitosis. Although a functioning SAC has been verified in a limited number of organisms, it is regarded as an evolutionarily conserved safeguard mechanism. In this report, we focus on the existence of the SAC in a single-celled parasitic eukaryote, Giardia intestinalis. Giardia belongs to Excavata, a large and diverse supergroup of unicellular eukaryotes in which SAC control has been nearly unexplored. We show that Giardia cells with absent or defective mitotic spindles due to the inhibitory effects of microtubule poisons do not arrest in mitosis; instead, they divide without any delay, enter the subsequent cell cycle and even reduplicate DNA before dying. We identified a limited repertoire of kinetochore and SAC components in the Giardia genome, indicating that this parasite is ill equipped to halt mitosis before the onset of anaphase via SAC control of chromosome-spindle microtubule attachment. Finally, based on overexpression, we show that Giardia Mad2, a core SAC protein in other eukaryotes, localizes along intracytoplasmic portions of caudal flagellar axonemes, but never within nuclei, even in mitotic cells with blocked spindles, where the SAC should be active. These findings are consistent with the absence of a conventional SAC, known from yeast and metazoans, in the parasitic protist Giardia. PMID- 27496293 TI - Bismuth Interfacial Doping of Organic Small Molecules for High Performance n-type Thermoelectric Materials. AB - Development of chemically doped high performance n-type organic thermoelectric (TE) materials is of vital importance for flexible power generating applications. For the first time, bismuth (Bi) n-type chemical doping of organic semiconductors is described, enabling high performance TE materials. The Bi interfacial doping of thiophene-diketopyrrolopyrrole-based quinoidal (TDPPQ) molecules endows the film with a balanced electrical conductivity of 3.3 S cm(-1) and a Seebeck coefficient of 585 MUV K(-1) . The newly developed TE material possesses a maximum power factor of 113 MUW m(-1) K(-2) , which is at the forefront for organic small molecule-based n-type TE materials. These studies reveal that fine tuning of the heavy metal doping of organic semiconductors opens up a new strategy for exploring high performance organic TE materials. PMID- 27496294 TI - Electrocardiographic Screening in National Collegiate Athletic Association Athletes. AB - The most effective protocol for cardiovascular screening of competitive athletes remains highly controversial. This study was a prospective, multicenter trial of cardiovascular screening at 35 National Collegiate Athletic Association institutions. Screening included a standardized history and physical examination (PE) as recommended by the American Heart Association and a 12-lead electrocardiogram (ECG) at rest. Centralized electrocardiographic interpretation was provided using the Seattle criteria. Athletes with screening abnormalities underwent additional evaluation directed by the host institution medical team. Primary outcomes included the proportion of total and false-positive screens; the sensitivity, specificity, and positive predictive value of history, PE, and ECG; and the prevalence of serious cardiovascular disorders associated with severe morbidity or sudden cardiac death. From August 2012 to June 2014, 5,258 athletes from 17 intercollegiate sports were screened: 55% men (mean age 20.1 years), 73% Caucasian, 16% African-American, and 11% other/mixed race. At least 1 positive cardiac symptom or family history response was reported by 1,750 athletes (33.3%). PE was abnormal in 108 athletes (2.1%), and electrocardiographic abnormalities were present in 192 athletes (3.7%). Thirteen athletes (0.25%) were identified with serious cardiac conditions including hypertrophic cardiomyopathy (1), large atrial septal defect with right ventricular dilation (1), and ventricular pre-excitation (11). The false-positive rate for history was 33.3%, PE 2.0%, and ECG 3.4%. The sensitivity/specificity/positive predictive value for history was 15.4%/66.9%/0.1%, PE 7.7%/98.2%/0.9%, and ECG 100%/96.6%/6.8%. In conclusion, electrocardiographic screening in National Collegiate Athletic Association athletes has a low false-positive rate and provides superior accuracy compared with a standardized history and PE to detect athletes with potentially dangerous cardiovascular conditions. PMID- 27496295 TI - Percutaneous Nephrolithotomy Increases the Risk of New-onset Hypertension: A Nationwide 6-Year Follow-up Study. AB - OBJECTIVE: To determine whether percutaneous nephrolithotomy or ureteroscopic lithotripsy leads to the development of hypertension, using the Taiwan National Health Insurance database. METHODS: Data were sourced from the Longitudinal Health Insurance Database (LHID2000) of Taiwan, Republic of China, compiled by the Taiwan National Health Insurance database from 1996 to 2010. Percutaneous nephrolithotomy and ureteroscopic lithotripsy were studied as time-dependent covariates in a Cox proportional hazard model to estimate the hazard ratio for the effect of new-onset hypertension. RESULTS: A total of 2552 patients were included, with 232 PNL percutaneous nephrolithotomy, 1160 ureteroscopic lithotripsy patients, and 1160 comparison patients. There was a significant difference between the incidence of new-onset hypertension between the percutaneous nephrolithotomy and comparison groups (adjusted hazard ratio 1.48, 95% confidence interval 1.13-1.95, P = .005). The percutaneous nephrolithotomy group also had a higher incidence of new-onset hypertension than the ureteroscopic lithotripsy group (adjusted hazard ratio 1.39, 95% confidence interval 1.06-1.83, P = .018). The incidence rate of new hypertension during the follow-up period was 44.5 per 1000 person-years in the percutaneous nephrolithotomy group, 33.0 per 1000 person-years in the ureteroscopic lithotripsy group, and 30.2 per 1000 person-years in the comparison group. CONCLUSION: An association exists between nephrolithiasis patients who were treated with percutaneous nephrolithotomy and subsequent hypertension diagnosis. Although the exact mechanisms for this phenomenon are not clear, patients who undergo percutaneous nephrolithotomy may need close monitoring of blood pressure during postoperative follow-up. PMID- 27496296 TI - Predictors of Recurrence and Successful Treatment Following Obstetric Fistula Surgery. AB - OBJECTIVE: To determine factors contributing to recurrence and successful treatment of obstetric fistula (OF). MATERIALS AND METHODS: Data were collected from OF patients in Saint Luc Hospital Kisantu (DR of Congo) between 2007 and 2013. Patients underwent surgical treatment and were evaluated after a follow-up period of 3 months. Successful treatment was defined as no or dry pads whereas recurrence was defined as the persisting need for wearing incontinence pads immediately after the surgery or after a period of dryness. Fistula classification was done according to Waaldijk. Univariate and multivariate analyses were performed using logistic regression, corrected for preoperative and intraoperative OF characteristics. RESULTS: Median age of 166 OF patients was 29.11 +/- 9. 6 years (range 5-61). The majority of OF was type I (57.2%) followed by type III (20.5 %). There were 20.5% who showed vaginal fibrosis during surgical treatment. The most common location of fistula was pericervical (39.8%). The global recurrence rate at 3 months was 28.3%, with type IIBb (100%) as most the common recurring, followed by IIAb (66.67%) and IIAa (41.18%). There were 71.7%, 15.7%, 12%, and 0.6% patients who were considered completely cured, partially cured (downstaged), persistent, and upstaged, respectively. OF patients with fibrosis were 68% less likely (odds ratio 0.32, 95% confidence interval 0.14 0.73; P = .0065) to be dry in comparison to those without fibrosis. Patients with urethral fistula were 73% less likely (odds ratio 0.27, 95% confidence interval 0.11-0.63; P = .0024) to be dry compared to other locations. CONCLUSION: This study showed that fibrosis and urethral location are independent risk factors for fistula recurrence or persistence following surgical fistula repair. PMID- 27496297 TI - Commentary: Does Asymptomatic Bacteriuria Reduce the Risk of Recurrence of Non muscle-invasive Bladder Tumors? PMID- 27496298 TI - Detailed Cost Analysis of Robotic Sacrocolpopexy Compared to Transvaginal Mesh Repair. AB - OBJECTIVE: To evaluate the hospital-realized cost difference between transvaginal mesh prolapse repair and robot-assisted sacrocolpopexy. METHODS: Consecutive transvaginal mesh prolapse surgery and robot-assisted sacrocolpopexy cases from January 2012 to December 2013 were evaluated. Patient clinical and operative data were recorded. The total institutional costs (direct and indirect) for each procedure were obtained and subcategorized by area. Independent sample t tests and chi-squared analysis were performed. RESULTS: One hundred twenty women underwent transvaginal mesh repair whereas 106 underwent robotic sacrocolpopexy. Body mass index was similar between groups (28.1 vs 27.5) as was midurethral sling placement (50% vs 59%). Robotic patients were younger (61 years vs 67 years., P < .001) and more likely to undergo concomitant hysterectomy (58.5% vs 26.7%). There were similar rates for additional compartment repairs. Amortized costs for robotic purchase and maintenance were included with all depreciated equipment and realized by all patients undergoing surgery. Overall mean robotic operative time was longer with and without hysterectomy (279 minutes vs 174 minutes, P < .001 and 201 minutes vs 91 minutes, P < .001). Mean total costs were higher with robotic technique ($9675 vs $6718, P < .001), primarily driven by anesthesia ($1141 vs $675, P < .001), and operative ($6883 vs $4487, P < .001) costs. No differences for total costs were seen in laboratory fees, recovery room, or inpatient nursing. CONCLUSION: Transvaginal prolapse repair is less costly than robotic sacrocolpopexy. Length of surgery and additional robotic supplies drive the majority of increased operative costs. Costs attributed to robot purchase and maintenance do not uniquely factor into the procedure costs. PMID- 27496299 TI - Improving Outcomes of Bulbomembranous Urethroplasty for Radiation-induced Urethral Strictures in Post-Urolume Era. AB - OBJECTIVE: To evaluate contemporary outcomes of excision and primary anastomosis (EPA) for the treatment of radiation-induced urethral strictures (RUS). PATIENTS AND METHODS: A retrospective review of 72 patients undergoing EPA for RUS from 2007 to 2015 by a single surgeon was performed. We analyzed overall and long-term success rates of EPA urethroplasty and compared patient cohorts from two groups, 2007-2012 vs 2013-2015 (post-Urolume). RESULTS: During the course of the study, we noted a near doubling of patient volume from the earlier (6.2 patients/year) to later (11.7 patients/year) cohorts. Among the 37 men treated from 2007 to 2012, we identified an EPA success rate of 70% compared with the improved 86% success rate in the subsequent cohort of 35 men treated from 2013 to 2015 (P = .07). Single dilation was successful in 50% of initial and 40% of subsequent cohort patients in the treatment of recurrence. Initial and subsequent cohorts varied only in regard to stricture length (mean 2.0 cm vs 3.0 cm in initial and subsequent cohorts, P = .001) and number treated with Urolume stent (initial 5 vs none in the later cohort, P = .03). Length of follow-up (median 50 [17-97] months for the initial and 22 [6-34] months for the later cohort) was not associated with recurrence. CONCLUSION: Increasing numbers of RUS patients are presenting for urethral reconstruction in the post-Urolume era. With increasing experience, we improved success rates of EPA urethroplasty to over 85% despite increased stricture length. PMID- 27496300 TI - Identifying Drivers of Episode Cost Variation With Radical Prostatectomy. AB - OBJECTIVE: To describe total and component radical prostatectomy (RP) episode costs across a diverse set of hospitals in Michigan, and examine drivers of variation in such payments. METHODS: We identified Medicare and private payer patients undergoing RP from 2012 to 2014 from the claims-based registry maintained by the Michigan Value Collaborative, a statewide consortium that provides hospitals with price-standardized and risk-adjusted 90-day episode costs for common medical and surgical procedures. We divided hospitals into quartiles based on mean total episode cost for RP. Total episode costs were further classified into 4 payment categories: index hospitalization, professional services, readmissions, and postacute care. Component payments were then compared across high-cost and low-cost hospitals. RESULTS: We identified 3077 patients undergoing RP in 42 hospitals. Mean 90-day total episode cost was $14,614, ranging from $13,043 to $16,749 across quartiles (28.4% difference, P < .001). Overall variation in total episode cost was divided nearly equally among readmissions (29%), postacute care (29%), and professional payments (26%). We noted significantly higher readmission ($1442 vs $288, P = .03) and postacute care payments at high-cost hospitals ($1686 vs $522, P = .002). CONCLUSION: Significant variation exists in 90-day total episode costs for RP, suggesting a potential target for bundled payments and other care improvement efforts. Focused efforts on reducing variation in readmissions and postacute care could improve cost-efficiency. PMID- 27496301 TI - The cost of local, multi-professional obstetric emergencies training. AB - INTRODUCTION: We aim to outline the annual cost of setting up and running a standard, local, multi-professional obstetric emergencies training course, PROMPT (PRactical Obstetric Multi-Professional Training), at Southmead Hospital, Bristol, UK - a unit caring for approximately 6500 births per year. MATERIAL AND METHODS: A retrospective, micro-costing analysis was performed. Start-up costs included purchasing training mannequins and teaching props, printing of training materials and assembly of emergency boxes (real and training). The variable costs included administration time, room hire, additional printing and the cost of releasing all maternity staff in the unit, either as attendees or trainers. Potential, extra start-up costs for maternity units without established training were also included. RESULTS: The start-up costs were ?5574 and the variable costs for 1 year were ?143 232. The total cost of establishing and running training at Southmead for 1 year was ?148 806. Releasing staff as attendees or trainers accounted for 89% of the total first year costs, and 92% of the variable costs. The cost of running training in a maternity unit with around 6500 births per year was approximately ?23 000 per 1000 births for the first year and around ?22 000 per 1000 births in subsequent years. CONCLUSIONS: The cost of local, multi professional obstetric emergencies training is not cheap, with staff costs potentially representing over 90% of the total expenditure. It is therefore vital that organizations consider the clinical effectiveness of local training packages before implementing them, to ensure the optimal allocation of finite healthcare budgets. PMID- 27496303 TI - Hodgkin lymphoma: Introduction. PMID- 27496304 TI - Hodgkin lymphoma: Pathology and biology. AB - The Hodgkin and Reed-Sternberg (HRS) tumor cells of classical Hodgkin lymphoma (HL), as well as the lymphocyte predominant (LP) cells of nodular lymphocyte predominant HL (NLPHL), are derived from mature B cells. However, HRS cells have largely lost their B-cell phenotype and show a very unusual expression of many markers of other hematopoietic cell lineages, which aids in the differential diagnosis between classical HL (cHL) and NLPHL and distinguishes cHL from all other hematopoietic malignancies. The bi- or multinucleated Reed-Sternberg cells most likely derive from the mononuclear Hodgkin cells through a process of incomplete cytokinesis. HRS cells show a deregulated activation of numerous signaling pathways, which is partly mediated by cellular interactions in the lymphoma microenvironment and partly by genetic lesions. In a fraction of cases, Epstein-Barr virus contributes to the pathogenesis of cHL. Recurrent genetic lesions in HRS cells identified so far often involve members of the nuclear factor-kappaB (NF-kappaB) and JAK/STAT pathways and genes involved in major histocompatibility complex expression. However, further lead transforming events likely remain to be identified. We here discuss the current knowledge on HL pathology and biology. PMID- 27496305 TI - Clinical presentation and staging of Hodgkin lymphoma. AB - In the present chapter the authors present a brief overview of the diagnostic methods proposed over time for Hodgkin lymphoma (HL) spread detection, moving from surgical procedures, through standard radiological and functional imaging techniques to the present state of the art for HL staging. The main body of the review will be dedicated to the recently published guidelines for lymphoma staging (including HL) agreed by the experts during the 12th International Congress for Malignant Lymphoma in Lugano. The recommendations of the panel on how to integrate flurodeoxyglucose positron emission tomography (FDG-PET) scan in the armamentarium of staging procedures will be presented and commented, with a special emphasis on the utility of special procedures, such as bone marrow trephine biopsy, which is deemed no longer needed in the PET era. While the HL diagnosis is straightforward in most cases, sometimes HL is a subtle disease, difficult to diagnose for the paucity of symptoms, the absence of physical findings, or for concomitant immunologic disorders: a compete overview of the common and rare patterns of HL clinical presentation will be also offered. The future perspective of PET scan use will be based on a operator-independent, quantitative readings of the scan thanks to a plethora of sophisticated dedicated software, which are now available, able to quantify every voxel captured by the tumor to display the metabolically active tumor volume. Moreover, new tracers are now available able to track the new pathways of cellular metabolism beside glycolysis such as amino acids or purine-analogues or specific oncoproteins; the preliminary, promising results will be reported. Preliminary results from other imaging techniques, such as diffusion-weighted magnetic resonance (DW-MRI) will be also reported. PMID- 27496302 TI - TRP channels in schistosomes. AB - Praziquantel (PZQ) is effectively the only drug currently available for treatment and control of schistosomiasis, a disease affecting hundreds of millions of people worldwide. Many anthelmintics, likely including PZQ, target ion channels, membrane protein complexes essential for normal functioning of the neuromusculature and other tissues. Despite this fact, only a few classes of parasitic helminth ion channels have been assessed for their pharmacological properties or for their roles in parasite physiology. One such overlooked group of ion channels is the transient receptor potential (TRP) channel superfamily. TRP channels share a common core structure, but are widely diverse in their activation mechanisms and ion selectivity. They are critical to transducing sensory signals, responding to a wide range of external stimuli. They are also involved in other functions, such as regulating intracellular calcium and organellar ion homeostasis and trafficking. Here, we review current literature on parasitic helminth TRP channels, focusing on those in schistosomes. We discuss the likely roles of these channels in sensory and locomotor activity, including the possible significance of a class of TRP channels (TRPV) that is absent in schistosomes. We also focus on evidence indicating that at least one schistosome TRP channel (SmTRPA) has atypical, TRPV1-like pharmacological sensitivities that could potentially be exploited for future therapeutic targeting. PMID- 27496306 TI - Prognostic factors in Hodgkin lymphoma. AB - During the last decades, the prognosis of Hodgkin lymphoma (HL) has been improved significantly with the introduction of effective chemotherapy and the implementation of risk-adapted treatment approaches. Identification of reliable risk factors is crucial to guide treatment over the course of disease. Both clinical and biological factors have been implicated in the prognosis of HL and are often used in prognostic scores to discriminate risk groups. To prevent under or overtreatment, patients are usually assigned to one of the three widely established risk groups for first-line treatment, based solely on clinical risk factors. To further individualize therapeutic approaches, functional imaging with positron emission tomography (PET) is becoming more widely implemented and precisely investigated within clinical trials. Biological prognostic factors have been widely evaluated but are still not a part of standard prognostication. This review will discuss the currently established factors and risk models at first diagnosis and in the setting of relapsed/refractory disease and also focus on biological factors and PET, summarizing current standards and future perspectives. PMID- 27496307 TI - Treatment of early-stage Hodgkin lymphoma. AB - Hodgkin lymphoma (HL) has become one of the best curable malignancies today. This is particularly true for patients with early-stage disease. Today, most patients in this risk group are treated with a combination of chemotherapy followed by small-field radiotherapy. More recent clinical trials such as the German Hodgkin Study Group (GHSG) HD10 study demonstrated, that even two cycles of ABVD followed by 20 Gy involved-field radiation therapy (IF-RT) are sufficient and result in more than 90% of patients being cured. The current treatment for early unfavorable patients is either four cycles of ABVD plus 30 Gy IF-RT or two cycles of BEACOPPbaseline followed by two cycles of ABVD plus IF-RT. Here, the European Organization for Research and Treatment of Cancer (EORTC) demonstrated that in positron emission tomography (PET)-positive patients after two cycles of ABVD, treatment switched to two cycles of BEACOPPbaseline plus radiotherapy results in significantly improved outcomes. Other aspects including attempts to further reduce intensity of treatment will be discussed. PMID- 27496308 TI - Treatment of advanced-stage Hodgkin lymphoma. AB - There is now good evidence that the escalated BEACOPP regimen (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) is more effective in controlling advanced-stage Hodgkin lymphoma (HL) than the widely used ABVD regimen (adriamycin, bleomycin, vinblastine, dacarbazine), but the extra efficacy comes at the expense of both short- and long-term toxicity, and there is debate as to whether overall survival is affected. Baseline prognostic factors have proven of limited utility for determining which patients require more intensive therapy and recent studies have sought to use interim fluoro-deoxyglucose positron emission tomography (FDG-PET) evaluation as a means to guide the modulation of treatment, both upwards and downwards in intensity. These suggest that if treatment starts with ABVD then patients remaining PET positive after 2 months can be salvaged with escalated BEACOPP in around 65% of cases, but those becoming PET-negative may still experience recurrences in 15% 20%, an event that is more common in those with more advanced disease at presentation. There are early data to suggest that starting with escalated BEACOPP may reduce the rate of recurrence after a negative interim PET to less than 10%. This may be an attractive approach for those with very high-risk features at presentation, but risks overtreating many patients if applied nonselectively. New regimens incorporating antibody-drug conjugates may shift the balance of efficacy and toxicity once again, and further studies are underway to evaluate this. PMID- 27496309 TI - Treatment of relapsed and refractory Hodgkin Lymphoma. AB - Despite the high first-line cure rates in patients with Hodgkin Lymphoma (HL) still 10%-20% of patients suffer from relapsed or refractory disease. High-dose chemotherapy (HDCT) followed by autologous stem cell transplant (ASCT) is standard of care for suitable patients with relapsed or refractory HL and allows for cure in approximately 50%. Due to the poor prognosis of high-risk patients even with HDCT and ASCT, consolidation strategies have been evaluated to improve the cure rates. For patients with recurrence after HDCT and ASCT, treatment is palliative in most cases. The anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) has been shown to induce high response rates in these patients; however, durable responses were reported in a small percentage of patients only. For carefully selected patients with multiple relapses, dose-reduced allogeneic transplant (RICallo) is a potentially curative option. The role of RICallo will have to be re-evaluated in the era of anti-programmed death-1 (PD1) antibodies. PMID- 27496310 TI - Novel agents in the treatment of Hodgkin lymphoma: Biological basis and clinical results. AB - Hodgkin Lymphoma (HL) is a lymphoproliferative disorder of B cells that commonly has a favorable prognosis when treated with either combination chemotherapy and radiation therapy, or chemotherapy alone. However, the prognosis for patients who relapse, or have evidence for refractory disease, is poor and new treatments are needed for patients with progressive disease. HL has a unique tumor microenvironment consisting of a predominance of inflammatory cells and a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells. This unique biology provides an opportunity for novel therapy approaches that either specifically target the malignant HRS cell or target the inflammatory tumor microenvironment. New therapies including antibody drug conjugates targeting CD30, small molecule inhibitors that inhibit critical cell signaling pathways, monoclonal antibodies that block immune checkpoints, or agents that modulate the immune microenvironment have all recently been tested in HL with significant clinical activity. Multiple clinical trials are currently ongoing testing these agents in the relapsed and refractory setting but also in earlier phases of therapy often in combination with more standard treatment. PMID- 27496311 TI - Nodular lymphocyte-predominant Hodgkin lymphoma. AB - Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma with distinct clinicopathologic features. It is typified by the presence of lymphocyte predominant (LP) cells, which are CD20(+) but CD15(-) and CD30(-) and are found scattered amongst small B lymphocytes arranged in a nodular pattern. Despite frequent and often late or multiple relapses, the prognosis of NLPHL is very favorable. There is an inherent risk of secondary aggressive non Hodgkin lymphoma (NHL) and studies support that risk is highest in those with splenic involvement at presentation. Given disease rarity, the optimal management is unclear and opinions differ as to whether treatment paradigms should be similar to or differ from those for classical Hodgkin lymphoma (CHL). This review provides an overview of the existing literature describing pathological subtypes, outcome and treatment approaches for NLPHL. PMID- 27496313 TI - Hodgkin lymphoma: Late effects of treatment and guidelines for surveillance. AB - Long-term survivors of Hodgkin lymphoma (HL) are at risk for a range of late effects, with second malignant neoplasm and cardiovascular diseases being the leading causes of death in these patients. The excess risks remain significantly elevated decades after treatment, and are clearly associated with extent of treatment exposures. Other late effects have also been identified, such as pulmonary dysfunction, endocrinopathies, muscle atrophy, and persistent fatigue. Systemic documentation of late effects and recognition of treatment- and patient related risk factors are important, as they inform optimal surveillance and risk reduction strategies, as well as guide therapeutic modifications in newly diagnosed patients to minimize treatment-related complications. As HL therapy evolves over time, with adoption of novel agents and contemporary treatment techniques, late effect risks and follow-up recommendations need to be continuously updated. PMID- 27496312 TI - Hodgkin lymphoma in the elderly, pregnant, and HIV-infected. AB - Hodgkin lymphoma (HL) presenting in patients with co-incidental advanced age, pregnancy, or human immunodeficiency virus (HIV) infection is uniquely challenging to manage. In this article we integrate recent evidence and clinical expertise to present recommendations for diagnosis and therapeutic management. Older patients with HL need to be carefully evaluated for comorbidies after which judicious choice of chemotherapy should minimize functional compromise. A pregnant patient with concurrent HL should be staged with minimal use of imaging requiring ionizing radiation and treated in an individualized manner optimally combining the strategies of treatment deferral when appropriate, use of single agent vinblastine for symptomatic disease and reservation of multi-agent chemotherapy for the small minority of patients with aggressive clinical presentation. Treatment of HL coincident with HIV infection requires a combination of highly active anti-retroviral agents (HAART), standard multi-agent chemotherapy with meticulous attention to drug-drug interactions, and vigorous supportive care to ensure the best chance of cure. PMID- 27496314 TI - Similarity of fractionated versus single dose(s) of gemtuzumab ozogamicin as part of the MIDAM salvage regimen in relapsed/refractory acute myeloid leukemia patients. PMID- 27496315 TI - Painful subcutaneous nodules in a patch of livedo reticularis. PMID- 27496316 TI - [About the ubiquity of the alpha coefficient in the validation studies]. PMID- 27496317 TI - Clinical concentrations of morphine are cytotoxic on proliferating human fibroblasts in vitro. AB - BACKGROUND: Morphine and other opioids are routinely used systemically and as wound infusions in the postoperative period. Their effect on wound and fracture healing remains unclear. OBJECTIVE: The primary outcome was to assess the potential cytotoxicity of clinically relevant concentrations of morphine on human fibroblasts. DESIGN: Laboratory in-vitro study. SETTING: Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich. MATERIALS: Monolayers of human fibroblasts. INTERVENTION(S): Exposure of human fibroblast monolayers to several concentrations of morphine, for different periods of time, with and without an artificially induced inflammatory process. MAIN OUTCOME MEASURES: Cell count, cell viability, cell proliferation and apoptosis. RESULTS: A concentration, time and exposure-dependent cytotoxic effect of morphine mediated apoptosis was observed. Simulated inflammatory conditions seemed to lessen toxic effects. CONCLUSION: Cytotoxic effects of morphine are exposure, time and concentration dependent. Simulating aspects of inflammatory conditions seems to increase resistance to morphine cytotoxicity especially in the presence of higher concentration and longer exposure times. PMID- 27496318 TI - Lung microbiome in human immunodeficiency virus infection. AB - The lung microbiome plays a significant role in normal lung function and disease. Because microbial colonization is likely influenced by immunodeficiency, one would speculate that infection with human immunodeficiency virus (HIV) alters the lung microbiome. Furthermore, how this alteration might impact pulmonary complications now seen in HIV-infected patients on antiretroviral therapy (ART), which has shifted from opportunistic infections to diseases associated with chronic inflammation, is not known. There have been limited publications on the lung microbiome in HIV infection, many of them emanating from the Lung HIV Microbiome Project. Current evidence suggests that the lung microbiome in healthy HIV-infected individuals with preserved CD4 counts is similar to uninfected individuals. However, in individuals with more advanced disease, there is an altered alveolar microbiome characterized by a loss of richness and evenness (alpha diversity) within individuals. Furthermore, as a group the taxa making up the HIV-infected and uninfected lung microbiome are different (differences in beta diversity), and the HIV-infected population is more spread out (greater dispersion) than the uninfected population. These differences decline with ART, but even after effective therapy the alveolar microbiome in HIV-infected individuals contains increased amounts of signature bacteria, some of which have previously been associated with chronic lung inflammation. Furthermore, more recent investigations into the lung virome in HIV infection suggest that perturbations in lung viral communities also exist in HIV infection, and that these too are associated with evidence of lung inflammation. Thus, it is likely both microbiome and virome alterations in HIV infection contribute to lung inflammation in these individuals, which has important implications on the changing spectrum of pulmonary complications in patients living with HIV. PMID- 27496320 TI - Priapism as a new symptom of anaphylaxis in a prepubescent child. PMID- 27496319 TI - 1-Alpha, 25-dihydroxyvitamin D3 alters the pharmacokinetics of mycophenolic acid in renal transplant recipients by regulating two extrahepatic UDP glucuronosyltransferases 1A8 and 1A10. AB - Mycophenolic acid (MPA) is an important immunosuppressant broadly used in renal transplantation. However, the large inter-patient variability in mycophenolic acid (MPA) pharmacokinetics (PK) limits its use. We hypothesize that extrahepatic metabolism of MPA may have significant impact on MPA PK variability. Two intestinal UDP-glucuronosyltransferases 1A8 and 1A10 plays critical role in MPA metabolism. Both in silico and previous genome-wide analyses suggested that vitamin D (VD) may regulate intestinal UGT1A expression. We validated the VD response elements (VDREs) across the UGT1A locus with chromatin immunoprecipitation (ChIP) and luciferase reporter assays. The impact of 1 alpha,25-dihydroxyvitamin D3 (D3) on UGT1A8 and UGT1A10 transcription and on MPA glucuronidation was tested in human intestinal cell lines LS180, Caco-2 and HCT 116. The correlation between transcription levels of VD receptor (VDR) and the two UGT genes were examined in human normal colorectal tissue samples (n = 73). PK alterations of MPA following the parent drug, mycophenolate mofetil (MMF), and D3 treatment was assessed among renal transplant recipients (n = 10). Our ChIP assay validate three VDREs which were further demonstrated as transcriptional enhancers with the luciferase assays. D3 treatment significantly increased transcription of both UGT genes as well as MPA glucuronidation in cells. The VDR mRNA level was highly correlated with that of both UGT1A8 and UGT1A10 in human colorectal tissue. D3 treatment in patients led to about 40% reduction in both AUC0-12 and Cmax while over 70% elevation of total clearance of MPA. Our study suggested a significant regulatory role of VD on MPA metabolism and PK via modulating extrahepatic UGT activity. PMID- 27496321 TI - Interferon-Inducible Mx Promoter-Driven, Long-Term Transgene Expression System of Interferon-beta for Cancer Gene Therapy. AB - Gene therapy techniques aiming to induce the long-term interferon-beta (IFN-beta) expression are desirable for inhibiting cancer growth. However, there has been no success in this regard because IFN-beta significantly inhibits transgene expression. This study used the IFN-inducible Mx promoter to promote IFN-beta expression. The pMx-IFN-beta plasmid was constructed to achieve long-term IFN beta expression. In cultured cells transfected with the Mx promoter-driven reporter protein plasmid, IFN-beta induced concentration-dependent expression of the reporter protein. After the hydrodynamic injection of pMx-IFN-beta into mice, the serum concentration of IFN-beta was maintained at >=100 pg/mL for >1 month. IFN-beta expression was significantly suppressed by the co-injection of small interfering RNA targeting the interferon-alpha/beta receptor (IFNAR), suggesting that IFN-beta binding to IFNAR increased IFN-beta expression. Moreover, the hydrodynamic injection of pMx-IFN-beta significantly suppressed the growth of colon26 tumors in mice. In contrast, a conventional promoter-driven plasmid was less effective than pMx-IFN-beta in all the experiments. Taken together, these results indicate that the interferon-inducible Mx promoter-driven expression system effectively achieves long-term expression of IFN-beta and represents a potential tool for cancer gene therapy. PMID- 27496322 TI - Practical low-coverage genomewide sequencing of hundreds of individually barcoded samples for population and evolutionary genomics in nonmodel species. AB - Today most population genomic studies of nonmodel organisms either sequence a subset of the genome deeply in each individual or sequence pools of unlabelled individuals. With a step-by-step workflow, we illustrate how low-coverage whole genome sequencing of hundreds of individually barcoded samples is now a practical alternative strategy for obtaining genomewide data on a population scale. We used a highly efficient protocol to generate high-quality libraries for ~6.5 USD from each of 876 Atlantic silversides (a teleost fish with a genome size ~730 Mb) that we sequenced to 1-4* genome coverage. In the absence of a reference genome, we developed a bioinformatic pipeline for mapping the genomic reads to a de novo assembled reference transcriptome. This provides an 'in silico' method for exome capture that avoids the complexities and expenses of using wet chemistry for target isolation. Using novel tools for analysis of low-coverage data, we extracted population allele frequencies, individual genotype likelihoods and polymorphism data for 2 504 335 SNPs across the exome for the 876 fish. To illustrate the use of the resulting data, we present a preliminary analysis of geographical patterns in the exome data and a comparison of complete mitochondrial genome sequences for each individual (constructed from the low coverage data) that show population colonization patterns along the US east coast. With a total cost per sample of less than 50 USD (including sequencing) and ability to prepare 96 libraries in only 5 h, our approach adds a viable new option to the population genomics toolbox. PMID- 27496323 TI - Mosquitoes boost body armor to resist insecticide attack. PMID- 27496325 TI - Quantitative genetics provides predictive power for paleontological studies of morphological evolution. PMID- 27496324 TI - Natural search algorithms as a bridge between organisms, evolution, and ecology. AB - The ability to navigate is a hallmark of living systems, from single cells to higher animals. Searching for targets, such as food or mates in particular, is one of the fundamental navigational tasks many organisms must execute to survive and reproduce. Here, we argue that a recent surge of studies of the proximate mechanisms that underlie search behavior offers a new opportunity to integrate the biophysics and neuroscience of sensory systems with ecological and evolutionary processes, closing a feedback loop that promises exciting new avenues of scientific exploration at the frontier of systems biology. PMID- 27496326 TI - Activated kinetics in a nonequilibrium thermal bath. PMID- 27496327 TI - ORChestrating the human DNA replication program. PMID- 27496328 TI - Eosinophils, galectins, and a reason to breathe. PMID- 27496329 TI - Quantum spin dynamics with pairwise-tunable, long-range interactions. AB - We present a platform for the simulation of quantum magnetism with full control of interactions between pairs of spins at arbitrary distances in 1D and 2D lattices. In our scheme, two internal atomic states represent a pseudospin for atoms trapped within a photonic crystal waveguide (PCW). With the atomic transition frequency aligned inside a band gap of the PCW, virtual photons mediate coherent spin-spin interactions between lattice sites. To obtain full control of interaction coefficients at arbitrary atom-atom separations, ground state energy shifts are introduced as a function of distance across the PCW. In conjunction with auxiliary pump fields, spin-exchange versus atom-atom separation can be engineered with arbitrary magnitude and phase, and arranged to introduce nontrivial Berry phases in the spin lattice, thus opening new avenues for realizing topological spin models. We illustrate the broad applicability of our scheme by explicit construction for several well-known spin models. PMID- 27496330 TI - Nuclear repartitioning of galectin-1 by an extracellular glycan switch regulates mammary morphogenesis. AB - Branching morphogenesis in the mammary gland is achieved by the migration of epithelial cells through a microenvironment consisting of stromal cells and extracellular matrix (ECM). Here we show that galectin-1 (Gal-1), an endogenous lectin that recognizes glycans bearing N-acetyllactosamine (LacNAc) epitopes, induces branching migration of mammary epithelia in vivo, ex vivo, and in 3D organotypic cultures. Surprisingly, Gal-1's effects on mammary patterning were independent of its glycan-binding ability and instead required localization within the nuclei of mammary epithelia. Nuclear translocation of Gal-1, in turn, was regulated by discrete cell-surface glycans restricted to the front of the mammary end buds. Specifically, alpha2,6-sialylation of terminal LacNAc residues in the end buds masked Gal-1 ligands, thereby liberating the protein for nuclear translocation. Within mammary epithelia, Gal-1 localized within nuclear Gemini bodies and drove epithelial invasiveness. Conversely, unsialylated LacNAc glycans, enriched in the epithelial ducts, sequestered Gal-1 in the extracellular environment, ultimately attenuating invasive potential. We also found that malignant breast cells possess higher levels of nuclear Gal-1 and alpha2,6-SA and lower levels of LacNAc than nonmalignant cells in culture and in vivo and that nuclear localization of Gal-1 promotes a transformed phenotype. Our findings suggest that differential glycosylation at the level of tissue microanatomy regulates the nuclear function of Gal-1 in the context of mammary gland morphogenesis and in cancer progression. PMID- 27496331 TI - The Hitchhiking Parasite: Why Human Movement Matters to Malaria Transmission and What We Can Do About It. AB - The failure of the Global Malaria Eradication Program (GMEP) during the 1960s highlighted the relevance of human movement to both re-introducing parasites in elimination settings and spreading drug-resistant parasites widely. Today, given the sophisticated surveillance of human movement patterns and key traveler groups, it is hoped that interventions can be implemented to protect and treat travelers, prevent onward transmission in low transmission settings, and eliminate sources of transmission, including sources of drug-resistant parasites. PMID- 27496332 TI - Comparative transcript profiling of alloplasmic male-sterile lines revealed altered gene expression related to pollen development in rice (Oryza sativa L.). AB - BACKGROUND: Cytoplasmic male sterility (CMS) is an ideal model for investigating the mitochondrial-nuclear interaction and down-regulated genes in CMS lines which might be the candidate genes for pollen development in rice. In this study, a set of rice alloplasmic sporophytic CMS lines was obtained by successive backcrossing of Meixiang B, with three different cytoplasmic types: D62A (D type), ZS97A (WA type) and XQZ-A (DA type). RESULTS: Using microarray, the anther transcript profiles of the three indica rice CMS lines revealed 622 differentially expressed genes (DEGs) in each of the three CMS lines compared with the maintainer line Meixiang B. GO and MapMan analysis indicated that these DEGs were mainly involved in lipid metabolism and cell wall organization. Compared with the gene expression of sporophytic and gametophytic CMS lines, 303 DEGs were identified and 56 of them were down-regulated in all the CMS lines of rice. These down-regulated DEGs in the CMS lines were found to be involved in tapetum or cell wall formation and their suppressed expression might be related to male sterility. Weighted gene co expression network analysis (WGCNA) revealed that two modules were significantly associated with male sterility and many hub genes that were differentially expressed in the CMS lines. CONCLUSION: A large set of putative genes involved in anther development was identified in the present study. The results will give some information for the nuclear gene regulation by different cytoplasmic genotypes and provide a rich resource for further functional research on the pollen development in rice. PMID- 27496333 TI - Peromyscus burrowing: A model system for behavioral evolution. AB - A major challenge to understanding the genetic basis of complex behavioral evolution is the quantification of complex behaviors themselves. Deer mice of the genus Peromyscus vary in their burrowing behavior, which leaves behind a physical trace that is easily preserved and measured. Moreover, natural burrowing behaviors are recapitulated in the lab, and there is a strong heritable component. Here we discuss potential mechanisms driving variation in burrows with an emphasis on two sister species: P. maniculatus, which digs a simple, short burrow, and P. polionotus, which digs a long burrow with a complex architecture. A forward-genetic cross between these two species identified several genomic regions associated with burrow traits, suggesting this complex behavior has evolved in a modular fashion. Because burrow differences are most likely due to differences in behavioral circuits, Peromyscus burrowing offers an exciting opportunity to link genetic variation between natural populations to evolutionary changes in neural circuits. PMID- 27496334 TI - Using cell deformation and motion to predict forces and collective behavior in morphogenesis. AB - In multi-cellular organisms, morphogenesis translates processes at the cellular scale into tissue deformation at the scale of organs and organisms. To understand how biochemical signaling regulates tissue form and function, we must understand the mechanical forces that shape cells and tissues. Recent progress in developing mechanical models for tissues has led to quantitative predictions for how cell shape changes and polarized cell motility generate forces and collective behavior on the tissue scale. In particular, much insight has been gained by thinking about biological tissues as physical materials composed of cells. Here we review these advances and discuss how they might help shape future experiments in developmental biology. PMID- 27496335 TI - Fast volumetric imaging of bound and pore water in cortical bone using three dimensional ultrashort-TE (UTE) and inversion recovery UTE sequences. AB - We report the three-dimensional ultrashort-TE (3D UTE) and adiabatic inversion recovery UTE (IR-UTE) sequences employing a radial trajectory with conical view ordering for bi-component T2 * analysis of bound water (T2 *(BW) ) and pore water (T2 *(PW) ) in cortical bone. An interleaved dual-echo 3D UTE acquisition scheme was developed for fast bi-component analysis of bound and pore water in cortical bone. A 3D IR-UTE acquisition scheme employing multiple spokes per IR was developed for bound water imaging. Two-dimensional UTE (2D UTE) and IR-UTE sequences were employed for comparison. The sequences were applied to bovine bone samples (n = 6) and volunteers (n = 6) using a 3-T scanner. Bi-component fitting of 3D UTE images of bovine samples showed a mean T2 *(BW) of 0.26 +/- 0.04 ms and T2 *(PW) of 4.16 +/- 0.35 ms, with fractions of 21.5 +/- 3.6% and 78.5 +/- 3.6%, respectively. The 3D IR-UTE signal showed a single-component decay with a mean T2 *(BW) of 0.29 +/- 0.05 ms, suggesting selective imaging of bound water. Similar results were achieved with the 2D UTE and IR-UTE sequences. Bi-component fitting of 3D UTE images of the tibial midshafts of healthy volunteers showed a mean T2 *(BW) of 0.32 +/- 0.08 ms and T2 *(PW) of 5.78 +/- 1.24 ms, with fractions of 34.2 +/- 7.4% and 65.8 +/- 7.4%, respectively. Single-component fitting of 3D IR UTE images showed a mean T2 *(BW) of 0.35 +/- 0.09 ms. The 3D UTE and 3D IR-UTE techniques allow fast volumetric mapping of bound and pore water in cortical bone. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27496336 TI - Efficacy and safety of sucroferric oxyhydroxide compared with sevelamer hydrochloride in Japanese haemodialysis patients with hyperphosphataemia: A randomized, open-label, multicentre, 12-week phase III study. AB - AIM: We aimed to investigate the non-inferiority of PA21 (sucroferric oxyhydroxide) to sevelamer hydrochloride (sevelamer) in terms of efficacy and safety in Japanese haemodialysis patients with hyperphosphataemia. METHODS: In this Phase III, open-label, multicentre study, 213 haemodialysis patients with hyperphosphataemia were randomized to PA21 or sevelamer treatment for 12 weeks. The primary outcome was adjusted serum phosphorus concentration at the end of treatment; the non-inferiority of PA21 was confirmed if the upper limit of the two-sided 95% confidence interval (CI) is <=0.32 mmol/L. Secondary outcomes were corrected serum calcium and intact-parathyroid hormone concentrations. Adverse events (AEs) and adverse drug reactions (ADRs) were evaluated. RESULTS: The adjusted mean serum phosphorus concentration at the end of treatment confirmed the non-inferiority of PA21 for lowering serum phosphorus compared with sevelamer (1.62 vs 1.72 mmol/L; difference, -0.11 mmol/L; 95% CI, -0.20 to -0.02 mmol/L). The mean daily tablet intake was 5.6 +/- 2.6 and 18.7 +/- 7.1 tablets in the PA21 and sevelamer groups, respectively. The incidences of AEs and ADRs were not significantly different between the two groups. CONCLUSION: The non-inferiority of PA21 to sevelamer was confirmed for the treatment of Japanese haemodialysis patients with hyperphosphataemia. PA21 was effective, safe, and well tolerated, while having a considerably lower pill burden than sevelamer. PMID- 27496337 TI - High levels of stromal cell-derived factor-1alpha predict secondary cardiac events in stable patients with a history of myocardial infarction. AB - BACKGROUND: We recently showed that stromal cell-derived factor (SDF)-1alpha, a pro-inflammatory mediator, is produced in infarcted myocardium and is associated with left ventricular (LV) adverse remodeling and progressive dysfunction following acute myocardial infarction (AMI). The current study examined whether SDF-1alpha levels in the peripheral vein can provide prognostic information of outcomes in stable patients with a history of MI. METHODS: Plasma levels of SDF 1alpha in the peripheral vein were measured by enzyme-linked immunosorbent assay in 192 stable patients with a history of MI. All patients were followed prospectively for a period of 90 months or until occurrence of one of the following cardiac events: cardiac death, non-fatal myocardial infarction, unstable angina requiring unplanned coronary revascularization, or worsening heart failure requiring hospital admission. RESULTS: During the follow-up period (77+/-26 months), 30 patients had cardiac events. Multivariate Cox analysis revealed that high levels of SDF-1alpha (>=2162pg/mL; a cut-off value determined by receiver-operating characteristic analysis) were a significant predictor of cardiac events, independent of traditional risk factors (HR: 1.98; 95% CI: 1.38 2.85; p<0.001). The addition of high levels of SDF-1alpha to conventional risk factors including brain natriuretic peptide improved net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.90, p<0.0001; and IDI 0.05, p=0.002). CONCLUSIONS: High levels of SDF-1alpha predicted secondary cardiac events in stable patients with a history of MI. SDF 1alpha levels may be a useful risk assessment tool in patients with a history of MI. PMID- 27496339 TI - Vitreous and subretinal fluid concentrations of orally administered dabigatran in patients with rhegmatogenous retinal detachment. AB - PURPOSE: One of the factors that was shown to contribute to the development of proliferative vitreoretinopathy (PVR) is the coagulation factor thrombin. Therefore, a specific oral thrombin inhibitor such as dabigatran might be a possible therapeutic option. An oral drug has the advantage of patient-friendly prolonged administration in contrast to drugs that can only be applied during vitrectomy, on condition that the drug reaches the target site. We tested whether dabigatran reaches the vitreous and subretinal fluid (SRF) after a single oral dose of dabigatran. METHODS: Twenty-eight patients with a retinal detachment received a single dose of 220 mg dabigatran etexilate 2-8 hr prior to surgery. During surgery, we took a blood sample and a vitreous or subretinal fluid sample. The concentration of dabigatran was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: The dabigatran concentration between 2 and 9 hr after administration was higher in SRF than in vitreous (max 8.5 and 3.8 ng/ml). Corresponding plasma concentrations ranged from 15 to 225 ng/ml. There was a significant relationship between SRF levels and plasma levels (rs = 0.68, p = 0.014); the levels in vitreous fluid showed no such relationship (rs = 0.20, p = 0.48). In addition, we measured the vitreous concentration of a non-study patient using 150 mg dabigatran twice daily. The concentration was approximately 10 times higher than after a single dosage (25.8 ng/ml). CONCLUSION: We demonstrate that oral intake of dabigatran, a candidate drug to modulate PVR, results in potentially relevant intraocular concentrations. We suggest that repeated dosing may lead to higher concentrations, but this should be further explored. PMID- 27496338 TI - Neural correlates of naturalistic social cognition: brain-behavior relationships in healthy adults. AB - Being able to infer the thoughts, feelings and intentions of those around us is indispensable in order to function in a social world. Despite growing interest in social cognition and its neural underpinnings, the factors that contribute to successful mental state attribution remain unclear. Current knowledge is limited because the most widely used tasks suffer from two main constraints: (i) They fail to capture individual variability due to ceiling effects and (ii) they use highly simplistic, often artificial stimuli inapt to mirror real-world socio cognitive demands. In the present study, we address these problems by employing complex depictions of naturalistic social interactions that vary in both valence (positive vs negative) and ambiguity (high vs low). Thirty-eight healthy participants (20 female) made mental state judgments while brain responses were obtained using functional magnetic resonance imaging (fMRI). Accuracy varied based on valence and ambiguity conditions and women were more accurate than men with highly ambiguous social stimuli. Activity of the orbitofrontal cortex predicted performance in the high ambiguity condition. The results shed light on subtle differences in mentalizing abilities and associated neural activity. PMID- 27496340 TI - A transcriptional blueprint for a spiral-cleaving embryo. AB - BACKGROUND: The spiral cleavage mode of early development is utilized in over one third of all animal phyla and generates embryonic cells of different size, position, and fate through a conserved set of stereotypic and invariant asymmetric cell divisions. Despite the widespread use of spiral cleavage, regulatory and molecular features for any spiral-cleaving embryo are largely uncharted. To address this gap we use RNA-sequencing on the spiralian model Platynereis dumerilii to capture and quantify the first complete genome-wide transcriptional landscape of early spiral cleavage. RESULTS: RNA-sequencing datasets from seven stages in early Platynereis development, from the zygote to the protrochophore, are described here including the de novo assembly and annotation of ~17,200 Platynereis genes. Depth and quality of the RNA-sequencing datasets allow the identification of the temporal onset and level of transcription for each annotated gene, even if the expression is restricted to a single cell. Over 4000 transcripts are maternally contributed and cleared by the end of the early spiral cleavage phase. Small early waves of zygotic expression are followed by major waves of thousands of genes, demarcating the maternal to zygotic transition shortly after the completion of spiral cleavages in this annelid species. CONCLUSIONS: Our comprehensive stage-specific transcriptional analysis of early embryonic stages in Platynereis elucidates the regulatory genome during early spiral embryogenesis and defines the maternal to zygotic transition in Platynereis embryos. This transcriptome assembly provides the first systems-level view of the transcriptional and regulatory landscape for a spiral cleaving embryo. PMID- 27496341 TI - Long noncoding RNA HULC promotes colorectal carcinoma progression through epigenetically repressing NKD2 expression. AB - Recently, long noncoding RNAs (lncRNAs) have been emerged as crucial regulators of human diseases and prognostic markers in numerous of cancers, including colorectal carcinoma (CRC). Here, we identified an oncogenetic lncRNA HULC, which may promote colorectal tumorigenesis. HULC has been found to be up-regulated and acts as oncogene in gastric cancer and hepatocellular carcinoma, but its expression pattern, biological function and underlying mechanism in CRC is still undetermined. Here, we reported that HULC expression is also over-expressed in CRC, and its increased level is associated with poor prognosis and shorter survival. Knockdown of HULC impaired CRC cells proliferation, migration and invasion, and facilitated cell apoptosis in vitro, and inhibited tumorigenicity of CRC cells in vivo. Mechanistically, RNA immunoprecipitation (RIP) and RNA pull down experiment demonstrated that HULC could simultaneously interact with EZH2 to repress underlying targets NKD2 transcription. In addition, rescue experiments determined that HULC oncogenic function is partly dependent on repressing NKD2. Taken together, our findings expound how HULC over-expression endows an oncogenic function in CRC. PMID- 27496342 TI - Association of HLA-A, B, DRB1* and DQB1* alleles and haplotypes in south Indian T2DM patients. AB - The genes of Human Leukocyte Antigen (HLA) system are implicated in the susceptibility of several diseases including Type 2 diabetes (T2DM). Therefore, we aimed to investigate the association of HLA alleles with T2DM in south India. A total of 344 patients (195 males; 149 females) and 309 controls (186 males; 123 females) were genotyped for HLA-DR/-DQ alleles. Based on predominant DR/DQ haplotypes, 222 patients and 222 age/sex matched controls were HLA-A/-B genotyped. HLA alleles were typed by PCR-SSP methods. Susceptible association was observed for the alleles A*33 (OR=13.8), A*01 (OR=3.69), A*02 (OR=2.91), B*07 (OR=4.12), DRB1*11 (OR=2.23), DRB1*04 (OR=1.51), DRB1*03 (OR=1.90) and DQB1*02 (OR=1.49). Protective association was observed for the alleles A*11 (OR=0.59), A*68 (OR=0.68), B*40 (OR=0.50), B*54 (OR=0.42), B*57 (OR=0.31), B*51 (OR=0.29) and DRB1*10 (OR=0.45). Gender stratified analysis too confirmed many of these associations. Predominant susceptible haplotypes were A*33-B*40 (OR=10.27), A*01 B*07 (OR=4.97), A*02-B*07 (OR=6.50), DRB1*03-DQB1*05 (OR=1.88), DRB1*03-DQB1*06 (OR=3.01), DRB1*04-DQB1*05 (2.63), A*01-B*07-DRB1*10 (OR=8.26) and A*11-B*35 DRB1*07 (OR=9.338). Haplotypes A*03-B*07 (OR=0.57; p<0.034) and DRB1*10-DQB1*05 (OR=0.57; p<0.033) were protectively associated. Further, a very strong susceptible association was documented for four-locus haplotypes such as A*11 B*40-DRB1*15-DQB1*06 (n=15; OR=16.01; p<0.001); A*01-B*07-DRB1*10-DQB1*05 (n=8; OR=8.26; p<0.043) and A*11-B*07-DRB1*07-DQB1*05 (n=8; OR=8.26; p<0.043). Thus, a number of HLA alleles and haplotypes showed susceptible and protective association(s) in T2DM patients from south India. PMID- 27496343 TI - Apolipoprotein A5 fifteen years anniversary: Lessons from genetic epidemiology. AB - Apolipoprotein A5 (APOA5) is a small protein, expressed predominantly in the liver. In plasma, it is located on triglyceride rich lipoprotein particles (chylomicrones and VLDL) and on HDL. Plasma concentration of apolipoprotein A5 is very low, suggesting rather regulatory (activation of lipoprotein lipase, ...) than structural function. APOA5 is an important determinant of plasma triglyceride concentration; this effect has been confirmed both on animal models, as well as on human studies. Minor alleles of three commonly analysed variants within this gene (rs662799, rs3135506, rs2075291) are associated with higher plasma TG values and increased risk of myocardial infarction, with some important interethnic differences observed. Further roles of APOA5; determination of BMI, diabetes and last but not least nutri- and pharmaco-genetic interactions are suggested, but without the definitive conclusions. PMID- 27496344 TI - Cough Suppressant and Fluoxetine in the Treatment of Pseudobulbar Affect: A Case Report. PMID- 27496345 TI - Statistics Commentary Series: Commentary #16-Regression Toward the Mean. PMID- 27496346 TI - The Ten Cs of Good Clinical Care. PMID- 27496349 TI - Fibronectin, the extracellular glue. AB - Fibronectin is an extracellular matrix protein that is present during periods of change within tissues. It is upregulated and necessary in a number of developmental contexts, and it is also present during pathological progression of tissues and during wound healing. Thus, it has been studied in a broad number of contexts from basic science to pathology. One of the unique features of fibronectin is its ability to specifically bind a large number of molecules including other components of the extracellular matrix, signaling molecules, and cell adhesion molecules. Cellular interactions with fibronectin lead to bidirectional crosstalk that directs cell function and also leads to cell dependent changes in the extracellular matrix. Interestingly, fibronectin exists in a functional form composed of fibers that are nm to MUm in diameter that is highly interwoven, and fibronectin molecules that constitute this material have a labile molecular conformation that can be altered through binding of allosteric partners and strain resulting from application of cell contractile forces. This review focuses on summarizing the many binding partners for fibronectin such as ECM proteins, growth factors, and synthetic binding partners with a particular interest in binding partners whose adhesiveness is impacted by the molecular conformation of the fibronectin fibers. PMID- 27496348 TI - Dynamic changes in heparan sulfate during muscle differentiation and ageing regulate myoblast cell fate and FGF2 signalling. AB - Satellite cells (SCs) are skeletal muscle stem cells residing quiescent around healthy muscle fibres. In response to injury or disease SCs activate, proliferate and eventually differentiate and fuse to one another to form new muscle fibres, or to existing damaged fibres to repair them. The sulfated polysaccharide heparan sulfate (HS) is a highly variable biomolecule known to play key roles in the regulation of cell fate decisions, though the changes that muscle HS undergoes during SC differentiation are unknown. Here we show that the sulfation levels of HS increase during SC differentiation; more specifically, we observe an increase in 6-O and 2-O-sulfation in N-acetylated disaccharides. Interestingly, a specific increase in 6-O sulfation is also observed in the heparanome of ageing muscle, which we show leads to promotion of FGF2 signalling and satellite cell proliferation, suggesting a role for the heparanome dynamics in age-associated loss of quiescence. Addition of HS mimetics to differentiating SC cultures results in differential effects: an oversulfated HS mimetic increases differentiation and inhibits FGF2 signalling, a known major promoter of SC proliferation and inhibitor of differentiation. In contrast, FGF2 signalling is promoted by an N-acetylated HS mimetic, which inhibits differentiation and promotes SC expansion. We conclude that the heparanome of SCs is dynamically regulated during muscle differentiation and ageing, and that such changes might account for some of the phenotypes and signalling events that are associated with these processes. PMID- 27496350 TI - Molecular pathology of the basement membrane zone in heritable blistering diseases:: The paradigm of epidermolysis bullosa. AB - Epidermolysis bullosa (EB), a phenotypically heterogeneous group of skin fragility disorders, is characterized by blistering and erosions with considerable morbidity and mortality. Mutations in as many as 18 distinct genes expressed at the cutaneous basement membrane zone have been shown to be associated with the blistering phenotype, attesting to the role of the corresponding proteins in providing stable association of the epidermis to the dermis through adhesion at the dermo-epidermal basement membrane zone. Thus, different forms of EB have been highly instructive in providing information on the physiological functions of these proteins as integral components of the supramolecular adhesion complexes. In addition, precise information of the underlying genes and distinct mutations in families with EB has been helpful in subclassification of the disease with prognostic implications, as well as for prenatal testing and preimplantation genetic diagnosis. Furthermore, knowledge of the types of mutations is a prerequisite for application of allele-specific treatment approaches that have been recently developed, including read-through of premature termination codon mutations and chaperone-facilitated intracellular transport of conformationally altered proteins to proper physiologic subcellular location. Collectively, EB serves as a paradigm of heritable skin diseases in which significant progress has been made in identifying the underlying genetic bases and associated aberrant pathways leading from mutations to the phenotype, thus allowing application of precision medicine for this, currently intractable group of diseases. PMID- 27496347 TI - Basement membranes and autoimmune diseases. AB - Basement membrane components are targets of autoimmune attack in diverse diseases that destroy kidneys, lungs, skin, mucous membranes, joints, and other organs in man. Epitopes on collagen and laminin, in particular, are targeted by autoantibodies and T cells in anti-glomerular basement membrane glomerulonephritis, Goodpasture's disease, rheumatoid arthritis, post-lung transplant bronchiolitis obliterans syndrome, and multiple autoimmune dermatoses. This review examines major diseases linked to basement membrane autoreactivity, with a focus on investigations in patients and animal models that advance our understanding of disease pathogenesis. Autoimmunity to glomerular basement membrane type IV is discussed in depth as a prototypic organ-specific autoimmune disease yielding novel insights into the complexity of anti-basement membrane immunity and the roles of genetic and environmental susceptibility. PMID- 27496351 TI - Does grafting of the tuberosities improve the functional outcomes of proximal humeral fractures treated with reverse shoulder arthroplasty? AB - BACKGROUND: Functional outcomes of reverse total shoulder arthroplasty (rTSA) can be improved by fixation of the tuberosities. This study compares clinical and radiologic results of patients with comminuted proximal humeral fractures treated with rTSA, with and without autologous grafting. METHODS: Thirty-three patients with proximal humeral fractures were treated with rTSA and tuberosity fixation. In 18 patients (group I; mean age, 75 years), tuberosity fixation was augmented with autografting; in 15 patients (group II; mean age, 71 years), graft augmentation was not used. The mean follow-up was 16.7 (range, 12-24) months in group I and 16.8 (range, 12-25) months in group II. RESULTS: Radiologic tuberosity union was achieved in 14 of 18 (77.8%) patients who underwent autograft augmentation and in 6 of 15 (40.0%) patients treated without autografting. The mean American Shoulder and Elbow Surgeons (ASES) score was 69.6 +/- 13.0 in group I and 51.0 +/- 20.0 in group II. The mean Disabilities of the Arm, Shoulder, and Hand (DASH) score was 31.9 +/- 24.0 in group I and 58.2 +/- 24.6 in group II. A significant difference was detected between groups for ASES and DASH scores. Among shoulder range of motion measures, only forward flexion differed significantly between groups I and II (124 degrees +/- 23 degrees vs. 98 degrees +/- 30 degrees , respectively). External rotation muscle strength was significantly higher in group I (3.36 +/- 1.46 kg) than in group II (2.39 +/- 2.00 kg). CONCLUSION: In the treatment of complex proximal humeral fractures in elderly patients by rTSA, cancellous block autograft augmentation can increase the rate of tuberosity union and improve functional outcomes. PMID- 27496352 TI - Initial medical management of rotator cuff tears: a demographic analysis of surgical and nonsurgical treatment in the United States Medicare population. AB - BACKGROUND: Rotator cuff tears have a lifetime incidence between 25% and 40% in the United States, but optimum treatment strategies and protocol have not yet been widely accepted. This study evaluated the proportions of patients treated with nonoperative and operative modalities and how this proportion has changed during an 8-year period (2005-2012) among patients with Medicare. METHODS: Using the PearlDiver patient record database, we identified Medicare patients having been diagnosed with a rotator cuff tear. These patients were then stratified on the basis of treatment with physical therapy, subacromial/glenohumeral injection, or rotator cuff repair. We analyzed the data in regard to standard demographic information, comorbidities, and the Charlson Comorbidity Index. RESULTS: During the study period, 878,049 patients were identified and 397,116 patients had rotator cuff repair. The proportion of patients treated initially with physical therapy dropped from 30.0% in 2005 to 13.2% in 2012, and the subacromial/glenohumeral injection proportion decreased from 6.00% to 4.19% (P < .001). The proportion of patients who had rotator cuff repair increased from 33.8% to 40.4% from 2005 to 2012 (P < .001). Charlson Comorbidity Indexes were significantly lower in operative patients compared with each nonoperative treatment examined. DISCUSSION: This analysis demonstrates a significant decrease in the initial trial of nonoperative treatment and an increase in the rate of surgery. Patients undergoing rotator cuff repair had fewer comorbidities than those undergoing nonoperative treatments. It also demonstrates that patients who had a trial of injection had a higher incidence of eventual rotator cuff repair compared with the patients with an initial trial of physical therapy. PMID- 27496353 TI - Intermediate-term outcome of hemiarthroplasty for comminuted proximal humerus fractures. AB - BACKGROUND: The purpose of this study was to evaluate the outcome of hemiarthroplasty for comminuted proximal humerus fractures and to verify the risk factors for functional and radiologic outcomes. MATERIALS AND METHODS: We treated 29 comminuted proximal humerus fractures by hemiarthroplasty with a low-profile prosthesis and a bone block graft, with an average follow-up period of 53.9 (24 119) months. The patients' mean age at surgery was 71.7 (52-85) years. We evaluated visual analog scale (VAS) scores for pain and satisfaction, active range of motion, modified University of California-Los Angeles (UCLA) score, and shortened Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score. Radiographs were checked for stem position, loosening, and tuberosity union. The statistical evaluation was conducted to compare 2 demographics. RESULTS: The mean VAS score was 2.1 (0-5) for pain and 8.0 (4-10) for satisfaction. Mean active forward flexion was 125 degrees (90 degrees -170 degrees ); external rotation, 42 degrees (25 degrees -70 degrees ); and internal rotation, at T11 (T7-L2). The mean modified UCLA score was 20 (12-30), and the mean QuickDASH score was 25 (12 38). All stems were stable without any loosening. All tuberosities were united except 2 tuberosity absorptions. DISCUSSION: Patients older than 70 years and patients with chronic debilitating disease, >5-mm displacement of the prosthetic head from the glenoid, and a critical shoulder angle of >38 degrees showed significantly poorer clinical outcome. CONCLUSION: Low-profile hemiarthroplasty with bone block graft had unique advantages for tuberosity union. During surgery, good prosthetic positioning with respect to the anatomic axis of the glenoid and critical shoulder angle (>38 degrees ) were essential. However, age (>70 years) and systemic comorbidity showed poor clinical outcome. These factors should be considered in standardizing the clinical results. PMID- 27496354 TI - Complications associated with arthroscopic rotator cuff tear repair: definition of a core event set by Delphi consensus process. AB - BACKGROUND: The literature does not consistently report on complications associated with arthroscopic rotator cuff repair (ARCR). Valid comparison of the occurrence of complications between ARCR interventions requires standardization. This project was implemented to define a core set of negative (untoward) events associated with ARCR along with their terms and definitions, which should be systematically documented and reported in routine care and clinical research. MATERIALS AND METHODS: A Delphi consensus process was applied. An international panel of experienced shoulder surgeons was nominated through professional societies and personal contacts. On the basis of a systematic review of terms and definitions, an organized list of relevant events associated with ARCR was developed and reviewed by panel members. Between each survey, all comments and suggestions were considered to revise the proposed core set, including local event groups along with definitions, specifications, and timing of occurrence. Consensus was defined as at least two-thirds agreement. RESULTS: Three successive online surveys were implemented involving 84 surgeons. Consensus with over 86% agreement was reached for a core list of local events including 3 intraoperative event groups (device, osteochondral, and soft tissue) and 9 postoperative event groups (device, osteochondral, pain, rotator cuff, surgical-site infection, peripheral neurologic, vascular, superficial soft tissue, and deep soft tissue). Experts agreed on a period for documentation of each event or group of events ranging from 3 to 24 months after ARCR. CONCLUSION: A structured core set of local events associated with ARCR has been developed by international consensus. Further evaluation and validation in the context of clinical studies are required. PMID- 27496355 TI - Validated programmed cell death ligand 1 immunohistochemistry assays (E1L3N and SP142) reveal similar immune cell staining patterns in melanoma when using the same sensitive detection system. AB - AIMS: Tumour cell and/or immune cell programmed cell death ligand 1 (PD-L1) expression is considered as a potential biomarker for anti-PD1 and anti-PD-L1 immunotherapy. Currently, different PD-L1 assays are used. This study aims to compare the staining patterns of two PD-L1 antibody clones in melanoma metastases and correlate them with PD-L1 mRNA expression. METHODS AND RESULTS: The immunohistochemistry assays were optimized and validated independently on a Ventana Benchmark Ultra (Ventana Medical Systems Inc., Tucson, AZ, USA) (E1L3N) and XT (SP142), using the same detection system. In total, 46 melanoma metastases were stained with both validated immunohistochemistry assays. Stained slides were digitized for qualitative and semi-quantitative evaluation; done by pathologist and semi-automated software analysis. A subset of 21 melanoma metastases was selected for quantification of the PD-L1 mRNA expression. Accuracy and precision criteria were met for both assays. PD-L1 protein and mRNA expression showed remarkably good Spearman's coefficients of 0.90 (E1L3N) and 0.87 (SP142). Despite the remarkable correlation between both PD-L1 assays in expression patterns and quantification values (rho > 0.90), E1L3N showed significantly more tumour cell staining than SP142. CONCLUSIONS: E1L3N and SP142 IHC assays were optimized and validated successfully and independently for sensitive and accurate PD-L1 detection. Concordance was best for immune cell scoring, while E1L3N tended to detect more tumour cells. Determination of the clinically relevant cut-off values for immune cell versus tumour cell detection requires further research. PMID- 27496356 TI - Avoiding costly hospitalisation at end of life: findings from a specialist palliative care pilot in residential care for older adults. AB - OBJECTIVES: Specialist palliative care is not a standardised component of service delivery in nursing home care in Australia. Specialist palliative care services can increase rates of advance care planning, decrease hospital admissions and improve symptom management in such facilities. New approaches are required to support nursing home residents in avoiding unnecessary hospitalisation and improving rates of dying in documented preferred place of death. This study examined whether the addition of a proactive model of specialist palliative care reduced resident transfer to the acute care setting, and achieved a reduction in hospital deaths. METHODS: A quasi-experimental design was adopted, with participants at 4 residential care facilities. The intervention involved a palliative care nurse practitioner leading 'Palliative Care Needs Rounds' to support clinical decision-making, education and training. Participants were matched with historical decedents using propensity scores based on age, sex, primary diagnosis, comorbidities and the Aged Care Funding Instrument rating. Outcome measures included participants' hospitalisation in the past 3 months of life and the location of death. RESULTS: The data demonstrate that the intervention is associated with a substantial reduction in the length of hospital stays and a lower incidence of death in the acute care setting. While rates of hospitalisation were unchanged on average, length of admission was reduced by an average of 3.22 days (p<0.01 and 95% CI -5.05 to -1.41), a 67% decrease in admitted days. CONCLUSIONS: The findings have significant implications for promoting quality outcomes through models of palliative care service delivery in residential facilities. PMID- 27496357 TI - Scientific Growth and Identity Development during a Postbaccalaureate Program: Results from a Multisite Qualitative Study. AB - This report builds upon our previous study, which described five patterns of why college graduates join National Institutes of Health (NIH)-funded diversity focused Postbaccalaureate Research Education Programs (PREP). A 2015 report from the NIH showed that a high fraction of PREP participants matriculate into PhD and MD/PhD programs. This current study reveals how participants change during PREP, the program elements that facilitate change, and how identity as a graduate student and future scientist develops. Data come from in-depth interviews done at the beginning and end of PREP with 48 individuals from seven PREP programs. Results reveal three domains of development: academics, research, and presentation of oneself; each domain contains a developmental continuum. Key attributes of PREP enabling development include opportunities to attend graduate level classes and seminars; time to practice reading literature; extended lab time with one's own project; high and explicit expectations from mentors; and multiple opportunities to talk about science and improve communication skills. PREP enabled participants to develop their identities as graduate students and to anticipate being seen by others as highly prepared for PhD training. After PREP, 85% (n = 41) started the PhD or MD/PhD, making PREP an intervention approach with great potential to broaden participation in biomedical PhD programs. PMID- 27496358 TI - Preparing Postbaccalaureates for Entry and Success in Biomedical PhD Programs. AB - Certain racial and ethnic groups, individuals with disabilities, and those from low socioeconomic backgrounds remain underrepresented (UR) in the biomedical sciences. This underrepresentation becomes more extreme at each higher education stage. To support UR scholars during the critical transition from baccalaureate to PhD, we established an intensive, 1-yr postbaccalaureate training program. We hypothesized that this intervention would strengthen each participant's competitiveness for leading PhD programs and build a foundation of skills and self-efficacy important for success during and after graduate school. Scholar critical analysis skills, lab technique knowledge, and Graduate Record Examination scores all improved significantly during the program. Scholars reported significant confidence growth in 21 of 24 categories related to success in research careers. In 5 yr, 91% (41/45) of scholars transitioned directly into PhD programs. Importantly, 40% (18/45) of participating postbaccalaureate scholars had previously been declined acceptance into graduate school; however, 17/18 of these scholars directly entered competitive PhD programs following our training program. Alumni reported they were "extremely well" prepared for graduate school, and 95% (39/41) are currently making progress to graduation with a PhD. In conclusion, we report a model for postbaccalaureate training that could be replicated to increase participation and success among UR scholars in the biomedical sciences. PMID- 27496359 TI - Fine-Tuning Summer Research Programs to Promote Underrepresented Students' Persistence in the STEM Pathway. AB - Although the importance of undergraduate research experiences in preparing students for graduate study and research careers is well documented, specific examination of program components is needed to assess the impact of these programs on underrepresented (UR) students. The Leadership Alliance, a consortium of leading PhD-granting and minority-serving institutions (MSIs), has leveraged its diverse partnership to place UR students from MSI and non-MSI institutions in competitive research environments through its national Summer Research Early Identification Program. Using longitudinal pre/post data collected from student surveys, we applied social cognitive career theory as a conceptual framework to examine how research engagement, skill development, and mentorship aspects of a summer research program affect students' commitment to pursue research careers. Self-reported knowledge of research skills, time engaged in research activity, and students' understanding of and attitudes toward pursuing graduate study were measured in relation to the classification of students' home undergraduate institution, level of students' pre-existing research experience, and demographic factors. Our results provide evidence of specific programmatic components that are beneficial for UR students from varying academic and cultural backgrounds. This study describes important aspects of summer research programs that will contribute to students' ability to persist in science careers. PMID- 27496360 TI - A "Scientific Diversity" Intervention to Reduce Gender Bias in a Sample of Life Scientists. AB - Mounting experimental evidence suggests that subtle gender biases favoring men contribute to the underrepresentation of women in science, technology, engineering, and mathematics (STEM), including many subfields of the life sciences. However, there are relatively few evaluations of diversity interventions designed to reduce gender biases within the STEM community. Because gender biases distort the meritocratic evaluation and advancement of students, interventions targeting instructors' biases are particularly needed. We evaluated one such intervention, a workshop called "Scientific Diversity" that was consistent with an established framework guiding the development of diversity interventions designed to reduce biases and was administered to a sample of life science instructors (N = 126) at several sessions of the National Academies Summer Institute for Undergraduate Education held nationwide. Evidence emerged indicating the efficacy of the "Scientific Diversity" workshop, such that participants were more aware of gender bias, expressed less gender bias, and were more willing to engage in actions to reduce gender bias 2 weeks after participating in the intervention compared with 2 weeks before the intervention. Implications for diversity interventions aimed at reducing gender bias and broadening the participation of women in the life sciences are discussed. PMID- 27496361 TI - Active Learning Outside the Classroom: Implementation and Outcomes of Peer-Led Team-Learning Workshops in Introductory Biology. AB - Study group meetings (SGMs) are voluntary-attendance peer-led team-learning workshops that supplement introductory biology lectures at a selective liberal arts college. While supporting all students' engagement with lecture material, specific aims are to improve the success of underrepresented minority (URM) students and those with weaker backgrounds in biology. Peer leaders with experience in biology courses and training in science pedagogy facilitate work on faculty-generated challenge problems. During the eight semesters assessed in this study, URM students and those with less preparation attended SGMs with equal or greater frequency than their counterparts. Most agreed that SGMs enhanced their comprehension of biology and ability to articulate solutions. The historical grade gap between URM and non-URM students narrowed slightly in Biology 2, but not in other biology and science, technology, engineering, and mathematics courses. Nonetheless, URM students taking introductory biology after program implementation have graduated with biology majors or minors at the same rates as non-URM students, and have enrolled in postcollege degree programs at equal or greater rates. These results suggest that improved performance as measured by science grade point average may not be necessary to improve the persistence of students from underrepresented groups as life sciences majors. PMID- 27496362 TI - Toward Inclusive STEM Classrooms: What Personal Role Do Faculty Play? AB - Private and public policies are increasingly aimed at supporting efforts to broaden participation of a diverse body of students in higher education. Unfortunately, this increase in student diversity does not always occur alongside changes in institutional culture. Unexamined biases in institutional culture can prevent diverse students from thriving and persisting in science, technology, engineering, and mathematics (STEM) fields. Given the daily personal interactions that faculty have with students, we suggest that individual educators have the opportunity, and responsibility, to improve the retention and persistence of diverse students. However, in our experience, faculty professional development programs often limit discussions of diversity to "comfortable" topics (such as learning styles) and miss opportunities to explore deeper issues related to faculty privilege, implicit bias, and cues for stereotype threat that we all bring to the classroom. In this essay, we present a set of social science concepts that we can extend to our STEM courses to inform our efforts at inclusive excellence. We have recommended strategies for meaningful reflection and professional development with respect to diversity and inclusion, and aim to empower faculty to be change agents in their classrooms as a means to broadening participation in STEM fields. PMID- 27496363 TI - Precision in donor selection: Identifying ideal stem-cell donors through their T cells. AB - HLA-identical siblings have always been considered ideal donors for allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the treatment of hematologic cancers. Recent data suggest that we should rethink this paradigm. In "High Graft CD8+ Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning," we identified a group of stem-cell donors whose grafts contain an optimal composition of T-cells, leading to a dramatic decrease in disease relapse risk and an improvement in overall survival following allo-HSCT. To demonstrate this, we analyzed the outcomes of 200 patients with hematologic malignancies who underwent allo-HSCT after reduced-intensity conditioning (RIC). The analysis focused on T-cell content of peripheral blood stem-cell grafts. We found that higher graft CD8+ T-cell dose (CD8hi), a trait found only in grafts collected from young donors, was associated with improved survival due to a reduction in the risk for cancer relapse without a significant increase in graft-versus-host disease (GVHD). Though not all young donors mobilized CD8hi grafts, we found that a low CD4:CD8 ratio in the peripheral blood could identify these ideal donors prior to transplant. The likelihood of finding CD8hi donors correlated inversely with age, and elderly RIC transplant recipients had a low chance of receiving an ideal graft from their similarly aged siblings. Here, we examine these findings and their implications on choosing donors according to age and relatedness. We also explore biological mechanisms that determine the CD4:CD8 ratio in healthy donors. PMID- 27496364 TI - Genetic and environmental influences on early literacy skills across school grade contexts. AB - Recent research suggests that the etiology of reading achievement can differ across environmental contexts. In the US, schools are commonly assigned grades (e.g. 'A', 'B') often interpreted to indicate school quality. This study explored differences in the etiology of early literacy skills for students based on these school grades. Participants included twins drawn from the Florida Twin Project on Reading (n = 1313 pairs) aged 4 to 10 years during the 2006-07 school year. Early literacy skills were assessed with DIBELS subtests: Oral Reading Fluency (ORF), Nonsense Word Fluency (NWF), Initial Sound Fluency (ISF), Letter Naming Fluency (LNF), and Phoneme Segmentation Fluency (PSF). School grade data were retrieved from the Florida Department of Education. Multi-group analyses were conducted separately for subsamples defined by 'A' or 'non-A' schools, controlling for school-level socioeconomic status. Results indicated significant etiological differences on pre-reading skills (ISF, LNF, and PSF), but not word-level reading skills (ORF and NWF). There was a consistent trend of greater environmental influences on pre-reading skills in non-A schools, arguably representing 'poorer' environmental contexts than the A schools. Importantly, this is the case outside of resources linked with school-level SES, indicating that something about the direct environment on pre-reading skills in the non-A school context is more variable than for A schools. PMID- 27496365 TI - Reaction to the letter to the editor of Huang et al. PMID- 27496367 TI - State anxiety modulates the return of fear. AB - Current treatments for anxiety disorders are effective but limited by the high frequency of clinical relapse. Processes underlying relapse are thought to be experimentally modeled in fear conditioning experiments with return fear (ROF) inductions. Thereby reinstatement-induced ROF might be considered a model to study mechanisms underlying adversity-induced relapse. Previous studies have reported differential ROF (i.e. specific for the danger stimulus) but also generalized ROF (i.e. for safe and danger stimuli), but reasons for these divergent findings are not clear yet. Hence, the response pattern (i.e. differential or generalized) following reinstatement may be of importance for the prediction of risk or resilience for ROF. The aim of this study was to investigate state anxiety as a potential individual difference factor contributing to differentiability or generalization of return of fear. Thirty-six participants underwent instructed fear expression, extinction and ROF induction through reinstatement while physiological (skin conductance response, fear potentiated startle) and subjective measures of fear and US expectancy were acquired. Our data show that, as expected, high state anxious individuals show deficits in SCR discrimination between dangerous and safe cues after reinstatement induced ROF (i.e. generalization) as compared to low state anxious individuals. The ability to maintain discrimination under aversive circumstances is negatively associated with pathological anxiety and predictive of resilient responding while excessive generalization is a hallmark of anxiety disorders. Therefore, we suggest that experimentally induced ROF might prove useful in predicting relapse risk in clinical settings and might have implications for possible interventions for relapse prevention. PMID- 27496366 TI - Exploring Patients' Views Toward Giving Web-Based Feedback and Ratings to General Practitioners in England: A Qualitative Descriptive Study. AB - BACKGROUND: Patient feedback websites or doctor rating websites are increasingly being used by patients to give feedback about their health care experiences. There is little known about why patients in England may give Web-based feedback and what may motivate or dissuade them from giving Web-based feedback. OBJECTIVE: The aim of this study was to explore patients' views toward giving Web-based feedback and ratings to general practitioners (GPs), within the context of other feedback methods available in primary care in England, and in particular, paper based feedback cards. METHODS: A descriptive exploratory qualitative approach using face-to-face semistructured interviews was used in this study. Purposive sampling was used to recruit 18 participants from different age groups in London and Coventry. Interviews were transcribed verbatim and analyzed using applied thematic analysis. RESULTS: Half of the participants in this study were not aware of the opportunity to leave feedback for GPs, and there was limited awareness about the methods available to leave feedback for a GP. The majority of participants were not convinced that formal patient feedback was needed by GPs or would be used by GPs for improvement, regardless of whether they gave it via a website or on paper. Some participants said or suggested that they may leave feedback on a website rather than on a paper-based feedback card for several reasons: because of the ability and ease of giving it remotely; because it would be shared with the public; and because it would be taken more seriously by GPs. Others, however, suggested that they would not use a website to leave feedback for the opposite reasons: because of accessibility issues; privacy and security concerns; and because they felt feedback left on a website may be ignored. CONCLUSIONS: Patient feedback and rating websites as they currently are will not replace other mechanisms for patients in England to leave feedback for a GP. Rather, they may motivate a small number of patients who have more altruistic motives or wish to place collective pressure on a GP to give Web-based feedback. If the National Health Service or GP practices want more patients to leave Web based feedback, we suggest they first make patients aware that they can leave anonymous feedback securely on a website for a GP. They can then convince them that their feedback is needed and wanted by GPs for improvement, and that the reviews they leave on the website will be of benefit to other patients to decide which GP to see or which GP practice to join. PMID- 27496368 TI - Premature Growth Plate Closure in a Ballet Dancer en Pointe. AB - A 13-year-old ballet dancer who had been dancing en pointe (on the tips of the toes) since 10 years presented to the clinic with a shortened right second toe. She had no previous history of pain or trauma. She was diagnosed with premature growth arrest of the second metatarsal head physes resulting in a shortened metatarsal. This is the first reported case of premature growth arrest in a ballet dancer as a result of dancing en pointe. PMID- 27496369 TI - Two-thirds receive no bystander cardiopulmonary resuscitation: could head rotation be the solution? PMID- 27496371 TI - Gender identity and the politics of etiology. PMID- 27496370 TI - Cognitive health and risk of ED revisit in underserved older adults. AB - OBJECTIVE: The objective was to examine associations between cognitive health and unplanned emergency department (ED) revisits 30, 60, and 90 days after the initial visit. METHODS: Sociodemographic, clinical, and cognitive measures were collected on 110 white and African American adults, 65 years and older, who sought care in an inner-city ED. The information was collected via face-to-face interviews and review of the electronic medical record. Returns to the study-site ED 30, 60, and 90 days later were identified through a search of the electronic medical record. RESULTS: The sample was mostly female (70.9%) and African American (73.6%), with an average age of 75 years (SD = 7.4). About half (56.4%) had 12 or more years of formal schooling. The overall cognitive score of 17.5 (SD 5.1) was 4.5 points less than standardized norms for persons 65 years and older. Each 1-point increase in cognitive score was associated with 24% and 21% decreased odds of 60-day (odds ratio [OR] = 0.76; 95% confidence interval [CI], 0.57-1.00) and 90-day revisit to the ED (OR = 0.79; 95% CI, 0.62-0.99), respectively. Cognitive health and odds of 30-day revisit (OR = 0.96; 95% CI, 0.72-1.26) had a nonsignificant association. CONCLUSIONS: Our sample of older, mostly female African Americans showed poorer cognitive health compared with standardized norms. However, higher cognitive health scores were linked to lower risk for unplanned ED revisit 60 and 90 days later. A clearer understanding of biological and nonbiological pathways that connect cognitive health to revisit risk in disadvantaged older populations might improve health outcomes, including the avoidance of return trips to the ED. PMID- 27496373 TI - Justinus Kerner and sausage poisoning: the birth of botulinum toxin. PMID- 27496372 TI - La Moisissure et la Bacterie: Deconstructing the fable of the discovery of penicillin by Ernest Duchesne. AB - Ernest Duchesne (1874-1912) completed his thesis on microbial antagonism in 1897 in Lyon. His work lay unknown for fifty years, but on being brought to light led to his being credited with having discovered penicillin prior to Alexander Fleming. The claims surrounding Duchesne are examined here both from the strictly microbiological perspective, and also for what they reveal about how the process of discovery is frequently misconstrued. The combined weight of evidence presented here militates strongly against the possibility that the species of Penicillium that Duchesne worked with produced penicillin. PMID- 27496374 TI - Targeting the gastrointestinal tract to treat type 2 diabetes. AB - The rising global rates of type 2 diabetes and obesity present a significant economic and social burden, underscoring the importance for effective and safe therapeutic options. The success of glucagon-like-peptide-1 receptor agonists in the treatment of type 2 diabetes, along with the potent glucose-lowering effects of bariatric surgery, highlight the gastrointestinal tract as a potential target for diabetes treatment. Furthermore, recent evidence suggests that the gut plays a prominent role in the ability of metformin to lower glucose levels. As such, the current review highlights some of the current and potential pathways in the gut that could be targeted to improve glucose homeostasis, such as changes in nutrient sensing, gut peptides, gut microbiota and bile acids. A better understanding of these pathways will lay the groundwork for novel gut-targeted antidiabetic therapies, some of which have already shown initial promise. PMID- 27496375 TI - ALTERED PARAFOVEAL MICROVASCULATURE IN TREATMENT-NAIVE CHOROIDAL MELANOMA EYES DETECTED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To determine whether parafoveal microvascular changes have occurred in choroidal melanoma eyes before radiotherapy. METHODS: A retrospective cohort study included 30 consecutive patients with unilateral choroidal melanoma. The microvascular structure was analyzed by optical coherence tomography angiography. Fellow eyes served as control for affected eyes. RESULTS: Optical coherence tomography angiography demonstrated no difference in superficial foveal avascular zone (P = 0.316), but showed significant enlargement in deep foveal avascular zone (P < 0.0001) in affected eyes as compared with fellow eyes. It also showed significant decrease in superficial (P = 0.004) and deep (P = 0.0003) capillary vascular density (CVD). In subgroup analyses, the presence of subretinal fluid contributed to significant enlargement of deep foveal avascular zone (P < 0.0001) as well as reduction in superficial (P = 0.0001) and deep (P = 0.001) CVD. By linear regression, greater tumor diameter correlated with reduction in deep CVD (y = -0.42x + 1.01, Pslope = 0.021); greater tumor thickness correlated with reduction in both superficial (y = -0.67x + 0.24, Pslope = 0.039) and deep (y = 0.82x + 0.56, Pslope = 0.002) CVD. CONCLUSION: Optical coherence tomography angiography documented significant enlargement of deep foveal avascular zone as well as reduction in superficial and deep CVD in affected eyes. These findings correlated with the presence of subretinal fluid and increasing tumor size, suggesting that tumor-related factors contribute to parafoveal microvascular ischemia. PMID- 27496377 TI - Should we consider devolution of "head and neck" surgery from the specialties of oral and maxillofacial surgery; ear, nose, and throat surgery; and plastic surgery? PMID- 27496378 TI - Reeconstruction of a mandibular defect after bisphosphonate-related osteonecrosis of the jaw. AB - We describe the reconstruction of a mandible damaged by bisphosphonate-related osteonecrosis of the jaw (BRONJ) using the simple and safe combination of a reconstruction plate and patching with a submandibular gland. PMID- 27496379 TI - Mst1 participates in the atherosclerosis progression through macrophage autophagy inhibition and macrophage apoptosis enhancement. AB - Emerging evidence favors the notion that macrophage autophagy plays a prominent role in the pathogenesis of vulnerable plaque, suggesting the therapeutic potential of targeting autophagy in atherosclerosis. Here ApoE(-/-) mice were crossed with Mst1 knockout or Mst1 Tg mice to generate ApoE(-/-):Mst1(-/-) and ApoE(-/-):Mst1Tg mice. All animals were fed high-fat-diet for 4months to induce arterial atherosclerosis. Murine macrophage RAW264.7 cells were subjected to ox LDL (50MUg/mL) in an effort to examine the cellular mechanisms. A significant increase in the levels of Mst1 and p-Mst1 was observed in the aorta of ApoE(-/-) mice. Mst1 knockout significantly reduced atherosclerotic area, decreased lipid core area and macrophage accumulation as compared with ApoE(-/-) mice. Along the same line, Mst1 overexpression increased plaque area, lipid core and macrophage accumulation as compared with ApoE(-/-) mice. Mst1 deficiency significantly increased levels of Beclin1 and LC3II, while decreased that of p62 in aortic atherosclerosis. Moreover, in vitro data indicated that Mst1 knockdown prompted more typical autophagosomes upon ox-LDL challenge. Mst1 knockdown also enhanced autophagic flux as evidenced by GFP-mRFP-LC3 staining, increased LC3-II expression and decreased p62 expression in the presence of bafilomycin A1. Mst1 knockdown decreased, while Mst1 overexpression increased macrophage apoptosis upon ox-LDL exposure. In conclusion, Mst1 deficiency diminishes atherosclerosis and stabilizes atherosclerotic plaques in ApoE(-/-) mice. Mst1 may participate in atherosclerosis progression through inhibition of macrophage autophagy and promotion of macrophage apoptosis. PMID- 27496381 TI - Chronic Diarrhea: Diagnosis and Management. AB - Chronic diarrhea is a common problem affecting up to 5% of the population at a given time. Patients vary in their definition of diarrhea, citing loose stool consistency, increased frequency, urgency of bowel movements, or incontinence as key symptoms. Physicians have used increased frequency of defecation or increased stool weight as major criteria and distinguish acute diarrhea, often due to self limited, acute infections, from chronic diarrhea, which has a broader differential diagnosis, by duration of symptoms; 4 weeks is a frequently used cutoff. Symptom clusters and settings can be used to assess the likelihood of particular causes of diarrhea. Irritable bowel syndrome can be distinguished from some other causes of chronic diarrhea by the presence of pain that peaks before defecation, is relieved by defecation, and is associated with changes in stool form or frequency (Rome criteria). Patients with chronic diarrhea usually need some evaluation, but history and physical examination may be sufficient to direct therapy in some. For example, diet, medications, and surgery or radiation therapy can be important causes of chronic diarrhea that can be suspected on the basis of history alone. Testing is indicated when alarm features are present, when there is no obvious cause evident, or the differential diagnosis needs further delineation. Testing of blood and stool, endoscopy, imaging studies, histology, and physiological testing all have roles to play but are not all needed in every patient. Categorizing patients after limited testing may allow more directed testing and more rapid diagnosis. Empiric antidiarrheal therapy can be used to mitigate symptoms in most patients for whom a specific treatment is not available. PMID- 27496380 TI - Inhibition of soluble epoxide hydrolase alleviated atherosclerosis by reducing monocyte infiltration in Ldlr(-/-) mice. AB - RATIONALE: Circulating monocytes play pivotal roles in chronic inflammatory diseases. Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, are known to have anti-inflammatory effects and are hydrolyzed by soluble epoxide hydrolase (sEH). OBJECTIVE: We aimed to investigate the effect of sEH inhibition in atherogenesis. METHODS AND RESULTS: Mice with low-density lipoprotein receptor deficiency (Ldlr(-/-)) with or without sEH inhibitor, and Ldlr/sEH double knockout (DK) mice were fed a Western-type diet (WTD) for 6weeks to induce arteriosclerosis. Both sEH inhibition and gene depletion decreased the WTD induced hyperlipidemia, plaque area and macrophage infiltration in mice arterial wall. Ly6C(hi) infiltration of monocytes remained similar in blood, spleen and bone marrow of DK mice, but was decreased in aortic lesions. To further assess the role of sEH or EETs in monocyte/macrophage infiltration in atherogenesis, we transplanted DK bone marrow into Ldlr(-/-) recipients, and then fed mice the WTD. Aortic lesions and Ly6C(hi) monocyte infiltration were reduced in mice with transplanted bone marrow of DK mice without diminishing the cholesterol level. Furthermore, sEH inhibition or gene depletion increased the ratio of EETs/DHETs and diminished the expression of P-selectin glycoprotein ligand 1 (PSGL-1) in mice peripheral-blood mononuclear cells. Monocyte adhesion to P-selectin and to tumor necrosis factor alpha-activated endothelial cells was also diminished by sEH inhibition. CONCLUSION: sEH inhibition and gene depletion attenuated atherosclerosis in mice by decreasing the infiltration of monocytes into the artery wall. EET and PSGL-1 may play pivotal roles in monocyte/macrophage infiltration and atherogenesis. PMID- 27496382 TI - Consumer quality use of medicines: An important element in public health. PMID- 27496383 TI - Transcriptomic/proteomic identification of allergens in the mite Tyrophagus putrescentiae. AB - While a number of allergens from house dust mites have been described, much remains to be discovered about allergens from storage mites. Here, next generation sequencing was combined with MS/MS shotgun proteomics to identify proteins, especially potential allergens from Tyrophagus putrescentiae, commonly found in stored food products, especially flour. cDNAs of suspected allergens were cloned and expressed from bacterial cells, and recombinant allergens were tested for binding to IgE in sera from T. putrescentiae-sensitive patients. These analyses identified three previously uncharacterized allergens, Tyr p 28, Tyr p 35, and Tyr p 36, which have been officially assigned by the WHO/IUIS Allergen Nomenclature Sub-committee. Recombinant proteins rTyr p 28, rTyr p 35, and rTyr p 36 bound with 47.1%, 82.4%, and 70.6% of T. putrescentiae-sensitive sera. We provide here a new method to identify allergens by the combination of transcriptomic and proteomic approaches. PMID- 27496384 TI - Study of the adaptability of preformed orthodontic archwires to the average dental arch form of a Moroccan population. AB - INTRODUCTION: The aim of this study is to determine which commercially available preformed archwires offer a good fit with the average dental arch form of our sample. MATERIALS AND METHOD: We measured the dental arch parameters of sample 1 comprising 30 dental models and compared them with the dimensions of 25 archwires (sample 2) offered for sale by orthodontic suppliers. RESULTS AND DISCUSSION: Of the 25 archwires tested, 10 correspond perfectly to the average dental arch form of our sample at canine and molar level (mean+/-1SD) and would be suitable for cases where the treatment plan involves no expansion. In addition, 3 archwires have a shape that is slightly wider than the average arch form in the sample and could be used for cases in which the treatment plan includes no extractions but simply a slight expansion. PMID- 27496385 TI - [Not Available]. PMID- 27496386 TI - Orthopedic treatment of Class III malocclusions using skeletal anchorage: A bibliographical review. AB - AIM: To summarize scientific articles relating to orthopedic treatment using skeletal anchorage for Class III malocclusions in 2016. MATERIALS AND METHODS: Exhaustive bibliographical research on PubMed with the following keywords "bone OR skeletal-anchored maxillary protraction". RESULTS: Twenty-one articles were noted between March 2008 and August 2015. Eleven were original articles with clinical series. Two reviews of the literature, two technical, two focus articles, three clinical cases and one animal study were also published. DISCUSSION: This is the first genuinely orthopedic technique for this indication, and it may in the medium term avoid recourse to a surgical-orthodontic protocol. However, its use is compromised by the ignorance of practitioners and operators, patient refusal to accept general anesthesia and less-than-perfect materials. PMID- 27496387 TI - [Not Available]. PMID- 27496388 TI - Enforcement of the Emergency Medical Treatment and Labor Act, 2005 to 2014. AB - STUDY OBJECTIVE: We determine the incidence of and trends in enforcement of the Emergency Medical Treatment and Labor Act (EMTALA) during the past decade. METHODS: We obtained a comprehensive list of all EMTALA investigations conducted between 2005 and 2014 directly from the Centers for Medicare & Medicaid Services (CMS) through a Freedom of Information Act request. Characteristics of EMTALA investigations and resulting citation for violations during the study period are described. RESULTS: Between 2005 and 2014, there were 4,772 investigations, of which 2,118 (44%) resulted in citations for EMTALA deficiencies at 1,498 (62%) of 2,417 hospitals investigated. Investigations were conducted at 43% of hospitals with CMS provider agreements, and citations issued at 27%. On average, 9% of hospitals were investigated and 4.3% were cited for EMTALA violation annually. The proportion of hospitals subject to EMTALA investigation decreased from 10.8% to 7.2%, and citations from 5.3% to 3.2%, between 2005 and 2014. There were 3.9 EMTALA investigations and 1.7 citations per million emergency department (ED) visits during the study period. CONCLUSION: We report the first national estimates of EMTALA enforcement activities in more than a decade. Although EMTALA investigations and citations were common at the hospital level, they were rare at the ED-visit level. CMS actively pursued EMTALA investigations and issued citations throughout the study period, with half of hospitals subject to EMTALA investigations and a quarter receiving a citation for EMTALA violation, although there was a declining trend in enforcement. Further investigation is needed to determine the effect of EMTALA on access to or quality of emergency care. PMID- 27496389 TI - Insight into the Inhibition of Drug-Resistant Mutants of the Receptor Tyrosine Kinase EGFR. AB - Targeting acquired drug resistance represents the major challenge in the treatment of EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we describe the structure-based design, synthesis, and biological evaluation of a novel class of covalent EGFR inhibitors that exhibit excellent inhibition of EGFR-mutant drug resistant cells. Protein X-ray crystallography combined with detailed kinetic studies led to a deeper understanding of the mode of inhibition of EGFR-T790M and provided insight into the key principles for effective inhibition of the recently discovered tertiary mutation at EGFR-C797S. PMID- 27496391 TI - Charles Desmond Ross Pengelly. PMID- 27496390 TI - Association Between Travel Distance and Choice of Treatment for Prostate Cancer: Does Geography Reduce Patient Choice? AB - OBJECTIVE: To determine whether the distance between a prostate cancer patient's home and treatment facility was related to the choice of treatment received among those opting for surgery or radiation. METHODS AND MATERIALS: We identified 222,804 patients diagnosed with National Comprehensive Cancer Network low-, intermediate-, or high-risk N0M0 prostate cancer and treated with local therapy (surgery or radiation alone, with or without hormone therapy) using the National Cancer Database. We used multivariable logistic regression to determine whether the choice of radiation therapy vs radical prostatectomy varied by distance among patients living in rural and urban areas. Analyses were adjusted for geographic location within the United States, age, race, Charlson/Deyo comorbidity score, year of diagnosis, income quartile, education quartile, Gleason score, prostate specific antigen level, and T stage. RESULTS: Patients living in urban or rural areas were less likely to receive radiation compared with surgery if they lived farther from the treatment facility. Among urban patients living <=5 miles from the treatment facility, 53.3% received radiation, compared with 47.0%, 43.6%, and 33.8% of those living 5 to 10, 10 to 15, or >15 miles away, respectively (P<.001 in all cases). Similarly, rural patients were less likely to receive radiation the farther they lived from the treatment facility (<=25 miles: 62.3%; 25-50 miles: 55.5%; 50-75 miles: 38.4%; >75 miles: 23.8%; P<.05 in all cases). These trends were also present when each risk group was analyzed separately. CONCLUSION: Patients with prostate cancer in both urban and rural settings were less likely to receive radiation therapy rather than surgery the farther away they lived from a treatment center. These findings raise the possibility that the geographic availability of radiation treatment centers may be an important determinant of whether patients are able to choose radiation rather than surgery for localized prostate cancer. PMID- 27496392 TI - Health professional advice, use of medications and smoking cessation: A population-based prospective cohort study. AB - INTRODUCTION: The mediating role of cessation medications in the association between health professional advice and quitting behaviors is unclear. METHODS: Data were from the Ontario Tobacco Survey longitudinal study, collected between July 2005 and June 2011 in Ontario, Canada. The analytic sample included 3437 baseline smokers who were seen by health professionals during follow-up. Logistic regression with generalized estimating equations and mediation analysis techniques were used to examine the impact of advice and medications on quitting outcomes (making a quit attempt, short-term quitting 1-6months and long-term quitting>6months). RESULTS: Those who received advice to quit smoking were more likely to use cessation medications than those who did not receive advice (21% vs. 13%, P<0.001). Receiving advice was associated with making a quit attempt (adjusted odds ratio (OR) 1.25, 95% confidence interval (CI) 1.10-1.41) and long term quitting (adjusted OR 1.49, 95% CI 1.10-2.02), but not with short-term quitting. Use of cessation medications was associated with making a quit attempt (adjusted OR 11.83, 95% CI 9.93-14.08), short-term quitting (adjusted OR 3.69, 95% CI 2.90-4.68), and long-term quitting (adjusted OR 2.73, 95% CI 1.95-3.82). Using prescription medications was associated with a higher likelihood of quitting short-term (adjusted OR 2.43, 95% CI 2.59-3.74) and long-term (adjusted OR 2.27, 95% CI 1.23-4.17) than using NRT. Use of cessation medications was a significant mediator in the pathway from receiving advice to quitting. CONCLUSION: Health professionals should advise smokers to quit and encourage them to use cessation medications, especially prescription medications when trying to quit. PMID- 27496393 TI - Smoking cessation and receipt of cessation advice from health professionals among older smokers in Taiwan. AB - OBJECTIVES: To examine the prevalence and correlates of smoking cessation and receiving professional cessation advice among older smokers in Taiwan. METHODS: Cross-sectional data from the 2008-2010 and 2012 Taiwan Adult Smoking Behavior Survey was used to form a sample of 4081 recent active smokers aged 50+, comprising current smokers and former smokers who quit smoking within the past 12months. We examined three outcome variables: quit attempt in the past 12months, successful cessation for at least 3months, and receipt of health professional cessation advice. Multivariate logistic regressions were used to identify significant correlates. RESULTS: During the study period, the annual quit attempt rate was 41.4%, annual successful cessation rate was 4.7%, and prevalence of receiving cession advice among smokers who visited health professionals within the past 12months was 72.3%. After controlling for other covariates, quit attempts were significantly higher in 2009 and positively associated with higher education, poorer health status, smoke-free homes, and receipt of cessation advice. Successful cessation was significantly higher in 2009, positively associated with older age, higher income, and smoke-free homes, and negatively associated with receiving cessation advice. Receipt of cessation advice was significantly lower in 2010 and 2012, positively associated with male gender, older age, and poorer health status, and negatively associated with higher education. CONCLUSIONS: Our results suggest that targeting lower educated and lower income subgroups, adopting effective strategies to increase voluntary smoke free home rules, and improving professional cessation advice will have great potential to further reduce smoking prevalence in older smokers. PMID- 27496394 TI - Association of sugar-sweetened beverage intake frequency and asthma among U.S. adults, 2013. AB - OBJECTIVES: Sugar-sweetened beverage (SSB) intake among U.S. adults is associated with obesity and type 2 diabetes. An association between SSB intake and asthma has been shown among U.S. children and Australian adults, but scant published information exists for U.S. adults. We examined associations between SSB intake and current asthma among U.S. adults, and the role of obesity in this association. METHODS: We analyzed 2013 Behavioral Risk Factor Surveillance System data for 146,990 adults (>=18years) from 23 states and the District of Columbia. We used multivariable logistic regression to estimate associations between current asthma and frequency (none, <1 time/day, once/day, >=2 times/day) of SSB intake (soda, fruit drink, sweet tea, and sports/energy drink). SSB intake was measured using two questions. Covariates included age, sex, race/ethnicity, education, and smoking. Obesity, based on self-reported height and weight, was assessed as an effect modifier. RESULTS: Overall, 9.1% of adults reported current asthma: 8.5% of adults who did not consume SSBs had current asthma vs 12.1% of adults who consumed SSBs >=2 times/day. There was no difference in asthma prevalence with SSB intake <1 time/day (8.7%) or once/day (8.7%). Among non-obese adults, the odds of having current asthma were higher among those who consumed SSBs >=2 times/day (aOR=1.66, 95%CI=1.39, 1.99) than non-SSB consumers. However, SSB intake frequency was not associated with asthma among obese adults. CONCLUSIONS: Frequent SSB consumption was associated with asthma among non-obese adults. Research on asthma prevention should further consider the potential adverse effects of high SSB intake among U.S. adults. PMID- 27496396 TI - Giant right atrial appendage aneurysm: Diagnosis with cardiac magnetic resonance imaging. PMID- 27496397 TI - Corrigendum to "Cited rationale for variance in the use of primary intraperitoneal chemotherapy following optimal cytoreduction for stage III ovarian carcinoma at a high intraperitoneal chemotherapy utilization center" [Gynecol. Oncol. 142 (2016) 13-18]. PMID- 27496395 TI - Unmet basic needs and health intervention effectiveness in low-income populations. AB - In the face of unmet basic needs, low SES adults are less likely to obtain needed preventive health services. The study objective was to understand how these hardships may cluster and how the effectiveness of different health-focused interventions might vary across vulnerable population sub-groups with different basic needs profiles. From June 2010-2012, a random sample of low-income adult callers to Missouri 2-1-1 completed a cancer risk assessment and received up to 3 health referrals for needed services (mammography, pap testing, colonoscopy, HPV vaccination, smoking cessation and smoke-free home policies). Participants received either a verbal referral only (N=365), verbal referral+tailored print reminder (N=372), or verbal referral+navigator (N=353). Participants reported their unmet basic needs at baseline and contacts with health referrals at 1-month post-intervention. We examined latent classes of unmet basic needs using SAS. Logistic regression examined the association between latent classes and contacting a health referral, by intervention condition. A 3 class solution best fit the data. For participants with relatively more unmet needs (C2) and those with money needs (C3), the navigator intervention was more effective than the tailored or verbal referral only conditions in leading to health referrals contacts. For participants with fewer unmet basic needs (C1), the tailored intervention was as effective as the navigator intervention. The distribution and nature of unmet basic needs in this sample of low-income adults was heterogeneous, and those with the greatest needs benefitted most from a more intensive navigator intervention in helping them seek needed preventive health services. PMID- 27496398 TI - Preface. PMID- 27496399 TI - Evaluation of the Motivation to Consent to and to Refuse Organ Donation Among Participants of Educational Meetings Concerning Organ Transplantation. AB - BACKGROUND: Improvement of the consent rate for solid organ donation from deceased donors is a key component of strategies applied in many countries aiming to increase the availability of organs for transplantation. Attitudes toward living and posthumous donation are favorable. Research shows that the outlook on organ donation and the degree of the willingness to become an organ donor are associated with a wide range of variables. The main objective of this study was to identify factors that influence the willingness to donate organs and the reasons for refusing consent. MATERIALS AND METHODS: The study included 191 participants (135 female and 56 male) aged 16 to 61 years (mean age 26.86 +/- 12.88). A cross-sectional study was conducted during educational meetings concerning organ donation that was addressed to students, teachers, and nurses. Survey tools included the Individual Questionnaire: Study of attitudes toward transplantation, consisting of 26 closed questions (with the consent of the Statistical Office in Krakow). RESULTS: In all, 97.4% of the respondents accepted transplantation from living donors, and 95.8% accepted deceased donations. Of the respondents, 78.5% agreed to posthumous life-saving organ donation. There was a significant difference between the respondents' sex, age, social group, place of living, and the reasons for their willingness to donate organs both posthumously and during their lifetime, as well as reasons for refusal. CONCLUSIONS: Our findings showed that the study group in general had favorable views on treatment involving transplantation and declared willingness to make a posthumous organ donation. These views vary depending on demographic variables. The education on the subject of organ and tissue donation has a positive impact on donation and transplantation rates. PMID- 27496400 TI - Central Register of Objections for Deceased Donation in Poland 1996 to 2014: The Country With an Opting-Out System. AB - BACKGROUND: Organ, tissue, and cell procurement from deceased donors for transplantation requires consent and authorization, documented donor's positive acceptance, or lack of objection to donation expressed while alive (consent). It also requires the fulfillment of other legal conditions required by law, such as person's legal abilities to act in this field or to obtain approval for donation (authorization). Consent to and authorization of donation from deceased donors requires regulations at the national level. Poland developed an opting-out policy with the Transplantation Act in 1996. The Central Register of Objections (CRO) was introduced on November 1, 1996. The purpose of this article is a formal analysis of all submitted objections and objection withdrawals managed by the CRO since the introduction of the registry in 1996 until the end of 2014. MATERIALS AND METHODS: All data collected by the CRO during 18 years of service was subject to analysis. The objections and withdrawals of objections are summarized in the tables, along with the age, sex, and place of residence of the registered residents. RESULTS: By December 31, 2014, a total of 29,288 records were registered, including 29,013 registered objections and 275 registered withdrawals of objections; this means that 0.075% of the country's population expressed objection to posthumous tissue and organ donation for transplantation. Legal representatives submitted 4208 declarations (15.6% of all declarations). The largest inflow of objections took place in 1997, the first full year of CRO activity. CONCLUSION: CRO is an indispensable option in a country with opt-out system as a part of organ donation authorization protocol. Number of registered objections is extremely low, in practice, this leads to a situation where the will of the deceased most often is obtained from his family. PMID- 27496401 TI - Liver Donation and Transplantation in Poland: Numbers, Indicators, and Trends. AB - We aim to provide a panorama of liver donation and transplantation in Poland, where each year around 300 liver transplantations from deceased donors and 20 liver fragment transplantations from living donors are performed. This means about 9 transplantations per population of 1 million. Each year, the number of deceased donors reaches more than 500. In more than 50% of cases, livers are used. The law allows liver procurement from living donors. Until the end of 2013, liver fragments were recovered from 236 living donors and transplanted mainly to pediatric recipients (n = 232). A living-donor registry was created to monitor and assess the health condition of donors. The range of the national waiting list and allocation is nationwide. It is managed with the use of the Web tool www.rejestry.net. There are 2 modes of recipient referral: "urgent" and "elective." Allocation is either patient oriented and center oriented. Disease groups, which comprise the most frequent indications for transplantation in adults, include the cirrhosis group (48%), in which the highest number of procedures was performed for patients with hepatitis C virus (24%); alcohol induced cirrhosis (14%); alcohol-induced hepatitis (8%), and hepatitis B virus cirrhosis (7%). Among pediatric recipients, the most frequent indications were congenital cholestatic diseases, which made up 38% of all transplantation indications. The results of liver transplantations are collected in the national transplant register. The 1-year graft and recipient survival with deceased donor transplantation are 81% and 84% and with living donor transplantation 86% and 89%. The 5-year graft and recipient survival in deceased donor transplantation are 69% and 73%, and in living donor transplantation are 80% and 83%. PMID- 27496402 TI - Liver Transplant Registry in Poland: Web-Netted Quality Tool in Liver Transplantation From Deceased and Living Donors. AB - BACKGROUND: Poltransplant managed a national transplant registry with the use of the Web tool www.rejestry.net. It collects information about all organ transplantations in the country along with outcomes. This article presents a formal analysis of data collected in the registry for the years 1998 to 2014. MATERIALS AND METHODS: Results presented are actual, not extrapolated, numbers; these were calculated only for the events for which the observation was complete, meaning that a given term of follow-up had passed and the information on recipient's and graft survivals were available. RESULTS: All liver transplant procedures were registered from the years 1998 to 2014, with follow-up data completeness of 89% to 99%. Detailed statistical descriptions of liver transplant results were significantly better for transplants from living donors, in comparison to deceased donors, for pediatric recipients. Results for pediatric and adult recipients did not vary if the organ was from a deceased donor. Elective and primary transplantations have significantly better results in comparison to urgent and re-transplanted cases. Results depend on indications for transplantation. Significantly better results were obtained in the case of cholestatic diseases and cirrhosis other than hepatitis C virus. Significantly worse results were obtained in acute liver failure, independently of etiology. Results in the case of hepatitis C virus cirrhosis, metabolic diseases, and neoplasms do not vary significantly. CONCLUSIONS: The strength of these findings are based on the registry's reliability and completeness. The registry fulfills its aims related to collecting records and monitoring graft function, and recipient survival. The data are an important source of information, to be used by transplantation institutions and referred to in the literature. PMID- 27496403 TI - Knowledge About Legal Regulations Regarding Organ Transplantation Among High School and University Students in Poland. AB - BACKGROUND: It has been reported in many studies that although young people have positive attitudes towards organ donation, their knowledge about transplantation is insufficient. This study focused on knowledge about legal regulations regarding organ transplantation in Poland. MATERIALS AND METHODS: A 59-item, self designed questionnaire was administered to 1011 young persons from Central Poland. Among the interviewees were 462 high school students, 184 students of the faculty of medicine, and 365 students from other faculties. The survey was divided into 4 parts: knowledge (basic information, maximum of 17 points; statistics, maximum of 5 points and legal regulations - maximum of 6 points), attitude, personal experience and general characteristics of the interviewees. RESULTS: High school and university students received 1.45 +/- 1.24 and 1.54 +/- 1.1 (P = .26) out of a maximal score of 6 with respect to knowledge of legal regulations. Medical students scored much higher (4.13 +/- 1.23). Only 20 respondents (including 19 medical students) answered correctly all 6 questions. Those who were willing to donate their organs after death achieved better result than those who did not want to donate (1.6 +/- 1.22 vs 1.34 +/- 1.1; P = .002). Personal experiences did not influence knowledge about transplantation. CONCLUSION: Knowledge about legal regulations regarding organ transplantation is insufficient among young people. Structured, well-considered education programs at various levels of school and academic education are needed to improve public awareness and attitude. PMID- 27496404 TI - Do Age and Religion Have an Impact on the Attitude to Organ Transplantation? AB - BACKGROUND: Religious issues may be a significant reason for the lack of organs for transplantation. Younger people have a more enthusiastic attitude toward organ donation. The goal of the present study was to determine whether age and religion affect people's attitudes to organ transplantation. METHODS: This trial was a diagnostic poll study using an original survey questionnaire involving 1273 people living in Podlaskie Voivodeship. RESULTS: Treatment with the use of organs from dead donors was approved by 88.3% of the respondents aged <=60 years and 70.5% of those aged >60 years; the highest number of those who opposed this procedure occurred in the group aged >60 years (22.3%). Baptists approved of the method more often than persons of other religions; Muslims disapproved of it more often than others (25%). Approximately 96% of the participants, regardless of religion, had a positive attitude toward organ transplantation, but only 81% aged >60 years had a positive attitude toward organ donation; there were significantly more Catholics in this group (P < .026). In the group aged >60 years, 63.8% expressed their consent; 66.7% of them were Muslims and Baptists. Approximately 86% of persons aged <=60 years were willing to donate their own organs after death. These people were significantly more often Catholic (P < .045). CONCLUSIONS: Age and religion have a considerable influence on positive attitudes toward transplantation. The majority of younger people, as well as Catholics, approve of the removal of organs from living donors and from dead donors. PMID- 27496405 TI - Opinions and Attitudes of University Students Concerning Organ Transplantation. AB - INTRODUCTION: Organ donation and transplantology are receiving more and more support and approval all over the world every year. However, there remains a considerable and growing difference between the number of patients awaiting transplantation and the number of donors. The aim of the work was to find out the opinions and attitudes of university students concerning organ donation and transplantology. MATERIAL AND METHODS: Our poll surveyed 405 students from 2 universities (Medical University of Bialystok [MU] and Bialystok University of Technology [UT]). The research tool used in the study was an original survey questionnaire. RESULTS: Treatment with the use of organs taken from living persons was approved by 55.6% of the students, from dead donors, by 73.6%, and 1.2% of the participants did not approve of that way of treatment. Of the students from the MU, 84% approved the removal of organs from close relatives after their death; 79.5% of those from the UT approved. Of the UT students, 8% were against the removal of organs from close relatives after their death; 4% of MU students were against it. Of MU students 94.5%, would agree to have their own organs removed after death; 85.3% of UT students would agree. Of MU students, 54.2% of students had informed their families about their will to have organs removed; 29.4% of UT students had informed their families. A greater number of medical students had a declaration of will (28.9% vs 13.2%; P < .001). The kind of university had a significant (P = .002) influence on the students' attitudes to transplantation. A positive attitude was displayed by 94.5% of MU students and 83.8% of UT students, whereas a negative one, by 2% of UT students and 0.5% of MU students. CONCLUSIONS: Different degrees of knowledge and acceptance of organ donation were manifested by university students. To a great extent, this depended on the kind of university. MU students understood the topic and approved of the treatment to a greater degree. A permanent educational campaign should be carried out among young people, especially those studying at universities other than medical. PMID- 27496406 TI - Effect of the Second Warm Ischemia Time and Its Components on Early and Long-term Kidney Graft Function. AB - BACKGROUND: During kidney transplantation, the total time of organ ischemia consists of first warm ischemia time (WIT1), cold ischemia time (CIT), and a second WIT (WIT2). Rising graft temperature during WIT2, which comprises the creation of vascular anastomoses, increases oxygen demand and tissue damage, especially in the kidney tubular cells. The aim of this study was to analyze the influence of WIT2 on early and long-term kidney graft function. METHODS: We performed a retrospective analysis of 554 consecutive adult recipients, who received their first kidney graft from a deceased donor between 2003 and 2013. RESULTS: Mean WIT2 was 25.2 min. Donors' sex, age, presence of hypertension, body mass index (BMI), and the cause of brain death showed no effect on WIT2. Weak positive correlations were found between the duration of WIT2 and both recipients' age (r = 0.11; P < .01) and BMI (r = 0.14; P < .01). Multivariate regression analysis confirmed the independent influence of age (beta = 0.107 [95% confidence interval, 0.017 to 0.197] per year; P = .02) but not BMI (P = .09). WIT2 influenced early graft function and was significantly longer in patients with primary graft nonfunction than in other recipients (35.3 vs 24.9 min; P < .01). According to receiver-operating characteristic curve analysis, a WIT2 value >26 min was predictive of primary graft nonfunction, with 64% specificity and 58% sensitivity. No correlations were found between WIT2 and estimated glomerular filtration rate in the long-term follow-up period. CONCLUSIONS: This study found that WIT2 may significantly influence the early graft function. We also found that the creation time of vascular anastomoses does not affect the long-term kidney graft excretory function. PMID- 27496407 TI - The Model of Postgraduate Studies for Transplant Coordinators in Poland: 500 Graduates in the Years 2007-2015. AB - BACKGROUND: Since 2007, the Medical University of Warsaw has been organizing the Transplant Coordinators Postgraduate Studies, which are funded by the National Programme for the Development of Transplantation Medicine. The aim of the studies is to recruit medical professionals for every hospital with the potential of deceased donations. The goal of the present study was to formally evaluate the previous 16 editions of Transplant Coordinators Postgraduate Studies by assessing graduate profiles and analyzing the efficiency and sustainability of their education. METHODS: Graduate profiles were determined by gathering sociodemographic information contained in student records. Training efficiency and sustainability were defined by assessing the actual performance of the coordinators' functions in the hospital after taking the course. RESULTS: As of May 2015, the number of Transplant Coordinators Postgraduate Studies graduates totals 501. Approximately one half of the graduates (n = 248) had nursing degrees; training was also finished by 199 physicians, and 54 individuals had other medical education. The number of graduates per million population across the whole country totals 13. A total of 226 of the graduates (45%) were employed in the years 2007-2015 in hospitals as transplant coordinators; physicians (93 graduates), nurses (107 graduates) and other medical proffessionals (26 graduates). CONCLUSIONS: The academic formula of the Transplant Coordinators Postgraduate Studies funded by public sources makes it possible to educate practicing staff (physicians and nurses alike) for a nationwide system of donor hospital transplant coordinators posted in >200 hospitals and maintained by a national transplant organization. PMID- 27496408 TI - Prostate-Specific Antigen: Nonspecific in Deceased Organ Donors. AB - Currently, there is no clear position regarding the donation of organs from donors with prostate carcinoma (CaP) in European countries, except Italy. The lengthening of life expectancy increases the probability of prostate cancer among potential organ donors. The concentration of prostate-specific antigen (PSA) >2 ng/mL at 60 years of age is related to the increasing possibility of identifying an advanced form of CaP. In recent years in Poland, the recommendation has been to determine tumor markers in potential donors. In the first year of the recommendation, 10% of potential male cadaveric donors were disqualified in West Pomerania, Poland, on the basis of elevated PSA levels (>10 ng/mL). To avoid reduction of the actual donor pool, each potential male donor reported to the center since January 2010 undergoes a routine histologic evaluation of the whole prostate, regardless of the PSA level, before organ implantation. In the study group (N = 52), histopathologic evaluation revealed 6 cases of CaP (12%). In CaP positive group Gleason score range from 2+2 to 3+4. In CaP donors PSA level have been noticed in range 1.79 ng/mL - 7.66 ng/mL. There was no correlation between histologically confirmed CaP and the PSA level. PMID- 27496409 TI - Prostate Cancer in Deceased Liver Donors. AB - BACKGROUND: Prostate cancer is the second most common malignant tumor (13%) among male subjects in Poland. The aim of this study was to assess the prevalence of prostate cancer in a group of deceased liver donors. METHODS: A total of 784 liver procurement attempts from deceased donors were performed in the Department of General, Transplant and Liver Surgery, Medical University of Warsaw, from January 1, 2012, to April 1, 2015; 700 grafts were actually used in a liver transplant. A retrospective analysis was performed based on these data. Among male donors (n = 486 [62%]), there were 30 (6.2%) cases of a frozen biopsy of the prostate performed before making the decision regarding liver graft utilization. RESULTS: In the group of 30 donors who underwent prostate examination, 3 (10%) were diagnosed as having prostate cancer of a moderate invasive stage. In 2 other cases, fresh frozen section suggested prostate cancer; however, this fact was not confirmed in routine section. liver transplantation was not performed in these cases of suspicion of prostate cancer (5 of 30 [17%]) in the frozen biopsy specimens. The difference between groups of donors with prostate cancer and benign pathology of the prostate gland according to prostate-specific antigen serum concentration (P = .578) or age (P = .730) was not statistically significant. CONCLUSIONS: Increased prostate-specific antigen serum concentrations without a diagnosis of prostate cancer in histopathologic examinations should not be an independent contraindication for performing organ transplantation. Nevertheless, for recipient safety, even when prostate cancer is only suspected in the frozen biopsy sample, the procured organ should not be used for transplantation. PMID- 27496410 TI - System of Monitoring Potential Deceased Organ Donations in Over 200 Hospitals in Poland Using a Web Tool: Implementation and Structure. AB - BACKGROUND: In 2010 the formation of the Polish Hospitals Network of Organ Donation Coordinators, originated by Poltransplant, began. One of the goals of this project is to report all deaths in hospital ICUs in which a coordinator is posted. The aim of this strategy is to monitor donation potential, following the recruitment process of potential donors and indicating stages of that process that may be improved to increase effective recruitment. Until the end of 2014 all data were forwarded to Poltransplant as Excel files, but since January 1, 2015, reporting and data collection have been are performed using web tool www.koordynator.net. AIMS: The aim of the paper is to present the essentials in functioning principles, structure, and usage of the www.koordynator.net system, its technical construction, and to display good practices (know-how) tested by 1 country, for countries such as Poland, that contend with organ insufficiency. METHODS: The application www.koordynator.net allows for remote addition of individual records with information about deceased patients in hospital ICUs, the forwarding of data about potential and actual organ donors, the generation of complete reports about deceased patients in each hospital monthly, and the introduction of historical data. SUMMARY: Introduction of a potential donation monitoring system in 209 hospitals with transplant coordinators increases the number of identified potential and effective actual donors due to self-assessment analysis. Eventually, the www.koordynator.net reporting system allowed for external evaluation by coordinators from other hospitals, regional coordinators, and Poltransplant. The system is a modern tool that improves and increases the quality system in the organ donation field (quality assurance program). PMID- 27496411 TI - Effective Application of a Quality System in the Donation Process at Hospital Level. AB - This article describes the application of a quality system at the hospital level at the Multidisciplinary Hospital in Warsaw-Miedzylesie in Poland. A quality system of hospital procedures (in accordance with the ISO system 9001:2008) regarding the donation process, from the identification of a possible donor to the retrieval of organs, was applied there in 2014. Seven independent documents about hospital procedures, were designed to cover the entire process of donation. The number of donors identified increased after the application of the quality system. The reason for this increase is, above all, the cooperation of the well trained team of specialists who have been engaged in the process of donation for many years, but formal procedures certainly organize the process and make it easier. PMID- 27496412 TI - Organ Donation From Elderly Deceased Donors and Transplantation to Elderly Recipients in Poland: Numbers and Outcomes. AB - The age of a donor and recipient is one medical criterion in the kidney allocation system. The number of elderly donors and recipients is steadily growing. The aim of the study was to retrospectively evaluate the 5-year results of kidney transplantation from donors over 65 years of age to recipients over 60 years of age. In the years 1998 to 2010, 8526 potential deceased donation after brain death organ donors and 8206 people (81%), who had been treated with transplantation of kidneys were referred to the Poltransplant. The actual number of deceased donors >65 years was 358 and <65 years was 7207. The actual 5-year survival of a kidney transplant from donors >65 years was 59.2% (55.3% of recipients >60 years and 60.7% of recipients <60 years of age; P < .0001) and from donors <65 years was 75.1% (67.5% of recipients >60 years and 75.7% of recipients <60 years; P < .0001). The actual 5-year survival of kidney recipients from all donors >65 years was 75.6% (79.5% younger recipients vs 65.9% elderly recipients; P < .0001). The 5-year survival of kidney recipients from all donors <65 years was 88.1% (P < .0001); 89% younger recipients and 74.3% elderly recipients (P < .0001). The above analysis of the material from the Polish registry displayed significantly worse results of kidney transplantation from donors >65 years, regardless of the age group of recipients. PMID- 27496413 TI - Polish Guidelines on Diagnosing Brain Death in Adults vs the International Perspective: Are We in Need of an Update? AB - INTRODUCTION: The Polish definition of brain death originated from the original Harvard criteria and has been revised several times. Practitioners worldwide are required to regularly update their national guidelines on the definition of brain death to fit the latest international research concerning this topic. AIMS: (1) Compare current Polish guidelines on diagnosing brain death in adults with the American, British, Australian, and New Zealand recommendations; and (2) evaluate existing differences for the purposes of updating the Polish guidelines. MATERIALS: Current guidelines on diagnosing brain death published by The American Academy of Neurology (USA, 2010), the Academy of Medical Royal Colleges (United Kingdom, 2008), the Australian and New Zealand Intensive Care Society (AU/NZ, 2013), and the Polish Ministry of Health (Poland, 2007). RESULTS: All guidelines outline similar recommendations regarding the need for a suitable observation period before clinical examination and for basic medical conditions and exclusions to be evaluated before testing, the obligatory role of clinical examination including brain stem reflexes and apnea testing, and the nonobligatory role of ancillary tests. There is no consensus regarding: the recommended time period of pretesting observation, the number, seniority, and specialty of clinicians performing the testing, the role of additional exclusion criteria, the repeatability of clinical tests, the methodology of apnea testing, and recommended confirmatory tests. CONCLUSIONS: Current Polish guidelines on diagnosing brain death in adults remain up-to-date in comparison to the guidelines analyzed, though additional recommendations concerning apnea testing, drug and toxin clearance, and medical exclusion criteria for potential brain dead patients might be considered an important point of interest in the future. PMID- 27496414 TI - Assessment of Donation Potential After Circulatory Death as the First Step in Implementing and Running a Hospital Program of Organ Procurement. AB - BACKGROUND: In Poland the potential for organ donation from donation after circulatory death (DCD) donors is not known. This assessment will allow the hospital to create a quality organ harvesting system from this group of donors. AIMS: The aim of this study was to assess the DCD potential based on retrospective analysis of hospital deaths at Hospital Infant Jesus in Warsaw. METHODS: Documentation of 718 deceased patients from 2010 to 2014 was analyzed. This population could be classified as potential DCD donors in IIb category. The deceased's characteristics were analyzed while undergoing the qualification process for DCD. The analysis was to confirm the presence or absence of factors disqualifying kidneys from donation and transplantation. Data from particular departments and from the entire hospital were analyzed. RESULTS: The total number of deaths was 718. Excluding factors from the DCD donation process were found in 664 cases (92%), mainly age >60 and concomitant diseases. The rest of the patients (n = 54.8%) did not have factors that would exclude DCD donation. Group characteristics are given in detail. SUMMARY: The attempt to measure donation potential was done at the Hospital of the Infant Jesus in Warsaw, a large, multispecialty hospital with intensive organ donation and transplantation programs. Results show a potential for DCD donation (54 potential donations over the last 4years), which allows us to create a quality system and algorithms for organ donation after circulation death. PMID- 27496415 TI - A Cell Graft or a Drug? Legal and Practical Aspects of Somatic Cells Application in Graft-Versus-Host Disease Experimental Treatment: The Polish Experience. AB - INTRODUCTION: Allogeneic hematopoietic stem and progenitor cell (HSPC) transplantation and organ transplantation are well-established treatments for different conditions. Graft versus host disease (GvHD) is a major complication in both methods. There has been a rapid increase in the application of nonhematopoietic somatic cells, such as mesenchymal stem cells and regulatory T cells in GvHD experimental therapy. According to current European Union (EU) law, human cells intended for human application can be considered either as cell grafts or as advanced therapy medicinal products (ATMPs). OBJECTIVE, MATERIALS AND METHODS: The aim of the paper is an attempt to answer, based on GvHD experimental treatment data as well as existing EU and Polish law, whether cells cease to be cells (cell grafts) and becomes drugs (ATMPs); if yes, when; and what are the consequences of such situation both for patients as well as for physicians engaged in the treatment process in Poland. RESULTS AND DISCUSSION: Data analysis confirmed the interest in the experimental GvHD cell therapy. In the vast majority of analyzed cases the in vitro culture step in the cell preparation protocols has been foreseen. Therefore, the answer to title question was unambiguous-expanded cells are recognized in EU as ATMPs. In borderline cases, a scientific recommendation by the Committee for Advanced Therapies (CAT) of the European Medicines Agency (EMA) can play an important auxiliary role; however, it is currently neither required by Polish law nor legally binding in Poland. PMID- 27496416 TI - National Transplants Registry in Poland: Early and Long-term Results of Organ Transplantations in the Years 1998 to 2014. AB - BACKGROUND: In 2006, the National Transplants Registry, administered by the national transplant organization, was introduced in Poland for monitoring the results of organ transplantations. Statistical analysis is published yearly in Poltransplant Bulletin and publicly available on the website and reported to European institutions. The Transplants Registry cooperates with another registers functioning on-line, based on the web-net tool www.rejestry.net. We present the formal analysis of data collected for the years 1998 to 2014. METHODS: Analysis covered the total number of organ transplantations in every transplant center; outcomes after 3 months and 1, 3, and 5 years; and if data were available after 10, 15, and 20 years from transplantation. Results presented are real, not extrapolated. RESULTS: Some examples are as follows. The total number of deceased kidney transplantations was 15,009; 1-year recipient survival was 95%, graft survival was 88% (data completeness of 81%), 5-year recipient survival was 87%, and graft survival was 74% (data completeness of 82%). The total number of deceased liver transplantations was 3143; 1-year recipient survival was 84%, graft survival was 81% (data completeness of 99%), 5-year recipient survival was 73%, and graft survival was 89% (data completeness of 99%). CONCLUSIONS: The National Transplant Registry is an important tool for quality and safety systems in the transplantation field on the national level. Nowadays, the Registry efficiently and effectively fulfills its tasks related to collecting records of all performed transplantations. Monitoring function for graft and recipient survival is also satisfied. Collected numbers are an important and unique source of information to be used by transplant institutions and referred to in the literature. PMID- 27496417 TI - Drug Susceptibility Assessment in Stenotrophomonas Maltophilia Strains Isolated From the Blood of Organ Transplantation Recipients in a Warsaw Teaching Hospital During 2011 to 2014. AB - BACKGROUND: Blood infections with multidrug-resistant Gram-negative carbapenem resistant bacilli are particularly dangerous and challenging to treat in organ transplant recipients. Resistance to carbapenems may be acquired, for example, in Enterobacteriaceae, Pseudomonas, or Acinetobacter spp. or innate, for example, in Stenotrophomonas maltophilia. The purpose of this study was to analyze blood infections caused by S maltophilia in organ transplant recipients and to compare drug susceptibility of these bacteria and the same species isolated from the blood of other inpatients. METHODS: A total of 26 S maltophilia strains isolated from blood samples of 26 patients (including 14 liver or kidney transplant recipients) hospitalized during 2011 to 2014 were evaluated in this study. Antibiotic susceptibility was determined via E-test and disk diffusion methods. RESULTS: Stenotrophomonas maltophilia strains isolated from blood exhibited sensitivity to trimethoprim/sulfamethoxazole (100%), levofloxacin (96.2%), ciprofloxacin (92.3%), ticarcillin/clavulanic acid (80.8%), and ceftazidime (53.9%). CONCLUSIONS: Because appropriate antibiotic therapy in the case of S maltophilia differs from the standard empirical therapy administered in the case of most other Gram-negative bacilli, early identification of this pathogen is of particular significance. The use of antibiotics to which this pathogen is sensitive eliminates the infection and helps avoid graft loss. PMID- 27496418 TI - Epidemiological and Drug-Resistance Types of Methicillin-Resistant Staphylococcus Aureus Strains Isolated From Surgical and Transplantation Ward Patients During 2010 to 2011. AB - BACKGROUND: The increasing prevalence of multi-drug-resistant methicillin resistant Staphylococcus aureus (MRSA) is a substantial problem in hospitals worldwide, especially in wards with immunocompromised patients undergoing organ transplant. Epidemiological characteristics and antibiotic susceptibility profiles of hospital-acquired (HA) MRSA strains isolated from surgical/transplantation ward patients were studied. METHODS: We analyzed 26 HA MRSA strains isolated from 22 patients hospitalized at 3 different surgical and transplantation wards at a Warsaw clinical hospital during 2010 to 2011. Eleven patients were MRSA-asymptomatic carriers. Strain relatedness was evaluated through the use of multi-locus sequence typing (MLST), multi-locus variable number tandem repeat analysis (MLVA), and random amplified polymorphic DNA/arbitrarily primed PCR (RAPD) methods. Antibiotic susceptibility was assessed the use of routine diagnostic methods. RESULTS: The evaluated strains belonged to 4 clonal complexes (CCs) and 4 sequence types (STs): CC30/ST36 (65.4%), CC8/ST8 (15.4%), CC5/ST1827 (11.5%), and CC1/ST1 (7.7%). Six MLVA types and 6 RAPD types were isolated. A ciprofloxacin-, erythromycin-, and clindamycin-resistant CC30/ST36 clone (MLVA type 1, RAPD type 1A) was isolated in all wards. The isolated HA-MRSA strains were most often resistant to ciprofloxacin (100%), erythromycin (96.2%), clindamycin (84.6%), and gentamycin (30.8%). CONCLUSIONS: A ciprofloxacin-, erythromycin-, and clindamycin-resistant HA-MRSA ST36 CC30 clone, which prevailed on transplantation wards in the years 2010 to 2011, is probably one of the international epidemic clones named UK EMRSA-16 or USA200. PMID- 27496419 TI - Clinical and Microbiological Evaluation of Removable Prosthetic Restorations in Patients Treated With an Organ Transplant. AB - BACKGROUND: Removable dentures improve function and aesthetics of masticatory organ. Their proper scheme of use and hygiene procedures have an impact on biofilm formation. Microorganisms in biofilm are often resistant to many antibiotics and may pose a potential threat to patients treated with organ transplant. The study provided for evaluation of dental prostheses hygiene standards with reference to staphylococcal microflora in kidney transplant recipients. METHODS: The study involved 62 patients with removable prostheses. Thirty-seven subjects of this group had renal replacement therapy. The other 25 were volunteers with normal renal function. Medical and dental history was collected. Denture hygiene was assessed and swab sampling for microbiological testing were performed on the impression surface of the denture plate. RESULTS: Denture hygiene standards and proper scheme of their use were significantly better in patients of the control group. In both groups, significantly with longer denture use, patient care to provide proper hygiene standards declines. Staphylococcal strains were found in 92% patients of the study group and 84% of the control group, 43% of which were multi-drug resistant strains. No relation was found between patients overall health conditions as well as denture use methods and composition of staphylococcal denture plaque. CONCLUSIONS: Overall health conditions and denture use methods might not have an influence on staphylococcal denture plaque composition. However, the studies conducted did not answer the question of whether the above factors cause quantitative differences. Multidrug-resistant staphylococcal strains inhabiting denture surface may pose a threat to the health of kidney transplant recipients. PMID- 27496420 TI - Evolution of Organ Transplantation in Poland 1966 to 2014: Dates and Numbers. AB - BACKGROUND: Several events inspired us to collect data on organ transplantation in Poland (2016: the 50th anniversary of the first transplantation and the 20th anniversary of Polish Transplant Coordinating Center Poltransplant). The paper aims at presenting comprehensive data on all organ transplants, beginning with the first in 1966 (deceased kidney) until the end of 2014. METHODS: Source documents were reports published in Poltransplant Bulletin, a website registry managed by Poltransplant, reports by the Transplantation Council and by the Transplantation Institute of Warsaw. A source data enabled us to establish a preliminary report, presented for verification during the 12th Congress of the Polish Transplantation Society. RESULTS: By the end of 2014, the total number of organ transplants was 26,691. Kidney transplantation is the most common (total number = 19,812). The number of living kidney transplants is low, about 50 per year. The number of liver part transplants from living donors is relatively high, 20 to 30 annually. The program of deceased liver transplantation results in more than 300 transplants yearly. The first heart transplantation was in 1985, but the number of these procedures has been decreasing. No significant increase in the number of lung transplantations was noted. CONCLUSIONS: The number of organ transplantations from deceased donors places Poland in the middle among European countries. The number of living donor kidney transplants is lower than in other countries; therefore a living donor liver transplantation program belongs to leading programs. Progress of lung transplantation has been slow. The development is highlighted by vascularized composite tissue transplantations of the hands and face. The strength of the report lies in its reliability and completeness. Numbers are the unique source of information to be used and referred to in the literature. PMID- 27496421 TI - Dietary Intake of Vitamins in Different Options of Treatment in Chronic Kidney Disease: Is There a Deficiency? AB - BACKGROUND: The importance of diet in the management of kidney transplantation (KT), as well as other treatment options of chronic kidney disease (CKD), is generally acknowledged. However, data regarding vitamin intake are very limited. Vitamins are essential in maintaining good nutritional status and preventing many chronic complications. It is still not clear which treatment modality imposes the highest risk of dietary vitamin deficiency and whether successful KT reverses such a threat. METHODS: We performed this observational study to assess dietary intake of vitamins in CKD patients: after successful KT, not yet dialyzed (ND), treated with hemodialysis (HD), and with peritoneal dialysis (PD). A total of 202 patients were recruited (45 KT, 50 ND, 45 HD, and 62 PD). Vitamin intakes were evaluated through the use of a 24-hour dietary recall and processed with the use of a computerized database. Each record was evaluated by a skilled dietitian. In general, vitamin intakes in all study groups were comparable, with KT and ND groups manifesting lower risk of deficiency than HD and PD groups. RESULTS: The content of fat-soluble vitamins in diet was insufficient, with remarkably high prevalence of vitamin D deficiency. Mean intakes of water-soluble vitamins were close to recommended, with the exception of folic acid, which was profoundly deficient in all groups. CONCLUSIONS: CKD patients are at risk of inadequate vitamin intake. Vitamin D and folic acid are universally deficient in diet. KT patients have the most satisfactory content of vitamins in their diet, whereas HD individuals are at highest risk of deficiency. PMID- 27496422 TI - Assessment of the Hemostatic Parameters and Platelet Function on Thromboelastometry and Impedance Aggregometry in Hemodialysis Patients Qualified for Kidney Transplantation: Preliminary Report. AB - BACKGROUND: Chronic kidney disease is one of the medical conditions that affect hemostasis. Patients undergoing hemodialysis present both hemorrhagic and prothrombotic tendencies. Platelet adhesion to the artificial surface of the dialyzer's membrane, blood vessel endothelial wall disruption, and quantitative and qualitative changes in clothing factors are thought to be causative agents of the above-mentioned conditions. Thromboelastometry and impedance aggregometry enable precise assessment of clot formation and platelet function abnormalities, including changes related to chronic renal failure in patients undergoing renal replacement therapy. METHODS: A prospective study with control group was designed. The study group consisted of 17 adults with diagnosed chronic renal failure undergoing hemodialysis. The control group consisted of 13 healthy volunteers. EXTEM and FIBTEM tests in rotational thromboelastometry and TRAPtest in impedance aggregometry analyzer were performed. RESULTS: EXTEM parameter test results were comparable between analyzed groups, whereas FIBTEM test results were significantly increased in the study group. Platelet aggregation as measured by the TRAPtests was significantly decreased in patients undergoing hemodialysis. CONCLUSIONS: In end-stage renal disease patients undergoing hemodialysis, whole blood clot formation is not disturbed, even though platelet dysfunction occurs. Increased fibrin clot formation reflected by FIBTEM results may compensate the observed platelet disorders. The compilation of ROTEM and Multiplate may support appropriate hemostatic control and decision-making during kidney transplantation. PMID- 27496423 TI - Do Patients With End-Stage Chronic Renal Failure Treated With the Use of Hemodialysis Have Healthy Skin? Evaluation of Skin Lesions and Basic Education About Risk Factors for Skin Cancer in This Patient Population. AB - BACKGROUND: Considering the increasing incidence of skin cancers in patients after renal transplantation, evaluation of skin condition in dialysis patients, from whom kidney transplant recipients are recruited, appears to be very important. Particular importance is attached to the identification of such dialysis patients in the population who require dermatologic care before qualifying for transplantation. The objective of this study was to determine the prevalence of skin diseases in the dialysis patient population. Education of the patients regarding risk factors for skin cancer and the need for sun protection was performed. METHODS: Full dermatologic examination, including dermatoscopy, was performed on a group of 77 dialysis patients (38 women, 39 men) and a control group of 77 healthy people (60 women, 17 men). RESULTS: Eight hemodialysis patients had healthy skin compared with 33 people from the control group. In the remaining hemodialysis patients, the following skin lesions were observed: 1) inflammatory and allergic skin disorders in 17 patients; 2) bacterial, fungal, and viral infections in 26 patients; 3) benign lesions in 39 patients; 4) malignant skin lesions and precancerous conditions in 4 patients; and 5) other skin changes in 63 patients. CONCLUSIONS: Skin lesions are common in the dialysis patient population. Only 10% of the examined population had completely healthy skin, compared with 43% of the control group. More than one-half of dialysis patients required dermatologic care compared with one-third of healthy control subjects. PMID- 27496424 TI - Pathologies in Living Kidney Donors Diagnosed in the Long-Term Care System. AB - Kidney donation should not lead to deterioration of the donor's health condition, both during the perisurgical period and in the long term. Safety of a living kidney donor becomes a prerequisite for his/her qualification. Detailed diagnostic procedures are performed to exclude any abnormalities of his/her health condition. Additionally, a long-term post-donation follow-up system for kidney donors has been set up in Poland besides the restrictive qualification system. Transplantation centers are obligated to provide a diagnostic procedures for living organ donors as a part of the monitoring of their health condition and to ensure them a medical follow-up for 10 years after the donation. A total of 141 cases of unilateral nephroureterectomy performed in 2003-2014 to obtain a kidney for transplantation were considered. Medical files of post-donation diagnostic or therapeutic methods and their outcomes were retrospectively analyzed. The aim of the study was to assess the efficacy of monitoring of donors' health condition within the framework of the long-term follow-up system for kidney donors in the aspect of detection of the donation-independent abnormalities. PMID- 27496425 TI - Human Pooled Immunoglobulin as Treatment of Active Antibody-Mediated Rejection of Transplanted Kidney. AB - BACKGROUND: Antibody-mediated rejection (ABMR) has emerged as the leading cause of renal graft loss. The optimal treatment protocol in ABMR remains unknown. This study aimed to assess the efficacy of intravenous immunoglobulin (IVIG) for treatment of ABMR in renal recipients. METHODS: Thirty-nine ABO-compatible cross match-negative renal recipients with biopsy-proven ABMR composed the study group. Pulses of methylprednisolone (MP) and appropriate enhancement of net state of immunosuppression were applied in all individuals; 17/39 recipients were administered IVIG (IVIG group); the remaining 22/39 patients, identified to be nonadherent or unsatisfactorily immunosuppressed, were kept on the initial treatment (MP group). Serum creatinine concentration was obtained at each of 10 intended visits, and glomerular filtration rate (GFR) was estimated with the use of the standard Modification of Diet in Renal Disease (MDRD) formula. Generalized linear mixed model was used for statistical analysis. RESULTS: Renal function (modeled as linear slope of MDRD-based GFR change over time, separately for the pre- and post-intervention periods) improved significantly in IVIG-treated recipients. Pre-intervention slopes were -0.72 and -0.46 mL/min/mo for IVIG and MP groups, respectively (P = NS), whereas post-intervention the slopes changed to -0.03 and -0.47 mL/min/mo (IVIG and MP, respectively; P < .005). Within-group changes of slopes at the time of intervention were 0.69 and -0.01 mL/min/mo in IVIG (P < .01) and MP (P = NS) groups, respectively. The relative slope change (pre- to post-intervention) was 0.7 mL/min/mo in favor of the IVIG group (P < .033). None of the classic immunologic or nonimmunologic graft function predictors influenced GFR during 12 months of follow-up. CONCLUSIONS: IVIG improved graft function in renal recipients diagnosed with ABMR. PMID- 27496426 TI - BICD1 and Chromosome 18 Polymorphisms Associated With Recipients' Telomere Length Affect Kidney Allograft Function After Transplantation. AB - BACKGROUND: Reports regarding recipient's nonmodifiable genetic factors affecting telomerase activity and thus allograft function are lacking. Therefore the aim of this study was to analyze the associations between recipients' rs2735940 hTERT, rs2630578 BICD1, and rs7235755 chromosome 18 polymorphisms and kidney function after transplantation. METHODS: The study enrolled 119 white Polish kidney allograft recipients (64 men, 55 women; overall mean age, 47.3 +/- 14.0 y). To identify genotypes of the studied polymorphisms, real-time polymerase chain reaction was performed. RESULTS: There were statistically significant differences in distribution of rs7235755 chromosome 18 polymorphism genotypes and alleles between recipients with delayed graft function (DGF) and without DGF (P = .03). The presence of A allele was significantly associated with higher risk of DGF occurrence (AA + GA vs GG: OR, 3.25 [95% CI, 1.16-9.14]; P = .02; GA vs GG: OR, 4.00 [1.35-11.82]; P = .01). Analysis of the rs2630578 BICD1 gene polymorphism genotypes revealed statistically significant differences in long-term creatinine concentrations. The presence of C allele of this polymorphism was significantly associated with higher creatinine concentrations 24, 36, and 18-48 months after transplantation (GC + CC vs GG: P = .008, P = .008, and P = .01, respectively). CONCLUSIONS: Recipients' polymorphisms of genes associated with telomere length, BICD1 and chromosome 18, but not hTERT, affect kidney allograft early and long term function after transplantation. There is an urgent need for explanation of these observations in genome-wide association studies. PMID- 27496428 TI - Enhanced Recovery After Kidney Transplantation Surgery. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have gained widespread recognition in general surgery, decreasing the length of hospital stay while maintaining equivalent or lower morbidity and increased patient satisfaction. The feasibility of the ERAS protocol has not been studied in kidney transplantation. In this single-center retrospective case series, we describe the outcomes of 45 consecutive deceased-donor kidney transplant recipients subjected to a modified ERAS protocol, and we discuss the potential for future developments. METHODS: Included in the analysis were 45 consecutive deceased donor kidney transplant recipients from August 2014 to July 2015 in the John Paul II Krakow Specialist Hospital, Krakow, Poland. All patients were subjected to a modified ERAS protocol. The primary outcomes were length of hospital stay and mortality and morbidity rates. A surrogate composite criterion for discharge was ability to attend the transplant clinic weekly with no need for dialysis. The secondary outcome was the rate of unplanned readmissions within the 1st 3 months after transplantation. RESULTS: The median hospital stay was 10 days (range, 6 46). There were no deaths or acute coronary or thromboembolic events. Serious complications requiring surgery occurred in 6.6% of recipients. Three-month graft survival was 97.8%. The unplanned readmission rate was 8.9%. CONCLUSIONS: ERAS protocol is feasible in deceased donor kidney transplantation and renders low morbidity rates and reasonable readmission rate. Further reduction of the length of the hospital stay can be expected with health care system financial policies. PMID- 27496427 TI - Early and Long-Term Outcomes of Kidney Grafts Procured From Multiple-Organ Donors and Kidney-Only Donors. AB - BACKGROUND: The deceased-donor kidney pool consists of 2 different populations: multiple-organ donors (MOD) and kidney donors alone (KDA). In MOD, more complicated procedure and lowest priority for kidney procurement may affect graft survival. On the other hand, poor donor status and higher comorbidity are more frequent in KDA transplants. The aim of this study was to provide detailed characteristics of the 2 groups of kidney donors (KDA vs MOD) in our center and to analyze the potential influence of the donor type on the early and long-term kidney graft function and recipient outcome. METHODS: We performed a retrospective analysis of 729 first cadaveric kidney transplant recipients: 499 of them received the organ from MOD, 230 from KDA. RESULTS: The frequency of delayed graft function (DGF) was higher in KDA than in MOD transplants (38.7 vs 25.1%; P < .001). Multivariate logistic regression analysis revealed that donor age, KDA, and early acute rejection independently increased the risk of DGF occurrence, whereas recipient age and cold ischemia time increased the risk of primary graft nonfunction. Kidney excretory function was significantly worse in KDA up to 10 years after transplantation. There were no differences in kidney graft and patient survivals, frequency of proteinuria, acute rejection, and cytomegalovirus episodes, and post-transplantation diabetes. CONCLUSIONS: (1) The use of a kidney from KDA negatively affects early and late kidney graft function compared with MOD. (2) The long-term kidney graft and patient survivals are not affected by the type of organ procurement. PMID- 27496430 TI - Influence of Body Mass on Kidney Graft Function in Patients After Kidney Transplantation. AB - BACKGROUND: Increasing evidence shows that body mass may play a role in complications after kidney transplantation and influence graft and patient survival. The aim of this study was to analyze the association between graft function and both the body mass and adipokines (leptin, visfatin, adiponectin) in kidney transplant recipients. METHODS: We studied 183 kidney transplant recipients from the Department of Nephrology, Transplantology and Internal Disease, Medical University of Gdansk. Anthropometry and body composition examinations were performed using an electronic scale, hand grip dynamometer, and BCM - Body Composition Monitor (Fresenius, Germany). Obesity, overweight, and underweight were defined according to body mass index (BMI) classification. Blood urea nitrogen, creatinine, blood morphology, lipidogram, albumin, and C-reactive protein were measured. Estimated glomerular filtration rate (eGFR) was calculated according to the Chronic Kidney Disease Epidemiology Collaboration formula. Leptin, visfatin, and adiponectin were measured by ELISA methods. RESULTS: Underweight was found in 16 (8.7%) KTR, overweight and obesity were observed in 68 (37.1%) and 26 (14.2%) patients, respectively. No relation between BMI and eGFR in all groups was noted, but in the early period after transplantation a correlation between BMI and creatinine and eGFR was observed. In all studied patients (also patients in the early posttransplantation period), eGFR significantly correlated with leptin and visfatin. Multiple regression analysis confirmed an association between eGFR and leptin and visfatin in all studied populations and between eGFR and BMI in the group examined shortly after transplantation. CONCLUSIONS: Sarcopenic overweight and obesity prevail in KTR. In the short-term but not long-term period after transplantation, worse graft function was associated with high BMI. An association between graft function and leptin and visfatin was noted. PMID- 27496429 TI - Donation and Transplantation of Kidneys Harvested From Deceased Donors Over the Age of 60 Years in the Upper Silesia Region. AB - BACKGROUND: Population aging and shortage of organs for transplantation result in increasing numbers of kidneys retrieved from elderly donors. The aim of this study was to analyze donation of kidneys from donors after brain death (DBD) over the age of 60 years (>=60), comorbidities that affect decisions on retrieval, and early results of kidney transplantation. METHODS: Ninety-six potential DBD >=60 and 309 aged 40-59 years (40-59) reported in Upper Silesia, Poland, from 2004 to 2013 were enrolled in the study. RESULTS: DBD >60 presented a higher rate of coexisting hypertension (53% vs 34%), limb ischemia (10% vs 1%), and past stroke (6% vs 1%) compared with DBD 40-59 (P < .05), but no differences were observed in serum creatinine concentration (85 vs 84 MUmol/L), coexisting coronary disease (14% vs 6%), or diabetes (10% vs 4%). The decision of withdrawal from retrieval was more frequent in DBD >=60 (16% vs 7%; P < .05). Twelve months after kidney transplantation, serum creatinine concentration was higher in recipients of kidneys from DBD >=60 compared with DBD 40-59 (169 vs 138 MUmol/L; P < .001). The survivals of recipients (93% vs 95%) and kidney grafts (90% vs 93%) as well as rates of proteinuria >1.0 g/24 h (6% vs 2%) did not differ between the groups. CONCLUSIONS: A higher rate of comorbidities in potential kidney DBD >=60 results in a lower retrieval rate in these donors. The function of kidneys harvested from DBD >=60 12 months after transplantation is worse than those from DBD 40-59, but still acceptable. PMID- 27496431 TI - Renal Transplantation Using Kidneys Procured From Elderly Donors Older Than 70 Years. AB - AIM: A major problem for the transplant society is a shortage of organs for transplantation compared with the number of patients on the waiting list. This study aimed to assess the results of the transplantation of kidneys procured from older donors. PATIENTS AND METHODS: A total of 27 kidneys procured from donors age 70 years or older were transplanted between January 1, 2010, and April 25, 2015. These represented only 4.1% of the 657 kidneys transplanted from deceased donors during this period at the same center. RESULTS: Delayed graft function (DGF) in the recipients of kidneys procured from donors age 70 or older occurred in 46.1% of patients, whereas the recipients of kidneys from younger donors showed DGF at a frequency of 32.7% (P = NS). The annual and 3-year survival rates of kidneys in the study group were 85% and 80%, respectively, and in the control group were 92.5% and 88.6%, respectively (P = NS). According to the Polish National Organ Procurement Organization (Poltransplant), the annual survival rate of a transplanted kidney in Poland stands at 89%, whereas the 3-year survival rate is 82%. We detected no significant posttransplantation differences in the serum creatinine concentration and in the estimated glomerular filtration rate between the study and control groups. The donor age and donor creatinine were the variables independently associated with DGF. CONCLUSIONS: The results of transplantation of kidneys from elderly donors were comparable to those of transplantation from younger donors. Kidneys harvested from elderly donors should be used for a transplant after a preliminary assessment. PMID- 27496432 TI - Impact of Obesity on Renal Graft Function-Analysis of Kidney Grafts From the Same Donor. AB - BACKGROUND: The epidemic of obesity has led to dilemmas facing all nephrologists who care for patients with chronic kidney disease and who must make decisions regarding whether or not the patient can undergo transplantation. The aim of the study was to assess the outcome of transplantation among obese compared to nonobese recipients. To minimize donor variability and bias, paired kidney analysis was applied. MATERIALS AND METHODS: Patients with a body mass index >30 who received transplants in our unit between January 2000 and December 2010 were selected. For the analysis, only obese transplant recipients (OTR) and their kidney donor pairs with a body mass index <30 (nonobese transplant recipients [NOTR]) were selected. A total of 37 pairs of patients were evaluated in terms of the graft function, patient and graft survival, and number of complications. RESULTS: Groups did not differ with respect to sex and comorbidities. OTR were older than NOTR (53.1 vs 46.02 years old, P < .05). One-year patient and graft survivals were similar (100% vs 97.29% and 100% vs 94.59% in OTR and NOTR, respectively). There were no significant differences between OTR and NOTR with respect to incidence of acute rejection (29.7% vs 18.9%), delayed graft function (35.13% vs 29.72%), and mean serum creatinine and estimated glomerular filtration rate (four-variable Modification of Diet in Renal Disease formula) assessed at discharge and after 3, 6, and 12 months, respectively. OTR had a significantly longer hospitalization time (25.56 vs 20.66 days; P < .05), and more often experienced wound breakdown (32.43% vs 8.1%; P < .05) and new-onset diabetes after transplantation (57.14% vs 6.25%; P < .05). CONCLUSIONS: Obesity did not negatively influence patient and graft survival. Transplantation in obese patients should not be postponed. PMID- 27496433 TI - Outcomes in Renal Transplant Recipients With Lupus Nephritis-A Single-Center Experience and Review of the Literature. AB - BACKGROUND: Renal transplantation is the renal replacement therapy of choice in patients with end-stage lupus nephritis (LN). The aim of this study was to evaluate the early and late outcomes of renal transplantation in LN patients in a single transplant center. PATIENTS AND METHODS: This study analyzed the clinical data of patients who received a renal transplant (RTx) at Gdansk Transplantation Centre between January 1999 and December 2014. RESULTS: There were 1296 RTx performed between January 1999 and December 2014, including 21 RTx in 19 LN patients (mean age 40 +/- 10 years, 89% female). During the follow-up period (between 1 month and 10.5 years), 1 patient died of urosepsis and 1 of pneumonia. Three RTx recipients with antiphospholipid syndrome lost 5 kidney allografts, including 3 due to acute rejection (AR) during the first posttransplantation month. Kidney allograft survival median was 64 months. Delayed graft function (DGF) and AR were observed in 48% and 33% vs 31% and 21% of LN patients and other RTx patients, respectively (P = .1 and P = .16 for DGF and AR, respectively). The most common early posttransplantation complications were AR (31%) and perirenal hematomas (29%), and late complications were urinary tract infections (75%). Recurrence of LN in renal allograft was observed in 1 patient and was successfully treated by increasing the basic immunosuppression. CONCLUSIONS: Secondary antiphospholipid syndrome has a major influence on the outcomes of RTx in LN patients. Recurrence of LN has no clinical significance. PMID- 27496434 TI - Performance of the MDRD, CKD-EPI, and Cockcroft-Gault Formulas in Relation to Nutritional Status in Stable Renal Transplant Recipients. AB - BACKGROUND: Monitoring of the function of the implanted kidney in renal transplant recipients (RTRs) is one of the superior elements of adequate therapeutic actions. The aim of this study was to assess the conventional and unconventional factors affecting the estimated glomerular filtration rate (eGFR) with the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Cockcroft-Gault (C-G) formulas among the RTRs. METHODS: The study included 144 RTRs (mean age 52 years). Clinical and laboratory data were analyzed; eGFR was calculated with MDRD, CKD-EPI, and C-G formulas. We compared the results with MDRD as a reference calculating the percentage of reclassifications of chronic kidney disease (CKD) stages. Nutritional status was assessed with a body composition analyzer, Tanita BC 418. RESULTS: Multivariable linear regression analysis with MDRD and CKD-EPI formula as a dependent variable retained the following independent predictors: hemoglobin (Hb) (B = .365; P = .000), and red blood cell distribution width (RDW) (B = .191; P = .024). Analysis of variance showed the existence of statistically significant differences (all P for trend <.05) between the CKD-EPI, MDRD, and C-G equations within the total scope of eGFR results (51.2 +/- 21.2 vs 47.5 +/- 18.7 vs 55.6 +/- 20.6, respectively) as well as in quartiles of eGFR. CONCLUSIONS: Our data indicate that (1) with a value of eGFR >60 mL/min/1.73 m(2), the MDRD formula shows values that are on average 11% lower than in the CKD-EPI and C-G formulas; (2) with a value of eGFR <60 mL/min/1.73 m(2), the MDRD and CKD-EPI formulas do not show statistically significant differences. PMID- 27496435 TI - Living-Donor Versus Deceased-Donor Kidney Transplantation: Comparison of Psychosocial Consequences for Recipients. AB - INTRODUCTION: Health benefits of a living-donor kidney transplantation are numerous and well known. There is, however, a dearth of knowledge on postoperative quality of life among the living-donor (LD) compared to deceased donor (DD) transplant recipients. MATERIALS AND METHODS: The study involved 89 patients after renal transplantation: 48 from LDs and 41 from DDs. Interview data indirectly indicated the patients' health, whereas physiological parameters directly pinpointed the patients' health and the graft function. All study participants completed questionnaires to measure quality of life and the specificity of emotional and cognitive functioning. RESULTS: LD kidney recipients were younger than DD recipients (40 years vs. 49 years). LD and DD transplantation patients were similar in health status assessed by indirect methods (data from an interview) and direct methods (laboratory tests results). They, however, differed in their psychosocial functioning. LD patients had a greater sense of happiness (P < .01) and of self-efficacy (P = .07). Moreover, these patients were more actively involved in their social lives (P < .02) and were more satisfied with their social relationships (P = .07). LD recipients also had a higher quality of life in terms of mental functioning (P < .01) and satisfaction with their environments (P < .01). Additionally, there were significant correlations between quality of life and the quality of cognitive and emotional functioning in the group of LD recipients. The perceived impact of health on physical and professional activity and daily routines was similar in LD and DD groups. CONCLUSIONS: LD post-transplantation patients may derive greater psychosocial benefits from this form of treatment. This effect is not dependent on somatic parameters (comparable data from an interview and laboratory tests results). This study suggests that patients should be assisted by a multidisciplinary healthcare team, and receive continuous support from relatives during the post-transplantation adaptation process. This facilitates the patients' postoperative quality of life. PMID- 27496436 TI - Prospective Assessment of Hepcidin in Relation to Delayed or Immediate Graft Function in Patients Undergoing Kidney Transplantation. AB - BACKGROUND: Hepcidin is a peptide hormone that regulates iron homeostasis. Hepcidin may represent an early, predictive biomarker of acute kidney injury, another model of ischemia-reperfusion injury. Urinary hepcidin-25 has been shown to be elevated in patients who do not develop acute kidney injury. Creatinine is an unreliable indicator during acute changes in kidney; therefore, the aim of the study was to assess whether hepcidin could predict renal outcome in 31 consecutive patients undergoing kidney allograft transplantation. Serum hepcidin was evaluated before and after 1, 3, 6, and 10 days after kidney transplantation, using commercially available kits. Serum creatinine was assessed at the same time. METHODS: We found a significant decrease in serum hepcidin, as early as after 1 day after kidney transplantation. Before transplantation, serum hepcidin was related to creatinine. In patients with delayed graft function, there was no decrease in serum hepcidin. RESULTS: Our findings may have important implications for the clinical treatment of patients undergoing kidney transplantation. The "window of opportunity" is narrow in delayed graft function to distinguish between acute rejection and calcineurin inhibitors nephrotoxicity, and time is limited to introduce proper treatment after initiating insult. CONCLUSIONS: Hepcidin must be investigated as a potential early marker for delayed graft function, especially in the upcoming setting of early dialysis treatment or anti rejection therapy and might contribute to early patient risk stratification. PMID- 27496437 TI - HRV Influence During Renal Transplantation Procedure on Long-Term Mortality. AB - BACKGROUND: The autonomic nervous system plays an important role in heart function regulation. One of the most acknowledged methods for noninvasive measurement of autonomic system activity is to determine heart rate variability (HRV). Reduced HRV parameters-heart rate rigidity/stiffness-are an independent prognostic factor of sudden cardiac death risk because of arrhythmia. Renal transplantation is an important factor in HRV changes because of hemodynamic and ion disturbances. The main purpose of this study was to determine the influence of HRV disturbances during renal transplantation procedures on long-term mortality in patients with chronic kidney disease. METHODS: A prospective observation study was performed in the Department of Anesthesiology, Intensive Care, and Acute Poisoning, Pomeranian Medical University, Szczecin, Poland. There were 75 patients (mean age, 47 +/- 12 years; 42 men) treated with renal transplantation between 2008 and 2010. Patients were monitored with electrocardiographic tracing with the use of 7 electrodes in position type B. The final stage of analysis was to determine the possible relationship between HRV parameters during the perioperative period and the number of deaths within a 5 year follow-up. RESULTS: HRV parameters during the perioperative period of renal transplantation and the number of deaths within a 5-year follow-up, measured by use of the Holter method, did not differ among patients in the studied population. CONCLUSIONS: HRV is a noninvasive and confirmed tool used for the evaluation of autonomic function and mortality risk in patients with end-stage renal disease. HRV parameters recorded in the perioperative period are not optimal stratification tools for estimating the risk of cardiac deaths in patients with end-stage renal disease. PMID- 27496438 TI - Psychological Well-Being in Patients After Preemptive Kidney Transplantation. AB - BACKGROUND: Preemptive kidney transplantation (PKT) is associated with improved patient and graft survival as compared with transplantation in previously dialyzed patients. Complications related to dialysis are avoided in preemptively transplanted patients. Psychological functioning of those patients is still under investigation. The aim of the study was to evaluate the acceptance of illness, satisfaction of life, and anxiety in patients preemptively transplanted (PET) and transplanted after dialysis (PTD). METHODS: The present study compares 23 pairs of PET and PTD patients after kidney transplantation from the same donor. Each patient completed a set of psychological questionnaires: Acceptance of Illness Scale, Satisfaction With Life Scale, and State-Trait Anxiety Inventory. Pairs were examined in the same moment, from 7 days to 5 years after transplantation. The PET and PTD groups did not differ significantly in respect to sex, underlying renal diseases, incidence of acute rejection, surgical complications, and graft function. More PTD patients had delayed graft function (P < .05). RESULTS: The statistical analysis revealed a significant lower acceptance of illness as well as satisfaction with life in PET recipients (P < .05). The groups differed significantly in the trait of anxiety but not in the state of anxiety. CONCLUSIONS: Although the medical benefits of PKT are widely known, numerous psychological problems may occur in patients who do not have difficulties of dialysis and who after transplantation are faced with unexpected discomfort, which influences psychological well-being. Further effort should focus on providing psychological support during qualification to the transplantation and in follow-up after surgery. PMID- 27496439 TI - Lowering of Messenger Ribonucleic Acid Toll-Like Receptors 2-4,9 in Peripheral Blood Mononuclear Cells in Kidney Allograft Recipients, Relationships With Immunosuppressive Treatment, and Delayed Graft Function Occurrence. AB - BACKGROUND: Both tacrolimus (Tac) and cyclosporine (CsA) inhibit control peripheral blood mononuclear cells (PBMC) after stimulation of various Toll-like receptors (TLR) at supra-pharmacological concentrations. Earlier studies demonstrated that 24 hours after kidney transplantation (KT), the expression of the TLR4 messenger RNA (mRNA) in PBMC from patients with subsequent delayed graft function (DGF+) was lower than in patients without DGF (DGF-). An assessment was made of the interaction of immunosuppression with TLR mRNA in PBMC and to verify whether the reduced expression of TLR-2,3,4,9 mRNA in PBMC is permanent in DGF+. METHODS: We investigated mRNA expression of TLR in non-stimulated PBMC. All patients were transplanted more than 1 month before PBMC acquisition. Patients were divided into groups with respect to positive or negative history of delayed graft function (DGF+/-). RESULTS: The expression of TLR2, TLR3, and TLR9 in patients was lower than that in the control group. We found an association of Tac C0 with expression of TLR4 only and CsA dose per 1 kg body weight with TLR2 or up to 6 months after KT with TLR9. Mofetil mycophenolate (MMF)contributed to the change of TLR4 expression in the CsA group but not in the Tac group. TLR3 and TLR9 were nearly equally sensitive to both Tac and CsA, with a decrease of expression with respect to control. DGF+ was associated with variable degree of reduction of TLR2, TLR3, TLR4, and TLR 9 expression. CONCLUSIONS: We showed the importance of immunosuppression and delayed graft function as factors that modify the overall expression of mRNA-TLR PBMC for a period of time after KT. Patients with a history of DGF have chronically decreased expression of mRNA TLR2, TLR3, TLR4, and TLR9. This fact is associated with poorer graft function. Measuring the expression of the TLR in the upper range of therapeutic doses of calcineurin inhibitors and MMF gives the opportunity to assess the strength, effectiveness, and toxicity of immunosuppression. PMID- 27496440 TI - Impact of Skin Cancer Awareness on Prophylactic Behavior Among Renal Transplant Recipients. AB - BACKGROUND: Renal transplant recipients (RTRs) have a risk for skin cancer. The most important risk factor, and the only one that depends on patient behavior, is the exposure to ultraviolet light. The aim of this study was to assess the level of skin cancer awareness and its impact on preventative behavior among RTRs. METHODS: Questionnaires were applied to assess the awareness of increased risk of skin cancer and its influence on preventative behavior among RTRs. RESULTS: Of the RTRs, 51.6% considered themselves as a group of patients with a high risk of skin cancer. Only 11.5% (group A) were able to fully explain the whole reason of the need for sun protection usage. A partial explanation was provided by 40.1% of the patients (group B). The other 48.5% of the patients (group C) provided no explanation. Among the patients, 53.9% of surveyed RTRs never applied any sunscreen. Of RTRs, 22.5% claimed to always avoid direct exposure to sunlight. Most of the patients admitted to having outdoor hobbies (81% of group A, 60.3% of group B, 58% of group C). In addition, 36.2% of RTRs thought that they were more attractive if they were tanned. CONCLUSIONS: The awareness of being in a group of increased risk of skin cancer is still poor among RTRs. Skin cancer awareness does not correlate with usage of different forms of sun prevention. There is a great need for active education of Polish RTRs. PMID- 27496441 TI - Should We Be Concerned About Asymptomatic Adnexal Masses in Female Kidney and Liver Graft Recipients? AB - BACKGROUND: Pathological changes of uterine adnexa are frequently encountered in patients after solid-organ transplantation. The aim of the study was to evaluate the incidence of malignancies among recipients operated with the diagnosis of adnexal tumor with or without clinical symptoms. METHODS: We retrospectively analyzed data from 146 solid-organ recipients who underwent surgery in the First Department of Obstetrics and Gynecology, Medical University of Warsaw, in the years 2000 to 2014. Among them, we identified 80 patients of mean age 40.9 +/- 11.1 years with suspected adnexal tumor. Data on symptoms reported by patients were compared with the results of histopathological examination after surgical treatment. RESULTS: Kidney recipients were 76.2% of the group studied (including 5 women after kidney and pancreas transplantation); the remaining 23.75% of patients were liver recipients (including 1 kidney and liver). The majority of patients (71.25%) reported no clinical symptoms. The remaining 28.75% of patients had clinical complaints, with the most common symptom being abdominal pain (in 60% of patients). Analysis of the results of histopathological examination revealed that in both groups, the most often encountered pathological findings were serous cystadenoma (33.3% and 47% of patients, respectively), endometrial cysts (24.6% and 21.7%, respectively), and functional cysts (22.8% and 17.3%, respectively). None of the asymptomatic patients were diagnosed as malignant, whereas 2 cases (both ovarian and fallopian tube cancer) were diagnosed among women who reported clinical symptoms. CONCLUSIONS: Observations of patients after organ transplantation indicate a recurring nature of adnexal changes, resulting in qualification for surgical treatment. The survey results suggest that solid organ recipients with pathology in the uterine adnexa, with non-suspicious ultrasound image and not reporting clinical symptoms, could safely be subjected to clinical observation providing strict supervision. PMID- 27496442 TI - Tissue Doppler Imaging and Intima-Media Thickness as Noninvasive Methods of Cardiovascular Risk Stratification in Patients After Kidney Transplantation. AB - BACKGROUND: Cardiovascular complications, including coronary artery disease and chronic heart failure, are the leading causes of death in patients with chronic kidney disease. New echocardiographic techniques, such as tissue Doppler imaging (TDI) with strain and strain rate, are noninvasive, easy-to-perform methods of the estimation of left ventricular (LV) systolic and diastolic function. The aim of the study was to analyze the utility of new noninvasive methods of cardiovascular risk stratification in patients after kidney transplantation. METHODS: We included 43 consecutive kidney transplant (KT) recipients, with 30 healthy subjects constituting the control group in the study. We evaluated LV morphology and LV systolic and diastolic function by means of echocardiography with TDI and intima-media thickness by ultrasonography of the carotid arteries. RESULTS: LV mass index was significantly higher in transplanted patients, and both mitral inflow E/A and Em/Am ratios from pulsed myocardial imaging were significantly lower in the KT group as compared with the control group. The systolic wave of TDI at the basal segments was much lower in KT patients than in the control patients (P < .05). The mean value of strain rate was reduced in KT recipients as compared with the control patients. IMT was significantly higher in KT recipients. CONCLUSIONS: Echocardiography with TDI provided more accurate information about systolic and diastolic LV function. KT recipients showed significant alterations in LV longitudinal myocardial function parameters estimated by strain and strain rate. Strain and strain rate are noninvasive methods, easy to repeat, and valuable for detecting myocardial LV dysfunction in asymptomatic KT recipients. PMID- 27496443 TI - Tacrolimus Metabolite M-III May Have Nephrotoxic and Myelotoxic Effects and Increase the Incidence of Infections in Kidney Transplant Recipients. AB - BACKGROUND: Tacrolimus (Tac) is one of the most commonly used immunosuppressive drugs after solid organ transplantation. Eight Tac metabolites have been described, but their clinical importance remains unclear. The aim of this study was quantification of the 2 major Tac metabolites, 13-O-demethyl (M-I) and 15-O demethyl (M-III), in kidney transplant recipients and to link them with parameters of kidney and liver function, peripheral blood cell counts, and infection incidence. METHODS: In 81 kidney transplant recipients, concentrations of Tac, M-I, and M-III were measured with the use of liquid chromatography combined with tandem mass spectrometry (LC-MS-MS). RESULTS: There was a negative correlation between M-III levels and estimated glomerular filtration rate (eGFR; r = -0.244; P < .05). Also, a negative correlation between M-III concentrations and red blood cell count (RBC) was found (r = -0.349; P < .05). Neither concentrations of Tac nor of M-I correlated with eGFR or RBC. M-I, M-III, and Tac were not related to alanine aminotransferase activity. Significantly higher Tac and M-III concentrations in the group with all types of infections in comparison with the group without infections were observed (6.95 +/- 2.09 ng/mL vs 5.73 +/- 2.43 ng/mL [P = .03] and 0.27 +/- 0.17 ng/mL vs 0.20 +/- 0.11 ng/mL [P = .04], respectively). CONCLUSIONS: The results suggest that higher concentrations of M III may have a nephrotoxic or myelotoxic effect and result in higher incidence of infections. Further studies are needed to confirm if monitoring of M-III could minimalize adverse effects such as nephrotoxicity or infections. PMID- 27496444 TI - Cardiovascular Risk Factors and Markers of Atherosclerosis in Stable Kidney Transplant Recipients. AB - BACKGROUND: There is limited evidence regarding the risk factors influencing vascular injury in kidney transplant recipients, except for accelerated vasculopathy and endothelial dysfunction in the pre-transplantation period of end stage renal failure. Therefore, we performed a cross-sectional study to evaluate the role of traditional and novel or potential nontraditional risk factors in vascular and endothelial dysfunction in a cohort of stable kidney transplant recipients. METHODS: One hundred forty-two kidney transplant recipients at 8.4 +/ 1.8 years after transplantation were enrolled into the study. Different markers of vascular injury, such as carotid intima-media thickness (IMT), pulse wave velocity (PWV), and peripheral arterial tonometry (PAT), were assessed. Inflammatory markers, oxidative stress and endothelial function surrogate markers, adhesion molecules, and parathormone and osteoprotegerin levels were measured. RESULTS: Among traditional risk factors, only age, pre-transplantation diabetes, left ventricular hypertrophy (LVH) and cardiovascular disease (CVD) were related to increased IMT and PWV, whereas PAT values were significantly decreased only in diabetics and patients with CVD and were similar in patients with and without LVH. In multivariate regression analysis, IMT was explained by age, previous CVD episodes, and higher high-sensitivity C-reactive protein levels, and PWV by age and pre-transplantation diabetes. The regression analysis failed to find any significant explanatory variables for PAT. CONCLUSIONS: 1. In stable kidney transplant recipients, age, pre-transplantation diabetes, previous cardiovascular episode, and systemic microinflammation were predictors of vascular injury. 2. PAT is poorly associated with traditional CV risk factors and does not correspond with levels of biochemical markers of endothelial dysfunction in those patients. PMID- 27496445 TI - Hydroxylated, Hydroxymethylated, Dihydroxylated, and Trihydroxylated Cyclosporine Metabolites Can Be Nephrotoxic in Kidney Transplant Recipients. AB - BACKGROUND: Cyclosporine (CsA) is an immunosuppressive agent whose use is associated with adverse effects, including nephrotoxicity. There are reports indicating that some CsA metabolites may contribute to these effects. This study was aimed at evaluation of CsA metabolites and correlating them with kidney function. METHODS: In 62 kidney transplant recipients (41.9% women; overall mean age, 48.44 +/- 11.75 years), concentrations of CsA and 4 groups of metabolites were assessed: hydroxylated (HCsA), hydroxymethylated (HMCsA), dihydroxylated (DHCsA), and trihydroxylated (THCsA). The results were normalized with the use of the metabolite-to-parent drug ratio, and results were linked with estimated glomerular filtration rate (eGFR) at 3 months before (-3M), point zero (0M), and after 3 (+3M) and 12 (+12M) months. RESULTS: Multivariate analysis demonstrated the negative influence of eGFR -3M on HMCsA/CsA (beta = -0.266; P < .05) and the negative influence of HCsA/CsA, HMCsA/CsA, DHCsA/CsA, and THCsA/CsA on eGFR +3M (beta = -0.339, beta = 0.396, beta = -0.314, and beta = -0.321, respectively; P < .005) and eGFR +12M (beta = -0.363, beta = -0.316, beta = -0.267, and beta = 0.312, respectively; P < .05). We did not detect such influence of CsA concentrations on eGFR +3M and +12M. The THCsA/CsA receiver operating characteristic cutoff value for prediction of improvement of kidney function at +12M was 0.143. CONCLUSIONS: Our results suggest that impaired function of the transplanted kidney affects the accumulation of HMCsA. It is possible that the increased metabolite (HCsA, HMCsA, DHCsA, and THCsA) to cyclosporine ratio could influence or could be a marker of cyclosporine nephrotoxicity. In this context, the most promising marker seems to be THCsA/CsA ratio, but its real significance requires further studies to determine. PMID- 27496446 TI - Congenital Infections in Neonates of Women With Liver or Kidney Transplants. AB - BACKGROUND: Immunosuppressive therapy is associated with an increased risk of pregnancy complications and may have adverse effects for the newborn. The aim of this study was to determine the frequency and the type of early congenital infections and to assess typical markers of infections in neonates of liver and kidney recipients. METHODS: A retrospective analysis of 71 neonates born to either liver (39 cases) or kidney transplanted women (32 cases) was conducted. The rate and the type of newborns' infections as well as laboratory and bacteriologic markers of infections were analyzed. RESULTS: There was no significant difference in the frequency of congenital infections between the LT and KT groups (8 vs 7 cases; P = .879).). The rate of infections was not significantly higher in both groups compared with the general population. Infections were detected in 23.9%, 13.6%, and 26.6% of neonates born to mothers using tacrolimus, cyclosporine, and azathioprine respectively. No significant differences in white blood count or levels of neutrocytes and lymphocytes were observed between the groups. No abnormalities in white blood smear, but 1 case of leukopenia in the kidney transplant group, were detected. CONCLUSIONS: The rate of congenital infections in neonates of allograft recipients is not significantly higher than in the general population. Immunosuppressive regimens with azathioprine seem to carry the greatest risk, it is a little lower in the tacrolimus group, and cyclosporine-based regimens have the lowest risk of congenital infections. Differences were not statistically significant. Prenatal exposure to immunosuppressive agents seems not to be associated with any hematologic disturbances in white blood count and white blood smear. PMID- 27496447 TI - Association of MYH9 rs3752462 and rs5756168 Polymorphisms With Transplanted Kidney Artery Stenosis. AB - Allelic variants of the MYH9 gene, encoding myosin nonmuscle heavy chain type IIA, have been shown to correlate with diminished glomerular filtration rates and end-stage kidney disease in individuals of Caucasian ancestry. Myosin nonmuscle heavy chain type IIA is expressed during development as well as in injured vessels and kidney structures. We hypothesized that MYH9 risk variants may correlate with kidney artery injury and dysfunctional healing, such as transplant renal artery stenosis (TRAS). Our study aimed at evaluating the association of MYH9 risk allelic variants (rs4821480, rs4821481, rs3752462, rs11089788, rs136211, rs5756168, rs2032487, and rs2239784) with TRAS, defined as >50% renal artery lumen reduction. Genotyping was performed with the use of custom Taqman genotyping assays on DNA samples (n = 295) from white deceased-donor kidney transplant recipients and genomic DNA from the corresponding donors. Statistical analysis was performed with the use of Kaplan-Meier estimates, log-rank tests, and proportional hazard Cox models. Recipients carrying TT in rs5756168 experienced diminished risk of TRAS (hazard ratio [HR], 0.31; P < .009), whereas organs carrying CC in rs3752462 were exposed to excessive TRAS risk (HR, 2.54; P < .047). In multivariate stepwise analysis TRAS was 10.9-fold increased in kidneys originating from rs3752462 CC, whereas the risk was decreased 3.45-fold (adjusted HR, 0.29) in recipients carrying rs5756168 TT (P < .007 and P < .033, respectively). Intracranial bleeding or trauma compared with other mechanisms of donor death diminished TRAS risk by 87% and 91%, respectively (P < .030 and P < .017). Our study is the first to identify genetic predisposition to transplant renal artery stenosis. PMID- 27496448 TI - Gastrointestinal Pathologies in Patients After Successful Renal Transplantation-A Pilot Study. AB - BACKGROUND: The beneficial effect of kidney transplantation in patients requiring continuous renal replacement therapy owing to chronic kidney disease is well known and accepted. Kidney transplantation protects the patient from complications that may develop during chronic dialysis. Unfortunately, there is also evidence that kidney transplant patients are more prone to developing cancer than healthy persons. The aim of this study was to evaluate the prevalence of gastrointestinal pathologies in patients after kidney transplantation. METHODS: Adult patients after kidney transplantation, who are under the care of the Outpatient Department of Nephrology in Gdansk, received alarm symptom questionnaires and referral for testing for the presence of fecal occult blood. Then, in 45 selected patients (29 men and 16 women) endoscopic examination was performed. Mean age was 57.6 +/- 10.1 (range, 35-83) years. RESULTS: Out of ~940 patients after kidney transplantation, resting under supervision of outpatient department, 181 patients completed the questionnaire and 100 gave a stool sample for testing: 32 results were positive. After analyzing the questionnaires and stool results, 88 patients were qualified for further investigation. The endoscopic examination had been performed so far in 45 patients and revealed gastritis and/or duodenitis in 33 patients, diverticular colon disease in 18, esophagitis in 8, colon polyps in 14, stomach polyps in 3, inflammatory bowel disease in 7, and cancers in 3. CONCLUSIONS: The preliminary results indicate that patients after kidney transplantation have significant risk of gastrointestinal pathologies and require detailed diagnostic endoscopy. PMID- 27496449 TI - Cardiovascular Risk Evaluated With the Use of Heartscore in Kidney Transplant Recipients-Three Years of Follow-up. AB - BACKGROUND: Cardiovascular (CV) complications are the major cause of death in kidney transplant (KT) patients. METHODS: During a 3-year follow-up, 112 KT recipients, from living (LD KTRs; n = 54), and deceased (DD KTRs; n = 58) donors, were assessed for 10-year risk of fatal CV events with the use of the Heartscore tool (www.heartscore.org). In post-KT months 6, 12, and 36, current and optimum (target) CV risks (CVRs) were estimated. RESULTS: Current risk was lower in the LD KTRs and remained stable. In DD KTRs, the risk was at the highest level in months 6 and 12 of follow-up and decreased in month 36. Change in CVR, ie, the difference between the current and target risk, was the highest in DD KTRs in month 36 of follow-up (P = .014). In the increased-CVR group, recipients were older (P < .01), primarily male (P = .08), and more frequently smokers (P < .01) and had a higher systolic blood pressure (P < .05) despite taking more hypotensive medicines (P < .01), and had higher total cholesterol (P < .01) and low-density lipoprotein (P < .01) levels. In this group, body mass index (BMI) was higher (P < .01) and metabolic syndrome was diagnosed significantly more often (P < .01). The high-risk group (estimated CVR, >=5) was different also in longer durations of pre-transplantation dialysis (P < .05) and higher rates of CV episodes before transplantation (P < .05). In logistic regression, higher BMI and lower estimated glomerular filtration rate (eGFR) were the parameters strongly correlated with higher CVR. CONCLUSIONS: Mean CVR applicable to all kidney transplant recipients was stable throughout the follow-up. Changes in the risk affected mainly DD KTRs. In months 6 and 12, CVR was the highest in this group and was substantially reduced in the 3rd year of follow-up, probably owing to medical interventions. In the high-CVR group, impaired function of the transplanted kidney was recorded. CVR scores in patients with renal conditions and after kidney transplantation should additionally account for eGFR. PMID- 27496450 TI - Successful Treatment of Urinary Tract Infection in Kidney Transplant Recipients Caused by Multiresistant Klebsiella pneumoniae Producing New Delhi Metallo-Beta Lactamase (NDM-1) With Strains Genotyping. AB - BACKGROUND: Klebsiella pneumoniae New Delhi metallo-beta-lactamase-1 (NDM-1) strains have recently become a new threat in kidney transplant recipients due to the strains' resistance to almost all antibiotics, including carbapenems. METHODS: We present a case series of 3 patients with urinary tract infections (UTIs) caused by multiresistant K pneumoniae NDM-1 strains who were treated with the same protocol. Genotyping sequencing with pulsed-field gel electrophoresis was performed in all cases. RESULTS: All patients were male and had undergone kidney transplantation 4, 7, and 8 months, respectively, before the admission. Combined antibiotic therapy consisting of imipenem/cilastatin in maximal doses, gentamicin and/or colistin for 21 to 27 days, followed by oral fosfomycin, was used in all cases. There were no further UTI episodes in 2 patients at the 12 month visit. Three months after initial treatment, the third patient presented with leukocyturia with no clinical symptoms and a urine culture positive for K pneumonia NDM-1 strain. Interestingly, the strain was susceptible to trimethoprim/sulfamethoxazole despite resistance in previous urine culture samples. The patient was successfully treated with trimethoprim/sulfamethoxazole 2 * 960 mg/d for 3 weeks followed by 480 mg/d and 3 doses of fosfomycin. Genotyping sequencing revealed identical DNA restriction fragments in bacterial strains from 2 patients. In the third case, although a difference in 2 restriction fragments was observed, the strain was considered related to the others. CONCLUSIONS: In cases of UTI caused by K pneumoniae NDM-1 strains, prolong combined treatment followed by oral fosfomycin prophylaxis can be successful. Strain genotyping should be performed to optimize further treatment protocols in such cases. PMID- 27496451 TI - Urinary Tract Infections in Kidney Transplant Recipients Hospitalized at a Transplantation and Nephrology Ward: 1-Year Follow-up. AB - INTRODUCTION: The aim of this study was to investigate risk factors for urinary tract infections (UTI), the causative organisms of UTI and also their management and treatment. In addition, we evaluated the effects of UTI on renal graft function. METHODS: This analysis included 107 kidney transplant recipients (64% women) with a diagnosis of UTIs confirmed by positive results on urine culture. Type of pathogens, sensitivity to drugs, risk factors for infection, incidence of urosepsis, hospitalization period, treatment methods, and recurrence rates were analyzed. Statistical analysis was performed by using Pearson's chi(2) test, Yates' chi(2) test, the Student t test, Welch's t test, the Mann-Whitney U test, Fisher's exact test, and the Shapiro-Wilk normality test. RESULTS: The most common species isolated from urine samples included Escherichia coli (42%), Klebsiella pneumoniae (15%), and Enterococcus faecalis (10%). The percentage of multidrug-resistant strains was 31%, and urosepsis was diagnosed in 16% of patients. Recurrences developed in 76% of infected patients. Bricker ureterointestinal anastomosis was performed in 11% of patients. Risk factors for severe infections included: pre-transplantation urinary tract surgery (P = .02), double-J stent insertion (more common in men) during KTx (N = 34; 32%), (P = .021), reoperations following transplantation (P = .36), elevated tacrolimus levels at the time of infection (P = .024). Severe infections were diagnosed in patients with lower eGFRs, were associated with a need for longer hospitalization (P = .04) and escalation of antibacterial treatment. Carbapenems were used in 22 patients (20.5%). CONCLUSIONS: UTIs were more common in women, in patients with impaired function of the kidney transplant, and in those with a history of urinary tract interventions. Severe infections were associated with a risk of urosepsis, longer hospitalization, and a need for escalation of antibiotic treatment. PMID- 27496452 TI - Comparison of Staphylococcal Flora in Denture Plaque and the Surface of the Pharyngeal Mucous Membrane in Kidney Transplant Recipients. AB - BACKGROUND: Biofilm occurring on removable prostheses is a reservoir of bacterial flora, consisting of both physiological and pathogenic multidrug-resistant microorganisms. Patients undergoing dialysis and organ transplantation are particularly prone to bacterial infections, which can have its source in denture plaque. This study was a comparison of the composition of staphylococcal flora within the surface of the pharyngeal mucous membrane as well as denture plaque in kidney transplant recipients. METHODS: The study included 44 subjects with removable prostheses who reported for a kidney transplant procedure. Swab samples were collected from prostheses and the pharyngeal wall. Isolated strains were identified and investigated for drug resistance. RESULTS: A total of 72 strains of Staphylococcus were isolated from the denture plaque and 53 from the pharynx. In the pharynx, the following species prevailed: Staphylococcus epidermidis, Staphylococcus warneri, and Staphylococcus aureus. The following species prevailed in denture plaque: S epidermidis, S aureus, and Staphylococcus haemolyticus. Among the pharyngeal strains, antibiotic resistance most commonly referred to natural penicillin (77%), constitutive macrolide-lincosamide streptogramin B resistance (28%), and tetracycline (26.4%). In case of denture plaque, the highest percentage of strains demonstrated resistance to natural penicillin (60%), fosfomycin (32%), and cefoxitin (25%). In 10 subjects (48%), Staphylococcus-induced infections occurred in the first year after transplantation, 5 of which had the same bacterial strain as cultured previously from dentures. CONCLUSIONS: The denture biofilm and surface of the pharynx differ in terms of bacterial composition and bacterial drug resistance profiles. Denture plaque constitutes a considerable reservoir of staphylococcal flora, which can be a potential source of infection in organ transplant recipients. PMID- 27496453 TI - Cooperation in Treatment as an Indicator of Adaptation of Kidney Transplant Patients to Chronic Therapy. AB - BACKGROUND: Cooperation between patients and physicians in chronic treatment is an important factor in the patients' adaptation to difficult circumstances. The search is ongoing for factors important to the physician-patient relationship, with the goal of identifying deficits and psychological resources of the patients and medical soft skills of the physicians that can affect the quality of cooperation. The aim of this study was to analyze the psychological mechanisms of patient cooperation with physicians in the area of treatment after kidney transplantation. METHODS: The study group consisted of 105 patients (62 male patients and 43 female patients) aged 25 to 82 years (mean age, 50.91 years) after kidney transplantation who remained in the follow-up protocol of the Outpatient Transplant Clinic. A questionnaire was used to examine the compatibility of ratings as expressed by the patients and their physicians in 10 areas of cooperation in treatment. The tests for a sense of self-efficacy (General Self-Efficacy Scale), optimism (Life Orientation Test-Revised), and the control of emotions (Courtauld Emotional Control Scale) in Juczynski's adaptation were used in the study of psychological factors. RESULTS: Only 1 case reached total congruity by the patients and their physicians in all 10 areas of cooperation. In 3 areas, compliance was achieved in 70%, 72%, and 76%, respectively; in 6 areas, 50% to 66%; and in 1 sphere, 37%. We found no significant impact of psychological factors on patient compliance. A comparison was made of 2 groups of patients (1 of which was characterized by a high compatibility between the physician and patient assessments, and the second which was characterized by the lack of conformity). Moreover, assessment of the functioning of the transplanted kidneys was rated higher in those patients who achieved a high compliance with the opinions of medical cooperation in the treatment. CONCLUSIONS: The quality of cooperation measured by using compliance assessments of the patients and physicians in health behaviors is satisfactory. This finding translated into a favorable assessment of the functioning of the transplanted kidney expressed by the patients. Qualitative information provides guidance for targeted increasing collaboration. PMID- 27496454 TI - Prognostic Value of Proinflammatory Markers in Patients After Kidney Transplantation in Relation to the Presence of Diabetes. AB - BACKGROUND: Patients who are receiving immunosuppressive treatment after kidney transplantation are at greater risk of developing new-onset diabetes after transplantation (NODAT). New biochemical markers that may contribute to a better assessment of the prognosis of renal failure for patients diagnosed with diabetes mellitus (DM) are needed. The aim of this study was to assess selected proinflammatory markers in patients after kidney transplantation depending on the prevalence of DM and to evaluate the predictive value of these cytokines. METHODS: A total of 82 patients were divided into 3 groups after kidney transplantation and were included in the analysis: group I, no DM; group II, DM diagnosed before transplantation; and group III, NODAT. Selected marker levels (platelet-derived growth factor, transforming growth factor beta1, tumor necrosis factor receptor II [TNF-RII], and high-sensitivity interleukin-6 [IL-6 HS]) were assessed by using enzyme-linked immunosorbent assays. For summary endpoint, a return to dialysis treatment and/or death of the patient was adopted. RESULTS: Patients with NODAT were characterized by higher levels of IL-6 HS and body mass index. There were no statistically significant differences in the levels of other assessed markers among the 3 analyzed groups. The summary endpoint was observed in 16 cases (19.5%). Patients with summary endpoint during the observation time at baseline had higher levels of TNF-RII (7180 vs 4632 pg/mL; P = .0002) and IL-6 HS (4.58 vs 2.72 pg/mL; P = .033). CONCLUSIONS: Levels of inflammatory markers in patients after kidney transplantation did not differ between groups with and without DM. In the study population, DM was not a significant risk factor for graft loss or death. Patients who experienced these complications at baseline were characterized by higher values of TNF-RII and IL-6 HS. PMID- 27496455 TI - Association Between HLA Type and Skin Cancer in Kidney Transplant Recipients. AB - BACKGROUND: Organ transplant recipients (OTRs) are more susceptible to various diseases, among them cancers. Nonmelanoma skin cancers (NMSC) represent the most common malignancies in OTRs in Europe. Due to the significantly higher morbidity, aggressive and rapid progression, and poor prognosis of NMSC in the OTR population, these patients require a special oncological approach. Intensive attention should therefore be paid to factors predisposing OTRs to the development of cancer. The aim of this study was to establish the role of genetic factors in the pathogenesis of skin cancer in kidney transplant recipients (KTRs). METHODS: This single-center study was performed in 39 KTRs with posttransplant NMSC. The frequency of particular types of HLA Class I (HLA-A and HLA-B) and Class II (HLA-DR) in each group were compared to establish the association between the HLA type and risk of skin cancer after renal transplantation. RESULTS: HLA-DR15 were more commonly detected in patients with MNSC than in the control group of KTRs (P = .014) There was also a positive correlation between HLA-B18 and skin squamous cell carcinoma. The antigen was more often recorded in KTRs with squamous cell carcinoma than in KTRs without NMSC (P = .03) and in the general population (P = .002). CONCLUSIONS: Patients who are positive for HLA-BR15 and HLA-B18 should be under special dermatologic surveillance due to the potentially high risk of skin cancer. PMID- 27496456 TI - Nephropathy Evolving Within the First Two Posttransplant Months With No Typical Cytopathic Lesions: Two Cases Presentation. AB - BACKGROUND: We report 2 cases of polyomavirus-associated nephropathy (PyVAN) emerging within the initial 8 posttransplant weeks. These cases were characterized by intraepithelial BK virus replication without typical nuclear inclusions in epithelial cells. METHODS AND RESULTS: A 70-year-old male recipient of a cadaveric kidney transplant had experienced unsatisfying graft function since the time of transplantation (Tx). One month after Tx, results of a graft biopsy revealed mild tubulointerstitial inflammation. No intraepithelial nuclear inclusions suggestive of viral infection were present at that time. The patient received intravenous methylprednisolone, and the dosage of tacrolimus was increased. Due to a further drop in the glomerular filtration rate, a subsequent kidney biopsy was performed during posttransplant week 10, which revealed lesions typical of PyVAN. Retrospectively performed SV40 staining revealed that intragraft polyomavirus replication was already present on posttransplant day 30. Basic immunosuppression reduction and ciprofloxacin administration were followed by BK viremia elimination, stabilization of graft function, and resolution of PyVAN. In another patient, a 62-year-old male recipient of a cadaveric renal graft, BK viremia was monitored from the time of Tx. Two months after Tx, the patient was found to have a BK viral load of 6 * 4 log(10)/mL. Results of the graft biopsy revealed fully preserved tubular epithelium, but SV40 staining was positive in some of these cells. After basic immunosuppression reduction and introduction of ciprofloxacin, the BK viral load dropped to 1 * log(10)/mL with graft function stabilization. CONCLUSIONS: PyVAN may emerge as early as 4 weeks after Tx, with near-normal or acute rejection-like graft morphology. The early monitoring of plasma BK viral load, as well as SV40 staining, avoids misdiagnosis of this severe posttransplant complication. PMID- 27496457 TI - Effects of Immunosuppressive Drugs on Serum Fatty Acids of Phospholipids Fraction in Renal Transplant Recipients. AB - BACKGROUND: Immunosuppressive medications often cause posttransplant hyperlipidemia. The effects of cyclosporine (CsA) and tacrolimus (Tac) on lipid profile is well-known; however, there are very few studies related to the effect of these immunosuppressants on fatty acids (FA) of phosholipids fraction (PL) in renal transplant recipients (RTR). We sought to analyze the FA profile in PL fraction of RTR treated with Tac or CsA. METHODS: The study included 65 renal transplant patients on CsA (n = 24, group I) or Tac (n = 41, group II), and 14 healthy controls. Individual serum FA concentrations were measured by gas chromatography. Chemstation software was used to analyze the data. RESULTS: No differences between studied groups and controls were noted for monounsaturated FA, polyunsaturated n-3 FA (PUFA n-3), PUFA n-6, or the ratio of PUFA n-6 to PUFA n-3. The following mean values of FA were significantly higher in the CsA-RTR and Tac-RTR as compared with controls: total FA (P < .01 in both cases), saturated FA (SFA; P < .02 in both cases), C12 (P < .003 in both cases), C18 (P < .003 in both cases), and C18:2 (P < .01 for CsA RTR; P < .02 for Tac RTR). No differences between the measurements in patients on CsA and in patients on Tac were noticed. Significant correlation between SFA and eGFR was observed only in the CsA RTR group (P < .05). A negative relationship between PUFA n-6 and the estimated glomerular filtration rate was seen, but the correlation was not significant. CONCLUSIONS: Immunosuppressive drugs may affect FA metabolism, but the FA profile does not depend on the type of immunosuppressive drug administered. PMID- 27496458 TI - Treatment of Persistent Hypercalcemia and Hyperparathyroidism With Cinacalcet After Successful Kidney Transplantation. AB - INTRODUCTION: Hypercalcemia caused by persistent hyperparathyroidism after successful kidney transplantation (KT) is a common problem and may negatively affect graft function, bone metabolism and the cardiovascular system. Cinacalcet is a novel, available tool to control hypercalcemia after KT. The aim of the study was to examine the efficacy of cinacalcet in lowering calcium in KT recipients with persistent hypercalcemia owing to hyperparathyroidism. METHODS: In this retrospective observational study, we analyzed 30 patients with persistent hypercalcemia >10.8 mg/dL. All patients in the study were started on cinacalcet at different points after KT, with the mean time of 43 +/- 37 months. The initial dose of 30 mg/d was adapted progressively based on serum calcium levels. RESULTS: During the observation period, graft function in all patients was stable (estimated glomerular filtration rate [Chronic Kidney Disease Epidemiology Collaboration formula] 64 +/- 25 mL/min/1.73 m(2)). The mean baseline calcemia was 11.9 +/- 0.7 mg/dL, the intact parathyroid hormone value was 490 +/- 228 pg/mL and phosphorus concentration was 2.2 +/- 0.5 mg/dL. Treatment with cinacalcet resulted in a significant decrease in serum calcium level (mean, 9.9 +/- 0.7 mg/dL; P < .001), a reduction in intact parathyroid hormone level (308 +/- 199 pg/dL; P < .001), and an increase in phosphorus concentration (mean, 2.8 +/- 0.6 mg/dL; P < .001). In 5 females, gastrointestinal side effects were observed, requiring withdrawal of cinacalcet in 1 case. CONCLUSIONS: Cinacalcet administered after KT seems to be an effective option for the management of persistent hypercalcemia owing to hyperparathyroidism with satisfactory tolerability and may be considered as a therapeutic alternative to surgical parathyroidectomy or as a bridging therapy to parathyroidectomy. PMID- 27496459 TI - Effect of Immunosuppressive Treatment on Carotid Atherosclerosis in Renal Transplant Recipients. AB - BACKGROUND: The aim of this study was to compare the effect of immunosuppressive regimens using either mammalian target of rapamycin inhibitors (mTORi) or calcineurin inhibitors (CNI) on the risk of atherosclerosis in renal transplant patients. MATERIALS AND METHODS: The study involved a group of 24 recipients treated with mTORi (mTORi group) and a group of 20 recipients treated with immunosuppressive regimen based on CNI (CNI group). Laboratory and clinical markers of cardiovascular risk in both groups were investigated. Carotid atherosclerosis was evaluated by measurement of the intima media thickness (IMT) of the common and internal carotid artery walls and detection of carotid plaques by a high-resolution ultrasonography. The study was performed 3-24 years after transplantation. RESULTS: The mTORi group showed higher level of total cholesterol (242 vs 201 mg/dL; P < .004), low-density lipoprotein cholesterol (140 vs 116 mg/dL; P < .05), and triglycerides (226 vs 168 mg/dL; P < .01). Posttransplant diabetes developed in 34% of mTORi group compared with 25% in the CNI group. The mean of IMT (left and right) of common and internal carotid arteries was similar in both groups. Carotid plaques were detected in 46% of patients from the mTORi group and 25% from CNI group (P < .02). The presence of carotid plaques combined with an IMT of >0.9 mm were associated with male gender, mTORi treatment (P = .03), and cardiovascular events. The incidence of coronary heart disease was higher in mTORi group than in CNI group (53% vs 20%; P = .03). CONCLUSIONS: There was not beneficial effect of immunosuppressive treatment with mTORi on carotid atherosclerosis in renal transplant patients. PMID- 27496460 TI - Influence of Double-J Catheters on Urinary Infections After Kidney Transplantation. AB - BACKGROUND: One of the most important problem in kidney transplantation is risk of the urinary anastomosis stricture. In uncertain cases the use of a double-J (or JJ) catheter is a standard solution. In case of urinary leak or fistula after the reanastomosis operation, transuretheral JJ implantation is used. A number of patients after JJ use present urinary infection. METHODS: Between 2012 and 2014, 283 kidney transplantations were performed in our center. In 77 cases (27.2%), a JJ was used at the time of operation, in 10 other cases (3.5%) during postoperative period. RESULTS: Urinary infection was observed in 95 patients (33.6%), with Proteus, Klebsiella, Enterobacter, Escherichia, Enterococcus, Pseudomonas, Morganella, and Staphylococcus cultures. In the group of patients without JJ catheters, infections were found in 27.6% of cases and in group with JJ, in 47.1% (46.8% in intraoperative use of catheters and 50% in postoperative curse). CONCLUSIONS: The analysis shows that use of JJ catheters gives urinary infections almost twice more frequent (47.1% vs 27.6%; P = .001) with no difference if the implantation took place during or after the operation. PMID- 27496461 TI - Does the Parathyroidectomy Endanger the Transplanted Kidney? AB - BACKGROUND: Some investigators maintain that a parathyroidectomy (PTX) performed for tertiary hyperparathyroidism may potentially cause graft malfunction or even loss of the transplanted kidney after the operation. The goal of this study was to determine if parathyroidectomy affects transplanted kidney function. METHODS: The study group consisted of 48 renal graft recipients who underwent operation due to tertiary hyperparathyroidism. Thirty-nine subtotal parathyroidectomies and 9 more selective, less than subtotal parathyroidectomies were performed. The estimated glomerular filtration rate (eGFR) was calculated retrospectively on days 2 to 3 and 4 to 5 and at 1, 3, 6, 12, 24, and 36 months after PTX; these findings were compared with preoperative values. The cumulative graft survival rate in the postoperative period was assessed. RESULTS: In the follow-up period, 4 of 48 patients returned to hemodialysis (after 1, 7, 22, and 57 months after PTX). In the first case, the patient had stopped taking the immunosuppressive drugs 1 month after PTX. Cumulative graft survival rate after PTX was 98.0% after 6 months, 96% after 12 months, and 93% after 2 and 3 years. The mean preoperative eGFR was 52 +/- 17.15 mL/min/1.73 m(2), and the median was 48.28 mL/min/1.73 m(2). Overall and in the subtotal parathyroidectomy group, eGFR was significantly lower (P < .001) only on days 2 to 3. There were no differences between preoperative and postoperative eGFR values in the other follow-up periods. In the more selective, less than subtotal parathyroidectomy group, the decrease in eGFR values was nonsignificant compared with preoperative findings in the early postoperative period as well as in all follow-up periods. CONCLUSIONS: In this study, PTX did not significantly impair transplanted kidney function, but in the early postoperative period, transient reductions in graft function did occur. PMID- 27496463 TI - Prevalence of Left Ventricular Hypertrophy and Left Ventricular Dysfunction in Older Renal Transplant Recipients. AB - OBJECTIVE: Left ventricular hypertrophy (LVH) is a risk factor for premature cardiovascular morbidity and mortality in chronic kidney disease. The aim of the study was to determine echocardiographic evaluation morphology and function of the left ventricle in older renal transplantation patients. MATERIAL AND METHODS: We retrospectively analyzed clinical data of renal transplant recipients who underwent routine echocardiography. We compared the data from 38 patients who were older than 65 years with 49 patients who were a mean age of 47.8 +/- 12 years (control group). RESULTS: At the time of cardiac evaluation, most patients were in stage 3 chronic kidney disease. In the older group of patients, the incidence of obesity and diabetes were significantly higher than in the control group. Also in the older patients, the serum level of albumin was lower (P < .001), and brain natriuretic peptide was higher (P = .046). The incidence of coronary heart disease, chronic heart failure, and atrial fibrillation were higher in the older patients (P = .011). LVH was common in older as well as younger patients (97.4% vs. 88.8%, P = .17). Left ventricle mass index ranged from 90.4 g/m(2) to 235.5 g/m(2) among examined kidney transplantation patients. In older patients, left ventricular mass index was 160.7 +/- 34.5 g/m(2) compared to 141.8 +/- 29.8 g/m(2) in younger patients (P = .008). Reduced ejection fraction was found only in 2 of 38 (5.3%) older patients. Diastolic dysfunction of left ventricle was present in 34 of 38 (89.5%) patients >65 years old and in 24 of 49 (49.9%) younger patients (P < .001). CONCLUSIONS: LVH and left ventricular dysfunction are more pronounced among older patients. Impaired renal function, proteinuria, diabetes, and severity of hypertension are the most important factors predisposing to LVH. PMID- 27496462 TI - Treatment of the Lymphocele After Kidney Transplantation: A Single-center Experience. AB - BACKGROUND: Lymphocele is one of the most common complications after kidney transplantation. It is usually asymptomatic, but can cause pressure on the kidney transplant, ureter, bladder, and adjacent vessels with deterioration of graft function, ipsilateral leg edema, and external iliac vein thrombosis. Peritoneal fenestration is a well-established method for treatment. In this report, we present the incidence of symptomatic lymphocele requiring treatment (LRT), demographic and surgical factors that influenced lymphocele formation, its clinical presentation, and 2 types of treatment: open and laparoscopic intraperitoneal drainage in the experience of our center. MATERIAL AND METHODS: We retrospectively analyzed all kidney transplantations performed between January 2007 and December 2014 in Gdansk Transplantation Center (n = 740) and selected patients with LRT. LRT occurred in 59 cases (8%). All other patients transplanted during the same time (n = 681) were treated as a control group in the univariate and multivariate analysis of risk factors of the lymphocele formation. RESULTS: Surgical intraperitoneal drainage was performed in an open method in 53 cases and laparoscopically in 6 patients. We observed recurrence of lymphocele in 11 cases (18.6%). Acute rejection episodes (ARE) and delayed graft function (DGF) were more frequent in patients with LRT. ARE and age were independent risk factors for LRT in multivariate analysis. The mean estimated glomerular filtration rate by the Modification of Diet in Renal Disease method at 1 month after the fenestration was higher than before the operation (51.7 and 43.6 mL/min, respectively). CONCLUSIONS: Fenestration is a safe and effective method of treatment of symptomatic lymphocele. ARE, DGF, and older age were associated with a greater risk of LRT. PMID- 27496464 TI - Psychological Predictors of Cooperation in the Chronic Treatment of Kidney Transplantation Patients. AB - INTRODUCTION: A patient who complies with doctor recommendations is an indicator of proper cooperation in treatment. It is affected by environmental factors, soft competences of the doctors, and properties of the human personality. We investigated the psychological characteristics of patients that may facilitate human contact and promote healthy behaviors. The aim of the study was to analyze the importance of psychological factors for the occurrence of health-related behaviors necessary for cooperation in treatment. MATERIAL AND METHODS: The study was conducted in a group of 105 patients (62 males and 43 females) aged from 25 years to 82 years old (mean, 50.4 years) after kidney transplantation who remained in follow-up at the Outpatient Transplant Clinic. We used two questionnaires: one for the patients and one for their doctors, including an assessment of healthy behaviors listed in 10 categories. The patients also completed the tests exploring the sense of self-efficacy (generalized self efficacy scale), optimism (life orientation test - revised) and the control of emotions (Courtauld emotional control scale) in a Polish adaptation by Zygfryd Juczynski. In the statistical analysis, the Spearman rank correlation coefficient and the Kanonicza analysis were used, adopting the significance level of P < .05. RESULTS: We found significant correlations between psychological factors and behaviors of the patients. The patients controlling the expression of anxiety often concentrated on cleanliness and hygiene (P = .013). The patients controlling the expression of anger (P = .008) and anxiety (P = .049) were less likely to perform self-observation, being of the opinion that the role of the physicians was to evaluate the development of the disease and advances in treatment. The patients with higher levels of optimism were perceived by the physicians as better cooperating in conducting self-observation (P = .024) and adherence to hygiene (P = .047); they were also less frequently struggling with ophthalmic problems (P = .004). The relationship between the factors associated with the disease and treatment (pressure, the efficiency of the transplanted kidney, and duration of treatment) and psychological factors (optimism, emotional control, and self-efficacy) has been confirmed. The emerged factors significantly affected each other, which indicated the matching of the model (P = .08). CONCLUSIONS: The analysis of the results shows that psychological and somatic functioning of patients has a strong relationship with certain pro-health behaviors that determine the collaboration in treatment. This can serve as a basis for modifying the rules of managing the patients. PMID- 27496465 TI - Clinical Utility of QuantiFERON-Cytomegalovirus Test in Management of Kidney Transplant Recipients. AB - Immune monitoring of cytomegalovirus (CMV) - specific T-cells responses has become an additional tool in the CMV risk assessment of kidney transplant recipients (KTRs). Some data demonstrated a potential use of QuantiFERON-CMV assay (QF-CMV) in stratifying CMV risk before transplantation, at the end of prophylaxis and during pre-emptive strategy. High risk for CMV disease was also reported in KTRs with indeterminate QF-CMV results in which both mitogen and CMV antigen responses were absent. Twenty-five KTRs in the first year after kidney transplantation (KT), including 17 KTRs after CMV infection treatment (CMV-KTR), were studied by QF-CMV assay. Positive QF assay (QF+) was present in 16 of 25 (64%) of KTRs, negative (QF-) in 5 of 25 (20%), and indeterminate (QF0) in 4 of 25 (16%). The QF0 patients, in comparison to the combined group of QF+ and QF-, presented an increased incidence of CMV disease (4 of 4 [100%] vs. 7 of 21 [33.3%]; P < .05) and severe infectious complications such as sepsis, and systemic mycosis (4 of 4 [100%] vs. 6 of 21 [29%]; P < .02). Of 17 CMV-KTRs, 11 of 17 (64.7%) were QF+, 2 of 17 (11.8%) were QF-, and 4 of 17 (23.5%) were QF0. The incidence of CMV disease and severe infectious complications was not different among these groups. CMV-KTRs with interferon-gamma <3.5 IU/mL vs. >3.5 IU/mL in mitogen tube, irrespective of QF-CMV status, showed an increased incidence of CMV disease (8 of 9 [88.9%] vs. 3 of 8 [37.5%]; P < .05) and severe infectious complications (8 of 9 [88.9%] vs. 2 of 8 [25%]; P < .02). In conclusion, indeterminate result of QF-CMV or interferon-gamma <3.5 IU/mL in mitogen tube seems to be related to impaired immunity. The QF-CMV assay appears to be a useful tool in clinical practice, identifying the group of KTRs with increased risk of infectious complications who may benefit from immunosuppression reduction and maintenance of antiviral prophylaxis. PMID- 27496466 TI - Associations of Selected Cytokines Levels in Organ Transplant Recipients Without and With Malignant Skin Neoplasms. AB - INTRODUCTION: Skin malignancies are the most prevalent neoplasms seen in organ transplant recipients (OTRs). Immunosuppressive treatment has been attributed to play a causative role in malignancy development. The aim of the study was to assess cytokine concentrations involved in cytotoxic and regulatory responses in patients after organ transplantation (Tx). We compared two OTR subgroups: those with malignant skin tumors and those without any known changes developed after Tx. MATERIALS AND METHODS: We enrolled 102 patients, 63: 3-360 (median: min-max) months after Tx, aged 54.3 +/- 9.9 (mean +/- SD) years (38.2% females). Seventeen patients were diagnosed with malignant skin neoplasms. The most frequent treatment schemes were cyclosporine A - mycophenolate mofetil - glucocorticosteroids (GS) (37.4%), mycophenolate mofetil-tacrolimus - GS (15.2%), and azathioprine-cyclosporine A-GS (14.1%). A 5-mL sample of venous blood was obtained from participants of two subgroups: those with malignant skin tumors and those without any known changes. The blood was tested for interleukin 2 (IL-2), interferon gamma, IL-10, and transforming growth factor beta concentrations (Multicytokine Flex Set, ELISA). The Kruskal-Wallis test was used to compare variables; P < .05 was considered valid. RESULTS: Age, gender distribution, and time from transplantation did not differ across the two subgroups. We found significantly lower blood concentrations of IL-2 and IL-10 in patients with post transplantation skin cancers versus patients without any known skin changes (0 pgmL(-1) vs. 21.22 pgmL(-1), and 4.93 pgmL(-1) vs. 7.36 pgmL(-1), respectively). The differences between interferon gamma and transforming growth factor beta levels were insignificant across studied groups. CONCLUSIONS: Our findings suggest that immunosuppressive response assessed by cytokine IL-2 and IL-10 levels may be used in the risk stratification for the development of skin cancer in organ recipient patients. PMID- 27496467 TI - Benign Cutaneous Disease Among Polish Renal Transplant Recipients. AB - BACKGROUND: Organ transplant recipients are an at-risk group for skin cancers and benign cutaneous diseases. Immunosuppression type, dosage, and treatment length dictates the frequency of benign lesions. MATERIAL AND METHODS: Two hundred twenty-three consecutive adult renal transplant recipients (RTRs) were enrolled and screened for benign skin lesions. During examination, swabs, skin scrapings, and nail clippings were collected from any suspected areas infection and any cutaneous lesions marked for quality and quantity on a special questionnaire. The aim was to examine the prevalence of benign cutaneous disease and risk factors. RESULTS: Fungal infections were the most common infections found (60%), most commonly in the oral cavity (40.8%). Viral warts occurred in 18.4%, being significantly more common in those transplanted over 5 years (P = .002). Hypertrichosis was the most common pilosebaceous disorder found (P <= .001). Other iatrogenic cutaneous effects included purpura (50.2%), xerosis (41.2%), and gingival hyperplasia (28.2%), the latter strongly associated with cyclosporine (P = .0005). Seborrhoeic warts (23.8%) were most common in patients older than 50 years (P < .001). One-third of subjects had skin tags (31%). DISCUSSION: This is the largest study of the prevalence and type of non-malignant cutaneous diseases in Polish RTRs. We see increasing numbers of patients with long-term side effects from immunosuppressive therapy, and treatment, gender, age, and time since transplantation should be considered with new skin lesions in everyday practice with RTRs. CONCLUSIONS: The study group had a high prevalence of benign cutaneous diseases and these should not be overlooked as they can cause aesthetic problems and reduced quality of life. PMID- 27496468 TI - Past Cardiovascular Episodes Deteriorate Quality of Life of Patients With Type 1 Diabetes and End-stage Kidney Disease After Kidney or Simultaneous Pancreas and Kidney Transplantation. AB - BACKGROUND: The beneficial influence of kidney (KTx) or simultaneous pancreas and kidney transplantation (SPK) on quality of life (QOL) in patients with end-stage kidney disease caused by type 1 diabetes mellitus was confirmed in many studies. The aim of this study was to identify factors that influence QOL of patients in long-term follow-up after SPK or KTx. METHODS: Twenty-seven SPK and 26 KTx patients with good function of transplanted organs at least 1 year after transplantation were enrolled into the analysis. To estimate QOL of the recipients the Kidney Disease and Quality of Life Short Form was applied. RESULTS: Within the whole analyzed group, the necessity of exogenous insulin administration correlated (P < .05) with symptom/problem list (gamma = -0.35), effects of kidney disease (-0.38), cognitive function (-0.47), sleep (-0.42), overall health (-0.47), physical functioning (-0.61), role-physical (-0.32), pain (-0.50), general health (-0.32), emotional well-being (-0.31), role-emotional ( 0.36), social function (-0.33), energy/fatigue (-0.44), and the SF-12 physical composite (-0.44). History of cardiovascular episode correlated (P < .05) with symptom/problem list (gamma = -0.59), effects of kidney disease (-0.46), burden of kidney disease (-0.56), sleep (-0.54), social support (-0.51), physical functioning (-0.55), role-physical (-0.70), pain (-0.60), general health (-0.57), emotional well-being (-0.45), role-emotional (-0.95), social function (-0.58), energy/fatigue (-0.59), SF-12 physical composite (-0.45), and SF-12 mental composite (-0.83). CONCLUSIONS: Exogenous insulin administration and history of cardiovascular episode are the most important factors influencing QOL in patients after SPK or KTx, particularly worsening its physical components. PMID- 27496469 TI - Surgical Complications Not Related to the Renal and Pancreatic Grafts After Simultaneous Kidney and Pancreas Transplantation. AB - BACKGROUND: Simultaneous pancreas and kidney transplantation (SPKTx) is the most commonly performed multiorgan transplantation procedure worldwide. Transplanted organs are the main source of complication; however, some postoperative complications are not directly related to the pancreatic or renal grafts. The goal of this study was to evaluate the prevalence, type, and severity of postoperative complications not related to transplanted kidney or pancreas among SPKTx recipients. METHODS: Complications unrelated to transplanted pancreas and kidneys among 112 SPKTx recipients were analyzed. The cumulative freedom from general surgical complications was assessed, and it was compared with cumulative freedom from complications related to kidney and pancreatic grafts. Severity of complications was classified according to a modified Clavien-Dindo scale. RESULTS: The general surgery complication rate was 22.2%. Cumulative freedom from general surgical complications at days 60 and 90 after transplantation was 0.89 and 0.87, respectively. Cumulative freedom from general surgical complications was comparable with cumulative freedom from complications related to kidney grafts but significantly higher than cumulative freedom from complications related to pancreatic grafts (log-rank test, P < .001). The rates for grades of severity II, IIIa, IIIb, and IVb were 19.4%, 9.7%, 64.5%, and 6.4%, respectively. The most frequent cause of complications was intra-abdominal hematoma or abscess (25.8%). CONCLUSIONS: The general surgical complication rate was comparable to the rate of complications originating from the renal grafts but significantly lower than the complication rate related to the transplanted pancreas. The incidence of general surgical complications could be defined as moderate, and the severity of this type of complication was low. PMID- 27496470 TI - Usefulness of Modified Dindo-Clavien Scale to Evaluate the Correlation Between the Severity of Surgical Complications and Complications Related to the Renal and Pancreatic Grafts After Simultaneous Kidney and Pancreas Transplantation. AB - OBJECTIVE: Simultaneous pancreas and kidney transplantation (spktx) is the multiorgan transplantation. Thus various complications originated from transplanted organs and the complications that are not directly related to pancreatic or renal grafts could be developed at the same recipient. AIM: The aim of this study is to explore whether there is a correlation between the severity of complications originated from transplanted pancreas, transplanted kidney and general surgical complication developed at the same spktx recipient. METHODS: Complications which developed among 112 spktx recipients were divided into three groups: related to the pancreatic graft (PTXc), to the renal graft (KTXc) and the general surgical complication (GNc). Severity of postoperative complications using modified Dindo-Clavien scale recipients was evaluated for each group. The correlation of severity of coexisting complications from different complication groups was analyzed. RESULTS: There were 22 recipients who developed the coexistence of complication between different complication groups. Complication originated from two and three complication groups developed 15 (68.2%) and 7 (31.8%) patients, respectively. There was not found correlation of the complication severity between: KTXc and GNc group, GNc and PTXc group, KTXc and PTXc group. The correlation (r = 0.84) of complication severity in recipients who developed concurrently complication from transplanted kidney, transplanted pancreas and general surgery complication was found. CONCLUSION: The modified Dindo-Clavien scale is an useful methodology for the correlation description of complication severity in complex multiorgan transplantation such is spktx, especially when the complications originated from different, potentially independent from the pathophysiological point of view, sources. PMID- 27496471 TI - Long-Term Outcomes of Kidney and Simultaneous Pancreas-Kidney Transplantation in Recipients With Type 1 Diabetes Mellitus: Silesian Experience. AB - BACKGROUND: Kidney transplantation (KTx) markedly reduces mortality in patients with end-stage kidney disease (ESKD) caused by type 1 diabetes mellitus (T1DM). The outstanding issue is whether transplantation should be limited only to KTx, with further insulinotherapy, or combined with pancreas transplantation in patients with ESKD/T1DM. The goal of this study was to compare the results of simultaneous pancreas-kidney transplantation (SPKTx) and deceased donor KTx and to identify factors affecting patient and kidney graft survival in patients with ESKD/T1DM. METHODS: Eighty-seven deceased donor KTx and 66 SPKTx operated on in the Silesia region of Poland between 1998 and 2013 were included in the retrospective analysis. RESULTS: During the mean 6.7 +/- 3.6 years of follow-up, fewer cardiovascular episodes were observed in SPKTx recipients than in KTx recipients (1.5% vs 12.6%; P < .05). Five-year patient survival (80.7% in SPKTx vs 77.5% in KTx) and kidney graft survival (66.1% in SPKTx vs 70.4% in KTx) did not differ between study groups. There were no differences in patient survival (log-rank test, P = .99) or kidney graft survival (P = .99) based on Kaplan-Meier curves. Multivariable Cox proportional hazard analysis failed to identify factors explaining patient and kidney graft survival. Five-year pancreas graft survival was 58.9%. SPKTx recipients had significantly higher estimated glomerular filtration rates during the 7-year posttransplant period and less frequently developed proteinuria (6.1% vs 23%; P < .01). CONCLUSIONS: Pancreas transplantation reduced cardiovascular risk and prevented the development of proteinuria but did not improve patient and kidney graft survival in recipients with T1DM in the 7-year follow-up period. PMID- 27496472 TI - Profile of Gut Microbiota Associated With the Presence of Hepatocellular Cancer in Patients With Liver Cirrhosis. AB - BACKGROUND: Changes within the gut microbiota contribute to the progression of chronic liver diseases. According to the results of several studies performed in animal models, gut dysbiosis plays an important role in hepatocarcinogenesis. The aim of this study was to explore the characteristics of gut microbiota associated with the presence of hepatocellular cancer (HCC) in patients with cirrhosis of the liver undergoing liver transplantation. METHODS: A total of 15 patients with HCC and 15 non-HCC patients matched according to etiology of cirrhosis and Model for End-Stage Liver Disease (MELD) scores who underwent liver transplantations between 2012 and 2014 were included. Analysis of their gut microbial profile was based on prospectively collected stool samples from the pretransplant period. RESULTS: Patients with and without HCC were similar with respect to age (P = .506), sex (P = .700), hepatitis C virus (P > .999) and hepatitis B virus (P = .715) infection status, alcoholic liver disease (P > .999), and MELD score (P = .337). Notably, the presence of HCC was associated with significantly increased fecal counts of Escherichia coli (P = .025). Prediction of HCC presence based on E coli counts was associated with the area under the receiver-operating curve of 0.742 (95% confidence interval, 0.564-0.920), with the optimal cutoff on the level of 17.728 (natural logarithm of colony-forming units per 1 g of feces). Sensitivity and specificity rates for the established cutoff were 66.7% and 73.3%, respectively. CONCLUSIONS: The profile of gut microbiota associated with the presence of HCC in cirrhotic patients is characterized by increased fecal counts of E coli. Therefore, intestinal overgrowth of E coli may contribute to the process of hepatocarcinogenesis. PMID- 27496473 TI - Factors Affecting Breathing Capacity and Early Tracheal Extubation After Liver Transplantation: Analysis of 506 Cases. AB - BACKGROUND: Early extubation is a standard procedure after liver transplantation (LT). METHODS: The preoperative and perioperative data of 506 adult patients undergoing LT from July 2000 to March 2015 were analyzed. The goal of this study was to determine preoperative and perioperative independent predictors of early tracheal extubation. RESULTS: Of the 506 study patients, 73.7% were extubated early after LT. Patients in this group exhibited better preoperative and perioperative outcomes. However, according to multivariate logistic regression analysis, only 3 parameters were independent predictors of early extubation: initial hemoglobin concentration (odds ratio [OR], 1.187 [95% confidence interval (CI), 1.033-1.364]), application of epidural anesthesia (OR, 2.762 [95% CI, 1.025 7.445), and units of perioperative packed red blood cells and fresh frozen plasma transfused (OR, 0.919 [95% CI, 0.888-0.952]). CONCLUSIONS: Early extubation of patients undergoing LT is a safe and widely used procedure. However, the decision regarding this procedure should be made after thorough analysis of the patient's current status, the course of operation, and the patient's preoperative parameters. Based on our findings, we believe that the decision regarding early extubation can be aided by taking into account the patient's initial hemoglobin concentration, the number of packed red blood cells and fresh frozen plasma transfused during surgery, and pain control by application of a thoracic epidural catheter. PMID- 27496474 TI - Assessment of the Quality of Life in Patients After Liver Transplantation as an Important Part of Treatment Results. AB - INTRODUCTION: Organ transplantation for many patients with end-stage liver disease is a life-saving operation. Progressing at a time and usually irreversible damage to the organ directly leads to many life-threatening complications as well as to progressive deterioration in health and the quality of life (QOL). On the other hand, the assessment of QOL after liver transplantation, apart from the survival analysis, should take into account general health perception, physical activity, a place in the family and in the environment, as well as the patient's social and professional activity. MATERIAL AND METHODS: The study group included 238 patients (128 women and 110 men) who underwent transplantation in various transplantation centers in Warsaw due to chronic and acute liver failure. To measure the QOL the author's questionnaire was used, which was made especially for this study. RESULTS: There were no significant correlations found between the subjective QOL of the examined patients and socio-demographic and clinical variables, such as age, gender, education, marital status, occupational status, and time from the organ transplantation. However, a significant correlation was found between the perceived QOL of patients and the following variables: physical activity, pain and other symptoms, social and family life, sex life, and psycho-emotional state. It was also proved that the problems with maintaining a normal body weight after liver transplantation significantly affected the overall health of patients. CONCLUSIONS: Liver transplantation in the vast majority of patients, despite numerous complaints, facilitates functioning in various fields of life. On the other hand, the indicated discomfort in the area of mental and emotional health requires easier access to a psychologist. At the same time, there is a justified requirement for education and nutritional counselling for patients after liver transplantation because of the proven risk of occurrence of cardiovascular disease. PMID- 27496475 TI - Predictive Value of the Model for End-Stage Liver Disease Score Excluding International Normalized Ratio One Year After Orthotopic Heart Transplantation. AB - BACKGROUND: The Model for End-Stage Liver Disease (MELD) scoring system incorporating a combination of hepatic and renal laboratory parameters does not adequately reflect the degree of multi-organ dysfunction in patients with heart failure, who need oral anticoagulation. In order to exclude the impact of oral anticoagulation on the international normalized ratio (INR), we used the MELD excluding INR (MELD-XI) score. The aims of the study were to calculate the individual preoperative MELD-XI score and its ability to predict 1-year mortality after heart transplantation and to identify other preoperative laboratory prognostic parameters. METHODS: We retrospectively analysed data of 87 consecutive adults undergoing heart transplantation between 2011 and 2014. Clinical data and laboratory parameters for the calculation of the MELD-XI score were obtained at the time of admission for the heart transplantation. RESULTS: The average age of the patients was 48.8 +/- 13.3 years and 68.9% of them were male. During the observation period, the mortality rate was 18.4%. Multivariate analysis of Cox proportional hazard confirmed that the pretransplantation MELD-XI score (hazard ratio [HR] = 1.625 [1.286-2.053]; P < .001), sodium serum concentration (HR = 0.824 [0.677-1.001]; P < .05) and highly sensitive C-reactive protein (hs-CRP) serum concentration (HR = 1.045 [1.008-1.083]; P < .02) were independent predictors of death during the first year after heart transplantation. Area under the receiver operating characteristic (ROC) curve (AUC) indicated a good discriminatory power of MELD-XI (AUC 0.997; P < .04) and plasma sodium concentration (AUC 0.901; P < .01) in death prediction. CONCLUSIONS: Our study confirms that the pretransplantation MELD-XI score, as well as serum sodium and hsCRP concentrations, may be used to estimate postoperative risk in heart transplant recipients during a 1-year follow-up. PMID- 27496476 TI - Liver Transplantation for Incurable Alveolar Echinococcosis: An Analysis of Patients Hospitalized in Department of Tropical and Parasitic Diseases in Gdynia. AB - INTRODUCTION: Alveolar echinococcosis is a parasitic disease caused by the larval stage of tapeworm Echinococcus multilocularis. It usually involves the liver, but can spread to other organs. The treatment of choice is a surgical resection supported by antiparasitic drugs. In the advanced stages of the disease a liver transplantation is the only option. AIM: This article presents the problems related to care of patients after liver transplantation for advanced alveolar echinococcosis. MATERIAL: Sixty-seven patients with alveolar echinococcosis were hospitalized in our clinic in the years 2000-2015. Liver transplantation has been a therapeutic option for 9 patients. We retrospectively analyzed data of qualification for the liver transplantation and the postoperative treatment. RESULTS: Follow-up time after liver transplantation ranged from 7 months to 155 months (average, 6.4 years). One patient, with a history of advanced disease (P4N1M0), died due to liver failure. One patient was lost to follow-up. After liver transplantation all patients were receiving albendazole treatment. Two patients did not follow the medical recommendations. In 1 patient, who decided to stop therapy after 1 year, the relapse of alveolar echinococcosis in the left lobe of the transplanted liver passing through the diaphragm to the pericardium was detected. In another case we suspected a relapse of alveolar echinococcosis in transplanted liver due to positive serological tests. CONCLUSION: The prognosis of patient after liver transplantation for alveolar echinococcosis is good. The main problem caused by immunosuppressive therapy is a recurrence of disease in the transplanted liver. PMID- 27496477 TI - Outcomes of Patients With Poorly Differentiated Hepatocellular Carcinoma After Liver Transplantation. AB - BACKGROUND: Liver transplantation (LT) outcomes for patients with poorly differentiated (G3) hepatocellular carcinoma (HCC) are unsatisfactory. The aim of this study was to evaluate outcomes in patients with poorly differentiated HCC undergoing LT. PATIENTS AND METHODS: There were 192 HCC patients after LT in the Department of General, Transplant and Liver Surgery, Medical University of Warsaw, between January 2001 and April 2014. The study group comprised 24 patients with poorly differentiated tumors. RESULTS: Disease-free survival (DFS) for all patients was 49.5% at 5 years. The 5-year DFS for patients who met the Milan criteria (n = 9, 88.9%) was significantly better compared to those who did not (n = 15, 28.0%, P = .025). Multivariable analysis revealed that only the largest tumor diameter (P = .014) and alpha-fetoprotein (AFP) concentration (P = .001) were independent risk factors for DFS. The optimal cut-off AFP and tumor size that could distinguish patients with the highest risk were >=500 ng/mL and >=3.5 cm, respectively. DFS for patients with AFP <500 ng/mL and tumor size <3.5 cm was 100% after 2.8 years, and for those with >=500 ng/mL or tumor size >=3.5 cm was 46.9% after 5 years. However, the DFS for patients with AFP >=500 ng/mL and tumor size >=3.5 cm was only 12.5% after 4.7 years (P = .002). CONCLUSIONS: Outcomes of patients with poorly differentiated HCC treated with LT can be characterized with acceptable survival when applying criteria based on tumor size <3.5 cm and AFP <500 ng/mL. PMID- 27496478 TI - Prognostic Factors and Outcomes of Patients After Liver Retransplantation. AB - BACKGROUND: Despite great progress and improvement in results of orthotopic liver transplantation (OLTx), 10%-20% of patients still require retransplantation (re OLTx). The aim of the study was to present long-term results of liver retransplantation and to determine the factors influencing outcomes. PATIENTS AND METHODS: From December 1994 to July 2014, a total of 1461 liver transplantations were performed in the Department of General, Transplant and Liver Surgery of Medical University of Warsaw. There were 92 retransplantations (6.3%), including 40 early re-OLTx (up to 30 days). The most common indication for re-OLTx were vascular complications (41/92, 44.6%). Influence of clinical variables on short- and long-term outcomes was analyzed. RESULTS: Postoperative mortality was 30.4% (28/92). One-year, 3-year and 5-year survival for all patients was 59.8%, 56.5% and 54.1%, respectively. The best results were achieved in patients undergoing retransplantation due to chronic rejection and biliary complications, whose 5 year survival rates were 75.0% and 72.9% respectively. There was no difference in long-term survival after early and late retransplantations (60.9% and 49.3%, respectively; P = .158). Multivariable analysis revealed factors associated with longer survival of patients, namely, higher preoperative hemoglobin concentration (P = .001), increased blood transfusions (P = .048), and decreased fresh frozen plasma transfusions (P = .004). CONCLUSIONS: Liver retransplantation is a method providing satisfactory outcomes in selected patients. The perioperative period has a major impact on patient outcome. PMID- 27496479 TI - High Frequency of Arterial Hypertension in Patients After Liver Transplantation. AB - BACKGROUND: Cardiovascular diseases are among the most frequent causes of patient death after liver transplantation. The aim of this retrospective clinical study was to estimate the prevalence of arterial hypertension among patients after successful liver transplantation and the role of immunosuppressive drugs in the pathogenesis of hypertension in these patients. PATIENTS AND METHODS: A total of 88 patients (age 47 .5 +/- 12.1 years; 33 women and 55 men) who had undergone successful liver transplantation and completed 24 months follow-up were studied. The results are presented as means with standard deviations. RESULTS: At 1, 12, and 24 months after liver transplantation, the prevalences of hypertension were 44.3%, 54.5%, and 62.5%, respectively. Systolic and diastolic blood pressure in these months were 124.1 +/- 14.8, 132.8 +/- 19.1, and 135.2 +/- 17.3 mm Hg and 83.3 +/- 12.0, 87.3 +/- 11.1, and 87.9 +/- 11.1 mm Hg, respectively. The estimated glomerular filtration rates were 77.8 +/- 32.3, 80.3 +/- 30.8, and 78.8 +/- 29.1 mL/min/1.73 m(2), respectively. Arterial hypertension was significantly more frequent in patients treated with cyclosporine A than in those treated with tacrolimus (P = .004) or everolimus (P = .005). In patients treated with tacrolimus, a positive correlation was found between tacrolimus blood concentration and systolic blood pressure (R = 0.34; P = .01) and a negative correlation was found between estimated glomerular filtration rate and systolic blood pressure (R = -0.28; P = .02). CONCLUSIONS: Based on study findings, the following conclusions were drawn: arterial hypertension occurs in more than 50% of patients after liver transplantation (significantly higher frequency than in the general population); calcineurin inhibitors may participate in the pathogenesis of arterial hypertension in patients after successful liver transplantation; and the clinical importance of these findings and the influence on cardiovascular outcome of the liver transplant recipients need further investigation. PMID- 27496480 TI - Dynamic Elastography in Diagnostics of Liver Fibrosis in Patients After Liver Transplantation Due to Cirrhosis in the Course of Hepatitis C. AB - BACKGROUND: Assessment of the dynamics and degree of liver fibrosis in patients after liver transplantation is a basic element in the process of determining transplant survival prognosis. It allows planning and early initiation of prophylaxis or treatment, which translates into increased chances of preventing cirrhosis and of long-term optimal function of the graft. The aim of this study was to compare the results of biopsy and dynamic elastography in diagnostics of transplanted liver fibrosis, as well as determination of the stiffness cut-off point for assessment of significant fibrosis. PATIENTS AND METHODS: The study included 36 patients who had undergone liver transplantation due to cirrhosis in the course of hepatitis C virus (HVC) infection. Fibrosis was assessed in bioptates according to the METAVIR score (F0-F4). Elastography was performed using FibroScan; receiver operating characteristic curve analysis was used to identify the cut-off point for significant fibrosis (>=F2). RESULTS: The median stiffness in kPa for the whole group F0-F4 was 6.3 (range 3.4-29.9); for >=F2 it was 6.9 (3.4-29.9), whereas for F0-F1 it was 4.4 (3.5-8.0). It was demonstrated that the value of 4.7 kPa in elastography is a statistically significant cut-off point for differentiation between the groups F0-F1 and F2-F4 (sensitivity: 93%, specificity: 57%, positive predictive value: 90%, negative predictive value: 66%), area under the receiver operating characteristic curve: 0.746 (95% confidence interval: 0.53-0.95, P < .05). CONCLUSIONS: Elastography is a promising tool for noninvasive assessment of significant liver fibrosis in patients after transplantation due to cirrhosis in the course of hepatitis C; it allows reduction in the number of biopsies performed. PMID- 27496481 TI - Hypertension in Pregnant Renal and Liver Transplant Recipients. AB - BACKGROUND: Pregnancies in transplant recipients involve risks for both grafts and the fetus, and need to be carefully managed. Hypertension is the most frequent complications in pregnant transplant recipients, especially in renal transplant recipients. Strict control of blood pressure is essential for a favorable obstetric outcome and long-term graft survival. The aim of the study was to evaluate the influence of hypertension on obstetric outcome and graft function in pregnant renal transplant recipients (RTR) or liver transplant recipients (LTR) in comparison with healthy pregnant women. PATIENTS AND METHODS: This retrospective analysis included 46 RTR and 55 LTR who delivered between the years 2000 and 2014. The control group consisted of 187 nontransplant patients aged 20-45 years who delivered between 2010 and 2013. The analyzed group was divided into 2 subgroups: patients with hypertension and patients without hypertension. Descriptive data analysis, Fisher Exact test, unpaired Student t test, and analysis of the variance were performed. RESULTS: Hypertension prevalence among the RTR, LTR, and control group was 73.5%, 34.5%, and 4.3% respectively. In the RTR group, the mean gestational age at delivery inp patients with hypertension vs without hypertension was 36 vs 34.5 weeks (P < .05); IUGR was diagnosed in 20% vs 8.5% pregnant women (P > .05). In the TRL group, the mean gestational age at delivery in group with hypertension vs without hypertension was 37 vs 3.9 weeks (P < .05); IUGR was diagnosed in 10.5% vs 5% of pregnant women (P > .05). Hypertension in RTR patients had a negative influence on graft function (P > .05). CONCLUSION: Hypertension is common in organ recipients, and is associated with adverse pregnancy outcomes and loss of graft function. PMID- 27496483 TI - Predictors of Tricuspid Valve Anulus Dilation in a Heart Recipient Population. AB - BACKGROUND: Tricuspid valve regurgitation in reported in >20% of heart recipients. It severity has not only clinical impact, but it is also associated with increased mortality. Risk factors for developing tricuspid valve dysfunction include allograft rejection, donor/recipient pericardial cavity mismatch, preoperative transpulmonary gradient and vascular resistance, biatrial anastomosis technique, and biopsy-induced injury. Tricuspid valve annulus distention is reported to causative factor for most common type of tricuspid valve dysfunction after heart transplantation. The aim of the study was to estimate possible early predictors for tricuspid valve regurgitation after orthotopic heart transplantation performed with standard Lower-Shumway technique on magnetic resonance imaging studies. METHODS: A total of 20 patients (18 men and 2 women) with a mean age of 45 +/- 12 years were enrolled into the study. Echocardiographic evaluation followed by magnetic resonance studies were performed. The mean duration from time of transplantation was 34 +/- 12 months. Magnetic resonance and echocardiographic imaging focused on tricuspid valve annulus diameter and atrium dimensions. RESULTS: The was a progressive distension of tricuspid valve annulus observed during the follow-up period. Mean tricuspid valve diameter increased from 3.0 +/- 0.3 to 3.34 +/- 0.3 mm (P < .05). There was a positive correlation observed between recipient native right atrium and overall right atrium diameter and tricuspid valve diameter distension. CONCLUSIONS: Overall right atrium diameter and native recipient right atrium diameter were found to be a risk factor for tricuspid valve annulus distension. PMID- 27496482 TI - Perioperative Risk Factors of Cardiac Allograft Vasculopathy in the Long-Term Follow-up. AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) still remains to be one of the most important limiting factors for heart transplant recipients' long-term survival. The aim of our study was to identify the perioperative risk factors impacting the occurrence of CAV during the long-term follow-up. METHODS: We retrospectively analysed the data from 198 consecutive adult patients, who underwent heart transplantation between 2007 and 2012, in whom at least one routine coronarography (CAG) was performed. CAV onset was defined as any lesion seen at least at one routine CAG. RESULTS: The average follow-up was 63.6 +/- 14.7 months. The frequency of CAV in the analysed population was 36 (18.1%). Multivariate stepwise logistic regression analysis confirmed that NT-proBNP plasma concentration directly before heart transplant [logNT-proBNP OR = 16.455 (4.587-31.036), P < .0001], fibrinogen plasma concentration a month after heart transplant [OR = 1.022 (1.009-1.035), P < .001] and occurrence of diabetes [OR = 12.355 (1.417-35.750), P < .001], were independent predictors of CAV. Area under the ROC curves (AUC) indicated a well discriminatory power of plasma fibrinogen [AUC 0.9278, P < .001] and plasma NTproBNP concentration [AUC 0.9514, P < .001] in CAV prediction. The optimal cut-off value of fibrinogen was 509 mg/dL, and of NT-proBNP was 10080 pg/mL. CONCLUSIONS: Our data show that NT-proBNP and fibrinogen plasma concentrations as well as occurence of diabetes, both preexisting and new onset after heart transplant can be used to identify patients at risk of developing CAV. PMID- 27496484 TI - BRCA1 Reflects Myocardial Adverse Remodeling in Idiopathic Dilated Cardiomyopathy. AB - BACKGROUND: The role of BRCA1 in chronic ischemic episodes seems to be pivotal for adverse remodeling and development of ischemic cardiomyopathy, because of its role in DNA repair and apoptosis. The aim of this study was to investigate the role of BRCA-1 in idiopathic dilated cardiomyopathy (IDCM). MATERIAL AND METHODS: The study group (IDCM) comprised myocardial samples from hearts explanted before transplantation owing to IDCM in 10 males (age 44 +/- 5.3 years) without clinical symptoms of ischemic heart disease. The control group consisted myocardial fragments taken from 10 male heart valve and pulmonary artery donors with diagnosed cerebral death (age 40 +/- 2.3 years). BRCA1 was detected immunohistochemically with rabbit anti-BRCA1 polyclonal antibody. The intensity of BRCA1 expression was semiquantitatively assessed for cardiocytes, small vessels including capillaries, and interstitial cells. The significances between groups were estimated using the Mann-Whitney U test. RESULTS: All IDCM cases were positive and presented nonuniform BRCA1 expression: hypertrophied cardiocytes showed very intense staining and typical cardiomyopathic cardiocytes were stained weakly forming mosaic. Control cases showed weak-to-moderate uniform staining. Intensity of staining was significantly higher in IDCM cardiocytes, whereas small vessels and interstitial were stained similarly in both groups. CONCLUSIONS: IDCM adverse remodeling results in more intense but nonuniform BRCA1 expression. This phenomenon seems to reflect IDCM biology: lower BRCA1 expression in myocytes with lower anti-apoptotic and DNA damage repair activity, with the opposite in hypertrophied myofibers. PMID- 27496485 TI - High-performance Liquid Chromatography Measured Metabolites of Endogenous Catecholamines and Their Relations to Chronic Kidney Disease and High Blood Pressure in Heart Transplant Recipients. AB - BACKGROUND: Patients after solid organ transplantation, especially heart and kidneys, are prone to be hypertensive. Recently chronic kidney disease and renalase metabolism of endogenous catecholamines are thought to make major contribution to the pathogenesis of hypertension. MATERIALS AND METHODS: We analyzed 75 heart recipients (80% male, 20% female), medium age 54.9 years (range, 25-75) at 0.5 to 22 years after heart transplantation (median, 10.74). Diagnosis of hypertension was made on the basis of ambulatory blood pressure monitoring. Complete blood count, urea, creatinine, estimated glomerular filtration rate (eGFR), renalase in serum, and levels of metanefrine, normetanefrine, and 3-metoxytyramine in 24-hour urine collection calculated with a high-performance liquid chromatography were recorded. RESULTS: Urine endogenous catecholamine metabolites were estimated according to creatinine clearance. Normetanefrine was correlated with age (r = 0.27; P < .05), urea (r = 0.64; P < .01), creatinine (r = 0.6; P < .01), eGFR (r = -0.51; P < .01), renalase (r = 0.5; P < .01), and diastolic blood pressure (r = 0.26; P < .05). Metanefrine was correlated with urea (r = 0.43; P < .01), creatinine (0.32; P < .01), eGFR (r = 0.4; P < .01), renalase (r = 0.34; P < .05), height (r = -0.26; P < .05), weight (r = -0.23; P < .05), and time after heart transplantation (r = 0.27; P < .05). 3 Metoxytyramine was correlated with urea (r = 0.43; P < .01), creatinine (r = 0.32; P < .01), and the eGFR (r = -0.24; P < .05). Creatinine was correlated with age (r = 0.36; P < .01), diastolic blood pressure (r = 0.26; P < .05), time after heart transplantation (r = 0.24; P < .05), and renalase (r = 0.69; P < .01). Systolic blood pressure was correlated with proteinuria (r = 0.26; P < .05). CONCLUSIONS: Chronic kidney disease and concomitant hypertension are the most prevalent comorbidities in the population of heart transplant recipients. Urine catecholamine metabolites were related to kidney function but not to blood pressure level in the studied population. PMID- 27496486 TI - Predictive Value of Hepatic and Renal Dysfunction Based on the Models for End Stage Liver Disease in Patients With Heart Failure Evaluated for Heart Transplant. AB - BACKGROUND: The evaluation of prognosis and determination of a long-term treatment strategy is an important element of management in patients with heart failure (HF). METHODS: The aim of the study was to determine the prognostic value of the Model for End-Stage Liver Disease (MELD) and its modifications, MELD and serum sodium (MELD-Na) and MELD excluding the international normalized ratio (MELD-XI), as well as other independent risk factors for death during a 4-year follow-up. We analyzed retrospectively 143 patients with advanced HF, evaluated for heart transplant between 2009 and 2011. Patients using warfarin were excluded from the study. The long-term follow-up data were obtained during follow-up visits and/or phone contact with the patients or their families. RESULTS: The age of the patients was 54 (48-59) years and 88.1% of patients were male. Mortality rate during the follow-up period was 49%. The MELD scores (hazard ratio [HR], 1.12; P < .001), as well as serum high-sensitivity C-reactive protein (hs-CRP; HR, 1.01; P < .01) and N-terminal pro-brain natriuretic peptide (NT-proBNP; HR, 1.01; P < .05) levels, were independent risk factors for death. Receiver operator characteristic analysis indicated that a MELD cutoff of 10 (area under the curve [AUC], 0.756; P < .0001], MELD-XI cutoff of 13.0 (AUC, 0.720; P < .0001), MELD-Na cutoff of 13.0 (AUC, 0.813; P < .0001), hs-CRP cutoff of 4.02 (AUC, 0.686; P < .001), and NT-proBNP cutoff of 1055 (AUC, 0.722; P < .001) were the best predictive values as predictors of death. CONCLUSIONS: MELD, MELD-Na, and MELD-XI scores are prognostic factors for death during a 4-year follow-up. A high MELD score is an independent prognostic factor for death. NT-proBNP and hs-CRP serum concentrations are other independent factors influencing death. PMID- 27496487 TI - Role of Personal Resources in Depression and Stress in Heart Transplant Recipients. AB - BACKGROUND: Heart transplantation is the primary option for heart failure treatment and increases the survival rate and the quality of life for recipients. However, this surgical intervention induces numerous psychological problems, such as depression and anxiety. Protective factors and personal recourses are a significant force behind healthy adjustment to life stresses. The aim of this study was to assess the role of personal recourses in terms of depression and stress in heart transplant recipients. METHODS: The study involved a sample of 131 post-heart transplant patients. Standardized instruments were used to measure the key constructs: Beck Depression Inventory Short Form for prevalence of depression, Perceived Stress Scale for prevalence distress, and Sense of Coherence (SOC-29), Life Orientation Test, and General Self-Efficacy Scale for measuring personal resources. RESULTS: We found that sense of coherence, optimism, and self-efficacy proved to be significant predictors for the prevalence of both depression and stress. CONCLUSIONS: These result suggest that the assessment of coping strategies and sense of coherence in heart transplant recipients requires exploration. Evaluating coping strategies and sense of coherence before surgery seems significant and begins with developing skills in this domain. PMID- 27496488 TI - Lack of Impact of Presence of Positive C4d Staining in Capillaries in Myocardial Biopsies on Long-term Survival of Heart Transplant Patients. AB - BACKGROUND: The long-term survival of 209 consecutive patients (mean age, 46 +/- 15 years) from a single center with >=1 diagnostic myocardial biopsy after heart transplantation was analyzed. METHODS: Patients were considered as C4d positive if a capillary staining (immunohistochemistry in paraffin samples) was observed in >=1 myocardial biopsy. Data were analyzed according to pathologic consensus of antibody mediated rejection definition of C4d+ positivity: 2004 definition in group A and the 2013 definition in group B and compared with their respective controls, composed of patients who do not meet those criteria. Age, follow-up time, and number of biopsies were comparable between patients with C4d+ and controls in both groups. Follow-up was 100% complete with mean of observation time 2143 days. RESULTS: During the follow-up period, 62 patients died (group A: C4d+ 32% vs controls 29%; group B: C4d+ 36% vs controls 29% [P = NS]). There were no differences in survival between patients with positive staining and without C4d+ staining when Kaplan-Meier survival curves were compared. CONCLUSIONS: The presence of C4d positive staining in myocardial capillaries of heart biopsies of patients after heart transplantation, as an isolated finding, was not related to worse long-term survival. PMID- 27496489 TI - Comparison of Mechanical Circulatory Support by the Use of Pulsatile Left Ventricular Assist Devices Polvad MEV and Continuous Flow Heart Ware and Heart Mate II in a Single-Center Experience. AB - BACKGROUND: Mechanical circulatory support is increasingly used in patients with heart failure as a bridge to transplant or recovery. Results of use the Polish POLVAD MEV pulsatile circulatory support system and its comparison with novel devices never was done. We compared the course of patients with left ventricular circulatory support (left ventricular assist device [LVAD]) supported by POLVAD MEV or continuous flow devices Heart Mate II (HM II) and Heart Ware (HW) in single-center cohort. METHODS: We retrospectively reviewed 44 patients who underwent Polvad Mev (group P; n = 24 [21M/3F]) or HW or HM II (group C; n = 20 [20M/0F]) implantation between April 2007 and February 2014. Patients were in INTERMACS 1 (6 in group P and 1 in group C) or 2. Preimplant demographics, and perioperative and postoperative clinical outcomes were reviewed between groups. We analyzed baseline signs of heart failure, comorbidities, complications, and the 30- and 90-day results. RESULTS: Among the groups, age, gender, weight, and cause of heart failure were comparable. Patients in group C suffered more frequently from hypercholesterolemia preoperatively. Patients in group P had more pulmonary complications (7 vs 0) after LVAD implantation and stay longer on intensive care unit than patients in group C (17.61 +/- 16.96 vs 9.56 +/- 9.42; P = .047). After exclusion, INTERMACS 1 patients it was not significant (14.8 +/- 10.8 vs 9.8 +/- 9.6 days; P = .065), the 30- and 90-day mortality was comparable. CONCLUSIONS: Implantation of pulsatile POLVAD MEV and continuous flow devices as LVAD support provides comparable results. A greater number of complications in group P can cause increased mortality over a longer observation period. PMID- 27496490 TI - Effects of Left Ventricular Assist Device Support on End-Organ Function in Patients With Heart Failure: Comparison of Pulsatile- and Continuous-Flow Support in a Single-Center Experience. AB - BACKGROUND: Limited data exist about the effects of continuous-flow versus pulsatile-flow left ventricular assist devices (LVADs) on end-organ function. We hypothesized that a pulsatile Polvad MEV (PM) would result in outcomes similar to those of similarly ill patients implanted with a continuous-flow LVAD (Heartware [HW] or Heartmate II [HMII]). We aimed to compare renal, hepatic, and hematologic functions in the 1st 30 days of support. METHODS: We retrospectively reviewed patients with 24 PM (21 M, 3 F; group P) and 15 HW and 5 HMII (20 M, 0 F); group C LVAD implantations from April 2007 to February 2014. Creatinine, bilirubin, aspartate (AST) and alanine (ALT) transaminases, hematocrit, platelet count, international normalized ratio (INR), and activated partial thromboplastin time (APTT) parameters were analyzed before implantation and during 30 days of support. Demographic parameters were similar. RESULTS: No significant differences were found between the groups regarding baseline renal, hepatic, or hematologic function. Baseline INR and APTT were significantly higher in group P. Levels of creatinine were similar between groups. They increased from baseline to postoperative day (POD) 1 and then decreased. Bilirubin levels were insignificantly higher in group P. Transaminases were significantly higher in group P (AST in PODs 3-6, ALT in PODs 3-7). INR values were significantly higher at baseline and in POD 0. APTT values were insignificantly higher in group P. CONCLUSIONS: The use of LVAD improved renal and hepatic function in our series. Patients in group P had more decreased hepatic function and presented slower regeneration. PMID- 27496491 TI - Endocan Concentration and Chronic Inflammatory Process Among Heart Transplant Recipients. AB - BACKGROUND: Endocan is a novel soluble dermatan sulfate proteoglycan derived from endothelium. It has the capacity of binding to different biologically active molecules associated with cellular signaling, adhesion, and regulating proliferation, differentiation, migration, and adhesion of different cell types in health and pathology. Its elevated level is connected with endothelial activation, neovascularization, and inflammation or carcinogenesis. METHODS: The level of serum endocan among 131 heart transplant recipients on 3-drug immunosuppression (calcineurin inhibitor, mycophenolate mofetil/mycophenolic acid, steroid) in correlation with other markers of endothelial damage was determined. In addition, 22 healthy volunteers were studied. In cross-sectional study, markers were measured with the use of commercially available assays of endothelial damage-endocan and von Willebrand factor (VWF)-inflammation-high sensitivity C-reactive protein (hsCRP), interleukin (IL) 6-and kidney function cystatin C. RESULTS: The endocan, VWF, IL-6, hsCRP, and cystatin C levels were significantly higher in heart transplant recipients compared with healthy volunteers. In our cohort, endocan level was correlated with renal function (estimated glomerular filtration rate: r = -0.21; P < .05), creatinine (r = 0.21; P < .05), erythrocyte count (r = -0.24; P < .01), hemoglobin (r = -0.33; P < .01), N-terminal pro-B-type natriuretic peptide (r = 0.25; P < .01), cholesterol (r = -0.22; P < .05), LDL (r = -0.21; P < .05), New York Heart Association functional class (r = 0.21; P < .05), hsCRP (r = 0.32; P < .01), IL-6 (r = 0.31; P < .01), and VWF (r = 0.27; P < .01). In multifactorial analysis, the predictors of endocan levels were cholesterol level, cystatin C, and IL-6, predicting 54% of variability. CONCLUSIONS: Endocan concentration among heart transplant recipients is potentially connected with endothelial damage caused by subclinical inflammation resulting from hyperlipidemia. PMID- 27496492 TI - Right Ventricular Function in Patients With Left Ventricular Assist Device Support by Pulsatile Polvad MEV and Continuous-Flow Pumps Heartware and Heartmate II. AB - BACKGROUND: Left ventricular assist device (LVAD) support is increasingly used in patients with heart failure. The right ventricle (RV) plays a main role in LVAD support. Little is known about the effects of pulsatile Polvad MEV devices or continuouseconds flow pumps on RV function. We compared hemodynamic parameters of RV in patients after implantation of Polvad MEV (PM) and Heartware (HW) or Heartmate II (HMII) LVADs. METHODS: Forty-four patients were retrospectively reviewed after implantation of PM (group P; n = 24 [21 M, 3 F]) or HW or HMII (group C; n = 20 [20 M, 0 F]) LVADs from April 2007 to February 2014. Hemodynamic data-mean pulmonary pressure (mPAP), central venous pressure (CVP), cardiac output (CO), and cardiac index (CI)-were collected before surgery, after surgery, and every 2 hours in the intensive care unit, with the time points numbered from 1 to 120. Right ventricular work (RVW) was calculated according to the equation: RCW = CO * (mPAP - CVP) * 0.0144 (g.m). RESULTS: Baseline characteristic of the patients were similar. mPAP values were similar between groups. CVP values were higher in group P, significantly at time points 5 and 7-33. CO values were higher in group C, significantly from point 3 and almost all the time to point 43. CI reached significance at point 9, 12-14, 16-19, and 30-41. RCW was higher in group P before implantation. Post-implantation RCW values were higher in group C, significantly at time points 19, 20, 32-34, 51-53, and 55-57. CONCLUSIONS: Continuous-flow pumps more effectively optimize RV function than pulsatile LVADs, which can result in more effective prevention of RV failure or insuffiency in that group. PMID- 27496493 TI - National Hematopoietic Stem Cells Transplant Registry in Poland: Nationwide Internet Reporting System and Results. AB - History of hematopoietic stem cell transplantations in Poland begins in early 1980s; the 1st bone marrow allotransplantation was performed in 1983 in the Central Clinical Hospital of the Military Medical Academy in Warsaw. Following years brought the 1st autologous stem cell transplantations. Ten years later, unrelated bone marrow transplantation was performed for the 1st time by the team of the Hematology and Blood and Marrow Transplantation Unit in Katowice. Since then, hematopoietic stem cell transplantation developed to be standard procedure and one of the most important therapies applied in leukemia treatment. The number of allotransplantations in Poland has grown significantly in the past 2 decades, which generated new needs and problems. In 2005, based on a new Transplant Law, a National Transplants Registry was created. Its main role is to collect data (registration of procedures and follow-up data) related to every transplantation case for stem cells and tissues as well as for organs. We present statistics concerning stem cell transplantations performed in Poland, as collected in the National Transplants Registry in the years 2006-2014. There are 18 centers transplanting hematopoietic stem cells in Poland. The total number of hematopoietic stem cell transplantations performed in 2006-2014 was 3,537, with allotransplantations from relatives accounted for 1,491 and from unrelated donors for 2,046. The main indication for allotransplantation in past years was acute leukemia. PMID- 27496494 TI - Rhinosinusitis in Acute Leukemia Patients Undergoing Allogeneic Stem Cell Transplantation-A Single-Center Experience. AB - BACKGROUND: Although rhinosinusitis constitutes a major clinical problem in general population, data on rhinosinusitis in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT) are scarce. Therefore, the aim of the study was to assess the frequency of rhinosinusitis, the impact of rhinosinusitis on post-alloHSCT outcome, and to analyze risk factors potentially predisposing to rhinosinusitis. METHODS: Retrospective analysis of acute leukemia patients undergoing alloHSCT. RESULTS: A total of 87 patients (49 male), with a median age of 36 years (range, 18-58), transplanted from 1999 to 2010, were enrolled; 61 patients suffered from acute myeloid leukemia (AML) and 26 of acute lymphoblastic leukemia (ALL). Fifteen patients (17.2%) experienced rhinosinusitis before transplantation, among whom 5 (33%) experienced rhinosinusitis after alloHSCT; 22 patients (25.3%), 12 AML and 10 ALL, experienced rhinosinusitis after alloHSCT. The median time to rhinosinusitis was 200 days (range, 1-2,044). 11 patients experienced rhinosinusitis during the 1st 100 days after transplantation, 8 during the 1st 30 days. Post-alloHSCT rhinosinusitis did not affect overall survival of transplant patients (P = .35). In univariate analysis only total body irradiation as part of conditioning (odds ratio [OR], 2.78; 95% CI, 1-7.77) and previous nasal packing (OR, 5.18; 95% CI, 1.22-23.43) were associated with higher incidence of rhinosinusitis. In multivariate analysis, none of the analyzed parameters was shown to have an impact on rhinosinusitis development. CONCLUSIONS: Rhinosinusitis is a frequent medical condition in patients undergoing alloHSCT. The overall survival of patients developing rhinosinusitis after HSCT is similar to survival of patients who do not. No risk factors for developing rhinosinusitis could be identified. PMID- 27496496 TI - Banking of Hematopoietic Stem Cells: Influence of Storage Time on Their Quality Parameters. AB - BACKGROUND: Banking of hematopoietic stem cells (HSCs) is a rapidly growing part of the transplant field. The essence of the banking process is to maintain the optimal quality parameters throughout the storage period, allowing successful transplantation. METHODS: Our laboratory research was carried out on 126 HSC samples that were collected by means of leukapheresis from patients with lymphoproliferative diseases. The samples were frozen in a controlled rate and stored up to 76 months in containers in vapor phase of liquid nitrogen. The evaluation was performed after thawing the probes. Viability of nuclear cells was assessed after incubation in Trypan blue, CD34+ phenotype cells were determined by means of cytometry with the use of 7-aminoactinomycin D (7-AAD), and an analysis of the proliferative potential of granulocyte-monocyte precursors was performed. For comparative statistical analysis, the material was divided into 3 groups according to storage time: A: <1 month (n = 45); B: 1-12 months (n = 50); C: >12 months (n = 31). RESULTS: In the examined groups, similar median values were observed of nuclear cell viability (A, 86%; B, 87%; and C, 83%) and CD34+ cells (95%, 94.5%, and 95.8%, respectively). A gradual, nonsignificant, reduction in the median of granulocyte-monocyte precursors was found: 68 * 10(4)/kg of body weight (kg bw), 48.5 * 10(4)/kg bw, and 47 * 10(4)/kg bw, respectively. Statistical analysis with the use of the Kruskal-Wallis test showed a P value of >.05 for all variables. CONCLUSIONS: There were no significant differences in the viability of nuclear cells, CD34+ cells, and proliferative potential granulocyte monocyte precursors between groups. Storage for up to 76 months does not change the essential quality parameters, and HSCs could be qualified for distribution. PMID- 27496495 TI - Azacitidine Use After Allogeneic Stem Cell Transplantation-Results From the Polish Adult Leukemia Group. AB - BACKGROUND: Relapse of primary hematologic disease constitutes an important reason for failure of allogeneic hematopoietic stem cell transplantation (alloHSCT). There are very few treatment modalities for this indications. Therefore, there is a need for novel effective therapies and even more for the prevention of relapse. There are scarce data that azacitidine can be used for these purposes. METHODS: At the Polish Adult Leukemia Group, we retrospectively analyzed the results of azacitidine treatment after alloHSCT. Relapsing patients, patients with minimal residual disease/mixed chimerism, and patients in complete remission with high risk of relapse were analyzed separately. There were 17 patients, 6 with myelodysplastic syndrome, 11 with acute myeloid leukemia, 8 male, and overall median age of 56 years (range, 15-78); 7 patients received donor lymphocyte infusion (DLI). RESULTS: Patients treated because of relapse received a median of 3 (range, 1-6) cycles of azacitidine, patients receiving preemptive treatment received a median of 4 cycles (range, 2-6), and those on maintenance received a median of 5 cycles (range, 3-5). Toxicity was considerable, especially in relapse-neutropenia (67%), anemia (67%), thrombocytopenia (100%), serious infections (78%)-and preemptive settings. Median overall survival of patients treated for relapse reached 6.8 months (95% confidence interval [CI], 0.7-infinity), with better survival observed in patients with temporary disease control (7.7 vs 4.7 mo) and without previous exposure to azacitidine (7.7 vs 3.4 mo). One-year overall survival reached 75% (95% CI, 13%-96%) for preemptive and 50% (95% CI, 0%-91%) for maintenance treatment. DLI did not aggravate graft-versus-host disease. CONCLUSIONS: Effectiveness of azacitidine in relapsing patients is disappointing. Azacitidine seems to be promising in preemptive and maintenance settings. Toxicity is considerable. Further research is needed. PMID- 27496497 TI - Liquid Storage of Hematopoietic Stem Cells Versus Proliferative Potential Colony Forming Unit Granulocyte-Monocytes: Validation of Cell Processing. AB - BACKGROUND: The material for transplantation must be of the highest quality. As far as we know, short-term storage is one of the crucial points of stem cell banking. According to the quality assurance system in a stem cell bank, each step of cell processing must be validated. The aim of this study was to assess the influence of short-term storage conditions into a clonogenic assay. METHODS: Material was collected from mobilized peripheral blood by means of leukapheresis from 15 patients. Samples were stored at 4 degrees C and 20 degrees C; samples were evaluated on the day of leukapheresis and after 24 hours and after 48 hours of storage. The number of colony-forming unit granulocyte-monocyte (CFU-GM) precursors was analyzed with the use of in vitro culture. The material was evaluated before freezing and after thawing. RESULTS: The average number of CFU GM precursors in the material stored at 4 degrees C before freezing on the day of collection was 84/10(5) nuclear cells (nc) and after 24 hours and 48 hours of storage was, respectively, 62/10(5) nc (P = .011719) and 36/10(5) nc (P = .02088). The average of the CFU-GM precursors in material stored at 20 degrees C after 24 hours and 48 hours of storage amounted to 33/10(5) nc (P = .004439) and 2/10(5) nc (P = .00346), respectively. CONCLUSIONS: In our study, the number of colonies of CFU-GM after 24 hours and 48 hours of storage, both at 4 degrees C and 20 degrees C, was significantly reduced compared with the number of colonies on the day of collection. Significantly greater numbers of CFU-GM precursors were observed in the material stored before freezing at 4 degrees C in comparison with the material stored at 20 degrees C. PMID- 27496498 TI - Autologous Hematopoietic Stem Cell Transplantation for Adults With Acute Myeloid Leukemia. AB - BACKGROUND: Hematopoietic stem cell transplantation (HSCT) remains the most efficacious therapy in patients with acute leukemia. For older patients and those lacking a related HLA-compatible donor, autologous transplantation (auto-HSCT) is a valid alternative therapeutic option. METHODS: From 1997 until 2014 in the Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, Poland, 29 auto-HSCT were performed in patients with acute myeloid leukemia (AML; 15 men and 14 women; median age, 52.2 years). The following FAB types of AML were diagnosed: M0, 3; M1, 4; M2, 6; M4, 10; and M5, 6. Patients with AML were classified into 3 cytogenetic prognostic groups: high risk, 9; intermediate risk, 16; and low risk, 4. Twenty-five were in first complete remission and 4 in second complete remission. The peripheral HSCs mobilized after chemotherapy (mainly second course of consolidation) and granulocyte colony stimulating factor were the source of the stem cells in all cases. The median number of infused CD34+ cells was 3.58 * 10(6)/kg. The conditioning regimen was busulfan and cyclophosphamide in all patients with AML. The intravenous form of busulfan was applied in the last 15 patients. RESULTS: The median time for absolute neutrophil count recovery >0.5 * 10(9)/L and for platelet count >20.0 * 10(9)/L was 12 and 16.5 days, respectively. Treatment-related mortality rate in the whole group was 3.4% (1 patient with sepsis in the aplastic period). The median follow-up time of survivors was 21.9 months (range, 11.7-142.4). The 3 year projected disease-free survival and overall survival rates were 60% and 68%, respectively. CONCLUSIONS: Our data confirm that auto-HSCT is a valuable therapeutic option for patients with AML, especially older patients and those lacking related HLA-compatible donors. PMID- 27496499 TI - Changes in Technique and Indications for Keratoplasty in Poland, 1989 to 2014: An Analysis of Corneal Transplantations Performed at Saint Barbara Hospital, Trauma Center, Sosnowiec, Poland. AB - BACKGROUND: The purpose of this work was to study the evolving trends in techniques and indications for corneal transplantation in Poland. METHODS: This retrospective, descriptive analysis of corneal transplantations was performed at the Ophthalmology Department of Saint Barbara Hospital, Trauma Center, Sosnowiec, Poland, between 1988 and 2014. Structure of indications and surgery type rates over 26 years were tabulated by means of 5-year intervals. RESULTS: Between 1989 and 2014, 1762 corneal transplantations were performed, including 1375 (78%) cases of penetrating keratoplasty, 137 (8%) lamellar keratoplasty, 112 (6%) patch grafts, and 138 (8%) keratolimbal allografts. The major indications and their respective overall percentage were corneal leucoma (24%), pseudophakic/aphakic bullous keratopathy (22%), Fuchs dystrophy (13%), keratoconus (13%), re-graft (11%), keratitis (9%), and limbal stem cell deficiency (8%), with changes in relative frequency of the leading indications over the following time intervals. The number of corneal transplantations gradually increased during the years reviewed. The rates of lamellar, keratolimbal, and patch grafts have grown dynamically since 2010, reaching 20%, 17%, and 12%, respectively, of procedures performed during 2010 to 2014. CONCLUSIONS: Over the past quarter of a century, there has been evolution in corneal transplantation service, from the first penetrating keratoplasty to the wide spectrum of procedures, including femtosecond laser-assisted keratoplasty. Although, since 2010, the rates of lamellar and keratolimbal allografts have grown rapidly, penetrating keratoplasty has remained the leading technique. PMID- 27496500 TI - Effect of Recombinant Human Prolactin Addition to Biolasol Solution on Biochemical Indicators in Perfundates of Porcine Kidneys. AB - BACKGROUND: The influence of recombinant human prolactin (rh-PRL) added to Biolasol solution (concentration 1 MUg/L) on selected markers (pH, osmolarity, Na(I) and K(I) concentration) and enzymatic activity (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and lactate dehydrogenase [LDH]) in perfundates was investigated during flushing and preservation of the isolated porcine kidneys. METHODS: The pH, osmolarity, concentration of K(I) and Na(I), and enzymatic activity were determined in perfundates collected after the 5th and 30th minutes of perfusion, after 24 hours of organ preservation, and in the 5th and 30th minutes of reperfusion. Kidneys had been flushed and stored in Biolasol (control group) and in Biolasol with rh-PRL (experimental group). Obtained results were compared with Biolasol solution. RESULTS: In the experimental group, the decrease in pH value in the 5th minute of reperfusion was noted. There was an increase in K(I) concentration, and Na(I) concentration decreased in the 5th and 30th minutes of reperfusion. ALT activity during perfusion and preservation increased, whereas at the 5th and 30th minutes of reperfusion it decreased. AST activity increased during perfusion and preservation and decreased in the 5th and 30th minutes of reperfusion. LDH activity was increased but decreased in the 5th minute of reperfusion. CONCLUSIONS: Addition of 1 MUg/L rh-PRL to Biolasol solution decreases pH and osmolarity values; influences Na(I) and K(I) concentration; increases ALT, AST activity during perfusion and preservation of organs; and decreases ALT, AST activity during reperfusion. PMID- 27496501 TI - Caspase-3 Expression and ALT, AST, and GGT Activity After 24 Hours of Porcine Liver Cold Storage, Depending on the Type of Transgenesis. AB - BACKGROUND: Because of an insufficient number of human organs for transplantation, xenotransplantation may become an effective alternative. We aimed to analyze if the type of transgenesis has an influence on the hepatic caspase-3 expression, the enzyme that executes apoptosis as well as ALT, AST, and GGT activity after 24 hours of cold storage. METHODS: The experiment was carried out on the 24 livers of Polish White Landrace pigs carrying human alpha1,2 fucosyltransferase and/or alpha-galactosidase (GAL) genes and livers without this genetic modification (control). Livers were perfused, stored for 24 hours in solution, and subsequently re-flushed. Hepatic concentration of the caspase-3 protein and its mRNA expression were measured just after the animal was killed as well as after 30 minutes of perfusion and after 24 hours of cold storage followed by 30 minutes of reperfusion. Caspase-3 mRNA level was detected with the RT-PCR method. Protein concentration (capsase-3 active and inactive) was assessed with the Western blotting technique. Kinetic methods were applied for the analysis of the ALT, AST, and GGT activity. RESULTS: The highest increase of the ALT activity after cold storage was observed in the group with GAL transgenesis, whereas the GGT activity was highest in the unmodified livers. There was no difference in the caspase-3 expression and AST activity after cold storage as compared with the respective initial results (P = .57 and P = .97, respectively). CONCLUSIONS: It appears that transgenesis does not aggravate ischemic injury of the liver. PMID- 27496502 TI - Endothelial Nitric Oxide Synthase and Endothelin-1 Expression in the Early Post Porcine Kidney Autotransplantation Period. AB - BACKGROUND: The aim of this study was the assessment of endothelial nitric oxide synthase (eNOS) and endothelin-1 (EDN-1) expression in porcine kidneys on the 14th and 30th days after the autotransplantation procedure. METHODS: The research was conducted on 12 animals that underwent a left renal transplantation procedure with further standardized rinsing and 24-hour storage in 4 degrees C; subsequently, the kidneys were implanted in the right retroperitoneal space after right-sided nephrectomy. Removed kidneys were examined (group 0). Six randomly chosen animals (group 1) were under observation for 14 days and 6 others (group 2) for 30 days. RESULTS: After these observation periods, euthanasia was performed on the animals and 4-g samples were collected from the renal cortex and medulla. The Western blot technique was used to detect the eNOS and EDN-1 expression at the protein level. The obtained results are presented as absolute values of integrated optical density. Stable graft function was observed in all animals from the 2nd day after the procedure. eNOS in group 1 reached the mean value of 1.064 and was statistically significantly lower than in group 2 (2.085) or in the control group 0 (3.318). In the case of EDN-1 expression on 14th day after transplantation, the medium level was reported (0.248), which was similar to group 0 (0.216), whereas group 2 presented values 2 times higher (0.743). CONCLUSIONS: A lowered eNOS level in the organ was observed on the 14th day after autotransplantation of a pig kidney; further enzyme normalization is associated with increased EDN-1 expression. PMID- 27496503 TI - Determination of Concentrations of Azathioprine Metabolites 6-Thioguanine and 6 Methylmercaptopurine in Whole Blood With the Use of Liquid Chromatography Combined With Mass Spectrometry. AB - BACKGROUND: 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are used in many autoimmune diseases and after solid-organ transplantation. Their properties are mediated by active metabolites, 6-thioguanine nucleotides (6-TGN), and 6-methylmercaptopurine (6-MMP). The most common adverse effects are myelo- and hepato-toxicity. The aim of the study was quantification of 6-TG and 6-MMP, with the use of liquid chromatography combined with tandem mass spectrometry (LC/MS/MS) in solid-organ transplant recipients. METHODS: In 33 patients, kidney transplant recipient (n = 25) and liver transplant recipient (n = 8) intra erythrocyte concentrations of 6-TG and 6-MMP were measured with the use of LC/MS/MS. RESULTS: The mean concentration of 6-TG was 205.35 +/- 157.62 pmol/8 * 10(8) red blood cells (RBC); median concentration of 6-MMP was 1064.1 (35.78 11,552.9) pmol/8 * 10(8) RBC. There were no correlations between 6-TG levels and peripheral blood parameters (white blood cell count, WBC; hemoglobin, Hb concentration; PLT, blood platelet count) or alanine aminotransferase activity (AlAT) activity. Relationships between 6-MMP concentrations and peripheral blood parameters (WBC, Hb, PLT) or AlAT activity have not been found. Subgroups with leukopenia, anemia, thrombocytopenia, and liver dysfunction did not differ in concentrations of 6-TG or 6-MMP. We have observed a negative correlation between daily azathioprine dose and WBC count (r = -0.37, P = .04). CONCLUSIONS: Relationships between concentrations of azathioprine metabolites and myelotoxicity or hepatotoxicity have not been confirmed. Further studies on larger groups of patients would be helpful in a more accurate understanding of the impact of azathioprine metabolites on parameters of bone marrow and liver function. PMID- 27496504 TI - Concentration of Tumor Necrosis Factor-alpha and Interleukin-1beta in Isolated Porcine Liver Depending on Type of Transgenesis. AB - BACKGROUND: Transgenic animals may serve as organ donors in human organ transplantation. However, the number of the studies addressing all doubts related to this issue is currently insufficient for the clinical application of this approach. The aim of this study was to analyze the hepatic tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) synthesis during a 24-hour cold preservation of the transgenic pig liver, depending on the type of transgenesis. MATERIALS AND METHODS: The study was carried out on wild-type and transgenic pig livers with transferred human alpha1,2-fucosyltransferase (FUT) and/or alpha-galactosidase (GAL) gene (four groups; n = 6). Harvested livers were perfused for 30 minutes and stored for 24 hours in Biolasol (Biochefa) solution at 4 degrees C with a subsequent 30-minute reperfusion (reflush). TNF-alpha and IL-1beta concentrations were analyzed with an enzyme-linked immunosorbent assay. Perfusates were collected during the initial perfusion as well as after 24 hours of preservation and during the reperfusion. Tissue samples were harvested just after animal sacrifice, and after organ perfusion and reperfusion. RESULTS: A decrease in TNF-alpha concentration in homogenates was noted after both perfusion and reperfusion in all experimental groups. In contrast, there was a significant decrease in IL-1beta concentration in the group with combined human FUT and GAL transgenes. Concurrently, increases in TNF-alpha and IL-1beta concentrations were observed in the reperfusion perfusates in all groups. CONCLUSION: This study shows that IL-1beta is synthesized in the ischemic livers of the transgenic animals with both human alpha1,2-fucosyltransferase and alpha-galactosidase transgenes. Further analysis is required to determine the importance of this observation. PMID- 27496505 TI - Kaposi Sarcoma in the Genital Area in a Kidney Transplant Patient: A Case Report and Literature Review. AB - BACKGROUND: Kaposi sarcoma (KS) is a cancer with an incidence in patients after transplantation (Tx) that is 500 times greater than that in the healthy population. The risk of KS increases significantly during therapy, especially when immunosuppressive therapy with cyclosporine A (CsA) is used. Most cases of KS develop during the first 2 years after transplantation. After a KS diagnosis, it is recommended to reduce the doses of immunosuppressive medications. Conversion of immunosuppressive treatment into mammalian target of rapamycin (m TOR) inhibitors is strongly suggested. PATIENTS AND METHODS: We present the case of a 65-year-old man with end-stage renal disease (ESRD) of unknown etiology, who had kidney transplantation in 2008. Immunosuppressive protocol was based on CsA, mycophenolate mofetil (MMF) and prednisolone (PRE). In 2011, during the dermatological consultation, on the penis glans a purple stain of uneven surface was noted. Histology study revealed the presence of KS. The treatment was modified. The patient was converted from CsA to everolimus. Before converting, the creatinine concentration was 1.79 mg/dl and proteinuria less than 0.3 g/day. RESULTS: The change in the scheme of immunosuppresion from CsA to everolimus was performed to treat the Kaposi sarcoma. Gradually, within a year, the KS was cured. However, the graft function deteriorated, and the graft was lost in one years' time. CONCLUSION: We present the first documented case of KS in the genital area of a kidney patient. The reduction in the strength of immunosuppression, and the introduction of an m-TOR inhibitor, may have contributed to the deterioration of kidney function, however it was substantial in the treatment of KS. PMID- 27496506 TI - Renal Tumor in Allogeneic Kidney Transplant Recipient. AB - BACKGROUND: Malignancies will be a leading cause of mortality in renal transplant recipients in the next 20 years. Renal cell cancer (RCC) is the most common urologic cancer in kidney transplant recipients. The risk of RCC development in kidney transplant recipients is 15-100 times higher than in the general population. The purpose of the current retrospective study was to assess the frequency of nephrectomies performed because of renal tumors in the native kidneys in kidney transplant recipients in the Department of General and Transplantation Surgery at the Medical University of Warsaw between 2010 and 2014 year; the identification of kidney recipients diagnosed with RCC; and epidemiologic, clinical, and histopathological aspects associated with RCC. PATIENTS AND METHODS: A total of 319 nephrectomies were performed in the Department of General and Transplantation Surgery at the Medical University of Warsaw between 2010 and 2014 year. Renal tumors were diagnosed in 25 renal transplant recipients. RESULTS: Among malignant tumors, 13 cases of RCC and 1 case of post-transplant lymphoproliferative disorder (PTLD) were observed. There was no significant difference between age and duration of pretransplantation dialysis in patients with RCC and patients with benign tumors (P = .14 and P = .91, respectively). Body mass index was significantly higher in patients with RCC than in patients with benign tumors (P = .04). CONCLUSIONS: Renal cell cancer is more common among male kidney recipients. There is a good Polish screening system allowing detection of kidney cancer in native kidney. We recommend performing periodic screening for kidney cancers to obtain an early diagnosis. PMID- 27496507 TI - Delayed, Uncommon Recurrence of Hepatocellular Carcinoma After Liver Transplantation: A Case Report. AB - We report a case of a 27-year-old man diagnosed with the infection of HBV delta in the 8th month of life. The treatment complied with evidence-based medical guidelines, comprising neoadiuvant chemotherapy and surgery. Liver transplantation from a deceased donor followed by chemotherapy was performed when the patient was 16 years 9 months of age because of recurrent HCC tumor. The patient qualified for immunosuppressive treatment (rapamycin, tacrolimus), lamivudine, anti-HBs globulin intravascular infusion, and anti-HBV vaccination as a prophylaxis against reinfection with HBV. In conclusion, this case demonstrates the importance of a postoperative follow-up of patients with HCC, even years after liver transplantation. PMID- 27496508 TI - Renal Artery Denervation in Patient After Heart and Kidney Transplantation With Refractory Hypertension. AB - We describe the case of a 54-year-old patient after renal and heart transplantation in whom uncontrolled hypertension was diagnosed. Despite combined antihypertensive therapy, no significant therapeutic effect was achieved. Clinical assessment of ambulatory blood pressure monitoring (ABPM) revealed the ineffectiveness of a bisoprolol, nitrendypin, klonidyn, ramipryl, furosemide, and doxasosine combination used at high doses. High blood pressure levels with their effect on a hypertrophic transplanted heart (left ventricular mass 254 g) and poor renal graft function (39 mL/kg/min) posed an extremely high risk of future cardiovascular complications, and were the reason to perform a native renal arteries denervation. The procedure was carried out through the right femoral artery with the use of a 6F guiding catheter. During a 1-year observation, significant decreases in ABPM systolic and diastolic blood pressures were observed after the procedure (168/88 mm Hg vs 154/77 mm Hg, respectively). Moreover a significant regression of left ventricular mass (215 g/m(2)) and stable renal graft function were noted. The presented case shows that native renal arteries denervation may be successful and safe in kidney and heart transplant recipients. Moreover, during the 1-year follow-up, the reduction in blood pressure was followed by a reduction in transplanted heart hypertrophy, both leading to regression of cardiovascular risk for the patient. PMID- 27496509 TI - Erratum. PMID- 27496510 TI - Erratum. PMID- 27496511 TI - Evaluation of Pastorex meningitis kit performance for the rapid identification of Neisseria meningitidis serogroup C in Nigeria. AB - BACKGROUND: Neisseria meningitidis serogroup C (NmC) has caused outbreaks in Nigeria of increasing size in three consecutive years since 2013. Rapid diagnostic tests (RDTs) for meningitis can facilitate quick identification of the causative pathogen; Pastorex can detect N. meningitidis serogroups A, C (NmC), Y/W135, N. meningitidis serogroup B/Escherichia coli K1, Haemophilus influenzae type b (Hib), Streptococcus pneumoniae, and group B Streptococcus. There is no published field evaluation of Pastorex in the identification of NmC. We report our experience with Pastorex in detecting NmC in field conditions. METHODS: During sequential outbreaks of NmC in Nigeria in 2013, 2014 and 2015, cerebrospinal fluid (CSF) was collected from suspected cases of meningitis that met the case definition. Pastorex latex agglutination rapid test was done in the field and trans-isolate media were inoculated with CSF for culture and/or PCR, which was used as the reference standard for 63 paired samples. RESULTS: The sensitivity of Pastorex for NmC was 80.0% (95% CI 65.4-90.4%) and the specificity was 94.4% (95% CI 72.7-99.9%). The positive likelihood ratio (LR) was 14.4 (95% CI 2.1-97.3) and negative LR was 0.2 (95% CI 0.1-0.4). The positive and negative predictive values (PPV and NPV) were 97.3% (95% CI 85.8-99.9) and 65.4% (95% CI 44.3-82.8), respectively, with a prevalence estimate of 71.4% (95% CI 58.6-82.1). CONCLUSION: Pastorex showed good performance in detecting NmC under field conditions. Prepositioning Pastorex at peripheral health facilities during non epidemic periods is constrained by a short shelf-life of 1 month after the kit is opened. There is need for development of RDTs that are cheaper and with less challenging requirements for storage and usage. PMID- 27496512 TI - The impact of a rural sanitation programme on safe disposal of child faeces: a cluster randomised trial in Odisha, India. AB - BACKGROUND: Unsafe disposal of child faeces is persistent and may lead to considerable impact on the health of young children. Research is limited on the impact of sanitation or hygiene interventions to improve child faeces disposal practices. METHODS: In the context of a randomised controlled trial to assess the health impact of a programme in Odisha, India, to promote rural sanitation under the Government of India's Total Sanitation Campaign, we explored whether the intervention affected the safe disposal of faeces of children under-5 years of age. RESULTS: At baseline, 1.1% of households practised 'safe' disposal of child faeces, either disposing it in a toilet or by burial. The intervention increased safe disposal of child faeces to 10.4% in intervention households, compared to 3.1% in the control households (RR 3.34; 95% CI 1.99-5.59). This increase in safe disposal is attributable to increases in latrine presence in the intervention communities; the intervention did not change safe disposal practices above and beyond the increase in latrine coverage. CONCLUSIONS: The very modest increase in safe disposal, while statistically significant, is not likely to have consequential health benefit. To achieve open defecation free communities, sanitation interventions will need to develop behaviour change approaches to explicitly target safe disposal behaviours. PMID- 27496513 TI - Can we replace HIV sentinel surveillance platform with prevention of parent-to child transmission (PPTCT) program data to assess HIV burden and trends in India? AB - BACKGROUND: Estimates of HIV burden in India are based on HIV sentinel surveillance (HSS), which has limitations such as insufficient sample size for district level analysis and ethical concerns. We analysed prevention of parent-to child transmission (PPTCT) program data, for its suitability for HIV surveillance in India. METHODS: Correlation and differences in ante-natal clinic (ANC) attendees' HIV prevalence from the last four rounds of HSS (2007-2012) and PPTCT data for the corresponding years were analysed at national, state and district levels. Sensitivity and region wise analysis were also done. RESULTS: The PPTCT program covered a higher number of districts and ANC attendees than HSS. Correlation of HIV prevalence from PPTCT data with HSS was high (0.99) at national level, moderate (0.66-0.86) at state level, and low (0.43-0.62) at district level. HIV prevalence levels from HSS were generally higher than those from PPTCT data. As the coverage of PPTCT program and HSS improved, the differences between HIV prevalence from these two data sources increased. Sensitivity analysis showed significant differences in ANC attendees' HIV prevalence from HSS and PPTCT, even among districts with high HIV test uptake level in PPTCT program. CONCLUSIONS: PPTCT program data can be utilised for HIV surveillance in India as it has better coverage and will avoid ethical issues and expenditures related to HSS. PMID- 27496514 TI - Evaluating the efficacy of a centrifugation-flotation method for extracting Ascaris ova from soil. AB - BACKGROUND: Soil transmitted helminths (STH) continue to be associated with high burdens of disease, with an estimated 1.45 billion people infected with STH globally. The promotion and construction of latrines is considered the first barrier to prevent transmission of STH. The absence of a reliable method to extract STH ova from soil makes it challenging to examine whether the use of latrines may or may not have an effect on environmental contamination with ova. The present study evaluated the recovery rate of a method developed to extract STH ova from soil. METHODS: The adapted centrifugation and flotation technique was applied to 15 soil types, which were seeded with Ascaris suum ova. Soil type, soil moisture content, soil texture and organic matter content were assessed for each soil sample. RESULTS: The average ova recovery rate was 28.2%, with the recovery rate of the method decreasing with increasing soil moisture content, particle size and organic matter content. The association between recovery rate and organic matter content was statistically significant. CONCLUSIONS: The present study identified a low recovery rate for an adapted centrifugation flotation method, although this was similar to the recovery rate demonstrated by other methods developed for soil. Soil organic matter content was significantly associated with ova recovery rates. PMID- 27496515 TI - Natural transovarial and transstadial transmission of Leishmania infantum by naive Rhipicephalus sanguineus ticks blood feeding on an endemically infected dog in Shiraz, south of Iran. AB - BACKGROUND: The visceral leishmaniasis parasite, Leishmania infantum, is naturally transmitted through the bites of phlebotomine sand flies. Alternative routes of transmission are questioned. The main aim is to verify the passage of L. infantum kDNA in ticks, Rhipicephalus sanguineus, blood feeding on a parasitemic dog in Shiraz, south of Iran. METHODS: A total of 180 Leishmania-free ticks collected from fields and bred on lab rodents, were divided into eight groups and allowed to feed on a dog (Canis familiaris) for fixed periods of time. These and all third generation stages of ticks were checked for L. infantum kDNA using conventional PCR protocol. RESULTS: The infection rate was significantly higher in female than male ticks (p=0.043). The rates were higher among nymphs (25/60; 42%) than adult ticks (37/120; 30.8%). The kDNA of L. infantum was not detected in ticks 24 h post-feeding. It was, however, positive among the second to fourth groups of nymphs (4/10; 40%, 10/20; 50% and 11/20; 55%) and adult (12/30; 40%, 14/30; 46.6% and 11/30; 36.6%) ticks. Eggs and unfed larvae recovered from the third and fourth adult groups (2 weeks, 4 weeks) were 100% PCR positive. The data revealed the passage of L. infantum kDNA in nymphs and adults of brown dog tick following fixed time intervals post blood feeding on an infected dog. CONCLUSIONS: The natural transovarial and transstadial passage of kDNA through ticks was shown by PCR. PMID- 27496516 TI - Characterization of enteropathogenic Escherichia coli of clinical origin from the pediatric population in Pakistan. AB - BACKGROUND: Enteropathogenic Escherichia coli (EPEC) is one of the leading causes of watery diarrhea among children. METHODS: In this study EPEC isolates from the pediatric population of Pakistan (2010-2012) were subjected to phylotyping, antibiotic susceptibility, extended-spectrum beta-lactamase (ESBL) profiling and evaluation of one representative strain from each panel of phylotypesin Galleria mellonella, infection model. RESULTS: A total of 46/225 (20.4%) stool samples were positive for EPEC. Isolates mainly belong to D phylogroup (18, 39%) followed by nontypeable (10, 22%), B1 (9, 20%), B2 (8, 17%) and A (1, 2%). High resistance was observed for ampicillin (42, 91%), erythromycin (41, 89%), cefaclor (37, 80%), trimethoprim/sulfamethoxazole (36, 78%), tetracycline (36, 78%). Among nalidixic acid resistant isolates 13 (28%) showed presence of single nucleotide polymorphism (SNP) in parC (C330-T330) whereas 1 (2%) isolate showed gyrB (A660 T660) SNP. Furthermore, 27 (59%) isolates were ESBL producers. Representative isolates of phlyotypes A and B2 showed enhance killing of G. mellonella compared to ones belonging to phylotypes B1 and D. CONCLUSIONS: Non-typeable EPEC strains were frequently observed. ESBL production in ESBL producers was found to be plasmid mediated. No significant association of antibiotic resistance profile with specific phylogroup of EPEC was found, however G. mellonella infection model differentiated representative phylotypes. PMID- 27496517 TI - B1c genetic subtype of coxsackievirus A16 associated with hand, foot and mouth disease in Andaman Islands, India. AB - BACKGROUND: An outbreak of hand, foot and mouth disease (HFMD) occurred in the Andaman Islands in 2013. Therefore, we aimed to identify the aetiological agent and to explore its genetic characteristics. METHODS: Clinical specimens were subjected to virus isolation, further confirmed by sequencing the partial VP1/2A region of enterovirus, and analysed using MEGA 6 software with intra-serotype reference sequences. RESULTS: Coxsackievirus A16 (CV A16) was found to be the causative agent, closely grouped with B1c genetic clusters of CV A16. However, it has significant genetic distance (K2P=0.059%) with B1c sub-clusters. CONCLUSION: Extended research work should be carried out to better understand the emerging nature of CV A16 associated with HFMD in these islands.GenBank accession numbers: KU523376-KU523387. PMID- 27496518 TI - Schistosomiasis and soil-transmitted helminth infections in schoolchildren in north-eastern Democratic Republic of the Congo. AB - BACKGROUND: There is a paucity of epidemiological data pertaining to schistosomiasis and soil-transmitted helminth (STH) infections in the Democratic Republic of the Congo (DRC). METHODS: A cross-sectional survey was carried out in the north-eastern part of DRC enrolling 400 schoolchildren aged 9-14 years. Stool and urine samples were subjected to standard diagnostic methods and examined under a microscope for helminth eggs. RESULTS: Four out of five children were infected with at least one helminth species. Schistosoma mansoni was the predominant species (57.8%). Urine examinations were all negative for S. haematobium. CONCLUSIONS: S. mansoni and STH infections are highly endemic in the surveyed part of the DRC, calling for interventions in school-aged children. PMID- 27496519 TI - Remimazolam: Pharmacologic Considerations and Clinical Role in Anesthesiology. AB - Midazolam, fentanyl, and propofol are commonly used for sedation in modern anesthesia practice. These agents possess characteristics that have afforded various anesthetics to be delivered and produce relatively safe and effective outcomes. However, each agent has certain drawbacks in clinical practice. Remimazolam, a novel benzodiazepine created out of so-called soft drug development, is an ultrashort-acting intravenous sedative-hypnotic currently being investigated in clinical trials. In this review, we evaluate the recent literature on the use of remimazolam in clinical practice as compared with current sedative agents, and we describe its potential roles for use in sedation. A literature search of the Medline database (2012-May 2016) was performed. Additional references were identified from a review of literature citations, manufacturer reports, and professional meeting abstracts. All premarket studies involving remimazolam as the primary study drug were evaluated. Literature describing the pharmacokinetics and pharmacodynamics of remimazolam, propofol, and midazolam was also included. Phase I and II studies in the United States have shown remimazolam to be a safe and effective option for procedural sedation. Unlike midazolam and propofol, remimazolam undergoes organ-independent metabolism to an inactive metabolite. Because remimazolam follows first-order pharmacokinetics, prolonged infusions or higher doses are unlikely to result in accumulation and extended effect, making it favorable for use as an intravenous anesthetic and for sedation in the intensive care unit. It is expected that phase III trials will further describe the niche that remimazolam may be able to occupy in clinical practice. Postmarket cost-benefit analyses will need to be performed. PMID- 27496521 TI - Hastened death in ALS: Damaged brains and bad decisions? PMID- 27496520 TI - Cognitive impairment, behavioral impairment, depression, and wish to die in an ALS cohort. AB - OBJECTIVE: To evaluate relationships among cognitive, behavioral, and psychiatric/psychosocial measures assessed in a multicenter cohort of patients with amyotrophic lateral sclerosis (ALS). METHODS: Recently diagnosed patients with definite or probable ALS diagnosis were administered 7 standardized psychiatric/psychosocial measures, including the Patient Health Questionnaire for diagnosis of depression and elicitation of wish to die. The Cognitive Behavioral Screen was used to classify both cognitive and behavioral impairment (emotional interpersonal function). An ALS version of the Frontal Behavioral Inventory and Mini-Mental State Examination were also administered. RESULTS: Of 247 patients included, 79 patients (32%) had neither cognitive nor behavioral impairment, 100 (40%) had cognitive impairment, 23 (9%) had behavioral impairment, and 45 (18%) had comorbid cognitive and behavioral decline. Cognitive impairment, when present, was in the mild range for 90% and severe for 10%. Thirty-one patients (12%) had a major or minor depressive disorder (DSM-IV criteria). Cognitive impairment was unrelated to all psychiatric/psychosocial measures. In contrast, patients with behavioral impairment reported more depressive symptoms, greater hopelessness, negative mood, and more negative feedback from spouse or caregiver. A wish to die was unrelated to either cognitive or behavioral impairment. CONCLUSIONS: While we found no association between cognitive impairment and depression or any measure of distress, behavioral impairment was strongly associated with depressive symptoms and diagnoses although seldom addressed by clinicians. Thoughts about ending life were unrelated to either cognitive or behavioral changes, a finding useful to consider in the context of policy debate about physician-assisted death. PMID- 27496522 TI - Oral NSAIDs versus other oral analgesic agents for acute soft tissue injury. PMID- 27496523 TI - Photodynamic therapy-triggered bullous pemphigoid. PMID- 27496524 TI - Characterization of clinically important dermatophytes in North of Iran using PCR RFLP on ITS region. AB - OBJECTIVE: Dermatophytosis is considered as one of the major public health problems in the world. Accurate identification of the dermatophytes species is important for recognition of the environment and animal sources of infection. In this survey, 1500 clinical specimens taken from outpatients suspected of dermatophytosis and they were examined by direct microscopy and culture. MATERIALS AND METHODS: In total, three hundred and twelve dermatophytes were isolates recovered in culture, they were identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method based on the ribosomal DNA internal transcribed spacer (ITS) regions. RESULTS: Tinea pedis was the most common clinical form (32.1%) followed by tinea cruris (24.4%), tinea manuum (16.4%), tinea unguium (8.3%), tinea corporis (7.3%), tinea faciei (6.4%), and tinea capitis (5.1%). Trichophyton interdigitale was the most frequent isolate (38.2%), followed by Trichophyton rubrum (29.8%), Epidermophyton floccosum (16.6%), Trichophyton tonsurans (14.8%) and Microsporum canis (0.6%). The frequency of dermatophytosis was higher in males than in females and in the age-group of 21-30 years. CONCLUSION: Our finding indicated that the incidence of dermatophytosis caused by anthropophilic dermatophytes in Mazandaran province is increasing. Also, this study provides valuable data for the prevention and control of dermatophytosis in the southern coast of the Caspian Sea. PMID- 27496525 TI - Fecal microbial transplantation in a pediatric case of recurrent Clostridium difficile infection and specific antibody deficiency. PMID- 27496526 TI - A comparison of autologous transplantation of retinal pigment epithelium (RPE) monolayer sheet graft with RPE-Bruch's membrane complex graft in neovascular age related macular degeneration. AB - PURPOSE: To compare the outcome after choroidal neovascular (CNV) membrane excision and retinal pigment epithelium (RPE) transplantation and make further evaluation of two types of RPE grafts on the visual function in patients with neovascular age-related macular degeneration (AMD), complicated by massive subretinal haemorrhage. METHODS: We retrospectively reviewed 80 patients who underwent CNV membrane excision with or without RPE transplantation. Two types of RPE grafts were adopted, RPE-Bruch's membrane complex graft (subgroup 1) and RPE monolayer sheet graft (subgroup 2). Outcome measures included pre- and postoperative visual acuity score (VAS), clinical findings, complications and recurrence rates. RESULTS: The mean VAS [Early Treatment of Diabetic Retinopathy Study (ETDRS)] in the CNV membrane excision group was 11.06 +/- 18.28 at baseline and 14.41 +/- 16.86 at follow-up (p = 0.12) in a mean follow-up period of 24.35 +/- 9.31 months. While in subgroup 1, VAS increased from 22.62 +/- 23.72 to 35.50 +/- 24.46 (p = 0.02) in a mean period of 20.63 +/- 6.25 months. The percentage of visual acuity (VA) improvement (at least two or more lines changed) in subgroup 1 is 62.5%, which is significantly higher than that in CNV excision group (23.5%), p = 0.02. In subgroup 2, VAS increased from 16.61 +/- 27.98 to 29.16 +/- 23.80 (p = 0.02) in a mean period of 21.72 +/- 11.09 months. The percentage of VA improvement in subgroup 2 is 58.0%, which is also significantly higher than that in CNV excision group (23.5%), p = 0.02. Postoperative VA elevation was comparable between the two subgroups (p = 0.05). Complications including retinal detachment, proliferative vitreal retinopathy and CNV recurrence occurred in both techniques. Central fixation stability was observed in eight eyes in subgroup 1 and five eyes in subgroup 2. CONCLUSIONS: The autologous RPE transplantation can increase the vision of patients with haemorrhagic AMD. Two types of autologous RPE grafts were both effective and comparable in restoring visual function and central fixation stability. PMID- 27496527 TI - Correlation of retinopathy with leukoaraiosis in patients with anterior circulation infarcts. AB - Although retinal and cerebral microvessels share similar embryological, anatomical and physiological characteristics, the correlation between retinopathy and leukoaraiosis (LA), a type of brain microvascular disease, is unclear. In the present study, the sample included 213 patients admitted to the department of neurology from January 2012 through October 2012. MRI and retinal photography were performed within 48hours of hospitalization, and patient demographics, comorbidities, preadmission medications and laboratory data were collected. MRI images were used to divide the patients into LA and non-LA groups. Using multivariate binary logistic regression, the effects of retinopathy on LA were investigated. Of the 213 patients enrolled, 168 were included in this study (LA, n=108; non-LA, n=60). Hypertension, coronary heart disease and carotid artery plaque were more common in the LA group, and these patients showed higher blood levels of C-reactive protein, homocysteine and triglycerides. The incidence of retinopathy was significantly increased in the LA group compared with the non-LA group, and there was a significant correlation between the severity of LA and incidence of retinopathy. Retinopathy is an independent risk factor for LA and can significantly increase the risk of LA when combined with age, coronary heart disease, C-reactive protein, carotid artery plaque or systolic pressure. Taken together, retinopathy is associated with LA in patients with anterior circulation infarcts. Retinopathy is an independent risk factor for LA and an increase the risk of LA, and thus facilitating the evaluation of LA. PMID- 27496528 TI - Pineal region schwannoma arising from the trochlear nerve. AB - Schwannomas arising from the trochlear nerve are very rare and to our knowledge, less than 35 histologically documented cases have been reported in the literature. There are no reports of a schwannoma in the pineal region. We report a 24-year-old woman who underwent a para-occipital trans-tentorial approach and gross total excision of a pineal region schwannoma arising from the trochlear nerve. This is the first such reported case. PMID- 27496529 TI - New frontiers in venous sinus stenting: Illustrative cases. AB - Idiopathic intracranial hypertension (IIH) occurs rarely, with severe patients recalcitrant to pharmacologic management often requiring cerebrospinal fluid diversion. We report two patients with variant IIH successfully treated with venous sinus stenting: 1) A 65-year-old man with severe vision loss, papilledema, and cognitive decline treated with four telescoped stents across a long, severely stenotic transverse-sigmoid system, and 2) a 58-year-old woman with headaches, vision loss, and papilledema secondary to a jugular paraganglioma causing severe jugular bulb stenosis that required contralateral venous sinus stenting. At 3 month and 1-month follow-up, respectively, ophthalmologic examinations showed vision improvement. The first patient also had improved cognition, and the second patient also had improved headaches. PMID- 27496530 TI - Effectiveness of ovarian age as the background risk for aneuploidy screening in an unselected pregnant population. AB - The aim of this study was to assess the performance of first-trimester combined screening when replacing the chronological maternal age by Anti-Mullerian hormone (AMH) and antral follicle count (AFC)-derived ovarian ages, as the background risk in trisomy risk estimation. A total of 639 pregnant women who completed first-trimester combined screening together with AMH and AFC determination were included. Trisomy risks were estimated based on three distinct 'maternal ages' as a-priori risk (chronological age, AMH- and AFC-derived ovarian age). The screening performance was assessed using three different approaches: received operator curve; detection rate and false positive rates for a fixed 1/250 threshold; and detection rates for a fixed 3% false positive rate. A non significant trend was shown for AMH-derived age for both an increased area under the curve (0.986 versus 0.979) and an increased detection rate (from 83% to 100%) for a 1/250 risk threshold. For a 3% false-positive rate, a non-significant trend for increased detection with the use of both AMH- and AFC-derived ovarian ages was observed (from 67% to 83%). These results indicate that, although ovarian derived ages seem to potentially reflect a more precise background risk for fetal trisomies, the improvement in screening performance is only residual. PMID- 27496531 TI - Bullous striae distensae. PMID- 27496532 TI - Metastatic potential to regional lymph nodes with Gleason score <=7, including tertiary pattern 5, at radical prostatectomy. AB - OBJECTIVES: To determine the risk of pelvic lymph node (LN) metastases at radical prostatectomy (RP) for Gleason score (GS) <=7: 3 + 3 = 6 (grade group [GG]1); 3 + 4 = 7 (GG2); 3 + 4 = 7 (GG2) with tertiary pattern 5 (T5); 4 + 3 = 7 (GG3); 4 + 3 = 7 (GG3) with T5, using the 2014 modified Gleason grading system and the novel GG system. MATERIALS AND METHODS: We searched our RP database to indentify cases of GS <=7 prostate cancer with simultaneous pelvic LN dissection (PLND) in the period between 2005 and 2014. Since 2005, we have graded all glomeruloid and cribriform cancer as Gleason pattern 4 and have graded mucinous adenocarcinoma based on the underlying architectural pattern, consistent with the 2014 modified Gleason grading system. All RPs were embedded in entirety, including the PLND. A total of 7 442 cases were identified, of which 73 had at least one positive LN (+LN). RESULTS: The incidence rates for regional LN metastases at RP for 3 + 3 = 6 (GG1), 3 + 4 = 7 (GG2), 3 + 4 = 7 (GG2) with T5, 4 + 3 = 7 (GG3) and 4 + 3 = 7 (GG3) with T5 were 0, 0.6, 0.4, 4.3 and 6.3%, respectively. There was a statistically significant difference in risk of +LNs at RP between the grade groups, as defined by the novel GG system. There was no statistically significant difference in risk of +LNs at RP for men with 3 + 4 (GG2) vs 3 + 4 (GG2) with T5 and for men with 4 + 3 (GG3) vs 4 + 3 (GG3) with T5. Non-pelvic LN involvement was identified in 0.2% of all RP cases. Two patients with GS 3 + 4 = 7 with <5% pattern 4 experienced LN metastases. CONCLUSION: This study supports our previous finding that men with GS 6 (GG1) at RP have no risk of LN metastases. These findings also support the 2014 revisions to the Gleason grading system where 3 + 3 with T4 (2005 modified grading system) is now considered 3 + 4 (GG2), with a comment on percent pattern 4, because <5% pattern 4 increases the risk of LN metastases. It also supports keeping 3 + 4 (GG2) with T5 (<5% pattern 5) and 4 + 3 (GG3) with T5 with their respective grade groups, with a notation of T5 because the <5% higher grade component did not increase the risk of LN metastases within a given GG. Our findings highlight that 3 + 4 (GG2) and 4 + 3 (GG3), even with a 5% higher grade component, are distinct groups with respect to LN metastases and should not be combined under the umbrella designation of GS 7 as is often the case in the literature with the Gleason grading system. PMID- 27496533 TI - A One Health approach to antimicrobial resistance surveillance: is there a business case for it? AB - Antimicrobial resistance is a global problem of complex epidemiology, suited to a broad, integrated One Health approach. Resistant organisms exist in humans, animals, food and the environment, and the main driver of this resistance is antimicrobial usage. A One Health conceptual framework for surveillance is presented to include all of these aspects. Global and European (regional and national) surveillance systems are described, highlighting shortcomings compared with the framework. Policy decisions rely on economic and scientific evidence, so the business case for a fully integrated system is presented. The costs of integrated surveillance are offset by the costs of unchecked resistance and the benefits arising from interventions and outcomes. Current estimates focus on costs and benefits of human health outcomes. A One Health assessment includes wider societal costs of lost labour, changes in health-seeking behaviour, impacts on animal health and welfare, higher costs of animal-origin food production, and reduced consumer confidence in safety and international trade of such food. Benefits of surveillance may take years to realise and are dependent on effective and accepted interventions. Benefits, including the less tangible, such as improved synergies and efficiencies in service delivery and more timely and accurate risk identification, should also be recognised. By including these less tangible benefits to society, animal welfare, ecosystem health and resilience, together with the savings and efficiencies through shared resources and social capital-building, a stronger business case for a One Health approach to surveillance can be made. PMID- 27496534 TI - Experiences With the Providers Share Workshop Method: Abortion Worker Support and Research in Tandem. AB - Abortion providers work in an environment characterized by the stresses of the helping professions as well as by the marginalization and devaluation that accompany work in a stigmatized field. We created the Providers Share Workshop (PSW), a five-session workshop carried out at seven abortion care sites around the United States, to support workers and better understand the complexities of working in abortion care. Qualitative analysis suggests that the experience of participating in the workshop fosters connection, and that the group process creates unique data about the abortion care team. Taken together, these results show that PSW fulfills the dual role of a supportive group intervention-helping create connections and foster resilience-and a research tool, producing rich, multi-perspective narratives of the abortion provision team. This method provides useful insight into supporting abortion care workers specifically, and may also prove useful in the study and support of other stigmatized workers generally. PMID- 27496536 TI - Synapse Dysfunction of Layer V Pyramidal Neurons Precedes Neurodegeneration in a Mouse Model of TDP-43 Proteinopathies. AB - TDP-43 is a major protein component of pathological neuronal inclusions that are present in frontotemporal dementia and amyotrophic lateral sclerosis. We report that TDP-43 plays an important role in dendritic spine formation in the cortex. The density of spines on YFP+ pyramidal neurons in both the motor and somatosensory cortex of Thy1-YFP mice, increased significantly from postnatal day 30 (P30), to peak at P60, before being pruned by P90. By comparison, dendritic spine density was significantly reduced in the motor cortex of Thy1-YFP::TDP 43A315T transgenic mice prior to symptom onset (P60), and in the motor and somatosensory cortex at symptom onset (P90). Morphological spine-type analysis revealed that there was a significant impairment in the development of basal mushroom spines in the motor cortex of Thy1-YFP::TDP-43A315T mice compared to Thy1-YFP control. Furthermore, reductions in spine density corresponded to mislocalisation of TDP-43 immunoreactivity and lowered efficacy of synaptic transmission as determined by electrophysiology at P60. We conclude that mutated TDP-43 has a significant pathological effect at the dendritic spine that is associated with attenuated neural transmission. PMID- 27496535 TI - Quantitative analyses of the hepatic proteome of methylmercury-exposed Atlantic cod (Gadus morhua) suggest oxidative stress-mediated effects on cellular energy metabolism. AB - BACKGROUND: Methylmecury (MeHg) is a widely distributed environmental pollutant with considerable risk to both human health and wildlife. To gain better insight into the underlying mechanisms of MeHg-mediated toxicity, we have used label-free quantitative mass spectrometry to analyze the liver proteome of Atlantic cod (Gadus morhua) exposed in vivo to MeHg (0, 0.5, 2 mg/kg body weight) for 2 weeks. RESULTS: Out of a toltal of 1143 proteins quantified, 125 proteins were differentially regulated between MeHg-treated samples and controls. Using various bioinformatics tools, we performed gene ontology, pathway and network enrichment analysis, which indicated that proteins and pathways mainly related to energy metabolism, antioxidant defense, cytoskeleton remodeling, and protein synthesis were regulated in the hepatic proteome after MeHg exposure. Comparison with previous gene expression data strengthened these results, and further supported that MeHg predominantly affects many energy metabolism pathways, presumably through its strong induction of oxidative stress. Some enzymes known to have functionally important oxidation-sensitive cysteine residues in other animals are among the differentially regulated proteins, suggesting their modulations by MeHg induced oxidative stress. Integrated analysis of the proteomics dataset combined with previous gene expression dataset showed a more pronounced effect of MeHg on amino acid, glucose and fatty acid metabolic pathways, and suggested possible interactions of the cellular energy metabolism and antioxidant defense pathways. CONCLUSIONS: MeHg disrupts mainly redox homeostasis and energy generating metabolic pathways in cod liver. The energy pathways appear to be modulated through MeHg-induced oxidative stress, possibly mediated by oxidation sensitive enzymes. PMID- 27496537 TI - Evaluation of the New World Health Organization Case Definition of Severe Acute Respiratory Infection for Influenza Surveillance During the Peak Weeks of Two Influenza Seasons in Quebec, Canada. AB - During the peak of the 2012-2013 and 2014-2015 influenza seasons in Quebec, Canada, the sensitivity of the new World Health Organization (WHO) case definition of severe acute respiratory infection (SARI) in <5-year-old children was 65% for polymerase chain reaction-confirmed influenza and 79% for other respiratory viruses (ORVs), whereas its specificity and positive predictive value were approximately 2- and 4-fold lower for influenza than ORVs (25% vs 40% and 18% vs 76%, respectively). The use of the WHO SARI definition for influenza surveillance in children should be interpreted with caution according to the specific surveillance goals. PMID- 27496539 TI - Does the degree of linguistic experience (native versus nonnative) modulate the degree to which listeners can benefit from a delay between the onset of the maskers and the onset of the target speech? AB - Background noise has a greater adverse effect on word recognition when people are listening in their second language (L2) as opposed to their first language (L1). The present study investigates the extent to which linguistic experience affects the ability of L2 listeners to benefit from a delay between the onset of a masker and the onset of a word. In a previous study (Ben-David, Tse & Schneider, 2012), word recognition thresholds for young L1s were found to improve with the increase in the delay between the onset of a masker (either a stationary noise or a babble of voices) and the onset of a word. The investigators interpreted this result as reflecting the ability of L1 listeners to rapidly segregate the target words from a masker. Given stream segregation depends, in part, on top-down knowledge-driven processes, we might expect stream segregation to be more "sluggish" for L2 listeners than for L1 listeners, especially when the masker consists of a babble of L2 voices. In the present study, we compared the ability of native English speakers to those who had either recent or long-term immersion in English as L2, to benefit from a delay between masker onset and word onset for English words. Results show that thresholds were higher for the two L2s groups than for the L1s. However, the rate at which word recognition improved with word-onset delay was unaffected by linguistic status, both when words were presented in noise, and in babble. Hence, for young listeners, stream segregation appears to be independent of linguistic status, suggesting that bottom-up sensory mechanisms play a large role in stream segregation in this paradigm. The implications of a failure of older L1 listeners (in Ben-David et al.) to benefit from a word-onset delay when the masker is a babble of voices are discussed. PMID- 27496538 TI - Controlled exploration of the effects of conductive hearing loss on wideband acoustic immittance in human cadaveric preparations. AB - Current clinical practice cannot distinguish, with any degree of certainty, the multiple pathologies that produce conductive hearing loss in patients with an intact tympanic membrane and a well-aerated middle ear without exploratory surgery. The lack of an effective non-surgical diagnostic procedure leads to unnecessary surgery and limits the accuracy of information available during pre surgical consultations with the patient. A non-invasive measurement to determine the pathology responsible for a conductive hearing loss prior to surgery would be of great value. This work investigates the utility of wideband acoustic immittance (WAI), a non-invasive measure of middle-ear mobility, in the differential diagnosis of pathologies responsible for conductive hearing loss. We focus on determining whether power reflectance (PR), a derivative of WAI, is a possible solution to this problem. PR is a measure of the fraction of sound power reflected from the middle ear when a sound stimulus is presented to the ear canal. PR and other metrics of middle-ear performance (such as ossicular motion via laser Doppler vibrometry) were measured in well-controlled human temporal bone preparations with simulated pathologies. We report measurements before and after simulation of stapes fixation (n = 8), malleus fixation (n = 10), ossicular disarticulation (n = 10), and superior canal dehiscence (n = 8). Our results are consistent with the small set of previously published reflectance measurements made in temporal bones and patients. In this present study, these temporal bone experiments with different middle- and inner-ear pathologies were compared to the initial normal state by analyzing both WAI and ossicular motion, demonstrating that WAI can be a valuable tool in the diagnosis of conductive hearing loss. PMID- 27496540 TI - In vitro proliferation and osteogenic differentiation of human dental pulp stem cells in injectable thermo-sensitive chitosan/beta glycerophosphate/hydroxyapatite hydrogel. AB - Injectable thermo-sensitive hydrogels have a potential application in bone tissue engineering for their sensitivities and minimal invasive properties. Human dental pulp stem cells have been considered a promising tool for tissue reconstruction. The objective of this study was to investigate the proliferation and osteogenic differentiation of dental pulp stem cells in injectable thermo-sensitive chitosan/beta-glycerophosphate/hydroxyapatite hydrogel in vitro. The chitosan /beta-glycerophosphate hydrogel and chitosan/beta-glycerophosphate/hydroxyapatite hydrogel were prepared using the sol-gel method. The injectability of chitosan /beta-glycerophosphate hydrogel and chitosan/beta-glycerophosphate/hydroxyapatite hydrogel was measured using a commercial disposable syringe. Scanning electron microscopy was used to observe the inner structure of hydrogels. Then dental pulp stem cells were seeded in chitosan /beta-glycerophosphate hydrogel and chitosan/beta-glycerophosphate/hydroxyapatite hydrogel, respectively. The growth of dental pulp stem cells was periodically observed under an inverted microscope. The proliferation of dental pulp stem cells was detected by using an Alamar Blue kit, while cell apoptosis was determined by using a Live/Dead Viability/Cytotoxicity kit. The osteogenic differentiations of dental pulp stem cells in chitosan /beta-glycerophosphate hydrogel and chitosan/beta glycerophosphate/hydroxyapatite hydrogel were evaluated by alkaline phosphatase activity assay and mRNA expression of osteogenesis gene for 21 days in osteogenic medium. The results indicated that there was no significant difference between chitosan /beta-glycerophosphate hydrogel and chitosan/beta glycerophosphate/hydroxyapatite hydrogel in injectability. Cells within the chitosan/beta-glycerophosphate/hydroxyapatite hydrogel displayed a typical adherent cell morphology and rapid proliferation with high cellular viability after 14 days of culture. Dental pulp stem cells seeded in chitosan/beta glycerophosphate/hydroxyapatite hydrogels had a higher alkaline phosphatase activity and better up-regulation of gene expression levels of Runx-2, Collagen I, alkaline phosphatase and osteocalcin than in chitosan /beta-glycerophosphate hydrogels after osteogenic differentiation. These results demonstrated that the chitosan/beta-glycerophosphate/hydroxyapatite hydrogel had excellent cellular compatibility and the superiority in promoting dental pulp stem cells osteogenic differentiation in vitro, showing that the combination of dental pulp stem cells and chitosan/beta-glycerophosphate/hydroxyapatite hydrogel has the potential to be used for bone tissue engineering. PMID- 27496541 TI - Infectious disease following travel to developed regions: a snapshot of presentations to an Australian travel medicine clinic. AB - Much of the travel medicine literature focuses on travel to 'developing' regions by travellers from 'developed' regions; however literature about travel to developed regions is scarce. This article examines presentations to a travel medicine clinic over a 17-year period with illnesses resulting from travel to developed regions. From a cohort of general presentations to the clinic of 1077 patients, 85 patients acquired infections due to travel to developed regions, with a total of 99 infectious diagnoses made. This serves to highlight the risk of infectious disease even among travel to only developed regions, and the importance of travel advice in these situations. PMID- 27496542 TI - Osmotic stress adaptation of Paracoccidioides lutzii, Pb01, monitored by proteomics. AB - The ability to respond to stressful conditions is essential for most living organisms. In pathogenic organisms, this response is required for effective transition from a saprophytic lifestyle to the establishment of pathogenic interactions within a susceptible host. Hyperosmotic stress has been used as a model to study signal transduction and seems to cause many cellular adaptations, including the alteration of protein expression and cellular volume as well as size regulation. In this work, we evaluated the proteomic profile of Paracoccidioides lutzii Pb01 yeast cells during osmotic stress induced by potassium chloride. We performed a high accuracy proteomic technique (NanoUPLC MS(E)) to identify differentially expressed proteins during osmotic shock. The data describe an osmoadaptative response of this fungus when subjected to this treatment. Proteins involved in the synthesis of cell wall components were modulated, which suggested cell wall remodeling. In addition, alterations in the energy metabolism were observed. Furthermore, proteins involved in amino acid metabolism and hydrogen peroxide detoxification were modulated during osmotic stress. Our study suggests that P. lutzii Pb01. presents a vast osmoadaptative response that is composed of different proteins that act together to minimize the effects caused by osmotic stress. PMID- 27496543 TI - Application of recombinant antigen 5 allergens from seven allergy-relevant Hymenoptera species in diagnostics. AB - BACKGROUND: Hymenoptera stings can cause severe anaphylaxis in untreated venom allergic patients. A correct diagnosis regarding the relevant species for immunotherapy is often hampered by clinically irrelevant cross-reactivity. In vespid venom allergy, cross-reactivity between venoms of different species can be a diagnostic challenge. To address immunological IgE cross-reactivity on molecular level, seven recombinant antigens 5 of the most important Vespoidea groups were assessed by different diagnostic setups. METHODS: The antigens 5 of yellow jackets, hornets, European and American paper wasps, fire ants, white faced hornets, and Polybia wasps were recombinantly produced in insect cells, immunologically and structurally characterized, and their sIgE reactivity assessed by ImmunoCAP, ELISA, cross-inhibition, and basophil activation test (BAT) in patients with yellow jacket or Polistes venom allergy of two European geographical areas. RESULTS: All recombinant allergens were correctly folded and structural models and patient reactivity profiles suggested the presence of conserved and unique B-cell epitopes. All antigens 5 showed extensive cross reactivity in sIgE analyses, inhibition assays, and BAT. This cross-reactivity was more pronounced in ImmunoCAP measurements with venom extracts than in sIgE analyses with recombinant antigens 5. Dose-response curves with the allergens in BAT allowed a differentiated individual dissection of relevant sensitization. CONCLUSIONS: Due to extensive cross-reactivity in various diagnostic settings, antigens 5 are inappropriate markers for differential sIgE diagnostics in vespid venom allergy. However, the newly available antigens 5 from further vespid species and the combination of recombinant allergen-based sIgE measurements with BAT represents a practicable way to diagnose clinically relevant sensitization in vespid venom allergy. PMID- 27496544 TI - Cultural Disparities in the Use of Prescription and Nonprescription Medications Among Midlife Women in Israel. AB - The study aimed to examine differences in medication use among midlife women from different cultural origins and to identify socio-demographic, health, and lifestyle characteristics associated with prescribed and non-prescribed medication use. Face-to-face interviews with women aged 45-64 years were conducted during 2004-2006 within three population groups: long-term Jewish residents (LTJR), immigrants from the former Soviet Union after 1989, and Arab women. The survey instrument included current use of medications and way of purchasing (with/without prescription). The level of prescribed and non prescribed medication use was categorized as taking none, taking 1-2, and taking 3 or more medications. The rates of medication use were 59.5% for prescribed medication and 47% for non-prescribed medications. Differences between the minority groups and LTJR were observed mainly for cardiovascular, vitamins, supplements, and hormonal medications. The analyses showed significantly lower use of prescribed medications among immigrants and of non-prescribed medications among Arab women after taking into account health and socioeconomic indicators. Increased use of prescribed and non-prescribed medications was associated with worse health status and older age. Education was associated with increased use of non-prescribed medications. The disparities in pharmaceutical care may be linked to barriers in access to health care and to cultural preferences among minorities. PMID- 27496545 TI - Experiencing Unmet Medical Needs or Delayed Care Because of Cost: Foreign-Born Adults in the U.S. by Region of Birth. AB - Healthy People 2020 in the United States highlights timely access to necessary health care as a major factor that can reduce health-related disparities. This study examined the prevalence of delaying/missing necessary health care because of cost among foreign-born adults (26+ years old) in the United States by their region of origin, after controlling for geographic clustering at the county and state levels. METHODS: Using the pooled 2007-2011 National Health Interview Survey and linked state/county-level data, this study analyzed data on 61,732 foreign-born adults from nine regions of birth. Three-level multilevel modeling (state > county > individual) was conducted. The age-adjusted percentages of foreign-born adults who delayed/missed necessary health care because of cost varied by region of birth, ranging from 7.0% (Southeast Asia) and 11.9% (Europe) to 15.5% (Mexico/Central America/Caribbean) and 16.7% (the Middle East). However, after controlling for geographic clustering and other individual-level covariates (e.g., insurance), adults from Mexico/Central America/Caribbean were less likely to delay or not receive necessary care compared to their counterparts from all other parts of the world except for those from Asian regions. This study implies that disparities can be reduced if some known risk factors (e.g., insurance) are improved among foreign-born adults. PMID- 27496546 TI - Trajectory analyses of sickness absence among industrial and municipal employees. AB - Background: Compared with the public sector, the private sector is more susceptible to changes in the economic environment and associated threats of downsizing, outsourcing and transfers of production. This might be assumed to be associated with more restrictive sickness absence practices. Aims: To investigate whether this difference is reflected in higher sickness absence rates in the public sector and to explore the potential of trajectory analysis in researching such absences. Methods: The sample consisted of industrial and municipal employees. Latent groups of differential sickness absence during a 6-year study period were searched with a two-response trajectory analysis that jointly captured the spells and the days. Multinomial logistic regressions were used to assess associations of the labour market sector with the set of trajectories obtained. Results: There were 2207 industrial and 3477 municipal employees in the study group. The analysis assigned the employees to three trajectory groups, the 'low-level', 'middle-range' and 'high-range' groups. The relative risk ratios for the middle-range and the high-range trajectories of public sector employees were not higher after controlling for age, gender and occupational. Conclusions: In this study, the labour market sector was not a major independent determinant of sickness absence practices. Trajectory analysis can be recommended as a way to determine differential absence practices. The trajectory approach might help occupational health services to identify more accurately the employees who need support to maintain their work ability. PMID- 27496547 TI - The effect of multimorbidity on sickness absence by specific diagnoses. AB - Background: As the world's population ages, the prevalence of multiple chronic and non-chronic health-related conditions is increasing. Research on multimorbidity, the co-occurrence of two or more health-related conditions, has mainly involved patient and older populations. Its effect in working populations, presumably younger and healthier, is not well known but could conceivably affect sickness absence (SA) and ability to return to work. Aims: To examine the effect of multimorbidity on the incidence and duration of SA episodes by frequent diagnostic groups. Methods: A prospective study (in 2006-2008) of workers in Spain. Information on health-related conditions was gathered with a standardized questionnaire and used to construct a sex-specific multidimensional multimorbidity score (MDMS). In order to estimate the effect of MDMS on incidence and duration of SA episodes due to cardiovascular diseases (CVD), musculoskeletal disorders (MSD) and mental health disorders (MHD), we fitted Cox models adjusted by age, occupational social class and number of prior SA episodes for both sexes. Results: The study population was 372370. Men with high MDMS showed a trend towards higher incidence risk for SA due to CVD and MSD [adjusted hazard ratio (aHR) = 2.03; 95% confidence interval (CI) 1.48-2.78 and aHR = 1.20; 95% CI 1.01 1.43, respectively]. Women showed a similar trend for MSD, but MHD had the strongest association (aHR = 4.78; 95% CI 1.97-11.62) for high MDMS. In both sexes, the effect of MDMS was strongest among those without a prior SA. No consistent associations with SA duration were observed. Conclusions: Multimorbidity increased the risk of incident musculoskeletal, mental and cardiovascular SA episodes but not their duration. PMID- 27496548 TI - Two insulin-like peptides differentially regulate malaria parasite infection in the mosquito through effects on intermediary metabolism. AB - Insulin-like peptides (ILPs) play important roles in growth and metabolic homeostasis, but have also emerged as key regulators of stress responses and immunity in a variety of vertebrates and invertebrates. Furthermore, a growing literature suggests that insulin signaling-dependent metabolic provisioning can influence host responses to infection and affect infection outcomes. In line with these studies, we previously showed that knockdown of either of two closely related, infection-induced ILPs, ILP3 and ILP4, in the mosquito Anopheles stephensi decreased infection with the human malaria parasite Plasmodium falciparum through kinetically distinct effects on parasite death. However, the precise mechanisms by which ILP3 and ILP4 control the response to infection remained unknown. To address this knowledge gap, we used a complementary approach of direct ILP supplementation into the blood meal to further define ILP-specific effects on mosquito biology and parasite infection. Notably, we observed that feeding resulted in differential effects of ILP3 and ILP4 on blood-feeding behavior and P. falciparum development. These effects depended on ILP-specific regulation of intermediary metabolism in the mosquito midgut, suggesting a major contribution of ILP-dependent metabolic shifts to the regulation of infection resistance and parasite transmission. Accordingly, our data implicate endogenous ILP signaling in balancing intermediary metabolism for the host response to infection, affirming this emerging tenet in host-pathogen interactions with novel insights from a system of significant public health importance. PMID- 27496549 TI - Two transgenic mouse models for beta-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations. AB - Succinate-CoA ligase (SUCL) is a heterodimer enzyme composed of Suclg1 alpha subunit and a substrate-specific Sucla2 or Suclg2 beta-subunit yielding ATP or GTP, respectively. In humans, the deficiency of this enzyme leads to encephalomyopathy with or without methylmalonyl aciduria, in addition to resulting in mitochondrial DNA depletion. We generated mice lacking either one Sucla2 or Suclg2 allele. Sucla2 heterozygote mice exhibited tissue- and age dependent decreases in Sucla2 expression associated with decreases in ATP-forming activity, but rebound increases in cardiac Suclg2 expression and GTP-forming activity. Bioenergetic parameters including substrate-level phosphorylation (SLP) were not different between wild-type and Sucla2 heterozygote mice unless a submaximal pharmacological inhibition of SUCL was concomitantly present. mtDNA contents were moderately decreased, but blood carnitine esters were significantly elevated. Suclg2 heterozygote mice exhibited decreases in Suclg2 expression but no rebound increases in Sucla2 expression or changes in bioenergetic parameters. Surprisingly, deletion of one Suclg2 allele in Sucla2 heterozygote mice still led to a rebound but protracted increase in Suclg2 expression, yielding double heterozygote mice with no alterations in GTP-forming activity or SLP, but more pronounced changes in mtDNA content and blood carnitine esters, and an increase in succinate dehydrogenase activity. We conclude that a partial reduction in Sucla2 elicits rebound increases in Suclg2 expression, which is sufficiently dominant to overcome even a concomitant deletion of one Suclg2 allele, pleiotropically affecting metabolic pathways associated with SUCL. These results as well as the availability of the transgenic mouse colonies will be of value in understanding SUCL deficiency. PMID- 27496551 TI - Improved Prediction of Sudden Cardiac Death Risk: Staying Within the Echocardiogram but Extending Beyond the Ejection Fraction. PMID- 27496550 TI - Echocardiographic Predictors of Sudden Cardiac Death: The Atherosclerosis Risk in Communities Study and Cardiovascular Health Study. AB - BACKGROUND: This study assessed the echocardiographic predictors of sudden cardiac death (SCD) within 2 population-based cohorts. METHODS AND RESULTS: Echocardiograms were obtained on 2383 participants (1993-1995) from the ARIC study (Atherosclerosis Risk in Communities; 100% black) and 5366 participants (1987-1989 and 1994-1995) from the CHS (Cardiovascular Health Study). The main outcome was physician-adjudicated SCD. We used Cox proportional-hazards models with incident coronary heart disease and heart failure as time-dependent covariates to assess the association between echocardiographic variables and SCD, adjusting for Framingham risk score variables, coronary heart disease, and renal function. Cohort-specific results were meta-analyzed. During a median follow-up of 7.3 and 13.1 years, 44 ARIC study participants and 275 CHS participants had SCD, respectively. In the meta-analyzed results, the adjusted hazard ratios (95% confidence intervals) for predictors of SCD were 3.07 (2.29-4.11) for reduced left ventricular ejection fraction; 1.85 (1.36-2.52) for mitral annular calcification; 1.64 (1.07-2.51) for mitral E/A >1.5, and 1.52 (1.14-2.02) for mitral E/A <0.7 (versus mitral E/A 0.7-1.5); 1.30 (1.15-1.48) per 1 SD increase in left ventricular mass; and 1.15 (1.02-1.30) per 1 SD increase in left atrial diameter. A receiver-operating characteristic model for prediction of SCD using Framingham risk score variables had a C statistic of 0.61 for ARIC study and 0.67 for CHS; the full multivariable model including all echocardiographic variables had a C statistic of 0.76 for ARIC study and 0.74 for CHS. CONCLUSIONS: In addition to reduced left ventricular ejection fraction, we identified other echocardiographic-derived variables predictive for SCD that provided incremental value compared with clinical risk factors. PMID- 27496552 TI - Cerebral blood flow in small vessel disease: A systematic review and meta analysis. AB - White matter hyperintensities are frequent on neuroimaging of older people and are a key feature of cerebral small vessel disease. They are commonly attributed to chronic hypoperfusion, although whether low cerebral blood flow is cause or effect is unclear. We systematically reviewed studies that assessed cerebral blood flow in small vessel disease patients, performed meta-analysis and sensitivity analysis of potential confounders. Thirty-eight studies (n = 4006) met the inclusion criteria, including four longitudinal and 34 cross-sectional studies. Most cerebral blood flow data were from grey matter. Twenty-four cross sectional studies (n = 1161) were meta-analysed, showing that cerebral blood flow was lower in subjects with more white matter hyperintensity, globally and in most grey and white matter regions (e.g. mean global cerebral blood flow: standardised mean difference-0.71, 95% CI -1.12, -0.30). These cerebral blood flow differences were attenuated by excluding studies in dementia or that lacked age-matching. Four longitudinal studies (n = 1079) gave differing results, e.g., more baseline white matter hyperintensity predated falling cerebral blood flow (3.9 years, n = 575); cerebral blood flow was low in regions that developed white matter hyperintensity (1.5 years, n = 40). Cerebral blood flow is lower in subjects with more white matter hyperintensity cross-sectionally, but evidence for falling cerebral blood flow predating increasing white matter hyperintensity is conflicting. Future studies should be longitudinal, obtain more white matter data, use better age-correction and stratify by clinical diagnosis. PMID- 27496554 TI - Greenebaum, Stanford Earn Comprehensive Status. AB - The NCI has granted Comprehensive Cancer Center status to the University of Maryland's Greenebaum Cancer Center in Baltimore and to the Stanford Cancer Institute in Palo Alto, CA. They join 45 other cancer centers in achieving this distinction. The honor recognizes the centers' leadership in cancer research, education, and clinical care. PMID- 27496553 TI - Carbogen-induced increases in tumor oxygenation depend on the vascular status of the tumor: A multiparametric MRI study in two rat glioblastoma models. AB - The alleviation of hypoxia in glioblastoma with carbogen to improve treatment has met with limited success. Our hypothesis is that the eventual benefits of carbogen depend on the capacity for vasodilation. We examined, with MRI, changes in fractional cerebral blood volume, blood oxygen saturation, and blood oxygenation level dependent signals in response to carbogen. The analyses were performed in two xenograft models of glioma (U87 and U251) recognized to have different vascular patterns. Carbogen increased fractional cerebral blood volume, blood oxygen saturation, and blood oxygenation level dependent signals in contralateral tissues. In the tumor core and peritumoral regions, changes were dependent on the capacity to vasodilate rather than on resting fractional cerebral blood volume. In the highly vascularised U87 tumor, carbogen induced a greater increase in fractional cerebral blood volume and blood oxygen saturation in comparison to the less vascularized U251 tumor. The blood oxygenation level dependent signal revealed a delayed response in U251 tumors relative to the contralateral tissue. Additionally, we highlight the considerable heterogeneity of fractional cerebral blood volume, blood oxygen saturation, and blood oxygenation level dependent within U251 tumor in which multiple compartments co exist (tumor core, rim and peritumoral regions). Finally, our study underlines the complexity of the flow/metabolism interactions in different models of glioblastoma. These irregularities should be taken into account in order to palliate intratumoral hypoxia in clinical trials. PMID- 27496560 TI - Neuropsychiatric disorders in patients with neurocysticercosis. AB - INTRODUCTION: The purpose of this study was to explore the presence of neuropsychiatric disorders in patients with neurocysticercosis (NCC). METHOD: Patients with untreated NCC (n = 45) and healthy controls (n = 45) underwent psychiatric and neuropsychological assessments. RESULTS: The majority of patients in the NCC group (64.4%) had at least 1 psychiatric diagnosis, compared with a minority in the control group (31.1%). The frequency of neurocognitive disorders, and particularly dementia (major neurocognitive disorder), was significantly higher in the group of patients with NCC. DISCUSSION: This study confirms the relationship between NCC and cognitive disorders. PMID- 27496559 TI - Angiotensin type 2 receptor null mice express reduced levels of renal angiotensin II type 2 receptor/angiotensin (1-7)/Mas receptor and exhibit greater high-fat diet-induced kidney injury. AB - INTRODUCTION: Renin-angiotensin system (RAS) components exert diverse physiological functions and have been sub-grouped into deleterious angiotensin converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin type 1 receptor (AT1R) and protective ACE2/angiotensin (1-7) (Ang-(1-7))/Mas receptor (MasR) axes. We have reported that chronic activation of angiotensin type 2 receptor (AT2R) alters RAS components and provides protection against obesity-related kidney injury. MATERIALS AND METHODS: We utilized AT2R knockout (AT2KO) mice in this study and evaluated the renal expression of various RAS components and examined the renal injury after placing these mice on high fat diet (HFD) for 16 weeks. RESULTS: The cortical ACE2 activity and MasR expression were significantly decreased in AT2KO mice compared to wild type (WT) mice. LC/MS analysis revealed an increase in renal Ang II levels and a decrease in Ang-(1-7) levels in AT2KO mice. Cortical expression of ACE and AT1R was increased but renin activity remained unchanged in AT2KO compared with WT mice. WT mice fed HFD exhibited increased systolic blood pressure, higher indices of kidney injury, mesangial matrix expansion score, and microalbuminuria, which were further increased in AT2KO mice. CONCLUSION: This study suggests that deletion of AT2R decreases the expression of the beneficial ACE2/Ang-(1-7)/MasR and increases the deleterious ACE/Ang II/AT1R axis of the renal RAS in mice. Further, AT2KO mice are more susceptible to HFD-induced renal injury. PMID- 27496561 TI - Specific oral tolerance induction in childhood. AB - Food allergy continues to be a significant public health concern for which there are no approved treatments and management strategies primarily include allergen avoidance and pharmacological measures for accidental exposures. Food allergy is thought to result from either a failure to establish oral tolerance or the breakdown of existing oral tolerance, and therefore, experimental preventative and treatment strategies are now aimed at inducing specific oral tolerance. This may occur in infancy prior to the development of food allergy through the optimal timing of dietary exposure (primary oral tolerance induction) or as a treatment for established food allergy through oral immunotherapy (secondary oral tolerance induction). Trials examining the effectiveness of early dietary allergen exposure to prevent food allergy have yielded promising results for peanut allergy but not so for other allergens, although the results of several trials are yet to be published. Although infant feeding guidelines no longer advise to avoid allergenic foods and exposure to food allergens orally is an important step in inducing food tolerance by the immune system, evidence regarding the optimal timing, dose and form of these foods into the infant's diet is lacking. Likewise, oral immunotherapy trials appear promising for inducing desensitization; however, the long-term efficacy in achieving sustained desensitization and optimal protocols to achieve this is unknown. More research is needed in this emerging field. PMID- 27496562 TI - Characterization of the response of taurine protons to PRESS at 9.4 T for Resolving choline and Determining taurine T2. AB - Point-resolved spectroscopy (PRESS), characterized by two TEs (TE1 and TE2 ), can be employed to perform animal magnetic resonance spectroscopy (MRS) studies at 9.4 T. Taurine (Tau) and choline (Cho) are relevant metabolites that can be measured by MRS. In this work, the response of the J-coupled protons of Tau as a function of PRESS TE1 and TE2 was characterized at 9.4 T to achieve two objectives. The first was to determine two TE1 and TE2 combinations that could be used to obtain T2 -corrected measures of Tau (3.42 ppm) that were minimally influenced by J coupling. The second was to exploit the Tau J coupling to find a timing combination that minimized the 3.25-ppm Tau signal to enable the Cho (3.22 ppm) resonance to be resolved from the overlapping Tau signal. The response of Tau protons was investigated both numerically and experimentally. It was numerically determined that the timings {TE1 , TE2 } = {17 ms, 10 ms} and {TE1 , TE2 } = {80 ms, 70 ms} yielded similar 3.42-ppm Tau resonance areas (5% difference), rendering them suitable for Tau T2 determination. {TE1 , TE2 } = {25 ms, 50 ms} was found to yield minimal 3.25-ppm Tau signal, reducing its interference with Cho. The efficacy of the timings was demonstrated on phantom solutions and in vivo in four Sprague Dawley rats. LCModel was employed to analyse the in vivo spectra and Tau T2 values were estimated by fitting the Tau peak areas obtained with {TE1 , TE2 } = {17 ms, 10 ms} and {TE1 , TE2 } = {80 ms, 70 ms} to a monoexponentially decaying function. An average Tau T2 of 106 ms (standard deviation, 12 ms) was obtained. LCModel analysis of rat spectra obtained with {TE1 , TE2 } = {25 ms, 50 ms} demonstrated negligible levels of Tau signal, compared with that obtained with short TE. PMID- 27496563 TI - Chronic perfluorooctanesulphonic acid (PFOS) exposure produces estrogenic effects in zebrafish. AB - Perfluorooctanesulphonic acid (PFOS) is a ubiquitous contaminant in the aquatic environment and our earlier studies demonstrated that chronic PFOS exposures lead to a female-biased sex ratio and decreased sperm quality in male zebrafish. The underlying mechanism for these reproductive effects is unknown. In the present study, 8 h post-fertilization (hpf) zebrafish were exposed to PFOS at 250 MUg/L for 5 months, and the levels of sex hormones, expression of sex determination related genes, and histological and ultrastructural changes of gonads were fully characterized. During the sex differentiation period, we observed elevated estradiol (E2) and decreased testosterone (T) levels in whole tissue homogenates from PFOS exposed juveniles. In fully mature adult male fish, serum E2 levels were slightly increased, however, the estrogen receptor alpha (esr1) was significantly elevated in PFOS treated male gonads. Histological and electron microscopic examinations revealed structural changes in the gonads of PFOS exposed male and female adult zebrafish. In summary, chronic PFOS exposure disrupts sex hormone level and related gene expression and impairs gonadal development, which may contribute to the previously reported PFOS reproductive toxicity. PMID- 27496564 TI - More than 500 million Chinese urban residents (14% of the global urban population) are imperiled by fine particulate hazard. AB - China's urbanization and the subsequent public vulnerability to degenerated environment is important to global public health. Among the environmental problems, fine particulate (PM2.5) pollution has become a serious hazard in rapidly urbanizing China. However, quantitative information remains inadequate. We thus collected PM2.5 concentrations and population census records, to illustrate the spatial patterns and changes in the PM2.5 hazard levels in China, and to quantify public vulnerability to the hazard during 2000-2010, following the air quality standards of World Health Organization. We found that 28% (2.72 million km2) of China's territory, including 78% of cities (154 cities) with a population of >1 million, was exposed to PM2.5 hazard in 2010; a 15% increase (1.47 million km2) from 2000 to 2010. The hazards potentially impacted the health of 72% of the total population (942 million) in 2010, including 70% of the young (206 million) and 76% of the old (71 million). This was a significant increase from the 42% of total the population (279 million) exposed in 2000. Of the total urban residents, 76% (501 million) were affected in 2010. Along with PM2.5 concentration increase, massive number of rural to urban migration also contributed greatly to China's urban public health vulnerability. PMID- 27496565 TI - Preparation and preliminary characterization of recombinant neurolysin for in vivo studies. AB - The goal of this study was to produce milligram quantities of pure, catalytically active, endotoxin-free recombinant neurolysin (rNln) in standard laboratory conditions for use as a research tool. To this end, we transformed E. coli cells with a plasmid construct for polyhistidine-tagged rNln, selected a high expressing clone and determined the optimal time-point for translation of rNln. rNln was purified to homogeneity from the soluble pool of the cell lysate using Ni-NTA affinity and size-exclusion chromatography, followed by removal of endotoxins. Using this protocol ~3mg pure, catalytically active and nearly endotoxin-free (~0.003EU/MUg protein) rNln was reproducibly obtained from 1l of culture. Lack of cytotoxicity of rNln preparation was documented in cultured mouse cells, whereas stability in whole mouse blood. Intraperitonealy administered rNln in mice reached the systemic circulation in intact and enzymatically active form with Tmax of 1h and T1/2 of ~30min. Administration of rNln (2 and 10mg/kg) did not alter arterial blood pressure, heart rate, body temperature and blood glucose levels in mice. These studies demonstrate that the rNln preparation is suitable for cell culture and in vivo studies and can serve as a research tool to investigate the (patho)physiological function of this peptidase. PMID- 27496566 TI - An omics approach to rational feed: Enhancing growth in CHO cultures with NMR metabolomics and 2D-DIGE proteomics. AB - Expression of recombinant proteins exerts stress on cell culture systems, affecting the expression of endogenous proteins, and contributing to the depletion of nutrients and accumulation of waste metabolites. In this work, 2D DIGE proteomics was employed to analyze differential expression of proteins following stable transfection of a Chinese Hamster Ovary (CHO) cell line to constitutively express a heavy-chain monoclonal antibody. Thirty-four proteins of significant differential expression were identified and cross-referenced with cellular functions and metabolic pathways to identify points of cell stress. Subsequently, 1D-(1)H NMR metabolomics experiments analyzed cultures to observe nutrient depletion and waste metabolite accumulations to further examine these cell stresses and pathways. From among fifty metabolites tracked in time-course, eight were observed to be completely depleted from the production media, including: glucose, glutamine, proline, serine, cystine, asparagine, choline, and hypoxanthine, while twenty-three excreted metabolites were also observed to accumulate. The differentially expressed proteins, as well as the nutrient depletion and accumulation of these metabolites corresponded with upregulated pathways and cell systems related to anaplerotic TCA-replenishment, NADH/NADPH replenishment, tetrahydrofolate cycle C1 cofactor conversions, limitations to lipid synthesis, and redox modulation. A nutrient cocktail was assembled to improve the growth medium and alleviate these cell stresses to achieve a ~75% improvement to peak cell densities. PMID- 27496570 TI - [About a case of uterine per-partum rupture, 37months after resection of a rectovaginal endometriosis nodule]. AB - Endometriosis is a common condition in women, whose main repercussions are painful symptoms. In addition, it was shown that endometriosis was a major cause of infertility and various obstetric complications could be related to this pathology. Uterine rupture is a rare but serious complication whose incidence tends to decrease with the screening of women at risk, however, its fetal, maternal morbidity and mortality causes remains important. We were confronted with a case of posterior uterine rupture in a patient of 36 years, primipare term exceeded in immediate postpartum period. The patient's primary antecedent of uterine surgery torus was responsible for infertility endometriosis. The outcome was favorable for the mother, after a surgical treatment by laparotomy, and for the child. In the literature, two cases have been reported of uterine rupture after endometriosis surgery, which is why we found it interesting to report this rare case. Given the increase in surgical management of this disease, it seems relevant to ask whether, in the future, we should be more vigilant in monitoring pregnancy for these women. PMID- 27496568 TI - Exosomal MicroRNAs Derived From Umbilical Mesenchymal Stem Cells Inhibit Hepatitis C Virus Infection. AB - : Hepatitis C virus (HCV) is a significant global public health problem, causing more than 350,000 deaths every year. Although the development of direct-acting antivirals has improved the sustained virological response rate in HCV patients, novel anti-HCV agents with higher efficacy as well as better tolerance and cheaper production costs are still urgently needed. Cell-based therapy, especially its unique and strong paracrine ability to transfer information to other cells via extracellular vesicles such as exosomes, has become one of the most popular therapeutic methods in recent years. In our study, exosomes secreted from umbilical mesenchymal stem cells (uMSCs), which are widely used in regenerative medicine, inhibited HCV infection in vitro, especially viral replication, with low cell toxicity. Our analysis revealed that microRNAs (miRNAs) from uMSC-derived exosomes (uMSC-Exo) had their unique expression profiles, and these functional miRNAs, mainly represented by let-7f, miR-145, miR 199a, and miR-221 released from uMSC-Exo, largely contributed to the suppression of HCV RNA replication. These four miRNAs possessed binding sites in HCV RNA as demonstrated by the target prediction algorithm. In addition, uMSC-Exo therapy showed synergistic effect when combined with U.S. Food and Drug Administration approved interferon-alpha or telaprevir, enhancing their anti-HCV ability and thus improving the clinical significance of these regenerative substances for future application as optimal adjuvants of anti-HCV therapy. SIGNIFICANCE: This work reported, for the first time, the identification of stem cell-derived exosomes of antiviral activity. Umbilical mesenchymal stem cell-secreted exosomes inhibited hepatitis C virus infection through transporting a mixture of microRNAs complementing the viral genomes to the host cells. This finding provides insights and prospects for physiologically secreted substances for antiviral therapy. PMID- 27496571 TI - [Does the paper speed in fetal heart monitoring during labour influence the variability in the interpretation by professionals?] AB - OBJECTIVE: Assessing inter- and intra- observer agreement in the reading of fetal heart rate (FHR) between two different paper speeds (1 and 2cm/min) using FIGO classification. MATERIAL AND METHODS: Single-centre experimental study consisting in reading 60minutes FHR tracings by six readers (3 midwives and 3 obstetricians) during 1cm and 2cm/min sessions within a period of three weeks. The reading guideline was based on FIGO classification. Inter- and intra-observer agreement was assessed thanks to Kappa coefficient (K) and percentage of agreement (PA) using the classification of FHR tracings drawn up by readers. RESULTS: Intra observer agreement reached 60% between the two paper speeds, and PA ranged from 48 to 67%. Inter-observer agreement was poor to moderate (K=0.42 for 1cm/min sessions and K=0.38 for 2cm/min sessions). Inter-observer agreement was significantly higher for normal tracings (PA ranged from 55.2% for 2cm/min sessions to 57.4% for 1cm/min sessions). The preterminal category had the lowest concordance rates (PA=19% for 1cm/min sessions and 20, 7% for 2cm/min sessions). CONCLUSION: This study did not highlight significant differences in intra- and inter-observer variability between the two FHR paper speeds. The 1cm/min paper speed, which is commonly used in France, is more economical and gives a better bedside overview of FHR. Therefore, it should be recommended. PMID- 27496572 TI - Microglial role in the development of chronic pain. AB - PURPOSE OF REVIEW: The review aims to present the latest research into microglia and their role in pain. RECENT FINDINGS: Microglia affect sex and age-dependent differences in pain. The various microglial phenotypes make their involvement in pain more complex but provide more potential as pain modulators. SUMMARY: Glial cells, composed of microglia, astrocytes, and oligodendrocytes, outnumber neurons in the central nervous system. The crosstalk between these cells and neurons is now established as participating in the development of chronic pain. There has been a great advance in the description of microglia reactivity from pro to anti inflammatory phenotypes. The modulation of these phenotypes could be a potential target for pain therapy. Recently, different microglial reactivity between man and woman and between neonates and adults, in response to nerve injury were described, which could explain some of the sex differences in pain sensitivity and the absence of neuropathic pain development in neonates. Clinical trials using microglia as a target have been carried out in various neurological diseases and pain, with limited efficacy in the latter, but there are nonetheless, indications that with some improvement in study strategies microglia could be a future target for pain control. PMID- 27496573 TI - A systematic review and meta-analysis of randomised controlled trials of treatments for clozapine-induced obesity and metabolic syndrome. AB - Metabolic complications are commonly found in people treated with clozapine. Reviews on the management of this problem have generally drawn conclusions by grouping different types of studies involving patients treated with various different antipsychotics. We carried out a systematic review and meta-analysis of pharmacological and non-pharmacological treatments for clozapine-induced obesity or metabolic syndrome. Two researchers independently searched PubMed and Embase for randomised controlled trials (RCTs) of treatments for clozapine-induced obesity or metabolic syndrome. All other types of studies were excluded. We only included RCTs where more than 50% of participants were taking clozapine. We identified 15 RCTs. Effective pharmacological treatments for clozapine-induced obesity and metabolic syndrome include metformin, aripiprazole, and Orlistat (in men only). Meta-analysis of three studies showed a robust effect of metformin in reducing body mass index and waist circumference but no effects on blood glucose, triglyceride levels, or HDL levels. In addition, there is limited evidence for combined calorie restriction and exercise as a non-pharmacological alternative for the treatment of clozapine-induced obesity, but only in an in-patient setting. Rosiglitazone, topiramate, sibutramine, phenylpropanolamine, modafinil, and atomoxetine have not shown to be beneficial, despite reports of efficacy in other populations treated with different antipsychotics. We conclude that randomised-controlled trial data support the use of metformin, aripiprazole, and Orlistat (in men only) for treating clozapine-induced obesity. Calorie restriction in combination with an exercise programme may be effective as a non pharmacological alternative. Findings from trials in different populations should not be extrapolated to people being treated with clozapine. PMID- 27496574 TI - Anticipation: Beyond synthetic biology and cognitive robotics. AB - The aim of this paper is to propose that current robotic technologies cannot have intentional states any more than is feasible within the sensorimotor variant of embodied cognition. It argues that anticipation is an emerging concept that can provide a bridge between both the deepest philosophical theories about the nature of life and cognition and the empirical biological and cognitive sciences steeped in reductionist and Newtonian conceptions of causality. The paper advocates that in order to move forward, cognitive robotics needs to embrace new platforms and a conceptual framework that will enable it to pursue, in a meaningful way, questions about autonomy and purposeful behaviour. We suggest that hybrid systems, part robotic and part cultures of neurones, offer experimental platforms where different dimensions of enactivism (sensorimotor, constitutive foundations of biological autonomy, including anticipation), and their relative contributions to cognition, can be investigated in an integrated way. A careful progression, mindful to the deep philosophical concerns but also respecting empirical evidence, will ultimately lead towards unifying theoretical and empirical biological sciences and may offer advancement where reductionist sciences have been so far faltering. PMID- 27496575 TI - Cyst-like lesion in mandibular coronoid process: an unusual location. PMID- 27496576 TI - Biologic and clinical aspects of integration of different bone substitutes in oral surgery: a literature review. AB - Many bone substitutes have been proposed for bone regeneration, and researchers have focused on the interactions occurring between grafts and host tissue, as the biologic response of host tissue is related to the origin of the biomaterial. Bone substitutes used in oral and maxillofacial surgery could be categorized according to their biologic origin and source as autologous bone graft when obtained from the same individual receiving the graft; homologous bone graft, or allograft, when harvested from an individual other than the one receiving the graft; animal-derived heterologous bone graft, or xenograft, when derived from a species other than human; and alloplastic graft, made of bone substitute of synthetic origin. The aim of this review is to describe the most commonly used bone substitutes, according to their origin, and to focus on the biologic events that ultimately lead to the integration of a biomaterial with the host tissue. PMID- 27496578 TI - Follow-up of oral cancer patients: three uneventful years may be enough. AB - OBJECTIVE: To explore the possibility of shortening the length of follow-up from 5 to 3 years in patients who have undergone curative treatment of an oral squamous cell carcinoma. STUDY DESIGN: The medical records of 225 patients who had undergone initial curative treatment at the VU University Medical Center in Amsterdam, the Netherlands, between 2004 and 2009 were analyzed. RESULTS: In 96 patients (42.7%) a secondary event occurred. Eighty-six percent of the secondary events were detected within 3 years. In the fourth and fifth years, 14% of the secondary events were found, consisting mainly of second primary tumors. CONCLUSIONS: Most secondary events occurred within the first 3 years of follow up. Therefore, the case can be made for an altered regimen of follow-up beyond 3 years based on certain risk factors unique to the patient as well as the patient's ability to adequately report symptoms that may be associated with recurrent disease. PMID- 27496577 TI - Intramuscular botulinum toxin injection additional to arthrocentesis in the management of temporomandibular joint pain. AB - OBJECTIVE: The aim of this study was to compare the effect of intramuscular injection of botulinum toxin (BTX-A) as an adjunct to arthrocentesis with the effect of BTX-A injections alone in the treatment of temporomandibular joint disorders (TMDs) with masticatory muscles tension. STUDY DESIGN: The clinical study included 20 TMD patients divided into 2 groups. The influence of daily activities on pain in the temporomandibular joint (TMJ) area was evaluated in both groups using the rating scale by List and Helkimo. Range of maximal interincisial opening (MIO) and joint pain as measured by the visual analogue scale (VAS) were examined to determine the clinical efficiency of the procedures before and after treatment. Group A consisted of 12 patients; they were treated with arthrocentesis and BTX-A injections in the temporal and masseter muscles. Group B consisted of 8 patients; they had only BTX-A injections in the same muscles as mentioned. RESULTS: In group A, VAS decreased significantly (P = .005), and MIO improved significantly (P < .005). CONCLUSIONS: Arthrocentesis with BTX-A seems to affect the clinical outcomes with regard to MIO and VAS compared with the results when BTX-A only was used. BTX-A in combination with arthrocentesis improved the TMJ area symptoms. PMID- 27496579 TI - Water soluble extracts from Actinidia arguta, PG102, attenuates house dust mite induced murine atopic dermatitis by inhibiting the mTOR pathway with Treg generation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Actinidia arguta is widespread in northeastern Asia, being found in Siberia, Korea, Japan, and northern China. These fruits have been documented to regulate the uncontrolled heat of body resulting in various allergic diseases in the Korean traditional medicine. PG102, a water-soluble extract from an edible fruit, A. arguta, has been previously shown to control various factors involved in allergic pathogenesis. AIM OF THE STUDY: In this study, we investigated whether PG102 prevents chronic allergic reactions via the generation of Tregs, which play a preventive role in the pathogenesis of allergic disease. METHODS AND RESULTS: In dust mite extract-induced chronic atopic dermatitis, orally administered PG102 inhibited symptoms of dermatitis, including ear swelling and erythema, and decreased lymphocyte infiltration into the inflamed region. Moreover, PG102 reduced inflammatory T cell responses and increased the expression levels of Foxp3 and other Treg-related genes. PG102 treatment enhanced the induction of CD4+Foxp3+ Tregs from naive CD4+CD62L+ T cells, probably via the inhibition of mTOR activation and the phosphorylation of STAT5 rather than using the TGF-beta signaling pathway. CONCLUSION: PG102 may have potential as an orally active immunosuppressor for preventing chronic inflammatory diseases. PMID- 27496580 TI - Chyawanprash: A review of therapeutic benefits as in authoritative texts and documented clinical literature. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chyawanprash (CP), a traditional immune booster recipe, has a long history of ethnic origin, development, household preparation and usage. There are even mythological stories about the origin of this recipe including its nomenclature. In the last six decades, CP, because of entrepreneurial actions of some research Vaidyas (traditional doctors) has grown to industrial production and marketing in packed forms to a large number of consumers/patients like any food or health care product. Currently, CP has acquired a large accepted user base in India and in a few countries out-side India. AIM OF THE STUDY: Authoritative texts, recognized by the Drugs and Cosmetics Act of India, describe CP as an immunity enhancer and strength giver meant for improving lung functions in diseases with compromised immunity. This review focuses on published clinical efficacy and safety studies of CP for correlation with health benefits as documented in the authoritative texts, and also briefs on its recipes and processes. MATERIALS AND METHODS: Authoritative texts were searched for recipes, processes, and other technical details of CP. Labels of marketing CP products (Indian) were studied for the health claims. Electronic search for studies of CP on efficacy and safety data were performed in PubMed/MEDLINE and DHARA (Digital Helpline for Ayurveda Research Articles), and Ayurvedic books were also searched for clinical studies. RESULTS: The documented clinical studies from electronic databases and Ayurvedic books evidenced that individuals who consume CP regularly for a definite period of time showed improvement in overall health status and immunity. However, most of the clinical studies in this review are of smaller sample size and short duration. Further, limitation to access and review significant data on traditional products like CP in electronic databases was noted. CONCLUSIONS: Randomized controlled trials of high quality with larger sample size and longer follow-up are needed to have significant evidence on the clinical use of CP as immunity booster. Additional studies involving measurement of current biomarkers of immunity pre- and post consumption of the product as well as benefits accruing with the use of CP as an adjuvant are suggested. PMID- 27496581 TI - Use of plants in oral health care by the population of Mahajanga, Madagascar. AB - BACKGROUND: The use of medicinal plants to address oral health problems is not well documented in Madagascar, yet the country is full of endemic flora. The aim of this study was to collect information on the use of plants in the region of Mahajanga, Madagascar, for the treatments of oral diseases mainly tooth decay. METHODS: The ethnobotanical survey with respect to the use of plants for curing dental problems was carried out in 2012. A cluster sampling at three levels was applied when choosing the study sites. The target population was made up of heads of household. The following data were collected from a semi-structured questionnaire: name of plants, part used, mode of preparation, and administration. The Informant Consensus Factor and Fidelity Level indexes were calculated for each condition treated and used plants. The Results revealed that 93 per cent of the targeted population has used plants to calm dental pain, whereas 44.2% have reported using plants due to financial problems. About 65 species of plants are commonly used for oral health care and 63 of them treated caries. Cajanus cajan (L.) Millsp. was the most plant used. It was mostly used in crushed form of 5 to 9 leaves which were prepared and placed directly on the affected oral part or in the tooth cavity. In general, the treatment lasted about 5 days or minus. The ICF were 0.83 for caries and 0.81 for periodontal diseases. CONCLUSION: This ethnobotanical survey will serve as database for further phytochemical and pharmacological study of plants in order to identify their active components and advise the population on the most effective administration. PMID- 27496582 TI - Effect of fenugreek on hyperglycaemia and hyperlipidemia in diabetes and prediabetes: A meta-analysis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fenugreek is a widely used herb for the treatment of diabetes mellitus (DM) but the effects in randomized controlled trials (RCTs) were controversial. Therefore, a meta-analysis was conducted to estimate the overall effects of fenugreek on hyperglycaemia and hyperlipidemia in diabetes and prediabetes. MATERIALS AND METHODS: PubMed, EMBASE, web of science, Chinese Biomedical Literature database (CBM), the Cochrane library, China Doctor Dissertations Full-text Database (CDFD), Wan Fang medical database, China Proceedings of Conference Full-text Database (CPCD), China national knowledge internet (CNKI) and China Master's Theses Full-text Database (CMFD) were searched to find the available literatures. RCTs with regard to the efficacy and safety of fenugreek on prediabetes or DM were included. The data of fasting blood glucose (FBG), postprandial 2h blood glucose (2hBG), glycosylated hemoglobin (HbA1c), triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-c) and high density lipoprotein cholesterol (HDL-c) were extracted to appraise the net change with fixed or randomized effect model. RESULTS: A total of 10 articles (12 studies) were included in the analysis. Pooled results showed fenugreek significantly decreased the levels of FBG (MD -0.84mmol/L; 95% CI -1.38 to -0.31; p=0.002), 2hBG (MD -1.30mmol/L; 95% CI -1.78 to -0.83; p<0.0001), HbA1c (MD -1.16; 95% CI -1.23 to -1.09; p<0.00001) and TC (MD -0.30mmol/L; 95% CI-0.56 to -0.03; p=0.03). In spite of the reductive trends in the TG or LDL-c levels and incremental trends of HDL-c, these results were not statistically significant or need further verification for fenugreek in the treatment of DM and prediabetes. Some studies were of low quality. No liver and kidney toxicity were found in all included studies, and the main side effects were gastrointestinal discomfort. CONCLUSIONS: The results suggest fenugreek has the hypoglycaemic and TC-lowering efficacy; however, the effects on TG, LDL-c and HDL-c need further confirmations. PMID- 27496583 TI - Ameliorative effect of two Ayurvedic herbs on experimentally induced arsenic toxicity in calves. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chronic arsenic poisoning due to contaminated subsoil water is a threat to society in West Bengal, India and in Bangladesh. The human being may also be affected by the exposed cattle from the affected area by consuming milk, egg, meat and others. In Ayurveda, several herbs like Haridra (turmeric), Shunthi (dried ginger root) and others are used for the management of arsenic poisoning. AIM OF THE STUDY: The study was conducted to find out the ameliorative effect of turmeric and ginger powder against experimentally induced arsenic toxicity in calves. MATERIALS AND METHODS: Twenty four calves were divided into four groups (group I, II, III and IV) having six animals in each group. Animals of group I, II and III were orally administered with sodium arsenite at 1mg/kg body weight for 90 days and in addition group II and group III animals were treated orally with turmeric and ginger powder respectively at 10mg/kg body weight from 46th day onwards. Group IV animals were given food and water without drug and served as control. Arsenic content was estimated in faeces, hair, urine and plasma in every 15 days. Bio-chemical, haematological and anti-oxidant parameters were also assessed. RESULTS: Turmeric and ginger powder significantly (P<0.05) reduced the plasma and hair arsenic levels through increased excretion via faeces and urine. Haemoglobin level, TEC and TLC were decreased in groups I, II and III, however these were improved significantly (P<0.05) from 75th day onwards in turmeric and ginger treated groups. Increased activity of AST and ALT were significantly decreased (P<0.05) from 75th day onwards in group II and III. Blood urea nitrogen and plasma creatinine were also significantly decreased (P<0.05) in group II and III than group I from 60th day onwards. The SOD and catalase activity were significantly (P<0.05) reduced in groups I, II and III, but these were restored at the end of the experiment in turmeric and ginger treated groups. CONCLUSION: The test drugs are found significantly effective not only to eliminate arsenic from the body but also give protection from possible damage caused by arsenic exposure, it may be concluded from the present study that turmeric and ginger can be helpful in the therapy of chronic arsenic toxicity in calves. PMID- 27496584 TI - The Influence of Nurse Manager Leadership Style on Staff Nurse Work Engagement. AB - BACKGROUND: Nursing literature supports the importance of an engaged nursing workforce as a means to positively influence performance. Nurse manager leadership style plays a critical role in engaging staff nurses. These relationships have been minimally studied in nurse managers and staff nurses. OBJECTIVE: The aim of this study is to evaluate the influence of nurse manager leadership style factors on staff nurse work engagement. METHODS: Using a descriptive correlational research design, 441 staff nurses working in 3 acute care hospitals were surveyed. Survey instruments included the Utrecht Work Engagement Scale and the Multifactorial Leadership Questionnaire 5X short form. RESULTS: Transactional and transformational leadership styles in nurse managers positively influenced staff nurse work engagement. Passive-avoidant leadership style in nurse managers negatively influenced staff nurse work engagement. CONCLUSIONS: Nurse managers who provide support and communication through transformational and transactional leadership styles can have a positive impact on staff nurse work engagement and ultimately improve organizational outcomes. PMID- 27496585 TI - Ventricular extrasystoles and ventricular dysfunction: Too close for comfort? PMID- 27496586 TI - Comparative study of the failure rates among 3 implantable defibrillator leads. AB - BACKGROUND: After the introduction of the Biotronik Linox S/SD high-voltage lead, several cases of early failure have been observed. OBJECTIVE: The purpose of this article was to assess the performance of the Linox S/SD lead in comparison to 2 other contemporary leads. METHODS: We used the prospective Erasmus MC ICD registry to identify all implanted Linox S/SD (n = 408), Durata (St. Jude Medical, model 7122) (n = 340), and Endotak Reliance (Boston Scientific, models 0155, 0138, and 0158) (n = 343) leads. Lead failure was defined by low- or high voltage impedance, failure to capture, sense or defibrillate, or the presence of nonphysiological signals not due to external interference. RESULTS: During a median follow-up of 5.1 years, 24 Linox (5.9%), 5 Endotak (1.5%), and 5 Durata (1.5%) leads failed. At 5-year follow-up, the cumulative failure rate of Linox leads (6.4%) was higher than that of Endotak (0.4%; P < .0001) and Durata (2.0%; P = .003) leads. The incidence rate was higher in Linox leads (1.3 per 100 patient-years) than in Endotak and Durata leads (0.2 and 0.3 per 100 patient years, respectively; P < .001). A log-log analysis of the cumulative hazard for Linox leads functioning at 3-year follow-up revealed a stable failure rate of 3% per year. The majority of failures consisted of noise (62.5%) and abnormal impedance (33.3%). CONCLUSION: This study demonstrates a higher failure rate of Linox S/SD high-voltage leads compared to contemporary leads. Although the mechanism of lead failure is unclear, the majority presents with abnormal electrical parameters. Comprehensive monitoring of Linox S/SD high-voltage leads includes remote monitoring to facilitate early detection of lead failure. PMID- 27496587 TI - Melody and rhythm in congenital heart disease. PMID- 27496588 TI - Demethylation and re-methylation dynamics in transgenerational epigenetic inheritance. PMID- 27496589 TI - Intravenous Heroin Abuse and Acute Myocardial Infarction: Association or Causality? PMID- 27496590 TI - Children on the autism spectrum update their behaviour in response to a volatile environment. AB - Typical adults can track reward probabilities across trials to estimate the volatility of the environment and use this information to modify their learning rate (Behrens et al., 2007). In a stable environment, it is advantageous to take account of outcomes over many trials, whereas in a volatile environment, recent experience should be more strongly weighted than distant experience. Recent predictive coding accounts of autism propose that autistic individuals will demonstrate atypical updating of their behaviour in response to the statistics of the reward environment. To rigorously test this hypothesis, we administered a developmentally appropriate version of Behrens et al.'s (2007) task to 34 cognitively able children on the autism spectrum aged between 6 and 14 years, 32 age- and ability-matched typically developing children and 19 typical adults. Participants were required to choose between a green and a blue pirate chest, each associated with a randomly determined reward value between 0 and 100 points, with a combined total of 100 points. On each trial, the reward was given for one stimulus only. In the stable condition, the ratio of the blue or green response being rewarded was fixed at 75:25. In the volatile condition, the ratio alternated between 80:20 and 20:80 every 20 trials. We estimated the learning rate for each participant by fitting a delta rule model and compared this rate across conditions and groups. All groups increased their learning rate in the volatile condition compared to the stable condition. Unexpectedly, there was no effect of group and no interaction between group and condition. Thus, autistic children used information about the statistics of the reward environment to guide their decisions to a similar extent as typically developing children and adults. These results help constrain predictive coding accounts of autism by demonstrating that autism is not characterized by uniform differences in the weighting of prediction error. PMID- 27496591 TI - A single center experience of Zilver PTX for femoro-popliteal lesions. AB - BACKGROUND: Clinical trial data show overall favorable outcomes of paclitaxel eluting stents for treatment of femoro-popliteal (FP) occlusive disease. However, external validity of trial results may be restricted to less complex FP lesions, and limited data on outcomes of paclitaxel-eluting stents in real world practice have been published. METHODS: This is a retrospective analysis of data of all patients who received Zilver(r) PTX(r) for FP lesion from February 2013 to October 2014 at our center. The primary endpoint was primary patency, defined as peak systolic velocity ratio <2.0 by Doppler ultrasound, or angiographic diameter stenosis <50%, or freedom from clinically driven target lesion revascularization. RESULTS: Seventy-eight patients received Zilver(r) PTX(r) for FP lesions in the pre-specified time period. Of them, 63 had follow-up data and were included in this study. Mean patient age was 66.3+/-9.4years, and 57.1% of the patients were men. Participants had a high prevalence of diabetes (49.2%), hypertension (93.7%), hyperlipidemia (93.7%), previous coronary revascularization (52.4%), or previous peripheral arterial disease (77.8%). Critical limb ischemia was present in 25.4% of the patients, Trans-Atlantic Inter-Society Consensus (TASC) class C or D in 76.2%, in-stent restenosis (ISR) in 36.5%, and total occlusion in 69.8%. Mean lesion length was 218.9+/-128.3mm, mean number of stents was 2.02+/-1.0, and total stent length was 189.0+/-128.5mm. Mean follow-up was 270.4+/-190.3days. Primary patency rate at 1year was 66.7% by Kaplan-Meier survival curve. When compared with patients with primary patency at follow up, those with an adverse outcome had higher prevalence of TASC II class C or D lesions (100% vs. 68.8%, p=0.013), and were more likely to have ISR (66.7% vs. 27.1%, p=0.012), longer lesion (291.3+/-138.7 vs. 195.7+/-117.1, p=0.011), and incomplete coverage of the lesion (full coverage of lesions: 40% vs. 77.1%, p=0.011). CONCLUSION: Post marketing use of Zilver(r) PTX(r) for the treatment of FP lesions is associated with lower patency rates compared with clinical trial data. This may be related to the high prevalence of TASC II class C or D lesions and ISR in real world practice. Future studies should be more representative of contemporary clinical practice. PMID- 27496592 TI - Prevalence of Mycobacterium tuberculosis Beijing genotype and its association with drug resistance in North India. AB - The global presence and rapid dissemination of Beijing genotype of Mycobacterium tuberculosis, makes it an important issue of public health. Its presence and association with multi-drug resistance has been shown in many settings. In present study we tried to find its prevalence and association with drug resistance in North India. One hundred and twenty four M. tuberculosis isolates were analyzed with spoligotyping, further drug susceptibility testing was done by 1% proportional method. Out of these, 11 (8.9%) M. tuberculosis isolates were identified as Beijing and 113 (91.1%) as non-Beijing genotypes. While looking at their drug susceptibility patterns, 6 (54.5%) & 22 (19.5%) were found to be multi drug resistant (MDR) among Beijing and non-Beijing isolates respectively. Our study concluded that the Beijing strains were not so common in north India and these strains do not fully associate with MDR. PMID- 27496593 TI - Prioritizing the mHealth Design Space: A Mixed-Methods Analysis of Smokers' Perspectives. AB - BACKGROUND: Smoking remains the leading cause of preventable disease and death in the United States. Therefore, researchers are constantly exploring new ways to promote smoking cessation. Mobile health (mHealth) technologies could be effective cessation tools. Despite the availability of commercial quit-smoking apps, little research to date has examined smokers' preferred treatment intervention components (ie, design features). Honoring these preferences is important for designing programs that are appealing to smokers and may be more likely to be adopted and used. OBJECTIVE: The aim of this study was to understand smokers' preferred design features of mHealth quit-smoking tools. METHODS: We used a mixed-methods approach consisting of focus groups and written surveys to understand the design preferences of adult smokers who were interested in quitting smoking (N=40). Focus groups were stratified by age to allow differing perspectives to emerge between older (>40 years) and younger (<40 years) participants. Focus group discussion included a "blue-sky" brainstorming exercise followed by participant reactions to contrasting design options for communicating with smokers, providing social support, and incentivizing program use. Participants rated the importance of preselected design features on an exit survey. Qualitative analyses examined emergent discussion themes and quantitative analyses compared feature ratings to determine which were perceived as most important. RESULTS: Participants preferred a highly personalized and adaptive mHealth experience. Their ideal mHealth quit-smoking tool would allow personalized tracking of their progress, adaptively tailored feedback, and real time peer support to help manage smoking cravings. Based on qualitative analysis of focus group discussion, participants preferred pull messages (ie, delivered upon request) over push messages (ie, sent automatically) and preferred interaction with other smokers through closed social networks. Preferences for entertaining games or other rewarding incentives to encourage program use differed by age group. Based on quantitative analysis of surveys, participants rated the importance of select design features significantly differently (P<.001). Design features rated as most important included personalized content, the ability to track one's progress, and features designed to help manage nicotine withdrawal and medication side effects. Design features rated least important were quit-smoking videos and posting on social media. Communicating with stop-smoking experts was rated more important than communicating with family and friends about quitting (P=.03). Perceived importance of various design features varied by age, experience with technology, and frequency of smoking. CONCLUSIONS: Future mHealth cessation aids should be designed with an understanding of smokers' needs and preferences for these tools. Doing so does not guarantee treatment effectiveness, but balancing user preferences with best practice treatment considerations could enhance program adoption and improve treatment outcomes. Grounded in the perspectives of smokers, we identify several design considerations, which should be prioritized when designing future mHealth cessation tools and which warrant additional empirical validation. PMID- 27496594 TI - Towards the development of a sustainable soya bean-based feedstock for aquaculture. AB - Soya bean (Glycine max (L.) Merr.) is sought after for both its oil and protein components. Genetic approaches to add value to either component are ongoing efforts in soya bean breeding and molecular biology programmes. The former is the primary vegetable oil consumed in the world. Hence, its primary usage is in direct human consumption. As a means to increase its utility in feed applications, thereby expanding the market of soya bean coproducts, we investigated the simultaneous displacement of marine ingredients in aquafeeds with soya bean-based protein and a high Omega-3 fatty acid soya bean oil, enriched with alpha-linolenic and stearidonic acids, in both steelhead trout (Oncorhynchus mykiss) and Kampachi (Seriola rivoliana). Communicated herein are aquafeed formulations with major reduction in marine ingredients that translates to more total Omega-3 fatty acids in harvested flesh. Building off of these findings, subsequent efforts were directed towards a genetic strategy that would translate to a prototype design of an optimal identity-preserved soya bean-based feedstock for aquaculture, whereby a multigene stack approach for the targeted synthesis of two value-added output traits, eicosapentaenoic acid and the ketocarotenoid, astaxanthin, were introduced into the crop. To this end, the systematic introduction of seven transgenic cassettes into soya bean, and the molecular and phenotypic evaluation of the derived novel events are described. PMID- 27496595 TI - Antihistamine updosing reduces disease activity in patients with difficult-to treat cholinergic urticaria. PMID- 27496596 TI - Half-life of IgE in serum and skin: Consequences for anti-IgE therapy in patients with allergic disease. AB - We present results from clinical studies on plasma infusion done in the late 1970s in patients with hypogammaglobulinemia in which we documented the short half-life of both total and allergen-specific IgE in serum. The development of specific allergic sensitization in the skin of those patients followed by the gradual decrease in sensitization over 50 days was also documented. The data are included here along with a discussion of the existing literature about the half life of IgE in both the circulation and skin. This rostrum reinterprets the earlier clinical studies in light of new insights and mechanisms that could explain the rapid removal of IgE from the circulation. These mechanisms have clinical implications that relate to the increasing use of anti-IgE mAbs for the treatment of allergic disease. PMID- 27496597 TI - Psychological dependence on antidepressants in patients with panic disorder: a cross-sectional study. AB - No study has investigated psychological dependence on antidepressants in patients with panic disorder, which was addressed in this study. This study was carried out in four psychiatric clinics in Tokyo, Japan. Individuals were eligible if they were outpatients aged 18 years or older and fulfilled the diagnostic criteria for panic disorder (ICD-10). Assessments included the Japanese Versions of the Severity of Dependence Scale (SDS), the Self-Report Version of Panic Disorder Severity Scale (PDSS-SR), and the Quick Inventory of Depressive Symptomatology-Self Report. Eighty-four individuals were included; of these, 30 patients (35.7%) showed psychological dependence on antidepressants (i.e. a total score of >=5 in the SDS). A multiple regression analysis showed that PDSS scores and illness duration were correlated positively with SDS total scores. A binary regression model showed that absence of remission (i.e. a total score of >=5 in the PDSS) and longer duration of illness increased the risk of dependence on antidepressants. Approximately one-third of the patients with panic disorder, receiving antidepressants, fulfilled the criteria for psychological dependence on these drugs. The results underscore the need for close monitoring, especially for those who present severe symptomatology or have a chronic course of the illness. PMID- 27496598 TI - What's New in Shock, Military Supplement September 2016. PMID- 27496599 TI - The National Trauma Research Repository: Ushering in a New ERA of trauma research (Commentary). AB - Despite being the leading cause of death in the United States for individuals 46 years and younger and the primary cause of death among military service members, trauma care research has been underfunded for the last 50 years. Sustained federal funding for a coordinated national trauma clinical research program is required to advance the science of caring for the injured. The Department of Defense is committed to funding studies with military relevance; therefore, it cannot fund pediatric or geriatric trauma clinical trials. Currently, trauma clinical trials are often performed within a single site or a small group of trauma hospitals, and research data are not available for secondary analysis or sharing across studies. Data-sharing platforms encourage transfer of research data and knowledge between civilian and military researchers, reduce redundancy, and maximize limited research funding. In collaboration with the Department of Defense, trauma researchers formed the Coalition for National Trauma Research (CNTR) in 2014 to advance trauma research in a coordinated effort. CNTR's member organizations are the American Association for the Surgery of Trauma (AAST), the American College of Surgeons Committee on Trauma (ACS COT), the Eastern Association for the Surgery of Trauma (EAST), the Western Trauma Association (WTA), and the National Trauma Institute (NTI). CNTR advocates for sustained federal funding for a multidisciplinary national trauma research program to be conducted through a large clinical trials network and a national trauma research repository. The initial advocacy and research activities underway to accomplish these goals are presented. PMID- 27496600 TI - Adult, previously untreated patients remain a significant therapeutic challenge. PMID- 27496601 TI - Varicella with rapidly progressive hepatitis presenting with multiple hepatic nodules in a child with acute leukemia. AB - Abdominal pain may precede the characteristic varicella skin lesions in immunocompromised patients with visceral varicella. The absence of skin lesions may delay timely diagnosis and treatment of varicella for those patients. Furthermore, abdominal imaging findings to provide information to diagnose visceral varicella have rarely been reported. Varicella was diagnosed in a 5-year old boy with acute lymphoblastic leukemia complaining of fever and abdominal pain followed by papulovesicular skin lesions. Later, the patient was found to have rapidly progressive acute hepatitis, and abdominal computed tomography showed multiple hypodense hepatic nodules. The patient was treated with intravenous acyclovir, intravenous immunoglobulin, and empirical antibiotic and antifungal therapy. However, his fever and abdominal pain persisted, and a laparoscopic liver biopsy was performed to differentiate other causes of the persisting symptoms. Eventually, the patient was diagnosed with visceral varicella based on histopathologic findings. In conclusion, visceral varicella should be considered in immunocompromised patients with abdominal pain and multiple hypodense hepatic nodules on abdominal imaging studies. However, bacteria, fungi, and tuberculosis can produce similar imaging findings; therefore, a biopsy may be necessary in patients not responding to antiviral therapy. PMID- 27496602 TI - Risk factors and microbiology of wound infections following cesarean delivery: Experience of a single institution. AB - AIMS: To determine the prevalence of wound infection following cesarean delivery, risk factors, common bacterial pathogens and their antibiotic sensitivity. MATERIAL-METHOD: The study population consisted of 5787 cesarean deliveries. All of the patients received 2 g doses of cephazolin perioperatively for antibiotic prophylaxis. Patients with wound infection who had two doses of 1 g cephazolin postoperatively and who were continued on oral preparations of 500 mg of cephuroxime twice daily for 5 days after hospital discharge were included in Group A. Patients with wound infection whose postoperative antibiotics and antibiotics after discharge were omitted were included in Group B. Patient related variables, gestational age, co-morbidities, cesarean section indications, neonatal intensive care requirements were assessed. Risk factors were evaluated according to the type of the procedure (elective or emergent) and administered antibiotic protocol. RESULTS: The incidence of wound infection following cesarean section was 0,37% in elective operations and 5,4% in emergency cases. On the other hand, wound infection rate was found to be 1,35% in antibiotic receiving group (Group A) and 1,12% in the group not receiving antibiotics (Group B). CONCLUSION: Increased rate of wound infections were remarkable in emergency cases and postoperative antibiotics did not have a major impact in reducing the rate of wound infection following cesarean section. PMID- 27496603 TI - Structure and properties of native and unfolded lysing enzyme from T. harzianum: Chemical and pH denaturation. AB - The effect of chemical denaturants and pH on the change of the conformation of the protein Lysing Enzyme from Trichoderma Harzianum has been investigated by dynamic light scattering (DLS) and turbidimetry. Chemical denaturants are frequently used to describe the mechanisms of folding and transition states. We have analyzed the pH effect on the properties and particle size of the protein. The compaction factor CI has shown that the protein is weakly disordered. The molecular dynamics simulations confirm, at neutral pH, that the protein has a low net charge and high hydrophobicity. PMID- 27496604 TI - Anomalous diffusion of poly(ethylene oxide) in agarose gels. AB - We report on the effect of probe size and diffusion time of poly(ethylene) oxide in agarose gels. Time-dependence of the diffusion coefficient, reflecting anomalous diffusion, was observed for poly(ethylene) oxide chains with hydrodynamic radii exceeding about 20nm at an agarose concentration of 2%. The main conclusion is that the pore distribution includes pores that are only several nm across, in agreement with scattering reports in the literature. Interpretation of the diffusion coefficient dependence on the probe size based on a model of entangled rigid rods yielded a rod length of 72nm. PMID- 27496605 TI - Enzymatically-gellable galactosylated chitosan: Hydrogel characteristics and hepatic cell behavior. AB - The influence of contents of galactose and phenolic hydroxyl (Ph) groups incorporated into chitosan was investigated on characteristics of the chitosan derivatives and the resultant gels as well as HepG2 cell attachment and growth behaviors. Introduction of galactose groups increased the solubility of the chitosan derivatives. The gelation time decreased with increasing content of Ph groups in the chitosan derivatives. The increase of galactose groups incorporated at a fixed content of Ph groups improved mechanical properties of the resultant gels. In vitro degradation rate of the resultant gels decreased by increasing Ph groups and decreasing galactose groups incorporated into the chitosan derivatives. The HepG2 cells formed dense spheroid cell clusters when the galactose groups were absent or incorporated at high level into chitosan (13.8mol%). However, the cells exhibited spreading morphology with spheroid formation on the gels containing 1.1 and 5.2mol% galactose groups. The albumin secretion level on a cellular basis also increased considerably when the galactose groups increased to 13.8mol%. The results demonstrated the potential of the chitosan derivative hydrogels for liver tissue engineering applications. PMID- 27496607 TI - Localised semicrystalline phases of MaSp1 proteins show high sensitivity to overshearing in beta-sheet nanocrystals. AB - We consider the effects of beta-sheet over-shearing on the development of semi crystallinity in clusters of MaSp1 spider dragline silk proteins. Using molecular dynamics methods, we find that the extent of crystalline matter in the localised region of an over-sheared nanocrystal can in fact increase through over-shearing beta-sheets. This is due to both; the influence of beta-sheets on surrounding amorphous matter and the influence of amorphous matter in destabilising beta sheets at their interfaces. In both cases the result is the development of increased molecular order. Beyond a critical distance of over-shearing, crystallinity decreases due to a decrease in the stability of both over-sheared beta-sheets and amorphous matter. Crystallinity of a system as a function of overshearing of beta-sheets follows a Gaussian form. Larger stacks of overshearing beta-sheets are energetically more stable than smaller stacks and are consequently able to develop the highest levels of crystallinity within the model systems. The elastic moduli computed herein indicate that the most crystalline oversheared systems are heightened in stiffness through overshearing, though there is concurrently a decrease in extensibility. PMID- 27496606 TI - Enhancement of cordyceps polysaccharide production via biosynthetic pathway analysis in Hirsutella sinensis. AB - The addition of various sulfates for enhanced cordyceps polysaccharide (CP) production in submerged cultivation of H. sinensis was investigated, and manganese sulfate was found the most effective. 2mM of manganese sulfate on 0day (d) was investigated as the optimal adding condition, and the CP production reached optimum with 5.33%, increasing by 93.3% compared with the control. Furthermore, the consumption of three main precursors of CP was studied over cultivation under two conditions. Intracellular mannose content decreased by 43.1% throughout 6days cultivation, which corresponded to CP accumulation rate sharply increased from 0 d to 6 d, and mannose was considered as the most preferred precursor for generating CP. Subsequently, mannose biosynthetic pathway was constructed and verified for the first time in H. sinensis, which constituted the important part of CP biosynthesis, and transcriptional levels of the biosynthetic genes were studied. Transcriptional level of gene cpsA was significantly up-regulated 5.35-fold and it was a key gene involved both in mannose and CP biosynthesis. This study demonstrated that manganese sulfate addition is an efficient and simple way to improve CP production. Transcriptional analysis based on biosynthetic pathway was helpful to find key genes and better understand CP biosynthesis. PMID- 27496608 TI - Alterations of testis-specific promoter methylation in cell-free seminal deoxyribonucleic acid of idiopathic nonobstructive azoospermic men with different testicular phenotypes. AB - OBJECTIVE: To explore the feasibility of quantification of testicular DNA methylation from cell-free seminal DNA (cfsDNA), and analyze promoter methylation alterations in men with idiopathic nonobstructive azoospermia (NOA). DESIGN: Comparison between testicular DNA and paired cfsDNA, and among NOA patients with different testicular phenotypes. SETTING: Academic research institute and andrology practice. PATIENT(S): Eighty-eight idiopathic NOA patients with different testicular phenotypes and 24 normozoospermic men. INTERVENTION(S): Testicular biopsies and semen analysis. MAIN OUTCOME MEASURE(S): Five testis specific methylated promoters were selected. Promoter methylation was quantified using MethyLight in testicular DNA and paired cfsDNA, and the mRNA level was determined by real-time quantitative polymerase chain reaction. RESULT(S): Correlations of methylation of the selected five promoters between testicular DNA and paired cfsDNA were observed; and promoter methylation was negatively related to the messenger RNA level in testis. The cfsDNA methylation of these promoters showed different dynamic changes among the subtypes of NOA and normozoospermia. Among them, CCNA1 and DMRT1 promoter methylation in the hypospermatogenesis group was higher than in other groups and showed diagnostic potential for the patient with hypospermatogenesis. CONCLUSION(S): Cell-free seminal DNA could be a novel, noninvasive biomarker for the detection of testicular epigenetic aberrations. Epigenetic information in cfsDNA related to spermatogenesis may serve to predict successful testicular sperm retrieval in NOA patients. PMID- 27496609 TI - 'False-friend' images on optical coherence tomography angiography: early choroidal neovascularization or artefact? PMID- 27496610 TI - Cross-hairs: a scatterplot for meta-analysis in R. AB - We describe a meta-analytic scatterplot that indicates precision of points for two variables paired within studies; this is equivalent in form to a 'cross hairs' plot used to portray specificity and sensitivity in diagnostic testing. At the user's discretion, the plot also displays boxplots for each of the X and Y variable distributions, means for each of the variables, and the correlation between the two. The cross-hairs may be suppressed for dense point clouds. The program is written in R, so it can be modified by the user and can serve as a companion to existing meta-analysis programs. Some of the program's novel uses are described and illustrated with (1) independent effect sizes, (2) dependent effect sizes, and (3) shrunken estimates. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27496611 TI - Re-emergence of syphilis in the biological era. PMID- 27496612 TI - Interaction of a Novel Chaperone PhLP2A With the Heat Shock Protein Hsp90. AB - PhLP2 is a small cytosolic protein that belongs to the highly conserved phosducin like family of proteins. In amniote genomes there are two PhLP2 homologs, PhLP2A and PhLP2B. It has been shown that mammalian PhLP2A modulates the CCT/TRiC chaperonin activity during folding of cytoskeletal proteins. In order to better understand the function of PhLP2A in cellular protein quality control system, in the present study we have searched for its protein targets. Applying immunoprecipitation followed by mass spectrometry analysis we have identified Hsp90 as a partner of PhLP2A. With pull down experiments, we have confirmed this interaction in protein lysate and using purified proteins we have shown that PhLP2A interacts directly with Hsp90. Furthermore, the proximity ligation assay (PLA) performed on mIMCD-3 cells has shown that PhLP2A forms complexes with Hsp90 which are mainly localized in the cytoplasm of these cells. Further analysis has indicated that the level of PhLP2A increases after heat shock or radicicol treatment, similarly as the level of Hsp90, and that expression of PhLP2A after heat shock is regulated at the transcriptional level. Moreover, using recombinant luciferase we have shown that PhLP2A stabilizes this enzyme in a folding competent state and prevents its denaturation and aggregation. In addition, overexpression of PhLP2A in HEK-293 cells leads to increased heat stress resistance. Altogether, our results have shown that PhLP2A interacts with Hsp90 and exhibits molecular chaperone activity toward denatured proteins. J. Cell. Biochem. 118: 420-429, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27496613 TI - ABA-dependent inhibition of the ubiquitin proteasome system during germination at high temperature in Arabidopsis. AB - During germination, endogenous and environmental factors trigger changes in the transcriptome, translatome and proteome to break dormancy. In Arabidopsis thaliana, the ubiquitin proteasome system (UPS) degrades proteins that promote dormancy to allow germination. While research on the UPS has focused on the identification of proteasomal substrates, little information is known about the regulation of its activity. Here we characterized the activity of the UPS during dormancy release and maintenance by monitoring protein ubiquitination and degradation of two proteasomal substrates: Suc-LLVY-AMC, a well characterized synthetic substrate, and FUSCA3 (FUS3), a dormancy-promoting transcription factor degraded by the 26S proteasome. Our data indicate that proteasome activity and protein ubiquitination increase during imbibition at optimal temperature (21 degrees C), and are required for seed germination. However, abscisic acid (ABA) and supraoptimal temperature (32 degrees C) inhibit germination by dampening both protein ubiquitination and proteasome activity. Inhibition of UPS function by high temperature is reduced by the ABA biosynthesis inhibitor, fluridone, and in ABA biosynthetic mutants, suggesting that it is ABA dependent. Accordingly, inhibition of FUS3 degradation at 32 degrees C is also dependent on ABA. Native gels show that inhibition of proteasome activity is caused by interference with the 26S/30S ratio as well as free 19S and 20S levels, impacting the proteasome degradation cycle. Transfer experiments show that ABA-mediated inhibition of proteasome activity at 21 degrees C is restricted to the first 2 days of germination, a time window corresponding to seed sensitivity to environmental and ABA-mediated growth inhibition. Our data show that ABA and high temperature inhibit germination under unfavourable growth conditions by repressing the UPS. PMID- 27496615 TI - An effective strategy to diagnose HIV infection: findings from a national audit of HIV partner notification outcomes in sexual health and infectious disease clinics in the UK. AB - OBJECTIVES: Partner notification (PN) is a key public health intervention in the control of STIs. Data regarding its clinical effectiveness in the context of HIV are lacking. We sought to audit HIV PN outcomes across the UK. METHODS: All UK sexual health and HIV services were invited to participate. Clinical audit consisted of retrospective case-note review for up to 40 individuals diagnosed with HIV per site during 2011 (index cases) and a review of PN outcomes for up to five contacts elicited by PN per index case. RESULTS: 169/221 (76%) clinical services participated (93% sexual health/HIV services, 7% infectious diseases/HIV units). Most (97%) delivered PN for HIV. Data were received regarding 2964 index cases (67% male; 50% heterosexual, 52% white). PN was attempted for 88% of index cases, and outcomes for 3211 contacts were audited (from an estimated total of 6400): 519 (16%) were found not to be at risk of undiagnosed HIV infection, 1399 (44%) were informed of their risk and had an HIV test, 310 (10%) were informed of the risk but not known to have tested and 983 (30%) were not informed of their risk of HIV infection. Of 1399 contacts tested through PN, 293 (21%) were newly diagnosed with HIV infection. Regular partners were most likely to test positive (p<0.001). CONCLUSIONS: HIV PN is a highly effective diagnostic strategy. Non completion of PN thus represents a missed opportunity to diagnose HIV in at-risk populations. Vigorous efforts should be made to pursue PN to identify people living with, and at risk of, HIV infection. PMID- 27496616 TI - Transareolar pulmonary bullectomy for primary spontaneous pneumothorax. AB - BACKGROUND: Conventional 3-port video-assisted thoracoscopic surgery is the classic approach for the diagnosis and treatment of primary spontaneous pneumothorax. Transareolar pulmonary bullectomy rarely has been attempted. This study aimed to evaluate the feasibility and safety of this novel minimally invasive technique in managing primary spontaneous pneumothorax. METHODS: From January 2013 to December 2014, a total of 112 male patients with primary spontaneous pneumothorax underwent transareolar pulmonary bullectomy by use of a 5-mm thoracoscope. RESULTS: All procedures were performed successfully, with a mean operating time of 26.5 minutes. The mean length of transareolar incision for the main operation was 2.0 +/- 0.2 cm, the mean length of incision for the camera port was 0.6 +/- 0.1 cm, and the mean postoperative cosmetic score was 3.0 +/- 0.8. All patients regained consciousness rapidly after surgery. One hundred seven patients (95.5%) were discharged on postoperative day 2 or 3, with the remainder discharged on postoperative day 4 or 5. Postoperative complications were minor. At 6 months postoperatively, there was no obvious surgical scar on the chest wall, and no patient complained of postoperative pain. No recurrent symptoms were observed. One-year follow-up revealed an excellent cosmetic result and degree of satisfaction. CONCLUSIONS: Transareolar pulmonary bullectomy is a safe and effective therapeutic procedure for primary spontaneous pneumothorax caused by pulmonary bullae. The incision is hidden in the areola with excellent cosmetic effects. This novel procedure shows promise as a treatment of primary spontaneous pneumothorax. PMID- 27496614 TI - Design and cellular studies of a carbon nanotube-based delivery system for a hybrid platinum-acridine anticancer agent. AB - A three-component drug-delivery system has been developed consisting of multi walled carbon nanotubes (MWCNTs) coated with a non-classical platinum chemotherapeutic agent ([PtCl(NH3)2(L)]Cl (P3A1; L=N-(2-(acridin-9-ylamino)ethyl) N-methylproprionimidamide) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [amino(polyethylene glycol)-5000] (DSPE-mPEG). The optimized P3A1-MWCNTs are colloidally stable in physiological solution and deliver more P3A1 into breast cancer cells than treatment with the free drug. Furthermore, P3A1-MWCNTs are cytotoxic to several cell models of breast cancer and induce S-phase cell cycle arrest and non-apoptotic cell death in breast cancer cells. By contrast, free P3A1 induces apoptosis and allows progression to G2/M phase. Photothermal activation of P3A1-MWCNTs to generate mild hyperthermia potentiates their cytotoxicity. These findings suggest that delivery of P3A1 to cancer cells using MWCNTs as a drug carrier may be beneficial for combination cancer chemotherapy and photothermal therapy. PMID- 27496618 TI - The left atrial appendage: Won't get fooled again. PMID- 27496617 TI - Off-pump versus on-pump coronary artery bypass surgery in patients with actively treated diabetes and multivessel coronary disease. AB - OBJECTIVES: We conducted a single-center analysis on short-term outcomes and long term survival in actively treated diabetic patients undergoing off-pump coronary artery bypass versus on-pump coronary artery bypass surgery. METHODS: The final population consisted of 2450 patients with actively treated diabetes (mean age, 66 +/- 9 years; female/male 545/1905, 22%). Of those, 1493 subjects were orally treated and 1011 subjects were taking insulin. Off-pump coronary artery bypass and on-pump coronary artery bypass were performed in 1253 and 1197 patients, respectively. Propensity score matching was used to compare the 2 matched groups. RESULTS: When compared with on-pump coronary artery bypass, off-pump coronary artery bypass was associated with a significant risk reduction for postoperative cerebrovascular accident (odds ratio, 0.49; 95% confidence interval [CI], 0.25 0.99; P = .04), need for postoperative intra-aortic balloon pump (odds ratio, 0.48; 95% CI, 0.30-0.77; P = .002), and reexploration for bleeding (odds ratio, 0.55; 95% CI, 0.33-0.94; P = .02). Off-pump coronary artery bypass did not significantly affect early (hazard ratio [HR], 1.32; 95% CI, 0.73-2.40; P = .36) and late (HR, 1.08; 95% CI, 0.92-1.28; P = .32) mortality. However, off-pump coronary artery bypass with incomplete revascularization was associated with reduced survival when compared with off-pump coronary artery bypass with complete revascularization (HR, 1.82; 95% CI, 1.34-2.46; P = .0002) and on-pump coronary artery bypass with complete revascularization (HR, 1.83; 95% CI, 1.36-2.47; P < .0001). CONCLUSIONS: Off-pump coronary artery bypass is a safe and feasible option for diabetic patients with multivessel disease, reduces the incidence of early complications including postoperative cerebrovascular events, and provides excellent long-term survival similar to on-pump coronary artery bypass surgery in case of complete revascularization. PMID- 27496619 TI - Functionalization of Hydrogenated Graphene: Transition-Metal-Catalyzed Cross Coupling Reactions of Allylic C-H Bonds. AB - The chemical functionalization of hydrogenated graphene can modify its physical properties and lead to better processability. Herein, we describe the chemical functionalization of hydrogenated graphene through a dehydrogenative cross coupling reaction between an allylic C-H bond and the alpha-C-H bond of tetrahydrothiophen-3-one using Cu(OTf)2 as the catalyst and DDQ as the oxidant. The chemical functionalization was confirmed by X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy and visualized by scanning electron microscopy. The functionalized hydrogenated graphene material demonstrated improved dispersion stability in water, bringing new quality to the elusive hydrogenated graphene (graphane) materials. Hydrogenated graphene provides broad possibilities for chemical modifications owing to its reactivity. PMID- 27496620 TI - Bayesian spatial analysis of the surgical incidence rate of human cystic echinococcosis in north-eastern Iran. AB - BACKGROUND: Cystic echinococcosis (CE) is a zoonotic disease that presents a public health challenge and a socioeconomic burden on developing areas in the Middle East. This study used spatial methods to assess the distribution of surgically managed CE cases in an endemic region of north-eastern Iran. METHODS: For the years 2001-2007, a case series of all 446 patients that were surgically treated for CE in a referral hospital in north-eastern Iran was evaluated. Patients seen at the referral hospital represent 35 counties in three provinces (Razavi Khorasan, North Khorasan, and South Khorasan). A Besag, York and Mollie (BYM) spatial model was used to produce smoothed standardized incidence ratios (SIRs) for surgically managed cases of CE for the 35 counties represented in this study. RESULTS: Out of 446 surgically managed patients, 54% were male. County level crude incidence rates ranged from 0 to 3.27 cases per 100,000 population. The highest smoothed SIR (3.46) was for Sarakhs County in the province of Razavi Khorasan, while the lowest smoothed SIR (0.05) was for Birjand County, located in the province of South Khorasan. CONCLUSION: SIRs for CE were highest for the province of Razavi Khorasan, which has large ranching and agricultural industries. Additional studies are needed to better evaluate the role of climate, land cover, and livestock rearing on local Echinococcus granulosus transmission in Iran. PMID- 27496621 TI - Detection of wild animals as carriers of Leptospira by PCR in the Pantanal biome, Brazil. AB - Leptospiral infection is widespread in wildlife. In this context, wild ecosystems in tropical countries hold a vast biodiversity, including several species that may act as potential reservoirs of leptospires. The Pantanal biome presents highly favorable environmental conditions for the occurrence of leptospirosis, such as high temperatures, constant flooding, and high biodiversity. The purpose of this study was to detect wild animals as carriers of Leptospira sp. using direct methods (PCR and culture) in the Pantanal biome, Brazil. A total of 35 animals were studied, namely Cerdocyon thous, Nasua nasua, Ozotoceros bezoarticus, and Sus scrofa species. Blood for serology (MAT) and urine for bacteriological culturing and PCR was sampled. The most prevalent serogroups were Javanica and Djasiman. Additionally, 40.6% of these animals presented PCR positive reactions. Seroreactivity associated with the high frequency of leptospiral carriers among the different studied species suggests a high level of exposure of the studied animals to pathogenic Leptospira strains. Our results are still limited and the actual role of the studied animals in the epidemiology of leptospirosis in the Pantanal region remains to be elucidated. PMID- 27496622 TI - Cutaneous leishmaniasis prevalence and morbidity based on environmental factors in Ilam, Iran: Spatial analysis and land use regression models. AB - The aim of this study was to investigate the impact of the environmental factors on cutaneous leishmaniasis (CL) prevalence and morbidity in Ilam province, western Iran, as a known endemic area for this disease. Accurate locations of 3237 CL patients diagnosed from 2013 to 2015, their demographic information, and data of 17 potentially predictive environmental variables (PPEVs) were prepared to be used in Geographic Information System (GIS) and Land-Use Regression (LUR) analysis. The prevalence, risk, and predictive risk maps were provided using Inverse Distance Weighting (IDW) model in GIS software. Regression analysis was used to determine how environmental variables affect on CL prevalence. All maps and regression models were developed based on the annual and three-year average of the CL prevalence. The results showed that there was statistically significant relationship (P value<=0.05) between CL prevalence and 11 (64%) PPEVs which were elevation, population, rainfall, temperature, urban land use, poorland, dry farming, inceptisol and aridisol soils, and forest and irrigated lands. The highest probability of the CL prevalence was predicted in the west of the study area and frontier with Iraq. An inverse relationship was found between CL prevalence and environmental factors, including elevation, covering soil, rainfall, agricultural irrigation, and elevation while this relation was positive for temperature, urban land use, and population density. Environmental factors were found to be an important predictive variables for CL prevalence and should be considered in management strategies for CL control. PMID- 27496623 TI - Radiation dermatitis: an overview. AB - Radiation therapy has been a commonly employed modality for a variety of ailments, including cancer. Patients undergoing radiation often experience acute and/or chronic skin changes that can be detrimental to their quality of life. Many topical agents and specialized wound dressings are being used for the prevention and management of radiation-induced skin changes. However, no single therapeutic option has been found to be consistently effective. PMID- 27496624 TI - The effects of gliclazide, methylcobalamin, and gliclazide+methylcobalamin combination therapy on diabetic peripheral neuropathy in rats. AB - AIMS: This study investigated the efficacies of gliclazide (GLZ), methylcobalamin (MCA), and GLZ+MCA combination therapy on DPN by evaluating the treatment-related changes in peripheral nerve function, the polyol pathway, and oxidative stress in the sciatic nerve of streptozotocin-induced diabetic rats. MATERIALS AND METHODS: The rat model of streptozotocin-induced diabetes was orally given GLZ (25mg/kg/day), MCA (175MUg/kg/day), and GLZ+MCA (25mg/kg/day+175MUg/kg/day) combination therapy for 8weeks, in order to observe its effects on the motor nerve conduction velocity (MNCV), on the activities of Na(+), K(+)-ATPase, aldose reductase(AR), AR mRNA expression, on the polyol contents, antioxidative enzyme activities and peroxidation products in the sciatic never tissue. KEY FINDINGS: Most of the indicators of DPN, such as delayed MNCV, altered/damaged nerve structure, inhibited Na(+),K(+)-ATPase activity, enhanced AR activity and AR mRNA expression, increased polyol contents, altered Cu,Zn-superoxide dismutase, catalase, and glutathione-peroxidase activities, and elevated malondialdehyde level in the sciatic nerves of the diabetic rats, were significantly ameliorated by treatment with either GLZ or MCA. Moreover, the combination of GLZ and MCA was found to enhance the curative effect on DPN in parts of above-mentioned parameters as compared to monotherapy. SIGNIFICANCE: Monotherapy with GLZ or MCA, and especially the combined application of GLZ and MCA, could be efficient therapeutic strategies for combating experimental DPN in diabetic rats. PMID- 27496625 TI - Are community level prescription opioid overdoses associated with child harm? A spatial analysis of California zip codes, 2001-2011. AB - BACKGROUND: Non-medical prescription opioid use is increasing globally within high-income countries, particularly the United States. However, little is known about whether it is associated with negative outcomes for children. In this study, we use prescription opioid overdose as a proxy measure for non-medical prescription opioid use and ask the following: Do California communities with greater rates of non-medical prescription opioid use also have higher rates of child maltreatment and unintentional child injury? METHODS: We used longitudinal population data to examine ecological associations between hospital discharges involving overdose of prescription opioids and those for child maltreatment or child injury in California zip codes between 2001 and 2011 (n=18,517 zip-code year units) using Bayesian space-time misalignment models. RESULTS: The percentage of hospital discharges involving prescription opioid overdose was positively associated with the number of hospital discharges for child maltreatment (relative rate=1.089, 95% credible interval (1.004, 1.165)) and child injury (relative rate=1.055, 95% credible interval (1.012, 1.096)) over the ten-year period, controlling for other substance use and environmental factors. CONCLUSIONS: Increases in community level prescription opioid overdoses between 2001 and 2011 are associated with a 2.06% increase in child maltreatment discharges and a 1.27% increase in discharges for child injury. Communities with higher rates of non-medical prescription opioid use may experience greater levels of child harms. PMID- 27496626 TI - Systemic-Pulmonary Shunt Facilitates the Growth of the Pulmonary Valve Annulus in Patients With Tetralogy of Fallot. AB - BACKGROUND: Transannular patching (TAP) frequently accompanies primary repairs (PRs) in symptomatic neonates with tetralogy of Fallot (TOF). If a systemic pulmonary shunt (SPS) facilitates the growth of the pulmonary valve annulus (PVA), patients with a marginally small PVA could benefit from a staged repair in terms of lowering the risk of TAP. METHODS: Among 216 infants with TOF who underwent surgical intervention between January 2004 and December 2013, 29 infants underwent SPS with a subsequent repair (SPS group), whereas 187 infants received a PR (PR group). Median age and the Z-score of the PVA (PVA [Z]) at SPS were 32 days and -3.5, respectively. There was one late death and one follow-up loss after SPS, and preservation of the PVA was achieved on repair in 16 patients (16 of 29; 55%). RESULTS: Multiple regression analysis showed that performance of SPS was the only indicator of the increase in the PVA (Z) in the entire cohort (n = 216). On mixed linear regression, the PVA (Z) increased significantly after the placement of an SPS (-3.6 + 0.2*duration in months, p = 0.001), whereas the prerepair changes in the PVA (Z) were not statistically significant in the PR group (p = 0.7), with a significant intergroup difference (p < 0.001). Receiver operating characteristic curve analysis showed that placement of TAP is expected when the preshunt PVA (Z) is smaller than -4.2 (area under the curve: 0.82; 95% confidence interval: 0.62 to 1.00; sensitivity, 100%; specificity, 73%). CONCLUSIONS: SPS facilitates outgrowth of the PVA over somatic growth in patients with TOF. However, preservation of the PVA may not be achieved on staged repair if the initial PVA is too small. PMID- 27496627 TI - Minimally Invasive Peratrial Device Closure of Perimembranous Ventricular Septal Defect Through a Right Infraaxillary Route: Clinical Experience and Preliminary Results. AB - BACKGROUND: Both percutaneous and perventricular device closures of perimembranous ventricular septal defects (PmVSD) present certain drawbacks. We report our experiences with a new, minimally invasive surgery using a peratrial device closure of PmVSD through a right infraaxillary route. METHODS: Between January 2014 and October 2015, 145 patients (71 male, 74 female) with PmVSD, aged 0.5 to 9.7 years (mean 2.8 +/- 2.2) and weighing between 6.1 kg and 43 kg (mean 14.0 +/- 6.6 kg) were included in this study. In patients with left lateral position, a 2- to 3-cm incision was made along the right midaxillary line. The thoracic cavity was entered through the fourth intercostal space. With the help of transesophageal echocardiography guidance, a specially designed hollow probe was inserted into the right atrium. The probe was passed through the tricuspid valve into the right ventricle. The tip of the probe was adjusted to point to or cross the defect. A flexible guidewire was inserted into the left ventricle through the channel of the probe to establish a delivery pathway. Then, the device was deployed to close the defect. RESULTS: A total of 142 cases (97.9%) were successfully occluded, whereas 3 cases failed and were converted to cardiopulmonary bypass operation through the original incision. The device size ranged from 4.0 to 10.0 mm (mean 5.1 +/- 1.4 mm), and all devices were concentric. Follow-up in all patients ranged from 1.0 to 22.8 months (mean 9.9 +/ 5.6) and revealed no evident valve regurgitation, no complete atrioventricular block, and no device dislocation. CONCLUSIONS: This new minimally invasive technique of peratrial device closure through a right infraaxillary route under transesophageal echocardiography guidance was shown to be a safe, effective, feasible, and cosmetically superior treatment for PmVSD. PMID- 27496628 TI - Impact of Operative and Postoperative Factors on Neurodevelopmental Outcomes After Cardiac Operations. AB - BACKGROUND: Neurodevelopmental disability is common after operations for congenital heart defects. We previously showed that patient and preoperative factors, center, and calendar year of birth explained less than 30% of the variance for the Psychomotor Development Index (PDI) and the Mental Development Index (MDI) of the Bayley Scales of Infant Development-Second Edition. Here we investigate how much additional variance in PDI and MDI is contributed by operative variables and postoperative events. METHODS: We analyzed neurodevelopmental outcomes after operations with cardiopulmonary bypass at age 9 months or younger between 1996 and 2009. We used linear regression to investigate the effect of operative factors (age, weight, and cardiopulmonary bypass variables) and postoperative events on neurodevelopmental outcomes, adjusting for center, type of congenital heart defect, year of birth, and preoperative factors. RESULTS: We analyzed 1,770 children from 22 institutions with neurodevelopmental testing at age 13.3 months (range, 6 to 30 months). Among operative factors, longer total support time was associated with lower PDI and MDI (p < 0.05). When postoperative events were added, use of either extracorporeal membrane oxygenation or ventricular assist device support, and longer postoperative length of stay were associated with lower PDI and MDI (p < 0.05). Longer total support time was not a significant predictor in these models. After adjusting for patient, preoperative, intraoperative, and postoperative factors, measured intraoperative and postoperative factors accounted for 5% of the variances in PDI and MDI. CONCLUSIONS: Operative factors may be less important than innate patient and preoperative factors and postoperative events in predicting early neurodevelopmental outcomes after cardiac operations in infants. Neurodevelopmental outcomes improved over calendar time when adjusted for patient and medical variables. PMID- 27496629 TI - Resting End-Tidal Carbon Dioxide Predicts Respiratory Complications in Patients Undergoing Thoracic Surgical Procedures. AB - BACKGROUND: Ventilatory efficiency (Ve/Vco2 slope [minute ventilation to carbon dioxide output slope]) has been shown to predict morbidity and mortality in lung resection candidates. Patients with increased Ve/Vco2 during exercise also exhibit an increased Ve/Vco2 ratio and a decreased end-tidal CO2 at rest. This study hypothesized that ventilatory values at rest predict respiratory complications and death in patients undergoing thoracic surgical procedures. METHODS: Inclusion criteria for this retrospective, multicenter study were thoracotomy and cardiopulmonary exercise testing as part of routine preoperative assessment. Respiratory complications were assessed from the medical records (from the hospital stay or from the first 30 postoperative days). For comparisons, Student's t test or the Mann-Whitney U test was used. Logistic regression and receiver operating characteristic analyses were performed for evaluation of measurements associated with respiratory complications. Data are summarized as mean +/- SD; p <0.05 is considered significant. RESULTS: Seventy six subjects were studied. Postoperatively, respiratory complications developed in 56 (74%) patients. Patients with postoperative respiratory complications had significantly lower resting tidal volume (0.8 +/- 0.3 vs 0.9 +/- 0.3L; p = 0.03), lower rest end-tidal CO2 (28.1 +/- 4.3vs 31.5 +/- 4.2 mm Hg; p < 0.01), higher resting Ve/Vco2 ratio (45.1 +/- 7.1 vs 41.0 +/- 6.4; p = 0.02), and higher Ve/Vco2 slope (34.9 +/- 6.4 vs 31.2 +/- 4.3; p = 0.01). Logistic regression (age and sex adjusted) showed resting end-tidal CO2 to be the best predictor of respiratory complications (odds ratio: 1.21; 95% confidence interval: 1.06 to 1.39; area under the curve: 0.77; p = 0.01). CONCLUSIONS: Resting end-tidal CO2 may identify patients at increased risk for postoperative respiratory complications of thoracic surgical procedures. PMID- 27496630 TI - Outcomes Using a Conservative Versus Liberal Red Blood Cell Transfusion Strategy in Infants Requiring Cardiac Operation. AB - BACKGROUND: The optimal hemoglobin for infants after cardiac operation is unknown. Red blood cells (RBCs) are commonly transfused to maintain high hemoglobin concentrations in the absence of a clinical indication. We hypothesized that infants can be managed with a postoperative conservative RBC transfusion strategy, resulting in lower daily hemoglobin concentrations, without evidence of impaired oxygen delivery (ie, lactate, arteriovenous oxygen difference [avO2diff]), or adverse clinical outcomes. METHODS: Infants weighing 10 kg or less undergoing biventricular repair or palliative (nonseptated) operation were randomly assigned to either a postoperative conservative or liberal transfusion strategy. Conservative group strategy was RBC transfusion for a hemoglobin less than 7.0 g/dL for biventricular repairs or less than 9.0 g/dL for palliative procedures plus a clinical indication. Liberal group strategy was RBC transfusion for hemoglobin less than 9.5 g/dL for biventricular repairs or less than 12 g/dL for palliative procedures regardless of clinical indication. RESULTS: After the operation of 162 infants (82 conservative [53 biventricular, 29 palliative], 80 liberal [52 biventricular, 28 palliative]), including 12 Norwood procedures (6 conservative, 6 liberal), daily hemoglobin concentrations were significantly lower within the conservative group than the liberal group by postoperative day 1 and remained lower for more than 10 days. The percentage of patients requiring a RBC transfusion, number of transfusions, and volume of transfusions were all significantly lower within the conservative group. Despite lower hemoglobin concentrations within the conservative group, lactate, avO2diff, and clinical outcomes were similar. CONCLUSIONS: Infants undergoing cardiac operation can be managed with a conservative RBC transfusion strategy. Clinical indications should help guide the decision for RBC transfusion even in this uniquely vulnerable population. Larger multicenter trials are needed to confirm these results, and focus on the highest risk patients would be of great interest. PMID- 27496631 TI - Early and Midterm Clinical and Hemodynamic Outcomes of Transcatheter Valve-in Valve Implantation: Results From a Multicenter Experience. AB - BACKGROUND: Transcatheter valve-in-valve (VIV) implantation is an alternative option in inoperable or high-risk patients with prosthetic valve dysfunction. Aim of this retrospective multicenter study was to evaluate early and midterm clinical and hemodynamic outcomes of patients undergoing aortic (VIV-A) and mitral VIV (VIV-M). METHODS: We analyzed data of 66 procedures performed in 65 patients who underwent VIV procedures in the VIV-A and VIV-M position at 5 Italian institutions from January 2008 to May 2015. VIV-A and VIV-M were 44 (68%) and 22 (32%), respectively; 1 patient underwent combined mitroaortic VIV. Study devices were both balloon-expandable and self-expandable. Outcomes were defined according to the updated Valve Academic Research Consortium definitions. RESULTS: Overall all-cause 30-day mortality was 6% (4 patients), and it was 4.5% and 9% in VIV-A and VIV-M, respectively (2 patients in each group). Mean follow-up was 14 +/- 14 months. Kaplan-Meier survival of the entire cohort at 1, 2, 3, and 4 years was 84.4% +/- 4.9%, 80.5% +/- 6%, 74.3 +/- 8.1%, and 62% +/- 13.2%, respectively. Age (hazard ratio: 1.1; 95% confidence interval: 1.0 to 1.3; p = 0.035) and diabetes (hazard ratio: 7.2, 95% confidence interval: 2.1 to 23.7; p = 0.001) were identified as independent predictors of mortality. Degenerated surgical aortic prostheses with an internal diameter (ID) less than 20 mm had significantly higher gradients if compared to prostheses with ID 21 to 23 mm and greater than 23 mm. After VIV-A, a severe stenosis (mean gradient greater than 35 mm Hg) was detected in 3 (6.8%) cases, all with ID less than 20 mm. CONCLUSIONS: VIV provides good early and midterm results in high-risk or inoperable patients with mitral or aortic bioprosthesis dysfunction. Age and diabetes are independently associated with mortality. Size of bioprosthesis ID has a significant impact on postoperative gradients. PMID- 27496632 TI - Red eye after strabismus surgery: community-acquired MRSA periocular infection. PMID- 27496633 TI - Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption. AB - HER2-targeting antibodies (i.e. trastuzumab and pertuzumab) prolong survival in HER2-positive breast cancer patients with extracranial metastases. However, the response of brain metastases to these drugs is poor, and it is hypothesized that the blood-brain barrier (BBB) limits drug delivery to the brain. We investigated whether we could improve the response by temporary disruption of the BBB using focused ultrasound in combination with microbubbles. To study this, we inoculated 30 nude rats with HER2-positive cells derived from a brain metastasis of a breast cancer patient (MDA-MB-361). The animals were divided into three groups: a control-group that received no treatment; an antibody-only group that received six weekly treatments of trastuzumab and pertuzumab; and an ultrasound+antibody group that received trastuzumab and pertuzumab in combination with six weekly sessions of BBB disruption using focused ultrasound. In two animals, the leakiness of the tumors before disruption was evaluated using contrast-enhanced T1-weighted magnetic resonance imaging and found that the tumors were not leaky. The same technique was used to evaluate the effectiveness of BBB disruption, which was successful in all sessions. The tumor in the control animals grew exponentially with a growth constant of 0.042+/-0.011mm(3)/day. None of the antibody-only animals responded to the treatment and the growth constant was 0.033+/-0.009mm(3)/day during the treatment period. Four of the ten animals in the ultrasound+antibody-group showed a response to the treatment with an average growth constant of 0.010+/-0.007mm(3)/day, compared to a growth constant 0.043+/ 0.013mm(3)/day for the six non-responders. After the treatment period, the tumors in all groups grew at similar rates. As the tumors were not leaky before BBB disruption and there were no responders in the antibody-only group, these results show that at least in some cases disruption of the BBB is necessary for a response to the antibodies in these brain metastases. Interestingly, only some of the rats responded to the treatment. We did not observe a difference in tumor volume at the start of the treatment, nor in HER2 expression or in contrast enhancement on MRI between the responders and non-responders to explain this. Better understanding of why certain animals respond is needed and will help in translating this technique to the clinic. In conclusion, we demonstrate that BBB disruption using focused ultrasound in combination with antibody therapy can inhibit growth of breast cancer brain metastasis. PMID- 27496634 TI - Repeated fractional intradermal dosing of an inactivated polio vaccine by a single hollow microneedle leads to superior immune responses. AB - The purpose of this study was to investigate the effect of various repeated fractional intradermal dosing schedules of inactivated polio vaccine serotype 1 (IPV1) on IPV1-specific IgG responses in rats. By utilizing an applicator that allowed for precisely controlled intradermal microinjections by using a single hollow microneedle, rats were immunized intradermally with 5 D-antigen units (DU) of IPV1 at 150MUm skin depth. This dose was administered as a bolus, or in a repeated fractional dosing schedule: 4 doses of 1.25 DU (1/4th of total dose) were administered on four consecutive days or every other day; 8 doses of 0.625 DU (1/8th of total dose) were administered on eight consecutive days; or 4 exponentially increasing doses (0.04, 0.16, 0.8 and 4 DU), either with or without an exponentially increasing CpG oligodeoxynucleotide 1826 (CpG) dose, were administered on four consecutive days. All of these fractional dosing schedules resulted in up to ca. 10-fold higher IPV1-specific IgG responses than intradermal and intramuscular bolus dosing. IPV1 combined with adjuvant CpG in exponential dosing did not significantly increase the IPV1-specific IgG responses further, which demonstrated that maximal responses were achieved by fractional dosing. In conclusion, repeated fractional intradermal IPV1 dosing leads to superior IPV1 specific IgG responses without the use of adjuvants. These results indicate that a controlled release delivery system for intradermal IPV1 delivery can potentiate IPV1-specific IgG responses. PMID- 27496635 TI - Nematode parasite diversity in birds: the role of host ecology, life history and migration. AB - Previous studies have found that migratory birds generally have a more diverse array of pathogens such as parasites, as well as higher intensities of infection. However, it is not clear whether this is driven by the metabolic and physiological demands of migration, differential selection on host life-history traits or basic ecological differences between migratory and non-migratory species. Parasitic helminths can cause significant pathology in their hosts, and many are trophically transmitted such that host diet and habitat use play key roles in the acquisition of infections. Given the concurrent changes in avian habitats and migratory behaviour, it is critical to understand the degree to which host ecology influences their parasite communities. We examined nematode parasite diversity in 153 species of Anseriformes (water birds) and Accipitriformes (predatory birds) in relation to their migratory behaviour, diet, habitat use, geographic distribution and life history using previously published data. Overall, migrators, host species with wide geographic distributions and those utilizing multiple aquatic habitats had greater nematode richness (number of species), and birds with large clutches harboured more diverse nematode fauna with respect to number of superfamilies. Separate analyses for each host order found similar results related to distribution, habitat use and migration; however, herbivorous water birds played host to a less diverse nematode community compared to those that consume some animals. Birds using multiple aquatic habitats have a more diverse nematode fauna relative to primarily terrestrial species, likely because there is greater opportunity for contact with parasite infectious stages and/or consumption of infected hosts. As such, omnivorous and carnivorous birds using aquatic habitats may be more affected by environmental changes that alter their diet and range. Even though there were no overall differences in their ecology and life history compared with non-migrators, migratory bird species still harboured a more diverse array of nematodes, suggesting that this behaviour places unique demands on these hosts and warrants further study. PMID- 27496636 TI - Disruption of host-seeking behaviour by the salmon louse, Lepeophtheirus salmonis, using botanically derived repellents. AB - The potential for developing botanically derived natural products as novel feed through repellents for disrupting settlement of the salmon louse, Lepeophtheirus salmonis (Caligidae) upon farmed Atlantic salmon, Salmo salar, was investigated using an established laboratory vertical Y-tube behavioural bioassay for assessing copepodid behaviour. Responses to artificial sea water conditioned with the odour of salmon, or to the known salmon-derived kairomone component, alpha isophorone, in admixture with selected botanical materials previously known to interfere with invertebrate arthropod host location were recorded. Materials included oils extracted from garlic, Allium sativum (Amaryllidaceae), rosemary, Rosmarinus officinalis (Lamiaceae), lavender, Lavandula angustifolia (Lamiaceae), and bog myrtle, Myrica gale (Myricaceae), and individual components (diallyl sulphide and diallyl disulphide from garlic; allyl, propyl, butyl, 4-pentenyl and 2-phenylethyl isothiocyanate from plants in the Brassica genus). Removal of attraction to salmon-conditioned water (SCW) or alpha-isophorone was observed when listed materials were presented at extremely low parts per trillion (ppt), that is picograms per litre or 10-12 level. Significant masking of attraction to SCW was observed at a level of 10 ppt for diallyl disulphide and diallyl sulphide, and allyl isothiocyanate and butyl isothiocyanate. The potential of very low concentrations of masking compounds to disrupt Le. salmonis copepodid settlement on a host fish has been demonstrated in vitro. PMID- 27496637 TI - Direct Transcatheter Heart Valve Implantation Versus Implantation With Balloon Predilatation: Insights From the Brazilian Transcatheter Aortic Valve Replacement Registry. AB - BACKGROUND: Direct transcatheter aortic valve replacement (TAVR) is regarded as having potential advantages over TAVR with balloon aortic valve predilatation (BAVP) in reducing procedural complications, but there are few data to support this approach. METHODS AND RESULTS: Patients included in the Brazilian TAVR registry with CoreValve and Sapien-XT prosthesis were compared according to the implantation technique, with or without BAVP. Clinical and echocardiographic data were analyzed in overall population and after propensity score matching. A total of 761 consecutive patients (BAVP=372; direct-TAVR=389) were included. Direct TAVR was possible in 99% of patients, whereas device success was similar between groups (BAVP=81.2% versus direct-TAVR=78.1%; P=0.3). No differences in clinical outcomes at 30 days and 1 year were observed, including all-cause mortality (7.6% versus 10%; P=0.25 and 18.1% versus 24.5%; P=0.07, respectively) and stroke (2.8% versus 3.8%; P=0.85 and 5.5% versus 6.8%; P=0.56, respectively). Nonetheless, TAVR with BAVP was associated with a higher rate of new onset persistent left bundle branch block with the CoreValve (47.7% versus 35.1%; P=0.01 at 1 year). Mean gradient and incidence of moderate/severe aortic regurgitation were similar in both groups at 1 year (11% versus 13.3%; P=0.57 and 9.8+/-5.5 versus 8.7+/ 4.3; P=0.09, respectively). After propensity score matching analysis, all-cause mortality and stroke remained similar. By multivariable analysis, BAVP and the use of CoreValve were independent predictors of new onset persistent left bundle branch block. CONCLUSIONS: The 2 TAVR strategies, with or without BAVP, provided similar clinical and echocardiographic outcomes over a midterm follow-up although BAVP was associated with a higher rate of new onset persistent left bundle branch block, particularly in patients receiving a CoreValve. PMID- 27496638 TI - Fungal Obstruction of Transcatheter Aortic Valve Replacement Valve. PMID- 27496639 TI - Allogeneic stem cell transplantation for sickle cell disease. AB - PURPOSE OF REVIEW: As the safety and availability of allogeneic hematopoietic stem cell transplantation (HSCT) have improved, this procedure is becoming a viable option for nonmalignant conditions such as sickle cell disease (SCD). There are very few treatment options available for SCD, and even with optimal care SCD patients still suffer from a myriad of comorbidities to multiple organ systems and have a decreased life span. In this review, we will summarize results from trials of HSCT for children or adults with SCD using a variety of graft sources as well as conditioning and graft-versus-host disease prophylaxis regimens, and discuss the unique challenges that arise in these patients. RECENT FINDINGS: AlloHSCT for SCD has been performed on small numbers of patients at multiple centers around the world using several different transplant platforms, and early outcomes are encouraging. Overall survival is excellent, although graft failure remains a challenge. SUMMARY: As alloHSCT becomes safer and more widely available, the procedure should be considered for patients with severe disease phenotypes in whom the potential benefits of transplantation outweigh the complications from the disease. AlloHSCT has been shown to reverse or at least halt the progression of end-organ damage secondary to SCD. More research is needed to understand the mechanisms underlying graft failure in SCD recipients, as well as to understand the biopsychosocial underpinnings of persistent pain in the posttransplant period to maximize the benefit from the transplant procedure. PMID- 27496640 TI - [Parental perception of their involvement in the care of their children in French neonatal units]. AB - BACKGROUND: The experience of becoming the parent of a sick or premature newborn can be particularly distressing for parents. They often encounter challenges to the development of their parenting roles. Perception of the hospital stay has never been analyzed on a large scale. OBJECTIVE: To analyze parents' perception of their involvement in the care of their newborn. METHODS: An internet-based survey started in France in February 2014 on the basis of a validated questionnaire composed of 222 neonatal care-related items. A quantitative and qualitative analysis was performed on the items dealing with parents' involvement until August 2014. RESULTS: The survey was completed by 1500 parents, 98 % of whom were mothers. The infants had a mean GA of 32 weeks and a mean birth weight of 1600g. Parents rated their first care of their infant with mixed emotions (joy, stress, etc.). Parents were willing to practice new skills through guided participation, even for more complex care. Skin-to-skin care was only proposed after 7 days for 20 % of the parents; 10 % of the parents did not feel secure during this practice. The need for privacy and professional guidance was essential for meaningful skin-to-skin contact. DISCUSSION: Parents' perception of participating actively in their infant's care was positive and they felt guided by the nursing team. Most of them would have been more active with guidance. Skin to-skin care was appreciated and desired, but could become stressful if the conditions were not optimal. PMID- 27496641 TI - Exendin-4 inhibits growth and augments apoptosis of ovarian cancer cells. AB - Glucagon-like peptide (GLP)-1 promotes proliferation and survival in beta-cell; however, whether GLP-1 receptor agonists promote growth of human ovarian cancer cells remain unknown. We aimed to explore the effects of GLP-1 agents on ovarian cancer cells. GLP-1 receptor expression in human ovarian cancer tissues was detected by immunohistochemical analysis. The effects of exendin-4, a GLP-1R agonist, were investigated on proliferation, migration and invasion, apoptosis in vitro and tumor formation in nude mice of ovarian cancer cells. Our study demonstrated that GLP-1R expressed in both human ovarian cancer tissues and cell lines. Exendin-4 inhibited growth, migration and invasion and enhanced apoptosis of ovarian cancer cells through inhibition of the PI3K/Akt pathway. And exendin-4 attenuated tumor formation by ovarian cancer cells in vivo. Our study suggests that GLP-1R agonists do not promote the growth of ovarian cancer and may even have anticancer effect on selected diabetic patients with ovarian cancer. PMID- 27496642 TI - Naringin protects against HIV-1 protease inhibitors-induced pancreatic beta-cell dysfunction and apoptosis. AB - INTRODUCTION: The protective effects of grapefruit-derived naringin against HIV-1 Protease Inhibitors (PIs)-associated oxidative damage to pancreatic beta-cells and apoptosis were investigated in RIN-5F cells in culture. METHODS: Cells in culture medium were challenged with 11-25 mM glucose with or without nelfinavir (1-10 MUM), saquinavir (1-10 MUM) and atazanavir (5-20 MUM), respectively for 24 h to determine insulin secretion. The cells were further treated with nelfinavir (10 MUM), saquinavir (10 MUM), atazanavir (20 MUM) with and without naringin or glibenclamide (10 MUM) for 24 h to determine insulin secretion, lipid peroxidation, Superoxide Dismutase (SOD) activity, glutathione (GSH) levels, ATP production and caspase-3 and-9 activities, respectively. RESULTS: Glucose dependent insulin secretion was significantly reduced by PIs in a concentration dependent manner. Treatment with either naringin or glibenclamide significantly reduced lipid peroxidation, Superoxide Dismutase (SOD) activities and also increased glutathione (GSH) and ATP levels in the cells that were treated with PIs. Furthermore, naringin or glibenclamide significantly reduced caspase-3 and caspase-9 activities in cells that were treated with PIs. CONCLUSIONS: PIs impair beta-cell functions by increasing oxidative stress and apoptosis. Treatment with naringin protected RIN-5F cells from PI-induced oxidative damage and apoptosis. Our results therefore suggest that nutritional supplements with naringin could prevent pancreatic beta-cell dysfunction and the attendant metabolic complications caused by PIs in patients on antiretroviral therapy. PMID- 27496643 TI - Crosstalk between C/EBP homologous protein (CHOP) and glucocorticoid receptor in lung cancer. AB - Loss of homeostasis triggers the endoplasmic reticulum (ER) stress response and activates the unfolded protein response (UPR) resulting in the induction of the CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP). Glucocorticoids (GCs), via the glucocorticoid receptor (GR), regulate numerous physiological processes in an effort to maintain homeostasis. Previous studies demonstrated that glucocorticoids suppress ER stress by enhancing correct folding of secreted proteins and degradation of misfolded proteins. Here, we describe a novel crosstalk between ER-stress and the glucocorticoid receptor signaling. We showed that treatment of wild type mice with Tunicamycin (inducer of ER-stress) increased GR protein levels in the lungs. Treatment of A549 cells (human lung cancer cells) with ER stress inducers modulated the Dexamethasone-induced subcellular localization of GR and the phosphorylated forms of GR (pGRSer211 and pGRSer203) with concomitant changes in the expression of primary GR-target genes. We demonstrated a significant protein-protein interaction between GR and CHOP, (GR-CHOP heterocomplex formation) under ER stress conditions. The functional consequences of ER stress- GR signaling crosstalk were assessed and demonstrated that long time exposure (24-48 h) of A549 cells to dexamethasone (10(-6) M) reversed the Tunicamycin-induced cell death, a phenomenon associated with parallel increases in GR protein content, increases in cell survival parameters and decreases in cell apoptosis-related parameters. Our study provides evidence that there is a cross talk between ER-stress and GR signaling, this being associated with mutual functional antagonism between CHOP and GR-mediated pathways in lung cells with important implications in lung cell function. PMID- 27496645 TI - Aged rats show dominant modulation of lower frequency hippocampal theta rhythm during running. AB - Aging causes considerable decline in both physiological and mental functions, particularly cognitive function. The hippocampal theta rhythm (4-12Hz) is related to both cognition and locomotion. Aging-related findings of the frequency and amplitude of hippocampal theta oscillations are inconsistent and occasionally contradictory. This inconsistency may be due to the effects of the sleep/wake state and different frequency subbands being overlooked. We assumed that aged rats have lower responses of the hippocampal theta rhythm during running, which is mainly due to the dominant modulation of theta frequency subbands related to cognition. By simultaneously recording electroencephalography, physical activity (PA), and the heart rate (HR), this experiment explored the theta oscillations before, during, and after treadmill running at a constant speed in 8-week-old (adult) and 60-week-old (middle-aged) rats. Compared with adult rats, the middle aged rats exhibited lower theta activity in all frequency ranges before running. Running increased the theta frequency (Frq, 4-12Hz), total activity of the whole theta band (total power, TP), activity of the middle theta frequency (MT, 6.5 9.5Hz), and PA in both age groups. However, the middle-aged rats still showed fewer changes in these parameters during the whole running process. After the waking baseline values were substracted, middle-aged rats showed significantly fewer differences in DeltaFrq, DeltaTP, and DeltaMT but significantly more differences in low-frequency theta activity (4.0-6.5Hz) and HR than the adult rats did. Therefore, the decreasing activity and response of the whole theta band in the middle-aged rats resulted in dominant modulation of the middle to lower frequency (4.0-9.5Hz) theta rhythm. The different alterations in the theta rhythm during treadmill running in the two groups may reflect that learning decline with age. PMID- 27496644 TI - Paranasal sinus osteomas: Diagnosis and treatment. AB - INTRODUCTION: Osteoma is the most common benign tumor of the nose and paranasal sinuses. It is a slow-growing bony tumor, often asymptomatic, occurring mainly in frontal and ethmoid sinuses. Theories regarding the origin of osteomas are still discussed. The aims of the study were to describe diagnosis circumstances in our series and to set out our respective indications for open and endoscopic approaches in the treatment of nasosinusal osteomas. PATIENTS AND METHODS: A retrospective study was conducted on the files of all the patients treated for a paranasal sinus osteoma in our department between 1990 and 2013. Diagnosis circumstances and kind of treatment were collected and analyzed. RESULTS: The files of 45 patients (mean age: 49.2; sex-ratio: 1.19) could be collected. The most common symptom was headache found in all patients. The most common location was the frontal sinus (30 cases). Thirty-nine open procedures were performed. Four osteomas were removed under endoscopic assistance. In one case, a combined approach has been used. Overall complication rate was 11.1%. Symptoms improved in all patients. Two recurrences were observed. DISCUSSION: Surgical indications in paranasal sinus osteomas are theorically well codified. However, approaches remain controversial. In our experience, the preferred approach was the open one. Endoscopic techniques, when indicated, are more challenging and need sophisticated instrumentation and a long learning curve. PMID- 27496646 TI - Now We Know: Assessing Sexual Assault Criminal Justice Case Processing in an Urban Community Using the Sexual Assault Nurse Practitioner Evaluation Toolkit. AB - Campbell and colleagues developed an evaluation Toolkit for use by sexual assault nurse examiners (SANEs) to assess criminal case outcomes in adult sexual assault cases seen by SANE programs (Campbell, Townsend, Shaw, Karim, & Markowitz, 2014; Campbell, Bybee, et al., 2014). The Toolkit provides step-by-step directions and an easy-to-use statistical program. This study describes implementation of the Toolkit in Salt Lake County, the first site outside the pilot sites to utilize the program. The Toolkit revealed that, in Salt Lake County from 2003 to 2011, only 6% of adult sexual assault cases were successfully prosecuted. These findings prompted multiple community discussions, media attention, and a call to action to improve the investigation and prosecution of adult sexual assault cases. The primary purpose of this case report is to encourage other SANE teams and communities to use the Toolkit by sharing the successful experience of Salt Lake County in implementing the Toolkit.Video Abstract available for additional insights from Dr. Valentine (see Supplemental Digital Content 1, http://links.lww.com/JFN/A19). PMID- 27496647 TI - Humor: Power Conveying Social Structures Inside Forensic Mental Health Nursing. AB - According to research literature, humor inside the staff-patient interaction seems to be significant in the area of forensic mental healthcare. However, existing literature on the subject is limited. Therefore, the aim of this study was to explore the characteristics of the use humor by forensic mental health staff members in interactions with forensic mental health inpatients. The study included 32 forensic mental health staff members, used 307 hours of participant observations, 48 informal interviews, and seven formal semistructured interviews. Outcomes identify four themes concerning the conveyance of power to, from, and between forensic mental health staff and patients as they interact: (a) "the informal use: the human-to-human approach," characterized by an informal use of humor and without any reference to mental health issues; (b) the "formal use of humor: the staff-patient approach," characterized as formal with a view on the patient as mentally ill, unable to understand humor, and with the aim of using humor to prevent conflicts or negative behavior; (c) "protest against requested care: the human-patient approach," characterized by the use of humor as a protest against requested care; and the use of (d) "inadequacy humor: the staff-human approach," characterized by the use of inadequacy-humor referring to, for example, patients' physical features. Recommendations and clinical implications are discussed. PMID- 27496648 TI - Illustrations of Unexpected Infant Sleep Deaths. AB - Case illustrations from central Indiana provide the narrative for infant suffocations because of unsafe sleep environments. Accidental strangulation or suffocation in bed is caused by co-bedding, blankets and pillows in cribs, or wedging and entrapment. Knowledge of the evidence-based risks associated with case data may assist further in the prevention of unexpected infant sleep deaths and may better inform best practice for death scene investigation including forensic nurses. PMID- 27496649 TI - The Histologic Classifications of Lung Adenocarcinomas Are Discriminable by Unique Lineage Backgrounds. AB - OBJECTIVES: Lung adenocarcinomas are a heterogeneous set of diseases with distinct genetic and histologic characteristics. Besides the discovery of oncogenic mutations and introduction of the histologic classifications (2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society and 2015 WHO), increasing evidence has linked this intertumor heterogeneity to the lung lineage-specific pathways and lineage genes. Therefore, in this study, we assessed the gene expression of identified lung lineage genes to study their role in distinguishing lung adenocarcinoma diversities. METHODS: A total of 278 surgically resected lung adenocarcinomas were included. Each case was evaluated for genetic mutations and histologic classification. Lineage genes associated with respiratory tract differentiation (NK2 homeobox 1 gene [NKX2-1], GATA protein binding 6 gene [GATA6], foxhead box J1 gene [FOXJ1], and SAM pointed domain containing ETS transcription factor gene [SPDEF]) and stem/basal-like status (inhibitor of DNA binding 2, HLH protein gene [ID2], POU class 5 homeobox 1 gene [POU5F1], SRY-box 2 gene [SOX2], and v-myc avian myelocytomatosis viral oncogene homolog gene [MYC]) were selected. mRNA expression of these genes in each tumor sample was assessed by quantitative real-time polymerase chain reaction and normalized to paired normal lung tissue. RESULTS: Distinct lineage gene expressions were found on the basis of genetic and histologic diversities. Expression of NKX2-1, GATA6, FOXJ1, and POU5F1 exhibited a significant linear relationship across histologic subgroups that was independent of genetic mutation status. Expression levels of NKX2-1 and POU5F1 were also associated with EGFR mutation status, independent of histologic subtypes. Further analysis revealed that the overexpression of SPDEF defined longer relapse-free survivals, especially in stage I disease. CONCLUSIONS: For the first time, we showed the unique lineage backgrounds of different histologic subtypes and oncogenic mutations. Assessing this added parameter might be beneficial in discriminating intertumor heterogeneity, advancing target exploration, developing theranostic/prognostic biomarkers, and designing clinical trials. PMID- 27496651 TI - Anatomical Segmentectomy and Wedge Resections Are Associated with Comparable Outcomes for Patients with Small cT1N0 Non-Small Cell Lung Cancer. AB - OBJECTIVES: Sublobar resection is advocated for patients with NSCLC and compromised cardiopulmonary reserve, and for selected patients with early stage disease. Anatomic segmentectomy (AS) has traditionally been considered superior to wedge resection (WR), but well-balanced comparative studies are lacking. We hypothesize that WR and AS are associated with comparable oncologic outcomes for patients with cT1N0 NSCLC. METHODS: A retrospective review of a prospective database was performed (2000-2014) for cT1N0 patients, excluding patients with multiple primary tumors, carcinoid tumors, adenocarcinoma in situ, and minimally invasive adenocarcinoma. Demographic, clinical, and pathological data were reviewed. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method and differences compared using log-rank test. Multivariable analysis (MVA) of factors affecting DFS was performed by Cox regression analysis. For further comparison of the effect of resection type on survival, propensity score matching (i.e., by age, sex, Charlson comorbidity index, percent forced expiratory volume in 1 second (FEV1%), clinical tumor size, and tumor maximum standardized uptake value) was performed to obtain balanced cohorts of patients undergoing WR and AS (n = 76 per group). RESULTS: Two hundred eighty-nine patients met our selection criteria, including WR in 160 and AS in 129. Poor performance status and limited cardiopulmonary reserve were the primary indications for sublobar resection in 76% of WR patients and in 62% of AS patients (p = 0.011). Thirteen patients (4.5%) had pN1/2 disease. Patients undergoing AS were more likely to have nodal sampling/dissection [123 (95%) versus 112 (70%); p < 0.001], more stations sampled (3 versus 2; p < 0.001), and more total nodes resected (7 versus 4; p = 0.001). However, there was no difference between patients undergoing WR versus AS in local recurrence [15 versus 14; p = 0.68] or 5-year DFS (51% versus 53%; p = 0.7; median follow-up 34 months). Univariate analysis showed no effect of extent of resection on DFS [hazard ratio 1.07 (95% confidence interval 0.74-1.56); p = 0.696]. MVA showed that only tumor maximum standardized uptake value was associated with worse DFS [hazard ratio 1.07 (95% confidence interval 1.01-1.13); p = 0.016]. In the propensity-matched analysis of balanced subgroups, there was also no difference (p = 0.950) in 3- or 5-year DFS in cT1N0 patients undergoing WR (65% and 49%) or AS (68% and 49%). CONCLUSIONS: Our data show that WR and AS are comparable oncologic procedures for carefully staged cT1N0 NSCLC patients. Although AS is associated with a more thorough lymph node dissection, this did not translate to a survival benefit in this patient population with a low rate of nodal metastases. PMID- 27496650 TI - Relationship between Overall Survival and Response or Progression-Free Survival in Advanced Non-Small Cell Lung Cancer Patients Treated with Anti-PD-1/PD-L1 Antibodies. AB - INTRODUCTION: Alternative predictive end points for overall survival (OS), such as tumor response and progression-free survival (PFS), are useful in the early detection of drug efficacy; however, they have not been fully investigated in patients with advanced NSCLC treated with anti-programmed death protein 1 (PD 1)/programmed death ligand 1 (PD-L1) antibodies. METHODS: In a systematic review of the reported prospective clinical trials, data for response rate, median PFS, and median OS were extracted from 12 arms in 10 reported clinical trials using anti-PD-1/PD-L1 antibody, and their correlation was investigated. In a retrospective analysis at our institution, OS was compared according to tumor response on 5- to 9-week computed tomography scans and status of being progression-free at 8, 16, and 24 weeks by landmark analysis in 71 patients with advanced NSCLC treated with anti-PD-1/PD-L1 antibodies between 2013 and 2015. RESULTS: In a systematic review, moderate correlations between median OS and median PFS (p = 0.120, r = 0.473) and between median OS and response rate (p = 0.141, r = 0.452) were identified using the Spearman correlation coefficient, although these correlations were not statistically significant. In a retrospective analysis of patients treated at our institution, disease control (partial response [PR]/stable disease versus progressive disease/not evaluable), and progression-free status at 8, 16, and 24 weeks significantly predicted OS (Cox proportional hazards model, PR/stable disease versus progressive disease/not evaluable, p = 0.0104, HR = 3.041; 8-week progression-free yes versus no, p = 0.0183, HR = 2.684; 16-week progression-free yes versus no, p = 0.0036, HR = 4.009; and 24-week progression-free yes versus no, p = 0.0002, HR = 12.726). CONCLUSIONS: Both disease control (PR plus stable disease status) and landmark progression-free survival were correlated with OS, with the longer interval landmark PFS being the best predictor of survival in patients with NSCLC treated with anti-PD-1/PD-L1 antibodies. PMID- 27496653 TI - Comment on "Further improvement on delay-range-dependent robust absolute stability for Lur'e uncertain systems with interval time-varying delays" by P. Liu [ISA Trans. 58(2015)58-66]. AB - In a recent paper (ISA Transactions (2015)58: 58-66), an integral inequality has been proposed to reduce the conservativeness of stability conditions for Lur'e uncertain systems. We point out that there exist some errors in Theorems 1-8, and the correct theorems are presented. Finally, the allowable maximum admissible upper bound (MAUB) listed in Tables 1-5 have been recalculated by using the correct results. PMID- 27496652 TI - LincRNA-p21 Impacts Prognosis in Resected Non-Small Cell Lung Cancer Patients through Angiogenesis Regulation. AB - INTRODUCTION: Long intergenic noncoding RNA-p21 (lincRNA-p21) is a long noncoding RNA transcriptionally activated by tumor protein p53 (TP53) and hypoxia inducible factor 1 alpha subunit (HIF1A). It is involved in the regulation of TP53 dependent apoptosis and the Warburg effect. We have investigated the role of lincRNA-p21 in NSCLC. METHODS: LincRNA-p21 expression was assessed in tumor and normal tissue from 128 patients with NSCLC and correlated with time to relapse and cancer-specific survival (CSS). H23, H1299, and HCC-44 cell lines were cultured in hypoxic conditions after silencing of lincRNA-p21. The TaqMan human angiogenesis array was used to explore angiogenesis-related gene expression. Levels of the protein vascular endothelial growth factor A were measured by enzyme-linked immunosorbent assay in the cell supernatants. Angiogenic capability was measured by human umbilical vein endothelial cell tube formation assay. Microvascular density in tumor samples was analyzed by immunohistochemistry. RESULTS: LincRNA-p21 was down-regulated in tumor tissue, but no association was observed with TP53 mutational status. High lincRNA-p21 levels were associated with poor CSS in all patients (p = 0.032). When patients were classified according to histological subtypes, the impact of lincRNA-p21 was confined to patients with adenocarcinoma in both time to relapse (p = 0.006) and CSS (p < 0.001). To explain the poor outcome of patients with high lincRNA-p21 expression, we studied the role of lincRNA-p21 in angiogenesis in vitro and observed a global downregulation in the expression of angiogenesis-related genes when lincRNA-p21 was inhibited. Moreover, supernatants from lincRNA-p21-inhibited cells were significantly less angiogenic and had lower levels of secreted vascular endothelial growth factor A than controls did. Finally, tumor samples with high lincRNA-p21 levels had higher microvascular density. CONCLUSIONS: Our findings suggest that lincRNA-p21 affects outcome in patients with NSCLC adenocarcinoma through the regulation of angiogenesis. PMID- 27496654 TI - Activation of delta-opioid receptor contributes to the antinociceptive effect of oxycodone in mice. AB - Oxycodone has been used clinically for over 90 years. While it is known that it exhibits low affinity for the multiple opioid receptors, whether its pharmacological activities are due to oxycodone activation of the opioid receptor type or due to its active metabolite (oxymorphone) that exhibits high affinity for the mu-opioid receptors remains unresolved. Ross and Smith (1997) reported the antinociceptive effects of oxycodone (171nmol, i.c.v.) are induced by putative kappa-opioid receptors in SD rat while others have reported oxycodone activities are due to activation of mu- and/or delta-opioid receptors. In this study, using male mu-opioid receptor knock-out (MOR-KO) mice, we examined whether delta-opioid receptor was involved in oxycodone antinociception. Systemic subcutaneous (s.c.) administration of oxycodone (above 40mg/kg) could induce a small but significant antinociceptive effect in MOR-KO mice by the tail flick test. Delta-opioid receptor antagonist (naltrindole, 10mg/kg or 20mg/kg, i.p.) could block this effect. When oxycodone was injected directly into the brain of MOR-KO mice by intracerebroventricular (i.c.v.) route, oxycodone at doses of 50nmol or higher could induce similar level of antinociceptive responses to those observed in wild type mice at the same doses by i.c.v. Delta-opioid receptor antagonists (naltrindole at 10nmol or ICI 154,129 at 20MUg) completely blocked the supraspinal antinociceptive effect of oxycodone in MOR-KO mice. Such oxycodone antinociceptive responses were probably not due to its active metabolites oxymorphone because (a) the relative low level of oxymorphone was found in the brain after systemically or centrally oxycodone injection using LC/MS/MS analysis; (b) oxymorphone at a dose that mimics the level detected in the mice brain did not show any significant antinocieption effect; (c) oxycodone exhibits equal potency as oxymorphone albeit being a partial agonist in regulating [Ca(2+)]I transients in a clonal cell line expressing high level of mu opioid receptor. These data suggest that oxycodone by itself can activate both the mu- and delta-opioid receptors and that delta-opioid receptors may contribute to the central antinociceptive effect of oxycodone in mice. PMID- 27496655 TI - "To Reverse or Not To Reverse?": The Answer Is Clear! PMID- 27496656 TI - Nondepolarizing Neuromuscular Blocking Agents, Reversal, and Risk of Postoperative Pneumonia. AB - BACKGROUND: Residual postoperative paralysis from nondepolarizing neuromuscular blocking agents (NMBAs) is a known problem. This paralysis has been associated with impaired respiratory function, but the clinical significance remains unclear. The aims of this analysis were two-fold: (1) to investigate if intermediate-acting NMBA use during surgery is associated with postoperative pneumonia and (2) to investigate if nonreversal of NMBAs is associated with postoperative pneumonia. METHODS: Surgical cases (n = 13,100) from the Vanderbilt University Medical Center National Surgical Quality Improvement Program database who received general anesthesia were included. The authors compared 1,455 surgical cases who received an intermediate-acting nondepolarizing NMBA to 1,455 propensity score-matched cases who did not and 1,320 surgical cases who received an NMBA and reversal with neostigmine to 1,320 propensity score-matched cases who did not receive reversal. Postoperative pneumonia incidence rate ratios (IRRs) and bootstrapped 95% CIs were calculated. RESULTS: Patients receiving an NMBA had a higher absolute incidence rate of postoperative pneumonia (9.00 vs. 5.22 per 10,000 person-days at risk), and the IRR was statistically significant (1.79; 95% bootstrapped CI, 1.08 to 3.07). Among surgical cases who received an NMBA, cases who were not reversed were 2.26 times as likely to develop pneumonia after surgery compared to cases who received reversal with neostigmine (IRR, 2.26; 95% bootstrapped CI, 1.65 to 3.03). CONCLUSIONS: Intraoperative use of intermediate nondepolarizing NMBAs is associated with developing pneumonia after surgery. Among patients who receive these agents, nonreversal is associated with an increased risk of postoperative pneumonia. PMID- 27496657 TI - Resting-state Network-specific Breakdown of Functional Connectivity during Ketamine Alteration of Consciousness in Volunteers. AB - BACKGROUND: Consciousness-altering anesthetic agents disturb connectivity between brain regions composing the resting-state consciousness networks (RSNs). The default mode network (DMn), executive control network, salience network (SALn), auditory network, sensorimotor network (SMn), and visual network sustain mentation. Ketamine modifies consciousness differently from other agents, producing psychedelic dreaming and no apparent interaction with the environment. The authors used functional magnetic resonance imaging to explore ketamine induced changes in RSNs connectivity. METHODS: Fourteen healthy volunteers received stepwise intravenous infusions of ketamine up to loss of responsiveness. Because of agitation, data from six subjects were excluded from analysis. RSNs connectivity was compared between absence of ketamine (wake state [W1]), light ketamine sedation, and ketamine-induced unresponsiveness (deep sedation [S2]). RESULTS: Increasing the depth of ketamine sedation from W1 to S2 altered DMn and SALn connectivity and suppressed the anticorrelated activity between DMn and other brain regions. During S2, DMn connectivity, particularly between the medial prefrontal cortex and the remaining network (effect size beta [95% CI]: W1 = 0.20 [0.18 to 0.22]; S2 = 0.07 [0.04 to 0.09]), and DMn anticorrelated activity (e.g., right sensory cortex: W1 = -0.07 [-0.09 to -0.04]; S2 = 0.04 [0.01 to 0.06]) were broken down. SALn connectivity was nonuniformly suppressed (e.g., left parietal operculum: W1 = 0.08 [0.06 to 0.09]; S2 = 0.05 [0.02 to 0.07]). Executive control networks, auditory network, SMn, and visual network were minimally affected. CONCLUSIONS: Ketamine induces specific changes in connectivity within and between RSNs. Breakdown of frontoparietal DMn connectivity and DMn anticorrelation and sensory and SMn connectivity preservation are common to ketamine and propofol induced alterations of consciousness. PMID- 27496659 TI - Corrigendum to 'Physical properties and depth of cure of a new short fiber reinforced composite' [Dent Mater 29 (8) (2013) 835-841]. PMID- 27496658 TI - Intergenerational associations in numerical approximation and mathematical abilities. AB - Although growing evidence suggests a link between children's math skills and their ability to estimate numerical quantities using the approximate number system (ANS), little is known about the sources underlying individual differences in ANS acuity and their relation with specific mathematical skills. To examine the role of intergenerational transmission of these abilities from parents to children, the current study assessed the ANS acuities and math abilities of 54 children (5-8 years old) and their parents, as well as parents' expectations about children's math skills. Children's ANS acuity positively correlated with their parents' ANS acuity, and children's math abilities were predicted by unique combinations of parents' ANS acuity and math ability depending on the specific math skill in question. These findings provide the first evidence of intergenerational transmission of an unlearned, non-verbal numerical competence and are an important step toward understanding the multifaceted parental influences on children's math abilities. PMID- 27496660 TI - Periprosthetic fracture in the elderly with anatomic modular cementless hemiarthroplasty. AB - BACKGROUND: The use of an anatomic cementless stem in hemiarthroplasties for femoral intracapsular proximal fracture has been debated, notably because of bone weakness and/or morphological defects related to osteoporosis. We therefore conducted a retrospective study in subjects over 75 years of age who had received an anatomic stem partially coated with hydroxyapatite. The objectives were to determine: 1) the incidence of periprosthetic fractures (PPFs) and, 2) the influence of anatomic factors, including the Cortical Bone Ratio (CBR) (the relation between the endosteal and external diameter of the femoral diaphysis 10cm below the lesser trochanter). HYPOTHESIS: The risk of PPF with an anatomic cementless implant is greater than with cemented stems. MATERIAL AND METHODS: We retrospectively analyzed 233 patients followed up for 5 years after their surgery. The stem used was an anatomic stem with a modular neck partially coated with hydroxyapatite. The risk factors examined were age, gender, history of osteoporotic fractures, diverse causes of secondary osteoporosis, and proximal bone stock according to various referenced radiological indices such as the CBR. RESULTS: Twenty patients (15%) were lost to follow-up, 74 had died (32%) but did not undergo revision for PPF, 15 of the 139 survivors at the last follow-up (10.8%) had had a PPF, five (3.6%; four females, one male) were early fractures (<=2 months after implantation), ten (7.2%; two females, eight males) were late fractures (>2 months). Male gender was protective for PPF occurrence (RR=0.129; 95%CI (0.04-0.39); P=0.0003), whereas secondary factors of osteoporosis (RR=2.035; 95%CI (1.11-3.72); P=0.0211), and CBR>0.49 (RR=227.42; 95%CI (1.072 48,226.76); P=0.0471) were found as risk factors of PPF. DISCUSSION: The PPF rate was greater than that related to cemented stems, requiring that morphological and clinical factors of bone weakness (collected with the patient history and related to osteoporosis) be taken into account. A CBR>0.49 requires caution on the use of this type of stem. LEVEL OF EVIDENCE: Level 4. Retrospective study. PMID- 27496661 TI - Predictors of 30-day mortality following hip/pelvis fractures. AB - INTRODUCTION: With the cost of healthcare in the United States reaching $2.9 trillion in 2013 and expected to increase with a growing geriatric population, the Center for Medicare and Medicaid Services (CMS) and Hospital Quality Alliance (HQA) began publicly reporting 30-day mortality rates so that hospitals and physicians may begin to confront clinical problems and promote high-quality and patient-centered care. Though the 30-day mortality is considered a highly effective tool in measuring hospital performance, little data actually exists that explores the rate and risk factors for trauma-related hip and pelvis fractures. Therefore, in this study, we sought to explore the risk factors associated with 30-day mortality in trauma-related hip and pelvic fractures. MATERIALS AND METHODS: Utilizing the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database, 341,062 patients undergoing orthopaedic procedures from 2005 to 2013 were identified through a Current Procedural Terminology (CPT) code search. A second CPT code search identified 24,805 patients who sustained a hip/pelvis fracture. Patient demographics, preoperative comorbidities, operative characteristics and postoperative complications were collected and compared using Chi-squared test, Wilcoxon-Mann-Whitney test and multivariate logistic regression analysis. RESULTS: Preoperative and postoperative risk factors for 30-day mortality following a hip/pelvis fracture were found: ASA classification, ascites, disseminated cancer, dyspnea, functional status, history of congestive heart failure (CHF), history of chronic obstructive pulmonary disease (COPD), a recent blood transfusion, and the postoperative complications: pneumonia, myocardial infarction, stroke, and septic shock. DISCUSSION: Several preoperative patient risk factors and postoperative complications greatly increased the odds for patient mortality following 30-days after initial surgery. Orthopaedic surgeons can utilize these predictive risk factors to better improve patient care. LEVEL OF EVIDENCE: Retrospective study. Level IV. PMID- 27496662 TI - A comparison of double Endobutton and triple Endobutton techniques for acute acromioclavicular joint dislocation. AB - PURPOSE OF THE STUDY: The purpose of this study was to evaluate the results of patients treated with either double Endobutton device or triple Endobutton device for acute acromioclavicular joint dislocations. PATIENTS AND METHODS: Eighty patients were randomized to operative stabilization either by double Endobutton device (group A, 40) or by triple Endobutton device (group B, 40). Preoperative variables included the patients' age, sex, the affected side, cause of injury, Rockwood classification and time from injury to surgery. Peri-operative variables were incision length, blood loss, the operative time and the radiation time, length of hospitalization and hospital costs. Postoperative variables were complications, the Constant and VAS scores and the ability to return to previous work. The coracoclavicular (CC) distance of the affected shoulder was assessed on a standard radiograph and compared with the contralateral normal one. RESULTS: The average follow-up time of group A was 26.5+/-7.3months and group B was 24.2+/ 6.6months. The overall complication rate was similar in both groups (26/40 vs. 24/40, P=0.644). There were no significant differences in the mean incision length, blood loss, the operative and radiation time, length of hospitalization, the Constant and VAS scores, and the ability to return to previous work between the two groups. However, the patients of group B had more hospital costs (3802.5+/-258.5 vs. 2433.6+/-182.5 USD, P=0.000). The radiological assessment revealed no significant difference in the CC distance between the two groups (P=0.625). DISCUSSIONS: Triple Endobutton technique did not show significant clinical advantages over double Endobutton technique. LEVEL OF EVIDENCE: Level II prospective randomized study. PMID- 27496663 TI - Fifty years of research and development of cosmeceuticals: a contemporary review. AB - Facial rejuvenation can be categorized into skincare and facial contouring. Research and development of cosmeceuticals is aimed at addressing the major signs of photoaging: wrinkles, dyschromia, and sallowness. Assessment of photoaging comes in clinical and photographic forms; a photonumeric scale developed by Griffiths et al. has been assured of its validity and reliability for the assessment of severity of photoaging in qualitative studies. Treatment of photoaging comes in two categories: preventive and reversal of signs; whilst sunfactors are the most efficient and essential in preventing photodamage, research and development of cosmeceuticals for facial rejuvenation has been robust, thanks to several landmark studies in the last fifty years, funded by some of the forerunners in contemporary cosmetic industry. Stem cell research remains the current forerunner in research concerning cosmeceuticals. Nevertheless, high-quality, randomized control trials remain scarce within the contemporary literature, and more research and trials without funding by the industry are required to give rise to impartial comparisons between various cosmeceutical products. The "perfect cream" for facial rejuvenation remains elusive. PMID- 27496665 TI - Comparison of Motor-Evoked Potentials Versus Somatosensory-Evoked Potentials as Early Indicators of Neural Compromise in Rat Model of Spinal Cord Compression. AB - STUDY DESIGN: Randomized controlled study comparing the efficacy of intraoperative somatosensory-evoked potentials (SSEPs) versus transcranial motor evoked potentials (TcMEPs) as early indicators of neural compromise and predictors of postoperative function in a rat model of spinal cord compression. OBJECTIVE: To compare the relative efficacy of SSEPs and TcMEPs to detect spinal cord compromise and predict postoperative functional deficit after spinal cord compression. SUMMARY OF BACKGROUND DATA: There is controversy regarding the efficacy of SSEPs versus TcMEPs to detect intraoperative spinal cord compromise and predict functional outcomes. Previous trials provide some guidance as to the role of each modality in spinal cord monitoring but randomized controlled trials, which are not feasible in humans, are lacking. METHODS: Twenty-four adult male Wistar rats were evenly divided into three experimental groups and one control group. The experimental groups were determined according to the length of time that 100% TcMEP signal loss was maintained: 0, 5, or 15 minutes. All animals had standardized preoperative functional testing. Spinal cord compromise was initiated utilizing a validated protocol, which involved compression via a balloon catheter introduced into the thoracic sublaminar space. Both SSEPs and TcMEPs were recorded during cord compression for each experimental group. Functional behavioral testing using two validated methods (tilt and modified Tarlov) was repeated 24 hours after termination of spinal cord compression. Post hoc, animals were redistributed into two functional subgroups, noncompromised and compromised, for statistical analysis. RESULTS: TcMEPs consistently detected spinal cord compromise either in advance of or at the same time as SSEPs; however, the delay in SSEP response was not significant for cases when compromised postoperative function resulted. Both SSEP and TcMEP amplitude recovery correlated well with postoperative functional scores. CONCLUSION: TcMEPs are more sensitive to spinal cord compromise than SSEPs, but the recovery profiles of both SSEP and TcMEP amplitudes are good predictors of postoperative function. LEVEL OF EVIDENCE: 2. PMID- 27496664 TI - Life Expectancy After Cervical En Bloc Laminoplasty: Analysis of Data Following More Than 20 Years. AB - STUDY DESIGN: Case series. OBJECTIVE: To clarify the following questions How long after cervical laminoplasty did the patients die? What were the causes of the death? Was the severity of the neurological dysfunction related to early death? SUMMARY OF BACKGROUND DATA: Life expectancy in patients with cervical myelopathy is unclear. Cervical laminoplasty was performed in 216 patients between 1981 and 1994. It was possible to follow 148 patients for more than 20 years. We used the data of the 68 survivors and the 80 patients had already died. METHODS: As for the patients who died by the final follow-up, the survival rate was analyzed by a Kaplan-Meier plot; the results were compared between the patients with cervical spondylosis (CS) and the patients with ossification of the posterior longitudinal ligament (OPLL). The causes of the death were assessed. The neurological evaluation was graded using the score devised by the Japanese Orthopaedic Association (JOA). The pre- and postoperative scores were compared between the patients in the died group (D group) and the surviving patients group (S group). RESULTS: The mean period from surgery to death was 13.4 +/- 7.4 years. There was no difference in the survival rate between patients with CS and patients with OPLL. The most frequent cause of death was malignant tumor followed by ischemic heart disease. Preoperative JOA score in the D group was lower than that in the S group. There was no statistical difference in postoperative JOA score between the two groups. CONCLUSION: The patients who underwent cervical laminoplasty caused by compression myelopathy due to CS and OPLL had a long life expectancy, averaging more than 13 years. Life expectancy did not differ between patients with CS and patients with OPLL. Neurological deficit did not directly affect the life expectancy. LEVEL OF EVIDENCE: 4. PMID- 27496666 TI - Adults With Idiopathic Scoliosis Diagnosed at Youth Experience Similar Physical Activity and Fracture Rate as Controls. AB - STUDY DESIGN: Cross-sectional. OBJECTIVE: To describe physical activity level and fracture rates in adults with idiopathic scoliosis, diagnosed before maturity, and to compare with a control group. SUMMARY OF BACKGROUND DATA: A previous study found a lower level of sporting activities in adults treated for idiopathic scoliosis compared with controls. Other studies have shown a lower bone mass in adults with idiopathic scoliosis compared with controls. METHODS: One thousand two hundred seventy-eight adults (aged 18-71 yr) with idiopathic scoliosis and 214 controls (aged 18-70 yr) were included and answered the International Physical Activity Questionnaire - Short Form (IPAQ-SF) and questions about previous fractures. The three scoliosis treatment groups (untreated n = 360, brace n = 460, and surgically treated n = 458) were compared. Furthermore, a comparison based on onset (juvenile n = 169 or adolescent n = 976) was performed. Achieved weekly moderate activity level and metabolic equivalent task (MET) minutes/week were assessed for patients and controls. Statistical comparisons were made with analysis of covariance with adjustments for age, body mass index, and sex. RESULTS: The proportion achieving weekly moderate activity level was 962 out of 1278 for individuals with idiopathic scoliosis (75%) and 157 out of 214 (73%) for controls (P = 0.40). The scoliosis patients reported 2016 MET minutes/week (median value) and the controls 2456 (P = 0.06). Fracture rates did not differ (P = 0.72). Fewer surgically treated individuals achieved moderate activity level (P = 0.046) compared with the untreated and the previously braced individuals. No difference was seen regarding MET-minutes/week (P = 0.86). No differences were seen between individuals with a juvenile onset compared with individuals with an adolescent onset (all P >= 0.05). CONCLUSION: Adults with idiopathic scoliosis have similar physical activity level and do not sustain more fractures compared with controls. Adults with surgically treated idiopathic scoliosis have slightly lower physical activity level than previously braced and untreated patients. Onset of idiopathic scoliosis does not affect physical activity level. LEVEL OF EVIDENCE: 2. PMID- 27496667 TI - Hospital-Acquired Conditions in Adult Spinal Deformity Surgery: Predictors for Hospital-Acquired Conditions and Other 30-Day Postoperative Outcomes. AB - STUDY DESIGN: A retrospective study of prospectively collected data. OBJECTIVE: The aim of this study was to identify risk factors in developing hospital acquired conditions (HACs) and association of HACs with other 30-day complications in the adult spinal deformity (ASD) population. SUMMARY OF BACKGROUND DATA: HACs are subject to a nonpayment policy by the Center for Medicare and Medicaid Services and provide an incentive for medical institutions to improve patient safety. HACs in the ASD population may further exacerbate the already high rates of postoperative morbidity and mortality. METHODS: The 2010 to 2014 ACS-NSQIP database was queried using Current Procedural Terminology (CPT) codes for adults who had fusion for spinal deformity. Patients were divided into two cohorts on the basis of the development of an HAC, as defined as a case of surgical site infection, urinary tract infection, or venous thromboembolism. Univariate and multivariate logistic regression analyses were employed to determine predictors for HACs and association of HACs with other 30-day postoperative outcomes. RESULTS: Five thousand eight hundred nineteen patients met the inclusion criteria for the study of whom 313 (5.4%) had an HAC. Multivariate logistic regression analysis revealed that age 61 to 70 versus <=50 years [odds ratio (OR) = 1.58, 1.10-2.27, P = 0.013], 71 to 80 versus <=50 years (OR = 1.94, 1.31-2.87, P = 0.001), and >80 versus <=50 years (OR = 2.30, 1.21 4.37, P = 0.011), dependent/partially dependent versus independent functional status (OR = 1.74, 1.13-2.68, P = 0.011), combined versus anterior surgical approach (OR = 2.46, 1.43-4.24, P = 0.001), and posterior versus anterior surgical approach (OR = 1.64, 1.19-2.25, P = 0.002), osteotomies (OR = 1.61, 1.22 2.13, P = 0.001), steroid use (OR = 2.19, 1.39-3.45, P = 0.001), obesity (OR = 1.38, 1.09-1.74, P = 0.007), and operation time >=4 hours (OR = 2.42, 1.82-3.21, P < 0.001) were predictive factors in developing an HAC. CONCLUSION: Several modifiable and nonmodifiable factors (age, functional status, surgical approach, utilization of osteotomies, steroid use, obesity, and operation time >=4 hours) were associated with developing an HAC. HACs were also risk factors for other postoperative complications. LEVEL OF EVIDENCE: 3. PMID- 27496668 TI - Transpars Microscopic Approach for the Treatment of Purely Foraminal Herniated Lumbar Disc: A Clinical, Radiological, Two-center Study. AB - STUDY DESIGN: This is a prospective two-center study. OBJECTIVE: The aim of this study was to assess the safety and efficacy of treating patients with lumbar foraminal disc herniations via a microscopic transpars approach, with a clinical and radiological follow-up evaluation. SUMMARY OF BACKGROUND DATA: Purely foraminal lumbar disc herniations comprise about 5% of all lumbar herniated intervertebral discs. Operative management can be technically difficult, and the optimum surgical treatment remains controversial. METHODS: From January 2012 to January 2015, 47 patients were prospectively recruited. Patients were followed-up as outpatients at 1 week after discharge, then at 1, 6, and 12 months.A clinical multiparametric evaluation of patients including numeric rating scale (NRS), drugs intake, Macnab criteria, and working days lost was used.Postoperative dynamic x-rays (flexion, extension) were performed in all cases 12 months after surgery. RESULTS: No surgery-related complications occurred.Among the 35 patients who were not retired at the time of the study, 29 patients returned to work and to normal daily activities within 60 days after surgery.Pain evaluation at discharge showed a significant improvement of NRS score, from 8.93 to 1.45 at 12 months. Root palsy significantly improved in all cases already at 1-month follow up. Drugs intake analysis showed that at 6-month follow-up, no patients used steroids, or opioids, 17 patients used non-steroidal anti-inflammatory drugs when needed, and 29 patients (61.7%) used no drugs for pain relief. No significant variations occurred at 12-month-follow-up.At 12-month follow-up, excellent or good outcome (following Macnab criteria) was achieved in 36 (76.6%) and 8 (17%) patients, respectively.There were no cases of spinal instability at 12-month radiological evaluation.No recurrence occurred at follow-up. CONCLUSION: Transpars microscopic approach is effective and safe for the treatment of FLDH, but larger studies are needed. LEVEL OF EVIDENCE: 3. PMID- 27496669 TI - Risks of inhibitors from recombinant factor VIII: a quarter of a century to reach the conclusion. PMID- 27496670 TI - Identification of a novel homozygous mutation Arg459Pro in SYNJ1 gene of an Indian family with autosomal recessive juvenile Parkinsonism. AB - BACKGROUND: A novel homozygous missense mutation (c.773G > A, p.Arg258Gln) in Synaptojanin 1 (SYNJ1, 21q22.2) has recently been reported in two Italian and one Iranian consanguineous families with autosomal recessive juvenile Parkinsonism (ARJP). Contribution of this synaptic gene related to Parkinsonism phenotypes in other populations still remains unidentified. METHODS: An ARJP family with two affected siblings characterized by frequent tremor with bradykinesia and rigidity was recruited in this study. Both siblings showed intense dyskinesia and dystonia on administration of Syndopa. The family was analyzed for both mutations and exon dosage variations in PARKIN, PINK1 and DJ1. Further, whole exome sequencing was performed in two affected and one unaffected sibling in the family. RESULTS: We identified a novel homozygous mutation (c.1376C > G, p.Arg459Pro) in SYNJ1 segregating in this family. This p.Arg459Pro mutation was not observed in 285 additional Parkinson disease (PD) samples (32 familial, 81 early onset and 172 late onset) screened by PCR-Sanger-sequencing. It was also absent in dbSNP, 1000 Genomes, ExAC, NHLBI-ESP database and in >250 ethnically matched exomes available in our laboratory. The arginine residue is highly conserved across species and predicted to be damaging by several in silico tools. As with the previous mutation p.Arg258Gln, p.Arg459Pro is also present in Sac 1 domain of SYNJ1 wherein p.Arg258Gln mutation has already been described to impair the phosphatase activity. CONCLUSIONS: We report another novel mutation in SYNJ1 of an Indian consanguineous ARJP family. Finding an additional mutation in this gene further supports the involvement of SYNJ1 in PD pathogenesis across different ethnicities. PMID- 27496671 TI - Imaging transcranial direct current stimulation (tDCS) of the prefrontal cortex correlation or causality in stimulation-mediated effects? AB - Transcranial current stimulation approaches include neurophysiologically distinct non-invasive brain stimulation techniques widely applied in basic, translational and clinical research: transcranial direct current stimulation (tDCS), oscillating transcranial direct current stimulation (otDCS), transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS). Prefrontal tDCS seems to be an especially promising tool for clinical practice. In order to effectively modulate relevant neural circuits, systematic research on prefrontal tDCS is needed that uses neuroimaging and neurophysiology measures to specifically target and adjust this method to physiological requirements. This review therefore analyses the various neuroimaging methods used in combination with prefrontal tDCS in healthy and psychiatric populations. First, we provide a systematic overview on applications, computational models and studies combining neuroimaging or neurophysiological measures with tDCS. Second, we categorise these studies in terms of their experimental designs and show that many studies do not vary the experimental conditions to the extent required to demonstrate specific relations between tDCS and its behavioural or neurophysiological effects. Finally, to support best-practice tDCS research we provide a methodological framework for orientation among experimental designs. PMID- 27496673 TI - Reply. PMID- 27496675 TI - A case of deep dissecting hematoma: different managements resulting in similar outcomes. PMID- 27496674 TI - Reply. PMID- 27496676 TI - Effect of the In Vitro Boundary Conditions on the Surface Strain Experienced by the Vertebral Body in the Elastic Regime. AB - The vertebral strength and strain can be assessed in vitro by both using isolated vertebrae and sets of three adjacent vertebrae (the central one is loaded through the disks). Our goal was to elucidate if testing single-vertebra-specimens in the elastic regime provides different surface strains to three-vertebrae-segments. Twelve three-vertebrae sets were extracted from thoracolumbar human spines. To measure the principal strains, the central vertebra of each segment was prepared with eight strain-gauges. The sets were tested mechanically, allowing comparison of the surface strains between the two boundary conditions: first when the same vertebra was loaded through the disks (three-vertebrae-segment) and then with the endplates embedded in cement (single-vertebra). They were all subjected to four nondestructive tests (compression, traction, torsion clockwise, and counterclockwise). The magnitude of principal strains differed significantly between the two boundary conditions. For axial loading, the largest principal strains (along vertebral axis) were significantly higher when the same vertebra was tested isolated compared to the three-vertebrae-segment. Conversely, circumferential strains decreased significantly in the single vertebrae compared to the three-vertebrae-segment, with some variations exceeding 100% of the strain magnitude, including changes from tension to compression. For torsion, the differences between boundary conditions were smaller. This study shows that, in the elastic regime, when the vertebra is loaded through a cement pot, the surface strains differ from when it is loaded through the disks. Therefore, when single vertebrae are tested, surface strain should be taken with caution. PMID- 27496677 TI - Anti-Inflammatory and Anti-Oxidant Effects of p-Chloro-phenyl-selenoesterol on TNBS-Induced Inflammatory Bowel Disease in Mice. AB - This study aims to investigate the protective effect of p-chloro-phenyl selenoesterol [PCS; 0,2 mg/kg; 10 ml/kg i.g.) in colitis induced by 2,4,6 trinitrobenzene sulfonic acid [TNBS; 2 mg/100 ul 50% ethanol; intrarectally) in mice. Several parameters including weight, length, histological analyses determination, thiobarbituric acid reactive species, reactive species levels, superoxide dismutase, catalase, and myeloperoxidase (MPO) activity of colon were evaluated. The serum levels of tumor necrosis factor alpha [TNF-alpha) and interleukin 6 [IL-6) were also assessed. Treatment with PCS reduced the clinical and histopathologic severity of TNBS-induced colitis, characterized by colon length reduction and increased colon weight and microscopic intestinal inflammation. The therapeutic effects of PCS in this model were associated with significant decrease in proinflammatory cytokines TNF-alpha and IL-6 and decrease in MPO activity. Furthermore, combined with improvements in inflammatory parameters, treatment with the PCS was able to decrease oxidative stress and to prevent the decrease in antioxidant defenses in animals with TNBS-induced colitis. This finding suggests that PCS can improve experimental colitis in mice and it could be a potential therapeutic agent for the treatment of patients with IBD. J. Cell. Biochem. 118: 709-717, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27496672 TI - Behavioral, emotional and neurobiological determinants of coronary heart disease risk in women. AB - Women have more of the stress-related behavioral profile that has been linked to cardiovascular disease than men. For example, women double the rates of stress related mental disorders such as depression and posttraumatic stress disorder (PTSD) than men, and have higher rates of exposure to adversity early in life. This profile may increase women's long-term risk of cardiometabolic conditions linked to stress, especially coronary heart disease (CHD). In addition to having a higher prevalence of psychosocial stressors, women may be more vulnerable to the adverse effects of these stressors on CHD, perhaps through altered neurobiological physiology. Emerging data suggest that young women are disproportionally susceptible to the adverse effects of stress on the risk of cardiovascular disease, both in terms of initiating the disease as well as worsening the prognosis in women who have already exhibited symptoms of the disease. Women's potential vulnerability to psychosocial stress could also help explain their higher propensity toward abnormal coronary vasomotion and microvascular disease compared with men. PMID- 27496678 TI - Pharmacokinetics of Cefepime in Patients with Cancer and Febrile Neutropenia in the Setting of Hematologic Malignancies or Hematopoeitic Cell Transplantation. AB - STUDY OBJECTIVE: To evaluate the steady-state pharmacokinetic parameters of standard cefepime dosing regimens in a hematologic malignancy and hematopoietic cell transplant patient population with febrile neutropenia. DESIGN: Open-label, single-center, prospective pharmacokinetic study. SETTING: National Cancer Institute-designated cancer center. PATIENTS: Nine adults with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia and were admitted to a hematology-oncology service between January and July 2014. INTERVENTION: Patients received empirical cefepime 2 g every 8 hours, administered as a 30-minute intravenous infusion, for febrile neutropenia. MEASUREMENTS AND MAIN RESULTS: Steady-state cefepime serum concentrations were measured after at least 2 days of continuous therapy. Venous blood samples were intensively sampled between 0 and 8 hours after the start of the 30-minute infusion at steady state. Seven of the nine patients had a hematologic malignancy diagnosis of acute leukemia, lymphoma, or myeloma, and two patients had a germ cell tumor diagnosis. Noncompartmental analysis revealed mean +/- SD parameters as follows at steady state: area under the plasma concentration-time curve from 0 8 hours 222.9 +/- 72.9 mg hour/L, maximum concentration 120.9 +/- 21.8 mg/L, clearance 9.7 +/- 3.7 L/hour, apparent volume of distribution 19.2 +/- 4.65 L, and elimination half-life 1.4 +/- 0.3 hours. A one-compartment pharmacokinetic model identified a mean +/- SD volume of distribution of 20.9 +/- 1.3 L and an elimination rate constant of 0.39 +/- 0.03 hour(-1) . The mean estimated percentage of time that drug concentration remains above the pathogen minimum inhibitory concentration (fT>MIC) in serum was 55%, 77%, and 99% at MICs of 16, 8, and 4 mg/L, respectively. CONCLUSION: Patients with hematologic malignancies or hematopoietic cell transplants who had febrile neutropenia demonstrated homogeneous calculated cefepime volumes and clearances. The population parameters presented in this study may aid in the calculation of patient-specific fT>MIC for similar patients. PMID- 27496679 TI - Thalidomide and POEMS syndrome: a cautious step forward. PMID- 27496681 TI - Shoulder Arthroscopy in Adults 60 or Older: Risk Factors That Correlate With Postoperative Complications in the First 30 Days. AB - PURPOSE: To investigate the 30-day postoperative adverse event (AE) rates of adults 60 years or older after shoulder arthroscopy and identify risk factors for complications in this patient population. METHODS: Patients aged 60 or more who underwent shoulder arthroscopy were identified in the American College of Surgeons National Surgery Quality Improvement Program database from 2006 to 2013 using 12 Current Procedural Terminology codes related to shoulder arthroscopy. Complications were categorized as severe AEs, minor AEs, and infectious AEs for separate analyses. Pearson's chi2 tests were used to identify associations between patient characteristics and AE occurrence and binary logistic regression for multivariate analysis of independent risk factors. RESULTS: In total, 7,867 patients were included for analysis. Overall, 1.6% (n = 127) of the older adults experienced at least one AE with 1.1% (n = 90) severe AEs, 0.6% (n = 46) minor AEs, and 0.4% (n = 28) infectious complications. Multivariate analysis revealed that age 80 years or older (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.2-2.7, P = .01), body mass index greater than 35 (OR = 1.8, 95% CI = 1.1-2.7, P = .01), functionally dependent status (OR = 2.9, 95% CI = 1.3-6.8, P = .01), American Society of Anesthesiologists class greater than 2 (OR = 1.5, 95% CI = 1.0-2.2, P = .04), congestive heart failure (OR = 6.1, 95% CI = 1.8-21.2, P = .03), disseminated cancer (OR = 7.9, 95% CI = 1.4-43.9, P = .02), and existence of an open wound at the time of surgery (OR = 4.0, 95% CI = 1.1-14.6, P = .03) were independently associated with the occurrence of an AE. Nineteen of the patients included in the study required readmission to the hospital within the 30 day period for an overall readmission rate of 0.2%. CONCLUSIONS: Patients 60 years or older who underwent shoulder arthroscopy for a variety of indications have a low overall 30-day postoperative complication rate of 1.6%. Although low, this is a higher rate than previously reported for the overall shoulder arthroscopy population. Independent patient characteristics associated with increased risk of AE occurrence included age 80 years or older, body mass index greater than 35, functional dependent status, American Society of Anesthesiologists score of 3 or 4, congestive heart failure, disseminated cancer, and existence of an open wound. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 27496680 TI - Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare cause of demyelinating neuropathy, with multi organ involvement characterised by plasma cell dyscrasia and VEGF overproduction. No treatments have been established for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide suppresses VEGF and plasma cell proliferation. We aimed to assess the safety and efficacy of thalidomide for the treatment of POEMS syndrome. METHODS: We did a randomised, double-blind, placebo-controlled, phase 2/3 trial at 12 hospitals in Japan. Adults (age >=20 years) with POEMS syndrome who were ineligible for autotransplantation were randomly assigned (1:1) by a minimisation method to treatment with oral dexamethasone (12 mg/m(2) per day on the first 4 days of every 28-day cycle) plus either oral thalidomide (200 mg daily) or placebo for six cycles. All study personnel and patients were masked to treatment allocation. The primary endpoint was the reduction rate of serum VEGF concentrations at 24 weeks. Analysis was by intention to treat. This study is registered with the UMIN Clinical Trials Registry, UMIN000004179. FINDINGS: Between Nov 11, 2010, and July 3, 2014, we randomly assigned 25 patients to receive either thalidomide (n=13) or placebo (n=12); one patient in the placebo group was excluded from analyses because of a protocol violation. The adjusted mean VEGF concentration reduction rate at 24 weeks was 0.39 (SD 0.34) in the thalidomide group compared with -0.02 (0.54) in the placebo group (adjusted mean difference 0.41, 95% CI 0.02-0.80; p=0.04). Mild sinus bradycardia was more frequent in the thalidomide group than in the placebo group (seven [54%] vs zero; p=0.006). Five patients had serious adverse events: three in the thalidomide group (transient cardiac arrest, heart failure, and dehydration) and two in the placebo group (ileus and fever). No deaths occurred during the randomised study. In the 48-week open-label study period (n=22), newly developed adverse events were sinus bradycardia (n=4), constipation (n=5), and mild sensory neuropathy (n=5). Two patients died in the open-label study; both patients were initially in the placebo group, and the cause of death was progression of the disease. INTERPRETATION: Thalidomide reduces serum VEGF concentrations and represents a new treatment for patients with POEMS syndrome who are not eligible for stem-cell transplantation. Thalidomide treatment poses a risk of bradycardia; however, the benefits are likely to exceed the risk. FUNDING: Japanese Ministry of Health, Labour, and Welfare, and Fujimoto Pharmaceuticals. PMID- 27496682 TI - The composition of surface wax on trichomes of Arabidopsis thaliana differs from wax on other epidermal cells. AB - To protect plants against biotic and abiotic stress, the waxy cuticle must coat all epidermis cells. Here, two independent approaches addressed whether cell-type specific differences exist between wax compositions on trichomes and other epidermal cells of Arabidopsis thaliana, possibly with different protection roles. First, the total waxes from a mutant lacking trichomes (gl1) were compared to waxes from wild type and a trichome-rich mutant (cpc tcl1 etc1 etc3). In the stem wax, compounds with aliphatic chains longer than 31 carbons (derived from C32 precursors) increased in relative abundance in cpc tcl1 etc1 etc3 over gl1. Similarly, the leaf wax from the trichome-rich mutant contained higher amounts of C32+ compounds as compared to gl1. Second, leaf trichomes were isolated, and their waxes were analyzed. The wax mixtures of the trichome-rich mutant and the wild type were similar, comprising alkanes and alkenes as well as branched and unbranched primary alcohols. The direct analyses of trichome waxes confirmed that they contained relatively high concentrations of C32+ compounds, compared with the pavement cell wax inferred from analysis of gl1 leaves. Finally, the cell type-specific wax compositions were put into perspective with expression patterns of wax biosynthesis genes in trichomes and pavement cells. Analyses of published transcriptome data (Marks et al., ) revealed that core enzymes involved in elongation of wax precursors to various carbon chain lengths are expressed differentially between epidermis cell types. By combining the chemical and gene expression data, we identified promising gene candidates involved in the formation of C32+ aliphatic chains. PMID- 27496683 TI - Antifouling booster biocides in coastal waters of Panama: First appraisal in one of the busiest shipping zones. AB - A baseline study for antifouling booster biocides in coastal waters of Panama is presented. Solid Phase Extraction (SPE) was used for extraction and Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS) was applied for the quantification of irgarol 1051, diuron, (2-thiocyanomethylthio)benzothiazole (TCMTB), 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) and dichlofluanid. TCMTB, DCOIT and dichlofluanid were not detected in any seawater sample, while irgarol 1051 and diuron were found in four out of thirteen areas (<0.3 to 5.0ngL 1 and <2.7 to 70ngL-1, respectively). Although the hotspots were identified in areas influenced by marinas and in one of the ports, diuron and irgarol 1051 levels were all lower than the threshold levels set by the Environmental Quality Standard of United Kingdom. However, this is only a snapshot of the status of costal water contamination by antifouling booster biocides and a more comprehensive assessment is needed to assess risks associated to long term exposure. PMID- 27496684 TI - Influence of geographic setting on thermal discharge from coastal power plants. AB - Characteristics of thermal discharge from three coastal power plants were studied in China. The three plants, Zhuhai Power Plant, Chaozhou Power Plant and Huilai Power Plant, are located in estuary, bay and open sea, respectively. The water temperatures and ocean currents surrounding the outlet of the three power plants were monitored. The results show that the temperature rise became smaller as the spread of thermal discharge moved toward the open sea, which confirms the results of previous studies. The results also indicated that the influence range of thermal discharge from a coastal power plant is determined by geographic setting. The temperature rise range of the Chaozhou Plant, which is located in a bay, was the largest, followed by that of the Zhuhai Plant located in an estuary, and the temperature rise range of the Huilai Plant located in an open sea was the smallest. PMID- 27496685 TI - Spatial and temporal analysis of the risks posed by polychlorinated biphenyl and metal contaminants in dab (Limanda limanda) collected from waters around England and Wales. AB - The metals cadmium, mercury and lead, and the ICES7 CB levels were analysed in the common dab Limanda limanda to investigate whether concentrations of these determinants are at levels above established OSPAR assessment criteria around England and Wales. The results indicate that CB118 is above the OSPAR derived EAC at 22 out of 29 sampled stations, with 15 showing significant reductions. Cadmium is increasing significantly at six stations with two sites in the North Sea breaching corresponding OSPAR EAC. Mean results for all other PCBs and metals stayed below the EAC thresholds, with Hg concentrations even falling below BAC levels at South Eddystone located in the western English Channel. This study shows that PCBs banned over 20years ago are still found at concentrations in fish liver tissues which may pose a health risk to both the individual fish and their predators. PMID- 27496686 TI - The Physician Payments Sunshine Act: a smokescreen if no action! PMID- 27496688 TI - Reply. PMID- 27496687 TI - The Management of Myelomeningocele Study: obstetrical outcomes and risk factors for obstetrical complications following prenatal surgery. AB - BACKGROUND: The Management of Myelomeningocele Study was a multicenter randomized trial to compare prenatal and standard postnatal closure of myelomeningocele. The trial was stopped early at recommendation of the data and safety monitoring committee and outcome data for 158 of the 183 randomized women published. OBJECTIVE: In this report, pregnancy outcomes for the complete trial cohort are presented. We also sought to analyze risk factors for adverse pregnancy outcome among those women who underwent prenatal myelomeningocele repair. STUDY DESIGN: Pregnancy outcomes were compared between the 2 surgery groups. For women who underwent prenatal surgery, antecedent demographic, surgical, and pregnancy complication risk factors were evaluated for the following outcomes: premature spontaneous membrane rupture <=34 weeks 0 days (preterm premature rupture of membranes), spontaneous membrane rupture at any gestational age, preterm delivery at <=34 weeks 0 days, nonintact hysterotomy (minimal uterine wall tissue between fetal membranes and uterine serosa, or partial or complete dehiscence at delivery), and chorioamniotic membrane separation. Risk factors were evaluated using chi2 and Wilcoxon tests and multivariable logistic regression. RESULTS: A total of 183 women were randomized: 91 to prenatal and 92 to postnatal surgery groups. Analysis of the complete cohort confirmed initial findings: that prenatal surgery was associated with an increased risk for membrane separation, oligohydramnios, spontaneous membrane rupture, spontaneous onset of labor, and earlier gestational age at birth. In multivariable logistic regression of the prenatal surgery group adjusting for clinical center, earlier gestational age at surgery and chorioamniotic membrane separation were associated with increased risk of spontaneous membrane rupture (odds ratio, 1.49; 95% confidence interval, 1.01-2.22; and odds ratio, 2.96, 95% confidence interval, 1.05-8.35, respectively). Oligohydramnios was associated with an increased risk of subsequent preterm delivery (odds ratio, 9.21; 95% confidence interval, 2.19 38.78). Nulliparity was a risk factor for nonintact hysterotomy (odds ratio, 3.68; 95% confidence interval, 1.35-10.05). CONCLUSION: Despite the confirmed benefits of prenatal surgery, considerable maternal and fetal risk exists compared with postnatal repair. Early gestational age at surgery and development of chorioamniotic membrane separation are risk factors for ruptured membranes. Oligohydramnios is a risk factor for preterm delivery and nulliparity is a risk factor for nonintact hysterotomy at delivery. PMID- 27496689 TI - Quality of life outcomes associated with treatment of human immunodeficiency virus (HIV) facial lipoatrophy. AB - Facial lipoatrophy (FLA), characterized by a decrease in facial volume, has a high prevalence in patients with human immunodeficiency virus (HIV) infection treated with long-term highly active antiretroviral therapy (HAART). The social stigmatization that results from such changes in facial appearance has led some HIV patients to discontinue HAART. The use of fillers is one method of restoring facial volume. A critical outcome of treatment concerns the patient's quality of life (QoL). Although many studies have assessed patient satisfaction, as well as the social and psychological outcomes associated with the correction of HIV FLA, fewer studies have assessed QoL. We reviewed treatment options for HIV FLA with a specific focus on QoL outcomes. Our analysis revealed that the following treatments were associated with improvements in QoL: poly-l-lactic acid; calcium hydroxylapatite; hyaluronic acid; polyacrylamide gel; polyalkylamide gel; polymethylmethacrylate; silicone oil; and autologous fat transfer. The treatment of HIV FLA with these agents appears to improve QoL as assessed by various QoL instruments. Additional studies are required to identify a unifying QoL instrument to effectively assess longitudinal QoL outcomes and to compare treatment modalities. PMID- 27496690 TI - BPTU, an allosteric antagonist of P2Y1 receptor, blocks nerve mediated inhibitory neuromuscular responses in the gastrointestinal tract of rodents. AB - P2Y1 receptors mediate nerve mediated purinergic inhibitory junction potentials (IJP) and relaxations in the gastrointestinal (GI) tract in a wide range of species including rodents and humans. A new P2Y1 antagonist, with a non nucleotide structure, BPTU, has recently been described using X-ray crystallography as the first allosteric G-protein-coupled receptor antagonist located entirely outside of the helical bundle. In this study, we tested its effect on purinergic responses in the gastrointestinal tract of rodents using electrophysiological and myographic techniques. BPTU concentration dependently inhibited purinergic inhibitory junction potentials and inhibition of spontaneous motility induced by electrical field stimulation in the colon of rats (EC50 = 0.3 MUM) and mice (EC50 = 0.06 MUM). Mechanical inhibitory responses were also concentration-dependently blocked in the stomach of both species. Compared to MRS2500, BPTU displays a lower potency. In the rat colon nicotine induced relaxation was also blocked by BPTU. BPTU also blocked the cessation of spontaneous contractility elicited by ADPbetaS and the P2Y1 agonist MRS2365. We conclude that BPTU is a novel antagonist with different structural and functional properties than nucleotidic antagonists that is able to block the P2Y1 receptor located at the neuromuscular junction of the GI tract. PMID- 27496691 TI - GLP-1 and estrogen conjugate acts in the supramammillary nucleus to reduce food reward and body weight. AB - The obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. Combining gut/brain peptide, GLP-1, with estrogen into a conjugate may represent a novel, safe and potent, strategy to treat diabesity. Here we demonstrate that the central administration of GLP-1 estrogen conjugate reduced food reward, food intake, and body weight in rats. In order to determine the brain location of the interaction of GLP-1 with estrogen, we avail of single-photon emission computed tomography imaging of regional cerebral blood flow and pinpoint a brain site unexplored for its role in feeding and reward, the supramammillary nucleus (SUM) as a potential target of the conjugated GLP-1-estrogen. We confirm that conjugated GLP-1 and estrogen directly target the SUM with site-specific microinjections. Additional microinjections of GLP-1-estrogen into classic energy balance controlling nuclei, the lateral hypothalamus (LH) and the nucleus of the solitary tract (NTS) revealed that the metabolic benefits resulting from GLP-1-estrogen injections are mediated through the LH and to some extent by the NTS. In contrast, no additional benefit of the conjugate was noted on food reward when the compound was microinjected into the LH or the NTS, identifying the SUM as the only neural substrate identified here to underlie the reward reducing benefits of GLP-1 and estrogen conjugate. Collectively we discover a surprising neural substrate underlying food intake and reward effects of GLP-1 and estrogen and uncover a new brain area capable of regulating energy balance and reward. PMID- 27496693 TI - Thirtieth Anniversary Issue of Clinical Rehabilitation: an introductory editorial. PMID- 27496692 TI - Oestrus synchronisation and superovulation alter the production and biochemical constituents of ovine cervicovaginal mucus. AB - Controlled breeding programmes utilising exogenous hormones are common in the Australian sheep industry, however the effects of such programmes on cervicovaginal mucus properties are lacking. As such, the aim of this study was to investigate cervicovaginal (CV) mucus from naturally cycling (NAT), progesterone synchronised (P4), prostaglandin synchronised (PGF2alpha), and superovulated (SOV) Merino ewes. Experiment 1; volume, colour, spinnbarkeit, chemical profile and protein concentration of mucus (NAT, P4, PGF2alpha and SOV; n=5 ewes/treatment) during the follicular (5 d) and luteal phases (8 d) was investigated. Experiment 2; in vivo mucus pH and in vitro mucus penetration by frozen-thawed spermatozoa (NAT, P4 and SOV; n=11 ewes/treatment) was investigated over oestrus (2 d) and the mid-luteal phase (pH only, 2 d). Oestrus mucus was more abundant, clearer in colour and less proteinaceous than luteal phase mucus (p<0.05). SOV increased mucus production and protein concentration (p<0.05) while PGF2alpha reduced mucus volume (p<0.05). Mucus pH (oestrus 6.2-6.5), chemical profile and mucus penetration by sperm were unchanged (p>0.05). Results indicate that exogenous hormones used for controlled breeding affect cervicovaginal mucus production, but few other tested characteristics. Further research is required to explain fertility differences between synchronised and naturally cycling animals following cervical AI. PMID- 27496694 TI - Having an impact, making a difference: the Editor's review of the first 30 years. AB - OBJECTIVES: To review publications in Clinical Rehabilitation over the last 30 years, discerning the original goals and whether they were met, and describing major trends over the 30 years. METHODS: Personal review, backed up by data from 'most read' articles and 'most cited' articles, from yearly lists of all controlled trials published in the journal and other sources. RESULTS: The original goals included making rehabilitation better understood both within and outside the speciality, and more scientific. The first goal is probably not achieved, but the scientific standard of publication is much higher and it routinely recommends the use of guidelines appropriate to the publication. The journal has established a pre-eminent position in publishing randomized controlled trials, systematic reviews and articles on goal-setting. It has developed a series describing rehabilitation interventions. It aims to increase consideration of the theoretical basis of rehabilitation practices. We would like to think its impact has increased - but we cannot prove that! CONCLUSION: The journal has established some credentials as being a source of clinically relevant evidence and guidance across the whole field of rehabilitation and across most disabling conditions. PMID- 27496695 TI - How have research questions and methods used in clinical trials published in Clinical Rehabilitation changed over the last 30 years? AB - Research in rehabilitation has grown from a rare phenomenon to a mature science and clinical trials are now common. The purpose of this study is to estimate the extent to which questions posed and methods applied in clinical trials published in Clinical Rehabilitation have evolved over three decades with respect to accepted standards of scientific rigour. Studies were identified by journal, database, and hand searching for the years 1986 to 2016.A total of 390 articles whose titles suggested a clinical trial of an intervention, with or without randomization to form groups, were reviewed. Questions often still focused on methods to be used (57%) rather than what knowledge was to be gained. Less than half (43%) of the studies delineated between primary and secondary outcomes; multiple outcomes were common; and sample sizes were relatively small (mean 83, range 5 to 3312). Blinding of assessors was common (72%); blinding of study subjects was rare (19%). In less than one-third of studies was intention-to-treat analysis done correctly; power was reported in 43%. There is evidence of publication bias as 83% of studies reported either a between-group or a within group effect. Over time, there was an increase in the use of parameter estimation rather than hypothesis testing and there was evidence that methodological rigour improved.Rehabilitation trialists are answering important questions about their interventions. Outcomes need to be more patient-centred and a measurement framework needs to be explicit. More advanced statistical methods are needed as interventions are complex. Suggestions for moving forward over the next decades are given. PMID- 27496696 TI - Promoting physical activity in low back pain patients: six months follow-up of a randomised controlled trial comparing a multicomponent intervention with a low intensity intervention. AB - OBJECTIVE: To assess a comprehensive multicomponent intervention against a low intensity intervention for promoting physical activity in chronic low back pain patients. DESIGN: Randomised controlled trial. SETTING: Inpatient rehabilitation and aftercare. SUBJECTS: A total of 412 patients with chronic low back pain. INTERVENTIONS: A multicomponent intervention (Movement Coaching) comprising of small group intervention (twice during inpatient rehabilitation), tailored telephone aftercare (twice after rehabilitation) and internet-based aftercare (web 2.0 platform) versus a low level intensity intervention (two general presentations on physical activity, download of the presentations). MAIN MEASURES: Physical activity was measured using a questionnaire. Primary outcome was total physical activity; secondary outcomes were setting specific physical activity (transport, workplace, leisure time) and pain. Comparative group differences were evaluated six months after inpatient rehabilitation. RESULTS: At six months follow-up, 92 participants in Movement Coaching (46 %) and 100 participants in the control group (47 %) completed the postal follow-up questionnaire. No significant differences between the two groups could be shown in total physical activity (P = 0.30). In addition to this, workplace (P = 0.53), transport (P = 0.68) and leisure time physical activity (P = 0.21) and pain (P = 0.43) did not differ significantly between the two groups. In both groups, physical activity decreased during the six months follow-up. CONCLUSIONS: The multicomponent intervention was no more effective than the low intensity intervention in promoting physical activity at six months follow-up. The decrease in physical activity in both groups is an unexpected outcome of the study and indicates the need for further research. PMID- 27496697 TI - The development and validation of a novel outcome measure to quantify mobility in the dysvascular lower extremity amputee: the amputee single item mobility measure. AB - OBJECTIVE: This study describes the development and psychometric evaluation of a novel patient-reported single-item mobility measure. DESIGN: Prospective cohort study. SETTING: Four Veteran's Administration Medical Centers. SUBJECTS: Individuals undergoing their first major unilateral lower extremity amputation; 198 met inclusion criteria; of these, 113 (57%) enrolled. INTERVENTIONS: None. MAIN MEASURES: The Amputee Single Item Mobility Measure, a single item measure with scores ranging from 0 to 6, was developed by an expert panel, and concurrently administered with the Locomotor Capabilities Index-5 (LCI-5) and other outcome measures at six weeks, four months, and 12 months post-amputation. Criterion and construct validity, responsiveness, and floor/ceiling effects were evaluated. Responsiveness was assessed using the standardized response mean. RESULTS: The overall mean 12-month Amputee Single Item Mobility Measure score was 3.39 +/-1.4. Scores for transmetatarsal, transtibial, and transfemoral amputees were 4.2 (+/-1.3), 3.2 (+/-1.5), and 2.9 (+/-1.1), respectively. Amputee Single Item Mobility Measure scores demonstrated "large" and statistically significant correlations with the LCI-5 scores at six weeks (r = 0.72), four months (r = 0.81), and 12 months (r = 0.86). At four months and 12 months, the correlation between Amputee Single Item Mobility Measure scores and hours of prosthetic use were r = 0.69 and r = 0.66, respectively, and between Amputee Single Item Mobility Measure scores and Trinity Amputation and Prosthesis Experience Scales functional restriction scores were r = 0.45 and r = 0.67, respectively. Amputee Single Item Mobility Measure scores increased significantly from six weeks to 12 months post-amputation. Minimal floor/ceiling effects were demonstrated. CONCLUSIONS: In the unilateral dysvascular amputee, the Amputee Single Item Mobility Measure has strong criterion and construct validity, excellent responsiveness, and does not exhibit floor/ceiling effects. PMID- 27496698 TI - Determinants of pain and functioning in knee osteoarthritis: a one-year prospective study. AB - OBJECTIVE: To identify predictors of pain and disability in knee osteoarthritis. DESIGN: A one-year prospective analysis of determinants of pain and functioning in knee osteoarthritis. STUDY SETTING: Primary care providers in a medium-sized city. PATIENTS: A total of 111 patients aged from 35 to 75 with clinical symptoms and radiographic grading (Kellgren-Lawrence 2-4) of knee osteoarthritis who participated in a randomized controlled trial. MAIN MEASURES: The outcome measures were self-reported pain and function, which were recorded at 0, 3 and 12 months. Disease-specific pain and functioning were assessed using the pain and function subscales of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index. Generic physical and mental functioning were assessed using the RAND-36 subscales for function, and physical and mental component summary scores. Possible baseline predictors for these outcomes were 1) demographic, socioeconomic and disease-related variables, and 2) psychological measures of resources, distress, fear of movement and catastrophizing. RESULTS: Multivariate linear mixed model analyses revealed that normal mood at baseline measured with the Beck Anxiety Inventory predicted significantly better results in all measures of pain (WOMAC P=0.02) and function (WOMAC P=0.002, RAND-36 P=0.002) during the one-year follow-up. Psychological resource factors (pain self-efficacy P=0.012, satisfaction with life P=0.002) predicted better function (RAND-36). Pain catastrophizing predicted higher WOMAC pain levels (P=0.013), whereas fear of movement (kinesiophobia) predicted poorer functioning (WOMAC P=0.046, RAND-36 P=0.024). CONCLUSIONS: Multiple psychological factors in people with knee osteoarthritis pain are associated with the development of disability and longer term worse pain. PMID- 27496699 TI - A prospective observational study of outcomes from rehabilitation of elderly patients with moderate to severe cognitive impairment. AB - OBJECTIVES: To evaluate rehabilitation outcomes in patients with moderate to severe cognitive impairment. DESIGN: Prospective observational cohort study. SETTING: Rehabilitation unit for older people. SUBJECTS: A total of 116 patients (70F) mean age (SD) 86.3 (6.4). Group 1: 89 patients with moderate cognitive impairment (Mini-Mental State Examination 11-20); and Group 2: 27 patients with severe cognitive impairment (Mini-Mental State Examination 0-10). INTERVENTION: A personalised rehabilitation plan. MAIN MEASURES: Barthel Activity of Daily Living score on admission and discharge, length of stay and discharge destination. RESULTS: Of 116 patients, 64 (55.2%) showed an improvement in Barthel score. Mini Mental State Examination was significantly higher in those who improved, 15.4 (SD 3.7) vs.13.2 (SD 5.1): p = 0.01. The mean Barthel score improved in both groups; Group 1 - 14.7 (SD 19.1) vs. Group 2 - 9.3 (SD 16.3): p = 0.17. Of 84 home admissions in Group 1, more patients returning home showed improvements of at least 5 points in the Barthel score compared with nursing/residential home discharges (32/37 - 86.5% vs. 10/28 - 35.7%: p = 0.0001). In Group 2 of 17 home admissions, 6/6 (100%) home discharges showed improvement compared with 3/7 (42.8%) discharges to nursing/residential home (p = 0.07). In Group 1, a discharge home was associated with significantly greater improvement in number of Barthel items than a nursing/residential home discharge (3.27 (SD 2.07) vs. 1.86 (SD 2.32): p = 0.007). A similar non-significant pattern was noted for severe cognitive impairment patients (3.5 (3.06) vs. 1.14 (1.06); p = 0.1). CONCLUSION: Patients with moderate to severe cognitive impairment demonstrated significant improvements in Barthel score and Barthel items showing that such patients can and do improve with rehabilitation. PMID- 27496700 TI - Short-term effects of goal-setting focusing on the life goal concept on subjective well-being and treatment engagement in subacute inpatients: a quasi randomized controlled trial. AB - OBJECTIVE: To investigate the short-term effects of the life goal concept on subjective well-being and treatment engagement, and to determine the sample size required for a larger trial. DESIGN: A quasi-randomized controlled trial that was not blinded. SETTING: A subacute rehabilitation ward. SUBJECTS: A total of 66 patients were randomized to a goal-setting intervention group with the life goal concept (Life Goal), a standard rehabilitation group with no goal-setting intervention (Control 1), or a goal-setting intervention group without the life goal concept (Control 2). INTERVENTIONS: The goal-setting intervention in the Life Goal and Control 2 was Goal Attainment Scaling. The Life Goal patients were assessed in terms of their life goals, and the hierarchy of goals was explained. The intervention duration was four weeks. MAIN MEASURES: Patients were assessed pre- and post-intervention. The outcome measures were the Hospital Anxiety and Depression Scale, 12-item General Health Questionnaire, Pittsburgh Rehabilitation Participation Scale, and Functional Independence Measure. RESULTS: Of the 296 potential participants, 66 were enrolled; Life Goal (n = 22), Control 1 (n = 22) and Control 2 (n = 22). Anxiety was significantly lower in the Life Goal (4.1 +/ 3.0) than in Control 1 (6.7 +/-3.4), but treatment engagement was significantly higher in the Life Goal (5.3 +/-0.4) compared with both the Control 1 (4.8 +/ 0.6) and Control 2 (4.9 +/-0.5). CONCLUSIONS: The life goal concept had a short term effect on treatment engagement. A sample of 31 patients per group would be required for a fully powered clinical trial. PMID- 27496701 TI - What are the barriers and facilitators to goal-setting during rehabilitation for stroke and other acquired brain injuries? A systematic review and meta-synthesis. AB - OBJECTIVE: To identify the barriers and facilitators to goal-setting during rehabilitation for stroke and other acquired brain injuries. DATA SOURCES: AMED, Proquest, CINAHL and MEDLINE. REVIEW METHODS: Two reviewers independently screened, extracted data and assessed study quality using the Mixed Methods Appraisal Tool and undertook thematic content analysis for papers examining the barriers and facilitators to goal-setting during stroke/neurological rehabilitation (any design). Last searches were completed in May 2016. RESULTS: Nine qualitative papers were selected, involving 202 participants in total: 88 patients, 89 health care professionals and 25 relatives of participating patients. Main barriers were: Differences in staff and patients perspectives of goal-setting; patient-related barriers; staff-related barriers, and organisational level barriers. Main facilitators were: individually tailored goal setting processes, strategies to promote communication and understanding, and strategies to avoid disappointment and unrealistic goals. In addition, patients' and staff's knowledge, experience, skill, and engagement with goal-setting could be either a barrier (if these aspects were absent) or a facilitator (if they were present). CONCLUSION: The main barriers and facilitators to goal-setting during stroke rehabilitation have been identified. They suggest that current methods of goal-setting during inpatient/early stage stroke or neurological rehabilitation are not fit for purpose. PMID- 27496702 TI - Drug eluting antimicrobial vascular catheters: Progress and promise. AB - Vascular catheters are critical tools in modern healthcare yet present substantial risks of serious bloodstream infections that exact significant health and economic burdens. Drug-eluting antimicrobial vascular catheters have become important tools in preventing catheter-related bloodstream infections and their importance is expected to increase as significant initiatives are expanded to eliminate and make the occurrence of these infections unacceptable. Here we review clinically significant and emerging drug-eluting antimicrobial catheters within the categories of antibiotic, antiseptic, novel bioactive agents and energy-enhanced drug eluting antimicrobial catheters. Important representatives of each category are reviewed from the standpoints of mechanisms of action, physical-chemical properties, safety, in vitro and clinical effectiveness. PMID- 27496703 TI - Anti-thrombotic technologies for medical devices. AB - Thrombosis associated with medical devices may lead to dramatic increases in morbidity, mortality and increased health care costs. Innovative strategies are being developed to reduce this complication and provide a safe biocompatible interface between device and blood. This article aims to describe the biological phenomena underlying device-associated thrombosis, and surveys the literature describing current and developing technologies designed to overcome this challenge. To reduce thrombosis, biomaterials with varying topographical properties and incorporating anti-thrombogenic substances on their surface have demonstrated potential. Overall, there is extensive literature describing technical solutions to reduce thrombosis associated with medical devices, but clinical results are required to demonstrate significant long-term benefits. PMID- 27496705 TI - Oral absorption of peptides and nanoparticles across the human intestine: Opportunities, limitations and studies in human tissues. AB - In this contribution, we review the molecular and physiological barriers to oral delivery of peptides and nanoparticles. We discuss the opportunities and predictivity of various in vitro systems with special emphasis on human intestine in Ussing chambers. First, the molecular constraints to peptide absorption are discussed. Then the physiological barriers to peptide delivery are examined. These include the gastric and intestinal environment, the mucus barrier, tight junctions between epithelial cells, the enterocytes of the intestinal epithelium, and the subepithelial tissue. Recent data from human proteome studies are used to provide information about the protein expression profiles of the different physiological barriers to peptide and nanoparticle absorption. Strategies that have been employed to increase peptide absorption across each of the barriers are discussed. Special consideration is given to attempts at utilizing endogenous transcytotic pathways. To reliably translate in vitro data on peptide or nanoparticle permeability to the in vivo situation in a human subject, the in vitro experimental system needs to realistically capture the central aspects of the mentioned barriers. Therefore, characteristics of common in vitro cell culture systems are discussed and compared to those of human intestinal tissues. Attempts to use the cell and tissue models for in vitro-in vivo extrapolation are reviewed. PMID- 27496706 TI - Device thrombosis and pre-clinical blood flow models for assessing antithrombogenic efficacy of drug-device combinations. AB - Thrombosis associated with blood-contacting devices is a complex process involving several component interactions that have eluded precise definition. Extensive investigations of individual biological modules such as protein adsorption, coagulation cascade activation and platelet activation/adhesion/aggregation have provided an initial foundation for developing biomaterials for blood-contacting devices, but a material that is intrinsically non-thrombogenic is yet to be developed. The well-recognized association between fluid dynamics parameters such as shear stress, vortices, stagnation and thrombotic processes such as platelet aggregation and coagulation aggravate thrombosis on most device geometries that elicit these flow disturbances. Thus, antithrombotic drugs that were developed to treat thrombosis associated with vascular diseases such as atherosclerosis have also been adapted to mitigate the risk of device thrombosis. However, balancing the risk of bleeding with the antithrombotic efficacy of these drugs continues to be a challenge, and surface modification of devices with these drug molecules to mitigate device thrombosis locally has been explored. Pre-clinical blood flow models to test the effectiveness of these drug-device combinations have also evolved and several in-vitro, ex-vivo, and in-vivo test configurations are available with their attendant merits and limitations. Despite considerable efforts toward iterative design and testing of blood contacting devices and antithrombogenic surface modifications, device thrombosis remains an unsolved problem. PMID- 27496708 TI - Androgen and Estrogen Receptors in Breast Cancer Coregulate Human UDP Glucuronosyltransferases 2B15 and 2B17. AB - Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERalpha), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDP-glucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced disease-specific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERalpha. In cell line models, ERalpha, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERalpha activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5alpha-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3' to the FOXA1 and ERalpha-binding sites. Although AR and FOXA1 bound the UGT promoters in AR positive/ERalpha-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERalpha+ tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERalpha binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERalpha+ breast cancer, which may have subtype-specific consequences for disease progression and outcomes. Cancer Res; 76(19); 5881-93. (c)2016 AACR. PMID- 27496707 TI - Cancer-Associated Fibroblasts in Pancreatic Cancer Are Reprogrammed by Tumor Induced Alterations in Genomic DNA Methylation. AB - Stromal fibrosis is a prominent histologic characteristic of pancreatic ductal adenocarcinoma (PDAC), but how stromal fibroblasts are regulated in the tumor microenvironment (TME) to support tumor growth is largely unknown. Here we show that PDAC cells can induce DNA methylation in cancer-associated fibroblasts (CAF). Upon direct contact with PDAC cells, DNA methylation of SOCS1 and other genes is induced in mesenchymal stem cells or in CAF that lack SOCS1 methylation at baseline. Silencing or decitabine treatment to block the DNA methylation enzyme DNMT1 inhibited methylation of SOCS1. In contrast, SOCS1 gene methylation and downregulation in CAF activated STAT3 and induced insulin-like growth factor 1 expression to support PDAC cell growth. Moreover, CAF facilitated methylation dependent growth of PDAC tumor xenografts in mice. The ability of patient-derived CAF with SOCS1 methylation to promote PDAC growth was more robust than CAF without SOCS1 methylation. Overall, our results reveal how PDAC cells can reprogram CAF to modify tumor-stromal interactions in the TME, which promote malignant growth and progression. Cancer Res; 76(18); 5395-404. (c)2016 AACR. PMID- 27496709 TI - Accumulation of MDSC and Th17 Cells in Patients with Metastatic Colorectal Cancer Predicts the Efficacy of a FOLFOX-Bevacizumab Drug Treatment Regimen. AB - Host immunity controls the development of colorectal cancer, and chemotherapy used to treat colorectal cancer is likely to recruit the host immune system at some level. Athough preclinical studies have argued that colorectal cancer drugs, such as 5-fluorouracil (5-FU) and oxaliplatin, exert such effects, their combination as employed in the oncology clinic has not been evaluated. Here, we report the results of prospective immunomonitoring of 25 metastatic colorectal cancer (mCRC) patients treated with a first-line combination regimen of 5-FU, oxaliplatin, and bevacizumab (FOLFOX-bevacizumab), as compared with 20 healthy volunteers. Before this therapy was initiated, T regulatory cells (Treg), Th17, and granulocytic myeloid-derived suppressor cells (gMDSC) were increased significantly in mCRC, but only a high level of gMDSC was associated with a poor prognosis. Chemotherapy modulated the Treg/Th17 balance by decreasing Treg and increasing Th17 cell frequency by 15 days after the start of treatment. Increased Th17 frequency was associated with a poor prognosis. FOLFOX-bevacizumab treatment elicited a decrease in gMDSC in 15 of 25 patients and was associated with a better survival outcome. Notably, the gMDSCs that expressed high levels of PD-L1, CD39, and CD73 exerted a robust immunosuppressive activity, relative to other myeloid cells present in blood, which could be reversed by blocking the CD39/CD73 and PD-1/PD-L1 axes. Our work underscores the critical prognostic impact of early modifications in Th17 and gMDSC frequency in mCRC. Furthermore, it provides a clinical rationale to combine FOLFOX-bevacizumab chemotherapy with inhibitors of ATP ectonucleotidases and/or anti-PD-1/PD-L1 antibodies to more effectively treat this disease. Cancer Res; 76(18); 5241-52. (c)2016 AACR. PMID- 27496704 TI - Beyond conventional antibiotics - New directions for combination products to combat biofilm. AB - Medical device related infections are a significant and growing source of morbidity and mortality. Biofilm formation is a common feature of medical device infections that is not effectively prevented or treated by systemic antibiotics. Antimicrobial medical device combination products provide a pathway for local delivery of antimicrobial therapeutics with the ability to achieve high local concentrations while minimizing systemic side effects. In this review, we present considerations for the design of local antimicrobial delivery systems, which can be facilitated by modeling local pharmacokinetics in the context of the target device application. In addition to the need for local delivery, a critical barrier to progress in the field is the need to incorporate agents effective against biofilm. This article aims to review key properties of antimicrobial peptides that make them well suited to meet the demands of the next generation of antimicrobial medical devices, including broad spectrum activity, rapid and biocidal mechanisms of action, and efficacy against biofilm. PMID- 27496710 TI - Nestin Mediates Hedgehog Pathway Tumorigenesis. AB - The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem-like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here, we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation, resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway-driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies. Cancer Res; 76(18); 5573-83. (c)2016 AACR. PMID- 27496712 TI - PAK4 Phosphorylates p53 at Serine 215 to Promote Liver Cancer Metastasis. AB - PAK4 kinase contributes to signaling pathways controlling cancer cell transformation, invasion, and survival, but its clinicopathological impact has begun to emerge only recently. Here we report that PAK4 overexpression in hepatocellular carcinoma (HCC) conveys aggressive metastatic properties. A novel nuclear splice isoform of PAK4 lacking exon 2 sequences was isolated as part of our studies. By stably overexpressing or silencing PAK4 in HCC cells, we showed that it was critical for their migration. Mechanistic investigations in this setting revealed that PAK4 directly phosphorylated p53 at S215, which not only attenuated transcriptional transactivation activity but also inhibited p53 mediated suppression of HCC cell invasion. Taken together, our results showed how PAK4 overexpression in HCC promotes metastatic invasion by regulating p53 phosphorylation. Cancer Res; 76(19); 5732-42. (c)2016 AACR. PMID- 27496711 TI - Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis. AB - Traditional approaches to evaluating antitumor agents using human tumor xenograft models have generally used cohorts of 8 to 10 mice against a limited panel of tumor models. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models that capture greater molecular/genetic heterogeneity of the cancer type. We retrospectively analyzed 67 agents evaluated by the Pediatric Preclinical Testing Program to determine whether a single mouse, chosen randomly from each group of a study, predicted the median response for groups of mice using 83 xenograft models. The individual tumor response from a randomly chosen mouse was compared with the group median response using established response criteria. A total of 2,134 comparisons were made. The single tumor response accurately predicted the group median response in 1,604 comparisons (75.16%). The mean tumor response correct prediction rate for 1,000 single mouse random samples was 78.09%. Models had a range for correct prediction (60%-87.5%). Allowing for misprediction of +/- one response category, the overall mean correct single mouse prediction rate was 95.28%, and predicted overall objective response rates for group data in 66 of 67 drug studies. For molecularly targeted agents, occasional exceptional responder models were identified and the activity of that agent confirmed in additional models with the same genotype. Assuming that large treatment effects are targeted, this alternate experimental design has similar predictive value as traditional approaches, allowing for far greater numbers of models to be used that more fully encompass the heterogeneity of disease types. Cancer Res; 76(19); 5798-809. (c)2016 AACR. PMID- 27496713 TI - Zika virus infection: epidemiology, clinical manifestations and diagnosis. AB - PURPOSE OF REVIEW: Zika virus (ZIKV) is an arbovirus previously believed to cause only a mild and self-limiting illness. Recently, it has emerged as a new public health threat that caused a large outbreak in French Polynesia in 2013-2014 and since 2015 an explosive outbreak in Brazil, with an increase in severe congenital malformations (microcephaly) and neurological complications, mainly Guillain Barre syndrome (GBS). Since then, it has spread through the Americas. On 1 February 2016, the WHO declared the ZIKV epidemic in Brazil a Public Health Emergency of International Concern. We reviewed the epidemiology of ZIKV infection, clinical presentations and diagnosis. We highlighted the clinical features and nonvector borne transmission of the virus. RECENT FINDINGS: Association between ZIKV infection and severe foetal outcomes, including microcephaly and other birth defects; increased rate of GBS and other neurological complications due to the ongoing ZIKV outbreak; increased evidence to date of ZIKV being the only arbovirus linked to sexual transmission; the challenge of ZIKV diagnosis; and the need for a specific point-of care test in epidemic scenarios. SUMMARY: The findings illustrate the emergence of a viral disease with the identification of new associated disorders, new modes of transmission, including maternal-foetal and sexual transmission. PMID- 27496714 TI - Perinatal BPA exposure alters body weight and composition in a dose specific and sex specific manner: The addition of peripubertal exposure exacerbates adverse effects in female mice. AB - Body weight (BW) and body composition were examined in CD-1 mice exposed perinatally or perinatally and peripubertally to 0, 0.25, 2.5, 25, or 250MUg BPA/kg BW/day. Our goal was to identify the BPA dose (s) and the exposure window(s) that increased BW and adiposity, and to assess potential sex differences in this response. Both perinatal exposure alone and perinatal plus peripubertal exposure to environmentally relevant levels of BPA resulted in lasting effects on body weight and body composition. The effects were dose specific and sex specific and were influenced by the precise window of BPA exposure. The addition of peripubertal BPA exposure following the initial perinatal exposure exacerbated adverse effects in the females but appeared to reduce differences in body weight and body composition between control and BPA exposed males. Some effects of BPA on body weight and body composition showed a non-linear dose response. PMID- 27496715 TI - Early-life exposures to persistent organic pollutants in relation to overweight in preschool children. AB - Current knowledge on obesogenic effects of persistent organic pollutants (POPs) is equivocal. We therefore evaluated the associations between early-life POP exposures and body mass index (BMI) in 444 Faroese children born in 2007-2009. POPs were measured in maternal 2-week postpartum serum and child age-5 serum. Linear regression and generalised linear models assessed the associations with continuous and dichotomous BMI z-scores, respectively, at ages 18 months and/or 5 years. Maternal serum concentrations of HCB, PFOS and PFOA were associated with increased BMI z-scores and/or overweight risk (i.e. BMI z-score>=85th WHO percentile). No clear association was found for maternal serum-PCBs, p,p'-DDE, PFHxS, PFNA and PFDA. In cross-sectional analyses, we observed a pattern of inverse associations between child serum-POPs and BMI z-scores at age 5, perhaps due to reverse causation that requires attention in future prospective analyses. Findings in this recent cohort support a role of maternal exposure to endocrine disruptors in the childhood obesity epidemic. PMID- 27496717 TI - Randomized, Prospective Comparison of Bioabsorbable and Steel Screw Fixation of Lisfranc Injuries. AB - OBJECTIVE: This study's objective is to compare outcomes of bioabsorbable versus steel screws for treating Lisfranc injuries. DESIGN: This research was conducted in a prospective and randomized manner between September 2008 and December 2013. SETTING: This study was performed in the outpatient setting at a tertiary-level care center in a single surgeon's practice. PATIENTS/PARTICIPANTS: Forty patients with acute Lisfranc injuries, amenable to open reduction and screw fixation, enrolled and presented for final follow-up. INTERVENTION: Through randomization, 20 and 20 patients received bioabsorbable versus steel screws, respectively. OUTCOME MEASUREMENTS: Function and pain were graded using the Foot and Ankle Ability Measures (FAAM) and a visual analog scale of pain. Radiographs were assessed for joint stability and degeneration. RESULTS: For those with steel screws, the mean FAAM score increased from 24.9 to 89.6 of 100 and pain score decreased from 6.5 to 1.9 of 10 by latest follow-up. For those with absorbable screws, the mean FAAM score increased from 32.5 to 91.2 and pain score decreased from 4.7 to 1.3 by latest follow-up. These differences in final mean function (P = 0.4) and pain (P = 0.25) between the study groups were not statistically significant. Final radiographs showed no Lisfranc instability in any study patients, but rather midfoot arthritis in 4 and 2 patients with steel versus bioabsorbable screws, respectively. None of the patients who received steel screws had hardware-related problems, but 1 patient who received absorbable fixation developed an inflammatory reaction at a nonresorbed screw head at 2 years after surgery. CONCLUSIONS: Bioabsorbable screws provide short-term results that are comparable and not significantly different from steel screws for treating unstable Lisfranc injuries. Both methods are predictable in improving function and pain, but using absorbable screws eliminates the need for hardware removal after such trauma. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 27496716 TI - Longitudinal effects of developmental bisphenol A and variable diet exposures on epigenetic drift in mice. AB - Environmental factors, including exogenous exposures and nutritional status, can affect DNA methylation across the epigenome, but effects of exposures on age dependent epigenetic drift remain unclear. Here, we tested the hypothesis that early-life exposure to bisphenol A (BPA) and/or variable diet results in altered epigenetic drift, as measured longitudinally via target loci methylation in paired mouse tail tissue (3 wks/10 mos old). Methylation was quantified at two repetitive elements (LINE-1, IAP), two imprinted genes (Igf2, H19), and one non imprinted gene (Esr1) in isogenic mice developmentally exposed to Control, Control+BPA (50MUg/kg diet), Mediterranean, Western, Mediterranean+BPA, or Western+BPA diets. Across age, methylation levels significantly (p<0.050) decreased at LINE-1, IAP, and H19, and increased at Esr1. Igf2 demonstrated Western-specific changes in early-life methylation (p=0.027), and IAP showed marginal negative modification of drift in Western (p=0.058) and Western+BPA (p=0.051). Thus, DNA methylation drifts across age, and developmental nutritional exposures can alter age-related methylation patterns. PMID- 27496719 TI - Factors associated with receiving anti-osteoporosis treatment among older persons with minimal trauma hip fracture presenting to an acute orthogeriatric service. AB - BACKGROUND/AIM: The aim of this study was to investigate factors that were associated with receiving anti-osteoporosis treatment (AOT) among patients with minimal trauma hip fracture admitted to an Australian tertiary trauma centre under the Acute Orthogeriatric Service (AOS) over a 6 month period. DESIGN: Observational study using prospectively collected data. METHODS: Demographic and clinical characteristics of 211 patients were extracted from the local hip fracture registry and electronic medical records. The outcome measure was receipt of AOT before separation from the AOS. Binary logistic regression was used to identify factors independently associated with treatment. RESULTS: 91 (45%) patients received AOT, including 51 (25.2%) treatment-naive patients. Factors significantly associated with receiving treatment included higher serum vitamin D level (OR 1.44, 95% CI 1.23-1.70, p<0.001) and trochanteric vs. cervical fracture (OR 2.67, 95% CI 1.30-5.49, p=0.007). Living in a residential aged care facility (RACF) prior to the index fracture (OR 0.2, 95% CI 0.08-0.54, p=0.001) and higher American Society of Anaesthesiologists (ASA) physical status score (OR 0.5, 95% CI 0.25-0.98, p=0.04) significantly lowered the likelihood of treatment. Age, gender, cognitive impairment, premorbid walking ability, previous fragility fracture and renal impairment did not correlate with treatment. CONCLUSION: A significant proportion (55%) of hip fracture patients did not receive AOT in hospital. The probability of receiving treatment appears to be significantly associated with serum vitamin D level, fracture type, place of residence and comorbidity burden. PMID- 27496718 TI - Hypothesis testing clarifies the systematics of the main Central American Chagas disease vector, Triatoma dimidiata (Latreille, 1811), across its geographic range. AB - The widespread and diverse Triatoma dimidiata is the kissing bug species most important for Chagas disease transmission in Central America and a secondary vector in Mexico and northern South America. Its diversity may contribute to different Chagas disease prevalence in different localities and has led to conflicting systematic hypotheses describing various populations as subspecies or cryptic species. To resolve these conflicting hypotheses, we sequenced a nuclear (internal transcribed spacer 2, ITS-2) and mitochondrial gene (cytochrome b) from an extensive sampling of T. dimidiata across its geographic range. We evaluated the congruence of ITS-2 and cyt b phylogenies and tested the support for the previously proposed subspecies (inferred from ITS-2) by: (1) overlaying the ITS-2 subspecies assignments on a cyt b tree and, (2) assessing the statistical support for a cyt b topology constrained by the subspecies hypothesis. Unconstrained phylogenies inferred from ITS-2 and cyt b are congruent and reveal three clades including two putative cryptic species in addition to T. dimidiata sensu stricto. Neither the cyt b phylogeny nor hypothesis testing support the proposed subspecies inferred from ITS-2. Additionally, the two cryptic species are supported by phylogenies inferred from mitochondrially-encoded genes cytochrome c oxidase I and NADH dehydrogenase 4. In summary, our results reveal two cryptic species. Phylogenetic relationships indicate T. dimidiata sensu stricto is not subdivided into monophyletic clades consistent with subspecies. Based on increased support by hypothesis testing, we propose an updated systematic hypothesis for T. dimidiata based on extensive taxon sampling and analysis of both mitochondrial and nuclear genes. PMID- 27496720 TI - Which patients risk segmental kyphosis after short segment thoracolumbar fracture fixation with intermediate screws? AB - INTRODUCTION: The use of intermediate screws in fractured vertebrae has been proposed to decrease the number of fused levels in thoracolumbar fractures and to enable short fixations. The aim of this study was to evaluate the results of this technique and to establish predictive factors involved in loss of segmental kyphosis correction (LKC). METHODS: Forty-three patients who underwent short segment spinal fixation with intermediate screws for a thoracolumbar spine fracture in a two-year time period were enrolled in the study. Patients had AO type A3, A4 and B2 thoracolumbar fractures. Radiological parameters included segmental kyphosis (SK), vertebral wedge angle (VWA) and loss of anterior and posterior vertebral body height. Patients were evaluated up to one-year follow up. The correlation between LKC and potential risk factors, such as smoking habit, sex, age, neurological status and BMI was evaluated. RESULTS: Mean preoperative SK was 16.5 degrees +/-6.5 degrees , and it decreased to 3.4 degrees +/-3.5 degrees postoperatively (P<0.01). At the one-year follow-up mean SK dropped to 5.5 degrees +/-3.9 degrees (P<0.01). Mean preoperative VWA was 20.0 degrees +/-8.1 degrees , and significantly improved to 6.3 degrees +/-3.1 degrees after surgery (P<0.01). There was a mean LKC of 1.8 degrees +/-2.1 degrees at one year. LKC mildly correlated with body mass index (BMI, r: +0.31), and obese patients (BMI>30) had an increased risk of LKC at the one-year follow-up (P=0.03; odds ratio [OR]=3.2). DISCUSSION: Analysis of the radiological data at one-year follow-up showed that all the evaluated parameters were associated with a mild loss of correction, with no impact on the clinical outcomes or implant failure. These findings confirm the trends reported in the literature. The correlation between LKC and clinical features, such as BMI, age, sex, smoking habit and preoperative neurological status was investigated. Interestingly, a positive correlation was observed between BMI and LKC, and obese patients with BMI>30 had an increased risk of LKC at one-year follow-up (OR 3.2); to our knowledge this finding has never before been reported. CONCLUSION: Short-segment fixation with intermediate screws is a viable technique with positive clinical and radiological outcomes at one-year follow-up. However, surgeons should be aware that in obese patients (BMI>30) this technique is associated with an increased risk of LKC. LEVEL OF EVIDENCE: 3. PMID- 27496721 TI - The role of sarcopenia with and without fracture. AB - INTRODUCTION: Bone and muscle tissues are in a close relationship. They are linked from a biological and functional point of view and both are related to an increased fracture risk in the elderly. The aging process is involved in the loss of functionality of both bones and muscles. In particular, aging-induced decline in muscle size and quality accompanies catabolic alterations in bone tissue; furthermore, age-related changes in bone alter its response to muscle-derived stimulation. The increased fracture risk in individuals with sarcopenia and osteoporosis is due to the decline of muscle mass and strength, the decrease in bone mineral density (BMD) and limited mobility. In this study, we investigated the role of sarcopenia and the main age-related bone diseases, osteoporosis (OP) and osteoarthritis (OA). METHODS: Muscular performance status was evaluated using the Physical Activity Scale for the Elderly (PASE) test in 27 female patients with OP who underwent total hip arthroplasty for hip fracture, and in 27 age matched female patients with OA who underwent total hip arthroplasty. Dual-energy X-ray absorptiometry (DEXA) was performed and the T-score values were used to discriminate between OP and OA patients. Body Mass Index (BMI) was calculated. As part of a multiparametric model of evaluation, biopsies of vastus lateralis muscle were analysed by immunohistochemical reaction to find a correlation with the above mentioned functional index. RESULTS: The PASE test showed that the OP patients had a low or moderate level of physical activity before fracture occurred, whereas the OA patients had more intensive pre-fracture physical performances. Histological analysis showed that osteoporosis is characterised by a preferential type II fibre atrophy; in particular, data correlation showed that lower PASE test scores were related to lower diameter of type II fibres. No correlation was found between bone mineral density (BMD) and PASE test results. DISCUSSION AND CONCLUSION: Osteoporosis is closely related to sarcopenia before and after fracture. Bone remodelling is influenced by muscle morphological and functional impairment and sarcopenia is considered one of the major factors for functional limitation and motor dependency in elderly osteoporotic individuals. Therefore, physical activity should be strongly recommended for OP patients at diagnosis. PMID- 27496722 TI - Cambridge Polytrauma Pathway: Are we making appropriately guided decisions? AB - Addenbrooke's Hospital, the Major Trauma Centre for the East of England Trauma Network, received 1070 major trauma patients between 1st January and 31st December 2014. In order to improve care, an audit was performed of 59 patients meeting our own selection criteria for orthopaedic polytrauma between 1st January 2013 and 31st December 2013. The Cambridge Polytrauma Pathway was devised through NCEPOD guidelines, literature review, internal and external discussion. It facilitates provision of best practice Early Appropriate Care, encompassing - multidisciplinary consultant decisions around the patient in our Neurological and Trauma Critical Care Unit, early full body trauma CT scans, serial measurements of lactate and fibrinogen levels, and out-of-hours orthopaedic theatre reserved for life-and-limb threatening injuries. Re-audit was conducted of 15 patients meeting selection criteria, admitted between 1st October 2014 and 31st March 2015. Significant improvements in recording of lactate and fibrinogen were demonstrated, both on admission (lactate - p<0.000, fibrinogen - p=0.015), and preoperatively (lactate - p=0.003, fibrinogen - p=0.030). Time to trauma CT was unchanged (p=0.536) with a median time to CT of 0.53h at re-audit (IQR 0.48 0.75). The number of patients receiving definitive orthopaedic intervention out of-hours reduced from 8 to zero (p=0.195). The approach of facilitating management decisions to be made at early daytime MDT meetings has been adopted. It is anticipated that this pathway will improve outcomes in orthopaedic polytrauma patients and it is recommended that either the GOS-E, or the EQ-5D scoring systems be introduced to assess this. PMID- 27496723 TI - Hertel 7 fracture of the humeral head. Can two different fixation systems (Diphos/PHP) lead to different outcomes? A retrospective study. AB - OBJECTIVE: To compare clinical outcomes and complication rates in the medium-to long-term follow-up of Hertel 7 humeral head fractures treated with two different locking plates. MATERIALS AND METHODS: A total of 52 patients with type 7 humeral head fracture (in accordance with Hertel classification) were enrolled retrospectively: 24 patients [4 male, 20 female; mean age (standard deviation [SD]): 68.9 (5.8) years] were treated with Diphos H plate (Group A) and 28 patients [6 male, 22 female; mean age (SD): 61.0 (7.5) years] with Proximal Humeral Plate (PHP; Group B). The mean follow-up periods were 25.6 and 18.9 months, respectively. Functional outcomes were assessed using the Constant score and Disabilities of the Arm, Shoulder and Hand (DASH) score; X-ray evaluation was also performed and complications were recorded. RESULTS: The mean Constant score in the Diphos and PHP groups at follow-up were 75.6 (SD 13.4) and 78.9 (SD 12.8), respectively (p>0.05). The DASH score was similar in both groups (Diphos: 18.6, range 0-51.5; PHP: 16.8, range 0-47.8) (p>0.05). In our series, 9.6% of patients had complications; these included a case of aseptic non-union and a case of avascular necrosis of the humeral head in each group, and a secondary screw perforation in a patient treated with Diphos. CONCLUSIONS: In patients with Hertel 7 proximal humeral fractures, Diphos and PHP lead to similar satisfactory functional outcomes and are associated with low complication rates; this confirms that both are useful implants for the treatment of this pattern of fracture. PMID- 27496724 TI - A feasibility study of pelvic morphology for curved implants. AB - OBJECTIVES: We hypothesize that inserting a curved intramedullary internal fixation device which follows curved osseous fixation paths (OFPs) would be more versatile and mechanically stronger than straight screws for fixation of pelvic ring and acetabular injuries. This study characterizes the dimensions of curved OFPs of the pelvic ring and acetabulum and suggests design parameters for such a curved device. METHODS: CT scans of intact pelves of 50 female and 50 male subjects were studied using MIM MaestroTM and SolidworksTM to determine the constriction points (smallest cross sections) and the tightest radii of curvature (RoC) in the anterior column, posterior column, iliosacral and pubic symphysis OFPs. RESULTS: The constriction point diameters for the superior pubic ramus and supra-acetabular areas were 13+/-3mm and 12+/-3mm, respectively. The anterior column RoC was greater than 65mm in all cases. The minimum observed RoC for the path from one ilium, across the SI joint, the sacrum and to the other ilium was 71mm, with 99% of the cases having a RoC of at least 80mm, in both the inlet and outlet views. CONCLUSION: This study shows that if a flexible implant which could be stiffened once in place was available, it would enable the use of larger and longer fixation taking advantage of the pelvis's curved intracortical spaces. Even for dysmorphic pelves, accessible tunnels support a long, strong, curved fixation device. PMID- 27496725 TI - Lumboiliac fixation in lumbosacral dislocation and associated injuries of the pelvis and lumbosacral junction: a long-term radiological and clinical follow-up. AB - INTRODUCTION: The goal of the study was to evaluate both clinical and radiological outcome of a consecutive series of 11 patients submitted to lumboiliac fixation after lumbopelvic disjunction or associated injuries of the pelvis and lumbosacral tract in mid- and long-term follow-up. MATERIAL AND METHODS: The following were evaluated from clinical charts: damage control preoperative procedures, surgery, and pre-, intra- and post-operative complications; imaging was also evaluated from the preoperative assessment to the final follow-up (4 to 13.2 years; average 7.2 years). RESULTS: One patient died a few days after surgery; therefore, long-term follow-up was possible in 10 patients. One of the 10 patients could be evaluated only radiologically because he was non-compliant due to severe mental illness. There were four early complications: one patient had a massive pulmonary embolism, which was fatal; one had wound dehiscence; one developed pulmonary infection and one had caecal fistula, which was repaired by the general surgeon. Late complications were as follows: three patients required hardware removal or substitution because of deep infection (after 1year), system breakage (after 9 years) and screws loosening (after 7 years). Clinical evaluation was available in nine patients and was assessed using Oswestry forms and a Visual Analogue Scale (VAS). All patients were able to walk at least 1 kilometre without external support, two patients were using pain medication regularly and three patients were classified with severe disability at final follow-up. Degenerative changes in the joints close to the fused area were observed in two patients more than 10 years after the operation, but the correlation with surgery is questionable. DISCUSSION: Lumbopelvic disjunctions generally follow high-energy trauma often involving internal thoracic and abdominal organs; therefore, a well-trained team approach is mandatory to preserve patient life and to provide adequate treatment of skeletal injuries. Mechanical complications may occur several years after surgery, thus a long-term follow-up is mandatory. CONCLUSIONS: Lumbopelvic fixation is an effective surgical technique for treatment of spinopelvic disjunction. The patient numbers in this series, and in the literature in general, are low; therefore, a multicentre study is advisable to give evidence and statistical importance to our findings. PMID- 27496726 TI - Expression, purification and characterization of Esx-1 secretion-associated protein EspL from Mycobacterium tuberculosis. AB - The Esx-1 cluster encodes a special secretion system that is important for granuloma formation and virulence when Mycobacterium tuberculosis infects the host. As one of the 'core' genes in the cluster, Rv3880c gene codes an Esx-1 secretion-associated protein EspL from Mycobacterium tuberculosis (MtEspL). It has been reported that EspL had a strong influence on the secretion of other two virulence factors, EsxA and EspE. However, so far little is known about the tertiary structure and specific function of MtEspL due to the difficulty in preparing the high-quality protein. In this study, we tried several fusion tags and various expression conditions to recombinantly express MtEspL. Through a four step purification procedure, ultimately, we successfully prepared the full-length MtEspL in Escherichia coli BL21 (DE3) with a purity of 98%. The yields of the purified MtEspL protein were 14 mg/L in Luria Bertani medium and 5.6 mg/L in M9 minimal medium, respectively. Biophysical experiments showed that MtEspL existed in a dimeric form. Moreover, the (1)H-(15)N HSQC spectrum recorded on MtEspL illustrates a favorable dispersion of the resonance peaks, indicating that the symmetric dimeric MtEspL adopted a well-folded structure and might be feasible to determine its solution structure by NMR spectroscopy. Moreover, we identified a strong DNA-binding ability of MtEspL with fluorescence quenching experiments. Our work lays the basis for further structural determination and functional exploration of MtEspL. PMID- 27496727 TI - Engineering, expression and purification of a chimeric fibrin-specific streptokinase. AB - Streptokinase is a valuable fibrinolytic agent used to cope with myocardial infarction and brain stroke. Despite its high efficiency in dissolving blood clots, streptokinase (SK) has no specificity in binding fibrin, causing some problems such as internal bleedings following its administration. To make streptokinase fibrin specific and limit the fibrinolytic process to the clot location, we engineered a chimeric streptokinase by fusing the fibrin binding Kringle 2 domain of tissue plasminogen activator (TPA) to the streptokinase N terminal end. The chimeric SK construct (KSK) with inserted Kringle 2 domain was cloned into pET28a expression vector. The expression of recombinant protein was carried out in Escherichia coli origami (DE3) and confirmed by SDS-PAGE and Western blotting analyses. We used the chromogenic substrate S-2251 method to assess the specific activities of the chimeric and control wild-type proteins. Then, the two proteins were added in amounts with equal activity to fibrin clots of identical size. Finally, the supernatant above the fibrin clots was collected and subjected to the chromogenic assay to analyze the specificity of the chimeric protein. The specific activities of the chimeric and wild-type proteins were found to be 0.06 U/mg and 0.07 U/mg, respectively. Because of the binding of the chimeric protein to fibrin, the mean specific activity was significantly lower in the KSK supernatant (0.01) compared with the control (approximately 0.06) (p < 0.05). Our in vitro results indicate that the chimeric streptokinase protein has strong fibrin-specific activity compared to the wild-type protein. However, further in vivo studies are needed to evaluate its potential fibrinolytic effects. PMID- 27496728 TI - Cloning, expression and characterization of potential immunogenic recombinant hemagglutinin-neuraminidase protein of Porcine rubulavirus. AB - Blue eye disease caused by Porcine rubulavirus (PorPV) is an endemic viral infection of swine causing neurological and respiratory disease in piglets, and reproductive failure in sows and boars. The hemagglutinin-neuraminidase (HN) glycoprotein of PorPV is the most abundant component in the viral envelope and the main target of the immune response in infected animals. In this study, we expressed the HN-PorPV-recombinant (rHN-PorPV) protein in an Escherichia coli system and analyzed the immune responses in mice. The HN gene was cloned from the reference strain PorPV-La Piedad Michoacan Virus (GenBank accession number BK005918), into the pDual expression vector. The expressed protein was identified at a molecular weight of 61.7 kDa. Three-dimensional modeling showed that the main conformational and functional domains of the rHN-PorPV protein were preserved. The antigenicity of the expressed protein was confirmed by Western blot with a monoclonal antibody recognizing the HN, and by testing against serum samples from pigs experimentally infected with PorPV. The immunogenicity of the rHN-PorPV protein was tested by inoculation of BALB/c mice with AbISCO-100((r)) as adjuvant. Analysis of the humoral immune responses in mice showed an increased level of specific antibodies 14 days after the first immunization, compared to the control group (P < 0.0005). The results show the ability of the rHN-PorPV protein to induce an antibody response in mice. Due to its immunogenic potential, the rHN-PorPV protein will be further evaluated in pig trials for its suitability for prevention and control of blue eye disease. PMID- 27496729 TI - Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. AB - Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8(+) T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8(+) T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1alpha. Improving bioenergetics by overexpression of PGC-1alpha enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism might enhance checkpoint blockade outcomes. PMID- 27496730 TI - Cell-Extrinsic MHC Class I Molecule Engagement Augments Human NK Cell Education Programmed by Cell-Intrinsic MHC Class I. AB - The effector potential of NK cells is counterbalanced by their sensitivity to inhibition by "self" MHC class I molecules in a process called "education." In humans, interactions between inhibitory killer immunoglobulin-like receptors (KIR) and human MHC (HLA) mediate NK cell education. In HLA-B(*)27:05(+) transgenic mice and in patients undergoing HLA-mismatched hematopoietic cell transplantation (HCT), NK cells derived from human CD34(+) stem cells were educated by HLA from both donor hematopoietic cells and host stromal cells. Furthermore, mature human KIR3DL1(+) NK cells gained reactivity after adoptive transfer to HLA-B(*)27:05(+) mice or bone marrow chimeric mice where HLA B(*)27:05 was restricted to either the hematopoietic or stromal compartment. Silencing of HLA in primary NK cells diminished NK cell reactivity, while acquisition of HLA from neighboring cells increased NK cell reactivity. Altogether, these findings reveal roles for cell-extrinsic HLA in driving NK cell reactivity upward, and cell-intrinsic HLA in maintaining NK cell education. PMID- 27496731 TI - The AIM2-like Receptors Are Dispensable for the Interferon Response to Intracellular DNA. AB - Detection of intracellular DNA triggers activation of the STING-dependent interferon-stimulatory DNA (ISD) pathway, which is essential for antiviral responses. Multiple DNA sensors have been proposed to activate this pathway, including AIM2-like receptors (ALRs). Whether the ALRs are essential for activation of this pathway remains unknown. To rigorously explore the function of ALRs, we generated mice lacking all 13 ALR genes. We found that ALRs are dispensable for the type I interferon (IFN) response to transfected DNA ligands, DNA virus infection, and lentivirus infection. We also found that ALRs do not contribute to autoimmune disease in the Trex1(-/-) mouse model of Aicardi Goutieres Syndrome. Finally, CRISPR-mediated disruption of the human AIM2-like receptor IFI16 in primary fibroblasts revealed that IFI16 is not essential for the IFN response to human cytomegalovirus infection. Our findings indicate that ALRs are dispensable for the ISD response and suggest that alternative functions for these receptors should be explored. PMID- 27496732 TI - The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction. AB - Although tumor-specific T cells recognize cancer cells, they are often rendered dysfunctional due to an immunosuppressive microenvironment. Here we showed that T cells demonstrated persistent loss of mitochondrial function and mass when infiltrating murine and human tumors, an effect specific to the tumor microenvironment and not merely caused by activation. Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1alpha (PGC1alpha), which programs mitochondrial biogenesis, induced by chronic Akt signaling in tumor specific T cells. Reprogramming tumor-specific T cells through enforced expression of PGC1alpha resulted in superior intratumoral metabolic and effector function. Our data support a model in which signals in the tumor microenvironment repress T cell oxidative metabolism, resulting in effector cells with metabolic needs that cannot be met. Our studies also suggest that modulation or reprogramming of the altered metabolism of tumor-infiltrating T cells might represent a potential strategy to reinvigorate dysfunctional T cells for cancer treatment. PMID- 27496733 TI - ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination. AB - Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) sense microbial ligands and initiate signaling to induce inflammatory responses. Although the quality of inflammatory responses is influenced by internalization of TLRs, the role of endosomal maturation in clearing receptors and terminating inflammatory responses is not well understood. Here, we report that Drosophila and mammalian Vps33B proteins play critical roles in the maturation of phagosomes and endosomes following microbial recognition. Vps33B was necessary for clearance of endosomes containing internalized PRRs, failure of which resulted in enhanced signaling and expression of inflammatory mediators. Lack of Vps33B had no effect on trafficking of endosomes containing non-microbial cargo. These findings indicate that Vps33B function is critical for determining the fate of signaling endosomes formed following PRR activation. Exaggerated inflammatory responses dictated by persistence of receptors in aberrant endosomal compartments could therefore contribute to symptoms of ARC syndrome, a disease linked to loss of Vps33B. PMID- 27496735 TI - Use of microextraction by packed sorbent directly coupled to an electron ionization single quadrupole mass spectrometer as an alternative for non separative determinations. AB - Sometimes it is not necessary to separate the individual compounds of a sample to resolve an analytical problem, it is enough to obtain a signal profile of the sample formed by all the components integrating it. Within this strategy, electronic noses based on the direct coupling of a headspace sampler with a mass spectrometer (HS-MS) have been proposed. Nevertheless, this coupling is not suitable for the analysis of non-volatile compounds. In order to propose an alternative to HS-MS determinations for non-volatile compounds, here we present the first 'proof of concept' use of the direct coupling of microextraction by packed sorbents (MEPS) to a mass spectrometer device using an electron ionization (EI) and a single quadrupole as ionization source and analyzer, respectively. As target compounds, a set of analytes with different physic-chemical properties were evaluated (2-ethyl-1-hexanol, styrene, 2-heptanone, among others). The use of MEPS extraction present many advantages, such as it is fast, simple, easy to automate and requires small volumes of sample and organic solvents. Moreover, MEPS cartridges are re-usable as samples can be extracted more than 100 times using the same syringe. In order to introduce into the system all the elution volume from the MEPS extraction, a programmable temperature vaporizer (PTV) is proposed as the injector device. Results obtained with the proposed methodology (MEPS-PTV/MS) were compared with the ones obtained based on the separative scheme, i.e. using gas chromatography separation (MEPS-PTV-GC/MS), and both methods provided similar results. Limits of detection were found to be between 3.26 and 146.6MUgL-1 in the non-separative scheme and between 0.02 and 1.72MUgL-1 when the separative methodology was used. Repeatability and reproducibility were evaluated with values below 17% in all cases. PMID- 27496736 TI - Intratumoral FoxP3 expression is associated with angiogenesis and prognosis in malignant canine mammary tumors. AB - The activity of regulatory T cells (Tregs) is closely associated with the expression of FoxP3 transcription factor. FoxP3 regulatory T cells (FoxP3Treg) have immunosuppressive properties and can work for prevention of harmful autoimmune responses, however can also interfere with beneficial anti-tumor immunity. In human breast cancer these cells play a crucial role in tumor progression. In canine mammary tumors (CMT) this topic is not well-documented. This study included 80 malignant CMT and studied, by immunohistochemistry, the intratumoral FoxP3 expression together with microvessel density (MVD), vascular endothelial growth factor (VEGF) and several clinicopathological characteristics. Abundant FoxP3Treg cells were associated with tumor necrosis (p=0.001), high mitotic grade (p<0.001), more marked nuclear polymorphism (p=0.001), poor differentiation of tumors (p<0.001), high histological grade of malignancy (HGM) (p<0.001), presence of neoplastic intravascular emboli (p<0.001) and presence of lymph node metastasis (p<0.001). Intratumoral FoxP3 was correlated with MVD (r=0.827; p<0.001) and associated with VEGF (p=0.001). Additionally tumors with abundant FoxP3Treg cells were associated with shorter overall survival (OS) time in univariate and multivariate analysis (p<0.001 Kaplan-Meier curves and 7.97 hazard ratio, p<0.001 Cox proportional hazard model). Results suggest that Treg cells play a role in CMT progression and may contribute to increased angiogenesis and aggression in these tumors. The association of intratumoral FoxP3 expression with shorter OS in multivariate analysis suggests the usefulness of Treg cells as an independent prognostic marker. PMID- 27496734 TI - Adipose-Resident Group 1 Innate Lymphoid Cells Promote Obesity-Associated Insulin Resistance. AB - Innate lymphoid cells (ILCs) function to protect epithelial barriers against pathogens and maintain tissue homeostasis in both barrier and non-barrier tissues. Here, utilizing Eomes reporter mice, we identify a subset of adipose group 1 ILC (ILC1) and demonstrate a role for these cells in metabolic disease. Adipose ILC1s were dependent on the transcription factors Nfil3 and T-bet but phenotypically and functionally distinct from adipose mature natural killer (NK) and immature NK cells. Analysis of parabiotic mice revealed that adipose ILC1s maintained long-term tissue residency. Diet-induced obesity drove early production of interleukin (IL)-12 in adipose tissue depots and led to the selective proliferation and accumulation of adipose-resident ILC1s in a manner dependent on the IL-12 receptor and STAT4. ILC1-derived interferon-gamma was necessary and sufficient to drive proinflammatory macrophage polarization to promote obesity-associated insulin resistance. Thus, adipose-resident ILC1s contribute to obesity-related pathology in response to dysregulated local proinflammatory cytokine production. PMID- 27496737 TI - Feeding a high dosage of zinc oxide affects suppressor of cytokine gene expression in Salmonella Typhimurium infected piglets. AB - Suppressor of cytokine signaling (SOCS) proteins play an important role in the regulation of the immune response by inhibiting cytokines. Here we investigated the effects of zinc oxide fed at three different dosages (LZN=57ppm, MZN=167ppm, HZN=2425ppm) to weaned piglets that were or were not orally infected with Salmonella enterica serovar Typhimurium DT 104. We detected higher expression of SOCS3 six days after weaning for all analyzed piglets, regardless of the infection or the zinc feeding, suggesting a stress induced immune response. Whereas, SOCS1 showed only higher transcript amounts in S. Typhimurium infected piglets, especially the LZN group. This might indicate an infection regulating effect of zinc oxide in the infection model. After 42days of infection, the expression of SOCS2, SOCS4, and SOCS7 was increased only in animals fed the highest concentrations of zinc oxide, while non-infected piglets at the age of 56days showed no regulation for these genes. The up-regulation of SOCS genes in the mesenteric lymph nodes of piglets fed a diet with a very high concentration of zinc over 6 weeks suggests that such treatments may impair the immune response. PMID- 27496738 TI - Comparative analysis of the immunologic response induced by the Sterne 34F2 live spore Bacillus anthracis vaccine in a ruminant model. AB - The Sterne 34F2 live spore vaccine (SLSV) developed in 1937 is the most widely used veterinary vaccine against anthrax. However, literature on the immunogenicity of this vaccine in a target ruminant host is scarce. In this study, we evaluated the humoral response to the Bacillus anthracis protective antigen (rPA), a recombinant bacillus collagen-like protein of anthracis (rBclA), formaldehyde inactivated spores (FIS) prepared from strain 34F2 and a vegetative antigen formulation prepared from a capsule and toxin deficient strain (CDC 1014) in Boer goats. The toxin neutralizing ability of induced antibodies was evaluated using an in vitro toxin neutralization assay. The protection afforded by the vaccine was also assessed in vaccinates. Anti-rPA, anti-FIS and lethal toxin neutralizing titres were superior after booster vaccinations, compared to single vaccinations. Qualitative analysis of humoral responses to rPA, rBclA and FIS antigens revealed a preponderance of anti-FIS IgG titres following either single or double vaccinations with the SLSV. Antibodies against FIS and rPA both increased by 350 and 300-fold following revaccinations respectively. There was no response to rBclA following vaccinations with the SLSV. Toxin neutralizing titres increased by 80-fold after single vaccination and 700-fold following a double vaccination. Lethal challenge studies in naive goats indicated a minimum infective dose of 36 B. anthracis spores. Single and double vaccination with the SLSV protected 4/5 and 3/3 of goats challenged with>800 spores respectively. An early booster vaccination following the first immunization is suggested in order to achieve a robust immunity. Results from this study indicate that this crucial second vaccination can be administered as early as 3 months after the initial vaccination. PMID- 27496739 TI - The effect of hypothermia on influx of leukocytes in the digital lamellae of horses with oligofructose-induced laminitis. AB - Sepsis-related laminitis (SRL) is a common complication in the septic/endotoxemic critically-ill equine patient, in which lamellar injury and failure commonly lead to crippling distal displacement of the distal phalanx. Similar to organ injury in human sepsis, lamellar injury in SRL has been associated with inflammatory events, including the influx of leukocytes into the lamellar tissue and markedly increased expression of a wide array of inflammatory mediators at the onset of Obel grade 1 (OG1) laminitis. The only treatment reported both clinically and experimentally to protect the lamellae in SRL, local hypothermia ("cryotherapy"), has been demonstrated to effectively inhibit lamellar expression of multiple inflammatory mediators when initiated at the time of administration of a carbohydrate overload in experimental models of SRL. However, the effect of hypothermia on leukocyte influx into affected tissue has not been assessed. We hypothesized that cryotherapy inhibits leukocyte emigration into the digital lamellae in SRL. Immunohistochemical staining using leukocyte markers MAC387 (marker of neutrophils, activated monocytes) and CD163 (monocyte/macrophage specific marker) was performed on archived lamellar tissue samples from an experimental model of SRL in which one forelimb was maintained at ambient temperature (AMB) and one forelimb was immersed in ice water (ICE) immediately following enteral oligofructose administration (10g/kg, n=14 horses). Lamellae were harvested at 24h post-oligofructose administration (DEV, n=7) or at the onset of OG1 laminitis (OG1, n=7). Both MAC387-positive and CD163-positive cells were counted by a single blinded investigator on images [n=10 (40* fields/digit for MAC387 and 20x fields/digit for CD163)] obtained using Aperio microscopy imaging analysis software. Data were assessed for normality and analyzed with a paired t-test and one-way ANOVA with significance set at p<0.05. MAC387-positive cells were present in low numbers in the lamellar tissue and were decreased in the hypothermic limbs (vs. AMB limbs, p<0.05) in the OG1 group; no change in CD163-positive cell numbers was noted across the conditions of the model. This study demonstrated that hypothermia of the distal limbs instituted early in the disease process in the horse at risk of SRL significantly attenuates the increase of MAC387-positive leukocytes in the digital lamellae, but has minimal effect on increases in lamellar concentrations of the major leukocyte cell type present in that tissue, CD163-positive mononuclear cells. PMID- 27496740 TI - Effects of rearing environment on the gut antimicrobial responses of two broiler chicken lines. AB - To reduce the risk of enteric disease in poultry, knowledge of how bird gut innate defences mature with age while also responding to different rearing environments is necessary. In this study the gut innate responses of two phylogenetically distinct lines of poultry raised from hatch to 35days, in conditions mimicing high hygiene (HH) and low hygiene (LH) rearing environments, were compared. Analyses focussed on the proximal gut antimicrobial activities and the duodenal and caecal AvBD1, 4 and 10 defensin profiles. Variability in microbial killing was observed between individual birds in each of the two lines at all ages, but samples from day 0 birds (hatch) of both lines exhibited marked killing properties, Line X: 19+/-11% (SEM) and Line Y: 8.5+/-12% (SEM). By day 7 a relaxation in killing was observed with bacterial survival increased from 3 (Line Y (LY)) to 11 (Line X (LX)) fold in birds reared in the HH environment. A less marked response was observed in the LH environment and delayed until day 14. At day 35 the gut antimicrobial properties of the two lines were comparable. The AvBD 1, 4 and 10 data relating to the duodenal and caecal tissues of day 0, 7 and 35 birds LX and LY birds revealed gene expression trends specific to each line and to the different rearing environments although the data were confounded by inter-individual variability. In summary elevated AvBD1 duodenal expression was detected in day 0 and day 7 LX, but not LY birds, maintained in LH environments; Line X and Y duodenal AvBD4 profiles were detected in day 7 birds reared in both environments although duodenal AvBD10 expression was less sensitive to bird age and rearing background. Caecal AvBD1 expression was particularly evident in newly hatched birds. These data suggest that proximal gut antimicrobial activity is related to the bird rearing environments although the roles of the AvBDs in such activities require further investigation. PMID- 27496741 TI - Generation and characterization of RAG2 knockout pigs as animal model for severe combined immunodeficiency. AB - Pigs with severe combined immunodeficiency (SCID) are versatile animal models for human medical research because of their biological similarities to humans, suitable body size, and longevity for practical research. SCID pigs with defined mutation(s) can be an invaluable tool for research on porcine immunity. In this study, we produced RAG2-knockout pigs via somatic cell nuclear transfer and analyzed their phenotype. The V(D)J recombination processes were confirmed as being inactivated. They consistently lacked mature T and B cells but had substantial numbers of cells considered to be T- or B-cell progenitors as well as NK cells. They also lacked thymic medulla and lymphoid aggregations in the spleen, mesenteric lymph nodes, and ileal Peyer's patches. We showed more severe immunological defects in the RAG2 and IL2RG double-knockout pig through this study. Thus, SCID pigs could be promising animal models not only for translational medical research but also for immunological studies of pigs themselves. PMID- 27496742 TI - Immune response induced by conjunctival immunization with polymeric antigen BLSOmp31 using a thermoresponsive and mucoadhesive in situ gel as vaccine delivery system for prevention of ovine brucellosis. AB - Control of ovine brucellosis with subcellular vaccines can solve some drawbacks associated with the use of Brucella melitensis Rev.1. Previous studies have demonstrated that the polymeric antigen BLSOmp31 administered by parenteral route was immunogenic and conferred significant protection against B. ovis in rams. Immunization with BLSOmp31 by conjunctival route could be efficient for the induction of mucosal and systemic immune responses. In this work, we evaluated the conjunctival immunization using a thermoresponsive and mucoadhesive in situ gel composed of Poloxamer 407 (P407) and chitosan (Ch) as vaccine delivery system for BLSOmp31 in rams. Serum samples, saliva, lacrimal, preputial and nasal secretions were analyzed to measure specific IgG and IgA antibodies. Cellular immune response was evaluated in vivo and in vitro. Immunization with BLSOmp31 P407-Ch induced high IgG antibody levels in serum and preputial secretions which remained at similar levels until the end of the experiment. Levels of IgG in saliva, lacrimal and nasal secretions were also higher compared to unvaccinated control group but decreased more rapidly. IgA antibodies were only detected in nasal and preputial secretions. BLSOmp31-P407-Ch stimulated a significant cellular immune response in vivo and in vitro. The induction of systemic and local immune responses indicates a promising potential of P407-Ch for the delivery of BLSOmp31 by conjunctival route. PMID- 27496743 TI - Characterization and use of new monoclonal antibodies to CD11c, CD14, and CD163 to analyze the phenotypic complexity of ruminant monocyte subsets. AB - The sequencing of the bovine genome and development of mass spectrometry, in conjunction with flow cytometry (FC), have afforded an opportunity to complete the characterization of the specificity of monoclonal antibodies (mAbs), only partially characterized during previous international workshops focused on antibody development for livestock (1991, Leukocyte Antigens in Cattle, Sheep, and Goats; 1993, Leukocyte Antigens of Cattle and Sheep; 1996, Third Workshop on Ruminant Leukocyte Antigens). The objective of this study was to complete the characterization of twelve mAbs incompletely characterized during the workshops that reacted with molecules predominantly expressed on bovine monocytes and use them to provide further information on the phenotypic complexity of monocyte subsets in ruminants. Analysis revealed that the mAbs could be grouped into three clusters that recognize three different molecules: CD11c, CD14, and CD163. Following characterization, comparison of the patterns of expression of CD14 and CD163 with expression of CD16, CD172a, and CD209 revealed the mononuclear cell population is comprised of multiple subsets with differential expression of these molecules. Further analysis revealed the epitopes recognized by mAbs to CD14 and CD163 are conserved on orthologues in sheep and goats. In contrast to CD14 that is also expressed on sheep and goat granulocytes, CD163 is a definitive marker for their monocytes. PMID- 27496744 TI - Capsular polysaccharide from Mycoplasma mycoides subsp. mycoides shows potential for protection against contagious bovine pleuropneumonia. AB - Contagious Bovine Pleuropneumonia (CBPP) is a severe respiratory disease caused by Mycoplasma mycoides subsp. mycoides (Mmm) which is widespread in Africa. The capsule polysaccharide (CPS) of Mmm is one of the few identified virulence determinants. In a previous study, immunization of mice against CPS generated antibodies, but they were not able to prevent multiplication of Mmm in this model animal. However, mice cannot be considered as a suitable animal model, as Mmm does not induce pathology in this species. Our aim was to induce antibody responses to CPS in cattle, and challenge them when they had specific CPS antibody titres similar or higher than those from cattle vaccinated with the live vaccine. The CPS was linked to the carrier protein ovalbumin via a carbodiimide mediated condensation with 1-ethyl-3(3-imethylaminopropyl) carbodiimide (EDC). Ten animals were immunized twice and challenged three weeks after the booster inoculation, and compared to a group of challenged non-immunized cattle. When administered subcutaneously to adult cattle, the vaccine elicited CPS-specific antibody responses with the same or a higher titre than animals vaccinated with the live vaccine. Pathology in the group of immunized animals was significantly reduced (57%) after challenge with Mmm strain Afade compared to the non-immunized group, a figure in the range of the protection provided by the live vaccine. PMID- 27496745 TI - Natural autoantibodies in Bos taurus calves during the first twelve weeks of life. AB - Natural autoantibodies (NAAb) have a role in maintaining physiological homeostasis and prevention of infections, and have been found in mammalian species tested so far. Albeit NAAb levels rise with age, little is known about the origin, function, regulation and initiation of NAAb in young animals. The present study addressed the presence of IgM and IgG NAAb binding glutamate dehydrogenase (GD), carbonic anhydrase (CA), myosin (MYO) and transferrin (TRANS) from before drinking colostrum until the first 12 weeks of life in plasma of female calves. In addition, NAAb to these four self-antigens were also measured in colostrum and in plasma of their mothers during three weeks before calving. Titers of NAAb binding GD, CA, MYO and TRANS were detected in plasma of cows before calving, in colostrum, and in plasma of calves before and after drinking of colostrum. Levels of NAAb in colostrum were positively related with levels of NAAb in plasma of cows. Before colostrum intake, levels of NAAb in plasma of calves were not related with levels of NAAb in plasma of their mother but were influenced by parity of their mother. After colostrum intake, levels of NAAb in plasma of calves in the first week of life were positively related with levels of NAAb in colostrum. Low NAAb levels in colostrum were related with low NAAb in plasma of calves in the first week of life, but after two weeks of life the relation between colostrum and plasma of calves was absent. In conclusion, NAAb are already present in the unborn calf, and levels of neonatal NAAb during the early weeks of life are affected by levels of maternal NAAb obtained via colostrum. PMID- 27496746 TI - Production a monoclonal antibody specific to granulocytes of swimming crab (Portunus trituberculatus) and its cross reactivity with other crustaceans. AB - In this study, a monoclonal antibody (mAb) 3F4 specific to granulocytes of swimming crab, Portunus trituberculatus, was obtained by immunizing mice with whole haemocytes. mAb 3F4 showed strong immunofluorescent reaction with granulocytes, but no reaction with hyalinocytes. The positive cell percentage of granulocytes was 86.3% detected by Flow cytometry (FCM). A special antigen with molecular weight of about 26kDa was further recognized by mAb 3F4 in haemocytes of P. trituberculatus. mAb 3F4 also showed strong cross-reactivity with haemocytes of Eriocheir sinensis and Petalomera japonica, but no reaction with other crustaceans tested. In E. sinensis, the positive cell percentage was 73.4% for granulocytes and 59.8% for hyalinocytes; while in P. japonica, the positive cell percentage was 81.2% for granulocytes and 7.1% for hyalinocytes. There was also a special antigen with molecular weight of about 31kDa identified by mAb 3F4 in haemocytes of E.sinensis, but no corresponding protein band in P. japonica haemocytes. These results demonstrated that mAb 3F4 can be used as a marker for granulocytes of crabs. PMID- 27496747 TI - Effects of injectable trace minerals on humoral and cell-mediated immune responses to Bovine viral diarrhea virus, Bovine herpes virus 1 and Bovine respiratory syncytial virus following administration of a modified-live virus vaccine in dairy calves. AB - Our objective was to evaluate the effect of an injectable trace mineral (ITM) supplement containing zinc, manganese, selenium, and copper on the humoral and cell mediated immune (CMI) responses to vaccine antigens in dairy calves receiving a modified-live viral (MLV) vaccine containing BVDV, BHV1, PI3V and BRSV. A total of 30 dairy calves (3.5 months of age) were administered a priming dose of the MLV vaccine containing BHV1, BVDV1 & 2, BRSV, PI3V, and an attenuated live Mannheimia-Pasteurella bacterin subcutaneously (SQ). Calves were randomly assigned to 1 of 2 groups: (1) administration of ITM SQ (ITM, n=15) or (2) injection of sterile saline SQ (Control; n=15). Three weeks later, calves received a booster of the same vaccine combination SQ, and a second administration of ITM, or sterile saline, according to the treatment group. Blood samples were collected on days 0, 7, 14, 21, 28, 42, 56, and 90 post-vaccination for determination of antibody titer, viral recall antigen-induced IFN-gamma production, and viral antigen-induced proliferation by peripheral blood mononuclear cells (PBMC). Administration of ITM concurrently with MLV vaccination resulted in higher antibody titers to BVDV1 on day 28 after priming vaccination compared to the control group (P=0.03). Calves treated with ITM showed an earlier enhancement in PBMC proliferation to BVDV1 following vaccination compared to the control group. Proliferation of PBMC after BVDV stimulation tended to be higher on day 14 after priming vaccination in calves treated with ITM than in the control group (P=0.08). Calves that received ITM showed higher PBMC proliferation to BRSV stimulation on day 7 after priming vaccination compared to the control group (P=0.01). Moreover, calves in the ITM group also had an enhanced production IFN-gamma by PBMC after stimulation with BRSV on day 21 after priming vaccination compared to day 0 (P<0.01). In conclusion, administration of ITM concurrently with MLV vaccination in dairy calves resulted in increased antibody titer to BVDV1, and greater PBMC proliferation to BVDV1 and BRSV recall stimulation compared to the control group, suggesting that ITM might represent a promising tool to enhance the humoral and CMI responses to MLV vaccines in cattle. PMID- 27496748 TI - Nasal delivery of chitosan-coated poly(lactide-co-glycolide)-encapsulated honeybee (Apis mellifera) venom promotes Th 1-specific systemic and local intestinal immune responses in weaned pigs. AB - Nasal delivery is a convenient and acceptable route for drug administration, and has been shown to elicit a much more potent local and systemic response compared with other drug delivery routes. We previously demonstrated that rectal administration of poly(lactide-co-glycolide)-encapsulated honeybee venom (P-HBV) could enhance systemic Th 1-specific immune responses. We therefore synthesized chitosan-coated P-HBV (CP-HBV) and then evaluated the immune-boosting efficacy of nasally administered CP-HBV on systemic and local intestinal immunity compared with non-chitosan-coated P-HBV. The nasally delivered CP-HBV effectively enhanced Th 1-specific responses, eliciting a significant increase in the CD3(+)CD4(+)CD8( ) Th cell population, lymphocyte proliferation capacity, and expression of Th 1 cytokines (IFN-gamma, IL-12, and IL-2) in peripheral blood mononuclear cells. Furthermore, these immune-boosting effects persisted up to 21days post CP-HBV administration. Nasal administration of CP-HBV also led to an increase of not only the CD4(+) Th 1 and IFN-gamma secreting CD4(+) Th 1 cell population but also Th 1-specific cytokines and transcription factors, including IL-12, IFN-gamma, STAT4, and T-bet, in isolated mononuclear cells from the spleen and ileum. PMID- 27496749 TI - Cluster of ulceroglandular tularemia cases in Slovenia. AB - In Slovenia, a small Central European country, where tularemia cases are very rare and mostly sporadic, six cases of ulceroglandular tularemia were recognised in 2012-2013 in patients residing in or visiting a small geographical area of <6km2. Epidemiological data indicated transmission by a tick bite in at least 3/6 patients. PMID- 27496750 TI - Breath-print analysis by e-nose may refine risk stratification for adverse outcomes in cirrhotic patients. AB - BACKGROUND & AIMS: The spectrum of volatile organic compounds in the exhaled breath (breath-print, BP) has been shown to characterize patients with cirrhosis and with worse hepatic function. However, the association of different BPs with clinically relevant outcomes has not been described yet. Hence, we aimed to evaluate the association between BPs, mortality and hospitalization in cirrhotic patients and to compare it with that of the "classical" prognostic indices (Child Pugh Classification [CPC] and MELD). METHODS: Eighty-nine cirrhotic patients (M/F 59/30, mean age 64.8 +/- 11.3, CPC A/B/C 37/33/19) were recruited and followed up for a median time of 23 months. Clinical and biochemical data were collected. Breath collection and analysis were obtained through Pneumopipe(r) and BIONOTE e nose respectively. RESULTS: Four different BP clusters (A, B, C, D) were identified. BP clusters A and D were associated with a significantly increased risk of mortality (HR 2.9, 95% confidence intervals [CI] 1.5-5.6) and hospitalization (HR 2.6, 95% CI 1.4-4.6), even in multiple adjusted models including CPC and MELD score (adjusted [a]HR 2.8, 95% CI 1.1-7.0 for mortality and aHR 2.2, 95% CI 1.1-4.2 for hospitalization). CPC C maintained the strongest association with both mortality (aHR 17.6, 95% CI 1.8-174.0) and hospitalization (aHR 12.4, 95% CI 2.0-75.8). CONCLUSIONS: This pilot study demonstrates that BP clusters are associated with significant clinical endpoints (mortality and hospitalization) even independently from "classical" prognostic indices. Even though further studies are warranted on this topic, our findings suggest that the e-nose may become an adjunctive aid to stratify the risk of adverse outcomes in cirrhotic patients. PMID- 27496751 TI - Targeting factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice. AB - : Essentials Platelet-Factor (F) VIII gene therapy is a promising treatment in hemophilia A. This study aims to evaluate if platelet-FVIII expression would increase the risk for thrombosis. Targeting FVIII expression to platelets does not induce or elevate thrombosis risk. Platelets expressing FVIII are neither hyper-activated nor hyper-responsive. SUMMARY: Background Targeting factor (F) VIII expression to platelets is a promising gene therapy approach for hemophilia A, and is successful even in the presence of inhibitors. It is well known that platelets play important roles not only in hemostasis, but also in thrombosis and inflammation. Objective To evaluate whether platelet-FVIII expression might increase thrombotic risk and thereby compromise the safety of this approach. Methods In this study, platelet-FVIII-expressing transgenic mice were examined either in steady-state conditions or under prothrombotic conditions induced by inflammation or the FV Leiden mutation. Native whole blood thrombin generation assay, rotational thromboelastometry analysis and ferric chloride-induced vessel injury were used to evaluate the hemostatic properties. Various parameters associated with thrombosis risk, including D-dimer, thrombin-antithrombin complexes, fibrinogen, tissue fibrin deposition, platelet activation status and activatability, and platelet-leukocyte aggregates, were assessed. Results We generated a new line of transgenic mice that expressed 30-fold higher levels of platelet-expressed FVIII than are therapeutically required to restore hemostasis in hemophilic mice. Under both steady-state conditions and prothrombotic conditions induced by lipopolysaccharide-mediated inflammation or the FV Leiden mutation, supratherapeutic levels of platelet-expressed FVIII did not appear to be thrombogenic. Furthermore, FVIII-expressing platelets were neither hyperactivated nor hyperactivatable upon agonist activation. Conclusion We conclude that, in mice, more than 30-fold higher levels of platelet-expressed FVIII than are required for therapeutic efficacy in hemophilia A are not associated with a thrombotic predilection. PMID- 27496753 TI - Glycogen Storage Disease Because of a PRKAG2 Mutation Causing Severe Biventricular Hypertrophy and High-Grade Atrio-Ventricular Block. PMID- 27496754 TI - Comprehensive Hemodynamic Assessment in a Single Echocardiography Still Frame. PMID- 27496752 TI - Role of interleukin-18 in the pathophysiology of allergic diseases. AB - Interleukin (IL)-18 is an IL-1 family cytokine expressed by macrophages, dendritic cells, epithelial cells, and keratinocytes and is implicated in various aspects of both the innate and adaptive immune systems. IL-18 signals similar to IL-1beta intracellularly to activate gene transcription. Since its discovery, IL 18 has been demonstrated to play a key role in pathogen defense from helminths and some bacteria. Recently however, evidence has accumulated that IL-18 expression is increased in many presentations of allergic disease. A pathologic role for IL-18 includes stimulating mast cell and basophil degranulation, recruiting granulocytes to sites of inflammation, increasing cytotoxic activity of natural killer (NK) and NK-T cells, inducing Immunoglobulin (Ig)E production and isotype switching, and affecting a broad range of T cells to promote a type II helper T cell (Th2) response. Evidence and importance of these effects are presented, including novel results from our lab implicating IL-18 in the direct expansion of mast cells, basophils, and other myeloid-lineage cells from bone marrow precursors. The development of urticaria, asthma, dermatitis, rhinitis, and eosinophilic disorders all have demonstrated correlations to increased IL-18 levels either in the tissue or systemically. IL-18 represents a novel site of immune regulation in not only allergic conditions, but also autoimmune diseases and other instances of aberrant immune functioning. Diagrammatic summarized abstract for readers convinance is presented in Fig. 1. PMID- 27496755 TI - Metabolism and functional effects of plant-derived omega-3 fatty acids in humans. AB - Alpha-linolenic acid (ALA) is an essential fatty acid and the substrate for the synthesis of longer-chain, more unsaturated omega-3 fatty acids, eicosapentaenoic acid (EPA), docosapentaenoic acid and docosahexaenoic acid (DHA). EPA and DHA are associated with human health benefits. The primary source of EPA and DHA is seafood. There is a need for sustainable sources of biologically active omega-3 fatty acids. Certain plants contain high concentrations of ALA and stearidonic acid (SDA). Here we review the literature on the metabolism of ALA and SDA in humans, the impact of increased ALA and SDA consumption on concentrations of EPA and DHA in blood and cell lipid pools, and the extent to which ALA and SDA might have health benefits. Although it is generally considered that humans have limited capacity for conversion of ALA to EPA and DHA, sex differences in conversion to DHA have been identified. If conversion of ALA to EPA and DHA is limited, then ALA may have a smaller health benefit than EPA and DHA. SDA is more readily converted to EPA and appears to offer better potential for health improvement than ALA. However, conversion of both ALA and SDA to DHA is limited in most humans. PMID- 27496756 TI - Editorial Comment. PMID- 27496758 TI - Chitosan conjugation enables intracellular bacteria susceptible to aminoglycoside antibiotic. AB - Most chronic infections are difficult to eradicate because bacteria capable of surviving in host-infected cells may be protected from the killing actions of antibiotics, leading to therapy failures and disease relapses. Here we demonstrated that covalent-coupling chitosan to streptomycin significantly improved intracellular bactericidal capacity towards multiple organisms within phagocytic or nonphagocytic cells. Structure-activity relationship investigations indicated that antibiotic contents, molecular size and positive charges of the conjugate were the key to retain this intracellular bactericidal activity. Mechanistic insight demonstrated the conjugate was capable to target and eliminate endocytic or endosomal escaped bacteria through facilitating the direct contact between the antibiotic and intracellular organism. In vivo acute infection models indicated that compared to equal dose of the antibiotic, chitosan-streptomycin (C-S) conjugate and especially the human serum album binding chitosan-streptomycin conjugate (HCS) complex formed by human serum album and C-S conjugate greatly decreased the bacteria burden in the spleen and liver in both wild type and immuno-suppressive mice. Furthermore, the HCS complex remarkably reduced mortality of infected TLR2 deficient mice, mimicking immune compromised persons who were more susceptible to bacterial infections. These findings might open up a new avenue to combat intracellular bacterial infection by aminoglycosides antibiotics at a lower effective dose. PMID- 27496757 TI - Estimating glycosaminoglycan-protein interaction affinity: water dominates the specific antithrombin-heparin interaction. AB - Glycosaminoglycan (GAG)-protein interactions modulate many important biological processes. Structure-function studies on GAGs may reveal probes and drugs, but their structural complexity and highly acidic nature confound such work. Productivity will increase if we are able to identify tight-binding oligosaccharides in silico. An extension of the CHARMM force field is presented to enable modeling of polysaccharides containing sulfamate functionality, and is used to develop a reliable alchemical free-energy perturbation protocol that estimates changes in affinity for the prototypical heparin-antithrombin system to within 2.3 kcal/mol using modest simulation times. Inclusion of water is crucial during simulation as solvation energy was equal in magnitude to the sum of all other thermodynamic factors. In summary, we have identified and optimized a reliable method for estimation of GAG-protein binding affinity, and shown that solvation is a crucial component in GAG-protein interactions. PMID- 27496759 TI - Rational design of a thermostable glycoside hydrolase from family 3 introduces beta-glycosynthase activity. AB - The thermostable beta-glucosidase from Thermotoga neapolitana, TnBgl3B, is a monomeric three-domain representative from glycoside hydrolase family 3. By using chemical reactivation with exogenous nucleophiles in previous studies with TnBg13B, the catalytic nucleophile (D242) and corresponding acid/base residue (E458) were determined. Identifying these residues led to the attempt of converting TnBgl3B into a beta-glucosynthase, where three nucleophilic variants were created (TnBgl3B_D242G, TnBgl3B_D242A, TnBgl3B_D242S) and all of them failed to exhibit glucosynthase activity. A deeper analysis of the TnBgl3B active site led to the generation of three additional variants, each of which received a single-point mutation. Two of these variants were altered at the -1 subsite (Y210F, W243F) and the third received a substitution near the binding site's aglycone region (N248R). Kinetic evaluation of these three variants revealed that W243F substitution reduced hydrolytic turnover while maintaining KM This key W243F mutation was then introduced into the original nucleophile variants and the resulting double mutants were successfully converted into beta-glucosynthases that were assayed using two separate biosynthetic methods. The first reaction used an alpha-glucosyl fluoride donor with a 4-nitrophenyl-beta-d-glucopyranoside (4NPGlc) acceptor, and the second used 4NPGlc as both the donor and acceptor in the presence of the exogenous nucleophile formate. The primary specificity observed was a beta-1,3-linked disaccharide product, while a secondary beta-1,4 linked disaccharide product was observed with increased incubation times. Additional analysis revealed that substituting quercetin-3-glycoside for the second reaction's acceptor molecule resulted in the successful production of quercetin-3,4'-diglycosides with yields up to 40%. PMID- 27496761 TI - Oligosaccharides from the 3-linked 2-sulfated alpha-L-fucan and alpha-L-galactan show similar conformations but different dynamics. AB - Here we have performed an nuclear magnetic resonance-based study on the ring and chain conformations as well as dynamics of oligosaccharides generated by acid hydrolysis on two structurally related glycans, a 3-linked 2-sulfated alpha-L galactan and a 3-linked 2-sulfated alpha-L-fucan. Results derived from scalar couplings have confirmed the 1C4 chair configuration to both alpha-L-fucose and alpha-L-galactose, and a similar solution 3D structure for the oligosaccharide chains of both sulfated glycans as seen on the basis of NOE patterns. Measurements of spin-relaxation rates have suggested, however, a slight difference dynamical property to these glycans. The fucose-based oligosaccharides showed an enhanced dynamical property if compared to the galactose-based oligosaccharides of same anomericity, sugar configuration, glycosidic bond and sulfation type. This distinction solely on the dynamical aspect has been driven therefore by the different sugar composition of the two studied sulfated glycans. PMID- 27496760 TI - Cryptococcus neoformans UGT1 encodes a UDP-Galactose/UDP-GalNAc transporter. AB - Cryptococcus neoformans, an opportunistic fungal pathogen, produces a glycan capsule to evade the immune system during infection. This definitive virulence factor is composed mainly of complex polysaccharides, which are made in the secretory pathway by reactions that utilize activated nucleotide sugar precursors. Although the pathways that synthesize these precursors are known, the identity and the regulation of the nucleotide sugar transporters (NSTs) responsible for importing them into luminal organelles remain elusive. The UDP galactose transporter, Ugt1, was initially identified by homology to known UGTs and glycan composition analysis of ugt1Delta mutants. However, sequence is an unreliable predictor of NST substrate specificity, cells may express multiple NSTs with overlapping specificities, and NSTs may transport multiple substrates. Determining NST activity thus requires biochemical demonstration of function. We showed that Ugt1 transports both UDP-galactose and UDP-N-acetylgalactosamine in vitro. Deletion of UGT1 resulted in growth and mating defects along with altered capsule and cellular morphology. The mutant was also phagocytosed more readily by macrophages than wild-type cells and cleared more quickly in vivo and in vitro, suggesting a mechanism for the lack of virulence observed in mouse models of infection. PMID- 27496762 TI - Saturation transfer difference nuclear magnetic resonance titrations reveal complex multistep-binding of l-fucose to norovirus particles. AB - Recently, combined nuclear magnetic resonance (NMR), native mass spectrometry (MS) and X-ray crystallographic studies have demonstrated that binding of histo blood group antigens (HBGAs) to norovirus capsid protein (P-dimers) is a cooperative process involving four binding pockets. Here, we show that binding to norovirus virus-like particles (VLPs) is even more complex. We performed saturation transfer difference (STD) NMR titration experiments with two representative genotypes of norovirus VLPs using l-fucose as a minimal HBGA. Compared to titrations with P-dimers, the corresponding binding isotherms reflect at least six distinct binding events. PMID- 27496763 TI - Chemical Glycobiology. PMID- 27496764 TI - The structural investigation of glycosaminoglycan binding to CXCL12 displays distinct interaction sites. AB - The stromal cell-derived factor 1alpha (CXCL12) belongs to the CXC chemokine family and plays an important role in tissue regeneration and the recruitment of stem cells. Here, a stable chemotactic gradient is essential that is formed by the interaction of CXCL12 with the extracellular matrix. Binding properties of CXCL12 to naturally occurring glycosaminoglycans (GAGs) as well as to the artificial highly sulfated hyaluronic acid (HA) are investigated by using a combination of NMR spectroscopy, molecular modeling and molecular dynamics simulations. Our results demonstrate a preferred protein binding for the sulfated GAGs heparin (HE) and highly sulfated HA. Furthermore, we could demonstrate that the orientation of the sulfate is crucial for binding. All sulfated GAGs interact with the CXCL12 GAG-binding motif (K24-H25-L26-K27-R41-K43-R47), where K27 and R41 represent the anchor points. Furthermore, differences could be observed in the second interaction interface of CXCL12: both HE and highly sulfated HA interfere with the receptor-binding motif, while chondroitin sulfate binds different amino acids in close proximity to this motif. CXCL12 does not interact with HA, which was directly demonstrated by NMR spectroscopy and molecular modeling and explained by the lack of sulfate groups of the HA molecule. PMID- 27496766 TI - Effects of domain composition on catalytic activity of human UDP glucose:glycoprotein glucosyltransferases. AB - Uridine diphosphate (UDP)-glucose:glycoprotein glucosyltransferase (UGGT) 1 is a soluble protein residing in the endoplasmic reticulum (ER) and partially in ER Golgi intermediate compartment. Characteristically, it is able to recognize incompletely folded proteins and re-glucosylate their high-mannose-type glycans. By virtue of this, UGGT1 acts as a folding sensor in the glycoprotein quality control system in the ER. On the other hand, human UGGT2 (HUGT2) has been believed to be an inactive homolog of human UGGT1 (HUGT1), whereas our recent study discovered its activity as UGGT. Although the activity of HUGT2 is significantly lower than HUGT1, C-terminal catalytic region, accounting for approximately 20% of the full-length enzyme, shares high amino acid sequence identity (>85%). In this study, we aimed to clarify the contribution of the noncatalytic domains by comparing activities of truncated forms of recombinant HUGT1/HUGT2 and HUGT1/HUGT2 chimeras with full-length enzymes. Our results obtained by using synthetic substrate indicate that the C-terminal catalytic regions of HUGTs are functional as UGGT. While the activity of HUGT1, but not that of HUGT2, was enhanced by the presence of N-terminal domains, activities of catalytic domains are similar between two homologs. PMID- 27496765 TI - LARGE2-dependent glycosylation confers laminin-binding ability on proteoglycans. AB - Both LARGE1 (formerly LARGE) and its paralog LARGE2 are bifunctional glycosyltransferases with xylosy- and glucuronyltransferase activities, and are capable of synthesizing polymers composed of a repeating disaccharide [ 3Xylalpha1,3GlcAbeta1-]. Post-translational modification of the O-mannosyl glycan of alpha-dystroglycan (alpha-DG) with the polysaccharide is essential for it to act as a receptor for ligands in the extracellular matrix (ECM), and both LARGE paralogs contribute to the modification in vivo. LARGE1 and LARGE2 have different tissue distribution profiles and enzymatic properties; however, the functional difference of the homologs remains to be determined, and alpha-DG is the only known substrate for the modification by LARGE1 or LARGE2. Here we show that LARGE2 can modify proteoglycans (PGs) with the laminin-binding glycan. We found that overexpression of LARGE2, but not LARGE1, mediates the functional modification on the surface of DG-/-, Pomt1-/- and Fktn-/- embryonic stem cells. We identified a heparan sulfate-PG glypican-4 as a substrate for the LARGE2 dependent modification by affinity purification and subsequent mass spectrometric analysis. Furthermore, we showed that LARGE2 could modify several additional PGs with the laminin-binding glycan, most likely within the glycosaminoglycan (GAG) protein linkage region. Our results indicate that LARGE2 can modify PGs with the GAG-like polysaccharide composed of xylose and glucuronic acid to confer laminin binding. Thus, LARGE2 may play a differential role in stabilizing the basement membrane and modifying its functions by augmenting the interactions between laminin globular domain-containing ECM proteins and PGs. PMID- 27496767 TI - Computational analysis of interactions in structurally available protein glycosaminoglycan complexes. AB - Glycosaminoglycans represent a class of linear anionic periodic polysaccharides, which play a key role in a variety of biological processes in the extracellular matrix via interactions with their protein targets. Computationally, glycosaminoglycans are very challenging due to their high flexibility, periodicity and electrostatics-driven nature of the interactions with their protein counterparts. In this work, we carry out a detailed computational characterization of the interactions in protein-glycosaminoglycan complexes from the Protein Data Bank (PDB), which are split into two subsets accounting for their intrinsic nature: non-enzymatic-protein-glycosaminoglycan and enzyme glycosaminoglycan complexes. We apply molecular dynamics to analyze the differences in these two subsets in terms of flexibility, retainment of the native interactions in the simulations, free energy components of binding and contributions of protein residue types to glycosaminoglycan binding. Furthermore, we systematically demonstrate that protein electrostatic potential calculations, previously found to be successful for glycosaminoglycan binding sites prediction for individual systems, are in general very useful for proposing protein surface regions as putative glycosaminoglycan binding sites, which can be further used for local docking calculations with these particular polysaccharides. Finally, the performance of six different docking programs (Autodock 3, Autodock Vina, MOE, eHiTS, FlexX and Glide), some of which proved to perform well for particular protein-glycosaminoglycan complexes in previous work, is evaluated on the complete protein-glycosaminoglycan data set from the PDB. This work contributes to widen our knowledge of protein-glycosaminoglycan molecular recognition and could be useful to steer a choice of the strategies to be applied in theoretical studies of these systems. PMID- 27496768 TI - Development of N- and O-linked oligosaccharide engineered Saccharomyces cerevisiae strain. AB - Yeast cells have been engineered for the production of glycoproteins as biopharmaceuticals with humanized N-linked oligosaccharides. The suppression of yeast-specific O-mannosylation is important to reduce immune response and to improve heterologous protein productivity in the production of biopharmaceuticals. However, so far, there are few reports of the engineering of both N-linked and O-linked oligosaccharides in yeast cells. In the present study, we describe the generation of a Saccharomyces cerevisiae strain capable of producing a glycoprotein with humanized Man5GlcNAc2 N-linked oligosaccharides, an intermediate of mammalian hybrid- and complex-type oligosaccharides, while suppressing O-mannosylation. First, a yeast strain that produces a glycoprotein with Man5GlcNAc2 was isolated by introducing msdS encoding alpha-1,2-mannosidase into a strain synthesizing Man8GlcNAc2 N-linked oligosaccharides. Next, to suppress O-mannosylation, an O-mannosyltransferase-deficient strain was generated by disrupting PMT1 and PMT2 Although the relative amount of O-linked oligosaccharides in the disruptant was reduced to approximately 40% of that in wild type cells, this strain exhibited growth defects and decreased protein productivity. To overcome the growth defects, we applied a mutagenesis technique that is based on the disparity theory of evolution. Finally, to improve protein productivity of the growth-recovered strain, vacuolar proteases PEP4 and PRB1 were further disrupted. Thus, by combining genetic engineering and disparity mutagenesis, we generated an Saccharomyces cerevisiae strain whose N- and O linked oligosaccharide synthetic pathways were engineered to effectively produce the heterologous protein. PMID- 27496769 TI - Increase in cannabis use may indirectly affect the health status of a freshwater species. AB - Cannabis is the most used illicit drug worldwide and in some countries a new regulatory policy makes it legal under some restrictions. This situation could lead to a substantial increase in environmental levels of the cannabis active principle (Delta-9-tetrahydrocannabinol [Delta-9-THC]) and its main metabolite, 11-nor-9-carboxy-Delta9 -tetrahydrocannabinol (THC-COOH). Although previous studies have highlighted the toxicity of Delta-9-THC, the adverse effects of THC COOH on aquatic organisms is completely unknown, even though such effects could be more significant because the environmental concentrations of THC-COOH are higher than those of the parent compound. The present study aimed to assess oxidative and genetic damage to the zebra mussel (Dreissena polymorpha) because of 14-d exposures to 3 THC-COOH concentrations, mimicking a current environmental situation (100 ng/L), as well as exposure to 2 possible worst-case scenarios (500 ng/L and 1000 ng/L), because of the potential increase in THC-COOH in surface waters. Variations in the activity of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione S-transferase (GST) were measured, as well as levels of lipid peroxidation and protein carbonyl content. Genetic injuries were investigated by single-cell gel electrophoresis assay, DNA diffusion assay, and the micronucleus test. A significant imbalance in antioxidant defense enzymes was noted in response to the 3 tested concentrations, whereas oxidative damage was noted only at the higher one. Moreover, an increase in DNA fragmentation in zebra mussel hemocytes, but no fixed genetic damage, was found. Although the results showed that THC-COOH toxicity was lower than that of Delta-9-THC, the increase in cannabis use might increase its levels in freshwaters, enhancing its hazard to bivalves and likely to the whole aquatic community. Environ Toxicol Chem 2017;36:472-479. (c) 2016 SETAC. PMID- 27496770 TI - High-dose rate brachytherapy as monotherapy in prostate cancer: A systematic review of its safety and efficacy. AB - CONTEXT: High-dose rate brachytherapy (HDR-BT) is an increasingly popular treatment for patients with localised prostate cancer (PC). OBJECTIVE: To assess the safety and efficacy of HDR-BT as monotherapy in PC. ACQUISITION OF EVIDENCE: A systematic literature review was conducted through searches on MEDLINE (PubMed), Cochrane Library, CDR, ClinicalTrials and EuroScan. We assessed safety and efficacy indicators. SUMMARY OF THE EVIDENCE: We selected 2 reviews and 12 uncontrolled studies, included in these 2 reviews. In terms of efficacy, local control in 6 studies was 97-100%. The biochemical progression-free survival varied as follows: 85-100% for low risk and 79-92% for high risk. Survival free of metastases was >95% at 8 years, except in one study where the survival rate was 87% at 5 years. The overall survival was >=95% in 8 studies. In terms of safety, most of the studies recorded acute and long-term genitourinary and gastrointestinal complications, especially grade >=2. Only 3 studies found grade 4 complications. All studies, except for one without complications, observed genitourinary complications that were more frequent and severe than the gastrointestinal complications. Two studies assessed the quality of life and showed an initial reduction in various domains and subsequent partial or total recovery, except in the sexual domain. CONCLUSIONS: HDR-BT is effective as monotherapy, especially in cases of low to intermediate risk. There is insufficient information on high-risk patients. The short to medium-term toxicity was acceptable. Further research needs to be funded to provide more information on the long-term safety and efficacy of this treatment. PMID- 27496771 TI - Adipocyte accumulation in corpus cavernosum: First clinical evidence and pathophysiological implications in erectile dysfunction. AB - OBJECTIVES: Animal models have shown that erectile dysfunction is associated with adipocyte accumulation under tunica albuginea, which could be involved in venous leakage and loss of penile rigidity. In the current sudy, we compared the histology of the penile sub-albuginean region of drug-refractory erectile dysfunction patients undergoing penile prosthesis implantation with potent patients with Peyronie's disease undergoing curvature correction procedures. MATERIALS AND METHODS: Seventeen refractory erectile dysfunction patients and fourteen potent patients with Peyronie's disease were recruited. Sub-albuginean tissue samples were taken in each surgery. An expert uropathologist analysed each section. A bivariate analysis was performed. Multivariate logistic regression was used to calculate adjusted odds ratios; P value<.05 was considered significant. RESULTS: Eleven patients (11/17) in the case group presented cavernous fat cell accumulation, while only one patient (1/14) in the control group presented this finding (P<.05). Adjusted odds ratio for erectile dysfunction was 40.72; 95% CI 2.28-727.29 (P=.012). CONCLUSIONS: Different studies have shown that androgen disruption could be involved in penile structural changes, leading to trabecular smooth muscle apoptosis and trans or de-differentiation into adipocytes. This is the first prospective study in humans to report an association between erectile dysfunction and sub-albuginean adipocyte accumulation. Venous leakage secondary to this phenomenon could be a factor in the pathophysiology of erectile dysfunction, especially in patients that do not respond to medical therapy. PMID- 27496772 TI - Is the adjustable TVA mesh effective for the long-term treatment of female stress incontinence? AB - OBJECTIVES: To assess the long-term safety and efficacy of the adjustable TVA mesh in treating stress urinary incontinence. MATERIAL AND METHODS: Pseudoexperimental study, before and after, conducted in a university urology department. Eighty-two patients were invited to participate from January 2002 to March 2005. Thirty-two patients agreed to participate and were implanted an adjustable TVA mesh. The preoperative study included a medical history review, physical examination with full bladder, flowmetry, residue study, complete urodynamic study and the self-administered questionnaires I-QoL and ICIQ-SF. In the postoperative assessment, the PGI-I questionnaire was added, but a complete urodynamic study was not performed. RESULTS: Twenty-nine (90.6%) and 28 (87.5%) patients were continent in the stress test at 1 and 10 years, respectively. Twenty (62.5%) and 16 (50%) patients had no urine escape at 1 and 10 years, respectively. Twenty-eight (87.5%) and 25 (78%) patients were satisfied 1 and 10 years after the surgery, respectively. Twenty-eight (87.5%) and 21 (62.5%) patients had a good quality of life at 1 year and at 10 years, respectively. There were no significant complications at the end of the study period. CONCLUSIONS: Treatment of stress urinary incontinence with the TVA mesh presented a high degree of objective healing and satisfaction at 10 years, with no severe adverse effects. The study showed that satisfaction does not always mean total continence but rather it reflects the improvement of symptoms and consequent quality of life. PMID- 27496773 TI - Carbon Catabolite Repression and Impranil Polyurethane Degradation in Pseudomonas protegens Strain Pf-5. AB - : Polyester polyurethane (PU) coatings are widely used to help protect underlying structural surfaces but are susceptible to biological degradation. PUs are susceptible to degradation by Pseudomonas species, due in part to the degradative activity of secreted hydrolytic enzymes. Microorganisms often respond to environmental cues by secreting enzymes or secondary metabolites to benefit their survival. This study investigated the impact of exposing several Pseudomonas strains to select carbon sources on the degradation of the colloidal polyester polyurethane Impranil DLN (Impranil). The prototypic Pseudomonas protegens strain Pf-5 exhibited Impranil-degrading activities when grown in sodium citrate but not in glucose-containing medium. Glucose also inhibited the induction of Impranil degrading activity by citrate-fed Pf-5 in a dose-dependent manner. Biochemical and mutational analyses identified two extracellular lipases present in the Pf-5 culture supernatant (PueA and PueB) that were involved in degradation of Impranil. Deletion of the pueA gene reduced Impranil-clearing activities, while pueB deletion exhibited little effect. Removal of both genes was necessary to stop degradation of the polyurethane. Bioinformatic analysis showed that putative Cbr/Hfq/Crc-mediated regulatory elements were present in the intergenic sequences upstream of both pueA and pueB genes. Our results confirmed that both PueA and PueB extracellular enzymes act in concert to degrade Impranil. Furthermore, our data showed that carbon sources in the growth medium directly affected the levels of Impranil-degrading activity but that carbon source effects varied among Pseudomonas strains. This study uncovered an intricate and complicated regulation of P. protegens PU degradation activity controlled by carbon catabolite repression. IMPORTANCE: Polyurethane (PU) coatings are commonly used to protect metals from corrosion. Microbiologically induced PU degradation might pose a substantial problem for the integrity of these coatings. Microorganisms from diverse genera, including pseudomonads, possess the ability to degrade PUs via various means. This work identified two extracellular lipases, PueA and PueB, secreted by P. protegens strain Pf-5, to be responsible for the degradation of a colloidal polyester PU, Impranil. This study also revealed that the expression of the degradative activity by strain Pf-5 is controlled by glucose carbon catabolite repression. Furthermore, this study showed that the Impranil-degrading activity of many other Pseudomonas strains could be influenced by different carbon sources. This work shed light on the carbon source regulation of PU degradation activity among pseudomonads and identified the polyurethane lipases in P. protegens. PMID- 27496774 TI - Multivalent Chromosomal Expression of the Clostridium botulinum Serotype A Neurotoxin Heavy-Chain Antigen and the Bacillus anthracis Protective Antigen in Lactobacillus acidophilus. AB - : Clostridium botulinum and Bacillus anthracis produce potent toxins that cause severe disease in humans. New and improved vaccines are needed for both of these pathogens. For mucosal vaccine delivery using lactic acid bacteria, chromosomal expression of antigens is preferred over plasmid-based expression systems, as chromosomal expression circumvents plasmid instability and the need for antibiotic pressure. In this study, we constructed three strains of Lactobacillus acidophilus NCFM expressing from the chromosome (i) the nontoxic host receptor binding domain of the heavy chain of Clostridium botulinum serotype A neurotoxin (BoNT/A-Hc), (ii) the anthrax protective antigen (PA), and (iii) both the BoNT/A Hc and the PA. The BoNT/A-Hc vaccine cassette was engineered to contain the signal peptide from the S-layer protein A from L. acidophilus and a dendritic cell-targeting peptide. A chromosomal region downstream of lba0889 carrying a highly expressed enolase gene was selected for insertion of the vaccine cassettes. Western blot analysis confirmed the heterologous expression of the two antigens from plasmid and chromosome locations. Stability assays demonstrated loss of the vaccine cassettes from expression plasmids without antibiotic maintenance. RNA sequencing showed high expression of each antigen and that insertion of the vaccine cassettes had little to no effect on the transcription of other genes in the chromosome. This study demonstrated that chromosomal integrative recombinant strains are promising vaccine delivery vehicles when targeted into high-expression chromosomal regions. Levels of expression match high-copy-number plasmids and eliminate the requirement for antibiotic selective maintenance of recombinant plasmids. IMPORTANCE: Clostridium botulinum and Bacillus anthracis produce potent neurotoxins that pose a biochemical warfare concern; therefore, effective vaccines against these bacteria are required. Chromosomal expression of antigens is preferred over plasmid-based expression systems since expressing antigens from a chromosomal location confers an advantage to the vaccine strains by eliminating the antibiotic maintenance required for plasmids and negates issues with plasmid instability that would result in loss of the antigen. Lactic acid bacteria, including Lactobacillus acidophilus, have shown potential for mucosal vaccine delivery, as L. acidophilus is bile and acid tolerant, allowing transit through the gastrointestinal tract where cells interact with host epithelial and immune cells, including dendritic cells. In this study, we successfully expressed C. botulinum and B. anthracis antigens in the probiotic L. acidophilus strain NCFM. Both antigens were highly expressed individually or in tandem from the chromosome of L. acidophilus. PMID- 27496775 TI - Extending CRISPR-Cas9 Technology from Genome Editing to Transcriptional Engineering in the Genus Clostridium. AB - : The discovery and exploitation of the prokaryotic adaptive immunity system based on clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) proteins have revolutionized genetic engineering. CRISPR Cas tools have enabled extensive genome editing as well as efficient modulation of the transcriptional program in a multitude of organisms. Progress in the development of genetic engineering tools for the genus Clostridium has lagged behind that of many other prokaryotes, presenting the CRISPR-Cas technology an opportunity to resolve a long-existing issue. Here, we applied the Streptococcus pyogenes type II CRISPR-Cas9 (SpCRISPR-Cas9) system for genome editing in Clostridium acetobutylicum DSM792. We further explored the utility of the SpCRISPR-Cas9 machinery for gene-specific transcriptional repression. For proof of-concept demonstration, a plasmid-encoded fluorescent protein gene was used for transcriptional repression in C. acetobutylicum Subsequently, we targeted the carbon catabolite repression (CCR) system of C. acetobutylicum through transcriptional repression of the hprK gene encoding HPr kinase/phosphorylase, leading to the coutilization of glucose and xylose, which are two abundant carbon sources from lignocellulosic feedstocks. Similar approaches based on SpCRISPR Cas9 for genome editing and transcriptional repression were also demonstrated in Clostridium pasteurianum ATCC 6013. As such, this work lays a foundation for the derivation of clostridial strains for industrial purposes. IMPORTANCE: After recognizing the industrial potential of Clostridium for decades, methods for the genetic manipulation of these anaerobic bacteria are still underdeveloped. This study reports the implementation of CRISPR-Cas technology for genome editing and transcriptional regulation in Clostridium acetobutylicum, which is arguably the most common industrial clostridial strain. The developed genetic tools enable simpler, more reliable, and more extensive derivation of C. acetobutylicum mutant strains for industrial purposes. Similar approaches were also demonstrated in Clostridium pasteurianum, another clostridial strain that is capable of utilizing glycerol as the carbon source for butanol fermentation, and therefore can be arguably applied in other clostridial strains. PMID- 27496776 TI - Epidemiological Investigation of Legionella pneumophila Serogroup 2 to 14 Isolates from Water Samples by Amplified Fragment Length Polymorphism and Sequence-Based Typing and Detection of Virulence Traits. AB - : The aim of this study is to explore the dispersion, clonality, and virulence of Legionella pneumophila serogroups 2 to 14 in the Greek environment. Eighty L. pneumophila serogroup 2 to 14 strains isolated from water distribution systems of hotels, hospitals, athletic venues, and ferries in Greece were tested by monoclonal antibodies (MAbs) for serogroup discrimination and molecularly by amplified fragment length polymorphism (AFLP) for genetic diversity. Fifty-six of 80 strains were also typed by the sequence-based typing (SBT) method. Alphall strains were further analyzed for detection of two pathogenicity loci: Legionella vir homologue (lvh) and repeats in structural toxin (rtxA). Thirty-seven strains (46.2%) belonged to serogroup 6, 26 strains (32.5%) to serogroup 3, and 7 (8.8%) to other serogroups (4, 5, 8, and 10). Ten strains (12.5%) were nontypeable (NT) into the known serogroups. Thirty-nine different AFLP types were found among the 80 L. pneumophila serogroup 2 to 14 strains, and 24 different SBT types were found among the 56 strains tested. Among the 80 strains, the lvh locus was present in 75 (93.8%), the rtxA locus was found in 76 (95%), and both loci were found in 73 (91.3%) strains. This study showed that there is genetic variability of L. pneumophila serogroups 2 to 14 in the Greek environment as well as a high percentage of the pathogenicity loci. Iotantroducing an effective diagnostic test for L. pneumophila serogroups 2 to 14 in urine and promoting the examination of respiratory specimens from patients hospitalized for pneumonia in Greek hospitals are essential. IMPORTANCE: In this study, the dispersion, clonality, and virulence of environmental isolates of Legionella pneumophila serogroups 2 to 14 (Lp2-14) in Greece were investigated. Genetic variability of Lp2-14 in the Greek environment was identified together with the presence of the pathogenicity loci in a high percentage of the isolates. Despite the high prevalence of Lp2-14 in the Greek environment, no clinical cases were reported, which may be due to underdiagnosis of the disease. Almost all the legionellosis cases are diagnosed in Greece by using the urine antigen test, which is specific for Lp1. There is an urgent need to improve the clinical diagnosis of legionellosis by introducing an effective diagnostic test for Lp2-14 in urine and by promoting the PCR examination of respiratory specimens from patients with compatible clinical symptoms. PMID- 27496777 TI - Evidence for the Existence of Autotrophic Nitrate-Reducing Fe(II)-Oxidizing Bacteria in Marine Coastal Sediment. AB - : Nitrate-reducing Fe(II)-oxidizing microorganisms were described for the first time ca. 20 years ago. Most pure cultures of nitrate-reducing Fe(II) oxidizers can oxidize Fe(II) only under mixotrophic conditions, i.e., when an organic cosubstrate is provided. A small number of nitrate-reducing Fe(II)-oxidizing cultures have been proposed to grow autotrophically, but unambiguous evidence for autotrophy has not always been provided. Thus, it is still unclear whether or to what extent Fe(II) oxidation coupled to nitrate reduction is an enzymatically catalyzed and energy-yielding autotrophic process or whether Fe(II) is abiotically oxidized by nitrite from heterotrophic nitrate reduction. The aim of the present study was to find evidence for the existence of autotrophic nitrate reducing Fe(II) oxidizers in coastal marine sediments. Microcosm incubations showed that with increasing incubation times, the stoichiometric ratio of reduced nitrate/oxidized Fe(II) [NO3-reduced/Fe(II)oxidized] decreased, indicating a decreasing contribution of heterotrophic denitrification and/or an increasing contribution of autotrophic nitrate-reducing Fe(II) oxidation over time. After incubations of sediment slurries for >10 weeks, nitrate-reducing activity ceased, although nitrate was still present. This suggests that heterotrophic nitrate reduction had ceased due to the depletion of readily available organic carbon. However, after the addition of Fe(II) to these batch incubation mixtures, the nitrate-reducing activity resumed, and Fe(II) was oxidized, indicating the activity of autotrophic nitrate-reducing Fe(II) oxidizers. The concurrent reduction of 14C-labeled bicarbonate concentrations unambiguously proved that autotrophic C fixation occurred during Fe(II) oxidation and nitrate reduction. Our results clearly demonstrated that autotrophic nitrate-reducing Fe(II) oxidizing bacteria were present in the investigated coastal marine sediments. IMPORTANCE: Twenty years after the discovery of nitrate-reducing Fe(II) oxidizers, it is still controversially discussed whether autotrophic nitrate reducing Fe(II)-oxidizing microorganisms exist and to what extent Fe(II) oxidation in this reduction/oxidation process is enzymatically catalyzed or which role abiotic side reactions of Fe(II) with reactive N species play. Most pure cultures of nitrate-reducing Fe(II) oxidizers are mixotrophic; i.e., they need an organic cosubstrate to maintain their activity over several cultural transfers. For the few existing autotrophic isolates and enrichment cultures, either the mechanism of nitrate-reducing Fe(II) oxidation is not known or evidence for their autotrophic lifestyle is controversial. In the present study, we provide evidence for the existence of autotrophic nitrate-reducing Fe(II) oxidizers in coastal marine sediments. The evidence is based on stoichiometries of nitrate reduction and Fe(II) oxidation determined in microcosm incubations and the incorporation of carbon from CO2 under conditions that favor the activity of nitrate-reducing Fe(II) oxidizers. PMID- 27496778 TI - Community-Based Culturally Preferred Physical Activity Intervention Targeting Populations at High Risk for Type 2 Diabetes: Results and Implications. AB - OBJECTIVES: In Canada, an ageing population, obesity rates and high risk among certain ethnocultural populations are driving diabetes prevalence. Given the burden associated with type 2 diabetes and its link to modifiable risk factors, this study aimed to implement culturally preferred physical activities at the community level, targeting individuals at high risk for type 2 diabetes. Glycated hemoglobin (A1C) levels were used to detect potential improvements in glycemic control. METHODS: Participants were screened for diabetes risk using a questionnaire and capillary point-of-care A1C blood testing. Participants were offered community-based physical activity classes 2 to 3 times per week for 6 months. A subset of participants (n=84) provided additional measurements. RESULTS: In total, 718 subjects were reached during recruitment. Substantial participant dropout took place, and 487 participants were exposed to the intervention. Among those who participated in the physical activity and provided follow up, mean A1C levels were reduced by 0.17 (p=0.002) after 3 months (n=84) and by 0.06 (p=0.35; n=49) after 6 months. The homeostatic model assessment (HOMA beta) showed a significant improvement of 23.6% after 3 months (n=20; p=0.03) and 45.2% after 6 months (n=12; p=0.02). Resting systolic blood pressure and diastolic blood pressure plus combined hand-grip strength improved after 6 months (n=12). CONCLUSIONS: Implementation of this community-based, culturally preferred physical activity program presented several challenges and was associated with significant participant dropout. After considering participant dropout, the relatively small group who participated and provided follow-up measures showed improvements various physiologic measures. Despite efforts to enhance accessibility, it appears that several barriers to physical activity participation remain and need to be explored to enhance the success of future programs. PMID- 27496780 TI - CNR 3/16, Societies' Communications. PMID- 27496779 TI - Chronic Osteomyelitis and Atrial Fibrillation: Revisiting the Link Between Inflammation Burden and Arrhythmia. PMID- 27496781 TI - Reply to Lagana et al.'s comment on "Risk of developing major depression and anxiety disorders among women with endometriosis: A longitudinal follow-up study". PMID- 27496782 TI - Prevalence of food allergy in infants and pre-schoolers in Brazil. AB - BACKGROUND: Food allergy is an increasing problem in public health, especially in childhood. Its incidence has increased in the last decade. Despite this, estimates of the actual incidence and prevalence are uncertain. The aim of this study was to estimate the prevalence of food allergy in infants and pre schoolers. METHODS: The parents of 3897 children completed questionnaires on the occurrence of any reaction to food. Children with parentally reported reactions were selected for further examination including a clinical interview, physical examination, allergic tests, and if necessary, oral food challenge to conclude the diagnosis of FA. RESULTS: The estimated prevalence of allergy in children aged 4-59 months was 0.61%, being, 1.9% in infants and 0.4% in pre-schoolers. Among the 604 patients physicians evaluated with parent-reported FA, 24 (4%) had a confirmed diagnosis of food allergy, and 580 (96%) were excluded in the remaining. Of these, approximately half (51/52.6%) of 97 infants and (128/48%) of 487 pre-schoolers already performed the diet exclusion suspected food for a period of time. CONCLUSION: This study shows that high overall prevalence of parental belief of current food allergy however the same was not observed in the in physician-diagnosed food allergy. The prevalence of food allergy was lower than that observed in the literature. This study alerts health professionals to the risk entailed by overestimation of cases of food allergy and unnecessary dietary exclusion, which may result in impairment in growth and development of children, especially in their first years of life. PMID- 27496783 TI - Impact of rhinitis on lung function in children and adolescents without asthma. AB - BACKGROUND: Subclinical spirometric abnormalities may be detected in patients with rhinitis without asthma, proportional to the severity established by ARIA (Allergic Rhinitis and Its Impact on Asthma) guidelines. New criteria of rhinitis classification were recently validated according to the ARIA modified (m-ARIA), which allow the discrimination between moderate to severe grades. The impact of rhinitis on lung function according to frequency and severity is unknown. OBJECTIVES: To investigate subclinical spirometric impairment in children and adolescents with allergic and non-allergic rhinitis without overt symptoms of asthma, according to the frequency and severity criteria of rhinitis classified by m-ARIA. METHODS: An observational cross-sectional study, including children and adolescents aged 5-18 years with allergic and non-allergic rhinitis without asthma. We analysed the functional abnormalities and bronchodilator response with spirometry in relation to the grade of rhinitis established by m-ARIA using an adjusted logistic model. A value of p<0.05 was considered statistically significant. RESULTS: We studied 189 patients; 22.2% showed spirometric abnormalities. Patients with persistent rhinitis had greater impairment of lung function compared to intermittent grade (p=0.026). Lung functional impairment was more frequent in severe and moderate rhinitis than mild grade (p=0.005) and was independent of the atopic status to both frequency (p=0.157) and severity (p=0.538). There was no difference in bronchodilator reversibility between groups (p>0.05). CONCLUSIONS: Impaired lung function was associated with persistence and severity of rhinitis and there was no significant difference between patients with moderate and severe rhinitis. The spirometric abnormality was demonstrated in patients with allergic and non-allergic rhinitis. PMID- 27496784 TI - Corneal Astigmatism and Aberrations After Combined Femtosecond-Assisted Phacoemulsification and Arcuate Keratotomy: Two-Year Results. AB - PURPOSE: To investigate the stability of corneal astigmatism and higher-order aberrations after combined femtosecond-assisted phacoemulsification and arcuate keratotomy. DESIGN: Retrospective, interventional case series. METHODS: Surgery was performed using a VICTUS (Bausch & Lomb Inc, Dornach, Germany) platform. A single, 450-MUm deep, arcuate keratotomy was paired at the 8-mm zone with the main phacoemulsification incision in the opposite meridian. The keratotomy incisions were not opened. Corneal astigmatism and higher-order aberration measurements obtained preoperatively and at 2 months and 2 years postoperatively were analyzed. RESULTS: Fifty eyes of 50 patients (mean age 66.2 +/- 10.5 years) were included. The mean preoperative corneal astigmatism was 1.35 +/- 0.48 diopters (D). This was reduced to 0.67 +/- 0.54 D at 2 months and 0.74 +/- 0.53 D at 2 years postoperatively (P < .001). There was no statistically significant difference between postoperative corneal astigmatism over 2 years (P = .392). Both magnitude of error and absolute angle of error were comparable between the 2 postoperative time points (P > .283). At postoperative 2 months and 2 years, 72% and 70% of eyes were within 15 degrees of preoperative meridian of astigmatism, respectively. All wavefront measurements increased significantly at 2 months and 2 years (P < .007), except spherical aberration (P > .150). There was no significant difference in higher-order aberrations between 2 months and 2 years postoperatively (P > .486). CONCLUSIONS: Our study showed the stability of femtosecond-assisted arcuate keratotomy. Further studies using other platforms and nomograms are needed to corroborate the findings of this study. PMID- 27496785 TI - Choriocapillaris Flow Features Follow a Power Law Distribution: Implications for Characterization and Mechanisms of Disease Progression. AB - PURPOSE: To investigate flow characteristics of the choriocapillaris using optical coherence tomography angiography. DESIGN: Retrospective observational case series. METHODS: Visualization of flow in individual choriocapillary vessels is below the current resolution limit of optical coherence tomography angiography instruments, but areas of absent flow signal, called flow voids, are resolvable. The central macula was imaged with the Optovue RTVue XR Avanti using a 10-MUm slab thickness in 104 eyes of 80 patients who ranged in age from 24 to 99 years of age. Automatic local thresholding of the resultant raw data with the Phansalkar method was analyzed with generalized estimating equations. RESULTS: The distribution of flow voids vs size of the voids was highly skewed. The data showed a linear log-log plot and goodness-of-fit methods showed the data followed a power law distribution over the relevant range. A slope intercept relationship was also evaluated for the log transform and significant predictors for variables included age, hypertension, pseudodrusen, and the presence of late age-related macular degeneration (AMD) in the fellow eye. CONCLUSIONS: The pattern of flow voids forms a scale invariant pattern in the choriocapillaris starting at a size much smaller than a choroidal lobule. Age and hypertension affect the choriocapillaris, a flat layer of capillaries that may serve as an observable surrogate for the neural or systemic microvasculature. Significant alterations detectable in the flow pattern in eyes with pseudodrusen and in eyes with late AMD in the fellow eye offer diagnostic possibilities and impact theories of disease pathogenesis. PMID- 27496786 TI - Assessing the temporal aspects of attention and its correlates in aging and chronic stroke patients. AB - Temporal dynamics of attention have been in the spotlight of research since the earliest days of cognitive psychology. Typically, researchers describe two different aspects of the temporal fluctuations of attention: one is in intervals of milliseconds (phasic alertness), and the other over minutes or even hours (tonic alertness or sustained attention). In order to evaluate individual capacities for sustained attention and phasic alertness, most studies rely on variations of the Continuous Performance Task (CPT). Indices of sustained attention and phasic alertness are typically based on reaction times to targets; phasic alertness is related to the change in reaction times following a cue, and sustained attention is related to variability of reaction times during the task. In the following study, we attempted to establish a new approach for studying sustained attention and phasic alertness, not reliant solely on reaction time measures. We developed a new variation of the CPT with conjunctive feature targets and forward and backward masking to induce a higher variability in accuracy. This allowed us to assess an individual's ability to maintain the same level of sensitivity to targets (d-prime) across a ten minute period on the task as an index for sustained attention. We also assessed reaction times as a function of previous trial type, and suggest previous trial RT benefit might be a marker for an individual's phasic alertness. We demonstrated the use of this task with healthy aging controls and stroke survivors. As a demonstration of external validity of the novel paradigm, we present a correlation between how individual performance drops over time and individual reports of distractibility in everyday life on the Cognitive Failures Questionnaire. In addition, we found significant differences between the patient and control groups in our proposed marker of phasic alertness. We discuss the implications of our study for current assessment tools, as well as general differences in phasic alertness between clinical and neurologically unimpaired groups. PMID- 27496787 TI - Explicit and implicit approach vs. avoidance tendencies towards high vs. low calorie food cues in patients with anorexia nervosa and healthy controls. AB - Patients with anorexia nervosa (AN) have a strong ability to limit food intake. Thus, dysfunctional approach vs. avoidance behaviors towards food are evident in AN. We applied an approach-avoidance task (AAT), in which n = 41 AN patients and n = 42 controls either approached ("pull") or avoided ("push") high (HC) vs. low calorie (LC) food pictures based solely on the presented picture format (landscape vs. portrait). We tested the hypothesis that -in opposition to controls displaying an approach bias towards HC food cues- AN patients would show an avoidance bias (measured as different response times) towards HC food. Explicit ratings of food cues were also performed. We found a significant interaction "group" x "direction" (p = 0.03). rm-ANOVAs performed for each of the two groups separately showed a main effect for "direction" of motion in controls (p = 0.02), but not in AN patients (p = 0.40). The two groups did not differ in their reaction times (RTs) with regard to "push" (p = 0.27). However, RTs with regard to "pull" were significantly different between the groups (p = 0.04). Controls show a clear approach bias, expressed by significantly faster RTs for "pull" compared to "push", independent of "calorie" content of the food stimuli. This approach bias is absent in the group of AN patients. This is indicative of a global loss of incentive value of food in AN. Implicit trainings as add-on to psychotherapy in AN patients are asked for. PMID- 27496788 TI - Effects on satiation, satiety and food intake of wholegrain and refined grain pasta. AB - Wholegrains have received much attention in recent years due to their role in prevention of obesity and its comorbidities. Many studies about energy regulation are focused on the effect between meals (satiety), but the effect within meal (satiation) for wholegrain foods has not been extensively studied. The objective was to investigate the effect of WG pasta (WGP) compared to refined grain pasta (RGP), on ad libitum energy intake (EI) within and at the subsequent meal as well as appetite. Two different ad libitum lunch meals (study A) and two different iso caloric lunch meals (study B) were administered in sixteen overweight/obese subjects in a crossover design. The test meals consisted of RGP and WGP served with tomato sauce. Study A: the ad libitum lunch meal was consumed then EI registered. Study B: the iso-caloric lunch meal was served, then subjective appetite sensation and breath hydrogen excretion were assessed for 240 min followed by an ad libitum meal where EI was calculated. Overall, WGP did not significantly differ in the effect on ad libitum EI within meal (p = 0.23) in study A. In study B, WGP resulted in an increased sensation of satiety (p < 0.001) and lower ratings of hunger (p < 0.001) without increased in breath hydrogen excretion (p = 0.11). Again, no overall effect on EI at the subsequent meal was seen (p = 0.12). In conclusion, WGP increased satiety, diminished hunger without modifying energy intake at the subsequent meals. PMID- 27496790 TI - Annual meeting of Scottish Urology Society, 2015: Date: 26-27 February 2015, Ayrshire. PMID- 27496789 TI - Death Certification: 800 years of practice; time to modernise teaching? AB - A short, personal perspective on the state of death certification teaching in the UK from two foundation doctors, with a focus on the importance of certifying death and the potential educational methods available to improve teaching on the topic. PMID- 27496791 TI - Association of serum chemerin concentrations with the presence of atrial fibrillation. AB - Objective Chemerin, a newly discovered adipokine, is correlated with hypertension, diabetes and coronary heart disease. The aim of this study is to investigate the association of serum chemerin concentrations with the presence of atrial fibrillation. Methods Serum chemerin concentrations were determined in 256 patients with atrial fibrillation and 146 healthy subjects. Atrial fibrillation patients were then divided into paroxysmal, persistent and permanent atrial fibrillation. Results Serum chemerin concentrations were significantly higher in atrial fibrillation patients compared with healthy controls. In subgroup studies, patients with permanent atrial fibrillation had higher serum chemerin concentrations than those with persistent and paroxysmal atrial fibrillation. Furthermore, significant higher serum chemerin concentrations were observed in persistent atrial fibrillation patients compared with paroxysmal atrial fibrillation subjects. Serum chemerin concentrations were associated with the presence of atrial fibrillation after logistic regression analysis. Pearson correlation analysis revealed a positive relation of serum chemerin concentrations with body mass index, systolic blood pressure, diastolic blood pressure, triglycerides, low-density lipoprotein cholesterol, blood urea nitrogen, creatinine, C-reactive protein and left atrial diameter. Conclusion Serum chemerin concentrations are associated with the presence of atrial fibrillation and atrial remodelling. PMID- 27496792 TI - Haemoglobin variants may cause significant differences in haemoglobin A1c as measured by high-performance liquid chromatography and enzymatic methods in diabetic patients: a cross-sectional study. AB - Background We aimed to determine whether the discrepancy between haemoglobin A1c values determined by high-performance liquid chromatography and enzymatic haemoglobin A1c measurements in diabetic patients was clinically relevant. Methods We randomly recruited 1421 outpatients undergoing diabetic treatment and follow-up who underwent at least three haemoglobin A1c measurements between April 2014 and March 2015 at our clinic. In 6369 samples, haemoglobin A1c was simultaneously measured by HA-8160 and MetaboLead (enzymatic assay), and the values were compared. Results haemoglobin A1c measurements by high-performance liquid chromatography and enzymatic assay were strongly correlated (correlation coefficient: 0.9828, linear approximation curve y = 0.9986x - 0.2507). Mean haemoglobin A1c (6.8 +/- 1.0%) measured by high-performance liquid chromatography was significantly higher than that measured by enzymatic assay (6.5 +/- 1.0%, P < 0.0001). During the sample processing, four (0.3%) subjects presented consistently lower haemoglobin A1c values (<0.7%) by high-performance liquid chromatography than those from enzymatic assay. Of these, three had Hb Toranomon [beta112 (G14) Cys->Trp]. The fourth had Hb Ube-2 [alpha68 (E17) Asn->Asp]. One other subject presented consistently higher haemoglobin A1c values (>1%) by high performance liquid chromatography than those from enzymatic assay and was diagnosed with a -77 (T > C) mutation in the delta-globin gene. These unrelated asymptomatic subjects had normal erythrocyte profiles, without anaemia. Conclusions We showed that haemoglobin A1c values measured by high-performance liquid chromatography were significantly higher than those measured by enzymatic assay in diabetic subjects. However, when an oversized deviation (>0.7%) between glycaemic control status and haemoglobin A1c is apparent, clinicians should check the methods used to measure haemoglobin A1c and consider the possible presence of a haemoglobin variant. PMID- 27496793 TI - Annexin A2 and its downstream IL-6 and HB-EGF as secretory biomarkers in the differential diagnosis of Her-2 negative breast cancer. AB - Background AnnexinA2 (AnxA2) membrane deposition has a critical role in HB-EGF shedding as well as IL-6 secretion in breast cancer cells. This autocrine cycle has a major role in cancer cell proliferation, migration and metastasis. The objective of the study is to demonstrate annexinA2-mediated autocrine regulation via HB-EGF and IL-6 in Her-2 negative breast cancer progression. Methods Secretory annexinA2, HB-EGF and IL-6 were analysed in the peripheral blood sample of Her-2 negative ( n = 20) and positive breast cancer patients ( n = 16). Simultaneously, tissue expression was analysed by immunohistochemistry. The membrane deposition of these secretory ligands and their autocrine regulation was demonstrated using triple-negative breast cancer cell line model. Results Annexina2 and HB-EGF expression are inversely correlated with Her-2, whereas IL-6 expression is seen in both Her-2 negative and positive breast cancer cells. RNA interference studies and upregulation of annexinA2 proved that annexinA2 is the upstream of this autocrine pathway. Abundant soluble serum annexinA2 is secreted in Her-2 negative breast cancer (359.28 +/- 63.73 ng/mL) compared with normal (286.10 +/- 70.04 ng/mL, P < 0.01) and Her-2 positive cases (217.75 +/- 60.59 ng/mL, P < 0.0001). In Her-2 negative cases, the HB-EGF concentrations (179.16 +/ 118.81 pg/mL) were highly significant compared with normal (14.92 +/- 17.33 pg/mL, P < 0.001). IL-6 concentrations were increased significantly in both the breast cancer phenotypes as compared with normal ( P < 0.001). Conclusion The specific expression pattern of annexinA2 and HB-EGF in triple-negative breast cancer tissues, increased secretion compared with normal cells, and their major role in the regulation of EGFR downstream signalling makes these molecules as a potential tissue and serum biomarker and an excellent therapeutic target in Her-2 negative breast cancer. PMID- 27496794 TI - Post-standardization of routine creatinine assays: are they suitable for clinical applications. AB - Introduction Reliable serum creatinine measurements are of vital importance for the correct classification of chronic kidney disease and early identification of kidney injury. The National Kidney Disease Education Programme working group and other groups have defined clinically acceptable analytical limits for creatinine methods. The aim of this study was to re-evaluate the performance of routine creatinine methods in the light of these defined limits so as to assess their suitability for clinical practice. Method In collaboration with the Dutch External Quality Assurance scheme, six frozen commutable samples, with a creatinine concentration ranging from 80 to 239 MUmol/L and traceable to isotope dilution mass spectrometry, were circulated to 91 laboratories in four European countries for creatinine measurement and estimated glomerular filtration rate calculation. Two out of the six samples were spiked with glucose to give high and low final concentrations of glucose. Results Results from 89 laboratories were analysed for bias, imprecision (%CV) for each creatinine assay and total error for estimated glomerular filtration rate. The participating laboratories used analytical instruments from four manufacturers; Abbott, Beckman, Roche and Siemens. All enzymatic methods in this study complied with the National Kidney Disease Education Programme working group recommended limits of bias of 5% above a creatinine concentration of 100 MUmol/L. They also did not show any evidence of interference from glucose. In addition, they also showed compliance with the clinically recommended %CV of <=4% across the analytical range. In contrast, the Jaffe methods showed variable performance with regard to the interference of glucose and unsatisfactory bias and precision. Conclusion Jaffe-based creatinine methods still exhibit considerable analytical variability in terms of bias, imprecision and lack of specificity, and this variability brings into question their clinical utility. We believe that clinical laboratories and manufacturers should work together to phase out the use of relatively non-specific Jaffe methods and replace them with more specific methods that are enzyme based. PMID- 27496795 TI - Bone turnover marker reference intervals in young females. AB - Background The use of bone turnover markers in clinical practice and research in younger people is limited by the lack of normative data and understanding of common causes of variation in bone turnover marker values in this demographic. To appropriately interpret bone turnover markers, robust reference intervals specific to age, development and sex are necessary. This study aimed to determine reference intervals of bone turnover markers in females aged 16-25 years participating in the Safe-D study. Methods Participants were recruited through social networking site Facebook and were asked to complete an extensive, online questionnaire and attend a site visit. Participants were tested for serum carboxy terminal cross-linking telopeptide of type 1 collagen and total procollagen type 1 N-propeptide using the Roche Elecsys automated analyser. Reference intervals were determined using the 2.5th to 97.5th percentiles of normalized bone turnover marker values. Results Of 406 participants, 149 were excluded due to medical conditions or medication use (except hormonal contraception) which may affect bone metabolism. In the remaining 257 participants, the reference interval was 230-1000 ng/L for serum carboxy-terminal cross-linking telopeptide of type 1 collagen and 27-131 ug/L for procollagen type 1 N-propeptide. Both marker concentrations were inversely correlated with age and oral contraceptive pill use. Therefore, intervals specific to these variables were calculated. Conclusions We defined robust reference intervals for cross-linking telopeptide of type 1 collagen and procollagen type 1 N-propeptide in young females grouped by age and contraceptive pill use. We examined bone turnover markers' relationship with several lifestyle, clinical and demographic factors. Our normative intervals should aid interpretation of bone turnover markers in young females particularly in those aged 16 to 19 years where reference intervals are currently provisional. PMID- 27496796 TI - Diabetic macular oedema. AB - Diabetic macular oedema, characterised by exudative fluid accumulation in the macula, is the most common form of sight-threatening retinopathy in people with diabetes. It affects one in 15 people with diabetes resulting in more than 20 million cases worldwide. Few epidemiological studies have been done to specifically investigate risk factors for diabetic macular oedema, although poor glycaemic and blood pressure control are associated with the presence and development of the disorder. The pathophysiological processes begin with chronic hyperglycaemia, and interplay between vascular endothelial growth factor (VEGF) and inflammatory mediators. Non-invasive imaging using optical coherence tomography has allowed clinicians to detect mild levels of diabetic macular oedema in order to monitor progress and guide treatment. Although focal or grid laser photocoagulation was the traditional mode of treatment, intraocular pharmacotherapy with anti-VEGF agents is now the standard of care. However, these therapies are expensive and resource intensive. Emerging therapeutic strategies include improving efficacy and duration of VEGF suppression, targeting alternative pathways such as inflammation, the kallikrein-kinin system, the angiopoietin-Tie2 system, and neurodegeneration, and using subthreshold and targeted laser therapy. Ongoing research should lead to improvements in screening, diagnosis, and management of diabetic macular oedema. PMID- 27496797 TI - Comparison of Nasal Potential Difference and Intestinal Current Measurements as Surrogate Markers for CFTR Function. AB - OBJECTIVES: Nasal potential difference (NPD) measurement is part of the diagnostic criteria for cystic fibrosis (CF) and now used routinely as an endpoint in clinical trials of correcting the basic defect in CF. Intestinal current measurement (ICM), measured ex vivo on a rectal biopsy, has been used to study cystic fibrosis transmembrane conductance regulator (CFTR) function but has not been compared to NPD in the same subject in adults and children. The aim of the study is to evaluate the potential usefulness of ICM as a marker of CFTR function for treatment studies compared NPD in patients with CF and in healthy control subjects. METHODS: ICM and NPD were performed on healthy controls and patients with CF. The healthy adults were individuals undergoing routine screening colonoscopy at the Beth Israel Deaconess Medical Center. The healthy children were undergoing colonoscopy for suspicion of inflammation in Hadassah Hebrew University Medical Center. The CF adults were recruited from Boston Children's Hospital CF Center and CF Center Worcester Mass, the children with CF from Hadassah CF Center. RESULTS: ICM measurements in healthy control subjects (n = 16) demonstrated a mean (+/-SE) carbachol response of 16.0 (2.2) MUA/cm, histamine response of 13.2 (2.1) MUA/cm and a forskolin response of 6.3 (2.0) MUA/cm. Basal NPD of -15.9 (1.9) and response to Cl free + isoproterenol of -13.8 (2.0). These responses were inverted in CF subjects (n = 12) for ICM parameters with carbachol response of -3.0 (0.5) MUA/cm, histamine -1.0 (0.8) MUA/cm and a forskolin response of 0.5 (0.3) and also for NPD parameters; basal NPD of -42.2 (4.3) and response to Cl free + isoproterenol of 4.3 (0.7). Pearson correlation test showed the comparability of ICM and NPD in assessing CFTR function. CONCLUSIONS: ICM is equivalent to NPD in the ability to distinguish patients with CF from controls and could be used as surrogate markers of CFTR activity in treatment protocols. PMID- 27496798 TI - Prevalence and Significance of Autoantibodies in Children With Acute Liver Failure. AB - OBJECTIVES: The purpose of the present study is to estimate autoantibody (auto AB) frequency, clinical characteristics, and 21-day outcome of participants in the Pediatric Acute Liver Failure Study Group (PALFSG) by antinuclear antibody, smooth muscle antibody, and liver-kidney microsomal (LKM) antibody status. METHODS: Auto-ABs were determined at local and/or central laboratories. Subjects were assigned to autoimmune hepatitis (AIH), indeterminate, and other diagnoses groups. RESULTS: Between 1999 and 2010, 986 subjects were enrolled in the PALFSG. At least 1 auto-AB result was available for 722 (73.2%). At least 1 auto-AB was positive for 202 (28.0%). Diagnoses for auto-AB+ subjects were AIH (63), indeterminate (75), and other (64). Auto-ABs were more common in Wilson disease (12/32, 37.5%) compared with other known diagnoses (52/253, 20.6%, P = 0.03). LKM+ subjects were younger (median 2.4 vs 9.1 years, P < 0.001) and more likely to undergo liver transplantation (53.3% vs 31.4% P = 0.02) than other auto AB+/LKM- subjects. Steroid treatment of subjects who were auto-AB+ was not significantly associated with survival and the subgroup with known diagnoses other than AIH had a higher risk of death. CONCLUSIONS: Auto-ABs are common in children with acute liver failure, occurring in 28%. Auto-AB+ subjects have similar outcomes to auto-AB negative subjects. LKM+ children are younger and more likely to undergo liver transplantation compared with other auto-AB+ subjects. Although auto-AB may indicate a treatable condition, positivity does not eliminate the need for a complete diagnostic evaluation because auto-ABs are present in other conditions. The significance of auto-AB in pediatric acute liver failure remains uncertain, but LKM+ appears to identify a unique population of children who merit further study. PMID- 27496799 TI - Factors Associated With Bleeding Secondary to Rupture of Esophageal Varices in Children and Adolescents With Cirrhosis. AB - OBJECTIVE: Bleeding of esophageal varices is the main cause of morbidity and mortality in children with portal hypertension. It is important to understand the factors related with a bleeding episode to evaluate more effective primary prophylaxis. The present study aims to describe the endoscopic and laboratory findings associated with upper gastrointestinal bleeding (UGIB) secondary to esophageal varices. METHOD: A cross-sectional study with 103 children and adolescents with cirrhosis, divided into a group that had experienced an episode of upper UGIB (35 patients) and a group without a history of UGIB (68 patients), was carried out. The esophageal and gastric varices were classified, and the portal hypertensive gastropathy, laboratory findings, and Child-Pugh classification were measured. RESULTS: Factors observed in univariate analysis to be associated with UGIB were the presence of esophageal varices of medium caliber or larger, portal hypertensive gastropathy, presence of red spots on esophageal varices, Child-Pugh class B or C, and hypoalbuminemia (P < 0.05). After multivariate logistic regression analysis, the significant factors were the presence of red spots on esophageal varices and the presence of gastric varices. When separated the autoimmune hepatitis, nonbiliary atresia patients (all patients except the patients with biliary atresia), and biliary atresia groups the findings in the univariate analysis were the presence of esophageal varices of medium or larger caliber, presence of red spots on varices, and presence of gastric varices in the autoimmune hepatitis patients and nonbiliary atresia patients and presence of red spots on esophageal varices, presence of gastric varices, and Child-Pugh classification B or C in biliary atresia group (P < 0.05). After multivariate logistic regression analysis, no statistical significance was found for any factor analyzed in any groups. CONCLUSIONS: The presence of gastric varices and red spots on esophageal varices were related to episodes of UGIB secondary to rupture of esophageal varices. When these findings are observed, indications for endoscopic primary prophylaxis should be evaluated. More studies are, however, necessary to better understand this problem. PMID- 27496800 TI - There Is No Iron in Human Milk. PMID- 27496802 TI - An examination of femicides in Peru between 2009 and 2014. PMID- 27496801 TI - The role of adaptive bone formation in the etiology of stress fracture. AB - Stress fractures are common injuries with load-bearing activities. Stress fractures have been reported in the scientific literature for over a century; however, the etiology continues to be investigated with important distinctions made between the contributions of the tissue-level processes of bone remodeling and modeling. In response to novel repetitive loading, increased bone remodeling may serve to replace fatigue-damaged bone while at the same time creating temporary porosity. Much attention has been given to the role of remodeling in the etiology of stress fracture; however, the role of bone modeling has received less attention. Modest increases in modeling, via bone formation on the periosteal surface of long bones in response to mechanical loading, greatly increases the fatigue resistance of bone. Thus, enhancing this adaptive bone formation is a promising target for stress fracture prevention, and a focus on adaptive bone formation may reveal novel risk factors for stress fracture. PMID- 27496803 TI - Theoretical modeling of multiprotein complexes by iSPOT: Integration of small angle X-ray scattering, hydroxyl radical footprinting, and computational docking. AB - Structural determination of protein-protein complexes such as multidomain nuclear receptors has been challenging for high-resolution structural techniques. Here, we present a combined use of multiple biophysical methods, termed iSPOT, an integration of shape information from small-angle X-ray scattering (SAXS), protection factors probed by hydroxyl radical footprinting, and a large series of computationally docked conformations from rigid-body or molecular dynamics (MD) simulations. Specifically tested on two model systems, the power of iSPOT is demonstrated to accurately predict the structures of a large protein-protein complex (TGFbeta-FKBP12) and a multidomain nuclear receptor homodimer (HNF 4alpha), based on the structures of individual components of the complexes. Although neither SAXS nor footprinting alone can yield an unambiguous picture for each complex, the combination of both, seamlessly integrated in iSPOT, narrows down the best-fit structures that are about 3.2A and 4.2A in RMSD from their corresponding crystal structures, respectively. Furthermore, this proof-of principle study based on the data synthetically derived from available crystal structures shows that the iSPOT-using either rigid-body or MD-based flexible docking-is capable of overcoming the shortcomings of standalone computational methods, especially for HNF-4alpha. By taking advantage of the integration of SAXS-based shape information and footprinting-based protection/accessibility as well as computational docking, this iSPOT platform is set to be a powerful approach towards accurate integrated modeling of many challenging multiprotein complexes. PMID- 27496806 TI - Pancreatic tail schwannoma. PMID- 27496807 TI - [Multidisciplinary units in tertiary referral hospitals to improve management of Wilson disease]. PMID- 27496805 TI - Peroxisome proliferator-activated receptor alpha-dependent renoprotection of murine kidney by irbesartan. AB - Activation of renal peroxisome proliferator-activated receptor alpha (PPARalpha) is renoprotective, but there is no safe PPARalpha activator for patients with chronic kidney disease (CKD). Studies have reported that irbesartan (Irbe), an angiotensin II receptor blocker (ARB) widely prescribed for CKD, activates hepatic PPARalpha. However, Irbe's renal PPARalpha-activating effects and the role of PPARalpha signalling in the renoprotective effects of Irbe are unknown. Herein, these aspects were investigated in healthy kidneys of wild-type (WT) and Ppara-null (KO) mice and in the murine protein-overload nephropathy (PON) model respectively. The results were compared with those of losartan (Los), another ARB that does not activate PPARalpha. PPARalpha and its target gene expression were significantly increased only in the kidneys of Irbe-treated WT mice and not in KO or Los-treated mice, suggesting that the renal PPARalpha-activating effect was Irbe-specific. Irbe-treated-PON-WT mice exhibited decreased urine protein excretion, tubular injury, oxidative stress (OS), and pro-inflammatory and apoptosis-stimulating responses, and they exhibited maintenance of fatty acid metabolism. Furthermore, the expression of PPARalpha and that of its target mRNAs encoding proteins involved in OS, pro-inflammatory responses, apoptosis and fatty acid metabolism was maintained upon Irbe treatment. These renoprotective effects of Irbe were reversed by the PPARalpha antagonist MK886 and were not detected in Irbe-treated-PON-KO mice. These results suggest that Irbe activates renal PPARalpha and that the resultant increased PPARalpha signalling mediates its renoprotective effects. PMID- 27496804 TI - miR-200b induces cell cycle arrest and represses cell growth in esophageal squamous cell carcinoma. AB - miR-200b is a pleiotropically acting microRNA in cancer progression, representing an attractive therapeutic target. We previously identified miR-200b as an invasiveness repressor in esophageal squamous cell carcinoma (ESCC), whereas further understanding is warranted to establish it as a therapeutic target. Here, we show that miR-200b mitigates ESCC cell growth by inducing G2-phase cell cycle arrest and apoptosis. The expression/activation of multiple key cell cycle regulators such as CDK1, CDK2, CDK4 and Cyclin B, and the Wnt/beta-Catenin signaling are modulated by miR-200b. We identified CDK2 and PAF (PCNA-associated factor), two important tumor-promoting factors, as direct miR-200b targets in ESCC. Correlating with the frequent loss of miR-200b in ESCC, both CDK2 and PAF levels are significantly increased in ESCC tumors compared to case-matched normal tissues (n = 119, both P < 0.0001), and correlate with markedly reduced survival (P = 0.007 and P = 0.041, respectively). Furthermore, CDK2 and PAF are also associated with poor prognosis in certain subtypes of breast cancer (n = 1802) and gastric cancer (n = 233). Although CDK2 could not significantly mediate the biological function of miR-200b, PAF siRNA knockdown phenocopied while restored expression of PAF abrogated the biological effects of miR-200b on ESCC cells. Moreover, PAF was revealed to mediate the inhibitory effects of miR-200b on Wnt/beta-Catenin signaling. Collectively, the pleiotropic effects of miR-200b in ESCC highlight its potential for therapeutic intervention in this aggressive disease. PMID- 27496808 TI - Ileocolic intussusception of ileal lipoma as a cause of lower gastrointestinal bleeding. PMID- 27496810 TI - Measurement in Family Nursing: Established Instruments and New Directions. PMID- 27496809 TI - Acute hepatitis due to hepatitis E virus after raw meat consumption. PMID- 27496811 TI - Development and Psychometric Testing of the Iceland-Family Illness Beliefs Questionnaire. AB - Illness beliefs affect how individuals and families deal with illness. A valid and reliable instrument has not yet been developed to measure "illness beliefs" in family nursing research and clinical practice. This article describes the purpose, reliability, validity, and the potential clinical and research applications of a new instrument, the Iceland-Family Illness Beliefs Questionnaire (ICE-FIBQ). The ICE-FIBQ is a short, self-report measure of an individual's beliefs about illness. Drawing from an advanced nursing practice model called the Illness Beliefs Model, the instrument was developed to measure illness beliefs about (a) cause of illness, that is, etiology; (b) control of illness on family and control of family on illness; (c) effect of illness on the individual and family; (d) illness suffering; and (e) support received from health care professionals during illness. The instrument was tested on 139 family caregivers of adolescents/youth with an illness or a disorder. Exploratory factor analysis reduced the original questionnaire from eight to seven items with a one factor solution (Cronbach's alpha = .780). Confirmatory factor analysis supported the one-factor solution (Cronbach's alpha = .789). Further research is needed to determine concurrent validity with other illness belief/illness perception scales and if the instrument is sensitive to capture change in illness beliefs following family nursing intervention. PMID- 27496813 TI - Reply to the Letter to the Editor entitled "Acute heart failure from noncompaction requiring emergency heart transplantation". PMID- 27496814 TI - Acute heart failure from noncompaction requiring emergency heart transplantation. PMID- 27496815 TI - JRSM in a Brexit world. PMID- 27496816 TI - Early 18th century evidence synthesis. PMID- 27496817 TI - A statistical note on Karl Pearson's 1904 meta-analysis. PMID- 27496818 TI - A statistical note on the analysis of the 1948 MRC streptomycin trial. PMID- 27496822 TI - Serum proatrial natriuretic peptide does not increase with higher systolic blood pressure in obese men. AB - OBJECTIVE: Obese persons have low circulating natriuretic peptide (NP) concentrations. It has been proposed that this 'natriuretic handicap' could play a role in obesity-related hypertension. The normal physiological response of the NP system to an increase in blood pressure (BP) is an increase in NP secretion with concomitant higher circulating NP concentrations. In this study, we investigated whether higher BP would also be related to higher circulating NP concentrations in obese men; furthermore, we verified that BP had affected the hearts of our study participants, by determining left ventricular mass (LVM). METHODS: We examined 103 obese healthy medication-free men. We measured 24-hour ambulatory BP (ABP). LVM was calculated using the Cornell voltage-duration product method. Fasting serum concentrations of midregional proatrial NP (MR proANP), a surrogate for active ANP, were measured. Linear regression analysis was used to calculate age-adjusted standardised regression coefficients (beta). RESULTS: LVM and BP increased across systolic ABP quartiles (mean LVM+/-SD: 1599.1+/-387.2 mm ms in first vs 2188.5+/-551.3 mm ms in fourth quartile, p<0.001; mean systolic ABP+/-SD: 114.5+/-4.2 mm Hg in first vs 149.0+/-7.7 mm Hg in fourth quartile, p<0.001). Systolic ABP was robustly associated with LVM (beta=0.48, p<0.001). Despite evidence of BP-related increases in LVM, serum MR proANP was negatively associated with systolic ABP (beta=-0.32, p=0.004) and with diastolic ABP (beta=-0.45, p<0.001). CONCLUSIONS: Contrary to known physiological BP responses, MR-proANP was negatively associated with ABP in our study. This suggests that a low amount of circulating NPs could play a role in the early stage of obesity-related hypertension. PMID- 27496823 TI - It is not just comfort: waterproof casting increases physical functioning in children with minimally angulated distal radius fractures. AB - : Waterproof casting has been reported to increase patient comfort and satisfaction, and decrease skin irritation. There are no available data on the influence of waterproof casting materials on physical function in pediatric patients. Our aim was to determine whether the use of waterproof casting would result in faster recovery of physical function while maintaining similar clinical outcomes as those obtained with nonwaterproof materials. Twenty-six children with nonangulated or minimally angulated distal radius fractures were assigned randomly to initially receive a short-arm cast made of one of two optional materials: a hybrid mesh material with a waterproof lining or fiberglass with a nonwaterproof skin protector. Two weeks later, the initial cast was removed and replaced with a short-arm cast made of the alternative option. We compared the rate of fracture displacement, physical function, pain, skin changes, itchiness, and patient satisfaction. No evidence of displacement was found in either group. The mean Activities Scale for Kids - Performance (ASK-P) (physical function) score was 10% higher during the period of time when a waterproof cast was used (P=0.04). When a waterproof cast was used during the first 2 weeks of treatment, the mean total ASK-P scores were 23% higher than that when a nonwaterproof one was used during the same period of time (P=0.003). Patients who received a waterproof cast as the initial treatment reported lower functional scores overall and in almost every domain of the ASK-P once they were in a nonwaterproof one; similarly, those who received a nonwaterproof cast as the initial treatment reported higher functional scores overall and in every domain of the ASK-P once they were in a waterproof cast. Compared with a nonwaterproof cast, the use of waterproof casting resulted in comparable levels of pain, itchiness, skin irritability, and overall patient satisfaction. The results of this randomized, cross-over trial suggest that the use of waterproof casting material for the treatment of nondisplaced or minimally displaced distal radius fractures in children can result in a faster recovery of physical function, while providing comparable stability, pain, itchiness, skin irritability, and overall patient satisfaction. LEVEL OF EVIDENCE: II. PMID- 27496824 TI - Alemtuzumab in paediatric kidney transplantation, five years' experience at the Pablo Tobon Uribe Hospital in Medellin, Colombia. PMID- 27496825 TI - Immediate ICU Care for Patients Following Aortic Arch Surgery. AB - Patients undergoing aortic arch surgery are at high risk for stroke, delirium, low cardiac output, respiratory failure, renal failure, and coagulopathy. A significantly higher mortality is seen in patients experiencing any of these complications when compared with those without complications. As surgical, perfusion, and anesthetic techniques improve, the incidence of major complications have decreased. A recent paradigm shift in cardiac surgery has focused on rapid postoperative recovery, and a similar change has affected the care of patients after arch surgery. Nevertheless, a small subset of patients experience significant morbidity and mortality after aortic arch surgery, and rapid identification of any organ dysfunction and appropriate supportive care is critical in these patients. In this article, the current state of postoperative care of the patient after open aortic arch surgery will be reviewed. PMID- 27496826 TI - Understanding How Overweight and Obese Emerging Adults Make Lifestyle Choices. AB - : To better understand health-related decision making among overweight and obese emerging adults. DESIGN AND METHODS: A cross-sectional design was used in the parent study involving overweight and obese emerging adults, ages 18-29 years. The goal of the parent study was to screen participants' diabetes risk and identify characteristics of emerging adults with prediabetes (N=107). A sub sample of respondents (n=34) from the parent study were invited to participate in focus group interviews depending on whether they had prediabetes (three groups) or they did not have prediabetes (four groups). Each focus group interview lasted 90-120 minutes following a semi-structured interview guide. Conventional content analysis was used in the data analysis. Because of the similarities between participants with and without prediabetes, the findings were synthesized and reported in the aggregate. Moreover, during the analysis, the authors decided that rational choice theory provided a useful organizing structure for presenting the data. RESULTS: Emerging adults' behavioral decisions were rational reactions to their personal competence, perception of health, environment, and availability of resources to handle problems. Calculation of trade-offs and estimations of resource availability were often used when making decisions. CONCLUSIONS: Emerging adults choose unhealthy behaviors due to inaccurate information and insufficient competence to practice healthy lifestyles rather than because of laziness or being irrational. PRACTICE IMPLICATIONS: Behavioral interventions for emerging adults need to help them develop skills to enhance health literacy and problem solving, thereby enhancing their awareness of available resources and decreasing the perceived cost of making healthy choices. PMID- 27496827 TI - Statins in the Management of Pediatric Dyslipidemia. AB - Hypercholesterolemia is a major concern in the USA, with studies identifying children as young as 2years old with early-stage atherosclerosis. Genetics play a major role in the dyslipidemia of children, but other factors, such as diet and lack of physical activity, confound the problem. Familial hypercholesterolemia (FH) is a genetic condition that causes lifelong elevations in low-density lipoprotein cholesterol (LDL-C). The heterozygous form of the disease affects around 1 in 200 people, and the homozygous form of the disease affects around 1 in 160,000-300,000 people. Early identification and appropriate management of patients with FH are essential to reduce cardiovascular disease morbidity and mortality. Consequently, US dyslipidemia guidelines recommend routine screening of all children aged 9-11years, and that LDL-C levels should be <110mg/dL in children and adolescents. The primary management strategy in all children with dyslipidemia is diet and lifestyle; a healthy diet (including fruits, vegetables, fish, and whole grains) and increased physical activity should be encouraged. Most patients with FH will also require pharmacotherapy to reduce LDL-C levels to <=130mg/dL. Statins are recommended as first-line therapy due to their proven efficacy in reducing LDL-C and improving other lipid parameters in children. They have also been shown to have a positive effect on atherosclerosis. Safety is of particular concern with children; however, studies have so far shown that the side-effect profile of statins in children is similar to that in adults. Despite improvements in disease management, FH remains underdiagnosed and undertreated, highlighting the need for greater awareness and understanding. PMID- 27496829 TI - "Pain Is What the Patient Says It Is": Nurse-Patient Communication, Information Seeking, and Pain Management. AB - Nurse-patient conversations about pain management are complex. Given recent increases in prescription pain pill abuse, such interactions merit scholarly attention. In-depth interviews with 21 nurses were conducted to explicitly explore nurses' information seeking about pain. The participants in this study gathered pain information from patients through a variety of means and reported facing challenges and dilemmas when communicating with patients about pain management and medicinal preferences. These results have important implications for nurses, patient outcomes, and the broader health-care system and imply that continued educational and intervention efforts are essential in this complicated communicative context. PMID- 27496828 TI - "Good Passengers and Not Good Passengers:" Adolescent Drivers' Perceptions About Inattention and Peer Passengers. AB - PURPOSE: The purpose of this qualitative focus group elicitation research study was to explore teen driver perceptions of peer passengers and driver inattention. DESIGN & METHODS: We utilized focus groups for data collection and content analysis to analyze the data, both of which were guided by the theory of planned behavior. We conducted 7 focus groups with 30 teens, ages 16-18, licensed for <=1year to examine attitudes, perceived behavioral control, and norms related to driving inattention and peer passengers. RESULTS: The sample was 50% male, mean age 17.39 (SD 0.52) with mean length of licensure 173.7days (SD 109.2). Three themes emerged: 1) "Good and not good" passengers; 2) Passengers and technology as harmful and helpful; and 3) The driver is in charge. CONCLUSIONS: While passengers can be a source of distraction, our participants also identified passenger behaviors that reduced risk, such as assistance with technology and guidance for directions. PRACTICAL IMPLICATIONS: An understanding of teens' perceptions of peer passengers can contribute to the development of effective interventions targeting teen driver inattention. Nurses are well-positioned to contribute to these teen crash prevention efforts. PMID- 27496830 TI - As Zika cases mount, patients seek advice from healthcare teams. PMID- 27496833 TI - Correction. PMID- 27496831 TI - New OSHA document reviews hazardous-drug safety for employees. PMID- 27496834 TI - Medicare delays mandate on claims for unused part of drug doses. PMID- 27496836 TI - Formalized mentorship program for newly hired pharmacists. PMID- 27496837 TI - Factors influencing pursuit of postgraduate year 2 pharmacy residency training. PMID- 27496838 TI - Lessons learned from summer introductory pharmacy practice experiences at an academic medical center. PMID- 27496839 TI - Models for student organizations in multicampus schools of pharmacy. PMID- 27496840 TI - Pharmacy: Profession of hope. PMID- 27496842 TI - Inaugural Address of the Incoming President: Pharmacy's true north. PMID- 27496841 TI - Identifying and optimizing communication in patients with hearing loss. PMID- 27496843 TI - 2016 Report of the President and Chair of the Board. PMID- 27496844 TI - 2016 Report of the Chief Executive Officer. PMID- 27496847 TI - ASHP Award of Excellence. PMID- 27496846 TI - Of philosophers and pharmacists. PMID- 27496851 TI - ASHP policy on the acceptance of advertising. PMID- 27496852 TI - Impact of a store-and-forward teledermatology intervention versus usual care on delay before beginning treatment: A pragmatic cluster-randomized trial in ambulatory care. AB - Introduction In France, 66% of patients forego getting specialized care by dermatologists because of difficulty obtaining appointments. Store-and-forward teledermatology could improve how promptly treatment begins by reducing the delay in obtaining a specialist's opinion. In this study, we compared the delay before care between general practitioners (GPs) using a store-and-forward teledermatology intervention and GPs addressing their patients with a standard referral letter. Methods We performed an open-label, pragmatic cluster-randomized controlled trial with two parallel arms. GP clinics in Paris (France) were randomly assigned to use either teledermatology referral (use of electronics to send clinical images taken using a mobile phone) or conventional referral (using standard letters) to care for patients for whom a dermatologist's advice was needed for the diagnosis or treatment of skin lesions. Dermatologists integrated responses to teledermatology requests in their usual schedule. Patients were followed up for three months. Primary outcome was the delay, in days, between the GP's consultation and a reply by the specialist allowing treatment to begin. Analyses were adjusted for clustering of GPs and identities of dermatologists. Results Between February and June 2014, 103 patients were included in the study (53 patients of 20 GPs in the intervention group). The median delay between the initial GP's consultation and the reply allowing for treatment to begin was four days in the intervention group and 40 days in the control group (adjusted hazard ratio = 2.55; p < 0.011). Discussion We showed that a simple store-and-forward teledermatology intervention significantly reduced the delay before beginning care (ClinicalTrials.gov identifier: NCT02122432). PMID- 27496854 TI - Crosstalk between E2f1 and c-Myc mediates hepato-protective effect of royal jelly on taxol-induced damages. AB - Previous histopathological studies have shown the hepatotoxicity of paclitaxel (TXL). However, there is little known about the molecular pathway(s) of TXL induced hepatotoxicity. Therefore, this study aimed to uncover the role of two transcription factors in the TXL-induced hepatotoxicity. Moreover, the hepato protective effect of royal jelly (RJ) on TXL-induced toxicity was investigated. Wistar rats were divided into control and test groups. The test groups along with TXL received various doses of RJ (0, 50, 100 and 150 mg/kg, body weight). Biochemical hepatic functional assays, histopathological studies and hepatic superoxide dismutase level were determined. Additionally, the expression of E2f1 and cellular-myelocytomatosis (c-Myc) at messenger RNA (mRNA) level in the liver was evaluated. The hepatic functional biomarkers showed a significant ( p < 0.05) elevation in the TXL-received animals, while RJ administration for 28 days resulted in a remarkable reduction in TXL-elevated alkaline phosphatase, alanine transaminase and lactate dehydrogenase levels. The TXL-treated animals showed a significant ( p < 0.05) up-regulation of E2f1 and down-regulation of c-Myc at mRNA level, respectively. RJ lowered the expression of E2f1 while enhanced the expression of c-Myc in a dose-dependent manner. Our data suggest the hepato protective effects of RJ on TXL-induced toxicity, which may attribute to a clear crosstalk between E2f1 and c-Myc as two regulators of liver growth. PMID- 27496853 TI - Maternal feed restriction during pregnancy in Wistar rats: Evaluation of offspring using classical and immunoteratology protocols. AB - Studies have revealed that impairment of the pregnant body weight reduces the fetal body weight and causes minor changes in skeletal development. The aim of the present study was to assess the effects of maternal feed restriction during pregnancy in offspring immune system development. Pregnant Wistar rats were distributed into 5 groups: 1 control in which dams received food ad libitum and 4 experimental groups in which dams were fed restricted amounts of rodent ration (16, 12, 9, or 6 g/rat/day) from the 6th to 17th gestation day. Teratogenicity was assessed using classical teratological evaluation and developmental immunotoxicology protocols. Maternal body weight gain, fetus weight, and placenta weight were reduced for feed-restricted females from the groups fed 12, 9, and 6 g/rat/day ( p < 0.05). No pup mortality was observed immediately after cesarean sections among the groups, and no visceral or skeletal malformations were detected. An immunoteratological study revealed an increase in the relative weight of the thymus and an increase in the phorbol myristate-acetate solution induced hydrogen peroxide release by inflammatory cells in 21-day-old pups. Alterations in the delayed-type hypersensitivity response and the humoral immune response against sheep red blood cells were observed in pups from feed-restricted mothers. Feed restriction in Wistar rats during organogenesis did not promote structural malformations but resulted in offspring with lower birth weights and promoted significant changes in the immune responses of the rat pups. PMID- 27496855 TI - Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy). AB - BACKGROUND: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. METHODS: This is a post hoc analysis of the RE-LY trial. RESULTS: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16-1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88-1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56-0.95 with VHD; HR, 0.84; 95% CI, 0.71-0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64-1.06) or without VHD (HR, 0.98; 95% CI, 0.83-1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37-0.93) and those without VHD (HR, 0.67; 95% CI, 0.52-0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65-1.45; and HR, 0.88; 95% CI, 0.70-1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. CONCLUSIONS: The presence of any VHD did not influence the comparison of dabigatran with warfarin. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600. PMID- 27496856 TI - Long-Term Outcomes of the Ross Procedure Versus Mechanical Aortic Valve Replacement: Propensity-Matched Cohort Study. AB - BACKGROUND: The ideal aortic valve substitute in young and middle-aged adults remains unknown. We sought to compare the long-term outcomes of patients undergoing the Ross procedure and those receiving a mechanical aortic valve replacement (AVR). METHODS: From 1990 to 2014, 258 patients underwent a Ross procedure and 1444 had a mechanical AVR at a single institution. Patients were matched into 208 pairs through the use of a propensity score. Mean age was 37.2+/ 10.2 years, and 63% were male. Mean follow-up was 14.2+/-6.5 years. RESULTS: Overall survival was equivalent (Ross versus AVR: hazard ratio, 0.91, 95% confidence interval, 0.38-2.16; P=0.83), although freedom from cardiac- and valve related mortality was improved in the Ross group (Ross versus AVR: hazard ratio, 0.22; 95% confidence interval, 0.034-0.86; P=0.03). Freedom from reintervention was equivalent after both procedures (Ross versus AVR: hazard ratio, 1.86; 95% confidence interval, 0.76-4.94; P=0.18). Long-term freedom from stroke or major bleeding was superior after the Ross procedure (Ross versus AVR: hazard ratio, 0.09; 95% confidence interval, 0.02-0.31; P<0.001). CONCLUSIONS: Long-term survival and freedom from reintervention were comparable between the Ross procedure and mechanical AVR. However, the Ross procedure was associated with improved freedom from cardiac- and valve-related mortality and a significant reduction in the incidence of stroke and major bleeding. In specialized centers, the Ross procedure represents an excellent option and should be considered for young and middle-aged adults undergoing AVR. PMID- 27496858 TI - Ross Procedure for Aortic Valve Replacement in Young Adults: Preferred Procedure or "Double, Double Toil and Trouble"? PMID- 27496860 TI - Healthy and wellbeing activities' promotion using a Big Data approach. AB - The aging population and economic crisis specially in developed countries have as a consequence the reduction in funds dedicated to health care; it is then desirable to optimize the costs of public and private healthcare systems, reducing the affluence of chronic and dependent people to care centers; promoting healthy lifestyle and activities can allow people to avoid chronic diseases as for example hypertension. In this article, we describe a system for promoting an active and healthy lifestyle for people and to recommend with guidelines and valuable information about their habits. The proposed system is being developed around the Big Data paradigm using bio-signal sensors and machine-learning algorithms for recommendations. PMID- 27496859 TI - Implementation of Birth-Cohort Testing for Hepatitis C Virus. AB - Hepatitis C virus infection affects approximately 2.2 to 3.2 million Americans. In 2012, the Centers for Disease Control and Prevention recommended a one-time antibody test of all persons belonging to the 1945-1965 birth cohort. Efforts to implement this recommendation in clinical settings are in their infancy; this case study report therefore seeks to share the experiences of three sites that implemented interventions to increase birth-cohort testing through participation in the Birth-cohort Evaluation to Advance Screening and Testing for Hepatitis C. At each site, project managers completed standardized questionnaires about their implementation experiences, and a qualitative analysis was conducted of the responses. The testing interventions used in-person recruitment, mail recruitment, and an electronic health record prompt. Sites reported that early efforts to obtain stakeholder buy-in were critical to effectively implement and sustain interventions and that the intervention required additional staffing resources beyond those being used for risk-based testing. In each case, administrative barriers were more extensive than anticipated. For the electronic health record-based intervention, technological support was critical in achieving study goals. Despite these barriers, interventions in all sites were successful in increasing rates of testing and case identification, although future studies will need to evaluate the relative costs and benefits of each intervention. PMID- 27496861 TI - Effect of technology on aging perception. AB - Technology can assist older adults to maintain an active lifestyle. To better understand the effect that technology has on aging perception, we conducted two studies. In the first study, through supraliminal priming, we analyzed the effects of aging- and technology-related stimuli on age estimation. In the second study, we conducted a technological intervention with a group of elders who used four interactive devices and analyzed effects on perceived aging. Results showed that technology-related stimuli did not affect estimated age. From the second study, we generated a sociotechnical model that explains the processes connecting technology use with successful aging. We concluded that the use of technology affects aging perception, although it depends on whether the elder people have a proactive attitude toward their aging process a priori. PMID- 27496857 TI - Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans. AB - BACKGROUND: Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms responsible for its pathogenicity are poorly defined. Because Lp(a) is the prominent carrier of proinflammatory oxidized phospholipids (OxPLs), part of its atherothrombosis might be mediated through this pathway. METHODS: In vivo imaging techniques including magnetic resonance imaging, (18)F-fluorodeoxyglucose uptake positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography were used to measure subsequently atherosclerotic burden, arterial wall inflammation, and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed with fluorescence-activated cell sorter analysis, inflammatory stimulation assays, and transendothelial migration assays. In vitro studies of the pathophysiology of Lp(a) on monocytes were performed with an in vitro model for trained immunity. RESULTS: We show that subjects with elevated Lp(a) (108 mg/dL [50-195 mg/dL]; n=30) have increased arterial inflammation and enhanced peripheral blood mononuclear cells trafficking to the arterial wall compared with subjects with normal Lp(a) (7 mg/dL [2-28 mg/dL]; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the proinflammatory response in monocytes derived from healthy control subjects (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apolipoprotein(a). CONCLUSIONS: These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates proinflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR5006 (VIPER Study). PMID- 27496862 TI - Detecting hospital-acquired infections: A document classification approach using support vector machines and gradient tree boosting. AB - Hospital-acquired infections pose a significant risk to patient health, while their surveillance is an additional workload for hospital staff. Our overall aim is to build a surveillance system that reliably detects all patient records that potentially include hospital-acquired infections. This is to reduce the burden of having the hospital staff manually check patient records. This study focuses on the application of text classification using support vector machines and gradient tree boosting to the problem. Support vector machines and gradient tree boosting have never been applied to the problem of detecting hospital-acquired infections in Swedish patient records, and according to our experiments, they lead to encouraging results. The best result is yielded by gradient tree boosting, at 93.7 percent recall, 79.7 percent precision and 85.7 percent F1 score when using stemming. We can show that simple preprocessing techniques and parameter tuning can lead to high recall (which we aim for in screening patient records) with appropriate precision for this task. PMID- 27496863 TI - A prediction model of blood pressure for telemedicine. AB - This paper presents a new study based on a machine learning technique, specifically an artificial neural network, for predicting systolic blood pressure through the correlation of variables (age, BMI, exercise level, alcohol consumption level, smoking status, stress level, and salt intake level). The study was carried out using a database containing a variety of variables/factors. Each database of raw data was split into two parts: one part for training the neural network and the remaining part for testing the performance of the network. Two neural network algorithms, back-propagation and radial basis function, were used to construct and validate the prediction system. According to the experiment, the accuracy of our predictions of systolic blood pressure values exceeded 90%. Our experimental results show that artificial neural networks are suitable for modeling and predicting systolic blood pressure. This new method of predicting systolic blood pressure helps to give an early warning to adults, who may not get regular blood pressure measurements that their blood pressure might be at an unhealthy level. Also, because an isolated measurement of blood pressure is not always very accurate due to daily fluctuations, our predictor can provide the predicted value as another figure for medical staff to refer to. PMID- 27496864 TI - Esquirol's change of view towards Pinel's mania without delusion. AB - We recount how Jean-Etienne Dominique Esquirol (1772-1840) gradually changed his position towards what Philipe Pinel (1745-1826) referred to as mania without delusion. Between 1805 and 1838, Esquirol moved from outright rejection, questioning the very idea of insane persons committing motiveless acts of violence without delusion, to relative acceptance. He eventually incorporated the clinical characteristics of mania without delusion in his description of homicidal monomania, dividing them between reasoning monomania and instinctive monomania. We examine this change by detailing each of Esquirol's points of disagreement, which decreased sharply between the completion of his thesis in 1805 and the publication of his chapter on homicidal monomania in 1838. PMID- 27496865 TI - Progression of EGFR-Mutant Lung Adenocarcinoma is Driven By Alveolar Macrophages. AB - PURPOSE: Lung adenocarcinomas with mutations in the EGFR have unprecedented initial responses to targeted therapy against the EGFR. Over time, however, these tumors invariably develop resistance to these drugs. We set out to investigate alternative treatment approaches for these tumors. EXPERIMENTAL DESIGN: To investigate the immunologic underpinnings of EGFR-mutant lung adenocarcinoma, we utilized a bitransgenic mouse model in which a mutant human EGFR gene is selectively expressed in the lungs. RESULTS: EGFR oncogene-dependent progression and remission of lung adenocarcinoma was respectively dependent upon the expansion and contraction of alveolar macrophages, and the mechanism underlying macrophage expansion was local proliferation. In tumor-bearing mice, alveolar macrophages downregulated surface expression of MHC-II and costimulatory molecules; increased production of CXCL1, CXCL2, IL1 receptor antagonist; and increased phagocytosis. Depletion of alveolar macrophages in tumor-bearing mice resulted in reduction of tumor burden, indicating a critical role for these cells in the development of EGFR-mutant adenocarcinoma. Treatment of mice with EGFR targeting clinical drugs (erlotinib and cetuximab) resulted in a significant decrease in alveolar macrophages in these mice. An activated alveolar macrophage mRNA signature was dominant in human EGFR-mutant lung adenocarcinomas, and the presence of this alveolar macrophage activation signature was associated with unfavorable survival among patients undergoing resection for EGFR-mutant lung adenocarcinoma. CONCLUSIONS: Because of the inevitability of failure of targeted therapy in EGFR-mutant non-small cell lung cancer (NSCLC), these data suggest that therapeutic strategies targeting alveolar macrophages in EGFR-mutant NSCLC have the potential to mitigate progression and survival in this disease. Clin Cancer Res; 23(3); 778-88. (c)2016 AACR. PMID- 27496867 TI - Missed Opportunities for HIV Diagnosis. AB - It has been previously shown that patients may present for multiple health issues in the years preceding their initial HIV diagnosis. This retrospective cohort study analyzed the data of patients with a new HIV diagnosis, at Ochsner Health System between January 1, 2011, and December 31, 2012. The primary end point was missed opportunities, the number of healthcare visits these patients made in the 2 years prior to being diagnosed with HIV. The 125 patients in the study cohort had 649 healthcare visits during which an HIV test was not performed. These missed opportunities are the key to capturing the undiagnosed and unaware HIV positive individual. Primary care is an ideal setting to conduct HIV testing for those who have access to regular health care. However, nontraditional providers should also be encouraged to conduct HIV testing regardless of their ability to provide treatment because evidence shows that knowledge of the diagnosis may change behavior. PMID- 27496866 TI - CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer. AB - PURPOSE: Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcgammaRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell-based immunity. EXPERIMENTAL DESIGN: CD137 expression on tumor infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were used in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells. RESULTS: CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab-treated patients with HNC, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcgammaRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of patients with HNC treated with cetuximab plus urelumab. CONCLUSIONS: These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC. Clin Cancer Res; 23(3); 707-16. (c)2016 AACR. PMID- 27496868 TI - Inositol 1,4,5-trisphosphate-mediated sarcoplasmic reticulum-mitochondrial crosstalk influences adenosine triphosphate production via mitochondrial Ca2+ uptake through the mitochondrial ryanodine receptor in cardiac myocytes. AB - AIMS: Elevated levels of inositol 1,4,5-trisphosphate (IP3) in adult cardiac myocytes are typically associated with the development of cardiac hypertrophy, arrhythmias, and heart failure. IP3 enhances intracellular Ca(2+ )release via IP3 receptors (IP3Rs) located at the sarcoplasmic reticulum (SR). We aimed to determine whether IP3-induced Ca(2+ )release affects mitochondrial function and determine the underlying mechanisms. METHODS AND RESULTS: We compared the effects of IP3Rs- and ryanodine receptors (RyRs)-mediated cytosolic Ca(2+ )elevation achieved by endothelin-1 (ET-1) and isoproterenol (ISO) stimulation, respectively, on mitochondrial Ca(2+ )uptake and adenosine triphosphate (ATP) generation. Both ET-1 and isoproterenol induced an increase in mitochondrial Ca(2+ )(Ca(2 +) m) but only ET-1 led to an increase in ATP concentration. ET-1 induced effects were prevented by cell treatment with the IP3 antagonist 2 aminoethoxydiphenyl borate and absent in myocytes from transgenic mice expressing an IP3 chelating protein (IP3 sponge). Furthermore, ET-1-induced mitochondrial Ca(2+) uptake was insensitive to the mitochondrial Ca(2+ )uniporter inhibitor Ru360, however was attenuated by RyRs type 1 inhibitor dantrolene. Using real time polymerase chain reaction, we detected the presence of all three isoforms of IP3Rs and RyRs in murine ventricular myocytes with a dominant presence of type 2 isoform for both receptors. CONCLUSIONS: Stimulation of IP3Rs with ET-1 induces Ca(2+ )release from the SR which is tunnelled to mitochondria via mitochondrial RyR leading to stimulation of mitochondrial ATP production. PMID- 27496870 TI - Comparative DNA methylation and gene expression analysis identifies novel genes for structural congenital heart diseases. AB - AIMS: For the majority of congenital heart diseases (CHDs), the full complexity of the causative molecular network, which is driven by genetic, epigenetic, and environmental factors, is yet to be elucidated. Epigenetic alterations are suggested to play a pivotal role in modulating the phenotypic expression of CHDs and their clinical course during life. Candidate approaches implied that DNA methylation might have a developmental role in CHD and contributes to the long term progress of non-structural cardiac diseases. The aim of the present study is to define the postnatal epigenome of two common cardiac malformations, representing epigenetic memory, and adaption to hemodynamic alterations, which are jointly relevant for the disease course. METHODS AND RESULTS: We present the first analysis of genome-wide DNA methylation data obtained from myocardial biopsies of Tetralogy of Fallot (TOF) and ventricular septal defect patients. We defined stringent sets of differentially methylated regions between patients and controls, which are significantly enriched for genomic features like promoters, exons, and cardiac enhancers. For TOF, we linked DNA methylation with genome-wide expression data and found a significant overlap for hypermethylated promoters and down-regulated genes, and vice versa. We validated and replicated the methylation of selected CpGs and performed functional assays. We identified a hypermethylated novel developmental CpG island in the promoter of SCO2 and demonstrate its functional impact. Moreover, we discovered methylation changes co-localized with novel, differential splicing events among sarcomeric genes as well as transcription factor binding sites. Finally, we demonstrated the interaction of differentially methylated and expressed genes in TOF with mutated CHD genes in a molecular network. CONCLUSION: By interrogating DNA methylation and gene expression data, we identify two novel mechanism contributing to the phenotypic expression of CHDs: aberrant methylation of promoter CpG islands and methylation alterations leading to differential splicing. PMID- 27496869 TI - Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering. AB - Proprotein convertase subtilisin kexin 9 (PCSK9) is a key regulator of low density lipoprotein receptor levels and LDL-cholesterol levels. Loss-of-function mutations in PCSK9 gene are associated with hypocholesterolaemia and protection against cardiovascular disease, identifying PCSK9 inhibition as a valid therapeutic approach to manage hypercholesterolaemia and related diseases. Although PCSK9 is expressed mainly in the liver, it is present also in other tissues and organs with specific functions, raising the question of whether a pharmacological inhibition of PCSK9 to treat hypercholesterolaemia and associated cardiovascular diseases might be helpful or deleterious in non-hepatic tissues. For example, PCSK9 is expressed in the vascular wall, in the kidneys, and in the brain, where it was proposed to play a role in development, neurocognitive process, and neuronal apoptosis. A link between PCSK9 and immunity was also proposed as both sepsis and viral infections are differentially affected in the presence or absence of PCSK9. Despite the increasing number of observations, the debate on the exact roles of PCSK9 in extrahepatic tissues is still ongoing, and as very effective drugs that inhibit PCSK9 have become available to the clinician, a better understanding of the biological roles of PCSK9 is warranted. PMID- 27496872 TI - Endothelial Jag1-RBPJ signalling promotes inflammatory leucocyte recruitment and atherosclerosis. AB - Aim: To determine the role of NOTCH during the arterial injury response and the subsequent chronic arterial-wall inflammation underlying atherosclerosis. Methods and results: We have generated a mouse model of endothelial-specific (Cdh5 driven) depletion of the Notch effector recombination signal binding protein for immunoglobulin kappa J region (RBPJ) [(ApoE-/-); homozygous RBPJk conditional mice (RBPJflox/flox); Cadherin 5-CreERT, tamoxifen inducible driver mice (Cdh5 CreERT)]. Endothelial-specific deletion of RBPJ or systemic deletion of Notch1 in athero-susceptible ApoE-/- mice fed a high-cholesterol diet for 6 weeks resulted in reduced atherosclerosis in the aortic arch and sinus. Intravital microscopy revealed decreased leucocyte rolling on the endothelium of ApoE-/-; RBPJflox/flox; Cdh5-CreERT mice, correlating with a lowered content of leucocytes and macrophages in the vascular wall. Transcriptome analysis revealed down regulation of proinflammatory and endothelial activation pathways in atherosclerotic tissue of RBPJ-mutant mice. During normal Notch activation, Jagged1 signalling up-regulation in endothelial cells promotes nuclear translocation of the Notch1 intracellular domain (N1ICD) and its physical interaction with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB). This N1ICD-NF-kappaB interaction is required for reciprocal transactivation of target genes, including vascular cell adhesion molecule-1. Conclusions: Notch signalling pathway inactivation decreases leucocyte rolling, thereby preventing endothelial dysfunction and vascular inflammation. Attenuation of Notch signalling might provide a treatment strategy for atherosclerosis. PMID- 27496871 TI - C-type natriuretic peptide and natriuretic peptide receptor B signalling inhibits cardiac sympathetic neurotransmission and autonomic function. AB - AIMS: B-type natriuretic peptide (BNP)-natriuretic peptide receptor A (NPR-A) receptor signalling inhibits cardiac sympathetic neurotransmission, although C type natriuretic peptide (CNP) is the predominant neuropeptide of the nervous system with expression in the heart and vasculature. We hypothesized that CNP acts similarly to BNP, and that transgenic rats (TGRs) with neuron-specific overexpression of a dominant negative NPR-B receptor would develop heightened sympathetic drive. METHODS AND RESULTS: Mean arterial pressure and heart rate (HR) were significantly (P < 0.05) elevated in freely moving TGRs (n = 9) compared with Sprague Dawley (SD) controls (n = 10). TGR had impaired left ventricular systolic function and spectral analysis of HR variability suggested a shift towards sympathoexcitation. Immunohistochemistry demonstrated co-staining of NPR-B with tyrosine hydroxylase in stellate ganglia neurons. In SD rats, CNP (250 nM, n = 8) significantly reduced the tachycardia during right stellate ganglion stimulation (1-7 Hz) in vitro whereas the response to bath-applied norepinephrine (NE, 1 MUM, n = 6) remained intact. CNP (250 nM, n = 8) significantly reduced the release of 3H-NE in isolated atria and this was prevented by the NPR-B antagonist P19 (250 nM, n = 6). The neuronal Ca2+ current (n = 6) and intracellular Ca2+ transient (n = 9, using fura-2AM) were also reduced by CNP in isolated stellate neurons. Treatment of the TGR (n = 9) with the sympatholytic clonidine (125 ug/kg per day) significantly reduced mean arterial pressure and HR to levels observed in the SD (n = 9). CONCLUSION: C-type natriuretic peptide reduces cardiac sympathetic neurotransmission via a reduction in neuronal calcium signalling and NE release through the NPR-B receptor. Situations impairing CNP-NPR-B signalling lead to hypertension, tachycardia, and impaired left ventricular systolic function secondary to sympatho-excitation. PMID- 27496873 TI - A mutation in the glutamate-rich region of RNA-binding motif protein 20 causes dilated cardiomyopathy through missplicing of titin and impaired Frank-Starling mechanism. AB - AIM: Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats results in missplicing of the sarcomeric gene titin (TTN). The functional and physiological consequences of RBM20 mutations outside the mutational hotspot of RBM20 have not been explored to date. In this study, we investigated the pathomechanism of DCM caused by a novel RBM20 mutation in human cardiomyocytes. METHODS AND RESULTS: We identified a family with DCM carrying a mutation (RBM20(E913K/+)) in a glutamate-rich region of RBM20. Western blot analysis of endogenous RBM20 protein revealed strongly reduced protein levels in the heart of an RBM20(E913K/+ )carrier. RNA deep sequencing demonstrated massive inclusion of exons coding for the spring region of titin in the RBM20(E913K/+ )carrier. Titin isoform analysis revealed a dramatic shift from the less compliant N2B towards the highly compliant N2BA isoforms in RBM20(E913K/+ )heart. Moreover, an increased sarcomere resting-length was observed in single cardiomyocytes and isometric force measurements revealed an attenuated Frank-Starling mechanism (FSM), which was rescued by protein kinase A treatment. CONCLUSION: A mutation outside the mutational hotspot of RBM20 results in haploinsufficiency of RBM20. This leads to disturbed alternative splicing of TTN, resulting in a dramatic shift to highly compliant titin isoforms and an impaired FSM. These effects may contribute to the early onset, and malignant course of DCM caused by RBM20 mutations. Altogether, our results demonstrate that heterozygous loss of RBM20 suffices to profoundly impair myocyte biomechanics by its disturbance of TTN splicing. PMID- 27496874 TI - Expression of sirtuins 1, 6, tumor necrosis factor, and interferon-gamma in psoriatic patients. AB - Sirtuins (SIRT) have been regarded as culprits in the pathogenesis of various diseases. Their exact role has not been explained. This study aimed to assess the expression of SIRT1, SIRT6, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma in psoriatic patients. Thirty psoriatic patients and 22 controls were enrolled. Clinical examination and Psoriasis Area and Severity Index (PASI) were obtained. Two skin biopsies (lesional, peri-lesional) and one from controls were obtained. Tissue levels of SIRT1, SIRT6, TNF-alpha, and IFN-gamma were measured using ELISA. SIRT1 was significantly lower in lesional skin with gradual increase in perilesional followed by control skin (P <0.001). SIRT6, TNF-alpha, and IFN gamma were significantly higher in lesional than perilesional and control skin (P <0.001). Significant positive correlations were found between SIRT1 and TNF alpha, IFN-gamma and between SIRT6 and TNF-alpha in peri-lesional skin. SIRT1 and SIRT6 are potentially involved in the pathogenesis of psoriasis. Modulating their action could offer a novel therapy for such disease. PMID- 27496876 TI - Hyperpolarization-activated cyclic nucleotide-gated channels in peripheral diaphragmatic lymphatics. AB - Diaphragmatic lymphatic function is mainly sustained by pressure changes in the tissue and serosal cavities during cardiorespiratory cycles. The most peripheral diaphragmatic lymphatics are equipped with muscle cells (LMCs), which exhibit spontaneous contraction, whose molecular machinery is still undetermined. Hypothesizing that spontaneous contraction might involve hyperpolarization activated cyclic nucleotide-gated (HCN) channels in lymphatic LMCs, diaphragmatic specimens, including spontaneously contracting lymphatics, were excised from 33 anesthetized rats, moved to a perfusion chamber containing HEPES-Tyrode's solution, and treated with HCN channels inhibitors cesium chloride (CsCl), ivabradine, and ZD-7288. Compared with control, exposure to 10 mM CsCl reduced ( 65%, n = 13, P < 0.01) the contraction frequency (FL) and increased end-diastolic diameter (DL-d, +7.3%, P < 0.01) without changes in end-systolic diameter (DL-s). Ivabradine (300 MUM) abolished contraction and increased DL-d (-14%, n = 10, P < 0.01) or caused an incomplete inhibition of FL (n = 3, P < 0.01), leaving DL-d and DL-s unaltered. ZD-7288 (200 MUM) completely (n = 12, P < 0.01) abolished FL, while DL-d decreased to 90.9 +/- 2.7% of control. HCN gene expression and immunostaining confirmed the presence of HCN1-4 channel isoforms, likely arranged in different configurations, in LMCs. Hence, all together, data suggest that HCN channels might play an important role in affecting contraction frequency of LMCs. PMID- 27496875 TI - Cardiac-deleterious role of galectin-3 in chronic angiotensin II-induced hypertension. AB - Galectin-3 (Gal-3), a member of the beta-galactoside lectin family, has an important role in immune regulation. In hypertensive rats and heart failure patients, Gal-3 is considered a marker for an unfavorable prognosis. Nevertheless, the role and mechanism of Gal-3 action in hypertension-induced target organ damage are unknown. We hypothesized that, in angiotensin II (ANG II) induced hypertension, genetic deletion of Gal-3 prevents left ventricular (LV) adverse remodeling and LV dysfunction by reducing the innate immune responses and myocardial fibrosis. To induce hypertension, male C57BL/6J and Gal-3 knockout (KO) mice were infused with ANG II (3 MUg.min-1.kg-1 sc) for 8 wk. We assessed: 1) systolic blood pressure by plethysmography, 2) LV function and remodeling by echocardiography, 3) myocardial fibrosis by histology, 4) cardiac CD68+ macrophage infiltration by histology, 5) ICAM-1 and VCAM-1 expression by Western blotting, 6) plasma cytokines, including interleukin-6 (IL-6), by enzyme-linked immunosorbent assay, and 7) regulatory T (Treg) cells by flow cytometry as detected by their combined expression of CD4, CD25, and FOXP3. Systolic blood pressure and cardiac hypertrophy increased similarly in both mouse strains when infused with ANG II. However, hypertensive C57BL/6J mice suffered impaired ejection and shortening fractions. In these mice, the extent of myocardial fibrosis and macrophage infiltration was greater in histological sections, and cardiac ICAM-1, as well as plasma IL-6, expression was higher as assessed by Western blotting. However, all these parameters were blunted in Gal-3 KO mice. Hypertensive Gal-3 KO mice also had a higher number of splenic Treg lymphocytes. In conclusion, in ANG II-induced hypertension, genetic deletion of Gal-3 prevented LV dysfunction without affecting blood pressure or LV hypertrophy. This study indicates that the ANG II effects are, in part, mediated or triggered by Gal-3 together with the related intercellular signaling (ICAM-1 and IL-6), leading to cardiac inflammation and fibrosis. PMID- 27496877 TI - Adaptation of the cerebrocortical circulation to carotid artery occlusion involves blood flow redistribution between cortical regions and is independent of eNOS. AB - Cerebral circulation is secured by feed-forward and feed-back control pathways to maintain and eventually reestablish the optimal oxygen and nutrient supply of neurons in case of disturbances of the cardiovascular system. Using the high temporal and spatial resolution of laser-speckle imaging we aimed to analyze the pattern of cerebrocortical blood flow (CoBF) changes after unilateral (left) carotid artery occlusion (CAO) in anesthetized mice to evaluate the contribution of macrovascular (circle of Willis) vs. pial collateral vessels as well as that of endothelial nitric oxide synthase (eNOS) to the cerebrovascular adaptation to CAO. In wild-type mice CoBF reduction in the left temporal cortex started immediately after CAO, reaching its maximum (-26%) at 5-10 s. Thereafter, CoBF recovered close to the preocclusion level within 30 s indicating the activation of feed-back pathway(s). Interestingly, the frontoparietal cerebrocortical regions also showed CoBF reduction in the left (-17-19%) but not in the right hemisphere, although these brain areas receive their blood supply from the common azygos anterior cerebral artery in mice. In eNOS-deficient animals the acute CoBF reduction after CAO was unaltered, and the recovery was even accelerated compared with controls. These results indicate that 1) the Willis circle alone is not sufficient to provide an immediate compensation for the loss of one carotid artery, 2) pial collaterals attenuate the ischemia of the temporal cortex ipsilateral to CAO at the expense of the blood supply of the frontoparietal region, and 3) eNOS, surprisingly, does not play an important role in this CoBF redistribution. PMID- 27496878 TI - Blood capillary rarefaction and lymphatic capillary neoangiogenesis are key contributors to renal allograft fibrosis in an ACE inhibition rat model. AB - Chronic allograft fibrosis is the major cause of graft loss in kidney transplantation. Progression can only be reduced by inhibition of the renin angiotensin system (RAS). We tested the hypothesis that the protection provided by angiotensin-converting enzyme (ACE) inhibition also decreases capillary rarefaction, lymphangiogenesis, and podocyte injury in allograft fibrosis. Fisher kidneys were transplanted into bilaterally nephrectomized Lewis rats treated with enalapril (60 mg/kg per day) (ACE inhibitor, ACEi) or vehicle. Proteinuria, blood urea nitrogen, and plasma creatinine were regularly assessed, and grafts were harvested for morphological and immunohistological analysis at various times up to 32 wk. In the vehicle group, many new lymphatic capillaries and severe and diffuse mononuclear infiltration of allografts were observed already 1 wk after transplantation. Lymphangiogenesis increased until week 4, by which time inflammatory infiltration became focal. Lymphatic capillaries were often located at sites of inflammation. Progressive interstitial fibrosis, glomerulosclerosis, capillary rarefaction, and proteinuria appeared later, at weeks 4-12 The number of lymphatic capillary cross sections strongly correlated with the interstitial fibrosis score. Podoplanin immunostaining, a marker of healthy podocytes, disappeared from inflamed or sclerotic glomerular areas. ACEi protected from lymphangiogenesis and associated inflammation, preserved glomerular podoplanin protein expression, and reduced glomerulosclerosis, proteinuria, tubulointerstitial fibrosis, and blood capillary rarefaction at 32 wk. In conclusion, ACEi considerably decreased and/or delayed both glomerulosclerosis and tubulointerstitial injury. Prevention of glomerular podoplanin loss and proteinuria could be attributed to the known intraglomerular pressure-lowering effects of ACEi. Reduction of lymphangiogenesis could contribute to amelioration of tubulointerstitial fibrosis and inflammatory infiltration after ACEi. PMID- 27496879 TI - Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure. AB - We previously reported that endoplasmic reticulum (ER) stress is induced in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) of heart failure (HF) rats and is reduced by inhibition of mitogen-activated protein kinase (MAPK) signaling. The present study further examined the relationship between brain MAPK signaling, ER stress, and sympathetic excitation in HF. Sham operated (Sham) and HF rats received a 4-wk intracerebroventricular (ICV) infusion of vehicle (Veh) or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 10 MUg/day). Lower mRNA levels of the ER stress biomarkers GRP78, ATF6, ATF4, and XBP-1s in the SFO and PVN of TUDCA-treated HF rats validated the efficacy of the TUDCA dose. The elevated levels of phosphorylated p44/42 and p38 MAPK in SFO and PVN of Veh-treated HF rats, compared with Sham rats, were significantly reduced in TUDCA-treated HF rats as shown by Western blot and immunofluorescent staining. Plasma norepinephrine levels were higher in Veh treated HF rats, compared with Veh-treated Sham rats, and were significantly lower in the TUDCA-treated HF rats. TUDCA-treated HF rats also had lower mRNA levels for angiotensin converting enzyme, angiotensin II type 1 receptor, tumor necrosis factor-alpha, interleukin-1beta, cyclooxygenase-2, and NF-kappaB p65, and a higher mRNA level of IkappaB-alpha, in the SFO and PVN than Veh-treated HF rats. These data suggest that ER stress contributes to the augmented sympathetic activity in HF by inducing MAPK signaling, thereby promoting inflammation and renin-angiotensin system activity in key cardiovascular regulatory regions of the brain. PMID- 27496880 TI - Comprehensive metabolic modeling of multiple 13C-isotopomer data sets to study metabolism in perfused working hearts. AB - In many forms of cardiomyopathy, alterations in energy substrate metabolism play a key role in disease pathogenesis. Stable isotope tracing in rodent heart perfusion systems can be used to determine cardiac metabolic fluxes, namely those relative fluxes that contribute to pyruvate, the acetyl-CoA pool, and pyruvate anaplerosis, which are critical to cardiac homeostasis. Methods have previously been developed to interrogate these relative fluxes using isotopomer enrichments of measured metabolites and algebraic equations to determine a predefined metabolic flux model. However, this approach is exquisitely sensitive to measurement error, thus precluding accurate relative flux parameter determination. In this study, we applied a novel mathematical approach to determine relative cardiac metabolic fluxes using 13C-metabolic flux analysis (13C-MFA) aided by multiple tracer experiments and integrated data analysis. Using 13C-MFA, we validated a metabolic network model to explain myocardial energy substrate metabolism. Four different 13C-labeled substrates were queried (i.e., glucose, lactate, pyruvate, and oleate) based on a previously published study. We integrated the analysis of the complete set of isotopomer data gathered from these mouse heart perfusion experiments into a single comprehensive network model that delineates substrate contributions to both pyruvate and acetyl-CoA pools at a greater resolution than that offered by traditional methods using algebraic equations. To our knowledge, this is the first rigorous application of 13C-MFA to interrogate data from multiple tracer experiments in the perfused heart. We anticipate that this approach can be used widely to study energy substrate metabolism in this and other similar biological systems. PMID- 27496881 TI - Ivabradine and metoprolol differentially affect cardiac glucose metabolism despite similar heart rate reduction in a mouse model of dyslipidemia. AB - While heart rate reduction (HRR) is a target for the management of patients with heart disease, contradictory results were reported using ivabradine, which selectively inhibits the pacemaker If current, vs. beta-blockers like metoprolol. This study aimed at testing whether similar HRR with ivabradine vs. metoprolol differentially modulates cardiac energy substrate metabolism, a factor determinant for cardiac function, in a mouse model of dyslipidemia (hApoB+/+;LDLR /-). Following a longitudinal study design, we used 3- and 6-mo-old mice, untreated or treated for 3 mo with ivabradine or metoprolol. Cardiac function was evaluated in vivo and ex vivo in working hearts perfused with 13C-labeled substrates to assess substrate fluxes through energy metabolic pathways. Compared with 3-mo-old, 6-mo-old dyslipidemic mice had similar cardiac hemodynamics in vivo but impaired (P < 0.001) contractile function (aortic flow: -45%; cardiac output: -34%; stroke volume: -35%) and glycolysis (-24%) ex vivo. Despite inducing a similar 10% HRR, ivabradine-treated hearts displayed significantly higher stroke volume values and glycolysis vs. their metoprolol-treated counterparts ex vivo, values for the ivabradine group being often not significantly different from 3-mo-old mice. Further analyses highlighted additional significant cardiac alterations with disease progression, namely in the total tissue level of proteins modified by O-linked N-acetylglucosamine (O GlcNAc), whose formation is governed by glucose metabolism via the hexosamine biosynthetic pathway, which showed a similar pattern with ivabradine vs. metoprolol treatment. Collectively, our results emphasize the implication of alterations in cardiac glucose metabolism and signaling linked to disease progression in our mouse model. Despite similar HRR, ivabradine, but not metoprolol, preserved cardiac function and glucose metabolism during disease progression. PMID- 27496888 TI - Imagine a world without borders: an immunologist's thoughts on Brexit. PMID- 27496882 TI - CXCL16 regulates renal injury and fibrosis in experimental renal artery stenosis. AB - Recent studies have shown that inflammation plays a critical role in the initiation and progression of hypertensive kidney disease, including renal artery stenosis. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We found that CXCL16 was induced in the kidney in a murine model of renal artery stenosis. To determine whether CXCL16 is involved in renal injury and fibrosis, wild-type and CXCL16 knockout mice were subjected to renal artery stenosis induced by placing a cuff on the left renal artery. Wild-type and CXCL16 knockout mice had comparable blood pressure at baseline. Renal artery stenosis caused an increase in blood pressure that was similar between wild-type and CXCL16 knockout mice. CXCL16 knockout mice were protected from RAS-induced renal injury and fibrosis. CXCL16 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the stenotic kidneys, which was associated with less expression of extracellular matrix proteins. Furthermore, CXCL16 deficiency inhibited infiltration of F4/80(+) macrophages and CD3(+) T cells in the stenotic kidneys compared with those of wild-type mice. Taken together, our results indicate that CXCL16 plays a pivotal role in the pathogenesis of renal artery stenosis-induced renal injury and fibrosis through regulation of bone marrow-derived fibroblast accumulation and macrophage and T-cell infiltration. PMID- 27496890 TI - Laboratory Animals Limited at FELASA Congress, 13-16 June 2016 Brussels, Belgium. PMID- 27496891 TI - The FELASA Award 2016 - A major award for laboratory animal science within Europe. PMID- 27496889 TI - A novel long intergenic noncoding RNA indispensable for the cleavage of mouse two cell embryos. AB - Endogenous retroviruses (ERVs) are transcriptionally active in cleavage stage embryos, yet their functions are unknown. ERV sequences are present in the majority of long intergenic noncoding RNAs (lincRNAs) in mouse and humans, playing key roles in many cellular processes and diseases. Here, we identify LincGET as a nuclear lincRNA that is GLN-, MERVL-, and ERVK-associated and essential for mouse embryonic development beyond the two-cell stage. LincGET is expressed in late two- to four-cell mouse embryos. Its depletion leads to developmental arrest at the late G2 phase of the two-cell stage and to MAPK signaling pathway inhibition. LincGET forms an RNA-protein complex with hnRNP U, FUBP1, and ILF2, promoting the cis-regulatory activity of long terminal repeats (LTRs) in GLN, MERVL, and ERVK (GLKLTRs), and inhibiting RNA alternative splicing, partially by downregulating hnRNP U, FUBP1, and ILF2 protein levels. Hnrnpu or Ilf2 mRNA injection at the pronuclear stage also decreases the preimplantation developmental rate, and Fubp1 mRNA injection at the pronuclear stage causes a block at the two-cell stage. Thus, as the first functional ERV associated lincRNA, LincGET provides clues for ERV functions in cleavage stage embryonic development. PMID- 27496893 TI - Simposio ORBEA. PMID- 27496892 TI - SECAL en el Congreso de FELASA (Bruselas). PMID- 27496895 TI - Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease. AB - Vitamin D deficiency is associated with asthma risk. Vitamin D deficiency may enhance the inflammatory response, and we have previously shown that airway remodeling and airway hyperresponsiveness is increased in vitamin D-deficient mice. In this study, we hypothesize that vitamin D deficiency would exacerbate house dust mite (HDM)-induced inflammation and alterations in lung structure and function. A BALB/c mouse model of vitamin D deficiency was established by dietary manipulation. Responsiveness to methacholine, airway smooth muscle (ASM) mass, mucus cell metaplasia, lung and airway inflammation, and cytokines in bronchoalveolar lavage (BAL) fluid were assessed. Gene expression patterns in mouse lung samples were profiled by RNA-Seq. HDM exposure increased inflammation and inflammatory cytokines in BAL, baseline airway resistance, tissue elastance, and ASM mass. Vitamin D deficiency enhanced the HDM-induced influx of lymphocytes into BAL, ameliorated the HDM-induced increase in ASM mass, and protected against the HDM-induced increase in baseline airway resistance. RNA-Seq identified nine genes that were differentially regulated by vitamin D deficiency in the lungs of HDM-treated mice. Immunohistochemical staining confirmed that protein expression of midline 1 (MID1) and adrenomedullin was differentially regulated such that they promoted inflammation, while hypoxia-inducible lipid droplet-associated, which is associated with ASM remodeling, was downregulated. Protein expression studies in human bronchial epithelial cells also showed that addition of vitamin D decreased MID1 expression. Differential regulation of these genes by vitamin D deficiency could determine lung inflammation and pathophysiology and suggest that the effect of vitamin D deficiency on HDM-induced allergic airways disease is complex. PMID- 27496894 TI - Cadmium attenuates the macrophage response to LPS through inhibition of the NF kappaB pathway. AB - Chronic obstructive pulmonary disease (COPD) in the U.S. is primarily caused by cigarette smoking. COPD patients are highly susceptible to respiratory infections in part due to alveolar macrophage dysfunction despite a substantial increase in macrophages in the lung. Cadmium (Cd) is a toxic metal that is concentrated within tobacco and accumulates in the lung of smokers. We hypothesized that Cd uptake into macrophages alters immune function thereby impairing the macrophage response to invading pathogens. Our hypothesis was tested by comparing primary human monocytes and macrophages, primary mouse bronchoalveolar lavage myeloid cells, and related cell lines. Strikingly, Cd exposure followed by LPS stimulation resulted in a dose-dependent, significant decrease in nuclear p65 activity in macrophages that was not observed in monocytes. This corresponded with Cd-mediated inhibition of IKKbeta and an impaired ability to transcribe and release cytokines in response to LPS challenge in vivo. These findings provide novel evidence that Cd has the capacity to disrupt macrophage immune function compared with monocytes. Importantly, Cd results in immune dysfunction in macrophages through inhibition of the NF-kappaB signaling pathway. Based on these findings, we provide new evidence that Cd contributes to immune dysfunction in the lung of COPD subjects and may increase susceptibility to infection. PMID- 27496896 TI - Staphylococcus aureus alpha-toxin-mediated cation entry depolarizes membrane potential and activates p38 MAP kinase in airway epithelial cells. AB - Membrane potential (Vm)-, Na(+)-, or Ca(2+)-sensitive fluorescent dyes were used to analyze changes in Vm or intracellular ion concentrations in airway epithelial cells treated with Staphylococcus aureus alpha-toxin (Hla), a major virulence factor of pathogenic strains of these bacteria. Gramicidin, a channel-forming peptide causing membrane permeability to monovalent cations, a mutated form of Hla, rHla-H35L, which forms oligomers in the plasma membranes of eukaryotic cells but fails to form functional transmembrane pores, or the cyclodextrin-derivative IB201, a blocker of the Hla pore, were used to investigate the permeability of the pore. Na(+) as well as Ca(2+) ions were able to pass the Hla pore and accumulated in the cytosol. The pore-mediated influx of calcium ions was blocked by IB201. Treatment of cells with recombinant Hla resulted in plasma membrane depolarization as well as in increases in the phosphorylation levels of paxillin (signaling pathway mediating disruption of the actin cytoskeleton) and p38 MAP kinase (signaling pathway resulting in defensive actions). p38 MAP kinase phosphorylation, but not paxillin phosphorylation, was elicited by treatment of cells with gramicidin. Although treatment of cells with rHla-H35L resulted in the formation of membrane-associated heptamers, none of these cellular effects were observed in our experiments. This indicates that formation of functional Hla transmembrane pores is required to induce the cell physiological changes mediated by alpha-toxin. Specifically, the changes in ion equilibria and plasma membrane potential are important activators of p38 MAP kinase, a signal transduction module involved in host cell defense. PMID- 27496897 TI - CCSP G38A polymorphism environment interactions regulate CCSP levels differentially in COPD. AB - Impaired airway homeostasis in chronic obstructive pulmonary disease (COPD) could be partly related to club cell secretory protein (CCSP) deficiency. We hypothesize that CCSP G38A polymorphism is involved and aim to examine the influence of the CCSP G38A polymorphism on CCSP transcription levels and its regulatory mechanisms. CCSP genotype and CCSP levels in serum and sputum were assessed in 66 subjects with stable COPD included in a 1-yr observational study. Forty-nine of them had an exacerbation. In an in vitro study, the impact on the CCSP promoter of 38G wild-type or 38A variant was assessed. BEAS-2B cells were transfected by either the 38G or 38A construct, in the presence/absence of cigarette smoke extract (CSE) or lipopolysaccharides (LPS). Cotransfections with modulating transcription factors, p53 and Nkx2.1, identified by in silico analysis by using ConSite and TFSEARCH were conducted. A allele carrier COPD patients had lower serum and sputum CCSP levels, especially among active smokers, and a decreased body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) score. In vitro, baseline CCSP transcription levels were similar between the wild and variant constructs. CSE decreased more profoundly the CCSP transcription level of 38A transfected cells. The opposite effect was observed with p53 cotransfection. LPS stimulation induced CCSP repression in 38A promoter transfected cells. Cotransfection with Nkx2.1 significantly activated the CCSP promoters irrespective of the polymorphism. Circulating CCSP levels are associated with smoking and the CCSP G38A polymorphism. CSE, LPS, and the Nkx2.1 and p53 transcription factors modulated the CCSP promoter efficiency. The 38A polymorphism exaggerated the CCSP repression in response to p53 and CSE. PMID- 27496898 TI - In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: Potential involvement in cystic fibrosis. AB - Cystic fibrosis (CF) is an inherited disease associated with chronic severe lung inflammation, leading to premature death. To develop innovative anti-inflammatory treatments, we need to characterize new cellular and molecular components contributing to the mechanisms of lung inflammation. Here, we focused on the potential role of "transient receptor potential vanilloid-4" (TRPV4), a nonselective calcium channel. We used both in vitro and in vivo approaches to demonstrate that TRPV4 expressed in airway epithelial cells triggers the secretion of major proinflammatory mediators such as chemokines and biologically active lipids, as well as a neutrophil recruitment in lung tissues. We characterized the contribution of cytosolic phospholipase A2, MAPKs, and NF kappaB in TRPV4-dependent signaling. We also showed that 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, i.e., four natural lipid-based TRPV4 agonists, are present in expectorations of CF patients. Also, TRPV4-induced calcium mobilization and inflammatory responses were enhanced in cystic fibrosis transmembrane conductance regulator-deficient cellular and animal models, suggesting that TRPV4 is a promising target for the development of new anti inflammatory treatments for diseases such as CF. PMID- 27496899 TI - The transition to clinical expert: enhanced decision making for children aged less than 5 years attending the paediatric ED with acute respiratory conditions. AB - BACKGROUND: Rates of unplanned paediatric admissions are persistently high. Many admissions are short-stay events, lasting less than 48 hours. OBJECTIVE: This qualitative research explores factors that influence clinical decision making in the paediatric ED (PED) for children under 5 attending with acute respiratory conditions, focusing on how management decisions adapt with increasing experience. METHOD: Semi-structured interviews were conducted with 15 PED clinicians (doctors, emergency nurse practitioners and registered nurses) with varying levels of experience in paediatric emergency medicine (PEM), emergency medicine or paediatrics. Audio-recorded interviews were transcribed and analysed thematically. RESULTS: There were clear differences in decision-making approaches between experienced clinicians and junior staff. The latter were more risk adverse, relying heavily on guidelines, set admission criteria, clinical theory and second opinions. This was particularly true for doctors. 'Informal' learning was apparent in accounts from less-experienced doctors and nurses, whereby tacit knowledge and risk management played an increasing role in the development of clinical intuition that permitted rapid assessment and treatment of young patients. CONCLUSIONS: The emergence of intuition entwined with approaches to risk management and the role of these skills in clinical decision making, carry implications for the development of training programmes for clinicians working in PEM. Enhanced training for such groups to permit development of the supplementary skills described in this study could have the ability to improve care delivery and even reduce paediatric admissions. PMID- 27496900 TI - Entheseal involvement in systemic lupus erythematosus: are we missing something? AB - Background Musculoskeletal involvement is extremely common in patients with systemic lupus erythematosus (SLE). Continuing the research initiated in patients with inflammatory arthritis, recent studies have shown the potential role of musculoskeletal ultrasound (MSUS) in the evaluation of clinical and subclinical lupus synovitis. The inflammatory process in SLE is traditionally considered to be localized at synovial tissue areas while enthesis is not included among the possible targets of the disease. Patients and methods Entheses included in the Glasgow Ultrasound Enthesitis Scoring System were scanned in a cohort of 20 SLE patients serving as disease controls in an MSUS study aimed at assessing enthesitis in patients with psoriatic arthritis. We describe in detail four cases with unexpected and unequivocal expressions of MSUS enthesitis according to the OMERACT definition. Three out of four patients had no predisposing factors for enthesopathy. Case no. 2 was treated with a variable-dose prednisone regimen. Results In the four cases MSUS examination revealed relevant grey-scale and power Doppler abnormalities at the entheseal level, most commonly at the distal insertion of the patellar tendon. Signs of clinical enthesitis were detected in only one patient. Conclusions This case series shows for the first time the presence of clearly evident MSUS findings indicative of enthesitis in four out of 20 SLE patients (20%), raising the hypothesis that enthesis could be a missing target in the clinical evaluation of SLE patients. Our case series justifies further investigations for a better evaluation of the prevalence, characteristics and clinical relevance of entheseal involvement in SLE. PMID- 27496901 TI - Relationship between health-related quality of life, disease activity and disease damage in a prospective international multicenter cohort of childhood onset systemic lupus erythematosus patients. AB - Previously, we described associations between health-related quality of life (HRQOL) and disease-related factors among childhood onset systemic lupus erythematosus (cSLE) patients. Here we determined the relationship between HRQOL, disease activity and damage in a large prospective international cohort of cSLE. We compared HRQOL, disease activity and disease damage across different continents and examined the relationship between children's and parents' assessments of HRQOL. Patients with cSLE and their parents completed HRQOL measures at enrollment and >=4 follow-up visits. Physicians assessed disease activity and damage. The multinational cohort ( n = 467) had relatively low disease activity and damage. Patient and parent HRQOL scores were significantly correlated. Asian and European patients had the highest HRQOL, while South and North American patients had lower HRQOL scores. Renal, CNS, skin and musculoskeletal systems exhibited the highest levels of damage. North and South American and Asian patients were more likely to have disease damage and activity scores above median values, compared with Europeans. Asians were more likely to use cyclophosphamide/rituximab. Female gender, high disease activity and damage, non-White ethnicity, and use of cyclophosphamide and/rituximab were related to lower HRQOL. HRQOL domain scores continue to emphasize that SLE has widespread impact on all aspects of children's and parents' lives. PMID- 27496902 TI - Response to letter regarding article 'Comparison of myelin water fraction values in periventricular white matter lesions between multiple sclerosis and neuromyelitis optica spectrum disorder'. PMID- 27496903 TI - Comparison of myelin water fraction values in periventricular white matter lesions between MS and NMOSD. PMID- 27496904 TI - Biomechanical Evaluation of Glenoid Version and Dislocation Direction on the Influence of Anterior Shoulder Instability and Development of Hill-Sachs Lesions. AB - BACKGROUND: Abnormal glenoid version is a risk factor for shoulder instability. However, the degree to which the variance in version (both anteversion and retroversion) affects one's predisposition for instability is not well understood. PURPOSE: To determine the influence of glenoid version on anterior shoulder joint stability and to determine if the direction of the humeral head dislocation is a stimulus for the development of Hill-Sachs lesions. STUDY DESIGN: Controlled laboratory study. METHODS: Ten human cadaveric shoulders (mean age, 59.4 +/- 4.3 years) were tested using a custom shoulder dislocation device placed in a position of apprehension (90 degrees of abduction with 90 degrees of external rotation). Glenoid version was adjusted in 5 degrees increments for a total of 6 version angles tested: +10 degrees , +5 degrees , 0 degrees , -5 degrees , -10 degrees , and -15 degrees (anteversion angles are positive, and retroversion angles are negative). Two humeral dislocation directions were tested. The first direction was true anterior through the anterior-posterior glenoid axis. The second dislocation direction was 35 degrees inferior from the anterior-posterior glenoid axis based on the deforming force role of the pectoralis major. The force and energy to dislocate were recorded. RESULTS: Changes in glenoid version manifested a linear effect on the dislocation force. The energy to dislocate increased as a second-order polynomial as a function of increasing glenoid retroversion. Glenoid version of +10 degrees anteversion and 15 degrees retroversion was highly unstable, resulting in spontaneous dislocation in one-quarter (10/40) and one-half (25/40) of the specimens anteriorly and posteriorly, respectively, in the absence of an applied dislocation force. The greater tuberosity was observed to engage with the anterior glenoid rim, consistent with Hill-Sachs lesions, 40% more frequently when the dislocation direction was true anterior compared with 35 degrees inferior from the anterior-posterior glenoid axis. The engagement of the greater tuberosity caused an increase in the energy required to dislocate. CONCLUSION: Glenoid version has a direct effect on the force required for a dislocation. An anterior-inferior dislocation direction requires less energy for a dislocation and results in a lower risk of the development of a Hill-Sachs lesion than a direct anterior dislocation direction. CLINICAL RELEVANCE: Consideration should be given to glenoid version when choosing a surgical treatment option for anterior shoulder instability. PMID- 27496905 TI - Diagnosis of Engaging Bipolar Bone Defects in the Shoulder Using 2-Dimensional Computed Tomography: A Cadaveric Study. AB - BACKGROUND: Anatomic studies have demonstrated that bipolar glenoid and humeral bone loss have a cumulative effect on shoulder instability and that these defects may engage in functional positions depending on their size and location, potentially resulting in failure of stabilization procedures. Determining which lesions pose a risk for engagement remains challenging, with arthroscopic assessments and a 3-dimensional computed tomography (CT)-based glenoid track method being accepted approaches at this time. PURPOSE: The purpose was to investigate the interaction of humeral and glenoid bone defects on shoulder engagement in a cadaveric model. Two alternative approaches to predicting engagement were evaluated: (1) CT of the shoulder in abduction and external rotation (ABER) and (2) measurement of the glenoid lesion width and measurement of a novel parameter, the intact anterior articular angle (IAAA), on conventional 2-dimensional multiplane reformats. STUDY DESIGN: Controlled laboratory study. METHODS: Hill-Sachs and glenoid defects of varying sizes were created in 12 cadaveric upper limbs, producing 45 bipolar defect combinations. The defect characteristics were assessed using CT with the shoulder in a neutral position. ABER CT was performed with the shoulder positioned in 60 degrees of glenohumeral abduction (corresponding to 90 degrees of abduction relative to the trunk) and 90 degrees of external rotation. The IAAA was measured as the cartilage arc angle anterior to the Hill-Sachs defect on the axial slice bisecting the humeral head. The performance of the ABER CT and IAAA approaches to predicting engagement were compared with the glenoid track method. RESULTS: Of the 45 defect combinations, 24 (53%) were classified as engaging using the glenoid track method. ABER CT predicted engagement accurately in 43 of 45 (96%), with a sensitivity and specificity of 92% and 100%, respectively. A logistic model based on the glenoid defect width and IAAA provided a prediction accuracy of 87%, with a sensitivity and specificity of 92% and 81%, respectively. CONCLUSION/CLINICAL RELEVANCE: Bipolar lesions at risk for engagement can be identified accurately using an ABER CT scan or by performing 2-dimensional measurements of the glenoid defect width and IAAA on conventional CT multiplane reformats. This information will be useful for surgical planning in the setting of bipolar bone defects before shoulder stabilization. PMID- 27496906 TI - Osteochondral Allograft Transplantation in Patients With Osteochondritis Dissecans of the Knee. AB - BACKGROUND: Osteochondritis dissecans (OCD) of the knee can be difficult to treat. Cartilage restoration techniques are often indicated when the lesion or fragment cannot be salvaged and the patient remains symptomatic. Fresh osteochondral allograft (OCA) transplantation can restore both bone and cartilage defects characteristic of OCD. HYPOTHESIS: We hypothesized that osteochondral allografting is a successful method for treating OCD of the knee. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This study comprised 135 patients (149 knees) who underwent OCA for OCD of the knee (type III or IV) between 1997 and 2013 and had a minimum follow-up of 2 years. The median age was 21 years (range, 12-55 years) and 75.8% of the patients were male. The mean allograft size was 7.3 cm2 (range, 2.2-25 cm2). Evaluation included the following: frequency and type of reoperations; modified Merle d'Aubigne and Postel (18-point) scale; International Knee Documentation Committee (IKDC) pain, function, and total scores; and Knee Society function (KS-F) and knee (KS-K) scores. Clinical failure was defined as revision OCA or conversion to arthroplasty. Graft survivorship was determined. RESULTS: The median follow-up time was 6.3 years (range, 1.9-16.8 years) and 62% of participants had more than 5-year follow-up. Thirty-four of 149 knees (23%) had reoperations, of which 12 (8%) were classified as allograft failures (7 OCA revisions, 3 unicompartmental knee arthroplasties, and 2 total knee arthroplasties). OCA survivorship was 95% at 5 years and 93% at 10 years. Of the 137 knees whose grafts were still in situ at the latest follow-up, the mean modified Merle d'Aubigne and Postel (18-point) score was 16.8; IKDC pain, function, and total scores were 2.1, 8.1, and 82.3; and KS-F and KS-K scores were 95.7 and 94.3, respectively. The majority of patients (95%) reported being satisfied with the outcome of their procedure. CONCLUSION: OCA transplantation was an effective treatment for OCD of the knee, with a low rate of graft failure, significant improvement in pain and function scores, and high patient satisfaction. PMID- 27496907 TI - Survivorship and Patient-Reported Outcomes After Comprehensive Arthroscopic Management of Glenohumeral Osteoarthritis: Minimum 5-Year Follow-up. AB - BACKGROUND: There are little data on midterm outcomes after the arthroscopic management of glenohumeral osteoarthritis (GHOA) in young active patients. PURPOSE: To report outcomes and survivorship for the comprehensive arthroscopic management (CAM) procedure for the treatment of GHOA at a minimum of 5 years postoperatively. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The CAM procedure was performed on a consecutive series of 46 patients (49 shoulders) with advanced GHOA who met criteria for shoulder arthroplasty but instead opted for a joint-preserving, arthroscopic surgical option. The procedure included glenohumeral chondroplasty, capsular release, synovectomy, humeral osteoplasty, axillary nerve neurolysis, subacromial decompression, loose body removal, microfracture, and biceps tenodesis. Outcome measures included the American Shoulder and Elbow Surgeons (ASES), Single Assessment Numeric Evaluation (SANE), Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), Short Form-12 (SF 12) Physical Component Summary (PCS), visual analog scale for pain, and satisfaction scores. Kaplan-Meier survivorship analysis was performed with failure defined as progression to total shoulder arthroplasty (TSA). RESULTS: Forty-six consecutive patients (49 shoulders) who underwent a CAM procedure at a minimum of 5 years from surgery were included. Two patients were excluded for refusing to participate before study initiation. The mean age at surgery was 52 years (range, 27-68 years) in 15 women and 29 men. All patients were recreational athletes with 7 former collegiate or professional athletes. Twelve shoulders (26%) progressed to TSA at a mean of 2.6 years (range, 0.5-8.2 years). For survivorship analysis, the status of the shoulder (preservation of the native joint or progression to TSA) at a minimum of 5 years was known for 45 of 47 (96%) shoulders. Survivorship was 95.6% at 1 year, 86.7% at 3 years, and 76.9% at 5 years. For surviving shoulders, minimum 5-year subjective outcome data were available for 28 of 32 (87.5%) shoulders at a mean of 5.7 years (range, 5-8 years). The mean (+/-SD) ASES score was 84.5 +/- 17, the mean SANE score was 82 +/- 18, the mean QuickDASH score was 15 +/- 13, the mean SF-12 PCS score was 51.0 +/- 9.1, and median patient satisfaction was 9 of a possible 10 points. CONCLUSION: This study demonstrates significant improvements in midterm clinical outcomes and high patient satisfaction after the arthroscopic CAM procedure for GHOA, with a 76.9% survivorship rate at a minimum of 5 years postoperatively. For patients looking for an alternative to TSA, the CAM procedure can provide reasonable outcomes and should be considered an effective procedure in appropriately selected, young active patients. Further studies are warranted to evaluate long-term outcomes and durability after this procedure. PMID- 27496908 TI - The Effect of Limited Perioperative Nonsteroidal Anti-inflammatory Drugs on Patients Undergoing Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to patients undergoing anterior cruciate ligament reconstruction (ACLR) is controversial because it may impair tissue healing and clinical outcomes. PURPOSE: To assess the effect of NSAID administration on patients undergoing ACLR. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Included patients were aged >15 years and were registered in the Norwegian Knee Ligament Registry from 2008 until 2013 after the primary ACLR. Patients with insufficient data regarding administration of NSAIDs and those with associated knee ligament injuries requiring surgical treatment were excluded from this study. Graft survival was estimated using Kaplan-Meier survival curves, and hazard ratios (HRs) for revision were evaluated using Cox regression analysis. Logistic regression analysis was used to calculate the odds ratio (OR) for a Knee Injury and Osteoarthritis Outcome Score (KOOS)-quality of life (QOL) subscale score <44 at 2-year follow-up. RESULTS: A total of 7822 patients were included in the analysis for graft survival and assessment for risk of revision. Of these, 4144 patients were administered NSAIDs postoperatively. The mean duration of follow-up was 2.8 years (range, 0-5.9 years). Administration of NSAIDs did not influence graft survival (P = .568). Adjusted Cox regression analyses demonstrated the same finding regarding risk of revision (HR, 1.0; 95% CI, 0.8-1.3). ACLR using a bone patellar tendon-bone autograft showed a reduced risk of revision (HR, 0.3; 95% CI, 0.1-0.8) among patients administered NSAIDs. In subgroup analyses of 3144 patients, administration of NSAIDs demonstrated a beneficial effect on the risk of a KOOS-QOL score <44 at 2-year follow-up (OR, 0.8; 95% CI, 0.6-0.9). CONCLUSION: Administration of NSAIDs to patients after ACLR does not have a negative effect on graft survival, risk of revision, or risk of a KOOS-QOL score <44 at 2-year follow-up. We emphasize using caution when administering NSAIDs by keeping the duration and dosage of NSAIDs as short and low as possible to ensure sufficient pain relief while limiting unwanted exposure to any known and unknown adverse effects of these drugs. PMID- 27496909 TI - Modified Brostrom Procedure for Chronic Lateral Ankle Instability in Patients With Generalized Joint Laxity. AB - BACKGROUND: Generalized joint laxity (GJL) has been considered a risk factor for late failure of ligament reconstruction in the knee; however, it is not known whether GJL is the cause of recurrent instability after the modified Brostrom procedure for chronic lateral ankle instability. PURPOSE: To compare the clinical results of the modified Brostrom procedure for chronic lateral ankle instability in patients with or without GJL. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 100 patients (100 ankles) who underwent the modified Brostrom procedure were divided into 2 groups, with or without GJL, according to the Beighton criteria. Age and body mass index were matched between the 2 groups. The mean follow-up duration was 43.3 months in the laxity group (44 ankles; Beighton score >=5) and 42.9 months in the nonlaxity group (56 ankles). RESULTS: The mean preoperative Karlsson and American Orthopaedic Foot and Ankle Society (AOFAS) scores were a respective 53.2 and 60.9 in the laxity group and 53.9 and 62.6 in the nonlaxity group, and these scores improved to 87.4 and 89.5, respectively, in the laxity group and to 94.1 and 94.8, respectively, in the nonlaxity group at final follow-up. The mean preoperative talar tilt angle and anterior talar translation were a respective 12.5 degrees and 8.8 mm in the laxity group and 10.8 degrees and 8.5 mm in the nonlaxity group, and these values improved to 7.3 degrees and 6.0 mm, respectively, in the laxity group and to 5.2 degrees and 5.0 mm, respectively, in the nonlaxity group at final follow up. Failure rates were 11.4% (5 patients) in the laxity group and 1.8% (1 patient) in the nonlaxity group. Significant differences were found between the 2 groups in terms of the Karlsson score, AOFAS score, talar tilt angle, anterior talar translation, and failure rate at final follow-up (P < .05). CONCLUSION: Patients with GJL showed inferior outcomes and a higher failure rate compared with patients without GJL. Therefore, GJL appears to be a risk factor associated with recurrent instability after the modified Brostrom procedure. PMID- 27496910 TI - Comparison of Lateral Closing-Wedge Versus Medial Opening-Wedge High Tibial Osteotomy on Knee Joint Alignment and Kinematics in the ACL-Deficient Knee. AB - BACKGROUND: Lateral closing-wedge (LCW) and medial opening-wedge (MOW) high tibial osteotomies (HTOs) correct varus knee alignment and stabilize the anterior cruciate ligament (ACL)-deficient knee. Tibiofemoral and patellofemoral alignment and kinematics after HTO are not well quantified. PURPOSE: To compare the effect of LCW and MOW HTO on tibiofemoral and patellofemoral alignment in the ACL deficient knee. STUDY DESIGN: Controlled laboratory study. METHODS: Anterior drawer, Lachman, and pivot-shift tests were performed on cadaveric specimens (N = 16), and anterior tibial translation and tibial rotation were measured for the native and ACL-sectioned knee. The right and left knee of each cadaveric specimen underwent an LCW and MOW HTO, respectively, and stability testing was repeated. All cadavers underwent pre- and postosteotomy computerized tomography with 3 dimensional computer modeling to determine the effect of HTO on posterior tibial slope, as well as tibial and patellofemoral axial plane alignment (tibial axial rotation and patellar axial tilt). RESULTS: Correction to neutral coronal alignment was obtained with both osteotomy techniques; however, larger posterior tibial slope neutralization was achieved with LCW compared with MOW (mean +/- SD, 11 degrees +/- 3.8 degrees vs 5 degrees +/- 5 degrees ). LCW demonstrated a greater decrease in anterior tibial translation (P < .05) during Lachman testing, with translation values approximating those of the native knee, especially for the lateral compartment. A similar decrease in anterior tibial translation with LCW was not found during anterior drawer testing. Anterior tibial translation did not improve for either the Lachman or the anterior drawer test after MOW. Osteotomy type did not affect tibial rotation with pivot shift. Relative to MOW, LCW resulted in greater tibial axial rotation and patellar axial tilt (7.7 degrees +/- 4 degrees and 5.6 degrees +/- 3.9 degrees [LCW], 2.8 degrees +/- 2.3 degrees and 2.4 degrees +/- 0.9 degrees [MOW], respectively; P < .05). CONCLUSION/CLINICAL RELEVANCE: LCW shows more reproducible posterior tibial slope neutralization and decreased anterior tibial translation in ACL deficiency compared with MOW; however, LCW is associated with increased external tibial axial rotation and lateral patellar tilt, which may adversely affect the patellofemoral joint. More work is needed to understand the clinical and functional outcome of these biomechanical findings in the ACL-deficient knee. PMID- 27496911 TI - Recent developments in the detection and management of acute kidney injury. AB - Acute kidney injury (AKI) is a common condition in children admitted to hospital and existing serum and urine biomarkers are insensitive. There have been significant developments in stratifying the risk of AKI in children and also in the identification of new AKI biomarkers. Risk stratification coupled with a panel of AKI biomarkers will improve future detection of AKI, however, paediatric validation studies in mixed patient cohorts are required. The principles of effective management rely on treating the underlying cause and preventing secondary AKI by the appropriate use of fluids and medication. Further therapeutic innovation will depend on improving our understanding of the basic mechanisms underlying AKI in children. PMID- 27496912 TI - Simultaneous detection and estimation of trait associations with genomic phenotypes. AB - Genomic phenotypes, such as DNA methylation and chromatin accessibility, can be used to characterize the transcriptional and regulatory activity of DNA within a cell. Recent technological advances have made it possible to measure such phenotypes very densely. This density often results in spatial structure, in the sense that measurements at nearby sites are very similar. In this article, we consider the task of comparing genomic phenotypes across experimental conditions, cell types, or disease subgroups. We propose a new method, Joint Adaptive Differential Estimation (JADE), which leverages the spatial structure inherent to genomic phenotypes. JADE simultaneously estimates smooth underlying group average genomic phenotype profiles and detects regions in which the average profile differs between groups. We evaluate JADE's performance in several biologically plausible simulation settings. We also consider an application to the detection of regions with differential methylation between mature skeletal muscle cells, myotubes, and myoblasts. PMID- 27496914 TI - Large-diameter total hip arthroplasty modular heads require greater assembly forces for initial stability. AB - OBJECTIVES: Modular junctions are ubiquitous in contemporary hip arthroplasty. The head-trunnion junction is implicated in the failure of large diameter metal on-metal (MoM) hips which are the currently the topic of one the largest legal actions in the history of orthopaedics (estimated costs are stated to exceed $4 billion). Several factors are known to influence the strength of these press-fit modular connections. However, the influence of different head sizes has not previously been investigated. The aim of the study was to establish whether the choice of head size influences the initial strength of the trunnion-head connection. MATERIALS AND METHODS: Ti-6Al-4V trunnions (n = 60) and two different sizes of cobalt-chromium (Co-Cr) heads (28 mm and 36 mm; 30 of each size) were used in the study. Three different levels of assembly force were considered: 4 kN; 5 kN; and 6 kN (n = 10 each). The strength of the press-fit connection was subsequently evaluated by measuring the pull-off force required to break the connection. The statistical differences in pull-off force were examined using a Kruskal-Wallis test and two-sample Mann-Whitney U test. Finite element and analytical models were developed to understand the reasons for the experimentally observed differences. RESULTS: 36 mm diameter heads had significantly lower pull off forces than 28 mm heads when impacted at 4 kN and 5 kN (p < 0.001; p < 0.001), but not at 6 kN (p = 0.21). Mean pull-off forces at 4 kN and 5 kN impaction forces were approximately 20% larger for 28 mm heads compared with 36 mm heads. Finite element and analytical models demonstrate that the differences in pull-off strength can be explained by differences in structural rigidity and the resulting interface pressures. CONCLUSION: This is the first study to show that 36 mm Co-Cr heads have up to 20% lower pull-off connection strength compared with 28 mm heads for equivalent assembly forces. This effect is likely to play a role in the high failure rates of large diameter MoM hips.Cite this article: A. R. MacLeod, N. P. T. Sullivan, M. R. Whitehouse, H. S. Gill. Large-diameter total hip arthroplasty modular heads require greater assembly forces for initial stability. Bone Joint Res 2016;5:338-346. DOI: 10.1302/2046-3758.58.BJR-2016 0044.R1. PMID- 27496913 TI - Incisional negative pressure wound therapy dressings (iNPWTd) in routine primary hip and knee arthroplasties: A randomised controlled trial. AB - OBJECTIVES: Wound complications are reported in up to 10% hip and knee arthroplasties and there is a proven association between wound complications and deep prosthetic infections. In this randomised controlled trial (RCT) we explore the potential benefits of a portable, single use, incisional negative pressure wound therapy dressing (iNPWTd) on wound exudate, length of stay (LOS), wound complications, dressing changes and cost-effectiveness following total hip and knee arthroplasties. METHODS: A total of 220 patients undergoing elective primary total hip and knee arthroplasties were recruited into in a non-blinded RCT. For the final analysis there were 102 patients in the study group and 107 in the control group. RESULTS: An improvement was seen in the study (iNPWTd) group compared to control in all areas. Peak post-surgical wound exudate was significantly reduced (p = 0.007). Overall LOS reduction (0.9 days, 95% confidence interval (CI) -0.2 to 2.5) was not significant (p = 0.07) but there was a significant reduction in patients with extreme values of LOS in the iNPWTd group (Moses test, p = 0.003). There was a significantly reduced number of dressing changes (mean difference 1.7, 95% CI 0.8 to 2.5, p = 0.002), and a trend to a significant four-fold reduction in reported post-operative surgical wound complications (8.4% control; 2.0% iNPWTd, p = 0.06). CONCLUSIONS: Based on the results of this RCT incisional negative pressure wound therapy dressings have a beneficial role in patients undergoing primary hip and knee arthroplasty to achieve predictable length of stay, especially to eliminate excessive hospital stay, and minimise wound complications.Cite this article: S. L. Karlakki, A. K. Hamad, C. Whittall, N. M. Graham, R. D. Banerjee, J. H. Kuiper. Incisional negative pressure wound therapy dressings (iNPWTd) in routine primary hip and knee arthroplasties: A randomised controlled trial. Bone Joint Res 2016;5:328 337. DOI: 10.1302/2046-3758.58.BJR-2016-0022.R1. PMID- 27496915 TI - Prevalence and associated factors of elder mistreatment: a cross sectional study from urban Nepal. AB - BACKGROUND: mistreatment of elderly people is internationally recognised as a serious public health issue. This study aimed at estimating the prevalence and risk factors associated with mistreatment in urban Nepal. METHODS: this was a descriptive cross-sectional study of 212 elderly people residing in Butwal sub metropolitan city, an urban area in Nepal; the study was conducted between March and October 2015. Two-stage cluster design with simple random sampling was adopted for the study. Information was collected using an interviewer administered semi-structured questionnaire of older people. Logistic regression analysis was used to identify factors associated with elder mistreatment. RESULTS: this study found a prevalence of 49.1% for mistreatment of the elderly population. Prevalence rates of caregiver neglect, financial, psychological or physical mistreatment and other types (including sexual assault) were 47.2%, 11.8%, 10.8%, 1.42% and 3.3%, respectively. Being a dalit (untouchable backward class in the traditional Hindu caste system), unemployed, widowed, divorced or separated, problems concentrating and smoking were independent factors associated with mistreatment. Smoking was found to be consistently associated with the three most common mistreatment types. CONCLUSIONS: mistreatment of older people is common in urban Nepal, with neglect, financial and psychological abuse most common. Along with standard risk factors, specific ethnic issues (membership of dalit community) are associated with increased risk. PMID- 27496916 TI - Diurnal and seasonal patterns in presentations with hip fracture-data from the national hip fracture database. AB - PURPOSE: we set out to examine diurnal and seasonal variation in hip fracture presentations to question their origin and to consider their implications for the organisation of health services for older people. METHODS: we used the National Hip Fracture Database to identify the time of presentation and surgery for 64,102 patients; all those older than 60 years who sustained this injury in England, Wales and Northern Ireland during 2014. RESULTS: we found marked diurnal variation in rates of presentation, increasing sharply after 0800 hours and decreasing only after 1800 hours. Among people who sustained their hip fracture in hospital (n = 2,761) or in a care home (n = 12,141), there were peaks in presentations around 0900 and 1800 hours. Time of presentation had a very marked effect on whether surgery was delayed by more than 24 hours but less against the national guidelines of surgery within 36 hours or by the next day. There were 15.6% more presentations during December compared to all other months (9.5% versus 8.2%, P < 0.001), a pattern also found among people living in care homes (9.1% versus 8.3%, P < 0.001). CONCLUSIONS: we have identified morning and evening peaks of presentation for inpatients and care home residents and a December increase in overall hip fracture numbers. These patterns warrant further investigation if those organising health services are to prevent this injury, and to provide appropriate beds and prompt operations for the people who sustain it. PMID- 27496917 TI - New horizons: urgent care for older people with frailty. AB - Urgent care for older people is a major public health issue and attracts much policy attention. Despite many efforts to curb demand, many older people with frailty and urgent care needs to access acute hospital services. The predominant model of care delivered in acute hospitals tends to be medically focussed, yet the evidence-based approaches that appear to be effective invoke a holistic model of care, delivered by interdisciplinary teams embedding geriatric competencies into their service. This article reviews the role for holistic care-termed Comprehensive Geriatric Assessment in the research literature-and how it can be used as an organising framework to guide future iterations of acute services to be better able to meet the multifaceted needs of older people. PMID- 27496921 TI - Effects of WiiActive exercises on fear of falling and functional outcomes in community-dwelling older adults: a randomised control trial. AB - BACKGROUND: the study compares the effects of a Nintendo Wii exercise programme and a standard Gym-based exercise intervention on fear of falling, knee strength, physical function and falls rate in older adults. METHODS: eighty community dwelling adults aged 60 years and above with short physical performance battery score of 5-9 points and modified falls efficacy scale (MFES) score of <=9 points participated in the parallel-group randomised trial. Each intervention arm involved an hour of intervention per week, totalling 12 sessions over 12 weeks. Besides 1-year fall incidence, the participants were evaluated on MFES, knee extensor strength (KES), timed-up-and-go test, gait speed, 6-minute walk test and narrow corridor walk test at weeks 13 and 24. RESULTS: at week 13, between interventions, the effect of MFES changes did not reach statistical significance (difference = -0.07 point, 95% CI -0.56 to 0.42, P = 0.78); at week 24, the Wii group showed statistically significant effects over the Gym group (difference = 0.8 point, 95% CI 0.27 to 1.29, P < 0.01). For KES, the two groups did not differ statistically at week 13 (difference = -2.0%, 95% CI -5.6 to -1.7, P = 0.29); at week 24, the Gym group had greater strength gains than the Wii group (difference = -5.1%, 95% CI -8.7 to -1.5, P < 0.01). No between-group differences were observed for other outcome measures. CONCLUSION: on completion of a 12-week Nintendo Wii exercise programme, there was no significant benefit seen on fear of falling when compared to a standard Gym-based exercise intervention; however, post-intervention there was an apparent reduction in fear of falling in the group allocated to Wii training, despite knee strength apparently improving more in those allocated to the Gym. It is possible that long-term gains after using the Wii might be due to a carry-over effect. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12610000576022. PMID- 27496922 TI - Association of socioeconomic status and cognitive functioning change among elderly Chinese people. AB - BACKGROUND AND OBJECTIVE: the inverse association between high socioeconomic status and impaired cognitive functioning in old age has been widely studied. However, it is still inconclusive whether higher socioeconomic status slows the rate of cognitive decline over ageing, especially in non-Western populations. We examined this association using a large population-based longitudinal survey of older Chinese persons. METHODS: the sample came from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) (from the years 2002 to 2011, N = 15,798 at baseline, aged 65-105). The Mini-Mental State Examination (MMSE) based on face-to face interviews was used to assess cognitive functioning. Socioeconomic status was assessed using educational attainment and household income per capita. Latent growth curve and selection model considering the attrition during the follow-up were utilised to assess the effect of socioeconomic status on the rate of change in cognitive functioning. RESULTS: at baseline, younger elderly people, urban residents and elderly people living alone had better cognitive performance in both genders. Educational attainment was positively associated with cognitive functioning at baseline but did not have a significant effect on the rate of change in cognitive functioning. Higher incomes were associated with better cognitive functioning at baseline, but this difference diminished during the follow-up. CONCLUSION: higher socioeconomic status was associated with better cognitive performance at baseline but could not protect against the rate of decline in cognitive functioning measured by MMSE in this longitudinal study for elderly Chinese people. PMID- 27496923 TI - Blood pressure and all-cause mortality: a prospective study of nursing home residents. AB - AIM: to explore the natural course of blood pressure development and its relation to mortality in a nursing home cohort. METHODS: a cohort of 406 nursing home residents in south east Sweden was followed prospectively for 30 months. Participants were divided into four groups based on systolic blood pressure (SBP) at baseline. Data were analysed using a Cox regression model with all-cause mortality as the outcome measurement; paired Student t-tests were used to evaluate blood pressure development over time. RESULTS: during follow-up, 174 (43%) people died. Participants with SBP < 120 mmHg had a hazard ratio for mortality of 1.56 (95% confidence interval, 1.08-2.27) compared with those with SBP 120-139 mmHg, adjusted for age and sex. Risk of malnutrition or present malnutrition was most common in participants with SBP < 120 mmHg; risk of malnutrition or present malnutrition estimated using the Mini Nutritional Assessment was found in 78 (71%). The levels of SBP decreased over time independent of changes in anti-hypertensive medication. CONCLUSIONS: in this cohort of nursing home residents, low SBP was associated with increased all-cause mortality. SBP decreased over time; this was not associated with altered anti hypertensive treatment. The clinical implication from this study is that there is a need for systematic drug reviews in elderly persons in nursing homes, paying special attention to those with low SBP. PMID- 27496924 TI - Age- and sex-related differences in use of guideline-recommended care and mortality among patients with incident heart failure in Denmark. AB - BACKGROUND: data are sparse on age- and sex-related differences in use of guideline-recommended care and subsequent mortality among patients with heart failure (HF). METHODS: we identified 24,308 incident patients with a verified primary diagnosis of HF recorded during 2003-2010 in the Danish Heart Failure Registry. The registry monitors guideline-recommended processes of care: echocardiography, New York Heart Association Classification, treatment with angiotensin converting enzyme inhibitors/angiotensin II receptor blockers, betablockers, physical training and patient education. RESULTS: older age was associated with lower use of recommended processes of care. Relative risk (RR) for receiving processes of care varied for men >80 years from 0.52 to 0.91 compared with men <=65 years. Corresponding RRs among women >80 years varied from 0.55 to 0.89 compared with women <=65 years. Older age was as expected associated with higher 1 year mortality (32.6% among men >80 years versus 5.4% among men <=65 years and 33.8% among women >80 years versus 6.6% among women <=65 years). The corresponding hazard ratios (HRs) were 4.54 (95% CI 3.93-5.25) and 4.08 (95% CI 3.51-4.75) for the oldest versus youngest men and women, after adjustment for patient characteristics. Adjustment for differences in care lowered HRs among the oldest age groups (adjusted HR 3.87 for men and 3.48 for women, respectively). The findings were also confirmed when stratifying the patients according to left ventricular ejection fraction <=40% and >40%. CONCLUSION: older patients with HF were less likely to receive guideline-recommended processes of care, irrespective of sex. Lower level of care may contribute to an excess mortality observed among the older patients. PMID- 27496925 TI - Calibrating EASY-Care independence scale to improve accuracy. AB - BACKGROUND: there is currently limited support for the reliability and validity of the EASY-Care independence scale, with little work carried out in low- or middle-income countries. Therefore, we assessed the internal construct validity and hierarchical and classical scaling properties among frail dependent older people in the community. OBJECTIVE: we assessed the internal construct validity and hierarchical and classical scaling properties among frail dependent older people in the community. METHODS: three primary care physicians administered EASY Care comprehensive geriatric assessment for 150 frail and/or dependent older people in the primary care setting. A Mokken model was applied to investigate hierarchical scaling properties of EASY-Care independence scale, and internal consistency (Cronbach's alpha) of the scale was also examined. RESULTS: we found that EASY-Care independence scale is highly internally consistent and is a strong hierarchical scale, hence providing strong evidence for unidimensionality. However, two items in the scale (unable to use telephone and manage finances) had much lower item Loevinger H coefficients than others. Exclusion of these two items improved the overall internal consistency of the scale. CONCLUSIONS: the strong performance of the EASY-Care independence scale among community-dwelling frail older people is encouraging. This study confirms that EASY-Care independence scale is highly internally consistent and a strong hierarchical scale. PMID- 27496926 TI - Corrigendum: Corrigendum to 'Tenacious goal pursuit and flexible goal adjustment in older people over 5 years: a latent profile transition analysis'. PMID- 27496927 TI - Older people's experiences and perspectives of elder abuse: what next? PMID- 27496928 TI - Smallest worthwhile effect of exercise programs to prevent falls among older people: estimates from benefit-harm trade-off and discrete choice methods. AB - BACKGROUND: the smallest worthwhile effect (SWE) of an intervention is the smallest treatment effect that justifies the costs, risks and inconveniences associated with that health intervention. OBJECTIVE: to estimate the SWE of exercise programs designed to prevent falls among older people and to compare estimates derived by two methodological approaches. STUDY DESIGN AND SETTING: discrete choice experiment (n = 220) and benefit-harm trade-off (subsample n = 66) methods were used. PARTICIPANTS: community-dwelling older people who reported a past fall or a mobility limitation answered online or face-to-face questionnaires. RESULTS: a substantial proportion of participants (82% in the discrete choice experiment and 50% in the benefit-harm trade-off study) did not consider that participation in the proposed exercise programs would be worthwhile, even if it reduced their risk of falling to 0%. Among remaining participants, the average SWE of participation in an exercise program was an absolute reduction in the risk of falling of 35% (standard deviation [SD] = 13) in the discrete choice experiment and 16% (SD = 11) in the benefit-harm trade-off study. CONCLUSIONS: many participants did not consider the hypothetical falls' risk reduction of the proposed exercise programs to be worth the associated costs and inconveniences. Greater community awareness of the fall prevention effects of exercise for older people is required. PMID- 27496929 TI - Centenarian athletes: Examples of ultimate human performance? AB - BACKGROUND: some centenarians are engaged in regular physical activity and sometimes in sporting events. OBJECTIVE: we aimed to identify world records of centenarian athletes in several sports and determine which represented the best performance when compared to all-age world records, all disciplines taken together. METHODS: all of the best performances achieved by centenarians were identified and compared in three disciplines: athletics, swimming and cycling. The performances were considered as an average of the respective speeds, except for jumping and throwing events for which the maximum distances performed were considered. Within each discipline, the decline in performance of centenarian athletes was expressed as a percentage of the world record for that discipline. In total, 60 performances of centenarian athletes were found. These performances belong to 19 individuals: 10 in athletics, 8 in swimming and 1 in cycling. RESULTS: the centenarian world record performed by Robert Marchand in one hour track cycling appears to be the best performance (-50.6% compared with the all age world record in this discipline) achieved by a centenarian. CONCLUSIONS: although the physiological characteristics of Robert Marchand are certainly exceptional, his remarkable performance could also be due to the lower age related decline for cycling performances compared with running and swimming. Our observations offer new perspectives on how the human body can resist the deleterious effects of ageing. PMID- 27496930 TI - STOPP/START version 2-development of software applications: easier said than done? AB - Explicit criteria, such as the STOPP/START criteria, are increasingly used both in clinical practice and in research to identify potentially inappropriate prescribing in older people. In an article on the STOPP/START criteria version 2, O'Mahony et al have pointed out the advantages of developing computerised criteria. Both clinical decision support systems to support healthcare professionals and software applications to automatically detect inappropriate prescribing in research studies can be developed. In the process of developing such tools, difficulties may occur. In the context of a research study, we have developed an algorithm to automatically apply STOPP/START criteria version 2 to our research database. We comment in this paper on different kinds of difficulties encountered and make suggestions that could be taken into account when developing the next version of the criteria. PMID- 27496931 TI - C-reactive protein level partially mediates the relationship between moderate alcohol use and frailty: the Health and Retirement Study. AB - BACKGROUND: frailty is an indicator of late-life decline marked by higher rates of disability and healthcare utilisation. Research has linked health benefits with moderate alcohol use, including frailty risk reduction. Past work suggests inflammation, measured by C-reactive protein (CRP), as one candidate mechanism for this effect. OBJECTIVE: this study aims to elucidate a possible mechanism - CRP modulation - by which moderate alcohol consumption may protect against frailty. METHODS: a cross-sectional study using data from the 2008 wave of the Health and Retirement Study (HRS) conducted by the University of Michigan. The HRS is a cohort study on health, retirement and aging on adults aged 50 and older living in the USA. A final sample of 3,229 stroke-free participants, over the age of 65 years and with complete data, was identified from the 2008 wave. Alcohol use was measured via self-report. Frailty was measured using the Paulson Lichtenberg Frailty Index. CRP was collected through the HRS protocol. RESULTS: results from structural equation modelling support the hypothesised model that moderate alcohol use is associated with less frailty and lower CRP levels. Furthermore, the indirect relationship from moderate alcohol use to frailty through CRP was statistically significant. CONCLUSIONS: overall findings suggest that inflammation measured by CRP is one mechanism by which moderate alcohol use may confer protective effects for frailty. These findings inform future research relating alcohol use and frailty, and suggest inflammation as a possible mechanism in the relationship between moderate alcohol use and other beneficial health outcomes. PMID- 27496932 TI - Digit Symbol Substitution test and future clinical and subclinical disorders of cognition, mobility and mood in older adults. AB - OBJECTIVE: to examine whether psychomotor speed predicts individual and combined disorders in cognition, mobility and mood and if white matter hyperintensities explain these associations. DESIGN AND SETTING: longitudinal; Cardiovascular Health Study. SUBJECTS: 5,888 participants (57.6% women, 15.7% black, 75.1 (5.5), mean years (SD)). METHODS: psychomotor speed (Digit Symbol Substitution Test (DSST)) and small vessel disease (white matter hyperintensities (WMH)) were measured in 1992-94. Global cognition (Modified Mini-Mental State (3MS) examination), mobility (gait speed (GS)) and mood (Center for Epidemiologic Studies Depression (CES-D) scale) were measured annually over 5 years and classified as clinical, subclinical or no disorders based on established values (3MS: 80 and 85 points; GS: 0.6 and 1.0 m/s; CES-D: 10 and 5 points). Analyses were adjusted for demographics, baseline status, education, diabetes, hypertension, ankle-arm index. RESULTS: among those with no disorder in cognition, mobility and mood (N = 619) in 1992-94, being in the lowest DSST quartile compared to the highest was associated with nearly twice the odds of developing 1+ clinical or subclinical disorders (N = 413) during follow-up. Associations were stronger for incident clinical disorders in cognition (OR: 8.44, p < 0.01) or mobility (OR: 9.09, p < 0.05) than for mood (OR: 1.88, p < 0.10). Results were similar after adjustment for WMH. CONCLUSIONS: slower psychomotor speed may serve as a biomarker of risk of clinical disorders of cognition, mobility and mood. While in part attributable to vascular brain disease, other potentially modifiable contributors may be present. Further studying the causes of psychomotor slowing with ageing might provide novel insights into age-related brain disorders. PMID- 27496933 TI - The accuracy of anatomical landmarks for locating the carotid sinus. AB - BACKGROUND: carotid sinus massage (CSM) is a valuable clinical test for carotid sinus syndrome (CSS) and relies on accurately locating the carotid sinus (CS). OBJECTIVE: in this study, we sought to examine the accuracy of using anatomical landmarks for locating the CS. METHODS: consecutive patients (n = 20) were recruited prospectively. Two clinicians, trained in CSM, were asked to locate the CS using anatomical landmarks. A point on the skin overlying the CS was then marked by a vascular technician using ultrasound. Accuracy of techniques was compared using intra-class correlation coefficients and Bland-Altman statistics. RESULTS: anatomical landmarks underestimated the CS location by 1.5 +/- 1.3 cm. Error extremes ranged from 4 cm below to 2 cm above CS using anatomical landmarks. A moderate correlation between ultrasound and anatomical landmarks was found, r = 0.371 (P = 0.031). CONCLUSION: this is the first study to characterise the accuracy of standard anatomical landmarks used in CSM. Results suggest that the point of maximal pulsation has the lowest associated error. Future work should examine CSM yield across this and a range of other methodological factors. PMID- 27496934 TI - A longitudinal comparative study of falls in persons with knee arthroplasty and persons with or at high risk for knee osteoarthritis. AB - OBJECTIVES: we determined the yearly prevalence of single and multiple falls in persons with or at risk of knee osteoarthritis (OA) and persons undergoing knee arthroplasty over an 8-year period. We also compared annual fall rates among persons with and without knee arthroplasty to determine if fall rates are associated with knee arthroplasty. METHODS: we studied 4,200 persons from the Osteoarthritis Imitative (OAI), a National Institutes of Health funded prospective study of persons 45-79 years and conducted from 2004 to 2012. All either had knee OA or were at risk of developing knee OA but did not have knee arthroplasty. The surgical group comprised 413 persons who underwent knee arthroplasty. Key fall risk factors were assessed at yearly study visits. Graphical depictions illustrated single and multiple fall trajectories. Multinomial regression adjusted for potential confounders compared fall rates for those with and without knee arthroplasty. RESULTS: fall rate trajectories for the two samples were generally flat and fall rates were similar. For the arthroplasty sample, fall rates did not increase in the immediate perioperative period relative to earlier and later periods. No differences in fall rates were found among the arthroplasty and non-arthroplasty samples after adjustment for potential confounding (P > 0.05). CONCLUSIONS: fall rates were generally stable and similar over an 8-year period among persons with and without knee arthroplasty. Clinicians should not assume that persons undergoing knee arthroplasty are at greater risk for falls either before or after surgery as compared to persons with or at risk for knee OA. PMID- 27496935 TI - The effect of aquatic exercise on physical functioning in the older adult: a systematic review with meta-analysis. AB - BACKGROUND: ageing and sedentary behaviour cause negative changes in the neuromuscular systems of healthy older adults resulting in a decrease in physical functioning. Exercising in water (aquatic exercise, AE) has been shown to be effective at improving physical functioning in this population; however, no systematic review with meta-analysis has been published. PURPOSE: to investigate the effect of AE on physical functioning in healthy older adults compared to control or land-based exercise (LE) through a systematic review with meta analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, Cinahl, PEDro, SPORTDiscus, Web of Science, Cochrane Library, published before 31st December 2015. STUDY SELECTION: in total, 28 studies met the inclusion criteria and were included in the systematic review; 24 studies with 1,456 subjects (89% female) and with mean age 66.4 years were included in the meta-analysis. DATA EXTRACTION: data were extracted and checked for accuracy by three independent reviewers. DATA SYNTHESIS: size of treatment effect was measured using the standardised mean difference with 95% confidence intervals (CIs). RESULTS: compared to control interventions, AE had a moderate positive effect on physical functioning 0.70 [95% CI 0.48 to 0.92]. Compared to LE, AE had a small positive effect on physical functioning 0.39 [0.12 to 0.66]. LIMITATIONS: there is a high risk of bias and low methodological quality in the studies particularly when comparing AE to LE with possible over estimation of the benefit of AE. CONCLUSIONS: AE may improve physical functioning in healthy older people and is at least as effective as LE. PMID- 27496936 TI - Thromboprophylaxis in atrial fibrillation and association with cognitive decline: systematic review. AB - OBJECTIVE: atrial fibrillation (AF) is associated with dementia. If AF-related cognitive decline is driven by cerebral embolic events, thromboprophylaxis may impact on this. This systematic review assessed the association between cognitive impairment and AF thromboprophylaxis. METHODS: two independent reviewers searched CINAHL, EMBASE, MEDLINE, PsycINFO, Web of Science Core Collection and Cochrane Library from inception until 12 November 2014. Eligible studies compared AF thromboprophylaxis to control with an outcome measure of cognition or dementia. Where data allowed, meta-analyses describing between-group differences in cognitive test scores or rates of incident dementia were performed. RESULTS: nineteen studies were eligible. For two prospective studies (one randomised controlled trial, RCT) comparing anticoagulation against antiplatelet therapy, change in Mini-Mental Score Examination (MMSE) score from baseline to last follow up (maximal duration: 5.9 years) suggested a difference favouring anticoagulation (mean difference: 0.90, 95% CI: 0.29-1.51), in keeping with a trend seen in the single RCT (mean difference MMSE: 0.80, 95% CI: -0.07 to 1.67). Pooled odds ratio (OR) suggested no association with incident dementia, comparing anticoagulant to antiplatelet therapy (two studies, OR: 1.23, 95% CI: 0.80-1.91) or no treatment (three studies, OR: 0.89, 95% CI: 0.47-1.69). CONCLUSION: our analyses show no definitive evidence of cognitive benefit or harm from anticoagulation. We demonstrated a potential benefit of anticoagulation in comparison to antiplatelet over time. Larger scale studies with longer follow-up are needed to determine the true cognitive impact of AF thromboprophylaxis. PMID- 27496937 TI - Older people remain on blood pressure agents despite being hypotensive resulting in increased mortality and hospital admission. AB - BACKGROUND: the use of antihypertensive medication in older people in order to prevent cardiovascular events is well established. The use of such agents has been encouraged by incentive schemes in the United Kingdom including the Quality and Outcomes Framework. In addition, many guidelines recommend good blood pressure (BP) control in the elderly. However, in older people antihypertensives can cause adverse effects related to hypotension. AIM: the aim of this study was to assess the prevalence of low BP and impact on outcomes, particularly in the presence of antihypertensive treatment, in a primary care population of older people. DESIGN: a retrospective observational cohort study in people over the age of 70 years registered with primary care providers in Kent. RESULTS: a total of 11,167 patients over 70 years old were analysed, 6,373 female (57%). Systolic blood pressure (SBP) was below 120 mmHg in 1,297 people (844 on antihypertensives), below 110 mmHg in 474 (313 on antihypertensives) and below 100 mmHg in 128 (89 on antihypertensives). Hypotension was independently associated with mortality, acute kidney injury and hospital admission. CONCLUSIONS: the results demonstrate that low SBP is associated with adverse events, it is possible that the pursuit of BP control at a population level may lead to over-treatment in certain groups of patients. This may result in an increased incidence of adverse events particularly in older people. PMID- 27496938 TI - Prevalence and risk factors for falls in older men and women: The English Longitudinal Study of Ageing. AB - BACKGROUND: falls are a major cause of disability and death in older people. Women are more likely to fall than men, but little is known about whether risk factors for falls differ between the sexes. We used data from the English Longitudinal Study of Ageing to investigate the prevalence of falls by sex and to examine cross-sectionally sex-specific associations between a range of potential risk factors and likelihood of falling. METHODS: participants were 4,301 men and women aged 60 and over who had taken part in the 2012-13 survey of the English Longitudinal Study of Ageing. They provided information about sociodemographic, lifestyle and behavioural and medical factors, had their physical and cognitive function assessed and responded to a question about whether they had fallen down in the last two years. RESULTS: in multivariable logistic regression models, severe pain and diagnosis of at least one chronic disease were independently associated with falls in both sexes. Sex-specific risk factors were incontinence (odds ratio (OR), 1.48; 95% CI, 1.19, 1.85) and frailty (OR 1.69, 95% CI 1.06, 2.69) in women, and older age (OR 1.02, 95% CI 1.04, 1.07), high levels of depressive symptoms (OR 1.33, 95% CI 1.05, 1.68), and being unable to perform a standing balance test (OR 3.32, 95% CI 2.09, 5.29) in men. CONCLUSION: although we found some homogeneity between the sexes in the risk factors that were associated with falls, the existence of several sex-specific risk factors suggests that gender should be taken into account in designing fall-prevention strategies. PMID- 27496939 TI - New opioid analgesic use and the risk of injurious single-vehicle crashes in drivers aged 50-80 years: A population-based matched case-control study. AB - BACKGROUND: the increasing trend in opioid analgesic use among older drivers has raised concerns about their risk of being involved in car crashes. AIM: to investigate if older drivers who started using opioid analgesics have a higher probability of being involved in injurious crashes. METHODS: population-based matched case-control study. Data from population registers were merged using a personal identity number. Cases were drivers aged 50-80 years responsible for a single vehicle crash between 01.07.05 and 31.12.09 that led to at least one injured passenger (n = 4,445). Four controls were randomly matched to each case by sex, birth month/year, and residence area from persons holding a valid driving license who did not crash during the study period. New use was defined as at least one dispensation within 1-30 days prior to the crash, but none within the previous 31-180 days; frequent use when >=3 dispensations were given within 0-180 days, with at least one within 31-180 days. Individuals using 1-2 non-opioid analgesic medications were used as reference category. Conditional logistic regression was used to estimate odds ratios (OR; 95% CI) adjusting for benzodiazepine use, co-morbidity, civil status and occupation. RESULTS: adjusted odds for new use were two-fold that of drivers using 1-2 non-opioid analgesics medications (2.0; 1.6-2.5). For frequent use, adjusted odds were also increased regardless of number of dispensations (3-4 = 1.7; 1.3-2.1, 5-6 = 1.6; 1.2-2.3, and >=7 = 1.7; 1.3-2.1). CONCLUSION: new, but also frequent opioid analgesic use, resulted in an increased probability of single vehicle crashes. While more epidemiologic evidence is needed, patients could be advised to refrain from driving when using opioid analgesics. PMID- 27496940 TI - Missed diagnosis of pulmonary embolism with age-adjusted d-dimer cut-off value. AB - Pulmonary embolism (PE) is a potentially severe diagnosis with high short-term mortality. Recently, age-adjusted cut-off values (age * 10 MUg/l) of D-dimer were introduced to improve the diagnostic workup in older patients. In clinical practice, PE is considered 'ruled out' in patients with a non-high clinical probability and a normal D-dimer. However, all diagnostic tests have a small false-negative rate. This small probability of misdiagnosis might be easily overlooked by clinicians when using simplified dichotomized flow charts. This case illustrates a normal D-dimer (age-adjusted) but with a PE. We recommend clinicians using the D-dimer test-either conventional or age-adjusted in a rule out strategy to be aware of the-albeit small probability of a false-negative result. PMID- 27496941 TI - Melatonin, hypnotics and their association with fracture: a matched cohort study. AB - OBJECTIVES: although melatonin prescribing in England has been increasing in recent years, there have been no large scale studies on the safety of melatonin compared to other medical treatments for insomnia. The primary aim of this study was to examine the association between exposure to melatonin, hypnotic benzodiazepines (temazepam, nitrazepam) or Z-drugs (zolpidem, zopiclone) and fracture risk. DESIGN: retrospective cohort study. SETTING: 309 general practices contributing to The Health Improvement Network (THIN) between 2008 and 2013. PARTICIPANTS: 1,377 patients aged 45 years and older prescribed melatonin; 880 patients prescribed hypnotic benzodiazepines; 1,148 patients prescribed Z-drugs and 2,752 unexposed controls matched by age, gender and practice. MAIN OUTCOME: fracture following prescription of study drugs ascertained from practice records. RESULTS: the unadjusted hazard ratios for fracture during the follow-up period were 1.90 (95% CI 1.41-2.57) for melatonin, 1.70 (95% CI 1.18-2.46) for hypnotic benzodiazepines and 2.03 (95% CI 1.45-2.84) for Z-drugs. After adjustment for 26 covariates, the hazard ratios were 1.44 (95% CI 1.01-2.04) for melatonin, 1.26 (95% CI 0.82-1.92) for hypnotic benzodiazepines and 1.52 (95% CI 1.04-2.23) for Z drugs. Only patients with three or more melatonin prescriptions had elevated risk. The mean time to fracture was 1.04 years and there was no significant difference in mean time to fracture between the cohorts. CONCLUSIONS: in this large cohort of patients attending UK primary care, prescriptions for melatonin and Z-drugs were associated with a significantly increased risk of fracture. With the use of melatonin increasing steadily overtime, this study adds to the literature on the safety profile of this drug. PMID- 27496942 TI - Social engagement and depressive symptoms: do baseline depression status and type of social activities make a difference? AB - OBJECTIVES: our purpose is to examine whether the association between social engagement and depressive symptoms differs by initial level of depressive symptoms and by the types of social engagement in which older adults engage. DESIGN: persons aged 60 years and older in 2006 (n = 4,098) were drawn from Wave 1 of the Korean Longitudinal Study of Ageing and followed through Wave 3 (2010). Growth curve analyses were conducted to identify the association between engagement in multiple types of social activities and 4-year change in depressive symptoms. Depression trajectories are examined separately by baseline depression status. RESULTS: attending religious services was related to an increase in depressive symptoms and participating in social gatherings with friends and neighbours was related to a decrease in depressive symptoms, but only among persons with CES-D 10 scale score below 10 at baseline. CONCLUSIONS: our findings suggest that the positive effects of participating in social gatherings with friends and family are manifest among older adults who have good mental health to begin with. Our findings also suggest that the association between social engagement and mental health varies by type of engagement and initial depression level. PMID- 27496944 TI - Nomogram to predict live birth rate after fertility-sparing surgery for borderline ovarian tumours. AB - STUDY QUESTION: Can a nomogram be used to predict the individual probability of live birth (LB) in women with borderline ovarian tumours (BOTs) receiving primary fertility-sparing surgery? SUMMARY ANSWER: A nomogram built according to the woman's age, histological subtype (serous versus mucinous), type of ovarian surgical treatment and FIGO stage can accurately predict the probability of LB in women with BOT. WHAT IS KNOWN ALREADY: Current prediction models determine the probability of pregnancy after medically assisted reproduction (MAR) and form the basis of patient counselling to guide the decision as to whether to consider in vitro fertilization but do not take into account prediction of the LB rate. STUDY DESIGN, SIZE, DURATION: This was a retrospective multi-centre study including 187 women with fertility-sparing surgery for BOT diagnosed between January 1980 and December 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: A multivariate logistic regression analysis of selected factors and a nomogram to predict the subsequent LB rate was constructed. A bootstrapping technique was used for internal validation. MAIN RESULTS AND THE ROLE OF CHANCE: Fifty-one women had LB (27.3%). Taking into account multiple pregnancies, the overall LB rate was 40.1% (75/187). Federation International of Gynaecology and Obstetric (FIGO) stage, age at diagnosis, histological subtype and surgery type were included in the nomogram. The predictive model had an AUC of 0.742 (95% CI, 0.644-0.825) and 0.72 (95% CI, 0.621-0.805) before and after the 200 repetitions of bootstrap sample corrections, respectively, and showed a good calibration. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study cannot exclude all biases. Our nomogram is based on simple criteria, but did not take into account the evaluation of ovarian reserve. It demonstrates a fair relevance, but requires external validation before routine use. WIDER IMPLICATIONS OF THE FINDINGS: Clinicians are increasingly interested in such tools to support the patient in making an informed decision about treatment options. This nomogram contributes to the decision-making by defining simple risk factors of poor LB probability that can help identify good candidates for MAR. STUDY FUNDING/COMPETING INTERESTS: No external funding was used for this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A. PMID- 27496943 TI - Assisted reproductive technology in Europe, 2012: results generated from European registers by ESHRE. AB - STUDY QUESTION: The 16th European IVF-monitoring (EIM) report presents the data of the treatments involving assisted reproductive technology (ART) and intrauterine insemination (IUI) initiated in Europe during 2012: are there any changes compared with previous years? SUMMARY ANSWER: Despite some fluctuations in the number of countries reporting data, the overall number of ART cycles has continued to increase year by year, the pregnancy rates (PRs) in 2012 remained stable compared with those reported in 2011, and the number of transfers with multiple embryos (3+) and the multiple delivery rates were lower than ever before. WHAT IS KNOWN ALREADY: Since 1997, ART data in Europe have been collected and re-ported in 15 manuscripts, published in Human Reproduction. STUDY DESIGN, SIZE, DURATION: Retrospective data collection of European ART data by the EIM Consortium for the European Society of Human Reproduction and Embryology (ESHRE). Data for cycles between 1 January and 31 December 2012 were collected from National Registers, when existing, or on a voluntary basis by personal information. PARTICIPANTS/MATERIALS, SETTING, METHODS: From 34 countries (+1 compared with 2011), 1111 clinics reported 640 144 treatment cycles including 139 978 of IVF, 312 600 of ICSI, 139 558 of frozen embryo replacement (FER), 33 605 of egg donation (ED), 421 of in vitro maturation, 8433 of preimplantation genetic diagnosis/preimplantation genetic screening and 5549 of frozen oocyte replacements (FOR). European data on intrauterine insemination using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 1126 IUI labs in 24 countries. A total of 175 028 IUI-H and 43 497 IUI-D cycles were included. MAIN RESULTS AND THE ROLE OF CHANCE: In 18 countries where all clinics reported to their ART register, a total of 369 081 ART cycles were performed in a population of around 295 million inhabitants, corresponding to 1252 cycles per million inhabitants (range 325-2732 cycles per million inhabitants). For all IVF cycles, the clinical PRs per aspiration and per transfer were stable with 29.4 (29.1% in 2011) and 33.8% (33.2% in 2011), respectively. For ICSI, the corresponding rates also were stable with 27.8 (27.9% in 2011) and 32.3% (31.8% in 2011). In FER cycles, the PR per thawing/warming increased to 23.1% (21.3% in 2011). In ED cycles, the PR per fresh transfer increased to 48.4% (45.8% in 2011) and to 35.9% (33.6% in 2011) per thawed transfer, while it was 45.1% for transfers after FOR. The delivery rate after IUI remained stable, at 8.5% (8.3% in 2011) after IUI-H and 12.0% (12.2% in 2011) after IUI-D. In IVF and ICSI cycles, 1, 2, 3 and 4+ embryos were transferred in 30.2, 55.4, 13.3 and 1.1% of the cycles, respectively. The proportions of singleton, twin and triplet deliveries after IVF and ICSI (added together) were 82.1, 17.3 and 0.6%, respectively, resulting in a total multiple delivery rate of 17.9% compared with 19.2% in 2011 and 20.6% in 2010. In FER cycles, the multiple delivery rate was 12.5% (12.2% twins and 0.3% triplets). Twin and triplet delivery rates associated with IUI cycles were 9.0%/0.4% and 7.2%/0.5%, following treatment with husband and donor semen, respectively. LIMITATIONS, REASONS FOR CAUTION: The method of reporting varies among countries, and registers from a number of countries have been unable to provide some of the relevant data such as initiated cycles and deliveries. As long as data are incomplete and generated through different methods of collection, results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The 16th ESHRE report on ART shows a continuing expansion of the number of treatment cycles in Europe, with more than 640 000 cycles reported in 2012 with an increasing contribution to birthrate in many countries. However, the need to improve and standardize the national registries, and to establish validation methodologies remains manifest. STUDY FUNDING/COMPETING INTERESTS: The study has no external funding; all costs are covered by ESHRE. There are no competing interests. PMID- 27496945 TI - The association of low ovarian reserve with cardiovascular disease risk: a cross sectional population-based study. AB - STUDY QUESTION: Is there a relationship between serum anti-Mullerian hormone (AMH) level and cardiovascular disease (CVD) risk in premenopausal women? SUMMARY ANSWER: There are indications that premenopausal women with very low ovarian reserve may have an unfavorable CVD risk profile. WHAT IS KNOWN ALREADY: Age at menopause is frequently linked to CVD occurrence. AMH is produced by ovarian antral follicles and provides a measure of remaining ovarian reserve Literature on whether AMH is related to CVD risk is still scarce and heterogeneous. STUDY DESIGN, SIZE, DURATION: Cross-sectional study in 2338 women (age range of 20-57 years) from the general population, participating in the Doetinchem Cohort Study between 1993 and 1997. PARTICIPANTS/MATERIALS, SETTING, METHODS: CVD risk was compared between 2338 premenopausal women in different AMH level-categories, with adjustment for confounders. CVD risk was assessed through levels of systolic and diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol and glucose, in addition to a summed score of CVD risk factors. Among other factors, analyses were corrected for smoking, oral contraceptive use and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: The relationship of serum AMH levels with CVD risk factor outcomes was nonlinear. Women with AMH levels <0.16 ug/l had 0.11 (95% confidence intervals (CIs) 0.01; 0.21) more metabolic risk factors compared with women with AMH levels >=0.16 ug/l. There was no association of individual risk factor levels with AMH levels, besides a tendency towards lower total cholesterol levels of 0.11 mmol/l (95% CI -0.23; 0.01) in women with AMH levels <0.002 ug/l compared with women with AMH levels >=0.16 ug/l. Although not statistically significant, these effect sizes were larger in women below 40 years of age. LIMITATIONS, REASONS FOR CAUTION: Causality and temporality of the studied association cannot be addressed here. Moreover, the clinical and statistical significance of the results of this exploratory study should be interpreted with caution due to the absence of adjustment for multiple statistical testing. WIDER IMPLICATIONS OF THE FINDINGS: This population-based study supports previous findings that premenopausal women with very low AMH levels may have an increased CVD risk. It lays the groundwork for future research to focus on this group of women. Longitudinal studies with more sensitive AMH assays may furthermore help better understand the implications of these results. STUDY FUNDING/COMPETING INTEREST: No financial support was received for this research or manuscript. The Doetinchem Cohort Study is conducted and funded by the Dutch National Institute for Public Health and the Environment F.J.M.B. has received fees and grant support from Merck Serono, Gedeon Richter, Ferring BV and Roche. TRIAL REGISTRATION NUMBER: N/A. PMID- 27496946 TI - Vitamin D deficiency and low ionized calcium are linked with semen quality and sex steroid levels in infertile men. AB - STUDY QUESTION: Are low vitamin D levels linked with semen quality and sex steroids in infertile men? SUMMARY ANSWER: Infertile men with vitamin D deficiency had lower sperm motility, total numbers of motile sperm, Inhibin B, sex-hormone-binding-globulin (SHBG) and testosterone/estradiol ratio, but higher levels of free sex steroids, than infertile men with normal vitamin D levels. WHAT IS KNOWN ALREADY: Low vitamin D levels have been associated with decreased sperm motility in healthy men, but a relationship between vitamin D and calcium with semen quality and especially sex steroids has not been sufficiently described in infertile men. STUDY DESIGN, SIZE, DURATION: This study comprises baseline characteristics of 1427 infertile men screened from 2011 to 2014 for inclusion in a randomized clinical trial, the Copenhagen-Bone-Gonadal Study. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total 1427 infertile men, consecutively referred to our tertiary andrological centre for fertility workup, underwent a physical examination and had semen quality assessed based on two samples and blood analysed for serum testosterone, SHBG, estradiol, inhibin B, luteinizing hormone, follicle-stimulating hormone (FSH), 25-hydroxyvitamin D (25 OHD), ionized calcium (Ca(2+)) and karyotype. There were 179 men excluded due to serious comorbidities or anabolic steroid usage, leaving 1248 patients for analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Men with 25-OHD >75 nmol/l had higher sperm motility and 66 and 111% higher total numbers of motile spermatozoa after 45 and 262 min, respectively, than men with 25-OHD <25 nmol/l (all P < 0.05). SHBG levels and testosterone/estradiol ratios were 15 and 14% lower, respectively, while free testosterone and estradiol ratios were 6 and 13% higher, respectively, in men with 25-OHD <25 nmol/l (all P < 0.05). Men with lower Ca(2+) levels had higher progressive sperm motility and inhibin B/FSH ratio but lower testosterone/estradiol ratio (all P < 0.05). LIMITATIONS, REASONS FOR CAUTION: All outcomes presented are predefined end-points but inferral of causality is compromised by the descriptive study design. It remains to be shown whether the links between vitamin D, calcium, semen quality and sex steroids in infertile men are causal. WIDER IMPLICATIONS OF THE FINDINGS: The associations between vitamin D deficiency and low calcium with semen quality and sex steroids support the existence of a cross-link between regulators of calcium homeostasis and gonadal function in infertile men. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Danish Agency for Science, Technology and Innovation, Horslev Fonden, Danish Cancer Society and Novo Nordisk Foundation. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: NCT01304927. DATE OF TRIAL REGISTRATION: 25 February 2011. DATE OF ENROLMENT OF FIRST PATIENT: 8 March 2011. PMID- 27496947 TI - Maternal first trimester serum levels of free-beta human chorionic gonadotrophin and male genital anomalies. AB - STUDY QUESTION: Are maternal first trimester levels of serum free-beta hCG associated with the development of hypospadias or undescended testis (UDT) in boys? SUMMARY ANSWER: Overall, first trimester maternal levels of serum free-beta hCG are not associated with hypospadias or UDT. However, elevated levels were found in severe phenotypes (proximal hypospadias and bilateral UDT) suggesting an altered pathway of hormonal release in early pregnancy. WHAT IS KNOWN ALREADY: Human chorionic gonadotrophin peaks in first trimester of pregnancy stimulating fetal testosterone production, which is key to normal male genital development. Endocrine-disrupting insults early in pregnancy have been associated with increased risk of common genital anomalies in males such as hypospadias and UDT. One plausible etiological pathway is altered release of hCG. STUDY DESIGN, SIZE, DURATION: We conducted a record-linkage study of two separate populations of women attending first trimester aneuploidy screening in two Australian states, New South Wales (NSW) and Western Australia (WA), in 2006-2009 and 2001-2003, respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included were women who gave birth to a singleton live born male infant. There were 12 099 boys from NSW and 10 518 from WA included, of whom 90 and 77 had hypospadias; and 107 and 109 UDT, respectively. Serum levels of free-beta hCG were ascertained from laboratory databases and combined with relevant birth outcomes and congenital anomalies via record linkage of laboratory, birth, congenital anomalies and hospital data. Median and quartile levels of gestational age specific free-beta hCG multiple of the median (MoM) were compared between affected and unaffected boys. Logistic regression was used to evaluate the association between levels of free-beta hCG MoM and hypospadias or UDT, stratified by suspected placental dysfunction and co existing anomalies. Where relevant, pooled analysis was conducted. MAIN RESULTS AND THE ROLE OF CHANCE: There was no difference in median hCG levels amongst women with an infant with hypospadias (NSW = 0.88 MoM, P = 0.83; WA = 0.84 MoM, P = 0.76) or UDT (NSW = 0.89 MoM, P = 0.54; WA = 0.95 MoM, P = 0.95), compared with women with an unaffected boy (NSW = 0.92 MoM; WA = 0.88 MoM). Low (<25th centile) or high (>75th centile) hCG levels were not associated with hypospadias or UDT, nor when stratifying by suspected placental dysfunction and co-existing anomalies. However, there was a tendency towards high levels for severe types, although confidence intervals were wide. When combining NSW and WA results, high hCG MoM levels (>75th centile) were associated with increased risk of proximal hypospadias (odds ratio (OR) 4.34; 95% CI: 1.08-17.4) and bilateral UDT (OR 2.86; 95% CI: 1.02-8.03). LIMITATIONS, REASONS FOR CAUTION: There were only small numbers of proximal hypospadias and bilateral UDT in both cohorts and although we conducted pooled analyses, results reported on these should be interpreted with caution. Gestational age by ultrasound may have been inaccurately estimated in small and large for gestational age fetuses affecting hCG MoM calculation in those pregnancies. Despite the reliability of our datasets in identifying adverse pregnancy outcomes, we did not have pathology information to confirm tissue lesions in the placenta and therefore our composite outcome should be considered as a proxy for placental dysfunction. WIDER IMPLICATIONS OF THE FINDINGS: This is one of the largest population-based studies examining the association between maternal first trimester serum levels of free-beta hCG and genital anomalies hypospadias and UDT; and the first to compare specific phenotypes by severity. Overall, our findings does not support the hypothesis that alteration in maternal hCG levels is associated with the development of male genital anomalies; however, high hCG free-beta levels found in severe types suggest different underlying etiology involving higher production and secretion of hCG. These findings require further exploration and replication. STUDY FUNDING/COMPETING INTERESTS: This work was funded by the National Health and Medical Research Council (NHMRC) grant APP1047263. N.N. is supported by a NHMRC Career Development Fellowship APP1067066. C.B. was supported by a NHMRC Principal Research Fellowship #634341. The funding agencies had no role in the design, analysis, interpretation or reporting of the findings. There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 27496948 TI - Novel Mechanisms for Heme-dependent Degradation of ALAS1 Protein as a Component of Negative Feedback Regulation of Heme Biosynthesis. AB - In eukaryotic cells, heme production is tightly controlled by heme itself through negative feedback-mediated regulation of nonspecific 5-aminolevulinate synthase (ALAS1), which is a rate-limiting enzyme for heme biosynthesis. However, the mechanism driving the heme-dependent degradation of the ALAS1 protein in mitochondria is largely unknown. In the current study, we provide evidence that the mitochondrial ATP-dependent protease ClpXP, which is a heteromultimer of CLPX and CLPP, is involved in the heme-dependent degradation of ALAS1 in mitochondria. We found that ALAS1 forms a complex with ClpXP in a heme-dependent manner and that siRNA-mediated suppression of either CLPX or CLPP expression induced ALAS1 accumulation in the HepG2 human hepatic cell line. We also found that a specific heme-binding motif on ALAS1, located at the N-terminal end of the mature protein, is required for the heme-dependent formation of this protein complex. Moreover, hemin-mediated oxidative modification of ALAS1 resulted in the recruitment of LONP1, another ATP-dependent protease in the mitochondrial matrix, into the ALAS1 protein complex. Notably, the heme-binding site in the N-terminal region of the mature ALAS1 protein is also necessary for the heme-dependent oxidation of ALAS1. These results suggest that ALAS1 undergoes a conformational change following the association of heme to the heme-binding motif on this protein. This change in the structure of ALAS1 may enhance the formation of complexes between ALAS1 and ATP dependent proteases in the mitochondria, thereby accelerating the degradation of ALAS1 protein to maintain appropriate intracellular heme levels. PMID- 27496949 TI - A Targeted Mutation Identified through pKa Measurements Indicates a Postrecruitment Role for Fis1 in Yeast Mitochondrial Fission. AB - The tail-anchored protein Fis1 is implicated as a passive tether in yeast mitochondrial fission. We probed the functional role of Fis1 Glu-78, whose elevated side chain pKa suggests participation in protein interactions. Fis1 binds partners Mdv1 or Dnm1 tightly, but mutation E78A weakens Fis1 interaction with Mdv1, alters mitochondrial morphology, and abolishes fission in a growth assay. In fis1Delta rescue experiments, Fis1-E78A causes a novel localization pattern in which Dnm1 uniformly coats the mitochondria. By contrast, Fis1-E78A at lower expression levels recruits Dnm1 into mitochondrial punctate structures but fails to support normal fission. Thus, Fis1 makes multiple interactions that support Dnm1 puncta formation and may be essential after this step, supporting a revised model for assembly of the mitochondrial fission machinery. The insights gained by mutating a residue with a perturbed pKa suggest that side chain pKa values inferred from routine NMR sample pH optimization could provide useful leads for functional investigations. PMID- 27496952 TI - The limbus of the fossa ovalis: an unusual location for incessant focal atrial tachycardia in children. PMID- 27496950 TI - Instability of the Human Cytochrome P450 Reductase A287P Variant Is the Major Contributor to Its Antley-Bixler Syndrome-like Phenotype. AB - Human NADPH-cytochrome P450 oxidoreductase (POR) gene mutations are associated with severe skeletal deformities and disordered steroidogenesis. The human POR mutation A287P presents with disordered sexual development and skeletal malformations. Difficult recombinant expression and purification of this POR mutant suggested that the protein was less stable than WT. The activities of cytochrome P450 17A1, 19A1, and 21A2, critical in steroidogenesis, were similar using our purified, full-length, unmodified A287P or WT POR, as were those of several xenobiotic-metabolizing cytochromes P450, indicating that the A287P protein is functionally competent in vitro, despite its functionally deficient phenotypic behavior in vivo Differential scanning calorimetry and limited trypsinolysis studies revealed a relatively unstable A287P compared with WT protein, leading to the hypothesis that the syndrome observed in vivo results from altered POR protein stability. The crystal structures of the soluble domains of WT and A287P reveal only subtle differences between them, but these differences are consistent with the differential scanning calorimetry results as well as the differential susceptibility of A287P and WT observed with trypsinolysis. The relative in vivo stabilities of WT and A287P proteins were also examined in an osteoblast cell line by treatment with cycloheximide, a protein synthesis inhibitor, showing that the level of A287P protein post inhibition is lower than WT and suggesting that A287P may be degraded at a higher rate. Current studies demonstrate that, unlike previously described mutations, A287P causes POR deficiency disorder due to conformational instability leading to proteolytic susceptibility in vivo, rather than through an inherent flavin binding defect. PMID- 27496951 TI - Protein Kinase A Subunit Balance Regulates Lipid Metabolism in Caenorhabditis elegans and Mammalian Adipocytes. AB - Protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent protein kinase composed of catalytic and regulatory subunits and involved in various physiological phenomena, including lipid metabolism. Here we demonstrated that the stoichiometric balance between catalytic and regulatory subunits is crucial for maintaining basal PKA activity and lipid homeostasis. To uncover the potential roles of each PKA subunit, Caenorhabditis elegans was used to investigate the effects of PKA subunit deficiency. In worms, suppression of PKA via RNAi resulted in severe phenotypes, including shortened life span, decreased egg laying, reduced locomotion, and altered lipid distribution. Similarly, in mammalian adipocytes, suppression of PKA regulatory subunits RIalpha and RIIbeta via siRNAs potently stimulated PKA activity, leading to potentiated lipolysis without increasing cAMP levels. Nevertheless, insulin exerted anti-lipolytic effects and restored lipid droplet integrity by antagonizing PKA action. Together, these data implicate the importance of subunit stoichiometry as another regulatory mechanism of PKA activity and lipid metabolism. PMID- 27496953 TI - Assessing cardiac autonomic function via heart rate variability analysis requires monitoring respiration. PMID- 27496954 TI - Assessing cardiac autonomic function via heart rate variability analysis requires monitoring respiration: reply. PMID- 27496955 TI - Access to and clinical use of cardiac implantable electronic devices and interventional electrophysiological procedures in the European Society of Cardiology Countries: 2016 Report from the European Heart Rhythm Association. AB - AIMS: The aim of this analysis was to provide comprehensive information on the access to and use of cardiac implantable electronic device (CIED) and catheter ablation therapy in the European Society of Cardiology (ESC) area. METHODS AND RESULTS: The European Heart Rhythm Association (EHRA) has been collecting descriptive and quantitative data on invasive arrhythmia therapies since 2008. This year 50 of the 56 ESC member countries provided data for the EHRA White Book. Up-to-date information on procedure rates for the last 5 years together with information on demographics, economy, vital statistics, local healthcare systems, and training activities is presented for each country and the 5 geographical ESC regions. Our analysis indicated that considerable heterogeneity in the access to arrhythmia therapies still exists across the ESC area. In 2015, the CIED implantation rates per million population were highest in the Western followed by the Southern and Northern European countries. The catheter ablation activity was largest in the Western followed by the Northern and Southern areas. Overall, the procedure rates were 3-10 times higher in the European than in the non-European ESC countries. Economic resources were not the only driver for utilization of arrhythmia therapies as in some Eastern European countries with relative low gross domestic product the procedure rates exceeded the average values. CONCLUSION: These data will help the healthcare professionals and stakeholders to identify and to understand in more depth the trends, disparities, and gaps in cardiac arrhythmia care and thereby promote harmonization of cardiac arrhythmias therapies in the ESC area. PMID- 27496956 TI - Opioid analgesics and chronic non-cancer pain: a prescription for research in primary care. PMID- 27496957 TI - Regulatory Function of Hexokinase 2 in Glucose Signaling in Saccharomyces cerevisiae. PMID- 27496958 TI - The Nuclear Hexokinase 2 Acts as a Glucose Sensor in Saccharomyces cerevisiae. PMID- 27496959 TI - PKD1 protein is involved in reactive oxygen species-mediated mitochondrial depolarization in cooperation with protein kinase Cdelta (PKCdelta). PMID- 27496960 TI - Cross-talk between insulin and Wnt signaling in preadipocytes. ROLE OF Wnt CO RECEPTOR LDL RECEPTOR-RELATED PROTEIN-5 (LRP5). PMID- 27496961 TI - Celastrol, a triterpene, enhances TRAIL-induced apoptosis through the down regulation of cell survival proteins and up-regulation of death receptors. PMID- 27496962 TI - Crotepoxide chemosensitizes tumor cells through inhibition of expression of proliferation, invasion, and angiogenic proteins linked to proinflammatory pathway. PMID- 27496963 TI - gamma-Tocotrienol but not gamma-tocopherol blocks STAT3 cell signaling pathway through induction of protein-tyrosine phosphatase SHP-1 and sensitizes tumor cells to chemotherapeutic agents. PMID- 27496964 TI - Gossypol induces death receptor-5 through activation of ROS-ERK-CHOP pathway and sensitizes colon cancer cells to TRAIL. PMID- 27496965 TI - Ursolic acid, a pentacyclin triterpene, potentiates TRAIL-induced apoptosis through p53-independent up-regulation of death receptors. EVIDENCE FOR THE ROLE OF REACTIVE OXYGEN SPECIES AND JNK. PMID- 27496966 TI - Nimbolide sensitizes human colon cancer cells to TRAIL through reactive oxygen species- and ERK-dependent up-regulation of death receptors, p53, and Bax. PMID- 27496967 TI - 3-Formylchromone interacts with cysteine 38 in p65 protein and with cysteine 179 in IkappaBalpha kinase, leading to down-regulation of nuclear factor-kappaB (NF kappaB)-regulated gene products and sensitization of tumor cells. PMID- 27496968 TI - Acute leukaemia and myelodysplastic syndromes with chromosomal rearrangement involving 11q23 locus, but not MLL gene. AB - AIMS: Chromosome 11q23 translocations, resulting in MLL (KMT2A) rearrangement, have been well characterised in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). However, little is known of haematopoietic neoplasms associated with 11q23 translocation but without MLL rearrangement (11q23+/MLL-). The aim of this study is to characterise such cases with 11q23+/MLL-. METHODS AND RESULTS: We retrospectively searched our database for cases with haematopoietic malignancies with 11q23+/MLL-. We identified nine patients, two with AML, two with B-lymphoblastic leukaemia (B-ALL); two with T lymphoblastic leukaemia (T-ALL), two with myelodysplastic syndrome (MDS) and one with chronic myelomonocytic leukaemia (CMML). The translocations included t(X;11)(p11.2;q23), t(2;11)(p21;q23), t(6;11)(q27;q23), t(8;9;11)(q13;q13;q23), t(11;11)(p15;q23), t(11;14)(q23;q24) and t(11;15)(q23;q14). Five of six patients with acute leukaemia had received chemotherapy and detection of 11q23 translocation occurred at time of disease relapse. Both patients with MDS and the patient with CMML had 11q23 translocation detected at time of initial diagnosis, all three patients progressed to AML after >1 year on hypomethylating agent therapy. All patients received risk-adapted therapies, including stem cell transplant in five patients. At the last follow-up, eight patients died with a median overall survival of 14 months. CONCLUSIONS: 11q23+/MLL- occurs rarely, involving different partner chromosomes and showing clinical and pathological features and disease subtypes different from those cases with MLL rearrangement. 11q23+/MLL- appears to be associated with clonal evolution/disease progression in acute leukaemia, a high risk for AML progression in MDS/CMML and a high incidence of disease relapse. PMID- 27496969 TI - DNA hypermethylation analysis in sputum of asymptomatic subjects at risk for lung cancer participating in the NELSON trial: argument for maximum screening interval of 2 years. AB - AIMS: Lung cancer is the major contributor to cancer mortality due to metastasised disease at time of presentation. The current study investigated DNA hypermethylation of biomarkers RASSF1A, APC, cytoglobin, 3OST2, FAM19A4, PHACTR3 and PRDM14 in sputum of asymptomatic high-risk individuals from the NELSON lung cancer low-dose spiral CT screening trial to detect lung cancer at preclinical stage. METHODS: Subjects were selected with (i) lung cancer in follow-up (cases; n=65), (ii) minor cytological aberrations (controls; n=120) and (iii) a random selection of subjects without cytological aberrations (controls; n=99). Median follow-up time for controls was 80 months. Cut-off values were based on high specificity to assess diagnostic value of the biomarkers. RESULTS: RASSF1A may denote presence of invasive cancer because of its high specificity (93% (95% CI 89% to 96%); sensitivity 17% (95% CI 4% to 31%), with best performance in a screening interval of 2 years. The panel of RASSF1A, 3OST2 and PRDM14 detected 28% (95% CI 11% to 44%) of lung cancer cases within 2 years, with specificity of 90% (95% CI 86% to 94%). Sputum cytology did not detect any lung cancers. CONCLUSIONS: In a lung cancer screening setting with maximum screening interval of 2 years, DNA hypermethylation analysis in sputum may play a role in the detection of preclinical disease, but complementary diagnostic markers are needed to improve sensitivity. PMID- 27496970 TI - Maternal Milk T Cells Drive Development of Transgenerational Th1 Immunity in Offspring Thymus. AB - Using multiple murine foster-nursing protocols, thereby eliminating placental transfer and allowing a distinction between dam- and pup-derived cells, we show that foster nursing by an immunized dam results in development of CD8(+) T cells in nonimmunized foster pups that are specific for Ags against which the foster dam was immunized (Mycobacterium tuberculosis or Candida albicans). We have dubbed this process "maternal educational immunity" to distinguish it from passive cellular immunity. Of the variety of maternal immune cells present in milk, only T cells were detected in pup tissues. Maternal T cells, a substantial percentage of which were CD4(+)MHC class II(+), accumulated in the pup thymus and spleen during the nursing period. Further analysis of maternal cells in the pup thymus showed that a proportion was positive for maternal immunogen-specific MHC class II tetramers. To determine the outcome of Ag presentation in the thymus, the maternal or foster pup origin of immunogen-responding CD8(+) cells in foster pup spleens was assessed. Whereas ~10% were maternally derived in the first few weeks after weaning, all immunogen-responding CD8(+) T cells were pup derived by 12 wk of age. Pup-derived immunogen-responsive CD8(+) cells persisted until at least 1 y of age. Passive cellular immunity is well accepted and has been demonstrated in the human population. In this study, we show an arguably more important role for transferred immune cells: the direction of offspring T cell development. Harnessing maternal educational immunity through prepregnancy immunization programs has potential for improvement of infant immunity. PMID- 27496972 TI - Zebrafish IRF1, IRF3, and IRF7 Differentially Regulate IFNPhi1 and IFNPhi3 Expression through Assembly of Homo- or Heteroprotein Complexes. AB - In mammals, IFN regulatory factor (IRF)1, IRF3, and IRF7 are three critical transcription factors that are pivotal for cooperative regulation of the type I IFN response. In this study, we explored the relative contribution of zebrafish (Danio rerio) IRF1 (DrIRF1), IRF3 (DrIRF3), and IRF7 (DrIRF7) (DrIRF1/3/7) to zebrafish IFNPhi1 (DrIFNPhi1) and IFNPhi3 (DrIFNPhi3) (DrIFNPhi1/3) activation. Following spring viremia of carp virus infection, DrIFNPhi1/3 and DrIRF1/3/7 transcripts are significantly induced in zebrafish tissues, which correlates with the replication of spring viremia of carp virus. DrIRF1/3/7 selectively bind to the IRF-binding element/IFN-stimulated regulatory element sites of DrIFNPhi1/3 promoters, with the exception that DrIRF3 has no preference for two IRF-binding element/IFN-stimulated regulatory element motifs within the DrIFNPhi3 promoter. Consistently, DrIRF3 alone activates DrIFNPhi1, but not DrIFNPhi3; DrIRF7 predominantly stimulates DrIFNPhi3; and DrIRF1 has similar potential to DrIFNPhi1 and DrIFNPhi3. Strikingly, DrIRF3 facilitates the binding of DrIRF1 and DrIRF7 to both zebrafish IFN promoters, and so does DrIRF7 for the binding of DrIRF1, particularly to the DrIFNPhi3 promoter. These binding properties correlate with differential responses of DrIFNPhi1 and DrIFNPhi3 to the combinatory stimulation of DrIRF1/3/7, depending on their relative amounts. Similar to the dual roles of human IRF3 in regulating IRF7-activated IFNalpha genes, DrIRF3 exerts dual effects on DrIRF1-mediated DrIFNPhi3 gene expression: an inhibitory effect at lower concentrations and a synergistic effect at higher concentrations. These data provide evidence that fish and mammals have evolved a similar IRF-dependent regulatory mechanism fine-tuning IFN gene activation. PMID- 27496971 TI - The ETS Family Transcription Factors Etv5 and PU.1 Function in Parallel To Promote Th9 Cell Development. AB - The IL-9-secreting Th9 subset of CD4 Th cells develop in response to an environment containing IL-4 and TGF-beta, promoting allergic disease, autoimmunity, and resistance to pathogens. We previously identified a requirement for the ETS family transcription factor PU.1 in Th9 development. In this report, we demonstrate that the ETS transcription factor ETS variant 5 (ETV5) promotes IL 9 production in Th9 cells by binding and recruiting histone acetyltransferases to the Il9 locus at sites distinct from PU.1. In cells that are deficient in both PU.1 and ETV5 there is lower IL-9 production than in cells lacking either factor alone. In vivo loss of PU.1 and ETV5 in T cells results in distinct effects on allergic inflammation in the lung, suggesting that these factors function in parallel. Together, these data define a role for ETV5 in Th9 development and extend the paradigm of related transcription factors having complementary functions during differentiation. PMID- 27496973 TI - T Cell Fates Zipped Up: How the Bach2 Basic Leucine Zipper Transcriptional Repressor Directs T Cell Differentiation and Function. AB - Recent data illustrate a key role for the transcriptional regulator bric-a-brac, tramtrack, and broad complex and cap'n'collar homology (Bach)2 in orchestrating T cell differentiation and function. Although Bach2 has a well-described role in B cell differentiation, emerging data show that Bach2 is a prototypical member of a novel class of transcription factors that regulates transcriptional activity in T cells at super-enhancers, or regions of high transcriptional activity. Accumulating data demonstrate specific roles for Bach2 in favoring regulatory T cell generation, restraining effector T cell differentiation, and potentiating memory T cell development. Evidence suggests that Bach2 regulates various facets of T cell function by repressing other key transcriptional regulators such as B lymphocyte-induced maturation protein 1. In this review, we examine our present understanding of the role of Bach2 in T cell function and highlight the growing evidence that this transcriptional repressor functions as a key regulator involved in maintenance of T cell quiescence, T cell subset differentiation, and memory T cell generation. PMID- 27496975 TI - Critique of World Health Organization Recommendation of a Dengue Vaccine. PMID- 27496974 TI - Chikungunya Virus: In Vitro Response to Combination Therapy With Ribavirin and Interferon Alfa 2a. AB - INTRODUCTION: We evaluated the antiviral activities of ribavirin (RBV) and interferon (IFN) alfa as monotherapy and combination therapy against chikungunya virus (CHIKV). METHODS: Vero cells were infected with CHIKV in the presence of RBV and/or IFN alfa, and viral production was quantified by plaque assay. A mathematical model was fit to the data to identify drug interactions for effect. We ran simulations using the best-fit model parameters to predict the antiviral activity associated with clinically relevant regimens of RBV and IFN alfa as combination therapy. The model predictions were validated using the hollow fiber infection model (HFIM) system. RESULTS: RBV and IFN alfa were effective against CHIKV as monotherapy at supraphysiological concentrations. However, RBV and IFN alfa were highly synergistic for antiviral effect when administered as combination therapy. Simulations with our mathematical model predicted that a standard clinical regimen of RBV plus IFN alfa would inhibit CHIKV burden by 2.5 log10 following 24 hours of treatment. In the HFIM system, RBV plus IFN alfa at clinical exposures resulted in a 2.1-log10 decrease in the CHIKV burden following 24 hours of therapy. These findings validate the prediction made by the mathematical model. CONCLUSIONS: These studies illustrate the promise of RBV plus IFN alfa as a potential therapeutic strategy for the treatment of CHIKV infections. PMID- 27496976 TI - Infection-Induced Vascular Permeability Aids Mycobacterial Growth. AB - Pathogenic mycobacteria trigger formation of organized granulomas. As granulomas mature, they induce angiogenesis and vascular permeability. Here, in a striking parallel to tumor pro-angiogenic signaling, we identify angiopoietin-2 (ANG-2) induction as an important component of vascular dysfunction during mycobacterial infection. Mycobacterial infection in humans and zebrafish results in robust induction of ANG-2 expression from macrophages and stromal cells. Using a small molecule inhibitor closely related to one currently in clinical trials, we link ANG-2/TIE2 signaling to vascular permeability during mycobacterial infection. Targeting granuloma-induced vascular permeability via vascular endothelial protein tyrosine phosphatase inhibition limits mycobacterial growth, suggesting a new strategy for host-directed therapies against tuberculosis. PMID- 27496977 TI - Population Perspectives and World Health Organization Recommendations for CYD-TDV Dengue Vaccine. PMID- 27496979 TI - Dietary fiber and the short-chain fatty acid acetate promote resolution of neutrophilic inflammation in a model of gout in mice. AB - : Gout is a disease characterized by the deposition of monosodium urate (MSU) crystals in the joints. Continuous gout episodes may lead to unresolved inflammatory responses and tissue damage. We investigated the effects of a high fiber diet and acetate, a short-chain fatty acid (SCFA) resulting from the metabolism of fiber by gut microbiota, on the inflammatory response in an experimental model of gout in mice. Injection of MSU crystals into the knee joint of mice induced neutrophil influx and inflammatory hypernociception. The onset of inflammatory response induced by MSU crystals was not altered in animals given a high-fiber diet, but the high-fiber diet induced faster resolution of the inflammatory response. Similar results were obtained in animals given the SCFA acetate. Acetate was effective, even when given after injection of MSU crystals at the peak of the inflammatory response and induced caspase-dependent apoptosis of neutrophils that accounted for the resolution of inflammation. Resolution of neutrophilic inflammation was associated with decreased NF-kappaB activity and enhanced production of anti-inflammatory mediators, including IL-10, TGF-beta, and annexin A1. Acetate treatment or intake of a high-fiber diet enhanced efferocytosis, an effect also observed in vitro with neutrophils treated with acetate. In conclusion, a high-fiber diet or one of its metabolic products, acetate, controls the inflammatory response to MSU crystals by favoring the resolution of the inflammatory response. Our studies suggest that what we eat plays a determinant role in our capacity to fine tune the inflammatory response. INTRODUCTION: PMID- 27496980 TI - The case for better case reports.... PMID- 27496978 TI - Efficacy of Vesicular Stomatitis Virus-Ebola Virus Postexposure Treatment in Rhesus Macaques Infected With Ebola Virus Makona. AB - The Ebola virus (EBOV) epidemic in West Africa increased the focus on vaccine development against this hemorrhagic fever-causing pathogen, and as a consequence human clinical trials for a few selected platforms were accelerated. One of these vaccines is vesicular stomatitis virus (VSV)-EBOV, also known as rVSV-ZEBOV, a fast-acting vaccine against EBOV and so far the only vaccine with reported efficacy against EBOV infections in humans in phase III clinical trials. In this study, we analyzed the potential of VSV-EBOV for postexposure treatment of rhesus macaques infected with EBOV-Makona. We treated groups of animals with 1 dose of VSV-EBOV either in a single injection at 1 or 24 hours after EBOV exposure or with 2 injections, half the dose at each time point; 1 control group received the same dose of the VSV-based Marburg virus vaccine at both time points; another group remained untreated. Although all untreated animals succumbed to EBOV infection, 33%-67% of the animals in each treatment group survived the infection, including the group treated with the VSV-based Marburg virus vaccine. This result suggests that protection from postexposure vaccination may be antigen unspecific and due rather to an early activation of the innate immune system. In conclusion, VSV-EBOV remains a potent and fast-acting prophylactic vaccine but demonstrates only limited efficacy in postexposure treatment. PMID- 27496981 TI - Thirty years of hand therapy: The 2014 practice analysis. AB - STUDY DESIGN: Quantitative and descriptive study. INTRODUCTION: In 2014, the Hand Therapy Certification Commission (HTCC), in consultation with Professional Examination Service, performed a practice analysis study of hand therapy, the fifth in a series of similar studies performed by HTCC over a 30-year period. PURPOSE: The purpose of the study was to gather data on current hand therapy practice to ensure the content of the Certified Hand Therapist (CHT) examination and credentialing program requirements match current practice. METHODS: Subject matter experts from the United States and Canada, representing a broad range of experiences and perspectives, developed an updated delineation of the domains, tasks, knowledge, and techniques and tools used in hand therapy practice. Practicing hand therapists from the United States, Canada, Australia, and 13 other countries reviewed the delineation in a large-scale online survey. RESULTS: The survey overwhelmingly validated the updated profile. Additionally, the survey explored trends in hand therapy practice and compared findings with previous studies. The results were analyzed and compared with findings from previous studies. CONCLUSION: This analysis led to the revision of the test specifications for the HTCC; the affirmation of the definition of hand therapy; the refinement of the scope of hand therapy practice; and guidance for HTCC policy decisions. LEVEL OF EVIDENCE: Not applicable. PMID- 27496982 TI - A scoping review of applications and outcomes of traction orthoses and constructs for the management of intra-articular fractures and fracture dislocations in the hand. AB - INTRODUCTION: Intra-articular hand fractures can have devastating consequences for movement and function. The unique nature of the injury and diverse management strategies are a challenge for conducting trials. PURPOSE OF THE STUDY: To conduct a scoping review of traction constructs for the management of intra articular hand fractures. METHODS: We conducted a systematic search of the literature, extracting data on the scope and nature of the evidence for traction constructs. RESULTS: Our search yielded 87 articles addressing 3 traction constructs: (1) static traction (n = 17), (2) dynamic external fixation (n = 53), and (3) dynamic orthoses (n = 17). Active range of motion of the target joint was the most frequently reported outcome. Study designs included 36 cohorts, 21 case series, and 9 case studies: 24% contained only technical information. CONCLUSIONS: The current literature addressing traction constructs consists primarily of small and low-quality studies. Evidence synthesis could improve the estimation of range of motion outcomes but would not be able to identify the best treatment. Consensus on classification of fracture patterns, routine use of outcome measures, and randomized trials are needed to compare different traction constructs and inform evidence-based care. STUDY DESIGN: Scoping review. LEVEL OF EVIDENCE: N/A. PMID- 27496984 TI - Adherence behavior in an acute pediatric hand trauma population: A pilot study of parental report of adherence levels and influencing factors. AB - INTRODUCTION: Descriptive and cross-sectional study. PURPOSE OF THE STUDY: The hand is a common site of injury in children; however, little is known regarding adherence to hand trauma management in this population. PURPOSE: This pilot study aimed to describe adherence to plaster slab immobilization, advice regarding return to sport, appointment attendance, and the factors influencing nonadherence. METHOD: Forty-seven parents of children with hand trauma completed an online questionnaire reporting their child's adherence to the initial medical management. RESULTS: Parents reported that 34% (16 of 47) of children were adherent to all aspects of management. Nonadherence with plaster slab immobilization was reported by 38% (18 of 47), and 45% (21 of 47) reported nonadherence with advice regarding return to sport. Hygiene, discomfort, and restriction were the most common reasons for plaster removal. Belief that sport would not cause harm and social factors influenced return to sport against medical advice. CONCLUSION: Nonadherence behavior is commonly reported in children with acute hand trauma. LEVEL OF EVIDENCE: 4. PMID- 27496983 TI - Reproducibility: Reliability and agreement of short version of Western Ontario Rotator Cuff Index (Short-WORC) in patients with rotator cuff disorders. AB - INTRODUCTION: Recently, a shorter version of Western Ontario Rotator Cuff Index (Short-WORC) was proposed as a subset of 7 items from the original 21-item WORC. However, the reproducibility of the Short-WORC has not been established. PURPOSE OF THE STUDY: To determine reproducibility (reliability and agreement) of the Short-WORC among patients with rotator cuff disorders (RCDs). METHODS: Patients (n = 153) diagnosed with RCD completed the WORC at baseline and at 3 months post operatively (n = 146). The Short-WORC was extracted from the full version of WORC. From this retrospective cohort, 43 patients were retested within 5 weeks, if they remained stable. Cronbach's alpha (alpha) and intra class correlation coefficients (ICC2,1) were used to assess internal consistency and test-retest reliability respectively. Standard error measurement (SEM), minimal detectable change (MDC90) and Bland Altman (BA) plots were used to assess agreement. RESULTS: No floor and ceiling effects were reported for either the Short-WORC or WORC. Cronbach's alpha were 0.84 and 0.90 at baseline and 0.89 and 0.95 at 3 month of follow up for Short-WORC and WORC respectively. The ICC2,1 were 0.89 and 0.91 for the Short-WORC and WORC respectively. The agreement parameters for the Short-WORC were: SEMagreement = 8.8, MDC90individual = 20.3, MDC90group = 5.1. We found substantial agreement between the two versions of WORC on BA plots with minimal (mean difference (d) <1) systematic differences between them. The limits of agreement (LOA) between two versions of WORC were similar across sessions and fell within range of -11.7 to 13.2 points at test and -14.7 to 14.7 points at retest. CONCLUSION: Short-WORC and WORC demonstrates strong reproducibility and can be used for group and individual comparison of health-related quality of life (HRQoL) among patients with RCD. Wider LOA may be expected when using the Short WORC for individual patient assessment. Reproducibility data is essential, but should be supplemented by validation of actual Short-WORC with samples representing the spectrum of RCD. LEVEL OF EVIDENCE: N/A. PMID- 27496985 TI - The effectiveness of orthoses in the conservative management of thumb CMC joint osteoarthritis: An analysis of functional pinch strength. AB - STUDY DESIGN: The study was a retrospective cohort analysis for a 19-month period from May 2013 to December 2014. INTRODUCTION: Although the use of orthoses has long been a staple of conservative treatment measures for individuals with osteoarthritis of the thumb carpometacarpal (CMC) joint, there remains little evidence exploring its effectiveness in improving functional outcomes for this client population. PURPOSE OF THE STUDY: The purpose of this study was to assess the effectiveness of 3 frequently used orthoses in improving the functional pinch strength of adults with a diagnosis of thumb CMC joint osteoarthritis. METHODS: A retrospective cohort analysis was conducted to determine whether pinch strength improved after orthotic fabrication, and fitting in patients referred to a hand therapy clinic. RESULTS: Patients who received a Colditz design orthosis had a mean increase of 2.64 lb with regard to functional pinch strength after orthotic fabrication and fitting. Patients who received a Comfort Cool orthosis (North Coast Medical, Morgan Hill, CA) had a mean increase of 2.47 lb, whereas patients who received a Thumb Spica orthosis had a mean increase of 3.25 lb. There was no evidence of any statistically significant difference in the average improvements in pinch strength between the Colditz design orthosis and the Comfort Cool orthosis. CONCLUSIONS: Results from this study demonstrate that orthosis wear consistently increases the functional pinch strength of individuals with thumb CMC joint osteoarthritis. Large-scale multisite research studies comparing various orthotic designs are necessary to help therapists determine best practice interventions for the conservative management of thumb CMC joint osteoarthritis. LEVEL OF EVIDENCE: 2(c). PMID- 27496986 TI - Coaching of patients with an isolated minimally displaced fracture of the radial head immediately increases range of motion. AB - STUDY DESIGN: Prospective cohort. INTRODUCTION: Elbow stiffness is the most common adverse event after isolated radial head fractures. PURPOSE OF THE STUDY: To assess the effect of coaching on elbow motion during the same office visit in patients with such fractures. METHODS: We enrolled 49 adult patients with minimally displaced radial head fractures, within 14 days of injury. After diagnosis, we measured demographics, catastrophic thinking, health anxiety, symptoms of depression, upper extremity-specific symptoms and disability, pain, and elbow and wrist motion. The patient was taught to apply an effective stretch in spite of the pain to limit stiffness, and elbow motion was measured again. RESULTS: With the exception of radial deviation and pronation, motion measures improved slightly but significantly on average immediately after coaching. Elbow flexion improved from 79% (110 degrees +/- 22 degrees ) of the uninjured side to 88% (122 degrees +/- 18 degrees ) after coaching (P < .001); elbow extension improved from 71% (29 degrees +/- 14 degrees ) to 78% (22 degrees +/- 15 degrees ) (P = .0012). DISCUSSION: Instruction that stretching exercises are healthy even when painful resulted in immediate improvements in motion. Prospective studies comparing different strategies for coaching patients regarding painful stretches might help clarify the optimal approach. LEVEL OF EVIDENCE: Therapeutic level 4. PMID- 27496987 TI - Clinical Relevance Commentary in Response to: Coaching of patients with and isolated minimally displaced fracture of the radial head immediately increases range of motion. PMID- 27496988 TI - Case Report: The casting motion to mobilize stiffness technique for rehabilitation after a crush and degloving injury of the hand. AB - STUDY DESIGN: Case report. INTRODUCTION: This case report describes the use of the casting motion to mobilize stiffness (CMMS) technique in the management of a crush and degloving injury of the hand. The patient was unable to attend multiple hand therapy sessions due to geographic constraints. The CMMS technique involved the application of a nonremovable plaster of paris cast that selectively immobilizes proximal joints in an ideal position while constraining distal joints to direct desired motion over a long period. This uses active motion only. Traditional hand therapy techniques or modalities are not used. This treatment approach was beneficial to the patient as a minimum of 2 appointments per month were needed to regain functional hand use. PURPOSE OF THE STUDY: To document the use of the CMMS technique as an effective treatment approach in the management of a crush and degloving injury of the hand. METHODS: The CMMS technique was applied to the patient's left (nondominant) hand 8 weeks after injury. The technique's aim was to improve the 30 degrees flexion deformity of the left wrist and flexion contractures of the index, middle, and ring fingers with a total active motion of 0 degrees . Orthotic devices and traditional therapy were applied once joint stiffness was resolved, and a normal pattern of motion was reinstated. RESULTS: At 6 months, substantial improvement was noted in wrist as well as metacarpophalangeal and interphalangeal joints. Total active motion exceeded 170 degrees in all fingers excellent functional outcome resulted as measured with the upper limb functional index short form-10. The upper limb functional index increased from 0% to 55% of preinjury status (or capacity) over the 18 months of therapy. DISCUSSION: Brief immobilization through casting causes certain functional losses, but these are temporary and reversible. CONCLUSION: Finger stiffness, edema, and tissue fibrosis were successfully managed with the CMMS technique without the need for attendance at multiple hand therapy sessions. LEVEL OF EVIDENCE: Level V. PMID- 27496989 TI - An alternative fabrication method of the dart thrower's motion orthosis (also known as the dart orthosis). AB - To allow safe early wrist motion after wrist injury, this author has modified an earlier version of a dart thrower's motion orthotic device using material that is currently available on the market and an inexpensive paper fastener as the rivet. - KristinValdes, OTD, OT, CHT, Practice Forum Editor. PMID- 27496990 TI - The challenge of the mallet orthosis: A simple solution. AB - This author provides instruction regarding an alternative, simple, and custom made orthotic device to manage the mallet finger that may stay in place more securely while also allowing for proximal interphalangeal joint flexion during the healing of the terminal tendon. - KristinValdes, OTD, OT, CHT, Practice Forum Editor, Journal of Hand Therapy. PMID- 27496991 TI - Mallet finger injuries-A new method to maintain distal interphalangeal joint extension. AB - Ensuring that distal interphalangeal joint extension is maintained is an important but challenging part of the treatment process. These authors describe a simple approach to ensuring distal interphalangeal joint extension for these patients. - VictoriaPriganc, PhD, OTR, CHT, CLT, Practice Forum Editor. PMID- 27496992 TI - Online coupling of high-resolution chromatography with extreme UV photon activation tandem mass spectrometry: Application to the structural investigation of complex glycans by dissociative photoionization. AB - The activation of ions by extreme-energy photons (XUV) produced by a synchrotron radiation beamline is a powerful method for characterizing complex glycans using tandem mass spectrometry (MS). As previously described, this activation method leads to rich fragmentation spectra with many structurally valuable cross-ring cleavages while maintaining labile modifications on the glycan structures. However, until now, the tandem MS event was too long to be compatible with liquid chromatography elution times. In this work, the duty cycle of the activation and detection of fragments was shortened, and the background signal on the spectra was drastically reduced. Both improvements allowed, for the first time, the successful coupling of a UHPLC system to XUV-activated tandem MS. The approach was used to characterize a complex mixture of oligo-porphyrans, which are a class of highly sulfated oligosaccharides, in a fully automated way. Due to an enhanced dynamic range and an increased sensitivity, some hypothetical structures of low abundance have been unequivocally confirmed in this study and others have been revised. Some previously undescribed species of oligo-porphyrans that exhibit lateral branching have been fully resolved. This work contributes to the scarce knowledge of the structure of porphyrans in red algae and pushes the current capacities of XUV-activation tandem MS by demonstrating the possibility of a direct coupling with UHPLC. This study will considerably broaden the applicability and practicality of this method in many fields of analytical biology. PMID- 27496993 TI - Advances in the determination of hindered amine light stabilizers - A review. AB - Within this paper we discuss analytical strategies for the characterization and quantitation of hindered amine light stabilizers (HALS) an important sub-group of polymer additives. For the determination of monomeric HALS a range of mature and reliable techniques exists, allowing their determination in polymer extracts. If qualitative or semi-quantitative information suffices, certain techniques are capable of sampling directly from the polymer surface with limited or no sample preparation. Different strategies for the determination of complex oligomeric HALS in extracts from polymer samples are discussed. Here, approaches providing only a sum parameter including all HALS oligomers have been distinguished from more sophisticated technologies allowing the determination of single oligomers, their degradation and by-products. Particularly, the latter issue is facing increased interest as it provides important information for polymers aging studies. A tabulated overview provides comprehensive information on different analytical techniques suitable for HALS determination. PMID- 27496994 TI - Recent applications of capillary electromigration methods to separation and analysis of proteins. AB - This review article describes the significant recent developments in analysis of proteins by capillary electromigration (CE) methods (zone electrophoresis, isotachophoresis, isoelectric focusing, affinity electrophoresis, electrokinetic chromatography and electrochromatography) during the period 2011-2015. Improvements in sample preparation, preconcentration, suppression of adsorption and control of electroosmotic flow, separations by particular CE methods, and the detection schemes used in the analysis of proteins are discussed. Innovative applications of the above CE methods for quality control of protein biopharmaceuticals, protein determination in complex biomatrices, peptide mapping of proteins, and determination of physicochemical parameters of proteins are presented. PMID- 27496995 TI - A new and consistent parameter for measuring the quality of multivariate analytical methods: Generalized analytical sensitivity. AB - Generalized analytical sensitivity (gamma) is proposed as a new figure of merit, which can be estimated from a multivariate calibration data set. It can be confidently applied to compare different calibration methodologies, and helps to solve literature inconsistencies on the relationship between classical sensitivity and prediction error. In contrast to the classical plain sensitivity, gamma incorporates the noise properties in its definition, and its inverse is well correlated with root mean square errors of prediction in the presence of general noise structures. The proposal is supported by studying simulated and experimental first-order multivariate calibration systems with various models, namely multiple linear regression, principal component regression (PCR) and maximum likelihood PCR (MLPCR). The simulations included instrumental noise of different types: independently and identically distributed (iid), correlated (pink) and proportional noise, while the experimental data carried noise which is clearly non-iid. PMID- 27496996 TI - Regression models based on new local strategies for near infrared spectroscopic data. AB - In this work, a comparative study of two novel algorithms to perform sample selection in local regression based on Partial Least Squares Regression (PLS) is presented. These methodologies were applied for Near Infrared Spectroscopy (NIRS) quantification of five major constituents in corn seeds and are compared and contrasted with global PLS calibrations. Validation results show a significant improvement in the prediction quality when local models implemented by the proposed algorithms are applied to large data bases. PMID- 27496997 TI - Electrodeposition of tantalum on carbon black in non-aqueous solution and its electrocatalytic properties. AB - In this work, we synthesized tantalum (Ta) nanoclusters on carbon black (Ta/CB) via simple electrodeposition in non-aqueous solvent, acetonitrile (ACN) at ambient temperature. Transmission electron microscopy (TEM) images showed that the electrodeposited Ta nanoclusters consisted of tiny Ta nanoparticles. X-ray photoelectron spectroscopy (XPS) result represented that the outermost Ta formed the native oxide on Ta/CB due to its ambient exposure to air. Electrochemical catalytic properties of prepared Ta/CB on glassy carbon electrode (Ta/CB/GC) were investigated toward reductions of oxygen and hydrogen peroxide, and oxidations of ascorbic acid and dopamine. For oxygen reduction reaction (ORR) in acid, Ta/CB/GC represented a decent electrocatalytic performance which was better or comparable to bare Pt. The operational stability in acidic condition was maintained up to 500 repetitive potential cycles presumably due to the protective native Ta oxide layer. Ta/CB/GC also showed high amperometric sensitivity (4.5 (+/-0.16) mA mM( 1) cm(-2), n = 5) for reduction of hydrogen peroxide in 0.1 M phosphate buffer solution (PBS, pH 7.4). In addition, Ta/CB/GC was demonstrated for the possibility of simultaneous detection of ascorbic acid and dopamine using differential pulse voltammetry (DPV). PMID- 27496998 TI - A novel nonenzymatic biosensor for evaluation of oxidative stress based on nanocomposites of graphene blended with CuI. AB - A high-sensitive nonenzymatic hydrogen peroxide (H2O2) biosensor based on cuprous iodide and graphene (CuI/Gr) composites has been explored for the detection of H2O2 released by living cells and monitoring the oxidative stress of cells under excellular stimulation. The biosensor properties were evaluated by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), amperometric i-t curve, and the redox-competition mode of scanning electrochemical microscopy (SECM). Our observations demonstrate that the CuI/Gr nanocomposites modified glassy carbon electrode (GCE) exhibits excellent catalytic activity for H2O2 with relatively low detection limit and a wide linear range from 0.5 MUM to 3 mM. Moreover, the redox-competition mode of SECM imaging study further illustrates the improved electrochemical catalytic capability for H2O2 reduction with CuI/Gr nanocomposites deposited on graphite electrode. Hence, the as-prepared nonenzymatic H2O2 biosensor could be used to detect H2O2 release from different kinds of living cells under stimulation while eliminating the interference of ascorbic acid. PMID- 27496999 TI - Sensitive electrochemical assaying of DNA methyltransferase activity based on mimic-hybridization chain reaction amplified strategy. AB - A mimic-hybridization chain reaction (mimic-HCR) amplified strategy was proposed for sensitive electrochemically detection of DNA methylation and methyltransferase (MTase) activity In the presence of methylated DNA, DNA-gold nanoparticles (DNA-AuNPs) were captured on the electrode by sandwich-type assembly. It then triggered mimic-HCR of two hairpin probes to produce many long double-helix chains for numerous hexaammineruthenium (III) chloride ([Ru(NH3)6](3+), RuHex) inserting. As a result, the signal for electrochemically detection of DNA MTase activity could be amplified. If DNA was non-methylated, however, the sandwich-type assembly would not form because the short double stranded DNAs (dsDNA) on the Au electrode could be cleaved and digested by restriction endonuclease HpaII (HapII) and exonuclease III (Exo III), resulting in the signal decrement. Based on this, an electrochemical approach for detection of M.SssI MTase activity with high sensitivity was developed. The linear range for M.SssI MTase activity was from 0.05 U mL(-1) to 10 U mL(-1), with a detection limit down to 0.03 U mL(-1). Moreover, this detecting strategy held great promise as an easy-to-use and highly sensitive method for other MTase activity and inhibition detection by exchanging the corresponding DNA sequence. PMID- 27497000 TI - A novel reagentless glutamate microband biosensor for real-time cell toxicity monitoring. AB - A reagentless glutamate biosensor was applied to the determination of glutamate released from liver hepatocellular carcinoma cells (HepG2) in response to toxic challenge from various concentrations of paracetamol. A screen printed carbon electrode (SPCE) containing the electrocatalyst Meldola's Blue (MB-SPCE) served as the electron mediator for the oxidation of NADH. A mixture of the enzyme glutamate dehydrogenase (GLDH), cofactor nicotinamide adenine dinucleotide (NAD(+)) and the biopolymer chitosan (CHIT) were drop-coated onto the surface of the transducer (MB-SPCE) in a simple one step fabrication process. The reagentless biosensor was used with amperometry in stirred solution at an applied potential of +0.1 V (vs. Ag/AgCl). All experiments were carried out at the following conditions: pH 7, temperature 37 degrees C, atmosphere 5% CO2. The linear range of the device was found to be 25-125 MUM in phosphate buffer (75 mM, containing 0.05 M NaCl) and 25-150 MUM in cell culture medium. The limits of detection (LOD) were found to be 1.2 MUM and 4.2 MUM based on three times signal to noise, using PBS and culture medium respectively. The sensitivity was calculated to be 106 nA MUM(-1) cm(-2) and 210 nA MUM(-1) cm(-2) in PBS and cell medium respectively. The response time was ~60 s in an agitated solution. HepG2 cells were exposed to various concentrations of paracetamol (1 mM, 5 mM and 10 mM) in order to investigate the drug-induced release of glutamate into the culture medium in real time. Two toxicity studies were investigated using different methods of exposure and analysis. The first method consisted of a single measurement of the glutamate concentration, using the method of standard addition, after 24 h incubation. The concentrations of glutamate were found to be 52 MUM, 93 MUM and 177 MUM, released on exposure to 1 mM, 5 mM and 10 mM paracetamol respectively. The second method involved the continuous monitoring of glutamate released from HepG2 cells upon exposure to paracetamol over 8 h. The concentrations of glutamate released in the presence of 1 mM, 5 mM and 10 mM paracetamol, increased in proportion to the drug concentration, ie: 16 MUM, 28 MUM and 62 MUM respectively. This result demonstrates the feasibility of using this approach to monitor early metabolic changes after exposure to a model toxic compound. PMID- 27497001 TI - Enzymatic biosensor of horseradish peroxidase immobilized on Au-Pt nanotube/Au graphene for the simultaneous determination of antioxidants. AB - A new electrochemical method has been proposed for the simultaneous determination of butylated hydroxyanisole (BHA) and propyl gallate (PG) in food matrices based on enzymatic biosensors. Spiny Au-Pt nanotubes (SAP NTs) was first synthesized and demonstrated to exhibit intrinsic peroxidase and catalase-like activity. The structure of SAP NTs provides large surface area and favorable medium for electron transfer, on which HRP were immobilized and acted as enzymatic biosensor for the simultaneous detection of BHA and PG. The results revealed that BHA and PG both have well-defined oxidation waves with peak potentials of 624 and 655 mV, respectively. Under the optimal conditions, the method behaved satisfactory analytical performance towards BHA and PG with a wide linear range of 0.3-50 mg L(-1) and 0.1-100 mg L(-1), as well as a detection limit of 0.046 mg L(-1) and 0.024 mg L(-1) (3sigma/slope), respectively. Besides, the proposed method exhibits good sensitivity, stability and reproducibility, providing an alternative to fabricate electrode and construct sensitive biosensors. PMID- 27497002 TI - C18-attached membrane funnel-based spray ionization mass spectrometry for quantification of anti-diabetic drug from human plasma. AB - In this work, sorbent-attached membrane funnel-based spray ionization mass spectrometry was explored for quantitative analysis of anti-diabetic drugs spiked in human plasma. C18-attached membrane funnel was fabricated for in situ extraction and clean-up to alleviate matrix suppression effect in the ionization process. Repaglinide was used as a target analyte of anti-diabetic drugs. Under optimal working conditions, good linearity (R(2) > 0.99) was obtained in the concentration range of 1-100 ng mL(-1). The method detection limit of target drugs spiked in the human plasma was around 0.30 ng mL(-1). Through the application of an isotope-labeled internal standard, the signal fluctuation caused by residual background matrices was largely alleviated and the precision of measurement (RSD) was below 15%. The recovery of repaglinide for 5, 25, and 100 ng mL(-1) of spiked human plasma matrixes ranged from 87% to 112%. The developed method was successfully applied to determine repaglinide in plasma volunteers who orally received a dose of drug association. Our results demonstrated that membrane funnel-based spray is a simple and sensitive method for rapid screening analysis of complex biological samples. PMID- 27497003 TI - Development of the HS-SPME-GC-MS/MS method for analysis of chemical warfare agent and their degradation products in environmental samples. AB - After World War II approximately 50,000 tons of chemical weapons were dumped in the Baltic Sea by the Soviet Union under the provisions of the Potsdam Conference on Disarmament. These dumped chemical warfare agents still possess a major threat to the marine environment and to human life. Therefore, continue monitoring of these munitions is essential. In this work, we present the application of new solid phase microextraction fibers in analysis of chemical warfare agents and their degradation products. It can be concluded that the best fiber for analysis of sulfur mustard and its degradation products is butyl acrylate (BA), whereas for analysis of organoarsenic compounds and chloroacetophenone, the best fiber is a co-polymer of methyl acrylate and methyl methacrylate (MA/MMA). In order to achieve the lowest LOD and LOQ the samples should be divided into two subsamples. One of them should be analyzed using a BA fiber, and the second one using a MA/MMA fiber. When the fast analysis is required, the microextraction should be performed by use of a butyl acrylate fiber because the extraction efficiency of organoarsenic compounds for this fiber is acceptable. Next, we have elaborated of the HS-SPME-GC-MS/MS method for analysis of CWA degradation products in environmental samples using laboratory obtained fibers The analytical method for analysis of organosulfur and organoarsenic compounds was optimized and validated. The LOD's for all target chemicals were between 0.03 and 0.65 ppb. Then, the analytical method developed by us, was used for the analysis of sediment and pore water samples from the Baltic Sea. During these studies, 80 samples were analyzed. It was found that 25 sediments and 5 pore water samples contained CWA degradation products such as 1,4-dithiane, 1,4-oxathiane or triphenylarsine, the latter being a component of arsine oil. The obtained data is evidence that the CWAs present in the Baltic Sea have leaked into the general marine environment. PMID- 27497004 TI - Calibration of the complex matrix effects on the sampling of polycyclic aromatic hydrocarbons in milk samples using solid phase microextraction. AB - Solid phase microextraction (SPME), a simple, fast and promising sampling technique, has been widely used for complex sample analysis. However, complex matrices could modify the absorption property of coatings as well as the uptake kinetics of analytes, eventually biasing the quantification results. In the current study, we demonstrated the feasibility of a developed calibration method for the analysis of polycyclic aromatic hydrocarbons (PAHs) in complex milk samples. Effects of the complex matrices on the SPME sampling process and the sampling conditions were investigated. Results showed that short exposure time (pre-equilibrium SPME, PE-SPME) could increase the lifetime of coatings, and the complex matrices in milk samples could significantly influence the sampling kinetics of SPME. In addition, the optimized sampling time, temperature and dilution factor for PAHs were 10 min, 85 degrees C and 20, respectively. The obtained LODs and LOQs of all the PAHs were 0.1-0.8 ng/mL and 1.4-4.7 ng/mL, respectively. Furthermore, the accuracy of the proposed PE-SPME method for milk sampling was validated by the recoveries of the studied compounds in two concentration levels, which ranged from 75% to 110% for all the compounds. Finally, the proposed method was applied to the screening of PAHs in milk samples. PMID- 27497005 TI - Evaluation of in vivo solid phase microextraction for minimally invasive analysis of nonvolatile phytochemicals in Amazonian plants. AB - INTRODUCTION: Although solid phase microextraction (SPME) has been used extensively for fingerprinting volatile compounds emitted by plants, there are very few such reports for direct insertion SPME. In this research, direct contact of SPME probes with the interstitial fluid of plants was investigated as a method for phytochemical analysis. OBJECTIVE: Medicinal plants from the Amazon have been the source of numerous drugs used in western medicine. However, a large number of species used in traditional medicine have not been characterized chemically, partly due to the difficulty of field work. In this project, the phytochemical composition of plants from several genera was fingerprinted by combining convenient field sampling by solid phase microextraction (SPME) with laboratory analysis by LC-MS. The new method was compared with classical sampling followed by liquid extraction (LE). METHODOLOGY: SPME probes were prepared by coating stainless steel wires with a mixture of polyacrylonitrile and either RP-amide or HS-F5 silica particles. Sampling was performed by inserting the microextraction probes into various tissues of living plants in their natural environment. After in vivo extraction, the probes were sealed under vacuum and refrigerated until analyzed. The probes were desorbed in mobile phase and analyzed on a Waters Acquity UPLC with triple quadrupole mass spectrometer in positive ion mode. RESULTS: Twenty Amazonian plant species were sampled and unique metabolomic fingerprints were obtained. In addition, quantitative analysis was performed for previously identified compounds in three species. Comparison of the fingerprints obtained by in vivo SPME with those obtained by LE showed that 27% of the chromatographic features were unique to SPME, 57% were unique to LE, and 16% were common to both methods. CONCLUSION: In vivo SPME caused minimal damage to the plants, was much faster than traditional liquid extraction, and provided unique fingerprints for all investigated plants. SPME revealed unique chromatographic features, undetected by traditional extraction, although it produced only half as many peaks as ethanol extraction. PMID- 27497006 TI - Effective methylation of phosphonic acids related to chemical warfare agents mediated by trimethyloxonium tetrafluoroborate for their qualitative detection and identification by gas chromatography-mass spectrometry. AB - The effective methylation of phosphonic acids related to chemical warfare agents (CWAs) employing trimethyloxonium tetrafluoroborate (TMO.BF4) for their qualitative detection and identification by gas chromatography-mass spectrometry (GC-MS) is presented. The methylation occurs in rapid fashion (1 h) and can be conveniently carried out at ambient temperature, thus providing a safer alternative to the universally employed diazomethane-based methylation protocols. Optimization of the methylation parameters led us to conclude that methylene chloride was the ideal solvent to carry out the derivatization, and that even though methylated products can be observed surfacing after only 1 h, additional time was not found to be detrimental but beneficial to the process particularly when dealing with analytes at low concentrations (~10 MUg mL(-1)). Due to its insolubility in methylene chloride, TMO.BF4 conveniently settles to the bottom during the reaction and does not produce additional interfering by-products that may further complicate the GC-MS analysis. The method was demonstrated to successfully methylate a variety of Schedule 2 phosphonic acids, including their half esters, resulting in derivatives that were readily detected and identified using the instrument's spectral library. Most importantly, the method was shown to simultaneously methylate a mixture of the organophosphorus-based nerve agent hydrolysis products: pinacolyl methylphosphonate (PMPA), cyclohexyl methylphosphonate (CyMPA) and ethyl methylphosphonate (EMPA) (at a 10 MUg mL(-1) concentration each) in a fatty acid ester-rich organic matrix (OPCW-PT-O3) featured in the 38th Organisation for the Prohibition of Chemical Weapons (OPCW) Proficiency Test. In addition, the protocol was found to effectively methylate N,N-diethylamino ethanesulfonic acid and N,N-diisopropylamino ethanesulfonic acid that are products arising from the oxidative degradation of the V-series agents VR and VX respectively. The work described herein represents the first report on the use of TMO.BF4 as a viable, stable and safe agent for the methylation of phosphonic acids and their half esters and within the context of an OPCW Proficiency Test sample analysis. PMID- 27497007 TI - Quantitative analysis of wild-type and V600E mutant BRAF proteins in colorectal carcinoma using immunoenrichment and targeted mass spectrometry. AB - The BRAF V600E mutation is one of the most common mutations implicated in the development of several types of cancer including colorectal cancer (CRC), where it is associated with aggressive disease phenotypes and poor outcomes. The status of the BRAF V600E mutation is frequently determined by direct DNA sequencing. However, no previous study has sought to quantify the BRAF V600E protein in cancer specimens. Here, we evaluated immunoenrichment coupled with two MS-based quantitative techniques, namely multiple reaction monitoring (MRM) and single ion monitoring conjugated accurate inclusion mass screening (SIM-AIMS), to detect and precisely quantify wild-type (WT) and V600E mutant BRAF proteins in DNA sequence confirmed CRC tissue specimens. WT and V600E BRAF proteins were immunoprecipitated from a CRC cell line (HT-29), and their representative peptides ((592)IGDFGLATVK(601) and (592)IGDFGLATEK(601), respectively) were confirmed by LC-MS/MS analysis and then quantified by MRM or SIM-AIMS with spiked stable isotope-labeled peptide standards. Both assays worked well for measuring WT BRAF from different amounts of HT-29 cell lysates, but the MRM assay was more sensitive than SIM-AIMS assay for quantifying lower levels of V600E BRAF. In protein extracts (2 mg) from 11 CRC tissue specimens, the MRM assay could measure WT BRAF in all 11 cases (0.32-1.66 ng) and the V600E BRAF in two cases (0.1-0.13 ng; mutant-to-WT ratio, 0.16-0.17). The SIM-AIMS assay could also detect WT and V600E BRAF in CRC specimens, but the measured levels of both targets were lower than those determined by MRM assay. Collectively, this study provides an effective method to precisely quantify WT and V600E BRAF proteins in complex biological samples using immunoenrichment-coupled targeted MS. Since the V600E BRAF protein has emerged as an important therapeutic target for cancer, the developed assay should facilitate future BRAF-related basic and clinical studies. PMID- 27497008 TI - An integrated electrophoretic mobility control device with split design for signal improvement in liquid chromatography-electrospray ionization mass spectrometry analysis of aminoglycosides using a heptafluorobutyric acid containing mobile phase. AB - Electrophoretic mobility control (EMC) was used to alleviate the adverse effect of the ion-pairing agent heptafluorobutyric acid (HFBA) in the liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) analysis of aminoglycosides. Aminoglycosides separated by LC were directed to a connecting column before their detection via ESI. Applying an electric field across the connecting column caused the positively charged aminoglycosides to migrate toward the mass spectrometer whereas the HFBA anions remained in the junction reservoir, thus alleviating the ion suppression caused by HFBA. To accommodate the flow rate of a narrow-bore column, minimize the effect of electrophoretic mobility on separation, and facilitate the operation, an integrated EMC device with a split design was fabricated. With the proposed EMC device, the signals of aminoglycosides were enhanced by a factor of 5-85 without affecting the separation efficiency or elution order. For the analysis of aminoglycosides in bovine milk, the proposed approach demonstrates a sensitivity that is at least 10 times below the maximum residue limits set by most countries. PMID- 27497009 TI - Analysis of a series of chlorogenic acid isomers using differential ion mobility and tandem mass spectrometry. AB - Chlorogenic acids are among the most abundant phenolics found in the human diet. Of these, the mono-caffeoylquinic acids are the predominant phenolics found in fruits, such as apples and pears, and products derived from them. In this research, a comprehensive study of the electrospray ionization (ESI) tandem mass spectrometric (MS/MS) dissociation behavior of the three most common mono caffeoylquinic acids, namely 5-O-caffeoylquinic acid (5-CQA), 3-O-caffeoylquinic acid (3-CQA) and 4-O-caffeoylquinic acid (4-CQA), were determined using both positive and negative ionization. All proposed structures of the observed product ions were confirmed with second-generation MS(3) experiments. Similarities and differences between the dissociation pathways in the positive and negative ion modes are discussed, confirming the proposed structures and the established MS/MS fingerprints. MS/MS dissociation was primarily driven via the cleavage of the ester bond linking the quinic acid moiety to the caffeic acid moiety within tested molecules. Despite being structural isomers with the same m/z values and dissociation behaviors, the MS/MS data in the negative ion mode was able to differentiate the three isomers based on ion intensity for the major product ions, observed at m/z 191, 179 and 173. This differentiation was consistent among various MS instruments. In addition, ESI coupled with high-field asymmetric waveform ion mobility spectrometry-mass spectrometry (ESI-FAIMS-MS) was employed for the separation of these compounds for the first time. By combining MS/MS data and differential ion mobility, a method for the separation and identification of mono-caffeoylquinic in apple/pear juice samples was developed with a run time of less than 1 min. It is envisaged that this methodology could be used to identify pure juices based on their chlorogenic acid profile (i.e., metabolomics), and could also be used to detect juice-to-juice adulteration (e.g., apple juice addition to pear juice). PMID- 27497010 TI - Distinguishing normal cells from cancer cells via lysosome-targetable pH biomarkers with benzo[a]phenoxazine skeleton. AB - In this paper, the design of a lysosome-targetable pH probe that has a fluorescent OFF (pH = 4) to ON (pH = 5-6) response is described to identify lysosomes in normal cells. The mechanism of photoinduced electron transfer with a fluorophore-based reaction (FBR-PET) was proposed. Benzo[a]phenoxazines with electro-donating aryl groups were selected, its (2,5-dimethoxyphenyl)imino-, (2 hydroxyphenyl)imino- and (2-hydroxy-5-methoxyphenyl)- imino-derivatives (probes 1a-c) were prepared and their optical responses towards pH were evaluated; their fluorescence pH titration experiments gave regularly changes with the increasing electro-donating abilities at the linked aryl groups, the (2-hydroxy-5 methoxyphenyl)iminobenzo[a]phenoxazine (probe 1c) exhibited a nearly OFF-ON response at 580-800 nm. All probes were reversible, and they showed excellent selectivity toward the proton over other competitive species. Fluorescence confocal images were performed with HeLa, KB cancer cells and V79 normal cells, probes 1a-c are all lysosome-targetable pH probes, and benzo[a]phenoxazine with (2-hydroxy-5-methoxyphenyl)imino-group (probe 1c) has potential applications in selective differentiation of normal cells from cancer cells. PMID- 27497011 TI - Reusable split-aptamer-based biosensor for rapid detection of cocaine in serum by using an all-fiber evanescent wave optical biosensing platform. AB - A rapid, facile, and sensitive assay of cocaine in biological fluids is important to prevent illegal abuse of drugs. A two-step structure-switching aptasensor has been developed for cocaine detection based on evanescent wave optical biosensing platform. In the proposed biosensing platform, two tailored aptamer probes were used to construct the molecular structure switching. In the existence of cocaine, two fragments of cocaine aptamer formed a three-way junction quickly, and the fluorophore group of one fragment was effectively quenched by the quencher group of the other one. The tail of the three-way junction hybridized with the cDNA sequences immobilized on the optical fiber biosensor. Fluorescence was excited by evanescent wave, and the fluorescence signal was proportional to cocaine concentration. Cocaine was detected in 450 s (300 s for incubation and 150 s for detection and regeneration) with a limit of detection (LOD) of 165.2 nM. The proposed aptasensor was evaluated in human serum samples, and it exhibited good recovery, precision, and accuracy without complicated sample pretreatments. PMID- 27497012 TI - A TPA-caged precursor of (imino)coumarin for "turn-on" fluorogenic detection of Cu(.). AB - We strategize to utilize the precursors of (imino)coumarin fluorophores to deliver novel reactive Cu(+) probes, where tris[(2-pyridyl)-methyl] amine (TPA) works as a reactive receptor towards Cu(+). To verify this strategy, CP1, a representative probe and relevant sensing behaviors towards Cu(+) are presented here. CP1 features good solubility and fast response for monitoring labile copper in aqueous solution and live cells. The sensing mechanism of CP1 is determined by HPLC titration and mass spectrometric analysis. The probe CP1 exhibits a 60-fold fluorescence enhancement and a detection limitation of 10.8 nM upon the detection of Cu(+). CP1 is further applied for imaging labile copper in live cells. This work provides a starting point for future development of Cu(+) probes, based on in situ formation of (imino)coumarin scaffolds, as well as their further investigations of copper signaling and biological events. PMID- 27497013 TI - Plasmonic-based colorimetric and spectroscopic discrimination of acetic and butyric acids produced by different types of Escherichia coli through the different assembly structures formation of gold nanoparticles. AB - We present a plasmonic-based strategy for the colourimetric and spectroscopic differentiation of various organic acids produced by bacteria. The strategy is based on our discovery that particular concentrations of dl-lactic, acetic, and butyric acids induce different assembly structures, colours, and optical spectra of gold nanoparticles. We selected wild-type (K-12 W3110) and genetically engineered (JHL61) Escherichia coli (E. coli) that are known to primarily produce acetic and butyric acid, respectively. Different assembly structures and optical properties of gold nanoparticles were observed when different organic acids, obtained after the removal of acid-producing bacteria, were mixed with gold nanoparticles. Moreover, at moderate cell concentrations of K-12 W3110 E. coli, which produce sufficient amounts of acetic acid to induce the assembly of gold nanoparticles, a direct estimate of the number of bacteria was possible based on time-course colour change observations of gold nanoparticle aqueous suspensions. The plasmonic-based colourimetric and spectroscopic methods described here may enable onsite testing for the identification of organic acids produced by bacteria and the estimation of bacterial numbers, which have applications in health and environmental sciences. PMID- 27497014 TI - Integrating Palliative Care into Primary Care. AB - Improved quality of life, care consistent with patient goals of care, and decreased health care spending are benefits of palliative care. Palliative care is appropriate for anyone with a serious illness. Advances in technology and pharmaceuticals have resulted in increasing numbers of seriously ill individuals, many with a high symptom burden. The numbers of individuals who could benefit from palliative care far outweighs the number of palliative care specialists. To integrate palliative care into primary care it is essential that resources are available to improve generalist palliative care skills, identify appropriate patients and refer complex patients to specialist palliative care providers. PMID- 27497015 TI - Animal-Assisted Therapy in Pediatric Palliative Care. AB - Animal-assisted therapy is an emerging complementary strategy with an increasing presence in the literature. Limited studies have been conducted with children, particularly those with life-threatening and life-limiting conditions. Although outcomes show promise in decreasing suffering of children receiving palliative care services, more work is needed to validate evidence to support implementation of animal-assisted therapy with this vulnerable population. PMID- 27497017 TI - Pain Management in the Individual with Serious Illness and Comorbid Substance Use Disorder. AB - Pain is a common occurrence in individuals with serious illnesses. Effective pain management can be complicated when the individual has a comorbid substance use disorder. Comprehensive pain assessment includes opioid risk screening to provide safe and effective pain management. An appropriate, safe treatment plan includes the use of "universal precautions" commonly used in managing chronic pain. PMID- 27497018 TI - A Review of Palliative Sedation. AB - Palliative sedation has become a standard practice to treat refractory symptoms at end-of-life. Dyspnea and delirium are the two most commonly treated symptoms. The medications used in palliative sedation are usually benzodiazepines, barbiturates, antipsychotics, and/or anesthetics. Some ethical considerations remain, especially surrounding the use of palliative sedation in psychological distress and existential suffering. PMID- 27497016 TI - Pain Assessment in Noncommunicative Adult Palliative Care Patients. AB - Palliative care patients who have pain are often unable to self-report their pain, placing them at increased risk for underrecognized and undertreated pain. Use of appropriate pain assessment tools significantly enhances the likelihood of effective pain management and improved pain-related outcomes. This paper reviews selected tools and provides palliative care clinicians with a practical approach to selecting a pain assessment tool for noncommunicative adult patients. PMID- 27497019 TI - Family Care During End-of-Life Vigils. AB - An end-of-life vigil is the act of being with another toward death. A family vigil at end-of-life occurs when significant others gather by the bedside of dying individuals in the weeks, days, or hours prior to the death event. It is not unusual for nurses to be present, bear witness, and share in this human experience. This article reviews seminal and current research regarding the meaning and structure of the lived experience of vigil keeping for a dying family member, and translates research to inform nurses regarding family care during the transition at end-of-life. PMID- 27497020 TI - Rituals at End-of-Life. AB - Understanding the significance of rituals at the end-of-life enables health care professionals to offer meaningful and compassionate interventions that enhance quality of life and support those dying and those who grieve. Rituals contribute to the strength, capacity, and health of providers who cope with death events. Rituals help the living create continuing bonds with those dying, help with coping skills, and allow healthy growth through opportunities for naming, honoring, and memorializing. The display of respect and a nonjudgmental attitude create a space for support, trust, sharing of emotion, empowerment, and quality of care during end-of-life events. PMID- 27497021 TI - Seeing the Light: End-of-Life Experiences-Visions, Energy Surges, and Other Death Bed Phenomena. AB - Spiritual care is an integral part of multidimensional palliative care and a major domain of care identified in definitions and guidelines. Death bed phenomena include visions, dreams, hallucinations, and premortem energy surges, which can be deeply spiritual experiences. Death bed occurrences are often a source of consolation. However, they have been underrecognized. The last hours of life are sacred; as holistic, multidimensional practitioners, nurses should remain open to experiences not easily explained within a traditional medical model. As the most consistent caregivers, nurses assess, recognize, and validate such experiences to assist patients in finding meaning, comfort, and a peaceful end-of-life. PMID- 27497022 TI - Providing Palliative Care to LGBTQ Patients. AB - Nurses should be familiar with and equipped to address the challenges that arise when caring for lesbian, gay, bisexual, transgender, or queer-identified (LGBTQ) patients. LGBTQ individuals have increased rates of certain physical diseases and are at greater risk of suffering from stress-sensitive mental health issues. Negative social attitudes, widespread discrimination and stigma, physical and psychological victimization, and less social support with aging contribute to the complexity of care for these individuals. Open communication, welcoming and accepting attitudes and environments, and sensitivity to unique multidimensional issues improve care to LGBTQ patients with serious advanced illness. Nursing can reach this vulnerable minority and positively impact the quality of care. PMID- 27497023 TI - Palliative Wound Care for Malignant Fungating Wounds: Holistic Considerations at End-of-Life. AB - Timely, holistic interventions aimed at easing the despair of patients with advanced cancer and malignant fungating wounds (MFWs) must incorporate patient and family goals of care in all aspects of decision-making. People with MFWs suffer from a devastating and often crippling symptom burden including disfigurement, pain, pruritus, malodor, exudates, and bleeding. These symptoms may lead to psychosocial and/or spiritual distress, isolation, and diminished quality of life. The complexity of caring for hospice patients with MFWs requires a pragmatic and holistic interdisciplinary approach guided by specialist-level palliative wound care. This article introduces a framework to assist clinicians in the assessment and management of terminally ill patients with MFWs. PMID- 27497024 TI - The Difference Between Palliative Care and End of Life Care: More than Semantics. PMID- 27497025 TI - Palliative and End-of-Life Care: Compassion, Care, Commitment, Communication, Communion. PMID- 27497026 TI - Revisiting IL-6 antagonism in multiple myeloma. AB - IL-6, a cytokine with broad functions in inflammation and immunity, has been extensively studied for its role on normal antibody-producing plasma cells. In addition, IL-6 is recognized as a proliferative factor for multiple myeloma (MM), a malignant plasma cell tumor developing in the bone marrow. Blocking IL-6 signaling was thus developed into a therapeutic approach for MM already early after its discovery, in 1991. Unfortunately, the first clinical trials did not demonstrate a clear benefit, but despite this apparent failure hopes on IL-6 antagonism are still high and trials ongoing. The cellular source of IL-6 has long been a matter of debate. IL-6 was first recognized as an autocrine factor produced by the malignant plasma cells themselves, but later reports clearly showed that IL-6 was a paracrine factor, produced by the microenvironment, mostly by cells from the myeloid lineage. Recently, we have confirmed that IL-6 originates from myeloid lineage cells, mainly from myeloid precursors. We have also demonstrated that IL-6 amplifies the pool of myeloid cells producing a second key factor for MM, a proliferation inducing ligand (APRIL). These findings form a new rationale for IL-6 inhibition in MM and for new ways to use IL-6 blocking in the clinics. PMID- 27497027 TI - Zevalin((r)) (ibritumomab tiuxetan): After more than a decade of treatment experience, what have we learned? AB - Non-Hodgkin's lymphoma (NHL) comprises a clinically and biologically heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer (NK) cells. The disease course may range from indolent to aggressive. Zevalin((r)) (ibritumomab tiuxetan) is a radioactive drug product, which is the combination of a beta-emitting isotope, (90)Y, linked to the anti-CD20 monoclonal antibody (mAb), rituximab. It has demonstrated therapeutic efficacy with durable responses and allows delivery of ionizing radiation directly to the tumor site, while minimizing toxicity to normal tissue. Ibritumomab tiuxetan is indicated for treatment of patients with relapsed or refractory low-grade, follicular NHL, including patients who are refractory to rituximab, and as consolidation therapy in previously untreated follicular NHL in patients who achieve a partial or complete response to first line chemotherapy. Despite the efficacy and acceptable safety profile of ibritumomab tiuxetan, utilization has not been broadly adopted in practice due to a number of factors. This manuscript will review the literature available for ibritumomab tiuxetan, including several new trials that are currently being studied, and discuss the rationale for use of ibritumomab tiuxetan in NHL. PMID- 27497028 TI - Oxaliplatin-based chemotherapy combined with traditional medicines for neutropenia in colorectal cancer: A meta-analysis of the contributions of specific plants. AB - This review assessed the effects on chemotherapy induced neutropenia (CIN) of combining oxaliplatin regimens with traditional plant-based medicines (TMs) in the management of colorectal cancer (CRC). 32 RCTs (2224 participants) were included. Meta-analysis showed reduced incidence of grade 3/4 CIN (RR 0.45[0.31, 0.65], I(2)=0%). No studies reported serious adverse events or reduction in tumour response rates associated with concurrent use of oxaliplatin and TM. Due to small sample sizes and risk of bias, these results should be interpreted with caution. Analyses of sub-groups of studies that used similar TM interventions assessed the relative contributions of individual plant-based ingredients to the results. Astragalus, Codonopsis, Atractylodes, Poria and Coix, in various combinations were consistently associated with reduced CIN incidence when administered orally. Experimental studies of these plants have reported reduced myelosuppression and/or enhanced immune response. Further studies of these plants may lead to the development of interventions to supplement conventional CIN treatment. PMID- 27497029 TI - The Experiences of Professionals Regarding Involvement of Parents in Neonatal Pain Management. AB - OBJECTIVE: To explore the experiences of health care professionals related to parent involvement during painful procedures carried out on their infants and to describe contextual facilitators and barriers that influence parent involvement during evidence-based, nonpharmacologic pain relief. DESIGN: Qualitative study with focus group interviews. SETTING: Two Level III NICUs and one Level II NICU in the German-speaking part of Switzerland. PARTICIPANTS: Convenience sample of 17 NICU nurses and six neonatologists. METHODS: Three interprofessional focus group interviews were conducted. Data were analyzed by thematic analysis. RESULTS: Contextual factors among professionals, such as know-how and communication skills regarding neonatal pain management; reflective and collaborative practice; and an attitude of partnership with parents and organizational resources, such as time and staffing, promoted a working atmosphere in which it was possible to talk about neonatal pain with parents. Within this context, parents could be successfully involved in their infant's pain management. In contrast, lack of the aforementioned contextual factors, including an attitude of paternalism toward parents, resulted in a working atmosphere in which professionals "kept silent about pain" and hindered parent involvement during painful procedures. CONCLUSION: The work culture and organizational features of a NICU facilitate or hinder parent involvement in neonatal pain management. Facilitators and barriers should be identified from the individual, team, and system perspectives. Facilitation of parent-centered pain management in infants should be promoted by the organization. PMID- 27497030 TI - Effect of Parent Presence During Multidisciplinary Rounds on NICU-Related Parental Stress. AB - OBJECTIVE: To evaluate the effect of parent presence during multidisciplinary rounds on NICU-related parental stress. DESIGN: Quasi-experimental study. SETTING: University-affiliated, 24-bed NICU located within a children's hospital that admits infants from birth to 6 months of age. PARTICIPANTS: One hundred thirty-two parents of infants admitted to the NICU for the first time. METHODS: All parents completed the Parent Stressor Scale: NICU (PSS:NICU) on Study Days 0 and 3. In addition to usual family communication practices, parents in the experimental group were offered the opportunity to participate in multidisciplinary rounds on their infants. RESULTS: A total of 132 parents completed the study; the first 46 parents were enrolled in the control group, and the subsequent 86 parents in the experimental group. Overall PSS:NICU scores decreased significantly in the experimental group between Study Days 0 and 3 (mean +/- standard error [SE] = -0.24 +/- 0.07, p < .001), but the change was not significantly different between the control and experimental groups (mean +/- SE = -0.12 +/- 0.10, p = .25). The PSS:NICU Parental Role Alteration subscale decreased by the largest margin in the experimental group (mean +/- SE = -0.42 +/ 0.09, p < .0001), but the change was not significantly different between groups (mean +/- SE = -0.26 +/- 0.14, p = .06). Overall PSS:NICU stress scores were higher in mothers than fathers (mothers, mean +/- SE = 3.4 +/- 0.81; fathers, mean +/- SE = 2.7 +/- 0.67; p < .001). CONCLUSION: Providing parents with the opportunity to participate in multidisciplinary rounds did not affect NICU related parental stress. Mothers reported higher levels of stress than fathers. PMID- 27497031 TI - Impact of WRF model PBL schemes on air quality simulations over Catalonia, Spain. AB - Here we analyze the impact of four planetary boundary-layer (PBL) parametrization schemes from the Weather Research and Forecasting (WRF) numerical weather prediction model on simulations of meteorological variables and predicted pollutant concentrations from an air quality forecast system (AQFS). The current setup of the Spanish operational AQFS, CALIOPE, is composed of the WRF-ARW V3.5.1 meteorological model tied to the Yonsei University (YSU) PBL scheme, HERMES v2 emissions model, CMAQ V5.0.2 chemical transport model, and dust outputs from BSC DREAM8bv2. We test the performance of the YSU scheme against the Assymetric Convective Model Version 2 (ACM2), Mellor-Yamada-Janjic (MYJ), and Bougeault Lacarrere (BouLac) schemes. The one-day diagnostic case study is selected to represent the most frequent synoptic condition in the northeast Iberian Peninsula during spring 2015; regional recirculations. It is shown that the ACM2 PBL scheme performs well with daytime PBL height, as validated against estimates retrieved using a micro-pulse lidar system (mean bias=-0.11km). In turn, the BouLac scheme showed WRF-simulated air and dew point temperature closer to METAR surface meteorological observations. Results are more ambiguous when simulated pollutant concentrations from CMAQ are validated against network urban, suburban, and rural background stations. The ACM2 scheme showed the lowest mean bias (-0.96MUgm-3) with respect to surface ozone at urban stations, while the YSU scheme performed best with simulated nitrogen dioxide (-6.48MUgm-3). The poorest results were with simulated particulate matter, with similar results found with all schemes tested. PMID- 27497032 TI - The association between ambient temperature and out-of-hospital cardiac arrest in Guangzhou, China. AB - Out-of-hospital cardiac arrest (OHCA) is becoming a considerable public health burden worldwide. The seasonal variation of OHCA has been observed, but the potential effects of ambient temperature on OHCA were rarely investigated. We, therefore, aimed to evaluate the association between ambient temperature and OHCA in Guangzhou, China. We collected daily emergency ambulance dispatches for OHCA from the Guangzhou Emergency Center from January 1, 2008 to December 31, 2012. We analyzed the associations using the time-series method. We applied the generalized linear model combined with the distributed lag non-linear model to estimate the potentially non-linear and lagged effects of temperature on OHCA. Time trends, day of the week, and air pollutants were controlled as covariates. We identified a total of 4369 cases of OHCD. The associations between daily mean temperature and OHCA were generally J-shaped. Both low and high temperatures could increase the risk of OHCA. The effects were strongest on the concurrent day (lag 0) and lasted for 6 or 7days. The cumulative risks of extreme cold (1st percentile of temperature) and extreme heat (99th percentile of temperature) over lags 0-21days were 3.75 (95% confidence interval [CI]: 1.63, 8.63) and 2.45 (95%CI: 1.15, 5.33), respectively, compared with the referent temperature (28 degrees C).This study suggested that both cold and hot temperatures could significantly increase the risk of OHCA in Guangzhou, China. Our results might have important public health implications for the prevention of OHCA. PMID- 27497033 TI - Litter and nutrient flows in tropical upland forest flooded by a hydropower plant in the Amazonian basin. AB - Extensive areas in the Brazilian Amazon have been flooded for the construction of hydroelectric dams. However, the water regime of these areas affects the dynamics of igarapes (streams) in adjacent terra firme (upland forests). When the reservoirs are filled, the water levels of streams rise above the normal levels and upland bank forests are flooded. We investigated how this flooding affects the litterfall and nutrient input in the upland forests upstream of a hydroelectric dam reservoir in the Central Amazonia. When the reservoir was filled, the forests were flooded and produced more than twice the litter (8.80Mg.ha-1yr-1), with three times more leaves (6.36Mg.ha-1yr-1) than when they were not flooded (4.20 and 1.92Mg.ha-1yr-1, respectively). During flooding, the decomposition rate was four times lower in flooded forests (0.328g.g-1yr-1) than in control forests (1.460g.g-1yr-1). Despite this, the flooding did not favor litter or nutrient accumulation. Therefore, dam construction changes the organic matter and nutrient cycling in upland Amazon rainforests. This may influence the important role that they play in organic matter dynamics and could have consequences for the regional carbon balance and, ultimately, global climate. PMID- 27497034 TI - Sequestration and bioavailability of perfluoroalkyl acids (PFAAs) in soils: Implications for their underestimated risk. AB - Different from typical hydrophobic organic contaminants (HOCs), perfluoroalkyl acids (PFAAs) are more soluble in water and less partitioned to soil than the HOCs. It remains unclear whether and to what extent PFAAs could be sequestrated in soil. In this study, sequential extraction of PFAAs in soil and bioaccumulation of PFAAs in earthworm were carried out to understand the sequestration and bioavailability of PFAAs in soils with different soil organic matter (SOM) and aged for different time periods (7 and 47d). Sequestration occurred in different degrees depending on the amount and compositions of SOM in soil, structural properties of PFAAs and aging time. Surprisingly, in one peat soil with high fraction of organic carbon (foc, 59%), the PFAAs were completely sequestrated in the soil. Aging might lead to further sequestration of PFAAs in soil with relatively lower foc. As a consequence of sequestration, the bioavailability of PFAAs in peat soils was reduced 3-10 times compared to that in the plain farmland soil. However, the sequestrated PFAAs were still bioaccumulative in earthworms to some extent. The results indicated that the risk of PFAAs in field soil with high content of SOM could be underestimated if only free PFAAs using mild solvent extraction were monitored. PMID- 27497035 TI - Determination of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in Brazilian cow milk. AB - The determination of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in raw cow milks have never been reported in Brazil. Since the consumption of food of animal origin, including milk and dairy products, is the major source of human exposure to these compounds, this study aimed to establish the levels and profile of seven PCDDs and ten PCDFs in raw cow milk samples collected in eight Brazilian states which among the major milk producer states. Raw milk samples were collected in 34 different dairy cattle farms during the summer of 2013. All PCDD/Fs congeners were found at least in some of the 34 samples studied. The octa-chlorinated congeners (OCDD and OCDF) were ubiquitous and also present in high concentrations. The mean values of WHO TEQ1998;2005 were respectively 1.66 and 1.36pgTEQg-1 fat and samples taken in Sao Paulo showed the highest WHO-TEQ values (2.46 TEQ1998g-1 fat and 2.10pgTEQ2005g-1 fat). Although all samples showed some contamination level, all values were below the limit established by European Union for total PCDD/Fs in cow milk (3pgWHO TEQ1998g-1 fat). Principal Component Analysis (PCA) showed that OCDD and OCDF were responsible for 73% and 20% of the total data variance, respectively and they presented an independent behavior, probably as a result of distinct origins. The use of TEQ as weights in the PCA, revealed the importance of the penta-chloro congeners and it was possible to identify sample distribution patterns probably associated with the main PeCDD and PeCDF. The importance of local sources to PCDD/Fs concentrations is still to be evaluated and determined. PMID- 27497036 TI - The sooner the better: innate immunity as a path toward the HIV cure. AB - To combat the diverse pathogens that infect humans, the immune system has evolved complex and diverse transcriptional signatures, which drive differential cellular and humoral responses. These signatures are induced by immune receptor sensing of pathogens and by cytokines produced at the earliest onset of infection. The specific nature of immune activation is as critical to pathogen clearance as the induction of an adaptive immune response. This is particularly true for HIV, which has developed numerous immune evasion mechanisms. In this review, we will highlight recent findings that show the differential role for early innate immune responses in promoting infection versus clearance and demonstrate the need for continued research on these pathways for development of effective HIV treatments. PMID- 27497038 TI - Small bowel obstruction secondary to paravesical hernia. AB - BACKGROUND: Bowel obstruction in the setting of the unscarred abdomen can be due to a wide variety of causes. Internal hernias are a rare cause of bowel obstruction with paravesical hernia being exceedingly rare. Paravesical hernia should form part of the differential diagnosis in the patient presenting with bowel obstruction. Prompt management and reduction of the incarcerated bowel are essential. This will prevent further complications especially related to bowel ischemia. CASE SUMMARY: The patient presented with a classical history of small bowel obstruction. Abdominal X-ray revealed distended loops of small bowel and absence of air in the rectum. An exploratory laparotomy revealed a paravesical internal hernia. A loop of terminal ileum had incarcerated and was the cause of the bowel obstruction. The defect was repaired after reducing the bowel and the patient made an uneventful recovery. CONCLUSION: Internal paravesical hernia although extremely rare should form part of the differential diagnosis in the patient presenting with small bowel obstruction especially in the previously unscarred abdomen. If the obstruction is complete then prompt exploration via laparotomy or laparoscopy is required. Delays in definitive management may result in marginally viable bowel becoming ischemic and requiring bowel resection. PMID- 27497037 TI - Detection of bowel inflammation with fused DWI/T2 images versus contrast-enhanced images in pediatric MR enterography with histopathologic correlation. AB - PURPOSE: To evaluate the fused, colorized diffusion weighted imaging (DWI) and anatomic T2 images compared to routine contrast-enhanced T1 images at pediatric magnetic resonance enterography (MRE). METHODS: Fused, colorized DWI/T2 images were created from patients with magnetic resonance enterography (MRE) and colonoscopy/biopsy. Radiologists noted inflammation in five bowel segments (terminal ileum-rectosigmoid colon) on postcontrast images and DWI/T2 images. Test characteristics and agreement were calculated. RESULTS: For 20 patients, sensitivity/specificity/positive predictive value (PPV)/negative predictive value (NPV) were 0.53/0.90/0.77/0.76 for DWI/T2 and 0.45/0.90/0.72/0.73 for postcontrast images. Intraobserver agreement was ?=0.45-0.73. Interobserver agreement was ?=0.53 for DWI/T2 and ?=0.63 for postcontrast images. CONCLUSION: DWI/T2 images are similar in sensitivity/specificity to contrast-enhanced images and with moderate intra/interobserver reliability. PMID- 27497039 TI - Left subclavian-carotid bypass in a 38-year old female with brain ischemic symptoms secondary to Takayasu's arteritis: A case report. AB - INTRODUCTION: Takayasu's arteritis (TA) is a rare form of vasculitis that affects the aorta, its branches and pulmonary arteries. TA is primarily treated by pharmacologic therapy; however revascularization procedures may be required to treat organ ischemia. Evidence-based consensus regarding the indications for surgical or endovascular therapy for patients with supra-aortic vessels lesions remains unclear. PRESENTATION OF CASE: We herein present a female patient with known TA since 2000, who experienced progressive and frequent episodes of amaurosis fugax in the left eye for 4 months. Computed tomography angiography (CTA) revealed focal stenotic segments in the right common carotid artery (CCA) and internal carotid artery (ICA) and near occlusion of the proximal left CCA. We opted to treat the left side first with open revascularization, and a subclavian carotid bypass was performed using a 6 millimeters (mm) externally supported ePTFE graft. Patient recovered well from the surgery, her neurological exam was normal and she was discharged home in stable condition in postoperative day three. At three months she remains symptoms-free and her bypass is patent. DISCUSSION/CONCLUSION: This case illustrates the clinical presentation of TA affecting both carotid arteries; open revascularization via carotid subclavian bypass grafting was successfully performed with minimal morbidity, complete resolution of symptoms and improvement of the patient's quality of life. Revascularization procedures when indicated should be performed while the disease is inactive and close surveillance is mandatory. PMID- 27497040 TI - Emergency total proctocolectomy in an uninsured patient with Familial Adenomatous Polyposis Syndrome and acute lower gastrointestinal hemorrhage in a community hospital: A case report. AB - INTRODUCTION: Rectal bleeding is the most common symptom of Familial Adenomatous Polyposis (FAP). This case investigates the efficacy of emergency surgery for FAP with total proctocolectomy end ileostomy for recurrent lower gastrointestinal (GI) hemorrhage in an uninsured patient in a 266-bed community hospital. The optimal treatment for FAP with acute lower GI hemorrhage and hemodynamic compromise unresponsive to conservative management is unclear. PRESENTATION OF CASE: A 41-year-old uninsured African American man with no past medical or family history presented to the emergency department with hematochezia lasting three days. A clinical diagnosis of FAP made on colonoscopy with biopsies revealed villous and tubulovillous adenomas without dysplasia. After blood products resuscitation, an emergency total proctocolectomy with end ileostomy was performed. A staged ileal J pouch to anal anastomosis and creation of protective loop ileostomy was performed months later after securing state funding. A final loop ileostomy reversal occurred six weeks later. His self reported quality of life is improved. DISCUSSION: Lower GI hemorrhage from FAP unresponsive to blood products may require emergency total proctocolectomy and end ileostomy with a staged ileal J pouch to anal anastomosis, which can be done in a community acute care hospital for an uninsured patient. CONCLUSION: A total proctocolectomy is feasible in the emergency setting in an uninsured patient with lower GI bleeding and FAP. A staged ileal J pouch-anal anastomosis is easier to justify to the hospital compared to a staged completion colectomy with proctectomy. It is essential to monitor the ileo-anal anastomosis with anoscopy. PMID- 27497041 TI - Uncommon presentation of orbital schwanomma: A case report. AB - INTRODUCTION: Schwannomas are well-differentiated solitary benign tumors that originate from the schwann cells of the nerve sheath, constitute 1-8% of all head and neck tumors and 1-4% of the orbital tumors. SUMMARY OF THE CLINICAL CASE: A 57-year-old female patient visited our department, because she has a blindness of the right eye associated with an irreducible exophthalmia classified grade III, 4 years ago. Radiological exploration showed a mass in the orbital cone in relation to a probable optic nerve schwannoma confirmed by biopsy. The affected eye was exenterated because of delayed diagnosis. DISCUSSION AND CONCLUSION: In this review we discuss the pertinent clinical findings of this rare lesion and review the literature relative to optic nerve and solitary orbital schwannomas and insist that aggressive surgery with total mass removal should be warned by early diagnosis. PMID- 27497042 TI - Intraoperative ICG fluorescence contrast imaging of the main artery watershed area in colorectal cancer surgery: Report of a case. AB - INTRODUCTION: Visualization of the main artery watershed area may be useful for determining the area that should be resected in colorectal cancer surgery. Resection of the main artery watershed area may result in complete resection of lymph nodes along the main artery and area of potential ischemia. PRESENTATION OF CASE: A man in his 60s with a chief complaint of hematochezia visited our hospital, was diagnosed with colorectal cancer and underwent surgery. A case that underwent colorectal resection with intraoperative indocyanine green (ICG) fluorescence angiography from the resection-side of the superior rectal artery (SRA) in order to confirm the watershed area is reported. Observation was performed using a PINPOINT((r)) bright-field, color, near-infrared fluorescence camera, and the watershed area of the SRA fluoresced 33s after the intra-arterial injection of ICG. After observation resection and anastomosis was performed. The patient's postoperative course was good. DISCUSSION: The method is simple and can be performed within a short time, and it enables visual evaluation of the blood flow in the intestinal tract before anastomosis. CONCLUSION: This method can be expected to provide useful information for complete resection of lymph nodes along the main artery and area of potential ischemia. PMID- 27497043 TI - The use of endo-vascular balloon tamponade technique for the removal of a misplaced nephrostomy tube in the inferior vena cava: A case report. AB - INTRODUCTION: Inadvertent placement of a nephrostomy tube into the inferior vena cava (IVC) is an extremely rare complication with few reported cases in the literature. CASE PRESENTATION: We present a lady with obstructive uropathy in a solitary kidney in whom an attempt by the community radiologist to place a nephrostomy tube was complicated by wrong insertion into the IVC. This report illustrates how a safe non- surgical removal of this tube using an intravenous balloon tamponade technique was successfully applied. DISCUSSION: Intravenous placement of nephrostomy catheters into the inferior vena cava is extremely rare complication. A few case reports have been published in the literature. The majority of these cases were removed in the operating room under general anesthesia. Using Intravenous balloon tamponade technique for removal has not been previously reported. CONCLUSION: Intravenous balloon tamponade technique is effective and is a good minimally invasive alternative to surgical removal of misplaced nephrostomy tube from IVC. PMID- 27497045 TI - Postponed pregnancies and risks of very advanced maternal age. AB - QUESTIONS UNDER STUDY: To evaluate pregnancy outcome in pregnant women aged >=45 years, termed very advanced maternal age (VAMA). METHODS: We retrospectively compared the outcome of pregnancies in VAMA patients with controls aged 30 years at time of delivery. Subgroups of singleton and multiple pregnancies were also analysed. Incidences of maternal and fetal adverse outcomes were measured. Statistical significance was set at p <0.05. Odds ratios (ORs) were adjusted where necessary. RESULTS: One hundred and twenty-seven VAMA pregnancies and 2066 control pregnancies of women aged 30 years were analysed. VAMA pregnancies had a higher rate of maternal complications such as gestational hypertension (3.9% vs 0.6%; OR 6.5), preeclampsia (14.2% vs 3.0%; OR 5.4, adjusted OR 4.4) and gestational diabetes (12.6% vs 3.6%; OR 3.8). Likewise, increased need for blood transfusion (3.2% vs 0.7%; OR 4.8, adjusted OR 4.4) and prolonged hospitalisation >7 days (37.8% vs 15.1%; OR 3.42) was found. Infant complications such as prematurity (44.9% vs 16.2%; OR 4.2) and low birthweight <5th percentile (11.0% vs 5.6%; OR 2.1) were also increased. CONCLUSION: Pregnant women of very advanced maternal age (>=45 years) have significantly increased maternal and fetal risks. Women postponing pregnancy or planning a pregnancy in very advanced age should be informed about these risks, in particular before artificial reproductive technologies are applied or "social freezing". PMID- 27497044 TI - Influence of sympathetic activity in the control of peripheral microvascular tone in preterm infants. AB - BACKGROUND: Microvascular dysregulation following preterm birth is associated with increased illness severity and hypotension, particularly in males. Sympathetic nervous vascular regulation is evident in females. We hypothesized that sympathetic dysfunction in male preterm infants may contribute to a failure of peripheral microvascular vasoconstriction. METHODS: Microvascular blood flow of infants 24-43 wk gestational age was assessed at 6, 24, and 72 h of age by laser Doppler. Blood flow Fourier transformed frequency distribution spectra (low frequency/high frequency ratio) were used to assess the influence of sympathetic tone on microvascular regulation. Total sympathetic output was assessed as urinary normetanephrine. RESULTS: Microvascular sympathetic activity at 24 h postnatal age decreased in early preterm males, but not females. Peripheral sympathetic activity increased with advancing postnatal age in females, but decreased in males. In early preterm infants, total normetanephrine outputs increase significantly with postnatal age, in both sexes. CONCLUSION: Sympathetic activation following preterm birth is sexually dimorphic, with preterm males having reduced sympathetic tone and reduced upregulation of sympathetic tone following birth. There is evidence of a disconnect between central sympathetic activity and local peripheral microcirculatory sympathetic drive. This may relate to autonomic nervous immaturity and highlights the need to understand how preterm birth may affect autonomic function. PMID- 27497046 TI - Effects of stocking density on antioxidant status, metabolism and immune response in juvenile turbot (Scophthalmus maximus). AB - This study was designed to evaluate the physiological and immune responses of juvenile turbot to stocking density. Turbot (average weight 185.4g) were reared for 120days in a land based recirculating aquaculture system (RAS) under three stocking densities: low density (LD, ~9.3-26.1kg/m2, initial to final density), medium density (MD, ~13.6-38.2kg/m2) and high density (HD, ~19.1-52.3kg/m2). Fish were sampled at days 0, 40, 80 and 120 to obtain growth parameters and liver tissues. No significant difference was detected in growth, biochemical parameters and gene expression among the three densities until at the final sampling (day 120). At the end of this trial, fish reared in HD group showed lower specific growth rate (SGR) and mean weight than those reared in LD and MD groups. Similarly, oxidative stress and metabolism analyses represented that antioxidants (superoxide dismutase (SOD), catalase (CAT), glutathione (GSH)) and metabolic enzymes (glycerol-3-phosphate dehydrogenase (G3PDH) and glucose-6-phosphate dehydrogenase (G6PDH)) clearly reduced in the liver of turbot reared in HD group. The gene expression data showed that glutathione S-transferase (GST), cytochrome P450 1A (CYP1A), heat shock protein 70 (HSP 70) and metallothionein (MT) mRNA levels were significantly up-regulated, and lysozyme (LYS) and hepcidin (HAMP) mRNA levels were significantly down-regulated in HD group on day 120. Overall, our results indicate that overly high stocking density might block the activities of metabolic and antioxidant enzymes, and cause physiological stress and immunosuppression in turbot. PMID- 27497047 TI - Aquaporins and plant transpiration. AB - Although transpiration and aquaporins have long been identified as two key components influencing plant water status, it is only recently that their relations have been investigated in detail. The present review first examines the various facets of aquaporin function in stomatal guard cells and shows that it involves transport of water but also of other molecules such as carbon dioxide and hydrogen peroxide. At the whole plant level, changes in tissue hydraulics mediated by root and shoot aquaporins can indirectly impact plant transpiration. Recent studies also point to a feedback effect of transpiration on aquaporin function. These mechanisms may contribute to the difference between isohydric and anisohydric stomatal regulation of leaf water status. The contribution of aquaporins to transpiration control goes far beyond the issue of water transport during stomatal movements and involves emerging cellular and long-distance signalling mechanisms which ultimately act on plant growth. PMID- 27497048 TI - Allosteric communication pipelines in G-protein-coupled receptors. AB - The binding of ligands to G-protein-coupled receptors (GPCRs) in the extracellular region transmits the signal to the intracellular region to initiate coupling to effector proteins. The mechanism of this allosteric communication remains largely unexplored. Knowledge of the residues involved in the pipeline of the allosteric communication from the extracellular to the intracellular region will provide means to (a) design ligands with bias in potency towards one signaling pathway over others, and (b) design allosteric modulators that show subtype selectivity in GPCRs. In this review we describe the current state of the computational methods that provide insights into the allosteric communication in GPCRs and elucidate how this information can be used to design allosteric modulators. PMID- 27497049 TI - Validation of the laryngopharyngeal reflux color and texture recognition compared to pH-probe monitoring. AB - OBJECTIVE/HYPOTHESIS: The objective of this study was to determine the validity of our laryngopharyngeal reflux (LPR) diagnostic system from our previous study (Witt et al.) against the results of a standard pH probe monitoring. We hypothesized that subjects with abnormal pH probe results demonstrate color and texture abnormalities that would be classified as LPR according to artificial neural network (ANN) analysis. STUDY DESIGN: Retrospective analysis. METHODS: Eighty-two subjects, including 18 pH-positive, 11 pH-negative, and 53 control subjects were tested for LPR through multichannel intraluminal impedance 24-hour pH (MII-24pH) monitoring. Laryngoscopic images of all subjects were obtained. The hue and texture values of seven areas of interest, including true vocal folds, false vocal folds, arytenoids, and interarytenoid, were quantified using a hue calculation and two-dimensional Gabor filtering. These served as inputs for the ANN. This was used to classify images through pattern recognition, and a receiver operating characteristic (ROC) analysis was performed to determine the effectiveness of the diagnosis. RESULTS: Classification accuracy for the combined hue and texture was 87.40%, with an area under the ROC curve of 0.910. CONCLUSION: Although a previous study conducted classification based on RFS, this study suggests that color and texture analysis may be used to classify images based on the results of pH probing, a more objective approach for diagnosis. Additional studies should include more subjects to produce an even more accurate reading, and will use the color/texture analysis tool to test and confirm this application in a clinical setting. LEVEL OF EVIDENCE: 3B. Laryngoscope, 127:665 670, 2017. PMID- 27497050 TI - Ocean acidification has little effect on developmental thermal windows of echinoderms from Antarctica to the tropics. AB - As the ocean warms, thermal tolerance of developmental stages may be a key driver of changes in the geographical distributions and abundance of marine invertebrates. Additional stressors such as ocean acidification may influence developmental thermal windows and are therefore important considerations for predicting distributions of species under climate change scenarios. The effects of reduced seawater pH on the thermal windows of fertilization, embryology and larval morphology were examined using five echinoderm species: two polar (Sterechinus neumayeri and Odontaster validus), two temperate (Fellaster zelandiae and Patiriella regularis) and one tropical (Arachnoides placenta). Responses were examined across 12-13 temperatures ranging from -1.1 degrees C to 5.7 degrees C (S. neumayeri), -0.5 degrees C to 10.7 degrees C (O. validus), 5.8 degrees C to 27 degrees C (F. zelandiae), 6.0 degrees C to 27.1 degrees C (P. regularis) and 13.9 degrees C to 34.8 degrees C (A. placenta) under present day and near-future (2100+) ocean acidification conditions (-0.3 pH units) and for three important early developmental stages 1) fertilization, 2) embryo (prehatching) and 3) larval development. Thermal windows for fertilization were broad and were not influenced by a pH decrease. Embryological development was less thermotolerant. For O. validus, P. regularis and A. placenta, low pH reduced normal development, albeit with no effect on thermal windows. Larval development in all five species was affected by both temperature and pH; however, thermal tolerance was not reduced by pH. Results of this study suggest that in terms of fertilization and development, temperature will remain as the most important factor influencing species' latitudinal distributions as the ocean continues to warm and decrease in pH, and that there is little evidence of a synergistic effect of temperature and ocean acidification on the thermal control of species ranges. PMID- 27497051 TI - Cell division of Streptococcus pneumoniae: think positive! AB - Bacterial cell division is achieved by a dynamic protein complex called the divisome. The accurate placement of the divisome, and more specifically that of the tubulin-like protein FtsZ which forms the contractile Z-ring at mid-cell, is finely regulated by different mechanisms tailored to each bacterial class. To give rise to two viable daughter cells with the same genetic heritage and cell shape, Streptococcus pneumoniae uses an original system that relies on the membrane protein MapZ. This system is required for identifying the division site as well as positioning the Z-ring at mid-cell. In addition, MapZ undergoes phosphorylation by the serine/threonine kinase StkP and controls the constriction of the Z-ring. Here, we discuss recent advances and concepts of the MapZ system. PMID- 27497052 TI - The motility of Entamoeba histolytica: finding ways to understand intestinal amoebiasis. AB - The pathogenic amoeba Entamoeba histolytica is able to migrate within various compartments of the human body. The present article reviews progress in understanding the mechanisms of cell motility in E. histolytica during human intestinal invasion and, in particular, how the three-dimensional characteristics of the environment regulate the parasite's behaviour. The amoeboid mode of migration that applies to E. histolytica's displacements on two-dimensional surfaces is also expected to apply to the three-dimensional environment in the human intestine although several unknown, distinct modalities may be involved. Recent advances in the field of tissue engineering have provided clues on how the construction of a human colon model could help us to understand the host's intestinal physiology and its changes following amoebic infection. PMID- 27497054 TI - Do German drivers use their smartphones safely?-Not really! AB - Research in the laboratory as well as in naturalistic driving studies has shown that texting while driving seems to be the most dangerous driver distraction. However, there is still some discussion about the extent to which drivers adapt their behavior to the traffic situation. Accordingly, they might use their phones only in easy driving situations but refrain from doing so when driving becomes more demanding. For Germany, no reliable data on these topics could be found although overall smartphone use has also increased exponentially in this country. As observational studies have proven to be an effective means to gather these data, such a study was done observing 11,837 drivers in three big German cities (Braunschweig, Hannover, Berlin) during daytime. An alarmingly high rate of texting while driving was found (4.5%) as compared to other international studies. This was even more frequent than the use of handheld (2.2%) and hands free (1.7%) phones combined. Thus, there seems to be a special problem in Germany with texting which should be further examined as this activity is highly distracting. Finally, there was some indication that drivers adapt their secondary task activities to the requirements of the driving task (e.g. somewhat less texting when moving than when stationary at a red traffic light). However, these adaptations were not very strong. Thus, drivers seem to underestimate the dangers due to distraction. This could be a starting point for countermeasures which increase this awareness of danger. PMID- 27497053 TI - Biogenesis of the Gram-positive bacterial cell envelope. AB - The Gram-positive cell envelope serves as a molecular platform for surface display of capsular polysaccharides, wall teichoic acids (WTAs), lipoteichoic acids (LTAs), lipoproteins, surface proteins and pili. WTAs, LTAs, and sortase assembled pili are a few features that make the Gram-positive cell envelope distinct from the Gram-negative counterpart. Interestingly, a set of LytR-CpsA Psr family proteins, found in all Gram-positives but limited to a minority of Gram-negative organisms, plays divergent functions, while decorating the cell envelope with glycans. Furthermore, a phylum of Gram-positive bacteria, the actinobacteria, appear to employ oxidative protein folding as the major folding mechanism, typically occurring in an oxidizing environment of the Gram-negative periplasm. These distinctive features will be highlighted, along with recent findings in the cell envelope biogenesis. PMID- 27497055 TI - Identifying cognitive distraction using steering wheel reversal rates. AB - The influence of driver distraction on driving performance is not yet well understood, but it can have detrimental effects on road safety. In this study, we examined the effects of visual and non-visual distractions during driving, using a high-fidelity driving simulator. The visual task was presented either at an offset angle on an in-vehicle screen, or on the back of a moving lead vehicle. Similar to results from previous studies in this area, non-visual (cognitive) distraction resulted in improved lane keeping performance and increased gaze concentration towards the centre of the road, compared to baseline driving, and further examination of the steering control metrics indicated an increase in steering wheel reversal rates, steering wheel acceleration, and steering entropy. We show, for the first time, that when the visual task is presented centrally, drivers' lane deviation reduces (similar to non-visual distraction), whilst measures of steering control, overall, indicated more steering activity, compared to baseline. When using a visual task that required the diversion of gaze to an in-vehicle display, but without a manual element, lane keeping performance was similar to baseline driving. Steering wheel reversal rates were found to adequately tease apart the effects of non-visual distraction (increase of 0.5 degrees reversals) and visual distraction with offset gaze direction (increase of 2.5 degrees reversals). These findings are discussed in terms of steering control during different types of in-vehicle distraction, and the possible role of manual interference by distracting secondary tasks. PMID- 27497056 TI - In situ injection of phenylboronic acid based low molecular weight gels for efficient chemotherapy. AB - Injectable low molecular weight gels (LMWGs) based on the derivatives of phenylboronic acid were prepared and used as substrates for efficient in situ chemotherapy. The gelators as well as LMWGs were characterized by (1)H NMR, UV vis, FTIR, MS and SEM. Anticancer drug doxorubicin hydrochloride (DOX) was encapsulated in the gels. The rheological properties and rapid recovery capability of both blank and drug-loaded gels were tested. The LMWGs were non toxic to both 3T3 fibroblasts and 4T1 breast cancer cells. The gels were formed rapidly after injected in vivo. The in vivo anticancer activities of DOX-loaded LMWGs were investigated in breast cancer bearing mice. The intratumoral injection of DOX loaded LMWGs with dose of 30 mg/kg revealed that the gels could coat around the tumor tissues to release DOX sustainingly and maintain effective DOX concentration for chemotherapy. The systemic toxicity of DOX was reduced significantly with the in situ administration of LMWGs formulations. The injectable LMWGs exhibited excellent therapeutic efficacy and low side effects in local chemotherapy. PMID- 27497057 TI - Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy. AB - The cancer stem cell (CSC) hypothesis postulates that cancer cells overexpressing CD44 are marked as CSCs that cause tumorigenesis and recurrence. This hypothesis suggests that CD44 is a potential therapeutic target that can interfere with CSCs qualities. MicroRNA-34a (miR-34a) is a promising candidate for CD44 repression based cancer therapy as it has been reported to inhibit proliferation, metastasis, and survival of CD44-positive CSCs. Here, we used nanovesicles containing PLI/miR complexes (NVs/miR) to systemically deliver miR-34a and induce miR-34a-triggered CD44 suppression in orthotopically and subcutaneously implanted tumors in nude mice. Poly(l-lysine-graft-imidazole) (PLI) condenses miRs and is functionally modified to deliver miRs to the site of action by buffering effect of imidazole residues under endosomal pH. Indeed, NVs/miR consisting of PEGylated lipids enveloping PLI/miR complexes greatly reduced inevitable toxicity of polycations by compensating their surface charge and markedly improved their in vivo stability and accumulation to tumor tissue compared to PLI/miR polyplexes. Our NVs-mediated miR-34a delivery system specifically increased endogenous target miR levels, thereby attenuating proliferation and migration of gastric cancer cells by repressing the expression of CD44 with decreased levels of Bcl-2, Oct 3/4 and Nanog genes. Our strategy led to a greater therapeutic outcome than PLI based delivery with highly selective tumor cell death and significantly delayed tumor growth in CD44-positive tumor-bearing mouse models, thus providing a fundamental therapeutic window for CSCs. PMID- 27497058 TI - Valve interstitial cell tensional homeostasis directs calcification and extracellular matrix remodeling processes via RhoA signaling. AB - AIMS: Valve interstitial cells are active and aggressive players in aortic valve calcification, but their dynamic mediation of mechanically-induced calcific remodeling is not well understood. The goal of this study was to elucidate the feedback loop between valve interstitial cell and calcification mechanics using a novel three-dimensional culture system that allows investigation of the active interplay between cells, disease, and the mechanical valve environment. METHODS & RESULTS: We designed and characterized a novel bioreactor system for quantifying aortic valve interstitial cell contractility in 3-D hydrogels in control and osteogenic conditions over 14 days. Interstitial cells demonstrated a marked ability to exert contractile force on their environment and to align collagen fibers with the direction of tension. Osteogenic environment disrupted interstitial cell contractility and led to disorganization of the collagen matrix, concurrent with increased alphaSMA, TGF-beta, Runx2 and calcific nodule formation. Interestingly, RhoA was also increased in osteogenic condition, pointing to an aberrant hyperactivation of valve interstitial cells mechanical activity in disease. This was confirmed by inhibition of RhoA experiments. Inhibition of RhoA concurrent with osteogenic treatment reduced pro-osteogenic signaling and calcific nodule formation. Time-course correlation analysis indicated a significant correlation between interstitial cell remodeling of collagen fibers and calcification events. CONCLUSIONS: Interstitial cell contractility mediates internal stress state and organization of the aortic valve extracellular matrix. Osteogenesis disrupts interstitial cell mechanical phenotype and drives disorganization, nodule formation, and pro-calcific signaling via a RhoA-dependent mechanism. PMID- 27497059 TI - Miltefosine-loaded lipid nanoparticles: Improving miltefosine stability and reducing its hemolytic potential toward erythtocytes and its cytotoxic effect on macrophages. AB - The toxic effects of miltefosine on the epithelial cells of the gastrointestinal tract and its hemolytic action on erythrocytes have limited its use as an antileishmanial agent. As part of our search for new strategies to overcome the side effects of miltefosine during the treatment of leishmaniasis, we have developed stable miltefosine-loaded lipid nanoparticles in an attempt to reduce the toxic effects of the drug. We have evaluated lipid nanoparticles containing varying amounts of miltefosine and cholesterol, prepared by sonication, in terms of their physicochemical properties, preliminary stability, hemolytic potential toward erythrocytes, and cytotoxicity to macrophages and to promastigote and amastigote forms of Leishmania (L.) chagasi. Miltefosine loading into lipid nanoparticles was 100% for low drug concentrations (7.0 to 20.0mg/mL). Particle size decreased from 143nm (control) to between 43 and 69nm. From fluorescence studies, it was observed that the presence of miltefosine and cholesterol (below 103MUM) promoted ordering effects in the phospholipid region of the nanoparticles. The formulation containing 15mg/mL miltefosine was stable for at least six months at 4 degrees C and in simulated gastrointestinal fluids, and did not promote epithelial gastrointestinal irritability in Balb/C mice. When loaded into lipid nanoparticles, the hemolytic potential of miltefosine and its cytotoxicity to macrophages diminished, while its antiparasitic activity remained unaltered. The results suggested that miltefosine-loaded lipid nanoparticles may be promising for the treatment of leishmaniasis and might be suitable for oral and parenteral use. PMID- 27497060 TI - Macroscopic amyloid fiber formation by staphylococcal biofilm associated SuhB protein. AB - Staphylococcus aureus is a commensal and opportunistic pathogen that causes lethal infections. Biofilm forming ability of S. aureus enhances its virulence since biofilm provides the bacteria protective shield against antibiotics and host immunity. Polysaccharide independent biofilm formation by several virulent S. aureus strains have been identified recently, where protein components substitute polysaccharide intercellular adhesin (PIA) involved in bacterial cell attachment. The suhB gene has been reported to be essential in staphylococcal PIA independent biofilm formation. Overexpression of staphylococcal SuhB (SasuhB) in E. coli produces extracellular macroscopic fibers made of recombinant SaSuhB protein. The amyloidic nature of the fiber is evaluated by high resolution electron microscopy, X-ray fiber diffraction and amyloid specific dyes, such as Congo red and thioflavin-T binding assay. The fibers appear to be sticky in nature and bind a large number of bacterial cells. The results suggest the possible role of SaSuhB-fibers as a structural component as well as an adhesin in biofilm matrix. PMID- 27497061 TI - Quantum dynamics of a hole migration through DNA: A single strand DNA model. AB - A model predicting the behavior of a hole acting on the DNA strand was investigated. The hole-DNA interaction on the basis of a quantum-classical, non linear DNA single strand model was described. The fact that a DNA molecule is formed by a furanose ring as its sugar, phosphate group and bases was taken into consideration. Based on the model, results were obtained for the probability of a hole location on the DNA base sequences, such as GTTGGG, GATGTGGG, GTTGTTGGG as well as on the sugar-phosphate groups mated with them. PMID- 27497062 TI - Habituation of self-reported anxiety and cortical hyper-vigilance during image based exposure to spiders. AB - BACKGROUND AND OBJECTIVES: The aim of the study was to examine habituation of subjective anxiety and electrophysiological correlates of cortical hyper vigilance during exposure to spider images among high (n = 12) and low (n = 11) spider fear groups. METHODS: Participants viewed a six-stage hierarchy of spider images. The images used at stage 1 and stage 6 were the same. Subjective anxiety was rated at four intervals during each three-minute exposure stage (0, 60, 120, and 180 s) and event-related potentials (ERPs) were averaged across these epochs (0-60, 60-120, 120-180). RESULTS: High spider fearfuls demonstrated greater habituation of self-reported anxiety within and between exposure stages compared to low fearfuls. Consistent with attentional hyper-vigilance, the high-fear group also demonstrated greater P1 amplitude in response to spider images. In both groups, habituation of P1 amplitude was found at later relative to earlier stages, but increased at stage six when the stage 1 image was re-presented, despite low subjective anxiety. LIMITATIONS: While the passive viewing paradigm mirrored image-based exposure, it was not possible to determine whether participants engaged in avoidance strategies. In addition, further research is needed to assess the relevance of habituation and reinstatement of P1 amplitude to therapeutic outcome. CONCLUSIONS: Habituation of subjective anxiety during image-based exposure is not necessarily accompanied by a reduction in measures of cortical hyper-vigilance. The reinstatement of the P1 response may indicate either re-activation of previous associations, less avoidance, or a more generalised dishabituation mechanism. PMID- 27497063 TI - Bone turnover markers and bone mineral density in healthy mother-daughter pairs from South India. AB - : Bone turnover markers (BTMs) provide important insights into the dynamics of bone remodelling and are subjected to preanalytical and ethnic variations in addition to influence of genetic and environmental factors. AIM/OBJECTIVES: To derive ethnicity specific reference range for BTMs and to study their correlation with Bone Mineral Density (BMD) in a cohort of healthy postmenopausal women and their premenopausal daughters and to look at the impact of maternal bone mineral status on daughters bone health. MATERIAL AND METHODS: This community based cross sectional study included 300 subjects (150 mother-daughter pairs). Demographic details were collected. Fasting blood and a second void morning urine samples were obtained for measurement of BTMs (sCTX, sPTNP1, sOC and urine DPD respectively) and bone mineral parameters. BMD was measured by DXA scan. RESULTS: Osteoporosis was seen in 44.7% of the postmenopausal women. Ethnicity specific reference ranges of BTMs were derived for the study population. Significant inverse correlation was found between all BTMs (except urine DPD) and BMD(P < 0.05). Daughters of mothers with osteoporosis at spine and femoral neck had lower BMD, compared to daughters of mothers without osteoporosis(P = 0.03 & 0.05). CONCLUSION: Apart from deriving the ethnicity specific reference range for BTMs and finding a significant inverse correlation between BTM and BMD, this study found significantly lower BMD in daughters of mothers with osteoporosis at spine and femoral neck implicating the probable interplay of genetic, epigenetic and similar environmental factors. PMID- 27497064 TI - A potential contribution of the less negatively charged cell wall to the high aluminum tolerance of Rhodotorula taiwanensis RS1. AB - Rhodotorula taiwanensis RS1 (Rt) is a high-aluminum (Al)-tolerant yeast that can survive Al at concentrations up to 200 mM. In this study, we compared Rt with an Al-sensitive congeneric strain, R. mucilaginosa AKU 4812 (Rm) and Al sensitive mutant 1 (alsm1) of Rt, to explore the Al tolerance mechanisms of Rt. The growth of Rm was completely inhibited by 1 mM Al, but that of Rt was not inhibited until Al concentration was more than 70 mM. The growth of alsm1 was inhibited much more by 70 mM and 100 mM Al than that of Rt. Compared with Rm cells, Rt cells accumulated less Al in the cell wall and cytoplasm. A time-course analysis showed that Al was absorbed by Rm cells much more rapidly than by Rt cells when exposed to the same Al concentration. Meanwhile, the Al content of alsm1 was higher than that of Rt. Although the cell wall of Rt was thicker than that of alsm1 and Rm under control and 0.1 mM Al, that of Rt was thinner than that of alsm1 under 70 mM Al despite that their cell walls were thickened. The alcian blue adsorption was lower and cell wall zeta-potential was higher in Rt and alsm1 than in Rm, indicating a less negative charge of cell wall of Rt and alsm1 than that of Rm. Taken together, the less negatively charged cell wall of Rt may restrict the adsorption of cationic Al in cells, potentially contributing to its high Al tolerance. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27497065 TI - Impaired cerebral blood flow networks in temporal lobe epilepsy with hippocampal sclerosis: A graph theoretical approach. AB - Graph theory is an emerging method to investigate brain networks. Altered cerebral blood flow (CBF) has frequently been reported in temporal lobe epilepsy (TLE), but graph theoretical findings of CBF are poorly understood. Here, we explored graph theoretical networks of CBF in TLE using arterial spin labeling imaging. We recruited patients with TLE and unilateral hippocampal sclerosis (HS) (19 patients with left TLE, and 21 with right TLE) and 20 gender- and age-matched healthy control subjects. We obtained all participants' CBF maps using pseudo continuous arterial spin labeling and analyzed them using the Graph Analysis Toolbox (GAT) software program. As a result, compared to the controls, the patients with left TLE showed a significantly low clustering coefficient (p=0.024), local efficiency (p=0.001), global efficiency (p=0.010), and high transitivity (p=0.015), whereas the patients with right TLE showed significantly high assortativity (p=0.046) and transitivity (p=0.011). The group with right TLE also had high characteristic path length values (p=0.085), low global efficiency (p=0.078), and low resilience to targeted attack (p=0.101) at a trend level. Lower normalized clustering coefficient (p=0.081) in the left TLE and higher normalized characteristic path length (p=0.089) in the right TLE were found also at a trend level. Both the patients with left and right TLE showed significantly decreased clustering in similar areas, i.e., the cingulate gyri, precuneus, and occipital lobe. Our findings revealed differing left-right network metrics in which an inefficient CBF network in left TLE and vulnerability to irritation in right TLE are suggested. The left-right common finding of regional decreased clustering might reflect impaired default-mode networks in TLE. PMID- 27497066 TI - In vivo and in vitro disease modeling with CRISPR/Cas9. AB - In the past few years, extensive progress has been made in the development of genome-editing technology. Among several genome-editing tools, the clustered regularly interspaced short palindrome repeat-associated Cas9 nuclease (CRISPR/Cas9) system is particularly widely used owing to the ease of sequence specific nuclease construction and the highly efficient introduction of mutations. The CRISPR/Cas9 system was originally constructed to induce small insertion and deletion mutations, but various methods have been developed to introduce point mutations, deletions, insertions, chromosomal translocations and so on. These methods should be useful for the reconstruction of disease-causing mutations in cultured cell lines and living organisms to elucidate disease pathogenesis and for disease prevention, treatment and drug discovery. This review summarizes the current technical aspects of the CRISPR/Cas9 system for disease modeling in cultured cells and living organisms, mainly mice. PMID- 27497067 TI - Supervised learning events: direct observation of procedural skills pilot. AB - BACKGROUND: Workplace-based assessment (WBA) is the assessment of specialist competence based on what a trainee doctor actually does in the workplace. Between January 2014 and January 2015, all UK occupational medicine (OM) trainees were invited to test a suite of direct observation of procedural skills (DOPS) tools designed in a supervised learning event (SLE) format. The Faculty of Occupational Medicine (FOM) Workplace-Based Assessment Advisory Group (WBAAG) studied feedback on the new format. AIMS: To assess the utility of the redesigned tools, including their acceptability, feasibility, usability and key aspects of their reliability and validity. METHODS: The face and content validity of the new forms were assessed by a comprehension trial (CT), inter-rater reliability by a video scoring exercise and usability and acceptability by an electronic survey of trainees and trainers. RESULTS: The CT of trainees and trainers indicated that the face and content validity of the revised tools were acceptable. Inter-rater reliability video assessments indicated there was consistency of grading among trainers. Sixty-eight per cent of trainees and 95% of trainers agreed that the redesigned tools were an improvement on the current WBA DOPS tools and 83% of trainees indicated the new tools encouraged them to reflect on their performance. CONCLUSIONS: The results from this pilot study provided evidence to support a request to the General Medical Council (GMC) for the new SLE-DOPS forms to be used for WBA in OM. These changes were accepted by the GMC in January 2016 for implementation in April 2016. PMID- 27497068 TI - Effect of Clinical Pharmacist Intervention on Hemoglobin A1C Reduction in Veteran Patients With Type 2 Diabetes in a Rural Setting. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM), if left uncontrolled, is associated with significant morbidity and mortality. Patients in rural areas may not have access to adequate resources to successfully treat diabetes. Clinical pharmacists may be utilized to bridge this gap. OBJECTIVE: To evaluate the impact of a clinical pharmacist on glycemic control in veterans with T2DM enrolled in a rural, outpatient clinic. METHODS: Retrospective chart review was performed on veterans with T2DM referred to the pharmacist-managed therapeutic monitoring clinic at a community-based outpatient clinic located in rural Jackson, TN. Patients served as their own controls. Patients with hemoglobin A1C (A1C) >=8% were included. The primary outcome was A1C change from baseline in patients managed by the clinical pharmacist. Secondary end points included blood pressure, cholesterol, and weight. RESULTS: Of 111 veterans identified as having a A1C >=8% in the pharmacist-managed clinic, 86 met inclusion criteria. At baseline, mean +/ SD A1C was 10.5% +/- 2.0% (range = 8.7%-16.2%). By the end of the intervention period, mean A1C had decreased by 2.8 percentage points to 7.7% +/- 1.4% (P < 0.001). At the end of the intervention, 34% (n = 29) had a A1C of <7%, 40% (n = 34) between 7% and 7.9%, and only 6% (n = 5) >10% (P < 0.001). Improvements in diastolic blood pressure (P = 0.001), total cholesterol (P = 0.001), and triglyceride levels (P = 0.036) were also statistically significant when baseline and intervention period values were compared. CONCLUSION: Pharmacist interventions at a rural, outpatient clinic had a statistically significant impact on A1C reduction in veterans with T2DM. PMID- 27497069 TI - Ramsay Hunt syndrome. PMID- 27497071 TI - Pediatric salivary gland carcinomas: Diagnostic and therapeutic management. AB - OBJECTIVES/HYPOTHESIS: To analyze clinical presentations, treatment modalities, and evolution of pediatric cases of salivary gland carcinomas to standardize care for these rare diseases. STUDY DESIGN: Multicentric, retrospective study. METHODS: We included in this retrospective study all children and adolescents (aged <=18 years) treated from 1992 to 2012 in six pediatric centers in Paris, France. Pathological tumor specimens of these cases were reviewed. RESULTS: Forty three children were included (sex ratio male/female = 19/24, median age = 13 years). The parotid gland was the most common (37 cases) location for tumors. Histological subtypes were mucoepidermoid carcinomas (n = 20), acinic cell carcinomas (n = 14), and other (n = 9). Initial fine-needle aspiration was performed in 15 cases (33%), and was concordant to final diagnosis in three cases (20%). Primary surgery was performed in 42 patients, leading to a complete microscopic resection in 80%. Associated lymph node dissection was performed in 28 patients (homolateral: 27, bilateral: 1) and showed lymph node metastases in only two patients. One patient had distant metastases. Adjuvant irradiation was delivered to 11 patients (median: 60 Gy; range: 50-65) and chemotherapy in five cases. After a median follow-up of 5 years, six tumors relapsed, but no deaths occurred. CONCLUSIONS: Childhood salivary gland carcinomas have a good prognosis despite possible recurrences. Treatment is mainly based on surgery, with simultaneous node dissection in cases of clinical or radiologic node enlargement. Radiation therapy seems to be restricted to inoperable high-grade tumors or after recurrence. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:140-147, 2017. PMID- 27497072 TI - Large scale deep learning for computer aided detection of mammographic lesions. AB - Recent advances in machine learning yielded new techniques to train deep neural networks, which resulted in highly successful applications in many pattern recognition tasks such as object detection and speech recognition. In this paper we provide a head-to-head comparison between a state-of-the art in mammography CAD system, relying on a manually designed feature set and a Convolutional Neural Network (CNN), aiming for a system that can ultimately read mammograms independently. Both systems are trained on a large data set of around 45,000 images and results show the CNN outperforms the traditional CAD system at low sensitivity and performs comparable at high sensitivity. We subsequently investigate to what extent features such as location and patient information and commonly used manual features can still complement the network and see improvements at high specificity over the CNN especially with location and context features, which contain information not available to the CNN. Additionally, a reader study was performed, where the network was compared to certified screening radiologists on a patch level and we found no significant difference between the network and the readers. PMID- 27497070 TI - Association of genetic polymorphisms with survival of pancreatic ductal adenocarcinoma patients. AB - Germline genetic variability might contribute, at least partially, to the survival of pancreatic ductal adenocarcinoma (PDAC) patients. Two recently performed genome-wide association studies (GWAS) on PDAC overall survival (OS) suggested (P < 10(-5)) the association between 30 genomic regions and PDAC OS. With the aim to highlight the true associations within these regions, we analyzed 44 single-nucleotide polymorphisms (SNPs) in the 30 candidate regions in 1722 PDAC patients within the PANcreatic Disease ReseArch (PANDoRA) consortium. We observed statistically significant associations for five of the selected regions. One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in the previous GWAS. In silico analysis strongly suggested a possible mechanistic link between these two SNPs and pancreatic cancer survival. Functional studies are warranted to confirm the link between these genes (or other genes mapping in those regions) and PDAC prognosis in order to understand whether these variants may have the potential to impact treatment decisions and design of clinical trials. PMID- 27497073 TI - RGD(Arg-Gly-Asp) internalized docetaxel-loaded pH sensitive liposomes: Preparation, characterization and antitumor efficacy in vivo and in vitro. AB - The goal of this research was to formulate dual-targeting liposomes (RGD/DTX-PSL) that can selectively release loaded contents in a low pH level environment and to actively target to the tumor using liposomes that had surface arginine-glycine aspartic (RGD) tripeptides. We investigated whether RGD/DTX-PSL could serve as an effective tumor-targeted nanoparticle that is capable of suppressing tumor growth. The results suggest that DTX is released from liposomes faster at pH 5.0 than pH 7.4, demonstrating their pH sensitivity. RGD/DTX-PSL has a longer blood circulation than Duopafei((r)) in rats. The RGD/DTX-PSL formulation displayed stronger antiproliferative effects than DTX alone and the strongest inhibition of tumor growth of the formulations tested, thus expanding therapeutic window of DTX. In conclusion, we established a novel, promising and easy-to-handle liposome formulation that has a considerable antitumor activity in vitro and in vivo. This study provides important prerequisite for the clinical application of dual targeting liposomes in delivering therapies. PMID- 27497074 TI - Comparative analysis of new peptide conjugates of antitubercular drug candidates Model membrane and in vitro studies. AB - Novel peptide conjugates of two antitubercular drug candidates were synthesised and characterised using new tuftsin peptide derivative (OT14) as carrier moiety. As antitubercular drug candidates two pyridopyrimidine derivatives, TB803 (2 allylamino-4-oxopyrido[1,2-a]pyrimidine-3-carbaldehyde) and TB820 (4-oxo-2 (pyrrolidin-1-yl)-pyrido[1,2-a]pyrimidin-3-carbaldehyde) inhibiting vital enzyme of Mycobacterium tuberculosis were applied. Membrane affinity of the compounds TB803 and TB820 and their peptide conjugates was evaluated using experimental lipid mono- and bilayer models. Penetration ability was assessed tensiometrically from Langmuir monolayer study and applying quartz crystal microbalance for the supported lipid bilayer (SLB) system. Minimal inhibitory concentration (MIC) values remained in a similar micromolar range for both of the conjugates while their cellular uptake rate was improved significantly compared to the drug candidates. A correlation was found between membrane affinity properties and results of in vitro biological investigations. Analysis of physical/structural properties of SLB in contact with bioactive components and visualization of the structural change by atomic-force microscopy (AFM) provided information on the type and route of molecular interaction of drug construction with lipid layers. The possible role of electrostatic interactions between lipid layer and drug candidates was tested in Langmuir-balance experiments using negatively charged lipid mixture (DPPC+DPPG). Especially the peptide conjugates presented increased membrane affinity due to cationic character of the peptide sequence selected for the conjugate formation. That is supposed to be one reason for the enhanced cellular uptake observed in vitro on MonoMac6 cell line. The conjugation of antitubercular agents to a peptidic carrier is a promising approach to enhance membrane affinity, cellular uptake rate and in vitro selectivity. PMID- 27497075 TI - Tuning self-assembled morphology of the Abeta(16-22) peptide by substitution of phenylalanine residues. AB - The effects of the two phenylalanine (Phe) residues in the blocked Abeta(16-22) peptide on its self-assembly have been investigated by replacing both of them with two cyclohexylalanines (Chas) or two phenylglycines (Phgs). TEM and SANS studies revealed that the flat and wide nanoribbons of Abeta(16-22) were transformed into thin nanotubes when replaced with Chas, and thinner and twisted nanofibrils when replaced with Phgs. The red-shifting degree of characteristic CD peaks suggested an increased twisting in the self-assembly of the derivative peptides, especially in the case of Ac-KLV(Phg)(Phg)AE-NH2. Furthermore, molecular dynamics (MD) simulations also indicated the increasing trend in twisting when Chas or Phgs were substituted for Phes. These results demonstrated that the hydrophobic interactions and spatial conformation between Cha residues were sufficient to cause lateral association of beta-sheets to twisted/helical nanoribbons, which finally developed into nanotubes, while for Phg residue, the loss of the rotational freedom of the aromatic ring induced much stronger steric hindrance for the lateral stacking of Ac-KLV(Phg)(Phg)AE-NH2 beta-sheets, eventually leading to the nanofibril formation. This study thus demonstrates that both the aromatic structure and the steric conformation of Phe residues are crucial in Abeta(16-22) self-assembly, especially in the significant lateral association of beta-sheets. PMID- 27497076 TI - RGD-TPGS decorated theranostic liposomes for brain targeted delivery. AB - The aim of this work was to formulate RGD-TPGS decorated theranostic liposomes, which contain both docetaxel (DTX) and quantum dots (QDs) for brain cancer imaging and therapy. RGD conjugated TPGS (RGD-TPGS) was synthesized and conjugation was confirmed by Fourier transform infrared (FTIR) spectroscopy and electrospray ionisation (ESI) mass spectroscopy (ESI-MS). The theranostic liposomes were prepared by the solvent injection method and characterized for their particle size, polydispersity, zeta-potential, surface morphology, drug encapsulation efficiency, and in-vitro release study. Biocompatibility and safety of theranostic liposomes were studied by reactive oxygen species (ROS) generation study and histopathology of brain. In-vivo study was performed for determination of brain theranostic effects in comparison with marketed formulation (DocelTM) and free QDs. The particle sizes of the non-targeted and targeted theranostic liposomes were found in between 100 and 200nm. About 70% of drug encapsulation efficiency was achieved with liposomes. The drug release from RGD-TPGS decorated liposomes was sustained for more than 72h with 80% of drug release. The in-vivo results demonstrated that RGD-TPGS decorated theranostic liposomes were 6.47- and 6.98-fold more effective than DocelTM after 2h and 4h treatments, respectively. Further, RGD-TPGS decorated theranostic liposomes has reduced ROS generation effectively, and did not show any signs of brain damage or edema in brain histopathology. The results of this study have indicated that RGD-TPGS decorated theranostic liposomes are promising carrier for brain theranostics. PMID- 27497077 TI - A microwave resonator integrated on a polymer microfluidic chip. AB - We describe a novel stacked split-ring type microwave (MW) resonator that is integrated into a 10mm by 10mm sized microfluidic chip. A straightforward and scalable batch fabrication process renders the chip suitable for single-use applications. The resonator volume can be conveniently loaded with liquid sample via microfluidic channels patterned into the mid layer of the chip. The proposed MW resonator offers an alternative solution for compact in-field measurements, such as low-field magnetic resonance (MR) experiments requiring convenient sample exchange. A microstrip line was used to inductively couple MWs into the resonator. We characterised the proposed resonator topology by electromagnetic (EM) field simulations, a field perturbation method, as well as by return loss measurements. Electron paramagnetic resonance (EPR) spectra at X-band frequencies were recorded, revealing an electron-spin sensitivity of 3.7.10(11)spins.Hz( 1/2)G(-1) for a single EPR transition. Preliminary time-resolved EPR experiments on light-induced triplet states in pentacene were performed to estimate the MW conversion efficiency of the resonator. PMID- 27497078 TI - Interactive effects of herbicide and enhanced UV-B on growth, oxidative damage and the ascorbate-glutathione cycle in two Azolla species. AB - A field experiment was conducted to investigate the impact of alone and combined exposures of herbicide pretilachlor (5, 10 and 20MUgml(-1)) and enhanced UV-B radiation (UV-B1; ambient +2.2kJm(-2) day(-1) and UV-B2; ambient +4.4kJm(-2) day( 1)) on growth, oxidative stress and the ascorbate-glutathione (AsA-GSH) cycle in two agronomically important Azolla spp. viz., Azolla microphylla and Azolla pinnata. Decreased relative growth rate (RGR) in both the species under tested stress could be linked to enhanced oxidative stress, thus higher H2O2 accumulation was observed, that in turn might have caused severe damage to lipids and proteins, thereby decreasing membrane stability. The effects were exacerbated when spp. were exposed to combined treatments of enhanced UV-B and pretilachlor. Detoxification of H2O2 is regulated by enzymes/metabolites of AsA-GSH cycle such as ascorbate peroxidase (APX) and glutathione reductase (GR) activity that were found to be stimulated. While, dehydroascorabte reductase (DHAR) activity, and the amount of metabolites: ascorbate (AsA), glutathione (GSH) and ratios of reduced/oxidized AsA (AsA/DHA) and GSH (GSH/GSSG), showed significant reduction with increasing doses of both the stressors, either applied alone or in combination. Glutathione-S-transferase (GST), an enzyme involved in scavenging of xenobiotics, was found to be stimulated under the tested stress. This study suggests that decline in DHAR activity and in AsA/DHA ratio might have led to enhanced H2O2 accumulation, thus decreased RGR was noticed under tested stress in both the species and the effect was more pronounced in A. pinnata. Owing to better performance of AsA-GSH cycle in A. microphylla, this study substantiates the view that A. microphylla is more tolerant than A. pinnata. PMID- 27497079 TI - Selenate mitigates arsenite toxicity in rice (Oryza sativa L.) by reducing arsenic uptake and ameliorates amino acid content and thiol metabolism. AB - Arsenic (As) is a toxic element with the potential to cause health effects in humans. Besides rice is a source of both amino acids (AAs) and mineral nutrients, it is undesired source of As for billions of people consuming rice as the staple food. Selenium (Se) is an essential metalloid, which can regulate As toxicity by strengthening antioxidant potential. The present study was designed to investigate As(III) stress mitigating effect of Se(VI) in rice. The level of As, thiolic ligands and AAs was analyzed in rice seedlings after exposure to As(III)/Se(VI) alone and As(III)+Se(VI) treatments. Selenate supplementation (As(III) 25MUM+Se(VI) 25MUM) decreased total As accumulation in both root and shoot (179 & 144%) as compared to As(III) alone treatment. The As(III)+Se(VI) treatment also induced the levels of non-protein thiols (NPTs), glutathione (GSH) and phytochelatins (PCs) as compared to As(III) alone treatment and also modulated the activity of enzymes of thiol metabolism. The content of amino acids (AAs) was significantly altered with Se(VI) supplementation. Importantly, essential amino acids (EAAs) were enhanced in As(III)+Se(VI) treatment as compared to As(III) alone treatment. In contrast, stress related non-essential amino acids (NEAAs) like GABA, Glu, Gly, Pro and Cys showed enhanced levels in As(III) alone treatment. In conclusion, rice supplemented with Se(VI) tolerated As toxicity with reduced As accumulation and increased the nutrition quality by increasing EAAs. PMID- 27497080 TI - Transcriptional response of mysid crustacean, Americamysis bahia, is affected by subchronic exposure to nonylphenol. AB - Nonylphenol (NP) has been classified as an endocrine-disrupting chemical. In this study, we conducted mysid DNA microarray analysis with which has 2240 oligo DNA probes to observe differential gene expressions in mysid crustacean (Americamysis bahia) exposed to 1, 3, 10 and 30 MUg/l of NP for 14 days. As a result, we found 31, 27, 39 and 68 genes were differentially expressed in the respective concentrations. Among these genes, the expressions of five particular genes were regulated in a similar manner at all concentrations of the NP exposure. So, we focused on one gene encoding cuticle protein, and another encoding cuticular protein analogous to peritrophins 1-H precursor. These genes were down-regulated by NP exposure in a dose-dependent manner, and it suggested that they were related in a reduction of the number of molting in mysids. Thus, they might become useful molecular biomarker candidates to evaluate molting inhibition in mysids. PMID- 27497081 TI - Elimination of oral candidiasis may increase stimulated whole salivary flow rate. AB - OBJECTIVES: Candida infections are frequently encountered fungal infections in the oral mucosa. This study aimed to evaluate the effect of eliminating Candida spp. on stimulated whole salivary flow rate (SWS) in patients with oral candidiasis. SUBJECTS AND METHODS: This study involved 66 patients with oral candidiasis. Fifty-two consecutive patients, successfully treated by antifungal therapy, were available to examine the effect of elimination of oral Candida spp. on SWS (success group); the 14 patients who tested positive for Candida after therapy were retrospectively included (control group). SWS were used to measure saliva production. Moreover, tongue pain and xerostomia were evaluated using visual analog score (VAS). RESULTS: By eliminating oral Candida spp., SWS significantly increased in the success group after antifungal therapy [SWS: mean value 0.89+/-0.51ml/min (median 0.82ml/min: 0.15-2.14) to mean value 1.16+/ 0.58ml/min (median 1.05ml/min: 0.2-2.93), P<0.001]. Furthermore, VAS scores for subjective tongue pain and xerostomia were significantly decreased compared with those before therapy in the success group [xerostomia: mean value 52.5+/-28.8 (median 53: 9-100) to 24.2+/-1.6 (median 17: 0-70), tongue pain: mean value 52.6+/-27.2 (median 56: 1-93) to 15.3+/-18.0 (median 9: 0-62). P<0.001]. There was no significant difference in SWS, subjective tongue pain, or xerostomia in the control group after antifungal therapy. [SWS: mean value 1.08+/-0.83ml/min (median 0.69ml/min: 0.2-2.7) to 0.98+/-0.59ml/min (median 0.8ml/min: 0.45-2.5), P=0.65], [xerostomia: mean value 62.8+/-5.3 (median 62: 28-70) to 64.0+/-8.8 (median 64: 56-73), P=0.58, tongue pain: mean value 64.3+/-18.6 (median 67: 31 87) to 58.4+/-20.0 (median 8: 20-78), respectively; P=0.24] CONCLUSION: Our study demonstrated that SWS may increase by eliminating oral Candida spp. in patients with oral candidiasis. PMID- 27497083 TI - Mapping distance-decay of cardiorespiratory disease risk related to neighborhood environments. AB - Neighborhood characteristics affect an individual's quality of life. Although several studies have examined the relationship between neighborhood environments and human health, we are unaware of studies that have examined the distance-decay of this effect and then presented the risk results spatially. Our study is unique in that is explores the health effects in a less developed country compared to most studies that have focused on developed countries. The objective of our study is to quantify the distance-decay cardiorespiratory diseases risk related to 28 neighborhood aspects in the Federal District, Brazil and present this information spatially through risk maps of the region. Toward this end, we used a quantile regression model to estimate risk and GIS modeling techniques to create risk maps. Our analysis produced the following findings: i) a 2500 m increase in highway length was associated with a 46% increase in cardiorespiratory diseases; ii) 46,000 light vehicles in circulation (considering a buffer of <=500 m from residences) was associated with 6 hospital admissions (95% CI: 2.6, 14.6) per cardiorespiratory diseases; iii) 74,000 m2 of commercial areas (buffer <=1700 m) was associated with 12 hospital admissions (95% CI: 2.2, 20.8); iv) 1km2 increase in green areas intra urban was associated with less two hospital admissions, and; vi) those who live <=500 m from the nearest point of wildfire are more likely to have cardiorespiratory diseases that those living >500 m. Our findings suggest that the approach used in this study can be an option to improve the public health policies. PMID- 27497082 TI - Bisphenol A exposure and symptoms of anxiety and depression among inner city children at 10-12 years of age. AB - BACKGROUND: Experimental and epidemiological studies suggest that gestational exposure to Bisphenol A (BPA), an ubiquitous endocrine disrupting chemical, may lead to neurobehavioral problems in childhood; however, not all results have been consistent. We previously reported a positive association between prenatal BPA exposure and symptoms of anxiety/depression reported by the mother at child age 7 9 years in boys, but not girls. OBJECTIVES: Here, in the same birth cohort, we investigated the association of prenatal BPA exposure with symptoms of depression and anxiety self-reported by the 10-12 year olds, hypothesizing that we would observe sex-specific differences in anxiety and depressive symptoms. METHODS: African-American and Dominican women living in Northern Manhattan and their children were followed from mother's pregnancy through children's age 10-12 years. BPA was quantified in maternal urine collected during the third trimester of pregnancy and in child urine collected at ages 3 and 5 years. Children were evaluated using the Revised Children's Manifest Anxiety Scale (RCMAS) and Children's Depression Rating Scale (CDRS). We compared the children in the highest tertile of BPA concentration to those in the lower two tertiles. Associations between behavior and prenatal (maternal) BPA concentration or postnatal (child) BPA concentration were assessed in regression models stratified by sex. RESULTS: Significant positive associations between prenatal BPA and symptoms of depression and anxiety were observed among boys. Postnatal BPA exposure was not significantly associated with outcomes. There was substantial co occurrence of anxiety and depressive symptoms in this sample. CONCLUSION: These results provide evidence that prenatal BPA exposure is associated with more symptoms of anxiety and depression in boys but not in girls at age 10-12 years. PMID- 27497084 TI - Enhancing fatty acid production in Escherichia coli by Vitreoscilla hemoglobin overexpression. AB - Our recent 13 C-metabolic flux analysis (13 C-MFA) study indicates that energy metabolism becomes a rate-limiting factor for fatty acid overproduction in E. coli strains (after "Push-Pull-Block" based genetic modifications). To resolve this bottleneck, Vitreoscilla hemoglobin (VHb, a membrane protein facilitating O2 transport) was introduced into a fatty-acid-producing strain to promote oxygen supply and energy metabolism. The resulting strain, FAV50, achieved 70% percent higher fatty acid titer than the parent strain in micro-aerobic shake tube cultures. In high cell-density bioreactor fermentations, FAV50 achieved free fatty acids at a titer of 7.02 g/L (51% of the theoretical yield). In addition to "Push-Pull-Block-Power" strategies, our experiments and flux balance analysis also revealed the fatty acid over-producing strain is sensitive to metabolic burden and oxygen influx, and thus a careful evaluation of the cost-benefit tradeoff with the guidance of fluxome analysis will be fundamental for the rational design of synthetic biology strains. Biotechnol. Bioeng. 2017;114: 463 467. (c) 2016 Wiley Periodicals, Inc. PMID- 27497085 TI - Distinct resting-state perfusion patterns underlie psychomotor retardation in unipolar vs. bipolar depression. AB - OBJECTIVE: Psychomotor abnormalities characterize both unipolar (UP) depression and bipolar (BP) depression. We aimed to assess their neurobiological correlates in terms of motor activity (AL) and resting-state cerebral blood flow (rCBF) and investigate their association in BP, UP, and healthy controls (HC). METHOD: We enrolled 42 depressed patients (22 BP, 20 UP) and 19 HC matched for age, gender, education, income. AL and rCBF were objectively assessed with the use of wrist actigraphy and arterial spin labeling. Group differences and the association of AL and rCBF were computed. RESULTS: Activity level was significantly reduced in patients, but no difference was found between BP and UP. Increased perfusion was found in BP compared with UP and HC, in multiple brain areas. We found positive correlations of rCBF and AL in BP and UP, in different parts of the insula and frontal regions. Only BP showed a cluster in the left precentral gyrus. In HC, only inverse correlations of AL and rCBF were found. CONCLUSION: The differences in rCBF and in the localization of the clusters of positive AL/rCBF correlations between BP and UP suggest that different neural impairments may underlie motor symptoms in the two disorders, but finally converge in phenotypically similar manifestations. PMID- 27497086 TI - Improve biogas production from low-organic-content sludge through high-solids anaerobic co-digestion with food waste. AB - Anaerobic co-digestion of sewage sludge and food waste was tested at two different total solid (TS) concentrations. In the low-solids group with TS 4.8%, the biogas production increased linearly as the ratio of food waste in substrate increased from 0 to 100%, but no synergetic effect was found between the two substrates. Moreover, the additive food waste resulted in the accumulation of volatile fatty acids and decelerated biogas production. Thus, the blend ratio of food waste should be lower than 50%. While in the high-solids group with TS 14%, the weak alkaline environment with pH 7.5-8.5 avoided excessive acidification but high concentration of free ammonia was a potential risk. However, good synergetic effect was found between the two substrates because the added food waste improved mass transfer in sludge cake. Thus, 50% was recommended as the optimum ratio of food waste in substrate because of the best synergetic effect. PMID- 27497087 TI - Symbiotic hollow fiber membrane photobioreactor for microalgal growth and bacterial wastewater treatment. AB - A hollow fiber membrane photobioreactor (HFMP) for microalgal growth and bacterial wastewater treatment was developed. C. vulgaris culture was circulated through one side of the HFMP and P. putida culture was circulated through the other. A symbiotic relationship was demonstrated as reflected by the photo autotrophic growth of C. vulgaris using CO2 provided by P. putida and biodegradation of 500mg/L glucose by P. putida utilizing photosynthetic O2 produced by C. vulgaris. Performance of the HFMP was significantly enhanced when the microalgal culture was circulated through the lumen side of the HFMP: the average percentage of glucose degraded per 8-h cycle was as high as 98% and microalgal biomass productivity was increased by 69% compared to the reversed orientation. Enhanced glucose biodegradation was achieved in an HFMP packed with more fibers indicating the easy scalability of the HFMP for increased wastewater treatment efficiency. PMID- 27497088 TI - Role of biochar amendment in mitigation of nitrogen loss and greenhouse gas emission during sewage sludge composting. AB - The objective of the present study was to mitigate the greenhouse gas (GHG) emissions during composting of dewatered fresh sewage sludge (DFSS) employing biochar combined with zeolite (B+Z) and low dosage of lime (B+L). The 12% biochar was mixed at a 10%, 15% and 30% of zeolite and 1% lime, while without any additives was used as control. The results indicated that the combine use of B+Z was significantly increased the enzymatic activities and reduced the ammonia loss 58.03-65.17% as compare to B+L amended treatment, while CH4 92.85-95.34% and N2O 95.14-97.28% decreased than control. The B+L1% amendment significantly increased the organic matter degradation but the reduction was lower than B+Z and that could reduce the CH4 and N2O emission by 55.17-63.08% and 62.24-65.53% as compare to control, respectively. Overall our results demonstrated that 12%B+Z10% addition into DFSS can be potentially used to improve the DFSS composting by mitigation of GHG emission and nitrogen loss. PMID- 27497089 TI - Hydro-liquefaction of microcrystalline cellulose, xylan and industrial lignin in different supercritical solvents. AB - The influences of solvent on hydro-liquefaction of cellulose, xylan, and lignin were investigated using micro-autoclave. The maximum conversion and bio-oil yield obtained from cellulose and xylan liquefaction were achieved in methanol, whereas similar liquefaction characteristics of lignin were observed in methanol and ethanol. The molecular simulation of interactions between solvents and subcomponents indicated that methanol and ethanol were highly miscible with raw materials. GC-MS and FT-ICR MS characterization revealed that the chemical compositions of liquid products highly depended on the utilized feedstocks. Esters, ketones, and aldehydes were mainly produced from cellulose and xylan conversion, whereas aromatic compounds were primarily derived from lignin conversion. EA results showed that methanol favored the hydrogenation and deoxygenation, resulting in the heating value increased. It could be concluded that the oil quality was highly improved in supercritical methanol. PMID- 27497090 TI - A pivotal role of the jasmonic acid signal pathway in mediating radiation-induced bystander effects in Arabidopsis thaliana. AB - Although radiation-induced bystander effects (RIBE) in Arabidopsis thaliana have been well demonstrated in vivo, little is known about their underlying mechanisms, particularly with regard to the participating signaling molecules and signaling pathways. In higher plants, jasmonic acid (JA) and its bioactive derivatives are well accepted as systemic signal transducers that are produced in response to various environmental stresses. It is therefore speculated that the JA signal pathway might play a potential role in mediating radiation-induced bystander signaling of root-to-shoot. In the present study, pretreatment of seedlings with Salicylhydroxamic acid, an inhibitor of lipoxigenase (LOX) in JA biosynthesis, significantly suppressed RIBE-mediated expression of the AtRAD54 gene. After root irradiation, the aerial parts of A. thaliana mutants deficient in JA biosynthesis (aos) and signaling cascades (jar1-1) showed suppressed induction of the AtRAD54 and AtRAD51 genes and TSI and 180-bp repeats, which have been extensively used as endpoints of bystander genetic and epigenetic effects in plants. These results suggest an involvement of the JA signal pathway in the RIBE of plants. Using the root micro-grafting technique, the JA signal pathway was shown to participate in both the generation of bystander signals in irradiated root cells and radiation responses in the bystander aerial parts of plants. The over-accumulation of endogenous JA in mutant fatty acid oxygenation up-regulated 2 (fou2), in which mutation of the Two Pore Channel 1 (TPC1) gene up-regulates expression of the LOX and allene oxide synthase (AOS) genes, inhibited RIBE mediated expression of the AtRAD54 gene, but up-regulated expression of the AtKU70 and AtLIG4 genes in the non-homologous end joining (NHEJ) pathway. Considering that NHEJ is employed by plants with increased DNA damage, the switch from HR to NHEJ suggests that over-accumulation of endogenous JA might enhance the radiosensitivity of plants in terms of RIBE. PMID- 27497091 TI - Emerging roles of calcium-activated K channels and TRPV4 channels in lung oedema and pulmonary circulatory collapse. AB - It has been suggested that the transient receptor potential cation (TRP) channel subfamily V (vanilloid) type 4 (TRPV4) and intermediate conductance calcium activated potassium (KCa3.1) channels contribute to endothelium-dependent vasodilation. Here, we summarize very recent evidence for a synergistic interplay of TRPV4 and KCa3.1 channels in lung disease. Among the endothelial Ca2+ permeable TRPs, TRPV4 is best characterized and produces arterial dilation by stimulating Ca2+ -dependent nitric oxide synthesis and endothelium-dependent hyperpolarization. Besides these roles, some TRP channels control endothelial/epithelial barrier functions and vascular integrity, while KCa3.1 channels provide the driving force required for Cl- and water transport in some cells and most secretory epithelia. The three conditions, increased pulmonary venous pressure caused by left heart disease, high inflation pressure and chemically induced lung injury, may lead to activation of TRPV4 channels followed by Ca2+ influx leading to activation of KCa3.1 channels in endothelial cells ultimately leading to acute lung injury. We find that a deficiency in KCa3.1 channels protects against TRPV4-induced pulmonary arterial relaxation, fluid extravasation, haemorrhage, pulmonary circulatory collapse and cardiac arrest in vivo. These data identify KCa3.1 channels as crucial molecular components in downstream TRPV4 signal transduction and as a potential target for the prevention of undesired fluid extravasation, vasodilatation and pulmonary circulatory collapse. PMID- 27497092 TI - Effects of carvedilol on ventricular remodeling and the expression of beta3 adrenergic receptor in a diabetic rat model subjected myocardial infarction. AB - BACKGROUND: This study was to assess effects of carvedilol on ventricular remodeling and expression of beta3-adrenergic receptor (beta3-AR) and Gi protein in a rat model of diabetes subjected to myocardial infarction (MI). METHODS: Rat model of type II diabetes was established by injection of streptozotion. MI was then induced by ligating the left anterior descending coronary artery. Rats were then randomly divided into two groups treated with either placebo (PL) or carvedilol (CA - 10mg.kg(-1).d(-)(1)). Additional controls consisted of sham operated rats with diabetes (DS) and rats fed a normal diet subjected to myocardial infarction (NM). Echocardiographic and hemodynamic studies were performed to assess the structural and functional changes. beta3-AR and Gi mRNA in the myocardium distal from the infarction region were measured, and beta3-AR and Gi protein were measured with western blot. RESULTS: There were no significant differences in MI size among the three MI groups. In the PL group, LVEDd, LVWI, E/A and CVF were significantly increased, while LVEF and PW% significantly decreased as compared with the DS and NM groups. Compared with the DS group, the expression of beta3-AR and Gi mRNA and protein in the PL group was significantly increased, however, in the CA group, beta3-AR and Gi mRNA and protein were decreased. CONCLUSIONS: The expression of beta3-AR and Gi mRNA and protein was increased in diabetic rats subjected to MI as compared with rats subject to either condition alone. Carvedilol treatment prevented many of these deleterious effects. PMID- 27497093 TI - Prevalence of coronary macro- and micro-vascular dysfunctions after drug-eluting stent implantation without in-stent restenosis. AB - BACKGROUND: The aim was to examine the prevalence and characteristics of epicardial vasomotor abnormality (EVA) and coronary microvascular dysfunction (CMD) including endothelium-dependent (EDCMD) or -independent (EICMD) in patients following a second-generation drug-eluting stent (second DES) implantation without in-stent restenosis. METHODS AND RESULTS: In 105 patients who underwent second DES implantation in the left anterior descending coronary artery (74 men; mean age, 67.9+/-9.6years), and in 105 suspected angina patients without stenting (65 men; mean age 66.4+/-9.1years), we evaluated EVA using the acetylcholine provocation test, EDCMD and EICMD by measuring the coronary flow reserve and the relationship between myocardial ischemia (intracoronary lactate production between aorta and coronary sinus and ST-T changes) or recurrent angina and vascular function. There was no difference in the incidence of EVA between DES and control (49.5% versus 55.2%; P=0.41). Given that the prevalence of CMD was higher in DES than in control (59.0% versus 29.5%; P<0.001), CMD may be associated with stent placement. Of the CMD patients, EDCMD alone, EICMD alone, and both CMDs were found in 40.3%, 22.6%, and 37.1%, respectively. Myocardial ischemia was detected in 42.4% of patients, and recurrent angina was more common in the presence of both EDCMD and EICMD in patients with EVA or CMD compared to patients with normal vascular function (EVA, 42.9% versus 7.7%, P=0.015: CMD, 39.1% versus 7.7%, P=0.007). CONCLUSIONS: Myocardial ischemia and recurrent angina may be caused by the presence of both EDCMD and EICMD after a second DES implantation without ISR. PMID- 27497094 TI - Serum sodium concentration, blood urea nitrogen, and outcomes in patients hospitalized for acute decompensated heart failure. AB - BACKGROUND: This study investigated the association of a low serum sodium and elevated blood urea nitrogen (BUN) with outcomes in acute decompensated heart failure (HF) patients. METHODS: Of the 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4438 patients discharged after hospitalization for acute decompensated HF were investigated to assess the association of a low serum sodium and/or elevated BUN at discharge with all-cause mortality. The patients were divided into four groups based on serum sodium (>136 or <=136mEq/l) and BUN (<25 or >=25mg/dl) at discharge. The median follow-up period after discharge was 517 (381-776) days. RESULTS: According to multivariate analysis, a low serum sodium (<=136mEq/l) or an elevated BUN (>=25mg/dl) was significantly associated with a higher risk of all-cause death compared with patients who had neither (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.22 to 1.94; P<0.001 and HR, 1.44; 95% CI, 1.19 to 1.73; P<0.001, respectively). Patients with both low serum sodium and elevated BUN had a higher risk of all cause death relative to patients with neither (HR, 2.64; 95% CI, 2.17 to 3.20; P<0.001) and also relative to patients with either low serum sodium alone or elevated BUN alone (HR, 1.72; 95% CI, 1.36 to 2.18; P<0.001 and HR, 1.84; 95% CI, 1.53 to 2.21; P<0.001, respectively). CONCLUSION: These findings demonstrated that a low serum sodium and an elevated BUN may be additive risk factors for postdischarge mortality in acute decompensated HF patients. PMID- 27497095 TI - Impact of catheter tip-tissue contact on three-dimensional left atrial geometries: Relationship between the external structures and anatomic distortion of 3D fast anatomical mapping and high contact force guided images. AB - BACKGROUND: A high catheter tip-tissue contact force (CF) with the myocardium may cause 3-dimensional (3D) map distortion, however, the influence of external structures surrounding the left atrium (LA) on that distortion remains unknown. This study characterized the impact of high CF mapping on the local LA geometry distortion. METHODS: Thirty AF patients underwent 3D-ultrasound merged with CT images (3D-Merge-CT). The LA area in contact with external structures was identified by enhanced CT. Fast-electroanatomical-mapping (FAM) geometries were created by two methods, point-by-point mapping with high (>10g) CFs (high-CF guided-FAM), followed by that with multielectrode-mapping catheters (conventional FAM). The resulting geometries were compared with the 3D-Merge-CT images. RESULTS: Three representative anatomical contact areas (ascending aorta-vs. anterior wall, descending aorta-vs.-left pulmonary vein [PV], and vertebrae-vs. posterior wall) were identified. The PV antrum distorted distance on the 3D-Merge CT was significantly longer for high-CF guided-FAMs than conventional-FAMs (1.7[0 3.6] vs. 0[0-1.8]mm, P<0.0001). In high-CF maps, the distorted distance significantly differed between regions with and without contact areas in both the PV antrum (0[0-0.17] vs. 1.7[0-3.9]mm, P=0.0201) and LA body region (0[0-1.5] vs. 1.7[0.7-2.2]mm, P<0.005). The catheter tip-tissue CF did not correlate with the distorted distance (r=0.08, P=0.46), and a multivariate analysis revealed that the absence of anatomical contact areas was strongly associated with significant local distortion, independent of the CF. CONCLUSIONS: High-CF guided mapping yields greater 3D-image anatomical distortion than conventional-FAM methods. That distortion was attenuated by regions with anatomical contact areas, suggesting that regional anatomic distortion is involved in the existence of external structures surrounding the LA. PMID- 27497096 TI - Assessment of coronary flow reserve using a combination of planar first-pass angiography and myocardial SPECT: Comparison with myocardial (15)O-water PET. AB - Coronary flow reserve (CFR), defined as the ratio of maximum coronary flow increase from baseline resting blood flow, is one of the most sensitive parameters to detect early signs of coronary arteriosclerosis at the microvascular level. Myocardial perfusion PET is a well-established technology for CFR measurement, however, availability is still limited. The aim of this study is to introduce and validate myocardial flow reserve measurement by myocardial perfusion SPECT. METHODS: Myocardial perfusion SPECT at rest and ATP stress (0.16mg/Kg/min) was performed in 10 patients with known coronary artery disease. Immediately after the injection of Tc-99m sestamibi (MIBI), left ventricular (LV) dynamic planar angiographic data were obtained for 90s. Coronary flow reserve index as measured by MIBI SPECT (CFRMIBI) was calculated as follows: CFRMIBI=CmsSbmb/CmbSbms, where subscripts b, s, Cm, and Sbm indicate baseline, during stress, myocardial counts with MIBI SPECT, and integral of LV counts with first pass angiography, respectively. Additionally, standard stress/rest (15)O water PET to estimate CFR was performed in all patients as standard of reference. RESULTS: CFRMIBI increased in conjunction with CFR, but underestimated blood flow at high flow rates. The relationship between CFRMIBI (Y) and CFRPET (X) was well fitted as follows: Y=1.40x(1-exp(1.79/x)) (r=0.84). CONCLUSIONS: The index of CFRMIBI reflects the CFR by (15)O-water PET but underestimates flow at high flows, maybe as a reflection of pharmacokinetic limitations of MIBI. PMID- 27497097 TI - Exercise training bradycardia is largely explained by reduced intrinsic heart rate. AB - INTRODUCTION: Resting heart rate (RHR) declines with exercise training. Possible mechanisms include: 1) increased parasympathetic tone, 2) decreased responsiveness to beta-adrenergic stimulation, 3) decreased intrinsic heart rate or 4) combination of these factors. OBJECTIVE: To determine whether an increase in resting parasympathetic tone or decrease in response to beta-adrenergic stimulation contributes to the decrease in RHR with training. METHODS: 51 screened healthy subjects aged 18-32 (n=20, mean age 26, 11 female) or 65-80 (n=31, mean age 69, 16 female) were tested before and after 6months of supervised exercise training. Heart rate response to parasympathetic withdrawal was assessed using atropine and beta-adrenergic responsiveness during parasympathetic withdrawal using isoproterenol. RESULTS: Training increased VO2 max by 17% (28.7+/-7.7 to 33.6+/-9.20ml/kg/min, P<0.001). RHR decreased from 62.8+/-6.6 to 57.6+/-7.2 beats per minute (P<0.0001). The increase in heart rate in response to parasympathetic withdrawal was unchanged after training (+37.3+/-12.8 pre vs. +36.4+/-12.2 beats per min post, P=0.41). There was no change in the heart rate response to isoproterenol after parasympathetic blockade with training (+31.9+/ 10.9 pre vs. +31.0+/-12.0 post beats per min, P=0.56). The findings were similar in all four subgroups. CONCLUSIONS: We did not find evidence that an increase in parasympathetic tone or a decrease in responsiveness to beta-adrenergic activity accounts for the reduction in resting heart rate with exercise training. We suggest that a decline in heart rate with training is most likely due to decrease in the intrinsic heart rate. PMID- 27497098 TI - Preclinical evaluation of a novel polyphosphazene surface modified stent. AB - BACKGROUND: Treatment options for patients with coronary artery disease at high risk for bleeding complications are limited. The aim of the current preclinical study was to evaluate neointimal coverage, endothelial recovery, inflammation and thrombogenicity in a novel thin-strut (71MUm thickness) Cobalt Chromium (CoCr) stent modified with a nano-thin Polyzene(r)-F (PzF) surface coating. METHODS AND RESULTS: Twenty-eight single PzF nano-coated stents and 20 bare metal control stents (BMS) were implanted in the coronary arteries of 24 pigs, with scheduled 5 (n=5), 28- (n=13), and 90-day (n=6) follow-up in addition to overlapping configuration (n=6 each), examined at 28-days. Histomorphometric analysis showed significantly lower neointimal thickness in PzF nano-coated stents than BMS controls at both 28- and 90-days (p=0.023 and 0.005) and reduced inflammation (p=0.06 and 0.13). Endothelial coverage over luminal surfaces at all time points was similar between nano-coated stents and BMS controls. We conducted supplementary in-vitro experiments using human monocytes and an ex-vivo swine carotid-jugular arterio-venous shunt model to better understand the healing properties afforded by the PzF nano-coating. Overall, the PzF-nano-coating showed reduced monocyte adhesion and thrombus formation compared to the un-coated controls. CONCLUSIONS: Stents modified with a nano-thin PzF-coating implanted in healthy swine indicate favorable vascular healing properties shown by reduced neointimal hyperplasia and inflammation, along with resistance to thrombus formation in an ex-vivo shunt model over unmodified stents. PMID- 27497099 TI - Usefulness of the d-ROMs test for prediction of cardiovascular events. AB - BACKGROUND: d-ROMs test developed to determine the degree of individual oxidative stress may predict cardiovascular events. METHODS AND RESULTS: 265 patients (204 men, 61 women; age, 65+/-13years) who had been treated for cardiovascular disease were divided evenly by quartile of baseline d-ROMs levels, and were followed up. During the observation periods of 2.66+/-1.47years, there were 14 (5%) deaths, 8 (3%) cardiovascular deaths, 13 (5%) major adverse cardiovascular events (MACEs), and 51 (19%) all cardiovascular events including heart failure, cardiovascular surgery, and revascularization. Log-rank tests demonstrated that the patients in the 4th quartile (d-ROMs?395.00U.CARR) had a higher incidence rate of cardiovascular death than those in the 2nd quartile (d-ROMs 286.00-335.00, p=0.022). In multivariate Cox regression analysis, even after adjustment for age, sex, coronary risk factors, C-reactive protein, and renal function, high d-ROMs was a risk factor for all-cause death [adjusted HR of 4th vs. 1st quartile, 10.791 (95% confidence interval 1.032-112.805), p=0.047], and all cardiovascular events [HR of 4th vs. 1st quartile, 2.651 (95% confidence interval 1.138-6.177), p=0.024]. CONCLUSIONS: Our results suggest that d-ROMs is a useful oxidative stress marker to assess prognosis and risk of further cardiovascular events. PMID- 27497100 TI - Increased risk of coronary artery calcification progression in subjects with high baseline Lp(a) levels: The Kangbuk Samsung Health Study. AB - BACKGROUND: Results from previous studies support the association of lipoprotein(a) [Lp(a)] levels and coronary artery disease risk. In this study, we analyzed the association between baseline Lp(a) levels and future progression of coronary artery calcification (CAC) in apparently healthy Korean adults. METHODS: A total of 2611 participants (mean age: 41years, 92% mend) who underwent a routine health check-up in 2010 and 2014 were enrolled. Coronary artery calcium score (CACS) were measured by multi-detector computed tomography. Baseline Lp(a) was measured by high-sensitivity immunoturbidimetric assay. Progression of CAC was defined as a change in CACS >0 over four years. RESULTS: Bivariate correlation analyses with baseline Lp(a) and other metabolic parameters revealed age, total cholesterol, HDL-C, LDL-C and CACS to have a significant positive correlation, while body weight, fasting glucose level, blood pressure and triglyceride level were negatively correlated with baseline Lp(a) level. After four years of follow-up, 635 subjects (24.3%) had CAC progression. The participants who had CAC progression were older, composed of more men, more obese, and had higher fasting glucose levels and worse baseline lipid profiles compared to those who did not have CAC progression. The mean serum Lp(a) level was significantly higher in subjects who had CAC progression compared to those who did not (32.5 vs. 28.9mg/dL, p<0.01). When the risk for CAC progression according to baseline Lp(a) was calculated, those with Lp(a) level>=50mg/dL had an odds ratio of 1.333 (95% CI 1.027-1.730) for CAC progression compared to those with Lp(a)<50mg/dL after adjusting for confounding factors. CONCLUSIONS: In this study, the subjects who had higher Lp(a) were at significantly higher risk for CAC progression after four years of follow-up, suggesting the role of high Lp(a) in CAC progression. PMID- 27497101 TI - Pharmaceutical services as a tool to improve outcomes in patients with cardiovascular diseases. AB - Despite the presence of effective and safe pharmacotherapy, and availability of multidimensional non-pharmacological treatment, the overall rate of major adverse cardiovascular outcomes remains still unsatisfactory. The clinical pharmacy activities and pharmaceutical care available in the community pharmacy settings have a significant impact on outcomes in cardiovascular patients, e.g. adherence, the level of blood pressure, total cholesterol or patients' health literacy. Pharmaceutical care in patients diagnosed with cardiovascular diseases remains beneficial both to the patients and the entire health care system. However, the prediction of results of pharmacists' interventions is particularly difficult and random. Many factors contribute to outcomes of community pharmacy services, e.g. time spent with the patients or quality of communication between patients and healthcare professionals. The most important issue in delivering effective pharmaceutical care is to develop an evidence-based model. Globally, the development of interprofessional collaboration between physicians and pharmacists, and preparing more sophisticated pharmacoeconomics analyses in the scope of pharmaceutical care are the next step in the improvement of advanced pharmaceutical services. Further research, particularly based on real data on this highly interesting topic is needed and recommended. PMID- 27497102 TI - Age-dependent impact of new ESC-Guideline recommended door-to-balloon times on mid-term survival in acute ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. AB - BACKGROUND: To investigate the age-dependent impact of the superfast door-to balloon (D2B) times of <=60min as recommended by the new ESC Guideline for patients with ST elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) on mid-term survival rates based on a single center registry dataset. PATIENTS AND METHODS: This study enrolled consecutive STEMI patients who underwent PPCI from Jan 1, 2009 through Sep 30, 2013. We compared demographics, clinical characteristics and the D2B-survival relationships between patients aged >=65 and <65. RESULTS: The younger group comprised 242 patients (68%) aged <65 and the elder group consisted of 115 patients (32%) aged >=65. In patients aged <65, the mortality rate decreased linearly with D2B time shortening (>90min vs. 61-90min vs. <=60min=14.9% vs. 13.3% vs. 1.2%, P=0.001). Contrarily, shortening of D2B time was not associated with reduced mortality rate in patients aged >=65 (>90min vs. 61-90min vs. <=60min=23.5% vs. 19% vs. 18.9%, P=0.99). In younger patients but not the elderly, a D2B time of <60min has sufficient power to predict mortality with a sensitivity of 0.83, specificity of 0.74, and Youden index of 0.57. CONCLUSIONS: Our results show that the new ESC Guideline recommendation of D2B time <=60min is associated with better survival rates in younger STEMI patients undergoing PPCI. Our findings stress the importance of guideline adherence to minimize reperfusion delay to improve survival in these patients. PMID- 27497103 TI - Biventricular unloading in patients with refractory cardiogenic shock. AB - BACKGROUND: Cardiogenic shock remains a clinical challenge with high mortality rate. Mechanical circulatory support (MCS) devices have become an integral component of the therapeutic armamentarium expanding the treatment options for refractory cardiogenic shock (RCS). METHODS: We included all consecutive patients with biventricular unloading with Impella-2.5 and VA-ECMO admitted for RCS between October 2013 and March 2015. Outcome data included survival to discharge, bridging to VAD and 28-day mortality. RESULTS: A total of 17 patients were included. Mean age was 63.3+/-10.5 and 15 (88%) patients were male. RCS resulted from acute myocardial infarction in 14 (82%), acute myocarditis in 1 (6%) dilated cardiomyopathy in 2 (12%) patients. Mean SAPS II and SOFA score on admission was 74.7+/-16.86 and 11.16+/-1.79, respectively. Vasopressor doses and lactate levels were significantly decreased within 72h on biventricular support (p=0.025 for norepinephrine and p=0.005 for lactate). Nine (53%) patients died while on support. Of the remaining 8 patients, 5 (29%) patients were weaned successfully and discharged in cardiac rehabilitation and 3 (18%) patients were successfully bridged to VAD. All 5 patients who were discharged to rehabilitation survived at day 28 after discharge, while 1 of 3 VAD patients died after VAD implantation, corresponding to an overall 28-day survival rate of 41%. CONCLUSIONS: Biventricular support with Impella-2.5 and VA-ECMO in patients with RCS is feasible and led to significant hemodynamic improvement and reduction of lactate levels. Despite high severity scores, ICU- and 28-day mortality rates were better than predicted. PMID- 27497104 TI - What is/are the trigger(s) of takotsubo syndrome in cancer patients receiving chemotherapy? PMID- 27497105 TI - Successful treatment of 2 complex cases of international traveller's pulmonary embolism using conventional therapy and novel oral anticoagulant. PMID- 27497106 TI - Reversal of cardiac remodeling after treatment of IgG4 related cholangitis. PMID- 27497107 TI - The prevention of statins against AKI and mortality following cardiac surgery: A meta-analysis. AB - OBJECTIVE: It is universally acknowledged that acute kidney injury (AKI) often comes following cardiac surgery with severe morbidity and mortality. The impact of statins on the incidence of AKI and mortality after cardiac surgery are controversial, therefore, it is urgent to explore the source of heterogeneity via the subgroup analysis. METHODS: We searched PubMed, ISI and Elsevier to May 31st 2016 for studies which investigated the effects of statins relevant to this theme. Statistical analysis was using RevMan5.2 and Stata12.0. The outcomes were the occurrence of AKI and the mortality after cardiac surgery. For the first time, we discussed the source of heterogeneity on the basis of the characters of patients in the following subgroup analysis. RESULTS: A total of 17 studies with 18,684 statins and 24,033 non-statin users were included. The meta-analysis suggested that statins not only reduced the occurrence of AKI [Odds Ratio (OR) 0.72, 95% Confidence Interval (CI) 0.55-0.94)] in the subjects without high risk factors, also decreased the mortality of the patients suffering AKI (OR 0.40, 95% CI 0.22-0.72). CONCLUSION: Patients undergoing cardiac surgery might benefit from statins by reducing the occurrence of AKI and the mortality of the patients suffering AKI. PMID- 27497108 TI - The time difference between clinical improvement and exercise tolerance increase following pulmonary thromboendarterectomy. PMID- 27497109 TI - Relation of body mass index (BMI) to the prevalence of hypertension in children: A 3years' school-based prospective study in Suzhou, China. AB - BACKGROUND: The prevalence of hypertension has been increasing in children and adolescents in China, which is considered to be accompanied with the epidemic of childhood overweight and obesity, but limited prospective studies have investigated the effect of body mass index (BMI) change on blood pressure among children, especially in China. METHODS: This school-based prospective study compared the blood pressure and prevalence of hypertension in students with different patterns of change in BMI between two periods (childhood and adolescence). 5465 children were followed-up since 2011(childhood) in Suzhou, China and had weight, height and blood pressure measured in 2011(childhood) and 2014(adolescence). RESULTS: Those who changed from being overweight in childhood to having normal BMI in adolescence had similar mean blood pressures to those who had a normal BMI at both two periods. In contrast, those who were overweight at both two periods or who had a normal BMI in childhood and were overweight in adolescence had higher blood pressure in adolescence than those who had a normal BMI at both two periods. Compared with students who had a normal BMI at both periods, those with combination of abnormal BMI in childhood and adolescence have higher ORs of hypertension (4.83 in boys, 3.44 in girls and 3.73 in total). CONCLUSION: These results suggest that obesity is a key determinant of blood pressure during childhood, and weight reduction may have important beneficial effects on blood pressure. PMID- 27497111 TI - Association between mortality and incidence rates of coronary heart disease and stroke: The Japan Public Health Center-based prospective (JPHC) study. AB - BACKGROUND: It is essential to have information on incidence rates to estimate the burden of cardiovascular diseases (CVD); however, it is not clear whether mortality measurements are eligible for incidence estimations. METHODS: We performed eight cohort studies from 1990 to 2010 in Japan, which consisted of total 94,657 residents aged 40-59years who were followed-up for a median of 18.5years. Incidence and mortality rates for coronary heart disease (CHD) and stroke events were ascertained. Sex-specified incidence rates were regressed to the mortality rates, adjusting for differences in community and age group. Further, incidence-to-mortality rate ratios were estimated using the Poisson regression with random intercepts. RESULTS: CHD or stroke mortality rates were highly associated with incidence rates in communities. Incidence-to-mortality rate ratios were 2.06 (95% confidence interval, 1.56-2.73) in men and 1.41 (1.01 1.95) in women for CHD; and 3.99 (3.32-4.80) in men and 4.44 (3.73-5.29) in women for stroke. There were no significant geographical variations in the ratio among the 8 areas. CONCLUSIONS: We determined that it is possible to estimate CHD and stroke occurrences in the population from their mortality rates reported in vital statistics. Accordingly, we should pay attention to the communities in which mortality rates due to CHD or stroke reported in vital statistics are higher, and promote CVD prevention positively. PMID- 27497110 TI - Long-term clinical outcome of titanium-nitride-oxide-coated stents versus everolimus-eluting stents in acute coronary syndrome: Final report of the BASE ACS trial. AB - BACKGROUND: The BASE ACS randomized trial demonstrated non-inferiority of titanium-nitride-oxide-coated bioactive stents (BAS), compared with everolimus eluting stents (EES), for the primary endpoint of major adverse cardiac events (MACE) in patients presenting with acute coronary syndrome (ACS) at 12-month follow-up. We report the final long-term clinical outcome of the trial. METHODS: We randomly assigned 827 patients with ACS to receive either BAS (417) or EES (410). The primary endpoint was MACE: a composite of cardiac death, non-fatal myocardial infarction (MI) or ischemia-driven target lesion revascularization (TLR) at 12-month follow-up. Analysis was performed by intention to treat. Follow up was planned at 12months, and yearly thereafter through 7years. RESULTS: Mean follow-up duration was 4.2+/-1.9years (median 5.0years). At 5-year follow-up, BAS was non-inferior to EES for the primary endpoint of MACE (14.4% versus 17.8%, respectively; hazard ratio for BAS versus EES, 0.82; 95% confidence interval, 0.58-1.16; p=0.26 for superiority; p<0.001 for non-inferiority). The rate of non fatal MI was lower in the BAS group (5.9% versus 9.7%, respectively, p=0.028). The rates of cardiac death and ischemia-driven TLR were comparable (2.8% versus 3.8%, and 8.3% versus 9.9%; p=0.76 and p=0.58, respectively). CONCLUSIONS: In the current final report of the randomized BASE ACS trial in patients with ACS, BAS implantation was associated with a rate of cumulative MACE at long-term follow-up that was statistically non-inferior to EES. PMID- 27497112 TI - Usefulness of the catheter extension in combination with the fractional flow reserve in coronary grafts. PMID- 27497113 TI - Doping control container for urine stabilization: a pilot study. AB - Urine collection containers used in the doping control collection procedure do not provide a protective environment for urine, against degradation by microorganisms and proteolytic enzymes. An in-house chemical stabilization mixture was developed to tackle urine degradation problems encountered in human sport samples, in cases of microbial contamination or proteolytic activity. The mixture consists of antimicrobial substances and protease inhibitors for the simultaneous inactivation of a wide range of proteolytic enzymes. It has already been tested in lab-scale, as part of World Anti-Doping Agency's (WADA) funded research project, in terms of efficiency against microbial and proteolytic activity. The present work, funded also by WADA, is a follow-up study on the improvement of chemical stabilization mixture composition, application mode and limitation of interferences, using pilot urine collection containers, spray coated in their internal surface with the chemical stabilization mixture. Urine in plastic stabilized collection containers have been gone through various incubation cycles to test for stabilization efficiency and analytical matrix interferences by three WADA accredited Laboratories (Athens, Ghent, and Rome). The spray-coated chemical stabilization mixture was tested against microorganism elimination and steroid glucuronide degradation, as well as enzymatic breakdown of proteins, such as intact hCG, recombinant erythropoietin and small peptides (GHRPs, ipamorelin), induced by proteolytic enzymes. Potential analytical interferences, observed in the presence of spray-coated chemical stabilization mixture, were recorded using routine screening procedures. The results of the current study support the application of the spray-coated plastic urine container, in the doping control collection procedure. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27497114 TI - Investigating genomic and phenotypic parallelism between piscivorous and planktivorous lake trout (Salvelinus namaycush) ecotypes by means of RADseq and morphometrics analyses. AB - Repeated adaptive ecological diversification has commonly been reported in fish and has often been associated with trophic niche diversity. The main goal of this study was to investigate the extent of parallelism in the genomic and phenotypic divergence between piscivorous and planktivorous lake trout ecotypes from Laurentian Shield lakes, Canada. This was achieved by documenting the extent of morphological differentiation using geometric morphometrics and linear measurements as well as the pattern of genomic divergence by means of RADseq genotyping (3925 filtered SNPs) in 12 lakes. Our results indicate that the two ecotypes evolved distinct body shape and several linear measurements in parallel. Neutral genetic differentiation was pronounced between all isolated populations (Mean FST = 0.433), indicating no or very limited migration and pronounced genetic drift. Significant genetic differentiation also suggested partial reproductive isolation between ecotypes in the two lakes where they are found in sympatry. Combining different outlier detection methods, we identified 48 SNPs putatively under divergent selection between ecotypes, among which 10 could be annotated and related to functions such as developmental processes and ionic regulation. Finally, our results indicate that parallel morphological divergence is accompanied by both parallel and nonparallel genomic divergence, which is associated with the use of different trophic niches between ecotypes. The results are also discussed in the context of management and conservation of this highly exploited species throughout northern North America. PMID- 27497115 TI - Removal and Burial of Weed Seeds by Ants (Hymenoptera: Formicidae) From the Soil Surface of a Cropped Area in Western Australia. AB - Although granivorous ants are known to collect weed seeds from cropping areas in Australia, the fate of these seeds has not been adequately investigated. Seeds of annual ryegrass (Lolium rigidum Gaud.) and wild radish (Raphanus raphanistrum L.) were placed around the nests of five native ant species (Iridomyrmex greensladei Shattuck, Rhytidoponera metallica Smith, Melophorus turneri Forel, Monomorium rothsteini Forel, and Pheidole hartmeyeri Forel) and tracked continuously over a 24-h period. Removal rates and seed preference of the ant species were evaluated. Ant nests were then excavated to determine the placement of seeds that were taken into each nest. Seed preference, seed removal efficiencies, activity, and seed storage all varied between the ant species. Annual ryegrass seed was collected by three species of ants and was removed from the soil surface more efficiently than wild radish seed. Most ant species stored seed below ground at a depth that is inhibitory to emergence, thereby potentially removing that portion of seed from the seed bank, but some seed was placed at germinable depths. Pheidole hartmeyeri was identified as a likely biological control agent for annual ryegrass seeds and wild radish, while Me. turneri and Mo. rothsteini have potential as biocontrol agents for annual ryegrass, but further research is needed. PMID- 27497116 TI - Supercooling Points of Murgantia histrionica (Hemiptera: Pentatomidae) and Field Mortality in the Mid-Atlantic United States Following Lethal Low Temperatures. AB - The harlequin bug, Murgantia histrionica (Hahn), is a serious pest of brassicaceous vegetables in southern North America. While this insect is limited in its northern range of North America, presumably by severe cold winter temperatures, specific information on its cold hardiness remains unknown. We determined the supercooling points (SCPs) for Maryland and Virginia adult populations and found no significant difference among these populations. SCPs were similar for adults ([Formula: see text] = -10.35 degrees C; [Formula: see text] 2.54) and early and late instar ([Formula: see text] = -11.00 degrees C; [Formula: see text] 4.92) and between adult males and females. However, SCPs for first instars ([Formula: see text] = -21.56 degrees C; [Formula: see text]1.47) and eggs ([Formula: see text] = -23.24 degrees C; [Formula: see text]1.00) were significantly lower. We also evaluated field survival of overwintering harlequin bug adults during extreme cold episodes of January 2014 and January 2015, which produced widespread air temperatures lower than -15 degrees C and subfreezing soil temperatures in the Mid-Atlantic Region. After the 48-h episode in 2014, bug mortality in exposed field sites averaged 88%, compared to <5% mortality of bugs sheltered in an unheated greenhouse (recorded minimum temperature 4.4 degrees C). After the 2015 episode, ~80% of adults that were established in the field the previous November and then sheltered in an unheated garage during the episode, died, in contrast to 96% mortality in exposed field sites. Our results provide new information on M. histrionica overwintering biology, and thermal limitations to its distribution, which leads to improved predictive capabilities to forecast pest severity. PMID- 27497117 TI - Prevalence and Amounts of Salmonella Found on Raw California Inshell Pistachios. AB - After harvest, pistachios are hulled with mechanical abrasion and then separated in a float tank containing water; the nuts that float (~15%; floaters) and those that sink (~85%; sinkers) are dried and stored separately. To determine the prevalence of Salmonella in pistachios, a total of 3,966 samples (1,032 floaters and 2,934 sinkers) were collected within 4 months of the 2010, 2011, and 2012 harvests from storage silos (12 samples from each silo, in most cases) and were stored at 4 degrees C; 100-g subsamples were enriched for the presence of Salmonella. Twenty-one of the floater samples and 11 of the sinker samples were positive for Salmonella: 2.0% prevalence (95% confidence interval [CI], 1.3 to 3.1%) and 0.37% prevalence (95% CI, 0.21 to 0.67%), respectively, for a weighted average prevalence of 0.61%. Levels of Salmonella were determined for positive samples using a most-probable-number (MPN) method with multiple 50-g, three 5.6 g, and three 0.56-g subsamples. Geometric mean levels of Salmonella in floaters and sinkers were 0.66 MPN/100 g (0.14 to 5.3 MPN/100 g) and 0.18 MPN/100 g (0.10 to 0.62 MPN/100 g), respectively. Seven different serovars were identified among the isolates, with nine pulsed-field gel electrophoresis fingerprints; as many as four serovars were isolated from some samples. Salmonella serovars Montevideo (44%), Enteritidis (19%), Senftenberg (16%), Worthington (12%), and Liverpool (9.4%) were most commonly isolated from the initial 100-g samples. The prevalence and levels of Salmonella in pistachios are within those observed for other tree nuts, but the limited number of serovars isolated suggests a narrow and persistent contamination source. PMID- 27497118 TI - Effect of Hydrogen Peroxide in Combination with Minimal Thermal Treatment for Reducing Bacterial Populations on Cantaloupe Rind Surfaces and Transfer to Fresh Cut Pieces. AB - Surface structure and biochemical characteristics of bacteria and produce play a major role in how and where bacteria attach, complicating decontamination treatments. Whole cantaloupe rind surfaces were inoculated with Salmonella, Escherichia coli O157:H7, and Listeria monocytogenes at 10(7) CFU/ml. Average population size of Salmonella, Escherichia coli O157:H7, and L. monocytogenes recovered after surface inoculation was 4.8 +/- 0.12, 5.1 +/- 0.14, and 3.6 +/- 0.13 log CFU/cm(2), respectively. Inoculated melons were stored at 5 and 22 degrees C for 7 days before washing treatment interventions. Intervention treatments used were (i) water (H2O) at 22 degrees C, (ii) H2O at 80 degrees C, (iii) 3% hydrogen peroxide (H2O2) at 22 degrees C, and (iv) a combination of 3% H2O2 and H2O at 80 degrees C for 300 s. The strength of pathogen attachment (SR value) at days 0, 3, and 7 of storage was determined, and then the efficacy of the intervention treatments to detach, kill, and reduce transfer of bacteria to fresh-cut pieces during fresh-cut preparation was investigated. Populations of E. coli O157:H7 attached to the rind surface at significantly higher levels (P < 0.05) than Salmonella and L. monocytogenes, but Salmonella exhibited the strongest attachment (SR value) at all days tested. Washing with 3% H2O2 alone led to significant reduction (P < 0.05) of bacteria and caused some changes in bacterial cell morphology. A combination treatment with H2O and 3% H2O2 at 8 degrees C led to an average 4-log reduction of bacterial pathogens, and no bacterial pathogens were detected in fresh-cut pieces prepared from this combination treatment, including enriched fresh-cut samples. The results of this study indicate that the microbial safety of fresh-cut pieces from treated cantaloupes was improved at day 6 of storage at 5 degrees C and day 3 of storage at 10 degrees C. PMID- 27497119 TI - Spatial and Temporal Distribution of Escherichia coli on Beef Trimmings Obtained from a Beef Packing Plant. AB - The objective of this study was to determine the immediate source of Escherichia coli on beef trimmings produced at a large packing plant by analyzing the E. coli on trimmings at various locations of a combo bin filled on the same day and of bins filled on different days. Ten 2,000-lb (907-kg) combo bins (B1 through B10) of trimmings were obtained from a large plant on 6 days over a period of 5 weeks. Thin slices of beef with a total area of approximately 100 cm(2) were excised from five locations (four corners and the center) at each of four levels of the bins: the top surface and 30, 60, and 90 cm below the top. The samples were enriched for E. coli in modified tryptone soya broth supplemented with 20 mg/liter novobiocin. The positive enrichment cultures, as determined by PCR, were plated on E. coli/coliform count plates for recovery of E. coli. Selected E. coli isolates were genotyped using multiple-locus variable-number tandem repeat analysis (MLVA). Of the 200 enrichment cultures, 43 were positive by PCR for E. coli, and 32 of these cultures yielded E. coli isolates. Two bins did not yield any positive enrichment cultures, and three PCR-positive bins did not yield any E. coli isolates. MLVA of 165 E. coli isolates (30, 62, 56, 5, and 12 from B6 through B10, respectively) revealed nine distinct genotypes. MLVA types 263 and 89 were most prevalent overall and on individual days, accounting for 49.1 and 37.6% of the total isolates, respectively. These two genotypes were also found at multiple locations within a bin. All nine genotypes belonged to the phylogenetic group A0 of E. coli, suggesting an animal origin. The finding that the trimmings carried very few E. coli indicates an overall effective control over contamination of beef with E. coli at this processing plant. The lack of strain diversity of the E. coli on trimmings suggests that most E. coli isolates may have come from common sources, most likely equipment used in the fabrication process. PMID- 27497120 TI - Prevalence and Characterization of Salmonella enterica and Salmonella Bacteriophages Recovered from Beef Cattle Feedlots in South Texas. AB - Asymptomatic Salmonella carriage in beef cattle is a food safety concern, and the beef feedlot environment may function as a reservoir of this pathogen. The goal of this study was to identify and isolate Salmonella and Salmonella bacteriophages from beef cattle feedlot environments in order to better understand the microbial ecology of Salmonella and identify phages that might be useful as anti-Salmonella beef safety interventions. Three feedlots in south Texas were visited, and 27 distinct samples from each source were collected from dropped feces, feed from feed bunks, drinking water from troughs, and soil in cattle pens (n = 108 samples). Preenrichment, selective enrichment, and selective/differential isolation of Salmonella were performed on each sample. A representative subset of presumptive Salmonella isolates was prepared for biochemical identification and serotyping. Samples were pooled by feedlot and sample type to create 36 samples and enriched to recover phages. Recovered phages were tested for host range against two panels of Salmonella hosts. Salmonella bacteria were identified in 20 (18.5%) of 108 samples by biochemical and/or serological testing. The serovars recovered included Salmonella enterica serovars Anatum, Muenchen, Altona, Kralingen, Kentucky, and Montevideo; Salmonella Anatum was the most frequently recovered serotype. Phage-positive samples were distributed evenly over the three feedlots, suggesting that phage prevalence is not strongly correlated with the presence of culturable Salmonella. Phages were found more frequently in soil and feces than in feed and water samples. The recovery of bacteriophages in the Salmonella-free feedlot suggests that phages might play a role in suppressing the Salmonella population in a feedlot environment. PMID- 27497121 TI - Contamination Revealed by Indicator Microorganism Levels during Veal Processing. AB - During site visits of veal processors, the U.S. Department of Agriculture, Food Safety Inspection Service (FSIS) has reported processing deficiencies that likely contribute to increased levels of veal contamination. Here, we report the results of measuring aerobic plate count bacteria (APC), Enterobacteriaceae, coliforms (CF), and Escherichia coli during eight sample collections at five veal processors to assess contamination during the harvest of bob veal and formula-fed veal before (n = 5 plants) and after (n = 3 plants) changes to interventions and processing practices. Hides of veal calves at each plant had mean log CFU/100 cm(2) APC, Enterobacteriaceae, CF, and E. coli of 6.02 to 8.07, 2.95 to 5.24, 3.28 to 5.83, and 3.08 to 5.59, respectively. Preintervention carcasses had mean log CFU/100 cm(2) APC, Enterobacteriaceae, CF, and E. coli of 3.08 to 5.22, 1.16 to 3.47, 0.21 to 3.06, and -0.07 to 3.10, respectively, before and 2.72 to 4.50, 0.99 to 2.76, 0.69 to 2.26, and 0.33 to 2.12, respectively, after changes were made to improve sanitary dressing procedures. Final veal carcasses had mean log CFU/100 cm(2) APC, Enterobacteriaceae, CF, and E. coli of 0.36 to 2.84, -0.21 to 1.59, -0.23 to 1.59, and -0.38 to 1.45 before and 0.44 to 2.64, -0.16 to 1.33, 0.42 to 1.20, and 0.48 to 1.09 after changes were made to improve carcass directed interventions. Whereas the improved dressing procedures resulted in improved carcass cleanliness, the changes to carcass-directed interventions were less successful, and veal processors are urged to use techniques that ensure uniform and consistent delivery of antimicrobials to carcasses. Analysis of results comparing bob veal to formula-fed veal found bob veal hides, preintervention carcasses, and final carcasses to have increased (P < 0.05) APC, Enterobacteriaceae, CF, and E. coli (with the exception of hide Enterobacteriaceae; P > 0.05) relative to formula fed veal. When both veal categories were harvested at the same plant on the same day, similar results were observed. Since identification by FSIS, the control of contamination during veal processing has started to improve, but challenges still persist. PMID- 27497122 TI - Isolation and Characterization of Antimicrobial-Resistant Nontyphoidal Salmonella enterica Serovars from Imported Food Products. AB - The objective of this study was to determine antimicrobial resistance and elucidate the resistance mechanism in nontyphoidal Salmonella enterica serovars isolated from food products imported into the United States from 2011 to 2013. Food products contaminated with antimicrobial-resistant nontyphoidal S. enterica were mainly imported from Taiwan, Indonesia, Vietnam, and China. PCR, DNA sequencing, and plasmid analyses were used to characterize antimicrobial resistance determinants. Twentythree of 110 S. enterica isolates were resistant to various antimicrobial classes, including beta-lactam, aminoglycoside, phenicol, glycopeptide, sulfonamide, trimethoprim, and/or fluoroquinolone antimicrobial agents. Twelve of the isolates were multidrug resistant strains. Antimicrobial resistance determinants blaTEM-1, blaCTX-M-9, blaOXA-1, tetA, tetB, tetD, dfrA1, dfrV, dhfrI, dhfrXII, drf17, aadA1, aadA2, aadA5, orfC, qnrS, and mutations of gyrA and parC were detected in one or more antimicrobial-resistant nontyphoidal S. enterica strains. Plasmid profiles revealed that 12 of the 23 antimicrobial-resistant strains harbored plasmids with incompatibility groups IncFIB, IncHI1, IncI1, IncN, IncW, and IncX. Epidemiologic and antimicrobial resistance monitoring data combined with molecular characterization of antimicrobial resistance determinants in Salmonella strains isolated from imported food products may provide information that can be used to establish or implement food safety programs to improve public health. PMID- 27497123 TI - Disinfectant and Antimicrobial Susceptibility Profiles of the Big Six Non-O157 Shiga Toxin-Producing Escherichia coli Strains from Food Animals and Humans. AB - The disinfectant and antimicrobial susceptibility profiles of 138 non-O157 Shiga toxin-producing Escherichia coli strains (STECs) from food animals and humans were determined. Antimicrobial resistance (AMR) was moderate (39.1% of strains) in response to 15 antimicrobial agents. Animal strains had a lower AMR prevalence (35.6%) than did human strains (43.9%) but a higher prevalence of the resistance profile GEN-KAN-TET. A decreasing prevalence of AMR was found among animal strains from serogroups O45 > O145 > O121 > O111 > O26 > O103 and among human strains from serogroups O145 > O103 > O26 > O111 > O121 > O45. One animal strain from serogroups O121 and O145 and one human strain from serogroup O26 had extensive drug resistance. A high prevalence of AMR in animal O45 and O121 strains and no resistance or a low prevalence of resistance in human strains from these serogroups suggests a source other than food animals for human exposure to these strains. Among the 24 disinfectants evaluated, all strains were susceptible to triclosan. Animal strains had a higher prevalence of resistance to chlorhexidine than did human strains. Both animal and human strains had a similar low prevalence of low-level benzalkonium chloride resistance, and animal and human strains had similar susceptibility profiles for most other disinfectants. Benzyldimethylammonium chlorides and C10AC were the primary active components in disinfectants DC&R and P-128, respectively, against non-O157 STECs. A disinfectant FS512 MIC >= 8 MUg/ml was more prevalent among animal O121 strains (61.5%) than among human O121 strains (25%), which may also suggest a source of human exposure to STEC O121 other than food animals. Bacterial inhibition was not dependent solely on pH but was correlated with the presence of dissociated organic acid species and some undissociated acids. PMID- 27497124 TI - Virulence and Antibiotic and Heavy Metal Resistance of Vibrio parahaemolyticus Isolated from Crustaceans and Shellfish in Shanghai, China. AB - Vibrio parahaemolyticus can cause serious human seafoodborne gastroenteritis and even death. In this study, we isolated and characterized 208 V. parahaemolyticus strains from 10 species of commonly consumed crustaceans and shellfish available in fish markets in Shanghai, People's Republic of China, in 2014. Most of these aquatic species had not been detected previously. The results revealed an extremely low occurrence of pathogenic V. parahaemolyticus carrying the toxin gene trh (1.9%). However, a high level of resistance to the antibiotics ampicillin (94.2%), rifampin (93.3%), and streptomycin (77.9%) was found. Approximately 74.5% of the isolates had multidrug-resistant phenotypes. Tolerance to the heavy metals Cu(2+), Pb(2+), and Cd(2+) was detected in the majority of antibiotic resistant isolates. The resistance patterns differed depending on the tested samples. The crustaceans Penaeus monodon and Marsupenaeus japonicus harbored more antibiotic-resistant bacteria, whereas the isolates from the crustacean Litopenaeus vannamei and the shellfish Busycon canaliculatus had high tolerance to eight heavy metals tested. In contrast to the wide distribution of multidrug resistance and tolerance to heavy metals, lower percentages of plasmid DNA (22.6%) and SXT/R391-like integrative and conjugative elements (4.8%) were detected in the isolates, suggesting that V. parahaemolyticus in these aquatic species may have adopted some other molecular mechanisms that mediated the high prevalence of resistance determinants. The results of this study support the need for food safety risk assessment of aquatic products. PMID- 27497125 TI - Enzymatic Digestion for Improved Bacteria Separation from Leafy Green Vegetables. AB - An effective and rapid method for the separation of bacteria from food matrix remains a bottleneck for rapid bacteria detection for food safety. Bacteria can strongly attach to a food surface or internalize within the matrix, making their isolation extremely difficult. Traditional methods of separating bacteria from food routinely involve stomaching, blending, and shaking. However, these methods may not be efficient at removing all the bacteria from complex matrices. Here, we investigate the benefits of using enzyme digestion followed by immunomagnetic separation to isolate Salmonella from spinach and lettuce. Enzymatic digestion using pectinase and cellulase was able to break down the structure of the leafy green vegetables, resulting in the detachment and release of Salmonella from the leaves. Immunomagnetic separation of Salmonella from the liquefied sample allowed an additional separation step to achieve a more pure sample without leaf debris that may benefit additional downstream applications. We have investigated the optimal combination of pectinase and cellulase for the digestion of spinach and lettuce to improve sample detection yields. The concentrations of enzymes used to digest the leaves were confirmed to have no significant effect on the viability of the inoculated Salmonella. Results reported that the recovery of the Salmonella from the produce after enzyme digestion of the leaves was significantly higher (P < 0.05) than traditional sample preparation methods to separate bacteria (stomaching and manually shaking). The results demonstrate the potential for use of enzyme digestion prior to separation can improve the efficiency of bacteria separation and increase the likelihood of detecting pathogens in the final detection assay. PMID- 27497126 TI - Enterotoxin Gene Profile and Molecular Characterization of Staphylococcus aureus Isolates from Bovine Bulk Milk and Milk Products of Tigray Region, Northern Ethiopia. AB - Staphylococcal food poisoning (SFP) is an important foodborne disease worldwide, and milk and milk products are commonly associated with SFP outbreaks. The objectives of this study were to investigate the distribution of staphylococcal enterotoxin (se) genes in Staphylococcus aureus from raw cow's milk and milk products and to assess their genetic background with the spa typing method. Of the 549 samples (297 bulk milk and 162 milk product samples) collected from Tigray region, Northern Ethiopia, 160 (29.1%) were positive for S. aureus, of which 82 (51%) were found to harbor se genes by a modified multiplex PCR. Nine se genes were identified: sea (n = 12), seb (n = 3), sec (n = 3), sed(n = 4), seg (n = 49), seh (n = 2), sei (n = 40), sej (n = 1), and tsst-1 (n = 24). The classical type of genes accounted for 27%. Of the 82 enterotoxigenic isolates, 41.5 and 12.4% harbored two or more se genes, respectively. The highest gene association was observed between sei and seg, whereas sea and seb were always found together with the new types of se genes. Altogether, 18 genotypes of toxin genes were identified, and 33% of the samples contained > 5 log CFU ml(-1) S. aureus. spa typing identified 22 spa types and three novel spa sequences, which showed the high genetic diversity of the isolates. No apparent relationship was observed between spa type and se genes. Of the 25 spa types, 13 (52%) were from raw milk, 3 (12%) from milk products, and 9 (36%) from both types of sample. Types t314 (20.7%,n = 17), t458 (18.3%, n = 15), and t6218 (9.8%, n= 8) were the most common spa types identified and were widely distributed in three of the eight studied localities. This is the first study from the Tigray region to report the high distribution of enterotoxigenic S. aureus with a diversified genetic background from dairy food. The study may provide valuable data for microbial food safety risk assessment, molecular epidemiology, and phylogenetic studies of S. aureus in Ethiopia. PMID- 27497127 TI - Inhibition of Listeria monocytogenes by Buffered Dry Vinegar in Reduced-Sodium Ready-to-Eat Uncured Turkey Stored at 4 degrees C. AB - A reduced-sodium ready-to-eat (RTE) uncured turkey was manufactured with buffered dry vinegar treatments to validate the inhibition of Listeria monocytogenes and spoilage microflora and to determine the effects on sensory and quality attributes. Samples were stored at 4 degrees C for 12 weeks, and the study was independently replicated three times. Two different five-strain inocula of L. monocytogenes obtained from different sources were used for evaluating the efficacy of the buffered dry vinegar treatments. The results showed that 0.6 and 0.8% buffered dry vinegar with a sodium base (BDV-SB) and buffered dry vinegar with a potassium base (BDV-PB) at 0.7 and 0.9% controlled L. monocytogenes for 12 weeks. The untreated control product containing no buffered dry vinegar showed >1 log increase in L. monocytogenes populations counts at the end of 2 weeks. Statistical analysis confirmed that the dry vinegar treatments inhibited (P > 0.05) the growth of L. monocytogenes compared with the untreated control. No significant differences (P > 0.05) were seen in the inhibition of L. monocytogenes between the two different five-strain inocula. Instrumental color results showed no significant differences between the treatments. Purge loss results showed no significant differences between the dry vinegar treatments, but significant differences were seen between the untreated control and dry vinegar treatments at a few testing intervals. The overall results indicated that the dry vinegar ingredients (6.66 to 8.83 mM acetic acid in the finished product) were effective in inhibiting L. monocytogenes obtained from multiple sources in reduced-sodium RTE uncured turkey stored at 4 degrees C without adversely impacting the quality attributes. PMID- 27497128 TI - Antibacterial, Antibiofilm Effect of Burdock (Arctium lappa L.) Leaf Fraction and Its Efficiency in Meat Preservation. AB - First, the antibacterial, antibiofilm effect and chemical composition of burdock (Arctium lappa L.) leaf fractions were studied. Then, the efficiency of burdock leaf fractions in pork preservation was evaluated. The results showed that burdock leaf fraction significantly inhibited the growth and biofilm development of Escherichia coli and Salmonella Typhimurium. MICs of burdock leaf fractions on E. coli and Salmonella Typhimurium were both 2 mg/ml. At a concentration of 2.0 mg/ml, the inhibition rates of the fraction on growth and development of E. coli and Salmonella Typhimurium biofilms were 78.7 and 69.9%, respectively. During storage, the log CFU per gram of meat samples treated with burdock leaf fractions decreased 2.15, compared with the samples without treatment. The shelf life of pork treated with burdock leaf fractions was extended 6 days compared with the pork without treatment, and the sensory property was obviously improved. Compared with the control group, burdock leaf fraction treatment significantly decreased the total volatile basic nitrogen value and pH of the meat samples. Chemical composition analysis showed that the burdock leaf fraction consisted of chlorogenic acid, caffeic acid, p-coumaric acid, rutin, cynarin, crocin, luteolin, arctiin, and quercetin. As a vegetable with an abundant source, burdock leaf is safe, affordable, and efficient in meat preservation, indicating that burdock leaf fraction is a promising natural preservative for pork. PMID- 27497129 TI - Postharvest Control of Botrytis cinerea and Monilinia fructigena in Apples by Gamma Irradiation Combined with Fumigation. AB - To extend the shelf life of apples in South Korea, we evaluated the effect of gamma irradiation alone or gamma irradiation combined with fumigation on the control of postharvest decay caused by Botrytis cinerea and Monilinia fructigena. An irradiation dose of 1.0 kGy caused the maximal inhibition of B. cinerea and M. fructigena spore germination. The gamma irradiation dose required to reduce the spore germination by 90% was 0.76 and 0.78 kGy for B. cinerea and M. fructigena, respectively. Inhibition of conidial germination of both fungal pathogens occurred at a greater level at the doses of 0.2 to 1.0 kGy compared with the nontreated control; 0.2 kGy caused 90.5 and 73.9% inhibition of B. cinerea and M. fructigena, respectively. Treatment in vitro with the ecofriendly fumigant ethanedinitrile had a greater effect compared with the nontreated control. The in vitro antifungal effects of the gamma irradiation and fumigation treatments allowed us to further study the effects of the combined treatments. Interestingly, when irradiation was combined with fumigation, the percentage of disease inhibition increased more at lower (<0.4 kGy) than at higher doses of irradiation, suggesting that the combined treatments reduced the necessary irradiation dose in phytosanitary irradiation processing under storage conditions. PMID- 27497130 TI - Characterization of Shiga Toxin-Producing Escherichia coli O157 Isolates from Bovine Carcasses. AB - The main purpose of this study was to determine the prevalence of Escherichia coli O157 on bovine carcasses before and after chilling at a large slaughterhouse located in the city of Barcelona, Spain, to assess the effectiveness of dry chilling on reducing E. coli O157 contamination of carcasses. In addition, the study characterized the E. coli O157 strains isolated in terms of virulence factors, antibiotic susceptibility, and their genetic diversity. Individual bovine carcasses were sampled before (n = 300) and after (n = 300) chilling over an 8-month period. Positive samples for E. coli O157 were subjected to virulence screening by PCR (stx1, stx2, and eaeA genes and the fliCH7 gene), antimicrobial susceptibility testing, and molecular typing by pulsed-field gel electrophoresis. A total of 9.7% (29 of 300) of the nonrefrigerated carcasses examined and 2.3% (7 of 300) of the refrigerated carcasses were positive for E. coli O157. All the isolates were serotype O157:H7, 92% (33 of 36) carried the stx1, stx2, and eaeA genes, and 8% (3 of 36) carried the stx2 and eaeA genes. Antimicrobial susceptibility testing showed a high degree of resistance: 29 strains (81%) were resistant to at least 1 antimicrobial of the 12 antimicrobials tested; 69% (25 of 36) were resistant to 4 or more antimicrobials. Molecular typing by pulsed-field gel electrophoresis found a high diversity of genetic types, implying little cross-contamination in the slaughterhouse. This study confirms that E. coli O157:H7 is present on the carcasses slaughtered in Spain, although its prevalence is reduced by the dry chilling process used. The recovered isolates showed potential pathogenesis and a high degree of multidrug resistance, confirming the importance of bovine meat monitoring. PMID- 27497131 TI - Prevalence of Antibiotic-Resistant Fecal Escherichia coli Isolates from Penned Broiler and Scavenging Local Chickens in Arusha, Tanzania. AB - We compared the prevalence of antibiotic-resistant Escherichia coli isolates from household-level producers of broiler (commercial source breeds) and local chickens in the Arusha District of Tanzania. Households were composed of a single dwelling or residence with independent, penned broiler flocks. Free-range, scavenging chickens were mixed breed and loosely associated with individual households. A total of 1,800 E. coli isolates (1,200 from broiler and 600 from scavenging local chickens) from 75 chickens were tested for their susceptibility against 11 antibiotics by using breakpoint assays. Isolates from broiler chickens harbored a higher prevalence of antibiotic-resistant E. coli relative to scavenging local chickens, including sulfamethoxazole (80.3 versus 34%), followed by trimethoprim (69.3 versus 27.7%), tetracycline (56.8 versus 20%), streptomycin (52.7 versus 24.7%), amoxicillin (49.6 versus 17%), ampicillin (49.1 versus 16.8%), ciprofloxacin (21.9 versus 1.7%), and chloramphenicol (1.5 versus 1.2%). Except for resistance to chloramphenicol, scavenging local chickens harbored fewer resistant E. coli isolates (P < 0.05). Broiler chickens harbored more isolates that were resistant to >=7 antibiotics (P < 0.05). The higher prevalence of antibiotic-resistant E. coli from broiler chickens correlated with the reported therapeutic and prophylactic use of antibiotics in this poultry population. We suggest that improved biosecurity measures and increased vaccination efforts would reduce reliance on antibiotics by these households. PMID- 27497132 TI - Strain Diversity of Pseudomonas fluorescens Group with Potential Blue Pigment Phenotype Isolated from Dairy Products. AB - The blue discoloration in Mozzarella cheese comes from bacterial spoilage due to contamination with Pseudomonas. Fourteen Pseudomonas fluorescens strains from international collections and 55 new isolates of dominant bacterial populations from spoiled fresh cheese samples were examined to assess genotypic and phenotypic strain diversity. Isolates were identified by 16S rRNA gene sequencing and tested for the production of the blue pigment at various temperatures on Mascarpone agar and in Mozzarella preserving fluid (the salty water in which the cheese is conserved, which becomes enriched by cheese minerals and peptides during storage). Pulsed-field gel electrophoresis analysis after treatment with the endonuclease SpeI separated the isolates into 42 genotypes at a similarity level of 80%. Based on the pulsotype clustering, 12 representative strains producing the blue discoloration were chosen for the multilocus sequence typing targeting the gyrB, glnS, ileS, nuoD, recA, rpoB, and rpoD genes. Four new sequence typing profiles were discovered, and the concatenated sequences of the investigated loci grouped the tested strains into the so-called ''blue branch'' of the P. fluorescens phylogenetic tree, confirming the linkage between pigment production and a specific genomic cluster. Growth temperature affected pigment production; the blue discoloration appeared at 4 and 14 degrees C but not at 30 degrees C. Similarly, the carbon source influenced the phenomenon; the blue phenotype was generated in the presence of glucose but not in the presence of galactose, sodium succinate, sodium citrate, or sodium lactate. PMID- 27497133 TI - Recipe Modification Improves Food Safety Practices during Cooking of Poultry. AB - Many consumers do not practice proper food safety behaviors when preparing food in the home. Several approaches have been taken to improve food safety behaviors among consumers, but there still is a deficit in actual practice of these behaviors. The objective of this study was to assess whether the introduction of food safety instructions in recipes for chicken breasts and ground turkey patties would improve consumers' food safety behaviors during preparation. In total, 155 consumers in two locations (Manhattan, KS, and Nashville, TN) were asked to prepare a baked chicken breast and a ground turkey patty following recipes that either did or did not contain food safety instructions. They were observed to track hand washing and thermometer use. Participants who received recipes with food safety instructions (n = 73) demonstrated significantly improved food safety preparation behaviors compared with those who did not have food safety instructions in the recipe (n = 82). In addition, the majority of consumers stated that they thought the recipes with instructions were easy to use and that they would be likely to use similar recipes at home. This study demonstrates that recipes could be a good source of food safety information for consumers and that they have the potential to improve behaviors to reduce foodborne illness. PMID- 27497134 TI - Internalization of Listeria monocytogenes in Whole Avocado. AB - In recent years, tree fruits have emerged as a new concern for Listeria monocytogenes contamination. The objective of the current study was to evaluate the potential internalization of L. monocytogenes from the surface of avocados into the edible portions of the fruit during certain postharvest practices simulated in a laboratory setting. One set of intact avocados was spot inoculated with L. monocytogenes on the stem scar, and the second set was hydrocooled in water contaminated with L. monocytogenes. Under these experimental conditions, L. monocytogenes internalized into the avocado pulp through the stem or stem scar after both spot inoculation and hydrocooling. In avocados spot inoculated with 50, 130, 500, and 1,300 CFU per fruit, bacteria were detected in the edible portion adjacent to the stem scar within 15 days postinoculation during storage at 4 degrees C. In avocados hydrocooled in water containing L. monocytogenes at 10(6) and 10(8) CFU/ml, bacteria reached the bottom end of the fruit, and the populations in the edible portion adjacent to the stem scar reached up to 5.90 to 7.19 log CFU/g within 10 to 15 days during storage at 4 degrees C. Dye mixed with inoculum was useful for guiding subsequent sampling, but dye penetration patterns were not always consistent with bacterial penetration. PMID- 27497135 TI - Prevalence of Multidrug-Resistant Bacteria on Fresh Vegetables Collected from Farmers' Markets in Connecticut. AB - This study determined the prevalence of multidrug-resistant (MDR) Acinetobacter baumannii on fresh vegetables collected from farmers' markets in Connecticut. One hundred samples each of fresh carrots, potatoes, and lettuce were sampled and streaked on selective media, namely Leeds Acinetobacter and MDR Acinetobacter agars. All morphologically different colonies from MDR Acinetobacter agar were identified by using Gram staining, biochemical tests, and PCR. In addition, susceptibility of the isolates to 10 antibiotics commonly used in humans, namely imipenem, ceftriaxone, cefepime, minocycline, erythromycin, colistin-sulfate, streptomycin, neomycin, doxycycline, and rifampin was determined by using an antibiotic disk diffusion assay. The results revealed that only two samples of potato and one sample of lettuce yielded A. baumannii. In addition, all carrot samples were found to be negative for the organism. However, several other opportunistic, MDR human pathogens, such as Burkholderia cepacia (1% potatoes, 5% carrots, and none in lettuce), Stenotrophomonas maltophilia (6% potatoes, 2% lettuce, and none in carrots), and Pseudomonas luteola (9% potatoes, 3% carrots, and none in lettuce) were recovered from the vegetables. Antibiotic susceptibility screening of the isolates revealed high resistance rates for the following: ceftriaxone (6 of 6), colistin-sulfate (5 of 6), erythromycin (5 of 6), and streptomycin (4 of 6) in B. cepacia; colistin-sulfate (11 of 11) and imipenem (10 of 11) in P. luteola; colistin-sulfate (8 of 8), ceftriaxone (8 of 8), cefepime (7 of 8), erythromycin (5 of 8), and imipenem (4 of 8) in S. maltophilia; and imipenem (3 of 3), ceftriaxone (3 of 3), erythromycin (3 of 3), and streptomycin (3 of 3) in A. baumannii. The results revealed the presence of MDR bacteria, including human pathogens on fresh produce, thereby highlighting the potential health risk in consumers, especially those with a compromised immune system. PMID- 27497136 TI - Nontuberculous Mycobacteria on Ready-to-Eat, Raw and Frozen Fruits and Vegetables. AB - The consumption of fruits and vegetables is increasing worldwide because of the positive impact of these foods on human health. Ready-to-eat, raw whole, and frozen fruits and vegetables were purchased from markets and examined for the presence of nontuberculous mycobacteria (NTM) using culture, real-time PCR (qPCR), and sequencing. Using qPCR, Mycobacterium sp. at 10(0) to 10(4) ge/g (genome equivalents per gram) was found in almost all of the 178 samples; members of the M. avium complex were found only sporadically. Culture and sequencing revealed the presence of 22 viable NTM isolates in 17 samples. In addition to NTM commonly found in the environment, several rarely described isolates of viable NTM were recovered. The presence of Mycobacterium shigaense, which has been previously isolated only from human patients, was found in lettuce, the first time that this species has been found in an environmental sample. Mycobacterium parmense, Mycobacterium palustre, and Mycobacterium llatzerense, which have been previously isolated from human patients and occasionally from soil and water, were recovered from leafy green vegetables. Strawberries and cut salad mixes contained Mycobacterium algericum, Mycobacterium fallax, and Mycobacterium minnesotense. NTM are primarily nonpathogenic. However, consumption of fruits or vegetables contaminated with NTM could represent a health risk for immunocompromised people, children, and the elderly. PMID- 27497137 TI - Histology as a Valid Tool To Differentiate Fresh from Frozen-Thawed Marinated Fish. AB - European Commission Regulation (EU) 1276/2011 requires that fishery products intended for raw consumption be frozen at -20 degrees C for not less than 24 h or at -35 degrees C for at least 15 h in order to kill viable parasites other than trematodes. But because marinating processes are not always effective in destroying nematode larvae, raw marinated fish preparations should be frozen before consumption. This study evaluated the performance of a standardized histological method to distinguish between fresh and frozen-thawed raw marinated fish. Sixty anchovy (Engraulis encrasicolus) fillets were sampled: 30 were marinated at +4 degrees C for 24 h, and 30 were frozen at -20 degrees C for 24 h before being marinated for 24 h. All 60 samples were fixed in formalin, processed for paraffin embedding, cut, and stained with hematoxylin and eosin. The slide preparations were examined microscopically by three independent histopathologists and classified as frozen-thawed or negative according to standard operating procedure criteria in use at our laboratory. Performance evaluation of the method showed 100% sensitivity (95% confidence interval [CI], 88.4 to 100%) and 100% specificity (95% CI, 88.4 to 100%), and the interrater agreement (Cohen's kappa) was 1 (95% CI, 0.85 to 1). Histology proved a valid and reliable tool to distinguish fresh from frozen-thawed marinated fish. It can be applied to deliver safe raw fishery products to consumers in order to minimize the risk of anisakidosis. PMID- 27497138 TI - A composite indicator to measure universal health care coverage in India: way forward for post-2015 health system performance monitoring framework. AB - BACKGROUND: There is limited work done on developing methods for measurement of universal health coverage. We undertook a study to develop a methodology and demonstrate the practical application of empirically measuring the extent of universal health coverage at district level. Additionally, we also develop a composite indicator to measure UHC. METHODS: A cross-sectional survey was undertaken among 51 656 households across 21 districts of Haryana state in India. Using the WHO framework for UHC, we identified indicators of service coverage, financial risk protection, equity and quality based on the Government of India and the Haryana Government's proposed UHC benefit package. Geometric mean approach was used to compute a composite UHC index (CUHCI). Various statistical approaches to aggregate input indicators with or without weighting, along with various incremental combinations of input indicators were tested in a comprehensive sensitivity analysis. FINDINGS: The population coverage for preventive and curative services is presented. Adjusting for inequality, the coverage for all the indicators were less than the unadjusted coverage by 0.1 6.7% in absolute term and 0.1-27% in relative term. There was low unmet need for curative care. However, about 11% outpatient consultations were from unqualified providers. About 30% households incurred catastrophic health expenditures, which rose to 38% among the poorest 20% population. Summary index (CUHCI) for UHC varied from 12% in Mewat district to 71% in Kurukshetra district. The inequality unadjusted coverage for UHC correlates highly with adjusted coverage. CONCLUSION: Our paper is an attempt to develop a methodology to measure UHC. However, careful inclusion of others indicators of service coverage is recommended for a comprehensive measurement which captures the spirit of universality. Further, more work needs to be done to incorporate quality in the measurement framework. PMID- 27497139 TI - Incidence and determinants of hysterectomy in a low-income setting in Gujarat, India. AB - Hysterectomy is a leading reason for use of health insurance amongst low-income women in India, but there are limited population-level data available to inform policy. This paper reports on the findings of a mixed-methods study to estimate incidence and identify predictors of hysterectomy in a low-income setting in Gujarat, India. The estimated incidence of hysterectomy, 20.7/1000 woman- years (95% CI: 14.0, 30.8), was considerably higher than reported from other countries, at a relatively low mean age of 36 years. There was strong evidence that among women of reproductive age, those with lower income and at least two children underwent hysterectomy at higher rates. Nearly two-thirds of women undergoing hysterectomy utilized private hospitals, while the remainder used government or other non-profit facilities. Qualitative research suggested that weak sexual and reproductive health services, a widespread perception that the post-reproductive uterus is dispensable and lack of knowledge of side effects have resulted in the normalization of hysterectomy. Hysterectomy appears to be promoted as a first or second-line treatment for menstrual and gynaecological disorders that are actually amenable to less invasive procedures. Most women sought at least two medical opinions prior to hysterectomy, but both public and private providers lacked equipment, skills and motivation to offer alternatives. Profit and training benefits also appeared to play a role in some providers' behaviour. Although women with insecure employment underwent the procedure knowing the financial and physical implications of undergoing a major surgery, the future health and work security afforded by hysterectomy appeared to them to outweigh risks. Findings suggest that sterilization may be associated with an increased risk of hysterectomy, potentially through biological or attitudinal links. Health policy interventions require improved access to sexual and reproductive health services and health education, along with surveillance and medical audits to promote high-quality choices for women through the life cycle. PMID- 27497140 TI - Sub-national health care financing reforms in Indonesia. AB - Indonesia has seen an emergence of local health care financing schemes over the last decade, implemented and operated by district governments. Often motivated by the local political context and characterized by a large degree of heterogeneity in scope and design, the common objective of the district schemes is to address the coverage gaps for the informal sector left by national social health insurance programs. This paper investigates the effect of these local health care financing schemes on access to health care and financial protection. Using data from a unique survey among District Health Offices, combined with data from the annual National Socioeconomic Surveys, the study is based on a fixed effects analysis for a panel of 262 districts over the period 2004-10, exploiting variation in local health financing reforms across districts in terms of type of reform and timing of implementation. Although the schemes had a modest impact on average, they do seem to have provided some contribution to closing the coverage gap, by increasing outpatient utilization for households in the middle quintiles that tend to fall just outside the target population of the national subsidized programs. However, there seems to be little effect on hospitalization or financial protection, indicating the limitations of local health care financing policies. In addition, we see effect heterogeneity across districts due to differences in design features. PMID- 27497141 TI - Prospective validation and adaptation of the HOSPITAL score to predict high risk of unplanned readmission of medical patients. AB - PRINCIPLES: The HOSPITAL score is a simple prediction model that accurately identifies patients at high risk of readmission and showed good performance in an international multicentre retrospective study. We aimed to demonstrate prospectively its accuracy to predict 30-day unplanned readmission and death. METHODS: We prospectively screened all consecutive patients aged >=50 years admitted to the department of general internal medicine of a large community hospital in Switzerland. We excluded patients who refused to give consent, who died during hospitalisation, or who were transferred to another acute care, rehabilitation or palliative care facility. The primary outcome was the first unplanned readmission or death within 30 days after discharge. Some of the predictors of the original score (discharge from an oncology service and length of stay) were adapted according to the setting for practical reasons, before the start of patient inclusion. We also assessed a simplified version of the score, without the variable "any procedure performed during hospitalisation". The performance of the score was evaluated according to its overall accuracy (Brier score), its discriminatory power (C-statistic), and its calibration (Hosmer Lemeshow goodness-of-fit test). RESULTS: Among the 346 included patients, 40 (11.6%) had a 30-day unplanned readmission or death. The HOSPITAL score showed very good accuracy (Brier score 0.10), good discriminatory power (C-statistic 0.70, 95% confidence interval [CI] 0.62-0.79), and an excellent calibration (p = 0.77). Patients were classified into three risk categories for the primary outcome: low (59%), intermediate (20.8%) and high risk (20.2%). The estimated risks of unplanned readmission/death for each category were 8.2%, 11.3% and 21.6%, respectively. The simplified score showed the same performance, with a Brier score of 0.10, a C-statistic of 0.70 (95% CI 0.61-0.79), and a goodness-of fit statistic of 0.40. CONCLUSIONS: The HOSPITAL score prospectively identified patients at high risk of 30-day unplanned readmission or death with good performance in medical patients in Switzerland. Its simplicity and good performance make it an easy-to-use tool to target patients who might most benefit from intensive transitional care interventions. PMID- 27497142 TI - Proposed cut-off value of the intrahepatic lipid content for metabolically normal persons assessed by proton magnetic resonance spectroscopy in a Japanese population. AB - AIMS: To determine the threshold intrahepatic lipid (IHL) content separating metabolically normal from abnormal in a Japanese population based on proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: A total of 305 Japanese subjects aged 20-69years were investigated. The subjects underwent general examination, blood tests, and (1)H-MRS of the liver after an overnight fast. They completed a questionnaire about daily drinking habits and their daily alcohol intake was calculated. RESULTS: The median IHL content was 4.7% in men and 1.7% in women, and it increased along with the number of features of metabolic syndrome (MetS). The optimum IHL cut-off value for separating normal subjects from those with at least one feature of MetS was 6.5% in men (AUC of ROC: 0.727, 95%-CI: 0.649-0.804) and 1.8% in women (0.765, 0.685-0.844). Alcohol intake was not correlated with the IHL content according to multiple logistic regression analysis. CONCLUSION: This study demonstrated a close association of IHL with features of MetS and identified IHL content cut-off values for metabolic normality in Japanese subjects. PMID- 27497143 TI - Detecting intrinsic muscle weakness of the hallux as an addition to early-stage screening of the feet in patients with diabetes. AB - AIMS: Present-day screening of the diabetic foot involves the Semmes Weinstein Monofilament Test for evaluating loss of sensibility, while testing for intrinsic muscle weakness is not implied. Just as with the early detection of sensibility loss, early detection of intrinsic muscle weakness might have important implications for the prevention of both ulceration and deformity in patients with diabetes. The purpose of this study is to investigate the prevalence of patients with diabetes presenting intrinsic muscle weakness of the hallux, but with a normal sensibility of the sole of the foot. METHODS: A cross-sectional study design was applied. Intrinsic muscle function of the hallux was measured with the Paper Grip Test, while sensibility of the sole of the foot was measured with the Semmes Weinstein Monofilament Test 5.07/10-g. RESULTS: In a period of three months a total of 266 patients with diabetes (mean age 60, 134 females (50%), 177 type 2 diabetes mellitus (67%)) met the inclusion criteria and were examined for both intrinsic muscle weakness of the hallux and sensibility of the soles of the feet. The results showed that intrinsic muscle weakness was present more frequent in patients with impaired sensibility (P=0.001), also 20% of the population had intrinsic muscle weakness in the presence of normal sensibility. Multivariate regression analysis showed that only age is associated with patients with diabetes presenting normal sensibility but impaired intrinsic muscle function (P=0.017). CONCLUSIONS: The Paper Grip Test could have added value to current physical examination of the feet in patients with diabetes. PMID- 27497144 TI - The local geographic distribution of diabetic complications in New York City: Associated population characteristics and differences by type of complication. AB - AIMS: To identify population characteristics associated with local variation in the prevalence of diabetic complications and compare the geographic distribution of different types of complications in New York City. METHODS: Using an all-payer database of emergency visits, we identified the proportion of unique adults with diabetes who also had cardiac, neurologic, renal and lower extremity complications. We performed multivariable regression to identify associations of demographic and socioeconomic factors, and diabetes-specific emergency department use with the prevalence of diabetic complications by Census tract. We also used geospatial analysis to compare local hotspots of diabetic complications. RESULTS: We identified 4.6million unique New York City adults, of which 10.5% had diabetes. Adjusting for demographic and socioeconomic factors, diabetes-specific emergency department use was associated with severe microvascular renal and lower extremity complications (p-values<0.001), but not with severe macrovascular cardiac or neurologic complications (p-values of 0.39 and 0.29). Our hotspot analysis demonstrated significant geographic heterogeneity in the prevalence of diabetic complications depending on the type of complication. Notably, the geographic distribution of hotspots of myocardial infarction were inversely correlated with hotspots of end-stage renal disease and lower extremity amputations (coefficients: -0.28 and -0.28). CONCLUSIONS: We found differences in the local geographic distribution of diabetic complications, which highlight the contrasting risk factors for developing macrovascular versus microvascular diabetic complications. Based on our analysis, we also found that high diabetes specific emergency department use was correlated with poor diabetic outcomes. Emergency department utilization data can help identify the location of specific populations with poor glycemic control. PMID- 27497145 TI - Cultural issues and other factors that affect self-management of Type 2 Diabetes Mellitus (T2D) by Chinese immigrants in Australia. AB - AIMS: To investigate the influence of cultural and other factors on diabetes self management behaviors among Australian Chinese immigrants with T2D. METHODS: A cross-sectional survey was conducted between June and October 2015. The questionnaire comprised several validated scales examining aspects of self management practice including medication adherence, acculturation and demographics. Participants were recruited from the community and Diabetes Center of the Royal Prince Alfred Hospital (RPAH), Sydney, Australia. RESULTS: Of the 139 participants, a majority were female, from mainland China, with high school level education and a mean age of 64 (SD+/-12) years. Participants were found to have poor self-management practices generally but moderate medication adherence. 13.7% of participants reported incorporating TCM into their diabetes treatment and 24% reported a cultural shame surrounding a diabetes diagnosis. Higher levels of acculturation predicted better medication adherence, whereas stronger beliefs in TCM predicted poorer medication adherence. Gender, education level and duration of diabetes were also predictors of diabetes self-management behaviors. CONCLUSIONS: This study provided insight into cultural influences on diabetes self-management and medication taking among Chinese immigrants in Australia. Health care providers should take these into account in delivering culturally sensitive care and advice to achieve better health outcomes. PMID- 27497146 TI - Expression and correlation of sex hormone-binding globulin and insulin signal transduction and glucose transporter proteins in gestational diabetes mellitus placental tissue. AB - OBJECTIVE: The aim of the present study was to investigate the probable pathogenesis of gestational diabetes mellitus (GDM) by analyzing the correlation between sex hormone-binding globulin (SHBG) secreted by the placenta during pregnancy and insulin signaling components and glucose transporter proteins (GLUTs) in the placental tissue. DESIGN AND METHODS: Placental tissue was collected from full-term and non-obese [body mass index <25kg/m(2)] pregnant women; 10 diagnosed with GDM and 10 with normal pregnancy. We used real-time polymerase chain reaction (PCR), immunohistochemistry and western blotting to detect expression of protein and mRNA of SHBG and insulin signaling components and GLUTs in placental tissue. RESULTS: In the placental tissue of non-obese women, there was a decrease in expression of SHBG protein and mRNA, with a concurrent decrease in expression of GLUT-4 protein and mRNA in women with GDM compared with normal controls. There was a decrease in GLUT-3 and insulin receptor substrate (IRS)-1 protein expression and lower IRS-2 mRNA expression was also observed in GDM placental tissue. Linear correlation analyses showed a positive correlation between SHBG and IRS-2 mRNA (P=0.038, R(2)=0.2178, y=0.249x+1.4208); positive correlation between SHBG and phosphatidylinositol 3 kinase (PI3K) p85alpha mRNA (P=0.035, R(2)=0.224, y=0.3506x+0.7433); positive correlation between SHBG and GLUT-4 mRNA (P=0.000, R(2)=0.5174, y=1.3822+1.7811x); positive correlation between IRS-2 and GLUT-4 mRNA (P=0.002, R(2)=0.4064, y=-0.8272+2.9592x); negative correlation between IRS-1 and PI3K p85alpha mRNA (P=0.005, R(2)=0.366, y=2.4492-0.1929x); negative correlation between IRS-1 and GLUT-3 mRNA (P=0.027, R(2)=0.243, y=0.9254-0.0714x); and positive correlation between IRS-2 and GLUT-1 mRNA (P=0.004, R(2)=0.3794, y=0.0225+0.6298x). CONCLUSION: The results confirm that defective receptors for insulin signal transduction and GLUT proteins are present in GDM placental tissue. Decreasing expression of SHBG may participate in regulation of insulin signaling, leading to a concomitant decrease in expression of relevant insulin signaling components in placental tissue, implying insulin resistance and eventual development of GDM. PMID- 27497147 TI - Nutrition and Diabetes. PMID- 27497148 TI - Excess Omega-6 Polyunsaturated Fatty Acid Intake Is Associated with Negative Cardiovascular, Intestinal and Metabolic Outcomes in Mice. PMID- 27497149 TI - Sickeningly Sweet: Does Sugar Cause Chronic Disease? No. PMID- 27497150 TI - Review of Dietary Practices of the 21st Century: Facts and Fallacies. AB - The prevalence of chronic metabolic diseases, such as diabetes, cardiovascular diseases and cancer, is increasing around the world. Nutritional interventions can reduce the prevalence and provide effective treatment, even when weight loss is not dramatic. The 2013 Canadian Diabetes Association Clinical Practice Guidelines concluded that certain dietary patterns and popular weight-loss diets had sufficient evidence to suggest their use by individuals with diabetes, but many other diet patterns and diets exist. Our specific objectives were to review the nutritional quality of various dietary patterns and diets, with emphasis on the evidence that they are efficacious for weight loss, glycemic control and cardiovascular risk factors. PMID- 27497151 TI - The Role of Pulses in the Dietary Management of Diabetes. AB - Pulses are highly nutritious foods that are included as part of Canada's Food Guide to promote healthful eating, and they have established health benefits that can contribute to the dietary management of diabetes. A review of studies that have examined the effects of pulse consumption on health outcomes, integral to the management of diabetes, provides credible evidence for improvements in glycemic control, reduction of blood lipids and regulation of body weight. Results from acute feeding trials suggest that postprandial blood glucose response is significantly attenuated by a single pulse serving of between three quarters and 1 cup. At lower doses, pulses attenuate postprandial blood glucose response more than similar amounts of starchy foods. Long-term pulse consumption of 5 cups per week appears to result consistently in improvements in glycemic control. There is high-quality evidence that supports a role for pulse consumption in the reduction of risk for cardiovascular disease; this provides a sound rationale for the regular incorporation of pulses at about two-thirds of a cup daily in the management of hyperlipidemia in persons with type 2 diabetes. Pulse consumption can contribute to improving satiety, reducing food intake and regulating body weight, which can reduce obesity risk and, in turn, improve diabetes management. Collectively, available evidence provides very good support for a role of regular pulse consumption in the prevention and management of diabetes. PMID- 27497152 TI - Polymorphism of the phosphoserine phosphatase gene in Streptococcus thermophilus and its potential use for typing and monitoring of population diversity. AB - The phosphoserine phosphatase gene (serB) of Streptococcus thermophilus is the most polymorphic gene among those used in Multilocus Sequence Typing schemes for this species and has been used for both genotyping of isolates and for evaluation of population diversity. However, the information on the potential of this gene as a marker for diversity in S. thermophilus species is still fragmentary. In this study, we evaluated serB nucleotide polymorphism and its potential impact on protein structure using data from traditional sequencing. In addition we evaluated the ability of serB targeted high-throughput sequencing in studying the diversity of S. thermophilus populations in cheese and starter cultures. Data based on traditional cultivation based techniques and sequencing provided evidence that the distribution of serB alleles varies significantly in some environments (commercial starter cultures, traditional starter cultures, cheese). Mutations had relatively little impact on predicted protein structure and were not found in domains that are predicted to be important for its functionality. Cultivation independent, serB targeted high-throughput sequencing provided evidence for significantly different alleles distribution in different cheese types and detected fluctuations in alleles abundance in a mixed strain starter reproduced by backslopping. Notwithstanding some shortcomings of this method that are discussed here, the cultivation independent approach appears to be more sensitive than cultivation based approaches based on isolation and traditional sequencing. PMID- 27497154 TI - The relationship between 63days of 24-h urinary free cortisol and hair cortisol levels in 10 healthy individuals. AB - BACKGROUND: Interest in measuring cortisol in scalp hair is increasing because of its assumed ability to provide a historical timeline of previous systemic levels of cortisol. Yet, it remains uncertain how well hair cortisol represents the total systemic secretion of cortisol over time. METHODS: Ten healthy individuals collected 24-h urine samples for 63 consecutive days and provided a hair sample at the end of the study period. 24-h urinary creatinine levels in every urine sample were determined to assess completeness of the samples. Cortisol levels in 24-h urine samples and in hair were measured with liquid chromatography tandem mass spectrometry. The correlations between urinary cortisol and hair cortisol were calculated using Kendall's tau. RESULTS: We found a nonsignificant moderate correlation between average urinary cortisol secretion and average hair cortisol concentration rt=0.422, p=0.089. CONCLUSIONS: Hair cortisol concentration correlates low to moderately with 24-h urinary cortisol concentration over a period of 63days. PMID- 27497153 TI - Corticotropin-releasing hormone receptor 1 (CRH-R1) polymorphisms are associated with irritable bowel syndrome and acoustic startle response. AB - BACKGROUND: Corticotropin-releasing hormone receptor 1 (CRH-R1) in the amygdala and the stria terminalis plays an important role in the activation of central stress circuits. Genetic factors may contribute to the hyperresponsiveness of these circuits in irritable bowel syndrome (IBS). AIMS: To determine if CRH-R1 SNPs are associated with: (1) a diagnosis of IBS, (2) gastrointestinal (GI) symptoms, and (3) acoustic startle response (ASR) to threat, which is mediated by the amygdala via CRH. METHODS: Three CRH-R1 SNPS (rs110402, rs242924, and rs7209436) were genotyped using salivary DNA from IBS and healthy control subjects (HCs). Eye blink ASR was obtained during safe (no shock), anticipation (abdominal shock may soon occur) and threat (abdominal shock likely) conditions in a subset of subjects. Associations between each SNP with IBS status, clinical traits and ASR were measured. RESULTS: 235 IBS patients (mean age 37.5 yrs, 74% F) and 264 HCs (mean age 32.1 yrs, 70% F) were studied. Of these, 57 IBS and 41 HCs underwent the ASR protocol. The presence of IBS was associated with the major allele for all three CRH-R1 SNPs (p=0.009-0.025). Within IBS, the major allele for all three SNPs (p=0.017-0.065) was associated with GI symptom anxiety scores. Within subjects with at least one copy of the major allele for the CRH-R1 SNPs, IBS had significantly lower ASR compared to HCs during threat conditions (p=0.001 0.002). Within IBS, CRH-R1 SNPs were associated with a graded increase in ASR to threat (p=0.007-0.008). CONCLUSION: These findings support that CRH-R1 contributes to the dysregulated stress responsiveness in IBS. PMID- 27497155 TI - Progranulin is increased in human and murine lipodystrophy. AB - AIMS: Lipodystrophies (LD) are genetic or acquired disorders sharing the symptom of partial or complete adipose tissue deficiency and a dysregulation of adipokines including leptin and adiponectin. Progranulin, an adipokine with proinflammatory and insulin resistance-inducing characteristics, has not been investigated in LD so far. METHODS: Circulating progranulin was determined in LD patients (N=37) and in age-, gender-, and body mass index-matched healthy control subjects (N=37). Additionally, we investigated progranulin expression in an LD mouse model as compared to wild-type mice. Moreover, we elucidated circulating progranulin before and during metreleptin supplementation in 10 patients with LD. RESULTS: Median [interquartile range] circulating progranulin was increased in patients with LD (82.9 [25.9] MUg/l) as compared to controls (73.6 [22.8] MUg/l) (p=0.005). C-reactive protein (CRP) remained an independent and positive predictor of progranulin in multivariate analysis. Progranulin mRNA was significantly upregulated in all adipose tissue depots, i.e. visceral, subcutaneous, and brown adipose tissue, and in muscle of LD animals versus wild type mice. Progranulin levels did not significantly change during metreleptin supplementation. CONCLUSIONS: Progranulin serum concentration is increased in patients with LD, and shows an independent and positive correlation with CRP. Different adipose tissue depots and muscle might be potential origins of elevated progranulin. PMID- 27497156 TI - Liquid chromatography-tandem mass spectrometric analysis of ten estrogen metabolites at sub-picogram levels in breast cancer women. AB - The measurement of estrogens at sub-picogram levels is essential for research on breast cancer and postmenopausal plasma. Heretofore, these concentration levels have rarely been achieved. However, it is possible through derivatization but still represent problems for monitoring catechol estrogens and 16alpha hydroxyestrone (16alpha-OH-E1). Estrogens possess poor ionization efficiency in MS/MS, which results in insufficient sensitivity for analyzing samples at trace concentrations. The method presented here was used to extract ten estrogen metabolites (EMs) with a derivatization step involving a new adduct. The electrospray ionization (ESI) MS/MS sensitivity for the EMs was enhanced by derivatization with 3-bromomethyl-propyphenazone (BMP). The lower limits of quantification (LLOQ) of the EMs were 12-100 femtogram on-column, equivalent to 0.3-3.6pg/mL plasma, and the limits of detection (LOD) were 0.1-0.8pg/mL plasma. The percentage coefficient of variation (CV%) at the LLOQ was <20 for all investigated EMs. Ionization suppression was minimized by reacting the excess reagent, BMP, with methanol. The method was successfully applied for the determination of ten EMs in the plasma of fifty healthy postmenopausal and fifty ductal breast cancer women aged 47-65 years old. 16alpha-OH-E1 and three catechol estrogen metabolites, 4-OH-E1, 2-OH-E2 and 4-OH-E2, were successfully measured in the plasma of healthy and breast cancer women. The methyl-propyphenazone-EM derivatives exhibited better sensitivity in ESI-MS (7.5-fold) compared to the commonly used dansylation procedure. PMID- 27497157 TI - Simultaneous determination of eugenol, isoeugenol and methyleugenol in fish fillet using gas chromatography coupled to tandem mass spectrometry. AB - Gas chromatography (GC) coupled with triple quadrupole tandem mass spectrometry (MS/MS) operated in electron ionization mode (EI) has been shown to have advantages in the trace analysis of chemical compounds. Employing the instrument, a method has been built to simultaneously determine eugenol, isoeugenol' and methyleugenol, which have been widely used as fish anesthetic, in the fish fillet. Procedure for the sample preparation was achieved by using hexane extraction followed by phenyl solid phase extraction (SPE) cleanup, which was free of such steps as rotary evaporation and nitrogen blowing by taking the volatility of eugenol and its isomers into consideration. The method was validated by conducting recovery studies on fortified fish fillet samples at four concentrations. The linearity in the range of 5-500MUg.L(-1) was forced through the origin giving a coefficient of determination (r(2)) greater than 0.9982. Limits of detection (LODs) for eugenol, isoeugenol' and methyleugenol were 0.4, 1.2' and 0.2MUg.kg(-1), respectively. The limits of quantification (LOQs) were 1.2, 4' and 0.7MUg.kg(-1) for eugenol, isoeugenol' and methyleugenol, respectively. The recoveries for eugenol and its isomers ranged from 76.4 to 99.9% with relative standard deviations (RSD) in a range from 2.18 to 15.5%. This method is quick, simple and suitable for determining the residues of eugenol, isoeugenol and methyleugenol simultaneously in batch samples of fish fillet. PMID- 27497158 TI - Micro RNA-19a suppresses IL-10 in peripheral B cells from patients with atherosclerosis. AB - BACKGROUND AND AIMS: The interleukin (IL)-10-production B cells play an important role in the pathogenesis of atherosclerosis (Asro) with unknown mechanism. Micro RNA (miR)-17-92 cluster has strong immune regulatory activities. This study tests a hypothesis that miR-17-92 cluster suppresses IL-10 expression in B cells of Asro patients. METHODS: Patients with Asro were recruited into this study. Peripheral blood samples were collected from the patients. B cells were isolated from the blood samples and analyzed to elucidate the role of miR-17-92 in the regulation of IL-10 expression. RESULTS: Peripheral B cells from patients with Asro show lower levels of IL-10 than that from healthy subjects. The IL-10 expression in the B cells is negatively correlated with the expression of miR-19a in the B cells. The serum levels of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and interleukin (IL)-4 in Asro patients were higher than healthy subjects. Exposure to TNF-alpha or IFN-gamma or IL-4 suppressed IL-10 expression in B cells via increasing the expression of miR-19a in B cells, which could be abolished by Inhibition of miR-19a. CONCLUSIONS: TNF-alpha or IFN-gamma or IL-4 suppresses IL-10 in B cells via up regulating miR-19a expression. PMID- 27497159 TI - Anti cytokine therapy in chronic inflammatory arthritis. AB - This is a review looking at anti cytokine therapy in Rheumatoid Arthritis (RA), Psoriatic Arthritis (PSA) and Ankylosing Spondylitis (AS). The review explores the similarities and differences in the clinical features, as well as treatments and cytokines involved in the development and propagation of the disease. Particular attention is paid to TNFalpha inhibitors IL-1ra, IL-6 and JAK kinase Inhibitors, anti IL23 and IL-12 and the new developments with anti-IL-17. PMID- 27497160 TI - Continuum Electrostatics Approaches to Calculating pKas and Ems in Proteins. AB - Proteins change their charge state through protonation and redox reactions as well as through binding charged ligands. The free energy of these reactions is dominated by solvation and electrostatic energies and modulated by protein conformational relaxation in response to the ionization state changes. Although computational methods for calculating these interactions can provide very powerful tools for predicting protein charge states, they include several critical approximations of which users should be aware. This chapter discusses the strengths, weaknesses, and approximations of popular computational methods for predicting charge states and understanding the underlying electrostatic interactions. The goal of this chapter is to inform users about applications and potential caveats of these methods as well as outline directions for future theoretical and computational research. PMID- 27497161 TI - Path Sampling Methods for Enzymatic Quantum Particle Transfer Reactions. AB - The mechanisms of enzymatic reactions are studied via a host of computational techniques. While previous methods have been used successfully, many fail to incorporate the full dynamical properties of enzymatic systems. This can lead to misleading results in cases where enzyme motion plays a significant role in the reaction coordinate, which is especially relevant in particle transfer reactions where nuclear tunneling may occur. In this chapter, we outline previous methods, as well as discuss newly developed dynamical methods to interrogate mechanisms of enzymatic particle transfer reactions. These new methods allow for the calculation of free energy barriers and kinetic isotope effects (KIEs) with the incorporation of quantum effects through centroid molecular dynamics (CMD) and the full complement of enzyme dynamics through transition path sampling (TPS). Recent work, summarized in this chapter, applied the method for calculation of free energy barriers to reaction in lactate dehydrogenase (LDH) and yeast alcohol dehydrogenase (YADH). We found that tunneling plays an insignificant role in YADH but plays a more significant role in LDH, though not dominant over classical transfer. Additionally, we summarize the application of a TPS algorithm for the calculation of reaction rates in tandem with CMD to calculate the primary H/D KIE of YADH from first principles. We found that the computationally obtained KIE is within the margin of error of experimentally determined KIEs and corresponds to the KIE of particle transfer in the enzyme. These methods provide new ways to investigate enzyme mechanism with the inclusion of protein and quantum dynamics. PMID- 27497162 TI - Accurate Calculation of Electric Fields Inside Enzymes. AB - The specific electric field generated by a protease at its active site is considered as an important source of the catalytic power. Accurate calculation of electric field at the active site of an enzyme has both fundamental and practical importance. Measuring site-specific changes of electric field at internal sites of proteins due to, eg, mutation, has been realized by using molecular probes with CO or CN groups in the context of vibrational Stark effect. However, theoretical prediction of change in electric field inside a protein based on a conventional force field, such as AMBER or OPLS, is often inadequate. For such calculation, quantum chemical approach or quantum-based polarizable or polarized force field is highly preferable. Compared with the result from conventional force field, significant improvement is found in predicting experimentally measured mutation-induced electric field change using quantum-based methods, indicating that quantum effect such as polarization plays an important role in accurate description of electric field inside proteins. In comparison, the best theoretical prediction comes from fully quantum mechanical calculation in which both polarization and inter-residue charge transfer effects are included for accurate prediction of electrostatics in proteins. PMID- 27497163 TI - Molecular Dynamics Studies of Proton Transport in Hydrogenase and Hydrogenase Mimics. AB - There is extensive interest in hydrogenases based on their ability to rapidly and efficiently interconvert H2 with protons and electrons, and their (typically) superior function relative to molecular mimics. Understanding the function of enzymes is one approach to implementing design features to make better catalysts and is an approach we have implemented in our work. In this review, we will discuss our efforts to develop design principles from enzymes, with specific focus on proton transport. We will also present computational studies of the mimics we have investigated with similar methodologies. We will discuss the mechanisms used by small scaffolds on molecular mimics which in many cases are surprisingly similar to those used by nature, while in other cases, computational analysis allowed us to reveal an unexpected role. Computational methods provide one of the best ways, and in some cases, the only way, to gain insight into the mechanistic details of enzymes. In this review, we illustrate the general computational strategy we used to study the proton pathway of [FeFe]-hydrogenase, and the similar strategy to investigate small molecules. We present the main results we obtained and how our computational work stimulated or worked in concert with experimental investigations. We also focus on estimation of errors and convergence of properties in the simulations. These studies demonstrate the powerful results that can be obtained by the close pairing of experimental and theoretical approaches. PMID- 27497164 TI - Modeling Mercury in Proteins. AB - Mercury (Hg) is a naturally occurring element that is released into the biosphere both by natural processes and anthropogenic activities. Although its reduced, elemental form Hg(0) is relatively nontoxic, other forms such as Hg(2+) and, in particular, its methylated form, methylmercury, are toxic, with deleterious effects on both ecosystems and humans. Microorganisms play important roles in the transformation of mercury in the environment. Inorganic Hg(2+) can be methylated by certain bacteria and archaea to form methylmercury. Conversely, bacteria also demethylate methylmercury and reduce Hg(2+) to relatively inert Hg(0). Transformations and toxicity occur as a result of mercury interacting with various proteins. Clearly, then, understanding the toxic effects of mercury and its cycling in the environment requires characterization of these interactions. Computational approaches are ideally suited to studies of mercury in proteins because they can provide a detailed molecular picture and circumvent issues associated with toxicity. Here, we describe computational methods for investigating and characterizing how mercury binds to proteins, how inter- and intraprotein transfer of mercury is orchestrated in biological systems, and how chemical reactions in proteins transform the metal. We describe quantum chemical analyses of aqueous Hg(II), which reveal critical factors that determine ligand binding propensities. We then provide a perspective on how we used chemical reasoning to discover how microorganisms methylate mercury. We also highlight our combined computational and experimental studies of the proteins and enzymes of the mer operon, a suite of genes that confer mercury resistance in many bacteria. Lastly, we place work on mercury in proteins in the context of what is needed for a comprehensive multiscale model of environmental mercury cycling. PMID- 27497165 TI - Steered Molecular Dynamics Methods Applied to Enzyme Mechanism and Energetics. AB - One of the main goals of chemistry is to understand the underlying principles of chemical reactions, in terms of both its reaction mechanism and the thermodynamics that govern it. Using hybrid quantum mechanics/molecular mechanics (QM/MM)-based methods in combination with a biased sampling scheme, it is possible to simulate chemical reactions occurring inside complex environments such as an enzyme, or aqueous solution, and determining the corresponding free energy profile, which provides direct comparison with experimental determined kinetic and equilibrium parameters. Among the most promising biasing schemes is the multiple steered molecular dynamics method, which in combination with Jarzynski's Relationship (JR) allows obtaining the equilibrium free energy profile, from a finite set of nonequilibrium reactive trajectories by exponentially averaging the individual work profiles. However, obtaining statistically converged and accurate profiles is far from easy and may result in increased computational cost if the selected steering speed and number of trajectories are inappropriately chosen. In this small review, using the extensively studied chorismate to prephenate conversion reaction, we first present a systematic study of how key parameters such as pulling speed, number of trajectories, and reaction progress are related to the resulting work distributions and in turn the accuracy of the free energy obtained with JR. Second, and in the context of QM/MM strategies, we introduce the Hybrid Differential Relaxation Algorithm, and show how it allows obtaining more accurate free energy profiles using faster pulling speeds and smaller number of trajectories and thus smaller computational cost. PMID- 27497166 TI - New Algorithms for Global Optimization and Reaction Path Determination. AB - We present new schemes to improve the convergence of an important global optimization problem and to determine reaction pathways (RPs) between identified minima. Those methods have been implemented into the CAST program (Conformational Analysis and Search Tool). The first part of this chapter shows how to improve convergence of the Monte Carlo with minimization (MCM, also known as Basin Hopping) method when applied to optimize water clusters or aqueous solvation shells using a simple model. Since the random movement on the potential energy surface (PES) is an integral part of MCM, we propose to employ a hydrogen bonding based algorithm for its improvement. We show comparisons of the results obtained for random dihedral and for the proposed random, rigid-body water molecule movement, giving evidence that a specific adaption of the distortion process greatly improves the convergence of the method. The second part is about the determination of RPs in clusters between conformational arrangements and for reactions. Besides standard approaches like the nudged elastic band method, we want to focus on a new algorithm developed especially for global reaction path search called Pathopt. We started with argon clusters, a typical benchmark system, which possess a flat PES, then stepwise increase the magnitude and directionality of interactions. Therefore, we calculated pathways for a water cluster and characterize them by frequency calculations. Within our calculations, we were able to show that beneath local pathways also additional pathways can be found which possess additional features. PMID- 27497167 TI - Simulation Studies of Protein and Small Molecule Interactions and Reaction. AB - Computational studies of protein and small molecule (protein-ligand/enzyme substrate) interactions become more and more important in biological science and drug discovery. Computer modeling can provide molecular details of the processes such as conformational change, binding, and transportation of small molecules/proteins, which are not easily to be captured in experiments. In this chapter, we discussed simulation studies of both protein and small molecules from three aspects: conformation sampling, transportations of small molecules in enzymes, and enzymatic reactions involving small molecules. Both methodology developments and examples of simulation studies in this field were presented. PMID- 27497168 TI - How to Run FAST Simulations. AB - Molecular dynamics (MD) simulations are a powerful tool for understanding enzymes' structures and functions with full atomistic detail. These physics-based simulations model the dynamics of a protein in solution and store snapshots of its atomic coordinates at discrete time intervals. Analysis of the snapshots from these trajectories provides thermodynamic and kinetic properties such as conformational free energies, binding free energies, and transition times. Unfortunately, simulating biologically relevant timescales with brute force MD simulations requires enormous computing resources. In this chapter we detail a goal-oriented sampling algorithm, called fluctuation amplification of specific traits, that quickly generates pertinent thermodynamic and kinetic information by using an iterative series of short MD simulations to explore the vast depths of conformational space. PMID- 27497169 TI - Bridging Enzymatic Structure Function via Mechanics: A Coarse-Grain Approach. AB - Flexibility is a central aspect of protein function, and ligand binding in enzymes involves a wide range of structural changes, ranging from large-scale domain movements to small loop or side-chain rearrangements. In order to understand how the mechanical properties of enzymes, and the mechanical variations that are induced by ligand binding, relate to enzymatic activity, we carried out coarse-grain Brownian dynamics simulations on a set of enzymes whose structures in the unbound and ligand-bound forms are available in the Protein Data Bank. Our results show that enzymes are remarkably heterogeneous objects from a mechanical point of view and that the local rigidity of individual residues is tightly connected to their part in the protein's overall structure and function. The systematic comparison of the rigidity of enzymes in their unbound and bound forms highlights the fact that small conformational changes can induce large mechanical effects, leading to either more or less flexibility depending on the enzyme's architecture and the location of its ligand-biding site. These mechanical variations target a limited number of specific residues that occupy key locations for enzymatic activity, and our approach thus offers a mean to detect perturbation-sensitive sites in enzymes, where the addition or removal of a few interactions will lead to important changes in the proteins internal dynamics. PMID- 27497170 TI - A Networks Approach to Modeling Enzymatic Reactions. AB - Modeling enzymatic reactions is a demanding task due to the complexity of the system, the many degrees of freedom involved and the complex, chemical, and conformational transitions associated with the reaction. Consequently, enzymatic reactions are not determined by precisely one reaction pathway. Hence, it is beneficial to obtain a comprehensive picture of possible reaction paths and competing mechanisms. By combining individually generated intermediate states and chemical transition steps a network of such pathways can be constructed. Transition networks are a discretized representation of a potential energy landscape consisting of a multitude of reaction pathways connecting the end states of the reaction. The graph structure of the network allows an easy identification of the energetically most favorable pathways as well as a number of alternative routes. PMID- 27497171 TI - Conformational Sub-states and Populations in Enzyme Catalysis. AB - Enzyme function involves substrate and cofactor binding, precise positioning of reactants in the active site, chemical turnover, and release of products. In addition to formation of crucial structural interactions between enzyme and substrate(s), coordinated motions within the enzyme-substrate complex allow reaction to proceed at a much faster rate, compared to the reaction in solution and in the absence of enzyme. An increasing number of enzyme systems show the presence of conserved protein motions that are important for function. A wide variety of motions are naturally sampled (over femtosecond to millisecond time scales) as the enzyme complex moves along the energetic landscape, driven by temperature and dynamical events from the surrounding environment. Areas of low energy along the landscape form conformational sub-states, which show higher conformational populations than surrounding areas. A small number of these protein conformational sub-states contain functionally important structural and dynamical features, which assist the enzyme mechanism along the catalytic cycle. Identification and characterization of these higher-energy (also called excited) sub-states and the associated populations are challenging, as these sub-states are very short-lived and therefore rarely populated. Specialized techniques based on computer simulations, theoretical modeling, and nuclear magnetic resonance have been developed for quantitative characterization of these sub-states and populations. This chapter discusses these techniques and provides examples of their applications to enzyme systems. PMID- 27497172 TI - Computation of Rate Constants for Diffusion of Small Ligands to and from Buried Protein Active Sites. AB - The diffusion of ligands to actives sites of proteins is essential to enzyme catalysis and many cellular signaling processes. In this contribution we review our recently developed methodology for calculation of rate constants for diffusion and binding of small molecules to buried protein active sites. The diffusive dynamics of the ligand obtained from molecular dynamics simulation is coarse grained and described by a Markov state model. Diffusion and binding rate constants are then obtained either from the reactive flux formalism or by fitting the time-dependent population of the Markov state model to a phenomenological rate law. The method is illustrated by applications to diffusion of substrate and inhibitors in [NiFe] hydrogenase, CO-dehydrogenase, and myoglobin. We also discuss a recently developed sensitivity analysis that allows one to identify hot spots in proteins, where mutations are expected to have the strongest effects on ligand diffusion rates. PMID- 27497173 TI - Calculation of Enzyme Fluctuograms from All-Atom Molecular Dynamics Simulation. AB - In this work, a computational framework is presented to compute the time evolution of force constants for a coarse grained (CG) elastic network model along an all-atom molecular dynamics trajectory of a protein system. Obtained via matching distance fluctuations, these force constants represent strengths of mechanical coupling between CG beads. Variation of coupling strengths with time is hence termed the fluctuogram of protein dynamics. In addition to the schematic procedure and implementation considerations, several ways of combining force constants and data analysis are presented to illustrate the potential application of protein fluctuograms. The unique angle provided by the fluctuogram expands the scope of atomistic simulations and is expected to impact upon fundamental understanding of protein dynamics as well as protein engineering technologies. PMID- 27497174 TI - Constructing Kinetic Network Models to Elucidate Mechanisms of Functional Conformational Changes of Enzymes and Their Recognition with Ligands. AB - Enzymes are biological macromolecules that catalyze complex reactions in life. In order to perform their functions effectively and efficiently, enzymes undergo conformational changes between different functional states. Therefore, elucidating the dynamics between these states is essential to understand the molecular mechanisms of enzymes. Although experimental methods such as X-ray crystallography and cryoelectron microscopy can produce high-resolution structures, the detailed conformational dynamics of many enzymes still remain obscure. While molecular dynamics (MD) simulations are able to complement the experiments by providing structure-based dynamics at atomic resolution, it is usually difficult for them to reach the biologically relevant timescales (hundreds of microseconds or longer). Kinetic network models (KNMs), in particular Markov state models (MSMs), hold great promise to overcome this challenge because they can bridge the timescale gap between MD simulations and experimental observations. In this chapter, we review the procedure of constructing KNMs to elucidate the molecular mechanisms of enzymes. First, we will give a general introduction of MSMs, including the methods to construct and validate MSMs. Second, we will present the applications of KNMs to study two important enzymes: the human Argonaute protein and the RNA polymerase II. We conclude by discussing the future perspectives regarding the potential of KNMs to investigate the dynamics of enzymes' functional conformational changes. PMID- 27497175 TI - Microscopic Characterization of Membrane Transporter Function by In Silico Modeling and Simulation. AB - Membrane transporters mediate one of the most fundamental processes in biology. They are the main gatekeepers controlling active traffic of materials in a highly selective and regulated manner between different cellular compartments demarcated by biological membranes. At the heart of the mechanism of membrane transporters lie protein conformational changes of diverse forms and magnitudes, which closely mediate critical aspects of the transport process, most importantly the coordinated motions of remotely located gating elements and their tight coupling to chemical processes such as binding, unbinding and translocation of transported substrate and cotransported ions, ATP binding and hydrolysis, and other molecular events fueling uphill transport of the cargo. An increasing number of functional studies have established the active participation of lipids and other components of biological membranes in the function of transporters and other membrane proteins, often acting as major signaling and regulating elements. Understanding the mechanistic details of these molecular processes require methods that offer high spatial and temporal resolutions. Computational modeling and simulations technologies empowered by advanced sampling and free energy calculations have reached a sufficiently mature state to become an indispensable component of mechanistic studies of membrane transporters in their natural environment of the membrane. In this article, we provide an overview of a number of major computational protocols and techniques commonly used in membrane transporter modeling and simulation studies. The article also includes practical hints on effective use of these methods, critical perspectives on their strengths and weak points, and examples of their successful applications to membrane transporters, selected from the research performed in our own laboratory. PMID- 27497177 TI - Preface. PMID- 27497176 TI - Detecting Allosteric Networks Using Molecular Dynamics Simulation. AB - Allosteric networks allow enzymes to transmit information and regulate their catalytic activities over vast distances. In principle, molecular dynamics (MD) simulations can be used to reveal the mechanisms that underlie this phenomenon; in practice, it can be difficult to discern allosteric signals from MD trajectories. Here, we describe how MD simulations can be analyzed to reveal correlated motions and allosteric networks, and provide an example of their use on the coagulation enzyme thrombin. Methods are discussed for calculating residue pair correlations from atomic fluctuations and mutual information, which can be combined with contact information to identify allosteric networks and to dynamically cluster a system into highly correlated communities. In the case of thrombin, these methods show that binding of the antagonist hirugen significantly alters the enzyme's correlation landscape through a series of pathways between Exosite I and the catalytic core. Results suggest that hirugen binding curtails dynamic diversity and enforces stricter venues of influence, thus reducing the accessibility of thrombin to other molecules. PMID- 27497178 TI - Editorial Comment. PMID- 27497179 TI - Editorial Comment. PMID- 27497180 TI - Editorial Comment. PMID- 27497181 TI - Comparison between the indocyanine green fluorescence and blue dye methods for sentinel lymph node biopsy using novel fluorescence image-guided resection equipment in different types of hospitals. AB - Sentinel lymph node biopsy (SLNB) has become a standard of care to detect axillary lymph metastasis in early-stage breast cancer patients with clinically negative axillary lymph nodes. Current SLNB detection modalities comprising a blue dye, a radioactive tracer, or a combination of both have advantages as well as disadvantages. Thus, near-infrared fluorescence imaging using indocyanine green (ICG) has recently been regarded as a novel method that has generated interest for SLNB around the world. However, the lack of appropriate fluorescence imaging systems has hindered further research and wide application of this method. Therefore, we developed novel fluorescence image-guided resection equipment (FIRE) to detect sentinel lymph nodes (SLNs). Moreover, to compare the ICG fluorescence imaging method with the blue dye method and to explore the universal feasibility of the former, a different type of hospital study was conducted. Ninety-nine eligible patients participated in the study at 3 different types of hospitals. After subcutaneous ICG allergy testing, all the patients were subcutaneously injected with methylene blue and ICG into the subareolar area. Consequently, 276 SLNs (range 1-7) were identified in 98 subjects (detection rate: 99%) by using the ICG fluorescence imaging method. In contrast, the blue dye method only identified 202 SLNs (range 1-7) in 91 subjects (detection rate: 91.92%). Besides, the results of the fluorescence imaging method were similar in the 3 hospitals. Our findings indicate the universal feasibility of the ICG fluorescence imaging method for SLNB using the fluorescence image-guided resection equipment in early breast cancer detection. PMID- 27497182 TI - Suppression of human alloreactive T cells by linear tetrapyrroles; relevance for transplantation. AB - The main limitation to successful transplantation is the antigraft response developed by the recipient immune system, and the adverse side effects of immunosuppressive agents which are associated with significant toxicity and counter indications such as infection and cancer. Furthermore, immunosuppressants do little to prevent ischemia-reperfusion injury during the transplantation procedure itself hence there is a growing need to develop novel immunosuppressive drugs specifically aimed at prolonging graft survival. Linear tetrapyrroles derived from the breakdown of mammalian heme have been shown in numerous studies to play a protective role in allograft transplantation and ischemia-reperfusion injury; however, commercial sources of these products have not been approved for use in humans. Plants and algae produce equivalent linear tetrapyrroles called bilins that serve as chromophores in light-sensing. One such marine-derived tetrapyrrole, phycocyanobilin (PCB), shows significant structural similarity to mammalian biliverdin (BV) and may prove to be a safer alternative for use in the clinic if it can exert direct effects on human immune cells. Using a mixed lymphocyte reaction, we quantified the allogeneic responses of recipient cells to donor cells and found that PCB, like BV, effectively suppressed proliferation and proinflammatory cytokine production. In addition, we found that BV and PCB can directly downregulate the proinflammatory responses of both innate dendritic cells and adaptive T cells. We therefore propose that PCB may be an effective therapeutic drug in the clinical setting of transplantation and may also have wider applications in regulating inappropriate inflammation. PMID- 27497183 TI - Detection of Felis catus gammaherpesvirus 1 (FcaGHV1) in peripheral blood B- and T-lymphocytes in asymptomatic, naturally-infected domestic cats. AB - The domestic cat is natural host to both feline immunodeficiency virus and Felis catus gammaherpesvirus 1 (FcaGHV1). Comparative data suggest that these agents might act as synergistic copathogens in feline AIDS-related lymphoma. To identify leucocyte subsets harbouring gammaherpesvirus DNA, whole blood from 5 healthy, FcaGHV1-infected cats was labelled with monoclonal antibodies to feline CD21, CD4, CD8 and CD14 for 4-way fluorescence-activated cell sorting. FcaGHV1gB qPCR was performed on DNA extracted from purified fractions and whole blood longitudinally. FcaGHV1 DNA was detected in CD21+, CD4+, CD8+, but not CD14+ cells. Variation in whole blood load, up to 19,788 copies/10(6)cells, was detected in individual cats over time. FcaGHV1 DNA was undetectable in one cat on one occasion highlighting that qPCR of whole blood from a single time point will not detect all cases of FcaGHV1 infection. Further investigation of the role of FcaGHV1 in feline lymphoid malignancies is warranted. PMID- 27497184 TI - African horse sickness virus infects BSR cells through macropinocytosis. AB - Cellular pathways involved in cell entry by African horse sickness virus (AHSV), a member of the Orbivirus genus within the Reoviridae family, have not yet been determined. Here, we show that acidic pH is required for productive infection of BSR cells by AHSV-4, suggesting that the virus is likely internalized by an endocytic pathway. We subsequently analyzed the major endocytic routes using specific inhibitors and determined the consequences for AHSV-4 entry into BSR cells. The results indicated that virus entry is dynamin dependent, but clathrin- and lipid raft/caveolae-mediated endocytic pathways were not used by AHSV-4 to enter and infect BSR cells. Instead, binding of AHSV-4 to BSR cells stimulated uptake of a macropinocytosis-specific cargo and inhibition of Na(+)/H(+) exchangers, actin polymerization and cellular GTPases and kinases involved in macropinocytosis significantly inhibited AHSV-4 infection. Altogether, the data suggest that AHSV-4 infects BSR cells by utilizing macropinocytosis as the primary entry pathway. PMID- 27497186 TI - HC-Pro viral suppressor from tobacco vein banding mosaic virus interferes with DNA methylation and activates the salicylic acid pathway. AB - Salicylic acid (SA) is an important signalling molecule that is synthesized by plants and induces the expression of resistance genes. The SA pathway is typically activated by DNA viruses as well as RNA viruses. Here, we demonstrated that heper-component protease (HC-Pro) encoded by tobacco vein banding mosaic virus (TVBMV) decreases in DNA methylation at the promoters of the regulators ACD6 and NPR1 in the SA pathway. We found that the overexpression of HC-Pro increases the expression of components in the SA pathway in plants. The results revealed that HC-Pro interferes in DNA methylation and activates the SA pathway in the HC-Pro transgenic plants and TVBMV-infected plants. We further found that the accumulation of siRNAs derived from the promoter repeats of ACD6 and NPR1 is greatly reduced in the HC-Pro plants. Our results suggested that HC-Pro-mediated interference with DNA methylation is likely caused by a reduction in accumulation of siRNAs. PMID- 27497185 TI - The HCMV US28 vGPCR induces potent Galphaq/PLC-beta signaling in monocytes leading to increased adhesion to endothelial cells. AB - US28 transcripts have been detected in primary monocytes and in THP-1 monocytes infected with HCMV but US28 protein expression has not yet been demonstrated in these cell types. Moreover, the mechanism(s) by which US28 signals and contributes to viral pathogenesis in monocytes remains unclear. Here, we show that US28 protein is robustly expressed in HCMV infected THP-1 monocytes and that US28 can trigger Galphaq dependent signaling in THP-1 cells infected with HCMV and in THP-1 cells stably expressing US28. US28 signaling in these cells is dependent on G-protein coupling, but independent of chemokine binding. Importantly, we demonstrate that this US28 signaling is functionally important as it stimulates the adhesion of monocytes to an endothelial monolayer. Our studies, which demonstrate that US28-driven Galphaq signaling has profound effects on monocyte biology, suggest that US28 driven phenotypic changes in HCMV infected monocytes may play important roles in HCMV dissemination and/or pathogenesis. PMID- 27497187 TI - Identification of adult knee primary bone tumour symptom presentation: A qualitative study. AB - OBJECTIVES: The aim of this study was to identify the symptom presentation of adult knee primary bone tumours from onset to Consultant diagnosis, from combined patient and healthcare professional perspectives. MATERIALS AND METHODS: A qualitative study using in-depth semi-structured interviews recruited a purposive sample of adult patients with a knee primary bone tumour (n = 8) and healthcare professionals with expertise in orthopaedic oncology (n = 6). Following informed consent, recorded interviews explored participants' experiences of symptom presentation. A grounded theory approach was utilised to analyse transcribed data, producing themes. Methods to increase rigour and trustworthiness were employed. Recruitment continued until data saturation was achieved. RESULTS: Four key themes were established: 1] Symptoms started with intermittent pain which became more severe and more constant, 2] Pain was mechanical in nature but became more difficult to ease; 3] The pain story was unusual with a protracted symptom duration and failure to improve with conservative treatment; 4] Non-painful symptoms included swelling, and systemic signs were uncommon. More similarities between healthcare professionals' and patients' perceptions were found at Consultant diagnosis compared to onset. CONCLUSION: New insights of symptom presentation, particularly in the early stages have been provided which are not reflected in current guidelines. Although starting similarly to routine musculoskeletal presentations, a number of distinctive features may enable earlier diagnosis. PMID- 27497188 TI - Effects of dry needling to the symptomatic versus control shoulder in patients with unilateral subacromial pain syndrome. AB - BACKGROUND: Initial reports suggest that treating myofascial trigger points in the infraspinatus with dry needling may be effective in treating patients with shoulder pain. However, to date, high quality clinical trials and thorough knowledge of the physiologic mechanisms involved is lacking. OBJECTIVES: To examine the effect of dry needling to the infraspinatus muscle on muscle function, nociceptive sensitivity, and shoulder range of motion (ROM) in the symptomatic and asymptomatic shoulders of individuals with unilateral subacromial pain syndrome. DESIGN: Within-subjects controlled trial. METHODS: Fifty-seven volunteers with unilateral subacromial pain syndrome underwent one session of dry needling to bilateral infraspinatus muscles. Outcome assessments, including ultrasonic measures of infraspinatus muscle thickness, pressure algometry, shoulder internal rotation and horizontal adduction ROM, and questionnaires regarding pain and related disability were taken at baseline, immediately after dry needling, and 3-4 days later. RESULTS: Participants experienced statistically significant and clinically relevant changes in all self-report measures. Pressure pain threshold and ROM significantly increased 3-4 days, but not immediately after dry needling only in the symptomatic shoulder [Pressure pain threshold: 5.1 (2.2, 8.0) N/cm2, internal rotation ROM: 9.6 (5.0, 14.1) degrees, horizontal adduction ROM: 5.9 (2.5, 9.4) degrees]. No significant changes occurred in resting or contracted infraspinatus muscle thickness in either shoulder. CONCLUSIONS: This study found changes in shoulder ROM and pain sensitivity, but not in muscle function, after dry needling to the infraspinatus muscle in participants with unilateral subacromial pain syndrome. These changes generally occurred 3-4 days after dry needling and only in the symptomatic shoulders. PMID- 27497189 TI - Evidences of abundant hemocyanin variants in shrimp Litopenaeus vannamei. AB - Hemocyanin (HMC) is a multifunctional immune molecule present in mollusks and arthropods and functions as an important antigen non-specific immune protein. Our previous evidences demonstrated that Litopenaeus vannamei HMC might display extensive molecular diversities. In this study, bioinformatics analysis showed dozens of variant sequences of the HMC subunit with higher molecular weight from L. vannamei (LvHMC). Three variant fragments, named as LvHMCV1-3, which shared 85 99% nucleotide identity with that of the classical form of LvHMC (AJ250830.1), were cloned and characterized. Spatial expression profiles showed that LvHMCV1-3 had different tissue-specific distribution, which were affected by stimulation with six pathogenic bacteria, including Escherichia coli K12, Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio fluvialis, Streptococcus pyogenes and Staphylococcus aureus, with each variant fragment showing a specific stress pattern to different bacterial pathogens. Full length cDNA of LvHMCV3 was further cloned and characterized. The deduced amino acid sequence shared 92% identity with that of LvHMC, possessed a conserved structure characteristic of the HMC family and could be clustered into one branch along with other arthropod HMC in a phylogenetic tree. In addition, the recombinant protein of LvHMCV3 (rLvHMCV3) showed obvious agglutination activities against three aquaculture pathogenic bacteria including E. coli K12, V. parahaemolyticus and S.aureus at concentrations ranging from 31.25-62.5g/mL. It also showed obvious antibacterial activity against V. parahaemolyticus at concentrations 0.02-0.5mg/mL, and possessed the best inhibitive effects compared with those of rLvHMCV4 and rLvHMC. Co-injection of V. parahaemolyticus and rLvHMCV3 in L. vannamei showed significant decrease of the mortality rate at 24-72h after injection. Therefore, these studies suggested that L. vannamei had abundant HMC variants, which possessed obvious resistance to pathogenic infection and might specifically target on different pathogens in shrimp. PMID- 27497190 TI - Exceptionally long CDR3H of bovine scFv antigenized with BoHV-1 B-epitope generates specific immune response against the targeted epitope. AB - We discovered that some bovine antibodies are amongst the largest known to exist due to the presence of an exceptionally long CDR3H (>=49 amino acids) with multiple cysteines that provide a unique knob and stalk structure to the antigen binding site. The large CDR3H size, unlike mouse and human, provides a suitable platform for antigenization with large configurational B-epitopes. Here we report the identification of a B-epitope on the gC envelope protein of bovine herpes virus type-1 (BoHV-1) recognized by a bovine IgG1 antibody. The identified 156 amino acid long gC fragment (gC156) was expressed as a recombinant protein. Subsequently, a functional scFv fragment with a 61 amino-acid long CDR3H (scFv1H12) was expressed such that gC156 was grafted into the CDR3H, replacing the "knob" region (gC156scFv1H12 or Ag-scFv). Importantly, the Ag-scFv could be recognized by a neutralizing antibody fragment (scFv3-18L), which suggests that the engraftment of gC156 into the CDR3H of 1H12 maintained the native conformation of the BoHV-1 B-epitope. A 3D model of gC156 was generated using fold-recognition approaches and this was grafted onto the CDR3H stalk of the 1H12 Fab crystal structure to predict the 3D structure of the Ag-scFv. The grafted antigen in Ag-scFv is predicted to have a compact conformation with the ability to protrude into the solvent. Upon immunization of bovine calves, the antigenized scFv (gC156scFv1H12) induced a higher antibody response as compared to free recombinant gC156. These observations suggest that antigenization of bovine scFv with an exceptionally long CDR3H provides a novel approach to developing the next generation of vaccines against infectious agents that require induction of protective humoral immunity. PMID- 27497191 TI - Evaluation of dried blood spot samples for hepatitis C virus detection and quantification. AB - BACKGROUND: Dried blood spots (DBS) could be an excellent alternative for HCV diagnosis, since it is less invasive and can be stored and transported without refrigeration. OBJECTIVES: The aim of this study was to optimize quantitative and qualitative methods for HCV detection in DBS. STUDY DESIGN: DBS and serum samples were collected from 99 subjects (59 anti-HCV/HCV RNA positive and 40 seronegative samples). Seven extraction methods and different PCR parameters were evaluated in DBS samples in the quantitative RT-PCR (qRT-PCR) developed to amplify the 5' noncoding region of HCV. A qualitative PCR for amplification of NS5B region of HCV was also valued and the nested-PCR sequenced. RESULTS: The qRT-PCR showed good correlation to commercial assay for HCV viral measurement in serum. To quantify HCV RNA in DBS, it was necessary to increase reverse transcriptase and cDNA concentration. HCV RNA quantification in DBS demonstrated sensitivity of 65.9%, 100% of specificity and kappa statistic of 0.65. The median viral load of DBS samples was 5.38 log10 copies/ml (minimum value=1.76 and maximum value=10.48 log10 copies/ml). HCV RNA was detected in NS5B regions and nucleotide sequences obtained in 43 serum and 11 DBS samples. The presence of the same subtype was observed in paired serum and DBS samples. CONCLUSIONS: In this study, it was possible to demonstrate that, despite the low sensitivity, the optimized protocol was able to determine the viral load, as well as, the infecting HCV genotype, validating the usefulness of DBS for viral load determination and molecular epidemiology studies of HCV. PMID- 27497192 TI - Task-shifting - A practical strategy to improve the global access to treatment for chronic hepatitis C. PMID- 27497193 TI - Circulating midkine in children with Henoch-Schonlein purpura: Clinical implications. AB - BACKGROUND: Midkine (MK) is a heparin-binding growth factor, which behaves like a cytokine, involved in various cellular processes such as cellular proliferation, differentiation, survival, adhesion, and migration. Studies provided evidence for a role of MK in acute and chronic inflammatory processes. The association between midkine and Henoch-Schonlein purpura (HSP) has not yet been explored. The aim of our study was to investigate the potential role of midkine in children with HSP. METHODS: A total of 152 cases consisting of 92 children with HSP and 60 age- and sex-matched healthy control children were enrolled in this prospective study. Circulating midkine, IL-2, IL-4, IL-6, IL-10, TNF, IFN-gamma, and IL-17A was measured in all of the 92 patients and 60 healthy controls. Midkine diagnostic value was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: Renal involvement occurred in 36 of the 92 patients. Circulating midkine level was elevated in children with HSPN than those of patients without renal involvement and of the controls (326.58 (266.58-459.25) pg/ml versus 280.72 (233.67-384.36) pg/ml and 217.3 (198.98-243.65) pg/ml, respectively; P<0.05). Midkine positively correlated with IL-4, IL-6, IL17A, IgA and IgE. The threshold MK concentration of HSPN was 295.58pg/ml, with the sensitivity and specificity of 80.6% and 88.3%, respectively. The area under the receiver operating characteristic (ROC) curve (AUCROC) of MK was 0.902. CONCLUSIONS: MK seems to be involved in the development of HSP. Measurement of serum levels of MK is helpful in confirming the diagnosis of HSP and predicting HSPN. PMID- 27497194 TI - Inhibition of curcumin on myeloid-derived suppressor cells is requisite for controlling lung cancer. AB - Lung cancer remains the leading cause of cancer mortality. Myeloid-derived suppressor cells (MDSCs) are potent immune-suppressive cells and present in most cancer patients. Recently, several studies have shown that curcumin inhibits the expansion of MDSCs in some cancers. However, it is not clear how curcumin modulates the suppressive function of MDSCs, and whether curcumin achieves anti tumor effects via regulating the expansion of MDSCs in lung cancer. Here, our results showed that curcumin significantly inhibited tumor growth in a Lewis lung carcinoma (LLC) isogenic tumor model. Curcumin reduced the accumulation of MDSCs in spleen and tumor tissue in LLC isogenic model. And curcumin promoted the maturation and differentiation of MDSCs in tumor tissue. Notably, curcumin inhibited the expression level of immune suppressive factors of MDSCs, arginase-1 (Arg-1) and ROS, in purified MDSCs from tumor tissue in vivo. Expectedly, curcumin also inhibited the immunosuppressive function of isolated MDSCs from tumor tissue and spleen of tumor bearing mice in vitro. Moreover, curcumin decreased the level of IL-6 in the tumor tissue and serum from LLC-bearing mice. Taken together, curcumin indeed possesses anti-cancer effect and inhibits the accumulation and function of MDSCs. And curcumin reduces the level of IL-6 in tumor-bearing mice to impair the expansion and function of MDSCs. These results suggest that inhibition of MDSCs in tumor is requisite for controlling lung cancer. PMID- 27497195 TI - Trifunctional molecular beacon-mediated quadratic amplification for highly sensitive and rapid detection of mercury(II) ion with tunable dynamic range. AB - Analyses of target with low abundance or concentration varying over many orders of magnitude are severe challenges faced by numerous assay methods due to their modest sensitivity and limited dynamic range. Here, we introduce a homogeneous and rapid quadratic polynomial amplification strategy through rational design of a trifunctional molecular beacon, which serves as not only a reporter molecule but also a bridge to couple two stage amplification modules without adding any reaction components or process other than basic linear amplification. As a test bed for our studies, we took mercury(II) ion as an example and obtained a high sensitivity with detection limit down to 200 pM within 30min. In order to create a tunable dynamic range, homotropic allostery is employed to modulate the target specific binding. When the number of metal binding site varies from 1 to 3, signal response is programmed accordingly with useful dynamic range spanning 50, 25 and 10 folds, respectively. Furthermore, the applicability of the proposed method in river water and biological samples are successfully verified with good recovery and reproducibility, indicating considerable potential for its practicality in complex real samples. PMID- 27497196 TI - Highly sensitive electrochemiluminescent immunosensor based on gold nanoparticles functionalized zinc oxide nanorod and poly(amidoamine)-graphene for detecting brombuterol. AB - beta-adrenergic agonists (beta-agonists) recognized as a growth promoter will reflect the health of human. Sensitive detection of beta-agonists in foodstuff is valuable for the health of animals and human. A novel ultrasensitive competition type electrochemiluminescent (ECL) immunosensor was developed for detecting brombuterol (Brom) based on CdTe Quantum dot (QDs) and polyamidoamine dendrimer (PAMAM, G2) modified graphene oxide (GO) (CdTe QDs-PAMAM-GO composite) as bioprobe for the first time. The surface of glassy carbon electrode (GCE) was coated with AuNPs-ZnO NRs composite film as the platform, which facilitated the electronic transmission rate to enhance the ECL intensity and provide enough active sites for capturing antibody. The resulting ECL immunosensor enabled the real samples detection of Brom with a lower detection limit of 0.3pgmL(-1) (S/N=3) and a wider linear range from 0.001 to 500ngmL(-1). The proposed immunosensor coupled with the excellent advantages of CdTe QDs-PAMAM-GO and AuNPs ZnO NRs composite displayed high sensitivity and long-term stability, and provided an approach for determining other important biomarkers. PMID- 27497197 TI - Electrochemical DNA probe for Hg(2+) detection based on a triple-helix DNA and Multistage Signal Amplification Strategy. AB - In this work, an ultrasensitive electrochemical sensor was developed for detection of Hg(2+). Gold nanoparticles decorated bovine serum albumin reduction of graphene oxide (AuNP-BSA-rGO) were used as subsurface material for the immobilization of triple-helix DNA. The triple-helix DNA containing a thiol labelled single-stranded DNA (sDNA) and a thymine-rich DNA (T-rich DNA), which could be unwinded in the present of Hg(2+) to form more stable thymine-Hg(2+) thymine (T-Hg(2+)-T) complex. T-Hg(2+)-T complex was then removed and the sDNA was left on the electrode. At this time, gold nanoparticle carrying thiol labelled cytosine-rich complementary DNA (cDNA-AuNP) could bind with the free sDNA. Meanwhile, the other free cDNA on AuNP could bind with each other in the present of Ag(+) to form the stable cytosine-Ag(+)-cytosine (C-Ag(+)-C) complex and circle amplification. Plenty of C-Ag(+)-C could form silver nanoclusters by electrochemical reduction and the striping signal of Ag could be measured for purpose of the final electrochemical detection of Hg(2+). This sensor could detect Hg(2+) over a wide concentration range from 0.1 to 130nM with a detection limit of 0.03nM. PMID- 27497198 TI - Fluorescent molecularly imprinted nanogels for the detection of anticancer drugs in human plasma. AB - Several fluorescent molecularly imprinted nanogels for the detection of the anticancer drug sunitinib were synthesized and characterized. A selection of functional monomers based on different aminoacids and coumarin allowed isolation of polymers with very good rebinding properties and sensitivities. The direct detection of sunitinib in human plasma was successfully demonstrated by fluorescence quenching of the coumarin-based nanogels. The plasma sample simply diluted in DMSO allowed the recovery of various amounts of sunitib, as determined by an averaged calibration curve. The LOD was 400nM, with within-run variability <9%, day to day variability <5%, and good accuracy in the recovery of sunitinib from spiked samples. PMID- 27497199 TI - Dual-responsive immunosensor that combines colorimetric recognition and electrochemical response for ultrasensitive detection of cancer biomarkers. AB - We developed a nanoroughened, biotin-doped polypyrrole immunosensor for the detection of tumor markers through dual-signal (electrochemical and colorimetric) channels, electrochemical and colorimetric, that demonstrates remarkable analytical performance. A rapid, one-step electric field-mediated method was employed to fabricate the immunosensor with nanoscale roughness by simply modulating the applied electrical potential. We demonstrated the successful detection of three tumor markers (CA125, CEA, and PSA) via the double enzymatic signal amplifications in the presence of a target antigen, ultimately leading to desired diagnostic accuracy and reliability. The addition of multiple horseradish peroxidase (HRP)- and antibody-labeled nanoparticles greatly amplified the signal and simplified the measurement of cancer biomarker proteins by sequentially magnifying electrochemical and colorimetric signals in a single platform. The two parallel assays performed using the proposed immunosensor have yielded highly consistent and reproducible results. Additionally, for the analysis of plasma samples in a clinical setting, the values obtained with our immunosensor were validated by correlating the results with those of a standard radioimmunoassay (RIA), which obtained very similar clinically valid responses. PMID- 27497200 TI - Experimental, computational and chemometrics studies of BSA-vitamin B6 interaction by UV-Vis, FT-IR, fluorescence spectroscopy, molecular dynamics simulation and hard-soft modeling methods. AB - The interaction of pyridoxine (Vitamin B6) with bovine serum albumin (BSA) is investigated under pseudo-physiological conditions by UV-Vis, fluorescence and FTIR spectroscopy. The intrinsic fluorescence of BSA was quenched by VB6, which was rationalized in terms of the static quenching mechanism. According to fluorescence quenching calculations, the bimolecular quenching constant (kq), dynamic quenching (KSV) and static quenching (KLB) at 310K were obtained. The efficiency of energy transfer and the distance between the donor (BSA) and the acceptor (VB6) were calculated by Foster's non-radiative energy transfer theory and were equal to 41.1% and 2.11nm. The collected UV-Vis and fluorescence spectra were combined into a row-and column-wise augmented matrix and resolved by multivariate curve resolution-alternating least squares (MCR-ALS). MCR-ALS helped to estimate the stoichiometry of interactions, concentration profiles and pure spectra for three species (BSA, VB6 and VB6-BSA complex) existed in the interaction procedure. Based on the MCR-ALS results, using mass balance equations, a model was developed and binding constant of complex was calculated using non-linear least squares curve fitting. FT-IR spectra showed that the conformation of proteins was altered in presence of VB6. Finally, the combined docking and molecular dynamics (MD) simulations were used to estimate the binding affinity of VB6 to BSA. Five-nanosecond MD simulations were performed on bovine serum albumin (BSA) to study the conformational features of its ligand binding site. From MD results, eleven BSA snapshots were extracted, at every 0.5ns, to explore the binding affinity (GOLD score) of VB6 using a docking procedure. MD simulations indicated that there is a considerable flexibility in the structure of protein that affected ligand recognition. Structural analyses and docking simulations indicated that VB6 binds to site I and GOLD score values depend on the conformations of both BSA and ligand. Molecular modeling results showed that VB6-BSA complex formed not only on the basis of electrostatic forces, but also on the basis of pi-pi staking and hydrogen bond. There was an excellent agreement between the experimental and computational results. The results presented in this paper, will offer a reference for detailed and systematic studies on the biological effects and action mechanism of small molecules with proteins. PMID- 27497201 TI - Anatomy and Disorders of the Oral Cavity of Ornamental Fish. AB - Ornamental fish represent the largest and most diverse group of exotic animals kept as pets. The specific oral anatomy of each family or selected species has evolved to suit the natural environment, feeding behaviors, food or prey type, and location of the food/prey in the water column. The anatomy can change over the life of the animal, from fry to adult. The oral cavity of fish is susceptible to many problems including infectious and parasitic diseases, trauma, and neoplasia. Diagnosis may involve wet mount preparations of exfoliative cytology from the lesion, histopathology, and bacterial or fungal culture. PMID- 27497202 TI - Anatomy and Disorders of the Oral Cavity of Reptiles and Amphibians. AB - A wide variety of disorders may be seen affecting the reptile and amphibian oral cavity. Owners can easily miss problems until they are at an advanced stage because of the difficulty of examining the oral cavity at home. Because many problems are secondary to an inappropriate environment or diet and may be related to systemic disease, a full history and clinical examination is always required. Treatment of oral disorders also requires a holistic approach including correction of any predisposing factors in order for long-term successful resolution of the problem. PMID- 27497203 TI - Anatomy and Disorders of the Beak and Oral Cavity of Birds. AB - Cranial kinesis of the avian beak is complex; particularly in birds with prokinetic beak movement, such as psittacine birds. A number of diseases can result in damage to the bony and soft tissue structures of the beak and can lead to secondary pathology, such as beak deviation, abnormal rhamphothecal growth and wear, and opportunistic infections. A solid understanding of species-specific anatomic variations is essential before attempting rhamphothecal restoration or surgical repair. Many diseases of the oral cavity can appear similar on initial clinical evaluation and therefore warrant appropriate diagnostic testing. PMID- 27497204 TI - Anatomy, Physiology and Non-dental Disorders of the Mouth of Pet Rabbits. AB - The first part of this review focuses on the anatomy and physiology of the rabbit mouth. Practical understanding is critical to comprehend the dynamic pathologic changes of dental disease, which is one of the most common presenting problems in rabbits. The major theories of the etiopathogenesis of dental disease are presented. The second part focuses on non-dental oral disorders, which encompass only a small incidence of stomatognathic diseases when compared with dental disease. These diseases are primarily composed of infections (treponematosis, oral papillomatosis), neoplasia (frequently involving calcified tissue proliferation), and congenital abnormalities (mandibular prognathism, absent peg teeth, supernumerary peg teeth). PMID- 27497205 TI - Diagnostic Imaging of Dental Disease in Pet Rabbits and Rodents. AB - Diagnostic imaging techniques are of paramount importance for dentistry and oral disorders of rabbits, rodents, and other exotic companion mammals. Aside from standard radiography, stomatoscopy is a complementary tool allowing a thorough and detailed inspection of the oral cavity. Computed tomography (CT) generates multiple 2-dimensional views and 3-dimensional reconstructions providing superior diagnostic accuracy also useful for prognosis and treatment of advanced dental disease and its related complications. MRI is a diagnostic imaging technique additional to CT used primarily to enhance soft tissues, including complex odontogenic abscesses. PMID- 27497206 TI - Intraoral Treatment of Dental Disease in Pet Rabbits. AB - The intraoral treatment of dental disease in pet rabbits follows a complete clinical examination, intraoral inspection under general anesthesia, and diagnostic imaging. It also implies thorough knowledge of dental disease in this species. The most common intraoral procedures are extraction of incisor teeth, coronal reduction, and extraction of cheek teeth. These dental procedures require specific instruments and equipment. They should be performed in conjunction with supportive and medical treatment followed by appropriate nutrition. PMID- 27497207 TI - Surgical Treatment of Facial Abscesses and Facial Surgery in Pet Rabbits. AB - Odontogenic facial abscesses associated with periapical infections and osteomyelitis of the jaw represent an important part of the acquired and progressive dental disease syndrome in pet rabbits. Complications such as retromasseteric and retrobulbar abscesses, extensive osteomyelitis of the mandible, and empyemas of the skull are possible sequelae. Standard and advanced diagnostic imaging should be pursued to make a detailed and proper diagnosis, and plan the most effective surgical treatment. This article reviews the surgical anatomy, the pathophysiology, and the classification of abscesses and empyemas of the mandible, the maxilla, and the skull. It also discusses surgical techniques for facial abscesses. PMID- 27497208 TI - Anatomy and Disorders of the Oral Cavity of Guinea Pigs. AB - Acquired dental disease represents the most common oral disorder of guinea pigs. Most patients are presented with nonspecific clinical signs and symptoms, such as weight loss, reduced food intake, difficulty chewing and/or swallowing. The physical examination must be followed by standard radiography and/or computed tomography, and thorough inspection under general anesthesia. Several complications may follow, including periodontal disease, subluxation of the temporomandibular joint, periapical infection, and abscessation. The dental treatment is aimed to restore the proper length and shape of both the incisor and cheek teeth, associated with medical and supportive treatment. Abscesses should be surgically addressed by complete excision. PMID- 27497209 TI - Anatomy and Disorders of the Oral Cavity of Chinchillas and Degus. AB - Dental disease is among the most common causes for chinchillas and degus to present to veterinarians. Most animals with dental disease present with weight loss, reduced food intake/anorexia, and drooling. Degus commonly present with dyspnea. Dental disease has been primarily referred to as elongation and malocclusion of the cheek teeth. Periodontal disease, caries, and tooth resorption are common diseases in chinchillas, but are missed frequently during routine intraoral examination, even performed under general anesthesia. A diagnostic evaluation, including endoscopy-guided intraoral examination and diagnostic imaging of the skull, is necessary to detect oral disorders and to perform the appropriate therapy. PMID- 27497210 TI - Anatomy and Disorders of the Oral Cavity of Rat-like and Squirrel-like Rodents. AB - The order Rodentia comprises more than 2000 species divided into 3 groups based on anatomic and functional differences of the masseter muscle. Myomorph and sciuromorph species have elodont incisors and anelodont cheek teeth, unlike hystrichomorph species which have full anelodont dentition. Diseases of incisors and cheek teeth of rat-like and squirrel-like rodents result in a wide variety of symptoms and clinical signs. Appropriate diagnostic testing and imaging techniques are required to obtain a definitive diagnosis, formulate a prognosis, and develop a treatment plan. A thorough review of elodontoma, odontoma, and pseudo-odontoma is provided, including treatment of pseudo-odontomas in prairie dogs. PMID- 27497211 TI - Anatomy and Disorders of the Oral Cavity of Ferrets and Other Exotic Companion Carnivores. AB - Exotic companion carnivores such as ferrets, skunks, fennec foxes, coatimundis, raccoons, and kinkajous presented in clinical practice share similar dental anatomy, function, and diseases. The domestic ferret serves as the representative species for this group with its anatomy, diseases, and conditions described in detail. Dog and cat guidelines for veterinary and home care seem to be relevant and applicable, including dental endodontic procedures. Annual or biannual dental examinations and prophylaxis are recommended. The most common dental and oral problems are tooth wear, plaque and calculus, teeth fractures, gingivitis and periodontitis, tooth loss, abscesses, oral ulceration, tonsillitis, and neoplasia. PMID- 27497212 TI - Anatomy and Disorders of the Oral Cavity of Miscellaneous Exotic Companion Mammals. AB - Unusual mammalian species such as the hedgehog, sugar glider, and miniature pig are encountered with increasing frequency in exotic companion medicine. Disease of the oral cavity can occur in any species; although occasionally encountered in exotic mammalian species, it is rarely described in the literature. Anatomy and dentition vary significantly; diagnosis and treatment are often extrapolated from that known in other species. The best-documented disease of the oral cavity in this group of species is oral neoplasia in the hedgehog. PMID- 27497213 TI - New Perspectives on Dentistry and Oral Disorders of Exotic Companion Animals. PMID- 27497214 TI - Prognostic value of imbalanced interhemispheric functional coordination in early therapeutic efficacy in major depressive disorder. AB - This study aims to explore the early response of antidepressant therapy by measuring the voxel-mirrored homotopic connectivity (VMHC) in major depressive disorder (MDD). Eighty-two MDD patients [n=42 treatment-responsive depression (RD) and n=40 non-responding depression (NRD)] and n=50 normal controls (NC) underwent clinical measures and a magnetic resonance imaging scan, and the VMHC values were calculated. Receiver operating characteristic (ROC) curve analysis was applied to determine the capability of altered VMHC to distinguish NRD. The NRD showed significantly decreased VMHC in bilateral precuneus (PCU) and inferior temporal gyrus (ITG), and increased VMHC in middle frontal gyrus (MFG) and caudate nucleus as compared to RD. When compared with NC, the NRD exhibited reduced VMHC in bilateral cerebellum anterior lobe, thalamus and postcentral gyrus. Moreover, VHMC in medial frontal gyrus, postcentral gyrus and precentral gyrus were significantly decreased in RD. Correlation analysis showed that reduced VMHC in PCU was negatively correlated with the baseline HAMD score of the NRD group. The ROC curve indicated that the combined changes of the three regional VMHC (PCU, ITG and MFG) could effectively identify NRD. The current study suggests that interhemispheric asynchrony may represents a novel neural trait underlying the prediction of early therapeutic outcome in MDD. PMID- 27497215 TI - Abnormal interhemispheric resting state functional connectivity of the insula in heroin users under methadone maintenance treatment. AB - Abnormal interhemispheric functional connectivity is attracting more and more attention in the field of substance use. This study aimed to examine 1) the differences in interhemispheric functional connections of the insula with the contralateral insula and other brain regions between heroin users under methadone maintenance treatment (MMT) and healthy controls, and 2) the association between heroin users' interhemispheric insular functional connectivity using resting functional magnetic resonance imaging (fMRI) and the results of urine heroin analysis. Sixty male right-handed persons, including 30 with heroin dependence under MMT and 30 healthy controls, were recruited to this study. Resting fMRI experiments and urine heroin analysis were performed. Compared with the controls, the heroin users had a significantly lower interhemispheric insular functional connectivity. They also exhibited lower functional connectivity between insula and contralateral inferior orbital frontal lobe. After controlling for age, educational level and methadone dosage, less deviation of the interhemispheric insula functional connectivity was significantly associated with a lower risk of a positive urine heroin analysis result. Our findings demonstrated that the heroin users under MMT had abnormal long-range and interhemispheric resting functional connections. Those with a less dysfunctional interhemispheric insula functional connectivity had a lower risk of a positive urine heroin test. PMID- 27497217 TI - Hidden Depths in the Hippocampal Circuitry. AB - Danielson et al. (2016) use calcium imaging in mice performing a treadmill task to reveal differences in space-coding dynamics between deep and superficial sublayers of hippocampal CA1, suggesting how the hippocampus might encode both stable and dynamic information simultaneously. PMID- 27497216 TI - Regulation of Plexin: A Ring of Structural Twists and Turns. AB - The regulation of the guidance receptor plexin is incompletely understood. In this issue, Kong et al. (2016) present crystal structures of the full-length extracellular region of class A plexins, revealing its dual role in both autoinhibition and activation. PMID- 27497218 TI - Disrupting the Grid Cells' Need for Speed. AB - Hinman et al. demonstrate the presence of two speed signals in the rodent medial entorhinal cortex that are differentially affected by muscimol inactivation of medial septum. The results reveal important constraints on several computational models of grid cell firing. PMID- 27497219 TI - A Nimble Working Memory. AB - In this issue of Neuron, Sprague et al. (2016) report fMRI evidence that a degraded working memory representation can be restored by a later cue. The findings raise new questions about the neural mechanisms that underlie such dynamic representational shifts. PMID- 27497220 TI - Clinical Concepts Emerging from fMRI Functional Connectomics. AB - Recent advances in connectomics have led to a synthesis of perspectives regarding the brain's functional organization that reconciles classical concepts of localized specialization with an appreciation for properties that emerge from interactions across distributed functional networks. This provides a more comprehensive framework for understanding neural mechanisms of normal cognition and disease. Although fMRI has not become a routine clinical tool, research has already had important influences on clinical concepts guiding diagnosis and patient management. Here we review illustrative examples. Studies demonstrating the network plasticity possible in adults and the global consequences of even focal brain injuries or disease both have had substantial impact on modern concepts of disease evolution and expression. Applications of functional connectomics in studies of clinical populations are challenging traditional disease classifications and helping to clarify biological relationships between clinical syndromes (and thus also ways of extending indications for, or "re purposing," current treatments). Large datasets from prospective, longitudinal studies promise to enable the discovery and validation of functional connectomic biomarkers with the potential to identify people at high risk of disease before clinical onset, at a time when treatments may be most effective. Studies of pain and consciousness have catalyzed reconsiderations of approaches to clinical management, but also have stimulated debate about the clinical meaningfulness of differences in internal perceptual or cognitive states inferred from functional connectomics or other physiological correlates. By way of a closing summary, we offer a personal view of immediate challenges and potential opportunities for clinically relevant applications of fMRI-based functional connectomics. PMID- 27497221 TI - Wireless Recording in the Peripheral Nervous System with Ultrasonic Neural Dust. AB - The emerging field of bioelectronic medicine seeks methods for deciphering and modulating electrophysiological activity in the body to attain therapeutic effects at target organs. Current approaches to interfacing with peripheral nerves and muscles rely heavily on wires, creating problems for chronic use, while emerging wireless approaches lack the size scalability necessary to interrogate small-diameter nerves. Furthermore, conventional electrode-based technologies lack the capability to record from nerves with high spatial resolution or to record independently from many discrete sites within a nerve bundle. Here, we demonstrate neural dust, a wireless and scalable ultrasonic backscatter system for powering and communicating with implanted bioelectronics. We show that ultrasound is effective at delivering power to mm-scale devices in tissue; likewise, passive, battery-less communication using backscatter enables high-fidelity transmission of electromyogram (EMG) and electroneurogram (ENG) signals from anesthetized rats. These results highlight the potential for an ultrasound-based neural interface system for advancing future bioelectronics based therapies. PMID- 27497222 TI - Defining preBotzinger Complex Rhythm- and Pattern-Generating Neural Microcircuits In Vivo. AB - Normal breathing in rodents requires activity of glutamatergic Dbx1-derived (Dbx1(+)) preBotzinger Complex (preBotC) neurons expressing somatostatin (SST). We combined in vivo optogenetic and pharmacological perturbations to elucidate the functional roles of these neurons in breathing. In transgenic adult mice expressing channelrhodopsin (ChR2) in Dbx1(+) neurons, photoresponsive preBotC neurons had preinspiratory or inspiratory firing patterns associated with excitatory effects on burst timing and pattern. In transgenic adult mice expressing ChR2 in SST(+) neurons, photoresponsive preBotC neurons had inspiratory or postinspiratory firing patterns associated with excitatory responses on pattern or inhibitory responses that were largely eliminated by blocking synaptic inhibition within preBotC or by local viral infection limiting ChR2 expression to preBotC SST(+) neurons. We conclude that: (1) preinspiratory preBotC Dbx1(+) neurons are rhythmogenic, (2) inspiratory preBotC Dbx1(+) and SST(+) neurons primarily act to pattern respiratory motor output, and (3) SST(+) neuron-mediated pathways and postsynaptic inhibition within preBotC modulate breathing pattern. PMID- 27497223 TI - Projection-Specific Dynamic Regulation of Inhibition in Amygdala Micro-Circuits. AB - Cannabinoid receptor type 1 (CB1R)-expressing CCK interneurons are key regulators of cortical circuits. Here we report that retrograde endocannabinoid signaling and CB1R-mediated regulation of inhibitory synaptic transmission onto basal amygdala principal neurons strongly depend on principal neuron projection target. Projection-specific asymmetries in the regulation of local inhibitory micro circuits may contribute to the selective activation of distinct amygdala output pathways during behavioral changes. PMID- 27497225 TI - Dopamine Does Double Duty in Motivating Cognitive Effort. PMID- 27497224 TI - Restoring Latent Visual Working Memory Representations in Human Cortex. AB - Working memory (WM) enables the storage and manipulation of limited amounts of information over short periods. Prominent models posit that increasing the number of remembered items decreases the spiking activity dedicated to each item via mutual inhibition, which irreparably degrades the fidelity of each item's representation. We tested these models by determining if degraded memory representations could be recovered following a post-cue indicating which of several items in spatial WM would be recalled. Using an fMRI-based image reconstruction technique, we identified impaired behavioral performance and degraded mnemonic representations with elevated memory load. However, in several cortical regions, degraded mnemonic representations recovered substantially following a post-cue, and this recovery tracked behavioral performance. These results challenge pure spike-based models of WM and suggest that remembered items are additionally encoded within latent or hidden neural codes that can help reinvigorate active WM representations. PMID- 27497226 TI - Tentonin 3/TMEM150c Confers Distinct Mechanosensitive Currents in Dorsal-Root Ganglion Neurons with Proprioceptive Function. PMID- 27497227 TI - Pilot study on arsenic removal from groundwater using a small-scale reverse osmosis system-Towards sustainable drinking water production. AB - Arsenic contamination of groundwater is posing a serious challenge to drinking water supplies on a global scale. In India and Bangladesh, arsenic has caused the most serious public health issue in the world for nearly two decades. The aim of this work was to study an arsenic removal system based on reverse osmosis at pilot scale treating two different water sources from two different locations in the State of Bihar, India. For this purpose two villages, Bind Toli and Ramnagar in the Patna District were selected, both located very close to the river Ganga. The trials were conducted with aerated and non-aerated groundwater. It is the first time that the arsenic removal efficiency for aerated and non-aerated groundwater by reverse osmosis technology in combination with an energy-saving recovery system have been studied. As the principle of reverse osmosis requires a relatively high pressure, its energy demand is naturally high. By using an energy recovery system, this demand can be lowered, leading to an energy demand per liter permeate of 3-4Wh/L only. Due to high iron levels in the groundwater and as a consequence the precipitation of ferric (hydr)oxides, it was necessary to develop a granular media filter for the trials under aeration in order to protect the membrane from clogging. Two different materials, first locally available sand, and second commercially available anthracite were tested in the granular media filter. For the trials with aerated groundwater, total arsenic removal efficiency at both locations was around 99% and the arsenic concentration in permeate was in compliance with the WHO and National Indian Standard of 10MUg/L. However, trials under anoxic conditions with non-aerated groundwater could not comply with this standard. Additionally a possible safe discharge of the reverse osmosis concentrate into an abandoned well was studied. It was observed that re injection of reject water underground may offer a safe disposal option. However, long-term hydrogeological studies need to be conducted for confirmation. PMID- 27497228 TI - Comparative performance evaluation of multi-metal resistant fungal strains for simultaneous removal of multiple hazardous metals. AB - In the present study, five fungal strains viz., Aspergillus terreus AML02, Paecilomyces fumosoroseus 4099, Beauveria bassiana 4580, Aspergillus terreus PD 17, Aspergillus fumigatus PD-18, were screened for simultaneous multimetal removal. Highest metal tolerance index for each individual metal viz., Cd, Cr, Cu, Ni, Pb and Zn (500mg/L) was recorded for A. fumigatus for the metals (Cd, 0.72; Cu, 0.72; Pb, 1.02; Zn, 0.94) followed by B. bassiana for the metals (Cd, 0.56; Cu, 0.14; Ni, 0.29; Zn, 0.85). Next, the strains were exposed to multiple metal mixture (Cd, Cr, Cu, Ni, Pb and Zn) of various concentrations (6, 12, 18, 30mg/L). Compared to other strains, B. bassiana and A. fumigatus had higher cube root growth (k) constants indicating their better adaptability to multi metal stress. After 72h, multimetal accumulation potential of B. bassiana (26.94+/ 0.07mg/L) and A. fumigatus (27.59+/-0.09mg/L) were higher than the other strains at initial multimetal concentration of 30mg/L. However, considering the post treatment concentrations of individual metals in multimetal mixture (at all the tested concentrations), A. fumigatus demonstrated exceptional performance and could bring down the concentrations of Cd, Cu, Ni, Pb and Zn below the threshold level for irrigation prescribed by Food and Agriculture Organization (FAO). PMID- 27497230 TI - Structural regulation of self-assembled iron oxide/polymer microbubbles towards performance-tunable magnetic resonance/ultrasonic dual imaging agents. AB - Fe3O4/polymer hybrid microcapsules were prepared via a template-free route which is based on polyamine-salt aggregates (PSAs) self-assembly approach. The measurements of transmission electron microscopy (TEM) indicated that the diameter and shell thickness of the microcapsules could be tuned by varying the experimental conditions, such as the concentration of reactants and evolution time employed during the PSA assembly. The results of vibrating sample magnetometer (VSM) demonstrated that the magnetic nanoparticles content of the synthesized microcapsules was tunable and all samples exhibited superparamagnetic behavior. After filling appropriate perfluorocarbon into the inner cavities of the microcapsules, the biomedical applications of the resultant microbubbles, including ultrasonic imaging (USI) and magnetic resonance imaging (MRI), were studied in vitro. It showed that the synthesized magnetic microbubbles possessed both strong ultrasound contrast enhancement capability and high relaxation rate. The excellent acoustic and magnetic properties of these self-assembled microbubbles ensure that the Fe3O4/polymer hybrid microbubbles have great potential as MRI/USI dual-modality contrast agents. PMID- 27497229 TI - Amelioration of premature aging in mtDNA mutator mouse by exercise: the interplay of oxidative stress, PGC-1alpha, p53, and DNA damage. A hypothesis. AB - The mtDNA mutator mouse lacks the proofreading capacity of the sole mtDNA polymerase, leading to accumulation of somatic mtDNA mutations, and a profound premature aging phenotype including elevated oxidative stress and apoptosis, and reduced mitochondrial function. We have previously reported that endurance exercise alleviates the aging phenotype in the mutator mice, reduces oxidative stress, and enhances mitochondrial biogenesis. Here we summarize our findings, with the emphasis on the central role of p53 in these adaptations. We demonstrate that mtDNA in sedentary and exercised PolG mice carry similar amounts of mutations in muscle, but in addition to that sedentary mice have more non mutational damage, which is mitigated by exercise. It follows therefore that the profound alleviation of the mtDNA mutator phenotype in muscle by exercise may not require a reduction in mtDNA mutational load, but rather a decrease of mtDNA damage and/or oxidative stress. We further hypothesize that the observed 'alleviation without a reduction of mutational load' implies that the oxidative stress in PolG muscle is maintained, at least in part, by the 'malicious cycle', a hypothetical positive feedback potentially driven by the 'transcriptional mutagenesis', that is the conversion of chemically modified nucleotides into mutant RNA bases by the mitochondrial RNA polymerase. PMID- 27497231 TI - Gold nanoparticles-decorated silver-bipyridine nanobelts for the construction of mediatorless hydrogen peroxide biosensor. AB - Au nanoparticles modified with 4-mercaptopyridine and 6-mercapto-1-hexanol were used as coordination agents to prepare a novel hybrid nanomaterial with Ag:4,4' bipyridine nanobelts. This nanohybrid was employed to modify glassy carbon electrodes and to construct a horseradish peroxidase-based mediatorless amperometric biosensor for H2O2. The electrode, poised at -100mV, exhibited a rapid response within 4s and a linear calibration range from 90pM to 6.5nM H2O2. The biosensor showed a high sensitivity of 283A/Mcm(2) and a very low detection limit of 45pM at a signal-to-noise ratio of 3. The enzyme biosensor showed high stability when stored at 4 degrees C under dry conditions, retaining over 96% and 78% of its initial activity after 15 and 30days of storage at 4 degrees C, respectively. PMID- 27497232 TI - Nanocrystallinity effects on osteoblast and osteoclast response to silicon substituted hydroxyapatite. AB - HYPOTHESIS: Silicon substituted hydroxyapatites (SiHA) are highly crystalline bioceramics treated at high temperatures (about 1200 degrees C) which have been approved for clinical use with spinal, orthopedic, periodontal, oral and craniomaxillofacial applications. The preparation of SiHA with lower temperature methods (about 700 degrees C) provides nanocrystalline SiHA (nano-SiHA) with enhanced bioreactivity due to higher surface area and smaller crystal size. The aim of this study has been to know the nanocrystallinity effects on the response of both osteoblasts and osteoclasts (the two main cell types involved in bone remodelling) to silicon substituted hydroxyapatite. EXPERIMENTS: Saos-2 osteoblasts and osteoclast-like cells (differentiated from RAW-264.7 macrophages) have been cultured on the surface of nano-SiHA and SiHA disks and different cell parameters have been evaluated: cell adhesion, proliferation, viability, intracellular content of reactive oxygen species, cell cycle phases, apoptosis, cell morphology, osteoclast-like cell differentiation and resorptive activity. FINDINGS: This comparative in vitro study evidences that nanocrystallinity of SiHA affects the cell/biomaterial interface inducing bone cell apoptosis by loss of cell anchorage (anoikis), delaying osteoclast-like cell differentiation and decreasing the resorptive activity of this cell type. These results suggest the potential use of nano-SiHA biomaterial for preventing bone resorption in treatment of osteoporotic bone. PMID- 27497233 TI - Biomimetic membrane-conjugated graphene nanoarchitecture for light-manipulating combined cancer treatment in vitro. AB - We report that through facile lipid self-assembly, biomimetic membrane-conjugated mesoporous silica-coated graphene oxide is constructed as targeting nanocarrier toward efficient combination of photothermal therapy and chemotherapy. Impressively, the simple surface modification with folate-contained lipid bilayer allows the graphene-based nanoarchitecture above to be selectively internalized by tumor cells overexpressing relevant receptors. Compared to pure drug, 7-fold doxorubicin is delivered into tumor cells by the nanoarchitecture. After cellular internalization, upon near infrared light illumination, graphene oxide in the nanoarchitecture can convert light energy into heat to kill cancer cells partially. Simultaneously, hyperthermia will drive rapid release of doxorubicin from the nanoarchitecture above to further cause the death of more cancer cells. Thus, integrated cancer treatment with higher efficacy is achieved in vitro compared to that of individual therapy. PMID- 27497234 TI - Evolution of camel CYP2E1 and its associated power of binding toxic industrial chemicals and drugs. AB - Camels are raised in harsh desert environment for hundreds of years ago. By modernization of live and the growing industrial revolution in camels rearing areas, camels are exposed to considerable amount of chemicals, industrial waste, environmental pollutions and drugs. Furthermore, camels have unique gene evolution of some genes to withstand living in harsh environments. In this work, the camel cytochrome P450 2E1 (CYP2E1) is compromised to detect its evolution rate and its power to bind with various chemicals, protoxins, procarcinogens, industrial toxins and drugs. In comparison with human CYP2E1, camel CYP2E1 more efficiently binds to small toxins as aniline, benzene, catechol, amides, butadiene, toluene and acrylamide. Larger compounds were more preferentially bound to the human CYP2E1 in comparison with camel CYP2E1. The binding of inhalant anesthetics was almost similar in both camel and human CYP2E1 coinciding with similar anesthetic effect as well as toxicity profiles. Furthermore, evolutionary analysis indicated the high evolution rate of camel CYP2E1 in comparison with human, farm and companion animals. The evolution rate of camel CYP2E1 was among the highest evolution rate in a subset of 57 different organisms. These results indicate rapid evolution and potent toxin binding power of camel CYP2E1. PMID- 27497235 TI - Regulatory T cells: balancing protection versus pathology. AB - Foxp3+ regulatory T cells (Tregs) maintain immune tolerance, prevent autoimmunity and modulate immune responses during infection and cancer. Recent studies have revealed considerable heterogeneity and plasticity within the Treg compartment, depending on the immunological context, which may result in Tregs losing their suppressive function in inflammatory environments. We review how dysfunctional Tregs contribute to disease pathogenesis in inflammatory conditions and how inappropriate regulatory responses may hamper protective immunity in the context of infection and cancer. We also discuss how Tregs might be targeted therapeutically to re-establish a proper balance between regulatory and effector responses in autoimmunity, infections, and cancer. PMID- 27497237 TI - Hepatotoxicity of illegal home-made alcohols. AB - OBJECTIVE AND AIM: Alcohol-related hepatotoxicity is not only caused by excessive alcohol consumption but also caused and even accelerated by hepatotoxic ingredients other than ethanol. Concentrations of hepatotoxic substances might be significantly high, particularly in illegally produced home-made alcohols. In this study we aim to analyze the hepatotoxic effects of a home-made alcohol traditionally called "bogma raki" in Turkey. MATERIALS AND METHOD: Fifty Wistar albino male rats were used. Five groups were randomly formed with ten animals in each. Besides laboratory diets, groups were fed as follows: Group 1 (control group) distilled water; Group 2 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day); Group 3 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day)+walnut (10 g/kg/day); Group 4 whisky with distilled water (%40 (v/v), 9.2 ml/kg/day); Group 5 distilled water + walnut (10 g/kg/day), for 28 days. The toxicological analysis of The spirits were analyzed using Hewlett-Packard (Palo Alto, CA) GC/MS system with HP 6890 gas chromatograph, an HP 5972 mass selective detector (MSD) and an HP 6890 automatic liquid sampler GC/MS; the pressure of the carrier gas helium was 6.0 bar and the split value with a ratio of 1:100. The injection unit temperature set to 250 degrees C and MS quadrupole temperature set to 280 degrees C. The MS quadrupole detector ionization energy set to 70 eV. The initial column temperature was 60 degrees C (for 4 min) programmed by 6 degrees C/min to final temperature 160 degrees C and kept for 8 min at 160 degrees C. Utilized whisky and bogma raki samples were analyzed for the amounts of trans-anethole, ethanol, methanol, 1-propanolol, butanol, 2-butanol, 2-methyl 1-propanolol (isobutanol) and 3-methylbutanol (isoamyl alcohol). Histopathological changes in liver tissues were graded as follows; normal = 0 (<10%), mild = 1 (10%-40%), moderate = 2 (40%-70%), severe = 3 (above 70%). RESULTS: Chemical composition of illegally produced raki sample (%v/v) was as follows: trans-anethole %1.93, ethanol %95.70, 2-methyl-1-propanolol (isobutanol) %0.19, asetic acid %0.25, 3-methylbutanol (isoamyl alcohol) %0.77, and others %1.16. Chemical composition of commercial whisky sample (%v/v) was as follows: ethanol %97.72, 2-methyl-1-propanolol (isobutanol) %0.57, asetic acid %0.23, 3 methylbutanol (isoamyl alcohol) %1.28, and others %0.2. No traces of trans anethole were detected in whisky. Normal liver morphology was recorded in control and walnut groups. However, bogma raki caused significant congestion and inflammatory cell infiltration compared to control and walnut group. On the other hand, whisky administration caused mild degeneration including inflammation in a limited area. CONCLUSION: Obtained findings suggest that trans-anethole containing alcoholic beverages are more hepatotoxic compared to commercial alcoholic beverages. PMID- 27497238 TI - Environmental contexts of combined alcohol and energy drink use: Associations with intoxication in licensed venues. AB - BACKGROUND: Environmental factors inside licensed venues have been found to influence the intoxication levels and consumption practices of patrons. The consumption of alcohol mixed with energy drinks (AmED) occurs primarily at or prior to attending licensed venues, however there is a lack of in situ research investigating AmED use in these contexts. Given that AmED use has been linked with increased alcohol consumption, intoxication, illicit substance use, and risk taking behaviours, this paper explores the environmental correlates and levels of intoxication associated with AmED use in licensed venues. METHODS: Structured observations were undertaken in five Australian cities on Friday and Saturday nights. Covert teams spent 4-5h in venues and recorded hourly observations on patron, venue, and staff characteristics, alcohol, illicit drug and AmED consumption patterns and intoxication levels. RESULTS: 898 hourly observations were recorded across 68 venues. All but one venue served energy drinks, and patron AmED use was observed during 34.9% of hourly records. AmED use was more prevalent after 12am and in nightclub venues compared to bars and pubs, and was positively associated with high intoxication levels, illicit drug use, and younger crowds. After controlling for environmental factors (i.e. venue crowding, service practices, venue characteristics, patron demographics and behaviour) AmED use did not predict high intoxication at a venue level in multivariable models. CONCLUSION: AmED consumption is ubiquitous in the licensed venues of Australian night-time entertainment districts, particularly busy nightclub venues where intoxication and risky consumption are heightened. However, AmED use was not associated with high patron intoxication when environmental factors were considered. PMID- 27497236 TI - Two anti-angiogenic TKI-PET tracers, [(11)C]axitinib and [(11)C]nintedanib: Radiosynthesis, in vivo metabolism and initial biodistribution studies in rodents. AB - INTRODUCTION: Tyrosine kinase inhibitors (TKIs) are very attractive targeted drugs, although a large portion of patients remains unresponsive. PET imaging with EGFR targeting TKIs ([(11)C]erlotinib and [(18)F]afatinib) showed promise in identifying treatment sensitive tumors. The aim of this study was to synthesize two anti-angiogenic TKI tracers, [(11)C]axitinib and [(11)C]nintedanib, and to evaluate their potential for PET. METHODS: Following successful tracer synthesis, biodistribution studies in VU-SCC-OE and FaDu xenograft bearing mice were performed. Furthermore, tracer stability studies in mice were performed employing (radio-)HPLC and LC-MS/MS techniques. For [(11)C]nintedanib an LC-MS/MS method was developed to detect the primary carboxylic acid metabolite, resulting from methylester cleavage, in plasma and tumors, because this metabolite is postulated to be important for nintedanib efficacy. LC-MS/MS was also explored to assess the metabolic fate of [(11)C]axitinib in vivo, since axitinib has an isomerizable double bond. RESULTS: [(11)C]axitinib and [(11)C]nintedanib were successfully synthesized with 10.5+/-2.6% and 25.6+/-3.3% radiochemical yield (corrected for decay), respectively. Biodistribution studies only demonstrated tumor uptake of [(11)C]nintedanib in FaDu xenografts of 1.66+/-0.02% ID/g at 60min p.i. In vivo stability analysis of [(11)C]axitinib at 45min p.i. revealed the formation of predominantly non-polar metabolites (36.6+/-6.8% vs 47.1+/-8.4% of parent tracer and 16.3+/-2.1% of polar metabolites), while for [(11)C]nintedanib mostly polar metabolites were found (70.9+/-4.1 vs 26.7+/-3.9% of parent tracer and only 2.4+/ 1.6 of a non-polar metabolites). No isomerization of [(11)C]axtinib was observed in vivo; however, a sulfoxide metabolite could be detected using LC-MS/MS. For [(11)C]nintedanib, LC-MS/MS revealed formation of the reported primary carboxylic acid metabolite when in vitro plasma incubations were performed, with large differences in plasmas from different species. In vivo metabolite analysis, however, did not demonstrate the presence of the carboxylic acid in plasma or tumor tissue. CONCLUSIONS: Reliable syntheses of [(11)C]axitinib and [(11)C]nintedanib were successfully developed. Tumor uptake was observed for [(11)C]nintedanib, albeit modest. The metabolic profiles of the tracers suggest that rapid metabolism is partly responsible for the modest tumor targeting observed. PMID- 27497239 TI - Disulfide stress in carbon monoxide poisoning. AB - OBJECTIVES: Carbon monoxide (CO) remains the most common cause of lethal poisoning around the world. The purpose of this study was to investigate the homeostasis between thiol-disulfide couples and to evaluate oxidative status comprehensively in acute CO poisoning, using new parameters along with other well known oxidant-antioxidant molecules. DESIGN AND METHODS: This case study consisted of 43 subjects who were diagnosed with carbon monoxide poisoning and 35 healthy individuals who were used as controls. Thiol-disulfide paired tests were examined in both groups using the method developed recently. RESULTS: Patients with CO poisoning had significantly higher levels of serum disulfide than the control patients (20.7+/-5.03 versus 16.43+/-3.97, p=0.001). Native thiol and total thiol levels were lower in the CO patient group than in the control group (p<0.001, for each variable). The disulfide/native thiol ratios and disulfide/total thiol ratios were significantly higher, while native thiol/total thiol ratios were significantly lower, in patients with acute CO poisoning than in the healthy controls (p<0.001, for all ratios). The disulfide/native ratios were negatively correlated with both total antioxidant response and paraoxonase and arylesterase values and were positively correlated with total oxidant status and ceruloplasmin values (p<0.05, for all correlations). CONCLUSIONS: Excessive disulfide levels and their related ratios were found in CO poisoning patients. In particular, the disulfide/native thiol ratio was identified as an indicator for overall oxidative status. Among CO poisoning patients, the thiol-disulfide balance was found to be impaired. Therefore, the disruption of thiol-disulfide homeostasis might be involved in CO toxicity. PMID- 27497240 TI - Identification and molecular characterisation of Lausanne Institutional Biobank participants with familial hypercholesterolaemia - a proof-of-concept study. AB - AIMS: We aimed to identify familial hypercholesterolaemia mutation carriers among participants to the Lausanne Institutional Biobank (BIL). Our experimental workflow was designed as a proof-of-concept demonstration of the resources and services provided by our integrated institutional clinical research support platform. METHODS: Familial hypercholesterolaemia was used as a model of a relatively common yet often underdiagnosed and inadequately treated Mendelian disease. Clinical and laboratory information was extracted from electronic hospital records. Patients were selected using elevated plasma cholesterol levels (total cholesterol >=7.5 mM or low-density lipoprotein cholesterol >=5 mM), premature coronary artery disease status and age (18-60 yr) as main inclusion criteria. LDLR, APOB and PCSK9 were analysed by high-throughput DNA sequencing. The most relevant mutations were confirmed by Sanger sequencing. RESULTS: Of 23 737 patients contacted by the BIL, 17 760 individuals consented to participate and 13 094 wished to be recontacted if there were findings requiring clinical action. Plasma cholesterol records were available for 5111 participants, of whom 94 were selected for genetic screening. Twenty-five of the tested patients presented with premature coronary artery disease while 69 had no such diagnosis. Seven heterozygous carriers of eight rare coding missense variants were identified. Three mutations were pathogenic (APOB p.R3527Q) or likely pathogenic (LDLR p.C27W, LDLR p.P526S) for hypercholesterolaemia, while the others were either benign or of unknown significance. One patient was a double heterozygote for variants APOB p.R3527Q and LDLR p.P526S. CONCLUSION: This work illustrates how clinical and translational research can benefit from a dedicated platform integrating both a hospital-based biobank and a data support team. PMID- 27497241 TI - Origin of year-long bean (Phaseolus dumosus Macfady, Fabaceae) from reticulated hybridization events between multiple Phaseolus species. AB - BACKGROUND AND AIMS: Improved understanding of the secondary gene pools of crops is essential for advancing genetic gain in breeding programmes. Common bean, Phaseolus vulgaris, is a staple crop with several wild relatives in its secondary gene pool. The year-long bean, P. dumosus, an important crop in Guatemala, is considered particularly closely related to P. vulgaris and a potential source of novel variation. However, the genetic diversity and relationship to other Phaseolus species of P. dumosus remain unclear. METHODS: We conducted the first comprehensive investigation of P. dumosus genetic diversity using both nuclear and chloroplast genome markers. Our nuclear marker set included over 700 markers present within the Phaseolus DArT (Diversity Arrays Technology) array, which we applied to P. dumosus and other relatives of P. vulgaris (including every secondary gene pool species: P. acutifolius, P. albescens, P. coccineus and P. costaricensis). KEY RESULTS: Phaseolus dumosus arose from hybridization of P. vulgaris and P. coccineus, followed by at least two later hybridizations with sympatric congener populations. Existing P. dumosus collections have low genetic diversity. CONCLUSIONS: The under-utilized crop P. dumosus has a complex hybrid origin. Further sampling in the region in which it arose may uncover additional germplasm for introgressing favourable traits into crops within the P. vulgaris gene pool. PMID- 27497242 TI - CN-Wheat, a functional-structural model of carbon and nitrogen metabolism in wheat culms after anthesis. I. Model description. AB - BACKGROUND AND AIMS: Improving crops requires better linking of traits and metabolic processes to whole plant performance. In this paper, we present CN Wheat, a comprehensive and mechanistic model of carbon (C) and nitrogen (N) metabolism within wheat culms after anthesis. METHODS: The culm is described by modules that represent the roots, photosynthetic organs and grains. Each of them includes structural, storage and mobile materials. Fluxes of C and N among modules occur through a common pool and through transpiration flow. Metabolite variations are represented by differential equations that depend on the physiological processes occurring in each module. A challenging aspect of CN Wheat lies in the regulation of these processes by metabolite concentrations and the environment perceived by organs. KEY RESULTS: CN-Wheat simulates the distribution of C and N into wheat culms in relation to photosynthesis, N uptake, metabolite turnover, root exudation and tissue death. Regulation of physiological activities by local concentrations of metabolites appears to be a valuable feature for understanding how the behaviour of the whole plant can emerge from local rules. CONCLUSIONS: The originality of CN-Wheat is that it proposes an integrated view of plant functioning based on a mechanistic approach. The formalization of each process can be further refined in the future as knowledge progresses. This approach is expected to strengthen our capacity to understand plant responses to their environment and investigate plant traits adapted to changes in agronomical practices or environmental conditions. A companion paper will evaluate the model. PMID- 27497243 TI - CN-Wheat, a functional-structural model of carbon and nitrogen metabolism in wheat culms after anthesis. II. Model evaluation. AB - BACKGROUND AND AIMS: Simulating resource allocation in crops requires an integrated view of plant functioning and the formalization of interactions between carbon (C) and nitrogen (N) metabolisms. This study evaluates the functional-structural model CN-Wheat developed for winter wheat after anthesis. METHODS: In CN-Wheat the acquisition and allocation of resources between photosynthetic organs, roots and grains are emergent properties of sink and source activities and transfers of mobile metabolites. CN-Wheat was calibrated for field plants under three N fertilizations at anthesis. Model parameters were taken from the literature or calibrated on the experimental data. KEY RESULTS: The model was able to predict the temporal variations and the distribution of resources in the culm. Thus, CN-Wheat accurately predicted the post-anthesis kinetics of dry masses and N content of photosynthetic organs and grains in response to N fertilization. In our simulations, when soil nitrates were non limiting, N in grains was ultimately determined by availability of C for root activity. Dry matter accumulation in grains was mostly affected by photosynthetic organ lifespan, which was regulated by protein turnover and C-regulated root activity. CONCLUSIONS: The present study illustrates that the hypotheses implemented in the model were able to predict realistic dynamics and spatial patterns of C and N. CN-Wheat provided insights into the interplay of C and N metabolism and how the depletion of mobile metabolites due to grain filling ultimately results in the cessation of resource capture. This enabled us to identify processes that limit grain mass and protein content and are potential targets for plant breeding. PMID- 27497244 TI - Foreword. PMID- 27497247 TI - Does IQ = IQ? Comparability of Intelligence Test Scores in Typically Developing Children. AB - Numerous intelligence tests are available to psychological diagnosticians to assess children's intelligence, but whether they yield comparable test results has been little studied. We examined test scores of 206 typically developing children aged 6 to 11 years on five German intelligence tests (Reynolds Intellectual Assessment Scales; Snijders Oomen Nonverbal Intelligence Test; Intelligence and Development Scales; Wechsler Intelligence Scale for Children, 4th edition; Culture Fair Intelligence Test Scale 2), which were individually administered. On a sample level, the test scores showed strong correlation and little or no mean difference. These results indicate that the tests measure a similar underlying construct, which is interpreted as general intelligence. On an individual level, however, test scores significantly differed across tests for 12% to 38% of the children. Differences did not depend on which test was used but rather on unexplained error. Implications for the application of intelligence assessment in psychological practice are discussed. PMID- 27497248 TI - RUNX3-mediated up-regulation of miR-29b suppresses the proliferation and migration of gastric cancer cells by targeting KDM2A. AB - RUNX3 is a transcriptional factor that has been shown to regulate protein-coding gene expression at the transcriptional level. However, the regulation of RUNX3 on miRNAs is not fully understood. In this study, we used miRNA microarray to identify the miRNAs that are regulated by RUNX3 and found that miR-29b showed the most up-regulation in RUNX3 over-expressed cells compared with the control cells. We used qRT-PCR to confirm the miRNA microarray results in several gastric cancer cells and found that RUNX3 could bind to the miR-29b promoter directly and cooperate with Smad3 to increase the promoter activity of miR-29b. In the clinical setting, both RUNX3 and miR-29b are down-regulated significantly in human gastric cancer tissues. A positive correlation between miR-29b and RUNX3 was found in the gastric cancer tissues. Additionally, we found that miR-29b suppressed the proliferation and metastasis of gastric cancer cells by directly targeting KDM2A. The miR-29b/KDM2A axis was involved in the RUNX3-mediated inhibition of gastric cancer cell proliferation and metastasis. Taken together, our results suggested that RUNX3-mediated up-regulation of miR-29b inhibited the proliferation and migration of gastric cancer cells by targeting KDM2A, representing a novel molecular mechanism for the tumor suppression action of RUNX3. PMID- 27497249 TI - Anxiety sensitivity and hazardous drinking among persons living with HIV/AIDS: An examination of the role of emotion dysregulation. AB - Hazardous drinking is prevalent among persons living with HIV/AIDS (PLWHA). Anxiety sensitivity is a vulnerability factor that is highly associated with hazardous drinking among seronegatives, but has yet to be tested in PLWHA. Additionally, there is a need to examine potential mechanisms underlying associations of anxiety sensitivity and hazardous drinking. Emotion dysregulation is one potential construct that may explain the association between anxiety sensitivity and hazardous drinking. The current study examined emotion dysregulation as a potential explanatory variable between anxiety sensitivity and four, clinically significant alcohol-related outcomes among PLWHA: hazardous drinking, symptoms of alcohol dependence, number of days consuming alcohol within the past month, and degree of past heavy episodic drinking. The sample included 126 PLWHA (Mage=48.3; SD=7.5; 65.9% male). Results indicated significant indirect effects of anxiety sensitivity via emotion dysregulation in all models. Indirect effects (kappa(2)) were of medium effect size. Alternative models were run reversing the predictor with mediator and, separately, reversing the mediator with the proposed outcome(s); alternative models yielded non-significant indirect effects in all but one case. Together, the current results indicate that anxiety sensitivity is associated emotion dysregulation, which, in turn, is associated with hazardous drinking outcomes. Overall, these findings may provide initial empirical evidence that emotion dysregulation may be a clinical intervention target for hazardous drinking. PMID- 27497250 TI - Biological therapies in lupus. PMID- 27497252 TI - T-cell-directed therapies in systemic lupus erythematosus. AB - Drug development for the treatment of systemic lupus erythematosus (SLE) has largely focused on B-cell therapies. A greater understanding of the immunopathogenesis of SLE coupled with advanced bioengineering has allowed for clinical trials centered on other targets for SLE therapy. The authors discuss the benefits and shortcomings of focusing on T-cell-directed therapies in SLE and lupus nephritis clinical trials. PMID- 27497253 TI - Targeted B cell therapies in the treatment of adult and pediatric systemic lupus erythematosus. AB - Belimumab (Benlysta) is a fully-humanized monoclonal antibody that inhibits B lymphocyte stimulator (also known as B cell activating factor) and was approved by the U.S. Federal Drug Administration and European Medicines Evaluation Agency for treatment in adults with autoantibody-positive systemic lupus erythematosus (SLE). Rituximab (Rituxan) is a chimeric anti-CD20 monoclonal antibody targeting B lymphocytes. This review discusses the key findings of the phase III trials in adults with SLE and of real-world use of belimumab and rituximab in the care of both adult and pediatric SLE patients. It highlights the safety profile of belimumab and rituximab and gives insight into the consideration of these therapies for specific SLE disease states. It concludes with a discussion of the current clinical trials investigating B cell therapies in specific SLE disease states and a look to the future, with ongoing clinical trials. PMID- 27497251 TI - Why targeted therapies are necessary for systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) continues to have important morbidity and accelerated mortality despite therapeutic advances. Targeted therapies offer the possibility of improved efficacy with fewer side effects. Current management strategies rely heavily on nonspecific immunosuppressive agents. Prednisone, in particular, is responsible for a considerable burden of later organ damage. There are a multitude of diverse mechanisms of disease activity, immunogenic abnormalities and clinical manifestations to take into consideration in SLE. Many targeted agents with robust mechanistic preclinical data and promising early phase studies have ultimately been disappointing in phase III, randomized, controlled studies. Recent efforts have focused on B-cell therapies, in particular given the success of belimumab in clinical trials, with limited success. We remain optimistic regarding other specific therapies being evaluated, including interferon-alpha blockade. It is likely that in SLE, given the heterogeneity of the population involved, precision medicine is needed, rather than expecting that any single biologic will be universally effective. PMID- 27497254 TI - Interferon-targeted therapy in systemic lupus erythematosus: Is this an alternative to targeting B and T cells? AB - Clinical trials of investigational agents in systemic lupus erythematosus (SLE) have focused on targeting dysregulated B and T cells; however, recent translational research findings of the importance of the dysregulation of the innate immune system in SLE have led to clinical trials that target interferon. Three biologics that target type I interferons have been tested for their efficacy and safety in active SLE patients; these phase II trials have tested the hypothesis that down-regulation of interferon-regulated gene expression (the interferon signature) lessen the clinical burden of SLE. Rontalizumab, an anti interferon-alpha monoclonal antibody, was studied in patients who had discontinued immunosuppressants. This study failed to show efficacy as assessed by both two outcome assessments; however, in low interferon signature patients, response was higher and corticosteroid usage was less in rontalizumab-treated patients. Sifalimumab, another anti-interferon-alpha monoclonal antibody, was studied in patients who remained on standard of care therapy. This study showed significantly better efficacy in patients treated with two sifalimumab dosages; significant differences were seen in the high interferon signature group. In a similar design and in a similar population as the sifalimumab study, anifrolumab, a monoclonal antibody that binds to a type I interferon receptor, was studied in patients who remained on standard of care therapy. In this study, one dosage group demonstrated efficacy and statistically significant effects were achieved in both tested dosage groups with secondary end points. Oral corticosteroid reduction to <=7.5 mg daily was achieved in one of the tested dosage groups and organ-specific outcomes were significantly improved in that same group. For all studies, no significant differences in serious adverse effects were seen; although, herpes zoster infections were increased in sifalimumab- and anifrolumab treated patients and influenza rates were increased in anifrolumab-treated patients. Anifrolumab is currently in pivotal phase III studies. Data appear to support the concept that targeting type I interferon in SLE patients associates with clinical efficacy and safety. Further data are forthcoming from ongoing phase III clinical trials of anifrolumab. Other drug development efforts should be considered that target plasmacytoid dendritic cells and toll like receptors given the effects these components have on interferon production. PMID- 27497255 TI - Rethinking biologics in lupus nephritis. AB - Lupus nephritis (LN) is a chronic and devastating complication of systemic lupus erythematosus. Despite advances in our understanding of LN and the availability of effective therapies, LN remains a difficult clinical problem, and progression to end stage renal disease remains a significant challenge. Though the advent of biologics has revolutionized the treatment of many rheumatological conditions, and several clinical trials of biologics have been conducted in LN, the promise of biologics remains unfulfilled. The experience gained from these initial clinical trials can help tailor approaches in future clinical trials, and the lessons learned can be applied to find a cure for this condition. PMID- 27497246 TI - The intestinal microbiome and surgical disease. PMID- 27497256 TI - Patient-reported outcomes in lupus clinical trials with biologics. AB - Therapeutic advances in systemic lupus erythematosus (SLE) are greatly needed. Despite advances in our knowledge of pathogenesis of the disease and targets, treatment remains a significant challenge. Finding effective and relatively safe medications remains one of the top priorities. SLE significantly impairs quality of life (QoL), and patient-reported outcomes (PROs) measure a unique aspect of the disease not captured by disease activity. Inclusion of PRO measurements is encouraged in SLE clinical trials, as they allow capturing benefits of a proposed intervention in language patients can relate to and in areas deemed pertinent and important to and by patients. Availability of patient-reported and patient centric clinical trials data may facilitate patients in informed and shared decision making, and allow for comparative cost-effectiveness evaluation for future resource allocation and reimbursements. Herein we review clinical trials with biologic therapies wherein PRO tools were included in the study design. PMID- 27497258 TI - Improved strategies for designing lupus trials with targeted therapies: learning from 65 years of experience. AB - The development of new agents to manage lupus erythematosus has lagged behind other autoimmune rheumatic diseases. This is in large part because lupus is a heterogeneous disorder affecting nine principal domains (organ systems) that are difficult to measure and quantify and can be at variance with each other. Over the last two decades, a variety of guidelines, definitions, candidate surrogate or biomarkers, metrics and composite indices have been presented as benchmarks that can be utilized to assess lupus in clinical trials. Despite this, over 20 agents have failed to achieve their primary outcome measure, some of which are generally believed to be clinically effective. This article presents constructive suggestions and improved strategies in trial design that will hopefully lead to the introduction of new agents for the disease. PMID- 27497257 TI - A critical review of clinical trials in systemic lupus erythematosus. AB - One challenge in caring for patients with systemic lupus erythematosus (SLE) is a paucity of approved therapeutics for treatment of the diverse disease manifestations. In the last 60 years, only one drug, belimumab, has been approved for SLE treatment. Critical evaluation of investigator initiated and pharma sponsored randomized controlled trials (RCTs) highlights barriers to successful drug development in SLE, including disease heterogeneity, inadequate trial size or duration, insufficient dose finding before initiation of large trials, handling of background medications, and choice of primary endpoint. Herein we examine lessons learned from landmark SLE RCTs and subsequent advances in trial design, as well as discuss efforts to address limitations in current SLE outcome measures that will improve detection of true therapeutic responses in future RCTs. PMID- 27497259 TI - Drug repositioning in SLE: crowd-sourcing, literature-mining and Big Data analysis. AB - Lupus patients are in need of modern drugs to treat specific manifestations of their disease effectively and safely. In the past half century, only one new treatment has been approved by the US Food and Drug Administration (FDA) for systemic lupus erythematosus (SLE). In 2014-2015, the FDA approved 71 new drugs, only one of which targeted a rheumatic disease and none of which was approved for use in SLE. Repositioning/repurposing drugs approved for other diseases using multiple approaches is one possible means to find new treatment options for lupus patients. "Big Data" analysis approaches this challenge from an unbiased standpoint whereas literature mining and crowd sourcing for candidates assessed by the CoLTs (Combined Lupus Treatment Scoring) system provide a hypothesis-based approach to rank potential therapeutic candidates for possible clinical application. Both approaches mitigate risk since the candidates assessed have largely been extensively tested in clinical trials for other indications. The usefulness of a multi-pronged approach to drug repositioning in lupus is highlighted by orthogonal confirmation of hypothesis-based drug repositioning predictions by "Big Data" analysis of differentially expressed genes from lupus patient samples. The goal is to identify novel therapies that have the potential to affect disease processes specifically. Involvement of SLE patients and the scientists that study this disease in thinking about new drugs that may be effective in lupus though crowd-sourcing sites such as LRxL-STAT (www.linkedin.com/in/lrxlstat) is important in stimulating the momentum needed to test these novel drug targets for efficacy in lupus rapidly in small, proof-of concept trials conducted by LuCIN, the Lupus Clinical Investigators Network (www.linkedin.com/in/lucinstat). PMID- 27497260 TI - Patient and general public preferences for health states: A call to reconsider current guidelines. AB - In economic evaluations of health care interventions, benefits are often expressed in terms of Quality-Adjusted Life-Years (QALYs). The QALY comprises length and quality of life into one measure which allows cross-disease comparability. The quality adjustment of the QALY is based on preferences for health states. An important normative choice is the question whose preferences for states of health we wish to capture. The answer to this question is directly related to the normative question regarding the appropriate maximand in health care decisions. Currently, preferences are commonly derived from the general public, rather than from actual patients. This choice, which can have large consequences on final outcomes of economic evaluations, has always been a topic of debate. This paper clarifies and furthers the discussion regarding the appropriate source of preferences for health state valuations, acknowledges the plurality of different perspectives, and argues that health economic guidelines could require analysis of benefit in terms of QALYs based on both patient and general public preferences. PMID- 27497261 TI - Partial hessian fitting for determining force constant parameters in molecular mechanics. AB - We present a new protocol for deriving force constant parameters that are used in molecular mechanics (MM) force fields to describe the bond-stretching, angle bending, and dihedral terms. A 3 * 3 partial matrix is chosen from the MM Hessian matrix in Cartesian coordinates according to a simple rule and made as close as possible to the corresponding partial Hessian matrix computed using quantum mechanics (QM). This partial Hessian fitting (PHF) is done analytically and thus rapidly in a least-squares sense, yielding force constant parameters as the output. We herein apply this approach to derive force constant parameters for the AMBER-type energy expression. Test calculations on several different molecules show good performance of the PHF parameter sets in terms of how well they can reproduce QM-calculated frequencies. When soft bonds are involved in the target molecule as in the case of secondary building units of metal-organic frameworks, the MM-optimized geometry sometimes deviates significantly from the QM-optimized one. We show that this problem is rectified effectively by use of a simple procedure called Katachi that modifies the equilibrium bond distances and angles in bond-stretching and angle-bending terms. (c) 2016 Wiley Periodicals, Inc. PMID- 27497262 TI - TAK1 adaptor proteins, TAB2 and TAB3, link the signalosome to B-cell receptor induced IKK activation. AB - Transforming growth factor-beta-activated kinase (TAK)1-binding proteins (TAB) activate nuclear factor-kappaB by linking TAK1 to signaling molecules. We investigated the mechanisms underlying B-cell receptor (BCR) signaling in TAB2- and TAB3-deficient and TAB3 domain deletion mutant DT40 B cell lines. Loss of TAB2 and TAB3 abolished BCR-induced inhibitor of kappaB kinase (IKK) activation and TAK1 binding to caspase recruitment domain membrane-associated guanylate kinase protein (CARMA)1. Deletion of TAB3, coupling of ubiquitin conjugation to ER degradation, coiled-coil, and zinc finger domains blocked IKK activation and association with CARMA1. Thus, TAB2 and TAB3 connect signaling molecules that activate IKK in BCR signaling. PMID- 27497263 TI - Quality of life in stabilized patients with schizophrenia is mainly associated with resilience and self-esteem. AB - OBJECTIVE: Improving quality of life (QoL) is an important objective in the treatment of schizophrenia. The aim of the current study was to examine to what extent resilience, self-esteem, hopelessness, and psychopathology are correlated with QoL. METHOD: We recruited 52 out-patients diagnosed with schizophrenia according to DSM-IV criteria and 77 healthy control subjects from the general community. In patients, psychopathology was quantified by the Positive and Negative Syndrome Scale. The following scales were used in both patients and control subjects: the Berliner Lebensqualitatsprofil, the Resilience Scale, the Rosenberg Self-Esteem Scale, and the Beck Hopelessness Scale to assess QoL, resilience, self-esteem, and hopelessness respectively. RESULTS: Patients with schizophrenia presented with significantly less QoL, resilience, self-esteem, and hope compared to healthy control subjects. In patients, QoL correlated moderately with resilience, self-esteem, and hopelessness and weakly with symptoms. With respect to the latter, particularly depression and positive symptoms were negatively correlated with QoL. CONCLUSION: Our results highlight the complex nature of QoL in patients suffering from schizophrenia. They underscore that significant efforts are necessary to enhance resilience and self-esteem and to diminish hopelessness as well as affective and positive symptoms in patients with schizophrenia. PMID- 27497265 TI - Risk of sensorineural hearing loss with macrolide antibiotics: A nested case control study. AB - OBJECTIVES: To determine the association between a diagnosis of sensorineural hearing loss (SNHL) and the prescription of a macrolide antibiotic. STUDY DESIGN: Retrospective nested case-control study. METHODS: From the LifeLink (IMS, Danbury, CT) health claims database, we randomly selected a cohort of subjects 15 to 60 years old from 2006 to 2014. Cases were identified as patients diagnosed with SNHL, each matched by age and calendar time to 10 controls selected from the same cohort. All macrolide prescriptions (erythromycin, azithromycin, clarithromycin, and telithromycin) were identified, and statistical comparison of usage was compared between cases and controls. Amoxicillin and fluoroquinolone antibiotics were used as positive controls to further investigate confounding by infection. Albuterol was used as a negative control because this is a drug class not expected to be associated with SNHL or with a confounding condition potentially causing SNHL. RESULTS: From a cohort of 6,110,723 subjects, we identified 5,989 cases of SNHL and 59,890 corresponding controls. The rate ratio for one prescription of a macrolide was 1.36 (95% confidence inteval [CI]: 1.24 1.49) and for multiple prescriptions was 1.66 (95% CI: 1.42-1.94). Similar rate ratios were observed with multiple prescriptions of amoxicillin and fluoroquinolones. CONCLUSION: A significant association between SNHL and macrolide use was likely due to confounding by indication for antibiotic treatment because the risk was also observed with fluoroquinolones and amoxicillin, antibiotics with no known ototoxic potential. Therefore, there does not appear to be an increased risk of SNHL in patients treated with macrolide antibiotics. LEVEL OF EVIDENCE: 3b. Laryngoscope, 127:229-232, 2017. PMID- 27497264 TI - Identification of a combined biomarker for malignant transformation in oral submucous fibrosis. AB - BACKGROUND: Oral submucous fibrosis (OSF) is a chronic progressive disease of the oral cavity that is considered a common potentially malignant disorder in South Asia. Areca nut chewing is the main etiological factor, but its carcinogenic mechanism has yet to be proven. The purpose of this study was to identify the useful biomarkers in predicting high-risk patients with OSF. METHODS: Thirty-six cases of OSF and six cases of normal oral mucosa (NOM) were used for this study. Immunohistochemical staining was performed for Ki67, cyclin D1, p16, p53, beta catenin, c-Jun, c-Met, and insulin-like growth factor II mRNA-binding protein 3 (IMP3). The expression patterns of NOM served as guidelines for the scoring system. RESULTS: The expression of Ki67, cyclin D1, c-Met, IMP3, and beta-catenin showed a significant difference between OSF and NOM samples. The combined biomarkers of Ki67 and p16 showed significantly different expression between the transformation and non-transformation groups. With discriminant analysis, we proposed a noble formula and cutoff value for predicting high-risk patients with OSF. CONCLUSION: The notable biomarkers in our present study were Ki67 and p16 showing significantly different expression levels between the transformation and non-transformation groups. With the identification of high-risk patients with OSF, we can expect to develop more intensive treatment modalities, leading to the reduction in cancer transformation rate from OSF. PMID- 27497266 TI - Effect of polishing instruments and polishing regimens on surface topography and phase transformation of monolithic zirconia: An evaluation with XPS and XRD analysis. AB - PURPOSE: Polishing procedures might alter monolithic zirconia (MZ) surface resulting in phase changes that can be deleterious for clinical performance and antagonist tooth wear. This study investigated the topographical features and phase transformation in MZ after polishing with different regimens simulating the clinical workflow. MATERIALS AND METHODS: MZ specimens (Katana Zirconia HT, Kuraray-Noritake) (12*12*1.8 mm(3)) were grinded and polished using one of the five systems assessed: BG: Silicone carbide polishers (Brownie, Greenie, Super Greenie); CG: Diamond impregnated ceramic polisher kit (Ceragloss); EV: Synthetically bonded grinder interspersed with diamond (EVE Kit); SL: Urethane coated paper with aluminium oxide grits (Soflex Finishing and Polishing System Kit) and DB: Diamond bur (8 um). Polished specimens were initially roughened with 220 um diamond burs (Grinding Bur-GB) (10 s, 160.000160,000 rpm) and considered for baseline measurements. Polishing regimens were performed for 10 s using a slow-speed hand piece under water-cooling except for SL, in a custom made device (750 g; 5000 and 75,000 rpm). Surface roughnesses, phase changes (XRD) were assessed, surface characterization was performed (SEM, EDS). RESULTS: The highest roughness was obtained with the EV system (1.11 um) compared to those of other systems (0.13-0.4 um) (ptheta and minor peak at 34.94 degrees 2theta. While GB, CG, EV, SL and DB exhibited a peak shift to the left, BG demonstrated a right peak shift on the 2theta scale. Monoclinic phase change was not noted in any of the groups. CONCLUSION: All polishing methods, except BG, exhibited a peak shift towards the lower angles of the 2-theta scale. Since the peak shifts were in the order of fractions of an angle they are attributed to stress formation rather than a phase change in the material. Thus, all polishing systems tested may not be detrimental for the phase transformation of MZ. EV system resulted in the highest roughness and none of the polishing regimens restored the polishability to the baseline level. PMID- 27497267 TI - Laryngeal ultrasound and pediatric vocal fold nodules. AB - OBJECTIVES/HYPOTHESIS: The term vocal fold nodules refers to bilateral thickening of the membranous folds with minimal impairment of the vibratory properties of the mucosa. Nodules are thought to be related to repetitive mechanical stress, associated with voice use patterns. Diagnosis is typically made in the office via either rigid or flexible laryngeal stroboscopy. Depending on the individual child, obtaining an optimal view of the larynx can be difficult if not impossible. Recent advances in high-frequency ultrasonography allows for transcervical examination of laryngeal structures. The goal of this project was to determine if laryngeal ultrasound (LUS) can be used to identify vocal fold nodules in dysphonic children. STUDY DESIGN: Prospective case-control study in which the patient acted as his or her own control. METHODS: Forty-six pediatric patients were recruited for participation in this study; the mean age was 4.8 years. Twenty-three did not have any vocal fold lesions and 23 had a diagnosis of vocal fold nodules on laryngeal stroboscopy. Recorded LUSs were reviewed by two pediatric radiologists who were blinded to the nodule status. RESULTS: There was substantial inter-rater agreement (kappa = 0.70, 95% confidence interval [CI]: 0.50-0.89) between the two radiologists regarding the presence of nodules. There was also substantial agreement (kappa = 0.87, 95% CI: 0.72-1) between LUS and laryngeal stroboscopy. Sensitivity of LUS was 100% (95% CI: 85%-100%) and specificity was 87% (95% CI: 66%-97%). CONCLUSIONS: LUS can be used to identify vocal fold nodules in children with substantial agreement with laryngeal stroboscopy. LEVEL OF EVIDENCE: 3b Laryngoscope, 127:676-678, 2017. PMID- 27497268 TI - Integrated molecular and bioprocess engineering for bacterially produced immunogenic modular virus-like particle vaccine displaying 18 kDa rotavirus antigen. AB - A high global burden of rotavirus disease and the unresolved challenges with the marketed rotavirus vaccines, particularly in the developing world, have ignited efforts to develop virus-like particle (VLP) vaccines for rotavirus. While rotavirus-like particles comprising multiple viral proteins can be difficult to process, modular VLPs presenting rotavirus antigenic modules are promising alternatives in reducing process complexity and cost. In this study, integrated molecular and bioprocess engineering approaches were used to simplify the production of modular murine polyomavirus capsomeres and VLPs presenting a rotavirus 18 kDa VP8* antigen. A single construct was generated for dual expression of non-tagged murine polyomavirus capsid protein VP1 and modular VP1 inserted with VP8*, for co-expression in Escherichia coli. Co-expressed proteins assembled into pentameric capsomeres in E. coli. A selective salting-out precipitation and a polishing size exclusion chromatography step allowed the recovery of stable modular capsomeres from cell lysates at high purity, and modular capsomeres were successfully translated into modular VLPs when assembled in vitro. Immunogenicity study in mice showed that modular capsomeres and VLPs induced high levels of VP8*-specific antibodies. Our results demonstrate that a multipronged synthetic biology approach combining molecular and bioprocess engineering enabled simple and low-cost production of highly immunogenic modular capsomeres and VLPs presenting conformational VP8* antigenic modules. This strategy potentially provides a cost-effective production route for modular capsomere and VLP vaccines against rotavirus, highly suitable to manufacturing economics for the developing world. Biotechnol. Bioeng. 2017;114: 397-406. (c) 2016 Wiley Periodicals, Inc. PMID- 27497269 TI - Population modeling for pesticide risk assessment of threatened species-A case study of a terrestrial plant, Boltonia decurrens. AB - Although population models are recognized as necessary tools in the ecological risk assessment of pesticides, particularly for species listed under the Endangered Species Act, their application in this context is currently limited to very few cases. The authors developed a detailed, individual-based population model for a threatened plant species, the decurrent false aster (Boltonia decurrens), for application in pesticide risk assessment. Floods and competition with other plant species are known factors that drive the species' population dynamics and were included in the model approach. The authors use the model to compare the population-level effects of 5 toxicity surrogates applied to B. decurrens under varying environmental conditions. The model results suggest that the environmental conditions under which herbicide applications occur may have a higher impact on populations than organism-level sensitivities to an herbicide within a realistic range. Indirect effects may be as important as the direct effects of herbicide applications by shifting competition strength if competing species have different sensitivities to the herbicide. The model approach provides a case study for population-level risk assessments of listed species. Population-level effects of herbicides can be assessed in a realistic and species specific context, and uncertainties can be addressed explicitly. The authors discuss how their approach can inform the future development and application of modeling for population-level risk assessments of listed species, and ecological risk assessment in general. Environ Toxicol Chem 2017;36:480-491. (c) 2016 SETAC. PMID- 27497270 TI - Does adaptive radiation of a host lineage promote ecological diversity of its bacterial communities? A test using gut microbiota of Anolis lizards. AB - Adaptive radiations provide unique opportunities to test whether and how recent ecological and evolutionary diversification of host species structures the composition of entire bacterial communities. We used 16S rRNA gene sequencing of faecal samples to test for differences in the gut microbiota of six species of Puerto Rican Anolis lizards characterized by the evolution of distinct 'ecomorphs' related to differences in habitat use. We found substantial variation in the composition of the microbiota within each species and ecomorph (trunk crown, trunk-ground, grass-bush), but no differences in bacterial alpha diversity among species or ecomorphs. Beta diversity analyses revealed subtle but significant differences in bacterial composition related to host phylogeny and species, but these differences were not consistently associated with Anolis ecomorph. Comparison of a trunk-ground species from this clade (A. cristatellus) with a distantly related member of the same ecomorph class (A. sagrei) where the two species have been introduced and are now sympatric in Florida revealed pronounced differences in the alpha diversity and beta diversity of their microbiota despite their ecological similarity. Comparisons of these populations with allopatric conspecifics also revealed geographic differences in bacterial alpha diversity and beta diversity within each species. Finally, we observed high intraindividual variation over time and strong effects of a simplified laboratory diet on the microbiota of A. sagrei. Collectively, our results indicate that bacterial communities are only weakly shaped by the diversification of their lizard hosts due to the strikingly high levels of bacterial diversity and variation observed within Anolis species. PMID- 27497271 TI - Avoiding long-term muscle damage upon ischaemia-reperfusion. PMID- 27497273 TI - Fit for Purpose, Psychometric Assessment of the Eating Attitudes Test-26 in an Irish Adolescent Sample. AB - The present study examined the psychometric properties of the Eating Attitudes Test-26 (EAT-26) in a sample of Irish adolescents (N=2444). Consistent with previous research, in adolescents, confirmatory factor analysis (CFA) failed to replicate the original three-factor structure of the EAT-26. Goodness-of-fit indices provided support for a recently published six-factor EAT-18 model. As the EAT-26 is typically used as a unitary measure by clinicians, a second-order factor model was investigated, which supported a general concept of eating problems. Convergent validity of the EAT-18 was assessed using the Eating Disorder Inventory-3 (EDI-3). Using the 90th percentile, a cut-off score of 13 was identified on the EAT-18 that discriminated between those indicative and non indicative of disordered eating attitudes and behaviors. Findings suggest that the revised factor structures may be more suitable for the general adolescent population than the original three-factor EAT-26. Clinical implications of the EAT-18 and future research recommendations are addressed. PMID- 27497274 TI - Validation of the Behaviour Rating Inventory of Executive Function - Adult Version (BRIEF-A) in the obese with and without binge eating disorder. AB - Obesity and binge eating disorder (BED) are both associated with deficiencies in executive function. The Behaviour Rating Inventory of Executive Function - Adult Version (BRIEF-A) is a self-report measure that assesses executive function. This study aimed to examine the psychometric properties of the BRIEF-A in an obese population, with and without BED, and to explore the differences on the BRIEF-A in the obese, with and without BED, compared to normative sample. 98 obese participants (70 BED) completed the BRIEF-A, DASS-21 and several performance based measures of executive function. 30 participants completed a repeat assessment two months later. There was evidence of good internal consistency and test-retest reliability, however evidence for construct and convergent validity was mixed. Additionally, it was found that obese individuals report significantly more executive function difficulties on the BRIEF-A than the normative sample. Further, obese with BED report more executive function difficulties than those without. This study shows some evidence of sound psychometric properties of the BRIEF-A in an obese sample, however more research is required to understand the nature of executive function being measured. PMID- 27497272 TI - Integrating metabolomics and transcriptomics data to discover a biocatalyst that can generate the amine precursors for alkamide biosynthesis. AB - The Echinacea genus is exemplary of over 30 plant families that produce a set of bioactive amides, called alkamides. The Echinacea alkamides may be assembled from two distinct moieties, a branched-chain amine that is acylated with a novel polyunsaturated fatty acid. In this study we identified the potential enzymological source of the amine moiety as a pyridoxal phosphate-dependent decarboxylating enzyme that uses branched-chain amino acids as substrate. This identification was based on a correlative analysis of the transcriptomes and metabolomes of 36 different E. purpurea tissues and organs, which expressed distinct alkamide profiles. Although no correlation was found between the accumulation patterns of the alkamides and their putative metabolic precursors (i.e., fatty acids and branched-chain amino acids), isotope labeling analyses supported the transformation of valine and isoleucine to isobutylamine and 2 methylbutylamine as reactions of alkamide biosynthesis. Sequence homology identified the pyridoxal phosphate-dependent decarboxylase-like proteins in the translated proteome of E. purpurea. These sequences were prioritized for direct characterization by correlating their transcript levels with alkamide accumulation patterns in different organs and tissues, and this multi-pronged approach led to the identification and characterization of a branched-chain amino acid decarboxylase, which would appear to be responsible for generating the amine moieties of naturally occurring alkamides. PMID- 27497275 TI - Multidisciplinary interventions in the management of atopic dermatitis. AB - Atopic dermatitis (AD) is the most common pediatric skin disease. AD has a significant effect on patient and family quality of life caused by intense pruritus, sleep disruption, dietary and nutritional concerns, and psychological stress associated with the disease and its management. Multidisciplinary approaches to AD care have been developed in appreciation of the complex interplay among biological, psychological, behavioral, and dietary factors that affect disease control and the wide range of knowledge, skills, and support that patients and families require to effectively manage and cope with this condition. Common components of multidisciplinary treatment approaches include medical evaluation and management by an AD specialist, education and nursing care, psychological and behavioral support, and nutritional assessment and guidance. Models of care include both clinical programs and structured educational groups provided as adjuncts to standard clinical care. Available evidence suggests beneficial effects of multidisciplinary interventions in improving disease severity and quality of life, particularly for patients with moderate-to-severe disease. Additional research is needed to identify the best candidates for the various multidisciplinary approaches and evaluate the cost-effectiveness of these programs. PMID- 27497276 TI - Cellular and molecular immunologic mechanisms in patients with atopic dermatitis. AB - Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti-IL-4 receptor alpha-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment. PMID- 27497277 TI - Multifactorial skin barrier deficiency and atopic dermatitis: Essential topics to prevent the atopic march. AB - Atopic dermatitis (AD) is the most common inflammatory skin disease in the industrialized world and has multiple causes. Over the past decade, data from both experimental models and patients have highlighted the primary pathogenic role of skin barrier deficiency in patients with AD. Increased access of environmental agents into the skin results in chronic inflammation and contributes to the systemic "atopic (allergic) march." In addition, persistent skin inflammation further attenuates skin barrier function, resulting in a positive feedback loop between the skin epithelium and the immune system that drives pathology. Understanding the mechanisms of skin barrier maintenance is essential for improving management of AD and limiting downstream atopic manifestations. In this article we review the latest developments in our understanding of the pathomechanisms of skin barrier deficiency, with a particular focus on the formation of the stratum corneum, the outermost layer of the skin, which contributes significantly to skin barrier function. PMID- 27497278 TI - Advances in asthma 2015: Across the lifespan. AB - In 2015, progress in understanding asthma ranged from insights to asthma inception, exacerbations, and severity to advancements that will improve disease management throughout the lifespan. 2015's insights to asthma inception included how the intestinal microbiome affects asthma expression with the identification of specific gastrointestinal bacterial taxa in early infancy associated with less asthma risk, possibly by promoting regulatory immune development at a critical early age. The relevance of epigenetic mechanisms in regulating asthma-related gene expression was strengthened. Predicting and preventing exacerbations throughout life might help to reduce progressive lung function decrease and disease severity in adulthood. Although allergy has long been linked to asthma exacerbations, a mechanism through which IgE impairs rhinovirus immunity and underlies asthma exacerbations was demonstrated and improved by anti-IgE therapy (omalizumab). Other key molecular pathways underlying asthma exacerbations, such as cadherin-related family member 3 (CDHR3) and orosomucoid like 3 (ORMDL3), were elucidated. New anti-IL-5 therapeutics, mepolizumab and reslizumab, were US Food and Drug Administration approved for the treatment of patients with severe eosinophilic asthma. In a clinical trial the novel therapeutic inhaled GATA3 mRNA specific DNAzyme attenuated early- and late-phase allergic responses to inhaled allergen. These current findings are significant steps toward addressing unmet needs in asthma prevention, severity modification, disparities, and lifespan outcomes. PMID- 27497279 TI - Assessing the effect of engineered nanomaterials on the environment and human health. PMID- 27497280 TI - Asthma and the Olympics. PMID- 27497282 TI - Dendritic cell targeting with C-type lectins for improvement of allergen immunotherapy. PMID- 27497283 TI - A touchscreen based global motion perception task for mice. AB - Global motion perception is a function of higher, or extrastriate, visual system circuitry. These circuits can be engaged in visually driven navigation, a behavior at which mice are adept. However, the properties of global motion perception in mice are unclear. Therefore, we developed a touchscreen-based, two alternative forced choice (2AFC) task to explore global motion detection in mice using random dot kinematograms (RDK). Performance data was used to compute coherence thresholds for global motion perception. The touchscreen-based task allowed for parallel training and testing with multiple chambers and minimal experimenter intervention with mice performing hundreds of trials per session. Parameters of the random dot kinematograms, including dot size, lifetime, and speed, were tested. Mice learned to discriminate kinematograms whose median motion direction differed by 90 degrees in 7-24days after a 10-14day pre-training period. The average coherence threshold (measured at 70% correct) in mice for this task was 22+/-5%, with a dot diameter of 3.88mm and speed of 58.2mm/s. Our results confirm the ability of mice to perform global motion discriminations, and the touchscreen assay provides a flexible, automated, and relatively high throughput method with which to probe complex visual function in mice. PMID- 27497284 TI - The Cytokine CXCL12 Promotes Basket Interneuron Inhibitory Synapses in the Medial Prefrontal Cortex. AB - Prenatally, the cytokine CXCL12 regulates cortical interneuron migration, whereas its postnatal functions are poorly understood. Here, we report that CXCL12 is expressed postnatally in layer V pyramidal neurons and localizes on their cell bodies in the medial prefrontal cortex (mPFC), while its receptors CXCR4/CXCR7 localize to the axon terminals of parvalbumin (PV) interneurons. Conditionally eliminating CXCL12 in neonatal layer V pyramidal neurons led to decreased axon targeting and reduced inhibitory perisomatic synapses from PV+ basket interneurons onto layer V pyramidal neurons. Consequently, the mPFC of Cxcl12 conditional mutants displayed attenuated inhibitory postsynaptic currents onto layer V pyramidal neurons. Thus, postnatal CXCL12 signaling promotes a specific interneuron circuit that inhibits mPFC activity. PMID- 27497285 TI - Componential Network for the Recognition of Tool-Associated Actions: Evidence from Voxel-based Lesion-Symptom Mapping in Acute Stroke Patients. AB - The study aimed to elucidate areas involved in recognizing tool-associated actions, and to characterize the relationship between recognition and active performance of tool use.We performed voxel-based lesion-symptom mapping in a prospective cohort of 98 acute left-hemisphere ischemic stroke patients (68 male, age mean +/- standard deviation, 65 +/- 13 years; examination 4.4 +/- 2 days post stroke). In a video-based test, patients distinguished correct tool-related actions from actions with spatio-temporal (incorrect grip, kinematics, or tool orientation) or conceptual errors (incorrect tool-recipient matching, e.g., spreading jam on toast with a paintbrush). Moreover, spatio-temporal and conceptual errors were determined during actual tool use.Deficient spatio temporal error discrimination followed lesions within a dorsal network in which the inferior parietal lobule (IPL) and the lateral temporal cortex (sLTC) were specifically relevant for assessing functional hand postures and kinematics, respectively. Conversely, impaired recognition of conceptual errors resulted from damage to ventral stream regions including anterior temporal lobe. Furthermore, LTC and IPL lesions impacted differently on action recognition and active tool use, respectively.In summary, recognition of tool-associated actions relies on a componential network. Our study particularly highlights the dissociable roles of LTC and IPL for the recognition of action kinematics and functional hand postures, respectively. PMID- 27497286 TI - Rice putative methyltransferase gene OsTSD2 is required for root development involving pectin modification. AB - Pectin synthesis and modification are vital for plant development, although the underlying mechanisms are still not well understood. Here, we report the functional characterization of the OsTSD2 gene, which encodes a putative methyltransferase in rice. All three independent T-DNA insertion lines of OsTSD2 displayed dwarf phenotypes and serial alterations in different zones of the root. These alterations included abnormal cellular adhesion and schizogenous aerenchyma formation in the meristematic zone, inhibited root elongation in the elongation zone, and higher lateral root density in the mature zone. Immunofluorescence (with LM19) and Ruthenium Red staining of the roots showed that unesterified homogalacturonan (HG) was increased in Ostsd2 mutants. Biochemical analysis of cell wall pectin polysaccharides revealed that both the monosaccharide composition and the uronic acid content were decreased in Ostsd2 mutants. Increased endogenous ABA content and opposite roles performed by ABA and IAA in regulating cellular adhesion in the Ostsd2 mutants suggested that OsTSD2 is required for root development in rice through a pathway involving pectin synthesis/modification. A hypothesis to explain the relationship among OsTSD2, pectin methylesterification, and root development is proposed, based on pectin's function in regional cell extension/division in a zone-dependent manner. PMID- 27497287 TI - ABA is required for the accumulation of APX1 and MBF1c during a combination of water deficit and heat stress. AB - Abscisic acid (ABA) plays a key role in plant acclimation to abiotic stress. Although recent studies suggested that ABA could also be important for plant acclimation to a combination of abiotic stresses, its role in this response is currently unknown. Here we studied the response of mutants impaired in ABA signalling (abi1-1) and biosynthesis (aba1-1) to a combination of water deficit and heat stress. Both mutants displayed reduced growth, biomass, and survival when subjected to stress combination. Focusing on abi1-1, we found that although its stomata had an impaired response to water deficit, remaining significantly more open than wild type, its stomatal aperture was surprisingly reduced when subjected to the stress combination. Stomatal closure during stress combination in abi1-1 was accompanied by higher levels of H2O2 in leaves, suggesting that H2O2 might play a role in this response. In contrast to the almost wild-type stomatal closure phenotype of abi1-1 during stress combination, the accumulation of ascorbate peroxidase 1 and multiprotein bridging factor 1c proteins, required for acclimation to a combination of water deficit and heat stress, was significantly reduced in abi1-1 Our findings reveal a key function for ABA in regulating the accumulation of essential proteins during a combination of water deficit and heat stress. PMID- 27497288 TI - Investigation of fluorescence methods for rapid detection of municipal wastewater impact on drinking water sources. AB - Fluorescence spectroscopy as a means to detect low levels of treated wastewater impact on two source waters was investigated using effluents from five wastewater facilities. To identify how best to interpret the fluorescence excitation emission matrices (EEMs) for detecting the presence of wastewater, several feature selection and classification methods were compared. An expert supervised regional integration approach was used based on previously identified features which distinguish biologically processed organic matter including protein-like fluorescence and the ratio of protein to humic-like fluorescence. Use of nicotinamide adenine dinucleotide-like (NADH) fluorescence was found to result in higher linear correlations for low levels of wastewater presence. Parallel factors analysis (PARAFAC) was also applied to contrast an unsupervised multiway approach to identify underlying fluorescing components. A humic-like component attributed to reduced semiquinone-like structures was found to best correlate with wastewater presence. These fluorescent features were used to classify, by volume, low (0.1-0.5%), medium (1-2%), and high (5-15%) levels by applying support vector machines (SVMs) and logistic regression. The ability of SVMs to utilize high-dimensional input data without prior feature selection was demonstrated through their performance when considering full unprocessed EEMs (66.7% accuracy). The observed high classification accuracies are encouraging when considering implementation of fluorescence spectroscopy as a water quality monitoring tool. Furthermore, the use of SVMs for classification of fluorescence data presents itself as a promising novel approach by directly utilizing the high dimensional EEMs. PMID- 27497289 TI - A combined spectroscopic and TDDFT study of natural dyes extracted from fruit peels of Citrus reticulata and Musa acuminata for dye-sensitized solar cells. AB - This study reports the novel spectroscopic investigations and enhanced the electron transfers of Citrus reticulata and Musa acuminata fruit peels as the photosensitizers for the dye-sensitized solar cells. The calculated TD-DFT UB3LYP/6-31+G(d,p)-IEFPCM(UAKS), experiment spectra of ultra-violet-visible spectroscopy, and Fourier transform infrared spectroscopy studies indicate the main flavonoid (hesperidin and gallocatechin) structures of the dye extracts. The optimized flavonoid structures are calculated using Density functional theory (DFT) at 6-31+G(d,p) level. The rutinosyl group of the hesperidin pigment (Citrus reticulata) will be further investigated compared to the gallocatechin (Musa acuminata) pigment. The acidity of the dye extract is treated by adding 2% acetic acid. The energy levels of the HOMO-LUMO dyes are measured by a combined Tauc plot and cyclic voltammetry contrasted with the DFT data. The electrochemical impedance spectroscopy will be performed to model the dye electron transfer. As for the rutinosyl group presence and the acidic treatment, the acidified Citrus reticulata cell under continuous light exposure of 100mW.cm-2 yields a short circuit current density (Jsc) of 3.23mA/cm2, a photovoltage (Voc) of 0.48V, and a fill factor of 0.45 corresponding to an energy conversion efficiency (eta) of 0.71% because the shifting down HOMO-LUMO edges and the broadening dye's absorbance evaluated by a combined spectroscopic and TD-DFT method. The result also leads to the longest diffusion length of 32.2MUm, the fastest electron transit of 0.22ms, and the longest electron lifetime of 4.29ms. PMID- 27497290 TI - Exploring the determinants of sanitation success in Sub-Saharan Africa. AB - Sub-Saharan Africa (SSA) missed the Millennium Development Goal (MDG) sanitation target by a wide margin. However, there are a few African countries which made remarkable progress towards achieving the sanitation target. While the general factors that influence sanitation success are widely known, some of the few studies that have investigated the SSA sanitation situation have arrived at different conclusions regarding the determinants of sanitation success. The objectives of this paper were to establish the key determinants of sanitation success in SSA countries and to classify the SSA countries based on factors associated with sanitation success. This was achieved by analysing data drawn from 46 SSA countries. An objective methodological approach, using regression and cluster analyses to reveal the underlying sanitation success factors, has been adopted. A total of 11 economic and socio-political independent variables were tested against the dependent variable; proportion of the 2015 population that has gained access to sanitation since 2000. Regression results showed consistent and robust association between sanitation success and education for the national, rural and socio-political samples (p values 0.018-0.038). These results suggest that the level of education contributed to sanitation success in SSA during the MDG period. For the urban sample, a negative association was demonstrated between sanitation success and access to improved water sources (p = 0.034). This implies that countries which made huge sanitation gains had low coverage of improved water sources. The results from cluster analysis showed that countries which achieved great sanitation success were characterized by the highest education levels, incomes, population densities, political stability and high proportions of urban population. The knowledge of the key determinants of sanitation success could help in the formulation and design of appropriate policies and interventions to improve sustainable sanitation access in the post-2015 development agenda. PMID- 27497291 TI - Characteristics of psychiatric hospitalizations with multiple mechanical restraint episodes versus hospitalization with a single mechanical restraint episode. AB - We investigated the characteristics of multiple episodes of mechanical restraint versus a single episode in a psychiatric ward of a public general hospital. The following characteristics were associated with multiple restraints: young age, length of hospital stay, not being readmitted within 30 days from previous discharge, and admission in the previous year before the implementation of an intervention program to reduce mechanical restraint. The study suggests that both organizational factors and patients' disturbed behaviour are associated with the risk of being mechanically restrained several times. PMID- 27497292 TI - An investigation of habit learning in Anorexia Nervosa. AB - Anorexia Nervosa (AN) is a disorder characterised by compulsive behaviour, such as self-starvation and excessive exercise, which develop in the pursuit of weight loss. Recent theory suggests that once established, compulsive weight-loss behaviours in AN may become habitual. In two parallel studies, we measured whether individuals with AN showed a bias toward habits using two outcome devaluation tasks. In Study 1, 23 women with AN (restrictive and binge/purge subtypes), and 18 healthy controls (HC) completed the slips-of-action paradigm, designed to assess reward-based habits. In Study 2, 13 women with restrictive AN, 14 women recovered from restrictive AN, and 17 female HC participants completed the slips-of-action paradigm, and an avoidance paradigm, designed to assess aversive habits. AN participants showed no deficit relative to HCs in the ability to use feedback to respond correctly to stimuli. Following devaluation of outcomes, all groups in both studies were equally able to withhold inappropriate responses, suggesting no deficit in the balance between goal-directed and habitual control of behaviour in these tasks in AN. These results suggest that individuals with AN do not show a generalised tendency to rely on habits in two outcome-devaluation tasks. Future research is needed to investigate the potential role of disorder-specific habits in the maintenance of behaviour in AN. PMID- 27497293 TI - Impact of psychotic symptoms on cognitive functioning in child and adolescent psychiatric inpatients with severe mood disorders. AB - Despite established differences in cognitive functioning of adults with mood disorder-related psychosis and those with non-affective psychotic disorders, there is limited evidence of the impact of psychotic symptoms on the cognitive functioning of children and adolescents with mood disorders. This study investigates IQ, working memory, and processing speed scores in 80 child and adolescent inpatients discharged from an intermediate care state psychiatric hospital, using a retrospective chart review. Associations between diagnosis based on DSM-IV criteria (7 with Major Depression- MDD; 43 with Bipolar Disorders BD, and 30 with Mood Disorders Not Otherwise Specified-NOS), presence of current psychotic features, and cognitive functioning (WISC-IV IQ, Coding, Symbol Search, and Digit Span) were investigated using Multivariate Analyses of Variance. No differences were found in cognitive functioning between patients with MDD and BD, or between those with severe Mood Disorders (MDD or BD) and those with NOS, when controlling for age, gender, and presence of psychotic features. However, patients with severe mood disorders and psychotic features showed lower IQs and greater working memory deficits than those without psychotic features or NOS. Results are discussed in terms of treatment planning for children and adolescents at risk for developing psychotic symptoms and severe mood disorders. PMID- 27497295 TI - Erratum to 'Melatonin improves methamphetamine-induced blood brain barrier impairment through NADPH oxidase-2 in primary rat brain microvascular endothelium cells' [Br. Ecol. Soc. 1646 (2016) 393-401]. PMID- 27497294 TI - Newly diagnosed panic disorder and the risk of erectile dysfunction: A population based cohort study in Taiwan. AB - Previous studies indicated that panic disorder is correlated with erectile dysfunction (ED). The primary aim of this study was to explore the incidence rate of ED among panic disorder patients in an Asian country. The secondary aim was to compare the risk of ED in panic disorder patients that were treated with different kinds of antidepressants, and to explore the possible mechanism between these two disorders. We identified 1393 male patients with newly diagnosed panic disorder from the Taiwan's National Health Insurance Database. Four matched controls per case were selected for the study group by propensity score. After adjusting for age, obesity and comorbidities, the panic disorder patients had a higher hazard ratio of ED diagnosis than the controls, especially among the untreated panic disorder patients. This retrospective dynamic cohort study supports the link between ED and prior panic disorder in a large sample of panic disorder patients. This study points out the need of early antidepressant treatment for panic disorder to prevent further ED. PMID- 27497296 TI - Oncolytic herpes simplex virus interactions with the host immune system. AB - Oncolytic viruses (OVs), like oncolytic herpes simplex virus (oHSV), are genetically engineered to selectively replicate in and kill cancer cells, while sparing normal cells. Initial OV infection, cell death, and subsequent OV propagation within the tumor microenvironment leads to a cascade of host responses (innate and adaptive), reflective of natural anti-viral immune responses. These host-virus interactions are critical to the balance between OV activities, anti-viral immune responses limiting OV, and induction of anti-tumor immunity. The host response against oHSV is complex, multifaceted, and modulated by the tumor microenvironment and immunosuppression. As a successful pathogen, HSV has multiple mechanisms to evade such host responses. In this review, we will discuss these mechanisms and HSV evasion, and how they impact oHSV therapy. PMID- 27497297 TI - The plant-specific CDKB1-CYCB1 complex mediates homologous recombination repair in Arabidopsis. AB - Upon DNA damage, cyclin-dependent kinases (CDKs) are typically inhibited to block cell division. In many organisms, however, it has been found that CDK activity is required for DNA repair, especially for homology-dependent repair (HR), resulting in the conundrum how mitotic arrest and repair can be reconciled. Here, we show that Arabidopsis thaliana solves this dilemma by a division of labor strategy. We identify the plant-specific B1-type CDKs (CDKB1s) and the class of B1-type cyclins (CYCB1s) as major regulators of HR in plants. We find that RADIATION SENSITIVE 51 (RAD51), a core mediator of HR, is a substrate of CDKB1-CYCB1 complexes. Conversely, mutants in CDKB1 and CYCB1 fail to recruit RAD51 to damaged DNA CYCB1;1 is specifically activated after DNA damage and we show that this activation is directly controlled by SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1), a transcription factor that acts similarly to p53 in animals. Thus, while the major mitotic cell-cycle activity is blocked after DNA damage, CDKB1-CYCB1 complexes are specifically activated to mediate HR. PMID- 27497298 TI - Loss of FBXO7 (PARK15) results in reduced proteasome activity and models a parkinsonism-like phenotype in mice. AB - Mutations in the FBXO7 (PARK15) gene have been implicated in a juvenile form of parkinsonism termed parkinsonian pyramidal syndrome (PPS), characterized by Parkinsonian symptoms and pyramidal tract signs. FBXO7 (F-box protein only 7) is a subunit of the SCF (SKP1/cullin-1/F-box protein) E3 ubiquitin ligase complex, but its relevance and function in neurons remain to be elucidated. Here, we report that the E3 ligase FBXO7-SCF binds to and ubiquitinates the proteasomal subunit PSMA2. In addition, we show that FBXO7 is a proteasome-associated protein involved in proteasome assembly. In FBXO7 knockout mice, we find reduced proteasome activity and early-onset motor deficits together with premature death. In addition, we demonstrate that NEX (neuronal helix-loop-helix protein-1)-Cre induced deletion of the FBXO7 gene in forebrain neurons or the loss of FBXO7 in tyrosine hydroxylase (TH)-positive neurons results in motor defects, reminiscent of the phenotype in PARK15 patients. Taken together, our study establishes a vital role for FBXO7 in neurons, which is required for proper motor control and accentuates the importance of FBXO7 in proteasome function. PMID- 27497300 TI - Transcriptome discovery in non-model wild fish species for the development of quantitative transcript abundance assays. AB - Environmental studies increasingly identify the presence of both contaminants of emerging concern (CECs) and legacy contaminants in aquatic environments; however, the biological effects of these compounds on resident fishes remain largely unknown. High throughput methodologies were employed to establish partial transcriptomes for three wild-caught, non-model fish species; smallmouth bass (Micropterus dolomieu), white sucker (Catostomus commersonii) and brown bullhead (Ameiurus nebulosus). Sequences from these transcriptome databases were utilized in the development of a custom nCounter CodeSet that allowed for direct multiplexed measurement of 50 transcript abundance endpoints in liver tissue. Sequence information was also utilized in the development of quantitative real time PCR (qPCR) primers. Cross-species hybridization allowed the smallmouth bass nCounter CodeSet to be used for quantitative transcript abundance analysis of an additional non-model species, largemouth bass (Micropterus salmoides). We validated the nCounter analysis data system with qPCR for a subset of genes and confirmed concordant results. Changes in transcript abundance biomarkers between sexes and seasons were evaluated to provide baseline data on transcript modulation for each species of interest. PMID- 27497299 TI - NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon recognition in mitochondrial translation. AB - Mitochondrial gene expression uses a non-universal genetic code in mammals. Besides reading the conventional AUG codon, mitochondrial (mt-)tRNAMet mediates incorporation of methionine on AUA and AUU codons during translation initiation and on AUA codons during elongation. We show that the RNA methyltransferase NSUN3 localises to mitochondria and interacts with mt-tRNAMet to methylate cytosine 34 (C34) at the wobble position. NSUN3 specifically recognises the anticodon stem loop (ASL) of the tRNA, explaining why a mutation that compromises ASL basepairing leads to disease. We further identify ALKBH1/ABH1 as the dioxygenase responsible for oxidising m5C34 of mt-tRNAMet to generate an f5C34 modification. In vitro codon recognition studies with mitochondrial translation factors reveal preferential utilisation of m5C34 mt-tRNAMet in initiation. Depletion of either NSUN3 or ABH1 strongly affects mitochondrial translation in human cells, implying that modifications generated by both enzymes are necessary for mt-tRNAMet function. Together, our data reveal how modifications in mt-tRNAMet are generated by the sequential action of NSUN3 and ABH1, allowing the single mitochondrial tRNAMet to recognise the different codons encoding methionine. PMID- 27497301 TI - Phosphorylation of phosphoenolpyruvate carboxykinase (PEPCK) and phosphoenolpyruvate carboxylase (PEPC) in the flesh of fruits. AB - This study determined whether phosphoenolpyruvate carboxykinase (PEPCK) and phosphoenolpyruvate carboxylase (PEPC) are phosphorylated in the flesh of a range of fruits. This was done by incubating fruit flesh with 32P[P] (where 32P[P] = 32PO43-), then PEPCK and PEPC were immunoprecipitated from extracts using specific antisera. The incorporation of 32P[P] into these enzymes was then determined by autoradiography of SDS-PAGE gels. Both enzymes were subject to phosphorylation in vivo in the flesh of grape, tomato, cherry and plum. PEPCK was also subject to phosphorylation in vivo in developing grape seeds. Proteolytic cleavage of PEPCK showed that it was phosphorylated at a site(s) located on its N terminal extension. Potentially phosphorylation of these enzymes could contribute to the coordinate regulation of their activities in the flesh of fruits and in developing seeds. PMID- 27497302 TI - Cold stress affects H+-ATPase and phospholipase D activity in Arabidopsis. AB - Low temperature is an environmental stress that greatly influences plant performance and distribution. Plants exposed to cold stress exhibit modifications of plasma membrane physical properties that can affect their functionality. Here it is reported the effect of low temperature exposure of Arabidopsis plants on the activity of phospholipase D and H+-ATPase, the master enzyme located at the plasma membrane. The H+-ATPase activity was differently affected, depending on the length of cold stress imposed. In particular, an exposure to 4 degrees C for 6 h determined the strong inhibition of the H+-ATPase activity, that correlates with a reduced association with the regulatory 14-3-3 proteins. A longer exposure first caused the full recovery of the enzymatic activity followed by a significant activation, in accordance with both the increased association with 14 3-3 proteins and induction of H+-ATPase gene transcription. Different time lengths of cold stress treatment were also shown to strongly stimulate the phospholipase D activity and affect the phosphatidic acid levels of the plasma membranes. Our results suggest a functional correlation between the activity of phospholipase D and H+-ATPase mediated by phosphatidic acid release during the cold stress response. PMID- 27497303 TI - Effects of dietary 2,2', 4,4'-tetrabromodiphenyl ether (BDE-47) exposure in growing medaka fish (Oryzias latipes). AB - In this research work, we addressed the effects of a diet fortified with BDE-47 (0, 10, 100, 1000ng/g) dosed to 4-7 day-old post-hatch medaka fish for 40 days, followed by an 80-day depuration period. BDE-47 accumulation and overall growth were evaluated throughout the dosing period, and its elimination was quantified over the following 60 days. The histological condition of the thyroid gland, liver and gonads from the 1000ng BDE-47-treated fish were assessed 5 and 70days after exposures finished. The phenotypic males to females ratio was also quantified 70days after treatments finished. Sixty days after the BDE-47 exposures, reproductive capacity (i.e. fecundity, fertility and hatchability) was evaluated in mating groups for a 20-day period. BDE-47 exposure via food from larval through juvenile life stages of medaka fish resulted in steady accumulation with time dose-dependently. This accumulation tendency rapidly decreased after dosing ended. The growth rates showed a significant increase only at the highest concentration 70days after exposures finished. The histological survey did not reveal BDE-47-related alterations in the condition of the potential target organs. However, a morphometrical approach suggested BDE-47 related differences in the thickness of the epithelium that lines thyroid follicles. The reproduction studies showed comparable values for the fecundity, fertility and hatching rates. Dietary BDE-47 dosed for 40days to growing medaka fish did not alter the phenotypic sex ratios at maturity. The dietary approach used herein could not provide conclusive evidence of effects on medaka development and thriving despite the fact that BDE-47 underwent rapid accumulation in whole fish during the 40-day treatment. PMID- 27497305 TI - Analytical characteristics and application of novel chitosan coated magnetic nanoparticles as an efficient drug delivery system for ciprofloxacin. Enhanced drug release kinetics by low-frequency ultrasounds. AB - A pH-responsive drug carrier based on chitosan coated iron oxide nanoparticles (CS-Fe3O4) for prolonged antibiotic release in a controlled manner is reported. As an antibiotic drug model, ciprofloxacin was loaded onto the nanocarrier via H bonding interactions. The nanoparticles were characterized using scanning electron microscopy, X-ray diffraction, energy-dispersive X-ray spectroscopy, photon correlation spectroscopy and Fourier transform infrared spectroscopy. The particle size of CS-Fe3O4 nanoparticles were found to lie in the range of 30 80nm. The analytical characteristics of the designed system were thoroughly investigated. The in vitro drug loading at pH 4.8 and release kinetics at pH 7.4 studies revealed that the drug delivery system can take 99% of ciprofloxacin load and quantitatively release the drug over a sustained period of 5 days. The release kinetics study indicated that the system follows a zero order kinetics via a diffusion-controlled mechanism. These results indicated that CS-Fe3O4 nanoparticles have the potential for use as controlled antibiotic delivery systems through oral administration by avoiding the drug release in the highly acidic gastric fluid region of the stomach. Furthermore, the ability of low frequency ultrasound in fast release of the encapsulated drug in less than 60min from the CS-Fe3O4 nanoparticles in a controlled manner was confirmed. PMID- 27497304 TI - Gene expression in Catla catla (Hamilton) subjected to acute and protracted doses of gamma radiation. AB - Studies on transcriptional modulation after gamma radiation exposure in fish are limited. Cell cycle perturbations and expression of apoptotic genes were investigated in the fish, Catla catla after acute and protracted exposures to gamma radiation over a 90day period. Significant changes in gene expression were observed between day 1 and 90 post-exposure. Gamma radiation induced a significant down-regulation of target genes gadd45alpha, cdk1 and bcl-2 from day 1 to day 3 after protracted exposure, whereas it persists till day 6 upon acute exposure. From day 12 onwards, Gadd45alpha, cdk1 and bcl-2 genes were up regulated following protracted exposure, indicating DNA repair, cell-cycle arrest and apoptosis. There exists a linear correlation between these genes (gadd45alpha - r=0.85, p=0.0073; cdk1 - r=0.86, p=0.0053; bcl-2 - r=0.89, p=0.0026) at protracted exposures. This is the first report on the dual role of bcl-2 gene in fish exposed to acute and protracted radiation and correlation among the aforementioned genes that work in concert to promote 'repair' and 'death' circuitries in fish blood cells. PMID- 27497306 TI - A study of the influence on diabetes of free and conjugated bisphenol A concentrations in urine: Development of a simple microextraction procedure using gas chromatography-mass spectrometry. AB - The association between bisphenol A (BPA) exposure and adult health status is examined by measuring the urinary BPA concentration using a miniaturized technique based on dispersive liquid-liquid microextraction (DLLME) in combination with gas chromatography-mass spectrometry (GC-MS). Both the free bioactive and the glucuronide conjugated forms of BPA were measured, the glucuronide form usually being predominant. The main analogs of BPA, including bisphenol Z (BPZ), bisphenol F (BPF) and biphenol (BP) were also determined. Several parameters affecting enzymatic hydrolysis, derivatization by in-situ acetylation and the DLLME stages were carefully optimized by means of multivariate designs. DLLME parameters were 2mL urine, 1mL acetone and 100MUL chloroform, and hydrolysis was performed using beta-glucuronidase and sulfatase at pH 5. No matrix effect was observed and quantification was carried out by aqueous calibration with a surrogate standard. Detection limits were in the range 0.01-0.04ngmL(-1). The intraday and interday precisions were lower than 11% in terms of relative standard deviation. Satisfactory values for all compounds were obtained in recovery studies (92-117%) at two concentration levels. Other bisphenols (BPF, BPZ and BP) were not detected in the urine samples, while BPA was the only bisphenol detected in the free form (creatinine adjusted) at concentration levels ranging from the detection limit to 15.9ngg(-1), and total BPA was detected at concentrations ranging from 0.46 to 24.5ngg(-1) levels. A comparison of the BPA content for both groups of patients revealed that slightly higher mean values were obtained for both free BPA and total BPA for diabetic patients, than for non-diabetic patients. However, a statistical comparison of the contents of BPA revealed that there were no significant differences. The procedure was validated using a certified reference material. PMID- 27497307 TI - Isolation and chatacterization of homoisoflavonoids from Dracaena cochinchinensis and their osteogenic activities in mouse mesenchymal stem cells. AB - Two new homoisoflavonoids, dracaeconolide A (1) and dracaeconolide B (2), together with ten known compounds, namely (3R)-7,4'-dihydroxy-8 methoxyhomoisoflavane (3), (3R)-7-hydroxy-3-(4-hydroxybenzyl)chromane (4), (3R) 7,4'-dihydroxy-5-methoxy-homoisoflavane (5), (3R)-6,4'-dihydroxy-8 methoxyhomoisoflavan (6), 7,4'-dihydroxy-8-methylflavan (7), (2R)-7,4'-dihydroxy 5-methoxy-8-methylflavan (8), 5,4'-dihydroxy-7-methoxy-6-methylflavane (9), 7,4' dihydroxy-3'-methoxyflavan (10), 7,4'-dihydroxyflavan (11), 4,4'-dihydroxy-2,6 dimethoxydihydrochlcone (12), were isolated from the red resin of Dracaena cochinchinensis (dragon's blood, DB). All the compounds were then evaluated for their effects on mouse bone marrow-derived mesenchymal stem cells (MSCs) proliferation using CCK8 assay and their abilities in promoting MSCs differentiating into osteoblast through the assay of alkaline phosphatase (ALP) activity in vitro. Compounds 2, 3, 4, 7, 9, and 11, at a concentration of 10MUM with no cytotoxicity, significantly promoted MSC osteogenic differentiation by increasing the levels of ALP activity to percents of 159.6+/-5.9, 167.6+/-10.9, 162.0+/-1.4, 151.3+/-4.0, 171.0+/-8.2, and 169.9+/-7.3 in relative to the control, respectively. The results of ALP staining were in accordance to that of ALP activity. PMID- 27497308 TI - End-of-life management of corrosive drywall. AB - Recently, gypsum drywall products imported to the United States (US) were found to cause metal corrosion and tarnishing in some homes, often necessitating that this drywall be discarded. Research assessed the potential implications of recycling and landfilling corrosive/imported drywall. Samples of corrosive drywall were collected from homes in Florida, US and these characteristics were assessed relative to domestically-produced drywall purchased from retail outlets. The total and synthetic precipitation leaching procedure (SPLP) leachable heavy metal concentrations were measured and compared to risk-based regulatory thresholds to assess the possible land application risk. In a majority of samples, concentrations were below levels of regulatory concern. The mean concentration of several elements exceeded the thresholds in a few samples for the direct exposure assessment (As) and the groundwater leaching assessment (Al, B, Hg, Mn, Sr and V); but the results did not suggest that corrosive drywall would present a greater risk than domestic drywall. To assess landfilling concerns, the potential for sulfur gases emissions upon disposal was evaluated. Experiments indicated that corrosive drywall would not pose a greater risk of long-term H2S emissions compared to domestic drywall. PMID- 27497309 TI - Synthesis of a water-soluble thiourea-formaldehyde (WTF) resin and its application to immobilize the heavy metal in MSWI fly ash. AB - Because of the high concentrations of heavy metals, municipal solid waste incineration (MSWI) fly ash is classified as a hazardous waste, which need to be treated to avoid damaging the environment. A novel water-soluble thiourea formaldehyde (WTF) resin was synthesized by two step reactions (hydroxymethylation reaction and condensation reaction) in the laboratory. Synthetic conditions, removal of free formaldehyde in the resin and the ability of immobilization heavy metals in the MSWI fly ash were studied. The possible molecular structure of the resin was also discussed by elemental analysis and FTIR spectra. Experimental results showed that the synthesis conditions of WTF resin were the formaldehyde/thiourea (T/F) mole ratio of 2.5:1, hydroxymethylation at pH 7.0-8.0 and 60 degrees C for 30min, and condensation of at pH 4.5-5.0 and 80 degrees C. In addition, the end point of condensation reaction was measured by turbidity point method. The result of elemental analysis and FTIR spectra indicated that thiourea functional group in the WTF resin chelated the heavy metal ions. Melamine can efficiently reduce the free formaldehyde content in the resin from 8.5% to 2%. The leaching test showed that the immobilization rates of Cr, Pb and Cd were 96.5%, 92.0% and 85.8%, respectively. Leaching concentrations of Cr, Pb and Cd in the treated fly ash were decreased to 0.08 mg/L, 2.44 mg/L and 0.23 mg/L, respectively. The MSWI fly ash treated by WTF resin has no harm to the environment. PMID- 27497310 TI - Pseudomonas-related populations associated with reverse osmosis in drinking water treatment. AB - Reverse osmosis membrane filtration technology (RO) is used to treat drinking water. After RO treatment, bacterial growth is still observed in water. However, it is not clear whether those microorganisms belong to species that can pose a health risk, such as Pseudomonas spp. The goal of this study is to characterize the bacterial isolates from a medium that is selective for Pseudomonas and Aeromonas which were present in the water fraction before and after the RO. To this end, isolates were recovered over two years and were identified by matrix assisted laser desorption/ionization-time of flight mass spectrometry. They were then biochemically phenotyped and the population similarity indexes were calculated. The isolates were analysed for their capacity to form biofilms in vitro and antimicrobial susceptibility. There were significant differences between the microbial populations in water before and after RO. Furthermore, the structures of the populations analysed at the same sampling point were similar in different sampling campaigns. Some of the isolates had the capacity to form a biofilm and showed resistance to different antibiotics. A successful level filtration via RO and subsequent recolonization of the membrane with different species from those in the feed water was found. Pseudomonas aeruginosa was not recovered from among the isolates. This study increases the knowledge on the microorganisms present in water after RO treatment, with focus in one of the genus causing problems in RO systems associated with human health risk, Pseudomonas. PMID- 27497311 TI - Selective coal mine overburden treatment with topsoil and compost to optimise pasture or native vegetation establishment. AB - Overburden at a coal mine in the Hunter Valley, New South Wales, was stored in a flat-topped artificial mound with 14-degree side slopes. Topsoil was scarce, dispersive and readily eroded. A split-plot factorial experiment applied an enhanced municipal solid waste compost at 0, 60 or 100 t ha(-1) to untreated overburden or to overburden covered with 0.1 m of topsoil. Two seeding treatments, of trees and shrubs or of pasture species, were applied to two 0.5-ha replicates of each surface treatment. Substrate physical and chemical properties and vegetation attributes were assessed 2.5 years later. Compost application to both topsoil and overburden significantly increased total N, P, Cu and Zn, soluble K, Ca and Mg, and significantly reduced soluble Na and pH. Mean tree density, size and total canopy cover were significantly greater with compost applied at 60 t ha(-1) to overburden than with all other treatments, especially those on topsoil where tree growth was inhibited by undesired species. Compost application to overburden and topsoil at 100 t ha(-1) significantly increased biomass of desired pasture species and significantly reduced undesired species cover compared with unamended topsoil and the extent of bare ground compared with unamended overburden. Successful development of woody species on overburden and pastures on both overburden and topsoil treated with compost provides opportunities for new combinations of landscape design, surface preparation and plant species introductions to increase the stability of final landforms, the effectiveness of resource use, and the delivery of commercial and biodiversity benefits from mine site rehabilitation. PMID- 27497313 TI - Corrigendum to "Clinical and biochemical indicators of homeostasis model assessment estimated insulin resistance in postmenopausal women" [J Chin Med Assoc 74 (2011) 442-447]. PMID- 27497312 TI - A critical review on textile wastewater treatments: Possible approaches. AB - Waste water is a major environmental impediment for the growth of the textile industry besides the other minor issues like solid waste and resource waste management. Textile industry uses many kinds of synthetic dyes and discharge large amounts of highly colored wastewater as the uptake of these dyes by fabrics is very poor. This highly colored textile wastewater severely affects photosynthetic function in plant. It also has an impact on aquatic life due to low light penetration and oxygen consumption. It may also be lethal to certain forms of marine life due to the occurrence of component metals and chlorine present in the synthetic dyes. So, this textile wastewater must be treated before their discharge. In this article, different treatment methods to treat the textile wastewater have been presented along with cost per unit volume of treated water. Treatment methods discussed in this paper involve oxidation methods (cavitation, photocatalytic oxidation, ozone, H2O2, fentons process), physical methods (adsorption and filtration), biological methods (fungi, algae, bacteria, microbial fuel cell). This review article will also recommend the possible remedial measures to treat different types of effluent generated from each textile operation. PMID- 27497315 TI - Did Viruses Evolve As a Distinct Supergroup from Common Ancestors of Cells? AB - The evolutionary origins of viruses according to marker gene phylogenies, as well as their relationships to the ancestors of host cells remains unclear. In a recent article Nasir and Caetano-Anolles reported that their genome-scale phylogenetic analyses based on genomic composition of protein structural-domains identify an ancient origin of the "viral supergroup" (Nasir et al. 2015. A phylogenomic data-driven exploration of viral origins and evolution. Sci Adv. 1(8):e1500527.). It suggests that viruses and host cells evolved independently from a universal common ancestor. Examination of their data and phylogenetic methods indicates that systematic errors likely affected the results. Reanalysis of the data with additional tests shows that small-genome attraction artifacts distort their phylogenomic analyses, particularly the location of the root of the phylogenetic tree of life that is central to their conclusions. These new results indicate that their suggestion of a distinct ancestry of the viral supergroup is not well supported by the evidence. PMID- 27497314 TI - Variation in the oxytocin receptor gene (OXTR) is associated with differences in moral judgment. AB - Moral judgments are produced through the coordinated interaction of multiple neural systems, each of which relies on a characteristic set of neurotransmitters. Genes that produce or regulate these neurotransmitters may have distinctive influences on moral judgment. Two studies examined potential genetic influences on moral judgment using dilemmas that reliably elicit competing automatic and controlled responses, generated by dissociable neural systems. Study 1 (N = 228) examined 49 common variants (SNPs) within 10 candidate genes and identified a nominal association between a polymorphism (rs237889) of the oxytocin receptor gene (OXTR) and variation in deontological vs utilitarian moral judgment (that is, judgments favoring individual rights vs the greater good). An association was likewise observed for rs1042615 of the arginine vasopressin receptor gene (AVPR1A). Study 2 (N = 322) aimed to replicate these findings using the aforementioned dilemmas as well as a new set of structurally similar medical dilemmas. Study 2 failed to replicate the association with AVPR1A, but replicated the OXTR finding using both the original and new dilemmas. Together, these findings suggest that moral judgment is influenced by variation in the oxytocin receptor gene and, more generally, that single genetic polymorphisms can have a detectable effect on complex decision processes. PMID- 27497316 TI - The Molecular Chaperone DnaK Is a Source of Mutational Robustness. AB - Molecular chaperones, also known as heat-shock proteins, refold misfolded proteins and help other proteins reach their native conformation. Thanks to these abilities, some chaperones, such as the Hsp90 protein or the chaperonin GroEL, can buffer the deleterious phenotypic effects of mutations that alter protein structure and function. Hsp70 chaperones use a chaperoning mechanism different from that of Hsp90 and GroEL, and it is not known whether they can also buffer mutations. Here, we show that they can. To this end, we performed a mutation accumulation experiment in Escherichia coli, followed by whole-genome resequencing. Overexpression of the Hsp70 chaperone DnaK helps cells cope with mutational load and completely avoid the extinctions we observe in lineages evolving without chaperone overproduction. Additionally, our sequence data show that DnaK overexpression increases mutational robustness, the tolerance of its clients to nonsynonymous nucleotide substitutions. We also show that this elevated mutational buffering translates into differences in evolutionary rates on intermediate and long evolutionary time scales. Specifically, we studied the evolutionary rates of DnaK clients using the genomes of E. coli, Salmonella enterica, and 83 other gamma-proteobacteria. We find that clients that interact strongly with DnaK evolve faster than weakly interacting clients. Our results imply that all three major chaperone classes can buffer mutations and affect protein evolution. They illustrate how an individual protein like a chaperone can have a disproportionate effect on the evolution of a proteome. PMID- 27497317 TI - Centromeres of the Yeast Komagataella phaffii (Pichia pastoris) Have a Simple Inverted-Repeat Structure. AB - Centromere organization has evolved dramatically in one clade of fungi, the Saccharomycotina. These yeasts have lost the ability to make normal eukaryotic heterochromatin with histone H3K9 methylation, which is a major component of pericentromeric regions in other eukaryotes. Following this loss, several different types of centromere emerged, including two types of sequence-defined ("point") centromeres, and the epigenetically defined "small regional" centromeres of Candida albicans Here we report that centromeres of the methylotrophic yeast Komagataella phaffii (formerly called Pichia pastoris) are structurally defined. Each of its four centromeres consists of a 2-kb inverted repeat (IR) flanking a 1-kb central core (mid) region. The four centromeres are unrelated in sequence. CenH3 (Cse4) binds strongly to the cores, with a decreasing gradient along the IRs. This mode of organization resembles Schizosaccharomyces pombe centromeres but is much more compact and lacks the extensive flanking heterochromatic otr repeats. Different isolates of K. phaffii show polymorphism for the orientation of the mid regions, due to recombination in the IRs. CEN4 is located within a 138-kb region that changes orientation during mating-type switching, but switching does not induce recombination of centromeric IRs. Our results demonstrate that evolutionary transitions in centromere organization have occurred in multiple yeast clades. PMID- 27497318 TI - Evolved Populations of Shigella flexneri Phage Sf6 Acquire Large Deletions, Altered Genomic Architecture, and Faster Life Cycles. AB - Genomic architecture is the framework within which genes and regulatory elements evolve and where specific constructs may constrain or potentiate particular adaptations. One such construct is evident in phages that use a headful packaging strategy that results in progeny phage heads packaged with DNA until full rather than encapsidating a simple unit-length genome. Here, we investigate the evolution of the headful packaging phage Sf6 in response to barriers that impede efficient phage adsorption to the host cell. Ten replicate populations evolved faster Sf6 life cycles by parallel mutations found in a phage lysis gene and/or by large, 1.2- to 4.0-kb deletions that remove a mobile genetic IS911 element present in the ancestral phage genome. The fastest life cycles were found in phages that acquired both mutations. No mutations were found in genes encoding phage structural proteins, which were a priori expected from the experimental design that imposed a challenge for phage adsorption by using a Shigella flexneri host lacking receptors preferred by Sf6. We used DNA sequencing, molecular approaches, and physiological experiments on 82 clonal isolates taken from all 10 populations to reveal the genetic basis of the faster Sf6 life cycle. The majority of our isolates acquired deletions in the phage genome. Our results suggest that deletions are adaptive and can influence the duration of the phage life cycle while acting in conjunction with other lysis time-determining point mutations. PMID- 27497319 TI - Trends in Medicalization of Children with Amplified Musculoskeletal Pain Syndrome. AB - Objective: The objective of this survey was to describe trends over time in medicalization of children with Amplified Musculoskeletal Pain Syndrome (AMPS). Design: A retrospective evaluation was conducted using self-reported data from patients presenting to the pain clinic between January 1, 2008 and December 31, 2014, who were diagnosed with AMPS. Setting and Subjects: This was a medical record review of 899 subjects ages 3-20 presenting with Amplified Musculoskeletal Pain Syndrome. Subjects were included if they presented to a single tertiary specialized clinic and obtained a diagnosis of AMPS between January 1, 2008 and December 31, 2014. Methods: Information collected from subjects' medical records included: past medications, current outpatient medications, procedures, aids, therapies, studies, professionals seen, hospitalizations, and surgeries. Trends in medicalization were analyzed by year of initial visit. Results: Medication use, procedures, studies, therapies, professionals seen, hospitalizations, and surgeries in children with AMPS all increased significantly by year ( P < 0.001). The degree of physical dysfunction, pain, and the use of aids did not significantly increase. Conclusions: Children with amplified musculoskeletal pain syndrome are becoming increasingly medicalized. Increased medicalization introduces risk of iatrogenic injury and burdens families with unnecessary medical costs. The significant increase in medicalization of children with AMPS is not related to an increase in patient reported pain, which is evidenced by the lack of significant increase in patients' pain score, pain duration, or functional disability at the time of their initial evaluation. PMID- 27497321 TI - Characterization of Macrophage/Microglial Activation and Effect of Photobiomodulation in the Spared Nerve Injury Model of Neuropathic Pain. AB - Objective: Neuropathic pain is common and debilitating with limited effective treatments. Macrophage/microglial activation along ascending somatosensory pathways following peripheral nerve injury facilitates neuropathic pain. However, polarization of macrophages/microglia in neuropathic pain is not well understood. Photobiomodulation treatment has been used to decrease neuropathic pain, has anti inflammatory effects in spinal injury and wound healing models, and modulates microglial polarization in vitro. Our aim was to characterize macrophage/microglia response after peripheral nerve injury and modulate the response with photobiomodulation. Methods: Adult male Sprague-Dawley rats were randomly assigned to sham (N = 13), spared nerve injury (N = 13), or injury + photobiomodulation treatment groups (N = 7). Mechanical hypersensitivity was assessed with electronic von Frey. Photobiomodulation (980 nm) was applied to affected hind paw (output power 1 W, 20 s, 41cm above skin, power density 43.25 mW/cm 2 , dose 20 J), dorsal root ganglia (output power 4.5W, 19s, in skin contact, power density 43.25 mW/cm 2 , dose 85.5 J), and spinal cord regions (output power 1.5 W, 19s, in skin contact, power density 43.25 mW/cm 2 , dose 28.5 J) every other day from day 7-30 post-operatively. Immunohistochemistry characterized macrophage/microglial activation. Results: Injured groups demonstrated mechanical hypersensitivity 1-30 days post-operatively. Photobiomodulation-treated animals began to recover after two treatments; at day 26, mechanical sensitivity reached baseline. Peripheral nerve injury caused region-specific macrophages/microglia activation along spinothalamic and dorsal column medial lemniscus pathways. A pro-inflammatory microglial marker was expressed in the spinal cord of injured rats compared to photobiomodulation treated and sham group. Photobiomodulation-treated dorsal root ganglion macrophages expressed anti-inflammatory markers. Conclusion: Photobiomodulation effectively reduced mechanical hypersensitivity, potentially through modulating macrophage/microglial activation to an anti-inflammatory phenotype. PMID- 27497322 TI - Pain Increases the Risk of Developing Frailty in Older Adults with Osteoarthritis. AB - Objective: While osteoarthritis (OA)-related pain increases the risk of physical inactivity, disability, and falls, less is known about whether pain increases the risk of frailty. We investigated if people with OA reporting pain are more likely to develop frailty than people with OA without pain. Design: Population-based prospective cohort study with a follow-up of 4.4 years. Setting: Community. Subjects: The subjects were 1,775 older men and women with osteoarthritis, enrolled in the Progetto Veneto Anziani. Methods: Pain was ascertained according to medical records, symptoms/signs, and use of analgesics. Participants were considered frail if they met three out of five criteria of Fried's Index. Results: Cross-sectional analysis at baseline demonstrated that after adjusting for potential confounders (age, gender, anthropometric and demographic data, comorbidities), people with OA and pain (n = 568) were significantly more likely to have frailty compared with those with OA without pain (n = 1,207; hand OA, OR = 1.86, 95% CI = 1.65-2.09; hip OA, OR = 1.62, 95% CI = 1.44-1.83; knee OA, OR = 1.42, 95% CI = 1.26-1.60; all p < 0.0001). Prospective analysis of 1,152 nonfrail subjects at baseline demonstrated that 19.9% developed incident frailty. A fully-adjusted logistic regression analysis demonstrated that lower limb OA related pain was associated with an increased risk of developing frailty compared with people with OA and no pain. Conclusions: Pain related to OA might be an important factor influencing the relationship between OA and the development of frailty. PMID- 27497320 TI - HIV Distal Neuropathic Pain Is Associated with Smaller Ventral Posterior Cingulate Cortex. AB - Objective: . Despite modern antiretroviral therapy, HIV-associated neuropathy is one of the most prevalent, disabling and treatment-resistant complications of HIV disease. The presence and intensity of distal neuropathic pain is not fully explained by the degree of peripheral nerve damage. A better understanding of brain structure in HIV distal neuropathic pain may help explain why some patients with HIV neuropathy report pain while the majority does not. Previously, we reported that more intense distal neuropathic pain was associated with smaller total cerebral cortical gray matter volumes. The objective of this study was to determine which parts of the cortex are smaller. Methods: . HIV positive individuals with and without distal neuropathic pain enrolled in the multisite (N = 233) CNS HIV Antiretroviral Treatment Effects (CHARTER) study underwent structural brain magnetic resonance imaging. Voxel-based morphometry was used to investigate regional brain volumes in these structural brain images. Results: . Left ventral posterior cingulate cortex was smaller for HIV positive individuals with versus without distal neuropathic pain (peak P = 0.017; peak t = 5.15; MNI coordinates x = -6, y = -54, z = 20). Regional brain volumes within cortical gray matter structures typically associated with pain processing were also smaller for HIV positive individuals having higher intensity ratings of distal neuropathic pain. Conclusions: . The posterior cingulate is thought to be involved in inhibiting the perception of painful stimuli. Mechanistically a smaller posterior cingulate cortex structure may be related to reduced anti-nociception contributing to increased distal neuropathic pain. PMID- 27497324 TI - High-Molecular-Weight Paired Helical Filaments from Alzheimer Brain Induces Seeding of Wild-Type Mouse Tau into an Argyrophilic 4R Tau Pathology in Vivo. AB - In Alzheimer disease, the development of tau pathology follows neuroanatomically connected pathways, suggesting that abnormal tau species might recruit normal tau by passage from cell to cell. Herein, we analyzed the effect of stereotaxic brain injection of human Alzheimer high-molecular-weight paired helical filaments (PHFs) in the dentate gyrus of wild-type and mutant tau THY-Tau22 mice. After 3 months of incubation, wild-type and THY-Tau22 mice developed an atrophy of the dentate gyrus and a tau pathology characterized by Gallyas and tau-positive grain like inclusions into granule cells that extended in the hippocampal hilus and eventually away into the alveus, and the fimbria. Gallyas-positive neuropil threads and oligodendroglial coiled bodies were also observed. These tau inclusions were composed only of mouse tau, and were immunoreactive with antibodies to 4R tau, phosphotau, misfolded tau, ubiquitin, and p62. Although local hyperphosphorylation of tau was increased in the dentate gyrus in THY-Tau22 mice, the development of neurofibrillary tangles made of mutant human tau was not accelerated in the hippocampus, indicating that wild-type human PHFs were inefficient in seeding tau aggregates made of G272V/P301S mutant human tau. Our results indicate thus that injection of human wild-type Alzheimer PHF seeded aggregation of wild-type murine tau into an argyrophilic 4R tau pathology, and constitutes an interesting model independent of expression of a mutant tau protein. PMID- 27497325 TI - Genotyping of the c.1423C>T (p.P475S) polymorphism in the ADAMTS13 gene by APLP and HRM assays: Northeastern Asian origin of the mutant. AB - ADAMTS13 is a von Willebrand factor-cleaving protease. The mutant types of p.P475S (c.1423C>T) polymorphism in ADAMTS13 have a reduced activity in comparison with the wild type. In the present study, we investigated the frequency of the C-to-T substitution in 2584 genomic DNA samples from 25 Asian, European, and African populations using APLP (amplified product length polymorphism) and/or HRM (high-resolution melting) assays. Allele T (ADAMTS13(*)T) was detected only in Asian populations and its frequency was observed to decrease gradually from north to south in 24 East Asian populations. Almost all ADAMTS13(*)T were associated with ABO(*)O. These results suggested that ADAMTS13(*)T had occurred on a chromosome with ABO(*)O in a northern part of East Asia. This SNP is useful as an ancestry-informative marker, and the present genotyping techniques are applicable to the investigation of an association between this SNP and aortic dissection (Kobayashi et al., 2012). PMID- 27497323 TI - IL-6 Contributes to Corneal Nerve Degeneration after Herpes Simplex Virus Type I Infection. AB - Herpes simplex virus type 1 (HSV-1) is a leading cause of neurotrophic keratitis characterized by decreased corneal sensation because of damage to the corneal sensory fibers. We and others have reported regression of corneal nerves during acute HSV-1 infection. To determine whether denervation is caused directly by the virus or indirectly by the elicited immune response, mice were infected with HSV 1 and topically treated with dexamethasone (DEX) or control eye drops. Corneal sensitivity was measured using a Cochet-Bonnet esthesiometer and nerve network structure via immunohistochemistry. Corneas were assessed for viral content by plaque assay, leukocyte influx by flow cytometry, and content of chemokines and inflammatory cytokines by suspension array. DEX significantly preserved corneal nerve structure and sensitivity on infection. DEX reduced myeloid and T-cell populations in the cornea and did not affect viral contents at 4 and 8 days post infection. The elevated protein contents of chemokines and inflammatory cytokines on infection were greatly suppressed by DEX. Subconjunctival delivery of neutralizing antibody against IL-6 to infected mice resulted in partial preservation of corneal nerve structure and sensitivity. Our study supports a role for the immune response, but not local virus replication in the development of HSV-1-induced neurotrophic keratitis. IL-6 is one of the factors produced by the elicited inflammatory response to HSV-1 infection contributing to nerve regression. PMID- 27497326 TI - Forensic age prediction for dead or living samples by use of methylation sensitive high resolution melting. AB - Age prediction with epigenetic information is now edging closer to practical use in forensic community. Many age-related CpG (AR-CpG) sites have proven useful in predicting age in pyrosequencing or DNA chip analyses. In this study, a wide range methylation status in the ELOVL2 and FHL2 promoter regions were detected with methylation-sensitive high resolution melting (MS-HRM) in a labor-, time-, and cost-effective manner. Non-linear-distributions of methylation status and chronological age were newly fitted to the logistic curve. Notably, these distributions were revealed to be similar in 22 living blood samples and 52 dead blood samples. Therefore, the difference of methylation status between living and dead samples suggested to be ignorable by MS-HRM. Additionally, the information from ELOVL2 and FHL2 were integrated into a logistic curve fitting model to develop a final predictive model through the multivariate linear regression of logit-linked methylation rates and chronological age with adjusted R(2)=0.83. Mean absolute deviation (MAD) was 7.44 for 74 training set and 7.71 for 30 additional independent test set, indicating that the final predicting model is accurate. This suggests that our MS-HRM-based method has great potential in predicting actual forensic age. PMID- 27497327 TI - An autopsy case of zinc chloride poisoning. AB - Ingestion of large amounts of zinc chloride causes corrosive gastroenteritis with vomiting, abdominal pain, and diarrhea. Some individuals experience shock after ingesting large amounts of zinc chloride, resulting in fatality. Here, we present the results of an administrative autopsy performed on a 70-year-old man who ingested zinc chloride solution and died. After drinking the solution, he developed vomiting, abdominal pain, and diarrhea, and called for an ambulance. Except for tachycardia, his vital signs were stable at presentation. However, he developed hypotension and severe metabolic acidosis and died. The patient's blood zinc concentration on arrival was high at 3030MUg/dL. Liver cirrhosis with cloudy yellow ascites was observed, however, there were no clear findings of gastrointestinal perforation. The gastric mucosa was gray-brown, with sclerosis present in all gastric wall layers. Zinc staining was strongly positive in all layers. There was almost no postmortem degeneration of the gastric mucosal epithelium, and hypercontracture of the smooth muscle layer was observed. Measurement of the zinc concentration in the organs revealed the highest concentration in the gastric mucosa, followed by the pancreas and spleen. Clinically, corrosive gastroenteritis was the cause of death. However, although autopsy revealed solidification in the esophagus and gastric mucosa, there were no findings in the small or large intestine. Therefore, metabolic acidosis resulting from organ damage was the direct cause of death. PMID- 27497328 TI - TPH1 A218 allele is associated with suicidal behavior in Turkish population. AB - BACKGROUND: Serotonergic dysfunction is implicated in depression, psychiatric disorders and suicidal behaviors. The first and rate-limiting step in the synthesis of serotonin is catalyzed by tryptophan hydroxylase (TPH) which is encoded by TPH1 and THP2 genes. Genetic association studies have revealed contradictory results about the effect of the TPH1 A218C (rs1800532) polymorphism on suicidal behavior in different populations. MATERIAL AND METHOD: In this study, we investigated A218C polymorphism in 109 suicide attempters and 98 healthy controls. Socio-demographic characteristics of participants were obtained through questionnaire. DNA was extracted from peripheral blood and genotyping was performed by Real Time PCR. Fisher's exact test was used to evaluate the significance of the difference among the independent variables. Hardy-Weinberg equilibrium was tested using Pearson's goodness-of-fit chi-squared test. RESULTS: The frequency of A allele was significantly higher in suicide attempters than controls (46.33% vs. 35.71%, p=0.0357). However, there were no differences in genotype frequencies of this locus between participants having attempted suicide and controls (p>0.05). Among males, frequencies of CC genotype and C allele were found to be significantly higher in controls (p=0.0125, p=0.0298). With regard to the female subjects and female controls, no significant association was detected between suicidal behavior and genotype/allele frequencies (p>0.05). CONCLUSION: Our results provide evidence that A allele of TPH1 A218C polymorphism may be associated with suicidal behavior in Turkish population. PMID- 27497329 TI - Acute restraint stress provokes sudden cardiac death in normotensive rats and enhances susceptibility to arrhythmogenic effects of adrenaline in spontaneously hypertensive rats. AB - BACKGROUND: A high incidence of cardiovascular events and sudden cardiac death (SCD) has been reported following unexpected acute psychosocial stress. The possible pathways by which acute restraint stress (ARS), a kind of acute psychosocial stress, leads to SCD were determined. METHODS: Using 16-week-old male normotensive Wistar Kyoto rats (WKY, n=24) as controls and spontaneously hypertensive rats (SHR, n=24) as the hypertensive subjects with left ventricular hypertrophy (LVH), we assessed ARS-related incidence of SCD, cardiac and myocardial autonomic nervous system dysfunction, gap junction connexin-43 (Cx43) channel remodeling, and ventricular repolarization abnormality, based on electrocardiography, an adrenaline test, heart rate variability (HRV), and reverse transcriptase polymerase chain reaction analyses. Rats with ARS were introduced into restrainers that allowed head, limb, and tail movement. RESULTS: In normotensive hearts without LVH, ARS induced a higher incidence of SCD attributed to lethal bradycardia, increased cardiac and myocardial sympathetic activation, and gap junction Cx43 channel remodeling, as evidenced by the increases in the ratio of low-frequency and high-frequency powers in HRV, the ratio of myocardial neuropeptide Y (NPY) and acetylcholinesterase (AChE) mRNA expressions, and the up-regulation of LV Cx43 mRNA expression; in hypertensive hearts with LVH, ARS enhanced susceptibility to the malignant arrhythmogenic effects of the adrenaline test (a kind of sympathetic stimuli) accompanied by abnormal ventricular repolarization, as evidenced by increased incidence of ventricular tachycardia and/or ventricular fibrillation during the adrenaline test and prolonged QTc immediately after ARS. CONCLUSIONS: ARS may trigger cardiac and myocardial sympathetic predominance, and then induce gap junction Cx43 channel remodeling, finally leading to lethal bradycardia in normotensive WKY. ARS-induced abnormal ventricular repolarization may be responsible for ARS enhanced susceptibility to sympathetic stimulation in SHR with LVH. Expressions of myocardial NPY, AChE, and Cx43 genes, HRV, QTc and LVH measures showed diagnostic and prognostic potential for predicting ARS-induced SCD. PMID- 27497330 TI - Y-STR markers from Ladakh in the Himalayas. AB - A total of 223 samples from the general population of Ladakh in Northwestern India were amplified at 17 Y-STR loci using the AmpFlSTR(r) YfilerTM system. The DNA profiles generated were employed to generate allelic frequencies, gene diversity, haplotype diversity and discrimination capacity values as well as number of different haplotypes, fraction of unique haplotypes and Rst pair wise genetic distances. Multidimensional Scaling (MDS) and Correspondence Analysis (CA) were performed with the Rst values and allelic frequencies, respectively. The 17-loci discrimination capacity of Ladakh was found to be 0.8093. Eleven out of the 16 loci have diversity values greater than 0.6, and 13 loci possess values greater than 0.5. Ladakh exhibits no significant genetic difference to seven of the 15 reference forensic databases after Bonferroni correction, three of which are located in South Central Asian and four are from the Himalayan region. Rst genetic distance values before and after Bonferroni corrections illustrate the capacity of the Yfiler system to discriminate among Himalayan populations. The intermediate position of the Ladakh population in the MDS and CA plots likely reflects genetic flow and admixture with neighboring populations. In addition, the longitudinal partition of populations in the MDS and CA plots likely reflect human dispersals such as the silk road migrations. PMID- 27497331 TI - Sudden death due to rupture of the right internal carotid artery in neurofibromatosis type 1: A case report. AB - Vascular involvement is a well-recognized manifestation of neurofibromatosis type 1 (NF1) which has the potential to be fatal when disrupted. We here present a case of sudden death due to the fatal arterial rupture resulted from infiltration of the neurofibromas. A 42-year-old man who suffered from NF1 presented a 1-h history of sudden onset of pain in his right cervical region. His condition worsened and became unconscious on his way to the emergency room. Despite resuscitation efforts, he died 30min later without regaining consciousness. Autopsy examination showed that a neurofibroma located around the right internal carotid artery, confirmed immunohistochemically with S-100, vimentin and CD34. Furthermore, proliferation of spindle cells positive for S-100 was seen in the wall of right internal carotid artery, which was disrupted and resulted in a hemorrhage. These findings suggest that the artery was disrupted by neurofibromas in the vascular wall, which led to fragility of the vessel. On the basis of these findings, we concluded that the cause of death was asphyxia resulting from airway obstruction compressed by the hematoma due to the arterial rupture. As the locality of the neurofibroma and hemorrhage were closed to the carotid baroreflex, we considered another possible mechanism of his sudden death, which could be cardiac inhibition induced by vagal stimulation. We hope this case will increase recognition of NF-1 vasculopathy when encountering any sudden death in NF1 patients. PMID- 27497332 TI - An autopsy case of acetyl fentanyl intoxication caused by insufflation of 'designer drugs'. AB - We present a fatal case of intoxication due to insufflation of acetyl fentanyl. His blood concentration of acetyl fentanyl was 270ng/mL, and the manner of death was classified as an accident. This is the first report of an autopsy case of acetyl fentanyl delivered by insufflation, rather than intravenous administration. He had been snoring loudly for at least 12h prior to death, and transport to a hospital during this time and treatment with naloxone may have saved his life. In this sense, it can be said that his death was preventable. This case reemphasizes the risk of death associated with drug overdose and the narrow range of acetyl fentanyl between the effective dose (ED50) and lethal dose (LD50). The case should also raise awareness among medical professionals of the effectiveness of naloxone and the need to establish a comprehensive system for toxicological analysis while keeping the possibility of use of 'designer drugs' in mind. PMID- 27497333 TI - Assessment of sex in a modern Turkish population using cranial anthropometric parameters. AB - The utilization of radiological imaging methods in anthropometric studies is being expanded by the application of modern imaging methods, leading to a decrease in costs, a decrease in the time required for analysis and the ability to create three-dimensional images. This retrospective study investigated 400 patients within the 18-45-years age group (mean age: 30.7+/-11.2years) using cranial computed tomography images. We measured 14 anthropometric parameters (basion-bregma height, basion-prosthion length, maximum cranial length and cranial base lengths, maximum cranial breadth, bizygomatic diameter, upper facial breadth, bimastoid diameter, orbital breadth, orbital length, biorbital breadth, interorbital breadth, foramen magnum breadth and foramen magnum length) of cranial measurements. The intra- and inter-observer repeatability and consistency were good. From the results of logistic regression analysis using morphometric measurements, the most conspicuous measurements in terms of dimorphism were maximum cranial length, bizygomatic diameter, basion-bregma height, and cranial base length. The most dimorphic structure was the bizygomatic diameter with an accuracy rate of 83% in females and 77% in males. In this study, 87.5% of females and 87.0% of males were classified accurately by this model including four parameters with a sensitivity of 91.5% and specificity of 85.0%. In conclusion, CT cranial morphometric analysis may be reliable for the assessment of sex in the Turkish population and is recommended for comparison of data of modern populations with those of former populations. Additionally, cranial morphometric data that we obtained from modern Turkish population may reveal population specific data, which may help current criminal investigations and identification of disaster victims. PMID- 27497334 TI - Population genetic study for 24 STR loci and Y indel (GlobalFilerTM PCR Amplification kit and PowerPlex(r) Fusion system) in 1000 Korean individuals. AB - Allele frequencies for 23 autosomal short tandem repeat loci (D3S1358, vWA, D16S539, CSF1PO, TPOX, D8S1179, D21S11, D18S51, TH01, FGA, D5S818, D13S317, D7S820, D2S441, D19S433, D22S1045, D10S1248, D1S1656, D12S391, D2S1338, SE33, Penta D, Penta E), 1 Y-chromosome short tandem repeat locus (DYS391) and Y indel were obtained from 1000 unrelated individuals of the Korean population. PMID- 27497335 TI - Estimation of stature and sex from scapular measurements by three-dimensional volume-rendering technique using in Chinese. AB - In order to develop population - specific discriminant function equations and stature prediction equations for predicting sex and stature from measurements of the scapula in a contemporary Chinese, 414 individual 3D CT images were collected from participants undergoing routine examination. Sex differences for the variables were tested by Student's t-test. Fisher's method has been followed for discriminant analysis. Regression analysis was applied to match the six linear parameters against stature. The stepwise analysis of all measurements yielded a sex classification accuracy rate of 86.7% and a sex bias of 3.1%. All the classification accuracy rates of the univariate discriminant function analyses are of more than 80%. For stature estimation, the accuracy of stature prediction ranged from 5.252 to 7.210cm for male, from 4.630 to 6.484cm for female, respectively. This paper provides indications that the scapula is an important bone for sex diagnosis and it could be effectively used as alternatives in forensic cases. Furthermore, the equations presented for stature estimation in this study should be used as alternatives in forensic cases when long bones were unavailable for stature estimation. PMID- 27497336 TI - Medicolegal aspects of PMA-related deaths. AB - Unlike amphetamine, amphetamine-like substances accessible on the drug market are less expensive and more easily available; they also produce hallucinogenic effects expected by the users. Such properties render them more attractive as compared to amphetamine. On the other hand, the knowledge of the toxicity of these compounds is very limited, what in consequence generates problems that create ever-expanding research areas, including analytical, clinical and medicolegal issues, thus leading to development of systemic databases. An example here is paramethoxyamphetamine (PMA), which appeared on the drug market in recent years as a result of creative inventiveness of producers of psychoactive substances, who aimed at PMA replacing the popular ecstasy (MDMA) as a less expensive and more available product. It is more potent than MDMA, but has a slower onset of action, which encourages users to take more. The problem is illustrated in the present paper by three fatal cases involving PMA, which were comprehensively investigated taking into consideration case histories, pathological and toxicological findings obtained with the use of LC-MS-MS method. In blood samples taken from all the three victims, very high concentrations of PMA were found (in the range of 10-27mg/L) and thus the cause of deaths was determined as overdoses of PMA with the underlying mechanism of acute cardiorespiratory failure. PMID- 27497337 TI - A rare case of steering wheel injury causing coronal-plane pancreatic lacerations. AB - The incidence of pancreatic injury after blunt abdominal trauma is extremely low. A timely and accurate diagnosis is important, as a delay could be life threatening. In this case, a 70-year-old driver crashed a car into a concrete wall at low speed. He was transported to the emergency hospital but died about 9.5h later with the cause of death unknown. An autopsy revealed that his pancreas was lacerated in the coronal plane and there was mesenteric contusion. Cause of death was determined to be blood loss resulting from pancreatic and mesenteric contusion. The mechanism of the injury was considered to be a very rare "degloving," caused by the impact from the steering wheel. It is therefore important to keep in mind possible pancreatic damage when examining blunt trauma to the abdomen, especially in traffic accident cases. PMID- 27497338 TI - Analysis of 12 X-chromosomal markers in the population of central Croatia. AB - Investigator(r) Argus X-12 Kit is a commercially available set that allows simultaneous PCR amplification of 12 X-STR markers belonging to four linkage groups (LG). To assess the forensic efficiency of these markers for the population of central Croatia and consequent applicability in routine forensic casework, DNA from 200 blood samples of unrelated donors (100 female and 100 male) was amplified by Investigator(r) Argus X-12 Kit and analyzed by capillary electrophoresis. Statistical computations based on allele and haplotype frequencies for LG1 - LG4 were performed using Arlequin 3.5 software and on-line tool available at ChrX-STR.org. In female samples, all X-STR markers were in Hardy-Weinberg equilibrium (HWE). The most informative marker for central Croatia population was DXS10135 with polymorphism information content (PIC) 0.9296. The least polymorphic locus was DXS8378 (PIC=0.6363). Power of discrimination (PD) varied from 0.6968 to 0.9336 in male and from 0.8476 to 0.9916 in female samples. Combined PD exceeded 0.999999999 in both men and women. In male samples, linkage disequilibrium (LD) test revealed significant association (P=0.0000) of one marker pair in LG4 and two marker pairs in LG3. Portion of observed haplotypes in the number of possible haplotypes varied from 2.86% to 7.47% across all LGs. LG1 was the most informative with haplotype diversity (H) 0.9972. High PD of all analyzed markers exhibited for central Croatia population confirms suitability of Investigator(r) Argus X-12 for forensic pertinence. Moreover, results of this study will be included in establishing a national reference X-STR database based on 12 X-STR loci, which is necessary for the correct interpretation of the forensic casework results. PMID- 27497339 TI - Development of a preparation method to produce a single sample that can be applied to both LC-MS/MS and GC-MS for the screening of postmortem specimens. AB - Simple and efficient extraction methods have been developed for the screening of a wide array of drugs in postmortem autopsy specimens. Acidic and basic compounds were targeted with two extraction methods that can be applied to both GC-MS and LC-MS/MS instrumentation. The extractions were achieved by utilizing lipid removal and solid-phase extraction cartridges while carefully monitoring the pH of the samples to ensure the adequate removal of interfering substances like lipids and amino acid derivatives. These methods were applied to actual autopsy cases, with 94 and 124 compounds detected by GC-MS and LC-MS/MS, respectively. The developed methods could easily be incorporated into a forensic laboratory's daily routine for screening many different compounds from postmortem samples. PMID- 27497340 TI - Effect of granulocyte colony-stimulating factor priming combined with low-dose cytarabine and homoharringtonine in higher risk myelodysplastic syndrome patients. AB - As sensitization of leukemia cells with granulocyte colony-stimulating factor (G CSF) can enhance the cytotoxicity of chemotherapy in myeloid malignancies, a pilot study was conducted in order to evaluate the effect of G-CSF priming combined with low-dose chemotherapy in patients with higher risk myelodysplastic syndrome (MDS). The regimen, G-HA, consisted of cytarabine (Ara-C) 7.5mg/m(2)/12h by subcutaneous injection, days 1-14, homoharringtonine (HHT) 1.5mg/m(2)/day by intravenous continuous infusion, days 1-14, and G-CSF 150mg/m(2)/day by subcutaneous injection, days 0-14. 56 patients were enrolled, 34 patients (61%, 95% confidence interval: 51.44-70.56%) achieved complete remission (CR). Median duration of neutropenia was 7days (ranging from 2 to 16days). Grade 1-2 nonhematologic toxicities were documented, including nausea and vomiting (5%), liver function abnormality (5%), and heart function abnormality (2%). No central nervous system toxicity was found. Mortality within the first 4 weeks was 4%. The G-HA regimen is effective in remission induction for higher risk MDS patients and well tolerated due to the acceptable toxicity in maintenance therapy in the patients who cannot undergo Hematopoietic cell transplantation (HCT). PMID- 27497341 TI - Influence of functional polymorphisms in DNA repair genes of myelodysplastic syndrome. AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell (HSC) malignances characterized by peripheral cytopenias and predisposition to acute myeloid leukemia transformation. Several studies show that the MDS pathogenesis is a complex and heterogeneous process that involves multiple steps through a sequence of genetic lesions in the DNA which lead to functional changes in the cell and the emergence and subsequent evolution of pre-malignant clone. Double strand breaks (DSB) lesions are the most severe type of DNA damage in HSCs, which, if not properly repaired, might contribute to the development of chromosomal abnormalities, which in turn may lead to leukemia development. We assessed the mRNA expression levels of ATM, BRCA1, BRCA2, RAD51, XRCC5, XRCC6 and LIG4 genes in bone marrow samples of 47 MDS patients in order to evaluate the association with functional polymorphisms rs228593, rs4793191, rs9567623, rs1801320, rs3835, rs2267437 and rs1805388, respectively, and try to detect clinical associations. We found that the rs228593, rs2267437 and rs1805388 functional polymorphisms probably alter the level of expression of the ATM, XRCC6 and LIG4 genes, respectively, being important in the maintenance of genomic instability in MDS. PMID- 27497342 TI - How are the kids holding up? A systematic review and meta-analysis on the psychosocial impact of maternal breast cancer on children. AB - BACKGROUND: Having a mother diagnosed with breast cancer can be a distressing time for a child. This review examines the impact maternal breast cancer has on the psychosocial functioning of children and what factors possibly moderate this relationship. METHODS: Using PRISMA guidelines, five electronic databases were systematically searched for published studies examining maternal breast cancer and the psychosocial functioning of children. RESULTS: A total of 15 studies contributed to the analysis. Results from a random effects meta-analysis show that children experience marginally elevated internalizing problems (standardized mean difference=.14, 95% CI .00, .28), significantly fewer total problem behaviors (standardized mean difference=-.13, 95% CI -.23, -.03), and no changes in externalizing problems (standardized mean difference=-.07, 95% CI -.19, .05) relative to comparison groups. Consistent with this, the narrative review suggests the children may experience elevated depression, anxiety and mental distress yet show more social competence and little aggressive or disruptive behavior. Significant moderating variables included informant type (i.e., self ratings vs mother's ratings vs other's ratings) and comparison group used (i.e., controls vs normative data). There is also evidence that illness severity and maternal mental health may impact the results. CONCLUSIONS: The results suggest that children may be at risk for internalizing-type problems, especially when their mother experiences depression and has serious medical complications. Research using larger and more diverse samples is needed to fully understand how maternal breast cancer impacts children. PMID- 27497343 TI - Challenging the dogma of colorectal peritoneal metastases as an untreatable condition: Results of a population-based study. AB - PURPOSE: To determine the impact of the implementation of novel systemic regimens and locoregional treatment modalities on survival at population level in colorectal cancer (CRC) patients presenting with peritoneal metastases (PMs). METHODS: All consecutive CRC patients with synchronous PM (<3 months) between 1995 and 2014 were extracted from the Eindhoven area of the Netherlands Cancer Registry. Trends in treatment and overall survival were assessed in four time periods. Multivariable regression analysis was used to analyse the impact of systemic and locoregional treatment modalities on survival. RESULTS: A total of 37,036 patients were diagnosed with primary CRC between 1995 and 2014. Synchronous PM was diagnosed in 1,661 patients, of whom 55% had also metastases at other sites (n = 917) and 77% received anticancer therapy (n = 1,273). Treatment with systemic therapy increased from 23% in 1995-1999 to 56% in 2010 2014 (p < 0.0001). Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) was applied since 2005 and increased from 10% in 2005 2009 to 23% in 2010-2014. Surgery for lymphatic or haematogenous metastases increased from 2% to 10% in these periods. Median overall survival of the complete cohort improved from 6.0 months in 1995-2000 to 12.5 months in 2010-2014 (p < 0.0001), with a doubling of survival for both PM alone and PM with other involved sites. The influence of year of diagnosis on survival (hazard ratio, 2010-2014 versus 1995-1999; 0.5, 95% confidence interval: 0.43-0.62; p < 0.0001) disappeared after including systemic therapy and locoregional treatment modalities in subsequent multivariable models. CONCLUSION: CRC patients presenting with PM are increasingly offered a multidisciplinary treatment approach, resulting in an increased overall survival for the entire cohort. PMID- 27497344 TI - MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects. AB - BACKGROUND: Mitogen-activated protein kinase kinase (MEK) inhibitors have aroused considerable interest in oncology. Activity has been demonstrated in various types of cancer, especially melanoma. MEK inhibitors induce a transient retinopathy, considered to be a class effect. At present, only sparse data are available on retinal effects with long-term MEK inhibition. PATIENTS AND METHODS: In this prospective, observational study, patients with advanced melanoma participating in different phase 1/2 or phase 3 clinical trials were treated with the MEK inhibitor binimetinib, with a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor, or with combination therapy. They underwent regular ophthalmological examinations including determination of visual function, biomicroscopy, dilated fundoscopy and optical coherence tomography (OCT) for a period of up to 2 years. Retinopathy was diagnosed on defined OCT criteria. RESULTS: Sixty-two patients were investigated between 1st October 2011 and 31st July 2015: 13 were treated with the MEK inhibitor binimetinib alone, 10 with a selective BRAF inhibitor, and 39 with combination therapy. In 92% of patients on monotherapy and 100% of those on combination treatment, binimetinib caused dose related lesions with serous neuroretinal detachments and oedema, strongly dependent on the time after medication. With continued treatment, retinal volume and thickness decreased to levels below baseline, without any apparent functional deficits or changes in structural integrity. CONCLUSIONS: Binimetinib induces a specific retinopathy with daily fluctuations depending on the time interval after medication. The retinopathy partially recovers, but can still be detected many months later. Retinal thinning, possible first signs of retinal atrophy have been observed after long-term treatment, but, so far, without functional relevance. PMID- 27497345 TI - Tumour-free margins in vulvar squamous cell carcinoma: Does distance really matter? AB - BACKGROUND: There is no consensus on the width of tumour-free margins after surgery for vulvar squamous cell carcinoma (VSCC). Most current guidelines recommend tumour-free margins of >=8 mm. The aim of this study was to investigate whether a margin of <8 mm is associated with an increased risk of local recurrence in VSCC. METHODS: A meta-analysis of the available literature and a cohort study of 148 VSCC patients seen at a referral centre from 2000 to 2012 was performed. The primary end-point of the cohort study was a histologically confirmed ipsilateral local recurrence within 2 years after primary treatment in relation to the margin distance. RESULTS: Based on 10 studies, the meta-analysis showed that a tumour-free margin of <8 mm is associated with a higher risk of local recurrence compared to a tumour-free margin of >=8 mm (pooled risk ratio, 1.99 [95% confidence interval {CI}: 1.13-3.51], p = 0.02). In the cohort study, we found no clear difference in the risk of local recurrence in the <8 versus >=8 mm group; however, 40% of the patients in the <8 mm group received additional treatment. Tumour-positive margin was the only independent risk factor for local recurrence in the multivariable analysis (hazard ratio, 0.21 [95% CI: 0.08 0.55]). CONCLUSIONS: This work provides important data to question the commonly used 8-mm margin as a prognosticator for local recurrence. More research is needed to address the question of whether additional treatment improves the prognosis in patients with a tumour-free margin of <8 mm. PMID- 27497346 TI - Assessment of trauma quality improvement activities at public hospitals in Thailand. AB - BACKGROUND: Given the current exceptional burden of injury in Thailand, the proven efficacy of quality improvement programs, and the current scarcity of national-level information on trauma quality improvement program (TQIP) implementation in Thailand, we aimed to examine the use of TQIPs and barriers to TQIP adoption in Thai public trauma centers. METHODS: We distributed a survey to 110 public hospitals which are designated to provide trauma care in Thailand. The survey assessed the presence or absence of the four core elements of the World Health Organization (WHO) recommended TQIPs (morbidity and mortality (M&M) conferences, preventable death panels, trauma registries, and audit filters), and provider perception of barriers and priorities in TQIP implementation. RESULTS: Responses were received from 80 (72%) respondents. Seventy-two (90%) reported having a trauma registry and seventy (88%) respondents reported use of audit filters. Seventy (88%) respondents reported conducting regular M&M conferences, and 45 (56%) respondents reported the presence of preventable death panels. Thirty-eight (48%) respondents reported presence of all four elements of WHO TQIPs. The most commonly reported barriers to implementing TQIPs were lack of interest (55; 68%) and lack of time (39; 48%)to implement TQIPs. Audit filters were reported by only 25 (31%) of respondents and optimization of audit filters was the most frequently identified next-step in further development of TQIP. CONCLUSIONS: Just under half of responding Thai public trauma centers reported implementation of all four elements of the WHO recommended TQIPs. Priority strategies to facilitate TQIP maturation in Thailand should address staff motivation, provision of staff time for TQIP development, and optimization of audit filter use to monitor quality of care. PMID- 27497347 TI - Extracellular polymeric substances facilitate the biosorption of phenanthrene on cyanobacteria Microcystis aeruginosa. AB - Phytoplankton-derived extracellular polymeric substances (EPS) are of vital importance for the biogeochemical cycles of hydrophobic organic pollutants in lake ecosystems. In this study, roles of loosely-bound EPS (LB-EPS) and tightly bound EPS (TB-EPS) in biosorption of phenanthrene (PHE) on a typical cyanobacteria Microcystis aeruginosa were investigated. The results showed that the biosorption of PHE on M. aeruginosa cell varied lasted 24 h, while the binding of PHE to LB-EPS and TB-EPS reached equilibrium within less than 2 h. The equilibrium biosorption capacities of M. aeruginosa cell, LB-EPS and TB-EPS were 6.78, 12.31, and 9.47 MUg mg(-1), respectively, indicating that the binding of PHE to EPS was a considerable process involved in biosorption. Fluorescence quenching titration revealed that increasing temperature induced more binding sites in EPS for PHE and the binding process was driven by electrostatic force and hydrophobic interactions. Interestingly, dynamic and static quenching processes occurred simultaneously for the binding of PHE to protein-like substances in EPS, whereas the binding of PHE to humic-like substances belonged to static quenching. The relatively higher contents of proteins in LB-EPS produced a stronger binding capacity of PHE. Overall, the interactions between hydrophobic organic pollutants and cyanobacterial EPS are favorable to the bioaccumulation of hydrophobic organic pollutants in cyanobacteria and facilitate the regulatory function of cyanobacterial biomass as a biological pump. PMID- 27497348 TI - A key parameter on the adsorption of diluted aniline solutions with activated carbons: The surface oxygen content. AB - A total of 11 different commercial activated carbons (AC) with well characterized textural properties and oxygen surface content were tested as adsorbents for the removal of aniline as a target water pollutant. The maximum adsorption capacity of aniline for the studied AC was from 138.9 to 257.9 mg g(-1) at 296.15 K and it was observed to be strongly related to the textural properties of the AC, mainly with the BET surface area and the micropore volume. It was not observed any influence of the oxygen surface content of the AC on the maximum adsorption capacity. However, it was found that at low aniline aqueous concentration, the presence of oxygen surface groups plays a dominant role during the adsorption. A high concentration of oxygen surface groups, mainly carboxylic and phenolic groups, decreases the aniline adsorption regardless of the surface area of the AC. PMID- 27497349 TI - Modeling of experimental data on trace elements and organic compounds content in industrial waste dumps. AB - The main objective of the study presented was to investigate the differences between 20 mine waste dumps located in the Silesian Region of Poland and Czech Republic, in terms of trace elements and polycyclic aromatic hydrocarbons contents. The Principal Component Analysis and Hierarchical Clustering Analysis were applied in exploration of the studied data. Since the data set was affected by outlying objects, the employment of a relevant analysis strategy was necessary. The final PCA model was constructed with the use of the Expectation Maximization iterative approach preceded by a correct identification of outliers. The analysis of the experimental data indicated that three mine waste dumps located in Poland were characterized by the highest concentrations of dibenzo(g,h,i)anthracene and benzo(g,h,i)perylene, and six objects located in Czech Republic and three objects in Poland were distinguished by high concentrations of chrysene and indeno (1.2.3-cd) pyrene. Three of studied mine waste dumps, one located in Czech Republic and two in Poland, were characterized by low concentrations of Cr, Ni, V, naphthalene, acenaphthene, fluorene, phenanthrene, anthracene, fluoranthen, benzo(a)anthracene, chrysene, benzo (b) fluoranthene, benzo (k) fluoranthene, benzo(a)pyrene, dibenzo(g,h,i)anthracene, benzo(g,h,i)perylene and indeno (1.2.3-cd) pyrene in comparison with the remaining ones. The analysis contributes to the assessment and prognosis of ecological and health risks related to the emission of trace elements and organic compounds (PAHs) from the waste dumps examined. No previous research of similar scope and aims has been reported for the area concerned. PMID- 27497350 TI - Concentrations and patterns of polychlorinated naphthalenes in urban air in Beijing, China. AB - Air samples were collected, using a high-volume air sampler, at an urban site in Beijing from April 2014 to March 2015. The polychlorinated naphthalene (PCN) concentration in the atmosphere in each season was determined. The total PCN (total target tri- to octachloronaphthalene congeners) concentrations were 1.99 19.0 pg/m(3), and the mean was 7.20 pg/m(3). The PCN concentrations were higher in fall than summer, indicating that the concentrations varied significantly over time. The trichloronaphthalene homolog was the predominant PCN homolog in all four seasons. The PCN toxic equivalent (TEQ) concentrations were 0.42-6.89 fg/m(3), and the mean was 1.74 fg/m(3). The CN-66/67 and CN-73 congeners were the predominant contributors to the TEQ concentrations. The mean seasonal TEQ concentration decreased in the order fall (3.18 fg/m(3)) > winter (1.41 fg/m(3)) > summer (1.11 fg/m(3)) > spring (1.03 fg/m(3)). The TEQ concentrations and the PCN concentrations did not follow the same seasonal trends, but the highest TEQ and PCN concentrations were both found in fall. Correlation analysis, ratio analysis, and principal component analysis were used to investigate the sources of PCNs to the Beijing atmosphere. The results suggested that combustion processes may be the main sources of PCNs to the Beijing atmosphere. PMID- 27497351 TI - Experimental study of clay-hydrocarbon interactions relevant to the biodegradation of the Deepwater Horizon oil from the Gulf of Mexico. AB - Adding clay to marine oil pollution represents a promising approach to enhance bacterial hydrocarbon degradation in nutrient poor waters. In this study, three types of regionally available clays (Ca-bentonite, Fuller's Earth and kaolin) were tested to stimulate the biodegradation of source and weathered oil collected from the Deepwater Horizon spill. The weathered oil showed little biodegradation prior to experimentation and was extensively degraded by bacteria in the laboratory in a similar way as the alkane-rich source oil. For both oils, the addition of natural clay-flakes showed minor enhancement of oil biodegradation compared to the non-clay bearing control, but the clay-oil films did limit evaporation. Only alkanes of a molecular weight (MW) > 420 showed significant reduction by enhanced biodegradation following natural clay treatment. In contrast, all fertilized clay flakes showed major bacterial degradation of the oil, with a 6-10 times reduction in alkane content, and an up to 8 fold increase in the rate of O2 consumption. Compared to the control, such treatment showed particular reduction of longer chained alkanes (MW > 226). The application of natural and fertilized clay flakes also showed selective reduction of PAHs, mainly in the MW range of 200-300, but without significant change in the toxicity indices measured. These results imply that a large variety of clays may be used to boost oil biodegradation by aiding attachment of fertilizing nutrients to the oil. PMID- 27497352 TI - Too little too late for young women with STEMI. PMID- 27497353 TI - The modern approach to endovascular carotid revascularisation. PMID- 27497354 TI - Longer pre-hospital delays and higher mortality in women with STEMI: the e-MUST Registry. AB - AIMS: The mortality rate in patients with STEMI is higher in women than in men. This higher mortality rate is partly accounted for by certain known characteristics inherent in the female population (age, diabetes). Using data from the e-MUST registry on STEMI patients in the Greater Paris area, we assessed the differences between men and women treated with reperfusion strategies. METHODS AND RESULTS: Patients presenting within 24 hours of pain onset between 2006 and 2010 were included in the study. The male and female subpopulations were compared according to their baseline characteristics, their management delays and their early outcomes. Five thousand eight hundred and forty males (78.9%) and 1,557 females (21.1%) were included in the study. In-hospital mortality was significantly higher in women than in men, 143 (9.4%) vs. 254 (4.4%), p<0.0001, with a longer time to treatment initiation, symptoms to call (2.7+/-3.6 vs. 2.2+/ 3.4 hours, p<0.0001), symptoms to first medical contact (FMC) (3.1+/-3.7 vs. 2.6+/-3.4 hours, p<0.0001), and call to FMC (25.6+/-23.5 vs. 23.6+/-18.3 min, p=0.02). After adjustment for clinical factors, severity criteria, myocardial infarction (MI) location and delays, mortality remained higher in women than in men with an odds ratio of 1.40 [1.06-1.84], p=0.017. CONCLUSIONS: We demonstrated longer pre-hospital delays and higher in-hospital mortality in women. The increase in the time to treatment alone does not completely explain the persistent increase in mortality. Further studies, public awareness programmes and physician education are necessary to reduce delays and improve the prognosis of STEMI in women. PMID- 27497355 TI - Two-year clinical outcomes of Absorb bioresorbable vascular scaffold implantation in complex coronary artery disease patients stratified by SYNTAX score and ABSORB II study enrolment criteria. AB - AIMS: This study presents the two-year clinical outcomes of the Amsterdam ABSORB registry stratified by lesion and patient characteristics complexity (SYNTAX score and ABSORB II study enrolment criteria). METHODS AND RESULTS: Patients treated with BVS were included in this prospective registry and stratified according to the ABSORB II trial inclusion and exclusion criteria and the SYNTAX score. The registry comprises 135 patients (59+/-11 years, 73% male, 18% diabetic) with 159 lesions. Median follow-up duration was 774 days (742-829). Median SYNTAX score was 11.5 (Q1-Q3: 6-17.5). Two-year event rates were cardiac death 0.7%, MI 5.3%, TVR 13.6%, TLR 11.4%, definite ST 3.0% and TVF 14.4%, respectively. Stratified analyses showed a significantly higher revascularisation rate in patients not meeting ABSORB II criteria (TVR: 2.3% vs. 19.2%, p=0.010, and TLR: 2.3% vs. 15.8%, p=0.025) and patients with SYNTAX score >=11.5 (TVR: 4.8% vs. 21.8%, p=0.006, and TLR: 3.2% vs. 17.4%, p=0.007). CONCLUSIONS: The use of Absorb BVS in patients meeting the ABSORB II trial inclusion criteria or those with low SYNTAX scores is associated with acceptable clinical outcomes at two year follow-up. Patients with more complex characteristics have significantly higher revascularisation rates. PMID- 27497356 TI - Absorb vs. DESolve: an optical coherence tomography comparison of acute mechanical performances. AB - AIMS: The aim of the study was to compare retrospectively the acute mechanical performance of the Absorb vs. DESolve scaffolds in terms of appropriate deployment with OCT. METHODS AND RESULTS: Final post-deployment OCT pullbacks of consecutive patients treated with either Absorb or DESolve were reviewed. The following parameters were calculated and compared: mean and minimal lumen area (MLA), residual in-scaffold area stenosis (RAS), incomplete strut apposition (ISA), tissue prolapse area, eccentricity index, asymmetry index, strut fracture and edge dissection. A total of 72 patients were included. The Absorb group consisted of 35 patients treated with 63 Absorb scaffolds and was compared to a well-matched group of 37 patients treated with 50 DESolve scaffolds. Baseline characteristics did not differ significantly between the two groups. Procedural characteristics were different with respect to maximal balloon inflation pressure (Absorb vs. DESolve: 21.5+/-0.4 atm vs. 16.8+/-3.8 atm, p<0.01) and mean NC balloon diameter used for post-dilatation (Absorb vs. DESolve 3.3+/-0.4 mm vs. 3.5+/-0.4 mm, p<0.01). OCT analysis showed similar MLA (Absorb vs. DESolve: 5.8+/ 1.9 mm2 vs. 6.1+/-2.6 mm2, p=0.43) and mean luminal area (Absorb vs. DESolve: 7.1+/-2.2 mm2 vs. 7.2+/-1.9 mm2, p=0.77). The mean eccentricity index was 0.85+/ 0.05 with Absorb and 0.80+/-0.05 with DESolve, p<0.01. There was no difference in the incidence of overall ISA. A smaller prolapse area was found with Absorb (Absorb vs. DESolve 1.0+/-1.1 mm2 vs. 3.6+/-6.2 mm2, p<0.01). CONCLUSIONS: The two scaffolds showed similar MLA while there was a trend towards a lower RAS and a larger maximum and minimum scaffold diameter with DESolve. The DESolve scaffold was more eccentric as compared to the Absorb. These results might be related to the DESolve's unique expansion properties or they may reflect baseline and procedural differences which cannot be excluded in a retrospective study. Randomised studies are needed to address this aspect. PMID- 27497357 TI - Evaluation of vascular healing of polymer-free sirolimus-eluting stents in native coronary artery stenosis: a serial follow-up at three and six months with optical coherence tomography imaging. AB - AIMS: Our aim was to assess vascular response after polymer-free sirolimus eluting stent (SES) implantation by using an optical coherence tomography (OCT) derived vascular healing score (HS), quantifying the deficiency of healing. METHODS AND RESULTS: In a prospective, multicentre, single-arm, open-label study, OCT examinations were performed at three months in 45 patients (47 lesions). Per protocol, 24 lesions which had not reached adequate vascular healing according to study criteria were scheduled for OCT examination at six months. The HS was calculated at two time points. Serial OCT imaging demonstrated that the proportion of covered stent struts increased from a median of 87.1% at three months to 98.6% at six months (p<0.001). The neointimal thickness increased from a median of 82.8 um to 112.2 um (p<0.001), whereas the median percentages of malapposed struts were 0.2% and 0.0% at the two respective time points. Neointimal volume obstruction increased from 6.3% to 12.8%, and the HS decreased from a median of 28.1 at three months to 2.4 at six months. CONCLUSIONS: In patients who had inadequate vascular healing three months after polymer-free SES implantation, serial OCT showed almost complete vascular healing at six months. PMID- 27497358 TI - Evaluation of myocardial blood flow and coronary flow reserve after implantation of a bioresorbable vascular scaffold versus metal drug-eluting stent: an interim one-month analysis of the VANISH trial. AB - AIMS: A randomised clinical trial of bioresorbable vascular scaffold (BVS) vs. metal drug-eluting stent (DES) was initiated, using positron emission tomography (PET) perfusion imaging to assess the effects of both treatments on (hyperaemic) myocardial blood flow (MBF) and coronary flow reserve (CFR) over a three-year period (VANISH trial). In the present study, early, i.e., after one month, MBF and CFR are reported. METHODS AND RESULTS: Sixty patients (45 men [75%], 55+/-7 years) with a documented single-vessel type A or B1 lesion were included in this single-blind randomised clinical trial. Patients were randomised to implantation of a BVS or DES in a one-to-one fashion. Approximately one month after percutaneous coronary intervention, patients underwent [15O]H2O PET to assess (hyperaemic) MBF, cold pressor test MBF, and CFR. One patient refused PET perfusion at one-month follow-up (in the DES arm). MBF of the treated myocardial territory during rest, CPT, and hyperaemia were not different in BVS-treated patients as compared to DES-treated patients (1.02+/-0.28 vs. 0.96+/-0.24 mL.min 1.g-1, p=0.38, 1.20+/-0.38 vs. 1.08+/-0.23 mL.min-1.g-1, p=0.16, and 3.04+/-0.80 vs. 3.33+/-0.77 mL.min-1.g-1, p=0.16, respectively). CFR of the treated myocardial territory was significantly lower in the BVS-treated patients (3.09+/ 0.94 vs. 3.57+/-0.85, p<0.05). CONCLUSIONS: No differences in PET-derived absolute myocardial perfusion were observed between BVS-treated patients as compared to DES-treated patients at one-month follow-up. CFR was attenuated in BVS-treated patients, although still within the normal range. PMID- 27497359 TI - Angiographic complexity of coronary artery disease according to SYNTAX score and clinical outcomes after revascularisation with newer-generation drug-eluting stents: a substudy of the BIOSCIENCE trial. AB - AIMS: We sought to assess the performance of drug-eluting stents combining an ultrathin cobalt-chromium platform with a biodegradable polymer across categories of increasing SYNTAX score (SS). METHODS AND RESULTS: Patients included in the BIOSCIENCE trial and randomly allocated to treatment with biodegradable polymer sirolimus-eluting stents (BP-SES) or durable polymer everolimus-eluting stents (DP-EES) were categorised according to SS tertiles (low <8, medium 8-15, high >15). The primary endpoint, target lesion failure (TLF), was defined as a composite of cardiac death, target vessel myocardial infarction and clinically indicated target lesion revascularisation. The patient-oriented endpoint (POCE) included death, myocardial infarction, or any repeat revascularisation. The SS was available in 2,041 out of 2,119 patients (96.3%). At two-year follow-up, patients with an SS >15 experienced higher rates of both TLF and POCE as compared to patients with medium and low SS (14.5% vs. 8.1% and vs. 5.9%, p<0.001; 22.7% vs. 14.9% and vs. 12.4%; p<0.001), respectively. Comparable rates of the composite endpoints were documented for both stent types in each category of SS. CONCLUSIONS: Increasing lesion complexity as assessed by SS was associated with higher rates of TLF and POCE in a contemporary PCI population with minimal exclusion criteria. BP-SES and DP-EES showed comparable performance across the entire spectrum of CAD severity. PMID- 27497360 TI - Early coverage of drug-eluting stents analysed by optical coherence tomography: evidence of the impact of stent apposition and strut characteristics on the neointimal healing process. AB - AIMS: Previous studies have associated issues such as incomplete stent apposition with delayed healing and adverse events (stent thrombosis). The aim of this study was to evaluate the impact of strut apposition and stent type on the progression of stent strut coverage. METHODS AND RESULTS: We evaluated in vivo in porcine models the follow-up response and coverage characteristics of well-apposed and malapposed segments of drug-eluting stents (DES) (CYPHER, PROMUS Element and Orsiro) and the Absorb bioresorbable vascular scaffold (BVS) by optical coherence tomography (OCT) sequentially, at baseline, and at one week and four weeks of follow-up. Supporting results were provided by histological analysis performed at four-week follow-up and computer simulation describing the shear characteristics around apposed and non-apposed struts. A total of 325 cross-sections containing 3,166 struts were analysed. The extent of malapposition decreased over time as a result of neointimal healing (from 7.1% at baseline to 0% at four weeks; p=0.03). At one week, 13.6% of struts in well-apposed segments were still uncovered versus 19.2% of struts in malapposed cross-sections and 77.8% of NASB struts (p<0.01). At four-week follow-up, 3.1% of struts were uncovered in well-apposed cross sections vs. 1.6% in malapposed cross-sections and 35.7% of NASB struts (p<0.01). A comparison of the apposed segments revealed that the thin-strut Orsiro had only 1.3% of uncovered struts at one week while PROMUS Element, CYPHER and BVS had 6.6%, 48.4% and 16.2% of struts still uncovered, respectively. CONCLUSIONS: This study shows that early coverage is influenced by stent apposition as well as platform strut characteristics (stent type). At four weeks, NASB struts remained a focus of delayed endothelialisation. PMID- 27497361 TI - Direct implantation of rapamycin-eluting stents with bioresorbable drug carrier technology utilising the Svelte coronary stent-on-a-wire: the DIRECT II study. AB - AIMS: Our aim was to demonstrate the safety and efficacy of the Svelte sirolimus eluting coronary stent-on-a-wire Integrated Delivery System (IDS) with bioresorbable drug coating compared to the Resolute Integrity zotarolimus-eluting stent with durable polymer in patients with de novo coronary artery lesions. METHODS AND RESULTS: Direct stenting, particularly in conjunction with transradial intervention (TRI), has been associated with reduced bleeding complications, procedure time, radiation exposure and contrast administration compared to conventional stenting with wiring and predilatation. The low-profile Svelte IDS is designed to facilitate TRI and direct stenting, reducing the number of procedural steps, time and cost associated with coronary stenting. DIRECT II was a prospective, multicentre trial which enrolled 159 patients to establish non inferiority of the Svelte IDS versus Resolute Integrity using a 2:1 randomisation. The primary endpoint was angiographic in-stent late lumen loss (LLL) at six months. Target vessel failure (TVF), as well as secondary clinical endpoints, will be assessed annually up to five years. At six months, in-stent LLL was 0.09+/-0.31 mm in the Svelte IDS group compared to 0.13+/-0.27 mm in the Resolute Integrity group (p<0.001 for non-inferiority). TVF at one year was similar across the Svelte IDS and Resolute Integrity groups (6.5% vs. 9.8%, respectively). CONCLUSIONS: DIRECT II demonstrated the non-inferiority of the Svelte IDS to Resolute Integrity with respect to in-stent LLL at six months. Clinical outcomes at one year were comparable between the two groups. PMID- 27497362 TI - Long-term clinical outcomes after percutaneous coronary intervention versus coronary artery bypass grafting for acute coronary syndrome from the DELTA registry: a multicentre registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment. AB - AIMS: Our aim was to compare, in a large unprotected left main coronary artery (ULMCA) all-comer registry, the long-term clinical outcome after percutaneous coronary intervention (PCI) with first-generation drug-eluting stents (DES) versus coronary artery bypass grafting (CABG) in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: Of a total of 2,775 patients enrolled in the Drug Eluting Stents for Left Main Coronary Artery Disease (DELTA) multicentre registry, 379 (13.7%) patients with ACS treated with PCI (n=272) or CABG (n=107) were analysed. Baseline demographics were considerably different in the two groups before propensity matching. No significant differences emerged for the composite endpoint of all-cause death, myocardial infarction (MI), and cerebrovascular accident (HR 1.11, 95% CI: 0.63-1.94; p=0.727), all-cause death (HR 1.26, 95% CI: 0.68-2.32; p=0.462), the composite endpoint of all-cause death and MI (HR 1.02, 95% CI: 0.56-1.84; p=0.956), and major adverse cardiac and cerebrovascular events (HR 0.82, 95% CI: 0.50-1.36; p=0.821). However, a higher incidence of target vessel revascularisation (HR 4.67, 95% CI: 1.33-16.47; p=0.008) was observed in the PCI compared with the CABG group, which was confirmed in the propensity score-matched analysis. CONCLUSIONS: In the DELTA all comer, multinational registry, PCI for ACS in ULMCA is associated with comparable clinical outcomes to those observed with CABG at long-term follow-up, despite the use of first-generation DES. PMID- 27497363 TI - Rotational atherectomy of undilatable coronary stents: stentablation, a clinical perspective and recommendation. AB - AIMS: Our aim was to examine procedural viability and midterm outcomes following the use of rotational atherectomy (RA) on malapposed, crippled, otherwise non salvageable metallic stents (i.e., stentablation [SA]), and convey important procedural pointers for practitioners encountering such situations. METHODS AND RESULTS: Data on twelve SA subjects were analysed. The primary endpoint was procedural success: effective ablation of the malapposed stent and successful implantation of a new device. Major adverse cardiac events (MACE) and all-cause death at six months following the index procedure were examined as a secondary endpoint. All twelve patients underwent successful SA and novel stent implantation, with sufficient salvage of coronary anatomy (residual stenosis <30%). At six-month follow-up, however, MACE amounted to 50% and all-cause mortality to 25% in the inspected subjects. CONCLUSIONS: We found that, although feasible as an acute salvage option, SA distinctively increases post-procedural midterm MACE and mortality rates. This places emphasis on the importance of avoiding eventual SA situations, underlining the importance of ample lesion preparation prior to stent implantation. PMID- 27497364 TI - The clinical impact of vascular complications as defined by VARC-1 vs. VARC-2 in patients following transcatheter aortic valve implantation. AB - AIMS: The Valve Academic Research Consortium (VARC) recommendations were devised to standardise clinical endpoint definitions which best reflect the safety and efficacy of transcatheter aortic valve implantation (TAVI). The categorisation of vascular complications (VC) is greatly affected by the definition, but the impact of its change is unclear. We sought to compare VC between VARC-1 and VARC-2 definitions as a predictor for survival. METHODS AND RESULTS: A series of 376 patients undergoing TAVI by the transfemoral or transapical approach was studied. We defined VC according to VARC-1 and VARC-2, and compared the mortality one year after the procedure. Kaplan-Meier curves showed numerically lower survival rates at one year by major VC with both definitions, but only VARC-2 had statistical significance: 79.3% vs. 60.7% with VARC-2 (p=0.014), and 78.9% vs. 70.5% with VARC-1 (p=0.20). Cox regression multivariable models showed major VC with VARC-2 definition to be an independent predictor of mortality (hazard ratio of 3.0, 95% confidence interval: 1.4-6.6, p=0.006), but not when it was substituted by the VARC-1 definition (p=0.15). CONCLUSIONS: The VARC-2 definition of VC offers better predictive value of survival than the VARC-1 definition, supporting its efficacy as a standard definition. PMID- 27497365 TI - Early European experience with the Venus P-valve(r): filling the gap in percutaneous pulmonary valve implantation. AB - AIMS: Our aim was to report the first five cases of percutaneous implantation of the Venus P-valve(r) in Europe. METHODS AND RESULTS: We successfully implanted Venus P-valves in five consecutive cases in patients whose anatomy was thought to be unfavourable for currently available percutaneous valve prostheses and who had relative contraindications to surgical valve replacement. The procedures were performed at Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. The primary diagnosis was variable with variable pulmonary artery morphology. The median age was 14 years (range 12-62 yrs). There was no mortality and no major morbidity, with satisfactory haemodynamic and angiographic outcomes in all patients. Post-procedural follow-up (median follow-up 8.5 months, range three to 15 months) with echocardiography and magnetic resonance imaging showed no restenosis or regurgitation with significant improvement in the right ventricular end-diastolic volumes. CONCLUSIONS: Preliminary results show that the Venus P valve can be safely and efficaciously used in dilated right ventricular outflow tracts of varying morphology. Rigorous trials will be required to evaluate this valve before more widespread use. PMID- 27497366 TI - Transcatheter closure of atrial septal defects without fluoroscopy: a well established procedure for alternative use in children. AB - AIMS: The feasibility of transcatheter closure of atrial septal defects (ASD) without fluoroscopy has been proven. However, the technique has not been accepted for routine use. We report our experience with trans-catheter closure of ASD without fluoroscopy and introduce a well-established technique for alternative use in children. METHODS AND RESULTS: From November 2013 to May 2015, a total of 114 children with isolated secundum ASD (diameter 6 mm to 24 mm, median 13.8 mm) underwent attempted transcatheter device closure under the guidance of transoesophageal echocardiography without fluoroscopy. Using a modified delivery system and procedure technique, ASD were successfully closed in 110 patients (96.5%, 52 males, 58 females, aged from three to 14 years, median 5.4 years, weight 12 to 46 kg, median 23.5 kg). Procedure time ranged from eight to 42 minutes (median 18 min). Three patients underwent percardiac device closure after failed procedures. In the early stage of our study, before delivery system and technique modification, one patient was converted to open heart surgery due to rupture of the left appendage. No intervention-related complications were detected during a median follow-up of nine months. CONCLUSIONS: Using a modified delivery system and a re-established procedure, we showed that transcatheter closure of ASD without fluoroscopy is a safe technique for alternative use in children. PMID- 27497367 TI - Carotid artery stenting with a new-generation double-mesh stent in three high volume Italian centres: clinical results of a multidisciplinary approach. AB - AIMS: Carotid artery stenting (CAS) is still associated with higher periprocedural cerebrovascular events (CEs) compared to vascular surgery. The Roadsaver carotid artery stent is a double layer micromesh stent which reduces plaque prolapse and embolisation by improving plaque coverage. Its clinical impact on neurological outcome was unknown. The aim of this study was therefore to report the clinical results of a large real-world population from three different centres receiving a Roadsaver stent to treat carotid artery disease. METHODS AND RESULTS: One hundred and fifty (150) patients (age 74+/-8 yrs, 75% male, symptomatic 29%) treated with CAS using the Roadsaver carotid stent in three high-volume Italian centres were included in the study. Intraprocedural optical coherence tomography (OCT) evaluation was performed in 26 patients, with an off-line analysis by a dedicated core laboratory. All patients underwent duplex ultrasound and neurological evaluation at 24 hours and at 30 days. CAS was technically successful in all cases (stent diameter: 8.6+/-0.8 mm, stent length: 25.0+/-4.5 mm). No in-hospital or 30-day CEs were observed. OCT evaluation detected a low rate of plaque prolapse (two patients, 7.7%). Duplex ultrasound showed stent and external carotid artery patency in all cases both before discharge and at 30-day follow-up. CONCLUSIONS: The Roadsaver stent is a safe and promising technology for CAS, with a low percentage of plaque prolapse and good short-term clinical outcome. Larger studies with longer follow-up are necessary to confirm this favourable clinical outcome. PMID- 27497369 TI - Meta-analysis: don't do what I did. PMID- 27497368 TI - Invasive aortic pulse wave velocity as a marker for arterial stiffness predicts outcome of renal sympathetic denervation. AB - AIMS: A recurrent finding of trials on renal sympathetic denervation is a certain percentage of non-responders. The aim of this study was to examine the influence of arterial stiffness to predict response. METHODS AND RESULTS: Eighty-eight patients were included in the study. Arterial stiffness was measured by invasive pulse wave velocity. Antihypertensive medication had to be unchanged during follow-up. Ambulatory blood pressure measurement (ABPM) was used to record blood pressure before and six months after denervation. Fifty-eight patients without changes in medication were included in the final analysis. Responders (n=37; blood pressure reduction -12.8+/-6.4 mmHg) had a significantly lower pulse wave velocity (14.4+/-4.4 m/s versus 17.7+/-4.5 m/s; p=0.009) compared to non responders (n=21; blood pressure reduction +3.0+/-4.5 mmHg; p<0.001 for comparison with responders). In multivariate analysis, invasive pulse wave velocity was the only significant predictor of blood pressure reduction after denervation (odds ratio 1.15, 95% confidence interval [CI] 1.014-1.327; p=0.03). Patients with increased stiffness were older (p=0.001), had a higher prevalence of diabetes (p=0.008), more often had isolated systolic hypertension (p=0.007), and had a higher invasive pulse pressure (p<0.001). CONCLUSIONS: Patients with lower pulse wave velocity showed a significantly better response to denervation. These findings emphasise that pulse wave velocity might be used as a selection criterion for renal denervation. PMID- 27497370 TI - Effects of low-level laser therapy on autogenous bone graft stabilized with a new heterologous fibrin sealant. AB - Autogenous bone grafts are used to repair bone defects, and the stabilization is needed for bone regeneration. Laser photobiomodulation is a modality of treatment in clinical practice for tissue regeneration, and it has therapeutic effects as an anti-inflammatory, analgesic and modulating cellular activity. The aim of the present study was to evaluate the effects of low-level laser therapy (LLLT) on an autogenous bone graft integration process stabilized with a new heterologous fibrin sealant. Forty rats were divided into two groups: Autogenous Fibrin Graft (AFG, n=20), in which a 5mm dome osteotomy was conducted in the right parietal bone and the graft was adhered to the left side using fibrin sealant; and Autogenous Fibrin Graft Laser (AFGL, n=20), which was subjected to the same procedures as AFG with the addition of LLLT. The treatment was performed immediately following surgery and then three times a week until euthanasia, using an 830nm laser (30mW, 6J/cm(2), 0.116cm(2), 258.6mW/cm(2), 2.9J). Five animals from each group were euthanized at 10, 20, 30 and 40days postoperative, and the samples were submitted to histomorphological and histomorphometric analysis. Partial bone regeneration occurred, with new bone tissue integrating the graft to the recipient bed and small areas of connective tissue. Comparative analysis of the groups at the same intervals revealed minor interfaces in group AFGL, with statistically significant differences (p<0.05) at all of the analyzed intervals (10days p=0.0087, 20days p=0.0012, 30days p<0.0001, 40days p=0.0142). In conclusion, low-level laser therapy stimulated bone regeneration and accelerated the process of integration of autogenous bone grafts. PMID- 27497371 TI - Network dynamics in dyslexia: Review and implications for remediation. AB - Extant neurobiological theories of dyslexia appear fractional in focusing on isolated brain regions, mechanisms, and functional pathways. A synthesis of current research shows support for an Interactive Specialization (IS) model of dyslexia involving the dysfunctional orchestration of a widely-distributed, attentionally-controlled, hierarchical, and interhemispheric circuit of intercommunicating neuronal networks. This circuitry is comprised principally of the frontostriatal-parietal cognitive control system of networks, the posterior corpus callosum, and the left arcuate fasciculus. During development, the coalescence of these functionally specialized regions, acting together, may be essential to preventing the core phonemic and phonological processing deficits defining the dyslexic phenotype. Research demonstrating an association of each with processing phonology presents the foundational outline for a comprehensive, integrative theory of dyslexia and suggests the importance of inclusive remedial efforts aimed at promoting interactions among all three networking territories. PMID- 27497372 TI - Aiding the diagnosis of AD/HD in childhood: Using actigraphy and a continuous performance test to objectively quantify symptoms. AB - The current gold standard for the diagnosis of AD/HD is based on subjective reports from teachers, parents, and clinicians. These measures can be problematic as they are open to rater biases and also fail to account for the developmental nature of symptoms. The current study examined the diagnostic accuracy of two objective measures, a computer-based Continuous Performance Task and actigraphy (e.g. motion tracking device) in differentiating children with AD/HD (N=70) from healthy controls (N=70). It was predicted that task-unrelated movement (measured via actigraphy) during a CPT and CPT performance would have high classification accuracy in differentiating children with AD/HD from healthy controls, and that the inclusion of age would increase this accuracy. Results indicated that total energy expenditure from the task-unrelated wrist and ankle movement during the CPT was higher in children with AD/HD than controls, and that CPT performance was poorer in AD/HD than controls. Discriminant function analyses revealed that the CPT Full-Scale Response Control Quotient and wrist and ankle energy expenditure provided optimal classification accuracy - correctly classifying 86% of cases, with sensitivity of 81.4% and specificity of 91.4%. The prediction that classification accuracy would increase with the inclusion of age was not supported by the data. When taken in conjunction with other clinical assessments, these findings suggest that actigraphy during a CPT and CPT performance may increase the probability of a correct AD/HD diagnosis. PMID- 27497373 TI - Mental health and positive change among Japanese mothers of children with intellectual disabilities: Roles of sense of coherence and social capital. AB - We investigated predictors of mental health and positive change among mothers of children with intellectual disabilities in Japan based on the concept of the Double ABCX model. We used variables of having a child with autism spectrum disorder (ASD) and dissatisfaction with systems as stressors, availability of social support and social capital (SC) as existing resources, sense of coherence (SOC) as appraisal of the stressor, and mental health and positive change as adaptation. A self-administered questionnaire was distributed to 10 intellectual disability-oriented special needs schools in Tokyo, and obtained 613 responses from mothers of children under age 20 attending these schools. The results showed that our Double ABCX model explained 46.0% of the variance in mothers' mental health and 38.9% of the variance in positive change. The most powerful predictor of this model was SOC, and SC may be directly and indirectly related to maternal mental health and positive change through mothers' SOC. Increasing opportunity for interaction between neighbors and family of children with disabilities may be one effective way to enhance SOC through SC. Since maternal SOC, SC, mental health, and positive change were significantly correlated with each other, synergy among these elements could be expected. PMID- 27497374 TI - Performance Equivalence and Validation of the Soleris Automated System for Quantitative Microbial Content Testing Using Pure Suspension Cultures. AB - Using United States Pharmacopeia-National Formulary (USP-NF) general method <1223> guidance, the Soleris((r)) automated system and reagents (Nonfermenting Total Viable Count for bacteria and Direct Yeast and Mold for yeast and mold) were validated, using a performance equivalence approach, as an alternative to plate counting for total microbial content analysis using five representative microbes: Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Candida albicans, and Aspergillus brasiliensis. Detection times (DTs) in the alternative automated system were linearly correlated to CFU/sample (R(2) = 0.94 0.97) with >=70% accuracy per USP General Chapter <1223> guidance. The LOD and LOQ of the automated system were statistically similar to the traditional plate count method. This system was significantly more precise than plate counting (RSD 1.2-2.9% for DT, 7.8-40.6% for plate counts), was statistically comparable to plate counting with respect to variations in analyst, vial lots, and instruments, and was robust when variations in the operating detection thresholds (dTs; +/-2 units) were used. The automated system produced accurate results, was more precise and less labor-intensive, and met or exceeded criteria for a valid alternative quantitative method, consistent with USP-NF general method <1223> guidance. PMID- 27497375 TI - Dual-energy computed tomographic imaging of pulmonary hypertension. AB - Dual-energy computed tomography (DECT) angiography of the chest provides a combined morphological and functional analysis of the lung, usually obtained in a single acquisition without extra radiation or injection of extra intravenous iodine contrast. The parenchymal iodine maps generated by DECT are well correlated with scintigraphy, and are becoming an essential tool for evaluating patients with pulmonary vascular diseases. With a single DECT acquisition, complete imaging of pulmonary hypertension is now available, displaying vascular anatomy, parenchymal morphology and functional assessment. Triangular pulmonary perfusion defects in chronic thromboembolic pulmonary hypertension may be clearly analysed even in the presence of distal arterial occlusion. Perfusion heterogeneities seen in patients with pulmonary arterial hypertension reflect mosaic perfusion and may be helpful for the diagnosis, severity assessment and prognosis of the disease. Vascular or parenchymal abnormalities can also be analysed with perfusion defects to determine their aetiology. Pulmonary arterial hypertension due to congenital heart disease can be assessed with a single DECT, even in the neonatal population. Furthermore, new applications are emerging with ventilation imaging or myocardial perfusion imaging obtained by DECT and should be considered. In conclusion, DECT of the thorax enables the simultaneous and noninvasive assessment of vascular anatomy, parenchymal morphology and functional pulmonary imaging in various groups of PH. PMID- 27497377 TI - Indian survey on practice patterns of lacrimal and eyelid disorders (iSUPPLE) report 1: Congenital nasolacrimal duct obstruction. AB - BACKGROUND: To assess the preferred practice patterns in the management of congenital nasolacrimal duct obstruction (CNLDO) among oculoplastic surgeons in India. The survey was aimed at obtaining data on the timing of intervention, procedure of choice, and the use of adjunctive techniques such as silicone intubation and nasal endoscopy. METHODS: An anonymized survey that included questions on the management of lacrimal disorders was sent in April 2015 to members of the Oculoplastic Association of India (OPAI), through an e-mail communication. The results were tabulated and analyzed. RESULTS: A large proportion (84%) of respondents indicated that they advise lacrimal sac compression up to 1 year of age. Fourteen percent (12/87) indicated 2 years as their upper age limit for advising sac compression. One year is the preferred minimum age for advising primary nasolacrimal duct (NLD) probing by majority (45%) of respondents and the upper age limit being 5 years for 62% of respondents. Based on experience, younger surgeons (<10 years experience) when compared to more experienced surgeons are more likely to offer a trial of primary probing in children between 8 and 12 years age (29% versus 8%). Nasal endoscope is used by 50% (44/88) respondents during primary NLD probing. Nearly a third of the respondents (29/88) use intubation in all cases of NLD probing. Eighty one percent (71/88) of the surgeons would rather repeat NLD probing with adjunctive procedures over dacryocystorhinostomy (17%). Balloon Dacryoplasty is rarely used for CNLDO amongst our respondents. CONCLUSIONS: This study highlights the variation in practice pattern in the management of CNLDO across India. While there are certain trends that are global phenomena, such as the shift towards the use of a nasal endoscope; use of silicone intubation in repeated procedures and time of performing primary NLD probing; issues like the use of balloon dacryoplasty showed lesser degree of agreement. PMID- 27497376 TI - Pediatric malignant salivary gland tumors: 60 year follow up. AB - OBJECTIVE: To evaluate the presentation, treatments and outcomes in pediatric patients with salivary gland malignancies. STUDY DESIGN: Retrospective chart review (1950-2012), Prospective phone interview. METHODS: Patients <=18 years old with a salivary gland malignancy treated at our institution were identified. Patients were also contacted by phone for a follow up survey. RESULTS: Fifty-six patients were identified. Tumor origin was 88% parotid (n = 49), 5% (n = 3) submandibular and 7% (n = 4) minor salivary glands. Time from onset of symptoms to diagnosis was over one year (mean = 14.4 years). Fifteen out of 52 patients with major gland malignancy had a locoregional recurrence and local recurrences were almost all after initial enucleation. Two of these patients died of disease (overall disease specific survival = 96%). Three out of 4 patients with minor gland malignancy had a local recurrence and two patients with high grade pathology developed metastases and died of their disease (overall survival = 50%). On long term follow up survey in 13 patients (25%), 100% reported normal facial movement and 54% described symptoms of Frey's syndrome, which is higher than other reported series in children. Recurrence was noted up to 45 years after initial treatment. CONCLUSIONS: The majority of malignant pediatric salivary gland tumors are low grade and have excellent survival, especially if found at an early stage. Minor salivary gland malignancies, particularly high grade, have a worse prognosis. Long term mild Frey's syndrome can be expected in approximately half of patients. We advocate a need for long term follow up and increased awareness among providers to diagnose these patients earlier. PMID- 27497378 TI - Management of posterior ankyloglossia and upper lip ties in a tertiary otolaryngology outpatient clinic. AB - OBJECTIVES: Recent studies have shown an association between ankyloglossia (tongue tie) and upper-lip ties to breastfeeding difficulties. Treatment is commonly multidisciplinary involving lactation consultants and surgical management with tongue tie and upper lip tie release. There is currently limited data looking at posterior ankyloglossia and upper lip ties. METHODS: Consecutive patients seen at an ENT outpatient clinic for ankyloglossia and upper-lip ties from May 2014-August 2015 were assessed for an outpatient frenotomy. Breastfeeding outcomes were assessed following the procedure. RESULTS: 43 babies were seen and 34 patients had a procedure carried out. Babies ranged from 2 to 20 weeks old with the median age being 6.6 weeks. The most common presenting complaint was latching issues (85%) with mothers' painful nipples being the second (65%). 21 patients (62%) had a tongue tie release, 10 (29%) had both a tongue tie and upper lip tie divided, whereas 3 (9%) had an upper-lip tie alone divided. 29 (85%) of the patients who had a procedure carried out had an immediate improvement in breastfeeding, while 28 (82%) had a continued improvement at 2 weeks follow up. CONCLUSIONS: Frenotomy for posterior ankyloglossia and upper lip ties is a simple procedure that can be carried out in an outpatient setting with apparent immediate benefit. Otolaryngologists are likely to have an increasing role to play in the evaluation and management of ankyloglossia and upper lip ties in babies with breastfeeding difficulties. PMID- 27497379 TI - Individual-level effects of antibiotics on colonizing otitis pathogens in the nasopharynx. AB - BACKGROUND: Although there is evidence of an association between antibiotic consumption and resistant bacteria on a population level, the relationship on an individual level has been less well studied, particularly in terms of nasopharyngeal colonization. We have therefore analysed this association, using data from a closely followed cohort of children taking part in a vaccination trial. METHODS: 109 children with early onset of acute otitis media (AOM) were randomised to heptavalent pneumococcal conjugate vaccine (PCV7) or no vaccination. They were followed for three years with scheduled appointments as well as sick visits. Nasopharyngeal cultures were obtained at all visits. Antibiotic treatments were recorded, as were risk factors for AOM, including siblings, short breast-feeding and parental smoking. Data were entered into a Cox regression model, and the findings of Streptococcus pneumoniae and Haemophilus influenzae with reduced susceptibility to the penicillin group were related to the number of previous courses of antibiotics. RESULTS: There was evidence of an association between the amount of previously consumed betalactams and colonization with beta-lactamasenegative ampicillin-resistant (BLNAR) H. influenzae (RR 1.21; 95% CI 1.03-1.43; p = 0.03), and also with the most commonly prescribed drug; amoxicillin (RR 1.39; 95% CI 1.09-1.76; p = 0.01). There was no evidence for an association between antibiotic consumption and betalactamase producing H. influenzae or S. pneumoniae with reduced susceptibility to penicillin. Furthermore, there was no evidence of an association between resistant bacteria and AOM risk factors or PCV7. CONCLUSION: In this subgroup of children, most of whom were given several courses of antibiotics in early childhood, there was evidence of an association between betalactam/amoxicillin consumption and nasopharyngeal colonization with BLNAR strains, bacteria that have increased in prevalence during the last 10-15 years, and that are notoriously difficult to treat with oral antibiotics. PMID- 27497380 TI - Radiologically-guided balloon sialoplasty for treatment of salivary duct stricture: A novel technique in young children. AB - OBJECTIVES: To describe our experience using radiologically-guided balloon sialoplasty to successfully treat sialadenitis in two children as a single modality intervention. METHODS: A retrospective case series. RESULTS: Both children were successfully treated using balloon sialoplasty with complete and lasting resolution of their symptoms. CONCLUSION: Paediatric sialadenitis secondary to salivary strictures are traditionally managed surgically. We believe that this is the first article to describe this intervention in such a series of children and that balloon sialoplasty is a safe technique and can be repeated as necessary, which should be considered as a management option in such paediatric cases. PMID- 27497381 TI - Follow-up care after grommet insertion in children: Review article. AB - BACKGROUND: Grommet insertion is a common procedure in children. A lengthy otolaryngology follow-up can have an adverse impact on clinic waiting times, new patient appointment availability, and pecuniary disadvantage for the hospital. OBJECTIVE OF REVIEW: To consolidate research and opinion concerning follow-up care following grommet insertion in a pediatric population. SEARCH STRATEGY: The literature between January 1990 and September 2015 was searched on MEDLINE (Ovid), Google Scholar, PubMed and Web of Science databases. RESULTS: Guidelines and consensus of opinion from the United States advocate that an initial post operative review should take place within 4 weeks, and subsequent appointments every 6 months until grommet extrusion. Recent audit reports from the United Kingdom have shown that some groups arrange their first post-operative review at 3 months, and subsequent appointments vary considerably from no further follow-up to up to 24 months. Up to 75% of follow-up appointments were scheduled despite normal audiometry and clinical findings after grommet insertion, suggesting a large cohort of patients may undergo unnecessary specialist clinic reviews. General practioners (GP), audiologists or specialist nurses are potential alternative providers of regular reviews to ensure normal hearing thresholds and an adequate tympanic membrane healing course. CONCLUSION: Follow-up schedules are largely driven by consensus of opinion. A significant number of follow-up appointments in otolaryngology clinic appear to be redundant. Recently attention has been drawn to earlier discharge from otolaryngology clinic with subsequent follow-up in less resource and cost intensive clinics coordinated by GPs, audiologist or nurses, which may help alleviate some outpatient workload on acute hospital trusts. PMID- 27497382 TI - Preliminary results of video Head Impulse Testing (vHIT) in children with cochlear implants. AB - OBJECTIVE: To evaluate the lateral semicircular canal high frequency vestibulo oculomotor reflex (LSC HF VOR) in children with cochlear implant. METHODS: 16 children (10 females and 6 males, age range = 5-17 years) receiving a unilateral (n = 12) or a bilateral (n = 4) cochlear implant were included and compared to a control group of 20 age-matched normal-hearing (NH) children. Both implanted and NH children received a vestibular function test battery, including a Vestibulo Ocular Reflex (VOR) gain assessment by means of a video-Head Impulse Test (vHIT), which represented the main outcome measure. In implanted subjects, vHIT was measured on both sides in the "CI-ON" and "CI-OFF" conditions. RESULTS: Overall, no significant LSC HF VOR gain difference was found between CI users and NH peers. In the unilaterally implanted group, the LSC HF VOR gain measured in the "CI-ON" condition was significantly higher than in the "CI-OFF" condition, both in the implanted and in the non-implanted ear. In the bilaterally implanted group there was no such a difference between the two conditions, on either side. CONCLUSION: This is the first study investigating the LSC HF VOR gain in children with unilateral and bilateral CI. The study demonstrates that the LSC HF VOR of bilaterally implanted children is comparable to normal hearing children. PMID- 27497383 TI - Speech outcomes in children with 22q11.2 deletion syndrome following surgery for velopharyngeal insufficiency. AB - OBJECTIVE: The purpose of this study was to identify prognostic factors associated with improved speech outcomes following surgical correction for velopharyngeal insufficiency (VPI) in pediatric patients with 22q11.2 deletion syndrome (22q11DS). METHODS: Eighteen patients were identified via retrospective chart review of patients with 22q11DS between 2005 and 2014. Patient characteristics, medical histories, associated comorbidities, surgical procedures, and pre- and postoperative perceptual hypernasality (subjectively rated 1-5 with 5 being the most severe) were gathered for each patient. RESULTS: 12 patients (67%) experienced improvement in hypernasality following corrective surgery for VPI. Higher severity of hypernasality preoperatively was found to be indicative of a lower chance of improvement with VPI surgery. Of 8 patients with a preoperative hypernasality score of 5, 3 (38%) showed improvement in hypernasality postoperatively, while 9 out of 10 (90%) of patients with a preoperative hypernasality score less than 5 showed postoperative improvement. Females were also found to have worse speech outcomes compared to males. CONCLUSION: 22q11DS patients presenting with severely hypernasal speech preoperatively are less likely to show improvement in hypernasality following corrective surgery for VPI. Those patients with moderate hypernasality are most likely to benefit from surgery. PMID- 27497384 TI - Pediatric head and neck injuries due to golf cart trauma. AB - INTRODUCTION: Golf carts are increasingly used off the golf course and are often viewed as innocuous modes of transportation. However, research has shown they can cause significant injuries, particularly to children. OBJECTIVES: Analyze golf cart related head and neck injuries in children and adults from a national database. METHODS: The National Electronic Injury Surveillance System (NEISS) was queried for golf cart injuries. The NEISS tracks consumer product related injuries from a sampling of approximately 100 emergency departments across the United States. Age, general diagnosis (concussion, fracture, laceration), body part injured, disposition (hospitalized, discharged), location injury occurred, and mechanism of injury were analyzed. RESULTS: Over an 11-year period, a total of 3433 total patients were identified. There were 1471 children (16 years old or younger), which compromised 42.9% of the cohort. Children were injured at home or on the road 44.7% of the time compared to only 16.6% of adults (p < 0.003). Children injured their head or neck 42.6% of the time compared to 28.6% of adults (p < 0.0001). Adults who were hit by a car while riding a golf cart or were ejected from the golf cart 44.6% of the time compared to 61.7% of children (p < 0.0001). There were 3.9% of children with a face, head, or neck fracture compared to only 2.4% of adults (p = 0.01). CONCLUSION: Children are more vulnerable to golf cart related injuries, specifically to the head and neck. PMID- 27497385 TI - Quality improvement utilizing in-situ simulation for a dual-hospital pediatric code response team. AB - OBJECTIVE: Given the rarity of in-hospital pediatric emergency events, identification of gaps and inefficiencies in the code response can be difficult. In-situ, simulation-based medical education programs can identify unrecognized systems-based challenges. We hypothesized that developing an in-situ, simulation based pediatric emergency response program would identify latent inefficiencies in a complex, dual-hospital pediatric code response system and allow rapid intervention testing to improve performance before implementation at an institutional level. METHODS: Pediatric leadership from two hospitals with a shared pediatric code response team employed the Institute for Healthcare Improvement's (IHI) Breakthrough Model for Collaborative Improvement to design a program consisting of Plan-Do-Study-Act cycles occurring in a simulated environment. The objectives of the program were to 1) identify inefficiencies in our pediatric code response; 2) correlate to current workflow; 3) employ an iterative process to test quality improvement interventions in a safe environment; and 4) measure performance before actual implementation at the institutional level. RESULTS: Twelve dual-hospital, in-situ, simulated, pediatric emergencies occurred over one year. The initial simulated event allowed identification of inefficiencies including delayed provider response, delayed initiation of cardiopulmonary resuscitation (CPR), and delayed vascular access. These gaps were linked to process issues including unreliable code pager activation, slow elevator response, and lack of responder familiarity with layout and contents of code cart. From first to last simulation with multiple simulated process improvements, code response time for secondary providers coming from the second hospital decreased from 29 to 7 min, time to CPR initiation decreased from 90 to 15 s, and vascular access obtainment decreased from 15 to 3 min. Some of these simulated process improvements were adopted into the institutional response while others continue to be trended over time for evidence that observed changes represent a true new state of control. CONCLUSIONS: Utilizing the IHI's Breakthrough Model, we developed a simulation-based program to 1) successfully identify gaps and inefficiencies in a complex, dual-hospital, pediatric code response system and 2) provide an environment in which to safely test quality improvement interventions before institutional dissemination. PMID- 27497387 TI - The effect of Nigella sativa oil on prevention of myringosclerosis in a Guinea pig model. AB - OBJECTIVES: In this study, our aim was to identify the possible effects of Nigella sativa L. (NS) [blackcumin] seed oil on the prevention of experimentally induced myringosclerosis (MS). MATERIALS AND METHODS: Fourteen Guinea pigs were used and they were divided into three groups. Tympanic membranes (TM) of all animals were perforated and then group I was treated with saline soaked gel foams as a control group, group II was treated with 0.5 ml NS oil soaked gel foams at 0, 24 and 48 h and group III was treated with 5 ml NS oil orally at 0, 24, 48, 72 and 120 h. After 15 days, all animals were euthanized. Tympanic membranes were evaluated macroscopically and histopathologically. RESULTS: Groups I showed extensive myringosclerosis in contrast to those of Groups II and III which had significantly less changes (p < 0.05). The fibrosis and inflammation in the lamina propria of the tympanic membranes of Groups I was found to be significantly more pronounced (p < 0.05). The tympanic membranes were found to be significantly thinner in Groups II and III when compared with Groups I (p < 0.05). CONCLUSIONS: The results of this study suggested that topical or oral administration of NS oil supressed the inflammation and fibroblastic activity in the lamina propria of the myringotomized TMs of the Guinea pigs. For providing further evidence to use plant extracts as antioxidant and antiinflammatory therapy after myringotomy or ventilation tube insertion, further clinical studies with larger population will be essential. PMID- 27497386 TI - An objective assessment of halitosis in children with adenoid vegetation during pre- and post-operative period. AB - OBJECTIVES: Although most specialists in otorhinolaryngology and pediatrics find halitosis to be a common problem in children with adenoid hypertrophy, there are no objective data on this topic in the literature. Whether adenoid hypertrophy is a risk factor for halitosis or whether halitosis is a sign of adenoid hypertrophy remains unclear. Thus, the aim of this study was to investigate whether children diagnosed with adenoid hypertrophy have a higher probability of halitosis than do children in the normal population and whether adenoidectomy can decrease oral malodor. METHODS: Forty children with adenoid hypertrophy and 40 healthy subjects aged 5-15 years were included in the study. The children with adenoid hypertrophy underwent adenoidectomy operations and were followed for 3 months. We measured volatile sulfur compounds (VSCs), hydrogen sulfide (H2S), methyl mercaptan (CH3SH), and dimethyl sulfide (CH3)2S using an objective method, a portable gas chromatograph (OralChroma; AbiMedical, Osaka, Japan). RESULTS: The mean CH3SH and (CH3)2S levels were significantly different (p < 0.05) between the adenoid hypertrophy group and the controls. The H2S, CH3SH, and (CH3)2S levels in the third postoperative month were significantly lower (p < 0.05) than those in the preoperative period, and there was no significant difference postoperatively between the patients with adenoid hypertrophy and controls. There was a positive correlation between age and VSC levels, and CH3SH levels were significantly higher in patients with ventilation tube insertion, rather than just adenoidectomy. CONCLUSIONS: There was a statistically significant association between halitosis and adenoid hypertrophy, and a significant improvement in halitosis was obtained following adenoidectomy. The present study provides an association between halitosis and adenoid hypertrophy. If there is no other oral pathology causing halitosis, halitosis can be a sign of adenoid hypertrophy in children. PMID- 27497388 TI - A study of cell proliferation using immunohistological staining: A case report of congenital granular cell epulis. AB - An unusual case of a 1-day-old Chinese female neonate with a solid tumor mass in the maxillary anterior ridge of the edentulous jaw is reported. Based on the clinical and histopathological features, the diagnosis was of obstructive congenital granular cell epulis (CGCE) which is an uncommon benign tumor that preferentially develops in female infants. Immunohistochemical analysis of the lesion was performed and the rate of cell proliferation was determined by immunostaining with Ki-67 and PCNA, which showed labeling indexes of 11.1% and 33.3%, respectively. No recurrence was observed in the follow-up. PMID- 27497389 TI - Management of unilateral hearing loss. AB - OBJECTIVE: A representative sample of literature regarding unilateral hearing loss (UHL) was reviewed to provide evidence of the effects of UHL and the intervention options available for children with UHL. Considerations during the assessment and management of children with UHL are illustrated using case illustrations. METHOD: Research articles published from 2013 to 2015 were searched in the PubMed database using the keywords "unilateral hearing loss". Articles from 1950 to 2013 were included from a previous literature review on minimal hearing loss [1]. A retrospective review of charts of 14 children with UHL was also conducted. RESULTS: The evidence indicates that children with UHL are more likely to have structural anomalies of the inner ear; may face challenges in six different domains, and have six intervention options available. Evidence also indicates that although some children appear to exhibit no delays or difficulties, others have significant challenges, some of which continue into adulthood. CONCLUSIONS: Children with UHL have to be treated on a case-by-case basis. Parent education regarding UHL, its effects, and all available management options is critical so they can make informed decisions. Close monitoring and good communication between professionals in different domains is crucial in order to minimize the potential negative effects of UHL. PMID- 27497390 TI - Morphological changes in the round window membrane associated with Haemophilus influenzae-induced acute otitis media in the chinchilla. AB - OBJECTIVE: The round window membrane (RWM) encloses the round window, the opening into the scala tympani (ST) from the middle ear. During the course of acute otitis media (AOM), structural changes of the RWM can occur that potentially affect sound transmission into and out of the cochlea. The relationship between such structural changes and conductive hearing loss during AOM has remained unclear. The focus of the current study was to compare the thickness distribution across the RWM surface between normal ears and those with AOM in the chinchilla. We assessed the occurrence of AOM-associated histological changes in this membrane compared to uninfected control animals after AOM of two relatively short durations. MATERIAL AND METHODS: AOM was induced by transbullar injection of the nontypeable Haemophilus influenzae strain 86-028NP into two groups of adult chinchillas (n = 3 each). Bullae were obtained from the two infected groups, at 4 days or 8 days post challenge. Structures and thickness of these RWMs were compared between the two infected treatment groups and to RWMs from uninfected control animals (n = 3) at seven different RWM locations. RESULTS: RWM thickness in infected chinchillas increased significantly at locations along the central line on the 4th day post bacterial challenge compared to values found for uninfected control animals. Lymphocyte infiltration and edema were the primary contributors to these thickness increases. No significant further increases in RWM thickness were observed when RWMs from chinchillas ears infected for 4 and 8 days were compared. Thickness and structural changes at the RWM lateral and medial areas were less visually obvious and not statistically significant among the three treatment groups. These latter RWM regions clearly were less affected during AOM than the central areas. CONCLUSIONS: This histological study establishes that H. influenzae-induced AOM causes significant acute changes in chinchilla RWM structure that are characterized by region-specific increases in thickness. Our new morphological findings comparing normal and diseased chinchilla RWMs identify yet another biomechanical mechanism by which nontypeable H. influenzae may contribute to hearing loss in AOM. PMID- 27497391 TI - Should obtaining a preoperative audiogram before tympanostomy tube placement be used as a quality metric? A survey of pediatric otolaryngologists. AB - INTRODUCTION: Obtaining a preoperative audiogram prior to tympanostomy tube placement is recommended by the American Academy of Otolaryngology-Head and Neck Surgery clinical practice guideline (CPG): Tympanostomy tubes in Children, and this process measure is also used as a quality metric by payers. However, whether audiograms should be mandated in cases of tube placement for both chronic otitis media with effusion (COME) and recurrent acute otitis media (RAOM) is controversial. The objective of this study is to determine reports of practice patterns of pediatric otolaryngologists regarding obtaining audiograms before and after tympanostomy tube placement and opinions regarding utility of CPGs and use of this process measure as a quality metric. METHODS: A 16-question cross sectional survey of American Society of Pediatric Otolaryngology (ASPO) members was conducted. Per ASPO policy, no repeated requests or other enhanced response techniques were permitted. Independent t-tests for proportions were used to compare responses. RESULTS: 127 pediatric otolaryngologists completed the survey (response rate 26.9%). Nearly 70% of respondents reported being in practice for >10 years. 74% of respondents reported obtaining preoperative audiograms "always" or "most of the time" for COME, vs. 56.7% for RAOM (p < 0.0001). 76% agreed that obtaining a preoperative audiogram was representative of high quality for COME, vs. 52% for RAOM (p < 0.0001). 12% of respondents "completely agreed" that compliance with all aspects of CPGs represented high quality, while 68.8% responded that they somewhat agreed. CONCLUSION: There is no consensus among pediatric otolaryngologists regarding the necessity of a preoperative audiogram in tympanostomy tube placement, especially for RAOM. Further evidence demonstrating the benefit of preoperative audiogram obtainment should be developed prior to inclusion as a guideline recommendation and as a quality metric. PMID- 27497392 TI - Paroxysmal vertigo with nystagmus in children. AB - INTRODUCTION: A pathological nystagmus is an objective sign that a patient feels vertigo. However, there have been few opportunities to observe and record pathological nystagmus during a paroxysmal vertigo attack. Furthermore, it can be difficult to obtain cooperation in pediatric patients. We present two cases of paroxysmal vertigo in children in whom we successfully recorded and analyzed their pathological nystagmus during a vertigo attack. METHODS: Of a total sample of 4349 patients seen at our hospital for dizziness in the last decade, a retrospective analysis revealed that 68 were children (<15 years old; 1.6%). Of these 68 children, we successfully identified pathological nystagmus during paroxysmal vertigo in only two (2.9%). RESULTS: Case 1 was a 4-year-old girl. She felt vertigo the strongest when her left ear was down in the supine position. We observed and recorded her nystagmus during a vertigo attack with her mother's permission. Her positional nystagmus in the supine position was horizontal persistent apogeotropic nystagmus. Rightward nystagmus in the left-ear-down supine position was stronger than leftward nystagmus in the right-ear-down supine position. Therefore, the diagnosis was right lateral canal type of benign paroxysmal positional vertigo, of which the pathophysiology was cupulolithiasis. The other patient was an 11-year-old boy. He had a family history of migraines. His vertigo attacks occurred after onset of a severe migraine and lasted between 2 and 48 h. During an attack that we observed, he showed nystagmus, which was direction-fixed right torsional and rightward in darkness. His mother had noticed that his eyes moved abnormally and that his left eye did not shift to the left side when he looked leftward. He was old enough to clearly express his own symptoms. Other neurological examinations were normal. The diagnosis was vestibular migraine. CONCLUSIONS: We analyzed a pathological nystagmus during paroxysmal vertigo in two children. We conclude that children can be diagnosed with a combination of careful history taking and accurate examinations of a pathological nystagmus. PMID- 27497393 TI - Factors contributing to hearing impairment in patients with cleft lip/palate in Malaysia: A prospective study of 346 ears. AB - OBJECTIVE: To determine the factors contributing towards hearing impairment in patients with cleft lip/palate. METHOD: A prospective analysis was conducted on 173 patients (346 ears) with cleft lip and palate (CL/P) who presented to the combined cleft clinic at University Malaya Medical Centre (UMMC) over 12 months. The patients' hearing status was determined using otoacoustic emission (OAE), pure tone audiometry (PTA) and auditory brainstem response (ABR). These results were analysed against several parameters, which included age, gender, race, types of cleft pathology, impact and timing of repair surgery. RESULTS: The patients' age ranged from 1-26 years old. They comprised 30% with unilateral cleft lip and palate (UCLP), 28% with bilateral cleft lip and palate (BCLP), 28% with isolated cleft palate (ICP) and 14% with isolated cleft lip (ICL). Majority of the patients (68.2%) had normal otoscopic findings. Out of the 346 ears, 241 ears (70%) ears had passed the hearing tests. There was no significant relationship between patients' gender and ethnicity with their hearing status. The types of cleft pathology significantly influenced the outcome of PTA and ABR screening results (p < 0.001). There was no significant difference between the repaired and unrepaired cleft groups and the outcome of hearing tests. However, hearing improvement occurred when palatal repair was performed at the age of <1year old (OR = 2.37, CI 1.2 = 4.6, p = 0.01). CONCLUSION: Majority of the cleft patients had normal hearing (70%). Hearing threshold varied significantly between the different types of cleft pathology. Surgery conferred no significant impact on the hearing outcome unless surgery was performed at the age of <1 year old. PMID- 27497394 TI - Do race/ethnicity or socioeconomic status affect why we place ear tubes in children? AB - INTRODUCTION: Despite recent concerns about potential overuse of tympanostomy tube (TT) placement to treat otitis media in children, utilization of this common procedure in the U.S. has been shown to be relatively less common among minority children. It is not known if the indications for TT differ by child race/ethnicity and/or socioeconomic status (SES). Our objective is to analyze the association of patient- and neighborhood-level demographics and SES with clinical indications for TT. METHODS: We conducted a retrospective chart review of children who underwent TT at single urban academic tertiary pediatric care center in a 6-month period (8/2013-3/2014). Children with congenital anomalies or syndromic diagnoses were excluded (50/137 children, 36.5%). Children were grouped by primary TT indication, recurrent acute otitis media (RAOM) or chronic otitis media with effusion (OME). Group characteristics were compared using t-tests and chi-square analyses, and logistic regression was performed to assess the association between demographics and TT indication. RESULTS: 87 children were included in this analysis (mean age = 2.8 years, 1-6 years). The most common indication for TT was RAOM (53%), and these children had a mean of 6 AOM episodes/year. Indications for TT varied significantly by the patient's neighborhood SES (median neighborhood income $70,969.09-RAOM vs $58, 844.95-OME, p-value = 0.009). Those undergoing TT for RAOM were less likely to live in a high poverty neighborhood (OR = 0.36,p-value = 0.02), whereas children who underwent TT for OME were more likely to live in a high-poverty neighborhood. There was no significant difference in indication by race/ethnicity or insurance type. CONCLUSIONS: In this population, TT indications differed by SES. Among children receiving tubes, those from high poverty areas were more likely than those from low poverty neighborhoods to receive tubes for the indication of OME as opposed to RAOM. This finding suggests that concerns for appropriate use of TT in the setting of RAOM may be specific to a more affluent population. Future prospective patient-centered research will evaluate cultural and economic influences for families pursuing TT placement, as well as factors considered by physicians who make surgical recommendations. PMID- 27497396 TI - The feasibility of pediatric TORS for lingual thyroglossal duct cyst. AB - A six-year-old boy who presented with symptoms of obstructive sleep apnea was found to have a midline tongue mass suspicious for lingual thyroglossal duct cyst (TGDC). Surgery was scheduled after workup confirmed the presence of functional, orthotopic thyroid tissue. The surgical robot was used to excise the mass endoscopically without removing any hyoid. He was extubated at the conclusion of the case. The child tolerated a soft diet and was discharged after an uneventful overnight stay in the ICU. Pathology confirmed TGDC. There have been no reported issues in eleven months of follow-up. Our report adds to the scarce literature on performing such a surgery in a child and demonstrates that with the correct circumstances, prompt extubation, discharge, and prolonged remission are possible. PMID- 27497395 TI - Association of microRNA 146 with middle ear hyperplasia in pediatric otitis media. AB - OBJECTIVE: Toll-like receptor signaling activated by bacterial otitis media pathogens in the middle ear has been shown to play a key role in OM susceptibility, pathogenesis and recovery. Recent studies implicate microRNA 146 (miR-146) in regulation of inflammation via negative feedback of toll-like receptor signaling (TLR) in a wide variety of tissues, however its involvement in otitis media is unknown. METHODS: Human middle ear epithelial cells were stimulated with proinflammatory cytokines, interleukin 1 beta or tumor necrosis factor alpha, for two to twenty-four hours. Middle ear biopsies were collected from children with otitis media with effusion (n = 20), recurrent otitis media (n = 9), and control subjects undergoing cochlear implantation (n = 10). miR-146a, miR-146b expression was assayed by quantitative PCR (qPCR). Expression of miR-146 targets involved in TLR signaling, IRAK1 and TRAF6, was assayed by qPCR in middle ear biopsies. Middle ear biopsies were cryosectioned and epithelial thickness measured by a certified pathologist. RESULTS: Proinflammatory cytokines induced expression of miR-146 in middle ear epithelial cells in vitro. Middle ear miR 146a and miR-146b expression was elevated in otitis media patients relative to control subjects and correlated with middle ear epithelial thickness. A trend towards inverse correlation was observed between miR-146 and TRAF6 expression in the clinical population. CONCLUSIONS: This report is the first to assess miRNA expression in a clinical population with OM. Findings herein suggest miR-146 may play a role in OM. PMID- 27497397 TI - Development and validation of a short version of the Spanish pediatric voice handicap index (P-VHI-10). AB - OBJECTIVES: A child's voice is used both as a tool for communication and as a form of emotional expression. Thus, voice disorders suffered by children have negative effects on their quality of life, which can be assessed using the "Pediatric Voice Handicap Index" (P-VHI). This questionnaire is completed by the parents of dysphonic patients and it has been validated in different languages: Italian, Korean, Arabic, and Spanish. More recently, the "Children Voice Handicap Index-10" test (C-VHI-10) was developed and validated, an Italian version reduced into 10 items that is answered by children themselves. The objective of this study was to develop and validate a short Spanish version of the P-VHI (P-VHI-10) and to assess whether it is comparable to the Italian C-VHI-10. MATERIALS AND METHODS: We conducted a cross-sectional study on 27 patients between 6-15 years of age. We developed an abbreviated version of the P-VHI that consisted of 10 statements to be answered by parents of children with dysphonia (P-VHI-10). These statements were based on the 10 items with the highest score in the validated Spanish version of the P-VHI. In addition, the validated Italian version of C-VHI 10 was translated into Spanish and this translation was reviewed and modified by three specialists, resulting in an adapted version to be answered by parents (C* VHI-10). The parents and children included in the study of this index were the same patients as those included in the study to validate the Spanish P-VHI. RESULTS: There were no significant differences in the results obtained with the extended version of the P-VHI (17.4) and with the P-VHI-10 (18.7: Pearson coefficient = 0.602, p < 0.36). A paired student's t-test identified significant differences (p < 0.0001) when comparing the P-VHI-10 and C*-VHI-10, both of which were answered by parents, with average scores of 18.7 and 9.48, respectively. Both these reduced versions have good internal consistency, with a satisfactory Cronbach's alpha coefficient (alpha = 0.75 to P-VHI-10 and alpha = 0.73 in C*-VHI 10). No statistically significant differences were found when the average total score between the C-VHI-10 and C*-VHI-10 were compared, with a Pearson's correlation coefficient of 0.559 (p < 0.9). CONCLUSION: The short version of the P-VHI10 questionnaire is a clinically valid tool that has good internal consistency. PMID- 27497398 TI - Chinese children with nonsyndromic cleft lip/palate: Factors associated with hearing disorder. AB - OBJECTIVES: This study examined the auditory status of Chinese children with nonsyndromic cleft lip/palate (NSCL/P), investigated factors associated with peripheral hearing loss and compared results with earlier studies in western countries. METHODS: Case history profiles and audiological data from 148 Chinese children with NSCL/P, aged between 6 and 15 years, who attended the Cleft Lip and Palate Clinic Center in a major Chinese urban hospital from July 2012 to September 2013 were acquired. The audiological status of the participants was reviewed, based on the results of their pure tone audiometry, tympanometry and acoustic reflex thresholds assessments. Factors including age, gender, cleft type, residential locality and school achievement were examined in relation to auditory status. RESULTS: Findings revealed that 17% of the Chinese children with NSCL/P had hearing impairment at the time of assessment. Unilateral hearing loss was noted in 12% of children and in 5% of cases bilateral hearing loss was noted. In the majority of cases the hearing loss was slight and conductive in nature. Age, gender, residential locality and school achievement were found to have no relationship with severity of hearing loss. Children with cleft lip showed a lower degree of hearing impairment than children with cleft palate or cleft lip and palate. CONCLUSION: Similar to studies for western children, Chinese children with CL/P associated with no known syndrome are at risk of peripheral hearing loss, generally of conductive type. However, the prevalence of peripheral hearing loss appears to be less than in western children with NSCL/P. Ethnic/racial factors may be a major contributing factor accounting for the discrepancies between the current results and western studies. PMID- 27497399 TI - Chiari malformations: An important cause of pediatric aspiration. AB - Chronic aspiration poses a major health risk to the pediatric population. We describe four cases in which work up for chronic aspiration with a brain MRI revealed a Chiari I malformation, a poorly described etiology of pediatric aspiration. All patients had at least one non-specific neurologic symptom but had swallow studies more characteristic of an anatomic than a neurologic etiology. Patients were referred to neurosurgery and underwent posterior fossa decompression with symptom improvement. A high index of suspicion for Chiari malformation should be maintained when the standard work up for aspiration is non diagnostic, particularly when non-specific neurologic symptoms are present. PMID- 27497400 TI - To anticoagulate? Controversy in the management of thrombotic complications of head & neck infections. AB - OBJECTIVE: To review the thrombotic complications of head and neck infections, including Lemierre's syndrome, and their management. METHODS: A retrospective review of pediatric patients presenting to McMaster Children's Hospital from 2009 to 2013 was undertaken. The literature was reviewed for evidence regarding the use of anticoagulation therapy in this population. RESULTS: Eleven cases (6 males, 5 females) were identified. The median age was 10.9 (range 14 months-17 years). The most frequent head and neck infection causing a thrombotic complication was mastoiditis (n = 6). All had thrombi identified on imaging, with the most common location being the sigmoid sinus (n = 6) followed by the internal jugular vein (n = 5). All 11 patients were anti-coagulated with low molecular weight heparin (LMWH) within a median of 2 days of diagnosis (average duration 105.8 days). Ten patients (90.9%) had thrombus improvement or resolution within a median of 3.4 months (range 1.0-13.9). Adverse sequelae from the thrombi were MCA infarct (n = 1), septic pulmonary emboli (n = 4), cranial nerve palsies (n = 3) and Horner's syndrome (n = 2). There were no adverse effects from anti coagulation therapy. Review of the literature revealed anticoagulant use in 63.7% of pediatric cases reported since 2002. CONCLUSION: Anticoagulation remains controversial in the management of thrombotic complications from head and neck infections. Based on this case series, certain recommendations can be made regarding the benefits of anticoagulation, which appear to outweigh the risks. Further research is required to establish evidence for consensus in the antithrombotic management of thrombotic sequelae of head and neck infections. PMID- 27497401 TI - Evaluation on health-related quality of life in deaf children with cochlear implant in China. AB - OBJECTIVE: Previous studies have shown that deaf children benefit considerably from cochlear implants. These improvements are found in areas such as speech perception, speech production, and audiology-verbal performance. Despite the increasing prevalence of cochlear implants in China, few studies have reported on health-related quality of life in children with cochlear implants. The main objective of this study was to explore health-related quality of life on children with cochlear implants in South-west China. STUDY DESIGN: A retrospective observational study of 213 CI users in Southwest China between 2010 and 2013. METHODS: Participants were 213 individuals with bilateral severe-to-profound hearing loss who wore unilateral cochlear implants. The Nijmegen Cochlear Implant Questionnaire and Health Utility Index Mark III were used pre-implantation and 1 year post-implantation. Additionally, 1-year postoperative scores for Mandarin speech perception were compared with preoperative scores. RESULTS: Health-related quality of life improved post-operation with scores on the Nijmegen Cochlear Implant Questionnaire improving significantly in all subdomains, and the Health Utility Index 3 showing a significant improvement in the utility score and the subdomains of ''hearing," ''speech," and "emotion". Additionally, a significant improvement in speech recognition scores was found. No significant correlation was found between increased in quality of life and speech perception scores. CONCLUSION: Health-related quality of life and speech recognition in prelingual deaf children significantly improved post-operation. The lack of correlation between quality of life and speech perception suggests that when evaluating performance post-implantation in prelingual deaf children and adolescents, measures of both speech perception and quality of life should be used. PMID- 27497402 TI - Botulinum toxin injections for chronic sialorrhoea in children are effective regardless of the degree of neurological dysfunction: A single tertiary institution experience. AB - OBJECTIVE: To determine the effectiveness of submandibular salivary gland Botulinum Toxin Type-A (BTX-A) injection in the treatment of drooling in children with varying degrees of neurological dysfunction. METHODS: A retrospective review of pre- and post-procedure drooling frequency and severity scores of patients receiving BTX-A between January 2008 and January 2013. Stratification to different subgroups of neurological impairment was performed according to Gross Motor Function Classification System (GMFCS) score. Drooling severity was assessed using Thomas-Stonell and Greenberg symptom questionnaires administered at time of initial consultation and 3 months after treatment. RESULTS: 48 sets of BTX-A injections in 26 patients with an average age of 9.45 years (range 7 months 18 years) were included in the study. Marked improvement in drooling was seen in 60.4% of patients, a marginal or brief improvement was seen in 20.8% and there was no improvement in 18.8%. No adverse events were reported following any of the BTX-A injections. BTX-A was safe and effective in the eight patients with pre existing swallowing dysfunction. Subsequent drooling surgery was performed in 15 (57.7%) of the cohort, all 15 patients responded to BTX-A injections. In patients with Cerebral Palsy, there was no correlation between the severity of the neurological dysfunction as measured by the Gross Motor Function Classification System (GMFCS) score and the response to BTX-A treatment. CONCLUSIONS: Injection of BTX-A to the submandibular glands of children with neurological disorders is a safe procedure and results in a reduction in drooling in the majority of patients. Children with severe neurological dysfunction respond to BTX-A injections as effectively as their less impaired peers and the degree of response does not appear to be associated with the severity of neurological disability. BTX-A injection is a good initial procedure when drooling surgery is being considered. PMID- 27497403 TI - Role of group 3 innate lymphoid cells during experimental otitis media in a rat model. AB - The objective of this study was to evaluate the role of group 3 innate lymphoid cells (ILC3) in the middle ear (ME) mucosal response to bacterial infection in a rat model. To confirm the role of ILC3 in bacterially induced otitis media (OM), the serum concentrations of IL-17 and IL-22 were determined by ELISA, and the tissue expression of IL-17 and IL-22 in infected ME mucosa was assessed by immunohistochemical staining. Immunohistochemical staining of specific cell surface markers was also assessed to confirm the origin of the cells expressing IL-17 and IL-22. Twenty Sprague-Dawley rats were used in the surgically-induced animal model of OM. OM was induced by inoculation of non-typeable Haemophilus influenzae into the ME cavity of the rats. The rats were divided into four experimental groups: three infected groups and one control group. Infected groups were subdivided into sets of 5 rats, one for each of the three time points (1, 4 and 7 days post-inoculation). For determination of rat IL-17 and IL-22 levels in infected rats and control rats, infected or control ME mucosa sections were analyzed by immunohistochemistry with specific antibodies directed against IL-17 and IL-22. Immunohistochemical staining for CD3, RORgammat, and NKp46 were also conducted on the samples to confirm the origin of cells expressing IL-17 and IL 22. IL-17 and IL-22 serum concentrations were significantly increased in the infected rats compared to control rats. Immunohistochemical staining revealed increased IL-17 and IL-22 expressions in all infected ME mucosae from the first day after inoculation. In addition, the results of tissue staining for the specific surface markers were negative for CD3 and NKp46, but were highly positive for RORgammat. IL-17 and IL-22 revealed their association with the bacterially induced proliferative and hyperplastic responses of ME mucosa, which are characteristic features in pathogenesis of OM. Surface marker examination showed that the source cells for IL-17 and IL-22 seemed to be lymphoid tissue inducer (LTi) cells. The results suggest that LTi cells release IL-17 and IL-22, and play a significant role in both the early phase of OM induction and recovery from it. PMID- 27497404 TI - Lactoferrin gene polymorphisms in Italian patients with recurrent tonsillitis. AB - INTRODUCTION: Recurrent tonsillitis is an oral pathology characterized by inflammation of tonsils. The disease susceptibility depends upon environmental and host factors, specifically the innate immune response, the first line of host defence could play an important role. Among innate immunity members, lactoferrin, known for its antimicrobial properties, was previously correlated with the risk of oral pathology as periodontitis and dental caries. METHODS: 89 Italian children presenting recurrent tonsillitis and 95 healthy children were genotyped for two LTF non-synonymous polymorphisms, called Thr29Ala and Arg47Lys, in order to investigate their potential role in recurrent tonsillitis susceptibility. RESULTS: no different allele, genotype and haplotype frequency distributions were detected comparing patients and controls. CONCLUSION: data from the current study indicate that LTF polymorphisms might not be involved in recurrent tonsillitis development in our Italian population. However, since the importance of lactoferrin in oral immunity has been previously assessed, further studies should be necessary to unravel the potential role of LTF genetic variants in oral cavity. PMID- 27497405 TI - Prevention of biofilm formation by polyquaternary polymer. AB - OBJECTIVE: Biofilm formation has been linked to device-associated infections in otolaryngology. This study was conducted to determine if a microbicidal polyquaternary polymer, poly diallyl-dimethylammonium chloride (pDADMAC) could prevent biofilm development by pathogens that commonly cause implant infections, Staphylococcus aureus and Pseudomonas aeruginosa. METHODS AND MATERIALS: This study was prospective and controlled in vitro microbiological study. Polyurethane tubes (20 per treatment) with and without a polyquaternary polymer coating were briefly exposed to plasma or saline, then to S. aureus or P. aeruginosa. Polyurethane tubes were incubated in growth media. After 4 days, antibiotics were added to kill planktonic bacteria. S. aureus or P. aeruginosa bacterial counts and scanning electron microscopy (SEM) were performed. RESULTS: S. aureus biofilm counts were reduced by 8 logs on tubes with polyquaternary polymer coating compared to the control tubes, either with plasma (3.67E+01 +/- 7.30E+01 vs 1.08E+09 +/- 4.81E+08; P < 0.0001) or without plasma (3.70E+00 +/- 1.10E+01 vs 6.50E+08 +/- 2.79E+08; P < 0.0001). P. aeruginosa biofilm formation was also reduced on tubes with polyquaternary polymer, either with plasma (2.90E+07 +/- 1.71E+07 vs 9.16E+08 +/- 4.43E+08; P < 0.0001) or without plasma (2.50E+07 +/- 9.54E+06 vs 3.35E+08 +/- 2.18E+08; P < 0.001), but the reduction was only 1 log. On control tubes, plasma promoted S. aureus (1.08E+09 +/- 4.81E+08 vs 6.05E+08 +/ 2.79E+08; P < 0.0001) and P. aeruginosa (9.16E+08 +/- 4.43E+08 vs 3.35E+08 +/- 2.18E+08; P < 0.0001) bacterial counts but not on the tubes coated with polyquaternary polymer. CONCLUSIONS: Incorporation of the microbicidal polyquaternary polymer, pDADMAC, into polyurethane dramatically inhibits S. aureus biofilm formation. Further research is warranted to evaluate the efficacy and safety of this technology in otolaryngologic implants. PMID- 27497406 TI - Informed consent for tonsillectomy: Do parents comprehend the information we provide? AB - OBJECTIVE: Informed consent is an important part of the surgical process. Based on our clinical experience, we hypothesized that parents providing consent for their children's tonsillectomy do not comprehend all the information that is given to them by the operating surgeon at the time of a conventional consent process. MATERIALS AND METHODS: Parents whose children were scheduled for tonsillectomy with or without adenoidectomy and/or tympanostomy tubes insertion were enrolled. Within one hour after the consent process, they were asked to complete a questionnaire designed to collect demographic data and to evaluate how much of the information that was given to them was actually understood. RESULTS: Ninety-seven parents were enrolled between October 2011 and March 2013. The average percentage of correct answers (score) for the 16 multiple-choice questions was 76.3%. The average scores were 84.8% for the native Hebrew-speaking parents and 71.9% for the parents whose first language was other than Hebrew (p < 0.01). The average scores were 83.3% for the parents who are healthcare system workers and 74.4% for those parents whose profession is not related to medicine (p < 0.05). Fifty parents (51.5%) responded incorrectly to at least one of two questions that we defined as essential: "What would you do if your child starts to bleed from the mouth" and "What kind of food is recommended for your child during the first week after the surgery". CONCLUSION: The current conventional method of obtaining informed consent for tonsillectomy is inadequate, as reflected by the low level of parental comprehension of essential information. Further studies which will evaluate methods for improving the consent process are highly warranted. PMID- 27497407 TI - Quality of life improvement after pressure equalization tube placement in Down syndrome: A prospective study. AB - OBJECTIVE: To evaluate quality-of-life changes after bilateral pressure equalization tube placement with or without adenoidectomy for the treatment of chronic otitis media with effusion or recurrent acute otitis media in a pediatric Down syndrome population compared to controls. STUDY DESIGN: Prospective case control observational study. METHODS: The OM Outcome Survey (OMO-22) was administered to both patients with Down syndrome and controls before bilateral tube placement with or without adenoidectomy and at an average of 6-7 months postoperatively. Thirty-one patients with Down syndrome and 34 controls were recruited. Both pre-operative and post-operative between-group and within-group score comparisons were conducted for the Physical, Hearing/Balance, Speech, Emotional, and Social domains of the OMO-22. RESULTS: Both groups experienced improvement of mean symptom scores post-operatively. Patients with Down syndrome reported significant post-operative improvement in mean Physical and Hearing domain item scores while control patients reported significant improvement in Physical, Hearing, and Emotional domain item scores. All four symptom scores in the Speech domain, both pre-operatively and post-operatively, were significantly worse for Down syndrome patients compared to controls (p <= 0.008). CONCLUSIONS: Surgical placement of pressure equalizing tubes results in significant quality of life improvements in patients with Down syndrome and controls. Problems related to speech and balance are reported at a higher rate and persist despite intervention in the Down syndrome population. It is possible that longer follow up periods and/or more sensitive tools are required to measure speech improvements in the Down syndrome population after pressure equalizing tube placement +/- adenoidectomy. PMID- 27497408 TI - The impact of submandibular duct relocation on drooling and the well-being of children with neurodevelopmental disabilities. AB - OBJECTIVE: The aim of this study was to evaluate the impact of a reduction in drooling after bilateral submandibular duct relocation (SMDR) with sublingual gland excision on daily life and care, as well as social and emotional consequences in children and adolescents with neurodevelopmental disabilities. METHODS: This prospective cohort study included 72 children and adolescents (46 males, 26 females) with moderate to severe drooling, and their caregivers. Mean age at the time of surgery was 15 years 2 months (SD 4y 3mo). Fifty-two children were diagnosed with cerebral palsy and 20 had other non-progressive developmental disabilities. A caregiver questionnaire to document the impact of drooling on daily care and economic consequences, social interaction and emotional development and self-esteem was administered before, and 8 and 32 weeks after surgery. RESULTS: Following bilateral SMDR the mean Visual Analogue Scale (VAS, 0 100) scores demonstrated a significant (p < 0.001) reduction in the severity of drooling from 81 at baseline to 28 and 36 after 8 and 32 weeks, respectively. This was accompanied by a decrease in the amount of daily care required and reduced economic consequences. In addition, an increase in social contact with other children and adults was reported by caregivers after surgery. CONCLUSION: Bilateral SMDR with sublingual gland excision provides a significant positive reduction in daily care of children suffering from drooling. Caregivers also report positive changes in their child's social interaction and sense of self esteem. PMID- 27497409 TI - Etiology and long-term functional swallow outcomes in pediatric unilateral vocal fold immobility. AB - OBJECTIVE: Unilateral vocal fold immobility (UVFI) results in deficits in phonatory, respiratory, and swallow function of the pediatric patient. Little is known about long-term functional swallow outcomes. METHODS: Medical records of children diagnosed with UVFI between 2005 and 2014 at a tertiary children's hospital were retrospectively reviewed. Etiology, laryngoscopy findings, and swallow status at diagnosis and follow-up were recorded. Swallow outcomes were compared by etiology using Fisher's exact test. McNemar's test was used to identify correlations between return of mobility and swallow recovery. Rates of pneumonia were compared with initial swallow evaluation results using a two tailed t-test. RESULTS: Eighty-eight patients with UVFI were identified and 73 patients (47% female, mean age 14.4 months, standard deviation (SD) 26.7 months) had complete medical records. Mean follow up time was 52.7 months (SD 36.8 months). Etiologies included cardiothoracic surgery (68.5%), idiopathic (12.3%), prolonged intubation (11.0%), central nervous system (CNS) abnormality (5.5%), and non-cardiac iatrogenic injury to the recurrent laryngeal nerve (2.7%). Forty seven patients underwent a follow up laryngoscopy, and recovery of vocal fold (VF) mobility was documented in 42.6% (20/47). At diagnosis, 31.5% fed orally, compared with 79.5% at follow-up. Direct correlation between recovery of VF mobility and swallow recovery was not demonstrated. Cardiac etiologies demonstrated higher rates of swallow recovery than CNS abnormalities (p = 0.0393). Twenty-five children aspirated on initial modified barium swallow (MBS) and 10 children developed pneumonias at some point during the follow up period. There was no significant difference in rates of pneumonia in patients with and without aspiration on MBS. CONCLUSION: Recovery of swallow in children with UVFI does not directly parallel return of VF mobility. Long-term swallow outcome is favorable in this population. Initial MBS does not indicate ultimate swallow outcome. PMID- 27497410 TI - Postoperative tonsillectomy bleeding complications in children: A comparison of three surgical techniques. AB - OBJECTIVE & HYPOTHESIS: Stated in the Null form: There will be no difference in primary or secondary hemorrhage rate in children undergoing tonsillectomy or adenotonsillectomy across three surgical techniques: PEAK Plasmablade, electric monopolar cautery, coblation. STUDY DESIGN: Retrospective chart analysis. SETTING: Academic Medical Center: Children's Hospital. SUBJECTS & METHODS: Electronic chart data were collected from patient's age 2-18 years who underwent tonsillectomy, with or without adenoidectomy, at a tertiary pediatric hospital between June 2011 to May 2013 by electric monopolar cautery, coblation, or PEAK PlasmaBlade. Treatment outcomes following each of these surgical approaches, relative to rate of post-operative primary and secondary bleeding, hospital admission, and emergency department visits were compared. RESULTS: A total of 1780 patients that had tonsillectomy or adenotonsillectomy were evaluated. There was a significant difference in bleed rate by age with older patients having more bleeding post-procedure than their younger counterparts. There was also a difference in bleeding frequency by diagnosis. Patients with a diagnosis of OSA were less likely to experience a postoperative bleed than children with either recurrent tonsillitis or both. Significance was evident between post-op hemorrhage rate and instrumentation (chi(2) = 11.17, df = 2, p = 0.004). The majority of bleeds occurred with coblation (58.9%), while PEAK had only 17.8% and cautery 23%. CONCLUSION: The null hypothesis was rejected. That is, PEAK PlasmaBlade was safe and effective, with statistically less postoperative bleeding and ED visits, especially when compared to coblation techniques. Coblation patients had the highest rates of postoperative bleeding. PMID- 27497411 TI - Corrigendum to "Identifying predictive factors for long-term complications following button battery impactions: A case series and literature review" [Int. J. Pediatr. Otorhinolaryngol. (2016) 198-202]. PMID- 27497412 TI - Presentation and management of nasal foreign bodies at a tertiary children's hospital in an American metro area. AB - OBJECTIVES: To examine rates of otolaryngology intervention in children presenting to our emergency department with nasal foreign bodies, factors associated with otolaryngology involvement, rates of complications, and details on nasal button battery exposure. METHODS: All patients presenting with a nasal foreign body to Children's Hospital Colorado from 2007 to 2012 were identified. Factors leading to referral to otolaryngology and operative intervention were examined, as well as complications. RESULTS: 102 patients were included. 36 (35%) patients were referred to the otolaryngology clinic, of which 58.9% required operating room intervention. 66 (64.7%) children had their nasal foreign bodies removed in the emergency room, however 30 (45%) of these were removed by an otolaryngology resident or attending physician. Overall, 64.7% of nasal foreign bodies required removal by otolaryngology. Of the 15 objects removed in the operating room, six were button batteries. No septal perforations occurred as a result of nasal button battery exposure. Multivariable logistic regression showed two significant predictors of OR removal: age and disc shaped objects. CONCLUSION: While emergency department providers are comfortable attempting removal of nasal foreign bodies, there was a high rate of otolaryngology intervention. Based on this data, there is a need to educate emergency room providers on nasal anatomy and techniques for nasal foreign body removal. PMID- 27497413 TI - Profile of pediatric traditional uvulectomy in North-West Nigeria: The need for caution and education. AB - OBJECTIVES: The study assessed the prevalence of complications associated with traditional uvulectomy and identified factors associated with favorable outcome after management in a pediatric population in North-Western Nigeria. STUDY DESIGN AND SETTING: This cross-sectional descriptive study was carried out at the accident and emergency section as well as at the otolaryngology out-patient clinic of the Federal Medical Centre, Birnin-Kebbi, Nigeria. METHODS: Patients with traditional uvulectomy complications were recruited on consecutive basis and sample size was dependent on the patients seen over the study period. This was done over a 6 month study period (January 2014-June 2014). RESULTS: A total of forty one participants, all within the paediatric age group (<15 years) participated in this study. The age of the participants ranged from 2 to 13 years while the mean age was 6.17 years +/- 2.47. The <=5 year age group constituted about 44% of the children studied. Gender distribution noted a slight male preponderance (Male: Female ratio = 1.05: 1). A total of 58.8% of the participants were fully immunized, while the Haemoglobin concentration status (packed cell volume) at hospital presentation of <10 g/dl (<30%) occurred in 34.1% of the participants of the study. The duration of hospital stay in pediatric patients with post-traditional uvulectomy complications was significantly associated with the maternal immunization status (p = 0.007). Also, subjects with completed maternal immunization status had about 0.1 times odds (CI = 0.19-0.64) likelihood to have a prolonged hospital stay when compared with subjects whose mothers were partially immunized or not immunized at all. CONCLUSION/SIGNIFICANCE: In conclusion, this study found that favorable outcome post-traditional uvulectomy is related to early presentation and maternal immunization status, but adversely affected by anemia. Traditional uvulectomy remains a cultural practice that should be discouraged using both advocacy and legislative measures. PMID- 27497414 TI - The effects of spinal anesthesia on auditory function in pediatric patients. AB - OBJECTIVES: Persistent or transient hearing loss (HL) is a less-recognized complication of spinal anesthesia (SA) in the pediatric population, although it has been previously reported in adults. The primary aim of this study was to investigate the effects of SA on auditory function in the pediatric population. METHODS: After gaining institutional approval and parental consent, 30 American Society of Anesthesiologists physical status I-II children between 4 and 15 years undergoing lower extremity orthopedic surgery were enrolled in this prospective study. Spinal blocks were performed in the midline with a 25G Quincke needle using 0.5% hyperbaric bupivacaine. Transient evoked otoacoustic emission (TEOAE) and distortion product otoacoustic emission (DPOAE) tests were administered before surgery and one-day postoperative. Children with detected HL were retested on postoperative day seven. Preoperative and postoperative results were compared. A Wilcoxin Signed-Ranks test (with Bonferroni correction) was used for statistical analyses. RESULTS: There was no statistically significant HL in the postoperative period compared to the preoperative period. In 29 of 30 patients, no difference was detected at any frequency tested. In one patient, TEOAE and DPOAE tests were found to be decreased on postoperative day one. In this patient, control tests were found to be improved on postoperative day seven. CONCLUSIONS: Administration of SA may results in a low probability of transient hearing loss with no clinical significance in children 4-15 years of age. PMID- 27497415 TI - Hearing loss in Down Syndrome revisited - 15 years later. AB - OBJECTIVE: In 2001, the senior authors published a study investigating hearing loss in young children (ages 11 months to 3.8 years) with Down Syndrome (DS). We re-visit this same study population to review current audiologic status, the incidence of pressure equalization tube (PET) placement(s), and rate of tympanic membrane (TM) perforations. We aim to better understand the natural history of ear disease and hearing loss in DS and assess potential complications. METHODS: This retrospective chart review included 57 children with DS who previously completed in 2006, a 5 year, longitudinal study investigating otolaryngologic problems in DS. Updated audiologic data was available for 54. Audiograms, age of ear specific testing, PET placement(s), and tympanic membrane(TM) descriptions were reviewed. RESULTS: Ages ranged from 14 to 18 years (mean 16.34 years). PET placement occurred in 88.8%, with mean of 3.5 procedures. 30% of PET's were placed after age 6. Ear specific testing was obtained in 92.5% (mean age 4.54 years). Normal hearing was present in 44% (right ear) and 38% (left ear). "Functional" hearing levels, defined as normal or mild hearing loss and speech reception threshold <= 30 dB, occurred in 83.3%. Sensorineural/mixed hearing loss was present in 11% (right ear) and 9% (left ear). TM perforations rate was 17%. No cholesteatomas were found. CONCLUSION: Chronic otitis media and indications for PET's persist as children with DS age. Although functional hearing occurred in 83.3%, there was an overall decrease in hearing levels as the children aged. Tympanic membrane perforations occurred in 17%. Continued surveillance of otologic and audiologic status in patients with Down syndrome is recommended. PMID- 27497416 TI - Pediatric sudden sensorineural hearing loss: Etiology, diagnosis and treatment in 20 children. AB - OBJECTIVES: 1. To report our experience in children with sudden-onset sensorineural hearing loss (SSNHL). 2. To describe the etiology and management of children with SSNHL. METHODS: Retrospective review of 20 children with SSNHL, from 2000 to 2013 at a tertiary pediatric facility. Patients had the following inclusion criteria: history of normal hearing, hearing loss occurring in less than 3 days, and audiogram documentation. RESULTS: The average age of patients presenting with SSNHL is 11 years 3 months (22months-18years). Only 6 (30%) children presented prior to 2 weeks. Tinnitus (55%) was the most common associated symptoms followed by otalgia (25%), and vertigo (20%). Eight patients had bilateral hearing loss, 6 only right and 6 only left. Hearing loss severity ranged from profound (45%) being most common to mild. Etiology was unknown (30%), viral (25%), anatomic abnormality (25%), Meniere's disease (5%), autoimmune (5%), perilymphatic fistula (5%), and suppurative labyrinthitis (5%). Eight patients had initial treatment with oral steroids of which 50% had improvement on audiograms. Two patients underwent intratympanic injections, both showed improvement. Of the 12 patients with no treatment, only 1 had improved hearing. CONCLUSIONS: The true incidence of pediatric SSNHL is not well established in our literature. Unique aspects of pediatric SSNHL are delayed presentation and higher percent of anatomic findings. In our study 70% presented more than 2 weeks after experiencing symptoms. Anatomic abnormalities are in 40% of patients. Hearing improvement occurred in 50% of children treated with oral steroids. Intratympanic steroid treatment is another option but may have practical limitation in the pediatric population. PMID- 27497417 TI - Extended cricotracheal resection with posterior costochondral grafting for complex pediatric subglottic stenosis. AB - BACKGROUND AND OBJECTIVE: Severe laryngotracheal stenosis in childhood poses a complex surgical challenge for specialists in airway surgery. Patients with severe subglottic stenosis with vocal cord involvement are particularly difficult to manage successfully. The goal of this work was to review our experience with extended CTR in a cohort of young children with severe SGS and determine which clinical parameters would be associated with surgical success. METHODS: Retrospective analysis of the outcome of consecutive patients with severe glottic subglottic stenosis submitted to an extended double-stage CTR between 2004 and 2014 at a large tertiary referral center. RESULTS: Twenty-five patients met inclusion criteria, with a mean age of 58.7 months at the time of repair. Overall decannulation rate was 80% (20/25), with a median time to deannulation of 120 days. Seven patients developed post-operative sequelae (4 arytenoid dislocations, 2 re-stenosis, and 1 anterior commissure adhesion). Patients with these sequelae had lower overall specific decannulation (42.8%) compared to those without any sequelae (94.4%) (Chi-square, p = 0.0123) with a longer time to decannulate (logrank, p = 0.0004). Notably, patients presenting with these sequelae on average had undergone a longer duration of post-operative stenting (27.14 days) compared to those presenting without any sequelae (14.8 days) (p = 0.0282). CONCLUSIONS: Extended CTR is an effective method for resolving a majority of severe glottic-subglottic stenosis cases in children. Duration of post-operative stenting may adversely impact overall outcome in these patients. PMID- 27497418 TI - Hospital clinical trial: Homeopathy (Agraphis nutans 5CH, Thuya occidentalis 5CH, Kalium muriaticum 9CH and Arsenicum iodatum 9CH) as adjuvant, in children with otitis media with effusion. AB - BACKGROUND: Otitis media with effusion (OME) is the most common cause of paediatric hearing loss. No single treatment has proved its effectiveness. There is a lack of evidence-based medicine studies in the area of homeopathy. METHOD: A prospective randomized, double blinded interventional placebo control study was conducted. Patients, from 2 months to 12 years, with OME diagnosed by pneumatic otoscopy (PNO) and tympanometry, were randomized into two groups. Both groups received aerosol therapy (mucolytics and corticosteroids). In addition, the experimental group (EG) received homeopathy (Agraphis nutans 5CH, Thuya Occidentalis 5CH, Kalium muriaticum 9CH and Arsenicum iodatum), and the placebo group (PG) placebo, both of them for 3 months. Patients were evaluated by PNO examination and tympanometry at baseline, at 45 and 90 days. RESULTS: 97 patients were enrolled. In the EG, 61.9% of individuals were cured (PNO went from negative in the 1st visit to positive in the 3rd visit) compared with 56.8% of patients treated with placebo. 4.8% of patients in the EG suffered a recurrence (positive PNO in the 2nd visit changed to negative in the 3rd visit) while 11.4% did in the PG. No significant difference was found. Adverse events were distributed similarly, except in the case of upper respiratory tract infections, which were less frequent in EG (3 vs. 13, p: 0.009). CONCLUSION: The homeopathic scheme used as adjuvant treatment cannot be claimed to be an effective treatment in children with OME. TRIAL REGISTRATION: EUDRACT number: 2011-006086-17, PROTOCOL code: 55005646. PMID- 27497419 TI - Tonsillectomies and respiratory complications in children: A look at pre-op polysomnography risk factors and post-op admissions. AB - OBJECTIVE: To identify predictors of post-operative respiratory complications in children undergoing tonsillectomy. METHODS: Consecutive case series with chart review of children who underwent polysomnography (PSG) and subsequent tonsillectomy with or without adenoidectomy for obstructive sleep apnea (OSA). Patients with craniofacial anomalies or significant cardiopulmonary comorbidities were excluded. Rates of post-surgical respiratory complication were reviewed and compared to patient specific factors and PSG findings to identify possible risk factors. RESULTS: Eighty-six patients (mean age 5.3 +/- 2.2 years) were included. There was a statistically significant (p = 0.03) relationship between an AHI >=40 (AHI40) and post-operative respiratory complications. AHI40 also had the greatest magnitude of association with postoperative respiratory complications (OR = 5.313). An AHI >=25 (AHI25) was marginally significant (p = 0.067). No significant difference in outcome occurrence was found when analyzing rates of complication in patients with BMI above and below 18 (p = 0.20) or oxygen (O2) nadir above and below 80% (p = 0.09). The AHI ranged from 0 to 112.2, and no postoperative respiratory complications were identified in children with an AHI less than 10. CONCLUSIONS: Our results indicate an association between an AHI >=40 and respiratory complications following an adenotonsillectomy, but we were not able to observe any significant difference at a cutoff of 25. An association between BMI or O2 nadir and postoperative respiratory complication was not able to be identified. Our results support the importance of AHI as a predictor of postoperative respiratory complications in children undergoing tonsillectomy for OSA. PMID- 27497420 TI - The assessment of the Newborn Hearing Screening Program in the Region of Murcia from 2004 to 2012. AB - OBJECTIVES: Newborn (NB) auditory deficit has a prevalence of 1-2% in the world. Since the 1990s different screening programs have been put into practice. The Newborn Hearing Screening Program has been in operation since 2002 in our hospital (HCUVA) in Murcia (Spain) and two years later it was introduced into the whole of the Autonomous Community of the Region of Murcia as part of universal healthcare. The objective of this study was to analyze and assess its results. METHOD: The newborn (NB) population is divided into two groups: not-at-risk NBs and at-risk NBs. In the first case we carry out acoustic otoemissions (AOEs) 48 h after birth and depending on the result the child is either discharged or, in negative cases, the infant undergoes a series of tests in a period of 30-45 days to confirm or rule out the existence of hearing anomalies. In the at-risk group we combine AOEs with brain trunk potentials (BERA) following the stages in a decision tree diagram similar to the ones for not-at-risk children in order to provide a clinical diagnosis in the first three months of life. RESULTS: The screening performance was assessed for the 156,122 children studied, of which 151,258 belonged to the group of not-at-risk children; and 4864 to the group at risk of hypoacusia. As a result of the screening only 410 (0.26%) were sent to consultation, 213 in the not-at-risk group (0.14%) and 197 (24.7%) in the at-risk group. A total of 7452 false positives were identified (4.7%), 6951 (4.5%) in the not-at-risk group; and 501 (10.3%) in the group with risk factors; and there were 53 false negatives (0.03%). Sensitivity in the screening program was 88.5%, with a specificity of 95%. CONCLUSIONS: The Region of Murcia has a Newborn Hearing Screening Program with tests that provide a high level of sensitivity and specificity in accordance with the findings of the literature. Our results endorse the program and the patients were treated in a way that met the objective of providing a correct diagnosis and the appropriate therapeutic action. PMID- 27497421 TI - The association of residential mold exposure and adenotonsillar hypertrophy in children living in damp environments. AB - BACKGROUND: There are many consequences of mold exposure related to respiratory system health of children This retrospective cohort study aims to find the association between adenoid hypertrophy and mold exposure in children living in damp environments. METHODS: Children with history of recurrent respiratory tract infections were enrolled in the study between June 2012 and June 2013 and were followed up for adenoid hypertrophy from June 2013 to June 2016. One hundred and forty two children were residents of moldy houses and 242 were living in normal houses. Skin prick test results for 60 common allergens, vitamin D levels, IgE levels, age, presence of comorbidities such as urticaria, atopic dermatitis, allergic conjunctivitis, allergic rhinitis, asthma, frequency of upper respiratory tract infections and lower respiratory tract infections, were evaluated in both groups. RESULTS: A total of 384 children (mean age +/- standard deviation = 53.37 +/- 36 months; 198 males and 186 females) were included. The children were classified into 2 groups (1)Children living normal houses (n = 242) (2); Children living in damp houses (n = 142) according to mold exposure. Children with adenoid hypertrophy (p < 0,001) and higher IgE levels (p < 0,001) were more common in mold exposed group. Lower respiratory tract infections were more common in children with mold exposure (p < 0,05). Bivariate correlation analysis showed no significant association between IgE levels and adenoid hypertrophy. Multiple linear regression analysis was performed to evaluate IgE levels, vitamin D levels, and presence of adenoid as independent variables; age as dependent variable among two groups and was found statistically significant (p < 0,001). Dermatophagoid sensitive group living in damp houses had a significant increase in adenoid hypertrophy (p = 0,01). Housedustmite sensitive children with recurrent lower respiratory tract infection and upper respiratory tract infection were mainly residents of damp houses (p < 0,001). Allergic comorbidities were significantly more in damp environment group (p < 0,001), but there was no significant increase in any of the subgroups. CONCLUSIONS: Children with mold exposure had significantly increased adenoid hypertrophy regardless of their atopic nature, however, they may have become more sensitized due to other environmental triggers and genetic factors. In damp environments, sensitization to dermatophagoids, was significantly increased in children with adenoid hypertrophy. During the period of infancy, when children were mostly vitamin D supplemented, they were not sensitized and had normal adenoids. As children with recurrent respiratory tract infections grow, they tend to have lower vitamin D levels, become more atopic and tend to have adenoid hypertrophy. PMID- 27497422 TI - Contrasting patterns of genetic variation in core and peripheral populations of highly outcrossing and wind pollinated forest tree species. AB - Gene flow tends to have a homogenising effect on a species' background genetic variation over large geographical areas. However, it is usually unknown to what extent the genetic structure of populations is influenced by gene exchange between core and peripheral populations that may represent stands of different evolutionary and demographic history. In this study, we looked at the patterns of population differentiation in Scots pine-a highly outcrossing and wind pollinated conifer species that forms large ecosystems of great ecological and economic importance in Europe and Asia. A set of 13 polymorphic nuclear microsatellite loci was analysed to infer the genetic relationships among 24 populations (676 individuals) from Europe and Asia Minor. The study included specimens from the primary continuous range and from isolated, marginal stands that are considered to be autochthonous populations representative of the species' putative refugial areas. Despite their presumably different histories, a similar level of genetic variation and no evidence of a population bottleneck was found across the populations. Differentiation among populations was relatively low (average FST = 0.035); however, the population structure was not homogenous, which was clearly evident from the allelic frequency spectra and Bayesian assignment analysis. Significant differentiation over short geographical distances was observed between isolated populations within the Iberian and Anatolian Peninsulas (Asia Minor), which contrasted with the absence of genetic differentiation observed between distant populations e.g., between central and northern Europe. The analysed populations were assigned to several groups that corresponded to the geographical regions of their occurrence. These results will be useful in genetics studies in Scots pine that aim to link nucleotide and phenotypic variation across the species distribution range and for development of sustainable breeding and management programs. PMID- 27497423 TI - Adjuvant endocrine therapy in women with oestrogen-receptor-positive breast cancer: how should the skeletal and vascular side effects be assessed and managed? AB - Adjuvant endocrine therapy provides oncological benefits in women with early oestrogen-receptor-positive breast cancer, but has adverse effects consequent to induced oestradiol deficiency. Bone loss is accelerated, predisposing to increased fracture risk. Metabolic effects include changes in lipid metabolism and body composition although effects on cardiovascular risk are still unclear. Women commencing endocrine therapy should be proactively counselled about and monitored for these and other therapy-related complications including arthralgia and vasomotor symptoms. We provide strategies for prevention and management of these adverse effects, based, where available, on randomized controlled trial evidence specific to breast cancer survivors receiving endocrine treatment. PMID- 27497424 TI - SIRT1 as a therapeutic target for Alzheimer's disease. AB - Alzheimer's disease (AD) is the most prevalent cause of dementia in the aging population worldwide. SIRT1 deacetylation of histones and transcription factors impinge on multiple neuronal and non-neuronal targets, and modulates stress response, energy metabolism and cellular senescence/death pathways. Collectively, SIRT1 activity could potentially affect multiple aspects of hippocampal and cortical neuron function and survival, thus modifying disease onset and progression. In this review, the known and potential mechanisms of action of SIRT1 with regard to AD, and its potential as a therapeutic target, are discussed. PMID- 27497425 TI - Pharmacokinetics of ceftriaxone in patients undergoing continuous renal replacement therapy. AB - BACKGROUND: The duration of time for which the serum levels exceed the minimum inhibitory concentration (MIC) is an important pharmacokinetics (PK)/pharmacodynamics (PD) parameter correlating with efficacy for the antibiotic, ceftriaxone (CTRX). However, no reports exist regarding the PK or PD in patients undergoing continuous renal replacement therapy (CRRT). The purpose of this study was to examine the PK and safety of CTRX in patients undergoing CRRT in order to establish safer and more effective regimens. METHODS: CTRX (1 g once a day) was intravenously administered four or more times to nine patients undergoing CRRT. Blood was collected after administration to measure CTRX concentrations in serum and the filtration fraction of CRRT by high-performance liquid chromatography. In addition to calculating PK parameters from serum CTRX, we (a) estimated by simulation CTRX concentrations when the dose interval was extended to once every 2 or 3 days, (b) calculated CTRX clearance via CRRT from CTRX concentrations in the filtration fraction, and (c) assessed the safety of CTRX use. RESULTS: Total body clearance and the half-life of CTRX were 7.46 mL/min (mean) and 26.5 h, respectively, in patients undergoing CRRT. CTRX was found in the filtration fraction, and the estimated clearance by CRRT was about 70% of total body clearance. Simulations revealed that even when the dose interval is increased to 2 or 3 days, CTRX would retain its efficacy. CONCLUSIONS: Our findings suggest that, depending on the condition of patients undergoing CRRT, CTRX could be used safely against pathogens with a CTRX MIC <=2 ug/mL, even when extending the dose interval. PMID- 27497426 TI - Emerging technologies for protease engineering: New tools to clear out disease. AB - Proteases regulate many biological processes through their ability to activate or inactive their target substrates. Because proteases catalytically turnover proteins and peptides, they present unique opportunities for use in biotechnological and therapeutic applications. However, many proteases are capable of cleaving multiple physiological substrates. Therefore their activity, expression, and localization are tightly controlled to prevent unwanted proteolysis. Currently, the use of protease therapeutics has been limited to a handful of proteases with narrow substrate specificities, which naturally limits their toxicity. Wider application of proteases is contingent upon the development of methods for engineering protease selectivity, activity, and stability. Recent advances in the development of high-throughput, bacterial and yeast-based methods for protease redesign have yielded protease variants with novel specificities, reduced toxicity, and increased resistance to inhibitors. Here, we highlight new tools for protease engineering, including methods suitable for the redesign of human secreted proteases, and future opportunities to exploit the catalytic activity of proteases for therapeutic benefit. Biotechnol. Bioeng. 2017;114: 33 38. (c) 2016 Wiley Periodicals, Inc. PMID- 27497427 TI - Chromatin programming by developmentally regulated transcription factors: lessons from the study of haematopoietic stem cell specification and differentiation. AB - Although the body plan of individuals is encoded in their genomes, each cell type expresses a different gene expression programme and therefore has access to only a subset of this information. Alterations to gene expression programmes are the underlying basis for the differentiation of multiple cell types and are driven by tissue-specific transcription factors (TFs) that interact with the epigenetic regulatory machinery to programme the chromatin landscape into transcriptionally active and inactive states. The haematopoietic system has long served as a paradigm for studying the molecular principles that regulate gene expression in development. In this review article, we summarize the current knowledge on the mechanism of action of TFs regulating haematopoietic stem cell specification and differentiation, and place this information into the context of general principles governing development. PMID- 27497428 TI - Efficacy of antibiotic prophylaxis prior to tympanoplasty for contaminated cholesteatoma. AB - OBJECTIVES: To evaluate the efficacy of combined antistaphylococcal and antipseudomonal preoperative antibiotics for preventing surgical site infections following tympanoplasty and mastoidectomy with contaminated cholesteatoma. STUDY DESIGN: Retrospective chart review. METHODS: Medical records of patients who underwent tympanoplasty +/- mastoidectomy for cholesteatoma were reviewed. Only cases considered to have contaminated or dirty surgical fields were included. The primary outcome measure was occurrence of postoperative surgical site infections, perichondritis, pinna abscess, periotic cellulitis, or periotic abscess requiring systemic antibiotic therapy or surgical intervention. RESULTS: The charts of 326 patients who underwent tympanoplasty +/- mastoidectomy were reviewed. Of those, 195 met inclusion criteria. Preoperative antibiotics included clindamycin and ceftazidime or gentamicin. Patients treated with no perioperative antibiotics had a surgical site infection rate of 11%, and those treated with perioperative antibiotics had a rate of 1% (P = 0.02). CONCLUSION: Administration of preoperative antibiotics to cover staphylococcal and pseudomonal species may prevent surgical site infections with tympanoplasty +/- mastoidectomy for contaminated cholesteatoma. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2363-2366, 2016. PMID- 27497429 TI - Freezing behaviours in wintering Cornus florida flower bud tissues revisited using MRI. AB - How plant tissues control their water behaviours (phase and movement) under subfreezing temperatures through adaptative strategies (freezing behaviours) is important for their survival. However, the fine details of freezing behaviours in complex organs and their regulation mechanisms are poorly understood, and non invasive visualization/analysis is required. The localization/density of unfrozen water in wintering Cornus florida flower buds at subfreezing temperatures was visualized with high-resolution magnetic resonance imaging (MRI). This allowed tissue-specific freezing behaviours to be determined. MRI images revealed that individual anthers and ovules remained stably supercooled to -14 to -21 degrees C or lower. The signal from other floral tissues decreased during cooling to -7 degrees C, which likely indicates their extracellular freezing. Microscopic observation and differential thermal analyses revealed that the abrupt breakdown of supercooled individual ovules and anthers resulted in their all-or-nothing type of injuries. The distribution of ice nucleation activity in flower buds determined using a test tube-based assay corroborated which tissues primarily froze. MRI is a powerful tool for non-invasively visualizing unfrozen tissues. Freezing events and/or dehydration events can be located by digital comparison of MRI images acquired at different temperatures. Only anthers and ovules preferentially remaining unfrozen are a novel freezing behaviour in flower buds. Physicochemical and biological mechanisms/implications are discussed. PMID- 27497430 TI - Process performance and product quality in an integrated continuous antibody production process. AB - Continuous manufacturing is currently being seriously considered in the biopharmaceutical industry as the possible new paradigm for producing therapeutic proteins, due to production cost and product quality related benefits. In this study, a monoclonal antibody producing CHO cell line was cultured in perfusion mode and connected to a continuous affinity capture step. The reliable and stable integration of the two systems was enabled by suitable control loops, regulating the continuous volumetric flow and adapting the operating conditions of the capture process. For the latter, an at-line HPLC measurement of the harvest concentration subsequent to the bioreactor was combined with a mechanistic model of the capture chromatographic unit. Thereby, optimal buffer consumption and productivity throughout the process was realized while always maintaining a yield above the target value of 99%. Stable operation was achieved at three consecutive viable cell density set points (20, 60, and 40 * 106 cells/mL), together with consistent product quality in terms of aggregates, fragments, charge isoforms, and N-linked glycosylation. In addition, different values for these product quality attributes such as N-linked glycosylation, charge variants, and aggregate content were measured at the different steady states. As expected, the amount of released DNA and HCP was significantly reduced by the capture step for all considered upstream operating conditions. This study is exemplary for the potential of enhancing product quality control and modulation by integrated continuous manufacturing. Biotechnol. Bioeng. 2017;114: 298-307. (c) 2016 Wiley Periodicals, Inc. PMID- 27497432 TI - Tumour muscle crosstalk more as regulation of muscle wasting - role of exercise. PMID- 27497431 TI - Genetic rescue in a severely inbred wolf population. AB - Natural populations are becoming increasingly fragmented which is expected to affect their viability due to inbreeding depression, reduced genetic diversity and increased sensitivity to demographic and environmental stochasticity. In small and highly inbred populations, the introduction of only a few immigrants may increase vital rates significantly. However, very few studies have quantified the long-term success of immigrants and inbred individuals in natural populations. Following an episode of natural immigration to the isolated, severely inbred Scandinavian wolf (Canis lupus) population, we demonstrate significantly higher pairing and breeding success for offspring to immigrants compared to offspring from native, inbred pairs. We argue that inbreeding depression is the underlying mechanism for the profound difference in breeding success. Highly inbred wolves may have lower survival during natal dispersal as well as competitive disadvantage to find a partner. Our study is one of the first to quantify and compare the reproductive success of first-generation offspring from migrants vs. native, inbred individuals in a natural population. Indeed, our data demonstrate the profound impact single immigrants can have in small, inbred populations, and represent one of very few documented cases of genetic rescue in a population of large carnivores. PMID- 27497433 TI - Temperature Influences Chorda Tympani Nerve Responses to Sweet, Salty, Sour, Umami, and Bitter Stimuli in Mice. AB - Temperature profoundly affects the perceived intensity of taste, yet we know little of the extent of temperature's effect on taste in the peripheral nervous system. Accordingly, we investigated the influence of temperature from 23 degrees C to 43 degrees C in 4 degrees C intervals on the integrated responses of the chorda tympani (CT) nerve to a large series of chemical stimuli representing sweet, salty, sour, bitter, and umami tastes in C57BL/J6 mice. We also measured neural responses to NaCl, Na-gluconate, Na-acetate, Na-sulfate, and MSG with and without 5 uM benzamil, an epithelial sodium channel (ENaC) antagonist, to assess the influence of temperature on ENaC-dependent and ENaC independent response components. Our results showed that for most stimuli (0.5M sucrose, glucose, fructose, and maltose; 0.02M saccharin and sucralose; 0.5M NaCl, Na-gluconate, Na-acetate, Na-sulfate, KCl, K-gluconate, K-acetate, and K sulfate; 0.05M citric acid, acetic acid, and HCl; 0.1M MSG and 0.05M quinine hydrochloride: QHCl), CT response magnitudes were maximal between 35 degrees C and 39 degrees C and progressively smaller at cooler or warmer temperatures. In contrast, the weakest responses to NH4Cl, (NH4)2SO4, and K-sulfate were at the lowest temperature, with response magnitude increasing monotonically with increasing temperature, while the largest responses to acetic acid were at the lowest temperature, with response magnitude decreasing with increasing temperature. The response to sweet and umami stimuli across temperatures were similar reflecting the involvement of TRPM5 activity, in contrast to bitter stimuli, which were weakly affected by temperature. Temperature-modulated responses to salts and acids most likely operate through mechanisms independent of ENaC and TRPM5. PMID- 27497434 TI - beta-Endorphin enhances the phospholipase activity of the dandruff causing fungi Malassezia globosa and Malassezia restricta. AB - beta-Endorphin is known to stimulate phospholipase production by Malassezia pachydermatis during canine dermatoses. The role of beta-endorphin in Malassezia infection in humans is not well studied. The present study compares the influence of beta-endorphin on Malassezia globosa and Malassezia restricta isolated from patients with seborrhoeic dermatitis/dandruff (SD/D) and healthy controls. Malassezia isolates (five each of the two species from patients and healthy controls) were grown on modified Dixon's agar with or without 100 nmol/L beta endorphin. Phospholipase activity was quantified based on its ability to hydrolyze L-alpha-phosphatidylcholine dimyristoyl (phospholipid substrate). Free fatty acid was measured by a colorimetry method. In isolates from patients, the phospholipase activity significantly increased after exposure to beta-endorphin (M. globosa, P = .04; M. restricta, P = .001), which did not occur in isolates from healthy controls. Moreover, after beta-endorphin exposure the patient isolates had significantly higher (P = .0004) phospholipase activity compared to the healthy control isolates. The results suggest that isolates of M. globosa and M. restricta from patients may differ from those of healthy humans. PMID- 27497436 TI - Effects of time and temperature on 48 routine chemistry, haematology and coagulation analytes in whole blood samples. AB - Background Phlebotomy for the purpose of blood analysis is often performed at remote locations, and samples are usually temporarily stored before transport to a central laboratory for analysis. The circumstances during storage and shipment may not meet the necessary requirements. If analysed anyway, false results may be generated. We therefore examined the influence of precentrifugation time and temperature of the most frequently requested tests in whole blood. Methods Healthy volunteers donated blood in which 48 analytes were tested. Routine chemistry was performed in lithium heparin tubes, haematology in ethylenediaminetetraacetic acid tubes, coagulation in citrate tubes and glucose in sodium fluoride tubes. One tube was measured directly. The others were kept at different temperatures (4, 8, 20 or 30C) and stored for 4, 6, 8 or 24 h before analysis. Additionally, some analytes were examined at 12, 16, 24 and 28C. The mean percentage deviation was compared with different decision levels, including the total allowable error. Results When using the total allowable error as an acceptable limit, most of the investigated analytes remained stable. However, bicarbonate is unstable at almost all tested time-points and temperatures. Calcium, lactate dehydrogenase, potassium and sodium are particularly affected at low temperatures, while phosphate is mainly affected at and above room temperature after 8 h. Conclusion We established the influence of time and temperature on a broad range of analytes, which may be applied to set the limits in transportation and storage of whole blood samples. PMID- 27497435 TI - Iron Deprivation Induces Transcriptional Regulation of Mitochondrial Biogenesis. AB - Mitochondria are essential organelles that adapt to stress and environmental changes. Among the nutrient signals that affect mitochondrial form and function is iron, whose depletion initiates a rapid and reversible decrease in mitochondrial biogenesis through unclear means. Here we demonstrate that, unlike the canonical iron-induced alterations to transcript stability, loss of iron dampens the transcription of genes encoding mitochondrial proteins with no change to transcript half-life. Using mass spectrometry, we demonstrate that these transcriptional changes are accompanied by dynamic alterations to histone acetylation and methylation levels that are largely reversible upon readministration of iron. Moreover, histone deacetylase inhibition abrogates the decreased histone acetylation observed upon iron deprivation and restores normal transcript levels at genes encoding mitochondrial proteins. Collectively, we demonstrate that deprivation of an essential nutrient induces transcriptional repression of organellar biogenesis involving epigenetic alterations. PMID- 27497437 TI - Non-fatal injuries treated outside a hospital in Hunan, China: results from a household interview survey. AB - Background: Injury morbidity data are collected through hospital-based surveillance in many countries. We assessed the extent of non-fatal injures treated outside a hospital. Methods: Data from the first provincial health household interview survey of Hunan, China, conducted in 2013, were used. Injury events were identified and included as medically significant when any of the following circumstances occurred in the prior 14 days: (i) receiving medical treatment from a doctor at a hospital following an injury; (ii) receiving medical treatment by self or others outside a hospital following an injury (e.g. taking medications, or receiving massage or hot compress); and/or (iii) being off work or school, or in bed for more than 1 day, following an injury. The 2-week prevalence of non-fatal injuries and 95% confidence intervals were calculated. We calculated the proportion of injury events treated outside a hospital and the reasons for not visiting a hospital for injury events occurring during the previous 2 weeks. Results: We captured 56 injury events during the previous 2 weeks. The weighted injury prevalence was 4.9 per 1000 persons during the last 2 weeks (95% confidence interval: 2.9-6.9 per 1000 persons). Of the 56 events, 14 (weighted proportion 41.2%) were treated outside a hospital. Primary explanations for skipping hospital visits included perceiving injuries were too minor and economic limitations to travel to hospitals or seek treatment. Conclusion: Results imply the burden of non-fatal injury may be underestimated by hospital based surveillance systems such as that used in China. PMID- 27497438 TI - The prevalence and impact of risk factors for ethnic differences in loneliness. AB - BACKGROUND: Previous studies have demonstrated that loneliness is more frequently present in citizens of ethnic minority groups than in natives. The current study investigates whether ethnic differences in emotional and social loneliness between Moroccan, Turkish, Surinamese and Dutch adults living in the Netherlands are due to ethnic differences in the presence and/or impact of an array of possible risk factors, such as partnership, health and socioeconomic status. METHODS: The data were collected in 2012 as a part of a general health questionnaire of the Public Health Services in the four major cities of the Netherlands, containing 20.047 Dutch, 1.043 Moroccan, 1.197 Turkish and 1.900 Surinamese respondents. RESULTS: Structural equation models showed that ethnic differences in emotional and social loneliness can be ascribed to ethnic differences in the prevalence and impact of several risk factors. Main findings were that all three ethnic minority groups reported feeling less healthy and more discriminated against than the Dutch group, which was related to increased loneliness. Perceived financial difficulties and people in the neighbourhood not getting along had more impact on feelings of loneliness for the Turkish group than loneliness for the other ethnic groups. Furthermore, members of the Turkish group were found more at risk to feel anxious or depressed, which was in turn related to increased loneliness. CONCLUSIONS: Policy makers are encouraged to develop multifaceted prevention strategies concerning those risk factors that are most changeable, thereby focusing per risk factor on those ethnic groups for which it is an important contribution to loneliness. PMID- 27497439 TI - genipe: an automated genome-wide imputation pipeline with automatic reporting and statistical tools. AB - : Genotype imputation is now commonly performed following genome-wide genotyping experiments. Imputation increases the density of analyzed genotypes in the dataset, enabling fine-mapping across the genome. However, the process of imputation using the most recent publicly available reference datasets can require considerable computation power and the management of hundreds of large intermediate files. We have developed genipe, a complete genome-wide imputation pipeline which includes automatic reporting, imputed data indexing and management, and a suite of statistical tests for imputed data commonly used in genetic epidemiology (Sequence Kernel Association Test, Cox proportional hazards for survival analysis, and linear mixed models for repeated measurements in longitudinal studies). AVAILABILITY AND IMPLEMENTATION: The genipe package is an open source Python software and is freely available for non-commercial use (CC BY NC 4.0) at https://github.com/pgxcentre/genipe Documentation and tutorials are available at http://pgxcentre.github.io/genipe CONTACT: louis philippe.lemieux.perreault@statgen.org or marie pierre.dube@statgen.orgSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27497440 TI - scphaser: haplotype inference using single-cell RNA-seq data. AB - Determination of haplotypes is important for modelling the phenotypic consequences of genetic variation in diploid organisms, including cis-regulatory control and compound heterozygosity. We realized that single-cell RNA-seq (scRNA seq) data are well suited for phasing genetic variants, since both transcriptional bursts and technical bottlenecks cause pronounced allelic fluctuations in individual single cells. Here we present scphaser, an R package that phases alleles at heterozygous variants to reconstruct haplotypes within transcribed regions of the genome using scRNA-seq data. The devised method efficiently and accurately reconstructed the known haplotype for >=93% of phasable genes in both human and mouse. It also enables phasing of rare and de novo variants and variants far apart within genes, which is hard to attain with population-based computational inference. AVAILABILITY AND IMPLEMENTATION: scphaser is implemented as an R package. Tutorial and code are available at https://github.com/edsgard/scphaser CONTACT: rickard.sandberg@ki.se SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 27497441 TI - Metrics for rapid quality control in RNA structure probing experiments. AB - MOTIVATION: The diverse functionalities of RNA can be attributed to its capacity to form complex and varied structures. The recent proliferation of new structure probing techniques coupled with high-throughput sequencing has helped RNA studies expand in both scope and depth. Despite differences in techniques, most experiments face similar challenges in reproducibility due to the stochastic nature of chemical probing and sequencing. As these protocols expand to transcriptome-wide studies, quality control becomes a more daunting task. General and efficient methodologies are needed to quantify variability and quality in the wide range of current and emerging structure probing experiments. RESULTS: We develop metrics to rapidly and quantitatively evaluate data quality from structure probing experiments, demonstrating their efficacy on both small synthetic libraries and transcriptome-wide datasets. We use a signal-to-noise ratio concept to evaluate replicate agreement, which has the capacity to identify high-quality data. We also consider and compare two methods to assess variability inherent in probing experiments, which we then utilize to evaluate the coverage adjustments needed to meet desired quality. The developed metrics and tools will be useful in summarizing large-scale datasets and will help standardize quality control in the field. AVAILABILITY AND IMPLEMENTATION: The data and methods used in this article are freely available at: http://bme.ucdavis.edu/aviranlab/SPEQC_software CONTACT: saviran@ucdavis.eduSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27497442 TI - A novel copy number variants kernel association test with application to autism spectrum disorders studies. AB - MOTIVATION: Copy number variants (CNVs) have been implicated in a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability and schizophrenia. Recent advances in high-throughput genomic technologies have enabled rapid discovery of many genetic variants including CNVs. As a result, there is increasing interest in studying the role of CNVs in the etiology of many complex diseases. Despite the availability of an unprecedented wealth of CNV data, methods for testing association between CNVs and disease-related traits are still under-developed due to the low prevalence and complicated multi-scale features of CNVs. RESULTS: We propose a novel CNV kernel association test (CKAT) in this paper. To address the low prevalence, CNVs are first grouped into CNV regions (CNVR). Then, taking into account the multi scale features of CNVs, we first design a single-CNV kernel which summarizes the similarity between two CNVs, and next aggregate the single-CNV kernel to a CNVR kernel which summarizes the similarity between two CNVRs. Finally, association between CNVR and disease-related traits is assessed by comparing the kernel-based similarity with the similarity in the trait using a score test for variance components in a random effect model. We illustrate the proposed CKAT using simulations and show that CKAT is more powerful than existing methods, while always being able to control the type I error. We also apply CKAT to a real dataset examining the association between CNV and autism spectrum disorders, which demonstrates the potential usefulness of the proposed method. AVAILABILITY AND IMPLEMENTATION: A R package to implement the proposed CKAT method is available at http://works.bepress.com/debashis_ghosh/ CONTACTS: xzhan@fhcrc.org or debashis.ghosh@ucdenver.eduSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27497443 TI - WebSTAR3D: a web server for RNA 3D structural alignment. AB - : The WebSTAR3D web server is a user-friendly online interface for the alignment of RNA 3D structures. The website takes as input two files, each of which can be in either PDB or mmCIF format, containing the desired structures to align, via a PDB code or user upload. In return, the user is presented with a visualization of the aligned structures in Jmol or JSmol, along with the corresponding sequence alignment, and the option to download the nucleotide mapping of the structures and a PDB file containing the aligned, superimposed structures. AVAILABILITY AND IMPLEMENTATION: The WebSTAR3D is available at http://rna.ucf.edu/WebSTAR3D CONTACT: shzhang@cs.ucf.edu. PMID- 27497444 TI - Rule-based modeling with Virtual Cell. AB - Rule-based modeling is invaluable when the number of possible species and reactions in a model become too large to allow convenient manual specification. The popular rule-based software tools BioNetGen and NFSim provide powerful modeling and simulation capabilities at the cost of learning a complex scripting language which is used to specify these models. Here, we introduce a modeling tool that combines new graphical rule-based model specification with existing simulation engines in a seamless way within the familiar Virtual Cell (VCell) modeling environment. A mathematical model can be built integrating explicit reaction networks with reaction rules. In addition to offering a large choice of ODE and stochastic solvers, a model can be simulated using a network free approach through the NFSim simulation engine. AVAILABILITY AND IMPLEMENTATION: Available as VCell (versions 6.0 and later) at the Virtual Cell web site (http://vcell.org/). The application installs and runs on all major platforms and does not require registration for use on the user's computer. Tutorials are available at the Virtual Cell website and Help is provided within the software. Source code is available at Sourceforge. CONTACT: vcell_support@uchc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 27497445 TI - Synergistic Activation of RD29A Via Integration of Salinity Stress and Abscisic Acid in Arabidopsis thaliana. AB - Plants perceive information from the surroundings and elicit appropriate molecular responses. How plants dynamically respond to combinations of external inputs is yet to be revealed, despite the detailed current knowledge of intracellular signaling pathways. We measured dynamics of Response-to-Dehydration 29A (RD29A) expression induced by single or combined NaCl and ABA treatments in Arabidopsis thaliana. RD29A expression in response to a combination of NaCl and ABA leads to unique dynamic behavior that cannot be explained by the sum of responses to individual NaCl and ABA. To explore the potential mechanisms responsible for the observed synergistic response, we developed a mathematical model of the DREB2 and AREB pathways based on existing knowledge, where NaCl and ABA act as the cognate inputs, respectively, and examined various system structures with cross-input modulation, where non-cognate input affects expression of the genes involved in adjacent signaling pathways. The results from the analysis of system structures, combined with the insights from microarray expression profiles and model-guided experiments, predicted that synergistic activation of RD29A originates from enhancement of DREB2 activity by ABA. Our analysis of RD29A expression profiles demonstrates that a simple mathematical model can be used to extract information from temporal dynamics induced by combinatorial stimuli and produce experimentally testable hypotheses. PMID- 27497446 TI - NDH-Mediated Cyclic Electron Flow Around Photosystem I is Crucial for C4 Photosynthesis. AB - C4 photosynthesis exhibits efficient CO2 assimilation in ambient air by concentrating CO2 around ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) through a metabolic pathway called the C4 cycle. It has been suggested that cyclic electron flow (CEF) around PSI mediated by chloroplast NADH dehydrogenase-like complex (NDH), an alternative pathway of photosynthetic electron transport (PET), plays a crucial role in C4 photosynthesis, although the contribution of NDH-mediated CEF is small in C3 photosynthesis. Here, we generated NDH-suppressed transformants of a C4 plant, Flaveria bidentis, and showed that the NDH-suppressed plants grow poorly, especially under low-light conditions. CO2 assimilation rates were consistently decreased in the NDH suppressed plants under low and medium light intensities. Measurements of non photochemical quenching (NPQ) of Chl fluorescence, the oxidation state of the reaction center of PSI (P700) and the electrochromic shift (ECS) of pigment absorbance indicated that proton translocation across the thylakoid membrane is impaired in the NDH-suppressed plants. Since proton translocation across the thylakoid membrane induces ATP production, these results suggest that NDH mediated CEF plays a role in the supply of ATP which is required for C4 photosynthesis. Such a role is more crucial when the light that is available for photosynthesis is limited and the energy production by PET becomes rate determining for C4 photosynthesis. Our results demonstrate that the physiological contribution of NDH-mediated CEF is greater in C4 photosynthesis than in C3 photosynthesis, suggesting that the mechanism of PET in C4 photosynthesis has changed from that in C3 photosynthesis accompanying the changes in the mechanism of CO2 assimilation. PMID- 27497447 TI - The Arabidopsis Iron-Sulfur Protein GRXS17 is a Target of the Ubiquitin E3 Ligases RGLG3 and RGLG4. AB - The stability of signaling proteins in eukaryotes is often controlled by post translational modifiers. For polyubiquitination, specificity is assured by E3 ubiquitin ligases. Although plant genomes encode hundreds of E3 ligases, only few targets are known, even in the model Arabidopsis thaliana. Here, we identified the monothiol glutaredoxin GRXS17 as a substrate of the Arabidopsis E3 ubiquitin ligases RING DOMAIN LIGASE 3 (RGLG3) and RGLG4 using a substrate trapping approach involving tandem affinity purification of RING-dead versions. Simultaneously, we used a ubiquitin-conjugating enzym (UBC) panel screen to pinpoint UBC30 as a cognate E2 UBC capable of interacting with RGLG3 and RGLG4 and mediating auto-ubiquitination of RGLG3 and ubiquitination of GRXS17 in vitro. Accordingly, GRXS17 is ubiquitinated and degraded in an RGLG3- and RGLG4 dependent manner in planta. The truncated hemoglobin GLB3 also interacted with RGLG3 and RGLG4 but appeared to obstruct RGLG3 ubiquitination activity rather than being its substrate. Our results suggest that the RGLG family is intimately linked to the essential element iron. PMID- 27497448 TI - "It Can't Happen Soon Enough." The Role of Readiness in Residential Moves by Older Parents. AB - My father moved from his home of 92 years to a care community in a distant location. This is the story of his move, from the perspective of a gerontologist and soon-to-be young-old daughter. I describe the events that prompted my father's decision to make the move, how I chose the care community, the transition arrangements, and the outcomes. I discuss key factors that contributed to the successful transition, all with a focus on readiness. Other factors included drawing on my knowledge as a gerontologist, using informal networks to identify a care community, visiting the care community repeatedly, and communicating openly and often with family. I briefly describe my father's quality of life after the move. I examine my experiences in the context of relevant research in gerontology, recommend how gerontologists can manage transitions to care communities for their aging parents, and offer suggestions for research. PMID- 27497449 TI - Interconnections Between My Research and Experience as a Caregiver: Impacts on Empirical and Personal Perspectives. AB - Shortly after I received my first R01 grant to study the health effects of caregiving, my sister and I became caregivers to our father. For the next 13 years, we helped him with activities of daily living (ADLs), accompanied him to doctors' appointments, arranged for home health care, and finally for home hospice. At first, I was able to connect our assistance with ADLs, frustration with coordinating his care, and our psychological stress with my epidemiologic studies. My familiarity with the language of caregiving and long-term care helped us to navigate the medical and home care systems, and to be advocates for my father. However, as my father's health declined, I felt an increasing disconnect between my research and my experience: communicating with physicians and other care providers, responding to crises and conversations with my sister about placing our father in a nursing home were greater sources of stress than my father's dementia. These discrepancies made me realize that I could help caregivers more by helping them to negotiate these challenges than through performing quantitative research. So I enrolled in a counseling psychology program. My manuscript will chronicle the ways that caregiving changed me; how my professional work did and did not help me as a caregiver; how the developmental and family theories that I am learning in my psychology classes have expanded my understanding of stressors facing adult child caregivers, and how this entire experience ties into generativity and Third Chapter careers that build on midlife experiences. PMID- 27497450 TI - The Insiders as Outsiders: Professionals Caring for an Aging Parent. AB - As professionals in geriatric medicine and social work, we are caregivers for our widowed mother of 90 years, a woman with neurocognitive disorder and multiple medical conditions. She has had repeated, problematic encounters with the health care system over the past 4 years. Caring successfully for an aging parent requires a comprehensive understanding of her unique medical, psychological, and functional status; need for social support; and overall goals of care. Poor communication between and among clinical teams-and with patients and families-is ubiquitous. The patient and family are not consistently listened to, or integrated, into the clinical team. We recount our experiences of one hospitalization and how we addressed the recurring obstacles we faced. Our training and experience gave us a firm understanding of the hazards of hospitalizing an elderly person and the need to be present, engaged, attentive, active, and vigilant. We caught and corrected major mistakes: failure to follow up abnormal test results, multiple medication errors, undertreatment of pain, poor fall prevention, and inappropriate assessment and placement for rehabilitation. In a dysfunctional health care system, the family is, and must be, the ultimate fail-safe mechanism. We identify potentially effective solutions for the problems we encountered: adoption of dementia-sensitive and patient- and family-centered care, improved communication, better management of information (including better systems for monitoring lab results and for dispensing and reconciling medications), expediting care, changing reimbursement and regulation, and improving discharge planning and placement. PMID- 27497451 TI - Synchronizing the patient-centered model and health behavior change. PMID- 27497452 TI - Caring for LGBTQ patients: Methods for improving physician cultural competence. AB - This article summarizes the components of a curriculum used to teach family medicine residents and faculty about LGBTQ patients' needs in a family medicine residency program in the Pacific Northwest region of the United States. This curriculum was developed to provide primary care physicians and physicians-in training with skills to provide better health care for LGBTQ-identified patients. The curriculum covers topics that range from implicit and explicit bias and appropriate terminology to techniques for crafting patient-centered treatment plans. Additionally, focus is placed on improving the understanding of specific and unique barriers to competent health care encountered by LGBTQ patients. Through facilitated discussion, learners explore the health disparities that disproportionately affect LGBTQ individuals and develop skills that will improve their ability to care for LGBTQ patients. The goal of the curriculum is to teach family medicine faculty and physicians in training how to more effectively communicate with and treat LGBTQ patients in a safe, non-judgmental, and welcoming primary care environment. PMID- 27497453 TI - Patient perceptions of weight loss: Implications for patients, providers, and trainees. AB - OBJECTIVES: The prevalence of overweight and obese individuals in the United States is growing, and primary health care represents a setting in which providers may address weight with their patients. However, many providers and medical trainees feel ill-prepared to address the full scope of complexities associated with weight loss. This study sought to investigate patients' perceptions of the barriers and facilitators they encountered in their weight loss journeys. The results of the mixed-methods study will be used to inform a better understanding among providers and medical students of how to address weight loss with their patients. This study was approved by the institutional review board of Medical College of Wisconsin. METHODS: Participants were selected from patient panels at a Family Medicine Residency Program. Participants who enrolled in the study completed a survey that collected attitudes and behaviors about weight loss and demographics. The patients also participated in a 60- to 90 min guided interview. Interviews were transcribed verbatim and analyzed using open-coding techniques and principles of grounded theory. RESULTS: To date, five participants completed the study. All were female with a mean age of 52 years. Two primary themes emerged from a grounded theory model. The first theme centered on individual's knowledge, attitudes, and behaviors to lost weight. The second theme emphasized that societal relationships serve as both a barrier and a facilitator to weight loss. CONCLUSION: The overarching conclusion of this study is that individuals often have the knowledge to make positive health behaviors changes, but multiple factors may prohibit this from occurring. When a supportive environment exists, healthy behavior changes are more attainable. Physicians, mid level providers, and medical trainees and even medical systems can provide appropriate support to join the patient on their weight loss journey. PMID- 27497454 TI - Comprehensive care of pain: Developing systems and tools to improve patient care and resident education. AB - Chronic non-cancer pain is a common condition associated with tremendous risk for morbidity and mortality. In many settings, the management of chronic non-cancer pain by primary care providers, although customary, can be difficult due to inadequate training and conflicts between patient expectations and best practices. Resident physicians, faculty, and staff of this family medicine residency program developed a comprehensive chronic pain management program to address these issues while improving patient outcomes. The program was aligned with evidence-based chronic non-cancer pain management strategies yet tailored to the needs of the providers and patients and the strengths of the clinic. In the end, the societal demand for improved chronic non-cancer pain management resulted in a massive curricular and clinical practice overhaul for this residency program. PMID- 27497455 TI - The elephant in the room: Dialogues about race within cross-cultural supervisory relationships. AB - OBJECTIVES: For centuries, the concept of race, a uniquely pervasive social construct, has often complicated dialogue and interactions between groups of people. This study assessed perceptions and attitudes of faculty and trainees with varied racial backgrounds within graduate medical and psychology programs. Self-reported responses addressed potential barriers and facilitating factors required for meaningful conversations about race. METHODS: A brief 18-question survey was developed and administered electronically to three professional and academic Listservs within a large metropolitan city in northeast United States. Quantitative and qualitative analysis were conducted using SPSS Statistical Software and Text analyzer. RESULTS: Results revealed that among participants (N = 57) a majority experienced cross-racial supervision, and more than half indicated engaging in conversations about race within supervision. Respondents endorsed lack of comfort and lack of opportunity/time as significant barriers to discussing race within supervision. When race-related dialogues occurred, a majority of supervisees and supervisors found it beneficial. Most Supervisors of Color(a) actively initiated these conversations in supervision, while White supervisees endorsed the least benefit from these conversations. Contrary to our expectations, few respondents endorsed limited training as a barrier. DISCUSSION: The current study revealed cross-racial dialogues about race may be occurring frequently in supervisory relationships. Supervisees of Color reported benefiting from these dialogues, in contrast to their White counterparts, who endorsed the least benefit. Lack of comfort in supervisory relationships appears to be a significant barrier to having these conversations. Therefore, it is important for supervisors to create supervisory relationships emphasizing safety and comfort. Directions for future research are discussed. PMID- 27497456 TI - Innovative patient-centered skills training addressing challenging issues in cancer communications: Using patient's stories that teach. AB - This workshop demonstrated the utility of a patient-centered web-based/digital Breaking Bad News communication training module designed to educate learners of various levels and disciplines. This training module is designed for independent, self-directed learning as well as group instruction. These interactive educational interventions are based upon video-recorded patient stories. Curriculum development was the result of an interdisciplinary, collaborative effort involving faculty from the East Tennessee State University (ETSU) Graduate Storytelling Program and the departments of Family and Internal Medicine at the James H. Quillen College of Medicine. The specific goals of the BBN training module are to assist learners in: (1) understanding a five-step patient-centered model that is based upon needs, preferences, and expectations of patients with cancer and (2) individualizing communication that is consistent with patient preferences in discussing emotions, informational detail, prognosis and timeline, and whether or not to discuss end-of-life issues. The pedagogical approach to the training module is to cycle through Emotional Engagement, Data, Modeled Practices, Adaptation Opportunities, and Feedback. The communication skills addressed are rooted in concepts found within the Reaching Common Ground communication training. A randomized control study investigating the effectiveness of the Breaking Bad News module found that medical students as well as resident physicians improved their communication skills as measured by an Objective Structured Clinical Examination. Four other similarly designed modules were also created: Living Through Treatment, Transitions: From Curable to Treatable/From Treatable to End-of-Life, Spirituality, and Family. PMID- 27497457 TI - Integrating motivational interviewing and narrative therapy to teach behavior change to family medicine resident physicians. AB - INTRODUCTION: Motivational interviewing is a useful skill to address the common problem of patient ambivalence regarding behavior change by uncovering and strengthening a person's own motivation and commitment to change. The Family Medicine Milestones underline the need for clear teaching and monitoring of skills in communication and behavior change in Family Medicine postgraduate training settings. METHODS: This article reports the integration of a motivational interviewing curriculum into an existing longitudinal narrative therapy-based curriculum on patient-centered communication. OUTCOMES: Observed structured clinical examination for six participants indicate that intern physicians are able to demonstrate moderate motivational interviewing skill after a brief 2-h workshop. Participant self-evaluations for 16 participants suggest a brief 2-h curriculum was helpful at increasing importance of learning motivational interviewing by participants, and that participants desire further training opportunities. CONCLUSION: A brief motivational interviewing curriculum can be integrated into existing communication training in a Family Medicine residency training program. PMID- 27497458 TI - Improving patient-centered communication while using an electronic health record: Report from a curriculum evaluation. AB - INTRODUCTION: Researchers and clinicians are concerned about the impact of electronic health record use and patient-centered communication. Training about patient-centered clinical communication skills with the electronic health record may help clinicians adapt and remain patient-centered. METHODS: We developed an interactive workshop eliciting challenges and opportunities of working with the electronic health record in clinical practice, introduction of specific patient centered behaviors and mindful practice techniques, and video demonstrating contrasts in common behavior and "better practices." One hundred thirty-nine resident physicians and faculty supervisors in five residency training programs at the University of Rochester Medical Center participated in the workshops. Participants were asked to complete an 11-item survey of behaviors related to their use of the electronic health record prior to training and after attending training. We used paired t-tests to assess changes in self-reported behavior from pre-intervention to post-intervention. RESULTS: We trained 139 clinicians in the workshops; 110 participants completed the baseline assessment and 39 completed both the baseline and post-intervention assessment. Data from post-curriculum respondents found a statistically significant increase in "I told the patient when turning my attention from the patient to the computer," from 60% of the time prior to the training to 70% of the time after. DISCUSSION: Data from our program evaluation demonstrated improvement in one communication behavior. Sample size limited the detection of other changes; further research should investigate effective training techniques for patient-centered communication while using the electronic health record. PMID- 27497459 TI - Inosine enhances recovery of grasp following cortical injury to the primary motor cortex of the rhesus monkey. AB - BACKGROUND: Inosine, a naturally occurring purine nucleoside, has been shown to stimulate axonal growth in cell culture and promote corticospinal tract axons to sprout collateral branches after stroke, spinal cord injury and TBI in rodent models. OBJECTIVE: To explore the effects of inosine on the recovery of motor function following cortical injury in the rhesus monkey. METHODS: After being trained on a test of fine motor function of the hand, monkeys received a lesion limited to the area of the hand representation in primary motor cortex. Beginning 24 hours after this injury and continuing daily thereafter, monkeys received orally administered inosine (500 mg) or placebo. Retesting of motor function began on the 14th day after injury and continued for 12 weeks. RESULTS: During the first 14 days after surgery, there was evidence of significant recovery within the inosine-treated group on measures of fine motor function of the hand, measures of hand strength and digit flexion. While there was no effect of treatment on the time to retrieve a reward, the treated monkeys returned to asymptotic levels of grasp performance significantly faster than the untreated monkeys. Additionally, the treated monkeys evidenced a greater degree of recovery in terms of maturity of grasp pattern. CONCLUSION: These findings demonstrate that inosine can enhance recovery of function following cortical injury in monkeys. PMID- 27497460 TI - Variability of hemodynamic parameters using the common viscosity assumption in a computational fluid dynamics analysis of intracranial aneurysms. AB - BACKGROUND: In most simulations of intracranial aneurysm hemodynamics, blood is assumed to be a Newtonian fluid. However, it is a non-Newtonian fluid, and its viscosity profile differs among individuals. Therefore, the common viscosity assumption may not be valid for all patients. OBJECTIVE: This study aims to test the suitability of the common viscosity assumption. METHODS: Blood viscosity datasets were obtained from two healthy volunteers. Three simulations were performed for three different-sized aneurysms, two using measured value-based non Newtonian models and one using a Newtonian model. The parameters proposed to predict an aneurysmal rupture obtained using the non-Newtonian models were compared with those obtained using the Newtonian model. RESULTS: The largest difference (25%) in the normalized wall shear stress (NWSS) was observed in the smallest aneurysm. Comparing the difference ratio to the NWSS with the Newtonian model between the two Non-Newtonian models, the difference of the ratio was 17.3%. CONCLUSIONS: Irrespective of the aneurysmal size, computational fluid dynamics simulations with either the common Newtonian or non-Newtonian viscosity assumption could lead to values different from those of the patient-specific viscosity model for hemodynamic parameters such as NWSS. PMID- 27497461 TI - A novel classification of screw placement accuracy in the cervical spine. AB - BACKGROUND: Goal of this study is to present an easily reproducible and reliable measurement to evaluate accuracy of screw placement in cervical spine. METHODS: Accuracy of cervical screw position was assessed in 52 patients treated with 163 screws. Each patient receiving pedicle, transarticular C1/2, lateral mass, or laminar screws and postoperative CT scan was included. Placement position was categorized in 5 grades: Grade 1 is ideal with pedicle wall perforation < 1 mm, grade 2 < 2 mm, grade 3 < 3 mm, and grade 4 < 4 mm. Grade 5 > 4 mm and/or obstruction of transverse foramen by more than half a screw diameter. Intraclass correlation coefficient (ICC) values were assessed for inter- and intraobserver reliability. RESULTS: The mode of individual evaluations was calculated to assign a single value to each screw. This yielded 89 grade 1 (54.6%), 48 grade 2 (29.4%), 14 grade 3 (8.6%), 3 grade 4 (1.8%), and 9 grade 5 (5.5%) screws. Intraobserver reliability ICC was 0.966 and 0.959 for measurements. Interobserver reliability ICC was 0.938. CONCLUSION: This study introduces a reliable classification of cervical spine instrumentation with various screw types. This should enable the use of a uniform and reproducible, and thus comparable classification for screw position in cervical spine. PMID- 27497462 TI - The QuickLine IL-6 lateral flow immunoassay improves the rapid intraoperative diagnosis of suspected periprosthetic joint infections. AB - BACKGROUND: When deciding upon the best treatment strategy in revision arthroplasty, it is absolutely crucial to use the best possible preoperative detection whether a periprosthetic joint infection (PJI) is present or not. New molecular markers investigated in serum samples and synovial fluid can help to improve the preoperative diagnosis. In 2001, a novel IL-6 lateral flow immunoassay testing device was introduced which has never been tested in synovial fluid so far. OBJECTIVE: For our study we investigated whether the test can be used safely, feasibly and time effectively with synovial fluid gathered from potentially infected THAs or TKAs and whether the already published cutoff for IL 6 in synovial fluid predicting a PJI can be reproduced using the QuickLine IL-6 immunoassay. METHODS: After ethic approval and within the scope of a prospective controlled trial we investigated 26 patients (m = 9, 34.6%; f= 17, 65.4%) with n = 13 (50%) potentially infected total hip arthroplasties (THAs) and n = 13 (50%) suspected PJIs of total knee arthroplasties (TKAs). Sterile aspirated synovial fluid was examined for total leukocyte count and cell differentiation by a blood count analyzer in body fluid mode as well as for IL-6 (Immulite, Siemens Medical Solutions Diagnostics GmbH, Eschborn, Germany). Another part of the joint aspirate was tested using the QuickLine IL-6 Test by Milenia Biotec (Milenia Biotec, Giebetaen, Germany). RESULTS: The mean concentration of IL-6 as determined from our reference laboratory testing (Siemens Immulight) for aseptic cases was 1,219 pg/mL (SD 1,369 pg/mL, min 134 pg/mL-max 4,214 pg/mL). The mean IL-6 concentration measured via the IL-6 QuickLine for aseptic cases was 410 pg/mL (SD 371 pg/mL, min 100 pg/mL-max 1562 pg/mL). The test showed no false negative or false positive results in the cases tested. In six patients, PJI was considered proven. The QuickLine Test indicated IL 6 concentrations > 10,000 pg/mL in these cases without further quantification above this maximum detection threshold. Results from the QuickLine Test and the laboratory tests were matched and a non-linear best fit curve (log-log-curve) was applied. The subsequent Spearman correlation showed a correlation coefficient of r = 0.92 (95% CI 0.81 0.97) which corresponds to a two-tailed p-value of < 0.0001, respectively. As a primary finding we were able to show that the Milenia QuickLine IL-6 Test can be used safely, feasibly and time effectively with synovial fluid gathered intraoperatively from potentially infected THAs or TKAs. The test as provided worked well in 84.6% of the samples tested and failed only due to very viscous synovial fluid. As a secondary result we found that the previously published cut off for IL-6 in synovial fluid predicting a PJI with a sensitivity of 46.88% and a specificity of 97.62% can be reproduced using the QuickLine IL-6 immunoassay. CONCLUSION: Taking the limitations of the low sample size as a given this relatively simple point of care (POC) assay showed promising results in our pilot trial and may help diagnosing PJI. It may help physicians and surgeons to choose the best and least invasive treatment strategy for patients presenting with painful arthroplasty. PMID- 27497463 TI - Potential impact of oxygenators with venous air trap on air embolism in veno arterial Extracorporeal Life Support. AB - BACKGROUND: Air embolism is a potentially fatal but underrecognized complication in Extracorporeal Life Support (ECLS). Oxygenators containing venous air traps have been developed to minimize the risk of air embolism in daily care. OBJECTIVE: We reproduced air embolism as occurring via a central venous catheter in an experimental setting to test the potential of oxygenators with and without venous bubble trap (VBT) to withhold air. METHODS: An in vitro ECLS circuit was created and a central venous catheter with a 3-way stopcock and a perforated male luer cap was inserted into the inflow line. Three different oxygenators with and without VBT and their capability to withhold air were examined. After 60 seconds of stable ECLS flow, the stopcock was opened towards the atmosphere for 3 minutes. Afterwards, air accumulation within the oxygenator was determined. RESULTS: Comparison of the total air entrapment showed a significant superiority of the oxygenators with VBT (p < 0.001). All oxygenators were able to partly withhold macro air boli, however, the capacity of oxygenators with VBT was higher. Passing through the oxygenator resulted in a reduction of microbubbles in all cases. CONCLUSIONS: Macro air emboli can be substantially reduced by usage of oxygenators that contain a VBT, whereas the capability to withhold microbubbles to a vast extent seems to depend on the intrinsic oxygenator's membrane. PMID- 27497464 TI - Rapid cross platform healthcare gaming design and implementation: The cost effective methodology. AB - There have been massive advances in E-Health and M-Health technology, with recent interest in the utility of games for healthcare and the promotion of well-being and recovery as well as patient empowerment. There has been various review demonstrating the clinical effectiveness and efficacy of games for healthcare. It is the aim of this technical note to illustrate how appropriate gaming engines could be used by non-expert clinicians to program games that could run across various platforms, as well as games that could integrate well with existing mechanical sensors. This would address the limitations with regards to the evidence base of games, as well as the limitations in the deployment of games to various participants. More importantly, games designed are also more likely to be cost-effective and lower in cost. The ability of integration with existing mechanical sensors would value-add existing games and enable recovery and remediation in various domains of health. This would further expand the potential of games as an adjunctive treatment for patients, or at least, to maintain the gains that they have made in their recovery process. PMID- 27497465 TI - Erratum. PMID- 27497466 TI - Unintentional injury after traumatic brain injury: Issues, assessment, and reducing risk. PMID- 27497467 TI - Using the public health model to address unintentional injuries and TBI: A perspective from the Centers for Disease Control and Prevention (CDC). AB - Traumatic brain injury (TBI) can have long term effects on mental and physical health, and can disrupt vocational, educational, and social functioning. TBIs can range from mild to severe and their effects can last many years after the initial injury. CDC seeks to reduce the burden of TBI from unintentional injuries through a focus on primary prevention, improved recognition and management, and intervening to improve health outcomes after TBI. CDC uses a 4-stage public health model to guide TBI prevention, moving from 1) surveillance of TBI, 2) identification of risk and protective factors for TBI, 3) development and testing of evidence-based interventions, to 4) bringing effective intervention to scale through widespread adoption. CDC's unintentional injury prevention activities focus on the prevention of sports-related concussions, motor vehicle crashes, and older adult falls. For concussion prevention, CDC developed Heads Up - an awareness initiative focusing on ways to prevent a concussion in sports, and identifying how to recognize and manage potential concussions. In motor vehicle injury prevention, CDC has developed a tool (MV PICCS) to calculate the expected number of injuries prevented and lives saved using various evidence-based motor vehicle crash prevention strategies. To help prevent TBI related to older adult falls, CDC has developed STEADI, an initiative to help primary care providers identify their patients' falls risk and provide effective interventions. In the future, CDC is focused on advancing our understanding of the public health burden of TBI through improved surveillance in order to produce more comprehensive estimates of the public health burden of TBI. PMID- 27497468 TI - Risk of hospitalization due to motor vehicle crashes among Iraq and Afghanistan War Veterans diagnosed with traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) was deemed the 'signature injury' of the Iraq and Afghanistan Wars (OEF/OIF/OND). Civilians with severe TBI have increased risks of motor vehicle crashes (MVCs). Little is known about MVC risk among Veterans with TBI, many of whom incurred TBIs that were mild in severity. OBJECTIVE: To examine associations between TBI and MVC-related hospitalizations among OEF/OIF/OND Veterans who use Veterans Health Administration (VA) healthcare. METHODS: Using national VA data, we identified 277,330 Veterans who enrolled in VA within one year of deployment. MVC, TBI, and other diagnoses were identified using ICD-9-CM codes. We estimated risk of subsequent MVC hospitalization for those with, versus without, TBI using time-to-event analyses. Time-varying Cox proportional hazards models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) while controlling for potential confounders, including psychiatric diagnoses. RESULTS: There were 28,551 Veterans diagnosed with TBI; 130 were subsequently hospitalized for MVC. In adjusted models, those with TBI were four times more likely to be hospitalized for MVC than those without (HR = 4.2; CI = 3.3-5.3). CONCLUSION: Veterans with TBI had substantially greater risk of MVC-related hospitalizations. These Veterans may benefit from enhanced driving safety interventions to reduce risk. PMID- 27497469 TI - Unintentional injuries after TBI: Potential risk factors, impacts, and prevention. AB - BACKGROUND: The top three causes of fatal unintentional injuries are falls, motor vehicle crashes, and being struck against or struck by objects or persons. These etiologies also happen to be the leading causes of TBI, a serious public health problem, in the US. Reduced cognitive functioning, poor decision making, increased risk taking, disinhibition, diminished safety skills and substance use, place individuals with TBI at an increased risk for subsequent unintentional injuries. The caregiving, psychological, social and financial burden of initial injuries is enormous. Unintentional injuries post-TBI add to that burden significantly. Many unintentional injuries can be prevented with simple education and environment and lifestyle changes. Injury prevention requires collaboration among many. OBJECTIVE: This literature review will share information regarding potential triggers or causes of unintentional injuries after TBI to identify potential issues. The many impacts of these injuries will be reviewed. Best practices in prevention will be presented. CONCLUSION: Ultimately, education, discussion, and awareness across multiple stakeholders can aid in preventing unintentional injuries after TBI. PMID- 27497470 TI - The Safety Assessment Measure for persons with traumatic brain injury: Item pool development and content validity. AB - BACKGROUND: Persons with moderate to severe TBI are at increased risk for unintentional injury or harm in the home and community; however, there is currently no standard measure of safety risk they face now and in the future. OBJECTIVE: To develop comprehensive and content valid scales and item pools for assessing safety and risk for persons with moderate to severe traumatic brain injuries. METHOD: Qualitative psychometric methods for developing scales and items were used including literature review, item development and revision, focus groups with interdisciplinary rehabilitation staff (n = 26) for rating content validity, and cognitive interviewing of TBI family members (n = 9) for assuring item clarity. RESULTS: The Safety Assessment Measure is comprised of 6 primary scales - Cognitive Capacity, Visuomotor Capacity, Wheelchair Use, Risk Perception, Self-Regulation, and Compliance Failures with Safety Recommendations in which family caregivers or clinicians rate the risk for unintentional injury or harm in adults who have sustained moderate or severe TBI. The scale item pools encompass a broad spectrum of everyday activities that pose risk in the home and community and were rated as having excellent levels of content validity. CONCLUSIONS: The Safety Assessment Measure scales and items cover a broad range of instrumental activities of daily living that can increase the risk of unintentional injuries or harm. Empirical evidence suggests that the Safety Assessment Measure items have excellent content validity. Future research should use modern psychometric methods to examine each scale unidimensionality, model fit, and precision. PMID- 27497472 TI - Differential transcriptional regulation by alternatively designed mechanisms: A mathematical modeling approach. AB - Cells maintain cellular homeostasis employing different regulatory mechanisms to respond external stimuli. We study two groups of signal-dependent transcriptional regulatory mechanisms. In the first group, we assume that repressor and activator proteins compete for binding to the same regulatory site on DNA (competitive mechanisms). In the second group, they can bind to different regulatory regions in a noncompetitive fashion (noncompetitive mechanisms). For both competitive and noncompetitive mechanisms, we studied the gene expression dynamics by increasing the repressor or decreasing the activator abundance (inhibition mechanisms), or by decreasing the repressor or increasing the activator abundance (activation mechanisms). We employed delay differential equation models. Our simulation results show that the competitive and noncompetitive inhibition mechanisms exhibit comparable repression effectiveness. However, response time is fastest in the noncompetitive inhibition mechanism due to increased repressor abundance, and slowest in the competitive inhibition mechanism by increased repressor level. The competitive and noncompetitive inhibition mechanisms through decreased activator abundance show comparable and moderate response times, while the competitive and noncompetitive activation mechanisms by increased activator protein level display more effective and faster response. Our study exemplifies the importance of mathematical modeling and computer simulation in the analysis of gene expression dynamics. PMID- 27497471 TI - Return to work after work-related traumatic brain injury. AB - BACKGROUND: Work-related traumatic brain injury (wrTBI) comprises up to 24% of TBIs, yet relatively little is known about it even though wrTBI incurs high costs to employers, insurers, and injured. OBJECTIVES: To compare demographic, clinical, and occupation-related factors following mild-to-moderate TBI of those who successfully returned to work (RTW) versus those who did not, and to determine perceived facilitators of and barriers to RTW. METHODS: Retrospective cohort study from a consecutive sample of persons with TBI seen in an outpatient assessment clinic. Surveys were mailed to eligible potential participants. Consenting participants were interviewed by telephone or returned a completed survey via mail. RESULTS: Fifty of 116 eligible individuals participated in the study. Half of the participants returned to work. Participants in this group were significantly younger and had more years of education than the no-RTW group. The most common factors perceived to assist the RTW group were support of family and friends (92%) and of treatment providers (80%), and employers who provided accommodations (76%). Difficulty thinking and concentrating (94%) and fatigue (94%) were the most common barriers to RTW. CONCLUSIONS: This study highlights the importance of support from family, friends and employers as RTW facilitators. These factors merit further investigation in TBI rehabilitation studies. PMID- 27497473 TI - Cholesteryl Ester Transfer Protein Intimately Involved in Dyslipidemia-Related Susceptibility to Cognitive Deficits in Type 2 Diabetic Patients. AB - BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in diabetic dyslipidemia. OBJECTIVE: We aim to test the hypothesis that CETP might be of importance in mediating dyslipidemia-related susceptibility to cognitive deficits in diabetic patients. METHODS: We recruited 190 type 2 diabetic patients and divided them into two groups according to the Montreal Cognitive Assessment (MoCA) score. The association between CETP and cognitive decline was analyzed with logistic regression and stratification. RESULTS: There were 110 diabetic patients with mild cognition impairment (MCI) and 80 healthy cognition subjects as controls. Dyslipidemia is more common among diabetic patients with MCI; they had a significant increase of serum CETP concentrations, which was negatively correlated with MoCA (r = -0.638; p < 0.001). Negative correlations were also found between the serum CETP concentration with the Auditory Verbal Learning Test (r = -0.266; p = 0.008), indicating memory deficit. Logistic regression analysis revealed that CETP concentration was an independent factor of diabetic MCI (p < 0.001). Further stratification study showed that high serum levels of CETP was an independent risk factor of MCI in diabetic patients with a low density lipoproteins level >=2.59 mmol/L, or high density lipoproteins level <=1.0 mmol/L for men and <=1.3 mmol/L for women, or TG level >=1.7 mmol/L, after adjusting for age, sex, education, and glucose control (all ps < 0.05). CONCLUSIONS: CETP was intimately involved in dyslipidemia-related susceptibility to cognitive decline, especially memory function in type 2 diabetic patients. PMID- 27497474 TI - Cognitive Stimulation for People with Dementia in Long-Term Care Facilities: Baseline Cognitive Level Predicts Cognitive Gains, Moderated by Depression. AB - BACKGROUND: Increasing evidence demonstrates the efficacy of cognitive stimulation (CS) in individuals with dementia. However, conducting studies in nursing homes engenders specific challenges that have limited the data gathered on this topic so far. OBJECTIVE: The aim of this randomized controlled trial was to investigate the effects of CS on cognition, quality of life (QoL), behavioral symptoms, and activities of daily life in persons with dementia living in nursing homes. We further aimed to identify predictors of the intervention's benefits. METHODS: Seventy-one persons with mild to moderate dementia were randomly allocated to the experimental group (EG; n = 36) that visited a CS program twice weekly for eight weeks or to the control group (CG; n = 35) that was receiving usual care. Neuropsychological tests were conducted before and after the intervention period and at six-week follow-up. RESULTS: There were no significant interaction effects Time*Group for the outcome measures. However, regression analysis revealed that a low cognitive baseline level predicted cognitive improvements. Furthermore, a low baseline level of QoL predicted a QoL benefit. For both findings, depression was a significant moderator, meaning that persons with fewer depressive symptoms had a higher probability of showing improvements. CONCLUSION: This study provides data on profiles of patients who are most likely to profit from CS intervention in nursing-home settings and demonstrates that treatment of depression is of the utmost relevance for a positive outcome of CS. Living conditions will have to be considered more thoroughly in future research. PMID- 27497475 TI - Late-Life Depressive Symptoms and Lifetime History of Major Depression: Cognitive Deficits are Largely Due to Incipient Dementia rather than Depression. AB - BACKGROUND: Late-life depression is frequently accompanied by cognitive impairments. OBJECTIVE: Whether these impairments indicate a prodromal state of dementia, or are a symptomatic expression of depression per se is not well studied. METHODS: In a cohort of very old initially non-demented primary care patients (n = 2,709, mean age = 81.1 y), cognitive performance was compared between groups of participants with or without elevated depressive symptoms and with or without subsequent dementia using ANCOVA (adjusted for age, sex, and education). Logistic regression analyses were computed to predict subsequent dementia over up to six years of follow-up. The same analytical approach was performed for lifetime major depression. RESULTS: Participants with elevated depressive symptoms without subsequent dementia showed only small to medium cognitive deficits. In contrast, participants with depressive symptoms with subsequent dementia showed medium to very large cognitive deficits. In adjusted logistic regression models, learning and memory deficits predicted the risk for subsequent dementia in participants with depressive symptoms. Participants with a lifetime history of major depression without subsequent dementia showed no cognitive deficits. However, in adjusted logistic regression models, learning and orientation deficits predicted the risk for subsequent dementia also in participants with lifetime major depression. CONCLUSION: Marked cognitive impairments in old age depression should not be dismissed as "depressive pseudodementia", but require clinical attention as a possible sign of incipient dementia. Non-depressed elderly with a lifetime history of major depression, who remained free of dementia during follow-up, had largely normal cognitive performance. PMID- 27497476 TI - FOXP2 Expression in Frontotemporal Lobar Degeneration-Tau. AB - FOXP2 is altered in a variety of language disorders. We found reduced mRNA and protein expression of FOXP2 in frontal cortex area 8 in Pick's disease, and frontotemporal lobar degeneration-tau linked to P301L mutation presenting with language impairment in comparison with age-matched controls and cases with parkinsonian variant progressive supranuclear palsy. Foxp2 mRNA and protein are also reduced with disease progression in the somatosensory cortex in transgenic mice bearing the P301S mutation in MAPT when compared with wild-type littermates. Our findings support the presence of FOXP2 expression abnormalities in sporadic and familial frontotemporal degeneration tauopathies. PMID- 27497477 TI - Breakdown of the Cerebrovasculature and Blood-Brain Barrier: A Mechanistic Link Between Diabetes Mellitus and Alzheimer's Disease. AB - Alzheimer's disease (AD) and diabetes mellitus (DM) are among the most pervasive and devastating disorders that afflict people throughout the world. Although typically associated with older demographics, recent epidemiologic studies have reported parallel trends in decreasing age of onset and increasing incidence of these conditions. Promising research continues to implicate the cerebrovasculature and blood-brain barrier (BBB) as playing key roles in AD pathoetiology. Similarly, complications accompanying DM, such as diabetic nephropathy/retinopathy, cardiovascular disease, and stroke, have been rooted in vascular compromise. Not surprisingly, DM is now considered a major risk factor for AD. The purpose of this review is to highlight investigations into the role of the cerebrovasculature in the development and progression of AD. We give particular attention to studies on humans and a variety of animal model systems that have demonstrated a link between BBB dysfunction and pathological changes in the brain consistent with aging and AD. Together, these studies suggest that the vascular complications associated with chronic, poorly managed DM can lead to subclinical BBB breakdown that precedes and drives the pathological changes progressing to symptomatic AD, providing a common mechanistic thread connecting these two disorders. Furthermore, this emphasizes the need to focus on the vasculature as a potential therapeutic target with the intent of limiting BBB breakdown involved in disease initiation and progression. In conclusion, AD may be more than just an associated comorbidity of DM, and instead another manifestation of the underlying vascular pathology that is common to both. PMID- 27497478 TI - Astrocytic GluN2A and GluN2B Oppose the Synaptotoxic Effects of Amyloid-beta1-40 in Hippocampal Cells. AB - Early-stage Alzheimer's disease (AD) is characterized by synaptic dysfunction, a phenomenon in which soluble oligomers of amyloid-beta (Abeta) and N-methyl-D aspartate receptor (NMDAR) are implicated. Here, we demonstrated that astrocytes express NMDARs and therefore have the potential to modulate the synaptotoxic actions of Abeta. We found that specific pharmacological antagonism of two of the major NMDAR subunits, GluN2A and GluN2B, exacerbates Abeta-induced synaptotoxicity suggesting, for the first time, that astrocytic GluN2A and GluN2B mediate synaptoprotection. From the perspective of the pathogenic mechanisms of Alzheimer's disease, in which Abeta and NMDAR play significant roles, these observations are striking since neuronal GluN2A and GluN2B are well known modulators of neurodegeneration. We did initial studies to understand the basis for the differential effects of astrocytic and neuronal GluN2A and GluN2B in the promotion of synapse survival, and identified a neurotrophin produced by astrocytes, nerve growth factor beta (beta-NGF), as a likely mediator of the synaptoprotective effects of astrocytic GluN2A and GluN2B activation. The results presented suggest that astrocytes may be suitable druggable targets for the prevention and/or delay of the synaptic loss that occurs during early stages of AD. PMID- 27497479 TI - Adenosine Type A2A Receptor in Peripheral Cell from Patients with Alzheimer's Disease, Vascular Dementia, and Idiopathic Normal Pressure Hydrocephalus: A New/Old Potential Target. AB - As the European population gets older, the incidence of neurological disorders increases with significant impact on social costs. Despite differences in disease etiology, several brain disorders in the elderly (e.g., Alzheimer's disease, vascular dementia, normal pressure hydrocephalus) share dementia as a common clinical feature. The current treatment for the majority of these diseases is merely symptomatic and does not modify the course of the illness. Symptoms of normal pressure hydrocephalus are the only ones that can be modified if they are recognized in time and treated appropriately. Therefore, an important clinical strategy may be disclosed by pathogenic pathways that can be modified and to find drugs that can slow down or even arrest disease progression. Possibly a way to answer this question could be by re-examining all the molecules which have so far succeeded in improving many aspects of cognitive deterioration in some neurodegenerative conditions, that were not considered because of controversial opinions. The main purpose of this summary is to further substantiate the hypothesis that the pathway of adenosine type A2A receptor could be used as a potential target to develop new/old therapeutic strategies. PMID- 27497480 TI - Multi-Vitamin B Supplementation Reverses Hypoxia-Induced Tau Hyperphosphorylation and Improves Memory Function in Adult Mice. AB - Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer's disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3beta phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK 3beta were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3beta. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia. PMID- 27497481 TI - Tau in Late-Life Depression: A Systematic Review and Meta-Analysis. AB - A lifetime history of major depressive disorder (MDD) increases the risk of developing Alzheimer's disease, of which neurofibrillary tangles due to abnormal tau proteins are a hallmark. We systematically reviewed the literature on tau in MDD and identified 49 relevant articles spanning a number of modalities, including cerebrospinal fluid (CSF) analysis, positron emission tomography, and clinicopathological correlation. We compared CSF total and phosphorylated tau proteins in MDD and controls using a meta-analytic approach. We found no difference in total or phosphorylated tau in MDD. We also found no difference in a comparison of a subgroup excluding studies with significant age differences. Positron emission tomography studies lacked specificity. Clinicopathological studies failed to associate neurofibrillary tangles with MDD. The available data on tau in MDD is limited. The involvement of tau in a subset of MDD cannot be ruled out and requires prospective exploration. PMID- 27497482 TI - Yokukansan in the Treatment of Behavioral and Psychological Symptoms of Dementia: An Updated Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Previous clinical studies found that yokukansan has a therapeutic effect on behavioral and psychological symptoms of dementia (BPSD) in dementia patients. OBJECTIVE: To perform an updated meta-analysis of randomized controlled trials (RCTs) testing yokukansan for patients with BPSD. METHODS: Primary efficacy and safety endpoints were BPSD total scores and all-cause discontinuation, respectively. Secondary outcomes were BPSD subscales, cognitive function scores [Mini-mental state examination (MMSE)], activities of daily living (ADL) scores, discontinuation due to adverse events (AEs), and incidences of AEs. RESULTS: Five RCTs with 381 patients with BPSD were included. Compared with controls [placebo+usual care (UC)], yokukansan significantly decreased BPSD total scores [standardized mean difference (SMD) = -0.32, 95% confidence interval (CI) = -0.53 to -0.11, p = 0.003, I2 = 0%, N = 5 studies, n = 361]. Yokukansan was more efficacious in reducing BPSD subscale scores (delusions: SMD = -0.51, 95% CI = -0.98 to -0.04, hallucinations: SMD = -0.54, 95% CI = -0.96 to -0.12, agitation/aggression: SMD = -0.37, 95% CI = -0.60 to -0.15) than placebo+UC. However, yokukansan was not superior to placebo+UC for BPSD total as well as any subscales scores only in Alzheimer's disease patients. Compared with UC, yokukansan treatment improved ADL scores (SMD = -0.32, 95% CI = -0.62 to -0.01). MMSE scores did not differ between the yokukansan and placebo+UC treatment groups. No significant differences were found in all-cause discontinuation, discontinuation due to AEs, and incidences of AEs between yokukansan and placebo+UC treatments. CONCLUSIONS: Our results suggest that yokukansan is beneficial for the treatment of patients with BPSD and is well-tolerated; it was not beneficial for BPSD total and any subscale scores only in Alzheimer's disease patients. PMID- 27497483 TI - Cerebral Arterial Occlusion Did Not Promote the Prevalence of Cerebral Amyloid Angiopathy. AB - BACKGROUND: An impairment of amyloid-beta (Abeta) clearance has been suggested in Alzheimer's disease. Perivascular drainage along cerebrovascular vessels is considered an important amyloid clearance pathway. OBJECTIVE: This study examined the effect of reduced arterial pulsation that could cause an impairment in cerebral amyloid drainage on the prevalence of cortical microbleeds (CMBs), a surrogate marker for cerebral amyloid angiopathy (CAA). METHODS: Patients who lost depiction of either side of the carotid artery or the middle cerebral artery on magnetic resonance angiography were studied. Those who showed acute cerebral infarction or a previous cortical cerebral infarction were excluded. The number of CMBs was counted on the occluded and non-occluded sides of the brain in each subject. The number of subjects who showed more CMBs on the occluded side of the brain was compared with the number of subjects who showed more CMBs on the non occluded side of the brain. RESULTS: Twenty-eight patients were studied. The extent of lacunar infarction and white matter lesions was not different, irrespective of the occluded vessels or the distribution of CMBs. The prevalence of CMBs was not different between the occluded and non-occluded sides of the brain. CONCLUSION: In this cross-sectional study, reduction of arterial pulsation was not associated with a higher prevalence of CAA. Therefore, reduced arterial pulsation alone may not be enough to promote CAA. PMID- 27497484 TI - Herpes and Alzheimer's Disease: Subversion in the Central Nervous System and How It Might Be Halted. AB - The last 8 or so years have seen a large increase in the number of studies supporting the concept of a major role for herpes simplex virus type 1 (HSV1) in Alzheimer's disease (AD). The main advances have been made through studies in humans and in mice, investigating the likelihood of reactivation of the latent virus in brain. Others have aimed to explain the mechanisms in cells whereby the increase in amyloid-beta (Abeta) production on HSV1 infection of cells and mouse brains occurs, and the reason that infected cells make this increase. The possibility that other herpesviruses are involved in the development of AD has been explored, and human herpesvirus type 6, Epstein-Barr virus, and cytomegalovirus, in particular, have been implicated. Epidemiological studies have further supported the role specifically of HSV1 and its reactivation in the disease. Antiviral studies have continued, comparing those acting by different mechanisms, such as restricting viral replication, or blocking viral entry into cells, to treat HSV1-infected cell cultures, and then examining the extent to which the virus-induced increases in Abeta and AD-like tau are reduced. All the studies support the usage of antiviral treatment to slow or halt the progression of AD. PMID- 27497486 TI - Is Axonal Degeneration a Key Early Event in Parkinson's Disease? AB - Recent research suggests that in Parkinson's disease the long, thin and unmyelinated axons of dopaminergic neurons degenerate early in the disease process. We organized a workshop entitled 'Axonal Pathology in Parkinson's disease', on March 23rd, 2016, in Cleveland, Ohio with the goals of summarizing the state-of-the-art and defining key gaps in knowledge. A group of eight research leaders discussed new developments in clinical pathology, functional imaging, animal models, and mechanisms of degeneration including neuroinflammation, autophagy and axonal transport deficits. While the workshop focused on PD, comparisons were made to other neurological conditions where axonal degeneration is well recognized. PMID- 27497487 TI - Brain networks under attack: robustness properties and the impact of lesions. AB - A growing number of studies approach the brain as a complex network, the so called 'connectome'. Adopting this framework, we examine what types or extent of damage the brain can withstand-referred to as network 'robustness'-and conversely, which kind of distortions can be expected after brain lesions. To this end, we review computational lesion studies and empirical studies investigating network alterations in brain tumour, stroke and traumatic brain injury patients. Common to these three types of focal injury is that there is no unequivocal relationship between the anatomical lesion site and its topological characteristics within the brain network. Furthermore, large-scale network effects of these focal lesions are compared to those of a widely studied multifocal neurodegenerative disorder, Alzheimer's disease, in which central parts of the connectome are preferentially affected. Results indicate that human brain networks are remarkably resilient to different types of lesions, compared to other types of complex networks such as random or scale-free networks. However, lesion effects have been found to depend critically on the topological position of the lesion. In particular, damage to network hub regions-and especially those connecting different subnetworks-was found to cause the largest disturbances in network organization. Regardless of lesion location, evidence from empirical and computational lesion studies shows that lesions cause significant alterations in global network topology. The direction of these changes though remains to be elucidated. Encouragingly, both empirical and modelling studies have indicated that after focal damage, the connectome carries the potential to recover at least to some extent, with normalization of graph metrics being related to improved behavioural and cognitive functioning. To conclude, we highlight possible clinical implications of these findings, point out several methodological limitations that pertain to the study of brain diseases adopting a network approach, and provide suggestions for future research. PMID- 27497489 TI - Reply: Glial mitochondropathy in infantile neuroaxonal dystrophy: pathophysiological and therapeutic implications. PMID- 27497488 TI - Healthy brain connectivity predicts atrophy progression in non-fluent variant of primary progressive aphasia. AB - Neurodegeneration has been hypothesized to follow predetermined large-scale networks through the trans-synaptic spread of toxic proteins from a syndrome specific epicentre. To date, no longitudinal neuroimaging study has tested this hypothesis in vivo in frontotemporal dementia spectrum disorders. The aim of this study was to demonstrate that longitudinal progression of atrophy in non fluent/agrammatic variant primary progressive aphasia spreads over time from a syndrome-specific epicentre to additional regions, based on their connectivity to the epicentre in healthy control subjects. The syndrome-specific epicentre of the non-fluent/agrammatic variant of primary progressive aphasia was derived in a group of 10 mildly affected patients (clinical dementia rating equal to 0) using voxel-based morphometry. From this region, the inferior frontal gyrus (pars opercularis), we derived functional and structural connectivity maps in healthy controls (n = 30) using functional magnetic resonance imaging at rest and diffusion-weighted imaging tractography. Graph theory analysis was applied to derive functional network features. Atrophy progression was calculated using voxel-based morphometry longitudinal analysis on 34 non-fluent/agrammatic patients. Correlation analyses were performed to compare volume changes in patients with connectivity measures of the healthy functional and structural speech/language network. The default mode network was used as a control network. From the epicentre, the healthy functional connectivity network included the left supplementary motor area and the prefrontal, inferior parietal and temporal regions, which were connected through the aslant, superior longitudinal and arcuate fasciculi. Longitudinal grey and white matter changes were found in the left language-related regions and in the right inferior frontal gyrus. Functional connectivity strength in the healthy speech/language network, but not in the default network, correlated with longitudinal grey matter changes in the non fluent/agrammatic variant of primary progressive aphasia. Graph theoretical analysis of the speech/language network showed that regions with shorter functional paths to the epicentre exhibited greater longitudinal atrophy. The network contained three modules, including a left inferior frontal gyrus/supplementary motor area, which was most strongly connected with the epicentre. The aslant tract was the white matter pathway connecting these two regions and showed the most significant correlation between fractional anisotropy and white matter longitudinal atrophy changes. This study showed that the pattern of longitudinal atrophy progression in the non-fluent/agrammatic variant of primary progressive aphasia relates to the strength of connectivity in pre determined functional and structural large-scale speech production networks. These findings support the hypothesis that the spread of neurodegeneration occurs by following specific anatomical and functional neuronal network architectures. PMID- 27497490 TI - Glial mitochondropathy in infantile neuroaxonal dystrophy: pathophysiological and therapeutic implications. PMID- 27497492 TI - Centre of epileptogenic tubers generate and propagate seizures in tuberous sclerosis. AB - SEE DUCHOWNY DOI101093/AWW216 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Multiple seizure foci, seizure propagation and epileptic spasms complicate presurgical seizure localization in tuberous sclerosis. Furthermore, controversy exists about the contribution of tubers, perituberal cortex and the underlying genetic abnormality to epileptogenesis. We aimed to determine the epileptogenic substrate in tuberous sclerosis by studying spatio-temporal patterns of seizure onset and propagation on intracranial EEG recordings in which multiple depth and surface electrodes sampled multiple tubers and perituberal cortex. Ten intracranial EEG recordings (seven extraoperative, three intraoperative) from 10 children with tuberous sclerosis were analysed. Notable thickening and signal abnormality in the centre of many tubers on magnetic resonance imaging led to tuber centres being recorded with depth electrodes. Spatially-meaningful bipolar montages were reformatted incorporating channels recording only from the tuber centre, tuber rim and perituberal cortex. Interictal epileptiform discharges and ictal rhythms were analysed visually for location, field, morphology, frequency, latency and temporal dispersion. Fifteen electroclinically distinct seizures were recorded in the 10 patients. Seizure onset was recorded in tubers in all 15 electroclinically distinct seizures; in 9/10 electroclinically distinct seizures recorded with optimal spatial sampling, seizure onset was recorded in the tuber centre, with or without involvement of the tuber rim but not perituberal cortex. Quantitative electroencephalography analysis by pairwise cross-correlation confirmed that the tuber centre led the tuber rim and perituberal cortex during interictal, preictal and ictal spike trains. Seizure propagation was observed in 10/15 electroclinically distinct seizures, being tuber-to-tuber in all. Seven of the 17 tubers showing seizure propagation activated an independent ictal rhythm, morphologically distinct from that seen in seizure onset region (intra-ictal activation). Of the total 48 tubers sampled, 16 exhibited seizure onset, 17 were involved in seizure propagation and 40 exhibited interictal epileptiform discharges, 33 independent and seven propagated. Seizure onsets were recorded in 16/33 tubers with independent interictal epileptiform discharges, but 0/7 tubers with only propagated epileptiform discharges or 0/8 tubers with no epileptiform discharges (P = 0.003). Seizure onsets were recorded from 4/7 tubers with and 0/10 tubers without intra-ictal activation (P = 0.015). Thus, focal seizures and interictal epileptiform discharges in tuberous sclerosis arise in the centre of epileptogenic tubers and propagate to the tuber rim, perituberal cortex and other epileptogenic tubers. Rhythmic interictal epileptiform discharges and intra-ictal activation of propagated ictal rhythms are potential biomarkers of epileptogenic tubers. Interictal and ictal EEG features of epileptogenic tubers have similarities to focal cortical dysplasia type II, consistent with the reported imaging, histological and molecular similarities. PMID- 27497491 TI - Delayed seizures after intracerebral haemorrhage. AB - Late seizures after intracerebral haemorrhage occur after the initial acute haemorrhagic insult subsides, and represent one of its most feared long-term sequelae. Both susceptibility to late seizures and their functional impact remain poorly characterized. We sought to: (i) compare patients with new-onset late seizures (i.e. delayed seizures), with those who experienced a recurrent late seizure following an immediately post-haemorrhagic seizure; and (ii) investigate the effect of late seizures on long-term functional performance after intracerebral haemorrhage. We performed prospective longitudinal follow-up of consecutive intracerebral haemorrhage survivors presenting to a single tertiary care centre. We tested for association with seizures the following neuroimaging and genetic markers of cerebral small vessel disease: APOE variants epsilon2/epsilon4, computer tomography-defined white matter disease, magnetic resonance imaging-defined white matter hyperintensities volume and cerebral microbleeds. Cognitive performance was measured using the Modified Telephone Interview for Cognitive Status, and functional performance using structured questionnaires obtained every 6 months. We performed time-to-event analysis using separate Cox models for risk to develop delayed and recurrent seizures, as well as for functional decline risk (mortality, incident dementia, and loss of functional independence) after intracerebral haemorrhage. A total of 872 survivors of intracerebral haemorrhage were enrolled and followed for a median of 3.9 years. Early seizure developed in 86 patients, 42 of whom went on to experience recurrent seizures. Admission Glasgow Coma Scale, increasing haematoma volume and cortical involvement were associated with recurrent seizure risk (all P < 0.01). Recurrent seizures were not associated with long-term functional outcome (P = 0.67). Delayed seizures occurred in 37 patients, corresponding to an estimated incidence of 0.8% per year (95% confidence interval 0.5-1.2%). Factors associated with delayed seizures included cortical involvement on index haemorrhage (hazard ratio 1.63, P = 0.036), pre-haemorrhage dementia (hazard ratio 1.36, P = 0.044), history of multiple prior lobar haemorrhages (hazard ratio 2.50, P = 0.038), exclusively lobar microbleeds (hazard ratio 2.22, P = 0.008) and presence of >= 1 APOE epsilon4 copies (hazard ratio 1.95, P = 0.020). Delayed seizures were associated with worse long-term functional outcome (hazard ratio 1.83, P = 0.005), but the association was removed by adjusting for neuroimaging and genetic markers of cerebral small vessel disease. Delayed seizures after intracerebral haemorrhage are associated with different risk factors, when compared to recurrent seizures. They are also associated with worse functional outcome, but this finding appears to be related to underlying small vessel disease. Further investigations into the connections between small vessel disease and delayed seizures are warranted. PMID- 27497493 TI - Nuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. AB - Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are two ends of a phenotypic spectrum of disabling, relentlessly progressive and ultimately fatal diseases. A key characteristic of both conditions is the presence of TDP-43 (encoded by TARDBP) or FUS immunoreactive cytoplasmic inclusions in neuronal and glial cells. This cytoplasmic mislocalization of otherwise predominantly nuclear RNA binding proteins implies a perturbation of the nucleocytoplasmic shuttling as a possible event in the pathogenesis. Compromised nucleocytoplasmic shuttling has recently also been associated with a hexanucleotide repeat expansion mutation in C9orf72, which is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and leads to accumulation of cytoplasmic TDP-43 inclusions. Mutation in C9orf72 may disrupt nucleocytoplasmic shuttling on the level of C9ORF72 protein, the transcribed hexanucleotide repeat RNA, and/or dipeptide repeat proteins translated form the hexanucleotide repeat RNA. These defects of nucleocytoplasmic shuttling may therefore, constitute the common ground of the underlying disease mechanisms in different molecular subtypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PMID- 27497494 TI - Morphological and neuroanatomical study of the mammary gland in the immature and mature European beaver (Castor fiber). AB - This study investigated general morphology and immunohistochemical properties of nerve fibres supplying the mammary gland (MG) in the European beaver. The microscopic analysis of the beaver mammary gland revealed the presence of morphological structures which are characteristic for mammals. There were no distinct differences in the morphological features of the mammary gland between the juvenile and non-pregnant mature beaver. The nerve fibres were visualized using antibodies against protein gene product 9.5 (PGP) and biologically active substances including beta-hydroxylase tyrosine (DbetaH), neuropeptide Y (NPY), calcitonine gene-related peptide (CGRP) and substance P (SP). The study has revealed that the MG in the juvenile and mature beaver is richly supplied with PGP-immunoreactive (PGP-IR) nerve fibres. The most abundant innervation was observed in the nipple and less numerous nerve terminals supplied the glandular tissue. Double-labelling immunohistochemistry disclosed that the majority of PGP IR nerve fibres associated with blood vessels and smooth muscle cells in both the nipple and glandular tissue were also DbetaH-IR. However, these nerve terminals were less numerous in the glandular tissue than in the nipple. Most of the DbetaH IR axons associated with arteries and smooth muscle cells in the entire gland also stained for NPY. Small number of DbetaH/NPY-IR fibres supplied veins. CGRP IR fibres were more abundant than those expressing SP. No distinct differences in the distribution and immunohistochemical characteristic of nerve fibres were observed between the juvenile and adult animals. The distribution and immunohistochemical properties of nerve fibres supplying the gland in the beaver remind those previously described in other mammalian species. PMID- 27497496 TI - Letter to the Editor: Surgical versus conservative management of congenital pulmonary airway malformation in children: A systematic review and meta-analysis" by Kapralik et al J Pediatr Surg 51 (2016) 508-512. PMID- 27497495 TI - Outcomes of arterial vascular extremity trauma in pediatric patients. AB - BACKGROUND: Vascular trauma in children, although rare, carries significant risk for repair. Here we report outcomes from a single trauma center for children with extremity vascular trauma, proximal to the digits. METHODS: Retrospective chart review of patients less than age 18years with an acute, non-iatrogenic traumatic arterial vascular injury of the upper and/or lower extremity between January 2008 and December 2013. Abstracted patient demographics, injury characteristics, surgical management, and disposition were summarized and compared with nonparametric methods. RESULTS: 23 children comprised the study cohort: median age of 8years (IQR: 4.6-12), 61% (n=14) males, 100% survival. Penetrating injuries were the predominate mechanism (n=17, 74%). The median time to presentation was 154min (IQR: 65-330). Acute operations for revascularization included a primary repair (n=15, 65%) or reversed vein graft (n=7, 30%). Fasciotomies were done for 3 (13%) patients. Three amputations were done for failed revascularization. Upper extremity vascular injury (n=15, 65%) was more common. The rate of associated extremity fracture was similar between upper (21%) and lower (33%) extremities (p=0.643). Eight (35%) patients required additional surgery most commonly for debridement, washouts and dressing changes. Three patients' hospital stays were complicated by infection. Impaired function was the most common short- and long-term complication (60%, 75%). CONCLUSION: Pediatric vascular injuries are commonly associated with penetrating injuries and male gender and occurred more frequently in the upper extremities. Overall patency rates after repair were 87%. Fasciotomies were done in 13% of patients, and the overall surgical amputation rate was 13%. There was no mortality in this cohort; however, multiple operations are commonly required, including the return to OR for washouts, debridements and dressing changes. The most common short- and long term complication was impaired function. Overall good results are achievable in pediatric vascular trauma treated with revascularization. PMID- 27497497 TI - The lost art of the splenorrhaphy. AB - BACKGROUND: In the case of the hemodynamically unstable child, splenorrhaphy is preferred to splenectomy to avert postsplenectomy sepsis. However, successful splenorrhaphy requires familiarity with the procedure. We sought to determine how many splenectomies or splenorrhaphies for trauma the average pediatric surgeon can be expected to perform during their career. METHODS: The Pediatric Health Information System (PHIS) Database was queried for patients <=18years coded with an International Classification of Diseases 9th Edition diagnosis code of a splenic injury from 2004 to 2013. Age, gender, grade of splenic injury, and operations performed were extracted. Numbers of pediatric surgeons per hospital were obtained. RESULTS: 9567 children were identified. 2.1% underwent a splenectomy and 0.8% underwent a splenorrhaphy. The average surgeon performed 0.6 (SD=0.6) splenectomies and 0.2 (SD=0.4) splenorrhaphies for trauma. If these rates remain constant over time, the average surgeon would perform 1.8 (SD =1.7) splenectomies and 0.6 (SD =1.1) splenorrhaphies for trauma over a 30-year surgical career. CONCLUSION: Nonoperative management is associated with a host of benefits, but has resulted in a decrease in the experience level of the pediatric surgeons expected to perform an emergency splenectomy or splenorrhaphy when the unusual occasion arises. PMID- 27497498 TI - [Are cancer outpatients ready for e-medicine?] AB - INTRODUCTION: E-health offers new opportunities for improving cancer outpatients' monitoring. The aim of this study was to assess the level and the use of electronic communication tools owned by cancer outpatients currently undergoing antitumoral treatment. METHODS: This observational study consecutively recruited patients undergoing treatment at two day hospital oncology units from 1st to 31 October 2015. Each patient completed one standardised, anonymous questionnaire. RESULTS: Overall, 386 questionnaires were analysed, of which 244 and 142 patients were from each hospital. Of these patients, 73% had access to the Internet either directly or through a third party. More than 90% of the patients owned a mobile phone, and half of them had a smartphone with Internet access. An increasing age and the socioeconomic class level were significantly associated with the use of the Internet and of a smartphone. Half of the patients had accessed websites dedicated to health topics and a quarter had used mobile applications on health topics. One-third of those patients found these electronic tools helpful. After adjustment, an increasing age was significantly associated with a decreased use of such tools. The majority (87%) of the patients enjoyed receiving text message reminders from their hospital about their consultation schedule. CONCLUSION: Three in four cancer outpatients under treatment have access to the Internet and half use websites dedicated to health topics, with an impact of the age and the socioeconomic class level. Developing e-communication tools between caregivers and patients might be considered to improve their home monitoring. PMID- 27497499 TI - Bandwidth and sample rate requirements for wearable head impact sensors. AB - Wearable inertial sensors measure human head impact kinematics important to the on-going development and validation of head injury criteria. However, sensor specifications have not been scientifically justified in the context of the anticipated field impact dynamics. The objective of our study is to determine the minimum bandwidth and sample rate required to capture the impact frequency response relevant to injury. We used high-bandwidth head impact data as ground truth measurements, and investigated the attenuation of various injury criteria at lower bandwidths. Given a 10% attenuation threshold, we determined the minimum bandwidths required to study injury criteria based on skull kinematics and brain deformation in three different model systems: helmeted cadaver (no neck), unhelmeted cadaver (no neck), and helmeted dummy impacts (with neck). We found that higher bandwidths are required for unhelmeted impacts in general and for studying strain rate injury criteria. Minimum gyroscope bandwidths of 300Hz in helmeted sports and 500Hz in unhelmeted sports are necessary to study strain rate based injury criteria. A minimum accelerometer bandwidth of 500Hz in unhelmeted sports is necessary to study most injury criteria. Current devices typically sample at 1000Hz, with gyroscope bandwidths below 200Hz, which are not always sufficient according to these requirements. With hard contact test conditions, the identified requirements may be higher than most soft contacts on the field, but should be satisfied to capture the worst contact, and often higher risk, scenarios relative to the specific sport or activity. Our findings will help establish standard guidelines for sensor choice and design in traumatic brain injury research. PMID- 27497500 TI - Cost-effective (gaming) motion and balance devices for functional assessment: Need or hype? AB - In the last decade, technological advances in the gaming industry have allowed the marketing of hardware for motion and balance control that is based on technological concepts similar to scientific and clinical equipment. Such hardware is attractive to researchers and clinicians for specific applications. However, some questions concerning their scientific value and the range of future potential applications have yet to be answered. This article attempts to present an objective analysis about the pros and cons of using such hardware for scientific and clinical purposes and calls for a constructive discussion based on scientific facts and practical clinical requests that are emerging from application fields. PMID- 27497501 TI - Modeling female and male rib geometry with logarithmic spirals. AB - In this study we present a novel six-parameter shape model of the human rib centroidal path using logarithmic spirals. It provides a reduction in parameter space from previous models of overall rib shape, while simultaneously reducing fitting error by 34% and increasing curvature continuity. Furthermore, the model directly utilizes geometric properties such as rib end-to-end span, aspect ratio, rib "skewness", and inner angle with the spine in its parameterization, making the effects of each parameter on overall shape intuitive and easy to visualize. The model was tested against 2197 rib geometries extracted from CT scans from a population of 100 adult females and males of uniformly distributed ages between 20 and 70. Significant size and shape differences between genders were identified, and shape model utility is demonstrated by the production of statistically average male and female rib shapes for all rib levels. Simulated mechanical loading of the resulting model rib shapes showed that the stiffness of statistically average male and female ribs matched well with the average rib stiffness from each separate population. This in-plane rib shape model can be used to characterize variation in human rib geometry seen throughout the population, including investigation of the overall changes in shape and resultant mechanical properties that ribs undergo during aging or disease progression. PMID- 27497502 TI - Flow characteristics around proximal and distal stenoses in a series of tandem stenosed vessels. AB - The flow characteristics around the proximal and distal stenoses in tandem vessel models are experimentally investigated with varying flow rates (Q=0.25, 0.5, 1.0L/min), interspacing distances (L=3, 6, 10 of diameter D) and severities (S=50%, 75% reduction in diameter). When the interspacing L is larger than 10 D, no fluid-dynamic interaction is observed. The flow between the proximal and distal stenoses becomes stabilized (turbulence intensity of <3%) as the interspacing distance decreases. When the severity S is 75%, the transition from laminar to turbulent flow occurs at a flow rate higher than 0.5L/min, although the interspacing distance L is 3 D. Formation of recirculation flow is restricted by the presence of distal stenosis as the interspacing distance decreases. In this case, the flow between the stenoses is focused on the central region. The center-line velocity at the neck of the distal stenosis is approximately 10-15% higher than that of the proximal stenosis with equal severity of S=50%. When the inlet flow is center-focused, the lengths of the recirculation and the jet core behind the distal stenosis increase with decrease in interspacing distance L. When the inlet flow is turbulent, the transition from laminar to turbulent flow occurs early as the interspacing distance L is reduced. When the upstream proximal stenosis exhibits increased severity, the pressure drop is measured to be 20% compared with that when the severity of the downstream distal stenosis is increased at the flow rate of Q=1.0L/min. PMID- 27497503 TI - Nephroureteral Obstructions: The Use of Stents and Ureteral Bypass Systems for Renal Decompression. AB - Canine and feline nephroureteral obstruction is a complex disease process that can be challenging to treat. Although the availability of various imaging modalities allows for a straightforward diagnosis to be made in most cases, the decision-making process for when a case should be taken to surgery and the optimal treatment modality that should be used for renal decompression remains controversial. In the following discussion, an overview of the perioperative management of cases with nephroureterolithiasis and nephroureteral obstruction is reviewed, with particular focus on the use of renal decompressive procedures, such as ureteral stenting and subcutaneous ureteral bypass system placement. PMID- 27497504 TI - Statin Intolerance: A Literature Review and Management Strategies. AB - Statin intolerance is a commonly encountered clinical problem for which useful management strategies exist. Although many patients report statin-related muscle symptoms, studies indicate that the majority of these patients can tolerate a statin upon re-challenge. Alternative statin dosing strategies are an effective way to modify and reintroduce statin therapy for patients reporting adverse symptoms. Correction of vitamin D deficiency and hypothyroidism may improve statin tolerability in some patients. CoQ10 supplementation has been found to be of no benefit for statin-related muscle symptoms in most recent clinical trials. PCSK9 inhibitors are a new therapeutic option that if confirmed as safe and effective by outcomes trials may be of substantial benefit to select patients at high ASCVD risk who are unable to achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on maximally tolerated statin therapy. Other available medications to lower LDL-C in statin intolerant patients include ezetimibe, bile acid sequestrants, niacin, and fibrates. PMID- 27497505 TI - Metabolic Syndrome: An Evolving Clinical Construct. AB - Metabolic syndrome (MetS), a clustering of metabolic risk factors, identifies individuals at increased risk of diabetes and cardiovascular disease (CVD). Measurement of waist circumference, high-density lipoprotein-cholesterol, triglycerides, blood pressure and fasting blood glucose are easily obtained in the clinic. At any level of low-density lipoprotein-cholesterol, presence of MetS increases the risk of adverse CVD outcomes including bothatherosclerotic CVD and atrial fibrillation. The MetS construct should focus the clinician on recommending behavioral lifestyle modification as this improves all of its components. The challenge, however, has been the lack of a standardized approach to achieve effective and sustained lifestyle modification in clinical practice. We briefly review various approaches useful to the clinician in counseling such patients. These include group lifestyle programs and emerging mobile technology. Technology alone may not be sufficient, but as an adjunct has the promise to improve low rates of behavioral change currently seen with traditional programs. PMID- 27497506 TI - The re-emergence of lipoprotein(a) in a broader clinical arena. AB - Lipoprotein(a) [Lp(a)] is a genetic, independent and likely causal risk factor for cardiovascular disease (CVD) and calcific aortic valve stenosis (CAVS). Lp(a) levels are primarily genetically determined and tend to fluctuate only mildly around a pre-determined level. In primary care settings, one Lp(a) measurement can reclassify up to 40% of patients in intermediate risk score categories. In secondary care settings, recent data from the JUPITER and AIM-HIGH trials demonstrate that elevated Lp(a) remains part of the "residual risk" despite achievement of low-density lipoprotein cholesterol levels <70 mg/dL. Recent reports suggest that statins can increase Lp(a) levels, potentially further contributing to this residual risk. Current therapies to lower Lp(a) are limited to niacin, mipomersen and proprotein convertase subtilisin kexin-type 9 inhibitors, but these drugs are limited by weak efficacy and not specifically approved for Lp(a) lowering. Emerging therapies to lower Lp(a) may shed new light into the potential clinical benefit of lowering Lp(a) in CVD and CAVS. PMID- 27497507 TI - Cholesterol Guidelines: More Similar Than Different. AB - A clinician has a large number of guidelines to follow. Searching the words "cardiovascular" and "guideline" on the website, www.guideline.gov yielded 502 cardiovascular guidelines, 40 alone in 2015. 1 [National Guideline Clearinghouse: Agency for Healthcare Research and 19 Quality (n.d.)] Similarly, searching the words "cholesterol" and "guideline" yielded 107 results, 6 alone in 2015. This information overload can decrease providers' self-efficacy in using guidelines, particularly if they have inconsistent messages. Moreover, a busy provider can easily be lost if the emphasis is on highlighting differences rather than similarities on the same topic. There are several guidelines for management of blood cholesterol and lipids. Despite being more similar than different, their similarities have not received as much attention as the differences between them. Unfortunately, there are still major gaps in current clinical practice even across these common themes. In this review, we will provide a brief overview of various cholesterol/lipid guidelines followed by a discussion of the differences but more importantly, similarities between them. PMID- 27497508 TI - Preliminary Experience with Transdermal Oxybutynin Patches for Hyperhidrosis. AB - BACKGROUND AND OBJECTIVE: Hyperhidrosis is very common and has a considerable impact on patients' quality of life. While oral oxybutynin is associated with good response rates, adverse effects are common and frequently cause patients to stop treatment. Following the recent launch of oxybutynin in a transdermal patch formulation in Spain, we undertook a preliminary study to assess treatment response and adverse effects in patients with hyperhidrosis. MATERIAL AND METHODS: This prospective study of 25 patients treated twice weekly with transdermal oxybutynin patches over 10 weeks assessed treatment response on 2 subjective scales: the Hyperhidrosis Disease Severity Scale (HDSS) and a visual analog scale (VAS) for sweating. RESULTS: Sixty percent of patients showed an improvement in HDSS scores. VAS scores improved in all cases, and 68% of patients achieved a reduction of 3 points or more. Just 2 patients (8%) experienced treatment-related adverse effects (irritant dermatitis at the patch application site in both cases). CONCLUSIONS: Although our results are based on a small sample, they suggest that transdermal oxybutynin could be a useful option for the treatment of hyperhidrosis and that it has an excellent safety and tolerability profile. PMID- 27497509 TI - Kidney Disease and Psoriasis. A New Comorbidity? AB - Psoriasis is a chronic inflammatory disease that has been associated with cardiovascular and metabolic comorbidities, particularly in young patients and patients with more severe forms of the disease. Recent studies have also linked psoriasis to kidney disease, and this would seem only logical, as the kidney is both a target of classic cardiovascular risk factors and susceptible to the toxic effects of some of the traditional drugs used to control psoriasis. In this article, we would like to draw readers' attention to this recently described comorbidity and stress the importance of early detection, as once chronic kidney disease develops, it cannot be reversed. When evaluating patients with psoriasis, particularly when they are candidates for systemic therapy, we believe it is important to order laboratory tests including glomerular filtration rate and a simple urine test to screen for albuminuria (albumin/creatinine ratio). PMID- 27497510 TI - Complement C3a Mobilizes Dental Pulp Stem Cells and Specifically Guides Pulp Fibroblast Recruitment. AB - INTRODUCTION: Complement activation is considered a major mechanism in innate immunity. Although it is mainly involved in initiating inflammation, recent data reported its involvement in other processes such as tissue regeneration. In the dental pulp, complement C5a fragment has been shown to be involved in the recruitment of dental pulp stem cells (DPSCs). This study sought to investigate the possible role of C3a, another complement fragment, in the early steps of dentin-pulp regeneration. METHODS: Expression of C3a receptor (C3aR) was investigated by immunofluorescence and reverse transcriptase polymerase chain reaction on cultured pulp fibroblasts, STRO-1-sorted DPSCs, as well as on human tooth sections in vivo. The effect of C3a on proliferation of both DPSCs and pulp fibroblasts was investigated by MTT assay. Cell migration under a C3a gradient was investigated by using microfluidic chemotaxis chambers. RESULTS: C3aR was expressed in vivo as well as in cultured pulp fibroblasts co-expressing fibroblast surface protein and in DPSCs co-expressing STRO-1. Addition of recombinant C3a induced a significant proliferation of both cell types. When subjected to a C3a gradient, DPSCs were mobilized but not specifically recruited, whereas pulp fibroblasts were specifically recruited following a C3a gradient. CONCLUSIONS: These results provide the first demonstration of C3aR expression in the dental pulp and demonstrate that C3a is involved in increasing DPSCs and fibroblast proliferation, in mobilizing DPSCs, and in specifically guiding fibroblast recruitment. This provides an additional link to the tight correlation between inflammation and tissue regeneration. PMID- 27497511 TI - 1-year In Vitro Evaluation of Tooth Discoloration Induced by 2 Calcium Silicate based Cements. AB - INTRODUCTION: The purpose of this study was to compare tooth discoloration that occurs in teeth filled with ProRoot MTA (DENTSPLY Tulsa Dental Specialties, Tulsa, OK) or Biodentine (Septodont, Saint Maur des Fosses, France) over the course of 1 year. METHODS: Twenty-eight intact premolars were resected 2 mm apical to the cementoenamel junction and the pulp tissues extirpated via the cervical cut. After the preparation of occlusal access to the pulp chamber, specimens were assigned into 4 groups according to a stratified randomization sampling process: group 1, negative control (dry sterile cotton pellet); group 2, positive control (blood-moistened cotton pellet); group 3, ProRoot WMTA (DENTSPLY Tulsa Dental Specialties); and group 4, Biodentine. The experimental materials were condensed into the crowns and the access sealed with glass ionomer restorative cement. Color was assessed at baseline (before placement of the materials), immediately after material filling, after 6 weeks of storage, and after 1 year using the Commission International de I'Eclairage L*a*b* system. Change in color, DeltaE, was compared among groups and over time using analysis of variance. RESULTS: The 4 groups showed a significant decrease in L* values over time. Differences between Biodentine and WMTA were detected after 1 year, with the greater variation associated with WMTA (P = .001). The 4 groups presented a significant increase in DeltaE from baseline to 1 year. All groups revealed perceptible color changes (DeltaE > 2.3) between immediately after material filling and after 6 weeks and after 6 weeks and 1 year. After 1 year, no differences could be detected between Biodentine and WMTA. CONCLUSIONS: Delayed tooth discoloration was detected for the 2 materials at the 1-year evaluation, but it was more evident for ProRoot MTA than Biodentine. Luminance was the most affected parameter, with a higher decrease for ProRoot MTA. PMID- 27497513 TI - Molecular imaging of the tumor microenvironment. AB - The tumor microenvironment plays a critical role in tumor initiation, progression, metastasis, and resistance to therapy. It is different from normal tissue in the extracellular matrix, vascular and lymphatic networks, as well as physiologic conditions. Molecular imaging of the tumor microenvironment provides a better understanding of its function in cancer biology, and thus allowing for the design of new diagnostics and therapeutics for early cancer diagnosis and treatment. The clinical translation of cancer molecular imaging is often hampered by the high cost of commercialization of targeted imaging agents as well as the limited clinical applications and small market size of some of the agents. Because many different cancer types share similar tumor microenvironment features, the ability to target these biomarkers has the potential to provide clinically translatable molecular imaging technologies for a spectrum of cancers and broad clinical applications. There has been significant progress in targeting the tumor microenvironment for cancer molecular imaging. In this review, we summarize the principles and strategies of recent advances made in molecular imaging of the tumor microenvironment, using various imaging modalities for early detection and diagnosis of cancer. PMID- 27497512 TI - Lipases from the genus Rhizopus: Characteristics, expression, protein engineering and application. AB - Lipases are versatile catalysts that hydrolyze ester bonds of water-insoluble glycerides or carry out reversible reactions at the water/lipid interface. The remarkable characteristics of lipases from the genus Rhizopus are their high sn 1,3-positional specificity, enantioselectivity and activity in nonaqueous media, which make them one of the most desirable enzymes for many applications, including lipid modification and biodiesel and chiral organic compound synthesis. sn-1,3-Position-specific Rhizopus lipases are particularly useful for the production of structured triacylglycerols. Significant progress has been made regarding lipases from the genus Rhizopus, including gene sequencing, elucidation of the protein structure and catalytic function, heterologous expression and redesigning Rhizopus lipases for valuable properties, which is receiving increasing academic and industrial attention. In this review, we present a comprehensive overview of Rhizopus lipases, focusing on (a) the characteristics of Rhizopus lipases, (b) Rhizopus lipase genes and structural features, (c) strategies for heterologous expression of Rhizopus lipase genes in yeast system, (d) progress in protein engineering for the improvement of the properties of Rhizopus lipases, and (e) development of biotechnological applications. PMID- 27497514 TI - A Mobile Phone HIV Medication Adherence Intervention: Acceptability and Feasibility Study. AB - We present the findings of a qualitative pilot study designed to describe the experience of HIV medication adherence using a mobile phone application. Nine semi-structured focus group discussions were conducted over a 3-month period at an AIDS Services Organization in Central Texas. The data were analyzed following the principles of thematic analysis. During analysis, four themes were identified, and relations between these themes were delineated to reflect the experiences of the 23 participants. The mobile phone application, Care4TodayTM Mobile Health Manager, was the intervention tool. Collection of focus group discussion outcomes over a 3-month period with baseline versus end-of-study data determined the feasibility and acceptability of this medication adherence intervention. The findings suggest that when individuals are offered the necessary resources, such as a mobile phone medication reminder application, they may have greater success in performing the behavior. PMID- 27497515 TI - Resuscitation following opioid overdose: Old ideas and new threats. PMID- 27497516 TI - Higher concentrations of branched-chain amino acids in breast milk of obese mothers. AB - OBJECTIVE: Nutrition during fetal life and early childhood is thought to play a crucial role in the risk for developing metabolic syndrome and cardiovascular diseases in the future adult and branched-chain amino acids (BCAA) intake may play a role in the development of obesity. The aim of this study was to compare the breast milk amino acid profiles of obese and normal weight (control) breast feeding mothers. METHODS: Fifty obese and 50 control breast-feeding mothers were enrolled. Age and parity were similar in both groups. Breast milk samples were collected at the end of the first month of lactation. Free amino acid (FAA) concentrations in breast milk were determined by ultra-performance liquid chromatography tandem mass spectrometry. Comparisons between groups were performed using a two-tailed paired t test. RESULTS: We analyzed 45 breast milk samples from each group. Body mass index was 34.3 +/- 3.9 kg/m(2) in the obese group and 21.6 +/- 1.4 kg/m(2) in the control group (P < 10(-4)). BCAA concentrations were higher in breast milk of obese mothers (95.5 +/- 38.2 MUM versus 79.8 +/- 30.9 MUM; P = 0.037), as was tyrosine concentration (13.8 +/- 7.1 MUM versus 10.6 +/- 5.2 MUM; P = 0.016). CONCLUSION: The mature breast milk of obese mothers contained 20% more BCAA and 30% more tyrosine than breast milk of control mothers. Whether altered breast milk FAA profile affects metabolic risk in the breast-fed child remains to be explored. PMID- 27497517 TI - Dietary guanidinoacetic acid increases brain creatine levels in healthy men. AB - OBJECTIVE: Guanidinoacetic acid (GAA) is an experimental dietary additive that might act as a creatine source in tissues with high-energy requirements. In this case study, we evaluated brain levels of creatine in white matter, gray matter, cerebellum, and thalamus during 8 wk oral GAA administration in five healthy men and monitored the prevalence and severity of side effects of the intervention. METHODS: Volunteers were supplemented daily with 36 mg/kg body weight (BW) of GAA for the first 4 wk of the intervention; afterward GAA dosage was titrated <=60 mg/kg BW of GAA daily. At baseline, 4, and 8 wk, the participants underwent brain magnetic resonance spectroscopy, clinical chemistry studies, and open-ended questionnaire for side-effect prevalence and severity. RESULTS: Brain creatine levels increased in similar fashion in cerebellum, and white and gray matter after GAA supplementation, with an initial increase of 10.7% reported after 4 wk, and additional upsurge (7.7%) from the weeks 4 to 8 follow-up (P < 0.05). Thalamus creatine levels decreased after 4 wk for 6.5% (P = 0.02), and increased nonsignificantly after 8 wk for 8% (P = 0.09). GAA induced an increase in N acetylaspartate levels at 8-wk follow-up in all brain areas evaluated (P < 0.05). No participants reported any neurologic adverse event (e.g., seizures, tingling, convulsions) during the intervention. CONCLUSIONS: Supplemental GAA led to a region-dependent increase of the creatine pool in the human brain. This might be relevant for restoring cellular bioenergetics in disorders characterized by low brain creatine and functional enzymatic machinery for creatine synthesis, including neurodegenerative diseases, brain tumors, or cerebrovascular disease. PMID- 27497518 TI - Mortality prediction of a body shape index versus traditional anthropometric measures in an Iranian population: Tehran Lipid and Glucose Study. AB - OBJECTIVES: A body shape index (ABSI) based on waist circumference (WC) adjusted for height and weight has been shown to be a risk factor for premature mortality. The aim of this study was to demonstrate that ABSI predicts mortality hazard better than other anthropometric measures in an Iranian population. METHODS: The study population included 9242 Iranian participants in Tehran, aged >=30 y, followed for a median 10 y. The risk for mortality was estimated by incorporating ABSI, body mass index (BMI), WC, waist-to-hip ratio (WHpR), and waist-to-height ratio (WHtR), one at a time, into multivariate models as well as in terms of the effect size, calibration, discrimination, and added predictive ability. RESULTS: We documented 487 deaths with the annual incidence rate of mortality per 1000 persons being 3.9 for women and 8.2 for men. ABSI was associated with all-cause mortality in a curvilinear fashion. ABSI was more strongly associated with all cause mortality than were BMI, WC, and WHtR. Among women, however, WHpR was observed to be a stronger predictor of all-cause mortality than ABSI. Among both men and women, ABSI improved the risk classification based on other anthropometric measures, the only exception being WHpR. None of the anthropometric measures studied could add any value to the predictive ability of the Framingham's general cardiovascular disease algorithm. CONCLUSION: ABSI was the strongest predictor of all-cause mortality among the anthropometric measurements, except WHpR in women. When ABSI was added to the Framingham general cardiovascular disease algorithm, it failed to improve the predictive ability. PMID- 27497520 TI - Is it time for a HIPAA for physicians? AB - Practices, hospitals, and healthcare systems are increasingly able to collect data about individual physician clinical performance. There is a strong temptation to use the data to make decisions about physicians' quality of care without first taking the time to establish a system that ensures valid conclusions. In addition, physicians are not informed that their data are being used, and thus do not have an opportunity to correct any inaccuracies. A HIPAA equivalent law or regulation for physicians would help patients and physicians more accurately address these and other issues related to complex healthcare data. FERPA provides a useful framework for these concerns. PMID- 27497519 TI - Fatty acid status and antioxidant defense system in mothers and their newborns after salmon intake during late pregnancy. AB - OBJECTIVE: The aim of the present study was to assess the maternal and newborn status of erythrocyte fatty acids and the antioxidant defense system after the intake of two portions of salmon per week during late pregnancy. METHODS: Pregnant women (N = 123) were randomly assigned to continue their habitual diet, which was low in oily fish (control group, n = 61) or to consume two 150-g salmon portions per week (salmon group, n = 62) beginning at 20 wk of gestation and lasting until delivery. Fatty acids, selenium, and glutathione concentrations and antioxidant defense enzyme activities were measured in maternal erythrocytes at 20, 34, and 38 wk of pregnancy, and in cord erythrocytes collected at birth. Plasma concentrations of antioxidant molecules were measured. RESULTS: Compared with the control group, consuming salmon had little effect on erythrocyte fatty acids in either mothers or newborns. Components of the antioxidant defense system did not differ between groups. Glutathione peroxidase activity and the concentrations of tocopherols, retinol, and coenzyme Q10 were significantly lower in cord blood compared with maternal blood at week 38 in both groups. CONCLUSION: Maternal and newborn erythrocyte fatty acids are not strongly affected by the intake of two portions of salmon per week during the second half of pregnancy, although erythrocyte docosahexaenoic acid might be increased in newborns. Maternal and newborn antioxidant defense systems are not impaired by intake of salmon from 20 wk gestation. PMID- 27497521 TI - Radiologist-Centered Decision Support Applications. PMID- 27497522 TI - The 2016 ACR Commission on Human Resources Workforce Survey. AB - PURPOSE: The ACR Commission on Human Resources conducts an annual electronic survey to better understand the present workforce scenario for radiologists. METHODS: The Practice of Radiology Environment Database was used to identify group leads, who were asked to complete an electronic survey developed by the Commission on Human Resources. The survey asked group leads to report the number of radiologists they currently employ or supervise, the number hired in 2015, and the numbers they plan to hire in 2016 and 2019. Leaders were asked to report the subspecialty area used as the main reason for hiring each physician, as well the ages and genders of their current workforce. RESULTS: Thirty-two percent of group leaders, corresponding to 13,074 radiologists or 39% of all practicing radiologists, responded to this survey. The percentage of practicing radiologists who are male is 78.6%, compared with 21.4% who are female. Six percent of radiologists are older than 65 years, and 22% are between the ages of 56 and 65 years. Nineteen percent of radiologists older than 65 years retired in 2015. Fifteen percent of all radiologists work part-time. Among the part-time radiologists, 9% are male and 30% are female. General radiologists now make up only 13.3% of the radiologist workforce. In 2015, 45% of new hires moved from existing jobs; 55% were first-time hires. In 2016, it is projected that between 1,713 and 2,223 new jobs will be available, a 16.2% increase from hiring in 2015. CONCLUSIONS: Job opportunities for radiologists have continued to increase since 2013. PMID- 27497523 TI - The renin angiotensin system, oxidative stress and mitochondrial function in obesity and insulin resistance. AB - Obesity is a complex disease characterized by excessive expansion of adipose tissue and is an important risk factor for chronic diseases such as cardiovascular disorders, hypertension and type 2 diabetes. Moreover, obesity is a major contributor to inflammation and oxidative stress, all of which are key underlying causes for diabetes and insulin resistance. Specifically, adipose tissue secretes bioactives molecules such as inflammatory hormone angiotensin II, generated in the Renin Angiotensin System (RAS) from its precursor angiotensinogen. Accumulated evidence suggests that RAS may serve as a strong link between obesity and insulin resistance. Dysregulation of RAS also occurs in several other tissues including those involved in regulation of glucose and whole body homeostasis as well as insulin sensitivity such as muscle, liver and pancreas and heart. Here we review the scientific evidence for these interactions and potential roles for oxidative stress, inflammation and mitochondrial dysfunction in these target tissues which may mediate effects of RAS in metabolic diseases. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy. PMID- 27497524 TI - The Role of the Kidney in Disorders of Volume: Core Curriculum 2016. PMID- 27497525 TI - von Willebrand Factor, ADAMTS13 Activity, and Decline in Kidney Function: A Population-Based Cohort Study. AB - BACKGROUND: Altered levels of von Willebrand factor (vWF) and ADAMTS13 can promote thrombosis and disturb blood flow in kidney microcirculations. We investigated the association of serum vWF:ADAMTS13 ratio in relation to decline in kidney function. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,479 individuals (mean age, 65.1+/-5.9 [SD] years; 43% men) from the population-based Rotterdam Study. PREDICTORS: vWF, ADAMTS13, and vWF:ADAMTS13 ratio. OUTCOMES & MEASUREMENTS: Annual decline in estimated glomerular filtration rate (eGFR), halving of eGFR, and new-onset eGFR<60mL/min/1.73m2 were assessed. RESULTS: During a median follow-up of 11 (range, 7.81-13.57) years, 500 cases of new-onset eGFR<60mL/min/1.73m2 occurred. The population had a mean eGFR decline of 0.96+/-0.92mL/min/1.73m2 per year. Higher vWF:ADAMTS13 ratio was associated with steeper annual decline in eGFR (difference, -0.06 [95% CI, -0.09 to -0.02] mL/min/1.73m2 per year) and higher risk for new-onset eGFR<60mL/min/1.73m2 (OR, 1.13; 95% CI, 1.01-1.27). Likewise, higher vWF:ADAMTS13 ratio was associated with higher risk for halving of eGFR (OR, 1.40; 95% CI, 1.02-1.93). After adjustment for cardiovascular risk factors and blood group, effect estimates remained the same. LIMITATIONS: No data available for albuminuria. Participants were classified based on a single measurement of vWF and ADAMTS13. CONCLUSIONS: In this population-based study, we showed that higher vWF:ADAMTS13 ratio is associated with decline in kidney function, suggesting a role of elevated prothrombotic factors in the development and progression of kidney disease. PMID- 27497526 TI - Update on Nephrolithiasis: Core Curriculum 2016. PMID- 27497528 TI - Combined treatment with chondroitinase ABC and treadmill rehabilitation for chronic severe spinal cord injury in adult rats. AB - There are more than 50 times the number of chronic-phase spinal cord injury (SCI) patients than there are acute patients, and over half of all SCI patients are severely disabled. However, research focusing on chronic severe contusional SCI remains very rare. Here, we evaluated whether chondroitinase ABC (C-ABC), a degradative enzyme directed against chondroitin sulfate proteoglycans (CSPGs), and treadmill rehabilitation could exert synergistic therapeutic actions against chronic severe contusional SCI. First, we induced severe contusional SCI in adult rats, and administered C-ABC intrathecally at 6 weeks post-injury for a period of one week. Next, we performed treadmill rehabilitation from weeks 6 to 14 after SCI, for a total period of eight weeks. The initiation of treadmill rehabilitation triggered slight recovery between weeks 6 and 9, whereas C-ABC administration stimulated a third phase of recovery between weeks 12 and 14. Histologically, the C-ABC-treated rats showed an increase in the transverse residual tissue area and the extent of neuronal fiber regeneration at a site caudal to the lesion epicenter, and regrowth of putatively regenerating serotonergic fibers was significantly increased at the epicenter. We suggest that, when combined with intensive rehabilitation, C-ABC may play a beneficial role, even in severe and chronic SCI. PMID- 27497529 TI - Leoligin, the major lignan from Edelweiss, inhibits 3-hydroxy-3-methyl-glutaryl CoA reductase and reduces cholesterol levels in ApoE-/- mice. AB - The health benefit through the control of lipid levels in hyperlipidaemic individuals is evident from a large number of studies. The pharmacological options to achieve this goal shall be as specific and personalized as the reasons for and co-factors of hyperlipidaemia. It was the goal of this study to reveal the impact of leoligin on cholesterol levels and to define its mechanism of action. Oral application of leoligin in ApoE-/- mice led to significantly reduced total serum cholesterol levels and a reduction in postprandial blood glucose peak levels. In the absence of biochemical signs of toxicity, leoligin treatment resulted in reduced weight gain in mice. The effects of leoligin on serum cholesterol levels may be due to a direct inhibition of 3-hydroxy-3-methyl glutaryl-CoA reductase (HMGCR) by a unique, non-statin-like binding mode. Postprandial serum glucose peaks may be reduced by a mild peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonistic activity of leoligin. No effect on atherosclerotic plaque size was observed. As a non-toxic, cholesterol-, peak glucose-, and weight gain-lowering compound, leoligin continues to fulfil characteristics of a potential agent for the treatment of cardiovascular disease (CVD). The counterregulatory overexpression of hepatic HMGCR in leoligin treated animals possibly explains the missing permanent anti-atherosclerotic effect. PMID- 27497530 TI - Nanosilver conductive ink: A case study for evaluating the potential risk of nanotechnology under hypothetical use scenarios. AB - Engineered nanomaterials (ENMs) are being incorporated into a variety of consumer products due to unique properties that offer a variety of advantages over bulk materials. Understanding of the nano-specific risk associated with nano-enabled technologies, however, continues to lag behind research and development, registration with regulators, and commercialization. One example of a nano enabled technology is nanosilver ink, which can be used in commercial ink-jet printers for the development of low-cost printable electronics. This investigation utilizes a tiered EHS framework to evaluate the potential nano specific release, exposure and hazard associated with typical use of both nanosilver ink and printed circuits. The framework guides determination of the potential for ENM release from both forms of the technology in simulated use scenarios, including spilling of the ink, aqueous release (washing) from the circuits and UV light exposure. The as-supplied ink merits nano-specific consideration based on the presence of nanoparticles and their persistence in environmentally-relevant media. The material released from the printed circuits upon aqueous exposure was characterized by a number of analysis techniques, including ultracentrifugation and single particle ICP-MS, and the results suggest that a vast majority of the material was ionic in nature and nano-specific regulatory scrutiny may be less relevant. PMID- 27497527 TI - Establishing Core Outcome Domains in Hemodialysis: Report of the Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Consensus Workshop. AB - Evidence-informed decision making in clinical care and policy in nephrology is undermined by trials that selectively report a large number of heterogeneous outcomes, many of which are not patient centered. The Standardized Outcomes in Nephrology-Hemodialysis (SONG-HD) Initiative convened an international consensus workshop on November 7, 2015, to discuss the identification and implementation of a potential core outcome set for all trials in hemodialysis. The purpose of this article is to report qualitative analyses of the workshop discussions, describing the key aspects to consider when establishing core outcomes in trials involving patients on hemodialysis therapy. Key stakeholders including 8 patients/caregivers and 47 health professionals (nephrologists, policymakers, industry, and researchers) attended the workshop. Attendees suggested that identifying core outcomes required equitable stakeholder engagement to ensure relevance across patient populations, flexibility to consider evolving priorities over time, deconstruction of language and meaning for conceptual consistency and clarity, understanding of potential overlap and associations between outcomes, and an assessment of applicability to the range of interventions in hemodialysis. For implementation, they proposed that core outcomes must have simple, inexpensive, and validated outcome measures that could be used in clinical care (quality indicators) and trials (including pragmatic trials) and endorsement by regulatory agencies. Integrating these recommendations may foster acceptance and optimize the uptake and translation of core outcomes in hemodialysis, leading to more informative research, for better treatment and improved patient outcomes. PMID- 27497532 TI - Communication: Physical origins of ionization potential shifts in mixed carboxylic acids and water complexes. AB - The ionization potential (IP) of the aromatic alpha hydroxy carboxylic acid, 9 hydroxy-9-fluorene carboxylic acid (9HFCA), is shifted by complexation with hydrogen bonding ligands such as water and formic acid. Generalized Kohn-Sham energy decomposition analysis decomposes the intermolecular binding energies into a frozen energy term, polarization, correlation, and/or dispersion energy terms, as well as terms of geometric relaxation and zero point energy. We observe that in each dimer the attractive polarization always increases upon ionization, enhancing binding in the cation and shifting the IP toward the red. For 9HFCA H2O, a substantial decrease of the repulsive frozen energy in cation further shifts the IP toward red. For 9HFCA-HCOOH, the increase of the frozen energy actually occurs in the cation and shifts the IP toward blue. Consistent with the experimental measurements, our analysis provides new, non-intuitive perspectives on multiple hydrogen bonds interactions in carboxylic acids and water complexes. PMID- 27497531 TI - Identifying Inherited and Acquired Genetic Factors Involved in Poor Stem Cell Mobilization and Donor-Derived Malignancy. AB - Analysis of the clinical characteristics of hematopoietic stem cell transplant (HSCT) donors has proven beneficial for identifying cases of heritable hematopoietic disorders. This study examines poor peripheral blood hematopoietic stem cell mobilization after granulocyte colony-stimulating factor administration among 328 donors as a potential marker for suspected familial predisposition to myeloid malignancies. Here, we present data comparing the clinical characteristics of poor-mobilizing versus nonpoor-mobilizing donors and the results of panel-based sequencing of hematopoietic genes in poor-mobilizing donors. From this analysis, we identified a novel case of a donor-derived myelodysplastic syndrome in an HSCT recipient that is consistent with clonal evolution of TET2-mutated clonal hematopoiesis of indeterminate potential (CHIP) within the donor. This study demonstrates the potential risk of using hematopoietic stem cells from a donor with CHIP and raises the question of whether there should be increased screening measures to identify such donors. PMID- 27497533 TI - Accelerated path integral methods for atomistic simulations at ultra-low temperatures. AB - Path integral methods provide a rigorous and systematically convergent framework to include the quantum mechanical nature of atomic nuclei in the evaluation of the equilibrium properties of molecules, liquids, or solids at finite temperature. Such nuclear quantum effects are often significant for light nuclei already at room temperature, but become crucial at cryogenic temperatures such as those provided by superfluid helium as a solvent. Unfortunately, the cost of converged path integral simulations increases significantly upon lowering the temperature so that the computational burden of simulating matter at the typical superfluid helium temperatures becomes prohibitive. Here we investigate how accelerated path integral techniques based on colored noise generalized Langevin equations, in particular the so-called path integral generalized Langevin equation thermostat (PIGLET) variant, perform in this extreme quantum regime using as an example the quasi-rigid methane molecule and its highly fluxional protonated cousin, CH5 (+). We show that the PIGLET technique gives a speedup of two orders of magnitude in the evaluation of structural observables and quantum kinetic energy at ultralow temperatures. Moreover, we computed the spatial spread of the quantum nuclei in CH4 to illustrate the limits of using such colored noise thermostats close to the many body quantum ground state. PMID- 27497534 TI - A many-body states picture of electronic friction: The case of multiple orbitals and multiple electronic states. AB - We present a very general form of electronic friction as present when a molecule with multiple orbitals hybridizes with a metal electrode. To develop this picture of friction, we embed the quantum-classical Liouville equation (QCLE) within a classical master equation (CME). Thus, this article extends our previous work analyzing the case of one electronic level, as we may now treat the case of multiple levels and many electronic molecular states. We show that, in the adiabatic limit, where electron transitions are much faster than nuclear motion, the QCLE-CME reduces to a Fokker-Planck equation, such that nuclei feel an average force as well as friction and a random force-as caused by their interaction with the metallic electrons. Finally, we show numerically and analytically that our frictional results agree with other published results calculated using non-equilibrium Green's functions. Numerical recipes for solving this QCLE-CME will be provided in a subsequent paper. PMID- 27497535 TI - Ultra-fast computation of electronic spectra for large systems by tight-binding based simplified Tamm-Dancoff approximation (sTDA-xTB). AB - The computational bottleneck of the extremely fast simplified Tamm-Dancoff approximated (sTDA) time-dependent density functional theory procedure [S. Grimme, J. Chem. Phys. 138, 244104 (2013)] for the computation of electronic spectra for large systems is the determination of the ground state Kohn-Sham orbitals and eigenvalues. This limits such treatments to single structures with a few hundred atoms and hence, e.g., sampling along molecular dynamics trajectories for flexible systems or the calculation of chromophore aggregates is often not possible. The aim of this work is to solve this problem by a specifically designed semi-empirical tight binding (TB) procedure similar to the well established self-consistent-charge density functional TB scheme. The new special purpose method provides orbitals and orbital energies of hybrid density functional character for a subsequent and basically unmodified sTDA procedure. Compared to many previous semi-empirical excited state methods, an advantage of the ansatz is that a general eigenvalue problem in a non-orthogonal, extended atomic orbital basis is solved and therefore correct occupied/virtual orbital energy splittings as well as Rydberg levels are obtained. A key idea for the success of the new model is that the determination of atomic charges (describing an effective electron-electron interaction) and the one-particle spectrum is decoupled and treated by two differently parametrized Hamiltonians/basis sets. The three-diagonalization-step composite procedure can routinely compute broad range electronic spectra (0-8 eV) within minutes of computation time for systems composed of 500-1000 atoms with an accuracy typical of standard time-dependent density functional theory (0.3-0.5 eV average error). An easily extendable parametrization based on coupled-cluster and density functional computed reference data for the elements H-Zn including transition metals is described. The accuracy of the method termed sTDA-xTB is first benchmarked for vertical excitation energies of open- and closed-shell systems in comparison to other semi empirical methods and applied to exemplary problems in electronic spectroscopy. As side products of the development, a robust and efficient valence electron TB method for the accurate determination of atomic charges as well as a more accurate calculation scheme of dipole rotatory strengths within the Tamm-Dancoff approximation is proposed. PMID- 27497536 TI - Comparison of fully internally and strongly contracted multireference configuration interaction procedures. AB - Multireference (MR) methods occupy an important class of approaches in quantum chemistry. In many instances, for example, in studying complex magnetic properties of transition metal complexes, they are actually the only physically satisfactory choice. In traditional MR approaches, single and double excitations are performed with respect to all reference configurations (or configuration state functions, CSFs), which leads to an explosive increase of computational cost for larger reference spaces. This can be avoided by the internal contraction scheme proposed by Meyer and Siegbahn, which effectively reduces the number of wavefunction parameters to their single-reference counterpart. The "fully internally contracted" scheme (FIC) is well known from the popular CASPT2 approach. An even shorter expansion of the wavefunction is possible with the "strong contraction" (SC) scheme proposed by Angeli and Malrieu in their NEVPT2 approach. Promising multireference configuration interaction formulations (MRCI) employing internal contraction and strong contraction have been reported by several authors. In this work, we report on the implementation of the FIC-MRCI and SC-MRCI methodologies, using a computer assisted implementation strategy. The methods are benchmarked against the traditional uncontracted MRCI approach for ground and excited states of small molecules (N2, O2, CO, CO(+), OH, CH, and CN). For ground states, the comparison includes the "partially internally contracted" MRCI based on the Celani-Werner ansatz (PC-MRCI). For the three contraction schemes, the average errors range from 2% to 6% of the uncontracted MRCI correlation energies. Excitation energies are reproduced with ~0.2 eV accuracy. In most cases, the agreement is better than 0.2 eV, even in cases with very large differential correlation contributions as exemplified for the d-d and ligand-to metal charge transfer transitions of a Cu[NH3]4 (2+) model complex. The benchmark is supplemented with the investigation of typical potential energy surfaces (i.e., N2, HF, LiF, BeH2, ethane C-C bond stretching, and the ethylene double bond torsion). Our results indicate that the SC-scheme, which is successful in the context of second- and third-order perturbation theory, does not offer computational advantages and at the same time leads to much larger errors than the PC and FIC schemes. We discuss the advantages and disadvantages of the PC and FIC schemes, which are of comparable accuracy and, for the systems tested, also of comparable efficiency. PMID- 27497537 TI - Size consistent formulations of the perturb-then-diagonalize Moller-Plesset perturbation theory correction to non-orthogonal configuration interaction. AB - In this paper we introduce two size consistent forms of the non-orthogonal configuration interaction with second-order Moller-Plesset perturbation theory method, NOCI-MP2. We show that the original NOCI-MP2 formulation [S. R. Yost, T. Kowalczyk, and T. VanVoorh, J. Chem. Phys. 193, 174104 (2013)], which is a perturb-then-diagonalize multi-reference method, is not size consistent. We also show that this causes significant errors in large systems like the linear acenes. By contrast, the size consistent versions of the method give satisfactory results for singlet and triplet excited states when compared to other multi-reference methods that include dynamic correlation. For NOCI-MP2 however, the number of required determinants to yield similar levels of accuracy is significantly smaller. These results show the promise of the NOCI-MP2 method, though work still needs to be done in creating a more consistent black-box approach to computing the determinants that comprise the many-electron NOCI basis. PMID- 27497538 TI - A robust and accurate formulation of molecular and colloidal electrostatics. AB - This paper presents a re-formulation of the boundary integral method for the Debye-Huckel model of molecular and colloidal electrostatics that removes the mathematical singularities that have to date been accepted as an intrinsic part of the conventional boundary integral equation method. The essence of the present boundary regularized integral equation formulation consists of subtracting a known solution from the conventional boundary integral method in such a way as to cancel out the singularities associated with the Green's function. This approach better reflects the non-singular physical behavior of the systems on boundaries with the benefits of the following: (i) the surface integrals can be evaluated accurately using quadrature without any need to devise special numerical integration procedures, (ii) being able to use quadratic or spline function surface elements to represent the surface more accurately and the variation of the functions within each element is represented to a consistent level of precision by appropriate interpolation functions, (iii) being able to calculate electric fields, even at boundaries, accurately and directly from the potential without having to solve hypersingular integral equations and this imparts high precision in calculating the Maxwell stress tensor and consequently, intermolecular or colloidal forces, (iv) a reliable way to handle geometric configurations in which different parts of the boundary can be very close together without being affected by numerical instabilities, therefore potentials, fields, and forces between surfaces can be found accurately at surface separations down to near contact, and (v) having the simplicity of a formulation that does not require complex algorithms to handle singularities will result in significant savings in coding effort and in the reduction of opportunities for coding errors. These advantages are illustrated using examples drawn from molecular and colloidal electrostatics. PMID- 27497539 TI - Development of DPD coarse-grained models: From bulk to interfacial properties. AB - A new Bayesian method was recently introduced for developing coarse-grain (CG) force fields for molecular dynamics. The CG models designed for dissipative particle dynamics (DPD) are optimized based on trajectory matching. Here we extend this method to improve transferability across thermodynamic conditions. We demonstrate the capability of the method by developing a CG model of n-pentane from constant-NPT atomistic simulations of bulk liquid phases and we apply the CG DPD model to the calculation of the surface tension of the liquid-vapor interface over a large range of temperatures. The coexisting densities, vapor pressures, and surface tensions calculated with different CG and atomistic models are compared to experiments. Depending on the database used for the development of the potentials, it is possible to build a CG model which performs very well in the reproduction of the surface tension on the orthobaric curve. PMID- 27497540 TI - Mixed quantum-classical simulations of the vibrational relaxation of photolyzed carbon monoxide in a hemoprotein. AB - We present mixed quantum-classical simulations on relaxation and dephasing of vibrationally excited carbon monoxide within a protein environment. The methodology is based on a vibrational surface hopping approach treating the vibrational states of CO quantum mechanically, while all remaining degrees of freedom are described by means of classical molecular dynamics. The CO vibrational states form the "surfaces" for the classical trajectories of protein and solvent atoms. In return, environmentally induced non-adiabatic couplings between these states cause transitions describing the vibrational relaxation from first principles. The molecular dynamics simulation yields a detailed atomistic picture of the energy relaxation pathways, taking the molecular structure and dynamics of the protein and its solvent fully into account. Using the ultrafast photolysis of CO in the hemoprotein FixL as an example, we study the relaxation of vibrationally excited CO and evaluate the role of each of the FixL residues forming the heme pocket. PMID- 27497541 TI - Global and local curvature in density functional theory. AB - Piecewise linearity of the energy with respect to fractional electron removal or addition is a requirement of an electronic structure method that necessitates the presence of a derivative discontinuity at integer electron occupation. Semi-local exchange-correlation (xc) approximations within density functional theory (DFT) fail to reproduce this behavior, giving rise to deviations from linearity with a convex global curvature that is evidence of many-electron, self-interaction error and electron delocalization. Popular functional tuning strategies focus on reproducing piecewise linearity, especially to improve predictions of optical properties. In a divergent approach, Hubbard U-augmented DFT (i.e., DFT+U) treats self-interaction errors by reducing the local curvature of the energy with respect to electron removal or addition from one localized subshell to the surrounding system. Although it has been suggested that DFT+U should simultaneously alleviate global and local curvature in the atomic limit, no detailed study on real systems has been carried out to probe the validity of this statement. In this work, we show when DFT+U should minimize deviations from linearity and demonstrate that a "+U" correction will never worsen the deviation from linearity of the underlying xc approximation. However, we explain varying degrees of efficiency of the approach over 27 octahedral transition metal complexes with respect to transition metal (Sc-Cu) and ligand strength (CO, NH3, and H2O) and investigate select pathological cases where the delocalization error is invisible to DFT+U within an atomic projection framework. Finally, we demonstrate that the global and local curvatures represent different quantities that show opposing behavior with increasing ligand field strength, and we identify where these two may still coincide. PMID- 27497542 TI - The adiabatic limit of the exact factorization of the electron-nuclear wave function. AB - We propose a procedure to analyze the relation between the exact factorization of the electron-nuclear wave function and the Born-Oppenheimer approximation. We define the adiabatic limit as the limit of infinite nuclear mass. To this end, we introduce a unit system that singles out the dependence on the electron-nuclear mass ratio of each term appearing in the equations of the exact factorization. We observe how non-adiabatic effects induced by the coupling to the nuclear motion affect electronic properties and we analyze the leading term, connecting it to the classical nuclear momentum. Its dependence on the mass ratio is tested numerically on a model of proton-coupled electron transfer in different non adiabatic regimes. PMID- 27497543 TI - Correlation consistent basis sets for lanthanides: The atoms La-Lu. AB - Using the 3rd-order Douglas-Kroll-Hess (DKH3) Hamiltonian, all-electron correlation consistent basis sets of double-, triple-, and quadruple-zeta quality have been developed for the lanthanide elements La through Lu. Basis sets designed for the recovery of valence correlation (defined here as 4f5s5p5d6s), cc pVnZ-DK3, and outer-core correlation (valence + 4s4p4d), cc-pwCVnZ-DK3, are reported (n = D, T, and Q). Systematic convergence of both Hartree-Fock and correlation energies towards their respective complete basis set (CBS) limits are observed. Benchmark calculations of the first three ionization potentials (IPs) of La through Lu are reported at the DKH3 coupled cluster singles and doubles with perturbative triples, CCSD(T), level of theory, including effects of correlation down through the 4s electrons. Spin-orbit coupling is treated at the 2-component HF level. After extrapolation to the CBS limit, the average errors with respect to experiment were just 0.52, 1.14, and 4.24 kcal/mol for the 1st, 2nd, and 3rd IPs, respectively, compared to the average experimental uncertainties of 0.03, 1.78, and 2.65 kcal/mol, respectively. The new basis sets are also used in CCSD(T) benchmark calculations of the equilibrium geometries, atomization energies, and heats of formation for Gd2, GdF, and GdF3. Except for the equilibrium geometry and harmonic frequency of GdF, which are accurately known from experiment, all other calculated quantities represent significant improvements compared to the existing experimental quantities. With estimated uncertainties of about +/-3 kcal/mol, the 0 K atomization energies (298 K heats of formation) are calculated to be (all in kcal/mol): 33.2 (160.1) for Gd2, 151.7 (-36.6) for GdF, and 447.1 (-295.2) for GdF3. PMID- 27497544 TI - Locality of correlation in density functional theory. AB - The Hohenberg-Kohn density functional was long ago shown to reduce to the Thomas Fermi (TF) approximation in the non-relativistic semiclassical (or large-Z) limit for all matter, i.e., the kinetic energy becomes local. Exchange also becomes local in this limit. Numerical data on the correlation energy of atoms support the conjecture that this is also true for correlation, but much less relevant to atoms. We illustrate how expansions around a large particle number are equivalent to local density approximations and their strong relevance to density functional approximations. Analyzing highly accurate atomic correlation energies, we show that EC -> -AC ZlnZ + BCZ as Z -> infinity, where Z is the atomic number, AC is known, and we estimate BC to be about 37 mhartree. The local density approximation yields AC exactly, but a very incorrect value for BC, showing that the local approximation is less relevant for the correlation alone. This limit is a benchmark for the non-empirical construction of density functional approximations. We conjecture that, beyond atoms, the leading correction to the local density approximation in the large-Z limit generally takes this form, but with BC a functional of the TF density for the system. The implications for the construction of approximate density functionals are discussed. PMID- 27497545 TI - How wet should be the reaction coordinate for ligand unbinding? AB - We use a recently proposed method called Spectral Gap Optimization of Order Parameters (SGOOP) [P. Tiwary and B. J. Berne, Proc. Natl. Acad. Sci. U. S. A. 113, 2839 (2016)], to determine an optimal 1-dimensional reaction coordinate (RC) for the unbinding of a bucky-ball from a pocket in explicit water. This RC is estimated as a linear combination of the multiple available order parameters that collectively can be used to distinguish the various stable states relevant for unbinding. We pay special attention to determining and quantifying the degree to which water molecules should be included in the RC. Using SGOOP with under sampled biased simulations, we predict that water plays a distinct role in the reaction coordinate for unbinding in the case when the ligand is sterically constrained to move along an axis of symmetry. This prediction is validated through extensive calculations of the unbinding times through metadynamics and by comparison through detailed balance with unbiased molecular dynamics estimate of the binding time. However when the steric constraint is removed, we find that the role of water in the reaction coordinate diminishes. Here instead SGOOP identifies a good one-dimensional RC involving various motional degrees of freedom. PMID- 27497547 TI - LCAO-based theoretical study of PbTiO3 crystal to search for parity and time reversal violating interaction in solids. AB - An experiment towards the search for the interaction of the Schiff moment (S) of the (207)Pb nuclei with electrons in PbTiO3 crystal which violates the time reversal (T) and space parity (P) symmetries was proposed by Mukhamedjanov and Sushkov [Phys. Rev. A 72, 034501 (2005)]. The interpretation of the experiment in terms of the Schiff moment requires knowledge of an electronic density gradient parameter (usually designated as X) on the Pb nucleus in the crystal, which is determined by the electronic structure of the crystal. Here we propose a theoretical approach to calculate the properties in solids which are directly sensitive to the changes of valence electron densities in atomic cores but not in the valence spatial regions (Mossbauer parameters, hyperfine structure (HFS) constants, parameters of T,P-odd Hamiltonians, etc. [L. V. Skripnikov and A. V. Titov, Phys. Rev. A 91, 042504 (2015)]). It involves constructing the crystalline orbitals via the linear combination of atomic orbitals and employs a two-step concept of calculating such properties that was earlier proposed by us for the case of heavy-atom molecules. The application of the method to the PbTiO3 crystal results in the energy shift, Deltaepsilon=0.82*10(6)S((207)Pb)eaB (3)eV, due to the T,P-odd interactions. The value is compared to the corresponding parameter in diatomic molecules (TlF, RaO, PbO), which have been proposed and used in the past decades in the search for the nuclear Schiff moment. We also present the calculation of the electric field gradient at the Pb nucleus in PbTiO3 for the comparison with other solid-state electronic structure approaches. PMID- 27497546 TI - Stochastic level-set variational implicit-solvent approach to solute-solvent interfacial fluctuations. AB - Recent years have seen the initial success of a variational implicit-solvent model (VISM), implemented with a robust level-set method, in capturing efficiently different hydration states and providing quantitatively good estimation of solvation free energies of biomolecules. The level-set minimization of the VISM solvation free-energy functional of all possible solute-solvent interfaces or dielectric boundaries predicts an equilibrium biomolecular conformation that is often close to an initial guess. In this work, we develop a theory in the form of Langevin geometrical flow to incorporate solute-solvent interfacial fluctuations into the VISM. Such fluctuations are crucial to biomolecular conformational changes and binding process. We also develop a stochastic level-set method to numerically implement such a theory. We describe the interfacial fluctuation through the "normal velocity" that is the solute solvent interfacial force, derive the corresponding stochastic level-set equation in the sense of Stratonovich so that the surface representation is independent of the choice of implicit function, and develop numerical techniques for solving such an equation and processing the numerical data. We apply our computational method to study the dewetting transition in the system of two hydrophobic plates and a hydrophobic cavity of a synthetic host molecule cucurbit[7]uril. Numerical simulations demonstrate that our approach can describe an underlying system jumping out of a local minimum of the free-energy functional and can capture dewetting transitions of hydrophobic systems. In the case of two hydrophobic plates, we find that the wavelength of interfacial fluctuations has a strong influence to the dewetting transition. In addition, we find that the estimated energy barrier of the dewetting transition scales quadratically with the inter plate distance, agreeing well with existing studies of molecular dynamics simulations. Our work is a first step toward the inclusion of fluctuations into the VISM and understanding the impact of interfacial fluctuations on biomolecular solvation with an implicit-solvent approach. PMID- 27497548 TI - Rovibrational states of Wigner molecules in spherically symmetric confining potentials. AB - The strong-localization limit of three-dimensional Wigner molecules, in which repulsively interacting particles are confined by a weak spherically symmetric potential, is investigated. An explicit prescription for computation of rovibrational wavefunctions and energies that are asymptotically exact at this limit is presented. The prescription is valid for systems with arbitrary angularly-independent interparticle and confining potentials, including those involving Coulombic and screened (i.e., Yukawa/Debye) interactions. The necessary derivations are greatly simplified by explicit constructions of the Eckart frame and the parity-adapted primitive wavefunctions. The performance of the new formalism is illustrated with the three- and four-electron harmonium atoms at their strong-correlation limits. In particular, the involvement of vibrational modes with the E symmetry is readily pinpointed as the origin of the "anomalous" weak-confinement behavior of the (1)S+ state of the four-electron species that is absent in its (1)D+ companion of the strong-confinement regime. PMID- 27497549 TI - Assessment of multireference approaches to explicitly correlated full configuration interaction quantum Monte Carlo. AB - The Full Configuration Interaction Quantum Monte Carlo (FCIQMC) method has proved able to provide near-exact solutions to the electronic Schrodinger equation within a finite orbital basis set, without relying on an expansion about a reference state. However, a drawback to the approach is that being based on an expansion of Slater determinants, the FCIQMC method suffers from a basis set incompleteness error that decays very slowly with the size of the employed single particle basis. The FCIQMC results obtained in a small basis set can be improved significantly with explicitly correlated techniques. Here, we present a study that assesses and compares two contrasting "universal" explicitly correlated approaches that fit into the FCIQMC framework: the [2]R12 method of Kong and Valeev [J. Chem. Phys. 135, 214105 (2011)] and the explicitly correlated canonical transcorrelation approach of Yanai and Shiozaki [J. Chem. Phys. 136, 084107 (2012)]. The former is an a posteriori internally contracted perturbative approach, while the latter transforms the Hamiltonian prior to the FCIQMC simulation. These comparisons are made across the 55 molecules of the G1 standard set. We found that both methods consistently reduce the basis set incompleteness, for accurate atomization energies in small basis sets, reducing the error from 28 mEh to 3-4 mEh. While many of the conclusions hold in general for any combination of multireference approaches with these methodologies, we also consider FCIQMC specific advantages of each approach. PMID- 27497550 TI - Accurate reaction-diffusion operator splitting on tetrahedral meshes for parallel stochastic molecular simulations. AB - Spatial stochastic molecular simulations in biology are limited by the intense computation required to track molecules in space either in a discrete time or discrete space framework, which has led to the development of parallel methods that can take advantage of the power of modern supercomputers in recent years. We systematically test suggested components of stochastic reaction-diffusion operator splitting in the literature and discuss their effects on accuracy. We introduce an operator splitting implementation for irregular meshes that enhances accuracy with minimal performance cost. We test a range of models in small-scale MPI simulations from simple diffusion models to realistic biological models and find that multi-dimensional geometry partitioning is an important consideration for optimum performance. We demonstrate performance gains of 1-3 orders of magnitude in the parallel implementation, with peak performance strongly dependent on model specification. PMID- 27497551 TI - Measuring a hidden coordinate: Rate-exchange kinetics from 3D correlation functions. AB - Nonexponential kinetics imply the existence of at least one slow variable other than the observable, that is, the system has a "hidden" coordinate. We develop a simple, but general, model that allows multidimensional correlation functions to be calculated for these systems. Homogeneous and heterogeneous mechanisms are both included, and slow exchange of the rates is allowed. This model shows that 2D and 3D correlation functions of the observable measure the distribution and kinetics of the hidden coordinate controlling the rate exchange. Both the mean exchange time and the shape of the exchange relaxation are measurable. However, complications arise because higher correlation functions are sums of multiple "pathways," each of which measures different dynamics. Only one 3D pathway involves exchange dynamics. Care must be used to extract exchange dynamics without contamination from other processes. PMID- 27497552 TI - DMRG-CASPT2 study of the longitudinal static second hyperpolarizability of all trans polyenes. AB - We have implemented internally contracted complete active space second order perturbation theory (CASPT2) with the density matrix renormalization group (DMRG) as active space solver [Y. Kurashige and T. Yanai, J. Chem. Phys. 135, 094104 (2011)]. Internally contracted CASPT2 requires to contract the generalized Fock matrix with the 4-particle reduced density matrix (4-RDM) of the reference wavefunction. The required 4-RDM elements can be obtained from 3-particle reduced density matrices (3-RDM) of different wavefunctions, formed by symmetry conserving single-particle excitations op top of the reference wavefunction. In our spin-adapted DMRG code chemps2 https://github.com/sebwouters/chemps2, we decompose these excited wavefunctions as spin-adapted matrix product states and calculate their 3-RDM in order to obtain the required contraction of the generalized Fock matrix with the 4-RDM of the reference wavefunction. In this work, we study the longitudinal static second hyperpolarizability of all-trans polyenes C2nH2n+2 [n = 4-12] in the cc-pVDZ basis set. DMRG-SCF and DMRG-CASPT2 yield substantially lower values and scaling with system size compared to RHF and MP2, respectively. PMID- 27497553 TI - Insights into the spurious long-range nature of local r-dependent non-local exchange-correlation kernels. AB - A systematic route to go beyond the exact exchange plus random phase approximation (RPA) is to include a physical exchange-correlation kernel in the adiabatic-connection fluctuation-dissipation theorem. In the previous study [D. Lu, J. Chem. Phys. 140, 18A520 (2014)], we found that non-local kernels with a screening length depending on the local Wigner-Seitz radius, rs(r), suffer an error associated with a spurious long-range repulsion in van der Waals bounded systems, which deteriorates the binding energy curve as compared to RPA. We analyze the source of the error and propose to replace rs(r) by a global, average rs in the kernel. Exemplary studies with the Corradini, del Sole, Onida, and Palummo kernel show that while this change does not affect the already outstanding performance in crystalline solids, using an average rs significantly reduces the spurious long-range tail in the exchange-correlation kernel in van der Waals bounded systems. When this method is combined with further corrections using local dielectric response theory, the binding energy of the Kr dimer is improved three times as compared to RPA. PMID- 27497554 TI - Dynamic NMR under nonstationary conditions: Theoretical model, numerical calculation, and potential of application. AB - An expression has been derived for the time dependence of the NMR line shape for systems with multi-site chemical exchange in the absence of spin-spin coupling, in a zero saturation limit. The dynamics of variation of the NMR line shape with time is considered in detail for the case of two-site chemical exchange. Mathematical programs have been designed for numerical simulation of the NMR spectra of chemical exchange systems. The analytical expressions obtained are useful for NMR line shape simulations for systems with photoinduced chemical exchange. PMID- 27497555 TI - Fragmentation pathways of tungsten hexacarbonyl clusters upon electron ionization. AB - Electron ionization of neat tungsten hexacarbonyl (W(CO)6) clusters has been investigated in a crossed electron-molecular beam experiment coupled with a mass spectrometer system. The molecule is used for nanofabrication processes through electron beam induced deposition and ion beam induced deposition techniques. Positive ion mass spectra of W(CO)6 clusters formed by electron ionization at 70 eV contain the ion series of the type W(CO)n (+) (0 <= n <= 6) and W2(CO)n (+) (0 <= n <= 12). In addition, a series of peaks are observed and have been assigned to WC(CO)n (+) (0 <= n <= 3) and W2C(CO)n (+) (0 <= n <= 10). A distinct change of relative fragment ion intensity can be observed for clusters compared to the single molecule. The characteristic fragmentation pattern obtained in the mass spectra can be explained by a sequential decay of the ionized organometallic, which is also supported by the study of the clusters when embedded in helium nanodroplets. In addition, appearance energies for the dissociative ionization channels for singly charged ions have been estimated from experimental ion efficiency curves. PMID- 27497556 TI - High-resolution photoelectron imaging spectroscopy of cryogenically cooled Fe4O( ) and Fe5O(.). AB - We report high-resolution photodetachment spectra of the cryogenically cooled iron monoxide clusters Fe4O(-) and Fe5O(-) obtained with slow photoelectron velocity-map imaging (cryo-SEVI). Well-resolved vibrational progressions are observed in both sets of spectra, and transitions to low-lying excited states of both species are seen. In order to identify the structural isomers, electronic states, and vibrational modes that contribute to the cryo-SEVI spectra of these clusters, experimental results are compared with density functional theory calculations and Franck-Condon simulations. The main bands observed in the SEVI spectra are assigned to the (15)A2<-(16)B2 photodetachment transition of Fe4O(-) and the (17)A'<-(18)A" photodetachment transition of Fe5O(-). We report electron affinities of 1.6980(3) eV for Fe4O and 1.8616(3) eV for Fe5O, although there is some uncertainty as to whether the (15)A2 state is the true ground state of Fe4O. The iron atoms have a distorted tetrahedral geometry in Fe4O(0/-) and a distorted trigonal-bipyramidal arrangement in Fe5O(0/-). For both neutral and anionic species, the oxygen atom preferably binds in a MU2-oxo configuration along the cluster edge. This finding is in contrast to prior predictions that Fe5O(0/-) exhibits a MU3 face-bound structure. PMID- 27497557 TI - Dynamical tunneling versus fast diffusion for a non-convex Hamiltonian. AB - This paper attempts to resolve the issue of the nature of the 0.01-0.1 cm(-1) peak splittings observed in high-resolution IR spectra of polyatomic molecules. One hypothesis is that these splittings are caused by dynamical tunneling, a quantum-mechanical phenomenon whereby energy flows between two disconnected regions of phase-space across dynamical barriers. However, a competing classical mechanism for energy flow is Arnol'd diffusion, which connects different regions of phase-space by a resonance network known as the Arnol'd web. The speed of diffusion is bounded by the Nekhoroshev theorem, which guarantees stability on exponentially long time scales if the Hamiltonian is steep. Here we consider a non-convex Hamiltonian that contains the characteristics of a molecular Hamiltonian, but does not satisfy the Nekhoroshev theorem. The diffusion along the Arnol'd web is expected to be fast for a non-convex Hamiltonian. While fast diffusion is an unlikely competitor for longtime energy flow in molecules, we show how dynamical tunneling dominates compared to fast diffusion in the nearly integrable regime for a non-convex Hamiltonian, as well as present a new kind of dynamical tunneling. PMID- 27497558 TI - The polar 2e/12c bond in phenalenyl-azaphenalenyl hetero-dimers: Stronger stacking interaction and fascinating interlayer charge transfer. AB - An increasing number of chemists have focused on the two-electron/multicenter bond (2e/mc) that was first introduced to interpret the bonding mechanism of radical dimers. Herein, we report the polar two-electron/twelve center (2e/12c) bonding character in a series of phenalenyl-azaphenalenyl radical hetero-dimers. Interestingly, the bonding energy of weaker polar hetero-dimer (P-TAP) is dominated by the overlap of the two different singly occupied molecular orbital of radicals, while that of stronger polar hetero-dimer (P-HAP) is dominated by the electrostatic attraction. Results show that the difference between the electronegativity of the monomers plays a prominent role in the essential attribution of the polar 2e/12c bond. Correspondingly, a stronger stacking interaction in the hetero-dimer could be effectively achieved by increasing the difference of nitrogen atoms number between the monomers. It is worthy of note that an interesting interlayer charge transfer character is induced in the polar hetero-dimers, which is dependent on the difference between the electronegativity of the monomers. It is our expectation that the new knowledge about the bonding nature of radical hetero-dimers might provide important information for designing radical based functional materials with various applications. PMID- 27497559 TI - Aging kinetics of levoglucosan orientational glass as a rate dispersion process and consequences for the heterogeneous dynamics view. AB - Aging kinetics of a glass is currently modeled in terms of slowing of its alpha relaxation dynamics, whose features are interpreted in terms of dynamic heterogeneity, i.e., formation and decay of spatially and temporally distinct nm size regions. To test the merits of this view, we studied the calorimetric effects of aging an orientational glass of levoglucosan crystal in which such regions would not form in the same way as they form in liquids, and persist in structural glasses, because there is no liquid-like molecular diffusion in the crystal. By measuring the heat capacity, Cp, we determined the change in the enthalpy, H, and the entropy, S, during two aging-protocols: (a) keeping the samples isothermally at temperature, Ta, and measuring the changes after different aging times, ta, and (b) keeping the samples at different Tas and measuring the changes after the same ta. A model-free analysis of the data shows that as ta is increased (procedure (a)), H and S decrease according to a dispersive rate kinetics, and as Ta is increased (procedure (b)), H and S first increase, reach a local maximum at a certain Ta, and then decrease. Even though there is no translational diffusion to produce (liquid-like) free volume, and no translational-rotational decoupling, the aging features are indistinguishable from those of structural glasses. We also find that the Kohlrausch parameter, originally fitted to the glass-aging data, decreases with decrease in Ta, which is incompatible with the current use of the aging data for estimating the alpha relaxation time. We argue that the vibrational state of a glass is naturally incompatible with its configurational state, and both change on aging until they are compatible, in the equilibrium liquid. So, dipolar fluctuations seen as the alpha-relaxation would not be the same motions that cause aging. We suggest that aging kinetics is intrinsically dispersive with its own characteristic rate constant and it does not yield the alpha-relaxation rate. In this view, thermodynamic and other properties define the fictive temperature; the real or imaginary components of a dynamic property do not define it. While particles' overall motions may still play a crucial role in (structural) glass physics, we conclude that translational diffusion alone is not a requirement for structure stabilization on aging of a kinetically frozen state. PMID- 27497560 TI - Dynamic measurements and simulations of airborne picolitre-droplet coalescence in holographic optical tweezers. AB - We report studies of the coalescence of pairs of picolitre aerosol droplets manipulated with holographic optical tweezers, probing the shape relaxation dynamics following coalescence by simultaneously monitoring the intensity of elastic backscattered light (EBL) from the trapping laser beam (time resolution on the order of 100 ns) while recording high frame rate camera images (time resolution <10 MUs). The goals of this work are to: resolve the dynamics of droplet coalescence in holographic optical traps; assign the origin of key features in the time-dependent EBL intensity; and validate the use of the EBL alone to precisely determine droplet surface tension and viscosity. For low viscosity droplets, two sequential processes are evident: binary coalescence first results from the overlap of the optical traps on the time scale of microseconds followed by the recapture of the composite droplet in an optical trap on the time scale of milliseconds. As droplet viscosity increases, the relaxation in droplet shape eventually occurs on the same time scale as recapture, resulting in a convoluted evolution of the EBL intensity that inhibits quantitative determination of the relaxation time scale. Droplet coalescence was simulated using a computational framework to validate both experimental approaches. The results indicate that time-dependent monitoring of droplet shape from the EBL intensity allows for robust determination of properties such as surface tension and viscosity. Finally, the potential of high frame rate imaging to examine the coalescence of dissimilar viscosity droplets is discussed. PMID- 27497561 TI - A theoretical study of the relaxation of a phenyl group chemisorbed to an RDX freestanding thin film. AB - Energy relaxation from an excited phenyl group chemisorbed to the surface of a crystalline thin film of alpha-1,3,5-trinitro-1,3,5-triazacyclohexane (alpha-RDX) at 298 K and 1 atm is simulated using molecular dynamics. Two schemes are used to excite the phenyl group. In the first scheme, the excitation energy is added instantaneously as kinetic energy by rescaling momenta of the 11 atoms in the phenyl group. In the second scheme, the phenyl group is equilibrated at a higher temperature in the presence of static RDX geometries representative of the 298 K thin film. An analytical model based on ballistic phonon transport that requires only the harmonic part of the total Hamiltonian and includes no adjustable parameters is shown to predict, essentially quantitatively, the short-time dynamics of the kinetic energy relaxation (~200 fs). The dynamics of the phenyl group for times longer than about 6 ps follows exponential decay and agrees qualitatively with the dynamics described by a master equation. Long-time heat propagation within the bulk of the crystal film is consistent with the heat equation. PMID- 27497562 TI - Complete equation of state for shocked liquid nitrogen: Analytical developments. AB - The thermodynamic response of liquid nitrogen has been studied extensively, in part, due to the long-standing interest in the high pressure and high temperature dissociation of shocked molecular nitrogen. Previous equation of state (EOS) developments regarding shocked liquid nitrogen have focused mainly on the use of intermolecular pair potentials in atomistic calculations. Here, we present EOS developments for liquid nitrogen, incorporating analytical models, for use in continuum calculations of the shock compression response. The analytical models, together with available Hugoniot data, were used to extrapolate a low pressure reference EOS for molecular nitrogen [R. Span et al., J. Phys. Chem. Ref. Data 29, 1361 (2000)] to high pressures and high temperatures. Using the EOS presented here, the calculated pressures and temperatures for single shock, double shock, and multiple shock compression of liquid nitrogen provide a good match to the measured results over a broad range of P-T space. These calculations provide the first comparison of EOS developments with recently measured P-T states under multiple shock compression. The present EOS developments are general and are expected to be useful for other liquids that have low pressure reference EOS information available. PMID- 27497563 TI - A comprehensive scenario of the thermodynamic anomalies of water using the TIP4P/2005 model. AB - The striking behavior of water has deserved it to be referred to as an "anomalous" liquid. The water anomalies are greatly amplified in metastable (supercooled and/or stretched) regions. This makes difficult a complete experimental description since, beyond certain limits, the metastable phase necessarily transforms into the stable one. Theoretical interpretation of the water anomalies could then be based on simulation results of well validated water models. But the analysis of the simulations has not yet reached a consensus. In particular, one of the most popular theoretical scenarios-involving the existence of a liquid-liquid critical point (LLCP)-is disputed by several authors. In this work, we propose to use a number of exact thermodynamic relations which may shed light on this issue. Interestingly, these relations may be tested in a region of the phase diagram which is outside the LLCP thus avoiding the problems associated to the coexistence region. The central property connected to other water anomalies is the locus of temperatures at which the density along isobars attain a maximum (TMD line) or a minimum (TmD). We have performed computer simulations to evaluate the TMD and TmD for a successful water model, namely, TIP4P/2005. We have also evaluated the vapor-liquid (VL) spinodal in the region of large negative pressures. The shape of these curves and their connection to the extrema of some response functions, in particular the isothermal compressibility and heat capacity at constant pressure, provides very useful information which may help to elucidate the validity of the theoretical proposals. In this way, we are able to present for the first time a comprehensive scenario of the thermodynamic water anomalies for TIP4P/2005 and their relation to the vapor-liquid spinodal. The overall picture shows a remarkable similarity with the corresponding one for the ST2 water model, for which the existence of a LLCP has been demonstrated in recent years. It also provides a hint as to where the long-sought for extrema in response functions might become accessible to experiments. PMID- 27497564 TI - Anomalous properties and the liquid-liquid phase transition in gallium. AB - A group of materials including water and silicon exhibit many anomalous behaviors, e.g., density anomaly and diffusivity anomaly (increase upon compression). These materials are hypothesized to have a liquid-liquid phase transition (LLPT) and the critical fluctuation in the vicinity of the liquid liquid critical point is considered as the origin of different anomalies. Liquid gallium was also reported to have a LLPT, yet whether it shows similar water-like anomalies is not yet studied. Using molecular dynamics simulations on a modified embedded-atom model, we study the thermodynamic, dynamic, and structural properties of liquid gallium as well as its LLPT. We find that, similar to water like materials predicted to have the LLPT, gallium also shows different anomalous behaviors (e.g., density anomaly, diffusivity anomaly, and structural anomaly). We also find that its thermodynamic and structural response functions are continuous and show maxima in the supercritical region, the loci of which asymptotically approach to the other and merge to the Widom line. These phenomena are consistent with the supercritical phenomenon in a category of materials with a liquid-liquid critical point, which could be common features in most materials with a LLPT. PMID- 27497565 TI - Emergence of linear elasticity from the atomistic description of matter. AB - We investigate the emergence of the continuum elastic limit from the atomistic description of matter at zero temperature considering how locally defined elastic quantities depend on the coarse graining length scale. Results obtained numerically investigating different model systems are rationalized in a unifying picture according to which the continuum elastic limit emerges through a process determined by two system properties, the degree of disorder, and a length scale associated to the transverse low-frequency vibrational modes. The degree of disorder controls the emergence of long-range local shear stress and shear strain correlations, while the length scale influences the amplitude of the fluctuations of the local elastic constants close to the jamming transition. PMID- 27497566 TI - A dissolution-precipitation mechanism is at the origin of concrete creep in moist environments. AB - Long-term creep (i.e., deformation under sustained load) is a significant material response that needs to be accounted for in concrete structural design. However, the nature and origin of concrete creep remain poorly understood and controversial. Here, we propose that concrete creep at relative humidity >= 50%, but fixed moisture content (i.e., basic creep), arises from a dissolution precipitation mechanism, active at nanoscale grain contacts, as has been extensively observed in a geological context, e.g., when rocks are exposed to sustained loads, in liquid-bearing environments. Based on micro-indentation and vertical scanning interferometry data and molecular dynamics simulations carried out on calcium-silicate-hydrate (C-S-H), the major binding phase in concrete, of different compositions, we show that creep rates are correlated with dissolution rates-an observation which suggests a dissolution-precipitation mechanism as being at the origin of concrete creep. C-S-H compositions featuring high resistance to dissolution, and, hence, creep are identified. Analyses of the atomic networks of such C-S-H compositions using topological constraint theory indicate that these compositions present limited relaxation modes on account of their optimally connected (i.e., constrained) atomic networks. PMID- 27497567 TI - Pseudogap and anharmonic phonon behavior in Ba8Ga16Ge30: An NMR study. AB - We have performed (69)Ga, (71)Ga, and (137)Ba NMR on Ba8Ga16Ge30, a clathrate semiconductor which has been of considerable interest due to its large figure of merit for thermoelectric applications. In measurements from 4 K to 450 K, we used measurements on the two Ga nuclei to separate the magnetic and electric quadrupole hyperfine contributions and thereby gain information about the metallic and phonon behavior. The results show the presence of a pseudogap in the Ga electronic states within the conduction band, superposed upon a large Ba contribution to the conduction band. Meanwhile the phonon contributions to the Ga relaxation rates are large and increase more rapidly with temperature than typical semiconductors. These results provide evidence for enhanced anharmonicity of the propagative phonon modes over a wide range, providing experimental evidence for enhanced phonon-phonon scattering as a mechanism for the reduced thermal conductivity. PMID- 27497568 TI - Left-right correlation in coupled F-center defects. AB - This work explores how left-right correlation, a textbook problem in electronic structure theory, manifests in a textbook example of electrons trapped in crystal defects. I show that adjacent F-center defects in lithium fluoride display symptoms of "strong" left-right correlation, symptoms similar to those seen in stretched H2. Simulations of UV/visible absorption spectra qualitatively fail to reproduce experiment unless left-right correlation is taken into account. This is of interest to both the electronic structure theory and crystal-defect communities. Theorists have a new well-behaved system to test their methods. Crystal-defect groups are cautioned that the approximations that successfully model single F-centers may fail for adjacent F-centers. PMID- 27497569 TI - Buckling failure of square ice-nanotube arrays constrained in graphene nanocapillaries. AB - Graphene confinement provides a new physical and mechanical environment with ultrahigh van der Waals pressure, resulting in new quasi-two-dimensional phases of few-layer ice. Polymorphic transition can occur in bilayer constrained water/ice system. Here, we perform a comprehensive study of the phase transition of AA-stacked bilayer water constrained within a graphene nanocapillary. The compression-limit and superheating-limit (phase) diagrams are obtained, based on the extensive molecular-dynamics simulations at numerous thermodynamic states. Liquid-to-solid, solid-to-solid, and solid-to-liquid-to-solid phase transitions are observed in the compression and superheating of bilayer water. Interestingly, there is a temperature threshold (~275 K) in the compression-limit diagram, which indicates that the first-order and continuous-like phase transitions of bilayer water depend on the temperature. Two obviously different physical processes, compression and superheating, display similar structural evolution; that is, square ice-nanotube arrays (BL-VHDI) will bend first and then transform into bilayer triangular AA stacking ice (BL-AAI). The superheating limit of BL-VHDI exhibits local maxima, while that of BL-AAI increases monotonically. More importantly, from a mechanics point of view, we propose a novel mechanism of the transformation from BL-VHDI to BL-AAI, both for the compression and superheating limits. This structural transformation can be regarded as the "buckling failure" of the square-ice-nanotube columns, which is dominated by the lateral pressure. PMID- 27497570 TI - Vibrational spectroscopic evidence for (NO)3 formation on Cu(111). AB - The formation of (NO)3 on Cu(111) was recently reported based on scanning tunneling microscopy observations [A. Shiotari et al., J. Chem. Phys. 141, 134705 (2014)]. We herein report studies into this system using electron energy loss spectroscopy and verify the above findings through vibrational analysis. For the surface covered with mixed isotopes of N(16)O and N(18)O, we observed four peaks corresponding to N-O stretching vibrations, which were ascribed to the four isotopic combinations of the trimer. Dynamic coupling within the trimer was evaluated from model calculations of the coupled oscillators. Furthermore, we observed hindered rotation and translation modes in the dipole scattering regime, suggesting that the molecular axis is tilted from the surface normal. These results provide spectroscopic support for the formation of (NO)3 on Cu(111). PMID- 27497572 TI - Role of density modulation in the spatially resolved dynamics of strongly confined liquids. AB - Confinement by walls usually produces a strong modulation in the density of dense liquids near the walls. Using molecular dynamics simulations, we examine the effects of the density modulation on the spatially resolved dynamics of a liquid confined between two parallel walls, using a resolution of a fraction of the interparticle distance in the liquid. The local dynamics is quantified by the relaxation time associated with the temporal autocorrelation function of the local density. We find that this local relaxation time varies in phase with the density modulation. The amplitude of the spatial modulation of the relaxation time can be quite large, depending on the characteristics of the wall and thermodynamic parameters of the liquid. To disentangle the effects of confinement and density modulation on the spatially resolved dynamics, we compare the dynamics of a confined liquid with that of an unconfined one in which a similar density modulation is induced by an external potential. We find several differences indicating that density modulation alone cannot account for all the features seen in the spatially resolved dynamics of confined liquids. We also examine how the dynamics near a wall depends on the separation between the two walls and show that the features seen in our simulations persist in the limit of large wall separation. PMID- 27497573 TI - Enhancement factor statistics of surface enhanced Raman scattering in multiscale heterostructures of nanoparticles. AB - Suitable metal nanostructures may induce surface-enhanced Raman scattering (SERS) enhancement factors (EFs) large-enough to reach single-molecule sensitivity. However, the gap hot-spot EF probability density function (PDF) has the character of a long-tail distribution, which dramatically mines the reproducibility of SERS experiments. Herein, we carry out electrodynamic calculations based on a 3D finite element method of two plasmonic nanostructures, combined with Monte Carlo simulations of the EF statistics under different external conditions. We compare the PDF produced by a homodimer of nanoparticles with that provided by a self similar trimer. We show that the PDF is sensitive to the spatial distribution of near-field enhancement specifically supported by the nanostructure geometry. Breaking the symmetry of the plasmonic system is responsible for inducing particular modulations of the PDF tail resembling a multiple Poisson distribution. We also study the influence that molecular diffusion towards the hottest hot-spot, or selective hot-spot targeting, might have on the EF PDF. Our results quantitatively assess the possibility of designing the response of a SERS substrate so as to contain the intrinsic EF PDF variance and significantly improving, in principle, the reproducibility of SERS experiments. PMID- 27497571 TI - Dependence of SERS enhancement on the chemical composition and structure of Ag/Au hybrid nanoparticles. AB - Noble metal nanoparticles (NPs) such as silver (Ag) and gold (Au) have unique plasmonic properties that give rise to surface enhanced Raman scattering (SERS). Generally, Ag NPs have much stronger plasmonic properties and, hence, provide stronger SERS signals than Au NPs. However, Ag NPs lack the chemical stability and biocompatibility of comparable Au NPs and typically exhibit the most intense plasmonic resonance at wavelengths much shorter than the optimal spectral region for many biomedical applications. To overcome these issues, various experimental efforts have been devoted to the synthesis of Ag/Au hybrid NPs for the purpose of SERS detections. However, a complete understanding on how the SERS enhancement depends on the chemical composition and structure of these nanoparticles has not been achieved. In this study, Mie theory and the discrete dipole approximation have been used to calculate the plasmonic spectra and near-field electromagnetic enhancements of Ag/Au hybrid NPs. In particular, we discuss how the electromagnetic enhancement depends on the mole fraction of Au in Ag/Au alloy NPs and how one may use extinction spectra to distinguish between Ag/Au alloyed NPs and Ag-Au core-shell NPs. We also show that for incident laser wavelengths between ~410 nm and 520 nm, Ag/Au alloyed NPs provide better electromagnetic enhancement than pure Ag, pure Au, or Ag-Au core-shell structured NPs. Finally, we show that silica-core Ag/Au alloy shelled NPs provide even better performance than pure Ag/Au alloy or pure solid Ag and pure solid Au NPs. The theoretical results presented will be beneficial to the experimental efforts in optimizing the design of Ag/Au hybrid NPs for SERS-based detection methods. PMID- 27497575 TI - On the determination of the crystal-vapor surface free energy, and why a Gaussian expression can be accurate for a system far from Gaussian. AB - The crystal-vapor surface free energy gamma is an important physical parameter governing physical processes, such as wetting and adhesion. We explore exact and approximate routes to calculate gamma based on cleaving an intact crystal into non-interacting sub-systems with crystal-vapor interfaces. We do this by turning off the interactions, DeltaV, between the sub-systems. Using the soft-core scheme for turning off DeltaV, we find that the free energy varies smoothly with the coupling parameter lambda, and a single thermodynamic integration yields the exact gamma. We generate another exact method, and a cumulant expansion for gamma by expressing the surface free energy in terms of an average of e(-betaDeltaV) in the intact crystal. The second cumulant, or Gaussian approximation for gamma is surprisingly accurate in most situations, even though we find that the underlying probability distribution for DeltaV is clearly not Gaussian. We account for this fact by developing a non-Gaussian theory for gamma and find that the difference between the non-Gaussian and Gaussian expressions for gamma consist of terms that are negligible in many situations. Exact and approximate methods are applied to the (111) surface of a Lennard-Jones crystal and are also tested for more complex molecular solids, the surface of octane and nonadecane. Alkane surfaces were chosen for study because their crystal-vapor surface free energy has been of particular interest for understanding surface freezing in these systems. PMID- 27497574 TI - Vibrational energy transfer near a dissociative adsorption transition state: State-to-state study of HCl collisions at Au(111). AB - In this work we seek to examine the nature of collisional energy transfer between HCl and Au(111) for nonreactive scattering events that sample geometries near the transition state for dissociative adsorption by varying both the vibrational and translational energy of the incident HCl molecules in the range near the dissociation barrier. Specifically, we report absolute vibrational excitation probabilities for HCl(v = 0 -> 1) and HCl(v = 1 -> 2) scattering from clean Au(111) as a function of surface temperature and incidence translational energy. The HCl(v = 2 -> 3) channel could not be observed-presumably due to the onset of dissociation. The excitation probabilities can be decomposed into adiabatic and nonadiabatic contributions. We find that both contributions strongly increase with incidence vibrational state by a factor of 24 and 9, respectively. This suggests that V-T as well as V-EHP coupling can be enhanced near the transition state for dissociative adsorption at a metal surface. We also show that previously reported HCl(v = 0 -> 1) excitation probabilities [Q. Ran et al., Phys. Rev. Lett. 98, 237601 (2007)]-50 times smaller than those reported here were influenced by erroneous assignment of spectroscopic lines used in the data analysis. PMID- 27497576 TI - Designing convex repulsive pair potentials that favor assembly of kagome and snub square lattices. AB - Building on a recently introduced inverse strategy, isotropic and convex repulsive pair potentials were designed that favor assembly of particles into kagome and equilateral snub square lattices. The former interactions were obtained by a numerical solution of a variational problem that maximizes the range of density for which the ground state of the potential is the kagome lattice. Similar optimizations targeting the snub square lattice were also carried out, employing a constraint that required a minimum chemical potential advantage of the target over select competing structures. This constraint helped to discover isotropic interactions that meaningfully favored the snub square lattice as the ground state structure despite the asymmetric spatial distribution of particles in its coordination shells and the presence of tightly competing structures. Consistent with earlier published results [W. Pineros et al., J. Chem. Phys. 144, 084502 (2016)], enforcement of greater chemical potential advantages for the target lattice in the interaction optimization led to assemblies with enhanced thermal stability. PMID- 27497577 TI - Stabilizing the hexagonal close packed structure of hard spheres with polymers: Phase diagram, structure, and dynamics. AB - We study the phase behaviour of a binary mixture of colloidal hard spheres and freely jointed chains of beads using Monte Carlo simulations. Recently Panagiotopoulos and co-workers predicted [Nat. Commun. 5, 4472 (2014)] that the hexagonal close packed (HCP) structure of hard spheres can be stabilized in such a mixture due to the interplay between polymer and the void structure in the crystal phase. Their predictions were based on estimates of the free-energy penalty for adding a single hard polymer chain in the HCP and the competing face centered cubic (FCC) phase. Here we calculate the phase diagram using free-energy calculations of the full binary mixture and find a broad fluid-solid coexistence region and a metastable gas-liquid coexistence region. For the colloid-monomer size ratio considered in this work, we find that the HCP phase is only stable in a small window at relatively high polymer reservoir packing fractions, where the coexisting HCP phase is nearly close packed. Additionally we investigate the structure and dynamic behaviour of these mixtures. PMID- 27497578 TI - Effect of five-membered ring and heteroatom substitution on charge transport properties of perylene discotic derivatives: A theoretical approach. AB - Density functional theory calculations were carried out to investigate the evolvement of charge transport properties of a set of new discotic systems as a function of ring and heteroatom (B, Si, S, and Se) substitution on the basic structure of perylene. The replacement of six-membered rings by five-membered rings in the reference compound has shown a prominent effect on the electron reorganization energy that decreases ~0.2 eV from perylene to the new carbon five membered ring derivative. Heteroatom substitution with boron also revealed to lower the LUMO energy level and increase the electron affinity, therefore lowering the electron injection barrier compared to perylene. Since the rate of the charge transfer between two molecules in columnar discotic systems is strongly dependent on the orientation of the stacked cores, the total energy and transfer integral of a dimer as a disc is rotated with respect to the other along the stacking axis have been predicted. Aimed at obtaining a more realistic approach to the bulk structure, the molecular geometry of clusters made up of five discs was fully optimized, and charge transfer rate and mobilities were estimated for charge transport along a one dimensional pathway. Heteroatom substitution with selenium yields electron transfer integral values ~0.3 eV with a relative disc orientation of 25 degrees , which is the preferred angle according to the dimer energy profile. All the results indicate that the tetraselenium-substituted derivative, not synthetized so far, could be a promising candidate among those studied in this work for the fabrication of n type semiconductors based on columnar discotic liquid crystals materials. PMID- 27497579 TI - Comment on "Replica-exchange-with-tunneling for fast exploration of protein landscapes" [J. Chem. Phys. 143, 224102 (2015)]. AB - In "Replica-exchange-with-tunneling for fast exploration of protein landscapes" [F. Yasar et al., J. Chem. Phys. 143, 224102 (2015)], a novel sampling algorithm called "Replica Exchange with Tunneling" was proposed. However, due to its violation of the detailed balance, the algorithm fails to sample from the correct canonical ensemble. PMID- 27497580 TI - Response to "Comment on 'Replica-exchange-with-tunneling for fast exploration of protein landscapes"' [J. Chem. Phys. 145, 057101 (2016)]. PMID- 27497581 TI - Erratum: "Van der Waals supercritical fluid: Exact formulas for special lines" [J. Chem. Phys. 135, 084503 (2011)]. PMID- 27497582 TI - Publisher's Note: "Permeation of the three aromatic dipeptides through lipid bilayers: Experimental and computational study" [J. Chem. Phys. 144, 245103 (2016)]. PMID- 27497583 TI - Erratum: "Ionic strength independence of charge distributions in solvation of biomolecules" [J. Chem. Phys. 141, 22D503 (2014)]. PMID- 27497584 TI - Cytogenetics of the Thorny Catfish Trachydoras paraguayensis (Eigenmann & Ward, 1907), (Siluriformes, Doradidae): Evidence of Pericentric Inversions and Chromosomal Fusion. AB - The karyotype and chromosomal characteristics of Trachydorasparaguayensis, a representative of the South American catfish family Doradidae, were analyzed by conventional (Giemsa staining, silver staining, C-banding) and molecular (FISH with rDNA and telomeric probes) cytogenetic techniques. The diploid chromosome number was 2n = 56, with 36 metacentric, 16 submetacentric, and 4 subtelocentric chromosomes in both sexes; however, a remarkable heteromorphism in pair 22 (submetacentric and metacentric elements) was detected in 6 individuals. Compared to other representatives of Doradidae which mostly have 58 chromosomes, the karyotype of T. paraguayensis suggests a reduction in 2n due to chromosomal fusion, as could be deduced from the presence of an interstitial telomere sequence in the submetacentric pair 19. Pale heterochromatic blocks were present in the terminal regions of some chromosomes, very similar to other species of Doradidae. The interstitial position of the NORs observed in the karyotype of T. paraguayensis differs from those reported for most Doradidae species, indicating that it is a derived character. FISH with 5S rDNA revealed 2 interstitial fluorescent signals in the submetacentric pair 22, and the polymorphism of these sites likely resulted from a pericentric inversion. PMID- 27497585 TI - Pollutant formation in the pyrolysis and combustion of Automotive Shredder Residue. AB - The present work has been carried out to verify the feasibility of thermal valorization of an automobile shredder residue (ASR). With this aim, the thermal decomposition of this waste has been studied in a laboratory scale reactor, analyzing the pollutants emitted under different operating conditions. The emission factors of carbon oxides, light hydrocarbons, PAHs, PCPhs, PCBzs, PBPhs, PCDD/Fs, dioxin-like PCBs and PBDD/Fs were determined at two temperatures, 600 and 850 degrees C, and under different oxygen ratios ranging from 0 (pure pyrolysis) to 1.5 (over-stoichiometric oxidation). After analyzing all these compounds, we conclude that thermal valorization of ASR is a clean way to treat this waste. PMID- 27497586 TI - A novel approach in calculating site-specific aftercare completion criteria for landfills in The Netherlands: Policy developments. AB - As part of a more circular economy, current attention on waste is shifting from landfilling towards the prevention, re-use and recycling of waste materials. Although the need for landfills is decreasing, there are many landfills around the world that are still operational or at the point of starting the aftercare period. With traditional aftercare management, these landfills require perpetual aftercare at considerable cost due to monitoring and regular maintenance of liners. In an attempt to lower these aftercare costs, and to prevent that future generations become responsible for finding a sustainable solution of present day waste, the Dutch government takes action to explore the possibilities of sustainable landfill management. A project was started to investigate whether the use of source-oriented treatment techniques (so-called active treatment) of landfills can result in a sustainable emission reduction to soil and groundwater. During the next decade, sustainable landfill management is tested at three selected pilot landfills in the Netherlands. To enable this pilot testing and to determine its success after the experimental treatment period, a new methodology and conceptual framework was developed. The aim of this paper is to describe the development of the new methodology, and in particular the policy decisions, needed to determine whether the pilot experiments will be successful. The pilot projects are considered successful when the concentrations in the leachate of the pilot landfills have sufficiently been reduced and for longer periods of time and comply with the derived site-specific Environmental Protection Criteria (EPC). In that case, aftercare can be reduced, and it can be determined whether sustainable landfill management is economically feasible for further implementation. PMID- 27497587 TI - Consecutive anaerobic-aerobic treatment of the organic fraction of municipal solid waste and lignocellulosic materials in laboratory-scale landfill bioreactors. AB - The scope of this study is to evaluate the use of laboratory-scale landfill bioreactors, operated consecutively under anaerobic and aerobic conditions, for the combined treatment of the organic fraction of municipal solid waste (OFMSW) with two different co-substrates of lignocellulosic nature, namely green waste (GW) and dried olive pomace (DOP). According to the results such a system would represent a promising option for eventual larger scale applications. Similar variation patterns among bioreactors indicate a relatively defined sequence of processes. Initially operating the systems under anaerobic conditions would allow energetic exploitation of the substrates, while the implementation of a leachate treatment system ultimately aiming at nutrient recovery, especially during the anaerobic phase, could be a profitable option for the whole system, due to the high organic load that characterizes this effluent. In order to improve the overall effectiveness of such a system, measures towards enhancing methane contents of produced biogas, such as substrate pretreatment, should be investigated. Moreover, the subsequent aerobic phase should have the goal of stabilizing the residual materials and finally obtain an end material eventually suitable for other purposes. PMID- 27497588 TI - Understanding biofilm formation in intravascular device-related infections. PMID- 27497589 TI - The ten wishes and hopes of the deputy editors of Intensive Care Medicine. PMID- 27497590 TI - Relative importance of local habitat complexity and regional factors for assemblages of oribatid mites (Acari: Oribatida) in Sphagnum peat bogs. AB - We investigated communities of oribatid mites in five peat bogs in the north-west of the East European plain. We aimed to determine the extent to which geographic factors (latitude, separation distance), local environment (Sphagnum moss species, ground water level, biogeochemistry) and local habitat complexity (diversity of vascular plants and bryophytes in the surrounding plant community) influence diversity and community composition of Oribatida. There was a significant north-to-south increase in Oribatida abundance. In the variance partitioning, spatial factors explained 33.1 % of variability in abundance across samples; none of the environmental factors were significant. Across all bogs, Oribatida species richness and community composition were similar in Sphagnum rubellum and Sphagnum magellanicum, but significantly different and less diverse in Sphagnum cuspidatum. Sphagnum microhabitat explained 52.2 % of variability in Oribatida species richness, whereas spatial variables explained only 8.7 %. There was no distance decay in community similarity between bogs with increased geographical distance. The environmental variables explained 34.9 % of the variance in community structure, with vascular plants diversity, bryophytes diversity, and ground water level all contributing significantly; spatial variables explained 15.1 % of the total variance. Overall, only 50 % of the Oribatida community variance was explained by the spatial structure and environmental variables. We discuss relative importance of spatial and local environmental factors, and make general inferences about the formation of fauna in Sphagnum bogs. PMID- 27497591 TI - Field application of menthol for Japanese honey bees, Apis cerana japonica (Hymenoptera: Apidae), to control tracheal mites, Acarapis woodi (Acari: Tarsonemidae). AB - The first record of tracheal mites, Acarapis woodi, in Japan was made in 2010. These mites have since caused serious damage to the colonies of Japanese honey bees, Apis cerana japonica. In the present study, to control the mites on Japanese honey bees with l-menthol, an agent used for European honey bees, Apis mellifera, we investigated (1) the seasonality of menthol efficacy, (2) the overwintering mortality of menthol-treated colonies, and (3) the menthol residue in honey under field conditions in cooperation with private beekeepers of Japanese honey bees. Seasonal menthol efficacy was tested by applying 30 g of l menthol for 1 month in different seasons. Mite prevalence was measured by dissecting the honey bee thorax. Overwintering mortality was monitored during winter after checking the mite prevalence in autumn, and was compared with that of untreated colonies reported in our previous study. The residual level of menthol in honey was measured by GC-MS. The results showed that the menthol treated colonies had a smaller rate of increase in mite prevalence than the untreated colonies. The effects of menthol were highest in March and April. The winter mortality was depressed by menthol treatment. Honey samples extracted from the menthol-treated colonies included 0.4 ppm of menthol residue on average. Our findings suggest that menthol treatment is effective for controlling the tracheal mites on Japanese honey bees. PMID- 27497592 TI - Biological and life table parameters of Typhlodromus laurentii and Iphiseius degenerans (Acari, Phytoseiidae) fed on Panonychus citri and pollen of Oxalis pes caprae under laboratory conditions. AB - Typhlodromus laurentii and Iphiseius degenerans are two generalist phytoseiid mites, broadly spread in the Mediterranean area, especially in citrus orchards. In the present work we report results on various biological and life table parameters of the two phytoseiids, fed on pollen of Oxalis pes-caprae and various stages of the tetranychid Panonychus citri. Iphiseius degenerans had the shortest post embryonic development (6.53 days), the highest oviposition rate (1.83 eggs/female/day) and the shortest mean time between eggs laid (0.55 day) on Oxalis pollen, whereas the two food types did not influence these parameters in T. laurentii. However, Oxalis pollen showed a positive effect on the survivorship of the latter phytoseiid, with a median life time (LT50) of 44.51 days, which was two times longer than that registered on prey with the same phytoseiid, and on both food types with I. degenerans. This latter species had a better performance on the pollen (rm = 0.243, lambda = 1.275, Ro = 22.88, DT = 2.85) than on prey (rm = 0.182, lambda = 1.199, Ro = 17.43, DT = 3.81). On the other hand, the pollen influenced the net reproductive rate (25.43 females/female) of T. laurentii positively but showed the same effect as the prey on the other demographic parameters. Our results improve knowledge on the feeding behaviour of the above mentioned phytoseiids on two food sources that could represent the main possibility to maintain a consistent population of these predators during winter. Moreover, both phytoseiids were shown to be good biocontrol candidates of P. citri populations. PMID- 27497593 TI - Differential deviant probability effects on two hierarchical levels of the auditory novelty system. AB - Deviance detection is a key functional property of the auditory system that allows pre-attentive discrimination of incoming stimuli not conforming to a rule extracted from the ongoing constant stimulation, thereby proving that regularities in the auditory scene have been encoded in the auditory system. Using simple-feature stimulus deviations, regularity encoding and deviance detection have been reported in brain responses at multiple latencies of the human Auditory Evoked Potential (AEP), such as the Mismatch Negativity (MMN; peaking at 100-250ms from stimulus onset) and Middle-Latency Responses (MLR; peaking at 12-50ms). More complex levels of regularity violations, however, are only indexed by AEPs generated at higher stages of the auditory system, suggesting a hierarchical organization in the encoding of auditory regularities. The aim of the current study is to further characterize the auditory hierarchy of novelty responses, by assessing the sensitivity of MLR components to deviant probability manipulations. MMNs and MLRs were recorded in 24 healthy participants, using an oddball location paradigm with three different deviant probabilities (5%, 10% and 20%), and a reversed-standard (91.5%). We analyzed differences in the MLRs elicited to each of the deviant stimuli and the reversed standard, as well as within deviant stimuli. Our results confirmed deviance detection at the level of both MLRs and MMN, but significant differences for deviant probabilities were found only for the MMN. These results suggest a functional dissociation between regularity encoding, already present at early stages of auditory processing, and the encoding of the probability with which this regularity is disrupted, which is only processed at higher stages of the auditory hierarchy. PMID- 27497594 TI - Advanced metal artifact reduction MRI of metal-on-metal hip resurfacing arthroplasty implants: compressed sensing acceleration enables the time-neutral use of SEMAC. AB - OBJECTIVE: Compressed sensing (CS) acceleration has been theorized for slice encoding for metal artifact correction (SEMAC), but has not been shown to be feasible. Therefore, we tested the hypothesis that CS-SEMAC is feasible for MRI of metal-on-metal hip resurfacing implants. MATERIALS AND METHODS: Following prospective institutional review board approval, 22 subjects with metal-on-metal hip resurfacing implants underwent 1.5 T MRI. We compared CS-SEMAC prototype, high-bandwidth TSE, and SEMAC sequences with acquisition times of 4-5, 4-5 and 10 12 min, respectively. Outcome measures included bone-implant interfaces, image quality, periprosthetic structures, artifact size, and signal- and contrast-to noise ratios (SNR and CNR). Using Friedman, repeated measures analysis of variances, and Cohen's weighted kappa tests, Bonferroni-corrected p-values of 0.005 and less were considered statistically significant. RESULTS: There was no statistical difference of outcomes measures of SEMAC and CS-SEMAC images. Visibility of implant-bone interfaces and pseudocapsule as well as fat suppression and metal reduction were "adequate" to "good" on CS-SEMAC and "non diagnostic" to "adequate" on high-BW TSE (p < 0.001, respectively). SEMAC and CS SEMAC showed mild blur and ripple artifacts. The metal artifact size was 63 % larger for high-BW TSE as compared to SEMAC and CS-SEMAC (p < 0.0001, respectively). CNRs were sufficiently high and statistically similar, with the exception of CNR of fluid and muscle and CNR of fluid and tendon, which were higher on intermediate-weighted high-BW TSE (p < 0.005, respectively). CONCLUSION: Compressed sensing acceleration enables the time-neutral use of SEMAC for MRI of metal-on-metal hip resurfacing implants when compared to high-BW TSE and image quality similar to conventional SEMAC. PMID- 27497595 TI - Performance of self-collected penile-meatal swabs compared to clinician-collected urethral swabs for the detection of Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and Mycoplasma genitalium by nucleic acid amplification assays. AB - Men were enrolled in a study to assess the performance and acceptability of self collected penile meatal swabs as compared to clinician-collected urethral swabs for sexually transmitted infections (STIs). We expected penile-meatal swabs to perform favorably to urethral swabs for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), Trichomonas vaginalis (TV), and Mycoplasma genitalium (MG) detection by nucleic acid amplification assays (NAATs). Of 203 swab pairs tested; for CT, penile-meatal swab sensitivity was 96.8% and specificity was 98.8%. NG sensitivity and specificity were 100% and 98.9%, respectively. For TV, sensitivity was 85.0% and specificity was 96.7%. For MG sensitivity and specificity were 79.3% and 99.4%, respectively. No significant statistical differences between sample type accuracy (CT: P=0.625; NG: P=0.248; TV: P=0.344; and MG: P=0.070) existed. Most men, 90.1%, reported self-collection of penile meatal swabs as "Very Easy" or "Easy". Self-collected penile-meatal swabs appeared acceptable for NAAT STI detection and an acceptable collection method by men. PMID- 27497596 TI - Exploring Olfactory Function and Its Relation with Behavioral and Cognitive Impairment in Amyotrophic Lateral Sclerosis Patients: A Cross-Sectional Study. AB - BACKGROUND: Behavioral and cognitive impairment are common in amyotrophic lateral sclerosis (ALS) and represent a continuum with frontotemporal dementia (FTD). Olfactory dysfunction has been described in a subset of ALS patients and might be associated with frontotemporal and insular cortex dysfunction. OBJECTIVE: To evaluate olfaction dysfunction in ALS patients and its relationship with either cognition or behavioral impairment. METHODS: 28 consecutive ALS patients underwent an extensive cognitive and behavioral battery and were classified as patients with normal cognition (ALS-N, n = 11) or with part of the ALS-FTD spectrum (n = 17), including either cognitive or behavioral impairment or dementia. Odor verbal and visual identification and discrimination were investigated in patients and age-matched controls using a test adapted from the Sniffin' Sticks. RESULTS: Olfactory function was significantly different between ALS-FTD spectrum patients and controls (p < 0.001) and inversely correlated with behavioral and cognitive performance. The 10-point cutoff distinguished ALS-N from ALS-FTD spectrum patients with a sensitivity and specificity of 71 and 100%, respectively. CONCLUSIONS: Hyposmia is common in a subset of ALS patients and strongly associated with behavioral and cognitive impairment. Olfactory testing may represent an early screening tool in order to identify ALS subjects with cognitive/behavioral dysfunction. Further studies in larger series are mandatory in order to better investigate clinical and pathological aspects in this group of patients. PMID- 27497598 TI - Regulation of mitochondrial metabolism during hibernation by reversible suppression of electron transport system enzymes. AB - Small hibernators cycle between periods of torpor, with body temperature (T b) approximately 5 degrees C, and interbout euthermia (IBE), where T b is approximately 37 degrees C. During entrance into a torpor bout liver mitochondrial respiration is rapidly suppressed by 70 % relative to IBE. We compared activities of electron transport system (ETS) complexes in intact liver mitochondria isolated from 13-lined ground squirrels (Ictidomys tridecemlineatus) sampled during torpor and IBE to investigate potential sites of this reversible metabolic suppression. Flux through complexes I-IV and II-IV was suppressed by 40 and 60 %, respectively, in torpor, while flux through complexes III-IV and IV did not differ between torpor and IBE. We also measured maximal enzyme activity of ETS enzymes in homogenized isolated mitochondria and whole liver tissue. In isolated mitochondria, activities of complexes I and II were significantly lower in torpor relative to IBE, but complexes III, IV, and V did not differ. In liver tissue, only activity of complex II was suppressed during torpor relative to IBE. Despite the significant differences in both ETS flux and maximal activity, the protein content of complexes I and II did not differ between torpor and IBE. These results suggest that the rapid, reversible suppression of mitochondrial metabolism is due to regulatory changes, perhaps by post-translational modification during entrance into a torpor bout, and not changes in ETS protein content. PMID- 27497597 TI - The Value of a Novel Panel of Cervical Cancer Biomarkers for Triage of HPV Positive Patients and for Detecting Disease Progression. AB - In the era of primary vaccination against HPV and at the beginning of the low prevalence of cervical lesions, introduction of screening methods that can distinguish between low- and high-grade lesions is necessary in order to maintain the positive predictive value of screening. This case-control study included 562 women who attended cervical screening or were referred for colposcopy and 140 disease free controls, confirmed by histology and/or cytology. The cases were stratified by age. Using routine exfoliated liquid based cytological samples RT PCR measurements of biomarker genes, high-risk HPV testing and liquid based cytology were performed and used to evaluate different testing protocols including sets of genes/tests with different test cut-offs for the diagnostic panels. Three new panels of cellular biomarkers for improved triage of hrHPV positive women (diagnostic panel) and for prognostic assessment of CIN lesions were proposed. The diagnostic panel (PIK3AP1, TP63 and DSG3) has the potential to distinguish cytologically normal hrHPV+ women from hrHPV+ women with CIN2+. The prognostic gene panels (KRT78, MUC5AC, BPIFB1 and CXCL13, TP63, DSG3) have the ability to differentiate hrHPV+ CIN1 and carcinoma cases. The diagnostic triage panel showed good likelihood ratios for all age groups. The panel showed age unrelated performance and even better diagnostic value under age 30, a unique feature among the established cervical triage tests. The prognostic gene-panels demonstrated good discriminatory power and oncogenic, anti-oncogenic grouping of genes. The study highlights the potential for the gene expression panels to be used for diagnostic triage and lesion prognostics in cervical cancer screening. PMID- 27497599 TI - Keeping an Eye on Noisy Movements: On Different Approaches to Perceptual-Motor Skill Research and Training. AB - Contemporary theorizing on the complementary nature of perception and action in expert performance has led to different emphases in the study of movement coordination and gaze behavior. On the one hand, coordination research has examined the role of variability in movement control, evidencing that variability facilitates individualized adaptations during both learning and performance. On the other hand, and at odds with this principle, the majority of gaze behavior studies have tended to average data over participants and trials, proposing the importance of universal 'optimal' gaze patterns in a given task, for all performers, irrespective of stage of learning. In this article, we discuss new lines of inquiry with the aim of reconciling these two distinct approaches. We consider the role of inter- and intra-individual variability in gaze behaviors and suggest directions for future research. PMID- 27497600 TI - Explosive Training and Heavy Weight Training are Effective for Improving Running Economy in Endurance Athletes: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Several strategies have been used to improve running economy (RE). Defined as the oxygen uptake required at a given submaximal running velocity, it has been considered a key aerobic parameter related to endurance running performance. In this context, concurrent strength and endurance training has been considered an effective method, although conclusions on the optimal concurrent training cannot yet be drawn. OBJECTIVE: To evaluate the effect of concurrent training on RE in endurance running athletes and identify the effects of subject characteristics and concurrent training variables on the magnitude of RE improvement. METHODS: We conducted a computerized search of the PubMed and Web of Science databases, and references of original studies were searched for further relevant studies. The analysis comprised 20 effects in 16 relevant studies published up to August 2015. The outcomes were calculated as the difference in percentage change between control and experimental groups (% change) and data were presented as mean +/- 95 % confidence limit. Meta-analyses were performed using a random-effects model and, in addition, simple and multiple meta regression analyses were used to identify effects of age, training status, number of sessions per week, training duration, type of strength training, and neuromuscular performance on % change in RE. RESULTS: The concurrent training program had a small beneficial effect on RE (% change = -3.93 +/- 1.19 %; p < 0.001). In addition, explosive (% change = -4.83 +/- 1.53; p < 0.001) and heavy weight (% change = -3.65 +/- 2.74; p = 0.009) training programs produced similar improvements in RE, while isometric training (% change = -2.20 +/- 4.37; p = 0.324) in selected studies did not induce a significant effect. The multiple linear meta-regression analysis showed that all the differences between % changes could be explained by including the above-mentioned characteristics of subjects and weight training program elements. This model showed that the magnitude of the % change in RE was larger for longer training duration (beta = -0.83 +/- 0.72, p = 0.02). CONCLUSION: Explosive training and heavy weight training are effective concurrent training methods aiming to improve RE within a few weeks. However, long-term training programs seem to be necessary when the largest possible improvement in RE is desired. PMID- 27497602 TI - Examining the Washington State Breastfeeding-Friendly Policy Development Process Using the Advocacy Coalition Framework. AB - Objectives Breastfeeding promotion is increasingly recognized as a key public health strategy. Policies can promote breastfeeding by creating supportive environments and addressing challenges. In 2014, the Washington State legislature considered bills to create a voluntary recognition system for breastfeeding friendly hospitals, clinics, worksites and childcare settings. These Breastfeeding-Friendly Washington (BFW) bills (SB 6298 and HB 2329) did not pass. Methods The purpose of this case study was to analyze the policy development process for the BFW bills using the Advocacy Coalition Framework. Data were collected through semi-structured interviews with key stakeholders in the state policy process, and document review. We used thematic analysis to identify deductive and inductive themes. Results Though all policy actors indicated general support for breastfeeding, two main coalitions (proponents and opponents) diverged in their support of the BFW bills as policy solutions to address barriers to breastfeeding. We conducted 29 interviews with mainly bill proponents, and 54 documents confirmed data about bill opponents. Proponents supported the bills given increasingly strong evidence of breastfeeding's benefits and that public policy could address environmental challenges to breastfeeding. Opponents saw the bills as government overreach into the private matter of choosing to breastfeed. Opposition to the bills came late in the session, and proponents felt opponents' messaging misconstrued the intent of the legislation. Conclusions for Practice Key learnings for developing breastfeeding friendly state policies include analyzing differences between proponents' and opponents' beliefs, framing advocacy messages beyond individuals and health, expanding the coalition outside of traditional health entities, and anticipating the opposition. PMID- 27497601 TI - Mechanism of antineoplastic activity of lonidamine. AB - Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, and photodynamic-therapy and hyperthermia. Although the mechanism of action remained unclear, LND treatment has been known to target metabolic pathways in cancer cells. It has been reported to alter the bioenergetics of tumor cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggested that it also inhibited l-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). Recent studies have demonstrated that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki 2.5MUM) and cooperatively inhibits l lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K0.5 and Hill coefficient values of 36-40MUM and 1.65-1.85, respectively. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50~7MUM) than other substrates including glutamate (IC50~20MUM). LND inhibits the succinate ubiquinone reductase activity of respiratory Complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through Complex II and has been reported to promote cell death by suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT mediated l-lactic acid efflux, Complex II and glutamine/glutamate oxidation. PMID- 27497603 TI - Changing Practice Patterns and Long-term Outcomes of Endothelial Versus Penetrating Keratoplasty: A Prospective Dutch Registry Study. AB - PURPOSE: To compare graft survival, best-corrected visual acuity (BCVA), endothelial cell density (ECD), and refraction following penetrating keratoplasty (PK) vs endothelial keratoplasty (EK) for Fuchs endothelial dystrophy (FED) and pseudophakic bullous keratopathy (PBK). DESIGN: Nonrandomized treatment comparison with national registry data. METHODS: All consecutive patients undergoing first keratoplasty for FED and PBK between 1998 and 2014 were analyzed, with a maximum follow-up of 5 years (mean +/- SD follow-up 39 +/- 20 months, range 0-60 months). Graft survival was analyzed using Kaplan-Meier survival curves and Cox regression analysis. BCVA, ECD, and refractive error were compared using linear mixed models. Main outcome measures were graft survival, BCVA, refraction, and ECD. RESULTS: A total of 5115 keratoplasties (PK = 2390; EK = 2725) were identified. Two-year graft survival following EK was lower compared with PK (94.5% vs 96.3%, HR = 1.56, P = .001). Five-year survival was comparable for EK and PK (93.4% vs 89.7%, HR = 0.89, P = .261). EK graft survival improved significantly over time while remaining stable for PK. One-year BCVA was better following EK vs PK (0.34 vs 0.47 logMAR, P < .001). Astigmatism was lower 1 year after EK vs PK (-1.69 vs -3.52 D, P < .001). One-year ECD was lower after EK vs PK (1472 vs 1859 cells/mm2, P < .001). At 3 years, ECD did not differ between EK and PK. CONCLUSIONS: Long-term graft survival after EK and PK is high and comparable despite lower short-term survival for EK. EK graft survival improved over time, suggesting a learning curve. EK results in better BCVA, lower astigmatism, and similar long-term ECD compared with PK for FED and PBK. PMID- 27497604 TI - Diagnostic performance of a new endoscopic scraper for malignant biliary strictures: a multicenter prospective study. AB - BACKGROUND AND AIMS: The efficacy of ERCP for histologic diagnosis of malignant biliary strictures is disappointingly low. The aim of this study was to investigate the diagnostic performance of a newly developed endoscopic device with scraping loops in combination with conventional biopsy forceps. METHODS: We performed a multicenter single-arm prospective study. Between February 2013 and December 2014, 123 patients with suspected malignant biliary strictures were enrolled in the study. The new device and conventional biopsy forceps were applied for histologic diagnosis by ERCP. The primary outcome was to evaluate cancer detectability by biopsy forceps, the new device, and their combined use. RESULTS: Of the 123 patients, 119 were diagnosed with a malignant stricture. Sufficient samples were collected in 83.7% (103/123), 93.5% (115/123), and 95.9% (118/123) of patients using biopsy forceps, the new device, and their combination, respectively. Cancer detectability of forceps biopsy, the new device, and their combination were 51.3% (61/119), 64.7% (77/119), and 74.8% (89/119), respectively. The new device had a significantly higher sample yield and cancer detectability than biopsy forceps (P < .01 and P = .018, respectively, McNemar test). Complementary use of the new device with biopsy forceps demonstrated a significantly additive effect in both sample yield and cancer detection (P < .01 each, McNemar test). The new device detected 48.3% (28/58) of cancers that were not diagnosed as malignant by biopsy forceps. CONCLUSIONS: The new endoscopic scraper demonstrated a large sample yield and high cancer detectability. It could be a first-line tissue-sampling device for biliary strictures. (University Hospital Medical Information Network Clinical Trial Registry [UMIN-CTR] (http://www.umin.ac.jp/ctr/index.htm) registration number: UMIN000009895.). PMID- 27497605 TI - Reliability and interexaminer agreement for induced tropia test: is normal always normal? AB - The purpose of this study was to evaluate the reliability of the fixation preference testing with 10 and 20 diopter prisms (Delta) in children without strabismus in order to extrapolate its utility to preverbal children and to determine interexaminer agreement. Fourty children (24 girls, 16 boys) aged between 5 and 16 years with normal ophthalmological examination except refractive errors were included in the study. The visual acuity, refractive errors, and orthoptic findings were recorded. The base-down prism fixation test was performed by two experienced examiners with 10Delta and 20Delta. The presence of corrective movement was recorded as positive result separately for each eye. Best-corrected visual acuity was 1.0 bilaterally for all patients. All patients had binocular single vision and stereopsis. First examiner noted bilateral fixation movement in 65 % patients with 10Delta and in 57.5 % with 20Delta, second examiner in 50 % with 10Delta, and in 37.5 % with 20Delta. Interexaminer agreement was 42.5 % for 10Delta and 54.5 % for 20Delta (p < 0.01). Both examiners observed the fixation movement to be less frequent in older children. The fixation movement can be absent or seen asymmetrically even in children with equal visual acuity and binocular vision. The rate of fixation movement seemed to be reduced with age possibly due to increased concentration and cooperation of the child. In addition, there was a remarkable interexaminer variability in both tests. It should be borne in mind that the findings of prism-guided fixation preference tests may be misleading in preverbal children. PMID- 27497607 TI - High-level phylogeny of the Coleoptera inferred with mitochondrial genome sequences. AB - The Coleoptera (beetles) exhibits tremendous morphological, ecological, and behavioral diversity. To better understand the phylogenetics and evolution of beetles, we sequenced three complete mitogenomes from two families (Cleridae and Meloidae), which share conserved mitogenomic features with other completely sequenced beetles. We assessed the influence of six datasets and three inference methods on topology and nodal support within the Coleoptera. We found that both Bayesian inference and maximum likelihood with homogeneous-site models were greatly affected by nucleotide compositional heterogeneity, while the heterogeneous-site mixture model in PhyloBayes could provide better phylogenetic signals for the Coleoptera. The amino acid dataset generated more reliable tree topology at the higher taxonomic levels (i.e. suborders and series), where the inclusion of rRNA genes and the third positions of protein-coding genes improved phylogenetic inference at the superfamily level, especially under a heterogeneous site model. We recovered the suborder relationships as (Archostemata+Adephaga)+(Myxophaga+Polyphaga). The series relationships within Polyphaga were recovered as (Scirtiformia+(Elateriformia+((Bostrichiformia+Scarabaeiformia+Staphyliniformia)+ ucujiformia))). All superfamilies within Cucujiformia were recovered as monophyletic. We obtained a cucujiform phylogeny of (Cleroidea+(Coccinelloidea+((Lymexyloidea+Tenebrionoidea)+(Cucujoidea+(Chrysomelo dea+Curculionoidea))))). This study showed that although tree topologies were sensitive to data types and inference methods, mitogenomic data could provide useful information for resolving the Coleoptera phylogeny at various taxonomic levels by using suitable datasets and heterogeneous-site models. PMID- 27497606 TI - Ethanol-induced changes in poly (ADP ribose) polymerase and neuronal developmental gene expression. AB - Prenatal alcohol exposure has profound effects on neuronal growth and development. Poly-ADP Ribose Polymerase (PARP) enzymes are perhaps unique in the field of epigenetics in that they directly participate in histone modifications, transcription factor modifications, DNA methylation/demethylation and are highly inducible by ethanol. It was our hypothesis that ethanol would induce PARP enzymatic activity leading to alterations in neurodevelopmental gene expression. Mouse E18 cortical neurons were treated with ethanol, PARP inhibitors, and nuclear hormone receptor transcription factor PPARgamma agonists and antagonists. Subsequently, we measured PARP activity and changes in Bdnf, OKSM (Oct4, Klf4, Sox2, c-Myc), DNA methylating/demethylating factors, and Ppargamma mRNA expression, promoter 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC), and PPARgamma promoter binding. We found that ethanol reduced Bdnf4, 9a, and Klf4 mRNA expression, and increased c-Myc expression. These changes were reversed with a PARP inhibitor. In agreement with its role in DNA demethylation PARP inhibition increased 5MC levels at the c-Myc promoter. In addition, we found that inhibition of PARP enzymatic activity increased PPARgamma promoter binding, and this corresponded to increased Bdnf and Klf4 mRNA expression. Our results suggest that PARP participates in DNA demethylation and reduces PPARgamma promoter binding. The current study underscores the importance of PARP in ethanol-induced changes to neurodevelopmental gene expression. PMID- 27497608 TI - Acupuncture for treating hot flashes in breast cancer patients: an updated meta analysis. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of acupuncture for treatment of hot flash in women with breast cancer. METHODS: The aspects considered in this study included searching for 12 data bases until April 2015 and consulting reference lists of reviews and related articles. Additional features studied comprised all articles on human patients with breast cancer treated with needle acupuncture with or without electrical stimulation for the treatment of hot flashes. The methodological quality was assessed using the modified Jadad score. RESULT: The searches identified 12 relevant articles for inclusion. The meta-analysis without any subgroup or moderator failed to show favorable effects of acupuncture on reducing the frequency of hot flashes after intervention (n = 680, SMD = - 0.478, 95 % CI -0.397 to 0.241, P = 0.632) but exhibited marked heterogeneity of the results (Q value = 83.200, P = 0.000, I^2 = 83.17, tau^2 = 0.310). CONCLUSION: The meta-analysis used had contradictory results and yielded no convincing evidence to suggest that acupuncture was an effective treatment of hot flash in patients with breast cancer. Multi-central studies including large sample size are required to investigate the efficiency of acupuncture for treating hot flash in patients with breast cancer. PMID- 27497609 TI - Palmitate-Induced MMP-9 Expression in the Human Monocytic Cells is Mediated through the TLR4-MyD88 Dependent Mechanism. AB - BACKGROUND/AIMS: Obese individuals are known to have increased Matrix metalloproteinase (MMP)-9 plasma levels and MMP-9 is reported to play an important role in obesity-associated adipose tissue inflammation. Since in obesity, the levels of circulatory saturated free fatty acid (FFA) palmitate (palimitic acid) are increased and modulate the expression of inflammatory mediators, the role of palmitate in the regulation of MMP-9 remains unclear. METHODS: Human monocytic cell line THP-1 and primary monocytes were stimulated with palmitate and TNF-alpha (positive control). MMP-9 expression was assessed with real time RT-PCR and ELISA. Signaling pathways were studied by using THP-1 XBlueTM cells, THP-1-XBlueTM-defMyD cells, anti-TLR4 mAb and TLR4 siRNA. Phosphorylation of NF-kB and c-Jun was analyzed by Western blotting. RESULTS: Here, we provide the evidence that palmitate induces MMP-9 expression at both mRNA (THP-1: 6.8 +/- 1.2 Fold; P = 0.01; Primary monocytes: 5.9 +/- 0.7 Fold; P = 0.0003) and protein (THP1: 1116 +/-14 pg/ml; P<0.001; Primary monocytes: 1426 +/- 13.8; P = 0.0005) levels in human monocytic cells. Palmitate-induced MMP-9 secretion was markedly suppressed by neutralizing anti-TLR-4 antibody (P < 0.05). Furthermore, genetic silencing of TLR4 by siRNA also significantly abrogated the palmitate-induced up-regulation of MMP-9. Additionally, MyD88-/- THP-1 cells did not express MMP-9 in response to palmitate treatment. Increased NF-kappaB/AP-1 activity (P<0.05) was also observed in palmitate-treated THP-1 cells. CONCLUSION: Altogether, these results show that palmitate induces TLR4-dependent activation of MMP-9 gene expression, which requires the recruitment of MyD88 leading to activation of NF-kB/AP-1 transcription factors. Thus, our findings suggest that the palmitate-induced MMP-9 secretion might be an underlying mechanism of its increased levels in obesity and related metabolic inflammation. PMID- 27497610 TI - Reasons for exclusion from intravenous thrombolysis in stroke patients admitted to the Stroke Unit. AB - Intravenous (IV) thrombolysis is the treatment in ischemic stroke, but only the minority of patients receive this medication. The primary objective of this study was to explore the reasons associated with the decision not to offer IV thrombolysis to stroke patients admitted to the Stroke Unit (SU). We conducted a retrospective analysis based on data collected from 876 consecutive stroke patients admitted to the SU <12 h of symptoms onset, treated or not with IV thrombolysis at the discretion of the treating neurologist. Of the 876 patients, 449 were thrombolysed and 427 non-thrombolysed. Stroke onset >4.5 h (p = 0.001) and unknown time of onset (or stroke present on awakening) (p = 0.004) were reasons listed in the current SPC of Actilyse reasons for exclusion even they occurred singly, whereas mild deficit (or rapidly improving symptoms) (p < 0.001), extra-cranial conditions with increased risk of bleeding (p = 0.004), and history of SNC diseases (p = 0.001) only when they occurred in combination. Severe pre-stroke disability (p = 0.003) was extra-SPC reason for exclusion even when it occurred singly, whereas early CT hypodensity (p < 0.001) only when it occurred in combination. After stratification for intra-SPC reasons for exclusion, early CT hypodensity was associated with decision not offer IV thrombolysis in patients with mild deficit (p < 0.001), age >80 years (p < 0.001), stroke onset >4.5 h (p = 0.005), and unknown time of onset (p = 0.037), while severe pre-stroke disability (p = 0.025) and admission under non-stroke specialist neurologist assessment (p = 0.018) in patients with age >80 years. There are often unjustified reasons for exclusion from IV thrombolysis in SU. PMID- 27497612 TI - Formulation of paracetamol-containing pastilles with in situ coating technology. AB - The focus of this research was to apply the in situ coating technology for producing paracetamol- (PCT-) containing pastilles for paediatric use from a eutectic of two sugar alcohols (sorbitol, xylitol) in one step. This type of melt technology is more cost-efficient and simpler than other conventional tableting technologies, whereby the formation of the pastilles and their coating occur upon the same fabrication step. We managed to produce pastilles having a softer core and a harder, resistant shell in one cooling step. Adding polyethylene glycol (PEG) 2000 or 6000 to the PCT-containing eutectic, the dissolution rate of PCT could be considerably increased, especially when using PEG 2000, reaching equal dissolution characteristics both under mouth- and gastric-specific conditions. Distributions of the components within the pastilles have been determined by X ray scattering and Raman spectroscopy. Physico-chemical parameters of the xylitol sorbitol eutectic and their changes upon adding PCT and PEGs have been determined, and it has been revealed that xylitol and sorbitol form a new entity with a distinguished crystal structure. The significant changes in viscosity were explained and the interaction in the eutectic mixture was investigated using Fourier transform infrared spectroscopy (FT-IR). The uniformity of the physical parameters of the pastilles (including size, weight and drug content) also demonstrates the feasibility of using the cost-efficient and simple one-step eutectic-cooling technology for manufacturing pastilles. PMID- 27497611 TI - Retinal sensitivity after selective retina therapy (SRT) on patients with central serous chorioretinopathy. AB - PURPOSE: To assess retinal sensitivity after selective retina therapy (SRT) in patients with central serous chorioretinopathy (CSCR). METHODS: Seventeen eyes of 17 patients with CSCR lasting longer than 3 months were treated with SRT (wavelength 527 nm Nd: YLF laser, 50-150 MUJ/pulse, spot diameter 200 MUm). Measurement of best-corrected visual acuity (BCVA), optical coherence tomography, fluorescence angiography, and microperimetry (MAIATM) were conducted before, and 1 and 3 months after treatment. Microperimetry was performed in the central 10 degrees of the macula, and at the test spots applied near the vascular arcade for energy titration. In addition to the treatment effect, all test irradiation spots were thoroughly analyzed with regard to their sensitivity changes. RESULTS: The mean logMAR BCVA had improved from 0.06 to 0.02 after 1 month (p = 0.11) and to 0.03 after 3 months (p = 0.003). Eleven out of 17 eyes (64.7%) showed complete resolution of subretinal fluid after 3 months. Retinal sensitivity in the central 10 degrees increased after 1 month (median: 25.9 dB) and 3 months (26.6 dB) as compared with that before treatment (23.0 dB) (p < 0.001). Analysis of the test spots revealed a slight decrease in retinal sensitivity after 1 month (DeltadB = 0.5 +/- 2.1, p = 0.006), while there was no significant difference from baseline after 3 months (DeltadB = -0.3 +/- 2.2, p = 0.09). No correlation was found between laser energy and the change in focal retinal sensitivity. CONCLUSIONS: Results suggest that SRT is a safe and effective treatment for persistent CSCR and does not leave permanent scotoma regardless of irradiation energy in the therapeutic range. PMID- 27497613 TI - Conversion of sustained release omeprazole loaded buccal films into fast dissolving strips using supercritical carbon dioxide (scCO2) processing, for potential paediatric drug delivery. AB - This study involves the development of thin oral solvent cast films for the potential delivery of the proton pump inhibitor, omeprazole (OME) via the buccal mucosa for paediatric patients. OME containing films were prepared from ethanolic gels (1% w/w) of metolose (MET) with polyethylene glycol (PEG 400) (0.5% w/w) as plasticiser, and L-arginine (l-arg) (0.2% w/w) as a stabilizer and dried in an oven at 40 degrees C. The blank and drug loaded films were divided into two groups, one group was subjected to supercritical carbon dioxide (scCO2) treatment and the other group untreated. The untreated and scCO2 treated films were then characterised using differential scanning calorimetry, thermogravimetric analysis, scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, hydration (swelling), mucoadhesion and in vitro drug dissolution studies. Treatment of the solvent cast films with scCO2 caused significant changes to the functional and physical properties of the MET films. The original drug loaded MET films showed a sustained release of OME (1h), whereas scCO2 treatment of the formulations resulted in fast dissolving films with >90% drug release within 15min. PMID- 27497614 TI - Dosing errors in preterm neonates due to flow rate variability in multi-infusion syringe pump setups: An in vitro spectrophotometry study. AB - BACKGROUND: Drug administration on the neonatal intensive care unit is often associated with adverse events. This may be due to dosing errors caused by multi infusion setups. We aim to investigate these dosing errors. MATERIAL AND METHODS: N=3 experiment using a medication schedule, multi-infusion setup (three pumps) and disposables as applied on the NICU. In-line and real-time absorption spectrophotometry was used with dyes as substitutes for pharmaceuticals. Three flow rate changes lasting 1h were initiated. Subsequently, the possible dosing errors were estimated in the parallel pumps. In addition, startup durations, the times the flow rates required to reach steady state after significant dosing errors, as well as the total dosing error were measured. RESULTS: Contribution of the start-up delays to the cumulative dosing errors was the largest. However, initiated flow rate changes resulted in significant dosing errors in the parallel pumps as well. The total dosing error was not significant. The significant peak errors were between 48.2% and -32.5% at flow rate increase and decrease, respectively. Startup delays of up to 42.6min were measured. CONCLUSIONS: Applying multi-infusion while following a neonatal medication schedule may temporarily result in dosing errors, which can be relevant for fast-acting medications. Awareness may mitigate the risks. PMID- 27497615 TI - Antibiotic resistance and virulence genes in coliform water isolates. AB - Widespread fecal pollution of surface water may present a major health risk and a significant pathway for dissemination of antibiotic resistance bacteria. The River Rhine is one of the longest and most important rivers in Europe and an important raw water source for drinking water production. A total of 100 coliform isolates obtained from River Rhine (Germany) were examined for their susceptibility to seven antimicrobial agents. Resistances against amoxicillin, trimethoprim/sulfamethoxazole and tetracycline were detected in 48%, 11% and 9% of isolates respectively. The antibiotic resistance could be traced back to the resistance genes blaTEM, blaSHV, ampC, sul1, sul2, dfrA1, tet(A) and tet(B). Whereby, the ampC gene represents a special case, because its presence is not inevitably linked to a phenotypic antibiotic resistance. Multiple antibiotics resistance was often accompanied by the occurrence of class 1 or 2 integrons. E. coli isolates belonging to phylogenetic groups A and B1 (commensal) were more predominant (57%) compared to B2 and D groups (43%) which are known to carry virulent genes. Additionally, six E. coli virulence genes were also detected. However, the prevalence of virulence genes in the E. coli isolates was low (not exceeding 4.3% per gene) and no diarrheagenic E. coli pathotypes were detected. This study demonstrates that surface water is an important reservoir of ARGs for a number of antibiotic classes such as sulfonamide, trimethoprim, beta-lactam antibiotics and tetracycline. The occurrence of antibiotic resistance in coliform bacteria isolated from River Rhine provides evidence for the need to develop management strategies to limit the spread of antibiotic resistant bacteria in aquatic environment. PMID- 27497616 TI - Modeling protein-DNA binding via high-throughput in vitro technologies. AB - Protein-DNA binding plays a central role in gene regulation and by that in all processes in the living cell. Novel experimental and computational approaches facilitate better understanding of protein-DNA binding preferences via high throughput measurement of protein binding to a large number of DNA sequences and inference of binding models from them. Here we review the state of the art in measuring protein-DNA binding in vitro, emphasizing the advantages and limitations of different technologies. In addition, we describe models for representing protein-DNA binding preferences and key computational approaches to learn those from high-throughput data. Using large experimental data sets, we test the performance of different models based on different measuring techniques. We conclude with pertinent open problems. PMID- 27497617 TI - Overexpression of microRNA-155 suppresses chemokine expression induced by Interleukin-13 in BEAS-2B human bronchial epithelial cells. AB - BACKGROUND: MicroRNAs are non-coding small RNAs that regulate expression of target genes by binding to 3' untranslated regions. In this study, we used bronchial epithelial cells to investigate in vitro the role of the microRNA miR 155 in the expression of chemokines associated with airway inflammation. miR-155 has previously been reported to regulate allergic inflammation. METHODS: BEAS-2B bronchial epithelial cells were cultured and transfected with mimic or inhibitor oligonucleotides to overexpress or downregulate miR-155, as confirmed by real time PCR. Cells were then stimulated with tumor necrosis factor-alpha, interleukin-13 (IL-13), and a double stranded RNA that binds Toll-like receptor 3. Expression and secretion of the chemokines CCL5, CCL11, CCL26, CXCL8, and CXCL10 were then quantified by real-time PCR and ELISA, respectively. Phosphorylation of signal transducer and activator of transcription 6 (STAT6), a target of the IL-13 receptor, was analyzed by ELISA. RESULTS: miR-155 overexpression significantly suppressed IL-13-induced secretion of CCL11 and CCL26. These effects were specific, and were not observed for other chemokines, nor in cells with downregulated miR-155. miR-155 overexpression also suppressed CCL11 and CCL26 mRNA, but did not affect expression of the IL-13 receptor or phosphorylation of STAT6. CONCLUSIONS: miR-155 specifically inhibits IL-13 induced expression of eosinophilic chemokines CCL11 and CCL26 in bronchial epithelial cells, even though the 3'-untranslated region of these genes do not contain a consensus binding site for miR-155. PMID- 27497618 TI - Serum TARC levels are strongly correlated with blood eosinophil count in patients with drug eruptions. AB - BACKGROUND: This study aims to evaluate the relationship between serum thymus and activation-regulated chemokine (TARC) levels with various clinicopathological conditions in patients with drug eruptions. The value of TARC in diagnosing drug induced hypersensitivity syndrome (DIHS) was also examined. METHODS: Study participants included 84 patients who presented with generalized eruptions suspected to be drug-related, including DIHS, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), maculopapular exanthema (MPE), erythema multiforme (EM), erythroderma, and toxicoderma. The correlation coefficients between serum TARC levels and clinical parameters in peripheral blood samples were calculated. RESULTS: Serum TARC levels in patients with DIHS were higher than those found in patients with SJS/TEN, MPE, EM, and toxicoderma. TARC levels had 100% sensitivity and 92.3% specificity in diagnosing DIHS, with a threshold value of 13,900 pg/mL. Serum TARC levels positively correlated with age, white blood cell (WBC) count, neutrophil count, eosinophil count, monocyte count, atypical lymphocyte (Aty-ly) count, serum blood urea nitrogen (BUN) levels, and creatinine (Cr) levels. It negatively correlated with serum total protein (TP), albumin (Alb), and estimated glomerular filtration rate (eGFR). Among these clinical parameters, blood eosinophil counts were most strongly correlated with serum TARC levels, with a correlation coefficient of 0.53. CONCLUSIONS: Serum TARC levels are well correlated with blood eosinophil counts in patients with generalized drug eruptions, indicating that Th2-type immune reactions underlie TARC production. Serum TARC measurements also have potent diagnostic value for DIHS, with high sensitivity and specificity. PMID- 27497619 TI - Perinatal Palliative Care. PMID- 27497620 TI - The Ep152R ORF of African swine fever virus strain Georgia encodes for an essential gene that interacts with host protein BAG6. AB - African swine fever virus (ASFV) is the etiological agent of a contagious and often lethal disease of domestic pigs that has significant economic consequences for the swine industry. The viral genome encodes for more than 150 genes, and only a select few of these genes have been studied in some detail. Here we report the characterization of open reading frame Ep152R that has a predicted complement control module/SCR domain. This domain is found in Vaccinia virus proteins that are involved in blocking the immune response during viral infection. A recombinant ASFV harboring a HA tagged version of the Ep152R protein was developed (ASFV-G-Ep152R-HA) and used to demonstrate that Ep152R is an early virus protein. Attempts to construct recombinant viruses having a deleted Ep152R gene were consistently unsuccessful indicating that Ep152R is an essential gene. Interestingly, analysis of host-protein interactions for Ep152R using a yeast two hybrid screen, identified BAG6, a protein previously identified as being required for ASFV replication. Furthermore, fluorescent microscopy analysis confirms that Ep152R-BAG6 interaction actually occurs in cells infected with ASFV. PMID- 27497621 TI - Immunogenicity and protective efficacy of recombinant fusion proteins containing spike protein of infectious bronchitis virus and hemagglutinin of H3N2 influenza virus in chickens. AB - Infectious bronchitis (IB) is an acute and highly contagious viral respiratory disease of chickens and vaccination is the main method for disease control. The S1 protein, which contains several virus neutralization epitopes, is considered to be a target site of vaccine development. However, although protective immune responses could be induced by recombinant S1 protein, the protection rate in chickens was still low (<50%). Here, we generated fused S1 proteins with HA2 protein (rS1-HA2) or transmembrane domain and cytoplasmic tail (rS1-H3(TM)) from hemagglutinin of H3N2 influenza virus. After immunization, animals vaccinated with fusion proteins rS1-HA2 and rS1-H3(TM) demonstrated stronger robust humoral and cellular immune responses than that of rS1 and inactivated M41 vaccine. The protection rates of groups immunized with rS1-HA2 (87%) were significantly higher than the groups inoculated with rS1 (47%) and inactivated M41 vaccine (53%). And chickens injected with rS1-H3(TM) had similar level of protection (73%) comparing to chickens vaccinated with rS1 (47%) (P=0.07). Our data suggest that S1 protein fused to the HA2 or TM proteins from hemagglutinin of H3N2 influenza virus may provide a new strategy for high efficacy recombinant vaccine development against IBV. PMID- 27497622 TI - A collaborative study of an alternative in vitro potency assay for the Japanese encephalitis vaccine. AB - The use of inactivated Japanese encephalitis (JE) vaccines has been ongoing in East Asia for 40 years. A mouse immunogenicity assay followed by a Plaque Reduction Neutralization (PRN) Test (PRNTest) is currently recommended for each lot release of the vaccine by many national authorities. We developed an alternative in vitro ELISA to determine the E antigen content of the Japanese encephalitis virus to observe the 3Rs strategy. A collaborative study for replacing the in vivo potency assay for the Japanese encephalitis vaccine with the in vitro ELISA assay was confirmed comparability between these two methods. The study demonstrated that an in vitro assay could perform faster and was more convenient than the established in vivo PRNTest. Moreover, this assay had better precision and reproducibility compared with the conventional in vivo assay. Additionally, the content of antigen determined using the in vitro ELISA correlated well with the potency of the in vivo assay. Furthermore, this method allowed discrimination between individual lots. Thus, we propose a progressive switch from the in vivo assay to the in vitro ELISA for JE vaccine quality control. PMID- 27497623 TI - Association of Universal Bilirubin Screening With Socioeconomic Disparities in Newborn Follow-up. AB - OBJECTIVE: To determine whether implementation of universal bilirubin screening in Ontario, Canada is associated with improved rates of recommended follow-up care across socioeconomic status (SES). METHODS: We conducted a retrospective population-based cohort study of all babies born at >=35 weeks' gestation and discharged to home within 72 hours from 97 hospitals between April, 2003 and February, 2011. We used linked administrative health data sets to measure recommended follow-up care (physician visit within 1 day of discharge for babies discharged <=24 hours after birth, or physician visit within 2 days for babies discharged 24-72 hours after birth). We used maternal postal code and the Canadian Deprivation Index to determine material deprivation quintile. We modeled the relationship between universal bilirubin screening and outcomes using generalized estimating equations to account for clustering according to hospital, underlying temporal trends, and important covariates. RESULTS: Universal bilirubin screening was associated with a modest increase in recommended follow up from 29.9% to 35.0% (n = 711,242; adjusted relative risk: 1.11; P = .047). Disparity in recommended follow-up increased after screening implementation, with 40% of the crude increase attributable to the highest SES quintile and none to the lowest SES quintile. CONCLUSIONS: Universal bilirubin screening has had only a modest effect in ensuring timely follow-up for Ontario newborn babies, which represents an ongoing weakness in efforts to prevent severe hyperbilirubinemia. The observed increase in SES disparity in access to recommended follow-up suggests that universal programs that fail to address root causes of disparities might lead to overall improvements in population outcomes but increased inequity. PMID- 27497624 TI - Pediatric Neurosurgical Outcomes Following a Neurosurgery Health System Intervention at Mulago National Referral Hospital in Uganda. AB - OBJECTIVE: Pediatric neurosurgical cases have been identified as an important target for impacting health disparities in Uganda, with over 50% of the population being less than 15 years of age. The objective of the present study was to evaluate the effects of the Duke-Mulago collaboration on pediatric neurosurgical outcomes in Mulago National Referral Hospital. METHODS: We performed retrospective analysis of all pediatric neurosurgical cases who presented at Mulago National Referral Hospital in Kampala, Uganda, to examine overall, preprogram (2005-2007), and postprogram (2008-2013) outcomes. We analyzed mortality, presurgical infections, postsurgical infections, length of stay, types of procedures, and significant predictors of mortality. Data on neurosurgical cases was collected from surgical logbooks, patient charts, and Mulago National Referral Hospital's yearly death registry. RESULTS: Of 820 pediatric neurosurgical cases, outcome data were complete for 374 children. Among children who died within 30 days of a surgical procedure, the largest group was less than a year old (45%). Postinitiation of the Duke-Mulago collaboration, we identified an overall increase in procedures, with the greatest increase in cases with complex diagnoses. Although children ages 6-18 years of age were 6.66 times more likely to die than their younger counterparts preprogram, age was no longer a predictive variable postprogram. When comparing pre- and postprogram outcomes, mortality among pediatric patients within 30 days after a neurosurgical procedure increased from 4.3% to 10.0%, mortality after 30 days increased slightly from 4.9% to 5.0%, presurgical infections decreased by 4.6%, and postsurgery infections decreased slightly by 0.7%. CONCLUSIONS: Our data show the provision of more complex neurological procedures does not necessitate improved outcomes. Rather, combining these higher-level procedures with essential pre- and postoperative care and continued efforts in health system strengthening for pediatric neurosurgical care throughout Uganda will help to address and decrease the burden throughout the country. PMID- 27497625 TI - Rapid simulated gastric fluid digestion of in-seed/grain proteins expressed in genetically engineered crops. AB - The speed of simulated gastric digestion of proteins expressed in genetically engineered (GE) crops is commonly used to inform the allergenicity risk assessment. However, persistence of purified proteins in simulated gastric fluid (SGF) is poorly correlated with the allergenic status of proteins. It has been proposed that the plant or food matrix may affect the digestion of proteins and should be considered in interpreting digestion results. Here the SGF digestion of several GE proteins both as purified preparations and in soybean, corn, and cotton seed/grain extracts (in-matrix) are compared. Cry1F, Cry1Ac, phosphinothricin acetyltransferase (PAT), aryloxyalkanoate dioxygenase-1 (AAD-1), aryloxyalkanoate dioxygenase-12 (AAD-12), and double mutant 5-enol pyruvylshikimate-3-phosphate synthase (2mEPSPS) were all found to rapidly digest both as purified protein preparations and in seed/grain extracts from GE crops expressing these proteins. Based on these results, purified protein from microbial sources is a suitable surrogate for proteins in-matrix when conducting SGF digestion studies. PMID- 27497626 TI - Long-term successional dynamics of microbial association networks in anaerobic digestion processes. AB - It is of great interest to elucidate underlying mechanisms to maintain stability of anaerobic digestion, an important process in waste treatment. By operating triplicate anaerobic digesters continuously for two years, we found that microbial community composition shifted over time despite stable process performance. Using an association network analysis to evaluate microbial interactions, we detected a clear successional pattern, which exhibited increasing modularity but decreasing connectivity among microbial populations. Phylogenetic diversity was the most important factor associated with network topology, showing positive correlations with modularity but negative correlations with network complexity, suggesting induced niche differentiation over time. Positive, but not negative, correlation strength was significantly related (p < 0.05) to phylogeny. Furthermore, among populations exhibiting consistent positive correlations across networks, close phylogenetic linkages were evident (e.g. Clostridiales organisms). Clostridiales organisms were also identified as keystone populations in the networks (i.e., they had large effects on other species), suggestive of an important role in maintaining process stability. We conclude that microbial interaction dynamics of anaerobic digesters evolves over time during stable process performance. PMID- 27497627 TI - Comparative analysis of the photocatalytic reduction of drinking water oxoanions using titanium dioxide. AB - Regulated oxidized pollutants in drinking water can have significant health effects, resulting in the need for ancillary treatment processes. Oxoanions (e.g., nitrate) are one important class of oxidized inorganic ions. Ion exchange and reverse osmosis are often used treatment processes for oxoanions, but these separation processes leave behind a concentrated waste product that still requires treatment or disposal. Photocatalysis has emerged as a sustainable treatment technology capable of catalytically reducing oxoanions directly to innocuous byproducts. Compared with the large volume of knowledge available for photocatalytic oxidation, very little knowledge exists regarding photocatalytic reduction of oxoanion pollutants. This study investigates the reduction of various oxoanions of concern in drinking water (nitrate, nitrite, bromate, perchlorate, chlorate, chlorite, chromate) using a commercial titanium dioxide photocatalyst and a polychromatic light source. Results showed that oxoanions were readily reduced under acidic conditions in the presence of formate, which served as a hole scavenger, with the first-order rate decreasing as follows: bromate > nitrite > chlorate > nitrate > dichromate > perchlorate, corresponding to rate constants of 0.33, 0.080, 0.052, 0.0074, 0.0041, and 0 cm2/photons * 1018, respectively. Only bromate and nitrite were reduced at neutral pH, with substantially lower rate constants of 0.034 and 0.0021 cm2/photons * 1018, respectively. No direct relationship between oxoanion physicochemical properties, including electronegativity of central atom, internal bond strength, and polarizability was discovered. However, observations presented herein suggest the presence of kinetic barriers unique to each oxoanion and provides a framework for investigating photocatalytic reduction mechanisms of oxoanions in order to design better photocatalysts and optimize treatment. PMID- 27497629 TI - Head and neck lymphatic malformation and treatment: Clinical study of 23 cases. AB - OBJECTIVES: Head and neck lymphatic malformation is a rare benign tumor, mainly affecting children under 1 year of age. Total resection is often difficult, and recurrence is frequent. Functional and esthetic sequelae are a major issue. MATERIALS AND METHODS: A single-center retrospective study recruited patients with head and neck lymphatic malformation managed surgically, with or without associated sclerosis by alcohol, bleomycin or aetoxisclerol, between January 1, 2004 and December 31, 2013. Local control, recurrence and complications rates were analyzed, as were swallowing disorder, tracheostomy and impaired phonation. RESULTS: Twenty-three patients, with a mean age of 15.80 years, were included. Location was suprahyoid in 17 cases (73.91%) and infrahyoid in 6 (26.09%). There were 11 macrocysts (47.82%), 2 microcysts (8.70%) and 10 mixed lesions (43.48%). Three patients showed spontaneous resolution; 12 patients (52.17%) underwent a single surgical procedure, 2 (8.7%) multiple procedures, 2 (8.7%) 1 surgical procedure and 1 sclerosis, 2 (8.7%) 1 surgical procedure and multiple scleroses, and 2 (8.7%) multiple procedures and multiple scleroses. The local control rate was 69.56%. There were 8 recurrences (34.78%), all in suprahyoid microcystic or mixed lesions. There were 2 complications (8.7%): 1 severe upper cervical edema following sclerosis of the floor of the mouth, and 1 postsurgical palsy of the marginal mandibular branch of the facial nerve. In 1 case (4.35%), a nasogastric tube was required for 6 days, without tracheostomy. CONCLUSION: Recurrence was frequent, with non-negligible functional and esthetic impact, especially in case of suprahyoid and microcystic lesion. PMID- 27497628 TI - Prognosis of Good syndrome: mortality and morbidity of thymoma associated immunodeficiency in perspective. AB - Good syndrome (GS) or thymoma-associated immunodeficiency, is a rare condition that has only been studied in retrospective case series. General consensus was that GS has a worse prognosis than other humoral immunodeficiencies. In this study, physicians of GS patients completed two questionnaires with a two year interval with data on 47 patients, 499 patient years in total. Results on epidemiology, disease characteristics, and outcome are presented. Mean age at diagnosis was 60years and median follow-up from onset of symptoms was 9years. There was a high frequency of respiratory tract infections due to encapsulated bacteria. Median survival was 14years. Survival was reduced compared to age matched population controls (5-year survival: 82% versus 95%, p=0.008). In this cohort survival was not associated with gender (HR 0.9, 95% CI 0.3-3.0), autoimmune diseases (HR 2.9, 95% CI 0.8-10.1) or immunosuppressive use (HR 0.3, 95% CI: 0.1-1.2). PMID- 27497630 TI - Genetic characterization of Shiga toxin-producing Escherichia coli (STEC) and atypical enteropathogenic Escherichia coli (EPEC) isolates from goat's milk and goat farm environment. AB - The aim of this study was to characterize a collection of 44 Shiga toxin producing (STEC) and enteropathogenic Escherichia coli (EPEC) isolated from goat milk and goat farm environment. Of the 19 STEC isolates, five (26.3%) carried the stx1 gene, four (21.1%) the stx2 gene and 10 (52.6%) presented both stx genes. Six (31.6%) STEC strains were eae-positive and belonged to serotypes related to severe human disease (O157:H7 and O5:HNM). Another seven STEC strains were of serotype O146:H21 and three of serotype O166:H28, also linked to human disease. The STEC strains isolated from goat milk were of serotypes potentially pathogenic for humans. All the 25 EPEC isolates were considered atypical (aEPEC) and one aEPEC strain was of serotype O26:H11, a serotype frequently isolated in children with diarrhea. Multilocus sequence typing (MLST) was carried out with seven housekeeping genes and 23 sequence types (ST) were detected, 14 of them newly described. Twelve STs grouped STEC isolates and 11 STs grouped EPEC isolates. Genetic typing by pulsed field gel electrophoresis (PFGE) resulted in 38 patterns which grouped in 10 clusters. Well-defined groups were also observed for strains of pathogenic serotypes. In conclusion, strains of STEC and aEPEC belonging to serotypes related to severe human disease have been detected in goat milk and the goat farm environment. Ruminants are an important reservoir of STEC strains and the role of these animals as carriers of other pathogenic types of E. coli seems to be an emerging concern. PMID- 27497631 TI - Co-administration of succinylated gelatine with a (99m)Tc-bombesin analogue, effects on pharmacokinetics and tumor uptake. AB - The bombesin analogue, [(99m)Tc-GGC]-(Ornithine)3-BN(2-14), (99m)Tc-BN-O, targeting gastrin releasing peptide receptors (GRPrs) on the surface of tumors, was pre-clinically investigated as potential imaging agent for single photon emission computed tomography (SPECT). In addition, the improvement of its pharmacokinetic profile (PK) was investigated through the co-administration of a succinylated gelatin plasma expander (Gelofusine), aiming to reduce its kidney accumulation and enhance its tumor-to-normal tissue contrast ratios. Biodistribution data were collected from normal mice and rats, and PC-3 tumor bearing mice, in reference to its PK, metabolism and tumor uptake. Imaging data were also collected from PC-3 tumor bearing mice. Biodistribution and imaging experiments showed that (99m)Tc-BN-O was able to efficiently localize the tumor (5.23 and 7.00% ID/g at 30 and 60min post injection, respectively), while at the same time it was rapidly cleared from the circulation through the kidneys. HPLC analysis of kidney samples, collected at 60min p.i. from normal mice and rats, showed that the majority of radioactivity detected was due to intact peptide i.e. 56% for mice and 73% for rats. Co-administration of (99m)Tc-BN-O with Gelo resulted in the reduction of kidney uptake in both animal models. The integrated area under the curve (AUC30-60 min) from the concentration-time plots of kidneys was decreased in both mice and rats by 25 and 50%, respectively. In PC-3 tumor bearing mice, an increase of tumor uptake (AUCtumor increased by 69%) was also observed with Gelo. An improvement in tumor-to-blood and tumor-to-normal tissue ratios was noted in all cases with the exception of the pancreas, which normally expresses GRPr. The results of this preclinical study may also be extended to other similar peptides, which are utilized in prostate cancer imaging and present similar PK profile. PMID- 27497634 TI - Protection from diclofenac-induced liver injury by Yulangsan polysaccharide in a mouse model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Millettia pulchra Kurz var-laxior (Dunn) Z. Wei, a wild-growing plant of the family Fabaceae is known to possess multifarious medicinal properties. Yulangsan polysaccharide (YLSPS) is a chief ingredient of its root, which has been used in Chinese traditional medicine with a long history for remedy of acute or chronic hepatitis and jaundice. AIM OF THE STUDY: To investigate the ability of the YLSPS to protect against diclofenac-induced hepatotoxicity in mice. MATERIALS AND METHODS: Mice were orally treated with YLSPS daily 1h after the injection of diclofenac for 2 weeks. Dimethyl diphenyl bicarboxylate was used as a reference drug. RESULTS: YLSPS effectively reduced the elevated levels of serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and enhanced the reduction of superoxide dismutase, catalase, and glutathione peroxidase activities in the liver. Moreover, the content of malondialdehyde was reduced by treatment with YLSPS, and histological findings also confirmed the anti-hepatotoxic activity. In addition, YLSPS significantly inhibited proinflammatory mediators, such as tumor necrosis factor-alpha and interleukin 1 beta. YLSPS also enhanced mitochondrial antioxidants and inhibited cell death by preventing the down-regulation of Bcl-2 and the up-regulation and release of Bax along with caspase 9 and 3 activity; thus, these findings confirm the involvement of mitochondria in diclofenac induced apoptosis. CONCLUSION: The results indicate that protective effects of YLSPS against diclofenac-induced acute hepatic injury may rely on its effect on reducing oxidative stress, suppressing inflammatory responses, and improving drug metabolizing enzyme activity in the liver. PMID- 27497632 TI - Paradoxical effects of Auger electron-emitting (111)In-DTPA-NLS-CSL360 radioimmunoconjugates on hCD45(+) cells in the bone marrow and spleen of leukemia engrafted NOD/SCID or NRG mice. AB - INTRODUCTION: (111)In-DTPA-NLS-CSL360 radioimmunoconjugates (RIC) recognize the overexpression of the interleukin-3 receptor alpha-subchain (CD123) relative to the beta-subchain (CD131) on leukemia stem cells (LSC). Our aim was to study Auger electron radioimmunotherapy (RIT) of acute myeloid leukemia (AML) with (111)In-DTPA-NLS-CSL360 in non-obese diabetic severe combined immunodeficiency (NOD/SCID) mice or NOD-Rag1(null)IL2rgamma(null) (NRG) mice engrafted with CD123(+) human AML-5 cells. METHODS: The toxicity of three doses of (111)In-DTPA NLS-CSL360 (3.3-4.8MBq; 11-15MUg each) injected i.v. every two weeks was studied in non-engrafted NOD/SCID or NRG mice pre-treated with 200cGy of gamma-radiation required for AML engraftment. Engraftment efficiency of (1-5)*10(6) cells AML-5 cells inoculated i.v. into NOD/SCID or NRG mice was assessed by flow cytometric analysis for human CD45(+) (hCD45(+)) cells in the bone marrow (BM) and spleen. AML-5 engrafted mice were treated with two or three doses (3.7MBq; 10MUg each) every two weeks of (111)In-DTPA-NLS-CSL360, non-specific (111)In-DTPA-NLS-hIgG, unlabeled CSL360 (10MUg) or normal saline. The percentage of hCD45(+) cells in the BM and spleen were measured at one week after completion of treatment. RESULTS: (111)In-DTPA-NLS-CSL360 in combination with 200cGy of gamma-radiation caused an initial transient decrease in body weight in NOD/SCID but not in NRG mice. There were no hematological, liver or kidney toxicities. The spleen exhibited 13-fold lower engraftment efficiency than the BM in NOD/SCID mice inoculated with 1*10(6) cells but both organs were highly (>85%) engrafted in NRG mice. Unexpectedly, (111)In-DTPA-NLS-CSL360 or non-specific (111)In-DTPA-NLS-hIgG caused a paradoxical 1.5-fold increase (P<0.0001) in the proportion of hCD45(+) cells in the BM of NOD/SCID mice compared to normal saline treated mice. (111)In DTPA-NLS-CSL360 reduced hCD45(+) cells in the spleen by 3.0-fold compared to (111)In-DTPA-NLS-hIgG (P=0.0015) but the proportion of hCD45(+) cells was not significantly different than in normal saline treated mice. Unlabeled CSL360 decreased the percentage of hCD45(+) cells in the BM (P=0.004) or spleen (P=0.007) in NOD/SCID mice by 1.6-fold and 2.5-fold, respectively. (111)In-DTPA NLS-CSL360 or unlabeled CSL360 did not decrease the proportion of hCD45(+) cells in the BM or spleen of NRG mice, due to a much higher leukemic burden. CONCLUSION: (111)In-DTPA-NLS-CSL360 and (111)In-DTPA-NLS-hIgG caused a paradoxical increase in the proportion of hCD45(+) cells in the BM of NOD/SCID mice. This may be due to a priming effect on the BM niche that promotes expansion of engrafted hCD45(+) cells, analogous to gamma-radiation required for AML engraftment. There appears to be a competition between this effect and the cytotoxic effects of the Auger electrons on leukemia cells. The effectiveness of (111)In-DTPA-NLS-CSL360 on reducing hCD45(+) cells in the BM or spleen of NOD/SCID and NRG mice was dependent on the leukemic burden. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This study demonstrates for the first time a paradoxical radiation priming effect of RIT on enhancing the hCD45(+) cell population in the BM and spleen of NOD/SCID or NRG mice. Our results have important implications for preclinical evaluation of radioimmunotherapies for patients with AML. PMID- 27497633 TI - Neuroprotective effects of melatonin as evidenced by abrogation of oxaliplatin induced behavioral alterations, mitochondrial dysfunction and neurotoxicity in rat brain. AB - Neurotoxicity is a burdensome consequence of platinum-based chemotherapy that neutralizes the administration of effective dosage and often prompts treatment withdrawal. Oxaliplatin (Oxa), a third-era platinum analogue that is active against both early-organize and progressed colorectal growth, produces critical neurotoxicity. It has been reported that the Melatonin (Mel) is a pineal hormone its metabolites display important antioxidant properties in nervous system. There is dearth of literature involving the role of mitochondria and cytosolic compartments mediated Oxa-induced neurotoxicity and its underlying mechanisms are still debatable. Rats were pre-treated with Mel (10mg/kg b.wt., i.p.) and treated with Oxa (4mg/kg b.wt. i.p.) for 5 consecutive days. For neurobehavioral performances, decreased locomotor activity and muscular strength were observed in rats. Treatment with Mel in Oxa treated rats could protect the Oxa induced alterations in motor activity and muscular strength. For painful neuropathy, thermal hyperalgesia/nociceptive tests were evaluated. In addition, pre-treatment of Mel could block or alter the inactivation of Bcl-2, caspase 3 apoptotic protein and alterations Cytochrome c (Cyt c) release in an Oxa rich environment. Pre-treatment of Mel have shown an alteration in hyperalgesia behaviour in Oxa treated rats. Oxidative stress biomarkers, levels of non-enzymatic antioxidants and mitochondrial complexes were evaluated against neurotoxicity induced by Oxa. Mel pre-treatment replenished the mitochondrial lipid peroxidation levels and protein carbonyl content induced by Oxa. Mel also modulated altered non enzymatic, enzymatic antioxidants and complex enzymes of mitochondria. Futures studies are also required to identify other molecular markers involved in neurotoxicity induced by Oxa and possible action of Mel in its modulation. PMID- 27497635 TI - The effects of Chuanxiong on the pharmacokinetics of warfarin in rats after biliary drainage. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chuanxiong Rhizoma (rhizomes of Ligusticum chuanxiong Hort), known as Chuanxiong in Chinese, has been used for treating cardiovascular diseases for centuries. Chuanxiong is a classical activating blood circulation herb in the treatment of thromboembolism heart diseases. Warfarin often combines with herbal prescriptions containing Chuanxiong in China. AIM OF THE STUDY: The herb-drug interaction involving enterohepatic circulation process remains unclear. This study aimed to elucidate the effects of Chuanxiong Rhizoma on the pharmacokinetics of warfarin in rats after biliary drainage. MATERIALS AND METHODS: Thirty-two rats were randomly divided into four groups: WN (healthy rats after the gastric-administration of 0.5mg/kg warfarin sodium), WO (a rat model of biliary drainage after the gastric-administration of 0.5mg/kg warfarin sodium), WCN (healthy rats after the gastric-administration of 0.5mg/kg warfarin sodium and 10g/kg Chuanxiong decoction), and WCO (a rat model of biliary drainage after the gastric-administration of 0.5mg/kg warfarin sodium and 10g/kg Chuanxiong decoction). The levels of warfarin and internal standard were quantified by LC MS/MS. Comparisons between groups were performed according to the main pharmacokinetic parameters calculated by the DAS 2.1.1 software. RESULTS: The established LC-MS/MS method was specific, precise and rapid. The pharmacokinetic parameters showed a significant difference between the WN and WO groups. There were significant differences in the area under the curve (AUC0-t), peak concentration (Cmax), total plasma clearance (CLz/F) and mean residence time (MRT0-t) between the WCO and WCN groups; the AUC0-t of warfarin in the WCN group was 2.42 times than that of the WN group (p<0.01); the WCO group displayed a decreased to 61.6% in the Cmax compared the WO group (p<0.01). CONCLUSION: Biliary drainage significantly influenced the disposition of warfarin, and Chuanxiong significantly affected the warfarin disposition in rat plasma. PMID- 27497636 TI - Protective effects of the roots of Angelica sinensis on strenuous exercise induced sports anemia in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sports anemia is a persistent and severe problem in athletes owing to strenuous exercise-induced oxidative stress and hepcidin upregulation. The roots of Angelica sinensis (AS), a familiar traditional Chinese medicine, has been used for replenishing blood since antiquity. AIM OF THE STUDY: To evaluate the effects of ethanolic AS extract in a 4-week study on sports anemia in female Wistar rats. MATERIALS AND METHODS: To induce anemia, a strenuous exercise protocol consisting of running and swimming was employed with increasing intensity. Animals were randomly assigned to the following groups: control group; strenuous exercise group; and strenuous exercise and AS extract treated group (300mgkg-1d-1). After 4 weeks, rats underwent exhaustive swimming and forelimb grip strength test. The blood biochemical markers and hepatic antioxidant activities were determined. Hepatic interleukin-6 and muscle glycogen were observed through immunohistochemical and Periodic acid-Schiff staining, respectively. RESULTS: AS extract (consisting of ferulic acid, Z-ligustilide, and n-butylidenephthalide) treatment improved forelimb grip strength and rescued exercise-induced anemia by significantly elevating the red blood cell counts and hemoglobin concentrations as well as hematocrit levels (p<0.05). AS modulated the iron metabolism through decreasing serum hepcidin-25 concentrations by 33.0% (p<0.05) and increasing serum iron levels by 34.3% (p<0.01). The hepatic injury marker serum alanine aminotransferase concentrations were also reduced, followed by increased antioxidant enzyme catalase expression in the liver (p<0.05). Furthermore, substantial attenuation of hepatic interleukin-6 expression and preservation of muscle glycogen content suggested the additional roles of AS acting on sports anemia and physical performance. CONCLUSION: Our findings evidenced a novel and promising therapeutic approach for AS treatment for rescuing the anemic condition induced following 4 weeks of strenuous exercise. PMID- 27497637 TI - Antitussive activity of the Schisandra chinensis fruit polysaccharide (SCFP-1) in guinea pigs models. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis (Turcz.) Baill. (S. chinensis), locally known as "Wuweizi", has been used in the treatment of chronic cough as prescription medications of Traditional Chinese Medicine for thousands of years. However, the components of antitussive activity of S. chinensis and the mechanism are poorly understood. AIM OF THE STUDY: This study aims to investigate the antitussive activity of polysaccharides extracted from S. chinensis. MATERIALS AND METHODS: S. chinensis fruit polysaccharide-1 (SCFP-1) was extracted by 95% ethanol and distilled water successively, and then the water extraction was isolated with chromatographic columns. The preliminary characterization of SCFP-1 was analyzed by gel permeation chromatography (GPC), gas chromatography mass spectrometry (GC-MS) and some other recognized chemical methods. Antitussive potential of SCFP-1 was estimated at dose of 250, 500, and 1000mg/kg respectively by peroral administration in a guinea pigs model with cough hypersensitivity induced by cigarette smoke (Chronic cough model) or acute cough guinea model induced by citric acid (Acute cough model). Also, the time-dependent antitussive effect of SCFP-1 were evaluated with acute cough model, and compared with codeine. RESULTS: The molecular of SCFP-1 was 3.18*104Da, mainly being composed of glucose and arabinose (66.5% and 29.4%, respectively). Peroral administration of SCFP-1 at 250, 500, and 1000mg/kg showed remarkable suppressive effects respectively on cough in both of chronic cough model and acute cough model. Meanwhile, inflammatory cell in BALF and some typical characteristics of nonspecific airway inflammation in animals exposed to CS was significantly attenuated after pretreatment with SCFP-1. The cough suppression of SCFP-1 (500 mg/kg) stablly lasted during the whole 5 h of time-dependent experiment, while no positive effect was observed after 300 min of oral administration of codeine. CONCLUSIONS: SCFP-1 is one of the antitussive components of S. chinensis. PMID- 27497638 TI - The total alkaloid fraction of bulbs of Fritillaria cirrhosa displays anti inflammatory activity and attenuates acute lung injury. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bulb of Fritillaria cirrhosa D.Don (BFC) has been wildly used in China for a long time for folk medicine since its significant therapeutic effects on respiratory diseases, such as cough, expectoration, pneumonia and bronchial inflammation, which are related to respiratory inflammatory response. However, there is a lack of investigation on the in vivo anti-inflammatory properties of BFC. AIM OF THE STUDY: The aim of this study was to evaluate the in vivo anti-inflammatory activity of the purified total alkaloid fraction of BFC (TAF) by using different animal models of inflammation to provide scientific evidence for its traditional use. MATERIALS AND METHODS: The total alkaloid fraction from BFC was prepared by using H-103 resin column. Anti inflammatory effect of TAF was evaluated by models of acetic acid-induced capillary permeability accentuation, carrageenan-induced rat paw edema, cotton pellet-induced granuloma formation and LPS-induced acute lung injury (ALI). The level of cytokines (TNF, IL-6, IL-4 and IL-10) was measured by ELISA. Histopathological analyses were performed by using hematoxylin and eosin staining. RESULTS: TAF can inhibit acetic acid-induced capillary permeability accentuation, carrageenan-induced paw edema, cotton pellet-induced granuloma formation, suppress inflammatory cells recruitment and cytokine production in the bronchoalveolar lavage fluid from LPS-induced ALI mice, and attenuate pathological changes in the lung tissues of ALI mice. CONCLUSION: This study provides scientific evidence for bulb of F. cirrhosa to treat respiratory inflammation. PMID- 27497639 TI - Identification of UQCRB as an oxymatrine recognizing protein using a T7 phage display screen. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sophora flavescens Aiton (Radix Sophorae Flavescentis, Kushen) is used in traditional Chinese medicine to treat chronic hepatitis B (CHB), and has the ability to clear heat and dampness from the body. Oxymatrine is one of the major bioactive compounds extracted from Sophora flavescens Aiton and constitutes more than 90% of the oxymatrine injection commonly used for CHB treatment in clinics in China. AIM OF THE STUDY: We aim to analyze the protein binding target of oxymatrine in treating CHB by screening a T7 phage display cDNA library of human CHB and examine the biochemistry of protein-ligand binding between oxymatrine and its ligands. MATERIALS AND METHODS: A T7 phage cDNA library of human CHB was biopanned by affinity selection using oxymatrine as bait. The interaction of oxymatrine with its candidate binding protein was investigated by affinity assay, molecular docking, Isothermal Titration Calorimetry (ITC) and Surface Plasmon Resonance (SPR). RESULTS: A library of potential oxymatrine binding peptides was generated. Ubiquinol cytochrome c reductase binding protein (UQCRB) was one of the candidate binding proteins of oxymatrine. UQCRB-displaying T7 phage binding numbers in the oxymatrine group were significantly higher than that in the control group, biotin group, and matrine group (p<0.05 or p<0.01). Three-dimensional structure modeling of the UQCRB with oxymatrine showed that their binding interfaces matched and oxymatrine inserted into a deeper pocket of UQCRB, which mainly involved amino acid residues Tyr21, Arg33, Tyr83, Glu84, Asp86, Pro88, and Glu91. The binding affinity constant (Kb) from SPR was 4.2mM. The Kb from ITC experiment was 3.9mM and stoichiometry was fixed as 1, which fit very well with the result of SPR. The binding of oxymatrine to UQCRB was driven by strong enthalpy forces such as hydrogen bonds and polar interactions as the heat released was about 157kcal/mol and DeltaG was less than zero. CONCLUSIONS: In this study, using the T7 phage display system, we have identified UQCRB as a direct binding protein of oxymatrine. Furthermore, the specificity and molecular interaction of oxymatrine with UQCRB were also determined. The binding of UQCRB to oxymatrine suggests that UQCRB is a potential target of oxymatrine in treating CHB. These results provide new understanding into the mechanism of oxymatrine and insights into the strategy on the treatment of CHB. PMID- 27497640 TI - The effects of Qi Teng Xiao Zhuo granules, traditional Chinese medicine, on the expression of genes in chronic glomerulonephritis rats. AB - BACKGROUND AND AIM: Chronic glomerulonephritis (CGN) is a primary glomerular disease that is related to immune-mediated inflammatory diseases. Qi Teng Xiao Zhuo granules have been proposed as a prescription of traditional Chinese medicine for treatment of CGN, but the comprehensive molecular mechanism underlying this therapeutic effect is not clear to date. The aim of this study was to evaluate and analyze the possible roles and molecular mechanisms of Qi Teng Xiao Zhuo granule-mediated treatment of CGN induced by adriamycin in rats. METHODS: For gene expression analysis, four samples of glomerular tissue from rats in the Qi Teng Xiao Zhuo granule group and four samples each from the adriamycin treated and control groups were hybridized with Agilent Rat 4*44K whole genome microarrays. KEGG and Gene Ontology (GO) analyses and LIMMA, String and Cytoscape software were used to analyze the functional microarray data and screen differentially expressed genes. Hub genes were identified using Pathway Studio software. Real-time PCR was performed to verify the selected genes. RESULTS: Microarray gene expression analysis showed that Pnoc, Cacfd1, Fos, Igll1, Lcn2, and Syk were among the most downregulated genes in the Qi Teng Xiao Zhuo granule group compared with the adriamycin treated group, whereas Cyp2c7, Hsd3b6, Acsm5, and Ugt2b15 were significantly upregulated. Functional analysis demonstrated that metabolism of xenobiotics by cytochrome P450, the B cell receptor signaling pathway, and cytokine-cytokine receptor interaction pathways were significantly downregulated in the Qi Teng Xiao Zhuo granule group and that GO terms related to positive regulation of immune response, immune response activating signal transduction, cell differentiation, cell cycle, proliferation, and adhesion were significantly affected. Fos and Syk were considered to be potential hub genes. CONCLUSIONS: In the adriamycin-induced CGN rat model, comprehensive molecular mechanisms were involved with complex gene expression alterations containing many altered pathways and GO terms. However, how Qi Teng Xiao Zhuo granules regulate these events warrants further investigation. PMID- 27497641 TI - A plasma modified cellulose-chitosan porous membrane allows efficient DNA binding and provides antibacterial properties: A step towards developing a new DNA collecting card. AB - In forensic DNA analyses, biological specimens are collected and stored for subsequent recovery and analysis of DNA. A cost-effective and efficient DNA recovery approach is therefore a need. This study aims to produce a plasma modified cellulose-chitosan membrane (pCE-CS) that efficiently binds and retains DNA as a potential DNA collecting card. The pCE-CS membrane was produced by a phase separation of ionic liquid dissolving CE and CS in water with subsequent surface-modification by a two-step exposure of argon plasma and nitrogen gas. Through plasma modification, the pCE-CS membrane demonstrated better DNA retention after a washing process and higher rate of DNA recovery as compared with the original CE-CS membrane and the commercial FTA card. In addition, the pCE-CS membrane exhibited anti-bacterial properties against both Escherichia coli and Staphylococcus aureus. The results of this work suggest a potential function of the pCE-CS membrane as a DNA collecting card with a high recovery rate of captured DNA. PMID- 27497642 TI - The origin of unknown source DNA from touched objects. AB - The presence of DNA in a criminal investigation often requires scrutiny in relation to how it came to be where it was found. There is a paucity of data with respect to the extent to which one can assume that the last person handling an object, which has previously been touched by others, will contribute to the DNA profile generated from it. There are limited data in detailing the extent to which any foreign DNA is picked-up from a previously touched object and transferred to subsequently touched objects. This study focuses on DNA transfer and persistence on a knife handle after multiple handlings with the knife by different individuals soon after each other, as well as handprints left on flat DNA-free surfaces immediately after touching a knife handle with a known history of prior handling. The profiles of later handlers of a knife are more prominent than earlier handlers; however, the last handler is not always the major contributor to the profile. Proportional contributions to the profiles retrieved from knife handles vary depending on the individuals touching the knife handle. They can also vary when knife handles have been handled in the same manner by the same individuals in the same sequence on different occasions. Hands readily pickup DNA left on objects by others and transfer it to subsequently touched objects. The quantity of foreign DNA picked up by a hand and deposited on subsequently touched objects diminishes as more DNA-free objects are handled soon after each other. Caution is advised when considering how DNA from different individuals may have been transferred to the object from which it was collected. PMID- 27497643 TI - Massively parallel sequencing of 10 autosomal STRs in Chinese using the ion torrent personal genome machine (PGM). AB - Massively parallel sequencing (MPS) technology is gaining interest in the forensic community. The capabilities of high throughput and simultaneously analyses of many markers enable MPS as an attractive method for human forensics. Recent studies have demonstrated the successful application of the MPS system to short tandem repeat (STR) typing. However, not only DNA sequence variations in the repeat regions of STR but also in flanking regions are required to facilitate profiles sharing with capillary electrophoresis (CE)-based typing method. In this study, we constructed a multiplex PCR system for the MPS analysis of 10 autosomal STR loci (D13S317, D16S539, D19S433, D2S441, D3S1358, D5S818, D6S1043, D7S820, TH01, TPOX) by designing amplicons in the size range of 168-273 base pairs. Sequencing results from 165 Chinese unrelated individuals demonstrated 11 variations in the flanking regions between amplification primer binding sites and core repeat motifs. In addition, three loci, D13S317, D5S818, and D7S820, displayed variants adjacent to the core repeats and caused discordances between sequence-based and length-based typing results. Four loci (D3S1358, D2S441, D19S433 and D7S820) demonstrated an increased allele number using MPS-based typing. This study demonstrated that STR typing by MPS could provide more genetic information from both repeat and flanking regions of STR loci, thus improving the diversity and discrimination power of the system in forensic detection. PMID- 27497644 TI - Genetic mapping of 15 human X chromosomal forensic short tandem repeat (STR) loci by means of multi-core parallelization. AB - Typing of X chromosomal short tandem repeat (X STR) markers has become a standard element of human forensic genetic analysis. Joint consideration of many X STR markers at a time increases their discriminatory power but, owing to physical linkage, requires inter-marker recombination rates to be accurately known. We estimated the recombination rates between 15 well established X STR markers using genotype data from 158 families (1041 individuals) and following a previously proposed likelihood-based approach that allows for single-step mutations. To meet the computational requirements of this family-based type of analysis, we modified a previous implementation so as to allow multi-core parallelization on a high performance computing system. While we obtained recombination rate estimates larger than zero for all but one pair of adjacent markers within the four previously proposed linkage groups, none of the three X STR pairs defining the junctions of these groups yielded a recombination rate estimate of 0.50. Corroborating previous studies, our results therefore argue against a simple model of independent X chromosomal linkage groups. Moreover, the refined recombination fraction estimates obtained in our study will facilitate the appropriate joint consideration of all 15 investigated markers in forensic analysis. PMID- 27497645 TI - Improving empirical evidence on differentiating closely related men with RM Y STRs: A comprehensive pedigree study from Pakistan. AB - Y-chromosomal short tandem repeat (Y-STR) markers are commonly used in forensic genetics. Male-specific haplotypes provided by commercial Y-STR kits allow discriminating between many - but not all - unrelated men, while they mostly fail to separate related ones. Aiming to improve male relative and paternal lineage differentiation, a set of 13 rapidly-mutating (RM) Y-STRs was previously identified and introduced to forensic Y-chromosome analysis. Recently, their value was highlighted by separating 99% of over 12,200 unrelated men from 111 global populations, as well as 29% of over 2500 male relative pairs, the vast majority were father-sons. Here, we provide improved empirical evidence on differentiating closely related men with RM Y-STRs, most notably beyond father sons, where previous data were limited. After careful quality control including genetic relationship testing, we used 572 Pakistani men belonging to 99 2-4 generation pedigrees covering 1568 pairs of men related by 1-6 meioses. Of those, 45% were differentiated by one or more of the 13 RM Y-STR markers. In contrast, only 14.7% of a subset of 1484 pairs from 94 pedigrees were separated by the commercial AmpFlSTR Y-filer kit. Combining previously published and new data, an overall differentiation rate of 35.3% was revealed for the RM Y-STR set based on 4096 pairs of men related by 1-20 meioses, compared to 9.6% with Y-filer based on 3645 pairs. Using father-son pair data from the present and previous studies, we provide updated RM Y-STR mutation rates. Locus-specific mutation rates ranged from 2.0*10-3 (7.0*10-4-4.3*10-3) to 6.9*10-2 (6.1*10-2-7.9*10-2) based on 2741 3143 meioses, with an average rate across all 13 RM Y-STR markers of 1.8*10-2 (1.7*10-2-1.9*10-2) based on 800 mutations from 44,922 meioses. The high haplotype diversity (h=0.9996) we observed among the unrelated men (N=105) underlines the value of this RM Y-STR set to differentiate paternal lineages even from endogamous populations such as from Pakistan. PMID- 27497646 TI - The neuromotor effects of transverse friction massage. AB - BACKGROUND: Transverse friction massage (TFM), as an often used technique by therapists, is known for its effect in reducing the pain and loosing the scar tissues. Nevertheless, its effects on neuromotor driving mechanism including the electromechanical delay (EMD), force transmission and excitation-contraction (EC) coupling which could be used as markers of stiffness changes, has not been computed using ultrafast ultrasound (US) when combined with external sensors. AIM: Hence, the aim of this study was to find out produced neuromotor changes associated to stiffness when TFM was applied over Quadriceps femoris (QF) tendon in healthy subjcets. METHODS: Fourteen healthy males and fifteen age-gender matched controls were recruited. Surface EMG (sEMG), ultrafast US and Force sensors were synchronized and signals were analyzed to depict the time delays corresponding to EC coupling, force transmission, EMD, torque and rate of force development (RFD). RESULTS: TFM has been found to increase the time corresponding to EC coupling and EMD, whilst, reducing the time belonging to force transmission during the voluntary muscle contractions. CONCLUSIONS: A detection of the increased time of EC coupling from muscle itself would suggest that TFM applied over the tendon shows an influence on changing the neuro-motor driving mechanism possibly via afferent pathways and therefore decreasing the active muscle stiffness. On the other hand, detection of decreased time belonging to force transmission during voluntary contraction would suggest that TFM increases the stiffness of tendon, caused by faster force transmission along non-contractile elements. Torque and RFD have not been influenced by TFM. PMID- 27497647 TI - Factors Associated With Timing of Return to Intercourse After Obstetric Anal Sphincter Injuries. AB - INTRODUCTION: The impact of obstetric perineal trauma on timing of return to intercourse is unclear, although sexual desire is clearly decreased in these women. In addition, studies examining timing of return to intercourse are cross sectional and therefore cannot delineate potential reasons that patients might delay return to intercourse. AIM: To identify factors associated with delayed return to intercourse after obstetric anal sphincter injuries. METHODS: This was a planned secondary analysis of a prospective cohort study of women sustaining obstetric anal sphincter injuries during delivery of a full-term singleton infant. Patients completed the Fecal Incontinence Severity Index at every postpartum visit (1, 2, 6, and 12 weeks) and the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire-12 once resuming vaginal intercourse. Intercourse was considered "delayed" if patients did not resume intercourse by the 12-week visit. This cutoff was chosen because it was subsequent to the 6-week visit, when patients were instructed to return to normal pelvic activity. Continuous variables were compared using the Student t-test (parametric) or Mann Whitney U-test (non-parametric). The chi(2) test was used for categorical variables. Statistical significance was assigned with a P value less than .05. MAIN OUTCOME MEASURES: Primary outcome measurements were differences in pelvic floor symptoms on validated surveys between the "delayed" and "not-delayed" groups at the first postpartum visit and at the time the subjects returned to intercourse. We used the Patient Health Questionnaire-9 for depression, the Urinary Distress Inventory-6 and Incontinence Impact Questionnaire-7 for urinary symptoms, the visual analog scale for pain, the Fecal Incontinence Severity Index for bowel symptoms, and the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire-12 at the return to intercourse visit only. RESULTS: One hundred ninety-nine women were included in this analysis. Most were Caucasian (77%) and primiparous (86%). One hundred nineteen women (60%) did not resume vaginal intercourse until after the 12-week visit and were deemed "delayed." Patients who delayed intercourse scored higher on the Fecal Incontinence Severity Index (more anal incontinence) than those who resumed intercourse before 12 weeks (15.4 +/- 12.3 vs 12.0 +/- 12.8, P = .02). The delayed group also had worse sexual function, shown as lower Pelvic Organ Prolapse/Incontinence Sexual Questionnaire 12 scores (35.4 +/- 5.9 vs 38.4 +/- 4.1, P <= .001) and persistently higher Fecal Incontinence Severity Index scores (4.1 +/- 7.3 vs 1.6 +/- 4.4, P = .001), at the first visit after returning to intercourse. CONCLUSION: Patients with obstetric anal sphincter injuries who do not resume intercourse by 12 weeks postpartum report more severe anal incontinence symptoms and worse sexual function after return to coitus. PMID- 27497648 TI - Simultaneous quantification of tenofovir, emtricitabine, rilpivirine, elvitegravir and dolutegravir in mouse biological matrices by LC-MS/MS and its application to a pharmacokinetic study. AB - Combination antiretroviral (cARV) treatment is more common in human immunodeficiency virus (HIV) infection. In many instances, treatment regimen includes two or more combination of drugs from six different classes. Some of the antiretroviral combination medications are under study at preclinical and clinical stages. A precise method is required to quantify the drug concentration in biological matrices to study pharmacokinetic behavior and tissue distribution profile in animals and/or humans. We have developed and validated a sensitive and precise liquid chromatography-tandem mass spectrometry method for simultaneous quantification of selected antiretroviral drugs, tenofovir (TNF), emtricitabine (FTC), rilpivirine (RPV), dolutegravir (DTG) and elvitegravir (EVG) in mouse biological matrices. This method involves a solid phase extraction, simple isocratic chromatographic separation using Restek Pinnacle DB BiPh column (50mm*2.1mm, 5MUm) and mass spectrometric detection by an API 3200 Q Trap instrument. The total run time for each sample was 6min. The method was validated in the concentration range of 5-2000ng/mL for FTC, RPV, DTG, EVG and 10-4000ng/mL for TNF respectively with correlation coefficients (r(2)) higher than 0.9976. The results of intra and inter-run assay precision and accuracy were within acceptance limits for all the five analytes. This method was used to support the study of pharmacokinetics and tissue distribution profile of nanoformulated antiretroviral drugs in mice. PMID- 27497649 TI - An integrated approach for profiling oxidative metabolites and glutathione adducts using liquid chromatography coupled with ultraviolet detection and triple quadrupole-linear ion trap mass spectrometry. AB - The use of liquid chromatography (LC) coupled with triple quadrupole linear ion trap (Qtrap) mass spectrometry (MS) for both quantitative and qualitative analysis in drug metabolism and pharmacokinetic studies is of great interest. Here, a new Qtrap-based analytical methodology for simultaneous detection, structural characterization and semi-quantitation of in vitro oxidative metabolites and glutathione trapped reactive metabolites was reported. In the current study, combined multiple ion monitoring and multiple reaction monitoring were served as surveying scans to trigger product ion spectral acquisition of oxidative metabolites and glutathione adduct, respectively. Then, detection of metabolites and recovery of their MS/MS spectra were accomplished using multiple data mining approaches. Additionally, on-line ultraviolet (UV) detection was employed to determine relative concentrations of major metabolites. Analyses of metabolites of clozapine and nomifensine in rat liver microsomes not only revealed multiple oxidative metabolites and glutathione adducts, but also identified their major oxidative metabolism and bioactivation pathways. The results demonstrated that the LC/UV/MS method enabled Qtrap to perform the comprehensive profiling of oxidative metabolites and glutathione adducts in vitro. PMID- 27497650 TI - (1)H-Nuclear magnetic resonance-based metabolic profiling of nonsteroidal anti inflammatory drug-induced adverse effects in rats. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs), which are globally prescribed, exhibit mainly anti-inflammatory and analgesic effects but also can cause adverse effects including gastrointestinal erosions, ulceration, bleeding, and perforation. The purpose of this study was to investigate surrogate biomarkers associated with the gastrointestinal (GI) damage caused by NSAID treatment using pattern recognition analysis of (1)H-nuclear magnetic resonance ((1)H NMR) spectra of rat urine. Urine was collected for 5h after oral administration of the following NSAIDs at low or high doses: acetylsalicylic acid (10 or 200mgkg(-1)), diclofenac (0.5 or 15mgkg(-1)), piroxicam (1 or 10mgkg(-1)), indomethacin (1 or 25mgkg(-1)), or ibuprofen (10, or 150mgkg(-1)) as nonselective COX inhibitors and celecoxib (10 or 100mgkg(-1)) as a COX-2 selective inhibitor. The urine was analyzed using 500MHz (1)H NMR for spectral binning and targeted profiling and the level of gastric damage was examined. The nonselective COX inhibitors caused severe gastric damage while no lesions were observed in the celecoxib-treated rats. The (1)H NMR urine spectra were divided into spectral bins (0.04ppm) for global profiling, and a total of 44 endogenous metabolites were assigned for targeted profiling. Multivariate data analyses were performed to recognize the spectral pattern of endogenous metabolites related to NSAIDs using partial least square-discrimination analysis (PLS-DA). The (1)H NMR spectra clustered differently according to gastric damage score in global profiling. In targeted profiling, the endogenous metabolites of citrate, allantoin, 2-oxoglutarate, acetate, benzoate, glycine, and trimethylamine N-oxide were selected as putative biomarkers for gastric damage caused by NSAIDs. These putative biomarkers might be useful for predicting the risk of adverse effects caused by NSAIDs in the early stage of drug development process. PMID- 27497651 TI - Development and validation of a bioanalytical method for five antidepressants in human milk by LC-MS. AB - The use of medications during lactation is a common practice; however, pharmacological treatments impose serious doubts to both professionals and nursing mothers regarding the safety of drugs used during this period. Most of drugs are excreted in breast milk and there is great variability in the amount of analytes that can be received by the infant. Dilemmas about breastfeeding arise most commonly in relation to postpartum depression. Depression is a major clinical problem during the postpartum period and the vulnerability to onset or recurrence of depressive symptoms increases the possibility of psychotropic drug use during lactation. Selective inhibitors of serotonin reuptake are commonly prescribed for the treatment of depressive disorders, including fluoxetine, sertraline, citalopram, and paroxetine. A validated bioanalytical method using liquid chromatography coupled to mass spectrometry was developed and validated for determination of antidepressants in human milk following protein precipation. The bioanalytical method was successfully applied to assess milk samples from nursing mothers. From found concentrations, infant absolute (4.36 12.26MUg/kg/day) and relative dose (0.60-2.90%,) were estimated and low values were obtained indicating safe use during laction. However, other factors such as complemantary feeding and hepatic or renal disorders in the infant should be considered. PMID- 27497652 TI - Identification, synthesis, isolation and characterization of formulation related impurity of Gabapentin. AB - An unknown impurity was observed during stability studies of Gabapentin capsules. This impurity has been identified, synthesized, isolated and characterized using modern analytical tool. The novel impurity was confirmed as adduct of Gabapentin and lactose; an excipient used in formulation. The elucidated impurity was further confirmed by its synthesis, which was formed due to Maillard reaction and Amadori rearrangement. PMID- 27497653 TI - Bioactivity evaluation-based ultra high-performance liquid chromatography coupled with electrospray ionization tandem quadrupole-time-of-flight mass spectrometry and novel distinction of multi-subchemome compatibility recognition strategy with Astragali Radix-Fructus Corni herb-pair as a case study. AB - The approach to investigate traditional Chinese medicine (TCM) is still in its infancy and has been facing enormous challenge. In this paper, a generally applicable strategy was developed for investigation on TCM systematically with an introduced interesting idea about a novel research system which called subchemome. A representative herb-pair, Astragali Radix-Fructus Corni, was successfully employed to expound this novel strategy. Firstly, subchemomes were prepared individually by applying the suitable column chromatography, each of them was detected by UV spectrophotometer or HPLC-DAD detector. The components in each part were then identified based on the mass spectrometric fragmentation patterns and tandem mass spectrometric data by using UHPLC-Q-TOF-MS. Using renal mesangial cell (RMC) viability assay as the evaluation of the pharmacological activity of each group, we developed the new mini herbal formulae aimed at diabetic nephropathy and identified fifteen marker components between the group of new mini herbal formulae and other groups from the angle of the constituent, and then explored the effects of new mini herbal formulae from another angle of the molecular mechanism. Overall, the presently developed strategy should be beneficial and widely used in the investigation on TCM from a new perspective. PMID- 27497654 TI - UHPLC-MS/MS method with protein precipitation extraction for the simultaneous quantification of ten antihypertensive drugs in human plasma from resistant hypertensive patients. AB - Today the management of resistant hypertension is a critical health problem: the main difficulty on this field is the discrimination of cases of poor therapeutic adherence from cases of real resistance. This gives rise to the need of high throughput and reliable quantification methods for the Therapeutic Drug Monitoring (TDM) of antihypertensive drugs. The aim of this work was the development and validation of a UHPLC-Tandem mass spectrometry assay for this application and its use in plasma from patients with resistant hypertension. The novelty of this method resides in the ability to simultaneously quantify a wide panel of antihypertensive drugs: amlodipine, atenolol, clonidine, chlortalidone, doxazosin, hydrochlorothiazide, nifedipine, olmesartan, ramipril and telmisartan. Moreover, this method stands out for its simplicity and cheapness, resulting feasible for clinical routine. Both standards and quality controls were prepared in human plasma. After the addition of internal standard, each sample underwent protein precipitation with acetonitrile and was then dried. Extracts were resuspended in water:acetonitrile 90:10 (0.05% formic acid) and then injected into the chromatographic system. Chromatographic separation was performed on an Acquity((r)) UPLC HSS T3 1.8MUm 2.1*150mm column, with a gradient of water and acetonitrile, both added with 0.05% formic acid. Accuracy, intra-day and inter day precision fitted FDA guidelines for all analytes, while matrix effects and recoveries resulted stable between samples for each analyte. Finally, we tested this method by monitoring plasma concentrations in 22 hypertensive patients with good results. This simple analytical method could represent a useful tool for the management of antihypertensive therapy. PMID- 27497655 TI - Analytical comparison of a US generic enoxaparin with the originator product: The focus on comparative assessment of antithrombin-binding components. AB - Enoxaparin sodium, a low-molecular-weight heparin (LMWH) prepared from porcine intestinal heparin, is widely used for the prevention and treatment of venous thromboembolism. The antithrombotic activity of heparin is mediated mainly through its activation of antithrombin (AT) and subsequent inhibition of coagulation factors. Heparin is a complex heteropolymer and the sulfation pattern of its alternating uronic acid and glucosamine sugar units is a major factor influencing its biological activity. The manufacturing process itself is associated with the introduction of exogenous microheterogeneities that may further affect its biological efficacy. This is important since enoxaparin is prepared by depolymerizing the heparin with the aim of optimizing its biological activity and safety. Changes during its manufacture could thus affect its biological activity and safety. The current study was performed to assess potential differences between the originator enoxaparin and a new generic enoxaparin commercialized by Teva. Heparinase digestion, AT affinity chromatography, gel permeation chromatography, anion exchange chromatography, and nuclear magnetic resonance methodologies were used. The results indicated differences in oligosaccharides related to the cleavage selectivity around the heparin AT-binding sequences of the Teva Enoxaparin Sodium Injection, USP and the originator Sanofi enoxaparin. These differences influence the strength of the AT binding affinity of the individual oligosaccharides, their ability to activate AT and, therefore, the inhibitory potency on the proteases of the coagulation cascade. This study, together with other published analytical reports, describes specific compositional differences between generics and originator LWMHs. However, it is yet to be established whether such variations might have any clinical relevance. PMID- 27497656 TI - Molecular characterization of a clinical Haemophilus parainfluenzae isolate with cefotaxime resistance and decreased susceptibility to fluoroquinolones. AB - We report an H. parainfluenzae clinical isolate resistant to cefotaxime and with decreased susceptibility to ciprofloxacin recovered from a patient with cystic fibrosis. The isolate had elevated MICs of ampicillin (256mg/L), amoxicillin clavulanate (8mg/L), cefuroxime (8mg/L) and cefotaxime (4mg/L), and showed a beta lactamase-producing amoxicillin-clavulanic acid-resistant (BLPACR) phenotype. A blaTEM-1 plus five amino acid substitutions in the PBP3 were found: Ser385Thr, Val511Ala, Ile519Val, Asn526Lys and Asp551Leu. MIC of ciprofloxacin was 0.5mg/L, and substitutions in gyrA (Ser84Tyr) and parC (Ser84Phe) genes were detected. PMID- 27497657 TI - Identification of a dominant Chlamydia trachomatis strain in patients attending sexual transmitted infection clinic and female sex workers in Tunisia using a high resolution typing method. AB - BACKGROUND: The distribution of Chlamydia trachomatis genotypes in Tunisia was previously studied using the reverse hybridization method. In this study, we used multilocus sequence typing (MLST) to describe Chlamydia trachomatis genetic diversity among heterosexual populations in Tunisia. The obtained sequence types (STs) were compared with those from a heterosexual population from Amsterdam, the Netherlands. METHODS: Clinical Tunisian patients and female sex workers provided 107 Chlamydia trachomatis positive samples that were used for MLST. Samples from 256 heterosexuals visiting the Amsterdam STI clinic were included as a reference group. Six highly variable genetic regions including the ompA gene were amplified and sequenced. The ST numbers were derived from a Chlamydia typing database (http://mlstdb.uu.se) and used to draw minimum spanning trees. RESULTS: ompA sequencing detected 7 genotypes among the Tunisian populations of which genotype E was the most prevalent (66.3%). This genotype E resolved into 23 different STs and among these the ST3 was predominant (53.5%). MLST displayed 43 STs, of which 28 (65%) were new in the database. Minimum spanning tree analysis of all Tunisian samples identified 4 clusters of which one formed a clonal cluster with samples presenting the most prevalent ST3. When comparing samples from the Tunisian and Dutch populations in one minimum spanning tree, there was little overlap between the Chlamydia trachomatis samples. CONCLUSION: The CT-hrMLST scheme allowed us to identify that the Tunisian distribution was dominated by one genotype E (ST3) strain which is also highly prevalent in many other countries worldwide. PMID- 27497658 TI - Obesity and novel cardiovascular markers in a population without diabetes and cardiovascular disease in China. AB - OBJECTIVE: To investigate associations of novel cardiovascular markers with obesity in a general population. METHODS: A total of 9361 individuals without diabetes or cardiovascular disease were studied between 2009 and 2012 in China. High-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), brachial-ankle pulse wave velocity (baPWV), pulse pressure, and central systolic blood pressure (cSBP) were assessed according to body mass index (BMI) levels and different BMI/metabolic syndrome (MetS) combinations. RESULTS: 'Levels of hs-cTnT, baPWV, pulse pressure, and cSBP increased across BMI levels. Obesity was positively associated with these markers in multivariate models (P<0.05 for all). When stratified by MetS, these associations remained significant in the non-MetS group, and compared with normal weight participants, the obese participants had 1.87 (95% confidence interval: 1.48, 2.36), 1.27 (1.02, 1.57), 1.89 (1.39, 2.57), and 2.71 (2.11, 3.47) fold risks for having elevated hs-cTnT, baPWV, pulse pressure, and cSBP, respectively, and had 1.61 (1.26, 2.05), 1.75 (1.27, 2.42), 2.45 (1.46, 4.11), and 3.14 (2.13, 4.62) fold risks for having 1, 2, 3, and 4 elevated cardiovascular markers, respectively; while no relationship was observed between obesity and these novel markers in the MetS group, after multivariate adjustment. These results were unchanged when using a waist-hip ratio, body fat per cent, and visceral adiposity index to redefine obesity. CONCLUSIONS: Obesity was positively associated with novel cardiovascular markers (except NT-proBNP) in participants without MetS rather than in participants with MetS. Obese participants without MetS also had higher odds of having more number of elevated cardiovascular markers. PMID- 27497659 TI - Reclaiming the streets for people: Insights from Ciclovias Recreativas in Latin America. AB - The Ciclovias comprise worldwide programs in which streets are closed to motor vehicles and open to individuals for leisure activities. Currently, 93% of the regular programs are in Latin American countries (LAC). The aims of this study were to describe the characteristics of regular Ciclovias in 7 LAC and to analyze the factors that influence the sustainability and scaling-up of five case studies. We conducted a survey of 67 Ciclovias in 2014-2015. In addition, we conducted semi-structured interviews with current and former program coordinators and reviewed policy documents from Ciclovias in 5 LAC. The greatest expansion of Ciclovias has occurred since 2000. The number of participants per event ranged from 40 to 1,500,000 (mean 41,399+/-193,330; median 1600), and the length ranged from 1 to 113.6km (mean 9.1+/-16.4; median 3). Ciclovia routes connect low-middle and high income neighborhoods (89.3%), and include the participation of minority populations (61.2%). The main complementary activity offered was physical activity (PA) classes (94.0%), and 80.0% of the programs included strategies to promote biking. All five case studies met definitions for sustainability and scaling-up. All programs shared some level of government support, alliances, community appropriation, champions, compatibility with the mission of the host organization, organizational capacity, flexibility, perceived benefits, and funding stability. However, they differed in operational conditions, political favorability, sources of funding, and number of alliances. The Ciclovias of LAC showed heterogeneity within their design and sustainability factors. Both their heterogeneity and flexibility to adjust to changes make them promising examples of socially inclusive programs to promote PA. PMID- 27497660 TI - The influence of prescription opioid use duration and dose on development of treatment resistant depression. AB - Long-term prescription opioid use is associated both with new-onset and recurrence of depression. Whether chronic opioid use interferes with depression management has not been reported, therefore we determined whether patients' longer duration of opioid use and higher opioid dose are associated with new onset treatment resistant depression (TRD) after controlling for confounding from pain and other variables. Data was obtained from Veteran Health Administration (VHA) de-identified patient medical records. We used a retrospective cohort design from 2000-2012. Eligible subjects (n=6169) were 18-80years of age, free of cancer and HIV, diagnosed with depression and opioid-free for the 24-month interval prior to the observation period. Duration of a new prescription for opioid analgesic was categorized as 1-30days, 31-90days and >90days. Morphine equivalent dose (MED) during follow-up categorized as <=50mg versus >50mg per day. Pain and other sources of confounding were controlled by propensity scores and inverse probability of treatment weighting. Cox proportional hazard models were computed to estimate the association between duration and dose of opioid and onset of TRD. After controlling for confounding by weighting data, opioid use for 31-90days and for >90days, compared to 1-30days, was significantly associated with new onset TRD (HR=1.25; 95% CI: 1.09-1.45 and HR=1.52; 95% CI: 1.32-1.74, respectively). MED was not associated with new onset TRD. The risk of developing TRD increased as time spent on opioid analgesics increased. Long-term opioid treatment of chronic pain may interfere with treatment of depression. PMID- 27497661 TI - Development and application of a general plasmid reference material for GMO screening. AB - The use of analytical controls is essential when performing GMO detection through screening tests. Additionally, the presence of taxon-specific sequences is analyzed mostly for quality control during GMO detection. In this study, 11 commonly used genetic elements involving three promoters (P-35S, P-FMV35S and P NOS), four marker genes (Bar, NPTII, HPT and Pmi), and four terminators (T-NOS, T 35S, T-g7 and T-e9), together with the reference gene fragments from six major crops of maize, soybean, rapeseed, rice, cotton and wheat, were co-integrated into the same single plasmid to construct a general reference plasmid pBI121 Screening. The suitability test of pBI121-Screening plasmid as reference material indicated that the non-target sequence on the pBI121-Screening plasmid did not affect the PCR amplification efficiencies of screening methods and taxon-specific methods. The sensitivity of screening and taxon-specific assays ranged from 5 to 10 copies of pBI121-Screening plasmid, meeting the sensitivity requirement of GMO detection. The construction of pBI121-Screening solves the lack of a general positive control for screening tests, thereby reducing the workload and cost of preparing a plurality of the positive control. PMID- 27497662 TI - Increased cryosurvival of osteosarcoma cells using an amphipathic pH-responsive polymer for trehalose uptake. AB - Amphipathic pH-responsive polymers have shown to increase the permeability of cell membranes to trehalose hence improving the cryopreservation of mammalian cells. However, the trafficking of both the polymer and trehalose across the cell membrane has not yet been thoroughly analysed. The objective of this study was to investigate the effect on cryopreservation of the trafficking of the disaccharide trehalose along PP-50, an amphipathic polymer, through an osteosarcoma cell line (SAOS-2). Confocal microscopy analysis confirmed the presence of intracellular labelled trehalose only when incubated in the presence of PP-50. Further analysis confirmed that both trehalose and PP-50 localised in the cytoplasm, accumulated mainly in the perinuclear area. Quantitative analysis of the colocalisation between trehalose and PP-50 showed Pearson and Manders coefficients of 0.862 +/- 0.008 and 0.766 +/- 0.033, respectively, suggesting a high degree of intracellular colocalisation between these molecules. Cryopreserved cells pre incubated with trehalose and PP-50 showed increased cryosurvival when compared with cells pre-incubated in the absence of the polymer. PP-50 showed to be directly involved in the uptake of trehalose, a critical characteristic towards use in cryopreservation and biomedical applications. PMID- 27497663 TI - Vitrification at Day3 stage appears not to affect the methylation status of H19/IGF2 differentially methylated region of in vitro produced human blastocysts. AB - One of the most widely used assisted reproductive technology (ART) is vitrification. The aim of this study is to evaluate DNA methylation of H19/IGF2 differentially methylation region (DMR) in in vitro produced human blastocysts derived from non-vitrified and vitrified day3 embryos. Day3 embryos derived from ICSI cycles from fertile couples referring for family balancing program were either biopsied or vitrified/warmed and subsequently biopsied. Following biopsy, embryos were cultured to day 5. Day5 blastocysts with desired sex were transferred or vitrified for future use. Blastocysts with un-desired sex were donated for research. The assessment of the embryos was performed in two non vitrified and vitrified groups. Methylation level of H19/IGF2 DMR was analysed by bisulfite conversion and sequencing at 18 CpG sites (CpGs) located in this region. Results showed that the overall methylated CpGs percentages of this region in the vitrified and non-vitrified groups were 35.3% +/- 3.6 and 38.27 +/- 4.1%, respectively. The difference between the two groups was not significant. Vitrification of day3 embryo appears to have no adverse effect on DNA methylation status of H19/IGF2 DMR of embryos cultured in vitro to blastocyst stage. These data may have implications for performing frozen embryo cycles transfer instead of fresh embryo transfer cycles, owing to the naturally synchronized uterus and subsequently improved endometrial receptivity in frozen embryo transfer instead of imbalanced hormonal milieu in fresh embryo transfer cycles. PMID- 27497664 TI - Kisspeptin2 stimulates the HPG axis in immature Nile tilapia (Oreochromis niloticus). AB - It has been suggested that kisspeptin influences reproduction and onset of puberty in fishes. Unlike mammals, which produce only one kisspeptin (Kiss1), some teleosts have two, Kiss1 and Kiss2, both thought to be involved in the stimulation of gonadotropin (GTH) secretion. In Nile tilapia (Oreochromis niloticus), however, only Kiss2 has been identified so far. The effect of Kiss2 on GTH release varies significantly depending on species and reproductive stage. Furthermore, its physiological function in this species is not clearly defined. In this study, kiss2 gene expression profiles were examined using quantitative real-time PCR (qRT-PCR) in the brain, pituitary, and gonads of Nile tilapia at different reproductive stages (male: immature, pre-spermiation, post-spermiation; female: immature, pre-spawning, post-spawning). The kiss2 mRNA expression profiles of the brain, pituitary, and gonads of both sexes shared a similar pattern their expression was significantly higher at the immature stage than at the mature or post-spawning stages, implying it is involved in early gonadal maturation in this species. To investigate the effect of kisspeptin on the hypothalamus-pituitary-gonad (HPG) axis in vivo, synthetic kisspeptin2 (FNYNPLSLRF) was injected into immature male and female tilapia intraperitoneally (i.p.) at a dose of 200pmol/g body weight. The results showed that synthetic Kiss2 administration increased the expression of GnRH I, fshbeta and lhbeta mRNA in the brain and increased 17beta-estradiol (E2) and 11-ketotestosterone (11-KT) levels in the plasma. These results suggest that Kiss2 stimulates the expression of GnRH and GTH genes in immature Nile tilapia. PMID- 27497665 TI - DNA methylation in a sea lamprey vasotocin receptor gene promoter correlates with tissue- and life-stage-specific mRNA expression. AB - The jawless vertebrate sea lamprey (Petromyzon marinus) genome has a different structure from both invertebrates and jawed vertebrates featuring high guanine cytosine (GC) content. This raises the question of whether DNA methylation of cytosine-guanine (CpG) dinucleotides could function to regulate lamprey gene transcription. We previously characterized a lamprey arginine vasotocin (AVT) receptor gene (Pm807) possessing characteristics of both arginine vasopressin (AVP) V1A and oxytocin (OXT) receptor genes of jawed vertebrates. Lamprey Pm807 mRNA is highly expressed in adult heart and larval liver but not expressed in adult liver. Using high-resolution melt (HRM) PCR on bisulfite-converted DNA, we pinpointed a region with tissue-specific differences in DNA melt characteristics, indicating differences in methylation level. Sequencing revealed a pattern of methylation at specific CpGs at consistently higher levels in adult heart and larval liver than adult liver. These CpGs are associated with putative transcription factor binding sequences organized similarly to functional OXTR promoters in mammals, suggesting functional similarity in lamprey gene transcription regulation. PMID- 27497667 TI - The curious case of cyberchondria: A longitudinal study on the reciprocal relationship between health anxiety and online health information seeking. AB - The current study is the first to longitudinally investigate the reciprocal relationship between online health information seeking and health anxiety, i.e., cyberchondria. Expectations were that health anxious individuals who go online to find health information, experience an increase in health anxiety, which in turn will reinforce online seeking. A 4-wave longitudinal survey study among 5322 respondents aged 16-93 was conducted. Our results showed that individuals who are more health anxious than others, search online for health information more. Moreover, the results provided initial evidence for the expected reciprocal relationship between health anxiety and online health information seeking in respondents with non-clinical levels of health anxiety at the start of the study. However, this reciprocal relationship could not be found in a subsample of clinically health anxious individuals. Although for these individuals online health information seeking did not seem to exacerbate health anxiety levels, it might still serve as a maintaining factor of clinical health anxiety. PMID- 27497666 TI - Different expression patterns of renal Na+/K+-ATPase alpha-isoform-like proteins between tilapia and milkfish following salinity challenges. AB - Euryhaline teleosts can survive in a broad range of salinity via alteration of the molecular mechanisms in certain osmoregulatory organs, including in the gill and kidney. Among these mechanisms, Na+/K+-ATPase (NKA) plays a crucial role in triggering ion-transporting systems. The switch of NKA isoforms in euryhaline fish gills substantially contributes to salinity adaptation. However, there is little information about switches in the kidneys of euryhaline teleosts. Therefore, the responses of the renal NKA alpha-isoform protein switch to salinity challenge in euryhaline tilapia (Oreochromis mossambicus) and milkfish (Chanos chanos) with different salinity preferences were examined and compared in this study. Immunohistochemical staining in tilapia kidneys revealed the localization of NKA in renal tubules rather than in the glomeruli, similar to our previous findings in milkfish kidneys. Protein abundance in the renal NKA pan alpha-subunit-like, alpha1-, and alpha3-isoform-like proteins in seawater acclimated tilapia was significantly higher than in the freshwater group, whereas the alpha2-isoform-like protein exhibited the opposite pattern of expression. In the milkfish, higher protein abundance in the renal NKA pan alpha-subunit-like and alpha1-isoform-like proteins was found in freshwater-acclimated fish, whereas no difference was found in the protein abundance of alpha2- and alpha3-isoform like proteins between groups. These findings suggested that switches for renal NKA alpha-isoforms, especially the alpha1-isoform, were involved in renal osmoregulatory mechanisms of euryhaline teleosts. Moreover, differences in regulatory responses of the renal NKA alpha-subunit to salinity acclimation between tilapia and milkfish revealed that divergent mechanisms for maintaining osmotic balance might be employed by euryhaline teleosts with different salinity preferences. PMID- 27497668 TI - Effects of oxidative stress on hyperglycaemia-induced brain malformations in a diabetes mouse model. AB - Pregestational diabetes mellitus (PGDM) enhances the risk of fetal neurodevelopmental defects. However, the mechanism of hyperglycaemia-induced neurodevelopmental defects is not fully understood. In this study, several typical neurodevelopmental defects were identified in the streptozotocin-induced diabetes mouse model. The neuron-specific class III beta-tubulin/forkhead box P1 labelled neuronal differentiation was suppressed and glial fibrillary acidic protein-labelled glial cell lineage differentiation was slightly promoted in pregestational diabetes mellitus (PGDM) mice. Various concentrations of glucose did not change the U87 cell viability, but glial cell line-derived neurotrophic factor expression was altered with varying glucose concentrations. Mouse maternal hyperglycaemia significantly increased Tunel(+) apoptosis but did not dramatically affect PCNA(+) cell proliferation in the process. To determine the cause of increased apoptosis, we determined the SOD activity, the expression of Nrf2 as well as its downstream anti-oxidative factors NQO1 and HO1, and found that all of them significantly increased in PGDM fetal brains compared with controls. However, Nrf2 expression in U87 cells was not significantly changed by different glucose concentrations. In mouse telencephalon, we observed the co localization of Tuj-1 and Nrf2 expression in neurons, and down-regulating of Nrf2 in SH-SY5Y cells altered the viability of SH-SY5Y cells exposed to high glucose concentrations. Taken together, the data suggest that Nrf2-modulated antioxidant stress plays a crucial role in maternal hyperglycaemia-induced neurodevelopmental defects. PMID- 27497670 TI - Sulforaphane Prevents Neuronal Apoptosis and Memory Impairment in Diabetic Rats. AB - BACKGROUND/AIMS: To explore the effects of sulforaphane (SFN) on neuronal apoptosis in hippocampus and memory impairment in diabetic rats. METHODS: Thirty male rats were randomly divided into normal control, diabetic model and SFN treatment groups (N = 10 in each group). Streptozotocin (STZ) was applied to establish diabetic model. Water Morris maze task was applied to test learning and memory. Tunel assaying was used to detect apoptosis in hippocampus. The expressions of Caspase-3 and myeloid cell leukemia 1(MCL-1) were detected by western blotting. Neurotrophic factor levels and AKT/GSK3beta pathway were also detected. RESULTS: Compared with normal control, learning and memory were apparently impaired, with up-regulation of Caspase-3 and down-regulation of MCL-1 in diabetic rats. Apoptotic neurons were also found in CA1 region after diabetic modeling. By contrast, SFN treatment prevented the memory impairment, decreased the apoptosis of hippocampal neurons. SFN also attenuated the abnormal expression of Caspase-3 and MCL-1 in diabetic model. Mechanically, SFN treatment reversed diabetic modeling-induced decrease of p-Akt, p-GSK3beta, NGF and BDNF expressions. CONCLUSION: SFN could prevent the memory impairment and apoptosis of hippocampal neurons in diabetic rat. The possible mechanism was related to the regulation of neurotropic factors and Akt/GSK3beta pathway. PMID- 27497669 TI - LEFTY2 Controls Migration of Human Endometrial Cancer Cells via Focal Adhesion Kinase Activity (FAK) and miRNA-200a. AB - BACKGROUND: LEFTY2, a suppressor of cell proliferation, tumor growth, regulator of stemness and embryonic differentiation, is a negative regulator of cancer cell reprogramming. Malignant transformation may lead to migration requiring loss of adhesion and gain of migratory activity. Signaling involved in the orchestration of migration, proliferation and spreading of cells include focal adhesion kinase (FAK) and adhesion molecule E-cadherin. AIMS: The present study explored whether LEFTY2 influences the proliferation marker MKi67, FAK activity, E-cadherin abundance and migration of Ishikawa human endometrial carcinoma cells. Moreover, the study explored the involvement of microRNA-200a (miR-200a), which is known to regulate cellular adhesion by targeting E-Cadherin. METHODS: FAK activity was estimated from FAK phosphorylation quantified by Western blotting, migration utilizing a wound healing assay, miR-200a and MKi67 expression levels utilizing qRT-PCR, cell proliferation and apoptosis using BrdU and Annexin V staining, respectively, and E-Cadherin (E-Cad) abundance, using confocal microscopy. RESULTS: LEFTY2 (25 ng/ml, 48 hours) treatment was followed by decrease of MKi67 expression, FAK activity and migration. LEFTY2 upregulated miRNA-200a and E-Cad protein level in Ishikawa cells. The effect of LEFTY2 on migration was mimicked by FAK inhibitor PF 573228 (50 uM). Addition of LEFTY2 in the presence of PF 573228 did not result in a further significant decline of migration. CONCLUSION: In conclusion, LEFTY2 down-regulates MKi67 expression and FAK activity, up regulates miR-200a and E-cadherin, and is thus a powerful negative regulator of endometrial cell proliferation and migration. PMID- 27497671 TI - N-Acetylcysteine Amide Exerts Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia. AB - BACKGROUND: Perinatal asphyxia and ensuing reoxygenation change the antioxidant capacity of cells and organs. OBJECTIVES: To analyze the neuroprotective effect of the antioxidant N-acetylcysteine amide (NACA) after perinatal hypoxia reoxygenation with an emphasis on proinflammatory cytokines and the transcription factor NF-kappaB in the prefrontal cortex of neonatal pigs. METHODS: Twenty-nine newborn pigs, aged 12-36 h, were subjected to global hypoxia and hypercapnia. One sham-operated group (n = 5) and 2 experimental groups (n = 12) were exposed to 8% oxygen, until the base excess was -20 mmol/l or the mean arterial blood pressure fell to <20 mm Hg (asphyxia with NACA or saline). The pigs were observed for 9.5 h after hypoxia. Samples of prefrontal cortex and plasma were analyzed. RESULTS: Cortex: there was no significant difference in mRNA expression between the intervention groups regarding IL-1beta, IL6, TNFalpha, MMP2, MMP9 or IL18. Pigs exposed to hypoxia-reoxygenation and treatment with NACA (NACA-pigs) had a significantly lower protein concentration of IL-1beta than pigs treated with saline (placebo controls), i.e. 8.8 +/- 3.9 versus 16.8 +/- 10.5 pg/mg protein (p = 0.02). The activation of the transcription factor NF-kappaB (measured as the fold-change of phosphorylated p65Ser 536), was reduced in the NACA-pigs when compared to the placebo controls (5.2 +/- 4.3 vs. 16.0 +/- 13.5; p = 0.02). No difference between the intervention groups regarding brain histopathology or in the levels of 8-oxoguanine measured in the prefrontal cortex were observed. Plasma: the NACA-pigs had a stronger reduction of TNFalpha in the first 30 min following asphyxia compared with the placebo controls, i.e. 36 (30-44) versus 24 (14-32)% (p = 0.01). CONCLUSION: The reduced levels of the pivotal inflammatory markers IL-1beta and TNFalpha and the transcription factor NF-kappaB may indicate that NACA has possible neuroprotective effects after perinatal asphyxia. PMID- 27497672 TI - Pulmonary Function in Patients with End-Stage Renal Disease: Effects of Hemodialysis and Fluid Overload. AB - BACKGROUND Respiratory system disorders are one of the most prevalent complications in end-stage renal disease patients on hemodialysis. However, the pathogenesis of impaired pulmonary functions has not been completely elucidated in these patients. We designed a study to investigate acute effects of hemodialysis treatment on spirometry parameters, focusing on the relationship between pulmonary function and fluid status in hemodialysis patients. MATERIAL AND METHODS We enrolled 54 hemodialysis patients in this study. Multifrequency bioimpedance analysis (BIA) was used to assess fluid status before and 30 min after the midweek of hemodialysis (HD). Overhydration (OH)/extracellular water (ECW)% ratio was used as an indicator of fluid status. Fluid overload was defined as OH/ECW >=7%. Spirometry was performed before and after hemodialysis. RESULTS Forced vital capacity (FVC), FVC%, and forced expiratory volume in the first second (FEV1) levels were significantly increased after hemodialysis. FVC, FVC%, FEV1, FEV1%, mean forced expiratory flow between 25% and 75% of the FVC (FEF25 75), FEF25-75%, peak expiratory flow rate (PEFR), and PEFR% were significantly lower in patients with fluid overload than in those without. OH/ECW ratio was negatively correlated with FVC, FVC%, FEV1, FEV1%, FEF25-75, FEF25-75%, PEFR, and PEFR%. Stepwise multiple regression analysis revealed that male sex and increased ultrafiltration volume were independently associated with higher FVC, whereas increased age and OH/ECW ratio were independently associated with lower FVC. CONCLUSIONS Fluid overload is closely associated with restrictive and obstructive respiratory abnormalities in HD patients. In addition, hemodialysis has a beneficial effect on pulmonary function tests, which may be due to reduction of volume overload. PMID- 27497674 TI - Variability in source sediment contributions by applying different statistic test for a Pyrenean catchment. AB - Information on sediment contribution and transport dynamics from the contributing catchments is needed to develop management plans to tackle environmental problems related with effects of fine sediment as reservoir siltation. In this respect, the fingerprinting technique is an indirect technique known to be valuable and effective for sediment source identification in river catchments. Large variability in sediment delivery was found in previous studies in the Barasona catchment (1509 km2, Central Spanish Pyrenees). Simulation results with SWAT and fingerprinting approaches identified badlands and agricultural uses as the main contributors to sediment supply in the reservoir. In this study the <63 MUm sediment fraction from the surface reservoir sediments (2 cm) are investigated following the fingerprinting procedure to assess how the use of different statistical procedures affects the amounts of source contributions. Three optimum composite fingerprints were selected to discriminate between source contributions based in land uses/land covers from the same dataset by the application of (1) discriminant function analysis; and its combination (as second step) with (2) Kruskal-Wallis H-test and (3) principal components analysis. Source contribution results were different between assessed options with the greatest differences observed for option using #3, including the two step process: principal components analysis and discriminant function analysis. The characteristics of the solutions by the applied mixing model and the conceptual understanding of the catchment showed that the most reliable solution was achieved using #2, the two step process of Kruskal-Wallis H-test and discriminant function analysis. The assessment showed the importance of the statistical procedure used to define the optimum composite fingerprint for sediment fingerprinting applications. PMID- 27497673 TI - Geographic Discordance Between Patient Residence and Incident Location in Emergency Medical Services Responses. AB - STUDY OBJECTIVE: The location of a patient's residence is often used for emergency medical services (EMS) system planning. Our objective is to evaluate the association between patient residence and emergency incident zip codes for 911 calls. METHODS: We used data from the 2013 National Emergency Medical Services Information System (NEMSIS) Public-Release Research Dataset. We studied all 911 calls with a valid complaint by dispatch, identifying zip codes for both the residence and incident locations (n=12,376,784). The primary outcomes were geographic and distance discordances between patient residence and incident zip codes. We used a multivariate logistic regression model to determine geographic discordance between residence and incident zip codes by dispatch complaint, age, and sex. We also measured distances between locations with geospatial processing. RESULTS: The overall proportion of geographic discordance for all 911 calls was 27.7% (95% confidence interval [CI] 27.7% to 27.8%) and the median distance discordance was 11.5 miles (95% CI 11.5 to 11.5 miles). Lower geographic discordance rates were found among patients aged 65 to 79 years (20.2%; 95% CI 20.1% to 20.2%) and 80 years and older (14.5%; 95% CI 14.5% to 14.6%). Motor vehicle crashes (63.5%; 95% CI 63.5% to 63.6%), industrial accidents (59.3%; 95% CI 58.0% to 60.6%), and mass casualty incidents (50.6%; 95% CI 49.6% to 51.5%) were more likely to occur outside a patient's residence zip code. Median network distance between home and incident zip centroid codes ranged from 8.6 to 23.5 miles. CONCLUSION: In NEMSIS, there was geographic discordance between patient residence zip code and call location zip code in slightly more than one quarter of EMS responses records. The geographic discordance rates between residence and incident zip codes were associated with dispatch complaints and age. Although a patient's residence might be a valid proxy for incident location for elderly patients, this relationship holds less true for other age groups and among different complaints. Our findings have important implications for EMS system planning, resource allocation, and injury surveillance. PMID- 27497675 TI - Early decision framework for integrating sustainable risk management for complex remediation sites: Drivers, barriers, and performance metrics. AB - As the environmental remediation industry matures, remaining sites often have significant underlying technical challenges and financial constraints. More often than not, significant remediation efforts at these "complex" sites have not achieved stringent, promulgated cleanup goals. Decisions then have to be made about whether and how to commit additional resources towards achieving those goals, which are often not achievable nor required to protect receptors. Guidance on cleanup approaches focused on evaluating and managing site-specific conditions and risks, rather than uniformly meeting contaminant cleanup criteria in all media, is available to aid in this decision. Although these risk-based cleanup approaches, such as alternative endpoints and adaptive management strategies, have been developed, they are under-utilized due to environmental, socio economic, and risk perception barriers. Also, these approaches are usually implemented late in the project life cycle after unsuccessful remedial attempts to achieve stringent cleanup criteria. In this article, we address these barriers by developing an early decision framework to identify if site characteristics support sustainable risk management, and develop performance metrics and tools to evaluate and implement successful risk-based cleanup approaches. In addition, we address uncertainty and risk perception challenges by aligning risk-based cleanup approaches with the concepts of risk management and sustainable remediation. This approach was developed in the context of lessons learned from implementing remediation at complex sites, but as a framework can, and should, be applied to all sites undergoing remediation. PMID- 27497676 TI - A 3D Toolbox to Enhance Physiological Relevance of Human Tissue Models. AB - We discuss the current challenges and future prospects of flow-based organoid models and 3D self-assembling scaffolds. The existing paradigm of 3D culture suffers from a lack of control over organoid size and shape; can be an obstacle for cell harvesting and extended cellular and molecular analysis; and does not provide access to the function of exocrine glands. Moreover, existing organ-on chip models are mostly composed of 2D extracellular matrix (ECM)-coated elastomeric membranes that do not mimic real organ architectures. A new comprehensive 3D toolbox for cell biology has emerged to address some of these issues. Advances in microfabrication and cell-culturing approaches enable the engineering of sophisticated models that mimic organ 3D architectures and physiological conditions, while supporting flow-based drug screening and secretomics-based diagnosis. PMID- 27497677 TI - The role of anxiety sensitivity in the relation between anxious arousal and cannabis and alcohol use problems among low-income inner city racial/ethnic minorities. AB - The current study explored anxiety sensitivity as a factor accounting for the association between anxious arousal and problems related to use of cannabis and alcohol among a health disparity sample (low income minorities). Specifically, participants were 130 low-income racial/ethnic minorities who reported daily cannabis use (Mage=37.7 SD=10.0; 28.5% female). There were significant indirect associations of anxious arousal via anxiety sensitivity in relation to: cannabis use problems, cannabis withdrawal symptoms, use of cannabis to cope, as well as hazardous drinking, alcohol use problems, and alcohol consumption. These data indicate anxiety sensitivity is a possible mechanism underlying the relation between anxious arousal and substance use problems among low-income racial/ethnic minorities. Future work could evaluate the efficacy of cannabis and alcohol use treatments incorporating anxiety sensitivity reduction techniques to facilitate amelioration of anxiety and substance use and offset mental health inequalities for this population. PMID- 27497678 TI - Prevalence of autism spectrum disorders in a semiurban community in south India. PMID- 27497680 TI - Associations of blood heavy metal levels with intraocular pressure. AB - PURPOSE: Whether or which blood heavy metal levels (BHMLs) influence elevating intraocular pressure (IOP) are unknown. We examined the relationship among blood lead, mercury, and cadmium levels, blood pressure (BP), and IOP and assessed whether BP mediates these BHMLs-IOP associations. METHODS: We analyzed data on 8371 adult (>=20 years) from the Korea National Health and Nutrition Examination Survey from 2008 to 2012. Mediation analysis was used to examine the contribution of BP to the BHMLs-IOP relationship. RESULTS: IOP and three BHMLs were significantly associated with systolic and diastolic BP. But IOP was associated with only blood lead and mercury levels. BP significantly mediated lead-IOP and mercury-IOP associations: BP accounted for 20.5% and 14.2% of the association with IOP. Blood lead and mercury levels were significantly associated with IOP. CONCLUSIONS: BP significantly mediates the effects of those blood lead and mercury levels on IOP outcome. Prospective studies are needed to further examine the causal pathway from BHMLs to IOP elevation. PMID- 27497679 TI - Early life growth, socioeconomic status, and mammographic breast density in an urban US birth cohort. AB - PURPOSE: Rapid infant and childhood growth has been associated with chronic disease later in life, including breast cancer. Early life socioeconomic status (SES) influences childhood growth, but few studies have prospective measures from birth to consider the effects of early life growth and SES on breast cancer risk. METHODS: We used prospectively measured early life SES and growth (percentile weight change in height and weight between each pair of consecutive time points at birth, 4 months, 1 and 7 years). We performed linear regression models to obtain standardized estimates of the association between 1 standard deviation increase in early life SES and growth and adult mammographic density (MD), a strong risk factor for breast cancer, in a diverse birth cohort (n = 151; 37% white, 38% black, 25% Puerto Rican; average age at mammogram = 42.4). RESULTS: In models adjusted for race/ethnicity, prenatal factors, birthweight, infant and childhood growth, and adult body mass index, percentile weight change from 1 year to 7 years was inversely associated with percent MD (standardized coefficient (Stdbeta) = -0.28, 95% CI: -0.55 to -0.01), and higher early life SES was positively associated with percent MD (Stdbeta = 0.24, 95% CI: 0.04-0.43). Similar associations were observed for dense area, but those estimates were not statistically significant. CONCLUSIONS: These results suggest opposite and independent effects of early life SES and growth on MD. PMID- 27497681 TI - Potential Role of Aminoprocalcitonin in the Pathogenesis of Alzheimer Disease. AB - Increasing evidence suggests that inflammatory responses cause brain atrophy and play a prominent and early role in the progression of Alzheimer disease. Recent findings show that the neuroendocrine peptide aminoprocalcitonin (NPCT) plays a critical role in the development of systemic inflammatory response; however, the presence, possible function, regulation, and mechanisms by which NPCT may be involved in Alzheimer disease neuropathology remain unknown. We explored the expression of NPCT and its interaction with amyloid-beta (Abeta), and proinflammatory and neurogenic effects. By using brain samples of Alzheimer disease patients and APP/PS1 transgenic mice, we evaluated the potential role of NPCT on Abeta-related pathology. We found that NPCT is expressed in hippocampal and cortical neurons and Abeta-induced up-regulation of NPCT expression. Peripherally administered antibodies against NPCT decreased microglial activation, decreased circulating levels of proinflammatory cytokines, and prevented Abeta-induced neurotoxicity in experimental models of Alzheimer disease. Remarkably, anti-NPTC therapy resulted in a significant improvement in the behavioral status of APP/PS1 mice. Our results indicate a central role of NPCT in Alzheimer disease pathogenesis and suggest NPCT as a potential biomarker and therapeutic target. PMID- 27497682 TI - The Wellness Theorem: A Test of the Hypothesis. PMID- 27497683 TI - Reactions to Rituximab in an Outpatient Infusion Center: A 5-Year Review. AB - BACKGROUND: Reactions to rituximab occur frequently, with up to 77% of patients developing a reaction during initial exposure. The safety of rechallenging patients after a reaction is not clear and standard guidelines are lacking. OBJECTIVE: To better understand clinical decision making surrounding rituximab reactions and subsequent rechallenge. METHODS: We performed a 5-year retrospective review of all rituximab reactions at a large academic outpatient infusion center. Patients' demographic characteristics, clinical symptoms, and management of reactions were reviewed. Reaction severity was classified using standard criteria. RESULTS: Between June 2006 and January 2011, 67 patients (mean age, 58 +/- 13 years, 54% men) with at least 1 rituximab reaction were identified. Most reactions occurred during the first exposure to rituximab (63%). Most reactions (n = 59 [88%]) were grade 1 or 2. Fifty-one patients (n = 51 [88%]) were rechallenged with rituximab on the same day as the initial reaction. Most patients with a grade 1 reaction tolerated rechallenge. Conversely, all 4 patients with a grade 3 reaction had a reaction during rechallenge. The outcome of same-day rechallenge after an initial grade 2 reaction was varied; most patients (26 of 31 [84%]) tolerated same-day challenge, but 5 patients had a reaction (all grade 1-2 severity). CONCLUSIONS: Consistent with previous data, our observations suggest that patients who experience grade 1 reactions to rituximab can be safely rechallenged the same day. A grade 3 or 4 reaction should prompt referral to an allergy specialist for risk assessment before additional rituximab administration. Further research is needed to understand the optimal management of patients with grade 2 reactions. PMID- 27497684 TI - Serum levels of copeptin are associated with type 2 diabetes and diabetic complications in Chinese population. AB - PURPOSE: The aim of this study was to investigate copeptin levels in serum, and assess their associations with type 2 diabetes (T2DM) and diabetic complications. METHODS: In this post hoc analysis, serum levels of copeptin were tested in 306 patients with T2DM. Clinical information including diabetic retinopathy (DR) and diabetic nephropathy (DN) were collected. The relation of serum copeptin with DR and DN were investigated with the use of logistic regression models according to equal quartiles of the distributions of serum copeptin. RESULTS: We found that serum copeptin levels were significantly higher in diabetes as compared to normal controls [9.4(IQR, 7.4-12.5) pmol/L vs. 4.1(IQR, 2.5-6.2) pmol/L; P<0.0001]. In multivariate analysis, there was an increased risk of T2DM associated with copeptin levels (OR 1.312, 95% CI: 1.204-1.403; P<0.0001) after adjusting for possible confounders. After adjustment for possible confounders, serum copeptin levels were positively associated with the DR (odds ratio [OR], 1.117; 95% confidence interval [CI], 1.072-1.241; P<0.001) and DN (OR, 1.259; 95% CI, 1.198 1.323; P<0.001). Compared with the first quartile of serum copeptin levels, the ORs for DR and DN were as follows: second quartile, 1.19 (95% CI, 0.94-1.51, P=0.12) and 1.37 (95% CI, 0.78-2.37, P=0.28); third quartile, 1.61 (95% CI, 1.18 2.43, P=0.005) and 2.12 (95% CI, 1.32-3.27, P=0.003); fourth quartile, 2.83 (95% CI, 2.04-4.93; P<0.001) and 3.48 (95% CI, 1.77-7.03; P<0.001), respectively. CONCLUSIONS: Using a post-hoc analysis our data show that elevated serum levels of copeptin are associated with type 2 diabetes and diabetic complications in Chinese population, suggesting a potential role of the AVP system (copeptin) in the pathophysiology of diabetes. PMID- 27497686 TI - Trivalent chromium alleviates oleic acid induced steatosis in SMMC-7721 cells by decreasing fatty acid uptake and triglyceride synthesis. AB - Trivalent chromium [Cr(III)] has been shown as an essential trace element for human health. Previous studies depict that Cr(III) plays important roles in maintaining normal glucose and lipid metabolism, whereas its effect on the hepatic lipid metabolism is still unknown. In the present study, we investigated the effects and underlying mechanisms of Cr on hepatic steatosis induced by oleic acid (OA) in human hepatoma SMMC-7721 cells. Hepatic steatosis model was co administered with Cr. Indexes of lipid accumulation were determined and associated genes expression were analyzed. The data showed that OA could induce lipid accumulation and triglyceride (TG) content in SMMC-7721 cells, and significantly increase the expression of cluster of differentiation 36 (CD36) and diacylglycerol acyltransferase 2 (DGAT2). This steatosis effect of OA was ameliorated by Cr. The TG accumulation and up-regulation of CD36 and DGAT2 genes followed steatosis induction were inhibited by Cr. After the treatment of Cr, excessive intracellular OA content was also attenuated. Furthermore, Cr still performed inhibitory effect of DGAT2 expression at the presence of DGAT2 agonist or inhibitor, which indicated that the inhibitory effect of Cr on lipogenesis is associated with the downregulation of DGAT2 expression. These findings demonstrate that Cr alleviates hepatic steatosis via suppressing CD36 expression to prevent fatty acid uptake, as well as suppressing DGAT2 expression to inhibit TG synthesis. It suggests that CD36 and DGAT2 might become the novel drug targets for their properties in hepatic steatosis. Most importantly, Cr may be a potential anti-steatosis candidate to offer protective effects against liver damage. PMID- 27497685 TI - Diabetes and increased lipid peroxidation are associated with systemic inflammation even in well-controlled patients. AB - BACKGROUND: The effect of the interaction between type 2 diabetes and dyslipidemia on inflammation and lipid peroxidation (LPO) has not been assessed. AIM: To investigate whether diabetes coupled with dyslipidemia alters oxidative metabolism leading to increased LPO products and inflammatory status. METHODS: 100 patients were divided into four groups based upon diabetic and dyslipidemic status: poorly controlled diabetes with dyslipidemia (DM-PC/D), well-controlled diabetes with dyslipidemia (DM-WC/D), normoglycemic individuals with dyslipidemia (NG/D), and normoglycemic individuals without dyslipidemia (NG/ND). Plasma was evaluated for an LPO product (MDA), antioxidant levels and inflammatory cytokines. RESULTS: Diabetics presented significantly higher levels of LPO (p<0.05) and the DM-PC/D had higher levels of proinflammatory cytokines and MDA in the plasma in comparison with normoglycemics (p<0.05). Interestingly IL1-beta, IL-6, and TNF-alpha in DM-WC/D were not statistically different from those in DM PC/D. Normoglycemic individuals with dyslipidemia presented significantly increased levels of IL-6 and TNF-alpha when compared to normoglycemic without dyslipidemia (p<0.05). MDA levels were also positively correlated with the presence of DM complications (r=0.42, p<0.01). CONCLUSIONS: These findings show that dyslipidemia is associated with an increased inflammatory status, even in well-controlled diabetics and in normoglycemics. Our results suggest that lipid metabolism and peroxidation are important for the development of inflammation, which is elevated in several complications associated with diabetes. PMID- 27497687 TI - New gold carbene complexes as candidate anticancer agents. AB - Three structurally related gold(I) carbene complexes with bulky hydrophobic ligands i.e. 1-3 were investigated in solution for further consideration as candidate anticancer agents. Cytotoxic assays were subsequently conducted on bone marrow-derived preosteoclast cell line of human origin (FLG 29.1) and human colon cancer cells (HCT-116). A far greater cytotoxic activity was measured for compound 1 against HCT-116 cells compared to 2 and 3; conversely, all compounds were highly and similarly active against FLG 29.1 cells. Results obtained for the reaction of complexes 1 and 2 with RNase A documented the occurrence of a weak interaction with this model protein and the formation of a tiny amount of the corresponding adduct. Moreover, a certain reactivity of the complex 2 was also detected toward GSH. The general implications of the obtained results are discussed. PMID- 27497689 TI - An Extended Loop of the Pup Ligase, PafA, Mediates Interaction with Protein Targets. AB - Pupylation, the bacterial equivalent of ubiquitylation, involves the conjugation of a prokaryotic ubiquitin-like protein (Pup) to protein targets. In contrast to the ubiquitin system, where many ubiquitin ligases exist, a single bacterial ligase, PafA, catalyzes the conjugation of Pup to a wide array of protein targets. As mediators of target recognition by PafA have not been identified, it would appear that PafA alone determines pupylation target selection. Previous studies indicated that broad specificity and promiscuity are indeed inherent PafA characteristics that probably dictate which proteins are selected for degradation by the Pup-proteasome system. Nonetheless, despite the canonical role played by PafA in the Pup-proteasome system, the molecular mechanism that dictates target binding by PafA remains uncharacterized since the discovery of this enzyme about a decade ago. In this study, we report the identification of PafA residues involved in the binding of protein targets. Initially, docking analysis predicted the residues on PafA with high potential for target binding. Mutational and biochemical approaches subsequently confirmed these predictions and identified a series of additional residues located on an extended loop at the edge of the PafA active site. Mutating residues in this loop rendered PafA defective in the pupylation of a wide variety of protein targets but not in its catalytic mechanism, suggesting an important role for this extended loop in the binding of protein targets. As such, these findings pave the way toward an understanding of the molecular determinants that dictate the broad substrate specificity of PafA. PMID- 27497688 TI - Dimerization Controls Marburg Virus VP24-dependent Modulation of Host Antioxidative Stress Responses. AB - Marburg virus (MARV), a member of the Filoviridae family that also includes Ebola virus (EBOV), causes lethal hemorrhagic fever with case fatality rates that have exceeded 50% in some outbreaks. Within an infected cell, there are numerous host viral interactions that contribute to the outcome of infection. Recent studies identified MARV protein 24 (mVP24) as a modulator of the host antioxidative responses, but the molecular mechanism remains unclear. Using a combination of biochemical and mass spectrometry studies, we show that mVP24 is a dimer in solution that directly binds to the Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) to regulate nuclear factor (erythroid-derived 2)-like 2 (Nrf2). This interaction between Keap1 and mVP24 occurs through the Kelch interaction loop (K-Loop) of mVP24 leading to upregulation of antioxidant response element transcription, which is distinct from other Kelch binders that regulate Nrf2 activity. N-terminal truncations disrupt mVP24 dimerization, allowing monomeric mVP24 to bind Kelch with higher affinity and stimulate higher antioxidative stress response element (ARE) reporter activity. Mass spectrometry-based mapping of the interface revealed overlapping binding sites on Kelch for mVP24 and the Nrf2 proteins. Substitution of conserved cysteines, C209 and C210, to alanine in the mVP24 K-Loop abrogates Kelch binding and ARE activation. Our studies identify a shift in the monomer-dimer equilibrium of MARV VP24, driven by its interaction with Keap1 Kelch domain, as a critical determinant that modulates host responses to pathogenic Marburg viral infections. PMID- 27497690 TI - Substrates and physiological functions of secretase rhomboid proteases. AB - Rhomboids are conserved intramembrane serine proteases with widespread functions. They were the earliest discovered members of the wider rhomboid-like superfamily of proteases and pseudoproteases. The secretase class of rhomboid proteases, distributed through the secretory pathway, are the most numerous in eukaryotes, but our knowledge of them is limited. Here we aim to summarise all that has been published on secretase rhomboids in a concise encyclopaedia of the enzymes, their substrates, and their biological roles. We also discuss emerging themes of how these important enzymes are regulated. PMID- 27497691 TI - Predicting the 5-Year Risk of Biochemical Relapse After Postprostatectomy Radiation Therapy in >=PT2, pN0 Patients With a Comprehensive Tumor Control Probability Model. AB - PURPOSE: To fit the individual biochemical recurrence-free survival (bRFS) data from patients treated with postprostatectomy radiation therapy (RT) with a comprehensive tumor control probability (TCP) model. METHODS AND MATERIALS: Considering pre-RT prostate-specific antigen (PSA) as a surrogate of the number of clonogens, bRFS may be expressed as a function of dose-per-fraction-dependent radiosensitivity (alphaeff), the number of clonogens for pre-RT PSA = 1 ng/mL (C), and the fraction of patients who relapse because of clonogens outside the treated volume (K), assumed to depend (linearly or exponentially) on pre-RT PSA and Gleason score (GS). Data from 894 node-negative, >=pT2, pN0 hormone-naive patients treated with adjuvant (n=331) or salvage (n=563) intent were available: 5-year bRFS data were fitted grouping patients according to GS (<7:392, =7:383, >7:119). RESULTS: The median follow-up time, pre-RT PSA, and dose were 72 months, 0.25 ng/mL, and 66.6 Gy (range 59.4-77.4 Gy), respectively. The best-fit values were 0.23 to 0.26 Gy(-1) and 10(7) for alphaeff and C for the model considering a linear dependence between K and PSA. Calibration plots showed good agreement between expected and observed incidences (slope: 0.90-0.93) and moderately high discriminative power (area under the curve [AUC]: 0.68-0.69). Cross-validation showed satisfactory results (average AUCs in the training/validation groups: 0.66 0.70). The resulting dose-effect curves strongly depend on pre-RT PSA and GS. bRFS rapidly decreases with PSA: the maximum obtainable bRFS (defined as 95% of the maximum) declined by about 2.7% and 4.5% for each increment of 0.1 ng/mL for GS <7 and >=7, respectively. CONCLUSIONS: Individual data were fitted by a TCP model, and the resulting best-fit parameters were radiobiologically consistent. The model suggests that relapses frequently result from clonogens outside the irradiated volume, supporting the choice of lymph-node irradiation, systemic therapy, or both for specific subgroups (GS <7: PSA >0.8-1.0 ng/mL; GS >=7: PSA >0.3 ng/mL). Early RT should be preferred over delayed RT; the detrimental effect of PSA increase can never be fully compensated by increasing the dose, especially for patients with GS >=7. PMID- 27497692 TI - Y-family DNA polymerase-independent gap-filling translesion synthesis across aristolochic acid-derived adenine adducts in mouse cells. AB - Translesion DNA synthesis (TLS) operates when replicative polymerases are blocked by DNA lesions. To investigate the mechanism of mammalian TLS, we employed a plasmid bearing a single 7-(deoxyadenosine-N6-yl)-aristolactam I (dA-AL-I) adduct, which is generated by the human carcinogen, aristolochic acid I, and genetically engineered mouse embryonic fibroblasts. This lesion induces A to T transversions at a high frequency. The simultaneous knockouts of the Polh, Poli and Polk genes did not influence the TLS efficiency or the coding property of dA AL-I, indicating that an unknown DNA polymerase(s) can efficiently catalyze the insertion of a nucleotide opposite the adduct and subsequent extension. Similarly, knockout of the Rev1 gene did not significantly affect TLS. However, knockout of the Rev3l gene, coding for the catalytic subunit of polzeta, drastically suppressed TLS and abolished dA-AL-I to T transversions. The results support the idea that Rev1 is not essential for the cellular TLS functions of polzeta in mammalian cells. Furthermore, the frequency of dA-AL-I to T transversion was affected by a sequence context, suggesting that TLS, at least in part, contributes to the formation of mutational hot and cold spots observed in aristolochic acid-induced cancers. PMID- 27497694 TI - Standardization of administered activities in paediatric nuclear medicine: the EANM perspective. PMID- 27497693 TI - Anatomic validation of the lateral malleolus as a cutaneous marker for the distal insertion of the calcaneofibular ligament. AB - PURPOSE: An anatomic study was performed to confirm whether the lateral malleolus could serve as a simple and reproducible anatomic reference for the distal insertion of the calcaneofibular ligament (CFL). METHODS: Dissection was performed after placement of a Kirschner wire to simulate the calcaneal tunnel for the distal insertion of the CFL. The skin was penetrated 1 cm distal and posterior to the tip of the lateral malleolus. The main information recorded was the distance from the Kirschner wire to the centre of the distal insertion of the CFL. Other elements were noted (characteristics of the CFL, distance between the distal insertion of the CFL-peroneal tubercle, nerve or tendon injuries). RESULTS: Thirty ankles were dissected. The mean distance from the Kirschner wire to the centre of the distal insertion of the CFL was 2.4 +/- 1.8 mm. Only one case of peroneal injury was noted. The sural nerve was usually located a mean 1.8 +/- 1.1 mm from the Kirschner wire. The posterior tibial vascular pedicle was a mean 27.8 +/- 3.5 mm from the point of exit of the Kirschner wire. CONCLUSION: Using the lateral malleolus as the cutaneous reference for the distal insertion of the CFL seems to be more reliable than the pure arthroscopic technique. This study describes a percutaneous technique to obtain a calcaneal tunnel for distal insertion of the CFL. The sural nerve is at the greatest risk of injury with this technique and requires careful subcutaneous incision to prevent injury. This new percutaneous technique is less invasive than a purely arthroscopic technique and more accurately identifies the location of the tunnel. It can be used to do calcaneal tunnel in clinical practice during anatomic ligament reconstruction for chronic ankle instability. PMID- 27497695 TI - Orthorexia nervosa by proxy? PMID- 27497697 TI - Cross-cultural validation of the ICOAP and physical function short forms of the HOOS and KOOS in a multi-country study of patients with hip and knee osteoarthritis. AB - OBJECTIVE: To evaluate the internal consistency and construct validity of the Physical Function short-forms for the Hip and Knee Injury Osteoarthritis Outcome Scores (HOOS-PS/KOOS-PS) and the Intermittent and Constant Osteoarthritis Pain (ICOAP) in a nine country study of patients consulting for total hip or knee replacement (THR or TKR). METHODS: Patients completed HOOS-PS or KOOS-PS, ICOAP and Western Ontario and McMaster Universities' Osteoarthritis Index (WOMAC) pain and physical function subscales at their consultation visit. Internal consistency was calculated using Cronbach's alpha. The association of HOOS-PS/KOOS-PS and ICOAP with WOMAC pain and function subscales was calculated with Spearman correlation coefficients with 95% confidence intervals. RESULTS: HOOS-PS/KOOS-PS and ICOAP demonstrated high internal consistency across countries (alpha 0.75 0.96 (hip) and 0.76-0.95 (knee)). Both HOOS-PS and KOOS-PS demonstrated high correlations (0.76-0.90 and 0.75-0.91, respectively) with WOMAC function in all countries. ICOAP exhibited moderate to high correlations with WOMAC pain and function subscales (0.53-0.84 (hip) and 0.43-0.84 (knee)). CONCLUSION: The psychometric properties of the HOOS-PS/KOOS-PS, and ICOAP were maintained across all countries. PMID- 27497698 TI - Simulation as an ethical imperative and epistemic responsibility for the implementation of medical guidelines in health care. AB - Guidelines orient best practices in medicine, yet, in health care, many real world constraints limit their optimal realization. Since guideline implementation problems are not systematically anticipated, they will be discovered only post facto, in a learning curve period, while the already implemented guideline is tweaked, debugged and adapted. This learning process comes with costs to human health and quality of life. Despite such predictable hazard, the study and modeling of medical guideline implementation is still seldom pursued. In this article we argue that to systematically identify, predict and prevent medical guideline implementation errors is both an epistemic responsibility and an ethical imperative in health care, in order to properly provide beneficence, minimize or avoid harm, show respect for persons, and administer justice. Furthermore, we suggest that implementation knowledge is best achieved technically by providing simulation modeling studies to anticipate the realization of medical guidelines, in multiple contexts, with system and scenario analysis, in its alignment with the emerging field of implementation science and in recognition of learning health systems. It follows from both claims that it is an ethical imperative and an epistemic responsibility to simulate medical guidelines in context to minimize (avoidable) harm in health care, before guideline implementation. PMID- 27497696 TI - Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants. AB - The Kelch-like ECH associated protein 1 (Keap1) is a component of a Cullin3-based Cullin-RING E3 ubiquitin ligase (CRL) multisubunit protein complex. Within the CRL, homodimeric Keap1 functions as the Cullin3 adaptor, and importantly, it is also the critical component of the E3 ligase that performs the substrate recognition. The best-characterized substrate of Keap1 is transcription factor NF E2 p45-related factor 2 (Nrf2), which orchestrates an elaborate transcriptional program in response to environmental challenges caused by oxidants, electrophiles and pro-inflammatory agents, allowing adaptation and survival under stress conditions. Keap1 is equipped with reactive cysteine residues that act as sensors for endogenously produced and exogenously encountered small molecules (termed inducers), which have a characteristic chemical signature, reactivity with sulfhydryl groups. Inducers modify the cysteine sensors of Keap1 and impair its ability to target Nrf2 for ubiquitination and degradation. Consequently, Nrf2 accumulates, enters the nucleus and drives the transcription of its target genes, which encode a large network of cytoprotective proteins. Here we summarize the early studies leading to the prediction of the existence of Keap1, followed by the discovery of Keap1 as the main negative regulator of Nrf2. We then describe the available structural information on Keap1, its assembly with Cullin3, and its interaction with Nrf2. We also discuss the multiple cysteine sensors of Keap1 that allow for detection of a wide range of endogenous and environmental inducers, and provide fine-tuning and tight control of the Keap1/Nrf2 stress sensing response. PMID- 27497699 TI - Overexpression of tropomyosin receptor kinase A improves the survival and Schwann like cell differentiation of bone marrow stromal cells in nerve grafts for bridging rat sciatic nerve defects. AB - BACKGROUND AIMS: Bone marrow stromal cells (BMSCs) can differentiate into Schwann like cells in vivo and effectively promote nerve regeneration and functional recovery as the seed cells for peripheral nerve repair. However, the survival rate and neural differentiation rate of the transplanted BMSCs are very low, which would limit their efficacy. METHODS: In this work, rat BMSCs were infected by recombinant lentiviruses to construct tropomyosin receptor kinase A (TrkA) overexpressing BMSCs and TrkA-shRNA-expressing BMSCs, which were then used in transplantation for rat sciatic nerve defects. RESULTS: We showed that lentivirus mediated overexpression of TrkA in BMSCs can promote cell survival and protect against serum-starve-induced apoptosis in vitro. At 8 weeks after transplantation, the Schwann-like differentiated ratio of the existing implanted cells had reached 74.8 +/- 1.6% in TrkA-overexpressing BMSCs-laden nerve grafts, while 40.7 +/- 2.3% and 42.3 +/- 1.5% in vector and control BMSCs-laden nerve grafts, but only 8.2 +/- 1.8% in TrkA-shRNA-expressing BMSCs-laden nerve grafts. The cell apoptosis ratio of the existing implanted cells in TrkA-overexpressing BMSCs-laden nerve grafts was 16.5 +/- 1.2%, while 33.9 +/- 1.9% and 42.6 +/- 2.9% in vector and control BMSCs-laden nerve grafts, but 87.2 +/- 2.5% in TrkA-shRNA expressing BMSCs-laden nerve grafts. CONCLUSIONS: These results demonstrate that TrkA overexpression can improve the survival and Schwann-like cell differentiation of BMSCs and prevent cell death in nerve grafts, which may have potential implication in advancing cell transplantation for peripheral nerve repair. PMID- 27497700 TI - A robust, good manufacturing practice-compliant, clinical-scale procedure to generate regulatory T cells from patients with amyotrophic lateral sclerosis for adoptive cell therapy. AB - Regulatory T cells (Tregs) play a fundamental role in the maintenance of self tolerance and immune homeostasis. Defects in Treg function and/or frequencies have been reported in multiple disease models. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting upper and lower motor neurons. Compelling evidence supports a neuroprotective role for Tregs in this disease. Indeed, rapid progression in ALS patients is associated with decreased FoxP3 expression and Treg frequencies. Thus, we propose that strategies to restore Treg number and function may slow disease progression in ALS. In this study, we developed a robust, Good Manufacturing Practice (GMP)-compliant procedure to enrich and expand Tregs from ALS patients. Tregs isolated from these patients were phenotypically similar to those from healthy individuals but were impaired in their ability to suppress T-cell effector function. In vitro expansion of Tregs for 4 weeks in the presence of GMP-grade anti-CD3/CD28 beads, interleukin (IL)-2 and rapamcyin resulted in a 25- to 200-fold increase in their number and restored their immunoregulatory activity. Collectively, our data facilitate and support the implementation of clinical trials of adoptive therapy with ex vivo expanded and highly suppressive Tregs in patients with ALS. PMID- 27497701 TI - Expanded and armed natural killer cells for cancer treatment. AB - The capacity of natural killer (NK) cells to recognize and kill transformed cells suggests that their infusion could be used to treat cancer. It is difficult to obtain large numbers of NK cells ex vivo by exposure to cytokines alone but the addition of stimulatory cells to the cultures can induce NK cell proliferation and long-term expansion. Some of these methods have been validated for clinical grade application and support clinical trials testing feasibility and safety of NK cell administration. Early data indicate that ex vivo expansion of NK cells from healthy donors or from patients with cancer is robust, allowing multiple infusions from a single apheresis. NK cells can transiently expand in vivo after infusion. Allogeneic NK cells are not direct effectors of graft-versus-host disease but this may occur if donor NK cells are infused after allogeneic hematopoietic stem cell transplant, which may activate T cell alloreactivity. NK cells can be directed with antibodies, or engineered using either transient modification by electroporation of mRNA or prolonged gene expression by viral transduction. Thus, expanded NK cells can be armed with activating receptors that enhance their natural anti-tumor capacity or with chimeric antigen receptors that can redirect them towards specific tumor targets. They can also be induced to express cytokines that promote their autonomous growth, further supporting their in vivo expansion. With the implementation of these approaches, expanded and armed NK cells should ultimately become a powerful component of immunotherapy of cancer. PMID- 27497703 TI - Epilepsy comorbidities: Is clonazepam a friend or a foe? PMID- 27497702 TI - Proposed caudal appendage classification system; spinal cord tethering associated with sacrococcygeal eversion. AB - INTRODUCTION: The most commonly used classification system for caudal appendages (aka human tails) dates from the 1980s and classifies appendages (tails) as either true tails or pseudotails. Advances in neuroimaging since the 1980s, however, as well as an ever-increasing number of reported cases, have made this system outdated. Sacrococcygeal eversion is a condition in which the distal sacral and coccygeal vertebrae are curved in a retroverted rather than anteverted direction. It can give rise to one type of caudal appendage. Sacrococcygeal eversion has never been associated with spinal cord tethering in any previously published reports. METHODS: We reviewed all cases of caudal appendage encountered by pediatric neurosurgeons at Children's Hospital Colorado since 2000 in which the appendage would be classified as a true tail by the most commonly used system mentioned above. We also reviewed cases of sacrococcygeal eversion encountered since 2000 by the same group of pediatric neurosurgeons. We searched the hospital electronic medical record system for additional appendages using the terms "caudal appendage" and "persistent human tail." RESULTS: We found 9 "true" tails (as classified by the most commonly used system). All 9 were associated with tethering or possible tethering of the spinal cord and 6 were associated with a low-lying conus medullaris. There were 8 cases of sacrococcygeal eversion, including 2 associated with Apert or Pfeiffer syndrome and fibroblast growth factor receptor 2 (FGFR2) mutations; these have previously been reported. There was a single case of sacrococcygeal eversion associated with Goldenhar or Turner syndrome; the former was associated with a potentially tethering lesion. Four cases of sacrococcygeal eversion not associated with any known syndrome were also found; two of these were associated with tethering or potentially tethering lesions. CONCLUSIONS: Most so-called true tails are likely cutaneous markers for spinal dysraphism and spinal cord tethering and are not remnants of the embryonic human tail. Sacrococcygeal eversion can be associated with spinal cord tethering. Based on our cases, and on review of the literature, we devised a five-category classification system for caudal appendages: (1) soft-tissue caudal appendages, (2) bony caudal appendages, (3) bony caudal prominences, (4) true tails, and (5) "other" caudal appendages. PMID- 27497704 TI - Storage and transportation of Prochilodus lineatus (Characiformes) sperm prior to cryopreservation. AB - In this study we compared post-thaw quality of P. lineatus sperm frozen shortly after collection, with sperm frozen after dilution and transportation, and up to 6h from collection. From each sperm sample (n=10 males) five aliquots were taken. One aliquot was diluted in the freezing medium (1 sperm:8 glucose:1 methyl glycol) and frozen ~20min after collection in the field (control), while the other four aliquots were transported to the laboratory where freezing took place 3 or 6h after collection. From the transported aliquots, two were diluted 1:4 in glucose solution before transportation (diluted samples), while the other two were kept undiluted until freezing (undiluted samples). Thus the five treatments were: control, undiluted-3h, diluted-3h, undiluted-6h and diluted-6h. Post-thaw sperm was evaluated for membrane integrity, motility rate and velocities (curvilinear=VCL; average path=VAP; straight line=VSL). Post-thaw membrane integrity did not differ among the five treatments (48-60% intact sperm). Sperm motility rate was similar (P>0.05) between control (64%) and undiluted samples (60-62%) and higher (P<0.05) than that in diluted samples (35-45%), regardless the time after collection when freezing took place. Velocities were higher in control and in undiluted-3h samples (VCL of 254-265MUm/s, VAP of 219-244MUm/s and VSL of 134-147MUm/s) than in diluted samples or samples frozen 6h after collection. P. lineatus sperm can be transported/shipped to the laboratory without decreasing its suitability for cryopreservation. Sperm should be kept undiluted during storage and be frozen within 3h. PMID- 27497705 TI - Peptidergic signaling in the crab Cancer borealis: Tapping the power of transcriptomics for neuropeptidome expansion. AB - The crab Cancer borealis has long been used as a model for understanding neural control of rhythmic behavior. One significant discovery made through its use is that even numerically simple neural circuits are capable of producing an essentially infinite array of distinct motor outputs via the actions of locally released and circulating neuromodulators, the largest class being peptides. While much work has focused on elucidating the peptidome of C. borealis, no investigation has used in silico transcriptome mining for peptide discovery in this species, a strategy proven highly effective for identifying neuropeptides in other crustaceans. Here, we mined a C. borealis neural transcriptome for putative peptide-encoding transcripts, and predicted 200 distinct mature neuropeptides from the proteins deduced from these sequences. The identified peptides include isoforms of allatostatin A, allatostatin B, allatostatin C, CCHamide, crustacean cardioactive peptide, crustacean hyperglycemic hormone, diuretic hormone 31 (DH31), diuretic hormone 44 (DH44), FMRFamide-like peptide, GSEFLamide, HIGSLYRamide, insulin-like peptide (ILP), intocin, leucokinin, neuroparsin, pigment dispersing hormone, pyrokinin, red pigment concentrating hormone, short neuropeptide F and SIFamide. While some of the predicted peptides were known previously from C. borealis, most (159) are new discoveries for the species, e.g., the isoforms of CCHamide, DH31, DH44, GSEFLamide, ILP, intocin and neuroparsin, which are the first members of these peptide families identified from C. borealis. Collectively, the peptides predicted here approximately double the peptidome known for C. borealis, and in so doing provide an expanded platform from which to launch new investigations of peptidergic neuromodulation in this species. PMID- 27497706 TI - Mitochondria and the insect steroid hormone receptor (EcR): A complex relationship. AB - The actions of the insect steroid molting hormones, ecdysteroids, on the genome of target cells has been well studied, but little is known of their extranuclear actions. We previously showed in Rhodnius prolixus that much of the ecdysteroid receptor (EcR) resides in the cytoplasm of various cell types and undergoes shuttling between nucleus and cytoplasm with circadian periodicity, possibly using microtubules as tracks for translocation to the nucleus. Here we report that cytoplasmic EcR appears to be also involved in extranuclear actions of ecdysteroids by association with the mitochondria. Western blots of subcellular fractions of brain lysates revealed that EcR is localized in the mitochondrial fraction, indicating an intimate association of EcR with mitochondria. Confocal laser microscopy and immunohistochemistry using anti-EcR revealed abundant co localization of EcR with mitochondria in brain neurons and their axons, especially intense in the subplasmalemmal region, raising the possibility of EcR involvement in mitochondrial functions in subplasmalemmal microdomains. When mitochondria are dispersed by disruption of microtubules with colchicine, EcR remains associated with mitochondria showing strong receptor association with mitochondria. Treatment in vitro with ecdysteroids of brains of developmentally arrested R. prolixus (containing neither ecdysteroids nor EcR) induces EcR and abundant co-localization with mitochondria in neurons, concurrently with a sharp increase of the mitochondrial protein COX 1, suggesting involvement of EcR in mitochondrial function. These findings align EcR with various vertebrate steroid receptors, where actions of steroid receptors on mitochondria are widely known and suggest that steroid receptors across distant phyla share similar functional attributes. PMID- 27497707 TI - Gender and gonadal maturity stage identification of captive Chinese sturgeon, Acipenser sinensis, using ultrasound imagery and sex steroids. AB - Long lifespan and late maturation make it difficult to establish gamete maturity and breeding age of captive endangered Chinese sturgeon, Acipenser sinensis. This greatly handicaps timely breeding and future conservation stocking efforts. We used ultrasound imagery and sex steroids to determine the gender and gonadal maturity stage of captive Chinese sturgeon (age, 10-17years old). The echogenicity of the reproductive organs and the respective morphology of the gonads were described and two quantitative parameters po (proportion of the ovary to the entire reproductive organs) and d (thickness of the reproductive organs) were measured to characterize sex and maturity stage of Chinese sturgeon. Females were accordingly placed fish into several categories: FII (FII-, FII, FII+), FIII (FIII, FIII+) and FIV (FIV, FIV+) and FVI and males as MII, MIII, MIV, MV and MVI. The accuracy of gender and maturity stage determination provided by ultrasonographic methods was 72.7% for FII- ovary (n=11) and 76.2% for MII testis (n=42). Accuracy of sex and maturity determination using only serum sex steroid of testosterone (T) and estradiol-17beta (E2) was low (58-73%, depending on maturity stage). However, when the two methods were used together, accuracy increased sharply, especially for immature (II stage) females. In summary, of 151 Chinese sturgeon, whose sex and maturity stage were independently confirmed, 88.1% (n=133), 62.9% (n=95), and 96.7% (n=146) were successfully sexed and staged using ultrasound, sex steroids, or both methods, respectively. The results provide reliable non-invasive techniques for determining sex and gonadal maturation of captive Chinese sturgeon. These methods can track individual gonad characteristics over multi-year reproductive cycles, which will assist captive broodstock management, artificial reproduction, and future conservation stocking. PMID- 27497708 TI - G-CSF prevents caspase 3 activation in Schwann cells after sciatic nerve transection, but does not improve nerve regeneration. AB - Exogenous granulocyte-colony stimulating factor (G-CSF) has emerged as a drug candidate for improving the outcome after peripheral nerve injuries. We raised the question if exogenous G-CSF can improve nerve regeneration following a clinically relevant model - nerve transection and repair - in healthy and diabetic rats. In short-term experiments, distance of axonal regeneration and extent of injury-induced Schwann cell death was quantified by staining for neurofilaments and cleaved caspase 3, respectively, seven days after repair. There was no difference in axonal outgrowth between G-CSF-treated and non-treated rats, regardless if healthy Wistar or diabetic Goto-Kakizaki (GK) rats were examined. However, G-CSF treatment caused a significant 13% decrease of cleaved caspase 3-positive Schwann cells at the lesion site in healthy rats, but only a trend in diabetic rats. In the distal nerve segments of healthy rats a similar trend was observed. In long-term experiments of healthy rats, regeneration outcome was evaluated at 90days after repair by presence of neurofilaments, wet weight of gastrocnemius muscle, and perception of touch (von Frey monofilament testing weekly). The presence of neurofilaments distal to the suture line was similar in G-CSF-treated and non-treated rats. The weight ratio of ipsi-over contralateral gastrocnemius muscles, and perception of touch at any time point, were likewise not affected by G-CSF treatment. In addition, the inflammatory response in short- and long-term experiments was studied by analyzing ED1 stainable macrophages in healthy rats, but in neither case was any attenuation seen at the injury site or distal to it. G-CSF can prevent caspase 3 activation in Schwann cells in the short-term, but does not detectably affect the inflammatory response, nor improve early or late axonal outgrowth or functional recovery. PMID- 27497709 TI - Group III mGluR8 negatively modulates TRPA1. AB - Several lines of evidence indicate group III metabotropic glutamate receptors (mGluRs) have systemic anti-hyperalgesic effects. We hypothesized this could occur through modulation of TRP channels on nociceptors. This study used a multifaceted approach to examine the interaction between group III mGluRs (mGluR8) and transient receptor potential ankyrin 1 (TRPA1) on cutaneous nociceptors in rats. Ca2+ imaging studies demonstrated co-localization and functional coupling of TRPA1 and mGluR8, since 1MUM (S)-3,4 dicarboxyphenylglycine (DCPG) (mGluR8 agonist) significantly reduced Ca2+ mobilization produced by 30MUM mustard oil (MO), a TRPA1 agonist. Behavioral studies demonstrated that 10mM MO produced mechanical hypersensitivity when topically applied to the hind paw, significantly decreasing paw withdrawal threshold (PWT) from 15g to 6g. However, administration of 30MUM DCPG prior to 10mM MO reversed this hypersensitivity such that PWT was not significantly different from baseline. At the single-fiber level, compared to vehicle, 30MUM MO significantly increased nociceptor activity and decreased mechanical threshold. However, 30MUM DCPG reversed both of these MO-induced effects. Furthermore, DCPG significantly reduced the number of MO-induced mechanically sensitive fibers. Inhibition of protein kinase A (PKA) using Rp-cyclic 3',5'-hydrogen phosphorothioate adenosine triethylammonium salt (RpCAMPS) (PKA inhibitor, 1 and 10MUM) significantly reduced MO-induced Ca2+ mobilization. Taken together, these results show that group III mGluRs negatively modulate TRPA1 activity on cutaneous nociceptors. Furthermore, it is likely that this modulation occurs intracellularly at the level of the cAMP/PKA pathway. This study demonstrates that group III agonists may be effective in the treatment of mechanical hypersensitivity which can develop as a result of inflammation, nerve injury, chemotherapy and other disease states. PMID- 27497711 TI - Computational Cardiology - A New Discipline of Translational Research. PMID- 27497710 TI - Successful lysis in massive pulmonary embolism with thrombus entrapped in PFO. PMID- 27497712 TI - Post-marketing safety evaluation of the intravenous anti-influenza neuraminidase inhibitor peramivir: A drug-use investigation in patients with high risk factors. AB - Peramivir, the only injectable anti-influenza neuraminidase inhibitor medically available in Japan at present, is considered first-line treatment in patients with high risk factors for influenza exacerbation. We conducted a drug-use investigation of peramivir in inpatients with high risk factors (old age, pregnancy, and underlying disease such as chronic respiratory disease) from January 2010 to March 2013. Data of 772 patients from 124 facilities across Japan were collected; peramivir's safety in 770 patients and effectiveness in 688 patients were examined. In total, 412 adverse events were observed in 219 patients (28.4%). Of these, 155 events were adverse drug reactions (ADRs) observed in 98 patients (12.7%). Major ADRs (>=2%) were increased aspartate aminotransferase (5.1%), increased alanine aminotransferase (3.8%) and decreased white blood cell count (2.5%). Fourteen serious ADRs were observed in 12 patients (1.6%). All serious ADRs were resolved or improved except for two events for which outcomes were unknown. Multivariate analyses revealed that ADR incidences were significantly associated with these four backgrounds of patients: medical history, no influenza vaccination, renal impairment and other infection(s). With regard to its effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration, which was the same as in other previous surveillance studies. This surveillance study indicated the safety of peramivir in the treatment of influenza inpatients with high risk factors under routine clinical settings. PMID- 27497713 TI - Development of a seminar on medical professionalism accompanying the dissection course. AB - INTRODUCTION: Medical professionalism is an increasingly important issue in medical education. The dissection course represents a profound experience for undergraduate medical students, which may be suitable to address competencies such as self-reflection and professional behavior. MATERIAL AND METHODS: Based on a needs assessment, a seminar on medical professionalism was developed to parallel the dissection course. The conceptual framework for the teaching intervention is experiential learning. Specific learning goals and an interview guideline were formulated. After a pilot run, peer-teaching was introduced. RESULTS: Over three terms (winter 2012/13, 2013/14, 2014/15), an average of 129 students voluntarily participated in the seminar, corresponding to 40% of the student cohort. The evaluation (n=38) shows a majority of students agreeing that the seminar offers support with this extraordinary situation in general and also that the seminar helps them to become first impressions on how to cope with death and dying in their later professional life as a doctor, and, that it also provides them the means to reflect upon their own coping mechanisms. CONCLUSION: Although not yet implemented as an obligatory course, the seminar is appreciated and positively evaluated. Medical professionalism is an implicit aspect of the dissection course. To emphasize its importance, a teaching intervention to explicitly discuss this topic is advisable. PMID- 27497714 TI - Chondral ossification centers next to dental primordia in the human mandible: A study of the prenatal development ranging between 68 to 270mm CRL. AB - The human mandible is said to arise from desmal ossification, which, however, is not true for the entire body of the mandible: Meckel's cartilage itself is prone to ossification, at least its anterior part in the canine and incisor region. Also, within the coronoid and in the condylar processes there are cartilaginous cores, which eventually undergo ossification. Furthermore, there are a number of additional single cartilaginous islets arising in fetuses of 95mm CRL and more. They are located predominantly within the bone at the buccal sides of the brims of the dental compartments, mostly in the gussets between the dental primordia. They become wedge-shaped or elongated with a diameter of around 150-500MUm and were also found in older stages up to 225mm CRL, which was the oldest specimen used in this study. This report is intended to visualize these single cartilaginous islets histologically and in 3-D reconstructions in stereoscopic images. Although some singular cartilaginous tissue within the mandible may be remains of the decaying Meckel's cartilage, our 3-D reconstructions clearly show that the aforementioned cartilaginous islets are independent thereof, as can be derived from their separate locations within the mandibular bone. The reasons that lead to these cartilaginous formations have remained unknown so far. PMID- 27497715 TI - Newer Therapies for Amyloid Cardiomyopathy. AB - The heart and the kidneys are the most commonly involved organs in systemic amyloidosis. Cardiac involvement is associated with an increased morbidity, treatment intolerance, and poorer overall survival. The most common types of amyloidosis that are associated with cardiac involvement include light chain (AL) amyloidosis and transthyretin (TTR) amyloidosis (both mutant and wild type). The traditional first-line treatment for AL amyloidosis includes alkylator-based chemotherapy or high-dose melphalan followed by autologous stem cell transplantation (ASCT). Novel agents, including proteasome inhibitors, immunomodulators, and monoclonal antibodies, have shown promising activity in both frontline and relapsed settings. Orthotopic heart transplantation (OHT) followed by ASCT has led to superior outcomes compared to OHT alone. Orthotopic liver transplantation (OLT) is the first-line treatment for TTR amyloidosis. However, progression of cardiac amyloidosis after OLT is often noted due to deposition of wild TTR. Combined OLT and OHT also has a role in treatment and leads to superior outcomes in carefully selected candidates. Pharmacologic agents, including diflunisal, tafamidis, small interfering ribonucleic acid, and doxycycline, have shown promising activity in stabilizing TTR from misfolding into fibrils and are being actively investigated. Best supportive care and management of heart failure symptoms with diuretics are a mainstay of treatment in all cardiac amyloidosis subtypes. Robust data on the benefit of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, or beta blockers in amyloid cardiomyopathy is lacking. PMID- 27497716 TI - A randomized and blinded comparison of qPCR and NGS-based detection of aneuploidy in a cell line mixture model of blastocyst biopsy mosaicism. AB - PURPOSE: A subset of preimplantation stage embryos may possess mosaicism of chromosomal constitution, representing a possible limitation to the clinical predictive value of comprehensive chromosome screening (CCS) from a single biopsy. However, contemporary methods of CCS may be capable of predicting mosaicism in the blastocyst by detecting intermediate levels of aneuploidy within a trophectoderm biopsy. This study evaluates the sensitivity and specificity of aneuploidy detection by two CCS platforms using a cell line mixture model of a mosaic trophectoderm biopsy. METHODS: Four cell lines with known karyotypes were obtained and mixed together at specific ratios of six total cells (0:6, 1:5, 2:4, 3:3, 4:2, 5:1, and 6:0). A female euploid and a male trisomy 18 cell line were used for one set, and a male trisomy 13 and a male trisomy 15 cell line were used for another. Replicates of each mixture were prepared, randomized, and blinded for analysis by one of two CCS platforms (quantitative polymerase chain reaction (qPCR) or VeriSeq next-generation sequencing (NGS)). Sensitivity and specificity of aneuploidy detection at each level of mosaicism was determined and compared between platforms. RESULTS: With the default settings for each platform, the sensitivity of qPCR and NGS were not statistically different, and 100 % specificity was observed (no false positives) at all levels of mosaicism. However, the use of previously published custom criteria for NGS increased sensitivity but also significantly decreased specificity (33 % false-positive prediction of aneuploidy). CONCLUSIONS: By demonstrating increased false-positive diagnoses when reducing the stringency of predicting an abnormality, these data illustrate the importance of preclinical evaluation of new testing paradigms before clinical implementation. PMID- 27497717 TI - Towards physics of neural processes and behavior. AB - Behavior of biological systems is based on basic physical laws, common across inanimate and living systems, and currently unknown physical laws that are specific for living systems. Living systems are able to unite basic laws of physics into chains and clusters leading to new stable and pervasive relations among variables (new physical laws) involving new parameters and to modify these parameters in a purposeful way. Examples of such laws are presented starting from the tonic stretch reflex. Further, the idea of control with referent coordinates is formulated and merged with the idea of hierarchical control and the principle of abundance. The notion of controlled stability of behaviors is linked to the idea of structured variability, which is a common feature across living systems and actions. The explanatory and predictive power of this approach is illustrated with respect to the control of both intentional and unintentional movements, the phenomena of equifinality and its violations, preparation to quick actions, development of motor skills, changes with aging and neurological disorders, and perception. PMID- 27497719 TI - Special Issue on the Adolescent Brain. PMID- 27497718 TI - The organizing actions of adolescent gonadal steroid hormones on brain and behavioral development. AB - Adolescence is a developmental period characterized by dramatic changes in cognition, risk-taking and social behavior. Although gonadal steroid hormones are well-known mediators of these behaviors in adulthood, the role gonadal steroid hormones play in shaping the adolescent brain and behavioral development has only come to light in recent years. Here we discuss the sex-specific impact of gonadal steroid hormones on the developing adolescent brain. Indeed, the effects of gonadal steroid hormones during adolescence on brain structure and behavioral outcomes differs markedly between the sexes. Research findings suggest that adolescence, like the perinatal period, is a sensitive period for the sex specific effects of gonadal steroid hormones on brain and behavioral development. Furthermore, evidence from studies on male sexual behavior suggests that adolescence is part of a protracted postnatal sensitive period that begins perinatally and ends following adolescence. As such, the perinatal and peripubertal periods of brain and behavioral organization likely do not represent two discrete sensitive periods, but instead are the consequence of normative developmental timing of gonadal hormone secretions in males and females. PMID- 27497720 TI - Influence of chronic endurance exercise training on conduit artery retrograde and oscillatory shear in older adults. AB - PURPOSE: With aging, there tends to be an increase in retrograde and oscillatory shear in peripheral conduit arteries of humans. Whether the increase in shear rate is due to the aging process or an effect of a less active lifestyle that often accompanies aging is unknown. Therefore, we examined whether chronic endurance exercise training attenuates conduit artery retrograde and oscillatory shear in older adults. METHODS: Brachial and common femoral artery mean blood velocities and diameter were determined via Doppler ultrasound under resting conditions, and shear rate was calculated in 13 young (24 +/- 2 years), 17 older untrained (66 +/- 3 years), and 16 older endurance exercise-trained adults (66 +/ 7 years). RESULTS: Brachial artery retrograde (-9.1 +/- 6.4 vs. -12.6 +/- 9.4 s( 1); P = 0.35) and oscillatory (0.14 +/- 0.08 vs. 0.14 +/- 0.08 arbitrary units; P = 0.99) shear were similar between the older trained and untrained groups, whereas brachial artery retrograde and oscillatory shear were greater in older untrained compared to young adults (-5.0 +/- 3.4, 0.08 +/- 0.05 s(-1) arbitrary units, P = 0.017 and 0.048, respectively). There was no difference between the young and older trained brachial retrograde (P = 0.29) and oscillatory (P = 0.07) shear. Common femoral artery retrograde (-6.3 +/- 2.9 s(-1)) and oscillatory (0.21 +/- 0.08 arbitrary units) shear were reduced in older trained compared to the older untrained group (-10.4 +/- 4.1 and 0.30 +/- 0.09 s(-1) arbitrary units, both P = 0.005 and 0.006, respectively), yet similar to young adults (-7.1 +/- 3.5 and 0.19 +/- 0.06 s(-1) arbitrary units, P = 0.81 and 0.87, respectively). CONCLUSION: Our results suggest that chronic endurance exercise training in older adults ameliorates retrograde and oscillatory shear rate patterns, particularly in the common femoral artery. PMID- 27497721 TI - Preparation of core-shell magnetic molecular imprinted polymer with binary monomer for the fast and selective extraction of bisphenol A from milk. AB - In the current study, a new strategy for the extraction of bisphenol A (BPA) from milk has been employed by using surface-imprinted core-shell magnetic beads, prepared by the reversible addition-fragmentation chain transfer (RAFT) polymerization. In order to obtain highly selective recognition cavities, an enhanced imprinting method based on binary functional monomers, e.g. 4 vinylpyridine (4-VP) and beta-cyclodextrin (beta-CD), was chosen for BPA imprinting. The morphological and magnetic properties of the Fe3O4-MIP beads were characterized by Transmission Electron Microscopy (TEM), Fourier Transform Infrared (FT-IR) Spectroscopy, Thermogravimetric Analysis (TGA), and Vibrating Sample Magnetometer (VSM). The characterization results suggested that MIP was synthesized evenly on Fe3O4-SiO2 surface. The adsorption experiments revealed that Fe3O4-MIPs showed better extraction capacity and selectivity toward BPA and its analogues than the non-imprinted polymers (NIPs). The saturation capacity of Fe3O4-MIP was 17.98mg/g. In milk samples, the present method displayed a lower the detection thresholds, down to 3.7MUg/L. The recoveries of BPA in milk samples for three concentrations were found to be within 99.21%, 98.07% and 97.23%, respectively to three concentrations: 1.0MUmol/L, 10.0mol/L, 100.0MUmol/L. Thus, the MIPs can be used for remove BPA in milk samples. PMID- 27497722 TI - Enantioselective determination of citrulline and ornithine in the urine of d amino acid oxidase deficient mice using a two-dimensional high-performance liquid chromatographic system. AB - Two-dimensional high-performance liquid chromatographic (2D-HPLC) and 2D-HPLC mass spectrometric (2D-HPLC-MS) systems have been designed and developed for the determination of the citrulline (Cit) and ornithine (Orn) enantiomers. Several d amino acids have already been identified as novel physiologically active molecules and biomarkers, and the enantioselective evaluation of the amounts, distributions and metabolisms of non-proteinogenic amino acids gain as well increasing interest. In the present study, highly selective analytical methods were developed using a capillary monolithic ODS column (0.53mm i.d. x 1000mm) for the reversed-phase separation of the target analytes from the matrix compounds in the first dimension, and a narrowbore-Pirkle type enantioselective column, KSAACSP-105S (1.5mm i.d. x 250mm), was used for the enantiomer separation in the second dimension. The amino acids were analyzed after pre-column derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) and detected by the fluorescence detector and MS. The systems were applied to the urine of d-amino acid oxidase (DAO) deficient B6DAO- mice and control C57BL mice to evaluate the presence and metabolism of the Cit and Orn enantiomers in mammals. As a result, all of the 4 target enantiomers (d-Cit, l-Cit, d-Orn, l-Orn) were found in the urine of both strains. The %D value of Cit (d-Cit/Cit*100) increased about 3-fold in the urine of the DAO deficient mice and that of Orn also tended to increase with the DAO deficiency. These results were definitely confirmed by a 2D-HPLC-MS detection system. Further investigations about the biological significance of these d-isomers are currently ongoing. PMID- 27497723 TI - Comparison of the homogeneity of mRNAs encoding SFRP5, FZD4, and Fosl1 in post injury intervals: Subcellular localization of markers may influence wound age estimation. AB - The inter-group heterogeneity and intra-group homogeneity of relative expression are very necessary when the mRNA were used to determine wound age accurately in forensic medicine. The aim of this study was to assess the intra-group homogeneity of SFRP5, FZD4 and Fosl1 mRNAs in post-injury intervals. The corresponding proteins show different subcellular locations. A total of 78 Sprague-Dawley rats were divided into control and contusion groups. At 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, or 48 h (n = 6 per group) after contusion (under anesthesia by chloral hydrate intraperitoneally), the rats were sacrificed using a lethal dose of pentobarbital, and samples of the injured muscles were collected. The raw Ct values of SFRP5, FZD4, and Fosl1 mRNAs were obtained using real-time PCR. After normalized to RPL13 mRNA levels, the coefficient of variation (CV) and the relative average deviation (d%) of each normalized Ct, and their relative expression levels, were calculated in each post-injury interval. Two methods were applied to compare the homogeneity of the three genes. First, each gene was given a score based on its CV value in each post-injury interval. Then, the sum of the 13 scores was calculated; a low sum indicated high homogeneity. Second, the 13 calculated CVs or d%s were used as raw data, which was described as the mean +/- SD. Based on this mean +/- SD, a CV of the CVs and a d% of the d%s were calculated to represent the variation; a low value indicated high homogeneity. The sum of the variability of FZD4 mRNA was lower than those of the SFRP5 and Fosl1 mRNAs, consistent with the results that the FZD4 mRNA had the lowest mean, the smallest CV of all CVs, and the smallest d% of all d%s, among the three genes. In conclusion, these data indicated that mRNA encoding membranous FZD4 was likely to be more homogeneous than those encoding SFRP5 and Fosl1 within post-injury intervals. PMID- 27497724 TI - The Care Programme Approach, sexual violence and clinical practice in mental health. AB - INTRODUCTION: Research in Sexual Assault Referral Centres has shown that 40% of those attending are known to mental health services. The question we posed in this study was to what extent do mental health services know about this group? This was a pertinent question to ask as in 2008 the Department of Health (DH) amended the Care Programme Approach (CPA) to include a question on sexual abuse/violence as part of the overall assessment. AIMS: To assess the extent to which Mental health Trusts were implementing DH guidance on the CPA in relation to assessment of sexual violence and abuse. METHOD: 1. Freedom of Information (FOI) requests were sent to all Mental Health Trusts. 2. The Information base at the Health and Social Care Information Centre (HSCIC) was interrogated as Trusts can make returns on this CPA question, however it is not mandatory. RESULTS: 1. The FOI requests revealed that: only 66% of staff were trained to 'ask the question' (range 35-100%) and only five out of 53 Trusts audited whether the question was asked. 2. The HSCIC data revealed that in 2014/15 there were 335,727 people in the CPA in England and there was a record in only 17% of cases of the question being asked. Over half (57%) of the 69 providers who did not submit any information on the indicator in 2014/15 as well as, for those 30 providers who did submit information, the data field was only 41% complete. CONCLUSIONS: The impetus for 'asking the question' first established in 2008 with the establishment of eight pilot training programmes, has been lost. It is clear that Trusts are not training adequate number of staff nor are they returning useable data to HSCIC. If 40% of people attending SARCs are known to mental health services we suspect that few staff in mental health trusts known much about such a referral. Research shows convincingly that sexual violence and abuse plays a clear role in the aetiology of mental health disorders. A history of such violence/abuse should be always established (or otherwise). PMID- 27497725 TI - The accuracy of body mass prediction for elderly specimens: Implications for paleoanthropology and legal medicine. AB - Different practices in paleoanthropology and legal medicine raise questions concerning the robustness of body mass (BM) prediction. Integrating personal identification from body mass estimation with skeleton is not a classic approach in legal medicine. The originality of our study is the use of an elderly sample in order to push prediction methods to their limits and to discuss about implications in paleoanthropology and legal medicine. The aim is to observe the accuracy of BM prediction in relation to the body mass index (BMI, index of classification) using five femoral head (FH) methods and one shaft (FSH) method. The sample is composed of 41 dry femurs obtained from dissection where age (c. 82 years) and gender are known, and weight (c. 59.5 kg) and height are measured upon admission to the body leg service. We show that the estimation of the mean BM of the elderly sample is not significantly different to the real mean BM when the appropriate formula is used for the femoral head diameter. In fact, the best prediction is obtained with the McHenry formula (1992), which was based on a sample with an equivalent average mass to that of our sample. In comparison, external shaft diameters, which are known to be more influenced by mechanical stimuli than femoral head diameters, yield less satisfactory results with the McHenry formula (1992) for shaft diameters. Based on all the methods used and the distinctive selected sample, overestimation (always observed with the different femoral head methods) can be restricted to 1.1%. The observed overestimation with the shaft method can be restricted to 7%. However, the estimation of individual BM is much less reliable. The BMI has a strong impact on the accuracy of individual BM prediction, and is unquestionably more reliable for individuals with normal BMI (9.6% vs 16.7% for the best prediction error). In this case, the FH method is also the better predictive method but not if we integrate the total sample (i.e., the FSH method is better with more varied BMI). Finally, the estimation of the mean BM of a sample can be used with more confidence compared to the estimation of individual BM. The former is very useful in an evolutionary perspective whereas the latter should be used in keeping with the information gathered on the studied specimen in order to reduce prediction errors. Finally, the BM estimation can be a parameter to consider for personal identification. PMID- 27497726 TI - Consideration of interaction between nanoparticles and food components for the safety assessment of nanoparticles following oral exposure: A review. AB - Nanoparticles (NPs) are increasingly used in food, and the toxicity of NPs following oral exposure should be carefully assessed to ensure the safety. Indeed, a number of studies have shown that oral exposure to NPs, especially solid NPs, may induce toxicological responses both in vivo and in vitro. However, most of the toxicological studies only used NPs for oral exposure, and the potential interaction between NPs and food components in real life was ignored. In this review, we summarized the relevant studies and suggested that the interaction between NPs and food components may exist by that 1) NPs directly affect nutrients absorption through disruption of microvilli or alteration in expression of nutrient transporter genes; 2) food components directly affect NP absorption through physico-chemical modification; 3) the presence of food components affect oxidative stress induced by NPs. All of these interactions may eventually enhance or reduce the toxicological responses induced by NPs following oral exposure. Studies only using NPs for oral exposure may therefore lead to misinterpretation and underestimation/overestimation of toxicity of NPs, and it is necessary to assess the synergistic effects of NPs in a complex system when considering the safety of NPs used in food. PMID- 27497727 TI - The immune responses in juvenile rockfish, Sebastes schlegelii for the stress by the exposure to the dietary lead (II). AB - The aim of this study was to evaluate the lead toxic effects on the stress parameters and immune responses of Sebastes schlegelii. Juvenile rockfish, S. schlegelii (mean length 14.2+/-1.9cm, and mean weight 57.3+/-5.2g) were exposed for 4 weeks with the different levels of dietary lead (Pb(2+)) at 0, 30, 60, 120 and 240mg/L. The plasma cortisol and heat shock protein 70 was evaluated as stress indicators. The plasma cortisol of S. schlegelii was significantly increased in response to the dietary lead exposure over 60mg/kg at 2 weeks. After 4 weeks, the significant increase in the plasma cortisol was observed at 30 and 60mg/kg, but the level was decreased over 120mg/kg. The heat shock protein 70 of S. schlegelii was also notably elevated over 60mg/kg for 4 weeks. In the immune response, the immunoglobulin M of S. schlegelii was considerably increased over 120mg/kg for 4 weeks. A significant increase was observed in lysozyme activity. The plasma lysozyme activity of S. schlegelii was elevated over 120mg/kg after 2 weeks and 60mg/kg after 4 weeks, and kidney lysozyme activity was also increased at 240mg/kg after 2 weeks and over 120mg/kg after 4 weeks. The results indicate that dietary Pb exposure can cause a significant stress and immune stimulation of S. schlegelii. PMID- 27497728 TI - Zidovudine and isoniazid induced liver toxicity and oxidative stress: Evaluation of mitigating properties of silibinin. AB - HIV/AIDS patients are more prone for opportunistic TB infections and they are administered the combined regimen of anti-retroviral drug zidovudine (AZT) and isoniazid (INH) for therapy. However, AZT+INH treatment has been documented to induce injury and remedial measures to prevent this adversity are not clearly defined. Silibinin (SBN) is a natural hepatoprotective principle isolated from medicinal plant Silybum marianum and is currently used for therapy of various liver diseases. This study investigate the hepatotoxic potentials of AZT alone, INH alone and AZT+INH treatments and the mitigating potentials of SBN against these drugs induced toxic insults of liver in rats. Separate groups of rats (n=6 in each group) were administered AZT alone (50mg/kg b.w.), INH alone (25mg/kg, b.w.), AZT+INH (50mg/kg, b.w. and 25mg/kg, b.w.), SBN alone (100mg/kg, b.w.) and SBN+AZT+INH daily for sub-chronic period of 45days orally. The control rats received saline/propylene glycol. INH alone and AZT+INH-induced parenchymal cell injury and cholestasis of liver was evidenced by highly significant increase in the activities of marker enzymes (aspartate and alanine transaminase, alkaline phosphatase, argino succinic acid lyase), bilirubin, protein, oxidative stress parameters (lipid peroxidation, superoxide dismutase, catalase, reduced glutathione, vitamins C and E) and membrane bound ATPases were evaluated in serum/liver tissue homogenates. Histopathological studies show ballooning degradation, inflammatory lesions, lipid deposition and hydropic changes in the liver tissue. All the above biochemical and pathological changes induced by AZT+INH treatments were mitigated in rats receiving SBN simultaneously with these hepatotoxins, indicating its hepatoprotective and antioxidant potentials against AZT+INH-induced hepatotoxicity. The moderate hepatoprotective and oxidant potentials of SBN could be due to its low bioavailability and this deficiency could be prevented by supplementation of phosphatidylcholines and studies are warranted on these lines to improve the therapeutic efficiency of SBN. PMID- 27497729 TI - beta-eudesmol, a sesquiterpene from Teucrium ramosissimum, inhibits superoxide production, proliferation, adhesion and migration of human tumor cell. AB - Reactive oxygen species are well-known mediators of various biological responses. Recently, new homologues of the catalytic subunit of NADPH oxidase have been discovered in non phagocytic cells. These new homologues (Nox1-Nox5) produce low levels of superoxides compared to the phagocytic homologue Nox2/gp91phox. In this study we examined the effect of beta-eudesmol, a sesquiterpenoid alcohol isolated from Teucrium ramosissimum leaves, on proliferation, superoxide anion production, adhesion and migration of human lung (A549) and colon (HT29 and Caco-2) cancer cell lines. Proliferation of tumor cells was inhibited by beta-eudesmol. It also significantly inhibited superoxide production in A549 cells. Furthermore, beta eudesmol inhibited adhesion and migration of A549 and HT29 cell. These results demonstrate that beta-eudesmol may be a novel anticancer agent for the treatment of lung and colon cancer by different ways: by inhibition of superoxide production or by blocking proliferation, adhesion and migration. PMID- 27497730 TI - A metabolic profiling analysis of the nephrotoxicity of acyclovir in rats using ultra performance liquid chromatography/mass spectrometry. AB - Acyclovir (ACV) exposure is a common cause of acute kidney injury (AKI). The toxicity mechanism of ACV has always been a matter of debate. The present study investigated into the time-effect relationship and dose-effect relationship of ACV-induced nephrotoxicity in rats using metabonomics. Twenty-four rats were randomly divided into four groups: a 0.9% NaCl solution group, and 100, 300, and 600mg/kg ACV-treated groups; the ACV or vehicle solution was administered with a single intravenous injection. Urine was collected at different time periods (12h before administration, and 0-6h, 7-12h, and 13-24h after administration). Routine urinalysis was conducted by a urine automatic analyzer. Renal markers, including urine urea nitrogen, urine creatinine, and urinary N-acetyl-beta-d glucosaminidase (NAG) activity, were determined using established protocols. Urinary metabolites were evaluated using ultra performance liquid chromatography/mass spectrometry (UPLC/MS). In the ACV-treated rats, increased levels of protein (PRO), occult blood (BLD), white blood cell (WBC), and NAG activity in urine were observed, while the urine creatinine and urea nitrogen levels showed a decrease compared with the control. Moreover, urine metabolites significantly changed after the treatment with ACV, and all the effects induced by ACV were dose-time dependent. Finally, 4 metabolites (guanine, 4 guanidinobutyric acid, creatinine, and urea) were identified, which can be used for further research on the mechanism of ACV-induced nephrotoxicity. PMID- 27497732 TI - Composite graft aortic root reconstruction: Reproducible, durable, and uncomplicated. PMID- 27497731 TI - Historical perspectives of The American Association for Thoracic Surgery: Richard A. Jonas. PMID- 27497733 TI - Functional induction of P-glycoprotein efflux pump by phenyl benzenesulfonamides: Synthesis and biological evaluation of T0901317 analogs. AB - N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1 (trifluoromethyl)ethyl]phenyl]-benzenesulfonamide (T0901317, 6) is a potent activator of pregnane-X-receptor (PXR), which is a nuclear receptor controlling P gp expression. Herein, we aimed to investigate P-gp induction activity of T0901317 and establish its structure-activity relationship. T0901317 along with a series of N-triazolyl-methylene-linked benzenesulfonamides were synthesized and screened for P-gp induction activity using a rhodamine-123 based efflux assay in the P-gp overexpressing human adenocarcinoma LS-180 cells, wherein several compounds showed potent P-gp induction activity at 5 MUM. Treatment with benzene sulphonamides led to the decrease in intracellular accumulation of a fluorescent P-gp substrate rhodamine-123 up to 48% (control 100%). In the western-blot studies, T0901317 (6) and its triazole linked analog 26e at 5 MUM displayed induction of P-gp expression in LS180 cells. These compounds were non-toxic in LS 180 and human neuroblastoma SH-SY5Y cells (IC50 > 50 MUM). The compound 26e showed significant P-gp induction even at 0.3 MUM, indicating an excellent therapeutic window. These results clearly indicate promise of this class of compounds as potential agents to enhance amyloid-beta clearance in Alzheimers patients. PMID- 27497734 TI - Attention, reward, and inhibition: symptomatic features of ADHD and issues for offenders in the criminal justice system. AB - Although the relationship between criminal activity and ADHD has been heavily studied, this paper reviews a largely neglected area of academic discourse: how symptoms of ADHD that often contribute to offending behavior may also potentially create further problems for offenders with ADHD after they come into contact with the criminal justice system and pilot their way through the legal process. The main symptoms of ADHD that are primarily connected to criminal offending are examined and contextualized with respect to diagnosed offenders' experiences with the justice system. Symptoms of ADHD, specifically reward deficiency, behavioral inhibition, and attention deficits, may affect whether individuals will be successful in their experiences in court, with probation, and during incarceration. This is especially true for individuals whose ADHD diagnoses are unknown to the criminal justice system or have never been formally diagnosed. Actors in the criminal justice need to be aware of the symptomatic features and behavioral patterns of offenders with ADHD in order to recognize and identify these offenders, and correspondingly, to refer them to mental health services. Recognizing that at least some of an offender's behavior may be related to symptoms of ADHD will help the criminal justice system better provide recommendations regarding sentencing, probation, and treatment provisions, as well as better ensure that offenders with ADHD have a more successful and just experience in their interactions with the criminal justice system. PMID- 27497735 TI - Effects of insulin therapy on porosity, non-enzymatic glycation and mechanical competence in the bone of rats with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus increases skeletal fragility; however, the contributing mechanisms and optimal treatment strategies remain unclear. We studied the effects of diabetes and insulin therapy on non-enzymatic glycation (NEG), cortical porosity (Ct.Po) and biomechanics of the bone tissue in Zucker Diabetic Fatty (ZDF) rats. Eleven-week old ZDF diabetic and non-diabetic rats were given insulin to achieve glycaemic control or vehicle seven days per week over twelve weeks (insulin dose adapted individually 0.5 international units (IU) at week 1 to 13.0IU at week 12). The right femora were excised, micro-CT scanned, and tested in 3-point bending to measure biomechanics. NEG of the midshaft was determined from bulk fluorescence. Diabetes led to increased NEG (+50.1%, p=0.001) and Ct.Po (+22.9%, p=0.004), as well as to reduced mechanical competence (max. stress: -14.2%, p=0.041, toughness: -29.7%, p=0.016) in the bone tissue. NEG and Ct.Po both correlated positively to serum glucose (NEG: R(2)=0.41, p<0.001, Ct.Po: R(2)=0.34, p=0.003) and HbA1c (NEG: R(2)=0.42, p<0.001, Ct.Po: R(2)=0.28, p=0.008) levels, while NEG correlated negatively with bone biomechanics (elastic modulus: R(2)=0.21, p=0.023, yield stress: R(2)=0.17, p=0.047). Twelve weeks of insulin therapy had no significant effect on NEG or Ct.Po, and was unable to improve the mechanical competence of the bone tissue. A reduction of mechanical competence was observed in the bone tissue of the diabetic rats, which was explained in part by increased collagen NEG. Twelve weeks of insulin therapy did not alter NEG, Ct.Po or bone biomechanics. However, significant correlations between NEG and serum glucose and HbA1c were observed, both of which were reduced with insulin therapy. This suggests that a longer duration of insulin therapy may be required to reduce the NEG of the bone collagen and restore the mechanical competence of diabetic bone. PMID- 27497736 TI - Sclerostin, cardiovascular disease and mortality: a systematic review and meta analysis. AB - BACKGROUND AND AIM: Chronic kidney disease mineral and bone disorder (CKD-MBD) is associated with increased morbidity and mortality. Several cross-sectional studies investigated the association of serum sclerostin levels with mortality and vascular calcification. We aimed to investigate the effect of sclerostin on cardiovascular events (CVE), all-cause/cardiovascular mortality and vascular calcification in patients with CKD through systematic review and meta-analysis. The primary outcome was the association between sclerostin level and development of fatal and nonfatal CVE and all-cause mortality. MATERIALS AND METHODS: A literature search was performed using electronic databases Medline Ovid/Medline, PubMed/Medline, EMBASE and ISI Web of Science. Extracted hazard ratios from the included study protocols were pooled separately using the random-effects model (DerSimonian Laird). The equivalent z test was performed for each pooled HR, and if p < 0.05 it was considered statistically significant. RESULTS: In our final analysis, we included nine observational prospective studies involving 1788 patients (minimum 91 and maximum 673 patients). For the all-cause mortality, three studies with 503 patients showed that sclerostin levels were not significantly associated with all-cause mortality risk (HR = 1.01, 95 % CI 0.99 1.03, p = 0.16; heterogeneity chi 2 = 12.24, I 2 = 84 %, p = 0.002). For cardiovascular mortality, two studies with 412 patients showed that sclerostin levels were not significantly associated with cardiovascular mortality risk (HR = 1.03, 95 % CI 0.99-1.07, p = 0.17; heterogeneity chi 2 = 10.74, I 2 = 91 %, p = 0.001). CONCLUSION: Although the studies are mostly small in size, heterogeneous and have conflicting results, we have demonstrated that serum sclerostin levels were not associated with all-cause and cardiovascular mortality. PMID- 27497737 TI - The effect of hemodialysis on balance measurements and risk of fall. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) have increased risk of falls and fall-related complications. Other than aging and factors related to chronic kidney disease, treatment of hemodialysis may also contribute to this increased risk. The aim of this study was to demonstrate the impairment of balance after a session of hemodialysis with a quantitative assessment and reveal an increased fall risk that would possibly be related to treatment of hemodialysis for patients on maintenance hemodialysis. METHODS: Fifty-six patients with ESRD on chronic hemodialysis program and 53 healthy individuals were involved in this study. Fall Index percentages were calculated, and fall risk categories were determined for all patients and healthy controls using Tetrax posturography device (Sunlight Medical Ltd Israel). The patient group was evaluated twice for balance, before and after a routine session of hemodialysis. RESULTS: Fall Index scores of healthy controls were lower than that of ESRD patients (p = 0.001). In the patient group, we found the mean Fall Index to be significantly higher at the post-dialysis assessment compared to the pre-dialysis assessment (p = 0.003). The number of patients with high risk of falling also increased at the post-dialysis assessment yet the difference did not reach significance. Fall Index was correlated with the increase in age only at the pre dialysis balance measurement (p = 0.038). Patients with better dialysis adequacy had significantly lower Fall Index scores than the others at the pre-dialysis balance measurement (p = 0.004). The difference was not significant at the post dialysis measurement. CONCLUSIONS: In the current study, we evaluated the balance of ESRD patients before and after a routine session of hemodialysis treatment. This is the first study to investigate the effect of hemodialysis on balance, using an electronic posturographic balance system. We found the Fall Index score to be significantly higher after hemodialysis, indicating a negative effect of hemodialysis on postural stability. As expected, our data showed an increased Fall Index score correlated with the increase in age both in ESRD patients and in healthy controls. However, the correlation with age was not observed for the patient group at the post-dialysis balance measurement. We might conceive that young patients with ESRD are also prone to fall risk after a session of hemodialysis. Methods that provide quantitative assessment for fall risk could be rather beneficial for high-risk populations such as patients on maintenance hemodialysis. PMID- 27497739 TI - Short-day signals are crucial for the induction of anthocyanin biosynthesis in Begonia semperflorens under low temperature condition. AB - The leaves of Begonia semperflorens accumulate anthocyanins and turn red in autumn in sub-temperate areas. This induction of anthocyanin biosynthesis in autumn has been attributed to the effects of low temperature, but the effects of different light regimes on this process are still being debated. In the present work, short days were found to be necessary for anthocyanin biosynthesis at low temperature. Under the same low-temperature conditions, Begonia seedlings grown under the short-day condition accumulated more carbohydrates and abscisic acid (ABA), which both induce anthocyanin biosynthesis. However, fewer carbohydrates and more gibberellin (GA) accumulated under the long-day conditions to maintain growth, which blocked anthocyanin biosynthesis and resulted in a lack of increases in the activities of dihydroflavonol 4-reductase (DFR) and flavonoid-3 O-glucosyl transferase (UFGT). Consequently, carbon flux, which was altered due to the blockade of anthocyanin synthesis, was channelled into the production of quercetin and phenolic acids but not lignin. PMID- 27497738 TI - Assortative mating can impede or facilitate fixation of underdominant alleles. AB - Underdominant mutations have fixed between divergent species, yet classical models suggest that rare underdominant alleles are purged quickly except in small or subdivided populations. We predict that underdominant alleles that also influence mate choice, such as those affecting coloration patterns visible to mates and predators alike, can fix more readily. We analyze a mechanistic model of positive assortative mating in which individuals have n chances to sample compatible mates. This one-parameter model naturally spans random mating (n=1) and complete assortment (n->infinity), yet it produces sexual selection whose strength depends non-monotonically on n. This sexual selection interacts with viability selection to either inhibit or facilitate fixation. As mating opportunities increase, underdominant alleles fix as frequently as neutral mutations, even though sexual selection and underdominance independently each suppress rare alleles. This mechanism allows underdominant alleles to fix in large populations and illustrates how life history can affect evolutionary change. PMID- 27497740 TI - Salt stress induces differential regulation of the phenylpropanoid pathway in Olea europaea cultivars Frantoio (salt-tolerant) and Leccino (salt-sensitive). AB - Olive tree (Olea europaea L.) is an important crop in the Mediterranean Basin where drought and salinity are two of the main factors affecting plant productivity. Despite several studies have reported different responses of various olive tree cultivars to salt stress, the mechanisms that convey tolerance and sensitivity remain largely unknown. To investigate this issue, potted olive plants of Leccino (salt-sensitive) and Frantoio (salt-tolerant) cultivars were grown in a phytotron chamber and treated with 0, 60 and 120mM NaCl. After forty days of treatment, growth analysis was performed and the concentration of sodium in root, stem and leaves was measured by atomic absorption spectroscopy. Phenolic compounds were extracted using methanol, hydrolyzed with butanol-HCl, and quercetin and kaempferol quantified via high performance liquid-chromatography electrospray-mass spectrometry (HPLC-ESI-MS) and HPLC-q-Time of Flight-MS analyses. In addition, the transcripts levels of five key genes of the phenylpropanoid pathway were measured by quantitative Real-Time PCR. The results of this study corroborate the previous observations, which showed that Frantoio and Leccino differ in allocating sodium in root and leaves. This study also revealed that phenolic compounds remain stable or are strongly depleted under long-time treatment with sodium in Leccino, despite a strong up-regulation of key genes of the phenylpropanoid pathway was observed. Frantoio instead, showed a less intense up-regulation of the phenylpropanoid genes but overall higher content of phenolic compounds. These data suggest that Frantoio copes with the toxicity imposed by elevated sodium not only with mechanisms of Na+ exclusion, but also promptly allocating effective and adequate antioxidant compounds to more sensitive organs. PMID- 27497741 TI - Overexpression of CHMP7 from rapeseed and Arabidopsis causes dwarfism and premature senescence in Arabidopsis. AB - Endosomal sorting complexes required for transport (ESCRT) are well known in mammalians and yeast and plays an essential role in the formation of multi vesicular bodies. Accumulating evidence has shown that ESCRT proteins contribute to proper plant development. CHMP7 (charged multi-vesicular body protein 7) is an ESCRT-III-related protein and functions in the endosomal sorting pathway in humans. However, its function in plants has not been explored in detail. In this study, we isolate the putative homolog of CHMP7 from rapeseed, BnCHMP7, which contains eight exons and encodes a protein consisting of 423 amino acid residues. Compared with the wild-type, overexpression of BnCHMP7 in Arabidopsis disturbs plant growth and decreases seed yield. Moreover, the transgenic plants also display early leaf senescence and hypersensitivity to dark treatment due to defects in autophagic degradation. Further study showed that BnCHMP7 is highly expressed in leaves and that YFP-BnCHMP7 is predominantly localized in endosome. Compared with human CHMP7, we found that BnCHMP7 not only interacts with ESCRT III subunits SNF7.2 (CHMP4B), but also with VPS2.2 and CHMP1B. As expected, microarray analysis revealed that the expression of ESCRT transport genes is significantly affected. Additionally, the expression of some genes that are involved in senescence, protein synthesis and protein degradation is also altered in BnCHMP7-overexpressing plants. Taken together, BnCHMP7 encodes an endosome localized protein, which causes dwarfism and leaf senescence as an ESCRT-III related component. PMID- 27497742 TI - Agrobacterium rhizogenes rolB gene affects photosynthesis and chlorophyll content in transgenic tomato (Solanum lycopersicum L.) plants. AB - Insertion of Agrobacterium rhizogenes rolB gene into plant genome affects plant development, hormone balance and defence. However, beside the current research, the overall transcriptional response and gene expression of rolB as a modulator in plant is unknown. Transformed rolB tomato plant (Solanum lycopersicum L.) cultivar Tondino has been used to investigate the differential expression profile. Tomato is a well-known model organism both at the genetic and molecular level, and one of the most important commercial food crops in the world. Through the construction and characterization of a cDNA subtracted library, we have investigated the differential gene expression between transgenic clones of rolB and control tomato and have evaluated genes specifically transcribed in transgenic rolB plants. Among the selected genes, five genes encoding for chlorophyll a/b binding protein, carbonic anhydrase, cytochrome b6/f complex Fe-S subunit, potassium efflux antiporter 3, and chloroplast small heat-shock protein, all involved in chloroplast function, were identified. Measurement of photosynthesis efficiency by the level of three different photosynthetic parameters (Fv/Fm, rETR, NPQ) showed rolB significant increase in non photochemical quenching and a, b chlorophyll content. Our results point to highlight the role of rolB on plant fitness by improving photosynthesis. PMID- 27497743 TI - Pulmonary Rehabilitation as a Mechanism to Reduce Hospitalizations for Acute Exacerbations of COPD: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Acute exacerbation of COPD (AECOPD) has a significant impact on health-care use, including physician visits and hospitalizations. Previous studies and reviews have shown that pulmonary rehabilitation (PR) has many benefits, but the effect on hospitalizations for AECOPD is inconclusive. METHODS: A literature search was carried out to find studies that might help determine, using a meta-analysis, the impact of PR on AECOPD, defined as unscheduled or emergency hospitalizations and ED visits. Cohort studies and randomized controlled trials (RCTs) reporting hospitalizations for AECOPD as an outcome were included. Meta-analyses compared hospitalization rates between eligible PR recipients and nonrecipients before and after rehabilitation. RESULTS: Eighteen studies were included in the meta-analysis. Results from 10 RCTs showed that the control groups had a higher overall rate of hospitalization than did the PR groups (control groups: 0.97 hospitalizations/patient-year; 95% CI, 0.67-1.40; PR groups: 0.62 hospitalizations/patient-year; 95% CI, 0.33-1.16). Five studies compared admission numbers in the 12 months before and after rehabilitation, finding a significantly higher admission rate before compared with after (before: 1.24 hospitalizations/patient-year; 95% CI, 0.66-2.34; after: 0.47 hospitalizations/patient-year; 95% CI, 0.28-0.79). The pooled result of three cohort studies found that the reference group had a lower admission rate compared with the PR group (0.18 hospitalizations/patient-year; 95% CI, 0.11-0.32 for reference group vs 0.28 hospitalizations/patient-year; 95% CI, 0.25-0.32 for the PR group). CONCLUSIONS: Although results from RCTs suggested that PR reduces subsequent admissions, pooled results from the cohort studies did not, likely reflecting the heterogeneous nature of individuals included in observational research and the varying standard of PR programs. PMID- 27497744 TI - A new concept and finite-element study on dental bond strength tests. AB - OBJECTIVE: Numerous bond strength tests have been performed on dental adhesion experiments. Yet, the validity of these bond strength tests is controversial due to the name (e.g., "shear" or "tensile") may not reflect to the true and complete stress situation, i.e., assumed uniform shear or uniaxial tensile conditions. Thus, the aim of this study was to simulate and compare the stress distribution of and between shear bond strength (SBS), tensile bond strength (TBS), mold enclosed shear bond strength (ME-SBS) and de novo lever-induced mold-enclosed shear bond strength (LIME-SBS) tests. METHODS: 3-Dimensional finite element method (FEM) was used on the dental resin-bonded surfaces (i.e., titanium alloy, dentine and porcelain) interphased with adhesive layer (thickness 5MUm) to simulate the mechanical tests. For ME-SBS, both polycarbonate and stainless steel molds were used. For LIME-SBS, stainless steel levers and molds with lengths of 3mm, 6mm, 12mm, 15mm and 18mm were used. The applied loads on these models were 50N, 100N and 200N. RESULTS: De novo LIME-SBS test was the most optimal configuration to evaluate "shear" bond strength of adhesive in regards to providing significantly high and uniform shear stress as well as eliminating tensile stress at the interface. The conventional SBS test created very high tensile stress at the load area, whereas the TBS created optimal tensile stress but shear stress indeed co-exist. The ME-SBS test could also eliminate some of the tensile stress. Similar stress distributions pattern appeared on the Ti adhesive models, the dentine-adhesive models and porcelain-adhesive models. SIGNIFICANCE: None of the bond strength tests could give purely "shear" or "tensile" bond strength, but LIME-SBS seems to be the best model to evaluate the bond strength under true "shear" mode. PMID- 27497745 TI - Mineralogenic characteristics of osteogenic lineage-committed human dental pulp stem cells following their exposure to a discoloration-free calcium aluminosilicate cement. AB - OBJECTIVES: An experimental discoloration-free calcium aluminosilicate cement has been developed with the intention of maximizing the beneficial attributes of tricalcium silicate cements and calcium aluminate cements. The present study examined the effects of this experimental cement (Quick-Set2) on the mineralogenic characteristics of osteogenic lineage-committed human dental pulp stem cells (hDPSCs), by comparing the cellular responses with a commercially available tricalcium silicate cement (white mineral trioxide aggregate (ProRoot((r)) MTA); WMTA). METHODS: The osteogenic potential of hDPSCs exposed to the cements was examined using qRT-PCR for osteogenic gene expressions, Western blot for osteogenic-related protein expressions, alkaline phosphatase enzyme activity, Alizarin red S staining, Fourier transform infrared spectroscopy and transmission electron microscopy of extracellular calcium deposits. RESULTS: Results of the six assays indicated that osteogenic differentiation of hDPSCs was significantly enhanced after exposure to the tricalcium silicate cement or the experimental calcium aluminosilicate cement, with the former demonstrating better mineralogenic stimulation capacity. SIGNIFICANCE: The better osteogenic stimulating effect of the tricalcium silicate cement on hDPSCs may be due to its relatively higher silicate content, or higher OH(-) and Ca(2+) release. Further investigations with the use of in vivo animal models are required to validate the potential augmenting osteogenic effects of the experimental discoloration-free calcium aluminosilicate cement. PMID- 27497746 TI - The zebrafish goosepimples/myosin Vb mutant exhibits cellular attributes of human microvillus inclusion disease. AB - Microvillus inclusion disease (MVID) is a life-threatening enteropathy characterised by malabsorption and incapacitating fluid loss due to chronic diarrhoea. Histological analysis has revealed that enterocytes in MVID patients exhibit reduction of microvilli, presence of microvillus inclusion bodies and intestinal villus atrophy, whereas genetic linkage analysis has identified mutations in myosin Vb gene as the main cause of MVID. In order to understand the cellular basis of MVID and the associated formation of inclusion bodies, an animal model that develops ex utero and is tractable genetically as well as by microscopy would be highly useful. Here we report that the intestine of the zebrafish goosepimples (gsp)/myosin Vb (myoVb) mutant shows severe reduction in intestinal folds - structures similar to mammalian villi. The loss of folds is further correlated with changes in the shape of enterocytes. In striking similarity with MVID patients, zebrafish gsp/myoVb mutant larvae exhibit microvillus atrophy, microvillus inclusions and accumulation of secretory material in enterocytes. We propose that the zebrafish gsp/myoVb mutant is a valuable model to study the pathophysiology of MVID. Furthermore, owing to the advantages of zebrafish in screening libraries of small molecules, the gsp mutant will be an ideal tool to identify compounds having therapeutic value against MVID. PMID- 27497747 TI - A framework for optimal whole-sample histological quantification of neurite orientation dispersion in the human spinal cord. AB - BACKGROUND: The complexity of fibre distributions in tissues is an important microstructural feature, now measurable in vivo by magnetic resonance imaging (MRI) through orientation dispersion (OD) indices. OD metrics have gained popularity for the characterisation of neurite morphology, but they still lack systematic validation. This paper demonstrates a framework for whole-sample histological quantification of OD in spinal cord specimens, potentially useful for validating MRI-derived OD estimates. NEW METHOD: Our methodological framework is based on (i) sagittal sectioning; (ii) Palmgren's silver staining; (iii) structure tensor (ST) analysis; (iv) directional statistics. Novel elements are the data-driven optimisation of the spatial scale of ST analysis, and a new multivariate, weighted directional statistical approach for anisotropy-informed quantification of OD. RESULTS: Palmgren's silver staining of sagittal spinal cord sections provides robust visualisation of neuronal elements, enabling OD quantification. The choice of spatial scale of ST analysis influences OD values, and weighted directional statistics provide OD maps with high contrast-to-noise. Segmentation of neurites prior to OD quantification is recommended. COMPARISON WITH EXISTING METHODS: Our framework can potentially provide OD even in demyelinating diseases, where myelin-based histology is not suitable. As compared to conventional univariate approaches, our multivariate weighted directional statistics improve the contrast-to-noise of OD maps and more accurately describe the distribution of ST metrics. CONCLUSIONS: Our framework enables practical whole-specimen characterisation of OD in the spinal cord. We recommend tuning the scale of ST analysis for optimal OD quantification, as well as neurite segmentation and weighted directional statistics, of which examples are provided herein. PMID- 27497748 TI - Identification of small molecules that improve ATP synthesis defects conferred by Leber's hereditary optic neuropathy mutations. AB - Inherited mitochondrial complex I mutations cause blinding Leber's hereditary optic neuropathy (LHON), for which no curative therapy exists. A specific biochemical consequence of LHON mutations in the presence of trace rotenone was observed: deficient complex I-dependent ATP synthesis (CIDAS) and mitochondrial O2 consumption, proportional to the clinical severity of the three primary LHON mutations. We optimized a high-throughput assay of CIDAS to screen 1600 drugs to 2, papaverine and zolpidem, which protected CIDAS in LHON cells concentration dependently. TSPO and cAMP were investigated as protective mechanisms, but a conclusive mechanism remains to be elucidated; next steps include testing in animal models. PMID- 27497750 TI - Thermodynamics of complex coacervation. AB - Isothermal titration calorimetry has routinely been used to understand the thermodynamic characteristics of complexation and coacervation. Most commonly, built-in models that assume independent binding sites have been employed in these studies. However, the non-covalent nature of interactions and steric effects accompanying macromolecules require (i) usage of new models such as overlapping binding sites and Satake-Yang's two-state binding models and (ii) reformed interpretations of the data as two-stage structuring. Fitting data with these models, forces driving the interaction of polyelectrolytes with oppositely charged polyelectrolytes, surfactants, and proteins have been identified as electrostatics and/or counterion release with possible contributions from hydrogen bonding and hydrophobic interactions. Additionally, for surfactant polyelectrolyte coacervation, ITC signals indicated separate regions for formation of polymer-induced micelles and free micelles. Regardless of the type of the coacervation system, thermodynamics of coacervation is affected by the following parameters: pH and ionic strength of the medium, charge density, molecular weight of the polyelectrolyte, concentration, and mixing order of macroions. Lastly, we present a brief comparison between ITC on one hand and surface plasmon resonance or capillary electrophoresis on the other regarding their application in coacervation. PMID- 27497749 TI - Children's white blood cell counts in relation to developmental exposures to methylmercury and persistent organic pollutants. AB - BACKGROUND: To explore possible markers of developmental immunotoxicity, we prospectively examined 56 children to determine associations between exposures to methylmercury and persistent organic pollutants since birth and the comprehensive differential counts of white blood cells (WBC) at age 5 years. MATERIALS AND METHODS: Extended differential count included: neutrophils, eosinophils, basophils, lymphocytes (includingT cells, NK cells, and B cells), and monocytes. Organochlorine compounds (OCs) including polychlorinated biphenyls (PCBs) and pesticides, five perfluoroalkyl substances (PFASs), and total mercury (Hg) were measured in maternal (n=56) and children's blood at 18 months (n=42) and 5 years (n=54). We constructed latent functions for exposures at three different ages using factor analyses and applied structural equation models adjusted for covariates. RESULTS: Prenatal mercury exposure was associated with depleted total WBC, especially for lymphocytes, where a one standard deviation (SD) increase in the exposure was associated with a decrease by 23% SD (95% CI: -43, -4) in the cell count. Prenatal exposure to OCs was marginally associated with decreases in neutrophil counts. In contrast, the 5-year PFASs concentrations were associated with higher basophil counts (B=46% SD, 95% CI: 13, 79). Significantly reduced subpopulations of lymphocytes such as B cells, CD4-positive T helper cells and CD4 positive recent thymic emigrants may suggest cellular immunity effects and dysregulation of T-cell mediated immunity. CONCLUSION: Developmental exposure to environmental immunotoxicants appears to have different impacts on WBC counts in childhood. PMID- 27497751 TI - A novel LAMP2 mutation associated with severe cardiac hypertrophy and microvascular remodeling in a female with Danon disease: a case report and literature review. AB - BACKGROUND: Danon disease (DD) is a rare disorder characterized by cardiomyopathy, intellectual disability, and proximal myopathy. It is caused by mutations in the LAMP2 gene on X chromosome. Female patients most often present with late-onset cardiomyopathy and slow disease progression, but early-onset cases with unfavorable prognosis have been reported. CASE REPORT: We describe the clinical, pathological, and molecular features of a novel LAMP2 c.453delT mutation in a female patient with severe hypertrophic cardiomyopathy, Wolff Parkinson White (WPW) syndrome and rapid progression to heart failure, requiring heart transplant. Immunohistochemical analysis of LAMP2 in the explanted heart revealed a mosaic pattern of distribution, with discrete clusters of either stained or unstained cardiac myocytes, the latter being more frequent in the septum. These findings paralleled X chromosome inactivation within the myocardium. Interestingly, multiple foci of microscarring were found on histology in the Left Ventricle (LV) free wall and septum, in a close spatial relationship with remodeling and severe stenosis of intramural coronary arterioles. CONCLUSIONS: Our findings suggest that several features may contribute to the early and severe cardiac phenotype in female DD patients. The type of mutation may account for the early disease onset, while both the inhomogeneous distribution of LAMP2 loss and the presence of microvascular remodeling may be determinant in the rapid progression to heart failure. PMID- 27497752 TI - Lumbar artery branches coursing vertically over the intervertebral discs of the lower lumbar spine: an anatomic study. AB - PURPOSE: Bleeding from the lumbar artery is a potential complication during the transpsoas approach to the lower lumbar intervertebral discs. In this anatomic study, the morphological relationships between the branches of the lumbar artery and the lower intervertebral disc were investigated to assess the risk of injury to the branches of the lumbar segmental arteries. METHODS: We studied 88 sites (86 lumbar arteries) at the third and fourth lumbar vertebrae bilaterally in 22 formalin-fixed cadavers. The branches of the lumbar artery coursing along the lateral sides of the lower intervertebral disc [muscular branch, anastomotic branch, and branch supplying the spinal nerve and plexus (BSNP)] and the iliolumbar artery running upward over the L4-5 disc were identified. Branches crossing the intervertebral discs vertically were evaluated. RESULTS: Muscular branches with a lumen structure longer than 2 cm coursed vertically over the middle third of the intervertebral disc in 3 of 88 sites (3.4 %). Anastomotic branches ran downward in 13 of 88 (14.8 %), and iliolumbar arteries ran upward on the posterior third of the lateral sides of the disc in 2 of 88 (2.3 %). BSNPs ran downward through the posterior third of the disc at 18 of 88 sites (20.5 %). Overall, the arterial branches coursed vertically over the posterior third of the lateral sides of the intervertebral discs in approximately 30 % of subjects. CONCLUSIONS: Lumbar artery branches coursed vertically over the middle third and the posterior third of the lateral sides of the intervertebral discs in approximately 3 and 30 % of subjects, respectively. PMID- 27497753 TI - Measurement of kyphosis and vertebral body height loss in traumatic spine fractures: an international study. AB - PURPOSE: To investigate whether wide variations are seen in the measurement techniques preferred by spine surgeons around the world to assess traumatic fracture kyphosis and vertebral body height loss (VBHL). METHODS: An online survey was conducted at two time points among an international community of spine trauma experts from all world regions. The first survey (TL-survey) focused on the thoracic, thoracolumbar and lumbar spine, the second survey (C-survey) on the subaxial cervical spine. Participants were asked to indicate which measurement technique(s) they used for measuring kyphosis and VBHL. Descriptive statistics, frequency analysis and the Fisher exact test were used to analyze the responses. RESULTS: Of the 279 invited experts, 107 (38.4 %) participated in the TL-survey, and 108 (38.7 %) in the C-survey. The Cobb angle was the most frequently used for all spine regions to assess kyphosis (55.6-75.7 %), followed by the wedge angle and adjacent endplates method. Concerning VBHL, the majority of the experts used the vertebral body compression ratio in all spine regions (51.4-54.6 %). The most frequently used combination for kyphosis was the Cobb and wedge angles. Considerable differences were observed between the world regions, while fewer differences were seen between surgeons with different degrees of experience. CONCLUSIONS: This study identified worldwide variations in measurement techniques preferred by treating spine surgeons to assess fracture kyphosis and VBHL in spine trauma patients. These results establish the importance of standardizing assessment parameters in spine trauma care, and can be taken into account to further investigate these radiographic parameters. PMID- 27497754 TI - Synthesis and characterization of chitosan/curcumin blends based polyurethanes. AB - In this work, new hexamethylene diisocyanate (HMDI) and hyroxylterminated polybutadiene (HTPB) based polyurethanes (PUs) were prepared following step growth polymerization by the introduction of varying mole ratio of chitosan (CH) and curcumin (CUR). Structural study of blends through infrared spectroscopy confirmed the incorporation of CH and CUR into the backbone of the PU. The scanning electron microscopic (SEM) study confirmed the well dispersion of incorporated chitosan/curcumin and homogeneity of surface of synthesized samples. Thermogravimetric analysis (TGA) of PU blends indicated a better thermal stability with 0.25M:0.75M of chitosan to curcumin. Mechanical properties such as modulus and tensile strength of PU blends were found to be better with higher contents of chitosan and curcumin. The same extender composition (1mol BDO, 075mol chitosan and 0.25mol curcumin) based PU showed higher substantial of antimicrobial activity as compared to the all other PUs. On the whole, this work is actually a step towards the generation of novel biocompatible materials preferably useful for biomedical applications. PMID- 27497755 TI - Reliability of 3D gait data across multiple laboratories. AB - The aim of this study was to analyze the repeatability of gait analysis studies performed across multiple trials, sessions, and laboratories. Ten healthy participants (6 male/4 female, mean age of 30, mean BMI of 24kg/m(2)) were assessed in 3 sessions conducted at each of the three Centers of Excellence for Amputee Care within the Department of Defense. For each test session, kinematic and kinetic parameters were collected during five walking trials for each limb. One independent examiner at each site placed markers on the subjects. Biomechanical data were collected at two walking speeds: self-selected and Froude speed. Variability of the gait data was attributed to inter-trial, inter-session, and inter-lab errors for each subject. These error sources were averaged across all ten subjects to obtain a pooled error estimate. The kinematic errors were fairly consistent at the two walking speeds tested. Median inter-lab kinematic errors were <5.0 degrees (median 2.3 degrees ) for all joint angle measurements. However, the kinetic error differed significantly between walking speeds. The median inter-lab kinetic error for the self-selected speed was 0.112Nm/kg (ICR 0.091-0.184) with a maximum of 0.226Nm/kg. The errors were greatly reduced when the subjects walked at their Froude speed. The median inter-lab error was 0.048Nm/kg (ICR 0.025-0.078, maximum 0.086). These data demonstrate that it is possible to get reliable data across multiple gait laboratories, particularly when gait speed is standardized across testing sessions. A key similarity between sites was the use of identical anatomical segment definitions for the respective gait models. PMID- 27497756 TI - Reliability and minimum detectable change of the gait profile score for post stroke patients. AB - The objectives of this work were (i) to determine Gait Profile Score (GPS) for hemiparetic stroke patients, (ii) to evaluate its reliability within and between sessions, and (iii) to establish its minimal detectable change (MDC). Seventeen hemiparetic patients (mean age 54.9+/-10.5years; 9 men and 8 women; 6 hemiparetic on the left side and 11 on the right side; mean time after stroke 6.1+/ 3.5months) participated in 2 gait assessment sessions within an interval of 2-7 days. Intra-session reliability was obtained from the intraclass correlation coefficient (ICC) between the three strides of each session. Inter-session reliability was estimated by the ICC from the averages of that three strides. GPS value of non paretic lower limb (NPLL) (13.9+/-2.4 degrees ) was greater than that of paretic lower limb (PLL) (12.0+/-2.8 degrees ) and overall GPS (GPS_O) was 13.7+/-2.5 degrees . The Gait Variable Scores (GVS), GPS and GPS_O exhibited intra-session ICC values between 0.70 and 0.99, suggesting high intra-day stability. Most of GVS exhibited excellent inter-session reliability (ICC between 0.81 and 0.93). Only hip rotation, hip abduction of PLL exhibited moderate reliability with ICC/MDC values of 0.57/10.0 degrees and 0.71/3.1 degrees , respectively. ICC/MDC values of GPS were 0.92/2.3 degrees and 0.93/1.9 degrees for PLL and NPLL, respectively. GPS_O exhibited excellent test-retest reliability (ICC=0.95) and MDC of 1.7 degrees . Given its reliability, the GPS has proven to be a suitable tool for therapeutic assessment of hemiparetic patients after stroke. PMID- 27497757 TI - Precision medicine in acute myeloid leukemia: Hope, hype or both? AB - Precision medicine is interchangeably used with personalized medicine, genomic medicine and individualized medicine. Collectively, these terms refer to at least 5 distinct concepts in the context of AML. 1st, using molecular or omics data (e.g. genomics, epigenomics, transcriptomics, proteomics) to delineate or define subtypes of AML. 2nd, using these data to select the best therapy for someone with an AML subtype, such as a person with a FLT3-mutation. 3rd, using these data to monitor therapy-response such as measurable residual disease [MRD]-testing. 4th, using results of MRD-testing to select from amongst therapy-options such as additional chemotherapy or a haematopoietic cell transplant. And 5th, using these data to identify persons with hereditary forms of AML with potential therapy and surveillance implications. Here, we review these 5 conceptions and delineate where precision medicine is likely to afford greatest hope and where instead our rhetoric may constitute hype. PMID- 27497758 TI - Yeast cells immobilized in spherical gellan particles cross-linked with magnesium acetate. AB - In this paper we report on the production of microbioreactors using ionically cross-linked gellan containing immobilized yeast cells with potential application in glucose fermentation. Cross-linking was achieved through a novel extrusion process in capillary by ionotropic gelation under the action of magnesium acetate. Compared to commonly used methods, this provides a host of practical advantages. The particles were physico-chemically and morphologically characterized as their mechanical stability, behavior in aqueous media, and bio catalytic activity are influenced by the amount of cross-linker used. This demonstrated their ability to be reused in a large number of fermentation cycles without losing their bio-catalytic activity. Our results are wholly comparable with the behavior of free yeast. We show that fermentation cycles can succeed either immediately or at variable intervals, ensuring high yields of glucose transformation, comparable-if not superior-to results currently obtained using free yeast. PMID- 27497759 TI - Development of fluorescence expression tools to study host-mycoplasma interactions and validation in two distant mycoplasma clades. AB - Fluorescence expression tools for stable and innocuous whole mycoplasma cell labelling have been developed. A Tn4001-derivative mini-transposon affording unmarked, stable mutagenesis in mycoplasmas was modified to allow the constitutive, high-level expression of mCherry, mKO2 and mNeonGreen. These tools were used to introduce the respective fluorescent proteins as chromosomal tags in the phylogenetically distant species Mycoplasma mycoides subsp. mycoides and Mycoplasma bovis. The production, selection and characterisation of fluorescent clones were straightforward and resulted in the unprecedented observation of red and green fluorescent mycoplasma colonies in the two species, with no apparent cytotoxicity. Equivalent fluorescence expression levels were quantified by flow cytometry in both species, suggesting that these tools can be broadly applied in mycoplasmas. A macrophage infection assay was performed to assess the usefulness of mNeonGreen-expressing strains for monitoring mycoplasma infections, and notably cell invasion. The presence of fluorescent mycoplasmas inside live phagocytic cells was detected and quantified by flow cytometry and corroborated by confocal microscopy, which allowed the identification of individual mycoplasmas in the cytoplasm of infected cells. The fluorescence expression tools developed in this study are suitable for host-pathogen interaction studies and offer innumerable perspectives for the functional analysis of mycoplasmas both in vitro and in vivo. PMID- 27497760 TI - Identification and characterization of polydimethylsiloxane-binding peptides (PDMS-tag) for oriented immobilization of functional protein on a PDMS surface. AB - In this study we focused on identifying and characterizing polydimethylsiloxane binding peptides (PDMS-tags) that show a strong binding affinity towards a PDMS surface. Three kinds of E. coli host proteins (ELN, OMC and TPA) that were preferentially adsorbed onto a PDMS surface were identified from the E. coli cell lysate via 2-D electrophoresis and MALDI TOF MS. Digestion of these PDMS-binding proteins by 3 types of proteases (trypsin, chymotrypsin and V8 protease) resulted in the production of a wide variety of peptide fragments with different amino acid biases. Nine types of peptide fragments showing binding affinities to a PDMS surface were identified, and they were genetically fused at the C-terminal region of glutathione S-transferase (GST). The adsorption kinetics of peptide-fused GSTs to a PDMS surface were evaluated using a quartz crystal microbalance (QCM) sensor equipped with a sensor chip coated with a PDMS thin film. Consequently, all GSTs fused with the peptides adsorbed at a level higher than that of wild-type GST. In particular, the adsorption levels of GSTs fused with ELN-V81, TPA-V81, and OMC V81 peptides were 8- to 10-fold higher than that of the wild-type GST. These results indicated that the selected peptides possessed a strong binding affinity towards a PDMS surface even in cases where they were introduced to the C-terminal region of a model protein. The remaining activities of GSTs with PDMS-binding peptides were also greater than that of the wild-type GST. Almost a third (30%) of enzymatic activity was maintained by genetic fusion of the peptide ELN-V81, compared with only 1.5% of wild-type GST in the adsorption state. Thus, the PDMS binding peptides (PDMS-tags) identified in this study will be considerably useful for the site-specific immobilization of functional proteins to a PDMS surface, which will be a powerful tool in the fabrication of protein-based micro-reactors and biosearation chips. PMID- 27497761 TI - Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. AB - BACKGROUND: Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. OBJECTIVES: To identify molecular subgroups of PC bone metastases of relevance for therapy. DESIGN, SETTING, AND PARTICIPANTS: Fresh-frozen bone metastasis samples from men with CRPC (n=40), treatment-naive PC (n=8), or other malignancies (n=12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription-polymerase chain reaction (RT-PCR) in an extended set of bone metastases (n=77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease (n=12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients (n=284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation. RESULTS AND LIMITATIONS: The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes (KLK2, KLK3, NKX3.1, STEAP2, TMPRSS2); 20% were non-AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3+ and CD68+ cells was lower in AR-driven than in non-AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression (HLA-A, TAP1, and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient. CONCLUSIONS: Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored. PATIENT SUMMARY: We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients. PMID- 27497763 TI - Re: Efficacy of High-Intensity Local Treatment for Metastatic Urothelial Carcinoma of the Bladder: A Propensity Score-Weighted Analysis from the National Cancer Data Base. PMID- 27497762 TI - Impact of Enzalutamide Compared with Bicalutamide on Quality of Life in Men with Metastatic Castration-resistant Prostate Cancer: Additional Analyses from the TERRAIN Randomised Clinical Trial. AB - BACKGROUND: Improving health-related quality of life (HRQoL) is an important goal in metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: To examine the impact of enzalutamide versus bicalutamide on HRQoL in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: TERRAIN is a multinational, phase 2, randomised, double-blind study in asymptomatic/mildly symptomatic men with mCRPC (ClinicalTrials.gov, NCT01288911). Patients were randomised (1:1) via an interactive voice and web response system to enzalutamide 160mg/d (n=184) or bicalutamide 50mg/d (n=191), with androgen deprivation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQoL was assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P), European Quality of Life 5-Domain Scale (EQ-5D), and Brief Pain Inventory, Short-form questionnaires every 12 wk. Primary and secondary analyses utilised mixed models for repeated measures and pattern mixture models, respectively. RESULTS AND LIMITATIONS: At 61 wk, 84 (46%) enzalutamide and 39 (20%) bicalutamide patients in the study were assessed. At 61 wk, changes from baseline favoured enzalutamide versus bicalutamide on three FACT P domains in mixed models for repeated measures analyses and seven in pattern mixture models analyses. There were no differences in changes for EQ-5D index/visual analogue scale scores. Risk of first deterioration was lower with enzalutamide for FACT-P total (hazard ratio: 0.64, 95% confidence interval: 0.46 0.89, p=0.007), FACT-G total (hazard ratio: 0.70, 95% confidence interval: 0.50 0.98, p=0.04), PCS pain (hazard ratio: 0.74, 95% confidence interval: 0.54-1.00, p=0.048), and EQ-5D index (hazard ratio: 0.66, 95% confidence interval: 0.47 0.93, p=0.02) scores versus bicalutamide. Brief Pain Inventory, Short-form scores increased in both groups. There was no difference in time-to-pain progression. Study limitations include the exploratory nature of the HRQoL analyses, lack of multiple comparisons corrections, and unknown effects of anxiety/depression on HRQoL. CONCLUSIONS: In patients with asymptomatic/mildly symptomatic mCRPC, enzalutamide provides HRQoL benefit versus bicalutamide. PATIENT SUMMARY: Enzalutamide treatment was associated with better health-related quality of life in several domains versus bicalutamide in asymptomatic/mildly symptomatic metastatic castration-resistant prostate cancer. This likely relates to previously reported lower rates of symptomatic disease progression. PMID- 27497765 TI - Evaluation of mutagenic, recombinogenic and carcinogenic potential of (+)-usnic acid in somatic cells of Drosophila melanogaster. AB - The main of this study was to evaluate the mutagenic and carcinogenic potential of (+) - usnic acid (UA), using Somatic Mutation and Recombination Test (SMART) and the test for detecting epithelial tumor clones (wts) in Drosophila melanogaster. Larvae from 72 +/- 4 h from Drosophila were fed with UA (5.0, 10.0 or 20.0 mM); urethane (10.0 mM) (positive control); and solvent (Milli-Q water, 1% Tween-80 and 3% ethanol) (negative control). ST cross produced increase in total mutant spots in the individuals treated with 5.0, 10.0 or 20.0 mM of UA. HB cross produced spot frequencies in the concentration of 5.0 mM that were higher than the frequency for the same concentration in the ST cross. In the highest concentrations the result was negative, which means that the difference observed can be attributed, in part, to the high levels of P450, suggesting that increasing the metabolic capacity maximized the toxic effect of these doses. In the evaluation of carcinogenesis using the wts test, the results obtained for the same concentrations of UA show a positive result for the presence of tumors when compared to the negative control. We conclude that UA has recombinogenic, mutagenic and carcinogenic effects on somatic cells in D. melanogaster. PMID- 27497764 TI - Prioritization of pesticides based on daily dietary exposure potential as determined from the SHEDS model. AB - A major pathway for exposure to many pesticides is through diet. The objectives were to rank pesticides by comparing their calculated daily dietary exposure as determined by EPA's Stochastic Human Exposure and Dose Simulation (SHEDS) to single pesticides for different age groups to acceptable daily intakes (ADI), characterize pesticide trends in exposures over different time periods, and determine commodities contributing to pesticide exposures. SHEDS was applied, using Pesticide Data Program (PDP) (1991-2011) and pesticide usage data on crops from USDA combined with NHANES dietary consumption data, to generate exposure estimates by age group. ADI data collected from EPA, WHO, and other sources were used to rank pesticides based on relativeness of the dietary exposure potential to ADI by age groups. Sensitivity analysis provided trends in pesticide exposures. Within SHEDS, commodities contributing the majority of pesticides with greatest exposure potential were determined. The results indicated that the highest ranking pesticides were methamidophos and diazinon which exceeded 100% of the ADI. Sensitivity analysis indicated that exposure to methamidophos, diazinon, malathion, ethion and formetanate hydrochloride had a marked decrease from 1991 1999 to 2000-2011. Contributions analysis indicated that apples, mushroom, carrots, and lettuce contributed to diazinon exposure. Beans and pepper contributed to methamidophos exposure. PMID- 27497766 TI - Patulin and ochratoxin A co-occurrence and their bioaccessibility in processed cereal-based foods: A contribution for Portuguese children risk assessment. AB - Patulin (PAT) and ochratoxin A (OTA) are well known enteropathogenic mycotoxins that are present in several foodstuffs. Processed cereal-based foods are among the first solid foods eaten by children, a particularly vulnerable population group. There is a lack of knowledge related to the co-occurrence of PAT and OTA in food intended for children consumption and their potential interactions during the digestion process. The present study aims to evaluate, for the first time, the co-occurrence of PAT and OTA in processed cereal-based foods for children consumption, the bioaccessibility of these two mycotoxins, and the contribution of the bioaccessibility data for human health risk assessment. PAT and OTA incidence were 75% and 50%, respectively. These mycotoxins co-occurred in 40% of analysed samples. Bioaccessibility assays revealed mean values of 52% and 56% for PAT, alone and combined with OTA; and 100% and 106% for OTA, alone and combined with PAT. Considering the human health risk assessment, and taking into account the co-occurrence and the bioaccessibility results, this study indicates a tolerable exposure to these mycotoxins representing a low risk for Portuguese children. The present work reinforces the importance of a holistic approach for risk assessment which gathers data from occurrence, exposure and bioaccessibility. PMID- 27497767 TI - Reducing Opioid Misuse: Evaluation of a Medicaid Controlled Substance Lock-In Program. AB - : Opioid misuse, abuse, and overdose are a rapidly growing public health epidemic. Medicaid Lock-In Programs (MLIPs) are designed to prevent overutilization of controlled substances by Medicaid patients. However, despite widespread use, there is little information on their effect. Using North Carolina (NC) Medicaid claims data from October 2008 through June 2013, we examined changes in Medicaid-reimbursed opioid prescriptions by patients enrolled in NC's MLIP. We used mixed effects models to examine the effect of MLIP enrollment on monthly opioid claims, number of pharmacies, total days' supply, total units (ie, pills), and total Medicaid payments for opioids. In our sample of 6,148 MLIP patients, the odds of having any opioid claim in a given month was 84% lower during MLIP enrollment relative to the period before enrollment (odds ratio = .16). MLIP enrollment also corresponded with a reduction in monthly number of opioid prescriptions by 1.13, monthly number of pharmacies by .61, and monthly Medicaid expenditures by $22.78. Although MLIPs may constitute a successful component of comprehensive efforts to reduce the potential overutilization of opioids, care should be taken to ensure that programs such as MLIPs do not constrain patients' legitimate needs for analgesic medications. PERSPECTIVE: Enrollment in NC's MLIP reduced the likelihood that patients would present a claim for an opioid prescription, and the number of opioid prescriptions patients secured each month. MLIPs may constitute a successful strategy for reducing the misuse, abuse, and diversion of prescription opioids. However, further research is needed to examine the program's potential unintended consequences. PMID- 27497769 TI - Child and Family Antecedents of Pain During the Transition to Adolescence: A Longitudinal Population-Based Study. AB - : Pediatric persistent pain is associated with poorer physical and psychosocial functioning in children, as well as immediate and long-term societal costs. Onset typically occurs in early adolescence, suggesting that late childhood is a key window for identifying potential intervention targets before pain symptoms become entrenched. This study used population-based data from the Longitudinal Study of Australian Children (n = 3,812) and adopted a biopsychosocial and ecological systems approach to investigate child, family, and sociodemographic factors associated with pain problems in children transitioning to adolescence. The prevalence of at least weekly parent-reported pain in the study sample was approximately 5% at 10 to 11 years of age, and pain continued at 12 to 13 years of age for 40% of these children. Key factors at 10 to 11 years that uniquely predicted parent-reported pain problems at 12 to 13 years were frequency of previous pain (1-3 times weekly: odds ratio [OR] = 7.49; 95% confidence interval [CI], 4.3-13.0; 4-7 times weekly: OR = 17.8; 95% CI, 8.7-36.5) and sleep difficulties (OR = 1.86; 95% CI, 1.16-2.97). This study highlights the importance of early intervention for persistent pain in childhood, because pain complaints in late childhood tend to persist into early adolescence. PERSPECTIVE: This article used a biopsychosocial and ecological systems approach to understanding predictors of pain problems during the transition to adolescence within a nationally representative community-based cohort. Sleep difficulties at 10 to 11 years uniquely predicted pain at ages 12 to 13 years, suggesting that early intervention using sleep interventions may be a promising direction for future research. PMID- 27497768 TI - Involvement of Opioid Receptors and alpha2-Adrenoceptors in Inhibitory Pain Modulation Processes: A Double-Blind Placebo-Controlled Crossover Study. AB - : In healthy humans, high-frequency electrical stimulation (HFS) of the forearm not only evokes local signs of central sensitization but also triggers broader ipsilateral inhibitory influences on pain akin to a lateralized form of conditioned pain modulation. Paradoxically, some of these inhibitory influences are augmented by alpha2-adrenoceptor blockade. To determine whether opioid peptides mediate inhibitory effects after HFS, the opioid receptor antagonist naltrexone was coadministered orally with the alpha2-adrenoceptor antagonist yohimbine in 16 healthy women in a double-blind placebo-controlled crossover study. In each session, mechanical sensitivity in the forearms and forehead was assessed before and after HFS. In addition, pain ratings to electrical stimulation of HFS-treated or control sites in the forearm were assessed during and after painful stimulation of each temple. Unlike yohimbine alone, the naltrexone with yohimbine combination blocked analgesia evoked by HFS in the ipsilateral forehead to blunt pressure, and opposed the ipsilateral inhibitory effect of pain in the temple on electrically-evoked pain at the HFS-treated site in the forearm. These findings imply involvement of opioid peptides in an ipsilateral analgesic response that complements the more generalized form of conditioned pain modulation. Opioid mediation of this ipsilateral analgesic response appears to override opposing alpha2-adrenoceptor effects. PERSPECTIVE: HFS not only evokes local signs of central sensitization but also triggers a broader ipsilateral antinociceptive mechanism mediated by opioid receptors. Dysfunction of this lateralized pain modulation process might contribute to painful unilateral disorders such as migraine or complex regional pain syndrome. PMID- 27497770 TI - SCN1A Mutation or Cross Talk? The Connection Between the Heart and Brain. PMID- 27497771 TI - Suicide Attempts in Ilam Province, Western Iran, 2010-2014: A Time Trend Study. AB - BACKGROUND: Suicide has become an increasingly widespread form of morbidity in the developing countries. There has been an increasing trend in morbidity and mortality due to suicide in Iran over the past few decades. This study surveyed attempts and completed suicide over a 5-year period. METHODS: Through a cross sectional study, overall identified suicides by systematic registration suicide data (SRSD) in Ilam Province, western Iran from 21 March 2010 to 11 December 2014 were enrolled. Multiple logistic regression analysis was used for measuring the association between the risk factors of interest and suicide. The statistical software package was Stata 11.2. RESULTS: A Suicide attempts have slightly increased in Ilam during 2010-2014, during which, 6,818 attempted suicides occurred of which 546 were completed. The odds of completed suicide was higher among older age groups than younger ones so that the crude OR estimates of completed suicide among people aged 50 to 59 yr against people aged <20 yr was (OR=6.99; 95% CI: 3.02, 11.07). The crude and adjusted odds ratio (OR) estimates of completed suicide in males against females were (OR=3.22; 95% CI: 2.58, 3.93) and (OR=3.66; 95% CI: 3.03, 4.11), respectively. Significant excess risk also appeared with academic against illiterate attempters (OR=2.31; 95% CI: 1.35, 3.95). Results showed no increasing trend in the suicide method. Some methods such as self-immolation had decreasing trend over time, although it was not statistically significant (P=0.089). CONCLUSIONS: We observed the variety of suicide risk factors that calls for more diversity in preventative programs. Distribution of suicide methods is diverse across the period of the study. PMID- 27497772 TI - Helicobacter Pylori Infection in Children with Type 1 Diabetes Mellitus: A Case Control Study. AB - BACKGROUND: Helicobacter pylori infection is one of the most common chronic bacterial infections. There is challenge on the real rate of prevalence of H. pylori in diabetic patients. This study was done to assess the prevalence of H. pylori infection in children suffering from type 1 insulin-dependent diabetes mellitus. METHODS: In this case-control study, 80 diabetic patients (as the target group) refer to the Endocrinology Clinic of Tabriz Educational and Treatment Center, Tabriz northwestern Iran and 80 non-diabetic patients (as the control group) from the group of children referring to the GI Clinic of the same center were enrolled in 2012 and 2013. Then H. pylori infection was assessed in two groups using measuring antibody (IgG) and stool antigen (HpSA). RESULTS: H. pylori infection tests were positive in 48 (60%) diabetic patients and in 32 (40%) in non-diabetic patients (P=0.030). There was a meaningful correlation between the frequency of H. pylori and the longer the duration of diabetes (P<0.001). No correlation was seen between H. pylori infection and other factors such as age of the patients (P=0.840), HbA1C level (P=0.312), age at which diabetes was diagnosed (P=0.800), average daily dosage of insulin (P=0.232), and presence of GI symptoms (P=0.430). CONCLUSIONS: Type 1 diabetic children especially cases with the longer duration of diabetes, are at risk acquiring H. pylori infection. Therefore, screening of H. pylori infection is helpful on the follow up of these patients. PMID- 27497773 TI - Predictors of Adherence to Type2 Diabetes Medication. AB - BACKGROUND: Despite the effectiveness of drug therapy in diabetes management high rates of poor adherence persist. The purpose of this study was to determine the factors influencing the medication adherence and dietary regiment in type2 diabetic patients. METHODS: This cross sectional study was conducted on 300 type2 diabetic patients referred to General Internal Medicine Clinic, Yazd Shohdaye Kargar Hospital,Yazd City, central Iran between September and December 2013. Each consented participant was interviewed by a trained study member using a questionnaire in three sections: Socio-demographic questions, self-reported Morisky medication adherence scale and Disease and medication beliefs Patient's questionnaire. Multivariable logistic regression model was developed to identify independent predictors of poor adherence. P<0.05 was considered statistically significant. RESULTS: Patients had diabetes for an average of 8.87 (SD: 6.0) yr with a mean age of 58.22 (SD: 10.27) yr. Totally, 101(33.7%) of the patients reported poor adherence with their diabetes medication. In multivariate analyses, good familial support (OR=0.11; 0.03, 0.37), and tendency to consume sweets (OR=1.21; 1.05, 1.39), belief about medication (OR=0.02; 0.018, 0.07) and tendency to consume vegetables (OR=0.75; 0.65, 0.88) were considered as predictive factors for poor adherence. CONCLUSIONS: Familial support, belief about medication, tendency to consume sweets and vegetables are logical goals for educational interventions to modify diabetes self-management. PMID- 27497774 TI - Analysis of the Factors Affecting the Interval between Blood Donations Using Log Normal Hazard Model with Gamma Correlated Frailties. AB - BACKGROUND: Time to donating blood plays a major role in a regular donor to becoming continues one. The aim of this study was to determine the effective factors on the interval between the blood donations. METHODS: In a longitudinal study in 2008, 864 samples of first-time donors in Shahrekord Blood Transfusion Center, capital city of Chaharmahal and Bakhtiari Province, Iran were selected by a systematic sampling and were followed up for five years. Among these samples, a subset of 424 donors who had at least two successful blood donations were chosen for this study and the time intervals between their donations were measured as response variable. Sex, body weight, age, marital status, education, stay and job were recorded as independent variables. Data analysis was performed based on log-normal hazard model with gamma correlated frailty. In this model, the frailties are sum of two independent components assumed a gamma distribution. The analysis was done via Bayesian approach using Markov Chain Monte Carlo algorithm by OpenBUGS. Convergence was checked via Gelman-Rubin criteria using BOA program in R. RESULTS: Age, job and education were significant on chance to donate blood (P<0.05). The chances of blood donation for the higher-aged donors, clericals, workers, free job, students and educated donors were higher and in return, time intervals between their blood donations were shorter. CONCLUSIONS: Due to the significance effect of some variables in the log-normal correlated frailty model, it is necessary to plan educational and cultural program to encourage the people with longer inter-donation intervals to donate more frequently. PMID- 27497775 TI - Restrictive Pattern of Pulmonary Symptoms among Photocopy and Printing Workers: A Retrospective Cohort Study. AB - BACKGROUND: According to the growth of photocopier usage in workplaces, the potential risk of occupational exposure to the airborne chemicals has been raised up. Hence, monitoring the photocopy worker's respiratory functions seems to be necessary. We aimed to evaluate the respiratory health on photocopy and printing workers so that a reliable description can be made about their occupational hygiene. METHODS: This study was performed in Shiraz, southwest Iran in 2014 and a group of 150 photocopy and printing workers were surveyed as exposed group in addition to a group of 114 office staff as unexposed group. The respiratory standard questionnaire was used to evaluate the prevalence of respiratory symptoms among the selected staff. Pulmonary function indexes including VC, FVC, FEV1 and the FEV1/FVC ratio were calculated. Finally, t-test, Chi Square and multiple logistic regressions were conducted. RESULTS: VC, FVC and FEV1 in photocopy and printing workers were lower than the unexposed group of which these differences for FVC and FEV1 were statistically significant (P<0.05). Moreover, the prevalence of all respiratory symptoms, except the shortness of breath, in exposed group was more than the unexposed group and the prevalence of coughing and wheezing was statistically significant (P<0.05). There was a significant difference in respiratory symptoms (cough and wheezing) between two groups after controlling for confounding variables, OR: 2.61 (95% CI: 1.21, 5.62) and 2.92 (95% CI: 1.25, 6.84), respectively. CONCLUSIONS: The prevalence of excess respiratory symptoms along with pattern of pulmonary restrictive sings in photocopy and printing workers revealed that the workplace conditions can result in occupational respiratory diseases. PMID- 27497776 TI - Integrating the Ergonomics Techniques with Multi Criteria Decision Making as a New Approach for Risk Management: An Assessment of Repetitive Tasks -Entropy Case Study. AB - BACKGROUND: Nowadays, the health work decision makers need to analyze a huge amount of data and consider many conflicting evaluation criteria and sub criteria. Therefore, an ergonomic evaluation in the work environment in order to the control occupational disorders is considered as the Multi Criteria Decision Making (MCDM) problem. In this study, the ergonomic risks factors, which may influence health, were evaluated in a manufacturing company in 2014. Then entropy method was applied to prioritize the different risk factors. METHODS: This study was done with a descriptive-analytical approach and 13 tasks were included from total number of employees who were working in the seven halls of an ark opal manufacturing (240). Required information was gathered by the demographic questionnaire and Assessment of Repetitive Tasks (ART) method for repetitive task assessment. In addition, entropy was used to prioritize the risk factors based on the ergonomic control needs. RESULTS: The total exposure score based on the ART method calculated was equal to 30.07 +/-12.43. Data analysis illustrated that 179 cases (74.6% of tasks) were in the high level of risk area and 13.8% were in the medium level of risk. ART- entropy results revealed that based on the weighted factors, higher value belongs to grip factor and the lowest value was related to neck and hand posture and duration. CONCLUSIONS: Based on the limited financial resources, it seems that MCDM in many challenging situations such as control procedures and priority approaches could be used successfully. Other MCDM methods for evaluating and prioritizing the ergonomic problems are recommended. PMID- 27497777 TI - Validating the Heat Stress Indices for Using In Heavy Work Activities in Hot and Dry Climates. AB - BACKGROUND: Necessity of evaluating heat stress in the workplace, require validation of indices and selection optimal index. The present study aimed to assess the precision and validity of some heat stress indices and select the optimum index for using in heavy work activities in hot and dry climates. METHODS: It carried out on 184 workers from 40 brick kilns workshops in the city of Qom, central Iran (as representative hot and dry climates). After reviewing the working process and evaluation the activity of workers and the type of work, environmental and physiological parameters according to standards recommended by International Organization for Standardization (ISO) including ISO 7243 and ISO 9886 were measured and indices were calculated. RESULTS: Workers engaged in indoor kiln experienced the highest values of natural wet temperature, dry temperature, globe temperature and relative humidity among studied sections (P<0.05). Indoor workplaces had the higher levels of all environmental parameters than outdoors (P=0.0001), except for air velocity. The wet-bulb globe temperature (WBGT) and heat stress index (HSI) indices had the highest correlation with other physiological parameters among the other heat stress indices. Relationship between WBGT index and carotid artery temperature (r=0.49), skin temperature (r=0.319), and oral temperature (r=0.203) was statistically significant (P=0.006). CONCLUSIONS: Since WBGT index, as the most applicable index for evaluating heat stress in workplaces is approved by ISO, and due to the positive features of WBGT such as ease of measurement and calculation, and with respect to some limitation in application of HSI; WBGT can be introduced as the most valid empirical index of heat stress in the brick workshops. PMID- 27497778 TI - Comment on: "Estimating Economic Burden of Cancer Deaths Attributable to Smoking in Iran in 2012". PMID- 27497779 TI - No effect of anti-inflammatory medication on postprandial and postexercise muscle protein synthesis in elderly men with slightly elevated systemic inflammation. AB - BACKGROUND: Based on circulating C-reactive protein (CRP) levels, some individuals develop slightly increased inflammation as they age. In elderly inflamed rats, the muscle response to protein feeding is impaired, whereas it can be maintained by treatment with non-steroidal anti-inflammatory drugs (NSAIDs). It is unknown whether this applies to elderly humans with increased inflammation. Thus, the muscle response to whey protein bolus ingestion with and without acute resistance exercise was compared between healthy elderly individuals and elderly individuals with slightly increased inflammation+/-NSAID treatment. METHODS: Twenty-four elderly men (>60years) were recruited. Of those, 14 displayed a slightly increased systemic inflammation (CRP>2mg/l) and were randomly assigned to NSAID (Ibuprofen 1800mg/day) or placebo treatment for 1week. The remaining 10 elderly individuals served as healthy controls (CRP<1mg/l). The muscle protein synthetic response was measured as the fractional synthetic rate (FSR) and p70S6K phosphorylation-to-total protein ratio. RESULTS: The basal myofibrillar FSR and the myofibrillar FSR responses to whey protein bolus ingestion with and without acute resistance exercise were maintained in inflamed elderly compared to healthy controls (p>0.05) and so was p70S6K phosphorylation. Moreover, NSAID treatment did not significantly improve the myofibrillar and connective tissue FSR responses or reduce the plasma CRP level in inflamed, elderly individuals (p>0.05). CONCLUSION: A slight increase in systemic inflammation does not affect the basal myofibrillar FSR or the myofibrillar FSR responses, which suggests that elderly individuals with slightly increased inflammation can benefit from protein ingestion and resistance exercise to stimulate muscle protein anabolism. Moreover, the NSAID treatment did not significantly affect the myofibrillar or connective tissue FSR responses to protein ingestion and acute resistance exercise. PMID- 27497781 TI - Multidisciplinary production of interactive environments to support occupational therapies. AB - This work focuses on proposing a multidisciplinary production of interactive environments as a technological support for rehabilitation of people with physical disabilities attending occupational therapy. Nowadays, some technologies and methods are used to develop software in order to assist the people who suffer some kind of physical disability but the physical therapies aren't limited to only one technique of rehabilitation. Current work promotes establish a multidisciplinary team such as therapists and technologists, they can collaborate for the production of interactive environments according the evolution of every patient's rehabilitation. The performance of current proposal is presented throughout a related work and a case study with several usability evaluations. PMID- 27497780 TI - A pilot study of a heuristic algorithm for novel template identification from VA electronic medical record text. AB - RATIONALE: Templates in text notes pose challenges for automated information extraction algorithms. We propose a method that identifies novel templates in plain text medical notes. The identification can then be used to either include or exclude templates when processing notes for information extraction. METHODS: The two-module method is based on the framework of information foraging and addresses the hypothesis that documents containing templates and the templates within those documents can be identified by common features. The first module takes documents from the corpus and groups those with common templates. This is accomplished through a binned word count hierarchical clustering algorithm. The second module extracts the templates. It uses the groupings and performs a longest common subsequence (LCS) algorithm to obtain the constituent parts of the templates. The method was developed and tested on a random document corpus of 750 notes derived from a large database of US Department of Veterans Affairs (VA) electronic medical notes. RESULTS: The grouping module, using hierarchical clustering, identified 23 groups with 3 documents or more, consisting of 120 documents from the 750 documents in our test corpus. Of these, 18 groups had at least one common template that was present in all documents in the group for a positive predictive value of 78%. The LCS extraction module performed with 100% positive predictive value, 94% sensitivity, and 83% negative predictive value. The human review determined that in 4 groups the template covered the entire document, with the remaining 14 groups containing a common section template. Among documents with templates, the number of templates per document ranged from 1 to 14. The mean and median number of templates per group was 5.9 and 5, respectively. DISCUSSION: The grouping method was successful in finding like documents containing templates. Of the groups of documents containing templates, the LCS module was successful in deciphering text belonging to the template and text that was extraneous. Major obstacles to improved performance included documents composed of multiple templates, templates that included other templates embedded within them, and variants of templates. We demonstrate proof of concept of the grouping and extraction method of identifying templates in electronic medical records in this pilot study and propose methods to improve performance and scaling up. PMID- 27497782 TI - MicroRNA-328, a Potential Anti-Fibrotic Target in Cardiac Interstitial Fibrosis. AB - BACKGROUND/AIMS: Deregulated myocardial fibrosis is associated with a wide spectrum of cardiac conditions, being considered one of the major causes for heart disease. Our study was designed to investigate the role of microRNA-328 (miR-328) in regulating cardiac fibrosis. METHODS: We induced cardiac fibrosis following MI by occlusion of the left coronary artery in C57BL/6 mice. Real-time PCR was employed to evaluate the level of miR-328. Masson's Trichrome stain was used to evaluate the development of fibrosis. Luciferase activity assay was performed to confirm the miRNA's binding site in the TGFbetaRIII gene. Western blot analysis was used to examine TGFbetaRIII, p-smad2/3 and TGF-beta1 at protein level. RESULTS: In this study, we found that miR-328 was significantly upregulated in the border zone of infarcted myocardium of wild type (WT) mice; TGFbetaRIII was downregulated whereas TGF-beta1 was upregulated along with increased cardiac fibrosis. And miR-328 stimulated TGF-beta1 signaling and promoted collagen production in cultured fibroblasts. We further found that the pro-fibrotic effect of miR-328 was mediated by targeting TGFbetaRIII. Additionally, cardiac fibrosis was significantly reduced in infarcted heart when treated with miR-328 antisense. CONCLUSIONS: These data suggest that miR-328 is a potent pro-fibrotic miRNA and an important determinant of cardiac fibrosis in diseased heart. PMID- 27497783 TI - Evaluation of the toxic potential of coffee wastewater on seeds, roots and meristematic cells of Lactuca sativa L. AB - Coffee wastewater (CWW) is an effluent produced through wet processing of coffee containing high concentration of organic matter, nutrients, salts and also agrochemicals. It is released directly into the argillaceous soil or into decantation tanks for later disposal into soils, by fertigation, subsurface infiltration or superficial draining. However, this practice is not followed by the monitoring the toxicity potential of this effluent. In this sense, the present work aimed to evaluate the phytotoxic, cytogenotoxic and mutagenic potential of CWW on seed germination, root elongation and cell cycle alterations in the plant model Lactuca sativa L. The effluent (CWW) collected was diluted in distilled water into six concentrations solutions (1.25%, 1.66%, 2.5%, 5.0%, 10%, 20%). A solution of raw CWW (100%) was also applied. Distilled water was used as negative control), and the DNA alkylating agent, metilmetano sulfonate (4*10( 4)M) as positive control. Physico-chemical parameters of the CWW was accessed and it was found that the effluent contained total phenols and inorganic matter in amounts within the limits established by the National Environment Council (CONAMA). Nevertheless, the biologicals assays performed demonstrated the phytotoxicity and cytogenotoxicty of CWW. Seed germination was totally inhibited after exposure of raw CWW. In addition, a decrease in seed germination speed as well as in root growth dose-dependently manner was noticed. Moreover, nuclear and chromosomal alterations were observed in the cell cycle, mostly arising from aneugenic action. PMID- 27497784 TI - Assessing the bioremediation potential of algal species indigenous to oil sands process-affected waters on mixtures of oil sands acid extractable organics. AB - Surface mining extraction of bitumen from oil sand in Alberta, Canada results in the accumulation of oil sands process-affected water (OSPW). In attempts to maximize water recycling, and because its constituents are recognized as being toxic, OSPW is retained in settling basins. Consequently, research efforts are currently focused on developing remediation strategies capable of detoxifying OSPW to allow for eventual release. One potential bioremediation strategy proposes to utilize phytoplankton native to the Alberta oil sand region to sequester, break down, or modify the complex oil sands acid extractable organic (AEO) mixtures in OSPW. Preliminary attempts to quantify changes in total oil sands AEO concentration in test solutions by ESI-MS following a 14-day algal remediation period revealed the presence of unknown organic acids in control samples, likely released by the phytoplankton strains and often of the same atomic mass range as the oil sands AEO under investigation. To address the presence of these "biogenic" organic acids in test samples, ESI-MS in MRM mode was utilized to identify oil sands AEO "marker ions" that were a) present within the tested oil sands AEO extract and b) unique to the oil sands AEO extract only (e.g. atomic masses different from biogenic organic acids). Using this approach, one of the 21 tested algal strains, Stichococcus sp. 1, proved capable of significantly reducing the AEO marker ion concentration at test concentrations of 10, 30, and 100mgL(-1). This result, along with the accelerated growth rate and recalcitrance of this algal strain with exposure to oil sands AEO, suggests the strong potential for the use of the isolated Stichococcus sp. 1 as a candidate for bioremediation strategies. PMID- 27497785 TI - Identification of interacting proteins with aryl hydrocarbon receptor in scallop Chlamys farreri by yeast two hybrid screening. AB - The aryl hydrocarbon receptor (AhR) belongs to the basic-helix-loop helix (bHLH) Per-Arnt-Sim (PAS) family of transcription factors. AhR has been known primarily for its role in the regulation of several drug and xenobiotic metabolizing enzymes, as well as the mediation of the toxicity of certain xenobiotics, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Although the AhR is well studied as a mediator of the toxicity of certain xenobiotics in marine bivalves, the normal physiological function remains unknown. In order to explore the function of the AhR, the bait protein expression plasmid pGBKT7-CfAhR and the cDNA library of gill from Chlamys farreri were constructed. By yeast two hybrid system, after multiple screening with the high screening rate medium, rotary verification, sequencing and bioinformatics analysis, the interactions of the CfAhR with receptor for activated protein kinase C 1 (RACK1), thyroid peroxidase like protein (TPO), Toll-like receptor 4(TLR 4), androglobin-like, store-operated Ca(2+) entry (SocE), ADP/ATP carrier protein, cytochrome b, thioesterase, actin, ferritin subunit 1, poly-ubiquitin, short-chain collagen C4-like and one hypothetical protein in gill cells were identified. This study suggests that the CfAhR played fundamental roles in immune system homeostasis, oxidative stress response, and in grow and development of C. farreri. The elucidation of these protein interactions is of much importance both in understanding the normal physiological function of AhR, and as potential targets for further research on protein function in AhR interactions. PMID- 27497786 TI - Pharmacist-based health coaching: A new model of pharmacist-patient care. AB - This paper describes a provider-patient communication process, which although not new to health care in general, is new to the pharmacy profession. Health coaching is a technique that empowers patients to make lasting health behavior changes that improve overall well-being. It provides patients with health care implementation options that better suit their lifestyle and abilities. Health coaching programs have the potential to foster better health outcomes, especially with patients who are chronically ill or represent an at risk population for medication non-adherence (e.g. elderly, patients on psychotropic medications). Other health professions (e.g. nursing and medicine) have had success with the implementation of health coaching models. For example, nurse coaching is recognized by the American Nurse Association and recent statistics show 3.1 million nurses in the U.S.A are also trained in nurse coaching. The pharmacy profession has yet to tap the patient-related benefits of health coaching. This commentary will discuss (i) The theoretical foundations of health coaching (ii) Distinctions between health coaching, motivational interviewing and traditional medication therapy counseling (iii) Training necessary for health coaching; and (iv) How pharmacists can use health coaching in practice. PMID- 27497787 TI - Triggering of Suicidal Erythrocyte Death by Psammaplin A. AB - BACKGROUND/AIMS: Psammaplin A, a natural product isolated from marine sponges, triggers apoptosis of tumor cells and is thus considered for the treatment of malignancy. In analogy to apoptosis of nucleated tumor cells, erythrocytes may enter eryptosis, a suicidal death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms stimulating eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress and ceramide. The present study explored, whether Psammaplin A induces eryptosis and to possibly shed some light on the underlying mechanisms. METHODS: Phosphatidylserine exposing erythrocytes were identified utilizing annexin-V-binding, cell volume was estimated from forward scatter, [Ca2+]i determined utilizing Fluo3-fluorescence, the abundance of reactive oxygen species (ROS) quantified with DCFDA dependent fluorescence, and ceramide abundance at the erythrocyte surface detected with specific antibodies. RESULTS: A 48 hours exposure of human erythrocytes to Psammaplin A (2 8 ug/ml) significantly decreased forward scatter and significantly increased the percentage of annexin-V-binding cells. Psammaplin A significantly increased Fluo3 fluorescence, the effect of Psammaplin A on annexin-V-binding and forward scatter was, however, not significantly blunted by removal of extracellular Ca2+. Psammaplin A significantly increased DCFDA fluorescence and ceramide abundance. CONCLUSIONS: Psammaplin A triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect paralleled by increase of [Ca2+]i, induction of oxidative stress and enhanced appearance of ceramide. PMID- 27497788 TI - Variable reporting of functional outcomes and return to play in superior labrum anterior and posterior tear. AB - BACKGROUND: Outcomes assessments after superior labrum anterior and posterior (SLAP) tear/repair are highly varied, making it difficult to draw comparisons across the literature. This study examined the inconsistency in outcomes reporting in the SLAP tear literature. We hypothesize that there is significant variability in outcomes reporting and that although most studies may report return to play, time to return reporting will be highly variable. METHODS: The PubMed, Medline, Scopus, and Embase databases were systematically reviewed for studies from January 2000 to December 2014 reporting outcomes after SLAP tear/repair. Two reviewers assessed each study, and those meeting inclusion criteria were examined for pertinent data. Outcomes included objective (range of motion, strength, clinical examinations, and imaging) and subjective (patient reported outcomes, satisfaction, activities of daily living, and return to play) measures. RESULTS: Of the 56 included studies, 43% documented range of motion, 14% reported strength, and 16% noted postoperative imaging. There was significant variation in use of patient-reported outcomes measures, with the 3 most commonly noted measures reported in 20% to 55% of studies. Return to play was noted in 75% of studies, and 23% reported time to return, with greater rates in elite athletes. Eleven studies (20%) did not report follow-up or noted data with <12 months of follow-up. CONCLUSIONS: The SLAP literature is characterized by substantial variability in outcomes reporting, with time to return to play noted in few studies. Efforts to standardize outcomes reporting would facilitate comparisons across the literature and improve our understanding of the prognosis of this injury. PMID- 27497789 TI - Prevalence of asymptomatic rotator cuff tear and their related factors in the Korean population. AB - BACKGROUND: No information is available about asymptomatic rotator cuff tears (RCTs) in the Korean population. This study evaluated the prevalence of rotator cuff tears without symptoms and their related risk factors. MATERIALS AND METHODS: The study included 486 volunteers (70.4% female; mean age, 53.1; range, 20-82 years) without any shoulder symptom complaints. Background data, medical history, clinical self-assessment, and physical examination were recorded. An ultrasonographic examination was conducted to identify rotator cuff pathology, but only full-thickness RCTs (FTRCTs) were included for the statistical analysis. RESULTS: FTRCTs were found in 23 subjects (4.7%) but only in those aged >=49 years. Subjects aged 50-59, 60-69, and >=70 years of age had FTRCT prevalence rates of 3.5%, 13.3%, and 11.1%, respectively. The prevalence of FTRCTs was higher in subjects with diabetes (P = .042) and a smoking history (P= .002), but no differences were noted for the presence of thyroid disease (P = .051). Almost half of those who had FTRCTs had some pain and limited daily activity that was not bothersome. After excluding these subjects from the analysis, the prevalence of asymptomatic FTRCTs decreased to 2.3%. CONCLUSIONS: The prevalence of asymptomatic FTRCTs was lower than expected. Half of asymptomatic FTRCTs were not actually symptom free after the clinical and physical assessments. The risk factors for a FTRCT were age, diabetes, and smoking. PMID- 27497790 TI - Single cell genomics reveals activation signatures of endogenous SCAR's networks in aneuploid human embryos and clinically intractable malignant tumors. AB - Somatic mutations and chromosome instability are hallmarks of genomic aberrations in cancer cells. Aneuploidies represent common manifestations of chromosome instability, which is frequently observed in human embryos and malignant solid tumors. Activation of human endogenous retroviruses (HERV)-derived loci is documented in preimplantation human embryos, hESC, and multiple types of human malignancies. It remains unknown whether the HERV activation may highlight a common molecular pathway contributing to the frequent occurrence of chromosome instability in the early stages of human embryonic development and the emergence of genomic aberrations in cancer. Single cell RNA sequencing analysis of human preimplantation embryos reveals activation of specific LTR7/HERVH loci during the transition from the oocytes to zygotes and identifies HERVH network signatures associated with the aneuploidy in human embryos. The correlation patterns' analysis links transcriptome signatures of the HERVH network activation of the in vivo matured human oocytes with gene expression profiles of clinical samples of prostate tumors supporting the existence of a cancer progression pathway from putative precursor lesions (prostatic intraepithelial neoplasia) to localized and metastatic prostate cancers. Tracking signatures of HERVH networks' activation in tumor samples from cancer patients with known long-term therapy outcomes enabled patients' stratification into sub-groups with markedly distinct likelihoods of therapy failure and death from cancer. Genome-wide analyses of human-specific genetic elements of stem cell-associated retroviruses (SCARs)-regulated networks in 12,093 clinical tumor samples across 29 cancer types revealed pan-cancer genomic signatures of clinically-lethal therapy resistant disease defined by the presence of somatic non-silent mutations (SNMs), gene-level copy number changes, and transcripts and proteins' expression of SCARs-regulated host genes. More than 73% of all cancer deaths occurred in patients whose tumors harbor the SNMs' signatures. Linear regression analysis of the cancer intractability in the United States population demonstrated that organ-specific cancer death rates are directly correlated with the percentages of patients whose tumors harbor the SNMs' signatures. Present analyses suggest that awakening of SCARs-regulated stemness networks in differentiated cells is associated with development of diverse spectrum of genomic aberrations in multiple types of clinically lethal malignant tumors contributing to emergence of therapy-resistant cancer phenotypes. PMID- 27497791 TI - Male Urethral Stricture: American Urological Association Guideline. AB - PURPOSE: The purpose of this Guideline is to provide a clinical framework for the diagnosis and treatment of male urethral stricture. MATERIALS AND METHODS: A systematic review of the literature using the Pubmed, Embase, and Cochrane databases (search dates 1/1/1990 to 12/1/2015) was conducted to identify peer reviewed publications relevant to the diagnosis and treatment of urethral stricture. The review yielded an evidence base of 250 articles after application of inclusion/exclusion criteria. These publications were used to create the Guideline statements. Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional guidance is provided as Clinical Principles and Expert Opinion when insufficient evidence existed. RESULTS: The Panel identified the most common scenarios seen in clinical practice related to the treatment of urethral strictures. Guideline statements were developed to aid the clinician in optimal evaluation, treatment, and follow-up of patients presenting with urethral strictures. CONCLUSIONS: Successful treatment of male urethral stricture requires selection of the appropriate endoscopic or surgical procedure based on anatomic location, length of stricture, and prior interventions. Routine use of imaging to assess stricture characteristics will be required to apply evidence based recommendations, which must be applied with consideration of patient preferences and personal goals. As scientific knowledge relevant to urethral stricture evolves and improves, the strategies presented here will be amended to remain consistent with the highest standards of clinical care. PMID- 27497792 TI - Standardized Reporting of Microscopic Renal Tumor Margins: Introduction of the Renal Tumor Capsule Invasion Scoring System. AB - PURPOSE: Renal tumor enucleation allows for maximal parenchymal preservation. Identifying pseudocapsule integrity is critically important in nephron sparing surgery by enucleation. Tumor invasion into and through the capsule may have clinical implications, although it is not routinely commented on in standard pathological reporting. We describe a system to standardize the varying degrees of pseudocapsule invasion and identify predictors of invasion. MATERIALS AND METHODS: We performed a multicenter retrospective review between 2002 and 2014 at Indiana University Hospital and Loyola University Medical Center. A total of 327 tumors were evaluated following removal via radical nephrectomy, standard margin partial nephrectomy or enucleation partial nephrectomy. Pathologists scored tumors using our i-Cap (invasion of pseudocapsule) scoring system. Multivariate analysis was done to determine predictors of higher score tumors. RESULTS: Tumor characteristics were similar among surgical resection groups. Enucleated tumors tended to have thinner pseudocapsule rims but not higher i-Cap scores. Rates of complete capsular invasion, scored as i-Cap 3, were similar among the surgical techniques, comprising 22% of the overall cohort. Papillary histology along with increasing tumor grade was predictive of an i-Cap 3 score. CONCLUSIONS: A capsule invasion scoring system is useful to classify renal cell carcinoma pseudocapsule integrity. i-Cap scores appear to be independent of surgical technique. Complete capsular invasion is most common in papillary and high grade tumors. Further work is warranted regarding the relevance of capsular invasion depth as it relates to the oncologic outcome for local recurrence and disease specific survival. PMID- 27497793 TI - Patient and clinician perspectives on the outpatient after-visit summary: a qualitative study to inform improvements in visit summary design. AB - Objective: We explored patients' and clinicians' perspectives on electronic health record (EHR)-generated outpatient after-visit summaries (AVSs) to inform efforts to maximize the document's utility. Materials and Methods: This qualitative study involved focus groups and semistructured interviews with patients ( n = 39) and clinicians ( n = 56) in adult primary care practices serving socioeconomically diverse communities in New York City; Long Island, New York; and Chicago, Illinois. Focus group and interview transcripts were coded and analyzed following standard qualitative methods. Results: Core themes included the use and purpose of the AVS, content modification and prioritization, formatting improvements, customization, privacy and accuracy concerns, and clinician workflow concerns. While most patients valued the document as a visit summary, others considered it a general summary of their health and health care issues, useful for sharing with family or clinicians even if they had access to their health records via web portals. Patients expressed a preference for the order of content items, and many wanted the reasons for medications and referrals stated. Additionally, some patients were confused by multiple medication lists indicating started, stopped, and modified medications, and a single "current" medication list was preferred by both patients and doctors. Concerns were raised about the risk of violating patient privacy and challenges to clinician workflow. Discussion: The AVS is valued by patients and clinicians. Both groups have identified numerous ways it can be improved, but also several obstacles to improvement and effective use. Conclusion: EHR vendors should work with stakeholder groups to improve the AVS to ensure that this important communication device achieves its patient-centered potential. PMID- 27497794 TI - Context-sensitive decision support (infobuttons) in electronic health records: a systematic review. AB - Objective: Infobuttons appear as small icons adjacent to electronic health record (EHR) data (e.g., medications, diagnoses, or test results) that, when clicked, access online knowledge resources tailored to the patient, care setting, or task. Infobuttons are required for "Meaningful Use" certification of US EHRs. We sought to evaluate infobuttons' impact on clinical practice and identify features associated with improved outcomes. Methods: We conducted a systematic review, searching MEDLINE, EMBASE, and other databases from inception to July 6, 2015. We included and cataloged all original research in any language describing implementation of infobuttons or other context-sensitive links. Studies evaluating clinical implementations with outcomes of usage or impact were reviewed in greater detail. Reviewers worked in duplicate to select articles, evaluate quality, and abstract information. Results: Of 599 potential articles, 77 described infobutton implementation. The 17 studies meriting detailed review, including 3 randomized trials, yielded the following findings. Infobutton usage frequency ranged from 0.3 to 7.4 uses per month per potential user. Usage appeared to be influenced by EHR task. Five studies found that infobuttons are used less often than non-context-sensitive links (proportionate usage 0.20-0.34). In 3 studies, users answered their clinical question in > 69% of infobutton sessions. Seven studies evaluated alternative approaches to infobutton design and implementation. No studies isolated the impact of infobuttons on objectively measured patient outcomes. Conclusions: Weak evidence suggests that infobuttons can help providers answer clinical questions. Research on optimal infobutton design and implementation, and on the impact on patient outcomes and provider behaviors, is needed. PMID- 27497795 TI - Inviting patients and care partners to read doctors' notes: OpenNotes and shared access to electronic medical records. AB - We examined the acceptability and effects of delivering doctors' visit notes electronically (via OpenNotes) to patients and care partners with authorized access to patients' electronic medical records. Adult patients and care partners at Geisinger Health System were surveyed at baseline and after 12 months of exposure to OpenNotes. Reporting on care partner access to OpenNotes, patients and care partners stated that they had better agreement about patient treatment plans and more productive discussions about their care. At follow-up, patients were more confident in their ability to manage their health, felt better prepared for office visits, and reported understanding their care better than at baseline. Care partners were more likely to access and use patient portal functionality and reported improved communication with patients' providers at follow-up. Our findings suggest that offering patients and care partners access to doctors' notes is acceptable and improves communication and patients' confidence in managing their care. PMID- 27497796 TI - Opening government health data to the public: benefits, challenges, and lessons learned from early innovators. AB - Objective: Government agencies are rapidly developing web portals to proactively publish "open" data that are searchable, available in nonproprietary formats, and with unlimited use and distribution rights. In this dynamic environment, we aimed to understand the experiences of 2 early leaders in open health data, the US Department of Health and Human Services and the New York State Department of Health. Materials and Methods: Semistructured interviews with 40 practitioners and policymakers elicited value propositions, capabilities required for successful open data programs, and strategies for improving impact and sustainability. Transcripts were analyzed using a grounded theory approach to identify common perspectives and divergent viewpoints. Results: Respondents were optimistic about the value of open data, reporting numerous opportunities to advance the triple aim of lower costs, improved health care quality, and better population health. Benefits to agencies include enhanced data quality and more efficient operations. External benefits include improved health literacy, data driven changes in health care delivery, consumer engagement, and community empowerment. Key challenges are resources, cultural resistance, navigating legal and regulatory issues, and data quality. Discussion: The open data movement will likely continue, but success requires sustained leadership, resources, organizational cultural change, promotion of data use, and governance. Jurisdictions that are initiating open data programs can incorporate these lessons from early innovators. Conclusions: The open data movement has a bright future but unknown long-term impact. To maintain momentum, important directions for the field include reconsidering legal guidance on protecting health data in the open data era and quantifying the return on investment. PMID- 27497797 TI - eHealth patient-provider communication in the United States: interest, inequalities, and predictors. AB - Objective: Health-related Internet use and eHealth technologies, including online patient-provider communication (PPC), are continually being integrated into health care environments. This study aimed to describe sociodemographic and health- and Internet-related correlates that influence adult patients' interest in and electronic exchange of medical information with health care providers in the United States. Methods: Nationally representative cross-sectional data from the 2014 Health Information National Trends Survey ( N = 3677) were analyzed. Descriptive statistics and multivariable regression analyses were performed to examine associations between patient-level characteristics and online PPC behavior and interests. Results: Most respondents were Internet users (82.8%), and 61.5% of information seekers designated the Internet as their first source for health information. Younger respondents (<50 years), Hispanics, those from higher-income households, and those perceiving access to personal health information as important were more likely to be interested in online PPC. Despite varying levels of patient interest, 68.5% had no online PPC in the last year. However, Internet users (odds ratio, OR = 2.87, 95% CI, 1.35-6.08), college graduates (OR = 2.92, 95% CI, 1.42-5.99), and those with frequent provider visits (OR = 1.94, 95% CI, 1.02-3.71) had a higher likelihood of online PPC via email or fax, while Hispanics and those from higher-income households were 2-3 times more likely to communicate via text messaging or phone/mobile apps. Conclusion: Patients' interest in and display of online PPC-related behaviors vary by age, race/ethnicity, education, income, Internet access/behaviors, and information type. These findings can inform efforts aimed at improving the use and adoption of eHealth technologies, which may contribute to a reduction in communication inequalities and health care disparities. PMID- 27497798 TI - Biomedical informatics advancing the national health agenda: the AMIA 2015 year in-review in clinical and consumer informatics. AB - The field of biomedical informatics experienced a productive 2015 in terms of research. In order to highlight the accomplishments of that research, elicit trends, and identify shortcomings at a macro level, a 19-person team conducted an extensive review of the literature in clinical and consumer informatics. The result of this process included a year-in-review presentation at the American Medical Informatics Association Annual Symposium and a written report (see supplemental data). Key findings are detailed in the report and summarized here. This article organizes the clinical and consumer health informatics research from 2015 under 3 themes: the electronic health record (EHR), the learning health system (LHS), and consumer engagement. Key findings include the following: (1) There are significant advances in establishing policies for EHR feature implementation, but increased interoperability is necessary for these to gain traction. (2) Decision support systems improve practice behaviors, but evidence of their impact on clinical outcomes is still lacking. (3) Progress in natural language processing (NLP) suggests that we are approaching but have not yet achieved truly interactive NLP systems. (4) Prediction models are becoming more robust but remain hampered by the lack of interoperable clinical data records. (5) Consumers can and will use mobile applications for improved engagement, yet EHR integration remains elusive. PMID- 27497799 TI - Comparison of heuristic and cognitive walkthrough usability evaluation methods for evaluating health information systems. AB - Objective: There are several user-based and expert-based usability evaluation methods that may perform differently according to the context in which they are used. The objective of this study was to compare 2 expert-based methods, heuristic evaluation (HE) and cognitive walkthrough (CW), for evaluating usability of health care information systems. Materials and methods: Five evaluators independently evaluated a medical office management system using HE and CW. We compared the 2 methods in terms of the number of identified usability problems, their severity, and the coverage of each method. Results: In total, 156 problems were identified using the 2 methods. HE identified a significantly higher number of problems related to the "satisfaction" attribute ( P = .002). The number of problems identified using CW concerning the "learnability" attribute was significantly higher than those identified using HE ( P = .005). There was no significant difference between the number of problems identified by HE, based on different usability attributes ( P = .232). Results of CW showed a significant difference between the number of problems related to usability attributes ( P < .0001). The average severity of problems identified using CW was significantly higher than that of HE ( P < .0001). Conclusion: This study showed that HE and CW do not differ significantly in terms of the number of usability problems identified, but they differ based on the severity of problems and the coverage of some usability attributes. The results suggest that CW would be the preferred method for evaluating systems intended for novice users and HE for users who have experience with similar systems. However, more studies are needed to support this finding. PMID- 27497801 TI - Surgical Treatment of Displaced Midshaft Clavicle Fractures: Precontoured Plates Versus Noncontoured Plates. AB - PURPOSE: To compare the outcomes and complications of open reduction and internal fixation using precontoured versus noncontoured plates for the treatment of midshaft clavicle fractures. METHODS: Open reduction and internal fixation using was performed on 130 patients with a midshaft clavicle fracture. Precontoured plates were used in 69 cases (group A) and noncontoured plates in 61 cases (group B). RESULTS: The average follow-up in both groups was approximately 21 months. There was a significant difference between the 2 groups in mean surgery duration and blood loss, although Disabilities of the Arm, Shoulder, and Hand and Constant Murley Shoulder scores at final follow-up were similar. Plate removal was required in 44.9% (31 of 69) of the precontoured group and 65.6% (40 of 61) of the noncontoured group. The indication was prominence of the hardware in 27.5% (19 of 69) of the precontoured group and 54.1% (33 of 61) of the noncontoured. In both groups, body mass index was lower in patients requiring implant removal because of hardware prominence. A higher proportion of females in both groups required implant removal. CONCLUSIONS: Precontoured plates are associated with a lower rate of hardware removal. Body mass index and gender may be factors that influence the rate of hardware removal. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 27497800 TI - Evaluating electronic health record data sources and algorithmic approaches to identify hypertensive individuals. AB - OBJECTIVE: Phenotyping algorithms applied to electronic health record (EHR) data enable investigators to identify large cohorts for clinical and genomic research. Algorithm development is often iterative, depends on fallible investigator intuition, and is time- and labor-intensive. We developed and evaluated 4 types of phenotyping algorithms and categories of EHR information to identify hypertensive individuals and controls and provide a portable module for implementation at other sites. MATERIALS AND METHODS: We reviewed the EHRs of 631 individuals followed at Vanderbilt for hypertension status. We developed features and phenotyping algorithms of increasing complexity. Input categories included International Classification of Diseases, Ninth Revision (ICD9) codes, medications, vital signs, narrative-text search results, and Unified Medical Language System (UMLS) concepts extracted using natural language processing (NLP). We developed a module and tested portability by replicating 10 of the best performing algorithms at the Marshfield Clinic. RESULTS: Random forests using billing codes, medications, vitals, and concepts had the best performance with a median area under the receiver operator characteristic curve (AUC) of 0.976. Normalized sums of all 4 categories also performed well (0.959 AUC). The best non NLP algorithm combined normalized ICD9 codes, medications, and blood pressure readings with a median AUC of 0.948. Blood pressure cutoffs or ICD9 code counts alone had AUCs of 0.854 and 0.908, respectively. Marshfield Clinic results were similar. CONCLUSION: This work shows that billing codes or blood pressure readings alone yield good hypertension classification performance. However, even simple combinations of input categories improve performance. The most complex algorithms classified hypertension with excellent recall and precision. PMID- 27497802 TI - Estimating Scaphoid Lengths Using Anatomical Measurements in the Wrist. AB - PURPOSE: In reconstructive surgery of scaphoid nonunions with humpback deformity, some surgeons recommend restoration of the normal scaphoid length whereas others overexpand the normal length to ensure carpal realignment and prevent late collapse. To be able to define overexpansion and investigate which levels of overexpansion yield optimal clinical results, a precise method for estimating the original scaphoid length is required. The purpose of this anatomic study was to investigate the precision of estimating normal scaphoid lengths based on intact adjacent bone dimensions, compared with using the contralateral scaphoid length. METHODS: From bilateral computed tomographic scans of 28 healthy wrist pairs, 3 dimensional virtual bone models were created. The left and right scaphoid lengths were determined at the central axis. The capitate length at the central axis and the distal radius width served to derive an ipsilateral scaphoid length estimate. Estimation precision for individual cases was based on the 95% range (+/-1.96 * SD) of the observed differences between the actual and estimated lengths. RESULTS: On average, the capitate length was 10% smaller than the scaphoid length; the radius width was 9% larger. Consequently, we averaged the capitate length and radius width for ipsilateral estimations. The average difference between the scaphoid length and the latter ipsilateral estimate was 0.1 mm. The average contralateral scaphoid length difference was also 0.1 mm. Estimation precisions, however, were +/-2.2 and +/-1.4 mm, respectively. CONCLUSIONS: Scaphoid length estimation based on the contralateral scaphoid is more precise than the estimating scaphoid length using the ipsilateral radius and capitate. CLINICAL RELEVANCE: Scaphoid overexpansion can be ensured if the restored length is at least 1.4 mm longer than the contralateral length. This may be valuable information when establishing a target length for reconstruction and investigating the consequences of scaphoid overexpansion on clinical function, such as range of motion, which are currently unknown. PMID- 27497803 TI - The use of deformable image registration to integrate diagnostic MRI into the radiotherapy planning pathway for head and neck cancer. AB - BACKGROUND AND PURPOSE: To assess the accuracy of gross tumour volume (GTV) delineation for head and neck squamous cell carcinoma (HNSCC) using a diagnostic position MRI (MRI-D) deformably registered to the planning CT (pCT), by comparison with a dedicated planning position MRI (MRI-RT). MATERIAL AND METHODS: Fourteen patients with HNSCC underwent a T1-weighted MRI-D and MRI-RT. A reference GTV was defined as that delineated on MRI-RT rigidly registered to pCT. GTVs were delineated on: MRI-D and then registered to pCT by deformable image registration over the whole image (DIR-whole); MRI-D and then registered to pCT with rigid registration over a region of interest defined as GTV+3cm (Rigid-ROI); and on the pCT alone. These were compared using positional metrics to the reference. RESULTS: GTVs delineated on MRI-D followed by DIR-whole were significantly more accurate than those delineated on CT alone. The mean Dice Similarity Coefficient was 0.6 and 0.72 for pCT and DIR-whole respectively. Use of MRI-D with Rigid-ROI provided no advantage over CT-only delineation. CONCLUSIONS: Contouring on MRI-RT rigidly registered to pCT should be considered as the gold standard for HNSCC. In radiotherapy centres lacking a dedicated MRI RT, the use of an MRI-D with DIR-whole offers a significant advantage for the accuracy of GTV delineation over contouring on pCT alone. PMID- 27497804 TI - Comparison of investigator-delineated gross tumour volumes and quality assurance in pancreatic cancer: Analysis of the on-trial cases for the SCALOP trial. AB - BACKGROUND AND PURPOSE: We performed a retrospective central review of tumour outlines in patients undergoing radiotherapy in the SCALOP trial. MATERIALS AND METHODS: The planning CT scans were reviewed retrospectively by a central review team, and the accuracy of investigators' GTV (iGTV) and PTV (iPTV) was compared to the trials team-defined gold standard (gsGTV and gsPTV) using the Jaccard Conformity Index (JCI) and Geographical Miss Index (GMI). The prognostic value of JCI and GMI was also assessed. The RT plans were also reviewed against protocol defined constraints. RESULTS: 60 patients with diagnostic-quality planning scans were included. The median whole volume JCI for GTV was 0.64 (IQR: 0.43-0.82), and the median GMI was 0.11 (IQR: 0.05-0.22). For PTVs, the median JCI and GMI were 0.80 (IQR: 0.71-0.88) and 0.04 (IQR: 0.02-0.12) respectively. Tumour was completely missed in 1 patient, and?50% of the tumour was missed in 3. Patients with JCI for GTV?0.7 had 7.12 (95% CIs: 1.83-27.67, p=0.005) higher odds of progressing by 9months in multivariate analysis. Major deviations in RT planning were noted in 4.5% of cases. CONCLUSIONS: Radiotherapy workshops and real-time central review of contours are required in RT trials of pancreatic cancer. PMID- 27497805 TI - Spatial and non-spatial aspects of visual attention: Interactive cognitive mechanisms and neural underpinnings. PMID- 27497806 TI - Cost-effectiveness of radial vs. femoral approach in primary percutaneous coronary intervention in STEMI - Randomized, control trial. AB - INTRODUCTION AND OBJECTIVES: Primary percutaneous coronary intervention infarction became the preferred method of treatment for myocardial ST segment elevation. Improved safety was reported in transradial access (radial) compared to transfemoral access (femoral). The aim of this study was to compare the cost between the two access points in ST segment elevation myocardial infarction. METHODS: This is a subanalysis of the OCEAN RACE trial in which 103 myocardial infarction patients were randomized to either the radial (n=52) or femoral (n=51) groups. The clinical safety and efficacy were recorded during the hospital stay. The procedural metrics were meticulously logged, and costs were evaluated using the micro-cost method. The indirect costs were estimated using the human capital approach. RESULTS: Clinical success was numerically higher in the radial group (90.4 vs. 80.4%, p=0.123). There were no differences in major adverse cardiac events (9.6% vs. 11.8%, p=0.48) and death (2.0% vs. 6.0%, p=0.31). The average in hospital cost per patient was 2,740 +/- 1,092 EUR. The cost of therapeutic success was lower in the radial group at 3,060 EUR vs. 3,374 EUR. The indirect costs related to absence at work were 138 EUR per patient, which were lower in the radial group compared to the femoral group. CONCLUSIONS: The total in hospital costs were similar between the study groups. The indirect costs were lower in the radial group. Introduction of radial access as the default approach in all centers may significantly reduce the overall financial burden from a social perspective. PMID- 27497807 TI - Cytokine response of human THP-1 macrophages to Trichomonas tenax. AB - Trichomonas tenax is a protozoan that inhabits the oral cavity of humans, most often those with poor oral hygiene. Although T. tenax is widely considered a commensal, recent studies have suggested a pathogenic role for the protozoan in persons with periodontitis. Here we investigated the capacity of T. tenax to induce pro-inflammatory cytokine secretion in human macrophages, with the idea that elicitation of inflammation may be one mechanism by which T. tenax contributes to oral pathology. Human THP-1 cells differentiated to the macrophage phenotype (dTHP-1) were incubated with live or sonicated T. tenax at trophozoite:dTHP-1 ratios of 1:5, 1:10, and 1:20. Culture media removed from the wells after 4, 8, and 16 h of stimulation were assayed by ELISA for tumor necrosis factor alpha, interleukin-1 beta, interleukin-8, and the immunoregulatory cytokine interleukin-10. Live T. tenax trophozoites failed to induce production of any of the cytokines tested, regardless of trophozoite:dTHP 1 cell ratio or length of co-incubation. T. tenax lysates stimulated interleukin 8 synthesis, but only after 16 h of incubation at the 1:5 trophozoite:dTHP-1 cell ratio. These results suggest that pro-inflammatory cytokine synthesis by human macrophages in direct response to T. tenax contributes little to oral pathology. PMID- 27497808 TI - Plasmin Enzyme-Assisted Vitrectomy in Pediatric Patients with Vitreoretinal Diseases. AB - PURPOSE: To evaluate the efficacy and safety of using plasmin-assisted vitrectomy in pediatric patients with vitreoretinal diseases. METHODS: We prospectively recruited children aged 16 years or younger who presented with vitreoretinopathies and underwent plasmin-assisted vitrectomy between 2012 and 2013. The main outcome measure was the induction of posterior vitreous detachment (PVD) using a suction power of 200 mm Hg or less during surgery. RESULTS: Eleven eyes of 11 patients (mean age: 3.7 years; average follow-up duration: 14.1 months) were included. Of these 11 patients, there were 3 (27%) cases of stage 5 retinopathy of prematurity, 2 (18%) cases of persistent fetal vasculature, 2 (18%) cases of rhegmatogenous retinal detachment, 2 (18%) cases of idiopathic epiretinal membrane, 1 (9%) case of traumatic macular pucker, and 1 (9%) case of traumatic vitreous hemorrhage (9%). PVD was achieved in all cases (100%) during surgery using low suction after plasmin treatment (mean: 150 +/- 39 mm Hg; range: 100-200). Overall, anatomical success was achieved in 8 eyes (73%). Visual acuity improved in all 5 (100%) patients for whom vision could be measured at 6 months after the operation. Cataracts were found in 4 eyes (36%), and a rise in transient intraocular pressure was observed in 1 eye (9%). CONCLUSIONS: Plasmin assisted vitrectomy offers an effective and less traumatic intervention for a variety of pediatric vitreoretinal diseases. PMID- 27497809 TI - MDA7 combined with targeted attenuated Salmonella vector SL7207/pBud-VP3 inhibited growth of gastric cancer cells. AB - BACKGROUND/AIM: To investigate the therapeutic effect of MDA7 combined with apoptin targeted attenuated Salmonella typhimurium vector SL7207/pBud-VP3 on gastric cancer cells. MATERIALS AND METHODS: MDA7 was inserted into pBud-VP3 using molecular cloning technology to obtain the eukaryotic expression plasmid pBud-VP3-MDA7 and it was transformed into attenuated Salmonella typhimurium SL7207 by high voltage electroporation to obtain SL7207/pBud-VP3-MDA7. Mice bearing a sarcoma of gastric cancer cells were treated with SL7207/pBud-VP3-MDA7 and the growth-suppressing effect was assessed by measurement of tumor volume. Western blot was used to identify the MDA7 expression products. IL-6, INF-gamma, TNF-alpha and caspase-3, VEGF in tumor tissue were detected by RT-PCR and immunohistochemistry. RESULTS: SL7207/pBud-VP3-MDA7 was successfully constructed and expression of the protein MDA7 was identified in tumor tissue. SL7207/pBud VP3-MDA7 significantly caused tumor inhibition and regression (p<0.05). The level of expression of cytokines IL-6, INF-gamma, TNF-alpha in tumor tissue was significantly higher than in the other groups (p<0.05). The expression of caspase 3 was up-regulated and VEGF was down-regulated (p<0.05). CONCLUSION: This study shows that SL7207/pBud-VP3-MDA7 has inhibitory effect on the growth of gastric cancer cells. The mechanism involved is related to the promotion of tumor apoptosis, immunity regulation and inhibition of tumor blood vessels. PMID- 27497810 TI - N-methyl-d-aspartate receptor autoimmunity affects cognitive performance in herpes simplex encephalitis. AB - OBJECTIVES: To investigate the prevalence and temporal development of N-methyl-d aspartate receptor (NMDAR) autoantibodies in relation to neurocognitive performance in patients with herpes simplex encephalitis (HSE). METHODS: This prospective observational study enrolled a total of 49 HSE patients within a randomized controlled trial of valacyclovir. Cerebrospinal fluid and serum samples were drawn in the initial stage of disease, after 2 to 3 weeks and after 3 months. Anti-NMDAR IgG was detected with HEK293 cells transfected with plasmids encoding the NMDA NR1 type glutamate receptor. A batch of neurocognitive tests, including the Mattis Dementia Rating Scale (MDRS), Glasgow Coma Scale (GCS), Reaction Level Scale (RLS85), Mini-Mental State Examination (MMSE) and National Institutes of Health (NIH) stroke scale, was performed during 24 months' follow up. RESULTS: Anti-NMDAR IgG was detected in 12 of 49 participants. None were antibody positive in the initial stage of disease. In ten of 12 positive cases, specific antibodies were detectable only after 3 months. Notably, the development of NMDAR autoantibodies was associated with significantly impaired recovery of neurocognitive performance. After 24 months' follow-up, the median increase in MDRS total score was 1.5 vs. 10 points in antibody-positive and -negative participants (p=0.018). CONCLUSIONS: Anti-NMDAR autoimmunity is a common complication to HSE that develops within 3 months after onset of disease. The association to impaired neurocognitive recovery could have therapeutical implications, as central nervous system autoimmunity is potentially responsive to immunotherapy. PMID- 27497811 TI - Pros and cons of circumcision: an evidence-based overview. AB - Based on three large randomized controlled trials (RCTs) conducted in Africa, it can clearly be stated that circumcision lowers the risk of infection with the human immunodeficiency virus (HIV) and some sexually transmitted infections (STIs) among males in settings of high HIV and STI endemicity. Similar effects on STI risk may exist for females, although this may result from an indirect effect of decreasing risk of infection among male partners. It is unknown whether circumcision prevents HIV acquisition in men who have sex with men (MSM), although there might be a protective effect for men who engage mainly in insertive anal intercourse. When the effects of adult circumcision on sexual function and satisfaction of men are examined, high-quality evidence strongly supports lack of harm. Whether circumcision alters sexual satisfaction of female partners is not known as fewer and smaller studies reported conflicting results. Circumcision rarely causes serious complications if practiced by trained practitioners, in a sterile setting, and with a proper follow-up. These conclusions are limited by the lack of high-quality data from areas outside of Africa. RCTs have not been conducted to assess the effects of circumcising infants or MSM. Circumcision has well-proven benefits for people residing in areas with high prevalence of STIs, including HIV, and is not unethical for those who choose to be circumcised or have their children circumcised on religious, social, or cultural grounds. For many others, a definite pro or con recommendation, based on a risk-benefit ratio, cannot be made. PMID- 27497812 TI - Closing the evidence gap in infectious disease: point-of-care randomization and informed consent. AB - The informed consent document is intended to provide basic rights to patients but often fails to do so. Patients' autonomy may be diminished by virtue of their illness; evidence shows that even patients who appear to be ideal candidates for understanding and granting informed consent rarely are, particularly those with acute infections. We argue that for low-risk trials whose purpose is to evaluate nonexperimental therapies or other measures towards which the medical community is in a state of equipoise, ethics committees should play a more active role in a more standardized fashion. Patients in the clinic are continually subject to spontaneous 'pseudo-randomizations' based on local dogma and the anecdotal experience of their physicians. Stronger ethics oversight would allow point-of care trials to structure these spontaneous randomizations, using widely available informatics tools, in combination with opt-out informed consent where deemed appropriate. PMID- 27497813 TI - The modulatory effect of nitric oxide in pro- and anti-convulsive effects of vasopressin in PTZ-induced seizures threshold in mice. AB - Vasopressin neuropeptides play an important role in the several cognitive, social, and neuroendocrine functions. Also, several studies report the involvement of nitrergic system in the vasopressin functions in central nervous system. This study investigates the effect of Arginine-Vasopressin (AVP) in pentylenetetrazol (PTZ)-induced seizures threshold and the probable role of nitric oxide (NO). AVP is administered intraperitoneally (0.01-20MUg/kg, i.p.) 30min before induction of seizures. Administration of AVP (0.1MUg/kg) significantly lowered the PTZ-induced seizures threshold. But, administration of AVP (10 and 20MUg/kg) increased the seizures threshold, significantly. Pretreatment of SR 49059 (V1a receptor antagonist, 2mg/kg, i.p.) just reversed the pro-convulsant effect of AVP. Meanwhile, SSR 149415 (V1b receptor antagonist, 10mg/kg, i.p.) pretreatment reversed both pro-and anti-convulsant effects of AVP. The nitric oxide precursor, L-arginine (60mg/kg, i.p.) increased pro-convulsant effect of AVP, but did not change anticonvulsant activity. The nitric oxide synthase (NOS) inhibitor L-NAME (10mg/kg, i.p.) reversed both pro- and anti convulsant effect of AVP. Selective inducible NOS inhibitor, aminoguanidine (100mg/kg, i.p.) just reversed the anti-convulsant effects of AVP. The results of the present study showed nitric oxide system may contribute to the biphasic effects of AVP on PTZ-induced seizures. V1a receptor may modulate only the proconvulsive effect. While, V1b receptors can mediate both the pro- and anti convulsive effect of AVP. PMID- 27497814 TI - How does vagal nerve stimulation (VNS) change EEG brain functional connectivity? AB - An effect of vagal nerve stimulation (VNS) on cortical synchronization has been postulated but remains to be verified. In this study we investigated the impact of VNS on functional connectivity (Fc) using direct intracerebral recordings (stereotactic EEG, SEEG). Five patients with epilepsy who underwent SEEG recordings during ongoing VNS therapy were investigated. Interdependencies between twenty-six selected bipolar SEEG channels were estimated by nonlinear regression analysis during ON and OF periods of stimulation. In comparison with OFF periods, the ON periods disclosed higher values for four patients (P1, P3, P4, P5) and lower values for one patient (P2). From thresholded graphs, we observed increased connections between several brain regions in P1 and P5 and decreased connections in P2. Finally, the only decreased Fc occurring during VNS corresponded to the responder patient, suggesting that therapeutic impact might be related to this mechanism. PMID- 27497817 TI - Correction to Lancet Diabetes Endocrinol 2016; 4: 647. PMID- 27497815 TI - Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment. AB - : Cutaneous skeletal hypophosphatemia syndrome (CSHS), caused by somatic RAS mutations, features excess fibroblast growth factor-23 (FGF23) and skeletal dysplasia. Records from 56 individuals were reviewed and demonstrated fractures, scoliosis, and non-congenital hypophosphatemia that in some cases were resolved. Phosphate and calcitriol, but not skin lesion removal, were effective at controlling hypophosphatemia. No skeletal malignancies were found. PURPOSE: CSHS is a disorder defined by the association of epidermal and/or melanocytic nevi, a mosaic skeletal dysplasia, and an FGF23-mediated hypophosphatemia. To date, somatic RAS mutations have been identified in all patients whose affected tissue has undergone DNA sequencing. However, the clinical spectrum and treatment are poorly defined in CSHS. The purpose of this study is to determine the spectrum of the phenotype, natural history of the disease, and response to treatment of hypophosphatemia. METHODS: Five CSHS subjects underwent prospective data collection at clinical research centers. A review of the literature identified 45 reports that included a total of 51 additional patients, in whom the findings were compatible with CSHS. Data on nevi subtypes, bone histology, mineral and skeletal disorders, abnormalities in other tissues, and response to treatment of hypophosphatemia were analyzed. RESULTS: Fractures, limb deformities, and scoliosis affected most CSHS subjects. Hypophosphatemia was not present at birth. Histology revealed severe osteomalacia but no other abnormalities. Skeletal dysplasia was reported in all anatomical compartments, though less frequently in the spine; there was no clear correlation between the location of nevi and the skeletal lesions. Phosphate and calcitriol supplementation was the most effective therapy for rickets. Convincing data that nevi removal improved blood phosphate levels was lacking. An age-dependent improvement in mineral abnormalities was observed. A spectrum of extra-osseous/extra-cutaneous manifestations that included both benign and malignant neoplasms was present in many subjects, though osteosarcoma remains unreported. CONCLUSION: An understanding of the spectrum, natural history, and efficacy of treatment of hypophosphatemia in CSHS may improve the care of these patients. PMID- 27497816 TI - Inhibition of HIF-1alpha enhances anti-tumor effects of dendritic cell-based vaccination in a mouse model of breast cancer. AB - Considerable evidence shows that the tumor microenvironment is an active participant in preventing immunosurveillance and limiting the efficacy of anticancer therapies. Hypoxia is a prominent characteristic of the solid tumor microenvironment. The transcription factor hypoxia-inducible factor-1alpha (HIF 1alpha) is an important mediator of hypoxic response of tumor cells that modulates the expression of specific genes involved in tumor immunosuppression. Using a 4T1 breast cancer model, we show that in vivo administration of PX-478, an inhibitor of oxygen-sensitive HIF-1alpha, led to reduced expression of Foxp3 and VEGF transcript and/or protein, molecules that are directly controlled by HIF 1. When combined with dendritic cell (DC)-based vaccination, HIF-1alpha inhibition resulted in an augmented cytotoxic T lymphocyte effector function, improved proliferation status of T cells, increased production of inflammatory cytokine IFN-gamma, as well as reduced regulatory function of T cells in association with slower tumor growth. Taken together, our findings indicate that the use of HIF-1alpha inhibition provides an immune adjuvant activity, thereby improves the efficacy of tumor antigen-based DC vaccine. PMID- 27497818 TI - Nucleotide variation of sFRP5 gene is not associated with obesity in children and adolescents. AB - Because sFRP5 was shown to be an important extracellular modulator of the Wnt pathway, regulating adipogenesis, we wanted to investigate the role of sFRP5 variants in human, monogenic obesity by performing mutation analysis. We screened the complete sFRP5 coding region in 622 obese children and adolescents and 503 lean control individuals by high-resolution melting curve analysis and direct sequencing. We found a total of 15 sequence variants in sFRP5, 10 of which resulted in a non-synonymous amino acid change. Five of these variants were, to our knowledge, not previously reported. For one of the variants (c.-3G>A), we identified a trend towards association between the variant frequency and the obese phenotype. We argue that, when looking at conservation and location inside known protein domains, several of the identified variants (D103N, A113V, K212N and H317L), may affect sFRP5 protein function. In addition, we found c.-3G>A, residing in the Kozak sequence, with a lower frequency in cases compared to controls. However, functional studies investigating the effect of sFRP5 variants on protein function are necessary to determine the true role of sFRP5 genetic variation in human, monogenic obesity. PMID- 27497819 TI - Minocycline ameliorates D-galactose-induced memory deficits and loss of Arc/Arg3.1 expression. AB - Dysfunction of learning and memory is widely found in many neurological diseases. Understanding how to preserve the normal function of learning and memory will be extremely beneficial for the treatment of these diseases. However, the possible protective effect of minocycline in memory impairment is unknown. We used the well-established D-galactose rat amnesia model and two behavioral tasks, the Morris water maze and the step-down task, for memory evaluation. Western blot and PCR were used to examine the protein and mRNA levels of Arc/Arg3.1. We report that minocycline supplementation ameliorates both the spatial and fear memory deficits caused by D-galactose. We also found that Arc/Arg3.1, c-fos, and brain derived neurotrophic factor levels are decreased in the D-galactose animal model, and that minocycline reverses the protein and mRNA levels of Arc in the hippocampus, suggesting the potential role of Arc/Arg3.1 in minocycline's neuroprotective mechanism. Our study strongly suggests that minocycline can be used as a novel treatment for memory impairment in neurological diseases. PMID- 27497820 TI - Gel based in vitro 3D model exploring the osteocytic potentiality of human CD34+ stem cells. AB - Osteocytic potentiality of human CD34+ stem cells explored in the present study by generating in vitro agarose gel 3D model to understand the bone ossification process. The G-CSF and IL-3 mobilized human CD34+ stem cells isolated apheretically from donor peripheral blood and purity of the cells was assessed by FACS and immunocytochemical (ICC) studies. The CD34+ stem cells were cultured in gel based 3D model with osteogenic stimulating medium for 21 days. The transition stages from undifferentiated to differentiated osteocytes through osteoblasts were studied with expression markers Differentiated cells at Day 7 showed positive reactivity with monoclonal anti-Runx2, an early osteoblastic marker. qPCR expression analysis showed early and mature osteoblastic markers like RUNX2, Osterix, RANKL, along with osteocyte markers SPARC, Sclerostin. While poor expression of OSCAR genes was observed apart from conspicuous expression of alkaline phosphatase. The expression of sclerostin and SPARC suggests that these differentiated cells are behaving like true osteocytes, sclerostin expression causes transformation of osteoblast into osteocytes and negligible expression of OSCAR, RANK, NFATc and cathepsin K genes explains there are no osteoclasts in the differentiated culture. These cells showed positive reaction with Alizarin red stain indicating expression of calcium bound bone morphogenic proteins like osteonectin. All these results clearly confirm the human CD34+ stem cells possess unique osteogenic differentiation potential and can be used in the early regeneration of injured bone. PMID- 27497821 TI - Accidents with biologic material in health services among persons with no presumed risk. AB - This study identified persons without presumed risk (PWPR) involved in accidents with blood and body fluids in 2 health care facilities between 1989 and 2012 in a state in Central Brazil. There were 181 accidents that occurred with PWPR, predominantly among women. Accidents with blood and body fluids involved needle and blood, some performed by untrained personnel. Most prematurely terminated clinical and laboratory monitoring. Accidents with blood and body fluids occur under similar circumstances to health care workers. PMID- 27497822 TI - Joinpoint regression analysis of pertussis crude incidence rates, Illinois, 1990 2014. AB - Pertussis incidence has increased in recent years; we obtained incidence data from 1990-2014 from the Illinois Department of Public Health Web site. We analyzed the crude incidence rates using Joinpoint regression software. Four joinpoints were observed (2001, 2004, 2007, and 2012). Disease modeling can be used for disease control and planning by extrapolating the trend in the incidence data and applying to annual population estimates. PMID- 27497823 TI - Profiling the fecal carriage of beta-lactamase genes in long-term care facility residents: A longitudinal study. AB - BACKGROUND: The fecal carriage of beta-lactamase (BL)-producing bacteria may play a major role in the spread of these organisms in long-term care facilities (LTCFs). The aims of this study were (1) to describe the gene profiles of fecal BL in 3 LCTFs in Taiwan and (2) to analyze the fecal carriage burden of BL genes between the residents (patient group) and staff (staff group) of LTCFs. METHODS: Thirty fecal samples were collected during June 2013 and July 2015: 20 were obtained from 10 residents both during hospitalization (T1) and 1 month after discharge (T2), and 10 were obtained from 10 staff members. RESULTS: In total, 80%, 70%, and 50% of the samples in the patient group at T1, staff group at T2, and patient group at T2, respectively, contained >2 BL genes. In the patient group, the predominant genes belonged to extended-spectrum BL genes (90%-100%) and AmpC BL genes (90%-100%). Furthermore, carbapenemase genes were approximately 20% during T1 and T2. The relative levels of SHV-type BLs were significantly higher (P < .05) in the patient group at T2 compared with the staff group. CONCLUSIONS: In this study, we found a high carriage of fecal BLs among LTCF residents and staff. The monitoring of fecal BL carriage in LTCFs is needed for infection control measures and antibiotic choice for health care-associated infections. PMID- 27497824 TI - Simethicone residue remains inside gastrointestinal endoscopes despite reprocessing. AB - BACKGROUND: During a study designed to assess endoscope reprocessing effectiveness, a borescope was used to examine lumens and ports. Cloudy, white, viscous fluid was observed inside fully reprocessed gastroscopes and colonoscopes. This fluid resembled simethicone, which is commonly administered to reduce foam and bubbles that impede visualization during gastrointestinal endoscopy. This article describes methods used to determine whether the observed fluid contained simethicone. METHODS: Photographs of residual fluid were taken using a borescope. Sterile cotton-tipped swabs were used to collect samples of fluid observed in 3 endoscope ports. Samples were evaluated using Fourier transform infrared spectroscopy (FTIR)-attenuated total reflection analysis. RESULTS: Residual fluid was observed inside 19 of 20 endoscopes. Fluid photographed in 8 endoscopes resembled simethicone solutions. FTIR analysis confirmed the presence of simethicone in 2 endoscopes. CONCLUSIONS: Fluid containing simethicone remained inside endoscopes despite reprocessing. Simethicone is an inert, hydrophobic substance that may reduce reprocessing effectiveness. Simethicone solutions commonly contain sugars and thickeners, which may contribute to microbial growth and biofilm development. Studies are needed to assess the prevalence of residual moisture and simethicone in endoscopes and determine the impact on reprocessing effectiveness. We recommend minimizing the use of simethicone pending further research into its safety. PMID- 27497825 TI - How Do Intensity and Duration of Rehabilitation Services Affect Outcomes From Severe Traumatic Brain Injury? A Natural Experiment Comparing Health Care Delivery Systems in 2 Developed Nations. AB - OBJECTIVE: To determine the effects of inpatient and outpatient treatment intensity on functional and emotional well-being outcomes at 1 year after severe traumatic brain injury (TBI). DESIGN: Prospective, quasiexperimental study comparing outcomes in a U.S. TBI treatment center with those in a Denmark (DK) center providing significantly greater intensity and duration of rehabilitation. SETTING: Inpatient and outpatient TBI rehabilitation. PARTICIPANTS: Persons with severe TBI (N=274). INTERVENTIONS: Inpatient rehabilitation interventions were counted daily by discipline. Outpatient treatments were estimated per discipline using a structured interview administered to patients, caregivers, or both, at 12 months. MAIN OUTCOME MEASURES: FIM, Glasgow Outcome Scale-Extended, Disability Rating Scale, Participation Assessment with Recombined Tools-Objective, Perceived Quality of Life, Medical Outcomes Study 12-Item Short-Form Health Survey, Brief Symptom Inventory-18-item version. RESULTS: Despite identical inclusion criteria, patient severity on admission was greater at the DK site. After adjustment for patient/injury characteristics, there were no site differences in either functional or emotional outcome at 12 months. Significantly more inpatient plus outpatient treatment was administered to DK patients than to those in the U.S. For functional but not emotional treatments, more severely impaired patients received higher doses. One-year outcomes were predicted by admission severity, age, employment, and other baseline characteristics. CONCLUSIONS: Contrary to expectation, DK patients who received significantly more rehabilitation services during the year after severe TBI did not differ in outcome from their less intensively treated U.S. counterparts, after adjusting for initial severity. The negative association of functional treatment dose with extent of early disability suggests that dose was driven by unmeasured factors reflecting need for services. Improved measures of injury-related factors driving treatment allocation are needed to model the independent effects of treatment on outcomes. PMID- 27497826 TI - Reliability, Validity, and Ability to Identify Fall Status of the Balance Evaluation Systems Test, Mini-Balance Evaluation Systems Test, and Brief-Balance Evaluation Systems Test in Older People Living in the Community. AB - OBJECTIVES: To assess the reliability, validity, and ability to identify fall status of the Balance Evaluation Systems Test (BESTest), Mini-BESTest, and Brief BESTest, compared with the Berg Balance Scale (BBS), in older people living in the community. DESIGN: Cross-sectional. SETTING: Community centers. PARTICIPANTS: Older adults (N=122; mean age +/- SD, 76+/-9y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants reported on falls history in the preceding year and completed the Activities-Specific Balance Confidence (ABC) Scale. The BBS, BESTest, and the Five Times Sit-To-Stand Test were administered. Interrater (2 physiotherapists) and test-retest relative (48-72h) and absolute reliabilities were explored with the intraclass correlation coefficient (ICC) equation (2,1) and the Bland and Altman method. Minimal detectable changes at the 95% confidence level (MDC95) were established. Validity was assessed by correlating the balance tests with each other and with the ABC Scale (Spearman correlation coefficients rho). Receiver operating characteristics assessed the ability of each balance test to differentiate between people with and without a history of falls. RESULTS: All balance tests presented good to excellent interrater (ICC=.71-.93) and test-retest (ICC=.50-.82) relative reliability, with no evidence of bias. MDC95 values were 4.6, 9, 3.8, and 4.1 points for the BBS, BESTest, Mini-BESTest, and Brief-BESTest, respectively. All tests were significantly correlated with each other (rho=.83-.96) and with the ABC Scale (rho=.46-.61). Acceptable ability to identify fall status (areas under the curve, .71-.78) was found for all tests. Cutoff points were 48.5, 82, 19.5, and 12.5 points for the BBS, BESTest, Mini BESTest, and Brief-BESTest, respectively. CONCLUSIONS: All balance tests are reliable, valid, and able to identify fall status in older people living in the community. Therefore, the choice of which test to use will depend on the level of balance impairment, purpose, and time availability. PMID- 27497827 TI - Comparing American Gastroenterological Association Pancreatic Cyst Management Guidelines with Fukuoka Consensus Guidelines as Predictors of Advanced Neoplasia in Patients with Suspected Pancreatic Cystic Neoplasms. AB - BACKGROUND: In 2015, the American Gastroenterological Association (AGA) published guidelines to provide recommendations for management of suspected pancreatic cystic neoplasms (PCNs). The aim of this study was to compare efficacy of these with the Fukuoka consensus guidelines in predicting advanced neoplasia (AN) in patients with suspected PCNs. STUDY DESIGN: We performed a retrospective study of 239 patients who underwent surgical resection for suspected mucinous PCN at a tertiary care center from 2000 to 2014. Surgical pathology was the gold standard. The AGA and Fukuoka criteria were applied, and their performance in predicting AN, defined as invasive cancer or high-grade dysplasia (HGD), was assessed. RESULTS: Advanced neoplasia was found in 71 of 239 (29.7%) patients (28 invasive cancer, 43 HGD). The Fukuoka "high-risk" (FG-HR) and AGA "high-risk" (AGA-HR) criteria identified patients with AN with sensitivities of 28.2% and 35.2%, specificities of 95.8% and 94.0%, positive predictive values of 74.1% and 71.4%, and negative predictive values of 75.9% and 77.5%, respectively. Overall, there was no significant difference between the guidelines for prediction of AN. There were 7 and 6 cases with invasive cancer, and 23 and 24 cases with HGD missed by the FG-HR and AGA-HR guidelines, respectively. CONCLUSIONS: In a retrospective analysis, the AGA guidelines are not superior to the Fukuoka guidelines in identifying AN in suspected PCNs. Both sets of guidelines have fair PPV for detection of AN, which would lead to avoidable resections in patients without AN. Additionally, the high-risk features of both guidelines do not accurately identify all patients with AN. PMID- 27497828 TI - The geographic distribution and complex evolutionary history of the NX-2 trichothecene chemotype from Fusarium graminearum. AB - Fusarium graminearum and 21 related species comprising the F. sambucinum species complex lineage 1 (FSAMSC-1) are the most important Fusarium Head Blight pathogens of cereal crops world-wide. FSAMSC-1 species typically produce type B trichothecenes. However, some F. graminearum strains were recently found to produce a novel type A trichothecene (NX-2) resulting from functional variation in the trichothecene biosynthetic enzyme Tri1. We used a PCR-RFLP assay targeting the TRI1 gene to identify the NX-2 allele among a global collection of 2515 F. graminearum. NX-2 isolates were only found in southern Canada and the northern U.S., where they were observed at low frequency (1.8%), but over a broader geographic range and set of cereal hosts than previously recognized. Phylogenetic analyses of TRI1 and adjacent genes produced gene trees that were incongruent with the history of species divergence within FSAMSC-1, indicating trans-species evolution of ancestral polymorphism. In addition, placement of NX-2 strains in the TRI1 gene tree was influenced by the accumulation of nonsynonymous substitutions associated with the evolution of the NX-2 chemotype, and a significant (P<0.001) change in selection pressure was observed along the NX-2 branch (omega=1.16) in comparison to other branches (omega=0.17) in the TRI1 phylogeny. Parameter estimates were consistent with positive selection for specific amino-acid changes during the evolution of NX-2, but direct tests of positive selection were not significant. Phylogenetic analyses of fourfold degenerate sites and intron sequences in TRI1 indicated the NX-2 chemotype had a single evolutionary origin and evolved recently from a type B ancestor. Our results indicate the NX-2 chemotype may be indigenous, and possibly endemic, to southern Canada and the northern U.S. In addition, we demonstrate that the evolution of TRI1 within FSAMSC-1 has been complex, with evidence of trans species evolution and chemotype-specific shifts in selective constraint. PMID- 27497829 TI - Trastuzumab Emtansine in HER2+ Recurrent Metastatic Non-Small-Cell Lung Cancer: Study Protocol. AB - The treatment outcome has been unsatisfactory for patients with non-small-cell lung cancer (NSCLC) refractory to standard first-line chemotherapy. Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with a vinca alkaloid, has been approved for clinical use in HER2+ breast cancer in many countries. Approximately 5% of NSCLC tumors possess HER2 alterations, and T-DM1 has shown excellent antitumor effects against HER2+ lung cancer cell lines in preclinical models. Therefore, we hypothesized that T-DM1 could significantly inhibit the growth of HER2+ lung cancers. We have launched a nonrandomized phase II trial of T-DM1 monotherapy for patients with HER2+ lung cancers. The major eligibility criteria are as follows: age >= 20 years, pathologically diagnosed NSCLC with documented HER2 positivity (immunohistochemistry 3+, both immunohistochemistry 2+ and fluorescence in situ hybridization positive, or exon 20 insertion mutation), and previous chemotherapy. Thirty patients will receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate. This trial will provide information on whether T-DM1 monotherapy is effective against HER2+ lung cancer. PMID- 27497830 TI - Efficient azo dye decolorization in a continuous stirred tank reactor (CSTR) with built-in bioelectrochemical system. AB - A continuous stirred tank reactor with built-in bioelectrochemical system (CSTR BES) was developed for azo dye Alizarin Yellow R (AYR) containing wastewater treatment. The decolorization efficiency (DE) of the CSTR-BES was 97.04+/-0.06% for 7h with sludge concentration of 3000mg/L and initial AYR concentration of 100mg/L, which was superior to that of the sole CSTR mode (open circuit: 54.87+/ 4.34%) and the sole BES mode (without sludge addition: 91.37+/-0.44%). The effects of sludge concentration and sodium acetate (NaAc) concentration on azo dye decolorization were investigated. The highest DE of CSTR-BES for 4h was 87.66+/-2.93% with sludge concentration of 12,000mg/L, NaAc concentration of 2000mg/L and initial AYR concentration of 100mg/L. The results in this study indicated that CSTR-BES could be a practical strategy for upgrading conventional anaerobic facilities against refractory wastewater treatment. PMID- 27497831 TI - Differences between colon and rectal cancer in complications, short-term survival and recurrences. AB - PURPOSE: Many apparent differences exist in aetiology, genetics, anatomy and treatment response between colon cancer (CC) and rectal cancer (RC). This study examines the differences in patient characteristics, prevalence of complications and their effect on short-term survival, long-term survival and the rate of recurrence between RC and CC. METHODS: For all stage II-III CC and RC patients who underwent resection with curative intent (2006-2008) in five hospitals in the Netherlands, occurrence of complications, crude survival, relative survival and recurrence rates were compared. RESULTS: A total of 767 CC and 272 RC patients underwent resection. Significant differences were found for age, gender, emergency surgery, T-stage and grade. CC patients experienced fewer complications compared to RC (p = 0.019), but CC patients had worse short-term mortality rates (1.5 versus 6.7 % for 30-day mortality, p = 0.001 and 5.2 versus 9.5 % for 90-day mortality, p = 0.032). The adjusted HR (overall survival) for CC patients with complications was 1.57 (1.23-2.01; p < 0.001) as compared to patients without complications; for RC, the HR was 1.79 (1.12-2.87; p = 0.015). Relative survival analyses showed high excess mortality in the first months after surgery and a sustained, prolonged negative effect on both CC and RC. Complications were associated with a higher recurrence rate for both CC and RC; adjusted analyses showed a trend towards a significant association. CONCLUSION: Large differences exist in patient characteristics and clinical outcomes between CC and RC. CC patients have a significantly higher short-term mortality compared to RC patients due to a more severe effect of complications. PMID- 27497833 TI - Increased aquaporin 1 and 5 membrane expression in the lens epithelium of cataract patients. AB - In this work we have analyzed the expression levels of the main aquaporins (AQPs) expressed in human lens epithelial cells (HLECs) using 112 samples from patients treated with cataract surgery and 36 samples from individuals treated with refractive surgery, with transparent lenses as controls. Aquaporin-1 (AQP1) is the main AQP, representing 64.1% of total AQPs in HLECs, with aquaporin-5 (AQP5) representing 35.9% in controls. A similar proportion of each AQP in cataract was found. Although no differences were found at the mRNA level compared to controls, a significant 1.65-fold increase (p=0.001) in AQP1protein expression was observed in HLECs from cataract patients, with the highest differences being found for nuclear cataracts (2.1-fold increase; p<0.001). A similar trend was found for AQP5 (1.47-fold increase), although the difference was not significant (p=0.161). Moreover we have shown increased membrane AQP5 protein expression in HLECs of patients with cataracts. No association of AQP1 or AQP5 expression levels with age or sex was observed in either group. Our results suggest regulation of AQP1 and AQP5 at the post-translational level and support previous observations on the implication of AQP1 and 5 in maintenance of lens transparency in animal models. Our results likely reflect a compensatory response of the crystalline lens to delay cataract formation by increasing the water removal rate. PMID- 27497832 TI - O-GlcNAcylation and neurodegeneration. AB - O-GlcNAcylation is a dynamic form of protein glycosylation which involves the addition of beta-d-N-acetylglucosamine (GlcNAc) via an O-linkage to serine or threonine residues of nuclear, cytoplasmic, mitochondrial and transmembrane proteins. The two enzymes responsible for O-GlcNAc cycling are O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA); their expression and activities in brain are age dependent. More than 1000 O-GlcNAc protein targets have been identified which play critical roles in many cellular processes. In mammalian brain, O GlcNAc modification of Tau decreases its phosphorylation and toxicity, suggesting a neuroprotective role of pharmacological elevation of brain O-GlcNAc for Alzheimer's disease treatment. Other observations suggest that elevating O-GlcNAc levels may decrease protein clearance or induce apoptosis. This review highlights some of the key findings regarding O-GlcNAcylation in models of neurodegenerative diseases. PMID- 27497835 TI - The postpartum triathlete. AB - The postpartum period in a woman's life is filled with numerous changes, including physical changes, changes in sleep habits, and learning how to best care for a newborn. A common goal among postpartum women is to either begin or resume an active lifestyle, which often includes physical activity such as running, biking and swimming. The postpartum athlete may discover barriers that prevent her from returning to or beginning an exercise routine. These obstacles include muscle weakness, fatigue, depression and physical changes that require exercise modification. The physical therapist is well-suited to properly assess, treat and manage the care of the postpartum athlete. Postpartum athletes wishing to begin or resume training for triathlons require special consideration, as the triathlete must balance training to compete in three different sports. The purpose of the paper is to identify the unique physical and physiological changes that occur to the female during the postpartum period. In addition, injuries that are more commonly seen during the postpartum period will be discussed. Recommendations for beginning or resuming an exercise program will be reviewed. Lastly, sport-specific training for the postpartum triathlete, including challenges presented with each triathlon component, will be discussed. PMID- 27497834 TI - Alterations in taste perception as a result of hyperbaric oxygen therapy. AB - The present study evaluates the effect of hyperbaric oxygen therapy on taste sensitivity, hedonic perception of taste, and food preferences. The studied groups included 197 people in total (79 in the study group; 118 in the control group). All patients from the study group were treated with hyperbaric oxygen therapy due to chronic non-healing wounds. The control group consisted of healthy people, who did not receive hyperbaric oxygen therapy. The taste intensity, recognition thresholds, and hedonic perception were examined using gustatory tests. The aqueous solutions of sucrose for sweet, sodium chloride for salty, citric acid for sour, quinine hydrochloride for bitter, and monosodium glutamate for umami taste were used. The participants fulfilled the questionnaire to examine pleasure derived from eating certain types of dishes. Gustatory tests and analyses of the pleasure derived from eating in the study group were carried out before the first exposure to hyperbaric oxygen and then at the end of therapy, after at least 25 sessions of treatment. In the control group, examination of perception of taste sensations was conducted only once. The results of comparing patients with non-healing wounds with healthy people are characterized by reduced taste sensitivity. After participation in hyperbaric oxygen therapy, the improvement in perception of taste sensations and changes in hedonic evaluation have occurred among patients with non-healing wounds. In terms of food preference, a decreased desire for eating sweet desserts, chocolate, and crisps was observed in those patients who received hyperbaric oxygen therapy. PMID- 27497836 TI - Progesterone attenuates impulsive action in a Go/No-Go task for sucrose pellets in female and male rats. AB - Impulsivity, or a tendency to act without anticipation of future consequences, is associated with drug abuse. Impulsivity is typically separated into two main measures, impulsive action and impulsive choice. Given the association of impulsivity and drug abuse, treatments that reduce impulsivity have been proposed as an effective method for countering drug addiction. Progesterone has emerged as a promising treatment, as it is associated with decreased addiction-related behaviors and impulsive action. The goal of the present study was to determine the effects of progesterone (PRO) on impulsive action for food: a Go/No-Go task. Female and male rats responded for sucrose pellets during a Go component when lever pressing was reinforced on a variable-interval 30-s schedule. During the alternate No-Go component, withholding a lever press was reinforced on a differential reinforcement of other (DRO) behavior 30-s schedule, where a lever press reset the DRO timer. Impulsive action was operationally defined as the inability to withhold a response during the No-Go component (i.e. the number of DRO resets). Once Go/No-Go behavior was stable, responding between rats treated with PRO (0.5mg/kg) or vehicle was examined. Progesterone significantly decreased the total number of DRO resets in both males and females, but it did not affect VI responding for sucrose pellets. This suggests that PRO decreases motor impulsivity for sucrose pellets without affecting motivation for food. Thus, PRO may reduce motor impulsivity, a behavior underlying drug addiction. PMID- 27497837 TI - Eculizumab epitope on complement C5: Progress towards a better understanding of the mechanism of action. AB - Eculizumab is an anti-complement C5 monoclonal antibody which has greatly improved the prognosis and outcomes of nocturnal paroxysmal hemoglobinuria and atypical hemolytic and uremic syndromes. It is also known to be very species specific for human C5, despite an important degree of conservation of the targeted macroglobulin domain, MG7, with that of other primates. However, the published eculizumab linear epitope does not explain this species specificity. Sequence analysis, in silico docking and reverse phase protein array were implemented to fully characterize the eculizumab epitope on human complement C5. Several residues potentially involved in the species specificity were identified outside the known epitope by sequence analysis. In silico docking confirmed the implication of a beta-hairpin located between residues 913 and 922, outside the known epitope, in the binding of eculizumab to C5. This beta-hairpin spreads from S913 to I922 and contains a tryptophan residue on position 917 which is unique to humans. The contribution of both this peptide and the already known one epitope, which spreads between residues C883 and S891, was validated by reverse phase protein assay, clearly demonstrating the discontinuous nature of the epitope. Two residues in particular, Arg885 and Trp917, were defined as major participants in the interaction of C5 and eculizumab. Their important role was confirmed by the recent publication of a crystal structure of eculizumab Fab bound to C5. The beta hairpin not only explains the fine species specificity of eculizumab but is also an important site at the C5/C5 convertase interface, revealing how eculizumab acts as a competitor of C5 convertases. PMID- 27497838 TI - Antenatal group consultations: Facilitating patient-patient education. AB - OBJECTIVE: This article investigates the perspectives of pregnant women attending antenatal group consultations to gain their understandings of whether and how peer learning is facilitated in this setting. METHODS: We conducted semi structured individual interviews with 16 women who had participated in group consultations at Aarhus University Hospital, Denmark, and analysed the data using qualitative content analysis. Our research design also included observations and patient guest book data. RESULTS: Women who were pregnant for the first time greatly appreciated the experiential knowledge of multiparous women in the group. Group consultations provided new learning opportunities, as individuals' questions prompted learning within the groups, as well as questions and answers. There was more time for reflection in group consultations than in dyadic communication. Midwives played a key role in facilitating peer learning. Some topics were not deemed appropriate for discussion. CONCLUSION: Antenatal group consultations can support learning, as individuals participate positively both in their own knowledge acquisition and that of others. We call such peer learning patient-patient education. PRACTICE IMPLICATIONS: Our study indicates the strengths of group consultations for learning from the perspective of the group members. It highlights how learning may be facilitated in group consultations, and thus has broad practical relevance. PMID- 27497839 TI - Mollusc models I. The snail Ilyanassa. AB - Ilyanassa obsoleta has been a model system for experimental embryology for over a century. Here we highlight new insight into early cell lineage specification in Ilyanassa. As in all molluscs and other spiralians, stereotyped cleavage patterns establish a homunculus of regional founder cells. Ongoing studies are beginning to dissect mechanisms of asymmetric cell division that specify these cells' fates. This is only part of the story: overlaid on intrinsic cell identities is a graded 'organizer' signal, and emerging evidence suggests wider roles for short range intercellular signaling. Modern methods, combined with the intrinsic experimental advantages of Ilyanassa, offer attractive opportunities for studying basic developmental cell biology as well as its evolution over a wide range of phylogenetic scales. PMID- 27497840 TI - Patient adherence and treatment outcome with exposure and response prevention for OCD: Which components of adherence matter and who becomes well? AB - Exposure and response prevention (EX/RP) is an evidence-based treatment for obsessive-compulsive disorder (OCD), yet not all patients achieve wellness with EX/RP. The degree to which patients adhere to EX/RP procedures outside of sessions has been found to predict therapy outcomes, including who achieves post treatment wellness. We sought to investigate which components of treatment adherence most relate to outcome and to develop adherence benchmarks to identify who does and does not become well to provide clinicians with prognostic tools. Adherence data came from 37 adult patients with DSM-IV OCD who received 17 sessions of EX/RP as part of a randomized controlled trial of augmentation strategies for incomplete response to serotonin reuptake inhibitors (SRIs). Therapists rated between-session patient adherence at each exposure session by quantifying: 1) the quantity of homework exposures attempted; 2) the quality of attempted exposures; and 3) the degree of success with response prevention. Each adherence item significantly correlated with post-treatment OCD severity. Success with response prevention proved particularly strongly linked to therapy outcome. Time course analysis of this item accurately identified, relatively early in treatment, who would achieve post-treatment wellness. These data provide an efficient method for differentiating between those patients who will and will not achieve wellness after EX/RP augmentation of SRIs. Limitations and clinical implications of the current findings are discussed. PMID- 27497841 TI - Low-frequency deep brain stimulation for movement disorders. AB - INTRODUCTION: Traditionally, deep brain stimulation (DBS) for movement disorders (MDs) is provided using stimulation frequencies equal to or above 100 Hz. However, recent evidence suggests that relatively low-frequency stimulation (LFS) below 100 Hz is an option to treat some patients with MDs. OBJECTIVES: We aimed to review the clinical and pathophysiological evidence supporting the use of stimulation frequencies below 100 Hz in different MDs. RESULTS: Stimulation of the subthalamic nucleus at 60 Hz has provided benefit in gait and other axial symptoms such as swallowing and speech. Stimulation of the pedunculopontine nucleus between 20 and 45 Hz can provide benefit in freezing of gait, cognition, and sleep quality in select patients with Parkinson's disease. Stimulation of the globus pallidus internus below 100 Hz in patients with dystonia has provided benefit at the beginning of the therapy, although progressively higher stimulation frequencies seem to be necessary to maintain the clinical benefit. Relative LFS can lower energy requirements and reduce battery usage-a useful feature, particularly in patients treated with high current energy. CONCLUSIONS: DBS at frequencies below 100 Hz is a therapeutic option in select cases of Parkinson's disease with freezing of gait and other axial symptoms, and in select patients with dystonia and other hyperkinetic movements, particularly those requiring an energy-saving strategy. PMID- 27497842 TI - Exploration of physical and chemical cues on retinal cell fate. AB - Identification of the key components in the physical and chemical milieu directing donor cells into a desired phenotype is a requirement in the investigation of bioscaffolds for the advancement of cell-based therapies for retinal neurodegeneration. We explore the effect of electrospun poly-epsilon caprolactone (PCL) fiber scaffold topography and functionalization and culture medium, on the behavior of mouse retinal cells. Dissociated mouse retinal post natal cells were seeded on random or aligned oriented fibers, with or without laminin coating and cultured with either basic or neurotrophins enriched medium for 7days. Addition of laminin in combination with neurotrophins clearly promoted cell- morphology, fate, and neurite extension. Nanotopography per se significantly affected cell morphology, with mainly bipolar profiles on aligned fibers and more multipolar profiles on random fibers. Laminin induced a remarkable 90 degrees switch of neurite orientation. Herewith, we demonstrate that the chemical cue is stronger than the physical cue for the orientation of retinal neurites and describe the requirement of both neurotrophins and extracellular matrix proteins for extended neurite outgrowth and formation of complex retinal neuronal networks. Therefore, tailor-made PCL fiber mats, which can be physically and chemically modified, indeed influence cell behavior and hence motivate further retinal restorative studies using this system. PMID- 27497843 TI - Multimodal correlative investigation of the interplaying micro-architecture, chemical composition and mechanical properties of human cortical bone tissue reveals predominant role of fibrillar organization in determining microelastic tissue properties. AB - The mechanical competence of bone is crucially determined by its material composition and structural design. To investigate the interaction of the complex hierarchical architecture, the chemical composition and the resulting elastic properties of healthy femoral bone at the level of single bone lamellae and entire structural units, we combined polarized Raman spectroscopy (PRS), scanning acoustic microscopy (SAM) and synchrotron X-ray phase contrast nano tomography (SR-nanoCT). In line with earlier studies, mutual correlation analysis strongly suggested that the characteristic elastic modulations of bone lamellae within single units are the result of the twisting fibrillar orientation, rather than compositional variations, modulations of the mineral particle maturity, or mass density deviations. Furthermore, we show that predominant fibril orientations in entire tissue units can be rapidly assessed from Raman parameter maps. Coexisting twisted and oscillating fibril patterns were observed in all investigated tissue domains. Ultimately, our findings demonstrate in particular the potential of combined PRS and SAM measurements in providing multi-scalar analysis of correlated fundamental tissue properties. In future studies, the presented approach can be applied for non-destructive investigation of small pathologic samples from bone biopsies and a broad range of biological materials and tissues. STATEMENT OF SIGNIFICANCE: Bone is a complex structured composite material consisting of collagen fibrils and mineral particles. Various studies have shown that not only composition, maturation, and packing of its components, but also their structural arrangement determine the mechanical performance of the tissue. However, prominent methodologies are usually not able to concurrently describe these factors on the micron scale and complementary tissue characterization remains challenging. In this study we combine X-ray nanoCT, polarized Raman imaging and scanning acoustic microscopy and propose a protocol for fast and easy assessment of predominant fibril orientations in bone. Based on our site-matched analysis of cortical bone, we conclude that the elastic modulations of bone lamellae are mainly determined by the fibril arrangement. PMID- 27497844 TI - Gelling kinetics and in situ mineralization of alginate hydrogels: A correlative spatiotemporal characterization toolbox. AB - Due to their large water content and structural similarities to the extracellular matrix, hydrogels are an attractive class of material in the tissue engineering field. Polymers capable of ionotropic gelation are of special interest due to their ability to form gels at mild conditions. In this study we have developed an experimental toolbox to measure the gelling kinetics of alginate upon crosslinking with calcium ions. A reaction-diffusion model for gelation has been used to describe the diffusion of calcium within the hydrogel and was shown to match experimental observations well. In particular, a single set of parameters was able to predict gelation kinetics over a wide range of gelling ion concentrations. The developed model was used to predict the gelling time for a number of geometries, including microspheres typically used for cell encapsulation. We also demonstrate that this toolbox can be used to spatiotemporally investigate the formation and evolution of mineral within the hydrogel network via correlative Raman microspectroscopy, confocal laser scanning microscopy and electron microscopy. STATEMENT OF SIGNIFICANCE: Hydrogels show great promise in cell-based tissue engineering, however new fabrication and modification methods are needed to realize the full potential of hydrogel based materials. The inclusion of an inorganic phase is one such approach and is known to affect both cell-material interactions and mechanical properties. This article describes the development of a correlative experimental approach where gel formation and mineralization has been investigated with spatial and temporal resolution by applying Raman microspectroscopy, optical and electron microscopy and a reaction-diffusion modeling scheme. Modeling allows us to predict gelling kinetics for other geometries and sizes than those investigated experimentally. Our experimental system enables non-destructive study of composite hydrogel systems relevant for, but not limited to, applications within bone tissue engineering. PMID- 27497845 TI - Biocompatibility and degradation of LAE442-based magnesium alloys after implantation of up to 3.5years in a rabbit model. AB - Magnesium as basic implant material has long been the center of orthopedic research. Latest progress is achieved with a European certification and clinical use of a magnesium based compression screw. However, long term studies with implantation duration that exceed one year considerably do not exist. The present examinations analyzed the degradation progress from nine months to 3.5year after implantation of cylindrical pins into the medullary cavity of New Zealand White rabbits. Evaluation included clinical assessment, in vivo MU-computed tomography, analysis of the implants by three-point-bending and examination of the adjacent tissue by means of histology and of inner organs by mass- and optical emission spectrometry using inductively coupled plasma. Clinical acceptance was without objections in all animals. Immoderate reaction of the surrounding bone could be found in neither of the applied techniques. While in vivo MU-computed tomography showed a very slow degradation rate up to 72weeks, three-point-bending revealed a percentage loss of F(max) of 41.1% for implants after 9months implantation and 88.47% for the implant after 3.5years implantation. Although the total amounts of RE detected in the inner organs were very low, the organs of rabbits with LAE442 cylinders showed 10-20-fold increased concentrations of the alloying elements lanthanum, cerium, neodymium and praseodymium compared to animals without any implanted material. STATEMENT OF SIGNIFICANCE: This is the first animal study investigating the degradation process of a magnesium alloy in vivo for up to 3.5years. Currently available data from different other in vivo studies cover only implantation durations up to one year. Therefore, the analysis of these long time effects in the present study is highly significant and of great interest. Comprehensive outcome achieved by different techniques was assessed. The degradation process was slow and homogenous. Maximum applied force (F(max)) reduced by 41.1% for implants after 9months and by 88.47% for the implant after 3.5years implantation. Total amounts of RE detected in the inner organs were very low; the organs of rabbits with LAE442 cylinders showed 10-20-fold increased concentrations. PMID- 27497846 TI - The Use of Anagrelide in Myeloproliferative Neoplasms, with Focus on Essential Thrombocythemia. AB - Anagrelide (ANA) is a drug with specific platelet-lowering activity, used primarily in ET, registered as a second-line drug in essential thrombocythemia (ET) in Europe and in some countries as first-line therapy, in USA licensed by FDA for thrombocythemia in myeloproliferative neoplasms (MPN). The platelet lowering efficacy is similar to that of hydroxycarbamide (HC), around 70 % complete response and 90 % partial response. Side effects are common, especially headache and tachycardia, but usually subside or disappear within a few weeks. Around 20 % of patients stop ANA therapy due to side effects or insufficient response. Studies of treatment patterns in Europe show that ANA is preferentially given to younger patients, probably because of the concern for a possible leukemogenic effect of the common first-line drug, HC. Only two randomized studies have compared the efficacy of ANA and HC in preventing thrombosis and haemorrhage, the larger of them showing a slightly better efficacy of HC, the other showing non-inferiority of ANA to HC. A recent observational 5-year study of 3600 patients shows a low and basically similar efficacy of ANA and other cytoreductive therapies in ET. ANA does not appear to inhibit fibrosis development, and probably due to its anticoagulation properties, the combination of ASA and ANA produces an increased rate of haemorrhage. Combination of ANA with HC or interferon (IFN) is feasible and effective in patients with insufficient platelet response to mono-therapy. PMID- 27497847 TI - Outcomes of pre-emptive and rescue use of percutaneous left ventricular assist device in patients with structural heart disease undergoing catheter ablation of ventricular tachycardia. AB - PURPOSE: Patient selection and timing of percutaneous left ventricular assist device (pLVAD) insertion for maximal benefit during ventricular tachycardia (VT) ablation is not well defined. We aimed to assess the outcomes of pre-emptive and rescue use of pLVAD during VT ablation in patients with ischemic and non-ischemic cardiomyopathy. METHODS: Between January 2009 and October 2011, 93 patients underwent VT ablation. Three groups were compared: (1) Rescue group (n = 12) patients who required emergent pLVAD insertion due to hemodynamic collapse during VT ablation, (2) Pre-emptive group (n = 24)-patients who had pre-ablation pLVAD insertion, and (3) Non-pLVAD group (n = 57)-patients who did not undergo pLVAD insertion. Procedural outcomes including 30-day mortality were compared. RESULTS: Thirty-day mortality was higher in the Rescue group compared to the Pre-emptive group (58 vs. 4 %, p = 0.003) and non-pLVAD (58 vs. 3 %, p = 0.001) group. There was no significant difference in 30-day mortality or long-term freedom of VT between the pre-emptive and non-pLVAD groups. CONCLUSIONS: Despite rescue pLVAD insertion, hemodynamic collapse during VT ablation is associated with a persistently high 30-day mortality. Further studies are warranted to predict hemodynamic collapse and to refine the role of pLVAD in this setting. PMID- 27497848 TI - Functional coupling of TRPV4 channels and BK channels in regulating spontaneous contractions of the guinea pig urinary bladder. AB - We investigated the role of TRPV4 channels (TRPV4) in regulating the contractility of detrusor smooth muscle (DSM) and muscularis mucosae (MM) of the urinary bladder. Distribution of TRPV4 in DSM and MM of guinea-pig bladders was examined by fluorescence immunohistochemistry. Changes in the contractility of DSM and MM bundles were measured using isometric tension recording. Intracellular Ca(2+) dynamics were visualized by Cal-520 fluorescent Ca(2+) imaging, while membrane potential changes were recorded using intracellular microelectrode technique. DSM and MM expressed TRPV4 immunoreactivity. GSK1016790A (GSK, 1 nM), a TRPV4 agonist, evoked a sustained contraction in both DSM and MM associated with a cessation of spontaneous phasic contractions in a manner sensitive to HC 067047 (10 MUM), a TRPV4 antagonist. Iberiotoxin (100 nM) and paxilline (1 MUM), large conductance Ca(2+)-activated K(+) (BK) channel blockers restored the spontaneous contractions in GSK. The sustained contractions in DSM and MM were reduced by nifedipine (10 MUM), a blocker of L-type voltage-dependent Ca(2+) channels (LVDCCs) by about 40 % and by nominally Ca(2+)-free solution by some 90 %. GSK (1 nM) abolished spontaneous Ca(2+) transients, increased basal Ca(2+) levels and also prevented spontaneous action potential discharge associated with DSM membrane hyperpolarization. In conclusion, Ca(2+) influx through TRPV4 appears to activate BK channels to suppress spontaneous contractions and thus a functional coupling of TRPV4 with BK channels may act as a self-limiting mechanism for bladder contractility during its storage phase. Despite the membrane hyperpolarization in GSK, Ca(2+) entry mainly through TRPV4 develops the tonic contraction. PMID- 27497849 TI - Highway increases concentrations of toxic metals in giant panda habitat. AB - The Qinling panda subspecies (Ailuropoda melanoleuca qinlingensis) is highly endangered with fewer than 350 individuals inhabiting the Qinling Mountains. Previous studies have indicated that giant pandas are exposed to heavy metals, and a possible source is vehicle emission. The concentrations of Cu, Zn, Mn, Pb, Cr, Ni, Cd, Hg, and As in soil samples collected from sites along a major highway bisecting the panda's habitat were analyzed to investigate whether the highway was an important source of metal contamination. There were 11 sites along a 30-km stretch of the 108th National Highway, and at each site, soil samples were taken at four distances from the highway (0, 50, 100, and 300 m) and at three soil depths (0, 5, 10 cm). Concentrations of all metals except As exceeded background levels, and concentrations of Cu, Zn, Mn, Pb, and Cd decreased significantly with increasing distance from the highway. Geo-accumulation index indicated that topsoil next to the highway was moderately contaminated with Pb and Zn, whereas topsoil up to 300 m away from the highway was extremely contaminated with Cd. The potential ecological risk index demonstrated that this area was in a high degree of ecological hazards, which were also due to serious Cd contamination. And, the hazard quotient indicated that Cd, Pb, and Mn especially Cd could pose the health risk to giant pandas. Multivariate analyses demonstrated that the highway was the main source of Cd, Pb, and Zn and also put some influence on Mn. The study has confirmed that traffic does contaminate roadside soils and poses a potential threat to the health of pandas. This should not be ignored when the conservation and management of pandas is considered. PMID- 27497850 TI - Polycyclic aromatic hydrocarbons and trace metals in mosque's carpet dust of Riyadh, Saudi Arabia, and their health risk implications. AB - The main objectives of this work were to identify and determine the concentrations of polycyclic aromatic hydrocarbons (PAHs) and trace metals in carpet dust samples from various mosques of the city of Riyadh and to assess the health risks associated with the exposure to these pollutants. Therefore, 31 samples of mosque's carpet dust from Riyadh were collected. The results showed that 14 PAHs were present in the dust samples with concentrations ranged from 90 to 22,146 ng g-1 (mean = 4096 +/- 4277 ng g-1) where low molecular weight compounds were dominant. The presence of PAHs were in the order of naphthalene > chrysene and benzo(b)fluoranthene > benzo(a)pyrene > acenaphthene and benzo(k)fluoranthene > pyrene and the absence of indeno(1,2,3-cd)pyrene and dibenz(a,h)anthracene. The diagnostic ratio coupled with principle component analysis (PCA) revealed mix sources of petrogenic from traffic, stack emission, and pyrogenic inputs from essence and perfumed wood burning. Trace metals were significant in the dust samples, and their concentrations decrease in the order of Zn, Mn, Cu, Cr, Pb, Ni, and V where Zn being the highest (94.4 +/- 91.5 MUg g 1) and indium was the lowest (1.9 +/- 9.3 MUg g-1). The trace metals were major in southern and central parts of Riyadh and followed the order of central Riyadh > southern Riyadh > western Riyadh > eastern Riyadh > northern Riyadh. Estimated risk based on the total PAHs was found to be 4.30 * 10-11 for adult and 1.56 * 10 11 for children. Elemental non-cancer risk for adults ranged from 7.9 * 10-4 for Co to 7.58 * 10-1 for Li and for children ranged from 3.70 * 10-3 for Co to 3.54 for Li. Policy implication and mitigations of PAHs in Riyadh and Saudi Arabia were highlighted. PMID- 27497851 TI - The effects of air pollution on human mortality: does gender difference matter in African countries? AB - The relationship between environmental factors and human health has long been a concern among academic researchers. We use two indicators of environmental pollution, namely particulate matter (PM10) and carbon dioxide (CO2) to examine the effects of poor air quality on human mortality. This study explores an issue that has largely been ignored, particularly in the African literature, where the effect of air pollution on human mortality could be influenced by gender specification. We analyse a panel data from 35 African countries and our result suggests that the elevated levels of PM10 and CO2 have a significant effect on the increasing mortality rates in infants, under-five children and adults. Although the effect of poor air quality on adults is found to differ between genders, such difference is not statistically significant. We conclude that the air pollution effects, on average, are similar between genders in the African countries. PMID- 27497852 TI - Geochemical indicators of the origins and evolution of methane in groundwater: Gippsland Basin, Australia. AB - Recent expansion of shale and coal seam gas production worldwide has increased the need for geochemical studies in aquifers near gas deposits, to determine processes impacting groundwater quality and better understand the origins and behavior of dissolved hydrocarbons. We determined dissolved methane concentrations (n = 36) and delta13C and delta2H values (n = 31) in methane and groundwater from the 46,000-km2 Gippsland Basin in southeast Australia. The basin contains important water supply aquifers and is a potential target for future unconventional gas development. Dissolved methane concentrations ranged from 0.0035 to 30 mg/L (median = 8.3 mg/L) and were significantly higher in the deep Lower Tertiary Aquifer (median = 19 mg/L) than the shallower Upper Tertiary Aquifer (median = 3.45 mg/L). Groundwater delta13CDIC values ranged from -26.4 to -0.4 0/00 and were generally higher in groundwater with high methane concentrations (mean delta13CDIC = -9.5 0/00 for samples with >3 mg/L CH4 vs. 16.2 0/00 in all others), which is consistent with bacterial methanogenesis. Methane had delta13CCH4 values of -97.5 to -31.8 0/00 and delta2HCH4 values of 391 to -204 0/00 that were also consistent with bacterial methane, excluding one site with delta13CCH4 values of -31.8 to -37.9 0/00, where methane may have been thermogenic. Methane from different regions and aquifers had distinctive stable isotope values, indicating differences in the substrate and/or methanogenesis mechanism. Methane in the Upper Tertiary Aquifer in Central Gippsland had lower delta13CCH4 (-83.7 to -97.5 0/00) and delta2HCH4 (-236 to -391 0/00) values than in the deeper Lower Tertiary Aquifer (delta13CCH4 = -45.8 to -66.2 0/00 and delta2HCH4 = -204 to -311 0/00). The particularly low delta13CCH4 values in the former group may indicate methanogenesis at least partly through carbonate reduction. In deeper groundwater, isotopic values were more consistent with acetate fermentation. Not all methane at a given depth and location is interpreted as being necessarily produced in situ. We propose that high dissolved sulphate concentrations in combination with high methane concentrations can indicate gas resulting from contamination and/or rapid migration as opposed to in situ bacterial production or long-term migration. Isotopes of methane and dissolved inorganic carbon (DIC) serve as further lines of evidence to distinguish methane sources. The study demonstrates the value of isotopic characterisation of groundwater including dissolved gases in basins containing hydrocarbons. PMID- 27497853 TI - Evaluating the effect of age and area of residence in the metal and metalloid contents in human hair and urban topsoils. AB - Monitoring the levels of trace elements in hair can allow estimating the effects of the geographical location and also can provide a notion of the metal body burden. However, the use of human hair is controversial due to the different confounding factors that could affect the presence of trace elements in hair. As a result, a comprehensive monitoring study was performed in Alcala de Henares, one of the major cities in the Madrid region, Spain. Trace elements have been monitored in urban topsoils and in human hair of two well-defined and healthy groups of population: children (6-9 years) and adolescents (13-16 years). The city was divided into four areas or zones with different characteristics to assess the possible effect of area of residence and age in the presence of Al, As, Be, Cd, Cr, Cu, Hg, Mn, Pb, Sn, Ti, Tl and Zn in soils and hair. There is no current hypothesis that explains the possible effect of the area of monitoring in the distribution of Be, Cr, Ni, Sn and Ti found in these urban soils, maybe because urban soils receive high disturbance, and there are many factors involved. The presence of most of the trace elements monitored was significantly higher in the hair of the children population, except for Sn and Zn. This could be attributed mainly to dietary habits. Other factors influencing metal content in hair such as environmental factors would have had a minimal effect in the population groups here studied. Finally, none of the levels of trace elements studied in hair were significantly correlated with levels measured in the topsoils of public parks in Alcala de Henares, with the exception of Pb in adolescent participants. PMID- 27497854 TI - Photocatalytic ozonation of pesticides in a fixed bed flow through UVA-LED photoreactor. AB - In this study, a fixed bed flow through UVA-LED photoreactor was used to compare the efficiency of ozone, photocatalysis and photocatalysis-ozone degradation, and mineralization of two pure pesticides, 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-methyl-4-chlorophenoxyacetic acid (MCPA), and a commercial one, Killex(r). For the degradation of the parent compounds, ozone-based processes were more effective. While for mineralization, photocatalytic processes were more effective. Photocatalytic ozonation was the most efficient process for both the degradation and mineralization of the parent compounds. The degradation rates and mineralization by photocatalytic ozonation were higher than the summation of the corresponding rates by ozonation and photocatalysis, indicating a symbiotic relationship.Overall, the photocatalytic ozonation process with the fixed bed TiO2 reduces the time needed for the degradation and mineralization of the pesticides, reduces the costs of powder catalyst separation and overcomes the reduced efficiency of immobilized catalysts, which makes the process quite attractive for practical applications. PMID- 27497855 TI - Fat type in phytosterol products influence their cholesterol-lowering potential: A systematic review and meta-analysis of RCTs. AB - The most common form of phytosterol (PS) fortified foods are fat spreads and dairy products. The predominant fats used are soybean/sunflower (SS) or rapeseed/canola (RC) oils and animal fat (D) in dairy products. This review aimed to investigate whether the carrier fat is a determinant of the hypocholesterolaemic effects of PS fortified foods. Databases were searched using relevant keywords and published RCTs from 1990 investigating the effects of dietary PS intervention (>=1.5g per day) on total cholesterol and LDL-C were included. After methodological quality assessment and data extraction, a total of 32 RCTs (RC, n=15; SS, n=9; D, n=8) were included. As expected, all fat groups significantly reduced TC and LDL-C (p<0.01). When compared across different carrier fats, RC as the main carrier fat, reduced LDL-C significantly more than the SS spreads (p=0.01). Therefore, a combination of monounsaturated fatty acid rich spread with adequate amounts of omega-3 fatty acids (as evident in RC spreads) may be the superior carrier fat for the delivery of PS for optimal blood cholesterol-lowering. The findings of this research provide useful evidence for optimising the hypocholesterolaemic effects of PS and support further investigation into the possible mechanisms behind these findings. PMID- 27497856 TI - Thrombotic Microangiopathy Care Pathway: A Consensus Statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group. AB - Thrombotic microangiopathies (TMAs) comprise a heterogeneous set of conditions linked by a common histopathologic finding of endothelial damage resulting in microvascular thromboses and potentially serious complications. The typical clinical presentation is microangiopathic hemolytic anemia accompanied by thrombocytopenia with varying degrees of organ ischemia. The differential diagnoses are generally broad, while the workup is frequently complex and can be confusing. This statement represents the joint recommendations from a multidisciplinary team of Mayo Clinic physicians specializing in the management of TMA. It comprises a series of evidence- and consensus-based clinical pathways developed to allow a uniform approach to the spectrum of care including when to suspect TMA, what differential diagnoses to consider, which diagnostic tests to order, and how to provide initial empiric therapy, as well as some guidance on subsequent management. PMID- 27497857 TI - Racial Disparities in Inhospital Outcomes for Hepatocellular Carcinoma in the United States. AB - OBJECTIVE: To study racial disparities in therapeutic interventions and hospitalization outcomes for hepatocellular cancer (HCC) in the United States. PATIENTS AND METHODS: Using the 2011 Nationwide Inpatient Sample (comprising hospitalizations between January 1 and December 31, 2011), we identified patients with HCC-related admissions using previously validated International Classification of Diseases, Ninth Revision, Clinical Modification codes. Among these, we also identified those that were procedure-related (associated with liver transplantation, hepatic resection, radiofrequency ablation, or transarterial chemoembolization). Multivariate regression was performed to identify the contribution of race to therapeutic interventions and outcomes. RESULTS: A total of 22,933 HCC-related hospitalizations were included, of which 10,285 were procedure related (45%). Blacks had a smaller proportion (35%) of procedure-related HCC hospitalizations than did whites (46%) (odds ratio [OR], 0.65; 95% CI, 0.49-0.86). Specifically, blacks had lower odds of liver transplantation (OR, 0.43; 95% CI, 0.26-0.71), hepatic resection (OR, 0.57; 95% CI, 0.33-0.98), and ablation (OR, 0.46; 95% CI, 0.29-0.74) (P=.002) than did whites. Overall, 10.9% of HCC-related admissions resulted in death in blacks as compared with 6.4% in whites (OR, 1.58; 95% CI, 1.12-2.24). CONCLUSION: Among patients admitted for HCC-related hospitalizations, blacks were less likely to receive liver transplantation, hepatic resection, and ablation than whites and had higher inhospital mortality. Identifying racial disparities in health care is a necessary first step to appropriately address and eliminate them. PMID- 27497858 TI - Measuring physicians' trust: A scoping review with implications for public policy. AB - Increasingly, physicians are expected to work in productive, trusting relationships with other health system stakeholders to improve patient and system outcomes. A better understanding of physicians' trust is greatly needed. This study assesses the state of the literature on physicians' trust in patients, other health care providers, institutions, and data systems or technology, and identifies key themes, dimensions of trust considered, quantitative measures used, and opportunities for further development via a scoping review. Peer reviewed, English-language research articles were identified for inclusion in this study based on systematic searches of the Ovid/Medline, Pubmed, Proquest, Scopus, Elsevier, and Web of Science databases. Search terms included "trust" along with "physician," "doctor," "primary care provider," "family practitioner," "family practice," "generalist," "general practitioner," "general practice," "internist," "internal medicine," or "health professional," and plausible variants. Among the relevant articles identified (n = 446), the vast majority focused on patient trust in physicians (81.2%). Among articles examining physicians' trust, rigorous investigations of trust are rare, narrowly focused, and imprecise in their discussion of trust. Robust investigations of the effects of trust or distrust-as opposed to trust's determinants-and studies using validated quantitative trust measures are particularly rare. Studies typically measured trust using the language of confidence, effective communication, or cooperation, rarely or never capturing other important dimensions of trust, such as fidelity, the trustee's reputation, social capital, vulnerability, and acceptance. Research employing new, validated measures of physicians' trust, especially trust in institutions, may be highly informative to health system leaders and policymakers seeking to hone and enhance tools for improving the effectiveness and efficiency of the health care system. PMID- 27497859 TI - "Whether something cool is good enough": The role of evidence, sales representatives and nurses' expertise in hospital purchasing decisions. AB - The emphasis on "value" within healthcare institutions has achieved unprecedented priority, particularly around the purchase of medical products and equipment. Health systems and institutions are implementing formal decision-making processes involving clinicians and supply chain professionals to rationalize purchasing and promote cost-effective investment. One particular form of this process is the "Value Analysis" process. Drawing from fieldwork (100 h), interviews (n = 51) and focus groups (n = 4) conducted from January 2012 to October 2014 at 4 acute care hospitals in the western United States, I analyze the ways that committee members constructed and evaluated a case for a product's value. Participants (n = 72) were a purposive sample including nurses, administrators, supply chain and industry professionals. Interpretive phenomenology served as the analytic approach to generating iterative themes. While trying to be evidence-based, Value Analysis committees lacked data related to a product's price or efficacy and relied heavily on local knowledge and expertise. Sales representatives were an integral part of the process, creating interest in the product and providing product information. As vehicles for cost-savings and quality improvement, purchasing committees need unique support that emphasizes local contexts and expertise, while maintaining rigor and minimizing bias. Drawing from participants' experiences, and principles of health technology assessment and economic evaluation, a guiding framework is proposed to support this decision making. PMID- 27497860 TI - Truth and lies: Disclosure and the power of diagnosis. AB - The moment at which a diagnosis is delivered to a patient, particularly when it is serious, is an important social moment. It not only dictates the clinical pathway, it also rewrites the patient narrative, shifts their identity, predicts potential outcomes, and foregrounds mortality. It may provide a sense of relief, or one of despair. Over time, and across cultures, there have been many different approaches used to palliate the potential impact of the diagnostic utterance on the patient. France, as one example, provides an interesting case study. Until the turn of the century, cancer diagnoses were often concealed from patients. However, recent legislation now requires full diagnostic disclosure according to prescribed protocols. Using Zerubavel's social patterning methodology, and transcultural historical methods, I seek to understand beliefs about the potential impact of the diagnostic moment by identifying common features across cultural and historical social contexts. I examine writings of French oncologists, and physicians in related fields, from the pre- and post-legislation era who discuss if and how a cancer diagnosis should be disclosed to the patient. While the approach to diagnostic disclosure has changed significantly, medical representations of diagnostic power have not. The diagnostic utterance is still cast by medical professionals as a terrifying and life-disrupting moment. PMID- 27497861 TI - Syrian crisis: aid delivery becoming increasingly difficult. PMID- 27497862 TI - Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. AB - BACKGROUND: CTX0E03 is an immortalised human neural stem-cell line from which a drug product (CTX-DP) was developed for allogeneic therapy. Dose-dependent improvement in sensorimotor function in rats implanted with CTX-DP 4 weeks after middle cerebral artery occlusion stroke prompted investigation of the safety and tolerability of this treatment in stroke patients. METHODS: We did an open-label, single-site, dose-escalation study. Men aged 60 years or older with stable disability (National Institutes of Health Stroke Scale [NIHSS] score >=6 and modified Rankin Scale score 2-4) 6-60 months after ischaemic stroke were implanted with single doses of 2 million, 5 million, 10 million, or 20 million cells by stereotactic ipsilateral putamen injection. Clinical and brain imaging data were collected over 2 years. The primary endpoint was safety (adverse events and neurological change). This trial is registered with ClinicalTrials.gov, number NCT01151124. FINDINGS: 13 men were recruited between September, 2010, and January, 2013, of whom 11 (mean age 69 years, range 60-82) received CTX-DP. Median NIHSS score before implantation was 7 (IQR 6-8) and the mean time from stroke was 29 (SD 14) months. Three men had subcortical infarcts only and seven had right-hemisphere infarcts. No immunological or cell-related adverse events were seen. Other adverse events were related to the procedure or comorbidities. Hyperintensity around the injection tracts on T2-weighted fluid-attenuation inversion recovery MRI was seen in five patients. At 2 years, improvement in NIHSS score ranged from 0 to 5 (median 2) points. INTERPRETATION: Single intracerebral doses of CTX-DP up to 20 million cells induced no adverse events and were associated with improved neurological function. Our observations support further investigation of CTX-DP in stroke patients. FUNDING: ReNeuron Limited. PMID- 27497863 TI - Age of PISCES: stem-cell clinical trials in stroke. PMID- 27497864 TI - Photoluminescence properties and thermal stability of blue-emitting Ba5 xCl(PO4)3:xEu2+ (0.004<=x<=0.016) phosphors. AB - A series of blue-emitting Ba5-xCl(PO4)3:xEu2+ (0.004<=x<=0.016) phosphors were synthesized by conventional high-temperature solid state reaction. The structure and photoluminescence (PL) properties of the phosphors were investigated. The as prepared phosphors exhibit broad excitation band ranging from 250 to 420nm, and strong asymmetric blue emission band peaking at 436nm. The optimum concentration of Eu2+ in the Ba5Cl(PO4)3:Eu2+ phosphor is x=0.01, and the concentration quenching mechanism is verified to be the combined actions of dipole-dipole interaction and radiation re-absorption mechanism. The thermal stability of Ba5Cl(PO4)3:Eu2+ was evaluated by temperature-dependent PL spectra. Compared with that of commercial BaMgAl10O17:Eu2+ (BAM) phosphor, the Ba5-xCl(PO4)3:xEu2+ phosphors exhibit similarly excellent thermal quenching property. In addition, the CIE chromaticity coordinates of Ba5-xCl(PO4)3:xEu2+ (0.004<=x<=0.016) were calculated to evaluate the color quality. All the results indicate that Ba5Cl(PO4)3:Eu2+ is a promising candidate phosphor for near-ultraviolet (n-UV) pumped LED. PMID- 27497865 TI - A theoretical study on monoatomic BN nanochains and nanorings. AB - Boron nitride (BN) nanochains were successfully synthesized recently. In this work, we investigate the electronic, energetic, and structural properties of BN nanochains and nanorings by means of density functional theory calculations. Our calculations support the experimental findings and offer additional physical insights into these new nanostructured materials. We show that BN nanochains are biracial compounds that tend to be closed and form a ring. They have single and double bonds alternately throughout the chain. The boron atoms are not saturated and are strong Lewis acids. Increase in the length of the chain tends to result in the conversion from a semiconductor to a semimetal material. The ring structures are stabler than the corresponding chains, and unlike the chains these structures are predicted to be insulators. The binding energy of the chains and rings increases with an increase in their size. Rings with odd or even numbers of BN units show different electronic properties. PMID- 27497866 TI - The association between oral health literacy and missed dental appointments. AB - BACKGROUND: In this study, the author identified associations among demographic characteristics, dental risk factors, health-seeking behaviors, oral health literacy level, and failure to keep dental appointments. METHODS: The author conducted an unmatched 1:2 case-control study at a university-based dental clinic from February through April 2015. The author used the Comprehensive Measure of Oral Health Knowledge questionnaire to record the oral health literacy of the respondents. The author obtained additional information about the various covariates using a questionnaire and checking the patients' electronic medical records. The author used a multivariate logistic regression analysis to test the associations between missed appointments and other risk factors in addition to oral health literacy. RESULTS: Data from 150 (50 case patients and 100 control patients) respondents were included in the analysis. The case and control patients were comparable in terms of sociodemographic characteristics and dental risk factors. The Comprehensive Measure of Oral Health Knowledge score was used to categorize the sample into low (<= 18) and high (> 18) oral health literacy groups. Low oral health literacy was associated with a 2-fold increase in the risk of having missed appointments (adjusted odds ratio, 2.38; 95% confidence interval, 1.05-5.40). Age was also independently associated with missed appointments (adjusted odds ratio, 1.03; 95% confidence interval, 1.01-1.06). CONCLUSIONS: After adjusting for the various demographic and dental risk factors, poor oral health literacy was found to be independently associated with missed dental appointments. Insights into the role of oral health literacy and clinic attendance could play an important role in addressing the problem of missed dental appointments. PRACTICAL IMPLICATIONS: Considering the effects of missed appointments on treatment outcomes, predictors of patient compliance behaviors may be useful in circumventing cancellations and no shows. PMID- 27497867 TI - The "de-aging" of the dentist workforce. PMID- 27497868 TI - Multiplex method for initial complex testing of antibodies to blood transmitted diseases agents. AB - Initial screening of donors and population at high risk of infection with blood transmitted diseases involves a number of analyses using monospesific diagnostic systems, and therefore is expensive labor- and time-consuming process. The goal of this work is to construct a multiplex test enabling to carry out rapid initial complex testing at a low price. The paper describes a kit making it possible to detect simultaneously antibodies to six agents of the most significant blood transmitted diseases: HIV virus, hepatitis B and C viruses, cytomegalovirus, T. pallidum and T. gondii in blood products. The kit comprises multiplex dot immunoassay based on plane protein arrays (immune chips) using colloidal gold conjugates and silver development. It provides an opportunity to carry out complex analysis within 70min at room temperature, and there is no need of well qualified personnel. We compared laboratory findings of the kit with monospecific kits for ELISA produced by two Russian commercial companies. Dot-assay results correlate well with data obtained using commercial kits for ELISA. Furthermore, multiplex analysis is quicker and cheaper in comparison with ELISA and can be carried out in non-laboratory conditions. The kit for multiplex dot-immunoassay of antibodies to blood transmitted agents can significantly simplify initial complex testing. PMID- 27497869 TI - Cytotoxic constituents of Alocasia macrorrhiza. AB - An indole alkaloid, 2-(5-hydroxy-1H-indol-3-yl)-2-oxo-acetic acid (1) isolated for the first time from nature, in addition to the nine known compounds 5-hydroxy 1H-indole-3-carboxylic acid methyl ester (2), alocasin B (3), hyrtiosin B (4), alpha-monopalmitin (5), 1-O-beta-D-glucopyranosyl-(2S, 3R, 4E, 8Z)-2-[(2(R) hydroctadecanoyl) amido]-4,8-octadecadiene-1,3-diol (6), 3-epi-betulinic acid (7), 3-epi-ursolic acid (8), beta-sitosterol (9) and beta-sitosterol 3-O-beta-D glucoside (10) were isolated from the rhizomes of Alocasia macrorrhiza (Araceae). Their structures were elucidated by 1D and 2D NMR spectroscopic data. Of these compounds, 6 exhibited the strongest cytotoxicity against the four tested human cancer cell lines (IC50 of about 10 uM against Hep-2 larynx cancer cells). PMID- 27497870 TI - Semiparametric Regression Estimation for Recurrent Event Data with Errors in Covariates under Informative Censoring. AB - Recurrent event data arise frequently in many longitudinal follow-up studies. Hence, evaluating covariate effects on the rates of occurrence of such events is commonly of interest. Examples include repeated hospitalizations, recurrent infections of HIV, and tumor recurrences. In this article, we consider semiparametric regression methods for the occurrence rate function of recurrent events when the covariates may be measured with errors. In contrast to the existing works, in our case the conventional assumption of independent censoring is violated since the recurrent event process is interrupted by some correlated events, which is called informative drop-out. Further, some covariates may be measured with errors. To accommodate for both informative censoring and measurement error, the occurrence of recurrent events is modelled through an unspecified frailty distribution and accompanied with a classical measurement error model. We propose two corrected approaches based on different ideas, and we show that they are numerically identical when estimating the regression parameters. The asymptotic properties of the proposed estimators are established, and the finite sample performance is examined via simulations. The proposed methods are applied to the Nutritional Prevention of Cancer trial for assessing the effect of the plasma selenium treatment on the recurrence of squamous cell carcinoma. PMID- 27497871 TI - Cloning and comparative analysis the proximal promoter activities of arginase and agmatinase genes in Apostichopus japonicus. AB - Our previous work demonstrated that Apostichopus japonicus arginase and agmatinase from l-arginine metabolism synergistically compete with NOS under pathogens challenge. Here we conducted a study to further investigate the mechanism in the regulation of arginase and agmatinase genes in l-arginine metabolism using EPC cell system. Luciferase analysis and progressive 5' deletion analysis suggested that Ajagmatinase promoter was a very robust promoter for its transcription, and the core region of Ajarginase promoter was located within -277 bp to -157 bp. Besides, their promoter activities were significantly activated by LPS and l-arginine challenge both in a time- and dose-dependent manners in EPC cells. When different truncated reporter vector and expression vector co transfection experiment revealed transcription factor NF-kappaB/Rel and STAT5 could significantly inhibited Ajarginase promoter activity, but not Ajagmatinase. Our findings were provided novel insights into the transcriptional regulation of Ajarginase and Ajagmatinase, and selectively change their expressions might prevent pathogens infection. PMID- 27497872 TI - Antibody repertoire development in fetal and neonatal piglets. XXIV. Hypothesis: The ileal Peyer patches (IPP) are the major source of primary, undiversified IgA antibodies in newborn piglets. AB - The ileal Peyers patches (IPP) of newborn germfree (GF) piglets were isolated into blind loops and the piglets colonized with a defined probiotic microflora. After 5 weeks, IgA levels in the intestinal lavage (IL) of loop piglets remained at GF levels and IgM comprised ~70% while in controls, IgA levels were elevated 5 fold and comprised ~70% of total Igs. Loop piglets also had reduced serum IgA levels suggesting the source of serum IgA had been interrupted. The isotype profile for loop contents was intermediate between that in the IL of GF and probiotic controls. Surprisingly, colonization alone did not result in repertoire diversification in the IPP. Rather, colonization promoted pronounced proliferation of fully switched IgA(+)IgM(-) B cells in the IPP that supply early, non-diversified "natural" SIgA antibodies to the gut lumen and a primary IgA response in serum. PMID- 27497873 TI - Mycobacterium tuberculosis strains exhibit differential and strain-specific molecular signatures in pulmonary epithelial cells. AB - Although pulmonary epithelial cells are integral to innate and adaptive immune responses during Mycobacterium tuberculosis infection, global transcriptomic changes in these cells remain largely unknown. Changes in gene expression induced in pulmonary epithelial cells infected with M. tuberculosis F15/LAM4/KZN, F11, F28, Beijing and Unique genotypes were investigated by RNA sequencing (RNA-Seq). The Illumina HiSeq 2000 platform generated 50 bp reads that were mapped to the human genome (Hg19) using Tophat (2.0.10). Differential gene expression induced by the different strains in infected relative to the uninfected cells was quantified and compared using Cufflinks (2.1.0) and MeV (4.0.9), respectively. Gene expression varied among the strains with the total number of genes as follows: F15/LAM4/KZN (1187), Beijing (1252), F11 (1639), F28 (870), Unique (886) and H37Rv (1179). A subset of 292 genes was commonly induced by all strains, where 52 genes were down-regulated while 240 genes were up-regulated. Differentially expressed genes were compared among the strains and the number of induced strain-specific gene signatures were as follows: F15/LAM4/KZN (138), Beijing (52), F11 (255), F28 (55), Unique (186) and H37Rv (125). Strain-specific molecular gene signatures associated with functional pathways were observed only for the Unique and H37Rv strains while certain biological functions may be associated with other strain signatures. This study demonstrated that strains of M. tuberculosis induce differential gene expression and strain-specific molecular signatures in pulmonary epithelial cells. Specific signatures induced by clinical strains of M. tuberculosis can be further explored for novel host-associated biomarkers and adjunctive immunotherapies. PMID- 27497874 TI - Shrimp with knockdown of LvSOCS2, a negative feedback loop regulator of JAK/STAT pathway in Litopenaeus vannamei, exhibit enhanced resistance against WSSV. AB - JAK/STAT pathway is one of cytokine signaling pathways and mediates diversity immune responses to protect host from viral infection. In this study, LvSOCS2, a member of suppressor of cytokine signaling (SOCS) families, has been cloned and identified from Litopenaeus vannamei. The full length of LvSOCS2 is 1601 bp, including an 1194 bp open reading frame (ORF) coding for a putative protein of 397 amino acids with a calculated molecular weight of ~42.3 kDa. LvSOCS2 expression was most abundant in gills and could respond to the challenge of LPS, Vibrio parahaemolyticus, Staphhylococcus aureus, Poly (I: C) and white spot syndrome virus (WSSV). There are several STAT binding motifs presented in the proximal promoter region of LvSOCS2 and its expression was induced by LvJAK or LvSTAT protein in a dose dependent manner, suggesting LvSOCS2 could be the transcriptional target gene of JAK/STAT pathway. Moreover, the transcription of DmVir-1, a read out of the activation of JAK/STAT pathway in Drosophila, was promoted by LvJAK but inhibited by LvSOCS2, indicating that LvSOCS2 could be a negative regulator in this pathway and thus can form a negative feedback loop. Our previous study indicated that shrimp JAK/STAT pathway played a positive role against WSSV. In this study, RNAi-mediated knockdown of LvSOCS2 shrimps showed lower susceptibility to WSSV infection and caused lessened virus loads, which further demonstrated that the JAK/STAT pathway could function as an anti-viral immunity in shrimp. PMID- 27497875 TI - Health and epidemiological approaches of Trypanosoma evansi and equine infectious anemia virus in naturally infected horses at southern Pantanal. AB - Equine infectious anemia virus (EIAV) and Trypanossoma evansi are endemic in Brazilian Pantanal Biome, an important area for livestock production. In this sense, we evaluated the epidemiological single and co-infection effects of T. evansi and EIAV in naturally infected horses in the southern Pantanal wetland by serological tests and hematological assays. Both higher seroprevalence and heath poor condition of the sampled animals were associated with differences in horse management between farms. We found that the negative animals for both infectious agents (NN) represented the major group in F1 (37%), and the smallest group in F2 (19%). Furthermore, we recorded higher EIAV seroprevalence (56%) in F2, compared to F1 (38%). We observed that T. evansi infection was mostly related to young horses, as seen by their higher seroprevalence, ranging from 70.7% in the beginning of the rainy season to 81% in the end of flood period, in comparison with the values of 42% and 68%, respectively, in working animals. on the other hand, working animals showed a higher seroprevalence for EIAV (48%) in both seasons than young horses. We observed that the management of working horses could be a risk factor of EIAV infection. On the other hand, as T. evansi is maintained in the study region by many species of wild mammals, the mechanical transmission through blood-sucking vectors ensures the infection to horses since early. Our results showed that single or co-infection by EIAV and T. evansi caused different degree of anemia in the infected animals. Moreover, the health of horses in Brazilian Pantanal is also influenced by differences in horse management and environmental circumstances. PMID- 27497876 TI - Comment on "Management of postprandial glucose: Recommended targets and treatment with biphasic insulin". PMID- 27497877 TI - Oral health-related quality of life improves in employees with disabilities following a workplace dental intervention. AB - This pilot study evaluated a dental intervention for employees with disabilities by measuring changes in self-rated oral health, dental behaviours and oral health related quality of life (OHRQol). Consenting employees with disabilities (>=18years) at two worksites in South Australia underwent dental examinations at baseline, three and six months. Referrals were arranged as needed to public dental clinics. At one and two months a dental hygienist provided group oral health education to the employees. Employees' demographics, self-rated oral health, dental behaviours and OHRQol were collected via face-to-face interviews. Of the 39 referred employees, 28 (72%) of them completed the recommended treatment. Self-rated oral health improved and there were significant reductions in the prevalence of oral health impact on quality of life (percentage of employees reporting 1+ items fairly/very often) from 27% to 11% (McNemar's test, p<0.05); the extent of impact (mean number of items reported fairly/very often) from 1.3 to 0.6 and the severity of impact (mean of summed OHIP item scores) from 3.6 to 1.8 (paired t-tests, p<0.01). As this pilot study indicates that enabling urgent referral for treatment and regular oral health education can improve OHRQol and self-rated oral health among employees with disabilities, a larger study with a control group should be undertaken. PMID- 27497878 TI - A Smart pH-responsive Nano-Carrier as a Drug Delivery System: A hybrid system comprised of mesoporous nanosilica MCM-41 (as a nano-container) & a pH-sensitive polymer (as smart reversible gatekeepers): Preparation, characterization and in vitro release studies of an anti-cancer drug. AB - A smart pH-responsive drug nano-carrier for controlled release of anti-cancer therapeutics was developed through a facile route. The nano-carrier consisted of two main parts: first, the nano-container part (that mesoporous silica nanoparticles (MCM-41) were selected for this aim); and second, pH-sensitive gatekeepers (that a pH-sensitive polymer, Poly4-vinylpyridine, played this role). In the first step, MCM-41 was synthesized via template assisted sol-gel process. In the second step, polymerizable functional groups were attached onto pore entrances rather than inside walls. In the third step, polymeric gatekeepers were introduced onto pore entrances via precipitation polymerization of functionalized MCM-41 with monomers. Different methods and analysis, such as Fourier Transform Infrared Spectroscopy (FT-IR), X-ray Powder Diffraction (XRD), Thermo-Gravimetric Analysis (TGA), Energy-Dispersive X-ray Spectroscopy (EDX), Zeta Potentials, Dynamic Light Scattering (DLS), Field Emission Scanning Electron Microscope (FE SEM) and Transmission Electron Microscopy (TEM) were employed to approve the successful attachment of gatekeepers. Furthermore, the release studies of methotroxate (MTX), an anti-cancer drug, were performed in different media (pH4, 5.8 and 7.4) at 37+/-1 degrees C. The release profiles and curves show that the release rates are completely pH-dependent and it proceeds with a decrease in pH. It is concluded that in the higher pH the gatekeepers are in their close state, but they switch to the open state as a consequence of repulsive forces between positively charged polymer chains appear in acidic media. The results suggest that this smart nano-carrier can be considered as an appropriate candidate to deliver therapeutics to cancerous tissues. PMID- 27497879 TI - In vivo tissue sampling using solid-phase microextraction for non-lethal exposome wide association study of CYP1A1 induction in Catostomus commersonii. AB - Fish are widely used for monitoring aquatic ecosystem health and water contamination by organic toxicants from natural and anthropogenic sources. However, most of these studies only focused on the measurement of specific toxicants and did not examine the impact of chemical mixtures. In this study, we examined whether the tissue exposome captured in vivo with solid-phase microextraction (SPME) without lethal sampling and analyzed by liquid chromatography-high resolution mass spectrometry can detect differences between Catostomus commersonii exhibiting a significant induction of CYP1A1, through case/control comparisons, controlling for false discovery rates. We observed the presence of environmental toxicants in induced case fish known as potential inducers of CYP1A1. We also found significant changes in the levels of anti oxidants, short-lived oxysterols and other lipids associated with CYP1A1 induction, possibly due to oxidative stress, lipid peroxidation and free fatty acids mobilization to maintain homeostatic state. In vivo SPME opens the way to perform repeated sampling on the same animal over the time and explore the individual internal exposome trajectory for better characterization of the links between toxicant load and health effects, at the individual scale. PMID- 27497881 TI - Nitric oxide and Kir6.1 potassium channel mediate isoquercitrin-induced endothelium-dependent and independent vasodilation in the mesenteric arterial bed of rats. AB - The vascular effect of flavonoid isoquercitrin was investigated in the perfused mesenteric vascular bed of rats. In preparations with functional endothelium isoquercitrin (100, 300 and 1000nmol) dose-dependently reduced the perfusion pressure by 13+/-2.2, 33+/-3.9, and 58+/-3.7mm Hg, respectively. Endothelium removal or inhibition of the nitric oxide synthase enzymes by l-NAME did not change the effects of 100 and 300 nmol isoquercitrin, but reduced by 30-40% the vasodilation induced by 1000 nmol isoquercitrin. Perfusion with nutritive solution containing 40mM KCl abolished the vasodilatory effect of all isoquercitrin doses. Treatment with glibenclamide, a Kir6.1 (ATP-sensitive) potassium channel blocker, inhibited vasodilation induced by 100 and 300 nmol isoquercitrin, but only partially reduced the effect of 1000 nmol isoquercitrin. The non-selective KCa (calcium-activated) potassium channel blocker tetraethylammonium, but not the selective KCa1.1 channel blocker iberiotoxin, reduced by around 60% vasodilation induced by all isoquercitrin doses. In addition, association of tetraethylammonium and glibenclamide, or l-NAME and glibenclamide, fully inhibited isoquercitrin-induced vasodilation. Our study shows that isoquercitrin induces vasodilation in resistance arteries, an effect mediated by K(+) channel opening and endothelial nitric oxide production. PMID- 27497880 TI - Balloon assisted retraction of a migrated CoreValve Evolut R bioprosthesis during cardiac arrest. AB - We describe a case of balloon assisted retraction of a migrated CoreValve Evolut R bioprosthesis during trans-femoral TAVI. PMID- 27497882 TI - Neuroprotective effects of Kaempferide-7-O-(4"-O-acetylrhamnosyl)-3-O-rutinoside on cerebral ischemia-reperfusion injury in rats. AB - In the present study, we aim to evaluate the potential neuroprotective effect and the underlying mechanism of Kaempferide-7-O-(4"-O-acetylrhamnosyl)-3-O-rutinoside (A-F-B) against cerebral I/R injury. Adult male rats were pretreated with A-F-B by intragastric administration once a day for 3 days. One hour after the third day administration, animals were subjected to 2h of transient middle cerebral artery occlusion (MCAO) followed by 24h of reperfusion. Neurological deficit, infarct volume, histopathological changes, oxidative stress-related biochemical parameters, neuronal apoptosis, apoptosis-related proteins and the expression of pro-inflammator cytokines genes were measured. A-F-B significantly decreased neurological and histological deficits, reduced the infarct volume, and decreased neuroapoptosis. Meanwhile, A-F-B inhibited the expression of Bax, cleaved caspase 3, cleaved caspase-9, and promoted Bcl-2 expression. In addition, the expression of pro-inflammator cytokines, including phospho-NF-kBp65, interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, intercellular adhesion molecule-1, cyclooxygenase-2 and inducible nitric oxide synthase, were also suppressed by A-F B pretreatment. Furthermore, pretreatment with A-F-B could significantly increase the activities of superoxide dismutase, glutathione peroxidase, but decrease the content of malondiadehyde in blood serum. These results suggest that A-F-B has the neuroprotective effect in ischemic stroke by suppressing neuroinflammation, reactive oxygen species and neuroapoptosis. PMID- 27497883 TI - New EGFR inhibitor, 453, prevents renal fibrosis in angiotensin II-stimulated mice. AB - Chronic activation of renin-angiotensin system (RAS) greatly contributes to renal fibrosis through the over expression of angiotensin (Ang) II, ultimately leading to chronic kidney disease (CKD). As the main peptide in the RAS, Ang II is a key regulator of nephrotic inflammation, fibrogenic destruction and hypertensive nephropathy. Controlled by growth factors such as TGF-beta, Ang II is thought to be affected by other such growth factors including epidermal growth factor (EGF) due to its ability to stimulate growth, regulate angiogenesis, and desensitize cells from apoptotic stimuli. Here we show that epidermal growth factor receptor (EGFR) plays a key role in Ang II induced renal fibrosis and its inhibition for the use as an effective treatment of CKD. 453, an AG1478 analog, was used to block the EGF-EGFR interaction in vivo in 4-week old mice treated with Ang II and 453. Along with the inhibition of EGFR and its downstream signaling pathways (AKT and ERK), 453 also prevented the activation of fibrotic (collagen, CFGF, TGF beta), inflammatory (COX2, IL-6, IL-1beta, TNF-alpha), apoptosis and oxidative stress pathways. These findings suggest the use of 453 as a novel EGFR-inhibitor for therapeutic use in CKD kidney dysfunction. PMID- 27497884 TI - Silencing of hypoxia inducible factor-1alpha gene attenuated angiotensin II induced abdominal aortic aneurysm in apolipoprotein E-deficient mice. AB - BACKGROUND AND AIMS: We aimed to determine the effect of HIF-1alpha, the main regulatory subunit of the hypoxia inducible factor 1 (HIF-1), on the development of the abdominal aortic aneurysm (AAA). METHODS: AAA was induced in ApoE(-/-) mice by angiotensinII (AngII) infusion. In vivo silencing of HIF-1alpha was achieved by transfection of lentivirus expressing HIF-1alpha shRNA. RESULTS: Time course analysis of the AngII infusion model revealed that HIF-1alpha was persistently upregulated during a 28-day period of AAA development. Silencing of the HIF-1alpha gene reduced the aneurysm size (2.84 +/- 1.96 mm vs. 1.41 +/- 0.85 mm respectively at day 28, p = 0.0002). Silencing of HIF-1alpha also alleviated infiltration of macrophages (38.8 +/- 14.7 vs. 11.4 +/- 4.4 macrophages/0.1 mm(2), p = 0.0006) and neovascularity (5.56 +/- 2.14 vs. 1.27 +/- 1.05 microvessels/0.1 mm(2), p = 0.0008) in the AngII infusion model, at day 28. The activity of MMP-2 and MMP-9 was also decreased by knockdown of HIF-1alpha. The early increased expression of pro-inflammatory factors, angiogenic factors, and MMPs during AAA induction was alleviated by HIF-1alpha silencing. CONCLUSIONS: Activation of HIF-1 signaling pathway participates in the Ang II-induced AAA formation in mice. PMID- 27497886 TI - A systematic review of preoperative predictors for postoperative clinical outcomes following lumbar discectomy. AB - BACKGROUND CONTEXT: Sciatica is often caused by a herniated lumbar intervertebral disc. When conservative treatment fails, a lumbar discectomy can be performed. Surgical treatment via lumbar discectomy is not always successful and may depend on a variety of preoperative factors. It remains unclear which, if any, preoperative factors can predict postsurgical clinical outcomes. PURPOSE: This review aimed to determine preoperative predictors that are associated with postsurgical clinical outcomes in patients undergoing lumbar discectomy. STUDY DESIGN: This is a systematic review. METHODS: This systematic review of the scientific literature followed the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. MEDLINE and PubMed were systematically searched through June 2014. Results were screened for relevance independently, and full-text studies were assessed for eligibility. Reporting quality was assessed using a modified Newcastle-Ottawa Scale. Quality of evidence was assessed using a modified version of Sackett's Criteria of Evidence Support. No financial support was provided for this study. No potential conflict of interest associated biases were present from any of the authors. RESULTS: The search strategy yielded 1,147 studies, of which a total of 40 high-quality studies were included. There were 17 positive predictors, 20 negative predictors, 43 non significant predictors, and 15 conflicting predictors determined. Preoperative predictors associated with positive postoperative outcomes included more severe leg pain, better mental health status, shorter duration of symptoms, and younger age. Preoperative predictors associated with negative postoperative outcomes included intact annulus fibrosus, longer duration of sick leave, worker's compensation, and greater severity of baseline symptoms. Several preoperative factors including motor deficit, side and level of herniation, presence of type 1 Modic changes and degeneration, age, and gender had non-significant associations with postoperative clinical outcomes. CONCLUSIONS: It may be possible for certain preoperative factors to be targeted for clinical evaluation by spine surgeons to assess the suitability of patients for lumbar discectomy surgery, the hope being to thereby improve postoperative clinical outcomes. Prospective cohort studies are required to increase the level of evidence with regard to significant predictive factors. PMID- 27497885 TI - Different end-points to assess effects in systemic lupus erythematosus patients exposed to pesticide mixtures. AB - Systemic Lupus Erythematosus (SLE) is an autoimmune disease with high female predominance in reproductive years. It is characterized by a pronounced inflammation and production of a variety of autoantibodies. SLE pathogenesis is influenced by genes, hormones and environmental agents. The aim of this study was assess the possible effect of environmental pesticide mixtures in SLE patients. Oxidative DNA damage was measured using the comet assay modified by enzyme Endo III for detection of oxidized bases (Endo Sites), and oxidative stress by the measurement of the activity of catalase (CAT), superoxide dismutase (SOD) and lipid peroxidation (TBARS). Eighty-nine patients with diagnosis of SLE were included, 46% of them came from areas highly sprayed with pesticides and were compared with patients from urban areas with the same clinical and socio demographic characteristics (p>=0.155). In order to identify factors that could predict DNA damage and oxidative stress, a binary logistic regression model with independent variables was developed: place of residence (p=0.007) have 75% of positive predictive value while smoking habit (p=0.186) have a 56% negative predictive value. The Odd Ratio (OR) obtained indicate that lupus patients living in rural areas presented 3.52 times more oxidative DNA damage compared to those living in the city. The prospects of applying biomarkers to assess exposure and biological effects, such as DNA damage and oxidative stress in autoimmune diseases, allow improving the characterization of individual risk. PMID- 27497887 TI - Insurance status and reportable quality metrics in the cervical spine fusion population. AB - BACKGROUND CONTEXT: The incidence of adverse care quality events among patients undergoing cervical fusion surgery is unknown using the definition of care quality employed by the Centers for Medicare and Medicaid Services (CMS). The effect of insurance status on the incidence of these adverse quality events is also unknown. PURPOSE: This study determined the incidence of hospital-acquired conditions (HAC) and patient safety indicators (PSI) in patients with cervical spine fusion and analyzed the association between primary payer status and these adverse events. STUDY DESIGN: This is a retrospective cohort design. PATIENT SAMPLE: All patients in the Nationwide Inpatient Sample (NIS) aged 18 and older who underwent cervical spine fusion from 1998 to 2011 were included. OUTCOME MEASURES: Incidence of HAC and PSI from 1998 to 2011 served as outcome variables. METHODS: We queried the NIS for all hospitalizations that included a cervical fusion during the inpatient episode from 1998 to 2011. All comparisons were made between privately insured patients and Medicaid or self-pay patients because Medicare enrollment is confounded with age. Incidence of nontraumatic HAC and PSI was determined using publicly available lists of International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. We built logistic regression models to determine the effect of primary payer status on PSI and nontraumatic HAC. RESULTS: We identified 419,424 hospitalizations with cervical fusion performed during an inpatient episode. The estimated national incidences of nontraumatic HAC and PSI were 0.35% and 1.6%, respectively. After adjusting for patient demographics and hospital characteristics, Medicaid or self pay patients had significantly greater odds of experiencing one or more HAC (odds ratio [OR] 1.51 95% conflict of interest [CI] 1.23-1.84) or PSI (OR 1.52 95% CI 1.37-1.70) than the privately insured cohort. CONCLUSIONS: Among patients undergoing inpatient cervical fusion, primary payer status predicts PSI and HAC (both indicators of adverse health-care quality used to determine hospital reimbursement by CMS). As the US health-care system transitions to a value-based payment model, the cause of these disparities must be studied to improve the quality of care delivered to vulnerable patient populations. PMID- 27497888 TI - The fatty degeneration of lumbar paraspinal muscles on computed tomography scan according to age and disc level. AB - BACKGROUND CONTEXT: Spinal degeneration can occur not only in the bone and disc but also in muscles. Fatty infiltration (FI) and decreased volume have been described as characteristic changes that occur in muscle degeneration. Many studies about the lumbar paraspinal muscles have been conducted on patients with spine problems. However, the natural changes of age-dependent degeneration in the paraspinal muscles have not been studied properly. PURPOSE: The purpose of this study is to investigate age- and level-dependent changes of the lumbar paraspinal muscles in the population without lumbar spinal symptoms. STUDY DESIGN: This study is a retrospective case-control study. PATIENT SAMPLE: A total of 887 patients who underwent computed tomography scan for abdomen and pelvis (APCT) between January 2013 and December 2013 were enrolled. After excluding 237 patients with medical history of spine surgery, low back pain, myopathy, muscular dystrophy, infectious disease, vertebral fracture, and deformity, 650 patients were finally subjected to this study. OUTCOME MEASURE: The patients were divided into three age groups: young (20-39 years old), middle (40-59 years old), and old (60-89 years old). The degree of FI was checked twice for multifidus muscle (MF), erector spinae muscle (ES), and psoas muscle (PS) at each disc level from L1 to S1 on APCT by two investigators. The FI was measured as the Hounsfield unit, a mean density (MD) on CT. METHODS: The age differences were compared with the data of the young group, and the level differences were compared with the data of the L1-L2 level. Student t test and intraclass correlation coefficient were checked for statistical analysis. RESULTS: The gender ratio was not significantly different among the groups. Comparing with the young group, the MD of MF significantly decreased at L5-S1 in the middle group (p<.05), and at L3-L4-L5-S1 in the old group (p<.05). The MD of ES was significantly decreased at all levels in the old group (p<.05) but not significant in the middle group. Comparing with the L1-L2 level, the MD of MF significantly decreased at L5-S1 in the middle group (p<.05) and at L4-L5-S1 in the old group (p<.05). The MD of ES was significantly decreased at L5-S1 in the young and middle groups (p<.05) and at L4 L5-S1 in the old group (p<.01) compared with those at L1-L2. According to the age and level-dependent changes of MD in the MF and ES, there was a tendency of progressive increase of FI in the muscles with age, which seemed to start from L5 S1 and spread to the upper levels. The age-dependent fatty degeneration appeared wider in the ES than the MF. The level-dependent FI of the ES showed a similar pattern with the MF, but the change of the ES seemed to start earlier in age than the MF at the L5-S1. There was no significant MD change in the PS according to age and level. Intraobserver and interobserver reliabilities were both high across all of the muscles (0.86-0.94 and 0.83-0.92). CONCLUSIONS: As a result, the degree of intramuscular fat infiltration seems to be affected by age, disc level, and muscle type. It seems to be more prominent in the extensor muscles, extending from lower to upper levels. PMID- 27497889 TI - Frequent neuromonitoring loss during the completion of vertebral column resections in severe spinal deformity surgery. AB - BACKGROUND CONTEXT: Intraoperative monitoring (IOM) is an essential method for preventing postoperative spinal deficits during posterior vertebral column resection (VCR) surgery for treatment of severe spine deformities, but the IOM features directing at VCR procedures are rarely reported and need to be further clarified. PURPOSE: To evaluate an important surgical point that will lead to the IOM loss frequently, and then remind the surgeons to pay close attention to impending monitoring changes during posterior VCR surgery. STUDY DESIGN/SETTING: Retrospective study. PATIENT SAMPLE: A total of 77 patients with severe spine deformities who underwent posterior VCR and deformity correction surgeries from January 2012 to May 2015 are retrospectively analyzed in our spine center. OUTCOME MEASURES: IOM (motor-evoked potentials [MEP] and somatosensory-evoked potentials) was used for intraoperative spinal function assessment. METHODS: Patients were divided into 2 groups according to their preoperative spinal function, including 27 patients with preoperative spinal deficits and 50 patients with spinal normal. And the IOM data during surgery, especially among VCR procedures, were mainly analyzed in the present study. RESULTS: With the VCR procedure almost complete, most patients showed varying degrees of IOM loss that included 37 cases showing obvious IOM degenerations and 21 cases showing significant IOM loss with alerts immediately. Moreover, the patients with preoperative spinal deficits have more significant decreasing percentage in MEP amplitude (81% vs. 68%, p<.05) than those patients without. CONCLUSIONS: With the VCR procedure almost complete, surgeons must pay closely attention to the IOM signals and should be ready to take corresponding surgical measures to deal with the impeding monitoring loss. PMID- 27497890 TI - Effectiveness of physiotherapy for seniors with recurrent headaches associated with neck pain and dysfunction: a randomized controlled trial. AB - BACKGROUND CONTEXT: A previous study demonstrated that in seniors, the presence of cervical musculoskeletal impairment was not specific to cervicogenic headache but was present in various recurrent headache types. Physiotherapy treatment is indicated in those seniors diagnosed with cervicogenic headache but could also be adjunct treatment for those with cervical musculoskeletal signs who are suspected of having transitional headaches. PURPOSE: This study aimed to determine the effectiveness of a physiotherapy program for seniors with recurrent headaches associated with neck pain and cervical musculoskeletal dysfunction, irrespective of the headache classification. STUDY DESIGN: This is a prospective, stratified, randomized controlled trial with blinded outcome assessment. PATIENT SAMPLE: Sixty-five participants with recurrent headache, aged 50-75 years, were randomly assigned to either a physiotherapy (n=33) or a usual care group (n=32). OUTCOME MEASURES: The primary outcome was headache frequency. Secondary outcomes were headache intensity and duration, neck pain and disability, cervical range of motion, quality of life, participant satisfaction, and medication intake. METHODS: Participants in the physiotherapy group received 14 treatment sessions. Participants in the usual care group continued with their usual care. Outcome measures were recorded at baseline, 11 weeks, 6 months, and 9 months. This study was funded by a government research fund of $6,850. No conflict of interest is declared. RESULTS: There was no loss to follow-up for the primary outcome measure. Compared with usual care, participants receiving physiotherapy reported significant reductions in headache frequency immediately after treatment (mean difference -1.6 days, 95% confidence interval [CI] -2.5 to -0.6), at 6-month follow-up (-1.7 days, 95% CI -2.6 to -0.8), and at 9-month follow-up (-2.4 days, 95% CI -3.2 to -1.5), and significant improvements in all secondary outcomes immediately posttreatment and at 6- and 9-month follow-ups, (p<.05 for all). No adverse events were reported. CONCLUSIONS: Physiotherapy treatment provided benefits over usual care for seniors with recurrent headache associated with neck pain and dysfunction. PMID- 27497891 TI - Are Modic changes associated with intervertebral disc cytokine profiles? AB - BACKGROUND CONTEXT: Degenerative changes including Modic changes (MCs) are commonly observed in patients with chronic low back pain. Although intervertebral disc (IVD) cytokine expression has been shown to be associated with low back pain, the cytokine profile for degenerative IVD with and without MC has not been compared. PURPOSE: This study aimed to evaluate the potential association between IVD cytokine expression and MCs. STUDY DESIGN: A laboratory study was carried out. METHODS: The IVD tissue samples from 10 patients with type II MCs and10 patients without MCs who underwent an anterior lumbar interbody and fusion for significant low back pain were collected. The expression levels of 42 cytokines were determined using a RayBio Human Cytokine Antibody Array 3 (RayBiotech Inc, Norcross, GA, USA) and the results were verified with enzyme-linked immunosorbent assay (ELISA). RESULTS: The cytokine array demonstrated a statistically significant increase in the expression of granulocyte-macrophage colony stimulating factor (GM-CSF) (p=.001) and epithelial-derived neutrophil-activating peptide 78 (ENA-78) (p=.04), and a trend toward an increase in interleukin-1beta (IL-1beta) (p=.12) and tumor necrosis factor-alpha (TNF-alpha) (p=.22) in IVDs associated with type II MCs. These results were validated with ELISA which demonstrated a 3.85-fold increase in the GM-CSF level between IVDs with type II MCs compared with those without MCs (p=.03). Similarly there was a significant increase in the level of both ENA-78 (3.68-fold, p=.02) and IL-1beta (2.11-fold, p=.01) in IVDs with type II MCs. Lastly, there was a trend (p=.07) toward an increase in TNF-alpha in IVDs with type II MCs (4.4-fold). CONCLUSION: Intervertebral discs with type II MCs demonstrate a significant increase in IL 1beta, GM-CSF, and ENA-78, and there is a trend toward an increase in TNF-alpha. These results further strengthen the association between MCs and low back pain. PMID- 27497892 TI - Pathogenesis of Photobacterium damselae subspecies infections in sea bass and sea bream. AB - Photobacterium damselae is a Gram negative bacterium causes photobacteriosis, a worldwide septicemic disease in aquaculture including sea bass (Dicentrarchus labrax) and sea bream (Sparus aurata). The pathogenicity of bacterial subspecies and the disease pathological changes in natural and experimental infections have thus far yielded inconsistency of effective preventive measures. This study aimed to represent a comprehensive analysis of the potential pathogenic capacities of the two subspecies of P. damselae in cultured sea bass and sea bream in the Northwestern region of Egypt. Diseased 321 sea bass and 257 sea bream, in addition to 99 healthy sea bass fingerlings were sampled from three farms located along the Mediterranean Sea. P. damselae subspecies were isolated from diseased fish and characterized using bacteriological, molecular, and antimicrobial susceptibility methods. Healthy fish were challenged by a virulent P. damselae subsp. piscicida, monitored for disease signs and mortality, and the histopathological abnormalities and hematological disorders were carried out. Clinical signs and gross lesions in naturally infected sea bass and sea bream showed great similarities with absence of a subspecies-specific characteristic sign or lesion. The two subspecies were recovered through the entire year from individual fish sample, suggests a coexistence of two subspecies endemic infection. In diseased sea bass, 38.32% and 16.20% were positive for P. damselae subsp. piscicida and subsp. damselae, respectively. However in diseased sea bream, 44.47% and 26.46% were positive for P. damselae subsp. piscicida and subsp. damselae, respectively. High mortalities and devastating clinicopathologic abnormalities represented by sever clinical signs, hematological disorders and histological abnormalities strengthen the pathogenicity of P. damselae subspecies in the two fish species and therefore, a vaccination strategy against both subspecies should be taken into account. PMID- 27497893 TI - Molecular characterization of genotype XIIIb Newcastle disease virus from central India during 2006-2012: Evidence of its panzootic potential. AB - Newcastle disease virus (NDV) is the causative agent of Newcastle disease (ND) in many avian species. ND is a serious problem in developing countries, causing huge loss in the poultry industry. Although there are reports of continuous outbreaks of ND leading to serious losses to the poultry farming, very less is known about the genetic characteristics of its strains circulating in different parts of India. In the present study, we have five isolates of NDV reported from different outbreaks in Central India between the years 2006-2012. Deduced amino acid sequence of the F protein cleavage site and phylogenetic analysis of all the five isolates showed circulation of NDV genotype XIIIb. All the isolates showed a unique virulent cleavage site 112RRQKR?F117. The close genetic similarity of all the isolates suggested circulation of the virulent NDV strains of the same ancestor in and around central India. Continuous isolation of genotype XIIIb NDV strains within the country suggests its panzootic potential. The study will be useful to understand the circulating strains of NDV and plan a vaccination strategy for poultry in India. PMID- 27497894 TI - Antimicrobial and enhancement of the antibiotic activity by phenolic compounds: Gallic acid, caffeic acid and pyrogallol. AB - The indiscriminate use of antimicrobial drugs has increased the spectrum of exposure of these organisms. In our studies, these phenolic compounds were evaluated: gallic acid, caffeic acid and pyrogallol. The antibacterial, antifungal and modulatory of antibiotic activities of these compounds were assayed using microdilution method of Minimum Inhibitory Concentration (MIC) to bacteria and Minimum Fungicide Concentration (MFC) to fungi. The modulation was made by comparisons of the MIC and MFC of the compounds alone and combined with drugs against bacteria and fungi respectively, using a sub-inhibitory concentration of 128 MUg/mL of substances (MIC/8). All substances not demonstrated clinically relevant antibacterial activity with a MIC above >=1024 MUg/mL. As a result, we observed that the caffeic acid presented a potentiating antibacterial effect over the 3 groups of bacteria studied. Pyrogallol showed a synergistic effect with two of the antibiotics tested, but only against Staphylococcus aureus. In general, caffeic acid was the substance that presented with the greatest number of antibiotics and with the greatest number of bacteria. In relation to the antifungal activity of all the compounds, the verified results were >=1024 MUg/mL, not demonstrating significant activity. Regarding potentiation of the effect of fluconazole, was observed synergistic effect only when assayed against Candida tropicalis, with all substances. Therefore, as can be seen, the compounds presented as substances that can be promising potentiating agents of antimicrobial drugs, even though they do not have direct antibacterial and antifungal action. PMID- 27497895 TI - Performance of Holstein calves fed whole milk with or without kefir. AB - A growing body of evidence suggests health-promoting effects of kefir consumption on different nonruminant species, leading to the speculation that kefir may act as a probiotic and benefit calf performance and health. Our objectives were to determine effects of feeding kefir on performance and health of calves in the first 70d of life. Thirty 3-d-old female Holstein calves (body weight=38.2+/ 3.1kg) were blocked by initial body weight and assigned randomly to 1 of 3 treatments (1 calf per pen; 10 pens per treatment). Kefir was added to whole milk (vol/vol) at 0:1 (control; KF0), 1:3 (KF1), or 1:1 (KF2) and fed twice per day (0800 and 1600h) from d3 through 45 and then once per day until weaning, which occurred on d50. Pre- and postweaning intake of starter, daily body weight gain, and gain-to-feed ratio exhibited no difference among treatments. Adding kefir to whole milk fed directly to calves had no effect on concentration of blood metabolites collected on d20, 40, and 70. Body length on d50 (weaning) and 70 was greater in kefir-fed calves. Kefir intake improved fecal scores and reduced days with diarrhea during the first 2wk of life. Apparent digestibility of organic matter, ether extract, crude protein, and neutral detergent fiber remained unaffected by treatment. Overall, it appears that directly feeding kefir to calves during the preweaning period did not improve the performance of calves under the conditions of the current study; however, its consumption marginally improved body length and fecal consistency in the first weeks of life, which is an important concern in intensive calf-rearing systems. Feeding kefir to neonatal calves may be a viable approach to improve the health of calves in commercial calf-rearing operations, although to validate its health-promoting effects additional research is needed to investigate its effects under different calf rearing conditions. PMID- 27497896 TI - Characterization of a heat-resistant extracellular protease from Pseudomonas fluorescens 07A shows that low temperature treatments are more effective in deactivating its proteolytic activity. AB - This work discusses the biological and biochemical characterization of an extracellular protease produced by Pseudomonas fluorescens. The enzyme has a molecular weight of 49.486 kDa and hydrolyzes gelatin, casein, and azocasein, but not BSA. Its maximum activity is found at 37 degrees C and pH 7.5, but it retained almost 70% activity at pH 10.0. It was shown to be a metalloprotease inhibited by Cu(2+), Ni(2+), Zn(2+), Hg(2+), Fe(2+), and Mg(2+), but induced by Mn(2+). After incubation at 100 degrees C for 5min, the enzyme presented over 40% activity, but only 14 to 30% when submitted to milder heat treatments. This behavior may cause significant problems under conditions commonly used for the processing and storage of milk and dairy products, particularly UHT milk. A specific peptide sequenced by mass spectrometer analysis allowed the identification of gene that encodes this extracellular protease in the genome of Pseudomonas fluorescens 07A strain. The enzyme has 477 AA and highly conserved Ca(2+)- and Zn(2+)-binding domains, indicating that Ca(2+), the main ion in milk, is also a cofactor. This work contributes to the understanding of the biochemical aspects of enzyme activity and associates them with its sequence and structure. These findings are essential for the full understanding and control of these enzymes and the technological problems they cause in the dairy industry. PMID- 27497897 TI - Short communication: Mid-infrared spectroscopy prediction of fine milk composition and technological properties in Italian Simmental. AB - The objective of this study was to evaluate the ability of mid-infrared predictions of fine milk composition and technological traits to serve as a tool for large-scale phenotyping of the Italian Simmental population. Calibration equations accurately predicted the fatty acid profile of the milk, but we obtained moderate or poor accuracy for detailed protein composition, coagulation properties, curd yield and composition, lactoferrin, and concentration of major minerals. To evaluate the role of infrared predictions as indicator traits of fine milk composition in indirect selective breeding programs, the genetic parameters of the traits predicted using mid-infrared spectra need to be estimated. PMID- 27497898 TI - Short communication: Associations between blood fatty acids, beta hydroxybutyrate, and alpha-tocopherol in the periparturient period in dairy cows: An observational study. AB - The objective of the present study was to examine the relationships between blood concentrations of fatty acids, beta-hydroxybutyrate (BHB), and alpha-tocopherol during the periparturient period in dairy cows. Blood samples were collected from 131 cows belonging to 4 different commercial dairy farms in southeastern Europe (Greece and Italy). We determined blood concentrations of fatty acids, BHB, and alpha-tocopherol at dry-off, at calving, and 30d postpartum. Results indicated that fatty acid concentrations were low at dry-off, reached maximum value at calving, and then declined at 30d postpartum. In fact, fatty acid concentrations at 30d postpartum were 50% lower than at calving. In contrast, BHB concentrations were low at dry-off, increased by 27% at calving, and continued to increase by another 20% at 30d postpartum. Overall, we found a weak correlation between fatty acids and BHB throughout the periparturient period. Concentrations of alpha tocopherol were lowest at calving, and we detected no differences in alpha tocopherol concentrations at dry-off or 30d postpartum. Negative correlations between fatty acids and alpha-tocopherol were highly significant at 30d postpartum and approached the level of significance at dry-off. However, both correlations became nonsignificant following the adjustment of alpha-tocopherol with cholesterol, indicating that the correlations were a reflection of changes in lipid transport. We found significant negative correlations (strong at dry-off and weak at 30d postpartum) between BHB and alpha-tocopherol after adjustment with cholesterol. The physiological basis for the negative correlations between BHB and alpha-tocopherol, especially that at dry-off, is not known and should not be taken to imply a cause-effect relationship. However, it opens the door to investigating the effects of vitamin E on liver function in dairy cows. PMID- 27497899 TI - Effects of air exposure, temperature and additives on fermentation characteristics, yeast count, aerobic stability and volatile organic compounds in corn silage. AB - Ensiling conditions strongly influence fermentation characteristics, yeast count, and aerobic stability. Numerous volatile organic compounds including esters are produced, which may negatively affect feed intake and animal performance and air quality. In addition to a farm survey, 3 laboratory experiments were carried out to study the effects of air (by delayed sealing or by air infiltration during anaerobic storage), temperature (20 and 35 degrees C), and various types of additives [blends of either sodium benzoate and sodium propionate (SBSP) or of sodium benzoate and potassium sorbate (SBPS); buffered mixture of formic and propionic acids (FAPA); homofermentative inoculant (LAB)]. After additive treatment, chopped whole corn plants were packed into 1.5-L glass jars and stored for several months. For treatments with air infiltration, glass jars with holes in the lid and body were used. The farm survey in 2009 revealed large variation in lactate, acetate, ethanol, n-propanol, and 1,2-propanediol concentrations. Whereas ethyl esters were detected in all silages, the mean ethyl lactate concentrations were higher than those for ethyl acetate (474 vs. 38mg/kg of dry matter). In the ensiling experiments, few unequivocal effects of the tested factors on the analyzed parameters were observed due to many interactions. Delayed ensiling without additives decreased lactic acid production but, in one trial, increased acetic acid and had no effect on ethanol. The effect of delayed sealing on yeast counts and aerobic stability differed widely among experiments. Air infiltration during fermentation tested in one trial did not alter lactic acid production, but resulted in more acetic acid in delayed and more ethanol than in promptly sealed untreated silages. Greater ethanol production was associated with increased yeast numbers. Storage at high temperature resulted in lower lactic acid and n-propanol, and a trend toward reduced ethanol production was observed. The additive FAPA consistently caused increased ethanol and reduced n-propanol levels with no effect on yeast counts and aerobic stability. When the additives SBSP and SBPS decreased n-propanol and ethanol, reduced yeast counts were also found. Ethyl ester formation was strongly correlated with those of ethanol and to a lesser degree with those of the respective acid. PMID- 27497900 TI - Relative frequency of 4 major strain types of Mycobacterium avium ssp. paratuberculosis in Canadian dairy herds using a novel single nucleotide polymorphism-based polymerase chain reaction. AB - Johne's disease is a worldwide concern, as it causes huge economic losses. The etiological agent, Mycobacterium avium ssp. paratuberculosis (MAP), has limited genetic diversity, impeding efforts to understand transmission and distribution of strain types. Whole-genome sequencing was previously performed on a representative set of MAP isolates from Canadian dairy herds and 9 divergent clades were identified. Four clades were of particular interest, as they were either MAP types rarely reported in North America, or they represented a substantial proportion of isolates recovered from dairy farms in Canada. One clade included type I/III isolates, whereas the remaining clades included type II isolates. Variant sites in the MAP genome are often separated by thousands of base pairs, limiting use of single nucleotide polymorphism (SNP)-based genotyping on a single genomic region. Therefore, a SNP-PCR assay was developed to facilitate interrogation of 5 SNP in 2 distant regions of the genome, linking them together in a single PCR reaction for subsequent Sanger sequencing. This high-throughput assay enabled discrimination of 602 MAP isolates from 264 herds (from all 10 provinces). More than 1 isolate was cultured from 133 herds, 14 of which included multiple subtypes. A previously identified dominant type included 87% of isolates, whereas the Bison type was more widespread than previously reported. The latter type and isolates from a second clade of interest were overrepresented in Quebec and Saskatchewan, respectively. In conclusion, the distribution and relative frequency of MAP subtypes within Canadian dairy herds were assessed using a novel SNP-based typing assay. These findings will contribute to understanding the clinical relevance and transmission dynamics of MAP in this population and elsewhere. PMID- 27497901 TI - Stochastic dynamic simulation modeling including multitrait genetics to estimate genetic, technical, and financial consequences of dairy farm reproduction and selection strategies. AB - The objective of this study was to develop a daily stochastic dynamic dairy simulation model that included multitrait genetics and to evaluate the effects of reduced genetic models and various reproduction and selection strategies on the genetic, technical, and financial performance of a dairy herd. The 12 correlated genetic traits included in the 2014 lifetime net merit (NM$) index were modeled for each animal. For each animal, a true breeding value (TBV) for each trait was calculated as the average of the sire's and dam's TBV, plus a fraction of the inbreeding and Mendelian sampling variability. Similarly, an environmental component for each trait was calculated and was partitioned into a permanent and a daily (temporary) effect. The combined TBV and environmental effects were converted into the phenotypic performance of each animal. Hence, genetics and phenotypic performances were associated. Estimated breeding values (EBV) were also simulated. Genetic trends for each trait for the service sire were based on expected trends in US Holsteins. Surplus heifers were culled based on various ranking criteria to maintain a herd size of 1,000 milking cows. In the first 8 scenarios, culling of surplus heifers was either random or based on the EBV of NM$. Four different genetic models, depending on the presence or absence of genetic trends or genetic and environmental correlations, or both, were evaluated to measure the effect of excluding multitrait genetics on animal performance. In the last 5 scenarios, the full genetic model was used and culling of surplus heifers was either random or based on the EBV of NM$ or the EBV of milk. Sexed semen use and reliability of the EBV were also varied. Each scenario was simulated for 15yr into the future. Results showed that genetic models without all 12 genetic trends and genetic and environmental correlations provided biased estimates of the genetic, technical, and financial performance of the dairy herd. Average TBV of NM$ of all cows in the herd was $263 greater in yr 15 in a scenario that combined sexed semen use in heifers and culling of surplus heifers with the lowest EBV of NM$, compared with a scenario that used only conventional semen and surplus heifers were culled randomly. The average TBV of daughter pregnancy rate of all cows in the herd was 1.25 percentage points greater in yr 15 in a scenario that combined using sexed semen in heifers as well as culling of surplus heifers ranked by EBV of NM$, compared with a scenario using conventional semen only as well as culling surplus heifers ranked by EBV of milk. In conclusion, the multitrait genetics model resulted in improved estimates of genetic, technical, and financial effects and appears useful to evaluate consequences of various reproduction and selection strategies within a dairy farm. PMID- 27497902 TI - Effect of milk replacer program on calf performance and digestion of nutrients in dairy calves to 4 months of age. AB - Calves fed >0.7kg of dry matter from milk replacer (MR) typically have greater growth preweaning but lower growth postweaning. This is partially explained by lower digestibility of starter due to less development of the rumen at and after weaning; however, it is unclear when digestibility matures postweaning to levels typical of mature ruminants. Thus, we fed Holstein calves (initially 2 to 3d of age) 3 MR programs (MOD=0.66kg daily for 39d, and then 0.33kg daily for 3d, n=15 calves; HIMOD=0.88kg daily for 5d, then 1.1kg daily for 23d, then 0.66kg daily for 18d, and then 0.33kg daily for 3d, n=16 calves; HI=0.88kg daily for 5d, then 1.1kg daily for 37d, and then 0.56kg daily for 7d, n=15 calves). The MR consisted of 28% crude protein and 20% fat and was reconstituted to 14% solids and fed at 0630 and 1400 h daily. A 39% starch textured starter (19% crude protein) was fed free-choice for the first 56d of a nursery trial with calves in individual pens. From 56 to 112d, calves were grouped by MR program into pens of 3 to 4 calves and offered a starter with the same ingredient composition blended with 5% chopped grass hay for ad libitum consumption. Digestion was estimated at 11 and 16wk. Measurements in the first and second 56d were analyzed separately in a completely randomized design using repeated measurements when applicable. Preplanned contrasts of MOD versus HIMOD and MOD versus HI were used to separate means. Milk replacer dry matter intake was 26.6, 42.4, and 48.7kg in calves fed MOD, HIMOD, and HI, respectively. Starter intake was less for calves fed HIMOD and HI versus MOD from 3 to 8wk. Efficiency of metabolizable energy and protein used for body weight gain did not differ among programs. During the second 56d, body weight gain and hip width changes were greater for calves fed MOD than HI. Total 112-d body weight gain and total hip width changes were 101.4, 101.3, and 101.7kg, and 9.0, 9.1, and 8.7cm for MOD, HIMOD, and HI, respectively. Digestibility of all nutrients except starch were greater at 16 versus 11wk of age. Digestibility of dry matter, organic matter, neutral detergent fiber, and acid detergent fiber were less for HI versus MOD at 11wk of age explaining much of the why postweaning body weight gain advantages were lost postweaning in calves fed the HI program. Feeding more than 0.66kg of dry matter intake from a MR during the preweaning phase did not increase total body weight or hip width gain from 0 to 4mo of age. PMID- 27497903 TI - The effect of conjugated linoleic acid supplements on oxidative and antioxidative status of dairy cows. AB - Dairy cows develop frequently negative energy balance around parturition and in early lactation, resulting in excessive mobilization of body fat and subsequently in increased risk of ketosis and other diseases. Dietary conjugated linoleic acid (CLA) supplements are used in dairy cows mainly for their depressing effect on milk fat content, but are also proposed to have antioxidative properties. As negative energy balance is associated with oxidative stress, which is also assumed to contribute to disease development, the present study was conducted to examine effects of CLA on oxidative and antioxidative status of lactating dairy cows. German Holstein cows (primiparous n=13, multiparous n=32) were divided into 3 dietary treatment groups receiving 100g/d of control fat supplement, containing 87% stearic acid (CON; n=14), 50g/d of control fat supplement and 50g/d of CLA supplement (CLA 50; n=15), or 100g/d of CLA supplement (CLA 100; n=16). The CLA supplement was lipid-encapsulated and contained 12% of trans-10,cis-12 CLA and cis-9,trans-11 CLA each. Supplementation took place between d1 and 182 postpartum; d 182 until 252 postpartum served as a depletion period. Blood was sampled at d -21, 1, 21, 70, 105, 140, 182, 224, and 252 relative to calving. The antioxidative status was determined using the ferric-reducing ability of plasma, alpha-tocopherol, alpha-tocopherol-to-cholesterol mass ratio, and retinol. For determination of oxidative status concentrations of hydroperoxides, thiobarbituric acid-reactive substances (TBARS), N'-formylkynurenine, and bityrosine were measured. Mixed models of fixed and random effects with repeated measures were used to evaluate period 1 (d -21 to 140) and 2 (d182-252) separately. Cows showed increased oxidative stress and lipid peroxidation during the periparturient period in terms of increased serum concentrations of hydroperoxides and TBARS, which decreased throughout lactation. During period 1, the supplemented cows had lower TBARS concentrations, which was not detectable in period 2. The other determined parameters were not affected by CLA supplementation. The obtained results show that dietary CLA supplementation in the chosen dosage, formulation, and application period had a marginal antioxidative effect in terms of lipid peroxidation in lactating dairy cows. PMID- 27497904 TI - Temporal dominance of sensations sensory profile and drivers of liking of artisanal Minas cheese produced in the region of Serra da Canastra, Brazil. AB - The Serra da Canastra region, located in southwestern Minas Gerais, Brazil, is recognized worldwide for its tradition of producing artisanal cheeses. However, as production is done by hand, great variability exists in the characteristics of artisanal Minas cheese. Thus, it is important to characterize the sensory profile of these products and verify the quality attributes that lead to their acceptance. Therefore, this study aimed to characterize the dynamic sensorial profile of artisanal Minas cheese produced in the Serra da Canastra region through temporal dominance of sensations and sensory acceptance tests and verify the attributes that lead to product quality. We observed that the texture and flavor profile varied among the evaluated artisanal Minas cheeses from Serra da Canastra, some cheeses being more characterized by creamy and soft or hard and firm sensations, whereas others had high dominance rates for crumbly texture. In relation to flavor, salty and bitter tastes were dominant in most cheeses, some also being characterized by a sour taste, and others by buttery and rancid attributes, which indicates a lack of product standardization. However, all samples obtained scores between 6 (liked slightly) and 7 (liked moderately), indicating good acceptability in relation to the texture and flavor of the evaluated cheeses. Moreover, it is possible to infer that creamy and soft or hard and firm are positive attributes for cheese texture, and bitter, buttery, salty, and acid taste drive cheese acceptance. This study provides important information for product standardization, quality improvement, and process origin indications, besides providing quality attributes that meet consumer desires. PMID- 27497905 TI - Isolation of RNA from milk somatic cells as an alternative to biopsies of mammary tissue for nutrigenomic studies in dairy ewes. AB - Nutrigenomic studies of mammary lipogenesis in ruminants often rely on the use of mammary tissue (MT) collected either by biopsy or at slaughter. However, isolating RNA from milk would be a useful and cost-effective technique that may avoid distress to the animal and facilitate the collection of samples in time series experiments. This assay was therefore conducted to test the hypothesis that RNA extracted from milk somatic cells (MSC) in dairy sheep would be a feasible alternative to the performance of MT biopsies for nutrigenomic analyses. To meet this objective, 8 lactating Assaf ewes were divided in 2 groups and offered a total mixed ration without supplementation (control) or supplemented with 2.4% dry matter of fish oil, which was known not only to elicit milk fat depression but also to downregulate the expression of some candidate genes involved in mammary lipogenesis. Total RNA was extracted from MSC and biopsied MT to examine whether the potential changes in the abundance of transcripts was similarly detected with both RNA sources. Milk fatty acid profile was also analyzed by gas chromatography, and variations in mRNA abundance were determined by reverse transcription quantitative PCR. Values of RNA integrity number were always >=7.7. The expected and designed decrease of milk fat concentration with fish oil (-29%), was associated with a lower transcript abundance of genes coding for enzymes involved in fatty acid activation (ACSS1), de novo synthesis (ACACA and FASN), uptake from plasma lipids (LPL), and esterification of fatty acids to glycerol (LPIN1), as well as of a transcription factor that may regulate their expression (INSIG1). Stable mRNA levels were showed in other candidate genes, such as FABP3, GPAT4, or SCD. Changes due to the dietary treatment were similarly detected with both RNA sources (MSC and MT biopsies), which supports the initial hypothesis and would validate the use of milk as an alternative RNA source for nutrigenomic analyses in dairy sheep. PMID- 27497906 TI - Effects of pregrazing herbage mass in late spring on enteric methane emissions, dry matter intake, and milk production of dairy cows. AB - Few studies have examined the effects of fresh forage quality on enteric methane (CH4) emissions of dairy cows under grazing conditions. The aim of the current study was to evaluate the effects of 2 contrasting forage qualities induced by different pregrazing herbage masses in late spring on enteric CH4 emissions and milk production of grazing dairy cows. The experiment was conducted as a crossover design with 24 lactating Holstein Friesian dairy cows randomly assigned to 1 of 2 treatments in 2 experimental periods. Each period had a duration of 3wk (2wk for diet adaptation and 1wk for measurements), and the interval between them was 2wk. Treatments consisted of 2 target pregrazing herbage masses [2,200 and 5,000kg of dry matter (DM)/ha above 3cm], generated by different regrowth periods, corresponding to low (LHM) and high (HHM) herbage mass treatments, respectively. Daily herbage allowance (Lolium perenne) for both treatments was 20kg of DM per cow measured above 3cm. Enteric CH4 emissions were individually determined during the last week of each period using the sulfur hexafluoride tracer technique. Daily herbage intakes by individual cows during the CH4 measurement weeks were estimated using the n-alkanes technique. During the CH4 measurement weeks, milk yield and body mass were determined twice daily, whereas milk composition was determined once in the week. The LHM pasture had a higher crude protein concentration, lower neutral detergent fiber and acid detergent fiber concentrations, and higher in vitro digestibility, with a lower proportion of ryegrass pseudostems, than the HHM pasture. Cows offered the LHM pasture had greater herbage (+13%) and total DM (+12%) intakes, increased milk (+13%) and energy-corrected milk (+11%) yields, and tendencies toward higher milk protein (+4.5%) and higher milk urea nitrogen (+15%) concentrations than their counterparts offered the HHM pasture. No differences were found between treatments in total daily CH4 production. However, the LHM treatment reduced enteric CH4 emissions per unit of milk yield (-11%) and enteric CH4 energy as a percentage of ingested gross energy (-9%) and tended to reduce CH4 per unit of dry matter intake (-8.2%) and energy-corrected milk yield (-10%) compared with the HHM treatment. The results from this study suggest that a grazing management that favors better quality pasture, as was the case of the LHM pasture in late spring compared with the HHM pasture, increases milk production of grazing dairy cows and reduces enteric CH4 emissions per unit of milk produced, constituting a viable CH4 mitigation strategy. PMID- 27497907 TI - Development of a real-time PCR assay for direct detection and quantification of Bacillus sporothermodurans in ultra-high temperature milk. AB - In our study, a new and highly sensitive real-time PCR Taqman assay was developed for the direct and specific detection of Bacillus sporothermodurans in UHT milk. The target region was selected based on the 16S rRNA gene profiles of 11 B. sporothermodurans from GenBank. A standard curve was created using a reference strain of B. sporothermodurans, DSM 10599. A low limit of detection for B. sporothermodurans in UHT milk (10 cfu/mL) was obtained. Furthermore, a total of 110 UHT milk samples from several supermarkets were directly assessed to detect and quantify B. sporothermodurans using the real-time PCR Taqman developed. The B. sporothermodurans counts obtained were highly correlated with the microbial plate counts in the UHT milk samples. This is the first time that B. sporothermodurans has been quantified directly from UHT milk. This technique could be applicable as a routine tool for preventing the growth of these bacteria by allowing for the rapid screening of raw milk samples in dairy plants. As expected, the probability of bacterial growth in UHT milk packages increased with the B. sporothermodurans counts in the raw milk. PMID- 27497908 TI - Severe aortic arch calcification predicts mortality in patients undergoing peritoneal dialysis. AB - BACKGROUND/PURPOSE: Vascular calcification can predict cardiovascular (CV) morbidity and mortality in patients with end-stage renal disease. We evaluated the prevalence, association factors, and outcomes of chest X-ray-detected aortic arch calcification (AoAC) in patients undergoing peritoneal dialysis (PD). METHODS: We included 190 patients undergoing PD (mean age, 52.6 +/- 14.3 years) for whom chest radiographs were available. AoAC revealed by chest X-ray was graded from 0 to 3 according to an AoAC score (AoACS). Multiple regression analyses were used to determine the factors associated with AoACS. After adjusting for age, sex, PD duration, diabetes mellitus, mean blood pressure, and history of CV disease, the association between AoAC grading and mortality were assessed using the Kaplan-Meier curve and Cox proportional hazard model. RESULTS: Age (p < 0.001), PD duration (p = 0.004), history of CV disease (p < 0.001), and renal Kt/V (p = 0.031) were associated with AoACS. After a mean follow-up of 55.1 +/- 32.1 months, patients with Grade 2 (p = 0.011) or Grade 3 (p < 0.001) AoAC had higher all-cause mortality than patients with Grade 0 AoAC. In addition, patients with Grades 2 and 3 AoAC had higher CV-related mortality than those with Grades 0 and 1 AoAC (p = 0.013). Grade 2 [hazard ratio (HR) = 2.736; 95% confidence interval (CI), 1.038-7.211; p = 0.042] and Grade 3 AoAC (HR = 3.289; 95% CI, 1.156-9.359; p = 0.026) remained associated with all-cause mortality after adjustment. Similarly, Grades 2 and 3 AoAC (HR = 36.05; 95% CI, 3.494-372; p = 0.026) significantly correlated with CV mortality after adjustment. CONCLUSION: In patients undergoing PD, CXR-detected severe AoAC was an independent risk factor for all-cause and CV mortalities. PMID- 27497909 TI - Mitochondrial H2O2 signaling is controlled by the concerted action of peroxiredoxin III and sulfiredoxin: Linking mitochondrial function to circadian rhythm. AB - Mitochondria produce hydrogen peroxide (H2O2) during energy metabolism in most mammalian cells as well as during the oxidation of cholesterol associated with the synthesis of steroid hormones in steroidogenic cells. Some of the H2O2 produced in mitochondria is released into the cytosol, where it serves as a key regulator of various signaling pathways. Given that mitochondria are equipped with several H2O2-eliminating enzymes, however, it had not been clear how mitochondrial H2O2 can escape destruction by these enzymes for such release. Peroxiredoxin III (PrxIII) is the most abundant and efficient H2O2-eliminating enzyme in mitochondria of most cell types. We found that PrxIII undergoes reversible inactivation through hyperoxidation of its catalytic cysteine residue to cysteine sulfinic acid, and that release of mitochondrial H2O2 likely occurs as a result of such PrxIII inactivation. The hyperoxidized form of PrxIII (PrxIII SO2H) is reduced and reactivated by sulfiredoxin (Srx). We also found that the amounts of PrxIII-SO2H and Srx undergo antiphasic circadian oscillation in mitochondria of the adrenal gland, heart, and brown adipose tissue of mice maintained under normal conditions. Cytosolic Srx was found to be imported into mitochondria via a mechanism that requires formation of a disulfide-linked complex with heat shock protein 90, which is likely promoted by H2O2 released from mitochondria. The imported Srx was found to be degraded by Lon protease in a manner dependent on PrxIII hyperoxidation state. The coordinated import and degradation of Srx underlie Srx oscillation and consequent PrxIII-SO2H oscillation in mitochondria. The rhythmic change in the amount of PrxIII-SO2H suggests that mitochondrial release of H2O2 is also likely a circadian event that conveys temporal information on steroidogenesis in the adrenal gland and on energy metabolism in heart and brown adipose tissue to cytosolic signaling pathways. PMID- 27497910 TI - The kinetics of angiotensin-I metabolism in human carotid atheroma: An emerging role for angiotensin (1-7). AB - AIM: Local levels of angiotensin peptides depend on their rates of production and degradation, which induce proatherogenic or atheroprotective effects. Here, we reveal the kinetics of Angiotensin-I metabolism in paired early and advanced atherosclerotic lesions. METHODS: Lesions were spiked with labeled Ang-I* and supernatants withdrawn after 0, 10, 20, 40 and 80min. The concentration of produced Ang-II*, Ang-III*, Ang-IV* and Ang-(1-7)* peptides were measured using multiple reaction monitoring mass spectrometry coupled to ultra-performance liquid chromatography, normalized to tissue weight and initial [Ang-I*]. RESULTS: Ang-(1-7)* was the major angiotensin peptide produced, showing increased levels in both tissue types, with 2-3 fold lower levels in advanced compared to early lesions. In contrast, Ang-II* was 2-3 fold higher in advanced compared to early lesions, showing a decrease between 0 and 40min then an increase at 80min in both tissue types. The levels of Ang-IV were stable in both tissue types across all time points. Finally, Ang-III was non-detectable in both lesions across all time points. CONCLUSION: Our results suggest that progression of atherosclerosis depends on the increased levels of Ang-II along with the decreased levels of Ang (1-7), which supports the use of Ang-(1-7) along with Angiotensin type-1 receptor (AT1R) blockers. PMID- 27497911 TI - Plasma MicroRNA-126-5p is Associated with the Complexity and Severity of Coronary Artery Disease in Patients with Stable Angina Pectoris. AB - BACKGROUND: Coronary artery disease (CAD) is a major problem worldwide. As an endothelium-enriched microRNA (miRNA), miR-126 has been reported to serve as a potential biomarker of acute myocardial infarction. However, the relationship between miR-126 and the severity of CAD remains unknown. This study was designed to test whether circulating miR-126 levels are associated with the severity of CAD. METHODS: The present study enrolled 40 patients who had risk factors for CAD without angiographically significant CAD, and 110 patients presenting with stable angina pectoris, who were validated left main coronary artery disease (LMCA) and/or multi-vessel disease by coronary angiography. The expression levels of plasma miR-126-5p from all enrolled subjects were estimated by quantitative real time polymerase chain reaction (qRT-PCR). Then, the relationships between plasma miR-126-5p levels, number of diseased vessels and the corresponding Synergy between PCI with Taxus and Cardiac surgery (SYNTAX) score were analyzed. RESULTS: The expression of circulating miR-126-5p was affected by some CAD risk factors including aging, dyslipidemia and DM. Furthermore, plasma miR-126-5p levels were significantly down-regulated in CAD patients with multi-vessel disease, higher SYNTAX score, rather than isolated LMCA and low SYNTAX score. CONCLUSION: Circulating miR-126-5p has emerged as a potential biomarker for complexity and severity of CAD in patients with stable angina pectoris. PMID- 27497912 TI - Pulmonary involvement in systemic sclerosis. AB - Systemic sclerosis (SSc) is a multi-systemic autoimmune disease that mainly affects the skin, lungs, gastrointestinal tract, heart and kidneys. Pulmonary disease in patients with SSc is strongly associated with mortality. The mechanisms involved into its pathophysiology include the activation of autoimmune cells and hyperplasia of fibroblasts with an increased capacity to produce collagen and diminished collagen breakdown. Although pulmonary biopsy is the gold standard for the diagnosis of interstitial lung disease in SSc, the most commonly used method is high-resolution computed tomography due to its high sensitivity and specificity. Herein, a comprehensive review on the pulmonary involvement in SSc is presented highlighting the radiologic-pathologic correlations. PMID- 27497913 TI - Parkinson's disease: Autoimmunity and neuroinflammation. AB - Parkinson's disease is a neurodegenerative disease that causes the death of dopaminergic neurons in the substantia nigra. The resulting dopamine deficiency in the basal ganglia leads to a movement disorder that is characterized by classical parkinsonian motor symptoms. Parkinson's disease is recognized as the most common neurodegenerative disorder after Alzheimer's disease. PD ethiopathogenesis remains to be elucidated and has been connected to genetic, environmental and immunologic conditions. The past decade has provided evidence for a significant role of the immune system in PD pathogenesis, either through inflammation or an autoimmune response. Several autoantibodies directed at antigens associated with PD pathogenesis have been identified in PD patients. This immune activation may be the cause of, rather than a response to, the observed neuronal loss. Parkinsonian motor symptoms include bradykinesia, muscular rigidity and resting tremor. The non-motor features include olfactory dysfunction, cognitive impairment, psychiatric symptoms and autonomic dysfunction. Microscopically, the specific degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are brain deposits containing a substantial amount of alpha-synuclein, have been recognized. The progression of Parkinson's disease is characterized by a worsening of motor features; however, as the disease progresses, there is an emergence of complications related to long-term symptomatic treatment. The available therapies for Parkinson's disease only treat the symptoms of the disease. A major goal of Parkinson's disease research is the development of disease-modifying drugs that slow or stop the neurodegenerative process. Drugs that enhance the intracerebral dopamine concentrations or stimulate dopamine receptors remain the mainstay treatment for motor symptoms. Immunomodulatory therapeutic strategies aiming to attenuate PD neurodegeneration have become an attractive option and warrant further investigation. PMID- 27497914 TI - The importance of glial cells in the homeostasis of the retinal microenvironment and their pivotal role in the course of diabetic retinopathy. AB - Diabetic retinopathy (DR) is a remarkable microvascular complication of diabetes and it has been considered the leading cause of legal blindness in working-age adults in the world. Several overlapping and interrelated molecular pathways are involved in the development of this disease. DR is staged into different levels of severity, from the nonproliferative to the advanced proliferative form. Over the years the progression of DR evolves through a series of changes involving distinct types of specialized cells: neural, vascular and glial. Prior to the clinically observable vascular complications, hyperglycemia and inflammation affect retinal glial cells which undergo a wide range of structural and functional alterations. In this review, we provide an overview of the status of macroglia and microglia in the course of DR, trying to briefly take into account the complex biochemical mechanisms that affect the intimate relationship among neuroretina, vessels and glial cells. PMID- 27497915 TI - What is herd immunity, and how does it relate to pediatric vaccination uptake? US parent perspectives. AB - In light of current concern over pediatric immunization rates, 53 US parents with at least one child kindergarten age or younger were surveyed and interviewed regarding vaccine decision making. Data were collected in 2014 in San Diego, California. Herd immunity was not a salient issue: only six (11.3%) referenced the term or concept spontaneously; others had to be prompted. Parents familiar with herd immunity (70%) variously saw it as not just unnecessary but unproven, illogical, unrealistic, and unreliable. For instance, parents questioned its attainability because many adults do not immunize themselves. Some understood the concept negatively, as an instance of "herd mentality." Further, having knowledge of herd immunity that public health experts would deem 'correct' did not lead to full vaccination. Implications of findings for understanding how the public makes use of scientific information, the potential role of public health messaging regarding altruism and 'free-riding,' and assumptions that vaccine-cautious parents would willfully take advantage of herd immunity are explored in relation to parent role expectations and American individualism. PMID- 27497916 TI - From clinical sample to complete genome: Comparing methods for the extraction of HIV-1 RNA for high-throughput deep sequencing. AB - The BEEHIVE (Bridging the Evolution and Epidemiology of HIV in Europe) project aims to analyse nearly-complete viral genomes from >3000 HIV-1 infected Europeans using high-throughput deep sequencing techniques to investigate the virus genetic contribution to virulence. Following the development of a computational pipeline, including a new de novo assembler for RNA virus genomes, to generate larger contiguous sequences (contigs) from the abundance of short sequence reads that characterise the data, another area that determines genome sequencing success is the quality and quantity of the input RNA. A pilot experiment with 125 patient plasma samples was performed to investigate the optimal method for isolation of HIV-1 viral RNA for long amplicon genome sequencing. Manual isolation with the QIAamp Viral RNA Mini Kit (Qiagen) was superior over robotically extracted RNA using either the QIAcube robotic system, the mSample Preparation Systems RNA kit with automated extraction by the m2000sp system (Abbott Molecular), or the MagNA Pure 96 System in combination with the MagNA Pure 96 Instrument (Roche Diagnostics). We scored amplification of a set of four HIV-1 amplicons of ~1.9, 3.6, 3.0 and 3.5kb, and subsequent recovery of near-complete viral genomes. Subsequently, 616 BEEHIVE patient samples were analysed to determine factors that influence successful amplification of the genome in four overlapping amplicons using the QIAamp Viral RNA Kit for viral RNA isolation. Both low plasma viral load and high sample age (stored before 1999) negatively influenced the amplification of viral amplicons >3kb. A plasma viral load of >100,000 copies/ml resulted in successful amplification of all four amplicons for 86% of the samples, this value dropped to only 46% for samples with viral loads of <20,000 copies/ml. PMID- 27497917 TI - Increased Activity and Number of Epidermal Melanocytes in Lesional Psoriatic Skin. AB - BACKGROUND: Psoriatic lesions may resolve with hypo- or hyperpigmentation. The involvement of melanocytes in this dichotomous clinical outcome is not fully investigated. OBJECTIVES: Qualitative and quantitative assessment of melanocytes in untreated lesional and non-lesional psoriatic skin (n = 15) and healthy controls (n = 10). METHODS: Skin biopsies were labelled immunohistochemically (APAAP technique) with the antimelanocyte monoclonal antibodies (MoAbs) HMB45, Melan A, tyrosinase and microphthalmia-associated transcription factor (MITF). The labelled melanocytes were evaluated by an independent investigator with a digital image analyser. RESULTS: Lesional melanocytes, in contrast to those in non-lesional and healthy skin, exhibited features of activation in the form of dilatation, prominent and long dendrites and intense labelling. The number of melanocytes was significantly increased in psoriatic lesions in comparison with non-lesional psoriatic and healthy skin as shown by counts of cells labelled with the MoAbs HMB45 (3-fold; p < 0.001), Melan A (1.6-fold; p < 0.01) and tyrosinase (1.5-fold; p < 0.01). In contrast, labelling with MITF revealed no significant difference (1.2-fold increase; p > 0.05). Likewise, no significant difference between non-lesional psoriatic and healthy skin control was found (p > 0.05). Furthermore, no positively labelled dermal cells were detected, apart from few only detected with Melan A. CONCLUSIONS: Epidermal melanocyte activity and numbers are increased in the epidermal compartment of psoriatic lesions providing an explanation for postinflammatory hyperpigmentation. PMID- 27497918 TI - Length of the memory retention period depends on the extent of protein synthesis in the terrestrial slug Limax. AB - The terrestrial slug Limax can form an odor-aversion memory by the single simultaneous presentation of a food odor and an aversive stimulus. We have previously demonstrated that the long-term retention of this memory was impaired by a high-dose injection of a protein synthesis inhibitor 30min prior to the conditioning. However, the onset of amnesia was delayed if the dose of the inhibitor was reduced or a less potent protein synthesis inhibitor was used. We thus speculated that the persistence of memory depends on the amount of newly synthesized protein following learning. In the present study, we further elaborated on this idea by injecting a high dose of anisomycin at different timings before or after conditioning, and tested the memory retention at 1, 2, 3, 7, or 14days after the conditioning. We found that the injection of anisomycin 6h before, or 1h after the conditioning had no effect on memory retention for 7days, and an injection at 30min before and just following the conditioning impaired the memory retention at 3days. Interestingly, the injection at 3h before and 30min after the conditioning did not impair the retention at 3days but did impair retention at 7days. Taking into account the time course of protein synthesis inhibition in the brain, our results further support the idea that the memory retention period is dependent on the amount of protein synthesized following memory acquisition. PMID- 27497919 TI - Salvianolic acid B improves the disruption of high glucose-mediated brain microvascular endothelial cells via the ROS/HIF-1alpha/VEGF and miR-200b/VEGF signaling pathways. AB - The study investigated the roles and mechanisms of Salvianolic acid B (Sal B) on permeability of rat brain microvascular endothelial cells (RBMECs) exposed to high glucose. The results demonstrated that Sal B greatly up-regulated the expression of tight junction (TJ) proteins and decreased the permeability of RBMECs compared with the control group. And the increase of reactive oxidative species (ROS) production, the upregulation of hypoxia-inducible factor-1 alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) protein induced by high glucose were antagonized by Sal B. In addition, a great decrease of microRNA 200b (miR-200b) was observed in the RBMECs under high-glucose condition, which was significantly increased by Sal B pretreatment. And overexpression of miR-200b markedly attenuated the RBMECs permeability and inhibited the expression of VEGF protein by targeting with 3'-UTR of its mRNA. This led to the conclusion that Sal B-mediated improvement of blood-brain barrier dysfunction induced by high-glucose is related to the ROS/HIF-1alpha/VEGF and miR-200b/VEGF signaling pathways. PMID- 27497920 TI - Acute single dose of ketamine relieves mechanical allodynia and consequent depression-like behaviors in a rat model. AB - Both chronic pain and depression are debilitating diseases, which often coexist in clinic. However, current analgesics and antidepressants exhibit limited efficacy for this comorbidity. The present study aimed to investigate the effect of ketamine on the comorbidity of inflammatory pain and consequent depression like behaviors in a rat model established by intraplantar administration of complete Freunds adjuvant (CFA). The mechanical withdrawal threshold, thermal withdrawal latency, open field test, forced swimming test, and sucrose preference test were evaluated after the CFA injection and ketamine treatment. The hippocampus was harvested to determine the levels of interleukin (IL)-6, IL 1beta, indoleamine 2,3-dioxygenase (IDO), kynurenine (KYN), 5-hydroxytryptamine (5-HT), and tryptophan (TRP). The inflammatory pain-induced depression-like behaviors presented on 7days and lasted to at least 14days after the CFA injection. Single dose of ketamine at 20mg/kg relieved both the mechanical allodynia and the associated depression-like behaviors as demonstrated by the attenuated mechanical withdrawal threshold, reduced immobility time in the forced swim test, and increased sucrose preference after ketamine treatment. The total distance had no significant change after the CFA injection or ketamine treatment in the open field test. Simultaneously, ketamine reduced the levels of IL-6, IL 1beta, IDO, and KYN/TRP ratio and increased the 5-HT/TRP ratio in the hippocampus. In conclusion, acute single dose of ketamine can rapidly attenuate mechanical allodynia and consequent depression-like behaviors and down-regulate hippocampal proinflammatory responses and IDO/KYN signal pathway in rats. PMID- 27497921 TI - Is there a generalized sweetness sensitivity for an individual? A psychophysical investigation of inter-individual differences in detectability and discriminability for sucrose and fructose. AB - Despite the historical interest in the taste of sweetness, a seemingly fundamental question has not been properly addressed. That is, whether an individual's sensitivity can be generalized across different sugars. An answer to this question has a close relevance to illuminating the sensory physiology of the gustatory system, as well as to practical research of sucrose substitution. A cross-disciplinary review highlights two weak links with the psychophysical methods that have been employed in the literature. The present paper describes an empirical investigation of inter-individual differences in detectability and discriminability for two types of common sugars - sucrose and fructose, using psychometric functions (PF) and a controlled sensory discrimination test. The study found six of the 12 judges had significantly different thresholds for sucrose and fructose (p<0.05), with no consistent pattern in the direction of differences. This observation challenges the conventional belief that people hold the same perception of relative difference in sweetness across substances. For seven judges, the individually-fitted PFs exhibited different shapes for the tested sugars, implying the detection processing might be substance-specific. Also, inter-individual differences were observed in the controlled discrimination task for sucrose and fructose at a supra-threshold level. These findings are discussed in relation to their theoretical, practical and methodological values. While this study uses sucrose and fructose as exemplars, the findings may provide important insights into sweetness perception in general. PMID- 27497922 TI - Voluntary running decreases nonexercise activity in lean and diet-induced obese mice. AB - PURPOSE: Determine whether voluntary wheel running triggers compensatory changes in nonexercise activity in lean and high-fat diet fed mice. METHODS: C57Bl/6 mice received a control (C) or a high-fat diet (H) and half of them had free access to a running wheel 5days/week (CE and HE, respectively) for 10weeks. Energy intake, nonexercise activity (global activity, distance covered and average speed of displacement in the home cage) and energy expenditure (EE) were evaluated at weeks 5 and 10 during the 2days without the wheels. RESULTS: High-fat diet increased weight gain in H (110%) and HE (60%) groups compared to C and CE groups, respectively, with no effect of exercise. Wheel running increased energy intake (26% CE, 11% HE in week 5; 7% CE, 45% HE in week 10) and decreased distance covered (26% for both CE and HE in week 5; 35% CE and 13% HE in week 10) and average speed (35% CE and 13% HE in week 5; 45% CE and 18% HE in week 10) compared to the respective nonexercised groups. In week 10 there was an interaction between diet and exercise for global activity, which was reduced nearly 18% in CE, H, and HE groups compared to C. Access to a running wheel increased EE in week 5 (11% CE and 16% HE) but not in week 10, which is consistent with the period of highest running (number of turns: weeks 1-5 nearly 100%>weeks 6-10 for CE and HE groups). EE was reduced in H (19%) and HE (12%) groups compared to C and CE, in week 10. CONCLUSION: Voluntary running causes a compensatory decrease in nonexercise activity and an increase in energy intake, both contributing to the lack of effect of exercise on body mass. PMID- 27497923 TI - Small field correction factors for the IBA Razor. AB - The IBA Razor diode supersedes the IBA SFD and is intended for use in small fields. However, its behaviour in small fields has not yet been quantified. In this work, we examine the response of the Razor diode against the air core scintillation dosimeter (FOD) and Gafchromic film in photon beams from three Varian linac beams. Fields between 4mm and 30mm in width were measured, both with and without a flattening filter and at two energies. The Razor exhibited an over response of up to 4.5% for MLC collimated fields and 7.1% for stereotactic cone collimated fields. The presence of the flattening filter altered the over response by up to 1.5%. The small field correction factors are tabulated and agree with the mathematical relation of Liu et al. (2014). Four samples of the Razor were used, two having received a significant prior dose. The correction factors for the four samples differed and may depend on their dose history. PMID- 27497924 TI - Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: a study of temporal lobe resections. AB - SEE BERNASCONI DOI101093/AWW202 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Temporal lobe epilepsy, the most prevalent form of chronic focal epilepsy, is associated with a high prevalence of cognitive impairment but the responsible underlying pathological mechanisms are unknown. Tau, the microtubule-associated protein, is a hallmark of several neurodegenerative diseases including Alzheimer's disease and chronic traumatic encephalopathy. We hypothesized that hyperphosphorylated tau pathology is associated with cognitive decline in temporal lobe epilepsy and explored this through clinico-pathological study. We first performed pathological examination on tissue from 33 patients who had undergone temporal lobe resection between ages 50 and 65 years to treat drug refractory temporal lobe epilepsy. We identified hyperphosphorylated tau protein using AT8 immunohistochemistry and compared this distribution to Braak patterns of Alzheimer's disease and patterns of chronic traumatic encephalopathy. We quantified tau pathology using a modified tau score created specifically for analysis of temporal lobectomy tissue and the Braak staging, which was limited without extra-temporal brain areas available. Next, we correlated tau pathology with pre- and postoperative cognitive test scores and clinical risk factors including age at time of surgery, duration of epilepsy, history of secondary generalized seizures, history of head injury, handedness and side of surgery. Thirty-one of 33 cases (94%) showed hyperphosphorylated tau pathology in the form of neuropil threads and neurofibrillary tangles and pre-tangles. Braak stage analysis showed 12% of our epilepsy cohort had a Braak staging III-IV compared to an age-matched non-epilepsy control group from the literature (8%). We identified a mixture of tau pathology patterns characteristic of Alzheimer's disease and chronic traumatic encephalopathy. We also found unusual patterns of subpial tau deposition, sparing of the hippocampus and co-localization with mossy fibre sprouting, a feature of temporal lobe epilepsy. We demonstrated that the more extensive the tau pathology, the greater the decline in verbal learning (Spearman correlation, r = -0.63), recall (r = -0.44) and graded naming test scores (r = 0.50) over 1-year post-temporal lobe resection (P < 0.05). This relationship with tau burden was also present when examining decline in verbal learning from 3 months to 1 year post-resection (r = -0.54). We found an association between modified tau score and history of secondary generalized seizures (likelihood ratio chi(2), P < 0.05) however there was no clear relationship between tau pathology and other clinical risk factors assessed. Our findings suggest an epilepsy-related tauopathy in temporal lobe epilepsy, which contributes to accelerated cognitive decline and has diagnostic and treatment implications. PMID- 27497925 TI - Spatiotemporal regulation of enhancers during cardiogenesis. AB - With the advance in chromatin immunoprecipitation followed by high-throughput sequencing, there has been a dramatic increase in our understanding of distal enhancer function. In the developing heart, the identification and characterisation of such enhancers have deepened our knowledge of the mechanisms of transcriptional regulation that drives cardiac differentiation. With next generation sequencing techniques becoming widely accessible, the quantity of data describing the genome-wide distribution of cardiac-specific transcription factor and chromatin modifiers has rapidly increased and it is now becoming clear that the usage of enhancers is highly dynamic and complex, both during the development and in the adult. The identification of those enhancers has revealed new insights into the transcriptional mechanisms of how tissue-specific gene expression patterns are established, maintained, and change dynamically during development and upon physiological stress. PMID- 27497927 TI - Long-term work participation among cystic fibrosis patients undergoing lung transplantation. AB - BACKGROUND: Patients with cystic fibrosis (CF) experience obstacles to employment, regardless of whether they have undergone lung transplantation (LTx). We investigated socioeconomic and clinical factors predicting long-term employment outcomes in CF patients receiving LTx. METHODS: Data from the United Network for Organ Sharing registry were used to identify CF patients 18-59years old who received LTx between 2000 and 2010 and survived greater than 5years. Long term employment status was determined by center-reported follow-up data on patients working for income, collected at the 5th transplant anniversary. After multiple imputation to complete missing data on covariates, multivariable logistic regression was used to identify associations between characteristics at or after LTx and long-term work participation. RESULTS: There were 745 patients who met inclusion criteria and contributed employment data within 365days of their 5th LTx anniversary. In this cohort, 48% (358/745) were working for income 5years after LTx. Younger age, male gender, better pulmonary function attained post-transplant, pre-transplant work participation, and private health insurance (compared to government Medicaid or Medicare insurance) at the time of transplant predicted greater odds of post-transplant employment. CONCLUSIONS: Lack of work experience and reliance on government health insurance at the time of transplant predict lower long-term work participation among LTx recipients with CF. By contrast, long-term employment outcomes were not negatively affected by comorbidities at or after transplantation in this cohort. Despite resolving some physiological obstacles to employment in patients with CF, LTx may introduce new socioeconomic barriers to employment. PMID- 27497928 TI - Magnetically Controlled Growing Rod in Early-Onset Scoliosis: A Minimum of 2-Year Follow-Up. AB - PURPOSE: The magnetically controlled growing rod technique decreases complications, costs, and loss of functionality by avoiding successive surgical corrections every 6 months in patients with early-onset scoliosis. However, only a few studies have presented clinical experience with the magnetically controlled growing rod. In this study we aimed to present our single-center experience in patients with early-onset scoliosis who underwent the magnetically controlled growing rod technique and follow-up for at least 2 years. MATERIALS AND METHODS: We made an observational study by evaluating patients with early-onset scoliosis who underwent the magnetically controlled growing rod technique between February 2012 and December 2013. Demographic and clinical data were obtained from the patients charts. We included patients who were followed up for at least 2 years. Radiological data were obtained from plain anterior-posterior and lateral scoliosis X-rays. RESULTS: Eight patients with early-onset scoliosis who underwent surgery using the magnetic system were treated with dual rods. None of the spines were fused to the sacrum. We observed no intra- and/or postsurgical complications. The average number of external rod lengthenings was 7.6. The average amount of lengthening was 30.6 mm on the right side and 27.8 mm on the left side by the time of last clinical follow-up. The average coronal and sagittal Cobb values at the final clinical evaluation were 10.5 degrees (thoracic coronal), 13.75 degrees (lumbar coronal), 6.25 degrees (lumbosacral coronal), 24.5 degrees (thoracic sagittal), and 40 degrees (lumbar sagittal), respectively. CONCLUSIONS: The magnetically controlled growing rod is beneficial in early-onset scoliosis, since it enables spinal growth and decreases additional surgeries, complications, and costs. Even though we had a small sample size, our follow-up period was enough to declare long-term outcomes of our patients. Multicenter and large sample-sized studies are needed to make more conclusive statements regarding this promising scoliosis treatment approach. PMID- 27497929 TI - Erratum to: Efficacy and Safety of the PCSK9 Inhibitor Evolocumab in Patients with Mixed Hyperlipidemia. PMID- 27497926 TI - Metazoan evolution of the armadillo repeat superfamily. AB - The superfamily of armadillo repeat proteins is a fascinating archetype of modular-binding proteins involved in various fundamental cellular processes, including cell-cell adhesion, cytoskeletal organization, nuclear import, and molecular signaling. Despite their diverse functions, they all share tandem armadillo (ARM) repeats, which stack together to form a conserved three dimensional structure. This superhelical armadillo structure enables them to interact with distinct partners by wrapping around them. Despite the important functional roles of this superfamily, a comprehensive analysis of the composition, classification, and phylogeny of this protein superfamily has not been reported. Furthermore, relatively little is known about a subset of ARM proteins, and some of the current annotations of armadillo repeats are incomplete or incorrect, often due to high similarity with HEAT repeats. We identified the entire armadillo repeat superfamily repertoire in the human genome, annotated each armadillo repeat, and performed an extensive evolutionary analysis of the armadillo repeat proteins in both metazoan and premetazoan species. Phylogenetic analyses of the superfamily classified them into several discrete branches with members showing significant sequence homology, and often also related functions. Interestingly, the phylogenetic structure of the superfamily revealed that about 30 % of the members predate metazoans and represent an ancient subset, which is gradually evolving to acquire complex and highly diverse functions. PMID- 27497930 TI - Pharmacological Agents Targeting Myocardial Metabolism for the Management of Chronic Stable Angina : an Update. AB - Despite continuous advances in myocardial revascularization procedures and intracoronary devices, patients with ischemic heart disease (IHD) still experience worse prognosis and poor quality of life (QoL). Indeed, chronic stable angina (CSA) is a common disease with a large burden on healthcare costs. Traditionally, CSA is interpreted as episodes of reversible myocardial ischemia related to the presence of stable coronary artery plaque causing myocardial demand/supply mismatch when myocardial oxygen consumption increases. Accordingly, revascularization procedures are performed with the aim to remove the flow limiting stenosis, whereas traditional medical therapy (hemodynamic agents) aims at reducing myocardial oxygen demands. However, although effective, none of these treatment strategies or their combination is either able to confer symptomatic relief in all patients, nor to reduce mortality. Failure to significantly improve QoL and prognosis may be attributed at least in part to this "restrictive" understanding of IHD. Despite for many years myocardial metabolic derangement has been overlooked, recently it has gained increased attention with the development of new pharmacological agents (metabolic modulators) able to influence myocardial substrate selection and utilization thus improving cardiac efficiency. Shifting cardiac metabolism from free fatty acids (FA) towards glucose is a promising approach for the treatment of patients with stable angina, independently of the underling disease (macrovascular and/or microvascular disease). In this sense cardiac metabolic modulators open the way to a "revolutionary" understanding of ischemic heart disease and its common clinical manifestations, where myocardial ischemia is no longer considered as the mere oxygen and metabolites demand/supply unbalance, but as an energetic disorder. Keeping in mind such an alternative approach to the disease, development of new pharmacological agents directed toward multiple metabolic targets is mandatory. PMID- 27497931 TI - A liquid crystal-based sensor for the simple and sensitive detection of cellulase and cysteine. AB - A liquid crystal (LC)-based sensor, which is capable of monitoring enzymatic activity at the aqueous/LC interface and detecting cellulase and cysteine (Cys), was herein reported. When functionalized with a surfactant, dodecyl beta-d glucopyranoside, the 4-cyano-4'-pentylbiphenyl (5CB) displays a dark-to-bright transition in the optical appearance for cellulase. We attribute this change to the orientational transition of LCs, as a result of enzymatic hydrolysis between cellulase and surfactant. Furthermore, by adding cellulase and Cu(2+), our surfactant-LCs system performs an interesting ability to detect Cys, even though Cys could not interact with surfactant or LC directly. Alternatively, through the strong binding between Cys and Cu(2+), cellulase was able to hydrolyze surfactant in the presence of Cu(2+), leading to the transition of LCs from dark to bright. The detection limit of the LC sensor was around 1*10(-5)mg/mL and 82.5MUM for cellulase and Cys, respectively. The LC-based sensor may contribute to the development of low-cost, expedient, and label-free detection for cellulase and Cys and the design strategy may also provide a novel way for detecting multiple analytes. PMID- 27497932 TI - Fluorescence labels may significantly affect the protein adsorption on hydrophilic nanomaterials. AB - Fluorescently labelled proteins are often used to study processes in vitro, e.g. the binding of proteins to cell surfaces or the adsorption of plasma proteins on drug nanocarriers. However, the fact that the fluorescent labelling may affect the protein properties is frequently neglected. On the example of a simple model system, we reiterate the importance of this issue by showing that even a single label may perturb interactions between hydrophilic starch-based nanocapsules and serum albumin and thus prevent binding. PMID- 27497933 TI - Efficiency of emulsifier-free emulsions and emulsions containing rapeseed lecithin as delivery systems for vectorization and release of coenzyme Q10: physico-chemical properties and in vitro evaluation. AB - To improve the encapsulation and release of coenzyme Q10 (CoQ10), emulsifier-free emulsions were developed with a new emulsification process using high-frequency ultrasound (HFU) at 1.7MHz. Nano-emulsions containing CoQ10 were prepared with or without rapeseed lecithin as an emulsifier. The emulsions prepared with HFU were compared with an emulsion of CoQ10 containing emulsifier prepared with the same emulsification technique as well as with emulsions prepared with low-frequency ultrasound coupled with high-pressure homogenization (LFU+HPH). The physico chemical properties of the emulsions were determined by average droplet size measurement with nano-droplet tracking analysis, droplet surface charge with zeta potential measurement, surface tension and rheological behaviour. Emulsions made by LFU+HPH with an emulsifier showed lower droplet sizes due to cavitation generated by the HFU process. Surface tension results showed that there was no significant difference between emulsions containing lecithin emulsifier regardless of the preparation process or the inclusion of CoQ10. In vitro biocompatibility tests were performed on human mesenchymal stem cells in order to show the cytotoxicity of various formulations and the efficiency of CoQ10-loaded emulsions. In vitro tests proved that the vectors were not toxic. Furthermore, CoQ10 facilitated a high rate of cell proliferation and metabolic activity especially when in an emulsifier-free formulation. PMID- 27497934 TI - Cholecystokinin-33, but not cholecystokinin-8 shows gastrointestinal site specificity in regulating feeding behaviors in male rats. AB - Two separate experiments were performed to localize the gastrointestinal sites of action regulating meal size (MS), intermeal interval (IMI) length and satiety ratio (SR, IMI/MS) by cholecystokinin (CCK) 8 and 33. Experiment 1: CCK-8 (0, 0.05, 0.15, 0.25nmol/kg) was infused in the celiac artery (CA, supplies stomach and upper duodenum) or the cranial mesenteric artery (CMA, supplies small and part of the large intestine) prior to the onset of the dark cycle in free feeding, male Sprague Dawley rats and MS (normal rat chow), IMI and SR were recorded. Experiment 2: CCK-33 (0, 0.05, 0.15, 0.25nmol/kg) were infused in the CA or the CMA, under the same experimental conditions above, and MS, IMI and SR were recorded. Experiment 1 found that CCK-8 reduces MS, prolongs the IMI and increases the SR at sites supplied by both arteries. Experiment 2 found that CCK 33 reduces MS and increases the SR at sites supplied by the CMA. We conclude that in male rats the feeding behaviors evoked by CCK-33, but not CCK-8, are regulated at specific gastrointestinal sites of action. PMID- 27497936 TI - Post-operative medical and surgical complications after primary total joint arthroplasty in solid organ transplant recipients: a case series. AB - PURPOSE: In a series of solid organ transplant (SOT) recipients who underwent a subsequent primary total joint arthroplasty (TJA) procedure, this study aimed to determine: (1) 90-day morbidity and mortality after primary total knee or hip arthroplasty (TKA and THA), (2) overall post-operative infection rates, and (3) how complication and infection rates compared across primary TJA procedure and type of transplant organ. METHODS: The University of Michigan Health System database was retrospectively searched using current procedural terminology codes for any primary TKA or THA performed at the institution in years 2000-2012 in a patient who previously received a successful SOT at any hospital. RESULTS: The search yielded 44 arthroplasties performed in 29 SOT recipients (average age 54.8 years, average follow-up about 30 months for both groups). No deaths were reported, but 13/27 (48.1%) THA patients and 2/6 (33.3%) TKA patients experienced a total of 29 complications within 90 days of surgery. One patient (3.7%) [1/27 patients, 1/37 joints] underwent revision hip arthroplasty to correct limb length. One THA patient and two TKA patients developed infection requiring revision surgery (3.7% and 33%, respectively). Type of transplant did not affect complication rates (P=0.65), and infection was more common after TKA (P=0.01). CONCLUSIONS: A series of SOT recipients demonstrated increased rates of infection and other complications following TJA. Surgical and medical teams should work closely to optimize this population for TJA surgery and minimize peri-operative complications. LEVEL OF EVIDENCE & STUDY DESIGN: Level IV, Prognostic Case Series. PMID- 27497937 TI - Challenges in epilepsy-associated tumors. PMID- 27497935 TI - Effort-related motivational effects of the pro-inflammatory cytokine interleukin 6: pharmacological and neurochemical characterization. AB - RATIONALE: Motivational dysfunctions such as anergia, fatigue, and reduced effort expenditure are common in patients with depression and other disorders. Pro inflammatory cytokines are implicated in depression, and cytokine administration induces motivational deficits in humans. OBJECTIVES: These studies focused on the effects of the cytokine interleukin-6 (IL-6) on effort-related decision-making. METHODS: Rats were assessed using the concurrent fixed ratio 5-lever pressing/chow feeding choice procedure, which measures the tendency of rats to work for a preferred food (high carbohydrate pellets) in the presence of a concurrently available but less preferred substitute (lab chow). RESULTS: IL-6 (2.0-8.0 MUg/kg IP) shifted choice behavior, significantly decreasing lever pressing and increasing chow intake. Further experiments showed that the adenosine A2A antagonist MSX-3 and the stimulant methylphenidate attenuated the effort-related impairments produced by IL-6, increasing lever pressing and decreasing chow intake in IL-6 treated rats. The same doses of IL-6 did not alter food intake or preference in parallel free-feeding choice studies, demonstrating that these low doses were not altering preference for the high carbohydrate pellets or generally suppressing appetite. Also, IL-6 did not affect body temperature. Microdialysis studies showed that 8.0 MUg/kg IL-6 significantly decreased extracellular dopamine in nucleus accumbens core. CONCLUSIONS: In summary, IL-6 reduces the tendency to work for food, even at low doses that do not produce fever or loss of appetite. Dopaminergic mechanisms may be involved in these effort-related effects. This research has implications for the involvement of cytokines in motivational dysfunctions such as anergia and fatigue. PMID- 27497938 TI - Pathological rupture of the normal spleen: Review with the literature. AB - INTRODUCTION: Atraumatic spontaneous rupture of the spleen is an uncommon but fatal condition that may coexist with other disease. Our case was presented with obvious CT findings of a spontaneous rupture of the spleen. PRESENTATION OF THE CASE: A 75-year-old woman admitted to the emergency service with abdominal pain. Although there was no evident splenomegaly in the abdominal CT examination, the patient was diagnosed with diffuse large B-cell lymphoma, and densities in harmony with the free air were detected in the spleen and the abdomen. DISCUSSION: It is clear that a healthy spleen does not rupture without marked trauma; hence, a doctor must carefully investigate the underlying pathology. Splenomegaly, the infiltration of the spleen and the capsule and consequently a splenic infarct and hemorrhage were set forth as the causes of the rupture of the spleen in lymphomas. However, our case had no splenomegaly or splenic involvement of lymphoma in the pathological examination. Even in the absence of splenomegaly, rupture may develop for such reasons as inflammation and embolism. Splenic infarcts are also in the developmental mechanism. CONCLUSION: Although atraumatic rupture of the spleen is not prevalent, it is a case which must be considered in an acute abdominal pain as it has highly fatal outcomes without CT exam. PMID- 27497939 TI - Effectiveness of a barbed suture in the repair of bile duct injury during laparoscopic cholecystectomy: Report of two cases. AB - INTRODUCTION: Bile duct injury during laparoscopic cholecystectomy occurs in rare cases. We report two cases using barbed suture for repair in bile duct injury during laparoscopic cholecystectomies. PRESENTATION OF CASES: The first patient was a 73-year-old woman who underwent elective laparoscopic cholecystectomy for cholecystolithiasis. When the gallbladder was dissected from the bed, bile spillage was observed and an injured small bile duct was detected. The bile duct could not be managed using a titanium clip. The second patient was an 83-year-old woman who underwent emergent laparoscopic cholecystectomy for gallbladder torsion. After the gallbladder was dissected from the bed, bile spillage was observed. In both cases, a running suture, of absorbable monofilament 3-0 barbed suture, was used to laparoscopically repair the injuries. DISCUSSION: Laparoscopic repair of a bile duct injury is technically challenging, especially in the gallbladder bed where suturing is very difficult because of the tangential approach and the risk of additional liver laceration. Barbed sutures have the benefit of being knotless, thus, performing a running suture is not difficult, even in laparoscopic procedures. Further, absorbable and monofilament threads are generally better suited for biliary surgery, compared with non-absorbable and braided sutures, because of the potential association of the other types of materials with bile duct stone and stricture formation. CONCLUSION: We believe that the V-LocTM device is an effective and appropriate option for bile duct injuries that occur during laparoscopic cholecystectomies, particularly around the gallbladder bed, and it is especially useful for surgeons unfamiliar with intracorporeal knot tying. PMID- 27497940 TI - The challenges of managing and following-up a case of short bowel in eastern europe. AB - INTRODUCTION: This article reflects on the plight of patients with short bowel syndrome (SBS) in developing countries. SBS is life threatening, rare, complex and often not considered a priority by healthcare planners in the developing countries because of the high cost of treatment. Data was collected and analyzed from 3 different hospitals in two different countries (Romania and Austria) from November 2013 to February 2016 CASE PRESENTATION: The patient had an emergency surgery for volvulus as a result of an extensive ischemic necrosis, with just 80cm of the bowel left and no ileocecal valve after enterectomy. Despite intensive care and surgeries for anastomotic joint ischemic necrosis and intestinal adhesion with just 70cm of the intestine left after primary anastomosis, the patient remained in a catabolic state (metabolic acidosis, severe malabsorption and loss of nutrients, water and electrolytes through diarrhea) and was transferred overseas where two more surgeries (intestinal stomas) and good intensive care helped to achieve enteral autonomy at the optimal time. DISCUSSION: This immune-deficient patient was exposed to various types of bacteria (Klebsiella pneumoniae, Pseudomonas aeruginosa). Two years after surgery an acute enterocolitis with salmonella infection and resultant intestinal failure treated in patient's country of origin failed to achieve enteral nutrition warranting a second overseas transfer. CONCLUSION: The lack of sufficient mucosal surface followed by long time intestinal adaptation process is crucial in determining bowel functional capacity. Long time hospital stay and cost was reduced through a parental home healthcare management training scheme. PMID- 27497941 TI - Bowel obstruction and perforation due to a large gallstone. A case report. AB - INTRODUCTION: Gallstone bowel obstruction is a rare form of mechanical ileus usually presenting in elderly patients, and is associated with chronic or acute cholecystitis episodes. CASE PRESENTATION: We present the case of an 80year old female with abdominal pain, inability to defecate and recurrent episodes of diarrhea for the past 8 months. CT examination uncovered a cholecystoduodenal fistula along with gas in the gall bladder and the presence of a >=2cm gallstone inside the small bowel lumen causing obstruction. Patient was admitted to the operating room, where a 3.2cm gallstone was located in the terminal ileus. A rupture was found in the antimesenteric part of a discolored small bowel segment, approximately 60cm from the ileocaecal valve, through which the gallstone was recovered. The bowel regained its peristalsis, and the rupture was debrided and sutured. Patient was discharged uneventfully on the 6th postoperative day. DISCUSSION: Gallstone ileus is caused due to the impaction of a gallstone inside the bowel lumen. It usually passes through a fistula connecting the gallstone with the gastrointestinal tract. It can present with nonspecific or acute abdominal symptoms. CT usually confirms the diagnosis, while there are a number of treatment options; conservative, minimal invasive and surgical. Our patient was successfully relieved of the obstruction through recovery of the gallstone using open surgery, with no repair of the fistula. CONCLUSSION: Although rare, gallstones must be suspected as a possible cause of bowel obstruction, especially in elderly patients reporting biliary symptoms. PMID- 27497942 TI - Difficult diagnosis of hemoperitoneum in a patient with a pelvic mass of large size. AB - INTRODUCTION: Intraperitoneal hemorrhage caused by a uterine myoma is rare (Tajima et al., 2015). PRESENTATION OF CASE: A 47-year-old woman was admitted to the emergency room for worsening abdominal pain. Ultrasound revealed fluid filled almost the entire abdominal cavity as well as the presence of a mass of about 20cm near the uterus. It was not easy to understand the nature of the fluid by ultrasound. It appeared to be ascites with a tumoral pelvic neoformation. On TC there was extravasation of contrast material, but the bleeding site was not identifiable. An emergency operation was performed. Bleeding was from a subserosalmyoma on the anterior wall of the uterus; myoma measured approximately 20cm in maximum diameter. Pathological assessment of the resected specimen revealed bleeding from ruptured tortuous veins on a serosal-type uterine myoma. DISCUSSION: Spontaneous rupture of a vein or an artery overlying a myoma has been documented in English literature on the subject, although it is extremely rare (Tajima et al., 2015). CONCLUSION: The differential diagnosis between ascites and hemoperitoneum is sometimes not easy. Ultrasound is a helpful instrument in expert hands to make a diagnosis of hemoperitoneum. The aid of other diagnostic methods as TC help the clinician to arrive at the correct diagnosis quickly. PMID- 27497943 TI - Mesenchymal stem cells enhance alpha-synuclein clearance via M2 microglia polarization in experimental and human parkinsonian disorder. AB - Microglia in the brain show distinctive phenotypes that serve different functions. In particular, M2-polarized microglia are anti-inflammatory and phagocytic cells that serve a restorative function. In this study, we investigated whether mesenchymal stem cells (MSCs) enhance the phagocytic clearance of alpha-synuclein via M2 microglia polarization, and thereby exert neuroprotective effects in alpha-synuclein-enriched experimental models and patients with multiple system atrophy (MSA). Treatment of BV2 cells with alpha synuclein induced an inflammatory phenotype, whereas co-culture of alpha synuclein-treated BV2 cells with MSCs induced an anti-inflammatory M2 phenotype, with decreased alpha-synuclein levels and increased lysosomal activity, leading to greater viability of neuronal cells co-cultured with BV2 cells. Using IL-4 receptor siRNA in BV2 cells and IL-4 siRNA in MSCs, we found that M2 microglia polarization was induced by IL-4 secreted from MSCs. In alpha-synuclein inoculated mice, MSC treatment induced M2 microglia polarization decreased alpha synuclein levels, and had a prosurvival effect on neurons. Using IL-4 and IL-4 receptor knockout mice, we further confirmed that IL-4 secreted from MSCs induced phagocytic clearance of alpha-synuclein through M2 microglia polarization. Next, we found that the cerebrospinal fluid (CSF) from MSC-transplanted MSA patients induced microglia M2 polarization and had a prosurvival effect via enhanced clearance of alpha-synuclein in alpha-synuclein-treated BV2 cells. Finally, a serial CSF study demonstrated that changes in oligomeric alpha-synuclein from baseline to 1-year follow-up were greater in the CSF of MSC-transplanted MSA patients than in placebo-transplanted MSA patients. These findings indicate that MSCs exert a neuroprotective effect via the clearance of extracellular alpha synuclein by controlling microglia M2 polarization, suggesting that MSCs could be used as a disease-modifying therapy for patients with alpha-synucleinopathies. PMID- 27497944 TI - Fully quantitative description of hybrid TiO2 nanoparticles by means of solid state (31)P NMR. AB - For the first time, an absolute quantification of hybrid materials obtained from the reaction of phenylphosphonic acid (PPA) with TiO2 nanoparticles under different reaction conditions is reported. Next to the amount of PPA involved in grafting to the TiO2 nanoparticles, also the PPA included in titaniumphenylphosphonate crystallites is described quantitatively. The quantitative analysis is based on solid state (31)P MAS NMR and is further applied to evaluate the stability of the resulting hybrid materials towards hydrolysis and organic solvent exposure. PMID- 27497946 TI - Sports hernia repair with adductor tenotomy. AB - PURPOSE: Sports hernias, or athletic pubalgia, is common in athletes, and primarily involves injury to the fascia, muscles, and tendons of the inguinal region near their insertion onto the pubic bone. However, management varies widely, and rectus and adductor tenotomies have not been adequately described. The purpose of this manuscript is to demonstrate a suture repair and a rectus and adductor longus tenotomy technique for sports hernias. METHODS: After magnetic resonance-imaging confirmation of sports hernias with rectus and adductor tendonitis, 22 patients underwent a suture herniorrhaphy with adductor tenotomy. The procedure is performed through a 4-cm incision, and a fascial release of the rectus abdominis and adductor tenotomy is performed to relieve the opposing vector forces on the pubic bone. RESULTS: All 22 patients returned to their respective sports and regained their ability to perform at a high level, including professional status. No further surgery was required. CONCLUSION: In athletes with MRI confirmation of rectus and adductor longus injuries, tenotomies along with a herniorraphy may improve outcomes. A suture repair to reinforce the inguinal floor prevents mesh-related complications, especially in young athletes. PMID- 27497947 TI - A rare case of intervertebral internal hernia. PMID- 27497948 TI - Principles of ipsilateral and contralateral cortico-cortical connectivity in the mouse. AB - Structural connectivity among cortical areas provides the substrate for information exchange in the cerebral cortex and is characterized by systematic patterns of presence or absence of connections. What principles govern this cortical wiring diagram? Here, we investigate the relation of physical distance and cytoarchitecture with the connectional architecture of the mouse cortex. Moreover, we examine the relation between patterns of ipsilateral and contralateral connections. Our analysis reveals a mirrored and attenuated organization of contralateral connections when compared with ipsilateral connections. Both physical distance and cytoarchitectonic similarity of cortical areas are related to the presence or absence of connections. Notably, our analysis demonstrates that the combination of these factors relates better to cortico-cortical connectivity than each factor in isolation and that the two factors relate differently to ipsilateral and contralateral connectivity. Physical distance is more tightly related to the presence or absence of ipsilateral connections, but its relevance greatly diminishes for contralateral connections, while the contribution of cytoarchitectonic similarity remains relatively stable. Our results, together with similar findings in the cat and macaque cortex, suggest that a common set of principles underlies the macroscale wiring of the mammalian cerebral cortex. PMID- 27497949 TI - Elevated plasma heparin-binding protein is associated with early death after resuscitation from cardiac arrest. AB - BACKGROUND: An intense systemic inflammatory response is observed following reperfusion after cardiac arrest. Heparin-binding protein (HBP) is a granule protein released by neutrophils that intervenes in endothelial permeability regulation. In the present study, we investigated plasma levels of HBP in a large population of patients resuscitated from out-of-hospital cardiac arrest. We hypothesized that high circulating levels of HBP are associated with severity of post-cardiac arrest syndrome and poor outcome. METHODS: Plasma was obtained from 278 patients enrolled in a prospective multicenter observational study in 21 intensive care units (ICU) in Finland. HBP was assayed at ICU admission and 48 h later. Multiple organ dysfunction syndrome (MODS) was defined as the 24 h Sequential Organ Failure Assessment (SOFA) score >= 12. ICU death and 12-month Cerebral Performance Category (CPC) were evaluated. Multiple linear and logistic regression tests and receiver operating characteristic curves with area under the curve (AUC) were performed. RESULTS: Eighty-two percent of patients (229 of 278) survived to ICU discharge and 48 % (133 of 276) to 1 year with a favorable neurological outcome (CPC 1 or 2). At ICU admission, median plasma levels of HBP were markedly elevated, 15.4 [9.6-31.3] ng/mL, and persisted high 48 h later, 14.8 [9.8-31.1] ng/mL. Admission levels of HBP were higher in patients who had higher 24 h SOFA and cardiovascular SOFA score (p < 0.0001) and in those who developed MODS compared to those who did not (29.3 [13.7-60.1] ng/mL vs. 13.6 [9.1-26.2] ng/mL, p < 0.0001; AUC = 0.70 +/- 0.04, p = 0.0001). Admission levels of HBP were also higher in patients who died in ICU (31.0 [17.7-78.2] ng/mL) compared to those who survived (13.5 [9.1-25.5] ng/mL, p < 0.0001) and in those with an unfavorable 12-month neurological outcome compared to those with a favorable one (18.9 [11.3-44.3] ng/mL vs. 12.8 [8.6-30.4] ng/mL, p < 0.0001). Admission levels of HBP predicted early ICU death with an AUC of 0.74 +/- 0.04 (p < 0.0001) and were independently associated with ICU death (OR [95 %CI] 1.607 [1.076-2.399], p = 0.020), but not with unfavorable 12-month neurological outcome (OR [95 %CI] 1.154 [0.834-1.596], p = 0.387). CONCLUSIONS: Elevated plasma levels of HBP at ICU admission were independently associated with early death in ICU. PMID- 27497950 TI - Predictors of hospital readmission 1 year after ischemic stroke. AB - Predictors of short-term readmission after ischemic stroke have been previously identified, but few studies analyzed predictors of long-term readmission, namely early imaging findings and treatment with intravenous thrombolysis (IVT). To characterize predictors of hospital readmission during the first year after hospitalization for ischemic stroke. The study consists of a retrospective cohort of consecutive ischemic stroke patients admitted in a Portuguese university hospital during 2013, who survived index hospitalization. We collected clinical and imaging information using the electronical clinical record. Information concerning 1-year unplanned hospital readmissions was assessed using the Portuguese electronic Health Data Platform. Descriptive and univariate analyses, Kaplan-Meier survival curve and multivariate survival analysis with Cox regression model were used. We included 480 patients, 50.6 % women, median age 79 years (interquartile range = 68-85). One-year hospital readmissions occurred in 165 patients [34.4 %, 95 % confidence interval (95 % CI) 30.2-38.7]. The main causes for readmission were infectious diseases (43.8 %), ischemic stroke or transient ischemic attack recurrence (13.2 %) and cardiac diseases (6.4 %). In hospital mortality associated with readmission was 23.0 %. The independent predictors of 1-year hospital readmission after ischemic stroke were admission mini-National Institute of Health Stoke Scale [hazards ratio (HR) 1.05, 95 % CI 1.02-1.08, p = 0.002], and mild or absent early signs of ischemia on admission computed tomography (CT) (HR 0.54, 95 % CI 0.32-0.91, p = 0.021) and IVT (HR 0.11, 95 % CI 0.01-0.80, p = 0.029). Hospital readmission during the first year after ischemic stroke occurs in 1/3 of patients and is associated with high in hospital mortality. Clinical stroke severity, early signs of ischemia on admission CT, and treatment with IVT are independent predictors of 1-year hospital readmission. PMID- 27497945 TI - Mitochondrial Ca2+ and regulation of the permeability transition pore. AB - The mitochondrial permeability transition pore was originally described in the 1970's as a Ca2+ activated pore and has since been attributed to the pathogenesis of many diseases. Here we evaluate how each of the current models of the pore complex fit to what is known about how Ca2+ regulates the pore, and any insight that provides into the molecular identity of the pore complex. We also discuss the central role of Ca2+ in modulating the pore's open probability by directly regulating processes, such as ATP/ADP balance through the tricarboxylic acid cycle, electron transport chain, and mitochondrial membrane potential. We review how Ca2+ influences second messengers such as reactive oxygen/nitrogen species production and polyphosphate formation. We discuss the evidence for how Ca2+ regulates post-translational modification of cyclophilin D including phosphorylation by glycogen synthase kinase 3 beta, deacetylation by sirtuins, and oxidation/ nitrosylation of key residues. Lastly we introduce a novel view into how Ca2+ activated proteolysis through calpains in the mitochondria may be a driver of sustained pore opening during pathologies such as ischemia reperfusion injury. PMID- 27497951 TI - Zika, dengue, and chikungunya co-infection in a pregnant woman from Colombia. AB - The clinical findings of a pregnant woman from Colombia with a triple co infection caused by dengue, chikungunya, and Zika viruses are described. Weekly obstetric ultrasounds from 14.6 to 29 weeks of gestation were normal. She remains under follow-up and management according to the standard guidelines for the management of Zika virus-infected pregnant women. PMID- 27497952 TI - Colistin resistance - is this pushing us over the edge into the abyss of pan resistance? PMID- 27497953 TI - Down-Regulation of MicroRNA-137 Improves High Glucose-Induced Oxidative Stress Injury in Human Umbilical Vein Endothelial Cells by Up-Regulation of AMPKalpha1. AB - BACKGROUND/AIMS: To investigate the effects of miR-137 on high glucose (HG) induced vascular injury, and to establish the mechanism underlying these effects. METHODS: Human umbilical vein endothelial cells (HUVECs) were transfected with miR-137 inhibitor or mimic, and then treated with normal or high glucose. Cell viability and apoptosis were detected by using the Cell Counting Kit-8 (CCK-8) assay and flow cytometry, respectively. Reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) were detected by fluorescent probe (DCFH-DA), thiobarbituric acid reaction, and the nitroblue tetrazolium assay, respectively. The mRNA and protein expressions of AMPKalpha1 were determined by qRT-PCR and Western blotting. RESULTS: Down-regulation of miR 137 dramatically reverted HG-induced decreases in cell viability and SOD levels and increases in apoptosis, ROS and MDA levels. Moreover, bioinformatics analysis predicted that the AMPKalpha1 was a potential target gene of miR-137. Luciferase reporter assay demonstrated that miR-137 could directly target AMPKalpha1. AMPKalpha1 overexpression had the similar effect as miR-137 inhibition. Down regulation of AMPKalpha1 in HUVECs transfected with miR-137 inhibitor partially reversed the protective effect of miR-137 inhibition on HG-induced oxidative stress in HUVECs. CONCLUSION: Down-regulation of miR-137 ameliorates HG-induced injury in HUVECs by overexpression of AMPKalpha1, leading to increasing cellular reductive reactions and decreasing oxidative stress. These results provide further evidence for protective effect of miR-137 inhibition on HG-induced vascular injury. PMID- 27497954 TI - State of inequality in diphtheria-tetanus-pertussis immunisation coverage in low income and middle-income countries: a multicountry study of household health surveys. AB - BACKGROUND: Immunisation programmes have made substantial contributions to lowering the burden of disease in children, but there is a growing need to ensure that programmes are equity-oriented. We aimed to provide a detailed update about the state of between-country inequality and within-country economic-related inequality in the delivery of three doses of the combined diphtheria, tetanus toxoid, and pertussis-containing vaccine (DTP3), with a special focus on inequalities in high-priority countries. METHODS: We used data from the latest available Demographic and Health Surveys and Multiple Indicator Cluster Surveys done in 51 low-income and middle-income countries. Data for DTP3 coverage were disaggregated by wealth quintile, and inequality was calculated as difference and ratio measures based on coverage in richest (quintile 5) and poorest (quintile 1) household wealth quintiles. Excess change was calculated for 21 countries with data available at two timepoints spanning a 10 year period. Further analyses were done for six high-priority countries-ie, those with low national immunisation coverage and/or high absolute numbers of unvaccinated children. Significance was determined using 95% CIs. FINDINGS: National DTP3 immunisation coverage across the 51 study countries ranged from 32% in Central African Republic to 98% in Jordan. Within countries, the gap in DTP3 immunisation coverage suggested pro rich inequality, with a difference of 20 percentage points or more between quintiles 1 and 5 for 20 of 51 countries. In Nigeria, Pakistan, Laos, Cameroon, and Central African Republic, the difference between quintiles 1 and 5 exceeded 40 percentage points. In 15 of 21 study countries, an increase over time in national coverage of DTP3 immunisation was realised alongside faster improvements in the poorest quintile than the richest. For example, in Burkina Faso, Cambodia, Gabon, Mali, and Nepal, the absolute increase in coverage was at least 2.0 percentage points per year, with faster improvement in the poorest quintile. Substantial economic-related inequality in DTP3 immunisation coverage was reported in five high-priority study countries (DR Congo, Ethiopia, Indonesia, Nigeria, and Pakistan), but not Uganda. INTERPRETATION: Overall, within-country inequalities in DTP3 immunisation persist, but seem to have narrowed over the past 10 years. Monitoring economic-related inequalities in immunisation coverage is warranted to reveal where gaps exist and inform appropriate approaches to reach disadvantaged populations. FUNDING: None. PMID- 27497955 TI - Trends in immunisation inequity: evidence, rights, and planning. PMID- 27497957 TI - Hanging Maneuver for Stomach Traction in Laparoscopic Distal Pancreatic Resections: An Original Technique Applied in 218 Patients. AB - BACKGROUND: Stomach traction done to expose the pancreas is still a problem in laparoscopic left pancreatic resections. We developed a simple hanging maneuver to retract the stomach rapidly and effectively. METHODS: After dividing the gastrocolic ligament, the stomach was encircled with a tape, turned along its horizontal axis and pulled with an epigastric trocar, which was later removed. This technique was used in all patients who underwent laparoscopic left pancreatic resections including 165 distal pancreatectomies (DP), 35 central pancreatectomies (CP) and 18 enucleations (En). Demographics, surgical and postoperative outcome data were recorded. RESULTS: There were no mortalities. The mean operative time for DP, CP and En were 174, 191 and 104 min, respectively. The transfusion (0-4%) and conversion (0-3%) rates were low for all procedures. Morbidity was mainly represented by pancreatic fistula and grades (B + C) for DP, CP and En were observed in 26, 22 and 17%, respectively. No complication related to hanging of the stomach, like gastric perforation, was observed. Re intervention and the mean hospital stay for DP, CP and En were observed in 5, 11 and 0% and were 16, 22 and 12, respectively. The readmission rate was low (0-9%). CONCLUSIONS: Hanging maneuver of the stomach is a simple procedure to rapidly, safely and effectively retract the stomach during left laparoscopic pancreatic resections. PMID- 27497959 TI - Postnatal Mother-to-Infant Attachment in Subclinically Depressed Mothers: Dyads at Risk? AB - BACKGROUND: Dyadic interactions between children and depressed mothers have been characterized as less synchronous and with lower maternal sensitivity, fostering an inharmonious, insecure attachment relationship between mother and child. Thus, these children may experience enhanced early life stress and are at higher risk of disturbed socioemotional development. Recently, this association has also been found in women with mild depressive symptoms. However, potential confounding effects of mother's history of own rearing experiences or infant temperament on the link between depressive symptoms and postnatal mother-to-infant attachment have not yet been investigated. METHODS: Differences in mother-to-infant attachment (e.g. quality of attachment, absence of hostility, and pleasure in interaction) between mothers with and without symptoms of depression 6-8 months postpartum were analyzed in a low-risk community sample (n = 38, 19 per group). Depressive symptomatology was measured with the Beck Depression Inventory (BDI II) and the Edinburgh Postnatal Depression Scale (EPDS). Depressed mothers indicated mild-to-moderate depressive symptomatology (mean BDI-II 11.26 +/- 3.86) but did not fulfill criteria for a major depressive episode and, thus, were referred to as 'subclinically' depressed. Potential confounders, namely maternal history of own rearing experiences and infant temperament, were explored by multivariate AN(C)OVA. RESULTS: Primiparous mothers with subclinical depression differed significantly from healthy control mothers, i.e. showed poorer mother-to infant attachment and higher infant-related hostility 6-8 months postpartum. As expected, infant temperament and mother's history of own rearing experiences were both associated with mother-to-infant attachment but did not explain the negative effects of subclinical depression on the mother-infant relationship. CONCLUSIONS: Given the high prevalence of maternal depression, the current findings give reason for increased concern for the developing mother-child relationship. Therefore, early interventions are needed that focus on the mother-child dyad and target not only clinically but also subclinically depressed mothers. PMID- 27497958 TI - Fis1 depletion in osteoarthritis impairs chondrocyte survival and peroxisomal and lysosomal function. AB - : Cumulative evidence suggests the importance of organelle homeostasis in regulating metabolic functions in response to various cellular stresses. Particularly, the dynamism and health of the mitochondria-peroxisome network through fission and fusion are essential for cellular function; dysfunctional dynamism underlies the pathogenesis of several degenerative diseases including Parkinson's disease. Here, we investigated the role of Fis1 in cartilage homeostasis and its relevance to osteoarthritis (OA). We found that Fis1 is significantly suppressed in human OA chondrocytes compared to that in normal chondrocytes. Fis1 depletion through siRNA induced peroxisomal dysfunction. Moreover, Fis1 suppression altered miRNA profiles, especially those implicated in lysosomal regulation. Lysosomal destruction using LAMP-1-specific targeted nanorods or lysosomal dysfunction through chloroquine treatment resulted in enhanced chondrocyte apoptosis and/or suppression of autophagy. Accordingly, lysosomal activity and autophagy were severely decreased in OA chondrocytes despite abundant LAMP-1-positive organelles. Moreover, Fis1 morpholino-injected zebrafish embryos displayed lysosome accumulation, mitochondrial dysfunction, and peroxisome reduction. Collectively, these data suggest interconnected links among Fis1-modulated miRNA, lysosomes, and autophagy, which contributes to chondrocyte survival/apoptosis. This study represents the first functional study of Fis1 with its pathological relevance to OA. Our data suggest a new target for controlling cartilage-degenerative diseases, such as OA. KEY MESSAGE: Fis1 suppression in OA chondrocytes induces accumulation and inhibition of lysosomes. Fis1 suppression alters miRNAs, especially those implicated in lysosomal regulation. Lysosomal destruction results in chondrocyte apoptosis and suppression of autophagy. Fis1 depletion in zebrafish causes lysosome accumulation, mitochondrial dysfunction, and peroxisome reduction. This is the first functional study of Fis1 and its pathological relevance to OA. PMID- 27497960 TI - Sorption kinetics of zinc and nickel on modified chitosan. AB - This study was conducted to evaluate the effect of equilibration time on adsorption of zinc [Zn(II)] and nickel [Ni(II)] on pure and modified chitosan beads. The initial adsorption of Zn(II) was high on molybdenum (Mo)-impregnated chitosan beads (MoCB) during the initial 60 min. However, after 240 min, Zn(II) adsorption occurred more on single super phosphate chitosan beads (SSPCB), followed by monocalcium phosphate chitosan beads (MCPCB), untreated pure chitosan beads (UCB), and MoCB. Similarly, Ni(II) adsorption was greatest on MoCB during the initial 60 min. At the conclusion of the experiment (at 240 min), the greatest adsorption was occurred on MCPCB, followed by MoCB, UCB, and SSPCB. Chemical sorption and intra-particle diffusion were probably the dominant processes responsible for Zn(II) and Ni(II) sorption onto chitosan beads. The results demonstrated that modified chitosan beads were effective in adsorbing Zn and Ni and hence, could be used for the removal of these toxic metals from soil. PMID- 27497961 TI - Polycyclic aromatic hydrocarbons in three commercially available fish species from the Bonny and Cross River estuaries in the Niger Delta, Nigeria. AB - The concentrations and compositional patterns of the USEPA 16 polycyclic aromatic hydrocarbons were investigated in three commercially available fish species, Chrysichthys nigrodigitatus, Cynoglossus senegalensis and Polydactylus quadratifilis, from the Bonny and Cross River systems in the eastern Niger Delta of Nigeria. The objective of the study was to provide useful information on the levels and sources of polycyclic aromatic hydrocarbons (PAHs) and the associated risks with their consumption. The 16 PAHs in the fish samples were extracted by ultrasonication with hexane/dichloromethane, and the concentrations of PAHs in the extracts were quantified by gas chromatography-mass spectrometry. The measured concentrations of the ?16 PAHs in Chrysichthys nigrodigitatus, Polydactylus quadratifilis and Cynoglossus senegalensis ranged from 106 to 491, from 43.1 to 1734 and from 96.4 to 937 MUg kg(-1) in the Bonny River system and from 20.0 to 975, from 24.7 to 506 and from 24.9 to 387 MUg kg(-1) in the Cross River system, respectively. The compositional patterns of the PAHs showed that the three- and four-ringed PAHs were the major contributors to the PAH burden in these fish species. The diagnostic ratios indicate that the PAHs in these fish samples originated mainly from combustion processes. The health risk assessment, as determined from the benzo[a]pyrene potency equivalent factor, margin of exposure and incremental lifetime cancer risk, indicates that PAHs in the majority of these fish species can induce potential carcinogenic effects. PMID- 27497962 TI - Mineralocorticoid Receptor Blockade Improves Insulin Sensitivity in the Rat Heart and a Possible Molecular Mechanism. AB - BACKGROUND/AIMS: Extensive research has explored the role of aldosterone in insulin resistance. Recent evidence suggests that the mineralocorticoid receptor (MR) mediates aldosterone-induced dysregulation of cytokines, and most of this research has focused on adjustments in fat tissue and adipocytes. However, the direct effect of MR blockade on insulin resistance in cardiomyocytes remains largely unknown. In the present study, we investigated whether MR blockade improves insulin-sensitizing factors in insulin-resistant rats and attenuates the dysregulation of the aldosterone-related transport of adiponectin and glucose in cardiomyocytes and examined the underlying mechanisms. METHODS: The effects of aldosterone, MR inhibitors (e.g., eplerenone), a peroxisome proliferator activated receptor (PPAR) alpha agonist, and a p38 mitogen-activated protein kinase (MAPK) inhibitor on adiponectin and glucose transport were studied at the mRNA and protein levels in vitro and in vivo. RESULTS: Our data revealed that aldosterone reduced the expression of adiponectin and inhibited the transport of glucose in cardiomyocytes and that MR blockade reversed these affects. In vivo, MR blockade improved insulin-sensitive parameters and increased adiponectin expression in the myocardia of high-fat diet rats. Furthermore, aldosterone promoted p38MAPK expression but negatively affected PPARalpha expression, and the downregulation of adiponectin by aldosterone was reversed by MR blockade, a PPARalpha agonist, and a p38 MAPK inhibitor. CONCLUSION: The above results suggested that aldosterone promoted insulin resistance in the heart and that this effect could be partly reversed by MR blockade through signal transduction in the P38 MAPK pathway and PPARalpha. PMID- 27497963 TI - Digital camera and smartphone as detectors in paper-based chemiluminometric genotyping of single nucleotide polymorphisms. AB - Chemi(bio)luminometric assays have contributed greatly to various areas of nucleic acid analysis due to their simplicity and detectability. In this work, we present the development of chemiluminometric genotyping methods in which (a) detection is performed by using either a conventional digital camera (at ambient temperature) or a smartphone and (b) a lateral flow assay configuration is employed for even higher simplicity and suitability for point of care or field testing. The genotyping of the C677T single nucleotide polymorphism (SNP) of methylenetetrahydropholate reductase (MTHFR) gene is chosen as a model. The interrogated DNA sequence is amplified by polymerase chain reaction (PCR) followed by a primer extension reaction. The reaction products are captured through hybridization on the sensing areas (spots) of the strip. Streptavidin horseradish peroxidase conjugate is used as a reporter along with a chemiluminogenic substrate. Detection of the emerging chemiluminescence from the sensing areas of the strip is achieved by digital camera or smartphone. For this purpose, we constructed a 3D-printed smartphone attachment that houses inexpensive lenses and converts the smartphone into a portable chemiluminescence imager. The device enables spatial discrimination of the two alleles of a SNP in a single shot by imaging of the strip, thus avoiding the need of dual labeling. The method was applied successfully to genotyping of real clinical samples. Graphical abstract Paper-based genotyping assays using digital camera and smartphone as detectors. PMID- 27497964 TI - Molecularly imprinted polymer nanoparticles-based electrochemical sensor for determination of diazinon pesticide in well water and apple fruit samples. AB - In this research, an electrochemical sensor based on molecularly imprinted polymer (MIP) nanoparticles for selective and sensitive determination of diazinon (DZN) pesticides was developed. The nanoparticles of diazinon imprinted polymer were synthesized by suspension polymerization and then used for modification of carbon paste electrode (CPE) composition in order to prepare the sensor. Cyclic voltammetry (CV) and square wave voltammetry (SWV) methods were applied for electrochemical measurements. The obtained results showed that the carbon paste electrode modified by MIP nanoparticles (nano-MIP-CP) has much higher adsorption ability for diazinon than the CPE based non-imprinted polymer nanoparticles (nano NIP-CP). Under optimized extraction and analysis conditions, the proposed sensor exhibited excellent sensitivity (95.08 MUA L MUmol(-1)) for diazinon with two linear ranges of 2.5 * 10(-9) to 1.0 * 10(-7) mol L(-1) (R (2) = 0.9971) and 1.0 * 10(-7) to 2.0 * 10(-6) mol L(-1) (R (2) = 0.9832) and also a detection limit of 7.9 * 10(-10) mol.L(-1). The sensor was successfully applied for determination of diaznon in well water and apple fruit samples with recovery values in the range of 92.53-100.86 %. Graphical abstract Procedure for preparation of electrochemical sensor based on MIP nanoparticles for determination of diazinon. PMID- 27497965 TI - Contaminant screening of wastewater with HPLC-IM-qTOF-MS and LC+LC-IM-qTOF-MS using a CCS database. AB - Non-target analysis has become an important tool in the field of water analysis since a broad variety of pollutants from different sources are released to the water cycle. For identification of compounds in such complex samples, liquid chromatography coupled to high resolution mass spectrometry are often used. The introduction of ion mobility spectrometry provides an additional separation dimension and allows determining collision cross sections (CCS) of the analytes as a further physicochemical constant supporting the identification. A CCS database with more than 500 standard substances including drug-like compounds and pesticides was used for CCS data base search in this work. A non-target analysis of a wastewater sample was initially performed with high performance liquid chromatography (HPLC) coupled to an ion mobility-quadrupole-time of flight mass spectrometer (IM-qTOF-MS). A database search including exact mass (+/-5 ppm) and CCS (+/-1 %) delivered 22 different compounds. Furthermore, the same sample was analyzed with a two-dimensional LC method, called LC+LC, developed in our group for the coupling to IM-qTOF-MS. This four dimensional separation platform revealed 53 different compounds, identified over exact mass and CCS, in the examined wastewater sample. It is demonstrated that the CCS database can also help to distinguish between isobaric structures exemplified for cyclophosphamide and ifosfamide. Graphical Abstract Scheme of sample analysis and database screening. PMID- 27497966 TI - Biosensors for liquid biopsy: circulating nucleic acids to diagnose and treat cancer. AB - The detection of cancer biomarkers freely circulating in blood offers new opportunities for cancer early diagnosis, patient follow-up, and therapy efficacy assessment based on liquid biopsy. In particular, circulating cell-free nucleic acids released from tumor cells have recently attracted great attention also because they become detectable in blood before the appearance of other circulating biomarkers, such as circulating tumor cells. The detection of circulating nucleic acids poses several technical challenges that arise from their low concentration and relatively small size. Here, possibilities offered by innovative biosensing approaches for the detection of circulating DNA in peripheral blood and blood-derived products such as plasma and serum blood are discussed. Different transduction principles are used to detect circulating DNAs and great advantages are derived from the combined use of nanostructured materials. PMID- 27497967 TI - Quantitative aspects of microchip isotachophoresis for high precision determination of main components in pharmaceuticals. AB - Although microchip electrophoresis (MCE) is intended to provide reliable quantitative data, so far there is only limited attention paid to these important aspects. This study gives a general overview of key aspects to be followed to reach high-precise determination using isotachophoresis (ITP) on the microchip with conductivity detection. From the application point of view, the procedure for the determination of acetate, a main component in the pharmaceutical preparation buserelin acetate, was developed. Our results document that run-to run fluctuations in the sample injection volume limit the reproducibility of quantitation based on the external calibration. The use of a suitable internal standard (succinate in this study) improved the repeatability of the precision of acetate determination from six to eight times. The robustness of the procedure was studied in terms of impact of fluctuations in various experimental parameters (driving current, concentration of the leading ions, pH of the leading electrolyte and buffer impurities) on the precision of the ITP determination. The use of computer simulation programs provided means to assess the ITP experiments using well-defined theoretical models. A long-term validity of the calibration curves on two microchips and two MCE equipments was verified. This favors ITP over other microchip electrophoresis techniques, when chip-to-chip or equipment to-equipment transfer of the analytical method is required. The recovery values in the range of 98-101 % indicate very accurate determination of acetate in buserelin acetate, which is used in the treatment of hormone-dependent tumors. This study showed that microchip ITP is suitable for reliable determination of main components in pharmaceutical preparations. PMID- 27497968 TI - Comparison of methods for wavelength combination selection from multi-wavelength fluorescence spectra for on-line monitoring of yeast cultivations. AB - The on-line monitoring with two-dimensional (2D) fluorescence spectroscopy of Saccharomyces cerevisiae batch cultivations was applied to monitor glucose, ethanol, and biomass concentrations. The measurement of one spectrum by the 2D fluorescence spectrometer has 120 fluorescence intensity values of excitation and emission wavelength combinations (WLCs); scattered light is not considered here. To identify which WLCs of the multi-wavelength fluorescence spectra carry important and relevant information regarding the analyte concentrations, three different methods were compared: a method based on loadings, variable importance in projection, and ant colony optimization. The five selected WLCs for a particular analyte from each method were evaluated by multiple linear regression models to find the most significant variable subsets for predicting the sample concentrations. The most significant WLCs relevant to the three sample properties contained seven different excitation and emission wavelengths, which can combine with each other to have 38 possible wavelength combinations in the fluorescence measurement. Partial least squares (PLS) models were calibrated with the 38 possible variables and the off-line data for the prediction of glucose, ethanol, and biomass concentrations. The best prediction from the PLS models had the percentage of root mean square error of prediction (pRMSEP) in the range of 3.1 6.3 %, which was similar to pRMSEPs of the PLS models with the full variables. Based on these results, it is promising to build up a specific inexpensive fluorescence sensor for the yeast cultivation process using light-emitting diodes and photodiodes. Graphical abstract Flow chart of the selection of important and relevant WLCs by the three methods to predict glucose, ethanol, and biomass concentrations. PMID- 27497969 TI - Nano selenium as antioxidant agent in a multilayer food packaging material. AB - Selenium nanoparticles (SeNPs) were incorporated in a flexible multilayer plastic material using a water-base adhesive as vehicle for SeNPs. The antioxidant performance of the original solutions containing spherical SeNPs of 50-60 nm diameter, the adhesive containing these SeNPs, and the final multilayer plastic material to be used as food packaging were quantitatively measured. The radical scavenging capacity due to SeNPs was quantified by a free radical assay developed in the laboratory and by the diphenyl-1-picrylhydrazyl (DPPH) method. DPPH was not efficient to measure the scavenging capacity in the multilayer when the free radical scavenger is not in the surface in contact with it. Several multilayer laminated structures composed by [PET (20 m)-adhesive-LDPE (with variable thickness from 35 to 90 MUm)] were prepared and measured, demonstrating for the first time that free radicals derived from oxygen (OH., O2., and O2H) cross the PE layer and arrive at the adhesive. SeNPs remain as such after manufacture and the final laminate is stable after 3 months of storage. The antioxidant multilayer is a non-migrating efficient free radical scavenger, able to protect the packaged product versus oxidation and extending the shelf life without being in direct contact with the product. Migration tests of both Se and SeNPs to simulants and hazelnuts demonstrated the non-migrating performance of this new active packaging. Graphical abstract ?. PMID- 27497970 TI - "Micromegaly": an update on the prevalence of acromegaly with apparently normal GH secretion in the modern era. AB - PURPOSE: Approximately 25 % of cases of clinically active acromegaly cases treated in our academic center between 1996 and 2000, were diagnosed in patients who had elevated plasma IGF-1 levels, but apparently "normal" 24-h mean plasma GH levels. The current study served to update the data for patients with acromegaly referred to our facility, after increasing awareness of this "normal" GH subpopulation throughout the medical community. METHODS: A retrospective chart review was conducted on 157 patients with acromegaly who underwent resection of a confirmed somatotroph pituitary adenoma at the University of Michigan Health System between the dates of 1 Jan 2001 to 23 Sept 2015. RESULTS: Overall prevalence of acromegalic patients with "normal" GH levels, defined as GH <4.7 ng/mL, was 31 %. Over time, the percentage of patients with "normal" GH at diagnosis did not decline: 26 % from 2001 to 2005, 19 % from 2006 to 2010, and 47 % from 2011 to 2015. Mean pituitary tumor size was 1.8 +/- 0.1 cm for the group with elevated GH, and 1.2 +/- 0.1 cm for the group with "normal" GH (p < 0.001). Percent microadenomas was higher in a group with "normal" GH as compared to those with elevated GH (48 vs. 12 %, p < 0.001), and tumors >2 cm in the maximal diameter were encountered more frequently in the group with elevated GH (43 vs. 14 %, p < 0.001). CONCLUSIONS: Our data show that a substantial percentage of patients with clinical acromegaly have "normal" GH, and therefore strengthens the growing body of evidence which supports the leading role of IGF-1 levels in diagnostic evaluation. At the present time, questions about the natural course of "micromegaly" and treatment benefits compared to the subpopulation with elevated GH levels remain unanswered, but research continues to build on our understanding of the heterogeneous population of individuals. PMID- 27497971 TI - Rituximab to treat gemcitabine-induced hemolytic-uremic syndrome (HUS) in pancreatic adenocarcinoma: a case series and literature review. AB - PURPOSE: Hemolytic-uremic syndrome (HUS) is a rare side effect of gemcitabine, which is reported as having a high morbidity and mortality despite interventions with standard HUS therapies including plasmapheresis. The purpose of this report was to describe the successful treatment of gemcitabine-induced HUS (G-HUS) with rituximab. It also aims to summarize the literature regarding the morbidity and mortality of G-HUS in pancreatic adenocarcinoma depending on the treatment given, ultimately providing some guidance for beneficial therapies. METHODS: This is a retrospective report of three patients with pancreatic adenocarcinoma who developed G-HUS and were treated with a combination of therapies including rituximab. RESULTS: All three patients received a combination of therapies to treat their HUS. One patient appeared to have some benefit with plasmapheresis. Resolution occurred following one course of rituximab for all three patients. This resolution has been long lasting with a minimum of eighteen month's follow up. Similarly, in our literature review a variety of therapies were utilized, but immune therapies appear to reverse HUS if other therapies are failing. CONCLUSION: Rituximab can be an effective therapy for reversal of hemolysis and stabilization of renal function in G-HUS when other therapies fail. PMID- 27497972 TI - Introducing extra NADPH consumption ability significantly increases the photosynthetic efficiency and biomass production of cyanobacteria. AB - Increasing photosynthetic efficiency is crucial to increasing biomass production to meet the growing demands for food and energy. Previous theoretical arithmetic analysis suggests that the light reactions and dark reactions are imperfectly coupled due to shortage of ATP supply, or accumulation of NADPH. Here we hypothesized that solely increasing NADPH consumption might improve the coupling of light reactions and dark reactions, thereby increasing the photosynthetic efficiency and biomass production. To test this hypothesis, an NADPH consumption pathway was constructed in cyanobacterium Synechocystis sp. PCC 6803. The resulting extra NADPH-consuming mutant grew much faster and achieved a higher biomass concentration. Analyses of photosynthesis characteristics showed the activities of photosystem II and photosystem I and the light saturation point of the NADPH-consuming mutant all significantly increased. Thus, we demonstrated that introducing extra NADPH consumption ability is a promising strategy to increase photosynthetic efficiency and to enable utilization of high-intensity lights. PMID- 27497973 TI - Mutation of a regulator Ask10p improves xylose isomerase activity through up regulation of molecular chaperones in Saccharomyces cerevisiae. AB - Economically feasible bioconversion of lignocelluloses into fuels and chemicals is dependent on efficient utilization of all available sugars in lignocellulosic biomass, including hextose and pentose. Previously, we constructed a xylose fermenting strain of Saccharomyces cerevisiae through metabolic engineering and enhanced its xylose utilization capability through evolutionary engineering. However, the key mechanism of improved xylose utilization and xylose isomerase activity was not identified. In this study, we applied the concept of inverse metabolic engineering to identify the factors involved in improving xylose utilization. Genomic sequencing of the evolved strain with fast xylose utilization capability was performed, and mutations possibly affecting xylose utilization were screened. Further genetic analysis of these mutant genes revealed that mutations in ASK10 (both the site-directed mutation ASK10M475R as well as ASK10 deletion), a stress response regulator-encoding gene, improved growth on xylose and enhanced xylose isomerase activity. We found that mutation of Ask10p did not increase xylose isomerase activity through interacting with the xylose isomerase protein or through directly regulating the xylA gene transcription. Although ASK10 deletion increased the copy number of the plasmid and improved the transcription of xylA, the site-direct mutation ASK10M475R did not change the plasmid copy number. Interestingly, we found that both the site directed mutation ASK10M475R and ASK10 deletion up-regulated the transcription of molecular chaperone-encoding genes HSP26, SSA1 and HSP104, thereby facilitating the protein folding of xylose isomerase and enhancing xylose isomerase activity. This study revealed the important mechanism of chaperones in xylose isomerase activity regulation, and it provides valuable insights for efficient xylose metabolic strain development. PMID- 27497974 TI - Quantification of Gait Abnormalities in Healthy-Looking Multiple Sclerosis Patients (with Expanded Disability Status Scale 0-1.5). AB - BACKGROUND: Gait impairment is a common symptom in multiple sclerosis (MS) patients, but there is a lack of evidence about gait performance in the group of MS patients with no apparent disability. The aim of our study was to evaluate gait characteristics in MS patients with no apparent impairment of walking and with an Expanded Disability Status Scale (EDSS 0-1.5), and to determine whether any abnormalities are detectable by common clinical tests. METHODS: This was an observational study of 64 MS patients with an EDSS 0-1.5 and 47 age- and sex matched healthy controls. We measured their performance in the timed 25-foot walk test (T25FWT) and the 2-minute walk test (2MWT). The spatiotemporal parameters of gait were measured using a GAITRite instrument. RESULTS: MS patients with no apparent disability (EDSS 0-1.5) performed worse in T25FWT and 2MWT than normal controls. During the self-selected walking speed test on GAITRite, MS patients had a prolonged double support phase, and during the fast walking speed test, they had lower cadence and decreased step length. PMID- 27497975 TI - Thoracic Surgery in Chronic Granulomatous Disease: a 25-Year Single-Institution Experience. AB - INTRODUCTION: Chronic granulomatous disease (CGD) is a genetic disorder in which phagocyte dysfunction leads to recurrent infection. Persistent pulmonary infections sometimes require thoracic surgical intervention. We reviewed our 25 year experience to identify outcomes and prognostic factors associated with thoracic surgery in these patients. METHODS: A retrospective single-institution review of all patients with CGD from 1990 through 2015 was performed. Univariate analysis identified prognostic variables to include in a Cox model. Overall survival was estimated by the Kaplan-Meier method. RESULTS: We identified 258 patients who had 2221 admissions (both scheduled and emergent). During the period examined, 51 thoracic operations were performed in 13.6 % (35/258) of patients and 2.3 % (35/2221) of overall admissions. Patients undergoing surgery did not have statistically significant differences in disease genotype compared to those that did not require surgery. Pathogens were identified from 67 % (34/51) of specimens. Complications occurred in 27 % (14/51), including 10 % (5/51) with wound and 12 % (6/51) with pulmonary infections. Mortality at 30 and 90 days was 0 and 6 % (3/51), respectively. Overall survival probabilities were 75 and 62 % at 5- and 10-year follow-up (median potential follow-up: 16.5 years), respectively. Undergoing thoracic surgery was associated with an increased hazard ratio for death of 3.71 (p < 0.0001). Both chest wall resection and EBL > 500 mL were negative prognostic factors (p < 0.05). CONCLUSIONS: A minority of CGD patients required thoracic surgery for infections refractory to antibiotic or antifungal therapy. Patients who had these operations had significant morbidity and relatively poor long-term survival, particularly in the cases of chest wall resection or significant blood loss. PMID- 27497976 TI - Ultrasound appearance of the normal Lisfranc ligament. AB - This study aims to prospectively evaluate the ultrasound appearance of the normal Lisfranc's ligament in 50 patients (100 ft) with no prior or current ligament injury. Fifty normal asymptomatic patients between the ages of 18 and 80 years were assessed. Three key features were recorded: ultrasound appearance, thickness, and length of the Lisfranc's ligament. Patients excluded from this study included pediatric patients and those with history of injury or symptoms related to the foot. The mean right- and left-sided ligament (RT) thickness were 0.096 (0.021) and 0.104 (0.023), respectively. The mean right- and left-sided ligament RT length was 0.54 (0.11) and 0.57 (0.11), respectively. The appearance of the ligament was similar in all patients with a central thin band of hypoechogenicity lined by hyperechoic lines on either side. Understanding the normal appearance, thickness, and length of the Lisfranc's ligament in a large sample is imperative to diagnose abnormal appearances of this ligament including sprains and tears by ultrasound. Ultrasound, with its easy accessibility, can be used in the emergency department to rapidly exclude injury of the ligament. Increased understanding and awareness of the Lisfranc's ligament on ultrasound can allow for more accurate diagnosis and treatment. PMID- 27497977 TI - Using Positive Deviance to reduce medication errors in a tertiary care hospital. AB - BACKGROUND: The number of medication errors occurring in healthcare is large and many are preventable. To analyze medication errors and evaluate whether Positive Deviance is effective in reducing them. METHODS: The study was divided into three phases: (2011- Phase I, control period; 2012 - Phase II, manager intervention, and 2013 - Phase III, frontline healthcare worker intervention). In Phases II and III, the Positive Deviance method (PD) was used to mitigate medication errors classified as "C" and higher according to the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP). The errors reported were compared across the three study phases, as well as by the location of the hospital unit, shift, cause, consequence, and the professional associated with the error. RESULTS: A total of 4013 reported medication errors were analyzed. The largest number of errors occurred at the time the medications were administered, accounting for 35.5 % of errors in Phase I; 43.1 % in Phase II, and 55.6 % in Phase III. Nursing staff was most commonly associated with errors; 46.4 % of errors in Phase I, 48.5 % in Phase II, and 58.7 % in Phase III. With each intervention, a decrease was observed in the reported error rate of 0.12 (CI 95 %, 0.18 to 0.07). CONCLUSION: Positive Deviance proved to be effective, primarily when healthcare professionals who were involved in errors participated, as was observed in Phase III of this study. PMID- 27497978 TI - Atypical case of central-variant posterior reversible encephalopathy syndrome. PMID- 27497979 TI - Rapid Quantification of Low-Viscosity Acetyl-Triacylglycerols Using Electrospray Ionization Mass Spectrometry. AB - Acetyl-triacylglycerols (acetyl-TAG) possess an sn-3 acetate group, which confers useful chemical and physical properties to these unusual triacylglycerols (TAG). Current methods for quantification of acetyl-TAG are time consuming and do not provide any information on the molecular species profile. Electrospray ionization mass spectrometry (ESI-MS)-based methods can overcome these drawbacks. However, the ESI-MS signal intensity for TAG depends on the aliphatic chain length and unsaturation index of the molecule. Therefore response factors for different molecular species need to be determined before any quantification. The effects of the chain length and the number of double-bonds of the sn-1/2 acyl groups on the signal intensity for the neutral loss of short chain length sn-3 groups were quantified using a series of synthesized sn-3 specific structured TAG. The signal intensity for the neutral loss of the sn-3 acyl group was found to negatively correlated with the aliphatic chain length and unsaturation index of the sn-1/2 acyl groups. The signal intensity of the neutral loss of the sn-3 acyl group was also negatively correlated with the size of that chain. Further, the position of the group undergoing neutral loss was also important, with the signal from an sn 2 acyl group much lower than that from one located at sn-3. Response factors obtained from these analyses were used to develop a method for the absolute quantification of acetyl-TAG. The increased sensitivity of this ESI-MS-based approach allowed successful quantification of acetyl-TAG in various biological settings, including the products of in vitro enzyme activity assays. PMID- 27497980 TI - Bioconversion of waste office paper to hydrogen using pretreated rumen fluid inoculum. AB - In this study, a microbial consortium from an acid-treated rumen fluid was used to improve the yields of H2 production from paper residues in batch reactors. The anaerobic batch reactors, which contained paper and cellulose, were operated under three conditions: (1) 0.5 g paper/L, (2) 2 g paper/L, and (3) 4 g paper/L. Cellulase was added to promote the hydrolysis of paper to soluble sugars. The H2 yields were 5.51, 4.65, and 3.96 mmol H2/g COD, respectively, with substrate degradation ranging from 56 to 65.4 %. Butyric acid was the primary soluble metabolite in the three reactors, but pronounced solventogenesis was detected in the reactors incubated with increased paper concentrations (2.0 and 4.0 g/L). A substantial prevalence of Clostridium acetobutylicum (99 % similarity) was observed in the acid-treated rumen fluid, which has been recognized as an efficient H2-producing strain in addition to ethanol and n-butanol which were also detected in the reactors. PMID- 27497981 TI - Bioconversion of piceid to resveratrol by selected probiotic cell extracts. AB - Resveratrol exerts several pharmacological activities, including anti-cancer, anti-inflammatory, cardioprotective, or antioxidant effects. However, due to its occurrence in plants more in glycosidic form as piceid, the bioavailability and bioactivity are limited. The enzymatic potential of probiotics for the transformation of piceid to resveratrol was elucidated. Cell extract from Bifidobacteria (B.) infantis, B. bifidum, Lactobacillus (L.) casei, L. plantarum, and L. acidophilus was evaluated for their effect in this bioconversion using high-performance liquid chromatography (HPLC) as analytical tool. Cell extract of B. infantis showed the highest effect on the deglycosylation of piceid to resveratrol, already after 30 min. Cell extracts of all other tested strains showed a significant biotransformation with no further metabolization of resveratrol. The conversion of piceid to resveratrol is of importance to increase bioavailability and bioactivity as shown for anti-inflammation in this study. Cell extracts from probiotics, especially from B. infantis, may be added to piceid containing products, for achieving higher biological effects caused by the bioactivity of resveratrol or by health promoting of the probiotics. These findings open a new perspective of novel combination of cell extracts from probiotics and piceid, in health-promoting pharmaceutical and food products. PMID- 27497982 TI - Synthesis and evaluation of Cy5.5-Rit tracer for specific near-infrared fluorescence imaging of sentinel lymph node. AB - Sentinel lymph nodes biopsy (SLNB) is a critically important technique to determine the metastatic status of primary breast cancer. Here we reported the new use of a conjugate, Cy5.5-Rituximab (Cy5.5-Rit), which is specific toward the CD20 receptor, as an imaging agent for non-invasive near-infrared fluorescence (NIRF) imaging of sentinel lymph nodes (SLN). The conjugate, Cy5.5-Rit, was synthesized with the ratio of dye to Rituximab close to 1.0. Both gel electrophoresis and mass spectrometry analysis confirmed the molecular integrity of Cy5.5-Rit. For in vivo NIRF imaging, the conjugate stayed in SLN as long as 9days post injection. The in vivo imaging results of SLN targeting were also confirmed by in vitro HE stain. In addition, the direct fluorescence signal of dissected lymph node demonstrated that Cy5.5-Rit binds to the surface of lymph node cells. All of these results showed that the conjugate Cy5.5-Rit has potential for non-invasive optical imaging of SLN. PMID- 27497983 TI - Newly synthesized bis-benzimidazole compound 8 induces apoptosis, autophagy and reactive oxygen species generation in HeLa cells. AB - Compound 8 (C8) is a newly synthesized bis-benzimidazole derivative and exerts significant anti-tumor activity in vitro. Previous studies demonstrated that C8 induced apoptosis and autophagy in human promyelocytic leukemia HL60 cells. However, cytotoxicity study on human peripheral blood mononuclear cells (hPBMC) showed that C8 exhibited less toxicity in normal cells. In this study, the molecular mechanism of C8 on human cervical carcinoma HeLa cells was investigated. The results showed that C8 inhibited the growth of HeLa cells and triggered both apoptotic and autophagic cell death. Subsequent experiment also indicated that reactive oxygen species (ROS) generation was induced in C8-treated HeLa cells. Since ROS scavenger decreased the ratio of apoptotic and autophagic cells, ROS generation contributed to C8-induced apoptosis and autophagy. Furthermore, inhibitors of apoptosis and autophagy also reduced ROS generation, respectively. Autophagy inhibition increased cell growth compared to C8-treated group and attenuated apoptotic cell death, indicating that C8-induced autophagy promoted apoptosis for cell death. However, the percentage of autophagic cells was enhanced when limiting apoptosis process. Taken together, C8 induced ROS mediated apoptosis and autophagy in HeLa cells, autophagy promoted apoptosis but the former was antagonized by the latter. The data also gave us a new perspective on the anti-tumor effect of C8. PMID- 27497984 TI - Allelic diversity of S-RNase alleles in diploid potato species. AB - KEY MESSAGE: The S-ribonuclease sequences of 16 S-alleles derived from diploid types of Solanum are presented. A phylogenetic analysis and partial phenotypic analysis support the conclusion that these are functional S-alleles. S Ribonucleases (S-RNases) control the pistil specificity of the self incompatibility (SI) response in the genus Solanum and several other members of the Solanaceae. The nucleotide sequences of S-RNases corresponding to a large number of S-alleles or S-haplotypes have been characterised. However, surprisingly, few S-RNase sequences are available for potato species. The identification of new S-alleles in diploid potato species is desirable as these stocks are important sources of traits such as biotic and abiotic resistance. S RNase sequences are reported here from three distinct diploid types of potato: cultivated Solanum tuberosum Group Phureja, S. tuberosum Group Stenotomum, and the wild species Solanum okadae. Partial S-RNase sequences were obtained from pistil RNA by RT-PCR or 3'RACE (Rapid Amplification of cDNA Ends) using a degenerate primer. Full-length sequences were obtained for two alleles by 5'RACE. Database searches with these sequences identified 16 S-RNases in total, all of which are novel. The sequence analysis revealed all the expected features of functional S-RNases. Phylogenetic analysis with selected published S-RNase and S like-RNase sequences from the Solanaceae revealed extensive trans-generic evolution of the S-RNases and a clear distinction from S-like-RNases. Pollination tests were used to confirm the self-incompatibility status and cross compatibility relationships of the S. okadae accessions. All the S. okadae accessions were found to be self-incompatible as expected with crosses amongst them exhibiting both cross-compatibility and semi-compatibility consistent with the S-genotypes determined from the S-RNase sequence data. The progeny analysis of four semi-compatible crosses examined by allele-specific PCR provided further confirmation that these are functional S-RNases. PMID- 27497985 TI - Berberine attenuates oxidative stress and hepatocytes apoptosis via protecting mitochondria in blunt snout bream Megalobrama amblycephala fed high-fat diets. AB - High-fat diets may have favorable effects on growth and cost, but high-fat diets often induce excessive fat deposition, resulting in liver damage. This study aimed to identify the hepatoprotective of a Chinese herb (berberine) for blunt snout bream (Megalobrama amblycephala). Fish were fed with a normal diet (LFD, 5 % fat), high-fat diet (HFD, 15 % fat) or berberine-supplemented diets (BSD, 15 % fat with berberine 50 or 100 mg/kg level) for 8 weeks. After the feeding, histology, oxidative status and mitochondrial function of liver were assessed. The results showed that HFD caused fat accumulation, oxidative stress and apoptosis in hepatocytes of fish. Hepatocytes in HFD group appeared to be hypertrophied, with larger liver cells diameter than these of LFD group. Berberine-supplemented diets could attenuate oxidative stress and hepatocytes apoptosis. HFD induced the decreasing mitochondrial complexes activities and bulk density and surface area density. Berberine improved function of mitochondrial respiratory chain via increasing the complex activities. Moreover, the histological results showed that berberine has the potential to repair mitochondrial ultrastructural damage and elevate the density in cells. In conclusion, our study demonstrated that berberine has attenuated liver damage induced by the high fat mainly via the protection for mitochondria. PMID- 27497986 TI - A Blockade of IGF Signaling Sensitizes Human Ovarian Cancer Cells to the Anthelmintic Niclosamide-Induced Anti-Proliferative and Anticancer Activities. AB - BACKGROUND/AIMS: Ovarian cancer is the most lethal gynecologic malignancy, and there is an unmet clinical need to develop new therapies. Although showing promising anticancer activity, Niclosamide may not be used as a monotherapy. We seek to investigate whether inhibiting IGF signaling potentiates Niclosamide's anticancer efficacy in human ovarian cancer cells. METHODS: Cell proliferation and migration are assessed. Cell cycle progression and apoptosis are analyzed by flow cytometry. Inhibition of IGF signaling is accomplished by adenovirus mediated expression of siRNAs targeting IGF-1R. Cancer-associated pathways are assessed using pathway-specific reporters. Subcutaneous xenograft model is used to determine anticancer activity. RESULTS: We find that Niclosamide is highly effective on inhibiting cell proliferation, cell migration, and cell cycle progression, and inducing apoptosis in human ovarian cancer cells, possibly by targeting multiple signaling pathways involved in ELK1/SRF, AP-1, MYC/MAX and NFkB. Silencing IGF-1R exert a similar but weaker effect than that of Niclosamide's. However, silencing IGF-1R significantly sensitizes ovarian cancer cells to Niclosamide-induced anti-proliferative and anticancer activities both in vitro and in vivo. CONCLUSION: Niclosamide as a repurposed anticancer agent may be more efficacious when combined with agents that target other signaling pathways such as IGF signaling in the treatment of human cancers including ovarian cancer. PMID- 27497987 TI - Effects of RNAs on chromatin accessibility and gene expression suggest RNA mediated activation. AB - The study of the interaction between RNA and DNA sequences in activating genes has important significance for understanding the mechanisms of RNA-mediated activation. Here, we used in vitro chromatin reconstitution approach to observe whether RNAs increase DNase I digestion, plasmid transfection to observe whether RNAs promote gene expression, and bioinformatics analysis to predict the binding ability of RNAs to centromere DNA (constitutive heterochromatin). Synthetic RNAs (23nt) that were complementary to mouse albumin gene and total liver RNA increased DNase I digestion sensitivity of mouse albumin gene, suggesting that RNAs can increase chromatin accessibility. Transcribed sense-antisense tandem Alu elements activated an enhanced green fluorescent protein reporter gene after stable transfection. Bioinformatics analysis showed that the binding strength of RNA population to centromere DNAs is significantly lower than that of their flanking sequences, which suggests that the centromere is not easily affected by RNAs produced from other transcribed regions and may be the reason why centromeres consist of constitutive heterochromatin. The results in this paper illustrate that RNAs complementary to DNA sequences play roles in activating genes. Since RNA is mainly produced from the cell's own DNA, the work presented in this paper suggests that RNAs transcribed from DNA create feedback that activates DNA transcription. PMID- 27497988 TI - Thioredoxin-interacting protein regulates lipid metabolism via Akt/mTOR pathway in diabetic kidney disease. AB - Abnormal lipid metabolism contributes to the renal lipid accumulation, which is associated with diabetic kidney disease, but its precise mechanism remains unclear. The growing evidence demonstrates that thioredoxin-interacting protein is involved in regulating cellular glucose and lipid metabolism. Here, we investigated the effects of thioredoxin-interacting protein on lipid accumulation in diabetic kidney disease. In contrast to the diabetic wild-type mice, the physical and biochemical parameters were improved in the diabetic thioredoxin interacting protein knockout mice. The increased renal lipid accumulation, expression of acetyl-CoA carboxylase, fatty acid synthase and sterol regulatory element binding protein-1, and phosphorylated Akt and mTOR associated with diabetes in wild-type mice was attenuated in diabetic thioredoxin-interacting protein knockout mice. Furthermore, thioredoxin-interacting protein knockout significantly increased the expression of peroxisome proliferator-activated receptor-alpha, acyl-coenzyme A oxidase 1 and carnitine palmitoyltransferaser 1 in diabetic kidneys. In vitro experiments, using HK-2 cells, revealed that knockdown of thioredoxin-interacting protein inhibited high glucose-mediated lipid accumulation, expression of acetyl-CoA carboxylase, fatty acid synthase and sterol regulatory element binding protein-1, as well as activation of Akt and mTOR. Moreover, knockdown of thioredoxin-interacting protein reversed high glucose-induced reduction of peroxisome proliferator-activated receptor-alpha, acyl-coenzyme A oxidase 1 and carnitine palmitoyltransferaser 1 expression in HK 2 cells. Importantly, blockade of Akt/mTOR signaling pathway with LY294002, a specific PI3K inhibitor, replicated these effects of thioredoxin-interacting protein silencing. Taken together, these data suggest that thioredoxin interacting protein deficiency alleviates diabetic renal lipid accumulation through regulation of Akt/mTOR pathway, thioredoxin-interacting protein may be a potential therapeutic target for diabetic kidney disease. PMID- 27497989 TI - Cell-specific paracrine actions of IL-6 family cytokines from bone, marrow and muscle that control bone formation and resorption. AB - Bone renews itself and changes shape throughout life to account for the changing needs of the body; this requires co-ordinated activities of bone resorbing cells (osteoclasts), bone forming cells (osteoblasts) and bone's internal cellular network (osteocytes). This review focuses on paracrine signaling by the IL-6 family of cytokines between bone cells, bone marrow, and skeletal muscle in normal physiology and in pathological states where their levels may be locally or systemically elevated. These functions include the support of osteoclast formation by osteoblast lineage cells in response to interleukin 6 (IL-6), interleukin 11 (IL-11), oncostatin M (OSM) and cardiotrophin 1 (CT-1). In addition it will discuss how bone-resorbing osteoclasts promote osteoblast activity by secreting CT-1, which acts as a "coupling factor" on osteocytes, osteoblasts, and their precursors to promote bone formation. OSM, produced by osteoblast lineage cells and macrophages, stimulates bone formation via osteocytes. IL-6 family cytokines also mediate actions of other bone formation stimuli like parathyroid hormone (PTH) and mechanical loading. CT-1, OSM and LIF suppress marrow adipogenesis by shifting commitment of pluripotent precursors towards osteoblast differentiation. Ciliary neurotrophic factor (CNTF) is released as a myokine from skeletal muscle and suppresses osteoblast differentiation and bone formation on the periosteum (outer bone surface in apposition to muscle). Finally, IL-6 acts directly on marrow-derived osteoclasts to stimulate release of "osteotransmitters" that act through the cortical osteocyte network to stimulate bone formation on the periosteum. Each will be discussed as illustrations of how the extended family of IL-6 cytokines acts within the skeleton in physiology and may be altered in pathological conditions or by targeted therapies. PMID- 27497990 TI - Polymorphisms of dopamine receptor genes and risk of visual hallucinations in Parkinson's patients. AB - BACKGROUND: Visual hallucinations (VHs) are frequent non-motor complication of Parkinson's disease (PD), associated to a negative prognosis. Previous studies showed an association between dopamine receptor (DR) gene (DR) variants and psychosis in Alzheimer's disease, addictions, schizophrenia, and bipolar disorder. However, there are only a few studies on DR variants and VHs in PD, which did not provide conclusive results. OBJECTIVES: The present study aimed to determine whether genetic differences of DR are associated with visual hallucinations (VHs) in a cohort of Parkinson's disease (PD) patients. METHODS: A case-control study of 84 PD subjects, 42 with and 42 without VHs,that were matched for age, gender, disease duration, and dopaminergic medication was conducted. Polymerase chain reaction for SNPs in both D1-like (DRD1A-48G [rs4532] and C62T [rs686], DRD5T798C [rs6283]) and D2-like DR (DRD2G2137A [rs1800497] and C957T [rs6277], DRD3G25A [rs6280] and G712C [rs1800828], DRD4C616G [rs747302] and nR VNTR 48bp) analyzed genomic DNA. RESULTS: Patients carrying allele T at DRD1C62T had an increased risk of VHs, expressed as OR (95 % CI, p value), of 10.7 (2.9-40, p = 0.0001). Moreover, patients with DRD1-48 GG and 62TT genotype displayed shorter time to VHs, whereas a longer time to VHs was found in subjects carrying the DRD4 CG alleles. CONCLUSIONS: PD patients with VHs display higher frequency of DR SNPs associated with increased D1-like activity and decreased D2 like activity. Our data are in line with associations reported in other neurodegenerative and psychiatric conditions. Results likely provide valuable information for personalizing pharmacological therapy in PD patients. PMID- 27497991 TI - Cost-utility analysis of 1-year treatment with adalimumab/standard care and standard care alone for ulcerative colitis in Poland. AB - PURPOSE: Until recently, surgery was the only remaining choice for moderate to severe chronic ulcerative colitis patients who failed standard treatment or when it was not tolerated. Anti-TNFalpha treatment is a new, non-invasive option for the management of ulcerative colitis. The objective of this study was to assess the cost-effectiveness of induction and maintenance treatment up to 1 year of ulcerative colitis with adalimumab/standard care and standard care alone in Poland. METHODS: A Markov model was used to estimate the expected costs and effects of adalimumab/standard care and a standard care alone. For each treatment option, the costs and quality adjusted life years were calculated to estimate the incremental cost-utility ratio. The analysis was performed from the perspective of the Polish public payer and society over a 30-year time horizon. Different direct and indirect costs and utility values were assigned to the various model health states. RESULTS: The treatment of ulcerative colitis patients with adalimumab/standard care up to 1 year instead of a standard care alone resulted in 0.14 additional years of life with full health (QALYs). The incremental cost utility ratio of adalimumab/standard care compared to the standard care alone is estimated to be 76,120 ?/QALY gained from NHF perspective and 71,457 ?/QALY gained from social perspective. CONCLUSIONS: The biologic treatment of ulcerative colitis patients with adalimumab/standard care is more effective but also more costly compared with standard care alone. PMID- 27497992 TI - In vitro promoter recognition by the catalytic subunit of plant phage-type RNA polymerases. AB - KEY MESSAGE: We identified sequence motifs, which enhance or reduce the ability of the Arabidopsis phage-type RNA polymerases RPOTm (mitochondrial RNAP), RPOTp (plastidial RNAP), and RPOTmp (active in both organelles) to recognize their promoters in vitro with help of a 'specificity loop'. The importance of this data for the evolution and function of the organellar RNA polymerases is discussed. The single-subunit RNA polymerase (RNAP) of bacteriophage T7 is able to perform all steps of transcription without additional transcription factors. Dicotyledonous plants possess three phage-type RNAPs, RPOTm-the mitochondrial RNAP, RPOTp-the plastidial RNAP, and RPOTmp-an RNAP active in both organelles. RPOTm and RPOTp, like the T7 polymerase, are able to recognize promoters, while RPOTmp displays no significant promoter specificity in vitro. To find out which promoter motifs are crucial for recognition by the polymerases we performed in vitro transcription assays with recombinant Arabidopsis RPOTm and RPOTp enzymes. By comparing different truncated and mutagenized promoter constructs, we observed the same minimal promoter sequence supposed to be needed in vivo for transcription initiation. Moreover, we identified elements of core and flanking sequences, which are of critical importance for promoter recognition and activity in vitro. We further intended to reveal why RPOTmp does not efficiently recognize promoters in vitro and if promoter recognition is based on a structurally defined specificity loop of the plant enzymes as described for the yeast and T7 RNAPs. Interestingly, the exchange of only three amino acids within the putative specificity loop of RPOTmp enabled the enzyme for specific promoter transcription in vitro. Thus, also in plant phage-type RNAPs the specificity loop is engaged in promoter recognition. The results are discussed with respect to their relevance for transcription in organello and to the evolution of RPOT enzymes including the divergence of their functions. PMID- 27497993 TI - Participation of protein kinases in cytotoxic and proapoptotic effects of ethylene glycol ethers and their metabolites in SH-SY5Y cells. AB - Ethylene glycol ethers (EGEs) are compounds widely used in many branches of industry. Their toxicological profile in the peripheral tissues is relatively well described, but little is known about their action on the central nervous system (CNS). In this study, we evaluated the effect of 2-ethoxyethanol (EE), 2 butoxyethanol (BE), 2-phenoxyethanol (PHE) and their metabolites on necrotic (estimated by cell viability and lactate dehydrogenase release) and apoptotic (caspase-3 activity and mitochondrial membrane potential) processes and reactive oxygen species' (ROS) production in human neuroblastoma (SH-SY5Y) cells. We have shown that, similar to the peripheral tissues, EGE metabolites in most of the performed assays revealed greater potential to damage than the parent compounds in the CNS cells. Subsequently, we investigated the participation of some selected protein kinases in the degenerative activity of PHE and its main metabolite, phenoxyacetic acid (PHA). It has been found that a GSK3beta inhibitor weakened the damaging effects of PHE and PHA in each of the performed assays. Furthermore, the kinases, p38-MAPK, JNK-MAPK and PKC, had a significant role in the cytotoxic and proapoptotic effects of PHA. These results indicate that the neurotoxic effect of EGEs may stem from their impact on many intracellular signal transduction pathways. PMID- 27497994 TI - In vitro toxicity of cationic micelles and liposomes in cultured human hepatocyte (HepG2) and lung epithelial (A549) cell lines. AB - The aim of this study was to compare the effects of cationic micelle and liposome drug delivery systems on liver and lung cells in a toxicological in vitro screening model, with observations on cytotoxicity and genotoxicity. A screening battery was established for assessment of a broad range of parameters related to adverse effects. Clear concentration response effects were observed related to impairment of mitochondrial function, membrane integrity and oxidative stress markers, but no effect was observed on genotoxicity. The adverse effects were highest for the liposomes. The High Content Screening seems optimal for initial screening of adverse effects, and combined with standard cytotoxicity measurements initial screening can be performed for predictive toxicological screening. PMID- 27497995 TI - The Metabolic Syndrome and the Phenotype of Frailty: A Causal Link? PMID- 27497996 TI - Multi-methodological investigation of the variability of the microstructure of HPMC hard capsules. AB - The objective of this study was to analyze differences in the subtle microstructure of three different grades of HMPC hard capsule shells using mechanical, spectroscopic, microscopic and tomographic approaches. Dynamic mechanical analysis (DMA), thermogravimetric analysis (TGA), vibrational spectroscopic, X-Ray scattering techniques as well as environmental scanning electron microscopy (ESEM) and optical coherence tomography (OCT) were used. Two HPMC capsules manufactured via chemical gelling, one capsule shell manufactured via thermal gelling and one thermally gelled transparent capsule were included. Characteristic micro-structural alterations (associated manufacturing processes) such as mechanical and physical properties relevant to capsule performance and processability were thoroughly elucidated with the integration of data obtained from multi-methodological investigations. The physico-chemical and physico mechanical data obtained from a gamut of techniques implied that thermally gelled HPMC hard capsule shells could offer an advantage in terms of machinability during capsule filling, owing to their superior micro- and macroscopic structure as well as specifically the mechanical stability under dry or humid conditions. PMID- 27497997 TI - A systematic evaluation of mechanisms, material effects, and protein-dependent differences on friction-related protein particle formation in formulation and filling steps. AB - Particle formation by physical degradation during the compounding step of biopharmaceuticals is a common concern and found in vessels with bottom mounted stirrers. It was potentially linked to sliding bearings, however, the exact mechanism was still unclear. In this study, custom designed small scale bearings in combination with an IgG1 antibody as model protein were used for investigations of the degradation mechanism inside a bearing. Thereby, abrasion of adsorbed proteins by contact sliding was identified as prevailing protein degradation mechanism and was quantified by an increase in turbidity and by monomer loss. As the protein degradation was highly dependent on combinations of the material of the bearing and the buffer solution, a test system was introduced which allowed to study these effects. Results from the test system using IgG1 and recombinant human growth hormone confirmed a protective effect of Polysorbate 80 by a reduction of protein adsorption, which was strongest in combination with a highly hydrophobic sliding material (PTFE). Finally, a comparison of degradation products from various stresses by ATR-FTIR revealed a high similarity between friction-related degradation products. Therefore, abrasion of adsorbed proteins is very likely the prevailing physical degradation mechanism in processing steps where contact sliding occurs. PMID- 27497998 TI - Powder dispersion mechanisms within a dry powder inhaler using microscale particle image velocimetry. AB - The goal of this work was to evaluate the ability of Particle Image Velocimetry (PIV) to visually assess dry powder dispersion within an inhaler. Herein, the study reports particle movement characterization of entrained low-micron particles within an inhaler to further scheme of potential mechanisms. Carrier based DPI formulations were prepared and placed in a transparent model Rotahaler(r) chamber for the aerosolization experiments. Then using the PIV, a high-speed camera, the dried powder dispersion was directly observed and analyzed for all, neat, binary and ternary systems. Powder dispersion mechanisms proposed include drag force, impact with obstacle and particle-particle collision; these different mechanisms depended on the powder flow properties. A revised ratio of aerodynamic response time (tauA) to the mean time between collisions (tauC) was found to be 6.8 indicating that particle collisions were of strong influence to particle dispersion. With image analysis techniques, visualization of particle flow pattern and collision regions was possible; suggesting that the various mechanisms proposed did govern the powder dispersion. PMID- 27497999 TI - A systematic review of community-based parenting interventions for adolescents with challenging behaviours. AB - Parenting skills training is an established means of treating challenging behaviours among young children, but there has been limited research on its efficacy when used to treat challenging adolescent behaviour. The aim of this systematic review was to evaluate the efficacy and effectiveness of community based parenting interventions designed for families with adolescents, as judged in terms of increased knowledge and skills among parents, improvements in adolescent behaviour, and program feasibility within community settings. Results indicated that intervention group parents typically made greater gains than did control group parents on measures of good parenting, with positive flow-on effects to some aspects of challenging adolescent behaviours. Limited evidence suggests that group and individual intervention formats may be equally effective and that there is no advantage to the participation of the target adolescent in the intervention. PMID- 27498000 TI - Brief report: Overgeneral autobiographical memory in adolescent major depressive disorder. AB - The current study examined whether overgeneral autobiographical memory (OGM) bias serves as a state-like marker of major depressive disorder (MDD) in adolescence or whether it would also be observed in currently nondepressed adolescents with a history of MDD. We examined differences in OGM to positive and negative cue words between adolescents (aged 11-18 years) with current MDD (n = 15), remitted MDD (n = 25), and no history of any depressive disorder (n = 25). Youth and their parents were administered a structured diagnostic interview and adolescents completed the autobiographical memory test. Compared to never depressed adolescents, adolescents with current or remitted MDD recalled less specific memories in response to positive and negative cue words. The difference between the two MDD groups was small and nonsignificant. These findings suggest that OGM is not simply a state-like marker in currently depressed adolescents, but is also evident in adolescents with remitted MDD, indicating that it may represent a trait-like vulnerability that increases risk for relapse. PMID- 27498001 TI - Interparental conflict and adolescents' self-representations: The role of emotional insecurity. AB - Adolescents' signs of emotional insecurity in the context of interparental conflict (IC) - emotional reactivity, internal representations (i.e., constructive/destructive; spillover) and behavioral responses (i.e., withdrawal; inhibition; involvement) - were examined as mediators in the relation between IC and adolescents' self-representations. Self-reported measures were filled out by 221 Portuguese adolescents (59.3% girls; Mage = 12.91), attending public elementary and secondary schools. IC predicted less favorable self representations. Adolescents' emotional reactivity and withdrawal mediated the relation between IC and emotional and physical appearance self-representations, while conflict spillover representations and constructive family representations mediated associations between IC and instrumental self-representations. This study emphasizes the importance of interparental conflict and adolescent emotional insecurity in the construction of their self-representations, having important theoretical and practical implications. It highlights the value of analyzing the specific role of several emotional insecurity dimensions, and informs practitioners' work aimed at promoting constructive conflict and adaptive emotional regulation skills. PMID- 27498002 TI - ATF7 ablation prevents diet-induced obesity and insulin resistance. AB - The activating transcription factor (ATF)2 family of transcription factors regulates a variety of metabolic processes, including adipogenesis and adaptive thermogenesis. ATF7 is a member of the ATF2 family, and mediates epigenetic changes induced by environmental stresses, such as social isolation and pathogen infection. However, the metabolic role of ATF7 remains unknown. The aim of the present study is to examine the role of ATF7 in metabolism using ATF7-dificeint mice. Atf7(-/-) mice exhibited lower body weight and resisted diet-induced obesity. Serum triglycerides, resistin, and adipose tissue mass were all significantly lower in ATF7-deficient mice. Fasting glucose levels and glucose tolerance were unaltered, but systemic insulin sensitivity was increased, by ablation of ATF7. Indirect calorimetry revealed that oxygen consumption by Atf7( /-) mice was comparable to that of wild-type littermates on a standard chow diet, but increased energy expenditure was observed in Atf7(-/-) mice on a high-fat diet. Hence, ATF7 ablation may impair the development and function of adipose tissue and result in elevated energy expenditure in response to high-fat-feeding obesity and insulin resistance, indicating that ATF7 is a potential therapeutic target for diet-induced obesity and insulin resistance. PMID- 27498003 TI - MiR-509-3-5p causes aberrant mitosis and anti-proliferative effect by suppression of PLK1 in human lung cancer A549 cells. AB - MicroRNAs (miRNAs) are potent post-transcriptional regulators of gene expression and play roles in DNA damage response (DDR). PLK1 is identified as a modulator of DNA damage checkpoint. Although down-regulation of PLK1 by certain microRNAs has been reported, little is known about the interplay between PLK1 and miR-509-3-5p in DDR. Here we have demonstrated that miR-509-3-5p repressed PLK1 expression by targeting PLK1 3'-UTR, thereby causing mitotic aberration and growth arrest of human lung cancer A549 cells. Repression of PLK1 by miR-509-3-5p was further evidenced by over-expression of miR-509-3-5p in A549, HepG2 and HCT116p53(-/-) cancer cells, in which PLK1 protein was suppressed. Consistently, miR-509-3-5p was stimulated, while PLK1 protein was down-regulated in A549 cells exposed to CIS and ADR, suggesting that suppression of PLK1 by miR-509-3-5p is a component of CIS/ADR-induced DDR pathway. Flow cytometry and immunofluorescence labeling showed that over-expression of miR-509-3-5p in A549 induced G2/M arrest and aberrant mitosis characterized by abnormal bipolar mitotic spindles, condensed chromosomes, lagging DNA and chromosome bridges. In addition, over-expression of miR-509-3-5p markedly blocked A549 cell proliferation and sensitized the cells to CIS and ADR treatment. Taken together, miR-509-3-5p is a feasible suppressor for cancer by targeting PLK1. Our data may provide aid in potential design of combined chemotherapy and in our better understanding of the roles of microRNAs in response to DNA damage. PMID- 27498004 TI - Ulinastatin attenuates pulmonary endothelial glycocalyx damage and inhibits endothelial heparanase activity in LPS-induced ARDS. AB - Acute respiratory distress syndrome (ARDS) is a syndrome of acute respiratory failure characterized by major pathologic mechanisms of increased microvascular permeability and inflammation. The glycocalyx lines on the endothelial surface, which determines the vascular permeability, and heparanase play pivotal roles in the degradation of heparan sulfate (HS). HS is the major component of the glycocalyx. The aim of this study is to examine the effects of Ulinastatin (UTI) on vascular permeability and pulmonary endothelial glycocalyx dysfunction induced by lipopolysaccharide (LPS). In our study, C57BL/6 mice and human umbilical vein endothelial cells were stimulated with LPS to induce injury models. After 6 h of LPS stimulation, pulmonary pathological changes, pulmonary edema, and vascular permeability were notably attenuated by UTI. UTI inhibited LPS-induced endothelial glycocalyx destruction and significantly decreased the production of HS as determined by ELISA and immunofluorescence. UTI also reduced the active form of heparanase (50 kDa) expression and heparanase activity. Moreover, lysosome pH was investigated because heparanase (65 kDa) can be reduced easily in its active form at 50 kDa in a low pH environment within lysosome. Results showed that UTI could inhibit LPS-induced pH elevation in lysosome. In conclusion, UTI protects pulmonary endothelial glycocalyx integrity and inhibits heparanase activity during LPS-induced ARDS. PMID- 27498005 TI - Cartilage oligomeric matrix protein prevents vascular aging and vascular smooth muscle cells senescence. AB - Aging-related vascular dysfunction contributes to cardiovascular morbidity and mortality. Cartilage oligomeric matrix protein (COMP), a vascular extracellular matrix protein, has been described as a negative regulatory factor for the vascular aging-related processes including atherosclerosis and vascular calcification. However, whether COMP is implicated in the process of vascular aging remains unclear. Here, we identified a novel function of COMP in preventing vascular aging and vascular smooth muscle cells (VSMCs) senescence. Firstly, vascular COMP expression was decreased in three different senescence-accelerated mouse models and was also declining with age. COMP(-/-) mice displayed elevated senescence-associated markers expression, including p53, p21 and p16, in the aortas compared with their wild type (WT) littermates. In accordance, COMP deficiency induced aging-related vascular dysfunction as evidenced by the significantly reduced phenylephrine-induced contraction and increased vascular stiffness as evaluated by pulse wave velocity. The aortic wall of COMP(-/-) mice was susceptible to senescence by displaying senescence-associated beta galactosidase (SA beta-gal) activity induced by periadventitial application of CaCl2 to the abdominal aorta. In vitro, COMP knockdown by small interfering (si) RNA led to the elevation of p53, p21 and p16 as well as SA beta-gal activity in VSMCs after H2O2 stimulation. VSMCs isolated from COMP(-/-) mice showed elevated senescence-associated markers expression and supplement of COMP adenovirus to COMP-deficient VSMCs greatly rescued cellular senescence. Taken together, these findings revealed the essential role of COMP in retarding the development of vascular aging and VSMC senescence. PMID- 27498006 TI - Osterix plays a critical role in BMP4-induced promoter activity of connexin43. AB - Osterix is an essential transcription factor for osteogenesis and is expressed in osteoblasts. Although Osterix has been shown to be induced by bone morphogenetic protein 4, the molecular mechanism underlying Osterix function during osteoblast differentiation remains unclear. Connexin43 (Cx43) is the most abundant gap junction protein in bone cells and plays a critical role in osteoblast differentiation. However, little is known about the functional interactions between Osterix and the Cx43 promoter. In the present study, we investigated the relationship between Osterix and Cx43 in HEK293 and C2C12 cells. Cx43 expression was significantly repressed by the addition of shRNA against Osterix, whereas overexpression of Osterix resulted in enhanced Cx43 expression. Furthermore, Osterix directly occupied the promoter region of Cx43 and subsequently increased Cx43 promoter activity in a dose-dependent manner. In addition, phosphorylation of the Ser76 and Ser80 residues in Osterix were found to be critical for its activity on the Cx43 promoter. Our results suggest that Osterix plays an important role in increasing bone morphogenetic protein 4-induced Cx43 activity. PMID- 27498007 TI - Concomitant beige adipocyte differentiation upon induction of mesenchymal stem cells into brown adipocytes. AB - The accumulation of fat, which results in obesity, is related to many metabolic disorders. Besides white and brown adipose tissue, beige adipose tissue has recently been recognized as a new type of accumulated fat. Mesenchymal stem cells (MSCs) have been shown to differentiate into brown adipocytes. Through analyzing levels of mRNA and protein markers associated with beige adipocyte, we found concomitant beige adipocyte differentiation upon induction of MSCs into brown adipocytes in a defined medium containing triiodothyronine, insulin, dexamethasone, and indomethacin. Moreover, we found that protein kinase A (PKA) modulators regulated MSC differentiation into brown or beige adipocytes. Activation of PKA by isobutylmethylxanthine or forskolin increased brown adipocyte differentiation and reduced beige adipocyte differentiation, while inactivation of PKA by KT-5720 or SC-3010 or the knockdown of PKA downstream cAMP response element-binding protein (CREB) decreased brown adipocyte differentiation and increased beige adipocyte differentiation. We also showed that increased brown adipocyte differentiation was accompanied by an increase in mitochondrial mass. In conclusion, we propose a model of beige/brown co-differentiation in MSCs and develop a method for controlling this differentiation via PKA modulation. PMID- 27498008 TI - The memory gene KIBRA is a bidirectional regulator of synaptic and structural plasticity in the adult brain. AB - Memory formation is associated with activity-dependent changes in synaptic plasticity. The mechanisms underlying these processes are complex and involve multiple components. Recent work has implicated the protein KIBRA in human memory, but its molecular functions in memory processes remain not fully understood. Here, we show that a selective overexpression of KIBRA in neurons increases hippocampal long-term potentiation (LTP) but prevents the induction of long-term depression (LTD), and impairs spatial long-term memory in adult mice. KIBRA overexpression increases the constitutive recycling of AMPA receptors containing GluA1 (GluA1-AMPARs), and favors their activity-dependent surface expression. It also results in dramatic dendritic rearrangements in pyramidal neurons both in vitro and in vivo. KIBRA knockdown in contrast, abolishes LTP, decreases GluA1-AMPARs recycling and reduces dendritic arborization. These results establish KIBRA as a novel bidirectional regulator of synaptic and structural plasticity in hippocampal neurons, and of long-term memory, highly relevant to cognitive processes and their pathologies. PMID- 27498009 TI - Laparoendoscopic single-site cholecystectomy and common bile duct exploration using conventional instruments. AB - BACKGROUND: Optimization of quality of life is an important goal in the advanced surgery. Herein we share our fifteen cases to demonstrate the feasibility of scarless laparoendoscopic single-site common bile duct (CBD) exploration using conventional instruments in the management of CBD stones. METHODS: Fifteen patients (4 male) underwent transumbilical laparoendoscopic single-site cholecystectomy and CBD exploration: the patients were diagnosed with CBD stones. The endoscopic nasobiliary drainage (ENBD), endoscopic retrograde biliary drainage (ERBD) or J-type tube was introduced into the CBD preoperatively or intraoperatively. A 2-cm periumbilical incision was made for the placement of three trocars. Conventional rigid laparoscopic instruments were solely used throughout the procedure, and operative techniques were carried out in the same fashion as for conventional T-tube-free laparoscopic cholecystectomy and CBD exploration. RESULTS: The procedures were completed uneventfully in the mean duration of 125.7 min. Three patients occurred pigtail J-tube displacement and all three were later excreted safely in stool. CONCLUSIONS: Laparoendoscopic single-site cholecystectomy and CBD exploration appears to be a technically feasible alternative to standard laparoscopic procedure, and can be performed using conventional laparoscopic instruments. Laparoscopic primary closure with preoperative ENBD and ERBD tubes and with intraoperative J-tubes is safe and feasible. PMID- 27498010 TI - Nitrous oxide emissions in a membrane bioreactor treating saline wastewater contaminated by hydrocarbons. AB - The joint effect of wastewater salinity and hydrocarbons on nitrous oxide emission was investigated. The membrane bioreactor pilot plant was operated with two phases: i. biomass acclimation by increasing salinity from 10gNaClL(-1) to 20gNaClL(-1) (Phase I); ii. hydrocarbons dosing at 20mgL(-1) with a constant salt concentration of 20gNaClL(-1) (Phase II). The Phase I revealed a relationship between nitrous oxide emissions and salinity. During the end of the Phase I, the activity of nitrifiers started to recover, indicating a partial acclimatization. During the Phase II, the hydrocarbon shock induced a temporary inhibition of the biomass with the suppression of nitrous oxide emissions. The results revealed that the oxic tank was the major source of nitrous oxide emission, likely due to the gas stripping by aeration. The joint effect of salinity and hydrocarbons was found to be crucial for the production of nitrous oxide. PMID- 27498011 TI - Towards high through-put biological treatment of municipal wastewater and enhanced phosphorus recovery using a hybrid microfiltration-forward osmosis membrane bioreactor with hydraulic retention time in sub-hour level. AB - This work uncovers an important feature of the forward osmosis membrane bioreactor (FOMBR) process: the decoupling of contaminants retention time (CRT) and hydraulic retention time (HRT). Based on this concept, the capability of the hybrid microfiltration-forward osmosis membrane bioreactor (MF-FOMBR) in achieving high through-put treatment of municipal wastewater with enhanced phosphorus recovery was explored. High removal of TOC and NH4(+)-N (90% and 99%, respectively) was achieved with HRTs down to 47min, with the treatment capacity increased by an order of magnitude. Reduced HRT did not affect phosphorus removal and recovery. As a result, the phosphorus recovery capacity was also increased by the same order. Reduced HRT resulted in increased system loading rates and thus elevated concentrations of mixed liquor suspended solids and increased membrane fouling. 454-pyrosequecing suggested the thriving of Bacteroidetes and Proteobacteria (especially Sphingobacteriales Flavobacteriales and Thiothrix members), as well as the community succession and dynamics of ammonium oxidizing and nitrite oxidizing bacteria. PMID- 27498012 TI - A novel approach of integrated bioprocessing of cane molasses for production of prebiotic and functional bioproducts. AB - In this work, the sugar industry by-product cane molasses was investigated as feedstock for acceptor reactions by dextransucrase from Leuconostoc mesenteroides MTCC 10508, leading to the biosynthesis of oligosaccharides. The starch industry corn fiber residue was used as a source for acceptor molecules, maltose, in the reaction. Production of approximately 124g oligosaccharides (DP3-DP6) per kg of fresh molasses was achieved. Further, cane molasses based medium was demonstrated as a sole carbon source for L. mesenteroides growth and dextransucrase production. d-Fructose released by dextransucrase activity as processing by product was transformed into the functional monosaccharide with zero caloric value, d-psicose, by inducing its epimerization. Quantitative analysis approximated 37g d-psicose per kg of fresh molasses. Thus, the study established a novel approach of integrated bioprocessing of cane molasses into prebiotic and functional food additives. PMID- 27498013 TI - Bioethanol production by recycled Scheffersomyces stipitis in sequential batch fermentations with high cell density using xylose and glucose mixture. AB - Here, it is shown three-step investigative procedures aiming to improve pentose rich fermentations performance, involving a simple system for elevated mass production by Scheffersomyces stipitis (I), cellular recycle batch fermentations (CRBFs) at high cell density using two temperature strategies (fixed at 30 degrees C; decreasing from 30 to 26 degrees C) (II), and a short-term adaptation action seeking to acclimatize the microorganism in xylose rich-media (III). Cellular propagation provided 0.52gdrycellweightgRS(-1), resulting in an expressive value of 45.9gdrycellweightL(-1). The yeast robustness in CRBF was proven by effective ethanol production, reaching high xylose consumption (81%) and EtOH productivity (1.53gL(-1)h(-1)). Regarding the short-term adaptation, S. stipitis strengthened its robustness, as shown by a 6-fold increase in xylose reductase (XR) activity. The short fermentation time (20h for each batch) and the fermentation kinetics for ethanol production from xylose are quite promising. PMID- 27498014 TI - Valorization of food waste into hydroxymethylfurfural: Dual role of metal ions in successive conversion steps. AB - This study aimed to transform food waste into a value-added chemical, hydroxymethylfurfural (HMF), and unravel the tangled effects induced by the metal catalysts on each single step of the successive conversion pathway. The results showed that using cooked rice and bread crust as surrogates of starch-rich food waste, yields of 8.1-9.5% HMF and 44.2-64.8% glucose were achieved over SnCl4 catalyst. Protons released from metal hydrolysis and acidic by-products rendered Bronsted acidity to catalyze fructose dehydration and hydrolysis of glycosidic bond. Lewis acid site of metals could facilitate both fructose dehydration and glucose isomerization via promoting the rate-limiting internal hydride shift, with the catalytic activity determined by its electronegativity, electron configuration, and charge density. Lewis acid site of a higher valence also enhanced hydrolysis of polysaccharide. However, the metals also catalyzed undesirable polymerization possibly by polarizing the carbonyl groups of sugars and derivatives, which should be minimized by process optimization. PMID- 27498016 TI - Learning in data-limited multimodal scenarios: Scandent decision forests and tree based features. AB - Incomplete and inconsistent datasets often pose difficulties in multimodal studies. We introduce the concept of scandent decision trees to tackle these difficulties. Scandent trees are decision trees that optimally mimic the partitioning of the data determined by another decision tree, and crucially, use only a subset of the feature set. We show how scandent trees can be used to enhance the performance of decision forests trained on a small number of multimodal samples when we have access to larger datasets with vastly incomplete feature sets. Additionally, we introduce the concept of tree-based feature transforms in the decision forest paradigm. When combined with scandent trees, the tree-based feature transforms enable us to train a classifier on a rich multimodal dataset, and use it to classify samples with only a subset of features of the training data. Using this methodology, we build a model trained on MRI and PET images of the ADNI dataset, and then test it on cases with only MRI data. We show that this is significantly more effective in staging of cognitive impairments compared to a similar decision forest model trained and tested on MRI only, or one that uses other kinds of feature transform applied to the MRI data. PMID- 27498015 TI - Increasing the impact of medical image computing using community-based open access hackathons: The NA-MIC and 3D Slicer experience. AB - The National Alliance for Medical Image Computing (NA-MIC) was launched in 2004 with the goal of investigating and developing an open source software infrastructure for the extraction of information and knowledge from medical images using computational methods. Several leading research and engineering groups participated in this effort that was funded by the US National Institutes of Health through a variety of infrastructure grants. This effort transformed 3D Slicer from an internal, Boston-based, academic research software application into a professionally maintained, robust, open source platform with an international leadership and developer and user communities. Critical improvements to the widely used underlying open source libraries and tools-VTK, ITK, CMake, CDash, DCMTK-were an additional consequence of this effort. This project has contributed to close to a thousand peer-reviewed publications and a growing portfolio of US and international funded efforts expanding the use of these tools in new medical computing applications every year. In this editorial, we discuss what we believe are gaps in the way medical image computing is pursued today; how a well-executed research platform can enable discovery, innovation and reproducible science ("Open Science"); and how our quest to build such a software platform has evolved into a productive and rewarding social engineering exercise in building an open-access community with a shared vision. PMID- 27498017 TI - Centre characteristics determine ambulatory care and referrals in patients with spondyloarthritis. AB - OBJECTIVE: To describe the variability in rheumatology visits and referrals to other medical specialties of patients with spondyloarthritis (SpA) and to explore factors that may influence such variability. METHODS: Nation-wide cross-sectional study performed in 2009-2010. Randomly selected records of patients with a diagnosis of SpA and at least one visit to a rheumatology unit within the previous 2 years were audited. The rates of rheumatology visits and of referrals to other medical specialties were estimated-total and between centres-in the study period. Multilevel regression was used to analyse factors associated with variability and to adjust for clinical and patient characteristics. RESULTS: 1168 patients' records (45 centres) were reviewed, mainly ankylosing spondylitis (55.2 %) and psoriatic arthritis (22.2 %). The patients had incurred in 5908 visits to rheumatology clinics (rate 254 per 100 patient-years), 4307 visits to other medical specialties (19.6 % were referrals from rheumatology), and 775 visits to specialised nurse clinics. An adjusted variability in frequenting rheumatology clinics of 15.7 % between centres was observed. This was partially explained by the number of faculties and trainees. The adjusted intercentre variability for referrals to other specialties was 12.3 %, and it was associated with urban settings, number of procedures, and existence of SpA dedicated clinics; the probability of a patient with SpA of being referred to other specialist may increase up to 25 % depending on the treating centre. CONCLUSION: Frequenting rheumatology clinics and referrals to other specialists significantly varies between centres, after adjustment by patient characteristics. PMID- 27498018 TI - On the electrophoretic mobility of succinoglycan modelled as a spherical polyelectrolyte: From Hermans-Fujita theory to charge regulation in multi component electrolytes. AB - Literature interpretations of the electrophoretic mobility of spherical polyelectrolytes are revisited using the capillary-electrophoresis data of Duval et al. (2006) for the extracellular polysaccharide succinoglycan as an example. Subtle changes in the polyelectrolyte mobility have recently been attributed to new electrokinetic theories that feature multi-component electrolytes, charge regulation, and the so-called polarization and relaxation phenomena. However, these calculations exhibit several unusual trends that have yet to be explained, and so the conclusions drawn from them are controversial. Here, independent computations strengthen conclusions drawn from the original model of Duval et al., i.e., the discrepancies between experiments and all the presently available electrokinetic theories reflect changes in the conformation of succinoglycan arising from changes in the electrolyte pH and ionic strength. PMID- 27498020 TI - Engineering biodegradable micelles of polyethylenimine-based amphiphilic block copolymers for efficient DNA and siRNA delivery. AB - Polycationic micelles have shown advantageous properties as nucleic acid delivery vectors both in vitro and in vivo. In contrast to polycationic micelles reported so far, we designed particles integrating a sufficient nucleic acid condensation capability by polycationic polyethylenimine (PEI) segments as well as only a mild cytotoxic behavior. The micelles composed of a hydrophobic oligoester core with glycolide units resulting in fast degradation after cellular internalization in combination with PEG moieties acting as shielding agents. By grafting branched 25kDa polyethylenimine (PEI25) and poly(ethylene glycol) (PEG) on poly[(epsilon caprolactone)-co-glycolide] (CG), amphiphilic PEI-CG-PEI and PEG-CG block copolymers were used to form a series of micelles via self-assembly of PEI-CG-PEI or co-assembly of both copolymers for DNA and siRNA delivery. This modular system enabled a systematic investigation of different parameters and their synergetic effects as different functions were introduced. The polyplex formation and serum stability, cytotoxicity, and transfection activity could be tailored by changing the CG chain length in PEI-based copolymer, incorporating PEG-CG, and varying the N/P ratio. All micelle-based polyplex compositions showed high DNA transfection activity according to reporter gene-expression and an exceptionally high knockdown in siRNA delivery experiments. Remarkably, the GFP expression of >99% cells was successfully knocked down by micelle-mediated siRNA interference, resulting in a decrease of two orders of magnitude in fluorescence intensity. Incorporation of PEG-CG in the micelles reduced the PEI-related cytotoxicity, and markedly enhanced the serum stability of both DNA and siRNA polyplexes. Compared with homo-PEI25, these micelles showed several advantages including the lower toxicity, higher siRNA transfection efficiency and higher polyplex stability in the presence of serum. This study therefore provides an effective approach to tune the structure, property and function of polycationic micelles for efficient DNA and siRNA delivery, which could contribute to the design and development of novel non-viral transfection vectors with superb functionality. PMID- 27498019 TI - Synthesis, characterization and evaluation of in vitro toxicity in hepatocytes of linear polyesters with varied aromatic and aliphatic co-monomers. AB - Polyesters are extensively used in drug delivery because of their controllable biodegradation properties and perceived favorable cytocompatibility. However, new ester-based materials are continually being sought which can be produced from readily accessible monomers, which can be tuned for drug encapsulation and which retain good cellular compatibilities. In this study, 5 polyesters of similar molar mass were synthesized by reacting 1,10-decanediol with different ratios of succinic acid/phenylsuccinic acid and the effect of the phenyl side-chain group addition on polymer properties relevant to drug delivery was investigated. A polymer with a 70/30 ratio of succinic acid and phenylsuccinic acid was selected based on its ability to encapsulate a model dye in nanoparticle (NP) formulations, and was found to be slowly degradable in phosphate buffered saline (PBS) but more rapidly degraded in the presence of a lipase. The compatibility of NP formulations of this polymer either with or without a Pluronic F68 stabilizing coating was assessed in vitro using the C3A hepatocyte cell line. Cell viability was assessed, at NP concentrations ranging from 4.68-300MUgmL-1 24h post exposure, using the Alamar Blue, CDFA and Neutral Red assays. C3A cells internalized both coated and uncoated polyester NPs to a similar extent, with uptake observed to increase over time (10-1440min). Although cell viability was >80% at the concentrations tested, in all assays, it was found that a Pluronic F68 coated poly (decanediol-phenylsuccinate-co-succinate) stimulated significant DNA damage driven by an oxidant mechanism, whereas the non-coated polyester analogue and the Pluronic F68 alone had no effect. The results obtained suggest that new polyesters can be synthesized with desirable properties from the materials perspective but formulation with additional excipients requires careful evaluation for drug delivery applications. PMID- 27498021 TI - CRISPR-Cas9 gene editing: Delivery aspects and therapeutic potential. AB - The CRISPR-Cas9 gene editing system has taken the biomedical science field by storm, initiating rumors about future Nobel Prizes and heating up a fierce patent war, but also making significant scientific impact. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), together with CRISPR-associated proteins (Cas) are a part of the prokaryotic adaptive immune system and have successfully been repurposed for genome editing in mammalian cells. The CRISPR Cas9 system has been used to correct genetic mutations and for replacing entire genes, opening up a world of possibilities for the treatment of genetic diseases. In addition, recently some new CRISPR-Cas systems have been discovered with interesting mechanistic variations. Despite these promising developments, many challenges have to be overcome before the system can be applied therapeutically in human patients and enabling delivery technology is one of the key challenges. Furthermore, the relatively high off-target effect of the system in its current form prevents it from being safely applied directly in the human body. In this review, the transformation of the CRISPR-Cas gene editing systems into a therapeutic modality will be discussed and the currently most realistic in vivo applications will be highlighted. PMID- 27498022 TI - Development of an automated mid-scale parallel protein purification system for antibody purification and affinity chromatography. AB - Protein purification is often a bottleneck during protein generation for large molecule drug discovery. Therapeutic antibody campaigns typically require the purification of hundreds of monoclonal antibodies (mAbs) during the hybridoma process and lead optimization. With the increase in high-throughput cloning, faster DNA sequencing, and the use of parallel protein expression systems, a need for high-throughput purification approaches has evolved, particularly in the midsize range between 20 ml and 100 ml. To address this we modified a four channel Gilson solid phase extraction system (referred to as MG-SPE) with switching valves and sample holding loops to be able to perform standard affinity purification using commercially available columns and micro-titer format deep well blocks. By running 4 samples in parallel, the MG-SPE has the capacity to purify up to 24 samples of greater than 50 ml each using a single-step affinity purification protocol or a two-step protocol consisting of affinity chromatography followed by desalting/buffer exchange overnight (~12 h run time). Our evaluation of affinity purification using mAbs and Fc-fusion proteins from mammalian cell supernatants demonstrates that the MG-SPE compared favorably with industry standard systems for both protein quality and yield. Overall the system is simple to operate and fills a void in purification processes where a simple, efficient, automated system is needed for affinity purification of midsize research samples. PMID- 27498023 TI - Axitinib Versus Sorafenib in First-Line Metastatic Renal Cell Carcinoma: Overall Survival From a Randomized Phase III Trial. AB - BACKGROUND: In a randomized phase III trial in treatment-naive patients with metastatic renal cell carcinoma (RCC), axitinib versus sorafenib yielded numerically longer progression-free survival (median, 10.1 vs. 6.5 months; hazard ratio [HR], 0.77; 1-sided P = .038) and significantly higher objective response rate (32% vs. 15%; 1-sided P = .0006). In this article, we report overall survival (OS) and updated safety results. PATIENTS AND METHODS: Previously untreated patients with metastatic RCC (n = 288), stratified according to Eastern Cooperative Oncology Group performance status (ECOG PS; 0 vs. 1), were randomized 2:1 to receive axitinib 5 mg twice per day (b.i.d.; n = 192) or sorafenib 400 mg b.i.d. (n = 96). RESULTS: Median OS (95% confidence interval [CI]) was 21.7 months (18.0-31.7) with axitinib versus 23.3 months (18.1-33.2) with sorafenib (stratified HR, 0.995; 95% CI, 0.731-1.356; 1-sided P = .4883). Among patients with ECOG PS of 0, median OS was numerically longer with axitinib than with sorafenib (41.2 vs. 31.9 months; HR, 0.811, 1-sided P = .1748), whereas among patients with ECOG PS 1, median OS was shorter with axitinib than with sorafenib (14.2 vs. 19.8 months; HR, 1.203; 1-sided; P = .7973). Incidence and severity of common adverse events were consistent with previous reports. CONCLUSION: OS was similar between axitinib and sorafenib in treatment-naive patients with metastatic RCC, and no new safety signals emerged. PMID- 27498025 TI - Neoblasts and the evolution of whole-body regeneration. AB - The molecular mechanisms underlying whole-body regeneration are best understood in the planarian flatworm Schmidtea mediterranea, where a heterogeneous population of somatic stem cells called neoblasts provides new tissue for regeneration of essentially any missing body part. Studies on Schmidtea have provided a detailed description of neoblasts and their role in regeneration, but comparatively little is known about the evolutionary history of these cells and their underlying developmental programs. Acoels, an understudied group of aquatic worms that are also capable of extensive whole-body regeneration, have arisen as an attractive group to study the evolution of regenerative processes due to their phylogenetically distant position relative to flatworms. Here, we review the phylogenetic distribution of neoblast cells and compare their anatomical locations, transcriptional profiles, and roles during regeneration in flatworms and acoels to understand the evolution of whole-body regeneration. While the general role of neoblasts appears conserved in species separated by 550 million years of evolution, the extrinsic inputs they receive during regeneration can vary, making the distinction between homology and convergence of mechanism unclear. A more detailed understanding of the precise mechanisms behind whole body regeneration in diverse phyla is necessary to understand the evolutionary history of this powerful process. PMID- 27498026 TI - Editorial commentary: The continuing evolution of primary PCI and clinical guidelines. PMID- 27498024 TI - Myocardial plasticity: cardiac development, regeneration and disease. AB - The adult mammalian heart is unable to recover from myocardial cell loss due to cardiac ischemia and infarction because terminally differentiated cardiomyocytes proliferate at a low rate. However, cardiomyocytes in other vertebrate animal models such as zebrafish, axolotls, newts and mammalian mouse neonates are capable of de-differentiating in order to promote cardiomyocyte proliferation and subsequent cardiac regeneration after injury. Although de-differentiation may occur in adult mammalian cardiomyocytes, it is typically associated with diseased hearts and pathologic remodeling rather than repair and regeneration. Here, we review recent studies of cardiac development, regeneration and disease that highlight how changes in myocardial identity (plasticity) is regulated and impacts adaptive and maladaptive cardiac responses. PMID- 27498027 TI - Isolation, structural analysis, and expression characteristics of the maize nuclear factor Y gene families. AB - NUCLEAR FACTOR-Y (NF-Y) has been shown to play an important role in growth, development, and response to environmental stress. A NF-Y complex, which consists of three subunits, NF-YA, NF-YB, and, NF-YC, binds to CCAAT sequences in a promoter to control the expression of target genes. Although NF-Y proteins have been reported in Arabidopsis and rice, a comprehensive and systematic analysis of ZmNF-Y genes has not yet been performed. To examine the functions of ZmNF-Y genes in this family, we isolated and characterized 50 ZmNF-Y (14 ZmNF-YA, 18 ZmNF-YB, and 18 ZmNF-YC) genes in an analysis of the maize genome. The 50 ZmNF-Y genes were distributed on all 10 maize chromosomes, and 12 paralogs were identified. Multiple alignments showed that maize ZmNF-Y family proteins had conserved regions and relatively variable N-terminal or C-terminal domains. The comparative syntenic map illustrated 40 paralogous NF-Y gene pairs among the 10 maize chromosomes. Microarray data showed that the ZmNF-Y genes had tissue-specific expression patterns in various maize developmental stages and in response to biotic and abiotic stresses. The results suggested that ZmNF-YB2, 4, 8, 10, 13, and 16 and ZmNF-YC6, 8, and 15 were induced, while ZmNF-YA1, 3, 4, 6, 7, 10, 12, and 13, ZmNF-YB15, and ZmNF-YC3 and 9 were suppressed by drought stress. ZmNF YA3, ZmNF-YA8 and ZmNF-YA12 were upregulated after infection by the three pathogens, while ZmNF-YA1 and ZmNF-YB2 were suppressed. These results indicate that the ZmNF-Ys may have significant roles in the response to abiotic and biotic stresses. PMID- 27498028 TI - Protein kinase C-delta inhibitor, Rottlerin inhibits growth and survival of mycobacteria exclusively through Shikimate kinase. AB - The molecular bases of disease provide exceptional prospect to translate research findings into new drugs. Nevertheless, to develop new and novel chemical entities takes huge amount of time and efforts, mainly due to the stringent processes. Therefore, drug repurposing is one of such strategies which is being used in recent times to identify new pharmacophores. The essential first step in discovery of the specific inhibitor with low toxicity is the identification and elucidation of pathways exclusive to target pathogen. One such target is the shikimate pathway, which is essential for algae, higher plants, bacteria and fungi. Since, this enzyme system is absent in higher eukaryotes and in mammals, the enzymes involved in the pathway provide an attractive target for the development of potentially selective and non toxic antimicrobial agents. Since, so far there is no specific inhibitor which is able to restrain mycobacterial shikimate pathway; we expanded the use of a known kinase inhibitor; Rottlerin, in order to predict the prototype in discovering the specific molecules against this enzyme. For the first time we have shown that Rottlerin inhibits extracellular mycobacteria by affecting Shikimate Kinase (SK) and this effect is further enhanced during the intracellular infection due to the added effect of PKC- delta down-regulation. The molecular docking of Rottlerin with both the mycobacterial SKs, corroborated the inhibition data, and revealed that the effects of SK, in slow and in fast grower mycobacteria are due to the changes in affinity of binding with the drug. PMID- 27498029 TI - Calotropin from Asclepias curasavica induces cell cycle arrest and apoptosis in cisplatin-resistant lung cancer cells. AB - Calotropin (M11), an active compound isolated from Asclepias curasavica L., was found to exert strong inhibitory and pro-apoptotic activity specifically against cisplatin-induced resistant non-small cell lung cancer (NSCLC) cells (A549/CDDP). Molecular mechanism study revealed that M11 induced cell cycle arrest at the G2/M phase through down-regulating cyclins, CDK1, CDK2 and up-regulating p53 and p21. Furthermore, M11 accelerated apoptosis through the mitochondrial apoptotic pathway which was accompanied by increase Bax/Bcl-2 ratio, decrease in mitochondrial membrane potential, increase in reactive oxygen species production, activations of caspases 3 and 9 as well as cleavage of poly ADP-ribose polymerase (PARP). The activation and phosphorylation of JNK was also found to be involved in M11-induced apoptosis, and SP610025 (specific JNK inhibitor) partially prevented apoptosis induced by M11. In contrast, all of the effects that M11 induce cell cycle arrest and apoptosis in A549/CDDP cells were not significant in A549 cells. Drugs with higher sensitivity against resistant tumor cells than the parent cells are rather rare. Results of this study supported the potential application of M11 on the non-small lung cancer (NSCLC) with cisplatin resistance. PMID- 27498030 TI - Crystal structure of the Epithiospecifier Protein, ESP from Arabidopsis thaliana provides insights into its product specificity. AB - Specifier proteins are important components of the glucosinolate-myrosinase system, which mediate plant defense against herbivory and pathogen attacks. Upon tissue disruption, glucosinolates are hydrolyzed to instable aglucones by myrosinases, and then aglucones will rearrange to form defensive isothiocyanates. Specifier proteins can redirect this reaction to form other products, such as simple nitriles, epithionitriles and organic thiocyanates instead of isothiocyanates based on the side chain structure of glucosinolate and the type of the specifier proteins. Nevertheless, the molecular mechanism underlying the different product spectrums of various specifier proteins was not fully understood. Here in this study, we solved the crystal structure of the Epithiospecifier Protein, ESP from Arabidopsis thaliana (AtESP) at 2.3 A resolution. Structural comparisons with the previously solved structure of thiocyanate forming protein, TFP from Thlaspi arvense (TaTFP) reveal that AtESP shows a dimerization pattern different from TaTFP. Moreover, AtESP harbors a slightly larger active site pocket than TaTFP and several residues around the active site are different between the two proteins, which might account for the different product spectrums of the two proteins. Together, our structural study provides important insights into the molecular mechanisms of specifier proteins and shed light on the basis of their different product spectrums. PMID- 27498031 TI - Adipogenesis, lipogenesis and lipolysis is stimulated by mild but not severe hypoxia in 3T3-L1 cells. AB - In-vitro investigation of the effects of hypoxia is limited by physical laws of gas diffusion and cellular O2 consumption, making prolonged exposures to stable O2 concentrations impossible. Using a gas-permeable cultureware, chronic effects of mild and severe hypoxia on triglyceride accumulation, lipid droplet size distribution, spontaneous lipolysis and gene expression of adipocyte-specific markers were assessed. 3T3-L1 cells were differentiated under 20%, 4% or 1% O2 using a gas-permeable cultureware. Triglyceride accumulation, expression of genes characteristic for advanced adipocyte differentiation and involvement of key lipogenesis enzymes were assessed after exposures. Lipogenesis increased by 375% under mild hypoxia, but dropped by 43% in severe hypoxia. Mild, but not severe, hypoxia increased formation of large lipid droplets 6.4 fold and strongly induced gene expression of adipocyte-specific markers. Spontaneous lipolysis increased by 488% in mild, but only by 135% in severe hypoxia. Inhibition of ATP-dependent citrate lyase suppressed hypoxia-induced lipogenesis by 81% and 85%. Activation of HIF inhibited lipogenesis by 59%. Mild, but not severe, hypoxia stimulates lipolysis and promotes adipocyte differentiation, probably through excess of acetyl-CoA originating from tricarboxylic acid cycle independently of HIF activation. PMID- 27498032 TI - Let-7a inhibits tumor cell growth and metastasis by directly targeting RTKN in human colon cancer. AB - Colorectal cancer (CRC) is the third most common cancer worldwide, with high morbidity. MicroRNAs (miRNAs) are endogenous small RNAs that play important roles in regulating multiple biological and pathologic processes. The differential expression of miRNAs in CRC was first reported in 2003. Accumulated evidence indicates that lethal-7a (let-7a, miRNA) generally functions as a tumor suppressor in several human cancers. However, the role of let-7a in human colon cancer remains unclear. The aim of this study was to investigate the biological functions of let-7a and its potential role in colon cancer. We first discovered that let-7a level was significantly decreased in colon cancer tissues and cell lines (HT-29, HCT-116, LoVo, SW480, and SW620). To explore the effects of let-7a on colon cancer, let-7a over-expressed HCT-116 and SW620 cells were constructed. Further studies demonstrated that over-expressed let-7a could remarkably inhibit HCT-116 and SW620 cell growth and metastasis by directly down-regulating Rhotekin (RTKN). When RTKN was reintroduced into let-7a mimic transfected HCT-116 or SW620 cells, the inhibition effects of let-7a on colon cancer cell growth and metastasis were markedly reversed. In conclusion, our research shows that let-7a can inhibit tumor cell growth and metastasis by directly targeting RTKN in human colon cancer. PMID- 27498033 TI - Dehydroascorbic acid-induced endoplasmic reticulum stress and leptin resistance in neuronal cells. AB - Due to its anti-obesity effects, an adipocyte-derived hormone, leptin, has become important for the treatment of obesity. However, most obese subjects are in a state of leptin resistance, and endoplasmic reticulum (ER) stress is suggested to be involved in the pathophysiology of leptin resistance. Dehydroascorbic acid (DHAA), an oxidized form of vitamin C, was found to be increased in diabetes. In the present study, we investigated the possible effects of DHAA on the activation of ER stress and leptin resistance. A human neuroblastoma cell line, stably transfected with the Ob-Rb leptin receptor (SH-SY5Y-ObRb), was treated with DHAA. We found that DHAA upregulated ER stress-related genes such as GRP78, CHOP, and spliced XBP1. Moreover, leptin-induced STAT3 phosphorylation was hindered by DHAA. These results suggested that increases in the levels of DHAA might be harmful to neurons, contributing to defective leptin-responsive signaling. PMID- 27498034 TI - [Traumatic hand injuries in children]. AB - Hand injuries in children are frequent in pediatric emergencies. Epidemiology of hand injuries in children depends on age and social context. The management of these injuries requires experienced pediatrics in order to obtain a functional hand to preserve the potential growth and to reduce the risk of cosmetic sequelae. We will describe the specificities of hand trauma in children and their therapeutic principles. PMID- 27498035 TI - A new Western blot assay for the detection of porcine cytomegalovirus (PCMV). AB - Porcine cytomegalovirus (PCMV) may be harmful for human recipients if xenotransplantation using pig cell, tissue or organ will be performed transmitting the virus from donor pigs to human recipients. PCMV is widespread in pigs and closely related to human pathogenic herpesviruses, however there are no data concerning infection of humans. In contrast, recently it had been shown that transplantation of organs from pigs infected with PCMV into non-human primate recipients resulted in a significant reduction of the survival time compared with the transplantation of organs from uninfected pigs. To prevent transmission of PCMV in future pig to human xenotransplantations, sensitive and specific detection methods should be used. Here a new Western blot assay using recombinant proteins corresponding to two domains of the glycoprotein gB of PCMV is described. With this assay, the presence of PCMV-specific antibodies in different pig breeds was analysed. Antibodies were detected in a high percentage of animals, in one breed up to 85%. PMID- 27498036 TI - An avian influenza H5N1 virus vaccine candidate based on the extracellular domain produced in yeast system as subviral particles protects chickens from lethal challenge. AB - Highly pathogenic avian influenza is an on-going problem in poultry and a potential human pandemic threat. Pandemics occur suddenly and vaccine production must be fast and effective to be of value in controlling the spread of the virus. In this study we evaluated the potential of a recombinant protein from the extracellular domain of an H5 hemagglutinin protein produced in a yeast expression system to act as an effective vaccine. Protein production was efficient, with up to 200 mg purified from 1 L of culture medium. We showed that the deletion of the multibasic cleavage site from the protein improves oligomerization and, consequentially, its immunogenicity. We also showed that immunization with this deleted protein protected chickens from challenge with a highly pathogenic avian influenza H5N1 virus. Our results suggest that this recombinant protein produced in yeast may be an effective vaccine against H5N1 virus in poultry. PMID- 27498039 TI - Your misery is no longer my pleasure: Reduced schadenfreude in Huntington's disease families. AB - Schadenfreude - pleasure at others' misfortunes - has been systematically related to ventral striatum activity. This brain region is affected early in individuals with manifest and pre-manifest Huntington's disease (HD). However, the experience of schadenfreude has not yet been investigated in HD. In this study, 21 manifest HD patients, 19 first-degree asymptomatic relatives, and 23 healthy controls performed an experimental task designed to trigger schadenfreude, envy (another social emotion acting as an affective control condition), and control situations. Both HD patients and first-degree relatives experienced lower schadenfreude in response to others' misfortunes, with no group differences in ratings of envy and control conditions. These results offer unprecedented evidence of a highly specific impairment in reward processing, extending previous reports in manifest and pre-manifest HD individuals. Moreover, these findings suggest that early striatal impairments may be related to reduced feelings of schadenfreude. In sum, our work contributes to the understanding of emotional impairments in early stages of HD, while shedding light on their neural correlates. PMID- 27498037 TI - Animal models of resistance exercise and their application to neuroscience research. AB - BACKGROUND: Numerous studies have demonstrated that participation in regular resistance exercise (e.g., strength training) is associated with improvements in mental health, memory, and cognition. However, less is known about the neurobiological mechanisms mediating these effects. The goal of this mini-review is to describe and evaluate the available animal models of resistance exercise that may prove useful for examining CNS activity. NEW METHOD: Various models have been developed to examine resistance exercise in laboratory animals. COMPARISON WITH EXISTING METHODS: Resistance exercise models vary in how the resistance manipulation is applied, either through direct stimulation of the muscle (e.g., in situ models) or through behavior maintained by operant contingencies (e.g., whole organism models). Each model presents distinct advantages and disadvantages for examining central nervous system (CNS) activity, and consideration of these attributes is essential for the future investigation of underlying neurobiological substrates. RESULTS: Potential neurobiological mechanisms mediating the effects of resistance exercise on pain, anxiety, memory, and drug use have been efficiently and effectively investigated using resistance exercise models that minimize stress and maximize the relative contribution of resistance over aerobic factors. CONCLUSIONS: Whole organism resistance exercise models that (1) limit the use of potentially stressful stimuli and (2) minimize the contribution of aerobic factors will be critical for examining resistance exercise and CNS function. PMID- 27498038 TI - Hydrocarbon stapled B chain analogues of relaxin-3 retain biological activity. AB - Relaxin-3 or insulin-like peptide 7 (INSL7) is the most recently discovered relaxin/insulin-like family peptide. Mature relaxin-3 consists of an A chain and a B chain held by disulphide bonds. According to structure activity relationship studies, the relaxin-3 B chain is more important in binding and activating the receptor. RXFP3 (also known as Relaxin-3 receptor 1, GPCR 135, somatostatin- and angiotensin- like peptide receptor or SALPR) was identified as the cognate receptor for relaxin-3 by expression profiles and binding studies. Recent studies imply roles of this system in mediating stress and anxiety, feeding, metabolism and cognition. Stapling of peptides is a technique used to develop peptide drugs for otherwise undruggable targets. The main advantages of stapling include, increased activity due to reduced proteolysis, increased affinity to receptors and increased cell permeability. Stable agonists and antagonists of RXFP3 are crucial for understanding the physiological significance of this system. So far, agonists and antagonists of RXFP3 are peptides. In this study, for the first time, we have introduced stapling of the relaxin-3 B chain at 14th and 18th positions (14s18) and 18th and 22nd position (18s22). These stapled peptides showed greater helicity than the unstapled relaxin-3 B chain in circular dichroism analysis. Both stapled peptides bound RXFP3 and activated RXFP3 as observed in an inhibition of forskolin-induced cAMP assay and a ERK1/2 activation assay, although with different potencies. Therefore, we conclude that stapling of the relaxin3 B chain does not compromise its ability to activate RXFP3 and is a promising method for developing stable peptide agonists and antagonists of RXFP3 to aid relaxin-3/RXFP3 research. PMID- 27498040 TI - Am I seeing myself, my friend or a stranger? The role of personal familiarity in visual distinction of body identities in the human brain. AB - Several brain regions appear to play a role in representing different body identities. The specific contribution of each of these regions is still unclear, however. Here we investigated which brain areas enable the visual distinction between self and other bodies of different familiarity, and between familiar and unfamiliar other individuals, and moreover, where identity-specific information on the three individuals was encoded. Participants were confronted with standardized headless human body stimuli either showing the participant's own, a personally familiar or an unfamiliar other body, while performing a luminance discrimination task. Employing multivariate pattern analysis, we were able to identify areas that allowed for the distinction of self from personal familiar other bodies within the medial prefrontal cortex (mPFC) and posterior cingulate cortex/precuneus. Successful distinction of self from unfamiliar others was possible in the left middle frontal gyrus, the right inferior frontal gyrus, the left pre-supplementary motor area and the right putamen. Personally familiar others could be distinguished from unfamiliar others in the right temporoparietal junction (TPJ). An analysis of identity-specific information revealed a spatial gradient ranging from inferior posterior to superior anterior portions of the mPFC that was associated with encoding identity-related information for self via familiar to unfamiliar other bodies, respectively. Furthermore, several midline and frontal regions encoded information on more than one identity. The TPJ's role in deviance detection was underlined, as only identity-specific information on unfamiliar others was encoded here. Together, our findings suggest substantial spatial overlap in neural correlates of self and other body representation and thus, support the hypothesis of a socially-related representation of the self. PMID- 27498041 TI - Different FDG-PET metabolic patterns at single-subject level in the behavioral variant of fronto-temporal dementia. AB - BACKGROUND: The diagnosis of probable behavioral variant of fronto-temporal dementia (bvFTD) according to current criteria requires the imaging evidence of frontal and/or anterior temporal atrophy or hypoperfusion/hypometabolism. Different variants of this pattern of brain involvement may, however, be found in individual cases, supporting the presence of heterogeneous phenotypes. OBJECTIVE: We examined in a case-by-case approach the FDG-PET metabolic patterns of patients fulfilling clinical criteria for probable bvFTD, assessing the presence and frequency of specific FDG-PET features. MATERIALS AND METHODS: Fifty two FDG-PET scans of probable bvFTD patients were retrospectively analyzed together with clinical and neuropsychological data. Neuroimaging experts rated the FDG-PET hypometabolism maps obtained at the single-subject level with optimized voxel based Statistical Parametric Mapping (SPM). The functional metabolic heterogeneity was further tested by hierarchical cluster analysis and principal component analysis (PCA). RESULTS: Both the SPM maps and cluster analysis identified two major variants of cerebral hypometabolism, namely the "frontal" and the "temporo-limbic", which were correlated with different cognitive profiles. Executive and language deficits were the cognitive hallmark in the "frontal" subgroup, while poor encoding and recall on long-term memory tasks was typical of the "temporo-limbic" subgroup. DISCUSSION: SPM single-subject analysis indicates distinct patterns of brain dysfunction in bvFTD, coupled with specific clinical features, suggesting different profiles of neurodegenerative vulnerability. These findings have important implications for the early diagnosis of bvFTD and for the application of the recent international consensus criteria. PMID- 27498042 TI - Distribution of type VI collagen in association with osteoblast lineages in the groove of Ranvier during rat postnatal development. AB - In the groove of Ranvier (GOR), osteoblast lineages form bone bark, which develops into endosteal cortical bone. This ossification process is thought to be regulated by the microenvironment in the GOR. Type VI collagen (Col VI), an extracellular matrix (ECM) protein found in the periosteum/perichondrium, mediates osteoblast differentiation via the cell-surface receptor neural/glial antigen 2 (NG2) chondroitin sulfate proteoglycan. In order to clarify the function of Col VI during osteoblast differentiation in the GOR, in the present study, we examined the distribution of Col VI and osteoblast lineages expressing NG2 in the rat tibia proximal end during postnatal growing periods by immunohistochemistry. Our data revealed that Col VI accumulated in the ECM of the GOR middle layer and that Col VI accumulation was reduced and disappeared in the inner and middle lower regions. Runt-related transcription factor 2 immunoreactive pre-osteoblasts expressed NG2 in Col VI-immunopositive areas. However, Osterix-immunoreactive mature osteoblasts were only found in the Col VI immunonegative area. These findings indicate that Col VI provided a characteristic microenvironment in the GOR and that NG2-Col VI interactions may regulate the differentiation of osteoblast lineages prior to terminal maturation. PMID- 27498043 TI - The importance of surfactant proteins-New aspects on macrophage phagocytosis. AB - Surfactant and its components have multiple functions. The so called collectins are surfactant proteins which opsonize bacteria and improve pulmonary host defense via the phagocytosis and clearance of microorganisms and particles. In this special issue of the Annals of Anatomy a new surfactant protein, Surfactant Associated 3, is highlighted. As outlined in this mini review Surfactant Associated 3 is regarded as an enhancer of phagocytosis. In addition, the role played by SP-A is updated and open research questions raised. PMID- 27498044 TI - The Effect of Waiting Times for Postoperative Radiotherapy on Outcomes for Women Receiving Partial Mastectomy for Breast Cancer: a Systematic Review and Meta Analysis. AB - AIMS: To determine the effect of delay in postoperative radiotherapy on local recurrence and overall survival in women receiving partial mastectomy for breast cancer. MATERIALS AND METHODS: This was a systematic review and meta-analysis of published literature. Relevant reports were identified from MEDLINE, EMBASE and the Cochrane Register of Controlled Trials in all languages from 1975 to April 2015, in addition to the abstracts from the annual meetings of major radiotherapy conferences from 2000 to 2011. Reference lists were hand searched to find additional relevant reports and OvidSP's 'Find Citing' function was used to find studies citing papers identified in the primary search. Studies were included if they met the following criteria: (i) all patients received partial mastectomy and radiotherapy, (ii) a delay from surgery to radiotherapy was reported and (iii) one or more of local control/failure and/or survival were reported. Observational studies and randomised controlled trials were included. Studies including patients with in situ disease were excluded. Studies were classified as high quality if they adequately controlled for factors known to be associated with the outcomes of interest. Study quality was independently assessed by three authors. Initial disagreements about three studies were resolved by consensus. Only high quality studies were included in the primary analysis. Delay was modelled as a continuous variable and the relative risk of local recurrence and the relative risk of death are reported per month of delay. The study results were combined using a fixed-effects model. RESULTS: Thirty-four relevant publications including 79 616 patients were identified in the systematic review. Ten high-quality publications reported on local recurrence (13 291 patients) and four high-quality studies reported on overall survival (2207 patients). The relative risk of local recurrence per month of delay was 1.08 (95% confidence interval 1.02-1.14). The relative risk of death per month of delay was 0.99 (95% confidence interval 0.94 1.05). CONCLUSIONS: Delays in post-lumpectomy radiotherapy are associated with a significant increase in the risk of local recurrence. We recommend that waiting times for radiotherapy should be kept as short as reasonably achievable. PMID- 27498045 TI - Withanolides from leaves of cultivated Acnistus arborescens. AB - Seven withanolides, including four previously unknown, were isolated from the acetone and ethanol extracts of cultivated specimens of Acnistus arborescens. These four compounds were identified as rel-(18R,22R)-5beta,6beta:18beta,20 diepoxy-3beta,18alpha-dimethoxy-4beta-hydroxy-1-oxowith-24-enolide, rel-(20R,22R) 5beta,6beta-epoxy-4beta,16alpha,20-trihydroxy-1-oxowitha-2,24dienolide, rel (20R,22R)-16alpha-acetoxy-6alpha-chloro-4beta,5beta,20-trihydroxy-1-oxowitha-2,24 dienolide and rel-(20R,22R)-16alpha-acetoxy-20-hydroxy-1-oxowitha-2,5,24 trienolide. Their structures were elucidated by interpretation of spectroscopic data (1D and 2D NMR), HRESIMS experiments and comparison with published data for similar compounds. Cytotoxicity of the isolated compounds was evaluated against a panel of four tumor cell lines (HL-60, HCT-116, SF-268 and PANC-1). Withanolide D was the most active, with an IC50 value in the range of 0.3-1.7 MUM, rel (18R,22R)-5beta,6beta:18beta,20-diepoxy-3beta,18alpha-dimethoxy-4beta-hydroxy-1 oxowith-24-enolide and rel-(20R,22R)-5beta,6beta-epoxy-4beta,16alpha,20 trihydroxy-1-oxowitha-2,24dienolide were moderately active, while all the others were non-cytotoxic. PMID- 27498046 TI - Absolute configurations of phytotoxic inuloxins B and C based on experimental and computational analysis of chiroptical properties. AB - The absolute configuration of phytotoxins inuloxins B and C, produced by Inula viscosa, and with potential herbicidal activity for the management of parasitic plants, has been determined by Time-dependent density functional theory computational prediction of electronic circular dichroism and optical rotatory dispersion spectra. The inuloxin B has been converted to its 5-O-acetyl derivative, which due to its more constrained conformational features facilitated the computational analysis of its chiroptical properties. The analysis based on experimental and computed data led to assignment of absolute configuration to naturally occurring (+)-inuloxin B and (-)-inuloxin C as (7R,8R,10S,11S) and (5S,7S,8S,10S), respectively. PMID- 27498047 TI - RACK1 overexpression associates with pancreatic ductal adenocarcinoma growth and poor prognosis. AB - OBJECTIVES: The receptor for activated protein kinase C (RACK1) is a scaffold protein involved in multiple intracellular signal pathways. Previous studies have shown that RACK1 is associated with the progression of multiple cancer types, including hepatocellular carcinoma and gastric cancer. However, the role of RACK1 in human pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: In this study, the expression of RACK1 was evaluated by Western blot analysis in 8 paired fresh PDAC tissues and immunohistochemistry on 179 paraffin-embedded slices. Then, we used Fisher exact test to analyze the correlation between RACK1 expression and clinicopathological characteristics. Starvation and re-feeding assay was used to assess cell cycle. Western blot, CCK8, flow cytometry assays, and colony formation analyses demonstrated that RACK1 played an essential role in PDAC development. Annexin-V/PI apoptotic assay and western blot showed that RACK1 was involved in regulating the apoptosis of PDAC cells. RESULTS: RACK1 was highly expressed in PDAC tissues and cell lines and was significantly associated with multiple clinicopathological factors. Univariate and multivariate analyses showed that high RACK1 expression was identified to be an independent prognostic factor for PDAC patients' survival. In vitro, serum starvation-refeeding experiment suggested that RACK1 was upregulated in proliferating PDAC cells, together with the percentage of cells at the S phase, and was correlated with the expression of Cyclin D1. Moreover, Overexpression of RACK1 facilitated the proliferation and cell cycle progression of PDAC cells, while downregulation of RACK1 induced growth impairment, G1/S cell cycle arrest and apoptosis in PDAC cells. Silencing RACK1 decreased bcl-2 expression, increased cleaved caspase3 expression level and induced the apoptosis of PDAC cells. CONCLUSIONS: Our results suggest that RACK1 could play an important role in the tumorigenesis of PDAC and serve as a potential therapeutical target in PDAC treatment. PMID- 27498048 TI - The genomic profile of pancreatic adenocarcinoma and its relationship to metastatic disease. PMID- 27498049 TI - Patched Receptors Sense, Interpret, and Establish an Epidermal Hedgehog Signaling Gradient. AB - By using the sensitivity of single-molecule fluorescent in situ hybridization, we have precisely quantified the levels and defined the temporal and spatial distribution of Hedgehog signaling activity during embryonic skin development and discovered that there is a Hedgehog signaling gradient along the proximal-distal axis of developing hair follicles. To explore the contribution of Hedgehog receptors Ptch1 and Ptch2 in establishing the epidermal signaling gradient, we quantitated the level of pathway activity generated in Ptch1- and Ptch1;Ptch2 deficient skin and defined the contribution of each receptor to regulation of the levels of Hedgehog signaling identified in wild-type skin. Moreover, we show that both the cellular phenotype and level of pathway activity featured in Ptch1;Ptch2 deficient cells faithfully recapitulates the Peak level of endogenous Hedgehog signaling detected at the base of developing follicles, where the concentration of endogenous Shh is predicted to be highest. Taken together, these data show that both Ptch1 and Ptch2 play a crucial role in sensing the concentration of Hedgehog ligand and regulating the appropriate dose-dependent response. PMID- 27498050 TI - A Co-Drug of Butyric Acid Derived from Fermentation Metabolites of the Human Skin Microbiome Stimulates Adipogenic Differentiation of Adipose-Derived Stem Cells: Implications in Tissue Augmentation. AB - We show that Staphylococcus epidermidis, a commensal bacterium in the human skin microbiome, produces short-chain fatty acids by glycerol fermentation that can induce adipogenesis. Although the antimicrobial and anti-inflammatory activities of short-chain fatty acids have been previously well characterized, little is known about the contribution of short-chain fatty acids to the adipogenic differentiation of adipose-derived stem cells (ADSCs). We show that ADSCs differentiated into adipocytes and accumulated lipids in the cytoplasm when cultured with butyric acid, a principal short-chain fatty acid in the fermentation metabolites of S. epidermidis. Additionally, a co-drug, butyric acid 2-(2-butyryloxyethoxy) ethyl ester (BA-DEG-BA), released active butyric acid when it was intradermally injected into mouse ears and induced ADSC differentiation, characterized by an increased expression of cytoplasmic lipids and perilipin A. The BA-DEG-BA-induced adipogenic differentiation was mediated via peroxisome proliferator-activated receptor gamma. Furthermore, intradermal injection of ADSCs along with BA-DEG-BA into mouse ears markedly enhanced the adipogenic differentiation of ADSCs, leading to dermal augmentation. Our study introduces BA DEG-BA as an enhancer of ADSC adipogenesis and suggests an integral interaction between the human skin microbiome and ADSCs. PMID- 27498051 TI - [Not Available]. PMID- 27498052 TI - Esthetic management of anterior dental anomalies: A clinical case. AB - Many types of dental abnormality can be observed in the anterior sectors, where they can cause genuine esthetic problems for our patients. While conventional prosthetic treatments offer the best solutions in terms of esthetic result and durability, they involve the sacrifice of significant quantities of mineralized dental material and cannot be undertaken before the periodontal tissues are mature. Other less invasive alternatives should be envisaged as transitional, or sometimes even permanent, solutions for the management of these anomalies in children and adolescents. This article discusses these options and presents a clinical case where composite resin veneers and microabrasion of the enamel were used to treat dental agenesis and enamel dysplasia. PMID- 27498053 TI - The neurotrophin receptor p75 mediates gp120-induced loss of synaptic spines in aging mice. AB - Human immunodeficiency virus 1 and its envelope protein gp120 reduce synaptodendritic complexity. However, the mechanisms contributing to this pathological feature are still not understood. The proneurotrophin brain-derived neurotrophic factor promotes synaptic simplification through the activation of the p75 neurotrophin receptor (p75NTR). Here, we have used gp120 transgenic (gp120tg) mice to investigate whether p75NTR has a role in gp120-mediated neurotoxicity. Old (~10 months) gp120tg mice exhibited an increase in proneurotrophin brain-derived neurotrophic factor levels in the hippocampus as well as a decrease in the number of dendritic spines when compared to age-matched wild type. These effects were not observed in 3- or 6-month-old mice. To test if the reduction in spine density and morphology is caused by the activation of p75NTR, we crossed gp120tg mice with p75NTR null mice. We found that deletion of only 1 copy of the p75NTR gene in gp120tg mice is sufficient to normalize the number of hippocampal spines, strongly suggesting that the neurotoxic effect of gp120 is mediated by p75NTR. These data indicate that p75NTR antagonists could provide an adjunct therapy against synaptic simplification caused by human immunodeficiency virus 1. PMID- 27498054 TI - Preservation of cell-survival mechanisms by the presenilin-1 K239N mutation may cause its milder clinical phenotype. AB - Presenilin 1 (PSEN1) mutations are the main cause of monogenic Alzheimer's disease. We studied the functional effects of the mutation K239N, which shows incomplete penetrance at the age of 65 years and compared it with the more aggressive mutation E120G. We engineered stable cell lines expressing human PSEN1 wild type or with K239N or E120G mutations. Both mutations induced dysfunction of gamma-secretase in the processing of amyloid-beta protein precursor, leading to an increase in the amyloid beta42/amyloid beta40 ratio. Analysis of homeostatic mechanisms showed that K239N induced lower basal and hydrogen peroxide induced intracellular levels of reactive oxygen species than E120G. Similarly, K239N induced lower vulnerability to apoptosis by hydrogen peroxide injury than E120G. Accordingly, the proapoptotic signaling pathways c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase maintained PSEN1-mediated negative regulation in K239N but not in E120G-bearing cells. Furthermore, the activation of the prosurvival signaling pathways mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/Akt was lower in E120G-bearing cells. Therefore, preservation of mechanisms regulating cell responses independent of amyloid-beta protein precursor processing may account for the milder phenotype induced by the PSEN1 K239N mutation. PMID- 27498055 TI - Impact of the high-frequency cutoff of bandpass filtering on ECG quality and clinical interpretation: A comparison between 40Hz and 150Hz cutoff in a surgical preoperative adult outpatient population. AB - BACKGROUND: In 1990 the American Heart Association (AHA) established a standard 0.05 to 150Hz bandwidth for the routine recording of 12-lead electrocardiograms (ECGs). However, subsequent studies have indicated a very high prevalence of deviations from the recommended cutoffs. OBJECTIVE: This prospective observational study investigates the impact of 40Hz compared to 150Hz high frequency cutoffs on ECG quality and clinical interpretation in a single-center surgical outpatient population. METHODS: 1582 consecutive adult patients underwent two standard 12-lead ECG tracings using different high-frequency cutoffs (40Hz and 150Hz). Two blinded cardiologists randomly reviewed and interpreted the recordings according to pre-defined parameters (PR and ST segment, Q and T wave abnormalities). An arbitrary score, ranging from 1 to 3, was established to evaluate the perceived quality of the recordings and the non interpretable ECGs were noted. The tracings were then matched to compare interpretations between 40 and 150Hz filters. RESULTS: A 40Hz high-frequency cutoff resulted in an increased rate of optimal quality ECGs compared to the 150Hz cutoff (93.4% vs 54.6%; p<0.001) and a lower rate of non-interpretable traces (0.25% vs 4.80%; p<0.001). Analyzing the morphologic parameters, no significant differences between the filter settings were found, except for a higher incidence of the J-point elevation in the 40Hz high-frequency cutoff (p=0.007) and a higher incidence of left ventricular hypertrophy in the 150Hz high-frequency cutoff (7.4% vs 5.4%, p<0.001). The latter was noted only in ECGs with borderline QRS amplitudes (between 3.3 and 3.7mV; p<0.001). CONCLUSION: Despite current recommendations, the large deviation from standard high-frequency cutoff in clinical practice does not seem to significantly affect ECG clinical interpretation and a 40Hz high-frequency cutoff of the band-pass filtering may be acceptable in a low risk population, allowing for a better quality of tracings. PMID- 27498056 TI - Endovascular treatment of atherosclerotic popliteal artery disease based on dynamic angiography findings. AB - OBJECTIVE: To evaluate efficacy, safety, and midterm patency of endovascular treatment of obstructive popliteal artery (PA) disease. METHODS: A retrospective evaluation of patients with atherosclerotic PA disease who underwent percutaneous transluminal balloon angioplasty and provisional stent, based on both conventional and dynamic angiographies, was conducted from June 2011 to June 2014. Forty-three patients were included in the study, and most patients had limited surgical revascularization options. Demographic characteristics, angiographic findings, interventional data, complications, vessel patency, limb salvage rates, and survival rates were analyzed. RESULTS: The median lesion length was 5 cm with 72.1% having total occlusions. The second popliteal segment (P2) was involved most frequently (60.5%, n = 26). Critical limb ischemia was present in 69.8%. The technical success rate was 92.9% (42/43 limbs), with 29 cases requiring adjunctive nitinol stents after balloon angioplasty (47.6% based on conventional angiography, 21.4% based on dynamic angiography, and 4.8% additional stents based on dynamic angiography). Complications included thromboembolism (2.3%), perforation (2.3%), pseudoaneurysm (2.3%), and myocardial infarction (2.3%). Stent fracture was present in three cases (7.1%) during the mean follow-up period of 18.3 months. The baseline ankle-brachial index significantly improved after the intervention, from 0.49 +/- 0.11 to 0.92 +/- 0.14 (P < .01). The Rutherford-Becker class decreased from 3.95 +/- 0.76 to 1.76 +/- 0.95 (P < .01) at 12 months. The 1-year primary, primary-assisted, and secondary patency rates were 75.2% +/- 6.8%, 82.4% +/- 6.0%, and 89.9% +/- 4.8%, respectively. The limb salvage and amputation-free survival rates at 12 months were 91.6% and 87.0%, respectively. CONCLUSIONS: Balloon angioplasty with a provisional stent based on dynamic angiography is a feasible, safe, and effective therapy for patients with obstructive PA disease. Although the occurrence of stent fracture is still inevitable, patients with critical limb ischemia who have limited surgical options may get more benefits from the endovascular treatment of PA obstructive diseases. PMID- 27498057 TI - Classifying nonsuicidal overdoses: Nonsuicidal self-injury, suicide attempts, or neither? AB - Self-injurious behaviors (SIBs) are leading causes of death and injury. Unfortunately, disagreement regarding whether and how to classify suicidal and nonsuicidal SIBs has contributed to their misclassification, likely hindering clinical care and impeding scientific progress. The present study utilized a data driven approach to facilitate classification and measurement of three forms of SIBs, with a particular focus on one with scant clinical and scientific attention: nonsuicidal overdoses (i.e. intentional overdoses where the person states that they had no intention of dying from the overdose). Results from this study demonstrated that nonsuicidal overdoses were similar to suicide attempts in terms of age of onset, and similar to nonsuicidal self-injury (NSSI) in terms of suicidal thoughts and desire to die when engaging in these behaviors. Nonsuicidal overdoses were unique from NSSI and suicide attempts in terms of the reported likelihood of dying from the behavior. The present study highlighted that current definitions for nonsuicidal behaviors (including requirements that the person has zero intent to die) may not accurately represent people's intent when engaging in these behaviors. Additionally, the present study highlighted that empirical analysis of SIBs can provide important insights for classification of SIBs. PMID- 27498058 TI - Retrieval and classification of food images. AB - Automatic food understanding from images is an interesting challenge with applications in different domains. In particular, food intake monitoring is becoming more and more important because of the key role that it plays in health and market economies. In this paper, we address the study of food image processing from the perspective of Computer Vision. As first contribution we present a survey of the studies in the context of food image processing from the early attempts to the current state-of-the-art methods. Since retrieval and classification engines able to work on food images are required to build automatic systems for diet monitoring (e.g., to be embedded in wearable cameras), we focus our attention on the aspect of the representation of the food images because it plays a fundamental role in the understanding engines. The food retrieval and classification is a challenging task since the food presents high variableness and an intrinsic deformability. To properly study the peculiarities of different image representations we propose the UNICT-FD1200 dataset. It was composed of 4754 food images of 1200 distinct dishes acquired during real meals. Each food plate is acquired multiple times and the overall dataset presents both geometric and photometric variabilities. The images of the dataset have been manually labeled considering 8 categories: Appetizer, Main Course, Second Course, Single Course, Side Dish, Dessert, Breakfast, Fruit. We have performed tests employing different representations of the state-of-the-art to assess the related performances on the UNICT-FD1200 dataset. Finally, we propose a new representation based on the perceptual concept of Anti-Textons which is able to encode spatial information between Textons outperforming other representations in the context of food retrieval and Classification. PMID- 27498059 TI - Sclerostin expression in skeletal sarcomas. AB - Sclerostin (SOST) is an extracellular Wnt signaling antagonist which negatively regulates bone mass. Despite this, the expression and function of SOST in skeletal tumors remain poorly described. Here, we first describe the immunohistochemical staining pattern of SOST across benign and malignant skeletal tumors with bone or cartilage matrix (n=68 primary tumors). Next, relative SOST expression was compared to markers of Wnt signaling activity and osteogenic differentiation across human osteosarcoma (OS) cell lines (n=7 cell lines examined). Results showed immunohistochemical detection of SOST in most bone forming tumors (90.2%; 46/51) and all cartilage-forming tumors (100%; 17/17). Among OSs, variable intensity and distribution of SOST expression were observed, which highly correlated with the presence and degree of neoplastic bone. Patchy SOST expression was observed in cartilage-forming tumors, which did not distinguish between benign and malignant tumors or correlate with regional morphologic characteristics. Finally, SOST expression varied widely between OS cell lines, with more than 97-fold variation. Among OS cell lines, SOST expression positively correlated with the marker of osteogenic differentiation alkaline phosphatase and did not correlate well with markers of Wnt/beta-catenin signaling activity. In summary, SOST is frequently expressed in skeletal bone- and cartilage-forming tumors. The strong spatial correlation with bone formation and the in vitro expression patterns are in line with the known functions of SOST in nonneoplastic bone, as a feedback inhibitor on osteogenic differentiation. With anti-SOST as a potential therapy for osteoporosis in the near future, its basic biologic and phenotypic consequences in skeletal tumors should not be overlooked. PMID- 27498060 TI - Overexpression of DIXDC1 correlates with enhanced cell growth and poor prognosis in human pancreatic ductal adenocarcinoma. AB - Disheveled-axin (DIX) domain containing 1 (DIXDC1), a protein containing a coiled coil domain and a DIX domain, is involved in the progression of multiple cancers. However, the role of DIXDC1 in human pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this study, we investigated the role and prognostic value of DIXDC1 in the development of human PDAC. Western blot analysis revealed that DIXDC1 was highly expressed in PDAC tissues and cell lines. Immunohistochemistry on 165 paraffin-embedded sections showed that high expression of DIXDC1 was significantly correlated with tumor size (P = .002), histological differentiation (P = .001), tumor node metastasis (TNM) stage (P = .001), and the proliferation marker Ki-67 (P = .000). Importantly, Kaplan-Meier analysis revealed that high expression of DIXDC1 was obviously correlated with worsened overall survival (P < .001). In vitro, using serum starvation-refeeding experiments, our results suggested that DIXDC1 was up-regulated in proliferating PDAC cells, together with the percentage of cells at the S phase, and was correlated with the expression of cyclin D1. In addition, depletion of DIXDC1 decreased PCNA and cyclin D1 levels. Accordingly, CCK-8, colony formation, and flow cytometry analyses revealed that knocking down DIXDC1 induced growth impairment and G1/S cell cycle arrest in PDAC cells, while overexpression of DIXDC1 led to accelerated cell proliferation and cell cycle progression. On the basis of these results, we propose that DIXDC1 could play an important role in the tumorigenesis of PDAC and serve as a potential therapeutical target to prevent PDAC progression. PMID- 27498061 TI - Characterization of the leiomyomatous variant of myofibroblastoma: a rare subset distinct from other smooth muscle tumors of the breast. AB - Mammary myofibroblastoma is a benign spindle cell tumor that can show variable morphologic patterns and lines of differentiation. Myofibroblastoma belongs to a family of CD34-positive tumors with similar morphology that show a deletion of 13q14, which includes RB1 and FOXO1A genes. A subset of these tumors demonstrates distinct smooth muscle differentiation. We aimed to characterize 4 cases of the leiomyomatous variant of myofibroblastoma arising in the breast by clinicopathological, immunohistochemical, and molecular means. All 4 examples arose in women aged 41 to 62 years (median, 46.5 years). Tumors ranged in size from 1.7 to 2.5 cm (median, 2.2 cm). Morphologically, all tumors were characterized by bundles of smooth muscle cells with elongated cigar-shaped nuclei and eosinophilic cytoplasm. All 4 tumors showed diffuse positive staining with desmin, caldesmon, smooth muscle actin, estrogen receptor, and Bcl-2. CD34 staining was diffusely positive in 2 cases, was weak and patchy in 1 case, and was negative in 1 case. Two (50%) of 4 tumors showed deletion of RB1 by fluorescence in situ hybridization. Loss of Rb staining was seen in 1 tumor with RB1 deletion by fluorescence in situ hybridization, whereas intact Rb staining was observed in 1 nondeleted case studied. In conclusion, this rare variant of myofibroblastoma is a distinct subgroup of tumors among an already uncommon category of (smooth muscle) breast tumors. Some reported examples of "parenchymal leiomyoma" may represent the leiomyomatous variant of myofibroblastoma. PMID- 27498062 TI - Renal oncocytoma with vascular invasion: a series of 22 cases. AB - Renal oncocytomas are benign neoplasms that are often excised, as clinically they cannot be distinguished with certainty from renal cell carcinoma. One of the least common findings in oncocytomas is vascular invasion, and their behavior is not well characterized with only reports of isolated examples and smaller case series. Whether vascular invasion is acceptable for the diagnosis of oncocytoma still remains controversial, even amongst genitourinary pathologists with expertise in renal tumor pathology. Of 1474 cases of renal oncocytoma identified at 3 large medical centers, 22 (1.5%) had vascular invasion. Patients included 12 men and 10 women with an average age at diagnosis of 67.5 years (range, 48-91 years). Thirteen cases showed large vessel invasion, and the remainder involved medium or small vessels. Tumor was grossly visible in the renal vein in 2 cases. Clinical data were available on 16 of the 22 cases with an average follow-up time of 29.9 months (range, 7.5-94.5 months). Of the cases with clinical follow-up, all but one individual was alive. All living individuals were free of recurrence or metastatic disease at the time of last follow-up. Our cohort showed no metastasis or recurrence and overall survival of 94.7% at 2.5 years following diagnosis, supporting the finding that vascular invasion does not alter the favorable prognosis of oncocytoma. The presence of vascular invasion should not lead to any uncertainty about the diagnosis in an otherwise typical oncocytoma. PMID- 27498063 TI - Collagen type III alpha1 as a useful diagnostic immunohistochemical marker for fibroepithelial lesions of the breast. AB - Phyllodes tumors (PTs) of the breast constitute an uncommon group of fibroepithelial neoplasms that are classified into benign, borderline, and malignant categories based on a constellation of histologic characteristics including cytologic atypia, mitotic count, degree of stromal cellularity, stromal overgrowth, and microscopic margins. Accurately and reproducibly differentiating these tumors is a long-standing diagnostic challenge. In addition, the distinction between benign PT from cellular fibroadenoma (FA) is especially difficult because of overlapping microscopic features. We have previously shown differential expression of various collagens, including collagen type III alpha1 (Col3A) in breast carcinomas. In this study, we evaluated clinicopathological characteristics of 95 cases of fibroepithelial lesions including 56 PTs and 39 FAs (25 cellular FA, 14 typical FA) and correlated them with the immunohistochemical staining pattern for Col3A. We found that stromal Col3A expression was significantly increased in PTs when compared with FAs (P < .0001). Among the PT groups, there was significantly increased expression from benign tumors through borderline to malignant tumors. High Col3A expression was associated with PT type, irregular margin status, and high mitotic activity. A distinct periductal cuffing pattern of Col3A staining was unique to PTs and absent in FAs. These findings suggest that Col3A can be a potential adjunct marker for both differentiating FA from PT and assessing malignant potential in PTs. PMID- 27498064 TI - Defining a new aggressiveness classification and using NFATc1 localization as a prognostic factor in cherubism. AB - Cherubism is a rare genetic disease characterized by bilateral giant cell reparative granuloma of the jaws consisting of a fibrotic stroma with giant multinucleated cells (GMCs) and osteoclastic features. Cherubism severity is highly variable, and recurrence after surgery is the most important risk. Currently, there are no prognostic indicators. The aims of this study were to evaluate the osteoclastogenesis phenotype by histologic examination of nuclear factor of activated T cells 1 (NFATc1) localization and tartrate-resistant acid phosphatase (TRAP) activity and to correlate the results to disease aggressiveness to define prognostic indicators. Based on cherubism evolution 1 year after surgery, 3 classes of cherubism aggressiveness were identified: mild (group A), moderate (group B), and severe (group C). Histologically, in grade A and B cherubism lesions, GMCs were negative for both TRAP activity and NFATc1 nuclear localization. In contrast, in grade C cherubism lesions, GMCs were all positive for TRAP activity and NFATc1 nuclear localization and displayed osteoclast-like features. Other histopathologic findings were not different among the 3 groups. Our results establish that TRAP activity and NFTAc1 nuclear localization are associated with aggressive cherubism and therefore could be added to routine pathologic examination to aid in prognosis and management of the disease. The finding of NFATc1 nuclear localization in aggressive tumors supports the addition of anticalcineurin treatment to the therapeutic arsenal for cherubism. PMID- 27498065 TI - Influence of the sickness benefit reform on sickness absence. AB - OBJECTIVES: To analyse short-term changes in sick-leave use after the implementation of sick-pay cut policy in Estonia on July 1, 2009. METHODS: The study is based on all sick-leave episodes of 20-64-year-old employees registered by the Estonian Health Insurance Fund in 2008 and 2011, which covers 227,981 persons in 2008 and 152,102 persons in 2011. Population- and absentee-level sickness absence measures were used to describe sickness absence. Multiple logistic regression analysis was performed to explore associations between sick pay cut and sickness absence measures. RESULTS: The main impact of the reform was that the total number of sick-leave episodes and sick-listed persons decreased by one third. The number of sick leave episodes lasting 4-20days decreased by half whereas the change in shorter and longer episodes was negligible. Chances of recurrent sick-leave lowered significantly. The mean duration of sick-leave episodes lengthened in a positive correlation with age. CONCLUSION: At the population level sickness absence decreased after the sick-pay cut, which was one of the goals of the reform. The sickness absence of absentees with long-lasting illnesses did not change, but people with shorter illnesses adapted their sickness absence behaviour. It indicates that health outcomes of people whose absence has decreased due to policy changes need to be followed. PMID- 27498067 TI - Computing disease incidence, prevalence and comorbidity from electronic medical records. AB - Electronic medical records (EMR) represent a convenient source of coded medical data, but disease patterns found in EMRs may be biased when compared to surveys based on sampling. In this communication we draw attention to complications that arise when using EMR data to calculate disease prevalence, incidence, age of onset, and disease comorbidity. We review known solutions to these problems and identify challenges for future work. PMID- 27498066 TI - Let's get Physiqual - An intuitive and generic method to combine sensor technology with ecological momentary assessments. AB - The emergence of wearables and smartwatches is making sensors a ubiquitous technology to measure daily rhythms in physiological measures, such as movement and heart rate. An integration of sensor data from wearables and self-report questionnaire data about cognition, behaviors, and emotions can provide new insights into the interaction of mental and physiological processes in daily life. Hitherto no method existed that enables an easy-to-use integration of sensor and self-report data. To fill this gap, we present 'Physiqual', a platform for researchers that gathers and integrates data from commercially available sensors and service providers into one unified format for use in Ecological Momentary Assessments (EMA) or Experience Sampling Methods (ESM), and Quantified Self (QS). Physiqual currently supports sensor data provided by two well-known service providers and therewith a wide range of smartwatches and wearables. To demonstrate the features of Physiqual, we conducted a case study in which we assessed two subjects by means of data from an EMA study combined with sensor data as aggregated and exported by Physiqual. To the best of our knowledge, the Physiqual platform is the first platform that allows researchers to conveniently aggregate and integrate physiological sensor data with EMA studies. PMID- 27498068 TI - Boosting backpropagation algorithm by stimulus-sampling: Application in computer aided medical diagnosis. AB - Neural networks (NNs), in general, and multi-layer perceptron (MLP), in particular, represent one of the most efficient classifiers among the machine learning (ML) algorithms. Inspired by the stimulus-sampling paradigm, it is plausible to assume that the association of stimuli with the neurons in the output layer of a MLP can increase its performance. The stimulus-sampling process is assumed memoryless (Markovian), in the sense that the choice of a particular stimulus at a certain step, conditioned by the whole prior evolution of the learning process, depends only on the network's answer at the previous step. This paper proposes a novel learning technique, by enhancing the standard backpropagation algorithm performance with the aid of a stimulus-sampling procedure applied to the output neurons. The network uses the observable behavior that varies throughout the training process by stimulating the correct answers through corresponding rewards/penalties assigned to the output neurons. The proposed model has been applied in computer-aided medical diagnosis using five real-life breast cancer, colon cancer, diabetes, thyroid, and fetal heartbeat databases. The statistical comparison to well-established ML algorithms proved beyond doubt its efficiency and robustness. PMID- 27498069 TI - A vision based proposal for classification of normal and abnormal gait using RGB camera. AB - Human gait is mainly related to the foot and leg movements but, obviously, the entire motor system of the human body is involved. We hypothesise that movement parameters such as dynamic balance, movement harmony of each body element (arms, head, thorax...) could enable us to finely characterise gait singularities to pinpoint potential diseases or abnormalities in advance. Since this paper deals with the preliminary problem pertaining to the classification of normal and abnormal gait, our study will revolve around the lower part of the body. Our proposal presents a functional specification of gait in which only observational kinematic aspects are discussed. The resultant specification will confidently be open enough to be applied to a variety of gait analysis problems encountered in areas connected to rehabilitation, sports, children's motor skills, and so on. To carry out our functional specification, we develop an extraction system through which we analyse image sequences to identify gait features. Our prototype not only readily lets us determine the dynamic parameters (heel strike, toe off, stride length and time) and some skeleton joints but also satisfactorily supplies us with a proper distinction between normal and abnormal gait. We have performed experiments on a dataset of 30 samples. PMID- 27498070 TI - Optical discrimination of benign and malignant oral tissue using Z-scan technique. AB - A new optical method to discriminate benign and malignant oral tissue is reported. Twenty four tissue biopsy of patients tumor have been prepared in standard method without coloring process. The CW He-Ne laser beam interrogated the samples in optical setup. Linear absorption of tissues in laser wavelength measured and nonlinear behavior of tissue biopsies has been investigated by Z scan setup. We used some simple optical instruments to focus on microsize region of biolayer to investigate less number of cells and to take repeatable test. Results show that the malignant samples have more attenuation than benign samples. Furthermore nonlinear refractive index (n2) of malignant biolayers has positive sign and n2 of benign biopsies has negative sign with the 10-8(cm2/W) order of magnitude. So this optical method may be used to discriminate malignant from benign tissues. PMID- 27498071 TI - Expression of the K+/Cl- cotransporter, KCC2, in cerebellar Purkinje cells is regulated by group-I metabotropic glutamate receptors. AB - The neuronal K+/Cl- symporter, KCC2, shapes synaptic responses mediated by Cl- permeant GABAA receptors. Moving from the evidence that excitatory neurotransmission drives changes in KCC2 expression in cerebellar neurons, we studied the regulation of KCC2 expression by group-I metabotropic glutamate (mGlu) receptors in the cerebellum of adult mice. Mice lacking mGlu5 receptors showed a large reduction in cerebellar KCC2 protein levels and a loss of KCC2 immunoreactivity in Purkinje cells. Similar changes were seen in mice treated with the mGlu5 receptor antagonist, MPEP, whereas treatment with the mGlu5 receptor positive allosteric modulator (PAM), VU0360172, increased KCC2 expression. In contrast, pharmacological inhibition of mGlu1 receptors with JNJ16259685 enhanced cerebellar KCC2 protein levels and KCC2 immunoreactivity in Purkinje cells, whereas treatment with the mGlu1 receptor PAM, RO0711401, reduced KCC2 expression. To examine whether the reduction in KCC2 expression caused by the absence or the inhibition of mGlu5 receptors could affect GABAergic transmission, we performed electrophysiological and behavioral studies. Recording of extracellular action potentials in Purkinje cells showed that the inhibitory effect of the GABAA receptor agonist, muscimol, was lost in cerebellar slices prepared from mGlu5-/- mice or from mice treated systemically with MPEP, in line with the reduction in KCC2 expression. Similarly, motor impairment caused by the GABAA receptor PAM, diazepam, was attenuated in mice pre-treated with MPEP. These findings disclose a novel function of mGlu5 receptors in the cerebellum and suggest that mGlu5 receptor ligands might influence GABAergic transmission in the cerebellum and affect motor responses to GABA-mimetic drugs. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'. PMID- 27498072 TI - Impact of baseline body mass index status on glucose lowering and weight change during sitagliptin treatment for type 2 diabetics. AB - AIMS: This study was designed to evaluate the efficacy of sitagliptin in Taiwanese diabetic subjects with different baseline BMI status. METHODS: This was a single-center, hospital-based, retrospective chart review in subjects (n=1874) with type 2 diabetes who received sitagliptin. Subjects were classified into subgroups depending upon their baseline BMI by Taiwan national weight classification: normal (BMI<24kg/m(2)) (n=504), overweight (BMI: 24-27kg/m(2)) (n=615), and obese (BMI?27kg/m(2)) (n=755). Changes in HbA1c and weight were evaluated over a 12month treatment period. RESULTS: For all three groups, the HbA1c levels declined over the first three months by about 8%, and subsequently plateaued for the next nine months. Obese subjects were slower in reducing HbA1c compared with normal and overweight subjects (P<0.05), but at nine months the reduction was similar across groups. Mean body weight increased over the first nine months of sitagliptin therapy in subjects with normal BMI (57.12-58.30kg), but there was no change in mean body weight in the overweight group. After three months the obese groups had significantly greater loss in body weight compared with the normal group. CONCLUSIONS: Baseline BMI status may influence the reduction of HbA1c levels within the first six months of sitagliptin therapy and affect weight change after three months. Being obese was associated with an initial lag in HbA1c reduction and greater weight loss compared with normal and overweight subjects. PMID- 27498073 TI - Effects of delay and probability combinations on discounting in humans. AB - To determine discount rates, researchers typically adjust the amount of an immediate or certain option relative to a delayed or uncertain option. Because this adjusting amount method can be relatively time consuming, researchers have developed more efficient procedures. One such procedure is a 5-trial adjusting delay procedure, which measures the delay at which an amount of money loses half of its value (e.g., $1000 is valued at $500 with a 10-year delay to its receipt). Experiment 1 (n=212) used 5-trial adjusting delay or probability tasks to measure delay discounting of losses, probabilistic gains, and probabilistic losses. Experiment 2 (n=98) assessed combined probabilistic and delayed alternatives. In both experiments, we compared results from 5-trial adjusting delay or probability tasks to traditional adjusting amount procedures. Results suggest both procedures produced similar rates of probability and delay discounting in six out of seven comparisons. A magnitude effect consistent with previous research was observed for probabilistic gains and losses, but not for delayed losses. Results also suggest that delay and probability interact to determine the value of money. Five trial methods may allow researchers to assess discounting more efficiently as well as study more complex choice scenarios. PMID- 27498075 TI - Sofosbuvir plus daclatasvir with or without ribavirin for chronic hepatitis C infection: Impact of drug concentration on viral load decay. AB - BACKGROUND: Sofosbuvir (SOF) plus daclatasvir (DCV) with or without ribavirin is one of the currently recommended treatment option for chronic hepatitis C. AIMS: Our objectives were to identify factors associated with SOF/DCV plasma concentrations [C] variations and to evaluate their impact on viral kinetics. METHODS: 130 consecutive HCV patients initiating SOF/DCV therapy with or without ribavirin were enrolled. Clinical, biological, virological and pharmacological data were collected at baseline, at week 4, 8, 12, and 24 of therapy and 12 weeks after the end of therapy. RESULTS: Mean age was 57 years, 68% of patients were males, 69% were infected by HCV genotype 1 and cirrhosis was observed in 76% of patients. Multivariate analysis showed that higher SOF [C] and DCV [C] during treatment were associated with eGFR impairment and absence of cirrhosis. We found a significant correlation between the magnitude of HCV viral load decrease from day 0 to week 4 and a higher SOF [C] at week 4 (p=0.032) and a higher DCV [C] at week 8 (p=0.013). CONCLUSIONS: Pharmacological monitoring showed significant associations between elevated SOF or DCV [C] and absence of cirrhosis, decreased eGFR and viral load decrease during the first month of treatment. PMID- 27498074 TI - Missed treatment in an Italian HBV infected patients cohort: HBV RER. AB - BACKGROUND AND AIMS: Very little is known about the access to treatment for Chronic Hepatitis B in the real clinical practice and the characteristics of the patients who do not receive antiviral therapy. METHODS: HBV-RER is an observational multicenter network that collected data of patients with HBV infection during a 3 years observational period (2009-2012). RESULTS: Among 2527 HBsAg positive patients, 1099 were never treated (NT); only 280 were included in the analysis due to different exclusion causes A minority was HBeAg-positive. The median age was 42. At liver biopsy most patients had Metavir score of F0-F1. Univariate analysis between 280 NT patients and the 290 naive to treatment showed that NT patients were mostly female (P=0.002), not Italian (P=0.044), younger (P<0.001). Metavir score was lower in NT (P0.002), such as the Fib4 score (P<0.001). HBV DNA level was significantly higher in NT. At multivariate analysis, independent variables associated with no-treatment were younger age, female gender, Metavir score F0-F1, Fib4 lower than 1.6 and lower blood level of HBV-DNA. CONCLUSIONS: There is a large number of patients eligible to treatment who do not receive it. A younger age and a less severe disease seem to be associated to deferral of treatment. PMID- 27498076 TI - Inhibition of late sodium current attenuates ionic arrhythmia mechanism in ventricular myocytes expressing LaminA-N195K mutation. AB - BACKGROUND: Lamin A and C are nuclear filament proteins encoded by the LMNA gene. Mutations in the LMNA gene cause many congenital diseases known as laminopathies, including Emery-Dreifuss muscular dystrophy, Hutchinson-Gilford progeria syndrome, and familial dilated cardiomyopathy (DCM) with conduction disease. A missense mutation (N195K) in the A-type lamins results in familial DCM and sudden arrhythmic death. OBJECTIVE: The purpose of this study was to investigate the ion current mechanism of arrhythmia and DCM caused by the LaminA-N195K variant. METHODS: A homozygous mouse line expressing the Lmna-N195K mutation (LmnaN195K/N195K) that exhibited arrhythmia, DCM, and sudden death was used. Using whole cell patch-clamp technique, we measured action potential duration (APD), Na+ currents (INa) in ventricular myocytes isolated from LmnaN195K/N195K, and wild-type mice. RESULTS: Both peak and late INa were significantly (P <.05) increased in LmnaN195K/N195K ventricular myocytes. Similarly, LmnaN195K/N195K ventricular myocytes exhibited significant (P <.005) prolongation of APD (time to 50% [APD50] and 90% [APD90] repolarization) and triggered activity. Acute application of ranolazine inhibited late INa, shortened APD, and abolished triggered activity in LmnaN195K/N195K ventricular myocytes. CONCLUSION: Inhibition of late INa may be an effective therapy in preventing arrhythmia in patients with LmnaN195K mutation-related DCM. PMID- 27498077 TI - Risk stratification in Brugada syndrome: Where is the finish line? PMID- 27498078 TI - The search for links between atrial fibrillation pathogenesis and ablation outcomes. PMID- 27498079 TI - Synchronous ventricular pacing with direct capture of the atrioventricular conduction system: Functional anatomy, terminology, and challenges. AB - Right ventricular apical pacing is associated with an increased incidence of heart failure, atrial fibrillation, and overall mortality. As a result, pacing the ventricles in a manner that closely mimics normal AV conduction with an intact His-Purkinje system has been explored. Recently, the sustainable benefits of selective His-bundle stimulation have been demonstrated and proposed as the preferred method of ventricular stimulation for appropriate patients. Ideally, conduction system pacing should be selective without myocardial capture, overcome distal bundle branch block when present, and not compromise tricuspid valve function. Contemporary literature on conduction system pacing is confusing largely because of inconsistent terminology and, at times, anatomically inaccurate terms used interchangeably for nonsynonymous anatomic sites. In this review, we discuss the functional anatomy of AV conduction access with specific emphasis on terminology, relationship to the membranous septum, tricuspid valve tissue, and proximity to atrial or ventricular myocardium. The potential benefits of each specific site as well as associated unique difficulties with those sites are described. PMID- 27498080 TI - Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. AB - BACKGROUND: A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance. METHODS: In this prospective phase 2 trial, we enrolled patients with treatment naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing. FINDINGS: Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38.1 months (IQR 29.4-48.9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14.9 months (95% CI 10.6-25.0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0.0403) and higher numbers of metastatic disease sites (p=0.0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma. INTERPRETATION: A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach. FUNDING: None. PMID- 27498081 TI - Delayed systemic treatment in metastatic renal-cell carcinoma. PMID- 27498082 TI - Tools for opening new chapters in the book of Treponema pallidum evolutionary history. AB - Treponema pallidum infections causing yaws disease and venereal syphilis are globally widespread in human populations, infecting hundreds of thousands and millions annually respectively; endemic syphilis is much less common, and pinta has not been observed in decades. We discuss controversy surrounding the origin, evolution and history of these pathogens in light of available molecular and anthropological evidence. These bacteria (or close relatives) seem to affect many wild African nonhuman primate (NHP) species, though to date only a single NHP Treponema pallidum genome has been published, hindering detection of spillover events and our understanding of potential wildlife reservoirs. Similarly, only ten genomes of Treponema pallidum infecting humans have been published, impeding a full understanding of their diversity and evolutionary history. Research efforts have been hampered by the difficulty of culturing and propagating Treponema pallidum. Here we highlight avenues of research recently opened by the coupling of hybridization capture and next-generation sequencing. We present data generated with such an approach suggesting that asymptomatic bones from NHP occasionally contain enough treponemal DNA to recover large fractions of their genomes. We expect that these methods, which naturally can be applied to modern biopsy samples and ancient human bones, will soon considerably improve our understanding of these enigmatic pathogens and lay rest to old yet unresolved controversies. PMID- 27498083 TI - Event-related potentials and cognition in Parkinson's disease: An integrative review. AB - Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD), but the nature of cognitive changes varies considerably between individuals. According to the dual-syndrome hypothesis, one cluster of patients is characterized by deficits in executive function that may be related to fronto striatal dysfunction. Other patients primarily show non-frontal cognitive impairments that progress rapidly to PD dementia (PDD). We provide a comprehensive review of event-related potential (ERP) studies to identify ERP measures substantiating the heterogeneity of cognitive impairment in PD. Our review revealed evidence for P3b and mismatch-negativity alterations in PDD, but not in non-demented PD, indicating that alterations of these ERPs constitute electrophysiological markers for PDD. In contrast, ERP correlates of executive functions, such as NoGo-P3, N2, and error(-related) negativity (Ne/ERN), appear to be attenuated in non-demented PD patients in a dopamine-dependent manner. Hence, ERP measures confirm and yield distinct electrophysiological markers for the heterogeneity of cognitive impairment in PD. We discuss limitations and open questions of the ERP approach and provide directions and predictions for future ERP research. PMID- 27498085 TI - Effects of combining ozone and hydrogren peroxide on tooth bleaching: A clinical study. AB - OBJECTIVES: The purpose of this study was to evaluate the efficiency of bleaching after combining ozone and 38% H2O2 in comparison to the sole use of 38% H2O2. METHODS: Consecutive 26 participants (13 males and 13 females) were recruited into this study. They were randomly allocated into 2 groups (n=13 for each group). In group 1 (test group); the participants' upper anterior teeth were treated with 38% H2O2 for 20min then the teeth were exposed to ozone for 60s (healOzone((r)) X4, KaVo Dental, Biberach, Germany). In group 2 (controls); the upper anterior teeth were treated with 20min of 38% H2O2 only. The shade of teeth was evaluated by recording the L* a* b* values and Vita Classic shades at study baseline and after bleaching in both groups. The statistically significant changes were set at P<=0.05. RESULTS: Tooth sensitivity and teeth shades were comparable between groups at study baseline (p>0.05). Controls reported more tooth sensitivity following bleaching (p<0.001). Teeth achieved better Vita shades, higher L* values (lighter shades), and lower a* and b* values (lighter shades) after bleaching in both groups (P<=0.05). However, teeth bleached with H2O2 and ozone achieved better Vita shades, higher L* values and lower a* values (lighter shades) than those bleached with H2O2 alone (p<0.001). Changes in b* values were not significantly different between groups. CONCLUSIONS: Bleaching with 38% H2O2 for 20min followed by 60s of ozone application would result in teeth with lighter shades than bleaching with 38% H2O2 alone. PMID- 27498084 TI - Sex differences in brain and behavior in adolescence: Findings from the Philadelphia Neurodevelopmental Cohort. AB - Sex differences in brain and behavior were investigated across the lifespan. Parameters include neurobehavioral measures linkable to neuroanatomic and neurophysiologic indicators of brain structure and function. Sexual differentiation of behavior has been related to organizational factors during sensitive periods of development, with adolescence and puberty gaining increased attention. Adolescence is a critical developmental period where transition to adulthood is impacted by multiple factors that can enhance vulnerability to brain dysfunction. Here we highlight sex differences in neurobehavioral measures in adolescence that are linked to brain function. We summarize neuroimaging studies examining brain structure, connectivity and perfusion, underscoring the relationship to sex differences in behavioral measures and commenting on hormonal findings. We focus on relevant data from the Philadelphia Neurodevelopmental Cohort (PNC), a community-based sample of nearly 10,000 clinically and neurocognitively phenotyped youths age 8-21 of whom 1600 have received multimodal neuroimaging. These data indicate early and pervasive sexual differentiation in neurocognitive measures that is linkable to brain parameters. We conclude by describing possible clinical implications. PMID- 27498086 TI - Structural biology of glucan phosphatases from humans to plants. AB - Glucan phosphatases are functionally conserved at the enzymatic level, dephosphorylating glycogen in animals and starch in plants. The human glucan phosphatase laforin is the founding member of the family and it is comprised of a carbohydrate binding module (CBM) domain followed by a dual specificity phosphatase (DSP) domain. Plants encode two glucan phosphatases: Starch EXcess4 (SEX4) and Like Sex Four2 (LSF2). SEX4 contains a DSP domain followed by a CBM domain, while LSF2 contains a DSP domain and lacks a CBM. This review demonstrates how glucan phosphatase function is conserved and highlights how each family member employs a unique mechanism to bind and dephosphorylate glucan substrates. PMID- 27498087 TI - The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination. AB - Cell-to-cell junctions are critical for the formation of endothelial barriers, and its disorganization is required for sprouting angiogenesis. Members of the angiomotin (AMOT) family have emerged as key regulators in the control of endothelial cell (EC) junction stability and permeability. However, the underlying mechanism by which the AMOT family is regulated in ECs remains unclear. Here we report that HECW2, a novel EC ubiquitin E3 ligase, plays a critical role in stabilizing endothelial cell-to-cell junctions by regulating AMOT-like 1 (AMOTL1) stability. HECW2 physically interacts with AMOTL1 and enhances its stability via lysine 63-linked ubiquitination. HECW2 depletion in human ECs decreases AMOTL1 stability, loosening the cell-to-cell junctions and altering subcellular localization of yes-associated protein (YAP) from cytoplasm into the nucleus. Knockdown of HECW2 also results in increased angiogenic sprouting, and this effect is blocked by depletion of ANG-2, a potential target of YAP. These results demonstrate that HECW2 is a novel regulator of angiogenesis and provide new insights into the mechanisms coordinating junction stability and angiogenic activation in ECs. PMID- 27498088 TI - Nonstatins and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Role in Non-Familial Hypercholesterolemia. AB - After maximizing statin and lifestyle adherence, some patients may benefit from additional low-density lipoprotein cholesterol (LDL-C) lowering. The potential for net benefit from added therapy can inform nonstatin decision-making. Considering patient risk and the LDL-C level on statin, the additional potential cardiovascular disease (CVD) risk reduction benefit from further lowering LDL-C depends on the magnitude of LDL-C lowering from the nonstatin. Ezetimibe is the only nonstatin shown to reduce atherosclerotic CVD events added to a statin, albeit modestly, since it modestly reduces LDL-C by about 20%. Proprotein Convertase Subtilisin-Like/Kexin Type 9 mononclonal antibodies lower LDL-Cby 45 65%, but definitive CVD outcomes and safety trials are pending. Niacin and fenofibrate do not clearly reduce CVD events in statin-treated patients, and may increase adverse events. Bile acid sequestrants have not been evaluated in CVD outcome trials in statin-treated patients, and have an excess of adverse effects. Cost also plays a role in access to nonstatin therapy. These considerations may inform shared decision-making. PMID- 27498089 TI - A discriminative feature selection approach for shape analysis: Application to fetal brain cortical folding. AB - The development of post-processing reconstruction techniques has opened new possibilities for the study of in-utero fetal brain MRI data. Recent cortical surface analysis have led to the computation of quantitative maps characterizing brain folding of the developing brain. In this paper, we describe a novel feature selection-based approach that is used to extract the most discriminative and sparse set of features of a given dataset. The proposed method is used to sparsely characterize cortical folding patterns of an in-utero fetal MR dataset, labeled with heterogeneous gestational age ranging from 26 weeks to 34 weeks. The proposed algorithm is validated on a synthetic dataset with both linear and non linear dynamics, supporting its ability to capture deformation patterns across the dataset within only a few features. Results on the fetal brain dataset show that the temporal process of cortical folding related to brain maturation can be characterized by a very small set of points, located in anatomical regions changing across time. Quantitative measurements of growth against time are extracted from the set selected features to compare multiple brain regions (e.g. lobes and hemispheres) during the considered period of gestation. PMID- 27498090 TI - A novel thiol-affinity micropipette tip method using zinc(II)-cyclen-attached agarose beads for enrichment of cysteine-containing molecules. AB - Cysteine-containing biomolecules are attractive targets in the study of thiol biology. Here we introduce a novel method for the selective enrichment of thiol containing molecules using a thiol-capture zinc(II) complex of 1,4,7,10 tetraazacyclododecane (Zn(2+)-cyclen). Recognition of N-acetylcysteine amide by Zn(2+)-cyclen has been studied by potentiometric pH titration, revealing formation of a 1:1 thiolate-bound Zn(2+)-cyclen complex with a large thiolate affinity constant of 10(6.2)M(-1) at 25 degrees C and I=0.10M (NaCl). The Zn(2+) bound thiolate anion is unexpectedly stable in aqueous solution at pH 7.8 under atmospheric conditions for a few days. These findings have contributed to the development of a convenient method for separation of thiol compounds by using a micropipette tip. A 200MUL micropipette tip containing 10MUL of hydrophilic cross linked agarose beads attached to Zn(2+)-cyclen moieties was prepared. All steps for thiol-affinity separation (binding, washing, and eluting) are conducted using aqueous buffers at room temperature. The entire separation protocol requires less than 15min per sample. We demonstrate practical example separations of cysteine containing molecules. This micropipette tip method would be used preferentially as an alternative to existing tools for reliable enrichment of thiol-containing molecules. PMID- 27498091 TI - Maternal Emotional Availability and Its Association with Maternal Psychopathology, Attachment Style Insecurity and Theory of Mind. AB - BACKGROUND/AIMS: High maternal emotional availability (EA) positively affects various domains of child development. However, the question of which factors promote or hinder maternal EA has not been investigated systematically. The present study investigated several maternal characteristics, namely maternal psychopathology, maternal attachment style insecurity, and theory of mind (ToM) as possible factors that influence maternal EA. METHODS: The sample was comprised of 56 mothers and their preschool-aged children. Half of the mothers were diagnosed with postpartum depression and or anxiety disorders according to DSM IV, and the other half were healthy controls. RESULTS: The results showed that both low maternal attachment style insecurity and high ToM skills significantly predicted maternal EA sensitivity, independently from maternal postpartum and concurrent psychopathology and education. Moreover, maternal attachment style insecurity fully mediated the link between maternal postpartum psychopathology and sensitivity. CONCLUSION: The findings suggest that maternal attachment style security can buffer negative effects of maternal psychopathology on maternal sensitivity in the mother-child interaction. PMID- 27498092 TI - Gene and Protein Expression of Chemokine (C-C-Motif) Ligand 19 is Upregulated in Unstable Carotid Atherosclerotic Plaques. AB - OBJECTIVE/BACKGROUND: The aim was to investigate the expression of genes associated with carotid plaque instability and their protein products at a local and systemic level. METHODS: Carotid plaques from 24 patients undergoing carotid endarterectomy (CEA) were classified as stable or unstable using clinical, histological, ultrasound, and transcranial Doppler criteria, and compared using whole genome microarray chips. Initial results of differentially expressed genes were validated by quantitative reverse transcriptase polymerase chain reaction in an independent group of 96 patients undergoing CEA. The protein product of genes significantly differentially expressed between patients with stable and unstable plaques were analysed by plaque immunohistochemistry and serum protein quantification by enzyme-linked immunosorbent assay on a further independent cohort. RESULTS: Expression of chemokine (c-c-motif) ligand 19 (CCL19) was significantly upregulated in plaques from patients with clinically unstable disease (p < .001). Cathepsin G expression was upregulated in histologically unstable plaques (p = .04). Serum concentration of CCL19 was significantly higher in patients with clinically unstable plaques (p = .02). Immunohistochemical staining for CCL19 demonstrated positive staining in histologically and clinically unstable plaques (p = .03). CCL19 also co-localised with CD3+ T-cell lymphocytes in the core region, around where CCL19 was expressed. CONCLUSIONS: CCL19 is significantly overexpressed in patients with unstable carotid atherosclerotic plaques and may be a possible novel biomarker for identifying high-risk patients in whom more urgent intervention may be indicated. PMID- 27498093 TI - [Simple strategy to promote well-being in cancer patients: Nurse-patient dialogue during the administration of chemotherapy]. PMID- 27498095 TI - Rosiglitazone influences adipose tissue distribution without deleterious impact on heart rate variability in coronary heart disease patients with type 2 diabetes. AB - INTRODUCTION: Obesity is associated with decreased heart rate variability (HRV). Rosiglitazone, a PPARgamma agonist, is generally associated with increases in body mass. PURPOSE: To assess whether the gain in body mass and adiposity expected from rosiglitazone treatment has an influence on HRV in patients with type 2 diabetes and coronary artery disease. METHODS: One hundred and twenty-five patients with type 2 diabetes and coronary artery disease aged between 40 and 75 years were studied. Anthropometric measurements: (1) body mass index (BMI), (2) waist circumference (WC), (3) abdominal computed tomography (CT) scan, and HRV (using a 24 h Holter) were measured at baseline and after 12 months of treatment. Patients were randomized to rosiglitazone or placebo regimen. RESULTS: In the rosiglitazone vs. placebo group, there were significant increases in body mass [3.5 (2.6;4.4); mean (95 % CI) vs. 0.2 (-0.4;0.8)] kg), BMI [1.3 (1.0;1.6) vs. 0.1 (-0.1;0.3) kg/m2], WC [2.1 (0.9;3.3) vs. 0.4 (-0.4;1.2) cm, all p <= 0.001] and subcutaneous adipose tissue [253 (187;319) vs. 6 (-24;36) cm3, p <= 0.001] without statistically significant changes in visceral adipose tissue [-22 ( 91;47) vs. 57 (43;71) cm3, p = 0.546], respectively. There was no change in HRV in either group after 12 months. There were no correlations between changes in HRV variables and fat distribution. CONCLUSION: Our results suggest that changes in adiposity indices observed after 12 months of rosiglitazone therapy have no deleterious influence on HRV in patients with type 2 diabetes and coronary artery disease. PMID- 27498097 TI - Further research needed for severe and chronic depression in specialist mental health services. PMID- 27498096 TI - Superficial siderosis associated with peripheral autonomic failure and tetraventricular hydrocephalus: a case report. AB - We describe the case of a man whose initial clinical presentation included sensorineural hearing loss and orthostatic hypotension. The patient was diagnosed with superficial siderosis associated with peripheral autonomic failure and tetraventricular hydrocephalus. PMID- 27498094 TI - Exchange of Sex for Drugs or Money in Adolescents and Young Adults: An Examination of Sociodemographic Factors, HIV-Related Risk, and Community Context. AB - The goal of this research was to examine associations among sociodemographic factors, HIV risk, and community context (e.g., economic insecurity, job training, housing instability, crime victimization, and perceived community norms) in adolescents and young adults who ever exchanged sex for drugs or money. Anonymous survey data were collected using ACASIs at community venues where adolescents and young adults congregate in resource-challenged, STI prevalent, urban, US neighborhoods. Conventional descriptive statistics, Fisher's exact tests, and generalized estimating equations approaches were used to examine associations. Participants (1818, 95.5 % of those screened eligible) were, on average, aged 21.0 years; 42.2 % were males, and 4.6 % were transgender. Almost one-third (32.1 %) identified as gay or lesbian, 18.1 % identified as bisexual; 66.2 % were Black and 21.0 % were Hispanic; 1.3 % was 'living on the street'. A sizeable proportion reported HIV-related risk: 16.3 % exchanged sex, 12.6 % had sex with someone they knew to be HIV-infected, 7.8 % had sex with someone who injected drugs, and 1.3 % injected drugs. Multivariate comparisons identified a number of variables (e.g., being male or transgender, homelessness, sex with a partner who has HIV, STI history, unemployment, job training access, housing instability, crime victimization, perceived community norms) that were significantly associated with exchange of sex (p < 0.05). This research contributes to the knowledge-base regarding exchange of sex among adolescents and young adults, particularly as it relates to community context. Longitudinal studies to describe the trajectory of social, health, and physical risks and consequences are needed for development of effective evidence-based prevention strategies. PMID- 27498098 TI - Efficacy and cost-effectiveness of a specialist depression service versus usual specialist mental health care to manage persistent depression: a randomised controlled trial. AB - BACKGROUND: Persistent moderate or severe unipolar depression is common and expensive to treat. Clinical guidelines recommend combined pharmacotherapy and psychotherapy. Such treatments can take up to 1 year to show an effect, but no trials of suitable duration have been done. We investigated the efficacy and cost effectiveness of outpatient-based, specialist depression services (SDS) versus treatment as usual (TAU) on depression symptoms and function. METHODS: We did a multicentre, single-blind, patient-level, parallel, randomised controlled trial (RCT), as part of the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) study, in three mental health outpatient settings in England. Eligible participants were in secondary care, were older than 18 years, had unipolar depression (with a current major depressive episode, a 17-item Hamilton Depression Rating Scale [HDRS17] score of >=16, and a Global Assessment of Function [GAF] score of <=60), and had not responded to 6 months or more of treatment for depression. Randomisation was stratified by site with allocation conveyed to a trial administrator, with research assessors masked to outcome. Patients were randomised (1:1) using a computer-generated pseudo-random code with random permuted blocks of varying sizes of two, four, or six to either SDS (collaborative care approach between psychiatrists and cognitive behavioural therapists for 12 months, followed by graduated transfer of care up to 15 months) or to the TAU group. Intention-to treat primary outcome measures were changes in HDRS17 and GAF scores between baseline and 6, 12, and 18 months' follow-up. We will separately publish follow up outcomes for months 24 and 36. Clinical efficacy and cost-effectiveness were examined from health and social care persp ectives at 18 months, as recommended by the National Institute for Health and Care Excellence. This trial is registered at ClinicalTrials.gov (NCT01047124) and the ISRCTN registry (ISRCTN10963342); the trial has ended. FINDINGS: 307 patients were assessed for eligibility between Dec 21, 2009, and Oct 31, 2012. 94 patients were assigned to TAU and 93 patients to SDS, and were included in intention-to-treat analyses. The changes from baseline to 6 months in HDRS17 and GAF scores did not significantly differ between treatment groups (mean change difference in HDRS17 score -1.01 [95% CI -3.30 to 1.28], p=0.385; and in GAF score 1.33 [-2.92 to 5.57], p=0.538). Primary outcome data were available for 134 (72%) patients at 12 months. We noted no differences at 12 months' follow-up between SDS and TAU for mean HDRS17 score (14.8 [SD 7.9] in the SDS group vs 17.2 [7.3] in the TAU group, p=0.056) or GAF score (60.4 [11.7] vs 55.8 [12.7], p=0.064), and the changes from baseline to 12 months in HDRS17 and GAF scores did not significantly differ between treatment groups (mean change difference in HDRS17 score -2.45 [95% CI -5.04 to 0.14], p=0.064; and in GAF score 4.12 [-0.11 to 8.35], p=0.056). The mean change in HDRS17 score from baseline to 18 months was significantly improved in the SDS group compared with the TAU group (13.6 [SD 8.8] in the SDS group vs 16.1 [6.6] in the TAU group; mean change difference -2.96 [95% CI -5.33 to -0.59], p=0.015), but the GAF scores showed no significant differences between the groups (61.2 [SD 13.0] vs 57.7 [11.9]; mean change difference 3.82 [-9.3 to 8.57], p=0.113). We reported no deaths, but one (1%) patient was admitted to hospital for myocardial infarction, and three episodes of self-harm were reported in three (2%) patients (two receiving TAU, one receiving SDS care). The incremental cost-effectiveness ratio of SDS versus TAU was L43 603 per quality-adjusted life-year. INTERPRETATION: Compared with usual specialist mental health secondary care, SDS might improve depression symptoms for patients with persistent moderate to severe depression, but functional outcomes and economic benefits are equivocal. FUNDING: National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care, UK Medical Research Council, Nottinghamshire Healthcare NHS Foundation Trust, Derbyshire Healthcare NHS Foundation Trust, Cambridgeshire and Peterborough NHS Foundation Trust, University of Nottingham. PMID- 27498100 TI - Pharmacokinetics, Pharmacodynamics and Population Pharmacokinetic/Pharmacodynamic Modelling of Bilastine, a Second-Generation Antihistamine, in Healthy Japanese Subjects. AB - BACKGROUND AND OBJECTIVES: Bilastine is a novel second-generation antihistamine for the symptomatic treatment of allergic rhinitis and urticaria. The objective of this study was to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of bilastine following single and multiple oral doses in healthy Japanese subjects. The pharmacokinetic and pharmacodynamic profiles were compared with those reported in Caucasian subjects. METHODS: In a single-blind, randomized, placebo-controlled, parallel-group, single- and multiple-ascending dose study, bilastine tablets were administered at single doses of 10, 20, and 50 mg (Part I), and once daily for 14 days at 20 and 50 mg (Part II). RESULTS: After single oral doses, maximum plasma concentrations (C max) were reached at 1.0-1.5 h postdose. Plasma exposure [C max and area under the plasma concentration-time curve (AUC)] increased dose-proportionally at single doses of 10-50 mg. In repeated-dose administration, no remarkable differences were observed between Day 1 and Day 14 for C max or AUC. For inhibitory effects on wheal and flare response, bilastine 20 and 50 mg showed significant inhibition from 1.5 h after administration as compared with placebo, and the significant effect persisted for 24 h after administration. The rates of adverse events (AEs) were comparable between bilastine and placebo in both Part I and Part II. In addition, no dose- or administration period-dependent tendency of increase in rate of AEs or worsening of severity was observed. CONCLUSION: Bilastine exhibits similar single and multiple-dose pharmacokinetic and pharmacodynamic characteristics in healthy Japanese subjects compared with those observed in Caucasian subjects in previous studies. PMID- 27498099 TI - How do different delivery schedules of tailored web-based physical activity advice for breast cancer survivors influence intervention use and efficacy? AB - PURPOSE: The purpose of the study is to investigate the impact of differing delivery schedules of computer-tailored physical activity modules on engagement and physical activity behaviour change in a web-based intervention targeting breast cancer survivors. METHODS: Insufficiently active breast cancer survivors (n = 492) were randomly assigned to receive one of the following intervention schedules over 12 weeks: a three-module intervention delivered monthly, a three module intervention delivered weekly or a single module intervention. Engagement with the website (number of logins, time on site, modules viewed, action plans completed) was measured using tracking software. Other outcomes (website acceptability, physical activity behaviour) were assessed using online surveys. Physical activity outcomes were analysed using regression models for both study completers and when applying intention-to-treat (using multiple imputation). RESULTS: Completers allocated to the monthly module group rated the intervention higher (b = 2.2 95 % CI = 0.02-4.53) on acceptability and had higher levels of resistance-training (IRR = 1.88, 95 % CI = 1.16-3.04) than those in the single module group. When accounting for missing data, these differences were no longer significant. The completion of at least two action plans was higher among those allocated to the monthly module group compared to those in the weekly module group (53 vs 40 %, p = 0.02); though the completion of at least two modules was higher in the weekly module group compared to the monthly module group (60 vs 46 %; p = 0.01). There were no other significant between group differences observed. CONCLUSION: This study provides preliminary evidence that web-based computer tailored interventions can be used to increase physical activity among breast cancer survivors. Further, there were some outcome differences based on how the tailored modules were delivered, with the most favourable outcomes observed in the monthly delivery group. IMPLICATIONS FOR CANCER SURVIVORS: This study will be useful for informing the design of future web-based interventions targeting breast cancer survivors. PMID- 27498102 TI - Computed tomography value and tunnel enlargement of round and rounded rectangular femoral bone tunnel for anterior cruciate ligament reconstruction. AB - INTRODUCTION: We developed a novel technique for anatomical single-bundle anterior cruciate ligament (ACL) reconstruction: creation of a rounded rectangular femoral bone tunnel. The purpose of this study was to compare the computed tomography (CT) value and tunnel enlargement ratio of the femoral bone tunnel with those of round tunnel ACL reconstruction. MATERIALS AND METHODS: We included 39 knees that underwent round tunnel ACL reconstruction and 42 that underwent rounded rectangular ACL reconstruction. To evaluate the CT value, we compared the CT images approximately 1 week after surgery. Making a parallel slice toward the opening of bone tunnels to a depth of 3 mm, we evaluated the CT value of eight directions in the bone tunnel wall. To evaluate tunnel enlargement, we compared CT images approximately 1 week after surgery with images taken 3 months after surgery. Using a parallel slice toward the opening of the bone tunnel, we measured the bone tunnel area and calculated the tunnel enlargement ratio. The level of significance was P < 0.05, and the t test was used for statistical analyses. RESULTS: The CT value was significantly increased for the rounded rectangular tunnel in comparison with the round tunnel in almost all directions (P < 0.05). The rounded rectangular tunnel area enlargement ratio was significantly lower (round, 110 +/- 38 %; rounded rectangular, 73 +/- 37 %; P = 0.001). CONCLUSION: The rounded rectangular tunnel could have a compression effect on the cancellous bone and reduce enlargement of the bone tunnel. PMID- 27498101 TI - ICU Management of the Potential Organ Donor: State of the Art. AB - End-organ failure is associated with high mortality and morbidity, in addition to increased health care costs. Organ transplantation is the only definitive treatment that can improve survival and quality of life in such patients; however, due to the persistent mismatch between organ supply and demand, waiting lists continue to grow across the world. Careful intensive care management of the potential organ donor with goal-directed therapy has the potential to optimize organ function and improve donation yield. PMID- 27498103 TI - Biomechanical comparison between the modified rolling-hitch and the modified finger-trap suture techniques. AB - PURPOSE: The purpose of this study was to characterize the biomechanical effect of two grasping suture techniques used during ligament reconstruction: the modified rolling-hitch (MRH) and the modified finger-trap (MFT). METHODS: Flexor profundus tendons were harvested from fresh pig hind-leg trotters. Each specimen was mounted on an electro-mechanic universal testing machine (Instron 3367). In half of all tendons (15 specimens), the suture was passed around the tendon following the MRH knot (Group 1). In the remaining half of all tendons (15 specimens), the suture was passed over a distance of 30 mm according to the MFT suture technique (Group 2). As per standard intra-operative technique, a 1 cm residual tendon stub was left free from suture in all samples. All specimens were preconditioned to a load of 50 N for 10 min, followed by three cycles loading between 50 and 120 N. At this point, each sample was cyclically tensioned between 35 and 240 N, at 1 Hz for 200 cycles. Load-to-failure test was then carried out at a rate of 200 mm/min. RESULTS: Rupture of the suture material at the knot was the mode of failure in all specimens during the loaded to failure test. Significant difference was found between Group 1 vs Group 2 for the elongation between the 0th cycle and 10th cycle, the elongation between the 10th cycle and 200th cycle, the mean stiffness at the 10th cycle, and the mean stiffness at the 190th cycle. No significant differences were noted between Group 1 and Group 2 concerning the ultimate load-to-failure. CONCLUSION: This study showed that both suture methods appear to be biomechanically effective in a porcine tendon model. However, the single-knot grasping technique (MRH) provided superior biomechanical properties compared with the MFT technique. PMID- 27498104 TI - Decreased QOL and muscle strength are persistent 1 year after intramedullary nailing of a tibial shaft fracture: a prospective 1-year follow-up cohort study. AB - INTRODUCTION: To evaluate the development in patient-reported quality of life (QOL) and muscle strength in the period from surgery to 12 months postoperatively after intramedullary nailing of a tibial shaft fracture. MATERIALS AND METHODS: The design was a prospective, follow-up cohort study. QOL was measured with the questionnaire Eq5D-5L and compared to norm data from a reference population. Recordings of pain and contralateral muscle strength (isometric maximal voluntary contraction (MVC) for knee flexion and extension were collected at 6 weeks, 3, 6, and 12 months postoperatively. Ipsilateral MVCs were recorded at 6 and 12 months. RESULTS: Forty-nine patients were included. The mean age at the time of fracture was 43.1 years (18-79 years). Twelve months postoperatively, the mean Eq5D-5L index was 0.792 (95 % CI 0.747-0.837). Throughout the 12 months postoperatively, patients reported worse QOL compared to the reference population. Six and 12 months after surgery patients demonstrated decreased muscle strength in the injured leg compared to the non-injured leg for knee extension and flexion (P < 0.001). Twelve months postoperatively, increasing relative difference in muscle strength during knee extension show a fair correlation to worse QOL (R = 0.541, P < 0.001). CONCLUSIONS: Throughout the 12 months postoperatively, patients reported worse QOL compared to the reference population. Muscle strength in the non-injured leg improved over time and was higher after 6 and 12 months compared with the injured leg. PMID- 27498105 TI - Three-dimensional analysis of the shoulder motion in patients with massive irreparable cuff tears after latissimus dorsi tendon transfer (LDT). AB - INTRODUCTION: Latissimus dorsi tendon transfer (LDT) is a recent method for surgical treatment of massive, irreparable posterosuperior cuff tears (MIPCT). So far, there are no studies on the quantitative motion analysis of the shoulder and latissimus dorsi (LD) muscle activation after LDT. The changes in shoulder movements after LDT can be objectively assessed by the 3-D motion analysis. These changes may not be due to an increased activity of the LD muscle as external rotator. MATERIALS AND METHODS: The shoulder kinematics of nine patients with MIPCT were recorded through a 3-D motion analysis system, before LTD (T0), and after 3 (T1) and 6 (T2) months post-LDT. Maximal shoulder flexion-extension, abduction-adduction, and horizontal abduction-adduction, and the internal and external circumduction of the shoulder joint were measured during upright standing posture. Surface EMG activity of the LD muscle was recorded during both internal rotation (IR) and external rotation (ER) tasks in three different postures. RESULTS: A significant increase of shoulder movements was observed at T2 compared with T0 for almost all motor tasks. A significant effect of LDT was also found on LD-IR/ER ratio in posture 1 at T2 compared with T0 and T1. No significant effects were found for the LD-IR/ER ratio in the other postures. CONCLUSIONS: Our study indicates that LDT is effective in shoulder motion recovery. Such improvement is not associated with a change in function of the LD muscle, which may be induced by a depression of the humeral head into the glenoid cavity instead. PMID- 27498106 TI - Return to prelesional Tegner level after anatomic anterior cruciate ligament reconstruction. AB - INTRODUCTION: Injury and surgery of the anterior cruciate ligament (ACL) are very frequent within the sports environment. The purpose of the present study is to assess the level at which a group of athletes were able to return to play (RTP) after ACL reconstruction, and most importantly, the time for RTP. MATERIALS AND METHODS: A prospective study with patients who presented an ACL injury and underwent ligament reconstruction surgery; a bone-tendon-bone reconstruction and a minimum follow-up of 24 months. The rates of RTP as well as correlations with IKDC and KT-1000 were collected. RESULTS: 42 patients were included (mean age 31.7 years old). Mean Tegner level was 6.7. 9.5 % of patients returned to sports 6 months after surgery, 52.3 % at 1 year, and 73.8 % at 2 years after ACL reconstruction. 11 patients did not achieve their preoperative Tegner level after 2 years of follow-up. Levels of KT-1000 of the operated side were normal, and IKDC levels reached 90 % of total. CONCLUSIONS: Fear to a new injury, psychological factors, personality, type of life, and sports level previous to the injury are factors that influence when it comes to RTP after an ACL surgery. Level of evidence Level II descriptive analysis. PMID- 27498107 TI - A simple approach for the preoperative assessment of sacral morphology for percutaneous SI screw fixation. AB - BACKGROUND: Percutaneous sacroiliac screw fixation under fluoroscopic control is an effective method for posterior pelvic ring stabilization. However, sacral dysmorphism has a high risk of L5 nerve injury. This study describes a simple method for the preoperative assessment of the sacral morphology using CT scans with widely available tools. MATERIALS AND METHODS: CT scans of 1000 patients were analyzed. True inlet, outlet, and lateral views of the sacrum were obtained using a two-dimensional reconstruction tool to align the sacrum in a reproducible manner. Corridor morphology in the inlet view was measured to calculate different morphological types: (1) Ascending type, (2) Horizontal type, and (3) Descending type. In a second step, the corridor was analyzed for the presence of an anterior indentation of the sacrum between the SI joint and the midsagittal plane with proximity to the nerve root L5, which, therefore, may be harmed during screw misplacement. RESULTS: A notch was found in the majority of cases with relative frequencies ranging from 69 % (upper quartile of S1) to 95 % (upper quartile of S2). Descending types were, by far, the most frequent corridor type with one exception: In the upper quartile of S1, the ascending type was the most frequent corridor (71 %). Horizontal types were less frequent with a relative incidence between 2 and 14 %. DISCUSSION: This study should increase the awareness for sacral dysmorphism, emphasize the importance of a preoperative assessment of the osseous corridor, and provide a simple method for the preoperative assessment with widely available tools. PMID- 27498108 TI - Preservation of bursal-sided tendon in partial-thickness articular-sided rotator cuff tears: a novel arthroscopic transtendon anatomic repair technique. AB - INTRODUCTION: The purpose of this study was to introduce a novel arthroscopic transtendon anatomic repair technique that spares the intact bursal-sided tendon in articular-sided partial-thickness rotator cuff tears (PTRCT) and to present shoulder functional outcomes in patients with symptomatic articular-sided PCRCT that involves more than 50 % of its thickness after arthroscopic repair using a novel technique. MATERIALS AND METHODS: Eighteen patients with symptomatic articular-sided PCRCT involving more than 50 % of the tendon's thickness underwent arthroscopic repair using a devised technique. The devised technique restores only the torn articular portion of the rotator cuff at the anatomical footprint using a suture anchor, and preserves the integrity of the corresponding bursal-sided tendon by tying knots at the most lateral bursal side on the subacromial space. Clinical and functional outcome using ASES and Constant scores were evaluated. The structural integrity of the rotator cuff was evaluated by MRI at 6 months postoperatively. RESULTS: Pain relief and shoulder functional outcomes were encouraging during the recovery phase after operation. ASES (preoperative 54.0 +/- 10.3 to postoperative 92.6 +/- 8.0), Constant score (61.2 +/- 8.5-88.0 +/- 5.3), VAS for pain (4.9 +/- 2.6-0.6 +/- 0.7) improved significantly after arthroscopic transtendon anatomic repair (p < 0.001). No patients had rotator cuff retears on 6-month MRI. No complications related to surgical procedures had occurred. CONCLUSION: The devised technique of arthroscopic transtendon repair provided satisfactory functional outcomes without postoperative discomforts. This technique minimizes over-tightening of the articular layer and reduces tension mismatches between the articular and bursal layers, which are considered as important factors for improvement of postoperative shoulder motion. PMID- 27498110 TI - Lupus nephritis biomarkers. AB - Lupus nephritis (LN), a potentially destructive outcome of SLE, is a real challenge in the management of SLE because of the difficulty in diagnosing its subclinical onset and identifying relapses before serious complications set in. Conventional clinical parameters such as proteinuria, GFR, urine sediments, anti dsDNA and complement levels are not sensitive or specific enough for detecting ongoing disease activity in lupus kidneys and early relapse of nephritis. There has long been a need for biomarkers of disease activity in LN. Such markers ideally should be capable of predicting early sub-clinical flares and could be used to gauge response to therapy, thus obviating the need for serial renal biopsies with their possible hazardous complications. Since urine can be readily obtained, it lends itself as an obvious biological substrate. In this review, the use of urine and serum as sources of lupus nephritis biomarkers is described, and the results of biomarker discovery studies using candidate and proteomic approaches are summarized. PMID- 27498109 TI - Changes of regulatory T cells, transforming growth factor-beta and interleukin-10 in patients with type 1 diabetes mellitus: A systematic review and meta-analysis. AB - Regulatory T lymphocyte cells (Treg) associated with interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) have implicated in the development of type 1 diabetes mellitus (T1DM), yet the existing evidence remains unclear. Hereby we performed a systematic review and meta-analysis to characterize the changes in T1DM patients. A total of 1407 T1DM patients and 1373 healthy controls from 40 case-control studies were eventually included in the pooling analysis. Compared with the controls, T1DM patients had decreased frequency of CD4(+)CD25(+)Treg (p=0.0003), CD4(+)CD25(+)Foxp3(+)Treg (p=0.020), and the level of TGF-beta (p=0.030). Decrease in IL-10 (p=0.14) was not significant. All the changes remained significant when the studies with low NOS scores and publication bias were excluded. In conclusion, peripheral Treg and serum TGF-beta are reduced in type 1 diabetes mellitus whereas changes in serum IL-10 are not significant. PMID- 27498111 TI - A dedicated vascular access clinic for children on haemodialysis: Two years' experience. AB - BACKGROUND: Arteriovenous fistula (AVF) formation for long-term haemodialysis in children is a niche discipline with little data for guidance. We developed a dedicated Vascular Access Clinic that is run jointly by a transplant surgeon, paediatric nephrologist, dialysis nurse and a clinical vascular scientist specialised in vascular sonography for the assessment and surveillance of AVFs. We report the experience and 2-year outcomes of this clinic. METHODS: Twelve new AVFs were formed and 11 existing AVFs were followed up for 2 years. All children were assessed by clinical and ultrasound examination. RESULTS: During the study period 12 brachiocephalic, nine basilic vein transpositions and two radiocephalic AVFs were followed up. The median age (interquartile range) and weight of those children undergoing new AVF creation were 9.4 (interquartile 3-17) years and 26.9 (14-67) kg, respectively. Pre-operative ultrasound vascular mapping showed maximum median vein and artery diameters of 3.0 (2-5) and 2.7 (2.0-5.3) mm, respectively. Maturation scans 6 weeks after AVF formation showed a median flow of 1277 (432-2880) ml/min. Primary maturation rate was 83 % (10/12). Assisted maturation was 100 %, with two patients requiring a single angioplasty. For the 11 children with an existing AVF the maximum median vein diameter was 14.0 (8.0 26.0) mm, and the median flow rate was 1781 (800-2971) ml/min at a median of 153 weeks after AVF formation. Twenty-two AVFs were used successfully for dialysis, a median kt/V of 1.97 (1.8-2.9), and urea reduction ratio of 80.7 % (79.3-86 %) was observed. One child was transplanted before the AVF was used. CONCLUSIONS: A multidisciplinary vascular clinic incorporating ultrasound assessment is key to maintaining young children on chronic haemodialysis via an AVF. PMID- 27498113 TI - The anatomical limits and oncological benefit of lymphadenectomy in muscle invasive bladder cancer. AB - BACKGROUND: Lymphadenectomy is part of standard treatment for muscle invasive bladder cancer. The objective of this review is to provide an up-to-date review on the available scientific evidence in this field. ACQUISITION OF EVIDENCE: We conducted a literature review in PubMed of relevant articles up to the present (2016). We found a systematic review published in 2014 that included the comparative studies published up to that year, and we updated the review with new relevant publications since that date. SYNTHESIS OF THE EVIDENCE: The number of lymph nodes is not the best indicator for determining the quality of the lymphadenectomy given that the number can vary depending on numerous factors that depend not only on the surgeon but also on the patient and on the pathologist. The definition of standard anatomical territories and a meticulous extraction of the lymph nodes in these territories are more reproducible than the numbers of nodes removed. The optimal extension of lymphadenectomy is a topic of debate. The evidence published to date indicates that any extension of lymphadenectomy is better than not performing it, although it appears that limited lymphadenectomy is insufficient for the oncological control of the disease and that superextended lymphadenectomy provides no oncological benefit versus extended lymphadenectomy. CONCLUSIONS: Despite a certain amount of controversy in terms of the optimal extension of lymphadenectomy, performing lymphadenectomy in all cases appears to be recommendable according to the available evidence. Extended lymphadenectomy provides greater oncological benefit than more limited dissections, while more extensive lymphadenectomies are not recommended. PMID- 27498112 TI - A prospective cohort study of depression course, functional disability, and NEET status in help-seeking young adults. AB - PURPOSE: To examine the associations between depression course, functional disability, and Not in Education or Training (NEET) status in a clinical sample of young adults with mental health problems. METHODS: Young adults aged 15-25 years seeking help from four primary mental health services were invited to participate in a prospective cohort study evaluating the course of psychiatric disorders in youth. Demographic and clinical characteristics, including depressive symptomatology and functioning, were evaluated through clinical interview and self-report at baseline and 12 month follow-up. RESULTS: A total of 448 young adults participated (70 % female; M: 20.05 years, SD = 2.85). A significant interaction effect for time and depression course was found, such that those who became depressed reported an increase in functional disability and those whose depression remitted reported a significant reduction in functional disability. Developing depression was not a significant predictor of becoming NEET and vice versa: remitted depression did not make a person more likely to reengage in employment or education. CONCLUSIONS: This is the first study to examine the course of depression, functional disability, and NEET rates among help-seeking young adults. This study confirms the importance of symptom reduction for improved functioning; however, functional disability remained greater than that seen in young people in the community and there was no association between a change in depression and a change in NEET status. These results argue that services need to address functional outcomes and reengagement with education and employment in addition to symptom reduction. PMID- 27498114 TI - Sublethal Concentration of Beta-Cypermethrin Influences Fecundity and Mating Behavior of Carposina sasakii (Lepidoptera: Carposinidae) Adults. AB - The purpose of this study was to evaluate the sublethal effects of the beta cypermethrin on calling behavior and fecundity of a major fruit-boring pest of apple, Carposina sasakii Matsumura. The mating rate, fertility (total number of eggs laid per female), and adult longevity of adults were remarkably decreased as compared with that in control when the adults were exposed to 10% lethal concentrations (LC10) of beta-cypermethrin (LC10? * LC10?), and the age-specific survival rate (lx) was also negatively affected by sublethal beta-cypermethrin especially for the LC10?* LC10? mating combination. However, the age-specific fecundity (mx) was stimulated particularly in the combination of CK?* LC10?. Furthermore, the oviposition period was prolonged and the number of eggs was significantly increased for combinations of CK?* LC10? and LC10?* CK?. In the mating experiments, males in control or LC10-beta-cypermethrin treatments preferred to mate with females in control. It might be because of lower calling rate of female survivors treated with sublethal beta-cypermethrin. Our data indicate that treatment of beta-cypermethrin had a sublethal effect on the development and production of C. sasakii, and their mating behavior changes in surviving adults that may contribute to assortative mating. PMID- 27498115 TI - Effects of Field History on Corn Root Injury and Adult Abundance of Northern and Western Corn Rootworm (Coleoptera: Chrysomelidae). AB - Western corn rootworm, Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae), and northern corn rootworm, Diabrotica barberi Smith & Lawrence, are major pests of corn (Zea mays L.). Corn producing Bacillus thuringiensis (Bt) toxins are widely used to manage Diabrotica spp.; however, Bt resistance by D. v. virgifera has led to high levels of feeding injury in the field. We tested whether field history affected root injury and abundance of adult Diabrotica spp. In 2013 and 2014, four types of cornfields were sampled: 1) recently rotated fields, 2) continuous cornfields, 3) fields with a history of injury to Bt corn (past problem fields), and 4) fields with greater than one node of injury to Bt corn at the time of sampling (current problem fields). Data were collected on field history, root injury, and the abundance of adult Diabrotica spp. from each field. Root injury and the abundance of D. v. virgifera were significantly greater in current problem fields compared to the other field types, while D. barberi were significantly more abundant in recently rotated fields. Root injury and the abundance of D. v. virgifera did not differ among recently rotated fields, continuous cornfields, and past problem fields. Analysis of field history showed that recently rotated fields were characterized by significantly less Bt corn, soil-applied insecticides, and years planted to corn continuously. These results suggest that greater cropping practice diversity can reduce management inputs for Diabrotica spp.; however, its effects on resistance evolution remain undetermined. PMID- 27498116 TI - The molecular chaperone Hsp70 promotes the proteolytic removal of oxidatively damaged proteins by the proteasome. AB - One hallmark of aging is the accumulation of protein aggregates, promoted by the unfolding of oxidized proteins. Unraveling the mechanism by which oxidized proteins are degraded may provide a basis to delay the early onset of features, such as protein aggregate formation, that contribute to the aging phenotype. In order to prevent aggregation of oxidized proteins, cells recur to the 20S proteasome, an efficient turnover proteolysis complex. It has previously been shown that upon oxidative stress the 26S proteasome, another form, dissociates into the 20S form. A critical player implicated in its dissociation is the Heat Shock Protein 70 (Hsp70), which promotes an increase in free 20S proteasome and, therefore, an increased capability to degrade oxidized proteins. The aim of this study was to test whether or not Hsp70 is involved in cooperating with the 20S proteasome for a selective degradation of oxidatively damaged proteins. Our results demonstrate that Hsp70 expression is induced in HT22 cells as a result of mild oxidative stress conditions. Furthermore, Hsp70 prevents the accumulation of oxidized proteins and directly promotes their degradation by the 20S proteasome. In contrast the expression of the Heat shock cognate protein 70 (Hsc70) was not changed in recovery after oxidative stress and Hsc70 has no influence on the removal of oxidatively damaged proteins. We were able to demonstrate in HT22 cells, in brain homogenates from 129/SV mice and in vitro, that there is an increased interaction of Hsp70 with oxidized proteins, but also with the 20S proteasome, indicating a role of Hsp70 in mediating the interaction of oxidized proteins with the 20S proteasome. Thus, our data clearly implicate an involvement of Hsp70 oxidatively damaged protein degradation by the 20S proteasome. PMID- 27498118 TI - Differentiating the Causes of Spontaneous Rib Fracture After Breast Cancer. AB - Spontaneous rib fracture after treatment for primary breast cancer is not uncommon. Although metastatic disease accounts for about 30% of spontaneous rib fractures and should constitute the first line of diagnostic investigation, other possible contributors include primary osteoporosis or secondary osteoporosis resulting from cancer treatments. Chemotherapy-induced menopause, aromatase inhibitors, radiation therapy, and long-term bisphosphonate use can all contribute to bone fragility, including spontaneous rib fractures in the latter 3. Drawing on recent breast cancer practice guidelines as well as population based studies of fracture risk for women with a history of breast cancer and systematic reviews, this Perspective will provide an update on recent developments in understanding how to differentiate the possible reasons for non traumatic rib fracture in women treated for breast cancer. In addition to describing the various possible causes of spontaneous rib fracture, the recommended medical and imaging procedures for differentiating among the potential causes will be presented. PMID- 27498117 TI - Inhibition of histone deacetylase reduces transcription of NADPH oxidases and ROS production and ameliorates pulmonary arterial hypertension. AB - Excessive levels of reactive oxygen species (ROS) and increased expression of NADPH oxidases (Nox) have been proposed to contribute to pulmonary artery hypertension (PAH) and other cardiovascular diseases (CVD). Nox enzymes are major sources of ROS but the mechanisms regulating changes in Nox expression in disease states remain poorly understood. Epigenetics encompasses a number of mechanisms that cells employ to regulate the ability to read and transcribe DNA. Histone acetylation is a prominent example of an epigenetic mechanism regulating the expression of numerous genes by altering chromatin accessibility. The goal of this study was to determine whether inhibition of histone deacetylases (HDAC) affects the expression of Nox isoforms and reduces pulmonary hypertension. In immune cells, we found that multiple HDAC inhibitors robustly decreased Nox2 mRNA and protein expression in a dose-dependent manner concomitant with reduced superoxide production. This effect was not restricted to Nox2 as expression of Nox1, Nox4 and Nox5 was also reduced by HDAC inhibition. Surprisingly, Nox promoter-luciferase activity was unchanged in the presence of HDAC inhibitors. In macrophages and lung fibroblasts, ChIP experiments revealed that HDAC inhibitors block the binding of RNA polymerase II and the histone acetyltransferase p300 to the Nox2, Nox4 and Nox5 promoter regions and decrease histones activation marks (H3K4me3 and H3K9ac) at these promoter sites. We further show that the ability of CRISPR-ON to drive transcription of Nox1, Nox2, Nox4 and Nox5 genes is blocked by HDAC inhibitors. In a monocrotaline (MCT) rat model of PAH, multiple HDAC isoforms are upregulated in isolated pulmonary arteries, and HDAC inhibitors attenuate Nox expression in isolated pulmonary arteries and reduce indices of PAH. In conclusion, HDAC inhibitors potently suppress Nox gene expression both in vitro and in vivo via epigenetically regulating chromatin accessibility. PMID- 27498119 TI - Factors Associated With Disease Recurrence in Breast Cancer Patients With Negative Sentinel Lymph Node Biopsy. AB - INTRODUCTION: The objective of our study was to assess recurrence after negative sentinel lymph node biopsy (SLNB) and to determine the risk factors related to local and distant recurrence in this group of patients. MATERIALS AND METHODS: We conducted a prospective observational study from 2006 to 2011. It included 607 patients with early-stage breast cancer and negative SLNB with a 5-year follow-up period. RESULTS: The disease-free survival rate was 98.5% and 96.5% at 2 and 5 years, respectively. Multivariate analysis identified the following prognostic factors for disease recurrence: tumor necrosis (hazard ratio [HR], 4.89; 95% confidence interval [CI], 1.61-14.89; P = .005), lymphovascular invasion (HR, 3.46; 95% CI, 1.14-10.55; P = .029), T2 tumor size (HR, 4.35; 95% CI, 1.40-13.52; P = .011), and moderate to severe lymphoplasmacytic stromal infiltration (HR, 3.06; 95% CI, 1.18-7.96; P = .022). CONCLUSION: Recurrence in patients with negative SLNB was satisfactorily low. Nevertheless, determining the prognostic factors related to a greater recurrence rate could help identify high-risk patients and influence systemic adjuvant therapy. PMID- 27498120 TI - Rapamycin reverses age-related increases in mitochondrial ROS production at complex I, oxidative stress, accumulation of mtDNA fragments inside nuclear DNA, and lipofuscin level, and increases autophagy, in the liver of middle-aged mice. AB - Rapamycin consistently increases longevity in mice although the mechanism of action of this drug is unknown. In the present investigation we studied the effect of rapamycin on mitochondrial oxidative stress at the same dose that is known to increase longevity in mice (14mgofrapamycin/kg of diet). Middle aged mice (16months old) showed significant age-related increases in mitochondrial ROS production at complex I, accumulation of mtDNA fragments inside nuclear DNA, mitochondrial protein lipoxidation, and lipofuscin accumulation compared to young animals (4months old) in the liver. After 7weeks of dietary treatment all those increases were totally or partially (lipofuscin) abolished by rapamycin, middle aged rapamycin-treated animals showing similar levels in those parameters to young animals. The decrease in mitochondrial ROS production was due to qualitative instead of quantitative changes in complex I. The decrease in mitochondrial protein lipoxidation was not due to decreases in the amount of highly oxidizable unsaturated fatty acids. Rapamycin also decreased the amount of RAPTOR (of mTOR complex) and increased the amounts of the PGC1-alpha and ATG13 proteins. The results are consistent with the possibility that rapamycin increases longevity in mice at least in part by lowering mitochondrial ROS production and increasing autophagy, decreasing the derived final forms of damage accumulated with age which are responsible for increased longevity. The decrease in lipofuscin accumulation induced by rapamycin adds to previous information suggesting that the increase in longevity induced by this drug can be due to a decrease in the rate of aging. PMID- 27498121 TI - Protective Role of Liriodendrin in Sepsis-Induced Acute Lung Injury. AB - In current study, we investigated the role of liriodendrin, a constituent isolated from Sargentodoxa cuneata (Oliv.) Rehd. Et Wils (Sargentodoxaceae), in cecal ligation and puncture (CLP)-induced acute lung inflammatory response and injury (ALI). The inflammatory mediator levels in bronchoalveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assay (ELISA). Pathologic changes in lung tissues were evaluated via pathological section with hematoxylin and eosin (H&E) staining. To investigate the mechanism whereby liriodendrin regulates lung inflammation, the phosphorylation of the NF-kB (p65) and expression of vascular endothelial growth factor (VEGF) were determined by western blot assay. We show that liriodendrin treatment significantly improved the survival rate of mice with CLP-induced sepsis. Pulmonary histopathologic changes, alveolar hemorrhage, and neutrophil infiltration were markedly decreased by liriodendrin. In addition, liriodendrin decreased the production of the proinflammatory mediators including (TNF-alpha, IL-1beta, MCP-1, and IL-6) in lung tissues. Vascular permeability and lung myeloperoxidase (MPO) accumulation in the liriodendrin-treated mice were substantially reduced. Moreover, liriodendrin treatment significantly suppressed the expression of VEGF and activation of NF-kB in the lung. We further show that liriodendrin significantly reduced the production of proinflammatory mediators and downregulated NF-kB signaling in LPS-stimulated RAW 264.7 macrophage cells. Moreover, liriodendrin prevented the generation of reactive oxygen species (ROS) by upregulating the expression of SIRT1 in RAW 264.7 cells. These findings provide a novel theoretical basis for the possible application of liriodendrin in clinic. PMID- 27498122 TI - Echocardiography does not predict mortality in hemodynamically stable elderly patients with acute pulmonary embolism. AB - BACKGROUND: The evidence on the prognostic value of transthoracic echocardiography (TTE) in elderly, hemodynamically stable patients with Pulmonary Embolism (PE) is limited. OBJECTIVES: To evaluate the prevalence of common echocardiographic signs of right ventricular (RV) dysfunction and their prognostic impact in hemodynamically stable patients aged >=65years with acute PE in a prospective multicenter cohort. METHODS: TTE was performed by cardiologists. We defined RV dysfunction as a RV/left ventricular ratio >0.9 or RV hypokinesis (primary definition) or the presence of >=1 or >=2 of 6 predefined echocardiographic signs (secondary definitions). Outcomes were overall mortality and mortality/non-fatal recurrent venous thromboembolism (VTE) at 30days, adjusting for the Pulmonary Embolism Severity Index risk score and highly sensitive troponin T values. RESULTS: Of 400 patients, 36% had RV dysfunction based on our primary definition, and 81% (>=1 sign) and 53% (>=2 signs) based on our secondary definitions, respectively. Using our primary definition, there was no association between RV dysfunction and mortality (adjusted HR 0.90, 95% CI 0.31-2.58) and mortality/non-fatal VTE (adjusted HR 1.09, 95% CI 0.40-2.98). Similarly, there was no statistically significant association between the presence of >=1 or >=2 echocardiographic signs (secondary definitions) and clinical outcomes. CONCLUSION: The prevalence of echocardiographic RV dysfunction varied widely depending upon the definition used. There was no association between RV dysfunction and clinical outcomes. Thus, TTE may not be suitable as a stand-alone risk assessment tool in elderly patients with acute PE. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov. Identifier: NCT00973596. PMID- 27498123 TI - Pharmacological properties of microneurotrophin drugs developed for treatment of amyotrophic lateral sclerosis. AB - Microneurotrophins (MNT's) are small molecule derivatives of dehydroepiandrosterone (DHEA) and do not have significant interactions with sex steroid receptors. MNT's retain high-affinity binding to protein tyrosine kinase (Trk) receptors and can mimic many pleiotropic actions of neurotrophin (NT) proteins on neurons. MNT's offer therapeutic potential for diseases such as amyotrophic lateral sclerosis (ALS) where motor neurons (MN) degenerate. MNT's cross artificial membranes mimicking the blood-brain barrier, are not major substrates for ABC (ATP-binding cassette) transporters and are metabolized rapidly by mouse but more slowly by human hepatocytes. A lead MNT (BNN27) and its mono-oxidation metabolites enter mouse brain rapidly. RNA-sequencing measured gene expression profiles of human H9eSC-(embryonic stem cell)-derived or CTL (control) subject iPSC-(induced pluripotential stem cell)-derived MN's exposed to NT proteins or MNT molecules. Expression ratios (relative to DMSO (dimethylsulfoxide) vehicle) were calculated, and the resulting top 500 gene lists were analyzed for Gene Ontology (GO) grouping using DAVID (Database for Annotation, Visualization and Integrated Discovery). The MNT's BNN20, BNN23, and BNN27 showed overlap of GO terms with NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor) in the H9eSC-derived MN's. In the iPSC-derived MN's two (BNN20, BNN27) showed overlap of GO terms with NGF or BDNF. Each NT protein had GO terms that did not overlap with any MNT in the MN cell lines. PMID- 27498124 TI - A Pharmacokinetic and Pharmacodynamic Study of Maraviroc as Acute Graft-versus Host Disease Prophylaxis in Pediatric Allogeneic Stem Cell Transplant Recipients with Nonmalignant Diagnoses. AB - Maraviroc is an allosteric small molecule antagonist of chemokine receptor type 5 (CCR5) and has been used in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients to prevent acute graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract and liver. The goal of this study was to establish feasibility and pharmacokinetic and pharmacodynamic profiles of maraviroc in pediatric HSCT recipients. Children ages 2 to 12 years were enrolled and maraviroc was added to standard GVHD prophylaxis, which included a calcineurin inhibitor and either steroids or mycophenolate mofetil. Maraviroc was started on day -3 and administered at a dose of approximately 300 mg/m(2) orally twice daily until day +30 after stem cell infusion. On days 0 and day +10, samples for pharmacokinetic analysis were collected before the dose and 1, 2, 4, 6, 8, and 12 hours after maraviroc administration. Additional trough concentrations were collected on days +7, 14, and 21. Patients were followed until day +100 for acute GVHD. Functional blockade of CCR5 was assessed in a pharmacodynamic assay by flow cytometry. Thirteen patients, median age of 4 years (range, 2 to 11 years), were prospectively enrolled. Underlying diagnoses included a primary immune deficiency (n = 6), hemoglobinopathy (n = 4), metabolic disorder (n = 1), and bone marrow failure syndrome (n = 2). Patients received either a myeloablative preparative regimen (n = 7) or a reduced-intensity conditioning regimen (n = 6). Cyclosporine and methylprednisolone (n = 7) was the predominant GVHD prophylactic regimen, followed by tacrolimus and mycophenolate mofetil (n = 4) and tacrolimus and steroids (n = 2). Two formulations of maraviroc (150-mg tablets and 20-mg/mL solution) were used on study. Mean (+/- SD) area under the concentration-time curve from 0 to 12 hours was 4805 +/- 3265 hour * ng/mL on day 0 and 5917 +/- 4048 hour * ng/mL on day +10. Four patients developed grade 1 or 2 acute skin GVHD before day +100 and were successfully treated. Two patients developed grade 3 acute GI GVHD on days +23 and +24 after HSCT and both had discontinued maraviroc before development of GI GVHD. No adverse effects attributable to maraviroc were observed and administration by enteral tubes was well tolerated by children and accepted by parents. All evaluable patients demonstrated functional CCR5 blockade on day 0. Administration of maraviroc is feasible in most pediatric HSCT recipients with good safety and tolerability profile. PMID- 27498125 TI - Characterization of a novel cell wall binding domain-containing Staphylococcus aureus endolysin LysSA97. AB - Endolysin from Staphylococcus aureus phage SA97 (LysSA97) was cloned and investigated. LysSA97 specifically lyse the staphylococcal strains and effectively disrupted staphylococcal biofilms. Bioinformatic analysis of LysSA97 revealed a novel putative cell wall binding domain (CBD) as well as two enzymatically active domains (EADs) containing cysteine, histidine-dependent amidohydrolases/peptidases (CHAP, PF05257) and N-acetylmuramoyl-L-alanine amidase (Amidase-3, PF01520) domains. Comparison of 98 endolysin genes of S. aureus phages deposited in GenBank showed that they can be classified into six groups based on their domain composition. Interestingly, approximately 80.61 % of the staphylococcal endolysins have a src-homology 3 (SH3, PF08460) domain as CBD, but the remaining 19.39 %, including LysSA97, has a putative C-terminal CBD with no homology to the known CBD. The fusion protein containing green fluorescent protein and the putative CBD of LysSA97 showed a specific binding spectrum against staphylococcal cells comparable to SH3 domain (PF08460), suggesting that the C-terminal domain of LysSA97 is a novel CBD of staphylococcal endolysins. PMID- 27498126 TI - High prevalence of DUOX2 gene mutations among children with congenital hypothyroidism in central China. AB - Congenial hypothyroidism (CH) is the most common congenital endocrine disease and is treatable when recognized early enough. We investigated the genetic variants in 12 children diagnosed with CH by newborn screening in Huangshi area central China. Twelve genes commonly involved in CH development were studied. Genomic DNA from peripheral blood was used to amplify all exons of the selected genes, and the constructed sequencing libraries were subjected to next generation high throughput DNA sequencing (NGS). Analysis of the sequencing results identified rare genetic variants in 11 of the 12 patients (91.7%), and two novel rare variants were found in DUOX2 gene and two in TPO gene. Mutations in DUOX2 gene were identified in 10 patients (83.3%), and all these patients were found to carry bi-allelic, tri-allelic mutations or compound mutations with other genes. Recurrent DUOX2 mutations include K530X, R683L, R1110Q, and L1343F. Truncating, splicing, and proven deleterious DUOX2 missense mutations were detected in 50% of the patients. Mutations in TG gene were identified in four patients, and mutations in TPO, THSR, SLC26A4 genes were identified, one in each patient, respectively. The high prevalence of DUOX2 mutations in this cohort of children with CH appears striking and surprising. The clinical implications were discussed. PMID- 27498127 TI - Societal cost of subcutaneous and intravenous trastuzumab for HER2-positive breast cancer - An observational study prospectively recording resource utilization in a Swedish healthcare setting. AB - INTRODUCTION: Trastuzumab is part of the standard treatment for HER2-positive breast cancer. The aim of this study was to estimate the societal value of trastuzumab administered through subcutaneous (SC) injection compared to intravenous (IV) infusion. METHODS: Female patients with HER2-positive breast cancer receiving SC or IV trastuzumab were consecutively enrolled from five Swedish oncology clinics from 2013 to 2015. Data on time and resource utilization was collected prospectively using patient and nurse questionnaires. Societal costs were calculated by multiplying the resource use by its corresponding unit price, including direct medical costs (pharmaceuticals, materials, nurse time, etc.), direct non-medical costs (transportation) and indirect costs (production loss, lost leisure time). Costs were reported separately for patients receiving trastuzumab for the first time and non-first time ("subsequent treatment"). RESULTS: In total, 101 IV and 94 SC patients were included in the study. The societal costs were lower with SC administration. For subsequent treatments the cost difference was ?117 (IV ?2099; SC ?1983), partly explained by a higher time consumption both for nurses (14 min) and patients (23 min) with IV administration. Four IV and 16 SC patients received trastuzumab for the first time and were analysed separately, resulting in a difference in societal costs of ?897 per treatment. A majority of patients preferred SC to IV administration. CONCLUSION: SC administration resulted in both less direct medical costs and indirect costs, and was consequently less costly than IV administration from a societal perspective in a Swedish setting. PMID- 27498128 TI - IHC4 score plus clinical treatment score predicts locoregional recurrence in early breast cancer. AB - PURPOSE: Immunohistochemical 4 (IHC4) score plus Clinical Treatment Score (CTS) is an inexpensive tool predicting risk of distant recurrence in women with early breast cancer (EBC). IHC4 score is based on ER, PR, HER2 and Ki67 index. This study explores the role of the combined score (IHC4 + CTS) in predicting risk of locoregional recurrence (LRR) in women with EBC who had breast conservation surgery (BCS) without adjuvant radiotherapy (study group). The secondary objective was to evaluate the clinicopathological differences between our study group and women who had adjuvant radiation following BCS (control group). METHODS AND MATERIALS: Patients were selected from the local database over a 13-year period. IHC testing was done where results were missing. Combined scores were calculated using the appropriate formulae. RESULTS: Patients in the study group (81 patients) had favorable clinicopathological features compared to the control group (1406 patients). The Cox regression indicated a statistically significant association between the combined score and the risk of LRR (p = 0.03). The incidence of LRR was zero, 20% and 33.3% in the low, intermediate and high risk groups respectively (p = 0.007). Margin status was the only variable not included in the combined score. The Cox regression analysis demonstrated that the combined score (p = 0.02) and the ordinal measure of margins (p = 0.03) were significant independent predictors of LRR. CONCLUSION: This is the first study of its kind. The IHC4 score + CTS can be used to identify low risk women who can potentially avoid adjuvant radiotherapy. PMID- 27498130 TI - Rheological Flow Behavior of Structural Polysaccharides from Edible Tender Cladodes of Wild, Semidomesticated and Cultivated 'Nopal' (Opuntia) of Mexican Highlands. AB - The aim of this study was to quantify the content of polysaccharides of edible tender cladodes (nopalitos) of three species of Opuntia and to evaluate the rheological flow behavior of isolated polysaccharides. A completely randomized experimental design was used to characterize a wild (O. streptacantha), a semidomesticated (O. megacantha) and a domesticated (O. ficus-indica) species. Mucilage content was higher (4.93 to 12.43 g 100 g-1 dry matter), tightly bound hemicelluloses were lower (3.32 to 1.81 g 100 g-1 dry matter) and pectins and loosely bound hemicelluloses were not different in wild than in domesticated species. Aqueous solution/suspensions of mucilage, pectins, hemicellulose and cellulose of all species showed non-Newtonian behavior under simple shear flow. The flow behavior of the structural polysaccharides was well described by the Ostwald de-Waele model. Pectins and mucilages exhibited the highest consistency indexes (K values ranged from 0.075 to 0.177 Pasn) with a moderated shear thinning behavior (n values ranged from 0.53 to 0.67). Cellulose dispersions exhibited the most shear-thinning behavior (n values ranged from 0.17 to 0.41) and hemicelluloses showed a tendency to Newtonian flow (n values ranged from 0.82 to 0.97). The rheological flow properties of these polysaccharides may be useful to improve the textural and sensory qualities of some foods and pharmaceutical materials. Moreover, they can emerge as functional ingredients mainly due to the nutraceutical properties that have been attributed to nopalitos. PMID- 27498129 TI - Toxicity of dual HER2-blockade with pertuzumab added to anthracycline versus non anthracycline containing chemotherapy as neoadjuvant treatment in HER2-positive breast cancer: The TRAIN-2 study. AB - BACKGROUND: The addition of pertuzumab to neoadjuvant trastuzumab-based chemotherapy improves pathologic complete response rates in HER2-positive breast cancer. However, increased toxicity has been reported with the addition of pertuzumab, and this may differ between various chemotherapy backbone regimens. We evaluated toxicities of pertuzumab when added to either FEC-T (5-fluorouracil, epirubicin, cyclophosphamide, trastuzumab) or weekly paclitaxel, trastuzumab, carboplatin (PTC). METHODS: The TRAIN-2 study is a neoadjuvant randomized controlled trial in stage II and III HER2-positive breast cancer (NCT01996267). Patients are randomly assigned to receive either three cycles of FEC-T plus pertuzumab or three cycles of PTC plus pertuzumab, followed by six cycles of PTC plus pertuzumab in both arms. Toxicities are described per treatment arm according to the Common Toxicity Criteria for Adverse Events version 4.03. RESULTS: This analysis includes 110 patients balanced over both treatment arms. Neutropenia was the most common hematologic toxicity, with grade 3-4 occurring in 53% in the FEC-T-arm and in 51% in the PTC-arm. Febrile neutropenia occurred in 9% in the FEC-T arm and did not occur in the PTC-arm. Secondary G-CSF prophylaxis was used in 35-40% of patients. Asymptomatic ejection fraction decrease grade 2 was observed in 24% in the FEC-T-arm and 11% in the PTC-arm. The most common grade 3-4 non-hematologic toxicity was diarrhea (5% in the FEC-T-arm and 18% in the PTC-arm). CONCLUSIONS: Pertuzumab in combination with FEC-T mostly causes neutropenia, and when added to PTC mostly causes diarrhea. Significant cardiac toxicity is rare with both regimens, and toxicity is overall well manageable. PMID- 27498131 TI - Editorial overview: Biotic interactions: Communicative interactions of plants: plant biology in the age of information. PMID- 27498132 TI - Computed tomography imaging to quantify the area of the endocardial subvalvular apparatus in hypertrophic cardiomyopathy - Relationship to outflow tract obstruction and symptoms. AB - BACKGROUND: Abnormalities of the endocardial subvalvular apparatus (SVA), which includes the papillary muscles directly attached to the mitral leaflet and left ventricular apical-basal muscle bundles, are occasionally identified in hypertrophic cardiomyopathy (HCM). Their associations with left ventricular outflow tract (LVOT) obstruction are unknown. METHODS: We retrospectively reviewed cardiac computed tomography image data sets of 107 consecutive patients with HCM [56 obstructive (HOCM) and 51 non-obstructive (HNOCM)] as well as 53 controls. We evaluated anomalies of the SVA, measured the cross-sectional area of the SVA at the level of the LVOT, and subsequently assessed its correlation with the LVOT pressure gradient with and without medication. RESULTS: The area of the SVA was greater in HOCM than in HNOCM patients and in the control group (2.5 +/- 1.3 cm(2), 1.4 +/- 0.8 cm(2), and 0.9 +/- 0.6 cm(2), respectively; p < 0.0001). Anomalies in the SVA were more often observed in the HOCM group than in the HNOCM patients and controls (abnormal papillary muscles, 14%, 8%, and 0%, respectively; P = 0.010; LV apical-basal muscle bundles, 73%, 65%, and 45%, respectively; P = 0.0094). Among HOCM patients, logistic regression analysis demonstrated that an SVA area of 2.2 cm(2) was an independent risk factor of residual severe LVOT obstruction (>=50 mmHg) after medication (odds ratio, 10.1; 95% confidence interval, 2.05-49.80). CONCLUSION: An increased area of the endocardial subvalvular apparatus could be an independent risk factor for clinically relevant LVOT obstruction refractory to medication. PMID- 27498133 TI - Reply to "Establishing the independence and clinical importance of non-alcoholic fatty liver disease as a risk factor for cardiovascular disease". PMID- 27498134 TI - Establishing the independence and clinical importance of non-alcoholic fatty liver disease as a risk factor for cardiovascular disease. PMID- 27498135 TI - Tracking cognitive processing stages with MEG: A spatio-temporal model of associative recognition in the brain. AB - In this study, we investigated the cognitive processing stages underlying associative recognition using MEG. Over the last four decades, a model of associative recognition has been developed in the ACT-R cognitive architecture. This model was first exclusively based on behavior, but was later evaluated and improved based on fMRI and EEG data. Unfortunately, the limited spatial resolution of EEG and the limited temporal resolution of fMRI have made it difficult to fully understand the spatiotemporal dynamics of associative recognition. We therefore conducted an associative recognition experiment with MEG, which combines excellent temporal resolution with reasonable spatial resolution. To analyze the data, we applied non-parametric cluster analyses and a multivariate classifier. This resulted in a detailed spatio-temporal model of associative recognition. After the visual encoding of the stimuli in occipital regions, three separable memory processes took place: a familiarity process (temporal cortex), a recollection process (temporal cortex and supramarginal gyrus), and a representational process (dorsolateral prefrontal cortex). A late decision process (superior parietal cortex) then acted upon the recollected information represented in the prefrontal cortex, culminating in a late response process (motor cortex). We conclude that existing theories of associative recognition, including the ACT-R model, should be adapted to include these processes. PMID- 27498136 TI - Effects of bisphenol A on male and couple reproductive health: a review. AB - Bisphenol A (BPA) is a ubiquitous environmental toxicant with endocrine disrupting properties and is suspected to affect human reproduction. The objective of this review was to summarize the potential effects of male exposure to BPA on markers of testicular function and couple reproductive outcomes. Five epidemiologic studies on BPA and reproductive hormones all found significant associations with at least one reproductive hormone; however, no consistent relationships were observed across studies. Six epidemiologic studies evaluated the relation between BPA and semen parameters, and although the majority reported negative associations with various parameters, there were few consistent trends across studies. Finally, three epidemiologic studies examined BPA and couple reproductive outcomes, and only one found an association. Overall, the evidence supporting an association between BPA exposure and adverse male reproductive health outcomes in humans remains limited and inconclusive. Reasons for the discrepancies in results could include, but are not limited to, differences in study populations (e.g., fertile vs. subfertile men), BPA urinary concentrations (occupationally vs. nonoccupationally exposed), misclassification of BPA exposure (e.g., using one urine sample to characterize exposure vs. multiple samples), sample sizes, study design (e.g., cross-sectional vs. prospective), and residual confounding (e.g., due to diet and lifestyle factors). It is also possible that some of the statistically significant findings were due to chance alone. Clearly, further studies are needed to further clarify the role of this ubiquitous endocrine-disrupting chemical on male reproductive health. PMID- 27498137 TI - delta-Opioid receptors: Pivotal role in intermittent hypoxia-augmentation of cardiac parasympathetic control and plasticity. AB - BACKGROUND: Intermittent hypoxia training (IHT) produces robust myocardial protection against ischemia-reperfusion induced infarction and arrhythmias. Blockade of this cardioprotection by antagonism of either beta1-adrenergic or delta-opioid receptors (delta-OR) suggests autonomic and/or opioidergic adaptations. PURPOSE: To test the hypothesis that IHT shifts cardiac autonomic balance toward greater cholinergic and opioidergic influence. METHODS: Mongrel dogs completed 20d IHT, non-hypoxic sham training, or IHT with the delta-OR antagonist naltrindole (200MUg/kgsc). The vagolytic effect of the delta-OR agonist met-enkephalin-arg-phe delivered by sinoatrial microdialysis was evaluated following IHT. Sinoatrial, atrial and left ventricular biopsies were analyzed for changes in delta-OR, the neurotrophic monosialoganglioside, GM-1, and cholinergic and adrenergic markers. RESULTS: IHT enhanced vagal bradycardia vs. sham dogs (P<0.05), and blunted the delta2-OR mediated vagolytic effect of met-enkephalin-arg-phe. The GM-1 labeled fibers overlapped strongly with cholinergic markers, and IHT increased the intensity of both signals (P<0.05). IHT increased low and high intensity vesicular acetylcholine transporter labeling of sinoatrial nodal fibers (P<0.05) suggesting an increase in parasympathetic arborization. IHT reduced select delta-OR labeled fibers in both the atria and sinoatrial node (P<0.05) consistent with moderation of the vagolytic delta2-OR signaling described above. Furthermore, blockade of delta-OR signaling with naltrindole during IHT increased the protein content of delta-OR (atria and ventricle) and vesicular acetylcholine transporter (atria) vs. sham and untreated IHT groups. IHT also reduced the sympathetic marker, tyrosine hydroxylase in ventricle (P<0.05). SUMMARY: IHT shifts cardiac autonomic balance in favor of parasympathetic control via adaptations in opioidergic, ganglioside, and adrenergic systems. PMID- 27498138 TI - Genetic variants in RNA-induced silencing complex genes and prostate cancer. AB - PURPOSE: The purpose of this study is to evaluate the potential association between genetic variants in genes encoding the components of RNA-induced silencing complex and prostate cancer (PCa) risk. Genetic variants chosen for this study are rs3742330 in DICER1, rs4961280 in AGO2, rs784567 in TARBP2, rs7813 in GEMIN4 and rs197414 in GEMIN3. METHODS: The study involved 355 PCa patients, 360 patients with benign prostatic hyperplasia and 318 healthy controls. For individuals diagnosed with PCa, clinicopathological characteristics including serum prostate-specific antigen level at diagnosis, Gleason score (GS) and clinical stage were determined. Genotyping was performed using high-resolution melting analysis, PCR-RFLP, TaqMan SNP Genotyping Assay and real-time PCR-based genotyping assay using specific probes. Allelic and genotypic associations were evaluated by unconditional linear and logistic regression methods. RESULTS: The study provided no evidence of association between the analyzed genetic variants and PCa risk. Nevertheless, allele A of rs784567 was found to confer the reduced risk of higher serum PSA level at diagnosis (P = 0.046; Difference = -66.64, 95 % CI -131.93 to 1.35, for log-additive model). Furthermore, rs4961280, as well as rs3742330, were shown to be associated with GS. These variants, together with rs7813, were found to be associated with the lower clinical stage of PCa. Also, rs3742330 minor allele G was found to be associated with lower PCa aggressiveness (P = 0.036; OR 0.14, 95 % CI 0.023-1.22, for recessive model). CONCLUSIONS: According to our data, rs3742330, rs4961280 and rs7813 qualify for potentially protective genetic variants against PCa progression. These variants were not shown to be associated with PCa risk. PMID- 27498139 TI - Partial nephrectomy versus ablative therapy for the treatment of renal tumors in an imperative setting. AB - PURPOSE: To compare partial nephrectomy (PN) and percutaneous ablative therapy (AT) for renal tumor in imperative indication of nephron-sparing technique (NST). MATERIALS AND METHODS: Between 2000 and 2015, 284 consecutive patients with a kidney tumor in an imperative indication of NST were retrospectively included in a multicenter study. PN [open (n = 146), laparoscopic (n = 9), or robotic approach (n = 17)] and AT [radiofrequency ablation (n = 104) or cryoablation (n = 8)] were performed for solitary kidney (n = 146), bilateral tumor (n = 78), or chronic kidney disease (CKD) (n = 60). RESULTS: Patients in the PN group had larger tumors and a higher RENAL score. There were no differences between the two groups with respect to age, reasons for imperative indication, and preoperative eGFR. Patients in the AT group had a higher ASA and CCI. PN had worse outcomes than AT in terms of transfusion rate, length of stay, and complication rate. Local radiological recurrence-free survival was better for PN, but metastatic recurrence was similar. Percentage of eGFR decrease was similar in the two groups. Temporary or permanent dialysis was not significantly different. On multivariate analysis, PN and AT had a similar eGFR change when adjusted for tumor complexity, reason of imperative indication and CCI. CONCLUSION: In imperative indication of nephron-sparing treatment for a kidney tumor, either PN or AT can be proposed. PN offers the ability to manage larger and more complex tumors while providing a better local control and a similar renal function loss. PMID- 27498140 TI - Cancer in Europe: Death sentence or life sentence? AB - With so many adults and children receiving successful treatment for their cancer, survivorship is now a 'new' and critical issue. It is increasingly recognised that the growing numbers of survivors face new challenges in their bid to return to 'normal' life. What is not yet so widely recognised is the need for a broad response to help them cope-with stigmatisation, misunderstanding, lifelong issues of confidence and social adaptation, and even access to employment and to financial services. As a further stage in its programme of attention to this aspect of cancer, the European Organisation for Research and Treatment of Cancer (EORTC) brought survivors, researchers, carers, authorities and policymakers together at a meeting in Brussels in March/April 2016, to learn at first hand about the posttreatment experience of cancer survivors. The meeting demonstrated that while research is well advanced in many of the medical consequences of survivorship, understanding is still lacking of many non-clinical, personal and administrative issues. The meeting raised the discussion of survivorship research beyond the individual to a population-based approach, exploring the related socioeconomic issues. Its exploration of initiatives across Europe countries provoked new thinking on the need for effective collaboration, with a new focus on non-clinical issues, including effective dialogue with financial service providers and employers, improvements in collecting, exchanging and accessing data, and above all, ways of translating research outcomes into action. This will require wider recognition that, as Francoise Meunier, Director Special Projects, EORTC, said, 'It is time for a new mind set'. PMID- 27498141 TI - GNAQ and GNA11 mutations occur in 9.5% of mucosal melanoma and are associated with poor prognosis. AB - BACKGROUND: Mucosal melanoma (MM) is a rare subtype of melanoma in Caucasians with extremely poor prognosis, and therapy strategy has not been clearly established for MM. We aimed to investigate the genetic aberrations possibly applicable in targeted therapy of MM. We examined the somatic mutations of GNAQ and GNA11 (GNAQ/11, encoding the guanine nucleotide-binding alpha subunits) in MM and evaluated their correlation to clinicopathologic features of MM. METHODS: This study collected samples from primary lesions of 284 MM patients. Tissue samples were analysed for mutations in exons 4 and 5 of GNAQ/11 in genomic DNA by polymerase chain reaction amplification and Sanger sequencing. Correlations of GNAQ/11 mutations to clinicopathologic features and prognosis of MM were evaluated. RESULTS: The overall mutation frequency of GNAQ/11 in MM was 9.5% (27 in 284), with a frequency of 4.6% and 4.9% for GNAQ and GNA11 mutations, respectively. The mutations in exon 5 of GNAQ/11 occurred exclusively in codon 209. GNAQ(Q209L) was the most prevalent variation (92.3% of missense GNAQ mutations). GNAQ/11 mutations were not significantly associated with age, gender, ulceration, and primary anatomic site. The median overall survival for MM patients with GNAQ mutations (16.0 versus 26.0 months, P = 0.031) or GNA11 mutations (15.0 versus 26.0 months, P = 0.039) were significantly shorter than those for patients with wild-type GNAQ and GNA11, respectively. CONCLUSIONS: Our study suggests that GNAQ and GNA11 mutations occur frequently in MM and may be a prognostic factor for MM. Our data implicate that GNAQ/11 may be potential targets for targeted therapy of MM. PMID- 27498142 TI - Oral pirfenidone protects against fibrosis by inhibiting fibroblast proliferation and TGF-beta signaling in a murine colitis model. AB - Inflammatory bowel disease (IBD), particularly Crohn's disease, frequently causes intestinal fibrosis that ultimately leads to formation of strictures requiring bowel resection. Currently there is no effective antifibrotic therapy available for this disease. Pirfenidone is a small compound that has a broad spectrum of antifibrogenic effect and has been used for the treatment of fibrotic diseases in various organs. The present study aimed to investigate the antifibrogenic effect of pirfenidone in a dextran sulfate sodium (DSS)-induced murine colitis model. C57BL/6 mice were used and animals were randomly divided into groups receiving pirfenidone or vehicle by oral or transanal routes. Inflammation- and fibrosis related indexes including body weight, colon length, disease activity, histological change, mRNA expression of pro-inflammatory and pro-fibrogenic cytokines were assessed. Furthermore, we performed in vitro analysis using CCD18 Co fibroblasts to evaluate cell proliferation, transdifferentiation, and viability after the cells were cultured with pirfenidone. It was found that oral administration of pirfenidone reduced deposition of collagen in colitis associated fibrosis, and significantly suppressed the mRNA expression of col1a2, col3a1, and TGF-beta. Moreover, pirfenidone inhibited the activation of TGF-beta related smad and MAPK pathways both in vitro and in vivo. Clinical and histological evaluation demonstrated that pirfenidone had no anti-inflammatory effect. The antifibrogenic effect was reduced when pirfenidone was administered in a delayed manner and was unobserved if given locally. Pirfenidone suppressed fibroblast proliferation and transdifferentiation without observed toxicity. Altogether, our results suggested that oral pirfenidone protects against fibrosis of DSS-induced colitis through inhibiting the proliferation of colonic fibroblasts and TGF-beta signaling pathways. PMID- 27498143 TI - Metabolism and gas exchange patterns in Rhodnius prolixus. AB - Insect's metabolic rate and patterns of gas-exchange varies according to different factors such as: species, activity, mass, and temperature among others. One particular striking pattern of gas-exchange in insects is discontinuous gas exchange cycles, for which many different hypotheses regarding their evolution have been stated. This article does not pretend to be an extensive review on the subject, rather to focus on the work performed on the haematophagous bug Rhodnius prolixus, a model organism used from the mid XX century until present days, with the great influence of Wigglesworth and his students/collaborator's work. I have no doubt that the renovated field of insect gas-exchange has a bright future and will advance at large gaits thank to the help of this model organism, R. prolixus, whose entire genome has recently being unraveled. PMID- 27498144 TI - Sclerotised spines in the female bursa associated with male's spermatophore production in cantharidin-producing false blister beetles. AB - Cantharidin is a defence chemical synthesised in only two beetle families Meloidae and Oedemeridae. In Meloidae, cantharidin is used as a defence chemical in eggs. However, in Oedemeridae the function of cantharidin remains unclear. Based on morphological comparison of female internal reproductive organs in 39 species of Oedemeridae, we found that some species have sclerotised spines in the bursa copulatrix (bursal spines), while others have no such spines. Molecular phylogenetic trees inferred from mitochondrial 16S and nuclear 28S rRNA gene sequences suggested multiple evolutionary origins of bursal spines from an ancestor without spines. In the species which lacked spines, males transferred small amounts of ejaculates to females; however, in species with spines, males transferred large spermatophores. Deposited spermatophores gradually disappeared in the bursa, probably owing to absorption. To compare the amounts of cantharidin in eggs laid by species with and without bursal spines, we constructed a new bioassay system using the small beetle Mecynotarsus tenuipes from the family Anthicidae. M. tenuipes individuals were attracted to droplets of cantharidin/acetone solution, and the level of attraction increased with cantharidin concentration. This bioassay demonstrated that the eggs of Nacerdes caudata and N. katoi, both of which species have conspicuous bursal spines, contain more cantharidin than the eggs of N. waterhousei, which lacks spines. In the former species, males transfer large spermatophores to the female, and spermatophores are eventually broken down and digested within the female's spiny bursa. Thus, females with bursal spines may be able to provide more cantharidin to their eggs. PMID- 27498145 TI - Early effects of Abeta1-42 oligomers injection in mice: Involvement of PI3K/Akt/GSK3 and MAPK/ERK1/2 pathways. AB - Neuronal and synaptic loss are the best pathological correlates for memory decline in Alzheimer's disease (AD). Soluble beta-amyloid oligomers (AbetaO) are considered to putatively play a crucial role in the early synapse loss and cognitive impairment observed in AD. Evidence suggests that oxidative stress and apoptosis are involved in the mechanism of Abeta-induced neurotoxicity and AD pathogenesis. This study aimed to explore the molecular mechanisms that contribute to the early memory deficits induced by intracerebroventricular injection of AbetaO in mice. Ten days after a single AbetaO injection memory impairments were observed, as measured by Morris water maze and novel object recognition tests. Cognitive decline was associated with increased oxidative stress, caspase-9 activation, and decreased hippocampal synaptophysin immunoreactivity. Furthermore, GSH levels were significantly higher in AbetaO injected mice than in sham mice, showing that a protective mechanism might develop due to oxidative stress. Additionally, AbetaO-induced toxicity was aligned with an increment of the activation of Akt and ERK1/2, and reduced activity of GSK3. These findings suggest that AbetaO injection triggers a cascade of events that mimic the key neuropathological hallmarks of AD. Abeta acute injection helps to better understand how this peptide impairs specific signaling pathways leading to synaptic and memory dysfunctions. Thus, this model is a valid tool for investigating AD and may suggest a new way to develop neuroprotective therapies at such early stages of the disease. PMID- 27498146 TI - GC-MS-based metabolomic study on the antidepressant-like effects of diterpene ginkgolides in mouse hippocampus. AB - Ginkgo biloba extract (GBE), including EGb-761, have been suggested to have antidepressant activity based on previous behavioral and biochemical analyses. However, because GBE contain many constituents, the mechanisms underlying this suggested antidepressant activity are unclear. Here, we investigated the antidepressant-like effects of diterpene ginkgolides (DG), an important class of constituents in GBE, and studied their effects in the mouse hippocampus using a GC-MS-based metabolomics approach. Mice were randomly divided into five groups and injected daily until testing with 0.9% NaCl solution, one of three doses of DG (4.06, 12.18, and 36.54mg/kg), or venlafaxine. Sucrose preference (SPT) and tail suspension (TST) tests were then performed to evaluate depressive-like behaviors in mice. DG (12.18 and 36.54mg/kg) and venlafaxine (VLX) administration significantly increased hedonic behavior in mice in the SPT. DG (12.18mg/kg) treatment also shortened immobility time in the TST, suggestive of antidepressant like effects. Significant differences in the metabolic profile in the DG (12.18mg/kg) compared with the control or VLX group indicative of an antidepressant-like effect were observed using multivariate analysis. Eighteen differential hippocampal metabolites were identified that discriminated the DG (12.18mg/kg) and control groups. These biochemical changes involved neurotransmitter metabolism, oxidative stress, glutathione metabolism, lipid metabolism, energy metabolism, and kynurenic acid, providing clues to the therapeutic mechanisms of DG. Thus, this study showed that DG has antidepressant like activities in mice and shed light on the biological mechanisms underlying the effects of diterpene ginkgolides on behavior, providing an important drug candidate for the treatment of depression. PMID- 27498147 TI - Telencephalic neural activation following passive avoidance learning in a terrestrial toad. AB - The present study explores passive avoidance learning and its neural basis in toads (Rhinella arenarum). In Experiment 1, two groups of toads learned to move from a lighted compartment into a dark compartment. After responding, animals in the experimental condition were exposed to an 800-mM strongly hypertonic NaCl solution that leads to weight loss. Control animals received exposure to a 300-mM slightly hypertonic NaCl solution that leads to neither weight gain nor loss. After 10 daily acquisition trials, animals in the experimental group showed significantly longer latency to enter the dark compartment. Additionally, 10 daily trials in which both groups received the 300-mM NaCl solution after responding eliminated this group effect. Thus, experimental animals showed gradual acquisition and extinction of a passive avoidance respond. Experiment 2 replicated the gradual acquisition effect, but, after the last trial, animals were sacrificed and neural activation was assessed in five brain regions using AgNOR staining for nucleoli-an index of brain activity. Higher activation in the experimental animals, relative to controls, was observed in the amygdala and striatum. Group differences in two other regions, lateral pallium and septum, were borderline, but nonsignificant, whereas group differences in the medial pallium were nonsignificant. These preliminary results suggest that a striatal amygdala activation could be a key component of the brain circuit controlling passive avoidance learning in amphibians. The results are discussed in relation to the results of analogous experiments with other vertebrates. PMID- 27498148 TI - Effects of environmental enrichment on anxiety-like behavior, sociability, sensory gating, and spatial learning in male and female C57BL/6J mice. AB - The influence of housing on cognition and emotional regulation in mice presents a problem for the study of genetic and environmental risk factors for neuropsychiatric disorders: standard laboratory housing may result in low levels of cognitive function or altered levels of anxiety that leave little room for assessment of deleterious effects of experimental manipulations. The use of enriched environment (EE) may allow for the measurement of a wider range of performance in cognitive domains. Cognitive and behavioral effects of EE in male mice have not been widely reproduced, perhaps due to variability in the application of enrichment protocols, and the effects of EE in female mice have not been widely studied. We have developed an EE protocol using common laboratory equipment that, without a running wheel for exercise, results in significant cognitive and behavioral effects relative to standard laboratory housing conditions. We compared male and female wild-type C57BL/6J mice reared from weaning age in an EE to those reared in a standard environment (SE), using common measures of anxiety-like behavior, sensory gating, sociability, and spatial learning and memory. Sex was a significant factor in relevant elevated plus maze (EPM) measures, and bordered on significance in a social interaction (SI) assay. Effects of EE on anxiety-like behavior and sociability were indicative of a general increase in exploratory activity. In male and female mice, EE resulted in reduced prepulse inhibition (PPI) of the acoustic startle response, and enhanced spatial learning and use of spatially precise strategies in a Morris water maze task. PMID- 27498149 TI - A Raf kinase inhibitor demonstrates antiviral activities both in vitro and in vivo against different genotypes of virulent Newcastle disease virus. AB - Newcastle disease (ND) is still one of the major plagues of birds worldwide. Combat actions are limited to vaccines, highlighting the urgent need for new and amply available antiviral drugs. Previous results have shown that Newcastle disease virus (NDV) downregulates the intracellular Raf kinase inhibitor protein (RKIP) expression for efficient replication, suggesting that this molecular may be a suitable target for antiviral intervention. In the present work, we investigated whether or not the Raf kinase inhibitor V (RKIV), which functions in the same way as RKIP by targeting the intracellular Raf kinase, is able to suppress the propagation of enzootic virulent NDV in vitro and in vivo. In vitro antiviral activity of RKIV was assessed by cell-based assay, and in vivo activity was determined in the chicken model. Our results clearly showed that RKIV treatment protected the cells from NDV-induced CPE with the effective concentrations on nM level, and inhibited virus replication in the lungs of infected chickens in a dose-dependent manner and protected chickens from the lethal infection by NDV. Thus, we conclude that the Raf kinase inhibitor compound RKIV, by inhibiting the host cellular target Raf kinase, might be very promising as a new class of antivirals against the enzootic virulent NDV infection. PMID- 27498150 TI - Are nestin-positive mesenchymal stromal cells a better source of cells for CNS repair? AB - In recent years there has been a great deal of research within the stem cell field which has led to the definition and classification of a range of stem cells from a plethora of tissues and organs. Stem cells, by classification, are considered to be pluri- or multipotent and have both self-renewal and multi differentiation capabilities. Presently there is a great deal of interest in stem cells isolated from both embryonic and adult tissues in the hope they hold the therapeutic key to restoring or treating damaged cells in a number of central nervous system (CNS) disorders. In this review we will discuss the role of mesenchymal stromal cells (MSCs) isolated from human olfactory mucosa, with particular emphasis on their potential role as a candidate for transplant mediated repair in the CNS. Since nestin expression defines the entire population of olfactory mucosal derived MSCs, we will compare these cells to a population of neural crest derived nestin positive population of bone marrow-MSCs. PMID- 27498151 TI - Long telomeres and cancer risk among 95 568 individuals from the general population. AB - BACKGROUND: Results regarding telomere length and cancer risk are conflicting. We tested the hypothesis that long telomeres are associated with increased risk of any cancer and specific cancer types in genetic and observational analyses. METHODS: Individuals (N = 95 568) from the Copenhagen City Heart Study and the Copenhagen General Population Study had the telomere length-associated genotypes rs7726159 (TERT), rs1317082 (TERC), and rs2487999 (OBFC1) determined, and 65 176 had telomere length measured. A total of 10 895 individuals had had a cancer diagnosis. Endpoints were any cancer and 25 specific cancer types. We conducted Cox regression analyses and logistic regression analyses. The three genotypes were combined as an allele sum. RESULTS: Telomere length increased 67 base-pairs [95% confidence interval (CI) 61-74] per allele. In logistic regression models, the per-allele odds ratio (OR) for cancer was 1.05 (95% CI 1.03-1.07) for the allele sum, 1.05 (1.02-1.09) for rs7726159, 1.05 (1.02-1.08) for rs1317082 and 1.07 (1.02-1.12) for rs2487999. In contrast, the hazard ratio for any cancer was 1.01 (1.00-1.01) per 200-base-pair increase in telomere length in multivariable adjusted observational analysis. In genetic analyses according to specific cancer types, the per-allele odds ratio was 1.19 (1.12-1.27) for melanoma and 1.14 (1.06 1.22) for lung cancer. CONCLUSIONS: Genetic determinants of long telomeres are associated with increased cancer risk, particularly melanoma and lung cancer. This genetic predisposition to enhanced telomere maintenance may represent a survival advantage for pre-cancerous cells, allowing for multiple cell divisions leading to cancer development. PMID- 27498152 TI - Epigenetic drift in the aging genome: a ten-year follow-up in an elderly twin cohort. AB - BACKGROUND: Current epigenetic studies on aging are dominated by the cross sectional design that correlates subjects' ages or age groups with their measured epigenetic profiles. Such studies have been more aimed at age prediction or building up the epigenetic clock of age rather than focusing on the dynamic patterns in epigenetic changes during the aging process. METHODS: We performed an epigenome-wide association study of intra-individual longitudinal changes in DNA methylation at CpG (cytosine-phosphate-guanine) sites measured in whole-blood samples of a cohort of 43 elderly twin pairs followed for 10 years (age at intake 73-82 years). Biological pathway analysis and survival analysis were also conducted on CpGs showing longitudinal change in their DNA-methylation levels. Classical twin models were fitted to each CpG site to estimate the genetic and environmental effects on DNA-methylation. RESULTS: Our analysis identified 2284 CpG sites whose DNA-methylation levels changed longitudinally over the follow-up. Twin modelling revealed that the longitudinal change for 90% of these CpG sites was explained solely by individual unique environmental factors and only for 10% of these sites was it influenced by familial factors (genetic or shared environment). Over 60% of the identified CpG sites were replicated (same direction and replication P < 0.05) in an independent cross-sectional sample of 300 twins aged from 30 to 74 years. The replication rate went up to 91% for the top 53 CpGs with P < 1 * 10-07. Pathway analysis of genes linked to these CpGs identified biologically meaningful gene-sets involved in cellular-signalling events and in transmission across chemical synapses, which are important molecular underpinnings of aging-related degenerative disorders. CONCLUSION: Our epigenome-wide association studies on a cohort of old twins followed up for 10 years identified highly replicable epigenetic biomarkers predominantly implicated in signalling pathways of degenerative disorders and survival in the elderly. PMID- 27498153 TI - Verbal memory and search speed in early midlife are associated with mortality over 25 years' follow-up, independently of health status and early life factors: a British birth cohort study. AB - BACKGROUND: Cognitive capabilities in childhood and in late life are inversely associated with mortality rates. However, it is unclear if adult cognition, at a time still relatively free from comorbidity, is associated with subsequent mortality, and whether this explains the associations of early life factors with adult mortality. METHODS: We used data from the MRC National Survey of Health and Development, a birth cohort study prospectively assessing 5362 participants born in 1946. The present analysis includes participants followed up from age 43 and undergoing cognitive assessment (verbal memory and search speed). Mortality outcomes were notified through linkage with a national register. Cox regression was used to estimate mortality hazards in relation to cognitive performance at age 43, adjusting for early life factors, socioeconomic position and health status. RESULTS: Data were available on 3192 individuals. Univariable analyses indicated that adult verbal memory and search speed, parental factors, childhood cognition and educational attainment were associated with mortality. However, multivariable models showed that the mortality associations with earlier life factors were explained by adult cognitive capability. A standard deviation increase in verbal memory and search speed scores was associated with lower mortality rates [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.77 0.97, P = 0.02; HR = 0.88, 95% CI 0.78-1.00, P = 0.05, respectively), after adjustment for adult health. CONCLUSIONS: Cognitive capability in early midlife was inversely associated with mortality rates over 25 years and accounted for the associations of family background, childhood cognitive ability and educational attainment with mortality. These findings, in a nationally representative cohort with long-term follow-up, suggest that building cognitive reserve may improve later life health and survival chances. PMID- 27498154 TI - Psychotic experiences in the context of depression: The cumulative role of victimization. AB - Previous studies have reported an association between depression and psychotic experiences, but little is known about what drives this co-occurrence. This study tests the hypothesis that exposure to trauma and bullying may strengthen the relation between depression and psychotic experiences. A total of 799 college students completed self-report questionnaires on psychotic experiences, depression, bullying, and sexual trauma. Hierarchical linear regression analyses were conducted to test the direct relationship between depression and psychotic experiences, as well as interactions. Approximately 20% of respondents reported a history of being bullied, and 7% reported exposure to childhood sexual trauma. There was a significant direct relationship between depression and psychotic experiences. The association between depression and psychotic experiences was significantly stronger among respondents who were victims of both bullying and sexual violence compared to those who experienced either exposure alone, or who were not exposed to either form of victimization. These findings suggest that cumulative exposure to trauma and victimization may contribute to the co occurrence of depression and psychotic experiences. History of victimization should be assessed among individuals with depressive symptoms to improve treatment plans and outcomes. PMID- 27498155 TI - Pure Delta9-tetrahydrocannabivarin and a Cannabis sativa extract with high content in Delta9-tetrahydrocannabivarin inhibit nitrite production in murine peritoneal macrophages. AB - Historical and scientific evidence suggests that Cannabis use has immunomodulatory and anti-inflammatory effects. We have here investigated the effect of the non-psychotropic phytocannabinoid Delta9-tetrahydrocannabivarin (THCV) and of a Cannabis sativa extract with high (64.8%) content in THCV (THCV BDS) on nitric oxide (NO) production, and on cannabinoid and transient receptor potential (TRP) channel expression in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. THCV-BDS and THCV exhibited similar affinity in radioligand binding assays for CB1 and CB2 receptors, and inhibited, via CB2 but not CB1 cannabinoid receptors, nitrite production evoked by LPS in peritoneal macrophages. THCV down-regulated the over-expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin 1beta (IL-1beta) proteins induced by LPS. Furthermore, THCV counteracted LPS-induced up-regulation of CB1 receptors, without affecting the changes in CB2, TRPV2 or TRPV4 mRNA expression caused by LPS. Other TRP channels, namely, TRPA1, TRPV1, TRPV3 and TRPM8 were poorly expressed or undetectable in both unstimulated and LPS challenged macrophages. It is concluded that THCV - via CB2 receptor activation - inhibits nitrite production in macrophages. The effect of this phytocannabinoid was associated with a down-regulation of CB1, but not CB2 or TRP channel mRNA expression. PMID- 27498156 TI - Timing and crosstalk of glucocorticoid signaling with cytokines, neurotransmitters and growth factors. AB - Glucocorticoid actions are tailored to the organs and cells responding thanks to complex integration with ongoing signaling mediated by cytokines, hormones, neurotransmitters, and growth factors. Disruption of: (1) the amount of signaling molecules available locally; (2) the timing with other signaling pathways; (3) the post-translational modifications on glucocorticoid receptors; and (4) the receptors-interacting proteins within cellular organelles and functional compartments, can modify the sensitivity and efficacy of glucocorticoid responses with implications in physiology, diseases and treatments. Tissue sensitivity to glucocorticoids is sustained by multiple systems that do not operate in isolation. We take the example of the interplay between the glucocorticoid and brain-derived neurotrophic factor signaling pathways to deconstruct context dependent glucocorticoid responses that play key roles in physiology, diseases and therapies. PMID- 27498157 TI - Integrins in glioblastoma: Still an attractive target? AB - Integrin-mediated signaling pathways have been found to promote the invasiveness and survival of glioma cells by modifying the brain microenvironment to support the formation of the tumoral niche. A variety of cells in the niche express integrin receptors, including tumor-associated macrophages, fibroblasts, endothelial cells and pericytes. In particular, RGD-binding integrins have been demonstrated to have an important role in the epithelial-mesenchymal transition process, considered the first step in the infiltration of tissue by cancer cells and molecular markers of which have been found in glioma cells. In simultaneous research, Small Molecule Integrin Antagonists (SMIA) yielded initially promising results in in vitro and in vivo studies, leading to clinical trials to test their safety and efficacy in combination with other anticancer drugs in the treatment of several tumor types. The initially high expectations, especially because of their antiangiogenic activity, which appeared to be a winning strategy against GBM, were not confirmed and this cast serious doubts on the real benefits to be gained from the use of SMIA for the treatment of cancer in humans. In this review, we provide an overview of recent findings concerning the functional roles of integrins, especially RGD-binding integrins, in the processes related to glioma cells survival and brain tissue infiltration. These findings disclose a new scenario in which recently developed SMIA might become useful tools to hinder glioblastoma cell dissemination. PMID- 27498158 TI - Pharmacogenetic predictors of toxicity to platinum based chemotherapy in non small cell lung cancer patients. AB - Platinum-based chemotherapy is the standard treatment for NSCLC patients with EGFR wild-type, and as alternative to failure to EGFR inhibitors. However, this treatment is aggressive and most patients experience grade 3-4 toxicities. ERCC1, ERCC2, ERCC5, XRCC1, MDM2, ABCB1, MTHFR, MTR, SLC19A1, IL6 and IL16 gene polymorphisms may contribute to individual variation in toxicity to chemotherapy. The aim of this study was to evaluate the effect of these polymorphisms on platinum-based chemotherapy in NSCLC patients. A prospective cohorts study was conducted, including 141 NSCLC patients. Polymorphisms were analyzed by PCR Real Time with Taqman((r)) probes and sequencing. Patients with ERCC1 C118T-T allele (p=0.00345; RR=26.05; CI95%=4.33, 515.77) and ERCC2 rs50872-CC genotype (p=0.00291; RR=4.06; CI95%=1.66, 10.65) had higher risk of general toxicity for platinum-based chemotherapy. ERCC2 Asp312Asn G-alelle, ABCB1 C1236T-TT and the IL1B rs12621220-CT/TT genotypes conferred a higher risk to present multiple adverse events. The subtype toxicity analysis also revealed that ERCC2 rs50872-CC genotype (p=0.01562; OR=3.23; CI95%=1.29, 8.82) and IL16 rs7170924-T allele (p=0.01007; OR=3.19; CI95%=1.35, 7.97) were associated with grade 3-4 hematological toxicity. We did not found the influence of ERCC1 C8092A, ERCC2 Lys751Gln, ERCC2 Asp312Asn, ERCC5 Asp1104His, XRCC1 Arg194Trp, MDM2 rs1690924, ABCB1 C3435T, ABCB1 Ala893Ser/Thr, MTHFR A1298C, MTHFR C677T, IL1B rs1143623, IL1B rs16944, and IL1B rs1143627 on platinum-based chemotherapy toxicity. In conclusion, ERCC1 C118T, ERCC2 rs50872, ERCC2 Asp312Asn, ABCB1 C1236T, IL1B rs12621220 and IL16 rs7170924 polymorphisms may substantially act as prognostic factors in NSCLC patients treated with platinum-based chemotherapy. PMID- 27498159 TI - Factors associated with self-rated health status in Southwestern Iran: a population-based study. AB - OBJECTIVE: This study aimed to reveal the relationship between self-rated health (SRH) and objective health status in the general population in the Southwest of Iran. STUDY DESIGN: A cross-sectional study. METHODS: Data were collected by face to-face interview with 3554 residents, aged >=18 years, who were selected by multistage sampling procedure. Collected data included sociodemographic, SRH status, and medical conditions; chronic diseases and mental symptoms. SRH was indicated by a single question in five scales of very good, good, fair, poor and very poor. An ordinal logistic regression analysis was used. Independent variables were organized into four blocks: block 1, age, gender, marital status, education level, employment status, size of household and monthly household income; block 2, chronic or long-term illness (coronary heart disease, hypertension and diabetes mellitus); block 3, psychological disorders (anxiety, impatience and sleep disorders); and block 4 (visual, skin, hearing and oral disorders). RESULTS: SRH status in most subjects reported to be positive, indicating 47.3% as very good, 30.8% good, 16.2% fair, 3.3% bad and 2.4% very bad. In studied subjects, poorer SRH was significantly related to older age (odds ratio [OR], 1.01), low-education level (OR, 1.09), single status (OR, 1.25), monthly household income (OR, 1.21), more chronic or long-term illness (OR, 1.61), greater psychological health disorders (OR, 1.69), more dermatologic disorders (OR, 1.30), and hearing problems (OR, 1.47). CONCLUSION: Results of this study revealed that subjects with worse SRH were older with low-education level, lower household monthly income, more chronic illness, greater psychological health disorders, and more visual, skin, hearing and oral disorders. So, SRH, as indicated globally, can be used as a population screening tool to identify subjects who are most in need of public health services. PMID- 27498160 TI - Reply. PMID- 27498161 TI - A nonlinear control scheme based on dynamic evolution path theory for improved dynamic performance of boost PFC converter working on nonlinear features. AB - This paper is concerned to performance improvement of boost PFC converter under large random load fluctuation, ensuring unity power factor (UPF) at source end and regulated voltage at load side. To obtain such performance, a nonlinear controller based on dynamic evolution path theory is designed and its robustness is examined under both heavy and light loading condition. In this paper, %THD and zero-cross-over dead-zone of input current is significantly reduced. Also, very less response time of input current and output voltage to that of load and reference variation is remarked. A simulation model of proposed system is designed and it is realized using dSPACE 1104 signal processor for a 390VDC, 500W prototype. The relevant experimental and simulation waveforms are presented. PMID- 27498162 TI - Finite-time synchronization for second-order nonlinear multi-agent system via pinning exponent sliding mode control. AB - In this paper we investigate the finite-time synchronization for second-order multi-agent system via pinning exponent sliding mode control. Firstly, for the nonlinear multi-agent system, differential mean value theorem is employed to transfer the nonlinear system into linear system, then, by pinning only one node in the system with novel exponent sliding mode control, we can achieve synchronization in finite time. Secondly, considering the 3-DOF helicopter system with nonlinear dynamics and disturbances, the novel exponent sliding mode control protocol is applied to only one node to achieve the synchronization. Finally, the simulation results show the effectiveness and the advantages of the proposed method. PMID- 27498163 TI - C-di-GMP Synthesis: Structural Aspects of Evolution, Catalysis and Regulation. AB - Cellular levels of the second messenger cyclic di-guanosine monophosphate (c-di GMP) are determined by the antagonistic activities of diguanylate cyclases and specific phosphodiesterases. In a given bacterial organism, there are often multiple variants of the two enzymes, which are tightly regulated by a variety of external and internal cues due to the presence of specialized sensory or regulatory domains. Dependent on the second messenger level, specific c-di-GMP receptors then control fundamental cellular processes, such as bacterial life style, biofilm formation, and cell cycle control. Here, I review the large body of data on structure-function relationships in diguanylate cyclases. Although the catalytic GGDEF domain is related to the respective domain of adenylate cyclases, the catalyzed intermolecular condensation reaction of two GTP molecules requires the formation of a competent GGDEF dimer with the two substrate molecules juxtaposed. This prerequisite appears to constitute the basis for GGDEF regulation with signal-induced changes within the homotypic dimer of the input domain (PAS, GAF, HAMP, etc.), which are structurally coupled with the arrangement of the GGDEF domains via a rigid coiled-coil linker. Alternatively, phosphorylation of a Rec input domain can drive GGDEF dimerization. Both mechanisms allow modular combination of input and output function that appears advantageous for evolution and rationalizes the striking similarities in domain architecture found in diguanylate cyclases and histidine kinases. PMID- 27498164 TI - Contribution of Bistability and Noise to Cell Fate Transitions Determined by Feedback Opening. AB - Alternative cell fates represent a form of non-genetic diversity, which can promote adaptation and functional specialization. It is difficult to predict the rate of the transition between two cell fates due to the strong effect of noise on feedback loops and missing parameters. We opened synthetic positive feedback loops experimentally to obtain open-loop functions. These functions allowed us to identify a deterministic model of bistability by bypassing noise and the requirement to resolve individual processes in the loop. Combining the open-loop function with kinetic measurements and reintroducing the measured noise, we were able to predict the transition rates for the feedback systems without parameter tuning. Noise in gene expression was the key determinant of the transition rates inside the bistable range. Transitions between two cell fates were also observed outside of the bistable range, evidenced by bimodality and hysteresis. In this case, a slow transient process was the rate-limiting step in the transitions. Thus, feedback opening is an effective approach to identify the determinants of cell fate transitions and to predict their rates. PMID- 27498165 TI - Compact Structure Patterns in Proteins. AB - Globular proteins typically fold into tightly packed arrays of regular secondary structures. We developed a model to approximate the compact parallel and antiparallel arrangement of alpha-helices and beta-strands, enumerated all possible topologies formed by up to five secondary structural elements (SSEs), searched for their occurrence in spatial structures of proteins, and documented their frequencies of occurrence in the PDB. The enumeration model grows larger super-secondary structure patterns (SSPs) by combining pairs of smaller patterns, a process that approximates a potential path of protein fold evolution. The most prevalent SSPs are typically present in superfolds such as the Rossmann-like fold, the ferredoxin-like fold, and the Greek key motif, whereas the less frequent SSPs often possess uncommon structure features such as split beta sheets, left-handed connections, and crossing loops. This complete SSP enumeration model, for the first time, allows us to investigate which theoretically possible SSPs are not observed in available protein structures. All SSPs with up to four SSEs occurred in proteins. However, among the SSPs with five SSEs, approximately 20% (218) are absent from existing folds. Of these unobserved SSPs, 80% contain two or more uncommon structure features. To facilitate future efforts in protein structure classification, engineering, and design, we provide the resulting patterns and their frequency of occurrence in proteins at: http://prodata.swmed.edu/ssps/. PMID- 27498166 TI - Traction force dynamics predict gap formation in activated endothelium. AB - In many pathological conditions the endothelium becomes activated and dysfunctional, resulting in hyperpermeability and plasma leakage. No specific therapies are available yet to control endothelial barrier function, which is regulated by inter-endothelial junctions and the generation of acto-myosin-based contractile forces in the context of cell-cell and cell-matrix interactions. However, the spatiotemporal distribution and stimulus-induced reorganization of these integral forces remain largely unknown. Traction force microscopy of human endothelial monolayers was used to visualize contractile forces in resting cells and during thrombin-induced hyperpermeability. Simultaneously, information about endothelial monolayer integrity, adherens junctions and cytoskeletal proteins (F actin) were captured. This revealed a heterogeneous distribution of traction forces, with nuclear areas showing lower and cell-cell junctions higher traction forces than the whole-monolayer average. Moreover, junctional forces were asymmetrically distributed among neighboring cells. Force vector orientation analysis showed a good correlation with the alignment of F-actin and revealed contractile forces in newly formed filopodia and lamellipodia-like protrusions within the monolayer. Finally, unstable areas, showing high force fluctuations within the monolayer were prone to form inter-endothelial gaps upon stimulation with thrombin. To conclude, contractile traction forces are heterogeneously distributed within endothelial monolayers and force instability, rather than force magnitude, predicts the stimulus-induced formation of intercellular gaps. PMID- 27498167 TI - Primary Health Care: Potential Home for Family-Focused Preventive Interventions. AB - Family-focused prevention programs have been shown to effectively reduce a range of negative behavioral health outcomes but have had limited reach. Three key barriers must be overcome to expand the reach of family-focused prevention programs and thereby achieve a significant public health impact. These barriers are (1) current social norms and perceptions of parenting programs; (2) concerns about the expertise and legitimacy of sponsoring organizations to offer parenting advice; and (3) a paucity of stable, sustainable funding mechanisms. Primary healthcare settings are well positioned to overcome these barriers. Recent changes within health care make primary care settings an increasingly favorable home for family-focused prevention and suggest possibilities for sustainable funding of family-focused prevention programs. This paper discusses the existing advantages of primary care settings and lays out a plan to move toward realizing the potential public health impact of family-focused prevention through widespread implementation in primary healthcare settings. PMID- 27498168 TI - Mycoextraction of radiolabeled cesium and strontium by Pleurotus eryngii mycelia in the presence of alumina nanoparticles: Sorption and accumulation studies. AB - Widespread use of products based on nanomaterials results in the release of nanoparticles into the environment. Nanoparticles can be taken up by organisms, but they can also coexist with other substances such as radionuclides, thus affecting their uptake or toxicity. In contrast, the sorption capacity of nanoparticles is exploited in water purification. The aim of the study was to investigate: (i) bioaccumulation of cesium and strontium by Pleurotus eryngii mycelia in the presence of alumina nanoparticles (Al2O3 NPs); and (ii) sorption of radionuclides on the surface of nanoparticles. For the experiments, living and dried mycelia were used to permit distinguishing between active uptake and passive sorption of the NPs by P. eryngii. The results are discussed from the perspective of the use of P. eryngii in the mycoextraction of radionuclides. The sorption capacity of Al2O3 NPs and the accumulation by P. eryngii mycelia differ for the applied radioisotopes. The efficiency of Cs and Sr sorption by alumina nanoparticles is 20% and 40%, respectively. Mycelia of P. eryngii have the ability to accumulate 30% of both radioisotopes from the medium. More than 60% of strontium can be removed accumulated from water by P. eryngii mycelia in coexistence with Al2O3 NPs, while the efficiency of cesium removal accumulation is negligible. It was found that alumina nanoparticles do not enhance uptake of radionuclides by P. eryngii mycelia; mycoextraction of radionuclides by mycelia and sorption by Al2O3 NPs are concurrent processes. There was no difference between live or dried mycelia uptake. PMID- 27498170 TI - Carcinogenesis explained within the context of a theory of organisms. AB - For a century, the somatic mutation theory (SMT) has been the prevalent theory to explain carcinogenesis. According to the SMT, cancer is a cellular problem, and thus, the level of organization where it should be studied is the cellular level. Additionally, the SMT proposes that cancer is a problem of the control of cell proliferation and assumes that proliferative quiescence is the default state of cells in metazoa. In 1999, a competing theory, the tissue organization field theory (TOFT), was proposed. In contraposition to the SMT, the TOFT posits that cancer is a tissue-based disease whereby carcinogens (directly) and mutations in the germ-line (indirectly) alter the normal interactions between the diverse components of an organ, such as the stroma and its adjacent epithelium. The TOFT explicitly acknowledges that the default state of all cells is proliferation with variation and motility. When taking into consideration the principle of organization, we posit that carcinogenesis can be explained as a relational problem whereby release of the constraints created by cell interactions and the physical forces generated by cellular agency lead cells within a tissue to regain their default state of proliferation with variation and motility. Within this perspective, what matters both in morphogenesis and carcinogenesis is not only molecules, but also biophysical forces generated by cells and tissues. Herein, we describe how the principles for a theory of organisms apply to the TOFT and thus to the study of carcinogenesis. PMID- 27498171 TI - Diversity in S-layers. AB - Surface layers, referred simply as S-layers, are the two-dimensional crystalline arrays of protein or glycoprotein subunits on cell surface. They are one of the most common outermost envelope components observed in prokaryotic organisms (Archaea and Bacteria). Over the past decades, S-layers have become an issue of increasing interest due to their ubiquitousness, special features and functions. Substantial work in this field provides evidences of an enormous diversity in S layers. This paper reviews and illustrates the diversity from several different aspects, involving the S-layer-carrying strains, the structure of S-layers, the S layer proteins and genes, as well as the functions of S-layers. PMID- 27498169 TI - Eukaryotic resectosomes: A single-molecule perspective. AB - DNA double-strand breaks (DSBs) disrupt the physical and genetic continuity of the genome. If unrepaired, DSBs can lead to cellular dysfunction and malignant transformation. Homologous recombination (HR) is a universally conserved DSB repair mechanism that employs the information in a sister chromatid to catalyze error-free DSB repair. To initiate HR, cells assemble the resectosome: a multi protein complex composed of helicases, nucleases, and regulatory proteins. The resectosome nucleolytically degrades (resects) the free DNA ends for downstream homologous recombination. Several decades of intense research have identified the core resectosome components in eukaryotes, archaea, and bacteria. More recently, these proteins have been characterized via single-molecule approaches. Here, we focus on recent single-molecule studies that have begun to unravel how nucleases, helicases, processivity factors, and other regulatory proteins dictate the extent and efficiency of DNA resection in eukaryotic cells. We conclude with a discussion of outstanding questions that can be addressed via single-molecule approaches. PMID- 27498172 TI - Measuring frailty in Dutch community-dwelling older people: Reference values of the Tilburg Frailty Indicator (TFI). AB - OBJECTIVES: The objectives of this study were to provide reference values of the Tilburg Frailty Indicator (TFI) for community-dwelling older people by age, sex, marital status, ethnicity, education, income, and residence, and examine the effects of these seven socio-demographic variables on frailty. METHODS: 47,768 individuals aged 65 years and older living in the Netherlands completed a health questionnaire (58.5% response rate), including the TFI. The TFI is a self-report questionnaire for measuring frailty, developed from an integral approach of frailty, including physical, psychological, and social domains. RESULTS: Reference values were provided for men and women separately, as a function of age. We found associations of all socio-demographic variables with frailty, also after controlling for the effects of age. These associations held for both sexes and for big cities as wells as more rural areas. For instance, the effect of age was large for total and physical frailty, women were more frail than men, and some very large average frailty differences between the ethnic groups were found, with autochthon people having the lowest frailty score. CONCLUSIONS: In conclusion, this study offers reference values of the TFI by socio-demographic characteristics and explains frailty using these characteristics. This information will support researchers, policymakers and health care professionals in interpreting scores of the TFI, which may guide their efforts to reduce frailty and its adverse outcomes. PMID- 27498173 TI - Effects of Coaching and Repeated Trials on Maximum Phonational Frequency Range in Children. AB - PURPOSE: Maximum phonational frequency range (MPFR) is the frequency range from the lowest to the highest pitch that an individual can produce. This study investigated the effects of coaching and repeated trials on MPFR in a group of school-age children. METHODS: Thirty girls aged 6-11 years were randomly assigned into two groups: coaching and non-coaching. All of the participants produced the lowest and the highest phonational frequency for 10 times each. The participants in the coaching group were prompted by the clinician with verbal encouragement and a visual cue (hand-sweeping) to produce their maximum performance. The participants in the non-coaching group were simply asked to repeat the task 10 times. RESULTS: The clinician's coaching helped the participants in the coaching group reach their MPFR in fewer trials. The MPFRs elicited in 10 trials were significantly greater than those elicited in fewer trials. CONCLUSIONS: These findings suggested that coaching and repeated trials could facilitate the elicitation of MPFR more efficiently. PMID- 27498174 TI - Prevalence of Voice Disorders in Iranian Primary School Students. AB - OBJECTIVES: The voice is the sound produced by vibration of our vocal cords and has an important role in verbal communication. A child's voice disorder may significantly impair his or her ability to be heard and understood. The purpose of this study was to determine the prevalence of voice disorders in primary school students. METHODS AND MATERIALS: In this descriptive-analytical study, a total of 501 fourth through fifth grade primary school students (boys = 51.6%, girls = 48.4%) with the age range of 10-12 years were selected from nine public school systems in Tehran that were assessed in October 2013 through March 2014. Presence of a voice disorder characterized by hoarseness was identified by a dual approach including investigator screening and parent identification. We used the grade of overall dysphonia, roughness, breathiness, asthenia, and strain scale for perceptual evaluation of voice. All children were assessed with video laryngoscopy examination by an otorhinolaryngologist. The recordings were made during spontaneous speech, counting numbers, sustained utterance of the (/a/) vowel, reading a standard passage in Farsi, and the ratio of /s/ and /z/. Statistical analysis was done via chi-square test and t test. RESULTS: Results indicated that the prevalence of voice disorders in primary school students is 53.2%. The results indicated significant differences between gender and subjects with lesions (P = 0.00000), gender and vocal disorders (P = 0.04), and s/z ratio and type of lesion (P = 0.0002). CONCLUSION: Phonotrauma seems to play an important role in child dysphonia, with nodules as main diagnosis. PMID- 27498175 TI - Dental Morbidities, Smoking, Oral Hygiene, and Inflammatory Bowel Diseases. PMID- 27498176 TI - Fecal Immunochemical Test Detects Sessile Serrated Adenomas and Polyps With a Low Level of Sensitivity. AB - BACKGROUND & AIMS: The serrated pathway is a distinct pathway of colorectal carcinogenesis that has been implicated in development of a substantial proportion of interval colorectal cancers. The fecal immunochemical test (FIT) detects early neoplasms with a higher level of sensitivity than the guaiac test. We investigated the sensitivity of the FIT in detection of sessile serrated adenomas/polyps (SSA/Ps). METHODS: We performed a prospective study of 6198 asymptomatic subjects (mean age, 59.0 +/- 7.0 years) who received concurrent screening colonoscopies and FITs at the Health Management Center of National Taiwan University Hospital from August 2010 through November 2014. The sensitivity of FIT for conventional adenoma, advanced adenoma, and SSA/P at different cutoffs was calculated, and results were compared by using multivariate analysis adjusted for potential confounders. RESULTS: Prevalence values of SSA/P, adenoma, and advanced adenoma were 1.4%, 20.2%, and 5.5%, respectively. At cutoffs of 10, 15, and 20 MUg hemoglobin/g feces, the FIT detected all SSA/Ps with 12.3%, 6.2%, and 6.2% sensitivity, large SSA/Ps with 18.4%, 10.5%, and 10.5% sensitivity, and advanced adenomas with 32.4%, 24.5%, and 20.9% sensitivity, respectively. Multivariate analysis revealed that positive results from the FIT did not differ significantly between individuals with SSA/P and those with non advanced adenoma or those with negative findings from colonoscopy. Patients with large SSA/Ps were less likely to have positive results from the FIT than patients with advanced adenoma, with odds ratios of 0.44 (95% confidence interval [CI], 0.18-1.05), 0.30 (95% CI, 0.10-0.90), and 0.37 (95% CI, 0.12-1.12) at cutoffs of 10, 15, and 20 MUg hemoglobin/g feces, respectively, after adjusting for lesion size, even with synchronous conventional adenoma. CONCLUSIONS: In a prospective study of 6198 subjects receiving the FIT and colonoscopy, we found that the FIT detected SSA/Ps with significantly lower levels of sensitivity than conventional adenoma. Further studies are needed to determine the effects of these findings on the effectiveness of FIT-based colorectal cancer screening program. PMID- 27498177 TI - Inkjet printed periodical micropatterns made of inert alumina ceramics induce contact guidance and stimulate osteogenic differentiation of mesenchymal stromal cells. AB - Bioinert high performance ceramics exhibit detrimental features for implant components with direct bone contact because of their low osseointegrating capability. We hypothesized that periodical microstructures made of inert alumina ceramics can influence the osteogenic differentiation of human mesenchymal stromal cells (hMSC). In this study, we manufactured pillared arrays made of alumina ceramics with periodicities as low as 100MUm and pillar heights of 40MUm employing direct inkjet printing (DIP) technique. The response of hMSC to the microstructured surfaces was monitored by measuring cell morphology, viability and formation of focal adhesion complexes. Osteogenic differentiation of hMSCs was investigated by alkaline phosphatase activity, mineralization assays and expression analysis of respective markers. We demonstrated that MSCs react to the pillars with contact guidance. Subsequently, cells grow onto and form connections between the microstructures, and at the same time are directly attached to the pillars as shown by focal adhesion stainings. Cells build up tissue-like constructs with heights up to the micropillars resulting in increased cell viability and osteogenic differentiating properties. We conclude that periodical micropatterns on the micrometer scale made of inert alumina ceramics can mediate focal adhesion dependent cell adhesion and stimulate osteogenic differentiation of hMSCs. PMID- 27498179 TI - Pathogen-associated porin turns IL-10 competent B-1a cells toward proinflammatory cytokine response. AB - Shigellosis is a major problem in the developing countries causing mortality and morbidity particularly among the children. Shigella spp. harbours the epithelial cells of the human colon to infect the host and spread the disease. We analyzed the response of B-1a cells, the major component of the mucosal immune system to porin of Shigella dysenteriae type 1. We show that porin while proliferating B-1a cells, deplete Siglec-G, the inhibitory molecule present on B-1a cells. Adjuvanticity of porin has been shown to govern innate signaling for promoting host adaptive immune response. Up-regulation of CD69 and CD40 denotes activation of the cells parallel to abrogation of Siglec-G. As a result of cell activation, porin stimulated the inflammatory cytokines of CD5+ B-1a cells, otherwise rich in IL-10. The work shows B-1a cell responses promote the immunopotentiating activity of porin. PMID- 27498178 TI - Combinatorial extracellular matrix microenvironments promote survival and phenotype of human induced pluripotent stem cell-derived endothelial cells in hypoxia. AB - Recent developments in cell therapy using human induced pluripotent stem cell derived endothelial cells (iPSC-ECs) hold great promise for treating ischemic cardiovascular tissues. However, poor post-transplantation viability largely limits the potential of stem cell therapy. Although the extracellular matrix (ECM) has become increasingly recognized as an important cell survival factor, conventional approaches primarily rely on single ECMs for in vivo co-delivery with cells, even though the endothelial basement membrane is comprised of a milieu of different ECMs. To address this limitation, we developed a combinatorial ECM microarray platform to simultaneously interrogate hundreds of micro-scale multi-component chemical compositions of ECMs on iPSC-EC response. After seeding iPSC-ECs onto ECM microarrays, we performed high-throughput analysis of the effects of combinatorial ECMs on iPSC-EC survival, endothelial phenotype, and nitric oxide production under conditions of hypoxia (1% O2) and reduced nutrients (1% fetal bovine serum), as is present in ischemic injury sites. Using automated image acquisition and analysis, we identified combinatorial ECMs such as collagen IV+gelatin+heparan sulfate+laminin and collagen IV+fibronectin+gelatin+heparan sulfate+laminin that significantly improved cell survival, nitric oxide production, and CD31 phenotypic expression, in comparison to single-component ECMs. These results were further validated in conventional cell culture platforms and within three-dimensional scaffolds. Furthermore, this approach revealed complex ECM interactions and non-intuitive cell behavior that otherwise could not be easily determined using conventional cell culture platforms. Together these data suggested that iPSC-EC delivery within optimal combinatorial ECMs may improve their survival and function under the condition of hypoxia with reduced nutrients. STATEMENT OF SIGNIFICANCE: Human endothelial cells (ECs) derived from induced pluripotent stem cells (iPSC-ECs) are promising for treating diseases associated with reduced nutrient and oxygen supply like heart failure. However, diminished iPSC-EC survival after implantation into diseased environments limits their therapeutic potential. Since native ECs interact with numerous extracellular matrix (ECM) proteins for functional maintenance, we hypothesized that combinatorial ECMs may improve cell survival and function under conditions of reduced oxygen and nutrients. We developed a high-throughput system for simultaneous screening of iPSC-ECs cultured on multi-component ECM combinations under the condition of hypoxia and reduced serum. Using automated image acquisition and analytical algorithms, we identified combinatorial ECMs that significantly improved cell survival and function, in comparison to single ECMs. Furthermore, this approach revealed complex ECM interactions and non-intuitive cell behavior that otherwise could not be easily determined. PMID- 27498180 TI - Stress and binge drinking: A toxic combination for the teenage brain. AB - Young adult university students frequently binge on alcohol and have high stress levels. Based on findings in rodents, we predicted that heavy current alcohol use and elevated stress and depression scores would be associated with deficits on high interference memory tasks, while early onset, prolonged binge patterns would lead to broader cognitive deficits on tests of associative encoding and executive functions. We developed the Concentration Memory Task, a novel computerized version of the Concentration card game with a high degree of interference. We found that young adults with elevated stress, depression, and alcohol consumption scores were impaired in the Concentration Memory Task. We also analyzed data from a previous study, and found that higher alcohol consumption scores were associated with impaired performance on another high interference memory task, based on Kirwan and Stark's Mnemonic Similarity Test. On the other hand, adolescent onset of binge drinking predicted poorer performance on broader range of memory tests, including a more systematic test of spatial recognition memory, and an associative learning task. Our results are broadly consistent with findings in rodents that acute alcohol and stress exposure suppress neurogenesis in the adult hippocampus, which in turn impairs performance in high interference memory tasks, while adolescent onset binge drinking causes more extensive brain damage and cognitive deficits. PMID- 27498182 TI - How to manage central nervous system MRI with a cardiac implantable electronic device? PMID- 27498181 TI - Nonagonal cadherins: A new protein family found within the Stramenopiles. AB - Cadherins, a group of molecules typically associated with planar cell polarity and Wnt signalling, have been little reported outside of the animal kingdom. Here, we identify a new family of cadherins in the Stramenopiles, termed Nonagonal after their 9 transmembrane passes, which contrast to the one or seven passes found in other known cadherin families. Manual curation and experimental validation reveal two subclasses of nonagonal cadherins, depending on the number of uninterrupted extracellular cadherin (EC) modules presented. Firstly, shorter mono-exonic, unimodular, protein models, with 3 to 12 EC domains occur as duplicate paralogs in the saprotrophic Labyrinthulomycetes Aurantiochytrium limanicum and Schizochytrium aggregatum, the gastrointestinal Blastocystis hominis (Blastocystae) and as a single copy gene in the autotrophic Pelagophyte Aureococcus anophagefferens. Larger, single copy, multi-exonal, tri-modular protein models, with up to 72 EC domain in total, are found in the Oomycete genera Albugo, Phytophthora, Pythium and Eurychasma. No homolog was found in the closely related autotrophic Phaeophyceae (brown algae) or Bacillariophyceae (diatoms), nor in several genera of plant and animal pathogenic oomycetes (Aphanomyces, Saprolegnia and Hyaloperonospora). This potential absence was further investigated by synteny analysis of the genome regions flanking the cadherin gene models, which are found to be highly variable. Novel to this new cadherin family is the presence of intercalated laminin and putative carbohydrate binding in tri-modular oomycete cadherins and at the N-terminus of thraustochytrid proteins. As we were unable to detect any homologs of proteins involved in signalling pathways where other cadherin families are involved, we present a conceptual hypothesis on the function of nonagonal cadherin based around the presence of putative carbohydrate binding domains. PMID- 27498183 TI - Characterization of efficient plant-growth-promoting bacteria isolated from Sulla coronaria resistant to cadmium and to other heavy metals. AB - The inoculation of plants with plant-growth-promoting rhizobacteria has become a priority in the phytoremediation of heavy-metal-contaminated soils. A total of 82 bacteria were isolated from Sulla coronaria root nodules cultivated on four soil samples differently contaminated by heavy metals. The phenotypic characterization of these isolates demonstrated an increased tolerance to cadmium reaching 4.1mM, and to other metals, including Zn, Cu and Ni. Polymerase Chain Reaction/Restriction Fragment Length Polymorphism (PCR/RFLP) analysis showed a large diversity represented by genera related to Agrobacterium sp., R. leguminosarum, Sinorhizobium sp., Pseudomonas sp., and Rhizobium sp. Their symbiotic effectiveness was evaluated by nodulation tests. Taking into consideration efficiency and cadmium tolerance, four isolates were chosen; their 16SrRNA gene sequence showed that they belonged to Pseudomonas sp. and the Rhizobium sullae. The selected consortium of soil bacteria had the ability to produce plant-growth-promoting substances such as indole acetic acid and siderophore. The intracellular Cd accumulation was enhanced by increasing the time of incubation of the four soil bacteria cultivated in a medium supplemented with 0.1mM Cd. The existence of a cadmium-resistant gene was confirmed by PCR. These results suggested that Sulla coronaria in symbiosis with the consortium of plant-growth-promoting rhizobacteria (PGPR) could be useful in the phytoremediation of cadmium-contaminated soils. PMID- 27498184 TI - Tensions and conflicts in 'choice': Womens' experiences of freebirthing in the UK. AB - BACKGROUND: the concept of choice is a central tenet of modern maternity care. However, in reality women's choice of birth is constrained by a paucity of resources and dominant medical and risk adverse discourses. In this paper we add to this debate through highlighting the tensions and conflicts that women faced when enacting a freebirthing choice. METHODS: secondary analysis of data collected to explore why women choose to freebirth in the UK was undertaken. Ten women were recruited from diverse areas of the UK via invitations on freebirthing websites. Women provided a narrative and/or participated in an in-depth interview. A thematic analysis approach was used. FINDINGS: we present three key themes. First 'violation of rights' highlights the conflicts women faced from maternity care systems who were unaware of women's legal rights to freebirth, conflating this choice with issues of child protection. 'Tactical planning' describes some of the strategies women used in their attempts to achieve the birth they desired and to circumnavigate any interference or reprisals. The third theme, 'unfit to be a mother' describes distressing accounts of women who were reported to social services. CONCLUSION AND IMPLICATIONS FOR PRACTICE: women who choose to freebirth face opposition and conflict from maternity providers, and often negative and distressing repercussions through statutory referrals. These insights raise important implications for raising awareness among health professionals about women's legal rights. They also emphasise a need to develop guidelines and care pathways that accurately and sensitively support the midwives professional scope of practice and women's choices for birth. PMID- 27498185 TI - Education, employment and practice: Midwifery graduates in Papua New Guinea. AB - BACKGROUND: Papua New Guinea has a very high maternal mortality rate (773/100,000), low rates of supervised births and a critical shortage of skilled midwives. A midwifery education initiative commenced in 2012, funded by the Australian Government and led by the National Department of Health. One specific objective of the initiative was to improve the standard of clinical teaching and practice in four schools of midwifery. There were 394 midwives educated over the 4 year period (2012-2015) representing half of all midwives in Papua New Guinea. A study was undertaken to describe the educational programme, employment, practices and experiences of graduates who studied midwifery in 2012 and 2013 as part of the initiative. OBJECTIVE: the aim of this paper is to explore the education, employment and practice of newly graduated midwives in Papua New Guinea. DESIGN: a mixed methods descriptive study design was used. Surveys and focus groups were used to gather data. Ethical approval was granted by the relevant Human Research Ethics Committees. SETTING AND PARTICIPANTS: all midwifery graduates in 2012 and 2013 from the four midwifery schools in Papua New Guinea were included in the study and almost 80% were contacted. FINDINGS: nearly 90% of graduates were working as midwives, with an additional 3% working as midwifery or nursing educators. This study discovered that graduates exhibited increased skills acquisition and confidence, leadership in maternal and newborn care services and a marked improvement in the provision of respectful care to women. The graduates faced challenges to implement evidence based care with barriers including the lack of appropriate resources and differences of opinion with senior staff. CONCLUSIONS: factors affecting the quality of midwifery education will need to be addressed if Papua New Guinea is to continue to improve the status of maternal and newborn health. Specifically, the length of the midwifery education, the quality of clinical practice and the exposure to rural and remote area practice need addressing in many contexts like Papua New Guinea. PMID- 27498186 TI - How optimal caseload midwifery can modify predictors for preterm birth in young women: Integrated findings from a mixed methods study. AB - OBJECTIVE: to identify possible mechanisms by which caseload midwifery reduces preterm birth for young childbearing women. DESIGN: a mixed methods triangulation, convergence design was used to answer the research question 'How does the way maternity care is provided affect the health and well-being of young women and their babies?' The project generated quantitative and qualitative findings which were collected and analysed concurrently then separately analysed and published. The research design enabled integration of the quantitative and qualitative findings for further interpretation through a critical pragmatic lens. SETTING: a tertiary maternity hospital in Australia providing care to approximately 500 pregnant young women (aged 21 years or less) each year. Three distinct models of care were offered: caseload midwifery, young women's clinic, and standard 'fragmented' care. PARTICIPANTS: a cohort study included data from 1971 young women and babies during 2008-2012. An ethnographic study included analysis of focus group interviews with four caseload midwives in the young women's midwifery group practice; as well as ten pregnant and postnatal young women receiving caseload midwifery care. FINDINGS: integrated analysis of the quantitative and qualitative findings suggested particular features in the model of care which facilitated young women turning up for antenatal care (at an earlier gestation and more frequently) and buying in to the process (disclosing risks, engaging in self-care activities and accepting referrals for assistance). We conceptualised that Optimal Caseload Midwifery promotes Synergistic Health Engagement between midwife and the young woman. KEY CONCLUSIONS: optimal Caseload Midwifery (which includes midwives with specific personal attributes and philosophical commitments, along with appropriate institutional infrastructure and support) facilitates midwives and young clients to develop trusting relationships and engage in maternity care. Health engagement can modify predictors for preterm birth that are common amongst pregnant adolescents by promoting earlier maternity booking, sufficient antenatal care, greater emotional resilience, ideal gestational weight gain, less smoking/drug use, and fewer untreated genito-urinary infections. IMPLICATIONS FOR PRACTICE: the institutional infrastructure and managerial support for caseload midwifery should value and prioritise the philosophical commitments and personal attributes required to optimise the model. Furthermore the location of visits, between appointment access to primary midwife, and back-up system should be organised to optimise the midwife-woman relationship in order to promote the young woman's engagement with maternity care. PMID- 27498187 TI - Poly(phosphorhydrazone) dendrimers: yin and yang of monocyte activation for human NK cell amplification applied to immunotherapy against multiple myeloma. AB - Human natural killer (NK) cells play a key role in anti-cancer and anti-viral immunity, but their selective amplification in vitro is extremely tedious to achieve and remains one of the most challenging problems to solve for efficient NK cell-based immuno-therapeutic treatments against malignant diseases. Here we report that, when added to ex vivo culture of peripheral blood mononuclear cells from healthy volunteers or from cancer patients with multiple myeloma, poly (phosphorhydrazone) dendrimers capped with amino-bis(methylene phosphonate) end groups enable the efficient proliferation of NK cells with anti-cancer cytotoxicity in vivo. We also show that the amplification of the NK population relies on the preliminary activation of monocytes in the framework of a multistep cross-talk between monocytes and NK cells before the proliferation thereof. Thus poly(phosphorhydrazone) dendrimers represent a novel class of extremely promising drugs to develop NK-cell based anti-cancer therapies. PMID- 27498189 TI - Recent advances in the structural biology of the 26S proteasome. AB - There is growing appreciation for the fundamental role of structural dynamics in the function of macromolecules. In particular, the 26S proteasome, responsible for selective protein degradation in an ATP dependent manner, exhibits dynamic conformational changes that enable substrate processing. Recent cryo-electron microscopy (cryo-EM) work has revealed the conformational dynamics of the 26S proteasome and established the function of the different conformational states. Technological advances such as direct electron detectors and image processing algorithms allowed resolving the structure of the proteasome at atomic resolution. Here we will review those studies and discuss their contribution to our understanding of proteasome function. PMID- 27498188 TI - Common Molecular Pathways in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age related neurodegenerative diseases in which predominantly motor neurons and cerebral cortex neurons, respectively, are affected. Several novel ALS and FTD disease genes have been recently discovered, pointing toward a few overarching pathways in ALS/FTD pathogenesis. Nevertheless, a precise picture of how various cellular processes cause neuronal death, or how different routes leading to ALS and FTD are functionally connected is just emerging. Moreover, how the most recent milestone findings in the ALS/FTD field might lead to improved diagnosis and treatment is actively being explored. We highlight some of the most exciting recent topics in the field, which could potentially facilitate the identification of further links between the pathogenic ALS/FTD pathways related to autophagy, vesicle trafficking, and RNA metabolism. PMID- 27498190 TI - Phosphatidylinositol-3-phosphate regulates response of cells to proteotoxic stress. AB - Human Nedd4 ubiquitin ligase, or its variants, inhibit yeast cell growth by disturbing the actin cytoskeleton organization and dynamics, and lead to an increase in levels of ubiquitinated proteins. In a screen for multicopy suppressors which rescue growth of yeast cells producing Nedd4 ligase with an inactive WW4 domain (Nedd4w4), we identified a fragment of ATG2 gene encoding part of the Atg2 core autophagy protein. Expression of the Atg2-C1 fragment (aa 1074-1447) improved growth, actin cytoskeleton organization, but did not significantly change the levels of ubiquitinated proteins in these cells. The GFP Atg2-C1 protein in Nedd4w4-producing cells primarily localized to a single defined structure adjacent to the vacuole, surrounded by an actin filament ring, containing Hsp42 and Hsp104 chaperones. This localization was not affected in several atg deletion mutants, suggesting that it might be distinct from the phagophore assembly site (PAS). However, deletion of ATG18 encoding a phosphatidylinositol-3-phosphate (PI3P)-binding protein affected the morphology of the GFP-Atg2-C1 structure while deletion of ATG14 encoding a subunit of PI3 kinase suppressed toxicity of Nedd4w4 independently of GFP-Atg2-C1. Further analysis of the Atg2-C1 revealed that it contains an APT1 domain of previously uncharacterized function. Most importantly, we showed that this domain is able to bind phosphatidylinositol phosphates, especially PI3P, which is abundant in the PAS and endosomes. Together our results suggest that human Nedd4 ubiquitinates proteins in yeast and causes proteotoxic stress and, with some Atg proteins, leads to formation of a perivacuolar structure, which may be involved in sequestration, aggregation or degradation of proteins. PMID- 27498191 TI - SOX9 regulates expression of the male fertility gene Ets variant factor 5 (ETV5) during mammalian sex development. AB - In humans, dysregulation of the sex determining gene SRY-box 9 (SOX9) leads to disorders of sex development (DSD). In mice, knock-out of Sox9 prior to sex determination leads to XY sex reversal, while Sox9 inactivation after sex determination leads to spermatogenesis defects. SOX9 specifies the differentiation and function of Sertoli cells from somatic cell precursors, which then orchestrate the development and maintenance of other testicular cell types, largely through unknown mechanisms. Here, we describe a novel testicular target gene of SOX9, Ets variant factor 5 (ETV5), a transcription factor responsible for maintaining the spermatogonial stem cell niche. Etv5 was highly expressed in wild type XY but not XX mouse fetal gonads, with ETV5 protein localized in the Sertoli cells, interstitial cells and germ cells of the testis. In XY Sox9 knock-out gonads, Etv5 expression was strongly down-regulated. Similarly, knock-down of SOX9 in the human Sertoli-like cell line NT2/D1 caused a decrease in ETV5 gene expression. Transcriptomic analysis of NT2/D1 cells over-expressing SOX9 showed that ETV5 expression was increased in response to SOX9. Moreover, chromatin immunoprecipitation of these cells, as well as of embryonic mouse gonads, showed direct binding of SOX9 to ETV5 regulatory regions. We demonstrate that SOX9 was able to activate ETV5 expression via a conserved SOX site in the 5' regulatory region, mutation of which led to loss of activation. In conclusion, we present a novel target gene of SOX9 in the testis, and suggest that SOX9 regulation of ETV5 contributes to the control of male fertility. PMID- 27498192 TI - Single and repeated exposures to the volatile anesthetic isoflurane do not impair operant performance in aged rats. AB - Postoperative Cognitive Dysfunction (POCD) is a complication that can occur in the elderly after anesthesia and surgery and is characterized by impairments in information processing, memory, and executive function. Currently, it is unclear whether POCD is due to the effects of surgery, anesthesia, or perhaps some interaction between these or other perioperative variables. Studies in rodents suggest that the development of POCD may be related directly to anesthesia induced neuroactivity. Volatile anesthetics have been shown to increase cellular inflammation and apoptosis within the hippocampus of aged rodents, while producing corresponding impairments in hippocampal-dependent brain functions. However, it is unclear whether volatile anesthetics can affect additional aspects of cognition that do not primarily depend upon the hippocampus. The purpose of this study was to use established operant tests to examine the effects of isoflurane on aspects of behavioral inhibition, learning, and motivation in aged rats. Twenty-one adult Sprague-Dawley rats (11 male, 10 female) were trained to perform fixed consecutive number (FCN), incremental repeated acquisition (IRA), and progressive ratio (PR) tasks for a minimum of 15 months prior to receiving anesthesia. At 23 months of age, rats were exposed to 1.3% isoflurane or medical grade air for 2h. Initial results revealed that a 2h exposure to isoflurane had no effect on IRA, FCN, or PR performance. Thus, rats received 3 additional exposures to 1.3% isoflurane or medical grade air: 2, 4 and 6h exposures with 2 weeks elapsing before exposure two, 3 weeks elapsing between exposures two and three, and 2 weeks elapsing between exposures three and four. These additional exposures had no observable effects on performance of any operant task. These results suggest that single and repeated exposures to isoflurane do not impair the performance of aged rats in tasks designed to measure behavioral inhibition, learning, and motivation. This lack of significant effect suggests that the impairments associated with isoflurane exposure may not generalize to all aspects of cognition, but may be selective to tasks that primarily measure spatial memory processes. PMID- 27498193 TI - Characterization of Roseomonas and Nocardioides spp. for arsenic transformation. AB - The metalloid arsenic predominantly exists in the arsenite [As(III)] and arsenate [As(V)]. These two forms are respectively oxidized and reduced by microbial redox processes. This study was designed to bioprospect arsenic tolerating bacteria from Lonar lake and to characterize their arsenic redoxing ability. Screening of sixty-nine bacterial species isolated from Lonar lake led to identification of three arsenic-oxidizing and seven arsenic-reducing species. Arsenite oxidizing isolate Roseomonas sp. L-159a being closely related to Roseomonas cervicalis ATCC 49957 oxidized 2mM As(III) in 60h. Gene expression of large and small subunits of arsenite oxidase respectively showed 15- and 17-fold higher expression. Another isolate Nocardioides sp. L-37a formed a clade with Nocardioides ghangwensis JC2055, exhibited normal growth with different carbon sources and pH ranges. It reduced 2mM As(V) in 36h and showed constitutive expression of arsenate reductase which increased over 4-fold upon As(V) exposure. Genetic markers related to arsenic transformation were identified and characterized from the two isolates. Moderate resistance against the arsenicals was exhibited by the two isolates in the range of 1-5mM for As(III) and 1-200mM for As(V). Altogether we provide multiple evidences to indicate that Roseomonas sp. and Nocardioides sp. exhibited arsenic transformation ability. PMID- 27498194 TI - Malignant Myoepithelioma of the Breast Clinically and Histologically Masquerading as Angiosarcoma: Cytological Findings and Review of the Literature. AB - BACKGROUND: Malignant myoepithelioma of the breast is an exceptionally rare, aggressive tumor with a diverse morphology, the cytological features of which have only occasionally been described. CASE REPORT: Our case comprises a 74-year old woman who was admitted to our hospital with an erythematous, inflammatory like mass of her left breast with nipple ulceration, and clinically fixed to the chest wall. The woman underwent fine-needle aspiration and biopsy. The aspirates consisted mainly of loose aggregates of large, highly pleomorphic, polygonal epithelioid cells as well as aggregates of spindle cells with prominent, easily detectable mitoses and single, multinucleated pleomorphic giant cells. The cytological diagnosis was consistent with high-grade malignancy. Histologically, the lesion consisted broadly of eosinophilic epithelioid cells with globoid cytoplasm in a reticulated, angiomatoid pattern and of spindle (sarcomatoid) cells in a storiform pattern, highly suspicious of angiosarcoma. A final diagnosis of malignant myoepithelioma was made. CONCLUSION: We present the cytological findings in comparison with the unusual histological features of a malignant myoepithelioma of the breast. A high degree of suspicion with a keen eye for morphological details coupled with relevant immunohistochemistry will aid in arriving at the correct diagnosis. PMID- 27498195 TI - Lipocalin-2 as a therapeutic target for brain injury: An astrocentric perspective. AB - Lipocalin-2 (LCN2) is a member of the secreted lipocalin protein family. LCN2 is also a representative gliocalin that is primarily released by glial cells, as well as acts upon them. Astrocytes are one of the major cellular sources of LCN2 under brain injury conditions. Astrocytes secrete LCN2 to promote neuroinflammation. Studies using Lcn2 knockout animals and cultured neural cells suggest an important role of LCN2 in regulating the development of hemorrhagic and ischemic stroke as well as other brain injuries. The clinical relevance of LCN2 is supported by studies on patients with stroke. Mechanistic studies have revealed that LCN2 is a molecular switch for determining the phenotypic fate of astrocytes under inflammatory conditions. LCN2 gene expression is regulated at the multiple levels; mostly at the transcription level, post-transcription level by microRNAs, and protein level by minor post-translational modification. Recent advances in LCN2 research strongly indicate that astrocytic LCN2 is a promising drug target for the injured brain. Future research should focus on its translational aspects, such as developing small-molecule inhibitors or neutralizing antibodies to target LCN2 for the treatment of brain injury. However, spatiotemporally complex roles of LCN2, which are either beneficial or deleterious, should be considered when targeting LCN2. The potential use of LCN2 as a biomarker for the diagnosis and prognosis of various brain disorders is also discussed. PMID- 27498196 TI - Ciprofloxacin provokes SOS-dependent changes in respiration and membrane potential and causes alterations in the redox status of Escherichia coli. AB - An in-depth understanding of the physiological response of bacteria to antibiotic induced stress is needed for development of new approaches to combatting microbial infections. Fluoroquinolone ciprofloxacin causes phase alterations in Escherichia coli respiration and membrane potential that strongly depend on its concentration. Concentrations lower than the optimal bactericidal concentration (OBC) do not inhibit respiration during the first phase. A dose higher than the OBC provokes immediate SOS-independent inhibition of respiration and growth that can contribute to a decreased SOS response and lowered susceptibility to high concentrations of ciprofloxacin. Cells retain their metabolic activity, membrane potential and accelerated K+ uptake and produce low levels of superoxide and H2O2 during the first phase. The time before initiation of the second phase is inversely correlated with the ciprofloxacin concentration. The second phase is SOS-dependent and characterized by respiratory inhibition, membrane depolarization, K+ and glutathione leakage and cessation of glucose consumption and may be considered as cell death. atpA, gshA and kefBkefC knockouts, which perturb fluxes of protons and K+, can modify the degree and duration of respiratory inhibition and potassium retention. Loss of K+ efflux channels KefB and KefC enhances the susceptibility of E. coli to ciprofloxacin. PMID- 27498197 TI - Incidence, Risk Factors and a Novel Prevention Technique for Inguinal Hernia after Robot-Assisted Radical Prostatectomy. AB - INTRODUCTION: To evaluate the incidence and risk factors for postoperative inguinal hernia (IH) after robot-assisted radical prostatectomy (RARP) and to assess whether a newly developed prevention technique reduces the incidence of IH after RARP. METHODS: We included 161 consecutive patients (322 groins) who underwent RARP between September 2011 and October 2013. The prevention technique was as follows: (1) sufficient incision of peritoneum around the internal inguinal ring; (2) separation of spermatic vessels; (3) dissection of vas deferens. RESULTS: Postoperative IH occurred in 14 cases (19.4%) occurring in the observation group compared to 2 cases (2.2%) in the prevention group. Patent processus vaginalis (PPV) was the only risk factor. Time-to-event analysis demonstrated a significant decrease in IH incidence in the IH prevention group (p = 0.005). CONCLUSION: Our data reveal a higher incidence of IH after RARP, with the existence of PPV as the only identified risk factor. Our simple IH-prevention technique, which does not involve the use of artificial materials, appears safe and effective. PMID- 27498198 TI - HIV Testing Among Internet-Using MSM in the United States: Systematic Review. AB - Regular HIV testing enables early identification and treatment of HIV among at risk men who have sex with men (MSM). Characterizing HIV testing needs for Internet-using MSM informs development of Internet-facilitated testing interventions. In this systematic review we analyze HIV testing patterns among Internet-using MSM in the United States who report, through participation in an online study or survey, their HIV status as negative or unknown and identify demographic or behavioral risk factors associated with testing. We systematically searched multiple electronic databases for relevant English-language articles published between January 1, 2005 and December 16, 2014. Using meta-analysis, we summarized the proportion of Internet-using MSM who had ever tested for HIV and the proportion who tested in the 12 months preceding participation in the online study or survey. We also identified factors predictive of these outcomes using meta-regression and narrative synthesis. Thirty-two studies that enrolled 83,186 MSM met our inclusion criteria. Among the studies reporting data for each outcome, 85 % (95 % CI 82-87 %) of participants had ever tested, and 58 % (95 % CI 53-63 %) had tested in the year preceding enrollment in the study, among those for whom those data were reported. Age over 30 years, at least a college education, use of drugs, and self-identification as being homosexual or gay were associated with ever having tested for HIV. A large majority of Internet-using MSM indicated they had been tested for HIV at some point in the past. A smaller proportion-but still a majority-reported they had been tested within the year preceding study or survey participation. MSM who self-identify as heterosexual or bisexual, are younger, or who use drugs (including non-injection drugs) may be less likely to have ever tested for HIV. The overall findings of our systematic review are encouraging; however, a subpopulation of MSM may benefit from targeted outreach. These findings indicate unmet needs for HIV testing among Internet using MSM and identify subpopulations that might benefit from targeted outreach, such as provision of HIV self-testing kits. PMID- 27498199 TI - Opicapone: A Review in Parkinson's Disease. AB - Oral opicapone (Ongentys((r))), a potent, third-generation, long-acting, peripheral catechol-O-methyltransferase (COMT) inhibitor, is approved as adjunctive treatment to levodopa (L-Dopa)/dopa-decarboxylase inhibitor (DDCI) therapy in adults with Parkinson's disease (PD) and end-of-dose motor fluctuations who cannot be stabilized on those combinations. In 14- to 15-week, double-blind, multinational trials and in 1-year, open-label extension studies in this patient population, opicapone was an effective and generally well tolerated adjunctive therapy to L-Dopa plus a DDCI and other PD therapy. During the double blind phase, adjunctive opicapone 50 mg once daily provided significantly greater improvements in motor fluctuations than placebo, with these improvements noninferior to those with entacapone. These beneficial improvements in motor fluctuations with opicapone were maintained in patients who continued adjunctive opicapone during the extension studies, with patients who switched from placebo or entacapone to opicapone experiencing significant improvements in motor fluctuations during this year. No new unexpected safety concerns were identified after ~1.4 years' treatment with opicapone, with no serious cases of hepatotoxicity reported in clinical trials. With its convenient once-daily regimen, oral opicapone is an emerging COMT inhibitor option for use as adjunctive therapy to L-Dopa/DDCI therapy in adults with PD and end-of dose motor fluctuations who cannot be stabilized on those combinations. PMID- 27498200 TI - Regulation and the Mechanism of Estrogen on Cav1.2 Gene in Rat-Cultured Cortical Astrocytes. AB - L-type calcium channel (LTCC) gene Cav1.2 is believed to play an important role in the alteration of Ca(2+) homeostasis in brain astrocytes. Increasing evidence shows that alteration of intracellular Ca(2+) concentration is related to the effect of 17beta-estradiol (E2) in a variety of neurophysiological and neuropathological conditions. In this study, we measured immunoreactivity of Cav1.2 protein expression in rat primary cortical astrocytes by using Western blots. We demonstrated that E2 upregulated Cav1.2 expression in a dose- and time dependent manner and the effect of E2 on Cav1.2 expression were blocked by an estrogen receptor (ER) antagonist, ICI-182,780. The ER subtype-selective ERalpha agonists propylpyrazole triole (PPT) and ERbeta agonist diarylpropionitrile (DPN) both increase the expression of Cav1.2 in a dose-dependent manner. Also, the PPT most closely mimicked the upregulation of Cav1.2 protein expression by E2. Similar experiments of 10 nM E2-treated ERalpha- or ERbeta-knockdown astrocytes have also shown that the E2 regulation of Cav1.2 protein expression is mediated through an ERalpha-dependent pathway. Furthermore, we established that E2 did not change the level of Cav1.2 mRNA. The induction of E2-mediated Cav1.2 expression was inhibited by cycloheximide (CHX) but not by actinomycin D (Act-D), suggesting that E2 regulation of Cav1.2 expression occurred at a posttranscriptional level. We also found that E2 may increase Cav1.2 levels by decreasing its ubiquitination and degradation rate. These findings provide new information about the effect of E2 on Cav1.2 in astrocytes, particularly necessary for the treatment of neurological disease. PMID- 27498202 TI - Management of locoregional recurrence in cutaneous squamous cell carcinoma of the head and neck. AB - Cutaneous squamous cell carcinomas often affect elderly patients. Follow-up monitoring is difficult in these patients due to their multi-morbidity and reduced compliance. Tumour recurrence is consequently diagnosed in advanced tumour stages. Surgical therapy with curative intention often requires extended resections. The study at hand should determine whether surgical concepts are warranted in this collective. Sixty-seven patients who underwent surgical procedure due to recurrent disease of cutaneous head and neck squamous cell carcinoma were included. The cohort was divided in patients with/without adjuvant therapeutic regimens. Data were assessed retrospectively. Complete tumour resection was achieved in 85 % of our patients. Patients with adjuvant treatment demonstrated a favorable 5-year-recurrence-free interval (78 vs 30 %) and overall survival (79 vs 46 %). Complete surgical resection of advanced recurrent head and neck cutaneous squamous cell carcinomas is possible and yields favorable results in terms of survival, especially if combined with adjuvant treatment. PMID- 27498201 TI - The Neurobiology and Age-Related Prevalence of the epsilon4 Allele of Apolipoprotein E in Alzheimer's Disease Cohorts. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease characterised by amyloid beta (Abeta) plaques and tau neurofibrillary tangles in the brain. Human apolipoprotein E (ApoE) is a lipid transport protein coded by the polymorphic APOE gene, with three major alleles: epsilon2, epsilon3 and epsilon4. After age, the epsilon4 allele is the greatest risk factor for developing sporadic AD, conferring an increased risk of 3-4 and 8-12 times for one or two copies of the allele, respectively. This risk is reported to vary by demographic factors including sex, ethnicity and geography. In order to understand the risk of ApoE epsilon4 in relation to age, the primary risk factor for developing AD, we need to understand how the prevalence of APOE genotypes changes with age. Here, we present the first data on age-related prevalence of APOE epsilon4 in AD in three AD cohorts in Australia and the USA. There is a significant association between age and epsilon4 prevalence, particularly for epsilon4 homozygotes, such that as age increases the prevalence of epsilon4 decreases. Further studies on a random, population-based sample of the population are needed to provide more generalizable data, particularly in the >90-year-old age group. PMID- 27498204 TI - Toward a theory of organisms: Three founding principles in search of a useful integration. AB - Organisms, be they uni- or multi-cellular, are agents capable of creating their own norms; they are continuously harmonizing their ability to create novelty and stability, that is, they combine plasticity with robustness. Here we articulate the three principles for a theory of organisms, namely: the default state of proliferation with variation and motility, the principle of variation and the principle of organization. These principles profoundly change both biological observables and their determination with respect to the theoretical framework of physical theories. This radical change opens up the possibility of anchoring mathematical modeling in biologically proper principles. PMID- 27498203 TI - Pretreatment factors associated with functional oral intake and feeding tube use at 1 and 6 months post-radiotherapy (+/- chemotherapy) for head and neck cancer. AB - A proportion of patients with head and neck cancer (HNC) experience significant swallowing difficulty during and post-radiotherapy/chemoradiotherapy (RT/CRT). Identifying patients during the pretreatment period who are anticipated to have compromised oral intake would allow for early and accurate patient education, and prioritisation of their management. Ascertaining a clear set of pretreatment predictors from the literature is challenging due to heterogeneity in study designs and patient cohorts, with minimal prospective data available (especially at 1-month post-treatment). The objectives of this study were to investigate which pretreatment factors predicted compromised oral intake and feeding tube use at 1 and 6 months post-RT/CRT. Prospective data were collected on 80 consecutive HNC patients receiving RT/CRT from 2011 to 2014. The primary outcome was to identify predictors of a modified diet at 1 and 6 months post-RT/CRT. Secondary outcomes were to identify predictors of feeding tube use at these time intervals, and <6 vs. >6 week duration of feeding tube use. Multivariate analysis revealed bilateral neck radiotherapy treatment was a strong predictor of modified diets at 1 month (p < 0.001), and T-stages T3/T4 a predictor of modified diets at 6 months (p = 0.03). Patients treated with concurrent CRT (p = 0.02) and bilateral neck treatment (p = 0.02) predicted feeding tube use at 1 month, and concurrent CRT predicted feeding tube use for >6 weeks (p = 0.04). Therefore, patients receiving bilateral neck treatment and/or CRT are at greatest risk of requiring modified diets and feeding tube use early post-treatment, and should be prioritised for intervention and ongoing support. PMID- 27498205 TI - Applying Data Mining Techniques to Improve Breast Cancer Diagnosis. AB - In the field of breast cancer research, and more than ever, new computer aided diagnosis based systems have been developed aiming to reduce diagnostic tests false-positives. Within this work, we present a data mining based approach which might support oncologists in the process of breast cancer classification and diagnosis. The present study aims to compare two breast cancer datasets and find the best methods in predicting benign/malignant lesions, breast density classification, and even for finding identification (mass / microcalcification distinction). To carry out these tasks, two matrices of texture features extraction were implemented using Matlab, and classified using data mining algorithms, on WEKA. Results revealed good percentages of accuracy for each class: 89.3 to 64.7 % - benign/malignant; 75.8 to 78.3 % - dense/fatty tissue; 71.0 to 83.1 % - finding identification. Among the different tests classifiers, Naive Bayes was the best to identify masses texture, and Random Forests was the first or second best classifier for the majority of tested groups. PMID- 27498206 TI - Plasmapheresis for the treatment of kidney diseases. AB - The purpose of this review is to examine the evidence supporting the application of plasma exchange in renal disease. Our review focuses on the following 6 most common renal indications for plasma exchange based on 2014 registry data from the Canadian Apheresis Group: (i) thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome; (ii) renal transplantation, (iii) anti-neutrophil cytoplasm antibodies-associated vasculitis, (iv) cryoglobulinemia, (v) focal segmental glomerulosclerosis, and (vi) Goodpasture syndrome. The rarity of these diseases and their rapid, often fatal course mean that randomized controlled studies of plasma exchange are rarely conducted. Although evidence from an adequately powered randomized controlled trial supports the use of plasma exchange to treat thrombotic thrombocytopenic purpura, the use of plasma exchange to treat other renal diseases is only supported by observational and mechanistic studies. Larger well-designed trials are needed to clarify the potential role of plasma exchange in renal disease. Growing international collaboration will improve the quality of future studies in this area. PMID- 27498207 TI - Neural Correlates of the Antinociceptive Effects of Stimulating the Anterior Pretectal Nucleus in Rats. AB - : Stimulation-evoked antinociception (SEA) from the anterior pretectal nucleus (APtN) activates mechanisms that descend to the spinal cord through the dorsolateral funiculus, but the encephalic route followed by the descending pathways from the APtN is not completely known. This study evaluated the changes in the SEA from the APtN in the Wistar rat tail-flick test after lidocaine induced neural block or N-methyl-d-aspartate-induced neurotoxic lesion of the deep mesencephalic nucleus (DpMe), tegmental pedunculopontine nucleus (PPTg), or lateral paragigantocellular nucleus (LPGi). The SEA from the APtN was less intense after neural block of the contralateral DpMe or PPTg or the ipsilateral LPGi, but was not changed by the neural block of the ipsilateral DpMe or PPTg or the contralateral LPGi. Antinociception did not occur when APtN stimulation was carried out 5 minutes after lidocaine or 6 days after N-methyl-d-aspartate injections into the contralateral DpMe and the ipsilateral LPGi, or into the contralateral PPTg and the ipsilateral LPGi. We conclude that the SEA from the APtN activates 2 descending pain inhibitory pathways, one relaying in the ipsilateral LPGi and another relaying sequentially in the contralateral DpMe and PPTg. PERSPECTIVE: The antinociceptive effect of the APtN stimulation involves 2 descending pathways: one relaying in the ipsilateral LPGi and another descending contralaterally via relays in the DpMe and PPTg. PMID- 27498208 TI - The potential implication of SCN1A and CYP3A5 genetic variants on antiepileptic drug resistance among Egyptian epileptic children. AB - PURPOSE: Despite the advances in the pharmacological treatment of epilepsy, pharmacoresistance still remains challenging. Understanding of the pharmacogenetic causes is critical to predict drug response hence providing a basis for personalized medications. Genetic alteration in activity of drug target and drug metabolizing proteins could explain the development of pharmacoresistant epilepsy. So the aim of this study was to explore whether SCN1A c.3184 A/G (rs2298771) and CYP3A5*3 (rs776746) polymorphisms could serve as genetic based biomarkers to predict pharmacoresistance among Egyptian epileptic children. METHODS: Genotyping of SCN1A c.3184 A/G and CYP3A5*3 polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was performed in 65 healthy control subjects and 130 patients with epilepsy, of whom 50 were drug resistant and 80 were drug responsive. RESULTS: There was a significant higher frequency of the AG genotype (p=0.001) and G allele (p=0.006) of SCN1A polymorphism in epileptic patients than in controls. Also their frequency was significantly higher in drug resistant patients in comparison with drug responders (p=0.005 and 0.054 respectively). No significant association between CYP3A5*3 polymorphism and drug-resistance was found. CONCLUSIONS: Overall, results confirmed the claimed role of SCN1A c.3184 A/G polymorphism in epilepsy and moreover in development of pharmacoresistance among Egyptian epileptic children. CYP3A5*3 variants have no contributing effect on pharmacoresistance among Egyptian epileptic children. PMID- 27498209 TI - Physical Therapy in the Treatment of Central Pain Mechanisms for Female Sexual Pain. AB - INTRODUCTION: The complexity of female sexual pain requires an interdisciplinary approach. Physical therapists trained in pelvic health conditions are well positioned to be active members of an interdisciplinary team addressing the assessment and treatment of female sexual pain. Changes within physical therapy practice in the last ten years have resulted in significant utilization of pelvic floor muscle relaxation and manual therapy techniques to address a variety of pelvic pain conditions, including female sexual pain. However, sexual pain is a complex issue giving credence to the necessity of addressing all of the drivers of the pain experience- biological, psychological and social. AIM: This review aims to reconcile current pain science with a plan for integrating a biopsychosocial approach into the evaluation and subsequent treatment for female sexual pain for physical therapists. METHODS: A literature review of the important components of skilled physical therapy interventions is presented including the physical examination, pain biology education, cognitive behavioral influences in treatment design, motivational interviewing as an adjunct to empathetic practice, and the integration of non-threatening movement and mindfulness into treatment. MAIN OUTCOME MEASURE: A single case study is used to demonstrate the biopsychosocial framework utilized in this approach. RESULTS: Appropriate measures for assessing psychosocial factors are readily available and inform a reasoned approach for physical therapy design that addresses both peripheral and central pain mechanisms. Decades of research support the integration of a biopsychosocial approach in the treatment of complex pain, including female sexual pain. CONCLUSION: It is reasonable for physical therapists to utilize evidence based strategies such as CBT, pain biology education, Mindfulness Based Stress Reduction (MBSR), yoga and imagery based exercises to address the biopsychosocial components of female sexual pain. PMID- 27498210 TI - The impact of outpatient systemic anti-cancer treatment on patient costs and work practices. AB - BACKGROUND: There is extensive focus on the rising costs of healthcare. However, for patients undergoing cancer treatment, there are additional personal costs, which are poorly characterised. AIM: To qualify indirect costs during anti-cancer therapy in a designated Irish cancer centre. METHODS: An anonymous questionnaire collected demographic data, current work practice, and personal expenditure on regular and non-regular indirect costs during treatment. Differences between groups of interest were compared using the Mann-Whitney U test. RESULTS: In total, there were 151 responders of median age 58 years; 60 % were female and 74 % were not working. Breast cancer (29 %) was the most frequent diagnosis. Indirect costs totalled a median of ?1138 (range ?21.60-?7089.84) per patient, with median monthly outgoings of ?354. The greatest median monthly costs were hair accessories (?400), transportation (?65), and complementary therapies (?55). The majority (74 %) of patients used a car and median monthly fuel expenditure was ?31 (range ?1.44-?463.32). Women spent more money during treatment (?1617) than men (?974, p = 0.00128). In addition, median monthly expenditure was greater for those less than 50 years old (?1621 vs ?1105; p = 0.04236), those who lived greater than 25 km away (?2015 vs ?1078; p = 0.00008) and those without a medical card (?2023 vs ?961; p = 0.00024). CONCLUSION: This study highlights the need for greater awareness of indirect expenditures associated with systemic anti-cancer therapy in Ireland. PMID- 27498211 TI - A systematic review of serious video games used for vaccination. AB - INTRODUCTION: Vaccination is an effective and proven method of preventing infectious diseases. However, uptake has not been optimal with available vaccines partly due to vaccination hesitancy. Various public health approaches have adressed vaccination hesitancy. Serious video games involving vaccination may represent an innovative public health approach. The aim of this study was to identify, describe, and review existing serious video games on vaccination. METHOD: A systematic review was performed. Various databases were used to find data on vaccination-related serious video games published from January 1st 2000 to May 15th 2015. Data including featured medical and vaccination content, publication characteristics and games classification were collected for each identified serious game. RESULTS: Sixteen serious video games involved in vaccination were identified. All games were developed in high-income countries between 2003 and 2014. The majority of games were available online and were sponsored by educational/health institutions. All games were free of charge to users. Edugame was the most prevalent serious game subcategory. Twelve games were infectious disease-specific and the majority concerned influenza. The main objective of the games was disease control with a collective perspective. Utilization data was available for two games. Two games were formally evaluated. DISCUSSION: The use of serious video games for vaccination is an innovative tool for public health. Evaluation of vaccination related serious video games should be encouraged to demonstrate their efficacy and utility. PMID- 27498212 TI - A decade of adaptation: Regulatory contributions of the World Health Organization to the Global Action Plan for Influenza Vaccines (2006-2016). AB - The Global Action Plan (GAP) for Influenza Vaccines is a decade-long initiative that brings together a diverse range of stakeholders to work towards reducing anticipated global shortage of influenza vaccines and ensuring more equitable access to vaccines during the next influenza pandemic. Since its inception in 2006, significant progress has been made towards all the main objectives of GAP, namely: (1) an increase in seasonal vaccine use, (2) an increase in vaccine production, and (3) progress in research and development of more effective vaccines. The Technology Transfer Initiative (TTI), conceived and managed by WHO under the GAP, contributed to increasing regional influenza vaccine production capacity. This was achieved by facilitating technology transfer in 14 low- and middle-income countries, through grants to manufacturers to establish or strengthen influenza vaccine production capacity and support to their national regulatory authorities. Five of the countries subsequently licensed locally produced influenza vaccines; two pandemic and three seasonal vaccines received WHO prequalification. The success of GAP can be largely attributed to the regulatory support provided by WHO to both manufacturers and regulators. This support had two components: (1) direct regulatory support to GAP/TTI, and (2) support to GAP-related WHO programmes, such as the Pandemic Influenza Vaccine Deployment Initiative in 2010 and the Pandemic Influenza Preparedness Framework since 2013, especially in non-vaccine-producing countries. Temporary adaptation of the assessment process for influenza vaccines in the WHO Vaccine Prequalification Programme to the A(H1N1) pandemic situation in 2009 was instrumental to the success of the WHO Pandemic Influenza Vaccine Deployment Initiative in its attempt to meet the demand for pandemic vaccines in countries that received donated vaccines. PMID- 27498213 TI - Enhancement of fibroblast activation protein alpha-based vaccines and adenovirus boost immunity by cyclophosphamide through inhibiting IL-10 expression in 4T1 tumor bearing mice. AB - Fibroblast activation protein alpha (FAPalpha) is expressed in cancer-associated fibroblasts (CAFs) of more than 90% of malignant epithelia carcinomas. CAFs are the main type of cells in the tumor microenvironment which offer nutrition and protection to the tumor and regulate immunosuppression. To eliminate CAFs, a vaccine targeting FAPalpha may be used with a heterologous prime-boost strategy to enhance the FAPalpha-specific cellular immunity. Here, a FAP vaccine using a recombinant adenovirus (rAd) vector was constructed as well as a DNA vaccine reported in our previous work. Although the DNA prime-rAd boost strategy enhanced FAPalpha-specific immune responses, improvement of anti-tumor immunity effects was not observed. Examination of immunosuppressive factors revealed that high expression of the IL-10 cytokine was considered the main cause of the failure of the prime-boost strategy. However, heterologous vaccination in combination with a low-dose of cyclophosphamide (CY), which was reported to reduce IL-10 production and promote a shift from immunosuppression to immunopotentiation, resulted in enhanced effects in terms of numbers of effector T cells and tumor growth inhibition rates, compared to the CY alone or DNA alone group. Tumor growth was inhibited markedly when the prime-boost strategy was combined with CY in both the prophylactic and therapeutic settings and the survival time of 4T1 tumor bearing mice was also prolonged significantly. With the reduction of IL-10, enhancement of the anti-tumor effect by the prime-boost strategy was observed. These results suggest that FAPalpha-targeted rAd boosting in combination with CY is an attractive approach to overcoming immunosuppression in cancer vaccines. PMID- 27498214 TI - Lubricin/proteoglycan 4 increases in both experimental and naturally occurring equine osteoarthritis. AB - OBJECTIVE: The goals of this study were (1) to quantify proteoglycan 4 (PRG4) gene expression; (2) to assess lubricin immunostaining; and (3) to measure synovial fluid lubricin concentrations in clinical and experimental models of equine carpal osteoarthritis (OA). DESIGN: Lubricin synovial fluid concentrations and cartilage and synovial membrane PRG4 expression were analyzed in research horses undergoing experimental OA induction (n = 8) and in equine clinical patients with carpal OA (n = 58). Lubricin concentrations were measured using a custom sandwich enzyme-linked immunosorbent assay, and PRG4 expression was quantified using qRT-PCR. Lubricin immunostaining was assessed in synovial membrane and osteochondral sections in the experimental model. RESULTS: Lubricin concentrations increased in synovial fluid following induction of OA, peaking at 21 days post-operatively in OA joints vs sham-operated controls (331 +/- 69 MUg/mL vs 110 +/- 19 MUg/mL, P = 0.001). Lubricin concentrations also increased in horses with naturally occurring OA as compared to control joints (152 +/- 32 MUg/mL vs 68 +/- 4 MUg/mL, P = 0.003). Synovial membrane PRG4 expression increased nearly 2-fold in naturally occurring OA (P = 0.003), whereas cartilage PRG4 expression decreased 2.5-fold (P = 0.025). Lubricin immunostaining was more pronounced in synovial membrane from OA joints as compared to controls, with intense lubricin localization to sites of cartilage damage. CONCLUSIONS: Although PRG4 gene expression decreases in OA cartilage, synovial membrane PRG4 expression, synovial fluid lubricin concentrations and lubricin immunostaining all increase in an equine OA model. Lubricin may be elevated to protect joints from post-traumatic OA. PMID- 27498215 TI - Adiponectin, TNF-alpha and inflammatory cytokines and risk of type 2 diabetes: A systematic review and meta-analysis. AB - AIMS: There has been growing evidence that adiponectin, tumor necrosis factor alpha (TNF-alpha) and inflammatory cytokines involved in insulin resistance and may be attractive candidates for assessing risk of the incident type 2 diabetes (T2DM). A systematic review and meta-analysis of prospective studies was conducted to assess the associations of levels of serum adiponectin, TNF-alpha and inflammatory markers (Interleukin-1 beta (IL-1beta), Interleukin-6 (IL-6), Interleukin-18 (IL-18), C-reactive protein (CRP)) with risk of T2DM. MATERIALS/METHODS: We searched PubMed, ISI Web of Knowledge, EMBASE, and Cochrane Library databases up until February 1, 2016 for eligible studies which were matched to search subjects. Either fixed-effects or random-effects models were used to estimate the summary risk incorporated between study variations. RESULTS: 19 studies comprising a total of 39,136 participants and 7924 cases were included in the meta-analysis. Our findings showed that an obvious association of elevated CRP levels with T2DM risk (relative risk [RR] 1.48 [95% CI 1.26-1.71]), with the absence of publication bias. For IL-6, the meta-analysis involved 16 cohorts with a total of 24,929 participants and 4751 cases. Using data from all trials, a strong positive correlation (1.32 [1.14, 1.51]) was observed between basal plasma IL-6 and T2DM, whereas relatively lower relation between TNF-alpha (1.16 [0.87, 1.45]), IL-18 (1.45 [1.16, 1.73]), IL-1beta (0.87, [0.59, 1.15]) and independently increased risk to occurrence of T2DM. Conversely, we also found that the level of adiponectin decreased significantly in patients with T2DM. Sensitivity analyses further supported the associations. CONCLUSIONS: This meta analysis indicates that T2DM risk as whole was strongly associated with elevated levels of inflammatory cytokines (IL-1beta, IL-6, IL-18, CRP), TNF-alpha and low levels of adiponectin. Despite an overall detectable association in the meta analysis, considerable heterogeneity existed between studies. Further work is needed, it seems clear that a complex interplay of inflammation and the development of DM. Moreover, these biomarkers are predictors of T2DM subjects and should take more attention to measure levels of these as well as to target therapy/interventions. PMID- 27498216 TI - Cryopreservation of human spermatozoa with minimal non-permeable cryoprotectant. AB - Cryopreservation of human spermatozoa is a commonly used technique in assisted reproduction, however freezing low concentrations of sperm while maintaining adequate post-thaw motility remains a challenge. In an effort to optimize post thaw motility yields, low volumes of human sperm were frozen in polyimide-coated fused silica micro-capillaries using 0.065 M, 0.125 M, 0.25 M, or 0.5 M trehalose as the only cryoprotectant. Micro-capillaries were either initially incubated in liquid nitrogen vapor before plunging into liquid nitrogen, or directly plunged into liquid nitrogen. Post thaw sperm counts and motility were estimated. Spermatozoa that were initially incubated in liquid nitrogen vapor had greater post thaw motility than those plunged immediately into liquid nitrogen independent of trehalose concentration. The protective effect of 0.125 M d glucose, 3-O-methyl-d-glucopyranose, trehalose, sucrose, raffinose, or stachyose were evaluated individually. Trehalose and sucrose were the most effective cryoprotectants, recovering 69.0% and 68.9% of initial sperm motility, respectively. PMID- 27498217 TI - Awareness of allergic enterocolitis among primary-care paediatricians: A web based pilot survey. AB - BACKGROUND: Allergic enterocolitis, also known as food protein-induced enterocolitis syndrome (FPIES), is an increasingly reported and potentially severe non-IgE mediated food allergy of the first years of life, which is often misdiagnosed due to its non-specific presenting symptoms and lack of diagnostic guidelines. OBJECTIVE: We sought to determine the knowledge of clinical, diagnostic and therapeutic features of FPIES among Italian primary-care paediatricians. METHODS: A 16-question anonymous web-based survey was sent via email to randomly selected primary care paediatricians working in the north of Italy. RESULTS: There were 194 completed surveys (48.5% response rate). Among respondents, 12.4% declared full understanding of FPIES, 49% limited knowledge, 31.4% had simply heard about FPIES and 7.2% had never heard about it. When presented with clinical anecdotes, 54.1% recognised acute FPIES and 12.9% recognised all chronic FPIES, whereas 10.3% misdiagnosed FPIES as allergic proctocolitis or infantile colic. To diagnose FPIES 55.7% declared to need negative skin prick test or specific-IgE to the trigger food, whereas 56.7% considered necessary a confirmatory oral challenge. Epinephrine was considered the mainstay in treating acute FPIES by 25.8% of respondents. Only 59.8% referred out to an allergist for the long-term reintroduction of the culprit food. Overall, 20.1% reported to care children with FPIES in their practice, with cow's milk formula and fish being the most common triggers; the diagnosis was self-made by the participant in 38.5% of these cases and by an allergist in 48.7%. CONCLUSION: There is a need for promoting awareness of FPIES to minimise delay in diagnosis and unnecessary diagnostic and therapeutic interventions. PMID- 27498218 TI - The use of structural modelling to infer structure and function in biocontrol agents. AB - Homology modelling can provide important insights into the structures of proteins when a related protein structure has already been solved. However, for many proteins, including a number of invertebrate-active toxins and accessory proteins, no such templates exist. In these cases, techniques of ab initio, template-independent modelling can be employed to generate models that may give insight into structure and function. In this overview, examples of both the problems and the potential benefits of ab initio techniques are illustrated. Consistent modelling results may indicate useful approximations to actual protein structures and can thus allow the generation of hypotheses regarding activity that can be tested experimentally. PMID- 27498219 TI - Viruses of commercialized insect pollinators. AB - Managed insect pollinators are indispensable in modern agriculture. They are used worldwide not only in the open field but also in greenhouses to enhance fruit set, seed production, and crop yield. Managed honey bee (Apis mellifera, Apis cerana) colonies provide the majority of commercial pollination although other members of the superfamily Apoidea are also exploited and commercialized as managed pollinators. In the recent past, it became more and more evident that viral diseases play a key role in devastating honey bee colony losses and it was also recognized that many viruses originally thought to be honey bee specific can also be detected in other pollinating insects. However, while research on viruses infecting honey bees started more than 50years ago and the knowledge on these viruses is growing ever since, little is known on virus diseases of other pollinating bee species. Recent virus surveys suggested that many of the viruses thought to be honey bee specific are actually circulating in the pollinator community and that pollinator management and commercialization of pollinators provide ample opportunity for viral diseases to spread. However, the direction of disease transmission is not always clear and the impact of these viral diseases on the different hosts remains elusive in many cases. With our review we want to provide an up-to-date overview on the viruses detected in different commercialized pollinators in order to encourage research in the field of pollinator virology that goes beyond molecular detection of viruses. A deeper understanding of this field of virology is urgently needed to be able to evaluate the impact of viruses on pollinator health and the role of different pollinators in spreading viral diseases and to be able to decide on appropriate measures to prevent virus-driven pollinator decline. PMID- 27498220 TI - Heat exposure on farmers in northeast Ghana. AB - Environmental health hazards faced by farmers, such as exposure to extreme heat stress, are a growing concern due to global climate change, particularly in tropical developing countries. In such environments, farmers are considered to be a population at risk of environmental heat exposure. The situation is exacerbated due to their farming methods that involve the use of primitive equipment and hard manual labour conducted in full sunshine under hot and humid conditions. However, there is inadequate information about the extent of heat exposure to such farmers, both at the household and farm levels. This paper presents results from a study assessing environmental heat exposure on rural smallholder farmers in Bawku East, Northern Ghana. From January to December 2013, Lascar USB temperature and humidity sensors and a calibrated Questemp heat stress monitor were deployed to farms and homes of rural farmers at Pusiga in Bawku East to capture farmers' exposure to heat stress in both their living and working environments as they executed regular farming routines. The Lascar sensors have the capability to frequently, accurately and securely measure temperature and humidity over long periods. The Questemp heat stress monitor was placed in the same vicinity and showed strong correlations to Lascar sensors in terms of derived values of wet bulb globe temperature (WBGT). The WBGT in the working environment of farmers peaked at 33.0 to 38.1 degrees C during the middle of the day in the rainy season from March to October and dropped to 14.0-23.7 degrees C in the early morning during this season. A maximum hourly WBGT of 28.9-37.5 degrees C (March October) was recorded in the living environment of farmers, demonstrating little relief from heat exposure during the day. With these levels of heat stress, exposed farmers conducting physically demanding outdoor work risk suffering serious health consequences. The sustainability of manual farming practices is also under threat by such high levels of heat exposure. PMID- 27498221 TI - Audio-visual speech perception in infants and toddlers with Down syndrome, fragile X syndrome, and Williams syndrome. AB - Typically-developing (TD) infants can construct unified cross-modal percepts, such as a speaking face, by integrating auditory-visual (AV) information. This skill is a key building block upon which higher-level skills, such as word learning, are built. Because word learning is seriously delayed in most children with neurodevelopmental disorders, we assessed the hypothesis that this delay partly results from a deficit in integrating AV speech cues. AV speech integration has rarely been investigated in neurodevelopmental disorders, and never previously in infants. We probed for the McGurk effect, which occurs when the auditory component of one sound (/ba/) is paired with the visual component of another sound (/ga/), leading to the perception of an illusory third sound (/da/ or /tha/). We measured AV integration in 95 infants/toddlers with Down, fragile X, or Williams syndrome, whom we matched on Chronological and Mental Age to 25 TD infants. We also assessed a more basic AV perceptual ability: sensitivity to matching vs. mismatching AV speech stimuli. Infants with Williams syndrome failed to demonstrate a McGurk effect, indicating poor AV speech integration. Moreover, while the TD children discriminated between matching and mismatching AV stimuli, none of the other groups did, hinting at a basic deficit or delay in AV speech processing, which is likely to constrain subsequent language development. PMID- 27498222 TI - Dietary galactooligosaccharide elicits positive effects on non-specific immune parameters and growth performance in Caspian white fish (Rutilus frisii kutum) fry. AB - An eight-weeks feeding trial was conducted to investigate the effects of galactooligosaccharide (GOS), on the skin and serum non-specific immune parameters and growth performance of Caspian white fish (Rutilus frisii kutum) fry. Fish (2.07 +/- 0.08 g) were fed different levels of GOS (0%, 1%, 2% and 3%). No significant (P > 0.05) difference was observed in mucus protease activity, but inclusion of 1% GOS significantly (P < 0.05) elevated total immunoglobulin (Ig) level and lysozyme activity. Evaluation of serum non-specific immune parameters revealed significant (P < 0.05) increase in serum total Ig and lysozyme activity of fish fed 1% or 2% GOS compared those of fish fed control diet. Furthermore, the serum alternative haemolytic complement activity (ACH50) was significantly (P < 0.05) elevated in all prebiotic groups regardless of inclusion levels. Administration of GOS in diet significantly (P < 0.05) improved growth performance and feed utilisation. The results of the present study revealed that GOS administration is beneficial by improving immune response and growth performance of Caspian white fish. PMID- 27498223 TI - Tobacco exposure and maternal psychopathology: Impact on toddler problem behavior. AB - Prenatal exposure to tobacco has consistently predicted later problem behavior for children. However, little is known about developmental mechanisms underlying this association. We examined a conceptual model for the association between prenatal tobacco exposure and child problem behavior in toddlerhood via indirect paths through fetal growth, maternal depression, and maternal aggressive disposition in early infancy and via maternal warmth and sensitivity and infant negative affect in later infancy. The sample consisted of 258 mother-child dyads recruited during pregnancy and assessed periodically at 2, 9, and 16months of child age. Pathways via maternal depression and infant negative affect to toddler problem behavior were significant. Further, combined tobacco and marijuana exposure during pregnancy and reduced fetal growth also demonstrated important associations with infant negative affect and subsequent problem behavior. These results highlight the importance of considering the role of maternal negative affect and poor fetal growth as risk factors in the context of prenatal exposure. PMID- 27498224 TI - First Things First: Vital Protein Marks by N-Terminal Acetyltransferases. AB - N-terminal (Nt) acetylation is known to be a highly abundant co-translational protein modification, but the recent discovery of Golgi- and chloroplast-resident N-terminal acetyltransferases (NATs) revealed that it can also be added post translationally. Nt-acetylation may act as a degradation signal in a novel branch of the N-end rule pathway, whose functions include the regulation of human blood pressure. Nt-acetylation also modulates protein interactions, targeting, and folding. In plants, Nt-acetylation plays a role in the control of resistance to drought and in regulation of immune responses. Mutations of specific human NATs that decrease their activity can cause either the lethal Ogden syndrome or severe intellectual disability and cardiovascular defects. In sum, recent advances highlight Nt-acetylation as a key factor in many biological pathways. PMID- 27498227 TI - A rare case of dorsal-cervical spine myeloid sarcoma detected on 18F-FDG PET/CT scan. PMID- 27498225 TI - Circadian Oscillators: Around the Transcription-Translation Feedback Loop and on to Output. AB - From cyanobacteria to mammals, organisms have evolved timing mechanisms to adapt to environmental changes in order to optimize survival and improve fitness. To anticipate these regular daily cycles, many organisms manifest ~24h cell autonomous oscillations that are sustained by transcription-translation-based or post-transcriptional negative-feedback loops that control a wide range of biological processes. With an eye to identifying emerging common themes among cyanobacterial, fungal, and animal clocks, some major recent developments in the understanding of the mechanisms that regulate these oscillators and their output are discussed. These include roles for antisense transcription, intrinsically disordered proteins, codon bias in clock genes, and a more focused discussion of post-transcriptional and translational regulation as a part of both the oscillator and output. PMID- 27498226 TI - Segmental outflow of aqueous humor in mouse and human. AB - The main and only modifiable risk factor in glaucoma, the group of usually late onset progressive and irreversible blinding optic neuropathies, is elevated intraocular pressure (IOP). The increase in IOP is due to impeded aqueous humor (AH) outflow through the conventional pathway. The aberrant increased resistance at the trabecular meshwork (TM), the filter-like region in the anterior eye chamber is the major contributory factor in causing the impeded outflow. In normal as well as in glaucoma eyes the regions of the TM are divided into areas of high and low flow. The collector channels and distal outflow regions are now increasingly being recognized as potential players in contributing to impede AH outflow. Structural and molecular make-up contributing to the segmental blockage to outflow is likely to provide greater insight. Establishing segmental blockage to outflow in model systems of glaucoma such as the mouse in parallel to human eyes will expand our repertoire of tools for investigation. Further study into this area of interest has the potential to ultimately lead to the development of new therapeutics focused on lowering IOP by targeting the various components of segmental blockage of outflow in the TM and in the distal outflow region. PMID- 27498228 TI - Evaluation of a new extraction protocol for yeast identification by mass spectrometry. AB - In this paper, we evaluate a rapid and safe pretreatment procedure using glass beads for MALDI-TOF yeast identification in a routine clinical laboratory avoiding the use of formic acid. We created a new yeast database library using 1186 yeasts, including 11 references strains. The database was tested using 2131 clinical isolates allowing accurate species-level identification in 98.9% (2107/2131) of cases with a score over 1.9 and in 99% (2123/2131) of the strains at the genus level. The new protocol is a rapid, reliable and safe procedure for the accurate identification of pathogenic Candida strains and requires minimal handling. PMID- 27498229 TI - In vivo near-infrared fluorescence imaging of Leishmania amazonensis expressing infrared fluorescence protein (iRFP) for real-time monitoring of cutaneous leishmaniasis in mice. AB - The use of Leishmania amazonensis-infected BALB/c mice is an important model for the study of experimental cutaneous leishmaniasis. Here we report the development of a non-invasive method to directly evaluate and measure parasite burden during the course of the infection, based on the near-infrared fluorescence detection of a recombinant L. amazonensis strain. So, we generated a L. amazonensis strain that stably expresses the near-infrared protein (iRFP) gene and compared the maintenance of its vitro and in vivo characteristics, such as fitness, pathogenicity and fluorescence emission. After that, we followed the disease development, as well as the parasite burden in BALB/c mice footpads infected with L. amazonensis-iRFP, by using an in vivo near-infrared fluorescence scanner. In vitro results showed a linear correlation between the fluorescence emission and the number of parasites. The in vivo study showed that the use of iRFP transfected L. amazonensis enables the monitoring of parasite burden by measuring fluorescence signals. Therefore, this technique can be confidently used to directly monitor parasitic load and infection overtime and could be an excellent tool for in vitro and in vivo screening of anti-leishmanial drugs and vaccine efficiency. This is the first report of the use of the near-infrared fluorescence imaging technique for monitoring in vivo cutaneous leishmaniasis. PMID- 27498230 TI - Characterization of a single-chain variable fragment specific to Cronobacter spp. from hybridoma based on outer membrane protein A. AB - Monoclonal antibody and polyclonal antibody specific to Cronobacter spp. had been reported in previous studies. However, the preparation of single-chain variable fragment (scFv) was faster and convenient. Hence, the aim of this study was to construct a scFv using outer membrane protein A (OmpA) of C. sakazakii as antigen. The protein sequences of OmpA of Cronobacter spp. were analyzed first. The results showed protein OmpA with length of 347 amino acids was conserved in Cronobacter genus (94.83%-100% of protein identity) and was greater than that observed for the other genera tested (8.28-91.64% of protein identity). Then, purified protein OmpA expressed in E. coli was used to prepare hybridoma and to construct scFv further. The scFv was named scFvH81 and analyzed by bioinformatics. The model of scFvH81 built by homologous modeling had a good quality (residues in disallowed regions: 3%) and showed that scFvH81 had a standard pocket-like site. Purified scFvH81 was prepared by denaturation and renaturation of inclusion body and it showed a good specificity and its affinity of Ka=2.39*10(6)M(-1). Therefore, it could be used in the detection and the pathogenesis study of Cronobacter spp. PMID- 27498231 TI - Hybridization accompanying FRET event in labeled natural nucleoside-unnatural nucleoside containing chimeric DNA duplexes. AB - Forster resonance energy transfer (FRET) is a highly efficient strategy in illuminating the structures, structural changes and dynamics of DNA, proteins and other biomolecules and thus is being widely utilized in studying such phenomena, in designing molecular/biomolecular probes for monitoring the hybridization event of two single stranded DNA to form duplex, in gene detection and in many other sensory applications in chemistry, biology and material sciences. Moreover, FRET can give information about the positional status of chromophores within the associated biomolecules with much more accuracy than other methods can yield. Toward this end, we want to report here the ability of fluorescent unnatural nucleoside, triazolylphenanthrene ((TPhen)BDo) to show FRET interaction upon hybridization with fluorescently labeled natural nucleosides, (Per)U or (OxoPy)U or (Per)U, forming two stable chimeric DNA duplexes. The pairing selectivity and the thermal duplex stability of the chimeric duplexes are higher than any of the duplexes with natural nucleoside formed. The hybridization results in a Forster resonance energy transfer (FRET) from donor triazolylphenanthrene of (TPhen)BDo to acceptor oxopyrene of (OxoPy)U and/or to perylene chromophore of (Per)U, respectively, in two chimeric DNA duplexes. Therefore, we have established the FRET process in two chimeric DNA duplexes wherein a fluorescently labeled natural nucleoside ((OxoPy)U or (Per)U) paired against an unnatural nucleoside ((TPhen)BDo) without sacrificing the duplex stability and B-DNA conformation. The hybridization accompanying FRET event in these classes of interacting fluorophores is new. Moreover, there is no report of such designed system of chimeric DNA duplex. Our observed phenomenon and the design can potentially be exploited in designing more of such efficient FRET pairs for useful application in the detection and analysis of biomolecular interactions and in material science application. PMID- 27498232 TI - A new dual-collimation batch reactor for determination of ultraviolet inactivation rate constants for microorganisms in aqueous suspensions. AB - We developed, characterized, and tested a new dual-collimation aqueous UV reactor to improve the accuracy and consistency of aqueous k-value determinations. This new system is unique because it collimates UV energy from a single lamp in two opposite directions. The design provides two distinct advantages over traditional single-collimation systems: 1) real-time UV dose (fluence) determination; and 2) simple actinometric determination of a reactor factor that relates measured irradiance levels to actual irradiance levels experienced by the microbial suspension. This reactor factor replaces three of the four typical correction factors required for single-collimation reactors. Using this dual-collimation reactor, Bacillus subtilis spores demonstrated inactivation following the classic multi-hit model with k=0.1471cm(2)/mJ (with 95% confidence bounds of 0.1426 to 0.1516). PMID- 27498233 TI - A comparative study on the nanoparticles for improved drug delivery systems. AB - Nanoparticles have attracted considerable recent interest for diverse biomedical applications because of the unique properties of the nanomaterials. It is already known that one of the major advances in the relative application of nanoparticles is the recognition of the steric stabilization which can increase the particle stability in the biological environment and provide the opportunities of the application of nanoparticles in the development of drug delivery systems (DDSs) for achieving drug targeting and controlled drug release. To facilitate their use in such applications, the appropriate design of surface ligands on these nanoparticles is necessary. In view of these, functionalized nanoparticles through surface modification can be utilized to specifically interact with the target molecules on the cell membrane or intracellular ones. This review briefly presents self-assembled nanoparticles with molecules of therapeutic significance with two strategies. The first strategy attempts to improve the placement of the drugs using conjugating the appropriate ligands or adding targeting moieties to the DDS. The second strategy utilizes trigger-controlled drug-release, which restricts drug release at the targeted site to kill cancer cells by externally controlled mechanisms. Among external stimulations, conveniently light has attracted much interest because it, as an orthogonal external stimulus, gives spatiotemporal control of payload release. PMID- 27498235 TI - Complete recovery of myocardial inflammation imaged by T2 mapping. PMID- 27498234 TI - Peromyscus as a model system for human hepatitis C: An opportunity to advance our understanding of a complex host parasite system. AB - Worldwide, there are 185 million people infected with hepatitis C virus and approximately 350,000 people die each year from hepatitis C associated liver diseases. Human hepatitis C research has been hampered by the lack of an appropriate in vivo model system. Most of the in vivo research has been conducted on chimpanzees, which is complicated by ethical concerns, small sample sizes, high costs, and genetic heterogeneity. The house mouse system has led to greater understanding of a wide variety of human pathogens, but it is unreasonable to expect Mus musculus to be a good model system for every human pathogen. Alternative animal models can be developed in these cases. Ferrets (influenza), cotton rats (human respiratory virus), and woodchucks (hepatitis B) are all alternative models that have led to a greater understanding of human pathogens. Rodent models are tractable, genetically amenable and inbred and outbred strains can provide homogeneity in results. Recently, a rodent homolog of hepatitis C was discovered and isolated from the liver of a Peromyscus maniculatus. This represents the first small mammal (mouse) model system for human hepatitis C and it offers great potential to contribute to our understanding and ultimately aid in our efforts to combat this serious public health concern. Peromyscus are available commercially and can be used to inform questions about the origin, transmission, persistence, pathology, and rational treatment of hepatitis C. Here, we provide a disease ecologist's overview of this new virus and some suggestions for useful future experiments. PMID- 27498236 TI - Transpulmonary resection of an interventricular septal fibroma in an adult patient. PMID- 27498237 TI - Preeclampsia: a fascinating syndrome due not only to oxidative stress. PMID- 27498239 TI - Pharmacokinetics and biodistribution of squalene-containing emulsion adjuvant following intramuscular injection of H5N1 influenza vaccine in mice. AB - Squalene is a component of oil-in-water emulsion adjuvants developed for potential use in some influenza vaccines. The biodistribution of the squalene containing emulsion adjuvant (AddaVaxTM) alone and as part of complete H5N1 vaccine was quantified in mechanistically and toxicologically relevant target tissues up to 336 h (14 days) following injection into quadriceps muscle. At 1 h, about 55% of the intramuscularly injected dose of squalene was detected in the local quadriceps muscles and this decreased to 26% at 48 h. Twenty-four hours after the injection, approximately 5%, 1%, and 0.6% of the injected dose was detected in inguinal fat, draining lymph nodes, and sciatic nerve, respectively. The peak concentration for kidney, brain, spinal cord, bone marrow, and spleen was each less than 1% of the injected dose, and H5N1 antigen did not significantly alter the biodistribution of squalene to these tissues. The area under-blood-concentration curve (AUC) and peak blood concentration (Cmax) of squalene were slightly higher (20-25%) in the presence of H5N1 antigen. A population pharmacokinetic model-based statistical analysis identified body weight and H5N1 antigen as covariates influencing the clearance of squalene. The results contribute to the body of knowledge informing benefit-risk analyses of squalene-containing emulsion vaccine adjuvants. PMID- 27498238 TI - The effect of some immunomodulatory and anti-inflammatory drugs on Li-pilocarpine induced epileptic disorders in Wistar rats. AB - Evidence shows that inflammatory and immune processes within the brain might account for the pathophysiology of epilepsy. Therefore, developing new antiepileptic drugs that can modulate seizures through mechanisms other than traditional drugs is required for the treatment of refractory epilepsy. This study aims to determine the relationship between brain inflammation and epilepsy, to examine the contribution of some biochemical parameters involved in brain inflammation, and to address the effect of pharmacological interventions using some anti-inflammatory and immunomodulatory drugs in an experimental epilepsy model. Adult male rats were divided into seven groups of 20. G1 was the normal, non-treated control. G2 was the epileptic, non-treated group. G3-G7 were treated with celecoxib, methotrexate, azathioprine, dexamethasone, and valproate, respectively, for a period of three weeks. Induction of status epilepticus (SE) by Li-pilocarpine was performed on groups G2-G7. EEG tracing was conducted, and inflammatory mediators (brain and serum IL-1beta, IL 6, PGE2, HSP70, TGF-beta2, and IFNgamma) were measured. The induction of SE increased the amplitude and frequency of EEG tracing and inflammatory mediators more than in the normal control group. Treatments of epileptic rats reduced the frequency and amplitude of EEG tracing and significantly decreased the levels of inflammatory mediators in some treated rats compared to G2. These findings demonstrate that some anti inflammatory and immunomodulatory drugs can lower the frequency and amplitude of seizures and reduce some inflammatory mediators in epilepsy treatments, strengthening the possibility that targeting these immunological and inflammatory pathways may represent another effective therapeutic approach to preventing epileptic seizures. PMID- 27498240 TI - Vessel traffic safety in busy waterways: A case study of accidents in western shenzhen port. AB - Throughout the world, busy waterways near large ports witness heavy vessel traffic in recent decades. The waterways are characterized by high risk in terms of loss of life, property, and pollution to environment. To facilitate maritime safety management with satisfactory efficiency and efficacy, the authors propose a framework of safety indexes to evaluate the risk level in busy waterways according to the accident severity, fatality rate and special indicators of maritime transportation. The safety indexes consist of Safety Evaluation Index (SEI) and Safety Warning Index (SWI), and are derived from the proposed risk criteria of Chinese vessel traffic. As a case study, data on vessel traffic accidents reported in the Western Shenzhen Port, South China from 1995 to 2015 are analyzed. The actual risk level of this area during the period is calculated under the framework. The implementation of the safety indexes indicate that the risk criteria and safety indexes are practicable and effective for the vessel traffic management. The methodology based on long-term accident data can significantly support the risk analysis in the macroscopic perspective for busy ports and waterways, such that SWI can act as threshold to trigger actions, while SEI can act as an indicator to measure safety status. PMID- 27498241 TI - Adult-onset stereotypical motor behaviors. AB - Stereotypies have been defined as non-goal-directed movement patterns repeated continuously for a period of time in the same form and on multiple occasions, and which are typically distractible. Stereotypical motor behaviors are a common clinical feature of a variety of neurological conditions that affect cortical and subcortical functions, including autism, tardive dyskinesia, excessive dopaminergic treatment of Parkinson's disease and frontotemporal dementia. The main differential diagnosis of stereotypies includes tic disorders, motor mannerisms, compulsion and habit. The pathophysiology of stereotypies may involve the corticostriatal pathways, especially the orbitofrontal and anterior cingulated cortices. Because antipsychotics have long been used to manage stereotypical behaviours in mental retardation, stereotypies that present in isolation tend not to warrant pharmacological intervention, as the benefit-to risk ratio is not great enough. PMID- 27498242 TI - Corrective limb osteotomy using patient specific 3D-printed guides: A technical note. AB - We describe the step-by-step process of a corrective osteotomy using 3D printed patient specific guides. Before surgery, bilateral computed tomography (CT) scans are made to plan correction in the affected limb. The digital pre-planning defines the location of the K-wires, drill holes, and the osteotomy site(s). Subsequently, a 3D printed patient specific guide is applied, which indicates the exact position of these drill holes and the osteotomies. This increases the accuracy of the surgery by means of patient specific fit of the guide. During surgery an incision is made and the guide is applied on the bone, which allows the surgeon to perform a very precise osteotomy. Next, the bone is reduced either directly using the plate and marked drill holes, or indirectly using a second reduction guide. In the latter case, the previously drilled K-wires are used to adequately position the reduction guide. Fixation of the bone fragments using plating osteosynthesis finalizes the process. Although this technique has its specific limitations, it might serve as a powerful tool in the treatment of malunion of both articular and nonarticular fractures of the limb. PMID- 27498243 TI - Manipulation under anesthesia for post traumatic stiff knee-pearls, pitfalls and risk factors for failure. AB - BACKGROUND: Stiffness is common following fractures around knee. Manipulation under anesthesia (MUA) is the initial noninvasive procedure usually performed for such patients. Though MUA has been extensively evaluated for knee arthroplasty, there is paucity of literature regarding its benefits in trauma cases. The purpose of this study was to define the role of manipulation in post traumatic stiff knees. METHODS: Hospital inpatient and outpatient records from January 2010 to June 2014 were retrospectively reviewed to identify patients undergoing MUA at our institution. Patients with more than one year follow up and adequate data were included. Clinical and radiographic parameters were analyzed to assess outcomes, complications, effect of timing on flexion gain as well as identify risk factors associated with failure. RESULTS: Out of 45 patients undergoing manipulation, 41 patients with 48 knees (34 unilateral and 7 bilateral) met inclusion criteria. Thirty six manipulations were successful while 3 were abandoned due to tight tissues and 9 developed complications.Successful MUA resulted in immediate gain of 62.36 degrees of flexion which decreased to 49.86 degrees at 1year. There was statistically significant loss of flexion of 12.5 degrees over a year (p value 0.0013). Arc of motion improved from 48.5 degrees to 106.1 degrees at 1year (p value <0.0001). Significant improvement was also seen in extension and fixed flexion deformity (p value <0.0001). No significant difference could be detected between early (<3 months) and late (>3 months) groups with respect to outcomes (p value 0.883)or complications (p value 0.3193). Failed group had significantly lower pre MUA flexion and pre MUA range of motion (p value 0.003). Univariate analysis showed that extensor mechanism ruptures during injury (p value <0.0001) and knees with Flexion <40 degrees (p value 0.0022) or ROM<30 degrees (p value 0.0002) were significantly associated with failures. CONCLUSION: MUA is a suitable non invasive treatment option for post traumatic stiffness. There is no effect of timing on outcome and late manipulation also results in good outcome. Extensor mechanism rupture and pre manipulation ROM<30 degrees or flexion <40 degrees are associated with failure and such cases should be considered for alternative options for better outcome. PMID- 27498244 TI - Increasing the reach: Involving local Muslim religious teachers in a behavioral intervention to eliminate urogenital schistosomiasis in Zanzibar. AB - In Zanzibar, United Republic of Tanzania, Madrassa schools are influential institutions, where children and adults can learn about the interpretation of the Koran. We aimed to explore the involvement of Madrassa teachers for behavior change interventions in a randomized operational research trial designed to investigate the impact of multiple approaches to eliminate urogenital schistosomiasis transmission from Zanzibar. Madrassa teachers performing in the 30 communities of the behavior change study arm were trained in new interactive and participatory teaching methods by the local behavioral team and provided with schistosomiasis-teaching tools for teaching about transmission and prevention in their Madrassa. In July 2014, in a qualitative research study, we conducted 25 semi-structured interviews with Madrassa teachers to find out how they perceived their involvement in interventions against schistosomiasis. In 2014, 5926 among the 8497 registered Madrassa students in 30 communities on Unguja and Pemba islands received health education and participated in interactive behavior change exercises about schistosomiasis. Madrassa teachers reported that they valued their inclusion in the study and the opportunity to educate their students about schistosomiasis transmission, prevention, and treatment. They also perceived personal and community benefits as a result of their training and strongly supported the inclusion of additional Madrassa teachers in future intervention activities. Madrassa teachers are influential in the Zanzibari society, and hence are important change agents within our community-level behavioral intervention. They might constitute an untapped resource that can help to expand and increase acceptance of and participation in schistosomiasis and other neglected tropical disease control activities in African Muslim communities. PMID- 27498245 TI - A single low dose of valproic acid in late prenatal life alters postnatal behavior and glutamic acid decarboxylase levels in the mouse. AB - RATIONALE: Rodents exposed to valproic acid (VPA) in prenatal life exhibit post natal characteristics analogous to autism spectrum disorder (ASD). Many previous studies used relatively high doses of VPA during early pregnancy, potentially confounding interpretation because the offspring are the 'survivors' of a toxic insult. Low dose or late gestation exposure has not been widely studied. OBJECTIVES: We examined the behavioral sequelae of late gestation exposure to low dose VPA in the mouse. We also examined postnatal levels of glutamic acid decarboxylase (GAD65 and GAD67) as markers for GABA neurons, because GABA pathology and subsequent excitatory/inhibitory imbalance is strongly implicated in ASD. METHODS: Pregnant C57BL/6N mice received a single subcutaneous injection of 100 or 200mg/kg on gestation day 17. The control group received a saline injection on the same day. The offspring were tested in a battery of behavioral tests in adolescence and adulthood. Six brain regions were harvested and GAD65 and GAD67 were measured by western blotting. RESULTS: Compared to saline-exposed controls, adult mice exposed to prenatal VPA had impaired novel object exploration and fear conditioning anomalies. GAD67 was decreased in midbrain, olfactory bulb, prefrontal cortex and increased in cerebellum, hippocampus and striatum; GAD65 was decreased in all 6 regions. CONCLUSIONS: Our results suggest that a low dose of VPA in late pregnancy has persistent effects on brain development, and in particular the GABA system, which may be relevant to ASD. Further attention to the impact of gestation time and dose of exposure in VPA induced ASD models is encouraged. PMID- 27498246 TI - Brain structure alterations and cognitive impairment following repetitive mild head impact: An in vivo MRI and behavioral study in rat. AB - Mild traumatic brain injury (mTBI) or concussion is a common health issue. Several people repeatedly experience head impact milder than that causing concussion. The present study aimed to confirm the effects of such repeated impact on the brain structure and cognitive abilities. Rat models were established by closed skull weight-drop injury. The animals were anesthetized, subjected to single (s)-sham, s-mTBI, repetitive (r)-sham, and r-mTBI, and recovery times were recorded. MRI, including T2-weighted and diffusion tensor imaging (DTI), as well as, neurological severity scores (mNSS) were assessed for the dynamics of the brain structure and neurological function. Morris water maze (MWM) was used to evaluate the cognitive function. The histological examination of r-mTBI rats revealed the basis of structural changes in the brain. There was no significant difference in the recovery time, MRI, mNSS, and MWM between the s sham and the s-mTBI groups. Compared with r-sham, r-mTBI induced significant differences in the following aspects. The recovery time was prolonged and beam balance test (BBT) in mNSS increased from day 5. MWM performances were worse even after the BBT was recovered. The volumes of the cortex (CT), hippocampus (HP), and lateral ventricle had changed from day 5, which reached a maximum at day 14. Abnormal DTI parameters were observed in CT, corpus callosum, and HP. Histological analyses showed that both in CT and HP, neuron counts reduced at the end of the experiment. Altogether, these findings indicate that non-symptomatic head injury may result in brain atrophy and cognitive impairment when occurred repeatedly. PMID- 27498247 TI - Galanin subtype 1 and subtype 2 receptors mediate opposite anxiety-like effects in the rat dorsal raphe nucleus. AB - About 40% of the dorsal raphe nucleus (DRN) neurons co-express serotonin (5-HT) and galanin. Serotonergic pathways from the DRN to the amygdala facilitate learned anxiety, while those from the DRN to the dorsal periaqueductal grey matter (DPAG) impair innate anxiety. Previously, we showed that galanin infusion in the DRN of rats induces anxiolytic effect by impairing inhibitory avoidance without changing escape behaviour in the elevated T-maze (ETM). Here, we evaluated: (1) which galanin receptors would be involved in the anxiolytic effect of galanin in the DRN of rats tested in the ETM; (2) the effects of galanin intra DRN on panic-like behaviours evoked by electrical stimulation of the DPAG. The activation of DRN GAL1 receptors by M617 (1.0 and 3.0nmol) facilitated inhibitory avoidance, whereas the activation of GAL2 receptors by AR-M1896 (3.0nmol) impaired the inhibitory avoidance in the ETM, suggesting an anxiogenic and an anxiolytic-like effect respectively. Both agonists did not change escape behaviour in the ETM or locomotor activity in the open field. The anxiolytic effect of AR-M1896 was attenuated by the prior administration of WAY100635 (0.18nmol), a 5-HT1A antagonist. Galanin (0.3nmol) administered in the DRN increased discreetly flight behaviours induced by electrical stimulation of the DPAG, suggesting a panicolytic effect. Together, our results showed that galanin mediates opposite anxiety responses in the DRN by activation of GAL1 and GAL2 receptors. The anxiolytic effect induced by activation of Gal2 receptors may depend on serotonergic tone. Finally, the role of galanin in panic related behaviours remains uncertain. PMID- 27498248 TI - Reply to letter by Dyverfeldt and Ebbers regarding the article "Estimation of turbulent kinetic energy using 4D phase-contrast MRI: Effect of scan parameters and target vessel size". PMID- 27498249 TI - Surgical Treatment of Tumors Involving Kidneys With Fusion Anomalies: A Contemporary Series. AB - OBJECTIVE: To report a contemporary series of surgically treated patients with tumors involving kidneys with fusion anomalies. MATERIALS AND METHODS: We retrospectively reviewed the medical records of all 10 patients treated at a single tertiary care institution for tumors involving kidneys with fusion anomalies between the years 2000 and 2015. One patient, diagnosed with lymphoma, did not undergo surgical treatment and was therefore excluded. Data regarding patient, tumor, and treatment characteristics were collected and described. RESULTS: The study cohort included 7 male and 2 female patients, at a median age of 52 years. Seven patients underwent open partial nephrectomy. Nephroureterectomy was performed on 2 patients; 1 open and 1 laparoscopic. All patients had localized disease at diagnosis. Tumor histologies were renal cell carcinoma in 5 patients, renal oncocytoma in 1 patient, urothelial carcinoma in 2 patients, and a well-differentiated liposarcoma involving the kidney in 1 patient. Accessory blood vessels were identified in 8 of 9 patients. Median estimated blood loss was 300 mL (interquartile range: 150-1000). Four patients had postoperative complications, including 3 major (Clavien grade >= 3) and 3 minor (Clavien grade <= 2) complications. During a median follow-up of 19.2 months (interquartile range: 3-34.8), 1 patient with urothelial carcinoma developed a bladder recurrence. None of the patients developed new-onset chronic kidney disease during the early postoperative period. CONCLUSION: Localized renal cortical tumors in kidneys with fusion anomalies may be treated with partial nephrectomy; however, complication rates are relatively high. Preoperative imaging of the blood vessels is necessary, as most patients have an accessory blood supply. PMID- 27498251 TI - Macromorphoscopic trait expression in a cranial sample from Medellin, Colombia. AB - Adjusting existing methods of human identification developed by forensic anthropologists in the United States for use with populations not included in the original development of an analytical method requires data collection using contemporary osteological collections from those populations, and an assessment of the within-group variation present. The primary purpose of this research is to document cranial macromorphoscopic trait variation using methods previously developed in the United States in a sample of 244 individuals from Antioquia, Medellin, Colombia. All individuals are of known age, sex, and birth region. The complex population and demographic history of Colombia makes ancestry assessment particularly difficult in that country. To that end, we explore inter-regional variation throughout Antioquia using birthplace to determine whether forensic anthropologists can provide finer levels of detail beyond identifying an unknown set of human remains as 'Colombian' or, more generally, Hispanic. State and local levels of identification resulting from the varied population histories of each state within Antioquia permit finer resolution, but only to a degree of certainty. Artificial neural networks (aNN) correctly classified only 18.6% of a validation sample, following modest classification accuracies of test/tuning (11.6%) and training (82.8%) samples to original birthplace. As with most neural networks, overfitting is an issue with these analyses. To remedy this overfitting and to document the applicability of aNNs to the assessment of ancestry in Colombia, we pooled the sample of Colombian data and compared that to modern American samples. In those analyses, the best aNN model correctly classified 48.4% (validation) of the sample. Given these results, finer levels of analysis in Colombia are not yet possible using only macromorphoscopic trait data. PMID- 27498250 TI - A comparison of different human papillomavirus tests in PreservCyt versus SurePath in a referral population-PREDICTORS 4. AB - BACKGROUND: Two transport media, PreservCyt and SurePath, are widely used for cervical cytology screening. There are concerns that they may perform differently for HPV testing. OBJECTIVES: A comparison of the performance of six different HPV tests in SurePath and PreservCyt in a referral population using two samples from each woman. The primary goal was to compare the performance of each test in the two media. Comparisons between assays and viral load comparisons between media were secondary aims. STUDY DESIGN: Two cervical samples were collected in random order at the same visit in women with abnormal cytology. One sample was placed in 20ml of PreservCyt and the other in 10ml of SurePath. Aliquots were taken for 4 DNA based tests: digene HC2 High-Risk HPV DNA Test, Abbott Realtime, BD Onclarity and Genera PapType, an RNA based test-: Hologic Aptima and a protein test: OncoHealth. RESULTS: 630 sample pairs were included in the analyses. For all tests except the protein test sensitivities were in excess of 90% for CIN2+ and 95% for CIN3+ for both media and with no significant differences except for a lower sensitivity for CIN2+ of Aptima in SurePath (93% vs 98%, P=0.005). Specificity for 4 weeks. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 4,963 patients, 3.3%, 1.6%, and 2.9% of patients stayed 1 to 2 weeks, 2 to 4 weeks, and>4 weeks in the ICU, respectively. In-hospital mortality was 11.1%, 26.6%, and 31.0% for patients with 1 to 2 weeks, 2 to 4 weeks, and>4 weeks ICU stay, respectively. Patients with ICU stays between 1 and 2 weeks had 6 months, 1 year, and 2 year survival rates of 84.4%, 80.0%, and 75.3% after discharge, respectively. Patients with ICU stay between 2 and 4 weeks had similar 6 months, 1 year, and 2 year survival rates of 84.7%, 79.9%, and 74.1%, respectively. In contrast, patients with>4 week ICU stays had significantly lower postdischarge survival rates of 63.3%, 56.4%, and 41.1% at 6 months, 1 year, and 2 years, respectively. Postoperative stroke conferred the greatest risk of death within 1 year after discharge (odds ratio 7.6, p = 0.0140). CONCLUSIONS: In-hospital mortality rates post-cardiac surgery correlate with length of ICU stay but appear to plateau after 4 weeks. However, a>4 week ICU length of stay confers a worse long-term outcome post-hospital discharge, especially in patients with postoperative stroke. PMID- 27498268 TI - Use of McGrath MAC Videolaryngoscope to Assist Transesophageal Echocardiography Probe Insertion in Intubated Patients. AB - OBJECTIVES: Transesophageal echocardiography (TEE) probe insertion with the conventional blind insertion technique may be difficult in anesthetized and intubated patients. The use of a videolaryngoscope may facilitate the insertion of the TEE probe. The aim of this study was to compare the conventional technique with the use of the McGrath MAC videolaryngoscope for TEE probe insertion in terms of success rate, duration of insertion, and complications in patients undergoing cardiovascular surgery. DESIGN: A prospective, randomized study. SETTING: Training and research hospital. PARTICIPANTS: Eighty-six adult patients undergoing cardiovascular surgery were included. INTERVENTIONS: Eighty-six adult patients were randomized into 2 groups: conventional group (n = 43) and McGrath videolaryngoscope group (n = 43). Success rates, duration of insertion, complications, and hemodynamic changes during insertion were recorded. MEASUREMENTS AND MAIN RESULTS: The success rate of TEE probe insertion at the first attempt was higher in the McGrath videolaryngoscope group (90.5%) than in the conventional group (43.9%) (p = 0.012). The mean duration for successful insertion of the TEE probe at the first attempt was longer in the McGrath videolaryngoscope group (24 s v 11 s) (p = 0.016). The total time for successful insertion of the TEE probe was similar in both groups. Pharyngeal injuries were observed more frequently in the conventional group (17.1% v 2.4%) (p = 0.037). The rate of blood presence on the probe tip in the conventional group was higher than in the McGrath group (21.9% v 4.8%). There were no statistical differences between the 2 groups in systolic blood pressure, mean arterial pressure, diastolic blood pressure, and heart rate before and after TEE insertion. CONCLUSIONS: The use of the McGrath MAC videolaryngoscope for TEE insertion in cardiovascular surgery patients increases the success rate and reduces pharyngeal injuries compared to the conventional technique. The use of the McGrath MAC videolaryngoscope for TEE insertion causes similar hemodynamic changes as in the conventional blind insertion technique. PMID- 27498269 TI - Etiologies of Dysphonia. PMID- 27498270 TI - Air in the Left Heart: A Perilous Situation in the Presence of a Left Ventricular Assist Device. PMID- 27498271 TI - Degradation of aniline by heterogeneous Fenton's reaction using a Ni-Fe oxalate complex catalyst. AB - A Ni-Fe oxalate complex catalyst was synthesized and characterized by means of Brunauer-Emmet-Teller (BET) method, scanning electron microscope (SEM) and X-ray photo-electron spectroscopy (XPS). The catalyst showed good catalytic activity for aniline degradation by heterogeneous Fenton's reaction, in which the synergetic index was 9.3. The effects of reaction temperature, catalyst dosage, hydrogen peroxide concentration and initial pH were investigated. Under the optimum conditions (T = 293 K, catalyst dosage = 0.2 g/L, H2O2 concentration = 4 mmol/L and initial pH = 5.4), 100% aniline could be removed within 35 min, and approximately 88% deamination efficiency was achieved in 60 min. The aniline degradation process followed the pseudo-first-order kinetic (k = 0.177 min(-1)) with activation energy (Ea) of 49.4 kJ mol(-1). Aniline could be removed in a broad initial pH (3-8) due to the excellent pH-tolerance property of the catalyst. The detected ammonium ion indicated that deamination occurred during aniline degradation. It was proposed that deamination synchronized with aniline removal, and aniline was attacked by free radicals to generate benzoquinonimine and phenol. This system is promising for the removal of aniline from water. PMID- 27498272 TI - Activating social strategies: Face-to-face interaction in technology-mediated citizen science. AB - The use of crowds in research activities by public and private organizations is growing under different forms. Citizen science is a popular means of engaging the general public in research activities led by professional scientists. By involving a large number of amateur scientists, citizen science enables distributed data collection and analysis on a scale that would be otherwise difficult and costly to achieve. While advancements in information technology in the past few decades have fostered the growth of citizen science through online participation, several projects continue to fail due to limited participation. Such web-based projects may isolate the citizen scientists from the researchers. By adopting the perspective of social strategy, we investigate within a measure manipulate-measure experiment if motivations to participate in a citizen science project can be positively influenced by a face-to-face interaction with the scientists leading the project. Such an interaction provides the participants with the possibility of asking questions on the spot and obtaining a detailed explanation of the citizen science project, its scientific merit, and environmental relevance. Social and cultural factors that moderate the effect brought about by face-to-face interactions on the motivations are also dissected and analyzed. Our findings provide an exploratory insight into a means for motivating crowds to participate in online environmental monitoring projects, also offering possible selection criteria of target audience. PMID- 27498273 TI - Rice bodies in the wrist joint. PMID- 27498274 TI - High serum uric acid is associated to poorly controlled blood pressure and higher arterial stiffness in hypertensive subjects. AB - INTRODUCTION: Serum uric acid (SUA) has been associated to incident hypertension and increased risk of cardiovascular diseases. MATERIALS AND METHODS: Among the 2191 subjects enrolled during the last population survey of the Brisighella Heart Study, we identified 146 new cases of arterial hypertension and 394 treated but uncontrolled hypertensive patients with different levels of SUA. Their hemodynamic characteristics have been compared with those of age- and sex-matched normotensive (N. 324) and controlled hypertensive (N. 470) subjects. Then, by logistic regression analysis, we evaluated which factors were associated with a worse BP control under pharmacological treatment. RESULTS: SUA levels were significantly higher in untreated hypertensive and uncontrolled hypertensive patients when compared to normotensives and controlled hypertensive patients. Pulse wave velocity (PWV) was significantly higher (p<0.001) in undiagnosed and uncontrolled hypertensive patients, while controlled hypertensive patients had PWV values comparable to normotensive controls. A similar trend has been observed for the augmentation index (AI). A worse BP control was associated with SUA levels (OR 1277, 95% CI 1134-1600 per mg/dL), AI (OR 1066, 95%CI 1041-1092 per unit), and PWV (OR 1201, 95% CI 1089-1423, per m/s), but not with age, body mass index, nor estimated glomerular filtration rate. CONCLUSION: Based on our data, SUA seems to be associated with an inadequate BP control in subjects treated with antihypertensive drugs, and subjects with both uncontrolled BP and relatively high SUA levels have also an increased arterial stiffness that (per se) could be a cause of worse BP control under treatment. PMID- 27498275 TI - In-depth analysis of protein inference algorithms using multiple search engines and well-defined metrics. AB - : In mass spectrometry-based shotgun proteomics, protein identifications are usually the desired result. However, most of the analytical methods are based on the identification of reliable peptides and not the direct identification of intact proteins. Thus, assembling peptides identified from tandem mass spectra into a list of proteins, referred to as protein inference, is a critical step in proteomics research. Currently, different protein inference algorithms and tools are available for the proteomics community. Here, we evaluated five software tools for protein inference (PIA, ProteinProphet, Fido, ProteinLP, MSBayesPro) using three popular database search engines: Mascot, X!Tandem, and MS-GF+. All the algorithms were evaluated using a highly customizable KNIME workflow using four different public datasets with varying complexities (different sample preparation, species and analytical instruments). We defined a set of quality control metrics to evaluate the performance of each combination of search engines, protein inference algorithm, and parameters on each dataset. We show that the results for complex samples vary not only regarding the actual numbers of reported protein groups but also concerning the actual composition of groups. Furthermore, the robustness of reported proteins when using databases of differing complexities is strongly dependant on the applied inference algorithm. Finally, merging the identifications of multiple search engines does not necessarily increase the number of reported proteins, but does increase the number of peptides per protein and thus can generally be recommended. SIGNIFICANCE: Protein inference is one of the major challenges in MS-based proteomics nowadays. Currently, there are a vast number of protein inference algorithms and implementations available for the proteomics community. Protein assembly impacts in the final results of the research, the quantitation values and the final claims in the research manuscript. Even though protein inference is a crucial step in proteomics data analysis, a comprehensive evaluation of the many different inference methods has never been performed. Previously Journal of proteomics has published multiple studies about other benchmark of bioinformatics algorithms (PMID: 26585461; PMID: 22728601) in proteomics studies making clear the importance of those studies for the proteomics community and the journal audience. This manuscript presents a new bioinformatics solution based on the KNIME/OpenMS platform that aims at providing a fair comparison of protein inference algorithms (https://github.com/KNIME-OMICS). Six different algorithms - ProteinProphet, MSBayesPro, ProteinLP, Fido and PIA- were evaluated using the highly customizable workflow on four public datasets with varying complexities. Five popular database search engines Mascot, X!Tandem, MS-GF+ and combinations thereof were evaluated for every protein inference tool. In total >186 proteins lists were analyzed and carefully compare using three metrics for quality assessments of the protein inference results: 1) the numbers of reported proteins, 2) peptides per protein, and the 3) number of uniquely reported proteins per inference method, to address the quality of each inference method. We also examined how many proteins were reported by choosing each combination of search engines, protein inference algorithms and parameters on each dataset. The results show that using 1) PIA or Fido seems to be a good choice when studying the results of the analyzed workflow, regarding not only the reported proteins and the high-quality identifications, but also the required runtime. 2) Merging the identifications of multiple search engines gives almost always more confident results and increases the number of peptides per protein group. 3) The usage of databases containing not only the canonical, but also known isoforms of proteins has a small impact on the number of reported proteins. The detection of specific isoforms could, concerning the question behind the study, compensate for slightly shorter reports using the parsimonious reports. 4) The current workflow can be easily extended to support new algorithms and search engine combinations. PMID- 27498276 TI - Systematic analysis of the lysine acetylome of the pathogenic bacterium Spiroplasma eriocheiris reveals acetylated proteins related to metabolism and helical structure. AB - Post-translational modifications such as acetylation are an essential regulatory mechanism of protein function. Spiroplasma eriocheiris, with no cell wall and a helical structure, is a novel pathogen of freshwater crustacean. There is no other evidence of acylation (such as succinylation and propionylation) except acetylation genes in S. eriocheiris concise genome. So the acetylation may play an important role in S. eriocheiris. Here, we conducted the first lysine acetylome in S. eriocheiris. We identified 2567 lysine acetylation sites in 555 proteins, which account for 44.69% of the total proteins in this bacterium. To date, this is the highest ratio of acetylated proteins that have been identified in bacteria. Fifteen types of acetylated peptide sequence motifs were revealed from the acetylome. Forty-five lysine-acetylated proteins showed homology with acetylated proteins previously identified from Escherichia coli, Vibrio parahemolyticus and Mycobacterium tuberculosis. Notably, most proteins in glycolysis and all proteins in the arginine deiminase system were acetylated. Meanwhile, the cell skeleton proteins (Fibril and Mrebs) were all acetylated the observed acetylation also played an important role in cell skeleton formation. The results imply previously unreported hidden layers of post-translational regulation in lysine acetylation that define the functional state of Spiroplasma. BIOLOGICAL SIGNIFICANCE: This is the first time to analyze PTM of Spiroplasma. This is the highest ratio of acetylated proteins that have been identified in bacteria. S. eriocheiris lysine acetylome reveals acetylated proteins related to metabolism and helical structure. These data provide an important resource to elucidate the role of acetylation in Spiroplasma cellular physiology. PMID- 27498278 TI - Reply to the Editor- Implantation of permanent devices in patients with Takotsubo syndrome. PMID- 27498279 TI - Color Doppler ultrasound assessment of morphology and types of fistulous tracts in hidradenitis suppurativa (HS). AB - BACKGROUND: Fistulous tracts in hidradenitis suppurativa (HS) are key signs of severity and their clinical evaluation alone may be limited for assessing their presence and morphology. There is also a need to determine the factors that allow reversibility of the anatomic changes in HS. OBJECTIVE: We sought to categorize fistulous tracts in HS. METHODS: A retrospective study of color Doppler ultrasound images of cases with positive clinical and sonographic criteria of HS with fistulous tracts was performed. The sonographic staging of HS, location, and anatomic characteristics of the tracts were registered and graded. Statistical analysis for correlating variables was performed using bivariate and multivariate studies. RESULTS: In all, 52 patients presenting 96 fistulous tracts met the criteria. Morphology was defined and a sonographic classification into 3 types of fistulae was developed. Type 3 concentrated 71% of the cases presenting communicating tracts, and type 2, 29%. Types 2 and 3 represented 63% of patients with multiple fistulous tracts. Fistulous tracts types 2 and 3 were significantly correlated with age 35 years or older and groin location. LIMITATIONS: Ultrasound cannot detect lesions less than 0.1 mm. CONCLUSION: Fistulous tracts in HS can be categorized using ultrasound, which may support earlier and more precise management. PMID- 27498277 TI - Validation of electromechanical wave imaging in a canine model during pacing and sinus rhythm. AB - BACKGROUND: Accurate determination of regional areas of arrhythmic triggers is of key interest to diagnose arrhythmias and optimize their treatment. Electromechanical wave imaging (EWI) is an ultrasound technique that can image the transient deformation in the myocardium after electrical activation and therefore has the potential to detect and characterize location of triggers of arrhythmias. OBJECTIVES: The objectives of this study were to investigate the relationship between the electromechanical and the electrical activation of the left ventricular (LV) endocardial surface during epicardial and endocardial pacing and during sinus rhythm as well as to map the distribution of electromechanical delays. METHODS: In this study, 6 canines were investigated. Two external electrodes were sutured onto the epicardial surface of the LV. A 64 electrode basket catheter was inserted through the apex of the LV. Ultrasound channel data were acquired at 2000 frames/s during epicardial and endocardial pacing and during sinus rhythm. Electromechanical and electrical activation maps were synchronously obtained from the ultrasound data and the basket catheter, respectively. RESULTS: The mean correlation coefficient between electromechanical and electrical activation was 0.81 for epicardial anterior pacing, 0.79 for epicardial lateral pacing, 0.69 for endocardial pacing, and 0.56 for sinus rhythm. CONCLUSION: The electromechanical activation sequence determined by EWI follows the electrical activation sequence and more specifically in the case of pacing. This finding is of key interest in the role that EWI can play in the detection of the anatomical source of arrhythmias and the planning of pacing therapies such as cardiovascular resynchronization therapy. PMID- 27498280 TI - New Automatic Tools to Identify Responders to Cardiac Resynchronization Therapy. AB - BACKGROUND: New echocardiographic parameters (apical rocking [AR], septal flash [SF]) are intended to detect patterns specific to responders to cardiac resynchronization therapy (CRT). The patterns are visually recognized and qualitatively described, requiring experience and training. Speckle-tracking echocardiography can reflect SF and AR by using newly developed, dedicated parameters, such as start systolic index (SSI) and peak longitudinal displacement (PLD). The aim of this study was to investigate whether SSI and PLD can identify potential CRT responders. METHODS: In 125 patients, echocardiograms from before and 9 +/- 3 months after CRT were retrospectively analyzed with dedicated EchoPAC prerelease software. From speckle-tracking baseline images, color-coded bull's eye displays of SSI and PLD were generated. Cutoff values for both parameters were derived from 25 randomly selected patients and applied to the remaining 100 patients to identify CRT response, defined as a decrease in end-systolic volume of >=15% during follow-up. The performance of SSI and PLD was compared with the visual assessment of AR and SF by expert and novice readers. RESULTS: Expert readers detected 77 patients with AR, identifying CRT responders with sensitivity and specificity of 85 +/- 2% and 82 +/- 2%, respectively. Novice readers reached 74 +/- 7% sensitivity and 55 +/- 11% specificity, while the sensitivity and specificity of the quantitative analysis were 72 +/- 3% and 84 +/- 4% for SSI and 80 +/- 1% and 75 +/- 2% for PLD, respectively. CONCLUSIONS: New speckle-tracking based quantitative assessment of mechanical dyssynchrony by SSI and PLD performs comparably in identifying CRT responders as visual analysis by expert readers and performs significantly better than novice readers. PMID- 27498281 TI - Double-targeted polymersomes and liposomes for multiple barrier crossing. AB - In order to treat metastasis in the brain, drug delivery systems must overcome multiple physical barriers between the point of administration and the target, such as the Blood-brain barrier, that hinder their free access across them. Multiple targeting approaches arise as a promising alternative to this barrier and target certain tissues inside the brain at a time. Herein, two surface modification methods are presented to obtain dual-targeted vesicle-like carriers functionalized with an MCF-7-specific phage protein and a BBB-specific peptide, providing the system the ability to cross a BBB model, target breast cancer cells and deliver its payload. The aim of this study was to compare new designed polymersomes with liposomes, a well-established delivery vehicle, in terms of drug loading, targeting, release and tumor cell killing. The bilayer structure of both systems allowed the conjugation with different ligands both by insertion and covalent binding. Different behaviour was observed in release, uptake and tumor cell killing corresponding to differences in membrane permeability of both vehicles and type of targeting and ligands' combination. Preliminary results showed that both formulations were able to cross the BBB monolayer without harming it, showing cytotoxic activity in the abluminal compartment. PMID- 27498283 TI - Editorial introduction: The effects of somatic disease and environmental insults on the stress response. PMID- 27498282 TI - Niosomal approach to brain delivery: Development, characterization and in vitro toxicological studies. AB - The majority of active agents do not readily permeate into brain due to the presence of the blood-brain barrier and blood-cerebrospinal fluid barrier. Currently, the most innovative and promising non-invasive strategy in brain delivery is the design and preparation of nanocarriers, which can move through the brain endothelium. Niosomes can perform brain delivery, in fact polysorbates, can act as an anchor for apolipoprotein E from blood plasma. The particles mimic LDL and interact with the LDL receptor leading to the endothelial cells uptake. The efficacy of niosomes for anticancer therapeutic applications was correlated to their physicochemical and drug delivery properties. Dimensions and zeta potential were characterized using dynamic light scattering and asymmetric flow field fractionation system. Lipid bilayer was characterized measuring the fluidity, polarity and microviscosity by fluorescent probe spectra evaluation. Morphology and homogeneity were characterized using atomic force microscopy. Physicochemical stability and serum stability (45% v/v fetal bovine and human serum) were evaluated as a function of time using dynamic light scattering. U87 MG human glioblastoma cells were used to evaluate vesicle cytotoxicity and internalisation efficiency. From the obtained data, the systems appear useful to perform a prolonged (modified) release of biological active substances to the central nervous system. PMID- 27498284 TI - Lactobacillus and lower genital tract infection. PMID- 27498285 TI - [Acne in Cameroon: Quality of life and psychiatric comorbidities]. AB - BACKGROUND AND AIMS: The impact of acne upon quality of life (QOL) among affected patients had not previously been investigated in Cameroon. The present study therefore sought to assess the QOL of patients with acne and related psychiatric comorbidities in this country. PATIENTS AND METHODS: This was a cross-sectional study conducted in three hospitals in Yaounde, Cameroon. We included patients diagnosed with acne after a consultation with a dermatologist, and who consented to participate in the study. The ECLA scale was used for the clinical evaluation of acne and the CADI score was used to assess QOL. PHQ-9 and GAD-7 questionnaires were used for the respective screening of depression and anxiety. RESULTS: We enrolled 181 patients aged between 13 and 56years. According to the ECLA table, the acne global severity score ranged from 3 to 26 points. Impairment was observed in all patients' QOL, which ranged from 1 to 15 points. We noted 11 cases of depression (6.1%) and 14 cases of anxiety (7.7%). There was a positive and significant correlation between the severity of acne and impairment of patients' QOL (r=0.46; P<0.001). Likewise, the severity of acne and of depression and anxiety scores were positively and significantly correlated with one other: r=0.347 (P<0.001) and r=0.291 (P<0.001), respectively. CONCLUSION: Acne negatively impacts the QOL of patients presenting acne in Cameroon and is associated with depression and anxiety, which must therefore be taken into account when treating these patients. PMID- 27498286 TI - Response to commentary re 'A critical appraisal of continence in bladder exstrophy: Long-term outcomes of the complete primary repair'. PMID- 27498287 TI - Response to Pembrolizumab in a Patient with Relapsing Thymoma. PMID- 27498288 TI - Slowing the Titanic: China's Epic Struggle with Tobacco. AB - China is home to a third of the world's smokers and, correspondingly, to a third of the world's cases of lung cancer. Beginning in the mid-1990s, a generation or so later than in many Western countries, the Chinese government commenced measures to control tobacco, limiting advertising, banning smoking in many public venues, and increasing taxation. At the time of this review, there are signs that these policies are having some effect, but hundreds of millions of Chinese continue to smoke and rates of diagnosis of lung cancer continue to rise. There is much work to be done and much premature death to be suffered before the epidemic is slowed to the levels reached in Australia or the United States. This article aims to provide, particularly for practicing lung cancer clinicians, a description of patterns of smoking in China, the lung cancer epidemic there, and the stimuli for and barriers to tobacco control imposed by the highly complex and unique regulatory setting of the Chinese tobacco industry. A particular challenge in developing this description has come from the variability of studies published about a huge nation that has enormous diversity in wealth, education, urbanization, and tradition. The studies vary because the data vary. Much information on lung cancer and smoking rates in China comes, for example, from studies of cohorts that may number in the millions yet represent only a small percentage of the population and sometimes only a tiny geographic area of such a vast nation. National registry data on lung cancer in China do not yet cover even a fifth of the national population. Even so, we argue that several major trends can be identified: (1) more than 50% of men smoke regularly; (2) there are more than 300 million smokers in China; (3) almost half a million new cases of lung cancer are diagnosed in China each year; (4) secondhand smoking is a significant problem in China (as elsewhere), accounting for a high proportion of lung cancer cases among women, most of whom do not smoke; (5) corrected for age and sex, lung cancer rates in the Chinese population are as least as high as in Western countries and arguably higher; and (6) a shift over time from squamous cell carcinoma (SCC) to adenocarcinoma is occurring in parallel with that noted in Western populations. Looking to the future, measures to control tobacco in China are strengthening but remain relatively weak. The reinforcement of control is hampered by the circumstance that the tobacco industry remains a powerful state owned monopoly that participates, through its membership of key government bodies, in the processes that oversee the implementation of tobacco control. The conflict between the government's dual responsibilities for both the production and distribution of tobacco and for the implementation of tobacco control carries inherent contradictions and bias. How long the Chinese government chooses to live with these contradictions will determine how quickly the smoking of tobacco will be reduced and how soon the burden of disease that tobacco inflicts on individuals and society as a whole will be eased. PMID- 27498289 TI - Overexpression of beta-Catenin and Cyclin D1 is Associated with Poor Overall Survival in Patients with Stage IA-IIA Squamous Cell Lung Cancer Irrespective of Adjuvant Chemotherapy. AB - INTRODUCTION: This study was aimed at understanding the effect of beta-catenin and cyclin D1 on overall survival in patients with early-stage NSCLC and at evaluating if the prognostic effect can be modified by adjuvant chemotherapy. METHODS: We retrospectively analyzed the expression of beta-catenin and cyclin D1 using immunohistochemistry in formalin-fixed paraffin-embedded tissues from 576 patients with early-stage NSCLC. RESULTS: The median duration of follow-up was 5.1 years. Overexpression of beta-catenin and cyclin D1 was found in 56% and 50% of 576 cases, respectively. Overexpression of beta-catenin and cyclin D1 was significantly associated with poor overall survival (p = 0.003 and p = 0.0009, respectively; log rank test) in squamous cell carcinomas, not in adenocarcinomas. The prognostic significance of each protein in the squamous cell carcinomas was limited to stages IA, IB, and IIA. In addition, simultaneous overexpression of beta-catenin and cyclin D1 in the squamous cell carcinomas synergistically increased hazard ratios (HRs) 15.79 (95% confidence interval [CI] = 1.09-51.23; p =0.04) for stage IA, 10.30 (95% CI = 2.29-46.41; p = 0.002) for stage 1B, and 3.55 (95% CI = 1.22-10.36; p = 0.02) times for stage 2A compared to those without overexpression of the two proteins, after adjusting for confounding factors. In addition, the effect was not dependent on adjuvant chemotherapy. CONCLUSIONS: The present study suggests that simultaneous overexpression of beta-catenin and cyclin D1 may be associated with poor overall survival irrespective of platinum based adjuvant chemotherapy in stage IA-IIA squamous cell carcinoma of the lung. PMID- 27498290 TI - Assessing cortisol from hair samples in a large observational cohort: The Whitehall II study. AB - Hair cortisol concentrations (HCC) have been suggested to reflect long-term integrated cortisol levels, but most evidence of associations with co-variates is from small samples of healthy volunteers. The objective of this study was to describe the collection of hair samples in a large cohort study and report associations of demographic and health measures with HCC. We examined HCC measured from the 3cm hair segment near the scalp in 3507 participants (aged 59 83y) from The Whitehall II occupational cohort study of British civil servants. Hair samples were analysed using a column switching LC-APCI-MS/MS assay. Findings from mutually adjusted linear regression analyses revealed lower HCC in participants who reported use of hair dye [% difference (95%CI); -12.5 (-22.0, 1.9), p value=0.022] and evidence suggestive of differences by length of sample storage and seasonal variation. With regard to demographic variables, HCC was lower in women compared to men [-17.0 (-24.8, -8.4), p value <0.001] and higher in Black compared to other ethnic groups. Prevalent diabetes, use of systemic corticosteroids and cardiovascular medication were independently associated with higher HCC. With regard to health, depressive symptoms were associated with higher HCC [20.0 (8.1, 33.3), p value=0.001] following adjustment for physical disease and medication. We conclude that hair steroid analysis presents significant opportunities for assessing cortisol in large scale cohorts. Demographic factors, sample storage, season of collection and hair characteristics should be considered in future analyses. Health status, both mental and physical, is linked to HCC. PMID- 27498291 TI - Impaired brain metabolism and neurocognitive function in childhood leukemia survivors despite complete hormone supplementation in adulthood. AB - Cranial radiotherapy is a known risk factor for neurocognitive impairment in survivors of childhood acute lymphoblastic leukemia (ALL). Understanding the nature of cognitive dysfunction during adulthood in ALL survivors is important as it has an impact on major life situations. Thirty-eight (21 women) ALL survivors were investigated 34 years after diagnosis. Median-age was 38 (27-46) years. All were treated with a CRT dose of 24Gy and 11 years (3-13) of complete hormone supplementation. Comparisons were made to 29 matched controls. Assessments of magnetic resonance spectroscopy (white and grey matter metabolic alterations), brain volume and neuropsychological tests were performed. ALL survivors demonstrate a generally lower performance in neuropsychological tests. ALL survivors scored lower than controls in vocabulary (p<0.001), memory (p<0.001), learning capacity (p<0.001), spatial ability (p<0.001), executive functions and attention (p<0.001) 34 years after ALL treatment. Compared to controls ALL survivors had reduced white matter (WM) (492 vs 536cm3, p<0.001) and grey matter (GM) volumes (525 vs 555cm3, p=0.001). ALL survivors had lower levels of WM N acetyl aspartate/creatin (NAA/Cr) (1.48 vs 1.63, p=0.004), WM NAA+NAAG (N acetylaspartylglutamate)/Cr (1.61 vs 1.85, p<0.001) and lower levels of GM NAA/Cr (1.18 vs 1.30, p=0.001) and GM NAA+NAAG/Cr (1.28 vs 1.34, p=0.01) compared to controls. ALL survivors had higher levels in WM MI (Myoinositol)/NAA (0.65 vs 0.56, p=0.01) concentrations compared to controls. There was a significantly negative correlation of years since ALL diagnosis to WM NAA+NAAG/Cr (r=-0.4, p=0.04) in ALL survivors. The present study shows impaired brain metabolism detected by MRS, reduced brain volumes and neurocognitive impairment in childhood ALL survivors treated with cranial radiotherapy and chemotherapy, despite complete hormone substitution. We also report an impairment of metabolites correlated to time since treatment and a progressive impairment in sustained attention, suggesting an accelerated aging in the irradiated brain. Following these survivors many decades, or throughout life, after treatment with cranial radiotherapy and chemotherapy is highly warranted for a broader understanding of long-term outcome in this patient group. PMID- 27498294 TI - Rewards boost sustained attention through higher effort: A value-based decision making approach. AB - Maintaining sustained attention over time is an effortful process limited by finite cognitive resources. Recent theories describe the role of motivation in the allocation of such resources as a decision process: the costs of effortful performance are weighed against its gains. We examined this hypothesis by combining methods from attention research and decision neuroscience. Participants first performed a sustained attention task at different levels of reward. They then performed a reward-discounting task, measuring the subjective costs of performance. Results demonstrated that higher rewards led to improved performance (Exp 1-3), and enhanced attentional effort (i.e. pupil diameter; Exp 2 & 3). Moreover, discounting curves constructed from the choice task indicated that subjects devalued rewards that came at the cost of staying vigilant for a longer duration (Exp 1 & 2). Motivation can thus boost sustained attention through increased effort, while sustained performance is regarded as a cost against which rewards are discounted. PMID- 27498295 TI - Anthocyanins protect from complex I inhibition and APPswe mutation through modulation of the mitochondrial fission/fusion pathways. AB - Anthocyanins are a distinguished class of flavonoids with powerful free radical scavenging activity that have been suggested as chemotherapeutic agents for the prevention of Alzheimer disease (AD). In this study, we examined the ability of nutraceutical Medox rich in purified cyanidin 3-O-glucoside (C3G), 3-O-b glucosides and delphinidin 3-O-glucoside (D3G) to counteract mitochondrial deficiency induced by complex I inhibition and/or amyloid-beta peptide (Abeta) induced toxicity. SH-SY5Y neuroblastoma cells were stably transfected with APP Swedish K670N/M671L double mutation (APPswe) or with the empty vector and treated with rotenone. We report that Medox treatment improves the metabolic activity and maintains cell integrity in both cell lines. At the mitochondrial level, APPswe and rotenone induced mitochondrial fragmentation, an effect that was counteracted by Medox through the modulation of fission and fusion proteins, resulting in a reshaped mitochondrial network. Although Medox was unable to fully neutralise the effects of rotenone on ATP levels and mitochondrial membrane potential, it was able to prevent rotenone-induced cytotoxicity. Our findings suggest that Medox anthocyanins, on top of their antioxidant capacity, ameliorate mitochondrial dysfunction generated by Abeta overproduction or by chemical inhibition of mitochondrial complex I via stabilization of the fusion/fission processes. Modulation of the mitochondrial network has been suggested as a novel therapeutic approach in diseases involving mitochondrial dysfunction and oxidative stress. Hence, increasing the understanding of how anthocyanins influence mitochondrial dynamics in a neurodegenerative context, could be of future therapeutic value. PMID- 27498296 TI - Commentary: Connections across life stages and disease risk: commentary on a study early in the life course of life course epidemiology. PMID- 27498293 TI - A nationwide survey of common viral infections in childhood among patients with primary immunodeficiency diseases. AB - OBJECTIVES: Patients with primary immunodeficiency diseases (PID) are highly susceptible to various microorganisms. However, no population-based studies have been performed among common viral pathogens, such as respiratory syncytial virus (RSV), rotavirus (RV), varicella-zoster virus (VZV) and influenza virus (IV). The objective of this study was to reveal the clinical burden of these four infections among PID patients in Japan. METHODS: We conducted a nationwide survey by sending questionnaires to 898 hospitals with pediatric departments throughout Japan. RESULTS: Nine hundred ten PID patients from 621 hospitals were registered (response rate: 69.2%). Fifty-four of the patients were hospitalized due to these viral infections. The durations of hospitalization due to RSV and RV infections differed significantly in the PID patients with and without cellular immunodeficiency (12.0 vs 6.5 days, p = 0.041; and 14.0 vs 6.0 days, p = 0.031, respectively). There was no significant difference in the duration of hospitalization in PID patients with and without cellular immunodeficiency who were hospitalized with IV infections (7.3 vs 6.1 days, p = 0.53). CONCLUSIONS: Special attention should be paid to PID patients with compromised cellular immunity who present with RSV and RV infection due to their high risk for severe disease. PMID- 27498292 TI - Known unknowns of cardiolipin signaling: The best is yet to come. AB - Since its discovery 75years ago, a wealth of knowledge has accumulated on the role of cardiolipin, the hallmark phospholipid of mitochondria, in bioenergetics and particularly on the structural organization of the inner mitochondrial membrane. A surge of interest in this anionic doubly-charged tetra-acylated lipid found in both prokaryotes and mitochondria has emerged based on its newly discovered signaling functions. Cardiolipin displays organ, tissue, cellular and transmembrane distribution asymmetries. A collapse of the membrane asymmetry represents a pro-mitophageal mechanism whereby externalized cardiolipin acts as an "eat-me" signal. Oxidation of cardiolipin's polyunsaturated acyl chains - catalyzed by cardiolipin complexes with cytochrome c. - is a pro-apoptotic signal. The messaging functions of myriads of cardiolipin species and their oxidation products are now being recognized as important intracellular and extracellular signals for innate and adaptive immune systems. This newly developing field of research exploring cardiolipin signaling is the main subject of this review. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum. PMID- 27498297 TI - Relationship of childhood weight status to morbidity in adults. AB - A cohort of white males who had attended elementary schools in Hagerstown, Md., between 1923 and 1928, and whose height-weight records for those years were available, was examined during 1961-63. A study of their childhood relative weight at ages 9-13, and of their adult relative weight 35-40 years later, was made in relation to selected physiological variables and diagnosed morbidity.Essential findings were as follows: Childhood relative weight at ages 9 13 had no significant relationship to adult levels of fasting blood sugar, serum cholesterol, beta-lipoprotein, or blood pressure, or to cardiovascular renal disease.Childhood relative weight at ages 9-13 was significantly related to hypertensive vascular disease. The below average weight group experienced a higher prevalence than observed in either average or moderately overweight childhood groups.Approximately 30 percent of the below average weight children became average weight adults and 21 percent became overweight adults. Of the average weight children, approximately 40 percent became overweight adults. Overweight children tended to remain overweight as adults.Adult relative weight of the same cohort, viewed 35-40 years later, was significantly associated with fasting blood sugar, beta-lipoprotein, and systolic and diastolic blood pressure. Elevated levels of each of these variables occurred with greater frequency in the overweight child.Adult relative weight was significantly associated with hypertensive vascular disease and cardiovascular renal disease; the higher prevalence occurred in the overweight adults.The highest risk for hypertensive vascular and cardiovascular renal disease was associated with the persons who acquired their overweight status as adults. The higher prevalence of these diseases among the overweight adults was largely attributable to the adults who moved from a below average childhood weight category to an overweight adult group. The moderately or markedly overweight adults who was similarly classified as a child did not appear to be at greater risk than the average weight adult who had been an average weight child. PMID- 27498298 TI - Commentary: Disentangling the contributions of childhood and adult weight to cardiovascular disease risk. PMID- 27498299 TI - Gluten Intolerance and Neurodevelopmental Disorders: Is Nitric Oxide the Common Biomarker Linking These Conditions? AB - Cruchet et al. attempt to tease out the myths and facts surrounding the growing popularity of certain dietary approaches in the management of neurodevelopmental disorders, like attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs). The authors identify a particular exclusionary-type approach that seeks to eliminate dietary gluten. Although the relationship between celiac disease (CD) and ADHD/ASD is not well established, a repeated clinical feature noted in CD is the elevated levels of nitric oxide in serum and urine. Elevated oxidative stress has also been observed in neurodevelopmental conditions, and the author of this correspondence has been the first to propose that chronic, environmental exposure to the air pollutant, nitrous oxide may contribute to these oxidative stress profiles through neural cholinergic perturbation. Therefore, the purpose of this correspondence is to highlight this biochemical connection between these conditions so as to identify the clinical populations who may realize the greatest benefit of these dietary approaches, while minimizing any potential risk of nutrient deficiencies. PMID- 27498300 TI - Impact of obesity on surgical outcomes of laparoscopic distal pancreatectomy: A Norwegian single-center study. AB - BACKGROUND: Obesity is known as a risk factor for intra- and postoperative complications in pancreatic operation. However, the operative outcomes in obese patients undergoing laparoscopic distal pancreatectomy remain unclear. METHODS: A total number of 423 patients underwent laparoscopic distal pancreatectomy at Oslo University Hospital-Rikshospitalet from April 1997 to December 2015. Patients were categorized into 3 groups based on the body mass index: normal weight (18.5 24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (>=30 kg/m2). After excluding underweight patients, 402 patients were enrolled in this study. RESULTS: Obese patients had significantly longer operative time and increased blood loss compared with overweight and normal weight patients (190 [61-480] minutes vs 158 [56-520] minutes vs 153 [29-374] minutes, P = .009 and 200 [0-2,800] mL vs 50 [0 6250] mL vs 90 [0-2,000] mL, P = .01, respectively). A multiple linear regression analysis identified obesity as predictive of prolonged operative time and increased blood loss during laparoscopic distal pancreatectomy. The rates of clinically relevant pancreatic fistula and severe complications (>=grade III by Accordion classification) were comparable in the 3 groups (P = .23 and P = .37, respectively). A multivariate logistic regression model did not demonstrate an association between obesity and postoperative morbidity (P = .09). The duration of hospital stay was comparable in the 3 groups (P = .13). CONCLUSION: In spite of longer operative time and greater blood loss, laparoscopic distal pancreatectomy in obese patients is associated with satisfactory postoperative outcomes, similar to those in normal weight and overweight patients. Hence, laparoscopic distal pancreatectomy should be equally considered both in obese and nonobese patients. PMID- 27498301 TI - Short- and long-term impact of reoperation for complications after major hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: The impact of reoperation for complications after major liver resection for hepatocellular carcinoma was evaluated. METHODS: In this retrospective study covering 25 years, patients with reoperation for complications after major liver resection for hepatocellular carcinoma were compared with patients without reoperation in terms of demographics, tumor characteristics, operative details, postoperative results, oncologic outcomes, and survival. Reasons for reoperation were also investigated. RESULTS: Forty-nine out of 1,092 patients underwent reoperation within a median of 0.2 days (range, 0 6.9 days) after hepatectomy. Patients with and without reoperation had similar baseline characteristics and liver function. Nonetheless, patients with reoperation had a higher indocyanine green retention rate at 15 minutes (12.55% vs 10.5%, P = .015), more operative blood loss (1.4 L vs 1 L, P = .012), a higher blood transfusion rate (44.9% vs 29.2%, P = .029), longer hospital stay (21 days vs 11 days, P < .001), a higher hospital mortality (38.8% vs 3.0%, P < .001), and a higher 90-day mortality (38.8% vs 4.7%, P < .001). Hemorrhage was the most common cause for reoperation (26/49, 53.1%), mainly resulting from coagulopathic bleeding from raw areas (12/26, 46.2%) and bleeding from diaphragmatic veins (6/26, 23.1%). However, reoperation did not affect 5-year overall survival (50.2% vs 48.3%, P = .468). CONCLUSION: Postoperative hemorrhage was associated with a high mortality, signifying the importance of meticulous hemostasis and careful perioperative management. Oncologic outcomes, however, were not affected by reoperation. PMID- 27498302 TI - Metabolic syndrome in liver transplantation: A preoperative and postoperative concern. AB - BACKGROUND: Metabolic syndrome is increasing among patients undergoing liver transplantation. Nonalcoholic steatohepatitis is a manifestation of metabolic syndrome and is an increasingly common cause of end-stage liver disease necessitating orthotopic liver transplantation. We sought to determine the effect of preoperative risk factors on the development of post-transplant metabolic syndrome, complications, readmissions, and mortality. METHODS: We conducted a review of 114 orthotopic liver transplantations at our institution from May 2012 to April 2014. RESULTS: Patients with (n = 19) and without (n = 95) metabolic syndrome were similar with regard to age, race, and model for end-stage liver disease at time of transplant. Donor and operative factors also were similar between the groups. Preoperative diabetes was found to be associated with an increased rate of readmission (odds ratio 3.45, P = .03). While preoperative metabolic syndrome itself was not a significant predictor of worse outcomes, postoperative metabolic syndrome was associated with significantly greater readmissions in the first year. Major predictors of new onset metabolic syndrome after orthotopic liver transplantation included preoperative diabetes and obesity (odds ratio 8.54 and odds ratio 5.49, P < .01 each). CONCLUSION: Efforts to decrease the incidence of postoperative metabolic syndrome after orthotopic liver transplantation may decrease readmissions and improve outcomes, along with decreasing resource utilization. PMID- 27498303 TI - Sex, strain, and estrous cycle influences on alcohol drinking in rats. AB - Although women appear to be more vulnerable to alcohol-induced pathophysiology than men, the neurobiological basis for sex differences is largely unknown, partially because most studies on alcohol drinking are conducted in male subjects only. The present study examined sex differences in alcohol consumption in two rat strains, Long Evans and Wistar, using multiple behavioral paradigms. The effects of the estrous cycle on alcohol consumption were monitored throughout the study. The results indicated that females drank more alcohol than males when given either continuous or intermittent access to alcohol (vs. water) in their home cages (voluntary drinking). Under operant conditions, no sex or strain differences were found in drinking prior to development of alcohol dependence. However, upon dependence induction by chronic, intermittent alcohol vapor exposure, Wistar rats of both sexes substantially escalated their alcohol intake compared with their nondependent drinking levels, whereas Long Evans rats only exhibited a moderate escalation of drinking. Under these conditions, the estrous cycle had no effect on alcohol drinking in any strain and drinking model. Thus, strain, sex, and drinking conditions interact to modulate nondependent and dependent alcohol drinking. The present results emphasize the importance of including sex and strain as biological variables in exploring individual differences in alcohol drinking and dependence. PMID- 27498304 TI - 6-Aryl-4-amino-pyrimido[4,5-b]indole 2'-deoxyribonucleoside triphosphates (benzo fused 7-deaza-dATP analogues): Synthesis, fluorescent properties, enzymatic incorporation into DNA and DNA-protein binding study. AB - Four 6-substituted 4-amino-pyrimido[4,5-b]indole 2'-deoxyribonucleoside triphosphates (dA(BX)TPs) were prepared by glycosylation of 4,6 dichloropyrimidoindole followed by ammonolysis, cross-coupling and triphosphorylation. They were found to be moderate to good substrates for DNA polymerases in primer extension. They also exerted fluorescence with emission maxima 335-378nm. When incorporated to oligonucleotide probes, they did not show significant mismatch discrimination but the 6-benzofuryl 4-amino-pyrimido[4,5 b]indole nucleotide displayed a useful sensitivity to protein binding in experiment with SSB protein. PMID- 27498306 TI - Serum granzyme-B, insulin resistance, metabolic syndrome and cardiovascular risk: statistical validity for risk assessment. PMID- 27498307 TI - Fast method for simultaneous quantification of tamoxifen and metabolites in dried blood spots using an entry level LC-MS/MS system. AB - The purpose of this study was to develop and validate a new liquid chromatography tandem mass spectrometric (LC-MSMS) assay for the simultaneous quantification of tamoxifen (TAM) and its main therapeutically active metabolites, N desmethyltamoxifen (NDT), 4-hydroxytamoxifen (4HT) and endoxifen (END) in dried blood spots. Ultrasound assisted methanolic extraction was used for TAM and metabolites extraction from dried blood spot. After evaporation and methanol reconstitution, the extract was injected into a LC-MSMS system. Reversed phase chromatography was performed on a C18 grafted column in gradient mode. TAM, metabolites, and internal standard (diazepam-d5; IS) were identified in positive electrospray ionization mode using m/z transition of 372.5>72.1 (TAM); 374.23>58.10 (END); 358.27>58.10 (NDT); 388.23>44.80 (4HT) and 290.00>198.00 (IS). Total analytical run time was 6.5min. Assay was linear from 1 to 500ng/mL for all substances and presented intra and inter-assay precision and accuracy <15%. TAM, NDT, 4HT and END limits of quantification and detection were of 1 and 0.5ng/mL; 1 and 3ng/mL; 1.7 and 3ng/mL; 0.6 and 2ng/mL, respectively. Recovery ranged from 83.8 to 96.3% with matrix effect ranged from 4.3 to 29.8% for TAM and its metabolites. Hematocrit value <=40% appeared to negatively influence accuracy of the method. In conclusion, the method described here is somewhat accessible, relatively fast, sensitive and selective with no interference. This assay might be used to investigate the level of TAM and its metabolites in DBS for therapeutic drug monitoring purposes. PMID- 27498305 TI - Polypharmacy and potentially inappropriate medication use in geriatric oncology. AB - Polypharmacy is a highly prevalent problem in older persons, and is challenging to assess and improve due to variations in definitions of the problem and the heterogeneous methods of medication review and reduction. The purpose of this review is to summarize evidence regarding the prevalence and impact of polypharmacy in geriatric oncology patients and to provide recommendations for assessment and management. Polypharmacy has somewhat variably been incorporated into geriatric assessment studies in geriatric oncology, and polypharmacy has not been consistently evaluated as a predictor of negative outcomes in patients with cancer. Once screened, interventions for polypharmacy are even more uncertain. There is a great need to create standardized interventions to improve polypharmacy in geriatrics, and particularly in geriatric oncology. The process of deprescribing is aimed at reducing medications for which real or potential harm outweighs benefit, and there are numerous methods to determine which medications are candidates for deprescribing. However, deprescribing approaches have not been evaluated in older patients with cancer. Ultimately, methods to identify polypharmacy will need to be clearly defined and validated, and interventions to improve medication use will need to be based on clearly defined and standardized methods. PMID- 27498308 TI - Fabrication and characterization of conductive poly (3,4-ethylenedioxythiophene) doped with hyaluronic acid/poly (l-lactic acid) composite film for biomedical application. AB - Poly 3,4-ethylenedioxythiophene (PEDOT), a polythiophene derivative, has been proved to be modified by chemical process as biocompatible conductive polymer for biomedical applications. In this study, novel hyaluronic acid (HA)-doped PEDOT nanoparticles were synthesized by the method of chemical oxidative polymerization, then conductive PEDOT-HA/poly(l-lactic acid) (PLLA) composite films were prepared. The physicochemical characteristics and biocompatibility of films were further investigated. FTIR, Raman and EDX analysis demonstrated that HA was successfully doped into PEDOT particles. Cyclic voltammograms indicated PEDOT-HA particles had favorable electrochemical stability. PEDOT-HA/PLLA films showed lower surface contact angle and faster degradation degree compared with PLLA films. Moreover, the cytotoxicity test of PEDOT-HA/PLLA films showed that neuron-like pheochromocytoma (PC12) cells adhered and spread well on the surface of PEDOT-HA/PLLA films and cell viability denoted by MTT assay had a significant increase. PEDOT-HA/PLLA films modified with laminin (LN) also exhibited an efficiently elongated cell morphology observed by fluorescent microscope and metallographic microscope. Furthermore, PEDOT-HA/PLLA films were subjected to different current intensity to elucidate the effect of electrical stimulation (ES) on neurite outgrowth of PC12 cells. ES (0.5 mA, 2 h) significantly promoted neurite outgrowth with an average value length of 122 +/- 5 MUm and enhanced the mRNA expression of growth-associated protein (GAP43) and synaptophysin (SYP) in PC12 cells when compared with other ES groups. These results suggest that PEDOT HA/PLLA film combined with ES are conducive to cell growth and neurite outgrowth, indicating the conductive PEDOT-HA/PLLA film may be an attractive candidate with ES for enhancing nerve regeneration in nerve tissue engineering. PMID- 27498310 TI - Growth in salpingectomy rates in the United States since 2000. PMID- 27498311 TI - Strategies and steps fostering the success of medication management services in community pharmacies. AB - OBJECTIVES: To identify and describe the steps and strategies that community pharmacies with established medication management services have used to integrate medication management services into their practice settings. DESIGN: Qualitative case study with semistructured interviews and focus groups. SETTING: Community pharmacy organizations in Minnesota. PARTICIPANTS: Pharmacists and pharmacy leadership from 4 different pharmacy organizations including independent, chain, and health system pharmacies. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Qualitative case study analysis of community pharmacy management and pharmacists' perceptions of the factors that led to the establishment and sustainability of their medication management programs. RESULTS: Focus groups and interviews were undertaken with 25 pharmacists and pharmacy leaders from 4 distinct community pharmacy organizations from April to June 2015. Five themes emerged, representing specific implementation and continuation stages of medication management services in community practice: Deciding to Act, Setting the Stage, Executing the Service, Sticking to It, and Continuing to Grow. CONCLUSION: This study sheds light on key stages that have commonly occurred across community pharmacies that are delivering medication management services. The results of this work may serve as a road map for other community pharmacies looking to integrate medication management services into their own practice settings. PMID- 27498312 TI - Establishing a clinical pharmacy technician at a United States Army military treatment facility. AB - OBJECTIVES: To describe the creation of a clinical pharmacy technician position within the U.S. Army and to identify the personal skills and characteristics required to meet the demands of this role. SETTING: An outpatient military treatment facility located in Maryland. PRACTICE DESCRIPTION: The clinical pharmacy technician position was designed to support clinical pharmacy services within a patient-centered medical home. PRACTICE INNOVATION: Funding and a position description were established to hire a clinical pharmacy technician. Expected duties included administrative (45%), patient education (30%), and dispensing (25%). Local policy, in accordance with federal law and U.S. Army regulations, was developed to define the expanded technician responsibility to deliver patient medication education. RESULTS: In the initial 3 months, the clinical pharmacy technician spent 24 hours per week on clinical activities, affording an additional 10-15 hours per week for clinical pharmacists to provide patient care. Completed consults increased from 41% to 56%, and patient pharmacist encounters increased from 240 to 290 per month. The technician, acting as a clinical pharmacist extender, also completed an average of 90 patient encounters independently each month. As a result of these improvements, the decision was made to hire a second technician. Currently, the technicians spend 28-40 hours per week on clinical activities, offsetting an average of 26 hours per week for the clinical pharmacists. CONCLUSION: A patient-centered medical home clinical pharmacy technician can reduce the administrative workload for clinical pharmacists, improve their efficiency, and enhance the use of clinical pharmacy services. Several characteristics, particularly medication knowledge, make pharmacy technicians particularly suited for this role. The results from the implementation of a clinical pharmacy technician at this military treatment facility resulted in an Army-wide expansion of the position and suggested applicability in other practice sites, particularly in federal pharmacies. PMID- 27498309 TI - Evaluation of the urinary microbiota of women with uncomplicated stress urinary incontinence. AB - BACKGROUND: Female urinary microbiota are associated with urgency urinary incontinence and response to medication. The urinary microbiota of women with stress urinary incontinence has not been described. OBJECTIVE: We sought to study the cross-sectional relationships between urinary microbiota features and demographic and clinical characteristics of women undergoing stress urinary incontinence surgery. STUDY DESIGN: Preoperative urine specimens were collected from women without urinary tract infection and were available from 197 women (174 voided, 23 catheterized) enrolled in a multicenter prospective randomized trial, the Value of Urodynamic Evaluation study. Demographic and clinical variables were obtained including stress and urgency urinary incontinence symptoms, menopausal status, and hormone use. The bacterial composition of the urine was qualitatively assessed by sequencing the bacterial 16S ribosomal RNA gene. Phylogenetic relatedness and microbial alpha diversity were compared to demographics and symptoms using generalized estimating equation models. RESULTS: The majority of 197 urine samples (86%) had detectable bacterial DNA. Bacterial diversity was significantly associated with higher body mass index (P = .02); increased Medical, Epidemiologic, and Social Aspects of Aging urge index score (P = .04); and hormonal status (P < .001). No associations were detected with stress urinary incontinence symptoms. Increased diversity was also associated with a concomitant lower frequency of Lactobacillus in hormone-negative women. CONCLUSION: Women undergoing stress urinary incontinence surgery have detectable urinary microbiota. This cross-sectional analysis revealed that increased diversity of the microbiota was associated with urgency urinary incontinence symptoms, hormonal status, and body mass index. In contrast, the female urinary microbiota were not associated with stress urinary incontinence symptoms. PMID- 27498313 TI - High lipid accumulation in Yarrowia lipolytica cultivated under double limitation of nitrogen and magnesium. AB - Yarrowia lipolytica cultivated under double nitrogen and magnesium limitation, but not under single nitrogen or single magnesium limitation, produced 12.2g/l biomass containing 47.5% lipids, which corresponds to a lipid production 5.8g/l. These yields are the higher described in the literature for wild strains of Y. lipolytica. Transcription of ACL1 and ACL2, encoding for ATP-citrate lyase (ATP:CL) was observed even under non-oleaginous conditions but high activity of ATP:CL was only detected under oleaginous conditions induced by low or zero activity of NAD(+) dependent isocitrate dehydrogenase. The low activity of malic enzyme (ME), a NADPH donor in typical oleaginous microorganisms, indicated that ME may not be implicated in lipid biosynthesis in this yeast, and NADPH may be provided by the pentose phosphate pathway (PPP). These findings underline the essential role of magnesium in lipogenesis, which is currently quite unexplored. The presence of organic nitrogen in low concentrations during lipogenesis was also required, and this peculiarity was probably related with the PPP functioning, being the NADPH donor of lipogenic machinery in Y. lipolytica. PMID- 27498314 TI - In vitro models of medulloblastoma: Choosing the right tool for the job. AB - The recently-defined four molecular subgroups of medulloblastoma have required updating of our understanding of in vitro models to include molecular classification and risk stratification features from clinical practice. This review seeks to build a more comprehensive picture of the in vitro systems available for modelling medulloblastoma. The subtype classification and molecular characterisation for over 40 medulloblastoma cell-lines has been compiled, making it possible to identify the strengths and weaknesses in current model systems. Less than half (18/44) of established medulloblastoma cell-lines have been subgrouped. The majority of the subgrouped cell-lines (11/18) are Group 3 with MYC-amplification. SHH cell-lines are the next most common (4/18), half of which exhibit TP53 mutation. WNT and Group 4 subgroups, accounting for 50% of patients, remain underrepresented with 1 and 2 cell-lines respectively. In vitro modelling relies not only on incorporating appropriate tumour cells, but also on using systems with the relevant tissue architecture and phenotype as well as normal tissues. Novel ways of improving the clinical relevance of in vitro models are reviewed, focusing on 3D cell culture, extracellular matrix, co-cultures with normal cells and organotypic slices. This paper champions the establishment of a collaborative online-database and linked cell-bank to catalyse preclinical medulloblastoma research. PMID- 27498315 TI - Modulation of heterologous expression from PBAD promoter in Escherichia coli production strains. AB - Promoter PBAD is frequently used for heterologous gene expression due to several advantages, such as moderately high expression levels, induction by an inexpensive and non-toxic monosaccharide L-arabinose and tight regulation of transcription, which is particularly important for expression of toxic proteins. A drawback of this promoter is all-or-none induction that occurs at subsaturating inducer concentrations. Although the overall expression level of the cell culture seems to correlate with increasing arabinose concentrations, the population is a mixture of induced and uninduced cells and with increasing arabinose concentrations, only the fraction of induced cells increases. This phenomenon is caused by autocatalytic gene expression - the expression of the arabinose transporter AraE is induced by the transported molecule. In this work the promoter PE, controlling the expression of araE, was exchanged for the stronger PBAD promoter in two Escherichia coli strains commonly used for heterologous protein production. This modification should increase a basal number of arabinose transporters in the cell wall and reduce the threshold concentration required for induction and thus reduce heterogeneity of cell population. Heterogeneity and level of expression in individual cells were analysed by flow cytometry using gfp as a reporter gene. In the strain BL21ai, the promoter exchange increased the number of induced cells at subsaturating arabinose concentrations as well as a yield of protein at saturating inducer concentration. In contrast, the modification did not improve these characteristics in RV308ai. In both strains it was possible to modulate the expression level in induced cells 3-6-fold even at subsaturating arabinose concentrations. PMID- 27498316 TI - A superstructure-based electrochemical assay for signal-amplified detection of DNA methyltransferase activity. AB - DNA methyltransferase (MTase) activity is highly correlated with the occurrence and development of cancer. This work reports a superstructure-based electrochemical assay for signal-amplified detection of DNA MTase activity using M.SssI as an example. First, low-density coverage of DNA duplexes on the surface of the gold electrode was achieved by immobilized mercaptohexanol, followed by immobilization of DNA duplexes. The duplex can be cleaved by BstUI endonuclease in the absence of DNA superstructures. However, the cleavage is blocked after the DNA is methylated by M.SssI. The DNA superstructures are formed with the addition of helper DNA. By using an electroactive complex, RuHex, which can bind to DNA double strands, the activity of M.SssI can be quantitatively detected by differential pulse voltammetry. Due to the high site-specific cleavage by BstUI and signal amplification by the DNA superstructure, the biosensor can achieve ultrasensitive detection of DNA MTase activity down to 0.025U/mL. The method can be used for evaluation and screening of the inhibitors of MTase, and thus has potential in the discovery of methylation-related anticancer drugs. PMID- 27498317 TI - Electrochemical detection of Nanog in cell extracts via target-induced resolution of an electrode-bound DNA pseudoknot. AB - Nanog is among the most important indicators of cell pluripotency and self-renew, so detection of Nanog is critical for tumor assessment and monitoring of clinical prognosis. In this work, a novel method for Nanog detection is proposed by using electrochemical technique based on target-induced conformational change of an electrode-bound DNA pseudoknot. In the absence of Nanog, the rigid structure of the pseudoknot will minimize the connection between the redox tag and the electrode, thus reducing the obtained faradaic current. Nevertheless, the Nanog binding may liberate the flexible single-stranded element that transforms the DNA pesudokont into DNA hairpin structure due to steric hindrance effect, thus making the electrochemical tag close to the electrode surface. Consequently, electron transfer can be enhanced and very well electrochemical response can be observed. By using the proposed method, Nanog can be determined in a linear range from 2nM to 25nM with a detection limit of 163 pM. Furthermore, the proposed method can be directly used to assay Nanog not only in purified samples but also in complex media (cell extracts), which shows potential applications in Nanog functional studies as well as clinical diagnosis in the future. PMID- 27498318 TI - Fluorescent imaging of Au(3+) in living cells with two new high selective Au(3+) probes. AB - Two new acetylenic compounds were designed and synthesized as the probes to realize the detection and recognition of Au(3+). The latent fluorophores was rearranged into the fluorescent coumarin derivatives with strong fluorescence by a gold ion-mediated hydroarylation reaction. In the meanwhile, the generated fluorescent substances were also isolated and characterized. The probes identified Au(3+) ions highly selectively over other biologically relevant metal ions, and detection concentration of Au(3+) was as low as 0.1uM or less. Fluorescent imaging of Au(3+) in living cells was also successfully demonstrated. PMID- 27498319 TI - Hotspots engineering by grafting Au@Ag core-shell nanoparticles on the Au film over slightly etched nanoparticles substrate for on-site paraquat sensing. AB - Paraquat (PQ) pollutions are ultra-toxic to human beings and hard to be decomposed in the environment, thus requiring an on-site detection strategy. Herein, we developed a robust and rapid PQ sensing strategy based on the surface enhanced Raman scattering (SERS) technique. A hybrid SERS substrate was prepared by grafting the Au@Ag core-shell nanoparticles (NPs) on the Au film over slightly etched nanoparticles (Au FOSEN). Hotspots were engineered at the junctions as indicated by the finite difference time domain calculation. SERS performance of the hybrid substrate was explored using p-ATP as the Raman probe. The hybrid substrate gives higher enhancement factor comparing to either the Au FOSEN substrate or the Au@Ag core-shell NPs, and exhibits excellent reproducibility, homogeneity and stability. The proposed SERS substrates were prepared in batches for the practical PQ sensing. The total analysis time for a single sample, including the pre-treatment and measurement, was less than 5min with a PQ detection limit of 10nM. Peak intensities of the SERS signal were plotted as a function of the PQ concentrations to calibrate the sensitivity by fitting the Hill's equation. The plotted calibration curve showed a good log-log linearity with the coefficient of determination of 0.98. The selectivity of the sensing proposal was based on the "finger print" Raman spectra of the analyte. The proposed substrate exhibited good recovery when it applied to real water samples, including lab tap water, bottled water, and commercially obtained apple juice and grape juice. This SERS-based PQ detection method is simple, rapid, sensitive and selective, which shows great potential in pesticide residue and additives abuse monitoring. PMID- 27498320 TI - Superhydrophilic cotton thread with temperature-dependent pattern for sensitive nucleic acid detection. AB - Cotton thread is promising in fabricating biosensors for diagnostic application due to its excellent characteristics. However, the enrichment of the capture molecules on a narrow zone of the cotton thread based biosensor is a big challenge because of its superhydrophilicity. Here, we report a simple, low-cost and accurate cotton thread based nucleic acid biosensor with temperature dependent pattern. Liquid wax is used to fabricate temperature-dependent pattern to restrict the test zone in a narrow area. This biosensor enables visual and quantitative detection of target DNA by accumulation of gold nanoparticles (GNPs) on the test zone with a detection limits of 0.75nM. In addition, the cotton thread based biosensor needs less sample than previous reported lateral flow strip and the sample solution wicks faster at the cotton thread which can lead to a shorter detection time. This simple, low-cost and fast detection method holds great potential to improve healthcare services in the developing regions. PMID- 27498322 TI - Binding induced colocalization activated hybridization chain reaction on the surface of magnetic nanobead for sensitive detection of adenosine. AB - Herein, a sensitive and enzyme-free assay for adenosine detection has been developed on the basis of binding induced colocalization activated hybridization chain reaction (HCR) strategy on the surface of magnetic nanobead. First, the recognition probe was fabricated and divided into two parts: the Apt-1 that composed a part of adenosine aptamer and toehold domain, and the Apt-2 that consisted of another part of adenosine aptamer and branch migration domain. The Apt-1 was immobilized on a streptavidin-magnetic nanobead (streptavidin-MNBs) that played the roles of enrichment and separation. Then the recognition event of adenosine could bring the two parts of aptamer together and induce the colocalization of toehold domain and branch migration domain, which could serve as an integrated initiator to trigger the HCR, producing a long nicked double stranded polymer. Finally, the intercalating dye SYBR Green I was inserted into the polymer, generating an enhanced fluorescence signal. In this strategy, the initiator was divided into two parts and could be suppressed effectively in the absence of adenosine. Utilizing the separated function, the spontaneous hybridization of H1 and H2 could be avoided, and a low background could be acquired. Moreover, through the double amplification of HCR and multimolecules binding of SYBR Green I, highly sensitive and enzyme-free detection were achieved. The detection limit for adenosine detection was 2.0*10(-7)mol/L, which was comparable or superior to the previous aptasensors. Importantly, adenosine analysis in human urines has been performed, and this strategy could significantly distinguish the adenosine content in normal human urines and cancer patient urines, suggesting that this proposed assay will become a reliable and sensitive adenosine detection method in early clinical diagnosis and medical research. PMID- 27498321 TI - Hemin on graphene nanosheets functionalized with flower-like MnO2 and hollow AuPd for the electrochemical sensing lead ion based on the specific DNAzyme. AB - Herein, integrated with DNAzyme highly specific to metal ions, hemin@reduced graphene oxide (hemin@rGO) functionalized with flower-like MnO2 and hollow AuPd (hAuPd-fMnO2-hemin@rGO) was used as electroactive probe and electrocatalyst to construct a universal platform for metal ion detection (lead ion Pb(2+) as the model). The proposed strategy with generality was mainly based on two aspects. Firstly, the designed probe not only showed high stability and excellent peroxidase-like activity originating from hemin, fMnO2 and hAuPd, but also possessed intrinsic redox performance from hemin, which resulted in the promotion of electron transfer and the enhancement of the response signal readout. Secondly, due to the introduction of Pb(2+), Pb(2+)-dependent DNAzyme bound in the electrode surface could be specifically identified and cleaved by Pb(2+), and the remained fragment (its supplementary sequence is a single-strand DNA S3) captured the nanocomposites S3-hAuPd-fMnO2-hemin@rGO by the hybridization reaction. Therefore, combined the cooperative catalysis of fMnO2, hAuPd and hemin to H2O2 reduction with highly specific interaction of Pb(2+)-dependent DNAzyme, the proposed Pb(2+) biosensor showed significant improvement of electrochemical analytical performance, which was involved in wide dynamic response in the range of 0.1pM-200nM, low detection limit of 0.034pM, high sensitivity and high specificity. This could facilitate the universal strategy to be a promising method for detection of other metal ions, only changing the corresponding DNAzyme specific to them. PMID- 27498323 TI - Paper-based fluorescent sensor for rapid naked-eye detection of acetylcholinesterase activity and organophosphorus pesticides with high sensitivity and selectivity. AB - Various strategies have been proposed for the sensing of acetylcholinesterase (AChE) activity and organophosphorus pesticides (OPs). However, the practical application of most methods is restricted by their intrinsic drawbacks such as complexity, long analysis time, and high cost. Thus, it is highly desirable to develop simple, fast and sensitive approaches for AChE activity and OPs detection. Herein, we reported a simple paper-based fluorescent sensor (PFS) based on the aggregation induced emission (AIE) effect of tetraphenylethylene (TPE) and the addition reaction capability of maleimide, which has been used as a powerful tool for rapid naked-eye detection of AChE activity and OPs. The introduction of TPE provides the probe with unique fluorescence property in solid state and is of great importance for improving the sensitivity of PFS. The hydrolysis product of acetylthiocholine catalyzed by AChE induced the maleimide ring destruction and activated the fluorescence performance of TPE. Given that AChE activity can be specifically inhibited by OPs, the as-proposed PFS can also be utilized for sensitive detection of OPs. Meanwhile, the variation of fluorescence signal can be readily detected by naked eyes, and low detection limits of 2.5mUmL(-1) and 0.5ngmL(-1) for AChE activity and OPs are obtained, respectively. Moreover, it has been successfully applied for AChE activity and OPs detection in diluted human serum samples, showing its great potential to be applied in real samples. Thus, this strategy possesses considerable advantages of simplicity, rapid detection, portability, cost efficiency and visualization. PMID- 27498324 TI - Terbium ion-coordinated carbon dots for fluorescent aptasensing of adenosine 5' triphosphate with unmodified gold nanoparticles. AB - This work reports on a novel time-resolved fluorescent aptasensing platform for the quantitative monitoring of adenosine 5'-triphosphate (ATP) by interaction of dispersive/agglomerate gold nanoparticles (AuNPs) with terbium ion-coordinated carbon dots (Tb-CDs). To construct such a fluorescent nanoprobe, Tb-CDs with high efficient fluorescent intensity are first synthesized by the microwave method with terbium ions (Tb(3+)). The aptasensing system consists of ATP aptamer, AuNP and Tb-CD. The dispersive/agglomerate gold nanoparticles are acquired through the reaction of the aptamer with target ATP. Upon target ATP introduction, the aptamers bind with the analytes to form new aptamer-ATP complexes and coat on the surface of AuNPs to inhibit their aggregation in the high salt solution. In this case, the fluorescent signal of Tb-CDs is quenched by the dispersive AuNPs on the basis of the fluorescence resonance energy transfer (FRET). At the absence of target analyte, gold nanoparticles tend to aggregate in the high salt state even if the aptamers are present. Thus, the added Tb-CDs maintain their intrinsic fluorescent intensity. Experimental results indicated that the aptasensing system exhibited good fluorescent responses toward ATP in the dynamic range from 40nM to 4.0MUM with a detection limit of 8.5nM at 3sblank criterion. The repeatability and intermediate precision is less than 9.5% at three concentrations including 0.04, 0.4 and 2.0MUM ATP. The selectivity was acceptable toward guanosine 5' triphosphate, uridine 5'-triphosphate and cytidine 5'-triphosphate. The methodology was applied to evaluate the blank human serum spiked with target ATP, and the recoveries (at 3 concentration levels) ranged between 97.0% and 103.7%. Importantly, this detection scheme is rapid, simple, cost-effective, and does not require extensive sample preparation or separation. PMID- 27498325 TI - Target-catalyzed autonomous assembly of dendrimer-like DNA nanostructures for enzyme-free and signal amplified colorimetric nucleic acids detection. AB - Self-assembly of DNA nanostructures is of great importance in nanomedicine, nanotechnology and biosensing. Herein, a novel target-catalyzed autonomous assembly pathway for the formation of dendrimer-like DNA nanostructures that only employing target DNA and three hairpin DNA probes was proposed. We use the sticky ended Y shape DNA (Y-DNA) as the assembly monomer and it was synthesized by the catalyzed hairpin assembly (CHA) instead of the DNA strand annealing method. The formed Y-DNA was equipped with three ssDNA sticky ends and two of them were predesigned to be complementary to the third one, then the dendrimer-like DNA nanostructures can be obtained via an autonomous assembly among these sticky ended Y-DNAs. The resulting nanostructure has been successfully applied to develop an enzyme-free and signal amplified gold nanoparticle (AuNP)-based colorimetric nucleic acids assay. PMID- 27498326 TI - DNA-based hybridization chain reaction and biotin-streptavidin signal amplification for sensitive detection of Escherichia coli O157:H7 through ELISA. AB - This study reported on a novel sandwich enzyme linked immunosorbent assay (ELISA) for the sensitive determination of Escherichia coli O157:H7 (E. coli O157:H7) by using DNA-based hybridization chain reaction (HCR) and biotin-streptavidin signal amplification. The anti-E. coli O157:H7 polyclonal antibody (pAb) was immobilized in the ELISA wells. The anti-E. coli O157:H7 monoclonal antibody (mAb) and initiator strand (DNA1) were labeled on gold nanoparticle (AuNP) to form a mAb AuNP-DNA1 complex. In the presence of the target E. coli O157:H7, the sandwiched immunocomplex, which is pAb-E. coli O157:H7-mAb-AuNP-DNA1, could be formed. Two types of biotinylated hairpin were subsequently added in the ELISA well. A nicked double-stranded DNA (dsDNA) that contained abundant biotins was formed after HCR. Detection was performed after adding horseradish peroxidase-streptavidin and substrate/chromogen solution. Under optimal conditions, E. coli O157:H7 could be detected in the range of 5*10(2) CFU/mL to 1*10(7) CFU/mL; the limit of detection was 1.08*10(2) CFU/mL in pure culture. The LOD of the novel ELISA was 185 times lower than that of traditional ELISA. The proposed method is considerably specific and can be applied in the detection of whole milk samples inoculated with E. coli O157:H7. The coefficient of variation of in pure culture and in whole milk was 0.99-5.88% and 0.76-5.38%, respectively. This method offers a promising application in the detection of low concentrations of food-borne pathogens. PMID- 27498327 TI - One-step multiplexed detection of foodborne pathogens: Combining a quantum dot mediated reverse assaying strategy and magnetic separation. AB - A rapid and multiplexed immunosensor was developed based on a quantum dot (QD) reverse assaying strategy (RAS) and immuno-magnetic beads (IMBs) for one-step and simultaneous detection of Escherichia coli O157: H7 and Salmonella. In a conventional QD-based immunosensor, the fluorescence signal of the "IMBs-target QD" immunoconjugate is directly used as the assaying readout. However, the fluorescence signal is affected by IMBs due to light scattering and the "IMBs target-QD" immunoconjugate needs multiple washing and re-suspension steps. To address these problems, we use the surplus QD-antibody conjugate as signal readout in the RAS, which prevents interference from the IMBs, increases the fluorescence signal, and avoids complex operations. Compared with conventional QD based immunosensor, the sensitivity of QD-RSA immunosensor for detection of Escherichia coli O157: H7 has been improved fifty-fold, and whole analysis procedure can be finished within 1h. Therefore, this RSA strategy is promising for improving the performance of QD-based immunosensors and could greatly broaden their applications. PMID- 27498328 TI - Easy and rapid multi-pass detection of antigen and antibody with micro-lens sensors. AB - We introduce a micro-lens imaging method that can perform easy and rapid multi pass detection of antigen/antibody (Ag/Ab) without the requirement of any labeling, expensive enzymes, pre-immobilization/modification, and post-washing. Our method detects Ag or Ab presenting in solutions in a quantitative or qualitative manner by using micro-lens as the sensor to monitor the refractive index variation of the solutions during the primary stage of Ag-Ab reaction. The detection can be taken rapidly and finished in two minutes, while requires very low sample volume (several micron liters) and its detection limit can be as low as ~pg/mL. The method is also able to provide kinetic and thermodynamic parameters of Ag-Ab reactions. The detections of ten Ag-Ab systems and two kinds of clinical samples demonstrated that our method is of high sensitivity, accuracy, reliability and permitting on-site analysis. PMID- 27498329 TI - Ultrasensitive, colorimetric detection of microRNAs based on isothermal exponential amplification reaction-assisted gold nanoparticle amplification. AB - MicroRNAs (miRNAs) play important roles in a wide range of biological processes, and their aberrant expressions are linked to a large number of human diseases and disorders. In this work, we developed a colorimetric method for rapid, ultrasensitive miRNA detection via isothermal exponential amplification reaction (EXPAR)-assisted gold nanoparticle (AuNP) amplification. The sensing probe designed with a tandem phosphorothioate modification in the backbone of the polyadenines at the 5' terminus was employed to directly assemble onto the surface of AuNP with high adsorption affinity. The recognition domain at the 3' terminus of the sensing probe hybridizes with target miRNAs to trigger EXPAR with exponential signal amplification. With the amplification reaction with the action of DNA polymerase, the sensing probe gradually detaches from the AuNP, resulting in the aggregation of bare AuNPs in the high-salt reaction environment due to lack of DNA protection. The presence of AuNP aggregation is conveniently measured by UV-vis spectroscopy. Our proposed method could provide a linear detection range from 50fM to 10nM with a detection limit of ~46fM within 60min, and also discriminate a single-nucleotide difference between homologous miRNAs. PMID- 27498330 TI - A cascade amplification approach for visualization of telomerase activity in living cells. AB - An intracellular cascade amplification strategy for ultrasensitive "off-on" imaging of telomerase activity in living cells was designed. The method was based on fabrication of a dual function module-encapsulated liposome nanoprobe, which consisted of a telomerase-targeting responder-transmitter DNA complex (HPT) module and a catalyzed hairpin assembly (CHA) signal amplification module. Upon transfected into living cells, the released HPT could be specifically recognized and extended by telomerase, leading to the release of the transmitter DNA. The transmitter could act as the initiator and catalyzer of CHA amplification, resulting in the lightening up of the reporter complex. The telomerase activity could be monitored in situ by the fluorescence signal without the need for obtaining cell extracts. Because of the recycling use of the transmitter, multiplied enhancement of signal outputs from one extension event was achieved. The proposed strategy could be employed for in situ monitoring of the change of intracellular telomerase activity in response to drugs to detect drug efficacy. Thus the method has great potential in the study of the molecular mechanisms of telomerase-related life processes. PMID- 27498331 TI - Dual-cyclical nucleic acid strand-displacement polymerization based signal amplification system for highly sensitive determination of p53 gene. AB - In the present study, we proposed a novel dual-cyclical nucleic acid strand displacement polymerization (dual-CNDP) based signal amplification system for highly sensitive determination of tumor suppressor genes. The system primarily consisted of a signaling hairpin probe (SHP), a label-free hairpin probe (LHP) and an initiating primer (IP). The presence of target DNA was able to induce one CNDP through continuous process of ligation, polymerization and nicking, leading to extensively accumulation of two nicked triggers (NT1 and NT2). Intriguingly, the NT1 could directly hybridize SHP, while the NT2 could act as the target analog to induce another CNDP. The resulting dual-CNDP contributed the striking signal amplification, and only a very weak blank noise existed since the ligation template of target was not involved. In this case, the target could be detected in a wide linear range (5 orders of magnitude), and a low detection limit (78 fM) was obtained, which is superior to most of the existing fluorescent methods. Moreover, the dual-CNDP sensing system provided a high selectivity towards target DNA against mismatched target and was successfully applied to analysis of target gene extracted from cancer cells or in human serum-contained samples, indicating its great potential for practical applications. PMID- 27498332 TI - Dual-component gene detection for H7N9 virus - The combination of optical trapping and bead-based fluorescence assay. AB - We present a strategy of dual-component gene detection for avian influenza A virus H7N9 by combining optical trapping and bead-based fluorescence bioassays. A low-cost 473nm continuous DPSS laser, polystyrene (PS) beads with two different sizes (3um and 5um in diameter) and streptavidin-modified 605nm quantum dots (SA QDs) were exploited in this platform. The beads were employed to enrich the targets using the classic sandwich mode and tagged with the SA-QDs, then the QDs tagged beads floating in the suspension were directly trapped and excited by the optical tweezers to give strong and stable fluorescence signal, which was applied to quantify the targets. The distinctive size information from the image of the trapped beads enabled the sorting of the different targets. The results show that tiny laser power 40MUW is applicable for both trapping and fluorescence excitation of the beads. Moreover, the limits of detection for hemagglutinin7 (H7) gene and neuraminidase 9 (N9) gene are 1.0-2.0pM with good selectivity for the complex sample, which is two orders of magnitude lower than that of the conventional method. More importantly, this strategy was successfully used to identify the subtype of the avian influenza A virus by simultaneous detection of H7 and N9 gene sequences. The high sensitivity, good selectivity, typing ability and the low cost of the laser make this strategy a promising method for life sciences and clinical applications. PMID- 27498333 TI - Anterior decompression with fusion versus posterior decompression with fusion for massive cervical ossification of the posterior longitudinal ligament with a >=50% canal occupying ratio: a multicenter retrospective study. AB - BACKGROUND CONTEXT: Previous studies have shown that compared with laminoplasty, anterior decompression with fusion (ADF) is superior for postoperative neurologic improvement in patients with massive cervical ossification of the posterior longitudinal ligament (OPLL) with a >=50% canal occupying ratio. However, it is unknown which method, ADF or posterior decompression with fusion (PDF), is more effective for the treatment of massive OPLL. PURPOSE: This study aimed to investigate the surgical outcomes of ADF and PDF for the treatment of massive OPLL. STUDY DESIGN: A multicenter retrospective case-control study was carried out. PATIENT SAMPLE: A total of 61 OPLL patients with a >=50% canal occupying ratio were included in this study. The mean age of the patients was 60.9 years (49 males and 12 females); 39 patients (31 males and 8 females, average age 61.1 years) underwent ADF, and 22 patients underwent PDF (18 males and 4 females, average age 60.6 years). OUTCOME MEASURES: The data collected from both groups included age, gender, neurologic symptoms evaluated based on the Japanese Orthopedic Association score, neck pain assessed using the visual analogue scale, and radiographic parameters, including cervical lordosis and the OPLL canal occupying ratio. METHODS: Clinical and radiological outcomes were compared between the ADF and PDF groups with a minimum of 2 years follow-up. RESULTS: There were no significant differences in the postoperative neurologic recovery rate between the two groups. However, in patients with kyphotic alignment (C2-C7 angle <0 degrees), the recovery rate was higher in the ADF group. Postoperative cervical pain was greater in the PDF group. The improvement in cervical alignment at C2-C7 was greater in the ADF group. The operating time was longer in the ADF group, whereas the intraoperative blood loss was greater in the PDF group. Approach-related complications were more frequently observed in the ADF group than in the PDF group. CONCLUSIONS: The present study demonstrated that the postoperative recovery rate was similar in the ADF and PDF group. In patients with massive OPLL with kyphotic alignment, neurologic recovery rate in the ADF was superior to that in the PDF (in situ fusion). Additionally, postoperative neck pain was less severe in the ADF group. However, the occurrence of perioperative complications was more common in the ADF group. PMID- 27498334 TI - Comparison of fusion rate and clinical results between CaO-SiO2-P2O5-B2O3 bioactive glass ceramics spacer with titanium cages in posterior lumbar interbody fusion. AB - BACKGROUND CONTEXT: The CaO-SiO2-P2O5-B2O3 glass ceramics spacer generates chemical bonding to adjacent bones with high mechanical stability to produce a union with the end plate, and ultimately stability. PURPOSE: The authors aimed to compare the clinical efficacy and safety of CaO-SiO2-P2O5-B2O3 glass ceramics with a titanium cage that is widely used for posterior lumbar interbody fusion (PLIF) surgery in the clinical field. STUDY DESIGN/SETTING: This is a prospective, stratified randomized, multicenter, single-blinded, comparator controlled non-inferiority trial. PATIENT SAMPLE: The present study was conducted in four hospitals and enrolled a total of 86 patients between 30 and 80 years of age who required one-level PLIF due to severe spinal stenosis, spondylolisthesis, or huge disc herniation. OUTCOME MEASURES: The Oswestry Disability Index (ODI), Short Form-36 Health Survey (SF-36), and pain visual analog scale (VAS) were assessed before surgery and at 3, 6, and 12 months after surgery. The spinal fusion rate was assessed at 6 and 12 months after surgery. METHODS: The spinal fusion rate and the area of fusion, subsidence of each CaO-SiO2-P2O5-B2O3 glass ceramics and titanium cage, and the extent of osteolysis were evaluated using a dynamic plain radiography and a three-dimensional computed tomography at 12 months after surgery. The present study was supported by BioAlpha, and some authors (JHL, C-KL, and B-SC) have stock ownership (<10,000 US dollars). RESULTS: From the plain radiography results, the 6-month fusion rates for the bioactive glass ceramics group and the titanium group were 89.7% and 91.4%, respectively. In addition, the 12-month fusion rates based on CT scan were 89.7% and 91.2%, respectively, showing no significant difference. However, the bone fusion area directly attached to the end plate of either bioactive glass ceramics or the titanium cage was significantly higher in the bioactive glass ceramics group than in the titanium group. The ODI, SF-36, back pain, and lower limb pain in both groups significantly improved after surgery, with no significant differences between the groups. No significant differences between the two groups were observed in the extent of subsidence and osteolysis. CONCLUSIONS: In lumbar posterior interbody fusion surgery, CaO-SiO2-P2O5-B2O3 glass ceramics spacer showed a similar fusion rates and clinical outcomes compared with titanium cage. PMID- 27498335 TI - Increased sensitivity in the interaction of the dopaminergic/adenosinergic system at the level of the adenylate cyclase activity in the striatum of the "weaver" mouse. AB - The specific antagonistic interaction between dopamine D1 and adenosine A1 receptors (D1/A1), as well as between dopamine D2 and adenosine A2a receptors (D2/A2a) exist not only at the receptor/receptor level, but also at the level of the secondary messengers. In this study, we examined the possible changes in these interactions at the level of cAMP formation in membrane preparation from "weaver" mouse striatum (a genetic model of Parkinson disease), by using specific agonists of these receptors. We also examined in the striatum of the "weaver" mouse the interaction between D1 and D2 dopamine receptors. Our results showed that in the striatum of "weaver" mice: a) the cAMP synthesis induced by D1 receptor activation (SKF 38393), was significantly reduced compared to control mice, while A1 receptor activation (L-PIA) leaded to a more intense inhibition of the D1-induced cAMP-formation compared to the controls, b) the cAMP synthesis which was induced by A2a receptor activation (CGS 21680), was significantly increased compared to the control mice. The specific D2 receptor agonist Quinpirole, added in low concentrations, caused a significant reduction of the A2a-induced cAMP formation, which was not observed in the control mouse. Furthermore, the D1 receptor induced cAMP synthesis was significantly higher in control compared to "weaver" striatum, which was more efficiently downregulated by D2 receptor agonist Quinpirole. These results suggest that the sensitivity to D1 and A2a receptor agonists is altered and that the interaction between D1/A1 and D2/A2a receptors is enhanced in the striatum of the "weaver" mutation, while an uncoupling between D1 and D2 receptors was observed. Since the adenylate cyclase basal activity did not differ between "weaver" and control striatum, the above-mentioned changes seem to be due to alterations in the function of the adenosine/dopamine receptors and their coupling to the G-proteins. PMID- 27498336 TI - Activation of CRHR1 receptors regulates social and depressive-like behaviors and expression of BDNF and TrkB in mesocorticolimbic regions following global cerebral ischemia. AB - Increased HPA axis activation and CRH release characterize the brain's response to global cerebral ischemia. Recently, CRH via activation of CRH type 1 receptors (CRHR1) has been shown to regulate Brain Derived Neurotrophic Factor (BDNF) secretion and emotional behavior. The current study investigates the impact of CRHR1 blockade on BDNF/TrkB signaling expression in the mesolimbic circuitry, and social and depressive-like behavior following global ischemia. Adult male Wistar rats were injected with Antalarmin (2MUg/MUl) or a vehicle 30min prior to 10min global cerebral ischemia (4VO model) or sham occlusion. The Three Chamber Social Approach Test (SIT) assessed sociability and preference for social novelty, and the novelty suppressed feeding test (NSFT), forced swim test (FST), and sucrose preference test characterized anxiety and depression. Corticosterone levels and organ (thymus, seminal and adrenal glands) weights were determined as additional physiological indices of stress. Immunohistochemistry, Western blot and Rt-PCR were used to assess BDNF and TrkB receptor levels in subregions of the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and ventral tegmental area (VTA) 30days post-ischemia. Our findings indicate reduced BDNF and TrkB protein and mRNA expression in the mPFC post-ischemia, while heightened levels were found in the NAc. Ischemia increased immobility in the FST and reduced sucrose preference and led to reduced latency to feed in the NSFT and heightened sociability and social novelty preference in the SIT. Antalarmin treatment normalized post-ischemic biochemical/behavioral changes. Our findings support lasting effects of CRHR1 activation on brain plasticity markers, likely playing a role in emotional impairments following cardio- or cerebro-vascular accidents. PMID- 27498337 TI - Fast dynamic electron paramagnetic resonance (EPR) oxygen imaging using low-rank tensors. AB - Hypoxic tumors are resistant to radiotherapy, motivating the development of tools to image local oxygen concentrations. It is generally believed that stable or chronic hypoxia is the source of resistance, but more recent work suggests a role for transient hypoxia. Conventional EPR imaging (EPRI) is capable of imaging tissue pO2in vivo, with high pO2 resolution and 1mm spatial resolution but low imaging speed (10min temporal resolution for T1-based pO2 mapping), which makes it difficult to investigate the oxygen changes, e.g., transient hypoxia. Here we describe a new imaging method which accelerates dynamic EPR oxygen imaging, allowing 3D imaging at 2 frames per minute, fast enough to image transient hypoxia at the "speed limit" of observed pO2 change. The method centers on a low rank tensor model that decouples the tradeoff between imaging speed, spatial coverage/resolution, and number of inversion times (pO2 accuracy). We present a specialized sparse sampling strategy and image reconstruction algorithm for use with this model. The quality and utility of the method is demonstrated in simulations and in vivo experiments in tumor bearing mice. PMID- 27498338 TI - Cantilever detected ferromagnetic resonance in thin Fe50Ni50, Co2FeAl0.5Si0.5 and Sr2FeMoO6 films using a double modulation technique. AB - In this work we introduce a new method, which employs commercial piezo cantilevers, for a ferromagnetic resonance (FMR) detection from thin, nm-size, films. Our setup has an option to rotate the sample in the magnetic field and it operates up to the high microwave frequencies of 160GHz. Using our cantilever based FMR spectrometer we have investigated a set of samples, namely quasi-bulk and 84nm film Co2FeAl0.5Si0.5 samples, 16nm Fe50Ni50 film and 150nm Sr2FeMoO6 film. Low frequency and room temperature test of our setup using 84nm Co2FeAl0.5Si0.5 film yielded a result identical to a standard X-Band spectrometer, namely a single line with quite small linewidth. Our measurements at low temperatures and high frequencies revealed a quite strong FMR response detected in all samples. The FMR spectra share common features, such as the emergence of the second line with an opposite angular dependence, and a drastic increase of the linewidths with increasing microwave frequency. We believe that these findings are results of the complicated dynamics of the magnetization at low temperatures and high frequencies, which we were able to probe using our cantilever based FMR setup. PMID- 27498339 TI - Toxicological properties of fenugreek (Trigonella foenum graecum). AB - Fenugreek (Trigonella foenum graecum), used as traditional medicine and natural additive food, has been shown to exert significant antiatherogenic, antidiabetic, antianorexic, antioxidant, anticarcinogenic, antihyperlipidemic, galactogogue and anti-inflammatory effects in several human and animal models. Besides, several medicinal pharmaceutical and nutraceutical properties, fenugreek have toxic effects as well. The aim of this review is discuss the cumulative evidence, which suggests that consumption of fenugreek induced some serious toxicological side effects. In this review, many teratogenic effects of fenugreek, from congenital malformations to death, were reported in human, rodent, rabbit, and chick. Moreover, results obtained in rats, mice and rabbits show a testicular toxicity and anti-fertility effects in male associated with oxidative stress and DNA damage, as well as anti-fertility, antiimplantation and abortifacient activity in females related to saponin compound of fenugreek which suggest that fenugreek is not recommended for use during pregnancy. Indeed, the consumption of fenugreek should be avoided for persons having peanut and chickpeas allergy because of possible cross-reactivity as well as chronic asthma. Accumulating evidence suggest also that fenugreek may have neurodevelopmental, neurobehavioral and neuropathological side effects. It is suggested that future studies would be conducted to identify molecular and cellular mechanisms underlying the fenugreek toxicological properties. PMID- 27498340 TI - Human Papillomavirus Awareness in Haiti: Preparing for a National HPV Vaccination Program. AB - STUDY OBJECTIVE: Cervical cancer morbidity and mortality are pressing public health issues that affect women in Haiti. To inform efforts to develop a human papillomavirus (HPV) vaccination program in Haiti, we sought to understand HPV awareness and willingness to get HPV vaccination in Haiti. DESIGN, SETTING, AND PARTICIPANTS: We interviewed a convenience sample of 475 women and men in 2 clinical settings in Port-au-Prince and Leogane, Haiti between April and July 2014. INTERVENTIONS AND MAIN OUTCOME MEASURES: HPV awareness and willingness to get HPV vaccine for daughters. RESULTS: Few participants (27%, 130/475) had heard of HPV. Awareness of HPV was higher among respondents with a previous sexually transmitted infection compared with those without a previous sexually transmitted infection (odds ratio, 2.38; 95% confidence interval, 1.10-5.13). Adults who had heard of genital warts were also more likely to be aware of HPV compared with those who had not (odds ratio, 4.37; 95% confidence interval, 2.59-7.38). Only 10% (24/250) of parents had previously heard of HPV vaccine; however, after researchers explained the purpose of the vaccine, nearly all (96%, 240/250) said they would be willing to get HPV vaccine for their daughters if it were available. CONCLUSION: Despite low awareness of HPV in Haiti, interest in HPV vaccination was nearly universal in our study of health care-seeking adults. This high acceptability suggests that HPV vaccination programs instituted in Haiti would be well received. PMID- 27498341 TI - Over 100-year sedimentary record of polycyclic aromatic hydrocarbons (PAHs) and organochlorine compounds (OCs) in the continental shelf of the East China Sea. AB - Historical records of polycyclic aromatic hydrocarbons (PAHs), organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were analyzed in two dated sediment cores (DH05 and DH11) collected from the continental shelf of the East China Sea (ECS) to investigate the influence of anthropogenic activities on marine sediment over the past century. The concentrations and fluxes of 15 PAHs were in the range of 28.6-96.5 ng g-1 and 7.6-35.2 ng cm-2 yr-1 in DH05 (1920s 2009), 18.8-76.4 ng g-1 and 13.9-30.9 ng cm-2 yr-1 in DH11 (1860s-2009). The sedimentary records of PAHs in the two cores generally reflected the economic development and energy consumption change in China. Identification of sources suggested that PAHs in ECS were predominantly from petrogenic origin and various combustion sources. A change of source from low- and moderate-temperature combustion to high-temperature combustion process was observed. Although a production ban of technical HCH and DDT was imposed in China in 1983, their sedimentary fluxes display increasing trends or strong rebounds from 1980s to 1990s as recorded in the core profiles. High proportions of DDD + DDE and gamma HCH suggested those OCPs mainly derived from early residuals. Temporal trends of PCBs presented relative high levels from 1970s to 1980s and high proportions of PCB congeners with 3-6 chlorines atoms indicated industrial sources. PMID- 27498342 TI - Use of soybean meal and papain to partially replace animal protein for culturing three marine fish species: Fish growth and water quality. AB - The main aim of this study was to investigate the feasibility of using soybean meal added with papain to replace half of the fishmeal used in the moist pellets (49% fishmeal and 45% trash fish) developed by the Hong Kong Agriculture, Fisheries and Conservation Department (AFCD) for culturing marine fish. Gold lined seabream (Rhabdosargus sarba), brown spotted grouper (Epinephelus bleekeri) and pompano (Trachinotus blochii) were farmed at one of the research stations (Kat-O) of AFCD, for a period of 340 days. Results indicated that diets containing papain resulted in better fish growth (reflected by relative weight gain and feed conversion ratio) than diets without papain. In general, wet weight gain of fish depends on the amount of papain added in diet rather than the diet composition. Soybean used in conjunction with papain also contributed to a more effective growth than fish fed with the moist pellets alone. A laboratory experiment (using tanks) was conducted to study the effects of the diets on concentrations of ammonia, nitrite and nitrate in the tank water. Results showed that concentrations of ammonia and nitrate were significantly lower (p < 0.05) when the fish were fed with papain-supplemented (with or without soybean meal) diets. It is envisaged that by using plant protein incorporated with enzymes could promote better growth of marine fish and lower the adverse impact of trash fish and fishmeal on water quality of the mariculture zones. PMID- 27498343 TI - TSLP Down-Regulates S100A7 and beta-Defensin 2 Via the JAK2/STAT3-Dependent Mechanism. AB - Elevated T-helper type 2 cytokines in atopic skin, such as IL-4 and IL-13, were thought to be responsible for an impaired expression of antimicrobial proteins, which may contribute to the increased susceptibility to skin infections in patients with atopic dermatitis. In this study, the relationship between thymic stromal lymphopoietin and antimicrobial proteins and the involved molecular pathway was defined in normal human epidermal keratinocytes and human skin equivalent model. Stimulation of normal human epidermal keratinocytes with thymic stromal lymphopoietin decreased both mRNA and levels of S100A7 and human beta defensin 2 in a dose-dependent manner, and the regulation was JAK2/STAT3 dependent. Thymic stromal lymphopoietin decreased the antimicrobial protein expression, even in the presence of IL-17, which is their strong inducer. STAT3 directly regulated the S100A7 and human beta-defensin 2 promoters in normal human epidermal keratinocytes. Immunohistochemically, lesional atopic skin stained more intensely with phospho-STAT3 compared with healthy control. Our results show that up-regulated thymic stromal lymphopoietin may contribute to the deficiency of antimicrobial proteins in atopic dermatitis, including S100A7 and human beta defensin 2, by a JAK2/STAT3-dependent mechanism and that STAT3/Sin3a might directly control the transcriptional activity of the antimicrobial protein promoters in normal human epidermal keratinocytes. Taken together, a key role of the JAK2/STAT3/Sin3a signaling pathway in thymic stromal lymphopoietin-mediated immune response in normal human epidermal keratinocytes might give us clues to understanding the pathological signal transductions in atopic dermatitis. PMID- 27498344 TI - A Bifunctional Approach of Immunostimulation and uPAR Inhibition Shows Potent Antitumor Activity in Melanoma. AB - Significant advancements of mutation-based targeted therapy and immune checkpoint blockade have been achieved in melanoma. Nevertheless, acquired resistance and nonresponders to therapy require different strategies. An innovative approach is presented here that is based on the combination of innate immune system activation and simultaneous targeting of the oncogene urokinase-type plasminogen activator receptor (uPAR). We generated two triphosphate-conjugated siRNAs targeting uPAR (ppp-uPAR) by in vitro transcription. Specific uPAR knockdown and simultaneous activation of the retinoic acid-inducible gene 1 (RIG-I) was shown in different human melanoma cells, fibroblasts, and melanocytes. The compounds induced massive apoptosis in melanoma cells, whereas fibroblasts and melanocytes were less sensitive. The effects were less pronounced when the IFN receptor was blocked. Treatment with ppp-uPAR led to accumulation of p53 and induction of RIG I-dependent proapoptotic signaling. The apoptotic effects induced by ppp-uPAR were maintained in melanoma cell lines that had acquired double resistance to B RAF and MEK/extracellular signal-regulated kinase inhibition. Systemic intraperitoneal application of ppp-uPAR in nude mice significantly reduced growth of human melanoma xenografts and elicited a systemic innate immune response with increased serum cytokine levels. Our data suggest that ppp-uPAR represents a therapeutically attractive compound that may help overcome the strong therapy resistance of melanoma. PMID- 27498345 TI - Targeted Exon Skipping Restores Type VII Collagen Expression and Anchoring Fibril Formation in an In Vivo RDEB Model. AB - Dystrophic epidermolysis bullosa is a group of orphan genetic skin diseases dominantly or recessively inherited, caused by mutations in COL7A1 encoding type VII collagen, which forms anchoring fibrils. Individuals with recessive dystrophic epidermolysis bullosa develop severe skin and mucosal blistering after mild trauma. The exon skipping strategy consists of modulating splicing of a pre mRNA to induce skipping of a mutated exon. We have targeted COL7A1 exons 73 and 80, which carry recurrent mutations and whose excision preserves the open reading frame. We first showed the dispensability of these exons for type VII collagen function in vivo. We then showed that transfection of primary recessive dystrophic epidermolysis bullosa keratinocytes and fibroblasts carrying null mutations in exon 73 and/or 80, with 2'-O-methyl antisense oligoribonucleotides, led to efficient ex vivo skipping of these exons (50-95%) and resulted in a significant level (up to 36%) of type VII collagen re-expression. Finally, one or two subcutaneous injections of antisense oligoribonucleotides at doses ranging from 400 MUg up to 1 mg restored type VII collagen expression and anchoring fibril formation in vivo in a xenograft model of recessive dystrophic epidermolysis bullosa skin equivalent. This work provides a proof of principle for the treatment of patients with recessive dystrophic epidermolysis bullosa by exon skipping using subcutaneous administration of antisense oligoribonucleotides. PMID- 27498346 TI - Adenosine A2A and A2B Receptors Differentially Modulate Keratinocyte Proliferation: Possible Deregulation in Psoriatic Epidermis. AB - Adenosine is a potent regulator of inflammation and immunity, but the role of adenosine receptors in keratinocytes remains controversial. We determined that in addition to A2B receptors, human epidermal keratinocytes also express A2A receptors, although to a lower extent. Through the use of selective adenosine receptor agonists and antagonists, we showed that physiological concentrations of adenosine activate A2B receptors in normal human keratinocytes, inducing cell cycle arrest through the increase of intracellular calcium but not through cAMP signaling. In contrast, the selective activation of A2A receptors by CGS-21680 induces keratinocyte proliferation via p38-mitogen-activated protein kinase activation. Adenosine and selective A2A and A2B agonists presented anti inflammatory profiles independent of adenosine receptors but mediated by membrane phosphatase activation. Finally, keratinocyte exposure to diverse inflammatory cytokines altered adenosine receptor expression by reducing A2B and increasing A2A, a pattern also observed in psoriatic epidermis. Because increased epidermal turnover and inflammatory response are characteristics of psoriatic disease, further studies are needed to assess the role and consequences of the altered adenosine receptor expression in lesional and nonlesional psoriatic keratinocytes. PMID- 27498347 TI - From mobility to crosstalk. A model of intracellular miRNAs motion may explain the RNAs interaction mechanism on the basis of target subcellular localization. AB - MicroRNAs (miRNAs), 22 nucleotides long molecules with the function to reduce gene expression by inhibiting mRNA translation through partial complementary to one or more messenger RNA (mRNA) molecules. A single miRNA can reduce the expression levels of hundreds of genes and one mRNA can be a target for many miRNAs. Despite the study models used so far, miRNAs and mRNAs cannot be seen as acting in an isolated manner or even "in pairs". They most likely exert their complex actions through numerous overlapping interrelations. One of the models depicting interdependence of intracytoplasmic RNAs is the crosstalk model. It is based on a competition between several target mRNAs which are regulated by the same miRNA. In this paper, we will discuss the mobility mechanism of miRNAs, recently suggested by data from "single particle tracking" experiments. These data suggests that miRNA intracellular mobility may be of "intermittent active transport"(IAT) type. IAT is a mobility model composed by alternation of active transport (AT) and Brownian motion (BM). Based on a mathematical model, we concluded that, AT phase may explain the efficiency in reaching far targets and the BM phase may explain the competition. Furthermore, we suggest that the interaction between miRNAs and their targets depends on the concentration of the molecules, the affinity between the molecules and also on the intracellular localization of the molecules. Hence, the probability that a miRNA interacts with its target depends also on the distance to the target and the macromolecular crowding. Taken together, our data proposes an intracytoplasmic mobility mechanism for miRNA and shows that this model can partially explain the RNA crosstalk. PMID- 27498348 TI - Preparation of a standardised faecal slurry for ex-vivo microbiota studies which reduces inter-individual donor bias. AB - BACKGROUND: In-vitro gut fermentation systems provide suitable models for studying gut microbiota composition and functionality. However, such methods depend on the availability of donors and the assumption of reproducibility between microbial communities before experimental treatments commence. The aim of this study was to develop a frozen standardised inoculum (FSI) which minimizes inter-individual variation and to determine its stability over time using culture dependent and culture-independent techniques. RESULTS: A method for the preparation difference of a FSI is described which involves pooling the faecal samples, centrifugation and pelleting of the cell biomass and finally homogenising the cell pellets with phosphate buffer and glycerol. Using this approach, no significant difference in total anaerobe cell viability was observed between the fresh standardised inoculum (before freezing) and the 12days post freezing FSI. Moreover, Quantitative PCR revealed no significant alterations in the estimated bacterial numbers in the FSI preparations for any of the phyla. MiSeq sequencing revealed minute differences in the relative abundance at phylum, family and genus levels between the FSI preparations. Differences in the microbiota denoted as significant were limited between preparations in the majority of cases to changes in percentage relative abundance of +/-0.5%. The independently prepared FSIs revealed a high degree of reproducibility in terms of microbial composition between the three preparations. CONCLUSIONS: This study provides a method to produce a standardised human faecal inoculum suitable for freezing. Based on culture-dependent and independent analysis, the method ensures a degree of reproducibility between preparations by lessening the effect of inter individual variation among the donors, thereby making the system more suitable for the accurate interpretation of the effects of experimental treatments. PMID- 27498350 TI - Why should rheumatologists care about fibroblasts?: Answering questions about tissue tropism and disease persistence. PMID- 27498349 TI - Bead-beating artefacts in the Bacteroidetes to Firmicutes ratio of the human stool metagenome. AB - We evaluated bead-beating cell-lysis in analysing the human stool metagenome, since this is a key step. We observed that two different bead-beating instruments from the same producer gave a three-fold difference in the Bacteroidetes to Firmicutes ratio. This illustrates that bead-beating can have a major impact on downstream metagenome analyses. PMID- 27498351 TI - Drug-induced hyperuricaemia and gout. AB - Hyperuricaemia is a common clinical condition that can be defined as a serum uric acid level >6.8 mg/dl (404 umol/l). Gout, a recognized complication of hyperuricaemia, is the most common inflammatory arthritis in adults. Drug-induced hyperuricaemia and gout present an emergent and increasingly prevalent problem in clinical practice. Diuretics are one of the most important causes of secondary hyperuricaemia. Drugs raise serum uric acid level by an increase of uric acid reabsorption and/or decrease in uric acid secretion. Several drugs may also increase uric acid production. In this review, drugs leading to hyperuricaemia are summarized with regard to their mechanism of action and clinical significance. Increased awareness of drugs that can induce hyperuricaemia and gout, and monitoring and prevention are key elements for reducing the morbidity related to drug-induced hyperuricaemia and gout. PMID- 27498352 TI - Developing anti-inflammatory therapeutics for patients with osteoarthritis. AB - OA is the most common joint disorder in the world, but there are no approved therapeutics to prevent disease progression. Historically, OA has been considered a wear-and-tear joint disease, and efforts to identify and develop disease modifying therapeutics have predominantly focused on direct inhibition of cartilage degeneration. However, there is now increasing evidence that inflammation is a key mediator of OA joint pathology, and also that the link between obesity and OA is not solely due to excessive load-bearing, suggesting therefore that targeting inflammation in OA could be a rewarding therapeutic strategy. In this review we therefore re-evaluate historical clinical trial data on anti-inflammatory therapeutics in OA patients, highlight some of the more promising emerging therapeutic targets and discuss the implications for future clinical trial design. PMID- 27498353 TI - Chronic hepatitis E in a patient treated with rituximab and mycophenolate mofetil for Sjogren's syndrome. PMID- 27498354 TI - Periostitis in secondary syphilis with prozone phenomenon. PMID- 27498355 TI - Safety and patient response as indicated by biomarker changes to binding immunoglobulin protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis. AB - OBJECTIVES: Binding immunoglobulin protein (BiP) is a human endoplasmic reticulum resident stress protein. In pre-clinical studies it has anti-inflammatory properties due to the induction of regulatory cells. This randomized placebo controlled, dose ascending double blind phase I/IIA trial of BiP in patients with active RA, who had failed accepted therapies, had the primary objective of safety. Potential efficacy was measured by DAS28-ESR and changes in biomarkers. METHODS: Twenty-four patients with active RA who had failed one or more DMARDs were sequentially assigned to three groups each of eight patients randomly allocated to receive placebo (two patients) or BiP (six patients), 1, 5 or 15 mg. Patients received a single i.v. infusion over 1 h and were observed as inpatients overnight. A 12-week follow-up for clinical, rheumatological and laboratory assessments for safety, efficacy (DAS28-ESR) and biomarker analysis was performed. RESULTS: No infusion reactions or serious adverse drug reactions were noted. Adverse events were evenly distributed between placebo and BiP groups with no BiP-related toxicities. Haematological, renal and metabolic parameters showed no drug-related toxicities. Remission was only achieved by patients in the 5 and 15 mg groups, and not patients who received placebo or 1 mg BiP. Good DAS28-ESR responses were achieved in all treatment groups. The BiP responding patients showed significantly lower serum concentrations of CRP, 2 weeks post-infusion compared with pre-infusion levels, and of VEGF and IL-8 from the placebo group. CONCLUSION: BiP (?15 mg) is safe in patients with active RA. Some patients had clinical and biological improvements in RA activity. BiP merits further study. TRIAL REGISTRATION: ISRCTN registry, http://isrctn.com, ISRCTN22288225 and EudraCT, https://eudract.ema.europa.eu, 2011-005831-19. PMID- 27498356 TI - Dysfunction of endothelial progenitor cells is associated with the type I IFN pathway in patients with polymyositis and dermatomyositis. AB - OBJECTIVE: Alterations in phenotype and function of endothelial progenitor cells (EPCs) have been associated with poor vascular outcomes and impaired vascular repair in various conditions. Our hypothesis was that patients with PM and DM have dysregulation of EPCs driven by type I IFN and IL-18 similar to other autoimmune diseases. METHODS: Quantification of circulating EPCs was performed by flow cytometry in patients with PM/DM and matched healthy controls. The ability of EPCs to differentiate into mature endothelial cells was investigated by light and fluorescence microscopy quantification in the presence or absence of PM/DM or control serum, neutralizing antibodies to type I IFN receptor or IL-18. Serum type I IFN activity was quantified by induction of type I IFN-inducible genes in HeLa cells. Circulating IL-18 concentrations were assessed by ELISA. RESULTS: Circulating EPCs were significantly lower in PM/DM patients compared with controls. PM/DM EPCs displayed a decreased capacity to differentiate into mature endothelial cells and PM/DM serum significantly inhibited differentiation of control EPCs. This effect was reversed in the majority of samples with neutralizing antibodies to IL-18 or to type I IFN receptor or by a combination of these antibodies. Patients with associated impairments in EPC function had higher type I IFN serum activity. CONCLUSION: PM/DM is associated with dysregulation of EPC phenotype and function that may be attributed, at least in part, to aberrant IL-18 and type I IFN pathways. The implication of these vasculopathic findings for disease prognosis and complications remains to be determined. PMID- 27498357 TI - T follicular helper cells, interleukin-21 and systemic lupus erythematosus. AB - SLE is a chronic systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and generation of high-affinity pathogenic autoantibodies. These autoantibodies form, with autoantigens, immune complexes that are involved in organ and tissue damages. Understanding how the production of these pathogenic autoantibodies arises is of prime importance. T follicular helper cells (Tfh) and IL-21 have emerged as central players in this process. This article reviews the pathogenic role of Tfh cells and IL-21 in SLE. PMID- 27498358 TI - Toluene downregulates filaggrin expression via the extracellular signal-regulated kinase and signal transducer and activator of transcription-dependent pathways. PMID- 27498359 TI - Common peptide epitopes induce cross-reactivity in hypersensitivity pneumonitis serodiagnosis. PMID- 27498360 TI - Granting Order-Writing Privileges to Registered Dietitian Nutritionists Can Decrease Costs in Acute Care Hospitals. PMID- 27498361 TI - Anti-endotoxin and anti-inflammatory effects of Chinese herbal medicinal alkaloid ingredients in vivo. AB - The aim of the research was to investigate the anti-endotoxin and anti inflammatory effects of sinomenine, fangchinoline, stachydrine, chuanxionggzine, oxymartrine, and evodiamine alkaloids commonly found in Chinese herbal medicines. In an endotoxin (LPS) control group, each mouse was challenged with 1 mg LPS/kg by intraperitoneal (IP) injection. In high-, middle- and low-dose alkaloid groups, mice were initially challenged with 1 mg LPS/kg by IP injection and, 3 h later, dosed intramuscularly (IM) with one of the six alkaloids at one of three levels (1, 5, or 10 mg/kg body weight). In the drug control group, mice were dosed IM with 10 mg/kg body weight of a given alkaloid; mice in a naive control group were administered the same volume of normal saline. The results revealed the six alkaloids could reduce the incidence/severity of LPS- induced toxicities, e.g., body temperature elevation, weight loss, systemic inflammation, multiple organ dysfunction. Taken together, the data suggested to us that these alkaloids might effectively regulate inflammatory responses and have a potential to be used in anti-endotoxin therapies. PMID- 27498362 TI - In vivo efficacy of single phage versus phage cocktail in resolving burn wound infection in BALB/c mice. AB - Klebsiella pneumoniae is one of the most predominant pathogens associated with burn wound infections, causing considerable morbidity and mortality. The indiscriminate usage of antibiotics has led to the development of resistant strains, which have contributed towards the inefficacy of antibiotics. Phage therapy is a promising alternative to hinder the progression of pathogenic bacteria. However, phage bacterial resistance is already well known but the use of phage cocktails can overcome this drawback. The aim of the study was to evaluate the therapeutic efficacy of monophage (Kpn1, Kpn2, Kpn3, Kpn4 and Kpn5) in comparison to phage cocktail in resolving the course of burn wound infection in mice. Although, animals receiving monophage therapy exhibited efficacy in resolving the course of infection but phage cocktail was highly effective in arresting the entire infection process (bacterial load, wound contraction, skin myeloperoxidase activity, collagen formation and histopathological analysis). In comparison to untreated control mice, a significant reduction in bacterial load to 4.32, 4.64, 4.42, 4.11 and 4.27 log CFU/ml in Kpn1, Kpn2, Kpn3 Kpn4 and Kpn5 treated animals was obtained respectively was on peak day (3rd day). However, the group receiving phage cocktail (group 7) showed maximum reduction in bacterial load in the skin tissue. The bacterial load was significantly reduced to 3.01 log CFU/ml on peak day. This accounts for a significant reduction of 6 log cycles (p < 0.01) as compared to that of untreated control animals where a peak of 8.81 log CFU/ml was seen followed by steady decrease thereafter. Thus, phage cocktail gave maximum protection against burn wound infection by K. pneumoniae B5055. Compared to any single phage, phage cocktail significantly checked the emergence of resistant mutants. Hence this approach can serve as an effective strategy in treating Klebsiella mediated burn wound infections in individuals who do not respond to conventional antibiotic therapy. PMID- 27498363 TI - Toxic effects of nano-ZnO on marine microalgae Skeletonema costatum: Attention to the accumulation of intracellular Zn. AB - To explore toxic mechanisms of nano-ZnO on marine microalgae, algal growth inhibition test was carried out, and total Zn in the cell and total dissolved Zn in f/2 medium were determined. It was found that nano-ZnO was more toxic than bulk-ZnO on marine microalgae Skeletonema costatum. No matter under nano-ZnO or bulk-ZnO treatment, accumulation of intracellular Zn had a good linear correlation with growth inhibition ratio (IR). The total Zn content in the cell of microalgae was the dominant toxic mechanism of ZnO. Intracellular total Zn could be an indispensable parameter to indicate the toxic effects of nano-ZnO. Higher intracellular total Zn under nano-ZnO treatment than bulk-ZnO resulted in more toxicity of nano-ZnO on microalgae. Compared with Zn(2+) released by nano ZnO into medium, lipid peroxidation (MDA level) injury, aggregation of nano-ZnO and transmembrane process of nano-ZnO also contributed to toxicity of nano-ZnO on Skeletonema costatum. The accumulation of intracellular Zn provides a new insight into toxic mechanisms of nano-ZnO. PMID- 27498364 TI - Dynamic modeling of copper bioaccumulation by Mytilus edulis in the presence of humic acid aggregates. AB - Copper (Cu) complexation by humic acids (HA) is expected to decrease Cu bioavailability for aquatic organisms as predicted by metal bioavailability models, such as the biotic ligand model (BLM). This has been confirmed for non feeding organisms such as marine invertebrate embryos or microalgae, but for filter-feeding organisms such as the mussel Mytilus edulis, Cu bioaccumulation was higher in the presence of HA, suggesting that part of the Cu-HA complexes were available for uptake. This study shows the dynamic modeling of Cu accumulation kinetics in the gills and rest of the soft-body of M. edulis in the absence and presence of HA. Assuming that truly dissolved Cu is taken in the body via the gills following BLM premises, and including uptake of Cu-HA aggregates via the gut into the rest compartment, this two-compartmental model could successfully explain the observed bioaccumulation data. This modeling approach gives strong evidence to the hypothesis that Cu-HA aggregates can be ingested by mussels leading to Cu absorption in the digestive system. PMID- 27498366 TI - Validating Use of Technology for Cognitive Test Assessment. PMID- 27498365 TI - Revaccination with Live Attenuated Vaccines Confer Additional Beneficial Nonspecific Effects on Overall Survival: A Review. AB - BACKGROUND: Live vaccines against measles (MV), tuberculosis (BCG), polio (OPV) and smallpox reduce mortality more than explained by target-disease prevention. The beneficial nonspecific effects (NSEs) of MV are strongest when MV is given in presence of maternal antibodies. We therefore hypothesised that revaccination in presence of prior immunity enhances beneficial NSEs. METHODS: Literature search for studies of revaccination and mortality. FINDINGS: In two randomised trials (RCTs), two doses versus one dose of MV reduced all-cause mortality by 63% (95% CI: 23-83%) from 9 to 18months of age. In a quasi-experimental study two doses before and after 9months compared with one dose of MV after 9months of age reduced mortality by 59% (25-81%). BCG-revaccination significantly enhanced BCG's effect against overall child mortality in two RCTs. In a natural experiment study of OPV campaigns over a 13-year-period in Guinea-Bissau, each additional dose of OPV was associated with a 13% (4-21%) reduction in mortality rate. The beneficial NSEs of smallpox vaccination for survival increased significantly with the number of smallpox vaccination scars. INTERPRETATION: Revaccination with live vaccines led to substantial reductions in overall mortality. These findings challenge current understanding of vaccines and may explain the beneficial effects of campaigns with live vaccines. PMID- 27498367 TI - Potent ameliorating effect of Hypoxia-inducible factor 1alpha (HIF-1alpha) antagonist YC-1 on combined allergic rhinitis and asthma syndrome (CARAS) in Rats. AB - Recent studies have implicated that Hypoxia-inducible factor 1alpha (HIF-1alpha) plays an integral role in the pathogenesis of allergic rhinitis and asthma. In the present study, we showed that HIF-1alpha antagonist YC-1, 3-(5-hydroxymethyl 2-furyl)-1-benzylindazole, elicited a potent allergy-ameliorating effect in a rat model of ovalbumin (OVA)-sensitized combined allergic rhinitis and asthma syndrome (CARAS). We revealed that YC-1 administration markedly impaired the total number and percentage of eosinophil in bronchoalveolar lavage fluid (BAL Fluid) of the rats, suggesting that YC-1 might attenuate lung and nasal mucosal inflammation in OVA-sensitized rats. Moreover, histological examination found that OVA-induced pathological alterations were evidently attenuated following YC 1 administration. In addition, immunohistochemistrial analysis indicated that YC 1 treatment decreased the expression of HIF-1alpha in rat lungs and nasal mucosa. Notably, Nuclear factor kappa B (NF-kappaB) p65 and Peroxisome proliferator activated receptor alpha (PPARalpha), two important regulators of inflammatory responses, were also significantly down-regulated following YC-1 administration. Real-time PCR analysis confirmed that YC-1 impaired the expression of HIF-1alpha, NF-kappaB and PPARalpha in CARAS model. These findings together indicated that YC 1 exerted remarkable anti-allergic effects through the modulation of inflammatory pathways, implying that YC-1 may potentially serve as a novel anti-CARAS medicine in clinical patients. PMID- 27498368 TI - Characterization of a selective inverse agonist for estrogen related receptor alpha as a potential agent for breast cancer. AB - The estrogen-related receptor alpha (ERRalpha) is an orphan nuclear receptor that plays a primary role in the regulation of cellular energy homeostasis and osteogenesis. It is reported that ERRalpha is widely expressed in a range of tissues and accumulating evidence has supported that the high expression of ERRalpha correlates with poor prognosis of various human malignancies, including breast, endometrium, colon, prostate and ovary cancers. Herein is described the discovery of a novel selective inverse agonist (HSP1604) of ERRalpha, but not of ERRbeta and ERRgamma, as determined using transient transfection luciferase reporter assay and a time-resolved fluorescence resonance energy transfer (TR FRET) co-activator assay. HSP1604 potently inhibits ERRalpha transcriptional activity with IC50=1.47+/-0.17MUM in cell-based luciferase reporter assay and also decreases the protein level of ERRalpha and the mRNA levels of its downstream target genes such as pyruvate dehydrogenase kinase 4 (PDK4), pS2 and osteopontin. HSP1604 has also suppressed the proliferation of different human cancer cell lines and the migration of breast cancer cells with high expression of ERRalpha. Representative in vivo results show that HSP1604 suppresses the growth of human breast cancer xenograft in nude mice as doses at 30mg/kg or 100mg/kg administered every other day during 28-day period. HSP1604 thus has the potential both as a new agent to inhibit the growth of tumors and as a chemical probe of ERRalpha biology. PMID- 27498369 TI - Neural correlates of envy: Regional homogeneity of resting-state brain activity predicts dispositional envy. AB - Envy differs from common negative emotions across cultures. Although previous studies have explored the neural basis of episodic envy via functional magnetic resonance imaging (fMRI), little is known about the neural processes associated with dispositional envy. In the present study, we used regional homogeneity (ReHo) as an index in resting-state fMRI (rs-fMRI) to identify brain regions involved in individual differences in dispositional envy, as measured by the Dispositional Envy Scale (DES). Results showed that ReHo in the inferior/middle frontal gyrus (IFG/MFG) and dorsomedial prefrontal cortex (DMPFC) positively predicted dispositional envy. Moreover, of all the personality traits measured by the Revised NEO Personality Inventory (NEO-PI-R), only neuroticism was significantly associated with dispositional envy. Furthermore, neuroticism mediated the underlying association between the ReHo of the IFG/MFG and dispositional envy. Hence, to the best of our knowledge, this study provides the first evidence that spontaneous brain activity in multiple regions related to self-evaluation, social perception, and social emotion contributes to dispositional envy. In addition, our findings reveal that neuroticism may play an important role in the cognitive processing of dispositional envy. PMID- 27498370 TI - A study of the electro-haemodynamic coupling using simultaneously acquired intracranial EEG and fMRI data in humans. AB - In current fMRI studies designed to map BOLD changes related to interictal epileptiform discharges (IED), which are recorded on simultaneous EEG, the information contained in the morphology and field extent of the EEG events is exclusively used for their classification. Usually, a BOLD predictor based on IED onset times alone is constructed, effectively treating all events as identical. We used intracranial EEG (icEEG)-fMRI data simultaneously recorded in humans to investigate the effect of including any of the features: amplitude, width (duration), slope of the rising phase, energy (area under the curve), or spatial field extent (number of contacts over which the sharp wave was observed) of the fast wave of the IED (the sharp wave), into the BOLD model, to better understand the neurophysiological origin of sharp wave-related BOLD changes, in the immediate vicinity of the recording contacts. Among the features considered, the width was the only one found to explain a significant amount of additional variance, suggesting that the amplitude of the BOLD signal depends more on the duration of the underlying field potential (reflected in the sharp wave width) than on the degree of neuronal activity synchrony (reflected in the sharp wave amplitude), and, consequently, that including inter-event variations of the sharp wave width in the BOLD signal model may increase the sensitivity of forthcoming EEG-fMRI studies of epileptic activity. PMID- 27498371 TI - Integrating cross-frequency and within band functional networks in resting-state MEG: A multi-layer network approach. AB - Neuronal oscillations exist across a broad frequency spectrum, and are thought to provide a mechanism of interaction between spatially separated brain regions. Since ongoing mental activity necessitates the simultaneous formation of multiple networks, it seems likely that the brain employs interactions within multiple frequency bands, as well as cross-frequency coupling, to support such networks. Here, we propose a multi-layer network framework that elucidates this pan spectral picture of network interactions. Our network consists of multiple layers (frequency-band specific networks) that influence each other via inter-layer (cross-frequency) coupling. Applying this model to MEG resting-state data and using envelope correlations as connectivity metric, we demonstrate strong dependency between within layer structure and inter-layer coupling, indicating that networks obtained in different frequency bands do not act as independent entities. More specifically, our results suggest that frequency band specific networks are characterised by a common structure seen across all layers, superimposed by layer specific connectivity, and inter-layer coupling is most strongly associated with this common mode. Finally, using a biophysical model, we demonstrate that there are two regimes of multi-layer network behaviour; one in which different layers are independent and a second in which they operate highly dependent. Results suggest that the healthy human brain operates at the transition point between these regimes, allowing for integration and segregation between layers. Overall, our observations show that a complete picture of global brain network connectivity requires integration of connectivity patterns across the full frequency spectrum. PMID- 27498372 TI - Temporal control of Dickeya dadantii main virulence gene expression by growth phase-dependent alteration of regulatory nucleoprotein complexes. AB - In bacteria, important genes are often controlled at the transcriptional level by several factors, forming a complex and intertwined web of interactions. Yet, transcriptional regulators are often studied separately and little information is available concerning their interactions. In this work, we dissect the regulation of the major virulence gene pelD in D. dadantii by taking into account the effects of individual binding sites for regulatory proteins FIS and CRP, and the impact of a newly discovered divergent promoter div. Using a combination of biochemistry and genetics approaches we provide an unprecedented level of detail on the multifactorial regulation of bacterial transcription. We show that the growth phase dependent regulation of pelD is under the control of changing composition of higher-order nucleoprotein complexes between FIS, CRP, div and pelD during the growth cycle that allow sequential expression of div and pelD in the early and late exponential growth phases, respectively. This work highlights the importance of "orphan" promoters in gene regulation and that the individual binding sites for a regulator can serve several purposes and have different effects on transcription, adding a new level of complexity to bacterial transcriptional regulation. PMID- 27498373 TI - Renoprotection by remote ischemic conditioning during elective coronary revascularization: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Remote ischemic conditioning (RIC) has been recognized an emerging non-invasive approach for preventing acute kidney injury (AKI) in patients undergoing either elective coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). On the other hand, accumulating evidence has indicated the involving role of pre-CABG contrast usage for coronary angiography in post-surgery AKI risk. Along with the shortening time delay of CABG after coronary angiography, and the prevalent hybrid coronary revascularization (HCR), the AKI prevention by RIC has faced challenges following coronary revascuralization. METHODS: Randomized controlled trials (RCTs) were searched from Pubmed, EMBase, and Cochrane library (until May 2016). The primary outcome was postoperative AKI. The second outcomes were included the requirement for renal replacement therapy (RRT), and in-hospital or 30-day mortality. RESULTS: Twenty eligible RCTs (CABG, 3357 patients; PCI, 1501 patients) were selected. RIC significantly halved the incidence of AKI following PCI when compared with controls [n=1501; odds ratio (OR)=0.51; 95% CI, 0.32 to 0.82; P=0.006; I(2)=29.6%]. However, RIC did not affect the incidence of AKI following CABG (n=1850; OR=0.94; 95% CI, 0.73 to 1.19; P=0.586; I(2)=12.4%). The requirement for RRT and in-hospital mortality was not affected by RIC in CABG (n=2049, OR=1.04, P=0.87; n=1920, OR=0.89, P=0.7; respectively). CONCLUSIONS: Our meta-analysis suggests that RIC for preventing AKI following CABG has faced with challenges in terms of AKI, the requirement for RRT, and mortality. However, RIC shows a renoprotective benefit for PCI. Hence, our findings may infer the preserved renal effects of RIC in CABG with preconditioning before the coronary angiography, or in HCR. PMID- 27498375 TI - Telephone vs. Web-based prescreening predicts early but not overall physician response to a mailed survey. PMID- 27498374 TI - Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper. AB - Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps. PMID- 27498376 TI - A systematic review of discontinued trials suggested that most reasons for recruitment failure were preventable. AB - OBJECTIVE: To collect and classify reported reasons for recruitment failure in discontinued randomized controlled trials (RCTs) and to assess reporting quality. METHODS: We systematically searched MEDLINE and EMBASE (2010-2014) and a previous cohort of RCTs for published RCTs reporting trial discontinuation due to poor recruitment. Teams of two investigators selected eligible RCTs working independently and extracted information using standardized forms. We used an iterative approach to classify reasons for poor recruitment. RESULTS: We included 172 RCTs discontinued due to poor recruitment (including 26 conference abstracts and 63 industry-funded RCTs). Of those, 131 (76%) reported one or more reasons for discontinuation due to poor recruitment. We identified 28 different reasons for recruitment failure; most frequently mentioned were overestimation of prevalence of eligible participants and prejudiced views of recruiters and participants on trial interventions. Few RCTs reported relevant details about the recruitment process such as how eligible participants were identified, the number of patients assessed for eligibility, and who actually recruited participants. CONCLUSION: Our classification could serve as a checklist to assist investigators in the planning of RCTs. Most reasons for recruitment failure seem preventable with a pilot study that applies the planned informed consent procedure. PMID- 27498377 TI - Series: Clinical Epidemiology in South Africa. Paper 3: Logic models help make sense of complexity in systematic reviews and health technology assessments. AB - OBJECTIVE: To describe the development and application of logic model templates for systematic reviews and health technology assessments (HTAs) of complex interventions. STUDY DESIGN AND SETTING: This study demonstrates the development of a method to conceptualize complexity and make underlying assumptions transparent. Examples from systematic reviews with specific relevance to Sub Saharan Africa (SSA) and other low- and middle-income countries (LMICs) illustrate its usefulness. RESULTS: Two distinct templates are presented: the system-based logic model, describing the system in which the interaction between participants, intervention, and context takes place; and the process-orientated logic model, which displays the processes and causal pathways that lead from the intervention to multiple outcomes. CONCLUSION: Logic models can help authors of systematic reviews and HTAs to explicitly address and make sense of complexity, adding value by achieving a better understanding of the interactions between the intervention, its implementation, and its multiple outcomes among a given population and context. They thus have the potential to help build systematic review capacity-in SSA and other LMICs-at an individual level, by equipping authors with a tool that facilitates the review process; and at a system-level, by improving communication between producers and potential users of research evidence. PMID- 27498379 TI - Body dysmorphic disorder in different settings: A systematic review and estimated weighted prevalence. AB - Our aim was to systematically review the prevalence of body dysmorphic disorder (BDD) in a variety of settings. Weighted prevalence estimate and 95% confidence intervals in each study were calculated. The weighted prevalence of BDD in adults in the community was estimated to be 1.9%; in adolescents 2.2%; in student populations 3.3%; in adult psychiatric inpatients 7.4%; in adolescent psychiatric inpatients 7.4%; in adult psychiatric outpatients 5.8%; in general cosmetic surgery 13.2%; in rhinoplasty surgery 20.1%; in orthognathic surgery 11.2%; in orthodontics/cosmetic dentistry settings 5.2%; in dermatology outpatients 11.3%; in cosmetic dermatology outpatients 9.2%; and in acne dermatology clinics 11.1%. Women outnumbered men in the majority of settings but not in cosmetic or dermatological settings. BDD is common in some psychiatric and cosmetic settings but is poorly identified. PMID- 27498378 TI - Propensity score model overfitting led to inflated variance of estimated odds ratios. AB - OBJECTIVE: Simulation studies suggest that the ratio of the number of events to the number of estimated parameters in a logistic regression model should be not less than 10 or 20 to 1 to achieve reliable effect estimates. Applications of propensity score approaches for confounding control in practice, however, do often not consider these recommendations. STUDY DESIGN AND SETTING: We conducted extensive Monte Carlo and plasmode simulation studies to investigate the impact of propensity score model overfitting on the performance in estimating conditional and marginal odds ratios using different established propensity score inference approaches. We assessed estimate accuracy and precision as well as associated type I error and type II error rates in testing the null hypothesis of no exposure effect. RESULTS: For all inference approaches considered, our simulation study revealed considerably inflated standard errors of effect estimates when using overfitted propensity score models. Overfitting did not considerably affect type I error rates for most inference approaches. However, because of residual confounding, estimation performance and type I error probabilities were unsatisfactory when using propensity score quintile adjustment. CONCLUSION: Overfitting of propensity score models should be avoided to obtain reliable estimates of treatment or exposure effects in individual studies. PMID- 27498380 TI - Nitrogen loss factors of nitrogen trace gas emissions and leaching from excreta patches in grassland ecosystems: A summary of available data. AB - Patches of excreta voided by grazing animals are nitrogen (N) transformation hotspots in grassland ecosystems and an important source of N trace gas emissions and leaching. Previous studies have focused on individual N losses from excreta, but no quantitative analysis has been performed on all the N losses via N trace gas emissions and leaching. To better understand the fate of N in excreta patches, we summarized 418, 15, 65, 22, 54, 11, and 81 measurements of nitrous oxide (N2O), nitric oxide (NO), ammonia (NH3), and ammonium (NH4+) leaching, nitrate (NO3-) leaching, dissolved organic nitrogen (DON) leaching, and aboveground plant N uptake, respectively. The results based on field studies indicated that the average fractions of N lost via N2O were 0.28%, 0.76%, 0.08%, and 0.35% for cattle dung, cattle urine, sheep dung, and sheep urine, respectively. Only 0.01-0.12% of excreta N was lost via NO, whereas 1.69-12.7%, 0 4.58%, 16.4-24.6%, and 1.43-5.91% were lost by NH3 and NH4+, NO3-, and DON leaching, respectively. Aboveground plant parts assimilated 10.4-31.4% of the excreta N. The N lost via N2O from urine patches decreased as NH3 losses increased, and greater NO3- leaching occurred with lower plant N uptake. The combined N2O emission factors for dung and urine from cattle and sheep were 0.59% and 0.26%, respectively. Each N loss factor was much higher in urine patches than in dung patches, irrespective of animal type. This study provides general estimates of N losses and plant N uptake from excreta patches on grazed grassland based on currently available field data. More field studies are needed in the future with longer measurement periods from a wide range of climate zones to refine these N loss factors. PMID- 27498381 TI - Life-history strategies constrain invertebrate community tolerance to multiple stressors: A case study in the Ebro basin. AB - CONTEXT: Multiple stressors constitute a serious threat to aquatic ecosystems, particularly in the Mediterranean region where water scarcity is likely to interact with other anthropogenic stressors. Biological traits potentially allow the unravelling of the effects of multiple stressors. However, thus far, trait based approaches have failed to fully deliver on their promise and still lack strong predictive power when multiple stressors are present. GOAL: We aimed to quantify specific community tolerances against six anthropogenic stressors and investigate the responses of the underlying macroinvertebrate biological traits and their combinations. METHODS: We built and calibrated boosted regression tree models to predict community tolerances using multiple biological traits with a priori hypotheses regarding their individual responses to specific stressors. We analysed the combinations of traits underlying community tolerance and the effect of trait association on this tolerance. RESULTS: Our results validated the following three hypotheses: (i) the community tolerance models efficiently and robustly related trait combinations to stressor intensities and, to a lesser extent, to stressors related to the presence of dams and insecticides; (ii) the effects of traits on community tolerance not only depended on trait identity but also on the trait associations emerging at the community level from the co occurrence of different traits in species; and (iii) the community tolerances and the underlying trait combinations were specific to the different stressors. CONCLUSION: This study takes a further step towards predictive tools in community ecology that consider combinations and associations of traits as the basis of stressor tolerance. Additionally, the community tolerance concept has potential application to help stream managers in the decision process regarding management options. PMID- 27498382 TI - Impact of sediment particle size on biotransformation of 17beta-estradiol and 17beta-trenbolone. AB - Soil/sediment particle size has been reported to influence the sorption and bioavailability of steroid hormones in the environment. However, the impact of particle size on biotransformation has not been well elucidated. The present study investigated the dissipation of 17beta-estradiol and 17beta-trenbolone and the formation and degradation of the subsequent transformation products in different size fractions of a sandy and a silt loam sediment. The results showed that the decay of 17beta-estradiol and 17beta-trenbolone associated with fine particles followed a biphasic pattern with more rapid decay in the initial phase followed by a second phase with slower decay of the residues compared to their decay rates in the sand fraction. Estrone and trendione were detected as a primary biotransformation product for 17beta-estradiol and 17beta-trenbolone, respectively. The parent-to-product conversion ratios and the degradation rates of estrone and trendione varied among different size fractions, but no consistent correlation was observed between decay rates and sediment particle size. Estrone and trendione decayed in the whole sediments at rates not statistically different from those associated with the fine fractions. These results indicate that fine particles may play an important role in influencing the persistence of and the potential risk posed by steroid hormones in the aquatic systems. PMID- 27498383 TI - Heart transplantation after donor circulatory death in patients bridged to transplant with implantable left ventricular assist devices. PMID- 27498385 TI - Distribution of 45S rDNA in Modern Rose Cultivars (Rosa hybrida), Rosa rugosa, and Their Interspecific Hybrids Revealed by Fluorescence in situ Hybridization. AB - To elucidate the evolutionary dynamics of the location and number of rDNA loci in the process of polyploidization in the genus Rosa, we examined 45S rDNA sites in the chromosomes of 6 modern rose cultivars (R. hybrida), 5 R. rugosa cultivars, and 20 hybrid progenies by fluorescence in situ hybridization. Variation in the number of rDNA sites in parents and their interspecific hybrids was detected. As expected, 4 rDNA sites were observed in the genomes of 4 modern rose cultivars, while 3 hybridization sites were observed in the 2 others. Two expected rDNA sites were found in 2 R. rugosa cultivars, while in the other 3 R. rugosa cultivars 4 sites were present. Among the 20 R. hybrida * R. rugosa offspring, 13 carried the expected number of rDNA sites, and 1 had 6 hybridization sites, which exceeded the expected number by far. The other 6 offspring had either 2 or 3 hybridization sites, which was less than expected. Differences in the number of rDNA loci were observed in interspecific offspring, indicating that rDNA loci exhibit instability after distant hybridization events. Abnormal chromosome pairing may be the main factor explaining the variation in rDNA sites during polyploidization. PMID- 27498384 TI - Cholesterol efflux capacity of high-density lipoprotein correlates with survival and allograft vasculopathy in cardiac transplant recipients. AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major cause of mortality after cardiac transplantation. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is inversely associated with coronary artery disease. In 2 independent studies, we tested the hypothesis that reduced CEC is associated with mortality and disease progression in CAV. METHODS: We tested the relationship between CEC and survival in a cohort of patients with CAV (n = 35). To determine whether reduced CEC is associated with CAV progression, we utilized samples from the Clinical Trials in Organ Transplantation 05 (CTOT05) study to determine the association between CEC and CAV progression and status at 1 year (n = 81), as assessed by average change in maximal intimal thickness (MIT) on intravascular ultrasound. RESULTS: Multivariable Cox proportional hazard models demonstrated that higher levels of CEC were associated with improved survival (hazard ratio 0.26, 95% confidence interval 0.11 to 0.63) per standard deviation CEC, p = 0.002). Patients who developed CAV had reduced CEC at baseline and 1-year post transplant. We observed a significant association between pre-transplant CEC and the average change in MIT, particularly among patients who developed CAV at 1 year (beta = -0.59, p = 0.02, R2 = 0.35). CONCLUSION: Reduced CEC is associated with disease progression and mortality in CAV patients. These findings suggest the hypothesis that interventions to increase CEC may be useful in cardiac transplant patients for prevention or treatment of CAV. PMID- 27498386 TI - A 10-Gene Yin Yang Expression Ratio Signature for Stage IA and IB Non-Small Cell Lung Cancer. AB - INTRODUCTION: Lung cancer is the leading killer cancer worldwide. There is an urgent need for easy-to-use and robust clinical gene signatures for improved prognosis and treatment prediction. METHODS: We used a gene expression signature termed the Yin and Yang mean ratio (YMR), which is based on two groups of genes with opposing function, to determine lung cancer prognosis. The YMR signature represents the relative state of an individual tumor on a gene expression spectrum ranging from malignancy to the normal healthy lung. The genes in the YMR signature have therefore been determined independently of survival time, which is different from previous regression models. We then leveraged the cross-platform utility of the YMR signature to optimize the signature into a smaller set of genes that validated the robustness of the signature in many independent lung cancer expression data sets. RESULTS: Four Yin and six Yang genes were optimized using 741 NSCLC cases from diverse platforms, including microarray and RNA sequencing. The 10-gene signature demonstrated significant differences in survival in eight individual independent data sets and a larger combined 1346 patient data set. When multivariate analysis taking into account other common predictors of survival was used, the 5-year recurrence-free rate of YMR (p = 6.4 * 10-6, HR =1.71 [1.36-2.16]) was secondary only to stage. The YMR signature significantly separated high- and low-risk patients with stage IA or 1B adenocarcinoma and squamous cell carcinomas of all stages. The YMR signature can also predict the benefit of adjuvant chemotherapy in high-risk patients with stage I NSCLC. CONCLUSIONS: The YMR signature has great potential for guiding clinical management for NSCLC, particularly early-stage disease. The signature appears more reproducible than older signatures and functions using a variety of common gene expression platforms. PMID- 27498387 TI - Sequential Therapy with Crizotinib and Alectinib in ALK-Rearranged Non-Small Cell Lung Cancer-A Multicenter Retrospective Study. AB - INTRODUCTION: Alectinib and crizotinib have been approved for the therapy of NSCLC caused by anaplastic lymphoma kinase gene (ALK) rearrangement. The effect of alectinib or crizotinib on overall survival (OS) in patients with ALK rearranged NSCLC remains unknown. METHODS: A multicenter retrospective study was conducted to compare OS between patients receiving alectinib and crizotinib and between patients treated with alectinib and those treated sequentially with crizotinib and then alectinib after crizotinib failure. The time to treatment failure (TTF), progression-free survival (PFS), and OS were compared. RESULTS: Sixty-one patients with ALK-rearranged NSCLC were enrolled. Forty-six patients were treated with anaplastic lymphoma kinase (ALK) inhibitors (31 with crizotinib, 28 with alectinib, and 13 with both ALK inhibitors). The response rate was 66.7% for the crizotinib-treated group and 80.8% for the alectinib treated group. Among all patients, TTF and PFS were significantly prolonged in the alectinib-treated group compared with in the crizotinib-treated group. Subgroup analyses revealed significantly prolonged TTF for alectinib compared with crizotinib therapy in the ALK inhibitor-naive population. OS was significantly longer in the alectinib-treated group than in the crizotinib treated group. The TTF and OS of patients treated sequentially with crizotinib and then with alectinib after crizotinib failure tended to be longer than those of patients treated with alectinib alone. CONCLUSIONS: Therapy with alectinib alone was significantly superior to therapy with crizotinib alone in terms of TTF, PFS, and OS, and sequential therapy with crizotinib and alectinib after crizotinib failure tended to provide a better OS benefit than did therapy with alectinib alone in patients with ALK-positive NSCLC. However, large-scale prospective studies are needed to confirm these observations. PMID- 27498388 TI - Population differentiation and genetic diversity of Trichophyton rubrum as revealed by highly discriminatory microsatellites. AB - Little is known regarding the population information of Trichophyton rubrum due to a lack of strains with clear sampling information and molecular markers with high discriminatory power. In the present study, we developed a set of microsatellite markers that have a cumulative discriminatory power was 0.993. Using these microsatellites loci, 243 strains T. rubrum that had clear sampling information were analysed. Three genetic diversity indices (Shannon's Information Index, Nei's unbiased gene diversity and allelic richness) were shown to be related to the human population size of the sampling city rather than mean annual temperature or humidity. Population structure analyses revealed that T. rubrum can be separated into two clusters. AMOVA results indicated that genetic variation was more significant between these two clusters than among geographical populations. Our work is the first to reveal population information of T. rubrum using highly discriminatory molecular markers, and suggest that T. rubrum populations in cities with larger population size might have better adaptability due to higher genetic diversity under selective pressures (such as antifungal agents). PMID- 27498389 TI - The Fate of Revision Total Knee Arthroplasty With Preoperative Abnormalities in Either Sedimentation Rate or C-Reactive Protein. AB - BACKGROUND: Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are important markers in the evaluation and treatment of painful total knee arthroplasty (TKA). Elevation of both markers usually occurs with infected TKAs while a normal ESR and CRP usually point to aseptic causes for failure. The purpose of this study is to compare (1) rate of revision, (2) infection, and (3) reason for reoperation in a group of patients undergoing revision TKA with a single abnormality in either ESR or CRP in an otherwise negative conventional infection work-up compared to patients with normal preoperative ESR and CRP. METHODS: We retrospectively reviewed 791 consecutive revision TKAs performed at our institution between years 2004 and 2011. Following exclusion for infection, periprosthetic fracture, prior revision TKA, positive cultures, incomplete records, and patients with less than 24-month follow-up, a total of 228 aseptic revisions (89 knees with 1 abnormal serologic marker) were available for final analysis. No patients met the current established criteria for infection. All knees underwent revision TKA using antibiotic-impregnated cement. The 2 groups were compared in terms of overall survivorship, infection rate, and rate and causes of subsequent aseptic revision. RESULTS: The average follow-up was 60 months (24-110). There were no significant differences between the 2 groups in terms of age, sex, American Society of Anesthesiologists class, and Charlson comorbidity index. A preoperative abnormality of either ESR or CRP significantly increased the risk for reoperation for all reasons (odds ratio [OR], 3.2; P = .0028), infection (OR, 4.0; P = .034), and revision for aseptic loosening (OR, 3.69; P = .044). There were no differences in reoperations for any other reason. The average time to revision in the study group was 28.3 months compared to 40.0 months in the control group (P = .213). CONCLUSION: A single abnormality in either the ESR or CRP increased the likelihood of both infection and reoperation following revision TKA. Conventional methods and criteria for infection detection may not be sufficiently sensitive or specific in these cases. Further work-up with additional modalities may help increase the confidence of aseptic failure before revision TKA. PMID- 27498390 TI - Blood-Sparing Efficacy of Oral Tranexamic Acid in Primary Total Hip Arthroplasty. AB - BACKGROUND: Tranexamic acid (TXA) has been shown to be effective in reducing blood loss, hemoglobin drop, and blood transfusion in primary total hip arthroplasty. Most studies used intravenous form or topical form. This study was to assess the blood-sparing efficacy and safety of oral TXA in total hip arthroplasty. METHODS: Patients with primary total hip arthroplasty from 2012 to 2015 were recruited. Trial group with 1 gm of oral TXA 2 hours preoperatively, and 6 hours and 12 hours postoperatively was compared with the control group without drug. Outcome measures were intraoperative blood loss, drain output, observed total blood loss, actual total blood loss, hidden blood loss, hemoglobin drop, blood transfusion requirement, thromboembolic complications, cerebrovascular or cardiovascular complications, and mortality. RESULTS: After exclusion, 108 patients were included-54 in trial group and 54 in control group. There was no significant difference in the baseline characteristics. The trial group had significantly higher postoperative hemoglobin (10.3 vs 9.4 g/dL), lower hemoglobin drop (3.0 vs 4.1 g/dL), lower hidden blood loss (149 vs 354 mL), and lower actual total blood loss (847 vs 1096 mL). There was no significant difference in thromboembolic complications or mortality. There was also no periprosthetic infection or drug allergy. CONCLUSION: Oral TXA is effective in blood sparing in terms of reduction in hemoglobin drop, hidden blood loss, and actual total blood loss. It is safe and is an alternative to the intravenous or topical form. PMID- 27498391 TI - Identifying potential markers in Breast Cancer subtypes using plasma label-free proteomics. AB - : Breast Cancer (BC) is the most common neoplasia among women and has a high mortality rate worldwide. Over the past several decades, increasing molecular knowledge of BC has resulted in its stratification into 4 major molecular subtypes according to hormonal receptor expression. Unfortunately, although the data accumulated thus far has improved BC prognosis and treatment, there have been few achievements in its diagnosis. In this study, we applied a Label-free Nano-LC/MSMS approach to reveal systemic molecular features and possible plasma markers for BC patients. Compared to healthy control plasma donors, we identified 191, 166, 182, and 186 differentially expressed proteins in the Luminal, Lumina HER2, HER2, and TN subtypes. In silico analysis demonstrated an overall downregulation of cellular basal machinery and, more importantly, brought new focus to the known pathways and signaling molecules in BC that are related to immune system alterations. Moreover, using western blot analysis, we verified high levels of BCAS3, IRX1, IRX4 and IRX5 in BC plasma samples, thus highlighting the potential use of plasma proteomics in investigations into cancer biomarkers. SIGNIFICANCE: The results of this study provide new insight into Breast Cancer (BC). We determined the plasma proteomic profile of BC subtypes. Furthermore, we report that the signaling pathways correlating with late processes in BC already exhibit plasma alterations in less aggressive subtypes. Additionally, we validated the high levels of particular proteins in patient samples, which suggests the use of these proteins as potential disease markers. PMID- 27498392 TI - An early dysregulation of FAK and MEK/ERK signaling pathways precedes the beta amyloid deposition in the olfactory bulb of APP/PS1 mouse model of Alzheimer's disease. AB - Olfactory dysfunction is an early event of Alzheimer's disease (AD). However, the mechanisms associated to AD neurodegeneration in olfactory areas are unknown. Here we used double-transgenic amyloid precursor protein/presenilin 1 (APPswe/PS1dE9) mice and label-free quantitative proteomics to analyze early pathological effects on the olfactory bulb (OB) during AD progression. Prior to beta-amyloid plaque formation, 9 modulated proteins were detected on 3-month-old APP/PS1 mice while 16 differential expressed proteins were detected at 6months, when beta-amyloid plaques appear, indicating a moderate imbalance in cytoskeletal rearrangement, and synaptic plasticity in APP/PS1 OBs. Moreover, beta-amyloid induced an inactivation of focal adhesion kinase (FAK) together with a transient activation of MEK1/2, leading to inactivation of ERK1/2 in 6-months APP/PS1 OBs. In contrast, the analysis of human OBs revealed a late activation of FAK in advanced AD stages, whereas ERK1/2 activation was enhanced across AD staging respect to controls. This survival potential was accompanied by the inhibition of the proapototic factor BAD in the OB across AD phenotypes. Our data contribute to a better understanding of the early molecular mechanisms that are modulated in AD neurodegeneration, highlighting significant differences in the regulation of survival pathways between APP/PS1 mice and sporadic human AD. SIGNIFICANCE: Loss of smell is involved in early stages of Alzheimer's disease (AD), usually preceding classic disease symptoms. However, the mechanisms governing this dysfunction are still poorly understood, losing its potential as a useful tool for clinical diagnosis. Our study characterizes potential AD-associated molecular changes in APP/PS1 mice olfactory bulb (OB) using MS-quantitative proteomics, revealing early cytoskeletal disruption and synaptic plasticity impairment. Moreover, an opposite pattern was found when comparing the activation status of specific survival pathways between APP/PS1 OBs and OBs derived from sAD subjects with different neuropathological grading. Our data reflect, in part, the progressive effect of APP overproduction and Abeta accumulation on the OB proteome during AD progression. PMID- 27498393 TI - Quantitative proteomics revealed novel proteins associated with molecular subtypes of breast cancer. AB - The early diagnosis and successful treatment of breast cancer (BC) is still a challenging task due to the diverse origin and functional heterogeneity of cancer cells. The heterogeneity of BC may likely to explained by molecular BC subtypes, comprises Luminal-A (LA), Luminal-B (LB), Triple-negative (TN) and HER2-positive (HP), which are governed by a variety of cancer associated pathways. To identify protein signatures in different BC subtypes, we performed isobaric tag for absolute and relative quantitation (iTRAQ) of enriched blood plasma samples of BC subtypes (N=32) and healthy subjects (N=8). After analyses of data, 58 proteins were found to be modulated in BC subtypes from healthy subjects (p<0.05) and among these; Fibronectin (FN1), Alpha-2-macroglobulin (A2M), and Complement component-4-binding protein-alpha (C4BPA) and Complement factor-B (CFB) were selected for validation in BC subtypes and healthy subjects in the independent set of blood plasma (N=100) and tissue samples (N=25). Statistical analysis showed the significant modulation of FN1 and C4BPA in LB, and A2M in TN patients in both plasma as well as tissues comparatively control (p<0.05). Further, FN1 and C4BPA in LB subtype revealed a good diagnostic accuracy in plasma level validation. The receiver operating characteristic (ROC) curve and regression analysis demonstrated that these proteins with associated criterion of expression could act as discriminating signatures among BC subtypes with diagnostic and prognostic relevance. SIGNIFICANCE: The heterogeneity of breast cancer (BC) has gained many challenges for successful management of BC, thus, the delineating proteomic alterations BC subtypes may provide great clinical values in diagnostic, prognostic and therapeutics of BC. The findings from the present quantitative proteomic study have deciphered the altered proteomic patterns and their possible molecular interactions in each BC subtype. The study showed a strong association of FN1, A2M, C4BPA and CFB in molecular subtypes of BC, in which, C4BPA and A2M demonstrated a potent signature in blood plasma and tissue samples of LB and TN subtypes in BC patients, respectively. The findings also revealed the altered level expressions of these selected proteins could classify BC subtypes through plasma and tissue based expression analysis in patients and control samples. Hence, these proteins could have clinical importance for the diagnosis and prognosis purposes among molecular BC subtypes. PMID- 27498394 TI - Ethical considerations in the de-adoption of ineffective or harmful aspects of healthcare. AB - De-adoption refers to the discontinuance of a medical practice or health service found to be ineffective or harmful following a previous period of adoption. As growing healthcare budgets threaten to cripple the societies that fund them, facilitating de-adoption may be integral to sustainable healthcare systems that provide high-quality care. This article explores ethical issues pertinent to de adoption including the underpinnings of beneficence, non-maleficence, justice, and autonomy. PMID- 27498395 TI - One-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node metastasis in endometrial cancer. AB - OBJECTIVE: To evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the diagnosis of sentinel lymph node (SLN) metastasis compared with histopathological examination in patients with endometrial carcinoma. METHODS: A total of 94 SLNs from 34 patients with endometrial carcinoma were enrolled. The central 1-mm portion of each node was subjected to semi-serial sectioning, sliced at 200-MUm intervals and examined by hematoxylin and eosin and cytokeratin 19 (CK19) immunohistochemical staining, and the remaining tissue was analysed by OSNA using CK19 mRNA. The accuracy of the OSNA assay was evaluated based on histopathological diagnosis. RESULTS: Histologically, 89 SLNs were determined to be metastasis negative, and the remaining five SLNs were metastasis positive. Using the breast cancer cutoff value for detecting lymph node metastasis (OSNA criteria for breast cancer, >250copies/MUl) the sensitivity of the OSNA assay was 100%; specificity was 87.6%; diagnostic accuracy was 88.3%. Discordant results were recorded for 11 of 94 SLNs. In all 11 cases, a positive result was given by the OSNA assay but not by histopathological examination. In two SLNs from the same patient, histopathological examination revealed the presence of benign epithelial inclusions that were CK19 positive; both SLNs yielded a positive result in the OSNA assay (true-false positive). All remaining nine histologically negative/OSNA-positive SLNs were classified as micrometastasis (+) by the OSNA assay. CONCLUSION: The OSNA assay shows high sensitivity and specificity, which suggests its utility as a novel tool for the molecular detection of SLN metastasis in patients with endometrial carcinoma. PMID- 27498396 TI - Knowledge equals health; why all healthcare professionals should know about familial hypercholesterolemia. PMID- 27498397 TI - Impact of statin therapy on plasma adiponectin concentrations: A systematic review and meta-analysis of 43 randomized controlled trial arms. AB - BACKGROUND AND AIMS: The effect of statin therapy on plasma adiponectin levels has not been conclusively studied. Therefore, we aimed to evaluate this effect through a systematic review and meta-analysis of available randomized controlled trials (RCTs). METHODS: Quantitative data synthesis was performed using a random effects model with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics. RESULTS: In 30 studies (43 study arms) with 2953 participants, a significant increase in plasma adiponectin levels was observed after statin therapy (WMD: 0.57 MUg/mL, 95% CI: 0.18, 0.95, p = 0.004). In subgroup analysis, atorvastatin, simvastatin, rosuvastatin, pravastatin and pitavastatin were found to change plasma adiponectin concentrations by 0.70 MUg/mL (95% CI: -0.26, 1.65), 0.50 MUg/mL (95% CI: -0.44, 1.45), -0.70 MUg/mL (95% CI: -1.08, -0.33), 0.62 MUg/mL (95% CI: -0.12, 1.35), and 0.51 MUg/mL (95% CI: 0.30, 0.72), respectively. With respect to duration of treatment, there was a significant increase in the subset of trials lasting >=12 weeks (WMD: 0.88 MUg/mL, 95% CI: 0.19, 1.57, p = 0.012) but not in the subset of <12 weeks of duration (WMD: 0.18 MUg/mL, 95% CI: -0.23, 0.58, p = 0.390). Random-effects meta regression suggested a significant association between statin-induced elevation of plasma adiponectin and changes in plasma low density lipoprotein cholesterol levels (slope: 0.04; 95% CI: 0.01, 0.06; p = 0.002). CONCLUSIONS: The meta analysis showed a significant increase in plasma adiponectin levels following statin therapy. Although statins are known to increase the risk for new onset diabetes mellitus, our data might suggest that the mechanism for this is unlikely to be due to a reduction in adiponectin expression. PMID- 27498398 TI - The relationship between the dietary inflammatory index and risk of total cardiovascular disease, ischemic heart disease and cerebrovascular disease: Findings from an Australian population-based prospective cohort study of women. AB - BACKGROUND AND AIMS: Recently, a pro-inflammatory diet based on a dietary inflammatory index (DII) has been related to higher CVD risk in general population, but this has not been investigated among women. METHODS: We investigated the relationship between DII and risk of total CVD and CVD subgroups (myocardial infarction, ischemic heart disease, stroke and cerebrovascular disease) in a prospective cohort of 6972 Australian women aged 50-55 years at baseline in 2001. We used clinical and procedure information from inpatient hospital separation registries, information on use of health care services, and from the causes-of-death registry to ascertain CVD outcomes during 11-year follow up. The association between baseline DII score and cardiovascular endpoints was analysed through cox-regression, with correction for demographic and cardiovascular risk factors. RESULTS: We identified 335 incident cases of CVD and 191 cases of ischaemic heart disease (including 69 myocardial infarctions) and 59 cases of cerebrovascular disease (including 40 cases of stroke). A statistically significant higher risk of myocardial infarction was observed in analyses using DII scores as a continuous variable with a hazard ratio of 1.46 (95% confidence interval 1.12-1.89), but this was attenuated by further adjustment for other known cardiovascular risk factors. No association was found for total CVD, ischaemic heart diseases, or cerebrovascular disease. CONCLUSIONS: There was no statistically significant association between the dietary inflammatory index and risk of total cardiovascular disease, ischemic heart disease, myocardial infarction, cerebrovascular disease or stroke in this population of mid-aged Australian women. Associations were not different for postmenopausal women. PMID- 27498399 TI - Vestibular-dependent inter-stimulus interval effects on sound evoked potentials of central origin. AB - Todd et al. (2014ab) have recently demonstrated the presence of vestibular dependent contributions to auditory evoked potentials (AEPs) when passing through the vestibular threshold as determined by vestibular evoked myogenic potentials (VEMPs), including a particular deflection labeled as an N42/P52 prior to the long-latency AEPs N1 and P2. In this paper we report the results of an experiment to determine the effect of inter-stimulus interval (ISI) and regularity on potentials recorded above and below VEMP threshold. Five healthy, right-handed subjects were recruited and evoked potentials were recorded to binaurally presented sound stimulation, above and below vestibular threshold, at seven stimulus rates with ISIs of 212, 300, 424, 600, 848, 1200 and 1696 ms. The inner five intervals, i.e. 300, 424, 600, 848, 1200 ms, were presented twice in both regular and irregular conditions. ANOVA on the global field power (GFP) were conducted for each of four waves, N42, P52, N1 and P2 with factors of intensity, ISI and regularity. Both N42 and P52 waves showed significant ANOVA effects of intensity but no other main effects or interactions. In contrast both N1 and P2 showed additional effects of ISI, as well as intensity, and evidence of non linear interactions between ISI and intensity. A source analysis was carried out consistent with prior work suggesting that when above vestibular threshold, in addition to bilateral superior temporal cortex, ocular, cerebellar and cingulate sources are recruited. Further statistical analysis of the source currents indicated that the origin of the interactions with intensity may be the ISI sensitivity of the vestibular-dependent sources. This in turn may reflect a specific vestibular preference for stimulus rates associated with locomotion, i.e. rates close to 2 Hz, or ISIs close to 500 ms, where saccular afferents show increased gain and the corresponding reflexes are most sensitive. PMID- 27498401 TI - Points of agreement and difference: A rejoinder to Fischer et al. PMID- 27498400 TI - Frequency discrimination in the common marmoset (Callithrix jacchus). AB - The common marmoset (Callithrix jacchus) is a highly vocal New World primate species that has emerged in recent years as a promising model system for studies of auditory and vocal processing. Our recent studies have examined perceptual mechanisms related to the pitch of harmonic complex tones in this species. However, no previous psychoacoustic work has measured marmosets' frequency discrimination abilities for pure tones across a broad frequency range. Here we systematically examined frequency difference limens (FDLs), which measure the minimum discriminable frequency difference between two pure tones, in marmosets across most of their hearing range. Results show that marmosets' FDLs are comparable to other New World primates, with lowest values in the frequency range of ~3.5-14 kHz. This region of lowest FDLs corresponds with the region of lowest hearing thresholds in this species measured in our previous study and also with the greatest concentration of spectral energy in the major types of marmoset vocalizations. These data suggest that frequency discrimination in the common marmoset may have evolved to match the hearing sensitivity and spectral characteristics of this species' vocalizations. PMID- 27498402 TI - Effect of temperature and water activity on growth and aflatoxin production by Aspergillus flavus and Aspergillus parasiticus on cured meat model systems. AB - Dry-cured hams may be colonised by aflatoxin-producing Aspergillus flavus and Aspergillus parasiticus during the ripening process. The objective of this study was to evaluate the interaction between non-ionic water stress and temperatures may have on lag phases prior to growth, growth rates and aflatoxin production by two strains of each A. parasiticus and A. flavus on meat matrices over a period of 12days. Results showed that A. flavus CBS 573.65 had shorter lag phases than A. parasiticus CECT 2688, however the growth rates were quite similar. For both species, no growth occurred at 10 degrees C and all aw tested and optimum growth happened at 25 degrees C and 0.95 aw. Similar aflatoxin B1 production profiles between both species were found, however A. flavus produced much higher concentration of such toxin than A. parasiticus. Both species produced aflatoxins when the temperature and the aw were >=15 degrees C and >=0.90. PMID- 27498404 TI - Expanding the view of breast cancer metabolism: Promising molecular targets and therapeutic opportunities. AB - The changes in breast cancer cells that contribute to tumor evolution, heterogeneity, metastasis and ultimately drug resistance are shaped by numerous genetic changes including alterations in cellular metabolism. These include intermediary metabolic pathways such as glycolysis, the citric acid cycle oxidative phosphorylation, amino acid synthesis and lipid metabolism. However, cancer cells also exhibit key alterations in other metabolic pathways involved in drug metabolism such as cytochrome P450 enzymes, sulfotransferase and steroid sulfatases that are involved in the synthesis of estrogens and themselves serve as drug targets. In this review we bring together these two sides of metabolism, discuss the evidence underpinning their role in breast cancer development and bring to light promising therapeutic targets and up and coming pharmacologic agents. PMID- 27498405 TI - The vascular adventitia: An endogenous, omnipresent source of stem cells in the body. AB - Until a decade ago it was believed that the wall of adult blood vessels exclusively contains terminally differentiated cell types. A paradigm shift was unavoidable since studies from different groups convincingly showed the presence of vascular wall-resident stem and progenitor cells (VW-SCs) which were identified to particularly reside in the sub-endothelial space and the so-called adventitial "vasculogenic zone". Data published during the last decade uncloaked the fact that VW-SCs have the capacity to differentiate into both vascular and non-vascular cell types. Up to date, little is known about the full capacity of VW-SCs, the exact composition of their endogenous niche and the mechanisms that govern their self-renewal, activation and differentiation. The aim of this review is to provide an overview about the current knowledge on VW-SCs and to highlight the impact of this endogenous niche on health and disease. In addition, we will discuss strategies how these adult stem cells could be manipulated in order to activate and expand them, ideally within their niche at sites of tissue damage and subsequently differentiate them into a desired cell type, e.g. an endothelial cell, a macrophage or a muscle cell. This would pave the way towards new pharmacological strategies for endogenous tissue repair and regeneration. PMID- 27498406 TI - Training motor responses to food: A novel treatment for obesity targeting implicit processes. AB - The present review first summarizes results from prospective brain imaging studies focused on identifying neural vulnerability factors that predict excessive weight gain. Next, findings from cognitive psychology experiments evaluating various interventions involving food response inhibition training or food response facilitation training are reviewed that appear to target these neural vulnerability factors and that have produced encouraging weight loss effects. Findings from both of these reviewed research fields suggest that interventions that reduce reward and attention region responses to high calorie food cues and increase inhibitory region responses to high calorie food cues could prove useful in the treatment of obesity. Based on this review, a new conceptual model is presented to describe how different cognitive training procedures may contribute to modifying eating behavior and important directions for future research are offered. It is concluded that there is a need for evaluating the effectiveness of more intensive food response training interventions and testing whether adding such training to extant weight loss interventions increases their efficacy. PMID- 27498407 TI - Expanding specificity of class I restricted CD8+ T cells for viral epitopes following multiple inoculations of swine with a human adenovirus vectored foot and-mouth disease virus (FMDV) vaccine. AB - The immune response to the highly acute foot-and-mouth disease virus (FMDV) is routinely reported as a measure of serum antibody. However, a critical effector function of immune responses combating viral infection of mammals is the cytotoxic T lymphocyte (CTL) response mediated by virus specific CD8 expressing T cells. This immune mechanism arrests viral spread by killing virus infected cells before new, mature virus can develop. We have previously shown that infection of swine by FMDV results in a measurable CTL response and have correlated CTL killing of virus-infected cells with specific class I major histocompatibility complex (MHC) tetramer staining. We also showed that a modified replication defective human adenovirus 5 vector expressing the FMDV structural proteins (Ad5 FMDV-T vaccine) targets the induction of a CD8+ CTL response with a minimal humoral response. In this report, we show that the specificity of the CD8+ T cell response to Ad5-FMDV-T varies between cohorts of genetically identical animals. Further, we demonstrate epitope specificity of CD8+ T cells expands following multiple immunizations with this vaccine. PMID- 27498408 TI - Characterization and functional studies of fowl adenovirus 9 dUTPase. AB - Deoxyuridine 5'-triphosphate pyrophosphatase (dUTPase), a ubiquitous enzyme that catalyzes the hydrolysis of dUTP to dUMP and found in many viruses, has yet to be identified in fowl adenovirus 9 (FAdV-9). By a multiple alignment of dUTPase amino acid sequences, FAdV-9 ORF1 contained the five conserved motifs that define the protein family, and encoded a functional dUTPase. Moreover, transcription and protein expression patterns were characterized, indicating that dUTPase was transcribed from 2h post-infection (h.p.i.) and translated from 6h.p.i., and both continued to the late phase of virus infection. An HA-tagged dUTPase recombinant virus was generated, and dUTPase was found to be localized in both the cytoplasm and nucleus in chicken hepatoma cells (CH-SAH). A dUTPase knockout virus was generated and compared with the wild-type virus, showing that dUTPase upregulated the expression of type I interferons, but was not required for viral DNA or virus replication in CH-SAH cells. PMID- 27498411 TI - Fusion of sparse representation and dictionary matching for identification of humans in uncontrolled environment. AB - Biomechanics based human identification is a major area of research. Biomechanics based approaches depend on accurately recognizing humans using body movements, the accuracy of these approaches is enhanced by incorporating the knee-hip angle to angle relationships. Current biomechanics based models are developed by considering the biomechanics of human walking and running. In biomechanics the joint angle characteristics, also known as gait features play a vital role in identification of humans. In general, identification of humans can be broadly classified into two approaches: biomechanics based approach, also known as Gait Recognition and biometric based Composite Sketch Matching. Gait recognition is a biomechanics based approach which uses gait traits for person authentication, it discriminates people by the way they walk. Gait recognition uses shape and motion information of a person and identifies the individual; this information is generally acquired from an image sequence. The efficiency of gait recognition is mainly affected by covariates such as observation view, walking speed, clothing, and belongings. Biometric based approach for human identification is usually done by composite sketch matching. Composite sketches are sketches generated using a computer. This obviates the need of using a skilled sketch artist; these sketches can be easily drawn by eyewitness using face design system software in a very short time period. This doesn't require any prior specialized software training but identifying humans using only composite sketches is still a challenging task owing to the fact that human faces are not always clearly visible from a distance. Hence drawing a composite sketch at all times is not feasible. The key contribution of this paper is a fusion system developed by combining biomechanics based gait recognition and biometric based composite sketch matching for identifying humans in crowded scenes. First various existing biomechanics based approaches for gait recognitionare developed. Then a novel biomechanics based gait recognition is developed using Sparse Representation to generate what we term as "score 1." Further another novel technique for composite sketch matching is developed using Dictionary Matching to generate what we term as "score 2." Finally, score level fusion using Dempster Shafer and Proportional Conflict Distribution Rule Number 5 is performed. The proposed fusion approach is validated using a database containing biomechanics based gait sequences and biometric based composite sketches. From our analysis we find that a fusion of gait recognition and composite sketch matching provides excellent results for real-time human identification. PMID- 27498409 TI - The absence of p53 during Human Cytomegalovirus infection leads to decreased UL53 expression, disrupting UL50 localization to the inner nuclear membrane, and thereby inhibiting capsid nuclear egress. AB - Our electron microscopy study (Kuan et al., 2016) found HCMV nuclear capsid egress was significantly reduced in p53 knockout cells (p53KOs), correlating with inhibited formation of infoldings of the inner nuclear membrane (IINMs). Molecular examination of these phenomena has found p53KOs expressed UL97 and phosphorylated lamins, however the lamina failed to remodel. The nuclear egress complex (NEC) protein UL50 was expressed in almost all cells. UL50 re-localized to the inner nuclear membrane (INM) in ~90% of wt cells, but only ~35% of p53KOs. UL53 expression was significantly reduced in p53KOs, and cells lacking UL50 nuclear staining, expressed no UL53. Re-introduction of p53 into p53KOs largely recovered UL53 positivity and UL50 nuclear re-localization. Nuclear rim located UL50/53 puncta, which co-localized with the major capsid protein, were largely absent in p53KOs. We believe these puncta were IINMs. In the absence of p53, UL53 expression was inhibited, disrupting formation of the NEC/IINMs, and reducing functional virion secretion. PMID- 27498410 TI - Human Cytomegalovirus nuclear egress and secondary envelopment are negatively affected in the absence of cellular p53. AB - Human Cytomegalovirus (HCMV) infection is compromised in cells lacking p53, a transcription factor that mediates cellular stress responses. In this study we have investigated compromised functional virion production in cells with p53 knocked out (p53KOs). Infectious center assays found most p53KOs released functional virions. Analysis of electron micrographs revealed modestly decreased capsid production in infected p53KOs compared to wt. Substantially fewer p53KOs displayed HCMV-induced infoldings of the inner nuclear membrane (IINMs). In p53KOs, fewer capsids were found in IINMs and in the cytoplasm. The deficit in virus-induced membrane remodeling within the nucleus of p53KOs was mirrored in the cytoplasm, with a disproportionately smaller number of capsids re-enveloped. Reintroduction of p53 substantially recovered these deficits. Overall, the absence of p53 contributed to inhibition of the formation and function of IINMs and re-envelopment of the reduced number of capsids able to reach the cytoplasm. PMID- 27498412 TI - Micro- and macro-metastasis in the axillary lymph node: A review. AB - Pathologists typically examine the sentinel lymph nodes excised from patients with invasive breast cancer more thoroughly than they have historically those from axillary lymph node clearance specimens. This, it is thought, increases the chances of detecting small metastatic foci (i.e. macrometastases (>2 mm), micrometastases (0.2-2 mm), or isolated tumour cell clusters (<0.2 mm or <200 cancer cells in one section)). However, the clinical significance of these small metastatic deposits remains unclear. Although an increasing nodal burden is known to proportionally decrease patient survival, the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial has, at the least, raised questions as to how best to manage nodal metastasis in early invasive breast cancer. These issues, and a brief overview of the biology of metastatic spread are presented in this review. PMID- 27498413 TI - Physical stability of R-(+)-Limonene emulsions stabilized by Ulva fasciata algae polysaccharide. AB - The physical stability of R-(+)-Limonene emulsions stabilized by Ulva fasciata polysaccharide (UFP) was investigated in this study. Emulsion physical stability was evaluated under different polysaccharide concentrations (1%-5%, wt/wt) and pH values (3.0-11.0). The stability of R-(+)-Limonene emulsions was demonstrated by droplet size distribution, rheological properties, zeta potential and visual phase separation. R-(+)-Limonene emulsions displayed monomodal droplet size distributions, high absolute values of zeta potential and good storage stability when 3% (wt/wt) UFP was used. The rheological properties and stability of R-(+) Limonene emulsions appeared to be dependent on polysaccharide concentration. The emulsion stability was impacted by pH. Higher zeta potential (-52.6mV) and smaller mean droplet diameter (2.45MUm) were achieved in neutral liquid environment (pH 7.0). Extreme acidity caused the flocculation of emulsions, which was manifested as phase separation, while emulsions were quite stable in an alkaline environment. Through comparing the stabilities of emulsions stabilized by different emulsifiers (i.e. UFP, GA and Gelatin), the result suggested that UFP was the best emulsifying agent among them. PMID- 27498414 TI - Polysaccharides from Pleurotus ostreatus alleviate cognitive impairment in a rat model of Alzheimer's disease. AB - This study was conducted to evaluate the effects of polysaccharides extracted from Pleurotus ostreatus (POP) on d-galactose and AlCl3-induced cognitive impairments. A behavioral test suggested that POP significantly decreased escape latency and increased crossing parameters of platform quadrant in a Morris water maze test. Furthermore, POP decreased error numbers and increased passive avoidance latency in a step-down test. Biochemical examinations revealed that POP significantly elevated superoxide dismutase, glutathione peroxidase, and catalase activities; and reduced malondialdehyde levels and acetylcholinesterase activity. Moreover, POP could decrease amyloid beta peptide formation and tau phosphorylation by elevating the expression of protein phosphatase 2A as well as by reducing the expression of amyloid precursor protein (APP), beta-site APP clearing enzyme1, and glycogen synthase kinase 3beta. These findings provide scientific evidence to support the exploitation of POP as a safe and effective drug to prevent and treat Alzheimer's disease. PMID- 27498415 TI - S-layer proteins from Lactobacillus sp. inhibit bacterial infection by blockage of DC-SIGN cell receptor. AB - Many species of Lactobacillus sp. possess Surface(s) layer proteins in their envelope. Among other important characteristics S-layer from Lactobacillus acidophilus binds to the cellular receptor DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin; CD209), which is involved in adhesion and infection of several families of bacteria. In this report we investigate the activity of new S-layer proteins from the Lactobacillus family (Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus helveticus and Lactobacillus kefiri) over the infection of representative microorganisms important to human health. After the treatment of DC-SIGN expressing cells with these proteins, we were able to diminish bacterial infection by up to 79% in both gram negative and mycobacterial models. We discovered that pre-treatment of the bacteria with S-layers from Lactobacillus acidophilus and Lactobacillus brevis reduced bacteria viability but also prevent infection by the pathogenic bacteria. We also proved the importance of the glycosylation of the S-layer from Lactobacillus kefiri in the binding to the receptor and thus inhibition of infection. This novel characteristic of the S-layers proteins may contribute to the already reported pathogen exclusion activity for these Lactobacillus probiotic strains; and might be also considered as a novel enzymatic antimicrobial agents to inhibit bacterial infection and entry to host cells. PMID- 27498416 TI - Novel nanocomposites with selective antibacterial action and low cytotoxic effect on eukaryotic cells. AB - In the present study we synthesized lignin-tetra ethoxysilane (TEOS) nanocomposite and characterized it using UV-spectroscopy, Fourier Transform Infra red spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), Field Emission Scanning Electron Microscopy (FE-SEM) and Scanning Electron Microscopy (SEM). XRD spectra and SEM micrographs confirmed a relatively high degree of crystallinity (peaks located at lower angle, 2theta=12 degrees and 2theta=22.0 degrees ) and porous nature of nanocomposite. The lignin-TEOS nanocomposites depicted antibacterial activity against the test microorganisms (Pseudomonas aerugenosa MTCC 741, Escherichia coli MTCC 739, Bacillus subtilis MTCC 441 and Staphylococcus aureus MTCC 96) whereas at the same concentration did not show any significant cytotoxicity against various tissue-specific cancer cell lines such as breast cancer: MCF-7, MDA-MB-231, MDA-MB-468, BT-549; lung cancer: A-549; prostate cancer: PC-3, Du-145; as well as primary control cells-Human hepatic stellate cells (HHSteCs). The present study suggests the plausible translational role of these nanocomposites as an antimicrobial agent for wound dressings due to its potent antimicrobial activity with low toxicity to non-target eukaryotic cells. Nevertheless, these nanocomposites may also be used as packaging materials due to their antimicrobial activity. PMID- 27498417 TI - Adsorption and intercalation of low and medium molar mass chitosans on/in the sodium montmorillonite. AB - Chitosan-montmorillonite composites can provide hydrophobicity and amino groups to enhance the performances of montmorillonite in wastewater treatment. In this paper, low molar mass chitosan (LC) and medium molar mass chitosan (MC) were selected to intercalate a sodium montmorillonite (Mt). The adsorption isotherm of LC and MC on the Mt and the pH dependency were measured. Thermo X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) were used to characterize the chitosan-Mt composites. Results showed that with hydrochloric acid as the solvent of chitosans, increasing pH from 3 to 5.5 enhanced the adsorption of both LC and MC on the Mt, and when the equilibrium concentration of chitosans approached 300mg/L at pH 5.5, the amount of adsorbed chitosan reached the highest level of 0.203mg/mg for LC and 0.190mg/mg for MC, respectively. When the Mt was saturated with the chitosan, the amino groups on the chitosan were bonded with the Mt through electrostatic interaction and there was monolayer of the chitosan in the interlayer space of Mt, which were confirmed by FTIR spectra and XRD patterns, respectively. PMID- 27498418 TI - Fgf23 and parathyroid hormone signaling interact in kidney and bone. AB - Fibroblast growth factor-23 (FGF23) is a bone-derived hormone, suppressing renal phosphate reabsorption and vitamin D hormone synthesis in proximal tubules, and stimulating calcium reabsorption in distal tubules of the kidney. Here, we analyzed the long term sequelae of deficient Fgf23 signaling on bone and mineral metabolism in 9-month-old mice lacking both Fgf23 or Klotho and a functioning vitamin D receptor (VDR). To prevent hypocalcemia in VDR deficient mice, all mice were kept on a rescue diet enriched with calcium, phosphate, and lactose. VDR mutants were normocalcemic and normophosphatemic, and had normal tibial bone mineral density. Relative to VDR mutants, Fgf23/VDR and Klotho/VDR compound mutants were characterized by hypocalcemia, hyperphosphatemia, and very high serum parathyroid hormone (PTH). Despite ~10-fold higher serum PTH levels in compound mutants, urinary excretion of phosphate and calcium as well as osteoclast numbers in bone remained unchanged relative to VDR mutants. The increase in plasma cAMP after hPTH(1-34) injection was similar in all genotypes. However, a 5-day infusion of hPTH(1-34) via osmotic minipumps resulted in reduced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in bone and kidney of Fgf23/VDR and Klotho/VDR compound mutants, relative to VDR and WT controls. Similarly, the PTH-mediated ERK1/2 phosphorylation was reduced in primary osteoblasts isolated from Fgf23 and Klotho deficient mice, but was restored by concomitant treatment with recombinant FGF23. Collectively, our data indicate that the phosphaturic, calcium-conserving, and bone resorption stimulating actions of PTH are blunted by Fgf23 or Klotho deficiency. Hence, FGF23 may be an important modulator of PTH signaling in bone and kidney. PMID- 27498420 TI - Hypothalamus and thermogenesis: Heating the BAT, browning the WAT. AB - Brown adipose tissue (BAT) has been also considered as the main thermogenic organ responsible of maintenance body temperature through heat production. However, a new type of thermogenic fat has been characterized during the last years, the beige or brite fat, that is developed from white adipose tissue (WAT) in response to different stimuli by a process known as browning. The activities of brown and beige adipocytes ameliorate metabolic disease, including obesity in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease. The hypothalamus is the main central place orchestrating the outflow signals that drive the sympathetic nerve activity to BAT and WAT, controlling heat production and energy homeostasis. Recent data have revealed new hypothalamic molecular mechanisms, such as hypothalamic AMP-activated protein kinase (AMPK), that control both thermogenesis and browning. This review provides an overview of the factors influencing BAT and WAT thermogenesis, with special focus on the integration of peripheral information on hypothalamic circuits controlling thermoregulation. PMID- 27498419 TI - Celecoxib treatment of fibrous dysplasia (FD) in a human FD cell line and FD-like lesions in mice with protein kinase A (PKA) defects. AB - Osteochondromyxomas (OMX) in the context of Carney complex (CNC) and fibrous dysplasia (FD)-like lesions (FDLL) in mice, as well as isolated myxomas in humans may be caused by inactivation of PRKAR1A, the gene coding for the type 1a regulatory subunit (R1alpha) of cAMP-dependent protein kinase (PKA). OMXs and FDLL in mice lacking Prkar1a grow from abnormal proliferation of adult bone stromal cells (aBSCs). Prkar1a and Prkaca (coding for Calpha) haploinsufficiency leads to COX2 activation and prostaglandin E2 (PGE2) production that, in turn, activates proliferation of aBSCs. Celecoxib is a cyclooxygenase-2 (COX2) inhibitor. We hypothesized that COX-2 inhibition may have an effect in FD and FDLL. In vitro treatment of a human cell line prepared from a FD patient with Celecoxib resulted in decreased PGE2 and cell proliferation. Treatment of mice haploinsufficient for R1alpha and Calpha with 1500 mg/kg Celecoxib led to decreased PGE2 and proliferation and increased apoptosis, with a corresponding gene expression profile, resulting in dramatic reduction of tumor growth. Furthermore, the treatment improved the organization of cortical bone that was adjacent to the tumor. We conclude that, in vitro and in vivo, Celecoxib had an inhibitory effect on FD cell proliferation and in mouse FDLL structure, respectively. We speculate that COX-2 inhibitors offer an attractive alternative to current treatments for benign tumors such as OMX and FD that, apart from tumor suppression, may mechanically stabilize affected bones. PMID- 27498421 TI - Increased prevalence of human cutaneous leishmaniasis in Israel and the Palestinian Authority caused by the recent emergence of a population of genetically similar strains of Leishmania tropica. AB - Twelve unlinked microsatellite markers were used to determine the microsatellite profiles of 50 newly and 46 previously typed strains of L. tropica from various Israeli and Palestinian foci. Their microsatellite profiles were compared to those of 99 previously typed strains of L. tropica from 15 countries. Israeli and Palestinian strains of L. tropica fell into three different groups, one of which contained 75 of the 96 Israeli and Palestinian strains. This population separated from all the others at the first hierarchical level by Bayesian statistics and formed a distinct monophyletic group on applying genetic distance and allele frequency analyses. The second cluster contained ten Israeli strains from a specific focus north of the Sea of Galilee, which were previously shown to differ from all other strains of L. tropica in their serological, biochemical and molecular biological parameters. This cluster was closely related to clusters comprising strains of L. tropica from Africa. Four Israeli and five Palestinian strains fell into different genetic entities mostly related to strains from Asian foci of CL. Importation during numerous migrations of humans and, perhaps, infected reservoir animals in the past and, now, through modern travel is the most likely explanation for the existence of so many locally encountered genetic variants of L. tropica in the Israeli-Palestinian region. Geographical and ecological variation may play a role in expanding the genetic heterogeneity once given importations had become established in different foci. Currently, one population is expanding in the area comprising almost all of the Palestinian and Israeli strains of L. tropica isolated since 1996 and investigated in this study, which differ clearly from all other strains of whatsoever origin. This population seems to result from the re-emergence of a previously existing genotype owing to environmental changes and human activities. PMID- 27498422 TI - Prediction of cyclic delamination lives of plasma-sprayed hydroxyapatite coating on Ti-6Al-4V substrates with considering wear and dissolutions. AB - This study aims at developing the prediction model of cyclic delamination lives of plasma-sprayed HAp coating on Ti-6Al-4V substrate by considering wear by interface contacts and dissolution effect by Simulated Body Fluid (SBF). Delamination of HAp coating can lead to loosening of implants stem and final failure in vivo. In the fracture mechanism of interfaces between HAp coating with Ti substrates, only adhesive strength (interracial tensile strength) or fatigue behavior by longitudinal cracking have been observed. Cyclic delamination mechanism by considering various loading modes and corrosion effect has not been revealed yet. The interface delamination rates by cyclic loading were much higher than those by static loading tests. The result clearly demonstrated that the interface demalination behaviors are dominated not by maximum stress, but by stress range. Surface profile measurement and SEM observation also demonstrated damages by interface contact or third body wear at delamination tips of HAp coating only in the cases of compressions. The mechanisms of acceleration on the delaminations are third-body wear or wedge effect by worn particles which increased mean stress level during cyclic loading. Cyclic loading tests under SBF also revealed that cyclic delamination lives were shortened probably due to crevice corrosion at interfaces. Dissolutions at the tips of delaminations were observed by SEM images under tensile loading condition in SBF. Linearly adding the effects of wear and dissolutions into Paris law could successfully predict the delamination lives of HAp coating for various loading ratios in SBF. PMID- 27498423 TI - Giant panda's tooth enamel: Structure, mechanical behavior and toughening mechanisms under indentation. AB - The giant panda's teeth possess remarkable load-bearing capacity and damage resistance for masticating bamboos. In this study, the hierarchical structure and mechanical behavior of the giant panda's tooth enamel were investigated under indentation. The effects of loading orientation and location on mechanical properties of the enamel were clarified and the evolution of damage in the enamel under increasing load evaluated. The nature of the damage, both at and beneath the indentation surfaces, and the underlying toughening mechanisms were explored. Indentation cracks invariably were seen to propagate along the internal interfaces, specifically the sheaths between enamel rods, and multiple extrinsic toughening mechanisms, e.g., crack deflection/twisting and uncracked-ligament bridging, were active to shield the tips of cracks from the applied stress. The giant panda's tooth enamel is analogous to human enamel in its mechanical properties, yet it has superior hardness and Young's modulus but inferior toughness as compared to the bamboo that pandas primarily feed on, highlighting the critical roles of the integration of underlying tissues in the entire tooth and the highly hydrated state of bamboo foods. Our objective is that this study can aid the understanding of the structure-mechanical property relations in the tooth enamel of mammals and further provide some insight on the food habits of the giant pandas. PMID- 27498424 TI - Characterization and investigation of the deformation behavior of porous magnesium scaffolds with entangled architectured pore channels. AB - We report a kind of porous magnesium with entangled architectured pore structure for potential applications in biomedical implant. The pore size, spatial structure and Young's modulus of the as-prepared porous Mg are suitable for bone tissue engineering applications. Particularly, with regard to the load-bearing conditions, a new analytical model is employed to investigate its structure and mechanical response under compressive stress based on Gibson-Ashby model. It is found that there are three types of stress-strain behaviors in the large range of porosity from 20% to 80%. When the porosity is larger than an upper critical value, the porous magnesium exhibits densifying behavior with buckling deformation mechanism. When the porosity is smaller than a lower critical value, the porous magnesium exhibits shearing behavior with cracking along the maximum shear stress. Between the two critical porosities, both the buckling deformation and shearing behavior coexist. The upper critical porosity is experimentally determined to be 60% for 270MUm pore size and 62% for 400MUm pore size, while the lower critical porosity is 40% for 270MUm pore size and 42% for 400MUm pore size. A new analytical model could be used to accurately predict the mechanical response of the porous magnesium. No matter the calculated critical porosity or yielding stress in a large range of porosity by using the new model are well consistent with the experimental values. All these results could help to provide valuable data for developing the present porous magnesium for potential bio applications. PMID- 27498425 TI - PLA-grafting of collagen chains leading to a biomaterial with mechanical performances useful in tendon regeneration. AB - With the aim to obtain a scaffold with improved mechanical properties with respect to collagen for tendon augmentation and regeneration, a novel collagen based material was prepared via heterogeneous phase derivatization of type I collagen sponges using polylactic acid. Compared to the untreated collagen, the functionalized sponge (Coll-PLA) was characterized by higher tensile properties and lower swelling capability; the degradation rate of Coll-PLA, in the presence of collagenase, was lower than that of the untreated collagen sponge. These results are related to an increased hydrophobic character of the collagen matrix due to the presence of PLA chains. In vitro tests, performed with human primary fibroblasts, showed that cell adhesion and proliferation rate on Coll-PLA were comparable to those obtained with the non-functionalized collagen. These findings suggest that the new biomaterial could be suitable as scaffold in tendon augmentation and regeneration. PMID- 27498426 TI - Rheological, mechanical and degradable properties of injectable chitosan/silk fibroin/hydroxyapatite/glycerophosphate hydrogels. AB - Silk fibroin (SF) and hydroxyapatite (HA) were incorporated into chitosan/glycerophosphate (GP) system to prepare new types of hydrogels. The formulated chitosan/SF/GP and chitosan/SF/HA/GP solutions were found to be injectable at room temperature, and able to form into hydrogels at near physiological temperature and pH. Rheological measurements showed that elastic modulus of certain chitosan/SF/GP and chitosan/SF/HA/GP gels could reach around 1.8 and 15kPa, respectively, and was much higher than their respective viscous modulus. Compressive measurements revealed that some chitosan/SF/GP and chitosan/SF/HA/GP gels had 8 and 20-fold modulus and strength higher than the chitosan/GP gel, respectively, confirming that compressive properties of these gels were greatly improved. Results obtained from in vivo degradation demonstrated that degradation endurance of the optimized chitosan/SF/GP and chitosan/SF/HA/GP gels was significantly enhanced as compared to the chitosan/GP gel, and the degradation rate of the gels could be regulated by the SF component alone or by the combination of SF and HA components. PMID- 27498427 TI - Fracture characteristics of PEEK at various stress triaxialities. AB - Polyether-ether-ketone (PEEK) is an alternative to metal alloys in orthopaedic applications. It gives significant advantages including excellent mechanical properties and non-toxicity. In this work, a set of specimens with different notched radii were selected to examine the effect of triaxial state of stress on the fracture behavior of PEEK. Fractographic analysis via scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX) further elucidated the fracture micromechanisms. Distinct fracture patterns were identified under different stress triaxialities. In addition, the microstructural inclusion properties in PEEK specimen such as inclusion size and chemical composition were analysed and determined. Finite element simulations were carried out to evaluate the correlation of observed fracture characteristics with different stress triaxialities. PMID- 27498428 TI - [Not Available]. PMID- 27498429 TI - Update on vaccine-derived polioviruses worldwide, January 2015-May 2016. PMID- 27498430 TI - Environmental isolation of circulating vaccine-derived poliovirus after interruption of wild poliovirus transmission, Nigeria, 2016. PMID- 27498431 TI - Response. PMID- 27498432 TI - Those were the days.... PMID- 27498433 TI - Letter to the editor. PMID- 27498434 TI - Leadership and change will bring us resilience. PMID- 27498435 TI - Introduction of revalidation for nurses and midwives a major success. PMID- 27498436 TI - So, you think you would like to publish? PMID- 27498437 TI - A pathway to clinician-led culture change in the operating theatre. PMID- 27498438 TI - Surgical safety checklists briefings: Perceived efficacy and team member involvement. AB - Researchers have shown inconsistencies in compliance, outcomes and attitudes of surgical team members related to surgical safety checklist briefings. The purpose of this study was to examine surgical circulator and scrub practitioners' perceptions of safety checklist briefings and team member involvement, and to identify potential improvements in the process based on those perceptions. An anonymous survey was conducted with members of the Association of periOperative Registered Nurses (AORN) and the Association of Surgical Technologists (AST). Questions focused on perceptions of checklist briefing efficacy and team member involvement in safety practices. From the 346 usable responses, a third respondent group of self-identified perioperative leaders emerged. Significant results were obtained related to leaders' perceptions, post-procedure briefings and various perceptions of team member involvement. Study results indicate that variances in safety practices continue as perceived by surgical team members thus presenting opportunities for further examination and improvement of processes in reducing surgical errors. PMID- 27498439 TI - One step closer to safer surgery--The National Safety Standards for Invasive Procedures (NatSIPPs). PMID- 27498441 TI - Consenting patients with femoral neck fractures--how well are we involving the patient's relatives? AB - The consent process is a vital part of the in-patient journey for patients admitted with a fractured neck of femur. However, an aspect that is frequently over-looked is the involvement of a patient's next of kin. We organised a pilot study in our institution to see what steps we could take to make improvements in the way that next of kin involvement was managed, in line with widespread national guidelines. PMID- 27498440 TI - Nursing postoperative visit as a quality indicator for surgical patient care. AB - The postoperative visit as a quality indicator for surgical patient care, demands some consideration from perioperative nurses. We evaluated the nursing perioperative interventions on postoperative visits, and adjusted them to the needs of the patients with postoperative pain. Our study indicated that 73% of patients visited didn't have postoperative pain whereas 27% had pain. The pain is aggravated when the patient is mobilised, one of the most common signs and symptoms being gastrointestinal changes. Pharmacological and non-pharmacological measures were used in pain management. The results showed that the percentage of patients with postoperative visits needs to be improved. We aim to have high quality perioperative nursing interventions which raise levels of patient satisfaction. PMID- 27498442 TI - Leucocyte count indicates carotid plaque instability in stroke patients. AB - BACKGROUND/AIM: Increasing evidence points to the inflammatory character of atherosclerosis and several parameters of inflammation have been proposed as cerebrovascular risk markers. The objective of the research was to examine the connection of serum inflammatory parameters and ultrasound (US) characteristics of the structure and size of carotid plaque. We assumed that the number of leukocytes (Le) was an indicator of carotid plaque instability and an increased risk of stroke. METHODS: Serum inflammatory parameters: erythrocyte sedimentation rate in the first (ESR I) and second hour (ESR II), the number of Le, high sensitivity C-reactive protein (hsCRP) and fibrinogen were measured by standard methods. All the subjects (n = 75) were divided into 3 groups (symptomatic, asymptomatic and control). US evaluation of extracranial carotid arteries was performed in a duplex system. Plaques were classified into categories according to stenosis percentage (>= 50%, < 50%) and pursuant to echomorphological characteristics (Gray-Weale classification). In the subjects with stroke an ischemic lesion was confirmed by computed tomography. RESULTS: The average values of biochemical parameters in the symptomatic group were: ESR I 29.57 +/- 29.87 cm, ESR II 51.60 +/- 36.87 cm, the number of Le 10.10 +/- 3.20 x 109 U/L, hsCRP 8.15 +/- 5.50 mg/L and fibrinogen 4.03 +/- 0.70 g/L. The average values of all testing biochemical parameters in symptomatic patients were significantly higher than in the asymptomatic ones and the control group: for ESR I (p < 0.05) and ESR II (p < 0.05); for the number of Le (p < 0.001); for hsCRP (p < 0.001) and fibrinogen (p < 0.001). Category I of echomorphological characteristics in the symptomatic group was present in 66.7% of the cases and it was significantly higher than in the asymptomatic (40.0%; p < 0.05) and the control group (20.0%; p < 0.01). Univariate logistic regression analysis confirmed that all testing biochemical parameters are indicators of stroke risk. Multivariate logistic regression analysis confirmed a statistically significant correlation of the number of Le and stroke risk, while the increase in the value by a unit of measurement was associated with the growth of risk by 3.22 times (from 1.67 to 6.22). CONCLUSION: The number of Le is associated with the phenomenon of carotid plaque instability and may be a useful additional marker of increased risk for developing acute cerebral infarction. PMID- 27498443 TI - Comparison of cefixime and amoxicillin plus metronidazole in the treatment of chronic periodontitis. AB - BACKGROUND/AIM: Despite significant advances in current medicine and improvement of overall health education, chronic periodontitis is still a widespread disease. Losing teeth is the most serious complication of this particular illness. The aim of this study was to examine patients with chronic periodontitis in order to evaluate the efficacy of non-surgical therapy and combination of amoxicillin and metronidazole compared with cefixime, which has not been so far used for the treatment of this disease. METHODS: Adult patients with chronic periodontitis (n = 90) underwent non-surgical periodontal treatment (zero-day) and then randomly divided into three groups. The group I served as a control, the group II was additionally treated with the combination of amoxicillin and metronidazole (for 7 days), while the group III was treated with cefixime (also for 7 days). To assess the condition of periodontium before and seven days after the therapy, four clinical parameters were used: gingival index (GI), bleeding on probing (BOP), probing depth (PD) and clinical attachment level (CAL). RESULTS: On the day 7 after the beginning of the therapy, we found that all the three groups of patients had statistically significant clinical improvement of three parameters: GI, BOP and PD, but not of the CAL. However, the improvement of PD was only statistically, but not clinically significant. The improvement in the control group of patients on the day 7 was 19% in BOP and 28% in GI; this improvement was statistically highly significant after the addition of amoxicillin plus metronodazole (71% in BOP and 77% in GI) or cefixime (62% in BOP and 82% in GI). Compared to the combination of amoxicillin and metronidazole, cefixim was statistically significantly more effective for GI (p < 0.05), while for the other three clinical parameters their effects were equal. CONCLUSION: The conjunction of amoxicillin plus metronidazole or cefixime to the causal treatment of patients with chronic periodontitis led to statistically significant improvement in efficacy in relation to GI and BOP parameters, while cefixime was statistically significantly more efficient than the combination of amoxicillin and metronidazole for GI. PMID- 27498445 TI - Modelling and assessment of the electric field strength caused by mobile phone to the human head. AB - BACKGROUND/AIM: Electromagnetic field exposure is the one of the most important physical agents that actively affects live organisms and environment. Active use of mobile phones influences the increase of electromagnetic field radiation. The aim of the study was to measure and assess the electric field strength caused by mobile phones to the human head. METHODS: In this paper the software "COMSOL Multiphysics" was used to establish the electric field strength created by mobile phones around the head. RESULTS: The second generation (2G) Global System for Mobile (GSM) phones that operate in the frequency band of 900 MHz and reach the power of 2 W have a stronger electric field than (2G) GSM mobile phones that operate in the higher frequency band of 1,800 MHz and reach the power up to 1 W during conversation. The third generation of (3G) UMTS smart phones that effectively use high (2,100 MHz) radio frequency band emit the smallest electric field strength values during conversation. The highest electric field strength created by mobile phones is around the ear, i.e. the mobile phone location. The strength of mobile phone electric field on the phantom head decreases exponentially while moving sidewards from the center of the effect zone (the ear), and constitutes 1-12% of the artificial head's surface. CONCLUSION: The highest electric field strength values of mobile phones are associated with their higher power, bigger specific energy absorption rate (SAR) and lower frequency of mobile phone. The stronger electric field emitted by the more powerful mobile phones takes a higher percentage of the head surface. The highest electric field strength created by mobile phones is distributed over the user's ear. PMID- 27498444 TI - Patterns of prescription antihypertensive drug utilization and adherence to treatment guidelines in the city of Novi Sad. AB - BACKGROUND/AIM: Hypertension is one of the leading causes of cardiovascular morbidity and mortality and more than a half of all health insurance expenditures for reimbursed medicines are allocated to antihypertensive drugs in Serbia. The aim of this study was to identify the antihypertensive drug utilization patterns among hypertensive outpatients in the city of Novi Sad, Serbia, determine the adherence to clinical guidelines and address the economic aspects of current prescribing practices. METHODS: This retrospective observational study was conducted in Novi Sad over a period of six months. The data on the number of packages, size their, and retail price of antihypertensives issued on prescription in outpatients with the diagnosis of essential arterial hypertension was collected from all state-owned pharmacies in Novi Sad. Drug consumption was analyzed using the Anatomical Therapeutic Chemical (ATC)/ defined daily dose (DDD) methodology. RESULTS: Total consumption of antihypertensives issued on prescription over a 6-month period in the city of Novi sad, Serbia was 283.48 DDD per 1,000 inhabitans per day (DID). Angiotensin converting enzyme inhibitors (ACEi) were most commonly prescribed drugs, and were used 3 times more often than calcium channel blockers and 5 times more than beta-blockers. The consumption of diuretics and angiotensin receptor antagonists was low within all the groups of outpatients. Both national and international guidelines state superiority and effectiveness of diuretics in treatment of hypertension in the elderly, but their consumption was unreasonable low despite the fact that over 70% of all antihypertensive drugs in the city of Novi Sad were dispensed in people aged > 60. The use of more expensive ACEi was observed despite the guidelines deeming all the drugs of this class equally effective in treatment of hypertension. CONCLUSION: Large differences in utilization of different groups of antihypertensive agents were noted in this study. Underutilization of valuable, efficacious, and cost-effective thiazide diuretics and overuse of expensive ACE inhibitors is unjustifiable. There is a potential for large savings with switching to low-price ACEi, modeling the practice of Scandinavian countries. PMID- 27498446 TI - Marketing communication in the area of breast and cervical cancer prevention. AB - BACKGROUND/AIM: Innovative marketing campaigns and promotional activities can successfully contribute to the improvement of public health by raising the level of general knowledge about health issues and benefits that the change of habits, eradication of undesirable behaviour and regular medical controls have. The focus should be on continuous marketing communication through various mass media or direct communication between medical staff and patients. The aim of this paper was to define the role that various communication channels have in the process of informing and educating the target group in case of breast and cervical cancer prevention. METHODS: The survey based on polling a sample of 2,100 female patients of the Serbian Railways Medical Centre was conducted in the period October- December 2013. The questionnaire included questions about demographic characteristics, prevention habits of women, their level of information on that topic and communication channels they prefer. RESULTS: There is a difference among respondents' awareness level about preventive measures depending on demographic and geographical criteria. The results indicate the existence of variations in frequency of performing gynaecological examinations and Pap tests depending on different age, educational and residential groups. Although the largest percentage of women stated familiarity with the way of performing breast self-examination (78%), the majority of them had never performed mammography or ultrasonography (67%). The greatest number of women were informed about the possibility of preventing breast and cervical cancer by posters or brochures in health institutions (71%) and mass media--television on the first place (74%), then specialized magazines about health (48%), radio (48%), web sites about health (42%), and daily newspapers (34%). The respondents consider the Ministry of Health and health institutions as the most responsible subjects for education of women about cancer prevention, while the self-initiative was given the least importance. CONCLUSION: Determined informing habits of the target group, their prevention habits and attitudes on the subject should be used as the basis for planning and implementation of prevention marketing campaigns that would be the most effective. PMID- 27498447 TI - Fever of unknown origin--diagnostic methods in a European developing country. AB - BACKGROUND/AIM: Fewer of unknown origin (FUO) remains amongst the most difficult diagnostic dilemmas in contemporary medicine. The aim of this study was to determine the causes of FU and to identify the methods of diagnosis in patients with FUO in a tertiary care setting in the Republic of Macedonia. METHODS: Retrospectively histories of 123 immunocompetent patients older than 14 years with classical FUO that had been examined at the University Hospital for Infectious Diseases and Febrile Conditions in the city of Skopje, during the period 2006-2012 were evaluated. FUO was defined as axillary fever of >= 37.5 degrees C on several occasions, fever duration of more than 21 days and failure to reach the diagnosis after the initial diagnostic workup comprised of several defined basic investigations. RESULTS: Infections were the cause of FUO in 51 (41.5%) of the patients, followed by non-infective inflammatory disorders (NIID) in 28 (22.8%), miscellaneous in 12 (9.7%) and neoplasm in 11 (8.9%) of the patients. Twenty one of the patients (17.1%) remained undiagnosed. The most common causes for FUO were visceral leishmaniasis, abscesses, urinary tract infections, subacute endocarditis, polymyalgia rheumatica and adult onset of Still disease. The final diagnosis was reached with histology in 24 (23.5%), imaging and endoscopic procedures in 21 (20.6%), clinical course and empiric therapy response in 20 (19.6%), serology in 18 (17.6%) and cultures in 16 (15.7%) of the cases. CONCLUSION: In the Republic of Macedonia infections are the leading cause of FUO, predominately visceral leishmaniasis. In the future in patients with prolonged fever, physicians should think more often of this disease, as well as of the possibility of atypical presentation of the common classical causes of FUO. PMID- 27498448 TI - Quantitative morphometric analysis of the myenteric nervous plexus ganglion structures along the human digestive tract. AB - BACKGROUND/AIM: All the functions of the digestive system are controlled, guided and initiated by the autonomic nervous system. A special part of this system placed in the wall of the gastrointestinal tract is known as the enteric or metasympathetic nervous system. The aim of this study was to analyse myenteric nervous plexus in different parts of the digestive tract. METHODS: We examined the myenteric nervous plexus of the esophagus, stomach, duodenum, jejunum, ileum, transverse colon and rectum in tissue samples taken from 30 cadavers of persons aged 20-84 years. After standard histological processing sections were stained with hematoxylin-eosin, cresyl violet (CV) and AgNO3 method. Multipurpose test system M42 was used in morphometric analysis. The results were analyzed by t-test and analysis of variance. RESULTS: The number of neurons per cm2 surface was the lowest in the esophagus (2.045 +/- 310.30) and the largest in the duodenum (65,511 +/- 5,639). The statistical processing showed significant differences (P < 0.001) in the number of neurons between the esophagus and all other parts of the digestive tract. The maximal value of the average surface of the myenteric nervous plexus neurons was observed in the esophagus (588.93 +/- 30.45 um2) and the lowest in the stomach (296.46 +/- 22.53 um2). CONCLUSION: There are differences in the number of ganglion cells among different parts of the human digestive tract. The differences range from a few to several tens of thousands of neuron/cm2. The myenteric nervous plexus of the esophagus was characterized by a significantly smaller number of neurons but their bodies and nuclei are significantly larger compared to other parts of the digestive tract. PMID- 27498449 TI - Efficacy of external warming in attenuation of hypothermia in surgical patients. AB - BACKGROUND/AIM: Hypothermia in surgical patients can be the consequence of long duration of surgical intervention, general anaesthesia and low temperature in operating room. Postoperative hypothermia contributes to a number of postoperative complications such as arrhythmia, myocardial ischemia, hypertension, bleeding, wound infection, coagulopathy, and prolonged effect of muscle relaxants. External heating procedures are used to prevent this condition. The aim of this study was to evaluate the efficiency of external warming system in alleviation of cold stress and hypothermia in patients who underwent major surgical procedures. METHODS: The study was conducted in the Military Medical Academy in Belgrade. A total of 30 patients of both genders underwent abdominal surgical procedures, randomly divided into two equal groups: the one was externally warmed using warm air mattress (W), while in the control group (C) surgical procedure was performed in regular conditions, without additional warming. Oesophageal temperature (Te) was used as indicator of changes in core temperature, during surgery and awakening postoperative period, and temperature of control sites on the right hand (Th) and the right foot (Tf) reflected the changes in skin temperatures during surgery. Te and skin temperatures were monitored during the intraoperative period, with continuous measurement of Te during the following 90 minutes of the postoperative period. Heart rates and blood pressures were monitored continuously during the intraoperative and awakening period. RESULTS: In the W group, the average Te, Tf and Th did not change significantly during the intraoperative as well as the postoperative period. In the controls, the average Te significantly decreased during the intraoperative period (from 35.61 +/- 0.35 degrees C at 0 minute to 33.86 +/- 0.51 degrees C at 120th minute). Compared to the W group, Te in the C group was significantly lower in all the observed periods. Average values of Tf and Th significantly decreased in the C group (from 30.83 +/- 1.85 at 20th minute to 29.0 +/- 1.39 degrees C at 120th minute, and from 32.75 +/- 0.96 to 31.05 +/- 1.09 degrees C, respectively). CONCLUSION: The obtained results confirm that the external warming using warm air mattress was able to attenuate hypothermia, i.e. substantial decrease in core temperature, compared with the similar exposure to cold stress in the control group. PMID- 27498450 TI - The assessment of the stability of the corneal structure after LASIK correction of myopia by different optical zone diameters. AB - BACKGROUND/AIM: Enlargement of optical zone (OZ) diameter during laser in situ keratomileusis (LASIK) correction of myopia postoperatively improves the optical outcome, however, it also leads to the increased stroma tissue consumption- progressive corneal thinning. The aim of this investigation was to present the possibility of safe OZ enlargement without impairing the structural stability of the cornea, while obtaining an improved optical outcome with LASIK treatment of short-sightedness. METHODS: Preoperative assessment of the cornea structure and prediction of the ablated stroma tissue consumption was conducted in 37 patients (74 eyes) treated for short-sightedness by means of the LASIK method. With the eyes that, according to their cornea structure, had the capacity for OZ diameter enlargement of 0.5 mm, LASIK treatment was performed within the wider OZ diameter of 7.0 mm compared to the standard 6.5 mm. The following two groups were formed, depending on the diameter of the utilized OZ: the group I (the eyes treated with the OZ 6.5 mm, n = 37) and the group II (the eyes treated with the OZ 7.0 mm, n = 37). RESULTS: No significant difference in the observed structural parameters of the cornea was detected between the groups of patients treated with different OZ diameters. The values of all the parameters were significantly bellow the threshold values for the development of postoperative ectasia. CONCLUSION: Diameter enlargement of the treated OZ, if there is a preoperative cornea capacity for such enlargement, will not impair the postoperative stability of the cornea structure, and will significantly improve the optical outcome. PMID- 27498451 TI - New metaphysics in Serbian rehabilitation medicine. PMID- 27498452 TI - Pheochromocytoma of the urinary bladder--A case report. AB - INTRODUCTION: Pheochromocytoma of the urinary bladder is a rare tumor and presents less than 0.06% of all urinary bladder tumors. CASE REPORT: We presented a 49-year-old female patient with a history of daily paroxysmal hypertension accompanied with flushing of the face and upper chest, palpitations and excessive sweating prior to micturition. Ultrasonography reported a 3 cm bladder wall tumor. The 131I-metaiodobenzylguanidine (131I-MIBG) scan showed a pathological isotope accumulation in the projection of the bladder. The patient underwent a partial cystectomy. One year following the operation the patient was normotensive and without recurrence. CONCLUSION: The most efficient treatment option for bladder pheochromocytoma is surgical resection. The most important fact in the diagnostics is suspicion on this rare condition. PMID- 27498453 TI - A series of drawings of a patient with schizophrenia-like psychosis associated with epilepsy: captured illustration of multifaced self- expression. AB - INTRODUCTION: Drawings may give an insight into the complex mental process, however they have been underutilized in patients with psychosis associated with epilepsy. CASE REPORT: A 33-year-old, right handed female, diagnosed with schizophrenia-like psychosis associated with epilepsy, was treated in the Day Unit due to psychosocial rehabilitation. Besides other treatments, the patient underwent group analysis of drawings once a week. Qualitative analysis of the form and content of drawings made by free associations were performed. The varying of size and motives with vivid colours and the curve of perspective were documentated in three figures, followed by the last drawing which was without such elements. CONCLUSION: A series of drawings of patients with psychosis associated with epilepsy is needed to record a possible variations and disturbance of the immediate mental process. Group sessions may additionally contribute to diminish stigma and enhance psychosocial reintegration. PMID- 27498454 TI - Clinical use of optical coherence tomography and fractional flow reserve. AB - INTRODUCTION: The aim of each diagnostic method is to serve as a guide in deciding about the right patient treatment. During myocardial revascularization the decision to perform revascularization is usually not easy to make, especially in case of borderline stenosis. It has been proven that it is not enough to base morphological evaluation of coronary artery vessel stenosis solely on angiography. It is necessary to include additional modern diagnostic methods for functional analysis and detailed morphological analysis using fractional flow reserve (FFR) and optical coherence tomography (OCT), respectively. CASE REPORTS: In the first case report we showed the significance of morphological analysis using OCT and proved that it was not lumen stenosis. The second and the third case reports showed the complementarity between functional analysis (FFR) and morphological analysis (OCT) of stenosis in solving a complex coronary disease. The fourth case report showed the significance of OCT in dealing with the recurrent stent restenosis. CONCLUSION: By these short case reports we confirmed that percutaneous coronary intervention (PCI) guided by angiography is definitely not enough in deciding about myocardial revascularization especially in patients with a complex coronary disease. In certain cases FFR and OCT procedures can be complementary methods and improve quality of revascularization, particularly in case of recurrent in-stent restenosis. PMID- 27498455 TI - PET/CT fusion in radiotherapy planning for lung cancer--Case reports. AB - INTRODUCTION: Application of imaging methods, namely computed tomography (CT), magnetic resonance imaging (MRI) and in recent years positron emission tomography/computed tomography (PET/CT), and the progress of computer technology have allowed the construction of effective computed systems for treatment planning (TPS) and introducing the concept of virtual simulation in 3D conformal radiotherapy planning. CASE REPORT: We hereby presented two patients with the diagnosis of non-small cell lung cancer who did PET/CT examination. Both patients had surgery earlier and local recidives are diagnosed with PET/CT. PET/CT of the first patient described the focus of intense 18F-fluorodeoxyglucose (18FDG) accumulation 2.99 x 2.9 x 2.1 cm in diameter in the projection of soft-tissue volume in the left corner, at operating clips height, corresponding to metabolically active recurrence of the tumor. Mediastinum and right lung parenchyma were without focal accumulation of 18FDG. Control PET/CT after 3 months was without detectable focus of intense pathological 18FDG accumulation- good therapeutic response, (metabolic disease remission). On the other hand, in the second case PET/CT showed a focus of intense 18FDG accumulation screening in the scar tissue of the apical part of the right lung, 20 x 16 mm, corresponding to metabolically active tumor recurrence. In the lung parenchyma on the left and in the mediastinum no visible focus of intense 18FDG accumulation was descrbed. Radiography included using 3D conformal radiotherapy with fusion PET/CT scan and CT simulations. CONCLUSION: PET/CT provides important information for planning conformal radiotherapy, especially in dose escalation, sparing of organ at risk and better locoregional control of the disease. PMID- 27498456 TI - Conflicting interests in biomedical research and medical practice. PMID- 27498457 TI - A vision for future service provision. PMID- 27498458 TI - To: all RCM members. PMID- 27498459 TI - Lords vote to end detention of pregnant immigrants. PMID- 27498460 TI - Student bursaries consultation. PMID- 27498461 TI - CONSULTATION INTO NMC CHANGES. PMID- 27498462 TI - Benefits of continuity of carer. PMID- 27498463 TI - SHOULD I STAT OR SHOULD I GO? PMID- 27498464 TI - 30 DAYS TO SAVE YOUR MIDWIFERY COMMITTEE. PMID- 27498465 TI - Challenging times ahead. PMID- 27498466 TI - 'They were so conditioned against thinking for themselves, because the penalties were so severe'. PMID- 27498467 TI - THE BREAST START TO LIFE. PMID- 27498469 TI - Reply FROM RCM DIRECTOR FOR ENGLAND JACQUE GERRARD. PMID- 27498468 TI - Incontinence advert gripe. PMID- 27498470 TI - Research request. PMID- 27498471 TI - THEY DON'T TELL YOU. PMID- 27498472 TI - Hang on to your vision. PMID- 27498473 TI - Yes, my lady. PMID- 27498474 TI - Exploring midwives' experience of public health in maternity care. PMID- 27498475 TI - Reducing the length of postnatal hospital stay. PMID- 27498476 TI - PART ONE. How to ... build and develop a birth centre. PMID- 27498477 TI - The next generation game. PMID- 27498478 TI - Taking kangaroo care to China. PMID- 27498480 TI - Caring for you. PMID- 27498479 TI - Rural retreat. PMID- 27498481 TI - Suffering in silence. PMID- 27498482 TI - Resourcing the public health role. PMID- 27498483 TI - The road to revalidation. PMID- 27498484 TI - Handsets at the ready. PMID- 27498485 TI - With a little help from my friends. PMID- 27498486 TI - Surviving shift work. PMID- 27498487 TI - Stillbirth: a renewed focus. PMID- 27498488 TI - Global village. PMID- 27498489 TI - Understanding preterm birth. PMID- 27498490 TI - Evaluation of acetylcholinesterase source from fish, Tor tambroides for detection of carbamate. AB - Acetylcholinesterase (AChE) from the brain tissue of local freshwater fish, Tor tambroides was isolated through affinity purification. Acetylthiocholine iodide (ATCi) was preferable synthetic substrate to purified AChE with highest maximal velocity (V(max)) and lowest biomolecular constant (K(m)) at 113.60 Umg(-1) and 0.0689 mM, respectively, with highest catalytic efficiency ratio (V(max)/K(m)) of 1648.77. The optimum pH was 7.5 with sodium phosphate buffer as medium, while optimal temperature was in the range of 25 to 35 degrees C. Bendiocarp, carbofuran, carbaryl, methomyl and propoxur significantly lowered the AChE activity greater than 50%, and the IC50 value was estimated at inhibitor concentration of 0.0758, 0.0643, 0.0555, 0.0817 and 0.0538 ppm, respectively. PMID- 27498491 TI - Effects of alternate drip irrigation and superabsorbent polymers on growth and water use of young coffee tree. AB - To obtain optimal irrigation management for young coffee tree, the effects of alternate drip irrigation (ADI) and superabsorbent polymers on physiology, growth, dry mass accumulation and water use on one-year old Coffea arabica L. tree were investigated. This experiment had three drip irrigation methods, i.e., conventional drip irrigation (CDI), alternate drip irrigation (ADI) and fixed drip irrigation (FDI), and two levels of superabsorbent polymers, i.e., no superabsorbent polymers (NSAP) and added superabsorbent polymers (SAP). Compared to CDI, ADI saved irrigation water by 32.1% and increased water use efficiency (WUE) by 29.9%. SAP increased root-shoot ratio, total dry mass and WUE by 20.3, 24.9 and 33.0%, respectively, when compared to NSAP. Compared to CDI with NSAP treatment, ADI with SAP treatment increased total dry mass by 13.8% and saved irrigation water by 34.4%, thus increased WUE by 73.4%, and it increased root activity, the contents of chlorophyll and soluble sugar in leaves by 162.4, 38.0 and 8.5%, but reduced the contents of proline and malondialdehyde in leaves by 7.2 and 9.7%, respectively. Thus, alternate drip irrigation with superabsorbent polymers increased the growth and WUE of young Coffea arabica L. tree and was optimal irrigation management for young coffee tree. PMID- 27498492 TI - Evaluating morpho-physiological and quality traits to compliment seed yield under changing climatic conditions in Brassicas. AB - A study was conducted under irrigated conditions to test the performance of improved cultivars of Indian mustard (B. juncea), Gobhi sarson (B. napus) and African sarson (B. carinata) under changing climatic conditions. The effect of cultivar, environment and their interactions were significant in mustard and canola gobhi sarson. Environment had significant impact on all the studied traits except for leaf area index (LAI). Cultivar x Year (G x Y) interaction was significant for flowering behavior, days to maturity, SPAD, photosynthetic active radiations (PAR), growth parameters, yield components and yield except photosynthesis photochemical efficiency, relative water content (RWC) and LAI. Cultivar RLC1 surpassed other B. juncea cultivars for yield and had low erucic acid ('0') while GSL1 (non canola), Hyola PAC401 (hybrid canola) and GSC6 (canola) of B. napus were superior in performance for seed yield and possessed low erucic and glucosinolate content ('00'). Higher seed yield was associated with more number of total siliquae/plant, seed weight, biomass, seeds/siliqua, SPAD and RWC. Correlation coefficient revealed high positive association for seed yield with days to maturity (0.639**), plant height (0.982**), secondary branches (0.826**), total siliquae/plant (0.913**), seed weight (0.761**) andbiomass (0.891**). PMID- 27498493 TI - The effects of selected pre-treatments on germination of seeds of Oriental hornbeam (Carpinus orientalis). AB - In the present study, the effect of some pre-treatments implemented on seeds of Oriental hornbeam (Carpinus orientalis), which has wide geographical variation along Turkey on germination percentage values were investigated. For this purpose, 13 different pre-treatments were implemented to seeds obtained from 17 different populations. According to the obtained results (except control seeds), pre-treatments leading to lowest germination percentage value (8.1%) in Oriental hornbeam seeds was PT10: Keeping seeds for 90 min in sulfuric acid, while highest germination percentage (86.58%) has been obtained with pre-treatment PT13: Implementation of 40% dose of Baikal EM1 + Biohoumous mixture to the seeds, while lowest germination percentage (40.50%) was observed on seeds collected from P7 (Bartin-Kozcagiz) population, highest germination percentage was observed in seeds obtained from P17 (Artvin-Hopa) population. PMID- 27498494 TI - Impact of acid mine drainage on haematological, histopathological and genotoxic effects in golden mahaseer, Tor putitora. AB - The present study was carried out to evaluate sub-lethal mechanism of acid mine drainage toxicity in fingerlings (9.5 +/- 2.4 cm) of golden mahseer, Tor putitora. Exposed fingerlings showed significant reduction (P < 0.01) in blood erythrocytes, neutrophils, thrombocytes, lymphocytes and leukocytes in contrast to increase in number of immature circulating cells. Hyperplasia, degeneration of glomeruli, presence of inflammatory cells and increased number of melanomacrophage aggregates, vacuolization of cell cytoplasm, hepatocyte swelling were marked in kidney and liver of fish. Ladder in, an increment of 180-200 bp of hepatic and kidney DNA, by electrophoresis were consistent with DNA damage. 10 day exposure to acid mine drainage resulted in reduction of double stranded DNA to 46.0 and 48.0 in hepatocytes and kidney cells respectively. Significant increase (P < 0.01) in tail length and percent tail DNA was evident by comet assay. The results suggest that exposure to acid mine drainage might cause irreversible damage to immune cells, tissue and DNA of fish, and this model of DNA damage may contribute in identifying novel molecular mechanism of interest for bioremediation application. PMID- 27498495 TI - Intervarietal variations in various oxidative stress markers and antioxidant potential of finger millet (Eleusine coracana) subjected to drought stress. AB - Drought is a major form of abiotic stress leading to lower crop productivity. Experiment was carried out for selecting the most tolerant genotype among six different genotypes of finger millet under drought stress. Seeds of six finger millet genotypes were sown in pots and grown for 35 days. After this period, drought was induced by withholding watering for stressed plants while control plants were watered regularly for comparison. Among all six different varieties of finger millet screened (PR202, PES400, PRM6107, VL283, VL328 and VL149) under varying intensities of drought stress,PRM6107 and PR202 showed highest stress tolerance by limiting excessive accumulation of reactive oxygen species (ROS) through activation of ROS scavenging antioxidative enzymes. A 200% increase in ascorbate content was recorded in PRM6107 and PR202, while in other varieties limited increase in ascorbate content was observed. Maximum decrease in chlorophyll content was observed in VL328 (83%) while least drop was observed in VL149 (65%). Relative water content indicated that PR202 was able to retain maximum water content under stress, as it recorded least drop in relative water content (55%), contributing to its better survival under stress. In conclusion finger millet genotypes PRM6107 and PR202 possessed maximum drought tolerance potential and thus may be used for allele mining of drought tolerant genes, which can further be employed for the development of more drought stress tolerant staple crops using biotechnological approach. PMID- 27498496 TI - Assessment of soil characteristics in the vicinity of open cast coal mine and its suitability for vegetative reclamation in Charhi and Kuju of Jharkhand, India. AB - Coal mining is inevitable for economic growth of a country, but at the same time deteriorates the quality of the environment. Open cast mine, especially affects the top soil most negatively. In the present study, soil samples from three representative areas of mining viz proposed, operational and abandoned sites from Charhi and Kuju of Jharkhand were collected and analysed for physicochemical parameters and metals with an objective to determine their suitability for vegetative reclamation. Soil samples appeared to be slightly acidic (5.97 +/- 0.66) with low EC values (101 +/- 76 MUScm(-1)), total organic carbon (0.71 +/- 0.35 %), organic matter (1.34 +/- 0.66%) and overall nutrient, especially nitrogen (167 +/- 64 kg ha(-1)) contents than required for reclamation by revegetation. However, bulk density was found conducive for reclamation. Total Cr (317 +/- 287 to 417 +/- 393 mg kg(-1)), Cu (121 +/- 72 to 344 +/- 143 mg kg(-1)), Ni (171 +/- 46 to 373 +/- 134 mg kg(-1)) and Pb (114 +/- 115 to 182 +/- 145 mg kg(-1)) content were found to be higher in soil. Sitewise variation was also significant for Cu and Ni. Pearson's correlation suggested significant (p <= 0.05) positive inter elemental correlation between Cr-Fe, Cr-Mn, Cu-Ni, Fe-Mn and Mn-Ni. Positive geoaccumulation index (Igeo) values for all the metals except Fe, overall contamination degree of 31.10 and significant enrichment factor indicated considerable contamination. This baseline data could be utilized for vegetative reclamation planning of the study area in future. PMID- 27498497 TI - Variation in antioxidant enzyme activities, growth and some physiological parameters of bitter melon (Momordica charantia) under salinity and chromium stress. AB - In general, salinity and heavy metals interfere with several physiological processes and reduce plant growth. In order to evaluate of three levels of salinity (0, 4 and 8 ds m(-1)) and three concentration of chromium (0, 10 and 20 mg kg(-1) soil) in bitter melon (Momordica charantia), a plot experiment was conducted in greenhouse at university of Shahrood, Iran. The results revealed that chromium treatment had no significant affect on fresh and dry weight, but salinity caused reduction of fresh and dry weight in growth parameter. Salinity and chromium enhanced antioxidant enzymes activities like catalase (CAT), guaiacol peroxidase (GPX) and sodium content in leaves. However salinity and chromium treatments had no effect on potassium, phosphorus in leaves, soluble carbohydrate concentration in leaves and root, but decreased the carotenoid content in leaves. On increasing salinity from control to 8 ds m(-1) chlorophyll a, b and anthocyanin content decreased by 41.6%, 61.1% and 26.5% respectively but chromium treatments had no significant effect on these photosynthetic pigments. PMID- 27498498 TI - Assessment of microbial quality of fish processing industrial effluent in bar mouth at Bhidia landing site, Veraval, Gujarat, India. AB - The present study was carried out to assess the microbial quality of fish processing industries effluent at Bhidia bar-mouth, Veraval, Gujarat during April, 2012 to March 2013. The total viable bacterial count (TVBC), total Enterobacteriaceae count, E. coli count (EC), Staphylococcus aureus and Fecal Streptococcal count in effluent ranged from 3.0 x 10(-1) to 6.8 x 10(6), 9.0 x 10(1) to 2.9 x 10(4), 0 to 0. 5 x 10(4), 0 to 0. 4 x 102 and 0.3 x 10(1) to 0. 1 x 10(4) cfu.(-1)respectively. Significantly higher load of TEC, E. coli, S.aureus, Fecal Streptococci, Total coliforms and Fecal coliforms were higher during summer whereas, TVBC was higher in the month of Sept.-Oct. Furthermore, the total coliform and fecal coliform counts were found to be higher with 1400+ /100 ml MPN value throughout the year of the study, except in the month of August. Overall occurrence of pathogenic strains of E. coli, S. aureus and Fecal streptococci were 41.67%, 25.00% and 66.67% respectively during this period. The antibiogram of the isolated E. coli isolates show that almost 50% were resistant to Cefazidime/Clavulanic acid (CAC), Amoxyclav (AMC), Ciprofloxacin (CIF) and Ampicillin (AMP). The present study indicated that the effluent of fish processing industry was heavily contaminated with E. coli, S. aureus and Fecal Streptococci which confirmed improper treatment of fish processing effluent. Moreover, the precedence of antibiotic resistant E. coli may pose threat to public health safety. PMID- 27498499 TI - Determination and optimization of Vitamin B complex in xylanase enzyme treated polished rice by response surface methodology. AB - The present study provides information about the concentrations of Vitamin B (thiamine, riboflavin, pyridoxine and niacin) in polished brown rice treated with xylanase. Xylanase enzyme was produced from Aspergillus awamori MTCC 9166. Brown rice was treated with 60-100% enzyme (40 ml of buffer -undiluted) for 30 to 150 min (with variation of 30 min) at 30 degrees C to 50 degrees C (with variation of 5 degrees C) to attain a saturated moisture level of 35.5 g100(-1)g .The enzyme acted upon selective degradation (polishing time 10-50 sec) of bran layer facilitating retention of more vital nutrients along with the vitamins. Vitamin B content, detected through HPLC and optimized by response surface methodology (RSM) with central composite design (CCRD), demonstrated that selective degradation of bran layers for polished rice facilitated increase of thiamine (57%), riboflavin (48%), pyridoxine (90%) and niacin (55%) concentration in bio polished rice over normally milled rice.Enzyme treated bio-polished rice was considered to be better source of vitamin B complex than mechanically milled rice, hence more nutritionally efficacious. PMID- 27498500 TI - Comparative evaluation of cyanide removal by adsorption, biodegradation, and simultaneous adsorption and biodegradation (SAB) process using Bacillus cereus and almond shell. AB - The present study aimed to investigate the removal efficiency of cyanide from contaminated water by adsorption, biodegradation and simultaneous adsorption and biodegradation (SAB) process individually in a batch reactor. Adsorption was achieved by using almond shell granules and biodegradation was conducted with suspended cultures of Bacillus cereus, whereas SAB process was carried out using Bacillus cereus and almond shell in a batch reactor. The effect of agitation time, pH, and initial cyanide concentration on the % removal of cyanide has been discussed. Under experimental conditions, optimum removal was obtained at pH 7 with agitation time of 48 hrs and temperature of 35 degrees C. Cyanide was utilized by bacteria as sole source of nitrogen for growth. The removal efficiencies of cyanide by adsorption, biodegradation, and SAB were found to be 91.38%, 95.87%, and 99.63%, respectively, at initial cyanide concentration of 100 mg l(-1). The removal efficiency of SAB was found to be better as compared to that of biodegradation and adsorption alone. PMID- 27498501 TI - Adhesive bond performance of heat-treated wood at various conditions. AB - Heat treatment of wood leads to chemical, structural and physical changes in wood constituents, which can significantly affect the bonding performance of wood in several ways depending on the adhesive type used. In the present study, fir (Abies bornmulleriana Mattf.) and beech (Fagus orientalis L.) were heat treated at 170 degrees C, 180 degrees C, 190 degrees C, 200 and 212 degrees C for 2 hours. Four different types of adhesives were used for bonding process: melamine urea-formaldehyde (MUF), melamine formaldehyde (MF), phenol formaldehyde (PF), and polyurethane (PUR). For all the pretreatment conditions, highest shear strength of adhesive bonds of each adhesive system was observed for untreated samples and shear strength decreased with increasing heat treatment. The strength of each adhesive bond of samples which were soaked in water was much less than dry samples, approximately half of the dry strength. Generally, the shear strength of the adhesive bonds after boiling was smaller than or similar to the values obtained for soaking. The untreated samples lost more strength after soaking and boiling than heat treated samples. With increasing heat treatment severity, reduction in shear strength increased in dry samples while decreased in soaking and boiling samples. For instance, after soaking, the untreated samples lost more strength (almost 39%) than heat treated samples (almost 24% for most severely heat treated samples). The results showed that the shear strength of adhesive bonds was influenced by heat treatment and depended on pretreatment of samples prior to testing. In general, all adhesives used performed in quite a similar way for all pretreatment conditions, and the bonding performance of heat treated fir wood was less satisfactory than that of beech wood for all adhesive system and condition. PMID- 27498502 TI - Isolation and identification of gold nanoparticles synthesizing fungi from Indian Kolar Gold Field mine soil. AB - An indigenous fungal strain was isolated from Indian Kolar Gold Field mine soil. The isolate was heterothallic, branched septate, deeply floccose, fast-growing, dull green with white background conidial columnar mycelium from Aspergillus section Fumigati. Diverse metabolic patterns of the isolate exhibit high metal, thermal resistance which grews well from 28 +/- 1 degrees C to 37 degrees C and pH concentration was significant on the growth of isolate. Phylogenetic analysis of 16srRNA beta-Tubulin gene sequence established relationship among isolate and other taxa. Molecular identification and morphological features of fungal isolate were consistent with those of Neosartorya udagawae. Heterothallic N. udagawae FJ830683 strain was closely related to homothallic N. aureola EF661890. Fungal isolate extract synthesized narrow sized stable Gold nanoparticles (AuNPs). PMID- 27498503 TI - Morphometric relations in the grey eel catfish Plotosus canius in the coastal waters of Port Dickson, Peninsular Malaysia. AB - Samples of grey eel catfish Plotosus canius were collected from the coastal waters of Port Dickson, Malaysia from January to December, 2012. A total of 341 specimens (172 males and 169 females) were used to estimate the length-weight relationship parameters. Mean population size of females were 0.72 cm taller than the males, however difference was not significant (t-test, P > 0.05). The overall relationship equations between total length (TL) and body weight (BW) were established for males as Log TW = 2.71 Log TL - 1.85 (R2 = 0.95) and for females as Log TW = 2.88 Log TL-2.10 (R2 = 0.95). The estimated relative growth co efficient (b) values were 2.71 for males and 2.88 for females. It is revealed that growth pattern of the species showed negative allometry. In both males and females, relationship between TL and SL gave highest regression coefficient (0.99). While relationship between TL and EL gave lowest regression coefficient in both males and females (0.87 and 0.81 respectively). The findings from this study contributed first information on morphometric relations of the fish from Malaysian coastal waters and could be useful for sustainable management options of P. canius in Malaysia. PMID- 27498504 TI - Biochemical and molecular dissection of thermo-sensitive genetic male sterility in diploid cotton (Gossypium arboreum L). AB - Diploid cotton, due to its inherent problem of stamen brittleness, its found unsuitable for traditional method of hybrid seed production which involves hand emasculation followed by pollination. Due to shortfall in other methods viz., Genetic Male Sterility (GMS), as well as, Cytoplasmic Genetic Male Sterility (CGMS), hybrid seed production in diploid cotton becomes costly and thereby, covers less area among the total cotton grown area. Thermo-sensitive genetic male sterility, which overcomes the drawbacks of both GMS and CGMS can be an effective tool in coming years for hybrid cotton research. Understanding fertility and sterility variations, their relation with biochemical changes in plant is important before its application in plant breeding. Hence, the available TGMS line, Ga TGMS-3 obtained at Cotton Research Centre, UAS, Dharwad was studied for callase activity and markers associated with TGMS. The line Ga TGMS-3 had fertile anthers and showed less callase enzyme activity at pre-meiosis stage, high enzyme activity at tetrad releasing microspore stage and no callase activity during other stages. The counterpart TGMS sterile anthers displayed little higher callase activity at pre-meiosis stage, high activity at tetrad stage, but poor activity at tetrad releasing microspore stage. During tetrad stage, TGMS sterile anthers showed high callase enzyme activity giving every chance for early release of poorly developed microspores as compared to fertile anthers. At tetrad releasing microspores stage during which fertile anthers had strong callase enzyme activity led to microspores being released normally and developed normal pollen grains as compared to sterile anthers. The present investigation revealed that NAU2176, NAU2096 and BNL1227 primers can be used as tightly linked markers for TGMS trait, as evident from their differential expression in fertile and sterile anthers. PMID- 27498505 TI - Studies on monitoring the heavy metal contents in water, sediment and snail species in Latipada reservoir. AB - The concentrations of zinc, copper, cadmium and lead in surface water, sediments and two native snail species, Bellamya bengalensis and Melanoides tuberculata from Latipada reservoir were determined. The concentrations of cadmium and lead in surface water were higher than the WHO recommended limits for drinking water standards; where as those of zinc and copper were within the permissible limits. The concentrations of zinc, copper, cadmium and lead were higher in sediments than in water. The observed bioaccumulated level of zinc, copper, cadmium and lead in Bellamya bengalensis were Zn- 197.22, Cu- 172.14, Cd- 11.59 and Pb- 112.57 MUg g(-1), while in Melanoides tuberculata were Zn- 136.59, Cu- 132.04, Cd 13.25 and Pb- 27.69 MUg g(-1). The metal concentrations in both species of snails were higher than those of the water and sediment. Bioaccumulated metal concentrations, Bio-Water Accumulation Factor (BWAF) and Bio-Sediment Accumulation Factor (BSAF) values indicated that Bellamya bengalensis had high potential for zinc, copper and lead bioaccumulation than Melanoides tuberculata, while Melanoides tuberculata had high potential for cadmium than Bellamya bengalensis. Therefore, Bellamya bengalensis is proposed as sentinel organism for monitoring zinc, copper and lead, while Melanoides tuberculata for monitoring cadmium in freshwater. PMID- 27498506 TI - Effect of fermented earthworm cast on egg production and egg quality as well as removal of odor in feces from egg laying hens. AB - The objective of the present study was to determine the effect of feeding fermented earthworm casts (EEC) to layers on egg-laying performance, blood lipid profiles, cecal microflora, and fecal odor removing performance. A total of 200 Hyline Brown layer chicks at 33-week-old were used in this study. They were randomly assigned to two numerically equal groups with 100 replications per treatment for 10 weeks. All the birds were caged individually. The control group was not treated with EEC. The EEC group was treated with top dressing containing 3.5% EEC. The present study revealed that egg production and egg weight were increased after feeding diet containing EEC at the top dressing level. Haugh unit, eggshell thickness, and eggshell breaking strength of EEC group were higher than those of control group. Egg yolk was determined for fatty acid profiling. It was found that EEC group had higher ratio of unsaturated- to saturated fatty acid as compared to control group. Lower ratios of n-6 to n-3 fatty acids were found in the egg yolk of EEC group. Plasma triglyceride and total cholesterol contents were lower in the EEC group. However, high density lipoprotein-cholesterol content was higher in the EEC group as compared to that in control group. The number of cecal Lactobacillus was increased while the population of Escherichia coli and coliform bacteria decreased in the EEC group. Fecal ammonia and hydrogen sulfide contents were lower in the EEC group as compared to those in control group. Taken together, these results suggested that EEC could improve egg production and egg quality. In addition, it could remove odour from laying-hen manure. PMID- 27498507 TI - In vitro evaluation of Pseudomonas bacterial isolates from rice phylloplane for biocontrol of Rhizoctonia solani and plant growth promoting traits. AB - The ability for biocontrol and plant growth promotion of three Pseudomonas bacterial isolates namely Pseudomonas fluorescens (UMB20), Pseudomonas aeruginosa (KMB25) and Pseudomonas asplenii (BMB42) obtained from rice plants was investigated. Fungal growth inhibition by the isolates ranged from 86.85 to 93.15% in volatile and 100% in diffusible metabolites test. Among the isolates, BMB42 showed fungal growth inhibition significantly in the volatile metabolite test. Isolates UMB20 and BMB42 were able to synthesis chitinase with chitinolytic indices of 13.66 and 13.50, respectively. In case of -1,3-glucanase, all the isolates showed activity to produce this enzyme at varied levels and isolate KMB25 showed significantly highest activity (53.53 ppm). Among the three isolates, KMB25 showed positive response to protease production and all of them were negative to pectinase and lipase and positive to the production of siderophore, and HCN, and were able to solubilize tricalcium phosphate. All the three bacterial isolates were capable of forming biofilm at different levels. Above results suggest that phylloplane Pseudomonas bacterial isolates have potential for antifungal activities and plant growth promotion. PMID- 27498508 TI - Land use change and its effects on water quality in typical inland lake of arid area in China. AB - Land-use change is very important for determining and assessing the influence of human activity on aquatic environment of rivers and lakes. The present work with Bosten River basin as the subject, analyzes features of dynamic land-use change of the basin from 1993 to 2013, in order to study the influence of land-use pattern change on the basin water quality, according to the land-use/land cover(LUCC) chart from 2000 to 2013 made by ArcGIS and ENVI. It shows cultivated land, wetland and forestland constitute most of Bosten River basin, taking up over 41.7% of the total; from 1993-2000, LUCC of the basin is relatively small, with an increase of cultivated land, residential-industry land, water wetlands by 15.09%-18.33%,most of which are transformed from forestland, grassland and unused land; from 2000-2013, LUCC of the basin is relatively significant, with a continuing and bigger increase of cultivated land and Residential-industry area, most of which are transformed from water wetlands and unused land. Based on analysis of landuse pattern and water quality index, it can be told that water pollution is positively correlated to cultivated land and residential-industry area and negatively correlated to water and grassland. Also, the influence of land-use pattern change on water quality has been discussed, whose finding can serve as the scientific evidence for land-use optimization and water pollution control. PMID- 27498509 TI - Degradation of acephate by Enterobacter asburiae, Bacillus cereus and Pantoea agglomerans isolated from diamondback moth Plutella xylostella (L), a pest of cruciferous crops. AB - Acephate-degrading bacterial isolates were isolated from the larval gut of diamondback moth Plutella xylostella, a notorious pest of cruciferous crops worldwide that has developed resistance to insecticides. Partial 16S rRNA gene sequencing identified the isolates as Bacillus cereus (PX-B.C.Or), Enterobacter asburiae (PXE), and Pantoae agglomerans (PX-Pt.ag.Jor). All isolates grew on minimal media (MM) in the presence of acephate at 100 and 200 ppm, with maximum growth at 200 ppm. LC-MS analyses of spent medium showed that E. asburiae degraded acephate to methamidophos and O, O-dimethyl phosporamidate and B. cereus O,S-dimethyl to phosphorothioate but P. agglomerans to an unnamed compound. All three isolates used acephate as a source of carbon and energy for growth; however, P. agglomerans used it also as source of sulphur. Strong evidence revealed that the bacterial communities present in the gut of diamondback moth might aid in acephate degradation and play a role in the development of insecticide resistance. PMID- 27498510 TI - Under pressure. PMID- 27498511 TI - Good social interactions help obese children to lose weight. PMID- 27498512 TI - New NICE guidance on domestic abuse. PMID- 27498513 TI - Early years sector takes action on oral health. PMID- 27498515 TI - Swaddling link to SIDS. PMID- 27498514 TI - UK needs to reduce inequalities, say Unicef. PMID- 27498516 TI - Dear Prime Minister.... PMID- 27498517 TI - The impact of perinatal loss on parents and the family. PMID- 27498519 TI - "We need to 'normalise' breastfeeding". PMID- 27498518 TI - Eczema and infant skin care. PMID- 27498520 TI - The latest evidence on Lyme disease. PMID- 27498521 TI - Streets ahead. PMID- 27498522 TI - Parental response to aType 1 diabetes diagnosis. PMID- 27498523 TI - The effect of climate change on our heath. PMID- 27498524 TI - Summer allergies. PMID- 27498525 TI - A cry for help. PMID- 27498526 TI - Listen and learn. PMID- 27498527 TI - EFFICIENCY OF ULTRASOUND GUIDED LOWER LIMB PERIPHERAL NERVE BLOCKS IN PERIOPERATIVE PAIN MANAGEMENT FOR KNEE ARTHROSCOPY IN CHILDREN. A RANDOMIZED STUDY. AB - INTRODUCTION: Ultrasound guided lower limb peripheral nerve blocks are efficient for perioperative pain treatment in children. The aim was to see if lower limb peripheral nerve blocks reduced the amount of propofol and opioid analgesics used intraoperatively, as well as the level of pain and consumption of systemic analgesics postoperatively. MATERIAL AND METHODS: A randomized, prospective clinical trial was carried out. It included 60 children between 11 and 18 years of age scheduled for elective knee arthroscopy. The patients were divided into two groups. Group A received general anesthesia, group B received lower limb peripheral nerve blocks with sedation or general anesthesia. Postoperative level ofpain was assessed using visual analogue scale. RESULTS: Less propofol and fentanyl was used to induce and maintain anesthesia in group B (p < 0.001). The level of postoperative pain was significantly lower in group B (p < 0.001), as well as the postoperative consumption of analgesics (p < 0.001). As mahbny as 47% of the patients were discharged without receiving any analgesics postoperatively. The average duration of peripheral nerve blocks was 468 minutes. CONCLUSIONS: Ultrasound guided lower limb peripheral nerve blocks are an efficient technique of regional anesthesia in children. They reduce the amount of general anesthetics and opioid analgesics needed intraoperatively as well as the level of postoperative pain and consumption of analgesics postoperatively. PMID- 27498528 TI - DRUG UTILIZATION IN TREATMENT OF THYROID DISORDERS DURING PREGNANCY IN SERBIA. AB - INTRODUCTION: Depleted uranium radiation and pollution with polychlorinated biphenyls resulting from bombings the territories of Serbia as well as the additional long-term stress may have affected the function of thyroid gland. The objective of this study was to determine the trend of drug utilization in the treatment of thyroid dysfunction during pregnancy in Novi Sad. MATERIAL AND METHODS: Women who had given birth at the Department of Gynecology in 1989, 1999, 2007 and 2011 were interviewed during a one-month period about thyroid diseases in the pregnancy as well as the drugs they had taken. RESULTS: Not a single pregnant woman was reported to have a thyroid disorder in 1989 and 1999, while in 2007 four women were reported to have a thyroid dysfunction. In 2011, fourteen out of 18 women with thyroid dysfunction were using levothyroxine and in most cases hypothyroidism was diagnosed as autoimmune Hashimoto thyroiditis. CONCLUSION: The study results suggest the necessity of performing more detailed analyses of the correlation between the frequency of the thyroid gland dysfunction and the effects of environmental pollution in Serbia. PMID- 27498529 TI - EXPRESSION OF COLLAGEN TYPE I IN UNALTERED AND OSTEOARTHRITIC MENISCI OF KNEE JOINT. AB - INTRODUCTION: Knee osteoarthritis is a progressive degenerative disease which affects meniscal tissue. The aim of this study was to determine the differences in collagen type I expression in macroscopically unaltered and osteoarthritic menisci, and correlate the expression with the grade of macroscopic damage, age and body mass index of patients, preoperative condition of anterior cruciate ligament, angulation and knee contracture. MATERIAL AND METHODS: The control group consisted of 10 macroscopically unaltered menisci, while the experimental group had 35 osteoarthritic menisci. Besides macroscopic grading of meniscal damage, the analysis of collagen type I expression was determined by immunohistochemical staining with the corresponding antibody using semiquantitative scale scores and quantitative parameters: intensity of expression and stained area size. RESULTS: The results of semiquantitative evaluation showed a statistically significant decrease in collagen type I expression in osteoarthritic menisci, which correlated with an increase in macroscopic damage grade. The results of quantitative evaluation did not show a statistically significant decrease in the expression. In posterior meniscal horns, a more intense collagen type I expression was seen in the women, as well as a positive correlation of quantitatively evaluated expression with body mass index. Collagen type I expression in the anterior horns was significantly lower in varus alignment. CONCLUSION: In the semiquantitative evaluation, collagen type I expression in osteoarthritic menisci was significantly lower compared to macroscopically unchanged menisci. The decrease in the expression level correlates with the increase in the grade of macroscopic meniscal damage. There was no statistically significant difference in the quantitative evaluation of expression. PMID- 27498531 TI - IMPORTANCE OF INTEGRATED MANAGEMENT SYSTEM APPLIED IN HEALTH ESTABLISHMENTS IN ORDER TO RAISE TREATMENT QUALITY. AB - INTRODUCTION: The term "management" is best characterized as "managing" economic or social processes to achieve objectives through a rational use of material and immaterial resources by applying the principles, functions, and management methods. This study has been aimed at evaluating the value of an integrated quality management system implemented at the Institute of Cardiovascular Diseases of Vojvodina to improve the quality of treatment. MATERIAL AND METHODS: In the period from 2008 to 2010 about 40 employees from the Institute of Cardiovascular Diseases of Vojvodina attended various courses given by the lecturers of the Faculty of Technical Sciences, where the function and significance of the "International Standards Organization" were explained, after which standards of interest were implemented at the Institute of Cardiovascular Diseases of Vojvodina. RESULTS: The Department of Cardiology has introduced 11 cardiac procedures with 5 special instructions, 14 general procedures, and 7 specific procedures with 2 instructions. The Department of Cardiac Surgery has introduced 7 procedures to be implemented. The "Vojvodina score" model was put into practice for the perioperative evaluation of cardiac surgery risk. During 2014, the Institute of Cardiovascular Diseases ofVojvodina obtained accreditation for the period of 7 years. CONCLUSION: The integrated quality management system must be applied in order to achieve a high level of health care in the shortest possible time and with the least possible consumption of material and human resources. The application of this system in practice gives a realistic insight into the working processes and facilitates their functioning. It demands and requires constant monitoring of the system efficiency along with continuous changes and improvements of all elements of the working processes and functional units. PMID- 27498530 TI - ALGORITHM OF OVULATION INDUCTION IN PATIENTS WITH POLYCISTIC OVARY SYNDROME. AB - INTRODUCTION: Polycystic ovary syndrome is the most frequent endocrine disturbance in the reproductive period of women's life and the most frequent cause of anovulatory infertility. Ovulation and pregnancy in patients having polycystic ovary syndrome may be a result of a wide range of therapeutic options, and the treatment assumes a gradual approach--from simple noninvasive to expensive and demanding procedures. MATERIAL AND METHODS: A systematic literature survey concerning the efficiency of particular ovulation induction methods in respect of the reproductive outcome was carried out with the aim of establishing the algorithm for ovulation induction in infertile patients having polycystic ovary syndrome. The search was confined to clinical investigations performed on human subjects, reported in English in the period from the beginning of 2010 to June of 2014. CONCLUSION: As a conclusion of this systematic survey of the efficiency of ovulation induction methods, which confirms and supplements the knowledge in this field, it is possible to form the algorithm for ovulation induction in infertile patients having polycystic ovary syndrome, consisting of the following subsequent steps: 1) modification of life style, 2) induction with clomiphene citrate 3) use of metformin, 4) use ofaromatase inhibitors, 5) application ofgonadotropins and laparoscopic ovarian drilling--as a second-line treatment, and 6) assisted reproductive techniques. PMID- 27498532 TI - CHEMOTHERAPY ANALYSIS IN MASSIVE TRANSFUSION SYNDROME. AB - INTRODUCTION: Massive transfusion is defined as blood transfusion in quantities equal to or greater than the estimated patients' blood volume over a relatively short period of time (3-4 hours). The study was aimed at analyzing the application of chemotherapy in treatment of patients with acute massive bleeding and evaluating the results of hemostasis and platelet counts screening tests in the patients receiving massive transfusions. MATERIAL AND METHODS: Attempts were made to fully compensate hemostatic factors in 24 patients (14 male and 10 female, aged 23 to 76 years) with acute massive and uncontrolled surgical bleeding (polytrauma, abdominal aortic aneurysm, digestive tract bleeding as a result of a farina overdose, mortus fetus) over the five-year period, wherein a circulating patients' blood volume was compensated over a relatively short period of time. First the surgical bleeding was stopped. The objective of chemotherapy was the combined use of resuspended red blood cells, fresh frozen plasma, cryoprecipitates and the platelet concentrate in order to maintain the patients' normal circulating blood volume and blood pressure (systolic blood pressure >= 100 mmHg) with hemoglobin value higher than 100 g/l and the hematocrit above 0.30 l/l. RESULTS: Transfusion treatment of 24 patients with acute bleeding consisted of an average of 16 to 18 units of resuspended red blood cells (ranging from 4,880 ml to 5,220 ml); fresh frozen plasma (980 ml to 1,220 ml); cryoprecipitates (an average of 10 to 15 units i.e. 500-750 ml) and concentrated platelets (approximately an average of 8 to 12 units i.e. 240 to 360 ml). CONCLUSION: In our study we have confirmed the pathophysiological mechanism shown in the available medical literature that after transfusion of a large red blood cell concentrate volume, dilutional coagulopathy develops, caused by a sharp drop in platelet count and the significantly reduced activity of unstable coagulation factors in the patient's circulation. PMID- 27498533 TI - OTOLOGICAL MANIFESTATIONS OF TURNER SYNDROME: CLINICAL AND RADIOLOGICAL FINDINGS. AB - INTRODUCTION: Turner syndrome is a chromosomal abnormality where all or a part of one of the X chromosomes is absent or it has other abnormalities. Besides characteristic abnormalities of short stature and infertility, women with Turner syndrome have increased risks for tumors of the central nervous system, especially meningioma and an otologic disease. Meningioma involving the middle ear is extremely rare, and this condition has never been published in association with Turner syndrome. CASE REPORT: We present an otologic manifestation associated with other abnormalities in a patient with Turner syndrome and discuss diagnosis and possible treatment options. CONCLUSION: Multidisciplinary team approach is essential in these patients in order to evaluate their vulnerability and define therapeutic priorities. PMID- 27498534 TI - HIDRADENITIS SUPPURATIVA: A CASE SERIES OF EIGHT PATIENTS. AB - INTRODUCTION: Hidradenitis suppurativa is a persistent, inflammatory and recurrent disease of the hair follicles which, in time, results in ugly scars. Inflammation and obstruction of channel of sweat glands used to be thought to be the basis of this disease. CASE REPORTS: This paper presents the cases of 8 patients operated on in the past 3 years. A possibility of an oversight in making the diagnosis, as well as an underestimation in the treatment should be taken into consideration. In addition to surgical methods the authors discuss other therapeutic possibilities taken from the available literature. This is a retrospective analysis of the surgical findings. The treatment was multidisciplinary but the surgical excision was the only option which provided healing without recurrence so far. In our series the excision could be done to the fascia or to leave a thin layer of adipose tissue. The reconstruction could be achieved by healing per secundam, by autologous skin or artificial graft, or by narrowing the wound with a skin portion. Our results achieved by stage, secondary stitches and rotation portions were satisfying. CONCLUSION: In case of advanced disease only surgery can lead to healing. We performed late surgery because the disease was diagnozed in advanced stages according to Hurlay. Wide excision was done in all our patients. The reconstruction was achieved with rotational flap in 3 patients, the wound healing per secundam in 4 patients and with primary suture in one patient. Our patients did not have recurrences of the primary disease. The disease was combined in one case with perianal fistula. PMID- 27498535 TI - ATYPICAL KAWASAKI DISEASE. AB - INTRODUCTION: Kawasaki disease is an acute vasculitis which occurs primarily in children under the age of 5. The etiology of the disease is still unknown. Diagnostic criteria for Kawasaki disease are fever and at least four of the five additional clinical signs. Incomplete Kawasaki disease should be taken into consideration in case of all children with unexplained fever for more than 5 days, associated with 2 or 3 of the main clinical findings of Kawasaki disease. The diagnosis of incomplete Kawasaki disease is based on echocardiographic findings indicating the involvement of the coronary arteries. Cardiac complications, mostly coronary artery aneurysm, can occur in 20% to 25% of untreated patients and in 4% of treated patients. CASE REPORT. In this report we present a case of atypical Kawasaki disease in a 3.5-month-old infant. As soon as the diagnosis was made, the patient received high doses of intravenous immunoglobulin, with the initial introduction of ibuprofen, then aspirin with a good clinical response. Due to the presence of aneurysm of coronary arteries, further therapy involved aspirin and clopidogrel over the following 3 months, and then only aspirin for 2 years. There was a gradual regression of the changes in the coronary blood vessels to the normalization of the echocardiographic findings after 2 years. CONCLUSION: Kawasaki disease is the second most common vasculitis of childhood, so it should be included in the differential diagnosis for any child with a prolonged unexplained fever. Atypical Kawasaki disease should be taken into consideration in cases when not all clinical criteria are present but coronary abnormalities are documented. PMID- 27498536 TI - HISTOPATHOLOGICAL ANALYSIS AND SURGICAL TREATMENT OF BREAST CANCER--OUR EXPERIENCE. AB - INTRODUCTION: The aim of this study was to show the descriptive and histopathological analysis and applied surgical technique with early and late post-operative complications in patients with breast cancer who were hospitalized and treated at the General Hospital in Novi Pazar during the period 2009-2011. MATERIAL AND METHODS: During the period from 2009 to 2011, 59 patients were operated for breast cancer at the General Hospital in Novi Pazar. The study included the size and type of the tumor, disease stage, surgical techniques and complications, the age of the patients at the moment of surgery and its correlation with the number of metastatic lymph nodes in the axilla and the tumor size, as well as the correlation of the tumor size with the number ofmetastases in the axillary lymph nodes. RESULTS: The dif- ference in the tumor size in relation to the age among the women under 50 and over 50 years of age was not statistically significant (T = -1.203, p > 0.05). There was no statistically significant difference between the number of positive lymph nodes in the women under and over 50 years of age (Mann-Whitney U test, p > 0.05). A significant positive correlation between the tumor size and the number of positive axillary lymph nodes was found (p = 0.308, p < 0.05). A significant positive correlation of the patient's age and breast cancer stage was also confirmed with nonparametric variance analysis by Spearman's Rho (p = 0.337, p < 0.05). CONCLUSION: The majority of women from this study sample were with Stage II of breast cancer, which points out the necessity for better prevention and education of women in order to improve early diagnosis of breast cancer. The number of positive axillary lymph nodes appears to be an important prognostic factor and a significant positive correlation between the tumor size and the number of positive axillary lymph nodes has been found. PMID- 27498537 TI - Mycobacterium sarraceniae sp. nov. and Mycobacterium helvum sp. nov., isolated from the pitcher plant Sarracenia purpurea. AB - Several fast- to intermediate-growing, acid-fast, scotochromogenic bacteria were isolated from Sarracenia purpurea pitcher waters in Minnesota sphagnum peat bogs. Two strains (DL734T and DL739T) were among these isolates. On the basis of 16S rRNA gene sequences, the phylogenetic positions of both strains is in the genus Mycobacterium with no obvious relation to any characterized type strains of mycobacteria. Phenotypic characterization revealed that neither strain was similar to the type strains of known species of the genus Mycobacterium in the collective properties of growth, pigmentation or fatty acid composition. Strain DL734T grew at temperatures between 28 and 32 degrees C, was positive for 3-day arylsulfatase production, and was negative for Tween 80 hydrolysis, urease and nitrate reduction. Strain DL739T grew at temperatures between 28 and 37 degrees C, and was positive for Tween 80 hydrolysis, urea, nitrate reduction and 3-day arylsulfatase production. Both strains were catalase-negative while only DL739T grew with 5 % NaCl. Fatty acid methyl ester profiles were unique for each strain. DL739T showed an ability to survive at 8 degrees C with little to no cellular replication and is thus considered to be psychrotolerant. Therefore, strains DL734T and DL739T represent two novel species of the genus Mycobacterium with the proposed names Mycobacterium sarraceniae sp. nov. and Mycobacterium helvum sp. nov., respectively. The type strains are DL734T (=JCM 30395T=NCCB 100519T) and DL739T (=JCM 30396T=NCCB 100520T), respectively. PMID- 27498538 TI - Mucilaginibacter puniceus sp. nov., isolated from wetland freshwater. AB - A non-motile, rod-shaped and pale-pink bacterium, designated strain WS71T, was isolated from freshwater collected from the Woopo Wetland (Republic of Korea). Cells were Gram-stain-negative, aerobic, catalase-positive and oxidase-negative. The major fatty acids were summed feature 3 (comprising C16 : 1omega6c and/or C16 : 1omega7c), iso-C17 : 0 3-OH, C16 : 0 and iso-C15 : 0. The strain contained menaquinone 7 (MK-7) and the DNA G+C content was 39.4+/-0.4 mol%. The major polar lipids were phosphatidylethanolamine and an unknown aminophospholipid. A phylogenetic tree based on 16S rRNA gene sequences showed that WS71T forms an evolutionary lineage within the radiation enclosing the members of genus Mucilaginibacterwith Mucilaginibacter. soyangensis HME6664T as its nearest neighbor (98.3 % sequence similarity). DNA-DNA relatedness between WS71T and M. soyangensis HME6664T was 61.3+/-1.0 %. A number of phenotypic characteristics distinguished WS71T from the other members of the genus Mucilaginibacter. On the basis of the evidence presented in this study, WS71T represents a novel species, for which the name Mucilaginibacterpuniceus sp. nov. is proposed. The type strain is WS71T (=KCTC 32270T=JCM 19495T). PMID- 27498539 TI - Vine nitrogen status and volatile thiols and their precursors from plot to transcriptome level. AB - BACKGROUND: Volatile thiols largely contribute to the organoleptic characteristics and typicity of Sauvignon blanc wines. Among this family of odorous compounds, 3-sulfanylhexan-1-ol (3SH) and 4-methyl-4-sulfanylpentan-2-one (4MSP) have a major impact on wine flavor. These thiols are formed during alcoholic fermentation by the yeast from odorless, non-volatile precursors found in the berries and the must. The present study investigates the effects of vine nitrogen (N) status on 3SH and 4MSP content in Sauvignon blanc wine and on the glutathionylated and cysteinylated precursors of 3SH (Glut-3SH and Cys-3SH) in the berries and the must. This is paralleled by a RNA-seq analysis of gene expression in the berries. The impact of N supply on the expression of the glutathione-S-transferase 3 and 4 (VviGST3 and VviGST4) and the gamma glutamyltranspeptidase (VviGGT), considered as key genes in their biosynthesis, was also evaluated. RESULTS: N supply (N100 treatment) increased the 3SH content in wine while no effect was noticed on 4MSP level. Furthermore, N supply increased Glut-3SH levels in grape berries at late berry ripening stages, and this effect was highly significant in must at harvest. No significant effect of N addition was noticed on Cys-3SH concentration. The transcript abundance of the glutathione-S-transferases VviGST3 and VviGST4 and the gamma glutamyltranspeptidase (VviGGT), were similar between the control and the N100 treatment. New candidate genes which might be implicated in the biosynthetic pathway of 3SH precursors were identified by whole transcriptome shotgun sequencing (RNA-seq). CONCLUSIONS: High vine N status has a positive effect on 3SH content in wine through an increase of Glut-3SH levels in grape berries and must. Candidate GSTs and glutathione-S-conjugates type transporters involved in this stimulation were identified by RNA-seq analysis. PMID- 27498540 TI - Erratum to: ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies. PMID- 27498541 TI - Lactococcus garvieae subsp. bovis subsp. nov., lactic acid bacteria isolated from wild gaur (Bos gaurus) dung, and description of Lactococcus garvieae subsp. garvieae subsp. nov. AB - A taxonomic investigation was performed on a Gram-stain-positive coccus, designated strain BSN307T, isolated from gaur (Indian bison, Bos gaurus) dung based on phenotypic and molecular approaches. Based on the biochemical tests, cellular morphology and 16S rRNA gene sequence similarity, this strain was found to be a member of the genus Lactococcus and closely related to Lactococcus garvieae ATCC 49156T (99.6 % 16S rRNA gene sequence similarity) and L.actococcus formosensis 516T (99.0 %). However, DNA-DNA hybridization studies showed that the level of relatedness between strain BSN307T and L. garvieae ATCC 49156T was 75.8 %, suggesting that it represented a novel subspecies of L. garvieae. The inability to grow in brain heart infusion (BHI) medium at pH 9.6, in tryptic soy agar (TSA) with 4 % (w/v) NaCl and at 42 degrees C (MRS agar) clearly differentiated BSN307T from L. garvieae ATCC 49156T. Rep-PCR fingerprint patterns, substantial differences in summed feature 8 (C18 : 1omega7c/C18 : 1omega6c), C19 : 0 cyclo omega8c and C16 : 0 also differentiated strain BSN307T from the reference strain of L. garvieae. Moreover, analysis of the housekeeping genes pheS and rpoA revealed sequence similarities that were at the limit for species differentiation (92.2 and 97.8 %, respectively). Combined genotypic and phenotypic data indicate that strain BSN307T represents a subspecies of L. garvieae for which the name Lactococcus garvieae subsp. bovis subsp. nov. is proposed. The type strain is BSN307T (=DSM 100577 T=MCC 2824T=KCTC 21083T). PMID- 27498542 TI - Lipoteichoic acids as a major virulence factor causing inflammatory responses via Toll-like receptor 2. AB - Lipoteichoic acid (LTA), a major cell wall component of Gram-positive bacteria, is associated with various inflammatory diseases ranging from minor skin diseases to severe sepsis. It is known that LTA is recognized by Toll-like receptor 2 (TLR2), leading to the initiation of innate immune responses and further development of adaptive immunity. However, excessive immune responses may result in the inflammatory sequelae that are involved in severe diseases such as sepsis. Although numerous studies have tried to identify the molecular basis for the pathophysiology of Gram-positive bacterial infection, the exact role of LTA during the infection has not been clearly elucidated. This review provides an overview of LTA structure and host recognition by TLR2 that leads to the activation of innate immune responses. Emphasis is placed on differential immunostimulating activities of LTAs of various Gram-positive bacteria at the molecular level. PMID- 27498543 TI - Can IFNL3 polymorphisms predict response to interferon/ribavirin treatment in hepatitis C patients with genotype 3? AB - Favourable genotypes of IFNL3 polymorphism CC for rs12979860 and TT for rs8099917 are strongly associated with the interferon/ribavirin treatment outcome in hepatitis C virus (HCV) patients with genotypes 1 and 4. Contrarily, conflicting results have been reported for patients with HCV genotypes 2 and 3. Therefore, we sought to investigate the association between IFNL3 with sustained virological response (SVR) after treatment to ascertain the predictive value of IFNL3 single nucleotide polymorphisms (SNPs) in HCV patients with genotype 3. For this purpose, we genotyped five IFNL3 SNPs, rs12980275, rs12979860, rs9109886, rs8099917 and rs7248668, in HCV patients with genotype 3 and assessed its association with SVR, individually and in haplotype. Interestingly, we report that the IFNL3 SNPs we genotyped have shown no association with SVR following treatment, either individually or in haplotype, indicating that genotyping IFNL3 SNPs have limited predictive value in HCV patients with genotype 3. Therefore, we propose that IFNL3 genotyping can be excluded from a patient's pre-treatment workup for subsequent treatment choice. This will greatly reduce the economic burden for HCV patients with genotype 3 in resource-limited regions, especially South Asia where genotype 3 is predominant. PMID- 27498544 TI - CD99 Is Strongly Expressed in Basal Cells of the Normal Adult Epidermis and Some Subpopulations of Appendages: Comparison with Developing Fetal Skin. AB - BACKGROUND: CD99 is a cell surface transmembrane glycoprotein expressed in various tissues. CD99 is differentially expressed between subpopulations of each tissue and is highly expressed in certain hematopoietic and precursor cells. However, there has been no comprehensive study of CD99 expression in normal skin. We evaluated CD99 expression in normal human skin and developing fetal skin. METHODS: Seventy-five adult skin samples containing normal skin and eight fetal skin samples of different gestational ages were collected. CD99 immunohistochemical staining was performed to evaluate expression pattern in adult and fetal skin samples. CD99 and CD34 expression were compared by double immunofluorescence. RESULTS: In normal adult skin, CD99 was strongly expressed in the membrane of epidermal basal keratinocytes, hair follicle bulges and outer root sheaths, and inner secretory cells of eccrine sweat glands. In fetal skin, CD99 was not expressed on the periderm at 16 weeks of gestation but was expressed in basal cells of fetal skin at around 19 weeks of gestation. CD99 expression became comparable to that of the adult skin after 20 weeks of gestation. CD99 and CD34 were co-expressed in hair follicle outer root sheaths, as seen by double immunofluorescence study. CONCLUSIONS: This is the first study examining CD99 expression pattern in normal adult and fetal skin. CD99 tends to be expressed in the basal/precursor cells of epidermis and in hair follicles. These results provide a basis for future investigation on functions of CD99 in the skin and provide a novel potential target for the treatment of dermatologic lesions. PMID- 27498545 TI - Differential Immunohistochemical Profiles for Distinguishing Prostate Carcinoma and Urothelial Carcinoma. AB - BACKGROUND: The pathologic distinction between high-grade prostate adenocarcinoma (PAC) involving the urinary bladder and high-grade urothelial carcinoma (UC) infiltrating the prostate can be difficult. However, making this distinction is clinically important because of the different treatment modalities for these two entities. METHODS: A total of 249 patient cases (PAC, 111 cases; UC, 138 cases) collected between June 1995 and July 2009 at Seoul St. Mary's Hospital were studied. An immunohistochemical evaluation of prostatic markers (prostate specific antigen [PSA], prostate-specific membrane antigen [PSMA], prostate acid phosphatase [PAP], P501s, NKX3.1, and alpha-methylacyl coenzyme A racemase [AMACR]) and urothelial markers (CK34betaE12, p63, thrombomodulin, S100P, and GATA binding protein 3 [GATA3]) was performed using tissue microarrays from each tumor. RESULTS: The sensitivities of prostatic markers in PAC were 100% for PSA, 83.8% for PSMA, 91.9% for PAP, 93.7% for P501s, 88.3% for NKX 3.1, and 66.7% for AMACR. However, the urothelial markers CK34betaE12, p63, thrombomodulin, S100P, and GATA3 were also positive in 1.8%, 0%, 0%, 3.6%, and 0% of PAC, respectively. The sensitivities of urothelial markers in UC were 75.4% for CK34betaE12, 73.9% for p63, 45.7% for thrombomodulin, 22.5% for S100P, and 84.8% for GATA3. Conversely, the prostatic markers PSA, PSMA, PAP, P501s, NKX3.1, and AMACR were also positive in 9.4%, 0.7%, 18.8%, 0.7%, 0%, and 8.7% of UCs, respectively. CONCLUSIONS: Prostatic and urothelial markers, including PSA, NKX3.1, p63, thrombomodulin, and GATA3 are very useful for differentiating PAC from UC. The optimal combination of prostatic and urothelial markers could improve the ability to differentiate PAC from UC pathologically. PMID- 27498546 TI - A Rare Case of Recurrent Metastatic Solid Pseudopapillary Neoplasm of the Pancreas. AB - A 61-year-old woman visited our hospital for bilateral multiple lung nodules and a mass in her thorax. She had a long history of multiple metastatic recurrences of solid pseudopapillary neoplasm (SPN); 24 years previously, the patient had undergone pylorus-preserving pancreaticoduodenectomy for a 9.9 * 8.6 cm mass in the pancreatic head. The tumor was diagnosed as an SPN. Nine years later, metastatic nodules were found on computed tomography in the patient's liver and peritoneum and were excised. She subsequently underwent an additional eight metastatectomy procedures in diverse organs. For the presented event, the lung nodules were removed. The prevalence of malignant SPN in the general population is 5%-15%. However, multiple metastatic recurrence of malignant SPN is rare; the lung is a particularly rare site of metastasis, found in only three cases in the literature. Here, we describe this exceptional case and provide a literature review. PMID- 27498547 TI - Adult Intussusception Caused by Inverted Meckel's Diverticulum Containing Mesenteric Heterotopic Pancreas and Smooth Muscle Bundles. PMID- 27498548 TI - SIRT7, H3K18ac, and ELK4 Immunohistochemical Expression in Hepatocellular Carcinoma. AB - BACKGROUND: SIRT7 is one of the histone deacetylases and is NAD-dependent. It forms a complex with ETS-like transcription factor 4 (ELK4), which deacetylates H3K18ac and works as a transcriptional suppressor. Overexpression of SIRT7 and deacetylation of H3K18ac have been shown to be associated with aggressive clinical behavior in some cancers, including hepatocellular carcinoma (HCC). The present study investigated the immunohistochemical expression of SIRT7, H3K18ac, and ELK4 in hepatocellular carcinoma. METHODS: A total of 278 HCC patients were enrolled in this study. Tissue microarray blocks were made from existing paraffin embedded blocks. Immunohistochemical expressions of SIRT7, H3K18ac and ELK4 were scored and analyzed. RESULTS: High SIRT7 (p = .034), high H3K18ac (p = .001), and low ELK4 (p = .021) groups were associated with poor outcomes. Age < 65 years (p = .028), tumor size >= 5 cm (p = .001), presence of vascular emboli (p = .003), involvement of surgical margin (p = .001), and high American Joint Committee on Cancer stage (III&V) (p < .001) were correlated with worse prognoses. In multivariate analysis, H3K18ac (p = .001) and ELK4 (p = .015) were the significant independent prognostic factors. CONCLUSIONS: High SIRT7 expression with poor overall survival implies that deacetylation of H3K18ac contributes to progression of HCC. High H3K18ac expression with poor prognosis is predicted due to a compensation mechanism. In addition, high ELK4 expression with good prognosis suggests another role of ELK4 as a tumor suppressor beyond SIRT7's helper. In conclusion, we could assume that the H3K18ac deacetylation pathway is influenced by many other factors. PMID- 27498549 TI - Different DHEA-S Levels and Response Patterns in Individuals with Chronic Neck Pain, Compared with a Pain Free Group-a Pilot Study. AB - Objective: To test, in this pilot study, whether DHEA-S (Dehydroepiandrosterone, sulfated form) plasma levels are lower among persons with chronic neck pain, compared to control persons, and to investigate the DHEA-S response after a physical exercise. Subjects: Included were 12 persons with chronic neck pain and eight controls without present pain, all 18 and 65 years of age. Exclusion criteria for both groups were articular diseases or tendinosis, fibromyalgia, systemic inflammatory and neuromuscular diseases, pain conditions due to trauma, or severe psychiatric diseases. Design and methods: The participants arm-cycled on an ergometer for 30 minutes. Blood samples were taken before, 60 minutes, and 150 minutes after this standardized physical exercise. Results: The estimated plasma DHEA-S levels at baseline were 2.0 umol/L (95% confidence interval [CI] 1.00; 4.01) in the pain group and 4.1 umol/L (95% CI2.0; 8.6) in the control group, adjusted for sex, age, body mass index (BMI), and Shirom-Melamed Burnout Questionnaire (SMBQ), with a ratio of 0.48 ( P = 0.094). Conclusions: In this pilot study, the plasma DHEA-S levels appeared to be lower among the persons with chronic neck pain, compared with the control group. It was indicated that DHEA-S decreased during the physical exercise in the control group, and either increased or was unaffected in the chronic pain group. PMID- 27498550 TI - Developmental Validation of the Huaxia Platinum System and application in 3 main ethnic groups of China. AB - STRs, scattered throughout the genome with higher mutation rate, are attractive to genetic application like forensic, anthropological and population genetics studies. STR profiling has now been applied in various aspects of human identification in forensic investigations. This work described the developmental validation of a novel and universal assay, the Huaxia Platinum System, which amplifies all markers in the expanded CODIS core loci and the Chinese National Database in one single PCR system. Developmental validation demonstrated that this novel assay is accurate, sensitive, reproducible and robust. No discordant calls were observed between the Huaxia Platinum System and other STR systems. Full genotypes could be achieved even with 250 pg of human DNA. Additionally, 402 unrelated individuals from 3 main ethnic groups of China (Han, Uygur and Tibetan) were genotyped to investigate the effectiveness of this novel assay. The CMP were 2.3094 * 10(-27), 4.3791 * 10(-28) and 6.9118 * 10(-27), respectively, and the CPE were 0.99999999939059, 0.99999999989653 and 0.99999999976386, respectively. Aforementioned results suggested that the Huaxia Platinum System is polymorphic and informative, which provides efficient tool for national DNA database and facilitate international data sharing. PMID- 27498551 TI - Combined Detection of Serum IL-10, IL-17, and CXCL10 Predicts Acute Rejection Following Adult Liver Transplantation. AB - Discovery of non-invasive diagnostic and predictive biomarkers for acute rejection in liver transplant patients would help to ensure the preservation of liver function in the graft, eventually contributing to improved graft and patient survival. We evaluated selected cytokines and chemokines in the sera from liver transplant patients as potential biomarkers for acute rejection, and found that the combined detection of IL-10, IL-17, and CXCL10 at 1-2 weeks post operation could predict acute rejection following adult liver transplantation with 97% specificity and 94% sensitivity. PMID- 27498552 TI - MicroRNA-27a Inhibits Cell Migration and Invasion of Fibroblast-Like Synoviocytes by Targeting Follistatin-Like Protein 1 in Rheumatoid Arthritis. AB - Fibroblast-like synoviocytes (FLS) with aberrant expression of microRNA (miRNA) are critical pathogenic regulators in rheumatoid arthritis (RA). Previous studies have found that overexpression or silencing of miRNA can contribute to the development of miRNA-based therapeutics in arthritis models. In this study, we explored the effects of miR-27a on cell migration and invasion in cultured FLS from RA patients. We found that miR-27a was markedly downregulated in the serum, synovial tissue, and FLS of RA patients. Meanwhile, the expression of follistatin like protein 1 (FSTL1) was upregulated, which suggests that FSTL1 plays a key role in RA development. The results of a Transwell assay showed that miR-27a inhibited FLS migration and invasion. However, miR-27a inhibition promoted the migration and invasion of FLS. In addition, the down-regulated expression of matrix metalloproteinases (MMP2, MMP9, and MMP13) and Rho family proteins (Rac1, Cdc42, and RhoA) was detected after treatment with miR-27a in RA-FLS by quantitative reverse transcription-PCR and western blot analysis. Then, a luciferase reporter assay validated that miR-27a targeted the 3-untranslated region (3'-UTR) of FSTL1. Moreover, miR-27a caused a significant decrease of FSTL1. In addition, the expression of TLR4 and NFkappaB was inhibited by miR-27a but increased by FSTL1 overexpression. In conclusion, we found that miR-27a inhibited cell migration and invasion of RA-FLS by targeting FSTL1 and restraining the TLR4/NFkappaB pathway. PMID- 27498553 TI - Serum metabolomic signatures discriminate early liver inflammation and fibrosis stages in patients with chronic hepatitis B. AB - Chronic HBV (CHB) infected patients with intermediate necroinflammation and fibrosis are recommended to receive antiviral treatment. However, other than liver biopsy, there is a lack of sensitive and specific objective method to determine the necroinflammation and fibrosis stages in CHB patients. This study aims to identify unique serum metabolomic profile associated with histological progression in CHB patients and to develop novel metabolite biomarker panels for early CHB detection and stratification. A comprehensive metabolomic profiling method was established to compare serum samples collected from health donor (n = 67), patients with mild (G < 2 and S < 2, CHB1, n = 52) or intermediate (G >= 2 or S >= 2, CHB2, n = 36) necroinflammation and fibrosis. Multivariate models were developed to differentiate CHB1 and CHB2 from controls. A set of CHB-associated biomarkers was identified, including lysophosphatidylcholines, phosphatidylcholines, phosphatidylinositol, phosphatidylserine, and bile acid metabolism products. Stratification of CHB1 and CHB2 patients by a simple logistic index, the PIPSindex, based on phosphatidylinositol (PI) and phosphatidylserine (PS), was achieved with an AUC of 0.961, which outperformed all currently available markers. A panel of serum metabolites that differentiate health control, CHB1 and CHB2 patients has been identified. The proposed metabolomic biosignature has the potential to be used as indicator for antiviral treatment for CHB management. PMID- 27498555 TI - How should the post-2015 response to AIDS relate to the drive for universal health coverage? AB - The drive for universal health coverage (UHC) now has a great deal of normative impetus, and in combination with the inauguration of the sustainable development goals, has come to be regarded as a means of ensuring the financial basis for the struggle against HIV and AIDS. The argument of this paper is that such thinking is a case of 'the right thing at the wrong time': it seriously underestimates the scale of the work against HIV and AIDS, and the speed with which we need to undertake it, if we are to consolidate the gains we have made to date, let alone reduce it to manageable proportions. The looming 'fiscal crunch' makes the challenges all the more daunting; even in the best circumstances, the time required to establish UHCs capable of providing both essential health services and a very rapid scale-up of the fight against HIV and AIDS is insufficient when set against the urgency of ensuring that AIDS does not eventuate as a global health catastrophe. PMID- 27498554 TI - Autophagy-associated alpha-arrestin signaling is required for conidiogenous cell development in Magnaporthe oryzae. AB - Conidiation patterning is evolutionarily complex and mechanism concerning conidiogenous cell differentiation remains largely unknown. Magnaporthe oryzae conidiates in a sympodial way and uses its conidia to infect host and disseminate blast disease. Arrestins are multifunctional proteins that modulate receptor down regulation and scaffold components of intracellular trafficking routes. We here report an alpha-arrestin that regulates patterns of conidiation and contributes to pathogenicity in M. oryzae. We show that disruption of ARRDC1 generates mutants which produce conidia in an acropetal array and ARRDC1 significantly affects expression profile of CCA1, a virulence-related transcription factor required for conidiogenous cell differentiation. Although germ tubes normally develop appressoria, penetration peg formation is dramatically impaired and Deltaarrdc1 mutants are mostly nonpathogenic. Fluorescent analysis indicates that EGFP-ARRDC1 puncta are well colocalized with DsRed2-Atg8, and this distribution profile could not be altered in Deltaatg9 mutants, suggesting ARRDC1 enters into autophagic flux before autophagosome maturation. We propose that M. oryzae employs ARRDC1 to regulate specific receptors in response to conidiation-related signals for conidiogenous cell differentiation and utilize autophagosomes for desensitization of conidiogenous receptor, which transmits extracellular signal to the downstream elements of transcription factors. Our investigation extends novel significance of autophagy-associated alpha-arrestin signaling to fungal parasites. PMID- 27498556 TI - Interdependent IL-7 and IFN-gamma signalling in T-cell controls tumour eradication by combined alpha-CTLA-4+alpha-PD-1 therapy. AB - Combination therapy with alpha-CTLA-4 and alpha-PD-1 has shown significant clinical responses in different types of cancer. However, the underlying mechanisms remain elusive. Here, combining detailed analysis of human tumour samples with preclinical tumour models, we report that concomitant blockade of CTLA-4 and PD-1 improves anti-tumour immune responses and synergistically eradicates tumour. Mechanistically, combination therapy relies on the interdependence between IL-7 and IFN-gamma signalling in T cells, as lack of either pathway abrogates the immune-boosting and therapeutic effects of combination therapy. Combination treatment increases IL-7Ralpha expression on tumour-infiltrating T cells in an IFN-gamma/IFN-gammaR signalling-dependent manner, which may serve as a potential biomarker for clinical trials with immune checkpoint blockade. Our data suggest that combining immune checkpoint blockade with IL-7 signalling could be an effective modality to improve immunotherapeutic efficacy. Taken together, we conclude that combination therapy potently reverses immunosuppression and eradicates tumours via an intricate interplay between IFN gamma/IFN-gammaR and IL-7/IL-7R pathways. PMID- 27498557 TI - A novel recombinant cell fluorescence biosensor based on toxicity of pathway for rapid and simple evaluation of DON and ZEN. AB - During an exposure, humans and animals are most often exposed to a mixture rather than individual mycotoxins. In this study, a Human Embryonic Kidney 293 cell (HEK 293) fluorescence sensor was developed to detect and evaluate mycotoxins, deoxynivalenol (DON) and zearalenone (ZEN) compounds, produced by Fusarium culmorum that are common food contaminants. TRE-copGFP (green fluorescent protein) and ERE-TagRFP (red fluorescent protein) plasmids were constructed and cotransfected into HEK-293 cells through a highly efficient, lipid-mediated, DNA transfection procedure. Results show that fluorescence intensity was proportional to DON and ZEN concentrations, ranging from 2 to 40 ng/mL and 10 to 100 ng/mL respectively, with a detection limit of 0.75 ng/mL and 3.2 ng/mL respectively. The EC50 of DON and ZEN are 30.13 ng/mL and 76.63 ng/mL respectively. Additionally, ZEN may have a synergistic effect on enhancing AP-1 activity of the toxicity pathway of DON. These data indicate the high sensitivity and effectiveness of our biosensor system in the evaluation of the combined toxicity of ZEN, DON and their derivatives. In addition, this approach is suitable for an early warning method for the detection of ZEN and DON family mycotoxins contamination without higher-priced, conventional analytical chemistry methods. PMID- 27498559 TI - Effective Strategy for Colorimetric and Fluorescence Sensing of Phosgene Based on Small Organic Dyes and Nanofiber Platforms. AB - Three o-phenylendiamine (OPD) derivatives, containing 4-chloro-7 nitrobenzo[c][1,2,5]oxadiazole (NBD-OPD), rhodamine (RB-OPD), and 1,8 naphthalimide (NAP-OPD) moieties, were prepared and tested as phosgene chemosensors. Unlike previously described methods to sense this toxic agent, which rely on chemical processes that transform alcohols and amines to respective phosphate esters and phosphoramides, the new sensors operate through a benzimidazolone-forming reaction between their OPD groups and phosgene. These processes promote either naked eye visible color changes and/or fluorescence intensity enhancements in conjunction with detection limits that range from 0.7 to 2.8 ppb. NBD-OPD and RB-OPD-embedded polymer fibers, prepared using the electrospinning technique, display distinct color and fluorescence changes upon exposure to phosgene even in the solid state. PMID- 27498558 TI - Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies. AB - Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) olaparib has been approved for treatment of advanced ovarian cancer associated with BRCA1 and BRCA2 mutations. BRCA1- and BRCA2-mutated cells, which are homologous recombination (HR) deficient, are hypersensitive to PARPi through the mechanism of synthetic lethality. Here we examine the effect of PARPi on HR-proficient cells. Olaparib pretreatment, PARP1 knockdown or Parp1 heterozygosity of Brca2(cko/ko) mouse embryonic stem cells (mESCs), carrying a null (ko) and a conditional (cko) allele of Brca2, results in viable Brca2(ko/ko) cells. PARP1 deficiency does not restore HR in Brca2(ko/ko) cells, but protects stalled replication forks from MRE11 mediated degradation through its impaired recruitment. The functional consequence of Parp1 heterozygosity on BRCA2 loss is demonstrated by a significant increase in tumorigenesis in Brca2(cko/cko) mice. Thus, while olaparib efficiently kills BRCA2-deficient cells, we demonstrate that it can also contribute to the synthetic viability if PARP is inhibited before BRCA2 loss. PMID- 27498561 TI - Cross-Cultural Sex Differences in Post-Conflict Affiliation following Sports Matches. AB - The nature of ancestral human social structure and the circumstances in which men or women tend to be more cooperative are subjects of intense debate. The male warrior hypothesis proposes that success in intergroup contests has been vital in human evolution and that men therefore must engage in maximally effective intragroup cooperation [1-3]. Post-conflict affiliation between opponents is further proposed to facilitate future cooperation [4], which has been demonstrated in non-human primates [5] and humans [6]. The sex that invests more in post-conflict affiliation, therefore, should cooperate more. Supportive evidence comes from chimpanzees, a close genetic relative to humans that also engages in male intergroup aggression [7]. Here we apply this principle to humans by testing the hypothesis that among members of a large community, following a conflict, males are predisposed to be more ready than females to repair their relationship via friendly contact. We took high-level sports matches as a proxy for intragroup conflict, because they occur within a large organization and constitute semi-naturalistic, standardized, aggressive, and intense confrontations. Duration or frequency of peaceful physical contacts served as the measure of post-conflict affiliation because they are strongly associated with pro-social intentions [8, 9]. Across tennis, table tennis, badminton, and boxing, with participants from 44 countries, duration of post-conflict affiliation was longer for males than females. Our results indicate that unrelated human males are more predisposed than females to invest in a behavior, post-conflict affiliation, that is expected to facilitate future intragroup cooperation. PMID- 27498560 TI - Differentiation of malignant cervical lymphadenopathy by dual-energy CT: a preliminary analysis. AB - The accurate diagnosis of malignant cervical lymphadenopathy remains challenging. In this study, we determined the value of quantitative parameters derived from dual-energy computed tomography (DECT) for differentiating malignant cervical lymphadenopathy caused by thyroid carcinoma (TC), salivary gland carcinoma (SC), squamous cell carcinoma (SCC) and lymphoma. We retrospectively analysed 92 patients with pathologically confirmed cervical lymphadenopathy due to TC, SC, SCC and lymphoma. All patients received a DECT scan before therapy. Using GSI (gemstone spectral imaging) Volume Viewer software, we analysed the enhanced monochromatic data, and the quantitative parameters we acquired included the iodine concentration (IC), water concentration (WC) and the slope of the spectral HU curve (lambdaHU). One-way ANOVA showed significant differences in the IC and lambdaHU among different groups (P < 0.05). Post-hoc pairwise comparisons demonstrated the IC and lambdaHU of TC group were significantly higher than those of SC, SCC and lymphoma groups (P < 0.05). In addition, the IC and lambdaHU of SC group were significantly higher than those of the SCC and lymphoma groups (P < 0.05). Other comparisons of IC and lambdaHU values showed no significant differences (P > 0.05). The quantitative parameters derived from DECT were useful supplements to conventional computed tomography images and were helpful for distinguishing different malignant cervical lymphadenopathies. PMID- 27498562 TI - Myosin Vc Is Specialized for Transport on a Secretory Superhighway. AB - A hallmark of the well-studied vertebrate class Va myosin is its ability to take multiple steps on actin as a single molecule without dissociating, a feature called "processivity." Therefore, it was surprising when kinetic and single molecule assays showed that human myosin Vc (MyoVc) was not processive on single actin filaments [1-3]. We explored the possibility that MyoVc is processive only under conditions that resemble its biological context. Recently, it was shown that zymogen vesicles are transported on actin "superhighways" composed of parallel actin cables nucleated by formins from the plasma membrane [4]. Loss of these cables compromises orderly apical targeting of vesicles. MyoVc has been implicated in transporting secretory vesicles to the apical membrane [5]. We hypothesized that actin cables regulate the processive properties of MyoVc. We show that MyoVc is unique in taking variable size steps, which are frequently in the backward direction. Results obtained with chimeric constructs implicate the lever arm/rod of MyoVc as being responsible for these properties. Actin bundles allow single MyoVc motors to move processively. Remarkably, even teams of MyoVc motors require actin bundles to move continuously at physiological ionic strength. The irregular stepping pattern of MyoVc, which may result from flexibility in the lever arm/rod of MyoVc, appears to be a unique structural adaptation that allows the actin track to spatially restrict the activity of MyoVc to specialized actin cables in order to co-ordinate and target the final stages of vesicle secretion. PMID- 27498563 TI - Wolbachia Protein TomO Targets nanos mRNA and Restores Germ Stem Cells in Drosophila Sex-lethal Mutants. AB - Wolbachia, endosymbiotic bacteria prevalent in invertebrates, manipulate their hosts in a variety of ways: they induce cytoplasmic incompatibility, male lethality, male-to-female transformation, and parthenogenesis. However, little is known about the molecular basis for host manipulation by these bacteria. In Drosophila melanogaster, Wolbachia infection makes otherwise sterile Sex-lethal (Sxl) mutant females capable of producing mature eggs. Through a functional genomic screen for Wolbachia genes with growth-inhibitory effects when expressed in cultured Drosophila cells, we identified the gene WD1278 encoding a novel protein we call toxic manipulator of oogenesis (TomO), which phenocopies some of the Wolbachia effects in Sxl mutant D. melanogaster females. We demonstrate that TomO enhances the maintenance of germ stem cells (GSCs) by elevating Nanos (Nos) expression via its interaction with nos mRNA, ultimately leading to the restoration of germ cell production in Sxl mutant females that are otherwise without GSCs. PMID- 27498564 TI - Glutamatergic Neurotransmission Links Sensitivity to Volatile Anesthetics with Mitochondrial Function. AB - An enigma of modern medicine has persisted for over 150 years. The mechanisms by which volatile anesthetics (VAs) produce their effects (loss of consciousness, analgesia, amnesia, and immobility) remain an unsolved mystery. Many attractive putative molecular targets have failed to produce a significant effect when genetically tested in whole-animal models [1-3]. However, mitochondrial defects increase VA sensitivity in diverse organisms from nematodes to humans [4-6]. Ndufs4 knockout (KO) mice lack a subunit of mitochondrial complex I and are strikingly hypersensitive to VAs yet resistant to the intravenous anesthetic ketamine [7]. The change in VA sensitivity is the largest reported for a mammal. Limiting NDUFS4 loss to a subset of glutamatergic neurons recapitulates the VA hypersensitivity of Ndufs4(KO) mice, while loss in GABAergic or cholinergic neurons does not. Baseline electrophysiologic function of CA1 pyramidal neurons does not differ between Ndufs4(KO) and control mice. Isoflurane concentrations that anesthetize only Ndufs4(KO) mice (0.6%) decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) only in Ndufs4(KO) CA1 neurons, while concentrations effective in control mice (1.2%) decreased sEPSC frequencies in both control and Ndufs4(KO) CA1 pyramidal cells. Spontaneous inhibitory postsynaptic currents (sIPSCs) were not differentially affected between genotypes. The effects of isoflurane were similar on evoked field excitatory postsynaptic potentials (fEPSPs) and paired pulse facilitation (PPF) in KO and control hippocampal slices. We propose that CA1 presynaptic excitatory neurotransmission is hypersensitive to isoflurane in Ndufs4(KO) mice due to the inhibition of pre-existing reduced complex I function, reaching a critical reduction that can no longer meet metabolic demands. PMID- 27498565 TI - Absence of Visual Input Results in the Disruption of Grid Cell Firing in the Mouse. AB - Grid cells are spatially modulated neurons within the medial entorhinal cortex whose firing fields are arranged at the vertices of tessellating equilateral triangles [1]. The exquisite periodicity of their firing has led to the suggestion that they represent a path integration signal, tracking the organism's position by integrating speed and direction of movement [2-10]. External sensory inputs are required to reset any errors that the path integrator would inevitably accumulate. Here we probe the nature of the external sensory inputs required to sustain grid firing, by recording grid cells as mice explore familiar environments in complete darkness. The absence of visual cues results in a significant disruption of grid cell firing patterns, even when the quality of the directional information provided by head direction cells is largely preserved. Darkness alters the expression of velocity signaling within the entorhinal cortex, with changes evident in grid cell firing rate and the local field potential theta frequency. Short-term (<1.5 s) spike timing relationships between grid cell pairs are preserved in the dark, indicating that network patterns of excitatory and inhibitory coupling between grid cells exist independently of visual input and of spatially periodic firing. However, we find no evidence of preserved hexagonal symmetry in the spatial firing of single grid cells at comparable short timescales. Taken together, these results demonstrate that visual input is required to sustain grid cell periodicity and stability in mice and suggest that grid cells in mice cannot perform accurate path integration in the absence of reliable visual cues. PMID- 27498566 TI - Neuromodulation of Courtship Drive through Tyramine-Responsive Neurons in the Drosophila Brain. AB - Neuromodulators influence the activities of collections of neurons and have profound impacts on animal behavior. Male courtship drive is complex and subject to neuromodulatory control. Using the fruit fly Drosophila melanogaster, we identified neurons in the brain (inferior posterior slope; IPS) that impact courtship drive and were controlled by tyramine-a biogenic amine related to dopamine, whose roles in most animals are enigmatic. We knocked out a tyramine specific receptor, TyrR, which was expressed in IPS neurons. Loss of TyrR led to a striking elevation in courtship activity between males. This effect occurred only in the absence of females, as TyrR(Gal4) mutant males exhibited a wild-type preference for females. Artificial hyperactivation of IPS neurons caused a large increase in male-male courtship, whereas suppression of IPS activity decreased male-female courtship. We conclude that TyrR is a receptor for tyramine, and suggest that it serves to curb high levels of courtship activity through functioning as an inhibitory neuromodulator. PMID- 27498568 TI - The Origin of High-Frequency Hearing in Whales. AB - Odontocetes (toothed whales) rely upon echoes of their own vocalizations to navigate and find prey underwater [1]. This sensory adaptation, known as echolocation, operates most effectively when using high frequencies, and odontocetes are rivaled only by bats in their ability to perceive ultrasonic sound greater than 100 kHz [2]. Although features indicative of ultrasonic hearing are present in the oldest known odontocetes [3], the significance of this finding is limited by the methods employed and taxa sampled. In this report, we describe a new xenorophid whale (Echovenator sandersi, gen. et sp. nov.) from the Oligocene of South Carolina that, as a member of the most basal clade of odontocetes, sheds considerable light on the evolution of ultrasonic hearing. By placing high-resolution CT data from Echovenator sandersi, 2 hippos, and 23 fossil and extant whales in a phylogenetic context, we conclude that ultrasonic hearing, albeit in a less specialized form, evolved at the base of the odontocete radiation. Contrary to the hypothesis that odontocetes evolved from low-frequency specialists [4], we find evidence that stem cetaceans, the archaeocetes, were more sensitive to high-frequency sound than their terrestrial ancestors. This indicates that selection for high-frequency hearing predates the emergence of Odontoceti and the evolution of echolocation. PMID- 27498567 TI - The Demographic Development of the First Farmers in Anatolia. AB - The archaeological documentation of the development of sedentary farming societies in Anatolia is not yet mirrored by a genetic understanding of the human populations involved, in contrast to the spread of farming in Europe [1-3]. Sedentary farming communities emerged in parts of the Fertile Crescent during the tenth millennium and early ninth millennium calibrated (cal) BC and had appeared in central Anatolia by 8300 cal BC [4]. Farming spread into west Anatolia by the early seventh millennium cal BC and quasi-synchronously into Europe, although the timing and process of this movement remain unclear. Using genome sequence data that we generated from nine central Anatolian Neolithic individuals, we studied the transition period from early Aceramic (Pre-Pottery) to the later Pottery Neolithic, when farming expanded west of the Fertile Crescent. We find that genetic diversity in the earliest farmers was conspicuously low, on a par with European foraging groups. With the advent of the Pottery Neolithic, genetic variation within societies reached levels later found in early European farmers. Our results confirm that the earliest Neolithic central Anatolians belonged to the same gene pool as the first Neolithic migrants spreading into Europe. Further, genetic affinities between later Anatolian farmers and fourth to third millennium BC Chalcolithic south Europeans suggest an additional wave of Anatolian migrants, after the initial Neolithic spread but before the Yamnaya related migrations. We propose that the earliest farming societies demographically resembled foragers and that only after regional gene flow and rising heterogeneity did the farming population expansions into Europe occur. PMID- 27498569 TI - Vision Guides Selection of Freeze or Flight Defense Strategies in Mice. AB - In prey species such as mice, avoidance of predators is key to survival and drives instinctual behaviors like freeze or flight [1, 2]. Sensory signals guide the selection of appropriate behavior [3], and for aerial predators only vision provides useful information. Surprisingly, there is no evidence that vision can guide the selection of escape strategies. Fleeing behavior can be readily triggered by a rapidly looming overhead stimulus [4]. Freezing behavior, however, has previously been induced by real predators or their odors [5]. Here, we discover that a small moving disk, simulating the sweep of a predator cruising overhead, is sufficient to induce freezing response in mice. Looming and sweeping therefore provide visual triggers for opposing flight and freeze behaviors and provide evidence that mice innately make behavioral choices based on vision alone. VIDEO ABSTRACT. PMID- 27498570 TI - Endolysosomes Are the Principal Intracellular Sites of Acid Hydrolase Activity. AB - The endocytic delivery of macromolecules from the mammalian cell surface for degradation by lysosomal acid hydrolases requires traffic through early endosomes to late endosomes followed by transient (kissing) or complete fusions between late endosomes and lysosomes. Transient or complete fusion results in the formation of endolysosomes, which are hybrid organelles from which lysosomes are re-formed. We have used synthetic membrane-permeable cathepsin substrates, which liberate fluorescent reporters upon proteolytic cleavage, as well as acid phosphatase cytochemistry to identify which endocytic compartments are acid hydrolase active. We found that endolysosomes are the principal organelles in which acid hydrolase substrates are cleaved. Endolysosomes also accumulated acidotropic probes and could be distinguished from terminal storage lysosomes, which were acid hydrolase inactive and did not accumulate acidotropic probes. Using live-cell microscopy, we have demonstrated that fusion events, which form endolysosomes, precede the onset of acid hydrolase activity. By means of sucrose and invertase uptake experiments, we have also shown that acid-hydrolase-active endolysosomes and acid-hydrolase-inactive, terminal storage lysosomes exist in dynamic equilibrium. We conclude that the terminal endocytic compartment is composed of acid-hydrolase-active, acidic endolysosomes and acid hydrolase inactive, non-acidic, terminal storage lysosomes, which are linked and function in a lysosome regeneration cycle. PMID- 27498571 TI - The impact of long working hours on psychosocial stress response among white collar workers. AB - This study examined the association between long working hours and psychosocial stress responses. In total, 1,122 white-collar workers from a company in Korea completed self-administered questionnaires following a lecture about the study aim, procedures, and confidentiality. Psychosocial stress responses were evaluated using the Psychosocial Well-being Index - Short Form (PWI-SF), and psychosocial working conditions were evaluated with the Korean Occupational Stress Scale - Short Form (KOSS-SF). Multivariate logistic regression analysis was performed after adjusting for demographic variables and psychosocial working conditions to examine associations between long working hours and psychosocial stress responses. In comparison with the reference group, which worked 40-44 hours per week, the crude odds ratio (OR) of the respondents who worked 60 or more hours was 4.56 (95% confidence interval (CI), 2.55-8.15) in terms of psychosocial stress responses. After adjusting for demographic variables, the adjusted OR of those working >=60 hours was 5.61 (95% CI, 3.01-10.47). After adjusting for both demographic variables and psychosocial working conditions, the adjusted OR of those working >=60 hours was 3.25 (95% CI, 1.56-6.79). This study found that long working hours are significantly related to psychosocial stress responses among white-collar workers in one Korean company. PMID- 27498572 TI - Effects of an ergonomics-based job stress management program on job strain, psychological distress, and blood cortisol among employees of a national private bank in Denpasar Bali. AB - The present work describes a newly developed ergonomics-based job stress management program - Ergo-JSI (Ergonomics-based Job Stress Intervention) - including a pilot study to ascertain the effects of the program on job strain, psychological distress, and blood cortisol levels among bank employees in Indonesia. A single-group, pre- and post-test experimental study was conducted in a sample of employees in a National Bank in Denpasar, Bali, Indonesia. The outcomes of the study focused on reductions in job strain index and psychological distress, measured by the Indonesian version of the Brief Job Stress Questionnaire (BJSQ), and improvement in blood cortisol levels following the study.A total of 25 male employees, with an average age of 39, received an eight week intervention with the Ergo-JSI. Compared to baseline, the job strain index decreased by 46% (p<0.05), and psychological distress decreased by 28% (p<0.05). These changes were accompanied by a 24% reduction in blood cortisol levels (p<0.05). The newly developed Ergo-JSI program may hence be effective for decreasing job strain, psychosocial distress, and blood cortisol among employees in Indonesia. PMID- 27498573 TI - Is age just a number: pancreaticoduodenectomy in elderly patients? PMID- 27498574 TI - Dietary supplementation in patients with alcoholic liver disease: a review on current evidence. AB - BACKGROUND: Alcoholic liver disease (ALD) is one of the main causes of liver disease worldwide. Although the pathogenesis of ALD has not yet been well elucidated, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species play a pivotal role in the clinical and pathological spectrum of the disease. This review summarizes the existing evidences on dietary supplements considered to have antioxidant, and/or anti-inflammatory properties, and their role in the management of ALD and the proposed mechanisms. DATA SOURCES: The present study reviewed all studies published in PubMed, ScienceDirect and Scopus, from 1959 to 2015, indicating the role of different dietary supplementation in attenuation of many pathophysiological processes involved in development and progression of ALD. Full-texts of citations were used except for those that were published in languages other than English. RESULTS: Significant progress has been made to understand the key events and molecular players for the onset and progression of ALD from both experimental and clinical studies; however, there is no successful treatment currently available. The present review discussed the role of a variety of dietary supplements (e.g. vitamin A, carotenoids, vitamins B3, C and E, in addition to antioxidants and anti-inflammatory agents) in treating ALD. It has been shown that supplementation with some carotenoids, vitamin B3, vitamin C, silymarin, curcumin, probiotics, zinc, S-adenosylmethionine and garlic may have potential beneficial effects in animal models of ALD; however, the number of clinical studies is very limited. In addition, supplementation should be accompanied with alcohol cessation. CONCLUSIONS: Since oxidative stress and inflammation are involved in the pathogenesis of ALD, dietary supplements that can modulate these pathologies could be useful in the treatment of ALD. In addition to alcohol cessation, these supplements have shown beneficial effects on animal models of ALD. Clinical trials are needed to validate the beneficiary role of these supplements in patients with ALD. PMID- 27498575 TI - Advances in understanding the molecular mechanism of pancreatic cancer metastasis. AB - BACKGROUND: Pancreatic cancer (PC) is usually diagnosed at the late-stage and therefore, has widespread metastasis and a very high mortality rate. The mechanisms underlying PC metastasis are not well understood. Recent advances in genomic sequencing have identified groups of gene mutations that affect PC metastasis, but studies elucidating their roles are lacking. The present review was to investigate the molecular mechanisms of PC metastasis. DATA SOURCES: Relevant articles on PC metastasis were searched in MEDLINE via PubMed prior to April 2015. The search was limited in English publications. RESULTS: PC metastatic cascades are multi-factorial events including both intrinsic and extrinsic elements. This review highlights the most important genetic alterations and other mechanisms that account for PC invasion and metastasis, with particular regard to epithelial-mesenchymal transition, inflammation, stress response, and circulating tumor cells. CONCLUSIONS: Analyses of relevant gene functions and signaling pathways are needed to establish the gene regulatory network and to define the pivotal modulators. Another promising area of study is the genotyping and phenotyping of circulating tumor cells, which could lead to a new era of personalized therapy by identifying specific markers and targets. PMID- 27498576 TI - Predictive value of tumor markers in patients with recurrent hepatocellular carcinoma in different vascular invasion pattern. AB - BACKGROUND: Four tumor markers for hepatocellular carcinoma (HCC), alpha fetoprotein (AFP), glypican-3 (GPC3), vascular endothelial growth factor (VEGF) and des-gamma-carboxy prothrombin (DCP), are closely associated with tumor invasion and patient's survival. This study estimated the predictability of preoperative tumor marker levels along with pathological parameters on HCC recurrence after hepatectomy. METHODS: A total of 140 patients with HCC who underwent hepatectomy between January 2012 and August 2012 were enrolled. The demographics, clinical and follow-up data were collected and analyzed. The patients were divided into two groups: patients with macroscopic vascular invasion (MaVI+) and those without MaVI (MaVI-). The predictive value of tumor markers and clinical parameters were evaluated by univariate and multivariate analysis. RESULTS: In all patients, tumor size (>8 cm) and MaVI were closely related to HCC recurrence after hepatectomy. For MaVI+ patients, VEGF (>900 pg/mL) was a significant predictor for recurrence (RR=2.421; 95% CI: 1.272-4.606; P=0.007). The 1- and 2-year tumor-free survival rates for MaVI+ patients with VEGF <=900 pg/mL versus for those with VEGF >900 pg/mL were 51.5% and 17.6% versus 19.0% and 4.8% (P<0.001). For MaVI- patients, DCP >445 mAu/mL and tumor size >8 cm were two independent risk factors for tumor recurrence (RR=2.307, 95% CI: 1.132-4.703, P=0.021; RR=3.150, 95% CI: 1.392-7.127, P=0.006; respectively). The 1- and 2-year tumor-free survival rates for the patients with DCP <=445 mAu/mL and those with DCP >445 mAu/mL were 90.4% and 70.7% versus 73.2% and 50.5% respectively (P=0.048). The 1- and 2-year tumor-free survival rates for the patients with tumor size <=8 cm and >8 cm were 83.2% and 62.1% versus 50.0% and 30.0%, respectively (P=0.003). CONCLUSIONS: The MaVI+ patients with VEGF <=900 pg/mL had a relatively high tumor-free survival than those with VEGF >900 pg/mL. In the MaVI- patients, DCP >445 mAu/mL and tumor size >8 cm were predictive factors for postoperative recurrence. PMID- 27498577 TI - Combined hepatectomy and radiofrequency ablation versus TACE in improving survival of patients with unresectable BCLC stage B HCC. AB - BACKGROUND: Combined hepatectomy and radiofrequency ablation (RFA) provides an additional treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) who are conventionally deemed unresectable. This study aimed to analyze the outcome of this combination therapy by comparing it with transarterial chemoembolization (TACE). METHODS: We retrospectively reviewed 51 patients with unresectable BCLC stage B HCC who had received the combination therapy. We compared the survival of these patients with that of 102 patients in the TACE group (control). Prognostic factors associated with worse survival in the combination group were analyzed. RESULTS: No differences in tumor status and liver function were observed between the TACE group and combination group. The median survival time for the combination group and TACE group was 38 (6-54) and 17 (3-48) months, respectively (P<0.001). The combination group required longer hospitalization than the TACE group [8 (5-14) days vs 4 (2-9) days, P<0.001]. More than two ablations decreased the survival rate in the combination group. CONCLUSIONS: Combined hepatectomy and RFA yielded a better long-term outcome than TACE in patients with unresectable BCLC stage B HCC. Patients with a limited ablated size (<=2 cm), a limited number of ablations (<=2), and adequate surgical margin should be considered candidates for combination therapy. PMID- 27498578 TI - Indocyanine green retention is a potential prognostic indicator after splenectomy and pericardial devascularization for cirrhotic patients. AB - BACKGROUND: Splenectomy and pericardial devascularization (SPD) is an effective treatment of upper gastrointestinal bleeding and hypersplenism in cirrhotic patients with portal hypertension. Indocyanine green retention at 15 minutes (ICGR15) was reported to offer better sensitivity and specificity than the Child Pugh classification in hepatectomy, but few reports describe ICGR15 in SPD. The present study was to evaluate the prognostic value of ICGR15 for cirrhotic patients with portal hypertension who underwent SPD. METHODS: From January 2012 to January 2015, 43 patients with portal hypertension and hypersplenism caused by liver cirrhosis were admitted in our center and received SPD. The ICGR15, Child Pugh classification, model for end-stage liver disease (MELD) score, and perioperative characteristics were analyzed retrospectively. RESULTS: Preoperative liver function assessment revealed that 34 patients were Child-Pugh class A with ICGR15 of 13.6%-43.0% and MELD score of 7-20; 8 patients were class B with ICGR15 of 22.8%-40.7% and MELD score of 7-17; 1 patient was class C with ICGR15 of 39.7% and MELD score of 22. The optimal ICGR15 threshold for liver function compensation was 31.2%, which offered a sensitivity of 68.4% and a specificity of 70.8%. Univariate analysis showed preoperative ICGR15, MELD score, surgical procedure, intraoperative blood loss, and autologous blood transfusion were significantly different between postoperative liver function compensated and decompensated groups. Multivariate regression analysis revealed that ICGR15 was an independent risk factor of postoperative liver function recovery (P=0.020). CONCLUSIONS: ICGR15 has outperformed the Child-Pugh classification for assessing liver function in cirrhotic patients with portal hypertension. ICGR15 may be a suitable prognostic indicator for cirrhotic patients after SPD. PMID- 27498579 TI - Differentiation of pyogenic hepatic abscesses from malignant mimickers using multislice-based texture acquired from contrast-enhanced computed tomography. AB - BACKGROUND: Pyogenic hepatic abscess may mimic primary or secondary carcinoma of the liver on contrast-enhanced computed tomography (CECT). The present study was to explore the usefulness of the analysis of multislice-based texture acquired from CECT in the differentiation between pyogenic hepatic abscesses and malignant mimickers. METHODS: This retrospective study included 25 abscesses in 20 patients and 33 tumors in 26 subjects who underwent CECT. To make comparison, we also enrolled 19 patients with hepatic single simple cyst. The images from CECT were analyzed using a Laplacian of Gaussian band-pass filter (5 filter levels with sigma weighting ranging from 1.0 to 2.5). We also quantified the uniformity, entropy, kurtosis and skewness of the multislice-based texture at different sigma weightings. Statistical significance for these parameters was tested with one-way ANOVA followed by Tukey honestly significant difference (HSD) test. Diagnostic performance was evaluated using the receiver operating characteristic (ROC) curve analysis. RESULTS: There were significant differences in entropy and uniformity at all sigma weightings (P<0.001) among hepatic abscesses, malignant mimickers and simple cysts. The significant difference in kurtosis and skewness was shown at sigma 1.8 and 2.0 weightings (P=0.002-0.006). Tukey HSD test showed that the abscesses had a significantly higher entropy and lower uniformity compared with malignant mimickers (P=0.000-0.004). Entropy (at a sigma 2.0 weighting) had the largest area under the ROC curve (0.888) in differentiating abscesses from malignant mimickers, with a sensitivity of 81.8% and a specificity of 88.0% when the cutoff value was set to 3.64. CONCLUSION: Multislice-based texture analysis may be useful for differentiating pyogenic hepatic abscesses from malignant mimickers. PMID- 27498580 TI - Effects of Salmonella infection on hepatic damage following acute liver injury in rats. AB - BACKGROUND: Acute liver injury is a common clinical disorder associated with intestinal barrier injury and disturbance of intestinal microbiota. Probiotic supplementation has been reported to reduce liver injury; however, it is unclear whether enteropathogen infection exacerbates liver injury. The purpose of this study was to address this unanswered question using a rat model. METHODS: Oral supplementation with Salmonella enterica serovar enteritidis (S. enteritidis) was given to rats for 7 days. Different degrees of acute liver injury were then induced by intraperitoneal injection of D-galactosamine. The presence and extent of liver injury was assayed by measuring the concentrations of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin. Histology was used to observe liver tissue damage. Additionally, we measured the changes in plasma endotoxin, serum cytokines and bacterial translocation to clarify the mechanisms underlying intestinal microbiota associated liver injury. RESULTS: The levels of liver damage and endotoxin were significantly increased in the Salmonella infected rats with severe liver injury compared with the no infection rats with severe liver injury (P<0.01); The peyer's patch CD3+ T cell counts were increased significantly when the Salmonella infection with severe injury group was compared with the normal group (P<0.05). S. enteritidis pretreatment enhanced intestinal barrier impairment and bacterial translocation. CONCLUSIONS: Oral S. enteritidis administration exacerbates acute liver injury, especially when injury was severe. Major factors of the exacerbation include inflammatory and oxidative stress injuries induced by the translocated bacteria and associated endotoxins, as well as over-activation of the immune system in the intestine and liver. PMID- 27498581 TI - Bio-compatibility and cytotoxicity studies of water-soluble CuInS2-ZnS-AFP fluorescence probe in liver cancer cells. AB - BACKGROUND: The oncogenesis of hepatocellular carcinoma (HCC) is not clear. The current methods of the pertinent studies are not precise and sensitive. The present study was to use liver cancer cell line to explore the bio-compatibility and cytotoxicity of ternary quantum dots (QDs) probe and to evaluate the possible application of QDs in HCC. METHODS: CuInS2-ZnS-AFP fluorescence probe was designed and synthesized to label the liver cancer cell HepG2. The cytotoxicity of CuInS2-ZnS-AFP probe was evaluated by MTT experiments and flow cytometry. RESULTS: The labeling experiments indicated that CuInS2-ZnS QDs conjugated with AFP antibody could enter HepG2 cells effectively and emit intensive yellow fluorescence by ultraviolet excitation without changing cellular morphology. Toxicity tests suggested that the cytotoxicity of CuInS2-ZnS-AFP probe was significantly lower than that of CdTe-ZnS-AFP probe (t test, F=0.8, T=-69.326, P<0.001). For CuInS2-ZnS-AFP probe, time-effect relationship was presented in intermediate concentration (>20%) groups (P<0.05) and dose-effect relationship was presented in almost all of the groups (P<0.05). CONCLUSION: CuInS2-ZnS-AFP QDs probe had better bio-compatibility and lower cytotoxicity compared with CdTe ZnS-AFP probe, and could be used for imaging the living cells in vitro. PMID- 27498582 TI - Long-term follow-up of children and adolescents with primary sclerosing cholangitis and autoimmune sclerosing cholangitis. AB - BACKGROUND: Sclerosing cholangitis (SC) is a chronic cholestatic hepatobiliary disease with uncertain long-term prognosis in pediatric patients. This study aimed to evaluate long-term results in children with SC according to the types of SC. METHODS: We retrospectively followed up 25 children with SC over a period of 4-17 years (median 12). The diagnosis of SC was based on biochemical, histological and cholangiographic findings. Patients fulfilling diagnostic criteria for probable or definite autoimmune hepatitis at the time of diagnosis were defined as having autoimmune sclerosing cholangitis (ASC); other patients were included in a group of primary sclerosing cholangitis (PSC). The incidence of the following complications was studied: obstructive cholangitis, portal hypertension, advanced liver disease and death associated with the primary disease. RESULTS: Fourteen (56%) patients had PSC and 11 (44%) had ASC. Patients with ASC were significantly younger at the time of diagnosis (12.3 vs 15.4 years, P=0.032) and had higher IgG levels (22.7 vs 17.2 g/L, P=0.003). The mentioned complications occurred in 4 (16%) patients with SC, exclusively in the PSC group: one patient died from colorectal cancer, one patient underwent liver transplantation and two patients, in whom severe bile duct stenosis was present at diagnosis, were endoscopically treated for acute cholangitis. Furthermore, two other children with ASC and 2 children with PSC had elevated aminotransferase levels. The 10-year overall survival was 95.8% in all patients, 100% in patients without complicated liver disease, and 75.0% in patients with complications. CONCLUSION: In children, ASC is a frequent type of SC, whose prognosis may be better than that in patients with PSC. PMID- 27498583 TI - Outcomes of pancreaticoduodenectomy in elderly patients. AB - BACKGROUND: Although the mortality and morbidity of pancreaticoduodenectomy (PD) have improved significantly over the past years, the concerns for elderly patients undergoing PD are still present. Furthermore, the frequency of PD is increasing because of the increasing proportion of elderly patients and the increasing incidence of periampullary tumors. This study aimed to analyze the outcomes of PD in elderly patients. METHODS: We studied all patients who had undergone PD in our center between January 1995 and February 2015. The patients were divided into three groups based on age: group I (patients aged <60 years), group II (those aged 60 to 69 years) and group III (those aged >=70 years). The primary outcome was the rate of total postoperative complications. Secondary endpoint included total operative time, hospital mortality, length of postoperative hospital stay, delayed gastric emptying, re-exploration, and survival rate. RESULTS: A total of 828 patients who had undergone PD for resection of periampullary tumor were included in this study. There were 579 (69.9%) patients in group I, 201 (24.3%) in group II, and 48 (5.8%) in group III. The overall incidence of complications was higher in elderly patients (25.9% in group I, 36.8% in group II, and 37.5% in group III; P=0.006). There were more patients complicated with delayed gastric emptying in group II compared with the other two groups. There was no significant difference in the incidence of postoperative pancreatic fistula, biliary leakage, pancreatitis, pulmonary complications and hospital mortality. CONCLUSIONS: PD can be performed safely in selected elderly patients. Advanced age alone should not be a contraindication for PD. The outcome of elderly patients who have undergone PD is similar to that of younger patients, and the increased rate of complications is due to the presence of associated comorbidities. PMID- 27498584 TI - Risk factors of infected pancreatic necrosis secondary to severe acute pancreatitis. AB - BACKGROUND: Severe acute pancreatitis (SAP) remains a clinical challenge with considerable morbidity and mortality. An early identification of infected pancreatic necrosis (IPN), a life-threatening evolution secondary to SAP, is obliged for a more preferable prognosis. Thus, the present study was conducted to identify the risk factors of IPN secondary to SAP. METHODS: The clinical data of patients with SAP were retrospectively analyzed. Univariate and multivariate logistic regression analyses were sequentially performed to assess the associations between the variables and the development of IPN secondary to SAP. A receiver operating characteristic (ROC) curve was created for each of the qualified independent risk factors. RESULTS: Of the 115 eligible patients, 39 (33.9%) progressed to IPN, and the overall in-hospital mortality was 11.3% (13/115). The early enteral nutrition (EEN) (P=0.0092, OR=0.264), maximum intra abdominal pressure (IAP) (P=0.0398, OR=1.131) and maximum D-dimer level (P=0.0001, OR=1.006) in the first three consecutive days were independent risk factors associated with IPN secondary to SAP. The area under ROC curve (AUC) was 0.774 for the maximum D-dimer level in the first three consecutive days and the sensitivity was 90% and the specificity was 58% at a cut-off value of 933.5 MUg/L; the AUC was 0.831 for the maximum IAP in the first three consecutive days and the sensitivity was 95% and specificity was 58% at a cut-off value of 13.5 mmHg. CONCLUSIONS: The present study suggested that the maximum D-dimer level and/or maximum IAP in the first three consecutive days after admission were risk factors of IPN secondary to SAP; an EEN might be helpful to prevent the progression of IPN secondary to SAP. PMID- 27498585 TI - Pancreatitis in pregnancy: etiology, diagnosis, treatment, and outcomes. AB - BACKGROUND: Acute pancreatitis in pregnancy is a rare and dangerous disease. This study aimed to examine the etiology, treatment, and outcomes of pancreatitis in pregnancy. METHOD: A total of 25 pregnant patients diagnosed with pancreatitis during the period of 1994 and 2014 was analyzed retrospectively. RESULTS: The pregnant patients were diagnosed with pancreatitis during a period of 21 years. Most (60%) of the patients were diagnosed with pancreatitis in the third trimester. The mean age of the patients at presentation was 25.7 years, with a mean gestational age of 24.4 weeks. Abdominal pain occurred in most patients and vomiting in one patient was associated hyperemesis gravidarum. The common cause of the disease was gallstone-related (56%), followed by alcohol-related (16%), post-ERCP (4%), hereditary (4%) and undetermined conditions (20%). The level of triglycerides was minimally high in three patients. ERCP and wire-guided sphincterotomy were performed in 6 (43%) of 14 patients with gallstone-related pancreatitis and elevated liver enzymes with no complications. Most (84%) of the patients underwent a full-term, vaginal delivery. There was no difference in either maternal or fetal outcomes after ERCP. CONCLUSIONS: Acute pancreatitis is rare in pregnancy, occurring most commonly in the third trimester, and gallstones are the most common cause. When laparoscopic cholecystectomy is not feasible and a common bile duct stone is highly suspected on imaging, endoscopic sphincterotomy or stenting may help to prevent recurrence and postpone cholecystectomy until after delivery. PMID- 27498586 TI - Kidney transplantation after liver transplantation. AB - Kidney transplantation after liver transplantation (KALT) offers longer survival and a better quality of life to liver transplantation recipients who develop chronic renal failure. This article aimed to discuss the efficacy and safety of KALT compared with other treatments. The medical records of 5 patients who had undergone KALT were retrospectively studied, together with a literature review of studies. Three of them developed chronic renal failure after liver transplantation because of calcineurin inhibitor (CNI)-induced nephrotoxicity, while the others had lupus nephritis or non-CNI drug-induced nephrotoxicity. No mortality was observed in the 5 patients. Three KALT cases showed good prognoses, maintaining a normal serum creatinine level during entire follow-up period. Chronic rejection occurred in the other two patients, and a kidney graft was removed from one of them. Our data suggested that KALT is a good alternative to dialysis for liver transplantation recipients. The cases also indicate that KALT can be performed with good long-term survival. PMID- 27498587 TI - Type 2 diabetes, high blood pressure and acute pancreatitis. PMID- 27498588 TI - Implication of genomic characterization in synchronous endometrial and ovarian cancers of endometrioid histology. AB - OBJECTIVES: Synchronous endometrial and ovarian carcinomas (SEOCs) present gynecologic oncologists with a challenging diagnostic puzzle: discriminating between double primary cancers and single primary cancer with metastasis. We aimed to determine the clonal relationship between simultaneously diagnosed endometrial and ovarian carcinomas. METHODS: Fourteen pairs of SEOCs of endometrioid type and two pairs of SEOCs with disparate histologic types (control for dual primary tumors) were subjected to massively parallel sequencing (MPS) and molecular inversion probe microarrays. RESULTS: Thirteen of the 14 pairs of SEOCs harbored somatic mutations shared by both uterine and ovarian lesions, indicative of clonality. High degree of chromosomal instability in the tumors from 10 patients who received adjuvant chemotherapy, of whom 9 had synchronous carcinomas with significantly overlapping copy number alterations (CNAs), suggestive of single primary tumors with metastasis. The clonal relationship determined by genomic analyses did not agree with clinicopathological criteria in 11 of 14 cases. Minimal CNAs were identified in both ovarian and endometrial carcinomas in 4 patients, who did not receive adjuvant chemotherapy and experienced no recurrent diseases. In contrast, two of the 10 patients with chromosomally unstable cancers developed recurrent tumors. CONCLUSION: Our findings support a recent paradigm-shifting concept that most SEOCs originate from a single tumor. It also casts doubt on the clinicopathological criteria used to distinguish between dual primary tumors and single primary tumor with metastasis. Testing of CNAs on SEOCs may help determining the need of adjuvant therapy. PMID- 27498589 TI - Comprehensive evaluation of liver microsomal cytochrome P450 3A (CYP3A) inhibition: comparison of cynomolgus monkey and human. AB - 1. Members of the cytochrome P450 3A (CYP3A) subfamily metabolize numerous compounds and serve as the loci of drug-drug interactions (DDIs). Because of high amino acid sequence identity with human CYP3A, the cynomolgus monkey has been proposed as a model species to support DDI risk assessment. 2. Therefore, the objective of this study was to evaluate 35 known inhibitors of human CYP3A using human (HLM) and cynomolgus monkey (CLM) liver microsomes. Midazolam was employed as substrate to generate IC50 values (concentration of inhibitor rendering 50% inhibition) in the absence and presence of a preincubation (30 mins) with NADPH. 3. In the absence of preincubation, the IC50 values generated with CLM were similar to those obtained with HLM (86% within 2-fold; 100% within 3-fold difference). However, significant differences (up to 48-fold) in preincubation IC50 were observed with 17% of the compounds (raloxifene, bergamottin, nicardipine, mibefradil, ritonavir, and diltiazem). 4. Our results indicate that in most cases the cynomolgus monkey can be a viable DDI model. However, significant species differences in time-dependent CYP3A inhibition can be observed for some compounds. In the case of raloxifene, such a difference can be ascribed to a specific CYP3A4 amino acid residue. PMID- 27498590 TI - Effective cleavage of phosphodiester promoted by the zinc(II) and copper(II) inclusion complexes of beta-cyclodextrin. AB - To construct the model of metallohydrolase, two inclusion complexes [MLCl2(beta CD)] (1, M=Zn(II); 2, M=Cu(II); L=N,N'-bis(2-pyridylmethyl)amantadine; beta CD=beta-cyclodextrin) were synthesized by mixing beta-CDs with the pre synthesized complexes G1, [ZnLCl2] and G2, [CuLCl2]. Structures of G1, G2, 1 and 2 were characterized by X-ray crystallography, respectively. In solution, two chloride anions of G1 and G2 underwent ligand exchange with solvent molecules according to ESI-MS analysis. The chemical equilibrium constants were determined by potentiometric pH titration. The kinetics of bis(4-nitrophenyl) phosphate (BNPP) hydrolysis catalyzed by G1, G2, 1 and 2 were examined at pHs ranging from 7.50 to 10.50 at 308+/-0.1K. The pH profile of rate constant of BNPP hydrolysis catalyzed by 1 exhibited an exponential increase with the second-order rate constant of 2.68*10-3M-1s-1 assigned to the di-hydroxo species, which was approximately an order of magnitude higher than those of reported mono-Zn(II) hydroxo species. The high reactivity was presumably hydroxyl-rich microenvironment provided by beta-CDs, which might effect in stabilizing either the labile zinc-hydroxo species or the catalytic transition state. PMID- 27498592 TI - Hexaarylbenzene: Evolution of Properties and Applications of Multitalented Scaffold. AB - The easily rotatable peripheral aromatic rings around central benzene in hexaarylbenzene (HAB) derivatives create a very intriguing nonplanar, propeller shaped geometry. Because of the very low susceptibility toward self-aggregation, HAB derivatives are much stronger candidates among various polyphenylenes/hetero oligophenylenes when poor molecular cohesion and inefficient packing is required. However, the native properties of hexaphenylbenzene (HPB) can be varied by proper tailoring and substitution of the HAB core. The cohesion and packing in the structures of HAB aggregates induce effective structural variations so as to modify the fundamental features. Recently, HAB derivatives attracted a lot of research interest because of their significant role as liquid crystalline materials, organic light-emitting diodes, photochemical switches, redox materials, and molecular receptors. Herein, detailed attention is given to the pioneering work based on synthetic optimization of different HAB cores, elaborated study of their crystal engineering, various interesting applications of HAB derivatives, and future possibilities and capabilities of this still underexplored scaffold. PMID- 27498593 TI - Globular-disorder transition in proteins: a compromise between hydrophobic and electrostatic interactions? AB - The charge-hydrophobicity correlation of globular and disordered proteins is explored using a generalized self-consistent field theoretical method combined with Monte Carlo simulations. Globular and disordered protein sequences with varied mean net charge and mean hydrophobicity are designed by theory, while Metropolis Monte Carlo generates a suitable ensemble of conformations. Results imply a transition of the dominant interactions between globular and disordered proteins across the charge-hydrophobicity boundary. It is observed that the charge-hydrophobicity boundary actually represents a trade-off between the repulsive and attractive interactions in a protein sequence. The attractive interactions predominate on the globular side of the boundary, while the repulsive interactions prevail on the disordered side. For globular proteins, core forming hydrophobic interactions are dominant leading to a minimally frustrated native conformation. For disordered proteins, the repulsive electrostatic interactions prevail yielding a minimally frustrated region comprising of an expanded, dynamic conformational ensemble. Thus, protein disorder, like protein folding, satisfies the principle of minimal frustration. All results are compared to real globular and disordered proteins. Thus this algorithm may be useful to probe the conformational characteristics of disordered proteins. PMID- 27498591 TI - Use of ferrous iron by metallo-beta-lactamases. AB - Metallo-beta-lactamases (MBLs) catalyse the hydrolysis of almost all beta-lactam antibacterials including the latest generation carbapenems and are a growing worldwide clinical problem. It is proposed that MBLs employ one or two zinc ion cofactors in vivo. Isolated MBLs are reported to use transition metal ions other than zinc, including copper, cadmium and manganese, with iron ions being a notable exception. We report kinetic and biophysical studies with the di-iron(II) substituted metallo-beta-lactamase II from Bacillus cereus (di-Fe(II) BcII) and the clinically relevant B1 subclass Verona integron-encoded metallo-beta lactamase 2 (di-Fe(II) VIM-2). The results reveal that MBLs can employ ferrous iron in catalysis, but with altered kinetic and inhibition profiles compared to the zinc enzymes. A crystal structure of di-Fe(II) BcII reveals only small overall changes in the active site compared to the di-Zn(II) enzyme including retention of the di-metal bridging water; however, the positions of the metal ions are altered in the di-Fe(II) compared to the di-Zn(II) structure. Stopped flow analyses reveal that the mechanism of nitrocefin hydrolysis by both di Fe(II) BcII and di-Fe(II) VIM-2 is altered compared to the di-Zn(II) enzymes. Notably, given that the MBLs are the subject of current medicinal chemistry efforts, the results raise the possibility the Fe(II)-substituted MBLs may be of clinical relevance under conditions of low zinc availability, and reveal potential variation in inhibitor activity against the differently metallated MBLs. PMID- 27498594 TI - Incompatibility between fasting and postprandial plasma glucose in patients with Cushing's syndrome. AB - It is shown that glucocorticoids have discordant effects on plasma glucose concentration through their effects on hepatic glycogen deposition, gluconeogenesis and peripheral insulin resistance. Cushing's syndrome caused by cortisol overproduction is frequently accompanied with diabetes mellitus, but fasting plasma glucose (FPG) and post-glucose load plasma glucose levels are not examined in patients with Cushing's syndrome. The aim of this study was to investigate FPG, HbA1c and oral glucose tolerance test (OGTT) 2-h PG and their relationship in patients with Cushing's syndrome, in comparison with control subjects. Sixteen patients with Cushing's syndrome (ACTH-dependent 31%, ACTH independent 69% and diabetes mellitus 50%) and 64 controls (32 patients with type 2 diabetes mellitus and 32 non-diabetic subjects matched for age, sex and BMI) were enrolled in this study. HbA1c and FPG in the patients with Cushing's syndrome were not different from the controls, whereas the FPG/HbA1c ratio was significantly lower in the patients with Cushing's syndrome than the controls. OGTT 2-h PG was significantly higher in the non-diabetic patients with Cushing's syndrome than the non-diabetic controls, while HbA1c was not different between both groups and FPG was significantly lower in the patients with Cushing's syndrome than the controls. HOMA-beta but not HOMA-R was significantly higher in the patients with Cushing's syndrome than the controls. In conclusion, FPG was rather lower in the patients with Cushing's syndrome than the controls. Postprandial PG or post-glucose loaded PG, but not FPG, is useful to evaluate the abnormality of glucose metabolism in patients with Cushing's syndrome. PMID- 27498595 TI - Early safety and efficacy outcomes of a novel technique of sacrocolpopexy for the treatment of apical prolapse. AB - OBJECTIVE: To assess the safety and efficacy of a modified technique of bilateral abdominal sacrocolpopexy in which both uterosacral ligaments are replaced with polyvinylidene fluoride mesh to provide support to the cervix (cervico-sacropexy [CESA]) or vaginal vault (vagino-sacropexy [VASA]). METHODS: A retrospective observational study was undertaken of women with posthysterectomy vault prolapse or recurrent apical prolapse following previous prolapse repair who underwent bilateral sacrocolpopexy between July 1, 2013, and December 31, 2014, in a tertiary referral unit in the UK. Before surgery and 3 months afterwards, prolapse was assessed using the Pelvic Organ Prolapse Quantification scale and functional outcomes were recorded using the International Consultation on Incontinence Questionnaire for vaginal symptoms and urinary incontinence. RESULTS: Fifty women were included. At 3 months, 47 (94%) patients reported no bulge symptoms and the mean point C was -7.6. Complications comprised bladder injury in 1 (2%) and minor wound problems in 3 (6%) patients. No mesh erosion was reported. CONCLUSION: Bilateral abdominal sacrocolpopexy seems to be a safe and effective option for apical prolapse. Longer-term follow-up is needed to detect prolapse recurrence and mesh-related complications. PMID- 27498596 TI - Breast reconstruction in older patients: A literature review of the decision making process. AB - AIM: Women not undergoing breast reconstruction after mastectomy tend to be older. This review aims to aid in effective, evidence-based choices regarding breast reconstruction in an older population, appraising the influencing patient factors described in the literature and those directing the reconstructive surgeon. This may refute current misconceptions and ensure surgical decisions are made based on evidence without ageist assumptions. The review forms the basis of an evidence-based algorithm addressing each step of the decision-making process. METHOD: A literature search was conducted using PubMed, Medline, Evidence.nhs.uk and the Cochrane database. Search terms initially were breast reconstruction, mastectomy, elderly, older, decision, reasons and rationale. A separate literature search was performed for each of the individual 'steps' in the decision-making process. RESULTS: Overall, 44 papers were obtained. For each section of the decision-making process, titles and abstracts were screened for relevance. Only English language papers were included. CONCLUSION: If reconstruction is oncologically plausible and co-morbidities and frailty formally assessed, older women should be actively informed about breast reconstruction, receive support and engage in 'shared decision-making'. The older patient is less likely to do research independently. Amongst other factors, body image, cancer fears, employment and carer responsibilities play a part in the decision. With adequate preoperative and frailty assessment and early involvement of the geriatrician and anaesthetist, microsurgical reconstruction is safe. Autologous reconstruction has better long-term outcomes than implant-based reconstructions in this age group, correlating with improved survival and longevity of reconstruction. Age alone should not be considered a contraindication to breast reconstruction. PMID- 27498597 TI - Fucoidan inhibits angiogenesis induced by multiple myeloma cells. AB - Multiple myeloma (MM) remains an incurable hematological neoplasms. Our previous studies showed that Fucoidan possessed anti-myeloma effect by inducing apoptosis and inhibiting invasion of myeloma cells. In this study, we evaluated the effect of Fucoidan on angiogenesis induced by human myeloma cells and elucidated its possible mechanisms. Multiple myeloma cells were treated with Fucoidan at different concentrations, then the conditioned medium (CM) was collected. The levels of VEGF in the CM were tested by ELISA. The results showed that Fucoidan significantly decreased VEGF secretion by RPMI-8226 and U266 cells. The tube formation assay and migration test on human umbilical vein endothelial cells (HUVECs) were used to examine the effect of Fucoidan on angiogenesis induced by human myeloma cells. The results showed that Fucoidan decreased HUVECs formed tube structures and inhibited HUVECs migration, and suppressed the angiogenic ability of multiple myeloma RPMI-8226 and U266 cells in a dose-dependent manner. The study also showed that Fucoidan downregulated the expression of several kinds of proteins, which may be correlated with the reduction of angiogenesis induced by myeloma cells. Moreover, results were compared from normoxic and hypoxic conditions, they showed that Fucoidan had anti-angiogenic activity. Furthermore, in a multiple myeloma xenograft mouse model, it indicated that Fucoidan negatively affected tumor growth and angiogenesis in vivo. In conclusion, our results demonstrate that Fucoidan was able to interfere with angiogenesis of multiple myeloma cells both in vitro and in vivo and may have a substantial potential in the treatment of MM. PMID- 27498598 TI - Re: Efficacy of High-intensity Local Treatment for Metastatic Urothelial Carcinoma of the Bladder: A Propensity Score-Weighted Analysis from the National Cancer Data Base. PMID- 27498599 TI - Familial Associations Between Prostate Cancer and Other Cancers. AB - : Prostate cancer (PCa) has a large familial component, but understanding of its genetic basis is fragmentary. Breast cancers may be associated with PCa, but whether this is true for other tumor types is poorly established. We used a novel approach to study familial associations of any type of cancer with PCa. We assessed the relative risk (RR) for all types of tumors as a function of the number of first-degree relatives diagnosed with PCa. We hypothesized that for a familial association to be real, the RR for a given type of cancer should increase with the number of PCa diagnoses. In families with multiple PCa patients, significantly increased risks were observed for female breast cancer (RR 1.37 for families with three men with PCa), kidney cancer (RR 2.32), nervous system tumors (RR 1.77; RR 2.40 when PCa was diagnosed before age 70 yr), and myeloma (RR 2.44; RR 6.29 when PCa was diagnosed before age 70 yr). Some evidence of association was also found for melanoma (RR 1.82) and endocrine tumors (RR 2.18). The consistency and magnitude of the effects suggest that familial PCa is genetically associated with breast, kidney, and nervous system tumors and myeloma. This suggestion has implications for clinical counseling and design of genetic studies. PATIENT SUMMARY: It is known that prostate cancer runs in families, but it is not known whether other cancers are common in such families. We showed that at least breast, kidney, and nervous system tumors and myeloma occur more often than by chance. PMID- 27498600 TI - Neuroprotective effects of caffeic acid phenethyl ester against sevoflurane induced neuronal degeneration in the hippocampus of neonatal rats involve MAPK and PI3K/Akt signaling pathways. AB - Millions of infants and children are exposed to anesthesia every year during medical care. Sevoflurane is a volatile anesthetic that is frequently used for pediatric anesthesia. However, previous reports have suggested that the administration of sevoflurane promotes neurodegeneration, raising concerns regarding the safety of its usage. The present study aimed to investigate caffeic acid phenethyl ester (CAPE) and its protective effect against sevoflurane-induced neurotoxicity in neonatal rats. Rat pups were administered with CAPE at 10, 20 or 40 mg/kg body weight from postnatal day 1 (P1) to P15. The P7 rats were exposed to sevoflurane (2.9%) for 6 h. Control group rats received no sevoflurane or CAPE. Neuronal apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. The expression levels of caspases (caspase-3, -8 and -9), apoptotic pathway proteins [Bcl-2-associated X protein (Bax), B cell CCL/lymphoma 2 (Bcl-2), Bcl-2-like 1 (Bcl-xL), Bcl-2-associated agonist of cell death (Bad) and phosphorylated (p)-Bad], mitogen-activated protein kinases (MAPK) signaling pathway proteins [c-Jun N-terminal kinase (JNK), p-JNK, extracellular signal-regulated kinase (ERK)1/2, p-ERK1/2, p38, p-p38 and p-c-Jun] and the phosphoinositide 3-kinase (PI3K)/Akt cascade were evaluated by western blotting following sevoflurane and CAPE treatment. In addition, the expression of cleaved caspase-3 was analyzed by immunohistochemistry. CAPE significantly reduced sevoflurane-induced apoptosis, downregulated the expression levels of caspases and pro-apoptotic proteins (Bax and Bad) and elevated the expression levels of Bcl-2 and Bcl-xL when compared with sevoflurane treatment. Furthermore, CAPE appeared to modify the expression levels of MAPKs and activate the PI3K/Akt signaling pathway. Thus, the present study demonstrated that CAPE effectively inhibited sevoflurane-induced neuroapoptosis by modulating the expression and phosphorylation of apoptotic pathway proteins and MAPKs, and by regulating the PI3K/Akt pathway. PMID- 27498601 TI - Sustained Impact of an Antibiotic Stewardship Intervention for Community-Acquired Pneumonia. AB - Antibiotic stewardship interventions targeting community-acquired pneumonia have been successful in reducing antibiotic overuse in the short term, but the sustainability of their effects has not been investigated. We report that improvements in antibiotic use due to a syndrome-focused intervention for community-acquired pneumonia were sustained 3 years later without additional intervention. Infect Control Hosp Epidemiol 2016;1-4. PMID- 27498602 TI - Choroidal and Retinal Thickness in Children With Different Refractive Status Measured by Swept-Source Optical Coherence Tomography. PMID- 27498603 TI - Right to property, inheritance, and contract and persons with mental illness. AB - Discrimination against people with mental illness is rife across the globe. Among different types of discrimination is the policy in many countries where persons with mental illness are forbidden to inherit property, and they are not able to enter into a contract in a large number of countries. Using various databases, legislations dealing with law of contract, law of succession/inheritance, and law relating to testamentary capacity (wills) of all UN Member states (193 countries) were studied. With respect to federal countries, the laws of the most populous state as a representative state in the respective country were studied. Only 40 Member States (21%) recognize/allow persons with mental health problems to enter into contracts. Of these, however, only 16 Member States (9%) recognize the right of persons with mental health problems to enter into a contract without any restrictions. The remaining 24 Member States (12%) allow a contract entered into by a person with mental health problems to be invalidated under certain conditions. These countries also make the validity of the contract subject to the capacity to consent or based on the level of understanding of the person with mental health problems. They may allow persons with mental health problems to enter into contracts only for transactions of an insignificant nature or of personal rights. Only 9% of the countries allow people with mental illness to enter into contracts in an unrestricted way. Furthermore, there remain variations between high income and low income states. In spite of international laws in many countries, laws remain discriminatory. PMID- 27498605 TI - The Ti-Mn system revisited: experimental investigation and thermodynamic modelling. AB - As the Ti-Mn phase diagram is part of numerous ternary and higher order systems of technological importance, the present paper defines phase relations which have been experimentally established throughout this work from 800 degrees C to the melting range based on Differential Thermal Analyses (DTA), X-ray powder diffraction, metallography and Electron Probe Micro Analysis (EPMA) techniques on ~50 alloys, which were prepared by arc melting or high frequency melting under high purity argon starting from freshly cleaned metal ingots. Novel compounds were identified and reaction isotherms were redefined accordingly. In the Ti-rich region a novel compound TiMn was detected, sandwiched between the known phases: TiMn1-x (~45 at% Mn) and TiMn1+x (~55 at% Mn). In the Mn-rich region the hitherto unknown crystal structure of TiMn~3 was solved from X-ray single crystal diffraction data and found to be of a unique structure type Ti6(Ti1-xMnx)6Mn25 (x = 0.462; space group Pbam (#55); a = 0.79081(3) nm, b = 2.58557(9) nm, c = 0.47931(2) nm), which consists of two consecutive layers of the hexagonal MgZn2 type Laves phase (TiMn2) and a combined layer of alternate structure blocks of MgZn2 type and Zr4Al3 type. Whereas TiMn can be considered as a line compound (solubility range <~1 at%), the homogeneity regions of the Ti-Mn compounds are significant (determined by EPMA): TiMn1-x (44.0 to 46.6 at% Mn), TiMn1+x (54.6 to 56.3 at% Mn), Ti1+xMn2-x (MgZn2-type, 59 to 69 at% Mn at 1000 degrees C: -0.08 < x < 0.23), TiMn~3 (unique type; 74 to 76.5 at% Mn) and TiMn~4 (R-phase: Ti8(TixMn1-x)6Mn39, 80 to 84 at% Ti). Supported by ab initio calculations of the ground state energy for the Laves phase, the new experimental results enabled thermodynamic modelling of the entire Ti-Mn phase diagram providing a complete and novel set of thermodynamic data thus providing a sound basis for future thermodynamic predictions of higher order Ti-Mn-X-Y systems. PMID- 27498606 TI - Long-Term Effects of Repeated Prefrontal Cortex Transcranial Direct Current Stimulation (tDCS) on Food Craving in Normal and Overweight Young Adults. AB - BACKGROUND: The dorsolateral prefrontal cortex (DLPFC) plays an important role in the regulation of food intake. Several previous studies demonstrated that a single session of transcranial direct current stimulation (tDCS) of the DLPFC reduces food craving and caloric intake. OBJECTIVES: We hypothesized that repeated tDCS of the right DLPFC cortex may exert long-term changes in food craving in young, healthy adults and that these changes may differ between normal and overweight subjects. METHODS: Thirty healthy individuals who reported frequent food cravings without a prior history of eating disorders were initially recruited. Subjects were randomized into an ACTIVE group who received 5 days of real tDCS (20 minutes, anode right-cathode left montage, 2 mA with current density kept at 0.06 mA/cm2, 1 min ramp-up/ramp-down), and a SHAM group, who received one day of real tDCS, on the first day (same parameters), followed by 4 days of sham tDCS. Food craving intensity was examined by Food Craving Questionnaires State and Trait and Food Craving Inventory before, during, (5 days) and one month (30-days) after tDCS. RESULTS: Single session of tDCS significantly reduced the intensity of current food craving (FCQ-S). Five days of active tDCS significantly reduced habitual experiences of food craving (FCQ-T), when compared to baseline pre-stimulation levels. Furthermore, both current (FCQ S) and habitual craving (FCQ-T) were significantly reduced 30 days after active tDCS, while sham tDCS, i.e. a single tDCS session did not have significant effects. Also, active tDCS significantly decreased craving for fast food and sweets, and to a lesser degree for fat, while it did not have significant effects on craving for carbohydrates (FCI). There were no significant differences between individual FCQ-T subscales (craving dimensions) after 5 or 30 days of either sham or active tDCS. Changes in craving were not significantly associated with the initial weight, or with weight changes 30 days after the stimulation in the subjects. CONCLUSIONS: The results confirm earlier findings that single session of tDCS has immediate effects in reducing food craving. They also show that repeated tDCS over the right DLPFC may increase the duration of its effects, which may be present 30 days after the stimulation. These results support further investigation of the use of tDCS in obesity. PMID- 27498604 TI - Cytokine decoy and scavenger receptors as key regulators of immunity and inflammation. AB - IL-1R2 was the first decoy receptor to be described. Subsequently receptors which act as pure decoys or scavengers or trigger dampening of cytokine signaling have been described for cytokines and chemokines. Here we review the current understanding of the mode of action and significance in pathology of the chemokine atypical receptor ACKR2, the IL-1 decoy receptor IL-1R2 and the atypical IL-1 receptor family IL-1R8. Decoy and scavenger receptors with no or atypical signaling have emerged as a general strategy conserved in evolution to tune the action of cytokines, chemokines and growth factors. PMID- 27498607 TI - Enhanced gas separation factors of microporous polymer constrained in the channels of anodic alumina membranes. AB - New composite membranes based on porous anodic alumina films and polymer of intrinsic microporosity (PIM-1) have been prepared using a spin-coating technique. According to scanning electron microscopy, partial penetration of polymer into the pores of alumina supports takes place giving rise to selective polymeric layers with fiber-like microstructure. Geometric confinement of rigid PIM-1 in the channels of anodic alumina causes reduction of small-scale mobility in polymeric chains. As a result, transport of permanent gases, such as CH4, becomes significantly hindered across composite membranes. Contrary, the transport of condensable gases (CO2, S4H10), did not significantly suffer from the confinement due to high solubility in the polymer matrix. This strategy enables enhancement of selectivity towards CO2 and C4H10 without significant loss of the membrane performance and seems to be prospective for drain and sweetening of natural gas. PMID- 27498609 TI - Stability and reactivity control of carbenoids: recent advances and perspectives. AB - Metal carbenoids such as lithium or Simmons-Smith-type reagents are widely used in organic synthesis, particularly in cyclopropanation and homologation reactions. These reagents are often highly reactive and thermally labile, thus limiting their isolation and hampering the development of new synthetic applications. Recent years however, have shown that by means of systematic stabilization a control of reactivity and the development of new applications is possible. This feature article documents recent developments in the control of carbenoid reactivity and stability and highlights structural and electronic properties as well as applications in main group element and transition metal chemistry. PMID- 27498608 TI - Structure-function aspects of the Porphyromonas gingivalis tyrosine kinase Ptk1. AB - The development of synergistically pathogenic communities of Porphyromonas gingivalis and Streptococcus gordonii is controlled by a tyrosine-phosphorylation dependent signaling pathway in P. gingivalis. The Ptk1 bacterial tyrosine (BY) kinase of P. gingivalis is required for maximal community development and for the production of extracellular polysaccharide. We show that the consensus BY kinase Walker A and B domains, the RK cluster, and the YC domain of Ptk1 are necessary for autophosphorylation and for substrate phosphorylation. Mass spectrometry showed that six tyrosine residues in a 16-amino-acid C-terminal region were phosphorylated in recombinant (r) Ptk1. Complementation of a ptk1 mutant with the wild-type ptk1 allele in trans restored community development between P. gingivalis and S. gordonii, and extracellular polysaccharide production by P. gingivalis. In contrast, complementation of Deltaptk1 with ptk1 containing a mutation in the Walker A domain failed to restore community development or extracellular polysaccharide production. rPtk1 was capable of phosphorylating the tyrosine phosphatase Ltp1 and the transcriptional regulator CdhR, both of which are involved in the development of P. gingivalis communities with S. gordonii. PMID- 27498611 TI - Fluoroquinolone resistance of Streptococcus pneumoniae isolates causing invasive disease: special focus on zabofloxacin. AB - The present study examined the in vitro activity of various antibiotics including zabofloxacin, against isolates responsible for invasive pneumococcal diseases. Between 1997 and 2008, a total of 208 isolates were collected from sterile fluids, including blood (n=196, 94.2%), pleural fluid (n=5, 2.4%), cerebrospinal fluid (n=5, 2.4%), and ascites (n=2, 1.0%). Zabofloxacin showed the lowest MIC50 (0.015MUg/mL) and MIC90 (0.025MUg/mL) values of all the tested antibiotics. Rates of isolates resistant to penicillin (MIC >=8MUg/mL), ceftriaxone (MIC >=4MUg/mL) and levofloxacin (MIC >=8MUg/mL) were 3.4%, 0.4% and 2.0%, respectively. Four isolates (2.0%) were resistant to levofloxacin, and zabofloxacin showed low MICs (range, 0.025-0.125MUg/mL). Zabofloxacin shows potent in vitro activity against S. pneumoniae isolates that caused invasive disease, even strains that are resistant to levofloxacin. PMID- 27498610 TI - Population structure of invasive Streptococcus pneumoniae isolates among Alaskan children in the conjugate vaccine era, 2001 to 2013. AB - Here we describe the relationships between serotypes, genotypes, and antimicrobial susceptibility among isolates causing invasive pneumococcal disease in Alaskan children during the pneumococcal conjugate vaccine (PCV) era. From 2001 to 2013 we received 271 isolates representing 33 serotypes. The most common serotypes were 19A (29.5%, n= 80), 7F (12.5%, n= 34), 15B/C (6.3%, n= 17), and 22F (4.8%, n= 13). Multilocus sequence typing identified 11 clonal complexes (CC) and 45 singletons. Five CCs accounted for 52% (141/271) of the total: CC199 (21% [n= 57], serotypes 19A, 15B/C), CC191 (12.2% [n= 33], serotype 7F), CC172 (10.3% [n= 28], serotypes 19A, 23A, 23B), CC433 (4.4% [n= 12], serotype 22F), and CC100 (4.4% [n= 12], serotype 33F). The proportion of isolates nonsusceptible to erythromycin and tetracycline increased after 13-valent PCV use (14% [n= 30] versus 29% [n= 14]; P= 0.010) and (4% [n= 9] versus 22% [n= 11]; P< 0.001), respectively. The genetic diversity also increased after 13-valent PCV use (Simpson's diversity index =0.95 versus 0.91; P= 0.022). PMID- 27498612 TI - Elevated progesterone on the trigger day does not impair the outcome of Human Menotrophins Gonadotrophin and Medroxyprogesterone acetate treatment cycles. AB - To demonstrate the incidence and effects of elevated progesterone (P) on the trigger day on the outcome of in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles using Medroxyprogesterone acetate (MPA) co-treated with Human Menotrophins Gonadotrophin (hMG + MPA), we performed a retrospective analysis including 4106 IVF/ICSI cycles. The cycles were grouped according to the P level on the trigger day: <1 ng/mL, between 1-1.5 ng/ml (including 1), between 1.5-2 ng/mL (including 1.5), and >=2 ng/mL. The primary outcome measure was live birth rate. The prevalence of P level categories was 12.93% (531/4106), 2.92% (120/4106), and 1.92% (79/4106) in women with P between 1-1.5 ng/mL, between 1.5 2 ng/mL, and >=2 ng/mL, respectively. The mean stimulation duration, total hMG dose, serum follicle stimulating hormone (FSH), estrogen(E2) on the trigger day and the number of oocytes in patients with elevated P were significantly higher than patients with P < 1 ng/mL (P < 0.05). However, there were no significant differences in the oocyte retrieval rates, fertilization rates, implantation rates, clinical pregnancy rates and live birth rates between the groups based on frozen embryo transfer (FET). We concluded that elevated P on the trigger day had no negative effect on the final outcome of the hMG + MPA treatment cycles based on FET. PMID- 27498613 TI - Incorporating structure context of HA protein to improve antigenicity calculation for influenza virus A/H3N2. AB - The rapid and consistent mutation of influenza requires frequent evaluation of antigenicity variation among newly emerged strains, during which several in silico methods have been reported to facilitate the assays. In this paper, we designed a structure-based antigenicity scoring model instead of those sequence based previously published. Protein structural context was adopted to derive the antigenicity-dominant positions, as well as the physic-chemical change of local micro-environment in correlation with antigenicity change. Then a position specific scoring matrix (PSSM) profile and local environmental change over above positions were integrated to predict the antigenicity variance. Independent testing showed a high accuracy of 0.875, and sensitivity of 0.986, with a significant ability to discover antigenic-escaping strains. When applying this model to the historical data, global and regional antigenic drift events can be successfully detected. Furthermore, two well-known vaccine failure events were clearly suggested. Therefore, this structure-context model may be particularly useful to identify those to-be-failed vaccine strains, in addition to suggest potential new vaccine strains. PMID- 27498614 TI - First-principles analysis on role of spinel (111) phase boundaries in Li4+3xTi5O12 Li-ion battery anodes. AB - The practical anode material Li4+3xTi5O12 is known to undergo a two-phase separation into Li7Ti5O12 and Li4Ti5O12 during charging/discharging. This phase separated Li4+3xTi5O12 exhibits electron conduction, although individual phases are expected to be insulators. To elucidate the role played by spinel (111) phase boundaries on these physical properties, first principles calculations were carried out using the GGA+U method. Two-phase Li7Ti5O12/Li4Ti5O12 models are found to exhibit metallic characteristics near their phase boundaries. These boundaries provide conduction paths not only for electrons, but also for Li ions. Judging from the formation energy of Li vacancies/interstitials, the phase boundaries preferentially uptake or release Li via in-plane conduction and then continuously shift in a direction perpendicular to the phase boundary planes. The continuous phase boundary shift leads to a constant electrode potential. A three dimensional network of cubic {111} planes may contribute to smooth electrochemical reactions. PMID- 27498615 TI - A new quinolinone from freshwater lake-derived fungus Myrothecium verrucaria. AB - One new quinolinone, 7-hydroxy-3-methoxyviridicatin (1), along with eight known compounds (2-9) was isolated from the fungus Myrothecium verrucaria, which was collected from lake water of Chenghai, Yunnan Province, China. Their structures were elucidated by detailed analysis of spectroscopic data and comparison with related known compounds. Compounds 1 and 2 exhibited weak antibacterial activity. To the best of our knowledge, this is the first report on quinolinones (1-4) as the secondary metabolites of M. verrucaria. PMID- 27498616 TI - The Culprit Is in the Cave: The Core Sites Explain the Binding Profiles of Amyloid-Specific Tracers. AB - The design of molecular probes and tracer molecules with specificity toward amyloid beta (Abeta) fibrils is of paramount importance for the selective diagnosis of Alzheimer's disease. This requires a detailed understanding of the binding sites in amyloid targets, their number, and their binding mechanism for various tracer molecules. We adopt an integrated approach including molecular docking, molecular dynamics, and generalized Born-based free energy calculations to investigate site-specific interactions of different amyloid binding molecules. Our study reproduces the experimental results on the relative binding affinity of the tracers and amyloid binders and explains the feature of "multiple binding sites" in amyloid targets as probed by competition binding experiments. A major outcome of this study is that it is the core sites of the Abeta fibrils that are responsible for the experimentally reported binding profiles of tracers in amyloid targets rather than the surface sites that received much focus in earlier investigations. PMID- 27498617 TI - Paragonimus westermani infection mimicking recurrent lung cancer: A case report. AB - Herein, we report a case of Paragonimus westermani infection, which required differentiation from recurrent lung cancer. A 66-year old Japanese man with a history of lung cancer who had undergone a lobectomy was referred to our clinic for treatment of cough, sputum, dyspnea, and a right pulmonary nodule. He had previously eaten seafood he visited China. P. westermani infection was confirmed by the presence of antibody against P. westermani antigen in the patient's serum and eggs in his sputum. Eventually, molecular identification by PCR-restriction fragment length polymorphism analysis and sequencing confirmed that the patient was infected with triploid forms of P. westermani. PMID- 27498618 TI - Development of a Method for the N-Arylation of Amino Acid Esters with Aryl Triflates. AB - A general method for the N-arylation of amino acid esters with aryl triflates is described. Both alpha- and beta-amino acid esters, including methyl, tert-butyl, and benzyl esters, are viable substrates. Reaction optimization was carried out by design of experiment (DOE) analysis using JMP software. The mild reaction conditions, which use t-BuBrettPhos Pd G3 or G4 precatalyst, result in minimal racemization of the amino acid ester. This method is the first synthetic application of the t-BuBrettPhos Pd G4 precatalyst. Mechanistic studies show that the observed erosion in enantiomeric excess is due to racemization of the amino acid ester starting material and not of the product. PMID- 27498620 TI - Transcriptional regulation of E-cadherin by small activating RNA: A new double stranded RNA. AB - Recent studies have reported that chemically synthesized small activating RNA (saRNA) targeting the promoter regions of a gene can activate its expression in different cell lines. This technique can be a powerful therapeutic method for diseases caused by complete inactivation or reduced expression of specific genes. E-cadherin is a typical tumor suppressor gene. Loss of E-cadherin mediates the transition from benign lesions to invasive, metastatic cancer. In this study, several 21-nt small double-stranded RNAs (dsRNAs) targeting the promoter regions of human E-cadherin were designed and synthesized and the features of their function were investigated to study the regulatory role of dsRNA on E-cadherin expression. A new saRNA (dsEcad-661) that can enhance E-cadherin expression by targeting non-coding regulatory regions in gene promoters was identified. Using dsRNA with modified base quantity and cholesterol-conjugated dsRNA, we found the antisense strand may be the guide strand of saRNA in the upregulation of E cadherin. These findings provide several important pieces of evidence that may improve understanding of the function of saRNA and may promote its development for clinical application. PMID- 27498619 TI - Identification of uterine leiomyoma-specific marker genes based on DNA methylation and their clinical application. AB - Differential diagnosis of uterine leiomyomas and leiomyosarcomas is needed to determine whether the uterus can be retained. Therefore, biomarkers for uterine leiomyomas, and reliable and objective diagnostic methods have been desired besides the pathological diagnosis. In the present study, we identified 12 genes specific to uterine leiomyomas based on DNA methylation. Using these marker genes specific to uterine leiomyomas, we established a hierarchical clustering system based on the DNA methylation level of the marker genes, which could completely differentiate between uterine leiomyomas and normal myometrium. Furthermore, our hierarchical clustering system completely discriminated uterine cancers and differentiated between uterine leiomyosarcomas and leiomyomas with more than 70% accuracy. In conclusion, this study identified DNA methylation-based marker genes specific to uterine leiomyomas, and our hierarchical clustering system using these marker genes was useful for differential diagnosis of uterine leiomyomas and leiomyosarcomas. PMID- 27498621 TI - XIAP inhibits mature Smac-induced apoptosis by degrading it through ubiquitination in NSCLC. AB - X-linked inhibitor of apoptosis protein (XIAP) and second mitochondrial-derived activator of caspase (Smac) are two important prognostic biomarkers for cancer. They are negatively correlated in many types of cancer. However, their relationship is still unknown in lung cancer. In the present study, we found that there was a negative correlation between Smac and XIAP at the level of protein but not mRNA in NSCLC patients. However, XIAP overexpression had no effect on degrading endogenous Smac in lung cancer cell lines. Therefore, we constructed plasmids with full length of Smac (fSmac) and mature Smac (mSmac) which located in cytoplasm instead of original mitochondrial location, and was confirmed by immunofluorescence. Subsequently, we found that mSmac rather than fSmac was degraded by XIAP and inhibited cell viability. CHX chase assay and ubiquitin assay were performed to illustrate XIAP degraded mSmac through ubiquitin pathway. Overexpression of XIAP partially reverted apoptotic induction and cell viability inhibition by mSmac, which was due to inhibiting caspase-3 activation. In nude mouse xenograft experiments, mSmac inhibited Ki-67 expression and slowed down lung cancer growth, while XIAP partially reversed the effect of mSmac by degrading it. In conclusion, XIAP inhibits mature Smac-induced apoptosis by degrading it through ubiquitination in NSCLC. PMID- 27498623 TI - Direct Evidence of Solution-Mediated Superoxide Transport and Organic Radical Formation in Sodium-Oxygen Batteries. AB - Advanced large-scale electrochemical energy storage requires cost-effective battery systems with high energy densities. Aprotic sodium-oxygen (Na-O2) batteries offer advantages, being comprised of low-cost elements and possessing much lower charge overpotential and higher reversibility compared to their lithium-oxygen battery cousins. Although such differences have been explained by solution-mediated superoxide transport, the underlying nature of this mechanism is not fully understood. Water has been suggested to solubilize superoxide via formation of hydroperoxyl (HO2), but direct evidence of these HO2 radical species in cells has proven elusive. Here, we use ESR spectroscopy at 210 K to identify and quantify soluble HO2 radicals in the electrolyte-cold-trapped in situ to prolong their lifetime-in a Na-O2 cell. These investigations are coupled to parallel SEM studies that image crystalline sodium superoxide (NaO2) on the carbon cathode. The superoxide radicals were spin-trapped via reaction with 5,5 dimethyl-pyrroline N-oxide at different electrochemical stages, allowing monitoring of their production and consumption during cycling. Our results conclusively demonstrate that transport of superoxide from cathode to electrolyte leads to the nucleation and growth of NaO2, which follows classical mechanisms based on the variation of superoxide content in the electrolyte and its correlation with the crystallization of cubic NaO2. The changes in superoxide content upon charge show that charge proceeds through the reverse solution process. Furthermore, we identify the carbon-centered/oxygen-centered alkyl radicals arising from attack of these solubilized HO2 species on the diglyme solvent. This is the first direct evidence of such species, which are likely responsible for electrolyte degradation. PMID- 27498622 TI - Protection associated with a TB vaccine is linked to increased frequency of Ag85A specific CD4(+) T cells but no increase in avidity for Ag85A. AB - There is a need to improve the efficacy of Bacille Calmette-Guerin (BCG) vaccination against tuberculosis in humans and cattle. Previously, we found boosting BCG-primed cows with recombinant human type 5 adenovirus expressing antigen 85A (Ad5-85A) increased protection against Mycobacterium bovis infection compared to BCG vaccination alone. The aim of this study was to decipher aspects of the immune response associated with this enhanced protection. We compared BCG primed Ad5-85A-boosted cattle with BCG-vaccinated cattle. Polyclonal CD4(+) T cell libraries were generated from pre-boost and post-boost peripheral blood mononuclear cells - using a method adapted from Geiger et al. (2009) - and screened for antigen 85A (Ag85A) specificity. Ag85A-specific CD4(+) T cell lines were analysed for their avidity for Ag85A and their Ag85A epitope specificity was defined. Boosting BCG with Ad5-85A increased the frequencies of post-boost Ag85A specific CD4(+) T cells which correlated with protection (reduced pathology). Boosting Ag85A-specific CD4(+) T cell responses did not increase their avidity. The epitope specificity was variable between animals and we found no clear evidence for a post-boost epitope spreading. In conclusion, the protection associated with boosting BCG with Ad5-85A is linked with increased frequencies of Ag85A-specific CD4(+) T cells without increasing avidity or widening of the Ag85A specific CD4(+) T cell repertoire. PMID- 27498624 TI - Reaching across the shores to strengthen primary care. PMID- 27498625 TI - Real and illusory issues in the illusion debate (Why two things are sometimes better than one): Commentary on Kopiske et al. (2016). PMID- 27498627 TI - RUNX3 plays an important role in As2O3-induced apoptosis and allows cells to overcome MSC-mediated drug resistance. AB - The interaction between bone marrow stromal cells and leukemia cells is critical for the persistence and progression of leukemia, and this interaction may account for residual disease. However, the link between leukemia cells and their environment is still poorly understood. In our study, runt-related transcription factor 3 (RUNX3) was identified as a novel target gene affected by As2O3 and involved in mesenchymal stem cell (MSC)-mediated protection of leukemia cells from As2O3-induced apoptosis. We observed induction of RUNX3 expression and the translocation of RUNX3 into the nucleus after As2O3 treatment in leukemia cells. In K562 chronic myeloid leukemia cells, downregulation of endogenous RUNX3 compromised As2O3-induced growth inhibition, cell cycle arrest, and apoptosis. In the presence of MSC, As2O3-induced expression of RUNX3 was reduced significantly and this reduction was modulated by CXCL12/CXCR4 signaling. Furthermore, overexpression of RUNX3 restored, at least in part, the sensitivity of leukemic cells to As2O3. We conclude that RUNX3 plays an important role in As2O3-induced cellular responses and allows cells to overcome MSC-mediated drug resistance. Therefore, RUNX3 is a promising target for therapeutic approaches to overcome MSC mediated drug resistance. PMID- 27498628 TI - Diaza [1,4] Wittig-type rearrangement of N-allylic-N-Boc-hydrazines into gamma amino-N-Boc-enamines. AB - Diaza [1,4] Wittig-type rearrangement of N-allylic-N-Boc-hydrazines into gamma amino-N-Boc-enamines was demonstrated. The scope and limitation, experimental mechanistic studies, and a proposed reaction mechanism were also described. PMID- 27498626 TI - Should urinary iodine concentrations of school-aged children continue to be used as proxy for different populations? Analysis of data from Chinese national surveys. AB - I deficiency is a worldwide public health problem. Median urinary I concentration in school-aged children has been used globally as a proxy for all populations. This study aims to determine whether median urinary I concentration of school aged children is an appropriate indicator of I nutritional status in different adult populations. This is a secondary data analysis of two national I Deficiency Disorder surveys (2011, 2014) and two regional surveys (in coastal areas, 2009, and in high-risk areas, 2009-2014). Population groups included in these surveys were school-aged children (8-10 years), pregnant women, lactating women, women of childbearing age and adults (men and women, 18-45 years). All participants were self-reported healthy without history of thyroid diseases or were not using thyroid medicines. The median urinary I concentration of school-aged children was matched with that of the other population at the county level. The matched populations had similar iodised salt supply, food and water I, food composition and I content in salt. Weak or moderate correlation of median urinary I concentrations was observed between school-aged children and pregnant women and between children and lactating women. However, the agreement was stronger between children and women of childbearing age and between children and adult men and women. The results could be affected by cut-off values, data aggregation level and sample size. Using median urinary I concentration of school-aged children tends to overestimate that of pregnant women and lactating women. Median urinary I concentration of school-aged children can be used for assessing I nutrition in the adult population. PMID- 27498629 TI - Tuberculosis in newly arrived asylum seekers: A prospective 12 month surveillance study at Friedland, Germany. AB - PURPOSE: In the European Union tuberculosis prevalence-rates are among the lowest in the world. The prevalence of active tuberculosis in migrant populations has to be analyzed to get valid data on the risk of tuberculosis and for the decision of screening activities. METHODS: Therefore, we prospectively quantified the risk of active tuberculosis among asylum seekers at time of arrival. Investigation was performed as regular part of the admission screenings for people arriving at Friedland, Germany, a primary major receiving center during one year. RESULTS: In 11.773 newly arrived asylum seekers 16 X-ray investigations gave the suspicion of active tuberculosis, thereof 11 cases could be verified by culture, thereof 9 cases were classified as microscopically positive. These data translate into rates of 136 per 100.000 suspected cases, 93 per 100.000 verified cases, and finally 76 per 100.000 infectious cases, respectively. Prevalence was higher in asylum seekers coming from Eritrea and Russia compared to the main origins of current migration Syria, Afghanistan, Iraq, Iran, and Lebanon. One case of MDR tuberculosis could be detected in a migrant from Russia. CONCLUSIONS: Prevalence rates of tuberculosis in newly arrived asylum seekers are higher than in native European populations. Rates seem to reflect the prevalence in the home countries. X-ray investigation during first examination may help identifying people needing further tests for detecting infectious tuberculosis and therefore may prevent transmission. However due to the low prevalence rates screening procedures have to be reviewed. PMID- 27498630 TI - Post-industrial river water quality-Fit for bathing again? AB - For the Ruhr River, bathing has been prohibited for decades. However, along with significant improvements of the hygienic water quality, there is an increasing demand of using the river for recreational purposes, in particular for bathing. In the "Safe Ruhr" interdisciplinary research project, demands, options and chances for lifting the bathing ban for the Ruhr River were investigated. As being the prominent reason for persisting recreational restrictions, microbiological water quality was in the focus of interest. Not only the faecal indicator organisms (FIOs) as required by the European Bathing Water Directive were considered, but also pathogens such as Salmonella, Pseudomonas aeruginosa, Legionella pneumophila, Campylobacter, Leptospira, enteroviruses and protozoan parasites. In this introductory paper, we firstly relate current recreational desires to historical experiences of river bathing. After recapitulating relevant microbial river contamination sources (predominantly sewage treatment plants, combined sewer overflows, and surface runoffs), we review existing knowledge about the relationships of FIOs and pathogens in rivers designated for recreational purposes, and then trace the evolution, rationale and validity of recreational freshwater quality criteria which are, despite obvious uncertainties, mostly relying on the FIO paradigm. In particular, the representativeness of FIOs is critically discussed. The working programme of Safe Ruhr, aiming at initiating and facilitating a process towards legalisation of Ruhr River bathing, is outlined. Sources of contamination can be technically handled which leaves the actual measures to political decisions. As contaminations are transient, only occasionally exceeding legal limits, a flexible bathing site management, warning bathers of non-safe situations, may amend technical interventions and offer innovative solutions. As a result, a situation-adapted system for lifting of the bathing ban for Ruhr River appears realistic. PMID- 27498631 TI - The role of carbohydrate component of recombinant alpha7 nicotinic acetylcholine receptor extracellular domain in its immunogenicity and functional effects of resulting antibodies. AB - Nicotinic acetylcholine receptors of alpha7 subtype (alpha7 nAChRs) attenuate the inflammatory cytokines production by macrophages and are involved in pathogenesis of Alzheimer disease by directly influencing the processing of amyloid-beta (Abeta) precursor protein in the brain. Previously we found that regular injections of bacterial lipopolysaccharide (LPS) decreased the level of alpha7 nAChRs and stimulated accumulation of Abeta peptide (1-42) in the brain of mice resulting in memory impairment. Similar effects were observed in mice immunized with recombinant extracellular domain (1-208) of alpha7 nAChR subunit. However, the mechanism of inflammation-like effect of alpha7-specific antibodies remained unclear. The aim of the present study was to reveal the impact of carbohydrate component of recombinant alpha7(1-208) produced in yeast in the functional effect of resulting antibodies. For this purpose, C57Bl/6 mice were immunized with either initial alpha7(1-208) or with that pre-treated with endoglycosidase. Control groups of mice obtained injections of either LPS or complete Freund's adjuvant. Mice were tested for memory performance, their blood sera were examined for the presence and fine specificity of alpha7(1-208)-specific antibodies and the brain preparations were studied for the levels of alpha7 nAChR, Abeta(1-42) and interleukin-6. It was found that the original alpha7(1-208) was more immunogenic than the deglycosylated one, and their epitopes were recognized with different efficiency. In contrast to LPS and original alpha7(1-208), deglycosylated alpha7(1-208) did not stimulate interleukin-6 elevation in the brain, i.e. had no pro-inflammatory effect. Nevertheless, immunizations with either the original or deglycosylated alpha7(1-208) resulted in similar decrease of alpha7 nAChRs, accumulation of Abeta(1-42) in the brain and significant episodic memory decline, comparable to those exerted by LPS injections. We conclude that the decrease of alpha7 nAChR density, caused by alpha7(1-208) specific antibody, is critical for Abeta(1-42) accumulation and episodic memory impairment, while pro-inflammatory capacity of alpha7(1-208)-specific antibody plays a secondary role for the development of Alzheimer-like symptoms. PMID- 27498632 TI - The Role of Molecular Dynamics Potential of Mean Force Calculations in the Investigation of Enzyme Catalysis. AB - The potential of mean force simulations, widely applied in Monte Carlo or molecular dynamics simulations, are useful tools to examine the free energy variation as a function of one or more specific reaction coordinate(s) for a given system. Implementation of the potential of mean force in the simulations of biological processes, such as enzyme catalysis, can help overcome the difficulties of sampling specific regions on the energy landscape and provide useful insights to understand the catalytic mechanism. The potential of mean force simulations usually require many, possibly parallelizable, short simulations instead of a few extremely long simulations and, therefore, are fairly manageable for most research facilities. In this chapter, we provide detailed protocols for applying the potential of mean force simulations to investigate enzymatic mechanisms for several different enzyme systems. PMID- 27498633 TI - Empirical Force Fields for Mechanistic Studies of Chemical Reactions in Proteins. AB - Following chemical reactions in atomistic detail is one of the most challenging aspects of current computational approaches to chemistry. In this chapter the application of adiabatic reactive MD (ARMD) and its multistate version (MS-ARMD) are discussed. Both methods allow to study bond-breaking and bond-forming processes in chemical and biological processes. Particular emphasis is put on practical aspects for applying the methods to investigate the dynamics of chemical reactions. The chapter closes with an outlook of possible generalizations of the methods discussed. PMID- 27498634 TI - Generalized Ensemble Sampling of Enzyme Reaction Free Energy Pathways. AB - Free energy path sampling plays an essential role in computational understanding of chemical reactions, particularly those occurring in enzymatic environments. Among a variety of molecular dynamics simulation approaches, the generalized ensemble sampling strategy is uniquely attractive for the fact that it not only can enhance the sampling of rare chemical events but also can naturally ensure consistent exploration of environmental degrees of freedom. In this review, we plan to provide a tutorial-like tour on an emerging topic: generalized ensemble sampling of enzyme reaction free energy path. The discussion is largely focused on our own studies, particularly ones based on the metadynamics free energy sampling method and the on-the-path random walk path sampling method. We hope that this minipresentation will provide interested practitioners some meaningful guidance for future algorithm formulation and application study. PMID- 27498635 TI - Methods for Efficiently and Accurately Computing Quantum Mechanical Free Energies for Enzyme Catalysis. AB - Enzyme activity is inherently linked to free energies of transition states, ligand binding, protonation/deprotonation, etc.; these free energies, and thus enzyme function, can be affected by residue mutations, allosterically induced conformational changes, and much more. Therefore, being able to predict free energies associated with enzymatic processes is critical to understanding and predicting their function. Free energy simulation (FES) has historically been a computational challenge as it requires both the accurate description of inter- and intramolecular interactions and adequate sampling of all relevant conformational degrees of freedom. The hybrid quantum mechanical molecular mechanical (QM/MM) framework is the current tool of choice when accurate computations of macromolecular systems are essential. Unfortunately, robust and efficient approaches that employ the high levels of computational theory needed to accurately describe many reactive processes (ie, ab initio, DFT), while also including explicit solvation effects and accounting for extensive conformational sampling are essentially nonexistent. In this chapter, we will give a brief overview of two recently developed methods that mitigate several major challenges associated with QM/MM FES: the QM non-Boltzmann Bennett's acceptance ratio method and the QM nonequilibrium work method. We will also describe usage of these methods to calculate free energies associated with (1) relative properties and (2) along reaction paths, using simple test cases with relevance to enzymes examples. PMID- 27498636 TI - Born-Oppenheimer Ab Initio QM/MM Molecular Dynamics Simulations of Enzyme Reactions. AB - There are two key requirements for reliably simulating enzyme reactions: one is a reasonably accurate potential energy surface to describe the bond forming/breaking process as well as to adequately model the heterogeneous enzyme environment; the other is to perform extensive sampling since an enzyme system consists of at least thousands of atoms and its energy landscape is very complex. One attractive approach to meet both daunting tasks is Born-Oppenheimer ab initio QM/MM molecular dynamics (aiQM/MM-MD) simulation with umbrella sampling. In this chapter, we describe our recently developed pseudobond Q-Chem-Amber interface, which employs a combined electrostatic-mechanical embedding scheme with periodic boundary condition and the particle mesh Ewald method for long-range electrostatics interactions. In our implementation, Q-Chem and the sander module of Amber are combined at the source code level without using system calls, and all necessary data communications between QM and MM calculations are achieved via computer memory. We demonstrate the applicability of this pseudobond Q-Chem-Amber interface by presenting two examples, one reaction in aqueous solution and one enzyme reaction. Finally, we describe our established aiQM/MM-MD enzyme simulation protocol, which has been successfully applied to study more than a dozen enzymes. PMID- 27498637 TI - QM/MM Calculations on Proteins. AB - In this chapter, I discuss combined quantum mechanics (QM) and molecular mechanics (MM; QM/MM) calculations for proteins. In QM/MM, a small but interesting part of the protein is treated by accurate QM methods, whereas the remainder is treated by faster MM methods. The prime problems with QM/MM calculations are bonds between the QM and MM systems, the selection of the QM system, and the local-minima problem. The two first problems can be solved by the big-QM approach, including in the QM calculation all groups within 4.5-6A of the active site and all buried charges in the protein. The third problem can be solved by calculating free energies. It is important to study QM/MM energy components to ensure that the results are stable and reliable. They can also be used to understand the reaction and the effect of the surroundings, eg, by dividing the catalytic effect into bonded, van der Waals, electrostatic, and geometric components and to deduce which parts of the protein contribute most to the catalysis. It should be ensured that the QM calculations are reliable and converged by extending the basis set to quadruple-zeta quality, including a proper treatment of dispersion, as well as years experience and method development calculations with both pure and hybrid density functional theory methods. If the latter give differing results, calibration with high-level QM methods is needed. Reactions that change the net charge should be avoided. QM/MM calculations can be combined with experimental methods. PMID- 27498638 TI - Enzymatic Cleavage of Glycosidic Bonds: Strategies on How to Set Up and Control a QM/MM Metadynamics Simulation. AB - Carbohydrates play crucial roles in many biological processes, from cell-cell adhesion to chemical signaling. Their complexity and diversity, related to alpha/beta anomeric configuration, ring substituents, and conformational variations, require a diverse set of enzymes for their processing. Among them, glycoside hydrolases (GHs) are responsible for the hydrolysis of one of the strongest bonds in nature: the glycosidic bond. These highly specialized biological catalysts select particular conformations their carbohydrate substrates to enhance catalysis. The evolution of this conformation during the reaction of glycosidic bond cleavage, known as the conformational catalytic itinerary, is of fundamental interest in glycobiology, with impact on inhibitor and drug design. Here we review some of the aspects and the main strategies one needs to take into account when simulating a reaction in a GH enzyme using QM/MM metadynamics. Several specific aspects are highlighted, from the importance of the distortion of the substrate at the Michaelis complex to the variable control during the metadynamics simulation or the analysis of the reaction mechanism and conformational itinerary. The increasing speed of computer power and methodological advances have added a vital tool to the study of GH mechanisms, as shown here and recent reviews. It is hoped that this chapter will serve as a first guide for those attempting to perform a metadynamics simulation of these relevant and fascinating enzymes. PMID- 27498639 TI - Toward Determining ATPase Mechanism in ABC Transporters: Development of the Reaction Path-Force Matching QM/MM Method. AB - Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are ubiquitous ATP-dependent membrane proteins involved in translocations of a wide variety of substrates across cellular membranes. To understand the chemomechanical coupling mechanism as well as functional asymmetry in these systems, a quantitative description of how ABC transporters hydrolyze ATP is needed. Complementary to experimental approaches, computer simulations based on combined quantum mechanical and molecular mechanical (QM/MM) potentials have provided new insights into the catalytic mechanism in ABC transporters. Quantitatively reliable determination of the free energy requirement for enzymatic ATP hydrolysis, however, requires substantial statistical sampling on QM/MM potential. A case study shows that brute force sampling of ab initio QM/MM (AI/MM) potential energy surfaces is computationally impractical for enzyme simulations of ABC transporters. On the other hand, existing semiempirical QM/MM (SE/MM) methods, although affordable for free energy sampling, are unreliable for studying ATP hydrolysis. To close this gap, a multiscale QM/MM approach named reaction path force matching (RP-FM) has been developed. In RP-FM, specific reaction parameters for a selected SE method are optimized against AI reference data along reaction paths by employing the force matching technique. The feasibility of the method is demonstrated for a proton transfer reaction in the gas phase and in solution. The RP-FM method may offer a general tool for simulating complex enzyme systems such as ABC transporters. PMID- 27498641 TI - Practical Aspects of Multiscale Classical and Quantum Simulations of Enzyme Reactions. AB - This chapter aims to present some basic multiscale approaches available for enzyme simulations, and to point out practical details and pitfalls that are not often discussed in the literature, but can greatly influence the outcome of any in silico enzyme study. We cover principle methodological steps of multiscale studies of general enzyme reactions. This includes choice of starting structures, boundary conditions, potential energy surfaces, reaction coordinates, simulation methods, as well as the choice of method for the treatment of nuclear quantum effects. Together, these and additional steps are crucial for the success of enzyme-modeling projects and should be considered prior to embarking on multiscale modeling. PMID- 27498640 TI - QM/MM Analysis of Transition States and Transition State Analogues in Metalloenzymes. AB - Enzymology is approaching an era where many problems can benefit from computational studies. While ample challenges remain in quantitatively predicting behavior for many enzyme systems, the insights that often come from computations are an important asset for the enzymology community. Here we provide a primer for enzymologists on the types of calculations that are most useful for mechanistic problems in enzymology. In particular, we emphasize the integration of models that range from small active-site motifs to fully solvated enzyme systems for cross-validation and dissection of specific contributions from the enzyme environment. We then use a case study of the enzyme alkaline phosphatase to illustrate specific application of the methods. The case study involves examination of the binding modes of putative transition state analogues (tungstate and vanadate) to the enzyme. The computations predict covalent binding of these ions to the enzymatic nucleophile and that they adopt the trigonal bipyramidal geometry of the expected transition state. By comparing these structures with transition states found through free energy simulations, we assess the degree to which the transition state analogues mimic the true transition states. Technical issues worth treating with care as well as several remaining challenges to quantitative analysis of metalloenzymes are also highlighted during the discussion. PMID- 27498643 TI - Use of QM/DMD as a Multiscale Approach to Modeling Metalloenzymes. AB - Enzymes are complex biomolecules capable of performing unique catalysis under physiological conditions at neutral temperature and pH. However, the architecture of enzymatic catalysis is often a combination of the quantum influence of the immediate active site, as well as the electrostatic and configurational influences of amino acids surrounding the active site. As a result of this cooperation between baseline chemical reactivity and electrostatic assistance, it has become important to model enzymes using multiscale methods that take advantage of treating the active site with quantum mechanical methods, while approximately treating the surrounding protein using cheaper, classically driven force-field molecular mechanics methods. Here we describe the use of a multiscale engine which utilizes a combination of density functional theory with discrete molecular dynamics (dubbed QM/DMD) to aid in the characterization of metalloenzymes. PMID- 27498642 TI - Examinations of the Chemical Step in Enzyme Catalysis. AB - Advances in computational and experimental methods in enzymology have aided comprehension of enzyme-catalyzed chemical reactions. The main difficulty in comparing computational findings to rate measurements is that the first examines a single energy barrier, while the second frequently reflects a combination of many microscopic barriers. We present here intrinsic kinetic isotope effects and their temperature dependence as a useful experimental probe of a single chemical step in a complex kinetic cascade. Computational predictions are tested by this method for two model enzymes: dihydrofolate reductase and thymidylate synthase. The description highlights the significance of collaboration between experimentalists and theoreticians to develop a better understanding of enzyme catalyzed chemical conversions. PMID- 27498644 TI - Adaptive Partitioning QM/MM Dynamics Simulations for Substrate Uptake, Product Release, and Solvent Exchange. AB - Combined quantum mechanics/molecular mechanics (QM/MM) plays an important role in multiscale simulations of biological systems including enzymes. The adaptive partitioning (AP) schemes surpass the conventional QM/MM methods in that they allow the on-the-fly, smooth exchange of particles between QM and MM subsystems in molecular dynamics simulations, leading to a seamless and dynamic integration of the QM and MM realms. Originally developed for simulating ion solvation in bulk solutions, the AP schemes have recently been extended to the treatment of proteins, fostering applications in the simulations of enzymes. The present contribution provides a detailed account of the AP schemes. We delineate the background of the algorithms and their parallel implementation, as well as offer practical advice and examples for their applications in the simulations of biological systems. PMID- 27498646 TI - Simulating Nuclear and Electronic Quantum Effects in Enzymes. AB - An accurate treatment of the structures and dynamics that lead to enhanced chemical reactivity in enzymes requires explicit treatment of both electronic and nuclear quantum effects. The former can be captured in ab initio molecular dynamics (AIMD) simulations, while the latter can be included by performing ab initio path integral molecular dynamics (AI-PIMD) simulations. Both AIMD and AI PIMD simulations have traditionally been computationally prohibitive for large enzymatic systems. Recent developments in streaming computer architectures and new algorithms to accelerate path integral simulations now make these simulations practical for biological systems, allowing elucidation of enzymatic reactions in unprecedented detail. In this chapter, we summarize these recent developments and discuss practical considerations for applying AIMD and AI-PIMD simulations to enzymes. PMID- 27498645 TI - Enzymatic Kinetic Isotope Effects from Path-Integral Free Energy Perturbation Theory. AB - Path-integral free energy perturbation (PI-FEP) theory is presented to directly determine the ratio of quantum mechanical partition functions of different isotopologs in a single simulation. Furthermore, a double averaging strategy is used to carry out the practical simulation, separating the quantum mechanical path integral exactly into two separate calculations, one corresponding to a classical molecular dynamics simulation of the centroid coordinates, and another involving free-particle path-integral sampling over the classical, centroid positions. An integrated centroid path-integral free energy perturbation and umbrella sampling (PI-FEP/UM, or simply, PI-FEP) method along with bisection sampling was summarized, which provides an accurate and fast convergent method for computing kinetic isotope effects for chemical reactions in solution and in enzymes. The PI-FEP method is illustrated by a number of applications, to highlight the computational precision and accuracy, the rule of geometrical mean in kinetic isotope effects, enhanced nuclear quantum effects in enzyme catalysis, and protein dynamics on temperature dependence of kinetic isotope effects. PMID- 27498647 TI - Using Molecular Simulation to Study Biocatalysis in Ionic Liquids. AB - The practice of computational biocatalysis in ionic liquids (ILs) is still in its infancy, and thus best simulation practices are still developing. Herein, we examine the computational and experimental literature to date featuring systems of enzymes in aqueous and neat ILs. The many different approaches taken to parameterize ILs and set up simulations of enzymes in ILs are discussed, and common analysis techniques are reviewed. We also shed light on potential drawbacks and limitations to simulating enzymes in ILs, which include a lack of experimental data with which to validate computational models and inadequate sampling arising from the slow dynamics of many ILs that can lead to inaccurate descriptions of transport and equilibrium thermodynamic properties. A small case study illustrates the effects of scaling IL partial charges, which is a common practice in the field, on the conformational transitions of alanine dipeptide. The degree of charge scaling has a significant effect on the transition times between states of the biomolecule and highlights the importance of carefully setting up systems of enzymes in ILs. Finally, we discuss means to overcome these challenges and briefly consider possible new directions for the field. PMID- 27498649 TI - Preface. PMID- 27498650 TI - A novel methodology for assessing the environmental sustainability of ionic liquids used for CO2 capture. AB - Ionic liquids (ILs) have been proposed as suitable sorbents for CO2 capture because of their high CO2 absorption capacity, thermal stability, negligible vapour pressure and physico-chemical tunability. However, the environmental implications of ILs are currently largely unknown because of a lack of data. The issue is further complicated by their complex chemical structures and numerous precursors for which environmental data are scarce or non-existent. In an attempt to address this issue, this paper presents a new methodology for estimating life cycle environmental impacts of novel ILs, with the aim of aiding synthesis and selection of more sustainable CO2 sorbents. The methodology consists of four main steps: (1) selection of an appropriate IL and synthesis route; (2) construction of a life cycle tree; (3) life cycle assessment; and (4) recommendations for improvements. The application of the methodology is illustrated using trihexyltetradecylphosphonium 1,2,4-triazolide ([P66614][124Triz]), a promising IL for CO2 capture currently under development. Following the above steps, the paper demonstrates how the data obtained from laboratory synthesis of the IL can be scaled up to industrial production to estimate life cycle impacts and identify environmental hotspots. In this particular case, the main hotspots are the precursors used in the synthesis of the IL. Comparison of impacts with monoethanolamine (MEA), currently the most widely-used CO2 sorbent, suggests that [P66614][124Triz] has much higher impacts than MEA, including global warming potential. However, human toxicity potential is significantly higher for MEA. Therefore, the proposed methodology can be used to optimise the design of ILs and to guide selection of more sustainable CO2 sorbents. Although the focus is on ILs, the methodology is generic and can be applied to other chemicals under development. PMID- 27498651 TI - A multi-centred open trial of ?Dr Michaels(r)? (also branded as Soratinex(r)) topical product family in psoriasis. AB - Psoriasis is a chronic, recurring skin disease affecting 2-4% of the population. Genetic predisposition and precipitating factors play a role in its etiology. The disease can occur in any age or gender group. The most frequently affected areas of the body include scalp, extensor surfaces of the extremities, skin folds and nails. While a number of therapies exist for the treatment of psoriasis with a total resolution of the skin, achieving remission in a high percentage of sufferers, a treatment that results in the maintenance of remission and is free of side effects is still a desirable goal. The aim of the study was to investigate the efficacy and tolerability of Dr Michaels(r) (Soratinex(r)) topical product family in psoriasis, in terms of decreasing parakeratosis, inflammation, infiltration and involved area. Seven-hundred-and-twenty-two subjects, mean age 42.3 years (range: 18-68 years) with mild to moderately severe psoriasis, with no other current anti-psoriatic therapy, consisting of 382 males and 340 females, above 18 years of age were included and the observations were subjected to statistical analysis. Triphasic application of Dr Michaels(r) (Soratinex(r)) products was employed for 8 weeks, using Cleansing Gel, Scalp and Body Ointment and Skin Conditioner. The treatment proved to be ineffective for 22 patients (3.1%) out of 722. 84 patients (11.6%) had moderate improvement with 26 50% of cleared skin lesions; 102 patients (14.1%) had good improvement with 51 75% of cleared skin lesions; 484 patients (67.0%) experienced outstanding improvement with 76-100% of the cleared skin lesions, with 52% of them achieving total resolution. Twelve patients worsened and discontinued treatment; 18 patients discontinued because of non-compliance; 33 patients developed folliculitis as a side effect. Based on the results of this study, the Dr Michaels(r) (Soratinex(r)) product family can be successfully applied in mild to moderately severe psoriasis when considering the exclusion criteria. PMID- 27498652 TI - A European prospective, randomized placebo-controlled doubleblind Study on the efficacy and safety of Dr Michaels(r) (also branded as Soratinex(r)) product family for stable chronic plaque psoriasis. AB - Psoriasis is a chronic, inflammatory, recurrent, genetically determined dermatitis that affects the skin and joints. Many patients affected by this condition seek alternatives and complementary treatment options such as herbal medicines. In order to establish the safety of these products, trials, according to medical standards should be performed to provide the highest quality of data. The aim of this study was to assess the efficacy and safety of an Australian series of herbal skincare products [Dr. Michaels(r) (Soratinex(r)) skin-care products for psoriasis] for the management of stable chronic plaque psoriasis. We studied 142 patients (68 females and 74 males) with mild to moderate, stable, chronic plaque psoriasis and they were randomly assigned to either verum or control group. Exclusion criteria were: severe psoriasis, arthropathic psoriasis, intertriginous psoriasis, palmoplantar psoriasis, use of any antipsoriatic treatment and any medication which could influence or interfere with the course of the disease. Both groups consisted of a cleansing gel, an ointment and an oil blend (skin conditioner), packed in neutral bottles, used twice daily for all lesions except the scalp, for 8 weeks. As control products, we used compositions of well-known neutral ointments and medicinal bathing oil. Assessment, using the Psoriasis Activity Severity Index (PASI) scores, was done before treatment and after 2, 4, 6 and 8 weeks. Patient improvement was determined by the percentage reduction of the PASI scores. Statistical analysis was carried out using the Mann Whitney-U Test with SPSS for Windows. Our investigation demonstrates that complementary methods can play a role in dermatologic therapy as long as they undergo standardised clinical trials and fulfil the basic requirements such as product safety and quality assurance. This study shows that Dr Michaels (Soratinex(r)) herbal skin-care products improve mild to moderate stable chronic plaque psoriasis significantly. PMID- 27498648 TI - The MOD-QM/MM Method: Applications to Studies of Photosystem II and DNA G Quadruplexes. AB - Quantum mechanics/molecular mechanics (QM/MM) hybrid methods are currently the most powerful computational tools for studies of structure/function relations and catalytic sites embedded in macrobiomolecules (eg, proteins and nucleic acids). QM/MM methodologies are highly efficient since they implement quantum chemistry methods for modeling only the portion of the system involving bond breaking/forming processes (QM layer), as influenced by the surrounding molecular environment described in terms of molecular mechanics force fields (MM layer). Some of the limitations of QM/MM methods when polarization effects are not explicitly considered include the approximate treatment of electrostatic interactions between QM and MM layers. Here, we review recent advances in the development of computational protocols that allow for rigorous modeling of electrostatic interactions in biomacromolecules and structural refinement, beyond the common limitations of QM/MM hybrid methods. We focus on photosystem II (PSII) with emphasis on the description of the oxygen-evolving complex (OEC) and its high-resolution extended X-ray absorption fine structure spectra (EXAFS) in conjunction with Monte Carlo structural refinement. Furthermore, we review QM/MM structural refinement studies of DNA G4 quadruplexes with embedded monovalent cations and direct comparisons to NMR data. PMID- 27498653 TI - A clinical examination of the efficacy of preparation of Dr Michaels(r) (also branded as Soratinex(r)) products in the treatment of psoriasis. AB - Psoriasis is a chronic inflammatory disease with negative impacts both physically and psychologically. It is a common disorder affecting 2-3% of the total world population, in some cases causing changes to the nail and joints as well as skin lesions. The cutaneous manifestations of psoriasis can vary in morphology and severity and therapy should be tailored accordingly. The aim of the study was to investigate the efficacy of Dr Michaels(r) (Soratinex(r)) product line in the treatment of psoriatic patients with different age and disease severity. A total number of 270 patients with verified psoriasis, aged 9-60 years old participated in the studies, including 128 children: 23 girls and 105 boys, (all of them selected from the Department of Dermato-allergology of the Russian Pediatric Hospital Clinic, Moscow, and of the 4th Department of Dermatology of the 52nd Moscow City Hospital Clinic). The patients were separated into 3 groups according to the severity of the disease (based on the PASI-index). All the patients have been treated with Dr Michaels(r) (Soratinex(r)) products twice daily, as three different forms were available for application: a cleansing gel, an ointment and a conditioner. The severity of the disease and the efficacy of the treatment have been defined with the evaluation of the PASI index of each patient. The obtained results were recorded in a graphic form showing the changes of the PASI-index on days 3, 7, 14, and 21 counted from the start of the trial. Clinical remission was achieved in 147 patients, a significant improvement in 73, partial improvement in 32, while no effect was seen in 12 patients and deterioration in 6. This open trial demonstrated the clinical efficacy of topical application of Dr Michaels(r) (Soratinex(r)) preparation. We observed clinical remissions of psoriasis in adults and in children. PMID- 27498654 TI - Nail psoriasis in an adult successfully treated with a series of herbal skin care products family ? a case report. AB - Psoriasis is a common chronic inflammatory dermatosis that causes significant distress and morbidity. Approximately 50% of patients with cutaneous psoriasis and 90% of patients with psoriatic arthritis demonstrate nail involvement of their psoriasis. Left untreated, nail psoriasis may progress to debilitating nail disease that leads to not only impairment of function but also on quality of life. We report the case of a 50-year-old male patient with recalcitrant nail dystrophies on the fingers since the age of 40, who responded successfully to Dr. Michaels(r) product family. The patient had a 35-year history of plaque psoriasis localised on the scalp, ears, groin, limbs, and trunk and with psoriatic arthritis. The nail symptoms consisted of onycholysis, onychomycosis, leukonychia, transverse grooves, nail plate crumbling and paronychia of the periungal skin. This case represents the efficacy and safety of the Dr. Michaels(r) (Soratinex(r) and Nailinex(r)) product family with successful resolution of nail dystrophies and surrounding paronychia with no reported adverse events. PMID- 27498655 TI - Clinical evaluation of the effectiveness of ?Dr Michaels(r)? (also branded as Soratinex(r)) products in the topical treatment of patients with plaque psoriasis. AB - Psoriasis is generally considered as an autoimmune inflammatory cutaneous systemic disease, with chronic course and high rate of recurrence, while its high risk of comorbidities affect the patients? quality of life significantly. Despite the good therapeutic response, most of the available options show tendency for poor tolerance and high rate of occurrence of side effects. Therefore, the interest of patients and doctors to investigate the possibility of treating psoriasis with natural substances is not surprising. The aim of this study was to investigate the efficacy and safety of the herbal skin-care product Dr Michaels(r) (Soratinex(r)) for the management of chronic plaque psoriasis, within a 6 to 8 week treatment course. Thirty patients of both sexes, aged between 24 and 70 years with mild to moderate psoriasis vulgaris were included in this study. The products of Dr Michaels(r) (Soratinex(r)) were applied in sequence: cleansing gel, ointment after 3-4 minutes and tonic care (for the fire-smeared ointment) 2 times per day for restorative care and cleansing gel for psoriasis within scalp 3 times a week. The study lasted six weeks. The severity and extent of the lesions were evaluated by PASI score (Psoriasis Area and Severity Index). Based on the obtained result, the products of ?Dr Michaels(r) (Soratinex(r))? have proved to be effective in the treatment of mild and moderate psoriasis vulgaris. In the study group, no improvement was observed in 10% of patients, a slight improvement in 20%, good in 40% and very good in 16.6% of patients. PMID- 27498656 TI - Successful treatment of a chronic eczema in a 48-year-old female with Dr Michaels(r) (Eczitinex(r) and Itchinex(r)) product family. A case report. AB - We report the case of a 48-year-old female with chronic atopic eczema who responded successfully to Dr Michaels(r) (Eczitinex(r) and Itchinex(r)) product family. The patient had a 41-year history of atopic eczema and presented with erythematous, excoriated lesions with telangiectasia and scattered purpura (bruising) covering 90% of her body surface area. The patient also regularly suffered blepharitis with red, itchy, watery eyes. The patient was treated with Dr Michaels(r) (Eczitinex(r) and Itchinex(r)) ointment and herbal supplements and presented total resolution of the atopic eczema and underlying inflammation within 6 weeks. This case also suggests that Dr Michaels(r) (Eczitinex(r) and Itchinex(r)) product family is safe and effective, even in cortisone acquired sensitive skin. PMID- 27498657 TI - Dr Michaels(r) (Soratinex(r)) product for the topical treatment of psoriasis: a Hungarian/Czech and Slovak study. AB - Psoriasis is a chronic inflammatory T cell-mediated skin disease, affecting about 2% of Hungarian population. Genetic predisposition as well as environmental triggering factors, and innate immune processes play a role in its etiology. Treatment of psoriasis during the initial stages and first years of disease tend to be conservative and frequently based on topical agents. The aim of this study was to investigate and to describe the efficacy and safety of Dr Michaels(r) (Soratinex(r)) skin-care products for the topical treatment of stable chronic plaque psoriasis in a Hungarian population. Two-hundred-and-eight-six (120 female/166 male) patients, aged 10-80 years old (mean age 43 years) with mild to moderate plaque psoriasis had participated in the study. The products, including cleansing gel containing a coal tar solution, herbal oils and emulsifiers, were used twice daily and in the same manner for all the skin lesions. The study period was eight weeks. Assessment, using the Psoriasis Activity Severity Index (PASI) scores and photographic analysis, was done 2 weeks before treatment, at time 0, and after 2, 4, 6 and 8 weeks. Patient?s improvement was determined by the percentage reduction of the PASI scores. Side effects and tolerability were also evaluated. After 8 weeks treatment course, 46 patients had a moderate improvement, with the regression of 25-50% of skin lesions; 77 patients showed a good improvement, with the resolution of 51-75% of lesions. Another 115 patients had an outstanding improvement, with the regression of 76-98.9% of lesions. Only 13 patients did not achieve an improvement of psoriasis. Fifteen patients experienced folliculitis, which resolved after cessation of treatment. Seven patients worsened and discontinued treatment. Thirteen patients dropped out because of non-compliance. Our investigation demonstrates that Dr Michaels(r) (Soratinex(r)) products, an Australian treatment, can be used successfully in the treatment of stable chronic plaque psoriasis. PMID- 27498658 TI - Successful treatment of mild to moderate acne vulgaris with Dr Michaels(r) (also branded as Zitinex(r)) topical products family: a clinical trial. AB - Acne vulgaris is an epidemic inflammatory skin disease of multi-factorial origin, frequently seen in adolescents and often persisting or occurring through to adulthood. Acne vulgaris is a nearly universal skin disease afflicting 79-95% of the adolescent population in westernized societies and is a significant cause of psychological morbidity in affected patients. Despite the various treatment options available for acne, there is still a need for a safe and effective option. The aim of the study was to investigate the efficacy and tolerability of Dr Michaels(r) (Zitinex(r)) product family in the treatment of papulo-pustular acne. 25 patients (17 female/8 male), aged 15-22, with a mild to moderate papulo pustular acne, localized on the face and on the trunk, were included in this study. None of the patients had used any other kind of treatment in the 3 months prior to commencing this study. All of the patients were treated with Dr Michaels(r) (Zitinex(r)) facial exfoliating cleanser, activator formula, a cream, PSC 200 and PSC 900 oral supplements. Application time of Dr Michaels(r) (Zitinex(r)) products was 12 weeks. The treatment was been evaluated clinically at 0, 4, 8 and 12 weeks. All of the patients showed an improvement in all parameters of their acne (comedones, papules, pustules, hyperpigmentation and scars). The acne lesions and erythema had mostly resolved. The hyperpigmentation and pitted scarring had significantly reduced also, with the skin appearing smoother. The treatment was well tolerated and no side effects have been described. Our study demonstrates that the Dr Michaels(r) (Zitinex(r)) facial exfoliating cleanser, activator formula, cream and oral supplements PSC 200 and PSC 900 are an effective therapeutic option for the treatment of moderately severe acne vulgaris. Moreover, it highlights the safety profile of the Dr Michaels(r) (Zitinex(r)) product family in a case of acne compared to traditional first-line treatments. PMID- 27498659 TI - Investigation of the efficacy and tolerability of Dr Michaels(r) (also branded as Eczitinex(r) and Itchinex Eczitinex(r)) topical products in the treatment of atopic dermatitis in children. AB - Atopic eczema is a chronic relapsing inflammatory skin disorder, characterized clinically by intensely pruritic eczematous skin lesions and a defective epidermal barrier. It affects more than 15% of children and up to 10%of adults, which makes the disease a social health problem still without a challenging treatment. The aim of this study was to evaluate the efficacy and tolerability of Dr Michaels(r) (Eczitinex(r)) topical product family in the treatment of atopic dermatitis in children. We studied a group of 30 patients (17 female, 13 male), aged 5 to 13 (mean age: 9), affected by atopic dermatitis since they were newborn. All patients had been unsuccessfully treated with conventional anti inflammatory therapies and ceased treatment 2 weeks before commencing research. The patients were treated with Dr Michaels(r) (Eczitinex(r) and Itchinex(r)) product family including a moisturising bar, topical ointment and PSC 900 oral herbal formulation. The treatment was evaluated clinically and photographically at 0, 1, 2, 4, 6, 8, 10, 12, and 14 weeks. Twenty-eight patients showed a significant improvement of cutaneous rashes and pruritus on the first week of treatment, with a complete remission at 10-12 weeks. Only two patients, brother and sister respectively, showed a slow response to treatment and reported an increasing itching. Following 14 weeks of treatment with the Dr Michaels(r) (Eczitinex(r) and Itchinex(r)) product family, patients demonstrated complete resolution of their AD. All patients showed a marked improvement in their condition within 3 days of treatment with most of the lesions and symptoms totally resolved within 10 to 12 weeks of treatment with Dr Michaels(r) (Eczitinex(r) and Itchinex(r)) family of products. This clinical report highlights that the Dr Michaels(r) (Eczitinex(r) and Itchinex(r)) product family is a safe and effective treatment option for AD. PMID- 27498660 TI - Treatment of ichthyosis lamellaris using a series of herbal skin care products family. AB - Lamellar ichthyosis (LI) is a genetically heterogeneous group of disorders of keratinization that are inherited in an autosomal recessive fashion, occurring in approximately 1 in 300,000 live births. The treatment of the large, dark, plate like scales that characterize the classic manifestation of the disease are still a challenge. The aim of this study was to evaluate the efficacy and tolerability of Dr. Michaels(r) skin-care products for the management of LI. A multi-centre European prospective study was conducted, including 10 patients (3 female/7 male) with lamellar ichthyosis, aged 38-54 years old (mean age: 46). Each patient had been treated with emollients plus other different systemic therapies, such as corticosteroids, Cyclosporin A or retinoids in the past. All patients were treated with Dr Michaels(r) product family including both topical and oral herbal supplements. The topical treatments used were the cleansing gel, activator formula and ointment. The oral medications were PSC 200, PSC 400 and PSC 900. Within 3 weeks of initiation of treatment, there were improvements observed on the skin including a reduction in scaling, fissuring, and intensity in erythema and pruritus with thinning of the hyperkeratotic plate. After 12-15 weeks, most of the plates and scales had been removed to reveal a normalised skin colour. Evidence of hair, eyelash and eyebrow growth was observed. There was partial nail resolution with a reduction in subungual hyperkeratosis. No adverse reactions were observed. Our patients showed excellent symptomatic response to treatment within a 14-week period, follow-up by an on-going regular assessment on a quarterly basis. The results show that Dr Michaels(r) product family is an effective and safe treatment option for LI. PMID- 27498661 TI - Investigation of the efficacy of Dr Michaels(r) (Soratinex(r)) family in maintaining a symptom-free state for patients with psoriasis in remission. A retrospective, comparative study. AB - Psoriasis is a chronic inflammatory disease, affecting about 3% of the worldwide population. Although there are many therapeutic options available today for psoriasis, none of them can be considered as the gold standard treatment for maintaining a sustained period of remission. The aim of this study was to investigate whether a maintenance dosage of Michaels(r) Soratinex(r) product family is effective in maintaining a symptom-free state for patients in remission. Fifty patients (23 male, 27 female), aged 18-58-years-old (mean age: 38.3), affected by mild to severe plaque psoriasis (mean duration: 29.5), were included in this retrospective study. All of them had completed previous treatment and achieved remission. Twenty-eight had been previously treated with an Australian series of herbal skin-care products (Dr. Michaels(r) Soratinex(r) skincare products for psoriasis) and 22 treated with biologics. We evaluated the clinical condition of the member of each group every 4 weeks, for 16 times following remission. Maintenance group continued treatment with Dr Michaels(r) (Soratinex(r)). Non-Maintenance group discontinued both forms of treatment. The evaluation was based on the PASI score, assuming that at baseline it was zero. Out of 34 patients who continued treatment with Dr Michaels(r) (Soratinex(r)) product family in the Maintenance group (22 previously treated with Dr Michaels and 12 previously treated with Biologic), 26 remained symptom free with baseline PASI of zero. Six patients had a mild flare with a PASI increase of 0-25%. Two patients were in the moderate group with a PASI increase of 26-50% and were initially treated with biologic. Out of 6 patients in Dr Michaels non-maintenance group, 3 patients remained symptom free, 1 had a rebound starting on week 36 and 2 rebounded at week 44. Out of 10 patients who were in the non-maintenance from the biologic group, 6 rebounded at week 12, 2 rebounded at week 16, 1 rebounded at week 24 and 1 rebounded at week 32. In the maintenance group no side effects were described, except for a mild form of folliculitis in 3 patients. Treatment did not have to be discontinued and all 3 patients cleared. Based on the results of this study, Dr. Michaels(r) (Soratinex(r)) product family can be safely and successfully applied to maintain a symptom-free state, after patients go into remission following treatment with Dr. Michaels(r) (Soratinex(r)) product family or biologics in mild to very severe psoriasis, when considering the exclusion criteria. PMID- 27498662 TI - Dr Michaels(r) product family (also branded as Soratinex(r)) versus Methylprednisolone aceponate - a comparative study of the effectiveness for the treatment of plaque psoriasis. AB - As one of the most common dermatologic chronic-recurrent disease, variable therapeutic options are available today for management of psoriasis. Although topical high potency corticosteroids, alone or in association with salicylic acid or vitamin D analogues, are still considered the best treatment, they do not seem to possess the capability for a long-term control of the disease or prevent recurrences, as their side effects are major contraindications for continuative use. The aim of this study was to investigate whether Dr. Michaels(r) product family is comparable to methylprednisolone aceponate (MPA) as a viable alternative treatment option for the treatment and management of stable chronic plaque psoriasis. Thirty adults (13 male, 17 female, mean age 40 years) with mild to severe stable chronic plaque psoriasis, were included in the study. Patients were advised to treat the lesions of the two sides of their body (left and right) with two different unknown modalities for 8 weeks; the pack of Dr. Michaels(r) products on the left side (consisting of a cleansing gel, an ointment and a skin conditioner) and a placebo pack on the right side, consisting of a cleansing gel, methylprednisolone ointment and a placebo conditioner. Assessment was done using the Psoriasis Activity Severity Index (PASI) scores before treatment and after 2, 4, 6 and 8 weeks. The results achieved with the Dr. Michaels(r) (Soratinex(r)) product family for the treatment of chronic plaque psoriasis were better than the results achieved with methylprednisolone aceponate (MPA), even though quicker resolution was achieved with the steroid with 45% of patients achieving resolution within 8-10 days in comparison to 5-6 weeks in the Dr. Michaels(r) (Soratinex(r)) group. Before therapy, the mean PASI score of the LHS in Dr. Michaels(r) (Soratinex(r)) group was 13.8+/-4.1 SD and 14.2+/-4.2 SD in the RHS methylprednisolone aceponate (MPA) group. After 8 weeks of treatment 62% of the Dr. Michaels(r) (Soratinex(r)) group had achieved resolution whilst in the methylprednisolone aceponate (MPA) group, the figure remained at 45%. The mean PASI score after 8 weeks of treatment was calculated and in the LHS Dr. Michaels(r) (Soratinex(r)) group it was 2.8+/-1.6 SD and 6.8+/-2.4 SD in the RHS methylprednisolone aceponate group. In the RHS -methylprednisolone aceponate (MPA) group, 22% of patients failed to respond to the treatment in comparison to 6% in the LHS Dr. Michaels(r) (Soratinex(r)) group. Based on the results of this study, Dr. Michaels(r) products are a more effective treatment option, with insignificant side effects, compared to local treatment with methylprednisolone aceponate (MPA). PMID- 27498663 TI - Successful treatment of alopecia areata with Dr. Michaels(r) (Alopinex) product family. AB - Alopecia areata is a highly prevalent organ restricted autoimmune disorder that leads to disfiguring hair loss and is thought to involve a T cell?mediated response to the hair follicle. The treatment of alopecia areata is often problematic and very frustrating, partly due to the unknown aetiology of the condition. The aim of this study was to evaluate the efficacy and tolerability of complementary medicine, Dr. Michaels(r) product family, in the treatment of alopecia areata. MATERIALS AND METHODS: 40 patients (27 female/13 male), with a mean age of 20.3 years, all of them with 1-3 lesions of stable alopecia areata localized on the scalp were included in this trial. Four patients suffered from Hashimoto thyroiditis, and one had a familial history of LES. Exclusion criteria were the use of any treatment or medication, which may influence or interfere with the course of the disease. All patients were treated with Dr. Michaels(r) StimOils - applied twice daily (morning and night), Hair Lotion ? applied twice daily (morning and night), and oral herbal formulation - PSC 900 2ml twice daily with food for 16 weeks. For each patient, photographs of typical lesions were taken at the beginning and at 4, 8, 12 and 16 weeks follow-up. Patient improvement was determined by the percentage of hair regrowth for each lesion. RESULTS: After 10 weeks of treatment using StimOils, Hair Lotion and PSC 900 from Dr. Michaels(r) product family, 18 patients had achieved an excellent response with regrowth in all the affected alopecia areata patches. 17 patients achieved the same results after 12 weeks of treatment; the other 5 patients had to continue the therapeutic protocol for another 2-3 weeks. CONCLUSION: This study demonstrates that the Dr. Michaels(r) StimOils, Hair Lotion and PSC 900 are an effective therapeutic option for the treatment of alopecia areata. This has important implications for resistant cases of alopecia areata where traditional systemic and topical corticosteroid therapies have failed. In addition, this treatment approach may be an attractive option for patients who have growing concern regarding side-effects of long-term corticosteroid therapy. PMID- 27498664 TI - Successful treatment of recalcitrant candidal intertrigo with Dr Michaels(r) (Fungatinex(r)) product family. AB - Candidal intertrigo is an infection of the skin caused by Candida albicans that typically occurs in opposing cutaneous or muco-cutaneous surfaces. Because Candidiasis requires a damaged and moist environment for infection, it typically occurs in areas of friction such as the skin folds of the body. Candidal intertrigo is often difficult to treat and results are often unsatisfactory. In addition, there is a lack of evidence-based literature supporting prevention and treatments for candidal intertrigo. The aim of the study was to evaluate the efficacy of Dr Michaels(r) (also branded as Fungatinex(r)) products in the treatment of fungal intertrigo, in 20 women and 2 men with a mean age of 72. Five patients (3 female and 2 male) had type 2 diabetes and 16 (14 female and 2 male) were obese. The patients were treated with Dr Michaels(r) (Fungatinex(r)) moisturising bar, topical ointment (twice daily application) and oral herbal formulation, PSC 200 two tablets twice daily with food. After 2 weeks of treatment, the lesions had mostly resolved in all patients with only slight erythema evident. After six weeks of treatment using the moisturising bar, topical ointment and oral herbal formulations from the Dr Michaels(r) (Fungatinex(r)) product family, the lesions had totally resolved in 18 patients, while 4 patients had to continue the therapeutic protocol for another 2 weeks. Our results demonstrate that the Dr Michaels(r) (Fungatinex(r)) complementary product family is efficacious in the treatment of recalcitrant candidal intertrigo. Furthermore, this study highlights that the Dr Michaels(r) (Fungatinex(r)) product family is fast-acting and well tolerated with no serious adverse events reported. These data have important implications for resistant cases of candidal intertrigo where traditional therapies have failed. PMID- 27498665 TI - Successful treatment of facial systemic lupus erythematosus lesions with Dr Michaels(r) (Soratinex(r)) product family. A case report. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which the body?s immune system mistakenly attacks healthy tissue. It can affect the skin, joints, kidneys, brain and other organs. We report the case of a 7-year-old female patient with facial lesions of SLE since the age of 5. There was no significant family history and patient had been a healthy child from birth. The child presented with a malar rash, also known as a butterfly rash, with distribution over the cheeks but sparing the nasal bridge. This case represents the efficacy of the Dr. Michaels(r) (Soratinex(r)) product family in the successful resolution of facial lesions of SLE. PMID- 27498666 TI - Scalp psoriasis: a promising natural treatment. AB - Psoriasis is a lifelong chronic inflammatory disease affecting 2-3% of the worldwide population. Scalp psoriasis is a particular form of psoriasis characterized by lesions on the scalp, which may occur isolated or in association with other skin lesions. The aim of this study was to investigate the efficacy and safeness of an innovative treatment of scalp psoriasis, which is based on the topical application of natural products. Fifty adult subjects with scalp psoriasis (23 females, 27 males) from different European dermatological centres were included in the study. Forty-six patients with severely infiltrated psoriatic lesions were invited to use the products of Dr Michaels(r) (Soratinex(r)), according to a three-phase application, twice a day (morning and evening). The other 4 patients followed a different regimen: after a shampoo in the evening, they applied the conditioner in the night and washed it in the morning with the cleansing gel. The application time of Dr Michaels(r) (Soratinex(r)) products was 8 weeks. The treatment was evaluated at 0, 1, 2, 3, 4, 5, 6, 7, and 8 weeks. The evaluation was based on the Psoriasis Scalp Severity Index (PSSI) and on a photographic analysis at each of the medical evaluation points. At the end of the study, all patients showed an outstanding improvement. Five patients referred a transient pruritus, which regressed spontaneously without discontinuing the application. No other side effects have been described. We observe that Dr Michaels(r) (Soratinex(r)) natural product family can be considered as a valid therapeutic tool for scalp psoriasis when considering the exclusion criteria. The tested products provided an outstanding improvement of lesions in all the patients, without side effects. PMID- 27498667 TI - An innovative, promising topical treatment for psoriasis: a Romanian clinical study. AB - Psoriasis is a chronic inflammatory disease with negative impacts both physically and psychologically. It is a common disorder affecting 2-3% of the total world population, in some cases causing changes to the nail and joints as well as skin lesions. The cutaneous manifestations of psoriasis can vary in morphology and severity and therapy should be tailored accordingly. Even if today many therapeutic options are available for psoriasis treatment, none of them provide excellent clinical results without the risk of side effects. The authors investigate the efficacy of Dr. Michaels(r) (Soratinex(r)) natural products in the topical treatments of a group of psoriatic patients. Sixty-two patients (34 male/28 female) from Romania, aged 18-70 years (mean age: 52 years), affected by a mild to severe form of chronic plaque psoriasis were included in this study. Each patient has been treated with a triphasic application of Dr. Michaels(r) (Soratinex(r)) natural products, twice a day for six weeks. The products were applied on skin and scalp lesions, but not on the face, genital and flexures. The evaluation of the tested products was based on the PASI of each patient at time 0, 1, 2, 3, 4, 5, and 6 weeks. The tested products were ineffective in five of 57 patients. Eleven patients had a moderate improvement (PASI decrease 26-50%); 11 patients had a good improvement (PASI decrease 51-75%) and 30 patients an outstanding one (PASI decrease 76-100%). Twenty-three% of patients developed folliculitis that regressed upon discontinuation of the application. Five patients developed pruritus, which regressed spontaneously. The cosmetic effect was evaluated as indifferent by 44% of patients, as good by 40% of patients and as excellent by 16% of patients. Ninety-five% of patients stated that they would continue to use the tested products, because it was effective and with poor side effects since the products were natural. In our experimental study, the topical application of Dr. Michaels(r) (Soratinex(r)) natural products proved to be an effective natural therapeutic option for psoriasis treatment. PMID- 27498668 TI - Efficacy and safety of Dr Michaels(r) (Soratinex(r)) product family for the topical treatment of psoriasis: a monitored status study. AB - The aim of the study was to investigate the efficacy and safety of Michaels(r) (Soratinex(r)) remedies in patients suffering from chronic plaque psoriasis in a Czech population. Seventy-five (34 female/41 male) patients, aged 18-72 years old (mean age: 38.5 years) with mild to severe plaque psoriasis participated in the study. The products, including cleansing gel, ointment and skin conditioner, containing fruit acid complex, herbal oils and emulsifiers, were used twice daily and in the same manner for all the skin lesions. The study period was eight weeks. Histologic variables and various blood picture parameters, including FW, glucose, cholesterol, triacylglyceroles, bilirubin, GMT, ALT, AST, creatinine, uric acid and urea in blood were monitored, before and after therapy with Michaels(r) (Soratinex(r)) treatment. Assessment, using the Psoriasis Activity Severity Index (PASI) scores and photographic analysis, was done at time 0, and after 2, 4, 6 and 8 weeks. Patient?s improvement was determined by the percentage reduction of the PASI scores. Side effects and tolerability were also evaluated. After 8 weeks using Dr Michaels(r) (Soratinex(r)) treatment course, 5 patients had a moderate improvement, with the resolution of 25-50% of skin lesions; 11 patients showed a good improvement, with the resolution of 51-75% of lesions. Another 50 patients had an outstanding improvement, with the regression of 76 100% of lesions. Only 4 patients did not achieve an improvement of psoriasis. Six patients experienced folliculitis, which resolved without cessation of treatment. Three patients worsened and discontinued treatment. Six patients dropped out because of non-compliance. The blood results and histologic findings were all normal. Our investigation shows that Dr Michaels(r) (Soratinex(r)) products can be safely and successfully used in the treatment of chronic plaque psoriasis. PMID- 27498669 TI - Quality of life aspects of patients with psoriasis using a series of herbal products. AB - Psoriasis is a chronic inflammatory disease affecting 1-3% of the general population. Due to the chronic nature of the disease, patients suffer from substantial psychosocial impact and impaired quality of life. Dr Michaels(r) (also branded as Soratinex(r)), an Australian series of topical herbal products, has been showing promising results for the treatment of patients with chronic plaque psoriasis and consequent improvement in their quality of life. This study aims to access the changes in quality of life of patients with Psoriasis using an Australian series of herbal skin-care products Dr Michaels(r) (Soratinex(r)) for psoriasis. The aim of this study is to observe and analyze the impact of Dr Michaels(r) product family on the quality of life of patients with psoriasis, 566 patients completed the Dermatology Quality of Life Index (DQLI) questionnaire in their initial consultation and at 3 follow up consultations, over a 6 months period. At the end of the data collection, all patients? answers were recorded and analyzed. The Psoriasis Area and Severity (PASI) Index were used to measure the severity and extent of psoriasis during the 3 consultations. The PASI for severe, moderate-severe, mild-moderate cases across time revealed a significant effect of the treatment within weeks, confirming the decreasing scores during the treatment. As well as PASI results, the final DLQI score showed a sensible reduction from mean =6.716 (at week 0) to 6.252 (at week 2), 4.015 (at week 6) and 2.407 (at week 10) signifying a 64.2% reduction of the initial score. This study demonstrates that Dr. Michaels(r) (Soratinex(r)) products, an Australian series of herbal-based skin products is effective for the treatment of psoriasis. This treatment also significantly improves patient?s quality of life. PMID- 27498670 TI - Rapid communication: a vegetable oil extract restores redox status in fibroblasts from psoriatic patients. AB - Psoriasis is an inflammatory skin disease that affects 2-5% of the worldwide population. It is a chronic immune-mediated hyperproliferative inflammatory skin disease of unknown etiology, characterized by the appearance of sore patches of thick, red skin with silvery scales. PMID- 27498671 TI - The power of two: an update on fixed-dose combinations for type 2 diabetes. AB - INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) are unlikely to maintain glycemic control with monotherapy, and will eventually require therapy with multiple antihyperglycemic agents (AHAs). Combination therapy regimens with multiple AHAs may be complex and negatively impact patient adherence. Fixed-dose combinations (FDCs) are used successfully for management of numerous chronic diseases. Areas covered: This article includes a brief overview of the add-on approach of current treatment guidelines for T2DM and reviews the evidence supporting the utility of oral FDCs in the treatment of T2DM, including recently developed oral FDCs (2010-2016). Benefits regarding safety and tolerability, adherence and cost are also discussed. Finally, the barriers limiting the use of FDCs and how these barriers may be overcome are addressed. Expert commentary: Therapeutic strategies including FDCs need to be implemented on a larger scale. FDCs have the potential to simplify treatment regimens, improve adherence and provide long-term glycemic control. PMID- 27498672 TI - Epigenetically deregulated miR-200c is involved in a negative feedback loop with DNMT3a in gastric cancer cells. AB - Aberrant methylation of miRNAs is commonly observed in cancers. In the present study, we investigated the regulation of the miR-200 family and its role in regulating DNA methylation events in gastric cancer (GC). We demonstrated that miR-200c was aberrantly expressed in GC and associated with histologic type and tumor progression. Hypermethylation of the promoter region was found to be responsible for the loss of miR-200c in GC cells. Demethylation agents led to recovery of miR-200c expression in GC cell lines. Moreover, DNMT3a knockdown abolished the hypermethylation of the miR-200c gene and induced upregulation of miR-200c expression, whereas ectopic DNMT3a expression increased miR-200c promoter methylation and decreased miR-200c expression. Conversely, transfection of miR-200c led to downregulation of DNMT3a protein and induced endogenous pre miR-200c and pri-miR-200c re-expression. Luciferase assays confirmed miR-200c binding to the DNMT3a 3'UTR. Finally, ectopic expression of miR-200c or knockdown of DNMT3a expression impeded GC cell growth, migration and invasion. Taken together, these observations demonstrates a novel epigenetic feedback loop between miR-200c and DNMT3a in the carcinogenesis and progression of GC. PMID- 27498673 TI - Oleuropein inhibits the proliferation and invasion of glioma cells via suppression of the AKT signaling pathway. AB - Oleuropein, the main phenolic compound of secoiridoids, has been proven to have inhibitory effects on various types of cancers. However, the antitumor effects and related mechanisms in glioma remain unclear. In the present study, U251 and A172 cells were used to assess the effects of oleuropein. Using cell viability assay, we found that oleuropein greatly inhibited the viability of the U251 and A172 cells. Additionally, flow cytometric apoptosis assay indicated that oleuropein induced the apoptosis of the two cell lines. Consistently, the inhibitory effects of oleuropein on migration and invasion were also observed in vitro. In regards to the mechanism, we found that oleuropein significantly decreased phosphorylation of AKT (p-AKT), accompanied by upregulation of Bax and downregulation of Bcl-2. We also found that there was a decrease in the expression levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 after treatment with oleuropein. Furthermore, a specific phosphatidylinositol 3 kinase (PI3K) inhibitor, LY294002, enhanced the pro-apoptotic and anti-invasive effects induced by oleuropein, which suggested that oleuropein suppressed the growth and invasion of glioma cells via inhibition of AKT activity. Taken together, our results indicated that treatment with oleuropein may be an effective therapy for malignant glioma through suppression of tumor proliferation and invasion by inhibition of the AKT signaling pathway. PMID- 27498674 TI - Severe Infections are Common in Thiamine Deficiency and May be Related to Cognitive Outcomes: A Cohort Study of 68 Patients With Wernicke-Korsakoff Syndrome. AB - BACKGROUND: Wernicke encephalopathy can have different clinical outcomes. Although infections may precipitate the encephalopathy itself, it is unknown whether infections also modify the long-term outcome in patients developing Korsakoff syndrome. OBJECTIVE: To determine whether markers of infection, such as white blood cell (WBC) counts and absolute neutrophil counts in the Wernicke phase, are associated with cognitive outcomes in the end-stage Korsakoff syndrome. METHOD: Retrospective, descriptive study of patients admitted to Slingedael Korsakoff Center, Rotterdam, The Netherlands. Hospital discharge letters of patients with Wernicke encephalopathy were searched for relevant data on infections present upon hospital admission. Patients were selected for further analysis if data were available on WBC counts in the Wernicke phase and at least 1 of 6 predefined neuropsychological tests on follow-up. RESULTS: Infections were reported in 35 of 68 patients during the acute phase of Wernicke-Korsakoff syndrome-meningitis (1), pneumonia (14), urinary tract infections (9), acute abdominal infections (4), sepsis (5) empyema, (1) and infection "of unknown origin" (4). The neuropsychological test results showed significant lower scores on the Cambridge Cognitive Examination nonmemory section with increasing white blood cell counts (Spearman rank correlation, rho = -0.34; 95% CI: -0.57 to 0.06; 44 patients) and on the "key search test" of the behavioral assessment of the dysexecutive syndrome with increasing absolute neutrophil counts (rho= -0.85; 95% CI: -0.97 to -0.42; 9 patients). CONCLUSIONS: Infections may be the presenting manifestation of thiamine deficiency. Patients with Wernicke-Korsakoff syndrome who suffered from an infection during the acute phase are at risk of worse neuropsychological outcomes on follow-up. PMID- 27498675 TI - All-cause mortality risk as a function of sedentary behavior, moderate-to vigorous physical activity and cardiorespiratory fitness. AB - OBJECTIVE: Emerging work demonstrates individual associations of sedentary behavior, moderate-to-vigorous physical activity (MVPA) and cardiorespiratory fitness (CRF) on mortality risk. Limited research has evaluated all three of these parameters in a model when considering mortality risk, and their potential additive association on mortality risk has not been fully evaluated, which was the purpose of this study. METHODS: Data from the 2003-2006 National Health and Nutrition Examination Survey were used (N = 2,295 adults 20-85 yrs), with follow up through 2011. Sedentary behavior and MVPA were objectively assessed (accelerometry) with cardiorespiratory estimated from a prediction equation taking into consideration participant demographic, anthropometric and behavioral characteristics. Using the median values, a PACS (Physical Activity Cardiorespiratory Sedentary) score was created that ranged from 0-3, indicating the number of these three positive characteristics. RESULTS: Those with below median sedentary behavior did not have a reduced all-cause mortality risk (HR = 0.59; 95% CI: 0.34-1.04; P = 0.07), but those with above median MVPA (HR = 0.35; 95% CI: 0.15-0.82; P = 0.02) and above median CRF did (HR = 0.20; 95% CI: 0.09 0.43; P < 0.001). Compared to those with a PACS score of 0, those with a PACS score of 1, 2, and 3, respectively, had a 67% (HR = 0.33; 95% CI: 0.17-0.63, P = 0.002), 82% (HR = 0.12; 95% CI: 0.05-0.30; P < 0.001) and 96% (HR = 0.04; 95% CI: 0.02-0.11; P < 0.001) reduced risk of all-cause mortality. CONCLUSION: Cardiorespiratory fitness and MVPA, but not sedentary behavior, were independently associated with reduced mortality risk. Adults with all three characteristics (below median sedentary and above median MVPA and CRF), however, had the lowest mortality risk. PMID- 27498676 TI - Editorial: Optimizing Chronic Heart Failure Care Beyond Randomised Controlled Trials - What are the problem areas and potential solutions? PMID- 27498677 TI - Sepsis Caused by Achromobacter Xylosoxidans in a Child with Cystic Fibrosis and Severe Lung Disease. AB - BACKGROUND Achromobacter xylosoxidans is an aerobic, motile, Gram-negative, opportunistic pathogen that can be responsible for various severe nosocomial and community-acquired infections. It has been found in immunocompromised patients and patients with several other underlying conditions, but the clinical role of this microorganism in cystic fibrosis is unclear. CASE REPORT We describe a case of septic shock caused by A. xylosoxidans in a 10-year-old child with cystic fibrosis and severe lung disease. CONCLUSIONS As the prevalence of A. xylosoxidans in cystic fibrosis patients is rising and patient-to-patient transmission is highly probable, further studies are warranted to determine its role and to document the appropriate treatment strategy for eradication and long term treatment of this organism. PMID- 27498678 TI - [Retracted] Systemic delivery of synthetic microRNA-451 is an effective therapeutic strategy for the treatment of lung cancer. AB - Following the publication of this article, an interested reader drew to our attention that Figs. 3B and 4B contained histological data which had previously been published in Figs. 3B and 4B, respectively, of the following article: Wiggins JF, Ruffino L, Kelnar K, Omotola M, Patrawala L, Brown D and Bader AG: Development of a lung cancer therapeutic based on the tumor suppressor microRNA 34. Cancer Res. 15: 5923-5930, 2010. We have tried to contact the authors of the above paper on several occasions for comment, but without success; therefore, the Editorial Board of the International Journal of Molecular Medicine has taken the decision to retract this publication. We thank the reader for drawing this matter to our attention. [the original article was published in the International Journal of Molecular Medicine 35: 1369-1373, 2015; DOI: 10.3892/ijmm.2015.2147]. PMID- 27498679 TI - Rodent Models of Vascular Cognitive Impairment. AB - Vascular cognitive impairment dementia (VCID), which is an increasingly important cause of dementia in the elderly, lacks effective treatments. Many different types of vascular disease are included under the diagnosis of VCID, including large vessel disease with multiple strokes and small vessel disease with lacunar infarcts and white matter disease. Animal models have been developed to study the multiple forms of VCID. Because of its progressive course, small vessel disease (SVD) is thought to be the optimal form of VCID for treatment. One theory is that the pathophysiology involves hypoxic hypoperfusion resulting in injury to the white matter and neuronal death. Bilateral occlusion of the common carotid arteries (BCAO) in a normotensive rat, which reduces cerebral blood flow, induces hypoxia with white matter damage; this model has been used to test drugs to block the injury. Another model is the spontaneously hypertensive/stroke prone rat (SHR/SP). Hypertension leads to small vessel disease resulting in progressive damage to the white matter, cortex, and hippocampus. Bilateral carotid artery stenosis (BCAS) with coils or ameroid constrictors produces a slower development of changes than BCAO, avoiding the acute ischemia. A few studies have been done with the two-clip, two-vessel occlusion renal model for induction of hypertension. There are benefits and drawbacks to each of these models with the model selected depending on the type of vascular damage that is to be studied. This review describes the most commonly used models, and the drugs that have been used to reduce the damage. PMID- 27498681 TI - Erratum to: Genetic Counselling for Psychiatric Disorders: Accounts of Psychiatric Health Professionals in the United Kingdom. PMID- 27498680 TI - How to Measure Recovery? Revisiting Concepts and Methods for Stroke Studies. AB - In clinical trials, assessing efficacy is based on validated scales, and the primary endpoint is usually based on a single scale. The aim of the review is to revisit the concepts and methods to design and analyze studies focused on restoration, recovery and or compensation. These studies are becoming more frequent with the development of restorative medicine. After discussing the definitions of recovery, we address the concept of recovery as the regain of lost capabilities, when the patient reaches a new equilibrium. Recovery is a dynamic process which assessment includes information from initial and final status, their difference, the difference between the final status of the patient and normality, and the speed of restoration. Finally, recovery can be assessed either for a specific function (focal restoration) or for a more global restoration. A single scale is not able to assess all the facets of a skill or a function, therefore complementary information should be collected and analyzed simultaneously to be tested in a single analysis. We are suggesting that recovery should be considered as a latent variable and therefore cannot be measured in pure form. We are also suggesting to customize the data collection and analysis according to the characteristics of the subjects, the mechanisms of action and consequences of the intervention. Moreover, recovery trials should benefit from latent variable analysis methods. Structural equation modeling is likely the best candidate for this approach applicable in pre-clinical and clinical studies. PMID- 27498682 TI - A novel variant of androgen receptor is associated with idiopathic azoospermia. AB - A variety of genetic variants can lead to abnormal human spermatogenesis. The androgen receptor (AR) is an important steroid hormone receptor that is critical for male sexual differentiation and the maintenance of normal spermatogenesis. In the present study, each exon of AR in 776 patients diagnosed with idiopathic azoospermia (IA) and 709 proven fertile men were sequenced using use panel re sequencing methods to examine whether AR is involved in the pathogenesis of IA. Two synonymous variants and seven missense variants were detected. Of the missense variants, a luciferase assay demonstrated that the R630W variant reduced the transcriptional regulatory function of AR. This novel variant (p. R630W) of AR is the first to be identified in association with IA, thereby highlighting the importance of AR during spermatogenesis. PMID- 27498683 TI - Ultrasonography and contrast-enhanced CT findings of tularemia in the neck. AB - PURPOSE: We aimed to evaluate the ultrasonography (US) and contrast-enhanced computed tomography (CECT) findings of tularemia in the neck. METHODS: US and CECT findings of 58 patients with serologically proven tularemia were retrospectively evaluated. Forty-eight patients underwent US and 42 patients underwent CECT. Lymph node characteristics and parotid preauricular region involvement were analyzed using US and CECT. In addition, involvement of larynx, oropharynx, and retropharynx; presence of periorbital edema; and neck abscess formation were evaluated using CECT. Fine needle aspiration cytology (FNAC) results of enlarged lymph nodes were analyzed in 29 patients. RESULTS: Hypoechoic pattern, round shape, absence of hilum, and cystic necrosis were seen in most of the lymph nodes especially at level 2 and 3 on US and CECT. Matting was more commonly observed than irregular nodal border on US and CECT. Parotid preauricular region involvement was seen in 20.8% of patients on US. Oropharyngeal, retropharyngeal, laryngeal and parotid preauricular region involvement and periorbital edema were seen in 52.4%, 19.1%, 4.8%, 31%, and 9.5% of tularemia patients, respectively. Neck abscess was found in 59.5% of patients on CECT. Suppurative inflammation was the most common finding of FNAC. CONCLUSION: Tularemia should be considered in the presence of level 2 and 3 lymph nodes with cystic necrosis, matting, absence of calcification, oropharyngeal and retropharyngeal region involvement, and neck abscess, particularly in endemic areas. PMID- 27498686 TI - Charge transfer reactions between gas-phase hydrated electrons, molecular oxygen and carbon dioxide at temperatures of 80-300 K. AB - The recombination reactions of gas-phase hydrated electrons (H2O)n(-) with CO2 and O2, as well as the charge exchange reaction of CO2(-)(H2O)n with O2, were studied by Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry in the temperature range T = 80-300 K. Comparison of the rate constants with collision models shows that CO2 reacts with 50% collision efficiency, while O2 reacts considerably slower. Nanocalorimetry yields internally consistent results for the three reactions. Converted to room temperature condensed phase, this yields hydration enthalpies of CO2(-) and O2(-), DeltaHhyd(CO2(-)) = -334 +/- 44 kJ mol(-1) and DeltaHhyd(O2(-)) = -404 +/- 28 kJ mol(-1). Quantum chemical calculations show that the charge exchange reaction proceeds via a CO4(-) intermediate, which is consistent with a fully ergodic reaction and also with the small efficiency. Ab initio molecular dynamics simulations corroborate this picture and indicate that the CO4(-) intermediate has a lifetime significantly above the ps regime. PMID- 27498687 TI - Genetic and clinical characteristics of Japanese patients with sporadic somatotropinoma. AB - Most of acromegaly is caused by a sporadic somatotropinoma and a couple of novel gene mutations responsible for somatotropinoma have recently been reported. To determine the cause of sporadic somatotropinoma in Japanese patients, we analyzed 61 consecutive Japanese patients with somatotropinoma without apparent family history. Comprehensive genetic analysis revealed that 31 patients harbored guanine nucleotide-binding protein, alpha stimulating (GNAS) mutations (50.8%) and three patients harbored aryl hydrocarbon receptor interacting protein (AIP) mutations (4.9%). No patients had G protein-coupled receptor 101 (GPR101) mutations. The patients in this cohort study were categorized into three groups of AIP, GNAS, and others and compared the clinical characteristics. The AIP group exhibited significantly younger age at diagnosis, larger tumor, and higher nadir GH during oral glucose tolerance test. In all patients with AIP mutation, macro- and invasive tumor was detected and repetitive surgery or postoperative medical therapy was needed. One case showed a refractory response to postoperative somatostatin analogue (SSA) but after the addition of cabergoline as combined therapy, serum IGF-I levels were controlled. The other case showed a modest response to SSA and the switching to cabergoline monotherapy was also effective. These data suggest that although resistance to SSA has been reported in patients with AIP mutations, the response to dopamine agonist (DA) may be retained. In conclusion, the cause of sporadic somatotropinoma in Japanese patients was comparable with the previous reports in Caucasians, patients with AIP mutations showed unique clinical characteristics, and DA may be a therapeutic option for patients with AIP mutations. PMID- 27498685 TI - Multiple independent transmission cycles of a tick-borne pathogen within a local host community. AB - Many pathogens are maintained by multiple host species and involve multiple strains with potentially different phenotypic characteristics. Disentangling transmission patterns in such systems is often challenging, yet investigating how different host species contribute to transmission is crucial to properly assess and manage disease risk. We aim to reveal transmission cycles of bacteria within the Borrelia burgdorferi species complex, which include Lyme disease agents. We characterized Borrelia genotypes found in 488 infected Ixodes ricinus nymphs collected in the Senart Forest located near Paris (France). These genotypes were compared to those observed in three sympatric species of small mammals and network analyses reveal four independent transmission cycles. Statistical modelling shows that two cycles involving chipmunks, an introduced species, and non-sampled host species such as birds, are responsible for the majority of tick infections. In contrast, the cycle involving native bank voles only accounts for a small proportion of infected ticks. Genotypes associated with the two primary transmission cycles were isolated from Lyme disease patients, confirming the epidemiological threat posed by these strains. Our work demonstrates that combining high-throughput sequence typing with networks tools and statistical modeling is a promising approach for characterizing transmission cycles of multi host pathogens in complex ecological settings. PMID- 27498688 TI - Autophagic degradation of epidermal growth factor receptor in gefitinib-resistant lung cancer by celastrol. AB - Drug resistance of non-small cell lung cancer (NSCLC) is highly correlated to the mutation of the epidermal growth factor receptor (EGFR). Although EGFR tyrosine kinase inhibitors (TKIs) are available clinically, the molecular complexity of NSCLC has made it necessary to search for alternative therapeutic approaches to overcome the drug resistance of NSCLC. In the present study, we identified a triterpene molecule derived from the herbal plant Tripterygium wilfordii, celastrol, as a novel autophagy inducer. We demonstrate that celastrol exhibited selective cytotoxic effect towards EGFR mutant NSCLCs. In addition, celastrol also facilitated the autophagic degradation of Hsp90 client protein including EGFR and Akt on both EGFR wild-type and mutant NSCLCs via calcium-mediated autophagy. Blockage of celastrol-induced autophagic degradation of EGFR by autophagic inhibitor or calcium chelator decreased celastrol-mediated cell death in gefitinib-resistant NSCLCs. Overall, our findings suggest that celastrol may be developed as an effective anticancer agent for treatment of gefitinib resistant NSCLC in the future. PMID- 27498689 TI - Spin-glass behavior and pyroelectric anomalies in a new lithium-based oxide, Li3FeRuO5. AB - The results of dc and ac magnetization, heat capacity, (57)Fe Mossbauer spectroscopy, dielectric, pyroelectric current and isothermal magneto-capacitance measurements of a recently reported lithium-rich layered oxide, Li3FeRuO5, related to LiCoO2-type (rhombohedral, space group R3[combining macron]m), are presented. The results reveal that the compound undergoes spin-glass freezing at 15 K. There is a peak around 34 K in pyroelectric data, which cannot be attributed to ferroelectricity, but to the phenomenon of thermally stimulated depolarization current. As revealed by magnetocapacitance data above and below the magnetic ordering temperature, magnetic and electric dipoles appear to be coupled, thereby offering evidence for magnetodielectric coupling. PMID- 27498690 TI - A novel transformation route from PbS to CH3NH3PbI3 for fabricating curved and large-area perovskite films. AB - We present a new transformation route from PbS to CH3NH3PbI3 for the facile preparation of perovskites with all kinds of shapes via vapor-assisted chemical bath deposition (VACBD). As such, curved and large-area CH3NH3PbI3 films with high quality are successfully achieved, which are suitable for the manufacturing scale-up of perovskite solar cells. PMID- 27498691 TI - Genetic screen: A network to guide precision cancer therapy. PMID- 27498694 TI - Iridium-based double perovskites for efficient water oxidation in acid media. AB - The development of active, cost-effective and stable oxygen-evolving catalysts is one of the major challenges for solar-to-fuel conversion towards sustainable energy generation. Iridium oxide exhibits the best available compromise between catalytic activity and stability in acid media, but it is prohibitively expensive for large-scale applications. Therefore, preparing oxygen-evolving catalysts with lower amounts of the scarce but active and stable iridium is an attractive avenue to overcome this economical constraint. Here we report on a class of oxygen evolving catalysts based on iridium double perovskites which contain 32 wt% less iridium than IrO2 and yet exhibit a more than threefold higher activity in acid media. According to recently suggested benchmarking criteria, the iridium double perovskites are the most active catalysts for oxygen evolution in acid media reported until now, to the best of our knowledge, and exhibit similar stability to IrO2. PMID- 27498695 TI - Surface modification of adamantane-terminated gold nanoclusters using cyclodextrins. AB - The surface functionality of Au38S2(SAdm)20 nanoclusters (-SAdm = adamantanethiolate) in the presence of alpha-, beta-, and gamma-cyclodextrins (CDs) is studied. The supramolecular chemistry and host-guest interactions of CDs and the protecting ligands of nanoclusters are investigated using UV-vis and NMR spectroscopies, MALDI mass spectrometry, and molecular dynamics simulations. In contrast to alpha- and gamma-CDs, the results show that beta-CDs are capable of efficiently chemisorbing onto the Au38S2(SAdm)20 nanoclusters to yield Au38S2(SAdm)20-(beta-CD)2 conjugates. MD simulations revealed that two -SAdm ligands of the nanoparticle with the least steric hindrance are capable to selectively be accommodated into hydrophobic cavity of beta-CDs, as furthermore confirmed by NMR spectroscopy. The conjugates largely improve the stability of the nanoclusters in the presence of strong oxidants (e.g., TBHP). Further, the electrochemical properties of Au38S2(SAdm)20 nanoclusters and Au38S2(SAdm)20 (beta-CD)2 conjugates are compared. The charge transfer to the redox probe molecules (e.g., K3Fe(CN)6) in solution was monitored by cyclic voltammetry. It is found that beta-CDs act as an umbrella to cover the fragile metal cores of the nanoclusters, thereby blocking direct interaction with destabilizing agents and hence quenching the charge transfer process. PMID- 27498693 TI - Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. AB - Dimethyl fumarate (DMF) possesses anti-inflammatory properties and is approved for the treatment of psoriasis and multiple sclerosis. While clinically effective, its molecular target has remained elusive - although it is known to activate anti-oxidant pathways. We find that DMF inhibits pro-inflammatory cytokine production in response to TLR agonists independently of the Nrf2-Keap1 anti-oxidant pathway. Instead we show that DMF can inhibit the E2 conjugating enzymes involved in K63 and M1 polyubiquitin chain formation both in vitro and in cells. The formation of K63 and M1 chains is required to link TLR activation to downstream signaling, and consistent with the block in K63 and/or M1 chain formation, DMF inhibits NFkappaB and ERK1/2 activation, resulting in a loss of pro-inflammatory cytokine production. Together these results reveal a new molecular target for DMF and show that a clinically approved drug inhibits M1 and K63 chain formation in TLR induced signaling complexes. Selective targeting of E2s may therefore be a viable strategy for autoimmunity. PMID- 27498692 TI - Network biology concepts in complex disease comorbidities. AB - The co-occurrence of diseases can inform the underlying network biology of shared and multifunctional genes and pathways. In addition, comorbidities help to elucidate the effects of external exposures, such as diet, lifestyle and patient care. With worldwide health transaction data now often being collected electronically, disease co-occurrences are starting to be quantitatively characterized. Linking network dynamics to the real-life, non-ideal patient in whom diseases co-occur and interact provides a valuable basis for generating hypotheses on molecular disease mechanisms, and provides knowledge that can facilitate drug repurposing and the development of targeted therapeutic strategies. PMID- 27498696 TI - The suppression of scale-free fMRI brain dynamics across three different sources of effort: aging, task novelty and task difficulty. AB - There is growing evidence that fluctuations in brain activity may exhibit scale free ("fractal") dynamics. Scale-free signals follow a spectral-power curve of the form P(f ) ? f(-beta), where spectral power decreases in a power-law fashion with increasing frequency. In this study, we demonstrated that fractal scaling of BOLD fMRI signal is consistently suppressed for different sources of cognitive effort. Decreases in the Hurst exponent (H), which quantifies scale-free signal, was related to three different sources of cognitive effort/task engagement: 1) task difficulty, 2) task novelty, and 3) aging effects. These results were consistently observed across multiple datasets and task paradigms. We also demonstrated that estimates of H are robust across a range of time-window sizes. H was also compared to alternative metrics of BOLD variability (SDBOLD) and global connectivity (Gconn), with effort-related decreases in H producing similar decreases in SDBOLD and Gconn. These results indicate a potential global brain phenomenon that unites research from different fields and indicates that fractal scaling may be a highly sensitive metric for indexing cognitive effort/task engagement. PMID- 27498697 TI - Expression pattern and methylation of estrogen receptor alpha in breast intraductal proliferative lesions. AB - Intraductal proliferative lesions of the breast including usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) are associated with increased risk, albeit of greatly different magnitudes, for the subsequent development of invasive carcinoma. Estrogen receptor alpha (ERalpha) has been widely accepted as a prognostic marker and a predictor for endocrine therapy response of breast cancer. To investigate the ERalpha expression and methylation in breast intraductal proliferative lesions, we analyzed ERalpha expression in breast intraductal proliferative lesions including pure UDH (N=98), ADH without DCIS (N=160), DCIS without invasive breast cancer (N=149) by immunohistochemistry. Furthermore, the methylation status of ERalpha by methylation-specific PCR (MSP) was defined in 217 cases of breast intraductal proliferative lesions. Immunohistochemistry showed that 98/98 (100%) of the UDH cases were positive for ERalpha expression. ERalpha protein expression in ADH (132/160) (92.5%) was higher than in DCIS (101/149) (67.8%). But the ERalpha expression pattern was different with histological diversity of breast intraductal proliferative lesions. The average percent cells staining positive for ERalpha was 35.33% in UDH, 87.75% in ADH and 71.45% in DCIS. ERalpha methylation in 32/60 (53.3%) UDH, 11/77 (10.2%) ADH and 32/80 (40.0%) DCIS. Our results demonstrated a strong negative correlation between the percent of cells staining positive for ERalpha and ERalpha methylation (r=-0.831, p<0.001). Taken together, our results underlined that ERalpha expression or methylation may be involved in the breast carcinogenesis and advancement, thus it is not parallel to breast cancer risk in breast intraductal proliferative lesions. No obvious watershed between ERalpha-positive and -negative breast carcinogenesis was established. Estrogen receptor (ER) methylation or expression is a reversible signal in breast carcinogenesis which affected biological behavior of cells. PMID- 27498698 TI - Nanoscale Structure, Dynamics, and Aging Behavior of Metallic Glass Thin Films. AB - Scanning tunnelling microscopy observations resolve the structure and dynamics of metallic glass Cu100-xHfx films and demonstrate scanning tunnelling microscopy control of aging at a metallic glass surface. Surface clusters exhibit heterogeneous hopping dynamics. Low Hf concentration films feature an aged surface of larger, slower clusters. Argon ion-sputtering destroys the aged configuration, yielding a surface in constant fluctuation. Scanning tunnelling microscopy can locally restore the relaxed state, allowing for nanoscale lithographic definition of aged sections. PMID- 27498699 TI - Suppression of superconductivity and structural phase transitions under pressure in tetragonal FeS. AB - Pressure is a powerful tool to study iron-based superconductors. Here, we report systematic high-pressure transport and structural characterizations of the newly discovered superconductor FeS. It is found that superconductor FeS (tetragonal) partly transforms to a hexagonal structure at 0.4 GPa, and then completely transforms to an orthorhombic phase at 7.4 GPa and finally to a monoclinic phase above 9.0 GPa. The superconducting transition temperature of tetragonal FeS was gradually depressed by pressure, different from the case in tetragonal FeSe. With pressure increasing, the S-Fe-S angles only slightly change but the anion height deviates farther from 1.38 A. This change of anion height, together with the structural instability under pressure, should be closely related to the suppression of superconductivity. We also observed an anomalous metal semiconductor transition at 6.0 GPa and an unusual increased resistance with further compression above 9.6 GPa. The former can be ascribed to the tetragonal orthorhombic structural phase transition, and the latter to the electronic structure changes of the high-pressure monoclinic phase. Finally, a phase diagram of tetragonal FeS as functions of pressure and temperature was mapped out for the first time, which will shed new light on understanding of the structure and physics of the superconducting FeS. PMID- 27498700 TI - ZCF32, a fungus specific Zn(II)2 Cys6 transcription factor, is a repressor of the biofilm development in the human pathogen Candida albicans. AB - As a human fungal pathogen, Candida albicans can cause a wide variety of disease conditions ranging from superficial to systemic infections. Many of these infections are caused by an inherent ability of the pathogen to form biofilms on medical devices resulting in high mortality. Biofilms formed by C. albicans are a complex consortium of yeast and hyphal cells embedded in an extracellular matrix and are regulated by a network of transcription factors. Here, we report the role of a novel Zn(II)2-Cys6 binuclear cluster transcription factor, ZCF32, in the regulation of biofilm formation. Global transcriptome analysis reveals that biofilm development is the most altered pathway in the zcf32 null mutant. To delineate the functional correlation between ZCF32 and biofilm development, we determined the set of genes directly regulated by Zcf32. Our data suggests that Zcf32 regulates biofilm formation by repressing the expression of adhesins, chitinases and a significant number of other GPI-anchored proteins. We establish that there is the lesser recruitment of Zcf32 on the promoters of biofilm genes in biofilm condition compared to the planktonic mode of growth. Taking together, we propose that the transcription factor ZCF32 negatively regulates biofilm development in C. albicans. PMID- 27498701 TI - Fibroblast growth factor 21 deficiency exacerbates chronic alcohol-induced hepatic steatosis and injury. AB - Fibroblast growth factor 21 (FGF21) is a hepatokine that regulates glucose and lipid metabolism in the liver. We sought to determine the role of FGF21 in hepatic steatosis in mice exposed to chronic alcohol treatment and to discern underlying mechanisms. Male FGF21 knockout (FGF21 KO) and control (WT) mice were divided into groups that were fed either the Lieber DeCarli diet containing 5% alcohol or an isocaloric (control) diet for 4 weeks. One group of WT mice exposed to alcohol received recombinant human FGF21 (rhFGF21) in the last 5 days. Liver steatosis and inflammation were assessed. Primary mouse hepatocytes and AML-12 cells were incubated with metformin or rhFGF21. Hepatic genes and the products involved in in situ lipogenesis and fatty acid beta-oxidation were analyzed. Alcohol exposure increased circulating levels and hepatic expression of FGF21. FGF21 depletion exacerbated alcohol-induced hepatic steatosis and liver injury, which was associated with increased activation of genes involved in lipogenesis mediated by SREBP1c and decreased expression of genes involved in fatty acid beta oxidation mediated by PGC1alpha. rhFGF21 administration reduced alcohol-induced hepatic steatosis and inflammation in WT mice. These results reveal that alcohol induced FGF21 expression is a hepatic adaptive response to lipid dysregulation. Targeting FGF21 signaling could be a novel treatment approach for alcoholic steatohepatitis. PMID- 27498704 TI - The resveratrol analogue, 3,4,5,4'-trans-tetramethoxystilbene, inhibits the growth of A375 melanoma cells through multiple anticancer modes of action. AB - Resveratrol is a natural dietary product that has demonstrated multifaceted anticancer activity. Several analogues of resveratrol have been synthesized in an effort to enhance the pharmacological potency and improve the pharmacokinetic properties of the compound. 3,4,5,4'-trans-tetramethoxystilbene (3,4,5,4'-TMS) is a methoxylated analogue of resveratrol that has demonstrated anti-proliferative activity in vitro (in cancer cell lines) and in vivo (in xenograft models). In the present study, the anticancer effects of 3,4,5,4'-TMS in A375 human melanoma cells were examined. 3,4,5,4'-TMS markedly inhibited the proliferation of A375 cells (IC50=0.7 uM), via a mechanism involving mitotic arrest at the prometaphase stage of cell division. This effect was accompanied by the upregulation of the expression of the mitogen activated protein kinases, JNK and p38, and the concomitant activation of p38, that was verified by the nuclear translocation of the phoshorylated form of the protein. The pharmacological inhibition of p38 by SB203580 (4 uM) attenuated the effects of 3,4,5,4'-TMS, as demonstrated by decreased cell cycle progression at the mitotic phase. Furthermore, 3,4,5,4'-TMS increased the total levels of Aurora A, while it inhibited the localization of the protein to the spindle poles. Finally, 3,4,5,4'-TMS exhibited anti-metastatic activity, inhibiting A375 cell migration and the attachment of the cells to a collagen type IV-coated surface. Collectively, the data suggest that 3,4,5,4'-TMS is an effective chemotherapeutic drug for the treatment of human melanoma and that it exerts its effects through multiple anticancer modes of action. PMID- 27498703 TI - Dynamic Covalent Chemistry-based Sensing: Pyrenyl Derivatives of Phenylboronic Acid for Saccharide and Formaldehyde. AB - We synthesized two specially designed pyrenyl (Py) derivatives of phenylboronic acid, PSNB1 and PSNB2, of which PSNB2 self-assemble to form dynamic aggregate in methanol-water mixture (1:99, v/v) via intermolecular H-bonding and pi-pi stacking. Interestingly, the dynamic aggregate shows smart response to presence of fructose (F) as evidenced by fluorescence color change from green to blue. More interestingly, the fluorescence emission of the resulted PSNB2-F changes from blue to green with the addition of formaldehyde (FA). The reason behind is formation of a PSNB2-F dimer via FA cross-linking. Based upon the reactions as found, sensitive and fast sensing of F and FA in water was realized, of which the experimental DLs could be significantly lower than 10 MUM for both analytes, and the response times are less than 1 min. It is believed that not only the materials as created may have the potential to find real-life applications but also the strategy as developed can be adopted to develop other dynamic materials. PMID- 27498702 TI - European Society of Cardiology Guideline-Adherent Antithrombotic Treatment and Risk of Mortality in Asian Patients with Atrial Fibrillation. AB - This study compared the risk of mortality in atrial fibrillation (AF) patients treated adherent to the 2012 European Society of Cardiology (ESC) guidelines for stroke prevention and those who were not treated according to guideline recommendations. This study used the Taiwan National Health Insurance Research Database. From 1996 to 2011, 354,649 newly diagnosed AF patients were identified as the study population. Among the study cohort, 45,595 and 309,054 patients were defined as Guideline-Adherent and Non-Adherent groups, respectively. During the follow up of 1,480,280 person-years, 133,552 (37.7%) patients experienced mortality. The risk of mortality was lower among AF patients whose treatment was adherent to the guideline recommendation for stroke prevention than those whose treatment was not (annual risk of mortality = 4.3% versus 10.0%) with an adjusted hazard ratio of 0.62 (95% confidence interval = 0.61-0.64, p value < 0.001) after adjusting for age, gender, CHA2DS2-VASc score and antiplatelet therapy. The findings were consistently observed after propensity matching analysis. In conclusion, the risk of mortality was lower for AF patients who were treated according to the antithrombotic recommendations of the 2012 ESC guidelines, guided by the CHA2DS2-VASc score. Better efforts to implement guidelines would lead to improved outcomes for patients with AF. PMID- 27498705 TI - Identification of brefelamide as a novel inhibitor of osteopontin that suppresses invasion of A549 lung cancer cells. AB - The contribution of aberrant osteopontin (OPN) expression to tumor progression and metastasis has been documented in a wide spectrum of malignancies, and targeted inhibition of OPN has therefore emerged as an attractive strategy for cancer therapy. Transcription of OPN is regulated by various transcription factors, and our recently published study demonstrated that downregulation of OPN is an important event in the TGF-beta cytostatic program. We report here that brefelamide exerts an inhibitory effect on OPN expression and function in A549 human lung carcinoma cells. The promoter, RNA, and protein levels of OPN were decreased in brefelamide-treated A549 cells, which was accompanied by reduced invasive ability in vitro. OPN inhibition by brefelamide was largely abrogated by disruption of a putative TGF-beta inhibitory element in the OPN promoter. Treatment with brefelamide induced Smad4 expression, and knockdown of Smad4 by RNA interference partially diminished the inhibitory effect of brefelamide on OPN. These results indicate that brefelamide inhibited OPN-mediated cell invasion through restoration of the OPN repression by TGF-beta/Smad signaling. Together with the reported antiproliferative property, our findings suggest that brefelamide might serve as a potential candidate for the development of a new antitumor and antimetastatic agent. PMID- 27498706 TI - beta-Elemene enhances the efficacy of gefitinib on glioblastoma multiforme cells through the inhibition of the EGFR signaling pathway. AB - Glioblastoma multiforme (GBM) is the most common and severe form of primary tumor in the central nervous system of adults which has poor prognosis and limited therapeutic options. Epidermal growth factor receptor (EGFR) inhibitor, such as gefitinib (brand name Iressa, ZD1839), has been approved as a targeted medicine for several types of tumor including glioblastoma multiforme. However, gefitinib exerted very limited effects on some glioblastoma multiforme patients after a period of treatment due to intrinsic and acquired drug resistance. beta-Elemene, a natural plant drug extracted from Curcuma wenyujin, has shown promising anticancer effects against a broad spectrum of tumors. In the present study, we found that beta-elemene could enhance the chemosensitivity of glioblastoma multiforme cells to gefitinib. The combination medication of beta-elemene and gefitinib not only inhibited the survival and proliferation of glioblastoma multiforme cells via inhibition of EGFR signaling pathway but also induced more distinct apoptosis and autophagy in the glioblastoma multiforme cells than the gefitinib monotherapy. These results showed that beta-elemene might be one potential adjuvant to enhance the effect of EGFR inhibitor and reduce the resistance of gefitinib in glioblastoma multiforme. PMID- 27498707 TI - Different infusion durations for preventing platinum-induced hearing loss in children with cancer. AB - BACKGROUND: Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is an update of a previously published Cochrane review. OBJECTIVES: To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. SEARCH METHODS: We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2016, Issue 4), MEDLINE (PubMed) (1945 to 18 May 2016) and EMBASE (Ovid) (1980 to 18 May 2016). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2015) and the American Society of Pediatric Hematology/Oncology (2014 and 2015). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (searched on 20 May 2016 and 24 May 2016 respectively). SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, risk of bias assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We identified one RCT and no CCTs; in this update no additional studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days 1 to 5 of the cycle but it is unclear if the infusion duration was a total of 5 days. Methodological limitations were present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. AUTHORS' CONCLUSIONS: Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high quality research is needed. PMID- 27498708 TI - Elevated IL-23R Expression and Foxp3+Rorgt+ Cells in Intestinal Mucosa During Acute and Chronic Colitis. AB - BACKGROUND IL-23/IL-23R signaling plays a pivotal role during the course of inflammatory bowel diseases (IBD). However, the underlying mechanisms are poorly characterized. Foxp3+ regulatory T cells are critical in the maintenance of gut immune homeostasis and therefore are important in preventing the development of IBD. This study was performed to clarify the association between IL-23/IL-23R signaling and Foxp3+ regulatory T cells in colitis. MATERIAL AND METHODS Acute and chronic mouse colitis models were established by administering mice DSS in drinking water. IL-23R, IL-23, IL-I7, and IFN-gamma expression level, as well as regulatory T cell, Th17-, and Th1-related transcription factors Foxp3, RORgt, and T-bet were assayed by real-time PCR. The frequency of Foxp3+ RORgammat+ cells in a Foxp3+ cell population in colon mucosa during acute and chronic colitis was evaluated through flow cytometry. The signaling pathway mediated by IL-23R in the colon mucosa from acute colitis mice and chronic colitis mice was monitored by Western blot analysis. RESULTS We detected elevated IL-23R, IL-23, and IFN-gamma expression in colon mucosa during acute and chronic colitis and found increased IL-17 in acute colitis mice. Transcription factors Foxp3 and T-bet were elevated in colon mucosa during acute and chronic colitis. Phosphorylation of Stat3 was greatly enhanced, indicating the activation of IL-23R function in colitis mice. The percentage of Foxp3+ T cells in acute and chronic colitis mice was comparable to control mice, but there was a 2-fold increase of Foxp3+ RORgammat+ cells among the Foxp3+ cell population in acute and chronic colitis mice compared to control mice. CONCLUSIONS These findings indicate that the induction of Foxp3+ RORgt+ T cells could be enhanced during inflammation in the intestine where IL-23R expression is greatly induced. Our study highlights the importance of IL-23R expression level and the instability of Foxp3+ regulatory T cells in the development of inflammatory bowel diseases. PMID- 27498710 TI - Local community playgroup participation and associations with social capital. AB - Issue addressed The study aim was to investigate the relationships between social capital measures and playgroup participation in a local residential area for parents with children of playgroup age (1-4 years) compared with non participation and participation in a playgroup outside the local residential area. Research indicates playgroup participation has benefits for families, however, less is known about the potential local community social capital for parents who participate in playgroups. Methods Data were collected through a cross-sectional survey from March 2013 to January 2014 in Perth, Western Australia. The data from a group of parents (n=405) who had at least one child aged between 1 and 4 years were analysed using multivariable regression. Reported playgroup participation (local, outside the area or non-participation) in the previous 12 months was investigated for associations with three measures (Neighbourhood Cohesion Index, Social Capital and Citizenship Survey and local reciprocity) that capture attributes of social capital. Results Participation in playgroup locally was generally associated with higher levels of social capital than both participation in playgroup outside the local area and non participation. Mothers with two or more children fared better for social capital measures than mothers with one child. Conclusions Participation in a locally placed playgroup may provide an important opportunity for families with children of playgroup age (1-4 years) to build social capital in their local community. So what? Playgroups in a family's local area have the potential to foster locally placed social capital through community interaction, social networks and cohesion, which are important for mental health promotion in communities. PMID- 27498709 TI - Epigallocatechin-3-gallate prevents oxidative stress-induced cellular senescence in human mesenchymal stem cells via Nrf2. AB - Human mesenchymal stem cells (hMSCs) have great therapeutic potential due to their high plasticity, immune privileged status and ease of preparation, as well as a lack of ethical barriers to their use. However, their ultimate usefulness is limited by cellular senescence occurring secondary to increased cellular levels of reactive oxygen species (ROS) during their propagation in culture. The underlying molecular mechanisms responsible for this process in hMSCs remain unclear. An antioxidant polyphenol epigallocatechin-3-gallate (EGCG) found in green tea, is known to activate nuclear factor-erythroid 2-related factor 2 (Nrf2), a master transcriptional regulator of antioxidant genes. Herein, we examined the EGCG-mediated antioxidant mechanism in hMSCs exposed to ROS which involves Nrf2 activation. The H2O2-exposed hMSCs showed cellular senescence with significantly increased protein levels of acetyl-p53 and p21 in comparison with the untreated hMSCs, and these effects were prevented by pre-treatment with EGCG. By contrast, in Nrf2-knockdown hMSCs, EGCG lost its antioxidant effect, exhibiting high levels of acetyl-p53 and p21 following EGCG pre-treatment and H2O2 exposure. This indicates that Nrf2 and p53/p21 may be involved in the anti senescent effect of EGCG in hMSCs. Taken together, these findings indicate the important role of EGCG in preventing oxidative stress-induced cellular senescence in hMSCs through Nrf2 activation, which has applications for the massive production of more suitable hMSCs for cell-based therapy. PMID- 27498711 TI - Proteomics applied to pediatric medicine: opportunities and challenges. AB - INTRODUCTION: Care in pediatrics often refers to treatments directed to adults. However, childhood is a specific life period, with molecular pathways connected to development and thereby it requires distinctive considerations and special treatments under disease. Proteomics can help to elucidate the molecular mechanisms underlying the human development and disease onset in pediatric age and this review is devoted to underline the results recently obtained in the field. AREAS COVERED: The contribution of proteomics to the characterization of physiological modifications occurring during human development is presented. The proteomic studies carried out to elucidate the molecular mechanisms underlying different pediatric pathologies and to discover new markers for early diagnosis and prognosis of disease, comprising genetic and systemic pathologies, sepsis and pediatric oncology are thereafter reported. The investigations concerning milk composition in human and farm mammals are also presented. Finally, the chances offered by the integration of different -omic platforms are discussed. Expert commentary: The growing utilization of holistic technologies such as proteomics, metabolomics and microbiomics will allow, in the near future, to define at the molecular level the complexity of human development and related diseases, with great benefit for future generations. PMID- 27498712 TI - Efficacy of Local and Systemic Antimicrobials in the Non-Surgical Treatment of Smokers With Chronic Periodontitis: A Systematic Review. AB - BACKGROUND: The aim of this systematic review is to evaluate whether use of local or systemic antimicrobials would improve clinical results of non-surgical periodontal therapy for smokers with chronic periodontitis (CP). METHODS: Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, and The Cochrane Central Register of Controlled Trials were searched up to and including March 2016. Randomized clinical trials of duration of at least 6 months were included if they reported on treatment of smokers (>=10 cigarettes per day for minimum 12 months) with CP with non-surgical periodontal therapy either alone or associated with local or systemic antimicrobials. Random-effects meta-analyses were undertaken to evaluate mean differences in probing depth (PD) and clinical attachment level (CAL). RESULTS: Of 108 potentially eligible articles, seven were included. Most individual studies (75%) testing locally delivered antibiotics reported that smokers benefited from this treatment approach. Pooled estimates found additional PD reduction of 0.81 mm (P = 0.01) and CAL gain of 0.91 mm (P = 0.01) at sites with baseline PD >=5 mm. Conversely, meta-analysis on systemic use of antimicrobials failed to detect significant differences in mean changes from baseline, and only one trial supported their use. CONCLUSIONS: In smokers with CP, adjunctive use of local antimicrobials improved efficacy of non-surgical periodontal therapy in reducing PD and improving CAL at sites presenting PD >=5 mm before treatment. Current evidence does not demonstrate similar gains when scaling and root planing plus systemic antimicrobial/antibiotics were associated with therapy. PMID- 27498713 TI - A Novel Treatment Decision Tree and Literature Review of Retrograde Peri Implantitis. AB - BACKGROUND: Although retrograde peri-implantitis (RPI) is not a common sequela of dental implant surgery, its prevalence has been reported in the literature to be 0.26%. Incidence of RPI is reported to increase to 7.8% when teeth adjacent to the implant site have a previous history of root canal therapy, and it is correlated with distance between implant and adjacent tooth and/or with time from endodontic treatment of adjacent tooth to implant placement. Minimum 2 mm space between implant and adjacent tooth is needed to decrease incidence of apical RPI, with minimum 4 weeks between completion of endodontic treatment and actual implant placement. The purpose of this study is to compile all available treatment modalities and to provide a decision tree as a general guide for clinicians to aid in diagnosis and treatment of RPI. METHODS: Literature search was performed for articles published in English on the topic of RPI. Articles selected were case reports with study populations ranging from 1 to 32 patients. Any case report or clinical trial that attempted to treat or rescue an implant diagnosed with RPI was included. RESULTS: Predominant diagnostic presentation of a lesion was presence of sinus tract at buccal or facial abscess of apical portion of implant, and subsequent periapical radiographs taken demonstrated a radiolucent lesion. On the basis of case reports analyzed, RPI was diagnosed between 1 week and 4 years after implant placement. Twelve of 20 studies reported that RPI lesions were diagnosed within 6 months after implant placement. A step by-step decision tree is provided to allow clinicians to triage and properly manage cases of RPI on the basis of recommendations and successful treatments provided in analyzed case reports. It is divided between symptomatic and asymptomatic implants and adjacent teeth with vital and necrotic pulps. CONCLUSIONS: Most common etiology of apical RPI is endodontic infection from neighboring teeth, which was diagnosed within 6 months after implant placement. Most common findings, radiographically and clinically, are lesions around implant apex and sinus tract. A small number of implants did not improve with treatment. Decision tree provides a path to diagnose and treat lesions to facilitate their management. Further studies are needed to focus on histologic data around periapical microbiota to establish specific etiology and differential diagnoses compared with marginal peri-implantitis and other implant-related conditions. PMID- 27498714 TI - An efficient and simple co-culture method for isolating primary human hepatic cells: Potential application for tumor microenvironment research. AB - Co-cultivation of non-parenchymal cells (NPCs) and tumor cells from the same donor is important for metastatic cancer research. This study aimed to optimize a protocol for liver NPC isolation. Two novel 3D organotypic co-culture models for hepatocyte, endothelial cell (EC) and Kupffer cell (KC) isolation were used. Long term cell co-culture, density gradient centrifugation and magnetic-activated cell sorting (MACS) were established. ECs were isolated from the co-culture system; the purity of the ECs was 92+/-1.2%. The island-like shape of hepatocytes was noted in the 3D co-culture system, and spindle cells were found in the rest space. Immunofluorescence analysis showed a net structure; the connective tissue was positively stained with VE-cadherin or CD68, which were ECs and KCs/macrophages. KCs were enriched in this system and separated by using selective adherence to plastic. Clec4f+ KCs consisted of 87+/-6.3% of these cells. Heterogeneous endothelium populations were detected, including sinusoid ECs, microvascular ECs and hepatic lymphatic vessel epithelial cells. In addition, hepatic progenitor cells were isolated and differentiated into hepatoblasts. Dendritic cells (DCs), invariant natural killer T (iNKT) cells were further separated by density gradient centrifugation and magnetic bead sorting. In the present study, high protein expression levels of desmin and GFAP were observed in the hepatic stellate cells (HSCs). Most of the HSCs were alpha-SMA positive cells, which underlined the identity of activated HSCs. Intrahepatic human biliary epithelial cells (hBECs) were semi-purified by centrifugation on a Percoll gradient and were further immunopurified. In conclusion, we provide an efficient long-term culture method to obtain liver NPCs in sufficient number and purity. PMID- 27498715 TI - Polyphenol-rich food general and on pregnancy effects: a review. AB - This review aimed to investigate possible protective or deleterious effects of polyphenol-rich foods (PRF) on chronic diseases, e.g. cardiovascular, and in pregnant women, along with their antioxidant and anti-inflammatory action. A great variety of foods and beverages, such as herbal teas, grape and orange derivatives, dark chocolate, and many others contain high concentrations of flavonoids and are freely consumed by the general population. In humans, PRF consumption reduces lipid peroxidation, and several studies have shown a positive correlation between an increased consumption of PRF and a decrease in the incidence of cardiovascular disease. On the other hand, current studies have suggested that maternal ingestion of PRF, especially during the third trimester of pregnancy, could be associated to fetal ductal constriction (DC). Fetuses exposed to this type of diet show higher ductal velocities and lower pulsatility indexes, as well as larger right ventricles than those exposed to minimal amounts of these substances. The underlying mechanism involved in these conditions has not been entirely elucidated, but it seems to be a result of the antioxidant and anti-inflammatory effects of polyphenols by some pathway. Furthermore, taking into account the deleterious effect in late-pregnancy against the numerous positive effects associated to polyphenols, this dual behavior deserves attention particularly to control the dietary ingestion of PRF during gestation. In this line, same PRF, natural constituents of human diet, may represent risk to fetal in late pregnancy compared to the use of nonsteroidal anti-inflammatory drugs. PMID- 27498716 TI - Acidic extracellular pH promotes prostate cancer bone metastasis by enhancing PC 3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesis of BM-EPCs. AB - Bone metastasis is a main cause of cancer-related mortality in patients with advanced prostate cancer. Emerging evidence suggests that the acidic extracellular microenvironment plays significant roles in the growth and metastasis of tumors. However, the effects of acidity on bone metastasis of PCa remain undefined. In the present study, PC-3 cells were cultured in acidic medium (AM; pH 6.5) or neutral medium (NM; pH 7.4), aiming to investigate the effects and possible mechanisms of acidic extracellular microenvironment in bone metastasis of PCa. Our results showed that AM can promote spheroid and colony formations, cell viability and expression of stem cell characteristic-related markers in PC-3 cells. Moreover, AM stimulates MMP-9 secretion and promotes invasiveness of PC-3 cells, and these effects can be inhibited by blocking of MMP 9. Furthermore, AM stimulates VEGF secretion of PC-3 and AM conditioned medium (CMAM) promotes vasculogenesis of BM-EPCs by increasing cell viability, migration, tube formation, which involved activating the phosphorylation of VEGFR 2, Akt and P38, when pH of NM conditioned medium (CMNM) was modulated the same as AM conditioned medium (CMAM). Further studies have shown that CMNM induced vasculogenesis of BM-EPCs can be inhibited by the inhibition of VEGFR2 with DMH4. These findings suggest that acidic extracellular microenvironment may have the potential to modulate prostate cancer bone metastasis by enhancing PC-3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesis of BM-EPCs. Improved anticancer strategies should be designed to selectively target acidic tumor microenvironment. PMID- 27498717 TI - Self gelating isoracemosol A, new racemosaceramide A, and racemosol E from Barringtonia racemosa. AB - Phytochemical investigation into the CHCl3 extract of the fruits of Barringtonia racemosa resulted in the isolation of two new metabolites along with isoracemosol A and betulinic acid as known metabolites. The new compounds were characterised as phytosphingosine-type ceramide [(2S,3S,4R)-2-[(2R)-2-hydroxyhexadecanoyl amino]-hexacos-8(E)-ene-1,3,4-triol, 1] and racemosol E [21beta-acetoxy-22alpha (2-methylbutyroxy)-olean-12-ene-3beta,16alpha,28-triol, 2] on the basis of extensive spectroscopic data analysis and chemical modifications. In addition, the self-gelating property of isoracemosol A (3) was investigated for the first time, which leads to the unexpected agglomerated porous-like morphology. PMID- 27498718 TI - Prediction of a new ground state of superhard compound B6O at ambient conditions. AB - Boron suboxide B6O, the hardest known oxide, has an Rm crystal structure (alpha B6O) that can be described as an oxygen-stuffed structure of alpha-boron, or, equivalently, as a cubic close packing of B12 icosahedra with two oxygen atoms occupying all octahedral voids in it. Here we show a new ground state of this compound at ambient conditions, Cmcm-B6O (beta-B6O), which in all quantum mechanical treatments that we tested comes out to be slightly but consistently more stable. Increasing pressure and temperature further stabilizes it with respect to the known alpha-B6O structure. beta-B6O also has a slightly higher hardness and may be synthesized using different experimental protocols. We suggest that beta-B6O is present in mixture with alpha-B6O, and its presence accounts for previously unexplained bands in the experimental Raman spectrum. PMID- 27498719 TI - Preliminary investigation of numerical estimation of coagulated region generated by interstitial microwave antenna. AB - Microwave coagulation therapy (MCT) is an effective treatment for hepatocellular carcinoma. During MCT, the target region is heated to induce coagulation in the tissue, including cancer cells. Several types of antennas for MCT have been developed, the heating performances of which were evaluated via specific absorption rate (SAR) and temperature distribution. However, for coagulation therapy, detailed evaluation of the coagulated region is important. Therefore, a newly developed algorithm is presented for calculating the coagulated region within biological tissue. To confirm the validity of the proposed method, the calculated result is compared with the experimental findings. PMID- 27498720 TI - Key toxicity issues with the WHO-recommended first-line antiretroviral therapy regimen. AB - INTRODUCTION: WHO recommends tenofovir, efavirenz, and lamivudine or emtricitabine for first-line antiretroviral therapy (ART) in adults, which replaced more toxic regimens using stavudine, zidovudine or nevirapine. Areas covered: We searched Pubmed to identify observational studies and randomized controlled trials reporting toxicity of these antiretrovirals published between 2011 and 2016, and hand-searched abstracts presented at major HIV conferences in 2015 and 2016, focusing on data from sub-Saharan Africa. Tenofovir's nephrotoxicity manifests as mild renal tubular dysfunction (common and of uncertain clinical significance), acute kidney injury (rare), and chronic declining glomerular filtration rate (common). African studies, which include high proportions of patients with renal dysfunction from opportunistic diseases, report population improvement in renal function after starting tenofovir-based ART. Tenofovir modestly decreases bone mineral density, and there is emerging data that this increases fracture risk. Efavirenz commonly causes early self limiting neuropsychiatric toxicity and hypersensitivity rashes. Recent studies have highlighted its long-term neuropsychiatric effects, notably suicidality and neurocognitive impairment, and metabolic toxicities (dyslipidemia, dysglycemia, and lipoatrophy). We point out the challenges clinicians face in the recognition and attribution of adverse drug reactions. Expert commentary: Tenofovir and efavirenz are generally well tolerated, but both are associated with potentially serious toxicities. Pharmacovigilance systems in resource-limited settings with high HIV burden should be strengthened. PMID- 27498721 TI - Facial eczema management protocols used on dairy farms in the North Island of New Zealand and associated concentrations of zinc in serum. AB - AIMS: To describe and evaluate the current practices used to manage and prevent facial eczema (FE) in North Island dairy herds, and determine the within-herd prevalence of cows with elevated activities of gamma glutamyl transferase (GGT), and with concentrations of Zn in serum <18 MUmol/L. METHODS: Between January and May 2014, 105 herd managers from throughout the North Island of New Zealand were invited to participate in the study when regional spore counts for Pithomyces chartarum started to rise towards 30,000 spores/g pasture. Managers selected 10 representative cattle that were weighed and blood-sampled by the herd veterinarian. Blood samples were analysed for concentrations of Zn in serum and GGT activity. Pasture samples were also collected and submitted for spore count estimation. Finally a survey of farm management practices relating to prevention of FE was completed by the herd manager. A mixed-effects logistic regression model was used to determine associations between herd-level and cow-level explanatory variables and the probability of a cow having a concentration of Zn in serum <18 umol/L. RESULTS: Of the 1,071 cows tested, 79 (7.3 (95% CI=5.8 9.0)%) had GGT activity in serum >300 IU/L, and 35/106 (33 (95% CI=24.2-42.8)%) herds had >=1 of the 10 cows sampled with GGT activity >300 IU/L. Of the 911 cows that were being treated with Zn, concentrations of Zn were between 18-35 MUmol/L in 398 (43.6 (95% CI=40.4-46.9)%) cows, were >35 MUmol/L in 32 (3.5 (95% CI=2.4 4.1)%) cows, and <18 MUmol/L in 479 (52.6 (95% CI=49.3-55.9)%) cows. After adjusting for the confounding effect of region, the odds of a cow having concentrations of Zn in serum <18 MUmol/L were 5.5 (95% CI=1.1-29) times greater for cows supplemented with zinc in water compared with those supplemented by drenching. Of the 105 herd managers, 103 (98%) stated that they had access to regional spore count data, but only 35/105 (33%) reported that they measured spore counts on their own farm. Overall, 98/105 (93%) managers reported that they had some form of FE management programme in place. Fungicides were used on their own or in combination with zinc treatments in 10 herds, ZnSO4 in water troughs was used in 68 herds, oral drenching with ZnO in nine herds, and ZnO supplied in feed in 26 herds. Estimated daily dose rates of zinc were less than that required to treat a 400 kg cow on 42/68 farms that administered ZnSO4 in the water or ZnO as a drench. CONCLUSION AND CLINICAL RELEVANCE: This study has shown that FE management on dairy farms in the North Island of New Zealand could be substantially improved. It is likely that improved FE management would occur if herd managers were provided with more feedback on the success (or otherwise) of their FE management programmes. PMID- 27498723 TI - Cyclotetrahalo-p-phenylenes: simulations of halogen substituted cycloparaphenylenes and their interaction with C60. AB - Density functional calculations are used to study the role of edge functionalization on the structure and electronic properties of cycloparaphenylene (CPPs) containing from six to twenty benzenoid rings. We substitute hydrogen by the halogens fluorine, chlorine and bromine. The resultant Cyclotetrahalo-p-phenylenes are compared with their hydrogenated equivalents, related linear paraphenyl and fluoro-paraphenyl polymers, and functionalised armchair edges in graphene nanoribbons. Notably we consider both structural and electronic evolution. Finally we examine C60@[10]CPP, i.e. C60 encapsulated within [10]CPP, with the various ring terminations. The effect of halogenation on electronic level position around the gap strongly affects their capacity to form donor-acceptor pairs with fullerenes. PMID- 27498722 TI - Physicochemical sequence characteristics that influence S-palmitoylation propensity. AB - Over the past 30 years, several hundred eukaryotic proteins spanning from yeast to man have been shown to be S-palmitoylated. This post-translational modification involves the reversible addition of a 16-carbon saturated fatty acyl chain onto the cysteine residue of a protein where it regulates protein membrane association and distribution, conformation, and stability. However, the large scale proteome-wide discovery of new palmitoylated proteins has been hindered by the difficulty of identifying a palmitoylation consensus sequence. Using a bioinformatics approach, we show that the enrichment of hydrophobic and basic residues, the cellular context of the protein, and the structural features of the residues surrounding the palmitoylated cysteine all influence the likelihood of palmitoylation. We developed a new palmitoylation predictor that incorporates these identified features, and this predictor achieves a Matthews Correlation Coefficient of .74 using 10-fold cross validation, and significantly outperforms existing predictors on unbiased testing sets. This demonstrates that palmitoylation sites can be predicted with accuracy by taking into account not only physiochemical properties of the modified cysteine and its surrounding residues, but also structural parameters and the subcellular localization of the modified cysteine. This will allow for improved predictions of palmitoylated residues in uncharacterized proteins. A web-based version of this predictor is currently under development. PMID- 27498725 TI - [Not Available]. PMID- 27498724 TI - Tour de France Champions born or made: where do we take the genetics of performance? AB - Cyclists in the Tour de France are endurance specialists. Twin and family studies have shown that approximately 50% of the variance in a number of performance related phenotypes (whether measured at baseline, i.e., natural talent, or in response to training) including those important to cycling can be explained by genetic variation. Research into the specific genetic variants that are responsible has identified over 200 genes containing common genetic variants involved in the genetic predisposition to physical performance. However, typically these explain only a small portion of the variance, perhaps 1-2% and collectively they rarely explain anything approaching the 50% of the variance identified in the twin and family studies. Thus, there is a gap in our understanding of the relationship between heritability and performance. This gap may be bridged by investigation of rare variants or epigenetic variation or by altering study designs through increased collaborations to pool existing cohorts together. Initial findings from such efforts show promising results. This mini review will touch on the genetics and epigenetics of sporting performance, how they relate to cyclists in the Tour de France and where best future efforts may be directed as well as discuss some preliminary research findings. PMID- 27498726 TI - Second primary malignancies among patients with myeloma-related-diseases in the KMF database. AB - The incidence of second primary malignancies (SPMs) in Japanese patients with myeloma or myeloma-related diseases was studied by using the Kansai Myeloma Forum (KMF) database registered from November 2012 to March 2015. We studied 1,571 cases. Hematologic malignancies were documented in 10 patients, and solid tumors in 36 during this period. The cumulative 5-year incidence was estimated to be 1.0% for hematological malignancies and 3.7% for solid tumors. In the patients with smoldering myeloma or MGUS without treatment, solid tumors but not hematologic malignancies developed, though the cumulative incidence of each malignancy did not differ significantly from that in patients receiving treatment. Although statistical analysis showed that treatment with melphalan, bortezomib, lenalidomide, or thalidomide had no effect on the occurrence of hematological malignancies, lenalidomide administration was more frequent in the patients with solid tumors. To evaluate the SPMs in myeloma or myeloma-related diseases more accurately, accumulation of a larger number of patients and longer observation are needed. PMID- 27498727 TI - The relation between clinical features of adult T-cell leukemia/lymphoma and the serum levels of soluble CD25 and CD30. AB - Adult T-cell leukemia (ATL) is an aggressive neoplasm of mature T cells. We aimed to ascertain the relationships between soluble CD25 (sIL-2R) and CD30 (sCD30) levels and nodal or extra-nodal involvement of ATL. Our study subjects were ATL patients whose sIL-2R and sCD30 levels were measured before initial therapy (n=32). Their sCD30 levels correlated significantly with the number of ATL cells in peripheral blood (PB) (rho=0.456; P=0.009), while sIL-2R levels correlated significantly with the number of nodal lesions (rho=0.660; P=0.001). We then also assessed the relationships of pulmonary lesions with the number of ATL cells in PB, lactate dehydrogenase levels, sIL-2R levels, and sCD30 levels in 24 patients whose pleural effusions and hilar lymphadenopathy were investigated before initial therapy. The results suggested that a high number of ATL cells in PB may be associated with pulmonary lesions. It is known that metalloproteinases shed and cleave cytokine receptors such as CD25 and CD30 from the cell surface as well as E-cadherin and extracellular matrix. It seems that serum levels of sIL-2R and sCD30 indicate the activation of metalloproteinases associated with ATL involvement in vivo. PMID- 27498728 TI - Rapid improvement of hyperammonemic encephalopathy by bortezomib treatment in IgD type multiple myeloma. AB - A 74-year-old man visited our hospital with complaints of anorexia, weight loss, and impaired activities of daily living. He presented mild consciousness disturbance at the first visit, but specific causes were identified. The IgD level was>2,000 mg/dl and bone marrow biopsy was performed after aspiration failed due to excessive density. He was diagnosed with IgD/lambda multiple myeloma (MM). He lapsed into a coma with an extremely high ammonia level of 484 MUg/dl on day 8 after admission. His diagnosis was established as hyperammonemic encephalopathy (HE). He was treated with dexamethasone (Dex) pulse therapy and continuous hemodiafiltration. Minor improvement of hyperammonemia was achieved. Combination therapy with bortezomib and Dex was commenced. His ammonia level rapidly decreased and his mental state improved. HE accompanied by MM is rare and further studies are needed to clarify outcomes in response to treatment using the novel agent Bor. Although HE is potentially fatal, we found Bor to be rapidly effective against HE. PMID- 27498729 TI - Successful allogeneic bone marrow transplantation with reduced intensity conditioning regimen for a pediatric relapsed ALK positive anaplastic large cell lymphoma. AB - Pediatric anaplastic large cell lymphoma (ALCL) is a chemosensitive malignancy, but about 30% of patients experience relapse. In most of these patients, a second complete remission is obtainable with salvage chemotherapy, though relapse free survival rates are as low as 30-60%. Herein, we report a 6-year-old boy with relapsed anaplastic lymphoma kinase (ALK) positive ALCL successfully treated with vinblastine monotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT), with a reduced intensity conditioning (RIC) regimen, from his father. One HLA locus from the father was mismatched. The boy had neither severe graft-versus-host disease nor transplantation related complications. He is currently well and has remained disease free for 10 months, to date, since transplantation. Allo-HSCT with a RIC regimen may be a promising treatment strategy for relapsed ALK positive ALCL based on obtaining graft-versus lymphoma effects as well as reducing transplantation-related mortality. PMID- 27498730 TI - Domestic dengue infection with hemophagocytic lymphohistiocytosis successfully treated by early steroid therapy. AB - A 34-year-old man, working at a park in Tokyo, Japan, was repeatedly bitten by mosquitoes while cutting grass. He was hospitalized with sudden fever, fatigue, and weakness. He was eventually diagnosed with dengue virus infection, detected using reverse transcription polymerase chain reaction for the genome and by the presence of nonstructural protein 1 in his peripheral blood. Symptomatic treatments such as acetaminophen for the fever were not effective. Moreover, peripheral blood examination showed drastically decreased white blood cells and platelets, as well as marked elevations of ferritin and soluble interleukin 2 receptor. Furthermore, bone marrow examination revealed increased macrophages with hemophagocytosis. Dengue infection with hemophagocytic lymphohistiocytosis (HLH) was ultimately diagnosed. Half-dose steroid pulse therapy for three days dramatically reduced his temperature, thereby ameliorating physical symptoms and restoring normal peripheral blood data. He was discharged 12 days after admission. Dengue infection with HLH is rare and this is the first report, to our knowledge, of domestic dengue infection with HLH in Japan. Early steroid therapy may be effective in such cases. PMID- 27498731 TI - Successful rituximab treatment in an elderly patient with recurrent thrombotic thrombocytopenic purpura. AB - An 81-year-old man presenting with fever, neurological symptoms, thrombocytopenia, and hemolytic anemia was diagnosed with acquired idiopathic thrombotic thrombocytopenic purpura (TTP). His disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) activity was <1% and the ADAMTS13 inhibitor titer was 3.2 BU/ml. He received plasma exchange and steroid administration until remission was achieved. Seven months later, he suffered from paralysis of the right hand, hemolytic anemia, and thrombocytopenia. We confirmed TTP recurrence based on ADAMTS13 activity <1% and an ADAMTS13 inhibitor titer of 19.4 BU/ml. Four infusions of rituximab were administered in addition to plasma exchange and steroid pulse therapy. Platelet count recovery was observed within 5 days. No severe side effects related to rituximab occurred. Although rituximab has not been approved for TTP in Japan, we report the efficacy and safety of rituximab in an elderly patient with recurrent TTP. We suggest that rituximab therapy should be started as soon as possible for recurrent TTP in patients with high titers of ADAMTS13 inhibitor. PMID- 27498732 TI - Musculoskeletal pain after stopping tyrosine kinase inhibitor in patients with chronic myeloid leukemia: a questionnaire survey. AB - We conducted a questionnaire survey to assess the state of patients with CML after discontinuation of TKI therapy. Nine of 27 patients developed musculoskeletal pain after TKI discontinuation. One had discontinued nilotinib and eight had discontinued imatinib therapy. Median time to symptom development after discontinuation was 2 weeks. Four experienced grade 3 symptoms as per the CTCAE ver. 4.0. One had pain persisting over a period of 21 months. There was a significant difference between patients with and without symptoms as regards female gender and the probability of persistent MMR. Awareness of this withdrawal syndrome after TKI discontinuation is imperative. PMID- 27498733 TI - Primary immune thrombocytopenia accompanied by pituitary apoplexy. AB - An 83-year-old woman was admitted to our hospital with a severe headache and purpura. She had previously been diagnosed with idiopathic thrombocytopenia purpura (ITP) and achieved complete remission with steroid therapy. Steroid therapy had been completed one week prior to the current admission. The recurrence of severe thrombocytopenia (<1.0*10(4) platelets/MUl) was detected and a CT scan revealed pituitary hemorrhage without pituitary adenoma. She received steroid therapy combined with intravenous immunoglobulin, which resulted in the amelioration of ITP and improvements in the pituitary hemorrhage. Intracranial hemorrhage, which is the most serious bleeding manifestation in ITP, is relatively uncommon. Pituitary apoplexy in ITP is extremely rare. PMID- 27498734 TI - Overview. PMID- 27498735 TI - Recent advances in inherited bone marrow failure syndrome research. AB - Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by bone marrow failure, congenital anomalies, and an increased risk of malignancies. Diagnosis is often difficult due to the wide variety of clinical expressions. The representative diseases are Diamond Blackfan anemia (DBA), Fanconi anemia (FA), congenital sideroblastic anemia (CSA), congenital dyserhthropoietic anemia, Shwachman Diamond syndrome, and dyskeratosis congenita. Next-generation sequencing technologies have facilitated the discovery of germline mutations that cause IBMFS. Recently, Japanese groups have identified novel causative genes for DBA, FA and congenital thrombocytopenia by applying whole exome-sequencing. In this review, we will highlight recent studies on DBA, FA and CSA in Japan, which have employed next-generation sequencing technologies to elucidate the genetic etiology of IBMFS. PMID- 27498736 TI - Inherited genetic variants associated with childhood acute lymphoblastic leukemia risk. AB - Numerous efforts have been made to elucidate the roles of individual genetic background factors in the risk of childhood acute lymphoblastic leukemia. Most have taken the form of case-control studies focusing on specific candidate gene polymorphisms. Recently, a more rigorous and comprehensive approach referred to as a genome-wide association study (GWAS) has been widely utilized and has achieved success. Case-control studies evaluating candidate gene associations have shown cumulative evidence of a role for folate metabolism and xenobiotic metabolism/transport pathway genetic variants. In addition, single nucleotide polymorphism (SNP)s identified by GWAS appear to indicate a strong role for genes encoding transcription factors involved in cellular differentiation. Further studies are needed to clarify the accumulating evidence obtained from both candidate gene and genome-wide investigations. PMID- 27498737 TI - Familial acute lymphoblastic leukemia. AB - Somatically acquired genomic alterations have been recognized as key hallmarks inducing acute lymphoblastic leukemia (ALL), though recent knowledge acquired from genome-wide association study (GWAS) has revealed that inherited genetic variations (germline) are associated with ALL susceptibility as well as disease onset. The proportion of ALL cases attributable to an inherited genetic predisposition has been recognized as being much higher in clinical practice than previously thought since familial cases with hematopoietic transcriptional factors (PAX5 and ETV6) were reported. Considering the characteristics related to inherited variants, issues associated with these variants persist from childhood throughout the patient's entire life, and specific approaches to both familial ALL cases and carriers with inherited variants are thus urgently needed. This review focuses on familial ALL caused by the two aforementioned transcriptional factors (PAX5 and ETV6). PMID- 27498738 TI - Pharmacogenomics for leukemia treatment. AB - The pharmacokinetics and pharmacodynamics of therapeutic drugs can greatly vary among individuals. For example, it is sometimes necessary to alter the treatment of childhood acute lymphoblastic leukemia from the standard protocol. Genetic variation is one important factor, which can exert a wide range of effects on sensitivities and responses to therapeutic agents. Thiopurine S-methyl transferase (TPMT) is a useful test for predicting 6-mercaptopurine (6-MP) sensitivity in Caucasians. However, it is not effective for predicting the 6-MP therapeutic responses of Japanese patients because the frequency of TPMT deficiency is lower in the Japanese population (approximately 1% versus approximately 10% in Caucasians). Recently, NUDT15 polymorphisms have been reported to be predictive factors contributing to responsiveness to thiopurine therapy in Asians. The associations between genetic variants and therapeutic responses have been reported in Western countries. However, questions remain about whether results studying other races are applicable to Japanese due to differences in genetic variant frequencies among races. To provide personalized therapy based on genetic factors, we need to ascertain the relationships between genetic variants and therapeutic responses in Japanese childhood acute lymphoblastic leukemia cases. PMID- 27498739 TI - Genetic abnormalities associated with the relapse of childhood leukemia. AB - Acute leukemia, especially acute lymphoblastic leukemia, is the most common tumor in childhood. Survival in pediatric acute leukemia cases has improved significantly, but once a relapse occurs, the long-term survival rates decrease markedly. Recently, SNP array and next-generation sequencing have revealed the relapse mechanism of pediatric leukemia and genetic alterations which drive leukemia recurrence. PMID- 27498740 TI - A comparative perspective on erythropoiesis. AB - The acquisition of fundamental information by the use of recent technologies, including omics-based molecular analyses and total RNA sequencing, has opened the door to further advances in physiological studies on new animal models. Currently, we are endeavoring to develop a comparative hematology protocol in order to build a discovery platform. All vertebrates, with the exception of a few species, have universally peripheral erythrocytes and hemoglobin, suggesting erythropoiesis to be an evolutionary index. PMID- 27498741 TI - Phylogenic insights into the enucleation of erythroblasts in human. AB - Two key questions remain unanswered in the erythropoiesis field: Why and how do erythroblasts enucleate in mammalian species? Recent studies have unveiled the roles of various molecules, cytoskeletal proteins, motor proteins, vesicle transport, signaling pathways, lipid rafts and actomyosin ring contraction in the enucleation process. However, few reports provide insights into the fitness benefit for mammalian species of having anucleate erythrocytes. Herein, we discuss the biological significance of enucleation of human erythroblasts based on our recent results and on evolutionary considerations related to the biology of hemoglobin and the comparative biochemistry of erythrocyte membrane cytoskeletal proteins, such as protein 4.1R. We specifically focus on the Mesozoic era, a geological period during which dinosaurs and the ancestors of mammalian species coexisted. Approximately 200 million years ago, at the beginning of this era, the earth's atmosphere was hypoxic. Interestingly, animals adopted different respiration systems to adapt to this hypoxic environment. Recent studies using state-of-the-art technologies have shown that dinosaurs might have had nucleated erythrocytes. After dinosaurs became extinct about 65.5 million years ago, their respiration system was maintained by birds. We propose a new adaptive theory that establishes a correlation between evolution towards nucleated or anucleate erythrocytes depending on organism respiration systems during the Mesozoic era. PMID- 27498742 TI - Embryonic regulation of the mouse erythropoietic niche and its clinical application. AB - Erythropoiesis has classically been described as occurring in two waves: first primitive and then definitive erythropoiesis. In the mouse embryo, definitive erythropoiesis begins in the yolk sac and then shifts to the liver, spleen, and bone marrow. The fetal liver serves as the primary organ for erythroid cell expansion and maturation at mid-gestation and its mechanisms have been well investigated with special attention to niche cells expressing cytokines such as SCF, TPO and IGF2. Previously, our group reported that DLK1(+) hepatoblasts support fetal liver hematopoiesis, particularly erythropoiesis, through EPO, SCF and matrix secretion. Loss of DLK1(+) hepatoblasts in Map2k4(-/-) mouse embryos resulted in decreased numbers of hematopoietic cells in the fetal liver. When sorted DLK1(+) hepatoblasts were further analyzed by microarray, several genes encoding proteinases and peptidases were highly expressed in DLK1(+) hepatoblasts. Based on the hypothesis that high molecular weight proteins are digested into small peptides that may regulate hematopoiesis, we screened out peptides, and identified KS-13 (PCT/JP2010/067011). Both KS-13 and modified KS 13, known as SL-13R, proliferate and increase the number of hematopoietic stem/progenitors from human cord blood cells in vitro. We hereby present our findings on the extrinsic regulation of embryonic erythropoiesis with special attention to niche cells, identification of niche-derived peptides, and implications for future hematotherapy. PMID- 27498743 TI - Roles of transferrin receptors in erythropoiesis. AB - Erythropoiesis requires large amounts of iron for hemoglobin synthesis, which is mainly provided by macrophages and the intestines in a transferrin (Tf)-bound form. Bone marrow erythroblasts incorporate Tf through endocytosis, which is mediated by transferrin receptor 1 (TFR1). Recently, human TFR1, aside from its role as a Tf receptor, was also found to be a receptor for the H-subunit of ferritin (FTH). In humans, hematopoietic erythroid precursor cells express high levels of TFR1 and specifically take up the FTH homopolymer (H-ferritin). H ferritin inhibits the formation of burst forming unit-erythroid colonies in vitro. TFR2, which is also a Tf receptor, is predominantly expressed in hepatocytes and erythroid precursor cells. In the liver, TFR2 forms a complex with HFE, a hereditary hemochromatosis-associated protein, and acts as an iron sensor. In mice, hepatocyte-specific knockout of the TFR2 gene has been shown to cause systemic iron-overload with decreased expression of hepcidin, the central regulator of iron homeostasis. In erythroid cells, TFR2 forms a complex with the erythropoietin receptor and facilitates its trafficking to the cell membrane. Moreover, hematopoietic cell-specific knockout of the TFR2 gene causes microcytic erythrocytosis in mice. This review focuses on the molecular evolution and functions of these TFRs and their ligands. PMID- 27498744 TI - [Not Available]. PMID- 27498746 TI - Potential Universal Application of High-intensity Interval Training from Athletes and Sports Lovers to Patients. AB - Recently, high-intensity interval training (HIIT) has received much attention as a promising exercise option not only to improve aerobic fitness, but also to prevent and improve lifestyle-related diseases. Epidemiological studies have shown that the exercise volume, as determined by the product of exercise intensity, duration, and frequency, has been shown to be important for improvements in muscle mitochondrial activity and subsequent improvements in aerobic fitness, insulin sensitivity, and metabolic variables. Therefore, continuous moderate-intensity training has been widely recommended. On the other hand, the main contributor of HIIT to improvements in aerobic fitness and metabolic variables is its high-intensity nature, and many recent studies have shown results favoring HIIT when compared with conventional continuous training, despite its shorter exercise duration and smaller exercise volume. In this review, we aim to show the possible universal application of HIIT in a hospital setting, where athletes, sports lovers, and patients have sought medical advice and have the opportunity to undergo detailed evaluations, including an exercise stress test. For athletes, HIIT is mandatory to achieve further improvements in aerobic fitness. For patients, though higher levels of motivation and careful evaluation are required, the time constraints of HIIT are smaller and both aerobic and resistance training can be expected to yield favorable results because of the high-intensity nature of HIIT. PMID- 27498747 TI - Dose response of dexmedetomidine-induced resistance to hypoxia in mice. AB - Tolerance to hypoxia can be induced by reducing oxygen consumption. Dexmedetomidine (DEX) decreases locomotor activity and induces bradycardia and hypothermia in mice. The present study examined the hypothesis that DEX improves hypoxia tolerance in mice. Adult mice received an intraperitoneal injection of 1, 5, 10, 20, 40, 80, 160 or 320 ug/kg DEX, 20 mg/kg propranolol or saline. Acute hypoxic conditions were induced by placing the mice in a limited enclosed container with soda lime. Core body temperature (CBT) and heart rate (HR) were measured prior to and 30 min after drug administration. Survival time was monitored in the sealed container. Survival times (mean +/- standard deviation) of mice in the saline, 1, 5, 10, 20, 40, 80, 160 and 320 ug/kg DEX, and the 20 mg/kg propranolol groups were 22.4+/-1.1, 23.4+/-1.1, 26.0+/-0.9, 36.9+/-5.2, 42.4+/-2.9, 43.2+/-2.3, 58.2+/-4.2, 80.5+/-4.0, 79.2+/-6.0, and 38.2+/-2.8 min, respectively. Pretreatment with propranolol and 10, 20, 40, 80, 160 or 320 ug/kg DEX, but not 1 or 5 ug/kg, significantly prolonged survival time compared with saline-injected mice (P<0.05 or P<0.01). CBT and HR decreased in a similar manner. The correlation coefficients between survival time and CBT, and survival time and HR were -0.802 and -0.726, respectively. Thus, DEX dose-dependently enhances hypoxia tolerance in mice. In conclusion, it is suggested that DEX may be used in clinical practice as a novel protective agent for organs and tissues during hypoxic injury. PMID- 27498748 TI - The diagnostic value of three sacroiliac joint pain provocation tests for sacroiliitis identified by magnetic resonance imaging. AB - OBJECTIVES: The aim of the current study was to investigate the diagnostic value of three sacroiliac (SI) joint pain provocation tests for sacroiliitis identified by magnetic resonance imaging (MRI) and stratified by gender. METHOD: Patients without clinical signs of nerve root compression were selected from a cohort of patients with persistent low back pain referred to an outpatient spine clinic. Data from Gaenslen's test, the thigh thrust test, and the long dorsal sacroilia ligament test and sacroiliitis identified by MRI were analysed. RESULTS: The median age of the 454 included patients was 33 (range 18-40) years and 241 (53%) were women. The prevalence of SI joints with sacroiliitis was 5%. In the whole study group, only the thigh trust test was associated with sacroiliitis, the area under the receiver operating characteristic (ROC) curve (AUC) was 0.58 [95% confidence interval (CI) 0.51-0.65], sensitivity 31% (95% CI 18-47), and specificity 85% (95% CI 82-87). In men, sacroiliitis was associated with all the SI joint tests assessed and multi-test regimens, with the greatest AUC found for at least one positive out of three tests [AUC 0.68 (95% CI 0.56-0.80), sensitivity 56% (95% CI 31-79), and specificity 81% (95% CI 77-85)]. In women, no significant associations were observed between the SI joint tests and sacroiliitis. CONCLUSIONS: Only in men were the SI joint tests found to be associated with sacroiliitis identified by MRI. Although, the diagnostic value was relatively low, the results indicate that the use of SI joint tests for sacroiliitis may be optimized by gender-separate analyses. PMID- 27498749 TI - Tricin, 4',5,7-trihydroxy-3',5'-dimethoxyflavone, exhibits potent antiangiogenic activity in vitro. AB - Tumor growth and metastasis depend on angiogenesis triggered by chemical signals, such as vascular endothelial growth factor (VEGF), released from tumor cells. Therefore, the specific perturbation of angiogenesis has been considered a powerful strategy for the treatment of cancer. Herein, we report that tricin, 4',5,7-trihydroxy-3',5'-dimethoxyflavone, exhibits potent antiangiogenic activity in vitro. Tricin effectively suppressed the proliferation as well as VEGF-induced invasion and tube formation of human umbilical vein endothelial cells (HUVECs) at subtoxic doses. Furthermore, tricin significantly inhibited the angiogenesis of the chorioallantoic membrane from growing chick embryos without showing cytotoxicity. We also found that tricin blocked tumor cell-induced angiogenesis. Notably, tricin downregulated not only the VEGFR2 signal transduction by reducing reactive oxygen species (ROS) generation in endothelial cells, but also the expression of VEGF by inhibiting hypoxia inducible factor-1alpha (HIF-1alpha) accumulation in tumor cells. Moreover, combined treatment with tricin and bevacizumab, an anti-VEGF drug, ameliorated the antiangiogenic effect of bevacizumab. Taken together, our findings demonstrate for the first time that tricin possesses promising antiangiogenic potential and thus may be applied to anticancer therapy by targeting tumor angiogenesis. PMID- 27498750 TI - Gas phase ultraviolet and infrared spectroscopy on a partial peptide of beta2 adrenoceptor SIVSF-NH2 by a laser desorption supersonic jet technique. AB - Laser desorption supersonic jet laser spectroscopy has been applied to a penta peptide, Ser-Ile-Val-Ser-Phe-NH2 (SIVSF-NH2), which is a partial sequence of a binding site in a beta2-adrenaline receptor protein. By comparing the resonance enhanced multiphoton ionization spectrum with the ultraviolet-ultraviolet hole burning (HB) spectrum, it is concluded that only a single conformer exists. The infrared (IR) spectrum of the X-H stretching region, measured by IR dip spectroscopy, shows that all of the OH and NH groups form hydrogen bonds. The structure of SIVSF-NH2 is assigned by the combination of a force field calculation (CONFLEX) and quantum chemical calculations both in S0 and S1. Over 20 000 stable conformations, given by CONFLEX, are classified into 6987 groups and 1068 groups in which all of the NH and OH bonds are hydrogen-bonded are selected. The most stable structure in each group was geometrically optimized by density functional theory (DFT) calculations, and theoretical IR spectra were calculated for the conformers for which the energies are within 10 kJ mol(-1) of the most stable one. It has been found that the most stable and the secondmost stable conformers well-reproduce the observed IR spectrum. The vibrational frequencies in S1 were also calculated for these two conformers. According to the reproduction of the vibrational frequencies in the HB spectrum, the structure of SIVSF-NH2 is assigned to the most stable conformer, which forms a hydrogen-bonded structure corresponding to a compact, distorted version of the beta hairpin of peptides and proteins. PMID- 27498751 TI - Erratum: MicroRNAs in Breast Cancer: One More Turn in Regulation. AB - In the article entitled, "MicroRNAs in Breast Cancer: One More Turn in Regulation" published in Current Drug Targets 2016 Volume 17, No. 9, pg no. 1083, the authors' names need to be replaced with the following as provided by the corresponding author. MicroRNAs in Breast Cancer: One More Turn in Regulation. Pilar Eroles, Eduardo Tormo, Begona Pineda, Estefania Espin and Ana Lluch. PMID- 27498752 TI - Effect of sudden addition of PCE and bioreactor coupling to ZVI filters on performance of fluidized bed bioreactors operated in simultaneous electron acceptor modes. AB - The present work evaluated the effects of (i) feeding a water contaminated with 80 mg/L PCE to bioreactors seeded with inoculum not acclimated to PCE, (ii) coupling ZVI side filters to bioreactors, and (iii) working in different biological regimes, i.e., simultaneous methanogenic aeration and simultaneous methanogenic-denitrifying regimes, on fluidized bed bioreactor performance. Simultaneous electron acceptors refer to the simultaneous presence of two compounds operating as final electron acceptors in the biological respiratory chain (e.g., use of either O2 or NO3- in combination with a methanogenic environment) in a bioreactor or environmental niche. Four lab-scale, mesophilic, fluidized bed bioreactors (bioreactors) were implemented. Two bioreactors were operated as simultaneous methanogenic-denitrifying (MD) units, whereas the other two were operated in partially aerated methanogenic (PAM) mode. In the first period, all bioreactors received a wastewater with 1 g chemical oxygen demand of methanol per liter (COD-methanol/L). In a second period, all the bioreactors received the wastewater plus 80 mg perchloroethylene (PCE)/L; at the start of period 2, one MD and one PAM were coupled to side sand-zero valent iron filters (ZVI). All bioreactors were inoculated with a microbial consortium not acclimated to PCE. In this work, the performance of the full period 1 and the first 60 days of period 2 is reported and discussed. The COD removal efficiency and the nitrate removal efficiency of the bioreactors essentially did not change between period 1 and period 2, i.e., upon PCE addition. On the contrary, specific methanogenic activity in PAM bioreactors (both with and without coupled ZVI filter) significantly decreased. This was consistent with a sharp fall of methane productivity in those bioreactors in period 2. During period 2, PCE removals in the range 86 to 97 % were generally observed; the highest removal corresponded to PAM bioreactors along with the highest dehalogenation efficiency (94 %). Principal component analysis as well as cluster analysis confirmed the trends mentioned above, i.e., the better performance of PAM over MD, and the unexpected no effect of the ZVI side filters on PCE removal and dehalogenation efficiencies. To the best of our knowledge, this is the first report on the combined treatment ZVI-biological of a water polluted with PCE, where the biological operation relied on simultaneous electron acceptors. PMID- 27498753 TI - Tailoring the properties of acetate-based ionic liquids using the tricyanomethanide anion. AB - The equilibrium and transport properties of mixtures of two ionic liquids - [C4C1Im][OAc] and [C4C1Im][C(CN)3] - were determined and interpreted at the molecular level using vibration spectroscopy, NMR and molecular dynamics simulation. The non-ideality of the mixtures [C4C1Im][OAc](1-x)[C(CN)3]x was characterized by V(E) = +0.28 cm(3) mol(-1) (293 K, x = 0.65) and H(E) = -2.2 kJ mol(-1) for x = 0.5. These values could be explained by a rearrangement of the hydrogen-bond network of the mixture that favours the interaction of the acetate anion with the imidazolium cation at position C2. The dynamic properties of the mixture are also dramatically influenced by the composition with a decrease of the viscosity and an increase of self-diffusion coefficients of the ions when the amount of tricyanomethanide anion increases in the mixture. PMID- 27498754 TI - Ringiculid bubble snails recovered as the sister group to sea slugs (Nudipleura). AB - Euthyneuran gastropods represent one of the most diverse lineages in Mollusca (with over 30,000 species), play significant ecological roles in aquatic and terrestrial environments and affect many aspects of human life. However, our understanding of their evolutionary relationships remains incomplete due to missing data for key phylogenetic lineages. The present study integrates such a neglected, ancient snail family Ringiculidae into a molecular systematics of Euthyneura for the first time, and is supplemented by the first microanatomical data. Surprisingly, both molecular and morphological features present compelling evidence for the common ancestry of ringiculid snails with the highly dissimilar Nudipleura-the most species-rich and well-known taxon of sea slugs (nudibranchs and pleurobranchoids). A new taxon name Ringipleura is proposed here for these long-lost sisters, as one of three major euthyneuran clades with late Palaeozoic origins, along with Acteonacea (Acteonoidea + Rissoelloidea) and Tectipleura (Euopisthobranchia + Panpulmonata). The early Euthyneura are suggested to be at least temporary burrowers with a characteristic 'bubble' shell, hypertrophied foot and headshield as exemplified by many extant subtaxa with an infaunal mode of life, while the expansion of the mantle might have triggered the explosive Mesozoic radiation of the clade into diverse ecological niches. PMID- 27498756 TI - Anion Redox Chemistry in the Cobalt Free 3d Transition Metal Oxide Intercalation Electrode Li[Li0.2Ni0.2Mn0.6]O2. AB - Conventional intercalation cathodes for lithium batteries store charge in redox reactions associated with the transition metal cations, e.g., Mn(3+/4+) in LiMn2O4, and this limits the energy storage of Li-ion batteries. Compounds such as Li[Li0.2Ni0.2Mn0.6]O2 exhibit a capacity to store charge in excess of the transition metal redox reactions. The additional capacity occurs at and above 4.5 V versus Li(+)/Li. The capacity at 4.5 V is dominated by oxidation of the O(2-) anions accounting for ~0.43 e(-)/formula unit, with an additional 0.06 e( )/formula unit being associated with O loss from the lattice. In contrast, the capacity above 4.5 V is mainly O loss, ~0.08 e(-)/formula. The O redox reaction involves the formation of localized hole states on O during charge, which are located on O coordinated by (Mn(4+)/Li(+)). The results have been obtained by combining operando electrochemical mass spec on (18)O labeled Li[Li0.2Ni0.2Mn0.6]O2 with XANES, soft X-ray spectroscopy, resonant inelastic X ray spectroscopy, and Raman spectroscopy. Finally the general features of O redox are described with discussion about the role of comparatively ionic (less covalent) 3d metal-oxygen interaction on anion redox in lithium rich cathode materials. PMID- 27498755 TI - Hydrogen prevents corneal endothelial damage in phacoemulsification cataract surgery. AB - In phacoemulsification, ultrasound induces hydroxyl radical (.OH) formation, damaging corneal endothelium. Whether H2 can prevent such oxidative damage in phacoemulsification was examined by in vitro and in vivo studies. H2 was dissolved in a commercial irrigating solution. The effects of H2 against .OH generation were first confirmed in vitro by electron-spin resonance (ESR) and hydroxyphenyl fluorescein (HPF). ESR showed a significantly decreased signal magnitude, and fluorescence intensity by oxidized HPF was significantly less in the H2-dissolved solution. The effects of H2 in phacoemulsification were evaluated in rabbits, comparing H2-dissolved and control solutions. Five hours after the procedure, the whole cornea was excised and subjected to image analysis for corneal edema, real-time semiquantitative PCR (qPCR) for heme oxygenase (HO) 1, catalase (CAT), superoxide dismutase 1 (SOD1), and SOD2 mRNA, and immunohistochemistry. Corneal edema was significantly less and the increases in anti-oxidative HO-1, CAT and SOD2 mRNA expressions were significantly suppressed in the H2 group. In addition, corneal endothelial cell expressions of two oxidative stress markers, 4-HNE and 8-OHdG, were significantly lower in the H2 group. In conclusion, H2 dissolved in the ocular irrigating solution protected corneal endothelial cells from phacoemulsification-induced oxidative stress and damage. PMID- 27498757 TI - Post-bronchiolitis wheezing is associated with toll-like receptor 9 rs187084 gene polymorphism. AB - Innate immunity receptors play a critical role in host defence, as well as in allergy and asthma. The aim of this exploratory study was to evaluate whether there are associations between TLR7 rs179008, TLR8 rs2407992, TLR9 rs187084 or TLR10 rs4129009 polymorphisms and viral findings, clinical characteristics or subsequent wheezing in infants with bronchiolitis. In all, 135 full-term infants were hospitalized for bronchiolitis at age less than 6 months: 129 of them were followed-up until the age of 1.5 years. The outcome measures were repeated wheezing, use of inhaled corticosteroids, atopic dermatitis during the first 1.5 years of life and total serum immunoglobulin E (IgE). There were no significant associations between the genotypes or allele frequencies of TLR7 rs179008, TLR8 rs2407992, TLR9 rs187084 or TLR10 rs4129009 polymorphisms and clinical characteristics or the severity of bronchiolitis during hospitalization. During follow-up, repeated wheezing was more common in children with TLR9 rs187084 variant genotype CC (30.5%) than in children with TLR9 wild-type genotype TT (12.2%) (p = 0.02, aOR 2.73, 95% CI 1.02-7.29). The TLR10 rs4129009 minor allele G was associated with elevated total serum IgE. TLR9 rs187084 gene polymorphism may be associated with post-bronchiolitis wheezing, and TLR10 rs4129009 gene polymorphism may be associated with atopy. PMID- 27498758 TI - Development, Implementation, and Evaluation of an Interdisciplinary Women's Health and Laboratory Course. AB - OBJECTIVES: To describe the creation, implementation, and evaluation of a case based, interdisciplinary course that highlights laboratory principles for students who have selected a career in obstetrics and gynecology. METHODS: We developed four case-based modules with questions that emphasize laboratory principles required to establish a diagnosis and treat and monitor each case based scenario. The cases were offered as a 4-hour elective course during the medical school capstone. A clinician and a clinical pathologist pair facilitated the case discussions with groups of six to nine medical students during 2 consecutive years. Pre- and postknowledge quizzes were given to the students. In addition, a structured evaluation of the course was performed. RESULTS: Twenty two students participated in the courses. Most found the format effective and the information useful. There was a significant increase in their related knowledge as established by pre- and posttesting. CONCLUSIONS: Case-based discussions gave learners a better understanding of the function and complexity of the clinical laboratories, and multidisciplinary facilitation highlighted the value of interacting with laboratory professionals to enhance clinical care. PMID- 27498759 TI - Distribution of Silver Nanoparticles to Breast Milk and Their Biological Effects on Breast-Fed Offspring Mice. AB - Recent rodent studies have shown that nanoparticles are distributed to breast milk, and more-detailed safety information regarding nanoparticle consumption by lactating mothers is required. Here, we used mice to investigate the safety of nanoparticle use during lactation. When Ag and Au nanoparticles were intravenously administered to lactating mice, the nanoparticles were distributed to breast milk without producing apparent damage to the mammary gland, and the amount of Ag nanoparticles distributed to breast milk increased with decreasing particle size. Orally administered Ag nanoparticles were also distributed to breast milk and subsequently to the brains of breast-fed pups. Ten-nanometer Ag nanoparticles were retained longer in the pups' brains than in their livers and lungs. Nevertheless, no significant behavioral changes were observed in offspring breast-fed by dams that had received orally administered 10 nm Ag nanoparticles. These data provide basic information for evaluating the safety of nanoparticle use during lactation. PMID- 27498760 TI - Synthesis of Zwitterionic Polymer Particles via Combined Distillation Precipitation Polymerization and Click Chemistry for Highly Efficient Enrichment of Glycopeptide. AB - Because of the low abundance of glycopeptide in natural biological samples, methods for efficient and selective enrichment of glycopeptides play a significant role in mass spectrometry (MS)-based glycoproteomics. In this study, a novel kind of zwitterionic hydrophilic interaction chromatography polymer particles, namely, poly(N,N-methylenebisacrylamide-co-methacrylic acid)@l-Cys (poly(MBAAm-co-MAA)@l-Cys), for the enrichment of glycopeptides was synthesized by a facile and efficient approach that combined distillation precipitation polymerization (DPP) and "thiol-ene" click reaction. In the DPP approach, residual vinyl groups explored outside the core with high density, then the functional ligand cysteine was immobilized onto the surface of core particles by highly efficient thiol-ene click reaction. Taking advantage of the unique structure of poly(MBAAm-co-MAA)@l-Cys, the resulting particles possess remarkable enrichment selectivity for glycopeptides from the tryptic digested human immunoglobulin G. The polymer particles were successfully employed for the analysis of human plasma, and 208 unique glycopeptides corresponding to 121 glycoproteins were reliably identified in triple independent nano-LC-MS/MS runs. The selectivity toward glycopeptides of these particles poly(MBAAm-co-MAA)@l-Cys is ~2 times than that of the commercial beads. These results demonstrated that these particles had great potential for large-scale glycoproteomics research. Moreover, the strategy with the combination of DPP and thiol-ene click chemistry might be a facile method to produce functional polymer particles for bioenrichment application. PMID- 27498761 TI - Crystal structure of the plant receptor-like kinase TDR in complex with the TDIF peptide. AB - In plants, leucine-rich repeat receptor-like kinases (LRR-RKs) perceive ligands, including peptides and small molecules, to regulate various physiological processes. TDIF, a member of the CLE peptide family, specifically interacts with the LRR-RK TDR to inhibit meristem differentiation into tracheary elements, and promotes cell proliferation. Here we report the crystal structure of the extracellular domain of TDR in complex with the TDIF peptide. The extracellular domain of TDR adopts a superhelical structure comprising 22 LRRs, and specifically recognizes TDIF by its inner concave surface. Together with our biochemical and sequence analyses, our structure reveals a conserved TDIF recognition mechanism of TDR among plant species. Furthermore, a structural comparison of TDR with other plant LRR-RKs suggested the activation mechanism of TDR by TDIF. The structure of this CLE peptide receptor provides insights into the recognition mechanism of the CLE family peptides. PMID- 27498763 TI - The diastereoselective synthesis of octahedral cationic iridium hydride complexes with a stereogenic metal centre. AB - We report herein the highly diastereoselective synthesis of octahedral cationic Ir(iii) hydride complexes with a stereogenic metal centre following various strategies. The configurational stability of these compounds has also been investigated. PMID- 27498762 TI - A VEGF-dependent gene signature enriched in mesenchymal ovarian cancer predicts patient prognosis. AB - We have previously reported surrogate biomarkers of VEGF pathway activities with the potential to provide predictive information for anti-VEGF therapies. The aim of this study was to systematically evaluate a new VEGF-dependent gene signature (VDGs) in relation to molecular subtypes of ovarian cancer and patient prognosis. Using microarray profiling and cross-species analysis, we identified 140-gene mouse VDGs and corresponding 139-gene human VDGs, which displayed enrichment of vasculature and basement membrane genes. In patients who received bevacizumab therapy and showed partial response, the expressions of VDGs (summarized to yield VDGs scores) were markedly decreased in post-treatment biopsies compared with pre treatment baselines. In contrast, VDGs scores were not significantly altered following bevacizumab treatment in patients with stable or progressive disease. Analysis of VDGs in ovarian cancer showed that VDGs as a prognostic signature was able to predict patient outcome. Correlation estimation of VDGs scores and molecular features revealed that VDGs was overrepresented in mesenchymal subtype and BRCA mutation carriers. These findings highlighted the prognostic role of VEGF-mediated angiogenesis in ovarian cancer, and proposed a VEGF-dependent gene signature as a molecular basis for developing novel diagnostic strategies to aid patient selection for VEGF-targeted agents. PMID- 27498765 TI - HIV: A recipe for inducing broadly neutralizing antibodies. PMID- 27498764 TI - Regulation of proinflammatory genes by the circulating microRNA hsa-miR-939. AB - Circulating microRNAs are beneficial biomarkers because of their stability and dysregulation in diseases. Here we sought to determine the role of miR-939, a miRNA downregulated in patients with complex regional pain syndrome (CRPS). Hsa miR-939 is predicted to target several proinflammatory genes, including IL-6, VEGFA, TNFalpha, NFkappaB2, and nitric oxide synthase 2 (NOS2A). Binding of miR 939 to the 3' untranslated region of these genes was confirmed by reporter assay. Overexpression of miR-939 in vitro resulted in reduction of IL-6, NOS2A and NFkappaB2 mRNAs, IL-6, VEGFA, and NOS2 proteins and NFkappaB activation. We observed a significant decrease in the NOS substrate l-arginine in plasma from CRPS patients, suggesting reduced miR-939 levels may contribute to an increase in endogenous NOS2A levels and NO, and thereby to pain and inflammation. Pathway analysis showed that miR-939 represents a critical regulatory node in a network of inflammatory mediators. Collectively, our data suggest that miR-939 may regulate multiple proinflammatory genes and that downregulation of miR-939 in CRPS patients may increase expression of these genes, resulting in amplification of the inflammatory pain signal transduction cascade. Circulating miRNAs may function as crucial signaling nodes, and small changes in miRNA levels may influence target gene expression and thus disease. PMID- 27498767 TI - AMP-activated protein kinase activator, HL156A reduces thioacetamide-induced liver fibrosis in mice and inhibits the activation of cultured hepatic stellate cells and macrophages. AB - Cirrhosis, the end-stage of hepatic fibrosis, is not only life-threatening by itself, but also a causative factor of liver cancer. Despite efforts to develop treatment for liver fibrosis, there are no approved agents as anti-fibrotic drugs to date. In the present study, we aimed to investigate the anti-fibrotic effect of the AMP-activated protein kinase (AMPK) activator, HL156A. A mouse model of thioacetamide (TAA)-induced liver fibrosis was used to examine the effect of HL156A in vivo. Mice received either TAA alone or a combination of TAA and HL156A intraperitoneally for a total duration of 6 weeks. Including HL156A during exposure to TAA significantly reduced extracellular matrix (ECM) deposition and production of the hepatic transforming growth factor-beta1 (TGF-beta1). Immunohistochemical analysis revealed that the activation of hepatic stellate cells and the capillarization of liver sinusoids were also diminished significantly by HL156A co-treatment. The anti-fibrotic effect of HL156A was further studied in vitro by using a rat hepatic stellate cell line, HSC-T6 cells. The induction of alpha-smooth muscle actin (alpha-SMA) by TGF-beta1 treatment was reversed by HL156A, which was likely via the activation of AMPK. Moreover, HL156A showed anti-inflammatory effects on macrophages. Treatment with HL156A diminished LPS-induced activation of both Raw264.7 macrophage cells and primary cultured mouse macrophages. Taken together, these results imply that the AMPK activator HL156A inhibits hepatic fibrosis via multiple mechanisms and could be a potentially effective agent for fibrosis treatment. PMID- 27498766 TI - Immunological aspects of intestinal mucus and mucins. AB - A number of mechanisms ensure that the intestine is protected from pathogens and also against our own intestinal microbiota. The outermost of these is the secreted mucus, which entraps bacteria and prevents their translocation into the tissue. Mucus contains many immunomodulatory molecules and is largely produced by the goblet cells. These cells are highly responsive to the signals they receive from the immune system and are also able to deliver antigens from the lumen to dendritic cells in the lamina propria. In this Review, we will give a basic overview of mucus, mucins and goblet cells, and explain how each of these contributes to immune regulation in the intestine. PMID- 27498768 TI - N-Terminal Peptide Detection with Optimized Peptide-Spectrum Matching and Streamlined Sequence Libraries. AB - We identified tryptic peptides in yeast cell lysates that map to translation initiation sites downstream of the annotated start sites using the peptide spectrum matching algorithms OMSSA and Mascot. To increase the accuracy of peptide-spectrum matching, both algorithms were run using several standardized parameter sets, and Mascot was run utilizing a, b, and y ions from collision induced dissociation. A large fraction (22%) of the detected N-terminal peptides mapped to translation initiation downstream of the annotated initiation sites. Expression of several truncated proteins from downstream initiation in the same reading frame as the full-length protein (frame 1) was verified by western analysis. To facilitate analysis of the larger proteome of Drosophila, we created a streamlined sequence library from which all duplicated trypsin fragments had been removed. OMSSA assessment using this "stripped" library revealed 171 peptides that map to downstream translation initiation sites, 76% of which are in the same reading frame as the full-length annotated proteins, although some are in different reading frames creating new protein sequences not in the annotated proteome. Sequences surrounding implicated downstream AUG start codons are associated with nucleotide preferences with a pronounced three-base periodicity N1^G2^A3. PMID- 27498769 TI - Simplified three-dimensional tissue clearing and incorporation of colorimetric phenotyping. AB - Tissue clearing methods promise to provide exquisite three-dimensional imaging information; however, there is a need for simplified methods for lower resource settings and for non-fluorescence based phenotyping to enable light microscopic imaging modalities. Here we describe the simplified CLARITY method (SCM) for tissue clearing that preserves epitopes of interest. We imaged the resulting tissues using light sheet microscopy to generate rapid 3D reconstructions of entire tissues and organs. In addition, to enable clearing and 3D tissue imaging with light microscopy methods, we developed a colorimetric, non-fluorescent method for specifically labeling cleared tissues based on horseradish peroxidase conversion of diaminobenzidine to a colored insoluble product. The methods we describe here are portable and can be accomplished at low cost, and can allow light microscopic imaging of cleared tissues, thus enabling tissue clearing and imaging in a wide variety of settings. PMID- 27498771 TI - [Corrigendum] VEGF in nuclear medicine: Clinical application in cancer and future perspectives (Review). AB - Following the publication of this article, after having re-examined our manuscript, we noted an error in the acknowledgements section, as regards the funding of our study. The correct version of acknowledgements section is shown below: Acknowledgements This study was supported by the Ministry of Health and Fondazione Roma and by NOBILE S.p.A. Thanks are also due to REGIONE LAZIO Prot. FILAS-RU-2014 - 1020 (E.A.). [the original article was published in the International Journal of Oncology 49: 437-447, 2016; DOI: 10.3892/ijo.2016.3553]. PMID- 27498770 TI - Alkaloid-Catalyzed Enantioselective [3 + 2] Cycloaddition of Ketenes and Azomethine Imines. AB - A new asymmetric synthesis of bicyclic pyrazolidinones through an alkaloid catalyzed formal [3 + 2] cycloaddition of in situ generated ketenes and azomethine imines is described. The products were formed in good to excellent yields (52-99% for 17 examples), with good to excellent diastereoselectivity (dr 5:1 to 27:1 for 11 examples), and with excellent enantioselectivity in all cases (>=96% ee). This method represents the first unambiguous example of an enantioselective reaction between ketenes and a 1,3-dipole. PMID- 27498772 TI - Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCepsilon-dependent activation of TRPV1. AB - AIM: Severe painful sensory neuropathy often occurs during paclitaxel chemotherapy. Since paclitaxel can activate mast cell and basophils, whereas quercetin, a polyphenolic flavonoid contained in various plants, which can specifically inhibit histamine release as a mast cell stabilizer. In this study we explore whether quercetin could ameliorate paclitaxel-induced neuropathic pain and elucidated the underlying mechanisms. METHODS: Quercetin inhibition on histamine release was validated in vitro by detecting histamine release from rat basophilic leukemia (RBL-2H3) cells stimulated with paclitaxel (10 MUmol/L). In the in vivo experiments, rats and mice received quercetin (20, 40 mg.kg(-1).d( 1)) for 40 and 12 d, respectively. Meanwhile, the animals were injected with paclitaxel (2 mg/kg, ip) four times on d 1, 3, 5 and 7. Heat hyperalgesia and mechanical allodynia were evaluated at the different time points. The animals were euthanized and spinal cords and dorsal root ganglions were harvested for analyzing PKCepsilon and TRPV1 expression levels. The plasma histamine levels were assessed in rats on d 31. RESULTS: Pretreatment with quercetin (3, 10, 30 MUmol/L) dose-dependently inhibited excessive histamine release from paclitaxel stimulated RBL-2H3 cells in vitro, and quercetin administration significantly suppressed the high plasma histamine levels in paclitaxel-treated rats. Quercetin administration dose-dependently raised the thresholds for heat hyperalgesia and mechanical allodynia in paclitaxel-treated rats and mice. Furthermore, quercetin administration dose-dependently suppressed the increased expression levels of PKCepsilon and TRPV1 in the spinal cords and DRGs of paclitaxel-treated rats and mice. Moreover, quercetin administration may inhibited the translocation of PKCepsilon from the cytoplasm to the membrane in the spinal cord and DRG of paclitaxel-treated rats. CONCLUSION: Our results reveal the underlying mechanisms of paclitaxel-induced peripheral neuropathy and demonstrate the therapeutic potential of quercetin for treating this side effect. PMID- 27498773 TI - DL0410, a novel dual cholinesterase inhibitor, protects mouse brains against Abeta-induced neuronal damage via the Akt/JNK signaling pathway. AB - AIM: 1,1'-([1,1'-Biphenyl]-4,4'-diyl)bis(3-(piperidin-1-yl)propan-1 one)dihydrochloride (DL0410) is a novel synthetic dual acetylcholinesterase (AChE)/butyrocholinesterase (BuChE) inhibitor, which has shown a potential therapeutic effect on Alzheimer's disease (AD). In this study we examined whether DL0410 produced neuroprotective effects in an AD cellular model and an Abeta1-42 induced amnesia mouse model. METHODS: The in vitro inhibitory activities against AChE and BuChE were estimated using Ellman's assay. Copper-induced toxicity in APPsw-SY5Y cells was used as AD cellular model, the cell viability was assessed using MTS assay, and cell apoptosis was evaluated based on mitochondrial membrane potential detection. Abeta1-42-induced amnesia mouse model was made in male mice by injecting aggregated Abeta1-42 (2 MUg in 2 MUL 0.1% DMSO) into the right cerebral ventricle. Before and after Abeta1-42 injection, the mice were orally administered DL0410 (1, 3, 9 mg.kg-1.d-1) or rivastigmine (2 mg.kg-1.d-1) for 3 and 11 d, respectively. Memory impairments were examined using Morris water maze (MWM) test and passive avoidance test. The expression levels of APP, CREB, BDNF, JNK and Akt in the mouse brains were measured with either immunohistochemistry or Western blotting. RESULTS: DL0410 exhibited in vitro inhibitory abilities against AChE and BuChE with IC50 values of 0.286+/-0.004 and 3.962+/-0.099 MUmol/L, respectively, which were comparable to those of donepezil and rivastigmine. In APPsw-SY5Y cells, pretreatment with DL0410 (1, 3, and 10 MUmol/L) decreased the phosphorylation of JNK and increased the phosphorylation of Akt, markedly decreased copper-stimulated Abeta1-42 production, reversed the loss of mitochondrial membrane potential, and dose-dependently increased the cell viability. In Abeta1-42-treated mice, DL0410 administration significantly ameliorated learning and memory deficits in MWM test and passive avoidance test. Furthermore, DL0410 administration markedly decreased Abeta1-40/42 deposits in mouse cerebral cortices, and significantly up-regulated neurotrophic CREB/BDNF. Meanwhile, Akt/JNK signaling pathway may play a key role in the neuroprotective effect of DL0410. CONCLUSION: DL0410 ameliorates cognitive deficit and exerts neuronal protection in AD models, implicating this compound as a candidate drug for the prevention and therapy of AD. PMID- 27498774 TI - Acetylcholinesterase-independent protective effects of huperzine A against iron overload-induced oxidative damage and aberrant iron metabolism signaling in rat cortical neurons. AB - AIM: Iron dyshomeostasis is one of the primary causes of neuronal death in Alzheimer's disease (AD). Huperzine A (HupA), a natural inhibitor of acetylcholinesterase (AChE), is a licensed anti-AD drug in China and a nutraceutical in the United Sates. Here, we investigated the protective effects of HupA against iron overload-induced injury in neurons. METHODS: Rat cortical neurons were treated with ferric ammonium citrate (FAC), and cell viability was assessed with MTT assays. Reactive oxygen species (ROS) assays and adenosine triphosphate (ATP) assays were performed to assess mitochondrial function. The labile iron pool (LIP) level, cytosolic-aconitase (c-aconitase) activity and iron uptake protein expression were measured to determine iron metabolism changes. The modified Ellman's method was used to evaluate AChE activity. RESULTS: HupA significantly attenuated the iron overload-induced decrease in neuronal cell viability. This neuroprotective effect of HupA occurred concurrently with a decrease in ROS and an increase in ATP. Moreover, HupA treatment significantly blocked the upregulation of the LIP level and other aberrant iron metabolism changes induced by iron overload. Additionally, another specific AChE inhibitor, donepezil (Don), at a concentration that caused AChE inhibition equivalent to that of HupA negatively, influenced the aberrant changes in ROS, ATP or LIP that were induced by excessive iron. CONCLUSION: We provide the first demonstration of the protective effects of HupA against iron overload-induced neuronal damage. This beneficial role of HupA may be attributed to its attenuation of oxidative stress and mitochondrial dysfunction and elevation of LIP, and these effects are not associated with its AChE-inhibiting effect. PMID- 27498775 TI - The structural basis of the dominant negative phenotype of the Galphai1beta1gamma2 G203A/A326S heterotrimer. AB - AIM: Dominant negative mutant G proteins have provided critical insight into the mechanisms of G protein-coupled receptor (GPCR) signaling, but the mechanisms underlying the dominant negative characteristics are not completely understood. The aim of this study was to determine the structure of the dominant negative Galphai1beta1gamma2 G203A/A326S complex (Gi-DN) and to reveal the structural basis of the mutation-induced phenotype of Galphai1beta1gamma2. METHODS: The three subunits of the Gi-DN complex were co-expressed with a baculovirus expression system. The Gi-DN heterotrimer was purified, and the structure of its complex with GDP was determined through X-ray crystallography. RESULTS: The Gi-DN heterotrimer structure revealed a dual mechanism underlying the dominant negative characteristics. The mutations weakened the hydrogen bonding network between GDP/GTP and the binding pocket residues, and increased the interactions in the Galpha-Gbetagamma interface. Concomitantly, the Gi-DN heterotrimer adopted a conformation, in which the C-terminus of Galphai and the N-termini of both the Gbeta and Ggamma subunits were more similar to the GPCR-bound state compared with the wild type complex. From these structural observations, two additional mutations (T48F and D272F) were designed that completely abolish the GDP binding of the Gi-DN heterotrimer. CONCLUSION: Overall, the results suggest that the mutations impede guanine nucleotide binding and Galpha-Gbetagamma protein dissociation and favor the formation of the G protein/GPCR complex, thus blocking signal propagation. In addition, the structure provides a rationale for the design of other mutations that cause dominant negative effects in the G protein, as exemplified by the T48F and D272F mutations. PMID- 27498776 TI - The POR rs1057868-rs2868177 GC-GT diplotype is associated with high tacrolimus concentrations in early post-renal transplant recipients. AB - AIM: Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes (CYP), and several POR SNPs have been shown to be important contributors to altered CYP activity or CYP-mediated drug metabolism. In this study we examined the association between 6 POR SNPs and tacrolimus concentrations in Chinese renal transplant recipients. METHODS: A total of 154 renal transplant recipients were enrolled. Genotyping of CYP3A5*3 and 6 POR SNPs was performed. All patients received a triple immunosuppressive regimen comprising tacrolimus, mycophenolate mofetil and prednisone. Dose adjusted tacrolimus trough concentrations were obtained on d 7 (C0D7/D) after transplantation when steady-state concentration of tacrolimus was achieved (dosage had been unchanged for more than 3 d). RESULTS: Tacrolimus C0D7/D in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype carriers was 1.62- and 2.72 fold higher than those in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype non-carriers and CYP3A5*1 carriers (220.17+/-48.09 vs 135.69+/-6.86 and 80.84+/ 5.27 ng/mL/mg/kg, respectively, P<0.0001). Of CYP3A5*3/*3/ POR rs1057868 rs2868177GC-GT diplotype carriers, 85.71% exceeded the upper limit of the target range (8 ng/mL), which was also significantly higher compared with the latter two groups (14.29% and 0.00%, respectively, P<0.0001). The CYP3A5*3 and POR rs1057868 rs2868177 GC-GT diplotype explained 31.7% and 5.7%, respectively, of the inter individual variability of tacrolimus C0D7/D, whereas the POR rs1057868-rs2868177 GC-GT diplotype could explain 10.9% of the inter-individual variability of tacrolimus C0D7/D in CYP3A5 non-expressers. CONCLUSION: The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype accounted for the inter-individual variation of tacrolimus C0D7/D. Genotyping of POR rs1057868-rs2868177 diplotypes would help to differentiate initial tacrolimus dose requirements and to achieve early target C0 ranges in Chinese renal transplant recipients. PMID- 27498777 TI - Vitamin K2 suppresses rotenone-induced microglial activation in vitro. AB - AIM: Increasing evidence has shown that environmental factors such as rotenone and paraquat induce neuroinflammation, which contributes to the pathogenesis of Parkinson's disease (PD). In this study, we investigated the molecular mechanisms underlying the repression by menaquinone-4 (MK-4), a subtype of vitamin K2, of rotenone-induced microglial activation in vitro. METHODS: A microglial cell line (BV2) was exposed to rotenone (1 MUmol/L) with or without MK-4 treatment. The levels of TNF-alpha or IL-1beta in 100 MUL of cultured media of BV2 cells were measured using ELISA kits. BV2 cells treated with rotenone with or without MK4 were subjected to mitochondrial membrane potential, ROS production, immunofluorescence or immunoblot assays. The neuroblastoma SH-SY5Y cells were treated with conditioned media (CM) of BV2 cells that were exposed to rotenone with or without MK-4 treatment, and the cell viability was assessed using MTT assay. RESULTS: In rotenone-treated BV2 cells, MK-4 (0.5-20 MUmol/L) dose dependently suppressed the upregulation in the expression of iNOS and COX-2 in the cells, as well as the production of TNF-alpha and IL-1beta in the cultured media. MK-4 (5-20 MUmol/L) significantly inhibited rotenone-induced nuclear translocation of NF-kappaB in BV2 cells. MK-4 (5-20 MUmol/L) significantly inhibited rotenone-induced p38 activation, ROS production, and caspase-1 activation in BV2 cells. MK-4 (5-20 MUmol/L) also restored the mitochondrial membrane potential that had been damaged by rotenone. Exposure to CM from rotenone-treated BV2 cells markedly decreased the viability of SH-SY5Y cells. However, this rotenone-activated microglia-mediated death of SH-SY5Y cells was significantly attenuated when the BV2 cells were co-treated with MK-4 (5-20 MUmol/L). CONCLUSION: Vitamin K2 can directly suppress rotenone-induced activation of microglial BV2 cells in vitro by repressing ROS production and p38 activation. PMID- 27498778 TI - Ethanol inhibits histaminergic neurons in mouse tuberomammillary nucleus slices via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites. AB - AIM: Ethanol, one of the most frequently used and abused substances in our society, has a profound impact on sedation. However, the neuronal mechanisms underlying its sedative effect remain unclear. In this study, we investigated the effects of ethanol on histaminergic neurons in the tuberomammillary nucleus (TMN), a brain region thought to be critical for wakefulness. METHODS: Coronal brain slices (250 MUm thick) containing the TMN were prepared from GAD67-GFP knock-in mice. GAD67-GFP was used to identify histaminergic neurons in the TMN. The spontaneous firing and membrane potential of histaminergic neurons, and GABAergic transmission onto these neurons were recorded using whole-cell patch clamp recordings. Drugs were applied through superfusion. RESULTS: Histaminergic and GAD67-expressing neurons in the TMN of GAD67-GFP mice were highly co localized. TMN GFP-positive neurons exhibited a regular spontaneous discharge at a rate of 2-4 Hz without burst firing. Brief superfusion of ethanol (64, 190, and 560 mmol/L) dose-dependently and reversibly suppressed the spontaneous firing of the neurons in the TMN; when synaptic transmission was blocked by tetrodotoxin (1 MUmol/L), ethanol caused hyperpolarization of the membrane potential. Furthermore, superfusion of ethanol markedly increased the frequency and amplitude of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs), which were abolished in the presence of the GABAA receptor antagonist bicuculline (20 MUmol/L). Finally, ethanol-mediated enhancement of sIPSCs and mIPSCs was significantly attenuated when the slices were pretreated with the GABAB agonist baclofen (30 MUmol/L). CONCLUSION: Ethanol inhibits the excitability of histaminergic neurons in mouse TMN slices, possibly via potentiating GABAergic transmission onto the neurons at both pre- and postsynaptic sites. PMID- 27498779 TI - Sweroside ameliorates alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice by regulating bile acids and suppressing pro-inflammatory responses. AB - AIM: Sweroside is an iridoid glycoside with diverse biological activities. In the present study we investigated the effects of sweroside on alpha naphthylisothiocyanate (ANIT)-induced cholestatic liver injury in mice. METHODS: Mice received sweroside (120 mg.kg(-1).d(-1), ig) or a positive control INT-747 (12 mg.kg(-1).d(-1), ig) for 5 d, and ANIT (75 mg/kg, ig) was administered on d 3. The mice were euthanized on d 5, and serum biochemical markers, hepatic bile acids and histological changes were analyzed. Hepatic expression of genes related to pro-inflammatory mediators and bile acid metabolism was also assessed. Primary mouse hepatocytes were exposed to a reconstituted mixture of hepatic bile acids, which were markedly elevated in the ANIT-treated mice, and the cell viability and expression of genes related to pro-inflammatory mediators were examined. RESULTS: Administration of sweroside or INT-747 effectively ameliorated ANIT-induced cholestatic liver injury in mice, as evidenced by significantly reduced serum biochemical markers and attenuated pathological changes in liver tissues. Furthermore, administration of sweroside or INT-747 significantly decreased ANIT induced elevation of individual hepatic bile acids, such as beta-MCA, CA, and TCA, which were related to its effects on the expression of genes responsible for bile acid synthesis and transport as well as pro-inflammatory responses. Treatment of mouse hepatocytes with the reconstituted bile acid mixture induced significant pro-inflammatory responses without affecting the cell viability. CONCLUSION: Sweroside attenuates ANIT-induced cholestatic liver injury in mice by restoring bile acid synthesis and transport to their normal levels, as well as suppressing pro-inflammatory responses. PMID- 27498781 TI - Synthetic Chlorins, Possible Surrogates for Chlorophylls, Prepared by Derivatization of Porphyrins. AB - Chlorophylls make Earth green, are the central constituents in the engine of photosynthesis, and not surprisingly have garnered immense attention. A chlorin, the core chromophore of a chlorophyll, is a dihydroporphyrin macrocycle that contains one pyrroline ring and three pyrrole rings. The dominant method for the synthesis of chlorins has entailed the derivatization of porphyrins. The present review covers the ostensibly simple conversion of porphyrins, regardless of synthetic or biological origin, to chlorins. The period covered encompasses the entire history since the beginnings of chlorin synthetic chemistry in the early 20th century through 2015. Representative transformations include hydrogenation, cycloaddition, annulation, and diverse "breaking and mending" approaches. Altogether, the synthesis of >1000 chlorins or chlorin-like compounds (containing >50 distinct pyrroline motifs) is described. Such diversity animates the question "what structural features are essential for a chlorin to resemble chlorophyll?" To begin to address the structure-spectrum relationship, > 250 absorption spectra are provided for representative structures. The synthesis and spectral properties of the vast collection of compounds described herein are expected to illuminate the scope to which synthetic chlorins can serve as surrogates for chlorophylls and be exploited in diverse ways. PMID- 27498780 TI - Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro. AB - AIM: Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors can not only lower blood glucose levels, but also alleviate cardiac remodeling after myocardial ischemia and hypertension. In the present study, we investigated the effects of a DPP-4 inhibitor (linagliptin) and a GLP-1 activator (liraglutide) on glucose- and angiotensin II (Ang II)-induced collagen formation and cytoskeleton reorganization in cardiac fibroblasts in vitro, and elucidated the related mechanisms. METHODS: Cardiac fibroblasts were isolated from the hearts of 6-week-old C57BL/6 mice, and then exposed to different concentrations of glucose or Ang II for 24 h. The expression of fibrotic signals (fibronectin, collagen-1, -3 and -4), as well as ERK1/2 and NF-kappaB-p65 in the fibroblasts was examined using Western blotting assays. F-actin degradation was detected under inverted laser confocal microscope in fibroblasts stained with Rhodamine phalloidin. RESULTS: Glucose (1-40 mmol/L) and Ang II (10-8-10-5 mol/L) dose dependently increased the expression of fibronectin, collagens, phospho-ERK1/2 and phospho-NF-kappaB-p65 in cardiac fibroblasts. High concentrations of glucose (>=40 mmol/L) and Ang II (>=10-6 mol/L) caused a significant degradation of F actin (less assembly F-actin fibers and more disassembly fibers). ERK1/2 inhibitor U0126 (10 MUmol/L) and NF-kappaB inhibitor JSH-23 (10 MUmol/L) both markedly suppressed glucose- and angiotensin II-induced fibronectin and collagen expressions in cardiac fibroblasts. Furthermore, pretreatment with liraglutide (10-100 nmol/L) or linagliptin (3 and 30 nmol/L) significantly decreased glucose- and Ang II-induced expression of fibrotic signals, phospho-ERK1/2 and phospho-NF kappaB-p65 in cardiac fibroblasts. Moreover, pretreatment with liraglutide (30 nmol/L) or liraglutide (100 nmol/L) markedly inhibited glucose-induced F-actin degradation, however, only liraglutide inhibited Ang II-induced F-actin degradation. CONCLUSION: Linagliptin and liraglutide inhibit glucose- and Ang II induced collagen formation in cardiac fibroblasts via activation of the ERK/NF kappaB/pathway. Linagliptin and liraglutide also markedly inhibit glucose-induced F-actin degradation in cardiac fibroblasts, but only liraglutide inhibits Ang II induced F-actin degradation. PMID- 27498782 TI - Decreased LIPF expression is correlated with DGKA and predicts poor outcome of gastric cancer. AB - Gastric cancer (GC) is a common and deadly digestive tract tumor worldwide. Unfortunately, diagnosis of GC is usually confused and misleading because of atypical symptoms or incomplete complaints. Accordingly, exploring gene expression profile and identifying genes with analogical variance trend will bring new perspective into the diagnosis and treatment of GC. Herein, a RNA-Seq dataset from Caucasian GC and their matched non-cancerous samples [Gene Expression Omnibus (GEO): SRP049809] and datasets from four microarrays constituted with tumor and non-tumor tissues (GEO: GSE13911, GSE19826, GSE29272, GSE33335) were analyzed to explore the differentially expressed genes (DGEs). As a result, we identified a core set of 373 DGEs. Among these genes, we found that most downregulated genes were related to lipid-metabolic functions. Especially, the gastric lipase (LIPF) gene, which was connected with various lipid metabolism processes, was significantly decreased among all datasets. We then performed immunohistochemistry experiments using gastric tissue arrays to investigate the clinical effects, and the expression of a LIPF target gene, diacylglycerol kinase alpha (DGKA). Among the 90 samples of gastric adenocarcinoma, the LIPF and DGKA levels were both decreased in cancer tissues [LIPF, 59.1% (53/90); DGKA, 77.8% (70/90)] compared to normal tissues [LIPF, 94.4% (85/90); DGKA, 90% (81/90)]. The expression level of these two proteins in GC was associated with local invasion and disease stage. Cox regression identified high DGKA expression (HR, 0.49; 95% CI, 0.26-0.94; P=0.03) as a predictor of good prognosis and LNM status (HR, 4.63; 95% CI, 1.39-15.51; P=0.01) as a predictor of poor prognosis. Thus we speculated that LIPF-DGKA might serve as a potential possible biomarkers for diagnosis of GC, and their downregulation may bring new perspective into the investigation of GC prognosis. PMID- 27498783 TI - Exceptional gravimetric and volumetric CO2 uptake in a palladated NbO-type MOF utilizing cooperative acidic and basic, metal-CO2 interactions. AB - A novel NbO-type MOF is reported based on a palladated organic linker, showing a remarkable gravimetric and volumetric CO2 uptake, reaching 201.8 cm(3) g(-1) (9.0 mmol g(-1), 39.7 wt%) and 187.8 cm(3) cm(-3) at 273 K and 1 bar, respectively. Accurate theoretical calculations revealed that the exceptional CO2 uptake is due to the combination of Lewis base Pd(ii)-CO2 (24.3 kJ mol(-1)) and Lewis acid Cu(ii)-CO2 (30.3 kJ mol(-1)) interactions, as well as synergistic pore size effects. PMID- 27498784 TI - Functional characterization of GmBZL2 (AtBZR1 like gene) reveals the conserved BR signaling regulation in Glycine max. AB - Brassinosteroids (BRs) play key roles in plant growth and development, and regulate various agricultural traits. Enhanced BR signaling leads to increased seed number and yield in Arabidopsis bzr1-1D (AtBZR1(P234L), gain-of-function mutant of the important transcription factor in BR signaling/effects). BR signal transduction pathway is well elucidated in Arabidopsis but less known in other species. Soybean is an important dicot crop producing edible oil and protein. Phylogenetic analysis reveals AtBZR1-like genes are highly conserved in angiosperm and there are 4 orthologues in soybean (GmBZL1-4). We here report the functional characterization of GmBZL2 (relatively highly expresses in flowers). The P234 site in AtBZR1 is conserved in GmBZL2 (P216) and mutation of GmBZL2(P216L) leads to GmBZL2 accumulation. GmBZL2(P216L) (GmBZL2*) in Arabidopsis results in enhanced BR signaling; including increased seed number per silique. GmBZL2* partially rescued the defects of bri1-5, further demonstrating the conserved function of GmBZL2 with AtBZR1. BR treatment promotes the accumulation, nuclear localization and dephosphorylation/phosphorylation ratio of GmBZL2, revealing that GmBZL2 activity is regulated conservatively by BR signaling. Our studies not only indicate the conserved regulatory mechanism of GmBZL2 and BR signaling pathway in soybean, but also suggest the potential application of GmBZL2 in soybean seed yield. PMID- 27498785 TI - Clinical effects of miR-101 on prognosis of hepatocellular carcinoma and carcinogenic mechanism of anti-miR-101. AB - The aim of this study was to verify whether anti-miR-101 participates in the treatment of hepatocellular carcinoma (HCC) as a small-molecule antitumor agent, and to explore the effect on phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Patients who received consecutive hepatectomies were followed-up, and miR-101 expressions in their tumor and paracancerous tissues were detected. Correlation between miR-101 expression and clinical pathological factors and prognosis was studied. High-throughput sequencing was used to detect the genetic and microRNA (miRNA) levels of tumor tissues. Expression of anti-miR-101 in different HCC cell lines was determined, and those of desired genes and proteins were detected by qRT-PCR and western blotting to obtain the target gene. miR-101 was significantly upregulated in HCC patients compared with that in paracancerous tissues. High miR-101 expression, vascular invasion, tumor size >=7 cm and late pathological stage were the risk factors of recurrence-free survival rate. High miR-101 expression was the independent prognostic factor of total and recurrence free survival rates. CXCL12, IL6R, FOXO3 and PTEN were screened as desired genes, and only PTEN was expressed significantly differently in three cell lines. miR 101 could bind 3'-UTR of WT-PTEN with reduced fluorescent intensity, suggesting that PTEN was the target gene. SMMC-7721, HepG2 and Huh7 were eligible cell lines for miR-101 studies. miR-101 was an applicable molecular marker of HCC. Anti-miR 101 regulated the transcription of PTEN and may promote cell proliferation, differentiation and apoptosis by regulating downstream genes with PTEN. The regulatory effects of anti-miR-101 on PTEN provide valuable evidence for finding novel miRNA drugs. PMID- 27498786 TI - Nitidine chloride inhibits the malignant behavior of human glioblastoma cells by targeting the PI3K/AKT/mTOR signaling pathway. AB - Recent studies have demonstrated that nitidine chloride (NC), a natural bioactive alkaloid, displays potent antitumor activity in various types of cancer. In the present study, NC was examined for efficacy in the treatment of human glioblastoma multiforme (GBM) as well as the molecular basis for its more general inhibitory effects in cancer. U251 and U87 GBM cell lines were exposed to three concentrations of NC (5, 25 and 50 uM) in vitro, and tumor cell growth was assessed on the basis of proliferation, migration and energy metabolism. Decreases in viability and proliferation reached ~50% for both cell lines with 50 uM NC at 24 h as assessed by cell viability Cell Counting Kit-8 (CCK-8) and EdU assays. In wound closure and Transwell assays, migration and invasion were inhibited at 50 uM after 24 h (~20 and 80%, respectively; P<0.05). ATP and L lactate levels were also decreased after treatment with NC (50 uM, 24 h; P<0.05 and P<0.01, respectively). Finally, in western blot analysis, phosphorylation of Akt and mTOR was suppressed by NC, but partially restored when cells were treated simultaneously with a novel Akt activator, SC79. Partial restoration was also observed in viability/proliferation (U251 and U87, ~15 vs. 40%; NC vs. NC + SC79; P<0.05) and invasion (U251 and U87, ~30 vs. 60%; NC vs. NC + SC79; P<0.05). Our results demonstrated that NC inhibits development of GBM by targeting the PI3K/Akt/mTOR signaling pathway and provides a potential therapeutic agent for the treatment of GBM. PMID- 27498787 TI - MicroRNA-140 represses glioma growth and metastasis by directly targeting ADAM9. AB - Glioma is the most frequent primary malignant tumor of the human brain. Recently, great progress has been made in the combined therapy of glioma. However, the clinical effects of these treatments and prognosis for patients with glioma remains poor. MicroRNAs (miRNAs) have been demonstrated to play important roles in the initiation and progression of various types of human cancers, also including glioma. The present study investigated the expression patterns of microRNA-140 (miR-140) in glioma, and the roles of miR-140 in glioma cell proliferation, migration and invasion. The results showed that miR-140 was significantly downreuglated in glioma tissues and cell lines, and low expression levels of miR-140 were correlated with World Health Organization (WHO) grade and Karnofsky performance score (KPS) of glioma patients. Restoration of miR-140 obviously suppressed glioma cell proliferation, migration and invasion. In addition, a disintegrin and metalloproteinase 9 (ADAM9) was identified as a novel direct target gene of miR-140 in glioma. Furthermore, knockdown of ADAM9 simulated the tumor suppressor functions of miR-140, while overexpression of ADAM9 abrogated these suppressive effects induced by miR-140 in glioma cells. In conclusion, the present study demonstrated the expression and clinical roles of miR-140 in glioma and suggested that miR-140 inhibited proliferation, migration and invasion of glioma cells, partially at least via suppressing ADAM9 expression. Therefore, miR-140 may be a novel candidate target for the development of therapeutic strategies for patients with glioma. PMID- 27498788 TI - Taxonomic reassessment of the genus Elizabethkingia using whole-genome sequencing: Elizabethkingia endophytica Kampfer et al. 2015 is a later subjective synonym of Elizabethkingia anophelis Kampfer et al. 2011. AB - The taxonomic status of all species of the genus Elizabethkingia was re-evaluated by comparative genomics based on whole-genome sequencing. From these results it is clear that Elizabethkingia endophytica is a later subjective synonym of Elizabethkingia anophelis. In addition, genome-based analysis revealed the misidentification of isolates previously identified by traditional approaches and indicates the presence of two more species. We propose a more rapid identification scheme on the basis of an in silico PCR assay derived from comparative genomics of whole-genome sequences (WGS) from 29 well-curated strains. PMID- 27498789 TI - Mycoplasma hyopneumoniae does not affect the interferon-related anti-viral response but predisposes the pig to a higher level of inflammation following swine influenza virus infection. AB - In pigs, influenza A viruses and Mycoplasma hyopneumoniae (Mhp) are major contributors to the porcine respiratory disease complex. Pre-infection with Mhp was previously shown experimentally to exacerbate the clinical outcomes of H1N1 infection during the first week after virus inoculation. In order to better understand the interactions between these pathogens, we aimed to assess very early responses (at 5, 24 and 48 h) after H1N1 infection in pigs pre-infected or not with Mhp. Clinical signs and macroscopic lung lesions were similar in both infected groups at early times post-H1N1 infection; and Mhp pre-infection affected neither the influenza virus replication nor the IFN-induced antiviral responses in the lung. However, it predisposed the animals to a higher inflammatory response to H1N1 infection, as revealed by the massive infiltration of neutrophils and macrophages into the lungs and the increased production of pro inflammatory cytokines (IL-6, IL-1beta and TNF-alpha). Thus, it seems it is this marked inflammatory state that would play a role in exacerbating the clinical signs subsequent to H1N1 infection. PMID- 27498790 TI - Paenibacillus solani sp. nov., isolated from potato rhizosphere soil. AB - A novel Gram-stain-positive, endospore-forming bacterium, designated FJAT-22460T, was isolated from a soil sample of a potato field in Xinjiang Autonomous Region, China. Cells were rods that were catalase-positive and motile by peritrichous flagella. The strain was found to grow at temperatures ranging from 10 to 40 degrees C (optimum 30 degrees C) and at pH 5.0-12.0 (optimum pH 7) with 0-5 % (w/v) NaCl (optimum 0 % NaCl). Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain FJAT-22460T belonged to the genus Paenibacillus and exhibited 16S rRNA gene sequence similarities of 97.3, 97.2, 97.2 and 97.0 % with Paenibacillus glucanolyticus DSM 5162T, Paenibacillus lautus DSM 3035T, Paenibacillus lactis MB 1871T and Paenibacillus chibensis JCM 9905T, respectively. DNA-DNA relatedness of strain FJAT-22460T with Paenibacillus glucanolyticusDSM 5162T and Paenibacillus lautus DSM 3035T was 62.6 % and 33.3 %, respectively, lower than the 70 % accepted for species delineation. The menaquinone was identified as MK-7. The major fatty acids detected were anteiso C15 : 0 (51.4 %), iso-C15 : 0 (5.3 %), C16 : 0 (12.1 %), iso-C16 : 0 (10.7 %) and anteiso-C17 : 0 (6.9 %). The DNA G+C content was determined to be 50.9 mol%. Phenotypic, chemotaxonomic and genotypic properties clearly indicated that isolate FJAT-22460T represents a novel species within the genus Paenibacillus, for which the name Paenibacillus solani sp. nov. is proposed. The type strain is FJAT-22460T (=DSM 100999T=CCTCC AB 2015207T). PMID- 27498791 TI - Pontibacter rugosus sp. nov., isolated from seawater. AB - A motile and rod-shaped bacterium, designated strain KYW1030T, was isolated from seawater collected from the Gwangyang bay (Republic of Korea). Cells were Gram reaction-negative, aerobic, catalase-positive and oxidase-negative. The major fatty acids were summed feature 4 (iso-C17 : 1 I and/or anteiso-C17 : 1 B), iso C15 : 0 and iso-C17 : 0 3-OH. The strain contained MK-7 as the major isoprenoid quinone, phosphatidylethanolamine and diphosphatidylglycerol as the major polar lipids and sym-homospermidine as the major polyamine. The DNA G+C content was 46 mol%. A phylogenetic tree based on 16S rRNA gene sequences showed that strain KYW1030T forms an evolutionary lineage within the radiation enclosing the members of the genus Pontibacter, with Pontibacterakesuensis AKS 1T (97.9 % 16S rRNA gene sequence similarity) as its nearest neighbour. A number of phenotypic characteristics distinguished strain KYW1030T from the related members of the genus Pontibacter. On the basis of the evidence presented in this study, a novel species, Pontibacter rugosus sp. nov., is proposed for strain KYW1030T (=KACC 18739T=JCM 31319T). PMID- 27498792 TI - Use of Reproductive Microhabitat by Melanophryniscus montevidensis (Anura: Bufonidae) from Uruguay. AB - This study describes the reproductive microhabitat of Melanophryniscus montevidensis and its use in two water bodies (WBs) in Barra de la Laguna de Rocha, Uruguay. Monthly field trips were performed between March 2012 and February 2013. Variables related to the WBs and vegetation, as well as parameters linked to the usage the amphibians make of the site (e.g: distance to the border of the pond, water depth and the vegetation use) were recorded. The behavior shown by the individuals during the breeding activity was recorded. This activity occurs in shallow temporary WBs with abundant hydrophilic vegetation. The individuals were found more frequently in areas near the edge of the pond, which has denser vegetation. The calling males were found closer to the border of the pond, and they showed better body condition than the non-calling males. In addition to calling activities, males used alternative tactics to find couples, such as active search of females, and aggressive behaviors, such as male displacing and physical combat. Such behaviors are common in anurans with explosive reproductive dynamics. The characterization of the reproductive microhabitats permits the proposal of strategies for the conservation of the species in Uruguay, given that the loss and fragmentation of habitats is one of the main causes considered for the decrease in their populations. PMID- 27498793 TI - The Size of Winter-Flooded Paddy Fields No Longer Limits the Foraging Habitat Use of the Endangered Crested Ibis (Nipponia nippon) in Winter. AB - Paddy fields have traditionally been viewed as the key foraging habitats for the endangered crested ibis (Nipponia nippon). With the population of this species now increasing, its distribution has expanded to both lowland areas and outside the nature reserve. However, little is known about the current foraging habitat preferences of these birds, especially during winter. In this research, a total of 54 used sites and 50 unused sites were investigated during winter from December 2011 to January 2012. The results of logistic regression analysis indicate that soil softness, human disturbance, and distance to the nearest road were important factors. For the site plots of winter-flooded paddy fields, the birds prefer the paddy fields with higher coverage of vegetation, except softer foraging sites and lower human-related disturbance. In lowland areas, the size of winter-flooded paddy fields was not a limiting factor, due to the availability of other wetlands capable of providing abundant food. The micro-habitat characteristics were important indicators of foraging habitat quality rather than the size of winter-flooded paddy fields, and the food accessibility may play an important role in the process of foraging habitat use. We suggest the improvement of the foraging micro-habitat and environmental characteristics would be effective in ensuring the availability of food in the dispersed lowland areas. The local people still needed to be encouraged and compensated by their single cropping cultivation, ploughed the paddy fields after harvesting and irrigated them with shallow water flooded in the original core areas of the nature reserve. PMID- 27498794 TI - Estimated Seed Shadow Generated by Japanese Martens(Martes melampus): Comparison with Forest-Dwelling Animals in Japan. AB - To evaluate the seed shadow generated by wild Japanese martens (Martes melampus), we combined data on their ranging behavior from the northern foot of Mt. Fuji, central Japan (seven males and three females) with data on gut passage time obtained from martens in Toyama Municipal Family Park Zoo (three males and one female). The movement distances varied, and mean distances for 0-1, 2-3, and 4-5 h intervals were 152.4, 734.7, and 1,162.4 m, respectively, with no significant sex difference. The mean gut passage time of ingested seeds was 7.4 h (range: 0.6 51.7 h), and two-thirds were defecated within 12 h. Seeds of fleshy fruits was frequently transported to 501-1,000 m, and 20% of ingested seeds were transported > 1,000 m from feeding sites. We found positive correlations between body size and home range of the animals in Japan and their seed dispersal distances. We conclude that Japanese martens are medium-range dispersers that can transport seeds from the source to open habitats conducive for germination and/or growth, partly due to scent marking behaviors. PMID- 27498795 TI - Comparative Analysis of Genome and Epigenome in Closely Related Medaka Species Identifies Conserved Sequence Preferences for DNA Hypomethylated Domains. AB - The genomes of vertebrates are globally methylated, but a small portion of genomic regions are known to be hypomethylated. Although hypomethylated domains (HMDs) have been implicated in transcriptional regulation in various ways, how a HMD is determined in a particular genomic region remains elusive. To search for DNA motifs essential for the formation of HMDs, we performed the genome-wide comparative analysis of genome and DNA methylation patterns of the two medaka inbred lines, Hd-rRII1 and HNI-II, which are derived from northern and southern subpopulations of Japan and exhibit high levels of genetic variations (SNP, ~ 3%). We successfully mapped > 70% of HMDs in both genomes and found that the majority of those mapped HMDs are conserved between the two lines (common HMDs). Unexpectedly, the average genetic variations are similar in the common HMD and other genome regions. However, we identified short well-conserved motifs that are specifically enriched in HMDs, suggesting that they may play roles in the establishment of HMDs in the medaka genome. PMID- 27498796 TI - De Novo Assembly of the Transcriptome of Turritopsis, a Jellyfish that Repeatedly Rejuvenates. AB - In most animals, aging is an irreversible process; however the species Turritopsis sp. has been observed to undergo a rejuvenation process as many as 14 times. In the present study, we used multiplexed RNA libraries to obtain the transcriptome from four developmental stages (St) of Turritopsis sp., including (I) immature medusa, (II) dumpling, (III) dumpling with a short stolon, and (IV) polyp, which had recently rejuvenated. A total of 4.02 billion paired-end reads were assembled de novo, yielding 90,327 contigs. Our analyses revealed that significant blast hits were recovered for 74% of the assembled contigs, and 19% were successfully annotated with gene ontology (GO) terms. A BLAST search demonstrated that 32% of the contigs were most similar to Hydra vulgarissequences. Raw reads from each sample were mapped against the contigs to find St-specific genes. This represents the first comprehensive set of de novo transcriptome data for this species, which may provide clues toward a better understanding of cyclical rejuvenation in multicellular animals. PMID- 27498797 TI - Ontogeny of the Appendicular Skeleton in Melanosuchus niger (Crocodylia: Alligatoridae). AB - The objective of the present study was to analyze chondrogenesis and the ossification pattern of the limbs of Melanosuchus niger in order to contribute with possible discussions on homology and the fusion pattern of autopodial elements and phylogeny. In the Reserva Extrativista do Lago Cunia, Rondonia, Brazil, six nests were marked and two eggs removed from each nest at 24-hour intervals until hatching. Embryos were cleared using KOH; bone tissue was stained with alizarin red S and cartilage with Alcian blue. Routine staining with HE was also performed. In the pectoral girdle, the scapula showed ossification centers before the coracoid process. In the pelvic girdle, the ilium and the ischium were condensed as a single cartilage, although ossification took place through two separate centers, forming distinct elements in the adult. The pubis developed from an independent cartilaginous center with free end, which reflects its function in breathing. In the initial stages, the stylopodium and the zeugopodium developed from the condensation of a Y-shaped cartilage in the limbs, and differentiation of the primary axis and digital arch were observed. The greatest changes were observed in the mesopodia. In their evolution, Crocodylia underwent a vast reduction in the number of autopodial elements as a consequence of fusions and ossification of some elements. This study shows that the chondrogenesis and ossification sequences are dissociated. Moreover, the differences between M. niger and other species show clear variation in the patterns for these events in Alligatoridae. PMID- 27498798 TI - Comparative Morphological Analysis of the Immature Stages of the Grass Blue Butterflies Zizeeria and Zizina (Lepidoptera: Lycaenidae). AB - The pale grass blue butterfly has been used to assess the biological effects of the Fukushima nuclear accident. Zizeeria and Zizina are two closely related genera of grass blue butterflies that are widely distributed in tropical to temperate Asia, Australia, and Africa, making them suitable environmental indicators for these areas. However, the morphological features of the immature stages have been examined only in fragmentary fashion. Here, we reared Zizeeria maha argia, Zizeeria maha okinawana, Zizeeria karsandra karsandra, Zizina emelina emelina, Zizina otis labradus, and Zizina otis riukuensis using a standard rearing method that was developed for Zizeeria maha, and comparatively identified morphological traits to effectively classify the immature stages of species or subspecies. Morphological information on these and other subspecies including Zizeeria knysna knysna and Zizina otis antanossa from Africa was also collected from literature. The subspecies were all reared successfully. The subspecies all had dorsal nectary and tentacle organs with similar morphology. For the subspecies of Zizeeria maha, only minor morphological differences were noted. Similarly, the subspecies of Zizina otis shared many traits. Most importantly, Zizeeria and Zizina differed in the shape of the sensory hairs that accompany the dorsal nectary organ; Zizeeriahad pointed hairs, and Zizina had blunt or rounded hairs. However, Zizina emelina exhibited several intermediate features between these two genera. Overall, the morphological traits did not completely reflect the conventional systematic relationships. This comparative study describes the efficient rearing of the grass blue butterflies and provides a morphological basis for the use of these species as environmental indicators. PMID- 27498799 TI - Phylogenetic Relationships of Japanese Auritibicen Species (Hemiptera: Cicadidae: Cryptotympanini) Inferred from Mitochondrial and Nuclear Gene Sequences. AB - We investigated the phylogenetic relationships and divergence times within the genus Auritibicen(Cicadidae: Cicadinae: Cryptotympanini), analyzing five Japanese species (A. japonicus, A. bihamatus,A. kyushyuensis, A. esakii and A. flammatus) and three species from East Asian mainland and Taiwan (A. atrofasciatus, A. intermedius and A. chujoi) using mitochondrial cytochrome oxidase subunit I (COI) and nuclear elongation factor 1-alpha (EF-1a) gene sequences. Although the EF-1a gene tree did not resolve the relationships among these Auritibicen species, the trees based on COI gene and the combined data set showed that Japanese taxa comprised three distinct lineages: the individual species A. flammatus and A. bihamatus, and the A. japonicus group, comprising A. japonicus, A. esakii and A. kyushyuensis from Japan and A. intermedius from Korea. In A. kyushyuensis, which comprises three populations in Kyushu, western Honshu and Shikoku, the specimens from western Honshu and Shikoku were closely related to each other, but not to the specimen from Kyushu; instead, they were sister to the Korean A. intermedius. The incongruence between the gene tree and species tree necessitates further population genetic and morphological studies to confirm the classification and species status of the western Honshu and Shikoku populations of A. kyushyuensis, which were originally described as two independent species. Divergence time estimation suggested that the most recent common ancestor of Auritibicen species studied dated back to the late Pliocene and that the species of the A. japonicus group diverged during the mid Pleistocene. Thus, the Pleistocene climatic fluctuation may have promoted the divergence of the Auritibicen species. PMID- 27498800 TI - Seawater Polluted with Highly Concentrated Polycyclic Aromatic Hydrocarbons Suppresses Osteoblastic Activity in the Scales of Goldfish, Carassius auratus. AB - We have developed an original in vitro bioassay using teleost scale, that has osteoclasts, osteoblasts, and bone matrix as each marker: alkaline phosphatase (ALP) for osteoblasts and tartrate-resistant acid phosphatase (TRAP) for osteoclasts. Using this scale in vitro bioassay, we examined the effects of seawater polluted with highly concentrated polycyclic aromatic hydrocarbons (PAHs) and nitro-polycyclic aromatic hydrocarbons (NPAHs) on osteoblastic and osteoclastic activities in the present study. Polluted seawater was collected from two sites (the Alexandria site on the Mediterranean Sea and the Suez Canal site on the Red Sea). Total levels of PAHs in the seawater from the Alexandria and Suez Canal sites were 1364.59 and 992.56 ng/l, respectively. We were able to detect NPAHs in both seawater samples. Total levels of NPAHs were detected in the seawater of the Alexandria site (12.749 ng/l) and the Suez Canal site (3.914 ng/l). Each sample of polluted seawater was added to culture medium at dilution rates of 50, 100, and 500, and incubated with the goldfish scales for 6 hrs. Thereafter, ALP and TRAP activities were measured. ALP activity was significantly suppressed by both polluted seawater samples diluted at least 500 times, but TRAP activity did not change. In addition, mRNA expressions of osteoblastic markers (ALP, osteocalcin, and the receptor activator of the NF-kappaB ligand) decreased significantly, as did the ALP enzyme activity. In fact, ALP activity decreased on treatment with PAHs and NPAHs. We conclude that seawater polluted with highly concentrated PAHs and NPAHs influences bone metabolism in teleosts. PMID- 27498802 TI - The Behavior of Chromosomes During Parthenogenetic Oogenesis in Marmorkrebs Procambarus fallax f. virginalis. AB - Parthenogenetic oogenesis varies among and even within species. Based on cytological mechanisms, it can largely be divided into apomixis (ameiotic parthenogenesis) producing genetically identical progeny, and automixis (meiotic parthenogenesis) producing genetically non-identical progeny. Polyploidy is common in parthenogenetic species, although the association between parthenogenesis and polyploidy throughout evolution is poorly understood. Marmorkrebs, or the marbled crayfish, was first identified as a parthenogenetic decapod and was tentatively named as Procambarus fallax f. virginalis. Previous studies revealed that Marmorkrebs is triploid and produces genetically identical offspring, suggesting that apomixis occurs during parthenogenetic oogenesis. However, the behavior of chromosomes during the process of oogenesis is still not well characterized. In this study, we observed parthenogenetic oogenesis around the time of ovulation in P. fallax f. virginalis by histology and immunohistochemistry. During oogenesis, the chromosomes were separated into two groups and behaved independently from each other, and one complete division corresponding to mitosis (the second meiosis-like division) was observed. This suggests that parthenogenetic oogenesis in Marmorkrebs exhibits gonomery, a phenomenon commonly found in apomictic parthenogenesis in polyploid animals. PMID- 27498803 TI - Specimens with an Artifact Appearing as 'Three Spines' in Milnesium tardigradum var. trispinosa Rahm, 1931 (Tardigrada). AB - Milnesium tardigradum trispinosa Rahm, 1931 is characterized by its three spines at the posterior end of the animal, but has never been reported since its original description. Among mounted specimens of Milnesium sp. from Japan and M. tardigradum s. s. from France, several cases with these 'three spines' were observed. In these samples, the character was formed by an artifact of the fixation process. Images of these specimens show such a striking similarity to Milnesium tardigradum trispinosa that this taxon must be considered as having been erroneously established as a result of misinterpretation of an artifact and no longer valid. PMID- 27498801 TI - A Stenohaline Medaka, Oryzias woworae, Increases Expression of Gill Na(+), K(+) ATPase and Na(+), K(+), 2Cl(-) Cotransporter 1 to Tolerate Osmotic Stress. AB - The present study aimed to evaluate the osmoregulatory mechanism of Daisy's medaka, O. woworae,as well as demonstrate the major factors affecting the hypo osmoregulatory characteristics of euryhaline and stenohaline medaka. The medaka phylogenetic tree indicates that Daisy's medaka belongs to the celebensis species group. The salinity tolerance of Daisy's medaka was assessed. Our findings revealed that 200/00 (hypertonic) saltwater (SW) was lethal to Daisy's medaka. However, 62.5% of individuals survived 100/00 (isotonic) SW with pre-acclimation to 50/00 SW for one week. This transfer regime, "Experimental (Exp.) 100/00 SW", was used in the following experiments. After 100/00 SW-transfer, the plasma osmolality of Daisy's medaka significantly increased. The protein abundance and distribution of branchial Na(+), K(+)-ATPase (NKA) and Na(+), K(+), 2Cl(-) cotransporter 1 (NKCC1) were also examined after transfer to 100/00 SW for one week. Gill NKA activity increased significantly after transfer to 100/00 SW. Meanwhile, elevation of gill NKA alphaalpha-subunit protein-abundance was found in the 100/00 SW-acclimated fish. In gill cross-sections, more and larger NKA immunoreactive (NKA-IR) cells were observed in the Exp. 100/00 SW medaka. The relative abundance of branchial NKCC1 protein increased significantly after transfer to 100/00 SW. NKCC1 was distributed in the basolateral membrane of NKA IR cells of the Exp. 100/00 SW group. Furthermore, a higher abundance of NKCC1 protein was found in the gill homogenates of the euryhaline medaka, O. dancena, than in that of the stenohaline medaka, O. woworae. PMID- 27498804 TI - Symbiotic Association of the Bivalve Tellimya fujitaniana (Galeommatoidea) with the Heart Urchin Echinocardium cordatum (Spatangoida) in the Northwestern Pacific. AB - The bivalve Tellimya fujitaniana ( Yokoyama, 1927 ) (Galeommatoidea, Heterodonta) was described based on a fossil shell. Until now, the biology of living animals has not been reported. In this study, we found T. fujitaniana in a commensal relationship with the heart urchin Echinocardium cordatum (Pennant, 1777) (Spatangoida, Echinoidea) on the intertidal mud flats of the Seto Inland Sea, Japan. We investigated the morphology, host associations, and reproductive biology of this bivalve species. The elongate-ovate shell is covered by a reddish brown ferruginous deposit. The mantle is exposed anteriorly to form a temporal siphon, while posteriorly one pair of short tentacles is exposed. Small individuals (shell length, SL, <= 2.1 mm) were attached to the host's body surface; middle-sized individuals (SL 3.0-3.2 mm) were attached to or stayed close to larger T. fujitanianathat were living freely in the host burrow. Nearly all the large individuals (SL >= 4.8 mm) lived freely in the host burrow, behind the urchin. This suggests that the host utilization pattern of T. fujitanianachanges with development. Specimens with SL >= 4.8 mm had mature gonads, mostly occupied by ova, and some individuals were brooding eggs or veliger larvae in the gills. This species was previously assigned to Fronsella. However, the morphology and ecology of this bivalve are very similar to those of Tellimya ferruginosa (the type species of the genus Tellimya) in the northeastern Atlantic Ocean. Thus, we have reassigned this species to genus Tellimya. We also confirmed that T. fujitaniana and T. ferruginosa can be genetically distinguished using the mitochondrial COI gene. PMID- 27498805 TI - Morphology, Biology, and Phylogenetic Position of the Bivalve Platomysia rugata (Heterodonta: Galeommatoidea), a Commensal with the Sipunculan Worm Sipunculus nudus. AB - The bivalve superfamily Galeommatoidea is characterized by its symbiotic associations with other marine invertebrates. However, for many galeommatoideans, the host species remains unknown. Platomysia (Galeommatoidea) is a monotypic genus including a single species P. rugata, which is distinguished from other galeommatoideans in having distinct and evenly spaced commarginal ribs on its shell surface. This species was described based on a single right valve shell collected in Nanao Bay, Japan Sea, by Habe in 1951 and has been known only from Japanese waters. However, the biology of living animals has never been reported. We found that this species lives in the burrows of the sipunculan worm Sipunculus nudus in mud flats in the Seto Inland Sea, Japan. We investigated its host association and described its shell morphology and anatomy. In addition, we performed a phylogenetic analysis using two nuclear (18S and 28S ribosomal RNA) genes to determine its phylogenetic position in Galeommatoidea. The result suggests that this species belongs to the clade of commensal bivalves together with Pseudopythina, Byssobornia, and Pergrinamor. Platomysia rugata and other two groups of sipunculan-associated galeommatoideans were not monophyletic, suggesting that association with sipunculans occurred at least three times in the galeommatoid evolution. PMID- 27498806 TI - The 'Antenna Balloon Anemone' Found in the Seto Inland Sea: New Genus and Species of Sea Anemone, Antennapeachia setouchi (Cnidaria, Actinaria, Haloclavidae). AB - In the present study, we report the identification of a sea anemone, Antennapeachia setouchi, collected in the Seto Inland Sea, which represents a new genus and new species. This new species has unusual tentacle and mesenterial arrangements that have not been observed in other species of Haloclavidae. There are 12 regular marginal tentacles and two 'antenna tentacles,' with the latter always rising upward and located on the oral disk near the mouth; the species is also characterized by its peculiar mesenterial pairs, consisting of a macrocneme and a microcneme. Furthermore, this species shows an interesting behavior: it can inflate its body like a balloon, lift above the seafloor, and drift with the sea current. The presence of a single, strong siphonoglyph, physa-like aboral end, and the lack of sphincter muscle classify this sea anemone within Haloclavidae. It resembles Peachia species, but cannot be classified in this genus as the new species has two pairs of mesenteries, consisting of a macrocneme and a microcneme, and irregular antenna tentacles. Therefore, we propose a new genus Antennapeachia to accommodate this species. PMID- 27498807 TI - Atomistic clustering-ordering and high-strain deformation of an Al0.1CrCoFeNi high-entropy alloy. AB - Computational investigations of structural, chemical, and deformation behavior in high-entropy alloys (HEAs), which possess notable mechanical strength, have been limited due to the absence of applicable force fields. To extend investigations, we propose a set of intermolecular potential parameters for a quinary Al-Cr-Co-Fe Ni alloy, using the available ternary Embedded Atom Method and Lennard-Jones potential in classical molecular-dynamics simulations. The simulation results are validated by a comparison to first-principles Korringa-Kohn-Rostoker (KKR) - Coherent Potential Approximation (CPA) [KKR-CPA] calculations for the HEA structural properties (lattice constants and bulk moduli), relative stability, pair probabilities, and high-temperature short-range ordering. The simulation (MD)-derived properties are in quantitative agreement with KKR-CPA calculations (first-principles) and experiments. We study AlxCrCoFeNi for Al ranging from 0 <= x <=2 mole fractions, and find that the HEA shows large chemical clustering over a wide temperature range for x < 0.5. At various temperatures high-strain compression promotes atomistic rearrangements in Al0.1CrCoFeNi, resulting in a clustering-to-ordering transition that is absent for tensile loading. Large fluctuations under stress, and at higher temperatures, are attributed to the thermo-plastic instability in Al0.1CrCoFeNi. PMID- 27498808 TI - A Gene Encoding Pentatricopeptide Repeat Protein Partially Restores Fertility in RT98-Type Cytoplasmic Male-Sterile Rice. AB - Cytoplasmic male sterility (CMS) lines in rice, which have the cytoplasm of a wild species and the nuclear genome of cultivated rice, are of value for the study of genetic interactions between the mitochondrial and nuclear genomes. The RT98-type CMS line RT98A and the fertility restorer line RT98C carry the cytoplasm of the wild species Oryza rufipogon and the nuclear genome of the Taichung 65 cultivar (Oryza sativa L.). Based on a classical crossing experiment, fertility is reported to be restored gametophytically by the presence of a tentative single gene, designated Rf98, which is derived from the cytoplasm donor. Fine mapping of Rf98 revealed that at least two genes, which are closely positioned, are required for complete fertility restoration in RT98A. Here, we identified seven pentatricopeptide repeat (PPR) genes that are located within a 170 kb region as candidates for Rf98 Complementation tests revealed that the introduction of one of these PPR genes, PPR762, resulted in the partial recovery of fertility with a seed setting rate up to 9.3%. We conclude that PPR762 is an essential fertility restorer gene for RT98-type CMS. The low rate of seed setting suggested that some other genes near the Rf98 locus are also necessary for the full recovery of seed setting. PMID- 27498809 TI - Sustained release of piroxicam from solid lipid nanoparticle as an effective anti inflammatory therapeutics in vivo. AB - This study aims to investigate the solid lipid nanoparticle (SLN) as a novel vehicle for the sustained release and transdermal delivery of piroxicam, as well as to determine the anti-inflammation effect of piroxicam-loaded SLN. SLN formulation was optimized and the particle size, polydispersity index, zeta potential (ZP), encapsulation efficiency, drug release, and morphological properties were characterized. The transdermal efficiency and mechanism of the piroxicam-loaded SLNs were investigated in vitro. With the inflammation induced edema model in rat, the anti-inflammatory efficiency of piroxicam-enriched SLNs (Pir-SLNs) was evaluated. The SLN formulation was optimized as: lecithin 100 mg, glycerin monostearate 200 mg, and Tween (1%, w/w). The particle size is around 102 +/- 5.2 nm with a PDI of 0.262. The ZP is 30.21 +/- 2.05 mV. The prepared SLNs showed high entrapment efficiency of 87.5% for piroxicam. There is no interaction between piroxicam and the vehicle components. The presence of polymorphic form of lipid with higher drug content in the optimized Pir-SLNs enables the Pir-SLNs to release the drug with a sustained manner. Pir-SLNs with oleic acid as enhancer can radically diffuse into both the stratum corneum and dermal layer, as well as penetrate through the hair follicles and sebaceous glands with significantly higher density than the other control groups. Pir-SLNs promptly inhibited the inflammation since the 3rd hour after the treatment by decreasing the PGE2 level. SLN was demonstrated to be a promising carrier for encapsulation and sustained release of piroxicam. Pir-SLN is a novel topical preparation with great potential for anti-inflammation application. PMID- 27498810 TI - [Medullary thyroid carcinoma in a 10-month-old child with multiple endocrine neoplasia 2B]. AB - In infants at risk of multiple endocrine neoplasia type 2B (MEN2B) the American Thyroid Association recommends genetic testing as soon as possible after birth and that thyroidectomy should be performed in MEN2B RET-mutation positive individuals as soon as possible and if possible within the first year of life. We present a ten-month-old girl with MEN2B who had prophylactic thyroidectomy. The surgical specimen showed medullary thyroid carcinoma. This case emphasizes the need for early diagnosis and prophylactic thyroidectomy in MEN2B patients. PMID- 27498811 TI - Oxidative Damage Induced by Arsenic in Mice or Rats: A Systematic Review and Meta Analysis. AB - In this meta-analysis, studies reporting arsenic-induced oxidative damage in mouse models were systematically evaluated to provide a scientific understanding of oxidative stress mechanisms associated with arsenic poisoning. Fifty-eight relevant peer-reviewed publications were identified through exhaustive database searching. Oxidative stress indexes assessed included superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), glutathione-s transferase (GST), glutathione reductase (GR), oxidized glutathione (GSSG), malondialdehyde (MDA), and reactive oxygen species (ROS). Our meta-analysis showed that arsenic exposure generally suppressed measured levels of the antioxidants, SOD, CAT, GSH, GPx, GST, and GR, but increased levels of the oxidants, GSSG, MDA, and ROS. Arsenic valence was important and GR and MDA levels increased to a significantly (P < 0.05) greater extent upon exposure to As3+ than to As5+. Other factors that contributed to a greater overall oxidative effect from arsenic exposure included intervention time, intervention method, dosage, age of animals, and the sample source from which the indexes were estimated. Our meta-analysis effectively summarized a wide range of studies and detected a positive relationship between arsenic exposure and oxidative damage. These data provide a scientific basis for the prevention and treatment of arsenic poisoning. PMID- 27498812 TI - Scalariform-to-simple transition in vessel perforation plates triggered by differences in climate during the evolution of Adoxaceae. AB - BACKGROUND AND AIMS: Angiosperms with simple vessel perforations have evolved many times independently of species having scalariform perforations, but detailed studies to understand why these transitions in wood evolution have happened are lacking. We focus on the striking difference in wood anatomy between two closely related genera of Adoxaceae, Viburnum and Sambucus, and link the anatomical divergence with climatic and physiological insights. METHODS: After performing wood anatomical observations, we used a molecular phylogenetic framework to estimate divergence times for 127 Adoxaceae species. The conditions under which the genera diversified were estimated using ancestral area reconstruction and optimization of ancestral climates, and xylem-specific conductivity measurements were performed. KEY RESULTS: Viburnum, characterized by scalariform vessel perforations (ancestral), diversified earlier than Sambucus, having simple perforations (derived). Ancestral climate reconstruction analyses point to cold temperate preference for Viburnum and warm temperate for Sambucus This is reflected in the xylem-specific conductivity rates of the co-occurring species investigated, showing that Viburnum lantana has rates much lower than Sambucus nigra CONCLUSIONS: The lack of selective pressure for high conductive efficiency during early diversification of Viburnum and the potentially adaptive value of scalariform perforations in frost-prone cold temperate climates have led to retention of the ancestral vessel perforation type, while higher temperatures during early diversification of Sambucus have triggered the evolution of simple vessel perforations, allowing more efficient long-distance water transport. PMID- 27498814 TI - Optimal multibipolar parameters should overcome heat-sink effect. PMID- 27498813 TI - The Impact of Carbapenem-Resistant Enterobacteriaceae Type on Clinical Outcomes After the Recovery of This Organism From Urine of Critically Ill Patients. PMID- 27498815 TI - Static and dynamic single leg postural control performance during dual-task paradigms. AB - Combining dynamic postural control assessments and cognitive tasks may give clinicians a more accurate indication of postural control under sport-like conditions compared to single-task assessments. We examined postural control, cognitive and squatting performance of healthy individuals during static and dynamic postural control assessments in single- and dual-task paradigms. Thirty participants (female = 22, male = 8; age = 20.8 +/- 1.6 years, height = 157.9 +/- 13.0 cm, mass = 67.8 +/- 20.6 kg) completed single-leg stance and single-leg squat assessments on a force plate individually (single-task) and concurrently (dual-task) with two cognitive assessments, a modified Stroop test and the Brooks Spatial Memory Test. Outcomes included centre of pressure speed, 95% confidence ellipse, squat depth and speed and cognitive test measures (percentage of correct answers and reaction time). Postural control performance varied between postural control assessments and testing paradigms. Participants did not squat as deep and squatted slower (P < 0.001) during dual-task paradigms (<=12.69 +/- 3.4 cm squat depth, <=16.20 +/- 4.6 cm . s-1 squat speed) compared to single-task paradigms (14.57 +/- 3.6 cm squat depth, 19.65 +/- 5.5 cm . s-1 squat speed). The percentage of correct answers did not change across testing conditions, but Stroop reaction time (725.81 +/- 59.2 ms; F2,58 = 7.725, P = 0.001) was slowest during single-leg squats compared to baseline (691.64 +/- 80.1 ms; P = 0.038) and single-task paradigms (681.33 +/- 51.5 ms; P < 0.001). Dynamic dual-task assessments may be more challenging to the postural control system and may better represent postural control performance during dynamic activities. PMID- 27498816 TI - A case of Parkinson's disease following dystonia. AB - Parkinsonism and dystonia are both disorders of the extrapyramidal motor system, and some patients exhibit a complex of the two symptoms. Although several reports have referred to the coexistence of these disorders as parkinsonian disorders with dystonia, in the majority of cases, dystonia appeared after parkinsonism. DAT-scan is useful for the early diagnosis of Parkinson's disease (PD) and other types of parkinsonism such as dementia with Lewy bodies. This case report describes a 67-year old woman diagnosed with axial dystonia without parkinsonism 6 years previously, which had worsened despite treatment with Botulinum toxin injections, and hindered the patient's gait. The patient visited the hospital because of gait disturbances and DAT-scan showed a levodopa transducer decrease in the putamen. A few weeks later, she was re-admitted to hospital and exhibited Parkinsonism. Levodopa improved the gait disturbances but axial dystonia was unchanged, and a clinical diagnosis of PD was made. In the authors' opinion, this was a rare case of parkinsonian disorders with dystonia, characterized by the development of PD after dystonia. DAT-scan may be helpful for the diagnosis of patients with parkinsonian disorders with dystonia. PMID- 27498817 TI - A dural arteriovenous fistula detected during the chronic phase of cerebral venous sinus thrombosis. AB - A 47-year-old woman developed a headache and tinnitus in her right ear followed by sudden-onset left hemiparesis. She had no history of trauma or thrombophilia. Arteriography showed an occlusion of the superior sagittal sinus, and a stenosis of the right transverse sinus. She was treated with anticoagulants; thereafter her deficits and sinus thrombosis immediately improved. However, 7 months after the onset, she noticed tinnitus in her left ear. Arteriography showed a dural arteriovenous fistula extending from the left occipital artery to the left transverse and sigmoid sinus, but no recurrence of the cerebral venous sinus thrombosis. After manual compression of the left occipital artery was initiated, the tinnitus and dural arteriovenous fistula did not worsen. A dural arteriovenous fistula may be detected in patients with cerebral venous sinus thrombosis during the chronic phase. PMID- 27498818 TI - A case of possible paraneoplastic neurological syndrome presenting as multiple cranial nerve palsies associated with gallbladder cancer. AB - We report the case of a patient who had developed multiple cranial nerve palsies in the course of possible paraneoplastic neurological syndrome (PNS) associated with gallbladder cancer. Twelve days prior to visiting our hospital, a 69-year old man began experiencing neurological symptoms, beginning with diplopia and progressing to ptosis of the left palpebra and subsequent complete closure of the eye within 8 days. Results of the initial medical examination indicated paresis of left oculomotor (III) and abducens (VI) nerves. MRI of the brain revealed no focal lesion that could have resulted in compression of the affected nerves, while further examination ruled out diabetes mellitus, infection, vasculitis, and other systemic autoimmune diseases as potential causes. Gadolinium-enhanced MRI revealed high intensity located in the oculomotor nerves, and steroid pulse therapy was performed based on the assumption of inflammatory diseases. Although slight improvement was observed with respect to the left extraocular paresis, subsequent emergence of bilateral facial nerve (VII) palsy, right abducens nerve palsy, and right oculomotor nerve palsy occurred in succession. PET/CT performed under suspicion of PNS, confirmed the presence of gallbladder cancer. Surgical extirpation of the cancer occurred 3 months following the appearance of left oculomotor paralysis, after which the patient underwent postoperative chemotherapy. All cranial nerve palsies resolved within 2 months after the operation, and both cancer and PNS have shown no recurrence for over 5 years. Pathological examination of the resected tumor revealed well-differentiated tubular adenocarcinoma showing some signs of epithelial-mesenchymal transition, typically an indicator of a poor prognosis. Nevertheless, lymph node metastasis did not progress beyond N2, and the cancer was completely removed by lymph node dissection. Therefore, the presence of multiple cranial palsies in this patient led to early detection of the asymptomatic gallbladder cancer and immediate administration of life-saving treatment. PMID- 27498820 TI - Anti-obesity effects of boiled tuna extract in mice with obesity induced by a high-fat diet. AB - The aim of this study was to examine the anti-obesity effects of boiled tuna extract in C57BL/6N mice with obesity induced by a high-fat diet (HFD). We determined the anti-obesity effects of boiled tuna extract (100, 200, or 400 mg/kg) on the progression of HFD-induced obesity for 10 weeks. The mice were divided into 5 groups as follows: the normal diet (ND) group (n=10); the HFD group (n=10); the mice fed HFD and 100 mg/kg boiled tuna extract group (n=10); those fed a HFD and 200 mg/kg boiled tuna extract group (n=10); and those fed a HFD and 400 mg/kg boiled tuna extract group (n=10). Changes in body weight, fat content, serum lipid levels and lipogenic enzyme levels were measured. The consumption of boiled tuna extract lowered epididymal tissue weight and exerted anti-obesity effects, as reflected by the serum glucose, triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), insulin and leptin levels. In addition, we demonstrated changes in liver adipogenic- and lipogenic-related protein expression by western blot analysis. Boiled tuna extract downregulated the levels of the CCAAT/enhancer-binding protein alpha, beta and delta (C/EBPalpha, beta, delta), and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) adipocyte marker genes. Boiled tuna extract also attenuated adipogenic and lipogenic gene expression, namely the levels of fatty acid synthase (FAS), lipoprotein lipase (LPL), acetyl-CoA carboxylase (ACC), glucose transporter type 4 (Glut4) and phosphorylated adenosine monophosphate-activated protein kinase alpha and beta (AMPKalpha, beta) in a dose-dependent manner. Moreover, the consumption of boiled tuna extract restored the levels of superoxide dismutase (SOD), catalase (CAT), glutamic oxaloacetic transaminase (GOT), glutamic-pyruvate transaminase (GPT), aspartate transaminase (AST) and alanine transaminase (ALT) to those of the control group. These results suggest that boiled tuna extract attenuates the progression of obesity by stimulating fatty acid oxidation through the upregulation of AMPK genes, as well as by inhibiting the synthesis of adipogenic and lipogenic enzymes. These characteristics of boiled tuna extract highlight its potential anti-obesity effects. PMID- 27498819 TI - Miniaturizing VEGF: Peptides mimicking the discontinuous VEGF receptor-binding site modulate the angiogenic response. AB - The angiogenic properties of VEGF are mediated through the binding of VEGF to its receptor VEGFR2. The VEGF/VEGFR interface is constituted by a discontinuous binding region distributed on both VEGF monomers. We attempted to reproduce this discontinuous binding site by covalently linking into a single molecular entity two VEGF segments involved in receptor recognition. We designed and synthesized by chemical ligation a set of peptides differing in length and flexibility of the molecular linker joining the two VEGF segments. The biological activity of the peptides was characterized in vitro and in vivo showing a VEGF-like activity. The most biologically active mini-VEGF was further analyzed by NMR to determine the atomic details of its interaction with the receptor. PMID- 27498821 TI - Lack of association between cytotoxic T-lymphocyte antigen-4 gene polymorphisms and lymphoid malignancy risk: evidence from a meta-analysis. AB - Cytotoxic T-lymphocyte antigen-4 (CTLA-4) polymorphisms have been associated with susceptibility to lymphoid malignancies. However, results from the published single studies are inconsistent. Therefore, the present meta-analysis was conducted to get a more accurate estimation of the relationship between CTLA-4 gene polymorphisms and the lymphoid malignancy risk. We identified nine independent studies accounting for 3090 subjects up to January 30, 2016. Summary odds ratios (OR) and 95 % confidence intervals (CI) were used to evaluate the risk of lymphoid malignancies. Overall, no significant association was found between +49A/G (rs231775), -318C/T (rs5742909), and +6230A/G (rs3087243) CTLA-4 gene polymorphisms and lymphoid malignancies. Furthermore, ethnicity (Asian and Caucasian) and histopathology subgroup analyses (non-Hodgkin's lymphoma) also failed to detect an association between the studied polymorphisms and lymphoid malignancy risk. Our study shows that common CTLA-4 gene polymorphisms may not contribute to lymphoid malignancy susceptibility based on the current evidence. PMID- 27498822 TI - Rod-like CuMnOx transformed from mixed oxide particles by alkaline hydrothermal treatment as a novel catalyst for catalytic combustion of toluene. AB - Rod-like copper manganese mixed oxides (CuMnx-NR) have been synthesized from copper manganese mixed oxide particles by sodium hydroxide hydrothermal treatment, and a higher BET surface area of 221 m(2) g(-1) is obtained on the nanorod-like sample, which exhibits superior catalytic activity toward toluene combustion at 210 degrees C due to the increase in its oxygen mobility of the chemisorbed oxygen species as well as the increase in surface concentrations of higher valance cations, Cu(2+), Mn(3+) and Mn(4+), in the samples. PMID- 27498823 TI - Pedobacterpsychrotolerans sp. nov., isolated from soil. AB - A Gram-stain-negative, non-motile, light-pink-pigmented, aerobic, rod-shaped bacterium, designated V5RDT, was isolated from soil of Damxung county in the Qinghai-Tibetan Plateau. Strain V5RDT grew luxuriously at 10 degrees C, at pH 9.0 and in the presence of 1 % NaCl (w/v). Phylogenetic analysis of 16S rRNA gene sequences placed strain V5RDT in the genus Pedobacter and found that it was most closely related to Pedobacter alluvionis DSM 19624T (97.3 %), Pedobacter ginsenosidimutans JCM 16721T (96.84 %), Pedobacter agri DSM 19486T (96.28 %), Pedobacter roseus JCM 13399T (96.22 %), Pedobacter sandarakinus KCTC 12559T (95.92 %) and Pedobacter borealis DSM 19626T (95.85 %). The G+C content of the genomic DNA of the type strain V5RDT was 37.40 mol%. DNA-DNA relatedness for the type strain V5RDT with respect to its closest phylogenetic relative, P. alluvionis DSM 19624T, was 62.5+/-1.7 %. The polar lipid profile of the strain consisted of phosphatidylethanolamine, one unidentified aminolipid, one unidentified glycolipid and two unidentified polar lipids. Menaquinone MK-7 was the predominant respiratory quinone, and summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), iso-C15 : 0 and iso-C17 : 0 3-OH were the major fatty acids. With respect to phenotypic characteristics, biochemical properties and phylogenetic inference, strain V5RDT represents a novel species of the genus Pedobacter, for which the name Pedobacter psychrotolerans sp. nov is proposed. The type strain is V5RDT (=CGMCC 1.15644T=DSM 103236T). PMID- 27498825 TI - Surface area-dependent second harmonic generation from silver nanorods. AB - The nonlinear optical (NLO) properties of metallic nanoparticles strongly depend on their size and shape. Metallic gold nanorods have already been widely investigated, but other noble metals could also be used for nanorod fabrication towards applications in photonics. Here we report on the synthesis and NLO characterization of silver nanorods (AgNRs) with controllable localized surface plasmon resonance. We have implemented an original, one-step and seedless synthesis method, based on a spontaneous particle growth technique in the presence of polyvinylpyrrolidone (PVP) as a capping agent. Colloidal solutions of AgNRs with various aspect ratios (5.0; 6.3; 7.5; 8.2 and 9.7) have been obtained and characterized using Harmonic light scattering (HLS) at 1064 nm, in order to investigate their quadratic NLO properties. From HLS experiments, we demonstrate that hyperpolarizability (beta) values of AgNRs display a strong dependence on their surface area. PMID- 27498824 TI - Evaluation of the effect of narrative writing on the stress sources of the parents of preterm neonates admitted to the NICU. AB - OBJECTIVE: Identification of the nurses' and families' understanding of the stresses in the facilitates nursing interventions and increases parental satisfaction. MATERIAL AND METHODS: The quasiexperimental study with pretest and posttest was administered to a sample size of 70 mothers with preterm neonates hospitalized in the NICUs of two teaching hospitals of Tehran University of Medical during 6 months. The Parental Stressor Scale (PSS) was used. The data were analyzed using descriptive and analytical statistical methods. RESULTS: Evaluation of the differences in the domains of the questionnaire between the 3rd and 10th day of admission using a multivariate analysis showed that narrative writing had significant effects on all three domains (Roys' largest root = 2.141, F = 47.11, p values < 0.001). The results showed that the highest stress reduction was observed in Infant Behavior and Appearance (-11.847) followed by Sights and Sounds of the Unit (-11.352) while the lowest stress reduction was observed in the Parental Role Alterations (-6.149) in the intervention group, while the control mothers experienced a stress increase in all domains. CONCLUSION: According to the findings, narrative writing may be considered an efficient supportive intervention to reduce the maternal stress Infant behavior and appearance in the NICUs. However, more research is needed to justify its implementation. PMID- 27498826 TI - Comparison of the live-attenuated Japanese encephalitis vaccine SA14-14-2 strain with its pre-attenuated virulent parent SA14 strain: similarities and differences in vitro and in vivo. AB - Japanese encephalitis virus (JEV) is the main cause of acute viral encephalitis, primarily affecting children and young adults in the Asia-Pacific region. JEV is a vaccine-preventable pathogen, with four types of JE vaccine licensed in different regions of the world. To date, the most common JEV strain used in vaccine development and production is SA14-14-2, an attenuated strain derived from its wild-type parental strain SA14. In this study, we directly compared the phenotypic and genotypic characteristics of SA14 and SA14-14-2 to determine the biological and genetic properties associated with their differential virulence. In susceptible BHK-21 cells, SA14-14-2 grew slightly more slowly and formed smaller plaques than SA14, but unlike SA14, it showed almost no expression of the viral protein NS1', the product of a conserved predicted RNA pseudoknot-mediated ribosomal frameshift. In weanling ICR mice, SA14-14-2 was highly attenuated in terms of both neuroinvasiveness and neurovirulence, with its median lethal doses invariably over five logs higher than those of SA14 when inoculated intramuscularly and intracerebrally. Interestingly, the neurovirulence of SA14-14 2 was dependent on mouse age, with the 1- to 7-day-old mice being highly susceptible and the 14- to 21-day-old mice becoming resistant to intracerebral inoculation. At the genome level, SA14-14-2 differed from SA14 by 57 nucleotides, including one silent G-to-A substitution at position 3599 within the predicted RNA pseudoknot for NS1' synthesis; of the 57 differences, 25 resulted in amino acid substitutions. Our data pave the way for the development of new genetically modified JE vaccines. PMID- 27498827 TI - Microbacterium diaminobutyricum sp. nov., isolated from Halimione portulacoides, which contains diaminobutyric acid in its cell wall, and emended description of the genus Microbacterium. AB - Three actinobacterial strains were isolated from roots of the salt-marsh plant Halimione portulacoides collected in Ria de Aveiro, Portugal. Molecular typing using enterobacterial repetitive intergenic consensus ERIC-PCR fingerprinting showed the strains to be highly similar. Phylogenetic analyses based on the 16S rRNA gene sequence and multilocus sequence analysis (MLSA) using gyrB, rpoB, recA and ppk and 16S rRNA genes sequences showed that the strains represented a member of the genus Microbacterium, with Microbacterium lacus DSM 18910T as the closest phylogenetic relative. DNA-DNA hybridization between strain RZ63T and its closest relative was below 70 %, supporting the hypothesis that it represented a distinct genomic species. Chemotaxonomic analyses of the novel strains and their DNA G+C contents confirmed their affiliation to the genus Microbacterium, however, the peptidoglycan of RZ63T contained diaminobutyric acid as the diagnostic diamino acid. In addition, physiological and fatty acid analyses revealed differences between these strains and their phylogenetic relatives, reinforcing their status as a distinct species. Based on the physiological, genetic and chemotaxonomic characterisation it is proposed that the strains studied represent a novel species of the genus Microbacterium for which the name Microbacterium diaminobutyricum sp. nov. is proposed (type strain RZ63T=DSM 27101T=CECT 8355T). PMID- 27498829 TI - Sphingobacterium jejuense sp. nov., with ginsenoside-converting activity, isolated from compost. AB - A Gram-stain-negative, strictly aerobic, non-motile, light yellow, short-rod bacterium (designated GJ30-7T) isolated from compost, was characterized using a polyphasic approach, in order to clarify its taxonomic position. Strain GJ30-7T was observed to grow optimally at 30 degrees C and at pH 7.0 on R2A agar medium. Strain Gsoil GJ30-7T possessed beta-glucosidase activity, which was responsible for its ability to transform ginsenosides Rb1 and Rc (the two main active components of ginseng) to ginsenoside F2. Phylogenetic analysis, based on 16S rRNA gene sequence similarities, indicated that GJ30-7T belongs to the genus Sphingobacterium of the family Sphingobacteriaceae and was most closely related to Sphingobacterium yanglingense JCM 30166T (92.6 %), Sphingobacterium psychroaquaticum KACC 18188T (92.6 %), and Sphingobacterium thermophilum KCTC 23708T (92.0 %). The DNA G+C content was 43 mol% and MK-7 was the major isoprenoid quinone. The main polar lipids were phosphatidylethanolamine, one unidentified phospolipid and one unknown polar lipid. In contrast to standard and reference strains, unidentified sphingolipid was also present. The predominant fatty acids of strain GJ30-7T were iso-C15 : 0, iso-C17 : 0 3-OH, C16 : 1omega7c and/or C16 : 1omega6c (summed feature 3) and iso-C17 : 1omega9c and/or C16 : 0 10 methyl (summed feature 9), supporting the affiliation of strain GJ30-7T to the genus Sphingobacterium. However, strain GJ30-7T could be distinguished genotypically and phenotypically from species of the genus Sphingobacterium with validly published names. The novel isolate therefore represents a novel species, for which the name Sphingobacterium jejuense sp. nov. is proposed, with the type strain GJ30-7T (=KACC 18625T=JCM 30948T). PMID- 27498830 TI - One-pot polyol synthesis of highly monodisperse short green silver nanorods. AB - Green silver nanorods (Ag NRs) of a low aspect ratio (2.8) have been produced in high yields via an optimized, simple, and robust one-pot polyol method in the presence of tannic acid, which favors the nucleation of decahedral seeds needed for the production of monodisperse Ag NRs. These Ag NRs were further used as sacrificial templates to produce Au hollow nanostructures via galvanic replacement reaction with HAuCl4 at room temperature. PMID- 27498831 TI - Antimicrobial evaluation of selected naturally occurring oxyprenylated secondary metabolites. AB - This study tested the antimicrobial activity of eight selected naturally occurring oxyprenylated secondary metabolites against Staphylococcus aureus ATCC 29213, S. epidermidis ATCC 35984, Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027 and Candida albicans ATCC 10231. Results showed a moderate antimicrobial activity. The most active compounds were 3-(4-geranyloxyphenyl)-1 ethanol (4) and 3-(4-isopentenyloxyphenyl)-1-propanol (5) that were tested on mature and in-formation biofilms of all micro-organisms, moreover the cytotoxic activity was evaluated. Except for S. epidermidis, both compounds reduced significantly (p < 0.05) the microbial biofilm formation at 1/2 MIC and 1/4 MIC, in particular, compounds 4 and 5 at each concentration, inhibited E. coli biofilm formation to a greater extent, the biofilm formation was never more than 44% in respect to the control, moreover both compounds showed a low cytotoxic effect. Oxyprenylated derivatives may be of great interest for the development of novel antimicrobial therapeutic strategies and the synthesis of semi-synthetic analogues with anti-biofilm efficacy. PMID- 27498832 TI - Antifungal and phytotoxic activity of essential oil from root of Senecio amplexicaulis Kunth. (Asteraceae) growing wild in high altitude-Himalayan region. AB - This work was aimed to evaluate the essential oil from root of medicinally important plant Senecio amplexicaulis for chemical composition, antifungal and phytotoxic activity. The chemical composition analysed by GC/GC-MS showed the presence of monoterpene hydrocarbons in high percentage with marker compounds as alpha-phellandrene (48.57%), o-cymene (16.80%) and beta-ocimene (7.61%). The essential oil exhibited significant antifungal activity against five phytopathogenic fungi, Sclerotium rolfsii, Macrophomina phaseolina, Rhizoctonia solani, Pythium debaryanum and Fusarium oxysporum. The oil demonstrated remarkable phytotoxic activity in tested concentration and significant reduction in seed germination percentage of Phalaris minor and Triticum aestivum at higher concentrations. The roots essential oil showed high yield for one of its marker compound (alpha-phellandrene) which makes it important natural source of this compound. PMID- 27498833 TI - Phenolic constituents from Wissadula periplocifolia (L.) C. Presl. and anti inflammatory activity of 7,4'-di-O-methylisoscutellarein. AB - This study reports the first phenolics from Wissadula genus (Malvaceae) and the anti-inflammatory activity of 7,4'-di-O-methylisoscutellarein. Using chromatographic methods, five phenolic compounds were isolated from aerial parts of Wissadula periplocifolia (L.) C. Presl. The compounds were identified as 4 hydroxybenzoic acid, 3-hydroxybenzoic acid, trans-cinnamic acid, tamgermanetin and 7,4'-di-O-methylisoscutellarein using spectroscopic methods. The flavone 7,4' di-O-methylisoscutellarein showed anti-inflammatory activity by inhibiting neutrophils recruitment in a mice model of pleurisy and by decreasing significantly the production of cytokines IL-1beta and TNF-alpha. PMID- 27498834 TI - miR-205 suppresses cell proliferation, invasion, and metastasis via regulation of the PTEN/AKT pathway in renal cell carcinoma. AB - The present study aimed to determine the importance of microRNA-205 (miR-205) in the proliferation, apoptosis, invasion and metastasis of renal cell carcinoma (RCC) cells and the underlying molecular mechanisms. Reverse transcription polymerase chain reaction was used to quantify the expression levels of miR-205 in RCC tissue, normal tissue adjacent to carcinoma, RCC cells and normal renal cells. It was determined that the expression levels of miR-205 in RCC tissue and cells were reduced compared with those in normal tissue and renal cells. miR-205 mimics and the negative control were prepared and transfected into RCC cells. Cell viability and apoptosis were investigated using methyl thiazolyl tetrazolium assay and Annexin V-fluorescein isothiocyanate/propidium iodide staining, respectively. Cell migration and invasion were evaluated with Transwell assays. The protein expression levels of E2F transcription factor 1 (E2F1), B-cell lymphoma-2 (Bcl-2), E-cadherin, vimentin, phosphatase and tensin homolog (PTEN) and phosphorylated AKT serine/threonine kinase 1 (p-AKT) were determined with western blot analysis. It was revealed that miR-205 promoted the apoptosis of RCC cells and suppressed their proliferation, metastasis and invasion compared with the negative control. The expression levels of E2F1, Bcl-2, vimentin and p-AKT were downregulated compared with the negative control. The expression levels of E cadherin and PTEN were upregulated in the cells transfected with miR-205 mimics compared with the negative control group. Therefore, it was concluded that miR 205 suppressed cell proliferation, invasion, and metastasis in RCC cells via regulation of the PTEN/AKT signaling pathway. The present study may contribute to future miRNA-based RCC therapy. PMID- 27498835 TI - Challenges in the Standardization of Autoantibody Testing: a Comprehensive Review. AB - Standardization and harmonization are complementary tools to achieve higher testing quality in laboratory medicine. Both are of great relevance and are strongly needed in autoimmune diagnostics, due to the impressive advance in basic research and technological development observed in this diagnostic field in recent years that has led to the introduction of many new tests and new analytical methods. It is, therefore, essential that this strong innovative thrust is translated into clinical practice in a coordinated way to avoid confusion and the risk of potentially harmful errors for the patient. However, while standardization of antibody assays is a very complex task, harmonization of procedures and behaviors is a more feasible target and should necessarily include all the phases of the total testing process-in the pre-analytical phase, appropriateness of test requests, harmonization of autoantibody terminology, and adoption of uniform nomenclature for laboratory tests; in the analytical phase, harmonization of measurements, and sharing of test profiles and diagnostic algorithms; and in the post-analytical phase, harmonization of data reporting, and criteria for interpreting immunoserological results, especially harmonization of units, reference intervals, decision limits, and definition and notification of critical values. We here provide and discuss some examples of harmonization initiatives related to anti-nuclear antibodies, TSH receptor, and anti-thyroid peroxidase antibodies and to antibodies associated with autoimmune hepatitis and with celiac disease. These initiatives could be the starting steps to achieve a wider consensus and a closer interaction among stakeholders in the path of autoimmune diagnostics harmonization to enhance clinical effectiveness and provide greater patient safety. PMID- 27498836 TI - Mucilaginibacter fluminis sp. nov., isolated from a freshwater river. AB - A bacterial strain, designated TTM-2T, was isolated from a water sample taken from the Caohu River in Taiwan and characterized using a polyphasic taxonomic approach. Cells of strain TTM-2T were Gram-stain-negative, aerobic, poly-beta hydroxybutyrate-accumulating, non-motile, rod-shaped and covered by large capsules; they formed light pink colonies. Growth occurred at 15-37 degrees C (optimum, 30 degrees C), at pH 4-8 (optimum, pH 6) and with 0-1 % (w/v) NaCl (optimum, 0.5 %, w/v). Phylogenetic analyses, based on 16S rRNA gene sequences, showed that strain TTM-2T belonged to the genus Mucilaginibacter. The sequence similarities between the 16S rRNA genes of strain TTM-2T and the type strains of other species of the genus Mucilaginibacter ranged from 93.6 to 97.4 %. The closest relatives of strain TTM-2T were Mucilaginibactersoli R9-65T (97.4 %) and Mucilaginibactedefluvii A5T (97.1 %). The predominant fatty acids were iso-C15 : 0 (36.9 %) and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c; 33.7 %). The polar lipid profile consisted of phosphatidylethanolamine and several uncharacterized aminophospholipids and phospholipids. The major isoprenoid quinone was MK-7. The DNA G+C content of the genomic DNA was 46.6 mol%. The DNA DNA relatedness of strain TTM-2T with respect to species of the genus Mucilaginibacterwith validly published names was less than 70 %. On the basis of the phylogenetic inference and phenotypic data, strain TTM-2T should be classified as a novel species, for which the name Mucilaginibacter fluminis sp. nov. is proposed. The type strain is TTM-2T (=BCRC 80785T=LMG 28455T=KCTC 42274T). PMID- 27498837 TI - Simultaneous neutron diffraction and microwave dielectric characterisation of ammine materials - a non-destructive, non-contact characterisation tool for determining ammonia content in solids. AB - We have investigated ammonia adsorption in group two halides (MgI2 and CaBr2) using custom-built apparatus that permits simultaneous neutron diffraction, microwave dielectric characterisation and out-gas mass spectroscopy of solid state materials during ammonia adsorption. Deuterated ammonia was flowed over the sample and the uptake - as measured by mass flow meters, mass spectroscopy and structure - compared with the change in dielectric constant. An excellent correlation between ammonia content and dielectric property was observed and, when linked to diffraction, mass flow and mass spectroscopy data, could be used to determine the amount of ammonia present within the solid. The combination of these techniques could also be used to differentiate physisorbed and metal coordinated ammonia and explain subtleties in the observed structural transformations. PMID- 27498838 TI - All-Integrated Bifunctional Separator for Li Dendrite Detection via Novel Solution Synthesis of a Thermostable Polyimide Separator. AB - Safe operation is crucial for lithium (Li) batteries, and therefore, developing separators with dendrite-detection function is of great scientific and technological interest. However, challenges have been encountered when integrating the function into commercial polyolefin separators. Among all polymer candidates, polyimides (PIs) are prominent due to their good thermal/mechanical stability and electrolyte wettability. Nevertheless, it is still a challenge to efficiently synthesize PI separators, let alone integrate additional functions. In this work, a novel yet facile solution synthesis was developed to fabricate a nanoporous PI separator. Specifically, recyclable LiBr was utilized as the template for nanopores creation while the polymer was processed at the intermediate stage. This method proves not only to be a facile synthesis with basic lab facility but also to have promising potential for low-cost industrial production. The as-synthesized PI separator exhibited excellent thermal/mechanical stability and electrolyte wettability, the latter of which further improves the ionic conductivity and thus battery rate capability. Notably, stable full-cell cycling for over 200 cycles with a PI separator was further achieved. Based on this method, the fabrication of an all-integrated PI/Cu/PI bifunctional separator for dendrite detection can be fulfilled. The as fabricated all-integrated separators prove efficient as early alarms of Li penetration, opening up the opportunity for safer battery design by separator engineering. PMID- 27498841 TI - Roles of nuclear trafficking in infection by cytoplasmic negative-strand RNA viruses: paramyxoviruses and beyond. AB - Genome replication and virion production by most negative-sense RNA viruses (NSVs) occurs exclusively in the cytoplasm, but many NSV-expressed proteins undergo active nucleocytoplasmic trafficking via signals that exploit cellular nuclear transport pathways. Nuclear trafficking has been reported both for NSV accessory proteins (including isoforms of the rabies virus phosphoprotein, and V, W and C proteins of paramyxoviruses) and for structural proteins. Trafficking of the former is thought to enable accessory functions in viral modulation of antiviral responses including the type I IFN system, but the intranuclear roles of structural proteins such as nucleocapsid and matrix proteins, which have critical roles in extranuclear replication and viral assembly, are less clear. Nevertheless, nuclear trafficking of matrix protein has been reported to be critical for efficient production of Nipah virus and Respiratory syncytial virus, and nuclear localization of nucleocapsid protein of several morbilliviruses has been linked to mechanisms of immune evasion. Together, these data point to the nucleus as a significant host interface for viral proteins during infection by NSVs with otherwise cytoplasmic life cycles. Importantly, several lines of evidence now suggest that nuclear trafficking of these proteins may be critical to pathogenesis and thus could provide new targets for vaccine development and antiviral therapies. PMID- 27498842 TI - Assessment of the Dominance Level of the R81T Target Resistance to Two Neonicotinoid Insecticides in Myzus persicae (Hemiptera: Aphididae). AB - Myzus persicae (Sulzer, 1776), a major crop pest worldwide, displays insecticide resistance to most molecules. The R81T substitution on the beta1 subunit of nicotinic receptors of acetylcholine (nAChR) confers target site resistance to neonicotinoids and is widespread in aphid populations colonizing peach tree orchards in Southern Europe. But the impact of this resistance in the field, as well as ways to optimize its management, depends largely on the dominance level of the R81T mutation. In this study, we measured by in vitro assays the response of R81T mutation to two neonicotinoids (imidacloprid and thiacloprid) in 23 M. persicae clones with different resistance genotypes in order to assess the dominance status of this allele. In this study, all homozygous clones for the R81T mutation (genotype 81(TT)) showed a much higher level of resistance to both active substances than other clones. The heterozygous clones 81(RT) displayed a slightly higher level of resistance than wild homozygous, though resistance phenotypes against both neonicotinoids in these two genotypes were overlapping. A great variation of resistance level was found within these two latter clones' categories. The dominance level of insecticide resistance (DLC) strongly suggested that the mutant allele 81T is semirecessive (the wild 81R allele being rather dominant) for both insecticide molecules under test. Mean DLC values were 0.316 for imidacloprid and 0.351 for thiacloprid. Cross-resistance was shown between imidacloprid and thiacloprid. This partial recessivity is valuable information to broaden the knowledge on neonicotinoid resistance, a prerequisite for devising adapted management strategies against insecticide-resistant populations of M. persicae. PMID- 27498840 TI - SPARC overexpression combined with radiation retards angiogenesis by suppressing VEGF-A via miR-410 in human neuroblastoma cells. AB - Neuroblastoma (NB) is the most common extra-cranial solid tumor in children and despite aggressive therapy survival rates remain low. One of the contributing factors for low survival rates is aggressive tumor angiogenesis, which is known to increase due to radiation, one of the standard therapies for neuroblastoma. Therefore, targeting tumor angiogenesis can be a viable add-on therapy for the treatment of neuroblastomas. In the present study, we demonstrate that overexpression of secreted protein acidic and rich in cysteine (SPARC) suppresses radiation induced angiogenesis in SK-N-BE(2) and NB1691 neuroblastoma cells. We observed that overexpression of SPARC in SK-N-BE(2) and NB1691 cells reduced radiation induced angiogenesis in an in vivo mouse dorsal skin model and an ex vivo chicken CAM (chorioallantoic-membrane) model and also reduced tumor size in subcutaneous mouse tumor models of NB. We also observed that SPARC overexpression reduces VEGF-A expression, in SK-N-BE(2) and NB1691 NB cells via miR-410, a VEGF A targeting microRNA. SPARC overexpression alone or in combination with miR-410 and radiation was shown to be effective at reducing angiogenesis. Moreover, addition of miR-410 inhibitors reversed SPARC mediated inhibition of VEGF-A in NB1691 cells but not in SK-N-BE(2) NB cells. In conclusion, the present study demonstrates that the overexpression of SPARC in combination with radiation reduced tumor angiogenesis by downregulating VEGF-A via miR-410. PMID- 27498839 TI - Local and global regulation of transcription initiation in bacteria. AB - Gene expression in bacteria relies on promoter recognition by the DNA-dependent RNA polymerase and subsequent transcription initiation. Bacterial cells are able to tune their transcriptional programmes to changing environments, through numerous mechanisms that regulate the activity of RNA polymerase, or change the set of promoters to which the RNA polymerase can bind. In this Review, we outline our current understanding of the different factors that direct the regulation of transcription initiation in bacteria, whether by interacting with promoters, with RNA polymerase or with both, and we discuss the diverse molecular mechanisms that are used by these factors to regulate gene expression. PMID- 27498843 TI - Approved oncology drugs lack in vivo activity against Trichuris muris despite in vitro activity. AB - Infections with soil-transmitted helminths (STHs) are considered among the most persistent global health problems. The few available drugs have limitations including low efficacy against Trichuris trichiura infections. As a starting point toward drug repositioning, we studied a set of FDA-approved oncology drugs for activity against Trichuris muris since targets relevant to cancer therapy might have a function in helminth biology. Drugs were tested in vitro on the larval and adult stage of T. muris. Compounds active in vitro were tested in the T. muris mouse model at single oral dosages of 200-400 mg/kg. Of the 114 drugs tested in vitro, 12 showed activity against T. muris larvae (>80 % drug effect at 50 MUM). Ten of these drugs were also active on the adult worm stage (>80 % drug effect at 50 MUM), of which six revealed IC50 values between 1.8 and 5.0 MUM. Except for tamoxifen citrate, all in vitro active drugs were protein kinase inhibitors. None of the drugs tested in vivo showed efficacy, revealing worm burden reductions of 0-24 % and worm expulsion rates of 0-7.9 %. The promising in vitro activities of protein kinases could not be confirmed in vivo. Drug discovery against STH should be strengthened including the definition of compound progression criteria. Follow-up structure-activity relationship studies with modified compounds might be considered. PMID- 27498844 TI - The influence of high-heeled shoes on strain and tension force of the anterior talofibular ligament and plantar fascia during balanced standing and walking. AB - High-heeled shoes have the capability to alter the strain and tension of ligamentous structures between the foot and ankle, which may result in ankle instability. However, high-heeled shoes can also reduce the strain on plantar fascia, which may be beneficial for the treatment of plantar fasciitis. In this study, the influence of heel height on strain and tension force applied to the anterior talofibular ligament (ATL) and plantar fascia were investigated. A three dimensional finite element model of coupled foot-ankle-shoe complex was constructed. Four heel heights were studied in balanced standing: 0 in. (0cm), 1 in. (2.54cm), 2 in. (5.08cm), and 3 in. (7.62cm). A walking analysis was performed using 2-in. (5.08cm) high-heeled shoes. During balanced standing, the tension force on the ATL increased from 14.8N to 97.0N, with a six-fold increase in strain from 0 in. to 3 in. (0-7.62cm). The tension force and the average strain on the plantar fascia decreased from 151.0N (strain: 0.74%) to 59.6N (strain: 0.28%) when the heel height increased from 0 in. to 2 in. (0-5.08cm). When heel height reached 3 in. (7.62cm), the force and average strain increased to 278.3N (strain: 1.33%). The walking simulation showed that the fascia stretched out while the ATL loading decreased during push off. The simulation outcome demonstrated the influence of heel height on ATL alteration and plantar fascia strain, which implies risks for ankle injury and suggests guidance for the treatment of plantar fasciitis. PMID- 27498845 TI - Brevibacterium massiliense (Roux and Raoult 2009) is a later heterotypic synonym of Brevibacterium ravenspurgense (Mages, Frodl, Bernard and Funke 2009), using whole-genome sequence analysis as a comparative tool. AB - A patient strain derived from urine was found by 16S rRNA gene sequencing to be closely related (99.6 % identity) to sequences derived from both Brevibacterium ravenspurgense CCUG 56047T and Brevibacterium massilienseCCUG 53855T. Those species had been described during the same 11 month period in 2008-2009. Further characterization revealed that those isolates could not be readily distinguished from each other biochemically, by cellular fatty acids, antimicrobial susceptibility, MALDI-TOF MS, 16S rRNA gene sequencing or by whole-genome sequence (WGS) analyses. By WGS comparison, these isolates had an aerage nucleotide identity using blastn (ANIb) scores of 95.7 % or higher to each other, DNA G+C content in the range of 62.3 mol%-62.4 mol%, with genome sizes ranging from 2.28*106 to 2.41*106 bases. Based on these data, we propose that the name B. massiliense is a later heterotypic synonym of B. ravenspurgense and provide an emended description of B. ravenspurgense. PMID- 27498847 TI - Estimating fetal age: how accurate is it really? PMID- 27498846 TI - Physiological and Pharmacological Control of BAK, BAX, and Beyond. AB - Cellular commitment to the mitochondrial pathway of apoptosis is accomplished when proapoptotic B cell chronic lymphocytic leukemia/lymphoma (BCL)-2 proteins compromise mitochondrial integrity through the process of mitochondrial outer membrane permeabilization (MOMP). For nearly three decades, intensive efforts focused on the identification and interactions of two key proapoptotic BCL-2 proteins: BCL-2 antagonist killer (BAK) and BCL-2-associated X (BAX). Indeed, we now have critical insights into which BCL-2 proteins interact with BAK/BAX to either preserve survival or initiate MOMP. In contrast, while mitochondria are targeted by BAK/BAX, a molecular understanding of how these organelles govern BAK/BAX function remains less clear. Here, we integrate recent mechanistic insights of proapoptotic BCL-2 protein function in the context of mitochondrial environment, and discuss current and potential pharmacological opportunities to control MOMP in disease. PMID- 27498848 TI - Wenzhouxiangella sediminis sp. nov., isolated from coastal sediment. AB - A novel Gram-stain-negative, non-spore-forming, non-motile, facultatively anaerobic, rod-shaped strain, designated XDB06T, was isolated from coastal sediment of Xiaoshi Island, Weihai, China. Optimal growth occurred at 37 degrees C, pH 7.5 and with 4.0 % (w/v) NaCl. Q-8 was the sole respiratory quinone. The major cellular fatty acids in strain XDB06T were iso-C15 : 0 and iso-C16 : 0. The polar lipids of strain XDB06T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, two unidentified glycolipids and four unidentified phospholipids. The genomic DNA G+C content of the strain was 65.0 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain XDB06T clusters within the genus Wenzhouxiangella and is most closely related to Wenzhouxiangella. marina MCCC 1K00261T, with a 16S rRNA gene sequence similarity of 96.50 %. Based on data from the current polyphasic study, strain XDB06T represents a novel species of the genus Wenzhouxiangella, for which the name Wenzhouxiangella sediminis sp. nov. is proposed. The type strain is XDB06T (=KCTC 52041T=MCCC 1K02285T). PMID- 27498849 TI - Sediminibacterium aquarii sp. nov., isolated from sediment in a fishbowl. AB - A novel bacterial strain, designated AA5T, was isolated from sediment in a fishbowl. Cells were Gram-stain-negative, rod-shaped and strictly aerobic, showing gliding motility. Strain AA5T was able to grow at 15-37 degrees C, at pH 5.0-8.0 and in the absence of NaCl. 16S rRNA gene sequence analysis revealed that strain AA5T was most closely related to species in the genus Sediminibacterium, showing highest similarity to the type strain of S.ediminibacterium goheungense (96.6 %). Concordantly, a phylogenetic tree based on 16S rRNA gene sequences indicated that strain AA5T belongs to the genus Sediminibacterium. The DNA G+C content was 44.7 mol%. The major polar lipids were phosphatidylethanolamine, four unidentified aminolipids, two unknown aminophospholipids and four unidentified polar lipids. The only respiratory quinone of strain AA5T was menaquinone 7 (MK 7) and the major fatty acids (>5 % of the total) were iso-C15 : 0, iso-C15 : 1 G, iso-C16 : 0 3-OH, iso-C17 : 0 3-OH and iso-C15 : 0 3-OH. Based on data from this polyphasic study, strain AA5T represents a novel species, for which the name Sediminibacterium aquarii sp. nov. is proposed. The type strain is AA5T (=KACC 18509T=JCM 31013T). PMID- 27498851 TI - Multi-observable Uncertainty Relations in Product Form of Variances. AB - We investigate the product form uncertainty relations of variances for n (n >= 3) quantum observables. In particular, tight uncertainty relations satisfied by three observables has been derived, which is shown to be better than the ones derived from the strengthened Heisenberg and the generalized Schrodinger uncertainty relations, and some existing uncertainty relation for three spin-half operators. Uncertainty relation of arbitrary number of observables is also derived. As an example, the uncertainty relation satisfied by the eight Gell-Mann matrices is presented. PMID- 27498850 TI - Association between the Absolute Baseline Lymphocyte Count and Response to Neoadjuvant Platinum-based Chemotherapy in Muscle-invasive Bladder Cancer. AB - AIMS: Platinum-based neoadjuvant chemotherapy (NAC) improves overall survival in muscle-invasive bladder cancer (MIBC). A pathological complete response (pCR) at radical cystectomy after NAC is associated with better overall survival, but there are no established predictive biomarkers of response to NAC in MIBC. The aim of this study was to find laboratory variables associated with pCR following NAC. MATERIALS AND METHODS: We carried out a retrospective review of MIBC patients treated with NAC followed by radical cystectomy at the Sheba Medical Center between 2005 and 2015. Overall survival was calculated using the Kaplan Meier product-limit method and compared between patients who achieved or did not achieve pCR using the Log-rank test. Baseline and pre-surgery laboratory values were collected and compared between patients who subsequently achieved pCR and those who did not using logistic regression. RESULTS: Fifty-eight patients underwent radical cystectomy after NAC, with a median follow-up of 32 (range 4.8 111.4) months from diagnosis. Of 55 patients with documented pathological outcome on radical cystectomy, 17 (31%) achieved pCR (complete responders). Of the 15 complete responders with follow-up data, 13 (87%) were still alive at time of last follow-up for this study (July 2015). Patients who did not achieve pCR had a significantly worse overall survival than complete responders (P = 0.0007). The baseline lymphocyte count, neutrophil-lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) were significantly associated with response (P = 0.037, P = 0.045, P = 0.042, respectively) on univariate analysis, whereas baseline albumin, haemoglobin, neutrophils, platelets and the total white blood count were not significantly associated with response. Lymphocyte counts were significantly higher in responders than non-responders throughout three time points (P = 0.003 using a generalised linear mixed model). CONCLUSIONS: A high baseline level of lymphocytes is associated with the achievement of pCR at radical cystectomy after NAC, which, in turn, is associated with a significantly longer overall survival. Our results suggest that chemosensitivity in MIBC is associated with lymphocyte count. PMID- 27498852 TI - Control of quorum sensing and virulence factors of Pseudomonas aeruginosa using phenylalanine arginyl beta-naphthylamide. AB - The spread of multidrug-resistant Pseudomonas aeruginosa isolates constitutes a serious clinical challenge. Bacterial efflux machinery is a crucial mechanism of resistance among P. aeruginosa. Efflux inhibitors such as phenylalanine arginyl beta-naphthylamide (PAbetaN) promote the bacterial susceptibility to antimicrobial agents. The pathogenesis of P. aeruginosa is coordinated via quorum sensing (QS). This study aims to find out the impact of efflux pump inhibitor, PAbetaN, on QS and virulence attributes in clinical isolates of P. aeruginosa. P. aeruginosa isolates were purified from urine and wound samples, and the antimicrobial susceptibility was carried out by disc diffusion method. The multidrug-resistant and the virulent isolates U16, U21, W19 and W23 were selected. PAbetaN enhanced their susceptibility to most antimicrobial agents. PAbetaN reduced QS signalling molecules N-3-oxo-dodecanoyl-l-homoserine lactone and N-butyryl-l-homoserine lactone without affecting bacterial viability. Moreover, PAbetaN eliminated their virulence factors such as elastase, protease, pyocyanin and bacterial motility. At the transcription level, PAbetaN significantly (P<0.01) diminished the relative expression of QS cascade (lasI, lasR, rhlI, rhlR, pqsA and pqsR) and QS regulated-type II secretory genes lasB (elastase) and toxA (exotoxin A) compared to the control untreated isolates U16 and U21. In addition, PAbetaN eliminated the relative expression of pelA (exopolysaccharides) in U16 and U21 isolates. Hence, P. aeruginosa-tested isolates became hypo-virulent upon using PAbetaN. PAbetaN significantly blocked the QS circuit and inhibited the virulence factors expressed by clinical isolates of P. aeruginosa. PAbetaN could be a prime substrate for development of QS inhibitors and prevention of P. aeruginosa pathogenicity. PMID- 27498853 TI - Neurokinin-1 receptor mediated breast cancer cell migration by increased expression of MMP-2 and MMP-14. AB - Breast cancer (BC) is a common reason of cancer-associated death in female. To develop novel strategy of therapeutics, it is crucial to comprehensively understand the receptor status of BC cells on the surface and inner, because chemical messengers can bind the receptors and promote tumorigenesis. Compared with normal and benign samples, BC cell lines and malignant biopsies showed higher expression of neurokinin-1 receptor (NK1). In current work, we examined the role and mechanism of NK1 receptor signaling in BC cell migration. Human hemokinin-1 (hHK-1) was the peripheral agonist of NK1 receptor. Our results showed that by activating NK1 receptor, hHK-1 promoted the migration of BC cells. Gelatin zymography and WB experiment showed that hHK-1 enhanced the levels of MMP 2 and MMP-14; inhibition of these two MMPs blocked hHK-1-induced cell migration. We further explored the underlying mechanism. hHK-1 incuced the phosphorylation of ERK1/2, JNK and Akt through PKC or PKA pathway. The phosphorylation of these kinases further regulated the activation of transcriptional factor AP-1 and NF kappaB. Inhibition of AP-1 and NF-kappaB reduced the up-regulation of MMP-2 and MMP-14 by hHK-1. Taken together, we showed NK1 receptor was an important regulator of human BC cell migration and a potential target for BC treatment. PMID- 27498854 TI - Amplification-Free Detection of Circulating microRNA Biomarkers from Body Fluids Based on Fluorogenic Oligonucleotide-Templated Reaction between Engineered Peptide Nucleic Acid Probes: Application to Prostate Cancer Diagnosis. AB - Highly abundant in cells, microRNAs (or miRs) play a key role as regulators of gene expression. A proportion of them are also detectable in biofluids making them ideal noninvasive biomarkers for pathologies in which miR levels are aberrantly expressed, such as cancer. Peptide nucleic acids (PNAs) are engineered uncharged oligonucleotide analogues capable of hybridizing to complementary nucleic acids with high affinity and high specificity. Herein, novel PNA-based fluorogenic biosensors have been designed and synthesized that target miR biomarkers for prostate cancer (PCa). The sensing strategy is based on oligonucleotide-templated reactions where the only miR of interest serves as a matrix to catalyze an otherwise highly unfavorable fluorogenic reaction. Validated in vitro using synthetic RNAs, these newly developed biosensors were then shown to detect endogenous concentrations of miR in human blood samples without the need for any amplification step and with minimal sample processing. This low-cost, quantitative, and versatile sensing technology has been technically validated using gold-standard RT-qPCR. Compared to RT-qPCR however, this enzyme-free, isothermal blood test is amenable to incorporation into low cost portable devices and could therefore be suitable for widespread public screening. PMID- 27498855 TI - MtDNA analysis reveals enriched pathogenic mutations in Tibetan highlanders. AB - Tibetan highlanders, including Tibetans, Monpas, Lhobas, Dengs and Sherpas, are considered highly adaptive to severe hypoxic environments. Mitochondrial DNA (mtDNA) might be important in hypoxia adaptation given its role in coding core subunits of oxidative phosphorylation. In this study, we employed 549 complete highlander mtDNA sequences (including 432 random samples) to obtain a comprehensive view of highlander mtDNA profile. In the phylogeny of a total of 36,914 sequences, we identified 21 major haplogroups representing founding events of highlanders, most of which were coalesced in 10 kya. Through founder analysis, we proposed a three-phase model of colonizing the plateau, i.e., pre-LGM Time (30 kya, 4.68%), post-LGM Paleolithic Time (16.8 kya, 29.31%) and Neolithic Time (after 8 kya, 66.01% in total). We observed that pathogenic mutations occurred far more frequently in 22 highlander-specific lineages (five lineages carrying two pathogenic mutations and six carrying one) than in the 6,857 haplogroups of all the 36,914 sequences (P = 4.87 * 10(-8)). Furthermore, the number of possible pathogenic mutations carried by highlanders (in average 3.18 +/- 1.27) were significantly higher than that in controls (2.82 +/- 1.40) (P = 1.89 * 10(-4)). Considering that function-altering and pathogenic mutations are enriched in highlanders, we therefore hypothesize that they may have played a role in hypoxia adaptation. PMID- 27498856 TI - Singapore grouper iridovirus protein VP088 is essential for viral infectivity. AB - Viral infection is a great challenge in healthcare and agriculture. The Singapore grouper iridovirus (SGIV) is highly infectious to numerous marine fishes and increasingly threatens mariculture and wildlife conservation. SGIV intervention is not available because little is known about key players and their precise roles in SGVI infection. Here we report the precise role of VP088 as a key player in SGIV infection. VP088 was verified as an envelope protein encoded by late gene orf088. We show that SGIV could be neutralized with an antibody against VP088. Depletion or deletion of VP088 significantly suppresses SGIV infection without altering viral gene expression and host responses. By precisely quantifying the genome copy numbers of host cells and virions, we reveal that VP088 deletion dramatically reduces SGIV infectivity through inhibiting virus entry without altering viral pathogenicity, genome stability and replication and progeny virus release. These results pinpoint that VP088 is a key player in SGIV entry and represents an ideal target for SGIV intervention. PMID- 27498857 TI - Association between GSTM1, GSTT1, and GSTP1 variants and the risk of end stage renal disease. AB - INTRODUCTION: There are some evidences indicating DNA damage by oxidant and mutant agents has an essential role in the chronic renal failure and end stage renal disease (ESRD). To investigate the possible association of GSTs variants with ESRD, we investigated the frequency of GST- T1, M1, and P1 genotypes, and the level of malondialdehyde (MDA) in patients with ESRD. MATERIALS AND METHODS: The present case-control study consisted of 136 ESRD patients treated with maintenance hemodialysis and 137 gender- and age-matched, unrelated healthy controls from the population of west of Iran. The GST- T1, M1, and P1 genotypes were determined in all individuals using multiplex-PCR and PCR-RFLP. The level of MDA was measured by high-performance liquid chromatography (HPLC). RESULTS: We found that GSTM1 and GSTT1 null genotypes (GSTT1-/GSTM1-) increased the risk of ESRD by 1.8 times (p < 0.001) and the increased risk of ESRD for GSTM-null (T1+ M1-) genotype was 3.04 times (p = 0.002). ESRD patients carriers the GST (GSTM1 null + GSTT1-null + GST-null) genotypes compared to GST normal genotype increased the risk of ESRD by 3.3 (p < 0.001) times. ESRD patients carriers of GST-null, GSTM1-null, and GSTT1-null genotypes had greater MDA concentration compared with the same genotypes of control subjects. Our results indicated that the GST-null allele (GSTT1-null/GSTM1-null) is a risk factor for ESRD and carriers of this allele have high levels of MDA. CONCLUSION: Our findings indicate that oxidative stress, impairment of the antioxidant system and abnormal lipid metabolism may play a role in the pathogenesis and progression of ESRD and its related complications. These data suggest that patients with ESRD are more susceptible to vascular diseases. PMID- 27498859 TI - Sox2 Suppresses Gastric Tumorigenesis in Mice. AB - Sox2 expression marks gastric stem and progenitor cells, raising important questions regarding the genes regulated by Sox2 and the role of Sox2 itself during stomach homeostasis and disease. By using ChIP-seq analysis, we have found that the majority of Sox2 targets in gastric epithelial cells are tissue specific and related to functions such as endoderm development, Wnt signaling, and gastric cancer. Unexpectedly, we found that Sox2 itself is dispensable for gastric stem cell and epithelial self-renewal, yet Sox2(+) cells are highly susceptible to tumorigenesis in an Apc/Wnt-driven mouse model. Moreover, Sox2 loss enhances, rather than impairs, tumor formation in Apc-deficient gastric cells in vivo and in vitro by inducing Tcf/Lef-dependent transcription and upregulating intestinal metaplasia-associated genes, providing a mechanistic basis for the observed phenotype. Together, these data identify Sox2 as a context-dependent tumor suppressor protein that is dispensable for normal tissue regeneration but restrains stomach adenoma formation through modulation of Wnt-responsive and intestinal genes. PMID- 27498858 TI - Insulin-like Signaling Promotes Glial Phagocytic Clearance of Degenerating Axons through Regulation of Draper. AB - Neuronal injury triggers robust responses from glial cells, including altered gene expression and enhanced phagocytic activity to ensure prompt removal of damaged neurons. The molecular underpinnings of glial responses to trauma remain unclear. Here, we find that the evolutionarily conserved insulin-like signaling (ILS) pathway promotes glial phagocytic clearance of degenerating axons in adult Drosophila. We find that the insulin-like receptor (InR) and downstream effector Akt1 are acutely activated in local ensheathing glia after axotomy and are required for proper clearance of axonal debris. InR/Akt1 activity, it is also essential for injury-induced activation of STAT92E and its transcriptional target draper, which encodes a conserved receptor essential for glial engulfment of degenerating axons. Increasing Draper levels in adult glia partially rescues delayed clearance of severed axons in glial InR-inhibited flies. We propose that ILS functions as a key post-injury communication relay to activate glial responses, including phagocytic activity. PMID- 27498860 TI - Interneuronal Transfer and Distal Action of Tetanus Toxin and Botulinum Neurotoxins A and D in Central Neurons. AB - Recent reports suggest that botulinum neurotoxin (BoNT) A, which is widely used clinically to inhibit neurotransmission, can spread within networks of neurons to have distal effects, but this remains controversial. Moreover, it is not known whether other members of this toxin family are transferred between neurons. Here, we investigate the potential distal effects of BoNT/A, BoNT/D, and tetanus toxin (TeNT), using central neurons grown in microfluidic devices. Toxins acted upon the neurons that mediated initial entry, but all three toxins were also taken up, via an alternative pathway, into non-acidified organelles that mediated retrograde transport to the somato-dendritic compartment. Toxins were then released into the media, where they entered and exerted their effects upon upstream neurons. These findings directly demonstrate that these agents undergo transcytosis and interneuronal transfer in an active form, resulting in long distance effects. PMID- 27498861 TI - MAPK-Mediated YAP Activation Controls Mechanical-Tension-Induced Pulmonary Alveolar Regeneration. AB - The pulmonary alveolar epithelium undergoes extensive regeneration in response to lung injuries, including lung resection. In recent years, our understanding of cell lineage relationships in the pulmonary alveolar epithelium has improved significantly. However, the molecular and cellular mechanisms that regulate pneumonectomy (PNX)-induced alveolar regeneration remain largely unknown. In this study, we demonstrate that mechanical-tension-induced YAP activation in alveolar stem cells plays a major role in promoting post-PNX alveolar regeneration. Our results indicate that JNK and p38 MAPK signaling is critical for mediating actin cytoskeleton-remodeling-induced nuclear YAP expression in alveolar stem cells. Moreover, we show that Cdc42-controlled actin remodeling is required for the activation of JNK, p38, and YAP in post-PNX lungs. Our findings together establish that the Cdc42/F-actin/MAPK/YAP signaling cascade is essential for promoting alveolar regeneration in response to mechanical tension in the lung. PMID- 27498862 TI - Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors exhibit no clearly defined therapeutic target. High-throughput drug screens using patient-derived cell lines found rare examples of sensitivity to monotherapy, with most models requiring combination therapy. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses. Out of more than 500 single and combination drug regimens tested, no single treatment was effective for the majority of PDAC tumors, and each case had unique sensitivity profiles that could not be predicted using genetic analyses. These data indicate a shortcoming of reliance on genetic analysis to predict efficacy of currently available agents against PDAC and suggest that sensitivity profiling of patient derived models could inform personalized therapy design for PDAC. PMID- 27498863 TI - NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice. AB - Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD(+) biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adipose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARgamma (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARgamma targets in adipose tissue. These deleterious alterations were normalized by administering rosiglitazone or a key NAD(+) intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance. PMID- 27498864 TI - Erk5 Is a Key Regulator of Naive-Primed Transition and Embryonic Stem Cell Identity. AB - Embryonic stem cells (ESCs) can self-renew or differentiate into any cell type, a phenomenon known as pluripotency. Distinct pluripotent states, termed naive and primed pluripotency, have been described. However, the mechanisms that control naive-primed pluripotent transition are poorly understood. Here, we perform a targeted screen for kinase inhibitors, which modulate the naive-primed pluripotent transition. We find that XMD compounds, which selectively inhibit Erk5 kinase and BET bromodomain family proteins, drive ESCs toward primed pluripotency. Using compound selectivity engineering and CRISPR/Cas9 genome editing, we reveal distinct functions for Erk5 and Brd4 in pluripotency regulation. We show that Erk5 signaling maintains ESCs in the naive state and suppresses progression toward primed pluripotency and neuroectoderm differentiation. Additionally, we identify a specialized role for Erk5 in defining ESC lineage selection, whereby Erk5 inhibits a cardiomyocyte-specific differentiation program. Our data therefore reveal multiple critical functions for Erk5 in controlling ESC identity. PMID- 27498865 TI - TRIM11 Suppresses AIM2 Inflammasome by Degrading AIM2 via p62-Dependent Selective Autophagy. AB - The AIM2 inflammasome is a key cytosolic signaling complex that is activated by double-stranded DNA, leading to the maturation of proinflammatory cytokines such as interleukin-1beta (IL-1beta) and IL-18. Dysregulated AIM2 inflammasome activity is associated with human inflammatory diseases and cancers, suggesting that its activity must be tightly regulated. However, the precise molecular mechanisms that control AIM2 levels and activity are still poorly understood. Here, we report tripartite motif 11 (TRIM11) as a key negative regulator of the AIM2 inflammasome. Upon DNA virus infection, TRIM11 binds to AIM2 via its PS domain and undergoes auto-polyubiquitination at K458 to promote an association between TRIM11 and the autophagic cargo receptor p62 to mediate AIM2 degradation via selective autophagy. These findings identify a role for TRIMs in AIM2 inflammasome activation where TRIM11 acts as a secondary receptor to deliver AIM2 to the autophagosomes for degradation in a p62-dependent manner. PMID- 27498866 TI - Hierarchical RNA Processing Is Required for Mitochondrial Ribosome Assembly. AB - The regulation of mitochondrial RNA processing and its importance for ribosome biogenesis and energy metabolism are not clear. We generated conditional knockout mice of the endoribonuclease component of the RNase P complex, MRPP3, and report that it is essential for life and that heart and skeletal-muscle-specific knockout leads to severe cardiomyopathy, indicating that its activity is non redundant. Transcriptome-wide parallel analyses of RNA ends (PARE) and RNA-seq enabled us to identify that in vivo 5' tRNA cleavage precedes 3' tRNA processing, and this is required for the correct biogenesis of the mitochondrial ribosomal subunits. We identify that mitoribosomal biogenesis proceeds co-transcriptionally because large mitoribosomal proteins can form a subcomplex on an unprocessed RNA containing the 16S rRNA. Taken together, our data show that RNA processing links transcription to translation via assembly of the mitoribosome. PMID- 27498867 TI - The miR-17~92 microRNA Cluster Is a Global Regulator of Tumor Metabolism. AB - A central hallmark of cancer cells is the reprogramming of cellular metabolism to meet the bioenergetic and biosynthetic demands of malignant growth. Here, we report that the miR-17~92 microRNA (miRNA) cluster is an oncogenic driver of tumor metabolic reprogramming. Loss of miR-17~92 in Myc(+) tumor cells leads to a global decrease in tumor cell metabolism, affecting both glycolytic and mitochondrial metabolism, whereas increased miR-17~92 expression is sufficient to drive increased nutrient usage by tumor cells. We mapped the metabolic control element of miR-17~92 to the miR-17 seed family, which influences cellular metabolism and mammalian target of rapamycin complex 1 (mTORC1) signaling through negative regulation of the LKB1 tumor suppressor. miR-17-dependent tuning of LKB1 levels regulates both the metabolic potential of Myc(+) lymphomas and tumor growth in vivo. Our results establish metabolic reprogramming as a central function of the oncogenic miR-17~92 miRNA cluster that drives the progression of MYC-dependent tumors. PMID- 27498868 TI - MLKL and FADD Are Critical for Suppressing Progressive Lymphoproliferative Disease and Activating the NLRP3 Inflammasome. AB - MLKL, a key component downstream of RIPK3, is suggested to be a terminal executor of necroptosis. Genetic studies have revealed that Ripk3 ablation rescues embryonic lethality in Fadd- or Caspase-8-deficient mice. Given that RIPK3 has also been implicated in non-necroptotic pathways including apoptosis and inflammatory signaling, it remains unclear whether the lethality in Fadd(-/-) mice is indeed caused by necropotosis. Here, we show that genetic deletion of Mlkl rescues the developmental defect in Fadd-deficient mice and that Fadd(-/ )Mlkl(-/-) mice are viable and fertile. Mlkl(-/-)Fadd(-/-) mice display significantly accelerated lymphoproliferative disease characterized by lymphadenopathy and splenomegaly when compared to Ripk3(-/-)Fadd(-/-) mice. Mlkl( /-)Fadd(-/-) bone-marrow-derived macrophages and dendritic cells have impaired NLRP3 inflammasome activation associated with defects in ASC speck formation and NF-kappaB-dependent NLRP3 transcription. Our findings reveal that MLKL and FADD play critical roles in preventing lymphoproliferative disease and activating the NLRP3 inflammasome. PMID- 27498869 TI - A Distinct Lung-Interstitium-Resident Memory CD8(+) T Cell Subset Confers Enhanced Protection to Lower Respiratory Tract Infection. AB - The nature and anatomic location of the protective memory CD8(+) T cell subset induced by intranasal vaccination remain poorly understood. We developed a vaccination model to assess the anatomic location of protective memory CD8(+) T cells and their role in lower airway infections. Memory CD8(+) T cells elicited by local intranasal, but not systemic, vaccination with an engineered non replicative CD8(+) T cell-targeted antigen confer enhanced protection to a lethal respiratory viral challenge. This protection depends on a distinct CXCR3(LO) resident memory CD8(+) T (Trm) cell population that preferentially localizes to the pulmonary interstitium. Because they are positioned close to the mucosa, where infection occurs, interstitial Trm cells act before inflammation can recruit circulating memory CD8(+) T cells into the lung tissue. This results in a local protective immune response as early as 1 day post-infection. Hence, vaccine strategies that induce lung interstitial Trm cells may confer better protection against respiratory pathogens. PMID- 27498870 TI - High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML. AB - Bromodomain and extra-terminal domain (BET) family inhibitors offer an approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML), as these polymerases are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1,400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3' to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter, while CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2, that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was upregulated, and inhibition of BET proteins sensitized t(8:21) containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET-inhibitor-induced cell death. PMID- 27498871 TI - Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer. AB - Disordered transcriptomes of cancer encompass direct effects of somatic mutation on transcription, coordinated secondary pathway alterations, and increased transcriptional noise. To catalog the rules governing how somatic mutation exerts direct transcriptional effects, we developed an exhaustive pipeline for analyzing RNA sequencing data, which we integrated with whole genomes from 23 breast cancers. Using X-inactivation analyses, we found that cancer cells are more transcriptionally active than intermixed stromal cells. This is especially true in estrogen receptor (ER)-negative tumors. Overall, 59% of substitutions were expressed. Nonsense mutations showed lower expression levels than expected, with patterns characteristic of nonsense-mediated decay. 14% of 4,234 rearrangements caused transcriptional abnormalities, including exon skips, exon reusage, fusions, and premature polyadenylation. We found productive, stable transcription from sense-to-antisense gene fusions and gene-to-intergenic rearrangements, suggesting that these mutation classes drive more transcriptional disruption than previously suspected. Systematic integration of transcriptome with genome data reveals the rules by which transcriptional machinery interprets somatic mutation. PMID- 27498872 TI - Direct Induction and Functional Maturation of Forebrain GABAergic Neurons from Human Pluripotent Stem Cells. AB - Gamma-aminobutyric acid (GABA)-releasing interneurons play an important modulatory role in the cortex and have been implicated in multiple neurological disorders. Patient-derived interneurons could provide a foundation for studying the pathogenesis of these diseases as well as for identifying potential therapeutic targets. Here, we identified a set of genetic factors that could robustly induce human pluripotent stem cells (hPSCs) into GABAergic neurons (iGNs) with high efficiency. We demonstrated that the human iGNs express neurochemical markers and exhibit mature electrophysiological properties within 6 8 weeks. Furthermore, in vitro, iGNs could form functional synapses with other iGNs or with human-induced glutamatergic neurons (iENs). Upon transplantation into immunodeficient mice, human iGNs underwent synaptic maturation and integration into host neural circuits. Taken together, our rapid and highly efficient single-step protocol to generate iGNs may be useful to both mechanistic and translational studies of human interneurons. PMID- 27498873 TI - Dis3l2-Mediated Decay Is a Quality Control Pathway for Noncoding RNAs. AB - Mutations in the 3'-5' exonuclease DIS3L2 are associated with Perlman syndrome and hypersusceptibility to Wilms tumorigenesis. Previously, we found that Dis3l2 specifically recognizes and degrades uridylated pre-let-7 microRNA. However, the widespread relevance of Dis3l2-mediated decay of uridylated substrates remains unknown. Here, we applied an unbiased RNA immunoprecipitation strategy to identify Dis3l2 targets in mouse embryonic stem cells. The disease-associated long noncoding RNA (lncRNA) Rmrp, 7SL, as well as several other Pol III transcribed noncoding RNAs (ncRNAs) were among the most highly enriched Dis3l2 bound RNAs. 3'-Uridylated Rmrp, 7SL, and small nuclear RNA (snRNA) species were highly stabilized in the cytoplasm of Dis3l2-depleted cells. Deep sequencing analysis of Rmrp 3' ends revealed extensive oligouridylation mainly on transcripts with imprecise ends. We implicate the terminal uridylyl transferases (TUTases) Zcchc6/11 in the uridylation of these ncRNAs, and biochemical reconstitution assays demonstrate the sufficiency of TUTase-Dis3l2 for Rmrp decay. This establishes Dis3l2-mediated decay (DMD) as a quality-control pathway that eliminates aberrant ncRNAs. PMID- 27498874 TI - Increased 4E-BP1 Expression Protects against Diet-Induced Obesity and Insulin Resistance in Male Mice. AB - Obesity is a major risk factor driving the global type II diabetes pandemic. However, the molecular factors linking obesity to disease remain to be elucidated. Gender differences are apparent in humans and are also observed in murine models. Here, we link these differences to expression of eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which, upon HFD feeding, becomes significantly reduced in the skeletal muscle and adipose tissue of male but not female mice. Strikingly, restoring 4E-BP1 expression in male mice protects them against HFD-induced obesity and insulin resistance. Male 4E-BP1 transgenic mice also exhibit reduced white adipose tissue accumulation accompanied by decreased circulating levels of leptin and triglycerides. Importantly, transgenic 4E-BP1 male mice are also protected from aging-induced obesity and metabolic decline on a normal diet. These results demonstrate that 4E BP1 is a gender-specific suppressor of obesity that regulates insulin sensitivity and energy metabolism. PMID- 27498875 TI - Distinct Roles of PKCiota/lambda and PKMzeta in the Initiation and Maintenance of Hippocampal Long-Term Potentiation and Memory. AB - PKMzeta has been proposed to be essential for maintenance of long-term potentiation (LTP) and long-term memory (LTM). However, recent data from PKMzeta knockout mice has called this role into question. Instead, the other atypical isoform, protein kinase C iota/lambda (PKCiota/lambda), has emerged as a potential alternative player. Therefore, the nature of the "memory molecule" maintaining learned information remains uncertain. Here, we report knockdown (KD) of PKCiota/lambda and PKMzeta in the dorsal hippocampus and find deficits in early expression and late maintenance, respectively, during both LTP and hippocampus-dependent LTM. Sequential increases in the active form of PKCiota/lambda and PKMzeta are detected during LTP or fear conditioning. Importantly, PKMzeta, but not PKCiota/lambda, KD disrupts previously established LTM. Thus, PKCiota/lambda and PKMzeta have distinct functions in LTP and memory, with PKMzeta playing a specific role in memory maintenance. This relaying pattern may represent a precise molecular mechanism by which atypical PKCs regulate the different stages of memory. PMID- 27498876 TI - Binding of Macrolide Antibiotics Leads to Ribosomal Selection against Specific Substrates Based on Their Charge and Size. AB - Macrolide antibiotic binding to the ribosome inhibits catalysis of peptide bond formation between specific donor and acceptor substrates. Why particular reactions are problematic for the macrolide-bound ribosome remains unclear. Using comprehensive mutational analysis and biochemical experiments with synthetic substrate analogs, we find that the positive charge of these specific residues and the length of their side chains underlie inefficient peptide bond formation in the macrolide-bound ribosome. Even in the absence of antibiotic, peptide bond formation between these particular donors and acceptors is rather inefficient, suggesting that macrolides magnify a problem present for intrinsically difficult substrates. Our findings emphasize the existence of functional interactions between the nascent protein and the catalytic site of the ribosomal peptidyl transferase center. PMID- 27498877 TI - Phospho-dependent Accumulation of GABABRs at Presynaptic Terminals after NMDAR Activation. AB - Here, we uncover a mechanism for regulating the number of active presynaptic GABAB receptors (GABABRs) at nerve terminals, an important determinant of neurotransmitter release. We find that GABABRs gain access to axon terminals by lateral diffusion in the membrane. Their relative accumulation is dependent upon agonist activation and the presence of the two distinct sushi domains that are found only in alternatively spliced GABABR1a subunits. Following brief activation of NMDA receptors (NMDARs) using glutamate, GABABR diffusion is reduced, causing accumulation at presynaptic terminals in a Ca(2+)-dependent manner that involves phosphorylation of GABABR2 subunits at Ser783. This signaling cascade indicates how synaptically released glutamate can initiate, via a feedback mechanism, increased levels of presynaptic GABABRs that limit further glutamate release and excitotoxicity. PMID- 27498878 TI - The Transcriptional Repressor Polycomb Group Factor 6, PCGF6, Negatively Regulates Dendritic Cell Activation and Promotes Quiescence. AB - Pro-inflammatory signals provided by the microenvironment are critical to activate dendritic cells (DCs), components of the innate immune system that shape both innate and adaptive immunity. However, to prevent inappropriate immune activation, mechanisms must be in place to restrain DC activation to ensure DCs are activated only once sufficient stimuli have been received. Here, we report that DC activation and immunogenicity are regulated by the transcriptional repressor Polycomb group factor 6 (PCGF6). Pcgf6 is rapidly downregulated upon stimulation, and this downregulation is necessary to permit full DC activation. Silencing PCGF6 expression enhanced both spontaneous and stimulated DC activation. We show that PCGF6 associates with the H3K4me3 demethylase JARID1c, and together, they negatively regulate H3K4me3 levels in DCs. Our results identify two key regulators, PCGF6 and JARID1c that temper DC activation and implicate active transcriptional silencing via histone demethylation as a previously unappreciated mechanism for regulating DC activation and quiescence. PMID- 27498880 TI - Nanoscale Morphology of PTB7 Based Organic Photovoltaics as a Function of Fullerene Size. AB - High efficiency polymer:fullerene photovoltaic device layers self-assemble with hierarchical features from angstroms to 100's of nanometers. The feature size, shape, composition, orientation, and order all contribute to device efficiency and are simultaneously difficult to study due to poor contrast between carbon based materials. This study seeks to increase device efficiency and simplify morphology measurements by replacing the typical fullerene acceptor with endohedral fullerene Lu3N@PC80BEH. The metal atoms give excellent scattering contrast for electron beam and x-ray experiments. Additionally, Lu3N@PC80BEH has a lower electron affinity than standard fullerenes, which can raise the open circuit voltage of photovoltaic devices. Electron microscopy techniques are used to produce a detailed account of morphology evolution in mixtures of Lu3N@PC80BEH with the record breaking donor polymer, PTB7 and coated using solvent mixtures. We demonstrate that common solvent additives like 1,8-diiodooctane or chloronapthalene do not improve the morphology of endohedral fullerene devices as expected. The poor device performance is attributed to the lack of mutual miscibility between this particular polymer:fullerene combination and to co crystallization of Lu3N@PC80BEH with 1,8-diiodooctane. This negative result explains why solvent additives mixtures are not necessarily a morphology cure all. PMID- 27498881 TI - Monitoring cow activity and rumination time for an early detection of heat stress in dairy cow. AB - The aim of this study was to explore the use of cow activity and rumination time by precision livestock farming tools as early alert for heat stress (HS) detection. A total of 58 Italian Friesian cows were involved in this study during summer 2015. Based on the temperature humidity index (THI), two different conditions were compared on 16 primiparous and 11 multiparous, to be representative of three lactation phases: early (15-84 DIM), around peak (85-154 DIM), and plateau (155-224 DIM). A separate dataset for the assessment of the variance partition included all the cows in the herd from June 7 to July 16. The rumination time (RT2h, min/2 h) and activity index (AI2h, bouts/2 h) were summarized every 2-h interval. The raw data were used to calculate the following variables: total daily RT (RTt), daytime RT (RTd), nighttime RT (RTn), total daily AI (AIt), daytime AI (AId), and nighttime AI (AIn). Either AIt and AId increased, whereas RTt, RTd, and RTn decreased with higher THI in all the three phases. The highest decrease was recorded for RTd and ranged from 49 % (early) to 45 % (plateau). The contribution of the cow within lactation phase was above 60 % of the total variance for AI traits and a share from 33.9 % (for RTt) to 54.8 % (RTn) for RT traits. These observations must be extended to different feeding managements and different animal genetics to assess if different thresholds could be identified to set an early alert system for the farmer. PMID- 27498879 TI - Metals in Alzheimer's and Parkinson's Disease: Relevance to Dementia with Lewy Bodies. AB - Despite being a common form of dementia, dementia with Lewy bodies is relatively under-researched when compared with Parkinson's disease and Alzheimer's disease. This has arisen from the fact that dementia with Lewy bodies has been historically difficult to diagnose resulting in a lack of well-defined clinical cohorts and post-mortem tissue available for scientific research. Dementia with Lewy bodies shares clinical and pathological features with both Parkinson's disease and Alzheimer's disease so it is therefore likely that it also has similar pathogenic mechanisms leading to disease. This review will discuss the role of biological metals in Parkinson's disease and Alzheimer's disease and whether there are indications that metals may also be involved in dementia with Lewy bodies. PMID- 27498882 TI - Impact of selected personal factors on seasonal variability of recreationist weather perceptions and preferences in Warsaw (Poland). AB - Weather and climate are important natural resources for tourism and recreation, although sometimes they can make outdoor leisure activities less satisfying or even impossible. The aim of this work was to determine weather perception seasonal variability of people staying outdoors in urban environment for tourism and recreation, as well as to determine if personal factors influence estimation of recreationist actual biometeorological conditions and personal expectations towards weather elements. To investigate how human thermal sensations vary upon meteorological conditions typical for temperate climate, weather perception field researches were conducted in Warsaw (Poland) in all seasons. Urban recreationists' preference for slightly warm thermal conditions, sunny, windless and cloudless weather, were identified as well as PET values considered to be optimal for sightseeing were defined between 27.3 and 31.7 degrees C. The results confirmed existence of phenomena called alliesthesia, which manifested in divergent thermal perception of comparable biometeorological conditions in transitional seasons. The results suggest that recreationist thermal sensations differed from other interviewees' responses and were affected not only by physiological processes but they were also conditioned by psychological factors (i.e. attitude, expectations). Significant impact of respondents' place of origin and its climate on creating thermal sensations and preferences was observed. Sex and age influence thermal preferences, whereas state of acclimatization is related with thermal sensations to some point. PMID- 27498884 TI - A bentonite-gold nanohybrid as a heterogeneous green catalyst for selective oxidation of silanes. AB - A highly efficient, environmentally benign and reusable heterogeneous bentonite gold nanohybrid catalyst was designed and synthesized. This heterogeneous catalyst could efficaciously catalyse the oxidation of organosilanes to silanols. The reaction is 98.7% atom economical and the products were obtained in excellent yield without the formation of disiloxanes as byproducts. The catalyst was also well applicable for the gram scale preparation of silanols. PMID- 27498883 TI - Hypoxic repression of pyruvate dehydrogenase activity is necessary for metabolic reprogramming and growth of model tumours. AB - Tumour cells fulfil the bioenergetic and biosynthetic needs of proliferation using the available environmental metabolites. Metabolic adaptation to hypoxia causes decreased mitochondrial function and increased lactate production. This work examines the biological importance of the hypoxia-inducible inhibitory phosphorylations on the pyruvate dehydrogenase E1alpha subunit. Pancreatic cancer cell lines were genetically manipulated to alter the net phosphorylation of PDH E1alpha through reduced kinase expression or enhanced phosphatase expression. The modified cells were tested for hypoxic changes in phosphorylated E1alpha, mitochondrial metabolism and growth as xenografted tumours. Even though there are four PDHK genes, PDHK1 is essential for inhibitory PDH phosphorylation of E1alpha at serine 232, is partially responsible for modification of serines 293 and 300, and these phosphorylations are necessary for model tumour growth. In order to determine the clinical relevance, a cohort of head and neck cancer patient biopsies was examined for phosphorylated E1alpha and expression of PDHK1. Patients with detectable 232 phosphorylation or expression of PDHK1 tend to have worse clinical outcome. These data show that PDHK1 activity is unique and non redundant in the family of PHDK enzymes and a PDHK1 specific inhibitor would therefore have anti-cancer activity with reduced chance of side effects from inhibition of other PDHKs. PMID- 27498885 TI - A Density Map of the Tick-Borne Encephalitis and Lyme Borreliosis Vector Ixodes ricinus (Acari: Ixodidae) for Germany. AB - The castor bean tick Ixodes ricinus (L.) is the principal vector for a variety of viral, bacterial, and protozoan pathogens causing a growing public-health issue over the past decades. However, a national density map of I. ricinus is still missing. Here, I. ricinus nymphs in Germany were investigated by compiling a high resolution map depicting the mean annually accumulated nymphal density, as observed by monthly flagging an area of 100 m2 Input data comprise ticks collected at 69 sampling sites. The model domain covers an area of about 357,000 km2 (regional scale). Two negative binomial regression models were fitted to the data to interpolate the tick densities to unsampled locations using bioclimatic variables and land cover, which were selected according to their significance by the Akaike information criterion (AIC). The default model was fitted to the complete dataset resulting in AIC = 842. An optimized model resulted in a significantly better value of AIC = 732. Tick densities are very low in urban (green) areas. Maximum annual densities up to 1,000 nymphs per 100 m2 are observed in broad-leaved forests. The tick maps were verified by leave-one-out cross-validation. Root mean square errors of RMSE = 137 and RMSE = 126 nymphs per 100 m2 were estimated for the two models, respectively. These errors are of the order of the interannual variation of the tick densities. The compilation of a high-resolution density map of unfed nymphal I. ricinus for Germany provides a novel, nationwide insight into the distribution of an important disease vector. PMID- 27498886 TI - Golimumab for moderately to severely active ulcerative colitis. AB - INTRODUCTION: Anti-TNF agents are the mainstay of therapy in patients with moderate to severe ulcerative colitis (UC) not responding to 5-aminosalisylic acid, corticosteroids, immunmodulators and for patients dependent on corticosteroids. There is a therapeutic gap of 30%- 60% with infliximab and adalimumab, which is required to be bridged by newer agents. The present review summarizes the literature on the role of golimumab, a new anti TNF agent, in ulcerative colitis. AREAS COVERED: Literature search was done on PubMed using the search terms 'golimumab' AND 'ulcerative colitis' from inception till March 2016. Golimumab, a fully human monoclonal antibody against TNF-alpha, was approved by FDA for clinical use in UC in 2013. In vitro studies showed golimumab to be better than infliximab and adalimumab in terms of affinity and neutralization of TNF-alpha and its conformational stability. Golimumab was found to be effective and safe in inducing and maintaining clinical remission, clinical response and mucosal healing in patients with UC in the two registration trials. Expert commentary: Although there is no difference in terms of efficacy between golimumab, infliximab and adalimumab, golimumab is better than infliximab in terms of route of administration (subcutaneous vs intravenous) and better than adalimumab in terms of frequency of dosing (4 weeks vs 2 weeks). PMID- 27498887 TI - Bedside teaching: an underutilized tool in medical education. PMID- 27498888 TI - Prediction of Filamentous Sludge Bulking using a State-based Gaussian Processes Regression Model. AB - Activated sludge process has been widely adopted to remove pollutants in wastewater treatment plants (WWTPs). However, stable operation of activated sludge process is often compromised by the occurrence of filamentous bulking. The aim of this study is to build a proper model for timely diagnosis and prediction of filamentous sludge bulking in an activated sludge process. This study developed a state-based Gaussian Process Regression (GPR) model to monitor the filamentous sludge bulking related parameter, sludge volume index (SVI), in such a way that the evolution of SVI can be predicted over multi-step ahead. This methodology was validated with SVI data collected from one full-scale WWTP. Online diagnosis and prediction of filamentous bulking sludge with real-time SVI prediction was tested through a simulation study. The results showed that the proposed methodology was capable of predicting future SVIs with good accuracy, thus providing sufficient time for predicting and controlling filamentous sludge bulking. PMID- 27498890 TI - Formant transitions in the fluent speech of Farsi-speaking people who stutter. AB - PURPOSE: Second formant (F2) transitions can be used to infer attributes of articulatory transitions. This study compared formant transitions during fluent speech segments of Farsi (Persian) speaking people who stutter and normally fluent Farsi speakers. METHODS: Ten Iranian males who stutter and 10 normally fluent Iranian males participated. Sixteen different "CVt" tokens were embedded within the phrase "Begu CVt an". Measures included overall F2 transition frequency extents, durations, and derived overall slopes, initial F2 transition slopes at 30ms and 60ms, and speaking rate. RESULTS: (1) Mean overall formant frequency extent was significantly greater in 14 of the 16 CVt tokens for the group of stuttering speakers. (2) Stuttering speakers exhibited significantly longer overall F2 transitions for all 16 tokens compared to the nonstuttering speakers. (3) The overall F2 slopes were similar between the two groups. (4) The stuttering speakers exhibited significantly greater initial F2 transition slopes (positive or negative) for five of the 16 tokens at 30ms and six of the 16 tokens at 60ms. (5) The stuttering group produced a slower syllable rate than the non stuttering group. CONCLUSIONS: During perceptually fluent utterances, the stuttering speakers had greater F2 frequency extents during transitions, took longer to reach vowel steady state, exhibited some evidence of steeper slopes at the beginning of transitions, had overall similar F2 formant slopes, and had slower speaking rates compared to nonstuttering speakers. Findings support the notion of different speech motor timing strategies in stuttering speakers. Findings are likely to be independent of the language spoken. Educational objectives This study compares aspects of F2 formant transitions between 10 stuttering and 10 nonstuttering speakers. Readers will be able to describe: (a) characteristics of formant frequency as a specific acoustic feature used to infer speech movements in stuttering and nonstuttering speakers, (b) two methods of measuring second formant (F2) transitions: the visual criteria method and fixed time criteria method, (c) characteristics of F2 transitions in the fluent speech of stuttering speakers and how those characteristics appear to differ from normally fluent speakers, and (d) possible cross-linguistic effects on acoustic analyses of stuttering. PMID- 27498891 TI - Delayed N2 response in Go condition in a visual Go/Nogo ERP study in children who stutter. AB - PURPOSE OF THE STUDY: The main aim of the study was to investigate the attentional and inhibitory abilities and their underlying processes of children who stutter by using behavioural measurement and event-related potentials (ERP) in a visual Go/Nogo paradigm. METHODS: Participants were 11 children who stutter (CWS; mean age 8.1, age range 6.3-9.5 years) and 19 typically developed children (TDC; mean age 8.1, age range 5.8-9.6 years). They performed a visual Go/Nogo task with simultaneous EEG recording to obtain ERP responses. RESULTS: Results showed that CWS had longer N2 and P3 latencies in the Go condition compared to the TDC. In contrast, the groups did not differ significantly in the Nogo condition or behavioural measures. CONCLUSIONS: Our findings did not confirm less efficient inhibitory control in CWS but suggest atypical attentional processing such as stimulus evaluation and response selection. EDUCATIONAL OBJECTIVES: The reader will be able to (a) describe recent findings on attention and inhibitory control in children who stutter, (b) describe the measurement of attentional processing, including inhibitory control, and (c) describe the findings on attentional processing in children who stutter as indexed by the event-related potentials in a visual Go/Nogo paradigm. PMID- 27498889 TI - A Highly Polymorphic Copy Number Variant in the NSF Gene is Associated with Cocaine Dependence. AB - Cocaine dependence is a complex psychiatric disorder involving both genetic and environmental factors. Several neurotransmitter systems mediate cocaine's effects, dependence and relapse, being the components of the neurotransmitter release machinery good candidates for the disorder. Previously, we identified a risk haplotype for cocaine dependence in the NSF gene, encoding the protein N Ethylmaleimide-Sensitive Factor essential for synaptic vesicle turnover. Here we examined the possible contribution to cocaine dependence of a large copy number variant (CNV) that encompasses part of the NSF gene. We performed a case-control association study in a discovery sample (359 cases and 356 controls) and identified an association between cocaine dependence and the CNV (P = 0.013), that was confirmed in the replication sample (508 cases and 569 controls, P = 7.1e-03) and in a pooled analysis (P = 1.8e-04), with an over-representation of low number of copies in cases. Subsequently, we studied the functional impact of the CNV on gene expression and found that the levels of two NSF transcripts were significantly increased in peripheral blood mononuclear cells (PBMC) along with the number of copies of the CNV. These results, together with a previous study from our group, support the role of NSF in the susceptibility to cocaine dependence. PMID- 27498892 TI - Stuttering, alcohol consumption and smoking. AB - PURPOSE: Limited research has been published regarding the association between stuttering and substance use. An earlier study provided no evidence for such an association, but the authors called for further research to be conducted using a community sample. The present study used data from a community sample to investigate whether an association between stuttering and alcohol consumption or regular smoking exists in late adolescence and adulthood. METHODS: Regression analyses were carried out on data from a birth cohort study, the National Child Development Study (NCDS), whose initial cohort included 18,558 participants who have since been followed up until age 55. In the analyses, the main predictor variable was parent-reported stuttering at age 16. Parental socio-economic group, cohort member's sex and childhood behavioural problems were also included. The outcome variables related to alcohol consumption and smoking habits at ages 16, 23, 33, 41, 46, 50 and 55. RESULTS: No significant association was found between stuttering and alcohol consumption or stuttering and smoking at any of the ages. It was speculated that the absence of significant associations might be due to avoidance of social situations on the part of many of the participants who stutter, or adoption of alternative coping strategies. CONCLUSION: Because of the association between anxiety and substance use, individuals who stutter and are anxious might be found to drink or smoke excessively, but as a group, people who stutter are not more likely than those who do not to have high levels of consumption of alcohol or nicotine. PMID- 27498893 TI - International Phase II clinical trial of CBTPsych: A standalone Internet social anxiety treatment for adults who stutter. AB - PURPOSE: CBTPsych is an individualized, fully automated, standalone Internet treatment program that requires no clinical contact or support. It is designed specifically for those who stutter. Two preliminary trials demonstrated that it may be efficacious for treating the social anxiety commonly associated with stuttering. However, both trials involved pre- and post-treatment assessment at a speech clinic. This contact may have increased compliance, commitment and adherence with the program. The present study sought to establish the effectiveness of CBTPsych in a large international trial with no contact of any kind from researchers or clinicians. METHOD: Participants were 267 adults with a reported history of stuttering who were given a maximum of 5 months access to CBTPsych. Pre- and post-treatment functioning was assessed within the online program with a range of psychometric measures. RESULTS: Forty-nine participants (18.4%) completed all seven modules of CBTPsych and completed the post-treatment online assessments. That compliance rate was far superior to similar community trials of self-directed Internet mental health programs. Completion of the program was associated with large, statistically and clinically significant reductions for all measures. The reductions were similar to those obtained in earlier trials of CBTPsych, and those obtained in trials of in-clinic CBT with an expert clinician. CONCLUSIONS: CBTPsych is a promising individualized treatment for social anxiety for a proportion of adults who stutter, which requires no health care costs in terms of clinician contact or support. EDUCATIONAL OBJECTIVES: The reader will be able to: (a) discuss the reasons for investigating CBTPsych without any clinical contact; (b) describe the main components of the CBTPsych treatment; (c) summarize the results of this clinical trial; (d) describe how the results might affect clinical practice, if at all. PMID- 27498894 TI - Phase II trial of a syllable-timed speech treatment for school-age children who stutter. AB - PURPOSE: A recent clinical trial (Andrews et al., 2012) showed Syllable Timed Speech (STS) to be a potentially useful treatment agent for the reduction of stuttering for school-age children. The present trial investigated a modified version of this program that incorporated parent verbal contingencies. METHODS: Participants were 22 stuttering children aged 6-11 years. Treatment involved training the children and their parents to use STS in conversation. Parents were also taught to use verbal contingencies in response to their child's stuttered and stutter-free speech and to praise their child's use of STS. Outcome assessments were conducted pre-treatment, at the completion of Stage 1 of the program and 6 months and 12 months after Stage 1 completion. RESULTS: Outcomes are reported for the 19 children who completed Stage 1 of the program. The group mean percent stuttering reduction was 77% from pre-treatment to 12 months post treatment, and 82% with the two least responsive participants removed. There was considerable variation in response to the treatment. Eleven of the children showed reduced avoidance of speaking situations and 18 were more satisfied with their fluency post-treatment. However, there was some suggestion that stuttering control was not sufficient to fully eliminate situation avoidance for the children. CONCLUSIONS: The results of this trial are sufficiently encouraging to warrant further clinical trials of the method. PMID- 27498895 TI - Affinity Crystallography: A New Approach to Extracting High-Affinity Enzyme Inhibitors from Natural Extracts. AB - Natural products are an important source of novel drug scaffolds. The highly variable and unpredictable timelines associated with isolating novel compounds and elucidating their structures have led to the demise of exploring natural product extract libraries in drug discovery programs. Here we introduce affinity crystallography as a new methodology that significantly shortens the time of the hit to active structure cycle in bioactive natural product discovery research. This affinity crystallography approach is illustrated by using semipure fractions of an actinomycetes culture extract to isolate and identify a cathepsin K inhibitor and to compare the outcome with the traditional assay-guided purification/structural analysis approach. The traditional approach resulted in the identification of the known inhibitor antipain (1) and its new but lower potency dehydration product 2, while the affinity crystallography approach led to the identification of a new high-affinity inhibitor named lichostatinal (3). The structure and potency of lichostatinal (3) was verified by total synthesis and kinetic characterization. To the best of our knowledge, this is the first example of isolating and characterizing a potent enzyme inhibitor from a partially purified crude natural product extract using a protein crystallographic approach. PMID- 27498897 TI - Editorial (Thematic Issue: Acute and Chronic Kidney Injury: From Basic Science to Clinical Practice). PMID- 27498896 TI - Widespread adaptive evolution during repeated evolutionary radiations in New World lupins. AB - The evolutionary processes that drive rapid species diversification are poorly understood. In particular, it is unclear whether Darwinian adaptation or non adaptive processes are the primary drivers of explosive species diversifications. Here we show that repeated rapid radiations within New World lupins (Lupinus, Leguminosae) were underpinned by a major increase in the frequency of adaptation acting on coding and regulatory changes genome-wide. This contrasts with far less frequent adaptation in genomes of slowly diversifying lupins and all other plant genera analysed. Furthermore, widespread shifts in optimal gene expression coincided with shifts to high rates of diversification and evolution of perenniality, a putative key adaptation trait thought to have triggered the evolutionary radiations in New World lupins. Our results reconcile long-standing debate about the relative importance of protein-coding and regulatory evolution, and represent the first unambiguous evidence for the rapid onset of lineage- and genome-wide accelerated Darwinian evolution during rapid species diversification. PMID- 27498898 TI - Acute Renal Failure - A Serious Complication in Patients After Kidney Transplantation. AB - Free radical-mediated injury releases proinflammatory cytokines and activates innate immunity. It has been suggested that the early innate response and the ischemic tissue damage play roles in the development of adaptive responses, which may lead to acute kidney rejection. Various durations of hypothermic kidney storage before transplantation add to ischemic tissue damage. The final stage of ischemic injury occurs during reperfusion that develops hours or days after the initial insult. Repair and regeneration processes occur together with cellular apoptosis, autophagy and necrosis and a favorable outcome is expected if regeneration prevails. Along the entire transplantation time course, there is a great demand for novel immune and nonimmune injury biomarkers. The use of these markers can be of great help in the monitoring of kidney injury in potential kidney donors, where acute kidney damage can be overlooked, in predicting acute transplant dysfunction during the early post-transplant periods, or in predicting chronic changes in long term followup. Numerous investigations have demonstrated that biomarkers that have the highest predictive value in acute kidney injury include NGAL, Cystatin C, KIM-1, IL-18, and L-FABP. Most investigations show that the ideal biomarker to fulfill all the needs in renal transplant has not been identified yet. Although, in many animal models, new biomarkers are emerging for predicting acute and chronic allograft damage, in human allograft analysis they are still not routinely accepted and renal biopsy still remains the gold standard. PMID- 27498899 TI - Adhesion and non-linear rheology of adhesives with supramolecular crosslinking points. AB - Soft supramolecular materials are promising for the design of innovative and highly tunable adhesives. These materials are composed of polymer chains functionalized by strongly interacting moieties, sometimes called "stickers". In order to systematically investigate the effect of the presence of associative groups on the debonding properties of a supramolecular adhesive, a series of supramolecular model systems has been characterized by probe-tack tests. These model materials, composed of linear and low dispersity poly(butylacrylate) chains functionalized in the middle by a single tri-urea sticker, are able to self associate by six hydrogen bonds and range in molecular weight (Mn) between 5 and 85 kg mol(-1). The linear rheology and the nanostructure of the same materials (called "PnBA3U") were the object of a previous study. At room temperature, the association of polymers via hydrogen bonds induces the formation of rod-like aggregates structured into bundles for Mn < 40 kg mol(-1) and the behavior of a soft elastic material was observed (G'?G'' and G'~omega(0)). For higher Mn materials, the filaments were randomly oriented and the polymers displayed a crossover towards viscous behavior although terminal relaxation was not reached in the experimental frequency window. All these materials show, however, similar adhesive properties characterized by a cohesive mode of failure and low debonding energies (Wadh < 40 J m(-2) for a debonding speed of 100 MUm s(-1)). The debonding mechanisms observed during the adhesion tests have been investigated in detail with an Image tools analysis developed by our group. The measure of the projected area covered by cavities growing in the adhesive layer during debonding can be used to estimate the true stress in the walls of the cavities and thus to characterize the in situ large strain deformation of the thin layer during the adhesion test itself. This analysis revealed in particular that the PnBA3U materials with Mn < 40 kg mol(-1) soften very markedly at large deformation like yield stress fluids, explaining the low adhesion energies measured for these viscoelastic gels. PMID- 27498900 TI - Change in Ankle-Brachial Index Over Time in a Screened Japanese Cohort - The Okinawa Peripheral Arterial Disease Study. AB - BACKGROUND: The temporal change in ankle-brachial index (ABI) in the general population, especially in those aged <40 years, remains unclear. METHODS AND RESULTS: ABIs of 23,673 individuals were measured in 1-day health checkups between 2003 and 2010. Among them, 1,117 participants aged 28-76 years (mean 53+/ 9 years) whose ABI was measured at least twice within an interval of >=4 years (mean: 4.9 years) were selected for this study. Baseline ABI was the lowest at age <40 years and increased with age. ABI significantly increased in participants aged <40 and 40-49 years, but not in participants aged 50-59 and >=60 years. ABI increased in participants with borderline-low baseline ABI (0.930). Extant evidence supports the association between obesity and adverse health outcomes among individuals with depressive disorders. In addition, the treatment of one condition (i.e. obesity or depressive disorders) appears to improve the course of the other condition. It might be beneficial to check for the other condition in patients presenting with one condition and treatment should be administered to treat both conditions. PMID- 27498908 TI - miR-124 inhibits proliferation and invasion of human retinoblastoma cells by targeting STAT3. AB - A growing body of evidence suggests that microRNA-124 (miR-124) functions as tumor-suppressor, and involves in tumor initiation, development and metastasis in major classes of human cancers; however, the biological role and underlying molecular mechanism of miR-124 in retinoblastoma (RB) remain unknown. Therefore, we investigated the biological activity and underlying molecular mechanism of miR 124 in human retinoblastoma. In the present study, our results demonstrated the downregulation of miR-124 in RB tissues and RB cell lines compared with normal retinal tissues. The ectopic expression of miR-124 in the RB cell lines (Y79 and SO-RB50) suppresses cell proliferation, migration and invasion, induced cell apoptosis in vitro. Furthermore, signal transducer and activator of transcription 3 (STAT3) was identified as a new target of miR-124, and overexpression of miR 124 decreased STAT3 expression on mRNA level and protein level in human RB cells. We also found that STAT3 mRNA expression was upregulated and inversely correlated with miR-124 expression in the RB tissues (r=-0.683; P<0.001). Restoration of the expression of STAT3 rescues the effects induced by miR-124 in RB cells. The findings of the present study suggested that miR-124 functioned as tumor suppressor in RB, at least in part, by targeting STAT3, and that it could serve as a potential candidate for RB therapeutics. PMID- 27498909 TI - Asbestos concerns in Australian buildings. PMID- 27498910 TI - Gene mutation linked to familial Barrett's oesophagus. PMID- 27498911 TI - Delirium in patients with advanced cancer. PMID- 27498912 TI - Are sarcomas hereditary? PMID- 27498913 TI - Monogenic and polygenic determinants of sarcoma risk: an international genetic study. AB - BACKGROUND: Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice. METHODS: In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls). FINDINGS: The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29-58), 170 (15%) of 1162 probands had multiple primary cancers, and 155 (17%) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55%) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1.43, 95% CI 1.24-1.64, p<0.0001), with 227 known or expected pathogenic variants occurring in 217 individuals. All classes of pathogenic variants (known, expected, or predicted) were associated with earlier age of cancer onset. In addition to TP53, ATM, ATR, and BRCA2, an unexpected excess of functionally pathogenic variants was seen in ERCC2. Probands were more likely than controls to have multiple pathogenic variants compared with the combined control cohort group and the LifePool control cohort (OR 2.22, 95% CI 1.57-3.14, p=1.2 * 10(-6)) and the cumulative burden of multiple variants correlated with earlier age at cancer diagnosis (Mantel-Cox log-rank test for trend, p=0.0032). 66 of 1162 probands carried notifiable variants following expert clinical review (those recognised to be clinically significant to health and about which patients should be advised), whereas 293 (25%) probands carried variants with potential therapeutic significance. INTERPRETATION: About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment. FUNDING: Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, National Cancer Institute, Liddy Shriver Sarcoma Initiative. PMID- 27498914 TI - Genetic variation within GRIN2B in adolescents with alcohol use disorder may be associated with larger left posterior cingulate cortex volume. AB - OBJECTIVE: Brain structure differences and adolescent alcohol dependence both show substantial heritability. However, exactly which genes are responsible for brain volume variation in adolescents with substance abuse disorders are currently unknown. The aim of this investigation was to determine whether genetic variants previously implicated in psychiatric disorders are associated with variation in brain volume in adolescents with alcohol use disorder (AUD). METHODS: The cohort consisted of 58 adolescents with DSM-IV AUD and 58 age and gender-matched controls of mixed ancestry ethnicity. An Illumina Infinium iSelect custom 6000 bead chip was used to genotype 5348 single nucleotide polymorphisms (SNPs) in 378 candidate genes. Magnetic resonance images were acquired and volumes of global and regional structures were estimated using voxel-based morphometry. To determine whether any of the genetic variants were associated with brain volume, association analysis was conducted using linear regression in Plink. RESULTS: From the exploratory analysis, the GRIN2B SNP rs219927 was associated with brain volume in the left posterior cingulate cortex (p<0.05), whereby having a G-allele was associated with a bigger volume. CONCLUSION: The GRIN2B gene is involved in glutamatergic signalling and may be associated with developmental differences in AUD in brain regions such as the posterior cingulate cortex. Such differences may play a role in risk for AUD, and deserve more detailed investigation. PMID- 27498915 TI - A mysterious case of fever and renal failure in a traveler from Finland: nephropathia epidemica. PMID- 27498916 TI - Inhaled corticosteroids increase blood neutrophil count by decreasing the expression of neutrophil adhesion molecules Mac-1 and L-selectin. AB - OBJECTIVE: The objective was to investigate the effect of commonly used inhaled corticosteroids on white blood cell count (WBC) and to examine the mechanisms involved. METHODS: This randomized comparative study comprised 60 healthy adults. We measured the effects of budesonide (by face mask inhalation or aerosol inhaler), fluticasone (by inhaler), and saline inhalation (control) on WBC and the differential leukocyte count, especially the absolute neutrophil count (ANC). To elucidate the mechanisms involved, we measured the expression of the adhesion neutrophil ligands Mac-1 (CD11b) and L-selectin (CD62L), and granulocyte colony stimulating factor serum levels. RESULTS: Six hours after a single-dose inhalation of budesonide, mean increases of 23.4% in WBC (95% confidence interval [CI], 11.3-35.4) and 30.1% in ANC (95% CI, 7.2-53.0) were noted. The percentage of neutrophils increased from 54.6% to 58.1% (P< .001). Inhaled fluticasone increased WBC and ANC by 12.6% (95% CI, 1.5-23.7) and 22.7% (95% CI, 6.2-39.2), respectively (P< .01 for both). The absolute lymphocyte and eosinophil counts did not change significantly from baseline. The expression of Mac-1 and L-selectin decreased by 51.0% (P< .01) and 30.9% (P= .02), respectively, following face mask inhalation of budesonide and by 39.8% (P= .01) and 17.4% (P= .17), respectively, following inhalation of fluticasone. No significant changes in granulocyte colony stimulating factor levels were noted. CONCLUSIONS: Glucocorticoid inhalation increases WBC by increasing ANC. Reduced neutrophil adhesion to the endothelial surface, mediated by decreased adhesion molecule expression on neutrophils, is a plausible mechanism. Physicians should be aware of the effect of inhaled corticosteroids on WBC, as it may influence clinical decisions, especially in the emergency department. PMID- 27498917 TI - Hospital-level variation and predictors of admission after ED visits for atrial fibrillation: 2006 to 2011. AB - BACKGROUND: Outpatient management of atrial fibrillation can be a safe alternative to inpatient admission after emergency department (ED) visits. We aim to describe trends and predictors of hospital admission for atrial fibrillation and determine the variation in admission among US hospitals. METHODS: We analyzed ED visits and hospital admissions for adult patients with a principal diagnosis of atrial fibrillation or atrial flutter in the Nationwide Emergency Department Sample 2006 to 2011. We identified patient and hospital characteristics associated with admission using hierarchical multivariate logistic regression. We analyzed admission rates overall and for patients at low risk of thromboembolic complications (CHA2DS2-VASc score 0). We compared hospital-level variance with residual variance to estimate the intraclass correlation in models with and without hospital characteristics. RESULTS: From 2006 to 2011, annual ED visits for atrial fibrillation and atrial flutter increased by 30.9% and admission rates decreased from 69.7% to 67.4% (P= .02). Admission was associated with setting (metropolitan teaching vs nonmetropolitan, odds ratio = 1.93 [1.62-2.29]) and region (Northeast vs West, odds ratio = 2.09 [1.67-2.60]). Among patients with 0 CHA2DS2-VASc score, the national average admission rate was 46.4%. The intraclass correlation was 20.7% adjusting for patient characteristics and hospital clustering, and 19.2% after additionally adjusting for hospital variables. CONCLUSIONS: From 2006 to 2011, ED visits for atrial fibrillation in the United States increased by almost a third, with a minimal change in ED admission rates. One-fifth of variation in admission rates is due to hospital site and not explained by hospital characteristics. Hospital-specific practice patterns may identify opportunities to increase outpatient management. PMID- 27498918 TI - Single rescuer ventilation using a bag-valve mask with internal handle: a randomized crossover trial. AB - OBJECTIVE: To compare tidal volume received during single rescuer ventilation with a modified bag-valve mask (BVM) with integrated internal handle vs standard BVM among healthy volunteers using a manikin model. METHODS: This study was a randomized crossover trial of adult healthcare provider volunteers performing ventilation on a manikin. We randomized participants to perform single rescuer ventilation first using either a modified BVM with integrated internal handle or a standard unmodified BVM. Participants were responsible for mask placement and delivery of 10 breaths per minute for 3 minutes as guided by a metronome. After a 3-minute rest period, they performed ventilation using the alternative device. The primary outcome measure was mean received tidal volume as measured by the manikin (IngMar RespiTrainer model). Secondary outcomes included participant reported device preference. RESULTS: Of 70 recruited participants, all completed the study. Mean received tidal volume was higher using the modified BVM with integrated internal handle vs standard BVM by 90 mL (95% confidence interval, 60 120 mL; P< .0001). There were no significant differences in mean received tidal volume based on the order of study arm allocation. Eighty percent of participants reported preference for the modified BVM over the standard BVM (95% confidence interval, 70.0%-80.0%). CONCLUSIONS: The modified BVM with integrated internal handle results in greater mean received tidal volume compared with standard BVM during single rescuer ventilation in a manikin model. This modified BVM design may prove a useful airway adjunct for ventilation. PMID- 27498920 TI - Hydrophobicity effects in iron polypyridyl complex electrocatalysis within Nafion thin-film electrodes. AB - Four polypyridyl redox catalysts Fe(bp)3(2+), Fe(ph)3(2+), Fe(dm)3(2+), and Fe(tm)3(2+) (with bp, ph, dm, and tm representing 2,2'-bipyridine, 1,10 phenanthroline, 4,4'-dimethyl-2,2'-bipyridine, and 3,4,7,8-tetramethyl-1,10 phenanthroline, respectively) are investigated for the electrocatalytic oxidation of three analytes (nitrite, arsenite, and isoniazid). The poly-pyridyl iron complex is exchanged into a Nafion film immobilized on a glassy carbon electrode, which is then immersed in 0.1 M Na2SO4. Cyclic voltammetry is employed for the evaluation of the mechanism and estimation of kinetic parameters. The electrocatalytic behaviour going from low to high substrate concentration is consistent with the Albery-Hillman cases of "LEty" switching to "LEk" (changing from the first order in the substrate to half order in the substrate), denoting a process that occurs in a reaction zone close to the electrode surface with diffusion of charge (from the electrode surface into the film) and of anionic or neutral analyte (from the Nafion-solution interface into the film). The relative hydrophobicity of the iron polypyridyl catalyst within the film is shown to affect both the diffusion of charge/electrons and analyte within the film with Fe(tm)3(2+) providing the mildest catalyst. All three analytes, nitrite, isoniazid, and arsenite, exhibit linear calibration ranges beneficial for analytical applications in the micro-molar to the milli-molar range. PMID- 27498919 TI - Imaging human teeth by phosphorus magnetic resonance with nuclear Overhauser enhancement. AB - Three-dimensional phosphorus MR images ((31)P MRI) of teeth are obtained at a nominal resolution of 0.5 mm in less than 15 minutes using acquisition pulse sequences sensitive to ultra-short transversal relaxation times. The images directly reflect the spatially resolved phosphorus content of mineral tissue in dentin and enamel; they show a lack of signal from pulp tissue and reduced signal from de-mineralized carious lesions. We demonstrate for the first time that the signal in (31)P MR images of mineralized tissue is enhanced by a (1)H-(31)P nuclear Overhauser effect (NOE). Using teeth as a model for imaging mineralized human tissue, graded differences in signal enhancement are observed that correlate well with known mineral content. From solid-state NMR experiments we conclude that the NOE is facilitated by spin diffusion and that the NOE difference can be assigned to a higher water content and a different micro structure of dentin. Thus, a novel method for imaging mineral content without ionizing radiation is proposed. This method has potential use in the assessment of de-mineralization states in humans, such as caries of teeth and osteoporosis of bones. PMID- 27498921 TI - The High-efficiency LED Driver for Visible Light Communication Applications. AB - This paper presents a LED driver for VLC. The main purpose is to solve the low data rate problem used to be in switching type LED driver. The GaN power device is proposed to replace the traditional silicon power device of switching LED driver for the purpose of increasing switching frequency of converter, thereby increasing the bandwidth of data transmission. To achieve high efficiency, the diode-connected GaN power transistor is utilized to replace the traditional ultrafast recovery diode used to be in switching type LED driver. This work has been experimentally evaluated on 350-mA output current. The results demonstrate that it supports the data of PWM dimming level encoded in the PPM scheme for VLC application. The experimental results also show that system's efficiency of 80.8% can be achieved at 1-Mb/s data rate. PMID- 27498922 TI - Combination of nadroparin with radiotherapy results in powerful synergistic antitumor effects in lung adenocarcinoma A549 cells. AB - Low-molecular-weight heparins (LMWHs), which are commonly used in venous thromboprophylaxis and treatment, have recently been reported to have effects on cancer metastasis in pre-clinical research studies. This study was planned to define the synergistic antitumor effects of nadroparin (a kind of LMWH) combined with radiotherapy in A549 cells. Six experimental groups were set up in our study according to the different treatment: control group; irradiation (IR) group; low dose of nadroparin group (LMWH50, L50); high dose of nadroparin group (LMWH100, L100); LMWH50+IR group; LMWH100+IR group. The viability of A549 cells was assessed by Cell Counting Kit-8 (CCK-8) assay. The apoptosis of tumor cells was analyzed by flow cytometry (FCM) after treatment. The concentration of transforming growth factor-beta1 (TGF-beta1) in the culture supernatants was measured by enzyme-linked immunosorbent assay (ELISA). The migration and invasion of the A549 cells were tested by the Transwell chamber assay. The expression of survivin, CD147 and matrix metalloproteinase-2 (MMP-2) was analyzed by western blotting. CCK-8 assay showed that irradiation or nadroparin alone slightly inhibited the cell viability while the combined treatments significantly inhibited the cell viability in a dose- and time-dependent manner. The apoptosis rate showed greater improvement dose- and time-dependently in the groups receiving combination therapy of nadroparin and irradiation than the control group or the group receiving nadroparin or irradiation alone by FCM. ELISA assay showed that the decreased TGF-beta1 secretion was found after combined treatments with nadroparin and irradiation compared to either treatment alone. The Transwell chamber assay showed that nadroparin not only significantly suppressed the migration and invasion of A549 cells but also inhibited the enhanced ability of migration and invasion induced by X-ray irradiation. Western blotting showed that nadroparin inhibited the upregulated effects of survivin and MMP-2 expression induced by radiation in the combined treatment groups in a dose- and time dependent manner. Moreover, the expression level of CD147 was the lowest in the combined treatment groups. This study identified that combination of nadroparin and irradiation had a strong synergistic antitumor effect in a dose- and time related manner in vitro, which was reflected in the inhibition of cell viability, invasion and metastasis, promotion of apoptosis, inhibited secretion level of TGF beta1 and downregulation of CD147, MMP-2 and survivin expression. PMID- 27498923 TI - Pd-Catalyzed C-S Activation/Isocyanide Insertion/Hydrogenation Enables a Selective Aerobic Oxidation/Cyclization. AB - Unique imidoylation of thioorganics with isocyanides endows an unprecedented aerobic oxidation process. Catalyzed by Pd(Ph3P)2Cl2 in the presence of Ph3SiH under N2 then upon exposure to air, a wide range of alpha-acyl ketene dithioacetals react with isocyanides to afford 5-hydroxy-alpha,beta-unsaturated gamma-lactams via a C-S bond activation, isocyanide migratory insertion, hydrogenation, selective aerobic oxidation, and intramolecular nucleophilic addition sequence. PMID- 27498924 TI - MicroRNA-186 suppresses cell proliferation and metastasis through targeting MAP3K2 in non-small cell lung cancer. AB - MicroRNAs are a class of small endogenous non-coding RNAs that play crucial roles in the initiation and progression of human cancers. miR-186 was found decreased in various human malignancies and function as a tumor suppressor. However, the regulating mechanism of miR-186 in growth and metastasis of human non-small cell lung cancer (NSCLC) is still poorly understood. We investigated the role of miR 186 in the growth and metastasis of human NSCLC. In the present study, we found that miR-186 was significantly decreased in lung cancer tissues and cells. Furthermore, overexpression of miR-186 suppressed lung cancer cell proliferation, migration and invasion, and induced cell apoptosis. Moreover, we found that confirmed mitogen-activated protein kinase kinase kinase 2 (MAP3K2) protein was increased in lung cancer tissues and confirmed that MAP3K2 is a target gene of miR-186. In addition, knockdown of MAP3K2 by RNA interference inhibited lung cancer cell proliferation, migration and invasion, and promoted cell apoptosis in vitro. Furthermore, we observed tthat the overexpression of MAP3K2 partially reversed the inhibitory effect of miR-186 on the proliferation and metastasis of A549 and HCC827 cell lines. Taken together, our data indicated that miR-186 regulates lung cancer growth and metastasis through suppressing MAP3K2 expression, at least partly. Therefore, miR-186-MAP3K2 may represent a new and useful potential clinical treatment and diagnosis target for NSCLC. PMID- 27498925 TI - Emerging roles for brain drug-metabolizing cytochrome P450 enzymes in neuropsychiatric conditions and responses to drugs. AB - P450s in the human brain were originally considered unlikely to contribute significantly to the clearance of drugs and other xenobiotic chemicals, since their overall expression was a small fraction of that found in the liver. However, it is now recognized that P450s play substantial roles in the metabolism of both exogenous and endogenous chemicals in the brain, but in a highly cell type- and region-specific manner, in line with the greater functional heterogeneity of the brain compared to the liver. Studies of brain P450 expression and the characterization of the catalytic activity of specific forms expressed as recombinant enzymes have suggested possible roles for xenobiotic metabolizing P450s in the brain. It is now possible to confirm these roles through the use of intracerebroventricular administration of selective P450 inhibitors in animal models, coupled with brain sampling techniques to measure drug concentrations in vivo, and modern neuroimaging techniques. The purpose of this review is to discuss the evidence behind the functional importance of P450s from the "xenobiotic-metabolizing" families, CYP1, CYP2 and CYP3 in the brain. Approaches used to define the quantitative and qualitative significance of these P450s in determining tissue-specific levels of xenobiotics in brain will be considered. Finally, the possible roles of these enzymes in brain biochemistry will be examined in light of the demonstrated activity of these enzymes in vitro and the association of particular P450 forms with disease states. PMID- 27498926 TI - Translocation of mineralo-organic nanoparticles from blood to urine: a new mechanism for the formation of kidney stones? AB - Recent studies indicate that mineralo-organic nanoparticles form in various human body fluids, including blood and urine. These nanoparticles may form within renal tubules and increase in size in supersaturated urine, eventually leading to the formation of kidney stones. Here, we present observations suggesting that mineralo-organic nanoparticles found in blood may induce kidney stone formation via an alternative mechanism in which the particles translocate through endothelial and renal epithelial cells to reach urine. We propose that this alternative mechanism of kidney stone formation and the study of mineralo-organic nanoparticles in general may provide novel strategies for the early detection and treatment of ectopic calcifications and kidney stones. PMID- 27498928 TI - Understanding the mechanism of LCST phase separation of mixed ionic liquids in water by MD simulations. AB - Recently, it has been found experimentally that two different amino acid ionic liquids (ILs) can be mixed to show unique lowest critical solution temperature (LCST) phase separation in water. However, little is known about the mechanism of phase separation in these IL/water mixtures at the molecular level. In this work, five kinds of amino acid ILs were chosen to study the mechanism of LCST-type phase separation by molecular dynamics (MD) simulations. Toward this end, a series of all-atom MD simulations were carried out on the ternary mixtures consisting of two different ILs and water at different temperatures. The various interaction energies and radial distribution functions (RDFs) were calculated and analyzed for these mixed systems. It was found that for amino acid ILs, the -NH2 or -COOH group of one anion could have a hydrogen bonding interaction with the COO(-) group of another anion. With the increase of temperature, this kind of hydrogen bonding interaction between anions was strengthened and then the anion H2O electrostatic interaction was weakened, which led to the LCST-type phase separation of the mixed ILs in water. In addition, a series of MD simulations for [P6668]1[Lys]n[Asp]1-n/H2O systems were also performed to study the effect of the mixing ratio of ILs on phase separation. It was also noted that the experimental critical composition corresponding to the lowest critical solution temperature was well predicted from the total electrostatic interaction energies as a function of mole fraction of [P6668][Lys] in these systems. The conclusions drawn from this study may provide new insight into the LCST-type phase behavior of ILs in water, and motivate further studies on practical applications. PMID- 27498927 TI - Metastatic clear cell renal cell carcinoma: Circulating biomarkers to guide antiangiogenic and immune therapies. AB - BACKGROUND: The therapeutic armamentarium for metastatic renal cell carcinoma has rapidly expanded over the past decade to include a number of anti-angiogenic therapies and more recently, an immunotherapy. Biomarkers in the peripheral circulation are easily accessible, can provide important prognostic value, and have the potential to give important information about disease progression and treatment sensitivity or response. MAIN FINDINGS: Herein, we review a variety of circulating markers including circulating protein markers (VEGF-A, inflammatory cytokines, and LDH), circulating nucleic acids (cell free DNA and micro RNAs), and circulating cellular factors (circulating tumor cells, circulating endothelial cells, and immune cell subsets). We discuss these biomarkers in the context of their ability to provide prognostic and predictive information to anti angiogenic and immunotherapeutic agents. PRINCIPAL CONCLUSIONS: While promising, there is still much work to be done, and prospective evaluation of any potential predictive biomarker for these therapies is greatly needed. PMID- 27498929 TI - Clinical feature and pathophysiology of acute pancreatitis. PMID- 27498930 TI - Progress of acute pancreatitis in basic study. PMID- 27498931 TI - The current situations and issues of early management for acute pancreatitis. PMID- 27498932 TI - Current status of ERCP pancreatitis and matters in future. PMID- 27498933 TI - Endoscopic management of the complications after acute pancreatitis. PMID- 27498934 TI - Chronic nonspecific multiple ulcers of the small intestine (CNSU) and chronic enteropathy associated with SLCO2A1 (CEAS). PMID- 27498935 TI - Efficacy of a diagnostic and therapeutic algorithm for Clostridium difficile infection. AB - In July 2012, metronidazole was approved for the treatment of Clostridium difficile infection (CDI). To clarify the selection criteria for the drug in terms of CDI severity, we established a diagnostic and therapeutic algorithm with reference to the SHEA-IDSA Clinical Practice Guidelines. We compared patients whose treatments were guided by the algorithm (29 cases, October 2012-September 2013) with patients treated prior to the development of the algorithm (37 cases, October 2011-September 2012). All cases treated with reference to the algorithm were diagnosed using enzyme immunoassay of C. difficile toxins A and B and glutamate dehydrogenase;an appropriate drug was prescribed in 93.1% of the cases. We found no significant between-group differences in the cure, recurrence, or complication rates. However, drug costs in cases wherein treatments were guided by the algorithm were markedly reduced. We have, thus, shown that algorithm guided treatment is efficacious and cost-effective. PMID- 27498936 TI - A case of large cell neuroendocrine carcinoma of the stomach with multiple liver metastases. AB - A 79-year-old man was admitted to our hospital to determine the cause of his melena. He underwent esophagogastric endoscopy and computed tomography, revealing a submucosal tumor on the anterior wall of the gastric antrum with multiple liver metastases. Endoscopic biopsy revealed a large cell neuroendocrine cell carcinoma. A subtotal gastrostomy was performed to prevent pyloric stenosis and anemia caused by tumor hemorrhage. Previous studies on gastric neuroendocrine carcinoma reported poor prognosis. Large- and small-cell types of gastric neuroendocrine carcinomas were differentiated for the first time in the 14th edition of the Japanese Classification of Gastric Carcinoma. It is expected that the number of reports of gastric neuroendocrine carcinomas classified as either the large-cell or small-cell type will increase. It is necessary to collect information on more cases to improve prognosis and to establish appropriate treatment guidelines. PMID- 27498937 TI - A case report on metastatic pancreatic tumor from pulmonary adenocarcinoma that difficult to differentiate from primary pancreatic ductal carcinoma. AB - A woman was admitted to our department for lung adenocarcinoma and she was treated with left upper lobectomy. The carcinoembryonic antigen level had increased. Enhanced computed tomography showed a hypovascular tumor in the pancreatic tail and in the extension of the distal main pancreatic duct. Endoscopic ultrasonography (EUS) clearly showed a low echoic lesion, and histological examination revealed adenocarcinoma. On immunostaining, the lesion was diagnosed as metastatic adenocarcinoma of the lungs. The patient was treated with chemotherapy for lung cancer and survived for 4 years after diagnosis. Differentiating a metastatic lesion to the pancreas from pancreatic ductal adenocarcinoma is very important. Accurate diagnosis enables administration of appropriate treatment. In this case, EUS was especially useful for assessing the tumor in the pancreas. When patients with a history of extra-pancreatic cancer present with a pancreatic lesion, pancreatic metastases should be considered, regardless of the time elapsed since occurrence of the primary cancer. EUS-fine needle aspiration (FNA) with histological examination is the best method for definitive diagnosis of pancreatic disease in this group of patients. This approach has very high sensitivity and accuracy for the diagnosis of pancreatic metastases. PMID- 27498938 TI - Autopsy of anaplastic carcinoma of the pancreas producing granulocyte colony stimulating factor. AB - A 50-year-old man presented to a nearby hospital with high fever and anorexia. An abdominal tumor was detected, and he was referred to our hospital. A pancreatic tumor was detected by computed tomography and abdominal ultrasonography. He had high fever, leukocytosis, and high serum granulocyte colony-stimulating factor (G CSF). We performed a tumor biopsy and histological examination revealed anaplastic carcinoma of the pancreas. Based on the diagnosis, we initiated chemotherapy using gemcitabine plus S-1. However, the tumor rapidly progressed and he deteriorated and died 123 days after admission. As immunohistochemical study showed positive staining for G-CSF in the tumor cell, we diagnosed the tumor producing G-CSF during autopsy. Anaplastic carcinoma of the pancreas producing G-CSF is very rare, with 10 cases, including ours, reported in the literature. PMID- 27498939 TI - A case of intraductal papillary mucinous neoplasm with high serum pepsinogen II level. AB - We report the case of a 65-year-old woman who had a high level of serum pepsinogen II. Several months earlier, she had found a mass on the right side of her upper abdomen. Esophagogastroduodenoscopy did not reveal atrophic or inflammatory findings. She had not taken proton pump inhibitors, and there was no indication of renal dysfunction. Imaging tests showed a mass of approximately 80mm in the pancreatic head. We performed pancreatoduodenectomy, and the histopathological examination revealed an intraductal papillary mucinous neoplasm (IPMN) of gastric type. Serum pepsinogen II levels substantially lowered after surgery. To the best of our knowledge, this is the first report on a relationship between IPMN and serum pepsinogen II. PMID- 27498940 TI - A case of adenosquamous carcinoma of the lower bile duct diagnosed preoperatively via transpapillary biopsy. AB - A 78-year-old man presented to our hospital with fever and brownish urine. Upon thorough examination, a diagnosis of obstructive jaundice and acute cholangitis associated with a lower bile duct tumor was made. Endoscopic retrograde cholangiopancreatography revealed entire circumferential stenosis of the lower bile duct. Examination of a transpapillary biopsy specimen of the lesion suggested adenosquamous carcinoma. The patient underwent subtotal stomach preserving pancreaticoduodenectomy. Histopathological examination revealed adenocarcinoma of the lower bile duct and squamous cell carcinoma components;a case of adenosquamous carcinoma was accordingly diagnosed. The lower bile duct tumor directly extended into the pancreatic parenchyma for approximately 1mm. We performed radical surgery and administered adjuvant chemotherapy with gemcitabine because of advanced neural invasion after consulting with the patient. There was no sign of recurrence 46 months after surgery. As adenosquamous carcinoma of the extrahepatic bile duct is rare, it is difficult to preoperatively diagnose the condition. Only a few cases have been reported till date. PMID- 27498941 TI - To the Editor. PMID- 27498942 TI - In vitro study comparing the efficacy of the water-soluble HSP90 inhibitors, 17 AEPGA and 17-DMAG, with that of the non-water-soluble HSP90 inhibitor, 17-AAG, in breast cancer cell lines. AB - Heat shock protein (HSP)90 has emerged as an important target in cancer therapeutics. Diverse HSP90 inhibitors are under evaluation. The aim of the present study was to investigate the growth inhibitory effects of the newly developed water-soluble HSP90 inhibitors, 17-[2-(Pyrrolidin-1-yl)ethyl]amino-17 demethoxygeldanamycin (17-AEPGA) and 17-dimethylaminoethylamino-17 demethoxygeldanamycin (17-DMAG), compared to that of the non-water-soluble HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG). The anti proliferative effects of the 3 drugs on the human breast cancer cell lines, MCF 7, SKBR-3 and MDA-MB-231, were examined in vitro. In addition, tumor progression factors, including human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor 1 (EGFR1) and insulin-like growth factor type 1 receptor (IGF1R), as well as apoptotic markers were analysed. We found a time- and dose dependent effect in all the tested cell lines. The effects of 17-AEPGA and 17 DMAG were equal or superior to those of 17-AAG. The 50% growth inhibition concentration was <2 uM for the water-soluble compounds following 72 h of exposure. The significant inhibition of HER2, EGFR1 and IGF1R protein expression was already evident at the concentration of 1 uM. Apoptosis was examined by caspase-3 and poly(ADP-ribose) polymerase (PARP) assay at the concentration of 1 uM of the inhibitors. HSP70 was upregulated, but HSP27 expression was not affected. Our data indicate that 17-AEPGA and 17-DMAG are highly active in breast cancer cell lines and may help to overcome the delivery issues associated with the use of 17-AAG. PMID- 27498943 TI - Advances in corneal cell therapy. AB - Corneal integrity is essential for visual function. Transplantation remains the most common treatment option for advanced corneal diseases. A global donor material shortage requires a search for alternative treatments. Different stem cell populations have been induced to express corneal cell characteristics in vitro and in animal models. Yet before their application to humans, scientific and ethical issues need to be solved. The in vitro propagation and implantation of primary corneal cells has been rapidly evolving with clinical practices of limbal epithelium transplantation and a clinical trial for endothelial cells in progress, implying cultivated ocular cells as a promising option for the future. This review reports on the latest developments in primary ocular cell and stem cell research for corneal therapy. PMID- 27498944 TI - High-level hands-free control of wheelchair - a review. AB - A vital perception in designing human-machine interfaces for people with disabilities is hands-free control. It is important in setting up communication among a machine and the part of human body. Nowadays, hands-free control is extensively used to help disabled people to control the wheelchair. The hands free control functions are not only helpful to elderly and disabled, but also useful for normal people who might require using their hands for other tasks at the same time. As a result, normal people are capable of manipulating multiple tasks at the same time. The wheelchair is manoeuvred using brainwaves, eyes and facial muscles movements, voice, tongue, gesture. The mobility using a powered wheelchair improves the quality of life of the aged people and the people with mobility impairments significantly. These powered wheelchairs can be actuated using various high-level control interfaces. In this review, the use of natural biological signals and non-biological signal to do the hands-free control of powered wheelchair is presented in this article. PMID- 27498945 TI - The association between nutritional exposures and metabolic syndrome in the Tehran Lipid and Glucose Study (TLGS): a cohort study. AB - OBJECTIVES: This study was conducted with the goal of investigating the effect of various food consumption on the incidence of metabolic syndrome (MetS). STUDY DESIGN: Prospective cohort study. METHODS: This study conducted on 3616 healthy adults aged >=20 years, who were not affected with MetS. Nutritional intake was determined at the beginning of the study (2008-2011) by the Food Frequency Questionnaire (FFQ), and the incidence of MetS was investigated after a median of 24.6 months follow-up. Data were analyzed by multiple logistic regression, with 95% confidence interval. RESULTS: After adjusting the effect of other variables in the model many foods in the whole grains group such as Sangak bread (OR = 0.35, 95% CI: 0.11-1.56), multiple types of vegetables and fruits - such as peach (OR = 0.11, 95% CI: 0.01-0.75), and mushroom (OR = 0.28, 95% CI: 0.11-0.71) had protective effects against MetS. From the dairy group yoghurt (OR = 0.43, 95% CI: 0.18-1.01) and ice cream (OR = 0.35, 95% CI: 0.12-1.06) had similar such effects. CONCLUSION: Based on our findings, there was a significant rise in the incidence of MetS in Iran. The daily consumption of foods from the whole grains, dairy, vegetable and fruit groups can help reduce the odds of MetS. PMID- 27498946 TI - A Step Forward to Empower Global Microbiome Research Through Local Leadership. PMID- 27498947 TI - Provision of hearing aids to children in Bangladesh: costs and cost-effectiveness of a community-based and a centre-based approach. AB - PURPOSE: The aim of this study is to provide evidence on the costs and health effects of two alternative hearing aid delivery models, a community-based and a centre-based approach. The study is set in Bangladesh and the study population is children between 12 and 18 years old. METHODS: Data on resource use by participants and their caregivers were collected by a household survey. Follow-up data were collected after two months. Data on the costs to providers of the two approaches were collected by means of key informant interviews. RESULTS: The total cost per participant in the community-based model was BDT 6,333 (USD 79) compared with BDT 13,718 (USD 172) for the centre-based model. Both delivery models are found to be cost-effective with an estimated cost per DALY averted of BDT 17,611 (USD 220) for the community-based model and BDT 36,775 (USD 460) for the centre-based model. CONCLUSIONS: Using a community-based approach to deliver hearing aids to children in a resource constrained environment is a cost effective alternative to the traditional centre-based approach. Further evidence is needed to draw conclusions for scale-up of approaches; rigorous analysis is possible using well-prepared data collection tools and working closely with sector professionals. Implications for Rehabilitation Delivery models vary by resources needed for their implementation. Community-based deliver models of hearing aids to children in low-income countries are a cost-effective alternative. The assessment of costs and effects of hearing aids delivery models in low-income countries is possible through planned collaboration between researchers and sector professionals. PMID- 27498949 TI - Association between inflammatory potential of diet and risk of depression in middle-aged women: the Australian Longitudinal Study on Women's Health. AB - Dietary factors and inflammation markers have been shown to play a role in the development of depression. However, there are very few studies that have explored the association between inflammatory potential of diet and risk of depression. In this study, we examined the association between the dietary inflammatory index (DII), which was developed specifically to measure the inflammatory potential of diet, and risk of depression in the middle-aged cohort of the Australian Longitudinal Study on Women's Health. A total of 6438 women with a mean age of 52.0 (sd 1.4) years at baseline were followed-up at five surveys over 12 years (2001-2013). Depression was defined as a score of >=10 on the Center for Epidemiologic Studies Depression-10 scale. The DII score, a literature-derived, population-based dietary index that has been validated against several inflammatory markers, was computed on the basis of dietary intake assessed using a validated FFQ. Generalised estimating equations were used to estimate relative risk (RR) of depression according to DII score. Models were adjusted for energy intake, highest education completed, marital status, menopause status and symptoms, personal illness or injury, smoking status, physical activity, BMI and depression diagnosis or treatment. In total, 1156 women (18 %) had scores>=10 on the CESD scale over the course of 9 years. Women with the most anti-inflammatory diet had an approximately 20 % lower risk of developing depression compared with women with the most pro-inflammatory diet (RRDII quartile 1 v. 4: 0.81; 95 % CI 0.69, 0.96; P trend=0.03). These results suggest that an anti-inflammatory diet is associated with lower risk of depression in middle-aged Australian women. PMID- 27498950 TI - Insufficient accuracy of the ultrasound-based determination of Achilles tendon cross-sectional area. AB - The accurate assessment of the Achilles tendon cross-sectional area (CSA) is a crucial prerequisite to investigate tendon adaptation and to calculate the tendon Young's modulus. Besides magnetic resonance imaging (MRI), ultrasonography emerged as an alternative imaging technique. The purpose of the present study was to assess the objectivity and reliability of the ultrasound-based methodology and its validity with respect to the established MRI-based assessment. The Achilles tendon CSA from 17 healthy males was assessed by ultrasonography at the proximal, medial and distal position five times each on two separate days and three observers segmented the CSAs. For the validation, MRI-based CSA measurements were provided accordingly. The analysis of the ultrasound-based method revealed significant observer and day effects (p<0.05), despite high intra-class correlation coefficients for the three observers (>0.93) and both days (>0.89), respectively. The mean typical percentage error of both days was 7.1%. Comparing both methods, ultrasonography underestimated (19%) the CSA values obtained by MRI (p<0.05). Although the correlation coefficients of both methods were high in all three positions (>0.88), the respective absolute difference of in average 12mm2 and limits of agreement of up to +28mm2 and -2mm2 (~37% of the mean CSA) evidence considerable inconsistency. Besides the dependency of the CSA determination from the observer, the ultrasound method is not sensitive enough to detect physiological changes in tendon morphology of the magnitude that is reported by intervention studies. Furthermore, the validity analysis revealed a lack of agreement between both methods. Therefore, the ultrasound-based methodology cannot be recommended for an accurate Achilles tendon CSA determination in vivo. PMID- 27498951 TI - Inter-limb differences in impulsive loading following anterior cruciate ligament reconstruction in females. AB - Anterior cruciate ligament injury and reconstruction (ACLR) dramatically increase the risk of knee osteoarthritis, but the contributing factors, and therefore the targets for intervention, are poorly understood. Differences in loading characteristics between the ACLR and contralateral limbs during routine activities such as walking may elucidate the mechanical pathogenesis of post traumatic knee osteoarthritis. Twenty-nine females with ACLR (age=21.7+/-3.1 years; time since ACL injury=48+/-41 months) performed walking gait at a self selected speed from which the overall peak vertical ground reaction force (vGRF) in the first 50% of the stance phase and its linear (slope of the vGRF-time curve) and instantaneous (first time-derivative) loading rates were calculated. The magnitude of the vGRF peak immediately following heelstrike and its linear and instantaneous loading rates were also identified. Subjects were further classified as "Impulsive Loaders" or "Normal Loaders" based on whether the transient vGRF peak immediately following heelstrike was objectively classified as a heelstrike transient in the majority of trials. The vGRF magnitude immediately following heelstrike and instantaneous loading rates (both overall and immediately following heelstrike) were greater in the ACLR limb. Additionally, vGRF linear and instantaneous loading rates were greater in subjects classified as Impulsive Loaders. As higher loading rates are associated with greater cartilage degradation in animal models, these data suggest that the greater loading rates in the ACLR limb may play an important role in development of post-traumatic knee osteoarthritis. Additionally, the heelstrike transient appears to be an objective indicator of impulsive loading. PMID- 27498952 TI - Little evidence for epithelial-mesenchymal transition in a murine model of airway fibrosis induced by repeated naphthalene exposure. AB - Recent evidence suggests that epithelial-mesenchymal transition (EMT) is involved in the pathogenesis of airway obstructive diseases, such as chronic obstructive pulmonary disease, asthma and bronchiolitis obliterans syndrome after lung transplantation. However, whether EMT occurs in an experimental model of airway fibrosis is not well known. We explored evidence of EMT in a murine model of airway fibrosis induced by repeated exposure to naphthalene. Mice were administered intraperitoneal injections of naphthalene or corn oil vehicle once weekly for 14 consecutive weeks. The animals were sacrificed 5days after the final injection of naphthalene or corn oil vehicle. EMT was evaluated in lung tissue sections using immunohistochemistry and immunofluorescence. Repeated naphthalene exposure induced loss of club cells, hyperplasia of epithelial cells and peribronchial fibrosis. However, we did not find any loss of E-cadherin expression or any acquisition of vimentin, S100A4 or alphaSMA in epithelial cells in control or naphthalene-exposed mice. These results suggest that EMT does not contribute significantly to naphthalene-induced airway fibrosis in mice. PMID- 27498953 TI - Erratum: Methylphenidate on Cognitive Improvement in Patients with Traumatic Brain Injury: A Meta-Analysis. AB - Due to an overlook on the author's side, author's affiliation in the article entitled as: "Methylphenidate on Cognitive Improvement in Patients with Traumatic Brain Injury: A Meta-Analysis" by Dr. Chi-Hsien Huang (Co-author) published in the journal "Current Neuropharmacology" Volume 14, No 3, Page no- 272-281 was incomplete. PMID- 27498954 TI - Stones: A novel RNAi therapy for PH1. PMID- 27498955 TI - Kidney cancer: OCT2 demethylation cracks open oxaliplatin resistance. PMID- 27498956 TI - Erratum to "Inhibition of botulinum neurotoxins interchain disulfide bond reduction prevents the peripheral neuroparalysis of botulism" [Biochem. Pharmacol. 98 (2015) 522-530]. PMID- 27498957 TI - The resveratrol analog HS-1793 enhances radiosensitivity of mouse-derived breast cancer cells under hypoxic conditions. AB - Tumor hypoxia is associated with treatment resistance, cell proliferation, and metastatic potential, all of which contribute to a poor prognosis. Resveratrol [RES (trans-3,4',5-trihydroxystilbene)], a naturally occurring polyphenol, is enriched in grapes and red wine. This study investigated whether the resveratrol analog HS-1793 modulates the hypoxic status and the level of perfusion in mouse breast cancer FM3A cells. Our data show that HS-1793 decreased the levels of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor protein under hypoxic conditions in FM3A cells. HS-1793 improved perfusion and hypoxic status in tumor tissues and inhibited angiogenesis through HIF-1alpha suppression in mice. Moreover, HS-1793 inhibited hypoxia-induced cancer stem cell properties and enhanced ionizing radiation-induced apoptosis in hypoxic FM3A cells. Collectively, the resveratrol analog HS-1793 might act as a potent radiosensitizer and be a useful adjuvant agent against radiotherapy-resistant hypoxic cells in solid tumors. PMID- 27498958 TI - Aseptic lung and liver abscesses: a diagnostic challenge. AB - A 67-year-old man known with systemic sarcoidosis was admitted to the department of internal medicine because of cough and chest pain for several weeks. Thoracic tomodensitometry demonstrated multiple pulmonary nodules. Biopsies revealed features compatible with abscesses. Cultures and serologic tests were negative and the patient was successfully treated with prednisone. Three years later, a thoraco-abdominal tomodensitometry showed a relapse in the lung and also the apparition of similar lesions in the liver. Blood test revealed elevated CRP level at 40 mg/L and mild cholestasis. Biopsies of the liver excluded neoplastic or infectious diseases and showed inflammatory granulation tissue with abscess formation. A diagnosis of sarcoidosis-associated aseptic abscesses syndrome was then made, which was successfully treated with corticosteroids. PMID- 27498959 TI - Cutaneous peripheral T-cell lymphoma, not otherwise specified: A single-center prognostic analysis. AB - BACKGROUND: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a rare and aggressive disease either originating in or secondarily involving the skin. OBJECTIVE: We sought to assess clinical, histopathologic, and prognostic features of patients with cutaneous PTCL-NOS. METHODS: This was a retrospective chart review of patients with cutaneous PTCL-NOS between 1993 and 2013. RESULTS: Thirty patients with PTCL-NOS were included. Fourteen had skin-only disease and 15 had concurrent skin and systemic disease at presentation. In primary cutaneous PTCL-NOS, the overall survival rate at 5 years was 61% (95% confidence interval, 37-100%; number still at risk, 2). The median overall survival was 5.6 years. Patients were diagnosed a median of 2.4 months from symptom onset. Patients with concurrent disease died a median of 2.1 years after diagnosis. The estimated overall survival rate at 5 years after diagnosis was 29% (95% confidence interval, 13-67%; number at risk, 3). The median overall survival was 3.9 years. Patients were diagnosed a median of 6 months from symptom onset, with a 53% increased risk of death for each year from symptom onset to diagnosis. LIMITATIONS: This was a retrospective study with a limited number of cases. CONCLUSIONS: Age at diagnosis and B-symptoms predict poor survival in patients with cutaneous PTCL-NOS. In addition, poorer survival is observed in patients with multifocal lesions and concomitant skin and systemic PTCL-NOS. PMID- 27498960 TI - Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long-term extension data in patients with plaque psoriasis. AB - BACKGROUND: Psoriasis is a systemic inflammatory condition that is associated with a higher risk of cardiovascular (CV) disease. Tofacitinib is being investigated as a treatment for psoriasis. OBJECTIVE: We sought to evaluate the effects of tofacitinib on CV risk factors and major adverse CV events (MACEs) in patients with plaque psoriasis. METHODS: Changes in select CV risk factors and the incidence rate (IR) of MACEs were evaluated in patients who were treated with tofacitinib. RESULTS: Tofacitinib treatment was associated with small, dose dependent increases in total cholesterol, low-density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol, while the total/HDL cholesterol ratio was unchanged. There were no changes in blood pressure and glycated hemoglobin levels; C-reactive protein levels decreased. The IRs of a MACE were low and similar for both tofacitinib doses. Among 3623 subjects treated with tofacitinib, the total patient-years of exposure was 5204, with a median follow-up of 527 days, and the IR of MACEs was 0.37 (95% confidence interval, 0.22-0.57) patients with events per 100 patient-years. LIMITATIONS: There was relatively short follow up time for patients who had MACEs. CONCLUSIONS: While treatment with tofacitinib is associated with a small increase in cholesterol levels, the total/HDL cholesterol ratio does not change, there are no unfavorable changes in several CV risk factors, and the incidence of MACEs is low. PMID- 27498961 TI - Tunable Heterogeneous Catalysis: N-Heterocyclic Carbenes as Ligands for Supported Heterogeneous Ru/K-Al2O3 Catalysts To Tune Reactivity and Selectivity. AB - Here we report, for the first time, an extensive characterization of an N heterocyclic carbene (NHC)-modified supported heterogeneous catalyst. The existence of the metal-carbene bond could be proven by (13)C-SS-NMR experiments. Furthermore, it could be shown that the modification with NHCs does not structurally change the catalyst itself. The effect of the nature and the loading of the NHC on the activity and selectivity of the heterogeneous catalyst is presented by a hydrogenation study, finally leading to an NHC-enabled tunable heterogeneous catalyst for chemoselective hydrogenation. PMID- 27498962 TI - Microbacterium faecale sp. nov., isolated from the faeces of Columba livia. AB - A novel, yellow, aerobic strain, YIM 101168T, isolated from the faeces of a dove (Columba livia), was studied to determine its taxonomic position. Cells were Gram stain-positive, short rod-shaped, oxidase-negative, catalase-positive and non motile. The strain could grow at 7-37 degrees C, at pH 6-10 and in the presence of 0-13 % (w/v) NaCl. The strain had a 16S rRNA gene sequence similarity and DNA DNA hybridization relatedness value with Microbacteriumgubbeenense NCIMB 30129T of 97.8 % and 41.5+/-8.7 %, respectively. Ornithine was detected as the diagnostic amino acid in the hydrolysate of the cell wall. Whole-cell sugars were found to be galactose, glucose, rhamnose, mannose and ribose. Major fatty acids (>10 %) were iso-C16 : 0, anteiso-C15 : 0 and anteiso-C17 : 0. Major menaquinones were identified as MK-10, MK-11 and MK-12. The polar lipids included diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, glycolipids and four unidentified lipids. The phylogenetic analyses as well as the chemotaxonomic and phenotypic characteristics indicate that strain YIM 101168T represents a novel species of the genus Microbacterium; the name Microbacterium faecale sp. nov. is proposed for the novel species and the type strain is YIM 101168T (=DSM 27232T=KCTC 39554T=CGMCC 1.15152T). PMID- 27498963 TI - Smartphone-enabled optofluidic exosome diagnostic for concussion recovery. AB - A major impediment to improving the treatment of concussion is our current inability to identify patients that will experience persistent problems after the injury. Recently, brain-derived exosomes, which cross the blood-brain barrier and circulate following injury, have shown great potential as a noninvasive biomarker of brain recovery. However, clinical use of exosomes has been constrained by their small size (30-100 nm) and the extensive sample preparation (>24 hr) needed for traditional exosome measurements. To address these challenges, we developed a smartphone-enabled optofluidic platform to measure brain-derived exosomes. Sample to-answer on our chip is 1 hour, 10x faster than conventional techniques. The key innovation is an optofluidic device that can detect enzyme amplified exosome biomarkers, and is read out using a smartphone camera. Using this approach, we detected and profiled GluR2+ exosomes in the post-injury state using both in vitro and murine models of concussion. PMID- 27498964 TI - Assessing emergency obstetric care provision in low- and middle-income countries: a systematic review of the application of global guidelines. AB - BACKGROUND: Lack of timely and quality emergency obstetric care (EmOC) has contributed significantly to maternal morbidity and mortality, particularly in low- and middle-income countries (LMICs). Since 2009, the global guideline, referred to as the 'handbook', has been used to monitor availability, utilization, and quality of EmOC. OBJECTIVE: To assess application and explore experiences of researchers in LMICs in assessing EmOC. DESIGN: Multiple databases of peer-reviewed literature were systematically reviewed on EmOC assessments in LMICs, since 2009. Following set criteria, we included articles, assessed for quality based on a newly developed checklist, and extracted data using a pre designed extraction tool. We used thematic summaries to condense our findings and mapped patterns that we observed. To analyze experiences and recommendations for improved EmOC assessments, we took a deductive approach for the framework synthesis. RESULTS: Twenty-seven studies met our inclusion criteria, with 17 judged as high quality. The highest publication frequency was observed in 2015. Most assessments were conducted in Nigeria and Tanzania (four studies each) and Bangladesh and Ghana (three each). Most studies (17) were done at subnational levels with 23 studies using the 'handbook' alone, whereas the others combined the 'handbook' with other frameworks. Seventeen studies conducted facility-based surveys, whereas others used mixed methods. For different reasons, intrapartum and very early neonatal death rate and proportion of deaths due to indirect causes in EmOC facilities were the least reported indicators. Key emerging themes indicate that data quality for EmOC assessments can be improved, indicators should be refined, a holistic approach is required for EmOC assessments, and assessments should be conducted as routine processes. CONCLUSIONS: There is clear justification to review how EmOC assessments are being conducted. Synergy between researchers, EmOC program managers, and other key stakeholders would be critical for improved assessments, which would contribute to increased accountability and ultimately service provision. PMID- 27498965 TI - Promoting good health research practice in low- and middle-income countries. AB - BACKGROUND: Good clinical practice (GCP) guidelines have been the source of improvement in the quality of clinical trials; however, there are limitations to the application of GCP in the conduct of health research beyond industry sponsored clinical trials. The UNICEF/UNDP/World Bank/WHO Special Program for Research and Training in Tropical Disease is promoting good practice in all health research involving human through the Good Health Research Practice (GHRP) training program initiative. OBJECTIVE: To report the results of piloting the GHRP training program and formulate further steps to harness GHRP for promoting good practices in all health research involving human, particularly in low- and middle-income countries (LMICs). DESIGN: The objective of this training is to impart knowledge and skills for the application of ethical and quality principles to the design, conduct, recording, and reporting of health research involving human participants based on the level of risk, to ensure a fit-for-purpose quality system. This has been formulated into five sequential modules to be delivered in a 4-day course. Four courses have been organized in the pilot phase (2014-2015). The courses have been evaluated and assessed based on course feedback (quantitative and qualitative data) collected during course implementation and qualitative email-based pre- and post-course evaluation. RESULTS: Participants were highly satisfied with the course content and its organization. The relevance and applicability of the course content resulted in positive feedback and an articulated willingness to adapt and disseminate the course. Action points to strengthen the training program have been identified, and showed the imminent need to develop a consensus with a broader range of key stakeholders on the final set of GHRP standards and means for implementation. CONCLUSIONS: There is an urgent need to harness the momentum to promote high quality and ethical health research in LMICs through scaling up GHRP training and further development of GHRP principles into international standards. PMID- 27498967 TI - Silicimonas algicola gen. nov., sp. nov., a member of the Roseobacter clade isolated from the cell surface of the marine diatom Thalassiosira delicatula. AB - A Gram-negative, aerobic, non-motile bacterium, designated strain KC90BT, was isolated from the surface of a cell of the marine diatom Thalassiosira delicatula. The bacterial cells were pleomorphic and formed very small, beige colonies on marine agar. Optimal growth was obtained at 25 degrees C, at pH 6.5 7.5 and in the presence of 1.5-2.0 % (w/v) NaCl. Phylogenetic analyses based on its 16S rRNA gene sequence revealed that strain KC90BT belonged to the Roseobacter clade and formed a monophyletic cluster with the sequences of Boseongicola aestuarii, Profundibacterium mesophilum, Hwanghaeicola aestuarii, Maribius pelagius and M. salinus, showing 91.4-95.7 % sequence similarities. Ubiquinone Q-10 was the predominant lipoquinone but a significant amount of ubiquinone Q-9 was also detected. The major cellular fatty acids were C18 : 1omega7c, 11-methyl C18 : 1omega7c and C18 : 0. Strain KC90BT also contained specific fatty acids (C17 : 0, anteiso-C15 : 0 and anteiso-C17 : 0) that were not detected in its closest described relatives. The major polar lipids of strain KC90BT comprised phosphatidylglycerol, phosphatidylcholine, diphosphatidylglycerol and an unidentified aminolipid. The DNA G+C content of strain KC90BT was 65.2 mol%. The phylogenetic analysis of strain KC90BT, together with the differential phenotypic and chemotaxonomic properties demonstrate that strain KC90BT is distinct from type strains of B. aestuarii, P. mesophilum, H. aestuarii, M. pelagius and M. salinus. Based on the data presented in this study, strain KC90BT represents a novel genus and species within the family Rhodobacteraceae, for which the name Silicimonas algicola gen. nov., sp. nov. is proposed. The type strain is KC90BT (=DSM 103371T=RCC 4681T). PMID- 27498966 TI - Neural changes in the primate brain correlated with the evolution of complex motor skills. AB - Complex motor skills of eventual benefit can be learned after considerable trial and error. What do structural brain changes that accompany such effortful long term learning tell us about the mechanisms for developing innovative behavior? Using MRI, we monitored brain structure before, during and after four marmosets learnt to use a rake, over a long period of 10-13 months. Throughout learning, improvements in dexterity and visuo-motor co-ordination correlated with increased volume in the lateral extrastriate cortex. During late learning, when the most complex behavior was maintained by sustained motivation to acquire the skill, the volume of the nucleus accumbens increased. These findings reflect the motivational state required to learn, and show accelerated function in higher visual cortex that is consistent with neurocognitive divergence across a spectrum of primate species. PMID- 27498968 TI - Molecular phylogenetic analysis of nuclear genes suggests a Cenozoic over-water dispersal origin for the Cuban solenodon. AB - The Cuban solenodon (Solenodon cubanus) is one of the most enigmatic mammals and is an extremely rare species with a distribution limited to a small part of the island of Cuba. Despite its rarity, in 2012 seven individuals of S. cubanus were captured and sampled successfully for DNA analysis, providing new insights into the evolutionary origin of this species and into the origins of the Caribbean fauna, which remain controversial. We conducted molecular phylogenetic analyses of five nuclear genes (Apob, Atp7a, Bdnf, Brca1 and Rag1; total, 4,602 bp) from 35 species of the mammalian order Eulipotyphla. Based on Bayesian relaxed molecular clock analyses, the family Solenodontidae diverged from other eulipotyphlan in the Paleocene, after the bolide impact on the Yucatan Peninsula, and S. cubanus diverged from the Hispaniolan solenodon (S. paradoxus) in the Early Pliocene. The strikingly recent divergence time estimates suggest that S. cubanus and its ancestral lineage originated via over-water dispersal rather than vicariance events, as had previously been hypothesised. PMID- 27498969 TI - Campylobacter hepaticus sp. nov., isolated from chickens with spotty liver disease. AB - Ten strains of an unknown Campylobacter species were isolated from the livers of chickens with spotty liver disease in Australia. The strains were Gram-stain negative, microaerobic, catalase- and oxidase-positive and urease-negative. Unlike most other species of the genus Campylobacter, most of the tested strains of this novel species hydrolysed hippurate and half of them could not reduce nitrate. All strains showed resistance, or intermediate resistance, to nalidixic acid and most of them were resistant to cephalothin. Examination of negatively stained cells under transmission electron microscopy revealed that they were S shaped, with bipolar unsheathed flagella. Phylogenetic analyses based on the 16S rRNA gene and the heat shock protein 60 (hsp60) gene sequences indicated that the strains formed a robust clade that was clearly distinct from recognized Campylobacter species. Unusually, they had a DNA G+C content of 27.9 mol%, lower than any previously described Campylobacter species, and they showed less than 84 % average nucleotide identity to the nearest sequenced species. Taken together, these data indicate that the strains belong to a novel Campylobacter species, for which the name Campylobacter hepaticus sp. nov. is proposed. The type strain is HV10T (=NCTC 13823T=CIP 111092T). PMID- 27498970 TI - The Influence of Surface Topography and Surface Chemistry on the Anti-Adhesive Performance of Nanoporous Monoliths. AB - We designed spongy monoliths allowing liquid delivery to their surfaces through continuous nanopore systems (mean pore diameter ~40 nm). These nanoporous monoliths were flat or patterned with microspherical structures a few tens of microns in diameter, and their surfaces consisted of aprotic polymer or of TiO2 coatings. Liquid may reduce adhesion forces FAd; possible reasons include screening of solid-solid interactions and poroelastic effects. Softening-induced deformation of flat polymeric monoliths upon contact formation in the presence of liquids enhanced the work of separation WSe. On flat TiO2-coated monoliths, WSe was smaller under wet conditions than under dry conditions, possibly because of liquid-induced screening of solid-solid interactions. Under dry conditions, WSe is larger on flat TiO2-coated monoliths than on flat monoliths with a polymeric surface. However, under wet conditions, liquid-induced softening results in larger WSe on flat monoliths with a polymeric surface than on flat monoliths with an oxidic surface. Monolithic microsphere arrays show antiadhesive properties; FAd and WSe are reduced by at least 1 order of magnitude as compared to flat nanoporous counterparts. On nanoporous monolithic microsphere arrays, capillarity (WSe is larger under wet than under dry conditions) and solid-solid interactions (WSe is larger on oxide than on polymer) dominate contact mechanics. Thus, the microsphere topography reduces the impact of softening-induced surface deformation and screening of solid-solid interactions associated with liquid supply. Overall, simple modifications of surface topography and chemistry combined with delivery of liquid to the contact interface allow adjusting WSe and FAd over at least 1 order of magnitude. Adhesion management with spongy monoliths exploiting deployment (or drainage) of interfacial liquids as well as induction or prevention of liquid-induced softening of the monoliths may pave the way for the design of artificial surfaces with tailored contact mechanics. Moreover, the results reported here may contribute to better understanding of the contact mechanics of biological surfaces. PMID- 27498971 TI - Catalyst-free dehydrocoupling of amines, alcohols, and thiols with pinacol borane and 9-borabicyclononane (9-BBN). AB - Contrary to recent reports, the dehydrocoupling of pinacol borane and 9 borabicyclononane with a variety of amines, alcohols and thiols can be achieved under mild conditions without catalyst. This process involves the formation of Lewis acid-base adducts featuring a hydridic B-H in close proximity to an acidic Nu-H. PMID- 27498972 TI - Characterization of multidrug-resistant osteosarcoma sublines and the molecular mechanisms of resistance. AB - Multidrug resistance (MDR) is a challenge for the treatment of cancer and the underlying molecular mechanisms remain elusive. The current study exposed MG63 osteosarcoma cells to increasing concentrations of vincristine (VCR) to establish four VCR-resistant MG63/VCR cell sublines (MG63/VCR1, 2, 3 and 4). The drug resistance indices (RI) of these sublines was detected with the CCK-8 assay and determined to be163, 476, 1,247, and 2,707-fold higher than that of parental cells, respectively. These sublines also exhibited cross-resistance to doxorubicin, paclitaxel and pirarubicin. With increased RI, the proliferative capacity of these sublines was gradually reduced and cell morphology was also altered, characterized by increased formation of pseudopodia and long cytoplasmic processes at opposite poles. However, the migration capacity and expression of certain drug resistance-associated genes were not in accordance with the increased RI; multidrug resistance protein 1 (MDR1) expression was significantly increased in these sublines compared with parental cells. However, in the highly resistant MG63/VCR3 and MG63/VCR4 cells, MDR-associated protein 1, topoisomerase II and LIM domain kinase 1 levels were significantly reduced compared with the moderately resistant MG63/VCR2 cells. Expression of glutathione S-transferase-pi mRNA was determined using reverse transcription-quantitative polymerase chain reaction and determined that it was not changed between MG63 and MG63/VCR cells. The data of the present study demonstrated that the molecular alterations of drug resistance may change with the degree of drug resistance. Taking cell morphology into consideration, the intratumor clonal and phenotypic heterogeneity may be responsible for drug resistance. These MG63/VCR sublines may be a valuable tool to assess drug resistance and the underlying mechanisms, and to identify novel drug resistance-associated genes or strategies to overcome MDR in human osteosarcoma. PMID- 27498974 TI - Salt Intake in an Adult Population of Bangladesh. PMID- 27498973 TI - Polyphenol-rich strawberry extract (PRSE) shows in vitro and in vivo biological activity against invasive breast cancer cells. AB - We describe the biological effects of a polyphenol-rich strawberry extract (PRSE), obtained from the "Alba" variety, on the highly aggressive and invasive basal-like breast cancer cell line A17. Dose-response and time-course experiments showed that PRSE is able to decrease the cellular viability of A17 cells in a time- and dose-dependent manner. PRSE effect on cell survival was investigated in other tumor and normal cell lines of both mouse and human origin, demonstrating that PRSE is more active against breast cancer cells. Cytofluorimetric analysis of A17 cells demonstrated that sub-lethal doses of PRSE reduce the number of cells in S phase, inducing the accumulation of cells in G1 phase of cell cycle. In addition, the migration of A17 cells was studied monitoring the ability of PRSE to inhibit cellular mobility. Gene expression analysis revealed the modulation of 12 genes playing different roles in the cellular migration, adhesion and invasion processes. Finally, in vivo experiments showed the growth inhibition of A17 cells orthotopically transplanted into FVB syngeneic mice fed with PRSE. Overall, we demonstrated that PRSE exerts important biological activities against a highly invasive breast cancer cell line both in vitro and in vivo suggesting the strawberry extracts as preventive/curative food strategy. PMID- 27498975 TI - Molecular epidemiology of carbapenem-resistant Acinetobacter baumannii in South America. AB - One hundred and twenty-six epidemiologically sequential, unrelated, carbapenem resistant Acinetobacter baumannii isolates from nine hospitals in six countries of South America were collected between July 2013 and June 2014. Genes coding for Ambler class D and B carbapenemases were sought by PCR. All isolates were typed using the 3-locus sequence typing and blaOXA-51-like sequence-based typing techniques. The blaOXA-23 gene was recovered in all the participating hospitals and in all the isolates of seven of nine medical centres. The blaOXA-72 gene was only recovered in the two medical centres from Guayaquil city, Ecuador. Trilocus sequence typing revealed the presence of sequence groups SG2, SG4 and SG5. blaOXA 51-like sequence-based typing revealed the presence of blaOXA-132, blaOXA-65, blaOXA-69 and blaOXA-64. Our results showed that the population of carbapenem resistant A. baumannii in South America was principally associated with ST79, ST25 and ST15 (92 %) and harboured the blaOXA-23 gene mainly. CC2 was not detected. PMID- 27498976 TI - Association of angiotensin-converting enzyme insertion/deletion polymorphism with type 1 diabetic nephropathy: a meta-analysis. AB - OBJECTIVE: This study aimed to systematically evaluate the effect of an angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism on type 1 diabetic nephropathy (DN). METHODS: Cochrane Library, Embase, PubMed, Science Direct, Web of science, Wanfang data, VIP database, China Knowledge Resource Integrated Database, and SinoMed were searched. A total of 17 case control studies analyzing ACE I/D polymorphism and type 1 DN risk were included in the present meta-analysis. RESULTS: Overall, a significant increased risk was found in allele comparison (OR = 1.16, 95% CI = 1.05-1.28, p = 0.04), dominant comparison (OR = 1.56, 95% CI = 1.14-2.15, p = 0.006) and homozygote comparison (OR = 1.52, 95% CI = 1.06-2.19, p = 0.02). In subgroup analyses according to ethnicity, the risk of type 1 DN in Asian population was increased in allele comparison (OR = 1.98, 95% CI = 1.15-3.42, p = 0.01), recessive comparison (OR = 2.48, 95% CI = 1.51-4.10, p = 0.0004), dominant comparison (OR = 3.15, 95% CI = 1.90-5.23, p < 0.00001), and homozygote comparison (OR = 2.87, 95% CI = 1.02 8.06, p = 0.05). However, there was no association between the ACE I/D genetic variants and type 1 DN in Caucasian populations. CONCLUSIONS: Our meta-analysis results indicate that the ACE I/D polymorphism may contribute to type 1 DN development, especially in the Asian groups with type 1 diabetes. The current findings need to be confirmed by future well-designed and larger sample size primary studies in populations with different ethnicities. PMID- 27498978 TI - Multi Stakeholders' Attitudes toward Bt rice in Southwest, Iran: Application of TPB and Multi Attribute Models. AB - Organisms that have been genetically engineered and modified (GM) are referred to as genetically modified organisms (GMOs). Bt crops are plants that have been genetically modified to produce certain proteins from the soil bacteria Bacillus thuringiensis (Bt), which makes these plants resistant to certain lepidopteran and coleopteran species. Genetically Modified (GM) rice was produced in 2006 by Iranian researchers from Tarom Mowla'ii and has since been called 'Bt rice'. As rice is an important source of food for over 3 billion inhabitants on Earth, this study aims to use a correlational survey in order to shed light on the predicting factors relating to the extent of stakeholders' behavioral intentions towards Bt rice. It is assumed and the results confirm that "attitudes toward GM crops" can be used as a bridge in the Attitude Model and the Behavioral Intention Model in order to establish an integrated model. To this end, a case study was made of the Southwest part of Iran in order to verify this research model. This study also revealed that as a part of the integrated research framework in the Behavior Intention Model both constructs of attitude and the subjective norm of the respondents serve as the predicting factors of stakeholders' intentions of working with Bt rice. In addition, the Attitude Model, as the other part of the integrated research framework, showed that the stakeholders' attitudes toward Bt rice can only be determined by the perceived benefits (e.g. positive outcomes) of Bt rice. PMID- 27498977 TI - MicroRNA-107 inhibits tumor growth and metastasis by targeting the BDNF-mediated PI3K/AKT pathway in human non-small lung cancer. AB - Abnormal expression of microRNA-107 (miR-107) was found in non-small cell lung cancer (NSCLC). However, little is known about its role and molecular mechanism in NSCLC progression and metastasis. Therefore, the aims of this study were to clarify the potential role of miR-107 and molecular mechanism in NSCLC progression and metastasis. Quantitative real-time polymerase chain reaction assay showed that miR-107 expression levels were significantly decreased in NSCLC tissue and cell lines. Low miR-107 levels in tumor tissue correlated with advanced TNM stage and lymph node metastasis. Function assays showed that overexpression of miR-107 suppressed cell proliferation, migration and invasion in A549 cells in vitro, and inhibited NSCLC tumor growth in vivo. Further mechanism assays suggested the brain-derived neurotrophic factor (BDNF) was identified as a target gene of miR-107 in NSCLC cells. In addition, BDNF expression was upregulated, and inversely correlated with miR-107 in NSCLC tissues. Enforced overexpression of BDNF effectively reversed the tumor suppressive functions of miR-107 on NSCLC proliferation, migration and invasion. miR-107 overexpression or downregulation of BDNF was able to inhibit activation of PI3K/AKT signaling pathway. Taken together, our findings present the first evidence that miR-107 could suppress NSCLC metastasis by targeting BDNF and indirectly regulating PI3K/AKT signaling pathway, which might lead to a potential therapeutic strategy focusing on miR-107 and BDNF for human NSCLC. PMID- 27498979 TI - Room-temperature synthesis of nanoporous 1D microrods of graphitic carbon nitride (g-C3N4) with highly enhanced photocatalytic activity and stability. AB - A one-dimensional (1D) nanostructure having a porous network is an exceptional photocatalytic material to generate hydrogen (H2) and decontaminate wastewater using solar energy. In this report, we synthesized nanoporous 1D microrods of graphitic carbon nitride (g-C3N4) via a facile and template-free chemical approach at room temperature. The use of concentrated acids induced etching and lift-off because of strong oxidation and protonation. Compared with the bulk g C3N4, the porous 1D microrod structure showed five times higher photocatalytic degradation performance toward methylene blue dye (MB) under visible light irradiation. The photocatalytic H2 evolution of the 1D nanostructure (34 MUmol g( 1)) was almost 26 times higher than that of the bulk g-C3N4 structure (1.26 MUmol g(-1)). Additionally, the photocurrent stability of this nanoporous 1D morphology over 24 h indicated remarkable photocorrosion resistance. The improved photocatalytic activities were attributed to prolonged carrier lifetime because of its quantum confinement effect, effective separation and transport of charge carriers, and increased number of active sites from interconnected nanopores throughout the microrods. The present 1D nanostructure would be highly suited for photocatalytic water purification as well as water splitting devices. Finally, this facile and room temperature strategy to fabricate the nanostructures is very cost-effective. PMID- 27498980 TI - Pathways to self-organization: Crystallization via nucleation and growth. AB - Crystallization, a prototypical self-organization process during which a disordered state spontaneously transforms into a crystal characterized by a regular arrangement of its building blocks, usually proceeds by nucleation and growth. In the initial stages of the transformation, a localized nucleus of the new phase forms in the old one due to a random fluctuation. Most of these nuclei disappear after a short time, but rarely a crystalline embryo may reach a critical size after which further growth becomes thermodynamically favorable and the entire system is converted into the new phase. In this article, we will discuss several theoretical concepts and computational methods to study crystallization. More specifically, we will address the rare event problem arising in the simulation of nucleation processes and explain how to calculate nucleation rates accurately. Particular attention is directed towards discussing statistical tools to analyze crystallization trajectories and identify the transition mechanism. PMID- 27498981 TI - Segregation of chain ends to the surface of a polymer melt: Effect of surface profile versus chain discreteness. AB - Silberberg has argued that the surface of a polymer melt behaves like a reflecting boundary on the random-walk statistics of the polymers. Although this is approximately true, independent studies have shown that violations occur due to the finite width of the surface profile and to the discreteness of the polymer molecule, resulting in an excess of chain ends at the surface and a reduction in surface tension inversely proportional to the chain length, N . Using self consistent field theory (SCFT), we compare the magnitude of these two effects by examining a melt of discrete polymers modeled as N monomers connected by Hookean springs of average length, a , next to a polymer surface of width [Formula: see text]. The effects of the surface width and the chain discreteness are found to be comparable for realistic profiles of [Formula: see text] ~ a. A semi analytical approximation is developed to help explain the behavior. The relative excess of ends at the surface is dependent on the details of the model, but in general it decreases for shorter polymers. The excess is balanced by a long-range depletion that has a universal shape independent of the molecular details. Furthermore, the approximation predicts that the reduction in surface energy equals one unit of kBT for every extra chain end at the surface. PMID- 27498982 TI - Robust Sierpinski triangle fractals on symmetry-mismatched Ag(100). AB - Sierpinski triangle fractals were constructed on both Ag(111) and symmetry mismatched fourfold Ag(100) surfaces through chemical reaction between H3PH molecules and Fe atoms under vacuum. Density functional theory calculations revealed that the fractals were stabilized by the strong coordination interaction between Fe and O atoms. In comparison, pure H3PH molecules formed fractals via moderately strong hydrogen bonds only on Ag(111), not on Ag(100). PMID- 27498983 TI - An Exploration of Behavioral Health Productivity and Billing Practices Within Pediatric Primary Care. AB - OBJECTIVES : To provide descriptive information on behavioral health (BH) productivity and billing practices within a pediatric primary care setting. METHODS : This retrospective investigation reviewed 30 months of electronic medical records and financial data. RESULTS : The percent of BH provider time spent in direct patient care (productivity) was 35.28% overall, with a slightly higher quarterly average (M = 36.42%; SD = 6.46%). In the 646.75 hr BH providers spent in the primary care setting, $52,050.00 was charged for BH services delivered ($80.48 hourly average). CONCLUSIONS : BH productivity and billing within pediatric primary care were suboptimal and likely multifactorially derived. To promote integrated primary care sustainability, the authors recommend three future aims: improve BH productivity, demonstrate the value-added contributions of BH services within primary care, and advocate for BH-supporting health care reform. PMID- 27498985 TI - Marinifilum albidiflavum sp. nov., isolated from coastal sediment. AB - A novel Gram-stain-negative, facultatively anaerobic, filamentous, and yellowish white-pigmented marine bacterium, designated strain FB208T, was isolated from marine sediment obtained off the coastal area of Weihai, China. Cells of strain FB208T were filamentous during exponential growth, fragmented to rods in the stationary growth phase and became spherical in aged cultures. It grew optimally at 33 degrees C, at pH 7.0-7.5 and in the presence of 2.0-3.0 % (w/v) NaCl. Based on the 16S rRNA gene sequence, strain FB208T was found to be closely related to Marinifilum flexuosum DSM 21950T (96.9 % similarity) and Marinifilum fragile JCM 15579T (96.4 %), with less than 90.0 % sequence similarity to other genera of the class Bacteroidia. Phylogenetic analysis, also based on 16S rRNA gene sequences, placed strain FB208T in the genus Marinifilum, family Marinifilaceae. The predominant isoprenoid quinone of strain FB208T was identified as menaquinone MK-7. The main cellular fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH and iso-C17 : 1omega9c, and the major polar lipids were an unidentified lipid and aminophospholipid. The G+C content of the genomic DNA was 43.8 mol%. Based on these phylogenetic and phenotypic data, strain FB208T represents a novel species of the genus Marinifilum, for which the name Marinifilum albidiflavum sp. nov. is proposed. The type strain is FB208T (=KCTC 42591T=MCCC 1H00113T). PMID- 27498986 TI - Quantitative determination of activation energies in mechanochemical reactions. AB - Mechanochemical reactions often result in 100% yields of single products, making purifying procedures obsolete. Mechanochemistry is also a sustainable and eco friendly method. The ever increasing interest in this method is contrasted by a lack in mechanistic understanding of the mechanochemical reactivity and selectivity. Recent in situ investigations provided direct insight into formation pathways. However, the currently available theories do not predict temperature T as an influential factor. Here, we report the first determination of an apparent activation energy for a mechanochemical reaction. In a temperature-dependent in situ study the cocrystallisation of ibuprofen and nicotinamide was investigated as a model system. These experiments provide a pivotal step towards a comprehensive understanding of milling reaction mechanisms. PMID- 27498987 TI - Guar gum as a new antimicrobial peptide delivery system against diabetic foot ulcers Staphylococcus aureus isolates. AB - Diabetic patients frequently develop diabetic foot ulcers (DFUs), particularly those patients vulnerable to Staphylococcus aureus opportunistic infections. It is urgent to find new treatments for bacterial infections. The antimicrobial peptide (AMP) nisin is a potential candidate, mainly due to its broad spectrum of action against pathogens. Considering that AMP can be degraded or inactivated before reaching its target at therapeutic concentrations, it is mandatory to establish effective AMP delivery systems, with the natural polysaccharide guar gum being one of the most promising. We analysed the antimicrobial potential of nisin against 23 S. aureus DFU biofilm-producing isolates. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), minimum biofilm inhibitory concentration (MBIC) and minimum biofilm eradication concentration (MBEC) were determined for nisin diluted in HCl and incorporated in guar gum gel. Statistical analysis was performed using the Wilcoxon matched-pair test. Nisin was effective against all isolates, including some multidrug-resistant clinical isolates, independent of whether it is incorporated in guar gum. While differences among MIC, MBC and MBIC values were observed for HCl- and guar gum- nisin, no significant differences were found between MBEC values. Inhibitory activity of both systems seems to differ only twofold, which does not compromise guar gum gel efficiency as a delivery system. Our results highlight the potential of nisin as a substitute for or complementary therapy to current antibiotics used for treating DFU infections, which is extremely relevant considering the increase in multidrug-resistant bacteria dissemination. The guar gum gel represents an alternative, practical and safe delivery system for AMPs, allowing the development of novel topical therapies as treatments for bacterial skin infections. PMID- 27498989 TI - Polaribacter marinaquae sp. nov., isolated from seawater. AB - A novel Gram-stain-negative, rod-shaped, non-spore-forming, non-flagellated, strictly aerobic strain, designated RZW3-2T, was isolated from seawater from near the Yellow Sea coast of PR China (35.475 degrees N 119.613 degrees E). The organism grew optimally between 24 and 28 degrees C, at pH 6.0-7.0 and in the presence of 2-3 % (w/v) NaCl. The strain requires seawater or artificial seawater for growth and NaCl alone does not support growth. RZW3-2T contained iso-C15 : 0, C16 : 1omega7c and/or C16 : 1omega6c and anteiso-C15 : 0 as the dominant fatty acids. The respiratory quinone detected in RZW3-2T was menaquinone 6 (MK6). The polar lipids of RZW3-2T comprised phosphatidylethanolamine (PE), four unidentified phospholipids (PL), two unidentified aminolipids (AL) and one unknown lipid (L). The DNA G+C content of RZW3-2T was 30.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that the novel strain was related most closely to Polaribacter reichenbachii KCTC 23969T, Polaribacter dokdonensis KCTC 12392T and Polaribacter irgensii CIP 106478T with 98.0, 97.8 and 97.0 % sequence similarities, respectively. The DNA-DNA hybridization values between RZW3-2T and its closest phylogenetic relatives, P. reichenbachii KCTC 23969T and P. dokdonensis KCTC 12392T, were 52.0+/-0.6 % and 49.8+/-1.21 % respectively. On the basis of polyphasic analyses, RZW3-2T represents a novel species of the genus Polaribacter, for which the name Polaribacter marinaquae sp. nov. is proposed. The type strain is RZW3-2T (=JCM 30825T=KCTC 42664T=MCCC 1K00696T). PMID- 27498988 TI - Oral Squamous Carcinoma Cells Express B7-H1 and B7-DC Receptors in Vivo. AB - B7-H1 and B7-DC ligands are members of the B7 family with important regulatory functions in cell-mediated immune response. Both receptors are ligands of the programmed death receptor PD-1. B7-H1 expression has been detected in the majority of human carcinomas in vivo. B7-H1 mediated signals are able to negatively regulate activated T cell functions and survival, and enable tumor cells to overcome host response. The aim of this study was to investigate the expression of B7-H1 and B7-DC proteins in oral squamous cell carcinomas (OSCC) in vivo. Tissues from 15 samples were cryo-sected and following histological routine staining (HE), incubated with antibodies against human B7-H1 and B7-DC. Immuno staining of pan-cytokeratin was performed to ascertain the epithelial origin of the tissue and CK 19 to demonstrate the proliferating stage. Confocal laser scanning microscopy confirmed the presence of both B7-H1 and B7-DC in all 15 OSCC. The B7-H1 and B7-DC staining was located in areas of the tissue that were identified as cancerous lesions in the previously stained HE sections before. Staining with Pan-CK and CK19 provided evidence for the epithelial origin and the proliferating stage of the tissue. The in vivo expression of the B7-H1 and B7-DC receptors in oral squamous cell carcinomas suggest that general mechanisms for immune evasion of tumors are also found in OSCC. PMID- 27498990 TI - The Other Face of the Nucleus Accumbens: Aversion. PMID- 27498991 TI - Innate immunity and the sensing of infection, damage and danger in the female genital tract. AB - Tissue homeostasis in the female genital tract is challenged by infection, damage, and even physiological events during reproductive cycles. We propose that the evolutionarily ancient system of innate immunity is sufficient to sense and respond to danger in the non-pregnant female genital tract. Innate immunity produces a rapidly inducible, non-specific response when cells sense danger. Here we provide a primer on innate immunity and discuss what is known about how danger signals are sensed in the endometrium and ovary, the impact of inflammatory responses on reproduction, and how endocrinology and innate immunity are integrated. Endometrial epithelial and stromal cells, and ovarian granulosa cells express pattern recognition receptors, similar to cells of the innate immune system. These pattern recognition receptors, such as the Toll-like receptors, bind pathogen-associated or damage-associated molecular patterns. Activation of pattern recognition receptors leads to inflammation, recruitment of immune cells from the peripheral circulation, and phagocytosis. Although the inflammatory response helps maintain or restore endometrial health, there may also be negative consequences for fertility, including perturbation of oocyte competence. The intensity of the inflammatory response reflects the balance between the level of danger and the systems that regulate innate immunity, including the endocrine environment. Understanding innate immunity is important because disease and inappropriate inflammatory responses in the endometrium or ovary cause infertility. PMID- 27498992 TI - Nonlinear machine learning and design of reconfigurable digital colloids. AB - Digital colloids, a cluster of freely rotating "halo" particles tethered to the surface of a central particle, were recently proposed as ultra-high density memory elements for information storage. Rational design of these digital colloids for memory storage applications requires a quantitative understanding of the thermodynamic and kinetic stability of the configurational states within which information is stored. We apply nonlinear machine learning to Brownian dynamics simulations of these digital colloids to extract the low-dimensional intrinsic manifold governing digital colloid morphology, thermodynamics, and kinetics. By modulating the relative size ratio between halo particles and central particles, we investigate the size-dependent configurational stability and transition kinetics for the 2-state tetrahedral (N = 4) and 30-state octahedral (N = 6) digital colloids. We demonstrate the use of this framework to guide the rational design of a memory storage element to hold a block of text that trades off the competing design criteria of memory addressability and volatility. PMID- 27498993 TI - Conscientious objection to abortion. PMID- 27498994 TI - Evaluation of CT-based SUV normalization. AB - The purpose of this study was to determine patients' lean body mass (LBM) and lean tissue (LT) mass using a computed tomography (CT)-based method, and to compare standardized uptake value (SUV) normalized by these parameters to conventionally normalized SUVs. Head-to-toe positron emission tomography (PET)/CT examinations were retrospectively retrieved and semi-automatically segmented into tissue types based on thresholding of CT Hounsfield units (HU). The following HU ranges were used for determination of CT-estimated LBM and LT (LBMCT and LTCT): 180 to -7 for adipose tissue (AT), -6 to 142 for LT, and 143 to 3010 for bone tissue (BT). Formula-estimated LBMs were calculated using formulas of James (1976 Research on Obesity: a Report of the DHSS/MRC Group (London: HMSO)) and Janmahasatian et al (2005 Clin. Pharmacokinet. 44 1051-65), and body surface area (BSA) was calculated using the DuBois formula (Dubois and Dubois 1989 Nutrition 5 303-11). The CT segmentation method was validated by comparing total patient body weight (BW) to CT-estimated BW (BWCT). LBMCT was compared to formula-based estimates (LBMJames and LBMJanma). SUVs in two healthy reference tissues, liver and mediastinum, were normalized for the aforementioned parameters and compared to each other in terms of variability and dependence on normalization factors and BW. Comparison of actual BW to BWCT shows a non-significant difference of 0.8 kg. LBMJames estimates are significantly higher than LBMJanma with differences of 4.7 kg for female and 1.0 kg for male patients. Formula-based LBM estimates do not significantly differ from LBMCT, neither for men nor for women. The coefficient of variation (CV) of SUV normalized for LBMJames (SUVLBM-James) (12.3%) was significantly reduced in liver compared to SUVBW (15.4%). All SUV variances in mediastinum were significantly reduced (CVs were 11.1-12.2%) compared to SUVBW (15.5%), except SUVBSA (15.2%). Only SUVBW and SUVLBM-James show independence from normalization factors. LBMJames seems to be the only advantageous SUV normalization. No advantage of other SUV normalizations over BW could be demonstrated. PMID- 27498995 TI - Sero-epidemiological analysis of vertical transmission relative risk of Borna disease virus infection in dairy herds. AB - Borna disease virus (BDV) is a virus that causes a neurological disease in domestic animals, including a variety of animal species in Japan. Few studies have examined the mode of transmission of this virus in cattle, and the exact mechanisms underlying the transmission of the virus need to be elucidated. This study aimed to examine the contribution of vertical transmission of the virus, which occurs when the virus is transmitted from the mother to offspring during gestation or birth. We used an epidemiological approach. The relative risk (RR) was calculated for cattle born to BDV sero-positive cows from farms with a higher within-herd prevalence of BDV (56.8%). We tested the sera of 1,122 dairy cattle from 24 dairy herds in Hokkaido Prefecture, Japan, for BDV infection using the ELISA and western blotting method. The overall level of BDV sero-prevalence was 22.1%. Seroprevalence was significantly higher in closed-breeding herds that do not have buying in cows (39.7%) than in farms that restock cattle by buying in cows (4.4%, P<0.01). The overall RR of BDV vertical transmission from infected mothers to their daughters was 1.86 (95% confidence interval (CI): 1.54-2.56). Our results show that vertical transmission contributes significantly to BDV transmission in the farms tested in this study. PMID- 27498996 TI - Recovery with a regular dose of antibiotics from bacillary hemoglobinuria in a Holstein cow. AB - One Holstein cow housed with 21 other cows exhibited clinical signs of pyrexia, anorexia and diarrhea along with severe hemoglobinuria. Hematological and biochemical analyses conducted before and after antibiotic therapy indicated severe hemolytic anemia and disruption of hepatic function. A general improvement in conditions was observed after an 11-day program of treatment comprising a regular dose of antibiotics and prescribed supportive therapies. A tentative diagnosis of bacillary hemoglobinuria was made based on the clinical and clinico pathologic features on day 7. A molecular diagnosis was made by a PCR amplification of the flagellin gene of Clostridium haemolyticum using DNA extracted from the whole blood. The cow was diagnosed with the first recorded occurrence of bacillary hemoglobinuria of Holstein cattle in Japan. PMID- 27498997 TI - Discovery of anti-inflammatory role of prostaglandin D2. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin are one of the most frequently used classes of drug worldwide and inhibit prostaglandin (PG) production by inhibiting cyclooxygenase activity. Although NSAIDs are broadly used against inflammatory diseases, they have side effects including alimentary canal disorders, kidney damage, infection and cardiovascular disorders. Thus, it is necessary to elucidate the pathophysiological role of each PG in various diseases to develop better therapies with fewer and milder side effects. PGD2 is a PG that was identified in 1973 by Hamberg and is produced by the activities of cyclooxygenase and either hematopoietic or lipocalin-type PGD synthase. PGD2 exerts its physiological effects by stimulating two distinct G protein-coupled receptors, namely D prostanoid receptor (DP) and chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2). The physiological role of PGD2 remains controversial. Some studies have reported that PGD2 has bronchoconstrictory and pro-inflammatory effects inducing immune cell accumulation. In contrast, other groups have reported that PGD2 has anti inflammatory effects by inhibiting the recruitment of dendritic cells and neutrophils. We have investigated the pathophysiological role of PGD2 using various disease models and reported on its anti-inflammatory actions. Here, we review the anti-inflammatory roles of PGD2 and the underlying mechanisms. PMID- 27498999 TI - Association Between Presence of Virulence Genes and Antibiotic Resistance in Clinical Klebsiella Pneumoniae Isolates. AB - OBJECTIVE: To investigate the presence of rmpA and wcaG virulence genes and Class 1, 2, and 3 integrons, and to evaluate a relationship between antibiotic resistance and virulence in Klebsiella pneumoniae METHODS: We collected a total of 200 K. pneumoniae isolates from hospitals in Tehran, Iran. Antibiotic susceptibility was determined using the disk diffusion method. The extended spectrum beta-lactamase (ESBL) producers were detected using the combination disk method. We detected the rmpA and wcaG genes and class 1, 2, and 3 integrons via polymerase chain reaction (PCR). The chi2 test was used for statistical evaluation. RESULTS: Of 200 isolates, 115 (57.5%) were ESBL producers; 74.0% carried the class 1 integron, and 1.0% carried the class 2 integron. The gene rmpA was detected in 7% of isolates and the gene wcaG in 23.5% of isolates. Integron-positive isolates showed a higher prevalence of wcaG compared with to integron-negative isolates (P <.05). CONCLUSION: Our results showed a correlation between presence of virulence gene and antibiotic resistance in K. pneumoniae. PMID- 27499000 TI - Phosphate and oxygen limitation induce respiratory nitrate reductase 3 synthesis in stationary-phase mycelium of Streptomyces coelicolor A3(2). AB - The saprophytic actinobacterium Streptomyces coelicolor A3(2) requires oxygen for filamentous growth. Surprisingly, the bacterium also synthesizes three active respiratory nitrate reductases (Nar), which are believed to contribute to survival, or general fitness, of the bacterium in soil when oxygen becomes limiting. In this study, we analysed Nar3 and showed that activity of the enzyme is restricted to stationary-phase mycelium of S. coelicolor. Phosphate limitation was shown to be necessary for induction of enzyme synthesis. Nar3 synthesis was inhibited by inclusion of 20 mM phosphate in a defined 'switch assay' in which highly dispersed mycelium from exponentially growing cultures was shifted to neutral MOPS-glucose buffer to induce Nar3 synthesis and activity. Quantitative assessment of nar3 transcripts revealed a 30-fold induction of gene expression in stationary-phase mycelium. Transcript levels in stationary-phase mycelium incubated with phosphate were reduced by a little more than twofold, suggesting that the negative influence of phosphate on Nar3 synthesis was mainly at the post transcriptional level. Furthermore, it was demonstrated that oxygen limitation was necessary to induce high levels of Nar3 activity. However, an abrupt shift from aerobic to anaerobic conditions prevented appearance of Nar3 activity. This suggests that the bacterium regulates Nar3 synthesis in response to the energy status of the mycelium. Nitrate had little impact on regulation of the Nar3 level. Together, these data identify Nar3 as a stationary-phase nitrate reductase in S. coelicolor and demonstrate that enzyme synthesis is induced in response to both phosphate limitation and hypoxia. PMID- 27499002 TI - Biallelic ATM alterations detected at diagnosis identify a subset of treatment naive chronic lymphocytic leukemia patients with reduced overall survival similar to patients with p53 deletion. AB - The prognostic impact of biallelic ATM abnormalities (ATM mutation and concurrent 11q deletion) remains unknown. We studied ATM, BIRC3, SF3B1, and NOTCH1 genes in 118 treatment-naive CLL patients at diagnosis. Patients with biallelic ATM alteration had a similar time to first treatment (TTFT) and shorter overall survival (OS) compared with patients with isolated 11q deletion and shorter TTFT and OS when compared to patients with wild-type ATM. Furthermore, biallelic ATM alteration (HR: 6.4; p <= 0.007) was significantly associated with an increased risk of death similar to p53 deletion (HR: 6.1; p <= 0.004), superior to 11q deletion alone (HR: 2.8; p <= 0.022) and independent of other significant parameters such as age, advanced clinical stage, and complex karyotype. Our results suggest the identification of ATM mutations in CLL patients with 11q deletion at diagnosis is clinically relevant and predicts disease progression, poor response to the treatment, and reduced OS independent of other molecular prognostic factors. PMID- 27499003 TI - Deficient Nucleotide Excision Repair in Squamous Cell Carcinoma Cells. AB - Squamous cell carcinomas (SCCs) are associated with ultraviolet radiation and multiple genetic changes, but the mechanisms leading to genetic instability are unclear. SCC cell lines were compared to normal keratinocytes for sensitivity to ultraviolet radiation, DNA repair kinetics and DNA repair protein expression. Relative to normal keratinocytes, four SCC cell lines were all variably sensitive to ultraviolet radiation and, except for the SCC25 cell line, were deficient in global repair of cyclobutane pyrimidine dimers, although not 6-4 photoproducts. Impaired DNA repair of cyclobutane pyrimidine dimers was associated with reduced mRNA expression from XPC but not DDB2 genes which each encode key DNA damage recognition proteins. However, levels of XPC or DDB2 proteins or both were variably reduced in repair-deficient SCC cell lines. p53 levels did not correlate with DNA repair activity or with XPC and DDB2 levels, but p63 levels were deficient in cell lines with reduced global repair. Repair-proficient SCC25 cells depleted of p63 lost XPC expression, early global DNA repair activity and UV resistance. These results demonstrate that some SCC cell lines are deficient in global nucleotide excision repair and support a role for p63 as a regulator of nucleotide excision repair in SCCs. PMID- 27499001 TI - Declining ecosystem health and the dilution effect. AB - The "dilution effect" implies that where species vary in susceptibility to infection by a pathogen, higher diversity often leads to lower infection prevalence in hosts. For directly transmitted pathogens, non-host species may "dilute" infection directly (1) and indirectly (2). Competitors and predators may (1) alter host behavior to reduce pathogen transmission or (2) reduce host density. In a well-studied system, we tested the dilution of the zoonotic Puumala hantavirus (PUUV) in bank voles (Myodes glareolus) by two competitors and a predator. Our study was based on long-term PUUV infection data (2003-2013) in northern Sweden. The field vole (Microtus agrestis) and the common shrew (Sorex araneus) are bank vole competitors and Tengmalm's owl (Aegolius funereus) is a main predator of bank voles. Infection probability in bank voles decreased when common shrew density increased, suggesting that common shrews reduced PUUV transmission. Field voles suppressed bank vole density in meadows and clear-cuts and indirectly diluted PUUV infection. Further, Tengmalm's owl decline in 1980 2013 may have contributed to higher PUUV infection rates in bank voles in 2003 2013 compared to 1979-1986. Our study provides further evidence for dilution effect and suggests that owls may have an important role in reducing disease risk. PMID- 27499005 TI - The effect of moisture on the structures and properties of lead halide perovskites: a first-principles theoretical investigation. AB - With efficiencies exceeding 20% and low production costs, lead halide perovskite solar cells (PSCs) have become potential candidates for future commercial applications. However, there are serious concerns about their long-term stability and environmental friendliness, heavily related to their commercial viability. Herein, we present a theoretical investigation based on the ab initio molecular dynamics (AIMD) simulations and the first-principles density functional theory (DFT) calculations to investigate the effects of sunlight and moisture on the structures and properties of MAPbI3 perovskites. AIMD simulations have been performed to simulate the impact of a few water molecules on the structures of MAPbI3 surfaces terminated in three different ways. The evolution of geometric and electronic structures as well as the absorption spectra has been shown. It is found that the PbI2-terminated surface is the most stable while both the MAI terminated and PbI2-defective surfaces undergo structural reconstruction, leading to the formation of hydrated compounds in a humid environment. The moisture induced weakening of photoabsorption is closely related to the formation of hydrated species, and the hydrated crystals MAPbI3.H2O and MA4PbI6.2H2O scarcely absorb the visible light. The electronic excitation in the bare and water absorbed MAPbI3 nanoparticles tends to weaken Pb-I bonds, especially those around water molecules, and the maximal decrease of photoexcitation-induced bond order can reach up to 20% in the excited state in which the water molecules are involved in the electronic excitation, indicating the accelerated decomposition of perovskites in the presence of sunlight and moisture. This work is valuable for understanding the mechanism of chemical or photochemical instability of MAPbI3 perovskites in the presence of moisture. PMID- 27499004 TI - Structure of a Highly Active Cephalopod S-crystallin Mutant: New Molecular Evidence for Evolution from an Active Enzyme into Lens-Refractive Protein. AB - Crystallins are found widely in animal lenses and have important functions due to their refractive properties. In the coleoid cephalopods, a lens with a graded refractive index provides good vision and is required for survival. Cephalopod S crystallin is thought to have evolved from glutathione S-transferase (GST) with various homologs differentially expressed in the lens. However, there is no direct structural information that helps to delineate the mechanisms by which S crystallin could have evolved. Here we report the structural and biochemical characterization of novel S-crystallin-glutathione complex. The 2.35-A crystal structure of a S-crystallin mutant from Octopus vulgaris reveals an active-site architecture that is different from that of GST. S-crystallin has a preference for glutathione binding, although almost lost its GST enzymatic activity. We've also identified four historical mutations that are able to produce a "GST-like" S crystallin that has regained activity. This protein recapitulates the evolution of S-crystallin from GST. Protein stability studies suggest that S-crystallin is stabilized by glutathione binding to prevent its aggregation; this contrasts with GST-sigma, which do not possess this protection. We suggest that a tradeoff between enzyme activity and the stability of the lens protein might have been one of the major driving force behind lens evolution. PMID- 27499006 TI - Utilization of Feeding Tubes in the Management of Feline Chronic Kidney Disease. AB - Esophagostomy feeding tubes are useful, and in many cases essential, for the comprehensive management of cats with moderate to advanced chronic kidney disease (CKD). They should be considered a lifelong therapeutic appliance to facilitate the global management of cats with CKD thus providing improved therapeutic efficacy and quality-of-life. Esophagostomy tubes facilitate the maintenance of adequate hydration and increase owner compliance by facilitating the administration of medications. Finally, feeding tubes provide a means to deliver a stage-appropriate dietary prescription for cats with CKD and maintain an adequate nutritional plane in a patient that otherwise would be subject to chronic wasting. PMID- 27499007 TI - Symmetric Dimethylarginine: Improving the Diagnosis and Staging of Chronic Kidney Disease in Small Animals. AB - Chronic kidney disease (CKD) is a common condition in cats and dogs, traditionally diagnosed after substantial loss of kidney function when serum creatinine concentrations increase. Symmetric dimethylarginine (SDMA) is a sensitive circulating kidney biomarker whose concentrations increase earlier than creatinine as glomerular filtration rate decreases. Unlike creatinine SDMA is unaffected by lean body mass. The IDEXX SDMA test introduces a clinically relevant and reliable tool for the diagnosis and management of kidney disease. SDMA has been provisionally incorporated into the International Renal Interest Society guidelines for CKD to aid staging and targeted treatment of early and advanced disease. PMID- 27499008 TI - Rhizobium favelukesii sp. nov., isolated from the root nodules of alfalfa (Medicago sativa L). AB - Strains LPU83T and Or191 of the genus Rhizobium were isolated from the root nodules of alfalfa, grown in acid soils from Argentina and the USA. These two strains, which shared the same plasmid pattern, lipopolysaccharide profile, insertion-sequence fingerprint, 16S rRNA gene sequence and PCR-fingerprinting pattern, were different from reference strains representing species of the genus Rhizobium with validly published names. On the basis of previously reported data and from new DNA-DNA hybridization results, phenotypic characterization and phylogenetic analyses, strains LPU83T and Or191 can be considered to be representatives of a novel species of the genus Rhizobium, for which the name Rhizobium favelukesii sp. nov. is proposed. The type strain of this species is LPU83T (=CECT 9014T=LMG 29160T), for which an improved draft-genome sequence is available. PMID- 27499009 TI - Mitochondrial DNA depletion causes decreased ROS production and resistance to apoptosis. AB - Mitochondrial DNA (mtDNA) depletion occurs frequently in many diseases including cancer. The present study was designed in order to examine the hypothesis that mtDNA-depleted cells are resistant to apoptosis and to explore the possible mechanisms responsible for this effect. Parental human osteosarcoma 143B cells and mtDNA-deficient (Rho or rho) 206 cells (derived from 143B cells) were exposed to different doses of solar-simulated ultraviolet (UV) radiation. The effects of solar irradiation on cell morphology were observed under both light and fluorescence microscopes. Furthermore, apoptosis, mitochondrial membrane potential (MMP) disruption and reactive oxygen species (ROS) production were detected and measured by flow cytometry. In both cell lines, apoptosis and ROS production were clearly increased, whereas MMP was slightly decreased. However, apoptosis and ROS production were reduced in the Rho206 cells compared with the 143B cells. We also performed western blot analysis and demonstrated the increased release of cytosolic Cyt c from mitochondria in the 143B cells compared with that in the Rho206 cells. Thus, we concluded that Rho206 cells exhibit more resistance to solar-simulated UV radiation-induced apoptosis at certain doses than 143B cells and this is possibly due to decreased ROS production. PMID- 27499010 TI - Epigenetic modulation of AR gene expression in prostate cancer DU145 cells with the combination of sodium butyrate and 5'-Aza-2'-deoxycytidine. AB - The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. Castration-resistant prostate cancer (CRPC) is a consequence of androgen deprivation therapy. Unchecked CRPC followed by metastasis is lethal. Some CRPCs show decreased AR gene expression due to epigenetic mechanisms such as DNA methylation and histone deacetylation. The aim of this study was to epigenetically modulate the methylated state of the AR gene leading to targeted demethylation and AR gene expression in androgen-independent human prostate cancer DU145 cell line, representing the CRPC model with very low or undetectable AR levels. The cell treatment was based on single and combined applications of two epigenetic inhibitors, sodium butyrate (NaB) as histone deacetylases inhibitor and 5'-Aza-2'-deoxycytidine (Aza-dC) as DNA methyltransferases inhibitor. We found that the Aza-dC in combination with NaB may help reduce the toxicity of higher NaB concentrations in cancer cells. In normal RWPE-1 cells and even stronger in cancer DU145 cells, the combined treatment induced both AR gene expression on the mRNA level and increased histone H4 acetylation in AR gene promoter. Also activation and maintenance of G2/M cell cycle arrest and better survival in normal RWPE-1 cells compared to cancer DU145 cells were observed after the treatments. These results imply the selective toxicity effect of both inhibitors used and their potentially more effective combined use in the epigenetic therapy of prostate cancer patients. PMID- 27499011 TI - Corticotropin-Releasing Factor From Rodents to Primates: Translational Hope Expresses Itself, Pun Intended. PMID- 27499012 TI - Gain in Translation: Is It Time for Thigmotaxis Studies in Humans? PMID- 27499014 TI - Twisted Cucurbit[n]urils. AB - Two new twisted cucurbiturils, cucurbit[13]uril (tQ[13]) and cucurbit[15]uril (tQ[15]), have been synthesized and separated, and their structures have been confirmed by NMR spectroscopy and MALDI-TOF mass spectrometry together with the X ray structures of two new complexes, {Dy(H2O)4Cd(H2O)4tQ[13]}.2.5[CdCl4].65H2O and {Cd0.5(H2O)2tQ[15]}.[CdCl4].47H2O. tQ[15] is the largest cucurbit[n]uril (Q[n]) in the Q[n] family reported to date. The X-ray diffraction studies of both complexes indicated that these large tQ[n]s effectively exhibit two different cavities-a central cavity and two side cavities. Preliminary host-guest behavior by each of the new systems was investigated by NMR studies. PMID- 27499013 TI - ATP-dependent substrate transport by the ABC transporter MsbA is proton-coupled. AB - ATP-binding cassette transporters mediate the transbilayer movement of a vast number of substrates in or out of cells in organisms ranging from bacteria to humans. Current alternating access models for ABC exporters including the multidrug and Lipid A transporter MsbA from Escherichia coli suggest a role for nucleotide as the fundamental source of free energy. These models involve cycling between conformations with inward- and outward-facing substrate-binding sites in response to engagement and hydrolysis of ATP at the nucleotide-binding domains. Here we report that MsbA also utilizes another major energy currency in the cell by coupling substrate transport to a transmembrane electrochemical proton gradient. The dependence of ATP-dependent transport on proton coupling, and the stimulation of MsbA-ATPase by the chemical proton gradient highlight the functional integration of both forms of metabolic energy. These findings introduce ion coupling as a new parameter in the mechanism of this homodimeric ABC transporter. PMID- 27499015 TI - Peridinin, a carotenoid, inhibits proliferation and survival of HTLV-1-infected T cell lines. AB - Human T-cell leukemia virus type 1 (HTLV-1) causes either adult T-cell leukemia (ATL) or chronic inflammatory disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis. These diseases are not curable as yet; therefore new agents for treatment and prevention are needed. Carotenoids are natural plant compounds with anti-carcinogenic activities. Peridinin is one of the most abundant carotenoids found in nature. Based on a series of past experiments, here we investigated the effects of peridinin extracted from Okinawan coral Isis hippuris on the proliferation and survival of HTLV-1-infected T-cell lines. The results of water-soluble tetrazolium-8 assay indicated that peridinin dose-dependently inhibits cell proliferation and viability of HTLV-1 infected T-cell lines. Flow cytometry showed that low concentration of peridinin induced cell cycle arrest at G1 phase, while higher concentration induced apoptosis. Peridinin caused cleavage of caspase-3, -8 and -9. Peridinin significantly reduced the expression of G1 cell cycle regulators, including cyclin D1, cyclin D2, CDK4, CDK6 and c-Myc, and anti-apoptotic proteins, including survivin, XIAP and Bcl-2, in a dose-dependent manner. Peridinin suppressed DNA binding of NF-kappaB. Peridinin inhibited phosphorylation of IkappaBalpha, RelA, Akt and p70 S6 kinase, and reduced protein expression level of 3-phosphoinositide-dependent protein kinase 1. Thus, peridinin exerts its anti proliferative and pro-apoptotic effects by suppressing NF-kappaB and Akt signaling in HTLV-1-infected T cells. Peridinin also reduced tumor growth in mice harboring ATL xenograft tumors. The results suggested that peridinin is a potentially suitable therapeutic agent against HTLV-1-associated diseases. PMID- 27499016 TI - Editorial (Thematic Selection: Mitochondrial Dysfunction & Neurological Disorders). PMID- 27499017 TI - Natural compound oblongifolin C inhibits autophagic flux, and induces apoptosis and mitochondrial dysfunction in human cholangiocarcinoma QBC939 cells. AB - The compounds, which are obtained from natural plants or microbes may offer potential as one of the strategies for the management of cholangiocarcinoma. Oblongifolin C (OC), a natural small molecule compound extracted and purified from Garcinia yunnanensis Hu, can activate the mitochondrial apoptotic pathway in human cervical cancer cells. However, the direct effects of OC on cholangiocarcinoma cells are not well defined. The effect of OC on cell apoptosis and its underlying mechanisms were investigated in cultured QBC939 cells by the methyl thiazol tetrazolium assay, mitochondrial membrane potential, ATP content and western blot analysis. The present study reported that the in vitro treatment of human cholangiocarcinoma QBC939 cells with different concentrations (5, 10, 20 and 40 uM) of OC decreased cell viability and induced apoptosis in a dose dependent manner. The results of the present study also showed that OC-induced QBC939 cell apoptosis was mediated through the inhibition of autophagy and mitochondrial dysfunction (MtD). Additionally, inhibiting autophagy increased OC induced apoptosis and MtD, whereas exposure to the autophagy inducer, rapmycin, attenuated these changes. Together, the results of the present study are the first, to the best of our knowledge, to identify OC as a chemotherapeutic agent against human cholangiocarcinoma QBC939 cells in vitro via the regulation of autophagy and MtD. PMID- 27499018 TI - Long-term efficacy and safety results of taliglucerase alfa through 5years in adult treatment-naive patients with Gaucher disease. AB - Taliglucerase alfa, the first available plant cell-expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD). PB-06-001, a pivotal phase 3, multicenter, randomized, double blind, parallel-dose study investigated taliglucerase alfa 30 or 60U/kg every other week through 9months in treatment-naive adults with GD; 30-month extension study PB-06-003 followed. Patients completing PB-06-001 and PB-06-003 could continue treatment in PB-06-007. Nineteen patients enrolled in PB-06-007 (30U/kg, n=8; 60U/kg, n=9; dose adjusted, n=2); 17 completed 5 total years of treatment. In these 3 groups, respectively, taliglucerase alfa resulted in mean decreases in spleen volume (-8.7, -6.9, -12.4 multiples of normal), liver volume (-0.6, -0.4, 0.5 multiples of normal), chitotriosidase activity (-83.1%, -93.4%, -87.9%), and chemokine (CC motif) ligand 18 concentration (-66.7%, -83.3%, -78.9%), as well as mean increases in hemoglobin concentration (+2.1, +2.1, +1.8mg/dL) and platelet count (+31,871, +106,800, +34,000/mm3). The most common adverse events were nasopharyngitis and arthralgia. Most adverse events were mild/moderate; no serious adverse events were considered treatment-related. These results demonstrate continued improvement of disease parameters during 5years of taliglucerase alfa therapy in 17 treatment-naive patients with no new safety concerns, extending the taliglucerase alfa clinical efficacy and safety dataset. This study was registered at www.clinicaltrials.gov as NCT01422187. PMID- 27499019 TI - Akkermansia glycaniphila sp. nov., an anaerobic mucin-degrading bacterium isolated from reticulated python faeces. AB - A Gram-stain-negative, non-motile, strictly anaerobic, oval-shaped, non-spore forming bacterium (strain PytT) was isolated from reticulated python faeces. Strain PytT was capable of using mucin as sole carbon, energy and nitrogen source. Cells could grow singly, in pairs, and were also found to aggregate. Scanning electron microscopy revealed the presence of filamentous structures connecting individual bacterial cells. Strain PytT could grow on a limited number of single sugars, including N-acetylglucosamine, N-acetylgalactosamine, glucose, lactose and galactose, but only when a plentiful protein source was provided. Phylogenetic analysis based on 16S rRNA gene sequencing showed strain PytT to belong to the Verrucomicrobiae class I, family Akkermansiaceae, genus Akkermansia, with Akkermansia muciniphila MucT as the closest relative (94.4 % sequence similarity). DNA-DNA hybridization revealed low relatedness of 28.3 % with A. muciniphila MucT. The G+C content of DNA from strain PytT was 58.2 mol%. The average nucleotide identity (ANI) of the genome of strain PytT compared to the genome of strain MucT was 79.7 %. Chemotaxonomic data supported the affiliation of strain PytT to the genus Akkermansia. Based on phenotypic, phylogenetic and genetic characteristics, strain PytT represents a novel species of the genus Akkermansia, for which the name Akkermansia glycaniphila sp. nov. is proposed. The type strain is PytT (=DSM 100705T=CIP 110913T). PMID- 27499020 TI - Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer. AB - We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of druggable kinase pathways. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Individual autopsy profiles developed using these hallmarks revealed clinically relevant pathway information potentially suitable for patient stratification and targeted therapies in late stage prostate cancer. Here, we describe phosphorylation-based cancer hallmarks using integrated personalized signatures (pCHIPS) that shed light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients. PMID- 27499021 TI - GPCR-G Protein-beta-Arrestin Super-Complex Mediates Sustained G Protein Signaling. AB - Classically, G protein-coupled receptor (GPCR) stimulation promotes G protein signaling at the plasma membrane, followed by rapid beta-arrestin-mediated desensitization and receptor internalization into endosomes. However, it has been demonstrated that some GPCRs activate G proteins from within internalized cellular compartments, resulting in sustained signaling. We have used a variety of biochemical, biophysical, and cell-based methods to demonstrate the existence, functionality, and architecture of internalized receptor complexes composed of a single GPCR, beta-arrestin, and G protein. These super-complexes or "megaplexes" more readily form at receptors that interact strongly with beta-arrestins via a C terminal tail containing clusters of serine/threonine phosphorylation sites. Single-particle electron microscopy analysis of negative-stained purified megaplexes reveals that a single receptor simultaneously binds through its core region with G protein and through its phosphorylated C-terminal tail with beta arrestin. The formation of such megaplexes provides a potential physical basis for the newly appreciated sustained G protein signaling from internalized GPCRs. PMID- 27499022 TI - Glycosylation-Dependent IFN-gammaR Partitioning in Lipid and Actin Nanodomains Is Critical for JAK Activation. AB - Understanding how membrane nanoscale organization controls transmembrane receptors signaling activity remains a challenge. We studied interferon-gamma receptor (IFN-gammaR) signaling in fibroblasts from homozygous patients with a T168N mutation in IFNGR2. By adding a neo-N-glycan on IFN-gammaR2 subunit, this mutation blocks IFN-gamma activity by unknown mechanisms. We show that the lateral diffusion of IFN-gammaR2 is confined by sphingolipid/cholesterol nanodomains. In contrast, the IFN-gammaR2 T168N mutant diffusion is confined by distinct actin nanodomains where conformational changes required for Janus activated tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) activation by IFN-gamma could not occur. Removing IFN-gammaR2 T168N bound galectins restored lateral diffusion in lipid nanodomains and JAK/STAT signaling in patient cells, whereas adding galectins impaired these processes in control cells. These experiments prove the critical role of dynamic receptor interactions with actin and lipid nanodomains and reveal a new function for receptor glycosylation and galectins. Our study establishes the physiological relevance of membrane nanodomains in the control of transmembrane receptor signaling in vivo. VIDEO ABSTRACT. PMID- 27499023 TI - Memory of Inflammation in Regulatory T Cells. AB - Eukaryotic cells can "remember" transient encounters with a wide range of stimuli, inducing lasting states of altered responsiveness. Regulatory T (Treg) cells are a specialized lineage of suppressive CD4 T cells that act as critical negative regulators of inflammation in various biological contexts. Treg cells exposed to inflammatory conditions acquire strongly enhanced suppressive function. Using inducible genetic tracing, we analyzed the long-term stability of activation-induced transcriptional, epigenomic, and functional changes in Treg cells. We found that the inflammation-experienced Treg cell population reversed many activation-induced changes and lost its enhanced suppressive function over time. The "memory-less" potentiation of Treg suppressor function may help avoid a state of generalized immunosuppression that could otherwise result from repeated activation. PMID- 27499024 TI - A case of recurrent fever in an older man caused by Coxiella burnetii. AB - Q fever is a zoonosis caused by the intracellular bacterium Coxiella burnetii. While it is mostly an asymptomatic infection, acute disease can manifest as fever associated with signs of pneumonia or hepatitis. Chronic Q fever develops in 1-5% of infected persons. Patients with a history of cardiac valve surgery, vascular prosthesis or vascular aneurysm, and to a lesser extent patients with pre existing valvular disease, immune deficiencies, or renal insufficiency, are at highest risk. Most common manifestations are Q fever endocarditis and Q fever vascular infection. We present a case of chronic Q fever, followed by a summary of available literature. PMID- 27499026 TI - Quantum Chemistry on Quantum Computers: A Polynomial-Time Quantum Algorithm for Constructing the Wave Functions of Open-Shell Molecules. AB - Quantum computers are capable to efficiently perform full configuration interaction (FCI) calculations of atoms and molecules by using the quantum phase estimation (QPE) algorithm. Because the success probability of the QPE depends on the overlap between approximate and exact wave functions, efficient methods to prepare accurate initial guess wave functions enough to have sufficiently large overlap with the exact ones are highly desired. Here, we propose a quantum algorithm to construct the wave function consisting of one configuration state function, which is suitable for the initial guess wave function in QPE-based FCI calculations of open-shell molecules, based on the addition theorem of angular momentum. The proposed quantum algorithm enables us to prepare the wave function consisting of an exponential number of Slater determinants only by a polynomial number of quantum operations. PMID- 27499025 TI - A subpopulation of high IL-21-producing CD4(+) T cells in Peyer's Patches is induced by the microbiota and regulates germinal centers. AB - The production of IL-21 by T follicular helper (Tfh) cells is vital in driving the germinal centre reaction and high affinity antibody formation. However, the degree of Tfh cell heterogeneity and function is not fully understood. We used a novel IL-21eGFP reporter mouse strain to analyze the diversity and role of Tfh cells. Through the analysis of GFP expression in lymphoid organs of IL-21eGFP mice, we identified a subpopulation of GFP(+), high IL-21 producing Tfh cells present only in Peyer's Patches. GFP(+)Tfh cells were found to be polyclonal and related to GFP(-)Tfh cells of Peyer's Patches in TCR repertoire composition and overall gene expression. Studies on the mechanisms of induction of GFP(+)Tfh cells demonstrated that they required the intestinal microbiota and a diverse repertoire of CD4(+) T cells and B cells. Importantly, ablation of GFP(+) cells resulted in a reduced frequency of Peyer's Patches IgG1 and germinal center B cells in addition to small but significant shifts in gut microbiome composition. Our work highlights the diversity among IL-21 producing CD4(+) Tfh cells, and the interrelationship between the intestinal bacteria and Tfh cell responses in the gut. PMID- 27499027 TI - Human Cytomegalovirus Increases the Risk of Future Hemorrhagic But Not Ischemic Stroke - A Nested Case-Control Study. AB - BACKGROUND: The cause-and-effect relationship between human cytomegalovirus (HCMV) and stroke has not been widely elucidated. We aimed to determine if HCMV infection has an increased risk of future stroke in hypertensive patients in rural areas of China. METHODS AND RESULTS: This was a nested case-control study from a prospective cohort study. A total of 300 newly diagnosed stroke cases with a median follow-up period of 8.4 years and 300 matched controls were selected for the present analysis. Adjusted odds ratio (OR) for stroke associated with HCMV DNA seropositivity was calculated by conditional logistic regression. HCMV DNA was detected in 38 of 300 samples from stroke patients and in 17 of 300 control samples (12.7% vs. 5.7%; P=0.023). Seropositivity for HCMV DNA increased the risk of incident stroke (unadjusted OR, 1.437; 95% confidence interval (CI), 1.023 2.020, P=0.037) and adjustment for other potential cardiovascular confounders only slightly changed the OR (1.464; 95% CI, 1.003-2.137, P=0.048). After controlling for potential cardiovascular confounders, the OR for hemorrhagic stroke associated with HCMV DNA was 1.718 (95% CI, 1.042-2.832), whereas the OR for ischemic stroke was 0.450 (95% CI, 0.142-1.428). CONCLUSIONS: Seropositivity for HCMV DNA was positively associated with total and hemorrhagic but not ischemic stroke, which persisted after controlling for other cardiovascular factors. (Circ J 2016; 80: 2235-2239). PMID- 27499028 TI - Do systemic antibiotics prevent dry socket and infection after third molar extraction? A systematic review and meta-analysis. AB - OBJECTIVES: The use of antibiotics to prevent dry socket and infection is a controversial but widespread practice. The aim of the study is to assess the efficacy of systemic antibiotics in reducing the frequencies of these complications after extraction. STUDY DESIGN: A systematic review and meta analysis, according to the PRISMA statement, based on randomized double-blind placebo-controlled trials evaluating systemic antibiotics to prevent dry socket and infection after third molar surgery. Databases were searched up to June 2015. Relative risks (RRs) were calculated with inverse variance-weighted, fixed effect, or random-effect models. RESULTS: We included 22 papers in the qualitative and 21 in the quantitative review (3304 extractions). Overall-RR was 0.43 (95% confidence interval [CI] 0.33-0.56; P < .0001); number needed to treat, 14 (95% CI 11-19). Penicillins-RR: 0.40 (95% CI 0.27-0.59). Nitroimidazoles-RR: 0.56 (95% CI 0.38-0.82). No serious adverse events were reported. CONCLUSIONS: Systemic antibiotics significantly reduce the risk of dry socket and infection in third molar extraction. PMID- 27499029 TI - Development and psychometric properties of a health knowledge test on six chronic conditions. AB - OBJECTIVES: The aim of this study was to develop and test the psychometric properties of a health knowledge test on common chronic conditions in the general population. METHODS: Operationalization based on a facet design led to 108 knowledge items on six conditions: cardiovascular disease, cancer, respiratory diseases, musculoskeletal system conditions, depression, and chronic pain. We refined the items (qualitative study 1; N=20) and selected the items by applying a mixed Rasch model (study 2; N=861). The psychometric properties (Study 3; N=4144) of the remaining 24 items were tested using exploratory (split sample N=2110) and confirmatory factor analyses (split sample N=2034). RESULTS: 108 items were refined within study 1, 24 of which were selected in study 2. In study 3, a general health knowledge factor was confirmed based on six subscales on specific conditions. Convergent validity was confirmed by the overlap of health knowledge with education and perceived health knowledge. CONCLUSION: The development and evaluation of the psychometric properties of a health knowledge test on six common conditions will improve future research on health knowledge. PRACTICAL IMPLICATIONS: Chronic conditions present a challenge; assessing the level of health knowledge is the first step to prevent and to cope with these conditions. PMID- 27499030 TI - Treatment effect expressed as the novel Delay of Event measure is associated with high willingness to initiate preventive treatment - A randomized survey experiment comparing effect measures. AB - OBJECTIVES: This study aimed to investigate patients' willingness to initiate a preventive treatment and compared two established effect measures to the newly developed Delay of Events (DoE) measure that expresses treatment effect as a gain in event-free time. METHODS: In this cross-sectional, randomized survey experiment in the general Swedish population,1079 respondents (response rate 60.9%) were asked to consider a preventive cardiovascular treatment. Respondents were randomly allocated to one of three effect descriptions: DoE, relative risk reduction (RRR), or absolute risk reduction (ARR). Univariate and multivariate analyses were performed investigating willingness to initiate treatment, views on treatment benefit, motivation and importance to adhere and willingness to pay for treatment. RESULTS: Eighty-one percent were willing to take the medication when the effect was described as DoE, 83.0% when it was described as RRR and 62.8% when it was described as ARR. DoE and RRR was further associated with positive views on treatment benefit, motivation, importance to adhere and WTP. CONCLUSIONS: Presenting treatment effect as DoE or RRR was associated with a high willingness to initiate treatment. PRACTICE IMPLICATIONS: An approach based on the novel time-based measure DoE may be of value in clinical communication and shared decision making. PMID- 27499031 TI - Red emission fluorescent probes for visualization of monoamine oxidase in living cells. AB - Here we report two novel red emission fluorescent probes for the highly sensitive and selective detection of monoamine oxidase (MAO) with large Stokes shift (227 nm). Both of the probes possess solid state fluorescence and can accomplish the identification of MAO on test papers. The probe MAO-Red-1 exhibited a detection limit down to 1.2 MUg mL(-1) towards MAO-B. Moreover, the cleavage product was unequivocally conformedby HPLC and LCMS and the result was in accordance with the proposed oxidative deamination mechanism. The excellent photostability of MAO-Red 1 was proved both in vitro and in vivo through fluorescent kinetic experiment and laser exposure experiment of confocal microscopy, respectively. Intracellular experiments also confirmed the low cytotoxity and exceptional cell imaging abilities of MAO-Red-1. It was validated both in HeLa and HepG2 cells that MAO Red-1 was capable of reporting MAO activity through the variation of fluorescence intensity. PMID- 27499032 TI - Requirement of HDAC6 for activation of Notch1 by TGF-beta1. AB - TGF-beta1 is enriched in the tumor microenvironment and acts as a key inducer of epithelial to mesenchymal transition (EMT) in lung cancer. The NOTCH signaling pathway is conserved across species and is an essential pathway for development, cell differentiation, and cancer biology. Dysregulation of Notch signaling is a common feature of non-small cell lung cancer (NSCLC) and is correlated with poor prognosis. Crosstalk exists between the NOTCH and TGF-beta signaling pathways in EMT. Herein we report that histone deacetylase 6 (HDAC6) modulates TGF-beta1 mediated activation of the Notch pathway. HDAC6, a primarily cytoplasmic deacetylase, mediates TGF-beta1-induced EMT in human lung cancer cells. Inhibition of HDAC6 with a small molecule inhibitor, namely tubacin or with siRNA attenuated TGF-beta1-induced Notch-1 signaling. We show that TGFbeta-1-induced EMT is accompanied by rapid HDAC6-dependent deacetylation of heat shock protein 90 (HSP90). Consistently, inhibition of HSP90 with its small molecule inhibitor 17AAG attenuated expression of TGF-beta1-induced Notch-1 target genes, HEY-1 and HES-1. These findings reveal a novel function of HDAC6 in EMT via mediating the TGF-beta-Notch signaling cascade, and support HDAC6 as a key regulator of TGFbeta induced EMT in NSCLC. This work suggests that HDAC6 may be an attractive therapeutic target against tumor progression and metastasis. PMID- 27499033 TI - Oscillatory Characteristics of the Vocal Folds Across the Tenor Passaggio. AB - INTRODUCTION: Recent research has revealed that classically trained tenors tend to constrict epilaryngeal structures when singing in and above the passaggio (ie, the frequency region where register events typically occur). These constrictions complicate visibility of vocal fold oscillatory patterns with transoral rigid high-speed video endoscopy, thus limiting the current understanding of laryngeal dynamics in the passaggio region of tenors. MATERIALS AND METHODS: This investigation analyzed seven professionally trained western classical tenors using high-speed digital imaging (HSDI) at 20,000 frames per second via transnasal flexible endoscopy. The participants produced transitions (a) from modal to falsetto register and (b) from modal to stage voice above the passaggio (SVaP) during ascending pitch glides from A3 (220 Hz) to A4 (440 Hz) on vowel /i/. HSDI data were complemented by simultaneous acoustic and electroglottographic recordings. RESULTS: For many subjects both transition types were associated with constrictions of the epilaryngeal structures during the pitch glide. These constrictions appeared to be more distinct for the SVaP than for falsetto. No major irregularities of vocal fold oscillations in the sense of fundamental frequency jumps were observed for either transition type. However, during the transitions, the open quotient derived from the glottal area waveform (OQGAW) increased; in falsetto, the OQGAW was greater and the electroglottographic cepstral peak prominence was lower than in SVaP. CONCLUSIONS: Epilaryngeal constrictions should be considered typical for tenors singing at high fundamental frequencies. Vocal fold oscillatory patterns are changing not only for the register shift from modal to falsetto but also for the transition from modal to SVaP, indicating a need for laryngeal adjustments during these transitions. PMID- 27499034 TI - Downregulation of DNA-PKcs suppresses P-gp expression via inhibition of the Akt/NF-kappaB pathway in CD133-positive osteosarcoma MG-63 cells. AB - The development of chemoresistance is closely linked to the plateau of the survival rate in osteosarcoma (OS) patients. CD133-positive (CD133+) OS cells are known as cancer stem cells (CSCs) in OS and exhibit the characteristic of chemoresistance. In this study, CD133+ and CD133-negative (CD133-) MG-63 cells were isolated by magnetic activated cell sorting (MACS). We verified that CD133+ MG-63 cells were more resistant to cisplatin (CDDP) than CD133- MG-63 cells. DNA dependent protein kinase catalytic subunit (DNA-PKcs) and P-glycoprotein (P-gp) were expressed at higher levels in the CD133+ MG-63 cells compared with those levels in the CD133- MG-63 cells, whereas downregulation of DNA-PKcs by small interfering RNA (siRNA) decreased chemoresistance to CDDP and P-gp expression at the mRNA and protein levels in these cells. This indicated that DNA-PKcs was correlated with P-gp expression in the CD133+ MG-63 cells. The Akt/NF-kappaB pathway was hyperactivated in the CD133+ MG-63 cells, whereas inhibition of the Akt/NF-kappaB pathway downregulated P-gp expression. In addition, downregulation of DNA-PKcs suppressed the activity of the Akt/NF-kappaB pathway. These results revealed that downregulation of DNA-PKcs could decrease P-gp expression via suppression of the Akt/NF-kappaB pathway in CD133+ MG-63 cells. Therefore, inhibition of DNA-PKcs decreases P-gp expression and sensitizes OS CSCs to chemotherapeutic agents in vitro, which needs to be further validated in vivo. PMID- 27499035 TI - An 'Omics' Perspective on Cardiomyopathies and Heart Failure. AB - Pathological enlargement of the heart, represented by hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), occurs in response to many genetic and non-genetic factors. The clinical course of cardiac hypertrophy is remarkably variable, ranging from lifelong absence of symptoms to rapidly declining heart function and sudden cardiac death (SCD). Unbiased omics studies have begun to provide a glimpse into the molecular framework underpinning altered mechanotransduction, mitochondrial energetics, oxidative stress, and extracellular matrix in the heart undergoing physiological and pathological hypertrophy. Omics analyses indicate that post-transcriptional regulation of gene expression plays an overriding role in the normal and diseased heart. Studies to date highlight a need for more effective bioinformatics to better integrate patient omics data with their comprehensive clinical histories. PMID- 27499036 TI - Increased expression levels of ppGalNAc-T13 in lung cancers: Significance in the prognostic diagnosis. AB - ppGalNAc-T13 is upregulated along with reduced expression of GM1 in high metastatic sublines of the murine Lewis lung cancer cell line, but little is known about the implication of ppGalNAc-T13 expression in human cancers. Since lung cancer cell lines showed high expression levels of ppGalNAc-T13, we analyzed ppGalNAc-T13 expression in surgical lung cancer specimens to examine whether ppGalNAc-T13 can be used as a prognostic marker or a therapeutic target. We analyzed mRNA expression levels of GALNT13 and its variant exon usages in surgical specimens by real-time RT-PCR, and the results were evaluated by correlating with clinical data. Ninety-one surgical specimens were analyzed. Consequently, recurrence-free survival was significantly shorter (P=0.045) in high expression group of GALNT13 mRNA. In the analysis of tumor specific exon usage in GALNT13 RNA sequence, one variant exon was significantly associated with worse prognosis. By contrast, in another variant exon, positive variant expression group showed better prognosis than negative group. We also tried to detect GALNT13 mRNA in 63 serum samples from patients with lung cancers to examine whether GALNT13 mRNA can be measured in body fluids, detecting significant levels in 4 samples. Finally, expression of GM1, ppGalNAc-T13 and trimeric Tn antigen was examined by immunohistochemistry in order to evaluate them as a prognostic factor. It was demonstrated that ppGalNAc-T13 and trimeric Tn antigen had a relationship with worse prognosis in 35 investigated lung cancer patients. In conclusion, our results suggest that ppGalNAc-T13 might be a useful prognostic factor of lung cancers. PMID- 27499037 TI - Deficiency of 53BP1 inhibits the radiosensitivity of colorectal cancer. AB - The present study aimed to observe the influence of p53 binding protein 1 (53BP1) silencing on the radiosensitivity of colorectal cancer (CRC) cells and investigated the potential underlying mechanisms. The differences in radiosensitivity among four CRC cells were detected by the clone formation assay, while the expression of their 53BP1 was detected by the western blot analysis. HCT116 cells with relatively high expression of 53BP1 were selected to silence the expression of 53BP1 by shRNA intervention. The influence on proliferation, apoptosis, and cell cycle distribution was detected by immunofluorescent staining of Ki-67 and flow cytometry. The expression of relevant proteins in the apoptotic pathway ATM-CHK2-p53 was further analyzed by western blot analysis. The expression of 53BP1 was found to be closely related to the radiosensitivity of the CRC cells. Decreased expression of 53BP1 led to the tolerance of HCT116 cells to radiation. The detection of tumor proliferation, apoptosis, and cell cycle showed that decreased expression of 53BP1 resulted in an increased S-phase percentage of HCT116 cells, an increased proliferating rate, and a decreased apoptotic rate after radiation. The analysis of the molecular pathway showed that the reduced expression of 53BP1 decreased the protein expression of ATM, CHK2, and the phosphorylated products associated with the p53 apoptotic pathway. In conclusion, decreased expression of 53BP1 leads to radiotolerance of CRC cells, and the underlying mechanism is probably related to the decreased expression of relevant proteins in the ATM-CHK2-p53 pathway, which affects cell cycle, apoptosis and proliferation. PMID- 27499038 TI - Insights into the percutaneous penetration of antidiabetic agents. AB - It has been suggested that destruction of beta cells through apoptosis leads to type 1 diabetes (T1DM) while type 2 diabetes (T2DM) is caused mainly by increased insulin resistance. Several therapeutic agents are available for the management of diabetes. While researchers continue to investigate disease-modifying compounds, it is also important to develop alternative drug delivery systems for existing medications with the goal of modulating bioavailability and/or pharmacokinetic half-life. Transdermal drug delivery offers a number of advantages including improved compliance, lack of gastric irritation and the possibility of altering bioavailability and and/or half-life. In this review, the percutaneous penetration of antidiabetic agents is discussed. This is particularly significant given the fact that several compounds with hypoglycemic properties are being developed by academic research laboratories and the biotechnological industry. Microneedles, sonophoresis, chemical penetration enhancers and iontophoresis are some of the approaches used for the transdermal delivery of antidiabetic agents. It is anticipated that with more research, some of these transdermal drug delivery systems will be incorporated into clinical practice. PMID- 27499039 TI - The role of a small-scale cutoff in determining molecular layers at fluid interfaces. AB - The existence of molecular layers at liquid/vapour interfaces has been a long debated issue. More than ten years ago it was shown, using computer simulations, that correlations at the liquid/vapour interface resemble those of bulk liquids, even though they can be detected in experiments only in a few cases, where they are so strong that they cannot be concealed by the geometrical smearing of capillary fluctuations. The results of the intrinsic analysis techniques used in computer experiments, however, are still often questioned because of their dependence on a free parameter that usually represents a small-scale cutoff used to determine the interface. In this work I show that there is only one value of the cutoff that can ensure a quantitative explanation of the intrinsic density correlation peaks in terms of successive layer contributions. The value of the cutoff coincides, with a high accuracy, with the molecular diameter. PMID- 27499040 TI - Reply: Evolutionary approach sheds light on the significance of vascular calcification. PMID- 27499041 TI - Editorial commentary: Fractional flow reserve-A diagnostic tool, a prognostic index. PMID- 27499042 TI - Distinct interacting core taxa in co-occurrence networks enable discrimination of polymicrobial oral diseases with similar symptoms. AB - Polymicrobial diseases, which can be life threatening, are caused by the presence and interactions of multiple microbes. Peri-implantitis and periodontitis are representative polymicrobial diseases that show similar clinical symptoms. To establish a means of differentiating between them, we compared microbial species and functional genes in situ by performing metatranscriptomic analyses of peri implantitis and periodontitis samples obtained from the same subjects (n = 12 each). Although the two diseases differed in terms of 16S rRNA-based taxonomic profiles, they showed similarities with respect to functional genes and taxonomic and virulence factor mRNA profiles. The latter-defined as microbial virulence types-differed from those of healthy periodontal sites. We also showed that networks based on co-occurrence relationships of taxonomic mRNA abundance (co occurrence networks) were dissimilar between the two diseases. Remarkably, these networks consisted mainly of taxa with a high relative mRNA-to-rRNA ratio, with some showing significant co-occurrence defined as interacting core taxa, highlighting differences between the two groups. Thus, peri-implantitis and periodontitis have shared as well as distinct microbiological characteristics. Our findings provide insight into microbial interactions in polymicrobial diseases with unknown etiologies. PMID- 27499043 TI - Selection and characterization of the novel anti-human PD-1 FV78 antibody from a targeted epitope mammalian cell-displayed antibody library. AB - Currently, display-based methods are well established and widely used in antibody engineering for affinity maturation and structural stability improvement. We obtained a novel anti-human programmed death 1 (PD-1) antibody using computer aided design and a mammalian cell display technology platform. We used computer aided modeling and distance geometry methods to predict and assign the key residues that contributed to the binding of human PD-L1 to PD-1. Then, we analyzed the sequence of nivolumab (an anti-human PD-1 antibody, referred to as MIL75 in the article) to determine the template for antibody design and library construction. We identified a series of potential substitutions on the obtained template and constructed a virtual epitope-targeted antibody library based on the physicochemical properties and each possible location of the assigned key residues. The virtual antibody libraries were displayed on the surface of mammalian cells as the antigen-binding fragments of full-length immunoglobulin G. Then, we used flow cytometry and sequencing approaches to sort and screen the candidates. Finally, we obtained a novel anti-human PD-1 antibody named FV78. FV78 competitively recognized the PD-1 epitopes that interacted with MIL75 and possessed an affinity comparable to MIL75. Our results implied that FV78 possessed equivalent bioactivity in vitro and in vivo compared with MIL75, which highlighted the probability and prospect of FV78 becoming a new potential antibody therapy. PMID- 27499045 TI - Corrigendum to 'Externalizing behaviors of Ukrainian children: The role of parenting' [Child Abuse Negl. 54 (2016) 23-32]. PMID- 27499044 TI - CD5 expression promotes IL-10 production through activation of the MAPK/Erk pathway and upregulation of TRPC1 channels in B lymphocytes. AB - CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukemia (CLL). Important functional properties are associated with CD5 expression in B cells, including signal transducer and activator of transcription 3 activation, IL-10 production and the promotion of B-lymphocyte survival and transformation. However, the pathway(s) by which CD5 influences the biology of B cells and its dependence on B cell receptor (BCR) co-signaling remain unknown. In this study, we show that CD5 expression activates a number of important signaling pathways, including Erk1/2, leading to IL-10 production through a novel pathway independent of BCR engagement. This pathway is dependent on extracellular calcium (Ca2+) entry facilitated by upregulation of the transient receptor potential channel 1 (TRPC1) protein. We also show that Erk1/2 activation in a subgroup of CLL patients is associated with TRPC1 overexpression. In this subgroup of CLL patients, small inhibitory RNA (siRNA) for CD5 reduces TRPC1 expression. Furthermore, siRNAs for CD5 or for TRPC1 inhibit IL-10 production. These findings provide new insights into the role of CD5 in B-cell biology in health and disease and could pave the way for new treatment strategies for patients with B-CLL. PMID- 27499047 TI - Selectivity in Small Molecule Splicing Modulation. AB - The dysregulation of RNA splicing is a molecular hallmark of disease, including different and often complex cancers. While gaining recognition as a target for therapeutic discovery, understanding the complex mechanisms guiding RNA splicing remains a challenge for chemical biology. The discovery of small molecule splicing modulators has recently enabled an evaluation of the mechanisms of aberrant splicing. We now report on three unique features within the selectivity of splicing modulators. First, we provide evidence that structural modifications within a splicing modulator can alter the splicing of introns in specific genes differently. These studies indicate that structure activity relationships not only have an effect on splicing activity but also include specificity for specific introns within different genes. Second, we find that these splicing modulators also target the mRNAs encoding components of the spliceosome itself. Remarkably, this effect includes the genes for the SF3B complex, a target of pladienolide B and related splicing modulators. Finally, we report on the first observation of a temporal phenomenon associated with small molecule splicing modulation. Combined, these three observations provide an important new perspective for the exploration of splicing modulation in terms of both future medicinal chemistry programs as well as understanding the key facets underlying its timing. PMID- 27499046 TI - Blunted apoptosis of erythrocytes in mice deficient in the heterotrimeric G protein subunit Galphai2. AB - Putative functions of the heterotrimeric G-protein subunit Galphai2-dependent signaling include ion channel regulation, cell differentiation, proliferation and apoptosis. Erythrocytes may, similar to apoptosis of nucleated cells, undergo eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) exposure. Eryptosis may be triggered by increased cytosolic Ca(2+) activity and ceramide. In the present study, we show that Galphai2 is expressed in both murine and human erythrocytes and further examined the survival of erythrocytes drawn from Galphai2-deficient mice (Galphai2(-/-)) and corresponding wild-type mice (Galphai2(+/+)). Our data show that plasma erythropoietin levels, erythrocyte maturation markers, erythrocyte counts, hematocrit and hemoglobin concentration were similar in Galphai2(-/-) and Galphai2(+/+) mice but the mean corpuscular volume was significantly larger in Galphai2(-/-) mice. Spontaneous PS exposure of circulating Galphai2(-/-) erythrocytes was significantly lower than that of circulating Galphai2(+/+) erythrocytes. PS exposure was significantly lower in Galphai2(-/-) than in Galphai2(+/+) erythrocytes following ex vivo exposure to hyperosmotic shock, bacterial sphingomyelinase or C6 ceramide. Erythrocyte Galphai2 deficiency further attenuated hyperosmotic shock-induced increase of cytosolic Ca(2+) activity and cell shrinkage. Moreover, Galphai2(-/-) erythrocytes were more resistant to osmosensitive hemolysis as compared to Galphai2(+/+) erythrocytes. In conclusion, Galphai2 deficiency in erythrocytes confers partial protection against suicidal cell death. PMID- 27499048 TI - Challenges in detecting disease modification in Parkinson's disease clinical trials. AB - Despite the wealth of encouraging data from numerous compounds that demonstrate "neuroprotection" in pre-clinical studies of Parkinson's disease, and despite numerous clinical trials, to date, no intervention has been demonstrated to able to modify the course of disease progression. While this "failure to translate" is likely due to numerous factors including our incomplete understanding of the pathogenic mechanisms underlying PD together with excessive reliance on data from the toxin-based animal models of PD, here we will discuss the "structural issues" pertaining to inadequate clinical trial design, selection of inappropriate endpoints and poor patient selection which are often not addressed following failed disease modification trials. Future directions to overcome these challenges such as reducing the heterogeneity of patient cohorts, identifying and utilising a pre-diagnostic population, embracing a personalised medicine approach and utilising novel trial designs may be required to ultimately fulfil the goal of conclusively demonstrating evidence of disease modification. PMID- 27499049 TI - Task specific dystonia in a juggler. PMID- 27499050 TI - High mobility group box 1 and tumor growth factor beta: useful biomarkers in pediatric patients receiving peritoneal dialysis. AB - BACKGROUND: Peritonitis, the most important limitation of peritoneal dialysis (PD), could be detected by biomarkers in dialysate effluent, representing a noninvasive method to indirectly assess the peritoneum status. The aim of our study was to test high mobility group box 1 (HMGB1) in PD patients, evaluating its role as precocious marker of peritoneum damage during peritonitis. Transforming growth factor (TGF)-beta was correlated with peritoneal transport characteristics. METHODS: Six patients, treated by ambulatory PD, were enrolled. Samples were collected at the onset of peritonitis (T1) and every day until its resolution (T-end). Serum (s) and peritoneal (p) white blood cell (WBC) count was also evaluated. Peritoneal Equilibration Test evaluated the filter activity of peritoneum. RESULTS: In patients with acute peritonitis, the highest serum and peritoneal HMGB1 values (64 +/- 3.6 and 70 +/- 5.3 ng/mL, respectively) were assessed, with a progressive decrease of their levels at the resolution time (T end: sHMGB1:36 +/- 2.5; pHMGB1:30.5 +/- 7.0 ng/mL). While no differences of sWBC and pWBC were observed between baseline and T-end values, pHMGB1 levels remained higher at T-end than those observed at T0 (pHMGB1:30.5 +/- 7.0 versus 6.9 +/- 3.6; p < 0.0001). TGF-beta levels were higher in patients with low peritoneal permeability than in medium or high transporter patients (81 +/- 15.5 versus 24.3 +/- 7.5 pg/mL; p = 0.01). An inverse correlation was found between TGF-beta levels and dialysate/plasmatic creatinine values (r = -0.83; p = 0.03). CONCLUSION: HMGB1 represents a useful biomarker for peritoneum evaluation in PD patients. A prognostic role of this alarmin, as a marker of response to therapy, could be hypothesized. TGF-beta could predict the peritoneal transport status and dialysis technique adequacy. PMID- 27499051 TI - The nomenclatural type of the genus Methanocorpusculum Zellner et al. 1988 and the selection of the correct name. AB - A recent Request for an Opinion has raised the issue of the inter-relationship between Methanocorpusculum parvum Zellner et al. 1988, the type species of the genus Methanocorpusculum Zellner et al. 1988 as defined at the time of valid publication of the genus name and the subsequent recognition of Methanocorpusculum aggregans (Ollivier et al., 1985) Xun et al.1989 as an earlier heterotypic synonym. Examination of the relevant literature indicates that there are a number of misunderstandings that have arisen. In particular misinterpretation of Rule 15 of the International Code of Nomenclature of Prokaryotes continues to be a source of confusion. Additional problems centre on whether the nomenclatural type of a taxon continues to be the nomenclatural type even if that name is not treated as the correct name and would not appear in a list of names in a given classification. It would be appropriate to clarify these issues. PMID- 27499052 TI - A shared N-terminal hydrophobic tail for the formation of nanoparticulates. AB - AIM: Nanoparticulate design is important for the production of nanotechnological materials and passive immunogens. Using lessons from our hepatitis E vaccine, we herein design protein-based nanoparticles through incorporation of an N-terminal hydrophobic tail (NHT, located on HEV ORF2 aa368-460). MATERIALS & METHODS: Flu HA1, HIV gp41/gp120/p24, HBsAg and HPV16 L2 were fused with NHT, expressed in Escherichia coli and subjected to self-assembly in vitro. Nanosized particles were characterized by size-exclusion chromatography and negative electron microscopy. Immunogenicity was assessed in mice. RESULTS: All the NHT-fused proteins spontaneously formed nanoparticulates and presented with immunogenicity approximately 2-log over their nonassembling forms. CONCLUSION: Protein self assembly provides an attractive means to create nanosized particles that bear specific antigens. Our strategy outlines a novel and shared method for the design of immunogenic nanoparticles. PMID- 27499053 TI - Streptococcus agalactiae from pregnant women: antibiotic and heavy-metal resistance mechanisms and molecular typing. AB - We investigated the antibiotic and heavy-metal resistance mechanisms, virulence genes and clonal relationships of macrolide- and/or lincosamide-resistant (M+/ LR) Streptococcus agalactiae (group B Streptococcus, GBS) isolates from pregnant women in La Rioja in Northern Spain, a region with a significant immigrant population. In total 375 GBS isolates were recovered during 2011. About three quarters of isolates were from European nationals and the remainder distributed among 23 other nationalities. Seventy-five (20%) were classified as M+/-LR strains and 28 (37%) of these were resistant to ?3 classes of antibiotics. Capsular serotypes III (29.3%), V (21.3%) and II (12%) were the most frequent. A wide variety of antibiotic resistance genes were detected in M+/-LR strains; notably, 5.3% harboured the lsa(C) gene associated with cross-resistance, and tet(W) was identified in a single strain. We report, for the first time, the detection of cadmium and copper resistance encoded by tcrB + cadA + cadC genes in 20 M+/-LR strains, which raises the possibility of co-selection of antibiotic and heavy-metal resistance disseminated through mobile genetic elements. The M+/-LR strains were highly diverse by DNA macrorestriction profiles (65 patterns) and 16 multilocus sequence types (STs) distributed among six clonal complexes; the most frequent were ST1, ST19, and ST12, and two strains were novel (ST586 and ST601). In conclusion, a wide diversity of genetic lineages of macrolide, lincosamide and heavy-metal- resistant GBS strains was observed in an ethnically diverse maternal population. PMID- 27499054 TI - Peer counselling for the promotion of long-acting, reversible contraception among teens: a randomised, controlled trial. AB - AIM: To evaluate the impact peer counselling has on same-day desire for long acting, reversible contraception (LARC) among adolescents attending a family planning clinic. METHODS: A randomised, controlled trial of 110 adolescent females attending an outpatient clinic for contraception in 2013. Adolescents received either brief peer counselling about LARC with routine contraceptive counselling, or routine counselling alone. Bivariate analyses and multivariable logistic regression assessed the primary outcome of same-day desire for LARC and secondary outcomes of change in knowledge and attitudes regarding LARC. RESULTS: Peer counselling was well received and 70% reported that it was helpful in contraceptive decision-making. Peer counselling did not affect same-day desire for LARC, however, adolescents who received the intervention were more likely to report increased knowledge and positive change in attitudes towards LARC (adjusted odds ratios: 6.6 (95% confidence interval: 2.0-22.0 and 6.4 (1.6-26.8), respectively). Factors positively associated with same-day LARC desire included greater reported peer contraceptive influence, peer use of LARC and social support. Twenty of the 36 adolescents who desired LARC at the end of their clinic visit did not receive one most commonly due to a need to schedule a specific appointment for the procedure and the need to return during a menstrual period for intrauterine device placement. CONCLUSION: While brief, point-of-care peer counselling is well received, and can increase adolescent knowledge and positive attitude about our most effective contraceptive methods, barriers to same-day LARC placement limit immediate use. PMID- 27499055 TI - The nonequilibrium glassy dynamics of self-propelled particles. AB - We study the glassy dynamics taking place in dense assemblies of athermal active particles that are driven solely by a nonequilibrium self-propulsion mechanism. Active forces are modeled as an Ornstein-Uhlenbeck stochastic process, characterized by a persistence time and an effective temperature, and particles interact via a Lennard-Jones potential that yields well-studied glassy behavior in the Brownian limit, which is obtained as the persistence time vanishes. By increasing the persistence time, the system departs more strongly from thermal equilibrium and we provide a comprehensive numerical analysis of the structure and dynamics of the resulting active fluid. Finite persistence times profoundly affect the static structure of the fluid and give rise to nonequilibrium velocity correlations that are absent in thermal systems. Despite these nonequilibrium features, for any value of the persistence time we observe a nonequilibrium glass transition as the effective temperature is decreased. Surprisingly, increasing departure from thermal equilibrium is found to promote (rather than suppress) the glassy dynamics. Overall, our results suggest that with increasing persistence time, microscopic properties of the active fluid change quantitatively, but the general features of the nonequilibrium glassy dynamics observed with decreasing the effective temperature remain qualitatively similar to those of thermal glass formers. PMID- 27499056 TI - Treatment with the selective serotonin reuptake inhibitor, fluoxetine, attenuates the fish hypoxia response. AB - The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX), the active ingredient of the antidepressant drug Prozac, inhibits reuptake of the neurotransmitter, serotonin (5-HT; 5-hydroxytryptamine), into cells by the 5-HT transporter (SERT). Given the role of 5-HT in oxygen detection and the cardiovascular and ventilatory responses of fish to hypoxia, we hypothesized that treatment of the Gulf toadfish, Opsanus beta, with FLX would interfere with their response to hypoxia. Toadfish treated intra-arterially with 3.4 MUg.g(-1) FLX under normoxic conditions displayed a transient tachycardia and a biphasic caudal arterial blood pressure (PCA) response that are in direct conflict with the typical hypoxia response. Fish injected intraperitoneally with FLX under normoxia had resting cardiovascular and ventilatory parameters similar to controls. Upon exposure to hypoxia, control toadfish exhibit a significant bradycardia, reduction in PCA and an increase in ventilatory amplitude (VAMP) without any changes in ventilatory frequency (fV). Fish treated IP with 10 MUg.g(-1) FLX showed an interference in the cardiovascular and ventilatory response to hypoxia. Interestingly, when treated with 25 MUg.g(-1) FLX, the bradycardia and VAMP response to hypoxia were similar to control fish while the PCA response to hypoxia was further inhibited. These results suggest that SERT inhibition by FLX may hinder survival in hypoxia. PMID- 27499057 TI - Blue-light activated rapid polymerization for defect-free bulk Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) crosslinked networks. AB - A visible-light (470 nm wavelength) sensitive Type II photoinitiator system is developed for bulk Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions in crosslinked networks. The accelerated photopolymerization eliminates UV mediated azide decomposition allowing for the formation of defect-free glassy networks which exhibit a narrow glass transition temperature. PMID- 27499058 TI - Enhanced electrocatalytic activity of nitrogen-doped olympicene/graphene hybrids for the oxygen reduction reaction. AB - Developing inexpensive and non-precious metal electrocatalysts for the oxygen reduction reaction (ORR) is among the major goals in fuel cells. Herein, by using density-functional theory calculations, we show that N-doped olympicene/graphene hybrids exhibit unexpectedly high ORR catalytic activity-even comparable to that of the Pt(111) surface. Both graphitic-type and pyridine-type N-doped olympicene/graphene hybrids are highly active for the ORR and have good CO tolerance. The formation of the second H2O molecule is the rate-determining step for the ORR with the graphitic-type hybrid, whereas on the pyridine-type hybrid, it is the formation of OOH. Note that N-doped olympicene/graphene hybrid materials combine the high reactivity of olympicene and the high electrical conductivity of graphene, which allows them to be potentially used as low-cost and non-precious-metal ORR catalysts. PMID- 27499059 TI - Clinical features and outcome of epinephrine-induced takotsubo syndrome: Analysis of 33 published cases. AB - BACKGROUND: Takotsubo syndrome (TS) may be triggered by innumerable physical stress factors including epinephrine administration. The aim of this study is to report on the clinical features and outcome of epinephrine-induced TS (Epi-TS) in a large cohort of published cases. METHODS: A computer assisted search of the electronic data base Pubmed was performed from 1990 to 2014. All cases deemed to have Epi-TS were retrieved and compared to the large recent report by Templin et al. (All-TS). RESULTS: Thirty-three cases of Epi-TS were retrieved from the literature and compared to 1750 cases of All-TS. Chest pain as a presenting symptom occurred in 45% of cases. The Epi-TS patients were on average 20.6years younger than All-TS patients (p<0.0001). The women were still predominating in Epi-TS but in a significantly lower percentage compared to ALL-TS (73% in Epi-TS vs 89.8% in All-TS, p=0.0054). One third of the Epi-TS cases had basal pattern of TS compared to 2.2% of cases reported in All-TS. Epi-TS cases were characterized by high complication rates, which occurred in 57.6%. The most important risk factor for the development of TS complication was the accidental administration (P<0.001) and the dose of >1mg epinephrine (p=0.02). In spite of high complication rates, the recovery was rapid with no in-hospital mortality. CONCLUSION: Epi-TS is characterized by a dramatic rapid onset of symptoms after epinephrine administration. Almost half of the cases had apical sparing and one third basal pattern of TS. In spite of high complication rates, the prognosis was good with no in-hospital mortality. PMID- 27499060 TI - Review: Stent fracture in the drug-eluting stent era. AB - Stent fracture has been recognized as one cause of stent failure and has been associated with in-stent restenosis and stent thrombosis, even in 2nd-generation drug-eluting stents. Given the wide use of drug-eluting stents and paucity of contemporary data available concerning stent fracture, we reviewed clinical studies and the Food and Drug Administration's Manufacturer and User Device Experience (MAUDE) database to analyze the current trends, mechanisms, predictors, outcomes and treatment for stent fracture. PMID- 27499061 TI - Aerobic versus Anaerobic Microbial Degradation of Clothianidin under Simulated California Rice Field Conditions. AB - Microbial degradation of clothianidin was characterized under aerobic and anaerobic California rice field conditions. Rate constants (k) and half-lives (DT50) were determined for aerobic and anaerobic microcosms, and an enrichment experiment was performed at various nutrient conditions and pesticide concentrations. Temperature effects on anaerobic degradation rates were determined at 22 +/- 2 and 35 +/- 2 degrees C. Microbial growth was assessed in the presence of various pesticide concentrations, and distinct colonies were isolated and identified. Slow aerobic degradation was observed, but anaerobic degradation occurred rapidly at both 25 and 35 degrees C. Transformation rates and DT50 values in flooded soil at 35 +/- 2 degrees C (k = -7.16 * 10(-2) +/- 3.08 * 10(-3) day(-1), DT50 = 9.7 days) were significantly faster than in 25 +/- 2 degrees C microcosms (k= -2.45 * 10(-2) +/- 1.59 * 10(-3) day(-1), DT50 = 28.3 days). At the field scale, biodegradation of clothianidin will vary with extent of oxygenation. PMID- 27499062 TI - Bilateral hamartomatous medullary lipoma within the nasal turbinate bones in a cynomolgus monkey (Macaca fascicularis). AB - A 15-year-old male cynomolgus monkey (Macaca fascicularis) showed large bilateral masses in the maxillary sinus. In histopathological examination, both masses revealed benign medullary lipomas within the turbinate bones. The tumors were composed of well-developed lipocytes, trabecular bones and a few blood vessels. Although we initially diagnosed the tumor as bilateral lipomas in the nasal turbinates, it was not differentiated from lipomatous hamartoma. Findings, such as unique symmetrical proliferation, lack of border from the normal marrow and the intact surrounding tissue, indicated a lipomatous hamartoma/hamartomatous lipoma, thought to be a suitable diagnosis of the lesion. Of most interest was that such a proliferating lesion occurred in the nasal turbinate. PMID- 27499063 TI - Free-energy studies reveal a possible mechanism for oxidation-dependent inhibition of MGL. AB - The function of monoacylglycerol lipase (MGL), a key actor in the hydrolytic deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2AG), is tightly controlled by the cell's redox state: oxidative signals such as hydrogen peroxide suppress MGL activity in a reversible manner through sulfenylation of the peroxidatic cysteines, C201 and C208. Here, using as a starting point the crystal structures of human MGL (hMGL), we present evidence from molecular dynamics and metadynamics simulations along with high-resolution mass spectrometry studies indicating that sulfenylation of C201 and C208 alters the conformational equilibrium of the membrane-associated lid domain of MGL to favour closed conformations of the enzyme that do not permit the entry of substrate into the active site. PMID- 27499065 TI - Erratum: Biomarkers in the Management of Difficult Asthma. AB - In the review entitled, 'Biomarkers in the Management of Difficult Asthma' published in Current Topics in Medicinal Chemistry, 2016, 16, 1561-1573, the authors name should be in the following format. Florence Schleich*, Sophie Demarche and Renaud Louis. Respiratory Medicine, GIGA I", CHU Sart-Tilman B35, 4000 Liege, Belgium. PMID- 27499064 TI - Long-term effectiveness of initiating non-nucleoside reverse transcriptase inhibitor- versus ritonavir-boosted protease inhibitor-based antiretroviral therapy: implications for first-line therapy choice in resource-limited settings. AB - INTRODUCTION: In many resource-limited settings, combination antiretroviral therapy (cART) failure is diagnosed clinically or immunologically. As such, there is a high likelihood that patients may stay on a virologically failing regimen for a substantial period of time. Here, we compared the long-term impact of initiating non-nucleoside reverse transcriptase inhibitor (NNRTI)- versus boosted protease inhibitor (bPI)-based cART in British Columbia (BC), Canada. METHODS: We followed prospectively 3925 ART-naive patients who started NNRTIs (N=1963, 50%) or bPIs (N=1962; 50%) from 1 January 2000 until 30 June 2013 in BC. At six months, we assessed whether patients virologically failed therapy (a plasma viral load (pVL) >50 copies/mL), and we stratified them based on the pVL at the time of failure <=500 versus >500 copies/mL. We then followed these patients for another six months and calculated their probability of achieving subsequent viral suppression (pVL <50 copies/mL twice consecutively) and of developing drug resistance. These probabilities were adjusted for fixed and time-varying factors, including cART adherence. RESULTS: At six months, virologic failure rates were 9.5 and 14.3 cases per 100 person-months for NNRTI and bPI initiators, respectively. NNRTI initiators who failed with a pVL <=500 copies/mL had a 16% higher probability of achieving subsequent suppression at 12 months than bPI initiators (0.81 (25th-75th percentile 0.75-0.83) vs. 0.72 (0.61-0.75)). However, if failing NNRTI initiators had a pVL >500 copies/mL, they had a 20% lower probability of suppressing at 12 months than pVL-matched bPI initiators (0.37 (0.29-0.45) vs. 0.46 (0.38-0.54)). In terms of evolving HIV drug resistance, those who failed on NNRTI performed worse than bPI in all scenarios, especially if they failed with a viral load >500 copies/mL. CONCLUSIONS: Our results show that patients who virologically failed at six months on NNRTI and continued on the same regimen had a lower probability of subsequently achieving viral suppression and a higher chance of evolving HIV drug resistance. These results suggest that improving access to regular virologic monitoring is critically important, especially if NNRTI-based cART is to remain a preferred choice for first-line therapy in resource-limited settings. PMID- 27499067 TI - Winner of the Annals of Science Prize for 2015. PMID- 27499066 TI - Erratum to: Abyssicoccus albus gen. nov., sp. nov., a novel member of the family Staphylococcaceae isolated from marine sediment of the Indian Ocean. PMID- 27499068 TI - Increased EZH2 and decreased osteoblastogenesis during local irradiation-induced bone loss in rats. AB - Radiation therapy is commonly used to treat cancer patients but exhibits adverse effects, including insufficiency fractures and bone loss. Epigenetic regulation plays an important role in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Here, we reported local bone changes after single-dose exposure to (137)CS irradiation in rats. Femur bone mineral density (BMD) and trabecular bone volume in the tibia were significantly decreased at 12 weeks after irradiation. Micro-CT results showed that tBMD, Tb.h and Tb.N were also significantly reduced at 12 weeks after irradiation exposure. ALP-positive OB.S/BS was decreased by 42.3% at 2 weeks after irradiation and was decreased by 50.8% at 12 weeks after exposure. In contrast to the decreased expression of Runx2 and BMP2, we found EZH2 expression was significantly increased at 2 weeks after single-dose (137)CS irradiation in BMSCs. Together, our results demonstrated that single-dose (137)CS irradiation induces BMD loss and the deterioration of bone microarchitecture in the rat skeleton. Furthermore, EZH2 expression increased and osteoblastogenesis decreased after irradiation. The underlying mechanisms warrant further investigation. PMID- 27499069 TI - Risk is for the rich? Childhood vaccination resistance and a Culture of Health. AB - Childhood vaccination resistance has given rise to outbreaks of diseases, which had been virtually eliminated in the developed world. A parent's decision to forego vaccination for their child is a private choice that can have collective outcomes. This article takes a two-pronged approach to unraveling the puzzle of perceiving vaccines as dangerous in view of evidence that testifies to their effectiveness and relative safety. First, it draws on fifty-seven years of newspaper articles on vaccines to outline the public narratives. Second, it uses school-level data from New York and California to explore how these public narratives shape a geography of vaccination rates. We have two main findings. First, we find that while risk has always been a feature of vaccine narratives, the perception that the risks of vaccines out-weigh the benefits has grown. By the millennium, some began to view medical treatments as sources of risk rather than cure. Second, our geography of childhood vaccination reveals two distinct vaccine worlds. Affluence governs one world. Poverty governs the other. The geographic locales where vaccination rates are low enable us to contrast the difference between imagining risk, the prerogative of the affluent, and being at risk, the fate of the poor. Vaccination resistance speaks directly to a Culture of Health as it poses questions about the collective perception of risk and its relation to social inequality and solidarity. PMID- 27499070 TI - Room temperature differential conductance measurements of triethylamine molecules adsorbed on Si(001). AB - We have measured the differential conductance of the triethylamine molecule (N(CH2CH3)3) adsorbed on Si(001)-2 * 1 at room temperature using scanning tunneling spectroscopy. Triethylamine can be engaged in a dative bonding with a silicon dimer, forming a Si-Si-N(CH2CH3)3 unit. We have examined the datively bonded adduct, either as an isolated molecule, or within an ordered molecular domain (reconstructed 4 * 2). The differential conductance curves, supported by DFT calculations, show that in the explored energy window (+/-2.5 near the Fermi level) the main features stem from the uncapped dangling bonds of the reacted dimer and of the adjacent unreacted ones that are electronically coupled The formation of a molecular domain, in which one dimer in two is left unreacted, is reflected in a shift of the up dimer atom occupied level away from the Fermi level, likely due to an increased pi-bonding strength. In stark contrast with the preceding, pairs of dissociated molecule (a minority species) are electronically decoupled from the dimer dangling bond states. DFT calculation show that the lone pair of the Si-N(CH2CH3)2 is a shallow level, that is clearly seen in the differential conductance curve. PMID- 27499071 TI - High expression of miR-15b predicts poor prognosis for hepatocellular carcinoma after curative hepatectomy. AB - The present study aimed to analyze the role and mechanism of miR-15b in hepatocellular carcinoma (HCC) after curative hepatectomy. Tissue samples from 13 patients with HCC who were operated on at the Chinese PLA General Hospital from March 2014 to May 2014 were collected. A consecutive 156 untreated patients with HCC who received curative hepatectomy at the Chinese PLA General Hospital (Beijing, China) from May 2008 to March 2009 were enrolled, and their corresponding para-tumoral and normal tissue samples were acquired. Subsequently, anti-miR-15b (inhibitor) was transfected into human HCC HepG2 cells. It was observed that high expression of miR-15b promoted cell proliferation of the HCC cells, while low expression of miR-15b suppressed cell growth and induced the apoptosis of HepG2 cells. It was found that overall survival of the patients with low miR-15b was increased, compared with the overall survival of the patients with high miR-15b expression. In addition, low expression of miR-15b suppressed the growth of HepG2 cells by suppression of transforming growth factor-beta (TGF beta), TbetaRI and Smad2 protein expression. Meanwhile, low expression of miR-15b significantly activated Bax protein expression and caspase-3 activity in the HepG2 cells. The study results revealed that high expression of miR-15b could predict the poor prognosis of hepatocellular carcinoma after curative hepatectomy through TGF-beta/TbetaRI-Smad2-cyclin D1/Bax. PMID- 27499072 TI - Mental illness and the right to vote. PMID- 27499074 TI - The effects of 405 nm light on bacterial membrane integrity determined by salt and bile tolerance assays, leakage of UV-absorbing material and SYTOX green labelling. AB - Bacterial inactivation by 405 nm light is accredited to the photoexcitation of intracellular porphyrin molecules resulting in energy transfer and the generation of reactive oxygen species that impart cellular oxidative damage. The specific mechanism of cellular damage, however, is not fully understood. Previous work has suggested that destruction of nucleic acids may be responsible for inactivation; however, microscopic imaging has suggested membrane damage as a major constituent of cellular inactivation. This study investigates the membrane integrity of Escherichia coli and Staphylococcus aureus exposed to 405 nm light. Results indicated membrane damage to both species, with loss of salt and bile tolerance by S. aureus and E. coli, respectively, consistent with reduced membrane integrity. Increased nucleic acid release was also demonstrated in 405 nm light exposed cells, with up to 50 % increase in DNA concentration into the extracellular media in the case of both organisms. SYTOX green fluorometric analysis, however, demonstrated contradictory results between the two test species. With E. coli, increasing permeation of SYTOX green was observed following increased exposure, with >500 % increase in fluorescence, whereas no increase was observed with S. aureus. Overall, this study has provided good evidence that 405 nm light exposure causes loss of bacterial membrane integrity in E. coli, but the results with S. aureus are more difficult to explain. Further work is required to gain greater understanding of the inactivation mechanism in different bacterial species, as there are likely to be other targets within the cell that are also impaired by the oxidative damage from photo-generated reactive oxygen species. PMID- 27499076 TI - Synthesis and Modification of Zn-doped TiO2 Nanoparticles for the Photocatalytic Degradation of Tetracycline. AB - The synthesis of Zn-doped TiO2 nanoparticles by solgel method was investigated in this study, as well as its modification by H2 O2 . The catalyst was characterized by transmission electron microscopy, X-ray diffraction, Brunauer-Emmett-Teller, UV-visible reflectance spectra and X-ray photoelectron spectroscopy (XPS). The results indicated that doping Zn into TiO2 nanoparticles could inhibit the transformation from anatase phase to rutile phase. Zn existed as the second valence oxidation state in the Zn-doped TiO2 . Zn-doped TiO2 that was synthesized by 5% Zn doping at 450 degrees C exhibited the best photocatalytic activity. Then, the H2 O2 modification further enhanced the photocatalytic activity. Zn doping and H2 O2 modifying narrowed the band gap and efficiently increased the optical absorption in visible region. The optimal degradation rate of tetracycline by Zn-doped TiO2 and H2 O2 modified Zn-doped TiO2 was 85.27% and 88.14%. Peroxide groups were detected in XPS analysis of H2 O2 modified Zn-doped TiO2 , favoring the adsorption of visible light. Furthermore, Zn-doped TiO2 modified by H2 O2 had relatively good reusability, exhibiting a potential practical application for tetracycline's photocatalytic degradation. PMID- 27499075 TI - Investigation of the functional role of human Interleukin-8 gene haplotypes by CRISPR/Cas9 mediated genome editing. AB - Interleukin-8 (IL-8) gene polymorphisms have been considered as susceptibility factors in periodontal disease. However, the functional roles of IL-8 gene haplotypes have not been investigated. Here, we demonstrate for the first time the use of the CRISPR/Cas9 system to engineer the IL-8 gene, and tested the functionality of different haplotypes. Two sgRNAs vectors targeting the IL-8 gene and the naked homologous repair DNA carrying different haplotypes were used to successfully generate HEK293T cells carrying the AT genotype at the first SNP - rs4073 (alias -251), TT genotype at the second SNP - rs2227307 (alias +396), TC or CC genotypes at the third SNP - rs2227306 (alias +781) at the IL-8 locus. When stimulated with Poly I:C, ATC/TTC haplotype, cells significantly up-regulated the IL-8 at both transcriptional and translational levels. To test whether ATC/TTC haplotype is functional, we used a trans-well assay to measure the transmigration of primary neutrophils incubated with supernatants from the Poly I:C stimulation experiment. ATC/TTC haplotype cells significantly increased transmigration of neutrophils confirming the functional role for this IL-8 haplotype. Taken together, our data provides evidence that carriage of the ATC/TTC haplotype in itself may increase the influx of neutrophils in inflammatory lesions and influence disease susceptibility. PMID- 27499077 TI - Herbivorax saccincola gen. nov., sp. nov., a cellulolytic, anaerobic, thermophilic bacterium isolated via in sacco enrichments from a lab-scale biogas reactor. AB - A novel Gram-stain-positive, rod-shaped, anaerobic, thermophilic bacterium, strain GGR1T, was isolated from a thermophilic lab-scale biogas fermenter. The novel organism was effectively degrading crystalline cellulose. It seems to play a role in remineralization of plant biomass by hydrolysing its polysaccharides. 16S rRNA gene comparative sequence analysis demonstrated that the isolate formed a hitherto unknown subline within the family Ruminococcaceae. The closest phylogenetic relative of GGR1T among the taxa with validly published names was Clostridiumthermocellum, sharing 94.3 % 16S rRNA gene sequence similarity. Strain GGR1T was catalase-negative, indole-negative and produced acetate and ethanol as major end-products during fermentative cellulose utilization. The major cellular fatty acids (>1 %) were 16 : 0 iso fatty acid and 16 : 0 fatty acid. Cells were rod shaped and grew optimally at 60 degrees C and pH 7.0. The DNA G+C content was 34.9 mol%. A novel genus and species, Herbivoraxsaccincola gen. nov., sp. nov., is proposed on the basis of phylogenetic analysis and physiological properties of the novel isolate. Strain GGR1T (=DSM 101079T=CECT 9155T) represents the type strain for the novel genus and novel species Herbivoraxsaccincola gen. nov., sp. nov. PMID- 27499078 TI - Identification of Mycobacterium tuberculosis in the cerebrospinal fluid of patients with meningitis using nested PCR. AB - Tuberculous meningitis (TBM) is the most severe form of tuberculosis. It is caused by Mycobacterium tuberculosis (M. tuberculosis; MT) and it is very difficult to diagnose. The symptoms are similar to other infectious neurological diseases, such as neurocysticercosis, neuroborreliosis, or herpes viral infection. The aim of this study was to identify tuberculosis (TB) in cases of meningitis with clinical and laboratory evidence suggestive of TBM, and to confirm our findings with molecular tests for TB infection. We recruited patients with neurological symptoms who were examined at the neurology services of Hospitals of Instituto Mexicano del Seguro Social (IMSS) in Mexico City. A total of 144 consecutive patients with suggestive infectious meningitis were initially included; 94 cases of meningitis with clinical and laboratory evidence suggestive of TBM were included, but only 50 of these cases fulfilled the criteria for probable TBM. As the controls, we included 50 cases of meningitis with clinical and laboratory evidence suggestive of non-TBM. Cerebrospinal fluid (CSF) was collected from all 100 patients (cases and controls) and tested for TB by multiplex and nested PCR analyses. Nested PCR detected 0.1 fg of M. tuberculosis DNA. TB infection was confirmed with molecular tests in 49 patients from the 50 cases suggestive of TBM and in 1 of the 50 non-TBM cases. The analysis exhibited a sensitivity of 98.0%, a specificity of 92.0%, a positive predictive value of 88.0% and a negative predictive value of 98.0%. The use CSF for the analyses proved to be effective for the rapid diagnosis of TBM using a developed system of multiplex and nested PCR analyses in patients presenting neurological symptoms. PMID- 27499079 TI - Computational screening of iodine uptake in zeolitic imidazolate frameworks in a water-containing system. AB - Iodine capture is of great environmental significance due to the high toxicity and volatility of I2. Here we conduct a systematic computational investigation of iodine adsorption in zeolitic imidazolate frameworks (ZIFs) by adopting the grand canonical Monte Carlo (GCMC) simulation and the density functional theory (DFT) method. The results confirm the vital structural factors for iodine adsorption at 298 K and moderate pressures including metal sites, organic linkers, symmetry, and topology types. The uptake will be enhanced by active metal sites, the simple imidazolate linker and single asymmetric linkers with polar functional groups. The symmetry effect is stronger than the surface properties. Meanwhile low steric hindrance is more beneficial than polar functional groups to iodine adsorption. The specific topology types like mer bringing large surface areas and large diameter cages result in high iodine capacities. Iodine molecules tend to locate in cages with large diameters and aggregates along the sides of cages. In contrast, water prefers small diameter cages. In hydrophilic materials, water has a negative impact on iodine uptake due to its similar adsorption sites to iodine. The selectivity of iodine over water increases with increasing water content due to the large diameter cages of ZIFs. This work proves that ZIFs can be identified as efficient and economical adsorbents with high diversity for iodine in a water containing system. Furthermore, it provides comprehensive insights into key structural factors for iodine uptake and separation in silver-free porous solids. PMID- 27499080 TI - Virus persistence and recrudescence after Ebola virus disease: what are the risks to healthcare workers? PMID- 27499081 TI - Loss and Gain of MeCP2 Cause Similar Hippocampal Circuit Dysfunction that Is Rescued by Deep Brain Stimulation in a Rett Syndrome Mouse Model. AB - Loss- and gain-of-function mutations in methyl-CpG-binding protein 2 (MECP2) underlie two distinct neurological syndromes with strikingly similar features, but the synaptic and circuit-level changes mediating these shared features are undefined. Here we report three novel signs of neural circuit dysfunction in three mouse models of MECP2 disorders (constitutive Mecp2 null, mosaic Mecp2(+/ ), and MECP2 duplication): abnormally elevated synchrony in the firing activity of hippocampal CA1 pyramidal neurons, an impaired homeostatic response to perturbations of excitatory-inhibitory balance, and decreased excitatory synaptic response in inhibitory neurons. Conditional mutagenesis studies revealed that MeCP2 dysfunction in excitatory neurons mediated elevated synchrony at baseline, while MeCP2 dysfunction in inhibitory neurons increased susceptibility to hypersynchronization in response to perturbations. Chronic forniceal deep brain stimulation (DBS), recently shown to rescue hippocampus-dependent learning and memory in Mecp2(+/-) (Rett) mice, also rescued all three features of hippocampal circuit dysfunction in these mice. PMID- 27499082 TI - Interaction between Spatial and Feature Attention in Posterior Parietal Cortex. AB - Lateral intraparietal (LIP) neurons encode a vast array of sensory and cognitive variables. Recently, we proposed that the flexibility of feature representations in LIP reflect the bottom-up integration of sensory signals, modulated by feature based attention (FBA), from upstream feature-selective cortical neurons. Moreover, LIP activity is also strongly modulated by the position of space-based attention (SBA). However, the mechanisms by which SBA and FBA interact to facilitate the representation of task-relevant spatial and non-spatial features in LIP remain unclear. We recorded from LIP neurons during performance of a task that required monkeys to detect specific conjunctions of color, motion direction, and stimulus position. Here we show that FBA and SBA potentiate each other's effect in a manner consistent with attention gating the flow of visual information along the cortical visual pathway. Our results suggest that linear bottom-up integrative mechanisms allow LIP neurons to emphasize task-relevant spatial and non-spatial features. PMID- 27499083 TI - Somatodendritic Expression of JAM2 Inhibits Oligodendrocyte Myelination. AB - Myelination occurs selectively around neuronal axons to increase the efficiency and velocity of action potentials. While oligodendrocytes are capable of myelinating permissive structures in the absence of molecular cues, structurally permissive neuronal somata and dendrites remain unmyelinated. Utilizing a purified spinal cord neuron-oligodendrocyte myelinating co-culture system, we demonstrate that disruption of dynamic neuron-oligodendrocyte signaling by chemical cross-linking results in aberrant myelination of the somatodendritic compartment of neurons. We hypothesize that an inhibitory somatodendritic cue is necessary to prevent non-axonal myelination. Using next-generation sequencing and candidate profiling, we identify neuronal junction adhesion molecule 2 (JAM2) as an inhibitory myelin-guidance molecule. Taken together, our results demonstrate that the somatodendritic compartment directly inhibits myelination and suggest a model in which broadly indiscriminate myelination is tailored by inhibitory signaling to meet local myelination requirements. PMID- 27499084 TI - Regrowth of Serotonin Axons in the Adult Mouse Brain Following Injury. AB - It is widely believed that damaged axons in the adult mammalian brain have little capacity to regrow, thereby impeding functional recovery after injury. Studies using fixed tissue have suggested that serotonin neurons might be a notable exception, but remain inconclusive. We have employed in vivo two-photon microscopy to produce time-lapse images of serotonin axons in the neocortex of the adult mouse. Serotonin axons undergo massive retrograde degeneration following amphetamine treatment and subsequent slow recovery of axonal density, which is dominated by new growth with little contribution from local sprouting. A stab injury that transects serotonin axons running in the neocortex is followed by local regression of cut serotonin axons and followed by regrowth from cut ends into and across the stab rift zone. Regrowing serotonin axons do not follow the pathways left by degenerated axons. The regrown axons release serotonin and their regrowth is correlated with recovery in behavioral tests. PMID- 27499085 TI - Neurons in Macaque Area V4 Are Tuned for Complex Spatio-Temporal Patterns. AB - To deepen our understanding of object recognition, it is critical to understand the nature of transformations that occur in intermediate stages of processing in the ventral visual pathway, such as area V4. Neurons in V4 are selective to local features of global shape, such as extended contours. Previously, we found that V4 neurons selective for curved elements exhibit a high degree of spatial variation in their preference. If spatial variation in curvature selectivity was also marked by distinct temporal response patterns at different spatial locations, then it might be possible to untangle this information in subsequent processing based on temporal responses. Indeed, we find that V4 neurons whose receptive fields exhibit intricate selectivity also show variation in their temporal responses across locations. A computational model that decodes stimulus identity based on population responses benefits from using this temporal information, suggesting that it could provide a multiplexed code for spatio-temporal features. PMID- 27499086 TI - Efficient Receptive Field Tiling in Primate V1. AB - The primary visual cortex (V1) encodes a diverse set of visual features, including orientation, ocular dominance (OD), and spatial frequency (SF), whose joint organization must be precisely structured to optimize coverage within the retinotopic map. Prior experiments have only identified efficient coverage based on orthogonal maps. Here we used two-photon calcium imaging to reveal an alternative arrangement for OD and SF maps in macaque V1; their gradients run parallel but with unique spatial periods, whereby low-SF regions coincide with monocular regions. Next we mapped receptive fields and found surprisingly precise micro-retinotopy that yields a smaller point-image and requires more efficient inter-map geometry, thus underscoring the significance of map relationships. While smooth retinotopy is constraining, studies suggest that it improves both wiring economy and the V1 population code read downstream. Altogether, these data indicate that connectivity within V1 is finely tuned and precise at the level of individual neurons. PMID- 27499087 TI - Erythrocytes Are Oxygen-Sensing Regulators of the Cerebral Microcirculation. AB - Energy production in the brain depends almost exclusively on oxidative metabolism. Neurons have small energy reserves and require a continuous supply of oxygen (O2). It is therefore not surprising that one of the hallmarks of normal brain function is the tight coupling between cerebral blood flow and neuronal activity. Since capillaries are embedded in the O2-consuming neuropil, we have here examined whether activity-dependent dips in O2 tension drive capillary hyperemia. In vivo analyses showed that transient dips in tissue O2 tension elicit capillary hyperemia. Ex vivo experiments revealed that red blood cells (RBCs) themselves act as O2 sensors that autonomously regulate their own deformability and thereby flow velocity through capillaries in response to physiological decreases in O2 tension. This observation has broad implications for understanding how local changes in blood flow are coupled to synaptic transmission. PMID- 27499088 TI - Identification of novel miRNAs from drought tolerant rice variety Nagina 22. AB - MicroRNAs regulate a spectrum of developmental and biochemical processes in plants and animals. Thus, knowledge of the entire miRNome is essential to understand the complete regulatory schema of any organism. The current study attempts to unravel yet undiscovered miRNA genes in rice. Analysis of small RNA libraries from various tissues of drought-tolerant 'aus' rice variety Nagina 22 (N22) identified 71 novel miRNAs. These were validated based on precursor hairpin structure, small RNA mapping pattern, 'star' sequence, conservation and identification of targets based on degradome data. While some novel miRNAs were conserved in other monocots and dicots, most appear to be lineage-specific. They were segregated into two different classes based on the closeness to the classical miRNA definition. Interestingly, evidence of a miRNA-like cleavage was found even for miRNAs that lie beyond the classical definition. Several novel miRNAs displayed tissue-enriched and/or drought responsive expression. Generation and analysis of the degradome data from N22 along with publicly available degradome identified several high confidence targets implicated in regulation of fundamental processes such as flowering and stress response. Thus, discovery of these novel miRNAs considerably expands the dimension of the miRNA-mediated regulation in rice. PMID- 27499089 TI - 12/15-Lipoxygenase Inhibition Reverses Cognitive Impairment, Brain Amyloidosis, and Tau Pathology by Stimulating Autophagy in Aged Triple Transgenic Mice. AB - BACKGROUND: The 12/15-lipoxygenase (12/15-LO) enzyme is upregulated in the brains of patients with Alzheimer's disease (AD), and its expression levels influence the onset of the AD-like phenotype in mouse models. However, whether targeting this pathway after the neuropathology and behavioral impairments have been established remains to be investigated. METHODS: Triple transgenic (3xTg) mice received either PD146176-a selective and specific pharmacological inhibitor of 12/15-LO-or placebo starting at 12 months of age for 12 weeks. They were then assessed for the effect of the treatment on neuropathologies and behavioral impairments. RESULTS: At the end of the study, mice in the control group showed a worsening of memory and learning abilities, whereas mice receiving PD146176 were undistinguishable from wild-type mice. The same group also had significantly lower amyloid beta levels and deposition, less tau neuropathology, increased synaptic integrity, and autophagy activation. Ex vivo and in vitro genetic and pharmacological studies found that the mechanism involved in these effects was the activation of neuronal autophagy. CONCLUSIONS: Our findings provide new insights into the disease-modifying action of 12/15-LO pharmacological inhibition and establish it as a viable therapeutic approach for patients with AD. PMID- 27499090 TI - Schisandrin B inhibits cell proliferation and induces apoptosis in human cholangiocarcinoma cells. AB - Cholangiocarcinoma (CCA) is the second most common hepatic cancer with high resistance to current chemotherapies and extremely poor prognosis. The present study aimed to examine the effects of schisandrin B (Sch B) on CCA cells both in vitro and in vivo and to examine its underlying mechanism. We found that Sch B inhibited the viability and proliferation of CCA cells in a dose- and time dependent manner as assessed by MTT and colony formation assays. The flow cytometric assay revealed G0/G1 phase arrest in the Sch B-treated HCCC-9810 and RBE cells. In addition, Sch B induced intrahepatic cholangiocarcinoma apoptosis as shown by the results of Annexin V/PI double staining. Rhodamine 123 staining revealed that Sch B decreased the mitochondrial membrane potential (DeltaPsim) in a dose-dependent manner. Mechanistically, western blot analysis indicated that Sch B induced apoptosis by upregulating Bax, cleaved caspase-3, cleaved caspase-9 and cleaved PARP, and by downregulating cyclin D1, Bcl-2 and CDK-4. Moreover, Sch B significantly inhibited HCCC-9810 xenograft growth in athymic nude mice. In summary, these findings suggest that Sch B exhibited potent antitumor activities via the induction of CCA apoptosis and that Sch B may be a promising drug for the treatment of CCA. PMID- 27499091 TI - 18beta-Glycyrrhetinic acid protects against methotrexate-induced kidney injury by up-regulating the Nrf2/ARE/HO-1 pathway and endogenous antioxidants. AB - OBJECTIVES: 18beta-glycyrrhetinic acid (18beta-GA) has multiple beneficial and therapeutic effects. However, its protective roles on methotrexate (MTX)-induced renal injury are not well defined. In the present study, we investigated the possible protective effects of 18beta-GA against MTX-induced nephrotoxicity in rats. MATERIALS: 18beta-GA (50 and 100 mg/kg) was administered for 7 days either before or after MTX. The rats were decapitated and kidney and serum samples were collected. RESULTS: MTX-induced renal injury in rats was evidenced by the significant (p < 0.001) increase in circulating kidney function markers and tumor necrosis factor alpha (TNF-alpha), as well as the histopathological alterations. MTX-induced rats exhibited significantly increased lipid peroxidation (p < 0.05) and nitric oxide (p < 0.001) levels, with concomitant marked (p < 0.001) decline in the antioxidant defenses. 18beta-GA, administered either before or after MTX, produced a significant amelioration of circulating kidney function markers, TNF alpha, kidney lipid peroxidation, nitric oxide, and antioxidant defenses. In addition, 18beta-GA supplementation significantly up-regulated the mRNA abundance of both nuclear factor-erythroid 2-related factor 2 (Nrf2) and hemoxygenase 1 (HO 1) in the kidney of MTX-induced rats. CONCLUSIONS: These results indicate that 18beta-GA has a protective effect on MTX-induced nephrotoxicity with possible mechanisms of attenuating oxidative stress and inflammation through up-regulating the Nrf2/ARE signaling. These findings make 18beta-GA candidate as a potent agent in preventing MTX-induced kidney injury. PMID- 27499092 TI - Design and characteristics evaluation of a novel teleoperated robotic catheterization system with force feedback for vascular interventional surgery. AB - In this paper, we proposed a novel master-slave robotic catheterization system with force feedback for VIS (Vascular Interventional Surgery). The force feedback to the operator on the master side is the key factor to improve the safety during VIS. The developed system used the MR (magneto rheological) fluid to realize force feedback, and it used the developed multidimensional monitoring interface to realize the visualization of force feedback, the developed multidimensional monitoring interface can monitor the motion information of the catheter and contact force between catheter tip or side wall and blood vessel wall, and the motion data of the catheter was collected and generated diagram for reference to surgeon. We have developed a force sensor array to detect the contact force between catheter tip or side wall and blood vessel wall. The force information was detected by the developed contact force sensor array when the catheter contacted with the blood vessel. The force feedback and multidimensional information monitoring interface evaluation experiments were done, the tracking characteristic evaluation experiments were also carried out, the experimental results indicated that the developed novel robotic catheterization system with force feedback and visualization of force feedback is effective for VIS, it can improve the safety during VIS. PMID- 27499093 TI - miR-625 suppresses tumour migration and invasion by targeting IGF2BP1 in hepatocellular carcinoma. PMID- 27499094 TI - Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular environment of thyroid cancer cells. PMID- 27499095 TI - Elevated hydrostatic pressure enhances the motility and enlarges the size of the lung cancer cells through aquaporin upregulation mediated by caveolin-1 and ERK1/2 signaling. AB - The mechanical characteristics presented in cancer microenvironment are known to have pivotal roles in cancer metastasis, which accounts for the leading cause of death from malignant tumors. However, while a uniformly distributed high interstitial fluid pressure (IFP) is a common feature in solid tumors, the effects of high IFP on the motility and invasiveness of cancer cells remain obscure. Using cell-culture devices that simulated increased IFP conditions by applying hydrostatic pressure (HP) ranging from 0 to 20 mm Hg to the cells, we found that the elevated HPs increased the migration speeds, invasiveness, cell volume, filopodial number and aquaporin-1 (AQP1), Snail and vinculin expression levels, as well as phosphorylation of caveolin-1 and extracellular signal regulated kinase1/2 (ERK1/2), in the lung cancer cells CL1-5 and A549. The increases of migration speed and cell volume correlated temporally with the increase of AQP1 expression. The elevated HP-induced migration acceleration was hindered by AQP1 knockdown using small interfering RNA (siRNA) transfection. Inhibition of ERK1/2 phosphorylation using the mitogen-activated protein kinase kinase inhibitor PD98059 abrogated the elevated HP-induced AQP1 upregulation and migration acceleration in the cancer cells. Caveolin-1 knockdown by siRNA transfection attenuated the HP-induced, ERK1/2-depedent AQP1 upregulation and migration acceleration. Further biochemical studies revealed that the caveolin-1 activation-driven ERK1/2 signaling is mediated by Akt1/2 phosphorylation. By contrast, the elevated HPs had negligible effects on the migration speed and volume of normal bronchial epithelial cells. These results disclose a novel mechanism relating high IFP to the invasiveness of cancer cells and highlight potential targets to impede cancer spreading. PMID- 27499096 TI - Bill of Rights for Persons with Mental Illness. PMID- 27499097 TI - PIN1 in hepatocellular carcinoma is associated with TP53 gene status. AB - Phosphorylation of proteins on serine/threonine residues that precede proline (pSer/Thr-Pro) is specifically catalyzed by the peptidyl-prolyl cis-trans isomerase PIN1. PIN1-mediated prolyl-isomerization induces cell cycle arrest and growth inhibition through the regulation of target proteins, including TP53. We examined whether PIN1 acts in a different manner according to TP53 gene status in hepatocellular carcinoma (HCC). We investigated the expression of PIN1 and TP53 proteins in 119 HCC tissue samples. We also analyzed PIN1 expression in combination with TP53 gene mutation and its correlation with the clinical outcome. In addition, we used synthetic small interfering RNA to silence PIN1 gene expression in TP53 wild-type and TP53 mutant HCC cell lines, and then evaluated cell proliferation, migration and invasion. Expression of PIN1 was strongly associated with expression of TP53 protein or TP53 mutation of HCC samples. PIN1 and TP53 expression in TP53 mutant HCC cell lines was higher than that in TP53 wild-type HCC cell lines. Silencing of PIN1 in HLE cells containing mutant TP53 significantly decreased cell proliferation, migration and invasion. In contrast to PIN1 silencing in HLE cells, PIN1 silencing in HepG2 cells containing functional wild-type TP53 resulted in enhanced tumor cell proliferation. HCC patients bearing PIN1 expression with wild-type TP53 were predicted to demonstrate favorable relapse-free survival. Our results suggest that PIN1 plays a role in cancer cell proliferation, migration and invasion in a different manner according to the TP53 gene mutation status in HCC. In particular, interaction of PIN1 with mutant TP53 can act as a tumor promoter and increase its oncogenic activities in HCC. PMID- 27499098 TI - The influence of social category cues on the happy categorisation advantage depends on expression valence. AB - Facial race and sex cues can influence the magnitude of the happy categorisation advantage. It has been proposed that implicit race or sex based evaluations drive this influence. Within this account a uniform influence of social category cues on the happy categorisation advantage should be observed for all negative expressions. Support has been shown with angry and sad expressions but evidence to the contrary has been found for fearful expressions. To determine the generality of the evaluative congruence account, participants categorised happiness with either sadness, fear, or surprise displayed on White male as well as White female, Black male, or Black female faces across three experiments. Faster categorisation of happy than negative expressions was observed for female faces when presented among White male faces, and for White male faces when presented among Black male faces. These results support the evaluative congruence account when both positive and negative expressions are presented. PMID- 27499099 TI - CD44 correlates with clinicopathological characteristics and is upregulated by EGFR in breast cancer. AB - Cluster of differentiation 44 (CD44), a well-known transmembrane glycoprotein, serves as a promoting factor in the carcinogenesis and progression of a variety of neoplasms. Previous studies have demonstrated that aberrant expression of CD44 was associated with the initiation, invasion, metastasis, and therapy-resistance of breast cancer, but whether there was any association between CD44 and pathological characteristics of breast cancer or epidermal growth factor receptor (EGFR) has not been clearly elucidated. In this study, we utilized public microarray data analysis and tissue microarray technologies to display that CD44 level was enhanced in breast cancer and was significantly correlated with histological grade and the status of estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 (HER2) and EGFR. Furthermore, mRNA expression of CD44 in breast tumors was positively correlated with basal cytokeratin markers KRT5 and KRT17, but inversely associated with luminal marker FOXA1. Besides, Kaplan-Meier analysis showed that high CD44 mRNA level had adverse impact on the progression-free survival of patients with HER2-expressing or basal-like breast cancer. Functionally, inhibition of EGFR activity by erlotinib impaired the invasion and migration ability of breast cancer cell lines. Western blot assays demonstrated that erlotinib treatment decreased the expression of CD44, accompanied with the reduced protein levels of mesenchymal and cancer stem cell markers. Collectively, this study suggested that the expression of CD44 was upregulated by EGFR pathway and CD44 had a robust impact on the development of breast cancer. PMID- 27499100 TI - Single-walled carbon nanotube-loaded doxorubicin and Gd-DTPA for targeted drug delivery and magnetic resonance imaging. AB - An aspargine-glycine-arginine (NGR) peptide modified single-walled carbon nanotubes (SWCNTs) system, developed by a simple non-covalent approach, could be loaded with the anticancer drug doxorubicin (DOX) and magnetic resonance imaging (MRI) contrast agent gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). This DOX- and Gd-DTPA-loaded NGR functionalized SWCNTs (DOX/NGR-SWCNTs/Gd-DPTA) retained both cytotoxicity of DOX and MRI contrast effect of Gd-DPTA. This drug delivery system showed excellent stability in physiological solutions. This DOX/NGR-SWCNTs/Gd-DPTA system could accumulate in tumors and enter into tumor cells, which facilitated combination chemotherapy with diagnosis of tumor in one system. An excellent in vitro anti-tumor effect was shown in MCF-7 cells treated by DOX/NGR-SWCNTs/Gd-DPTA, compared with DOX solution, DOX/SWCNTs and DOX/SWCNTs/Gd-DPTA. In vivo data of DOX/NGR-SWCNTs/Gd-DPTA group in tumor-bearing mice further confirmed that this system performed much higher tumor targeting capacity and anti-tumor efficacy than other control groups. PMID- 27499101 TI - Use of potassium titanyl phosphate (KTP) laser Dermastat in the treatment of recurrent anterior epistaxis - a new technique. AB - OBJECTIVE: To evaluate the short- to medium-term effectiveness of potassium titanyl phosphate (KTP) laser Dermastat in patients with recurrent anterior epistaxis. METHOD: Fifty-eight patients presenting with recurrent anterior epistaxis were treated using potassium titanyl phosphate laser Dermastat. Those with recurrent epistaxis arising from prominent vessels in Little's area, and/or those for whom treatment with silver nitrate cautery failed, were included. The main outcome measure was resolution of epistaxis at two months. RESULTS: Fifty eight patients were treated; 27 were under 18 years old. Thirty patients had prominent vessels. Thirty-one patients had undergone previous cautery treatment. Thirty-eight patients had treatment to the left side, 19 to the right and 1 to both. At two months, 74 per cent reported resolution of epistaxis with no complications. This increased to 78 per cent at further follow up. CONCLUSION: Our technique is a successful, safe treatment for recurrent anterior epistaxis in an otherwise treatment-resistant group. A single procedure is effective. The handpiece and tip are reusable and sterilisable, resulting in cost-effectiveness. PMID- 27499102 TI - "MedTRIS" (Medical Triage and Registration Informatics System): A Web-based Client Server System for the Registration of Patients Being Treated in First Aid Posts at Public Events and Mass Gatherings. AB - First aid (FA) services are provisioned on-site as a preventive measure at most public events. In Flanders, Belgium, the Belgian Red Cross-Flanders (BRCF) is the major provider of these FA services with volunteers being deployed at approximately 10,000 public events annually. The BRCF has systematically registered information on the patients being treated in FA posts at major events and mass gatherings during the last 10 years. This information has been collected in a web-based client server system called "MedTRIS" (Medical Triage and Registration Informatics System). MedTRIS contains data on more than 200,000 patients at 335 mass events. This report describes the MedTRIS architecture, the data collected, and how the system operates in the field. This database consolidates different types of information with regards to FA interventions in a standardized way for a variety of public events. MedTRIS allows close monitoring in "real time" of the situation at mass gatherings and immediate intervention, when necessary; allows more accurate prediction of resources needed; allows to validate conceptual and predictive models for medical resources at (mass) public events; and can contribute to the definition of a standardized minimum data set (MDS) for mass-gathering health research and evaluation. Gogaert S , Vande veegaete A , Scholliers A , Vandekerckhove P . "MedTRIS" (Medical Triage and Registration Informatics System): a web-based client server system for the registration of patients being treated in first aid posts at public events and mass gatherings. Prehosp Disaster Med. 2016;31(5):557-562. PMID- 27499103 TI - Preliminary investigation of five novel long non-coding RNAs in hepatocellular carcinoma cell lines. AB - Hepatocellular carcinoma (HCC) is a highly prevalent cancer with a high mortality rate and HCC is always accompanied with a hepatitis B virus (HBV) infection, unlike many other types of cancers. Over the past few years, cancer-related long non-coding RNAs (lncRNAs) and virus-related lncRNAs have attracted the attention of many researchers, and a number of previous studies have examined the relationship between lncRNAs and various cancers and viruses. The current study used The Cancer Genome Atlas database to screen for lncRNAs up-regulated in HCC in order to identify cancer biomarkers. Results revealed five lncRNAs that were the most up-regulated. This result was then verified in 10 HCC cell lines and two normal liver cell lines. Quantitative real-time PCR revealed that the five lncRNAs were substantially up-regulated in HCC cell lines. Several of the five lncRNAs were expressed at higher levels in a few HCC cell lines that were infected with HBV or that were positive for its protein or DNA than in HCC cell lines that were not infected with HBV or that were negative for its protein or DNA. These findings suggest that the five lncRNAs might play a role in the progression of HCC and/or HBV infection, and these findings need to be studied in further detail. PMID- 27499104 TI - Assessment of the mean glandular dose using LiF:Mg,Ti, LiF:Mg,Cu,P, Li2B4O7:Mn and Li2B4O7:Cu TL detectors in mammography radiation fields. AB - The aim of this paper is the characterization of four thermoluminescence detectors (TLD), namely, LiF:Mg,Ti, LiF:Mg,Cu,P, Li2B4O7:Mn and Li2B4O7:Cu for the measurement of the entrance surface air kerma (ESAK) and estimation of the mean glandular dose (MGD) in digital mammography examinations at hospitals and clinics. Low-energy x-ray beams in the typical energy ranges of mammography, produced with a tungsten target and additional 60 um molybdenum filtration were implemented and characterized at the Laboratory of Metrology of Ionizing Radiation at Instituto Superior Tecnico. These beams were used for the characterization of the TLDs in terms of sensitivity, linearity, reproducibility, energy dependence and fading at 40 degrees C. The energy dependence test was further extended using clinical beams produced by mammography units at hospitals and clinics. The method proposed by the International Atomic Energy Agency was used for the measurement of ESAK and assessment of MGD. The combined standard uncertainty for the measurement of ESAK (and MGD) was determined in accordance to the Guide to the expression of uncertainty in measurement. The x-ray beams generated in the 23-40 kVp range presented HVL values from 0.36 to 0.46 mm Al. The beam produced at 28 kVp (HVL 0.39 mm Al) was considered as reference. The radiation field defined a circle with 84 mm diameter with a maximum variation of the beam intensity of less than 1% at the top flat (plateau) within 4 cm of the central axis. The estimated total uncertainty for the measurement of air kerma was 0.42%. All the TL detectors tested showed good performance except the commercial Li2B4O7:Mn (or TLD-800) which was excluded due to its poor sensitivity in our experimental set up. Both lithium fluorides showed better linearity and reproducibility as well as lower energy dependence and fading when compared to lithium borates. The stable behaviour of LiF:Mg,Ti and LiF:Mg,Cu,P detectors is reflected in the low combined standard uncertainty of +/-5.6% and +/-4.3% respectively (or +/-5.1% and +/-3.6% if fading is neglected). In general a total combined uncertainty lower than +/-10% for the measurement of ESAK was obtained for the four TL materials studied. PMID- 27499105 TI - Structural insight into beta-Clamp and its interaction with DNA Ligase in Helicobacter pylori. AB - Helicobacter pylori, a gram-negative and microaerophilic bacterium, is the major cause of chronic gastritis, gastric ulcers and gastric cancer. Owing to its central role, DNA replication machinery has emerged as a prime target for the development of antimicrobial drugs. Here, we report 2A structure of beta-clamp from H. pylori (Hpbeta-clamp), which is one of the critical components of DNA polymerase III. Despite of similarity in the overall fold of eubacterial beta clamp structures, some distinct features in DNA interacting loops exists that have not been reported previously. The in silico prediction identified the potential binders of beta-clamp such as alpha subunit of DNA pol III and DNA ligase with identification of beta-clamp binding regions in them and validated by SPR studies. Hpbeta-clamp interacts with DNA ligase in micromolar binding affinity. Moreover, we have successfully determined the co-crystal structure of beta-clamp with peptide from DNA ligase (not reported earlier in prokaryotes) revealing the region from ligase that interacts with beta-clamp. PMID- 27499106 TI - Mycobacterium oryzae sp. nov., a scotochromogenic, rapidly growing species is able to infect human macrophage cell line. AB - Gram-stain-positive, acid-fast-positive, rapidly growing, rod-shaped bacteria (designated as strains JC290T, JC430 and JC431) were isolated from paddy cultivated soils on the Western Ghats of India. Phylogenetic analysis placed the three strains among the rapidly growing mycobacteria, being most closely related to Mycobacterium tokaiense 47503T (98.8 % 16S rRNA gene sequence similarity), Mycobacterium murale MA112/96T (98.8 %) and a few other Mycobacterium species. The level of DNA-DNA reassociation of the three strains with M. tokaiense DSM 44635T was 23.4+/-4 % (26.1+/-3 %, reciprocal analysis) and 21.4+/-2 % (22.1+/-4 %, reciprocal analysis). The three novel strains shared >99.9 % 16S rRNA gene sequence similarity and DNA-DNA reassociation values >85 %. Furthermore, phylogenetic analysis based on concatenated sequences (3071 bp) of four housekeeping genes (16S rRNA, hsp65, rpoB and sodA) revealed that strain JC290T is clearly distinct from all other Mycobacteriumspecies. The three strains had diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositolmannosides, unidentified phospholipids, unidentified glycolipids and an unidentified lipid as polar lipids. The predominant isoprenoid quinone for all three strains was MK-9(H2). Fatty acids were C17 : 1omega7c, C16 : 0, C18 : 1omega9c, C16 : 1omega7c/C16 : 1omega6c and C19 : 1omega7c/C19 : 1omega6c for all the three strains. On the basis of phenotypic, chemotaxonomic and phylogenetic data, it was concluded that strains JC290T, JC430 and JC431 are members of a novel species within the genus Mycobacterium and for which the name Mycobacterium oryzae sp. nov. is proposed. The type strain is JC290T (=KCTC 39560T=LMG 28809T). PMID- 27499107 TI - Multi-residue determination of 210 drugs in pork by ultra-high-performance liquid chromatography-tandem mass spectrometry. AB - This paper presents a multi-residue analytical method for 210 drugs in pork using ultra-high-performance liquid chromatography-Q-Trap tandem mass spectrometry (UPLC-MS/MS) within 20min via positive ESI in scheduled multi-reaction monitoring (MRM) mode. The 210 drugs, belonging to 21 different chemical classes, included macrolides, sulfonamides, tetracyclines, beta-lactams, beta-agonists, aminoglycosides, antiviral drugs, glycosides, phenothiazine, protein anabolic hormones, non-steroidal anti-inflammatory drugs (NSAIDs), quinolones, antifungal drugs, corticosteroids, imidazoles, piperidines, piperazidines, insecticides, amides, alkaloids and others. A rapid and simple preparation method was applied to process the animal tissues, including solvent extraction with an acetonitrile/water mixture (80/20, v/v), defatting and clean-up processes. The recoveries ranged from 52% to 130% with relative standard deviations (RSDs)<20% for spiked concentrations of 10, 50 and 250MUg/kg. More than 90% of the analytes achieved low limits of quantification (LOQs)<10MUg/kg. The decision limit (CCalpha), detection capability (CCbeta) values were in the range of 2-502MUg/kg and 4-505MUg/kg, respectively. This method is significant for food safety monitoring and controlling veterinary drug use. PMID- 27499109 TI - Editorial overview: Vaccines: novel technologies for vaccine development. PMID- 27499108 TI - Implementation of high slurry concentration and sonication to pack high efficiency, meter-long capillary ultrahigh pressure liquid chromatography columns. AB - Slurry packing capillary columns for ultrahigh pressure liquid chromatography is complicated by many interdependent experimental variables. Previous results have suggested that combination of high slurry concentration and sonication during packing would create homogeneous bed microstructures and yield highly efficient capillary columns. Herein, the effect of sonication while packing very high slurry concentrations is presented. A series of six, 1m*75MUm internal diameter columns were packed with 200mg/mL slurries of 2.02MUm bridged-ethyl hybrid silica particles. Three of the columns underwent sonication during packing and yielded highly efficient separations with reduced plate heights as low as 1.05. PMID- 27499110 TI - Driving with advanced vehicle technology: A qualitative investigation of older drivers' perceptions and motivations for use. AB - For older drivers, in-vehicle technology offers much potential to improve safety and increase longevity of retaining both licensure and community mobility. However, little is known about how older drivers perceive Advanced Vehicle Technologies (AVTs) based on everyday driving experience. Interviews with 35 older drivers (20 men; 15 women) aged 60-85 who owned a vehicle with at least two AVTs (e.g., back-up camera, lane departure warning) were conducted to explore the meanings that older drivers assigned to AVTs and motivations for use, including whether age-related functional changes were part of their automobile purchase decision. Findings indicate that age-related changes are not a primary reason for why older adults seek out AVTs, but they still perceived and experienced AVTs to counteract age-related changes in driving performance based upon changes they felt occurring within the body. Older drivers also described AVTs as generating a sense of comfort behind-the-wheel. Comfort with this technology was equated with convenience, ease of use, and increased feelings of safety. Discussion emphasizes how assessments of the quality of driving performance and value of technology occur in relation to an aging body. PMID- 27499111 TI - Metastatic bone disease: A review of survival, prognostic factors and outcomes following surgical treatment of the appendicular skeleton. AB - Survival data and prognostic factors may help to provide insight when deciding on the appropriate orthopaedic treatment for patients presenting with metastatic bone disease. This review was conducted to look at the outcomes following orthopaedic surgery for metastatic lesions in the extremities. The literature was identified through the Medline and Embase database and further refined via a set of inclusion and exclusion criteria. Overall, patients presenting with metastatic bone disease from renal cell cancer or breast cancer had the longest survival rate. Important factors found to predict prognosis was the presence of visceral metastasis, multiple metastases, pathological fracture and the type of primary tumour involved. These prognostic factors may help to direct future inquiry into metastatic bone disease and help determine the type of surgery to use in a metastatic setting in order to avoid complications and unnecessary revisions as well as provide durability. PMID- 27499112 TI - Novel Synthetic PEGylated Conjugate of alpha-Lipoic Acid and Tempol Reduces Cell Death in a Neuronal PC12 Clonal Line Subjected to Ischemia. AB - alpha-Lipoic acid (alpha-LA), a natural thiol antioxidant, and Tempol, a synthetic free radical scavenger, are known to confer neuroprotection following ischemic insults in both in vivo and in vitro models. The aim of this study was to synthesize and characterize a conjugate of alpha-LA and Tempol linked by polyethylene glycol (PEG) in order to generate a more efficacious neuroprotectant molecule. AD3 (alpha-Tempol ester-omega-lipo ester PEG) was synthesized, purified, and characterized by flash chromatography and reverse phase high pressure liquid chromatography and by 1H nuclear magnetic resonance, infrared spectroscopy, and mass spectrometry. AD3 conferred neuroprotection in a PC12 pheochromocytoma cell line of dopaminergic origin, exposed to oxygen and glucose deprivation (OGD) insult measured by LDH release. AD3 exhibited EC50 at 10 MUM and showed a 2-3-fold higher efficacy compared to the precursor moieties, indicating an intrinsic potent neuroprotective activity. AD3 attenuated by 25% the intracellular redox potential, by 54% lipid peroxidation and prevented phosphorylation of ERK, JNK, and p38 by 57%, 22%, and 21%, respectively. Cumulatively, these findings indicate that AD3 is a novel conjugate that confers neuroprotection by attenuation of MAPK phosphorylation and by modulation of the redox potential of the cells. PMID- 27499113 TI - Self-organized centripetal movement of corneal epithelium in the absence of external cues. AB - Maintaining the structure of the cornea is essential for high-quality vision. In adult mammals, corneal epithelial cells emanate from stem cells in the limbus, driven by an unknown mechanism towards the centre of the cornea as cohesive clonal groups. Here we use complementary mathematical and biological models to show that corneal epithelial cells can self-organize into a cohesive, centripetal growth pattern in the absence of external physiological cues. Three conditions are required: a circumferential location of stem cells, a limited number of cell divisions and mobility in response to population pressure. We have used these complementary models to provide explanations for the increased rate of centripetal migration caused by wounding and the potential for stem cell leakage to account for stable transplants derived from central corneal tissue, despite the predominantly limbal location of stem cells. PMID- 27499114 TI - Does the type of sagittal spinal shape influence the clinical results of lumbar disc arthroplasty? AB - INTRODUCTION: It has been suggested that the indication for lumbar total disc replacement (LTDR) takes into account the local parameters, such as the type of disc disease demonstrated on MRI and the presence or absence of facet joint osteoarthritis. The type of preoperative sagittal curvature could also be taken into account. This study reports the clinical results of LTDRs depending on the type of sagittal spinal alignment. MATERIAL AND METHODS: Eighty patients were included in this prospective study, with a mean age of 41.7years (range, 27 56years). The clinical analysis took into account the lumbar VAS, the Oswestry Disability Index (ODI), and the preoperative frequency of painkiller use, at 1year and at the last follow-up. The satisfaction index, return to work, and willingness to undergo the same treatment were also collected. The radiological study included the analysis of lumbar-pelvic parameters to distribute the patients according to the Roussouly classification. RESULTS: The mean follow-up was 59.1months (range, 14-96months). The type 1 group included four cases. Reduction of the VAS, the ODI score, and the frequency of painkiller use at the last follow-up were significant in type 2 and 3 patients, and non-significant for type 4. Eighty-five percent of type 2 patients and 87.5% of type 3 patients were satisfied or very satisfied with the surgery versus only 68% of the type 4 patients. In addition, 63% of the type 4 patients declared they would be willing to undergo the same treatment again versus 85% of the type 2 patients and 82.5% of the type 3 patients. It should also be noted that 67% of the patients in this series returned to work. DISCUSSION AND CONCLUSION: This study underscores the influence of the type of sagittal curvature on the clinical results of LTDR, with type 4 patients showing inferior clinical results because of a higher rate of residual lower back pain. The indication in LTDR should be reconsidered for discogenic lower back pain in type 4 patients. PMID- 27499115 TI - Pre- and postoperative complications of adult forearm fractures treated with plate fixation. AB - INTRODUCTION: Adult forearm fractures account for 1-2% of all fractures of the limbs. The main objective of this retrospective multicenter study was to evaluate pre- and postoperative complications of forearm fractures. The secondary objective was to evaluate functional and radiological results of plate osteosynthesis for these fractures. MATERIAL AND METHODS: Between January 2008 and March 2014, 131 forearm fractures were reviewed retrospectively. Fractures were classified preoperatively according to the AO classification. Clinical outcomes were classified into four categories according to the Tschnerne and Oestern classification. Pre- and postoperative complications were sought systematically. RESULTS: Before surgery, 12 patients had neurological impairment (9%). At the last follow-up, nine patients had persistent neurological disorders (6.9%). Union of forearm fractures was obtained in 122 patients at 4.6 months on average (+/-2.6). Nine patients with nonunion were observed (6.9%) and five patients had radioulnar synostosis (3.8%). DISCUSSION: The frequency of neurological complications concomitant to forearm fractures is noteworthy. Similar cases with essentially irritative neurological disease have been reported in the literature, in particular for the ulnar nerve. Fracture nonunion is a relatively common complication: between 2 and 10% of cases depending on the study. LEVEL OF EVIDENCE: IV. PMID- 27499116 TI - Reply to the Letter by Siamak Sabour, Fariba Ghassemi. PMID- 27499117 TI - Subscapularis and deltoid preserving anterior approach for reverse shoulder arthroplasty. AB - HYPOTHESIS: We hypothesize that performing a RSA using an anterior approach without cutting the subscapularis tendon and the deltoid muscle could provide patients with superior short-term clinical outcomes and immediate active range of motion (ROM) without immobilization. METHODS: Between August 2013 and June 2015, all patients who had a primary RSA were considered potentially eligible for inclusion in this prospective study. RESULTS: No immediate intra- or postoperative complications were noted. A statistically significant improvement of VAS (from 6.7 to 1; P<.001), SANE (from 34 to 80; P<.001), and elevation (from 103 degrees to 128 degrees ; P=.02) was observed. In some cases, patients who had pseudoparalysis preoperative were able to achieve full anterior elevation few days after the operation. DISCUSSION: Using a subscapularis and deltoid preserving anterior approach is an option for patients requiring RSA. Leaving this tendon intact and preserving the deltoid minimize the need for immediate postoperative immobilization and allow for faster recovery of shoulder ROM, without risking the concern of humeral anterior dislocation. Overall duration of hospital stay as well as length of postoperative physical therapy may be minimized, with substantial long-term economic gain. Longer follow-up and comparison with standard approaches is necessary in the future. LEVEL OF EVIDENCE OF THE STUDY: Level IV, case series with no comparative group. PMID- 27499118 TI - Inhibitory effect of metformin combined with gemcitabine on pancreatic cancer cells in vitro and in vivo. AB - Pancreatic cancer is a malignant digestive system tumor with a particularly poor prognosis, and is the fourth leading cause of cancer-associated mortality in the USA. The anti-diabetic therapeutic agent, metformin (MET) has been demonstrated to exert anti-tumor effects. The present study assessed the ability of MET, alone or in combination with gemcitabine (GEM), to inhibit the growth of the human CFPAC-1 pancreatic cancer cell line in vitro and in vivo. Cell counting kit-8 assays were performed to measure CFPAC-1 cell viability and apoptosis was detected with annexin V/propidium iodide. Cell cycle analysis was conducted by flow cytometry. The mRNA and protein levels of B-cell lymphoma-extra large (Bcl xL), Bcl2 associated X protein (Bax), caspase-3, survivin and cyclin D1 in CFPAC 1 cells and tumor tissues were detected by reverse transcription-polymerase chain reaction and western blotting, respectively. Furthermore, the expression levels of caspase-3 and proliferating cell nuclear antigen in tumor tissues were detected by immunohistochemistry. The results demonstrated that following MET treatment, the growth of CFPAC-1 cells and xenografts in nude mice was inhibited, the expression levels of Bcl-xL, survivin and cyclin D1 were downregulated, while the expression levels of Bax and caspase-3 were upregulated. These effects were enhanced when MET was administered in combination with GEM. The mechanism underlying the anti-tumor effect of MET may be associated with the induction of cell apoptosis and the inhibition of proliferation. PMID- 27499119 TI - CSF hypotension: A review of its manifestations, investigation and management. AB - Intracranial cerebrospinal fluid (CSF) hypotension usually arises in the context of known or suspected leak of CSF. This can be spontaneous, or due to central nervous system trauma or dural defects created during lumbar puncture or epidural anaesthesia. Spontaneous intracranial hypotension (SIH) is increasingly being recognised as a cause for orthostatic headache or spontaneous subdural haematoma where no other obvious cause is found. We review CSF physiology, the mechanism of symptom generation in CSF hypotension and the investigation and management of the syndrome. Whilst commonly mild and self-limiting, CSF hypotension may result in life threatening complications and is most often treatable. When the syndrome is severe, prolonged or complicated, epidural blood patching (EBP) is the mainstay of treatment. PMID- 27499120 TI - Striatal silent lacunar infarction is associated with changes to the substantia nigra in patients with early-stage Parkinson's disease: A diffusion kurtosis imaging study. AB - A recent study has shown that striatal silent infarction may occur secondary to the degeneration of dopaminergic neurons in the substantia nigra (SN) of mice. However, it is uncertain whether this phenomenon occurs in patients with early stage Parkinson's disease (PD) and can be detected by diffusion kurtosis imaging (DKI). A total of 72 untreated patients with early-stage PD underwent conventional MRI and DKI. Participants were divided into control and striatal silent lacunar infarction (SSLI) groups. The differences in mean kurtosis (MK) values of the SN, Hoehn-Yahr (H-Y) staging, and Unified Parkinson's Disease Rating Scale (UPDRS) III score between groups, were analyzed. Linear regression analysis was used to correlate age, SSLI count, silent lacunar infarction count in other brain areas and age-related white matter change score with MK values of the SN. Spearman correlation coefficient analysis was used to correlate MK values of the SN and SSLI count with H-Y staging and UPDRS III score. There was no significant difference in the severity of disease between two groups; however, MK values of the SN with SSLI present were significantly higher than in SN without SSLI. In addition, SSLI count had linear correlation with MK values of the SN, which had positive correlation with H-Y-staging and UPDRS III score. SSLI is associated with structural changes to the SN in patients with early-stage PD, detectable by DKI, and may aggravate their motor impairments. PMID- 27499121 TI - Transcortical selective amygdalohippocampectomy technique through the middle temporal gyrus revisited: An anatomical study laboratory investigation. AB - The anterior temporal lobectomy (ATL) and selective amygdalohippocampectomy (SelAH) have been used for surgical treatment of mesial temporal lobe epilepsy. We examined the comprehensive white matter tract anatomy of the temporal lobe to gain an insight into the trans-middle temporal gyrus, a lateral approach which has been commonly used. The transmiddle temporal gyrus approach was performed in a stepwise manner on cadaveric human heads to examine the traversing white matter pathways through it and the structures located in the temporal horn. We reviewed the literature to compare the trans-middle temporal gyrus approach with other SelAH techniques based on surgical outcomes. There does not appear to be a significant difference in seizure outcome between SelAH and ATL. However, the SelAH provides a better neuropsychological outcomes than the ATL in selected patients. Each SelAH approach has individual advantages and disadvantages. Based on our anatomical study, in the transcortical amygdalohippocampectomy technique through the middle temporal gyrus the white matter pathways to be encountered. In the temporal horn, the collateral eminence, hippocampus, lateral ventricular sulcus, choroidal fissure, inferior choroidal point, choroid plexus, fimbria of the fornix, and amygdala are exposed. The subpial dissection is performed along the lateral ventricular sulcus from the collateral eminence on lateral side and from the choroidal fissure on medial side by microdissector for en bloc resection of the hippocampus proper. The trans-middle temporal gyrus approach is commonly used in treatment of mesial temporal lobe epilepsy patients. A better anatomical and functional understanding of the structures of the temporal lobe is crucial for safer and more accurate surgery. PMID- 27499122 TI - Complications following cranioplasty and relationship to timing: A systematic review and meta-analysis. AB - The optimal timing of cranioplasty after decompressive craniectomy has not been well established. The purpose of this study was to evaluate the relationship between timing of cranioplasty and related complications. A systematic search of MEDLINE, Scopus, and the Cochrane databases was performed using PRISMA guidelines for English-language articles published between 1990 and 2015. Case series, case control and cohort studies, and clinical trials reporting timing and complication data for cranioplasty after decompressive craniectomy in adults were included. Extracted data included overall complications, infections, reoperations, intracranial hemorrhage, extra-axial fluid collections, hydrocephalus, seizures, and bone resorption for cranioplasty performed within (early) and beyond (late) 90days. Twenty-five of 321 articles met inclusion criteria for a total of 3126 patients (1421 early vs. 1705 late). All were retrospective observational studies. Early cranioplasty had significantly higher odds of hydrocephalus than late cranioplasty (Odds Ratio [OR] 2.38, 95% Confidence Interval [CI] 1.25-4.52, p=0.008). There was no difference in odds of overall complications, infections, reoperations, intracranial hemorrhage, extra-axial fluid collections, seizures, or bone resorption. Subgroup analysis of trauma patients revealed a decreased odds of extra-axial fluid collection (OR 0.30, p=0.02) and an increased odds of hydrocephalus (OR 4.99, p=0.05). Early cranioplasty within 90days after decompressive craniectomy is associated with an increased odds of hydrocephalus than with later cranioplasty, but no difference in odds of developing other complications. Earlier cranioplasty in the trauma population is associated with fewer extra-axial fluid collections. PMID- 27499123 TI - Objective Detection of Oral Carcinoma with Multispectral Fluorescence Lifetime Imaging In Vivo. AB - Successful early detection and demarcation of oral carcinoma can greatly impact the associated morbidity and mortality rates. Current methods for detection of oral cancer include comprehensive visual examination of the oral cavity, typically followed by tissue biopsy. A noninvasive means to guide the clinician in making a more objective and informed decision toward tissue biopsy can potentially improve the diagnostic yield of this process. To this end, we investigate the potential of fluorescence lifetime imaging (FLIM) for objective detection of oral carcinoma in the hamster cheek pouch model of oral carcinogenesis in vivo. We report that systematically selected FLIM features can differentiate between low-risk (normal, benign and low-grade dysplasia) and high risk (high-grade dysplasia and cancer) oral lesions with sensitivity and specificity of 87.26% and 93.96%, respectively. We also show the ability of FLIM to generate "disease" maps of the tissue which can be used to evaluate relative risk of neoplasia. The results demonstrate the potential of multispectral FLIM with objective image analysis as a noninvasive tool to guide comprehensive oral examination. PMID- 27499124 TI - Serpentinicella alkaliphila gen. nov., sp. nov., a novel alkaliphilic anaerobic bacterium isolated from the serpentinite-hosted Prony hydrothermal field, New Caledonia. AB - A novel anaerobic, alkaliphilic, Gram-stain-positive, spore-forming bacterium was isolated from a carbonaceous hydrothermal chimney in Prony Bay, New Caledonia. This bacterium, designated strain 3bT, grew at temperatures from 30 to 43 degrees C (optimum 37 degrees C) and at pH between 7.8 and 10.1 (optimum 9.5). Added NaCl was not required for growth (optimum 0-0.2 %, w/v), but was tolerated at up to 4 %. Yeast extract was required for growth. Strain 3bT utilized crotonate, lactate and pyruvate, but not sugars. Crotonate was dismutated to acetate and butyrate. Lactate was disproportionated to acetate and propionate. Pyruvate was degraded to acetate plus trace amounts of hydrogen. Growth on lactate was improved by the addition of fumarate, which was used as an electron acceptor and converted to succinate. Sulfate, thiosulfate, elemental sulfur, sulfite, nitrate, nitrite, FeCl3, Fe(III)-citrate, Fe(III)-EDTA, chromate, arsenate, selenate and DMSO were not used as terminal electron acceptors. The G+C content of the genomic DNA was 33.2 mol%. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that the isolate is a member of the family Clostridiaceae, order Clostridiales within the phylum Firmicutes. Strain 3bT was most closely related to 'Alkaliphilus hydrothermalis' FatMR1T (92.2 % 16S rRNA gene sequence similarity), and was positioned approximately equidistantly between the genera Alkaliphilus, Anaerovirgula and Natronincola. On the basis of phylogenetic, genetic, chemotaxonomic and physiological properties, strain 3bT is proposed to represent a novel species of a new genus, for which the name Serpentinicella alkaliphila gen. nov., sp. nov. is proposed. The type strain of Serpentinicella alkaliphila is 3bT (=DSM 100013T=JCM 30645T). PMID- 27499126 TI - Formulation, characterisation and in vivo evaluation of lipid-based nanocarrier for topical delivery of diflunisal. AB - Diflunisal (DIF) is non-steroidal anti-inflammatory drug used in the treatment of rheumatoid arthritis, osteoarthritis. The current engrossment was aimed at formulation and assessment of DIF-loaded solid lipid nanoparticles (SLNs) for topical/dermal application. SLNs formulated by hot homogenisation method based on microemulsification technique were spherical with a mean size of 124.0 +/- 2.07 nm; PDI 0.294 +/- 0.15. The cumulative amount permeated/area was 109.99 +/- 0.008 MUg/cm(2), along with permeation flux (6.30 +/- 0.09 MUg/cm(2)/h) and skin retention (11.74 +/- 0.155 MUg/cm(2)) across mice skin. The SLNs of DIF showed significant decrease in fluid volume, granuloma tissue weight, leukocyte count/mm(3) after application of SLN formulation in mice air pouch model. Similarly, in mice ear oedema and rat paw oedema model, there was 2.30 and 1.29 time increase in percentage inhibition of oedema after SLN formulation application, respectively, as compared with conventional cream. Hence, the SLNs of DIF may prove to be a potential nanocarrier to effectively treat the local inflammatory conditions associated with arthritis. PMID- 27499125 TI - Schistosome sex matters: a deep view into gonad-specific and pairing-dependent transcriptomes reveals a complex gender interplay. AB - As a key event for maintaining life cycles, reproduction is a central part of platyhelminth biology. In case of parasitic platyhelminths, reproductive processes can also contribute to pathology. One representative example is the trematode Schistosoma, which causes schistosomiasis, an infectious disease, whose pathology is associated with egg production. Among the outstanding features of schistosomes is their dioecious lifestyle and the pairing-dependent differentiation of the female gonads which finally leads to egg synthesis. To analyze the reproductive biology of Schistosoma mansoni in-depth we isolated complete ovaries and testes from paired and unpaired schistosomes for comparative RNA-seq analyses. Of >7,000 transcripts found in the gonads, 243 (testes) and 3,600 (ovaries) occurred pairing-dependently. Besides the detection of genes transcribed preferentially or specifically in the gonads of both genders, we uncovered pairing-induced processes within the gonads including stem cell associated and neural functions. Comparisons to work on neuropeptidergic signaling in planarian showed interesting parallels but also remarkable differences and highlights the importance of the nervous system for flatworm gonad differentiation. Finally, we postulated first functional hints for 235 hypothetical genes. Together, these results elucidate key aspects of flatworm reproductive biology and will be relevant for basic as well as applied, exploitable research aspects. PMID- 27499127 TI - Generation of a Chiral Giant Micelle. AB - Over the past few years, chiral supramolecular assemblies have been successfully used for recognition, sensing and enantioselective transformations. Several approaches are available to control chirality of discrete assemblies (e.g., cages and capsules), but few are efficient in assuring chirality for micellar aggregates. Optically active amino acid-derived surfactants are commonly used to generate chiral spherical micelles. To circumvent this limitation, we benefited from the uniaxial growth of spherical micelles into long cylindrical micelles usually called wormlike or giant micelles, upon the addition of cosolutes. This paper describes the unprecedented formation of chiral giant micelles in aqueous solutions of cetyltrimethylammonium bromide (CTAB) upon increasing addition of enantiopure sodium salt of 1,1'-bi-2-naphthol (Na-binaphtholate) as a cosolute. Depending on the concentrations of CTAB and Na-binaphtholate, chiral gel-like systems are obtained. The transition from spherical to giant micellar structures was probed using rheology, cryo-transmission electron microscopy, polarimetry, and electronic circular dichroism (CD). CD can be effectively used to monitor the incorporation of Na-binaphtholate into the micelle palisade as well as to determine its transition to giant micellar structures. Our approach expands the scope for chirality induction in micellar aggregates bringing the possibility to generate "smart" chiral systems and an alternative asymmetric chiral environment to perform enantioselective transformations. PMID- 27499128 TI - Cell division cycle associated 1 as a novel prognostic biomarker and therapeutic target for oral cancer. AB - Oral cavity carcinoma (OCC) is one of the most common causes of cancer-related death worldwide and has poor clinical outcome after standard therapies. Therefore, new prognostic biomarkers and therapeutic targets for OCC are urgently needed. We selected cell division cycle associated 1 (CDCA1) as a candidate OCC biomarker. Immunohistochemical analysis confirmed that CDCA1 protein was expressed in 67 of 99 OCC tissues (67.7%), but not in healthy oral epithelia. CDCA1 expression was significantly associated with poor prognosis in OCC patients (P=0.0244). Knockdown of CDCA1 by siRNAs significantly increased apoptosis of tumor cells. These data suggest that CDCA1 represents a novel prognostic biomarker and therapeutic target for OCC. PMID- 27499129 TI - Paraburkholderiapallidirosea sp. nov., isolated from a monsoon evergreen broad leaved forest soil. AB - A Gram-stain-negative, rod-shaped, aerobic and motile bacterial strain, DHOK13T, was isolated from the forest soils of Dinghushan Biosphere Reserve, Guangdong Province, PR China (112 degrees 31' E, 23 degrees 10' N). It grew optimally at 28-33 degrees C and pH 7.0-7.5. The main fatty acids were C16 : 0, C17 : 0 cyclo, C19 : 0 cycloomega8c, summed feature 2 (C12 : 0 aldehyde and/or unknown 10.9525) and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). The organism contained ubiquinone Q-8 as the predominant isoprenoid quinone. The total DNA G+C content of strain DHOK13T was 62.0 mol%. Phylogenetic analysis of the 16S rRNA gene, as well as the sequence of the partial housekeeping genes, gyrB and recA, showed consistently that strain DHOK13T formed an independent cluster with Paraburkholderia phenazinium LMG 2247T. DNA-DNA hybridization studies showed relatively low relatedness values (39 %) of strain DHOK13T with P. phenazinium LMG 2247T. The phenotypic, chemotaxonomic and phylogenetic data showed that strain DHOK13T represents a novel species of the genus Paraburkholderia for which the name Paraburkholderia pallidirosea sp. nov. is proposed. The type strain is DHOK13T (=KCTC 42626T=LMG 28846T). PMID- 27499130 TI - Time-varying coefficient vector autoregressions model based on dynamic correlation with an application to crude oil and stock markets. AB - This paper proposes a new time-varying coefficient vector autoregressions (VAR) model, in which the coefficient is a linear function of dynamic lagged correlation. The proposed model allows for flexibility in choices of dynamic correlation models (e.g. dynamic conditional correlation generalized autoregressive conditional heteroskedasticity (GARCH) models, Markov-switching GARCH models and multivariate stochastic volatility models), which indicates that it can describe many types of time-varying causal effects. Time-varying causal relations between West Texas Intermediate (WTI) crude oil and the US Standard and Poor's 500 (S&P 500) stock markets are examined by the proposed model. The empirical results show that their causal relations evolve with time and display complex characters. Both positive and negative causal effects of the WTI on the S&P 500 in the subperiods have been found and confirmed by the traditional VAR models. Similar results have been obtained in the causal effects of S&P 500 on WTI. In addition, the proposed model outperforms the traditional VAR model. PMID- 27499131 TI - Emissions and temperature benefits: The role of wind power in China. AB - BACKGROUND: As a non-fossil technology, wind power has an enormous advantage over coal because of its role in climate change mitigation. Therefore, it is important to investigate how substituting wind power for coal-fired electricity will affect emission reductions, changes in radiative forcing and rising temperatures, particularly in the context of emission limits. METHODS: We developed an integrated methodology that includes two parts: an energy-economy-environmental (3E) integrated model and an emission-temperature response model. The former is used to simulate the dynamic relationships between economic output, wind energy and greenhouse gas (GHG) emissions; the latter is used to evaluate changes in radiative forcing and warming. RESULTS: Under the present development projection, wind energy cannot serve as a major force in curbing emissions, even under the strictest space-restraining scenario. China's temperature contribution to global warming will be up to 21.76% if warming is limited to 2 degrees. With the wind for-coal power substitution, the corresponding contribution to global radiative forcing increase and temperature rise will decrease by up to 10% and 6.57%, respectively. CONCLUSIONS: Substituting wind power for coal-fired electricity has positive effects on emission reductions and warming control. However, wind energy alone is insufficient for climate change mitigation. It forms an important component of the renewable energy portfolio used to combat global warming. PMID- 27499132 TI - The Stepwise Increase in the Number of Transcription Factor Families in the Precambrian Predated the Diversification of Plants On Land. AB - The colonization of the land by streptophytes and their subsequent radiation is a major event in Earth history. We report a stepwise increase in the number of transcription factor (TF) families and subfamilies in Archaeplastida before the colonization of the land. The subsequent increase in TF number on land was through duplication within existing TF families and subfamilies. Almost all subfamilies of the Homeodomain (HD) and basic Helix-Loop-Helix (bHLH) had evolved before the radiation of extant land plant lineages from a common ancestor. We demonstrate that the evolution of these TF families independently followed similar trends in both plants and metazoans; almost all extant HD and bHLH subfamilies were present in the first land plants and in the last common ancestor of bilaterians. These findings reveal that the majority of innovation in plant and metazoan TF families occurred in the Precambrian before the Phanerozoic radiation of land plants and metazoans. PMID- 27499133 TI - Characterization of the Poplar Pan-Genome by Genome-Wide Identification of Structural Variation. AB - Many recent studies have emphasized the important role of structural variation (SV) in determining human genetic and phenotypic variation. In plants, studies aimed at elucidating the extent of SV are still in their infancy. Evidence has indicated a high presence and an active role of SV in driving plant genome evolution in different plant species.With the aim of characterizing the size and the composition of the poplar pan-genome, we performed a genome-wide analysis of structural variation in three intercrossable poplar species: Populus nigra, Populus deltoides, and Populus trichocarpa We detected a total of 7,889 deletions and 10,586 insertions relative to the P. trichocarpa reference genome, covering respectively 33.2 Mb and 62.9 Mb of genomic sequence, and 3,230 genes affected by copy number variation (CNV). The majority of the detected variants are inter specific in agreement with a recent origin following separation of species.Insertions and deletions (INDELs) were preferentially located in low-gene density regions of the poplar genome and were, for the majority, associated with the activity of transposable elements. Genes affected by SV showed lower-than average expression levels and higher levels of dN/dS, suggesting that they are subject to relaxed selective pressure or correspond to pseudogenes.Functional annotation of genes affected by INDELs showed over-representation of categories associated with transposable elements activity, while genes affected by genic CNVs showed enrichment in categories related to resistance to stress and pathogens. This study provides a genome-wide catalogue of SV and the first insight on functional and structural properties of the poplar pan-genome. PMID- 27499134 TI - Metabolomic analysis of CSF indicates brain metabolic impairment precedes hematological indices of anemia in the iron-deficient infant monkey. AB - OBJECTIVES: Iron deficiency (ID) anemia leads to long-term neurodevelopmental deficits by altering iron-dependent brain metabolism. The objective of the study was to determine if ID induces metabolomic abnormalities in the cerebrospinal fluid (CSF) in the pre-anemic stage and to ascertain the aspects of abnormal brain metabolism affected. METHODS: Standard hematological parameters [hemoglobin (Hgb), mean corpuscular volume (MCV), transferrin (Tf) saturation, and zinc protoporphyrin/heme (ZnPP/H)] were compared at 2, 4, 6, 8, and 12 months in iron sufficient (IS; n = 7) and iron-deficient (ID; n = 7) infant rhesus monkeys. Five CSF metabolite ratios were determined at 4, 8, and 12 months using 1H NMR spectroscopy at 16.4 T and compared between groups and in relation to hematologic parameters. RESULTS: ID infants developed ID (Tf saturation < 25%) by 4 months of age and all became anemic (Hgb < 110 g/L and MCV < 60 fL) at 6 months. Their heme indices normalized by 12 months. Pyruvate/glutamine and phosphocreatine/creatine (PCr/Cr) ratios in CSF were lower in the ID infants by 4 months (P < 0.05). The PCr/Cr ratio remained lower at 8 months (P = 0.02). ZnPP/H, an established blood marker of pre-anemic ID, was positively correlated with the CSF citrate/glutamine ratio (marginal correlation, 0.34; P < 0.001; family wise error rate = 0.001). DISCUSSION: Metabolomic analysis of the CSF is sensitive for detecting the effects of pre-anemic ID on brain energy metabolism. Persistence of a lower PCr/Cr ratio at 8 months, even as hematological measures demonstrated recovery from anemia, indicate that the restoration of brain energy metabolism is delayed. Metabolomic platforms offer a useful tool for early detection of the impact of ID on brain metabolism in infants. PMID- 27499135 TI - Rapid discovery and identification of anti-inflammatory constituents from traditional Chinese medicine formula by activity index, LC-MS, and NMR. AB - The traditional activity-guided approach has the shortcoming of low accuracy and efficiency in discovering active compounds from TCM. In this work, an approach was developed by integrating activity index (AI), liquid chromatography - mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR) to rapidly predict and identify the potential active constituents from TCM. This approach was used to discover and identify the anti-inflammatory constituents from a TCM formula, Gui Zhi-Jia-Shao-Yao-Tang (GZJSYT). The AI results indicated that, among the 903 constituents detected in GZJSYT by LC-MS, 61 constituents with higher AI values were very likely to have anti-inflammatory activities. And eight potential active constituents of them were isolated and validated to have significant inhibitory effects against NO production on LPS-induced RAW 264.7 cell model. Among them, glycyrrhisoflavone (836), glisoflavanone (893) and isoangustone A (902) were reported to have anti-inflammatory effects for the first time. The proposed approach could be generally applicable for rapid and high efficient discovery of anti-inflammatory constituents from other TCM formulae or natural products. PMID- 27499136 TI - HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia. AB - Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1 and IDH1/IDH2. A striking selective overexpression of specific HOXA and HOXB gene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivo responses to venetoclax showed significant inverse correlation to beta2 microglobulin expression and to a lesser degree to BCL-XL and BAX expression. As new therapy options for AML are urgently needed, the specific HOX gene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials. PMID- 27499137 TI - The novel PI3K-delta inhibitor TGR-1202 enhances Brentuximab Vedotin-induced Hodgkin lymphoma cell death via mitotic arrest. PMID- 27499138 TI - Rictor has a pivotal role in maintaining quiescence as well as stemness of leukemia stem cells in MLL-driven leukemia. AB - Little is known about the roles of Rictor/mTORC2 in the leukemogenesis of acute myeloid leukemia. Here, we demonstrated that Rictor is essential for the maintenance of mixed lineage leukemia (MLL)-driven leukemia by preventing leukemia stem cells (LSCs) from exhaustion. Rictor depletion led to a reactive activation of mTORC1 signaling by facilitating the assembly of mTORC1. Hyperactivated mTORC1 signaling in turn drove LSCs into cycling, compromised the quiescence of LSCs and eventually exhausted their capacity to generate leukemia. At the same time, loss of Rictor had led to a reactive activation of FoxO3a in leukemia cells, which acts as negative feedback to restrain greater over reactivation of mTORC1 activity and paradoxically protects leukemia cells from exhaustion. Simultaneous depletion of Rictor and FoxO3a enabled rapid exhaustion of MLL LSCs and a quick eradication of MLL leukemia. As such, our present findings highlighted a pivotal regulatory axis of Rictor-FoxO3a in maintaining quiescence and the stemness of LSCs. PMID- 27499139 TI - Human memory B cells. AB - A key feature of the adaptive immune system is the generation of memory B and T cells and long-lived plasma cells, providing protective immunity against recurring infectious agents. Memory B cells are generated in germinal center (GC) reactions in the course of T cell-dependent immune responses and are distinguished from naive B cells by an increased lifespan, faster and stronger response to stimulation and expression of somatically mutated and affinity matured immunoglobulin (Ig) genes. Approximately 40% of human B cells in adults are memory B cells, and several subsets were identified. Besides IgG+ and IgA+ memory B cells, ~50% of peripheral blood memory B cells express IgM with or without IgD. Further smaller subpopulations have additionally been described. These various subsets share typical memory B cell features, but likely also fulfill distinct functions. IgM memory B cells appear to have the propensity for refined adaptation upon restimulation in additional GC reactions, whereas reactivated IgG B cells rather differentiate directly into plasma cells. The human memory B-cell pool is characterized by (sometimes amazingly large) clonal expansions, often showing extensive intraclonal IgV gene diversity. Moreover, memory B-cell clones are frequently composed of members of various subsets, showing that from a single GC B-cell clone a variety of memory B cells with distinct functions is generated. Thus, the human memory B-cell compartment is highly diverse and flexible. Several B-cell malignancies display features suggesting a derivation from memory B cells. This includes a subset of chronic lymphocytic leukemia, hairy cell leukemia and marginal zone lymphomas. The exposure of memory B cells to oncogenic events during their generation in the GC, the longevity of these B cells and the ease to activate them may be key determinants for their malignant transformation. PMID- 27499140 TI - Anti-CD44 antibodies inhibit both mTORC1 and mTORC2: a new rationale supporting CD44-induced AML differentiation therapy. PMID- 27499141 TI - Emended description of Mycobacterium abscessus, Mycobacterium abscessus subsp. abscessus and Mycobacteriumabscessus subsp. bolletii and designation of Mycobacteriumabscessus subsp. massiliense comb. nov. AB - The taxonomic position of members of the Mycobacterium abscessus complex has been the subject of intensive investigation and, in some aspects confusion, in recent years as a result of varying approaches to genetic data interpretation. Currently, the former species Mycobacterium massiliense and Mycobacterium bolletii are grouped together as Mycobacterium abscessus subsp. bolletii. They differ greatly, however, as the former M. bolletii has a functional erm(41) gene that confers inducible resistance to macrolides, the primary therapeutic antimicrobials for M. abscessus, while in the former M. massiliense the erm(41) gene is non-functional. Furthermore, previous whole genome studies of the M. abscessus group support the separation of M. bolletii and M. massiliense. To shed further light on the population structure of Mycobacterium abscessus, 43 strains and three genomes retrieved from GenBank were subjected to pairwise comparisons using three computational approaches: verage ucleotide dentity, enome to enome istance and single nucleotide polymorphism analysis. The three methods produced overlapping results, each demonstrating three clusters of strains corresponding to the same number of taxonomic entities. The distances were insufficient to warrant distinction at the species level, but met the criteria for differentiation at the subspecies level. Based on prior erm(41)-related phenotypic data and current genomic data, we conclude that the species M. abscessus encompasses, in adjunct to the presently recognized subspecies M. abscessus subsp. abscessus and M. abscessus subsp. bolletii, a third subspecies for which we suggest the name M. abscessus subsp. massiliense comb. nov. (type strain CCUG 48898T=CIP 108297T=DSM 45103T=KCTC 19086T). PMID- 27499142 TI - Use of video-based education and tele-health home monitoring after liver transplantation: Results of a novel pilot study. AB - BACKGROUND: In this observational study, we analyzed the feasibility and early results of a perioperative, video-based educational program and tele-health home monitoring model on postoperative care management and readmissions for patients undergoing liver transplantation. METHODS: Twenty consecutive liver transplantation recipients were provided with tele-health home monitoring and an educational video program during the perioperative period. Vital statistics were tracked and monitored daily with emphasis placed on readings outside of the normal range (threshold violations). Additionally, responses to effectiveness questionnaires were collected retrospectively for analysis. RESULTS: In the study, 19 of the 20 patients responded to the effectiveness questionnaire, with 95% reporting having watched all 10 videos, 68% watching some more than once, and 100% finding them effective in improving their preparedness for understanding their postoperative care. Among these 20 patients, there was an observed 19% threshold violation rate for systolic blood pressure, 6% threshold violation rate for mean blood glucose concentrations, and 8% threshold violation rate for mean weights. This subset of patients had a 90-day readmission rate of 30%. CONCLUSION: This observational study demonstrates that tele-health home monitoring and video-based educational programs are feasible in liver transplantation recipients and seem to be effective in enhancing the monitoring of vital statistics postoperatively. These data suggest that smart technology is effective in creating a greater awareness and understanding of how to manage postoperative care after liver transplantation. PMID- 27499143 TI - Discussion. PMID- 27499144 TI - Cancer surgeons' attitudes and practices about discussing the chance of operative "cure". AB - BACKGROUND: While physician attitudes about treatment goals have been examined around end-of-life care, surgeon attitudes regarding communication of therapeutic goals prior to cancer-directed operations have not been investigated. We examined how surgeons discuss the potential for cancer "cure" prior to operative treatment and how surgeons perceive patient priorities and treatment goals. METHODS: Surgeons were invited to complete a Web-based survey about attitudes and practices when discussing cancer-directed operations, including how they defined cancer cure and whether and how they discussed cure as a treatment goal. RESULTS: A total of 551 e-mail invitations were sent and opened; 205 responses were received (response rate 37.2%). While 44.9% of surgeons reported being asked about cure in all or most discussions, only 37.6% used the word cure as often. When discussing cure, an equal number of surgeons reported using qualitative versus quantitative language to express probability of cure (45.7% and 47.4%, respectively). Roughly one third of surgeons (n = 65, 31.7%) defined cure as 5 year, disease-free survival; 36.1% (n = 74) defined cure as absence of recurrence over the patient's lifetime; and 21 (10.2%) defined cure as return to baseline population risk for that specific cancer. Over half of surgeons (n = 112, 56.9%) perceived that to "be cured" was among the top 2 priorities of patients presenting for operative treatment. CONCLUSION: When discussing relative benefits and goals of therapy, surgeon self-reported discussions of cure varied considerably. Despite identifying cure as a top priority for patients, surgeons were not inclined to incorporate cure into discussions of risks, benefits, and goals of therapy. PMID- 27499145 TI - Prioritizing qualitative research in surgery: A synthesis and analysis of publication trends. AB - BACKGROUND: Over the past 2 decades, researchers have recognized the value of qualitative research. Little has been done to characterize its application to surgery. We describe characteristics and overall prevalence of qualitative surgical research. METHODS: We searched PubMed and CINAHL using "surgery" and 7 qualitative methodology terms. Four researchers extracted information; a fifth researcher reviewed 10% of abstracts for inter-rater reliability. RESULTS: A total of 3,112 articles were reviewed. Removing duplicates, 28% were relevant (N = 878; kappa = 0.70). Common qualitative methodologies included phenomenology (34.3%) and grounded theory (30.2%). Interviews were the most common data collection method (81.9%) of patients (64%) within surgical oncology (15.4%). Postdischarge was the most commonly studied topic (30.8%). Overall, 41% of studies were published in nursing journals, while 8% were published in surgical journals. More than half of studies were published since 2011. CONCLUSION: Results suggest qualitative surgical research is gaining popularity. Most is published in nonsurgical journals, however, utilizing only 2 methodologies (phenomenology, grounded theory). The surgical journals that have published qualitative research had study topics restricted to a handful of surgical specialties. Additional surgical qualitative research should take advantage of a greater variety of approaches to provide insight into rare phenomena and social context. PMID- 27499146 TI - Discussion. PMID- 27499147 TI - Delayed interventions and mortality in trauma damage control laparotomy. AB - BACKGROUND: In damage control laparotomy, operative principles include hemorrhage and contamination control. However, required components of initial damage control laparotomy are unknown, and nonemergency injury repair is sometimes delayed for resuscitation, angiography, or nonabdominal operations. The frequency and effects of delayed interventions are unknown. METHODS: A retrospective review of patients undergoing damage control laparotomy at a single, urban trauma center was performed. Interventions initially performed at the second laparotomy were considered delayed interventions. RESULTS: In the study, 330 damage control laparotomy patients survived to reoperation. Of all interventions, 13.9% were first performed at the second laparotomy, including 11.9% of visceral interventions and 27.2% of vascular interventions. Overall, 29.7% of patients underwent an unplanned re-exploration, and 21.8% of patients underwent re exploration for hemorrhage control. There was no significant increase in mortality (33.3% vs 23.9%, P = .09), intra-abdominal infection (37.9% vs 28.0%; P = .10), anastomotic leak (8.0% vs 5.8%, P = .45), or enterocutaneous fistula formation (9.2% vs 9.1%, P = 1.00) with delayed interventions overall. However, mortality was increased in patients undergoing delayed vascular interventions (59.1% vs 22.8%, P = .003), unplanned re-exploration (45.9% vs 18.1%, P < .001) and re-exploration for hemorrhage control (50.0% vs 19.8%, P < .001). CONCLUSION: Delayed interventions are common in damage control laparotomy, with abdominal interventions often spread over multiple explorations. Mortality is increased in patients undergoing emergent re-exploration and with delayed repair of major vascular injuries. Ideal treatment of damage control laparotomy patients may include addressing injuries more completely at the first laparotomy instead of deferring care for other priorities. PMID- 27499148 TI - Achieving low anastomotic leak rates utilizing clinical perfusion assessment. AB - BACKGROUND: Anastomotic leak after colorectal resection increases morbidity, mortality, and in the setting of cancer, increases recurrences rates and reduces survival odds. Recent reports suggest that fluorescence evaluation of perfusion after colorectal anastomosis creation is associated with low anastomotic leak rates (1.4%). The purpose of this work was to evaluate whether a similar low anastomotic leak rate after left-sided colorectal resections could be achieved using standard assessment of blood flow to the bowel ends. METHODS: We performed a retrospective chart review at an academic tertiary referral center, evaluating 317 consecutive patients who underwent a pelvic anastomosis after sigmoid colectomy, left colectomy, or low anterior resection. All operations were performed by a single surgeon from March 2008 to January 2015 with only standard clinical measures used to assess perfusion to the bowel ends. The primary outcome measure was the anastomotic leak rate as diagnosed by clinical symptoms, exam, or routine imaging. RESULTS: The average patient age was 59.7 years with an average body mass index of 28.8 kg/m(2). Rectal cancer (128, 40.4%) was the most common indication for operation while hypertension (134, 42.3%) was the most common comorbidity. In total, 177 operations were laparoscopic (55.8%), 13 were reoperative resections (4.1%), and 108 were protected with a loop ileostomy (34.1%). Preoperative chemotherapy was administered to 25 patients (7.9%) while preoperative chemo/radiation was administered to 64 patients (20.2%). The anastomotic leak rate was 1.6% (5/317). CONCLUSION: Our data suggests that standard, careful evaluation of adequate blood flow via inspection and confirmation of pulsatile blood flow to the bowel ends and meticulous construction of the colorectal or coloanal anastomoses can result in very low leak rates, similar to the rate reported when intraoperative imaging is used to assess perfusion. PMID- 27499149 TI - Diborane-Mediated Deoxygenation of o-Nitrostyrenes To Form Indoles. AB - A mild, transition metal-free, diborane-mediated deoxygenation of nitro groups was discovered that in situ generates nitrosoarene reactive intermediates. This new reactivity mode of B2pin2 was leveraged to construct indoles from o nitrostyrenes through a reductive-cyclization reaction that exhibits a Hammett rho-value of +0.97 relative to sigmapara values. Our new deoxygenation reaction is efficient, practical, and scaleable, enabling access to a broad range of indoles. PMID- 27499150 TI - Is there an influence of hepatic steatosis on fibrosis and necroinflammation in young patients with chronic viral hepatitis B? AB - OBJECTIVES: Our aim was to investigate the association of liver fibrosis and necroinflammation with HS in untreated young patients with chronic hepatitis B (CHB). MATERIALS AND METHODS: A retrospective study was conducted in a military hospital in Turkey. A total of 254 subjects with CHB were included in this study. These subjects were divided into two groups: group 1 consisted of patients with hepatic steatosis (HS) according to ultrasonography (USG) and group 2 consisted of non-HS subjects. Sociodemographic, biochemical, histopathological, virological and USG results were recorded for both groups retrospectively. Statistical analysis was performed using SPSS 22.0. RESULTS: The prevalence of HS was found to be 11.4%. A significant statistical difference was found between group 1 and group 2 regarding the fibrosis degree (p = 0.045). No statistically significant difference was noted between two groups for age, levels of ALT, AST, HBeAg, HBV DNA levels, HAI scores, diagnosis age and duration of CHB. No difference was noted between the grade of HS and variables. A positive correlation was found between fibrosis groups and the grade of HS (p = 0.012, r = 0.158) and between HAI groups and the grade of HS (p = 0.029, r = 0.137). CONCLUSION: The prevalence of steatosis was not higher in patients with CHB. HS is associated with advanced hepatic fibrosis, but not viral liver disease. PMID- 27499151 TI - OTUD7B and NIK expression in non-small cell lung cancer: Association with clinicopathological features and prognostic implications. AB - PURPOSE: To investigate the correlation among OTUD7B and NIK expression and the clinicopathological characteristics in NSCLC patients. METHODS: One hundred and twenty patients were involved in this study. We detected OTUD7B and NIK expression by immunohistochemistry and analyzed their correlation with clinicopathological data. RESULTS: The expression of OTUD7B and NIK were negatively correlated in NSCLC tumor samples (rs=-0.421, P<0.001). The higher expression of OTUD7B was associated with smaller tumor size(P=0.018), less lymph node metastasis (P=0.012) and earlier TNM stage(P=0.039), while the higher expression of NIK was only related to more lymph node metastasis(P=0.031) and later TNM stage(P=0.011). MMP-9 was negatively correlated with OTUD7B and positively correlated with NIK. In addition, the high expression of OTUD7B was associated with good prognosis of NSCLC patients (log-rank=6.714, P=0.0096), and a high OTUD7B/low NIK index can predict an even better prognosis (log rank=11.794, P=0.0006). Moreover, the multivariate Cox regression analysis showed that OTUD7B rather than NIK is an independent marker of overall survival in NSCLC patients(HR=1.602, 95% CI 1.009-2.544, P=0.046). CONCLUSIONS: OTUD7B and NIK may play important roles in the development of lung cancer. The combination of OTUD7B and NIK expression may be a good index for predicting the prognosis of NSCLC. PMID- 27499152 TI - Distinctive interrelation of p53 with SCO2, COX, and TIGAR in human gastric cancer. AB - PURPOSE: p53, widely known as a tumor-suppressing gene, has recently been reported to regulate glucose metabolism in human cancers through the synthesis of cytochrome c oxidase 2 (SCO2), cytochrome c oxidase complex (COX), and TP53 induced glycolysis and apoptosis regulator (TIGAR). In this study, we investigated the interrelations of the aforementioned proteins, particularly in human gastric cancer, with cancer progression, other clinicopathological parameters, and patient outcomes. MATERIALS AND METHODS: One hundred and ten cases of primary gastric cancer occurring from June 2006 to June 2009 were investigated and classified into two groups according to the intensity of immunohistochemical staining for p53, SCO2, COX, and TIGAR. The clinicopathological data were organized and analyzed based on electronic medical records. RESULTS: In accordance with previous reports, the expression of p53 showed an inverse correlation with the expression of TIGAR (p=0.032) in gastric cancer cells. However, the expression of SCO2 and COX were not shown to be associated with the regulatory role of p53, unlike TIGAR expression. Nevertheless, a significantly high recurrence rate was found in a patient group with high COX expression (p=0.012). CONCLUSIONS: This study demonstrated that a high p53 expression could be associated with the promotion of glycolysis in gastric cancer via the modulation of TIGAR expression. In addition, a high COX expression appeared to be interrelated with poor prognosis of gastric cancer. However, further studies regarding the underlying molecular interactions are required to provide more evidence to propose a novel mechanism that explains our findings in gastric cancer. PMID- 27499153 TI - Orbital meningeal melanocytoma: Histological, immunohistochemical and molecular characterization of a case and review of the literature. AB - AIMS: We provide morphological, immunohistochemical and molecular characterization of the 3rd "intermediate-grade" orbital meningeal melanocytoma, testing for the first time Vysis Melanoma FISH Probe Kit. We reviewed the literature in order to discuss the main differential diagnoses and to provide a better molecular description of these unusual tumors of difficult diagnosis and controversial management. METHODS: Histochemical stains (Haematoxylin and Eosin, Perls, reticulin), immunohistochemistry (HMB45, p16, Melan-A, S100, EMA, Ki67, CD68), polymerase chain reaction amplification and sequence analysis (BRAF, exon 15; NRAS exons 2 and 3; c-KIT, exons 11, 13, 17, 18; GNAQ, exons 4 and 5; GNA11, exons 4 and 5) and fluorescent in situ hybridization (RREB1, 6p25; MYB, 6q23; CCND1, 11q13; CEP 6, 6p11.1-q11.1) were performed on paraffin-embedded, formalin fixed material. RESULTS: Histological diagnosis of "intermediate-grade" melanocytoma was supported by zonal necrosis and increased Ki67-index (12%). Immunophenotype: HMB45+(strong, >75%), Melan-A+(strong, >75%), p16+(~20%), S100 /+ (<5%), EMA -/+ (<5%), CD68 - (positive histiocytes). No gene mutations nor copy-number alterations were identified. The patient was asymptomatic and disease free 3 years after total surgical excision. CONCLUSIONS: Adequate sampling and accurate immunohistochemical characterization are important for a correct diagnosis. Molecular analysis could provide important additional information (especially for "intermediate-grade" tumors), but further data are needed. PMID- 27499154 TI - Distribution pattern of Ki67 immunoreactivity in ductal intraepithelial neoplasia: Correlation with lesion grade and potential utility. AB - BACKGROUND: In this study, the pattern of distribution of the nuclei immunoreactive with Ki67 was examined in DIN1c (DCIS, grade 1/low grade), DIN2 (DCIS, grade 2/intermediate grade), and DIN3 (DCIS, grade 3/high grade). The lesions were evaluated to determine if distinctive patterns could be identified in correlation with lesion grade. METHODS: Fifty seven (n=57) consecutive DIN cases were investigated. Of these, 15 qualified as DIN1c, 28 as DIN2 and 14 as DIN3. The patterns of distribution were recorded for each case as either basal/peripheral or haphazard within the epithelial proliferation. RESULTS: There was a statistically significant difference between the DIN1c, DIN2 and DIN3 in terms of basal/peripheral versus haphazard distribution of Ki67 immunostaining (Chi-square test, P<0.0001). Basal/peripheral staining pattern was dominant among the DIN1c cases, while haphazard staining pattern was the dominant distribution among the DIN3 cases. One half of the DIN2 cases showed basal/peripheral staining pattern, while the other half showed a haphazard staining pattern. CONCLUSION: High grade DIN lesions show haphazard Ki67 staining while low grade DIN lesions show basal/peripheral Ki67 staining in the proliferating epithelial cells. This feature could be practical in separating DIN lesions into low grade (basal/peripheral-Ki67) and high grade (haphazard-Ki67) eliminating the grade 2/intermediate category. PMID- 27499156 TI - Description of Altererythrobacter aerius sp. nov., isolated from air, and emended description of the genus Altererythrobacter. AB - A Gram-stain-negative, yellow-pigmented, ovoid to rod-shaped, strictly aerobic bacterial strain, designated 100921-2T, was isolated from air at the foot of Xiangshan Mountain. Phylogenetic and phenotypic analysis of the organism revealed that the isolate belongs to the genus Altererythrobacter. Strain 100921-2T showed high 16S rRNA gene sequence similarity (96.01-94.70 %) to other type strains of the genus Altererythrobacter, with the highest similarity to Altererythrobactermarensis MSW-14T. Growth of strain 100921-2T was observed at 4 50 degrees C (optimum, 30 degrees C), at pH 4.5-10.0 (optimum, pH 7.0) and at salinities of 0-10 % (w/v) NaCl (optimum 0-0.5 %). The major fatty acids were C18 : 1omega7c (27.8 %), C17 : 1omega6c (23.1 %), 11-methyl C18 : 1omega7c(11.9 %), summed feature 3 (9.1 %) and C15 : 0 2-OH (7.9 %). The predominant respiratory quinone was ubiquinone-10 (Q-10). Polar lipid analysis indicated the presence of diphosphatidylglycerol, sphingoglycolipid, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, two unknown phospholipids, five unknown polar lipids and two unknown glycolipids. The DNA G+C content of the type strain was 67.5 mol%. On the basis of the data from the polyphasic characterization, strain 100921-2T represents a novel species, for which the name Altererythrobacter aerius sp. nov. is proposed. The type strain is 100921-2T (=CFCC 14287T=KCTC 42844T). PMID- 27499155 TI - Genetic markers of pigmentation are novel risk loci for uveal melanoma. AB - While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 (OR = 0.529, 95% CI 0.415-0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419-0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339-0.637; p = 3.04E-07) are correlated (r(2) > 0.5) and map at 15q12 in the region of HERC2/OCA2, which determines eye-color in the human population. Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility. PMID- 27499158 TI - Driving electrocatalytic activity by interface electronic structure control in a metalloprotein hybrid catalyst for efficient hydrogen evolution. AB - The rational design of metalloprotein hybrid structures and precise calculations for understanding the role of the interfacial electronic structure in regulating the HER activity of water splitting sites and their microscopic effect for obtaining robust hydrogen evolution possess great promise for developing highly efficient nano-bio hybrid HER catalysts. Here, we employ high-accuracy linear scaling density functional theory calculations using a near-complete basis set and a minimal parameter implicit solvent model within the self-consistent calculations, on silver (Ag) ions assimilated on bacteriorhodopsin (bR) at specific binding sites. Geometry optimization indicates the formation of active sites at the interface of the metalloprotein complex and the density of states reflects the metallic nature of the active sites. The reduced value of the canonical orbital gap indicates the state of dynamic nature after Ag ion assimilation on active sites and smooth electron transfer. These incorporated active protein sites are more efficient in electrolytic splitting of water than pristine sites due to their low value of Gibbs free energy for the HER in terms of hydrogen coverages. Volcano plot analysis and the free energy diagram are compared for understanding the hydrogen evolution efficiency. Moreover, the essential role of the interfacial electronic properties in regulating the HER catalytic activity of water splitting sites and enhancing the efficiency is elucidated. PMID- 27499157 TI - Conventional versus Drug-Eluting Bead Transarterial Chemoembolization for Neuroendocrine Tumor Liver Metastases. AB - PURPOSE: To compare outcomes of conventional transarterial chemoembolization with drug-eluting bead (DEB) chemoembolization for treatment of neuroendocrine tumor liver metastases. MATERIALS AND METHODS: This single-center, retrospective study evaluated 177 transarterial chemoembolization treatments (78 conventional chemoembolization treatments using ethiodized oil-based cisplatin, mitomycin C, and doxorubicin and 99 DEB chemoembolization treatments using doxorubicin-loaded 100-300 MUm DEBs) from 2012 to 2015. Hepatic disease distribution was 93% bilobar for both groups with largest lesion size 5.0 cm +/- 2.7. No difference was noted in regard to lesion size or distribution, carcinoid syndrome, or pancreastatin production. Clinical outcomes including complications; liver function tests (LFTs); and radiologic (modified Response Evaluation Criteria in Solid Tumors), biochemical (pancreastatin levels), and symptomatic responses were evaluated at 1 month follow-up. RESULTS: Higher symptomatic response (complete and partial) was identified with conventional transarterial chemoembolization compared with DEB chemoembolization (47% vs 30%; P < .05). Patients receiving DEB transarterial chemoembolization experienced lower elevation of LFTs (aspartate aminotransferase, 39 U/L vs 122 U/L; alanine aminotransferase, 20 U/L vs 93 U/L; bilirubin, 0.001 mg/dL vs 0.123 mg/dL; P < .05) and less postembolization syndrome (50% vs 67%; P < .05). Patients undergoing first-time DEB transarterial chemoembolization had lower periprocedural octreotide maximum rate requirements (58 MUg/h vs 66 MUg/h; P < .05). No difference was observed in biochemical (P = .60) or radiologic (P < .20) responses. CONCLUSIONS: Conventional transarterial chemoembolization yields better symptomatic response and may be preferred for patients experiencing carcinoid symptoms. DEB transarterial chemoembolization, with lower LFT elevations and postembolization syndrome incidence, may be preferred for patients with poor liver function. PMID- 27499159 TI - How flexible is a protein: simple estimates using FRET microscopy. AB - Flexible proteins are frequently used to link subunits of larger complexes in various contexts, for instance, in the construction of unimolecular sensors used in FRET microscopy, and fusion proteins. How flexible such linkers are can be an important question in the overall design of the complex, and yet sometimes suprisingly difficult to establish. Such difficulties can arise because the actual flexibility of a protein depends significantly on its interactions with the solvent, and when the local environment is a subcellular compartment, even the conditions of the solvent, may not be known. In this communication we propose a simple numerical procedure through which the flexibility of such proteins can be extracted from FRET based microscopy data. PMID- 27499160 TI - Hypoxia upregulates Malat1 expression through a CaMKK/AMPK/HIF-1alpha axis. AB - Increased expression levels of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (Malat1) have been associated with enhanced proliferation and metastasis of several cancer cell types. Hypoxia, a hallmark characteristic of solid tumors, has been linked to an increase in the activity of the ATP-generating AMPK protein. Since Malat1 was recently shown to be upregulated during hypoxia, the objective of this study was to determine the contribution of AMPK in the mechanistic pathways regulating Malat1 expression in low oxygen conditions. Compared to those cultured in 21% O2 conditions, HeLa cells incubated in 1.5% O2 expressed more Malat1 transcripts. This observation was mimicked in HEK293T cells using a synthetic reporter construct containing 5.6 kb of the human Malat1 promoter, suggesting that hypoxia directly impacted Malat1 gene transcription. Interestingly, pharmacological stimulation of AMPK increased Malat1 promoter transactivation in 21% O2 conditions, whereas inhibition of either AMPK or its upstream activator CaMKK completely abolished the augmentation of Malat1 under hypoxia. Pharmacological modulation of LKB1, another major regulator of AMPK, had no impact on Malat1 promoter transactivation, suggesting that calcium inputs are important in the control of Malat1 expression by AMPK. Overexpression of hypoxia-inducible factor-1alpha (HIF-1alpha) increased Malat1 expression in 21% O2 conditions, whereas pharmacological inhibition of HIF-1alpha blocked the impact of hypoxia on the Malat1 promoter. Taken together, these findings strongly suggest that Malat1 expression is regulated in hypoxic conditions by a CaMKK/AMPK/HIF-1alpha axis. More research is needed in physiological settings to test the clinical relevance of this pathway. PMID- 27499161 TI - A Systematic Review of the Economic Evaluation of Telemedicine in Japan. AB - OBJECTIVES: There is no systematic review on economic evaluations of telemedicine in Japan, despite over 1000 trials implemented. Our systematic review aims to examine whether Japan's telemedicine is cost-saving or cost-effective, examine the methodological rigorousness of the economic evaluations, and discuss future studies needed to improve telemedicine's financial sustainability. METHODS: We searched five databases, including two Japanese databases, to find peer-reviewed articles published between January 1, 2000 and December 31, 2014 in English and Japanese that performed economic evaluations of Japan's telemedicine programs. The methodological rigorousness of the economic analyses was assessed with a well established checklist. We calculated the benefit-to-cost ratio (BCR) when a reviewed study reported related data but did not report the BCR. All cost values were adjusted to 2014 US dollars. RESULTS: Among the 17 articles identified, six studies reported on settings connecting physicians for specialist consultations, and eleven studies on settings connecting healthcare providers and patients at home. There are three cost-benefit analyses and three cost-minimization analyses. The remaining studies measured the benefit of telemedicine only, using medical expenditure saved or users' willingness-to-pay. There was substantial diversity in the methodological rigorousness. Studies on teledermatology and teleradiology indicated a favorable level of economic efficiency. Studies on telehomecare gave mixed results. One cost-benefit analysis on telehomecare indicated a low economic efficiency, partly due to public subsidy rules, e.g., a too short budget period. CONCLUSIONS: Overall, telemedicine programs in Japan were indicated to have a favorable level of economic efficiency. However, the scarcity of the economic literature indicates the need for further rigorous economic evaluation studies. PMID- 27499162 TI - Helicobacter pylori Infection and Risk of Gastric Cancer in Korea: A Quantitative Systematic Review. AB - OBJECTIVES: In the context of the global decrease in mortality due to gastric cancer, previous studies have reported that the effect of chronic Helicobacter pylori (H. pylori) infection on the incidence of gastric cancer varies among regions. This systematic review was conducted to investigate H. pylori as a risk factor for gastric cancer in Korea, where the incidence of gastric cancer is among the highest in the world. METHODS: A search strategy was established to identify articles published in Korean as well as in English. Ultimately, we included observational studies conducted among Korean patients that designed with an age-matched and sex-matched control group that reported the odds ratio associated with H. pylori. Gastric cancer cases were subdivided into overall (OGC), cardia (CGC), non-cardia (NGC), early (EGC), advanced, intestinal (IGC), and diffuse forms of gastric cancer. Summary odds ratios (SORs) with 95% confidence intervals (CIs) were calculated in the meta-analysis using a random effect model. RESULTS: Eleven case-control studies were ultimately selected. H. pylori was associated with an SOR of 1.81 (95% CI, 1.29 to 2.54) for OGC. Additionally, statistically significant risks were observed for CGC, NGC, EGC, and IGC. CONCLUSIONS: Chronic H. pylori infection was found to raise the risk of gastric cancer among Koreans, with the highest risk observed for CGC and EGC (SOR=2.88 for both). Follow-up clinical epidemiologic studies are needed to assess the effects of current treatments aimed at eradicating H. pylori infections. PMID- 27499163 TI - Short-term Effect of Fine Particulate Matter on Children's Hospital Admissions and Emergency Department Visits for Asthma: A Systematic Review and Meta analysis. AB - OBJECTIVES: No children-specified review and meta-analysis paper about the short term effect of fine particulate matter (PM2.5) on hospital admissions and emergency department visits for asthma has been published. We calculated more precise pooled effect estimates on this topic and evaluated the variation in effect size according to the differences in study characteristics not considered in previous studies. METHODS: Two authors each independently searched PubMed and EMBASE for relevant studies in March, 2016. We conducted random effect meta analyses and mixed-effect meta-regression analyses using retrieved summary effect estimates and 95% confidence intervals (CIs) and some characteristics of selected studies. The Egger's test and funnel plot were used to check publication bias. All analyses were done using R version 3.1.3. RESULTS: We ultimately retrieved 26 time-series and case-crossover design studies about the short-term effect of PM2.5 on children's hospital admissions and emergency department visits for asthma. In the primary meta-analysis, children's hospital admissions and emergency department visits for asthma were positively associated with a short term 10 MUg/m3 increase in PM2.5 (relative risk, 1.048; 95% CI, 1.028 to 1.067; I2=95.7%). We also found different effect coefficients by region; the value in Asia was estimated to be lower than in North America or Europe. CONCLUSIONS: We strengthened the evidence on the short-term effect of PM2.5 on children's hospital admissions and emergency department visits for asthma. Further studies from other regions outside North America and Europe regions are needed for more generalizable evidence. PMID- 27499164 TI - The Impact of Educational Status on 10-Year (2004-2014) Cardiovascular Disease Prognosis and All-cause Mortality Among Acute Coronary Syndrome Patients in the Greek Acute Coronary Syndrome (GREECS) Longitudinal Study. AB - OBJECTIVES: The association between educational status and 10-year risk for acute coronary syndrome (ACS) and all-cause mortality was evaluated. METHODS: From October 2003 to September 2004, 2172 consecutive ACS patients from six Greek hospitals were enrolled. In 2013 to 2014, a 10-year follow-up (2004-2014) assessment was performed for 1918 participants (participation rate, 88%). Each patient's educational status was classified as low (<9 years of school), intermediate (9 to 14 years), or high (>14 years). RESULTS: Overall all-cause mortality was almost twofold higher in the low-education group than in the intermediate-education and high-education groups (40% vs. 22% and 19%, respectively, p<0.001). Additionally, 10-year recurrent ACS events (fatal and non fatal) were more common in the low-education group than in the intermediate education and high-education groups (42% vs. 30% and 35%, p<0.001), and no interactions between sex and education on the investigated outcomes were observed. Moreover, patients in the high-education group were more physically active, had a better financial status, and were less likely to have hypertension, diabetes, or ACS than the participants with the least education (p<0.001); however, when those characteristics and lifestyle habits were accounted for, no moderating effects regarding the relationship of educational status with all cause mortality and ACS events were observed. CONCLUSIONS: A U-shaped association may be proposed for the relationship between ACS prognosis and educational status, with participants in the low-education and high-education groups being negatively affected by other factors (e.g., job stress, depression, or loneliness). Public health policies should be aimed at specific social groups to reduce the overall burden of cardiovascular disease morbidity. PMID- 27499165 TI - The Effect of Geographic Units of Analysis on Measuring Geographic Variation in Medical Services Utilization. AB - OBJECTIVES: We aimed to evaluate the effect of geographic units of analysis on measuring geographic variation in medical services utilization. For this purpose, we compared geographic variations in the rates of eight major procedures in administrative units (districts) and new areal units organized based on the actual health care use of the population in Korea. METHODS: To compare geographic variation in geographic units of analysis, we calculated the age-sex standardized rates of eight major procedures (coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, surgery after hip fracture, knee replacement surgery, caesarean section, hysterectomy, computed tomography scan, and magnetic resonance imaging scan) from the National Health Insurance database in Korea for the 2013 period. Using the coefficient of variation, the extremal quotient, and the systematic component of variation, we measured geographic variation for these eight procedures in districts and new areal units. RESULTS: Compared with districts, new areal units showed a reduction in geographic variation. Extremal quotients and inter-decile ratios for the eight procedures were lower in new areal units. While the coefficient of variation was lower for most procedures in new areal units, the pattern of change of the systematic component of variation between districts and new areal units differed among procedures. CONCLUSIONS: Geographic variation in medical service utilization could vary according to the geographic unit of analysis. To determine how geographic characteristics such as population size and number of geographic units affect geographic variation, further studies are needed. PMID- 27499166 TI - Food Security in Households of People Living With Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome: A Cross-sectional Study in a Subdivision of Darjeeling District, West Bengal. AB - OBJECTIVES: Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) adversely impacts food security in households of people living with HIV/AIDS (PLWHA). Little research has focused on food insecurity among PLWHA in India. The purpose of this study was to identify the prevalence of and factors relating to food security in households of PLWHA in the Siliguri subdivision of Darjeeling, West Bengal, India. METHODS: A cross-sectional community-based study was carried out among 173 PLWHA residing in Siliguri and registered at the Anti retroviral Therapy Centre of North Bengal Medical College & Hospital. Data was collected at the household level with interviews of PLWHA using a food security survey instrument. We analyzed the associations using logistic regression. RESULTS: The prevalence of household food security among the participants was 50.9% (88/173). Five years or more of schooling, higher socioeconomic class and males were found to be significantly associated with a higher likelihood of food security. A later stage of the disease and the presence of other family members with HIV/AIDS were significantly associated with a lower likelihood of food security. The major coping strategies to deal with food insecurity in the acute phase HIV infection included borrowing money (56.1%), followed by spousal support, loans from microfinance institutions, banks, or money lenders, borrowing food, or selling agricultural products. CONCLUSIONS: The present study revealed that only about half of households with PLWHA were food secure. Prior interventions relating to periods of food and economic crisis as well as strategies for sustaining food security and economic status are needed in this area. PMID- 27499167 TI - Use of Protective Gloves in Nail Salons in Manhattan, New York City. AB - OBJECTIVES: Nail salon owners in New York City (NYC) are required to provide their workers with gloves and it is their responsibility to maintain healthy, safe working spaces for their employees. The purpose of this study was to determine the frequency with which nail salon workers wear protective gloves. METHODS: A Freedom of Information Law request was submitted to New York Department of State's Division of Licensing Services for a full list of nail salons in Manhattan, NYC. A sample population of 800 nail salons was identified and a simple random sample (without replacement) of 30% (n=240) was selected using a random number generator. Researchers visited each nail salon from October to December of 2015, posing as a potential customer to determine if nail salon workers were wearing gloves. RESULTS: Among the 169 salons in which one or more workers was observed providing services, a total of 562 workers were observed. For 149 salons, in which one or more worker was observed providing services, none of the workers were wearing gloves. In contrast, in six of the salons observed, in which one or more workers was providing services, all of the workers (1 in 2 sites, 2 in 1 site, 3 in 2 sites, and 4 in 1 site) were wearing gloves. Almost three-quarters of the total number of workers observed (n=415, 73.8%) were not wearing gloves. CONCLUSIONS: The findings of this study indicate that, despite recent media attention and legislation, the majority of nail salon workers we observed were not wearing protective gloves when providing services. PMID- 27499168 TI - A pivotal role of vacuolar H(+)-ATPase in regulation of lipid production in Phaeodactylum tricornutum. AB - Microalgal lipids have been considered as a promising source for biodiesel production. Alkaline pH can induce neutral lipid accumulation in microalgae cells. However, whether and how proton pumps, especially vacuolar H(+)-ATPase (V ATPase), function in these processes is not well known. In this study, we treated Phaeodactylum tricornutum with V-ATPase specific inhibitor bafilomycin A1 (BFA1) to determine its role in lipid production. Firstly, V-ATPase activity was increased in the latter phase of microalgae growth. BFA1 treatment decreased the cell density and lipid contents. Further analysis showed that BFA1 treatment reduced the number and size of oil bodies. GC-MS analysis showed that lipid components were not affected by BFA1 treatment. Intracellular pH was decreased and nitrogen depletion was delayed after BFA1 treatment. RNA-Seq analysis showed that expression of genes involved in calcium signaling, sulfur metabolism, cell cycle, glycolysis, pentose phosphate pathway, porphyrin, chlorophyll metabolism and lipid catabolic metabolism were upregulated, while expression of genes involved in ion transmembrane transport, ubiquitin mediated proteolysis, SNARE interactions in vesicular transport, fatty acid biosynthesis were downregulated under BFA1 treatment. Our findings provided insights into the molecular mechanisms underlying lipid accumulation and the key genes involved in lipid metabolism in Phaeodactylum tricornutum in response to BFA1. PMID- 27499170 TI - An annulative transfer hydrogenation strategy enables straightforward access to tetrahydro fused-pyrazine derivatives. AB - A ruthenium-catalysed annulative transfer hydrogenation strategy, enabling straightforward access to tetrahydro fused-pyrazine derivatives from N-heteroaryl diamines and vicinal diols, has been demonstrated for the first time. Such a synthesis proceeds with unprecedented synthetic effectiveness including high step and atom efficiency, generation of water as the sole by-product, short reaction time and no need for external high pressure H2 gas, offering an important basis for the transformation of vicinal diols, a class of bio-mass derived resources, into functionalized products. PMID- 27499169 TI - Efficient shortcuts to adiabatic passage for three-dimensional entanglement generation via transitionless quantum driving. AB - We propose an effective scheme of shortcuts to adiabaticity for generating a three-dimensional entanglement of two atoms trapped in a cavity using the transitionless quantum driving (TQD) approach. The key point of this approach is to construct an effective Hamiltonian that drives the dynamics of a system along instantaneous eigenstates of a reference Hamiltonian to reproduce the same final state as that of an adiabatic process within a much shorter time. In this paper, the shortcuts to adiabatic passage are constructed by introducing two auxiliary excited levels in each atom and applying extra cavity modes and classical fields to drive the relevant transitions. Thereby, the three-dimensional entanglement is obtained with a faster rate than that in the adiabatic passage. Moreover, the influences of atomic spontaneous emission and photon loss on the fidelity are discussed by numerical simulation. The results show that the speed of entanglement implementation is greatly improved by the use of adiabatic shortcuts and that this entanglement implementation is robust against decoherence. This will be beneficial to the preparation of high-dimensional entanglement in experiment and provides the necessary conditions for the application of high dimensional entangled states in quantum information processing. PMID- 27499171 TI - Valence-force model and nanomechanics of single-layer phosphorene. AB - In order to understand the relation of strain and material properties, both a microscopic model connecting a given strain to the displacement of atoms, and a macroscopic model relating applied stress to induced strain, are required. Starting from a valence-force model for black phosphorous [Kaneta et al., Solid State Communications, 1982, 44, 613] we use recent experimental and computational results to obtain an improved set of valence-force parameters for phosphorene. From the model we calculate the phonon dispersion and the elastic properties of single-layer phosphorene. Finally, we use these results to derive a complete continuum model, including the bending rigidities, valid for long-wavelength deformations of phosphorene. This continuum model is then used to study the properties of pressurized suspended phosphorene sheets. PMID- 27499173 TI - A technical application of quantitative next generation sequencing for chimerism evaluation. AB - At present, the most common genetic diagnostic method for chimerism evaluation following hematopoietic stem cell transplantation is microsatellite analysis by capillary electrophoresis. The main objective was to establish, through repeated analysis over time, if a complete chimerism was present, or if the mixed chimerism was stable, increasing or decreasing over time. Considering the recent introduction of next generation sequencing (NGS) in clinical diagnostics, a detailed study evaluating an NGS protocol was conducted, coupled with a custom bioinformatics pipeline, for chimerism quantification. Based on the technology of Ion AmpliSeq, a 44-amplicon custom chimerism panel was designed, and a custom bioinformatics pipeline dedicated to the genotyping and quantification of NGS data was coded. The custom chimerism panel allowed identification of an average of 16 informative recipient alleles. The limit of detection of the protocol was fixed at 1% due to the NGS background (<1%). The protocol followed the standard Ion AmpliSeq library preparation and Ion Torrent Personal Genome Machine guidelines. Overall, the present study added to the scientific literature, identifying novel technical details for a possible future application of NGS for chimerism quantification. PMID- 27499174 TI - A Comparison of Single-Molecule Emission in Aluminum and Gold Zero-Mode Waveguides. AB - The effect of gold and aluminum zero-mode waveguides (ZMWs) on the brightness of immobilized single emitters was characterized by probing fluorophores that absorb in the green and red regions of the visible spectrum. Aluminum ZMWs enhance the emission of Atto565 fluorophores upon green excitation, but they do not enhance the emission of Atto647N fluorophores upon red excitation. Gold ZMWs increase emission of both fluorophores with Atto647N showing enhancement that is threefold higher than that observed for Atto565. This work indicates that 200 nm gold ZMWs are better suited for single-molecule fluorescence studies in the red region of the visible spectrum, while aluminum appears more suited for the green region of the visible spectrum. PMID- 27499175 TI - Accumulation of microcystins in a dominant Chironomid Larvae (Tanypus chinensis) of a large, shallow and eutrophic Chinese lake, Lake Taihu. AB - Although there have been numerous studies on microcystin (MC) accumulation in aquatic organisms recently, the bioaccumulation of MCs in relatively small sized organisms, as well as potential influencing factors, has been rarely studied. Thus, in this study, we investigated the bioaccumulation of three MC congeners ( LR, -RR and -YR) in the chironomid larvae of Tanypus chinensis (an excellent food source for certain fishes), the potential sources of these MCs, and potentially relevant environmental parameters over the course of one year in Lake Taihu, China. MC concentrations in T. chinensis varied temporally with highest concentrations during the warmest months (except August 2013) and very low concentrations during the remaining months. Among the three potential MC sources, only intracellular MCs were significantly and positively correlated with MCs in T. chinensis. Although MC concentrations in T. chinensis significantly correlated with a series of physicochemical parameters of water column, cyanobacteria species explained the most variability of MC accumulation, with the rest primarily explained by extraMC-LR. These results indicated that ingestion of MC producing algae of cyanobacteria accounted for most of the MC that accumulated in T. chinensis. The high MC concentrations in T. chinensis may pose a potential health threat to humans through trophic transfer. PMID- 27499176 TI - Internal medicine network: Is it a newsworthy idea? PMID- 27499172 TI - The molecular mechanisms of action of PPAR-gamma agonists in the treatment of corneal alkali burns (Review). AB - Corneal alkali burns (CAB) are characterized by injury-induced inflammation, fibrosis and neovascularization (NV), and may lead to blindness. This review evaluates the current knowledge of the molecular mechanisms responsible for CAB. The processes of cytokine production, chemotaxis, inflammatory responses, immune response, cell signal transduction, matrix metalloproteinase production and vascular factors in CAB are discussed. Previous evidence indicates that peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists suppress immune responses, inflammation, corneal fibrosis and NV. This review also discusses the role of PPAR-gamma as an anti-inflammatory, anti-fibrotic and anti angiogenic agent in the treatment of CAB, as well as the potential role of PPAR gamma in the pathological process of CAB. There have been numerous studies evaluating the clinical profiles of CAB, and the aim of this systematic review was to summarize the evidence regarding the treatment of CAB with PPAR-gamma agonists. PMID- 27499177 TI - Marijuana users do not have increased healthcare utilization: A National Health and Nutrition Examination Survey (NHANES) study. PMID- 27499178 TI - Long-term clinical outcome of elderly patients with acute coronary syndrome treated with early percutaneous coronary intervention: Insights from the BASE ACS randomized controlled trial: Bioactive versus everolimus-eluting stents in elderly patients. AB - BACKGROUND: The BASE ACS trial demonstrated an outcome of titanium-nitride-oxide coated bioactive stents (BAS) that was non-inferior to everolimus-eluting stents (EES) in patients presenting with acute coronary syndrome (ACS). We performed a post hoc analysis of elderly versus non-elderly patients from the BASE ACS trial. METHODS: We randomized 827 patients (1:1) presenting with ACS to receive either BAS or EES. The primary endpoint was major adverse cardiac events (MACE): a composite of cardiac death, non-fatal myocardial infarction (MI), or ischemia driven target lesion revascularization (TLR). Follow-up was planned at 12months and yearly thereafter for up to 7years. Elderly age was defined as >=65years. RESULTS: Of the 827 patients enrolled in the BASE ACS trial, 360 (43.5%) were elderly. Mean follow-up duration was 4.2+/-1.9years. MACE was more frequent in elderly versus younger patients (19.7% versus 12.0%, respectively, p=0.002), probably driven by more frequent cardiac death and non-fatal MI events (5.3% versus 1.5%, and 9.7% versus 4.5%, p=0.002 and p=0.003, respectively). The rates of ischemia-driven TLR were comparable (p>0.05). In propensity score-matched analysis (215 pairs), only cardiac death was more frequent in elderly patients (6% versus 1.4%, respectively, p=0.01). Diabetes independently predicted both MACE and cardiac death in elderly patients. CONCLUSIONS: Elderly patients treated with stent implantation for ACS had worse long-term clinical outcome, compared with younger ones, mainly due to a higher death rate. PMID- 27499179 TI - "From father to son": Early onset gout in Guidobaldo I da Montefeltro, Duke of Urbino (1472-1508). PMID- 27499180 TI - The Minimum Basic Data Set (MBDS) as a tool for cancer epidemiological surveillance. AB - OBJECTIVE: This work aims to evaluate the Minimum Basic Data Set (MBDS) as a data source in the detection of malignant tumors and explore its usefulness as a tool for epidemiological surveillance of cancer. MATERIALS AND METHODS: MBDS hospital data discharge from Prince of Asturias University Hospital (HUPA, Alcala de Henares, Madrid, Spain) and cancer cases recorded in the Hospital Cancer Registry (HCR) have been collected for the period between January 2012 and June 2014. Both databases have been linked by the number of clinical history. For the process of evaluation of MBDS, the types of cancer with more than 100 cases have been analyzed and sensitivity, specificity, positive and negative predictive values(PPV, NPV) of MBDS were calculated using as reference the diagnoses recorded in the HCR. RESULTS: 3438 cases of cancer were accounted in the MBDS and 2445 in the HCR. The MBDS has a sensitivity to detect cases of cancer above 60%, although it varies depending on the type of tumor, reaching the highest values for bladder cancer. The specificity and the VPN were very high for all types of cancer studied, always on top of 95%. Finally, the VPP is generally moderate, between 50% and 70%. CONCLUSIONS: The systematic exploitation of the MBDS can provide a valuable tool in the monitoring of cancer by its acceptable sensitivity and high specificity, allowing obtaining information without the delays involved in the consolidation of the annotations of the HCR. Furthermore, its use could partly mitigate the lack of data in important regions of Spain. PMID- 27499181 TI - PTK7 overexpression in colorectal tumors: Clinicopathological correlation and prognosis relevance. AB - Colorectal cancer (CRC) has one of the highest mortality rates in the worldwide and its incidence has been increasing in recent years. Protein tyrosine kinase-7 (PTK7) is an inactive member of receptor protein tyrosine kinase (RPTK)-like molecules, which is involved in tumorigenesis of a variety of cancers. Our study aimed to investigate expression of PTK7 in colorectal tumors (including benign adenomas and malignant carcinomas), and its potential function in tumorigenesis and prognosis. A total of 209 CRC patients and 28 colonic adenoma patients were included in this study. Reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time PCR were performed in 14 pairs of fresh frozen tissues to evaluate mRNA expression of PTK7. Expression of PTK7 protein in 209 CRC tissues with paired non-cancerous mucosa and 28 adenoma specimens were tested using immunohistochemistry. The expression difference and its correlation with clinicopathological features and overall survival were assessed by SPSS statistics (version 22). P<0.05 was considered significant. RT-PCR and quantitative real-time PCR showed a higher expression of PTK7 mRNA in CRC compared with non-tumorous mucosa (4.87+/-3.71 vs. 1.33+/-1.05; P<0.001). PTK7 expression was significantly higher in adenoma (75%) and CRC (68.3%) than in non tumorous mucosa (P<0.001). PTK7 expression was correlated with tumor differentiation (P=0.027), lymph node metastasis (P=0.005), distant metastasis (P=0.001) and TNM stage (P=0.028) of CRC patients. Significant correlation between PTK7 overexpression and favorable overall survival of CRC patients was observed (P=0.005). Therefore, it may act as a candidate biomarker to predict the occurrence and prognosis of colorectal tumor. PMID- 27499182 TI - Severe Babesia microti infection in an American immunocompetent patient diagnosed in Spain. AB - We report a severe Babesia microti infection in an immunocompetent patient diagnosed in Spain. A 66-year-old woman coming from USA presented with fever, thrombocytopenia, and multiorgan failure. Intraerythrocytic parasites were observed in Giemsa-stained peripheral blood smears and B. microti was first suspected by optical microscopy and afterward confirmed by specific polymerase chain reaction (PCR). Patient received antibiotic therapy, vital support measures and one red blood cell (RBC) exchange procedure. After 15 days, patient recovered and she was transferred to her reference hospital. This case report highlights the importance of clinical suspicion by physicians in non-endemic areas to diagnose this entity, the differential diagnosis with malaria infection, and the indication of RBC exchange as a therapeutic apheresis modality in the management of severe forms. PMID- 27499183 TI - Are prions transported by plasma exosomes? AB - Blood has been shown to contain disease-associated misfolded prion protein (PrP(TSE)) in animals naturally and experimentally infected with various transmissible spongiform encephalopathy (TSE) agents, and in humans infected with variant Creutzfeldt-Jakob disease (vCJD). Recently, we have demonstrated PrP(TSE) in extracellular vesicle preparations (EVs) containing exosomes from plasma of mice infected with mouse-adapted vCJD by Protein Misfolding Cyclic Amplification (PMCA). Here we report the detection of PrP(TSE) by PMCA in EVs from plasma of mice infected with Fukuoka-1 (FU), an isolate from a Gerstmann-Straussler Scheinker disease patient. We used Tga20 transgenic mice that over-express mouse cellular prion protein, to assay by intracranial injections the level of infectivity in a FU-infected brain homogenate from wild-type mice (FU-BH), and in blood cellular components (BCC), consisting of red blood cells, white blood cells and platelets, plasma EVs, and plasma EVs subjected to multiple rounds of PMCA. Only FU-BH and plasma EVs from FU-infected mice subjected to PMCA that contained PrP(TSE) transmitted disease to Tga20 mice. Plasma EVs not subjected to PMCA and BCC from FU-infected mice failed to transmit disease. These findings confirm the high sensitivity of PMCA for PrP(TSE) detection in plasma EVs and the efficiency of this in vitro method to produce highly infectious prions. The results of our study encourage further research to define the role of EVs and, more specifically exosomes, as blood-borne carriers of PrP(TSE). PMID- 27499184 TI - Competing Orders and Anomalies. AB - A conservation law is one of the most fundamental properties in nature, but a certain class of conservation "laws" could be spoiled by intrinsic quantum mechanical effects, so-called quantum anomalies. Profound properties of the anomalies have deepened our understanding in quantum many body systems. Here, we investigate quantum anomaly effects in quantum phase transitions between competing orders and striking consequences of their presence. We explicitly calculate topological nature of anomalies of non-linear sigma models (NLSMs) with the Wess-Zumino-Witten (WZW) terms. The non-perturbative nature is directly related with the 't Hooft anomaly matching condition: anomalies are conserved in renormalization group flow. By applying the matching condition, we show massless excitations are enforced by the anomalies in a whole phase diagram in sharp contrast to the case of the Landau-Ginzburg-Wilson theory which only has massive excitations in symmetric phases. Furthermore, we find non-perturbative criteria to characterize quantum phase transitions between competing orders. For example, in 4D, we show the two competing order parameter theories, CP(1) and the NLSM with WZW, describe different universality class. Physical realizations and experimental implication of the anomalies are also discussed. PMID- 27499185 TI - Serological evidence of infection with rodent-borne hepatitis E virus HEV-C1 or antigenically related virus in humans. AB - Zoonotic potential of a rat-derived hepatitis E virus (HEV), designated as HEV C1, remains unknown. To evaluate the risk for HEV-C1 infection in humans, paired sera of 208 hospitalized febrile patients collected from 2001 to 2003 in Hanoi, Vietnam, were examined for IgG antibodies to HEV-C1 and genotype 1 HEV (HEV-1), which is common in humans. IgG antibodies to virus-like particles (VLPs) of HEV C1 and/or HEV-1 were detected from 99 of the 208 convalescent sera in enzyme linked immunosorbent assay (ELISA). IgG antibody titers to HEV-C1 antigen in 3 of the 99 sera were more than 8-fold higher than those to HEV-1 antigen. IgM antibodies to HEV-C1 antigen were detected in acute sera from 2 of the 3 patients in ELISA and Western blotting. However, no HEV genome was detected. Clinical information was available for 1 of the 2 patients. Hepatic enzymes, aspartate aminotransferase and alanine aminotransferase, were mildly elevated (156 IU/l and 68 IU/l, respectively), and hepatomegaly was detected by ultrasonography. The patient recovered from the illness after 17 days. These results indicated that HEV-C1 or its variants infect humans in Vietnam and may cause acute febrile illness with mild liver dysfunction. PMID- 27499186 TI - Marked Sexual Dimorphism in the Role of the Ryanodine Receptor in a Model of Pain Chronification in the Rat. AB - Hyperalgesic priming, an estrogen dependent model of the transition to chronic pain, produced by agonists at receptors that activate protein kinase C epsilon (PKCepsilon), occurs in male but not in female rats. However, activation of second messengers downstream of PKCepsilon, such as the ryanodine receptor, induces priming in both sexes. Since estrogen regulates intracellular calcium, we investigated the interaction between estrogen and ryanodine in the susceptibility to develop priming in females. The lowest dose of ryanodine able to induce priming in females (1 pg) is 1/100,000(th) that needed in males (100 ng), an effect dependent on the activation of ryanodine receptors. Treatment of female rats with antisense to estrogen receptor alpha (ERalpha), but not beta (ERbeta), mRNA, prevented the induction of priming by low dose ryanodine, and the ERalpha agonist, PPT, induced ryanodine receptor-dependent priming. In vitro application of ryanodine in low concentration (2 nM) to small DRG neurons cultured from females, significantly potentiated calcium release via ryanodine receptors induced by caffeine. This effect was only observed in IB4+ neurons, cultured in the presence of beta-estradiol or PPT. Our results demonstrate a profound regulatory role of ERalpha in ryanodine receptor-dependent transition to chronic pain. PMID- 27499187 TI - Clustering of adherence to personalised dietary recommendations and changes in healthy eating index within the Food4Me study. AB - OBJECTIVE: To characterise clusters of individuals based on adherence to dietary recommendations and to determine whether changes in Healthy Eating Index (HEI) scores in response to a personalised nutrition (PN) intervention varied between clusters. DESIGN: Food4Me study participants were clustered according to whether their baseline dietary intakes met European dietary recommendations. Changes in HEI scores between baseline and month 6 were compared between clusters and stratified by whether individuals received generalised or PN advice. SETTING: Pan European, Internet-based, 6-month randomised controlled trial. SUBJECTS: Adults aged 18-79 years (n 1480). RESULTS: Individuals in cluster 1 (C1) met all recommended intakes except for red meat, those in cluster 2 (C2) met two recommendations, and those in cluster 3 (C3) and cluster 4 (C4) met one recommendation each. C1 had higher intakes of white fish, beans and lentils and low-fat dairy products and lower percentage energy intake from SFA (P<0.05). C2 consumed less chips and pizza and fried foods than C3 and C4 (P<0.05). C1 were lighter, had lower BMI and waist circumference than C3 and were more physically active than C4 (P<0.05). More individuals in C4 were smokers and wanted to lose weight than in C1 (P<0.05). Individuals who received PN advice in C4 reported greater improvements in HEI compared with C3 and C1 (P<0.05). CONCLUSIONS: The cluster where the fewest recommendations were met (C4) reported greater improvements in HEI following a 6-month trial of PN whereas there was no difference between clusters for those randomised to the Control, non-personalised dietary intervention. PMID- 27499188 TI - Human behaviors elevating the risk of exposure to Ixodes ricinus larvae and nymphs in two types of lowland coniferous forests in west-central Poland. AB - Ixodes ricinus L. is the commonest tick encountered by humans in Central Europe and the most important vector of tick-borne diseases (TBD) in Europe. Foresters represent a group at elevated risk of exposure to I. ricinus throughout Europe. Here, we employed an experimental design similar to one used previously to determine what behavioral factors heighten exposure to questing Ixodes pacificus nymphs in a hardwood forest in the far-western United States. Five activities were evaluated systematically in a coniferous forest and a mixed broadleaved forest in west-central Poland: (i) walking in low-cut running shoes; (ii) sitting atop logs; (iii) sitting on leaf litter; (iv) sitting against tree trunks; and (v) gathering firewood. In total, 540 I. ricinus ticks were collected (198 larvae, 327 nymphs, 15 adults) in spring and late summer. Many more ticks were collected in spring than in late summer, and in the mixed broadleaved forest versus the coniferous forest. The riskiest behavior for acquiring nymphs in both spring and late summer was gathering firewood, though sitting atop logs was nearly as perilous in late summer. In contrast, the riskiest behaviors for encountering larvae in spring and late summer were sitting against trunks and sitting on leaf litter, respectively. Pairwise comparisons revealed only two significant associations among the variables explored for the nymphs: season and human gender, and season and type of forest. For larval ticks, the most significant associations were gender and sitting behaviors and for type of forest and sitting on leaf litter or against tree trunks. The most commonly infested body region was the lower legs. PMID- 27499189 TI - Physiological Proteins in Therapeutics: A Current Review on Interferons. AB - Interferons are produced in vivo and are one of the prime components of natural defense system of animals. They are released by the viral infected cells and provide protection to the neighboring cells against viral infection. The cyto protective property of the proteins ignited the thought of their pharmaceutical adaptation for therapeutic use against viral diseases in individuals in whom the interferons released naturally are not sufficient to combat the situation. Interferon supplements have been found to complement various antiviral drugs. Considering the efficacy of interferons in regulating angiogenesis and immunomodulation, they can be adapted for therapy of the killer diseases like cancer and AIDS. We have come ahead more than twenty five years after the approval of clinical use of interferon as drugs and are today really in a position to promise a disease free life to our present and next generation. Interferon therapy will be contributing a big share to the upcoming remedies for the new diseases and we are thus armed to fight back the deadly viral threats. Interferons have been modified [pegylated etc.] and have already been adapted to some extent in certain diseases and are in regular use in some. Thus interferons if modified as per need and used in combination with either antiviral drugs, antibiotics, antioxidants may strengthen our defense system effectively to bring about a strong protection against wide range of diseases. PMID- 27499190 TI - Glycosylation and Activities of Natural Products. AB - Natural products are widely found in nature, their number and variety are numerous, the structures are complex and diverse. These natural products have many physiological and pharmacological activities. Glycosylation can increase the diversity of structure and function of natural product, it has become the focus of drug research and development. The impacts of glycosylation of natural products to water solubility, pharmacological activities, bioavailability, or others were described in this review, which provides a reference for the development and application of glycosylated natural products. PMID- 27499191 TI - Prospective observational study on central line-associated bloodstream infections and central venous catheter occlusions using a negative displacement connector with an alcohol disinfecting cap. AB - BACKGROUND: Major complications of central venous catheter (CVC) use include bloodstream infection and occlusion. We performed a prospective, observational study to determine the rate of central line-associated bloodstream infection (CLABSI) and CVC occlusion using a negative displacement connector with an alcohol disinfecting cap. METHODS: Patients were followed from the time of CVC insertion through 2 days after removal, at the time of hospital discharge if there was no documentation of removal, or 90 days after the insertion of the CVC if it was not removed. CLABSI was defined using National Healthcare Safety Network criteria. Data for evidence of lumen occlusions were extracted from the electronic health record. Direct observations were performed to assess adherence to hospital policy regarding CVC insertion practice. RESULTS: A total of 2,512 catheters from 2,264 patients were enrolled for this study. There were 21 CLABSIs (0.84%; 95% confidence interval [CI], 0.48%-1.19%; 0.62 per 1,000 line days) and 378 occlusions (15.05%; 95% CI, 13.65%-16.45%; 11.23 per 1,000 line days). Eighty five direct observations demonstrated insertion protocol adherence in 881 of 925 (95.24%; 95% CI, 93.87%-96.61%) measured criteria. CONCLUSIONS: Lines placed following a standardized protocol using a negative displacement connector with an alcohol cap have low rates of infection compared with historically published findings. We also established that the occlusion rate is >15-fold the CLABSI rate. PMID- 27499192 TI - Association between chronic hemodialysis and bloodstream infections caused by chromosomally mediated AmpC-producing Enterobacteriaceae. AB - BACKGROUND: The combination of inherent antimicrobial resistance and high mortality after bloodstream infections (BSIs) caused by chromosomally mediated AmpC-producing Enterobacteriaceae (CAE) emphasizes the importance of identifying patients at risk of BSI because of these bacteria. This retrospective case control study examines chronic hemodialysis among other risk factors for BSI caused by CAE. METHODS: Hospitalized adults with Enterobacteriaceae BSI from January 1, 2010-June 30, 2014, at 2 large community hospitals in the Southeastern United States were identified. Multivariate logistic regression was used to examine risk factors for CAE BSI. RESULTS: Among 831 Enterobacteriaceae bloodstream isolates, 106 (13%) met the phenotypic definition of CAE. Enterobacter spp accounted for 47% (50/106) of CAE BSIs. Chronic hemodialysis was an independent risk factor for CAE BSI (adjusted odds ratio [aOR], 2.34; 95% confidence interval [CI], 1.21-4.44). Other predictors of CAE BSI included nosocomial acquisition (aOR, 1.72; 95% CI, 1.02-2.87) and exposure to beta-lactam antibiotics within the last 30 days (aOR, 2.39; 95% CI, 1.37-4.14). CONCLUSIONS: To our knowledge, this is the first study to demonstrate an increased risk of CAE BSI in patients with end-stage renal disease undergoing chronic hemodialysis. This highlights the importance of effective infection prevention and antimicrobial stewardship interventions in hemodialysis clinics. Further studies to examine the impact of antibiotics on intestinal microbiota and rates of CAE colonization in this patient population are warranted. PMID- 27499193 TI - Ebola: Emergency preparedness and perceived response of Malaysian health care providers. AB - We studied the emergency preparedness and perceived response for Ebola virus disease among various health care providers in Malaysia using a self-report questionnaire. Most of the health care providers felt that they were able to respond to Ebola virus disease and were aware of the level of preparedness needed during emergency. PMID- 27499194 TI - Knowledge, source of information, and perception of Portuguese medical students and junior doctors of infection control precautions. AB - Medical education should include infection control precautions (ICPs). Portuguese medical students showed reasonable knowledge in ICPs; however, contact isolation and glove and mask use should be reinforced. Only 25% referred to the curriculum as the most important information source. There was a positive association between academic year (P = .032), previous training in ICPs (P = .016), and knowledge. Main strategies proposed to acquire competences in ICPs were bedside teaching (26.9%) and curriculum and bedside teaching (20.2%). PMID- 27499195 TI - Control of an outbreak of postoperative bone mucormycosis: An intervention study of contiguous cohorts. AB - An outbreak of postoperative bone mucormycosis following arthroscopic anterior cruciate ligament reconstruction in a tertiary referral center in Parana, Argentina, could have been transmitted through an arthroscopic anterior cruciate ligament reconstruction-exclusive contaminated item. The outbreak was controlled after changing from a system of direct delivery of implants and instruments to the operating room without proper verification, to a controlled and centralized process; specifically, the institution's pharmacy verified the quality and traceability of implants, and instruments were processed only by the institution's central sterile services department. PMID- 27499196 TI - Isolation and evaluation of proteolytic actinomycete isolates as novel inducers of pearl millet downy mildew disease protection. AB - Native endophytic actinomycetes isolated from pearl millet roots were examined for their efficacy to protect pearl millet against downy mildew. Nineteen of 39 isolates were found to be proteolytic, of which 7 strains could directly suppress the sporangium formation of Sclerospora graminicola, the pearl millet downy mildew pathogen. Thus, mycelial suspensions containing either spores or cell-free extract of these 7 isolates were used for seed-coating and -soaking treatments to test for their induction of downy mildew resistance. Results indicated that seed coating overall provided better protection to downy mildew than seed-soaking. In both treatments, the tested isolates demonstrated differential abilities in downy mildew disease protection, with Streptomyces griseus SJ_UOM-07-09 and Streptosporangium roseum SJ_UOM-18-09 showing the highest protection rates. Additionally, the levels of disease protection conferred by the actinomycetes were just slightly lower than that of the systemic fungicide Apron, suggesting their effectiveness. Further studies revealed that the more rapid root colonization by SJ_UOM-18-09 resulted in faster and higher induced resistance in comparison with SJ_UOM-07-09 under greenhouse conditions, indicating that SJ_UOM 18-09 was superior than SJ_UOM-07-09 in inducing resistance. Results from this study provide comprehensive information on biocontrol functions of SJ_UOM- 18-09 with great potential to control downy mildew disease in pearl millet. PMID- 27499197 TI - Legal protection of the right to work and employment for persons with mental health problems: a review of legislation across the world. AB - The right to work and employment is indispensable for social integration of persons with mental health problems. This study examined whether existing laws pose structural barriers in the realization of right to work and employment of persons with mental health problems across the world. It reviewed disability specific, human rights legislation, and labour laws of all UN Member States in the context of Article 27 of the UN Convention on the Rights of Persons with Disabilities (CRPD). It wes found that laws in 62% of countries explicitly mention mental disability/impairment/illness in the definition of disability. In 64% of countries, laws prohibit discrimination against persons with mental health during recruitment; in one-third of countries laws prohibit discontinuation of employment. More than half (56%) the countries have laws in place which offer access to reasonable accommodation in the workplace. In 59% of countries laws promote employment of persons with mental health problems through different affirmative actions. Nearly 50 years after the adoption of the International Covenant on Economic, Social, and Cultural Rights and 10 years after the adoption of CRPD by the UN General Assembly, legal discrimination against persons with mental health problems continues to exist globally. Countries and policy-makers need to implement legislative measures to ensure non-discrimination of persons with mental health problems during employment. PMID- 27499198 TI - Dynamics of ionic liquids in bulk and in confinement by means of (1)H NMR relaxometry - BMIM-OcSO4 in an SiO2 matrix as an example. AB - (1)H nuclear magnetic resonance relaxometry is applied to reveal information on the translational and rotational dynamics of the ionic liquid: 1-butyl-3-methyl imidazoliumoctyl sulfate (BMIM-OcSO4) in bulk and in a confinement formed by a nanoporous SiO2 matrix. The experimental studies were performed in a very broad frequency range, from 8 kHz to 40 MHz (referring to the (1)H resonance frequency), in order to probe motional processes at very different time scales using a single experiment, and in the temperature range of 243-303 K. The relaxation results for BMIM-OcSO4 in bulk are interpreted in terms of three relaxation contributions: a term associated with the translational dynamics of the ions (it has been assumed that the translational dynamics of cations and anions can be described by one diffusion coefficient) and two terms associated with the rotational motion of the anion and the cation, respectively. The relationships between the obtained dynamic parameters (rotational correlation times and translational diffusion coefficients) are thoroughly discussed and used as a "reference" for the dynamics of BMIM-OcSO4 confined in an SiO2 matrix. Analysis of the corresponding relaxation data for the confined liquid shows that the confinement does not significantly affect the rotational dynamics, but it has a considerable impact on the translational motion. It is demonstrated that the relaxation term associated with the translational dynamics stems from two contributions: a contribution from a core (bulk-like) fraction of the liquid and from a fraction moving near the pore surface and therefore being for some time adsorbed on the pore walls. The translational diffusion coefficient for the last fraction is determined and several conclusions regarding the residence lifetime of the ions on the surface are drawn. Moreover, an additional motional process on the timescale of ns or shorter is revealed in the confinement. PMID- 27499199 TI - Haemopedia: An Expression Atlas of Murine Hematopoietic Cells. AB - Hematopoiesis is a multistage process involving the differentiation of stem and progenitor cells into distinct mature cell lineages. Here we present Haemopedia, an atlas of murine gene-expression data containing 54 hematopoietic cell types, covering all the mature lineages in hematopoiesis. We include rare cell populations such as eosinophils, mast cells, basophils, and megakaryocytes, and a broad collection of progenitor and stem cells. We show that lineage branching and maturation during hematopoiesis can be reconstructed using the expression patterns of small sets of genes. We also have identified genes with enriched expression in each of the mature blood cell lineages, many of which show conserved lineage-enriched expression in human hematopoiesis. We have created an online web portal called Haemosphere to make analyses of Haemopedia and other blood cell transcriptional datasets easier. This resource provides simple tools to interrogate gene-expression-based relationships between hematopoietic cell types and genes of interest. PMID- 27499200 TI - Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with Kit(Wv) Mutations. AB - In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous Kit(Wv) mutations into C57BL/6.Rag2(null)Il2rg(null) mice with NOD-Sirpa (BRGS) strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34(+)CD38(-) cord blood cells, these newly generated C57BL/6.Rag2(null)Il2rg(null)NOD-Sirpa Kit(Wv/Wv) (BRGSK(Wv/Wv)) mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice. Strikingly, this mouse displayed a robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow. Furthermore, depletion of host macrophages by clodronate administration resulted in the presence of human erythrocytes and platelets in the circulation. Thus, attenuation of mouse KIT signaling greatly enhances the multi-lineage differentiation of human hematopoietic stem and progenitor cells (HSPCs) in mouse bone marrow, presumably by outcompeting mouse HSPCs to occupy suitable microenvironments. The BRGSK(Wv/Wv) mouse model is a useful tool to study human multi-lineage hematopoiesis. PMID- 27499201 TI - A Cas9 Variant for Efficient Generation of Indel-Free Knockin or Gene-Corrected Human Pluripotent Stem Cells. AB - While Cas9 nucleases permit rapid and efficient generation of gene-edited cell lines, the CRISPR-Cas9 system can introduce undesirable "on-target" mutations within the second allele of successfully modified cells via non-homologous end joining (NHEJ). To address this, we fused the Streptococcus pyogenes Cas9 (SpCas9) nuclease to a peptide derived from the human Geminin protein (SpCas9 Gem) to facilitate its degradation during the G1 phase of the cell cycle, when DNA repair by NHEJ predominates. We also use mRNA transfection to facilitate low and transient expression of modified and unmodified versions of Cas9. Although the frequency of homologous recombination was similar for SpCas9-Gem and SpCas9, we observed a marked reduction in the capacity for SpCas9-Gem to induce NHEJ mediated indels at the target locus. Moreover, in contrast to native SpCas9, we demonstrate that transient SpCas9-Gem expression enables reliable generation of both knockin reporter cell lines and genetically repaired patient-specific induced pluripotent stem cell lines free of unwanted mutations at the targeted locus. PMID- 27499203 TI - Applications of N-heterocyclic imines in main group chemistry. AB - The imidazolin-2-imino group is an N-heterocyclic imino functionality that derives from the class of compounds known as guanidines. The exocyclic nitrogen atom preferably bonds to electrophiles and its electron-donating character is markedly enhanced by efficient delocalization of cationic charge density into the five-membered imidazoline ring. Thus, this imino group is an excellent choice for thermodynamic stabilization of electron-deficient species. Due to the variety of available imidazoline-based precursors to this ligand, its steric demand can be tailored to meet the requirements for kinetic stabilization of otherwise highly reactive species. Consequently, it does not come as a surprise that the imidazolin-2-iminato ligand has found widespread applications in transition-metal chemistry to furnish pincer complexes or "pogo stick" type compounds. In comparison, the field of main-group metal compounds of this ligand is still in its infancy; however, it has received growing attention in recent years. A considerable number of electron-poor main-group element species have been described today which are stabilized by N-heterocyclic iminato ligands. These include low-valent metal cations and species that are marked by formerly unknown bonding modes. In this article we provide an overview on the present chemistry of main-group element compounds of the imidazolin-2-iminato ligand, as well as selected examples for the related imidazolidin- and benzimidazolin-2-imino system. PMID- 27499202 TI - Constraints on the Radical Cation Center of Cytochrome c Peroxidase for Electron Transfer from Cytochrome c. AB - The tryptophan 191 cation radical of cytochrome c peroxidase (CcP) compound I (Cpd I) mediates long-range electron transfer (ET) to cytochrome c (Cc). Here we test the effects of chemical substitution at position 191. CcP W191Y forms a stable tyrosyl radical upon reaction with peroxide and produces spectral properties similar to those of Cpd I but has low reactivity toward reduced Cc. CcP W191G and W191F variants also have low activity, as do redox ligands that bind within the W191G cavity. Crystal structures of complexes between Cc and CcP W191X (X = Y, F, or G), as well as W191G with four bound ligands reveal similar 1:1 association modes and heme pocket conformations. The ligands display structural disorder in the pocket and do not hydrogen bond to Asp235, as does Trp191. Well-ordered Tyr191 directs its hydroxyl group toward the porphyrin ring, with no basic residue in the range of interaction. CcP W191X (X = Y, F, or G) variants substituted with zinc-porphyrin (ZnP) undergo photoinduced ET with Cc(III). Their slow charge recombination kinetics that result from loss of the radical center allow resolution of difference spectra for the charge-separated state [ZnP(+), Cc(II)]. The change from a phenyl moiety at position 191 in W191F to a water-filled cavity in W191G produces effects on ET rates much weaker than the effects of the change from Trp to Phe. Low net reactivity of W191Y toward Cc(II) derives either from the inability of ZnP(+) or the Fe-CcP ferryl to oxidize Tyr or from the low potential of the resulting neutral Tyr radical. PMID- 27499205 TI - Cash dieting-calories per dollar: A novel approach to inform food choices? PMID- 27499204 TI - Beta rhythm modulation by speech sounds: somatotopic mapping in somatosensory cortex. AB - During speech listening motor regions are somatotopically activated, resembling the activity that subtends actual speech production, suggesting that motor commands can be retrieved from sensory inputs. Crucially, the efficient motor control of the articulators relies on the accurate anticipation of the somatosensory reafference. Nevertheless, evidence about somatosensory activities elicited by auditory speech processing is sparse. The present work looked for specific interactions between auditory speech presentation and somatosensory cortical information processing. We used an auditory speech identification task with sounds having different place of articulation (bilabials and dentals). We tested whether coupling the auditory task with a peripheral electrical stimulation of the lips would affect the pattern of sensorimotor electroencephalographic rhythms. Peripheral electrical stimulation elicits a series of spectral perturbations of which the beta rebound reflects the return-to baseline stage of somatosensory processing. We show a left-lateralized and selective reduction in the beta rebound following lip somatosensory stimulation when listening to speech sounds produced with the lips (i.e. bilabials). Thus, the somatosensory processing could not return to baseline due to the recruitment of the same neural resources by speech stimuli. Our results are a clear demonstration that heard speech sounds are somatotopically mapped onto somatosensory cortices, according to place of articulation. PMID- 27499206 TI - Predictors of dietary diversity in children ages 6 to 23 mo in largely food insecure area of South Wollo, Ethiopia. AB - OBJECTIVE: The aim of this study was to assess the level and predictors of dietary diversity (DD) in predominantly food-insecure area of South Wollo, Ethiopia among children ages 6 to 23 mo. METHODS: The study was conducted in October 2014. We selected 2080 children using a multistage sampling technique. DD in the preceding day of the survey was assessed with the standard seven-food group score. Predictors of DD were identified via Poisson regression model and the outputs are presented using adjusted incidence rate ratio (IRR) with 95% confidence interval (CI). RESULTS: Only 7% (95% CI, 5.9%-8.1%) of the children met the recommended minimum DD. Child age and maternal knowledge of infant and young child feeding (IYCF) were significant predictors of DD with IRR of 1.027 (95% CI, 1.022-1.032) and 1.026 (95% CI, 1.010-1.043). Households with moderate and severe food insecurity had 9% (95% CI, 3.8-13.9%) and 24.9% (95% CI, 14.6 44%) reduced chance of providing diversified food. Husbands' direct involvement in IYCF increased DD by 13.7% (95% CI, 7.4-20.4). Caregivers who discussed IYCF with health extension workers, participated in cooking demonstrations, and heard radio spots about IYCF in the preceding 3 mo had 11.7% (95% CI, 3.4-20.7%), 18.9% (95% CI, 0.3-40.9%), and 11.4% (95% CI, 4.8-18.4) higher chance of providing diversified food, respectively. Backyard gardening (IRR, 1.088; 95% CI, 1.031 1.148) and number of chickens owned (IRR, 1.011; 95% CI, 1.001-1.021) also were significant predictors. CONCLUSIONS: In predominately food-insecure areas, nutrition education, implementation of nutrition-sensitive agriculture, and husband involvement in IYCF can improve children's DD. PMID- 27499207 TI - Vascular toxicity of silver nanoparticles to developing zebrafish (Danio rerio). AB - Nanoparticles (NPs, 1-100 nm) can enter the environment and result in exposure to humans and other organisms leading to potential adverse health effects. The aim of the present study is to evaluate the effects of early life exposure to polyvinylpyrrolidone-coated silver nanoparticles (PVP-AgNPs, 50 nm), particularly with respect to vascular toxicity on zebrafish embryos and larvae (Danio rerio). Previously published data has suggested that PVP-AgNP exposure can inhibit the expression of genes within the vascular endothelial growth factor (VEGF) signaling pathway, leading to delayed and abnormal vascular development. Here, we show that early acute exposure (0-12 h post-fertilization, hpf) of embryos to PVP AgNPs at 1 mg/L or higher results in a transient, dose-dependent induction in VEGF-related gene expression that returns to baseline levels at hatching (72 hpf). Hatching results in normoxia, negating the effects of AgNPs on vascular development. Interestingly, increased gene transcription was not followed by the production of associated proteins within the VEGF pathway, which we attribute to NP-induced stress in the endoplasmic reticulum (ER). The impaired translation may be responsible for the observed delays in vascular development at later stages, and for smaller larvae size at hatching. Silver ion (Ag(+)) concentrations were < 0.001 mg/L at all times, with no significant effects on the VEGF pathway. We propose that PVP-AgNPs temporarily delay embryonic vascular development by interfering with oxygen diffusion into the egg, leading to hypoxic conditions and ER stress. PMID- 27499208 TI - Iron depletion-induced downregulation of N-cadherin expression inhibits invasive malignant phenotypes in human esophageal cancer. AB - Esophageal carcinomas often have a poor prognosis due to early lymph node metastasis. Epithelial-mesenchymal transition (EMT) is strongly associated with the acquisition of cancer metastasis and invasion. However, there is no established treatment to eliminate the EMT of cancer cells. Iron is an essential element for both normal and cancer cells in humans. Recently, iron depletion has been discovered to suppress tumor growth. Therefore, we hypothesized that decreased iron conditions would regulate EMT phenotypes, as well as suppressing tumor growth. The human TE esophageal cancer cell lines and OE19 were used in our study. Decreased iron conditions were made using an iron-depletion diet in mice and the iron chelator deferasirox for cell studies. Migration and invasion abilities of cells were measured using migration, invasion, and sphere-formation assays. Esophageal subcutaneous tumor growth was suppressed in decreased iron conditions. In vitro study showed that decreased iron conditions inhibited esophageal cancer cell proliferation as well as migration and invasion abilities, with downregulation of N-cadherin expression. Also, migration and invasion abilities were suppressed by inhibiting expression of N-cadherin. In conclusion, decreased iron conditions revealed a profound anticancer effect by the suppression of tumor growth and the inhibition of migration and invasion abilities via N-cadherin. PMID- 27499210 TI - Role of the pectoralis major myofascial flap in preventing pharyngocutaneous fistula following salvage laryngectomy. AB - OBJECTIVE: This study aimed to assess the utility of onlay pectoralis major myofascial flap in preventing pharyngocutaneous fistula following salvage total laryngectomy. METHODS: A retrospective analysis was performed of 172 patients who underwent salvage laryngectomy for recurrent carcinoma of the larynx or hypopharynx between 1999 and 2014. One hundred and ten patients underwent primary closure and 62 patients had pectoralis major myofascial flap onlay. RESULTS: The overall pharyngocutaneous fistula rate was 43 per cent, and was similar in both groups (primary closure group, 43.6 per cent; onlay flap group, 41.9 per cent; p = 0.8). Fistulae in the onlay flap group healed faster: the median and mean fistula duration were 37 and 55 days, respectively, in the primary closure group and 20 and 25 days, respectively, in the onlay flap group (p = 0.008). CONCLUSION: Use of an onlay pectoralis major myofascial flap did not decrease the pharyngocutaneous fistula rate, although fistula duration was shortened. A well designed randomised-controlled trial is needed to establish parameters for its routine use in clinical practice. PMID- 27499209 TI - Dynamic contrast-enhanced MRI detects acute radiotherapy-induced alterations in mandibular microvasculature: prospective assessment of imaging biomarkers of normal tissue injury. AB - Normal tissue toxicity is an important consideration in the continued development of more effective external beam radiotherapy (EBRT) regimens for head and neck tumors. The ability to detect EBRT-induced changes in mandibular bone vascularity represents a crucial step in decreasing potential toxicity. To date, no imaging modality has been shown to detect changes in bone vascularity in real time during treatment. Based on our institutional experience with multi-parametric MRI, we hypothesized that DCE-MRI can provide in-treatment information regarding EBRT induced changes in mandibular vascularity. Thirty-two patients undergoing EBRT treatment for head and neck cancer were prospectively imaged prior to, mid course, and following treatment. DCE-MRI scans were co-registered to dosimetric maps to correlate EBRT dose and change in mandibular bone vascularity as measured by Ktrans and Ve. DCE-MRI was able to detect dose-dependent changes in both Ktrans and Ve in a subset of patients. One patient who developed ORN during the study period demonstrated decreases in Ktrans and Ve following treatment completion. We demonstrate, in a prospective imaging trial, that DCE-MRI can detect dose-dependent alterations in mandibular bone vascularity during chemoradiotherapy, providing biomarkers that are physiological correlates of acute of acute mandibular vascular injury and recovery temporal kinetics. PMID- 27499211 TI - Comparative Assessment of Models and Methods To Calculate Grid Electricity Emissions. AB - Due to the complexity of power systems, tracking emissions attributable to a specific electrical load is a daunting challenge but essential for many environmental impact studies. Currently, no consensus exists on appropriate methods for quantifying emissions from particular electricity loads. This paper reviews a wide range of the existing methods, detailing their functionality, tractability, and appropriate use. We identified and reviewed 32 methods and models and classified them into two distinct categories: empirical data and relationship models and power system optimization models. To illustrate the impact of method selection, we calculate the CO2 combustion emissions factors associated with electric-vehicle charging using 10 methods at nine charging station locations around the United States. Across the methods, we found an up to 68% difference from the mean CO2 emissions factor for a given charging site among both marginal and average emissions factors and up to a 63% difference from the average across average emissions factors. Our results underscore the importance of method selection and the need for a consensus on approaches appropriate for particular loads and research questions being addressed in order to achieve results that are more consistent across studies and allow for soundly supported policy decisions. The paper addresses this issue by offering a set of recommendations for determining an appropriate model type on the basis of the load characteristics and study objectives. PMID- 27499212 TI - Leishmania exosomes and other virulence factors: Impact on innate immune response and macrophage functions. AB - Leishmania parasites are the causative agents of the leishmaniases, a collection of vector-borne diseases that range from simple cutaneous to fatal visceral forms. Employing potent immune modulation mechanisms, Leishmania is able to render the host macrophage inactive and persist inside its phagolysosome. In the last few years, the role of exosomes in Leishmania-host interactions has been increasingly investigated. For instance, it was reported that Leishmania exosome release is augmented following temperature shift, a condition mimicking parasite's entry into its mammalian host. Leishmania exosomes were found to strongly affect macrophage cell signaling and functions, similarly to whole parasites. Importantly, these vesicles were shown to be pro-inflammatory, capable to recruit neutrophils at their inoculation site exacerbating the pathology. In this review, we provide the most recent insights on the role of exosomes and other virulence factors, especially the surface protease GP63, in Leishmania-host interactions, deepening our knowledge on leishmaniasis and paving the way for the development of new therapeutics. PMID- 27499213 TI - RNAi-mediated HOXD3 knockdown inhibits growth in human RKO cells. AB - Numerous studies have shown that the multifunctional Homeobox-containing (HOX) D3 gene is involved in various physiological and pathological processes. To elucidate the role and mechanism of HOXD3 in colorectal cancer (CRC), we measured its expression in five CRC cell lines. After determining that HOXD3 was highly expressed in the human RKO cancer cell line, we used lentiviral-mediated small interfering RNAs (siRNAs) to knock down HOXD3 expression and assessed proliferation, cell cycle distribution, apoptosis and colony formation using cell proliferation, flow cytometric, and colony formation assays. The expression of HOXD3 was strongly suppressed in the RKO cells infected with the lentiviruse expressing an HOXD3 short hairpin RNA (shRNA). The downregulation of HOXD3 expression in RKO cells significantly decreased proliferation and colony formation, and increased apoptosis in vitro, compared to the cells infected with the mock control (p<0.01). Moreover, specific downregulation of HOXD3 led to the accumulation of cells at the G2 phase of the cell cycle. Our findings revealed that the HOXD3 gene promotes CRC cell growth and plays a pivotal role in the development and survival of malignant human colorectal cancer cells. PMID- 27499214 TI - Noninvasive Cardiac Output Estimation by Inert Gas Rebreathing in Mechanically Ventilated Pediatric Patients. AB - OBJECTIVE: To assess the feasibility and accuracy of inert gas rebreathing (IGR) pulmonary blood flow (Qp) estimation in mechanically ventilated pediatric patients, potentially providing real-time noninvasive estimates of cardiac output. STUDY DESIGN: In mechanically ventilated patients in the pediatric catheterization laboratory, we compared IGR Qp with Qp estimates based upon the Fick equation using measured oxygen consumption (VO2) (FickTrue); for context, we compared FickTrue with a standard clinical short-cut, replacing measured with assumed VO2 in the Fick equation (FickLaFarge, FickLundell, FickSeckeler). IGR Qp and breath-by-breath VO2 were measured using the Innocor device. Sampled pulmonary arterial and venous saturations and hemoglobin concentration were used for Fick calculations. Qp estimates were compared using Bland-Altman agreement and Spearman correlation. RESULTS: The final analysis included 18 patients aged 4 23 years with weight >15 kg. Compared with the reference FickTrue, IGR Qp estimates correlated best and had the least systematic bias and narrowest 95% limits of agreement (results presented as mean bias +/-95% limits of agreement): IGR -0.2 +/- 1.1 L/min, r = 0.90; FickLaFarge +0.7 +/- 2.2 L/min, r = 0.80; FickLundell +1.6 +/- 2.9 L/min, r = 0.83; FickSeckeler +0.8 +/- 2.5 L/min, r = 0.83. CONCLUSIONS: IGR estimation of Qp is feasible in mechanically ventilated patients weighing >15 kg, and agreement with FickTrue Qp estimates is better for IGR than for other Fick Qp estimates commonly used in pediatric catheterization. IGR is an attractive option for bedside monitoring of Qp in mechanically ventilated children. PMID- 27499215 TI - Time Perception during Neonatal Resuscitation. AB - OBJECTIVE: To assess the accuracy of time perception during a simulated complex neonatal resuscitation. STUDY DESIGN: Participants in 5 neonatal resuscitation program courses were directly involved in a complex simulation scenario. They were asked to assume the role of team leader, assistant 1, or assistant 2. At the end of the scenario, each participant completed a questionnaire on perceived time intervals for key resuscitation interventions. During the scenario, actual times were documented by an external observer and video recorded for later review. In addition, participants were asked to evaluate their self-perceived level of stress and preparation. RESULTS: Health care providers (68 physicians and 40 nurses) were involved in 36 scenarios. Perceived time intervals for the initiation of key resuscitation interventions were shorter than the actual time intervals, regardless of the participant's role in the scenario. Self-assessed levels of stress and preparation did not influence time perception. CONCLUSIONS: Health care providers underestimate the passage of time, irrespective of their role in a simulated complex neonatal resuscitation. Participant's self-assessed levels of stress and preparation were not related to the accuracy of their time perception. These findings highlight the importance of assigning a dedicated individual to document interventions and the passage of time during a neonatal resuscitation. PMID- 27499216 TI - Impact of Early-Onset Acute Otitis Media on Multiple Recurrences and Associated Health Care Use. AB - OBJECTIVE: To quantify the critical age period of first episode of acute otitis media (AOM) and its consequences for AOM recurrences and AOM health care use. STUDY DESIGN: Children enrolled in the Wheezing-Illnesses-STudy-LEidsche-Rijn cohort with at least 1 episode of AOM documented in their primary care health record before 2 years of age were followed until 6 years of age. Data on episodes of AOM and associated primary care consultations, antibiotic prescriptions, and specialist referrals were retrieved. Regression models assessed the presence and shape of the associations between age of first AOM and subsequent episodes of AOM and health care use. RESULTS: A total of 796 of 2026 children (39%) experienced a first AOM before 2 years of age. Each month decrease in age at first AOM in the first 2 years of life increased the risk of developing recurrent AOM (>=3 AOM episodes in 6 months or >= 4 in 1 year) linearly by 6% (adjusted risk ratio: 1.06; 95% CI: 1.02-1.10). For first AOM occurring before 9 months, the cumulative 6-year primary care consultation rate increased by 8% (adjusted incidence rate ratio: 1.08; 95% CI: 1.03-1.15) and the associated specialist referral increased by 16% (adjusted risk ratio: 1.16; 95% CI: 1.07-1.27) for each month decrease in age. No associations were found between age at first AOM and total AOM episodes or antibiotic prescriptions. CONCLUSIONS: The association between earlier age of first AOM and recurrent AOM as well as total health care use during childhood is particularly strong before 9 months of age. PMID- 27499217 TI - Diagnosis and Treatment of Systemic Juvenile Idiopathic Arthritis. PMID- 27499218 TI - Relationship of Cardiac Structure and Function to Cardiorespiratory Fitness and Lean Body Mass in Adolescents and Young Adults with Type 2 Diabetes. AB - OBJECTIVE: To investigate the relationships of cardiac structure and function with body composition and cardiorespiratory fitness (CRF) among adolescents with type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth study. STUDY DESIGN: Cross-sectional evaluation of 233 participants (median age 18.3 [min-max 12.4-24.2] years, 63% females, median hemoglobin A1c 6.8%) who had echocardiography measurements of left ventricular (LV) mass, ejection fraction, left atrial dimensions, LV diastolic function (early transmitral flow velocity to early mitral annular velocity ratio from tissue Doppler imaging), and right ventricular function (tricuspid annular plane systolic excursion [TAPSE]) and body composition (dual-energy x-ray absorptiometry) and CRF (cycle ergometry determination of physical work capacity at heart rate of 170 beats per minute). RESULTS: LV mass correlated positively with CRF (r = 0.5, P < .0001), lean body mass (LBM) (r = 0.7, P < .0001), and fat mass (FM) (r = 0.2, P = .00047); LV ejection fraction did not. Early transmitral flow velocity to early mitral annular velocity was positively related to FM (r = 0.14, P = .03) and % body fat (r = 0.18, P = .007), and left atrial internal diameter correlated with FM (r = 0.4, P < .0001), LBM (r = 0.3, P < .001), and CRF (r = 0.2, P = .0033). TAPSE weakly correlated with CRF (r = 0.2, P = .0014) and LBM (r = 0.13, P < .05) but not with FM. In multivariable regression analyses, LBM (beta = 2.13, P < .0001) and CRF (beta = 0.023, P = .008) were related to LV mass independent of race, sex, age, hemoglobin A1c, hypertension, smoking, and diabetes medications. CRF (beta = 0.0002, P = .0187) and hemoglobin A1c (beta = -0.022, P = .0142) were associated with TAPSE. CONCLUSIONS: In youth with type 2 diabetes, LV size is related to physical fitness. LV ejection fraction is within normal limits. LV diastolic function is inversely related to FM. Greater fitness may counteract adverse effects of poor glycemic control on right ventricular function. TRIAL REGISTRATION: ClinicalTrials.gov:NCT00081328. PMID- 27499219 TI - Rice (Oryza sativa) Laccases Involved in Modification and Detoxification of Herbicides Atrazine and Isoproturon Residues in Plants. AB - Atrazine (ATR) and isoproturon (IPU) as herbicides have become serious environmental contaminants due to their overuse in crop production. Although ATR and IPU in soils are easily absorbed by many crops, the mechanisms for their degradation or detoxification in plants are poorly understood. This study identified a group of novel genes encoding laccases (EC 1.10.3.2) that are possibly involved in catabolism or detoxification of ATR and IPU residues in rice. Transcriptome profiling shows at least 22 differentially expressed laccase genes in ATR/IPU-exposed rice. Some of the laccase genes were validated by RT-PCR analysis. The biochemical properties of the laccases were analyzed, and their activities in rice were induced under ATR/IPU exposure. To investigate the roles of laccases in degrading or detoxifying ATR/IPU in rice, transgenic yeast cells (Pichia pastoris X-33) expressing two rice laccase genes (LOC_Os01g63180 and LOC_Os12g15680) were generated. Both transformants were found to accumulate less ATR/IPU compared to the control. The ATR/IPU-degraded products in the transformed yeast cells using UPLC-TOF-MS/MS were further characterized. Two metabolites, hydroxy-dehydrogenated atrazine (HDHA) and 2-OH-isopropyl-IPU, catalyzed by laccases were detected in the eukaryotic cells. These results indicate that the laccase-coding genes identified here could confer degradation or detoxification of the herbicides and suggest that the laccases could be one of the important enzymatic pathways responsible for ATR/IPU degradation/detoxification in rice. PMID- 27499220 TI - Pathophysiology of acute coronary syndromes in the elderly. AB - Elderly patients represent an important proportion of the acute coronary syndrome (ACS) population. Furthermore, this group of ACS patients is continuously growing because of the progressive ageing of the population. The ageing process implies marked changes in patient physiology that directly impact in their risk. However, there is a differential distribution in the risk of elderly patients, revealing the existence of a discrepancy between the chronological and the "biological age". This discrepancy has highlighted the need of performing individual risk assessment in order to identify those patients at higher risk. In addition, the lack of representation of elderly patients in clinical trials leads to the underutilization of evidence-based therapies in this group of patients. All these factors influence not only the high prevalence of ACS presentation in the elderly but also their worse prognosis after suffering an ischaemic event. Herein we will explore the pathophysiological mechanisms behind the age-related changes at the vascular and the cardiac level that explain the high risk of elderly subjects of suffering ACS and their worse prognosis. PMID- 27499221 TI - Oral sirolimus: A possible treatment for refractory angina pectoris in the elderly. AB - Refractory angina pectoris (RAP) is a clinical problem, frequently encountered in the elderly, associated with high health-care costs. Until recently, the goal of RAP treatment aimed at improving the quality of life (QoL) because it was thought that mortality rates were not different between stable angina pectoris and RAP. Our purpose was at determining whether any mortality rate difference exists and whether any novel therapeutical solution might be translated into clinical practice. We therefore performed a literature review to assess current optimal treatment of RAP patients, including all studies involving the use of oral sirolimus and stents, although no consistent evidence was found for any specific treatment to improve survival, apart from minor QoL amelioration. A large mortality difference was seen between RAP and stable angina pectoris. On the other hand, therapeutic approaches to RAP patients showed frequent complications and several contraindications, depending on the procedure. We propose to inhibit instead of stimulating angiogenesis, by giving oral sirolimus, an immunosuppressive drug, thereby decreasing the atherosclerotic process and its evolution. Sirolimus was shown to decrease left ventricular mass (thus indirectly decreasing myocardial oxygen needs and consumption). It might stop and, in some cases, even enable regression of plaque progression. Sirolimus side effects are mild to moderate and wash-out rapidly at treatment discontinuation. Compared with current therapies sirolimus treatment is more health-care cost efficient. It should be important to design a trial in RAP patients powered to reduce mortality and QoL increase. PMID- 27499222 TI - The no-reflow phenomenon in the young and in the elderly. AB - BACKGROUND: The objectives of this study were to evaluate the incidence of no reflow as independent predictor of adverse events and to assess whether baseline pre-procedural treatment options may affect clinical outcomes. METHODS: Data were derived from the ISACS-TC registry (NCT01218776) from October 2010 to January 2015. No-reflow was defined as post-PCI TIMI flow grades 0-1, in the absence of post-procedural significant (>=25%) residual stenosis, abrupt vessel closure, dissection, perforation, thrombus of the original target lesion, or epicardial spasm. The outcome measure was in-hospital mortality. RESULTS: No-reflow was identified in 128 of 5997 patients who have undergone PCI (2.1%). On multivariate analysis, patients with no-reflow were more likely to be older (OR: 1.20, 95% CI: 1.01-1.44), to have a history of hypercholesterolemia (OR: 1.95, 95% CI: 1.31 2.91) and to be admitted with a diagnosis of STEMI (OR: 2.96, 95% CI: 1.85-4.72). Angiographic characteristics associated with no-reflow phenomenon were: stenosis >=50% of the right coronary artery, presence of multivessel disease and pre procedural TIMI blood flow grades 0-1. No-reflow was highly predictive of in hospital mortality (17.2% vs. 4.2%; adjusted OR: 4.60, 95% CI: 2.61-8.09). Administration of pre-procedural unfractioned heparin or 600mg clopidogrel loading dose was associated with less incidence of no-reflow (OR: 0.65, 95% CI: 0.43-0.99 and 0.61, 95% CI: 0.37-1.00, respectively). Aspirin, enoxaparin, and 300mg clopidogrel loading dose, did not significantly impact the occurrence of the no-reflow. CONCLUSIONS: We found that pre-procedural administration of 600mg loading dose of clopidogrel and/or unfractioned heparin is associated with reduced incidence of no-reflow. PMID- 27499223 TI - Immunological complications of blood transfusions. AB - Most adverse blood transfusion (BT) events are immune-mediated and in the majority of severe reactions antibodies can be identified as causal factors. Alloimmunization not only causes symptomatic reactions, transfused cells can also be (silently) destroyed. Immunization by BT can contribute to hemolytic disease of the newborn as well as to allograft rejection after transplantation. Reversely, pregnancy and transplantation may evoke immunity hampering transfusion therapy. Besides causing mortality and morbidity, alloimmunization has a huge economic impact. Transfusion reactions prolong hospital stay, require diagnostic tests and complex donor selection procedures and create the need for typed donor registries. In the 1970s, Opeltz and colleagues described that pre transplantation BT impaired rejection of renal transplants. Leukocytes were essential for this immunosuppressive BT effect that raised concern about negative effects on cancer growth and resistance against infections. Studies on the mechanism were however preliminary abandoned when calcineurin inhibitors for prevention of graft rejection became available and since all blood products underwent leukoreduction in most countries as precautionary measure against transmission of variant Creutzfeldt-Jacob disease. Whether current leukoreduced BT are immunosuppressive and for which patients or circumstances this may contribute to worse outcome, is unknown. The last decades of the previous century, leukoreduction of cellular blood products for leukemia patients significantly reduced the incidence of immunological platelet transfusion refractoriness. The first decade of this century the avoidance of plasma- and platelet-products from females, that may contain donor-derived leukocyte antibodies, decreased transfusion related acute lung injury (TRALI) by more than 30%. These were major achievements. Challenge for the near future is to further reduce alloimmunization in particular against red blood cells (RBC) as a cause of severe hemolytic transfusion reactions and problems to find compatible donors. This can be achieved by extended matching. Inventory limitations prevent to match all BT for clinically relevant RBC antigens. A (European-wide) registration of clinical and genetic risk factors associated with alloimmunization could support effective use of matched blood products. PMID- 27499224 TI - [Upper gastrointestinal bleeding in portal hypertensive gastropathy reveals a wandering spleen]. PMID- 27499225 TI - [Research on usual care: Methodological issues]. PMID- 27499226 TI - Patient safety: The pharmacist's contribution to a multidisciplinary Internal Medicine patient-care team. PMID- 27499228 TI - Smartphone addiction proneness in relation to sleep and morningness-eveningness in German adolescents. AB - Background Mobile phones are an important part of adolescents' life. In this study, the relationships among smartphone addiction, age, gender, and chronotype of German adolescents were examined. Materials and methods Two studies focused on two different measures of smartphone addiction. The Smartphone Addiction Proneness Scale (SAPS) was applied to 342 younger adolescents (13.39 +/- 1.77; 176 boys, 165 girls, and 1 not indicated) in Study 1 and the Smartphone Addiction Scale was applied to 208 older adolescents (17.07 +/- 4.28; 146 girls and 62 boys) in Study 2, both samples in southwest Germany. In addition, a demographic questionnaire and the Composite Scale of Morningness (CSM) and sleep measures were implemented. Results The most remarkable result of this study was that morningness-eveningness (as measured by CSM scores) is an important predictor for smartphone addiction; even stronger than sleep duration. Evening oriented adolescents scored higher on both smartphone addiction scales. In addition, gender is an important predictor for smartphone addiction and girls are more prone to become addicted. In addition, while sleep duration on weekdays negatively predicted SAPS, age, sleep duration on weekends, and midpoint of sleep on weekdays and weekends did not predicted smartphone addiction in both scales. The analysis of covariance revealed statistically significant effects of the covariates gender and age in both studies, as well as the main effect of chronotype. According to the t-test results, girls had higher scores than boys in smartphone addiction. Conclusion Evening types and girls are more prone to become smartphone addicted. PMID- 27499227 TI - Predictors and patterns of problematic Internet game use using a decision tree model. AB - Background and aims Problematic Internet game use is an important social issue that increases social expenditures for both individuals and nations. This study identified predictors and patterns of problematic Internet game use. Methods Data were collected from online surveys between November 26 and December 26, 2014. We identified 3,881 Internet game users from a total of 5,003 respondents. A total of 511 participants were assigned to the problematic Internet game user group according to the Diagnostic and Statistical Manual of Mental Disorders Internet gaming disorder criteria. From the remaining 3,370 participants, we used propensity score matching to develop a normal comparison group of 511 participants. In all, 1,022 participants were analyzed using the chi-square automatic interaction detector (CHAID) algorithm. Results According to the CHAID algorithm, six important predictors were found: gaming costs (50%), average weekday gaming time (23%), offline Internet gaming community meeting attendance (13%), average weekend and holiday gaming time (7%), marital status (4%), and self-perceptions of addiction to Internet game use (3%). In addition, three patterns out of six classification rules were explored: cost-consuming, socializing, and solitary gamers. Conclusion This study provides direction for future work on the screening of problematic Internet game use in adults. PMID- 27499229 TI - Curcumin causes DNA damage and affects associated protein expression in HeLa human cervical cancer cells. AB - Cervical cancer is one of the most common cancers in women worldwide and it is a prominent cause of cancer mortality. Curcumin is one of the major compounds from Turmeric and has been shown to induce cytotoxic cell death in human cervical cancer cells. However, there is no study to show curcumin induced DNA damage action via the effect on the DNA damage and repair protein in cervical cancer cells in detail. In this study, we investigated whether or not curcumin induced cell death via DNA damage, chromatin condensation in human cervical cancer HeLa cells by using comet assay and DAPI staining, respectively, we found that curcumin induced cell death through the induction of DNA damage, and chromatin condensation. Western blotting and confocal laser microscopy examination were used to examine the effects of curcumin on protein expression associated with DNA damage, repair and translocation of proteins. We found that curcumin at 13 uM increased the protein levels associated with DNA damage and repair, such as O6 methylguanine-DNA methyltransferase, early-onset breast cancer 1 (BRCA1), mediator of DNA damage checkpoint 1, p-p53 and p-H2A.XSer140 in HeLa cells. Results from confocal laser systems microscopy indicated that curcumin increased the translocation of p-p53 and p-H2A.XSer140 from cytosol to nuclei in HeLa cells. In conclusion, curcumin induced cell death in HeLa cells via induction of DNA damage, and chromatin condensation in vitro. PMID- 27499230 TI - Adsorption Behavior of Metasilicate on N-Methyl d-Glucamine Functional Groups and Associated Silicon Isotope Fractionation. AB - Significant isotope fractionation of silicon provides a powerful geochemical tracer for biological and physicochemical processes in terrestrial and marine environments. The exact mechanism involved in silicon uptake as part of the biological process is not well known. The silicon uptake in biological processes is investigated using silicate adsorption onto the N-methylglucamine functional group (sugarlike structure, abbreviated as L) of Amberlite IRA-743 resin as an analogue of the formation of silicate-sugar complexes in plants. This study provides new evidence that certain sugars can react readily with basic silicic acid to form sugar-silicate chelating complexes, and the equilibrium adsorption behavior of silicate can be well described by the Langmuir isotherm with a Gibbs free energy (DeltaG) of -11.94 +/- 0.21 kJ.mol(-1) at 293 K. The adsorption kinetics corresponds well to a first-order kinetic model in which the adsorption rate constant ka of 1.25 * 10(-4) s(-1) and the desorption rate constant kd of 4.00 * 10(-6) s(-1) are obtained at 293 K. Both ka and kd increase with increasing temperature. The bonding configurations of silicate-sugar complexes imply the principal coordination complex of hexacoordinated silicon (silicon/L = 1:3) in the liquid phase and the dominant tetracoordinated silicon in the solid phase. Similar to those of many natural processes, the biological uptake via the sugar-silicate chelating complexes favors the preferential enrichment of light Si isotopes into solids, and the Rayleigh model controls the dynamic isotope fractionation with an estimated silicon isotope fractionation factor (i.e., alphasolid-solution = [Formula: see text]) of 0.9971. This study advanced the fundamental understanding of the dynamic isotope fractionation of silicon during silicon cycling from the lithosphere to the biosphere and hydrosphere in surficial processes. PMID- 27499231 TI - Concentric dual pi aromaticity in bowl-like B30 cluster: an all-boron analogue of corannulene. AB - A chemical bonding model is presented for the bowl-like C5v B30 global-minimum cluster with a central pentagonal hole. The B30 cluster is composed of three concentric boron rings: first B5, second B10, and third B15. The first and second B rings constitute an inner double-chain ribbon and support a delocalized pi sextet. The second and third rings form an outer double-chain ribbon, where 14pi delocalized electrons are situated. The unique pi systems lead to concentric dual pi aromaticity for B30, a concept established from concerted computational data on the bases of canonical molecular orbital (CMO) analysis, adaptive natural density partitioning (AdNDP), nucleus-independent chemical shifts (NICS), and natural charge calculations. A proposal is put forward that the bowl-like B30 cluster is an exact all-boron analogue of corannulene (C20H10), a fragment of C60 fullerene. The bonding nature of corannulene is revisited and fully elucidated herein. A comparison of the bonding patterns in bowl-like C5v B30 cluster and two other structural isomers (Cs and C1) unravels the mechanism as to why the defective hole prefers to be positioned at the center. PMID- 27499232 TI - Two-coordinate terminal zinc hydride complexes: synthesis, structure and preliminary reactivity studies. AB - The first examples of essentially two-coordinate, monomeric zinc hydride complexes, LZnH (L = -N(Ar)(SiR3)) (Ar = C6H2{C(H)Ph2}2R'-2,6,4; R = Me, R' = Pr(i) (L'); R = Pr(i), R' = Me (L*); R = Pr(i), R' = Pr(i) (L(?))) have been prepared and shown by crystallographic studies to have near linear N-Zn-H fragments. The results of computational studies imply that any PhZn interactions in the compounds are weak at best. Preliminary reactivity studies reveal the compounds to be effective for the stoichiometric hydrozincation and catalytic hydrosilylation of carbonyl compounds. PMID- 27499233 TI - CENPs and Sweet Nucleosomes Face the FACT. AB - Chaperones mediate vital interactions between histones and DNA during chromatin assembly and reorganization. Two recent studies reveal novel substrates for the essential and conserved histone chaperone FAcilitates Chromatin Transcription (FACT). Prendergast et al. show that FACT helps deposit important histone-fold proteins on centromeres. Raj et al. find that FACT preferentially binds O GlcNAcylated nucleosomes, suggesting that FACT may contribute to nutrient regulated cellular programs. PMID- 27499234 TI - Linking Long Noncoding RNA Localization and Function. AB - Recent studies have revealed the regulatory potential of many long noncoding RNAs (lncRNAs). Most lncRNAs, like mRNAs, are transcribed by RNA polymerase II and are capped, polyadenylated, and spliced. However, the subcellular fates of lncRNAs are distinct and the mechanisms of action are diverse. Investigating the mechanisms that determine the subcellular fate of lncRNAs has the potential to provide new insights into their biogenesis and specialized functions. PMID- 27499235 TI - A new animal model containing human SCARB2 and lacking stat-1 is highly susceptible to EV71. AB - Enterovirus 71 (EV71) is a major threat to children worldwide. Children infected with EV71 could develop subclinical infection and hand-foot-and -mouth disease (HFMD). In severe cases, patients could develop encephalitis, paralysis, pulmonary edema, and death. A more user-friendly and robust animal model is essential to investigating EV71 pathogenesis. Here, we established a hybrid (hSCARB2(+/+)/stat-1(-/-)) mouse strain from crossbreeding SCARB2 transgenic and stat-1 KO mice, and compared the susceptibilities to EV71 infection and pathogenesis between parental and hybrid mice. Virus-encoded VP1 protein can be detected in the streaking nerve fibers in brain and spinal cord. This hybrid mouse strain at 2-week-old age can still be infected with different genotypes of EV71 at 1000-fold lower titer via an ip route. Infected hybrid mice developed earlier onset of CNS disease, paralysis, and death at a higher incidence. These advantages of this novel model meet the urgent need from the scientific community in basic and preclinical research in therapeutics and pathogenesis. PMID- 27499236 TI - Organ-specific radiation-induced cancer risk estimates due to radiotherapy for benign pigmented villonodular synovitis. AB - Pigmented villonodular synovitis (PVNS) is a benign disease affecting synovial membranes of young and middle-aged adults. The aggressive treatment of this disorder often involves external-beam irradiation. This study was motivated by the lack of data relating to the radiation exposure of healthy tissues and radiotherapy-induced cancer risk. Monte Carlo methodology was employed to simulate a patient's irradiation for PVNS in the knee and hip joints with a 6 MV photon beam. The average radiation dose received by twenty-two out-of-field critical organs of the human body was calculated. These calculations were combined with the appropriate organ-, age- and gender-specific risk coefficients of the BEIR-VII model to estimate the lifetime probability of cancer development. The risk for carcinogenesis to colon, which was partly included in the treatment fields used for hip irradiation, was determined with a non-linear mechanistic model and differential dose-volume histograms obtained by CT-based 3D radiotherapy planning. Risk assessments were compared with the nominal lifetime intrinsic risk (LIR) values. Knee irradiation to 36 Gy resulted in out-of-field organ doses of 0.2-24.6 mGy. The corresponding range from hip radiotherapy was 1.2-455.1 mGy whereas the organ equivalent dose for the colon was up to 654.9 mGy. The organ-specific cancer risks from knee irradiation for PVNS were found to be inconsequential since they were at least 161.5 times lower than the LIRs irrespective of the patient's age and gender. The bladder and colon cancer risk from radiotherapy in the hip joint was up to 3.2 and 6.6 times smaller than the LIR, respectively. These cancer risks may slightly elevate the nominal incidence rates and they should not be ignored during the patient's treatment planning and follow-up. The probabilities for developing any other solid tumor were more than 20 times lower than the LIRs and, therefore, they may be considered as small. PMID- 27499237 TI - Cancer-associated fibroblast suppresses killing activity of natural killer cells through downregulation of poliovirus receptor (PVR/CD155), a ligand of activating NK receptor. AB - Cancer-associated fibroblasts (CAFs) play an important role in cancer expansion and progression in tumor microenvironment (TME), via both direct and indirect interactions. Natural killer (NK) cells play a crucial role in anticancer immunity. We investigated the inhibitory effects of CAFs on NK cell activity. CAFs were isolated from endometrial cancer tissue, while normal endometrial fibroblasts (NEFs) were obtained from normal endometrium with no pathological abnormality. NK cells were obtained from allogenic healthy volunteers. CAFs or NEFs were co-cultured at an NK/fibroblast ratio of 1:1 with or without inserted membrane. For NK cell activity, K562 cells were cultured as target cells. NK cell killing activity was determined by calculating the ratio of PI-positive K562 cells in the presence of NK cells co-cultured with fibroblasts versus NK cells alone. To examine whether NK cell activity was suppressed by IDO pathway, we inhibited IDO activity using the IDO inhibitor 1-MT. We demonstrated that CAFs derived from endometrial cancer induced greater suppression of the killing activity of allogenic NK cells compared with normal endometrial fibroblasts (NEFs). The suppression of NK cell activity by CAFs was inhibited when a membrane was inserted between the CAFs and NK cells, but not by 1-MT, an inhibitor of IDO. We focused on receptor-ligand interactions between CAFs and NK cell and found that cell-surface poliovirus receptor (PVR/CD155), a ligand of activating NK receptor DNAM-1, was downregulated in the CAFs compared with NEFs. To confirm whether PVR downregulation results in the decrease of NK cell-killing activity, PVR expression in NEFs was knocked down using siRNA against PVR (PVRsi). NK cell activity was suppressed by co-culture with PVR-knockdown NEFs, to a similar extent than CAF-induced suppression. CAFs showed increased suppression of NK cell killing activity compared with NEFs, due to decreased PVR cell surface expression, a ligand of an NK activating receptor. This study demonstrated a novel mechanism of suppression of NK cell activity by CAFs in the TME. PMID- 27499238 TI - Voluntary exercise increases IgA concentration and polymeric Ig receptor expression in the rat submandibular gland. AB - Salivary IgA-a primary factor in local immunity of the oral cavity-plays an important role in maintaining local immune function in the oral cavity and prevent upper respiratory tract infections. Oral IgA levels are known to fluctuate in an exercise-dependent manner; thus, we investigated the effects of voluntary exercise on salivary IgA secretion in rats to better understand the mechanism by which this occurs. Six-week-old male Wistar rats were placed in individual cages with or without access to exercise wheels for three weeks. Notably, animals who engaged in voluntary exercise demonstrated significant increases in IgA concentration in saliva and submandibular gland tissue, as well as a markedly higher salivary IgA flow rate. Moreover, active rats also exhibited elevated polymeric Ig receptor (pIgR) mRNA expression in submandibular gland tissue. Collectively, these results suggest that voluntary exercise may increase salivary IgA concentration and boost immune function in the oral cavity. PMID- 27499239 TI - The diagnostic utility of line probe assays for multidrug-resistant tuberculosis. AB - Owing to the burden of multidrug-resistant tuberculosis, molecular techniques have been approved by the WHO for the rapid diagnosis of the same. The objectives of this prospective, diagnostic study, conducted at Christian Medical College, a tertiary care center in South India, were to compare the performance of line probe assay (GenoTypeMTBDRplus) with culture, as well as the Xpert MTB/Rif assay on sputum samples. Ninety-one consecutive suspects of multidrug-resistant pulmonary tuberculosis patients from January 2013 to June 2013 were enrolled in this study and the results of line probe assay compared to culture and Xpert MTB/Rif. Compared to culture, the assay demonstrated a sensitivity and specificity of 81.5% (95%CI 67.4-91.1%) and 87.5% (95%CI 71-96.5%) for the detection of tuberculosis, with sensitivity and specificity of 100% (95%CI 85.2 100%) and 93.8% (95%CI 69.8-99.8%), respectively, for rifampicin resistance. For isoniazid resistance, sensitivity and specificity were 89.3% (95%CI 71.8-97.7%) and 100% (95%CI 71.5-100%), respectively. Compared to Xpert MTB/Rif assay, the assay showed a sensitivity of 80% (95%CI 68.2-88.9%) and specificity of 100% (95%CI 85.8-100%) for the detection of tuberculosis a sensitivity of 94.3% (95%CI 80.8-99.3%) and specificity of 94.1% (95%CI 71.3-99.9%) for rifampicin resistance was attained. This assay performed well on smear positive samples, but poorly on smear negative and scanty samples, and can serve as a rapid diagnostic tool, particularly in isoniazid monoresistant cases of tuberculosis, which are not diagnosed by Xpert MTB/Rif. PMID- 27499240 TI - The benefits of errorless learning for people with amnestic mild cognitive impairment. AB - The aim of this study was to explore whether errorless learning leads to better outcomes than errorful learning in people with amnestic mild cognitive impairment (MCI), and to examine whether accuracy in error recognition relates to any observed benefit of errorless over errorful learning. Nineteen participants with a clinical diagnosis of amnestic MCI were recruited. A word-list learning task was used and learning was assessed by free recall, cued recall and recognition tasks. Errorless learning was significantly superior to errorful learning for both free recall and cued recall. The benefits of errorless learning were less marked in participants with better error recognition ability. Errorless learning methods are likely to prove more effective than errorful methods for those people with MCI whose ability to monitor and detect their own errors is impaired. PMID- 27499241 TI - Quantity and quality of natural organic matter influence the ecotoxicity of titanium dioxide nanoparticles. AB - Nanoparticles' fate is amongst other parameters determined by the quantity and quality of natural organic matter (NOM). Consequently, the ecotoxicity of nanoparticles is modified, while only little information is available on the NOM characteristics triggering this interplay. This study systematically examined how NOM quantity and quality influences the acute ecotoxicity of titanium dioxide nanoparticles (nTiO2) towards Daphnia magna. Therefore, two nTiO2 products (A-100 and P25; ~100 nm) were investigated in combination with seven NOM types of variable quality at four levels each (up to 4.00 mg total organic carbon/L). The results showed that - independent of the applied nTiO2 product and NOM type - nTiO2 ecotoxicity decreased up to a factor of >18 with increasing NOM concentration. More importantly, increasing levels of aromaticity and hydrophobicity of the NOM decreased the magnitude of toxic effects caused by nTiO2, which was again independent of the nTiO2 product tested. In the light of the ubiquitary presence of NOM, the ecotoxicological risk of nTiO2 in surface waters with high NOM loads is likely moderate. However, interactions of nTiO2 and NOM in combination with other natural or chemical stressors are not well understood but seem to be fundamental for a reliable risk assessment of nanoparticles. PMID- 27499242 TI - Ultrasonic synthesis of stable oil filled microcapsules using thiolated chitosan and their characterization by AFM and numerical simulations. AB - An experimental protocol has been developed for synthesizing stable core-shell microcapsules using a biopolymer, chitosan, lacking cross-linkable thiol functional groups. In the first step, thiol moieties were introduced into the backbone of chitosan using dl-N-acetylhomocysteine thiolactone (AHT). In the second step, AHT-modified chitosan shelled microcapsules, encapsulating an oil core, were successfully prepared using high intensity 20 kHz ultrasound. The size of chitosan and AHT modified chitosan microcapsules was found to be in the range of 1-15 MUm. The thickness of the microcapsule shell increased with an increase in thiol content. The mechanical properties of microcapsules were evaluated by subjecting the microcapsules to compressive forces by colloidal probe AFM. The stiffness and the Young's modulus of the shell of microcapsules were determined by analyzing the force versus indentation data using Reissner's theory for indentation of thin elastic shells. The stiffness of AHT modified chitosan microcapsules was found to be higher than unmodified chitosan microcapsules. The viability of microcapsules to be embedded into processed food, pharmaceutical and cosmetic products was tested via numerical simulations. The confined capsule in the micro-channel was subjected to linear shear and uniform flows. We used finite element numerical simulations to determine the deformation of microcapsules in flow as a function of shear rate and thickness of the shell. The deformation of capsule was found to be linear with an increase in the shear rate. The deformation decreased with an increase in the thickness of the shell. Based on the simulations, we predict that the microcapsules would survive processing conditions and shear rates used in industrial applications. PMID- 27499243 TI - Medical complications of psychoactive substances with abuse risks: Detection and assessment by the network of French addictovigilance centres. AB - The use of psychoactive substances, whether occasional or regular, can induce a large number of clinical and/or biological complications. These complications may be related to the effects of the active substance itself and/or adulterants, but also to the modalities for use (administrations route, contexts of use). The detection and evaluation of these potentially severe complications are a public health issue. Beyond the assessment of the potential for abuse of and dependence on psychoactive substances, the collection and evaluation of complications related to the use of the substances are one of the roles of addictovigilance centres. In this article, the expertise of the French addictovigilance centres in the detection and assessment of medical complications related to psychoactive substances, adulterants or route of administration of substances is advanced through a few recent examples. PMID- 27499245 TI - A case of atorvastatin-induced solar urticaria. PMID- 27499246 TI - Is experience the name each surgeon gives to his mistakes? PMID- 27499247 TI - How can neuroplasticity be utilized to improve neuropathy symptoms? PMID- 27499244 TI - beta-Catenin C-terminal signals suppress p53 and are essential for artery formation. AB - Increased activity of the tumour suppressor p53 is incompatible with embryogenesis, but how p53 is controlled is not fully understood. Differential requirements for p53 inhibitors Mdm2 and Mdm4 during development suggest that these control mechanisms are context-dependent. Artery formation requires investment of nascent endothelial tubes by smooth muscle cells (SMCs). Here, we find that embryos lacking SMC beta-catenin suffer impaired arterial maturation and die by E12.5, with increased vascular wall p53 activity. beta-Catenin deficient SMCs show no change in p53 levels, but greater p53 acetylation and activity, plus impaired growth and survival. In vivo, SMC p53 inactivation suppresses phenotypes caused by loss of beta-catenin. Mechanistically, beta catenin C-terminal interactions inhibit Creb-binding protein-dependent p53 acetylation and p53 transcriptional activity, and are required for artery formation. Thus in SMCs, the beta-catenin C-terminus indirectly represses p53, and this function is essential for embryogenesis. These findings have implications for angiogenesis, tissue engineering and vascular disease. PMID- 27499249 TI - Cutaneous involvement in the deep mycoses: A review. Part II -Systemic mycoses. AB - In the second part of this review on the deep mycoses, we describe the main systemic mycoses-paracoccidioidomycosis, coccidioidomycosis, histoplasmosis, mucormycosis, and cryptococcosis-and their cutaneous manifestations. Skin lesions are only occasionally seen in deep systemic mycoses either directly, when the skin is the route of entry for the fungus, or indirectly, when the infection has spread from a deeper focus. These cutaneous signs are often the only clue to the presence of a potentially fatal infection. As with the subcutaneous mycoses, early diagnosis and treatment is important, but in this case, even more so. PMID- 27499248 TI - Regulation of SLD5 gene expression by miR-370 during acute growth of cancer cells. AB - SLD5 is a member of the GINS complex, essential for DNA replication in eukaryotes. It has been reported that SLD5 is involved in early embryogenesis in the mouse, and cell cycle progression and genome integrity in Drosophila. SLD5 may be involved in malignant tumor progression, but its relevance in human cancer has not been determined. Here, we found strong SLD5 expression in both human bladder cancer tissues from patients and cell lines. Knockdown of SLD5 using small interfering RNA resulted in reduction of cell growth both in vitro and an in vivo xenograft model. Moreover, we found that high levels of SLD5 in bladder cancer cells result from downregulation of microRNA (miR)-370 that otherwise suppresses its expression. High level expression of DNA-methyltransferase (DNMT) 1 and IL-6 were also observed in bladder cancer cells. Knockdown of IL-6 led to downregulation of DNMT1 and SLD5 expression, suggesting that IL-6-induced overexpression of DNMT1 suppresses miR-370, resulting in high SLD5 expression. Our findings could contribute to understanding tumorigenic processes and progression of human bladder cancer, whereby inhibition of SLD5 could represent a novel strategy to prevent tumor growth. PMID- 27499250 TI - Frontal Fibrosing Alopecia in Men: Presentations in 12 Cases and a Review of the Literature. AB - BACKGROUND: Frontal fibrosing alopecia (FFA) is a scarring disease in which the hairline recedes and the eyebrows can be affected. Usually seen in postmenopausal women, FFA is much less common in men. OBJECTIVE: To describe the clinical characteristics of FFA in a case series of men and compare this series to those reported in the literature. MATERIAL AND METHODS: Men with FFA being treated in our dermatology department from January 2010 to December 2015 were included prospectively for this descriptive study. We collected patient information and clinical and treatment characteristics. RESULTS: Twelve men (mean age, 75 years) were recruited. Alopecia was the reason for seeking medical care in only 4 cases. The hairline had receded 3cm on average. Half the patients had facial papules, and 83% had androgenetic alopecia or hair loss on eyebrows or extremities. Follicular hyperkeratosis and erythema were present in 66%, and only 25% of the men reported pruritus. The most commonly prescribed treatments were topical: corticosteroids in 8 patients (66%) and minoxidil in 4 (33%). CONCLUSIONS: Facial papules, androgenetic alopecia, and loss of body hair are more often observed in men with FFA than in women. The men in this series were older on average than in other FFA case series in the literature, possibly accounting for the higher prevalence of associated androgenetic alopecia and the fact that most of these men were seeking care for conditions other than hair loss. PMID- 27499251 TI - Effect of Substitution on the Aniline Moiety of the GPR88 Agonist 2-PCCA: Synthesis, Structure-Activity Relationships, and Molecular Modeling Studies. AB - GPR88, an orphan receptor richly expressed in the striatum, is implicated in a number of basal ganglia-associated disorders. In order to elucidate the functions of GPR88, an in vivo probe appropriate for CNS investigation is required. We previously reported that 2-PCCA was able to modulate GPR88-mediated cAMP production through a Galphai-coupled pathway. Early structure-activity relationship (SAR) studies suggested that the aniline moiety of 2-PCCA is a suitable site for diverse modifications. Aimed at elucidating structural requirements in this region, we have designed and synthesized a series of analogues bearing a variety of substituents at the phenyl ring of the aniline moiety. Several compounds (e.g., 5j, 5o) showed improved or comparable potency, but have lower lipophilicity than 2-PCCA (clogP 6.19). These compounds provide the basis for further optimization to probe GPR88 in vivo functions. Computational studies confirmed the SAR trends and supported the notion that 4' substituents on the biphenyl ring exit through a largely hydrophobic binding site to the extracellular loop. PMID- 27499252 TI - Dynamic Emotional Faces Generalise Better to a New Expression but not to a New View. AB - Prior research based on static images has found limited improvement for recognising previously learnt faces in a new expression after several different facial expressions of these faces had been shown during the learning session. We investigated whether non-rigid motion of facial expression facilitates the learning process. In Experiment 1, participants remembered faces that were either presented in short video clips or still images. To assess the effect of exposure to expression variation, each face was either learnt through a single expression or three different expressions. Experiment 2 examined whether learning faces in video clips could generalise more effectively to a new view. The results show that faces learnt from video clips generalised effectively to a new expression with exposure to a single expression, whereas faces learnt from stills showed poorer generalisation with exposure to either single or three expressions. However, although superior recognition performance was demonstrated for faces learnt through video clips, dynamic facial expression did not create better transfer of learning to faces tested in a new view. The data thus fail to support the hypothesis that non-rigid motion enhances viewpoint invariance. These findings reveal both benefits and limitations of exposures to moving expressions for expression-invariant face recognition. PMID- 27499253 TI - Establishment and characterization of a cell line derived from Eptesicus nilssonii. AB - Bats of the genus Eptesicus have several non-retroviral RNA virus-derived sequences in their genomes, among which an endogenous bornavirus-like L element, named eEBLL-1, was suggested to encode functional proteins in the hosts. However, the function of eEBLL-1 remains unclear due to a lack of appropriate investigation tools, such as cultured cells expressing eEBLL-1. Here, we established a continuous cell line, named HAMOI-EnK cells, from kidney of Eptesicus nilssonii. HAMOI-EnK cells are robust and could be passaged for at least 10 months. eEBLL-1 in the genomes of HAMOI-EnK cells retains an intact open reading frame. Additionally, eEBLL-1 is transcribed in the sense-orientation in cells. To our knowledge, this is the first report to demonstrate that eEBLL-1 is transcribed in cultured cells. PMID- 27499254 TI - A two excited state model to explain the peculiar photobehaviour of a flexible quadrupolar D-pi-D anthracene derivative. AB - The peculiar photobehaviour of a symmetrical arylenevinylene anthracene derivative bearing mild electron donors (alkoxy groups) at the sides of its structure has been fully comprehended through this study. An investigation into the effect of solvent polarity and temperature on the stationary fluorescence spectrum allowed a clear dual emission to be revealed. A further valuable insight was obtained, thanks to the employment of ultrafast spectroscopies. Fluorescence up-conversion measurements and the Time Resolved Area Normalised Spectra analysis provided a clear-cut proof of the presence of two distinct fluorescent states ((1)A* and (1)B*), with (1)A* being responsible for the steady-state emission in highly polar and viscous media. Femtosecond transient absorption spectra were acquired in several organic solvents of different polarity and viscosity. Interestingly, the lifetime of (1)A* was found to be dependent on solvent viscosity whereas the lifetime of (1)B* showed a trend which matches the change in solvent polarity. Indeed, the Density functional theory calculations predicted a structural rearrangement in the fully relaxed lowest excited singlet state. The (1)A* -> (1)B* transition is thus likely accompanied by large amplitude motions of the molecular structure, with the (1)B* state also exhibiting a small intramolecular charge transfer character. The investigated flexible quadrupolar D pi-D system arouses therefore great interest as a novel material for applications in organic electronics and photonics. PMID- 27499255 TI - [Contribution of the physical and rehabilitation medicine in pediatric plastic surgery]. AB - Physical, non-painful processes guide the scar reshaping in children in order to prevent growth anomalies due to cutaneous shrinkage. The objective of the surgical treatment, coordinated with the reeducation care, is to improve the physical abilities of the skin, to restore the function and avoid the deformations. Reeducation uses various techniques (i.e. sensitive-motility, massage and mobilizations) with or without physical agent (water, aspiration and touch-drive technique). Posture and positioning rely on the small or major aids, from orthosis to prosthesis. Compression is obtained by the adjustment of aids on molding and compression garment. Indications of the reeducation treatment depend on the timing of cutaneous covering and the advance of the healing process. It also depends on the underlying condition including skin traumas (frictions, wounds, burns), skin surgeries (purpura fulminans consequences, skin graft reconstruction after giant nevus resection, malignant lesion or vascular malformations). The final goal is the rehabilitation and development of the child and the adolescent in its entire somatopsychic dimension. PMID- 27499256 TI - [Non syndromic craniosynostosis]. AB - Craniosynostosis are rare congenital malformations of the skull resulting from the premature fusion of one or several cranial sutures. Prevalence is considered in approximately 1 on 2000 births. Non syndromic craniosynostosis (NSC) or isolated form are the most frequent forms (85 % of the cases). They are classified most of the time according to the synostotic suture(s) and the engendered cranial deformation: sagittal synostosis or scaphocephaly, metopic synostosis or trigonocephaly, bicoronal synostosis or brachycephaly, coronal synostosis or plagiocephaly and oxycephaly. Although the multifactorial origin is commonly admitted, the precise mechanisms which lead to the premature fusion of a suture, remain incompletely resolute. The main risks are the intracranial high blood pressure and its consequences on the psychomotor development, the visual or respiratory infringement which can require a surgery in emergency. The treatment is realized by multidisciplinary teams allowing to provide a strategy adapted to every situation. The decision-making process depends on patient's age, on the type and severity of the craniosynostosis, and on the patient's health. This surgery is ideally performed before the age of 1 year and indication only in morphological purpose is widely recognized to avoid any social damage to the child. The follow-up is essential and is made throughout the growth in particular to detect a recurrence or the evolution towards a complex form of craniosynostosis. PMID- 27499257 TI - Dermatitis herpetiformis: a cutaneous manifestation of coeliac disease. AB - Dermatitis herpetiformis (DH) is an itchy blistering skin disease with predilection sites on elbows, knees, and buttocks. Diagnosis is confirmed by showing granular immunoglobulin A deposits in perilesional skin. DH is one manifestation of coeliac disease; the skin symptoms heal with gluten free diet (GFD) and relapse on gluten challenge. Of the first-degree relatives, 5% may be affected by either condition. Tissue transglutaminase (TG2) is the autoantigen in coeliac disease and epidermal transglutaminase (TG3) in DH. Both diseases conditions exhibit TG2-specific autoantibodies in serum and small bowel mucosa; patients with DH have IgA-TG3 in the skin. There are some divergencies between these two phenotypes. One-fourth of DH patients do not have small bowel mucosal villous atrophy, but virtually all have coeliac-type inflammatory changes. The skin symptoms respond slowly to GFD. The incidence of coeliac disease is increasing, whereas the opposite is true for DH. A female predominance is evident in coeliac disease, while DH may be more common in males. Coeliac disease carries the risk of small intestinal T-cell lymphoma; in DH B-cell lymphomas at any site may prevail. Adult coeliac disease carries a slightly increased elevated mortality risk, whereas in DH, the relative mortality rate is significantly decreased. Key messages Dermatitis herpetiformis is a cutaneous manifestation of coeliac disease; both conditions are genetically determined and gluten-dependent. Gastrointestinal symptoms and the degree of villous atrophy are less obvious in dermatitis herpetiformis than in coeliac disease. Both show tissue transglutaminase (TG2) specific autoantibodies in serum and small bowel mucosa. In addition, TG3-targeted IgA antibodies are found in the skin of DH patients Both conditions carry an increased elevated risk of lymphoma, in coeliac disease small intestinal T-cell lymphoma, in dermatitis herpetiformis mainly B-cell lymphoma at various sites. Coeliac disease is currently eight times more common that DH; the incidence of DH is decreasing in contrast to that of coeliac disease, where it is increasing. PMID- 27499258 TI - Electronically tunable extraordinary optical transmission in graphene plasmonic ribbons coupled to subwavelength metallic slit arrays. AB - Subwavelength metallic slit arrays have been shown to exhibit extraordinary optical transmission, whereby tunnelling surface plasmonic waves constructively interfere to create large forward light propagation. The intricate balancing needed for this interference to occur allows for resonant transmission to be highly sensitive to changes in the environment. Here we demonstrate that extraordinary optical transmission resonance can be coupled to electrostatically tunable graphene plasmonic ribbons to create electrostatic modulation of mid infrared light. Absorption in graphene plasmonic ribbons situated inside metallic slits can efficiently block the coupling channel for resonant transmission, leading to a suppression of transmission. Full-wave simulations predict a transmission modulation of 95.7% via this mechanism. Experimental measurements reveal a modulation efficiency of 28.6% in transmission at 1,397 cm(-1), corresponding to a 2.67-fold improvement over transmission without a metallic slit array. This work paves the way for enhancing light modulation in graphene plasmonics by employing noble metal plasmonic structures. PMID- 27499259 TI - Fluoxetine regulates cell growth inhibition of interferon-alpha. AB - Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-alpha) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-alpha-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-alpha-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-alpha) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-alpha partially rescued bladder carcinoma cells from IFN-alpha-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-alpha. These results indicated that activation of PPAR-alpha and STAT-1 participated, at least in part, in growth inhibition of IFN-alpha in the presence of fluoxetine. PMID- 27499260 TI - Evaluating the healthiness of chain-restaurant menu items using crowdsourcing: a new method - ERRATUM. PMID- 27499261 TI - Regulation of DEK expression by AP-2alpha and methylation level of DEK promoter in hepatocellular carcinoma. AB - DEK is overexpressed in multiple invasive tumors. However, the transcriptional regulatory mechanism of DEK remains unclear. In the present study, progressive type truncation assay indicated that CpG2-2 (-167 bp/+35 bp) was the DEK core promoter, whose methylation inhibited DEK expression. Bisulfite genomic sequencing analysis indicated that the methylation levels of the DEK promoter in normal hepatic cells and tissues were higher than those in hepatocellular carcinoma (HCC) cells. TFSEARCH result revealed transcription factor binding sites in CpG2-2. Among the sites, the AP-2alpha binding site showed the most significant methylation difference; hence, AP-2alpha is a key transcription factor that regulates DEK expression. Point or deletion mutation of the AP-2alpha binding site significantly reduced the promoter activity. Chromatin immunoprecipitation assay demonstrated the binding of AP-2alpha to the core promoter. Furthermore, knock down of endogenous AP-2alpha downregulated DEK expression, whereas overexpression of AP-2alpha upregulated DEK expression. Thus, AP-2alpha is an important transcription factor of DEK expression, which is correlated with the methylation level of the DEK core promoter in HCC. PMID- 27499262 TI - Host-guest inclusion system of rhein with polyamine-modified beta-cyclodextrins: characterization and cytotoxicity. AB - We report the preparation of inclusion complexes between rhein and four polyamine modified beta-cyclodextrins, namely amino-beta-cyclodextrins (NH2-betaCD), ethylenediamine-beta-cyclodextrins (EN-betaCD), diethylenetriamine-beta cyclodextrins (DETA-betaCD) and triethylenetetramine-beta-cyclodextrins (TETA betaCD) using suspension method. The solution and solid state forms of the inclusion complexes of rhein with polyamine-beta-cyclodextrins were characterized by multiple techniques. Additionally, saturated solution and MTT methods were implemented to assess the water solubilization and in vitro cytotoxicity of the inclusion complexes, respectively. The results suggested that rhein was encapsulated within the CD cavity to form a 1:1 host-guest inclusion complex. Notably, a significant enhancement of the water solubility and in vitro cytotoxicity of rhein was found in the form of inclusion complex with polyamine beta-cyclodextrin. PMID- 27499263 TI - Legislative provisions related to marriage and divorce of persons with mental health problems: a global review. AB - Realization of right to marry by a person is an exercise of personal liberty, even if concepts of marriage and expectations from such commitment vary across cultures and societies. Once married, if an individual develops mental illness the legal system often starts to discriminate against the individual. There is no doubt that every individual's right to marry or remain married is regulated by their country's family codes, civil codes, marriage laws, or divorce laws. Historically mental health condition of a spouse or intending spouse has been of interest to lawmakers in a number of ways from facilitating divorce to helping the individual with mental illness. There is no doubt that there are deeply ingrained stereotypes that persons with mental health problems lack capacity to consent and, therefore, cannot enter into a marital contract of their own free will. These assumptions lead to discrimination both in practice and in law. Furthermore, the probability of mental illness being genetically transmitted and passed on to offspring adds yet another dimension of discrimination. Thus, the system may also raise questions about the ability of persons with mental health problems to care, nurture, and support a family and children. Internationally, rights to marry, the right to remain married, and dissolution of marriage have been enshrined in several human rights instruments. Domestic laws were studied in 193 countries to explore whether laws affected the rights of people with mental illness with respect to marriage; it was found that 37% of countries explicitly prohibit marriage by persons with mental health problems. In 11% (21 countries) the presence of mental health problems can render a marriage void or can be considered grounds for nullity of marriage. Thus, in many countries basic human rights related to marriage are being flouted. PMID- 27499264 TI - Integrated solid-state nanopore platform for nanopore fabrication via dielectric breakdown, DNA-speed deceleration and noise reduction. AB - The practical use of solid-state nanopores for DNA sequencing requires easy fabrication of the nanopores, reduction of the DNA movement speed and reduction of the ionic current noise. Here, we report an integrated nanopore platform with a nanobead structure that decelerates DNA movement and an insulating polyimide layer that reduces noise. To enable rapid nanopore fabrication, we introduced a controlled dielectric breakdown (CDB) process into our system. DNA translocation experiments revealed that single nanopores were created by the CDB process without sacrificing performance in reducing DNA movement speed by up to 10 MUs/base or reducing noise up to 600 pArms at 1 MHz. Our platform provides the essential components for proceeding to the next step in the process of DNA sequencing. PMID- 27499265 TI - Proteomic characterization of peroxisome proliferator-activated receptor-gamma (PPARgamma) overexpressing or silenced colorectal cancer cells unveils a novel protein network associated with an aggressive phenotype. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor of the nuclear hormone receptor superfamily implicated in a wide range of processes, including tumorigenesis. Its role in colorectal cancer (CRC) is still debated; most reports support that PPARgamma reduced expression is associated with poor prognosis. We employed 2-Dimensional Differential InGel Electrophoresis (2-D DIGE) followed by Liquid Chromatography (LC)-tandem Mass Spectrometry (MS/MS) to identify differentially expressed proteins and the molecular pathways underlying PPARgamma expression in CRC progression. We identified several differentially expressed proteins in HT29 and HCT116 CRC cells and derived clones either silenced or overexpressing PPARgamma, respectively. In Ingenuity Pathway Analysis (IPA) they showed reciprocal relation with PPARgamma and a strong relationship with networks linked to cell death, growth and survival. Interestingly, five of the identified proteins, ezrin (EZR), isoform C of prelamin-A/C (LMNA), alpha-enolase (ENOA), prohibitin (PHB) and RuvB-like 2 (RUVBL2) were shared by the two cell models with opposite expression levels, suggesting a possible regulation by PPARgamma. mRNA and western blot analysis were undertaken to obtain a technical validation and confirm the expression trend observed by 2-D DIGE data. We associated EZR upregulation with increased cell surface localization in PPARgamma-overexpressing cells by flow cytometry and immunofluorescence staining. We also correlated EZR and PPARgamma expression in our series of CRC specimens and the expression profiling of all five proteins levels in the publicly available colon cancer genomic data from Oncomine and Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) datasets. In summary, we identified a panel of proteins correlated with PPARgamma expression that could be associated with CRC unveiling new pathways to be investigated for the selection of novel potential prognostic/predictive biomarkers and/or therapeutic targets. PMID- 27499267 TI - Non-motor neurological symptoms in patients with amyotrophic lateral sclerosis. PMID- 27499266 TI - Genomic characterization of the Atlantic cod sex-locus. AB - A variety of sex determination mechanisms can be observed in evolutionary divergent teleosts. Sex determination is genetic in Atlantic cod (Gadus morhua), however the genomic location or size of its sex-locus is unknown. Here, we characterize the sex-locus of Atlantic cod using whole genome sequence (WGS) data of 227 wild-caught specimens. Analyzing more than 55 million polymorphic loci, we identify 166 loci that are associated with sex. These loci are located in six distinct regions on five different linkage groups (LG) in the genome. The largest of these regions, an approximately 55 Kb region on LG11, contains the majority of genotypes that segregate closely according to a XX-XY system. Genotypes in this region can be used genetically determine sex, whereas those in the other regions are inconsistently sex-linked. The identified region on LG11 and its surrounding genes have no clear sequence homology with genes or regulatory elements associated with sex-determination or differentiation in other species. The functionality of this sex-locus therefore remains unknown. The WGS strategy used here proved adequate for detecting the small regions associated with sex in this species. Our results highlight the evolutionary flexibility in genomic architecture underlying teleost sex-determination and allow practical applications to genetically sex Atlantic cod. PMID- 27499268 TI - Toward Chemical Perfection of Graphene-Based Gene Carrier via Ugi Multicomponent Assembly Process. AB - The graphene-based materials with unique, versatile, and tunable properties have brought new opportunities for the leading edge of advanced nanobiotechnology. In this regard, the use of graphene in gene delivery applications is still at early stages. In this study, we successfully designed a new complex of carboxylated graphene (G-COOH) with ethidium bromide (EtBr) and used it as a nanovector for efficient gene delivery into the AGS cells. G-COOH, with carboxyl functions on its surface, in the presence of EtBr, formaldehyde, and cyclohexylisocyanide were participated in Ugi four component reaction to fabricate a stable amphiphilic graphene-EtBr (AG-EtBr) composite. The coupling reaction was confirmed by further analyses with FT-IR, AFM, UV-vis, Raman, photoluminescence, EDS, and XPS. The AG EtBr nanocomposite was able to interact with a plasmid DNA (pDNA). This nanocomposite has been applied for transfection of cultured mammalian cells successfully. Moreover, the AG-EtBr composites showed a remarkable decreased cytotoxicity in compared to EtBr. Interestingly, the advantages of AG-EtBr in cell transfection are more dramatic (3-fold higher) than Lipofectamine2000 as a commercial nonviral vector. To the best of our knowledge, this is the first report in which EtBr is used as an intercalating agent along with graphene to serve as a new vehicle for gene delivery application. PMID- 27499269 TI - Nanoscale studies link amyloid maturity with polyglutamine diseases onset. AB - The presence of expanded poly-glutamine (polyQ) repeats in proteins is directly linked to the pathogenesis of several neurodegenerative diseases, including Huntington's disease. However, the molecular and structural basis underlying the increased toxicity of aggregates formed by proteins containing expanded polyQ repeats remain poorly understood, in part due to the size and morphological heterogeneity of the aggregates they form in vitro. To address this knowledge gap and technical limitations, we investigated the structural, mechanical and morphological properties of fibrillar aggregates at the single molecule and nanometer scale using the first exon of the Huntingtin protein as a model system (Exon1). Our findings demonstrate a direct correlation of the morphological and mechanical properties of Exon1 aggregates with their structural organization at the single aggregate and nanometric scale and provide novel insights into the molecular and structural basis of Huntingtin Exon1 aggregation and toxicity. PMID- 27499270 TI - Impaired renal function is associated with recurrence after cryoballoon catheter ablation for paroxysmal atrial fibrillation: A potential effect of non-pulmonary vein foci. AB - BACKGROUND: Atrial fibrillation (AF) and chronic kidney disease (CKD) are closely related. The present study aimed to evaluate the association between estimated glomerular filtration rate (eGFR) and outcomes after cryoballoon catheter ablation for AF. METHODS: We included a total of 110 patients (64.0+/-10.1 years, 64% men) with paroxysmal AF who underwent second-generation cryoballoon catheter ablation in this study. Recurrence and change in renal function after ablation were assessed by stratification of eGFR sub-groups. RESULTS: During a mean follow up period of 9 months, 20 (18%) patients had AF recurrence after the first catheter ablation procedure. Multivariate Cox regression analysis showed that eGFR [hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.93-0.99, p=0.047], non-pulmonary vein (PV) ectopic beats at initial ablation (HR 2.92, 95% CI 1.03 8.27, p=0.043), and history of stroke (HR 7.47, 95% CI 2.30-24.2, p=0.001) were independent predictors of recurrence after the ablation. Among the CKD groups, recurrence was found in 7% (1/15), 12% (9/73), and 46% (10/22) of the eGFR >=90mL/min/1.73m2, eGFR 60-89.9mL/min/1.73m2, and eGFR 30-59.9mL/min/1.73m2 groups, respectively (p=0.001). Kaplan-Meier survival curves demonstrated that patients with eGFR 30-59.9mL/min/1.73m2 had significantly worse prognosis than did the other groups (log-rank p<0.001). In addition, non-PV ectopic beats at initial ablation were detected in 7% (1/15), 14% (10/73), and 50% (11/22) of the patients among the three CKD groups, respectively (p<0.001). No patients developed contrast-induced nephropathy after the catheter ablation procedure. CONCLUSIONS: Low eGFR at baseline was an independent predictor of recurrence after cryoballoon ablation for paroxysmal AF. The presence of non-PV ectopic beats was significantly increased in patients with impaired renal function, which might be associated with a poor outcome. PMID- 27499271 TI - Reduction of c-kit positive cardiac stem cells in patients with atrial fibrillation. AB - BACKGROUND: We aimed to determine expression patterns of cardiac stem cells in the left atrium (LA) tissue from patients with atrial fibrillation. METHODS: LA appendages were obtained during open-heart surgery and processed for explant cell culture and tissue analysis (n=319). The total number of grown cells and c-kit positive cells were analyzed by flow cytometry after 4 weeks of culture. The remaining tissue was used for Masson's trichrome staining to determine the area of the fibrosis. RESULTS: The diameter of the LA, as measured by echocardiography, was significantly larger in the AF group than in the sinus rhythm group. Reverse transcription polymerase chain reaction analysis revealed higher expression of collagen in the AF group and an increase in the expression of basic fibrosis growth factor and transforming growth factor-2 and -3. Masson's trichrome staining showed progression of fibrosis in the AF tissue. In addition, the expression of apoptosis-related genes were significantly higher in AF group. There was no difference in the expression of connexin-40 between groups, while the expression of connexin-43 was decreased and that of connexin-45 was increased in the AF group. The total numbers of grown cells as well as c-kit positive cells after 4 weeks of cardiac tissue culture were significantly lower in the AF group. CONCLUSION: Progression of remodeling in LA tissue was observed in AF patients. The number of c-kit positive cells cultured from LA appendages was reduced in AF patients, suggesting impairments in self-renewal. PMID- 27499272 TI - Wogonin inhibits the proliferation and invasion, and induces the apoptosis of HepG2 and Bel7402 HCC cells through NF-kappaB/Bcl-2, EGFR and EGFR downstream ERK/AKT signaling. AB - The anticancer effects of the natural flavonoid, wogonin, have been reported. However, its molecular mechanisms of action have not yet been fully explored. In the present study, we aimed to examine the molecular mechanisms of action of wogonin and its effects on the biological behavior of the HepG2 and Bel7402 hepatocellular carcinoma (HCC) cell lines. We also examined the effects of wogonin on nuclear factor-kappaB (NF-kappaB)/Bcl-2 and epidermal growth factor receptor (EGFR) signaling, as well as on downstream pathways of EGFR, namely extracellular signal-regulated kinase (ERK)/AKT signaling. We found that treatment with wogonin inhibited the proliferation and invasion, and induced the apoptosis of the HepG2 and Bel7402 cells. In addition, treatment with wogonin decreased cyclin D1, cyclin E, CDK4/6, Bcl-2 and matrix metalloproteinase 2 (MMP2) expression, and promoted the cleavage of caspase-3 and caspase-9 in a concentration-dependent manner. Further experiments revealed that wogonin inhibited NF-kappaB/Bcl-2 signaling by decreasing the IkappaB and p65 phosphorylation levels. Wogonin also inhibited the activation of the EGFR (Tyr845) signaling pathway, and that of downstream pathways of EGFR, namely ERK/AKT/MMP2 signaling. The depletion of EGFR by siRNA partly abolished the inhibitory effects of wogonin on cyclin D1, MMP2 expression. On the whole, our our findings demonstrate that wogonin effectively suppresses the proliferation, invasion and survival of HCC cells through the modulation of the NF-kappaB and EGFR signaling pathways. PMID- 27499273 TI - Downstream Migration and Fragmentation of a Spontaneous Calcific Embolus after Thrombolysis in a Patient with Ischemic Stroke. AB - We report a successful treatment experience with systemic thrombolysis in a patient with acute ischemic stroked caused by spontaneous calcific embolus, which resulted in clinical improvement and embolus fragmentation. PMID- 27499274 TI - Anteromedial dome impaction in acetabular fractures: Issues and controversies. PMID- 27499275 TI - Finding Knowledge Gaps in Aerobic Granulation Technology. AB - This review identifies the knowledge gaps in aerobic granulation technology and defines some problems for future studies. In particular, extracellular polymeric substances (EPSs) should be further characterized to understand the intermolecular interactions among these polymers, the role of chelating agents in destabilizing EPS ionic bridges needs further elucidation, and early detection of the quorum-quenching enzymes should be considered to avoid granule segregation and process failure. Furthermore, the process should be supplemented with volatile fatty acids as electron donors/carbon sources, and appropriate anoxic/anaerobic conditions should be provided for enhanced nitrogen and phosphorus removal. Finally, the biodegradation, bioaccumulation, biosorption, and mass transfer behaviors of the emerging contaminants within the granules need further investigation. PMID- 27499276 TI - Strategies for Derisking Translational Processes for Biomedical Technologies. AB - Inefficient translational processes for technology-oriented biomedical research have led to some prominent and frequent failures in the development of many leading drug candidates, several designated investigational drugs, and some medical devices, as well as documented patient harm and postmarket product withdrawals. Derisking this process, particularly in the early stages, should increase translational efficiency and streamline resource utilization, especially in an academic setting. In this opinion article, we identify a 12-step guideline for reducing risks typically associated with translating medical technologies as they move toward prototypes, preclinical proof of concept, and possible clinical testing. Integrating the described 12-step process should prove valuable for improving how early-stage academic biomedical concepts are cultivated, culled, and manicured toward intended clinical applications. PMID- 27499277 TI - Textile Processes for Engineering Tissues with Biomimetic Architectures and Properties. AB - Textile technologies in which fibers containing biological factors and cells are formed and assembled into constructs with biomimetic properties have attracted significant attention in the field of tissue engineering. This Forum article highlights the most prominent advances of the field in the areas of fiber fabrication and construct engineering. PMID- 27499278 TI - Commentary to "Biometry of the hypospadic penis after hormone therapy (testosterone and estrogen): A randomized double-blind controlled trial". PMID- 27499279 TI - Spontaneous bladder rupture in non-augmented bladder exstrophy. AB - OBJECTIVE: Bladder perforation is not commonly described in bladder exstrophy patients without bladder augmentation. The goal of this study was to identify the risk factors of spontaneous perforation in non-augmented exstrophy bladders. METHODS: The study was a retrospective multi-institutional review of bladder perforation in seven male and two female patients with classic bladder exstrophy epispadias (E-E). RESULTS: Correction of E-E was performed using Kelly repair in two and staged repair in seven (Table). Bladder neck repair was performed in eight patients at a mean age of 6 years. Three patients had additional urethral surgery. Before rupture, six patients were voiding only per urethra. Two patients were voiding urethrally but were also performing occasional CIC via a Mitrofanoff. One patient was performing CIC 3 hourly per urethra. Six were dry during the day. Six of the patients had lower urinary tract symptoms: five had frequency and four were straining to void. Two had suffered episodes of urinary retention. Pre-rupture ultrasound showed that the upper urinary tract was dilated in four patients. Micturating cystourethrogram was performed in six showing vesico-ureteral reflux in five. Two had urethral stenosis. Nuclear medicine was done in three patients with two abnormal differential function. Urodynamics was performed in two patients with low capacity (100 mL) and hypocompliant (<10) bladders. Both had high leak point pressures: 60 cmH2O at 100 mL. The mean age at rupture was 11 years, with a range of 5-20 years. Patients presented with abdominal pain, associated with signs of intestinal obstruction in seven and fever in two. Eight patients underwent laparotomy and one prolonged drainage via SPC. Simple closure was performed in seven and bladder neck closure in one, because of extension of the rupture inferiorly. All patients recovered well. Following rupture, five underwent augmentation and Mitrofanoff. One of these suffered a recurrent rupture. Two other patients refused augmentation and Mitrofanoff and one of these has since had a subsequent rupture. CONCLUSIONS: The limitations of this series include the small number of patients and its retrospective nature, without knowledge of the incidence. Bladder rupture is a risk even in non-augmented bladder exstrophy. It is potentially life-threatening and most often requires laparotomy. Rupture occurs because of poor bladder emptying and/or high pressure. Urodynamics may identify those at risk. CIC with or without augmentation should not be delayed once poor bladder emptying and/or high pressure are identified. PMID- 27499280 TI - Maternal and fetal risk factors for bladder exstrophy: A nationwide Swedish case control study. AB - INTRODUCTION: Bladder exstrophy is a rare, congenital, complex malformation where the underlying cause is largely unknown. Both environmental and genetic mechanisms are thought to be involved. There are divergent results concerning the prevalence, birth descriptive data, and potential maternal risk factors for bladder exstrophy. Few previous studies have reflected nationwide populations, population registers, or spanned a longer period of time. OBJECTIVE: To describe and assess bladder exstrophy and the potential maternal risk factors, for a time period of four decades, by conducting a nationwide register study of bladder exstrophy in Sweden. METHODS: A matched-design, case-control, linkage-analysis study nested within the entire pool of live births in Sweden between 1973 and 2011 was performed. Cases with bladder exstrophy were identified using nationwide population-based birth and health registers. Inclusion criteria were people born in Sweden with the classification of bladder exstrophy according to the ICD coding system. Cases were matched with five controls per patient, based on birth year and sex. Prevalence was assessed and birth descriptive data were compiled. Potential maternal risk factors were obtained from medical birth registers of cases and assessed using conditional and multivariate logistic regression models to obtain odds ratios as a measure of the relative risk. Classification of the diagnosis in the registers constituted a possible limitation for determining the correct study population, which demanded strict validation and inclusion criteria. All data were collected prospectively, thereby avoiding potential recall bias. RESULTS: The prevalence was calculated to be approximately 3 per 100,000 live births, with a male-to-female ratio of 1.14:1. In 92.5% of the cases, bladder exstrophy was an isolated malformation without associated major malformations. However, 41% had had surgery for congenital inguinal hernia and 11% of the male subjects had been operated on for cryptorchidism. A significantly higher proportion of cases had a birth weight <1500 g compared with controls, but other characteristics were comparable with controls. High maternal age was the only significant potential associated maternal risk factor. CONCLUSIONS: One hundred and twenty children born with bladder exstrophy in Sweden during the last four decades were identified; this resulted in prevalence in Sweden of 3 per 100,000. The prevalence was stable over time and the sex ratio was equal. Birth characteristics were comparable to controls, and bladder exstrophy generally occurred as an isolated malformation without major associated malformations. Advanced maternal age was the only significant potential maternal risk factor. PMID- 27499281 TI - ESPU Editorial. PMID- 27499282 TI - Editorial comment for Protective effect of tunica albuginea incision with tunica vaginalis flap coverage on tissue damage and oxidative stress following testicular torsion: Role of duration of ischemia. PMID- 27499283 TI - Effects of electrode gap and wastewater condition on the performance of microbial fuel cell coupled constructed wetland. AB - The effects of electrode gap, PB solution concentration and azo dye on the wastewater treatment and electricity generation of microbial fuel cell coupled constructed wetland (CW-MFC) were studied. The electrode gap had obvious influence on the decolorization, while the influence of PB concentration on the decolorization was not obvious. The best decolorization efficiency was 91.05% and was gained when the electrode gap was 13.2 cm. The smaller the electrode gap, the smaller the ohmic resistance. However, a too small electrode gap would reduce the electricity generation. The best PB concentration in this study was 50 mM. In the glucose group, when the PB concentration was 50 mM, the power density was enhanced to 0.38 W/m3, while the PB concentration was 5 mM, the power density was only 0.14 W/m3. In the ABRX3 group, when the PB concentration was 50 mM, the power density was 0.18 W/m3, while when the PB concentration was 5 mM, the power density was 0.12 W/m3. The electricity generation performance of the CW-MFC was enhanced with an increase in running time. Long-time running CW-MFC got a higher cathode potential and a smaller internal resistance. PMID- 27499284 TI - [Changes in features of diabetes care in Hungary in the period of years 2001 2014. Aims and methods of the database analysis of the National Health Insurance Fund]. AB - In the last couple of years, database analyses have become increasingly popular among clinical-epidemiological investigations. In Hungary, the National Health Insurance Fund serves as central database of all medical attendances in state departments and purchases of drug prescriptions in pharmacies. Data from in- and outpatient departments as well as those from pharmacies are regularly collected in this database which is public and accessible on request. The aim of this retrospective study was to investigate the database of the National Health Insurance Fund in order to analyze the diabetes-associated morbidity and mortality in the period of years 2001-2014. Moreover, data of therapeutic costs, features of hospitalizations and practice of antidiabetic treatment were examined. The authors report now on the method of the database analysis. It is to be hoped that the upcoming results of this investigation will add some new data to recent knowledge about diabetes care in Hungary. Orv. Hetil., 2016, 157(32), 1259-1265. PMID- 27499285 TI - [Peripheral arterial disease and diabetes related lower limb amputations. Presentation of the epidemiological data and the analysis of potentialities in preventive strategy]. AB - Lower limb amputation as one of the most devastating consequences of peripheral arterial disease and diabetes mellitus needs peculiar attention. This review aims at comparing Hungarian and international amputation data. Realizing the great variability of the global amputation incidence and trends data, the main determinants of this variety are assessed. These factors involve methodological differences in reporting, demographic, epidemiological, economic, societal and cultural variation of the affected populations and differences in the health care service. The amputation hazard can be considered as an example of lifetime risk that can be characterized by complex interaction of contionuously changing risk factor pattern. In that sense an effective preventive strategy planning needs complex measure implementations that associate with multidisciplinary approach, timely complex preventive interventions and centralized vascular care. Research and development on amputation field shows clear priority that can contribute to the better understanding of this extremely complex scenario with significant public health consequences. Orv. Hetil., 2016, 157(32), 1266-1274. PMID- 27499286 TI - [Genetic and epigenetic factors of polycystic ovary syndrome]. AB - The development of polycystic ovary syndrome and its exact pathophysiological mechanism is still unclear, but environmental and genetic factors likely play a role. Exposition to teratogenic effects during the prenatal development can lead to chronic diseases in the postnatal period. This finding confirms the common familial aggregation as well. A literature search was conducted up to January 1, 2016 for articles dealing with the genetic or epigenetic factors of polycystic ovary syndrome. This review will discuss the current understanding of the genetic basis and clinical presentation of this disease. Orv. Hetil., 2016, 157(32), 1275 1281. PMID- 27499287 TI - [Prognostic significance of the culprit vessel in patients with ST-elevation myocardial infarction treated with primary coronary intervention]. AB - INTRODUCTION: To the best of the authors' knowledge, very few publications are available which report on the prognostic significance of the culprit vessel in patients with ST elevation myocardial infarction treated with successful primary percutaneous coronary intervention. AIM: The aim of the authors was to obtain data on the significance of the culprit vessel in patients with ST elevation myocardial infarction treated successfully by primary percutaneous coronary intervention. METHOD: The authors performed a retrospective study in 10,763 patients with ST elevation myocardial infarction who underwent successful primary percutaneous coronary intervention. The culprit vessels were the left main artery, left anterior descendent artery, left circumflex artery, and right coronary artery. The authors constructed univariate survival curves for different culprit vessels and also performed multivariate modelling of time-to-death, controlling for age, sex, and comorbidities. RESULTS: The majority of the culprit lesions were found in the left anterior descendent artery (44.3%), the right coronary artery (40.9%), and the left circumflex artery (13.7%). The culprit vessel was overall a highly significant (p<0.0001) factor of survival, with right coronary artery exhibiting a highly significantly better prognosis (hazard ratio 0.69, 95% CI 0.61-0.79, p<0.0001) and left main artery exhibiting a significantly worse prognosis (hazard ratio 1.56, 95% CI 1.04-2.35, p = 0.0321) than the reference vessel (left anterior descendent artery). CONCLUSION: These data demonstrate that the culprit vessel has independent prognostic significance. Orv. Hetil., 2016, 157(32), 1282-1288. PMID- 27499288 TI - [Self-citations: the stepchildren of scientometrics?]. AB - Self-references, self-citations are considered by some as the sign of vanity, and deemed to be omitted from scientometrics analyses. In fact, self-citations reveal information in the study of scientific communications that is different but not less valuable than citations received from others. In the practice of self citation severe ethical issues may emerge that can be bandled by the co-operation of the authors, editors and publishers. Orv. Hetil., 2016, 157(32), 1289-1293. PMID- 27499289 TI - [Miscellaneous]. PMID- 27499290 TI - Persistence of Escherichia coli in batch and continuous vermicomposting systems. AB - Vermicomposting is a biooxidation process in which epigeicearthworms act in synergy with microbial populations to degrade organic matter. Vermicomposting does not go through a thermophilic stage as required by North American legislations for pathogen eradication. We examined the survival of a Green Fluorescent Protein (GFP) labeled Escherichia coli MG1655 as a model for the survival of pathogenic bacteria in both small-scale batch and medium-scale continuously-operated systems to discern the influence of the earthworm Eisenia fetida, nutrient content and the indigenous vermicompost microbial community on pathogen abundance. In batch systems, the microbial community had the greatest influence on the rapid decline of E. coli populations, and the effect of earthworms was only visible in microbially-impoverishedvermicomposts. No significant earthworm density-dependent relationship was observed on E. coli survival under continuous operation. E. coli numbers decreased below the US EPA compost sanitation guidelines of 10(3)Colony Forming Units (CFU)/g (dry weight) within 18-21days for both the small-scale batch and medium-scale continuous systems, but it took up to 51days without earthworms and with an impoverished microbial community to reach the legal limit. Nutrient replenishment (i.e. organic carbon) provided by continuous feed input did not appear to extend E. coli survival. In fact, longer survival of E. coli was noticed in treatments where less total and labile sugars were available, suggesting that sugars may support potentially antagonist bacteria in the vermicompost. Total N, pH and humidity did not appear to affect E. coli survival. Several opportunistic human pathogens may be found in vermicompost, and their populations are likely kept in check by antagonists. PMID- 27499291 TI - Assessing the economics of processing end-of-life vehicles through manual dismantling. AB - Most dismantling enterprises in a number of developing countries, such as China, usually adopt the "manual+mechanical" dismantling approach to process end-of-life vehicles. However, the automobile industry does not have a clear indicator to reasonably and effectively determine the manual dismantling degree for end-of life vehicles. In this study, five different dismantling scenarios and an economic system for end-of-life vehicles were developed based on the actual situation of end-of-life vehicles. The fuzzy analytic hierarchy process was applied to set the weights of direct costs, indirect costs, and sales and to obtain an optimal manual dismantling scenario. Results showed that although the traditional method of "dismantling to the end" can guarantee the highest recycling rate, this method is not the best among all the scenarios. The profit gained in the optimal scenario is 100.6% higher than that in the traditional scenario. The optimal manual dismantling scenario showed that enterprises are required to select suitable parts to process through manual dismantling. Selecting suitable parts maximizes economic profit and improves dismantling speed. PMID- 27499293 TI - Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix. AB - TM4SF20 (transmembrane 4 L6 family 20) is a polytopic membrane protein that inhibits proteolytic processing of CREB3L1 (cAMP response element-binding protein 3-like 1), a membrane-bound transcription factor that blocks cell division and activates collagen synthesis. Here we report that ceramide stimulates CREB3L1 cleavage by inverting the orientation of TM4SF20 in membranes. In the absence of ceramide, the N terminus of the first transmembrane helix of TM4SF20 is inserted into the endoplasmic reticulum (ER) lumen. This translocation requires TRAM2 (translocating chain-associated membrane protein 2), a membrane protein containing a putative ceramide-interacting domain. In the presence of ceramide, the N terminus of the first transmembrane domain of TM4SF20 is exposed to cytosol. Consequently, the membrane topology of TM4SF20 is inverted, and this form of TM4SF20 stimulates CREB3L1 cleavage. In the presence of ceramide, translocation of TM4SF20 is TRAM2-independent. We designate this mechanism causing regulated inversion of the membrane topology as "regulated alternative translocation." PMID- 27499292 TI - The Flexible Ends of CENP-A Nucleosome Are Required for Mitotic Fidelity. AB - CENP-A is a histone variant, which replaces histone H3 at centromeres and confers unique properties to centromeric chromatin. The crystal structure of CENP-A nucleosome suggests flexible nucleosomal DNA ends, but their dynamics in solution remains elusive and their implication in centromere function is unknown. Using electron cryo-microscopy, we determined the dynamic solution properties of the CENP-A nucleosome. Our biochemical, proteomic, and genetic data reveal that higher flexibility of DNA ends impairs histone H1 binding to the CENP-A nucleosome. Substituting the 2-turn alphaN-helix of CENP-A with the 3-turn alphaN helix of H3 results in compact particles with rigidified DNA ends, able to bind histone H1. In vivo replacement of CENP-A with H3-CENP-A hybrid nucleosomes leads to H1 recruitment, delocalization of kinetochore proteins, and significant mitotic and cytokinesis defects. Our data reveal that the evolutionarily conserved flexible ends of the CENP-A nucleosomes are essential to ensure the fidelity of the mitotic pathway. PMID- 27499295 TI - DNA Repair Profiling Reveals Nonrandom Outcomes at Cas9-Mediated Breaks. AB - The repair outcomes at site-specific DNA double-strand breaks (DSBs) generated by the RNA-guided DNA endonuclease Cas9 determine how gene function is altered. Despite the widespread adoption of CRISPR-Cas9 technology to induce DSBs for genome engineering, the resulting repair products have not been examined in depth. Here, the DNA repair profiles of 223 sites in the human genome demonstrate that the pattern of DNA repair following Cas9 cutting at each site is nonrandom and consistent across experimental replicates, cell lines, and reagent delivery methods. Furthermore, the repair outcomes are determined by the protospacer sequence rather than genomic context, indicating that DNA repair profiling in cell lines can be used to anticipate repair outcomes in primary cells. Chemical inhibition of DNA-PK enabled dissection of the DNA repair profiles into contributions from c-NHEJ and MMEJ. Finally, this work elucidates a strategy for using "error-prone" DNA-repair machinery to generate precise edits. PMID- 27499294 TI - Cerebellar Ataxia and Coenzyme Q Deficiency through Loss of Unorthodox Kinase Activity. AB - The UbiB protein kinase-like (PKL) family is widespread, comprising one-quarter of microbial PKLs and five human homologs, yet its biochemical activities remain obscure. COQ8A (ADCK3) is a mammalian UbiB protein associated with ubiquinone (CoQ) biosynthesis and an ataxia (ARCA2) through unclear means. We show that mice lacking COQ8A develop a slowly progressive cerebellar ataxia linked to Purkinje cell dysfunction and mild exercise intolerance, recapitulating ARCA2. Interspecies biochemical analyses show that COQ8A and yeast Coq8p specifically stabilize a CoQ biosynthesis complex through unorthodox PKL functions. Although COQ8 was predicted to be a protein kinase, we demonstrate that it lacks canonical protein kinase activity in trans. Instead, COQ8 has ATPase activity and interacts with lipid CoQ intermediates, functions that are likely conserved across all domains of life. Collectively, our results lend insight into the molecular activities of the ancient UbiB family and elucidate the biochemical underpinnings of a human disease. PMID- 27499297 TI - OCT4 Acts as an Integrator of Pluripotency and Signal-Induced Differentiation. AB - Cell type specification relies on the capacity of undifferentiated cells to properly respond to specific differentiation-inducing signals. Using genomic approaches along with loss- and gain-of-function genetic models, we identified OCT4-dependent mechanisms that provide embryonic stem cells with the means to customize their response to external cues. OCT4 binds a large set of low accessible genomic regions. At these sites, OCT4 is required for proper enhancer and gene activation by recruiting co-regulators and RAR:RXR or beta-catenin, suggesting an unexpected collaboration between the lineage-determining transcription factor and these differentiation-initiating, signal-dependent transcription factors. As a proof of concept, we demonstrate that overexpression of OCT4 in a kidney cell line is sufficient for signal-dependent activation of otherwise unresponsive genes in these cells. Our results uncover OCT4 as an integral and necessary component of signal-regulated transcriptional processes required for tissue-specific responses. PMID- 27499296 TI - Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function. AB - Mitochondria are essential for numerous cellular processes, yet hundreds of their proteins lack robust functional annotation. To reveal functions for these proteins (termed MXPs), we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry. Our data connect MXPs to diverse mitochondrial processes, including multiple aspects of respiratory chain function. Building upon these observations, we validated C17orf89 as a complex I (CI) assembly factor. Disruption of C17orf89 markedly reduced CI activity, and its depletion is found in an unresolved case of CI deficiency. We likewise discovered that LYRM5 interacts with and deflavinates the electron-transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ). Finally, we identified a dynamic human CoQ biosynthetic complex involving multiple MXPs whose topology we map using purified components. Collectively, our data lend mechanistic insight into respiratory chain-related activities and prioritize hundreds of additional interactions for further exploration of mitochondrial protein function. PMID- 27499298 TI - Development and pilot study of an essential set of indicators for general surgery services. AB - INTRODUCTION: At present there is a lack of appropriate quality measures for benchmarking in general surgery units of Spanish National Health System. The aim of this study is to present the selection, development and pilot-testing of an initial set of surgical quality indicators for this purpose. METHODS: A modified Delphi was performed with experts from the Spanish Surgeons Association in order to prioritize previously selected indicators. Then, a pilot study was carried out in a public hospital encompassing qualitative analysis of feasibility for prioritized indicators and an additional qualitative and quantitative three-rater reliability assessment for medical record-based indicators. Observed inter-rater agreement, prevalence adjusted and bias adjusted kappa and non-adjusted kappa were performed, using a systematic random sample (n=30) for each of these indicators. RESULTS: Twelve out of 13 proposed indicators were feasible: 5 medical record-based indicators and 7 indicators based on administrative databases. From medical record-based indicators, 3 were reliable (observed agreement >95%, adjusted kappa index >0.6 or non-adjusted kappa index >0.6 for composites and its components) and 2 needed further refinement. CONCLUSIONS: Currently, medical record-based indicators could be used for comparison purposes, whilst further research must be done for validation and risk-adjustment of outcome indicators from administrative databases. Compliance results in the adequacy of informed consent, diagnosis-to-treatment delay in colorectal cancer, and antibiotic prophylaxis show room for improvement in the pilot-tested hospital. PMID- 27499299 TI - Factors Influencing Consumption of Fruits and Vegetables in Older Adults in New Orleans, Louisiana. AB - BACKGROUND: OBJECTIVES: The objective of this study was to identify demographic, social and structural factors associated with intake of fruit and vegetables in older adults in New Orleans, Louisiana. DESIGN: A cross-sectional randomly sampled, address-based telephone survey of households in Orleans Parish, Louisiana was conducted with the household's main grocery shopper. SETTING: All participants were in the New Orleans metro area and were surveyed in 2011. PARTICIPANTS: Participants were 2,834 residents identified as the households' main grocery shopper in Orleans Parish, Louisiana. Participants were primarily female (75%), African-American (53%), approximately 10 percent of the sample reported receipt of government assistance. Approximately 37% of the sample was age 65 and older. MEASUREMENTS: Measures included a telephone administered survey assessing demographic characteristics, food intake, access to supermarkets and other food sources, transportation, self-reported health, and frequency of grocery shopping. RESULTS: Older adults consumed fewer fresh fruits and vegetables (FV) than younger adults (p<0.01). Bivariate associations with decreased FV included older age, receipt of government assistance, African American race, use of mobility aid, and poorer health. Multivariate factors associated with lower consumption include age, African American race, and poorer self-reported health. Women reported more fruit and vegetable consumption than men. CONCLUSIONS: FV consumption is associated with improved health and reduced mortality. Older adults are less likely to consume fruits and vegetables, therefore addressing reduced FV consumption in older adults is a potential target for improving health outcomes in older adults. Specifically targeting African Americans and those with poorer health, as well as males may be an important focus for interventions. PMID- 27499300 TI - Identifying Low Muscle Mass in Patients with Hip Fracture: Validation of Biolectrical Impedance Analysis and Anthropometry Compared to Dual Energy X-ray Absorptiometry. AB - BACKGROUND: Older hip fracture patients often have reduced muscle mass, which is associated with adverse outcomes. Dual energy X-ray absorptiometry (DXA) can determine muscle mass, but is not practical in the acute phase. We investigated bioelectrical impedance analysis (BIA) and anthropometry compared against DXA for detecting low muscle mass in hip fracture patients. METHODS: This was a cross sectional validation study at two Norwegian hospitals on 162 hip fracture patients aged >= 65 years. Appendicular lean mass (ALM) was determined by DXA, BIA and anthropometry 3 months after hip fracture. ALM by BIA was calculated by the Kyle, Janssen, Tengvall and Sergi equations, and ALM by anthropometry by the Heymsfield and Villani equations. The area under the receiver operating characteristic curve (AUC) was used to compare BIA and anthropometry for determining low ALM (<=5.67 kg/m2 for women and <=7.25kg/m2 for men). RESULTS: Mean age was 79 years (SD 7.9), 74% were female. Mean ALM by DXA was 14.8 kg (SD 2.3) for women and 20.8 kg (SD 4.2) for men and 45% of women and 60% of men had low ALM. BIA (Kyle) in women (AUC 0.81, 95% confidence interval 0.72-0.89) and BIA (Sergi) in men (AUC 0.89, 95% CI 0.80-0.98) were best able to discriminate between low and normal ALM. Anthropometry (Heymsfield) was less accurate than BIA in women (AUC 0.64, 95% CI 0.54-0.75), and equal to BIA in men (AUC 0.72, 95% CI 0.72 0.56-0.87). CONCLUSION: BIA (Sergi, Kyle and Tengvall) and anthropometry (Heymsfield) can identify low muscle mass in hip fracture patients. PMID- 27499301 TI - Association of Dietary Variety with Body Composition and Physical Function in Community-dwelling Elderly Japanese. AB - OBJECTIVES: To examine the associations of dietary variety with body composition and physical function in community-dwelling elderly Japanese. DESIGN: Cross sectional study. SETTING: Community-based. PARTICIPANTS: A total of 1184 community-dwelling elderly adults aged 65 and over. MEASUREMENTS: Dietary variety was assessed with a food frequency questionnaire (maximum, 10 points) that encompassed the 10 main food components of Japanese meals (meat, fish/shellfish, eggs, milk, soybean products, green/yellow vegetables, potatoes, fruit, seaweed, and fats/oils). Body composition was determined by multifrequency bioelectrical impedance analysis. Physical function was assessed by measuring grip strength and usual walking speed. Multiple linear regression analysis was used to examine the associations of dietary variety with body composition and physical function. RESULTS: After adjusting for potential confounders, higher dietary variety scores were independently associated with higher lean mass (beta (SE): 0.176 (0.049), p<0.001) and appendicular lean mass (beta (SE): 0.114 (0.027), p<0.001) but not with body fat mass. Elders with a higher dietary variety score had greater grip strength and faster usual walking speed (beta (SE): 0.204 (0.071), p=0.004, and beta (SE): 0.008 (0.003), p=0.012, respectively). CONCLUSION: Greater dietary variety was significantly associated with greater lean mass and better physical function in Japanese elders. The causal relationship warrants investigation in a prospective study. PMID- 27499302 TI - Swallowing Function and Nutritional Status in Japanese Elderly People Receiving Home-care Services: A 1-year Longitudinal Study. AB - OBJECTIVES: Malnutrition is a serious health concern for frail elderly people. Poor oral function leading to insufficient food intake can contribute to the development of malnutrition. In the present study, we explored the longitudinal association of malnutrition with oral function, including oral health status and swallowing function, in elderly people receiving home nursing care. DESIGN: Prospective observational cohort study with 1-year follow-up. SETTING: Two mid sized cities in Fukuoka, Japan from November 2010 to March 2012. PARTICIPANTS: One hundred and ninety-seven individuals, aged >= 60 years, living at home and receiving home-care services because of physical disabilities, without malnutrition. MEASUREMENTS: Oral health status, swallowing function, taking modified-texture diets such as minced or pureed foods, nutritional status, cognitive function, and activities of daily living were assessed at baseline. The associations between malnutrition at 1-year follow-up and these related factors were analyzed using a logistic regression model. RESULTS: Swallowing disorders [risk ratio (RR): 5.21, 95% confidence interval (95% CI): 1.65-16.43] were associated with malnutrition. On the other hand, oral health status did not have a direct association with malnutrition. CONCLUSION: Swallowing disorders may be associated with the incidence of malnutrition in elderly people receiving home care. The findings indicate that maintaining swallowing function may contribute to the prevention of malnutrition in frail elderly people. PMID- 27499303 TI - Malnutrition in Very Old Hospitalized Patients: A New Etiologic Factor of Anemia? AB - BACKGROUND: Anemia and malnutrition are highly prevalent, frequently concomitant and associated with negative outcomes and mortality in the elderly. OBJECTIVES: To evaluate the association between these two entities, and test the hypothesis that protein-energy deficit could be etiology of anemia. DESIGN: Prospective case control study. SETTING: Geriatric and Rehabilitation Hospital, Geneva University Hospitals, Switzerland. PARTICIPANTS: 392 patients (mean age 84.8 years old, 68.6% female). MAIN OUTCOME MEASURES: Hematological (hemoglobin (Hb)), chemical (iron work up, cyanocobalamin, folates, renal function, C-Reactive Protein (CRP)) and nutrition (albumin, prealbumin) parameters, and mini nutritional assessment short form (MNA-SF). RESULTS: The prevalence of anemia (defined as Hb<120 g/l) was 39.3%. Anemic patients were more frequently malnourished or at risk of malnutrition according to the MNA-SF (p=0.047), with lower serum albumin (p <0.001) and prealbumin (p <0.001) levels. Thirty-eight percent of these patients had multiple causes and 14.3% had no cause found for anemia. Among the latter 90.9% of patients with unexplained anemia had albumin levels lower than 35g/l. After exclusion of iron,vitamin B12 and folic acid deficits, anemic patients had lower albumin (p<0.001) and prealbumin (p 0.007) levels. Albumin level explained 84.5% of the variance in anemia. In multivariate analysis albumin levels remain associated with Hb only in anemic patients, explaining 6.4% of Hb variance (adj R2) and 14.7% (adj R2) after excluding inflammatory parameters (CRP>10). CONCLUSIONS: Albumin levels are strongly associated with anemia in the elderly. Screening for undernutrition should be included in anemia assessment in those patients. Further prospective studies are warranted in order to explore the effect of protein and energy supplementation on hemoglobin level. PMID- 27499304 TI - Should Sensory Impairment Be Considered in Frailty Assessment? A Study in the GAZEL Cohort. AB - OBJECTIVES: The assessment of sensory difficulties is sometimes included in the screening of frailty in ageing population. This study aimed to compare the prevalence of frailty and associated risk of adverse outcomes depending on whether sensory difficulties participated in the definition of frailty. DESIGN: Prospective cohort study - GAZEL cohort. SETTING: France. PARTICIPANTS: The 13,128 subjects who completed a questionnaire in 2012. MEASUREMENTS: According to the Strawbridge questionnaire, subjects were considered frail if they reported difficulties in two domains or more among physical, nutritive, cognitive and sensory domains. The risk of adverse health outcomes was assessed by using logistic regression models (hospitalisations, onset of difficulty in performing movements of everyday life) and multivariate Cox proportional hazards models (mortality). RESULTS: Mean age was 66.8 +/- 3.4 years and 73.8% were males. The prevalence of frailty varied from 4.4 to 14.2% depending on whether the sensory domain was excluded or included. During follow-up, 182 deaths (1.4%), 479 hospitalisations (3.6%) and 703 cases of new disability (8.0%) were observed. Both definitions of frailty predicted the onset of difficulties to perform everyday movements, with 2 to 3-fold increase in the risk. The inclusion of the sensory domain in the definition made frailty predictive of hospitalisations (Odds Ratio 1.31 [1.01-1.70]) but the association with mortality was only observed when sensory difficulties were ignored (Hazard Ratio 2.28 [1.32-3.92]). CONCLUSION: The inclusion of a sensory domain into a frailty screening instrument has a major impact in terms of prevalence and modifies the risk profile associated with frailty. In order to develop the use of frailty screening instruments in clinical practice, further researches will need to carefully evaluate the impact on risk prediction of the different domains involved. PMID- 27499305 TI - Characterizing Magnitude and Selectivity of Attrition in a Study of Mild Cognitive Impairment. AB - OBJECTIVES: Attrition is one of the greatest difficulties in longitudinal studies on cognitive ageing because of the associated risk of underestimating declines. The aims of this paper were to characterize the magnitude and selectivity of attrition in a study of mild cognitive impairment. DESIGN: Forty two patients with multiple-domain amnestic MCI, 71 with single-domain amnestic MCI, 35 with non-amnestic MCI and 318 healthy controls were recruited from primary care centers and assessed at baseline. MEASUREMENTS: All participants underwent extensive neuropsychological evaluation, including the Mini-Mental State Examination, the Californian Verbal Learning Test, the CAMCOG-R battery, the Counting Span task and Listening Span task, and the Subjective Memory Complaints Questionnaire. RESULTS: 21.5% of the participants at baseline did not participate in the follow-up assessment. Comparison between respondents and non-returners did not reveal differences in cognitive performance in the MCI group. Data obtained at the initial assessment regarding comorbidity, social activities and attention given to memory training enabled prediction of the status of the participants in the follow-up assessment. CONCLUSION: Identification of potential non- returners is relevant, especially in MCI studies, in order to develop retention strategies to minimize attrition. PMID- 27499307 TI - Editorial: What Is New in Exercise Regimes for Frail Older People - How Does the Erasmus Vivifrail Project Take Us Forward? PMID- 27499306 TI - Impact of Cognitive Frailty on Daily Activities in Older Persons. AB - OBJECTIVES: To identify the relationships between physical and/or cognitive frailty and instrumental activities of daily living (IADL) functioning in community living older persons. DESIGN: Cross sectional observation study. SETTING: Data extracted from the 2011-2013 of the National Center for Geriatrics and Gerontology-Study of Geriatric Syndromes (NCGG-SGS) database. PARTICIPANTS: A total of 8,864 older adults aged >= 65 years who were enrolled in the NCGG-SGS. MEASUREMENTS: We characterized physical frailty as limitations in three or more of the following five domains: slow walking speed, muscle weakness, exhaustion, low activity and weight loss. To screen for cognitive impairment, we used the National Center for Geriatrics and Gerontology-Functional Assessment Tool (NCGG FAT) which included tests of word list memory, attention and executive function (tablet version of the Trail Making Test, part A and B), and processing speed (tablet version of the Digit Symbol Substitution Test). Two or more cognitive impairments indicated by an age-adjusted score of at least 1.5 standard deviations below the reference threshold was characterized as cognitive impairment. Each participant reported on their IADL status (use of public transportation, shopping, management of finances, and housekeeping) and several potential confounders such as demographic characteristics. RESULTS: The overall prevalence of physical frailty, cognitive impairment, and cognitive frailty, i.e. co-occurrence of frailty and cognitive impairment, was 7.2%, 5.2%, and 1.2%, respectively. We found significant relationships between IADL limitations and physical frailty (Odds Ratio (OR) 1.24, 95% confidence interval (95% CI) 1.01 to 1.52), cognitive impairment (OR 1.71, 95% CI 1.39 to 2.11), and cognitive frailty (OR 2.63, 95% CI 1.74 to 3.97). CONCLUSION: Using the NCGG-SGS frailty criteria, we found more participants with physical frailty than with cognitive frailty. The individuals with cognitive frailty had the highest risks of IADL limitations. Future investigation is necessary to determine whether this population is at increased risk for incidence of disability or mortality. PMID- 27499308 TI - Physical Activity and Early Rehabilitation in Hospitalized Elderly Medical Patients: Systematic Review of Randomized Clinical Trials. AB - BACKGROUND: To critically review the effect of interventions incorporating exercise and early rehabilitation (physical therapy, occupational therapy, and physical activity) in the functional outcomes (i.e., active daily living tests, such as Barthel Index Scores, Timed-up-and go, mobility tests), and feasibility in hospitalized elderly medical patients. DESIGN: Systematic review of the literature. METHODS: A literature search was conducted using the following databases and medical resources from 1966 to January 2014: PubMed (Medline), PEDro, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews, Google Scholar, ClinicalTrials.gov, Clinical Evidence, SportsDiscus, EMBASE and UptoDate. Studies must have mentioned the effects of early rehabilitation on the above mentioned functional outcomes and feasibility. Data on the mortality, economic profile and average stay were also described. RESULTS: From the 6564 manuscripts potentially related to exercise performance in hospitalized elderly patients, the review focused on 1086, and 17 articles were ultimately included. Regarding functional outcomes after discharge, four studies observed significant improvement in functional outcomes following early rehabilitation, even up to twelve months after discharge. Eight studies directly or indirectly assessed the economic impact of exercise intervention. Five of them did not show any increase in costs, while three concluded that the intervention was cost effective. No adverse effect related with the interventions were mentioned. CONCLUSION: The introduction of an exercise program for hospitalized elderly patients may be feasible, and may not increase costs. Importantly, early rehabilitation may also improve the functional and healthcare. PMID- 27499309 TI - Accelerometer Assessment of Physical Activity and Its Association with Physical Function in Older Adults Residing at Assisted Care Facilities. AB - OBJECTIVES: To describe levels of physical activity among older adults residing at assisted care facilities and their association with physical function. DESIGN: Cross-sectional analysis. SETTING: Assisted care facilities within the greater Boston, MA area. PARTICIPANTS: Older adults aged 65 years and older (N = 65). MEASUREMENTS: Physical Activity Level (PAL) as defined by quartiles from accelerometry (counts and steps), Short Physical Performance Battery (SPPB) Score, gait speed, and handgrip strength. RESULTS: Participants in the most active accelerometry quartile engaged in 25 minutes/week of moderate to vigorous physical activity (MVPA) and walked 2,150 steps/day. These individuals had an SPPB score, 400 meter walk speed, and handgrip strength that was 3.7-3.9 points, 0.3-0.4 meters/second, and 4.5-5.1 kg greater respectively, than individuals in the lowest activity quartile, who engaged in less than 5 min/wk of MVPA or took fewer than 460 steps/day. CONCLUSION: Despite engaging in physical activity levels far below current recommendations (150 min/week of MVPA or > 7000 steps/day), the most active older adults in this study exhibited clinically significant differences in physical function relative to their less active peers. While the direction of causality cannot be determined from this cross-sectional study, these findings suggest a strong association between PAL and physical function among older adults residing in an assisted care facility. PMID- 27499310 TI - A comparison of Frailty Indexes Based on a Comprehensive Geriatric Assessment for the Prediction of Adverse Outcomes. AB - OBJECTIVE: To compare the ability of different frailty indexes based on a standardized comprehensive geriatric assessment (FI-CGAs) for predicting adverse outcomes. DESIGN AND SETTING: Prospective cohort study. Geriatric wards of a general hospital. PARTICIPANTS: 307 hospitalized patients >= 65 years. MEASUREMENTS: The FI-CGA-10D (potential health deficits in ten functional domains), the FI-CGA-10D+CM (aforementioned potential health deficits and co morbidity burden) and the FI-CGA-MIHD (multiple, individual potential health deficits, including functional deficits, co-morbid diseases, amongst others) were assessed at baseline during the patients' hospital stay. The FI-CGAs were analyzed as categorical (according to a FI-CGA score < and >= 0.25) and continuous variables. Patients were followed up over 6 months. RESULTS: The FI CGA-10D, FI-CGA-10+CM and the FI-CGA-MIHD predicted 6-month mortality when expressed as categorical (area under the receiver operating characteristic curve (AUC): AUC = 0.611, AUC = 0.637, AUC = 0.616, all p < 0.050, respectively) or continuous variables (AUC = 0.769, AUC = 0.837, AUC = 0.834, all p < 0.001, respectively). AUC comparisons showed that all three FI-CGAs exhibited a comparable ability to predict 6-month mortality when the FI-CGAs were expressed as categorical variables (all p > 0.200) and the FI-CGA-10D+CM and the FI-CGA MIHD showed a better ability to predict 6-month mortality than the FI-CGA-10D, when the FI-CGAs were expressed as continuous variables (p < 0.001 and p = 0.007, respectively). None of the FI-CGAs predicted any of the other outcomes, i.e., unplanned re-admission to hospital and a fall during follow-up, irrespective of whether the FI-CGAs were expressed as categorical or continuous variables (all p >= 0.050). CONCLUSIONS: The more complex FI-CGAs, i.e., the FI-CGA-10D+CM and the FI-CGA-MIHD, revealed better ability to predict 6 month mortality than the more simple FI-CGA, i.e., the FI-CGA-10D. PMID- 27499311 TI - The Randomized Control Trial of the Effects of Testosterone and a Nutritional Supplement On Hospital Admissions in Undernourished, Community Dwelling, Older People. AB - OBJECTIVE: In a pilot single centre study we found that treatment of undernourished older, community dwelling people for one year with oral testosterone (placebo-controlled) and a nutritional supplement (no control) was associated with a significant reduction in hospitalizations. A larger, multicentre study was conducted to investigate further this potentially important finding. DESIGN: One year, randomized, placebo-controlled, multi-centre, double blind, trial. SETTING: Community. PARTICIPANTS: 53 undernourished men and women aged 65 years and older. INTERVENTION: Oral testosterone undecanoate (40 mg/day women, 160 mg/day men) and high energy oral nutritional supplement (2108-2416 kJ/day) or placebo medication and low energy (142-191 kJ/day) "placebo" oral nutritional supplementation. MEASUREMENTS: Hospital admissions, falls and other variables were assessed. RESULTS: 53 subjects were recruited (64% male and mean age 77 years), which was substantially less than planned. Sixteen subjects (30%) were admitted to hospital at least once, with a total of 29 admissions. Eight subjects (32%) in the placebo arm were admitted to hospital, whilst in the intervention group also there were eight (29%) subjects admitted to hospital during the study period. There was no difference in the number of hospitalisations (P = 0.842), length of hospitalization (P=0.645) or quality of life [mental health P=0.195 and physical health P=0.451) between the treatment arms. CONCLUSIONS: In undernourished older people, treatment with testosterone and a nutritional supplementation did not reduce the number and length of hospitalisations or improve quality of life. PMID- 27499313 TI - Identification and Quantitation of the Lipation Product 2-Amino-6-(3 methylpyridin-1-ium-1-yl)hexanoic Acid (MP-Lysine) in Peanuts. AB - The lipid peroxidation product acrolein was semiquantitated by GC-MS (EI) in unheated and heated peanut oil, respectively, representing a model system for peanut roasting. Depending on the heating time, acrolein levels significantly increased from 0.2 to 10.7 mg/kg oil. As a result of heating N(alpha)-acetyl-l lysine and acrolein, the pyridinium derivative 2-acetamido-6-(3-methylpyridin-1 ium-1-yl)hexanoic acid (MP-acetyl lysine) was identified. In addition, the lysine derivative 2-amino-6-[5-(hydroxymethyl)-3,6-dihydro-2H-pyridin-1-yl]hexanoic acid was identified after reduction and hydrolysis. After preparation of 2-amino-6-(3 methylpyridin-1-ium-1-yl)hexanoic acid (MP-lysine) as reference material, its amounts were quantitated in acrolein-modified peanut proteins by HPLC-ESI-MS/MS after acid hydrolysis, showing that at low acrolein concentrations, the modification of lysine could be entirely explained by the formation of MP-lysine. Furthermore, for the first time, MP-lysine was quantitated in peanut samples in amounts up to 10.2 mg/kg, showing an increase depending on the roasting time. Thus, MP-lysine might represent a marker to evaluate the extent of food protein lipation by acrolein. PMID- 27499312 TI - Sarcopenic Obesity: An Appraisal of the Current Status of Knowledge and Management in Elderly People. AB - Today's increased life expectancy highlights both age-related changes in body composition and a higher prevalence of obesity. Sarcopenic obesity (SO) is assuming a prominent role in cardio-metabolic risk because of the double metabolic burden derived from low muscle mass (sarcopenia) and excess adiposity (obesity). This review evaluates the related studies that have been published over the past 10 years in order to give an updated overview of this new syndrome. There is no consensus on the definition of SO due to the wide heterogeneity of diagnostic criteria and choice of body composition components needed to assess this phenotype. There is a growing body of evidence that the ethio-pathogenesis of SO is complex and multi-factorial, as the consequences are a combination of the outcomes of both sarcopenia and obesity, where the effects are maximised. In order to manage SO, it is important to make lifestyle changes that incorporate weight loss, physical exercise and protein supplementation. PMID- 27499314 TI - An integrin alphavbeta3 antagonistic modified peptide inhibits tumor growth through inhibition of the ERK and AKT signaling pathways. AB - HM-3, an RGD (Arg-Gly-Asp)-modified antitumor polypeptide designed independently, has been demonstrated for its robust inhibitory effects on tumors. However, the intravenous administration and short half-life in vivo are inconvenient to its clinical application. To solve these issues, PEGylated HM-3 (mPEG-SC20k-HM-3) with prolonged half-time in vivo and subcutaneous administration was obtained after repeated screening of different types of PEG and numerous efficacy assays. The present study aimed to evaluate the antitumor activity and investigate the mechanism of the modified peptide to interpret the antitumor properties of mPEG SC20k-HM-3 comprehensively and clearly. The results of the antitumor activity assays in vitro indicated that mPEG-SC20k-HM-3 exhibited a marked inhibitory activity on tumor metastasis and angiogenesis. mPEG-SC20k-HM-3 (73.4 mg/kg, sc) achieved a tumor inhibitory rate of 70.1% in an H460 (human non-small cell lung cancer) xenograft model with scarce cytotoxicity, compared with a rate of 72.2% for Avastin (10.0 mg/kg, iv). The mechanistic study showed that mPEG-SC20k-HM-3 could target integrin alphavbeta3 to block the downstream ERK and Akt pathways, as the expression levels of VEGF, Akt1, p-Akt1, ERK1/2, p-ERK1/2, MEK1, p-MEK1, integrin alphav and beta3 were reduced after HUVECs were incubated with mPEG SC20k-HM-3 for 24 h. In conclusion, the antitumor activity of mPEG-SC20k-HM-3 in vitro and in vivo is promising and the mechanism was clearly reflected in the present study. PMID- 27499315 TI - Are all case reports worth publishing? PMID- 27499316 TI - Is there crosstalk between subchondral bone, cartilage, and meniscus in the pathogenesis of osteoarthritis? AB - OBJECTIVES: This study aims to investigate if there is any crosstalk between subchondral bone, cartilage, and meniscus in the pathogenesis of osteoarthritis. PATIENTS AND METHODS: Twelve female patients (mean age 64 years; range 59 to 71 years) with osteoarthritis in medial compartment were included in the study. The samples of subchondral bone, cartilage and meniscus were obtained during total knee arthroplasty. Degenerated tissue samples obtained from medial compartment were used as the experimental group (12 samples of subchondral bone and cartilage, 1x1 cm each; and 12 samples of meniscus, 1x1 cm each). Healthy tissue samples obtained from lateral compartment were used as the control group (12 samples of subchondral bone and cartilage; 1x1 cm each; and 12 samples of meniscus, 1x1 cm each). After decalcification, tissue samples were evaluated with light and transmission electron microscopy. RESULTS: In the experimental group, light microscopic evaluation of subchondral bone samples demonstrated that the cartilage-to-bone transition region had an irregular structure. Degenerated cartilage cells were observed in the transition region and bone cells were significantly corrupted. In the experimental group, light microscopic evaluation of the meniscus samples demonstrated that the intercellular tissue was partly corrupted. Separation and concentration of the collagen fibers were evident. All findings were supported with ultra structural evaluations. CONCLUSION: Our findings indicate that degeneration of subchondral bone, cartilage, and meniscus probably plays a role in the pathogenesis of osteoarthritis with crosstalk. PMID- 27499317 TI - Is axial shape of distal femur different in normal and osteoarthritic female patients? AB - OBJECTIVES: This study aims to investigate whether the axial shape of the distal femur is different between normal and osteoarthritic female knees using statistical shape analysis. PATIENTS AND METHODS: A total of 126 knee magnetic resonance images of 126 female patients were examined in this study conducted between May 2013 and May 2014. Patients were divided into two groups as study and control groups. The study group consisted of 41 patients (median age 65 years; min. 36 - max. 88 years) who were determined to have knee osteoarthritis, while the control group consisted of 85 patients (median age 43 years; min. 20 - max. 81 years) without knee osteoarthritis. Anatomic and constructive landmarks were selected and marked on each two-dimensional digital image in the axial section of the distal femur. The mean axial shapes of the distal femur were compared between the groups by statistical shape analysis. Shape deformations were investigated by thin plate spline analysis. RESULTS: There were significant differences between the groups regarding the axial shape of the distal femur. Maximal deformation was observed in the femoral notch area. CONCLUSION: This study showed that there are deformations in the axial shape of the distal femur in female patients with knee osteoarthritis. Further studies are required to determine whether these differences are important for implant design and surgical technique of total knee replacement. PMID- 27499318 TI - Comparison of the clinical and radiological outcomes of open reduction via medial and anterior approach in devleopmental dysplasia of the hip. AB - OBJECTIVES: This study aims to investigate the effects of surgical approach on the clinical and radiological outcomes, the incidence of avascular necrosis (AVN), and the need for revision surgery in children undergoing open reduction via medial or anterior approach for developmental dysplasia of the hip (DDH). PATIENTS AND METHODS: Forty-three hips of 36 patients (9 males, 27 females; mean age 13.8 month; range 6 to 18 months) treated for DDH, followed-up regularly for at least four years between January 1997 and December 2010, and who were aged five or above in the final control were included in this retrospective study. Patients were divided into two groups according to surgical approaches. Group 1 consisted of 21 hips of 19 patients who underwent open reduction through medial approach. Group 2 consisted of 22 hips of 17 patients who underwent open reduction through anterior approach. Groups were compared in terms of clinical and radiological outcomes as well as the incidence of AVN and the need for revision surgery. RESULTS: There was no statistically significant difference between the groups with respect to clinical and radiological outcomes (p=0.407 and p=0.661, respectively). Similarly, there was no statistically significant difference between the groups in terms of AVN incidence and need for revision surgery (p=0.993 and p=0.170, respectively). On the other hand, acetabular index improved significantly in both groups at follow-up. CONCLUSION: This study showed that open reduction via medial or anterior approach in DDH has similar clinical and radiological results, significant improvement was achieved in the acetabular index with both approaches, and no significant difference was present in the incidence of AVN and the need for revision surgery between the groups. PMID- 27499319 TI - [Early-term hip development following Pemberton osteotomy: a radiological follow up]. AB - OBJECTIVES: This study aims to evaluate the relationship of early-term radiological changes with development of the hip joint after Pemberton osteotomy. PATIENTS AND METHODS: This study, which was conducted between January 2010 and December 2014, included 101 hips (26 bilateral) of 75 patients (25 males, 50 females; mean age 31.5 months; range 15 to 71 months) which were performed Pemberton osteotomy due to developmental dysplasia of the hip. Radiologically, we assessed the parameters of center-edge angle, acetabular index (AI), and acetabular depth index (ADI). We measured the surface area of the femoral head ossific nucleus on anterior-posterior pelvic X-rays. We graded the degree of hip dislocation according to Tonnis classification while the femoral head avascular necrosis was graded according to Kalamchi-MacEwen classification. We separated the operated hips in all patients and in only unilaterally operated patients in three groups according to their follow-up durations as 12 months, 12 to 24 months, and more than 24 months. We analyzed the associations of radiological parameters in all follow-up durations. RESULTS: Mean follow-up duration was 22.5 months (range, 6 to 66 months). Preoperative mean AI was 42.25 degrees (range, 29 degrees to 60 degrees ) and last follow-up mean AI was 20.45 degrees (range, 10 degrees to 32 degrees ). Preoperative mean ADI was 16.48 degrees (range, 9 degrees -30 degrees ) and last follow-up mean ADI was 26.1 degrees (range, 23 degrees -47 degrees ). Sixty hips were Tonnis type 4, 26 hips were type 3, and 15 hips were type 2. According to follow-up duration classification; there were 32 hips (21 unilateral) with 12 month-follow-up, 43 hips (17 unilateral) with 12-24 month-follow-up, and 26 hips (11 unilateral) with more than 24-month follow-up. We applied shortening osteotomy to 18 femurs. According to Kalamchi-MacEwen classification; avascular necrosis type 1 was present in 16 hips, type 2 in two hips, type 3 in three hips, and type 4 in two hips. We performed revision operations for five hips because of recurrent subluxations. CONCLUSION: We observed progressive improvements in hip joints and consequently in radiological parameters in the early-term after Pemberton osteotomy. PMID- 27499320 TI - Effect of ulnar styloid fracture on outcomes after conservative treatment of distal radius fracture. AB - OBJECTIVES: This study aims to investigate the effect of accompanying ulnar styloid fracture (USF) on clinical outcomes and hand-wrist muscle strength in conservatively treated active patients after displaced distal radius fracture (DRF). PATIENTS AND METHODS: The retrospective study, which was conducted November 2012 and September 2016, included 56 patients (34 males, 22 females; mean age 28.8 years; range 20 to 40 years) with displaced DRF treated with closed reduction and casting. Patients were divided into three groups according to ulnar styloid status as group A (intact ulnar styloid), group B (USF non-union), and group C (healed USF). Grip strength, quick-disabilities of the arm, shoulder and hand (DASH) score, and joint range of motions were evaluated; the results were combined with measurements of isokinetic muscle strengths of hand-wrist region. Magnetic resonance imaging was performed to evaluate the accompaniment of distal radioulnar joint injury and triangular fibrocartilage complex (TFCC) lesion. RESULTS: There were no significant differences between the groups regarding joint range of motion, grip strength, and quick-DASH scores. However, the peak torque and total work of supination was better in group A compared to group B (p=0.008 and p=0.006, respectively). According to the magnetic resonance imaging findings, of the 10 patients with detected TFCC lesion, four were in group C, five in group B, and one was in group A. CONCLUSION: Results of this study suggest that USF should not be the focus of attention during initial treatment of DRF and surgical intervention might be considered in case of an accompanying TFCC lesion. PMID- 27499321 TI - Primary malignant fibrous histiocytoma of long bones: long-term follow-up. AB - OBJECTIVES: This study aims to evaluate patients diagnosed with malignant fibrous histiocytoma and investigate the possible prognostic factors associated with duration of survival. PATIENTS AND METHODS: The study, which was conducted between May 1994 and September 2013, included 14 patients diagnosed as malignant fibrous histiocytoma (12 males, 2 females; median age 48 years; range 17 to 64 years). We evaluated patients' demographic features, location of the pathology, histological findings, surgical margins, and treatment modalities and investigated the effects of these parameters on survival. RESULTS: Femur was the most frequently involved bone, followed by tibia and humerus. The median follow up duration of the patients was 129 months. We performed limb salvage surgeries in 13 patients and amputation in one patient. Surgical margins were marginal in three patients and postoperative radiotherapy was performed for local control of the disease. Although there was no local recurrence in these patients, distant metastasis developed in two patients, indicating the importance of surgical margin as a significant factor on survival. Five-year survival rate was 81.9% in patients with wide surgical margins and 33.3% in patients with marginal margins. CONCLUSION: Surgical excision with wide margins and adjuvant chemotherapy provided adequate control of the disease and longer survival. The only prognostic factor statistically significantly associated with duration of survival was surgical margins. Neoadjuvant chemotherapy may be used when there is a suspicion of not obtaining adequately wide surgical margin perioperatively due to close association with neurovascular structures. PMID- 27499322 TI - Less invasive surgery using external fixator for the treatment of subtrochanteric femur fracture in a high-risk geriatric patient. AB - A 90-year-old female patient was admitted to our clinic complaining of pain in her left hip which occurred due to fall from a chair. Her medical history included memory loss and mental changes associated with Alzheimer's disease and depression. Patient's cooperation and orientation were weak. Range of motion of the left hip was restricted and painful. Radiographs of the left hip demonstrated subtrochanteric comminuted fracture of femur. Laboratory tests revealed anemia and liver insufficiency. Departments of internal medicine and anesthesiology reported high risk for surgery. Surgery was performed under spinal anesthesia on radiolucent table and in supine position. Using fluoroscopy, subtrochanteric comminuted fracture of femur was reduced. Proximally, two Schanz screws were placed through femoral neck and head in axial plane, and distally, three Schanz screws were placed through femoral shaft in coronal plane. Finally, fixation of the screws was achieved with an external fixator which was made of carbon fiber rods. Patient was allowed to sit in the bed and move around with a wheelchair as of the day of surgery. No infection or loosening of fixator occurred. PMID- 27499323 TI - Painful, pediatric sacral aneurysmal bone cyst treated by curettage and fresh frozen allograft. AB - In this article, we report a rarely localized sacral aneurysmal bone cyst (ABC) successfully treated by curettage and bone grafting with fresh frozen fibular allograft (FFA) in a 14-year-old girl patient. The cyst was at S1-2 level and treated with aggressive curettage and bone grafting with two FFAs. All complaints of the patient resolved at the 24th month of treatment and bony union of the cystic cavity was observed radiologically. Curettage and FFA may be safely used for filling the cavity in the treatment of sacral ABC in pediatric age to provide a structural and biological reinforcement. PMID- 27499324 TI - Malignant transformation of aggressive osteoblastoma to ostesarcoma. AB - Osteoblastoma is a rare, bone-forming tumor, characterized by osteoid and woven bone production. A 13-year-old boy patient presented to our clinic with complaint of pain in his left proximal tibia. We performed curettage and bone grafting for the lesion diagnosed as osteoblastoma. Two years later, the patient admitted to the hospital with a mass in the same region which was diagnosed by biopsy to be osteosarcoma. Patient was performed reconstruction operation with local resection and mega prosthesis. Fourteen months after termination of chemotherapy, lung metastasis developed and the patient died consequently. In this article, we reported a patient with aggressive osteoblastoma of the left proximal tibia which recurred as an osteosarcoma and discussed the difficulties in the histopathological diagnosis and management of these patients. As some other cases in the literature, our case indicates that osteoblastomas may undergo malignant transformation. PMID- 27499325 TI - Open Galeazzi fracture with ipsilateral elbow dislocation. AB - Combination of the Galeazzi fracture and dislocation of the elbow joint in same extremity is very rare. In this article, we report a 26-year-old male patient with a posterolateral dislocation of the elbow and ipsilateral volar type Galeazzi fracture. We performed closed reduction for the elbow dislocation during admission to the emergency department. Patient was taken to the operating room in the sixth hour of his application to emergency department and open wound on the ulnovolar region of the wrist was closed primarily after irrigation and debridement. We performed open reduction and internal fixation of the radial fracture with a dynamic compression plate. After fixation, we evaluated the stability of the elbow joint and distal radioulnar joint. Distal radioulnar joint was unstable under fluoroscopic examination and fixed with one 1.8 mm Kirschner wire in a pronated position. Then, elbow joint was stable. One year after surgery, patient had no pain or sings of instability. At the last follow-up, range of motion of the elbow was 10 degrees -135 degrees and forearm pronation and supination were 70 degrees . PMID- 27499326 TI - Above-knee amputation followed by femoral replantation: 21-year follow-up results after lower limb replantation. AB - In this article, we report successful treatment of serious complications of replantation after traumatic mid-third femoral amputation. To the best of our knowledge, no similar case has been reported in the literature. A 38-year-old healthy male sustained a mid-third right traumatic femoral amputation. We performed replantation. Oliguria and anuria occurred and were treated successfully with hemofiltration and hemodialysis. Six years later, patient walked wearing orthopedic shoes and also protective sensibility recovered on the limb. Serious complications of proximal lower limb replantation can be treated successfully and the limb can be saved. PMID- 27499328 TI - Molecular and structural basis of low interfacial energy of complex coacervates in water. AB - Complex coacervate refers to a phase-separated fluid, typically of two oppositely charged polyelectrolytes in solution, representing a complex fluid system that has been shown to be of essential interest to biological systems, as well as for soft materials processing owing to the expectation of superior underwater coating or adhesion properties. The significance and interest in complex coacervate fluids critically rely on its low interfacial tension with respect to water that, in turn, facilitates the wetting of macromolecular or material surfaces under aqueous conditions, provided there is attractive interaction between the polyelectrolyte constituents and the surface. However, the molecular and structural bases of these properties remain unclear. Recent studies propose that the formation of water-filled and bifluidic sponge-like nanostructured network, driven by the tuning of electrostatic interactions between the polyelectrolyte constituents or their complexes may be a common feature of complex coacervate fluids that display low fluid viscosity and low interfacial tension, but more studies are needed to verify the generality of these observations. In this review, we summarize representative studies of interfacial tension and ultrastructures of complex coacervate fluids. We highlight that a consensus property of the complex coacervate fluid is the observation of high or even bulk like water dynamics within the dense complex coacervate phase that is consistent with a low cohesive energy fluid. Our own studies on this subject are enabled by the application of magnetic resonance relaxometry methods relying on spin labels tethered to polyelectrolyte constituents or added as spin labeled probe molecules that partition into the dense versus the equilibrium coacervate phase, permitting the extraction of information on local polymer dynamics, polymer packing and local water dynamics. We conclude with a snapshot of our current perspective on the molecular and structural bases of the low interfacial tension of complex coacervate fluids. PMID- 27499327 TI - Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). AB - Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. We analysed PKD1 and PKD2, in a large cohort of 440 unrelated Italian patients with ADPKD and 203 relatives by direct sequencing and MLPA. Molecular and detailed phenotypic data have been collected and submitted to the PKD1/PKD2 LOVD database. This is the first large retrospective study in Italian patients, describing 701 variants, 249 (35.5%) already associated with ADPKD and 452 (64.5%) novel. According to the criteria adopted, the overall detection rate was 80% (352/440). Novel variants with uncertain significance were found in 14% of patients. Among patients with pathogenic variants, in 301 (85.5%) the disease is associated with PKD1, 196 (55.7%) truncating, 81 (23%) non truncating, 24 (6.8%) IF indels, and in 51 (14.5%) with PKD2. Our results outline the high allelic heterogeneity of variants, complicated by the presence of variants of uncertain significance as well as of multiple variants in the same subject. Classification of novel variants may be particularly cumbersome having an important impact on the genetic counselling. Our study confirms the importance to improve the assessment of variant pathogenicity for ADPKD; to this point databasing of both clinical and molecular data is crucial. PMID- 27499329 TI - Crosstalk between Beclin-1-dependent autophagy and caspase-dependent apoptosis induced by tanshinone IIA in human osteosarcoma MG-63 cells. AB - The aim of the present study was to ascertain whether or not autophagy is induced by tanshinone IIA (TanIIA), and to explore the crosstalk between autophagy and apoptosis in regards to the antitumor effects of TanIIA on MG-63 cells and the potential mechanism. MG-63 cells were cultured in vitro with various concentrations of TanIIA (0, 2.5, 5, 10 and 20 mg/l) for 0, 24, 48 and 72 h, respectively. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MTT assay was used to evaluate the inhibition of the proliferation of osteosarcoma MG 63 cells by TanIIA or in the presence/absence of chloroquine (CQ). Autophagic vacuoles and characteristic autophagosomes were observed by transmission electron microscopy (TEM). TanIIA-induced autophagy in MG-63 cells was confirmed by GFP LC3 punctate fluorescence. The expression levels of apoptosis-related proteins caspase-3, caspase-8, caspase-9 and cleaved-PARP and autophagy-related proteins LC3II/LC3I and Beclin-1 were detected by western blotting. FITC-Annexin V/propidium iodide (PI) staining, flow cytometry and Hoechst 33258 staining were used to analyze the apoptotic rate. Fluorescence intensity of reactive oxygen species (ROS) was examined under a fluorescence microscope using an analysis software system. Cell proliferation was obviously inhibited by TanIIA in a dose- and time-dependent manner. Generation of autophagy was triggered by TanIIA (0-20 mg/l) treatment, and in a Beclin-1-dependent manner. Compared with the control group, the apoptosis ratio following treatment with 2.5 mg/l TanIIA failed to achieve statistical significance. Expression of caspase-3, -8 and -9, and cleaved PARP in the other groups was gradually enhanced in dose-dependent manner. Our analysis also suggested that the influence of autophagy on TanIIA cytotoxicity had a phase effect; with low-dose drugs and shorter treatment periods, autophagy functioned as a damage repair mechanism. In conrast, when the cells were treated with higher doses of TanIIA for longer treatment periods, autophagic cell death contributed to apoptosis. Furthermore, generation of ROS occurred in a dose dependent manner and pretreatment with NAC, a selective ROS scavenger, blocked the coexistence of Beclin-1 autophagy and caspase-dependent apoptosis. In conclusion, our findings provide strong evidence that TanIIA may be a potential therapeutic drug against osteosarcoma. Moreover, its cytotoxity can be enhanced with ROS agonists. PMID- 27499330 TI - Non-ceruloplasmin bound copper and ATP7B gene variants in Alzheimer's disease. AB - ATP7B, a protein mainly expressed in the hepatocytes, is a copper chaperone that loads the metal into the serum copper-protein ceruloplasmin during its synthesis and also escorts superfluous copper into the bile, by a sophisticated trafficking mechanism. Impaired function of this ATPase is associated with a well-known inborn error of copper metabolism, Wilson's disease (WD). Several mutations of ATP7B are known, involving different regions of the protein, thus resulting in a plethora of phenotypes in WD patients. It is a consolidated notion that copper dysmetabolism occurs in Alzheimer's disease (AD) as well. Besides the molecular mechanisms relating copper to the protein hallmarks of this disease and neurodegeneration, more recently the observation that a free-copper in the serum, not bound to ceruloplasmin (non-Cp-Cu), characterizes AD patients, prompted our research to identify possible genetic defects of the ATP7B gene in AD patients. Four specific single nucleotide polymorphisms and a WD rare mutation have a statistical association with AD. They contribute to characterize a copper subtype of AD. Additional facets of this AD phenotype, typified by higher levels of non Cp-Cu, are presented and discussed in the framework of copper failure as an accelerator risk factor of neurological disorders with different aetiology. PMID- 27499331 TI - Clinical disposition, metabolism and in vitro drug-drug interaction properties of omadacycline. AB - 1. Absorption, distribution, metabolism, transport and elimination properties of omadacycline, an aminomethylcycline antibiotic, were investigated in vitro and in a study in healthy male subjects. 2. Omadacycline was metabolically stable in human liver microsomes and hepatocytes and did not inhibit or induce any of the nine cytochrome P450 or five transporters tested. Omadacycline was a substrate of P-glycoprotein, but not of the other transporters. 3. Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300 mg oral dose of [14C]-omadacycline (36.6 MUCi). Absorption was rapid with peak radioactivity (~610 ngEq/mL) between 1-4 h in plasma or blood. The AUClast of plasma radioactivity (only quantifiable to 8 h due to low radioactivity) was 3096 ngEq h/mL and apparent terminal half-life was 11.1 h. Unchanged omadacycline reached peak plasma concentrations (~563 ng/mL) between 1-4 h. Apparent plasma half-life was 17.6 h with biphasic elimination. Plasma exposure (AUCinf) averaged 9418 ng h/mL, with high clearance (CL/F, 32.8 L/h) and volume of distribution (Vz/F 828 L). No plasma metabolites were observed. 4. Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer. PMID- 27499332 TI - 18(th)World Congress of Psychophysiology (IOP2016), Havana, Cuba. PMID- 27499334 TI - Isolation and Characterization of a Highly Mutated Chinese Isolate of Enterovirus B84 from a Patient with Acute Flaccid Paralysis. AB - Enterovirus B84 (EV-B84) is a newly identified serotype within the species Enterovirus B (EV-B). To date, only ten nucleotide sequences of EV-B84 are published and only one full-length genome sequence (the prototype strain) is available in the GenBank database. Here, a highly mutated EV-B84 (strain AFP452/GD/CHN/2004) was recovered from a patient with acute flaccid paralysis in the Guangdong province of China in 2004 making this the first report of EV-B84 in China. Sequence comparison and phylogenetic dendrogram analysis revealed high variation from the global EV-B84 strains (African and Indian strains) and frequent intertypic recombination in the non-structural protein region, suggesting high genetic diversity in EV-B84. The Chinese EV-B84 strain, apparently evolving independently of the other ten strains, strongly suggests that the EV-B84 strain has been circulating for many years. However, the extremely low isolation rate suggests that it is not a prevalent EV serotype in China or worldwide. This study provides valuable information about the molecular epidemiology of EV-B84 in China, and will be helpful in future studies to understand the association of EV-B84 with neurological disorders; it also helps expand the number of whole virus genome sequences of EV-B84 in the GenBank database. PMID- 27499336 TI - Migration of an ingested fish bone into the paraglottic space. AB - BACKGROUND: Ingested foreign bodies are common emergencies encountered in otolaryngology practice. The vast majority can be managed with endoscopic removal. Migration of foreign bodies into the paraglottic space is a rare event that often necessitates using a more invasive procedure for removal. CASE REPORT: A 68-year-old man presented with sore throat and odynophagia 4 days after ingesting a fish bone. RESULTS: A computed tomography scan revealed a 2.5 cm linear foreign body embedded in the larynx within the right paraglottic space. The patient underwent endoscopic examination and transcervical exploration of the paraglottic space via a posterolateral approach, with successful removal of the foreign body on the second attempt. CONCLUSION: This is the first case report of an ingested paraglottic space foreign body managed by transcervical exploration using a posterolateral approach to the paraglottic space. PMID- 27499337 TI - Effects of Carnitine on Valproic Acid Pharmacokinetics in Rats. AB - The long-term administration of valproic acid (VPA) may decrease the plasma concentrations of l-carnitine in epileptic patients. l-Carnitine is essential for the beta-oxidation of fatty acids. The aim of this study is to determine whether endogenous l-carnitine affects the pharmacokinetics of VPA in l-carnitine deficient (CD) rats. An l-carnitine deficiency was induced in rats using sodium pivalate. The pharmacokinetics of VPA were examined following its intravenous or oral administration to rats. The plasma and urine concentrations of VPA and its metabolites were determined using gas chromatography-mass spectrometry methods. Plasma VPA concentrations were slightly higher in CD rats than in control rats, whereas no significant differences were observed in the area under the curve or mean residence times of VPA between the 2 groups. After i.v. administration, the slope of the elimination phase (k) was significantly higher in CD rats than in control rats (p < 0.01). Some of the beta-oxidation metabolites of VPA in plasma and urine decreased, while the glucuronide metabolites of VPA in urine increased complementarily in CD rats. Based on these results, it was concluded that hypocarnitinemia could affect the pharmacokinetics of VPA. PMID- 27499335 TI - Resin embedded multicycle imaging (REMI): a tool to evaluate protein domains. AB - Protein complexes associated with cellular processes comprise a significant fraction of all biology, but our understanding of their heterogeneous organization remains inadequate, particularly for physiological densities of multiple protein species. Towards resolving this limitation, we here present a new technique based on resin-embedded multicycle imaging (REMI) of proteins in situ. By stabilizing protein structure and antigenicity in acrylic resins, affinity labels were repeatedly applied, imaged, removed, and replaced. In principle, an arbitrarily large number of proteins of interest may be imaged on the same specimen with subsequent digital overlay. A series of novel preparative methods were developed to address the problem of imaging multiple protein species in areas of the plasma membrane or volumes of cytoplasm of individual cells. For multiplexed examination of antibody staining we used straightforward computational techniques to align sequential images, and super-resolution microscopy was used to further define membrane protein colocalization. We give one example of a fibroblast membrane with eight multiplexed proteins. A simple statistical analysis of this limited membrane proteomic dataset is sufficient to demonstrate the analytical power contributed by additional imaged proteins when studying membrane protein domains. PMID- 27499338 TI - New and Evolving Techniques for the Characterization of Peptide Therapeutics. AB - Advances in technologies related to the design and manufacture of therapeutic peptides have enabled researchers to overcome the biological and technological challenges that have limited their application in the past. As a result, peptides of increasing complexity have become progressively important against a variety of disease targets. Developing peptide drug products brings with it unique scientific challenges consistent with the unique physicochemical properties of peptide molecules. The identification of the proper characterization tools is required in order to develop peptide formulations with the appropriate stability, manufacturability, and bioperformance characteristics. This knowledge supports the build of critical quality attributes and, ultimately, regulatory specifications. The purpose of this review article is to provide an overview of the techniques that are employed for analytical characterization of peptide drug products. The techniques covered are highlighted in the context of peptide drug product understanding and include chemical and biophysical approaches. Emphasis is placed on summarizing the recent literature experience in the field. Finally, the authors provide regulatory perspective on these characterization approaches and discuss some potential areas for further research in the field. PMID- 27499339 TI - Who's responsible for publication ethics? All of us. PMID- 27499340 TI - Quantitative parameters for the examination of InGaN QW multilayers by low-loss EELS. AB - We present a detailed examination of a multiple InxGa1-xN quantum well (QW) structure for optoelectronic applications. The characterization is carried out using scanning transmission electron microscopy (STEM), combining high-angle annular dark field (HAADF) imaging and electron energy loss spectroscopy (EELS). Fluctuations in the QW thickness and composition are observed in atomic resolution images. The impact of these small changes on the electronic properties of the semiconductor material is measured through spatially localized low-loss EELS, obtaining band gap and plasmon energy values. Because of the small size of the InGaN QW layers additional effects hinder the analysis. Hence, additional parameters were explored, which can be assessed using the same EELS data and give further information. For instance, plasmon width was studied using a model-based fit approach to the plasmon peak; observing a broadening of this peak can be related to the chemical and structural inhomogeneity in the InGaN QW layers. Additionally, Kramers-Kronig analysis (KKA) was used to calculate the complex dielectric function (CDF) from the EELS spectrum images (SIs). After this analysis, the electron effective mass and the sample absolute thickness were obtained, and an alternative method for the assessment of plasmon energy was demonstrated. Also after KKA, the normalization of the energy-loss spectrum allows us to analyze the Ga 3d transition, which provides additional chemical information at great spatial resolution. Each one of these methods is presented in this work together with a critical discussion of their advantages and drawbacks. PMID- 27499341 TI - Ovarian cancer in the older woman. AB - Ovarian cancer is the seventh most common cancer in women worldwide and accounts for nearly 4% of all new cases of cancer in women. Almost half of all patients with ovarian cancer are over the age of 65 at diagnosis, and over 70% of deaths from ovarian cancer occur in this same age group. As the population ages, the number of older women with ovarian cancer is increasing. Compared to younger women, older women with ovarian cancer receive less surgery and chemotherapy, develop worse toxicity, and have poorer outcomes. They are also significantly under-represented in clinical trials and thus application of standard treatment regimens can be challenging. Performance status alone has been shown to be an inadequate tool to predict toxicity of older patients from chemotherapy. Use of formal geriatric assessment tools is a promising direction for stratifying older patients on trials. Elderly-specific trials, adjustments to the eligibility criteria, modified treatment regimens, and interventions to decrease morbidities in the vulnerable older population should be encouraged. PMID- 27499342 TI - Fluorescence based Aptasensors for the determination of hepatitis B virus e antigen. AB - This research is aimed at selecting specific aptamer of hepatitis B e antigen by SELEX and its applications. Hepatitis B e antigen (HBeAg) seroconversion is used as an indicator of virological response when treating patients suffering from chronic hepatitis B. HBeAg also indicates a high viremia and high infectivity in untreated patients. With HBeAg modified magnetic beads as targets, three groups of aptamers are successfully selected. These are the first reported DNA aptamers that can specifically bind to HBeAg. Based on the property that the conformation changes upon binding to its target, aptamer has emerged as ideal candidate in a variety of sensing applications. In this study, we present a simple strategy for aptamer-based fluorescence biosensors for the quantitative detection of HBeAg, in which a fluorescence labeled HBeAg aptamer serves as the molecular recognition element and a short DNA molecule that is complementary to the aptamer serves as the competitor. The LOD for HBeAg is 609 ng/mL. Later, the fluorescence system is deployed in HBeAg positive and negative blood serum (p < 0.05). The total detection assay could be completed in 2 min. These newly isolated aptamers could assist the diagnosis of chronic hepatitis B. PMID- 27499343 TI - Dynamic Variables Fail to Predict Fluid Responsiveness in an Animal Model With Pericardial Effusion. AB - OBJECTIVES: The reliability of dynamic and volumetric variables of fluid responsiveness in the presence of pericardial effusion is still elusive. The aim of the present study was to investigate their predictive power in a porcine model with hemodynamic relevant pericardial effusion. DESIGN: A single-center animal investigation. PARTICIPANTS: Twelve German domestic pigs. INTERVENTIONS: Pigs were studied before and during pericardial effusion. Instrumentation included a pulmonary artery catheter and a transpulmonary thermodilution catheter in the femoral artery. Hemodynamic variables like cardiac output (COPAC) and stroke volume (SVPAC) derived from pulmonary artery catheter, global end-diastolic volume (GEDV), stroke volume variation (SVV), and pulse-pressure variation (PPV) were obtained. MEASUREMENTS AND MAIN RESULTS: At baseline, SVV, PPV, GEDV, COPAC, and SVPAC reliably predicted fluid responsiveness (area under the curve 0.81 [p = 0.02], 0.82 [p = 0.02], 0.74 [p = 0.07], 0.74 [p = 0.07], 0.82 [p = 0.02]). After establishment of pericardial effusion the predictive power of dynamic variables was impaired and only COPAC and SVPAC and GEDV allowed significant prediction of fluid responsiveness (area under the curve 0.77 [p = 0.04], 0.76 [p = 0.05], 0.83 [p = 0.01]) with clinically relevant changes in threshold values. CONCLUSIONS: In this porcine model, hemodynamic relevant pericardial effusion abolished the ability of dynamic variables to predict fluid responsiveness. COPAC, SVPAC, and GEDV enabled prediction, but their threshold values were significantly changed. PMID- 27499344 TI - Giant Peripheral Pulmonary Artery Aneurysm Rupture Under Anesthesia-A Sequela of Positive-Pressure Ventilation. PMID- 27499345 TI - Demographics and Scholarly Productivity of American Board of Anesthesiology Volunteers: Results of an Internet-Based Bibliometric Analysis. AB - OBJECTIVE: The American Board of Anesthesiology (ABA) has been responsible for certification of anesthesiologists since 1938. Selected ABA diplomates provide their expertise to write the ABA's written and oral examinations and to administer the oral examination required for primary certification. The demographics, administrative and educational duties, and scholarly productivity of ABA volunteers and their dependence on subspecialty certification, transesophageal echocardiography (TEE) credentials, and grant funding are unknown. DESIGN: Observational study. SETTING: Internet analysis. PARTICIPANTS: ABA volunteers who participated in the 2015 primary certification examinations identified from the 2016 issue of ABA News. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The 2016 issue of ABA News was downloaded from the public ABA website and was used to identify all volunteers who participated in any aspect of the 2015 primary certification process. Each individual's practice type, faculty rank if applicable, and affiliation were identified using Google with the keyword "anesthesiology." The practice location, time, and interval after original ABA certification; additional ABA subspecialty certification; the number of publications and citations; publication rate; citations per publication; and the H-, M-, and i-10 indices were obtained using the ABA and Scopus databases. Credentials in TEE were identified for each individual using the National Board of Echocardiography database. National Institutes of Health (NIH) and Foundation for Anesthesia Education and Research (FAER) funding for each volunteer was evaluated using NIH Research Portfolio Online Reporting Tools and the FAER alumni databases, respectively. Three hundred ninety-three ABA volunteers were identified and analyzed. Three hundred ten individuals currently hold academic appointments (83.5%), whereas 83 (16.5%) hold private practice or military positions. Sixty-seven volunteers have major administrative roles (eg, dean, chief executive officer, associate or assistant dean, chair, vice chair). Thirty five individuals are program directors of anesthesiology residencies or fellowships. Volunteers published 10,072 manuscripts that have been cited 194,835 times. Volunteers also received 51 NIH grants and 36 FAER grants. The median H-, M-, and i10-indices of volunteers were 4, 0, and 3, respectively. Scholarly productivity was dependent on academic rank, career duration, additional degrees, and extramural funding, but not on practice location, subspecialty certification, TEE credentials, or sex. CONCLUSIONS: These results indicated that ABA volunteers are leaders in anesthesiology with established records of administrative, educational, and scholarly accomplishment. PMID- 27499347 TI - Why Are There Different Languages? The Role of Adaptation in Linguistic Diversity. AB - Why are there different languages? A common explanation is that different languages arise from the gradual accumulation of random changes. Here, we argue that, beyond these random factors, linguistic differences, from sounds to grammars, may also reflect adaptations to different environments in which the languages are learned and used. The aspects of the environment that could shape language include the social, the physical, and the technological. PMID- 27499346 TI - Worldwide Opinion on Multicenter Randomized Interventions Showing Mortality Reduction in Critically Ill Patients: A Democracy-Based Medicine Approach. AB - OBJECTIVES: Democracy-based medicine is a combination of evidence-based medicine (systematic review), expert assessment, and worldwide voting by physicians to express their opinions and self-reported practice via the Internet. The authors applied democracy-based medicine to key trials in critical care medicine. DESIGN AND SETTING: A systematic review of literature followed by web-based voting on findings of a consensus conference. PARTICIPANTS: A total of 555 clinicians from 61 countries. INTERVENTIONS: The authors performed a systematic literature review (via searching MEDLINE/PubMed, Scopus, and Embase) and selected all multicenter randomized clinical trials in critical care that reported a significant effect on survival and were endorsed by expert clinicians. Then they solicited voting and self-reported practice on such evidence via an interactive Internet questionnaire. Relationships among trial sample size, design, and respondents' agreement were investigated. The gap between agreement and use/avoidance and the influence of country origin on physicians' approach to interventions also were investigated. MEASUREMENTS AND MAIN RESULTS: According to 24 multicenter randomized controlled trials, 15 interventions affecting mortality were identified. Wide variabilities in both the level of agreement and reported practice among different interventions and countries were found. Moreover, agreement and reported practice often did not coincide. Finally, a positive correlation among agreement, trial sample size, and number of included centers was found. On the contrary, trial design did not influence clinicians' agreement. CONCLUSIONS: Physicians' clinical practice and agreement with the literature vary among different interventions and countries. The role of these interventions in affecting survival should be further investigated to reduce both the gap between evidence and clinical practice and transnational differences. PMID- 27499348 TI - The Psychology and Neuroscience of Financial Decision Making. AB - Financial decisions are among the most important life-shaping decisions that people make. We review facts about financial decisions and what cognitive and neural processes influence them. Because of cognitive constraints and a low average level of financial literacy, many household decisions violate sound financial principles. Households typically have underdiversified stock holdings and low retirement savings rates. Investors overextrapolate from past returns and trade too often. Even top corporate managers, who are typically highly educated, make decisions that are affected by overconfidence and personal history. Many of these behaviors can be explained by well-known principles from cognitive science. A boom in high-quality accumulated evidence-especially how practical, low-cost 'nudges' can improve financial decisions-is already giving clear guidance for balanced government regulation. PMID- 27499349 TI - Sulforaphane increases the efficacy of anti-androgens by rapidly decreasing androgen receptor levels in prostate cancer cells. AB - Prostate cancer (PCa) cells utilize androgen for their growth. Hence, androgen deprivation therapy (ADT) using anti-androgens, e.g. bicalutamide (BIC) and enzalutamide (ENZ), is a mainstay of treatment. However, the outgrowth of castration resistant PCa (CRPC) cells remains a significant problem. These CRPC cells express androgen receptor (AR) and utilize the intratumoral androgen towards their continued growth and invasion. Sulforaphane (SFN), a naturally occurring isothiocyanate found in cruciferous vegetables, can decrease AR protein levels. In the present study, we tested the combined efficacy of anti-androgens and SFN in suppressing PCa cell growth, motility and clonogenic ability. Both androgen-dependent (LNCaP) and androgen-independent (C4-2B) cells were used to monitor the effects of BIC and ENZ, alone and in combination with SFN. Co exposure to SFN significantly (p<0.005) enhanced the anti-proliferative effects of anti-androgens and downregulated expression of the AR-responsive gene, prostate specific antigen (PSA) (p<0.05). Exposure to SFN decreased AR protein levels in a time- and dose-dependent manner with almost no AR detected at 24 h with 15 uM SFN (p<0.005). This rapid and potent AR suppression by SFN occurred by both AR protein degradation, as suggested by cycloheximide (CHX) co-exposure studies, and by suppression of AR gene expression, as evident from quantitative RT-PCR experiments. Pre-exposure to SFN also reduced R1881-stimulated nuclear localization of AR, and combined treatment with SFN and anti-androgens abrogated the mitogenic effects of this AR-agonist (p<0.005). Wound-healing assays revealed that co-exposure to SFN and anti-androgens can significantly (p<0.005) reduce PCa cell migration. In addition, long-term exposures (14 days) to much lower concentrations of these agents, SFN (0.2 uM), BIC (1 uM) and/or ENZ (0.4 uM) significantly (p<0.005) decreased the number of colony forming units (CFUs). These findings clearly suggest that SFN may be used as a promising adjunct agent to augment the efficacy of anti-androgens against aggressive PCa cells. PMID- 27499350 TI - Mental illness and the right to vote: a review of legislation across the world. AB - The right to vote is an important right signifying freedom of thought as well as full citizenship in any setting. Right to vote is enshrined and protected by international human rights treaties. The right of 'everyone' to take part in the political process and elections is based on universal and equal suffrage. Although these International Conventions have been ratified by the large majority of United Nations Member States, their application across the globe is by no means universal. This study sets out to examine the domestic laws of UN Member States in order to explore whether individuals with mental health problems have the right to vote in actuality and, thu,s can participate in political life. Through various searches, electoral laws and Constitutions of 193 Member States of the United Nations were studied. The authors were able to find legislation and/or Constitutional provisions in 167 of the 193 Member States. Twenty-one countries (11%) only placed no restrictions on the right to vote by persons with mental health problems. Over one third of the countries (36%) deny all persons with any mental health problems a right to vote without any qualifier. Some of these discriminatory attitudes are reflected in the multiplicity of terms used to describe persons with mental health problems. Another 21 countries (11%) denied the right to vote to detained persons; of these, nine Member States specifically denied the right to vote to persons who were detained under the mental health law, while the remainder denied the right to vote to all those who were interdicted or judicially interdicted. It would appear that in many countries the denial of voting rights is attributed to a lack of ability to consent by the individuals with mental illness. Further exploration of explanation is required to understand these variations, which exist in spite of international treaties. PMID- 27499351 TI - Molecular mechanism of hepatic steatosis: pathophysiological role of autophagy. AB - Steatosis is an early characteristic in the pathogenesis of fatty liver disease (FLD). Mechanisms of hepatic steatosis are aetiology-dependent. Activation of autophagy in liver ameliorates hepatic steatosis. A modulation of hepatic autophagy affects the degree of hepatocyte steatosis and the progression of FLD as demonstrated by pre-clinical models and clinical trials. This review summarises recent advances on pathophysiological roles of autophagy in hepatic lipid metabolism. A comprehensive regulation of autophagic networks holds promise for the improvement of hepatic steatosis. Autophagic signalling pathway may be a novel therapeutic target against FLD. HIGHLIGHTS: * Hepatic steatosis is a pathological condition wherein vacuoles of triglyceride (TG) fat are overaccumulated in liver because of abnormal metabolism of lipids. * Hepatic autophagy regulates lipid metabolism as demonstrated by macrolipophagy in response to starvation and hepatic overabundance of TG in obesity. * Autophagic signals are closely associated with apoptotic pathways. There is distinctive relationship between hepatic autophagy and apoptosis, which affects the progression of fatty liver. * Regulation of autophagic process can be a novel therapeutic strategy for fatty liver disease. PMID- 27499352 TI - Nonionic surfactant structure on the drug release, formulation and physical properties of ethylcellulose microspheres. AB - Evaluate the effects of nonionic surfactants Brij 58 and Tween 40 with different structures but similar hydrophilic lipophilic balances (HLBs) on theophylline (TH)-loaded ethylcellulose (EC) microspheres. Microspheres were formulated using ratios of the surfactants with matching HLB values but different chemical structures at temperatures (22/35 degrees C) by hydrophobic solvent-emulsion evaporation. Particle size, GMD, drug loading, encapsulation efficiency and dissolution were evaluated. Drug release was determined using the zero- and first order, Higuchi and Hixson-Crowell models. EC microspheres prepared with surfactant Brij 58 showed discrete, free-flowing spherical particles, solid interiors and increased particle smoothness as temperature increased; those prepared with Tween 40 appeared porous with coarser surface morphology as temperature increased; both were CHLB (Combined HLB) dependent. Dissolution obeyed the Higuchi model drug release for both microspheres prepared with Tween 40 and Brij 58 except for those prepared with Brij 58 at 35 degrees C, which presented as zero order. The results were ascribed to the different chemical structure of Brij 58 versus Tween 40 and preparation temperature. Surfactant chemical structure is an unreported processing parameter shown here to be important in microsphere formulation. Brij 58 possesses properties unique to its chemical structure that influence pharmaceutical and molecular biopharmaceutical research. PMID- 27499353 TI - Wastewater Reuse for Agriculture: Development of a Regional Water Reuse Decision Support Model (RWRM) for Cost-Effective Irrigation Sources. AB - Water scarcity has become a critical problem in many semiarid and arid regions. The single largest water use in such regions is for crop irrigation, which typically relies on groundwater and surface water sources. With increasing stress on these traditional water sources, it is important to consider alternative irrigation sources for areas with limited freshwater resources. One potential irrigation water resource is treated wastewater for agricultural fields located near urban centers. In addition, treated wastewater can contribute an appreciable amount of necessary nutrients for plants. The suitability of reclaimed water for specific applications depends on water quality and usage requirements. The main factors that determine the suitability of recycled water for agricultural irrigation are salinity, heavy metals, and pathogens, which cause adverse effects on human, plants, and soils. In this paper, we develop a regional water reuse decision-support model (RWRM) using the general algebraic modeling system to analyze the cost-effectiveness of alternative treatment trains to generate irrigation water from reclaimed wastewater, with the irrigation water designed to meet crop requirements as well as California's wastewater reuse regulations (Title 22). Using a cost-minimization framework, least-cost solutions consisting of treatment processes and their intensities (blending ratios) are identified to produce alternative irrigation sources for citrus and turfgrass. Our analysis illustrates the benefits of employing an optimization framework and flexible treatment design to identify cost-effective blending opportunities that may produce high-quality irrigation water for a wide range of end uses. PMID- 27499354 TI - Effects of mutants in bHLH region on structure stability and protein-DNA binding energy in DECs. AB - The human DEC subfamily contains two highly conserved members belonging to basic helix-loop-helix (bHLH) transcription factors. This conserved family is spread widely among various species with the function of regulating various crucial molecular signaling pathways. Due to the significance of DECs for important biological processes, their relationship with diseases and the lack of experimentally proven structures, we have implemented a comparative modeling for the bHLH region of DECs as homodimers with themselves and heterodimers with HES 1. Three mutants with predicted roles in reducing intramolecular binding (H57A, R65A, and LL7879AA in DEC1 and LL7071AA in DEC2) were investigated on DEC monomers. Molecular dynamics (MD) simulations were also employed to evaluate the behavior of the mutant molecules in aqueous solution. The monomer was divided into subregions for accurate investigation. The fluctuation in the basic region of mutants was higher than that of wild-type molecules. The binding energy value between protein and DNA obviously increased in the homodimer harboring R65A mutants, which led to more unstable status between protein and DNA. Thus, the mutant R65A interfered DNA-binding affinity. A study on the spatial structures of wild-type and mutant DECs may facilitate functional prediction for mutation effects and dynamic behavior under various conditions and may ultimately help in targeted drug design. PMID- 27499355 TI - The global diabetes epidemic: what does it mean for infectious diseases in tropical countries? AB - Tropical countries are experiencing a substantial rise in type 2 diabetes, which is often undiagnosed or poorly controlled. Since diabetes is a risk factor for many infectious diseases, this increase probably adds to the large infectious disease burden in tropical countries. We reviewed the literature to investigate the interface between diabetes and infections in tropical countries, including the WHO-defined neglected tropical diseases. Although solid data are sparse, patients with diabetes living in tropical countries most likely face increased risks of common and health-care-associated infections, as well as infected foot ulcers, which often lead to amputation. There is strong evidence that diabetes increases the severity of some endemic infections such as tuberculosis, melioidosis, and dengue virus infection. Some HIV and antiparasitic drugs might induce diabetes, whereas helminth infections appear to afford some protection against future diabetes. But there are no or very scarce data for most tropical infections and for possible biological mechanisms underlying associations with diabetes. The rise in diabetes and other non-communicable diseases puts a heavy toll on health systems in tropical countries. On the other hand, complications common to both diabetes and some tropical infections might provide an opportunity for shared services-for example, for eye health (trachoma and onchocerciasis), ulcer care (leprosy), or renal support (schistosomiasis). More research about the interaction of diabetes and infections in tropical countries is needed, and the infectious disease burden in these countries is another reason to step up global efforts to improve prevention and care for diabetes. PMID- 27499356 TI - Dosimetric characteristics of four PTW microDiamond detectors in high-energy proton beams. AB - Small diamond detectors are useful for the dosimetry of high-energy proton beams. However, linear energy transfer (LET) dependence has been observed in the literature with such solid state detectors. A novel synthetic diamond detector has recently become commercially available from the manufacturer PTW-Freiburg (PTW microDiamond type 60019). This study was designed to thoroughly characterize four microDiamond detectors in clinical proton beams, in order to investigate their response and their reproducibility in high LET regions. Very good dosimetric characteristics were observed for two of them, with good stability of their response (deviation less than 0.4% after a pre-irradiation dose of approximately 12 Gy), good repeatability (coefficient of variation of 0.06%) and a sensitivity of approximately 0.85 nC Gy(-1). A negligible dose rate dependence was also observed for these two microDiamonds with a deviation of the sensitivity less than 0.7% with respect to the one measured at the reference dose rate of 2.17 Gy min(-1), in the investigated dose rate range from 1.01 Gy min(-1) to 5.52 Gy min(-1). Lateral dose profile measurements showed the high spatial resolution of the microDiamond oriented with its stem perpendicular to the beam axis and with its small sensitive thickness of about 1 MUm in the scanning profile direction. Finally, no significant LET dependence was found with these two diamond dosimeters in comparison to a reference ionization chamber (model IBA PPC05). These good results were in accordance to the literature. However, this study showed also a non reproducibility between the devices in terms of stability, sensitivity and LET dependence, since the two other microDiamonds characterized in this work showed different dosimetric characteristics making them not suitable for proton beam dosimetry with a maximum difference of the peak to-plateau ratio of 6.7% relative to the reference ionization chamber in a clinical 138 MeV proton beam. PMID- 27499357 TI - The EGFR pathway is involved in the regulation of PD-L1 expression via the IL 6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer. AB - Negative regulation of the signal mediated by the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway can effectively inhibit the function of T and B cells, which play a key role in the regulation of immune response. Recently, emerging evidence has suggested that the expression of PD-L1 is related to the mutation status of the epidermal growth factor receptor (EGFR). Moreover, the activation of the EGFR signaling pathway can induce expression of PD-L1. In the present study, we demonstrated that activated EGFR can upregulate the expression of PD-L1 through the interleukin 6/Janus kinase/signal transducer and activator of transcription 3 (IL-6/JAK/STAT3) signaling pathway in non-small cell lung cancer (NSCLC) cells. Cells treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) can downregulate the activation of the IL-6/JAK/STAT3 pathway, which subsequently reduces the expression of PD L1. Furthermore, silencing of PD-L1 expression in NSCLC cells correlated with inhibition of cell proliferation and enhanced tumor cell apoptosis. In summary, our research indicates that EGFR is involved in the regulation of PD-L1 expression and cell proliferation via the IL-6/JAK/STAT3 signaling pathway in NSCLC. The present study suggests the potential of combined targeted therapy with immunotherapy in the treatment of NSCLC. PMID- 27499358 TI - Characteristics of a professional: survey of primary care and non-primary care residents. PMID- 27499359 TI - The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations. AB - Fluoroalkylation reaction, featuring the transfer of a fluoroalkyl group to a substrate, is a straightforward and efficient method for the synthesis of organofluorine compounds. In fluoroalkylation reactions, fluorine substitution can dramatically influence the chemical outcome. On the one hand, the chemistry of alkylation with non-fluorinated reagents may not be applicable to fluoroalkylations, so it is necessary to tackle the fluorine effects to achieve efficient fluoroalkylation reactions. On the other hand, fluorine substitution may bring about new reactivities and transformations that cannot be realized in alkylation with non-fluorinated reagents; thus, fluorine substitution can be used to explore new synthetic methods. This tutorial review provides a brief overview of the unique fluorine effects in recently developed nucleophilic, electrophilic, radical, and transition metal-mediated fluoroalkylation reactions by comparing with either their non-fluorinated counterparts or fluorinated counterparts with different numbers of fluorine substituents. PMID- 27499361 TI - Safety and tolerability of long-acting injectable versus oral antipsychotics: A meta-analysis of randomized controlled studies comparing the same antipsychotics. AB - OBJECTIVE: We aimed to assess whether long-acting injectable antipsychotics (LAIs), which are initiated in a loading strategy or overlapping with oral antipsychotics (OAPs) and which cannot be stopped immediately, are associated with greater safety/tolerability issues than OAPs. METHOD: Systematic review and meta-analysis of randomized controlled trials (RCTs) comparing LAIs and OAPs, including only LAI-OAP pairs of the same OAP (allowing oral risperidone and paliperidone as comparators for either risperidone or paliperidone LAI). Primary outcome was treatment discontinuation due to adverse events. Secondary outcomes included serious adverse events, death, >=1 adverse event and individual adverse event rates. RESULTS: Across 16 RCTs (n=4902, mean age=36.4years, males=65.8%, schizophrenia=99.1%) reporting on 119 adverse event outcomes, 55 (46.2%) adverse events were reported by >=2 studies allowing a formal meta-analysis. Out of all 119 reported adverse events, LAIs and OAPs did not differ significantly regarding 115 (96.6%). LAIs were similar to OAPs regarding the frequency of treatment discontinuation due to adverse events, serious adverse events, all-cause death and death for reasons excluding accident or suicide. Compared to OAPs, LAIs were associated with significantly more akinesia, low-density lipoprotein cholesterol change and anxiety. Conversely, LAIs were associated with significantly lower prolactin change. CONCLUSION: LAIs and OAPs did not differ on all serious and >90% of individual adverse events. However, more studies focusing on adverse event frequencies, severity and time course associated with LAI vs OAP formulations of the same antipsychotic are needed. Additionally, adverse events data for LAIs after stopping overlapping oral antipsychotic treatment are needed. PMID- 27499362 TI - Subcortical grey matter alterations in cocaine dependent individuals with substance-induced psychosis compared to non-psychotic cocaine users. AB - After prolonged psychostimulant abuse, transient psychotic symptoms referred to as "substance-induced psychosis" (SIP) can develop - closely resembling symptoms observed in schizophrenia spectrum disorders. The comparability in psychotic presentation between SIP and schizophrenias suggests that similar underlying neural deficits may contribute to the expression of psychosis across these disorders. To date, neuroanatomical characterization of grey matter structural alterations in SIP has been limited to methamphetamine associated psychosis, with no studies controlling for potential neurotoxic effects of the psychostimulant that precipitates psychosis. To investigate grey matter subcortical alterations in SIP, a voxel-based analysis of magnetic resonance images (MRI) was performed between a group of 74 cocaine dependent nonpsychotic individuals and a group of 29 individuals with cocaine-associated psychosis. The cocaine-associated psychosis group had significantly smaller volumes of the thalamus and left hippocampus, controlling for age, total brain volume, current methamphetamine dependence, and current marijuana dependence. No differences were present in bilateral caudate structures. The findings of reduced thalamic and hippocampal volumes agree with previous reports in the schizophrenia literature, suggesting alterations of these structures are not specific to schizophrenia, but may be common to multiple forms of psychosis. PMID- 27499360 TI - Exploring the risk factors for differences in the cumulative incidence of coeliac disease in two neighboring countries: the prospective DIABIMMUNE study. AB - BACKGROUND: During the last several decades the prevalence of coeliac disease (CD) has increased worldwide. AIM: To compare the cumulative incidence of CD between Estonian and Finnish children and to identify the risk factors. MATERIALS AND METHODS: Children were recruited as part of the DIABIMMUNE Study. In the birth cohort (BC) 258 children from Estonia and 305 from Finland, and in the young children's cohort (YCC) 1363 and 1384 children were followed up, respectively. The diagnosis of CD was made in accordance with the ESPGHAN guidelines-the presence of IgA-tTG antibodies and small bowel villous atrophy. RESULTS: During the study period 29 children developed CD. The cumulative incidence of CD was significantly higher in Finland (0.77% vs 0.27%; P=0.01). No difference was seen between the children with CD and the controls in the duration of breastfeeding or the age at cereal introduction. The BC children with CD had had significantly more episodes of infections with fever by the age of 12 months compared to the controls (3.4 vs 1.4; P=0.04). CONCLUSION: The 5-year cumulative incidence of childhood CD is significantly higher in Finland than in Estonia. Sequential infections early in life may increase the risk for developing CD. PMID- 27499363 TI - A workshop on leadership for senior MD-PhD students. AB - Leadership skills are essential for a successful career as a physician-scientist, yet many MD-PhD training programs do not offer formal training in leadership. The Vanderbilt Medical Scientist Training Program (MSTP) previously established a 2 day leadership workshop that has been held biennially since 2006 for students in the first and second years of the graduate school portion of combined MD and PhD training (G1/G2 students). Workshop attendees have consistently rated this workshop as a highly effective experience. However, opportunities for structured training in leadership competencies during the subsequent 3-5 years of MD-PhD training are limited. Given the success of the G1/G2 leadership workshop and the need for continuity in this model of leadership training, we developed a half-day workshop for MSTP students in the clinical years of medical school (M3/M4 students) to foster continued training in leadership. Our workshop curriculum, based in part on original cases drafted by Vanderbilt MSTP students, provides concrete strategies to manage conflict and navigate leadership transitions in the physician-scientist career path. The curriculum emphasizes both short-term competencies, such as effective participation as a member of a clinical team, and long-term competencies, such as leadership of a research team, division, or department. Our inaugural senior leadership workshop, held in August, 2015, was judged by student participants to be well organized and highly relevant to leadership concepts and skills. It will be offered biennially in our training curriculum for M3 and M4 MSTP students. PMID- 27499364 TI - What and how do students learn in an interprofessional student-run clinic? An educational framework for team-based care. AB - BACKGROUND: The student-run clinic (SRC) has the potential to address interprofessional learning among health professions students. PURPOSE: To derive a framework for understanding student learning during team-based care provided in an interprofessional SRC serving underserved patients. METHODS: The authors recruited students for a focus group study by purposive sampling and snowballing. They constructed two sets of semi-structured questions for uniprofessional and multiprofessional groups. Sessions were audiotaped, and transcripts were independently coded and adjudicated. Major themes about learning content and processes were extracted. Grounded theory was followed after data synthesis and interpretation to establish a framework for interprofessional learning. RESULTS: Thirty-six students from four professions (medicine, physician assistant, occupational therapy, and pharmacy) participated in eight uniprofessional groups; 14 students participated in three multiprofessional groups (N = 50). Theme saturation was achieved. Six common themes about learning content from uniprofessional groups were role recognition, team-based care appreciation, patient experience, advocacy-/systems-based models, personal skills, and career choices. Occupational therapy students expressed self-advocacy, and medical students expressed humility and self-discovery. Synthesis of themes from all groups suggests a learning continuum that begins with the team huddle and continues with shared patient care and social interactions. Opportunity to observe and interact with other professions in action is key to the learning process. DISCUSSION: Interprofessional SRC participation promotes learning 'with, from, and about' each other. Participation challenges misconceptions and sensitizes students to patient experiences, health systems, advocacy, and social responsibility. Learning involves interprofessional interactions in the patient encounter, reinforced by formal and informal communications. Participation is associated with interest in serving the underserved and in primary care careers. The authors proposed a framework for interprofessional learning with implications for optimal learning environments to promote team-based care. Future research is suggested to identify core faculty functions and best settings to advance and enhance student preparation for future collaborative team practice. PMID- 27499366 TI - Is there a role for gut microbiota in type 1 diabetes pathogenesis? AB - Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by insufficient insulin production due to the destruction of insulin secreting beta cells in the Langerhans islets. A variety of factors, including chemicals, viruses, commensal bacteria and diet have been proposed to contribute to the risk of developing the disorder. In the last years, gut microbiota has been proposed as a main factor in T1D pathogenesis. Several alterations of gut microbiota composition were described both in animal model and in humans. The decrease of Firmicutes/Bacteroides ratio was the most frequent pattern described, in particular, in human studies. Furthermore, Bacteroides, Clostridium cluster XIVa, Lactobacillus, Bifidobacterium, and Prevotella relative abundances were different in healthy and affected subjects. Dysbiosis would seem to increase intestinal permeability and thus promote the development of a pro-inflammatory niche that stimulates beta-cell autoimmunity in predisposed subjects. Preliminary studies on animal models were realized to investigate the role of gut microbiota modulation as therapy or prevention approach in predisposed animals: promising and stimulating results have been reported. Key message Dietary antigens and microbiota-derived products might act as triggers of T1D by causing a pro inflammatory and metabolic dysfunctional environment. PMID- 27499367 TI - miR-17 inhibits ovarian cancer cell peritoneal metastasis by targeting ITGA5 and ITGB1. AB - An essential step in the peritoneal spread of ovarian cancer is the adhesion and implantation of tumor cells to the mesothelium layer. Integrin alpha5 and beta1 have been reported to mediate the initial adhesion process and to correlate with disease survival in ovarian cancer. However, the molecular mechanism of integrin alpha5beta1 dysregulation in tumorigenesis and metastasis remained enigmatic. In the present study, using the US NCI60 database, we identified miR-17 as a candidate regulator targeting both integrin alpha5 and beta1. The level of miR-17 was evidently inversely correlated with that of alpha5 and beta1 in ovarian cancer cell lines. Specifically, miR-17 bound directly to the 3' untranslated region (3'UTR) of alpha5 and beta1 and suppressed their expression. Forced expression of miR-17 led to markedly diminished adhesion and invasion of ovarian cancer cells in vitro, and notably reduced metastatic nodules inside the peritoneal cavity in in vivo SKOV3 xenografts model. Moreover, ectopic expression of miR-17 in ovarian cancer cells resulted in repressed ILK phosphorylation as well as decreased production of active matrix metalloproteinase-2 (MMP-2). Our results indicated that miR-17 hampered ovarian cancer peritoneal propagation by targeting integrin alpha5 and beta1. These findings supported the utility of miR 17/alpha5beta1 to be considered as valuable marker for metastatic potential of ovarian cancer cells, or a therapeutic target in ovarian cancer treatment. PMID- 27499365 TI - Real-time optical diagnosis of gastric cancer with serosal invasion using multiphoton imaging. AB - A real-time optical biopsy, which could determine tissue histopathology, would be of extraordinary benefit to staging laparoscopy for gastric cancer with serosal invasion (T4) that requires downstage treatment. We investigated the feasibility of using multiphoton imaging to perform a real-time optical diagnosis of gastric cancer with or without serosal invasion. First, a pilot study was performed to establish the optical diagnostic features of gastric cancer with or without serosal invasion using multiphoton imaging compared with hematoxylin-eosin staining and Masson's trichrome staining. Second, a blinded study was performed to compare the diagnostic sensitivity, specificity, and accuracy of multiphoton imaging and endoscopic ultrasonography (EUS) for T4 gastric cancer. In the pilot study, multiphoton imaging revealed collagen loss and degradation and cellular and nuclear pleomorphism in gastric cancer with serosal invasion. The collagen content in gastric cancer with or without serosal invasion was 0.36 +/- 0.18 and 0.79 +/- 0.16 (p < 0.001), respectively. In the blinded study, the sensitivity, specificity, and accuracy of EUS and multiphoton imaging for T4 gastric cancer were 70% and 90% (p = 0.029), 66.67% and 96.67% (p = 0.003), and 68.33% and 93.33% (p = 0.001), respectively. It is feasible to use multiphoton imaging to make a real-time optical diagnosis of gastric cancer with or without serosal invasion. PMID- 27499368 TI - In vitro cytotoxicity of novel 2,5,7-tricarbo-substituted indoles derived from 2 amino-5-bromo-3-iodoacetophenone. AB - A series of novel 2,5,7-tricarbo-substituted indoles were prepared via sequential Sonogashira and Suzuki-Miyaura cross-coupling of 2-amino-5-bromo-3 iodoacetophenone with terminal acetylenes and aryl/styrylboronic acids followed by palladium chloride-mediated heteroannulation of the incipient 5-aryl/styryl substituted 2-amino-3-(arylalkynyl)acetophenones. These polycarbo-substituted indole derivatives were evaluated for potential in vitro antiproliferative activity against the human breast adenocarcinoma (MCF-7) and human cervical cancer (HeLa) cell lines. Compounds 6f, 6i, 6k, 6m and 6n were found to exhibit significant cytotoxicity and selectivity against the HeLa cells. Compounds 6i and 6m were chosen as representative examples to evaluate their pro-apoptotic efficacy against the HeLa cell line. The compounds induced apoptosis through cell membrane alteration and DNA fragmentation caspase-dependent pathways. PMID- 27499370 TI - Comparison between beta radiation dose distribution due to LDR and HDR ocular brachytherapy applicators using GATE Monte Carlo platform. AB - Eye applicators with 90Sr/90Y and 106Ru/106Rh beta-ray sources are generally used in brachytherapy for the treatment of eye diseases as uveal melanoma. Whenever, radiation is used in treatment, dosimetry is essential. However, knowledge of the exact dose distribution is a critical decision-making to the outcome of the treatment. The Monte Carlo technique provides a powerful tool for calculation of the dose and dose distributions which helps to predict and determine the doses from different shapes of various types of eye applicators more accurately. The aim of this work consisted in using the Monte Carlo GATE platform to calculate the 3D dose distribution on a mathematical model of the human eye according to international recommendations. Mathematical models were developed for four ophthalmic applicators, two HDR 90Sr applicators SIA.20 and SIA.6, and two LDR 106Ru applicators, a concave CCB model and a flat CCB model. In present work, considering a heterogeneous eye phantom and the chosen tumor, obtained results with the use of GATE for mean doses distributions in a phantom and according to international recommendations show a discrepancy with respect to those specified by the manufacturers. The QC of dosimetric parameters shows that contrarily to the other applicators, the SIA.20 applicator is consistent with recommendations. The GATE platform show that the SIA.20 applicator present better results, namely the dose delivered to critical structures were lower compared to those obtained for the other applicators, and the SIA.6 applicator, simulated with MCNPX generates higher lens doses than those generated by GATE. PMID- 27499371 TI - CyberKnife beam output factor measurements: A multi-site and multi-detector study. AB - PURPOSE: New promising detectors are available for measuring small field size output factors (OFs). This study focused on a multicenter evaluation of two new generation detectors for OF measurements on CyberKnife systems. METHODS: PTW 60019 microDiamond and W1 plastic scintillation detector (PSD) were used to measure OFs on eight CyberKnife units of various generations for 5-60mm fixed cones. MicroDiamond and PSD OF were compared to routinely used silicon diodes data corrected applying published Monte Carlo (MC) factors. PSD data were corrected for Cerenkov Light Ratio (CLR). The uncertainties related to CLR determination were estimated. RESULTS: Considering OF values averaged over all centers, the differences between MC corrected diode and the other two detectors were within 1.5%. MicroDiamond exhibited an over-response of 1.3% at 7.5mm and a trend inversion at 5mm with a difference of 0.2%. This behavior was consistent among the different units. OFs measured by PSD slightly under-responded compared to MC corrected diode for the smaller cones and the differences were within 1%. The observed CLR variability was 2.5% and the related variation in OF values was 1.9%. CONCLUSION: This study indicates that CyberKnife microDiamond OF require corrections below 2%. The results are enhanced by the consistency observed among different units. Scintillator shows a good agreement to MC corrected diode but CLR determination remains critical requiring further investigations. The results emphasized the value of a multi-center validation over a single center approach. PMID- 27499369 TI - Ca-asp bound X-ray structure and inhibition of Bacillus anthracis dihydroorotase (DHOase). AB - Dihydroorotase (DHOase) is the third enzyme in the de novo pyrimidine synthesis pathway and is responsible for the reversible cyclization of carbamyl-aspartate (Ca-asp) to dihydroorotate (DHO). DHOase is further divided into two classes based on several structural characteristics, one of which is the length of the flexible catalytic loop that interacts with the substrate, Ca-asp, regulating the enzyme activity. Here, we present the crystal structure of Class I Bacillus anthracis DHOase with Ca-asp in the active site, which shows the peptide backbone of glycine in the shorter loop forming the necessary hydrogen bonds with the substrate, in place of the two threonines found in Class II DHOases. Despite the differences in the catalytic loop, the structure confirms that the key interactions between the substrate and active site residues are similar between Class I and Class II DHOase enzymes, which we further validated by mutagenesis studies. B. anthracis DHOase is also a potential antibacterial drug target. In order to identify prospective inhibitors, we performed high-throughput screening against several libraries using a colorimetric enzymatic assay and an orthogonal fluorescence thermal binding assay. Surface plasmon resonance was used for determining binding affinity (KD) and competition analysis with Ca-asp. Our results highlight that the primary difference between Class I and Class II DHOase is the catalytic loop. We also identify several compounds that can potentially be further optimized as potential B. anthracis inhibitors. PMID- 27499373 TI - Origin of Pressure-induced Superconducting Phase in KxFe2-ySe2 studied by Synchrotron X-ray Diffraction and Spectroscopy. AB - Pressure dependence of the electronic and crystal structures of KxFe2-ySe2, which has pressure-induced two superconducting domes of SC I and SC II, was investigated by x-ray emission spectroscopy and diffraction. X-ray diffraction data show that compressibility along the c-axis changes around 12 GPa, where a new superconducting phase of SC II appears. This suggests a possible tetragonal to collapsed tetragonal phase transition. X-ray emission spectroscopy data also shows the change in the electronic structure around 12 GPa. These results can be explained by the scenario that the two SC domes under pressure originate from the change of Fermi surface topology. Our results here show the pronounced increase of the density of states near the Fermi surface under pressure with a structural phase transition, which can help address our fundamental understanding for the appearance of the SC II phase. PMID- 27499372 TI - Adipocyte in vascular wall can induce the rupture of abdominal aortic aneurysm. AB - Abdominal aortic aneurysm (AAA) is a vascular disease involving the gradual dilation of the abdominal aorta. It has been reported that development of AAA is associated with inflammation of the vascular wall; however, the mechanism of AAA rupture is not fully understood. In this study, we investigated the mechanism underlying AAA rupture using a hypoperfusion-induced animal model. We found that the administration of triolein increased the AAA rupture rate in the animal model and that the number of adipocytes was increased in ruptured vascular walls compared to non-ruptured walls. In the ruptured group, macrophage infiltration and the protein levels of matrix metalloproteinases 2 and 9 were increased in the areas around adipocytes, while collagen-positive areas were decreased in the areas with adipocytes compared to those without adipocytes. The administration of fish oil, which suppresses adipocyte hypertrophy, decreased the number and size of adipocytes, as well as decreased the risk of AAA rupture ratio by 0.23 compared to the triolein administered group. In human AAA samples, the amount of triglyceride in the adventitia was correlated with the diameter of the AAA. These results suggest that AAA rupture is related to the abnormal appearance of adipocytes in the vascular wall. PMID- 27499374 TI - Effects of adult day care services on disability in older persons: Evaluation of a designed service package in Iran. AB - OBJECTIVE: To assess the effects of a rehabilitation service package designed by the State Welfare Organization of Iran for adult day care centres on the disability of older clients. METHODS: A case-control study, with 46 older participants in the case group and 46 participants, matched for level of disability, in a control group. The World Health Organization Disability Assessment Schedule 2 was used to collect data at 4 time-points: baseline and 2, 4, and 6 months later. Data were analysed using repeated-measures analysis of variation. RESULTS: The rehabilitation service package had significant effects on the disability scores of older users of day care services. The disability scores significantly changed within the subjects (p = 0.010) and between the 2 groups (p < 0.001). Within-subjects effects in all 6 domains ("understanding and communication" (p = 0.002), "getting around" (p = 0.046), "self-care" (p < 0.001), "getting along with people" (p < 0.001), "life activity" (p < 0.001) and "participation" (p < 0.001)) and between-subjects effects, in all except the "self-care" domain, showed significant differences during the 6-month study period (p = 0.003, p < 0.001, p <0.001, p < 0.001, and p < 0.001, respectively). CONCLUSION: The adult day care service package may have a positive role in decreasing measures of disability among older persons over a 6-month period. PMID- 27499375 TI - Disorder engineering and conductivity dome in ReS2 with electrolyte gating. AB - Atomically thin rhenium disulphide (ReS2) is a member of the transition metal dichalcogenide family of materials. This two-dimensional semiconductor is characterized by weak interlayer coupling and a distorted 1T structure, which leads to anisotropy in electrical and optical properties. Here we report on the electrical transport study of mono- and multilayer ReS2 with polymer electrolyte gating. We find that the conductivity of monolayer ReS2 is completely suppressed at high carrier densities, an unusual feature unique to monolayers, making ReS2 the first example of such a material. Using dual-gated devices, we can distinguish the gate-induced doping from the electrostatic disorder induced by the polymer electrolyte itself. Theoretical calculations and a transport model indicate that the observed conductivity suppression can be explained by a combination of a narrow conduction band and Anderson localization due to electrolyte-induced disorder. PMID- 27499376 TI - Structural origin of proton mobility in a protic ionic liquid/imidazole mixture: insights from computational and experimental results. AB - The structure, dynamics, and phase behavior of a binary mixture based on the protic ionic liquid 1-ethylimidazolium bis(trifluoromethanesulfonyl)imide (C2HImTFSI) and imidazole are investigated by (1)H NMR spectroscopy, vibrational spectroscopy, diffusion NMR, calorimetric measurements, and molecular dynamics simulations. Particular attention is given to the nature of the H-bonds established and the consequent occurrence of the Grotthuss mechanism of proton transfer. We find that due to their structural similarity, the imidazolium cation and the imidazole molecule behave as interchangeable and competing sites of interaction for the TFSI anion. All investigated properties, that is the phase behavior, strength of ion-ion and ion-imidazole interactions, number of specific H-bonds, density, and self-diffusivity, are composition dependent and show trend changes at mole fractions of imidazole (chi) approximately equal to 0.2 and 0.5. Beyond chi = 0.8 imidazole is not miscible in C2HImTFSI at room temperature. We find that at the equimolar composition (chi ~ 0.5) a structural transition occurs from an ionic network mainly stabilized by coulombic forces to a mixed phase held together by site specific H-bonds. The same composition also marks a steeper decrease in density and increase in diffusivity, resulting from the preference of imidazole molecules to H-bond to each other in a chain-like manner. As a result of these structural features the Grotthuss mechanism of proton transfer is less favored at the equimolar composition where H-bonds are too stable. By contrast, the Grotthuss mechanism is more pronounced in the low concentration range where imidazole acts as a base pulling the proton of the imidazolium cation. At high imidazole concentrations the contribution from the vehicular mechanism dominates. PMID- 27499377 TI - Composite End Points in Acute Heart Failure Research: Data Simulations Illustrate the Limitations. AB - Composite end points are frequently used in clinical trials of investigational treatments for acute heart failure, eg, to boost statistical power and reduce the overall sample size. By incorporating multiple and varying types of clinical outcomes they provide a test for the overall efficacy of the treatment. Our objective is to compare the performance of popular composite end points in terms of statistical power and describe the uncertainty in these power estimates and issues concerning implementation. We consider several composites that incorporate outcomes of varying types (eg, time to event, categorical, and continuous). Data are simulated for 5 outcomes, and the composites are derived and compared. Power is evaluated graphically while varying the size of the treatment effects, thus describing the sensitivity of power to varying circumstances and eventualities such as opposing effects. The average z score offered the most power, although caution should be exercised when opposing effects are anticipated. Results emphasize the importance of an a priori assessment of power and scientific basis for construction, including the weighting of individual outcomes deduced from data simulations. The interpretation of a composite should be made alongside results from the individual components. The average z score offers the most power, but this should be considered in the research context and is not without its limitations. PMID- 27499378 TI - SuPAR Predicts Cardiovascular Events and Mortality in Patients With Asymptomatic Aortic Stenosis. AB - BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory marker associated with subclinical cardiovascular damage and cardiovascular events. Whether suPAR is of prognostic value in asymptomatic patients with aortic stenosis (AS) remains unknown. METHODS: Plasma suPAR levels were measured in 1503 patients with a mean age of 68 years who were recruited in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Cox regression analysis was performed to evaluate associations between suPAR and the composite end points of ischemic cardiovascular events (ICEs), aortic valve events (AVEs), cardiovascular and all-cause mortality after adjusting for traditional cardiovascular risk factors, and allocation to treatment. RESULTS: The multivariate adjusted hazard ratio (HR) (95% confidence interval [CI]) per unit log2 ng/mL increase in suPAR was HR, 1.5; 95% CI, 1.2-1.9; P = 0.002 for ICEs; HR, 1.2; 95% CI, 0.9-1.5; P = 0.071) for AVEs; HR, 2.0; 95% CI, 1.2-3.3; P = 0.007) for cardiovascular mortality, and HR, 2.0; 95% CI, 1.4-2.9; P < 0.001 for all-cause mortality. CONCLUSIONS: In patients with mild-moderate AS, suPAR is independently associated with the incidence of ICEs, cardiovascular mortality, and all-cause mortality. PMID- 27499379 TI - Antibody-Dependent Cellular Cytotoxicity Activity of Effector Cells from HIV Infected Elite and Viral Controllers. AB - Carriage of alleles encoding certain inhibitory natural killer (NK) cell receptor/HLA ligand KIR3DL1/HLA-B combinations is associated with protection from HIV infection and slow time to AIDS, implicating NK cells in HIV control. NK cells also mediate antibody-dependent cellular cytotoxicity (ADCC). ADCC has been identified as a correlate of protection in secondary analyses of the modestly protective RV144 Thai HIV vaccine trial. In ADCC, HIV envelope (Env)-specific antibodies (Abs) bridge HIV-infected or gp120-coated target cells and NK cells expressing CD16 receptors for Ab Fc domains. CD16 engagement activates NK cells to secrete cytokines/chemokines, degranulate, deliver granzyme B (GrB) to target cells, and cytolysis. A subset of HIV+ subjects, known as slow progressors (SPs), maintains low-level viremia without treatment. HIV+ SPs versus progressors have higher titers and/or a greater breadth of ADCC-competent Abs. Investigations of the functional capacity of NK effector cells following CD16 engagement in HIV+ subjects are lacking. We used the ADCC-GranToxiLux (ADCC-GTL) assay to assess the frequency of GrB+ (%GrB+) cells generated by effector cells from 37 HIV+ SPs and 15 progressors to gp120-coated CEM.NKr.CCR5 target cells in the presence of anti Env Abs. Subject groups were stratified according to whether or not they carried educating KIR3DL1/HLA-B combinations able to confer NK cells with functional potential. No differences were observed in %GrB+ target cells generated by effector cells from carriers of educating versus noneducating KIR3DL1/HLA-B pairs. The absence of an effect of NK cell education on this readout may be due to loss of the ability of educated NK cells from SPs to respond to Ab-dependent stimulation and/or the lower frequency of KIR3DL1+ than KIR3DL1- NK cells that coexpress CD16. That KIR/HLA genotypes have minimal impact on interindividual differences in ADCC potency has relevance for therapeutic interventions that target ADCC for HIV control. PMID- 27499380 TI - Aptamer-mediated universal enzyme assay based on target-triggered DNA polymerase activity. AB - We herein describe an innovative method for a universal fluorescence turn-on enzyme assay, which relies on the target enzyme-triggered DNA polymerase activity. In the first target recognition step, the target enzyme is designed to destabilize detection probe derived from an aptamer specific to DNA polymerase containing the overhang sequence and the complementary blocker DNA, which consequently leads to the recovery of DNA polymerase activity inhibited by the detection probe. This target-triggered polymerase activity is monitored in the second signal transduction step based on primer extension reaction coupled with TaqMan probe. Utilizing this design principle, we have successfully detected the activities of two model enzymes, exonuclease I and uracil DNA glycosylase with high sensitivity and selectivity. Since this strategy is composed of separated target recognition and signal transduction modules, it could be universally employed for the sensitive determination of numerous different target enzymes by simply redesigning the overhang sequence of detection probe, while keeping TaqMan probe-based signal transduction module as a universal signaling tool. PMID- 27499381 TI - Electrochemically reduced graphene and iridium oxide nanoparticles for inhibition based angiotensin-converting enzyme inhibitor detection. AB - In this work, a novel biosensor based on electrochemically reduced graphene oxide and iridium oxide nanoparticles for the detection of angiotensin-converting enzyme inhibitor drug, captopril, is presented. For the preparation of the biosensor, tyrosinase is immobilized onto screen printed electrode by using 1 Ethyl-3-(3-dimethylaminopropyl)-carbodiimide and N-Hydroxysuccinimide coupling reagents, in electrochemically reduced graphene oxide and iridium oxide nanoparticles matrix. Biosensor response is characterized towards catechol, in terms of graphene oxide concentration, number of cycles to reduce graphene oxide, volume of iridium oxide nanoparticles and tyrosinase solution. The designed biosensor is used to inhibit tyrosinase activity by Captopril, which is generally used to treat congestive heart failure. It is an angiotensin-converting enzyme inhibitor that operates via chelating copper at the active site of tyrosinase and thioquinone formation. The captopril detections using both inhibition ways are very sensitive with low limits of detection: 0.019uM and 0.008uM for chelating copper at the active site of tyrosinase and thioquinone formation, respectively. The proposed methods have been successfully applied in captopril determination in spiked human serum and pharmaceutical dosage forms with acceptable recovery values. PMID- 27499382 TI - Investigate electrochemical immunosensor of cortisol based on gold nanoparticles/magnetic functionalized reduced graphene oxide. AB - A sensitively competitive electrochemical immunosensor for the detection of cortisol was successfully developed based on gold nanoparticles and magnetic functionalized reduced graphene oxide (AuNPs/MrGO). In order to construct the base of the immunosensor, the MrGO was initially fabricated by chemical cross linking and used to modify the nafion pretreated glassy carbon electrode. Subsequently, the surface of electrode was modified by AuNPs via electrochemical deposition. A variety of cortisol (Cor) can be firmly loaded in the AuNPs/MrGO with large specific surface area and good bioactivity to construct the basic electrode (Cor/AuNPs/MrGO/Nafion@GCE), which was characterized by the cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), respectively. Due to the cortisol on the surface of basic electrode and samples can competitively combine with the cortisol antibody labelled by horseradish peroxidase (HRP-Strept-Biotin-Ab). Finally, the detection signal of electrochemical immunosensor (HRP-Strept-Biotin-Ab-Cor/AuNPs/MrGO/Nafion@GCE) in the test liquid had negative correlations with the concentration of cortisol in samples. The AuNPs/MrGO with excellent electrical conductivity being applied, the electrochemical response of the immunosensor was immensely amplified. The immunosensor displayed excellent analytical performance for the detection of cortisol range from 0.1 to 1000ng/mL with a detection limit of 0.05ng/mL at 3sigma. Moreover, compared the developed immunoassay with commercially available enzyme linked immunosorbent assay, the proposed method showed good precision, acceptable stability and reproducibility, indicating the immunosensor could be used for the sensitive, efficient and real-time detection of cortisol in real samples. Therefore, the present strategy provides a novel and convenient method for clinical determination of cortisol. PMID- 27499383 TI - Mitochondria-based biosensors with piezometric and RELS transduction for potassium uptake and release investigations. AB - Dysfunctional mitochondria appear to be involved in many diseases through their role in respiration, reactive oxygen species generation, and energy production. To aid in the design of new biosensors based on mitochondria (MT), we have investigated the feasibility of detecting ion fluxes through the MT-membrane K+ ion channels using piezosensors with MTs immobilized either by hydrogen bonding or thin polypyrrole (PPy) binding film. We have demonstrated for the first time that the mitochondria-based piezosensors are able to detect ion fluxes and thus be utilized for drug development aimed at ion channel opener- or inhibitor function. The quartz crystal resonator responding only to mass changes in the lower part of the MT film, penetrated by the acoustic wave, is able to detect a pronounced cationic dynamics in PPy-bonded MT piezosensors despite of the undoped PPy preference for pure anion dynamics. The control experiments performed by resonance elastic light scattering (RELS) confirmed MT swelling/shrinking, ion dynamics, and osmotic water transfer in MTs, as well as the effects of exposure to a drug valinomycin at sub-nanomolar concentrations. PMID- 27499384 TI - Comment on "Heavy metals in agricultural soil of the European Union with implications for food safety" by Toth, G., Hermann, T., Da Silva, M.R. and Montanarella, L. PMID- 27499386 TI - Pollution effects on biochemical pathways determined in the polychaete Hediste diversicolor collected in three Portuguese estuaries. AB - Biomonitoring is an important tool for the assessment of the quality and functions of ecosystems, providing information about the pollutants present and the direct effects that they exert on organisms. Biomonitoring relies upon the quantification of variables that can be biochemical, genetic, morphological and physiological changes. Such variables are designated as biomarkers, and multiple biomarkers are usually determined simultaneously in order to have a more integrated analysis and information about sublethal early effects of contaminants. In this work, we quantified biomarkers, associated with oxidative stress (glutathione-S-transferases GSTs, and catalase CAT, activities; levels of peroxidative alterations, by the thiobarbituric acid reactive substances assay, TBARS) and neurotoxicity (acetylcholinesterase activity, AChE) in the polychaete Hediste diversicolor. Organisms were collected at three distinct estuaries, Ria de Aveiro (Laranjo and Sao Jacinto), Douro River (Sao Paio, Afurada, and Ribeira da Granja), both impacted by human activities, and Minho River (Seixas), which has been used as a reference site. Obtained data showed the occurrence of anti oxidant responses, in most samples from contaminated sites, which was not followed however by the occurrence of oxidative damage in organisms from Ria de Aveiro. None of the analyzed organisms had significant impairment of cholinesterasic activity, suggesting the absence of a prior exposure to neurotoxic compounds. In fact, organisms collected at Ria de Aveiro had largely increased AChE activity, suggesting an uncommon paradoxical biological response that is further discussed. PMID- 27499385 TI - Association between hepatitis B co-infection and elevated liver stiffness among HIV-infected adults in Lusaka, Zambia. AB - OBJECTIVE: To describe liver disease epidemiology among HIV-infected individuals in Zambia. METHODS: We recruited HIV-infected adults (>=18 years) at antiretroviral therapy initiation at two facilities in Lusaka. Using vibration controlled transient elastography, we assessed liver stiffness, a surrogate for fibrosis/cirrhosis, and analysed liver stiffness measurements (LSM) according to established thresholds (>7.0 kPa for significant fibrosis and >11.0 kPa for cirrhosis). All participants underwent standardised screening for potential causes of liver disease including chronic hepatitis B (HBV) and C virus co infection, herbal medicine, and alcohol use. We used multivariable logistic regression to identify factors associated with elevated liver stiffness. RESULTS: Among 798 HIV-infected patients, 651 had a valid LSM (median age, 34 years; 53% female). HBV co-infection (12%) and alcohol use disorders (41%) were common and hepatitis C virus co-infection (<1%) was rare. According to LSM, 75 (12%) had significant fibrosis and 13 (2%) had cirrhosis. In multivariable analysis, HBV co infection as well as male sex, increased age and WHO clinical stage 3 or 4 were independently associated with LSM >7.0 kPa (all P < 0.05). HBV co-infection was the only independent risk factor for LSM >11.0 kPa. Among HIV-HBV patients, those with elevated ALT and HBV viral load were more likely to have significant liver fibrosis than patients with normal markers of HBV activity. CONCLUSIONS: HBV co infection was the most important risk factor for liver fibrosis and cirrhosis and should be diagnosed early in HIV care to optimise treatment outcomes. PMID- 27499387 TI - Synthesized Peptides from Yam Dioscorin Hydrolysis in Silico Exhibit Dipeptidyl Peptidase-IV Inhibitory Activities and Oral Glucose Tolerance Improvements in Normal Mice. AB - RRDY, RL, and DPF were the top 3 of 21 peptides for inhibitions against dipeptidyl peptidase-IV (DPP-IV) from the pepsin hydrolysis of yam dioscorin in silico and were further investigated in a proof-of-concept study in normal ICR mice for regulating glucose metabolism by the oral glucose tolerance test (OGTT). The sample or sitagliptin (positive control) was orally administered by a feeding gauge; 30 min later, the glucose loads (2.5 g/kg) were performed. RRDY, yam dioscorin, or sitagliptin preload, but not DPF, lowered the area under the curve (AUC0-120) of blood glucose and DPP-IV activity and elevated the AUC0-120 of blood insulin, which showed significant differences compared to control (P < 0.05 or 0.001). These results suggested that RRDY and yam dioscorin might be beneficial in glycemic control in normal mice and need further investigations in diabetic animal models. PMID- 27499388 TI - Registration procedure for spatial correlation of physical energy deposition of particle irradiation and cellular response utilizing cell-fluorescent ion track hybrid detectors. AB - The hybrid technology cell-fluorescent ion track hybrid detector (Cell-Fit-HD) enables the investigation of radiation-related cellular events along single ion tracks on the subcellular scale in clinical ion beams. The Cell-Fit-HD comprises a fluorescent nuclear track detector (FNTD, the physical compartment), a device for individual particle detection and a substrate for viable cell-coating, i.e. the biological compartment. To date both compartments have been imaged sequentially in situ by confocal laser scanning microscopy (CLSM). This is yet in conflict with a functional read-out of the Cell-Fit-HD utilizing a fast live-cell imaging of the biological compartment with low phototoxicity on greater time scales. The read-out of the biological from the physical compartment was uncoupled. A read-out procedure was developed to image the cell layer by conventional widefield microscopy whereas the FNTD was imaged by CLSM. Point mapping registration of the confocal and widefield imaging data was performed. Non-fluorescent crystal defects (spinels) visible in both read-outs were used as control point pairs. The accuracy achieved was on the sub-um scale. The read-out procedure by widefield microscopy does not impair the unique ability of spatial correlation by the Cell-Fit-HD. The uncoupling will enlarge the application potential of the hybrid technology significantly. The registration allows for an ultimate correlation of microscopic physical beam parameters and cell kinetics on greater time scales. The method reported herein will be instrumental for the introduction of a novel generation of compact detectors facilitating biodosimetric research towards high-throughput analysis. PMID- 27499389 TI - Nystatin and lidocaine pastilles for the local treatment of oral mucositis. AB - Oral mucositis (OM) is a common adverse reaction to radiotherapy and chemotherapy in oncology. Its treatment requires oral formulations that enhance therapy compliance, improve administration and ensure drug effectiveness. Solid dosage forms that act by slow dissolution, such as pastilles, are an effective alternative to mouthwashes, for their versatility, ease of administration and extended residence time in the oral cavity. The present work describes the development and stability studies of an innovative formulation of nystatin and lidocaine pastilles for the treatment of oral mucositis. Full pharmaceutical quality testing was carried out, including disintegration and dissolution testing, texture profile analysis, grittiness and an antifungal activity testing. A soft pastille formulation containing 0.25% lidocaine and 78,000 IU nystatin was obtained, presenting suitable pharmaceutical characteristics, as a disintegration time of 17 +/- 2 min, dissolution rate and microbiological and physicochemical for 30 days when stored at 2-8 degrees C under light protection. Palatability was also evaluated, being well accepted by a panel of 38 healthy volunteers. This formulation allows an accurate drug dosing by the prescriber, while enabling the patients to control the retention time of the drugs in the oral cavity and consequently manage their pain treatment. PMID- 27499391 TI - Hospital malnutrition in Latin America: A systematic review. AB - BACKGROUND: Disease-related malnutrition is a major public health issue in both industrialised and emerging countries. The reported prevalence in hospitalised adults ranges from 20% to 50%. Initial reports from emerging countries suggested a higher prevalence compared with other regions, with limited data on outcomes and costs. METHODS: We performed a systematic literature search for articles on disease-related malnutrition in Latin American countries published between January 1995 and September 2014. Studies reporting data on the prevalence, clinical outcomes, or economic costs of malnutrition in an adult (>=18 years) inpatient population with a sample size of >=30 subjects were eligible for inclusion. Methodological quality of the studies was assessed by two independent reviewers using published criteria. RESULTS: We identified 1467 citations; of these, 66 studies including 29 ,474 patients in 12 Latin American countries met the criteria for inclusion. There was considerable variability in methodology and in the reported prevalence of disease-related malnutrition; however, prevalence was consistently in the range of 40%-60% at the time of admission, with several studies reporting an increase in prevalence with increasing duration of hospitalisation. Disease-related malnutrition was associated with an increase in infectious and non-infectious clinical complications, length of hospital stay, and costs. CONCLUSION: Disease-related malnutrition is a highly prevalent condition that imposes a substantial health and economic burden on the countries of Latin America. Further research is necessary to characterise screening/assessment practices and identify evidence-based solutions to this persistent and costly public health issue. PMID- 27499392 TI - Comment on: Muscle strength gains during resistance exercise training are attenuated with soy compared with dairy or usual protein intake in older adults: A randomized controlled trial. PMID- 27499390 TI - Targeted alternative splicing of TAF4: a new strategy for cell reprogramming. AB - Reprogramming of somatic cells has become a versatile tool for biomedical research and for regenerative medicine. In the current study, we show that manipulating alternative splicing (AS) is a highly potent strategy to produce cells for therapeutic applications. We demonstrate that silencing of hTAF4-TAFH activity of TAF4 converts human facial dermal fibroblasts to melanocyte-like (iMel) cells. iMel cells produce melanin and express microphthalmia-associated transcription factor (MITF) and its target genes at levels comparable to normal melanocytes. Reprogramming of melanoma cells by manipulation with hTAF4-TAFH activity upon TAFH RNAi enforces cell differentiation towards chondrogenic pathway, whereas ectoptic expression of TAF4 results in enhanced multipotency and neural crest-like features in melanoma cells. In both cell states, iMels and cancer cells, hTAF4-TAFH activity controls migration by supporting E- to N cadherin switches. From our data, we conclude that targeted splicing of hTAF4 TAFH coordinates AS of other TFIID subunits, underscoring the role of TAF4 in synchronised changes of Pol II complex composition essential for efficient cellular reprogramming. Taken together, targeted AS of TAF4 provides a unique strategy for generation of iMels and recapitulating stages of melanoma progression. PMID- 27499393 TI - Nutritional status of older patients with oropharyngeal dysphagia in a chronic versus an acute clinical situation. AB - BACKGROUND: Oropharyngeal dysphagia (OD) is a prevalent risk factor for malnutrition (MN) in older patients and both conditions are related to poor outcome. OBJECTIVE: To explore the nutritional status in older patients with OD in a chronic and an acute clinical situation. DESIGN: We examined 95 older (>=70 years) patients with OD associated to chronic neurological diseases or aging, and 23 older patients with OD and acute community-acquired pneumonia (CAP) with videofluoroscopy; and 15 older people without OD. We collected nutritional status, measured with the Mini Nutritional Assessment (MNA(r)), anthropometric measurements, and biochemistry and bioimpedance for body composition. Functional status was assessed with the Barthel index. RESULTS: 1) Taking into consideration patients with OD with chronic conditions, 51.1% presented a MNA(r) <=23.5; 16.7%, sarcopenia and a) reduced visceral and muscular protein compartments and fat compartment; b) muscular weakness c) intracellular water depletion, and d) reduced body weight. Patients with OD and MNA(r) <=23 needed higher levels of nectar viscosity for a safe swallow and had increased oropharyngeal residue at spoon-thick viscosity. 2) Patients with OD and CAP, 69.5%, presented an MNA(r) <=23.5 and 29.4% sarcopenia, the inflammatory response of the pneumonia adding to the more severe depletion in visceral protein and muscular mass. CONCLUSIONS: Prevalence of impaired nutritional status (malnutrition risk, and sarcopenia) among older patients with OD associated with either chronic or acute conditions is very high. In patients with OD and chronic diseases, poor nutritional status further impairs OD with an increase in oropharyngeal residue at spoon-thick viscosity. In the acute setting there is inflammation and an additional protein deficiency. These findings will help develop specific products both for OD and nutritional status in each specific clinical situation. PMID- 27499394 TI - 2016 National Rheumatic Fever Week: The status of rheumatic heart disease in South Africa. AB - There is evidence of early progress in the efforts to eliminate acute rheumatic fever (ARF) and control rheumatic heart disease (RHD) in South Africa. The caseload of ARF and RHD in paediatric units appears to be falling in some provinces such as Gauteng, and the mortality attributed to rheumatic heart disease at a population level has fallen from 1.3/100 000 in 2001 to 0.7/100 000 in 2012. However, the incidence of congestive heart failure due to RHD in adults remains high (~25/100 000/year) in Gauteng Province, and is associated with a high case fatality rate of up to 35% in 6 months. There is a need to intensify the application of comprehensive interventions to enhance the primary and secondary prevention and treatment of ARF/RHD in a registry-based national programme. PMID- 27499395 TI - Asymptomatic rheumatic heart disease in South African schoolchildren: Implications for addressing chronic health conditions through a school health service. AB - When new evidence comes to light, it compels us to contemplate the implications of such evidence for health policy and practice. This article examines recent research evidence on the prevalence of asymptomatic rheumatic heart disease (RHD) in South Africa and considers the implications for the Integrated School Health Programme (ISHP). RHD is still a major burden of disease in developing countries, and elimination of this preventable condition ranks high among World Heart Federation goals. If left untreated, it becomes a chronic health condition that individuals have to cope with into their adult lives. The ISHP regards the health needs of children with chronic health conditions, which include conditions such as RHD, as a key service component. However, the chronic health component of the ISHP is still poorly developed and can benefit from good evidence to guide implementation. A recent study to ascertain the prevalence of RHD in asymptomatic schoolchildren through mass screening affords an opportunity to reflect on whether, and how, asymptomatic chronic health conditions in schoolchildren could be addressed, and what the implications would be if this were done through a school-based programme such as the ISHP. PMID- 27499396 TI - A successful lifestyle intervention model replicated in diverse clinical settings. AB - Lifestyle interventions can treat metabolic syndrome and prevent type 2 diabetes mellitus, but they remain underutilised in routine practice. In 2010, an LI model was created in a rural primary care practice and spread with few resources to four other rural practices. A retrospective chart review evaluated changes in health indicators in two practice environments by following 372 participants, mainly women (mean age 52 years). Participants had a mean body mass index of 37 kg/m2at baseline and lost an average of 12% of their initial body weight as a result of the intervention. Among participants at the first intervention site for whom cardiometabolic data were available, the prevalence of metabolic syndrome decreased from 58% at baseline to 19% at follow-up. Taken as a whole, our experience suggests that LIs are feasible and deliver meaningful results in routine primary care practice. PMID- 27499397 TI - Severe hypertension in pregnancy: Using dynamic checklists to save lives. AB - Severe hypertension is a major cause of morbidity and mortality. The South African Saving Mothers report (2011 - 2013) indicates that cerebral injury due to severe hypertension is resulting in avoidable maternal deaths. This demands that management of severe hypertension in pregnancy needs to be improved. A rapid acting antihypertensive is recommended for the initial management of severe hypertension during pregnancy. A single dose of a rapid-acting agent may be ineffective, in which case incremental doses of the same medication or another antihypertensive may be required for adequate blood pressure control. To ensure that appropriate antihypertensives at the correct doses are administered, the use of a guideline in a dynamic checklist format is advocated and discussed in this article. It is envisaged that the use of dynamic checklists will be valuable to all healthcare professionals providing care during pregnancy and the puerperium. PMID- 27499398 TI - The World Health Organization's mechanisms for increasing the health sector budget: The South African context. AB - South Africa (SA) has limited scope for raising income taxes, and the proposed National Health Insurance (NHI) scheme will necessitate growth in the health sector budget. The NHI White Paper suggests five funding scenarios to meet the expected shortfall. These scenarios are a mixture of a surcharge on taxable income, an increase in value-added tax and a payroll tax. Five alternative options, suggested by the World Health Organization, are interrogated as ways to decrease the general taxation proposed in the White Paper. The five mechanisms (corporate tax, financial transaction levy, and taxes on tobacco, alcohol and unhealthy foods) were chosen based on their fund-raising potential and their mandatory element. A literature review provides the information for a discussion of the potential costs of each mechanism. Within specific assumptions, potential budgetary contribution is compared with the requirement. First, raising corporate tax rates could raise enough funds, but the losses due to capital flight might be too much for the local economy to bear. Second, a levy on currency transactions is unlikely to raise the required resources, even without a probable decrease in the number of transactions. Third, the increase in the tax on tobacco and alcohol would need to be very large, even assuming that consumption patterns would remain unchanged. Lastly, a tax on unhealthy food products is a new idea and could be explored as an option - especially as the SA Treasury has announced its future implementation. Implementing only one of the mechanisms is unlikely to increase available funding sufficiently, but if they are implemented together the welfare maximising tax rate for each mechanism may be high enough to fulfil the NHI scheme's budgetary requirement, moderating the increases in the tax burden of the SA population. PMID- 27499399 TI - Implications of the 2015 World Health Organization isoniazid preventive therapy recommendations on tuberculosis prevention efforts in Namibia. AB - The World Health Organization recently released guidelines recommending 36-month use of isoniazid preventive therapy in adults and adolescents living with HIV in resource-limited settings. Namibia continues to grapple with one of the highest incidences of tuberculosis (TB) worldwide. Implementation of these guidelines requires considerations of TB epidemiology, health infrastructure, programmatic priorities and patient adherence. This article explores the challenges Namibia currently faces in its fight against TB and the implications of the new guidelines on Namibian TB prevention efforts. PMID- 27499400 TI - Antifibrinolytic drugs for acute traumatic injury. AB - In South Africa, trauma is a major concern, with violence and road traffic accidents being the fifth and seventh leading causes of death, respectively. Antifibrinolytic agents have been used in trauma and major surgery to prevent fibrinolysis and reduce blood loss. We highlight an updated Cochrane review investigating the effect of antifibrinolytic drugs in patients with acute traumatic injury. The review authorsconducted comprehensive literature searches in January 2015 with regard to all randomised controlled trials comparing antifibrinolytic agents after acute traumatic injury. Three randomised controlled trials, of which two (n=20 451) assessed the effect of tranexamic acid (TXA), were included. The authors concluded that TXA safely reduces mortality in trauma with bleeding without increasing the risk ofadverse events. TXA should be administered as early as possible, and within 3 hours of injury. There is still uncertainty with regard to the effect of TXA on patients with traumatic brain injury; however, ongoing randomised controlled trials should shed more light on this. PMID- 27499401 TI - The microbiome in chronic inflammatory airway disease: A threatened species. AB - The human body is exposed to a multitude of microbes and infectious organisms throughout life. Many of these organisms colonise the skin, gastrointestinal tract (GIT) and airway. We now recognise that this colonisation includes the lower airway, previously thought to be sterile. These colonising organisms play an important role in disease prevention, including an array of chronic inflammatory conditions that are unrelated to infectious diseases. However, new evidence of immune dysregulation suggests that early colonisation, especially of the GITand airway, by pathogenic micro-organisms, has deleterious effects that may contribute to the potential to induce chronic inflammation in young children, which may only express itself in adult life. PMID- 27499402 TI - Intravenous glutathione for skin lightening: Inadequate safety data. AB - BACKGROUND: Glutathione (GSH) is the most abundant naturally occurring non protein thiol that protects mammalian cells from oxidative stress. Intravenous (IV) GSH for skin lightening is advertised by clinics in South Africa and internationally online, yet to date no published review on the subject exists. Methods. We conducted a MEDLINE search (to 30 September 2015) of GSH use for skin lightening and of all indications in medicine, to evaluate its safety. Results. Two controlled clinical trials (GSH capsules: 60 patients; 2% glutathione disulphide lotion: 30 patients) and a case series (GSH lozenges: 30 patients) reported a significantly decreased melanin index. A case series (GSH soap: 15 patients) reported skin lightening based on photography. Two systematic reviews of IV GSH for preventing chemo-induced toxicity and a third review of adjuvant therapy for Parkinson's disease altogether included 10 trials. Most trials reported either no or minimal GSH adverse effects, but all had treatment durations of a few doses (IV) or 4 -12 weeks. No study reported long-term IV GSH use. Conclusion. In spite of widespread reported use, there are no studies of IV GSH use for skin lightening or of its safety for chronic use (for any indication). The switch from brown to red melanin production may increase the risk of sun-induced skin cancers in previously protected individuals. Regulatory assessment of systemic GSH administration for cosmetic use by the Medicines Control Council seems urgently warranted to protect consumers from potential side effects and from complications of IV infusions. This is especially concerning because of reports of GSH bought online. Effective topical GSH may be useful for hyperpigmented skin disorders, but this requires scientific scrutiny. The debate on the merits of cosmetic skin lightening is best handled by multidisciplinary teams. PMID- 27499403 TI - When may doctors give nurses telephonic treatment instructions? AB - Doctors are expected to examine their patients before issuing telephonic instructions to nurses. However, in emergencies or when they are aware of the health status of their patients, it may be justified for a doctor to issue telephonic instructions to nurses without examining the patient. Doctors on call owe a special duty to patients, who they may have to examine or arrange for another doctor to do so before issuing telephonic instructions. In deciding whether doctors acted reasonably in issuing telephonic instructions to nurses, the courts will decide whether they exercised the same degree of skill and care as reasonably competent practitioners in their branch of the profession. Suggestions are made concerning doctors giving telephonic instructions to nurses regarding patients they have not examined. PMID- 27499404 TI - Cardiogenic shock: A look at acute functional mitral incompetence. AB - A 44-year-old man presented with cardiogenic shock secondary to acute functional mitral incompetence as well as septic shock related to pneumonia. The patient deteriorated haemodynamically despite adequate medical therapy. An echocardiogram revealed a massive mitral incompetence and an ejection fraction of 32%. An intra aortic balloon pump was placed and the patient improved dramatically. On day 6 after admission the echocardiogram was repeated, revealing a mild mitral incompetence and an ejection fraction of 58%. PMID- 27499405 TI - Clinical awareness for health care professionals: Fatal encephalopathy complicating persistent vomiting in pregnancy. AB - Women with persistent vomiting during pregnancy need early referral to appropriate health facilities. Delayed referral and inappropriate management may lead to metabolic encephalopathy from a variety of causes, including electrolyte derangements or thiamine deficiency (Wernicke's encephalopathy) (WE). We present a case of persistent vomiting in pregnancy in which there was delayed referral, inappropriate treatment and failure to associate neurological signs such as terminal neck stiffness with WE, resulting in poor fetomaternal outcomes. In this report, we discuss the following lessons: (i) the need for early transfer of a patient with persistent vomiting and enigmatic clinical features to a higher healthcare facility; (ii) failure to associate neurological signs with complications of hyperemesis gravidarum/WE; (iii) lack of thiamine supplementation; and (iv) the advantages of magnetic resonance imaging over a computed tomography scan in the diagnosis of WE. PMID- 27499406 TI - A case of renal cell carcinoma and angiomyolipoma in an adolescent girl. AB - We describe a case of renal cell carcinoma in the right kidney together with an angiomyolipoma in the left kidney, encountered in an adolescent girl at Potchefstroom Provincial Hospital, North West Province, South Africa. PMID- 27499407 TI - Evaluation and management of patients referred to a tertiary-level hypertension clinic in Cape Town, South Africa. AB - BACKGROUND: Hypertension remains a global health burden, with a high incidence of long-term morbidity and mortality. OBJECTIVE: To evaluate blood pressure (BP) control, factors associated with poor BP control, target organ damage (TOD), white-coat hypertension, treatment-resistant hypertension and secondary hypertension in patients referred to a tertiary-level hypertension clinic. METHOD: This was a prospective case-control study of patients referred for specialist hypertension management. Patient parameters recorded included age, gender, body mass index, uric acid, cholesterol, screening BP, follow-up BP, TOD and medications. We also recorded causes of secondary hypertension. Net BP change and the percentage achieving target BP were calculated in all patients followed up. RESULTS: A total of 175 patients were sampled (72 males and 103 females, mean age 46.5 years). Of the patients 16.6% had a normal screening BP; 62.9% of patients were followed up, and 43.6% of these achieved BP control. After intervention, there was a net drop of 13.2 mmHg (range 7.9 - 18.4) in systolic BP and of 3.8 mmHg (4.4 - 12.0) in diastolic BP. Of all the patients, 12.6% had resistant hypertension, 49.1% had evidence of left ventricular hypertrophy and 18.3% had microalbuminuria; 13.1% of the patients were diagnosed with secondary hypertension. CONCLUSION: Specialist intervention was useful in identifying patients with white-coat and secondary hypertension, as well as in improving hypertension control in patients with apparent treatment-resistant hypertension. However, a significant percentage of patients did not reach target BP, and further efforts are required to identify the underlying causes for this. PMID- 27499408 TI - Pan computed tomography for blunt polytrauma: Are we doing too many? AB - BACKGROUND: Pan computed tomography (CT) is widely used in the evaluation of patients with blunt polytrauma, but there is growing concern about the radiation risks imposed. OBJECTIVE: To ascertain whether we were possibly overutilising pan CT in our trauma service, and whether we could safely cut down on scans without missing significant injuries. METHODS: We audited all pan scans performed in the Metropolitan Trauma Service, Pietermaritzburg, South Africa, during the 12-month period 1 January - 31 December 2012. An analysis was done to determine what injuries were identified and how these findings influenced our management. RESULTS: Of the 140 pan scans, 108 (77.1%) influenced management. These included the following components: 62 brain scans (44.3%), 16 cervical spine scans (11.4%), 50 chest scans (35.7%) and 31 abdominal scans (22.1%). The remaining 32 pan scans (22.9%) did not influence management. However, it turned out that many of these 'clinically negative' scans were in fact clinically important, ruling out injury in patients in whom clinical assessment was regarded as unreliable: 3 patients (2.1%) were hypoxic and had to be sedated, intubated and ventilated; 14 (10.0%) had a Glasgow Coma Score (GCS) of <15; and 9 (6.4%) had major distracting injuries. This left only 6 pan scans (4.3%) that were not regarded as clinically helpful. CONCLUSION: In our setting, the majority of pan scans influence management. By ruling out significant injuries, clinically negative scans are valuable in patients who are obtunded, intubated and ventilated, or have major distracting injuries. In patients with a GCS of 15, not sedated and ventilated and with no major distracting injuries, clinical assessment and alternative imaging modalities may suffice. PMID- 27499409 TI - South African healthcare provider perspectives on transitioning adolescents into adult HIV care. AB - BACKGROUND: The first generation of South African (SA) children perinatally infected with HIV is entering adulthood, and there is now a pressing need for systematised transfer of these patients from paediatric to adult care. OBJECTIVES: Previous research has investigated the HIV healthcare transition in North America and Europe, yet none has been conducted in SA. Our study is the first to describe the perspectives of healthcare providers overseeing the transition in resource-limited settings. METHODS: We approached healthcare providers working in government paediatric HIV clinics and hospitals in the Western Cape Province, SA. Seven physicians and counsellors in adolescent/paediatric care, representing five clinics, were interviewed, and 43 completed a written survey. Interviews addressed the current state of the transition, barriers and facilitators, and model components. Interviews were assessed for major themes using framework analysis, while logistic regression was applied to survey responses to identify associations with measured covariates. RESULTS: Analysis of interview transcripts revealed several overarching perspectives that were corroborated by survey responses. One barrier identified was the healthcare providers' difficulty in letting go of their relationships with the adolescent patients. Since healthcare providers regarded their patients as particularly vulnerable, they felt a strong and protective attachment towards them. A second barrier identified was a lack of structure and effective communication between adult and paediatric providers; accordingly, healthcare providers feared that they were transferring their adolescents unprepared, to a judgemental, depersonalised and overburdened environment. All interviewees and a majority of survey respondents (>80%) agreed that the formation of adolescent support groups in adult care clinics as well as a later transition age would improve the transition process. CONCLUSION: This study highlights the need for a systematic healthcare transition for HIV-positive adolescents cared for in the Western Cape, while acknowledging the limitations of the current healthcare infrastructure. Several feasible recommendations have been identified, including forming support groups and greater involvement of adolescent healthcare providers to facilitate the transition. PMID- 27499410 TI - Sialendoscopic treatment of recurrent juvenile parotitis: A South African case series. AB - BACKGROUND: Recurrent juvenile parotitis (RJP) is a well-recognised cause of parotitis in childhood. Sialendoscopy has been extensively used for the investigation and treatment of many benign salivary disorders, and now offers a minimally invasive approach to RJP. OBJECTIVES: To investigate the epidemiology and disease profile of RJP, and review the efficacy of sialendoscopy for its investigation and treatment. METHODS: The relevant literature on RJP was reviewed, and a retrospective folder review was performed for all patients who had undergone sialendoscopy for RJP at two South African (SA) hospitals between April 2013 and September 2015. Patients' epidemiological and clinical data were recorded, as well as the findings and outcomes of ultrasonography and sialendoscopy. In particular, the time following treatment without any further recurrences was recorded as a measure of success. RESULTS: Five children underwent sialendoscopic investigation and treatment for RJP. Their demographic and disease profiles and the results of investigations and treatments were in keeping with published literature. No surgical complications occurred, and no patients reported any further symptoms postoperatively, with an average follow-up of 22 months. CONCLUSION: Although small in sample size, this is the first reported case series in the SA literature on the use of sialendoscopy for RJP, and the results are consistent with internationally published data. Sialendoscopy is regarded as safe and effective for the diagnosis and management of RJP, and should be considered for patients who remain symptomatic after conservative management. PMID- 27499411 TI - Salvageability of renal function following renal revascularisation in children with Takayasu's arteritis-induced renal artery stenosis. AB - BACKGROUND: Renal artery revascularisation procedures are usually carried out on children with renal artery stenosis from varied causes, including Takayasu's arteritis. Reports on the outcome of such procedures in children usually refer to the improvement in blood pressure, with only minimal mention of effects on renal function. OBJECTIVE: Salvageability of renal function in children who underwent renal revascularisation for Takayasu's arteritis-induced renal artery stenosis (TARAS) was the focus of this study. METHODS: We undertook a retrospective analysis of children aged <=16 years with angiographically confirmed TARAS who underwent renal artery revascularisation procedures between 1990 and 2010. Outcomes of renal function were studied over a period of 2 years and were defined as: (i) improvement: >20% increase in estimated glomerular filtration rate (e GFR) from presurgery value; (ii) stabilisation: e-GFR within 20% of presurgery value; and (iii) failure: >20% deterioration in e-GFR from presurgery value. The GFR was estimated using the Schwartz formula. RESULTS: Twenty children (9 males and 11 females, age range 2 - 14 years) had 27 renal artery revascularisation procedures. Thirteen of the patients (65.0%) had bilateral renal artery stenosis. The baseline mean e-GFR was 88.6 (standard deviation (SD) 25.4) mL/min/1.73 m2 and the mean duration of follow-up was 28.80 (SD 25.62) months. All the patients had stable or improved renal function until the 2-year follow-up, when the proportion decreased to 92.3% (12/13), as failure was recorded in one child. Bilateral revascularisation was found to be significantly associated with improvement in renal function in the early postoperative period (p=0.04). CONCLUSION: Renal artery revascularisation procedures are successful in salvaging renal function in children with TARAS. PMID- 27499412 TI - Feasibility of Pulse Oximetry Pre-discharge Screening Implementation for detecting Critical Congenital heart Lesions in newborns in a secondary level maternity hospital in the Western Cape, South Africa: The 'POPSICLe' study. AB - BACKGROUND: Early detection of critical congenital heart disease (CCHD) through newborn pulse oximetry (POx) screening is an effective strategy for reducing paediatric morbidity and mortality rates and has been adopted by much of the developed world. OBJECTIVES: To document the feasibility of implementing pre discharge POx screening in well babies born at Mowbray Maternity Hospital, a busy government hospital in Cape Town, South Africa. Parent and staff acceptance was assessed. METHODS: We conducted a prospective study of predischarge POx screening in one postnatal ward, following informed parental consent. RESULTS: During the 4 month study period, 1 017 of 2 256 babies discharged (45.1%) were offered POx screening and 1 001 were screened; 94.0% of tests took <3 minutes to perform, 4.3% 3 - 5 minutes and 1.7% >5 minutes. Eighteen patients needed second screens and three required third screens. Only 3.1% protocol errors were made, all without consequence. The vast majority (91.6%) of nursing staff reported insufficient time to perform the study screening in addition to their daily tasks, but ~75% felt that with a full nursing staff complement and if done routinely (not part of a study), pre-discharge POx screening could be successfully instituted at our facility. Over 98% of the mothers had positive comments. Two babies failed screening and required echocardiograms; one was diagnosed with CCHD and the other with neonatal sepsis. The sensitivity and specificity were 50% (95% confidence interval (CI) 1.3 - 98.7%) and 99.9% (95% CI 99.4 - 100%), respectively, with a percentage correct of 99.8%. CONCLUSIONS: POx screening was supported and accepted by staff and parents. If there are no nursing staff shortages and if it is done routinely before discharge, not as part of a study, we conclude that POx screening could be implemented successfully without excessive false positives or errors, or any additional burden to cardiology services. PMID- 27499413 TI - Attitudes to female genital mutilation/cutting among male adolescents in Ilorin, Nigeria. AB - BACKGROUND: The central role of males in female reproductive health issues in patriarchal societies makes them an important group in the eradication of female genital mutilation/cutting (FGM/C). OBJECTIVE: To determine knowledge about and attitudes to FGM/C among male adolescents, and their preparedness to protect their future daughters from it. METHODS: A cross-sectional survey among male adolescent students in Ilorin, Nigeria. Participants completed a self administered questionnaire after consent had been obtained from them or their parents. Statistical analysis was with SPSS version 20.0 (IBM, USA). A p-value of <0.05 was taken as significant. RESULTS: Of 1 536 male adolescents (mean age 15.09 (standard deviation 1.84) years, range 14 - 19), 1 184 (77.1%) were aware of FGM/C, 514 (33.5%) supported female circumcision, 362 (23.6%) would circumcise their future daughters, 420 (27.3%) were of the opinion that FGM/C had benefits, mostly as a necessity for womanhood (109, 7.1%), and 627 (40.8%) perceived it as wickedness against females; 546 (35.5%) were aware of efforts to eradicate FGM/C, and 42.2% recommended education as the most important intervention to achieve this. CONCLUSION: Education and involvement in advocacy may transform male adolescents into agents for eradication of FGM/C. PMID- 27499414 TI - A clinical audit of the utilisation of red cell products in elective total hip replacement surgery. AB - BACKGROUND: Previous studies have documented a marked variation in transfusion practice for total hip replacement (THR) surgery. OBJECTIVE: To audit red cell product utilisation for THR at two Western Cape tertiary referral hospitals (HY and HG). METHODS: The folders of 207 consecutive patients undergoing elective THR surgery from January 2013 to December 2013 were reviewed. Information relating to age, sex, clinical observations, indications for surgery, pre- and postoperative haemoglobin (Hb) values, comorbidities, length of hospital stay and transfusion history was recorded. RESULTS: The transfusion rate at HY (41.6%) was significantly higher than that at HG (10.0%). The mean postoperative Hb in the transfused patients at HG was 8.3 g/dL v. 9.1 g/dL at HY. Females had a significantly higher transfusion rate (33.0%) than males (15.0%) (p<0.05), and the mean age of transfused patients was significantly greater than that of untransfused patients (p<0.005). Although patients with comorbidities had a higher transfusion rate than those without, this did not reach statistical significance. Of 120 patients with complete data, 113 (94.2%) had a blood bank order, of which the vast majority, 102/113 (90.3%), were group-and-screen (G&S) requests; 29/113 (25.7%) were converted to a full crossmatch. CONCLUSIONS: Overall, the transfusion rate for both hospitals was 25.8%, which is well within published rates. A guideline Hb trigger of 8.0 g/dL is recommended as per published guidelines, with the caveat that the clinical judgement of the attending clinician whether a transfusion is indicated is paramount. Causes of preoperative anaemia should be investigated and treated. Routine cross-matching preoperatively is unnecessary, and a G&S order is sufficient. PMID- 27499415 TI - Targeting composite treatment of type 2 diabetes in middle-income countries. PMID- 27499416 TI - Oxidative metabolism of koumine is mainly catalyzed by microsomal CYP3A4/3A5. AB - 1. Gelsemium elegans Benth (Loganiaceae) is a toxic plant that can be used for committing suicide besides alleviating pains. Its anti-inflammatory and analgesic effect mainly come from its active ingredient, namely koumine. Koumine, an indole alkaloid, possesses widely pharmacological effects especially inhibition of neuropathic pain. 2. This study aimed to investigate the metabolic profile of koumine using human liver microsomes (HLMs), selective chemical inhibitors and recombinant human CYP isoforms. Ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) was used to detect and identify metabolites. 3. Four major metabolites of koumine were found after incubation with HLMs or individual CYP isoforms. The metabolic pathways of koumine included demethylation, dehydrogenation, oxidation and demethyl-dehydrogenation. Chemical inhibition study showed that the inhibitor of CYP3A4/3A5 significantly decreased (93%) the formation of koumine metabolites. Further, CYP3A4/3A5 was shown as the most efficient isoform in biotransformation of koumine, among a series of CYP isoforms tested. 4. In conclusion, koumine was metabolized into four oxidative metabolites in HLMs. And CYP3A4/3A5 was probably the main contributor to the hepatic oxidative metabolism of koumine. PMID- 27499417 TI - Multimaterial 4D Printing with Tailorable Shape Memory Polymers. AB - We present a new 4D printing approach that can create high resolution (up to a few microns), multimaterial shape memory polymer (SMP) architectures. The approach is based on high resolution projection microstereolithography (PMUSL) and uses a family of photo-curable methacrylate based copolymer networks. We designed the constituents and compositions to exhibit desired thermomechanical behavior (including rubbery modulus, glass transition temperature and failure strain which is more than 300% and larger than any existing printable materials) to enable controlled shape memory behavior. We used a high resolution, high contrast digital micro display to ensure high resolution of photo-curing methacrylate based SMPs that requires higher exposure energy than more common acrylate based polymers. An automated material exchange process enables the manufacture of 3D composite architectures from multiple photo-curable SMPs. In order to understand the behavior of the 3D composite microarchitectures, we carry out high fidelity computational simulations of their complex nonlinear, time dependent behavior and study important design considerations including local deformation, shape fixity and free recovery rate. Simulations are in good agreement with experiments for a series of single and multimaterial components and can be used to facilitate the design of SMP 3D structures. PMID- 27499418 TI - Sustainability and prevention in occupational health and safety. PMID- 27499419 TI - The Role of Paracetamol for Closing Patent Ductus Arteriosus. A Challenging Alternative for Ductal Closure? PMID- 27499420 TI - Heritability of fear of humans in urban and rural populations of a bird species. AB - Flight initiation distance (FID), a measure of an animal's tolerance to human disturbance and a descriptor of its fear of humans, is increasingly employed for conservation purposes and to predict the response of species to urbanization. However, most work devoted to understanding variability in FID has been conducted at the population level and little is still known about inter-individual variability in this behaviour. We estimated the heritability of FID, a factor fundamental to understanding the strength and evolutionary consequences of selection of particular phenotypes associated with human disturbances. We used a population of burrowing owls (Athene cunicularia) monitored long-term and for which FID was previously shown to be highly consistent across an individual's lifespan. Heritability estimates varied between 0.37 and 0.80, depending on the habitat considered (urban-rural) and method used (parent-offspring regressions or animal models). These values are unusually high compared with those previously reported for other behavioural traits. Although more research is needed to fully understand the underlying causes of this resemblance between relatives, selection pressures acting on this behaviour should be seriously considered as an important evolutionary force in animal populations increasingly exposed to human disturbance worldwide. PMID- 27499421 TI - Excited-state torsional relaxation dynamics of meso-meso directly linked corrole dimers: importance of linking position. AB - Herein, we present a combined spectroscopic and computational study on 5,5' linked and 10,10'-linked corrole dimers, 5CD and 10CD, respectively, to reveal their strikingly different excited-state dynamics. The excited-state dynamics of 10CD indicate relatively small electronic interactions between the two corrole units, which is similar to the case of the meso-meso directly linked Zn(ii) porphyrin dimer. On the other hand, 5CD exhibits characteristic excitation wavelength-dependent dual fluorescence. Transient absorption spectra of 10CD on the picosecond timescale showed torsional relaxation with a time constant of 25 ps, whereas the torsional relaxation of 5CD was faster, exhibiting a time constant of 10 ps. Quantum calculations have indicated that the eccentric dual fluorescence and the faster torsional relaxation process of 5CD are consequences of a large pi-orbital coefficient at the connecting 5-position, which enhances the conjugative stabilization in the excited-state. In contrast, a small pi orbital coefficient at the 10-position and a larger torsional barrier of 10CD cause monomer-like characters in the excited-state. PMID- 27499423 TI - Corrigendum to "Investigations of motor-cortex cortical plasticity following facilitatory and inhibitory transcranial theta-burst stimulation in schizophrenia: A proof-of-concept study" [J. Psychiatr. Res. 61 (2015 Feb) 196 204]. PMID- 27499422 TI - The Single-Case Reporting Guideline In BEhavioural Interventions (SCRIBE) 2016 Statement. AB - We developed a reporting guideline to provide authors with guidance about what should be reported when writing a paper for publication in a scientific journal using a particular type of research design: the single-case experimental design. This report describes the methods used to develop the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016. As a result of 2 online surveys and a 2-day meeting of experts, the SCRIBE 2016 checklist was developed, which is a set of 26 items that authors need to address when writing about single case research. This article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016 ) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. We recommend that the SCRIBE 2016 is used by authors preparing manuscripts describing single-case research for publication, as well as journal reviewers and editors who are evaluating such manuscripts. SCIENTIFIC ABSTRACT Reporting guidelines, such as the Consolidated Standards of Reporting Trials (CONSORT) Statement, improve the reporting of research in the medical literature (Turner et al., 2012 ). Many such guidelines exist and the CONSORT Extension to Nonpharmacological Trials (Boutron et al., 2008 ) provides suitable guidance for reporting between-groups intervention studies in the behavioural sciences. The CONSORT Extension for N-of-1 Trials (CENT 2015) was developed for multiple crossover trials with single individuals in the medical sciences (Shamseer et al., 2015 ; Vohra et al., 2015 ), but there is no reporting guideline in the CONSORT tradition for single-case research used in the behavioural sciences. We developed the Single-Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016 to meet this need. This Statement article describes the methodology of the development of the SCRIBE 2016, along with the outcome of 2 Delphi surveys and a consensus meeting of experts. We present the resulting 26-item SCRIBE 2016 checklist. The article complements the more detailed SCRIBE 2016 Explanation and Elaboration article (Tate et al., 2016 ) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single-case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. PMID- 27499424 TI - Structural basis of metallo-beta-lactamase, serine-beta-lactamase and penicillin binding protein inhibition by cyclic boronates. AB - beta-Lactamases enable resistance to almost all beta-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as 'transition state analogue' inhibitors of nucleophilic serine enzymes, including serine-beta lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent beta-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-beta-lactamases, and which could also have antimicrobial activity through inhibition of PBPs. PMID- 27499425 TI - Comparison of age-related changes in anti-Mullerian hormone levels and other ovarian reserve tests between healthy fertile and infertile population. AB - In this study, we aimed to determine whether anti-Mullerian hormone (AMH) levels vary between fertile and infertile populations and compare them with basal follicle-stimulating hormone (FSH) levels and antral follicle count (AFC). This was a prospective study that included 177 primarily infertile patients who underwent IVF treatment and 162 healthy fertile patients admitted to our clinic for benign diseases. FSH and AMH levels and the AFC of the infertile and fertile populations were compared between the age categories <30, 30-39 and >=40. Correlations between AMH, basal FSH, and AFC with age were evaluated. AFC and AMH levels did not differ between the fertile and infertile groups in all age categories. AMH was inversely correlated with age in both the fertile and infertile populations. However, AFC revealed a stronger correlation with age in both the fertile and infertile populations compared with basal FSH and AMH. Age was positively correlated with basal FSH and inversely correlated with AMH and AFC. In conclusion, there was no significant difference between the fertile and infertile populations in terms of AMH or AFC. The decrease in ovarian reserve in infertile patients is directly related to age, not infertility. PMID- 27499426 TI - Previous Gardening Experience and Gardening Enjoyment Is Related to Vegetable Preferences and Consumption Among Low-Income Elementary School Children. AB - OBJECTIVE: To examine if gardening experience and enjoyment are associated with vegetable exposure, preferences, and consumption of vegetables among low-income third-grade children. DESIGN: Cross-sectional study design, using baseline data from the Texas! Grow! Eat! Go! STUDY: SETTING: Twenty-eight Title I elementary schools located in different counties in Texas. PARTICIPANTS: Third-grade students (n = 1,326, 42% Hispanic) MAIN OUTCOME MEASURES: Gardening experience, gardening enjoyment, vegetable exposure, preference, and consumption. ANALYSIS: Random-effects regression models, adjusted for age, sex, ethnicity, and body mass index percentile of child, estimated means and standard errors of vegetable consumption, exposure, and preference by levels of gardening experience and enjoyment. Wald chi2 tests evaluated the significance of differences in means of outcomes across levels of gardening experience and enjoyment. RESULTS: Children with more gardening experience had greater vegetable exposure and higher vegetable preference and consumed more vegetables compared with children who reported less gardening experience. Those who reported that they enjoyed gardening had the highest levels of vegetable exposure, preference, and consumption. CONCLUSIONS AND IMPLICATIONS: Garden-based interventions can have an important and positive effect on children's vegetable consumption by increasing exposure to fun gardening experiences. PMID- 27499427 TI - Sustained remission after long-term biological therapy in patients with large vessel vasculitis: an analysis of ten cases. AB - OBJECTIVES: To describe the results obtained in clinical practice with the use of biological therapy (BT) in patients diagnosed with Takayasu arteritis (TA) and giant cell arteritis (GCA). METHODS: Retrospective single center study of TA/GCA patients who received BT (infliximab [IFX], etanercept [ETN] and tocilizumab [TCZ]). In TA, active disease was defined according to a previous National Institutes of Health study. In GCA, active disease was defined with a modified criteria and clinical manifestations secondary to temporal artery involvement or polymyalgia rheumatica symptoms. Clinical data and outcomes are reported using descriptive statistics. RESULTS: Five patients with TA and 5 with GCA were included. The main reason for starting BT was lack of response to prior therapy and/or >=2 relapses during GC tapering. Five patients started IFX, four TCZ and 1 ETN. Remission was observed before 6 months in all cases. Only one patient had a relapse during long-term follow-up and the overall GC daily dose was reduced by 70%. Two AEs were considered attributable to IFX and one to TCZ. CONCLUSION: A favorable and sustained response to BT was observed in our patients with TA and GCA. Thus, BT might be considered as an alternative in patients with large vessel arteritis refractory to conventional treatment or with GC related comorbidities. PMID- 27499428 TI - Van Neck-Odelberg disease: Another cause of limp in childhood. PMID- 27499429 TI - Methylation of the SEPT9_v2 promoter as a novel marker for the detection of circulating tumor DNA in breast cancer patients. AB - The aim of the present study was to evaluate the promoter methylation status of SEPT9_v2 in breast cancer and to detect this methylated gene in circulating tumor DNA (ctDNA) in plasma. Bisulfite sequencing was performed with a next generation sequencer. Methylation of the SEPT9_v2 promoter was found in 67% (8/12) of breast cancer cell lines and 53% (10/19) of breast tumor tissue, but not in normal breast tissue (0/19). A clear inverse correlation was observed between the expression of SEPT9_v2 mRNA and the methylation index (MI) both in cell lines and breast cancer tissues. The MI of SEPT9_v2 was significantly higher in non-basal subtype of breast cancer (13.0%, n=84) than in basal subtype (3.0%, n=23) (P<0.0001). Methylated SEPT9_v2 ctDNA in plasma was detected in 11% (9/82) of primary breast cancer patients and 52% (26/50) of metastatic breast cancer patients, but not in the healthy controls (0/51). These results indicate that SEPT9_v2 promoter hypermethylation, which silences the expression of SEPT9_v2 mRNA, is observed in a significant proportion of breast tumors, and that methylated SEPT9_v2 may serve as a novel tumor marker for breast cancer. PMID- 27499430 TI - Investigation on the neutral and anionic BxAlyH2 (x + y = 7, 8, 9) clusters using density functional theory combined with photoelectron spectroscopy. AB - The structure and bonding nature of neutral and negatively charged BxAlyH2 (x + y = 7, 8, 9) clusters are investigated with the aid of previously published experimental photoelectron spectra combined with the present density functional theory calculations. The comparison between the experimental photoelectron spectra and theoretical simulated spectra helps to identify the ground state structures. The accuracy of the obtained ground state structures is further verified by calculating their adiabatic electron affinities and vertical detachment energies and comparing them against available experimental data. The results show that the structures of BxAlyH2 transform from three-dimensional to planar structures as the number of boron atoms increases. Moreover, boron atoms tend to bind together forming Bn units. The hydrogen atoms prefer to bind with boron atoms rather than aluminum atoms. The analyses of the molecular orbital on the ground state structures further support the abovementioned results. PMID- 27499431 TI - Serum uric acid change and modification of blood pressure and fasting plasma glucose in an overall healthy population sample: data from the Brisighella heart study. AB - BACKGROUND: Serum uric acid (SUA) is an emerging risk factor for incident hypertension and type 2 diabetes. It is less clear if changes in SUA are associated to different incidence in these main cardiovascular risk factors. METHODS: From the cohort of the Brisighella Heart Study, we selected non-diabetic subjects that in 2008 were untreated with SUA-lowering drugs nor antihypertensive ones. Then we divided the subjects in four main groups: the ones that maintained their SUA level unchanged during the next 4 years, the ones that increased it >1 mg/dL without treatment, the ones that reduced it >1 mg/dL without drug treatment and the ones that reduced it >1 mg/dL with the continuous use of allopurinol. RESULTS: Compared with 2008, SBP significantly increased in subjects with worsened (and untreated) SUA level, while improved in subjects treated with allopurinol (p < 0.05). In 2012, subjects with worsened (and untreated) SUA level had a significantly higher SBP compared with subjects with unchanged SUA and those with SUA improved after allopurinol treatment (p < 0.05). An identical trend has been observed as it regards FPG. CONCLUSION: It seems that SUA improvement could positively influence the age-related worsening of SBP and FPG in general population. Key messages Serum uric acid (SUA) is an emerging risk factor for incident hypertension and type 2 diabetes. SUA improvement could positively influence the age-related worsening of SBP and FPG in general population. PMID- 27499432 TI - In vitro growth of multidrug-resistant Neisseria gonorrhoeae isolates is inhibited by ETX0914, a novel spiropyrimidinetrione. AB - Antimicrobial resistance in Neisseria gonorrhoeae has severely limited the number of treatment options, and the emergence of extended-spectrum cephalosporin resistance threatens the effectiveness of the last remaining recommended treatment regimen. This study assessed the in vitro susceptibility of N. gonorrhoeae to ETX0914, a novel spiropyrimidinetrione that inhibits DNA biosynthesis. In vitro activity was determined by agar dilution against 100 N. gonorrhoeae isolates collected from men presenting with urethritis in the USA during 2012-2013 through the Gonococcal Isolate Surveillance Project. The minimum inhibitory concentration (MIC) that inhibited growth in 50% (MIC50) and 90% (MIC90) of isolates was calculated for each antimicrobial agent. ETX0914 demonstrated a high level of antimicrobial activity against N. gonorrhoeae, including isolates with decreased susceptibility or resistance to currently available agents. The ability of ETX0914 to inhibit the growth of N. gonorrhoeae was similar to ceftriaxone, which is currently recommended in combination with azithromycin to treat gonorrhoea. The data presented in this study strongly suggest that ETX0914 should be evaluated in a clinical trial for the treatment of N. gonorrhoeae. PMID- 27499433 TI - HIV aspartic peptidase inhibitors are effective drugs against the trypomastigote form of the human pathogen Trypanosoma cruzi. AB - There is a general lack of effective and non-toxic chemotherapeutic agents against Chagas' disease despite more than a century of research. In this regard, we have verified the impact of human immunodeficiency virus aspartic peptidase inhibitors (HIV-PIs) on the viability and morphology of infective trypomastigote forms of Trypanosoma cruzi as well as on the aspartic peptidase and proteasome activities produced by this parasite. The effects of HIV-PIs on viability were assessed by counting motile parasites in a Neubauer chamber. Morphological alterations were detected by light microscopy of Giemsa-stained smears and scanning electron microscopy. Modulation of aspartic peptidase and proteasome activities by the HIV-PIs was measured by cleavage of fluorogenic peptide substrates. The majority of the HIV-PIs (6/9) were able to drastically decrease the viability of trypomastigotes after 4 h of treatment, with nelfinavir and lopinavir being the most effective compounds presenting LD50 values of 8.6 uM and 10.6 uM, respectively. Additionally, both HIV-PIs were demonstrated to be effective in a time- and cell density-dependent manner. Treatment with nelfinavir and lopinavir caused many morphological/ultrastructural alterations in trypomastigotes; parasites became round in shape, with reduced cell size and flagellar shortening. Nelfinavir and lopinavir were also capable of significantly inhibiting the aspartic peptidase and proteasome activities measured in trypomastigote extracts. These results strengthen the data on the positive effects of HIV-PIs on parasitic infections, possibly by targeting the parasite aspartic peptidase(s) and proteasome(s), opening a new possibility for the use of these clinically approved drugs as an alternative chemotherapy to treat Chagas' disease. PMID- 27499434 TI - Characterisation of class 3 integrons with oxacillinase gene cassettes in hospital sewage and sludge samples from France and Luxembourg. AB - In this study, antibiotic resistance class 3 integrons in Gram-negative bacteria isolated from hospital sewage and sludge and their genetic contents were characterised. Two samples of hospital effluent from France and Luxembourg and one sample of sludge from a wastewater treatment plant in France were collected in 2010 and 2011. Bacteria were cultured on selective agar plates and integrons were detected in colonies by quantitative PCR. Integron gene cassette arrays and their genetic environments were analysed by next-generation sequencing. Three class 3 integron-positive isolates were detected, including Acinetobacter johnsonii LIM75 (French hospital effluent), Aeromonas allosaccharophila LIM82 (sludge) and Citrobacter freundii LIM86 (Luxembourg hospital effluent). The gene cassettes were all implicated in antibiotic (aminoglycoside and beta-lactam) or antiseptic resistance. An oxacillinase gene cassette (blaOXA-10, blaOXA-368 or blaOXA-2) was found in each integron. All of the class 3 integrons were located on small mobilisable plasmids. This study highlights the role of class 3 integrons in the dissemination of clinically relevant antibiotic resistance genes, notably oxacillinase genes, in hospital effluent. PMID- 27499435 TI - The influence of human papillomavirus on nasopharyngeal carcinoma in Japan. AB - OBJECTIVE: Although Japan is a non-endemic area with nasopharyngeal carcinoma (NPC), the proportion of WHO type I NPC in Japan are different from that in non endemic areas such as North America and Europe. Recently, it is said that not only Epstein-Barr virus (EBV) but also human papillomavirus (HPV) has an influence on NPC in non-endemic areas. The aim of this study is to clarify the influence of HPV on NPC in Japan. METHODS: Paraffin-embedded tumor specimens were available for 59 patients with NPC diagnosed between 1996 and 2015. We detected the virus status by p16 immunohistochemistry, HPV PCR, and in situ hybridization for Epstein-Barr virus (EBV)-encoded RNA. Kaplan-Meier curves were used to compare the overall survival by viral status. RESULTS: Among the 59 patients, 49 (83%) were EBV-positive/HPV-negative, 2 (3%) were EBV-positive/HPV-positive, and 8 (16%) were EBV-negative/HPV-negative. All HPV-positive NPCs were co-infected with EBV. There were no significant differences between the overall survival in the three groups (p=0.111). CONCLUSION: In Japan, HPV was detected in a few patients with NPC, and we suggest that HPV has no influence on NPC carcinogenesis in this population. PMID- 27499436 TI - New inflammatory parameters in laryngopharyngeal reflux. AB - OBJECTIVES: To investigate new inflammatory markers in patients with laryngopharyngeal reflux and determine whether these inflammatory parameters change in response to laryngopharyngeal reflux treatment. METHODS: Complete blood count was evaluated to obtain platelet count and mean platelet volume and calculate neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio. Laryngopharyngeal reflux patients underwent three-month lansoprazole treatment. RESULTS: The study included 45 laryngopharyngeal reflux patients (9 men (20 per cent); mean age, 37.4 +/- 11.6 years) and 35 healthy age- and sex-matched controls (7 men (20 per cent); mean age, 38.6 +/- 8.9 years). The study group had significantly higher platelet-to-lymphocyte ratios and lower mean platelet volumes than the control group (p = 0.004 and p = 0.047, respectively). There was a significant correlation between platelet-to-lymphocyte ratios and initial inflammatory symptoms (reflux symptom index, p = 0.025; reflux finding score, p = 0.013). There was also a significant correlation between mean platelet volume increase and symptom resolution in the first and third months of treatment (p = 0.04 and p = 0.03, respectively). CONCLUSION: Platelet-to-lymphocyte ratio, a new inflammatory marker of chronic inflammation, was significantly higher in laryngopharyngeal reflux patients. Moreover, these patients had significantly lower mean platelet volume values, which increased with post-treatment symptom improvement. PMID- 27499437 TI - CCL22 and IL-37 inhibit the proliferation and epithelial-mesenchymal transition process of NSCLC A549 cells. AB - In the present study, we aimed to investigate the effects of CC chemokine ligand 22 (CCL22) and interleukin-37 (IL-37) on the proliferation and epithelial mesenchymal transition (EMT) of non-small cell lung cancer (NSCLC) A549 cells. pDsRed-CCL22 and pEGFP-IL-37 plasmids were constructed. A549 cells were divided into six groups: the control, the pDsRed-N1 blank plasmid, the pEGFP-C1 blank plasmid, the pDsRed-CCL22 plasmid, the pEGFP-IL-37 plasmid and the pDsRed-CCL22 + pEGFP-IL-37 plasmid group. Expression levels and localization of CCL22 and IL-37 in cells were detected by confocal microscopy. Phase-contrast microscopy was applied for observing cellular morphology. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used for detecting the mRNA levels of vimentin, N-cadherin and E-cadherin, and their protein expression levels were tested using western blotting. Constructed plasmids expressed CCL22 and IL-37, both of which had a co-localization in the cell membrane. MTT assay and cell observation results revealed that CCL22 and IL-37 inhibited the proliferation and EMT process of the A549 cells. The results of RT-qPCR and western blotting revealed that decreased vimentin and N-cadherin mRNA and protein expression levels, and increased E-cadherin mRNA and protein expression levels were found in the pDsRed-CCL22 plasmid, pEGFP-IL-37 plasmid and pDsRed-CCL22 + pEGFP-IL-37 plasmid groups when compared with the control, the pDsRed-N1 blank plasmid and the pEGFP-C1 blank plasmid groups (all P<0.05), and decreased vimentin and N cadherin mRNA and protein expression levels and increased E-cadherin mRNA and protein expression levels were found in the pDsRed-CCL22 + pEGFP-IL-37 plasmid group when compared with the pDsRed-CCL22 plasmid and the pEGFP-IL-37 plasmid groups (all P<0.05). CCL22 and IL-37 with a co-localization in the A549 cells inhibited the proliferation and EMT process in A549 cells. The antitumor effects of CCL22 and IL37 provide a strategy for the treatment of NSCLC. PMID- 27499438 TI - Structural Basis for a New Templated Activity by Terminal Deoxynucleotidyl Transferase: Implications for V(D)J Recombination. AB - Eukaryotic DNA polymerase of the polX family, such as pol MU and terminal deoxynucleotidyl transferase (TdT), are key components of the non-homologous end joining or V(D)J recombination machinery, respectively. The established role of TdT is to add random nucleotides during V(D)J recombination. Here we show that TdT also has a templated-polymerase activity, similar to pol MU, in the presence of higher concentrations of a downstream DNA duplex, and performs a micro homology single base-pair search to align the DNA synapsis. To understand the molecular basis of this alignment, we solve crystal structures of TdT with four DNA strands and study the influence of the 3' protruding end. Two mutations in TdT inspired by sequence alignments with pol MU further improve the templated activity. We propose that both templated and untemplated activities of TdT are needed to explain the distributions of lengths of N regions observed experimentally in T cell receptors and antibodies. PMID- 27499439 TI - Tankyrase Sterile alpha Motif Domain Polymerization Is Required for Its Role in Wnt Signaling. AB - Tankyrase-1 (TNKS1/PARP-5a) is a poly(ADP-ribose) polymerase (PARP) enzyme that regulates multiple cellular processes creating a poly(ADP-ribose) posttranslational modification that can lead to target protein turnover. TNKS1 thereby controls protein levels of key components of signaling pathways, including Axin1, the limiting component of the destruction complex in canonical Wnt signaling that degrades beta-catenin to prevent its coactivator function in gene expression. There are limited molecular level insights into TNKS1 regulation in cell signaling pathways. TNKS1 has a sterile alpha motif (SAM) domain that is known to mediate polymerization, but the functional requirement for SAM polymerization has not been assessed. We have determined the crystal structure of wild-type human TNKS1 SAM domain and used structure-based mutagenesis to disrupt polymer formation and assess the consequences on TNKS1 regulation of beta-catenin dependent transcription. Our data indicate the SAM polymer is critical for TNKS1 catalytic activity and allows TNKS1 to efficiently access cytoplasmic signaling complexes. PMID- 27499440 TI - Structural Basis for Receptor Recognition by the Human CD59-Responsive Cholesterol-Dependent Cytolysins. AB - Cholesterol-dependent cytolysins (CDCs) are a family of pore-forming toxins that punch holes in the outer membrane of eukaryotic cells. Cholesterol serves as the receptor, but a subclass of CDCs first binds to human CD59. Here we describe the crystal structures of vaginolysin and intermedilysin complexed to CD59. These studies, together with small-angle X-ray scattering, reveal that CD59 binds to each at different, though overlapping, sites, consistent with molecular dynamics simulations and binding studies. The CDC consensus undecapeptide motif, which for the CD59-responsive CDCs has a proline instead of a tryptophan in the motif, adopts a strikingly different conformation between the structures; our data suggest that the proline acts as a selectivity switch to ensure CD59-dependent CDCs bind their protein receptor first in preference to cholesterol. The structural data suggest a detailed model of how these water-soluble toxins assemble as prepores on the cell surface. PMID- 27499442 TI - The Dynamic Basis for Signal Propagation in Human Pin1-WW. AB - Allostery is the structural manifestation of information transduction in biomolecules. Its hallmark is conformational change induced by perturbations at a distal site. An increasing body of evidence demonstrates the presence of allostery in very flexible and even disordered proteins, encouraging a thermodynamic description of this phenomenon. Still, resolving such processes at atomic resolution is difficult. Here we establish a protocol to determine atomistic thermodynamic models of such systems using high-resolution solution state nuclear magnetic resonance data and extensive molecular simulations. Using this methodology, we study information transduction in the WW domain of a key cell-cycle regulator Pin1. Pin1 binds promiscuously to phospho-Ser/Thr-Pro motifs, however, disparate structural and dynamic responses have been reported upon binding different ligands. Our model consists of two topologically distinct states whose relative population may be specifically skewed by an incoming ligand. This model provides a canonical basis for the understanding of multi functionality in Pin1. PMID- 27499441 TI - Structural Basis for the Recognition of Eukaryotic Elongation Factor 2 Kinase by Calmodulin. AB - Binding of Ca(2+)-loaded calmodulin (CaM) activates eukaryotic elongation factor 2 kinase (eEF-2K) that phosphorylates eEF-2, its only known cellular target, leading to a decrease in global protein synthesis. Here, using an eEF-2K-derived peptide (eEF-2KCBD) that encodes the region necessary for its CaM-mediated activation, we provide a structural basis for their interaction. The striking feature of this association is the absence of Ca(2+) from the CaM C-lobe sites, even under high Ca(2+) conditions. eEF-2KCBD engages CaM largely through the C lobe of the latter in an anti-parallel 1-5-8 hydrophobic mode reinforced by a pair of unique electrostatic contacts. Sparse interactions of eEF-2KCBD with the CaM N lobe results in persisting inter-lobe mobility. A conserved eEF-2K residue (W85) anchors it to CaM by inserting into a deep hydrophobic cavity within the CaM C lobe. Mutation of this residue (W85S) substantially weakens interactions between full-length eEF-2K and CaM in vitro and reduces eEF-2 phosphorylation in cells. PMID- 27499443 TI - Chimneys and sandwiches for endovascular arch repair in patients with Marfan syndrome: Are we snorkeling in cloudy waters? PMID- 27499444 TI - Bioprosthetic leaflet perforation associated with suture tails. PMID- 27499445 TI - Phenolic profile and antioxidant activity from non-toxic Mexican Jatropha curcas L. shell methanolic extracts. AB - Jatropha curcas seed shells are the by-product obtained during oil extraction process. Recently, its chemical composition has gained attention since its potential applications. The aim of this study was to identify phenolic compounds profile from a non-toxic J. curcas shell from Mexico, besides, evaluate J. curcas shell methanolic extract (JcSME) antioxidant activity. Free, conjugate and bound phenolics were fractionated and quantified (606.7, 193.32 and 909.59 MUg/g shell, respectively) and 13 individual phenolic compounds were detected by HPLC. The radical-scavenging activity of JcSME was similar to Trolox and ascorbic acid by DPPH assay while by ABTS assay it was similar to BHT. Effective antioxidant capacity by ORAC was found (426.44 +/- 53.39 MUmol Trolox equivalents/g shell). The Mexican non-toxic J. curcas shell is rich in phenolic compounds with high antioxidant activity; hence, it could be considerate as a good source of natural antioxidants. PMID- 27499446 TI - Unified Electromagnetic-Electronic Design of Light Trapping Silicon Solar Cells. AB - A three-dimensional unified electromagnetic-electronic model is developed in conjunction with a light trapping scheme in order to predict and maximize combined electron-photon harvesting in ultrathin crystalline silicon solar cells. The comparison between a bare and light trapping cell shows significant enhancement in photon absorption and electron collection. The model further demonstrates that in order to achieve high energy conversion efficiency, charge separation must be optimized through control of the doping profile and surface passivation. Despite having a larger number of surface defect states caused by the surface patterning in light trapping cells, we show that the higher charge carrier generation and collection in this design compensates the absorption and recombination losses and ultimately results in an increase in energy conversion efficiency. The fundamental physics behind this specific design approach is validated through its application to a 3 MUm thick functional light trapping solar cell which shows 192% efficiency enhancement with respect to the bare cell of same thickness. Such a unified design approach will pave the path towards achieving the well-known Shockley-Queisser (SQ) limit for c-Si in thin-film (<30 MUm) geometries. PMID- 27499447 TI - Biphasic influence of PGE2 on the resorption activity of osteoclast-like cells derived from human peripheral blood monocytes and mouse RAW264.7 cells. AB - Osteoclasts are large bone-resorbing cells of hematopoietic origin. Their main function is to dissolve the inorganic component hydroxyapatite and to degrade the organic bone matrix. Prostaglandin E2 (PGE2) indirectly affects osteoclasts by stimulating osteoblasts to release factors that influence osteoclast activity. The direct effect of PGE2 on osteoclasts is still controversial. To study the influence of PGE2 on osteoclast activity, human peripheral blood monocytes (hPBMC) and mouse RAW264.7 cells were cultured on osteoblast-derived extracellular matrix. hPBMC and RAW264.7 cells were differentiated by the addition of macrophage colony-stimulation factor and receptor activator of NFkappaB ligand and treated with PGE2 before and after differentiation induction. The pit area, an indicator of resorption activity, and the activity of tartrate resistant acid phosphatase were dose-dependently inhibited when PGE2 was present ab initio, whereas the resorption activity remained unchanged when the cells were exposed to PGE2 from day 4 of culture. These results lead to the conclusion that PGE2 treatment inhibits only the differentiation of precursor osteoclasts whereas differentiated osteoclasts are not affected. PMID- 27499448 TI - Docosahexaenoic acid supplementation (DHA) and the return on investment for pregnancy outcomes. AB - The Kansas University DHA Outcomes Study (KUDOS) found a significant reduction in early preterm births with a supplement of 600mg DHA per day compared to placebo. The objective of this analysis was to determine if hospital costs differed between groups. We applied a post-hoc cost analysis of the delivery hospitalization and all hospitalizations in the following year to 197 mother infant dyads who delivered at Kansas University Hospital. Hospital cost saving of DHA supplementation amounted to $1678 per infant. Even after adjusting for the estimated cost of providing 600mg/d DHA for 26 weeks ($166.48) and a slightly higher maternal care cost ($26) in the DHA group, the net saving per dyad was $1484. Extrapolating this to the nearly 4 million US deliveries per year suggests universal supplementation with 600mg/d during the last 2 trimesters of pregnancy could save the US health care system up to USD 6 billion. PMID- 27499449 TI - Comparison of the effects of EPA and DHA alone or in combination in a murine model of myocardial infarction. AB - The aim of this project was to investigate the impact of two dietary omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alone or in combination, on infarct size. Adult, male Sprague-Dawley rats were fed for 14 days with different omega-3 diets. The animals were subjected to ischemia for 40min followed by reperfusion. Infarct size, Akt (protein kinase B) activation level, caspase-3 activity and mitochondrial permeability transition pore (mPTP) opening were measured. The results indicate that EPA or DHA alone significantly reduced infarct size compared to the other diets. Akt activity was increased in the group fed EPA or DHA alone, whereas no significant activation was observed in the other groups compared to no omega-3 PUFA. DHA alone reduced caspase-3 activity and conferred resistance to mPTP opening. In conclusion, our results demonstrate that EPA and DHA are individually effective in diminishing infarct size in our experimental model while their combination is not. PMID- 27499451 TI - Dissimilatory Nitrate Reduction Processes in Typical Chinese Paddy Soils: Rates, Relative Contributions, and Influencing Factors. AB - Using soil slurry-based (15)N tracer combined with N2/Ar technique, the potential rates of denitrification, anaerobic ammonium oxidation (anammox), and dissimilatory nitrate reduction to ammonium (DNRA), and their respective contributions to total nitrate reduction were investigated in 11 typical paddy soils across China. The measured rates of denitrification, anammox, and DNRA varied from 2.37 to 8.31 nmol N g(-1) h(-1), 0.15 to 0.77 nmol N g(-1) h(-1) and 0.03 to 0.54 nmol N g(-1) h(-1), respectively. The denitrification and anammox rates were significantly correlated with the soil organic carbon content, nitrate concentration, and the abundance of nosZ genes. The DNRA rates were significantly correlated with the soil C/N, extractable organic carbon (EOC)/NO3(-) ratio, and sulfate concentration. Denitrification was the dominant pathway (76.75-92.47%), and anammox (4.48-9.23%) and DNRA (0.54-17.63%) also contributed substantially to total nitrate reduction. The N loss or N conservation attributed to anammox and DNRA was 4.06-21.24 and 0.89-15.01 g N m(-2) y(-1), respectively. This study reports the first simultaneous investigation of the dissimilatory nitrate reduction processes in paddy soils, highlighting that anammox and DNRA play important roles in removing nitrate and should be considered when evaluating N transformation processes in paddy fields. PMID- 27499450 TI - Impact of co-payment for outpatient utilization among Medical Aid beneficiaries in Korea: A 5-year time series study. AB - BACKGROUND: The Korean government implemented an outpatient co-payment scheme in July 2007 to control Medical-Aid beneficiaries' overutilization of healthcare services. OBJECTIVES: To assess changes in the utilization of medical services resulting from the outpatient co-payment scheme. METHODS: 410,142 subjects were selected and health insurance reimbursement data from July 2006 to June 2011 was examined. We assessed the changes in the total medical cost, total adjusted patient days, inpatient days, inpatient total medical cost, the number of outpatient visits, and outpatient total medical cost using segmented regression analysis. RESULTS: Following the introduction of the policy, the number of outpatient visits per person fell by 0.16 days in July 2008, and by 0.06 days in July 2010, compared to June 2007. The outpatient total medical cost per person rose by $4.11 in July 2010 compared to June 2007. The inpatient utilization increased constantly during the period of the study. So the total medical cost as well as the total adjusted number of patient days also increased constantly. CONCLUSION: The outpatient co-payment policy was effective for reducing the number of outpatient visits. It could not control the cost per outpatient visit and inpatient utilization. So the total medical cost was increased. PMID- 27499452 TI - Osseous Injury Associated With Ligamentous Tear of the Knee. AB - One of the most common knee injuries is ligament tear, which may initially manifest as an osseous injury in radiographs. Radiologists should therefore be able to recognize ligament tears of the knee as osseous abnormalities in images. This review focuses on the imaging features of knee ligament injuries and their related osseous injuries: anterior cruciate ligament (ACL) tear with Segond fracture; associated marrow contusion; ACL avulsion fracture; posterior cruciate ligament (PCL) tear with osseous avulsion of the ligament including arcuate sign; reverse Segond fracture; PCL avulsion fracture; medial collateral ligament tear with Pellegrini-Stieda disease; lateral collateral ligament tear with avulsion fracture of the fibular head; and patellar ligament injuries with Osgood Schlatter and Sinding-Larsen-Johansson. PMID- 27499453 TI - Isolation of three new annonaceous acetogenins from Graviola fruit (Annona muricata) and their anti-proliferation on human prostate cancer cell PC-3. AB - Bioassay-guided fractionation of the fruit powder of Graviola (Annona muricata) was continued to be conducted and yielded three more novel bioactive compounds: C 35 annonaceous acetogenins, muricins M and N, and C-37 annonaceous acetogenins, muricenin. They all contain a mono-tetrahydrofuran ring and four hydroxyl groups. The structures were elucidated by spectral methods and chemical modification after isolation via open column chromatographic separation and HPLC purification. Especially, murices M and N demonstrated more potent anti-proliferative activities against human prostate cancer PC-3 cells. PMID- 27499454 TI - Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors. AB - Features from a high throughput screening (HTS) hit and a previously reported scaffold were combined to generate 1,7-naphthyridones as novel KDM5 enzyme inhibitors with nanomolar potencies. These molecules exhibited high selectivity over the related KDM4C and KDM2B isoforms. An X-ray co-crystal structure of a representative molecule bound to KDM5A showed that these inhibitors are competitive with the co-substrate (2-oxoglutarate or 2-OG). PMID- 27499455 TI - Discovery and structure-activity relationships of a novel isothiazolone class of bacterial type II topoisomerase inhibitors. AB - There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile. PMID- 27499457 TI - Distinct clinical characteristics and therapeutic modalities for diabetic ketoacidosis in type 1 and type 2 diabetes mellitus. AB - AIMS: Patients with type 1 diabetes often develop diabetic ketoacidosis (DKA). Reportedly, DKA in type 2 diabetes has higher mortality despite its limited occurrence. The exact clinical characteristics and therapeutic modalities yielding successful outcomes in DKA type 2 diabetes remain unknown. METHODS: This retrospective study compared the clinical features and detailed treatment of consecutive type 1 and type 2 diabetes patients hospitalized with DKA between January 2001 and December 2014. RESULTS: We report on 127 patients with type 1 and 74 patients with type 2 diabetes whose DKA was successfully treated. The most frequent precipitating cause for DKA was infectious disease for patients with type 1 diabetes and consumption of sugar-containing beverages for those with type 2 diabetes. Type 2 diabetes patients showed higher mean plasma glucose levels than those with type 1 diabetes (48.4+/-21.6, vs. 37.1+/-16.4mmol/l, P<0.01) and higher serum creatinine, blood urea nitrogen, and hemoglobin levels, which normalized after DKA resolution. Compared with type 1 diabetes patients, those with type 2 diabetes required distinctly higher daily total insulin dosage (35.9+/-37.0U, vs. 20.2+/-23.3U, P<0.01), larger replacement fluid volumes (4.17+/-2.69L, vs. 2.29+/-1.57L, P<0.01) and greater potassium supplementation (23.9+/-36.5mEq, vs. 11.2+/-17.9mEq, P<0.01) to resolve DKA and reduce plasma glucose level to <=16.7mmol/l. CONCLUSIONS: DKA patients with type 2 diabetes required management with a modified treatment protocol to resolve their profound hyperglycemia and dehydration compared with those with type 1 diabetes. PMID- 27499456 TI - Empagliflozin in combination with oral agents in young and overweight/obese Type 2 diabetes mellitus patients: A pooled analysis of three randomized trials. AB - AIMS: This analysis aimed to evaluate efficacy and safety of empagliflozin in combination therapy in <65 y.o. patients, overweight/obese, and with uncontrolled T2DM. METHODS: Pooled analysis from three phase-III trials, in <65 y.o. patients, with BMI 25-35kg/m2, and HbA1c >=8% at baseline. Patients (N=439) were randomized to placebo (n=138), empagliflozin 10mg (n=160), or empagliflozin 25mg (n=141) once daily (24weeks) as add-on to metformin, to metformin plus sulfonylurea, or to pioglitazone +/- metformin. RESULTS: At week 24, adjusted mean (SE) changes from baseline in HbA1c were -0.19% (0.07) for placebo vs. -1.10% (0.07) and 1.10% (0.07) for empagliflozin 10 and 25mg, respectively (both p<0.001). Adjusted mean (SE) changes from baseline in weight were -0.33kg (0.21) for placebo vs. 1.94kg (0.19) and -2.14kg (0.20) for empagliflozin 10 and 25mg, respectively (both p<0.001). Adverse events were reported in 57.2% on placebo, 64.4% on empagliflozin 10mg and 59.6% on empagliflozin 25mg. Genital infection AEs were reported in 1.4% on placebo, 3.8% on empagliflozin 10mg, and 5.0% on empagliflozin 25mg. CONCLUSIONS: In this specific population, empagliflozin in combination with other oral agents, significantly reduced HbA1c and body weight and was well tolerated. PMID- 27499458 TI - Efficacy and safety of linagliptin in type 2 diabetes patients with self-reported hepatic disorders: A retrospective pooled analysis of 17 randomized, double blind, placebo-controlled clinical trials. AB - AIMS: Liver disease is highly prevalent among people with type 2 diabetes mellitus (T2DM). We evaluated the dipeptidyl peptidase-4 inhibitor linagliptin in subjects with T2DM and hepatic disorders. METHODS: Data were pooled from 17 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2DM subjects that included individuals with self-reported history of hepatic disorders at baseline. The primary endpoint was change in HbA1c from baseline to week 24. RESULTS: Of the 7009 participants (56% white, 39% Asian), 574 had hepatic disorders, most commonly hepatic steatosis (60%). At week 24, adjusted mean+/-standard error (SE) change in HbA1c from baseline in those with hepatic disorders was -0.75%+/-0.05 with linagliptin and -0.20%+/-0.08 with placebo [treatment difference: -0.54% (95% confidence interval-0.72 to -0.36); P<.0001]. There was no significant difference in HbA1c reduction between subjects with or without baseline hepatic disorders (P=.4042). Among subjects with hepatic disorders, 13.5% and 14.8% of the linagliptin and placebo groups, respectively, reported drug-related adverse events while 10.4% and 15.9%, respectively, reported hypoglycemia. Overall, adverse event rates were similar in individuals with or without hepatic disorders. CONCLUSIONS: This large pooled analysis suggests that linagliptin is effective and well tolerated in people with T2DM and liver disease. PMID- 27499460 TI - Antimicrobial effects of Piper hispidum extract, fractions and chalcones against Candida albicans and Staphylococcus aureus. AB - Three chalcones, 2'-hydroxy-4,4',6'-trimethoxychalcone, 2'-hydroxy-4,4',6' tetramethoxychalcone, and 3,2'-dihydroxy-4,4',6'-trimethoxychalcone, were isolated from the leaves of Piper hispidum in a bioguided fractionation of crude extract. The antimicrobial activity of crude extract of P. hispidum leaves was determined against bacteria Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus and yeasts Candida albicans, C. parapsilosis and C. tropicalis. Fractions and chalcones were tested against C. albicans and S. aureus. The checkerboard assay was performed to assess synergic interactions between extract and antifungal drugs, and the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) reduction assay was used to evaluate anti biofilm effects of extract. The extract was active against yeasts, S. aureus and B. subtilis with MIC values between 15.6 and 62.5MUg/mL. Synergistic effects of extract associated with fluconazole and nystatin were observed against C. albicans, with fractional inhibitory concentration indices of 0.37 and 0.24, respectively. The extract was also effective against C. albicans and S. aureus biofilm cells at concentrations of 62.5 and 200MUg/mL, respectively. Thus, P. hispidum may be a possible source of bioactive substances with antimicrobial properties. PMID- 27499459 TI - Parathyroid hormone/parathyroid hormone-related peptide regulate osteosarcoma cell functions: Focus on the extracellular matrix (Review). AB - Osteosarcoma (OS) is a primary bone tumor of mesenchymal origin mostly affecting children and adolescents. The OS extracellular matrix (ECM) is extensively altered as compared to physiological bone tissue. Indeed, the main characteristic of the most common osteoblastic subtype of OS is non-mineralized osteoid production. Parathyroid hormone (PTH) is a polypeptide hormone secreted by the chief cells of the parathyroid glands. The PTH-related peptide (PTHrP) may be comprised of 139, 141 or 173 amino acids and exhibits considerate N-terminal amino acid sequence homology with PTH. The function of PTH/PTHrP is executed through the activation of the PTH receptor 1 (PTHR1) and respective downstream intracellular pathways which regulate skeletal development, bone turnover and mineral ion homeostasis. Both PTHR1 and its PTH/PTHrP ligands have been shown to be expressed in OS and to affect the functions of these tumor cells. This review aims to highlight the less well known aspects of PTH/PTHrP functions in the progression of OS by focusing on ECM-dependent signaling. PMID- 27499461 TI - Evaluation of antifungal activity of standardized extract of Salvia rhytidea Benth. (Lamiaceae) against various Candida isolates. AB - OBJECTIVES: Salvia species have long been described in traditional medicine for various indications. Owing to the widespread use of this genus by ethnic populations, especially for various infections ranging from skin disease to gastrointestinal disorders, we were encouraged to determine whether Salvia rhytidea could be effective against fungal infections. Given the increased incidence of candidiasis in the past decade, limits on the use of antifungal drugs, emergence of azole-resistant Candida species and increased incidence of treatment failures, it is necessary to identify a novel agent with antifungal properties. Aim of the study was to evaluate the antifungal properties of S. rhytidea against various Candida isolates. MATERIALS AND METHODS: In this study, at first rosmarinic acid content of plant extract was determined. A total of 96 Candida isolates were tested, including the following species: Candida albicans (n=42), Candida glabrata (n=16), Candida tropicalis (n=11), Candida krusei (n=9), Candida parapsilosis (n=9), Candida lusitaniae (n=7) and Candida guilliermondii (n=2). The in vitro antifungal activity of methanolic extracts of S. rhytidea Benth. was evaluated against Candida isolates and compared with that of the standard antifungal drug nystatin by using a broth microdilution method, according to CLSI. RESULTS: Phytochemical screening results showed that the methanolic extract of S. rhytidea Benth. was rich in flavonoids and tannins. The minimal inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values of S. rhytidea Benth. ranged from 3.125 to>100MUg/ml and 6.25 to>100MUg/ml respectively. The growth inhibition value displayed that C. tropicalis, C. krusei and C. albicans isolates were most susceptible to S. rhytidea. CONCLUSIONS: Findings show that S. rhytidea possesses an antifungal effect against Candida isolates. PMID- 27499462 TI - Prisoners of Solitude: Bringing History to Bear on Prison Health Policy. PMID- 27499463 TI - Improving the quality of written feedback using written feedback. AB - BACKGROUND: Educational feedback is amongst the most powerful of all learning interventions. RESEARCH QUESTIONS: (1) Can we measure the quality of written educational feedback with acceptable metrics? (2) Based on such a measure, does a quality improvement (QI) intervention improve the quality of feedback? STUDY DESIGN: We developed a QI instrument to measure the quality of written feedback and applied it to written feedback provided to medical students following workplace assessments. We evaluated the measurement characteristics of the QI score using generalisability theory. In an uncontrolled intervention, QI profiles were fed back to GP tutors and pre and post intervention scores compared. STUDY RESULTS: A single assessor scoring 6 feedback summaries can discriminate between practices with a reliability of 0.82.The quality of feedback rose for two years after the introduction of the QI instrument and stabilised in the third year. The estimated annual cost to provide this feedback is L12 per practice. Interpretation and recommendations: It is relatively straightforward and inexpensive to measure the quality of written feedback with good reliability. The QI process appears to improve the quality of written feedback. We recommend routine use of a QI process to improve the quality of educational feedback. PMID- 27499464 TI - Evaluation of paediatric radiology services in hospitals in the UK. AB - AIM: To compare paediatric radiology provision across the UK with national standards published by the Department of Health and the Royal College of Radiologists (RCR). MATERIALS AND METHODS: Audit standards and indicators for paediatric imaging were derived from "Delivering quality imaging services for children",1 "Standards for imaging in cases of suspected non-accidental injury"2 and "Improving paediatric interventional radiology services"3 and agreed jointly by the Clinical Radiology Audit Committee and the British Society of Paediatric Radiology. A questionnaire was sent to all hospitals and NHS trusts imaging children aged 16 or younger in the UK in October 2013. The target for all indicators was 100%. Eighty-seven of 196 (44%) eligible institutions submitted data, the size distribution of the institutions was representative when compared to data from "Facing the future: a review of paediatric services"4 published by the Royal College of Paediatrics and Child health. RESULTS: Only 65% of paediatric images were obtained by staff who had had specific training and only 60% were reported by radiographers or radiologists with appropriate training. Sixty-two percent of centres did not have access to a paediatric opinion 24 hours a day, 7 days a week all year; only 34% of radiographers who regularly imaged children had had any access to continuing professional development (CPD) in the 12 months of the audit. Although all hospitals had facilities for image transfer, only 57% had any formal funding arrangements in place for external reporting of images. CONCLUSIONS: The standards set for a network approach to paediatric radiology provision in "Delivering quality imaging services for children" are largely unmet. This failure to make the most of the workforce and resources puts vulnerable children at risk. The authors urge NHS England to work with the RCR to organise and administer a national network for paediatric imaging. PMID- 27499465 TI - Commentary on: evaluation of paediatric radiology service in hospitals in the UK. PMID- 27499466 TI - Stiffness at shear-wave elastography and patient presentation predicts upgrade at surgery following an ultrasound-guided core biopsy diagnosis of ductal carcinoma in situ. AB - AIM: The aim of this study is to establish predictors of invasion in lesions yielding an ultrasound-guided biopsy diagnosis of ductal carcinoma in situ (DCIS). MATERIALS AND METHODS: Patients subjected to ultrasound-guided core biopsy yielding DCIS were studied. At shear-wave elastography (SWE) a threshold of 50 kPa was used for mean elasticity (Emean) to dichotomise the elasticity data between invasive and non-invasive masses. Data recorded included the mammographic and ultrasound features, the referral source, and grade of DCIS in the biopsy. The chi-square test was used to detect statistical significance. RESULTS: Of 57 lesions, 24 (42%) had invasion at excision. Symptomatic patients and patients with stiff lesions were more likely to have invasion than patients presenting through screening and with soft lesions (58% [14 of 24] versus 30% [10 of 33], p=0.03) and (51% [20 of 39] versus 22% [4 of 18], p=0.04). No other factors showed a relationship with invasion. Combining the two predictors of invasion improved risk stratification with symptomatic and stiff lesions having a risk of invasion of 67% (12 of 18) and soft lesions presenting at screening having only a 17% (2 of 12) risk of invasion (p=0.02). CONCLUSION: Stiffness on SWE and the referral source of the patient are predictors of occult invasion in women with an ultrasound-guided core biopsy diagnosis of DCIS. PMID- 27499467 TI - Analysis and Diagnosis of Upper Facial Region. PMID- 27499468 TI - Botulinum Toxin Use in the Upper Face. PMID- 27499469 TI - Injectable Fillers in the Upper Face. PMID- 27499470 TI - Skin Resurfacing Procedures of the Upper Face. PMID- 27499471 TI - Upper Eyelid Blepharoplasty. PMID- 27499472 TI - Lower Transcutaneous Blepharoplasty. PMID- 27499473 TI - Transconjunctival Lower Blepharoplasty. AB - There is no secret to achieving successful results with lower belpharoplasties; as is the case with any surgical procedure, proper patient evaluation and development of a comprehensive, anatomic-based treatment plan are prerequisites for success. For situations in which a patient has little lid laxity and pseudoherniated periorbital fat, transconjunctival lower blepharoplasty is the treatment of choice. Transconjunctival lower blepharoplasty enables the surgeon to reposition fat, effectively blending the lid-cheek junction and filling the tear trough deformity. In order to better enable clinicians to achieve optimal outcomes, the authors advocate an anatomic-based approach for patient evaluation and treatment planning. PMID- 27499474 TI - Management of Lower Eyelid Laxity. PMID- 27499475 TI - Open Brow Lift Surgery for Facial Rejuvenation. PMID- 27499476 TI - The Endoscopic Brow Lift. PMID- 27499477 TI - Management of Complications Associated with Upper Facial Rejuvenation. PMID- 27499478 TI - Rejuvenation of the Facial Upper Third. PMID- 27499480 TI - Editors' Introduction. PMID- 27499479 TI - Upregulation of microRNA-370 promotes cell apoptosis and inhibits proliferation by targeting PTEN in human gastric cancer. AB - Growing evidence suggests that microRNA plays an essential role in the development and metastasis of many tumors, including gastric cancer. Aberrant miR 370 expression has been indicated in tumor growth, but the mechanism of miR-370 inhibits both the proliferation and metastatic ability for gastric cancer remains unclear. Accumulating evidence reported that PTEN signaling pathway plays an important role in the cellular processes, such as apoptosis, cell growth and proliferation. The goal of this study was to identify whether miR-370 could inhibit the growth, migration, invasion, proliferation and metastasis of gastric cancer through targeting PTEN. Real-time PCR (RT-PCR) was used to quantify miR 370 expression in vitro experiments. The biological functions of miR-370 were determined via cell proliferation. Our study indicated that miR-370 targeted PTEN leading to activation of apoptosis signaling and the cell proliferation of cervical cancer cells, ameliorating gastric cancer growth and progression. In addition, the combination of miR-370 and PTEN inactivated AKT, MDM2 and mTOR while stimulated caspase-3, p53 and GSK3beta expression, promoting apoptosis and suppressing proliferation of gastric cancer cells. Therefore, our study revealed the mechanistic links between miR-370 and PTEN in the pathogenesis of gastric cancer through modulation of cell apoptosis and proliferation. Additionally, targeting miR-370 could serve as a novel strategy for future gastric cancer therapy clinically. PMID- 27499481 TI - Henry Beecher's Contributions to the Ethics of Clinical Research. AB - In the 1950s and '60s, Henry Beecher pioneered the discussion of the ethics of clinical research, leading eventually to the publication of the famous New England Journal of Medicine article summarizing 22 research studies that Beecher suggests were unethical. Those studies generally showed a pattern of posing serious risks to subjects without anticipated proportional benefit. Beecher famously claimed that the problem was not that researchers were malicious or evil; rather, he claimed the problem was they manifested thoughtlessness or carelessness. He called for more rigorous self-scrutiny rather than public review.This article argues that Beecher's reliance on conscientious investigators is problematic. In particular, it focuses on benefits and harms to the exclusion of other moral criteria. However, both research subjects and public regulators are also concerned about autonomy and the consent requirement, confidentiality, and fairness in subject selection and research design. The movement in the 1970s toward more public scrutiny was critical, even though Beecher was right in holding that it was not "vicious disregard for subject welfare" that explained unethical protocols. PMID- 27499482 TI - "Ethics and Clinical Research" in Biographical Perspective. AB - Henry K. Beecher (1904-1976) played an important role in the development of bioethics. His 1966 article "Ethics and Clinical Research" in the New England Journal of Medicine intensified concern about the welfare of patients participating in clinical research, and his leadership in the 1968 Harvard Ad Hoc Committee on Brain Death redefined the determination of death. Beecher deserves, and even demands, explanation and explication. This essay offers a biographical perspective on the Harvard professor. In addition to his early life and education in both Kansas and Boston, the essay explores how Beecher's experiences in World War II and in the new geopolitical realities of the Cold War shaped his views about the ethical dilemmas of clinical research. PMID- 27499483 TI - Beecher as Clinical Investigator: Pain and the Placebo Effect. AB - Among the many contributions by Henry Beecher to science and clinical practice, pain and the placebo effect certainly represent two of the most important aspects. On the one hand, Beecher considered the pain experience not only as arising from the peripheral injured tissues, but also as an emotional experience that is capable of modulating the nociceptive input. On the other hand, he analyzed the placebo effect at an unprecedented level for that time. His ideas sparked from his work on wounded soldiers during World War II. In spite of the unusual situation and the lack of sophisticated experimental tools on the battlefield, Beecher succeeded in putting forward several important concepts, and his ideas still pervade modern health care and research. PMID- 27499484 TI - Moving Bioethics Toward Its Better Self: a sociologist's perspective. AB - The value and belief questions with which bioethics deals have social, cultural, moral, and societal implications that are not confined to certain spheres of biology and medicine, health and illness, and the delivery of medical care. And yet, throughout its history, the field has continued to be focused on a narrow array of medically associated phenomena to which it has applied a limited set of ethical precepts that originate in Western and American philosophical thought. It has done so in an intellectual atmosphere that has not been characterized by vigorous debate. This paper reflects on these attributes of bioethics, offers some suggestions about how it might expand its topical, ethical, cross-cultural, and international orbit, and invites participants in the field to bring this about through a self-critical process. PMID- 27499485 TI - Henry Knowles Beecher, Jay Katz, and the Transformation of Research with Human Beings. AB - The modern history of experimentation with human beings is notable for its ethical lacunae, when even the clearest directives fail to prevent violations of subjects' rights and welfare. One such lacuna occurred during the 25 years between 1947, when the Nuremberg Code was articulated in the judgment passed on the men who had performed medical experiments in the Nazi concentration camps, and 1972, when the revelation of the 40-year-long Tuskegee Syphilis Study shocked the public and pushed Congress to adopt legislation that eventually transformed the governance of human subjects research. The work that Henry Beecher and Jay Katz did on the ethics of human experimentation beginning in 1964-which was mutually supportive but also divergent in its premises and prescriptions-played a prominent role in the policy-making processes. Beecher, whose detailed disclosure of the ethical lapses of leading researchers in his renowned 1966 New England Journal of Medicine article initiated the policy reform process, proved less influential in shaping those reforms than Katz. Ultimately, Beecher was one of the last and best exemplars of "medical ethics," while Katz-in his service on the Tuskegee Syphilis Study Ad Hoc Advisory Panel and in his testimony before, and work with, the Senate Health subcommittee-was an early practitioner of bioethics, a field in which the rules are not all written and applied by the medical profession but arise through a messier process involving outsiders and formal regulatory decisions. PMID- 27499486 TI - Henry Beecher and Consent to Research: a critical re-examination. AB - Henry Beecher is an iconic figure in research ethics, best known for blowing the whistle on unethical clinical research in 1966. This article traces the evolution of Beecher's view on consent to research and juxtaposes these views with his own practices relating to informed consent in the conduct of clinical research. Additionally, critical examination of Beecher's conception of informed consent as an ideal has important implications for contemporary research ethics. PMID- 27499487 TI - Henry K. Beecher and the Oversight of Research in Children. AB - Henry K. Beecher was a pioneer of research ethics and a prominent whistleblower with regard to ethically problematic studies. Most of his work focused on research in adults, not children, but he did speculate about the implications of his ethical concerns for research in minors. This paper reviews Beecher's response to Krugman's studies of hepatitis at the Willowbrook State School and the debate that Beecher's article stimulated between Ramsey and McCormick. That debate shaped the terms that were used in current federal regulations for research in children. The paper then speculates about whether Beecher would have approved of our current regulatory system. PMID- 27499488 TI - Acid Brothers: Henry Beecher, Timothy Leary, and the psychedelic of the century. AB - Henry Knowles Beecher, an icon of human research ethics, and Timothy Francis Leary, a guru of the counterculture, are bound together in history by the synthetic hallucinogen lysergic acid diethylamide (LSD). Both were associated with Harvard University during a critical period in their careers and of drastic social change. To all appearances the first was a paragon of the establishment and a constructive if complex hero, the second a rebel and a criminal, a rogue and a scoundrel. Although there is no evidence they ever met, Beecher's indirect struggle with Leary over control of the 20th century's most celebrated psychedelic was at the very heart of his views about the legitimate, responsible investigator. That struggle also proves to be a revealing bellwether of the increasingly formalized scrutiny of human experiments that was then taking shape. PMID- 27499489 TI - The Role of the Virtuous Investigator in Protecting Human Research Subjects. AB - In his famous 1966 New England Journal of Medicine article, Henry Beecher concluded that a critical safeguard for protecting human participants, more reliable than informed consent, was the "presence of an intelligent, informed, conscientious, compassionate, responsible investigator." This article examines Beecher's appeal to reliance on the "virtuous" investigator in light of the critical role that investigators play in research ethics and the systems of research protections that have been developed since Beecher's writing. It addresses the extent to which research ethics rely on virtuous investigators; the meaning of virtuous, as distinct from compliance with the rules and regulations that guide ethical research; the particular virtues that it might be important for investigators to have; and the impact of the existing system of human subjects protections on the virtuous investigator. The virtuous investigator who is motivated to take ethical responsibilities seriously is an essential safeguard for the protection of human research participants and an important complement to the system of oversight protections. However, since the current human subjects protection system does not promote virtue or ethical resourcefulness by investigators, attention to enhancing a culture of professional responsibility might serve to forge a synergy between the protections afforded by the current oversight system and those provided by the virtuous investigator. PMID- 27499490 TI - Clinical Trials Without Consent? AB - Fifty years after Beecher's landmark article, an old question is being debated anew: is it ethical to conduct clinical research without consent? This paper provides a systematic analysis of this question. First, it describes five clinical trials that have either been conducted (or proposed) without the subjects providing consent. Second, it reviews a number of conditions that are often provided to justify bypassing of consent and finds that only some of them qualify as necessary conditions for bypassing consent. When those conditions are applied to the clinical trials, only one trial without consent (a type of cluster randomized trial) appears clearly justified; bypassing consent in the remaining four trials is more questionable. The present analysis may be useful in the interpretation of the current U.S. regulations that provide for waivers and alterations of informed consent. PMID- 27499491 TI - Electronic Processes within Quantum Dot-Molecule Complexes. AB - The subject of this review is the colloidal quantum dot (QD) and specifically the interaction of the QD with proximate molecules. It covers various functions of these molecules, including (i) ligands for the QDs, coupled electronically or vibrationally to localized surface states or to the delocalized states of the QD core, (ii) energy or electron donors or acceptors for the QDs, and (iii) structural components of QD assemblies that dictate QD-QD or QD-molecule interactions. Research on interactions of ligands with colloidal QDs has revealed that ligands determine not only the excited state dynamics of the QD but also, in some cases, its ground state electronic structure. Specifically, the article discusses (i) measurement of the electronic structure of colloidal QDs and the influence of their surface chemistry, in particular, dipolar ligands and exciton delocalizing ligands, on their electronic energies; (ii) the role of molecules in interfacial electron and energy transfer processes involving QDs, including electron-to-vibrational energy transfer and the use of the ligand shell of a QD as a semipermeable membrane that gates its redox activity; and (iii) a particular application of colloidal QDs, photoredox catalysis, which exploits the combination of the electronic structure of the QD core and the chemistry at its surface to use the energy of the QD excited state to drive chemical reactions. PMID- 27499492 TI - Dose estimation derived from the exposure to radon, thoron and their progeny in the indoor environment. AB - The annual exposure to indoor radon, thoron and their progeny imparts a major contribution to inhalation doses received by the public. In this study, we report results of time integrated passive measurements of indoor radon, thoron and their progeny concentrations that were carried out in Garhwal Himalaya with the aim of investigating significant health risk to the dwellers in the region. The measurements were performed using recently developed LR-115 detector based techniques. The experimentally determined values of radon, thoron and their progeny concentrations were used to estimate total annual inhalation dose and annual effective doses. The equilibrium factors for radon and thoron were also determined from the observed data. The estimated value of total annual inhalation dose was found to be 1.8 +/- 0.7 mSv/y. The estimated values of the annual effective dose were found to be 1.2 +/- 0.5 mSv/y and 0.5 +/- 0.3 mSv/y, respectively. The estimated values of radiation doses suggest no important health risk due to exposure of radon, thoron and progeny in the study area. The contribution of indoor thoron and its progeny to total inhalation dose ranges between 13-52% with mean value of 30%. Thus thoron cannot be neglected when assessing radiation doses. PMID- 27499493 TI - Left ventricular area on non-contrast cardiac computed tomography as a predictor of incident heart failure - The Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: The use of non-contrast cardiac computed tomography measurements to predict heart failure (HF) has not been studied. In the present study we evaluated the prognostic value of left ventricular area adjusted for the body surface area (LVA-BSA) measured by non-contrast cardiac CT to predict incident HF and cardiovascular disease (CVD) events. METHODS: We studied left ventricular dimensions and calculated LVA-BSA in 6781 participants of the MESA study (mean age: was 62 +/- 10 years, 53% females; 62% non-white) free from prior HF who underwent non-contrast cardiac CT to evaluate the coronary artery calcium score (CAC) at baseline and were followed up for a median of 10.2 years. RESULTS: During follow up, 237 (3.5%) incident HF and 475 (7.0%) CVD events occurred. After adjustment for clinical variables and CAC, LVA-BSA was significantly associated with incident HF (hazard ratio [HR]: 1.10 per 100 mm2/m2, p < 0.001) and CVD events (HR: 1.07 per 100 mm2/m2, p < 0.001). The area under the ROC curve for the prediction of incident HF improved from 0.787 on a model including only risk factors to 0.798 when CAC was added (p = 0.02), and to 0.816 with the additional inclusion of LVA-BSA (p = 0.007). Similar improvements for the prediction of CVD events were noted. CONCLUSION: In an ethnically diverse population of asymptomatic individuals free from baseline CVD or HF, the left ventricular area measured by non-contrast cardiac CT is a strong predictor of incident HF events beyond traditional risk factors and CAC score. PMID- 27499494 TI - The Ratio of Regulatory (FOXP3+) to Total (CD3+) T Cells Determined by Epigenetic Cell Counting and Cardiovascular Disease Risk: A Prospective Case-cohort Study in Non-diabetics. AB - BACKGROUND: Experimental and clinical evidence indicate that inflammatory processes in atherogenesis and the development of cardiovascular complications are promoted by a loss of regulatory T cell (Treg)-mediated immunological tolerance to plaque antigens. Yet, the association between alterations of systemic Treg frequency and cardiovascular disease incidence remains uncertain. METHODS: A nested case-cohort study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg, comprising a random subcohort (n=778) and primary cases of myocardial infarction (MI, n=276) and ischemic stroke (n=151). Pre-diagnostic FOXP3+ Treg and total CD3+ T-lymphocyte (tTL) frequencies in blood were measured by epigenetic-based, quantitative real time PCR-assisted cell counting. RESULTS: Multivariate, Prentice-weighted Cox regression analyses revealed that lower Treg/tTL ratios were not associated with the risk of either MI (lowest vs. highest sex-specific quartile; hazard ratio: 0.72, 95% confidence interval: 0.46 to 1.13; Ptrend=0.51) or stroke (HR: 0.90, 95% CI: 0.51 to 1.60; Ptrend=0.78). There were no correlations of Treg/tTL ratios with C-reactive protein, HbA1c, and various lipid parameters. CONCLUSIONS: Among middle-aged adults from the general population, imbalances in the relative frequency of Tregs within the total T cell compartment do not confer an increased risk of MI or stroke. PMID- 27499495 TI - Hostile takeover: Manipulation of HIF-1 signaling in pathogen-associated cancers (Review). AB - Hypoxia-inducible factor (HIF)-1 is a central regulator in the adaptation process of cell response to hypoxia (low oxygen). Emerging evidence has demonstrated that HIF-1 plays an important role in the development and progression of many types of human diseases, including pathogen-associated cancers. In the present review, we summarize the recent understandings of how human pathogenic agents including viruses, bacteria and parasites deregulate cellular HIF-1 signaling pathway in their associated cancer cells, and highlight the common molecular mechanisms of HIF-1 signaling activated by these pathogenic infection, which could act as potential diagnostic markers and new therapeutic strategies against human infectious cancers. PMID- 27499496 TI - The difference in activity of daily living (ADL) and mortality in patients aged over 80 years with femoral neck fracture treated with hemiarthroplasty or osteosynthesis at 2 years of follow-up. AB - INTRODUCTION: Hip fractures are one of the major causes of morbidity and mortality in the elderly and outcomes following hip fracture have been the focus of several studies over recent decades. Among all types of fall-related injuries, hip fractures cause the greatest number of deaths, lead to severe health problems and reduce quality of life. Improving the outcome of hip fracture surgery has thus become one of the main areas of interest for orthopaedic surgeons. The aim of this study was to compare the difference in activity of daily living (ADL) and mortality between patients aged over 80 years with hip fracture treated with osteosynthesis versus prosthesis at 2 years of follow-up. MATERIALS AND METHODS: The data were collected on admission and during in-hospital stay. Information recorded on admission included: age, sex, type and mechanism of fracture, functional and cognitive status, comorbidity, and severity of illness. Prefracture functional status was measured. The follow-up was clinical and radiographical, or was by telephone for patients who were not able to come to the clinic. Patients aged over 80 years who underwent a single surgical procedure treated with intramedullary nail or hemiarthroplasty were included in the study. RESULTS: A total of 174 patients (45 male and 129 female) were included in the study. The two treatment groups were comparable for all preoperative parameters except for preoperative haemoglobin, which was an average of 1g/dl higher in the patients given hemiarthroplasty compared with those treated with intramedullary nail (t-test: p<0.05). The average observation period was 594.99days; the number of deaths was 62 of 164 contacted patients, and the survival rate at 2 years was 62.2%. There was increased mortality in patients who underwent hemiarthroplasty (Log-rank Mantel-Cox, p: 0,048). The difference in ADL between preoperative and follow-up is not statistically significant between the two groups. DISCUSSION: In the literature, there are few specific studies that consider these parameters in this population. However, these findings are consistent with the findings from other studies. CONCLUSION: Patients who received hemiarthroplasty have a higher mortality risk than those treated with intramedullary nail; there are no differences in ADL at follow-up. PMID- 27499497 TI - Investigating distribution pattern of species in a warm-temperate conifer broadleaved-mixed forest in China for sustainably utilizing forest and soils. AB - The maintaining mechanisms and potential ecological processes of species diversity in warm temperate- conifer-broadleaved-mixed forest are far from clear understanding. In this paper, the relative neighborhood density Omega was used to analyze the spatial distribution patterns of 34 species with >=11 individuals in a warm- temperate-conifer-broadleaved-mixed forest, northern China. Then we used canonical correspondence analysis (CCA) and Torus-translation test (TTT) to explain the distribution of observed species. Our results show that aggregated distribution is the dominant pattern in warm-temperate natural forest and four species regular distribution at the spatial scale >30m. The aggregated percentage and intensity decline with spatial scale, abundance and size classes increasing. Rare species are aggregated more than intermediate and abundant species. These results prove sufficiently the effects existence of scale separation, self thinning and Janzen-Connell hypothesis. In addition, functional traits (dispersal modes and shade tolerance) also have a significant influence on distribution of species. The results of CCA confirm that slope and convexity are the most important factors affecting the distribution of tree species distribution, elevation and slope of shrub species though the combination of topographic variables only explained 1% of distribution of tree species and 2% of shrub species. Most species don't have habitat preference; however 47.1% (16/34) species including absolutely dominant tree (Pinus tabulaeformis and Quercus wutaishanica) and shrub species (Rosa xanthina) and most other species with important value in the front, are strongly positively or negatively associated with at least one habitat. The valley and ridge are most distinct habitat with association of 12 species in the plot. However, high elevation slope with 257 quadrats is the most extensive habitat with only four species. Therefore, there is obvious evidence that habitat heterogeneity play an important role on shaping spatial distribution of species in warm temperate forest. Our research results provide significant evidence that dispersal limitation and habitat heterogeneity have a contribution jointly to regulating the spatial distribution pattern of species in warm-temperate-forest in China. PMID- 27499498 TI - Evaluating the evolution of the Heihe River basin using the ecological network analysis: Efficiency, resilience, and implications for water resource management policy. AB - One of the most critical challenges in the anthropocentric age is the sustainable management of the planet's increasingly strained water resources. In this avenue, there is a need to advance holistic approaches and objective tools which allow policy makers to better evaluate system-level properties and trade-offs of water resources. This research contributes to the expanding literature in this area by examining the changes to system-level network configurations of the middle reaches of the Heihe River basin from 2000 to 2009. Specifically, through the ecological network analysis (ENA) approach, this research examines changes to the system-level properties of efficiency, redundancy, and evaluates the trade-offs to the resiliency of ecosystem water services of the middle reaches of the Heihe River basin. Our results indicate that while the efficiency of the middle reaches has increased from 2000 to 2009 by 6% and 78% more water is released to the lower reaches, the redundancy of the system has also decreased by 6%. The lower level of redundancy, particularly due to the changes in the groundwater body levels, has critical long-term consequences for the resilience of the water ecosystem services of the middle reaches. In consideration of these holistic trade-offs, two hypothetical alternative scenarios, based on water recycling and saving strategies, are developed to improve the long-term health and resilience of the water system. PMID- 27499499 TI - Analysing the impact of multiple stressors in aquatic biomonitoring data: A 'cookbook' with applications in R. AB - Multiple stressors threaten biodiversity and ecosystem integrity, imposing new challenges to ecosystem management and restoration. Ecosystem managers are required to address and mitigate the impact of multiple stressors, yet the knowledge required to disentangle multiple-stressor effects is still incomplete. Experimental studies have advanced the understanding of single and combined stressor effects, but there is a lack of a robust analytical framework, to address the impact of multiple stressors based on monitoring data. Since 2000, the monitoring of Europe's waters has resulted in a vast amount of biological and environmental (stressor) data of about 120,000 water bodies. For many reasons, this data is rarely exploited in the multiple-stressor context, probably because of its rather heterogeneous nature: stressors vary and are mixed with broad-scale proxies of environmental stress (e.g. land cover), missing values and zero inflated data limit the application of statistical methods and biological indicators are often aggregated (e.g. taxon richness) and do not respond stressor specific. Here, we present a 'cookbook' to analyse the biological response to multiple stressors using data from biomonitoring schemes. Our 'cookbook' includes guidance for the analytical process and the interpretation of results. The 'cookbook' is accompanied by scripts, which allow the user to run a stepwise analysis based on his/her own data in R, an open-source language and environment for statistical computing and graphics. Using simulated and real data, we show that the recommended procedure is capable of identifying stressor hierarchy (importance) and interaction in large datasets. We recommend a minimum number of 150 independent observations and a minimum stressor gradient length of 75% (of the most relevant stressor's gradient in nature), to be able to reliably rank the stressor's importance, detect relevant interactions and estimate their standardised effect size. We conclude with a brief discussion of the advantages and limitations of this protocol. PMID- 27499500 TI - A proposal for the organization of the referral of patients with chronicnon specific low back pain. AB - BACKGROUND: Low back pain in general and specifically chronic low back pain forms a major burden for the patient and society. Recently studies demonstrated that up to 65% of patients evolve to chronic pain as opposed to the previously accepted 8%. As low back pain patients present first with their general practitioner, the latter should establish a treatment plan, including the appropriate referrals. There are, however, no clear guidelines as to how to refer low back pain patients. The process of trial and error of different specialties and treatment possibilities often results in a long and costly trajectory. A better understanding of the subtypes of chronic low back pain, the risks for chronification and fast adequate referral may result in higher patient satisfaction and cost reduction. Proposed solutions: We propose a classification system based on the clinical and anatomical characteristics of axial low back pain, separated from radicular pain. It is important to recognize the risks for chronification, such as degenerative and/or herniated disk, a smaller cross sectional area of the multifidus, erector spinae, and psoas muscles and psychological and social factors, to be able to provide appropriate management. Also stratification of the patients according to the degree of disability may help in defining the correct treatment approach. A one-and-a-half line approach, where a spine physician assistant works under the supervision of the general practitioner to establish the sub-diagnosis, the risk factors for chronicity and to explain the proposed management plan to the patient, may be helpful for an early appropriate treatment selection for the patient with chronic low back pain. PMID- 27499501 TI - Sugar beet factory lime affects the mobilization of Cd, Co, Cr, Cu, Mo, Ni, Pb, and Zn under dynamic redox conditions in a contaminated floodplain soil. AB - The impact of sugar beet factory lime (SBFL) on the release dynamics and mobilization of toxic metals (TMs) under dynamic redox conditions in floodplain soils has not been studied up to date. Therefore, the aim of this study was to verify the scientific hypothesis that SBFL is able to immobilize Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, and Zn under different redox potentials (EH) in a contaminated floodplain soil. For this purpose, the non-treated contaminated soil (CS) and the same soil treated with SBFL (CS+SBFL) were flooded in the laboratory using a highly sophisticated automated biogeochemical microcosm apparatus. The experiment was conducted stepwise from reducing (-13 mV) to oxidizing (+519 mV) soil conditions. Soil pH decreased under oxic conditions in CS (from 6.9 to 4.0) and in CS+SBFL (from 7.5 to 4.4). The mobilization of Cu, Cr, Pb, and Fe were lower in CS+SBFL than in CS under both reducing/neutral and oxic/acidic conditions. Those results demonstrate that SBFL is able to decrease concentrations of these elements under a wide range of redox and pH conditions. The mobilization of Cd, Co, Mn, Mo, Ni, and Zn were higher in CS+SBFL than in CS under reducing/neutral conditions; however, these concentrations showed an opposite behavior under oxic/acidic conditions and were lower in CS+SBFL than in CS. We conclude that SBFL immobilized Cu, Cr, Pb, and Fe under dynamic redox conditions and immobilized Cd, Co, Mn, Mo, Ni, and Zn under oxic acidic conditions; however, the latter elements were mobilized under reducing neutral conditions in the studied soil. Therefore, the addition of SBFL to acid floodplain soils contaminated with TMs might be an important alternative for ameliorating these soils with view to a sustainable management of these soils. PMID- 27499502 TI - Use of sediment source fingerprinting to assess the role of subsurface erosion in the supply of fine sediment in a degraded catchment in the Eastern Cape, South Africa. AB - Sediment source fingerprinting has been successfully deployed to provide information on the surface and subsurface sources of sediment in many catchments around the world. However, there is still scope to re-examine some of the major assumptions of the technique with reference to the number of fingerprint properties used in the model, the number of model iterations and the potential uncertainties of using more than one sediment core collected from the same floodplain sink. We investigated the role of subsurface erosion in the supply of fine sediment to two sediment cores collected from a floodplain in a small degraded catchment in the Eastern Cape, South Africa. The results showed that increasing the number of individual fingerprint properties in the composite signature did not improve the model goodness-of-fit. This is still a much debated issue in sediment source fingerprinting. To test the goodness-of-fit further, the number of model repeat iterations was increased from 5000 to 30,000. However, this did not reduce uncertainty ranges in modelled source proportions nor improve the model goodness-of-fit. The estimated sediment source contributions were not consistent with the available published data on erosion processes in the study catchment. The temporal pattern of sediment source contributions predicted for the two sediment cores was very different despite the cores being collected in close proximity from the same floodplain. This highlights some of the potential limitations associated with using floodplain cores to reconstruct catchment erosion processes and associated sediment source contributions. For the source tracing approach in general, the findings here suggest the need for further investigations into uncertainties related to the number of fingerprint properties included in un-mixing models. The findings support the current widespread use of <=5000 model repeat iterations for estimating the key sources of sediment samples. PMID- 27499503 TI - Melatonin mediated antidepressant-like effect in the hippocampus of chronic stress-induced depression rats: Regulating vesicular monoamine transporter 2 and monoamine oxidase A levels. AB - The hippocampus is sensitive to stress which activates norepinephrine terminals deriving from the locus coeruleus. Melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behaviour. Thus, in the present study, an examination was made of the effect of chronic melatonin treatment on norepinephrine content, synthesis, uptake, vesicular transport and degradation in the hippocampus of rats exposed to CUMS. This entailed quantifying the norephinephrine, mRNA and protein levels of DBH, NET, VMAT 2, MAO-A and COMT. The results show that CUMS evoked prolonged immobility. Melatonin treatment decreased immobility in comparison with the placebo group, reflecting an antidepressant-like effect. Compared with the placebo group, a dramatic decrease in norepinephrine content, decreased VMAT2 mRNA and protein and increased MAO-A protein levels in the hippocampus of the CUMS rats were observed. However, no significant differences in the levels of DBH, NET, COMT mRNA and protein and MAO A mRNA levels between the placebo and the stressed groups were found. The results showed the restorative effects of melatonin on the stress-induced decline in the norepinephrine content of the hippocampus. It was observed that melatonin treatment in the CUMS rats prevented the stress-induced decrease in VMAT2 mRNA and protein levels, whereas it reduced the increase of the mRNA of COMT and protein levels of MAO-A. Chronic treatment with melatonin failed to alter the gene expression of DBH or NET in the hippocampus of the CUMS rats. Additionally, the results show that melatonin enhances VMAT2 expression and norepinephrine storage, whilst it reduces norepinephrine degrading enzymes. PMID- 27499504 TI - Simple mesothelial pericardial cyst in a rare location. AB - Pericardial cysts are rare and generally benign intrathoracic lesions, most frequently located in the cardiophrenic angles, but other locations have been described. We present a case of a pericardial cyst in a previously undescribed site. Our patient presented with a cyst in the interventricular septum which was discovered as an incidental finding. After surgical excision of the cyst, it was described pathologically as a simple mesothelial pericardial cyst. The explanation of this rare condition is uncertain, but some hypotheses can be outlined. PMID- 27499505 TI - Active fixation coronary sinus lead extraction - A safe procedure. PMID- 27499506 TI - Editorial. PMID- 27499507 TI - Editorial. PMID- 27499508 TI - Changes in lung sounds during asthma progression in a guinea pig model. AB - BACKGROUND: Lung sound analysis is useful for objectively evaluating airways even in children with asymptomatic asthma. However, the relationship between lung sounds and morphological changes in the airways has not been elucidated. We examined the relationship between lung sounds and chronic morphological changes in the airways during the progression of asthma from onset in guinea pigs. METHODS: Eleven male guinea pigs were examined; of these, seven were used as asthma models and four as controls. The asthma models were sensitized and repeatedly challenged by inhaling albumin chicken egg. We measured lung sounds and lung function twice a week for 21 weeks. After the final antigen challenge, the lungs were excised for histological examination. We measured the ratio of airway wall thickness to the total airway area and the ratio of the internal area to the total airway area in the trachea, third bronchi, and terminal bronchioles. RESULTS: Among the lungs sounds, the difference between the two groups was greatest with respect to inspiratory sound intensity. The ratio of airway wall thickness to the total airway area of the terminal bronchioles was greater in the asthma models than in the controls, and it correlated best with the changes in inspiratory sound intensity in the 501-1000-Hz range (r = 0.76, p < 0.003). CONCLUSIONS: Lung sound intensity in the middle frequency range from 501 to 1000 Hz correlated with peripheral airway wall thickness. Inspiratory sound intensity appeared to be an indicator of morphological changes in small airways in asthma. PMID- 27499509 TI - Nutrition in the spotlight: metabolic effects of environmental light. AB - Use of artificial light resulted in relative independence from the natural light dark (LD) cycle, allowing human subjects to shift the timing of food intake and work to convenient times. However, the increase in artificial light exposure parallels the increase in obesity prevalence. Light is the dominant Zeitgeber for the central circadian clock, which resides within the hypothalamic suprachiasmatic nucleus, and coordinates daily rhythm in feeding behaviour and metabolism. Eating during inappropriate light conditions may result in metabolic disease via changes in the biological clock. In this review, we describe the physiological role of light in the circadian timing system and explore the interaction between the circadian timing system and metabolism. Furthermore, we discuss the acute and chronic effects of artificial light exposure on food intake and energy metabolism in animals and human subjects. We propose that living in synchrony with the natural daily LD cycle promotes metabolic health and increased exposure to artificial light at inappropriate times of day has adverse effects on metabolism, feeding behaviour and body weight regulation. Reducing the negative side effects of the extensive use of artificial light in human subjects might be useful in the prevention of metabolic disease. PMID- 27499510 TI - Ambident Reactivity of Acetyl- and Formyl-Stabilized Phosphonium Ylides. AB - The kinetics and mechanism of the reactions of formyl-stabilized ylide Ph3P?CHCHO (1) and acetyl-stabilized ylide Ph3P?CHCOMe (2) with benzhydrylium ions (Ar2CH(+), 3) were investigated by UV-vis and NMR spectroscopy. As ambident nucleophiles, ylides 1 and 2 can react at oxygen as well as at the alpha-carbon. For some reactions, it was possible to determine the second-order rate constant for O-attack as well as for C-attack and to derive the nucleophile-specific parameters N and sN according to the correlation lg k (20 degrees C) = sN(E + N) for both nucleophilic sites. Generally, O-attack of benzhydrylium ions is faster than C-attack. However, the initially formed benzhydryloxyvinylphosphonium ions can only be observed by NMR spectroscopy when benzhydryl cations with high Lewis acidity are employed. In other cases, rearrangement to the thermodynamically more stable products arising from C-attack occurs. The results derived from our investigations are employed to rationalize the behavior of ambident nucleophiles 1 and 2 in reactions with carbon-centered electrophiles in general. It is shown that the principle of hard and soft acids and bases (HSAB) and the related Klopman-Salem concept of charge and orbital control lead to incorrect predictions of regioselectivity. We also show that the rate of the Wittig reaction of ylide 2 with aldehyde 14 is significantly faster than the rate of either C- or O-attack calculated using lg k (20 degrees C) = sN(E + N), thus indicating that the oxaphosphetane is formed by a concerted [2 + 2] cycloaddition. PMID- 27499511 TI - Increase of prevalence of craniosynostosis. AB - INTRODUCTION: Craniosynostosis represents premature closure of cranial sutures. Prevalence is approximately 3.1-6.4 in 10.000 live births, which is reportedly rising. This epidemiologic study aims to provide insight into this rise through an accurate description of the prevalence, exploring regional variation and change over time. METHODS: The Dutch Association for Cleft Palate and Craniofacial Anomalies was consulted to identify patients with craniosynostosis born between 2008 and 2013. Data were verified using data provided by all hospitals that treated these patients. The following data were collected: date of birth, gender, diagnosis and postal code. Previously reported data from 1997 until 2007 were included to assess for change in prevalence over the years. RESULTS: Between 2008 and 2013 759 patients with craniosynostosis were born in the Netherlands. Prevalence of craniosynostosis was 7.2 per 10.000 live births. Sagittal synostosis was the most common form (44%). Poisson regression analysis showed a significant mean annual increase of prevalence of total craniosynostosis (+12.5%), sagittal (+11.7%) and metopic (+20.5%) synostosis from 1997 to 2013. CONCLUSION: The prevalence of craniosynostosis is 7.2 per 10.000 live born children in the Netherlands. Prevalence of total craniosynostosis, sagittal and metopic suture synostosis has risen significantly from 1997 until 2013, without obvious cause. PMID- 27499512 TI - Clinical assessment scoring system for tracheostomy (CASST) criterion: Objective criteria to predict pre-operatively the need for a tracheostomy in head and neck malignancies. AB - BACKGROUND: Tracheostomy is a mainstay modality for airway management for patients with head-neck cancer undergoing surgery. This study aims to define factors predicting need of tracheostomy and define an effective objective criterion to predict tracheostomy need. METHODS: 486 patients undergoing composite resections were studied. Factors analyzed were age, previous surgery, extent of surgery, trismus, extent of mandibular resection and reconstruction etc. Factors were divided into major and minor, using the clinical assessment scoring system for tracheostomy (CASST) criterion. RESULTS: Sixty seven (13.7%) patients required tracheostomy for their peri-operative management. Elective tracheostomies were done in 53 cases during surgery and post-operatively in 14 patients. All patients in whom tracheostomies were anticipated had a score of seven or more. CONCLUSION: A decision on whether or not an elective tracheotomy in head and neck surgery is necessary and can be facilitated using CASST criterion, which has a sensitivity of 95.5% and a negative predictive value (NPV) of 99.3%. It may reduce post-operative complications and contribute to safer treatment. PMID- 27499513 TI - Simultaneous maxillo-mandibular distraction in early adolescence as a single treatment modality for durable correction of type II unilateral hemifacial microsomia: Follow-up till completion of growth. AB - BACKGROUND: Timing of surgical intervention in hemifacial microsomia (HFM) is controversial. Although mandibular osteodistraction in childhood for HFM is popular, recent data for single-stage distraction in growing HFM patients demonstrated long-term relapse. Literature suggests that adolescents in the late mixed dentition age or permanent dentition age (11-16-year-old) had more stable outcomes post-distraction than younger children. We present favorable experience using single-treatment simultaneous maxillo-mandibular distraction in early adolescent Pruzansky-Kaban type II HFM patients. METHODS: This was a retrospective longitudinal study of seven consecutive type IIa/b HFM growing patients (12-16-year-old) treated with simultaneous maxillo-mandibular distraction. Oral commissure cant was photographically measured preoperatively and at 6 months and annually ranging 3-7 years post-distraction. Ramus height and chin deviation were measured from radiographs done preoperatively and at distractor-removal, 1 year, 2 years, and 4 years post-distraction. RESULTS: Average age at osteodistraction and at latest follow-up was 13.7 and 18.6 years, respectively. Improvement was significant (p < 0.05) and sustained for mean oral commissure cant (5.1 degrees -0.41 degrees ), mean ramus height ratio (0.59 0.86), and average chin deviation (15.9 mm-1.2 mm). Two subjects had mandibular branch palsy and one had mild pin-tract infection - all resolved. All were satisfied with their facial appearance. CONCLUSION: We have demonstrated good lasting outcomes at completion of growth with single-stage simultaneous maxillo mandibular distraction for type II HFM adolescents in the late mixed-dentition or older age, and advocate this as an alternative to osteodistraction or orthognathic surgery upon skeletal maturity. PMID- 27499514 TI - Radiochemotherapy for locally advanced squamous cell carcinoma of the head and neck: Higher-dose cisplatin every 3 weeks versus cisplatin/5-fluorouracil every 4 weeks. AB - Many patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) receive cisplatin-based radiochemotherapy. The optimal regimen is still unclear when considering both efficacy and feasibility. This study compared two regimens for locoregional control (LRC), overall survival (OS), and adverse events. Data of 329 patients with LASCCHN receiving definitive or postoperative radiochemotherapy were retrospectively analyzed. A total of 131 patients received 100 mg/m(2) cisplatin on days 1, 22, and 43 (group A), and 198 patients received 20 mg/m(2) cisplatin plus 600/1000 mg/m(2) 5-FU on days 1-5 and days 29-33 (group B). Radiochemotherapy regimens plus nine factors were compared for LRC and OS, and radiochemotherapy regimens additionally for adverse events. On univariate analysis, chemotherapy type was not associated with LRC (p = 0.36). On multivariate analysis, performance score (p = 0.039), N-category (p = 0.007), histologic grade (p = 0.007), upfront surgery (p = 0.030), and pre radiochemotherapy hemoglobin levels (p < 0.001) were associated with LRC. On univariate analysis, chemotherapy type had no impact on OS (p = 0.64). On multivariate analysis, performance score (p < 0.001), T-category (p = 0.025), N category (p < 0.001), histologic grade, and hemoglobin levels (p < 0.001) were associated with OS. Renal failure occurred significantly more often in group A (p = 0.008). Otherwise, adverse events were not significantly different. Thus, both radiochemotherapy regimens appeared similarly effective for LASCCHN. Patients receiving 100 mg/m(2) of cisplatin require close monitoring of their renal function. PMID- 27499515 TI - Peroneal artery-vein index as a potential factor of thrombosis occurrence in free osteocutaneous fibula flap. AB - BACKGROUND: Despite high popularity and great success rates of free osteocutaneous fibula flaps, the flap failure caused by vascular thrombosis is still a challenging problem. The authors present their evaluation of a potential thrombosis risk factor - a peroneal artery-vein index. METHODS: The authors evaluated the diameters of peroneal vessels and peroneal artery-vein indexes based on the computed tomography angiographies in 10 patients who underwent a mandible reconstruction with a free fibula flap and compared the results with clinical outcome. RESULTS: In one case the flap was lost, because of thrombosis in the donor vein. This patient presented superficial varicose veins of both lower extremities. Peroneal vein diameters in this patient ranged from 5,05 mm to 6,68 mm and were higher than in patients without complications. The peroneal artery-vein index in the patient with thrombosis ranged from 0,37 to 0,50 with median 0,40 and was lower than in patients without complications. CONCLUSIONS: High disproportion between peroneal artery and concomitant veins might be a potential risk factor of the occurrence of venal thrombosis. Detailed perioperative examination of peroneal veins in patients with varicosities should be considered. PMID- 27499516 TI - Visible tumor surface response to physical plasma and apoptotic cell kill in head and neck cancer. AB - The aim of the study was to learn, whether clinical application of cold atmospheric pressure plasma (CAP) is able to cause (i) visible tumor surface effects and (ii) apoptotic cell kill in squamous cell carcinoma and (iii) whether CAP-induced visible tumor surface response occurs as often as CAP-induced apoptotic cell kill. Twelve patients with advanced head and neck cancer and infected ulcerations received locally CAP followed by palliative treatment. Four of them revealed tumor surface response appearing 2 weeks after intervention. The tumor surface response expressed as a flat area with vascular stimulation (type 1) or a contraction of tumor ulceration rims forming recesses covered with scabs, in each case surrounded by tumor tissue in visible progress (type 2). In parallel, 9 patients with the same kind of cancer received CAP before radical tumor resection. Tissue specimens were analyzed for apoptotic cells. Apoptotic cells were detectable and occurred more frequently in tissue areas previously treated with CAP than in untreated areas. Bringing together both findings and placing side by side the frequency of clinical tumor surface response and the frequency of analytically proven apoptotic cell kill, detection of apoptotic cells is as common as clinical tumor surface response. There was no patient showing signs of an enhanced or stimulated tumor growth under influence of CAP. CAP was made applicable by a plasma jet, kINPen((r)) MED (neoplas tools GmbH, Greifswald, Germany). PMID- 27499517 TI - Results of the 2-Year Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) Randomized Trial. AB - PURPOSE: The Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) trial was designed to evaluate the long-term efficacy and safety profile of ocriplasmin for the treatment of symptomatic vitreomacular adhesion (VMA)/vitreomacular traction, including full-thickness macular hole (FTMH). DESIGN: Phase 3b, randomized, sham-controlled, double masked, multicenter clinical trial. PARTICIPANTS: Sample size was 220 subjects (146 ocriplasmin, 74 sham) randomized in a 2:1 ratio to receive intravitreal ocriplasmin 0.125 mg or sham injection. METHODS: The trial involved 12 visits over 24-months. Inclusion criteria included presence of VMA and best-corrected visual acuity (BCVA) of 20/32 or worse in the study eye. Exclusion criteria included FTMH >400 MUm, presence of epiretinal membrane (ERM), and aphakia in the study eye. MAIN OUTCOME MEASURES: The primary efficacy end point was the proportion of subjects with pharmacologic VMA resolution at day 28. Secondary efficacy end points were assessed at month 24 and included proportion of subjects with BCVA gain from baseline, nonsurgical FTMH closure, vitrectomy, and Visual Function Questionnaire 25 (VFQ-25) outcomes. RESULTS: The OASIS trial met its primary end point with pharmacologic VMA resolution at day 28 being significantly higher in the ocriplasmin group (41.7%) compared with the sham group (6.2%). The treatment effect was maintained until study end. In the ocriplasmin group, pharmacologic VMA resolution at day 28 was higher in subgroups with the following baseline characteristics compared with the complementary subgroups without them: presence of focal VMA, presence of FTMH, absence of ERM, and phakic lens status. In the ocriplasmin group, 50.5% of subjects had a >=2-line improvement in BCVA from baseline compared with 39.1% of subjects in the sham group. The nonsurgical FTMH closure rate was 30.0% for the ocriplasmin group compared with 15.4% for the sham group. All other secondary end points also favored ocriplasmin over sham. Regarding safety, most adverse events were mild to moderate, had a short onset time, and were transient, with no new safety signals identified. CONCLUSIONS: The OASIS trial demonstrates the long-term efficacy and safety of ocriplasmin, providing improved resolution of symptomatic VMA compared with previous phase 3 trials with no additional safety signals identified. PMID- 27499518 TI - Biomechanical evaluation of two arthroscopic techniques for biceps tenodesis: triple loop suture versus simple suture. AB - BACKGROUND: Several techniques and procedures have been described to treat long head of the biceps pathology; however, tenodesis and tenotomy are the 2 most common procedures performed. This study evaluated the initial fixation strength of the biceps tenodesis triple loop suture (TLS) technique and compared it with that of the simple suture technique (SST). METHODS: Twenty fresh frozen cadaveric human shoulders (humeral head and neck with attached biceps tendons) were harvested. The biceps tendon was tenotomized proximally before reattachment to the bicipital groove of the matching humerus using suture anchors. Tenodesis was performed using the SST or the TLS technique. Specimens were tested biomechanically for load to failure, stress, and stiffness. The mechanism of failure was evaluated and compared between the 2 suture techniques. RESULTS: Maximal load to failure was significantly greater using the TLS technique (122.2 +/- 26.73 N) than the SST (46.12 +/- 14.37 N, P < .001). There was no difference in the mean stiffness (SST: 7.33 +/- 4.41 N/mm, TLS: 7.46 N/mm +/- 2.67, P = .94). The failure mechanism in all SST samples occurred by suture cutout through the longitudinal fibers of the tendon. In all TLS samples, the failure occurred by suture slippage. CONCLUSION: This study demonstrated superior load to failure of the TLS compared with the SST technique for biceps tenodesis. Furthermore, this study provides the first description of the TLS technique as a possible application in biceps tenodesis. Clinical application of the TLS must be carefully considered, because although it achieved a superior biomechanical profile, experience with this stitch is limited. PMID- 27499519 TI - Adoption of Robotic vs Fluoroscopic Guidance in Total Hip Arthroplasty: Is Acetabular Positioning Improved in the Learning Curve? AB - BACKGROUND: Acetabulum positioning affects dislocation rates, component impingement, bearing surface wear rates, and need for revision surgery. Novel techniques purport to improve the accuracy and precision of acetabular component position, but may have a significant learning curve. Our aim was to assess whether adopting robotic or fluoroscopic techniques improve acetabulum positioning compared to manual total hip arthroplasty (THA) during the learning curve. METHODS: Three types of THAs were compared in this retrospective cohort: (1) the first 100 fluoroscopically guided direct anterior THAs (fluoroscopic anterior [FA]) done by a surgeon learning the anterior approach, (2) the first 100 robotic-assisted posterior THAs done by a surgeon learning robotic-assisted surgery (robotic posterior [RP]), and (3) the last 100 manual posterior (MP) THAs done by each surgeon (200 THAs) before adoption of novel techniques. Component position was measured on plain radiographs. Radiographic measurements were taken by 2 blinded observers. The percentage of hips within the surgeons' "target zone" (inclination, 30 degrees -50 degrees ; anteversion, 10 degrees -30 degrees ) was calculated, along with the percentage within the "safe zone" of Lewinnek (inclination, 30 degrees -50 degrees ; anteversion, 5 degrees -25 degrees ) and Callanan (inclination, 30 degrees -45 degrees ; anteversion, 5 degrees -25 degrees ). Relative risk (RR) and absolute risk reduction (ARR) were calculated. Variances (square of the standard deviations) were used to describe the variability of cup position. RESULTS: Seventy-six percentage of MP THAs were within the surgeons' target zone compared with 84% of FA THAs and 97% of RP THAs. This difference was statistically significant, associated with a RR reduction of 87% (RR, 0.13 [0.04-0.40]; P < .01; ARR, 21%; number needed to treat, 5) for RP compared to MP THAs. Compared to FA THAs, RP THAs were associated with a RR reduction of 81% (RR, 0.19 [0.06-0.62]; P < .01; ARR, 13%; number needed to treat, 8). Variances were lower for acetabulum inclination and anteversion in RP THAs (14.0 and 19.5) as compared to the MP (37.5 and 56.3) and FA (24.5 and 54.6) groups. These differences were statistically significant (P < .01). CONCLUSION: Adoption of robotic techniques delivers significant and immediate improvement in the precision of acetabular component positioning during the learning curve. While fluoroscopy has been shown to be beneficial with experience, a learning curve exists before precision improves significantly. PMID- 27499520 TI - Body Mass Index Class Is Independently Associated With Health-Related Quality of Life After Primary Total Hip Arthroplasty: An Institutional Registry-Based Study. AB - BACKGROUND: The purpose of this study was to compare the health-related quality of life (HRQoL) of patients across World Health Organization (WHO) body mass index (BMI) classes before and after total hip arthroplasty (THA). METHODS: Patients with end-stage hip osteoarthritis who received elective primary unilateral THA were identified through an institutional registry and categorized based on the World Health Organization BMI classification. Age, sex, laterality, year of surgery, and Charlson-Deyo comorbidity index were recorded. The primary outcome was the EQ-5D-3L index and visual analog scale (EQ-VAS) scores at 2 years postoperatively. Inferential statistics and regression analyses were performed to determine associations between BMI classes and HRQoL. RESULTS: EQ-5D-3L scores at baseline and at 2 years were statistically different across BMI classes, with higher EQ-VAS and index scores in patients with lower BMI. There was no difference observed for the 2-year change in EQ-VAS scores, but there was a statistically greater increase in index scores for more obese patients. In the regression analyses, there were statistically significant negative effect estimates for EQ-VAS and index scores associated with increasing BMI class. CONCLUSION: BMI class is independently associated with lower HRQoL scores 2 years after primary THA. While absolute scores in obese patients were lower than in nonobese patients, obese patients enjoyed more positive changes in EQ-5D index scores after THA. These results may provide the most detailed information on how BMI influences HRQoL before and after THA, and they are relevant to future economic decision analyses on the topic. PMID- 27499522 TI - Changes in gene expression profiles in patients with pulmonary arterial hypertension associated with scleroderma treated with tadalafil. AB - OBJECTIVE: Pulmonary arterial hypertension (PAH) is one of the most devastating complications in scleroderma (SSc) patients and has a poorer outcome than other PAH subgroups. Tadalafil (Adcirca(r)) is a phosphodiesterase-5 inhibitor (PDE5-I) approved by the FDA for treatment of PAH; however, its effectiveness specifically in SSc-PAH patients is unclear. We investigated whether there were differences in gene expression associated with 16 weeks of treatment with tadalafil and, if so, whether these changes differed with respect to treatment outcome. METHODS: We enrolled 10 SSc-PAH subjects who were naive to PDE5-I treatment, profiled gene expression in whole blood prior to and following treatment with tadalafil, measured changes in genomic profiles before and after treatment with tadalafil, and correlated them with changes in clinical outcomes, such as cardiopulmonary hemodynamics, six-min walk distance (6MWD), Borg Dyspnea Index (BDI), NYHA/WHO functional class (FC), B-type natriuretic peptide (BNP), and cardiac magnetic resonance imaging (cMRI). RESULTS: Genes associated with IL-12 signaling and extracellular matrix maintenance were coordinately up- or down-regulated with treatment, respectively, across all subjects. Interestingly, we found that genes encoding voltage-gated potassium channels and genes related to innate immunity were coordinately up-regulated in subjects who improved with tadalafil treatment compared to those patients who did not. In contrast, up-regulation of Golgi related gene sets was associated with clinical worsening during the treatment period. CONCLUSION: The results of this pilot study suggest that outcomes of SSc PAH patients treated with tadalafil are associated with specific changes in gene expression and biological pathways. PMID- 27499524 TI - Corrigendum to "Trajectories of changes over twelve years in the health status of Canadians from late middle age" [Exp. Gerontol. 47/12 (2012) 893-899]. PMID- 27499523 TI - Transforming Growth Factor beta Drives Hemogenic Endothelium Programming and the Transition to Hematopoietic Stem Cells. AB - Hematopoietic stem cells (HSCs) are self-renewing multipotent stem cells that generate mature blood lineages throughout life. They, together with hematopoietic progenitor cells (collectively known as HSPCs), emerge from hemogenic endothelium in the floor of the embryonic dorsal aorta by an endothelial-to-hematopoietic transition (EHT). Here we demonstrate that transforming growth factor beta (TGFbeta) is required for HSPC specification and that it regulates the expression of the Notch ligand Jagged1a in endothelial cells prior to EHT, in a striking parallel with the epithelial-to-mesenchymal transition (EMT). The requirement for TGFbeta is two fold and sequential: autocrine via Tgfbeta1a and Tgfbeta1b produced in the endothelial cells themselves, followed by a paracrine input of Tgfbeta3 from the notochord, suggesting that the former programs the hemogenic endothelium and the latter drives EHT. Our findings have important implications for the generation of HSPCs from pluripotent cells in vitro. PMID- 27499525 TI - Research Methods in Healthcare Epidemiology and Antimicrobial Stewardship Mathematical Modeling. AB - Mathematical modeling is a valuable methodology used to study healthcare epidemiology and antimicrobial stewardship, particularly when more traditional study approaches are infeasible, unethical, costly, or time consuming. We focus on 2 of the most common types of mathematical modeling, namely compartmental modeling and agent-based modeling, which provide important advantages-such as shorter developmental timelines and opportunities for extensive experimentation over observational and experimental approaches. We summarize these advantages and disadvantages via specific examples and highlight recent advances in the methodology. A checklist is provided to serve as a guideline in the development of mathematical models in healthcare epidemiology and antimicrobial stewardship. Infect Control Hosp Epidemiol 2016;1-7. PMID- 27499521 TI - The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype. AB - Homozygous loss of SMN1 causes spinal muscular atrophy (SMA), the most common and devastating childhood genetic motor-neuron disease. The copy gene SMN2 produces only ~10% functional SMN protein, insufficient to counteract development of SMA. In contrast, the human genetic modifier plastin 3 (PLS3), an actin-binding and bundling protein, fully protects against SMA in SMN1-deleted individuals carrying 3-4 SMN2 copies. Here, we demonstrate that the combinatorial effect of suboptimal SMN antisense oligonucleotide treatment and PLS3 overexpression-a situation resembling the human condition in asymptomatic SMN1-deleted individuals-rescues survival (from 14 to >250 days) and motoric abilities in a severe SMA mouse model. Because PLS3 knockout in yeast impairs endocytosis, we hypothesized that disturbed endocytosis might be a key cellular mechanism underlying impaired neurotransmission and neuromuscular junction maintenance in SMA. Indeed, SMN deficit dramatically reduced endocytosis, which was restored to normal levels by PLS3 overexpression. Upon low-frequency electro-stimulation, endocytotic FM1-43 (SynaptoGreen) uptake in the presynaptic terminal of neuromuscular junctions was restored to control levels in SMA-PLS3 mice. Moreover, proteomics and biochemical analysis revealed CORO1C, another F-actin binding protein, whose direct binding to PLS3 is dependent on calcium. Similar to PLS3 overexpression, CORO1C overexpression restored fluid-phase endocytosis in SMN-knockdown cells by elevating F-actin amounts and rescued the axonal truncation and branching phenotype in Smn-depleted zebrafish. Our findings emphasize the power of genetic modifiers to unravel the cellular pathomechanisms underlying SMA and the power of combinatorial therapy based on splice correction of SMN2 and endocytosis improvement to efficiently treat SMA. PMID- 27499526 TI - Coral reef health response to chronic and acute changes in water quality in St. Thomas, United States Virgin Islands. AB - It is suspected that land cover alteration on the southern coast of St. Thomas, USVI has increased runoff, degrading nearshore water quality and coral reef health. Chronic and acute changes in water quality, sediment deposition, and coral health metrics were assessed in three zones based upon perceived degree of human influence. Chlorophyll (p<0.0001) and turbidity (p=0.0113) were significantly higher in nearshore zones and in the high impact zone during heavy precipitation. Net sediment deposition and terrigenous content increased in nearshore zones during periods of greater precipitation and port activity. Macroalgae overgrowth significantly increased along a gradient of decreasing water quality (p<0.0001). Coral bleaching in all zones peaked in November with a regional thermal stress event (p<0.0001). However, mean bleaching prevalence was significantly greater in the most impacted zone compared to the offshore zone (p=0.0396), suggesting a link between declining water quality and bleaching severity. PMID- 27499527 TI - The impact of oral care on oral health status and prevention of ventilator associated pneumonia in critically ill patients. AB - BACKGROUND: Ventilator-associated pneumonia is one of the most common nosocomial infections which increase mortality rate and length stay of hospitalisation. Oral care would not only improve patient's oral health and well-being, but it can also reduce the incidence rate of ventilator-associated pneumonia. OBJECTIVES: The objective of this study was to identify the impact of oral care practices on oral health status of patients in intensive care unit and the incidence rate of ventilator-associated pneumonia. METHODS: This clinical trial recruited 100 participants who were randomly assigned to a control group (receiving oral care by nurses) and an intervention group (receiving systematic care by the researcher) during 2015-2016. Beck Oral Assessment Scale was used to determine the required number of times for receiving oral care with regard to patient's oral health in the intervention group. Each care included adjusting endotracheal tube cuff pressure, brushing with toothpaste, using antiseptics and moistening the lips. The oral cavity was examined using BOAS and Mucosal-Plaque Score, and Clinical Pulmonary Infection Score was used for detecting pneumonia. RESULTS: The BOAS scoring showed significant differences between the two groups from the first to fifth day (P<0.001). The mucosal-plaque index was significantly different between the two groups from the third day to fifth day (P<0.001). The incidence rate of pneumonia on the third and fifth day was 10% (5) and 14% (7) in the control group, and 4% (2) and 10% (5) in the intervention group, respectively. The Fisher test did not show significant difference (P=0.538), however, the incidence rate in the intervention group reduced compared with the control group. CONCLUSION: Although following a systematic oral care program could not significantly decrease the incidence of ventilator-associated pneumonia in critically ill patients compared to the conventional oral care practices, it significantly improved the oral health and mucosal-plaque index. PMID- 27499528 TI - Structure-Based Identification of a Potent Inhibitor Targeting Stp1-Mediated Virulence Regulation in Staphylococcus aureus. AB - The increasing threats of antibiotic resistance urge the need for developing new strategies against bacterial infections. Targeting eukaryotic-like Ser/Thr phosphatase Stp1-mediated virulence regulation represents a promising approach for combating staphylococcal infection yet to be explored. Here, we report the 2.32-A resolution crystal structure of Stp1. Stp1 binds an unexpected fourth metal ion, which is important for Stp1's enzymatic activity as demonstrated by amino acid substitution studies. Inspired by the structural details of Stp1, we identified a potent and selective Stp1 inhibitor, aurintricarboxylic acid (ATA). Transcriptome analysis and biochemical studies supported Stp1 as the target of ATA inhibition within the pathogen, preventing upregulation of virulence genes. Notably, ATA did not affect in vitro growth of Staphylococcus aureus, while simultaneously attenuating staphylococcal virulence in mice. Our findings demonstrate that ATA is a potent anti-virulence compound against staphylococcal infection, laying the foundation for further developing new scaffolds for Stp1 targeted small molecules. PMID- 27499531 TI - Author Reply. PMID- 27499530 TI - Global Cysteine-Reactivity Profiling during Impaired Insulin/IGF-1 Signaling in C. elegans Identifies Uncharacterized Mediators of Longevity. AB - In the nematode Caenorhabditis elegans, inactivating mutations in the insulin/IGF 1 receptor, DAF-2, result in a 2-fold increase in lifespan mediated by DAF-16, a FOXO-family transcription factor. Downstream protein activities that directly regulate longevity during impaired insulin/IGF-1 signaling (IIS) are poorly characterized. Here, we use global cysteine-reactivity profiling to identify protein activity changes during impaired IIS. Upon confirming that cysteine reactivity is a good predictor of functionality in C. elegans, we profiled cysteine-reactivity changes between daf-2 and daf-16;daf-2 mutants, and identified 40 proteins that display a >2-fold change. Subsequent RNAi-mediated knockdown studies revealed that lbp-3 and K02D7.1 knockdown caused significant increases in lifespan and dauer formation. The proteins encoded by these two genes, LBP-3 and K02D7.1, are implicated in intracellular fatty acid transport and purine metabolism, respectively. These studies demonstrate that cysteine reactivity profiling can be complementary to abundance-based transcriptomic and proteomic studies, serving to identify uncharacterized mediators of C. elegans longevity. PMID- 27499532 TI - Editorial Comment. PMID- 27499529 TI - Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy. AB - Heat shock protein 70 (Hsp70) is a chaperone that normally scans the proteome and initiates the turnover of some proteins (termed clients) by linking them to the degradation pathways. This activity is critical to normal protein homeostasis, yet it appears to fail in diseases associated with abnormal protein accumulation. It is not clear why Hsp70 promotes client degradation under some conditions, while sparing that protein under others. Here, we used a combination of chemical biology and genetic strategies to systematically perturb the affinity of Hsp70 for the model client, tau. This approach revealed that tight complexes between Hsp70 and tau were associated with enhanced turnover while transient interactions favored tau retention. These results suggest that client affinity is one important parameter governing Hsp70-mediated quality control. PMID- 27499533 TI - Genetic diversity and distribution of bradyrhizobia nodulating peanut in acid neutral soils in Guangdong Province. AB - To reveal the genetic diversity and geographic distribution of peanut (Arachis hypogaea L.) rhizobia in Guangdong Province, one of the main peanut producing regions in China, 216 bradyrhizobial isolates were trapped by peanut plants inoculated with soil samples (pH 4.7-7.4) collected from ten sites in Guangdong. Based on BOX-PCR fingerprinting analysis, 71 representative isolates were selected for sequence analyses of ribosomal IGS, recA, atpD and symbiotic gene nodA. As a result, 22 genospecies were detected in the peanut rhizobia, including eight minor groups or single strains corresponding to Bradyrhizobium diazoefficiens, B. japonicum, B. yuanmingense, B. arachidis, B. guangdongense, B. guangxiense, B. iriomotense and B. liaoningense, as well as 14 novel Bradyrhizobium genospecies covering the majority of isolates. Five symbiotic clusters were obtained based on the phylogenetic relationships of nodA genes, related to the soybean-nodulating or peanut-nodulating reference strains. Biogeographic patterns, which were mainly correlated with potassium content and pH, were detected in the peanut bradyrhizobial community in Guangdong Province. These findings enriched the diversity of peanut rhizobia, and added the K content as a special determinant for peanut rhizobial distribution in acid soils. PMID- 27499534 TI - 61-Year-Old Man With Right Knee Pain and Chronic Anemia. PMID- 27499536 TI - Biologics in practice: A unique opportunity for allergist/immunologist expertise. PMID- 27499535 TI - Serum Potassium, Mortality, and Kidney Outcomes in the Atherosclerosis Risk in Communities Study. AB - OBJECTIVES: To investigate the association between serum potassium, mortality, and kidney outcomes in the general population and whether potassium-altering medications modify these associations. PATIENTS AND METHODS: We studied 15,539 adults in the Atherosclerosis Risk in Communities Study. Cox proportional hazard regression was used to investigate the association of serum potassium at baseline (1987-1989), evaluated categorically (hypokalemia, <3.5 mmol/L; normokalemia, >=3.5 and <5.5 mmol/L; hyperkalemia, >=5.5 mmol/L) and continuously using linear spline terms (knots at 3.5 and 5.5 mmol/L), with mortality, sudden cardiac death, incident chronic kidney disease, and end-stage renal disease. The end date of follow-up for all outcomes was December 31, 2012. We also evaluated whether classes of potassium-altering medications modified the association between serum potassium and adverse outcomes. RESULTS: Overall, 413 (2.7%) of the participants had hypokalemia and 321 (2.1%) had hyperkalemia. In a fully adjusted model, hyperkalemia was significantly associated with mortality (hazard ratio, 1.24; 95% CI, 1.04-1.49) but not sudden cardiac death, chronic kidney disease, or end-stage renal disease. Hypokalemia as a categorical variable was not associated with any outcome; however, associations of hypokalemia with all-cause mortality and kidney outcomes were observed among those who were not taking potassium-wasting diuretics (all P for interaction, <.001). CONCLUSIONS: Higher values of serum potassium were associated with a higher risk of mortality in the general population. Lower levels of potassium were associated with adverse kidney outcomes and mortality among participants not taking potassium-wasting diuretics. PMID- 27499537 TI - The immunology of asthma: Asthma phenotypes and their implications for personalized treatment. AB - OBJECTIVES: To review current thinking regarding the role of personalized phenotype-driven as opposed to broad guideline-based therapies in asthma and to speculate on the relative contributions of innate (lung) and adaptive (T and B lymphocyte) roles in asthma pathogenesis. DATA SOURCES: PubMed literature review. STUDY SELECTIONS: Articles pertaining to asthma pathogenesis, with emphasis on those that included biotherapeutic interventions. RESULTS: Current methods allow asthma to be divided into phenotypes characterized by the presence or absence of eosinophilic inflammation. Corticosteroids are likely to be only effective in the context of eosinophilic inflammation. Similarly, interventions with biotherapeutic agents currently available or in development have efficacious only when administered to patients with asthma of relevant phenotypes. CONCLUSION: The availability of biotherapeutic agents that target IgE, interleukin (IL) 5, and, in the near future, IL-13 is an exciting vindication of molecular medicine. However, these biotherapeutic agents are only effective when targeted to patients with specific asthma phenotypes. In Promising biotherapeutic targets are the airway epithelial-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin. Targeting these lung epithelial-derived mediators, instead of products of the adaptive immune system, may be more likely to improve day-to-day asthma symptoms in contrast to agents that target the adaptive immune system, approaches that primarily act to ameliorate asthma exacerbations. PMID- 27499538 TI - Hypersensitivity and immunologic reactions to biologics: opportunities for the allergist. AB - OBJECTIVE: There has been a great expanse in the use of biological agents during the past decade. However, there are significant differences between biologics and typical pharmaceutical drugs. This review focuses on 3 separate types of adverse reactions to biologics, namely high cytokine reactions, hypersensitivity reactions, and secondary immunodeficiency. DATA SOURCES: A PubMed literature search restricted to the previous 10 years using combinations of search terms, including omalizumab, rituximab, TGN1412, biologic agent, anaphylaxis, hypogammaglobulinemia, desensitization, and cytokine storm, was performed. The results were manually filtered to identify relevant articles with additional references identified from bibliographies. STUDY SELECTION: Reports were selected for TGN1412 cytokine storm, omalizumab anaphylaxis and desensitization, rituximab induced hypogammaglobulinemia, rituximab anaphylaxis and serum sickness, and monoclonal antibody desensitization. RESULTS: A phase 1 clinical trial using a humanized anti-CD28 monoclonal antibody (TGN1412) caused severe cytokine storm reactions in all 6 subjects, resulting in multiorgan failure. Omalizumab has been reported to cause anaphylaxis in fewer than 0.1% of patients, many with delayed reactions. The mechanism for this anaphylactic reaction is unclear. Rituximab has been associated with hypogammaglobulinemia, serum sickness-like reactions, and anaphylaxis. Rapid drug desensitizations to monoclonal antibodies, including rituximab, suspected of causing immunoglobulin E-mediated reactions have been found to be generally safe and effective. CONCLUSION: Hypersensitivity reactions and immune dysregulation from biologic agents are not rare. The allergist and immunologist should be involved in managing these patients for optimal care. PMID- 27499539 TI - Characterization of asthma endotypes: implications for therapy. AB - OBJECTIVE: To describe the concept of precision medicine in treating severe asthma and the utility of relevant biomarkers. DATA SOURCES: PubMed was searched for published articles on human clinical trials using biologics for T-helper type 2 cell (TH2)-low and TH2-high asthma. STUDY SELECTIONS: Studies were selected if they were double-masked, randomized, placebo-controlled trials published in peer reviewed journals and relevant to the topic. RESULTS: Multiple immune response modifiers have been evaluated in TH2-high asthma geared at blocking interleukin (IL)-5, IL-13, immunoglobulin E, prostaglandin D2, and other pathways. Currently, 3 immune response modifiers approved by the Food and Drug Administration are available for treating severe TH2-high asthma (1 anti-immunoglobulin E and 2 anti IL-5 monoclonal antibodies) and other TH2-high therapies are in various stages of clinical development. Thus far, many of the TH2-high therapies have shown better efficacy when certain biomarkers are elevated, especially blood eosinophils. The TH2-low endotype does not have any readily available point-of-care biomarkers, so TH2-low asthma is often diagnosed based on a lack of TH2-high biomarkers. These patients tend to have greater resistance to steroids and the development of therapies has lagged behind that for TH2-high asthma. CONCLUSION: Two major endotypes for asthma have been described, TH2-high, manifested by increased eosinophils in the sputum and airways of patients, and TH2-low, with increased neutrophils or a pauci-granulocytic profile. Using these classifications and specific biomarkers has led to promising new therapeutics, especially for TH2 high asthma. PMID- 27499540 TI - The transforming power of proximity food challenges. PMID- 27499542 TI - Mobile health applications in clinical practice: pearls, pitfalls, and key considerations. PMID- 27499541 TI - Basic science for the clinician: Mechanisms of sublingual and subcutaneous immunotherapy. AB - OBJECTIVE: To discuss the general immunologic changes that occur during immunotherapy, focusing on the differences between subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). DATA SOURCES: PubMed literature review. STUDY SELECTIONS: Articles pertaining to SCIT and SLIT, with specific emphasis on those that included immune mechanistic studies. RESULTS: Both SCIT and SLIT are characterized by the induction of regulatory B and T cells, decreased allergen-specific T-cell proliferation, a shift from a TH2 to TH1 cytokine milieu and from an IgE to an IgG4/IgA antibody response. These changes are accompanied by clinical improvement in symptoms. CONCLUSION: Immunotherapy using allergen extracts administered via both subcutaneous and sublingual approaches have demonstrated efficacy in the treatment of allergic rhinoconjunctivitis and other allergic conditions. There are subtle differences between the approaches, and understanding these differences may help clinicians select a preferred route of therapy for particular patients or allergens, depending on the immune response that is being targeted. PMID- 27499543 TI - Evaluation of the association between sensitization to common inhalant fungi and poor asthma control. AB - BACKGROUND: Fungi are well-known airborne allergens that are predisposing environmental factors to asthma. Few comparative studies have evaluated sensitization to common inhalant fungi in relation to poor asthma control in patients with asthma. OBJECTIVE: To evaluate the association between sensitization to individual fungi and asthma control and elucidate the characteristics of patients with poorly controlled asthma sensitized to fungi. METHODS: This cross-sectional study was performed at Showa University Hospital between September 2014 and December 2014. The specific IgE levels for several major aeroallergens, including house dust mites, Japanese cedar, various types of pollen, furry animals, or insects, were measured with a fluorescent enzyme immunoassay in 160 patients with adult asthma. RESULTS: Fungal sensitization was predominant in men with asthma, and it was associated with poor asthma control. Sensitization to house dust mites, Japanese cedar, pollen, furry animals, or insects was not associated with poor asthma control. Logistic regression analyses revealed that patients sensitized to Aspergillus and Penicillium had a significantly increased risk of poor asthma control. More Penicillium IgE positive patients were men and pet owners compared with Penicillium IgE-negative patients; in addition, Penicillium IgE-positive patients had higher total IgE levels. The Asthma Control Test level was significantly higher in Penicillium IgE positive patients than in Penicillium IgE-negative patients. However, there were no differences in fractional exhaled nitric oxide, forced vital capacity, and forced expiratory volume in 1 second. Finally, sensitization to Aspergillus, Cladosporium, and Trichophyton were positively correlated with sensitization to Penicillium. CONCLUSION: Sensitization to fungi is predominant in men, and it is associated with poor asthma control. In particular, sensitization to Penicillium and Aspergillus is a risk factor for asthma severity. These results have potential relevance in asthma management. PMID- 27499545 TI - Erratum. PMID- 27499544 TI - Allergic contact dermatitis to balsam of Peru. PMID- 27499546 TI - The Best of Both Worlds: The Benefits of Open-specialized and Closed-diverse Syndication Networks for New Ventures' Success. AB - Open networks give actors non-redundant information that is diverse, while closed networks offer redundant information that is easier to interpret. Integrating arguments about network structure and the similarity of actors' knowledge, we propose two types of network configurations that combine diversity and ease of interpretation. Closed-diverse networks offer diversity in actors' knowledge domains and shared third-party ties to help in interpreting that knowledge. In open-specialized networks, structural holes offer diversity, while shared interpretive schema and overlap between received information and actors' prior knowledge help in interpreting new information without the help of third parties. In contrast, actors in open-diverse networks suffer from information overload due to the lack of shared schema or overlapping prior knowledge for the interpretation of diverse information, and actors in closed-specialized networks suffer from overembeddedness because they cannot access diverse information. Using CrunchBase data on early-stage venture capital investments in the U.S. information technology sector, we test the effect of investors' social capital on the success of their portfolio ventures. We find that ventures have the highest chances of success if their syndicating investors have either open-specialized or closed-diverse networks. These effects are manifested beyond the direct effects of ventures' or investors' quality and are robust to controlling for the possibility that certain investors could have chosen more promising ventures at the time of first funding. PMID- 27499547 TI - An Example of an Improvable Rao-Blackwell Improvement, Inefficient Maximum Likelihood Estimator, and Unbiased Generalized Bayes Estimator. AB - The Rao-Blackwell theorem offers a procedure for converting a crude unbiased estimator of a parameter theta into a "better" one, in fact unique and optimal if the improvement is based on a minimal sufficient statistic that is complete. In contrast, behind every minimal sufficient statistic that is not complete, there is an improvable Rao-Blackwell improvement. This is illustrated via a simple example based on the uniform distribution, in which a rather natural Rao Blackwell improvement is uniformly improvable. Furthermore, in this example the maximum likelihood estimator is inefficient, and an unbiased generalized Bayes estimator performs exceptionally well. Counterexamples of this sort can be useful didactic tools for explaining the true nature of a methodology and possible consequences when some of the assumptions are violated. [Received December 2014. Revised September 2015.]. PMID- 27499548 TI - Can survival analyses detect hunting pressure in a highly connected species? Lessons from straw-coloured fruit bats. AB - Animal behaviour, social structure and population dynamics affect community structure, interspecific interactions, and a species' resilience to harvesting. Building on new life history information for the straw-coloured fruit bat (Eidolon helvum) from multiple localities across Africa, we used survival analyses based on tooth-cementum annuli data to test alternative hypotheses relating to hunting pressure, demography and population connectivity. The estimated annual survival probability across Africa was high (>= 0.64), but was greatest in colonies with the highest proportion of males. This difference in sex survival, along with age and sex capture biases and out-of-phase breeding across the species' distribution, leads us to hypothesize that E. helvum has a complex social structure. We found no evidence for additive mortality in heavily hunted populations, with most colonies having high survival with constant risk of mortality despite different hunting pressure. Given E. helvum's slow life history strategy, similar survival patterns and rate among colonies suggest that local movement and regional migration may compensate for local excess hunting, but these were also not clearly detected. Our study suggests that spatio-temporal data are necessary to appropriately assess the population dynamics and conservation status of this and other species with similar traits. PMID- 27499549 TI - Underlayer Effect on Perpendicular Magnetic Anisotropy in Co20Fe60B20?MgO Films. AB - Perpendicular Magnetic Tunneling Junctions (pMTJs) with Ta?CoFeB?MgO have been extensively studied in recent years. However, the effects of the underlayer on the formation of the CoFeB perpendicular magnetic anisotropy (PMA) are still not well understood. Here we report the results of our systematic use of a wide range of elements (Ti, V, Cr, Zr, Nb, Mo, Ru, Rh, Pd, Ag, Hf, Ta, W, Re, Os, Ir, Pt and Au) encompassed by columns IVA, VA, VIA, VIIA and VIIIA of the periodic table as the underlayer in a underlayer?Co20Fe60B20?MgO stack. Our goals were to survey more elements which could conceivably create a PMA in CoFeB and thereby to explore the mechanisms enabling these underlayers to enhance or create the PMA. We found underlayer elements having both an outer shell of 4d electrons (Zr, Nb Mo, and Pd) and 5d electrons (Hf, Ta, W, Re, Ir, and Pt) resulted in the development of a PMA in the MgO-capped Co20Fe60B20. Hybridization between the 3d electrons of the Fe or Co (in the Co20Fe60B20) at the interface with the 4d or 5d electrons of the underlayer is thought to be the cause of the PMA development. PMID- 27499550 TI - Effect of Using 2mm Voxels on Observer Performance for PET Lesion Detection. AB - Positron emission tomography (PET) images are typically reconstructed with an in plane pixel size of approximately 4mm for cancer imaging. The objective of this work was to evaluate the effect of using smaller pixels on general oncologic lesion-detection. A series of observer studies was performed using experimental phantom data from the Utah PET Lesion Detection Database, which modeled whole body FDG PET cancer imaging of a 92kg patient. The data comprised 24 scans over 4 days on a Biograph mCT time-of-flight (TOF) PET/CT scanner, with up to 23 lesions (diam. 6-16mm) distributed throughout the phantom each day. Images were reconstructed with 2.036mm and 4.073mm pixels using ordered-subsets expectation maximization (OSEM) both with and without point spread function (PSF) modeling and TOF. Detection performance was assessed using the channelized non-prewhitened numerical observer with localization receiver operating characteristic (LROC) analysis. Tumor localization performance and the area under the LROC curve were then analyzed as functions of the pixel size. In all cases, the images with ~2mm pixels provided higher detection performance than those with ~4mm pixels. The degree of improvement from the smaller pixels was larger than that offered by PSF modeling for these data, and provided roughly half the benefit of using TOF. Key results were confirmed by two human observers, who read subsets of the test data. This study suggests that a significant improvement in tumor detection performance for PET can be attained by using smaller voxel sizes than commonly used at many centers. The primary drawback is a 4-fold increase in reconstruction time and data storage requirements. PMID- 27499551 TI - Ontogenic differences in sexual size dimorphism across four plover populations. AB - Sexual size dimorphism (SSD) among adults is commonly observed in animals and is considered to be adaptive. However, the ontogenic emergence of SSD, i.e. the timing of divergence in body size between males and females, has only recently received attention. It is widely acknowledged that the ontogeny of SSD may differ between species, but it remains unclear how variable the ontogeny of SSD is within species. Kentish Plovers Charadrius alexandrinus and Snowy Plovers C. nivosus are closely related wader species that exhibit similar, moderate (c. 4%), male-biased adult SSD. To assess when SSD emerges we recorded tarsus length variation among 759 offspring in four populations of these species. Tarsus length of chicks was measured on the day of hatching and up to three times on recapture before fledging. In one population (Mexico, Snowy Plovers), males and females differed in size from the day of hatching, whereas growth rates differed between the sexes in two populations (Turkey and United Arab Emirates, both Kentish Plovers). In contrast, a fourth population (Cape Verde, Kentish Plovers) showed no significant SSD in juveniles. Our results suggest that adult SSD can emerge at different stages of development (prenatal, postnatal and post-juvenile) in different populations of the same species. We discuss the proximate mechanisms that may underlie these developmental differences. PMID- 27499552 TI - 'Mortgaged lives': the biopolitics of debt and housing financialisation. AB - The paper expands the conceptual framework within which we examine mortgage debt by reconceptualising mortgages as a biotechnology: a technology of power over life that forges an intimate relationship between global financial markets, everyday life and human labour. Taking seriously the materiality of mortgage contracts as a means of forging new embodied practices of financialisation, we urge for the need to move beyond a policy- and macroeconomics-based analysis of housing financialisation. We argue that more attention needs to be paid to how funnelling land-related capital flows goes hand in hand with signing off significant parts of future labour, decisionmaking capacity and well-being to mortgage debt repayments. The paper offers two key insights. First, it exemplifies how macroeconomic and policy changes could not have led to the financialisation of housing markets without a parallel biopolitical process that mobilised mortgage contracts to integrate the social reproduction of the workforce into speculative global real-estate practices. Second, it expands the framework of analysis of emerging literature on financialisation and subjectification. Focusing on the mortgage defaults and evictions crisis in Spain, we document how during Spain's 1997-2007 real-estate boom the promise of mortgages as a means to optimise income and wealth enrolled livelihoods into cycles of global financial and real-estate speculation, as home security and future wealth became directly dependent on the fluctuations of financial products, interest rates and capital accumulation strategies rooted in the built environment. When, after 2008 unemployment escalated and housing prices collapsed, mortgages became a punitive technology that led to at least 500 000 foreclosures and over 250 000 evictions in Spain. PMID- 27499553 TI - Foraging choices of vampire bats in diverse landscapes: potential implications for land-use change and disease transmission. AB - In Latin America, the common vampire bat Desmodus rotundus is the primary reservoir of rabies, a zoonotic virus that kills thousands of livestock annually and causes sporadic and lethal human rabies outbreaks. The proliferation of livestock provides an abundant food resource for this obligate blood-feeding species that could alter its foraging behaviour and rabies transmission, but poor understanding of the dietary plasticity of vampire bats limits understanding of how livestock influences rabies risk.We analysed individual- and population-level foraging behaviour by applying delta13C and delta15N stable isotope analysis to hair samples from 183 vampire bats captured from nine colonies in Peru. We also assessed the isotopic distributions of realized prey by analysing blood meals extracted from engorged bats and samples collected from potential prey species. In two adjacent but contrasting areas of the Amazon with scarce and abundant livestock, we used questionnaires to evaluate the incidence of feeding on humans.Population-level isotopic signatures suggested substantial among-site variation in feeding behaviour, including reliance on livestock in some colonies and feeding on combinations of domestic and wild prey in others. Isotopic heterogeneity within bat colonies was among the largest recorded in vertebrate populations, indicating that individuals consistently fed on distinct prey resources and across distinct trophic levels. In some sites, isotopic values of realized prey spanned broad ranges, suggesting that bats with intermediate isotopic values could plausibly be dietary specialists rather than generalists.Bayesian estimates of isotopic niche width varied up to ninefold among colonies and were maximized where wildlife and livestock were present at low levels, but declined with greater availability of livestock. In the Amazon, the absence of livestock was associated with feeding on humans and wildlife. Policy implications. We provide the first insights into the foraging behaviour of vampire bats in habitats with common depredation on humans and show how vampire bat foraging may respond to land-use change. Our results demonstrate risks of rabies transmission from bats to other wildlife and are consistent with the hypothesis that introducing livestock might reduce the burden of human rabies in high-risk communities. PMID- 27499554 TI - Father's Migration and Leaving the Parental Home in Rural Mozambique. AB - Migration is an increasingly common demographic phenomenon and has important implications for the well-being of family members left behind. Although extensive research has examined the impact of parental labor migration on school-age children, less is known about its effect on adolescents. In this study, the authors used longitudinal survey data collected in rural Mozambique (N = 515) to assess the association between father's migration and adolescent children's leaving the parental home, an important component of the transition to adulthood. The results showed that father's migration delays home-leaving for adolescent girls and that these effects are not mediated by school enrollment. The results for boys were inconclusive. The authors also found that remittances and longer durations of paternal migration were negatively associated with the transition out of the home. On the basis of the findings, they argue that father's migration delays girls' marriage. PMID- 27499555 TI - Resource Scarcity and Prescriptive Attitudes Generate Subtle, Intergenerational Older-Worker Exclusion. AB - Prior work describes specific, prescriptive resource tensions between generations, comprising active Succession, passive Consumption, and symbolic Identity (SCI; North & Fiske, 2013a, 2013b). The current paper focuses on how these domains potentially drive intergenerational exclusion in work-related networking and training spheres. Studies 1a-1c-each focusing on a different SCI domain-manipulated perceived resource availability between generations, then introduced a professional networking opportunity. Across studies, scarcity reduced the likelihood of young participants' networking engagement with older workers who violated SCI resource expectations. Study 2 impelled participants to allocate scarce training resources among three similarly qualified but different aged employees (younger, middle-aged, and older). Older workers received the lowest such investment, particularly among younger participants-an effect driven by Succession beliefs, per mediation analyses. Overall, the findings emphasize resource tensions in driving older workers' subtle exclusion by younger generations; minimizing such tensions will be critical for aging, increasingly intergenerational workplaces. PMID- 27499557 TI - Health and Greater Manchester in Historical Perspective. AB - This article maps the history of health organisation across Greater Manchester (GM), primarily since the Second World War, to show how against a continuing backdrop of health inequalities, services have been driven (and constrained) by the needs and the politics of each period. Defining 'success' as benefits for patients the article identifies examples such as Salford's mental health services (1950s and 1960s), public health in North Manchester (1970s and 1980s), the creation of centres for diabetes, sickle-cell and thalassaemia (1980s) and the formation of the Joint Health Unit in 2002. What this history shows is that over the period the common factors influencing the 'success' of health organisation across GM have been the championing of particular issues by multi-disciplinary groups working across health and social care and stability in structures and personnel. PMID- 27499556 TI - Fossilization of melanosomes via sulfurization. AB - Fossil melanin granules (melanosomes) are an important resource for inferring the evolutionary history of colour and its functions in animals. The taphonomy of melanin and melanosomes, however, is incompletely understood. In particular, the chemical processes responsible for melanosome preservation have not been investigated. As a result, the origins of sulfur-bearing compounds in fossil melanosomes are difficult to resolve. This has implications for interpretations of original colour in fossils based on potential sulfur-rich phaeomelanosomes. Here we use pyrolysis gas chromatography mass spectrometry (Py-GCMS), fourier transform infrared spectroscopy (FTIR) and time of flight secondary ion mass spectrometry (ToF-SIMS) to assess the mode of preservation of fossil microstructures, confirmed as melanosomes based on the presence of melanin, preserved in frogs from the Late Miocene Libros biota (NE Spain). Our results reveal a high abundance of organosulfur compounds and non-sulfurized fatty acid methyl esters in both the fossil tissues and host sediment; chemical signatures in the fossil tissues are inconsistent with preservation of phaeomelanin. Our results reflect preservation via the diagenetic incorporation of sulfur, i.e. sulfurization (natural vulcanization), and other polymerization processes. Organosulfur compounds and/or elevated concentrations of sulfur have been reported from melanosomes preserved in various invertebrate and vertebrate fossils and depositional settings, suggesting that preservation through sulfurization is likely to be widespread. Future studies of sulfur-rich fossil melanosomes require that the geochemistry of the host sediment is tested for evidence of sulfurization in order to constrain interpretations of potential phaeomelanosomes and thus of original integumentary colour in fossils. PMID- 27499558 TI - Orthogonalizing EM: A design-based least squares algorithm. AB - We introduce an efficient iterative algorithm, intended for various least squares problems, based on a design of experiments perspective. The algorithm, called orthogonalizing EM (OEM), works for ordinary least squares and can be easily extended to penalized least squares. The main idea of the procedure is to orthogonalize a design matrix by adding new rows and then solve the original problem by embedding the augmented design in a missing data framework. We establish several attractive theoretical properties concerning OEM. For the ordinary least squares with a singular regression matrix, an OEM sequence converges to the Moore-Penrose generalized inverse-based least squares estimator. For ordinary and penalized least squares with various penalties, it converges to a point having grouping coherence for fully aliased regression matrices. Convergence and the convergence rate of the algorithm are examined. Finally, we demonstrate that OEM is highly efficient for large-scale least squares and penalized least squares problems, and is considerably faster than competing methods when n is much larger than p. Supplementary materials for this article are available online. PMID- 27499559 TI - From recreational to functional drug use: the evolution of drugs in American higher education, 1960-2014. AB - The increasing prevalence of so-called cognitive-enhancing drugs is well documented in American higher education. There has been little historical analysis, however, specifically exploring the role of postsecondary institutions in this evolving drug narrative. This paper traces substance use and research trends in American higher education over the past half-century, divided into three eras defined by their disparate approaches to drug policy and public health. Contextualised by historic events, shifting policies and epidemiological data, this multidisciplinary analysis contends that functional, academically oriented drug use is likely to continue rising on US campuses, while recreational drug use will evolve and persist. As history provides a useful lens for understanding the involvement of academe in the first era of drug concern in America, ongoing innovations in medical and social science may be instructive to help ensure that institutions respond judiciously in the present era of new drug synthesis and drug policy recession. PMID- 27499560 TI - Do Migrants Degrade Coastal Environments? Migration, Natural Resource Extraction and Poverty in North Sulawesi, Indonesia. AB - Recent literature on migration and the environment has identified key mediating variables such as how migrants extract resources from the environment for their livelihoods, the rate and efficiency of extraction, and the social and economic context within which their extraction occurs. This paper investigates these variables in a new ecological setting using data from coastal fishing villages in North Sulawesi, Indonesia. We do not find as many differences between migrant and non-migrant families regarding destructive fishing behavior, technology, and investment as might have been expected from earlier theories. Instead, the context and timing of migrant assimilation seems to be more important in explaining apparent associations of migration and environmental impacts than simply migrants themselves. This finding fits well with recent literature in the field of international migration and immigrant incorporation. PMID- 27499561 TI - Trust: The Missing Dimension in the Food Retail Transition in Thailand. AB - Thailand has experienced dramatic growth of large national and international modern food retailers, such as supermarkets, hypermarkets and convenience stores in large cities and regional centres in the last two decades. Nevertheless, Thai consumers continue to purchase perishables (fruits, vegetables and animal products) from fresh markets (wet markets, talat sot) contradicting predictions from analysts that modern food retail chains will rapidly replace fresh markets as the preferred venue for purchasing all types of foods. This paper examines trust in food retail systems as an under-explored dimension lying behind the continued patronage by Thais of fresh markets to purchase perishable items. It derives from a research program commenced in 2005 that includes fieldwork visits, interviews and questionnaires. In the context of the Thai food retail transition, we propose that trust affects relationships between consumers and (1) individual fresh market-based vendors, (2) the food products sold at fresh markets and (3) the food retail system more broadly. If fresh markets can be maintained in the face of sustained pressure from modern national and international food retailers, Thais will continue to use them. Meanwhile, trust is a relatively unrecognised dimension that is supporting the continued existence of traditional food retail formats. PMID- 27499562 TI - Serious Psychological Distress Among African Americans: Findings from the National Survey of American Life. AB - Despite their low social standing, there remains a paucity of research on psychological distress among African Americans. We use data from the 2001-2003 National Survey of American Life to explore a wide array of social and economic predictors of psychological distress among African American adults ages 18 and older, including previous incarceration, history of welfare receipt, and having a family member who is either currently incarcerated or homeless. Younger age, lower income, lower educational attainment, and lower self-rated health and childhood health are associated with higher levels of psychological distress among African Americans. We also find a strong association between higher levels of material hardship, previous incarceration history, and the presence of a family member who is either incarcerated or homeless and higher levels of psychological distress. The findings highlight the importance of considering unique types of social disadvantage experienced by African Americans living in a highly stratified society. PMID- 27499563 TI - Knowledge, attitudes and perceptions of nurses and nursing students towards HIV/AIDS. AB - OBJECTIVE: To describe attitudes, knowledge and perceptions of nurses and nursing students towards the people who live with HIV/AIDS (PLWHA). METHODOLOGY: Bibliographic study in which six electronic databases were searched using the key words: "attitude", "knowledge", "nursing", perceptions", "HIV/AIDS". Publications between 1998 and 2007 were considered. RESULTS: 560 articles limited by scientific researches or ministerial reports membership were retrieved. Finally a total of 38 publications were selected, the analysis showed that the level of knowledge of nurses and nursing students about PLWHA is good and the attitudes towards HIV/AIDS have improved over time. Nurses and nursing students have been able to identify both positive and negative aspects in the PLWHA care personally and professionally because there is a more favourable perception. CONCLUSION: There are few studies in Latin America and Chile that study the attitudes and knowledge of the studied population towards PLWHA. According to publications found the knowledge and attitudes have improved because the perception is more favourable. PMID- 27499565 TI - Optimal Convergence Rates Results for Linear Inverse Problems in Hilbert Spaces. AB - In this article, we prove optimal convergence rates results for regularization methods for solving linear ill-posed operator equations in Hilbert spaces. The results generalizes existing convergence rates results on optimality to general source conditions, such as logarithmic source conditions. Moreover, we also provide optimality results under variational source conditions and show the connection to approximative source conditions. PMID- 27499564 TI - Asymptotically Normal and Efficient Estimation of Covariate-Adjusted Gaussian Graphical Model. AB - A tuning-free procedure is proposed to estimate the covariate-adjusted Gaussian graphical model. For each finite subgraph, this estimator is asymptotically normal and efficient. As a consequence, a confidence interval can be obtained for each edge. The procedure enjoys easy implementation and efficient computation through parallel estimation on subgraphs or edges. We further apply the asymptotic normality result to perform support recovery through edge-wise adaptive thresholding. This support recovery procedure is called ANTAC, standing for Asymptotically Normal estimation with Thresholding after Adjusting Covariates. ANTAC outperforms other methodologies in the literature in a range of simulation studies. We apply ANTAC to identify gene-gene interactions using an eQTL dataset. Our result achieves better interpretability and accuracy in comparison with CAMPE. PMID- 27499566 TI - Central Limit Theorems under additive deformations. AB - Additive deformations of statistical systems arise in various areas of physics. Classical central limit theory is then no longer applicable, even when standard independence assumptions are preserved. This paper investigates ways in which deformed algebraic operations lead to distinctive central limit theory. We establish some general central limit results that are applicable to a range of examples arising in nonextensive statistical mechanics, including the addition of momenta and velocities via Kaniadakis addition, and Tsallis addition. We also investigate extensions to random additive deformations, and find evidence (based on simulation studies) for a universal limit specific to each statistical system. PMID- 27499567 TI - Using the mouse grimace scale and behaviour to assess pain in CBA mice following vasectomy. AB - Mice used in biomedical research should have pain reduced to an absolute minimum through refinement of procedures or by the provision of appropriate analgesia. Vasectomy is a common and potentially painful surgical procedure carried out on male mice to facilitate the production of genetically modified mice. The aim of our study was to determine if 0.05 mg/kg buprenorphine would ameliorate pain associated changes following abdominal vasectomy and to determine if the mouse grimace scale is an appropriate tool for the assessment of pain in this model. Eight male CBA mice underwent abdominal vasectomy as part of a genetically modified mouse-breeding programme. Here we assessed pain using a previously validated behaviour-based method and the mouse grimace scale. All mice received buprenorphine (0.05 mg/kg s.c.) pre-surgery. Behaviour and grimace scores were compared between baseline (pre-surgery), 30 min, 5 h, 24 h and 25 h post surgery. Following 24 h post-op, all mice were administered 5 mg/kg meloxicam (s.c.) as additional analgesia. Significant increases in specific pain behaviours and mouse grimace scale score were found 30 min post surgery. At 5 h post surgery, scores were returning to baseline levels. Frequency of rearing was significantly decreased at both 30 min and 5 h post surgery compared to baseline, demonstrating a longer lasting change in normal exploratory behaviour. Buprenorphine (0.05 mg/kg) was ineffective at ameliorating these pain-associated changes in CBA mice and should be considered inadequate at this dose. By 24 h post surgery, pain associated behaviours, grimace scale and rearing had all returned to baseline levels. There was no change in pain behaviours or MGS following administration of meloxicam indicating that an additional dose of meloxicam does not appear to offer benefit at this point. Using the mouse grimace scale to assess pain in mice, appeared to be effective in the immediate post vasectomy period in CBA mice demonstrating the same duration of increased score as the pain associated behaviours. PMID- 27499568 TI - Balsscallichirus Sakai, 2011 (Decapoda: Axiidea: Callianassidae) in the fossil record: systematics and palaeobiogeography. AB - The fossil record of the ghost shrimp genus Balsscallichirus Sakai, 2011 (Crustacea: Decapoda: Callianassidae) is revised. Barnardcallichirus Sakai, 2011 and Tirmizicallichirus Sakai, 2011 are considered subjective synonyms of Balsscallichirus. Based on the examination of extant species it is argued that the morphology of the major cheliped merus, in combination with other hard part morphology characters, is sufficient for assignment of the fossil material into the genus. Main identifying characters are on merus which is keeled along its midline and its lower half is tuberculated; its lower margin possesses broad proximal meral hook continuing into a lobe distally; the entire lower margin is subdivided into numerous irregularly spaced spines. Three species, Callianassa sismondai A. Milne-Edwards, 1860, C. floriana Glaessner, 1928, and Podocallichirus laepaensis Hyzny & Muniz, 2012, originally described from the Miocene of Italy, Austria and Spain, respectively, are assigned to Balsscallichirus herein. Neocallichirus wellsi Schweitzer, Feldmann & Gingerich, 2004 from the Upper Eocene of Pakistan is tentatively assigned to that genus as well. Spatial and temporal distribution of the genus indicates that at least since the Oligocene, and possibly even sooner (the Late Eocene), the genus has been restricted to the Western Tethys Region. Later, it migrated also into West Atlantic establishing present day communities. PMID- 27499569 TI - Surface conductance of graphene from non-contact resonant cavity. AB - A method is established to reliably determine surface conductance of single-layer or multi-layer atomically thin nano-carbon graphene structures. The measurements are made in an air filled standard R100 rectangular waveguide configuration at one of the resonant frequency modes, typically at TE103 mode of 7.4543 GHz. Surface conductance measurement involves monitoring a change in the quality factor of the cavity as the specimen is progressively inserted into the cavity in quantitative correlation with the specimen surface area. The specimen consists of a nano-carbon-layer supported on a low loss dielectric substrate. The thickness of the conducting nano-carbon layer does not need to be explicitly known, but it is assumed that the lateral dimension is uniform over the specimen area. The non contact surface conductance measurements are illustrated for a typical graphene grown by chemical vapor deposition process, and for a high quality monolayer epitaxial graphene grown on silicon carbide wafers for which we performed non gated quantum Hall resistance measurements. The sequence of quantized transverse Hall resistance at the Landau filling factors nu = +/-6 and +/-2, and the absence of the Hall plateau at nu = 4 indicate that the epitaxially grown graphene is a high quality mono-layer. The resonant microwave cavity measurement is sensitive to the surface and bulk conductivity, and since no additional processing is required, it preserves the integrity of the conductive graphene layer. It allows characterization with high speed, precision and efficiency, compared to transport measurements where sample contacts must be defined and applied in multiple processing steps. PMID- 27499570 TI - The Unilateralist's Curse and the Case for a Principle of Conformity. AB - In some situations a number of agents each have the ability to undertake an initiative that would have significant effects on the others. Suppose that each of these agents is purely motivated by an altruistic concern for the common good. We show that if each agent acts on her own personal judgment as to whether the initiative should be undertaken, then the initiative will be undertaken more often than is optimal. We suggest that this phenomenon, which we call the unilateralist's curse, arises in many contexts, including some that are important for public policy. To lift the curse, we propose a principle of conformity, which would discourage unilateralist action. We consider three different models for how this principle could be implemented, and respond to an objection that could be raised against it. PMID- 27499571 TI - Validation of Nonparametric Two-Sample Bootstrap in ROC Analysis on Large Datasets. AB - The nonparametric two-sample bootstrap is applied to computing uncertainties of measures in ROC analysis on large datasets in areas such as biometrics, speaker recognition, etc., when the analytical method cannot be used. Its validation was studied by computing the SE of the area under ROC curve using the well established analytical Mann-Whitney-statistic method and also using the bootstrap. The analytical result is unique. The bootstrap results are expressed as a probability distribution due to its stochastic nature. The comparisons were carried out using relative errors and hypothesis testing. They match very well. This validation provides a sound foundation for such computations. PMID- 27499572 TI - Inhibition of neutrophil superoxide generation by shikonin is associated with suppression of cellular Ca(2+) fluxes. AB - Shikonin, an anti-inflammatory compound of "Shikon", inhibits the neutrophil superoxide (O2 (*-)) generation by NADPH oxidase 2 (Nox2); however, the mechanisms of how shikonin affects Nox2 activity remained unclear. We aimed to elucidate the relationship between the inhibition of Nox2 activity and influences on intracellular Ca(2+) concentration ([Ca(2+)]i) by shikonin. For this purpose, we used a simultaneous monitoring system for detecting changes in [Ca(2+)]i (by fluorescence) and O2 (*-) generation (by chemiluminescence) and evaluated the effects of shikonin on neutrophil-like HL-60 cells stimulated with N-formyl-l methionyl-l-leucyl-l-phenylalanine (fMLP). Since fMLP activates Nox2 by elevation in [Ca(2+)]i via fluxes such as inositol 1,4,5-trisphosphate-induced Ca(2+) release (IICR) and store-operated Ca(2+) entry (SOCE), we also evaluated the effects of shikonin on IICR and SOCE. Shikonin dose-dependently inhibited the fMLP-induced elevation in [Ca(2+)]i and O2 (*-) generation (IC50 values of 1.45 and 1.12 uM, respectively) in a synchronized manner. Analyses of specific Ca(2+) fluxes showed that shikonin inhibits IICR and IICR-linked O2 (*-) generation (IC50 values: 0.28 and 0.31 uM for [Ca(2+)]i and O2 (*-), respectively), as well as SOCE and SOCE-linked O2 (*-) generation (IC50 values: 0.39 and 0.25 uM for [Ca(2+)]i and O2 (*-), respectively). These results suggested that shikonin inhibits the O2 (*-) generation by Nox2 in fMLP-stimulated neutrophils by targeting Ca(2+) fluxes such as IICR and SOCE. PMID- 27499573 TI - The effect of astaxanthin on vascular endothelial growth factor (VEGF) levels and peroxidation reactions in the aqueous humor. AB - We explored the effect of astaxanthin on vascular endothelial growth factor in the aqueous humor, by measuring vascular endothelial growth factor levels and oxidation-related parameters, including O2 (*-) scavenging activity, H2O2 level, and total hydroperoxide level in the aqueous humor, obtained from 35 patients before and after astaxanthin administration. We evaluated the relationship between vascular endothelial growth factor and the oxidation-related parameters as well as the patient's diabetic status, age, and sex. Vascular endothelial growth factor levels did not change significantly but O2 (*-) scavenging activity and total hydroperoxide level significantly (p<0.05) increased and decreased, respectively. Both pre- and post- astaxanthin intake, vascular endothelial growth factor and total hydroperoxide levels were positively correlated (Pearson: r = 0.42, p<0.05; r = 0.55, p<0.01, respectively). Analysis of vascular endothelial growth factor levels and O2 (*-) scavenging activities gave a negative correlation but only pre-astaxanthin intake (r = -0.37, p<0.05). Differences in levels pre- and post-astaxanthin only showed association between vascular endothelial growth factor and total hydroperoxide (r = 0.49, p<0.01) analyzed by multiple linear regression. Using multivariate analysis, pre-astaxanthin vascular endothelial growth factor level was associated with two factors of total hydroperoxide and O2 (*-) scavenging activity (r = 0.49, p<0.05), and post astaxanthin vascular endothelial growth factor level with two factors of total hydroperoxide and sex (r = 0.60, p<0.01). Astaxanthin intake may have affected vascular endothelial growth factor level through its antioxidant effects by increasing O2 (*-) scavenging activity and suppressing peroxide production. PMID- 27499574 TI - Lipid peroxides as endogenous oxidants forming 8-oxo-guanosine and lipid-soluble antioxidants as suppressing agents. AB - The oxidation of guanosine to 8-oxo-2'-deoxyguanosine (8-oxo-dG) in DNA is closely associated with induction of various diseases, but the endogenous oxidant species involved remains unclear. Hydrogen peroxides (H2O2) have been considered to be the oxidant, while lipid peroxides are another possible oxidant because generated easily in bio-membranes surrounding DNA. The oxidant potency was compared between lipid peroxides and H2O2. Linoleic acid hydroperoxides (LOOH) formed 8-oxo-dG at a higher level than H2O2 in guanosine or double-stranded DNA. In the presence of a physiological concentration of Fe(2+) to produce hydroxyl radicals, LOOH was also a stronger oxidant. In a lipid micelle, LOOH markedly produced 8-oxo-dG at a concentration one-tenth of that of H2O2. Upon adding to rat hepatic mitochondria, phosphatidylcholine hydroperoxides produced 8-oxo-dG abundantly. Employing HepG2 cells after pretreated with glutathione peroxidase inhibitor, LOOH formed 8-oxo-dG more abundantly than H2O2. Then, antioxidants to suppress the 8-oxo-dG formation were examined, when the nuclei of pre-incubated HepG2 with antioxidants were exposed to LOOH. Water-soluble ascorbic acid, trolox, and N-acetyl cysteine showed no or weak antioxidant potency, while lipid soluble 2,6-dipalmitoyl ascorbic acid, alpha-tocopherol, and lipid-soluble phytochemicals exhibited stronger potency. The present study shows preferential formation of 8-oxo-dG upon LOOH and the inhibition by lipid-soluble antioxidants. PMID- 27499575 TI - F-fucoidan from Saccharina japonica is a novel inducer of galectin-9 and exhibits anti-allergic activity. AB - Fucoidan is a sulfated polysaccharide from brown sea algae. In the present study, it was demonstrated that oral administration of F-fucoidan from Saccharina japonica possessed anti-allergic effects using the passive cutaneous anaphylaxis reaction, but not by intraperitoneal administration. The inhibitory mechanism was dependent on galectin-9, which belongs to a soluble lectin family that recognizes beta-galactoside and prevents IgE binding to mast cells. The anti-allergy properties of F-fucoidan were cancelled by an intravenous dose of anti-galectin-9 antibody or lactose, which bind competitively with galectin-9 before the passive cutaneous anaphylaxis reaction. F-fucoidan increased the expression level of galectin-9 mRNA in intestinal epithelial cells and serum galectin-9 levels. Oral treatment with F-fucoidan suppressed allergic symptoms through the induction of galectin-9. This is the first report that F-fucoidan can induce the secretion of galectin-9. PMID- 27499576 TI - Cheonggukjang, a soybean paste fermented with B. licheniformis-67 prevents weight gain and improves glycemic control in high fat diet induced obese mice. AB - In this study, we investigated the anti-obesity effects of soybean paste Cheonggukjang, fermented with poly gamma glutamic acid producing Bacillus licheniformis-67 in diet induced obese C57BL/6J mice. Forty male C57BL/6J mice aged 4 weeks were divided into four dietary groups; normal diet control, high fat diet control, high fat diet containing 30% of unfermented soybean and high fat diet containing 30% Cheonggukjang fermented with Bacillus licheniformis-67. After 13 weeks of dietary intervention the mice were sacrificed; serum and tissue samples were examined. Serum and hepatic lipid profile, blood glucose, insulin, leptin level were lower (<0.05) along with the body weight and epididymal fat pad weight in the 30% Cheonggukjang supplemented group compared with the high fat diet control group. The expression level of lipid anabolic gene was significantly decreased; whereas the expression level of lipid catabolic genes were significantly increased in the 30% Cheonggukjang supplemented group compared to the high fat diet control group. Collectively, these results suggested that intake of Cheonggukjang fermented with Bacillus licheniformis-67 significantly prevents obesity related parameters. PMID- 27499578 TI - Changes in salivary flow rate following Chlorella-derived multicomponent supplementation. AB - Decreases in saliva secretion compromise food mastication and swallowing, reduce mucosal immune function, and increase the risk for oral diseases like dental caries. Chlorella is a green alga that contains a variety of nutrients including amino acids, vitamins, and minerals. In our previous study, Chlorella-derived multicomponent supplementation did not affect salivary flow rates in healthy young individuals, but Chlorella-derived supplementation attenuated a decrease in saliva secretion that was observed during a kendo training camp. Hence, we hypothesized that Chlorella-derived supplementation increases saliva secretion in individuals with lower rates of saliva flow. Sixty-four subjects took Chlorella derived tablets for four weeks. Before and after supplementation, saliva samples were collected by chewing cotton. In the complete study group, there was no difference in saliva production before and after supplementation (1.91 +/- 0.11 ml/min before vs 2.01 +/- 0.12 ml/min after). Analysis of subgroups based on saliva production before supplementation found an increase in saliva secretion in the lower saliva flow group (1.18 +/- 0.06 vs 1.38 +/- 0.08 ml/min), but no change in the higher saliva flow group (2.63 +/- 0.11 vs 2.64 +/- 0.15 ml/min). These results suggest that Chlorella-derived multicomponent supplementation increases saliva production in individuals with lower levels of saliva secretion. PMID- 27499577 TI - Pre-germinated brown rice prevented high fat diet induced hyperlipidemia through ameliorating lipid synthesis and metabolism in C57BL/6J mice. AB - Pre-germinated brown rice (PGBR) can ameliorate hyperlipidemia, but the action mechanism is not clear. We focus the mechanisms of PGBR prevented hyperlipidemia. Six-week-old mice were divided into: standard-regular diet (SRD), high-fat diet (HFD) and HFD with PGBR (HFD + PGBR) groups for 16 weeks. The HFD group has higher concentrations of TG, TC, HDL and Non-HDL in the blood, and a higher atherosclerosis index (AI). The TG levels in the liver, and TG, bile acid levels in the feces were enhanced; and the total adipocytokines level in adipose tissue was reduced. The HFD group had higher protein expressions of SREBP-1, SCD-1, FAS, LDLR, and CYP7alpha1 in the liver. Moreover, the greater expressions of SREBP-1, SCD-1, FAS and the less expressions of PPAR-alpha and adiponectin were in adipose tissue. In the HFD + PGBR group, the PGBR regulated the levels of TG, TC, HDL, Non-HDL, AI and adipocytokines. PGBR increased more cholesterol and bile acid exhaust in feces. The SREBP-1, SCD-1, FAS, HMGCR, LDLR, CYP7alpha1 and PPAR-alpha proteins in the liver; and the SREBP-1, SCD-1, FAS, PPAR-alpha and adiponectin proteins in adipose tissue were reversed by PGBR. Taken together, PGBR can improve lipid synthesis and metabolism, and we suggest PGBR is a recommendable food for controlling hyperlipidemia. PMID- 27499579 TI - Infectious disease during hospitalization is the major causative factor for prolonged hospitalization: multivariate analysis of diagnosis procedure combination (DPC) data of 20,876 cases in Japan. AB - This study aimed to evaluate causative factors for prolonged hospitalization based on hospitalization status, type of hospital ward, and comorbidities, specifically diabetes mellitus and infectious diseases, in 20,876 patients hospitalized in Saga University Hospital from April 1, 2012, to February 28, 2015. Prolonged hospitalization was defined as hospital days exceeding period 3 in the diagnosis procedure combination system. Among all factors, causative (risk) factors for prolonged hospitalization were evaluated by multiple logistic regression analysis. Multivariate analysis indicated causative factors for prolonged hospitalization were aging, comorbid diabetes mellitus, time spent in the intensive care unit, and infectious diseases contracted during hospitalization. The risk factors for contracting infectious diseases during hospitalization were aging, male sex, comorbid diabetes mellitus, and increased number of days spent in period 3 in the diagnosis procedure combination code. These data indicated that critical factors for discharge from hospital within an appropriate time frame were prevention of infectious diseases during hospitalization, and a fast and effective therapeutic approach to patients in the intensive care unit. PMID- 27499580 TI - The expression of IGF-1R in Helicobacter pylori-infected intestinal metaplasia and gastric cancer. AB - Overexpression of IGF-1R has been demonstrated in gastrointestinal cancers, and its expression is reported as the result of the loss of tumor suppressors. IL-16 is involved in the pathophysiological process of chronic inflammatory diseases. The aim of this study is to determine the changes in the expression of IGF-1R in intestinal metaplasia (IM) and gastric cancer (GC) as well as the effect of Helicobacter pylori (H. pylori) and IL-16 on cell proliferation and IGF-1R expression in gastric cells. AGS cells were incubated with combinations of IL-16 and H. pylori. Gastric cell proliferation was studied by BrdU uptake. In H. pylori infected mucosa, IGF-1R was significantly higher in IM than chronic gastritis (CG), and also higher in GC than CG and IM. H. pylori significantly decreased BrdU uptake. IL-16 increased BrdU uptake and IGF-1R on AGS cells which had been decreased by H. pylori. Co-incubation with IL-16 increased the expression of IGF-1R mRNA in H. pylori infected cells. We conclude that the expression of IGF-1R in H. pylori infected gastric mucosa may indicate an early stage of carcinogenesis. The IL-16 secretion by H. pylori can be a trigger for the expression of IGF-1R, and it may also be a factor for gastric carcinogenesis. PMID- 27499581 TI - Effect of vitamin A and Zn supplementation on indices of vitamin A status, haemoglobin level and defecation of children with persistent diarrhea. AB - To investigate the effect of vitamin A and Zn supplementation on vitamin A status, haemoglobin level and defecation of children with persistent diarrhea, a total of 160 paediatric patients were randomly assigned to one of four intervention groups: daily supplementation of 1,500 IU VA for 14 days; daily Zn supplementation for 14 days; daily supplementation with both VA and Zn for 14 days; no supplementation. One hundred twenty-seven children with persistent diarrhea finished intervention (33 were lost to follow-up). Among the 127 children, 41 (32.28%) had anaemia, 104 (81.89%) had a VA deficiency and 38 (29.92%) had an iron insufficiency. Supplementation with VA or VA + Zn enhanced the serum VA levels and ameliorated anaemia. Supplementation with Zn and VA + Zn for 5 days significantly improved defecation, where the VA + Zn treatment resulted in superior outcomes. After 14 days of intervention, the total effectiveness rates were 93.94%, 96.77% and 96.67% in the three groups, significantly greater than that of the non-supplementation group (72.73%). These results indicate that single VA or concurrent VA + Zn supplementation can improve vitamin A status, haemoglobin level and defecation. However, concurrent VA + Zn supplementation is the optimal option and can shorten the duration of persistent diarrhea and markedly improve nutritional status. (www.clinicaltrials.gov registration number: ChiCTR-IOR-14005498). PMID- 27499582 TI - Comparison of the gut microbial community between obese and lean peoples using 16S gene sequencing in a Japanese population. AB - Altered gut microbial ecology contributes to the development of metabolic diseases including obesity. In this study, we performed 16S rRNA sequence analysis of the gut microbiota profiles of obese and lean Japanese populations. The V3-V4 hypervariable regions of 16S rRNA of fecal samples from 10 obese and 10 lean volunteers were sequenced using the Illumina MiSeq(TM)II system. The average body mass index of the obese and lean group were 38.1 and 16.6 kg/m(2), respectively (p<0.01). The Shannon diversity index was significantly higher in the lean group than in the obese group (p<0.01). The phyla Firmicutes and Fusobacteria were significantly more abundant in obese people than in lean people. The abundance of the phylum Bacteroidetes and the Bacteroidetes/Firmicutes ratio were not different between the obese and lean groups. The genera Alistipes, Anaerococcus, Corpococcus, Fusobacterium and Parvimonas increased significantly in obese people, and the genera Bacteroides, Desulfovibrio, Faecalibacterium, Lachnoanaerobaculum and Olsenella increased significantly in lean people. Bacteria species possessing anti-inflammatory properties, such as Faecalibacterium prausnitzii, increased significantly in lean people, but bacteria species possessing pro-inflammatory properties increased in obese people. Obesity-associated gut microbiota in the Japanese population was different from that in Western people. PMID- 27499583 TI - Persistent reflux symptoms cause anxiety, depression, and mental health and sleep disorders in gastroesophageal reflux disease patients. AB - Some patients with gastroesophageal reflux disease experience persistent reflux symptoms despite proton pump inhibitor therapy. These symptoms reduce their health-related quality of life. Our aims were to evaluate the relationship between proton pump inhibitor efficacy and health-related quality of life and to evaluate predictive factors affecting treatment response in Japanese patients. Using the gastroesophageal reflux disease questionnaire, 145 gastroesophageal reflux disease patients undergoing proton pump inhibitor therapy were evaluated and classified as responders or partial-responders. Their health-related quality of life was then evaluated using the 8-item Short Form Health Survey, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale questionnaires. Sixty-nine patients (47.6%) were partial responders. These patients had significantly lower scores than responders in 5/8 subscales and in the mental health component summary of the 8-item Short Form Health Survey. Partial responders had significantly higher Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale scores, including anxiety and depression scores, than those of responders. Non-erosive reflux disease and double proton pump inhibitor doses were predictive factors of partial responders. Persistent reflux symptoms, despite proton pump inhibitor therapy, caused mental health disorders, sleep disorders, and psychological distress in Japanese gastroesophageal reflux disease patients. PMID- 27499584 TI - Erratum. AB - [This corrects the article DOI: 10.3164/jcbn.15-90.]. PMID- 27499586 TI - An objectively-analyzed method for measuring the useful penetration of x-ray imaging systems. AB - The ability to detect wires is an important capability of the cabinet x-ray imaging systems that are used in aviation security as well as the portable x-ray systems that are used by domestic law enforcement and military bomb squads. A number of national and international standards describe methods for testing this capability using the so called useful penetration test metric, where wires are imaged behind different thicknesses of blocking material. Presently, these tests are scored based on human judgments of wire visibility, which are inherently subjective. We propose a new method in which the useful penetration capabilities of an x-ray system are objectively evaluated by an image processing algorithm operating on digital images of a standard test object. The algorithm advantageously applies the Radon transform for curve parameter detection that reduces the problem of wire detection from two dimensions to one. The sensitivity of the wire detection method is adjustable and we demonstrate how the threshold parameter can be set to give agreement with human-judged results. The method was developed to be used in technical performance standards and is currently under ballot for inclusion in a US national aviation security standard. PMID- 27499587 TI - Error Propagation Dynamics of PIV-based Pressure Field Calculations: How well does the pressure Poisson solver perform inherently? AB - Obtaining pressure field data from particle image velocimetry (PIV) is an attractive technique in fluid dynamics due to its noninvasive nature. The application of this technique generally involves integrating the pressure gradient or solving the pressure Poisson equation using a velocity field measured with PIV. However, very little research has been done to investigate the dynamics of error propagation from PIV-based velocity measurements to the pressure field calculation. Rather than measure the error through experiment, we investigate the dynamics of the error propagation by examining the Poisson equation directly. We analytically quantify the error bound in the pressure field, and are able to illustrate the mathematical roots of why and how the Poisson equation based pressure calculation propagates error from the PIV data. The results show that the error depends on the shape and type of boundary conditions, the dimensions of the flow domain, and the flow type. PMID- 27499585 TI - Fifteen years of cold matter on the atom chip: promise, realizations, and prospects. AB - Here we review the field of atom chips in the context of Bose-Einstein Condensates (BEC) as well as cold matter in general. Twenty years after the first realization of the BEC and 15 years after the realization of the atom chip, the latter has been found to enable extraordinary feats: from producing BECs at a rate of several per second, through the realization of matter-wave interferometry, and all the way to novel probing of surfaces and new forces. In addition, technological applications are also being intensively pursued. This review will describe these developments and more, including new ideas which have not yet been realized. PMID- 27499588 TI - Greetings from the new chief editors. PMID- 27499589 TI - Calcium fortification or supplementation in postmenopausal females: Recent controversy. PMID- 27499590 TI - Coronary artery disease and its association with Vitamin D deficiency. AB - Coronary artery disease (CAD) has become the latest scourge of humankind and referred to in this article as CAD, is the end result of the accumulation of atheromatous plaques within the walls of coronary arteries that supply the myocardium, a process also known as atherosclerosis and manifests mostly in the form of chronic stable angina or acute coronary syndrome. Vitamin D has attracted considerable interest recently due to its role in a number of extraskeletal disease processes including multiple sclerosis, malignancies, diabetes mellitus, and CAD. It is also known as sunshine vitamin due to its production in the body following exposure to ultraviolet rays, and it is a unique vitamin as it acts like a hormone with its receptor present in a wide range of tissues including endothelium, which is the important mediator of atherosclerosis and subsequent CAD. A large number of studies conducted in the past have provided the basic scientific framework and this article attempts to explore the role of Vitamin D deficiency in the pathogenesis of CAD and stresses the need for further research to fill up gap in our knowledge. PMID- 27499591 TI - Role of therapeutic fasting in women's health: An overview. AB - Fasting is a therapeutic tool practiced since millennia by different cultures and medical systems heterogeneously. PubMed and Google Scholar search engines were searched using the keywords "fasting," "intermittent fasting," "calorie restriction," "women's health," "women's disorders," "fasting and aging," and "fasting and health." All the animal and human studies which address women's health and disorders were included in the review. Fasting has shown to improve the reproductive and mental health. It also prevents as well as ameliorates cancers and musculoskeletal disorders which are common in middle-aged and elderly women. The present studies available have limitations such as majority of the studies are preclinical studies and human studies are with lesser sample size. Future studies should address this gap by designing medically supervised fasting techniques to extract better evidence. Nevertheless, fasting can be prescribed as a safe medical intervention as well as a lifestyle regimen which can improve women's health in many folds. PMID- 27499593 TI - Type II endometrial cancers: A case series. AB - INTRODUCTION: Endometrial carcinoma ranks 3(rd) in India among gynecological malignancies. Endometrial cancer (EC) can be classified into two distinct groups type I and type II, based on histology, which differs in molecular, clinical and histopathological profiles. Type II is nonestrogen dependent, nonendometrioid, more aggressive and carries poor prognosis. Although type II cancers contribute only about 10% of EC incidence, they present at advanced age and cause approximately 50% recurrence and deaths with a low 5-year, overall survival rate. Type II EC are also characterized by genetic alterations in p53, human epidermal growth factor-2/neu, p16 and E-cadherin. MATERIALS AND METHODS: Endometrial carcinomas diagnosed from endometrial biopsies and hysterectomy specimens received in the Department of Pathology, Kasturba Medical College, Mangalore, from January 2007 to June 2012 were included in the study. Clinicopathological analysis of the 84 cases of EC was done with emphasis on morphology. p53 immunostaining was performed in two cases of serous carcinoma. RESULTS: Out of a total of 84 cases of EC, ten cases were of type II (11.9%). Out of which, eight were serous carcinoma (9.5%) and two clear cell (2.4%). p53 immunostain was strongly positive in the serous papillary carcinomas. The age of the patients ranged from 45 to 75 years. Myometrial invasion was more than half. Treatment was hysterectomy followed by aggressive chemotherapy. CONCLUSION: Of the type II EC, serous carcinoma is the most common type. Clinical presentation and prognosis differs in comparison to type I EC, thus the recognition of this type of EC is pivotal. PMID- 27499592 TI - Postoperative pain relief following hysterectomy: A randomized controlled trial. AB - BACKGROUND: Women experience moderate to severe postoperative pain following total abdominal hysterectomy (TAH). The transversus abdominis plane (TAP) block is a new modality for providing postoperative pain relief in these patients. MATERIALS AND METHODS: The present study was a single center, prospective randomized trial. After the Institutional Ethics Committee approval and informed consent, patients were randomized to either epidural group: Epidural block placement + general anesthesia (GA) or TAP group: Single shot TAP block + GA. Patients in both the groups received standard general anesthetic technique and intravenous tramadol patient-controlled analgesia in the postoperative period. Patients were monitored for tramadol consumption, visual analog scale (VAS) both at rest and on coughing, hemodynamics, and side effects at 0, 2, 4, 6, 8, 12, and 24 h postoperatively. RESULTS: The total consumption of tramadol in 24 h was greater in TAP group as compared to epidural group (68.8 [25.5] vs. 5.3 [11.6] mg, P < 0.001). The VAS scores at rest and on coughing were higher in TAP group as compared to the epidural group at 6, 8, 12, and 24 h postoperatively (P < 0.05). None of the patients in either group had any adverse effects. CONCLUSION: Epidural analgesia provided greater tramadol-sparing effect with superior analgesia postoperatively as compared to TAP block in patients up to 24 h following TAH. PMID- 27499594 TI - Abnormal uterine bleeding in perimenopausal women: Correlation with sonographic findings and histopathological examination of hysterectomy specimens. AB - BACKGROUND: Abnormal uterine bleeding (AUB) is a frequently encountered gynecologic complaint in perimenopausal woman and also the most common cause of hysterectomy in this age group. OBJECTIVE: Evaluation of various clinical presentations of perimenopausal AUB and it is ultrasonographic and histopathological correlation of hysterectomy specimens. MATERIALS AND METHODS: This study was carried out in the Department of Obstetrics and Gynaecology among perimenopausal women who underwent hysterectomy for AUB. The clinical presentations, ultrasonographic findings, and histopathological reports of hysterectomy specimen were correlated. RESULTS: Among 103 number of hysterectomized cases for AUB, most of the patients were between 40 and 45 years of age (67.97%) and menorrhagia was the dominant clinical presentation. The majority (45.63%) of cases were diagnosed as fibroid uterus by ultrasonography with 89.13% sensitivity and 89.47% specificity. Histopathological reports of myometrium showed 44.66% fibromyoma, followed by 34.95% of the normal myometrium. Histopathology of endometrium revealed hyperplasia in the most cases (56.31%) where simple typical type was the predominant. CONCLUSION: Uterine fibroid was the leading cause of AUB and radiological, pathological evaluation correlated well to diagnose fibroid. PMID- 27499595 TI - Clinical, radiological, and histopathological analysis of paraovarian cysts. AB - INTRODUCTION: Paraovarian cyst arise from either mesothelium or from paramesonephric remnant. These present as either adneal mass or as an incidental finding. Diagnosis is usually established on ultrasound and it is important to differentiate these from ovarian cyst. MATERIAL AND METHODS: The present study is a retrospective analysis of 32 women with a confirmed diagnosis of paraovarian cyst after surgery. The clinical profile, symptoms and radiological findings of these patients were noted from the hospital records. A correlation was made with the surgical findings and the final histopathological diagnosis. RESULTS: Only 2 patients were postmenopausal and one case was diagnosed during pregnancy. Ultrasound accurately diagnosed paraovarian cyst in 87.5% patients. 78% paraovarian cysts were found to be simple and none had any malignant change. We reported a higher incidence of cystic adenomatoid tumor in these paraovarian cysts. CONCLUSION: In our study, most paraovarian cysts occur in reproductive age group and present as an adnexal mass. Ultrasound is the diagnostic modality and a paraovarian cyst needs to be differentiated from ovarian cyst. Most of them were simple cysts on histopathology. PMID- 27499596 TI - Burgeoning menopausal symptoms: An urgent public health concern. AB - INTRODUCTION: Demographic and epidemiological transitions have increased the life expectancy of people in India. This has resulted in higher burden of morbidities related to aging. The National Health programmes have focused mainly on the health of women in reproductive age groups and neglected their health thereafter. Thus, there is a need to explore the bio-social correlates of menopausal symptoms among women, which can influence their quality of life. SUBJECTS AND METHODS: This cross-sectional community-based study was conducted in the urban slum of Mysore for 3 months. A total of 100 postmenopausal women in the age group of 40 65 years residing in the field practice area of Urban Health Training Centre were selected by simple random sampling method from the database of households. Details regarding socio-demographic characteristics, postmenopausal symptoms, and factors associated with them were collected in a pretested structured pro forma by interview technique. RESULTS: Among 100 women included in the present study, mean age at menarche and menopause was 13.45 +/- 1.72 and 46.7 +/- 5.2 years, respectively. The most common postmenopausal symptom was joint pain (92%) followed by physical and mental exhaustion (84%), depression (76%), irritability (73%), hot flushes, and night sweats (65%). There was a significant positive correlation between age of the women, duration of life after menopause, and postmenopausal symptoms. CONCLUSION: There is a high burden of postmenopausal symptoms which have shown an increasing trend with advancement of age. This calls for establishment of specific health interventions for postmenopausal women in the health-care settings. PMID- 27499597 TI - Xanthogranulomatous endometritis presenting as pyometra and mimicking carcinoma on imaging. AB - Xanthogranulomatous endometritis (XGE) is an uncommon but well-established histopathological entity seen affecting the kidney and gallbladder. Involvement of the endometrium is very rare, with only a few case reports in world literature till date. Histologically, it is characterized by the replacement of the endometrium by sheets of foamy histiocytes, plasma cells, lymphocytes, giant cells, and siderophages. We present a case of a 74-year-old female who presented with foul-smelling discharge and postmenopausal bleeding of a short duration. Clinical examination and imaging studies revealed a pyometra, cervical stenosis. A suspicion of carcinoma was raised. Since XGE may mimic an endometrial carcinoma clinically and pathologically, knowledge of this unusual and rare inflammatory pathology is important for both the gynecologists and the pathologists. PMID- 27499598 TI - Complete molar pregnancy in postmenopausal women. AB - Gestational trophoblastic disease (GTD) is an abnormal proliferation of trophoblastic tissue during pregnancy. It is a disease of reproductive age, and a few cases have also been seen in women with advanced age, although it is extremely rare in postmenopausal women. Here, we describe an uncommon case of complete hydatidiform mole (CHM) in a postmenopausal woman, who has presented to us with complaints of bleeding per vagina, vomiting with 22 weeks size gravid uterus. Ultrasound finding along with raised serum beta-human chorionic gonadotropin (beta-HCG) 400,000 mIU/ml suggested the diagnosis of CHM. In view of postmenopausal status and future risk of postmolar gestational trophoblastic neoplasia, we performed a total abdominal hysterectomy. Uterus was 20 cm * 15 cm * 15 cm filled with cystic, grapes such as vesicles. Microscopic examination demonstrated generalized trophoblastic proliferation with hydropic degenerated villi suggested of benign CHM. Follow-up showed steady fall in serum beta-HCG level and no evidence of any residual disease. A suspicion of GTD should be kept in mind while evaluating a patient with peri- or post-menopausal bleeding so that it will prevent a delay in diagnosis and treatment. PMID- 27499599 TI - A rare case of renal metastasis from squamous cell carcinoma of the cervix. AB - Cervical cancer is the most frequent type of cancer in women in many developing countries. Squamous cell carcinoma of the cervix spreads principally by lymphatics and less commonly through blood vessels. The most frequent sites for those who develop distant metastasis include lungs (21%), lumbar and thoracic spine (16%), and para-aortic lymph nodes (7%). Metastasis to the kidney is extremely rare with <10 previously reported cases. We report a case of renal metastasis from squamous cell carcinoma of the cervix detected in end-stage kidney due to hydronephrosis. PMID- 27499600 TI - A transvaginal removal and repair of vesicovaginal fistula due to mesh erosion. AB - Vesicovaginal fistula (VVF) is a devastating social problem. It can either result from obstetric trauma or following gynecological surgeries, malignancy, or radiation. We present a case of a 70-year-old woman who had a VVF following mesh augmentation surgery for anterior compartment prolapse. She required a transvaginal removal of the eroded mesh followed by a transvaginal repair of VVF using a Martius flap, 6 weeks later. Transvaginal removal of mesh is technically feasible and a good approach. Timing and route of surgery should be individualized. PMID- 27499601 TI - Temporary agency work, migration and the crisis in Greece: labour market segmentation intensified. AB - This article focuses on the under-researched temporary agency employment in Greece. It shows that the development of the temporary employment agency sector has gone hand in hand with the flow of undocumented and exploitable migrant labour in Greece over the past 25 years, reflecting the segmentation of the Greek labour market along ethnic lines. Using empirical research evidence on the operation of temporary employment agencies in the Greek hospitality and health care sectors, the article highlights the precarious or even illicit nature of agency employment in a context in which labour outsourcing and flexible employment are promoted by policy-makers. Last but not least, it suggests that the segmented landscape of the Greek labour market has become more complex during the economic crisis, with more and more Greeks drawn to agency-mediated precarious employment. PMID- 27499602 TI - Implications of Teacher Life-Work Histories for Conceptualisations of 'Care': Narratives from Rural Zimbabwe. AB - Schools are increasingly seen as key sites for support to HIV-affected and other vulnerable children, and teachers are assigned the critical role of identifying and providing psychosocial support. Drawing on the life-work history narratives of 12 teachers in Zimbabwe, this paper explores the psychosocial processes underpinning teachers' conceptualisations of these caring roles. The influence of prolonged adversity, formative relationships, and broader patterns of social and institutional change in teacher identity formation processes speak to the complex and embodied nature of understandings of 'care'. In such extreme settings teachers prioritise the material and disciplinary aspects of 'care' that they see as essential for supporting children to overcome hardship. This focus not only means that emotional support as envisaged in international policy is commonly overlooked, but also exposes a wider ideological clash about childrearing. This tension together with an overall ambivalence surrounding teacher identities puts further strain on teacher-student relationships. We propose the current trainings on providing emotional support are insufficient and that more active focus needs to be directed at support to teachers in relation with their students. (c) 2015 The Authors. Journal of Community & Applied Social Psychology published by John Wiley & Sons Ltd. PMID- 27499603 TI - Identification of novel natural compound inhibitors for human complement component 5a receptor by homology modeling and virtual screening. AB - ABSTRACT: Neuropathic pain and inflammatory pain are two common types of pathological pain in human health problems. To date, normal painkillers are only partially effective in treating such pain, leading to a tremendous demand to develop new chemical entities to combat pain and inflammation. A promising pharmacological treatment is to control signal transduction via the inflammatory mediator-coupled receptor protein C5aR by finding antagonists to inhibit C5aR activation. Here, we report the first computational study on the identification of non-peptide natural compound inhibitors for C5aR by homology modeling and virtual screening. Our study revealed a novel natural compound inhibitor Acteoside with better docking scores than all four existing non-peptidic natural compounds. The MM-GBSA binding free energy calculations confirmed that Acteoside has a decrease of ~39 kcal/mol in the free energy of binding compared to the strongest binding reference compound. Main contributions to the higher affinity of Acteoside to C5aR are the exceptionally strong lipophilic interaction, enhanced electrostatics and hydrogen bond interactions. Detailed analysis on the physiochemical properties of Acteoside suggests further directions in lead optimization. Taken together, our study proposes that Acteoside is a potential lead molecule targeting the C5aR allosteric site and provides helpful information for further experimental studies. GRAPHICAL ABSTRACT: PMID- 27499604 TI - Synthesis, antibacterial and antiproliferative potential of some new 1 pyridinecarbonyl-4-substituted thiosemicarbazide derivatives. AB - In this study, the antibacterial, cytotoxic and antiproliferative activities of novel thiosemicarbazide derivatives were assessed. Our results demonstrated that some of the novel compounds possess good antibacterial properties against Staphylococcus epidermidis, Streptococcus mutans and Streptococcussanguinis and are only slightly cytotoxic; thus, they exhibit an excellent therapeutic index, which is higher than that of ethacridine lactate. Moreover, our data showed that compounds 2 and 4 have an antiproliferative activity against human breast adenocarcinoma and human hepatocellular carcinoma cell lines. We expect that the novel thiosemicarbazide derivatives can be used as agents for treatment of dental caries and also for chemotherapy support. PMID- 27499605 TI - Anisotropic fractional diffusion tensor imaging. AB - Traditional diffusion tensor imaging (DTI) maps brain structure by fitting a diffusion model to the magnitude of the electrical signal acquired in magnetic resonance imaging (MRI). Fractional DTI employs anomalous diffusion models to obtain a better fit to real MRI data, which can exhibit anomalous diffusion in both time and space. In this paper, we describe the challenge of developing and employing anisotropic fractional diffusion models for DTI. Since anisotropy is clearly present in the three-dimensional MRI signal response, such models hold great promise for improving brain imaging. We then propose some candidate models, based on stochastic theory. PMID- 27499606 TI - Emotion Regulation Therapy for Generalized Anxiety Disorder. AB - Despite the success of cognitive behavioral therapies (CBT) for emotional disorders, a sizable subgroup of patients with complex clinical presentations, such as patients with generalized anxiety disorder, fails to evidence adequate treatment response. Emotion Regulation Therapy (ERT) integrates facets of traditional and contemporary CBTs, mindfulness, and emotion-focused interventions within a framework that reflects basic and translational findings in affect science. Specifically, ERT is a mechanism-targeted intervention focusing on patterns of motivational dysfunction while cultivating emotion regulation skills. Open and randomized controlled psychotherapy trials have demonstrated considerable preliminary evidence for the utility of this approach as well as for the underlying proposed mechanisms. This article provides an illustration of ERT through the case of "William." In particular, this article includes a case conceptualization of William from an ERT perspective while describing the flow and progression of the ERT treatment approach. PMID- 27499607 TI - Advances in Photocatalysis: A Microreview of Visible Light Mediated Ruthenium and Iridium Catalyzed Organic Transformations. AB - Photocatalytic organic transformations utilizing ruthenium and iridium complexes have garnered significant attention due to the access they provide to new synthetic spaces through new reaction mechanisms. A survey of the photophysical data and the diversity of transformations that may be accomplished utilizing commercially available photocatalysts is contained herein. PMID- 27499610 TI - Comments on: Probability Enhanced Effective Dimension Reduction for Classifying Sparse Functional Data. PMID- 27499609 TI - Tissue factor induces VEGF expression via activation of the Wnt/beta-catenin signaling pathway in ARPE-19 cells. AB - PURPOSE: The purpose of the present study was to investigate the potential signal mechanism of tissue factor (TF) in the regulation of the expression of vascular endothelial growth factor (VEGF) in human retinal pigment epithelial (ARPE-19) cells. METHODS: An in vitro RPE cell chemical hypoxia model was established by adding cobalt chloride (CoCl2) in the culture medium. The irritative concentration of CoCl2 was determined with a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay kit. VEGF production in ARPE-19 cells was measured with enzyme-linked immunosorbent assay (ELISA) and western blotting. The Wnt signaling pathway-associated molecules, including phospho-glycogen synthase kinase 3beta (p-GSK3beta), GSK3beta, p-beta-catenin and beta-catenin, were detected with western blotting. pEGFP-N3-hTF was constructed and verified with digestion of the restriction enzyme and sequencing analysis. Human TF overexpression and silencing plasmids were transfected into the ARPE-19 cells to clarify the causal relationship between TF and VEGF expression. The Transwell coculture system of ARPE-19 cells and RF/6A rhesus macaque choroid-retinal endothelial cells was performed to evaluate cell invasion and tube formation ability. RESULTS: Our anoxic model of ARPE-19 cells showed that TF expression was upregulated in accordance with variations in hypoxia-inducible factor 1-alpha (HIF-1alpha) and VEGF levels. Silencing and overexpression of TF decreased and increased VEGF expression, respectively. The Wnt/beta-catenin signaling pathway played an important role in this effect. Results from the ARPE-19 cell and RF/6A cell coculture system showed that the enhancement of TF expression in the ARPE-19 cells led to significantly faster invasion and stronger tube-forming ability of the RF/6A cells, while siRNA-mediated TF silencing caused the opposite effects. Pharmacological disruption of Wnt signaling IWR-1-endo inhibited the effects compared to the TF-overexpressing group, indicating the importance of the Wnt/beta-catenin signaling pathway in the process of TF-induced VEGF expression and angiogenesis. CONCLUSIONS: Involvement of the activation of the Wnt/beta catenin signaling pathway is an important mediator for TF-induced VEGF production during the process of angiogenesis. Thus, our findings may ascertain the molecular regulation of TF in neovessel formation and show significant therapeutic implications. PMID- 27499611 TI - Axial length, refraction, and retinal vascularization 1 year after ranibizumab or bevacizumab treatment for retinopathy of prematurity. AB - PURPOSE: The purpose of this study was to report on the axial length, refraction, and retinal vascularization 1 year after ranibizumab or bevacizumab treatment for threshold retinopathy of prematurity. METHODS: The authors conducted a comparative, consecutive, original study. RESULTS: Twenty-five eyes of 13 patients with threshold retinopathy of prematurity received one intravitreal ranibizumab treatment, and 15 eyes of eight patients received one intravitreal bevacizumab treatment. In the ranibizumab group, the mean gestational age was 26.15+/-2.08 weeks, with a mean birth weight of 811.15+/-287.3 g. In the bevacizumab group, the mean gestational age was 26.50+/-2.14 weeks, with a mean birth weight of 938.38+/-200.4 g. The mean axial length was 20.34+/-0.97 mm and the mean spherical equivalent was 0.46+/-1.36 D in the ranibizumab group, with complete vascularization in 15 of 25 (60%) eyes. The mean axial length was 20.91+/-1.54 mm and the mean spherical equivalent was -0.60+/-3.86 D in the bevacizumab group, with complete vascularization in seven of 15 (46.7%) eyes. CONCLUSION: There were no significant differences in the axial length and refraction between children with threshold retinopathy of prematurity who received intravitreal bevacizumab compared to those who received ranibizumab after 1 year of follow-up. It appeared that the ranibizumab treatment could achieve more complete retinal vascularization than the bevacizumab treatment; however, there was no statistical significance and long-term follow-up is needed. PMID- 27499608 TI - The cellular and compartmental profile of mouse retinal glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and ~P transferring kinases. AB - PURPOSE: The homeostatic regulation of cellular ATP is achieved by the coordinated activity of ATP utilization, synthesis, and buffering. Glucose is the major substrate for ATP synthesis through glycolysis and oxidative phosphorylation (OXPHOS), whereas intermediary metabolism through the tricarboxylic acid (TCA) cycle utilizes non-glucose-derived monocarboxylates, amino acids, and alpha ketoacids to support mitochondrial ATP and GTP synthesis. Cellular ATP is buffered by specialized equilibrium-driven high-energy phosphate (~P) transferring kinases. Our goals were twofold: 1) to characterize the gene expression, protein expression, and activity of key synthesizing and regulating enzymes of energy metabolism in the whole mouse retina, retinal compartments, and/or cells and 2) to provide an integrative analysis of the results related to function. METHODS: mRNA expression data of energy-related genes were extracted from our whole retinal Affymetrix microarray data. Fixed-frozen retinas from adult C57BL/6N mice were used for immunohistochemistry, laser scanning confocal microscopy, and enzymatic histochemistry. The immunoreactivity levels of well characterized antibodies, for all major retinal cells and their compartments, were obtained using our established semiquantitative confocal and imaging techniques. Quantitative cytochrome oxidase (COX) and lactate dehydrogenase (LDH) activity was determined histochemically. RESULTS: The Affymetrix data revealed varied gene expression patterns of the ATP synthesizing and regulating enzymes found in the muscle, liver, and brain. Confocal studies showed differential cellular and compartmental distribution of isozymes involved in glucose, glutamate, glutamine, lactate, and creatine metabolism. The pattern and intensity of the antibodies and of the COX and LDH activity showed the high capacity of photoreceptors for aerobic glycolysis and OXPHOS. Competition assays with pyruvate revealed that LDH-5 was localized in the photoreceptor inner segments. The combined results indicate that glycolysis is regulated by the compartmental expression of hexokinase 2, pyruvate kinase M1, and pyruvate kinase M2 in photoreceptors, whereas the inner retinal neurons exhibit a lower capacity for glycolysis and aerobic glycolysis. Expression of nucleoside diphosphate kinase, mitochondria-associated adenylate kinase, and several mitochondria-associated creatine kinase isozymes was highest in the outer retina, whereas expression of cytosolic adenylate kinase and brain creatine kinase was higher in the cones, horizontal cells, and amacrine cells indicating the diversity of ATP-buffering strategies among retinal neurons. Based on the antibody intensities and the COX and LDH activity, Muller glial cells (MGCs) had the lowest capacity for glycolysis, aerobic glycolysis, and OXPHOS. However, they showed high expression of glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate thiokinase, GABA transaminase, and ~P transferring kinases. This suggests that MGCs utilize TCA cycle anaplerosis and cataplerosis to generate GTP and ~P transferring kinases to produce ATP that supports MGC energy requirements. CONCLUSIONS: Our comprehensive and integrated results reveal that the adult mouse retina expresses numerous isoforms of ATP synthesizing, regulating, and buffering genes; expresses differential cellular and compartmental levels of glycolytic, OXPHOS, TCA cycle, and ~P transferring kinase proteins; and exhibits differential layer-by-layer LDH and COX activity. New insights into cell-specific and compartmental ATP and GTP production, as well as utilization and buffering strategies and their relationship with known retinal and cellular functions, are discussed. Developing therapeutic strategies for neuroprotection and treating retinal deficits and degeneration in a cell-specific manner will require such knowledge. This work provides a platform for future research directed at identifying the molecular targets and proteins that regulate these processes. PMID- 27499612 TI - Characterization of the serological biomarkers associated with Sjogren's syndrome in patients with recalcitrant dry eye disease. AB - PURPOSE: The purpose was to characterize the biomarkers associated with Sjogren's syndrome (SS) identified in the serological samples of patients with recalcitrant dry eye disease; additionally, the modalities utilized in the treatment of dry eye disease were evaluated for subsets of patients with and without SS. PATIENTS AND METHODS: Data for this retrospective, single-center, pilot study were based on a chart review of 48 sequential patients with recalcitrant dry eye who were evaluated for SS via serological analysis. Data presented include the presence of the autoantibodies identified through the serological biomarker analysis and identification of the concurrent dry eye treatment modalities. RESULTS: Eleven out of 48 patients (23%) tested positive for biomarkers associated with SS. Autoantibodies for salivary protein-1, parotid secretory protein 1, and carbonic anhydrase VI, markers associated with the early development of SS, were detected in 91% (ten out of eleven) of the patients who tested positive for SS, whereas 27% (three out of eleven) of patients tested positive for the traditional SS markers, SS-A and/or SS-B. Common treatment modalities utilized in SS patients included omega-3 supplements (82%), topical cyclosporine (74%), and artificial tear solutions (64%), as compared to omega-3 supplements (80%), hot-mask therapy (77%), and artificial tear solutions (77%), in SS-negative patients. CONCLUSION: Evaluation for salivary protein-1, parotid secretory protein 1, and carbonic anhydrase VI biomarkers allows for identification of a subset of patients with biomarkers associated with SS that may not be identified through the traditional assessments (SS-A/SS-B). Earlier recognition of SS biomarkers allows for a confirmatory diagnosis and appropriate management of this systemic, progressive condition. PMID- 27499613 TI - Frequency and risk factors associated with dry eye in patients attending a tertiary care ophthalmology center in Mexico City. AB - PURPOSE: The purpose of this study was to ascertain the frequency and risk factors of dry eye (DE) among patients attending a tertiary care ophthalmology center in Mexico. METHODS: Approximately 338 consecutive new patients attending a tertiary care ophthalmology center in Mexico City underwent an ocular surface examination, which included tear film break-up time, fluorescein corneal staining, Schirmer's test, and evaluation of meibum quality. Symptoms of DE were evaluated by the Ocular Surface Disease Index and Dry Eye Questionnaire-5. Information on demographics, exposures, past medical and ocular history, and medications was also collected. RESULTS: The frequency of severe DE symptoms was found to be 43% based on the Ocular Surface Disease Index and 30% based on Dry Eye Questionnaire-5. Risk factors significantly associated with increased DE symptoms included dry mouth and gastrointestinal ulcer medications. With regard to signs, aqueous tear deficiency was a less-frequent finding (22%) in our population than evaporative deficiency (94%). Risk factors associated with aqueous tear deficiency were dry mouth and diuretic use. No risk factors were associated with evaporative deficiency. Risk factors associated with meibomian gland dysfunction included old age, male sex, arthritis, and use of an antihypertensive. The only risk factor associated with corneal staining was dry mouth. CONCLUSION: This is the first study to demonstrate the frequency of symptomatic and clinical DE in a tertiary care ophthalmology center in Mexico. The frequency of DE ranged from 30% using a symptomatic definition to 94% using objective measures. Different risk factors were found for different aspects of DE, suggesting differing underlying pathophysiologies behind different DE subtypes. PMID- 27499614 TI - The psychometric properties of Chinese version of SCI Exercise Self-Efficacy Scale in patients with stroke. AB - OBJECTIVE: To test the Chinese version of the SCI Exercise Self-Efficacy Scale (C ESES) in stroke patients and evaluate its validity and reliability. BACKGROUND: Physical inactivity is a well established and changeable risk factor for stroke, and regular exercise of 3-7 days per week is essential for stroke survivors and the general population. Though regular exercise is beneficial, it has been proved that duration, frequency, and intensity of exercise are generally low in stroke survivors. METHODS: The performance of the instrument was assessed in 350 Chinese stroke survivors and repeated in 50 patients to examine test-retest reliability. Questionnaires included a form on demographic and socioeconomic characteristics, C-ESES, and the Chinese version of the General Self-Efficacy Scale. The AMOS 20.0 and SPSS 17.0 were chosen to evaluate their validity and reliability. RESULTS: Even though 350 participants answered the questionnaires in the present study, useful data were obtained from 321 participants (response rate: 91.71%). Correlation between item and the total scale score (Item-Total Correlation) ranged from 0.551 to 0.718, indicating that no item needed to be omitted; two factors, with factor loading 0.620 and 0.806, were obtained from an exploratory principal components analysis, assuming 59.745% of the total variance. The two factors were named internal motivation and external motivation. A confirmatory factor analysis supported the results with a suitable model (chi (5)=291.157; df=185; P<0.001; root mean square error of approximation =0.044; goodness-of-fit index =0.938; adjusted goodness-of-fit index =0.914; comparative fit index =0.858). The C-ESES correlated well with the validated General Self-Efficacy Scale (r=0.827, P<0.01). Good internal consistency (Cronbach's alpha=0.757 to 0.879) and test-retest reliability (r=0.750, P<0.01) were obtained. CONCLUSION: The C-ESES is a short, easy to understand, and psychometrically sound measurement to evaluate exercise self-efficacy in Chinese-speaking stroke survivors. PMID- 27499615 TI - Alexithymia in patients with type 2 diabetes mellitus: the role of anxiety, depression, and glycemic control. AB - OBJECTIVE: This study was aimed at determining the prevalence of alexithymia in patients with type 2 DM and the factors affecting it. METHODS: This cross sectional study was conducted with 326 patients with type 2 DM. Study data were collected with the Personal Information Form, Toronto Alexithymia Scale, and Hospital Anxiety and Depression Scale. Glycemic control was assessed by glycated haemoglobin (HbA1c) results. The analysis was performed using descriptive statistics, chi-square test, Pear-son's correlation, and logistic regression analysis. RESULTS: Of the patients, 37.7% were determined to have alexithymia. A significant relationship was determined between alexithymia and HbA1c, depression, and anxiety. According to binary logistic regression analyses, alexithymia was 2.63 times higher among those who were in a paid employment than those who were not, 2.09 times higher among those whose HbA1c levels were >=7.0% than those whose HbA1c levels were <7.0%, 3.77 times higher among those whose anxiety subscale scores were >=11 than those whose anxiety subscale scores were <=10, and 2.57 times higher among those whose depression subscale scores were >=8 than those whose depression subscale scores were <=7. CONCLUSION: In this study, it was determined that two out of every five patients with DM had alexithymia. Therefore, their treatment should be arranged to include mental health care services. PMID- 27499616 TI - Sex differences in the quality of life of patients with acute coronary syndrome treated with percutaneous coronary intervention after a 3-year follow-up. AB - BACKGROUND: The aims of this study were to analyze the dynamics of quality of life (QoL) changes after 36 months from the percutaneous coronary intervention (PCI) depending on sex and identify baseline predictors of the follow-up QoL of patients hospitalized for acute coronary syndrome (ACS) and subjected to PCI. METHODS AND RESULTS: The study included 137 patients, females (n=67) and males (n=70), with ACS who underwent PCI. The QoL was assessed using the MacNew Heart Disease Health-Related Quality of Life questionnaire. The group of females scored lower in all the domains of the MacNew Heart Disease Health-Related Quality of Life questionnaire in the initial measurement (B 1), in the measurement after 6 months (B 2), and in the long-term follow-up measurement (36 months - B 3). Despite the fact that both groups achieved improved QoL, its values were higher in the males. The average growth rate of the QoL score in the period from the sixth month to 36th month was higher in females than in males. In the univariate and multivariate analyses, significant independent predictors with a negative influence on the long-term QoL score included female sex (rho=-0.190, beta= 0.21), age >60 years (rho=-0.255, beta=-0.186), and diabetes (rho=-0.216, beta= 0.216). CONCLUSION: In a 36-month follow-up of ACS patients treated with PCI, there were no statistically significant differences in QoL between sexes. In the entire cohort, there was improvement in QoL, which was higher in the case of the females studied. For the entire group, significant independent determinants of lower QoL 3 years after ACS included female sex, age >60 years, and diabetes. PMID- 27499617 TI - OSG-GEM: Gene Expression Matrix Construction Using the Open Science Grid. AB - High-throughput DNA sequencing technology has revolutionized the study of gene expression while introducing significant computational challenges for biologists. These computational challenges include access to sufficient computer hardware and functional data processing workflows. Both these challenges are addressed with our scalable, open-source Pegasus workflow for processing high-throughput DNA sequence datasets into a gene expression matrix (GEM) using computational resources available to U.S.-based researchers on the Open Science Grid (OSG). We describe the usage of the workflow (OSG-GEM), discuss workflow design, inspect performance data, and assess accuracy in mapping paired-end sequencing reads to a reference genome. A target OSG-GEM user is proficient with the Linux command line and possesses basic bioinformatics experience. The user may run this workflow directly on the OSG or adapt it to novel computing environments. PMID- 27499618 TI - Legislative and ethical aspects of introducing new technologies in medical care for senior citizens in developed countries. AB - INTRODUCTION: The majority of developed countries are currently experiencing demographic aging. The most frequently expressed concerns related to the changing age structure are the increased costs of social and medical care, a lack of labor force in the job market, and financial sustainability of the pension system. These concerns are often based on the pessimistic view of population aging. This view understands aging as a prolonged period of illness and suffering. On the other hand, optimists believe that a longer life span is a result of increased quality of life and better health care. The quality of life may be improved not only by medicaments, but also by rapidly developing area of medical devices, which allow better care for seniors in many areas. AIM: This contribution aims to assess the legislative environment and ethical questions related to the use of medical devices, especially medical devices, in medical care for senior citizens. METHODS: The methods used in this study are literature reviews of legislative and ethical environment in the European Union (EU) and the US. RESULTS: Main findings of this study result from assessing the state of medical device regulations in Europe and the US. Namely, the US regulation seems to be better arranged, which is probably due to the fact that there is only one responsible body - the US Food and Drug Administration, which is responsible for all medical device regulations. On the other hand, in the EU, talks about new legislation are led by ministers from all the EU member states and it may take a long time before all the EU countries come to an agreement. PMID- 27499619 TI - The differential effects of inspiratory, expiratory, and combined resistive breathing on healthy lung. AB - Combined resistive breathing (CRB) is the hallmark of obstructive airway disease pathophysiology. We have previously shown that severe inspiratory resistive breathing (IRB) induces acute lung injury in healthy rats. The role of expiratory resistance is unknown. The possibility of a load-dependent type of resistive breathing-induced lung injury also remains elusive. Our aim was to investigate the differential effects of IRB, expiratory resistive breathing (ERB), and CRB on healthy rat lung and establish the lowest loads required to induce injury. Anesthetized tracheostomized rats breathed through a two-way valve. Varying resistances were connected to the inspiratory, expiratory, or both ports, so that the peak inspiratory pressure (IRB) was 20%-40% or peak expiratory (ERB) was 40% 70% of maximum. CRB was assessed in inspiratory/expiratory pressures of 30%/50%, 40%/50%, and 40%/60% of maximum. Quietly breathing animals served as controls. At 6 hours, respiratory system mechanics were measured, and bronchoalveolar lavage was performed for measurement of cell and protein concentration. Lung tissue interleukin-6 and interleukin-1beta levels were estimated, and a lung injury histological score was determined. ERB produced significant, load-independent neutrophilia, without mechanical or permeability derangements. IRB 30% was the lowest inspiratory load that provoked lung injury. CRB increased tissue elasticity, bronchoalveolar lavage total cell, macrophage and neutrophil counts, protein and cytokine levels, and lung injury score in a dose-dependent manner. In conclusion, CRB load dependently deranges mechanics, increases permeability, and induces inflammation in healthy rats. ERB is a putative inflammatory stimulus for the lung. PMID- 27499620 TI - A year in the life of German patients with COPD: the DACCORD observational study. AB - INTRODUCTION: Randomized interventional trials generally recruit highly selected patients. In contrast, long-term, noninterventional studies can reflect standard of care of real-life populations. DACCORD (Die ambulante Versorgung mit langwirksamen Bronchodilatatoren: COPD-Register in Deutschland [Outpatient Care With Long-Acting Bronchodilators: COPD Registry in Germany]) is an ongoing observational study, conducted in primary and secondary care in Germany, aiming to describe the impact of disease and treatments on real-life patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients had a clinical and spirometry diagnosis of COPD, were aged >=40 years, and were initiating or changing COPD maintenance medication. The only exclusion criteria were asthma and participation in a randomized clinical trial. Exacerbation data were collected every 3 months. COPD medication, COPD Assessment Test, and forced expiratory volume in 1 second (FEV1) were recorded at the end of the 1 year period. RESULTS: In the 6 months prior to baseline, 26.5% of the 3,974 patients experienced >=1 exacerbation, compared with 26.1% over the 1-year follow-up (annualized rate 0.384). Importantly, only previous exacerbations and not poor lung function alone predicted an increased exacerbation risk. There was a general shift to lower disease severity from baseline to 1 year, predominantly as a consequence of a lower proportion of patients considered at high risk due to exacerbations. COPD Assessment Test mean change from baseline was -1.9, with 48.9% of patients reporting a clinically relevant improvement. Overall persistence to medication was high, with 77.2% of patients still receiving the same class of medication at 1 year. CONCLUSION: DACCORD suggests that in clinical practice, the large majority of COPD patients are symptomatic but seldom exacerbate and that widely used tools and treatment recommendations do not reflect this fully. PMID- 27499621 TI - Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticle encapsulated aspirin and curcumin in combination with free sulforaphane in BALB/c mice. AB - Our previous studies have established the efficacy of chemopreventive regimens of aspirin and curcumin (CUR) encapsulated within solid lipid nanoparticles (SLNs) in combination with free sulforaphane (ACS combination) to prevent or delay the initiation and progression of pancreatic cancer, classified as one of the deadliest diseases with very low chances of survival upon diagnosis. Although toxicity of individual drugs and SLN has been studied previously, there are no studies in current literature that evaluate the potential toxicity of a combined regimen of ACS, especially when encapsulated within chitosan-SLNs (c-SLNs). Hence, objective of the current study was to investigate the potential toxic effects of ACS c-SLN combined chemopreventive regimens following acute (3 days), subacute (28 days), and subchronic (90 days) administrations by oral gavage in BALB/c mice. Mice were administered the following regimens: saline, blank c-SLN, low-dose ACS c-SLN (2+4.5+0.16 mg/kg), medium-dose ACS c-SLN (20+45+1.6 mg/kg), and high-dose ACS c-SLN (60+135+4.8 mg/kg). The potential toxicity was evaluated based on animal survival, body weight, hematology, blood chemistry, and organ histopathology. During 3-day, 28-day, and 90-day study periods, no animal deaths were observed. Treatment with ACS c-SLNs did not cause alteration in complete blood counts and blood chemistry data. Histopathological examination of various organ sections (pancreas, heart, liver, kidney, and brain) appeared normal. Based on the results of this study, no signs of toxicity in acute, subacute, and subchronic studies following oral administration of ACS c-SLNs were found indicating that the oral dosing regimens were safe at the levels tested for long term administration to prevent the onset of pancreatic cancer. PMID- 27499622 TI - Proretinal nanoparticles: stability, release, efficacy, and irritation. AB - Despite many potent biological activities, retinoids such as retinoic acid (RA) and retinal possess dose-related broad side effects. In this study, we show that this problem, which has been unsolvable for a long time, can be tackled through a controlled release strategy in which retinal is continuously delivered to the skin via sustained release from proretinal nanoparticles. The water dispersible proretinal nanoparticles are stable when kept in water at neutral pH and at room temperature for 8 months under light-proof conditions, and show sustained release of retinal into human synthetic sebum at a pH of 5. In the daily topical application tests performed for 4 weeks on rats' skin, the nanoparticles showed superior ability to increase epidermal thickness compared to RA and retinal, with no skin irritation observed for the proretinal particles, but severe skin irritation observed for RA and free retinal. When tested under occlusion conditions in human volunteers, insignificant skin irritation was observed for the proretinal nanoparticles. The 12-week, double-blind, split-face study on human volunteers indicates better antiaging efficacy of the particles as compared to the free RA. PMID- 27499624 TI - Endothelial glycocalyx conditions influence nanoparticle uptake for passive targeting. AB - Cardiovascular diseases are facilitated by endothelial cell (EC) dysfunction and coincide with EC glycocalyx coat shedding. These diseases may be prevented by delivering medications to affected vascular regions using circulating nanoparticle (NP) drug carriers. The objective of the present study was to observe how the delivery of 10 nm polyethylene glycol-coated gold NPs (PEG-AuNP) to ECs is impacted by glycocalyx structure on the EC surface. Rat fat pad endothelial cells were chosen for their robust glycocalyx, verified by fluorescent immunolabeling of adsorbed albumin and integrated heparan sulfate (HS) chains. Confocal fluorescent imaging revealed a ~3 um thick glycocalyx layer, covering 75% of the ECs and containing abundant HS. This healthy glycocalyx hindered the uptake of PEG-AuNP as expected because glycocalyx pores are typically 7 nm wide. Additional glycocalyx models tested included: a collapsed glycocalyx obtained by culturing cells in reduced protein media, a degraded glycocalyx obtained by applying heparinase III enzyme to specifically cleave HS, and a recovered glycocalyx obtained by supplementing exogenous HS into the media after enzyme degradation. The collapsed glycocalyx was2 um thick with unchanged EC coverage and sustained HS content. The degraded glycocalyx showed similar changes in EC thickness and coverage but its HS thickness was reduced to 0.7 um and spanned only 10% of the original EC surface. Both dysfunctional models retained six- to sevenfold more PEG-AuNP compared to the healthy glycocalyx. The collapsed glycocalyx permitted NPs to cross the glycocalyx into intracellular spaces, whereas the degraded glycocalyx trapped the PEG-AuNP within the glycocalyx. The repaired glycocalyx model partially restored HS thickness to 1.2 um and 44% coverage of the ECs, but it was able to reverse the NP uptake back to baseline levels. In summary, this study showed that the glycocalyx structure is critical for NP uptake by ECs and may serve as a passive pathway for delivering NPs to dysfunctional ECs. PMID- 27499623 TI - Nanobody-derived nanobiotechnology tool kits for diverse biomedical and biotechnology applications. AB - Owing to peculiar properties of nanobody, including nanoscale size, robust structure, stable and soluble behaviors in aqueous solution, reversible refolding, high affinity and specificity for only one cognate target, superior cryptic cleft accessibility, and deep tissue penetration, as well as a sustainable source, it has been an ideal research tool for the development of sophisticated nanobiotechnologies. Currently, the nanobody has been evolved into versatile research and application tool kits for diverse biomedical and biotechnology applications. Various nanobody-derived formats, including the nanobody itself, the radionuclide or fluorescent-labeled nanobodies, nanobody homo- or heteromultimers, nanobody-coated nanoparticles, and nanobody-displayed bacteriophages, have been successfully demonstrated as powerful nanobiotechnological tool kits for basic biomedical research, targeting drug delivery and therapy, disease diagnosis, bioimaging, and agricultural and plant protection. These applications indicate a special advantage of these nanobody derived technologies, already surpassing the "me-too" products of other equivalent binders, such as the full-length antibodies, single-chain variable fragments, antigen-binding fragments, targeting peptides, and DNA-based aptamers. In this review, we summarize the current state of the art in nanobody research, focusing on the nanobody structural features, nanobody production approach, nanobody-derived nanobiotechnology tool kits, and the potentially diverse applications in biomedicine and biotechnology. The future trends, challenges, and limitations of the nanobody-derived nanobiotechnology tool kits are also discussed. PMID- 27499625 TI - The major risk factors for delirium in a clinical setting. AB - OBJECTIVE: We aimed to determine the major risk factors for the development of delirium in patients at a single general hospital by comparison with a control group. SUBJECTS AND METHODS: We reviewed the medical records of 260 delirium patients and 77 control patients. We investigated age, sex, and risk factors for delirium in the total delirium group (n=260), the delirium medical subgroup (n=142), and the delirium surgical subgroup (n=118). Logistic regression analysis adjusting for age and sex was performed to identify the odds ratio. RESULTS: The mean age and the percentage of males were significantly higher in the delirium group compared with the control group (68.9 vs 54.3 years and 70% vs 41.6%, respectively). Risk factors for the delirium group were lower plasma albumin, hypertension, mechanical ventilation, and antipsychotic drug use. Plasma sodium level and hypertension were important risk factors for the delirium medical subgroup. Stroke history, hypertension, ICU care, and medication were important risk factors for the delirium surgical subgroup. CONCLUSION: Lower plasma albumin, hypertension, mechanical ventilation, and antipsychotic drug use are important risk factors for delirium. PMID- 27499627 TI - Correction to "Breast Volume Asymmetry Value, Ratio, and Cancer Risk". AB - [This corrects the article on p. 87 in vol. 9, PMID: 26691819.]. PMID- 27499626 TI - Effect of biological factors on successful measurements with skeletal-muscle (1)H MRS. AB - BACKGROUND: Our purpose in this study was to clarify whether differences in subject group attributes could affect data acquisition in proton magnetic resonance spectroscopy ((1)H-MRS). METHODS: Subjects without diabetes mellitus (DM) were divided into two groups (group A, in their 20s; group B, 30-60 years old). Subjects with DM formed group C (30-60 years old). The numbers of subjects were 19, 27, and 22 for group A, B, and C respectively. For all subjects, (1)H MRS measurements were taken of the soleus muscle (SOL) and the anterior tibial muscle (AT). We defined the success of the measurements by the detection of intramyocellular lipids. Moreover, we also measured the full width at half maximum of the water peaks for all subjects. RESULTS: The success rate was significantly higher for the AT (100%) than for the SOL (81.6%) (P<0.01). For the SOL, the success rate was 100% in group A, 85.2% in group B, and 77.3% in group C. There was a significant difference (P<0.05) between groups A and B, as well as between groups A and C. In all subjects, there was a significant difference (P<0.01) in the full width at half maximum (Hz) of the water peak between the AT and SOL measurements. CONCLUSION: We conclude that differences in the age and DM history of subjects could affect the probability of successful (1)H-MRS data acquisition. PMID- 27499628 TI - Theoretical domains framework to assess barriers to change for planning health care quality interventions: a systematic literature review. AB - BACKGROUND: Theoretical domains framework (TDF) provides an integrative model for assessing barriers to behavioral changes in order to suggest interventions for improvement in behavior and ultimately outcomes. However, there are other tools that are used to assess barriers. OBJECTIVE: The objective of this study is to determine the degree of concordance between domains and constructs identified in two versions of the TDF including original (2005) and refined version (2012) and independent studies of other tools. METHODS: We searched six databases for articles that studied barriers to health-related behavior changes of health care professionals or the general public. We reviewed quantitative papers published in English which included their questionnaires in the article. A table including the TDF domains of both original and refined versions and related constructs was developed to serve as a reference to describe the barriers assessed in the independent studies; descriptive statistics were used to express the results. RESULTS: Out of 552 papers retrieved, 50 were eligible to review. The barrier domains explored in these articles belonged to two to eleven domains of the refined TDF. Eighteen articles (36%) used constructs outside of the refined version. The spectrum of barrier constructs of the original TDF was broader and could meet the domains studied in 48 studies (96%). Barriers in domains of "environmental context and resources", "beliefs about consequences", and "social influences" were the most frequently explored in 42 (84%), 37 (74%), and 33 (66%) of the 50 articles, respectively. CONCLUSION: Both refined and original TDFs cataloged barriers measured by the other studies that did not use TDF as their framework. However, the original version of TDF explored a broader spectrum of barriers than the refined version. From this perspective, the original version of the TDF seems to be a more comprehensive tool for assessing barriers in practice. PMID- 27499629 TI - Nab-paclitaxel and trastuzumab combination: a promising approach for neoadjuvant treatment in HER2-positive breast cancer. AB - Neoadjuvant therapy is a well-established approach for the treatment of locally advanced or inflammatory breast cancer (BC) and has been increasingly used in recent years not only as a management strategy but also as a research tool. Recently, nanoparticle albumin-bound paclitaxel (nab-paclitaxel)/trastuzumab combinations have been associated with promising activity in different clinical settings. In the present case, we report a complete pathological response after neoadjuvant treatment with the trastuzumab/nab-paclitaxel combination in a locally advanced human epidermal growth factor receptor 2 (HER2)-positive BC patient, with a good toxicity profile. This combination may represent a valid therapeutic option in the neoadjuvant therapy for HER2-positive locally advanced BC. PMID- 27499630 TI - Inhibition of microRNA-126 promotes the expression of Spred1 to inhibit angiogenesis in hepatocellular carcinoma after transcatheter arterial chemoembolization: in vivo study. AB - MicroRNA-126 (miR-126) has been found to promote angiogenesis, but the underlying mechanisms are still unclear. So, we conducted this study to explore the effect of miR-126 expression on angiogenesis in hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). The expression levels of miR-126 and sprouty-related, EVH1 domain containing protein (Spred)1 in surgically resected HCC tissue, HCC tissue with TACE + operation, and tumor-adjacent tissues were determined by quantitative real-time polymerase chain reaction. The expression levels of miR-126, Spred1, and vascular endothelial growth factor were found by quantitative real-time polymerase chain reaction and Western blot. The microvessel density (MVD) of tumor tissues was determined by immunohistochemical staining. The miR-126 and Spred1 expressions in HCC tissue with TACE + operation were elevated and decreased, respectively, as compared to those in surgically resected HCC tissues and tumor-adjacent tissues (all P<0.001), which indicated that the expression of Spred1 was negatively correlated with miR-126 (P<0.001, r= 0.6224). Based on the bioinformatics analysis and luciferase reporter gene activity detection, Spred1 was found to target miR-126 (P<0.001). Inhibition of miR-126 expression reduces the degree of weight loss and tumor size in TACE model rats. The MVD in TACE + operation group was increased compared to that in the control group; inhibition of miR-126 expression had a reversal effect, to a certain extent, on MVD increase after TACE (all P<0.05). Inhibition of miR-126 expression increased Spred1 expression and decreased vascular endothelial growth factor expression (P<0.01). In summary, this study unveiled the potential mechanism by which miR-126 regulates angiogenesis in HCC tissues through embolization treatment by targeting Spred1, and also showed that the feasibility of TACE with the miR-126 inhibitor has a certain value in the medical treatment of HCC. PMID- 27499631 TI - Coffee consumption and risk of hepatocellular carcinoma: a meta-analysis of eleven epidemiological studies. AB - Growing evidence has shown that coffee consumption is inversely related with the risk of hepatocellular carcinoma. It is suggested that caffeine maintains strong antioxidative activity. With this property, coffee intake may lead to the inhibition of cell proliferation of liver cancer cells; also, some compounds contained in coffee can reduce the genotoxicity of aflatoxin B1 in vitro and lower the damage caused by some carcinogens. A computerized search was performed in PubMed to identify relevant articles published before August 2015. Eleven relevant studies were included with a total of 2,795 cases and 340,749 control subjects. According to the meta-analysis we performed, the pooled odds ratio (OR) from all included studies was 0.49 (95% confidence interval [CI] =0.46-0.52). The subgroup analysis indicated that the pooled ORs for Asian studies and other populations were 0.27 (95% CI =0.23-0.31) and 0.82 (95% CI =0.77-0.87), respectively. The overall pooled OR for high consumption was decreased to 0.21 (95% CI =0.18-0.25) and significance was observed. Among other populations, the pooled OR of subjects with high coffee consumption was 0.65 (95% CI =0.56-0.73) compared to the nondrinker. The corresponding OR of five Asian studies was 0.13 (95% CI =0.09-0.17). The findings from this meta-analysis further confirmed the inverse association between the coffee consumption and hepatocellular carcinoma risk with quantitative evidence. The protective effect can be detected among healthy population and patients with chronic liver diseases, and the consumption can also prevent the development of liver cirrhosis. PMID- 27499632 TI - The expression status of TRX, AR, and cyclin D1 correlates with clinicopathological characteristics and ER status in breast cancer. AB - BACKGROUND: The ER signaling pathway plays a critical role in breast cancer. ER signaling pathway-related proteins, such as TRX, AR, and cyclin D1, may have an important function in breast cancer. However, the ways that they influence breast cancer development and progression are still unclear. PATIENTS AND METHODS: A total of 101 Chinese female patients diagnosed with invasive ductal breast adenocarcinoma were retrospectively enrolled in the study. The expression levels of TRX, AR, and cyclin D1 were detected by immunohistochemistry and analyzed via correlation with clinicopathological characteristics and the expression status of ER, PR, and HER2. RESULTS: The expression status of TRX, AR, and cyclin D1 was not associated with the patient's age, menopausal status, tumor size, or histological differentiation (P>0.05), but was positively correlated with ER and PR (P<0.001, respectively). Most (66/76, 86.8) TRX-positive patients were also HER2-positive (P=0.003). Of AR- or cyclin D1-positive patients, most had relatively earlier I-II tumor stage (P=0.005 and P=0.047, respectively) and no metastatic lymph node involvement (P=0.008 and P=0.005, respectively). CONCLUSION: TRX was found to be positively correlated with ER and PR expression, whereas it was negatively correlated with HER2 expression. In addition, we found that the positive expression of AR and cyclin D1 was correlated with lower TNM stage and fewer metastatic lymph nodes, and it was more common in ER-positive breast cancer than in the basal-like subtype. This may indicate that AR and cyclin D1 are good predictive and prognostic factors and closely interact with ER signaling pathway. Further studies will be necessary to investigate the response and clinical outcomes of treatment targeting TRX, AR, and cyclin D1. PMID- 27499633 TI - MK-2206 co-treatment with 5-fluorouracil or doxorubicin enhances chemosensitivity and apoptosis in gastric cancer by attenuation of Akt phosphorylation. AB - The anticancer effect of MK-2206, an Akt inhibitor, has been explored in some types of cancers, but its effect on gastric cancer is unclear. In this study, we aimed to investigate its anticancer effect in gastric cancer cells. Cell viability and colony formation assays showed that MK-2206 effectively inhibited the proliferation of SGC-7901 and MKN45 cells. The 50% inhibitory concentration values after 24, 48, and 72 hours' treatment were 22.92, 13.68, and 8.55 MUM in SGC-7901 cells and 19.21, 13.10, and 9.11 MUM in MKN45 cells, respectively. Treatment with MK-2206 induced apoptosis in SGC-7901 cells as indicated by flow cytometry assay. The combination indexes of MK-2206 and doxorubicin were 0.59 in SGC-7901 cells and 0.57 in MKN45 cells, whereas for 5-fluorouracil (5-FU) the indexes were 0.17 in SGC-7901 cells and 0.73 in MKN45 cells, indicating that MK 2206 could work synergistically with doxorubicin or 5-FU to inhibit cell growth. Furthermore, a small dose (1 MUM) of MK-2206 co-treatment with doxorubicin or 5 FU was sufficient for complete inhibition of chemotherapeutic alteration of phosphorylated Akt expression and significant enhancement of pro-apoptosis effect through the activation of caspase pathway. Therefore, MK-2206 effectively inhibits gastric cancer cell growth by attenuation of Akt phosphorylation and synergistically enhances the antitumor effect of doxorubicin and 5-FU via caspase dependent apoptosis. PMID- 27499634 TI - FAT10 is associated with the malignancy and drug resistance of non-small-cell lung cancer. AB - Lung cancer has become one of the leading causes of cancer mortality worldwide, and non-small-cell lung cancer (NSCLC) accounts for ~85% of all lung cancer cases. Currently, platinum-based chemotherapy drugs, including cisplatin and carboplatin, are the most effective treatment for NSCLC. However, the clinical efficacy of chemotherapy is markedly reduced later in the treatment because drug resistance develops during the treatment. Recently, a series of studies has suggested the involvement of FAT10 in the development and malignancy of multiple cancer types. In this study, we focused our research on the function of FAT10 in NSCLC, which has not been previously reported in the literature. We found that the expression levels of FAT10 were elevated in quick chemoresistance NSCLC tissues, and we demonstrated that FAT10 promotes NSCLC cell proliferation, migration, and invasion. Furthermore, the protein levels of FAT10 were elevated in cisplatin- and carboplatin-resistant NSCLC cells, and knockdown of FAT10 reduced the drug resistance of NSCLC cells. In addition, we gained evidence that FAT10 regulates NSCLC malignancy and drug resistance by modulating the activity of the nuclear factor kappa B signaling pathway. PMID- 27499636 TI - JAK2 inhibitor combined with DC-activated AFP-specific T-cells enhances antitumor function in a Fas/FasL signal-independent pathway. AB - OBJECTIVE: Combination therapy for cancer is more effective than using only standard chemo- or radiotherapy. Our previous results showed that dendritic cell activated alpha-fetoprotein (AFP)-specific T-cells inhibit tumor in vitro and in vivo. In this study, we focused on antitumor function of CD8(+) T-cells combined with or without JAK2 inhibitor. METHODS: Proliferation and cell cycle were analyzed by CCK-8 and flow cytometry. Western blot was used to analyze the expression level of related protein and signaling pathway. RESULTS: We demonstrated reduced viability and induction of apoptosis of tumor cells with combination treatment. Intriguingly, cell cycle was blocked at the G1 phase by using AFP-specific CD8(+) T-cells combined with JAK2 inhibitor (AG490). Furthermore, an enhanced expression of BAX but no influence on Fas/FasL was detected from the tumor cells. CONCLUSION: These results indicate a Fas/FasL independent pathway for cellular apoptosis in cancer therapies with the treatment of AFP-specific CD8(+) T-cells combined with JAK2 inhibitor. PMID- 27499635 TI - Functions and mechanisms of long noncoding RNAs in lung cancer. AB - Lung cancer is a heterogeneous disease, and there is a lack of adequate biomarkers for diagnosis. Long noncoding RNAs (lncRNAs) are emerging as an important set of molecules because of their roles in various key pathophysiological pathways, including cell growth, apoptosis, and metastasis. We review the current knowledge of the lncRNAs in lung cancer. In-depth analyses of lncRNAs in lung cancer have increased the number of potential effective biomarkers, thus providing options to increase the therapeutic benefit. In this review, we summarize the functions, mechanisms, and regulatory networks of lncRNAs in lung cancer, providing a basis for further research in this field. PMID- 27499637 TI - Congenital anomalies of the genitourinary system can help in diagnosis of the primary site of metastatic cancer: a case report and a review of the literature. AB - OBJECTIVE: To analyze whether the presence of congenital anomalies of the genitourinary system that are accompanied by specific types of cancer and predispose patients to many complications, including infection, obstruction, stasis, calculus formation, and impaired renal function, could help in the diagnosis of the primary site of a metastatic tumor. CASE PRESENTATION: We report a case of a 58-year-old man with metastatic adenocarcinoma, in whom congenital anomalies of the genitourinary system proved helpful for the diagnosis of the primary site of cancer originating in the seminal vesicles. CONCLUSION: We report an extremely rare case of primary adenocarcinoma arising probably from the left seminal vesicle associated with ipsilateral renal agenesis. The lesion was detected on ultrasound and contrast-enhanced computed tomography and confirmed histologically with ultrasound-guided biopsy. Serum markers, ie, CA19-9 and CA125, were elevated, while prostate-specific antigen and carcinoembryonic antigen were within normal limits. Such a constellation of markers strengthened the diagnosis. Our patient unfortunately presented very late in the course of the disease. Hence, we decided to initiate antiandrogen therapy and best supportive care in a hospice setting. Only early detection seems to be the key factor that may result in improved cure rates for cancer of the seminal vesicles. We also performed a literature search for current concepts related to the diagnosis and clinical management of primary adenocarcinoma of seminal vesicles. PMID- 27499638 TI - Targeting breast cancer stem cells by dendritic cell vaccination in humanized mice with breast tumor: preliminary results. AB - BACKGROUND: Breast cancer (BC) is one of the leading cancers in women. Recent progress has enabled BC to be cured with high efficiency. However, late detection or metastatic disease often renders the disease untreatable. Additionally, relapse is the main cause of death in BC patients. Breast cancer stem cells (BCSCs) are considered to cause the development of BC and are thought to be responsible for metastasis and relapse. This study aimed to target BCSCs using dendritic cells (DCs) to treat tumor-bearing humanized mice models. MATERIALS AND METHODS: NOD/SCID mice were used to produce the humanized mice by transplantation of human hematopoietic stem cells. Human BCSCs were injected into the mammary fat pad to produce BC humanized mice. Both hematopoietic stem cells and DCs were isolated from the human umbilical cord blood, and immature DCs were produced from cultured mononuclear cells. DCs were matured by BCSC-derived antigen incubation for 48 hours. Mature DCs were vaccinated to BC humanized mice with a dose of 10(6) cells/mice, and the survival percentage was monitored in both treated and untreated groups. RESULTS: The results showed that DC vaccination could target BCSCs and reduce the tumor size and prolong survival. CONCLUSION: These results suggested that targeting BCSCs with DCs is a promising therapy for BC. PMID- 27499639 TI - Lapatinib induces autophagic cell death and differentiation in acute myeloblastic leukemia. AB - Lapatinib is an oral-form dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR or ErbB/Her) superfamily members with anticancer activity. In this study, we examined the effects and mechanism of action of lapatinib on several human leukemia cells lines, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL) cells. We found that lapatinib inhibited the growth of human AML U937, HL-60, NB4, CML KU812, MEG-01, and ALL Jurkat T cells. Among these leukemia cell lines, lapatinib induced apoptosis in HL-60, NB4, and Jurkat cells, but induced nonapoptotic cell death in U937, K562, and MEG-01 cells. Moreover, lapatinib treatment caused autophagic cell death as shown by positive acridine orange staining, the massive formation of vacuoles as seen by electronic microscopy, and the upregulation of LC3-II, ATG5, and ATG7 in AML U937 cells. Furthermore, autophagy inhibitor 3 methyladenine and knockdown of ATG5, ATG7, and Beclin-1 using short hairpin RNA (shRNA) partially rescued lapatinib-induced cell death. In addition, the induction of phagocytosis and ROS production as well as the upregulation of surface markers CD14 and CD68 was detected in lapatinib-treated U937 cells, suggesting the induction of macrophagic differentiation in AML U937 cells by lapatinib. We also noted the synergistic effects of the use of lapatinib and cytotoxic drugs in U937 leukemia cells. These results indicate that lapatinib may have potential for development as a novel antileukemia agent. PMID- 27499640 TI - Mast cells positive to tryptase, endothelial cells positive to protease-activated receptor-2, and microvascular density correlate among themselves in hepatocellular carcinoma patients who have undergone surgery. AB - BACKGROUND: Mast cells (MCs) can stimulate angiogenesis, releasing several proangiogenic cytokines stored in their cytoplasm. In particular MCs can release tryptase, a potent in vivo and in vitro proangiogenic factor via proteinase activated receptor-2 (PAR-2) activation and mitogen-activated protein kinase phosphorylation. Nevertheless, no data are available concerning the relationship between MC density positive to tryptase (MCDPT), endothelial cells positive to PAR-2 forming microvascular density (PAR-2-MVD), and classical MVD (C-MVD) in hepatocellular carcinoma (HCC) angiogenesis. This study analyzed the correlation between MCDPT, PAR-2-MVD, and C-MVD, each correlated to the others and to the main clinicopathological features, in early HCC patients who underwent surgery. METHODS: A series of 53 HCC patients with early stage (stage 0 according to the Barcelona Clinic Liver Cancer Staging Classification) were selected and then underwent surgery. Tumor tissue samples were evaluated by means of immunohistochemistry and image analysis methods in terms of number of MCDPT, PAR 2-MVD, and C-MVD. RESULTS: A significant correlation between MCDPT, PAR-2-MVD, and C-MVD groups, each correlated to the others, was found by Pearson t-test analysis (r ranged from 0.67 to 0.81; P-value ranged from 0.01 to 0.03). No other significant correlation was found. CONCLUSION: Our in vivo pilot data suggest that MCDPT and PAR-2-MVD may play a role in HCC angiogenesis and could be further evaluated as a target of antiangiogenic therapy. PMID- 27499641 TI - Association between cyclin D1 G870A polymorphism and hepatocellular carcinoma risk: a meta-analysis. AB - BACKGROUND: Cyclin D1 (CCND1) G870A polymorphism may be associated with hepatocellular carcinoma (HCC) risk, but the results of previous studies were inconsistent. Available evidence was meta-analyzed to assess their potential association. METHODS: Databases PubMed, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature database, China National Knowledge Infrastructure, and Google Scholar were systematically searched. Meta-analyses were performed to investigate the association of G870A polymorphism with HCC risk by calculating odds ratios (ORs) and 95% confidence intervals (CIs) from the data of relevant case-control studies. RESULTS: Results of this meta-analysis of six case-control studies involving 1,030 cases and 1,683 controls indicate that G870A polymorphism was not associated with HCC risk in any of the five genetic models tested (recessive model: AA vs GG + AG: OR =1.38, 95% CI =0.95-2.00, P=0.09; dominant model: AG + AA vs GG: OR =1.38, 95% CI =0.87-2.20, P=0.17; homozygous model: AA vs GG: OR =1.60, 95% CI =0.87-2.94, P=0.13; heterozygous model: AG vs GG: OR =1.24, 95% CI =0.86-1.79, P=0.25; allelic model: A vs G: OR =1.30, 95% CI =0.95 1.80, P=0.10). Subgroup analyses according to ethnicity showing marginally significant association between this single nucleotide polymorphism and HCC risk indicate that G870A may be significantly associated with HCC risk in Caucasian populations (recessive model: AA vs GG + AG: OR =2.34, 95% CI =1.60-3.42, P<0.0001; dominant model: AG + AA vs GG: OR =2.44, 95% CI =1.19-4.97, P=0.01; homozygous model: AA vs GG: OR =3.42, 95% CI =1.80-6.50, P=0.0002; allelic model: A vs G: OR =2.06, 95% CI =1.31-3.24, P=0.002), but not in Asian populations. CONCLUSION: Available evidence suggests that no significant association between G870A polymorphism and HCC risk was found in either total populations or Asian populations. However, significant association was found in Caucasian populations. These results should be verified and extended in further detailed and well designed studies involving larger, multiethnic samples. PMID- 27499642 TI - Stigmatization and self-perception in children with atopic dermatitis. AB - Atopic dermatitis (AD) is one of the most common skin diseases. Prevalence of AD is highest in childhood. Because of chronicity and often visible lesions, AD may lead to stigmatization and problems with self-perception. However, problems of self-perception and stigmatization in AD children are poorly studied. Literature data on general tendencies of children's development, clinical course, and epidemiologic tendencies of AD in different age groups make it possible to highlight three main periods in the formation of self-perception and stigmatization. The first period is from early infancy till 3 years of age. The child's problems in this period depend on parental exhaustion, emotional distress, and security of the mother-child attachment. The child's AD may form a kind of vicious circle in which severe AD causes parental distress and exhaustion that in turn lead to exacerbation of AD and psychological problems in children. The second period is from 3 till 10 years of age. During this period, development of AD children may be influenced by teasing, bullying, and avoiding by their peers. However, the majority of children in this age group are very optimistic. The third period is from 10 years till adulthood. Problems related to low self esteem are characteristic during this period. It is important to identify children with AD and their parents who need psychological help and provide them with needs-based consultation and care. Appropriate treatment, medical consultations, and educational programs may help to reduce emotional problems in AD children and their parents. PMID- 27499643 TI - Mevalonate kinase deficiency: current perspectives. AB - Mevalonate kinase deficiency (MKD) is a recessively inherited autoinflammatory disorder with a spectrum of manifestations, including the well-defined clinical phenotypes of hyperimmunoglobulinemia D and periodic fever syndrome and mevalonic aciduria. Patients with MKD have recurrent attacks of hyperinflammation associated with fever, abdominal pain, arthralgias, and mucocutaneous lesions, and more severely affected patients also have dysmorphisms and central nervous system anomalies. MKD is caused by mutations in the gene encoding mevalonate kinase, with the degree of residual enzyme activity largely determining disease severity. Mevalonate kinase is essential for the biosynthesis of nonsterol isoprenoids, which mediate protein prenylation. Although the precise pathogenesis of MKD remains unclear, increasing evidence suggests that deficiency in protein prenylation leads to innate immune activation and systemic hyperinflammation. Given the emerging understanding of MKD as an autoinflammatory disorder, recent treatment approaches have largely focused on cytokine-directed biologic therapy. Herein, we review the current genetic and pathologic understanding of MKD, its various clinical phenotypes, and the evolving treatment approach for this multifaceted disorder. PMID- 27499644 TI - Animal models of GM2 gangliosidosis: utility and limitations. AB - GM2 gangliosidosis, a subset of lysosomal storage disorders, is caused by a deficiency of the glycohydrolase, beta-N-acetylhexosaminidase, and includes the closely related Tay-Sachs and Sandhoff diseases. The enzyme deficiency prevents the normal, stepwise degradation of ganglioside, which accumulates unchecked within the cellular lysosome, particularly in neurons. As a result, individuals with GM2 gangliosidosis experience progressive neurological diseases including motor deficits, progressive weakness and hypotonia, decreased responsiveness, vision deterioration, and seizures. Mice and cats are well-established animal models for Sandhoff disease, whereas Jacob sheep are the only known laboratory animal model of Tay-Sachs disease to exhibit clinical symptoms. Since the human diseases are relatively rare, animal models are indispensable tools for further study of pathogenesis and for development of potential treatments. Though no effective treatments for gangliosidoses currently exist, animal models have been used to test promising experimental therapies. Herein, the utility and limitations of gangliosidosis animal models and how they have contributed to the development of potential new treatments are described. PMID- 27499645 TI - First-in-Human Phase 1 Trial of Agarose Beads Containing Murine RENCA Cells in Advanced Solid Tumors. AB - PURPOSE: Agarose macrobeads containing mouse renal adenocarcinoma cells (RMBs) release factors, suppressing the growth of cancer cells and prolonging survival in spontaneous or induced tumor animals, mediated, in part, by increased levels of myocyte-enhancing factor (MEF2D) via EGFR-and AKT-signaling pathways. The primary objective of this study was to determine the safety of RMBs in advanced, treatment-resistant metastatic cancers, and then its efficacy (survival), which is the secondary objective. METHODS: Thirty-one patients underwent up to four intraperitoneal implantations of RMBs (8 or 16 macrobeads/kg) via laparoscopy in this single-arm trial (FDA BB-IND 10091; NCT 00283075). Serial physical examinations, laboratory testing, and PET-CT imaging were performed before and three months after each implant. RESULTS: RMBs were well tolerated at both dose levels (mean 660.9 per implant). AEs were (Grade 1/2) with no treatment-related SAEs. CONCLUSION: The data support the safety of RMB therapy in advanced malignancy patients, and the preliminary evidence for their potential efficacy is encouraging. A Phase 2 efficacy trial is ongoing. PMID- 27499646 TI - Design and methods for a Scandinavian pharmacovigilance study of osteonecrosis of the jaw and serious infections among cancer patients treated with antiresorptive agents for the prevention of skeletal-related events. AB - OBJECTIVE: Osteonecrosis of the jaw (ONJ) is a recognized complication of potent antiresorptive therapies, especially at the doses indicated to prevent skeletal complications for cancer patients with bone metastases. This paper describes the rationale and methods for a prospective, post-authorization safety study of cancer patients treated with antiresorptive therapies. METHODS: As part of a comprehensive pharmacovigilance plan, developed with regulators' input, the study will estimate incidence of ONJ and of serious infections among adult cancer patients with bone metastases treated with denosumab (120 mg subcutaneously) or zoledronic acid (4 mg intravenously, adjusted for renal function). Patients will be identified using routinely collected data combined with medical chart review in Denmark, Sweden, and Norway. Followup will extend from the first administration of antiresorptive treatment to the earliest of death, loss-to follow-up, or 5 years after therapy initiation. Results will be reported for three treatment cohorts: denosumab-naive patients, zoledronic acid-naive patients, and patients who switch from bisphosphonate treatment to denosumab. ONJ cases will be identified in three newly established national ONJ databases and adjudicated by the committee that functioned during the XGEVA((r)) clinical trials program. CONCLUSION: This study will provide a real world counterpart to the clinical trial-estimated risks for ONJ and serious infections for cancer patients initiating denosumab or zoledronic acid. The establishment of ONJ databases in the three Scandinavian countries will have potential benefits outside this study for the elucidation of ONJ risk factors and the evaluation of ONJ treatment strategies. PMID- 27499647 TI - Combined uterine and urinary bladder rupture: an unusual complication of obstructed labor in a primigravida. AB - BACKGROUND: Combined uterine and urinary bladder rupture following prolonged obstructed labor is indeed a momentous uro-obstetric emergency. The urinary bladder involvement is distinctly rare in the absence of factors that predispose the bladder to be adherent to the lower uterine segment and is quite unusual in a primigravida. OBJECTIVE: To report a rare case of uterine rupture involving urinary bladder secondary to a prolonged obstructed labor in a primigravida from a low resource setting. CASE: A 17-year-old married unbooked primigravida who presented with a 3-day history of spontaneous onset of labor at term that was initially managed at home and later in a primary health care center where she had fundal pressure and oxytocin augmentation, respectively. The labor was complicated by combined uterine and urinary bladder rupture with sepsis. She was resuscitated and had exploratory laparotomy with uterine and urinary bladder repair. The postoperative period was uneventful and she was followed-up at the gynecology and family planning clinics. CONCLUSION: There is a need for community reawakening on the inherent risks of teenage pregnancy, bad obstetric practices, and unsupervised pregnancy, labor, and delivery, particularly in the rural settings as in the index patient. A high index of suspicion and prompt appropriate intervention will reduce the sequel of morbidity and occasional mortality from this predicament. PMID- 27499648 TI - The experiences of women with polycystic ovary syndrome on a very low-calorie diet. AB - Polycystic ovary syndrome (PCOS) is variously reported to affect between 5% and 26% of reproductive age women in the UK and accounts for up to 75% of women attending fertility clinics due to anovulation. The first-line treatment option for overweight/obese women with PCOS is diet and lifestyle interventions. However, optimal dietary guidelines are missing, with very little research having been done in this area. This paper presents the findings from a qualitative study (using semistructured interviews) of ten obese women who had PCOS and who had used LighterLife Total (LLT), a commercial weight loss program which utilizes a very low-calorie diet in conjunction with behavioral change therapy underpinned by group support. We investigated the women's history of obesity, their experiences of other diets compared with LLT, and the on-going impact that this has had on their lives. Findings show that most women reported greater success using this weight loss program in terms of achieving and maintaining weight loss when compared with other diets. Furthermore, all the women nominated LLT as their model weight loss intervention with only a few modifications. PMID- 27499650 TI - A newborn with very rare von Voss-Cherstvoy syndrome: a case report. AB - INTRODUCTION: von Voss-Cherstvoy syndrome is a part of a group of syndromes with radial and hematologic abnormalities, and until now approximately ten cases have been reported in the literature. This syndrome is characterized by a triad of radial ray defects, occipital encephalocele, and urogenital abnormalities. CASE PRESENTATION: We report a neonate from Indian ethnicity who was diagnosed with von Voss-Cherstvoy syndrome. The neonate had radial ray defect, occipital encephalocele, tetralogy of Fallot, and bilateral agenesis of kidney, ureter, and bladder. The neonate was suspected to have von Voss-Cherstvoy syndrome on the basis of clinical features, which was further confirmed by fibroblast analysis showing somatic mosaicism for del(13q). CONCLUSION: von Voss-Cherstvoy syndrome is a very rare syndrome that can be suspected on the basis of typical clinical features and confirmed by fibroblast analysis showing somatic mosaicism for del(13q). This adds a second case of this chromosome anomaly described in this syndrome. PMID- 27499651 TI - New developments in the treatment of early-onset spinal deformity: role of the Shilla growth guidance system. AB - Early-onset scoliosis is a complex condition with multiple facets. The goal of treating any spinal deformity is to improve the condition of the patient with the least intervention necessary. A system that allows for continuation of natural spinal growth while correcting the deformity should be the goal of treating this complex condition. The SHILLA growth guidance system allows for continued growth of the pediatric spine while correcting and guiding the apex and guiding the future growth of the curvature. The system involves selective fusion across the apex of the curvature, and minimally invasive instrumentation is then used above and below the apex to allow for continued growth of the spine. A review of recent literature on the SHILLA growth guidance system shows promising results. Early animal models showed continued growth across unfused levels with minimal facet articular damage. Comparative studies to traditional growing rods showed significantly less total surgeries along with comparable correction and longitudinal growth. The SHILLA growth guidance system is a good option for this complex patient group. Results are comparable with other growing constructs with significantly less operative interventions. The SHILLA system allows for natural growth of the pediatric spine while correcting the scoliotic deformity in a minimally invasive method. The goal of this article is to present a comprehensive review of the SHILLA system surgical technique and the associated literature concerning this topic. PMID- 27499649 TI - Fetal alcohol-spectrum disorders: identifying at-risk mothers. AB - Fetal alcohol-spectrum disorders (FASDs) are a collection of physical and neurobehavioral disabilities caused by prenatal exposure to alcohol. To prevent or mitigate the costly effects of FASD, we must identify mothers at risk for having a child with FASD, so that we may reach them with interventions. Identifying mothers at risk is beneficial at all time points, whether prior to pregnancy, during pregnancy, or following the birth of the child. In this review, three approaches to identifying mothers at risk are explored: using characteristics of the mother and her pregnancy, using laboratory biomarkers, and using self-report assessment of alcohol-consumption risk. At present, all approaches have serious limitations. Research is needed to improve the sensitivity and specificity of biomarkers and screening instruments, and to link them to outcomes as opposed to exposure. Universal self-report screening of all women of childbearing potential should ideally be incorporated into routine obstetric and gynecologic care, followed by brief interventions, including education and personalized feedback for all who consume alcohol, and referral to treatment as indicated. Effective biomarkers or combinations of biomarkers may be used during pregnancy and at birth to determine maternal and fetal alcohol exposure. The combination of self-report and biomarker screening may help identify a greater proportion of women at risk for having a child with FASD, allowing them to access information and treatment, and empowering them to make decisions that benefit their children. PMID- 27499652 TI - A novel implantable device for a minimally invasive surgical treatment of obstructive sleep apnea: design and preclinical safety assessment. AB - BACKGROUND: In obstructive sleep apnea (OSA), occlusion of the upper airway by soft tissue causes intermittent hypoxemia and can have serious sequelae. A novel implantable medical device for OSA is composed of a linear silicone elastic element held in an extended state by a bioabsorbable external sheath. The implant is delivered to the tongue base or soft palate via a minimally invasive approach. Normal tissue healing anchors the device at the attachment points before the bioabsorbable material dissolves and the elastic element contracts to stabilize the surrounding tissue. METHODS: Device prototypes were evaluated in multiple investigations: 1) a finite elements analysis model simulated the movement of the tongue base during sleep with and without the implant; 2) dynamic mechanical testing simulated 10 years' normal use; 3) cadaveric implantations were conducted; 4) an ovine study in which implants of varying design were evaluated via gross pathology and histological assessment; and 5) a canine study in which implants of varying design in the tongue base and soft palate were evaluated via gross pathology and histological assessment. RESULTS: 1) The implant was capable of reducing ~95% of tongue base movement during simulated sleep; 2) implants remained intact throughout the testing with no evidence of creep fatigue or change in dynamic modulus; 3) the device could be reliably deployed in the desired placement locations and was appropriate for various anatomies; and 4) all implants were well tolerated through 1 year, with minimal inflammatory responses. CONCLUSION: This new minimally invasive device for OSA has been demonstrated, through various bench and animal testing, to be safe, well tolerated, suitable for long-term use, and to function as intended. No adverse health consequences were observed in the animals, and histological evaluation indicated good healing. This study establishes proof of concept and supports human trials. PMID- 27499654 TI - A Public Health Priority: Disparities in Gynecologic Cancer Research for African Born Women in the United States. AB - African-born immigrants comprise one of the fastest growing populations in the U.S., nearly doubling its population size in recent years. However, it is also one of the most underrepresented groups in health-care research, especially research focused on gynecologic and breast malignancies. While the opportunity exists for access to an advanced health-care system, as immigrants migrate to the U.S., they encounter the same health-care inequalities that are faced by the native-born population based on ethnicity and social class, potentiated by limitations of health literacy and lack of familiarity with U.S. health systems. Given the continued influx of African-born immigrants in the U.S., we sought to understand the representation of this population in cervical and breast cancer research, recognizing the population's high risk for these diseases at baseline while residing in their native countries. We determined that there is limited research in these diseases that disproportionately affect them; yet, there are identifiable and potentially modifiable factors that contribute to this paucity of evidence. This clinical commentary seeks to underscore the clear lack of research available involving African-born immigrants with respect to gynecologic and breast malignancies in the existing literature, demonstrate the need for more robust research in this population, and provide fundamental insights into barriers and solutions critical to the continued health of this growing population. PMID- 27499653 TI - Revisiting the mouse model of oxygen-induced retinopathy. AB - Abnormal blood vessel growth in the retina is a hallmark of many retinal diseases, such as retinopathy of prematurity (ROP), proliferative diabetic retinopathy, and the wet form of age-related macular degeneration. In particular, ROP has been an important health concern for physicians since the advent of routine supplemental oxygen therapy for premature neonates more than 70 years ago. Since then, researchers have explored several animal models to better understand ROP and retinal vascular development. Of these models, the mouse model of oxygen-induced retinopathy (OIR) has become the most widely used, and has played a pivotal role in our understanding of retinal angiogenesis and ocular immunology, as well as in the development of groundbreaking therapeutics such as anti-vascular endothelial growth factor injections for wet age-related macular degeneration. Numerous refinements to the model have been made since its inception in the 1950s, and technological advancements have expanded the use of the model across multiple scientific fields. In this review, we explore the historical developments that have led to the mouse OIR model utilized today, essential concepts of OIR, limitations of the model, and a representative selection of key findings from OIR, with particular emphasis on current research progress. PMID- 27499655 TI - Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method. AB - BACKGROUND: Buprenorphine is a partial u-opioid receptor agonist used for maintenance treatment of opioid dependence. Because of the partial agonism and high receptor affinity, it may precipitate withdrawal symptoms during induction in persons on full u-opioid receptor agonists. Therefore, current guidelines and drug labels recommend leaving a sufficient time period since the last full agonist use, waiting for clear and objective withdrawal symptoms, and reducing pre-existing full agonist therapies before administering buprenorphine. However, even with these precautions, for many patients the induction of buprenorphine is a difficult experience, due to withdrawal symptoms. Furthermore, tapering of the full agonist bears the risk of relapse to illicit opioid use. CASES: We present two cases of successful initiation of buprenorphine treatment with the Bernese method, ie, gradual induction overlapping with full agonist use. The first patient began buprenorphine with overlapping street heroin use after repeatedly experiencing relapse, withdrawal, and trauma reactivation symptoms during conventional induction. The second patient was maintained on high doses of diacetylmorphine (ie, pharmaceutical heroin) and methadone during induction. Both patients tolerated the induction procedure well and reported only mild withdrawal symptoms. DISCUSSION: Overlapping induction of buprenorphine maintenance treatment with full u-opioid receptor agonist use is feasible and may be associated with better tolerability and acceptability in some patients compared to the conventional method of induction. PMID- 27499656 TI - Comparative Study on the Effects of Boiling, Steaming, Grilling, Microwaving and Superheated Steaming on Quality Characteristics of Marinated Chicken Steak. AB - The effects of five different cooking methods (boiling, steaming, grilling, microwaving, and superheated steaming) on proximate composition, pH, color, cooking loss, textural properties, and sensory characteristics of chicken steak were studied. Moisture content and lightness value (L*-value) were higher in superheated steam cooked chicken steak than that of the other cooking treatments such as boiling, steaming, grilling and microwaving cooking (p<0.05), whereas protein content, redness value (a*-value), hardness, gumminess, and chewiness of superheated steam cooked chicken steak was lower than that in the other cooking treatments (p<0.05). Fat content and ash content, springiness, and cohesiveness were not significantly different among the chicken steak cooked using various methods (p>0.05). Among the sensory characteristics, tenderness score, juiciness score and overall acceptability score were the highest for the superheated steam samples (p<0.05), whereas no difference in flavor scores were observed among the other treatments (p>0.05). These results show that marinated chicken steak treated with superheated steam in a preheated 250C oven and 380C steam for 5 min until core temperature reached 75C improved the quality characteristics and sensory properties the best. Therefore, superheated steam was useful to improve cooked chicken steak. PMID- 27499657 TI - Effects of Soy Protein Hydrolysates Prepared by Varying Subcritical Media on the Physicochemical Properties of Pork Patties. AB - This study investigated the effect of soy protein hydrolysates (SPH) prepared by varying subcritical media on the physicochemical properties of pork patties. For resource of SPH, two different soybean species (Glycine max Merr.) of Daewonkong (DWK) and Saedanbaek (SDB) were selected. SPH was prepared by subcritical processing at 190C and 25 MPa under three different of media (water, 20% ethanol and 50% ethanol). Solubility and free amino group content revealed that water was better to yield larger amount of SPH than ethanol/water mixtures, regardless of species. Molecular weight (Mw) distribution of SPH was also similar between two species, while slightly different Mw distribution was obtained by subcritical media. For pork patty application, 50% ethanol treatment showed clear red color comparing to control after 14 d of storage. In addition, ethanol treatment had better oxidative stability than control and water treatment based on thiobarbituric acid-reactive substances (TBARS) analysis. For eating quality, although 20% ethanol treatment in SDB showed slightly higher cooking loss than control, generally addition of SPH did not affect the water-binding properties and hardness of pork patties. Consequently, the present study indicated that 50% ethanol was the best subcritical media to produce SPH possessing antioxidant activity, and the SPH produced from DWK exhibited better antioxidant activity than that produced SDB. PMID- 27499658 TI - Induction of Oral Tolerance by Gamma-Irradiated Ovalbumin Administration. AB - Oral administration of soluble antigen can induce peripheral tolerance to the antigen. This study was conducted to evaluate whether gamma-irradiated ovalbumin (OVA) can induce oral tolerance. To investigate this, we administrated intact or irradiated OVA to mice, induced allergic response using intact OVA and alum, then compared humoral and cellular immune responses. Mice treated with gammairradiated OVA had less OVA-specific IgE compared with those who were administered intact OVA. There was no difference in levels of OVA-specific IgG+A+M, IgG1, and IgG2a. Splenocytes of mice administered irradiated OVA showed similar OVA-specific T cell proliferation and secretion of IFN-gamma and IL-4. However, there was an increase in IL-2 and a decrease of IL-6 secretion in mice treated with irradiated OVA. These results indicate that gamma-irradiated OVA have similar effects to intact OVA on antigen tolerance. PMID- 27499659 TI - Sensory Property Improvement of Jokbal (Korean Pettitoes) Made from Frozen Pig Feet by Addition of Herbal Mixture. AB - This study was conducted to improve sensory quality of Jokbal (Korean Pettitoes) made from frozen pig feet by addition of herbal mixture (glasswort, raspberry and Sansa powders). After adding herbal mixture, lipid oxidation (2-thiobarbituric acid values, TBARS), sensory property, and textural property were determined. Herbs were individually added into cooking soup at concentration of 6% (low concentration treatment, LCT) or 12% (high concentration treatment, HCT) of raw pig feet. Refrigerated pig feet were used as control. Thawed feet without any herbal mixture were used as freezing treatment (FT). TBARS in LCT or HCT were lower than that in FT, and showed the similar to that in Control. Addition of the herbal mixture was effective in improving the flavor and textural property of thawed feet by inhibiting lipid oxidation and protein denaturation in a dose dependent manner. PMID- 27499660 TI - Impact of Cooking, Storage, and Reheating Conditions on the Formation of Cholesterol Oxidation Products in Pork Loin. AB - This study investigates the effect of cooking, storage, and reheating conditions on the formation of cholesterol oxidation products (COPs) in pork loin. Samples of pork loin procured 24 h postmortem were initially processed and assessed for total fat and cholesterol content. The cooking methods evaluated were pan roasting, steaming, oven grilling, and microwaving. Cooked pork loin samples were stored at 4C and reheated after 3 and 6 d of storage using the original method of preparation or alternately, microwaving. Fat content increased significantly with cooking as a result of the loss in moisture but cholesterol content remained unchanged. Pan roasting and microwave cooking caused a significantly higher production of COPs, as with the process of reheating using microwave, pan roasting, and oven grilling methods. The major COPs found in pork loin were cholestanetriol, 20-hydroxycholesterol, and 25-hydroxycholesterol, whose concentrations varied according to the different cooking and reheating methods used. Moreover, the aerobic storage of cooked pork loin under a refrigerated condition also increased the formation of cholesterol oxides on reheating. PMID- 27499661 TI - Pork Quality Traits According to Postmortem pH and Temperature in Berkshire. AB - This study was performed to investigate the role of pH and temperature postmortem, and to demonstrate the importance of these factors in determining meat quality. Postmortem pH 45min (pH at 45 min postmortem or initial pH) via analysis of Pearson's correlation showed high positive correlation with pH change pH c24 (pH change from pH 45min to pH 24h postmortem). However, postmortem pH after 24 h (pH 24h or ultimate pH) had a high negative correlation with pH change, pH c24 , CIE L*, and protein content. Initial temperature postmortem (T 1h ) was positively associated with a change in temperature from 45 min to 24 h postmortem (T c24 ) and cooking loss, but negatively correlated with water holding capacity. Temperature at 24 h postmortem (T 24h ) was negatively associated with T c24 . Collectively, these results indicate that higher initial pH was associated with higher pH c24 , T 1h , and T c24 . However, higher initial pH was associated with a reduction in carcass weight, backfat thickness, CIE a* and b*, water holding capacity, collagen and fat content, drip loss, and cooking loss as well as decreased shear force. In contrast, CIE a* and b*, drip loss, cooking loss, and shear force in higher ultimate pH was showed by a similar pattern to higher initial pH, whereas pH c24 , carcass weight, backfat thickness, water holding capacity, fat content, moisture content, protein content, T 1h , T 24h , and T c24 were exhibited by completely differential patterns (p<0.05). Therefore, we suggest that initial pH, ultimate pH, and temperatures postmortem are important factors in determining the meat quality of pork. PMID- 27499662 TI - Screening of Cholesterol-lowering Bifidobacterium from Guizhou Xiang Pigs, and Evaluation of Its Tolerance to Oxygen, Acid, and Bile. AB - Cardiovascular and cerebrovascular diseases seriously harm human health, and Bifidobacterium is the most beneficial probiotic in the gastrointestinal tract of humans. This work aimed to screen cholesterol-lowering Bifidobacterium from Guizhou Xiang Pig and evaluate its tolerance to oxygen, acid, and bile. Twenty seven aerotolerant strains with similar colony to Bifidobacterium were isolated through incubation at 37C in 20% (v/v) CO2-80% (v/v) atmospheric air by using Mupirocin lithium modified MRS agar medium, modified PTYG with added CaCO3, and modified PTYG supplemented with X-gal. Ten strains with cholesterol-lowering rates above 20% (w/w) were used for further screening. The selected strains' tolerance to acid and bile was then determined. A combination of colony and cell morphology, physiological, and biochemical experiments, as well as 16S rRNA gene sequence analysis, was performed. Results suggested that BZ25 with excellent characteristics of high cholesterol-removal rate of 36.32% (w/w), as well as tolerance to acid and bile, was identified as Bifidobacterium animalis subsp. lactis. To further evaluate Bifidobacterium BZ25's growth characteristic and tolerance to oxygen, culture experiments were performed in liquid medium and an agar plate. Findings suggested that BZ25 grew well both in environmental 20% (v/v) CO2-80% (v/v) atmospheric air and in 100% atmospheric air because BZ25 reached an absorbance of 1.185 at 600 nm in 100% atmospheric air. Moreover, BZ25 was aerotolerant and can grow in an agar medium under the environmental condition of 100% atmospheric air. This study can lay a preliminary foundation for the potential industrial applications of BZ25. PMID- 27499663 TI - Correlation between Antioxidant Enzyme Activity, Free Iron Content and Lipid Oxidation in Four Lines of Korean Native Chicken Meat. AB - This study was conducted to observe the association between antioxidant enzyme activity, free iron content and lipid oxidation of Korean native chicken (KNC) meat during refrigerated storage. Four lines of KNC (Yeonsan ogye, Hyunin black, Hoengseong yakdak and Hwangbong) were raised under similar conditions. A total of 16 roosters were randomly sampled and slaughtered at the age of 12 mon. The breast and thigh meats were stored aerobically for 10 d at 4C. Although thigh meat had higher antioxidant enzyme activity, it was more susceptible to lipid oxidation and released more iron during storage than breast meat. Aerobic refrigerated storage for 10 d significantly decreased the activity of antioxidant enzymes and increased the amount of free iron and malondialdehyde. The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were negatively correlated with lipid oxidation, whereas that of catalase was not. The amount of free iron was positively associated with lipid oxidation. We concluded that chicken line did not affect strongly on antioxidant enzyme activity and lipid oxidation in breast meat of KNC. However, the thigh meat of Hwangbong and Hyunin black had higher SOD and GSH-Px activity, respectively, and lower malondialdehyde contents than that of other chickens. SOD, GSH-Px and free iron play significant roles in meat lipid oxidation during refrigerated storage. PMID- 27499664 TI - Effects of Drying Temperature on Antioxidant Activities of Tomato Powder and Storage Stability of Pork Patties. AB - This study was performed to evaluate the antioxidant activity of oven-dried tomato powder (OTP) as affected by drying temperature and the effect of OTP on the product quality of pork patties. Three OTP products were obtained by drying of fresh tomato at 60, 80 and 100C oven until constant weight was obtained. Total phenolic content of three kinds of OTPs ranged from 1.95 to 5.94 g/100 g. The highest amount of total phenolic compound was observed in OTP dried at 100C. Antioxidant activity of three kinds of OTPs was measured by 1,1-diphenyl-2 pycrylhydrazyl (DPPH)-radical scavenging activity, iron chelating ability, reducing power and measurement of lipid peroxide in linoleic acid emulsion system. In all parameters, OTP at 100C showed the higher antioxidant activity than other temperatures (p<0.05). Based on the model study, the physicochemical properties, and antioxidant and antimicrobial activities of pork patties containing 1% OTP were measured. Redness of pork patties were increased with the addition of OTPs (p<0.05). Thiobarbituric acid reactive substances (TBARS) values of raw pork patties containing OTPs were lower than those of control (CTL) until 7 d of storage, regardless of drying temperatures (p<0.05). Peroxide values of pork patties made with OTP (1%) were lower than those of CTL until the end of storage time (p<0.05). However, no antimicrobial activities were observed among the treatments (p>0.05). Therefore, OTPs could be used as a natural antioxidant in meat products. PMID- 27499665 TI - Effects of Mixed Bone and Brisket Meat on Physico-Chemical Characteristics of Shank Bone and Rib Extracts from Hanwoo. AB - This study was conducted to investigate the effects of mixed bone and brisket meat on the quality characteristics and nutritional components of shank bone extract and rib extract from Hanwoo. The pH values were influenced by the raw bones, mixed bone, brisket meat and their interactions (p<0.05). The salinity, sugar content, turbidity, and essential amino acid values increased significantly with addition of mixed bone and brisket meat. All attributes of sensory evaluation score were the highest in T6 (Rib 500 g + Mixed bone 500 g + Brisket meat 400 g) (p<0.05). The mixed bone significantly increased the saturated fatty acids of shank bone extract (p<0.001). Thus, the addition of mixed bone and brisket meat had a positive effect on the quality and nutritional components in shank and rib extracts of Hanwoo cattle. PMID- 27499666 TI - Effect of Aging Time on Physicochemical Meat Quality and Sensory Property of Hanwoo Bull Beef. AB - This study was conducted to investigate the meat quality and sensory properties of 12 major cuts from 10 Hanwoo bulls (25-32 mon of age) after they were aged at 2C for 0, 7, 14, and 21 d. Protein content (%) was between 19.17 and 22.50%. Intramuscular fat content ranged from 2.79 to 8.39%. The collagen content of the chuck roll, chuck tender, and short plate muscles was higher (1.97-2.04%) than that of the striploin muscles (1.48%) (p<0.05). CIE lightness (L*) values increased with an increase in aging days for tenderloin, loin, chuck roll, oyster blade, short plate, top sirloin, and eye of round muscles (p<0.05). Most muscles, except the short plate, showed no significant changes in redness CIE (a*) and yellowness (b*) color values during aging. The tenderloin, loin, and striploin showed significantly higher water holding capacity (58.60-62.06%) than that of chuck roll and short plate (53.86-57.07%) muscles (p<0.05). The Warner-Bratzler shear force values of most muscles decreased significantly as the aging period increased (p<0.05), exception the tenderloin. The chuck tender muscles showed the highest cooking loss, whereas tenderloin muscle showed the lowest (p<0.05). The tenderloin muscle had the longest sarcomere length (SL) (3.67-3.86 MUm) and the bottom round muscle had the shortest SL (2.21-2.35 MUm) (p<0.05). In the sensory evaluation, tenderness and overall-likeness scores of most muscles increased with increase in aging days. The tenderloin and oyster blade showed relatively higher tenderness and overall-likeness values than did the other muscles during the aging period. No significant differences were noted in juiciness and flavor likeness scores among muscles and aging days. PMID- 27499667 TI - Anti-obesity Effect of Yogurt Fermented by Lactobacillus plantarum Q180 in Diet induced Obese Rats. AB - This study aimed to investigate the anti-obesity effects of yogurt fermented by Lactobacillus plantarum Q180 in diet-induced obese rats. To examine the effects, male Sprague-Dawley rats were fed on six different diets, as follows: Group A was fed an ND and orally administrated saline solution; Group B, an HFD and orally administrated saline solution; Group C, an HFD and orally administrated yogurt fermented by ABT-3 and L. plantarum Q180; Group D, an HFD and orally administrated yogurt with added Garcinia cambogia extract, fermented by ABT-3 and L. plantarum Q180; Group E, an HFD and orally administrated yogurt fermented by L. plantarum Q180; and Group F, an HFD and orally administrated yogurt with added Garcinia cambogia extract, fermented by L. plantarum Q180 for eight weeks. After eight weeks, the rate of increase in bodyweight was 5.14%, 6.5%, 3.35% and 10.81% lower in groups C, D, E and F, respectively, compared with group B; the epididymal fat weight of groups E and F was significantly lower than that of group B; and the level of triglyceride and leptin was significantly reduced in groups C, D, E and F compared to group B. In addition, the level of AST was reduced in group C compared to the other groups. To examine the effects of yogurt on the reduction of adipocyte size, the adipocyte sizes were measured. The number of large-size adipose tissue was less distributed in groups A, C, D, E and F than in group B. PMID- 27499668 TI - Comparison of Carcass and Meat Quality Traits among Three Rabbit Breeds. AB - The objective of this study was to compare carcass composition and meat quality traits in the longissimus dorsi and biceps femoris muscles in the Hyla, Champagne and Tianfu Black rabbit breeds. Tianfu Black rabbits had the heaviest head, skin, thoracic viscera and commercial carcass percentage (p<0.05). In addition, Tianfu Black had the highest pH0 h value, followed by the Champagne and Hyla breeds (p<0.01) in the longissimus dorsi and biceps femoris muscles. Tianfu Black had a higher a* (0 h and 24 h) than the other two breeds in both longissimus dorsi and biceps femoris muscles (p<0.05). The Hyla, Champagne, and Tianfu Black breeds showed a similar pattern of differences for meat quality traits (pH, L*, a* and b*) measured in fresh meat (0 h) and meat stored for 24 h. Hyla had the highest IMF values of the three breeds (p<0.01). The lower intramuscular fat of Tianfu Black and Champagne rabbits gives them an advantage over Hyla rabbits among most consumers seeking lean rabbit meat. PMID- 27499669 TI - Enhanced Microbial, Functional and Sensory Properties of Herbal Yogurt Fermented with Korean Traditional Plant Extracts. AB - This study evaluated the effects of two Korean traditional plant extracts (Diospyros kaki THUNB. leaf; DK, and Nelumbo nucifera leaf; NN) on the fermentation, functional and sensory properties of herbal yogurts. Compared to control fermentation, all plant extracts increased acidification rate and reduced the time to complete fermentation (pH 4.5). Supplementation of plant extracts and storage time were found to influence the characteristics of the yogurts, contributing to increased viability of starter culture and phenolic compounds. In particular, the increase in the counts of Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus was highest (2.95 and 1.14 Log CFU/mL respectively) in DK yogurt. Furthermore, supplementation of the plant extracts significantly influenced to increase the antioxidant activity and water holding capacity and to produce volatile compounds. The higher antioxidant activity and water holding capacity were observed in NN yogurt than DK yogurt. Moreover, all of the sensory characteristics were altered by the addition of plant extracts. Addition of plant extracts increased the scores related to flavor, taste, and texture from plain yogurt without a plant extract, as a result of volatile compounds analysis. Thus, the overall preference was increased by plant extracts. Consequently, supplementation of DK and NN extracts in yogurt enhanced the antioxidant activity and physical property, moreover increased the acceptability of yogurt. These findings demonstrate the possibility of using plant extracts as a functional ingredient in the manufacture of herbal yogurt. PMID- 27499671 TI - Determination of Energy and Nutrient Utilization of Enzyme-treated Rump Round Meat and Lotus Root Designed for Senior People with Young and Age d Hens as an Animal Model. AB - This study aimed to examine the nutrient utilization of rump round meat and lotus root using young (32 wk) and aged hens (108 wk) as an animal model. Rump round meat and lotus root were prepared with or without enzymatic treatment. For each age group of laying hens, a total of 24 Hy-Line Brown laying hens were randomly allotted to one of two dietary treatments with six replicates. For rump round meat, the true total tract retention rate (TTTR) of dry matter (DM) and nitrogen (N) were unaffected by either enzymatic treatment or hen age. However, aged hens had greater (p<0.01) TTTR of energy and crude fat than young hens. Enzymatic treatment did not influence the TTTR of energy or crude fat. In addition, we did not observe any significant interaction between the TTTR of DM, energy, N, or crude fat in rump round meat and hen age or enzymatic treatment. The TTTR of DM remained unchanged between controls and enzyme-treated lotus root for young hens. However, enzyme-treated lotus root exhibited greater (p<0.05) TTTR of DM than control lotus root for aged hens, resulting in a significant interaction (p<0.05). The TTTR of energy and N in lotus roots were greater (p<0.01) for aged hens than for young hens. In conclusion, enzymatic treatment exerted beneficial effects on energy and nutrient utilization in aged hens, suggesting the aged hen model is practical for simulation of metabolism of elderly individuals. PMID- 27499670 TI - Inactivation of Salmonella on Eggshells by Chlorine Dioxide Gas. AB - Microbiological contamination of eggs should be prevented in the poultry industry, as poultry is one of the major reservoirs of human Salmonella. ClO2 gas has been reported to be an effective disinfectant in various industry fields, particularly the food industry. The aims of this study were to evaluate the antimicrobial effect of chlorine dioxide gas on two strains of Salmonella inoculated onto eggshells under various experimental conditions including concentrations, contact time, humidity, and percentage organic matter. As a result, it was shown that chlorine dioxide gas under wet conditions was more effective in inactivating Salmonella Enteritidis and Salmonella Gallinarum compared to that under dry conditions independently of the presence of organic matter (yeast extract). Under wet conditions, a greater than 4 log reduction in bacterial populations was achieved after 30 min of exposure to ClO2 each at 20 ppm, 40 ppm, and 80 ppm against S. Enteritidis; 40 ppm and 80 ppm against S. Gallinarum. These results suggest that chlorine dioxide gas is an effective agent for controlling Salmonella, the most prevalent contaminant in the egg industry. PMID- 27499672 TI - Effects on the Qualities of Proteolysis to Beef by Non-coating and Coating Protease Treatment. AB - This study was performed to improve the techniques used for tenderizing red meat as elderly food. Beef meat was immersed in liposome encapsulated enzyme solution and the effect of protease encapsulation on the beef properties was analyzed. The protease encapsulation properties were analyzed according to the size distribution and enzymatic activity. After enzyme reaction on the beef, the chemical properties of the meat such as pH, water holding capacity, shear rate, lipid oxidation and total volatile basic nitrogen (TVB-N) were analyzed. The pH of the beef increased during the reaction and coating protease (CP) was higher than non-coating protease (NCP). Total color differences were increased remarkably after 36 h and generally, the difference in CP was relatively lower than in NCP. WHC was significantly decreased within 24 h, and no effect from the protease coating was observed. Protease activity was significantly increased within 48 h and no differences in the enzyme coating were observed. The TVB-N value of NCP was increased within 24 h while CP was sustained for up to 36 h. The TVB-N value of protease treated meat increased after 36 h and no effect from the protease coating was detected. Consequently, liposome encapsulated protease was found to have similar properties as non-coated protease. Application of liposome seems to be an interesting option for injecting various functional materials without changing the properties of meat. PMID- 27499673 TI - Evaluation of Mixed Probiotic Starter Cultures Isolated from Kimchi on Physicochemical and Functional Properties, and Volatile Compounds of Fermented Hams. AB - The objective of this study was to investigate the effects of mixed starter cultures isolated from kimchi on physicochemical properties, functionality and flavors of fermented ham. Physicochemical properties, microbial counts, shear force, cholesterol contents and volatile compounds of fermented ham were investigated during processing (curing and ripening time). Curing process for 7 d increased saltiness, however, decreased hunter color values (L, a, and b values). Ripening process for 21 d increased most parameters, such as saltiness, color values, weight loss, shear force and cholesterol content due to the drying process. The mixed starter culture had higher lactic acid bacteria than the commercial one. While eight volatile compounds were identified from fermented hams during curing process, total fiftyeight volatile compounds were identified from fermented hams during ripening process. The main volatile compounds were alcohols, esters and furans. However, no differences in volatile compounds were observed between two batches. Fermented hams (batch B) manufactured with probiotic starter culture (LPP) had higher sensory score in texture, color and overall acceptability than counterparts (batch A), while the opposite trend was observed in flavor. Therefore, mixed probiotic starter culture isolated from kimchi might be used as a starter culture to be able to replace with commercial starter culture (LK-30 plus) for the manufacture of fermented ham. PMID- 27499674 TI - Effect of Chicory Fiber and Smoking on Quality Characteristics of Restructured Sausages. AB - This study was conducted to investigate the effects of chicory fiber for the replacement of fat and smoking on quality characteristics of restructured sausages. Treatments were as follows; CONTROL: Pork backfat 20%, T1: Pork backfat 10% + Chicory fiber 10%, T2: CONTROL + Smoking, T3: T1 + Smoking. The addition of chicory fiber significantly reduced the moisture, fat, hardness and pH values, whereas the smoking treatment increased the fat, redness and pH values of restructured sausages (p<0.01). Additionally, interaction of them significantly affected the ash, chewiness and hardness values of restructured sausages. As a result, although the addition of chicory fiber decreased the quality characteristics of sausage, smoking treatment improved the reduced quality. Therefore, the chicory fiber and smoking treatment is helpful to develop restructured sausage products with reduced fat and compensated quality. PMID- 27499675 TI - Taphonomy and diversity of Middle Miocene decapod crustaceans from the Novohrad Nograd Basin, Slovakia, with remarks on palaeobiography. AB - Decapod crustacean assemblages from the Middle Miocene (lower 'Badenian'=Langhian) volcanoclastic Plastovce Beds (Sebechleby Formation) in the Slovakian part of the Novohrad-Nograd Basin comprise five species in five families (Callianassidae, Laomediidae, Munididae, Cancridae and Retroplumidae) and are dominated by the cancrid crab Tasadia carniolica (Bittner, 1884). Munida sp. constitutes the first record of this genus from Slovakia and the second from the European Neogene. Burrowing shrimp (Jaxea kuemeli Bachmayer, 1954) are associated with burrows tentatively attributed to this species. The occurrence of Retropluma slovenica Gasparic & Hyzny, 2014, previously recorded from the Lower Miocene of Slovenia, extends both the geographical distribution and stratigraphical range of the species. Differential decapod diversity at four localities in the Plastovce area can be explained by collecting bias and palaeoenvironmental factors. The palaeosetting is interpreted as a muddy-bottom, nearshore zone with a water depth of approximately 100 m. Abundant articulated crabs suggest rapid burial. Third maxillipeds in open posture in some specimens may indicate respiratory stress of the animals, suggesting episodic events of rapid volcanoclastic flows responsible for killing crabs and promoting their preservation. Species composition of the decapod fauna of the Plastovce Beds further strengthens similarities with Miocene faunas from the North Sea Basin. PMID- 27499676 TI - Health activism and the logic of connective action. A case study of rare disease patient organisations. AB - This exploratory work investigates the role of digital media in expanding health discourse practices in a way to transform traditional structures of agency in public health. By focusing on a sample of rare disease patient organisations as representative of contemporary health activism, this study investigates the role of digital communication in the development of (1) bottom-up sharing and co production of health knowledge, (2) health public engagement dynamics and (3) health information pathways. Findings show that digital media affordances for patient organisations go beyond the provision of social support for patient communities; they ease one-way, two-way and crowdsourced processes of health knowledge sharing, exchange and co-production, provide personalised routes to health public engagement and bolster the emergence of varied pathways to health information where experiential knowledge and medical authority are equally valued. These forms of organisationally enabled connective action can help the surfacing of personal narratives that strengthen patient communities, the bottom up production of health knowledge relevant to a wider public and the development of an informational and eventually cultural context that eases patients' political action. PMID- 27499677 TI - Accounting for failure: risk-based regulation and the problems of ensuring healthcare quality in the NHS. AB - In this paper, we examine why risk-based policy instruments have failed to improve the proportionality, effectiveness, and legitimacy of healthcare quality regulation in the National Health Service (NHS) in England. Rather than trying to prevent all possible harms, risk-based approaches promise to rationalise and manage the inevitable limits of what regulation can hope to achieve by focusing regulatory standard-setting and enforcement activity on the highest priority risks, as determined through formal assessments of their probability and consequences. As such, risk-based approaches have been enthusiastically adopted by healthcare quality regulators over the last decade. However, by drawing on historical policy analysis and in-depth interviews with 15 high-level UK informants in 2013-2015, we identify a series of practical problems in using risk based policy instruments for defining, assessing, and ensuring compliance with healthcare quality standards. Based on our analysis, we go on to consider why, despite a succession of failures, healthcare regulators remain committed to developing and using risk-based approaches. We conclude by identifying several preconditions for successful risk-based regulation: goals must be clear and trade offs between them amenable to agreement; regulators must be able to reliably assess the probability and consequences of adverse outcomes; regulators must have a range of enforcement tools that can be deployed in proportion to risk; and there must be political tolerance for adverse outcomes. PMID- 27499678 TI - Enhancement of Plant Productivity in the Post-Genomics Era. AB - Obtaining high plant yield is not always achievable in agricultural activity as it is determined by various factors, including cultivar quality, nutrient and water supplies, degree of infection by pathogens, natural calamities and soil conditions, which affect plant growth and development. More noticeably, sustainable plant productivity to provide sufficient food for the increasing human population has become a thorny issue to scientists in the era of unpredictable global climatic changes, appearance of more tremendous or multiple stresses, and land restriction for cultivation. Well-established agricultural management by agrotechnological means has shown no longer to be effective enough to confront with this challenge. Instead, in order to maximize the production, it is advisable to implement such practices in combination with biological applications. Nowadays, high technologies are widely adopted into agricultural production, biological diversity conservation and crop improvement. Wang et al. has nicely outlined the utilization of DNA-based technologies in this field. Among these are the applications of (i) DNA markers into cultivar identification, seed purity analysis, germplasm resource evaluation, heterosis prediction, genetic mapping, cloning and breeding; and (ii) gene expression data in supporting the description of crop phenology, the analytic comparison of crop growth under stress versus non-stress conditions, or the study of fertilizer effects. Besides, various purposes of using transgenic technologies in agriculture, such as generating cultivars with better product quality, better tolerance to biotic or abiotic stress, are also discussed in the review. One of the important highlights in this issue is the review of the benefits brought by high-throughput sequencing technology, which is also known as next-generation sequencing (NGS). It is not so difficult to recognize that its application has allowed us to carry out biological studies at much deeper level and larger scale. In their article, Onda and Mochida detailed how to use these technologies in fully characterizing the genetic diversity or multigenecity within a particular plant species. The authors discussed the constant innovation of sequencing platforms which has made sequencing technologies become more superior and more powerful than ever before. Additionally, the efforts result in not only further cut down of the sequencing cost and increase in the sequencing speed, but also improvement in sequencing accuracy and extended sequencing application to studies at both DNA and RNA levels. Such knowledge will help the scientists interpret, at least partially, how plants can adapt to various environmental conditions, or how different cultivars can respond differently to the same stress. Another article by Ong et al. also laid emphasis on the importance of various high-throughput sequencing platforms, thanks to which a large number of genomic databases supplied with detailed annotation and useful bioinformatics tools have been established to assist geneticists. Readers can find in this review the summary of available plant-specific genomic databases up-to-date and popular web-based resources that are relevant for comparative genomics, plant evolution and phylogenomics studies. These, along with other approaches, such as quantitative trait locus and genome-wide association study, will lay foundation for prediction and identification of genes or alleles responsible for valuable agronomic traits, contributing to the enhancement of plant productivity by genetic engineering approach. In this thematic issue, specific examples for crop improvement are also demonstrated. The first showcase is given by Nongpiur et al. who provided evidence that synergistic employment of genomics approaches and high-throughput gene expression methods have aided in dissecting the salinity-responsive signaling pathway, identifying genes involved in the stress response and selecting candidate genes for further characterization aimed at generating new cultivars with better salinity stress tolerance. This paper is also a good reference source for readers who wish to get an overview about the general process from gene prediction to validation by experiments, including the details on techniques and approaches used. Another demonstration is provided by Khan et al. whose interest is enhancement of drought tolerance in crops. The focus of this article is to overview our current understanding of mechanisms regulating plants responses to drought. Evaluation of plant performance to drought and production of new elite varieties with better drought tolerance on the basis of using phenotyping and genomics-assisted breeding are also well discussed. In addition to the topics of environmental stress tolerance in plants, current knowledge on improving biotic stress tolerance is also summarized in our issue. Current picture on crosstalk of signaling mechanisms in rice between its immune system and symbiosis with microorganisms is presented by Akamatsu et al. Rice responses to bacteria and fungi via interactions between the plant pattern recognition receptors and the molecular microbe-associated molecular patterns are described in detail and suggested as targets for manipulation in order to increase disease resistance in crops. On the other hand, Bouain et al. are concerned about nutrient deficiency; specifically, how plant root system develops under growing conditions with inadequate phosphate. The authors overviewed our current understanding of the low phosphate-responsive mechanisms in Arabidopsis model plant, which was gained by using a combination of various advanced methods, including high-througput phenotyping, system biology analysis and "omics" technologies. Stress management in plants is proposed to be also achievable by regulating activities of cyclic nucleotide-gated ion channels. As emphasized in the paper of Jha et al., the application of such channels is important in mediating cellular ion homeostasis and plant tolerance to both biotic and abiotic stresses. In summary, with recent progresses in biological and biotechnological areas, especially rapid development of advanced technologies in biological system modeling, functional genomics, computer-based analyzing tools, genetic engineering and molecular breeding, biological control and biotechnological applications in agriculture have brought about an extraordinary revolution and have been considered the most powerful approaches in maintaining or even increasing crop yield. Therefore, in this issue, we would like to introduce to the audience a collection of various strategies used for enhancing crop productivity, with the focus on advanced biological-biotechnological platforms in the post-genomics era. PMID- 27499679 TI - Crosstalk of Signaling Mechanisms Involved in Host Defense and Symbiosis Against Microorganisms in Rice. AB - Rice is one of the most important food crops, feeding about half population in the world. Rice pathogens cause enormous damage to rice production worldwide. In plant immunity research, considerable progress has recently been made in our understanding of the molecular mechanisms underlying microbe-associated molecular pattern (MAMP)-triggered immunity. Using genome sequencing and molecular techniques, a number of new MAMPs and their receptors have been identified in the past two decades. Notably, the mechanisms for chitin perception via the lysine motif (LysM) domain-containing receptor OsCERK1, as well as the mechanisms for bacterial MAMP (e.g. flg22, elf18) perception via the leucine-rich repeat (LRR) domain-containing receptors FLS2 and EFR, have been clarified in rice and Arabidopsis, respectively. In chitin signaling in rice, two direct substrates of OsCERK1, Rac/ROP GTPase guanine nucleotide exchange factor OsRacGEF1 and receptor like cytoplasmic kinase OsRLCK185, have been identified as components of the OsCERK1 complex and are rapidly phosphorylated by OsCERK1 in response to chitin. Interestingly, OsCERK1 also participates in symbiosis with arbuscular mycorrhizal fungi (AMF) in rice and plays a role in the recognition of short-chitin molecules (CO4/5), which are symbiotic signatures included in AMF germinated spore exudates and induced by synthetic strigolactone. Thus, OsCERK1 contributes to both immunity and symbiotic responses. In this review, we describe recent studies on pathways involved in rice immunity and symbiotic signaling triggered by interactions with microorganisms. In addition, we describe recent advances in genetic engineering by using plant immune receptors and symbiotic microorganisms to enhance disease resistance of rice. PMID- 27499680 TI - Recent Advances in Understanding the Molecular Mechanisms Regulating the Root System Response to Phosphate Deficiency in Arabidopsis. AB - Phosphorus (P) is an essential macronutrient for plant growth and development. Inorganic phosphate (Pi) is the major form of P taken up from the soil by plant roots. It is well established that under Pi deficiency condition, plant roots undergo striking morphological changes; mainly a reduction in primary root length while increase in lateral root length as well as root hair length and density. This typical phenotypic change reflects complex interactions with other nutrients such as iron, and involves the activity of a large spectrum of plant hormones. Although, several key proteins involved in the regulation of root growth under Pi deficiency have been identified in Arabidopsis, how plants adapt roots system architecture in response to Pi availability remains an open question. In the current post-genomic era, state of the art technologies like high-throughput phenotyping and sequencing platforms,"omics" methods, together with the widespread use of system biology and genome-wide association studies will help to elucidate the genetic architectures of root growth on different Pi regimes. It is clear that the large-scale characterization of molecular systems will improve our understanding of nutrient stress phenotype and biology. Herein, we summarize the recent advances and future directions towards a better understanding of Arabidopsis root developmental programs functional under Pi deficiency. Such a progress is necessary to devise strategies to improve the Pi use efficiency in plants that is an important issue for agriculture. PMID- 27499681 TI - Role of Cyclic Nucleotide Gated Channels in Stress Management in Plants. AB - Tolerance of plants to a number of biotic and abiotic stresses such as pathogen and herbivore attack, drought, salinity, cold and nutritional limitations is ensued by complex multimodule signaling pathways. The outcome of this complex signaling pathways results in adaptive responses by restoring the cellular homeostasis and thus promoting survival. Functions of many plant cation transporter and channel protein families such as glutamate receptor homologs (GLRs), cyclic nucleotide-gated ion channel (CNGC) have been implicated in providing biotic and abiotic stress tolerance. Ion homeostasis regulated by several transporters and channels is one of the crucial parameters for the optimal growth, development and survival of all living organisms. The CNGC family members are known to be involved in the uptake of cations such as Na(+), K(+) and Ca(2+) and regulate plant growth and development. Detail functional genomics approaches have given an emerging picture of CNGCs wherein these protein are believed to play crucial role in pathways related to cellular ion homeostasis, development and as a 'guard' in defense against biotic and abiotic challenges. Here, we discuss the current knowledge of role of CNGCs in mediating stress management and how they aid plants in survival under adverse conditions. PMID- 27499682 TI - Genome-assisted Breeding For Drought Resistance. AB - Drought stress caused by unpredictable precipitation poses a major threat to food production worldwide, and its impact is only expected to increase with the further onset of climate change. Understanding the effect of drought stress on crops and plants' response is critical for developing improved varieties with stable high yield to fill a growing food gap from an increasing population depending on decreasing land and water resources. When a plant encounters drought stress, it may use multiple response types, depending on environmental conditions, drought stress intensity and duration, and the physiological stage of the plant. Drought stress responses can be divided into four broad types: drought escape, drought avoidance, drought tolerance, and drought recovery, each characterized by interacting mechanisms, which may together be referred to as drought resistance mechanisms. The complex nature of drought resistance requires a multi-pronged approach to breed new varieties with stable and enhanced yield under drought stress conditions. High throughput genomics and phenomics allow marker-assisted selection (MAS) and genomic selection (GS), which offer rapid and targeted improvement of populations and identification of parents for rapid genetic gains and improved drought-resistant varieties. Using these approaches together with appropriate genetic diversity, databases, analytical tools, and well-characterized drought stress scenarios, weather and soil data, new varieties with improved drought resistance corresponding to grower preferences can be introduced into target regions rapidly. PMID- 27499683 TI - Genomics Approaches For Improving Salinity Stress Tolerance in Crop Plants. AB - Salinity is one of the major factors which reduces crop production worldwide. Plant responses to salinity are highly complex and involve a plethora of genes. Due to its multigenicity, it has been difficult to attain a complete understanding of how plants respond to salinity. Genomics has progressed tremendously over the past decade and has played a crucial role towards providing necessary knowledge for crop improvement. Through genomics, we have been able to identify and characterize the genes involved in salinity stress response, map out signaling pathways and ultimately utilize this information for improving the salinity tolerance of existing crops. The use of new tools, such as gene pyramiding, in genetic engineering and marker assisted breeding has tremendously enhanced our ability to generate stress tolerant crops. Genome editing technologies such as Zinc finger nucleases, TALENs and CRISPR/Cas9 also provide newer and faster avenues for plant biologists to generate precisely engineered crops. PMID- 27499684 TI - Exploring Genetic Diversity in Plants Using High-Throughput Sequencing Techniques. AB - Food security has emerged as an urgent concern because of the rising world population. To meet the food demands of the near future, it is required to improve the productivity of various crops, not just of staple food crops. The genetic diversity among plant populations in a given species allows the plants to adapt to various environmental conditions. Such diversity could therefore yield valuable traits that could overcome the food-security challenges. To explore genetic diversity comprehensively and to rapidly identify useful genes and/or allele, advanced high-throughput sequencing techniques, also called next generation sequencing (NGS) technologies, have been developed. These provide practical solutions to the challenges in crop genomics. Here, we review various sources of genetic diversity in plants, newly developed genetic diversity-mining tools synergized with NGS techniques, and related genetic approaches such as quantitative trait locus analysis and genome-wide association study. PMID- 27499686 TI - Applications of DNA Technologies in Agriculture. AB - With the development of molecular biology, some DNA-based technologies have showed great potentiality in promoting the efficiency of crop breeding program, protecting germplasm resources, improving the quality and outputs of agricultural products, and protecting the eco-environment etc., making their roles in modern agriculture more and more important. To better understand the application of DNA technologies in agriculture, and achieve the goals to promote their utilities in modern agriculture, this paper describes, in some different way, the applications of molecular markers, transgenic engineering and gene's information in agriculture. Some corresponding anticipations for their development prospects are also made. PMID- 27499685 TI - Bioinformatics Approach in Plant Genomic Research. AB - The advance in genomics technology leads to the dramatic change in plant biology research. Plant biologists now easily access to enormous genomic data to deeply study plant high-density genetic variation at molecular level. Therefore, fully understanding and well manipulating bioinformatics tools to manage and analyze these data are essential in current plant genome research. Many plant genome databases have been established and continued expanding recently. Meanwhile, analytical methods based on bioinformatics are also well developed in many aspects of plant genomic research including comparative genomic analysis, phylogenomics and evolutionary analysis, and genome-wide association study. However, constantly upgrading in computational infrastructures, such as high capacity data storage and high performing analysis software, is the real challenge for plant genome research. This review paper focuses on challenges and opportunities which knowledge and skills in bioinformatics can bring to plant scientists in present plant genomics era as well as future aspects in critical need for effective tools to facilitate the translation of knowledge from new sequencing data to enhancement of plant productivity. PMID- 27499687 TI - Low carbohydrate diet-based intervention for obstructive sleep apnea and primary hypothyroidism in an obese Japanese man. AB - BACKGROUND: Obesity is a major risk factor for obstructive sleep apnea (OSA), and weight loss is necessary in the overall management of obese patients with OSA. However, primary care physicians can provide only limited weight loss with lifestyle interventions, usually reducing a patient's body weight by only 2.5 kg or less after 6-18 months. CASE PRESENTATION: A 45-year-old Japanese man was referred to our clinic owing to obesity, daytime sleepiness, and snoring during sleep. His weight was 130.7 kg and his body mass index (BMI) was 41.0 kg/m(2). He underwent polysomnography, which revealed OSA with an apnea-hypopnea index of 71.2 events/h (normal, <5 events/h). His laboratory results were as follows: thyroid stimulating hormone, >500 MUIU/mL; free triiodothyronine, 1.4 pg/mL; free thyroxine, <0.15 ng/dL; thyroid peroxidase antibody, 10 IU/mL; thyroglobulin antibody, >4000 IU/mL; total cholesterol (TC), 335 mg/dL; high-density lipoprotein cholesterol, 45 mg/dL; triglycerides (TGs), 211 mg/dL; low-density lipoprotein cholesterol, 248 mg/dL; fasting blood sugar, 86 mg/dL; and glycated hemoglobin (HbA1c), 6.1 %. These results showed that he also had primary hypothyroidism (Hashimoto's disease). Continuous positive airway pressure (CPAP), levothyroxine replacement, and a low-carbohydrate diet (LCD) were initiated. CPAP use and a euthyroid condition induced by 175 MUg/day levothyroxine allowed the patient to proactively reduce his body weight. After 18 months, the patient achieved a weight reduction of 32.4 kg (25 % of his initial weight) and a BMI reduction of 10.2 kg/m(2), as well as improved laboratory results, including an HbA1c level of 5.3 %, TC level of 194 mg/dL, and TG level of 89 mg/dL. CONCLUSION: An LCD may be an effective intervention for weight loss in obese Japanese patients with OSA. Further studies are needed to investigate the weight loss effect of an LCD compared with a conventional calorie-restricted diet. Hopefully, this case report will help to improve the management of obese Asian patients with OSA who typically consume a higher amount of carbohydrates. PMID- 27499688 TI - Pain Characteristics after Total Laparoscopic Hysterectomy. AB - Background. Total laparoscopic hysterectomy (TLH) causes various types of postoperative pain, and the pain pattern has not been evaluated in detail to date. This prospective observational study investigated the types of postoperative pain, intensity in the course of time, and pain characteristics during the first postoperative 72 hr after TLH. Methods. Sixty four female patients undergoing TLH were enrolled, which finally 50 patients were included for the data analyses. The locations of pain included overall pain, abdominal visceral and incisional pains, shoulder pain, and perineal pain. Assessments were made at rest and in motion, and pain level was scored with the use of the 100 mm visual analog scale. The pain was assessed at baseline, and at postoperative 30 min, 1 hr, 3 hr, 6 hr, 24 hr, 48 hr, and 72 hr. Results. Overall, visceral, and incisional pains were most intense on the day of operation and then decreased following surgery. In contrast, shoulder pain gradually increased, peaking at postoperative 24 hr. Shoulder pain developed in 90% of all patients (44/50). It was not more aggravated in motion than at rest, in comparison with other pains, and right shoulder pain was more severe than left shoulder pain (p=0.006). In addition, the preoperative exercise habit of patients increased the threshold of shoulder pain. Most patients (46/50) had perineal pain, which was more severe than abdominal pain in approximately 30% of patients (17/50). Conclusion. Pain after TLH showed considerably different duration, severity, and characteristics, compared with other laparoscopic procedures. Shoulder pain was most intense at postoperative 24 hr, and the intensity was associated with the prior exercise habit of patients and the high level of analgesic request. PMID- 27499689 TI - Heat-killed Lactobacillus Reuteri GMNL-263 Prevents Epididymal Fat Accumulation and Cardiac Injury in High-Calorie Diet-Fed Rats. AB - High-calorie diet-induced obesity leads to cardiomyocyte dysfunction and apoptosis. Impaired regulation of epididymal fat content in obese patients has been known to increase the risk of cardiac injury. In our study, a lactic acid bacteria, Lactobacillus reuteri GMNL-263, was evaluated for its potential to reduce body weight and body fat ratio and to prevent heart injury in rats with high-fat diet-induced obesity. Lactic acid bacteria supplementation restored the cardiac function and decreased the physiological changes in the heart of the obese rats. In addition, the Fas/Fas-associated protein pathway-induced caspase 3/e Poly polymerase mediated apoptosis in the cardiomyocytes of the obese rats was reversed in the Lr263-treated rats. These results reveal that fed with Lr-263 reduces body fat ratio, inhibits caspase 3-mediated apoptosis and restores cardiac function in obese rats through recovery of ejection fraction and fractional shortening. Our results indicated that the administration of Lr263 lactic acid bacteria can significantly down-regulate body fat and prevent cardiomyocyte injury in obese rats. PMID- 27499690 TI - Progress on Complications of Direct Bypass for Moyamoya Disease. AB - Moyamoya disease (MMD) involves progressive occlusion of the intracranial internal carotid artery resulting in formation of moyamoya-like vessels at the base of the brain. It can be characterized by hemorrhage or ischemia. Direct vascular bypass is the main and most effective treatment of MMD. However, patients with MMD differ from those with normal cerebral vessels. MMD patients have unstable intracranial artery hemodynamics and a poor blood flow reserve; therefore, during the direct bypass of superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis, perioperative risk factors and anesthesia can affect the hemodynamics of these patients. When brain tissue cannot tolerate a high blood flow rate, it becomes prone to hyperperfusion syndrome, which leads to neurological function defects and can even cause intracranial hemorrhage in severe cases. The brain tissue is prone to infarction when hemodynamic equilibrium is affected. In addition, bypass vessels become susceptible to occlusion or atrophy when blood resistance increases. Even compression of the temporalis affects bypass vessels. Because the STA is used in MMD surgery, the scalp becomes ischemic and is likely to develop necrosis and infection. These complications of MMD surgery are difficult to manage and are not well understood. To date, no systematic studies of the complications that occur after direct bypass in MMD have been performed, and reported complications are hidden among various case studies; therefore, this paper presents a review and summary of the literature in PubMed on the complications of direct bypass in MMD. PMID- 27499691 TI - The Neutrophil to Lymphocyte Ratio on Admission and Short-Term Outcomes in Orthogeriatric Patients. AB - AIM: To investigate the association of the neutrophil to lymphocyte ratio (NLR) at admission with presence of fracture, comorbid conditions, and its prognostic value for short-term outcomes in orthogeriatric patients. METHODS: On 415 consecutive patients (mean age 78.8 +/-8.7[SD] years, 281 women, 255 with a non vertebral bone fracture, including 167 with a hip fracture, HF) admitted to the Department of Orthopaedic Surgery at the Canberra hospital (2010 - 2011) data on clinical and laboratory characteristics were collected prospectively. The validation dataset included 294 consecutive patients (mean age 82.1 +/- 8.0 years, 72.1% women) with HF. RESULTS: Multivariate regression revealed four variables, presence of HF, hypoalbuminaemia (<33g/L), anaemia (<120g/L) and hyperparathyroidism (PTH>6.8 pmol/L), as independent determinants of admission NLR>=5.1. There was a dose-graded relationship between presence of fracture, especially HF, postoperative complications and levels of NLR categorized as tertiles. Compared to patients with NLR<5.1(first tertile), patients with NLR 5.1 8.5 (second tertile) had a 1.8-, 3.1-, 2.6-, and 2.5-fold higher risk for presence of any fracture, HF, developing postoperative myocardial injury (troponin I rise) and a high inflammatory response/infection (CRP>100mg/L after the 3rd postoperative day), respectively, while in subjects with NLR>8.5 (third tertile) these risks were 2.6-, 4.9-, 5.9- and 4.5-times higher, respectively; subjects with NLR>8.5 had a 9.7 times higher chance of dying in the hospital compared to patients with NLR 5.1-8.5; the NLR retained its significance on multivariate analyses. The NLR >=5.1 predicted postoperative myocardial injury with an area under the curve (AUC) of 0.626, CRP>100mg/L with AUC of 0.631 and the NLR >8.5 predicted in-hospital mortality with an AUC of 0.793, showing moderately high sensitivity (86.7%, 80% and 90%, respectively) and negative predictive value (92.9%, 71.2%, 99.6%, respectively), but low specificity. Admission NLR was superior to other, except hypoalbuminaemia, prognostic markers; combined use of both NLR>=5.1 and albumin<33g/L only moderately increased the accuracy of prediction. The validation study confirmed the prognostic value of the admission NLR. CONCLUSIONS: In orthogeriatric patients, high NLR on admission is an independent indicator of fracture presence, a significant risk factor and moderate predictor of postoperative myocardial injury, high inflammatory response/infection and in-hospital death. PMID- 27499692 TI - Wnt5a Suppresses beta-catenin Signaling during Hair Follicle Regeneration. AB - Hair follicles display periodic growth. Wnt signaling is a critical regulator for hair follicle regeneration. Previously, we reported that Wnt5a inhibits the telogen-to-anagen transition of hair follicles, but the mechanism by which this process occurs has not yet been reported. Here, we determined the expression patterns of Wnt signaling pathway molecules by quantitative reverse transcription polymerase chain reaction, western blot, and immunohistochemistry and found that beta-catenin signaling was suppressed by Wnt5a. We then compared the phenotypes and expression patterns following beta-catenin knockdown and Wnt5a overexpression during hair follicle regeneration induced by hair depilation and observed similar patterns. In addition, we performed a rescue experiment in the JB6 cell line and found that the inhibitory effect of Wnt5a on cell proliferation could be rescued by the addition of Wnt3a. Our data reveal that Wnt5a suppresses the activation of beta-catenin signaling during hair follicle regeneration. PMID- 27499693 TI - NLS-RARalpha Inhibits the Effects of All-trans Retinoic Acid on NB4 Cells by Interacting with P38alpha MAPK. AB - Nuclear localization signal retinoic acid receptor alpha(NLS-RARalpha), which forms from the cleavage of promyelocytic leukemia-retinoic acid receptor alpha(PML-RARalpha) protein by neutrophil elastase(NE), possesses an important role in the occurrence and development of acute promyelocytic leukemia(APL). However, the potential mechanism underlying the effects of NLS-RARalpha on APL is still not entirely clear. Here, we investigated the effects of NLS-RARalpha on APL NB4 cells and its mechanism. We found that all-trans retinoic acid(ATRA) could promote differentiation while inhibit proliferation of APL NB4 cells via upregulating the expression of phosphorylated p38alpha mitogen-activated protein kinase(p-p38alpha MAPK). We also found that NLS-RARalpha could inhibit differentiation while accelerate proliferation of NB4 cells via downregulating the expression of p-p38alpha protein in the presence of ATRA. Furthermore, immunofluorescence and co-immunoprecipitation assays confirmed NLS-RARalpha interacted with p38alpha protein directly. Finally, application of PD169316, an inhibitor of p38alpha protein, suggested that recruitment p38alpha-combinded NLS RARalpha by ATRA eventually caused activation of p38alpha protein. In summary, our study demonstrated that ATRA cound promote differentiation while inhibit proliferation of APL NB4 cells via activating p38alpha protein after recruiting p38alpha-combinded NLS-RARalpha, while NLS-RARalpha could inhibit the effects of ATRA in the process. PMID- 27499694 TI - Predictive Value of Echocardiographic Abnormalities and the Impact of Diastolic Dysfunction on In-hospital Major Cardiovascular Complications after Living Donor Kidney Transplantation. AB - Patients with end-stage renal disease (ESRD) show characteristic abnormalities in cardiac structure and function. We evaluated the influence of these abnormalities on adverse cardiopulmonary outcomes after living donor kidney transplantation in patients with valid preoperative transthoracic echocardiographic evaluation. We then observed any development of major postoperative cardiovascular complications and pulmonary edema until hospital discharge. In-hospital major cardiovascular complications were defined as acute myocardial infarction, ventricular fibrillation/tachycardia, cardiogenic shock, newly-onset atrial fibrillation, clinical pulmonary edema requiring endotracheal intubation or dialysis. Among the 242 ESRD study patients, 9 patients (4%) developed major cardiovascular complications, and 39 patients (16%) developed pulmonary edema. Diabetes, ischemia-reperfusion time, left ventricular end-diastolic diameter (LVEDd), left ventricular mass index (LVMI), right ventricular systolic pressure (RVSP), left atrium volume index (LAVI), and high E/E' ratios were risk factors of major cardiovascular complications, while age, LVEDd, LVMI, LAVI, and high E/E' ratios were risk factors of pulmonary edema. The optimal E/E' cut-off value for predicting major cardiovascular complications was 13.0, showing 77.8% sensitivity and 78.5% specificity. Thus, the patient's E/E' ratio is useful for predicting in hospital major cardiovascular complications after kidney transplantation. We recommend that goal-directed therapy employing E/E' ratio be enacted in kidney recipients with baseline diastolic dysfunction to avert postoperative morbidity. (http://Clinical Trials.gov number: NCT02322567). PMID- 27499695 TI - Role of the ERK1/2 Signaling Pathway in Osteogenesis of Rat Tendon-Derived Stem Cells in Normoxic and Hypoxic Cultures. AB - BACKGROUND: Ectopic ossification and increased vascularization are two common phenomena in the chronic tendinopathic tendon. The increased vascularization usually leads to an elevated local oxygen tension which is one of micro environments that can influence differentiate status of stem cells. OBJECTIVE: This study aimed to investigate the osteogenesis capacity of rat tendon-derived stem cells TDSCs (rTDSCs) in normoxic and hypoxic cultures, and to study the role of ERK1/2 signaling pathway in this process. METHODS: rTDSCs were subjected to osteogenesis inductive culture in hypoxic (3% O2) and normoxic (20% O2) conditions. The inhibitor U0126 was added along with culture medium to determine the role of ERK1/2 signaling pathway. Cell viability, cell proliferation, alizarin red staining, alkaline phosphatase (AKP) activity, gene expression (ALP, osteocalcin, collagen I and RUNX2) and protein expression (p-ERK1/2 and RUNX2) of osteogenic-cultured rTSDCs were analyzed in this study. RESULTS: Hypoxic and normoxic culture had no effects on cell viability of rTDSCs, whereas the proliferation potential of rTDSCs was significantly increased in hypoxic culture. The osteogenesis capacity of rTDSCs in normoxic culture was significantly promoted compared with hypoxic culture, which was reflected by an increased alizarin red staining intensity, an elevated ALP activity, and the up-regulated gene (ALP, osteocalcin, collagen I and RUNX2) or protein (RUNX2) expression of osteogenic makers. However, the osteogenesis capacity of rTDSCs in both hypoxic and normoxic cultures was attenuated by the inhibitor U0126. CONCLUSION: Normoxic culture promotes osteogenic differentiation of rTDSCs compared with the hypoxic culture, and the ERK1/2 signaling pathway is involved in this process. PMID- 27499696 TI - Elevated Plasma Matrix Metalloproteinase-9 and Its Correlations with Severity of Disease in Patients with Ventilator-Associated Pneumonia. AB - Ventilator-associated pneumonia (VAP) increases patient mortality and medical expenditure, and a real-time and reliable method for the rapid diagnosis of VAP may help reduce fatal complications. Matrix metalloproteinases-9 (MMP-9) is considered significant in the pathogenesis of lung inflammation and infection. Therefore, we examined its relationship with the clinical course of VAP. This retrospective observational study recruited 30 healthy volunteers, 12 patients who used mechanical ventilation without the development of VAP (hereafter, patients without VAP), and 30 patients with a clinical diagnosis of VAP (hereafter, patients with VAP). The activity and level of plasma MMP-9 were determined through a gelatin zymography assay and ELISA. Our results report that both plasma MMP-9 activity and concentration were significantly elevated in the acute stage of patients with VAP when compared with control group and patients without VAP (p < 0.001). Subsequently, the plasma MMP-9 of patients with VAP decreased significantly after antibiotic treatment. Furthermore, plasma MMP-9 concentration was positively correlated with the clinical pulmonary infection score (r = 0.409, p = 0.007), WBCs (r = 0.620, p < 0.001), and neutrophils counts (r = 0.335, p = 0.035). In addition, plasma MMP-9 is an excellent tool for recognizing VAP when the cutoff level is set to 92.62 ng/mL (AUC = 0.863, 95% CI = 0.761 to 0.932). In conclusions, we concluded that MMP-9 levels play a role in the development of VAP and might have the potential to be applied in the development of VAP therapies. PMID- 27499697 TI - NOX2 Antisense Attenuates Hypoxia-Induced Oxidative Stress and Apoptosis in Cardiomyocyte. AB - Heart ischemia is a hypoxia related disease. NOX2 and HIF-1alpha proteins were increased in cardiomyocytes after acute myocardial infarction. However, the relationship of the hypoxia-induced HIF-1alpha. NOX2-derived oxidative stress and apoptosis in cardiomyocyte remains unclear. In the current study, we use NOX2 antisense strategy to investigate the role of NOX2 in hypoxia-induced oxidative stress and apoptosis in rat cardiomyocytes. Here, we show that transduction of ADV-NOX2-AS induces potent silencing of NOX2 in cardiomyocytes, and resulting in attenuation of hypoxia-induced oxidative stress and apoptosis. This study indicates the potential of antisense-based therapies and validates NOX2 as a potent therapeutic candidate for heart ischemia. PMID- 27499698 TI - Cross-scale integration of knowledge for predicting species ranges: a metamodeling framework. AB - AIM: Current interest in forecasting changes to species ranges have resulted in a multitude of approaches to species distribution models (SDMs). However, most approaches include only a small subset of the available information, and many ignore smaller-scale processes such as growth, fecundity, and dispersal. Furthermore, different approaches often produce divergent predictions with no simple method to reconcile them. Here, we present a flexible framework for integrating models at multiple scales using hierarchical Bayesian methods. LOCATION: Eastern North America (as an example). METHODS: Our framework builds a metamodel that is constrained by the results of multiple sub-models and provides probabilistic estimates of species presence. We applied our approach to a simulated dataset to demonstrate the integration of a correlative SDM with a theoretical model. In a second example, we built an integrated model combining the results of a physiological model with presence-absence data for sugar maple (Acer saccharum), an abundant tree native to eastern North America. RESULTS: For both examples, the integrated models successfully included information from all data sources and substantially improved the characterization of uncertainty. For the second example, the integrated model outperformed the source models with respect to uncertainty when modelling the present range of the species. When projecting into the future, the model provided a consensus view of two models that differed substantially in their predictions. Uncertainty was reduced where the models agreed and was greater where they diverged, providing a more realistic view of the state of knowledge than either source model. MAIN CONCLUSIONS: We conclude by discussing the potential applications of our method and its accessibility to applied ecologists. In ideal cases, our framework can be easily implemented using off-the-shelf software. The framework has wide potential for use in species distribution modelling and can drive better integration of multi source and multi-scale data into ecological decision-making. PMID- 27499699 TI - Review article: outcomes in endoscopic sinus surgery. AB - Chronic rhinosinusitis has a significant impact on health-related and generic quality-of-life, has a high cost burden to both society and patients, and may be associated with absenteeism, loss of productivity and poor respiratory function. Though there is a paucity of level 1 evidence, endoscopic sinus surgery may be considered in medically refractory patients and a variety of objective and subjective outcome measures exist to assess the effectiveness of intervention. We outline the outcome measurements available and review in-depth the published outcomes to date. Furthermore we discuss the literature that indicates that endoscopic sinus surgery can have a positive effect on respiratory function in asthma. How patient selection, timing and extent of surgery, and post-operative care interventions may optimise surgical outcomes is explored. PMID- 27499700 TI - Tinnitus- related distress: evidence from fMRI of an emotional stroop task. AB - BACKGROUND: Chronic tinnitus affects 5 % of the population, 17 % suffer under the condition. This distress seems mainly to be dependent on negative cognitive emotional evaluation of the tinnitus and selective attention to the tinnitus. A well-established paradigm to examine selective attention and emotional processing is the Emotional Stroop Task (EST). Recent models of tinnitus distress propose limbic, frontal and parietal regions to be more active in highly distressed tinnitus patients. Only a few studies have compared high and low distressed tinnitus patients. Thus, this study aimed to explore neural correlates of tinnitus-related distress. METHODS: Highly distressed tinnitus patients (HDT, n = 16), low distressed tinnitus patients (LDT, n = 16) and healthy controls (HC, n = 16) underwent functional magnetic resonance imaging (fMRI) during an EST, that used tinnitus-related words and neutral words as stimuli. A random effects analysis of the fMRI data was conducted on the basis of the general linear model. Furthermore correlational analyses between the blood oxygen level dependent response and tinnitus distress, loudness, depression, anxiety, vocabulary and hypersensitivity to sound were performed. RESULTS: Contradictory to the hypothesis, highly distressed patients showed no Stroop effect in their reaction times. As hypothesized HDT and LDT differed in the activation of the right insula and the orbitofrontal cortex. There were no hypothesized differences between HDT and HC. Activation of the orbitofrontal cortex and the right insula were found to correlate with tinnitus distress. CONCLUSIONS: The results are partially supported by earlier resting-state studies and corroborate the role of the insula and the orbitofrontal cortex in tinnitus distress. PMID- 27499701 TI - Dried blood spot omega-3 and omega-6 long chain polyunsaturated fatty acid levels in 7-9 year old Zimbabwean children: a cross sectional study. AB - BACKGROUND: Omega-3 long chain-polyunsaturated fatty acids (LC-PUFAs) docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and eicosapentaenoic acid (EPA)- and omega-6 LC-PUFA arachidonic acid (ARA), are essential for optimum physical and mental development in children. Prior to this study, the blood omega 3 LC-PUFA levels were unknown in Zimbabwean children, particularly in those aged 7-9 years, despite the documented benefits of LC-PUFAs. Documentation of the LC PUFA levels in this age group would help determine whether interventions, such as fortification, are necessary. This study aimed to determine dried whole blood spot omega-3 and omega-6 LC-PUFA levels and LC-PUFA reference intervals among a selected group of Zimbabwean children aged 7-9 years old. METHODS: We conducted a cross sectional study from September 2011 to August 2012 on a cohort of peri urban, Zimbabwean children aged 7-9 years. The children were born to mothers enrolled at late pregnancy into an HIV prevention program between 2002 and 2004. Dried whole blood spots were sampled on butylated hydroxytoluene antioxidant impregnated filter papers and dried. LC-PUFAs were quantified using gas liquid chromatography. Differences in LC-PUFAs between groups were compared using the Kruskal Wallis test and reference intervals determined using non-parametric statistical methods. RESULTS: LC-PUFAs levels were determined in 297 Zimbabwean children of whom 170 (57.2 %) were girls. The study determined that LC-PUFAs (wt/wt) ranges were EPA 0.06-0.55 %, DPA 0.38-1.98 %, DHA 1.13-3.52 %, ARA 5.58 14.64 % and ARA: EPA ratio 15.47-1633.33. Sixteen participants had omega-3 LC PUFAs levels below the determined reference intervals, while 18 had higher omega 6 LC-PUFAs. The study did not show gender differences in omega-3 and omega-6 LC PUFAs levels (all p > 0.05). EPA was significantly higher in the 8 year age group compared to those aged 7 and 9 years (median; 0.20 vs 0.17 vs 0.18, respectively, p = 0.049). ARA: EPA ratio was significantly higher in the 7 year age group compared to those aged 8 and 9 years (median; 64.38 vs 56.43 vs 55.87 respectively, p = 0.014). CONCLUSIONS: In this cohort of children, lower EPA levels and higher ARA: EPA ratios were observed compared to those reported in apparently healthy children elsewhere. The high ARA: EPA ratios might increase the vulnerability of these children to inflammatory pathologies. Identification and incorporation into diet of locally produced foodstuffs rich in omega-3 LC PUFAs is recommended as well as advocating for dietary supplementation with omega 3 fish oils and algae based oils. PMID- 27499702 TI - Pre-term and post-term births: predictors and implications on neonatal mortality in Northern Ethiopia. AB - BACKGROUND: Pre-term and post-term births are major determinants of neonatal mortality, including short- and long-term morbidity. In developing countries, where pre-term and post-term births are disproportionately common, the magnitude and underlying causes are not well understood, and evidence is required to design appropriate interventions. This study measured the incidence and identified risk factors of pre-term birth and post-term births in Ethiopia. In addition, it examined the effects of pre-term and post-term birth on neonatal mortality. METHOD: This study is a portion of prospective cohort study conducted on 1152 live births born between April and July 2014 in seven hospitals in Tigray region, Northern Ethiopia. Neonatal mortality and birth outcomes were considered as dependent variables. Data were collected using a structured questionnaire and weekly neonatal follow up directed at midwives. Data were described using frequency, percentage, ratio of relative risk (RRR), and 95 % confidence interval (CI). We used multinomial and binary logistic regression to identify independent predictors of birth outcome and neonatal mortality respectively. RESULT: The prevalence of pre-term and post term births was 8.1 % and 6.0 % respectively. Underweight maternal body mass index (RRR: 0.47, CI: 0.22-0.99), medium reported income (RRR: 0.26, CI: 0.12-0.5), length of neonate (RRR: 0.05, CI: 0.01-0.41), and multiple births (RRR: 2.86, CI: 1.4-5.650) were associated with pre-term birth. Predictors for post-term birth were overweight maternal body mass index (RRR: 3.88, CI: 1.01-15.05), high reported income mothers (RRR: 2.17, CI:1.1 4.3), as well as unmarried, widowed and divorced marital status (RRR:2.43, CI:1.02-5.80). With regards to binary logistic regression, pre-term birth (RR: 2.45, CI: 1.45-4.04) was an independent predictor for neonatal mortality, but this was not true for post-term births (RR: 0.45, CI: 0.07-2.96). CONCLUSION: Socioeconomic and proximate factors are important predictors for pre-term and post-term births. Empowering women in terms of income status and controlling body mass index within the normal range are recommended. In addition, early detection and close antenatal follow-ups for mothers, who are at risk before and during pregnancy, are necessary to prevent both pre-term and post-term births. PMID- 27499703 TI - MiR-20a-5p represses multi-drug resistance in osteosarcoma by targeting the KIF26B gene. AB - BACKGROUND: Chemoresistance hinders curative cancer chemotherapy in osteosarcoma (OS), resulting in only an approximately 20 % survival rate in patients with metastatic disease at diagnosis. Identifying the mechanisms responsible for regulating chemotherapy resistance is crucial for improving OS treatment. METHODS: This study was performed in two human OS cell lines (the multi chemosensitive OS cell line G-292 and the multi-chemoresistant OS cell line SJSA 1). The levels of miR-20a-5p and KIF26B mRNA expression were determined by quantitative real-time PCR. KIF26B protein levels were determined by western blot analysis. Cell viability was assessed by MTT assay. Apoptosis was evaluated by flow cytometry. RESULTS: We found that miR-20a-5p was more highly expressed in G 292 cells than in SJSA-1 cells. Forced expression of miR-20a-5p counteracted OS cell chemoresistance in both cell culture and tumor xenografts in nude mice. One of miR-20a-5p's targets, kinesin family member 26B (KIF26B), was found to mediate the miR-20a-5p-induced reduction in OS chemoresistance by modulating the activities of the MAPK/ERK and cAMP/PKA signaling pathways. CONCLUSIONS: In addition to providing mechanistic insights, our study revealed that miR-20a-5p and KIF26B contribute to OS chemoresistance and determined the roles of these genes in this process, which may be critical for characterizing drug responsiveness and overcoming chemoresistance in OS patients. PMID- 27499704 TI - Vitamin D3 improves the effects of low dose Der p 2 allergoid treatment in Der p 2 sensitized BALB/c mice. AB - BACKGROUND: Airborne allergens can induce an immunological chronic disease characterized by airway hyper responsiveness and inflammation, mediated by exaggerated Th2 immune response. Allergen-specific immunotherapy (AIT) is effective for treating this condition because it is able to modify its natural course by opposing the underlying pathogenic mechanisms and determining immune suppression, immune deviation and tolerance. The rational for the present study was to investigate the possibility of improving allergoid-based IT in terms of efficacy and safety. Recently, 1alpha,25-dihydroxyvitamin D3 (VD3), the active metabolite of vitamin D3, was described to be a potent inducer of T regulatory cells and to be a good adjuvant in AIT settings. METHODS: We investigated whether the co-administration of VD3 could potentiate the effect of AIT even when added to a low dose of chemically-modified monomeric allergoid of Der p 2 (d2-OID), in a Derp p 2 (d2)-sensitized BALB/c mice model. Control groups where treated with sham, VD3 alone or d2-OID only. RESULTS: The d2-OID alone was not fully successful, as expected for a low dose. VD3 administration was associated with some valuable, although limited, changes in the immunological parameters in the lung. On the contrary, the VD3 adjuvated allergoid vaccine induced the most prominent reduction of airway eosinophilia and Th2 cytokines and concomitant increase of T regulatory cells and IL-10 in the lung and Der p 2-specific IgG2a in the serum. CONCLUSIONS: The addition of VD3 to a conventional AIT protocol would allow the reduction of allergoid dose needed and therefore, the production costs. Moreover, beneficial immunomodulatory effects have been achieved by the oral administration which might favour the management of the therapy by the patients and their adherence, possibly enhancing the efficacy of the treatment. PMID- 27499705 TI - The Utility of Template Analysis in Qualitative Psychology Research. AB - Thematic analysis is widely used in qualitative psychology research, and in this article, we present a particular style of thematic analysis known as Template Analysis. We outline the technique and consider its epistemological position, then describe three case studies of research projects which employed Template Analysis to illustrate the diverse ways it can be used. Our first case study illustrates how the technique was employed in data analysis undertaken by a team of researchers in a large-scale qualitative research project. Our second example demonstrates how a qualitative study that set out to build on mainstream theory made use of the a priori themes (themes determined in advance of coding) permitted in Template Analysis. Our final case study shows how Template Analysis can be used from an interpretative phenomenological stance. We highlight the distinctive features of this style of thematic analysis, discuss the kind of research where it may be particularly appropriate, and consider possible limitations of the technique. We conclude that Template Analysis is a flexible form of thematic analysis with real utility in qualitative psychology research. PMID- 27499706 TI - Severe personality disorder, treatment engagement and the Legal Aid, Sentencing and Punishment of Offenders Act 2012: what you need to know. AB - Empirical research has demonstrated a link between legal coercion and treatment engagement following conviction among those with severe personality disorder. Legal coercive pressures were often applied by the Indeterminate Sentence for Public Protection (IPP), until it was replaced by the Extended Determinate Sentence by the Legal Aid, Sentencing and Punishment of Offenders Act 2012. In this paper, it is proposed that use of the new determinate sentence will lessen motivation for treatment engagement. One effect of treatment refusal may be greater reliance by the Secretary of State for Justice on his jurisdiction to transfer prisoners due for release to secure hospital transfers under the Mental Health Act 1983. Not only will this risk posturing undermine the principal aim of the Offender Personality Disorder Implementation Pathway to improve treatment engagement among the target group, it will also have negative implications for medical practitioners working in secure forensic hospitals. To demonstrate what is at stake, the paper briefly recapitulates empirical findings familiar to readers of the journal, before drawing on original unpublished data. PMID- 27499707 TI - Measuring Community Resilience to Coastal Hazards along the Northern Gulf of Mexico. AB - The abundant research examining aspects of social-ecological resilience, vulnerability, and hazards and risk assessment has yielded insights into these concepts and suggested the importance of quantifying them. Quantifying resilience is complicated by several factors including the varying definitions of the term applied in the research, difficulties involved in selecting and aggregating indicators of resilience, and the lack of empirical validation for the indices derived. This paper applies a new model, called the resilience inference measurement (RIM) model, to quantify resilience to climate-related hazards for 52 U.S. counties along the northern Gulf of Mexico. The RIM model uses three elements (exposure, damage, and recovery indicators) to denote two relationships (vulnerability and adaptability), and employs both K-means clustering and discriminant analysis to derive the resilience rankings, thus enabling validation and inference. The results yielded a classification accuracy of 94.2% with 28 predictor variables. The approach is theoretically sound and can be applied to derive resilience indices for other study areas at different spatial and temporal scales. PMID- 27499708 TI - Tension on dsDNA bound to ssDNA-RecA filaments may play an important role in driving efficient and accurate homology recognition and strand exchange. AB - It is well known that during homology recognition and strand exchange the double stranded DNA (dsDNA) in DNA/RecA filaments is highly extended, but the functional role of the extension has been unclear. We present an analytical model that calculates the distribution of tension in the extended dsDNA during strand exchange. The model suggests that the binding of additional dsDNA base pairs to the DNA/RecA filament alters the tension in dsDNA that was already bound to the filament, resulting in a non-linear increase in the mechanical energy as a function of the number of bound base pairs. This collective mechanical response may promote homology stringency and underlie unexplained experimental results. PMID- 27499709 TI - Fast Sequential Creation of Random Realizations of Degree Sequences. AB - We examine the problem of creating random realizations of very large degree sequences. Although fast in practice, the Markov chain Monte Carlo (MCMC) method for selecting a realization has limited usefulness for creating large graphs because of memory constraints. Instead, we focus on sequential importance sampling (SIS) schemes for random graph creation. A difficulty with SIS schemes is assuring that they terminate in a reasonable amount of time. We introduce a new sampling method by which we guarantee termination while achieving speed comparable to the MCMC method. PMID- 27499710 TI - Personalizing Patient Care. PMID- 27499711 TI - Gastro-Hep News. PMID- 27499712 TI - Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection. AB - Chronic hepatitis C virus (HCV) infection is associated with many extrahepatic manifestations that contribute to morbidity and mortality. It is especially important to be aware of metabolic manifestations and serious complications that affect other organs and cancer risks. Chronic HCV infection itself contributes to de novo development of insulin resistance and hepatic steatosis, both of which increase the risk of cardiovascular diseases. Through these metabolic pathways (as well as through other hypothesized mechanisms that involve lipid metabolism, systemic inflammatory signals, and endothelial dysfunction), chronic HCV infection also contributes to significant systemic cardiovascular morbidity and mortality. While chronic HCV infection contributes to incident development of metabolic complications, the presence of concurrent metabolic diseases also contributes to disease progression, such as higher risks of hepatocellular carcinoma and progression to advanced fibrosis, among patients with chronic HCV infection. The implications of these observations are particularly important given the rising prevalence of obesity and metabolic syndrome in the United States and worldwide. Furthermore, concurrent nonalcoholic fatty liver disease, either as a result of underlying metabolic syndrome or as a direct result of HCV induced fatty liver disease, further complicates the management of chronic HCV infected patients. Greater awareness is needed toward the systemic manifestations of chronic HCV infection, with focused attention on the associated metabolic manifestations and complications. Successful treatment and cure of chronic HCV infection with the currently available, highly effective antiviral therapies will significantly improve long-term outcomes among these patients. It is also important to recognize and address the associated metabolic manifestations and complications to reduce cardiovascular-related morbidity and mortality. PMID- 27499714 TI - Henoch-Schonlein Purpura With Gastrointestinal Involvement in an Adult Patient. PMID- 27499713 TI - A Personalized Approach to Managing Inflammatory Bowel Disease. AB - The management of inflammatory bowel disease (IBD) requires a personalized approach to treat what is a heterogeneous group of patients with inherently variable disease courses. In its current state, personalized care of the IBD patient involves identifying patients at high risk for rapid progression to complications, selecting the most appropriate therapy for a given patient, using therapeutic drug monitoring, and achieving the individualized goal that is most appropriate for that patient. The growing body of research in this area allows clinicians to better predict outcomes for individual patients. Some paradigms, especially within the realm of therapeutic drug monitoring, have begun to change as therapy is targeted to individual patient results and goals. Future personalized medical decisions may allow specific therapeutic plans to draw on serologic, genetic, and microbial data for Crohn's disease and ulcerative colitis patients. PMID- 27499715 TI - Effects of Opioids on Esophageal Dysfunction. PMID- 27499716 TI - Sedation in Colonoscopy. PMID- 27499717 TI - Management of Lysosomal Acid Lipase Deficiency for the Gastroenterologist and Hepatologist. PMID- 27499718 TI - Clostridium difficile Infection and Inflammatory Bowel Disease. PMID- 27499719 TI - Acute Compartment Syndrome of the Lower Leg: A Review. AB - Acute compartment syndrome (ACS) of the lower leg is a time-sensitive orthopedic emergency that relies heavily on precise clinical findings. Late findings of ACS can lead to limb amputation, contractures, paralysis, multiorgan failure, and death. Hallmark symptoms of ACS include the 6 P's: pain, poikilothermia, pallor, paresthesia, pulselessness, and paralysis. Suspicion of ACS is confirmed by measurement of intracompartmental pressure of the affected compartment. The definitive treatment of ACS is timely fasciotomy. We review the pathophysiology, common causes, diagnosis, and treatment of this potentially devastating condition. PMID- 27499720 TI - Quantification of angiotensin II-regulated proteins in urine of patients with polycystic and other chronic kidney diseases by selected reaction monitoring. AB - BACKGROUND: Angiotensin-II (Ang II) mediates progression of autosomal-dominant polycystic kidney disease (ADPKD) and other chronic kidney diseases (CKD). However, markers of kidney Ang II activity are lacking. We previously defined 83 Ang II-regulated proteins in vitro, which reflected kidney Ang II activity in vivo. METHODS: In this study, we developed selected reaction monitoring (SRM) assays for quantification of Ang II-regulated proteins in urine of ADPKD and CKD patients. We demonstrated that 47 of 83 Ang II-regulated transcripts were differentially expressed in cystic compared to normal kidney tissue. We then developed SRM assays for 18 Ang II-regulated proteins overexpressed in cysts and/or secreted in urine. Methods that yielded CV <= 6 % for control proteins, and recovery ~100 % were selected. Heavy-labeled peptides corresponding to 13 identified Ang II-regulated peptides were spiked into urine samples of 17 ADPKD patients, 9 patients with CKD predicted to have high kidney Ang II activity and 11 healthy subjects. Samples were then digested and analyzed on triple-quadrupole mass spectrometer in duplicates. RESLUTS: Calibration curves demonstrated linearity (R(2) > 0.99) and within-run CVs < 9 % in the concentration range of 7/13 peptides. Peptide concentrations were normalized by urine creatinine. Deamidated peptide forms were monitored, and accounted for <15 % of the final concentrations. Urine excretion rates of proteins BST1, LAMB2, LYPA1, RHOB and TSP1 were significantly different (p < 0.05, one-way ANOVA) between patients with CKD, those with ADPKD and healthy controls. Urine protein excretion rates were highest in CKD patients and lowest in ADPKD patients. Univariate analysis demonstrated significant association between urine protein excretion rates of most proteins and disease group (p < 0.05, ANOVA) as well as sex (p < 0.05, unpaired t test). Multivariate analysis across protein concentration, age and sex demonstrated good separation between ADPKD and CKD patients. CONCLUSIONS: We have optimized methods for quantification of Ang II-regulated proteins, and we demonstrated that they reflected differences in underlying kidney disease in this pilot study. High urine excretion of Ang II-regulated proteins in CKD patients likely reflects high kidney Ang II activity. Low excretion in ADPKD appears related to lack of communication between cysts and tubules. Future studies will determine whether urine excretion rate of Ang II-regulated proteins correlates with kidney Ang II activity in larger cohorts of chronic kidney disease patients. PMID- 27499721 TI - Biosynthesis of glycerol phosphate is associated with long-term potentiation in hippocampal neurons. AB - INTRODUCTION: Neurons have a very high energy requirement, and their metabolism is tightly regulated to ensure delivery of adequate substrate to sustain neuronal activity and neuroplastic changes. The mechanisms underlying the regulation of neuronal metabolism, however, are not completely clear. OBJECTIVE: The objective of this study was to investigate the central carbon metabolism in neurons, in order to identify the regulatory pathways governing neuronal anabolism and catabolism. METHODS: Here we first have applied MS-based endometabolomics to elucidate the metabolic dynamics in cultured hippocampal primary neurons. Using nanoLC-ESI-LTQ Orbitrap MS approach followed by statistical analysis, we measure the dynamics of uniformly labeled 13C-glucose entering neurons. We adapted the method by coupling offline patch-clamp setup with MS to confirm findings in vivo. RESULTS: According to non-parametric statistical analysis of metabolic dynamics, in cultured hippocampal neurons, the glycerol phosphate shuttle is active and correlates with the metabolic flux in the pentose phosphate pathway. In the hippocampus, glycerol-3-phosphate biosynthesis was activated in response to long term potentiation together with the upregulation of glycolysis and the TCA cycle, but was inactive or silenced in basal conditions. CONCLUSIONS: We identified the biosynthesis of glycerol-3-phosphate as a key regulator in mechanisms implicated in learning and memory. Notably, defects in enzymes linked with the glycerol phosphate shuttle have been implicated in neurological disorders and intellectual disability. These results could improve our understanding of the general mechanisms of learning and memory and facilitate the development of novel therapies for metabolic disorders linked with intellectual disability. PMID- 27499722 TI - Bone Marrow-Derived Cells in the Pathogenesis of Lung Fibrosis. AB - Progressive pulmonary fibrosis is characterized by failed alveolar reepithelialization and fibroblast/myofibroblast accumulation, with deposition of extracellular matrix. This results in loss of lung elasticity, alveolar collapse and fibrosis, impaired gas exchange and progressive decline in pulmonary function. Myofibroblasts represent an activated, contractile cellular phenotype that are potent producers of collagen and other extracellular matrix proteins. It is generally thought that myofibroblasts derive from local tissue fibroblasts. However, recent evidence suggests a portion of the progenitors for these cells may arise from the bone marrow. Fibrocytes, which share both leukocyte and mesenchymal markers, are found in increased numbers in bone marrow and lung of injured mice. Fibrocytes circulate in blood and are recruited to injured sites via chemotactic signals. Studies with bone marrow chimeric and parabiotic mice suggest that fibroblasts (and in some cases myofibroblasts) arise from circulating bone marrow precursors. Chemokine and chemokine receptor interactions are critical for the recruitment of bone marrow-derived progenitors. Once fibrocytes arrive in injured tissues, local factors induce their differentiation into fibroblasts/myofibroblasts. This review will summarize the experimental findings, supporting a role for the participation of bone marrow-derived cells in animal models of lung fibrosis, and potential implications for the pathogenesis of fibrotic lung diseases. PMID- 27499723 TI - Gender differences in age of smoking initiation and its association with health. AB - BACKGROUND: It is generally accepted that smoking starts in adolescence and earlier initiation is associated with more negative health outcomes. Some research suggests that women initiate smoking at later ages and have more negative health outcomes than men. The purpose of this study was to examine gender differences in age of initiation and its association with health. METHODS: The sample included men (n=8,506) and women (n=8,479) with a history of smoking from the 2001-2002 National Epidemiological Survey of Alcohol Related Conditions. Logistic regression was used to examine gender differences in the effect of late smoking initiation on physical and mental health status after adjusting for covariates. RESULTS: At mostly all ages after 16, women exceeded men in rates of smoking initiation (59.8% vs. 50.3%, p<.001). Among late initiators (>=16), women were more likely than men to have hypertension (OR:1.24,CI:1.09-1.41), heart disease (OR:1.20,CI:1.00-1.45), major depressive disorder (OR:2.54,CI:2.22-2.92) and generalized anxiety disorder (OR:2.34,CI:1.84-2.99). Among early initiators (<16), women were more likely than men to have major depressive disorder (OR:2.42,CI:2.11-2.77) and generalized anxiety disorder (OR:2.01,CI:1.59-2.54) but there were no gender differences in the likelihood of having hypertension (OR:1.04,CI:0.89-1.22) and heart disease (OR:1.11,CI:0.90-1.36). CONCLUSIONS: In late adolescence and adulthood, women exceed men in smoking initiation. Late initiation was associated with more significant physical health risks for women than men. Our findings raise questions about generally accepted notions on the age at which smoking initiation occurs and its association with health. PMID- 27499724 TI - Barriers to practicing risk reduction strategies among people who inject drugs. AB - INTRODUCTION AND AIMS: People who inject drugs (PWID) engage in practices that put them at risk for various infections and overdose. The primary aim of this study was to examine common barriers to engaging in two risk reduction practices cleaning one's skin at the injection site and always using new needles to inject - among heroin injectors in Denver, CO. METHOD: In 2010, 48 PWIDs were recruited through street outreach and completed a structured interview that included questions on the frequency of specific risk reduction practices (skin cleaning and using new needles) and barriers associated with these practices. RESULTS: Though many of the reported barriers were similar across the two practices, the most common barriers associated with skin cleaning included being in withdrawal and not being prepared with materials prior to injection. Fear of being arrested and being in withdrawal were most frequently reported for using new needles. Multivariate and t-test analyses demonstrated that individuals who skin cleaned and used new needles more frequently reported less barriers to these practices. CONCLUSIONS: Participants reported a number of barriers to risk reduction, including those that are within the personal control of the injector, barriers that are consequences of addiction or psychological problems, and those that are structural or a function of the risk environment. Statistical analysis found that PWIDs who were more likely to skin clean and use new needles reported less barriers. Addressing barriers when intervening with PWID appears important to increase the success of risk reduction interventions. PMID- 27499725 TI - Barriers and facilitators to preventive cancer screening in Limited English Proficient (LEP) patients: Physicians' perspectives. AB - BACKGROUND: Limited English proficient (LEP) patients receive fewer recommended preventive screenings than English-speaking patients. Studies have explored patients' perceptions of the factors that contribute to this disparity, but little research has focused on physicians' perceptions. OBJECTIVE: To describe physicians' perceptions of the barriers and facilitators to preventive cancer screening in LEP patients. DESIGN: Qualitative interview study using a semi structured interview guide. PARTICIPANTS: Eight primary care physicians from Wisconsin. APPROACH: Each interview was systematically coded to illuminate important themes. KEY RESULTS: A variety of barriers specifically hinder LEP patients' receipt of cancer screening, including poor language proficiency, lack of transportation, unfamiliarity with the concept of prevention, complex scheduling systems, poor interpretation, and limited physician time to discuss preventive care. While physicians identified many factors that facilitate preventive screening in general, they mentioned few that are perceived as specific to LEP patients. CONCLUSION: We found that primary care physicians attribute the low rates of preventive cancer screening among LEP populations to a variety of patient, provider, interpreter, and system factors, most of which go beyond simple language barriers. Interventions designed to reduce these barriers and enhance the impact of identified facilitators should be multifactorial and designed to engage primary care physicians. PMID- 27499726 TI - Evidence mapping for decision making: feasibility versus accuracy - when to abandon high sensitivity in electronic searches. AB - BACKGROUND: Mapping the evidence is a relatively new methodological approach and may be helpful for the development of research questions and decisions about their relevance and priority. However, the amount of data available today leads to challenges for scientists sometimes being confronted with literature searches retrieving over 30,000 results for screening. OBJECTIVES: We conducted an evidence mapping of the topic "diabetes and driving" to investigate its suitability for an evidence-based national clinical guideline. In addition, we compared a highly sensitive search with a highly specific one. METHODS: Based on a systematic review, our database searches were limited to publications from 2002 to present in English and German language. RESULTS: Due to the strongly focused topic and the limits, our sensitive search identified a manageable number of references including sufficient evidence to answer our research question. Using the specific search strategy, we achieved a reduction of citations by 25%, concurrently identifying 88% of relevant references. CONCLUSIONS: Evidence mapping with the intention of gaining an overview of a research field does not require high level accuracy in contrary to systematic reviews. Keeping this distinction in mind, a mass of extraneous information will be avoided by using specific instead of highly sensitive search strategies. PMID- 27499727 TI - Controlled mechanical buckling for origami-inspired construction of 3D microstructures in advanced materials. AB - Origami is a topic of rapidly growing interest in both the scientific and engineering research communities due to its promising potential in a broad range of applications. Previous assembly approaches of origami structures at the micro/nanoscale are constrained by the applicable classes of materials, topologies and/or capability of control over the transformation. Here, we introduce an approach that exploits controlled mechanical buckling for autonomic origami assembly of 3D structures across material classes from soft polymers to brittle inorganic semiconductors, and length scales from nanometers to centimeters. This approach relies on a spatial variation of thickness in the initial 2D structures as an effective strategy to produce engineered folding creases during the compressive buckling process. The elastic nature of the assembly scheme enables active, deterministic control over intermediate states in the 2D to 3D transformation in a continuous and reversible manner. Demonstrations include a broad set of 3D structures formed through unidirectional, bidirectional, and even hierarchical folding, with examples ranging from half cylindrical columns and fish scales, to cubic boxes, pyramids, starfish, paper fans, skew tooth structures, and to amusing system-level examples of soccer balls, model houses, cars, and multi-floor textured buildings. PMID- 27499728 TI - Guided Formation of 3D Helical Mesostructures by Mechanical Buckling: Analytical Modeling and Experimental Validation. AB - Three-dimensional (3D) helical mesostructures are attractive for applications in a broad range of microsystem technologies, due to their mechanical and electromagnetic properties as stretchable interconnects, radio frequency antennas and others. Controlled compressive buckling of 2D serpentine-shaped ribbons provides a strategy to formation of such structures in wide ranging classes of materials (from soft polymers to brittle inorganic semiconductors) and length scales (from nanometer to centimeter), with an ability for automated, parallel assembly over large areas. The underlying relations between the helical configurations and fabrication parameters require a relevant theory as the basis of design for practical applications. Here, we present an analytic model of compressive buckling in serpentine microstructures, based on the minimization of total strain energy that results from various forms of spatially dependent deformations. Experiments at micro- and millimeter-scales, together with finite element analyses (FEA), were exploited to examine the validity of developed model. The theoretical analyses shed light on general scaling laws in terms of three groups of fabrication parameters (related to loading, material and 2D geometry), including a negligible effect of material parameters and a square root dependence of primary displacements on the compressive strain. Furthermore, analytic solutions were obtained for the key physical quantities (e.g., displacement, curvature and maximum strain). A demonstrative example illustrates how to leverage the analytic solutions in choosing the various design parameters, such that brittle fracture or plastic yield can be avoided in the assembly process. PMID- 27499730 TI - Meta-Analysis of Tourette Syndrome and Attention Deficit Hyperactivity Disorder Provides Support for a Shared Genetic Basis. AB - Gilles de la Tourette Sydrome (TS) is a childhood onset neurodevelopmental disorder, characterized phenotypically by the presence of multiple motor and vocal tics. It is often accompanied by multiple psychiatric comorbidities, with Attention Deficit/Hyperactivity Disorder (ADHD) among the most common. The extensive co-occurrence of the two disorders suggests a shared genetic background. A major step toward the elucidation of the genetic architecture of TS was undertaken by the first TS Genome-wide Association Study (GWAS) reporting 552 SNPs that were moderately associated with TS (p < 1E-3). Similarly, initial ADHD GWAS attempts and meta-analysis were not able to produce genome-wide significant findings, but have provided insight to the genetic basis of the disorder. Here, we examine the common genetic background of the two neuropsychiatric phenotypes, by meta-analyzing the 552 top hits in the TS GWAS with the results of ADHD first GWASs. We identify 19 significant SNPs, with the top four implicated genes being TBC1D7, GUCY1A3, RAP1GDS1, and CHST11. TBCD17 harbors the top scoring SNP, rs1866863 (p:3.23E-07), located in a regulatory region downstream of the gene, and the third best-scoring SNP, rs2458304 (p:2.54E-06), located within an intron of the gene. Both variants were in linkage disequilibrium with eQTL rs499818, indicating a role in the expression levels of the gene. TBC1D7 is the third subunit of the TSC1/TSC2 complex, an inhibitor of the mTOR signaling pathway, with a central role in cell growth and autophagy. The top genes implicated by our study indicate a complex and intricate interplay between them, warranting further investigation into a possibly shared etiological mechanism for TS and ADHD. PMID- 27499729 TI - Cyclic ADP-Ribose and Heat Regulate Oxytocin Release via CD38 and TRPM2 in the Hypothalamus during Social or Psychological Stress in Mice. AB - Hypothalamic oxytocin (OT) is released into the brain by cyclic ADP-ribose (cADPR) with or without depolarizing stimulation. Previously, we showed that the intracellular free calcium concentration ([Ca(2+)]i) that seems to trigger OT release can be elevated by beta-NAD(+), cADPR, and ADP in mouse oxytocinergic neurons. As these beta-NAD(+) metabolites activate warm-sensitive TRPM2 cation channels, when the incubation temperature is increased, the [Ca(2+)]i in hypothalamic neurons is elevated. However, it has not been determined whether OT release is facilitated by heat in vitro or hyperthermia in vivo in combination with cADPR. Furthermore, it has not been examined whether CD38 and TRPM2 exert their functions on OT release during stress or stress-induced hyperthermia in relation to the anxiolytic roles and social behaviors of OT under stress conditions. Here, we report that OT release from the isolated hypothalami of male mice in culture was enhanced by extracellular application of cADPR or increasing the incubation temperature from 35 degrees C to 38.5 degrees C, and simultaneous stimulation showed a greater effect. This release was inhibited by a cADPR dependent ryanodine receptor inhibitor and a nonspecific TRPM2 inhibitor. The facilitated release by heat and cADPR was suppressed in the hypothalamus isolated from CD38 knockout mice and CD38- or TRPM2-knockdown mice. In the course of these experiments, we noted that OT release differed markedly between individual mice under stress with group housing. That is, when male mice received cage-switch stress and eliminated due to their social subclass, significantly higher levels of OT release were found in subordinates compared with ordinates. In mice exposed to anxiety stress in an open field, the cerebrospinal fluid (CSF) OT level increased transiently at 5 min after exposure, and the rectal temperature also increased from 36.6 degrees C to 37.8 degrees C. OT levels in the CSF of mice with lipopolysaccharide-induced fever (+0.8 degrees C) were higher than those of control mice. The TRPM2 mRNA levels and immunoreactivities increased in the subordinate group with cage-switch stress. These results showed that cADPR/CD38 and heat/TRPM2 are co-regulators of OT secretion and suggested that CD38 and TRPM2 are potential therapeutic targets for OT release in psychiatric diseases caused by social stress. PMID- 27499731 TI - Zebra Finches As a Model Species to Understand the Roots of Rhythm. PMID- 27499733 TI - Noninvasive Focused Ultrasound Stimulation Can Modulate Phase-Amplitude Coupling between Neuronal Oscillations in the Rat Hippocampus. AB - Noninvasive focused ultrasound stimulation (FUS) can be used to modulate neural activity with high spatial resolution. Phase-amplitude coupling (PAC) between neuronal oscillations is tightly associated with cognitive processes, including learning, attention, and memory. In this study, we investigated the effect of FUS on PAC between neuronal oscillations and established the relationship between the PAC index and ultrasonic intensity. The rat hippocampus was stimulated using focused ultrasound at different spatial-average pulse-average ultrasonic intensities (3.9, 9.6, and 19.2 W/cm(2)). The local field potentials (LFPs) in the rat hippocampus were recorded before and after FUS. Then, we analyzed PAC between neuronal oscillations using a PAC calculation algorithm. Our results showed that FUS significantly modulated PAC between the theta (4-8 Hz) and gamma (30-80 Hz) bands and between the alpha (9-13 Hz) and ripple (81-200 Hz) bands in the rat hippocampus, and PAC increased with incremental increases in ultrasonic intensity. PMID- 27499732 TI - The Broad Autism (Endo)Phenotype: Neurostructural and Neurofunctional Correlates in Parents of Individuals with Autism Spectrum Disorders. AB - Autism Spectrum Disorders (ASD) are a set of neurodevelopmental disorders with an early-onset and a strong genetic component in their pathogenesis. According to genetic and epidemiological data, ASD relatives present personality traits similar to, but not as severe as the defining features of ASD, which have been indicated as the "Broader Autism Phenotype" (BAP). BAP features seem to be more prevalent in first-degree relatives of individuals with ASD than in the general population. Characterizing brain profiles of relatives of autistic probands may help to understand ASD endophenotype. The aim of this review was to provide an up to-date overview of research findings on the neurostructural and neurofunctional substrates in parents of individuals with ASD (pASD). The primary hypothesis was that, like for the behavioral profile, the pASD express an intermediate neurobiological pattern between ASD individuals and healthy controls. The 13 reviewed studies evaluated structural magnetic resonance imaging (MRI) brain volumes, chemical signals using magnetic resonance spectroscopy (MRS), task related functional activation by functional magnetic resonance imaging (fMRI), electroencephalography (EEG), or magnetoencephalography (MEG) in pASD.The studies showed that pASD are generally different from healthy controls at a structural and functional level despite often not behaviorally impaired. More atypicalities in neural patterns of pASD seem to be associated with higher scores at BAP assessment. Some of the observed atypicalities are the same of the ASD probands. In addition, the pattern of neural correlates in pASD resembles that of adult individuals with ASD, or it is specific, possibly due to a compensatory mechanism. Future studies should ideally include a group of pASD and HC with their ASD and non-ASD probands respectively. They should subgrouping the pASD according to the BAP scores, considering gender as a possible confounding factor, and correlating these scores to underlying brain structure and function. These types of studies may help to understand the genetic mechanisms involved in the various clinical dimension of ASD. PMID- 27499734 TI - The Mechanism of Regulated Release of Lasso/Teneurin-2. AB - Teneurins are large cell-surface receptors involved in axon guidance. Teneurin-2 (also known as latrophilin-1-associated synaptic surface organizer (Lasso)) interacts across the synaptic cleft with presynaptic latrophilin-1, an adhesion G protein-coupled receptor that participates in regulating neurotransmitter release. Lasso-latrophilin-1 interaction mediates synapse formation and calcium signaling, highlighting the important role of this trans-synaptic receptor pair. However, Lasso is thought to be proteolytically cleaved within its ectodomain and released into the medium, making it unclear whether it acts as a proper cell surface receptor or a soluble protein. We demonstrate here that during its intracellular processing Lasso is constitutively cleaved at a furin site within its ectodomain. The cleaved fragment, which encompasses almost the entire ectodomain of Lasso, is potentially soluble; however, it remains anchored on the cell surface via its non-covalent interaction with the transmembrane fragment of Lasso. Lasso is also constitutively cleaved within the intracellular domain (ICD). Finally, Lasso can be further proteolytically cleaved within the transmembrane domain. The third cleavage is regulated and releases the entire ectodomain of Lasso into the medium. The released ectodomain of Lasso retains its functional properties and binds latrophilin-1 expressed on other cells; this binding stimulates intracellular Ca(2+) signaling in the target cells. Thus, Lasso not only serves as a bona fide cell-surface receptor, but also as a partially released target-derived signaling factor. PMID- 27499735 TI - Adaptation of Saccadic Sequences with and without Remapping. AB - It is relatively easy to adapt visually-guided saccades because the visual vector and the saccade vector match. The retinal error at the saccade landing position is compared to the prediction error, based on target location and efference copy. If these errors do not match, planning processes at the level(s) of the visual and/or motor vector processing are assumed to be inaccurate and the saccadic response is adjusted. In the case of a sequence of two saccades, the final error can be attributed to the last saccade vector or to the entire saccadic displacement. Here, we asked whether and how adaptation can occur in the case of remapped saccades, such as during the classic double-step saccade paradigm, where the visual and motor vectors of the second saccade do not coincide and so the attribution of error is ambiguous. Participants performed saccades sequences to two targets briefly presented prior to first saccade onset. The second saccade target was either briefly re-illuminated (sequential visually-guided task) or not (remapping task) upon first saccade offset. To drive adaptation, the second target was presented at a displaced location (backward or forward jump condition or control-no jump) at the end of the second saccade. Pre- and post-adaptation trials were identical, without the re-appearance of the target after the second saccade. For the 1st saccade endpoints, there was no change as a function of adaptation. For the 2nd saccade, there was a similar increase in gain in the forward jump condition (52% and 61% of target jump) in the two tasks, whereas the gain decrease in the backward condition was much smaller for the remapping task than for the sequential visually-guided task (41% vs. 94%). In other words, the absolute gain change was similar between backward and forward adaptation for remapped saccades. In conclusion, we show that remapped saccades can be adapted, suggesting that the error is attributed to the visuo-motor transformation of the remapped visual vector. The mechanisms by which adaptation takes place for remapped saccades may be similar to those of forward sequential visually-guided saccades, unlike those involved in adaptation for backward sequential visually guided saccades. PMID- 27499736 TI - Amplitude of Sensorimotor Mu Rhythm Is Correlated with BOLD from Multiple Brain Regions: A Simultaneous EEG-fMRI Study. AB - The mu rhythm is a field oscillation in the ~10Hz range over the sensorimotor cortex. For decades, the suppression of mu (event-related desynchronization) has been used to index movement planning, execution, and imagery. Recent work reports that non-motor processes, such as spatial attention and movement observation, also desynchronize mu, raising the possibility that the mu rhythm is associated with the activity of multiple brain regions and systems. In this study, we tested this hypothesis by recording simultaneous resting-state EEG-fMRI from healthy subjects. Independent component analysis (ICA) was applied to extract the mu components. The amplitude (power) fluctuations of mu were estimated as a time series using a moving-window approach, which, after convolving with a canonical hemodynamic response function (HRF), was correlated with blood-oxygen-level dependent (BOLD) signals from the entire brain. Two main results were found. First, mu power was negatively correlated with BOLD from areas of the sensorimotor network, the attention control network, the putative mirror neuron system, and the network thought to support theory of mind. Second, mu power was positively correlated with BOLD from areas of the salience network, including anterior cingulate cortex and anterior insula. These results are consistent with the hypothesis that sensorimotor mu rhythm is associated with multiple brain regions and systems. They also suggest that caution should be exercised when attempting to interpret mu modulation in terms of a single brain network. PMID- 27499737 TI - Short-Term Plasticity in a Monosynaptic Reflex Pathway to Forearm Muscles after Continuous Robot-Assisted Passive Stepping. AB - Both active and passive rhythmic limb movements reduce the amplitude of spinal cord Hoffmann (H-) reflexes in muscles of moving and distant limbs. This could have clinical utility in remote modulation of the pathologically hyperactive reflexes found in spasticity after stroke or spinal cord injury. However, such clinical translation is currently hampered by a lack of critical information regarding the minimum or effective duration of passive movement needed for modulating spinal cord excitability. We therefore investigated the H-reflex modulation in the flexor carpi radialis (FCR) muscle during and after various durations (5, 10, 15, and 30 min) of passive stepping in 11 neurologically normal subjects. Passive stepping was performed by a robotic gait trainer system (Lokomat((r))) while a single pulse of electrical stimulation to the median nerve elicited H-reflexes in the FCR. The amplitude of the FCR H-reflex was significantly suppressed during passive stepping. Although 30 min of passive stepping was sufficient to elicit a persistent H-reflex suppression that lasted up to 15 min, 5 min of passive stepping was not. The duration of H-reflex suppression correlated with that of the stepping. These findings suggest that the accumulation of stepping-related afferent feedback from the leg plays a role in generating short-term interlimb plasticity in the circuitry of the FCR H-reflex. PMID- 27499739 TI - Retraction: Revisiting hydrocephalus as a model to study brain resilience. AB - [This retracts the article on p. 181 in vol. 5, PMID: 22232589.]. PMID- 27499738 TI - Temporal Dynamics of the Default Mode Network Characterize Meditation-Induced Alterations in Consciousness. AB - Current research suggests that human consciousness is associated with complex, synchronous interactions between multiple cortical networks. In particular, the default mode network (DMN) of the resting brain is thought to be altered by changes in consciousness, including the meditative state. However, it remains unclear how meditation alters the fast and ever-changing dynamics of brain activity within this network. Here we addressed this question using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to compare the spatial extents and temporal dynamics of the DMN during rest and meditation. Using fMRI, we identified key reductions in the posterior cingulate hub of the DMN, along with increases in right frontal and left temporal areas, in experienced meditators during rest and during meditation, in comparison to healthy controls (HCs). We employed the simultaneously recorded EEG data to identify the topographical microstate corresponding to activation of the DMN. Analysis of the temporal dynamics of this microstate revealed that the average duration and frequency of occurrence of DMN microstate was higher in meditators compared to HCs. Both these temporal parameters increased during meditation, reflecting the state effect of meditation. In particular, we found that the alteration in the duration of the DMN microstate when meditators entered the meditative state correlated negatively with their years of meditation experience. This reflected a trait effect of meditation, highlighting its role in producing durable changes in temporal dynamics of the DMN. Taken together, these findings shed new light on short and long-term consequences of meditation practice on this key brain network. PMID- 27499740 TI - Effects of Calcium Spikes in the Layer 5 Pyramidal Neuron on Coincidence Detection and Activity Propagation. AB - The role of dendritic spiking mechanisms in neural processing is so far poorly understood. To investigate the role of calcium spikes in the functional properties of the single neuron and recurrent networks, we investigated a three compartment neuron model of the layer 5 pyramidal neuron with calcium dynamics in the distal compartment. By performing single neuron simulations with noisy synaptic input and occasional large coincident input at either just the distal compartment or at both somatic and distal compartments, we show that the presence of calcium spikes confers a substantial advantage for coincidence detection in the former case and a lesser advantage in the latter. We further show that the experimentally observed critical frequency phenomenon, in which action potentials triggered by stimuli near the soma above a certain frequency trigger a calcium spike at distal dendrites, leading to further somatic depolarization, is not exhibited by a neuron receiving realistically noisy synaptic input, and so is unlikely to be a necessary component of coincidence detection. We next investigate the effect of calcium spikes in propagation of spiking activities in a feed-forward network (FFN) embedded in a balanced recurrent network. The excitatory neurons in the network are again connected to either just the distal, or both somatic and distal compartments. With purely distal connectivity, activity propagation is stable and distinguishable for a large range of recurrent synaptic strengths if the feed-forward connections are sufficiently strong, but propagation does not occur in the absence of calcium spikes. When connections are made to both the somatic and the distal compartments, activity propagation is achieved for neurons with active calcium dynamics at a much smaller number of neurons per pool, compared to a network of passive neurons, but quickly becomes unstable as the strength of recurrent synapses increases. Activity propagation at higher scaling factors can be stabilized by increasing network inhibition or introducing short term depression in the excitatory synapses, but the signal to noise ratio remains low. Our results demonstrate that the interaction of synchrony with dendritic spiking mechanisms can have profound consequences for the dynamics on the single neuron and network level. PMID- 27499741 TI - CoSMoMVPA: Multi-Modal Multivariate Pattern Analysis of Neuroimaging Data in Matlab/GNU Octave. AB - Recent years have seen an increase in the popularity of multivariate pattern (MVP) analysis of functional magnetic resonance (fMRI) data, and, to a much lesser extent, magneto- and electro-encephalography (M/EEG) data. We present CoSMoMVPA, a lightweight MVPA (MVP analysis) toolbox implemented in the intersection of the Matlab and GNU Octave languages, that treats both fMRI and M/EEG data as first-class citizens. CoSMoMVPA supports all state-of-the-art MVP analysis techniques, including searchlight analyses, classification, correlations, representational similarity analysis, and the time generalization method. These can be used to address both data-driven and hypothesis-driven questions about neural organization and representations, both within and across: space, time, frequency bands, neuroimaging modalities, individuals, and species. It uses a uniform data representation of fMRI data in the volume or on the surface, and of M/EEG data at the sensor and source level. Through various external toolboxes, it directly supports reading and writing a variety of fMRI and M/EEG neuroimaging formats, and, where applicable, can convert between them. As a result, it can be integrated readily in existing pipelines and used with existing preprocessed datasets. CoSMoMVPA overloads the traditional volumetric searchlight concept to support neighborhoods for M/EEG and surface-based fMRI data, which supports localization of multivariate effects of interest across space, time, and frequency dimensions. CoSMoMVPA also provides a generalized approach to multiple comparison correction across these dimensions using Threshold-Free Cluster Enhancement with state-of-the-art clustering and permutation techniques. CoSMoMVPA is highly modular and uses abstractions to provide a uniform interface for a variety of MVP measures. Typical analyses require a few lines of code, making it accessible to beginner users. At the same time, expert programmers can easily extend its functionality. CoSMoMVPA comes with extensive documentation, including a variety of runnable demonstration scripts and analysis exercises (with example data and solutions). It uses best software engineering practices including version control, distributed development, an automated test suite, and continuous integration testing. It can be used with the proprietary Matlab and the free GNU Octave software, and it complies with open source distribution platforms such as NeuroDebian. CoSMoMVPA is Free/Open Source Software under the permissive MIT license. Website: http://cosmomvpa.org Source code: https://github.com/CoSMoMVPA/CoSMoMVPA. PMID- 27499742 TI - Control of Transmembrane Protein Diffusion within the Postsynaptic Density Assessed by Simultaneous Single-Molecule Tracking and Localization Microscopy. AB - Postsynaptic transmembrane proteins are critical elements of synapses, mediating trans-cellular contact, sensitivity to neurotransmitters and other signaling molecules, and flux of Ca and other ions. Positioning and mobility of each member of this large class of proteins is critical to their individual function at the synapse. One critical example is that the position of glutamate receptors within the postsynaptic density (PSD) strongly modulates their function by aligning or misaligning them with sites of presynaptic vesicle fusion. In addition, the regulated ability of receptors to move in or out of the synapse is critical for activity-dependent plasticity. However, factors that control receptor mobility within the boundaries of the synapse are not well understood. Notably, PSD scaffold molecules accumulate in domains much smaller than the synapse. Within these nanodomains, the density of proteins is considerably higher than that of the synapse as a whole, so high that steric hindrance is expected to reduce receptor mobility substantially. However, while numerical modeling has demonstrated several features of how the varying protein density across the face of a single PSD may modulate receptor motion, there is little experimental information about the extent of this influence. To address this critical aspect of synaptic organizational dynamics, we performed single-molecule tracking of transmembrane proteins using universal point accumulation-for-imaging-in nanoscale-topography (uPAINT) over PSDs whose internal structure was simultaneously resolved using photoactivated localization microscopy (PALM). The results provide important experimental confirmation that PSD scaffold protein density strongly influences the mobility of transmembrane proteins. A protein with a cytosolic domain that does not bind PSD-95 was still slowed in regions of high PSD-95 density, suggesting that crowding by scaffold molecules and perhaps other proteins is sufficient to stabilize receptors even in the absence of binding. Because numerous proteins thought to be involved in establishing PSD structure are linked to disorders including autism and depression, this motivates further exploration of how PSD nanostructure is created. The combined application PALM and uPAINT should be invaluable for distinguishing the interactions of mobile proteins with their nano-environment both in synapses and other cellular compartments. PMID- 27499743 TI - Visceral Hypersensitivity Is Provoked by 2,4,6-Trinitrobenzene Sulfonic Acid Induced Ileitis in Rats. AB - BACKGROUND AND AIMS: Crohn's Disease (CD), a chronic Inflammatory Bowel Disease, can occur in any part of the gastrointestinal tract, but most frequently in the ileum. Visceral hypersensitivity contributes for development of chronic abdominal pain in this disease. Currently, the understanding of the mechanism underlying hypersensitivity of Crohn's ileitis has been hindered by a lack of specific animal model. The present study is undertaken to investigate the visceral hypersensitivity provoked by 2,4,6-trinitrobenzene sulfonic (TNBS)-induced ileitis rats. METHODS: Male Sprague-Dawley rats were anaesthetized and laparotomized for intraileal injection of TNBS (0.6 ml, 80 mg/kg body weight in 30% ethanol, n = 48), an equal volume of 30% Ethanol (n = 24), and Saline (n = 24), respectively. Visceral hypersensitivity was assessed by visceromotor responses (VMR) to 20, 40, 60, 80, and 100 mmHg colorectal distension pressure (CRD) at day 1, 3, 7, 14, 21, and 28. Immediately after CRD test, the rats were euthanized for collecting the terminal ileal segment for histopathological examinations and ELISA of myleoperoxidase and cytokines (TNF-alpha, IL-1beta, IL 6), and dorsal root ganglia (T11) for determination of calcitonin gene-related peptide by immunohistochemistry, respectively. RESULTS: Among all groups, TNBS treatment showed transmural inflammation initially at 3 days, reached maximum at 7 days and persisted up to 21 days. The rats with ileitis exhibited (P < 0.05) VMR to CRD at day 7 to day 21. The calcitonin gene-related peptide-immunoreactive positive cells increased (P < 0.05) in dorsal root ganglia at day 7 to 21, which was persistently consistent with visceral hypersensitivity in TNBS-treated rats. CONCLUSION: TNBS injection into the ileum induced transmural ileitis including granuloma and visceral hypersensitivity. As this model mimics clinical manifestations of CD, it may provide a road map to probe the pathogenesis of gut inflammation and visceral hypersensitivity, as well as for establishing the therapeutic protocol for Crohn's ileitis. PMID- 27499744 TI - Using Multigroup-Multiphase Latent State-Trait Models to Study Treatment-Induced Changes in Intra-Individual State Variability: An Application to Smokers' Affect. AB - Sometimes, researchers are interested in whether an intervention, experimental manipulation, or other treatment causes changes in intra-individual state variability. The authors show how multigroup-multiphase latent state-trait (MG-MP LST) models can be used to examine treatment effects with regard to both mean differences and differences in state variability. The approach is illustrated based on a randomized controlled trial in which N = 338 smokers were randomly assigned to nicotine replacement therapy (NRT) vs. placebo prior to quitting smoking. We found that post quitting, smokers in both the NRT and placebo group had significantly reduced intra-individual affect state variability with respect to the affect items calm and content relative to the pre-quitting phase. This reduction in state variability did not differ between the NRT and placebo groups, indicating that quitting smoking may lead to a stabilization of individuals' affect states regardless of whether or not individuals receive NRT. PMID- 27499745 TI - Incubation and Intuition in Creative Problem Solving. AB - Creative problem solving, in which novel solutions are required, has often been seen as involving a special role for unconscious processes (Unconscious Work) which can lead to sudden intuitive solutions (insights) when a problem is set aside during incubation periods. This notion of Unconscious Work during incubation periods is supported by a review of experimental studies and particularly by studies using the Immediate Incubation paradigm. Other explanations for incubation effects, in terms of Intermittent Work or Beneficial Forgetting are considered. Some recent studies of divergent thinking, using the Alternative Uses task, carried out in my laboratory regarding Immediate vs. Delayed Incubation and the effects of resource competition from interpolated activities are discussed. These studies supported a role for Unconscious Work as against Intermittent Conscious work or Beneficial Forgetting in incubation. PMID- 27499746 TI - Aldo-Keto Reductases 1B in Adrenal Cortex Physiology. AB - Aldose reductase (AKR1B) proteins are monomeric enzymes, belonging to the aldo keto reductase (AKR) superfamily. They perform oxidoreduction of carbonyl groups from a wide variety of substrates, such as aliphatic and aromatic aldehydes or ketones. Due to the involvement of human aldose reductases in pathologies, such as diabetic complications and cancer, AKR1B subgroup enzymatic properties have been extensively characterized. However, the issue of AKR1B function in non pathologic conditions remains poorly resolved. Adrenal activities generated large amount of harmful aldehydes from lipid peroxidation and steroidogenesis, including 4-hydroxynonenal (4-HNE) and isocaproaldehyde (4-methylpentanal), which can both be reduced by AKR1B proteins. More recently, some AKR1B isoforms have been shown to be endowed with prostaglandin F synthase (PGFS) activity, suggesting that, in addition to possible scavenger function, they could instigate paracrine signals. Interestingly, the adrenal gland is one of the major sites for human and murine AKR1B expression, suggesting that their detoxifying/signaling activity could be specifically required for the correct handling of adrenal function. Moreover, chronic effects of ACTH result in a coordinated regulation of genes encoding the steroidogenic enzymes and some AKR1B isoforms. This review presents the molecular mechanisms accounting for the adrenal-specific expression of some AKR1B genes. Using data from recent mouse genetic models, we will try to connect their enzymatic properties and regulation with adrenal functions. PMID- 27499747 TI - Functional Characterization of a Hexose Transporter from Root Endophyte Piriformospora indica. AB - Understanding the mechanism of photosynthate transfer at symbiotic interface by fungal monosaccharide transporter is of substantial importance. The carbohydrate uptake at the apoplast by the fungus is facilitated by PiHXT5 hexose transporter in root endophytic fungus Piriformospora indica. The putative PiHXT5 belongs to MFS superfamily with 12 predicted transmembrane helices. It possess sugar transporter PFAM motif (PF0083) and MFS superfamily domain (PS50850). It contains the signature tags related to glucose transporter GLUT1 of human erythrocyte. PiHXT5 is regulated in response to mutualism as well as glucose concentration. We have functionally characterized PiHXT5 by complementation of hxt-null mutant of Saccharomyces cerevisiae EBY.VW4000. It is involved in transport of multiple sugars ranging from D-glucose, D-fructose, D-xylose, D-mannose, D-galactose with decreasing affinity. The uncoupling experiments indicate that it functions as H(+)/glucose co-transporter. Further, pH dependence analysis suggests that it functions maximum between pH 5 and 6. The expression of PiHXT5 is dependent on glucose concentration and was found to be expressed at low glucose levels (1 mM) which indicate its role as a high affinity glucose transporter. Our study on this sugar transporter will help in better understanding of carbon metabolism and flow in this agro-friendly fungus. PMID- 27499748 TI - Serological Evidence of Immune Priming by Group A Streptococci in Patients with Acute Rheumatic Fever. AB - Acute rheumatic fever (ARF) is an autoimmune response to Group A Streptococcus (GAS) infection. Repeated GAS exposures are proposed to 'prime' the immune system for autoimmunity. This notion of immune-priming by multiple GAS infections was first postulated in the 1960s, but direct experimental evidence to support the hypothesis has been lacking. Here, we present novel methodology, based on antibody responses to GAS T-antigens, that enables previous GAS exposures to be mapped in patient sera. T-antigens are surface expressed, type specific antigens and GAS strains fall into 18 major clades or T-types. A panel of recombinant T antigens was generated and immunoassays were performed in parallel with serum depletion experiments allowing type-specific T-antigen antibodies to be distinguished from cross-reactive antibodies. At least two distinct GAS exposures were detected in each of the ARF sera tested. Furthermore, no two sera had the same T-antigen reactivity profile suggesting that each patient was exposed to a unique series of GAS T-types prior to developing ARF. The methods have provided much-needed experimental evidence to substantiate the immune-priming hypothesis, and will facilitate further serological profiling studies that explore the multifaceted interactions between GAS and the host. PMID- 27499749 TI - Hospital Effluents Are One of Several Sources of Metal, Antibiotic Resistance Genes, and Bacterial Markers Disseminated in Sub-Saharan Urban Rivers. AB - Data concerning the occurrence of emerging biological contaminants such as antibiotic resistance genes (ARGs) and fecal indicator bacteria (FIB) in aquatic environments in Sub-Saharan African countries is limited. On the other hand, antibiotic resistance remains a worldwide problem which may pose serious potential risks to human and animal health. Consequently, there is a growing number of reports concerning the prevalence and dissemination of these contaminants into various environmental compartments. Sediments provide the opportunity to reconstruct the pollution history and evaluate impacts so this study investigates the abundance and distribution of toxic metals, FIB, and ARGs released from hospital effluent wastewaters and their presence in river sediments receiving systems. ARGs (bla TEM, bla CTX-M, bla SHV, and aadA), total bacterial load, and selected bacterial species FIB [Escherichia coli, Enterococcus (ENT)] and species (Psd) were quantified by targeting species specific genes using quantitative PCR (qPCR) in total DNA extracted from the sediments recovered from 4 hospital outlet pipes (HOP) and their river receiving systems in the City of Kinshasa in the Democratic Republic of the Congo. The results highlight the great concentration of toxic metals in HOP, reaching the values (in mg kg(-1)) of 47.9 (Cr), 213.6 (Cu), 1434.4 (Zn), 2.6 (Cd), 281.5 (Pb), and 13.6 (Hg). The results also highlight the highest (P < 0.05) values of 16S rRNA, FIB, and ARGs copy numbers in all sampling sites including upstream (control site), discharge point, and downstream of receiving rivers, indicating that the hospital effluent water is not an exclusive source of the biological contaminants entering the urban rivers. Significant correlation were observed between (i) all analyzed ARGs and total bacterial load (16S rRNA) 0.51 to 0.72 (p < 0.001, n = 65); (ii) ARGs (except bla TEM) and FIB and Psd 0.57 < r < 0.82 (p < 0.001, n = 65); and (iii) ARGs (except bla TEM) and toxic metals (Cd, Cr, Cu, and Zn) 0.44 to 0.72, (p < 0.001, n = 65). These findings demonstrate that several sources including hospital and urban wastewaters contribute to the spread of toxic metals and biological emerging contaminants in aquatic ecosystems. PMID- 27499750 TI - Strong Inference in Mathematical Modeling: A Method for Robust Science in the Twenty-First Century. AB - While there are many opinions on what mathematical modeling in biology is, in essence, modeling is a mathematical tool, like a microscope, which allows consequences to logically follow from a set of assumptions. Only when this tool is applied appropriately, as microscope is used to look at small items, it may allow to understand importance of specific mechanisms/assumptions in biological processes. Mathematical modeling can be less useful or even misleading if used inappropriately, for example, when a microscope is used to study stars. According to some philosophers (Oreskes et al., 1994), the best use of mathematical models is not when a model is used to confirm a hypothesis but rather when a model shows inconsistency of the model (defined by a specific set of assumptions) and data. Following the principle of strong inference for experimental sciences proposed by Platt (1964), I suggest "strong inference in mathematical modeling" as an effective and robust way of using mathematical modeling to understand mechanisms driving dynamics of biological systems. The major steps of strong inference in mathematical modeling are (1) to develop multiple alternative models for the phenomenon in question; (2) to compare the models with available experimental data and to determine which of the models are not consistent with the data; (3) to determine reasons why rejected models failed to explain the data, and (4) to suggest experiments which would allow to discriminate between remaining alternative models. The use of strong inference is likely to provide better robustness of predictions of mathematical models and it should be strongly encouraged in mathematical modeling-based publications in the Twenty-First century. PMID- 27499751 TI - Evolution and Diversity of Listeria monocytogenes from Clinical and Food Samples in Shanghai, China. AB - Listeria monocytogenes is a significant foodborne pathogen causing severe systemic infections in humans with high mortality rates. The objectives of this work were to establish a phylogenetic framework of L. monocytogenes from China and to investigate sequence diversity among different serotypes. We selected 17 L. monocytogenes strains recovered from patients and foods in China representing serotypes 1/2a, 1/2b, and 1/2c. Draft genome sequences were determined using Illumina MiSeq technique and associated protocols. Open reading frames were assigned using prokaryotic genome annotation pipeline by NCBI. Twenty-four published genomes were included for comparative genomic and phylogenetic analysis. More than 154,000 single nucleotide polymorphisms (SNPs) were identified from multiple genome alignment and used to reconstruct maximum likelihood phylogenetic tree. The 41 genomes were differentiated into lineages I and II, which consisted of 4 and 11 subgroups, respectively. A clinical strain from China (SHL009) contained significant SNP differences compared to the rest genomes, whereas clinical strain SHL001 shared most recent common ancestor with strain SHL017 from food. Moreover, clinical strains SHL004 and SHL015 clustered together with two strains (08-5578 and 08-5923) recovered from an outbreak in Canada. Partial sequences of a plasmid found in the Canadian strain were also present in SHL004. We investigated the presence of various genes and gene clusters associated with virulence and subgroup-specific genes, including internalins, L. monocytogenes pathogenicity islands (LIPIs), L. monocytogenes genomic islands (LGIs), stress survival islet 1 (SSI-1), and clustered regularly interspaced short palindromic repeats (CRISPR)/cas system. A novel genomic island, denoted as LGI-2 was identified. Comparative sequence analysis revealed differences among the L. monocytogenes strains related to virulence, survival abilities, and attributes against foreign genetic elements. L. monocytogenes from China were genetically diverse. Strains from clinical specimens and food related closely suggesting foodborne transmission of human listeriosis. PMID- 27499753 TI - Cold Shock Proteins: A Minireview with Special Emphasis on Csp-family of Enteropathogenic Yersinia. AB - Bacteria have evolved a number of mechanisms for coping with stress and adapting to changing environmental conditions. Many bacteria produce small cold shock proteins (Csp) as a response to rapid temperature downshift (cold shock). During cold shock, the cell membrane fluidity and enzyme activity decrease, and the efficiency of transcription and translation is reduced due to stabilization of nucleic acid secondary structures. Moreover, protein folding is inefficient and ribosome function is hampered. Csps are thought to counteract these harmful effects by serving as nucleic acid chaperons that may prevent the formation of secondary structures in mRNA at low temperature and thus facilitate the initiation of translation. However, some Csps are non-cold inducible and they are reported to be involved in various cellular processes to promote normal growth and stress adaptation responses. Csps have been shown to contribute to osmotic, oxidative, starvation, pH and ethanol stress tolerance as well as to host cell invasion. Therefore, Csps seem to have a wider role in stress tolerance of bacteria than previously assumed. Yersinia enterocolitica and Yersinia pseudotuberculosis are enteropathogens that can spread through foodstuffs and cause an enteric infection called yersiniosis. Enteropathogenic Yersinia are psychrotrophs that are able to grow at temperatures close to 0 degrees C and thus they set great challenges for the modern food industry. To be able to efficiently control psychrotrophic Yersinia during food production and storage, it is essential to understand the functions and roles of Csps in stress response of enteropathogenic Yersinia. PMID- 27499752 TI - Bacterial Diversity and Community Structure of Supragingival Plaques in Adults with Dental Health or Caries Revealed by 16S Pyrosequencing. AB - Dental caries has a polymicrobial etiology within the complex oral microbial ecosystem. However, the overall diversity and structure of supragingival plaque microbiota in adult dental health and caries are not well understood. Here, 160 supragingival plaque samples from patients with dental health and different severities of dental caries were collected for bacterial genomic DNA extraction, pyrosequencing by amplification of the 16S rDNA V1-V3 hypervariable regions, and bioinformatic analysis. High-quality sequences (2,261,700) clustered into 10,365 operational taxonomic units (OTUs; 97% identity), representing 453 independent species belonging to 122 genera, 66 families, 34 orders, 21 classes, and 12 phyla. All groups shared 7522 OTUs, indicating the presence of a core plaque microbiome. alpha diversity analysis showed that the microbial diversity in healthy plaques exceeded that of dental caries, with the diversity decreasing gradually with the severity of caries. The dominant phyla of plaque microbiota included Bacteroidetes, Actinobacteria, Proteobacteria, Firmicutes, Fusobacteria, and TM7. The dominant genera included Capnocytophaga, Prevotella, Actinomyces, Corynebacterium, Neisseria, Streptococcus, Rothia, and Leptotrichia. beta diversity analysis showed that the plaque microbial community structure was similar in all groups. Using LEfSe analysis, 25 differentially abundant taxa were identified as potential biomarkers. Key genera (27) that potentially contributed to the differential distributions of plaque microbiota between groups were identified by PLS-DA analysis. Finally, co-occurrence network analysis and function predictions were performed. Treatment strategies directed toward modulating microbial interactions and their functional output should be further developed. PMID- 27499755 TI - Unveiling the Role of the Integrated Endoplasmic Reticulum Stress Response in Leishmania Infection - Future Perspectives. AB - The integrated endoplasmic reticulum stress response (IERSR) is an evolutionarily conserved adaptive mechanism that ensures endoplasmic reticulum (ER) homeostasis and cellular survival in the presence of stress including nutrient deprivation, hypoxia, and imbalance of Ca(+) homeostasis, toxins, and microbial infection. Three transmembrane proteins regulate integrated signaling pathways that comprise the IERSR, namely, IRE-1 that activates XBP-1, the pancreatic ER kinase (PERK) that phosphorylates the eukaryotic translation initiation factor 2 and transcription factor 6 (ATF6). The roles of IRE-1, PERK, and ATF4 in viral and some bacterial infections are well characterized. The role of IERSR in infections by intracellular parasites is still poorly understood, although one could anticipate that IERSR may play an important role on the host's cell response. Recently, our group reported the important aspects of XBP-1 activation in Leishmania amazonensis infection. It is, however, necessary to address the relevance of the other IERSR branches, together with the possible role of IERSR in infections by other Leishmania species, and furthermore, to pursue the possible implications in the pathogenesis and control of parasite replication in macrophages. PMID- 27499754 TI - Utilization of Dimethyl Fumarate and Related Molecules for Treatment of Multiple Sclerosis, Cancer, and Other Diseases. AB - Several drugs have been approved for treatment of multiple sclerosis (MS). Dimethyl fumarate (DMF) is utilized as an oral drug to treat this disease and is proven to be potent with less side effects than several other drugs. On the other hand, monomethyl fumarate (MMF), a related compound, has not been examined in greater details although it has the potential as a therapeutic drug for MS and other diseases. The mechanism of action of DMF or MMF is related to their ability to enhance the antioxidant pathways and to inhibit reactive oxygen species. However, other mechanisms have also been described, which include effects on monocytes, dendritic cells, T cells, and natural killer cells. It is also reported that DMF might be useful for treating psoriasis, asthma, aggressive breast cancers, hematopoeitic tumors, inflammatory bowel disease, intracerebral hemorrhage, osteoarthritis, chronic pancreatitis, and retinal ischemia. In this article, we will touch on some of these diseases with an emphasis on the effects of DMF and MMF on various immune cells. PMID- 27499757 TI - Overexpression of a Modified Plant Thionin Enhances Disease Resistance to Citrus Canker and Huanglongbing (HLB). AB - Huanglongbing (HLB or citrus greening disease) caused by Candidatus Liberibacter asiaticus (Las) is a great threat to the US citrus industry. There are no proven strategies to eliminate HLB disease and no cultivar has been identified with strong HLB resistance. Citrus canker is also an economically important disease associated with a bacterial pathogen (Xanthomonas citri). In this study, we characterized endogenous citrus thionins and investigated their expression in different citrus tissues. Since no HLB-resistant citrus cultivars have been identified, we attempted to develop citrus resistant to both HLB and citrus canker through overexpression of a modified plant thionin. To improve effectiveness for disease resistance, we modified and synthesized the sequence encoding a plant thionin and cloned into the binary vector pBinPlus/ARS. The construct was then introduced into Agrobacterium strain EHA105 for citrus transformation. Transgenic Carrizo plants expressing the modified plant thionin were generated by Agrobacterium-mediated transformation. Successful transformation and transgene gene expression was confirmed by molecular analysis. Transgenic Carrizo plants expressing the modified thionin gene were challenged with X. citri 3213 at a range of concentrations, and a significant reduction in canker symptoms and a decrease in bacterial growth were demonstrated compared to nontransgenic plants. Furthermore, the transgenic citrus plants were challenged with HLB via graft inoculation. Our results showed significant Las titer reduction in roots of transgenic Carrizo compared with control plants and reduced scion Las titer 12 months after graft inoculation. These data provide promise for engineering citrus disease resistance against HLB and canker. PMID- 27499756 TI - Identification of microRNAs and Their Target Genes Explores miRNA-Mediated Regulatory Network of Cytoplasmic Male Sterility Occurrence during Anther Development in Radish (Raphanus sativus L.). AB - MicroRNAs (miRNAs) are a type of endogenous non-coding small RNAs that play critical roles in plant growth and developmental processes. Cytoplasmic male sterility (CMS) is typically a maternally inherited trait and widely used in plant heterosis utilization. However, the miRNA-mediated regulatory network of CMS occurrence during anther development remains largely unknown in radish. In this study, a comparative small RNAome sequencing was conducted in floral buds of CMS line 'WA' and its maintainer line 'WB' by high-throughput sequencing. A total of 162 known miRNAs belonging to 25 conserved and 24 non-conserved miRNA families were isolated and 27 potential novel miRNA families were identified for the first time in floral buds of radish. Of these miRNAs, 28 known and 14 potential novel miRNAs were differentially expressed during anther development. Several target genes for CMS occurrence-related miRNAs encode important transcription factors and functional proteins, which might be involved in multiple biological processes including auxin signaling pathways, signal transduction, miRNA target silencing, floral organ development, and organellar gene expression. Moreover, the expression patterns of several CMS occurrence-related miRNAs and their targets during three stages of anther development were validated by qRT-PCR. In addition, a potential miRNA-mediated regulatory network of CMS occurrence during anther development was firstly proposed in radish. These findings could contribute new insights into complex miRNA-mediated genetic regulatory network of CMS occurrence and advance our understanding of the roles of miRNAs during CMS occurrence and microspore formation in radish and other crops. PMID- 27499758 TI - Geography Plays a More Important Role than Soil Composition on Structuring Genetic Variation of Pseudometallophyte Commelina communis. AB - Pseudometallophytes are excellent models to study microevolution and local adaptation to soil pollution, as they can grow both on metalliferous and contrasting non-metalliferous soils. Although, there has been accumulating evidence for the effects of edaphic conditions and geographical isolation on the genetic structure of pesudometallophytes, it is still a difficult problem in evolutionary biology to assess their relative importance. In this study, we investigated the spatial patterns of genetic variability, population differentiation and genetic groups in pseudometallophyte Commelina communis with 12 microsatellite loci. Eight metallicolous and six non-metallicolous populations of C. communis were sampled from cupriferous sites and surrounding non contaminated areas in China. Neither significant reduction in genetic diversity nor apparent founder and bottleneck effects were observed in metallicolous populations of C. communis. Based on Bayesian and Neighbor-Joining clustering analyses and a principal coordinates analysis, all sampled populations were found to be mainly separated into three genetic groups, corresponding well to their geographical locations rather than edaphic origins. Moreover, a significant and strong correlation between population genetic divergence and geographical distance were detected by Mantel test (r = 0.33; P < 0.05) and multiple matrix regression with randomization (MMRR; betaD = 0.57, P < 0.01). However, the effect of copper concentration on genetic patterns of C. communis was not significant (MMRR; betaE = -0.17, P = 0.12). Our study clearly demonstrated that the extreme edaphic conditions in metalliferous areas had limited effects on the genetic variability in C. communis. Geographic distance played a more important role in affecting the genetic structure of C. communis than soil composition did. In C. communis, the geographically disjunctive populations on metalliferous soils had multiple origins and evolved independently from nearby non-metallicolous populations. PMID- 27499759 TI - A Protein-Based Genetic Screening Uncovers Mutants Involved in Phytochrome Signaling in Arabidopsis. AB - Plants perceive red and far-red region of the light spectrum to regulate photomorphogenesis through a family of photoreceptors called phytochromes. Phytochromes transduce the light signals to trigger a cascade of downstream gene regulation in part via a subfamily of bHLH transcription factors called Phytochrome Interacting Factors (PIFs). As the repressors of light signaling pathways, most PIFs are phosphorylated and degraded through the ubiquitin/26S proteasome pathway in response to light. The mechanisms involved in the phosphorylation and degradation of PIFs have not been fully understood yet. Here we used an EMS mutagenesis and luminescent imaging system to identify mutants defective in the degradation of one of the PIFs, called PIF1. We identified five mutants named stable PIF (spf) that showed reduced degradation of PIF1 under light treatment in both luminescent imaging and immunoblot assays. The amounts of PIF1 in spf3, spf4, and spf5 were similar to a PIF1 missense mutant (PIF1-3M) that lacks interactions between PIF1 and phyA/phyB under light. The hypocotyl lengths of spf1 and spf2 were slightly longer under red light compared to the LUC PIF1 control, while only spf1 displayed weak phenotype under far-red light conditions. Interestingly, the spf3, spf4, and spf5 displayed high abundance of PIF1, yet the hypocotyl lengths were similar to the wild type under these conditions. Cloning and characterization of these mutants will help identify key players in the light signaling pathways including, the light-regulated kinase(s) and the E3 ligase(s) necessary for the light-induced degradation of PIFs. PMID- 27499760 TI - Changes in H(+)-ATP Synthase Activity, Proton Electrochemical Gradient, and pH in Pea Chloroplast Can Be Connected with Variation Potential. AB - Local stimulation induces generation and propagation of electrical signals, including the variation potential (VP) and action potential, in plants. Burning induced VP changes the physiological state of plants; specifically, it inactivates photosynthesis. However, the mechanisms that decrease photosynthesis are poorly understood. We investigated these mechanisms by measuring VP-connected systemic changes in CO2 assimilation, parameters of light reactions of photosynthesis, electrochromic pigment absorbance shifts, and light scattering. We reveal that inactivation of photosynthesis in the pea, including inactivation of dark and light reactions, was connected with the VP. Inactivation of dark reactions decreased the rate constant of the fast relaxation of the electrochromic pigment absorbance shift, which reflected a decrease in the H(+) ATP synthase activity. This decrease likely contributed to the acidification of the chloroplast lumen, which developed after VP induction. However, VP-connected decrease of the proton motive force across the thylakoid membrane, possibly, reflected a decreased pH in the stroma. This decrease may be another mechanism of chloroplast lumen acidification. Overall, stroma acidification can decrease electron flow through photosystem I, and lumen acidification induces growth of fluorescence non-photochemical quenching and decreases electron flow through photosystem II, i.e., pH decreases in the stroma and lumen, possibly, contribute to the VP-induced inactivation of light reactions of photosynthesis. PMID- 27499761 TI - Nitrogen Addition Enhances Drought Sensitivity of Young Deciduous Tree Species. AB - Understanding how trees respond to global change drivers is central to predict changes in forest structure and functions. Although there is evidence on the mode of nitrogen (N) and drought (D) effects on tree growth, our understanding of the interplay of these factors is still limited. Simultaneously, as mixtures are expected to be less sensitive to global change as compared to monocultures, we aimed to investigate the combined effects of N addition and D on the productivity of three tree species (Fagus sylvatica, Quercus petraea, Pseudotsuga menziesii) in relation to functional diverse species mixtures using data from a 4-year field experiment in Northwest Germany. Here we show that species mixing can mitigate the negative effects of combined N fertilization and D events, but the community response is mainly driven by the combination of certain traits rather than the tree species richness of a community. For beech, we found that negative effects of D on growth rates were amplified by N fertilization (i.e., combined treatment effects were non-additive), while for oak and fir, the simultaneous effects of N and D were additive. Beech and oak were identified as most sensitive to combined N+D effects with a strong size-dependency observed for beech, suggesting that the negative impact of N+D becomes stronger with time as beech grows larger. As a consequence, the net biodiversity effect declined at the community level, which can be mainly assigned to a distinct loss of complementarity in beech-oak mixtures. This pattern, however, was not evident in the other species-mixtures, indicating that neighborhood composition (i.e., trait combination), but not tree species richness mediated the relationship between tree diversity and treatment effects on tree growth. Our findings point to the importance of the qualitative role ('trait portfolio') that biodiversity play in determining resistance of diverse tree communities to environmental changes. As such, they provide further understanding for adaptive management strategies in the context of global change. PMID- 27499762 TI - An Adaptive Defect Weighted Sampling Algorithm to Design Pseudoknotted RNA Secondary Structures. AB - Computational design of RNA sequences that fold into targeted secondary structures has many applications in biomedicine, nanotechnology and synthetic biology. An RNA molecule is made of different types of secondary structure elements and an important RNA element named pseudoknot plays a key role in stabilizing the functional form of the molecule. However, due to the computational complexities associated with characterizing pseudoknotted RNA structures, most of the existing RNA sequence designer algorithms generally ignore this important structural element and therefore limit their applications. In this paper we present a new algorithm to design RNA sequences for pseudoknotted secondary structures. We use NUPACK as the folding algorithm to compute the equilibrium characteristics of the pseudoknotted RNAs, and describe a new adaptive defect weighted sampling algorithm named Enzymer to design low ensemble defect RNA sequences for targeted secondary structures including pseudoknots. We used a biological data set of 201 pseudoknotted structures from the Pseudobase library to benchmark the performance of our algorithm. We compared the quality characteristics of the RNA sequences we designed by Enzymer with the results obtained from the state of the art MODENA and antaRNA. Our results show our method succeeds more frequently than MODENA and antaRNA do, and generates sequences that have lower ensemble defect, lower probability defect and higher thermostability. Finally by using Enzymer and by constraining the design to a naturally occurring and highly conserved Hammerhead motif, we designed 8 sequences for a pseudoknotted cis-acting Hammerhead ribozyme. Enzymer is available for download at https://bitbucket.org/casraz/enzymer. PMID- 27499763 TI - Body mass index in girls with idiopathic central precocious puberty during and after treatment with GnRH analogues. AB - BACKGROUND: In girls with Idiopathic Central Precocious Puberty (ICPP) concern has been raised by the potential impact of GnRH-analogues (GnRHa) treatment on body weight. We evaluated the effect of GnRHa on Body Mass Index (BMI) in girls with ICPP according to weight status at diagnosis. METHODS: One hundred seventeen ICPP girls were divided according to pretreatment weight status in: normal weight (NW), overweight (OW) and obese (OB). BMI at one and two years of treatment was assessed. BMI-SDS of 60 patients who reached adult height (AH) was compared to that of 33 ICPP untreated girls. RESULTS: NW girls significantly increased their baseline BMI-SDS at 1 and 2 years of treatment. OW girls only had a significant increment at one year of treatment while OB girls showed no BMI-SDS change. Patients evaluated at AH (at least four years after GnRHa withdrawal) showed a significant decrease on BMI compared to baseline and a significantly lower BMI than the untreated group. CONCLUSION: In ICPP girls the BMI increase under GnRHa was inversely related to the pretreatment weight status. In the long term follow up, no detrimental effect of GnRHa on body weight was observed. BMI-SDS was lower in treated than in untreated girls. PMID- 27499764 TI - Reproducibility of serum IgE, Ara h2 skin prick testing and fraction of exhaled nitric oxide for predicting clinical peanut allergy in children. AB - BACKGROUND: Ara h2 sIgE serum levels improve the diagnostic accuracy for predicting peanut allergy, but the use of Ara h2 purified protein as a skin prick test (SPT), has not been substantially evaluated. The fraction of exhaled nitric oxide (FeNO) shows promise as a novel biomarker of peanut allergy. Reproducibility of these measures has not been determined. The aim was to assess the accuracy and reproducibility (over a time-period of at least 12 months) of SPT to Ara h2 in comparison with four predictors of clinical peanut allergy (Peanut SPT, Ara h2 specific Immunoglobulin E (sIgE), Peanut sIgE and FeNO). METHODS: Twenty-seven children were recruited in a follow-up of a prospective cohort of fifty-six children at least 12 months after an open-labelled peanut food challenge. Their repeat assessment involved a questionnaire, SPT to peanut and Ara h2 purified protein, FeNO and sIgE to peanut and Ara h2 measurements. RESULTS: Ara h2 SPT was no worse in accuracy when compared with peanut SPT, FeNO, Ara h2 sIgE and peanut sIgE (AUC 0.908 compared with 0.887, 0.889, 0.935 and 0.804 respectively) for predicting allergic reaction at previous food challenge. SPT for peanut and Ara h2 demonstrated limited reproducibility (ICC = 0.51 and 0.44); while FeNO demonstrated good reproducibility (ICC = 0.73) and sIgE for peanut and Ara h2 were highly reproducible (ICC = 0.81 and 0.85). CONCLUSIONS: In this population, Ara h2 SPT was no worse in accuracy when compared with current testing for the evaluation of clinical peanut allergy, but had-like peanut SPT poor reproducibility. FeNO, peanut sIgE and Ara h2 sIgE were consistently reproducible despite an interval of at least 12 months between the repeated measurements. PMID- 27499765 TI - Prevalence and clinical features of adverse food reactions in Portuguese adults. AB - BACKGROUND: Only one previous study, via telephone call, on the prevalence of self-reported food allergies has been performed in Portugal, in a small sample of adults. The objective of this study was to determine the prevalence of self reported and probable food allergy, analyze the clinical features and involved foods in Portuguese adults. METHODS: Population-based, cross-sectional study performed in various healthcare centres from central Portugal. All 1436 randomly selected individuals (median age: 45 years, 50.6 % female) replied to a validated food allergy questionnaire by phone. Those who reported an adverse food reaction were invited to come to the hospital, where clinical history was taken, skin prick (SPT) and prick-prick skin (SPPT) tests were performed and food allergen specific IgE levels (sIgE) were determined. An open oral challenge was performed in selected cases. Cases of positive clinical history of immediate (up to 2 h after ingestion) reaction in association with positive food sIgE levels and/or skin prick tests were classified as IgE-associated probable food allergy. Cases of positive clinical history of delayed (more than 2 h after ingestion) and negative food sIgE levels independently of positive SPT or SPPT results were classified as non-IgE associated probable food allergy. RESULTS: The prevalence of probable food allergy in our sample was 1 %, with shellfish and fish as the most frequently implicated foods. IgE-mediated probable food allergy occurred in 0.71 % of cases, with shellfish, peanut and nuts mainly involved. Cutaneous symptoms were most frequently reported. Prevalence values and food types were discrepant between self-reported and probable food allergies. CONCLUSIONS: The prevalence of probable food allergies in Portuguese adults is low, is mostly related to shellfish, peanut and nuts and most frequently involves cutaneous symptoms. PMID- 27499766 TI - Specific immunotherapy ameliorates ulcerative colitis. AB - BACKGROUND: Hypersensitivity reaction to certain allergens plays a role in the pathogenesis of inflammatory bowel disease (IBD). This study aims to observe the effect of specific immunotherapy in a group of IBD patients. METHODS: Patients with both ulcerative colitis (UC) and food allergy were recruited into this study. Food allergy was diagnosed by skin prick test and serum specific IgE. The patients were treated with specific immunotherapy (SIT) and Clostridium butyricum (CB) capsules. RESULTS: After treating with SIT and CB, the clinical symptoms of UC were markedly suppressed as shown by reduced truncated Mayo scores and medication scores. The serum levels of specific IgE, interleukin (IL)-4 and tumor necrosis factor (TNF)-alpha were also suppressed. Treating with SIT alone or CB alone did not show appreciable improvement of the clinical symptoms of UC. CONCLUSIONS: UC with food allergy can be ameliorated by administration with SIT and butyrate-production probiotics. PMID- 27499767 TI - A role for auto-immunity in chronic rhinosinusitis? Lessons learned from sub epidermal bullous disorders of the skin. AB - Chronic rhinosinusitis (CRS) is a frequent chronic condition, which has origins in complex interactions between genetic, immunological and microbial factors. The role of auto-immunity in CRS remains unclear, although recent studies have started to emerge in CRS patient refractory to maximal medical management. We discuss the possible auto-immunity link between CRS and other skin diseases, in particular acquired bullous dermatoses, and review the current evidence. We raise additional considerations for auto-immunity from both research and clinical standpoints. PMID- 27499768 TI - The Diagnosis of HIV Infection in Infants and Children. AB - It is estimated that the number of HIV infected children globally has increased from 1.6 million in 2001 to 3.3 million in 2012. The number of children below 15 years of age living with HIV has increased worldwide. Published data from recent studies confirmed dramatic survival benefit for infants started anti-retroviral therapy (ART) as early as possible after diagnosis of HI. Early confirmation of HIV diagnosis is required in order to identify infants who need immediate ART. WHO has designed recommendations to improve programs for both early diagnoses of HIV infection and considering ART whenever indicated? It is strongly recommended that HIV virologocal assays for diagnosis of HIV have sensitivity of at least 95% and ideally greater than 98% and specificity of 98% or more under standardized and validated conditions. Timing of virological testing is also important. Infants infected at or around delivery may take short time to have detectable virus. Therefore, sensitivity of virological tests is lower at birth. In utero HIV infection, HIV DNA or RNA can be detected within 48 h of birth and in infants with peripartum acquisition it needs one to two weeks. Finally it is emphasized that all laboratories performing HIV tests should follow available services provided by WHO or CDC for quality assurance programs. Both clinicians and staffs providing laboratory services need regular communications, well-defined SOPs and nationally validated algorithms for optimal use of laboratory tests. Every country should use assays that have been validated by national reference laboratory. PMID- 27499769 TI - Validity of Selected WBC Differentiation Flags in Sysmex XT-1800i. AB - BACKGROUND: Automatic Cell Counter devises make the CBC differential very easy and delivering the results in few second. However, the problem with this device is facing a flag requires a time-consuming microscopic review of the specimen which causes unacceptable wait times for patient as well as costs for laboratories. In this study, we calculated the validity of WBC diff flags in Sysmex XT-1800i. In addition, we verified the correlation between manual and automated samples. METHODS: Overall, 1095 flagged samples were selected in the period of 6 weeks (Imam Hospital complex, Tehran Iran, 2014). The results of both automated and manual counting of the samples were carefully studied and compared. Totally, 624 NRBC flags, 450 Blast flags, 155 abnormal WBC Scatter gram flags, 140 Eosinophilia flags and 468 Monocytosis flags were identified. RESULTS: Considering NRBC and blast flags there was a significant difference between our manual counted and automated counted NRBCs and blasts (P<0.05). There was no significant difference between automated and manual counting of flags for WBC Scatter gram. A significant difference between automated and manual counting data in flags, eosinophilia and monocytosis was foun (P<0.05). CONCLUSION: We propose the NRBC flags to be ignored and report negative except for the neonatal ward, and the Blasts flags to be ignored and report negative in all the cases. The WBC Scatter gram should be report positive. For eosinophilia and monocytosis flags, we propose, the Sysmex results should be considered correct and the manual checking would not be necessary. PMID- 27499770 TI - Maspin Gene Expression in Invasive Ductal Carcinoma of Breast. AB - BACKGROUND: The breast cancer is the most prevalent cancer among women, on the other hand absence of myoepithelial cells play a pivotal role in pathogenesis of this cancer. Thus we aimed to investigate the possible abilities of the molecular assay technique to find a relationship between mammary serine protease inhibitor (Maspin) gene expression possibly secreted by myoepithelial cells, grade of breast cancer and other prognostics factors (ER, PR, and c-erb-B2). METHODS: Paraffin embedded blocks of 31 breast cancer patients together with two normal breast tissues were used for IHC staining and Maspin gene RNA detection uses the real-time PCR method. Applying QIAGEN kit, we were able to measure Maspin RNA and Extract the cDNA of different samples for evaluating the Maspin RNA level. RESULTS: We found that the RNA level was considerably lowerin these cancer samples compared with normal samples. In addition, different grades of breast cancer in the obtained results adopt some distinguishable values. The Maspin expression in samples with grades II and III is much lower than the ones in normal group (P<0.05) which could be considered as a promising way in diagnosing of this disease. The results showed no considerable differences in Maspin gene expression of the c-erb-B2 scores in the tumor group except the samples having score 0. The other observation of this research study confirmed that Maspin gene expression couldn't show any differences between the values of both ER and PR in different scores of the tumor group. On the other hand, the cDNA of these patients showed lower values compared with normal samples. CONCLUSION: Maspin expression was reduced in samples with grade II& III of invasive ductal carcinoma. Based on expression of Maspin Inc-erb-B2, it seems that more expression happened in normal group comparing with different scores of it. We could suggest that there was a reverse relationship between tumor formation and Maspin gene expression. These results showed possible role of Maspin as prognostic factor. PMID- 27499771 TI - Designing and Construction of a DNA Vaccine Encoding Tb10.4 Gene of Mycobacterium tuberculosis. AB - BACKGROUND: Tuberculosis (TB) remains as a major cause of death. Construction of a new vaccine against tuberculosis is an effective way to control it. Several vaccines against this disease have been developed. The aim of the present study was to cloning of tb10.4 gene in pcDNA3.1(+) plasmid and evaluation of its expression in eukaryotic cells. METHODS: Firstly, tb10.4 fragment was amplified by PCR and the PCR product was digested with restriction enzymes. Next, it was cloned into pcDNA3.1(+) plasmid. Following that, pcDNA3.1(+)/tb10.4 recombinant plasmid was transfected into eukaryotic cells. RESULTS: 5700 bp band for pcDNA3.1(+)/tb10.4 recombinant plasmid and 297 bp fragment for tb10.4 were observed. Cloning and transfection were successful. CONCLUSION: Successful cloning provides a basis for the development of new DNA vaccines against tuberculosis. PMID- 27499772 TI - Correlation between Gleason Scores in Needle Biopsy and Corresponding Radical Prostatectomy Specimens: A Twelve-Year Review. AB - BACKGROUND: Presence of discordance between the Gleason score on needle biopsy and the score of radical prostatectomy specimen is common and universal. In this study, we determined the accuracy of Gleason grading of biopsies in predicting histological grading of radical prostatectomy specimens and the degree of overgrading and undergrading of prostatic adenocarcinoma in our center, which is one of the referral centers in Tehran. METHODS: In this retrospective study, we analyzed the results of prostate needle biopsies and subsequent prostatectomies diagnosed at the Pathobiology Laboratory Center, Tehran, Iran in 45 patients between 2002 and 2013. Preoperative clinical data and the information from biopsy and prostatectomy specimens were collected. The accuracy, sensitivity, specificity, and positive and negative predictive values of different grades and groups were assessed. Pearson and Spearman correlation coefficient were used to determine the relation of different variables. RESULTS: The biopsy Gleason score was identical to the scores in prostatectomy specimens in 68.2% cases, while 31.8% were discrepant by 1 or 2 Gleason score. We had 9.1% downgrading and 22.7% cases upgraded after prostatectomy. The sensitivity and positive predictive value was 86% and 79% for low grade, 67% and 75% for moderate grade, and 80% and 80% for high-grade tumors, respectively. CONCLUSION: Overall, the reliability of Gleason grading of needle biopsies in predicting final pathology was satisfavory. Moderate grade group was the most difficult to diagnose in needle biopsy. PMID- 27499773 TI - Immunogenicity of Four Doses of Double-Strength Intramuscular Hepatitis B. AB - BACKGROUND: Hepatitis B virus potentially accelerates graft rejection and mortality in renal transplantation population. Vaccination of graft candidates without prior immunization against HBV seems essential before transplantation but some candidates of transplantation have not received HBV vaccine at the time of receiving graft. We aimed to evaluate immunogenicity of an enhanced regimen (4 doses of double-strength intramuscular shots) after kidney transplantation in candidates without history of prior HBV vaccination. METHODS: This quasi experimental study was conducted, 49 renal graft recipients in Sina Hospital (Tehran University of Medical Sciences, Tehran, Iran) of age >18, receiving graft within past 6 months and negative history of hepatitis B vaccination from 2010 2011. Participants received 40 MUg intramuscular (IM) shots of a recombinant vaccine in the months 0, 1, 2 and 6. The titer of HBsAb was measured 8 weeks after the 3(rd) and 4(th) injections. Cases with HBsAb titers less than 10 mIu/ml were considered as non-responder while antiHBs>=10 mIu/ml was considered protective. RESULTS: The overall response rate was 57.14% (28/49 patients). Protective HBsAb titers were detected in 44.89% patients following 3(rd) dose and reached to 57.14% after injecting the 4(th) shots. The mean HBsAb titers were 50.00 (+/-88.35) mIu/ml and 229.45 (+/-356.56) mIu/ml after the 3(rd) and 4(th) shots respectively. Responders showed significantly younger age in comparison to non-responders (P=0.013). The vaccine was well tolerated in all patients with no side effects. CONCLUSIONS: Regarding the relative good response rate following HBV vaccination in graft recipients, we suggest a post-transplantation enhanced regimen of 4-dose double-strength IM shots against HBV in patients without prior immunization. PMID- 27499774 TI - Can Trimodal Distribution of HbS Levels in Sickle Cell Traits Be Used To Predict the Associated Alpha-Thalassemia For Screening Cases in Central India? AB - BACKGROUND: Until now, trimodal distribution of HbS has been seen by six different studies in the world when associated with alpha-thalassemia with confirmation by corresponding alpha-genotyping studies. The RBC indices reduce as alpha-globin genes reduce in sickle cell trait (SCT) patients, which decreases the extent of intra-vascular sickling and thus betters the clinical course of the patients. This is a pioneer study conducted on Central Indian poor population to use the already proven six studies to screen associated alpha-thalassemia in SCT patients thus, circumventing the much costlier alpha-genotyping studies. Moreover, it aimed to study the haematological parameters in such cases. METHODS: The study was performed at RHDMC, IGGMC, Nagpur, India from 2003 to 2012. The sample population was suspected cases of haemolytic anaemia. CBC and RBC indices were obtained by a cell analyzer. The sickle solubility test positively screened cases were confirmed by agar-gel haemoglobin electrophoresis at pH 8.6. Finally, quantitative assessment of haemoglobin variants was performed by HPLC. RESULTS: Out of total 5819 cases over ten years, 933 cases were sickle heterozygotes. Overall, 180/933 subjects were predicted to be homozygous alpha-thalassemia and 338/933 were heterozygous alpha-thalassemia, based on trimodal distribution of HbS. CONCLUSION: Genotyping is costlier for majority of the poor non-affording patients in Indian government set-ups, so this study is suitable to screen for associated alpha-thalassemia in SCT patients. PMID- 27499775 TI - Molecular Detection of Ureaplasma urealyticum from Prostate Tissues using PCR RFLP, Tehran, Iran. AB - BACKGROUND: In most cases, prostatitis can be caused by a bacterial agent such as Ureaplasma urealyticum. Considering to the cumbersome of the culture method for the detection of Ureaplasma species in clinical samples such as prostate; PCR method that is faster and more appropriate than the cultivation methods, can be utilized for the detection of U. urealyticum and U. parvum. PCR-RFLP method can differentiate both biovars and assist in studies of the clinical diagnosis, epidemiology and pathology of this species in human. The aim of this study was to molecular detection of U. urealyticumin in prostate tissue samples based on PCR- RFLP. METHODS: Two hundred prostate tissue samples were collected from patient suffering from prostatitis. The PCR assay was used to amplify a 559 bp fragment of 16S-23SRNA interspace region of Ureaplasma. After sequencing, PCR products from positive samples were digested with TaqI restriction enzyme. RESULTS: Seven cases (3.5%) out of 200 prostate tissue samples were positive for U. urealyticum. Results of PCR products sequencing demonstrated that all isolates were U. parvum biovar. PCR-RFLP results shown that there was not any differentiation in pattern of enzymatic digestion, in addition, all isolates were U. parvum, serovar 3. DISCUSSION: U. urealyticum can be one of the causing agents of prostatitis. Using PCR-RFLP with specific primer and restriction enzyme is a rapid and cost-effect method for detection and differentiation of Ureaplasma from clinical samples. PMID- 27499776 TI - Comparing Rapid and Specific Detection of Brucella in Clinical Samples by PCR ELISA and Multiplex-PCR Method. AB - BACKGROUND: Rapid diagnosis and differentiation of Brucella is of high importance due to the side effects of antibiotics for the treatment of brucellosis. This study aimed to identify and compare PCR-ELISA as a more accurate diagnositc test with other common molecular and serological tests. METHODS: In this experimental and sectional study, during March 2014 to Sep 2015, 52 blood samples of suspected patients with clinical symptoms of brucellosis were evaluated in medical centers all over Iran with serum titers higher than 1:80. Using two pairs of specific primers of Brucella abortus, B. melitensis and DIG-dUTP, Fragment IS711 (The common gene fragment in B. melitensis and B. abortus) was amplified. DIG-ELISA was performed using specific probes of these 2 species of Brucella and patterns were subsequently analyzed, then positive responses were compared by detecting gel electrophoresis. RESULTS: PCR-ELISA method detected all 28 samples from 52 positive samples. Its sensitivity was 6.0 pg concentration of genomic DNA of Brucella. In gel electrophoresis method, 22 samples of all positive samples were detected. PCR-ELISA was more efficient than PCR and bacterial culture method at P value <0.05. CONCLUSION: PCR-ELISA molecular method is more sensitive than other molecular methods, lack of mutagenic color and also a semi-quantitative ability. This method is more effective and more accurate compared to PCR, serology and culture of bacteria. PCR-ELISA does not have false responses. The limitation of this method is detection of bacteria in the genus compared to Multiplex PCR and Gel Electrophoresis. PMID- 27499777 TI - Preanalytical Errors in Hematology Laboratory- an Avoidable Incompetence. AB - BACKGROUND: Quality assurance in the hematology laboratory is a must to ensure laboratory users of reliable test results with high degree of precision and accuracy. Even after so many advances in hematology laboratory practice, pre analytical errors remain a challenge for practicing pathologists. This study was undertaken with an objective to evaluate the types and frequency of preanalytical errors in hematology laboratory of our center. METHODS: All the samples received in the Hematology Laboratory of Dayanand Medical College and Hospital, Ludhiana, India over a period of one year (July 2013-July 2014) were included in the study and preanalytical variables like clotted samples, quantity not sufficient, wrong sample, without label, wrong label were studied. RESULTS: Of 471,006 samples received in the laboratory, preanalytical errors, as per the above mentioned categories was found in 1802 samples. The most common error was clotted samples (1332 samples, 0.28% of the total samples) followed by quantity not sufficient (328 sample, 0.06%), wrong sample (96 samples, 0.02%), without label (24 samples, 0.005%) and wrong label (22 samples, 0.005%). CONCLUSION: Preanalytical errors are frequent in laboratories and can be corrected by regular analysis of the variables involved. Rectification can be done by regular education of the staff. PMID- 27499778 TI - Rad51 Expression in Nasopharyngeal Carcinoma and Its Association with Tumor Reduction: A Preliminary Study in Indonesia. AB - BACKGROUND: Overexpression of Rad51 protein in many tumor cells has been proven to increase radioresistance and can be related to the resistance of chemosensitivity of tumor cells. This preliminary study was conducted to determine the relationship between the Rad51 expression level in nasopharyngeal carcinoma and the response of the treatment based on the measurement of the tumor reduction. METHODS: Thirteen cases of the NPCs were analyzed. The expression levels of the Rad51 were examined from the pretreatment biopsies. Furthermore, tumor reductions were determined based on the change in sum longest diameter of the nasopharyngeal CT-scan before and after therapy. RESULTS: The expression level of the Rad51 was associated with the reduction of tumor mass. The P value was 0.049 and the correlation coefficient was 0.479. CONCLUSION: The tumor cells Rad51 expression levels may affect the tumor reduction of NPC after the therapy. PMID- 27499779 TI - Pituitary Chondrosarcoma presenting as a sellar and suprasellar mass with parasellar extension: An Unusual presentation. AB - Chondrosarcoma is a mesenchymal tumor composed of tumor cells producing cartilage. It is more common in older age and often affects the axial skeleton. We report a rare case of chondrosarcoma mimicking a sellar and suprasellar mass with parasellar extension. A 40 yr woman presented with decreasing visual acuity and headache. Magnetic resonance (MR) image revealed a cystic sellar and suprasellar mass with parasellar extension showing mild enhancing solid component. It favored the diagnosis of craniopharyngioma. The patient underwent trans-sphenoidal partial resection of the tumor resulting in removal of the sellar mass. However, the suprasellar mass could not be excised completely due to limited surgical field. The pathologic diagnosis was chondrosarcoma. Eight months after the operation, pterional approach was performed to remove the remaining mass. Intraoperative findings confirmed that the mass originated from dorsum sellae. PMID- 27499780 TI - Apocrine Metaplasia in Intraductal Papilloma with Foci of DCIS: A Friend or Foe? AB - Malignant papillary neoplasms of the breast comprise a number of microscopically distinct lesions, where apocrine metaplasia is commonly found in papillomas compared to other papillary lesions including papillary carcinomas. However, association of apocrine metaplasia in papilloma with Ductal Carcinoma in Situ (DCIS) is not very well defined. The lesions with apocrine metaplasia are not only difficult to categories, but also there is controversy regarding their relative risk of subsequent carcinoma development. A case of extensive apocrine differentiation in duct papilloma with DCIS developing in the background of papillomatosis, posing a diagnostic dilemma for the pathologist and a therapeutic challenge for the surgeon, is hereby reported for its uniqueness and rarity. Awareness of this association should be kept in mind by both the pathologist as well as clinician for optimal therapeutic intervention. PMID- 27499781 TI - Granulomatous Response with Breast Cancer: A Case Report. AB - Granulomatous response in association with breast cancer and within the cancer draining lymph nodes is an extremely rare phenomenon. Granulomatous inflammation is an immune response commonly seen against infectious agents and certain non neoplastic conditions. The etiopathogenesis of granulomas associated with malignancies is not clear but it may be because of an immunologic reaction to tumour antigens. We hereby report a 50-yr-old postmenopausal female presented to Surgical Outpatient Department, Aligarh Muslim University, India, with complaints of lump and pain in her left breast for 6 months. We have also discussed about its etiopathogenesis, final diagnosis, treatment & patient outcome. PMID- 27499782 TI - Recurrent Ancient Intraosseous Neurilemmoma of Maxilla: A Rare Case Report. AB - Neurilemmomas are benign tumors of peripheral nerve sheath Schwann cells. One of the variants of neurilemmoma is the ancient type of neurilemmoma characterized by degenerative features such as cystic degeneration, calcification, hemorrhage and hyalinization which could be easily misdiagnosed. Their occurrence in oral cavity is extremely rare and intraosseous type occurring in maxilla is exceedingly rare with very few cases being published in literature. A 38 year old male patient reported with a chief complaint of swelling over the left cheek and left upper back region since 10 months. The case is of recurrent intraosseous ancient neurilemmoma in the maxilla in the patient which is distinctive for the lesion. This unique case presented with distinct histologic architectural pattern of ancient neurilemmoma showing degenerative changes such as cystic degeneration and recurred within a short duration of time. PMID- 27499783 TI - Acinic Cell Carcinoma of the Parotid Gland with Four Morphological Features. AB - Acinic cell carcinoma arising in salivary glands is a rare tumor, accounting for 2% to 5% of the primary neoplasms of the parotid gland. When these tumors are well-differentiated, the neoplasia has innocuous aspect, due to the similarity to normal parotid tissue. This makes the diagnosis difficult. Initially the malignancy of this tumor was uncertain; however, recent studies have declared it as malignant. The female / male ratio is 3:2. The nodule usually presents as solitary and well defined shape. Several authors have used different terms to describe histomorphological patterns of these tumors. Four descriptive categories (solid, microcystic, papillary-cystic and follicular) are useful for pathologists. Here we report a case of a 49 yr old man with a left parotid nodule of 5 cm. Parotidectomy was performed at the Hospital Universitario Miguel Servet, in Zaragoza (Spain). The microscopy showed a tumor with acinic semblance, having the four morphologic patterns previously described. The morphological and immunohistochemical study was consistent with the diagnosis of acinic cell carcinoma. PMID- 27499784 TI - Localized Leishmania Lymphadenitis Etiologic Agent Identified as Leishmania tropica Using Gene Sequencing. PMID- 27499785 TI - Anemia during Hospitalization in the Patients with Ebola Virus Disease. PMID- 27499786 TI - Ebola Infection and Diabetes Mellitus. PMID- 27499787 TI - Inhibition of P-glycoprotein expression and function by anti-diabetic drugs gliclazide, metformin, and pioglitazone in vitro and in situ. AB - P-glycoprotein (P-gp) is a trans-membrane drug efflux pump. Several drugs are P gp substrates. Some drugs may affect the activity of P-gp by inhibiting its function, resulting in significant drug-drug interactions (DDIs). It is critical to understand which drugs are inhibitors of P-gp so that adverse DDIs can be minimized or avoided. This study investigated the effects of gliclazide, metformin, and pioglitazone on the function and expression of P-gp. Rhodamine 123 (Rh 123) efflux assays in Caco-2 cells and western blot testing were used to study in vitro the effect of the drugs on P-gp function and expression. The in situ rat single-pass intestinal permeability model was developed to study the effect of the drugs on P-gp function. Digoxin and verapamil were used as a known substrate and inhibitor of P-gp, respectively. Digoxin levels in intestinal perfusion samples were analyzed by high-performance liquid chromatography. Intestinal effective permeability (Peff) of digoxin in the presence of 0.1, 10, and 500 MUM gliclazide, 100 and 7000 MUM metformin, and 50 and 300 MUM pioglitazone was significantly increased relative to the digoxin treated cells (P < 0.01). P-gp expression was decreased by gliclazide, metformin and pioglitazone. Intracellular accumulation of Rh 123 by the drugs increased, but the differences were not significant relative to the control cells (P > 0.05). It was found that gliclazide, metformin, and pioglitazone inhibited P-gp efflux activity in situ and down-regulated P-gp expression in vitro. Further investigations are necessary to confirm the obtained results and to define the mechanism underlying P-gp inhibition by the drugs. PMID- 27499788 TI - Theoretical design of a new chimeric protein for the treatment of breast cancer. AB - p28 and NRC peptides are two anticancer peptides with various mechanisms have shown to be effective against breast cancer. Therefore, it seems that construction of a chimeric protein containing the two peptides might cause synergistic cytotoxic effects. However, since the two peptides bear opposite charges, production of a chimeric protein in which the two moieties do not intervene each other is difficult. In this study, our goal was to find a suitable peptide linker for the new chimeric protein in a manner that none of the peptides intervene the other's function. We selected some linkers with different characteristics and lengths and created a small library of the chimeric proteins harboring these linkers. Homology modeling and molecular dynamic simulation revealed that (PA)5P and (EAAAK)3 linkers can separate the p28 and NRC peptides effectively. Thus, the chimeric protein linked with (PA)5P or (EAAAK)3 linkers might show synergistic and stronger anticancer effects than the separate peptide moieties because they could exert their cytotoxic effects freely which is not influenced by the other part. PMID- 27499789 TI - Antidiarrhoeal assessment of hydroalcoholic and hexane extracts of Dracocephalum kotschyi Boiss. and apigenin in mice. AB - Dracocephalum kotschyi Boiss, a member of Labiatae family, is a native plant to Iran, which has been reported to have immunomodulatory, antihyperlipidemic and antispasmodic activities. The objective of this research was to study the antispasmodic and antidiarrhoeal activities of hydroalcoholic and hexane extracts of D. kotschyi in mice. Furthermore, the antidiarrhoeal and antispasmodic effect of apigenin, a flavonoid constituent of D. kotschyi, was also studied. Hydroalcoholic and hexane extracts were obtained from aerial part of D. kotschyi using percolation method. Antispasmodic effect of the test compounds was assessed by measurement of small intestine transit following oral administration of a charcoal meal. Diarrhoea was induced by administration of either castor oil (0.5 ml) or magnesium sulphate (MgSO4) (10% w/v solution). Both the hydroalcoholic and hexane extracts of D. kotschyi (10 and 20 mg/kg) reduced the intestinal charcoal meal transit. Loperamide (2 mg/kg) and apigenin (2 and 10 mg/kg) inhibited intestinal movement of the charcoal meal and also inhibited castor oil and MgSO4 induced diarrhoea. The hydroalcoholic and hexane extracts of D. kotschyi (10 and 20 mg/kg) also significantly inhibited the castor oil and MgSO4-induced diarrhoea in mice in comparison with the vehicle-treated control groups. This study confirms that both the hydroalcoholic and hexane extracts of D. kotschyi has antispasmodic and antidiarrhoeal properties in vivo and could be a suitable remedy for treatment of gastrointestinal disorders in which smooth muscle spasm and/or diarrhoea plays a significant roles. PMID- 27499790 TI - Synthesis and cytotoxicity evaluation of some new 6-nitro derivatives of thiazole containing 4-(3H)-quinazolinone. AB - Quinazolinones are a group of fused heterocyclic compounds which have valuable biological properties including cytotoxic, antibacterial and antifungal activities. Thiazole group-containing compounds have been also reported to have a wide range of biological activities such as antitumor, anti-inflammatory, analgesic and antibacterial effects. Due to valuable cytotoxic effects of both thiazole groups and quinazoline derivatives, in this study a series of quinazolinone-thiazole hybrids were synthesized and evaluated for their cytotoxic effects on three cell lines including MCF-7, HT-29, and PC-3. Among tested compounds (quinazolinones and three intermediates), k5 and k6 showed highest cytotoxic activities against PC3 cell line. K6 and C were most active compounds against MCF7 and K6 showed best cytotoxicity on HT-29 cell line. PMID- 27499791 TI - Wound-healing and antimicrobial properties of dichloromethane fraction of Dialium guineense (Wild) fruit coat. AB - This research established the scientific bases for the folkloric use of the neglected Dialium guineense fruit coat in wound and microbial infection management in Nigeria. The phytochemical analysis of the crude extract, fractions and sub-fractions was performed by standard methods. Agar well diffusion protocol was adopted for the antimicrobial assay while the wound healing properties was determined by full thickness skin excision wound model. Phytochemical analysis showed high relative proportion of alkaloids (6.05 +/- 0.98 %), saponins (3.91 +/ 0.02 %) and tannins (1.86 +/- 0.05 %). The only active fraction (DF) and sub fraction (DF-5) were effective against Gram-positive (inhibition zone diameters, IZDs, 8-10 mm and 11-15 mm) and Gram-negative (IZDs, 15-19 mm and 16-21 mm) bacteria and fungi (6-8 mm) compared with 20-24 mm and 18-19 mm of the standard (ciprofloxacin) respectively. Fifty mg/kg of the DF-5 showed nearly equal percentage wound healing post-surgery days to Cicatrin(r). The 50 mg/kg dose of DF and DF-5 showed more than 50 % wound healing at 10(th) day post-surgery, 50 mg/kg crude extract showed 54 % on day 14 while distilled water showed 56 % wound healing on day 17 with no sign of infection in all animal groups. All the treatments were significantly (P<0.01) different from control (distilled water) in wound healing by the 10(th) and 17(th) post-surgery days. The studies revealed that the fruit coat, which hitherto was treated as wastes could be explored for antimicrobial and wound healing properties against the backdrop of continually emerging antibiotic resistant strains of microorganisms. PMID- 27499792 TI - Effect of hydroalcoholic extract of Anethum graveolens leaves on the dentate gyrus of the hippocampus in the epileptic mice: a histopathological and immunohistochemical study. AB - Anethum graveolens or Dill (local name: Shevid) belongs to the family of Apiaceae (Umbelliferae) and is used traditionally for the treatment of convulsion and diabetes in Iran. This study aimed to investigate the effect of hydroalcoholic extract of A. graveolens leaves on the histology of the dentate gyrus of the hippocampus in the epileptic mice kindled by Pentylenetetrazole (PTZ). In this experimental study, the epileptic BALB/c mice kindled by PTZ were randomly divided into four groups of 10 animals each. Three experimental groups received 250, 500 and 750 mg/kg/day of A. graveolens extract for 21 days. The control group received phosphate-buffered saline (PBS). After the treatment period, the mice were anesthetized, and their hippocampi were dissected for the histopathological analysis, and immunohistochemical analysis for caspase-3 activity. Histopathological examinations showed that the mean numbers of the healthy neuronal cells in the dentate gyrus of the mice received 500 mg/kg/day of A. graveolens extracts were significantly higher than those of the mice received 250 and 750 mg/kg/day of the extracts as well as the control group (P < 0.05 and P < 0.001, respectively). In addition, the results of immunohistochemical analysis revealed that in mice treated with 500 mg/kg/day of A. graveolens; the numbers of caspase-3-positive cells in the dentate gyrus were significantly lower than those of the two other test and the control groups. The findings of this study suggest that 500 mg/kg/day of the A. graveolens extract could have protective effect on the dentate gyrus of the hippocampus in the epileptic mice. PMID- 27499793 TI - Incidence rate and pattern of clinically relevant potential drug-drug interactions in a large outpatient population of a developing country. AB - The objective of this study was to determine incidence rate, type, and pattern of clinically relevant potential drug-drug interactions (pDDIs) in a large outpatient population of a developing country. A retrospective, descriptive cross sectional study was conducted on outpatients' prescriptions in Khorasan Razavi province, Iran, over 12 months. A list of 25 clinically relevant DDIs, which are likely to occur in the outpatient setting, was used as the reference. Most frequent clinically relevant pDDIs, most common drugs contributing to the pDDIs, and the pattern of pDDIs for each medical specialty were determined. Descriptive statistics were used to report the results. In total, out of 8,169,142 prescriptions, 6,096 clinically relevant pDDIs were identified. The most common identified pDDIs were theophyllines-quinolones, warfarin-nonsteroidal anti inflammatory drugs, benzodiazepines-azole antifungal agents, and anticoagulants thyroid hormones. The most common drugs contributing to the identified pDDIs were ciprofloxacin, theophylline, warfarin, aminophylline, alprazolam, levothyroxine, and selegiline. While the incidence rate of clinically relevant pDDIs in prescriptions of general practitioners, internists, and cardiologists was the highest, the average pDDI incidence per 10,000 prescriptions of pulmonologists, infectious disease specialists, and cardiologists was highest. Although a small proportion of the analyzed prescriptions contained drug pairs with potential for clinically relevant DDIs, a significant number of outpatients have been exposed to the adverse effects associated with these interactions. It is recommended that in addition to training physicians and pharmacists, other effective interventions such as computerized alerting systems and electronic prescribing systems be designed and implemented. PMID- 27499794 TI - Phytochemical and biological evaluation of some Sargassum species from Persian Gulf. AB - Sea algae are widely consumed in the world. There are several seaweeds including brown algae which are authorized for human consumption. These plants contain important phytochemical constituents and have various potential biological activities. The present study investigated the presence of phytochemical constituents and total phenolic quantity of the seaweeds Sargassum angustifolium, Sargassum oligocystum and Sargassum boveanum. Cytotoxicity of seaweeds was tested against HT-29, HeLa and MCF-7 cell lines. Antioxidant potential of these 3 Sargassum species was also analyzed. Cytotoxicity was characterized by IC50 of human cancer cell lines using sulforhodamine assay. Antioxidant activities were evaluated using 2,2-diphenyl-1- picrylhydrazil. The analysis revealed that tannins, saponins, sterols and triterpenes were the most abundant compounds in these Sargassum species while cyanogenic and cardiac glycosides were the least ones. Sargassum angustifolium had the highest content of total phenolics (0.061 mg/g) and showed the highest antioxidant activity (IC50 = 0.231). Cytotoxic results showed that all species could inhibit cell growth effectively, especially MCF-7 cell line (IC50 = 67.3, 56.9, 60.4 for S. oligocystum, S. angustifolium and S. boveanum respectively). Considerable phytochemicals and moderate cytotoxic activity of S. angustifolium, S. oligocystum and S. boveanum make them appropriate candidate for further studies and identification of their bioactive principles. PMID- 27499795 TI - Identification of novel bacterial DNA gyrase inhibitors: An in silico study. AB - Owing to essential role in bacterial survival, DNA gyrase has been exploited as a validated drug target. However, rapidly emerging resistance to gyrase-targeted drugs such as widely utilized fluoroquinolones reveals the necessity to develop novel compounds with new mechanism of actions against this enzyme. Here, an attempt has been made to identify new drug-like molecules for Shigella flexneri DNA gyrase inhibition through in silico approaches. The structural similarity search was carried out using the natural product simocyclinone D8, a unique gyrase inhibitor, to virtually screen ZINC database. A total of 11830 retrieved hits were further screened for selection of high-affinity compounds by implementing molecular docking followed by investigation of druggability according to Lipinski's rule, biological activity and physiochemical properties. Among the hits initially identified, three molecules were then confirmed to have reasonable gyrase-binding affinity and to follow Lipinski's rule. Based on these in silico findings, three compounds with different chemical structures from previously identified gyrase inhibitors were proposed as potential candidates for the treatment of fluoroquinolone-resistant strains and deserve further investigations. PMID- 27499796 TI - Frequency distribution of polymorphisms of CYP2C19, CYP2C9, VKORC1 and SLCO1B1 genes in the Yakut population. AB - Allele frequencies of single nucleotide polymorphisms (SNPs) are variable among different populations; therefore the study of SNPs in ethnic groups is important for establishing the clinical significance of the screening of these polymorphisms. The main goal of the research is to study the polymorphisms of CYP2C9, CYP2C19, VKORC1, and SLCO1B1 in Yakuts. Genomic DNA from 229 Yakut subjects were analyzed by real-time polymerase chain reaction (PCR) (SLCO1B1 +521T > C, VKORC1 -1639G>A, CYP2C19 +681G>A, +636G>A, CYP2C9 +430S>T, +1075A>C). Genotype frequencies of polymorphisms in the population of the Yakuts were more characteristic of the Asian population. The results have been included in the software application "Lekgen" that we developed for the interpretation of pharmacogenetic testing. The data of our study obtained on frequency carriers of polymorphisms of genes SLCO1B1, CYP2C19, CYP2C9, VKORC1 among the Yakuts may be useful in developing recommendations for a personalized therapy. PMID- 27499797 TI - XAFS Data Interchange: A single spectrum XAFS data file format. AB - We propose a standard data format for the interchange of XAFS data. The XAFS Data Interchange (XDI) standard is meant to encapsulate a single spectrum of XAFS along with relevant metadata. XDI is a text-based format with a simple syntax which clearly delineates metadata from the data table in a way that is easily interpreted both by a computer and by a human. The metadata header is inspired by the format of an electronic mail header, representing metadata names and values as an associative array. The data table is represented as columns of numbers. This format can be imported as is into most existing XAFS data analysis, spreadsheet, or data visualization programs. Along with a specification and a dictionary of metadata types, we provide an application-programming interface written in C and bindings for programming dynamic languages. PMID- 27499798 TI - Impact of Psychoeducational Content Delivered Online to a Positive Psychology Aware Community. AB - Happiness-increasing interventions demonstrate significant variation in outcomes, suggesting that the people who use them might be as important as the interventions themselves to determine efficacy. In light of this, instructive interventions might not be necessary to increase happiness given a population with knowledge of happiness-increasing strategies. We recruited 270 participants with knowledge of positive psychology to receive six weeks of online psychoeducation. We explored participants' use of the website, reported use of happiness strategies, and changes in well-being. Those who spent more time on the website reported smaller changes in well-being than those who spent less time on the website. Conversely, those who reported employing more happiness strategies reported greater increases in well-being than those who used fewer strategies. This shows that for those already familiar with positive psychology, information, rather than instruction, might increase well-being. This has implications for studies evaluating the efficacy of happiness-increasing interventions more broadly. PMID- 27499799 TI - Habsburg Austria: Experiments in Non-Territorial Autonomy. AB - In the early twentieth century, three provinces of the Austrian half of the Habsburg Empire enacted national compromises in their legislation that had elements of non-territorial autonomy provisions. Czech and German politicians in Moravia reached an agreement in 1905. In the heavily mixed Bukovina, Romanian, Ukrainian, German, Jewish and Polish representatives agreed on a new provincial constitution in 1909. Last but not least, Polish and Ukrainian nationalists compromised in spring 1914, just a few months before the outbreak of the First World War vitiated the new provisions. Even though the provisions of these agreements varied substantially, new electoral laws introducing national registers were at their heart. These were designed to ensure a fairer representation of national groups in the provincial assemblies and to keep national agitation out of electoral campaigns. The earliest compromise in Moravia went furthest in consociational power sharing. However, the national bodies within the provincial assembly had no right to tax their respective national communities, and the provisions of the provincial constitutions kept the non nationally defined nobility as an important counterbalance. The compromises in Bukovina and Galicia, even if they categorised all inhabitants nationally, contented themselves with even less autonomous agency for the national bodies in the provincial assemblies and rather emphasised the symbolic elements of national autonomy. The non-territorial approach in all three crownlands, however, was an instrument to reorganise multi-ethnic provinces that increasingly became the model for national compromises in other Austrian provinces. PMID- 27499800 TI - The flagellar motor of Caulobacter crescentus generates more torque when a cell swims backward. AB - Caulobacter crescentus, a monotrichous bacterium, swims by rotating a single right-handed helical filament. CW motor rotation thrusts the cell forward 1, a mode of motility known as the pusher mode; CCW motor rotation pulls the cell backward, a mode of motility referred to as the puller mode 2. The situation is opposite in E. coli, a peritrichous bacterium, where CCW rotation of multiple left-handed filaments drives the cell forward. The flagellar motor in E. coli generates more torque in the CCW direction than the CW direction in swimming cells 3,4. However, monotrichous bacteria including C. crescentus swim forward and backward at similar speeds, prompting the assumption that motor torques in the two modes are the same 5,6. Here, we present evidence that motors in C. crescentus develop higher torques in the puller mode than in the pusher mode, and suggest that the anisotropy in torque-generation is similar in two species, despite the differences in filament handedness and motor bias (probability of CW rotation). PMID- 27499801 TI - An improved Four-Russians method and sparsified Four-Russians algorithm for RNA folding. AB - BACKGROUND: The basic RNA secondary structure prediction problem or single sequence folding problem (SSF) was solved 35 years ago by a now well-known [Formula: see text]-time dynamic programming method. Recently three methodologies Valiant, Four-Russians, and Sparsification-have been applied to speedup RNA secondary structure prediction. The sparsification method exploits two properties of the input: the number of subsequence Z with the endpoints belonging to the optimal folding set and the maximum number base-pairs L. These sparsity properties satisfy [Formula: see text] and [Formula: see text], and the method reduces the algorithmic running time to O(LZ). While the Four-Russians method utilizes tabling partial results. RESULTS: In this paper, we explore three different algorithmic speedups. We first expand the reformulate the single sequence folding Four-Russians [Formula: see text]-time algorithm, to utilize an on-demand lookup table. Second, we create a framework that combines the fastest Sparsification and new fastest on-demand Four-Russians methods. This combined method has worst-case running time of [Formula: see text], where [Formula: see text] and [Formula: see text]. Third we update the Four-Russians formulation to achieve an on-demand [Formula: see text]-time parallel algorithm. This then leads to an asymptotic speedup of [Formula: see text] where [Formula: see text] and [Formula: see text] the number of subsequence with the endpoint j belonging to the optimal folding set. CONCLUSIONS: The on-demand formulation not only removes all extraneous computation and allows us to incorporate more realistic scoring schemes, but leads us to take advantage of the sparsity properties. Through asymptotic analysis and empirical testing on the base-pair maximization variant and a more biologically informative scoring scheme, we show that this Sparse Four Russians framework is able to achieve a speedup on every problem instance, that is asymptotically never worse, and empirically better than achieved by the minimum of the two methods alone. PMID- 27499802 TI - The Single-Case Reporting Guideline In BEhavioural Interventions (SCRIBE) 2016 Statement. AB - Reporting guidelines, such as the Consolidated Standards of Reporting Trials (CONSORT) Statement, improve the reporting of research in the medical literature (Turner et al., 2012). Many such guidelines exist and the CONSORT Extension to Nonpharmacological Trials (Boutron et al., 2008) provides suitable guidance for reporting between-groups intervention studies in the behavioral sciences. The CONSORT Extension for N-of-1 Trials (CENT 2015) was developed for multiple crossover trials with single individuals in the medical sciences (Shamseer et al., 2015; Vohra et al., 2015), but there is no reporting guideline in the CONSORT tradition for single case research used in the behavioral sciences. We developed the Single Case Reporting guideline In BEhavioural interventions (SCRIBE) 2016 to meet this need. This statement article describes the methodology of the development of the SCRIBE 2016, along with the outcome of 2 Delphi surveys and a consensus meeting of experts. We present the resulting 26-item SCRIBE 2016 checklist. The article complements the more detailed SCRIBE 2016 explanation and elaboration article (Tate et al., 2016) that provides a rationale for each of the items and examples of adequate reporting from the literature. Both these resources will assist authors to prepare reports of single case research with clarity, completeness, accuracy, and transparency. They will also provide journal reviewers and editors with a practical checklist against which such reports may be critically evaluated. PMID- 27499803 TI - On table POCUS assessment for the IVC following abdominal packing: how I do it. AB - BACKGROUND: Some surgeons may lack proper experience in abdominal packing. Overpacking may directly compress the inferior vena cava (IVC). This reduces the venous return and possibly causes hypotension. Here, a new on table Point-of-Care Ultrasound application that has been recently used to assess the effect of abdominal packing on the IVC diameter is described. Following abdominal packing, a small print convex array probe with low frequency (2-5 MHz) is used to visualize the IVC. Using the B mode, the IVC can be directly evaluated through a hepatic window between the ribs. The ultrasound beam should be vertical to the IVC longitudinal section at its midpoint. The abdominal towels will be in front of the IVC. This will enable us to judge whether there was overpacking on the IVC. RESULTS: Our method demonstrates that overpacking does not compress the IVC in a patient whose blood pressure has improved. The IVC diameter progressively increases on table and in the ICU with active resuscitation implying that bleeding stopped and the resuscitation was successful. Furthermore, presence of intra-peritoneal fluid can be excluded. CONCLUSIONS: This new application of ultrasound evaluation of IVC patency after abdominal packing is simple, practical, easily reproducible, and can guide a less experienced surgeon in determining if overpacking of the abdomen is the cause of hypotension. Ultrasound findings should be correlated with the clinical picture to be useful. PMID- 27499804 TI - The learning curve of single-port laparoscopic appendectomy performed by emergent operation. AB - BACKGROUND: Single-port laparoscopic appendectomy (SPLA) has the advantage of minimizing abdominal incision scars with patient satisfaction. However, it has the following disadvantages: it provides a narrower surgical field than conventional laparoscopic appendectomy, which requires a considerably longer operative time to achieve surgical skills. This study was conducted to evaluate the learning curve for SPLA. METHODS: This study included a total of 120 patients with acute abdomen who visited our emergency department and were diagnosed with acute appendicitis between March 2013 and February 2015. They underwent SPLA by a single surgeon. Patients were divided into 4 groups of 30 patients each according to operation dates. Operative time, time to resume oral intake, length of hospital stay, and postoperative complications were analyzed. RESULTS: The mean operative time was 59.9 +/- 19.9 min. It was shortened after completion of 30 operations and remained unchanged until it was further shortened after completion of 90 operations. There was no significant difference in time to resumption of oral intake or length of hospital stay between the 4 groups. Postoperative complications occurred in 18 patients, but the frequency of the complications was not significantly different between the 4 groups. CONCLUSIONS: The results of this study suggest that surgeons can achieve surgical skills for SPLA after completion of 30 operations and more experienced surgical skills by SPLA successfully after completion of 90 operations. PMID- 27499805 TI - Situated learning in translation research training: academic research as a reflection of practice. AB - Situated learning has become a dominant goal in the translation classroom: translation didactics is being developed in a learner-, situation- and experience based direction, following constructivist and participatory teaching philosophies. However, the explicit use of situated approaches has, so far, not been the centre of attention in translation theory teaching and research training. As a consequence, translation theory often remains unconnected to the skills learned and topics tackled in language-specific translation teaching and the challenges experienced in real-life translation practice. This article reports on the results of an exploratory action research project into the teaching of academic research skills in translation studies at Master's level. The goal of the project is to develop and test possibilities for employing situated learning in translation research training. The situatedness perspective has a double relevance for the teaching project: the students are involved in an authentic, ongoing research project, and the object of the research project itself deals with authentic translation processes at the workplace. Thus, the project has the potential to improve the expertise of the students as both researchers and reflective practitioners. PMID- 27499806 TI - A German e-learning-training in the context of early preventive intervention and child protection: preliminary findings of a pre-post evaluation. AB - BACKGROUND: In recent years, a number of government-sponsored initiatives have been implemented in Germany that are focused on early preventive intervention in child protection. In response to the need for interdisciplinary training in this area, the internet-based e-learning program "Early Preventive Intervention and Child Protection" was developed for professionals in the child welfare and health care systems working with families with infants and toddlers. The program is currently undergoing evaluation for effectiveness and user satisfaction. METHODS: In a pre-post design, users are requested to complete questionnaires that assess three measures of expertise: theoretical knowledge of relevant fields, the ability to correctly identify subtle signals of infant communication, and the ability to assess maternal sensitivity. This article presents the contents of the program and the pre-training results (N = 1.294 participants). Descriptive analyses as well as Pearson correlations and Bonferroni corrections of error were conducted using the statistical program SPSS v. 21.0. RESULTS: The findings show that a wide range of professionals are making use of the program, and that their existing theoretical knowledge about early preventive intervention, as well as their ability to identify subtle signals of infant communication, is relatively good. However, their ability to assess maternal sensitivity, which is considered a crucial indicator for the risk of child abuse, was low. CONCLUSIONS: The outcome of the pre-training results indicates that professionals working in the area of child protection need to develop more capability in recognizing maternal sensitivity, in order to ensure early detection of families who are at risk and thus in need of support. Finally, the number of years of professional experience did not correlate with the scores on any of the three measures, which emphasizes the importance of providing interdisciplinary training in this area for all those working in child and family services, regardless of background. PMID- 27499807 TI - Mixed tenure communities as a policy instrument for educational outcomes in a deprived urban context? AB - This article considers mixed community strategies, enacted through planning and regeneration policies, as a policy approach to the improvement of educational outcomes in schools. Analysis is undertaken of educational outcomes across secondary schools in Glasgow. The level of owner occupation in the catchment is positively associated with both examination results at S4 and positive destinations post-school, particularly at the more deprived end of the school spectrum. The results suggest that tenure mix may be both directly and indirectly related to school performance, with neighbourhood context effects not being entirely mediated through the school context. PMID- 27499808 TI - Mental illness stigma and engagement in an implementation trial for Cognitive Processing Therapy at a diverse community health center: a qualitative investigation. AB - The present study aimed to describe associations between various types of mental health stigma and help-seeking behaviors among ethnically diverse clients with posttraumatic stress disorder (PTSD) served by an urban community health clinic. The present study draws qualitative data from a parent National Institute of Mental Health Study that aims to identify barriers and facilitators of implementing Cognitive Processing Therapy (CPT) for PTSD. A total of 24 participants from the initial phase of the trial were included in the present study. Mental health stigma emerged as one notable barrier to seeking mental health treatment, as participants described how experiences of environment-level stigma, internalized (self-)stigma and perceived (felt) stigma from their family, friends and previous healthcare providers influenced their decisions to seek care. Despite these barriers to help seeking, many clients also reported that positive interactions with informal and formal support systems, and encouragement from study therapists, helped to combat mental health stigma and facilitate decisions to participate in an implementation trial for CPT. Findings suggest that providers in community health settings may need to attend directly to stigma at the initiation of mental health treatment. PMID- 27499809 TI - Evaluation of the two-step treatment with ionic liquids and alkali for enhancing enzymatic hydrolysis of Eucalyptus: chemical and anatomical changes. AB - BACKGROUND: The biomass recalcitrance resulting from its chemical compositions and physical structures impedes the conversion of biomass into fermentable sugars. Pretreatment is a necessary procedure to increase the cellulase accessibility for bioconversion of lignocelluloses into bioethanol. Alternatively, ionic liquids, a series of promising solvents, provide unique opportunities for pretreating a wide range of lignocellulosic materials. In this study, a two-step treatment including ionic liquids pretreatment and successive alkali fractionations was performed on Eucalyptus to achieve a high enzymatic digestibility. The compositional and structural changes of Eucalyptus cell walls and their possible effect on saccharification ratio were comprehensively investigated. RESULTS: After the ionic liquids pretreatment, the cell walls became loose and even swelled, accompanying with the decrease of cellulose crystallinity. As compared to the simplex ionic liquids pretreatment, the integrated process resulted in the significant removal of hemicelluloses and lignin, enhancing the disruption of the cell walls and increasing the exposure of cellulose, which led to a higher conversion of cellulose to glucose. The glucose yield of Eucalyptus underwent the combination of [Bmim]OAc and alkali treatments reached the maximum (90.53 %), which was 6.6 times higher than that of the untreated Eucalyptus. The combination of chemical compositions and physical structure of Eucalyptus affected the efficiency of cellulose enzymatic hydrolysis. Especially, the changes of cellulose crystallinity played a major role in enhancing the enzymatic digestibility of Eucalyptus in this study. CONCLUSIONS: The two-step treatment with ionic liquids pretreatment and successive alkali fractionation can be considered as a promising method to improve the conversion of cellulose to glucose. The detailed information obtained about chemical and anatomical changes was helpful to understand the underlying mechanism of the integrated treatment process acting on Eucalyptus for enhancing enzymatic digestibility. PMID- 27499810 TI - Exploring xylose metabolism in Spathaspora species: XYL1.2 from Spathaspora passalidarum as the key for efficient anaerobic xylose fermentation in metabolic engineered Saccharomyces cerevisiae. AB - BACKGROUND: The production of ethanol and other fuels and chemicals from lignocellulosic materials is dependent of efficient xylose conversion. Xylose fermentation capacity in yeasts is usually linked to xylose reductase (XR) accepting NADH as cofactor. The XR from Scheffersomyces stipitis, which is able to use NADH as cofactor but still prefers NADPH, has been used to generate recombinant xylose-fermenting Saccharomyces cerevisiae. Novel xylose-fermenting yeasts species, as those from the Spathaspora clade, have been described and are potential sources of novel genes to improve xylose fermentation in S. cerevisiae. RESULTS: Xylose fermentation by six strains from different Spathaspora species isolated in Brazil, plus the Sp. passalidarum type strain (CBS 10155(T)), was characterized under two oxygen-limited conditions. The best xylose-fermenting strains belong to the Sp. passalidarum species, and their highest ethanol titers, yields, and productivities were correlated to higher XR activity with NADH than with NADPH. Among the different Spathaspora species, Sp. passalidarum appears to be the sole harboring two XYL1 genes: XYL1.1, similar to the XYL1 found in other Spathaspora and yeast species and XYL1.2, with relatively higher expression level. XYL1.1p and XYL1.2p from Sp. passalidarum were expressed in S. cerevisiae TMB 3044 and XYL1.1p was confirmed to be strictly NADPH-dependent, while XYL1.2p to use both NADPH and NADH, with higher activity with the later. Recombinant S. cerevisiae strains expressing XYL1.1p did not show anaerobic growth in xylose medium. Under anaerobic xylose fermentation, S. cerevisiae TMB 3504, which expresses XYL1.2p from Sp. passalidarum, revealed significant higher ethanol yield and productivity than S. cerevisiae TMB 3422, which harbors XYL1p N272D from Sc. stipitis in the same isogenic background (0.40 vs 0.34 g gCDW (-1) and 0.33 vs 0.18 g gCDW (-1) h(-1), respectively). CONCLUSION: This work explored a new clade of xylose-fermenting yeasts (Spathaspora species) towards the engineering of S. cerevisiae for improved xylose fermentation. The new S. cerevisiae TMB 3504 displays higher XR activity with NADH than with NADPH, with consequent improved ethanol yield and productivity and low xylitol production. This meaningful advance in anaerobic xylose fermentation by recombinant S. cerevisiae (using the XR/XDH pathway) paves the way for the development of novel industrial pentose-fermenting strains. PMID- 27499811 TI - 14q32.3-qter trisomic segment: a case report and literature review. AB - BACKGROUND: Segmental duplication of the long arm of chromosome 14 (14q) has commonly been reported to affect the proximal segment of 14q, while distal duplication is a rare condition and often associated with segmental monosomy of other chromosomes. CASE PRESENTATION: We report the clinical and genetic characterization of a 4-year-old male patient with 14q32.3-qter trisomy resulting from an adjacent segregation of a paternal reciprocal translocation (14;21)(q32.1;p12). The child shows minor facial anomalies, severe developmental delay, growth retardation, and a history of congenital hypothyroidism and neonatal transitory hyperglycemic crises. CONCLUSIONS: To the best of our knowledge, only 15 other cases of segmental 14q trisomy were documented. We compared molecularly defined cases to identify a minimal common duplicated region and to find genes with a hypothetical role in the phenotype. The presented case supports the previous suggestion of a pure "distal 14q partial duplication" and underlines the clinical variability. PMID- 27499813 TI - SEX RATIO AT BIRTH AND THE IDEAL FAMILY IN CHI LINH DISTRICT, VIETNAM. AB - Chi Linh district, which locates in the Red Delta River region, has been recognized as the "hot pot" of high sex ratio at birth in Vietnam. This paper used community-based periodic Demographic-Epidemiologic Surveillance System (CHILILAB) to describe sex ratio at birth (SRB) and identify social - economic factors that related to the SRB. A total 5,940 births born from August 1, 2004 to August 31, 2011 was included in analysis. The SRB of 116.6 boys/100 girls (CI: 110.7 - 122.5) was significantly higher than normal. SRB were found high among second child having only older sister(s), among third child and higher birth order, among mothers who were 35 years and older, running small business or homemakers. Interestingly, a SRB of 91.4 boys/100 girls (CI: 81.8 - 102) was found among second children having an older brother, this is significantly lower than the normal level. Further research should be done to assert if abortion is practiced both to have a son and to have a daughter. PMID- 27499812 TI - Cardiac Repair and Regeneration: The Value of Cell Therapies. AB - Ischaemic heart disease is the predominant contributor to cardiovascular morbidity and mortality; one million myocardial Infarctions occur per year in the USA, while more than five million patients suffer from chronic heart failure. Recently, heart failure has been singled out as an epidemic and is a staggering clinical and public health problem associated with significant mortality, morbidity and healthcare expenditures, particularly among those aged >=65 years. Death rates have improved dramatically over the last four decades, but new approaches are nevertheless urgently needed for those patients who go on to develop ventricular dysfunction and chronic heart failure. Over the past decade, stem cell transplantation has emerged as a promising therapeutic strategy for acute or chronic ischaemic cardiomyopathy. Multiple candidate cell types have been used in preclinical animal models and in humans to repair or regenerate the injured heart, either directly or indirectly (through paracrine effects), including: embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), neonatal cardiomyocytes, skeletal myoblasts (SKMs), endothelial progenitor cells, bone marrow mononuclear cells (BMMNCs), mesenchymal stem cells (MSCs) and, most recently, cardiac stem cells (CSCs). Although no consensus has emerged yet, the ideal cell type for the treatment of heart disease should: (a) improve heart function; (b) create healthy and functional cardiac muscle and vasculature, integrated into the host tissue; (c) be amenable to delivery by minimally invasive clinical methods; (d) be available 'off the shelf' as a standardised reagent; (e) be tolerated by the immune system; (f) be safe oncologically, i.e. not create tumours; and (g) circumvent societal ethical concerns. At present, it is not clear whether such a 'perfect' stem cell exists; what is apparent, however, is that some cell types are more promising than others. In this brief review, we provide ongoing data on agreement and controversy arising from clinical trials and touch upon the future directions of cell therapy for heart disease. PMID- 27499814 TI - Systematics, phylogeny, and taphonomy of ghost shrimps (Decapoda): a perspective from the fossil record. AB - Ghost shrimps of Callianassidae and Ctenochelidae are soft-bodied, usually heterochelous decapods representing major bioturbators of muddy and sandy (sub)marine substrates. Ghost shrimps have a robust fossil record spanning from the Early Cretaceous (~ 133 Ma) to the Holocene and their remains are present in most assemblages of Cenozoic decapod crustaceans. Their taxonomic interpretation is in flux, mainly because the generic assignment is hindered by their insufficient preservation and disagreement in the biological classification. Furthermore, numerous taxa are incorrectly classified within the catch-all taxon Callianassa. To show the historical patterns in describing fossil ghost shrimps and to evaluate taphonomic aspects influencing the attribution of ghost shrimp remains to higher level taxa, a database of all fossil species treated at some time as belonging to the group has been compiled: 250 / 274 species are considered valid ghost shrimp taxa herein. More than half of these taxa (160 species, 58.4%) are known only from distal cheliped elements, i.e., dactylus and / or propodus, due to the more calcified cuticle locally. Rarely, ghost shrimps are preserved in situ in burrows or in direct association with them, and several previously unpublished occurrences are reported herein. For generic assignment, fossil material should be compared to living species because many of them have modern relatives. Heterochely, intraspecific variation, ontogenetic changes and sexual dimorphism are all factors that have to be taken into account when working with fossil ghost shrimps. Distal elements are usually more variable than proximal ones. Preliminary results suggest that the ghost shrimp clade emerged not before the Hauterivian (~ 133 Ma). The divergence of Ctenochelidae and Paracalliacinae is estimated to occur within the interval of Hauterivian to Albian (133-100 Ma). Callichirinae and Eucalliacinae likely diverged later during the Late Cretaceous (100-66 Ma), whereas Callianassinae did not appear before the Eocene (56 Ma). PMID- 27499816 TI - Comparing Sexuality Communication Among Offspring of Teen Parents and Adult Parents: a Different Role for Extended Family. AB - This brief report examined teenagers' sexuality communication with their parents and extended families. It compared who teens of early parents (those who had children when they were adolescents) and teens of later parents (those who were adults when they had children) talk to about sex. Eighth grade students (N=1281) in 24 schools completed survey items about their communication about sex. Structural equation modeling was used to predict communication profiles, while adjusting for the nesting of students within schools. After controlling for teens' age, gender, race/ethnicity, grades, parent/guardian closeness, and social desirability of survey responses, as well as family status and median family income, results showed that teens of early (teen) parents were more likely than teens of later (adult) parents to talk with both parents and extended family about sex and less likely than later parents to talk only with parents. These findings indicate that realities of teen sexuality communication for teens of early parents may extend beyond a parent-teen model to include extended family. Extended family involvement in educational outreach is a potential untapped resource to support sexual health for teens of early parents. PMID- 27499815 TI - LINCing defective nuclear-cytoskeletal coupling and DYT1 dystonia. AB - Mechanical forces generated by nuclear-cytoskeletal coupling through the LINC (linker of nucleoskeleton and cytoskeleton) complex, an evolutionarily conserved molecular bridge in the nuclear envelope (NE), are critical for the execution of wholesale nuclear positioning events in migrating and dividing cells, chromosome dynamics during meiosis, and mechanotransduction. LINC complexes consist of outer (KASH (Klarsicht, ANC-1, and Syne homology)) and inner (SUN (Sad1, UNC-84)) nuclear membrane proteins. KASH proteins interact with the cytoskeleton in the cytoplasm and SUN proteins in the perinuclear space of the NE. In the nucleoplasm, SUN proteins interact with A-type nuclear lamins and chromatin binding proteins. Recent structural insights into the KASH-SUN interaction have generated several questions regarding how LINC complex assembly and function might be regulated within the perinuclear space. Here we discuss potential LINC regulatory mechanisms and focus on the potential role of AAA+ (ATPases associated with various cellular activities) protein, torsinA, as a LINC complex regulator within the NE. We also examine how defects in LINC complex regulation by torsinA may contribute to the pathogenesis of the human neurological movement disorder, DYT1 dystonia. PMID- 27499817 TI - Cardiac Dual-source Computed Tomography for the Detection of Left Main Compression Syndrome in Patients with Pulmonary Hyper-tension. AB - INTRODUCTION: Left Main Compression Syndrome (LMCS) represents an entity described as the extrinsic compression of the left main coronary artery (LMCA) by a dilated pulmonary artery (PA) trunk. We examined the presence of LMCS in patients with pulmonary hypertension (PH) using dual-source computed tomography (DSCT), as a non-invasive diagnostic tool. METHODS: The following parameters were measured: PA trunk diameter (PAD), the distance between PAD and LMCA (LMPA) and the distance between PA and aorta (AoPA). These measurements were related with demographic, echocardiographic, hemodynamic and clinical parameters. Angiography was performed in two patients with LMCS suspected by cardiac computed tomographic angiography. Patients without PH but with angina were examined as controls, using DSCT cardiac angiography to assess the same measurements and to detect the prevalence of coronary artery disease. RESULTS: PA diameter value over 40.00 mm has been associated with PH and LMCS. Furthermore, LMCS did not occur at a distance smaller than 0.50 mm between the PA and the LMCA, and did not correlate with the distance between the PA and the aorta or with cardiac index and NT proBNP. CONCLUSION: DSCT may represent the initial testing modality in PH patients with dilated PA trunk to exclude LMCS. A periodical rule-out of this rare entity, as assessed by DSCT, in patients with a severely dilated PA seems to be mandatory for PH patients contributing to survival improvement. PMID- 27499818 TI - Allogeneic Blood Product Usage in Coronary Artery Bypass Grafting (CABG) with minimalized Extracorporeal Circulation System (MECC) Versus Standard On-Pump Coronary Artery Bypass Grafting. AB - AIM: Intraoperative allogeneic blood product transfusion (ABPT) in cardiac surgery is associated with worse overall outcome, including mortality. The objective of this study was to evaluate the ABPTs in minimalized extracorporeal cardiopulmonary (MECC(TM)) compared with standard open system on-pump coronary revascularization. METHODS: Data of 156 patients undergoing myocardial revascularization between September 2008 and September 2010 were reviewed. 83 patients were operated by the MECC technique and 73 were treated by standard extracorporeal circulation (sECC). ABPT and overall early postoperative complications were analyzed. RESULTS: Operative mortality and morbidity were similar in both groups. ABPT in the MECC group was significantly lower than in the sECC group both intraoperatively (7.2 vs. 60.3% of patients p<0.001) and during the first five postoperative days (19.3 vs. 57.5%; p<0.001). "Skin to skin"- (214 +/- 45 vs. 232 +/- 45 min; p=0.012), cardiopulmonary bypass (CPB) - (82 +/- 25 vs. 95 +/- 26 min; p=0.014), and X-clamp- times (50 +/- 16 vs. 56 +/- 17 min; p=0.024) were significantly lower in the MECC group than in the sECC group. Length of ICU (intensive care unit) - and hospital stay were also significantly lower in the MECC group vs. the sECC group (26.7 +/- 20.2 vs. 54.5 +/- 68.9 h; p<0.001, and 12.0 +/- 4.1 vs. 14.5 +/- 4.6 days; p<0.001). CONCLUSION: Application of MECC as on-pump coronary artery bypass graft (CABG) results in significantly lower ABPT as well as shorter ICU and in-hospital stay. In order to achieve these benefits of MECC autologous retrograde priming, Bispectral index (BIS) monitoring, intraoperative cell salvage, meticulous hemostasis and strict peri- and postoperative volume management are crucial. PMID- 27499819 TI - Child Abuse Syndrome (CAS): A Newly Recognized Distinct Entity. PMID- 27499820 TI - Efficacy and Safety of Modified Pranlukast (Prakanon((r))) Compared with Pranlukast (Onon((r))): A Randomized, Open-Label, Crossover Study. AB - INTRODUCTION: Pranlukast is a leukotriene receptor antagonist (LTRA) that is used as an additional controller of mild to moderate asthma. This study compared the efficacy and side effects of two bioequivalent preparations of pranlukast: original pranlukast (Onon((r)); Ono Pharmaceutical, Japan) and a modified formulation of pranlukast (Prakanon((r)); Yuhan Co, Korea) in patients with mild to moderate asthma. METHODS: Of the 34 subjects screened, 30 patients who were using standard medication to control asthma and scored less than 20 points on the Asthma Control Test(TM) (ACT) were assigned randomly to one of the two groups in a prospective, open label, crossover study: group 1 received Prakanon((r)) (150 mg/day) and group 2 received Onon((r)) (450 mg/day) for 8 weeks each; after a 1 week rest period, the groups were switched to the alternative medication for further 8 weeks and monitored for 2 more weeks without study medication. Evaluation parameters included the ACT, quality of life questionnaire adult Korean asthmatics (QLQAKA), pulmonary function tests, peripheral blood tests, vital signs, and adverse events. RESULTS: Thirty patients were enrolled and 21 completed the trial: 10 in group 1 and 11 in group 2. The baseline data of the two groups did not differ. No statistical significant differences were observed in efficacy and lung function at each time and in changes from baseline value between the two kinds of pranlukast. The final asthma control rate was 81% with Prakanon((r)) and 76% with Onon((r)). There were no differences in vital signs and laboratory data at each time and in changes from baseline value between the two drugs. There were no differences in adverse events between the two drugs. The most common side effect was abdominal pain. Drug compliance was high, without differences between the two drugs. CONCLUSION: These findings suggest that Prakanon((r)) which is an improved formulation of pranlukast at a lower dose than the original formulation, Onon((r)), has a similar efficacy and side effect profile in the control of persistent asthma. PMID- 27499821 TI - Pilot Study of a New Adjustable Thermoplastic Mandibular Advancement Device for the Management of Obstructive Sleep Apnoea-Hypopnoea Syndrome: A Brief Research Letter. AB - BACKGROUND: Prefabricated adjustable thermoplastic mandibular advancement devices (PAT-MADs) are a practical short-term treatment for obstructive sleep apnoea hypopnoea syndrome (OSAHS) in patients who have failed or refused continuous positive airway pressure (CPAP) therapy. OBJECTIVE: To assess the effectiveness of a new professionally-fitted PAT-MAD in patients with OSAHS in Morocco. METHOD: Twenty-four adults with mild, moderate or severe OSAHS were fitted with the PAT MAD (BluePro((r)); BlueSom, France). Respiratory parameters (apnoea-hypopnoea index (AHI), oxygen desaturation index (ODI)) and daytime sleepiness using the Epworth Sleepiness scale (ESS) were assessed before and after treatment. Adverse events were recorded. RESULTS: Mean treatment duration was 106.3 +/- 73.4 days. Mean AHI score decreased from 21.4 +/- 7.4 to 9.3 +/- 4.1 after treatment (p<0.0001) (mean reduction of 57.0 +/- 12.3%). Mean ESS and ODI also decreased at EOS (from 10.4 +/- 2.8 to 7.3 +/- 2.3, mean reduction 30.3 +/- 12.2%, p=0.0001; and 7.0 +/- 6.9 to 4.7 +/- 4.0, mean reduction 30.5 +/- 25.0%, p=0.2, respectively). Treatment was considered to have been successful in 22 patients (91.7%) who had mild OSAHS or an AHI score of <=5 at the end of the study. The device was well-tolerated. CONCLUSION: This new PAT-MAD appears to be effective at reducing respiratory parameters and improving daytime alertness in patients with OSAHS. Long term studies in a larger number of patients are warranted to assess the long-term efficacy, retention and side-effects of this device. PMID- 27499823 TI - Incidence of Venous Thromboembolism in Patients Undergoing Major Hip Surgeries at a Single Institution: A Prospective Study. AB - BACKGROUND: Venous thoromboembolism (VTE) is one of the most significant complications after hip surgeries. Many studies have been reported about the incidence of VTE after THA, but a small number of reports were found concerning Periacetabular osteotomy, Revision THA and Surgery for hip fracture postoperatively. Furthermore, there exists no comparative study of the incidence of VTE among major hip surgeries at a single institution. We reported the incidence of VTE among hip surgeries performed at a single institution. METHODS: A total of 820 Hip surgeries were performed at same institution. The procedures included 420 hips that underwent primary total hip arthroplasties (THA), 91 revision or removal of total hip arthroplasties (Revision THA), 144 periacetabular osteotomy (PAO) and 165 surgery for hip fracture (SHF) between 2006 and 2012. VTE was detected by Multidetector computed tomography (MDCT) that scanned 768 cases and by ultrasound that scanned 52cases postoperative 10-14 days. RESULTS: The overall incidence of VTE was 12.2% (100 of 820). The incidence of VTE after THA was 13.1% (55 of 420), Revision THA was 13.2% (12 of 91), PAO was 2.1% (3 of 144) and SHF was 18.1% (30 of 165). The incidence of VTE was significantly higher in SHF than in PAO. CONCLUSION: This data indicates that the incidence of VTE after PAO is significantly lower than SHF and relatively lower than THA and Revision THA. A younger age and non-invasion of the bone marrow of the femur may have affected the result. Prophylaxis therapy was effective especially on SHF. PMID- 27499822 TI - Particle Disease: A Current Review of the Biological Mechanisms in Periprosthetic Osteolysis After Hip Arthroplasty. AB - BACKGROUND: Inflammatory responses to wear debris cause osteolysis that leads to aseptic prosthesis loosening and hip arthroplasty failure. Although osteolysis is usually associated with aseptic loosening, it is rarely seen around stable implants. Aseptic implant loosening is a simple radiologic phenomenon, but a complex immunological process. Particulate debris produced by implants most commonly causes osteolysis, and this is called particle-associated periprosthetic osteolysis (PPO). OBJECTIVE: The objective of this review is to outline the features of particle-associated periprosthetic osteolysis to allow the physician to recognise this condition and commence early treatment, thereby optimizing patient outcome. METHODS: A thorough literature search was performed using available databases, including Pubmed, to cover important research published covering particle-associated PPO. RESULTS: Although osteolysis causes bone resorption, clinical, animal, and in vitro studies of particle bioreactivity suggest that particle-associated PPO represents the culmination of several biological reactions of many cell types, rather than being caused solely by the osteoclasts. The biological activity is highly dependent on the characteristics and quantity of the wear particles. CONCLUSION: Despite advances in total hip arthroplasty (THA), particle-associated PPO and aseptic loosening continue to be major factors that affect prosthetic joint longevity. Biomarkers could be exploited as easy and objective diagnostic and prognostic targets that would enable testing for osteolysis after THA. Further research is needed to identify new biomarkers in PPO. A comprehensive understanding of the underlying biological mechanisms is crucial for developing new therapeutic interventions to reverse or suppress biological responses to wear particles. PMID- 27499824 TI - Primary Intracranial Choriocarcinoma Located in the Suprasellar Region. AB - A 10 year old girl was admitted to our hospital due to headache, nausea, and weight loss for about half a year. She also had visual field disorders. Suprasellar tumor was found by X-ray computed tomography, and magnetic resonance imaging showed a ring-like lobulated enhanced mass with hemorrhage and necrosis. Biopsy of this lesion showed primary intracranial choriocarcinoma on histopathological examination. The serum human chorionic gonadotropin (hCG) level was measured after the biopsy and was elevated at 71,298.2 IU/L. The patient died due to hydrocephalus caused by an increase in the size of the tumor with a larger amount of hemorrhage than the preoperative features. If young patients present with a suprasellar lobulated mass with hemorrhage, the serum hCG level should be measured before operation. PMID- 27499826 TI - A Neurotized Anterolateral Thigh Flap With a Unique Anastomosis to the Gastroepiploic Artery: A Case Report of a Reconstruction of Composite Abdominal Wall Defect. PMID- 27499825 TI - Recurrent urinary tract infections in healthy and nonpregnant women. AB - Recurrent urinary tract infections (RUTI) are prevalent and pose significant clinical challenges. Although the term RUTI has long been vaguely defined, a consensus definition has emerged in recent years. The exact etiology behind RUTI remains under debate, with valid arguments for both ascending reinfections as well as persistent infection inside the bladder. These persistent infections exist in the form of quiescent intracellular reservoirs in the mouse model and may represent a novel concept to explain UTI recurrence in humans. Manageable risk factors such as behavioral patterns alongside nonmanageable risk factors including genetic susceptibility are growing fields of investigation. Acute UTI have been studied through two model bacterial strains: Escherichia coli UTI89 and CFT073. However, the clinical relevance to RUTI of these two strains has not been firmly established. Current treatment strategies for RUTI are limited and remain dominated by antibiotic usage despite variable efficacy. The majority of studies in humans have focused on younger groups of women with little information available about the postmenopausal population despite a heightened risk of RUTI in this age group. PMID- 27499827 TI - Draft genomic sequence of a chromate- and sulfate-reducing Alishewanella strain with the ability to bioremediate Cr and Cd contamination. AB - Alishewanella sp. WH16-1 (= CCTCC M201507) is a facultative anaerobic, motile, Gram-negative, rod-shaped bacterium isolated from soil of a copper and iron mine. This strain efficiently reduces chromate (Cr(6+)) to the much less toxic Cr(3+). In addition, it reduces sulfate (SO4 (2-)) to S(2-). The S(2-) could react with Cd(2+) to generate precipitated CdS. Thus, strain WH16-1 shows a great potential to bioremediate Cr and Cd contaimination. Here we describe the features of this organism, together with the draft genome and comparative genomic results among strain WH16-1 and other Alishewanella strains. The genome comprises 3,488,867 bp, 50.4 % G + C content, 3,132 protein-coding genes and 80 RNA genes. Both putative chromate- and sulfate-reducing genes are identified. PMID- 27499828 TI - MORPHOMETRIC ANALYSIS OF HIPPOCAMPUS AND LATERAL VENTRICLE REVEALS REGIONAL DIFFERENCE BETWEEN COGNITIVELY STABLE AND DECLINING PERSONS. AB - Alzheimers disease (AD) is a progressive neurodegenerative disease most prevalent in the elderly. Distinguishing disease-related memory decline from normal age related memory decline has been clinically difficult due to the subtlety of cognitive change during the preclinical stage of AD. In contrast, sensitive biomarkers derived from in vivo neuroimaging data could improve the early identification of AD. In this study, we employed a morphometric analysis in the hippocampus and lateral ventricle. A novel group-wise template-based segmentation algorithm was developed for ventricular segmentation. Further, surface multivariate tensor-based morphometry and radial distance on each surface point were computed. Using Hotellings T2 test, we found significant morphometric differences in both hippocampus and lateral ventricle between stable and clinically declining subjects. The left hemisphere was more severely affected than the right during this early disease stage. Hippocampal and ventricular morphometry has significant potential as an imaging biomarker for onset prediction and early diagnosis of AD. PMID- 27499829 TI - APPLYING SPARSE CODING TO SURFACE MULTIVARIATE TENSOR-BASED MORPHOMETRY TO PREDICT FUTURE COGNITIVE DECLINE. AB - Alzheimer's disease (AD) is a progressive brain disease. Accurate diagnosis of AD and its prodromal stage, mild cognitive impairment, is crucial for clinical trial design. There is also growing interests in identifying brain imaging biomarkers that help evaluate AD risk presymptomatically. Here, we applied a recently developed multivariate tensor-based morphometry (mTBM) method to extract features from hippocampal surfaces, derived from anatomical brain MRI. For such surface based features, the feature dimension is usually much larger than the number of subjects. We used dictionary learning and sparse coding to effectively reduce the feature dimensions. With the new features, an Adaboost classifier was employed for binary group classification. In tests on publicly available data from the Alzheimers Disease Neuroimaging Initiative, the new framework outperformed several standard imaging measures in classifying different stages of AD. The new approach combines the efficiency of sparse coding with the sensitivity of surface mTBM, and boosts classification performance. PMID- 27499830 TI - Video capsule endoscopy in inflammatory bowel disease. AB - Video capsule endoscopy (VCE) has evolved to become an important tool for the non invasive examination of the small bowel, which hitherto had been relatively inaccessible to direct visualisation. VCE has been shown to play a role in monitoring the activity of small bowel Crohn's disease and can be used to assess the response to anti-inflammatory treatment in Crohn's disease. For those patients with Crohn's disease who have undergone an intestinal resection, VCE has been assessed as a tool to detect post-operative recurrence. VCE may also aid in the reclassification of patients with a diagnosis of Inflammatory Bowel Disease Unclassified to Crohn's disease. The evolution of colon capsule endoscopy (CCE) has expanded the application of this technology further. The use of CCE to assess the activity of ulcerative colitis has been described. This advance in capsule technology has also fuelled interest in its potential role as a minimally invasive tool to assess the whole of GI tract opening the possibility of its use for the panenteric assessment of Crohn's disease. VCE is a safe procedure. However, the risk of a retained capsule is higher in patients with suspected or confirmed Crohn's disease compared with patients having VCE examination for other indications. A retained video capsule is rare after successful passage of a patency capsule which may be utilised to pre-screen patients undergoing VCE. This paper describes the use of VCE in the assessment of inflammatory bowel disease. PMID- 27499831 TI - Endoscopic full thickness resection for gastric tumors originating from muscularis propria. AB - AIM: To do systematic review of current literature for endoscopic full thickness resection (EFTR) technique for gastric tumors originating from muscularis propria. METHODS: An extensive English literature search was done till December 2015; using PubMed and Google scholar to identify the peer reviewed original and review articles using keywords-EFTR, gastric tumor, muscularis propria. Human only studies were included. The references of pertinent studies were manually searched to identify additional relevant studies. The indications, procedural details, success rates, clinical outcomes, complications and limitations were considered. For the purpose of review, data from individual studies was combined to calculate mean. No other statistical test was applied. RESULTS: A total of 9 original articles were identified. Four articles were from same institute and the time frames of these studies were overlapping. To avoid duplication of data, only the study with patients over the longest time interval was included and other three were excluded. In total six studies were included in the final review. In our systematic review, the mean success rate for EFTR of gastric tumors originating from muscularis propria was 96.8%. The mean procedure time varied from a minimum of 37 min to a maximum of 105 min. There was no reported mortality from the technique itself. The most common histological diagnosis was gastrointestinal stromal tumors and leiomyoma. Gastric wall defect closure by either metallic clips or over the scope clip (OTSC) had similar outcomes although experience with OTSC was limited to smaller lesions (< 3 cm). CONCLUSION: EFTR is a minimally invasive technique to resect gastric submucosal tumors originating from muscularis propria with a high success rate and low complication rate. PMID- 27499832 TI - Splenic artery aneurysm presenting as a submucosal gastric lesion: A case report. AB - We are reporting the rare case of splenic artery aneurysm of 4 cm of diameter presenting as a sub mucosal lesion on gastro-duodenal endoscopy. This aneurysm was treated by endovascular coil embolization and stent graft implantation. The procedure was uneventful. On day 1, the patient presented an acute severe epigastric pain and cardiovascular arrest. Abdominal computed tomography scan showed an active leak of the intravenous contrast dye in the peritoneum from the splenic aneurysm. We performed an emergent resection of the aneurysm, and peritoneal lavage. Postoperatively, hemorrhagic choc was refractory to large volumes replacement, and intravenous vaso-active drugs. On day 2, he presented massive hematochezia. We performed a total colectomy with splenectomy and cholecystectomy for ischemic colitis, with spleen and gallbladder infarction. Despite vaso-active drugs and aggressive treatment with Factor VIIa, the patient died after uncontrolled disseminated intravascular coagulation. PMID- 27499833 TI - A Literature Review: Website Design and User Engagement. AB - Proper design has become a critical element needed to engage website and mobile application users. However, little research has been conducted to define the specific elements used in effective website and mobile application design. We attempt to review and consolidate research on effective design and to define a short list of elements frequently used in research. The design elements mentioned most frequently in the reviewed literature were navigation, graphical representation, organization, content utility, purpose, simplicity, and readability. We discuss how previous studies define and evaluate these seven elements. This review and the resulting short list of design elements may be used to help designers and researchers to operationalize best practices for facilitating and predicting user engagement. PMID- 27499834 TI - 'I Haue Ben Crised and Besy': Illness and Resilience in the Fifteenth-Century Stonor Letters. AB - The modern and medieval meanings of words reporting ill health often bear little resemblance to one another. This article compares the use of 'diseased' and 'sick' in the fifteenth-century Stonor family letters. It examines the word 'crased', which implies physical ill health most directly, but also suggests emotional, psychological, or spiritual distress in female family members especially. The article then turns to the practical implications of poor health, asking how and why it affected the day-to-day concerns of the Stonors and their associates. It uncovers compelling evidence for resilience in the face of many and competing calls of duty. Finally, the article presents unique palaeographical evidence for the impact of illness, where a correspondent is so 'seke' that he can scarcely hold his pen. PMID- 27499835 TI - Recurrent Syncope and Cardiac Arrest in a Patient with Systemic Light Chain Amyloidosis Treated with Bortezomib. AB - About 10-15% of patients with multiple myeloma develop light chain (AL) amyloidosis. AL amyloidosis is a systemic disease that may involve multiple organs, often including the heart. It may present clinically with bradyarrhythmia and syncope. The proteasome inhibitor bortezomib has been used with clinical efficacy in treating patients with AL amyloidosis but also implicated as a possible cause of cardiomyocyte injury. We report a case of a 48-year-old man with AL amyloidosis and increased frequency of syncope and cardiac arrest after starting bortezomib. The biologic and clinical plausibility of a heightened risk for cardiac arrest in patients with cardiac AL amyloidosis and history of syncope being treated with bortezomib is a possibility that is not well documented in the medical literature and warrants further investigation. PMID- 27499836 TI - CD30+ Primary Cutaneous Post-transplant Lymphoproliferative Disorder with Signet ring Cell Features. AB - We report a case of primary cutaneous CD30+ post-transplant lymphoproliferative disorder with an uncommon finding of signet ring cell features in a heart transplant patient. The neoplastic cells were CD4 and CD30 positive, and negative for S-100, pancytokeratin, myeloperoxidase, and CD56. In situ hybridization for Epstein Barr Virus (EBV) was negative, even though the patient did have EBV viremia. PMID- 27499837 TI - Autoimmune Syndromes Presenting as a Paraneoplastic Manifestation of Myelodysplastic Syndromes: Clinical Features, Course, Treatment and Outcome. AB - Autoimmune manifestations (AIM) are reported in up to 10-30% of myelodysplastic syndromes (MDS) patients; this association is not well defined. We present herein a retrospective chart review of single center MDS patients for AIM, a case discussion and a literature review. Of 252 MDS patients examined, 11 (4.4%) had AIM around MDS diagnosis. International Prognostic Scoring System scores were: low or intermediate (int)-1 (n=7); int-2 or high (n=4). AIM were: culture negative sepsis (n=7); inflammatory arthritis (n=3); vasculitis (n=4); sweats; pericarditis; polymyalgia rheumatica (n=2 each); mouth ulcers; pulmonary infiltrates; suspicion for Behcet's; polychondritis and undifferentiated (n=1 each). AIM treatment and outcome were: prednisone +/- steroid sparing agents, n=8, ongoing symptoms in 5; azacitidine (n=3), 2 resolved; and observation, n=1, ongoing symptoms. At a median follow up of 13 months, seven patients are alive. In summary, 4.4% of MDS patients presented with concomitant AIM. MDS should remain on the differential diagnosis of patients with inflammatory symptoms. PMID- 27499838 TI - Refractory Ascites with Liver Fibrosis Developed in Late Phase Allogeneic Hematopoietic Stem Cell Transplantation: Report of Three Patients. AB - We report cases of three patients of refractory ascites without other fluid retention that occurred around five months after allogeneic hematopoietic stem cell transplantation (allo-HSCT). All three patients expired and postmortem examinations revealed unexpected liver fibrosis lacking histological evidences of graft-versus-host-disease (GVHD). The three patients showed normal hepatic function and size before transplantation. During their clinical courses, serum biochemistry test showed no elevation of hepatic enzymes and bilirubin; however, imaging studies demonstrated hepatic atrophy at the onset of ascites. One of the liver specimens showed bile obstruction, which could be seen in hepatic damage by GVHD. Although ascites resulting from venoocclusive disease in early phase allo HSCT is well documented, ascites associated with hepatic fibrosis in late phase allo-HCST has not been reported. Further clinico-pathological studies on similar patients should be required to ascertain refractory ascites associated with liver fibrosis after allo-HSCT. PMID- 27499839 TI - Shedding light on the 'dark side' of phylogenetic comparative methods. AB - Phylogenetic comparative methods are becoming increasingly popular for investigating evolutionary patterns and processes. However, these methods are not infallible - they suffer from biases and make assumptions like all other statistical methods.Unfortunately, although these limitations are generally well known in the phylogenetic comparative methods community, they are often inadequately assessed in empirical studies leading to misinterpreted results and poor model fits. Here, we explore reasons for the communication gap dividing those developing new methods and those using them.We suggest that some important pieces of information are missing from the literature and that others are difficult to extract from long, technical papers. We also highlight problems with users jumping straight into software implementations of methods (e.g. in r) that may lack documentation on biases and assumptions that are mentioned in the original papers.To help solve these problems, we make a number of suggestions including providing blog posts or videos to explain new methods in less technical terms, encouraging reproducibility and code sharing, making wiki-style pages summarising the literature on popular methods, more careful consideration and testing of whether a method is appropriate for a given question/data set, increased collaboration, and a shift from publishing purely novel methods to publishing improvements to existing methods and ways of detecting biases or testing model fit. Many of these points are applicable across methods in ecology and evolution, not just phylogenetic comparative methods. PMID- 27499840 TI - Refining the Enrolment Process in Emergency Medicine Research. AB - Research in the emergency setting involving patients with acute clinical conditions is needed if there are to be advances in diagnosis and treatment. But research in these areas poses ethical and practical challenges. One of these is the general inability to obtain informed consent due to the patient's lack of mental capacity and insufficient time to contact legal representatives. Regulatory frameworks which allow this research to proceed with a consent 'waiver', provided patients lack mental capacity, miss important ethical subtleties. One of these is the varying nature of mental capacity among emergency medicine patients. Not only is their capacity variable and often unclear, but some patients are also likely to be able to engage with the researcher and the context to varying degrees. In this paper we describe the key elements of a novel enrolment process for emergency medicine research that refines the consent waiver and fully engages with the ethical rationale for consent and, in this context, its waiver. The process is verbal but independently documented during the 'emergent' stages of the research. It provides appropriate engagement with the patient, is context-sensitive and better addresses ethical subtleties. In line with regulation, full written consent for on-going participation in the research is obtained once the emergency is passed. PMID- 27499841 TI - Droplet-based microfluidics for artificial cell generation: a brief review. AB - Artificial cells are best defined as micrometre-sized structures able to mimic many of the morphological and functional characteristics of a living cell. In this mini-review, we describe progress in the application of droplet-based microfluidics for the generation of artificial cells and protocells. PMID- 27499842 TI - Single mode waveguide platform for spontaneous and surface-enhanced on-chip Raman spectroscopy. AB - We review an on-chip approach for spontaneous Raman spectroscopy and surface enhanced Raman spectroscopy based on evanescent excitation of the analyte as well as evanescent collection of the Raman signal using complementary metal oxide semiconductor (CMOS)-compatible single mode waveguides. The signal is either directly collected from the analyte molecules or via plasmonic nanoantennas integrated on top of the waveguides. Flexibility in the design of the geometry of the waveguide, and/or the geometry of the antennas, enables optimization of the collection efficiency. Furthermore, the sensor can be integrated with additional functionality (sources, detectors, spectrometers) on the same chip. In this paper, the basic theoretical concepts are introduced to identify the key design parameters, and some proof-of-concept experimental results are reviewed. PMID- 27499843 TI - Adaptation of sensor morphology: an integrative view of perception from biologically inspired robotics perspective. AB - Sensor morphology, the morphology of a sensing mechanism which plays a role of shaping the desired response from physical stimuli from surroundings to generate signals usable as sensory information, is one of the key common aspects of sensing processes. This paper presents a structured review of researches on bioinspired sensor morphology implemented in robotic systems, and discusses the fundamental design principles. Based on literature review, we propose two key arguments: first, owing to its synthetic nature, biologically inspired robotics approach is a unique and powerful methodology to understand the role of sensor morphology and how it can evolve and adapt to its task and environment. Second, a consideration of an integrative view of perception by looking into multidisciplinary and overarching mechanisms of sensor morphology adaptation across biology and engineering enables us to extract relevant design principles that are important to extend our understanding of the unfinished concepts in sensing and perception. PMID- 27499844 TI - Development of an open technology sensor suite for assisted living: a student-led research project. AB - Many countries have a rapidly ageing population, placing strain on health services and creating a growing market for assistive technology for older people. We have, through a student-led, 12-week project for 10 students from a variety of science and engineering backgrounds, developed an integrated sensor system to enable older people, or those at risk, to live independently in their own homes for longer, while providing reassurance for their family and carers. We provide details on the design procedure and performance of our sensor system and the management and execution of a short-term, student-led research project. Detailed information on the design and use of our devices, including a door sensor, power monitor, fall detector, general in-house sensor unit and easy-to-use location aware communications device, is given, with our open designs being contrasted with closed proprietary systems. A case study is presented for the use of our devices in a real-world context, along with a comparison with commercially available systems. We discuss how the system could lead to improvements in the quality of life of older users and increase the effectiveness of their associated care network. We reflect on how recent developments in open source technology and rapid prototyping increase the scope and potential for the development of powerful sensor systems and, finally, conclude with a student perspective on this team effort and highlight learning outcomes, arguing that open technologies will revolutionize the way in which technology will be deployed in academic research in the future. PMID- 27499845 TI - Infrastructure sensing. AB - Design, construction, maintenance and upgrading of civil engineering infrastructure requires fresh thinking to minimize use of materials, energy and labour. This can only be achieved by understanding the performance of the infrastructure, both during its construction and throughout its design life, through innovative monitoring. Advances in sensor systems offer intriguing possibilities to radically alter methods of condition assessment and monitoring of infrastructure. In this paper, it is hypothesized that the future of infrastructure relies on smarter information; the rich information obtained from embedded sensors within infrastructure will act as a catalyst for new design, construction, operation and maintenance processes for integrated infrastructure systems linked directly with user behaviour patterns. Some examples of emerging sensor technologies for infrastructure sensing are given. They include distributed fibre-optics sensors, computer vision, wireless sensor networks, low power micro-electromechanical systems, energy harvesting and citizens as sensors. PMID- 27499846 TI - Electroactive polymers for sensing. AB - Electromechanical coupling in electroactive polymers (EAPs) has been widely applied for actuation and is also being increasingly investigated for sensing chemical and mechanical stimuli. EAPs are a unique class of materials, with low moduli high-strain capabilities and the ability to conform to surfaces of different shapes. These features make them attractive for applications such as wearable sensors and interfacing with soft tissues. Here, we review the major types of EAPs and their sensing mechanisms. These are divided into two classes depending on the main type of charge carrier: ionic EAPs (such as conducting polymers and ionic polymer-metal composites) and electronic EAPs (such as dielectric elastomers, liquid-crystal polymers and piezoelectric polymers). This review is intended to serve as an introduction to the mechanisms of these materials and as a first step in material selection for both researchers and designers of flexible/bendable devices, biocompatible sensors or even robotic tactile sensing units. PMID- 27499847 TI - Metal-organic frameworks as biosensors for luminescence-based detection and imaging. AB - Metal-organic frameworks (MOFs), formed by the self-assembly of metal centres or clusters and organic linkers, possess many key structural and chemical features that have enabled them to be used in sensing platforms for a variety of environmentally, chemically and biomedically relevant compounds. In particular, their high porosity, large surface area, tuneable chemical composition, high degree of crystallinity, and potential for post-synthetic modification for molecular recognition make MOFs promising candidates for biosensing applications. In this review, we separate our discussion of MOF biosensors into two categories: quantitative sensing, focusing specifically on luminescence-based sensors for the direct measurement of a specific analyte, and qualitative sensing, where we describe MOFs used for fluorescence microscopy and as magnetic resonance imaging contrast agents. We highlight several key publications in each of these areas, concluding that MOFs present an exciting, versatile new platform for biosensing applications and imaging, and we expect to see their usage grow as the field progresses. PMID- 27499848 TI - Children view own-age faces qualitatively differently to other-age faces. AB - Like most own-group biases in face recognition, the own-age bias (OAB) is thought to be based either on perceptual expertise or socio-cognitive motivational mechanisms [Wolff, N., Kemter, K., Schweinberger, S. R., & Wiese, H. (2013). What drives social in-group biases in face recognition memory? ERP evidence from the own-gender bias. Social Cognitive and Affective Neuroscience. doi:10.1093/scan/nst024]. The present study employed a recognition paradigm with eye-tracking in order to assess whether participants actively viewed faces of their own-age differently to that of other-age faces. The results indicated a significant OAB (superior recognition for own-age relative to other-age faces), provided that they were upright, indicative of expertise being employed for the recognition of own-age faces. However, the eye-tracking results indicate that viewing other-age faces was qualitatively different to the viewing of own-age faces, with more nose fixations for other-age faces. These results are interpreted as supporting the socio-cognitive model of the OAB. PMID- 27499850 TI - From hepatoprotection models to new therapeutic modalities for treating liver diseases: a personal perspective. AB - A variety of rodent models of hepatoprotection have been developed in which tolerance to acetaminophen-induced hepatotoxicity occurs. Autoprotection/heteroprotection is a phenomenon where prior exposure to a mildly toxic dose of toxicant confers protection against a subsequently administered higher dose of the same toxicant (as in the case of autoprotection) or to a different toxicant (referred to as heteroprotection). Multiple mechanisms regulate this adaptive response, including hepatocellular proliferation, proteostasis, enhanced expression of cytoprotective genes, and altered tissue immune response. In this review, we will discuss recent findings that highlight the complexity of these adaptive mechanisms and we also outline the usefulness of these findings to devise therapeutic and/or diagnostic tools for acetaminophen induced liver damage in patients. PMID- 27499849 TI - Recent advances in phototherapy for psoriasis. AB - Phototherapy involves repeated exposure of the skin to ultraviolet light to treat various inflammatory skin conditions such as psoriasis. Recent studies have identified specific immunologic effects of phototherapy that may underlie phototherapy efficacy. Furthermore, recent advancements have been made in developing safe and effective targeted phototherapy modalities for difficult-to treat areas such as scalp psoriasis. Targeted phototherapy in the form of the excimer laser holds potential for more aggressive, effective treatment and long lasting remission of psoriasis. Phototherapy is now also used successfully with biologic agents as combination therapy to treat recalcitrant psoriasis. Therefore, though one of the oldest therapeutic modalities for psoriasis, phototherapy remains a mainstay treatment with promise for further advancement. PMID- 27499851 TI - (13)C glucose labelling studies using 2D NMR are a useful tool for determining ex vivo whole organ metabolism during hypothermic machine perfusion of kidneys. AB - BACKGROUND: The aim of this study is to determine the feasibility of using nuclear magnetic resonance (NMR) tracer studies ((13)C-enriched glucose) to detect ex vivo de novo metabolism in the perfusion fluid and cortical tissue of porcine kidneys during hypothermic machine perfusion (HMP). METHODS: Porcine kidneys (n = 6) were subjected to 24 h of HMP using the Organ Recovery Systems LifePort Kidney perfusion device. Glucose, uniformly enriched with the stable isotope (13)C ([U-(13)C] glucose), was incorporated into KPS-1-like perfusion fluid at a concentration of 10 mM. Analysis of perfusate was performed using both 1D (1)H and 2D (1)H,(13)C heteronuclear single quantum coherence (HSQC) NMR spectroscopy. The metabolic activity was then studied by quantifying the proportion of key metabolites containing (13)C in both perfusate and tissue samples. RESULTS: There was significant enrichment of (13)C in a number of central metabolites present in both the perfusate and tissue extracts and was most pronounced for lactate and alanine. The total amount of enriched lactate (per sample) in perfusion fluid increased during HMP (31.1 +/- 12.2 nmol at 6 h vs 93.4 +/- 25.6 nmol at 24 h p < 0.01). The total amount of enriched alanine increased in a similar fashion (1.73 +/- 0.89 nmol at 6 h vs 6.80 +/- 2.56 nmol at 24 h p < 0.05). In addition, small amounts of enriched acetate and glutamic acid were evident in some samples. CONCLUSIONS: This study conclusively demonstrates that de novo metabolism occurs during HMP and highlights active metabolic pathways in this hypothermic, hypoxic environment. Whilst the majority of the (13)C-enriched glucose is metabolised into glycolytic endpoint metabolites such as lactate, the presence of non-glycolytic pathway derivatives suggests that metabolism during HMP is more complex than previously thought. Isotopic labelled ex vivo organ perfusion studies using 2D NMR are feasible and informative. PMID- 27499852 TI - Carriage of multidrug-resistant organisms in a tertiary university hospital in Albania-a point prevalence survey. AB - BACKGROUND: Antimicrobial resistance has been recognised as a serious global Public Health problem. Prevalence of Multiple-Drug-Resistant (MDR) organism carriage in Albania is largely unknown since no national surveillance system is in place and few publications are accessible in the literature. METHODS: A 1-day point-prevalence-survey (PPS) screening for nasal methicillin-resistant Staphylococcus aureus (MRSA) and rectal MDR Gram-negative carriage was carried out at the high-dependency wards in the country's only tertiary care hospital, in Tirana. RESULTS: A total of 106 nasal and 104 rectal swabs were collected. 14.2 % of patients (95 % Confidence Interval [95 CI]: 8.1-22.3 %) were MRSA nasal carriers. Resistance to aminoglycosides and fluoroquinolones was common in these isolates (>=80 %) but no resistance was identified against glycopeptides, nitrofurantoin and the relatively newer agents, tigecycline and linezolid. Fifty Enterobacteriaceae isolates were cultivated from 33 of 104 screened patients (31.7 % [95 CI: 22.9-41.6 % 95 CI]). The prevalence of Extended Spectrum Beta Lactamase (ESBL) production in Enterobacteriaceae was 41.3 % (95 CI: 31.8-51.4 %). The two more commonly isolated Enterobacteriaceae were E. coli ([n = 28], 24 ESBL positive; 1 AmpC positive and 3 without an identified mechanism of resistance) and Klebsiella pneumoniae ([n = 13], all ESBL positive; 1 also AmpC and metallo-beta-lactamase (MBL) positive). Susceptibility to carbapenems (>=98 %), fosfomycin (90 %) and amikacin (70 + 20 % intermediate) was high but a high level of resistance to all other agents tested was noted. Non-fermenting Gram negative bacilli were less commonly isolated {22 isolates: Acinetobacter baumannii (9); Pseudomonas aeruginosa (8) and Stenotrophomonas maltophilia (5)}. CONCLUSION: Although a significant rate of MRSA carriage was identified, the main resistance challenge in Albania appears to be linked with Gram-negative organisms, particularly ESBL in Enterobacteriaceae. PMID- 27499853 TI - Increased maternal consumption of methionine as its hydroxyl analog promoted neonatal intestinal growth without compromising maternal energy homeostasis. AB - BACKGROUND: To determine responses of neonatal intestine to maternal increased consumption of DL-methionine (DLM) or DL-2-hydroxy-4-methylthiobutanoic acid (HMTBA), eighteen primiparous sows (Landrace * Yorkshire) were allocated based on body weight and backfat thickness to the control, DLM and HMTBA groups (n = 6), with the nutritional treatments introduced from postpartum d0 to d14. RESULTS: The DLM-fed sows showed negative energy balance manifested by lost bodyweight, lower plasma glucose, subdued tricarboxylic acid cycle, and increased plasma lipid metabolites levels. Both villus height and ratio of villus height to crypt depth averaged across the small intestine of piglets were higher in the DLM and HMTBA groups than in the control group. Piglet jejunal oxidized glutathione concentration and ratio of oxidized to reduced glutathione were lower in the HMTBA group than in the DLM and control groups. However, piglet jejunal aminopeptidase A, carnitine transporter 2 and IGF-II precursor mRNA abundances were higher in the DLM group than in the HMTBA and control groups. CONCLUSION: Increasing maternal consumption of methionine as DLM and HMTBA promoted neonatal intestinal growth by increasing morphological development or up-regulating expression of genes responsible for nutrient metabolism. And increasing maternal consumption of HMTBA promoted neonatal intestinal antioxidant capacity without compromising maternal energy homeostasis during early lactation. PMID- 27499854 TI - Mechanical loading inhibits hypertrophy in chondrogenically differentiating hMSCs within a biomimetic hydrogel. AB - Three dimensional hydrogels are a promising vehicle for delivery of adult human bone-marrow derived mesenchymal stem cells (hMSCs) for cartilage tissue engineering. One of the challenges with using this cell type is the default pathway is terminal differentiation, a hypertrophic phenotype and precursor to endochondral ossification. We hypothesized that a synthetic hydrogel consisting of extracellular matrix (ECM) analogs derived from cartilage when combined with dynamic loading provides physiochemical cues for achieving a stable chondrogenic phenotype. Hydrogels were formed from crosslinked poly(ethylyene glycol) as the base chemistry and to which (meth)acrylate functionalized ECM analogs of RGD (cell adhesion peptide) and chondroitin sulfate (ChS, a negatively charged glycosaminoglycan) were introduced. Bone-marrow derived hMSCs from three donors were encapsulated in the hydrogels and cultured under free swelling conditions or under dynamic com pressive loading with 2.5 ng/ml TGF-beta3. hMSC differentiation was assessed by quantitative PCR and immunohistochemistry. Nine hydrogel formulations were initially screened containing 0, 0.1 or 1mM RGD and 0, 1 or 2wt% ChS. After 21 days, the 1% ChS and 0.1 mM RGD hydrogel had the highest collagen II gene expression, but this was accompanied by high collagen X gene expression. At the protein level, collagen II was detected in all formulations with ECM analogs, but minimally detectable in the hydrogel without ECM analogs. Collagen X protein was present in all formulations. The 0.1 mM RGD and 1% ChS formulation was selected and subjected to five loading regimes: no loading, 5% strain 0.3Hz (1.5%/s), 10% strain 0.3 Hz (3%/s), 5% strain 1 Hz (5%/s), and 10% strain 1Hz (10%/s). After 21 days, ~70-90% of cells stained positive for collagen II protein regardless of the culture condition. On the contrary, only ~20-30% of cells stained positive for collagen X protein under 3 and 5%/s loading conditions, which was accompanied by minimal staining for RunX2. The other culture conditions had more cells staining positive for collagen X (40-60%) and was accompanied by positive staining for RunX2. In summary, a cartilage-like biomimetic hydrogel supports chondrogenesis of hMSCs, but dynamic loading only under select strain rates is able to inhibit hypertrophy. PMID- 27499856 TI - EDITORIAL. PMID- 27499855 TI - Environmentally induced, occupational diseases with emphasis on chronic kidney disease of multifactorial origin affecting tropical countries. AB - BACKGROUND: Environmentally induced, occupational diseases are increasing worldwide, especially in rural agricultural communities. Poverty-associated malnutrition, environmental hazards and pollution, and lack of access to clean water, safe sanitation, and modern healthcare facilities are often associated with these chronic illnesses. METHOD: The authors systematically reviewed occupational public health issues that have been related to the environment. General interpretations of results were included as per the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Pertinent publications from research databases were reviewed on (A) the risk-benefits, (B) the prevalence of risk factors for various diseases, (C) the benefits of not ignoring the risk factors (i.e., broader evidence), and (D) the risks, effects, and outcomes of different types of interventions. The authors used chronic kidney disease of multifactorial origin (CKDmfo) as an example to explore the theme. Emphasis was given to the regions with emerging economies and developing countries located in the vicinity of the equator. FINDINGS: Geographical, socio economic and aetiological similarities exist for many chronic non-communicable diseases that are affecting tropical countries around the equator. The authors identified manufacturing, mining, and agriculture as the biggest polluters of the environment. In addition, deforestation and associated soil erosion, overuse of agrochemicals, and irresponsible factory discharge (e.g., chemicals and paint, from rubber and textile factories, etc.), all contribute to pollution. To decrease the escalating incidences of environmentally induced diseases, governments should work proactively to protect the environment, especially watersheds, and take steps to minimise harmful occupational exposures and strictly enforce environmental regulations. CONCLUSION: Creating public awareness of environmental issues and their relationship to public health is essential. This includes regular monitoring and periodic publication of the quality of water, air and soil; preventing deforestation and man-made soil erosion, increasing forest and ground cover, preventing occupational injuries, judicious and safe use of agrochemicals, sustainable agriculture and development programs, and implementing legislation to protect and conserve water heriage and the environment. These actions are essential both for a healthier environment and for the health of the people who live in that environment. Such measures would also decrease public health threats from such, including global-warming-related erratic environmental changes and the occurrence and the spread of non communicable diseases, such as CKDmfo. PMID- 27499857 TI - Experimentally induced metamorphosis in axolotls reduces regenerative rate and fidelity. AB - While most tetrapods are unable to regenerate severed body parts, amphibians display a remarkable ability to regenerate an array of structures. Frogs can regenerate appendages as larva, but they lose this ability around metamorphosis. In contrast, salamanders regenerate appendages as larva, juveniles, and adults. However, the extent to which fundamental traits (e.g., metamorphosis, body size, aging, etc.) restrict regenerative ability remains contentious. Here we utilize the ability of normally paedomorphic adult axolotls (Ambystoma mexicanum) to undergo induced metamorphosis by thyroxine exposure to test how metamorphosis and body size affects regeneration in age-matched paedomorphic and metamorphic individuals. We show that body size does not affect regeneration in adult axolotls, but metamorphosis causes a twofold reduction in regeneration rate, and lead to carpal and digit malformations. Furthermore, we find evidence that metamorphic blastemal cells may take longer to traverse the cell cycle and display a lower proliferative rate. This study identifies the axolotl as a powerful system to study how metamorphosis restricts regeneration independently of developmental stage, body size, and age; and more broadly how metamorphosis affects tissue-specific changes. PMID- 27499858 TI - Position-specific induction of ectopic limbs in non-regenerating blastemas on axolotl forelimbs. AB - Ectopic retinoic acid (RA) has been hypothesized to reprogram the positional identity of cells in developing and regenerating limbs to a single positional value corresponding to the posterior-ventral-proximal (PVPr) position on the limb. We tested this hypothesis by using RA to reprogram the information of blastema cells that were induced to form at different positions around the limb circumference. We observed that RA treatment of blastemas in anterior and dorsal locations, but not posterior and ventral locations, resulted in the induction of complete ectopic limbs. These position-specific differences in limb induction are probably due to differences in the positional disparity between the RA reprogrammed blastema cells and the cells at the periphery of the wound. These observations are consistent with the hypothesis that RA treatment reprograms the information in blastema cells to the PVPr position on the limb, since anterior and dorsal positions have the largest disparity and posterior and ventral have the smallest disparity from the PVPr identity. PMID- 27499859 TI - Ectopic blastema induction by nerve deviation and skin wounding: a new regeneration model in Xenopus laevis. AB - Recently, the accessory limb model (ALM) has become an alternative study system for limb regeneration studies in axolotls instead of using an amputated limb. ALM progresses limb regeneration study in axolotls because of its advantages. To apply and/or to compare knowledge in axolotl ALM studies to other vertebrates is a conceivable next step. First, Xenopus laevis, an anuran amphibian, was investigated. A Xenopus frog has hypomorphic regeneration ability. Its regeneration ability has been considered intermediate between that of non regenerative higher vertebrates and regenerative urodele amphibians. Here, we successfully induced an accessory blastema in Xenopus by skin wounding and rerouting of brachial nerve bundles to the wound site, which is the regular ALM surgery. The induced Xenopus ALM blastemas have limited regenerative potential compared with axolotl ALM blastemas. Comparison of ALM blastemas from species with different regenerative potentials may facilitate the identification of the novel expression programs necessary for the formation of cartilage and other tissues during limb regeneration. PMID- 27499860 TI - Implication of two different regeneration systems in limb regeneration. AB - Limb regeneration is a representative phenomenon of organ regeneration in urodele amphibians, such as an axolotl. An amputated limb starts regenerating from a remaining stump (proximal) to lost finger tips (distal). In the present case, proximal-distal (PD) reorganization takes place in a regenerating tissue, called a blastema. It has been a mystery how an induced blastema recognizes its position and restores an exact replica of missing parts. Recently, a new experimental system called the accessory limb model (ALM) has been established. The gained ALM phenotypes are demanding to reconsider the reorganization PD positional values. Based on the ALM phenotype, it is reasonable to hypothesize that reorganization of positional values has a certain discontinuity and that two different regeneration systems cooperatively reorganize the PD axis to restore an original structure. In this review, PD axis reestablishments are focused on limb regeneration. Knowledge from ALM studies in axolotls and Xenopus is providing a novel concept of PD axis reorganization in limb regeneration. PMID- 27499861 TI - Temporal and spatial analysis of enteric nervous system regeneration in the sea cucumber Holothuria glaberrima. AB - There is limited information on the regeneration of the enteric nervous system (ENS) following major reconstruction of the digestive tract. We have studied ENS regeneration in the sea cucumber Holothuria glaberrima which undergoes an organogenic process forming a new digestive tract at the tip of the mesentery. Our results show that (1) a degeneration of nerve fibers occurs early in the regeneration process, prior to eventual regeneration; (2) nerve fibers that innervate the regenerating intestine are of extrinsic and intrinsic origin; (3) innervation by extrinsic fibers occurs in a gradient that begins in the proximal area of the regenerate; (4) late events include the appearance of nerve fibers that project from the serosa into the connective tissue and of nerve bundles in the mesothelial layer; (5) neurons and neuroendocrine cells appear early following the formation of the epithelial layers. Our results provide not only a comparative biological approach to study ENS regeneration but also an alternative point of view for the study of enteric neuropathologies and for the innervation of organs made in vitro. PMID- 27499863 TI - Plasticity for axolotl lens regeneration is associated with age-related changes in gene expression. AB - Mexican axolotls lose potential for lens regeneration 2 weeks after hatching. We used microarrays to identify differently expressed genes before and after this critical time, using RNA isolated from iris. Over 3700 genes were identified as differentially expressed in response to lentectomy between young (7 days post hatching) and old (3 months post-hatching) axolotl larvae. Strikingly, many of the genes were only expressed in the early or late iris. Genes that were highly expressed in young iris significantly enriched electron transport chain, transcription, metabolism, and cell cycle gene ontologies, all of which are associated with lens regeneration. In contrast, genes associated with cellular differentiation and tissue maturation were uniquely expressed in old iris. Many of these expression differences strongly suggest that young and old iris samples were collected before and after the spleen became developmentally competent to produce and secrete cells with humoral and innate immunity functions. Our study establishes the axolotl as a powerful model to investigate age-related cellular differentiation and immune system ontogeny within the context of tissue regeneration. PMID- 27499862 TI - Angiogenesis is inhibitory for mammalian digit regeneration. AB - The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti-angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551-559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium-derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration. PMID- 27499864 TI - Distinct patterns of endosulfatase gene expression during Xenopus laevis limb development and regeneration. AB - The heparan sulfate 6-O-endosulfatases sulf1 and sulf2 regulate multiple cellular processes and organ development. Sulfs modulate a range of heparan-sulfate dependent extracellular pathways, including the fibroblast growth factor, bone morphogenetic protein, and wingless/wnt signaling pathways. Known patterns of sulf transcript expression together with functional experiments have implicated the sulfs in chondrogenesis and muscle regeneration in mammals. Here, we describe the expression patterns of Xenopus laevis sulf1 and sulf2 in developing forelimbs and hindlimbs and demonstrate novel expression of the sulf transcripts in the regenerating hindlimbs, with prominent sulf2 expression in the proliferating blastema and transient expression of sulf1 in the redeveloping apical epidermal ridge. These findings further suggest involvement of the sulfs in successful limb regeneration in amphibians. PMID- 27499866 TI - TALEN-mediated gene editing of the thrombospondin-1 locus in axolotl. AB - Loss-of-function genetics provides strong evidence for a gene's function in a wild-type context. In many model systems, this approach has been invaluable for discovering the function of genes in diverse biological processes. Axolotls are urodele amphibians (salamanders) with astonishing regenerative abilities, capable of regenerating entire limbs, portions of the tail (including spinal cord), heart, and brain into adulthood. With their relatively short generation time among salamanders, they offer an outstanding opportunity to interrogate natural mechanisms for appendage and organ regeneration provided that the tools are developed to address these long-standing questions. Here we demonstrate targeted modification of the thrombospondin-1 (tsp-1) locus using transcription-activator like effector nucleases (TALENs) and identify a role of tsp-1 in recruitment of myeloid cells during limb regeneration. We find that while tsp-1-edited mosaic animals still regenerate limbs, they exhibit a reduced subepidermal collagen layer in limbs and an increased number of myeloid cells within blastemas. This work presents a protocol for generating and genotyping mosaic axolotls with TALEN mediated gene edits. PMID- 27499865 TI - Reintegration of the regenerated and the remaining tissues during joint regeneration in the newt Cynops pyrrhogaster. AB - Urodele amphibians, such as newts, can regenerate a functional limb, including joints, after amputation at any level along the proximal-distal axis of the limb. The blastema can regenerate the limb morphology largely independently of the stump after proximal-distal identity has been established, but the remaining and regenerated tissues must be structurally reintegrated (matched in size and shape). Here we used newt joint regeneration as a model to investigate reintegration, because a functionally interlocking joint requires structural integration between its opposing skeletal elements. After forelimbs were amputated at the elbow joint, the joint was regenerated between the remaining and regenerated skeletal elements. The regenerated cartilage was thick around the amputated joint to make a reciprocally interlocking joint structure with the remaining bone. Furthermore, during regeneration, the extracellular matrix of the remaining tissues was lost, suggesting that the remaining tissues might contribute to the morphogenesis of regenerating cartilage. Our results showed that the area of the regenerated cartilage matched the area of the apposed remaining cartilage, thus contributing to formation of a functional structure. PMID- 27499867 TI - The regeneration blastema of lizards: an amniote model for the study of appendage replacement. AB - Although amniotes (reptiles, including birds, and mammals) are capable of replacing certain tissues, complete appendage regeneration is rare. Perhaps the most striking example is the lizard tail. Tail loss initiates a spontaneous epimorphic (blastema-mediated) regenerative program, resulting in a fully functional but structurally non-identical replacement. Here we review lizard tail regeneration with a particular focus on the blastema. In many lizards, the original tail has evolved a series of fracture planes, anatomical modifications that permit the tail to be self-detached or autotomized. Following tail loss, the wound site is covered by a specialized wound epithelium under which the blastema develops. An outgrowth of the spinal cord, the ependymal tube, plays a key role in governing growth (and likely patterning) of the regenerate tail. In some species (e.g., geckos), the blastema forms as an apical aggregation of proliferating cells, similar to that of urodeles and teleosts. For other species (e.g., anoles) the identification of a proliferative blastema is less obvious, suggesting an unexpected diversity in regenerative mechanisms among tail regenerating lizards. PMID- 27499868 TI - The axolotl limb blastema: cellular and molecular mechanisms driving blastema formation and limb regeneration in tetrapods. AB - The axolotl is one of the few tetrapods that are capable of regenerating complicated biological structures, such as complete limbs, throughout adulthood. Upon injury the axolotl generates a population of regeneration-competent limb progenitor cells known as the blastema, which will grow, establish pattern, and differentiate into the missing limb structures. In this review we focus on the crucial early events that occur during wound healing, the neural-epithelial interactions that drive the formation of the early blastema, and how these mechanisms differ from those of other species that have restricted regenerative potential, such as humans. We also discuss how the presence of cells from the different axes of the limb is required for the continued growth and establishment of pattern in the blastema as described in the polar coordinate model, and how this positional information is reprogrammed in blastema cells during regeneration. Multiple cell types from the mature limb stump contribute to the blastema at different stages of regeneration, and we discuss the contribution of these types to the regenerate with reference to whether they are "pattern forming" or "pattern-following" cells. Lastly, we explain how an engineering approach will help resolve unanswered questions in limb regeneration, with the goal of translating these concepts to developing better human regenerative therapies. PMID- 27499869 TI - The art of fin regeneration in zebrafish. AB - The zebrafish fin provides a valuable model to study the epimorphic type of regeneration, whereby the amputated part of the appendage is nearly perfectly replaced. To accomplish fin regeneration, two reciprocally interacting domains need to be established at the injury site, namely a wound epithelium and a blastema. The wound epithelium provides a supporting niche for the blastema, which contains mesenchyme-derived progenitor cells for the regenerate. The fate of blastemal daughter cells depends on their relative position with respect to the fin margin. The apical compartment of the outgrowth maintains its undifferentiated character, whereas the proximal descendants of the blastema progressively switch from the proliferation program to the morphogenesis program. A delicate balance between self-renewal and differentiation has to be continuously adjusted during the course of regeneration. This review summarizes the current knowledge about the cellular and molecular mechanisms of blastema formation, and discusses several studies related to the regulation of growth and morphogenesis during fin regeneration. A wide range of canonical signaling pathways has been implicated during the establishment and maintenance of the blastema. Epigenetic mechanisms play a crucial role in the regulation of cellular plasticity during the transition between differentiation states. Ion fluxes, gap junctional communication and protein phosphatase activity have been shown to coordinate proliferation and tissue patterning in the caudal fin. The identification of the downstream targets of the fin regeneration signals and the discovery of mechanisms integrating the variety of input pathways represent exciting future aims in this fascinating field of research. PMID- 27499870 TI - Current advances in tissue repair and regeneration: the future is bright. AB - The fifth EMBO conference on 'The Molecular and Cellular Basis of Regeneration and Repair' took place in the peaceful coastal town of Sant Feliu de Guixols (Spain) on September 2014. The meeting was organised by Emili Salo (U. Barcelona, Spain), Kimberly Mace (U. Manchester, UK), Patrizia Ferretti (University College London, UK) and Michael Brand (Centre for Regenerative Therapies Dresden, Germany) and received the generous support of Society for Developmental Biology, The Company of Biologists, Centre for Regenerative Therapies Dresden, Garland Science and the journals Regeneration and Cell Signalling. The natural surroundings provided an inspiring setting for 185 researchers from all over the world to share their latest findings and views on the field. The conference showcased the great diversity of model organisms used for studying regeneration and tissue repair, including invertebrate and vertebrate species (Fig. 1). Importantly, this diversity in animal models allowed for a global overview of the mechanisms that promote regeneration. In addition, it highlighted some of the unique aspects that confer differences in regenerative capacities among different species. These differences might lie in each of the different steps involved in performing regeneration, including triggering the regenerative response, controlling cellular plasticity, re-stablishing the correct tissue patterns, as well as determining the roles of extrinsic factors, such as the role of inflammation in regeneration. A deeper understanding of these processes in the naturally regenerating species is a prerequisite for advancing the field of regenerative medicine and tissue repair in humans. PMID- 27499871 TI - The mammalian blastema: regeneration at our fingertips. AB - In the mouse, digit tip regeneration progresses through a series of discrete stages that include inflammation, histolysis, epidermal closure, blastema formation, and redifferentiation. Recent studies reveal how each regenerative stage influences subsequent stages to establish a blastema that directs the successful regeneration of a complex mammalian structure. The focus of this review is on early events of healing and how an amputation wound transitions into a functional blastema. The stepwise formation of a mammalian blastema is proposed to provide a model for how specific targeted treatments can enhance regenerative performance in humans. PMID- 27499872 TI - Epidermal closure regulates histolysis during mammalian (Mus) digit regeneration. AB - Mammalian digit regeneration progresses through consistent stages: histolysis, inflammation, epidermal closure, blastema formation, and finally redifferentiation. What we do not yet know is how each stage can affect others. Questions of stage timing, tissue interactions, and microenvironmental states are becoming increasingly important as we look toward solutions for whole limb regeneration. This study focuses on the timing of epidermal closure which, in mammals, is delayed compared to more regenerative animals like the axolotl. We use a standard wound closure device, Dermabond (2-octyl cyanoacrylate), to induce earlier epidermal closure, and we evaluate the effect of fast epidermal closure on histolysis, blastema formation, and redifferentiation. We find that fast epidermal closure is reliant upon a hypoxic microenvironment. Additionally, early epidermal closure eliminates the histolysis stage and results in a regenerate that more closely replicates the amputated structure. We show that tools like Dermabond and oxygen are able to independently influence the various stages of regeneration enabling us to uncouple histolysis, wound closure, and other regenerative events. With this study, we start to understand how each stage of mammalian digit regeneration is controlled. PMID- 27499873 TI - Regeneration and repair of human digits and limbs: fact and fiction. AB - A variety of digit and limb repair and reconstruction methods have been used in different clinical settings, but regeneration remains an item on every plastic surgeon's "wish list." Although surgical salvage techniques are continually being improved, unreplantable digits and limbs are still abundant. We comprehensively review the structural and functional salvage methods in clinical practice, from the peeling injuries of small distal fingertips to multisegmented amputated limbs, and the developmental and tissue engineering approaches for regenerating human digits and limbs in the laboratory. Although surgical techniques have forged ahead, there are still situations in which digits and limbs are unreplantable. Advances in the field are delineated, and the regeneration processes of salamander limbs, lizard tails, and mouse digits and each component of tissue engineering approaches for digit- and limb-building are discussed. Although the current technology is promising, there are many challenges in human digit and limb regeneration. We hope this review inspires research on the critical gap between clinical and basic science, and leads to more sophisticated digit and limb loss rescue and regeneration innovations. PMID- 27499874 TI - Positional information in axolotl and mouse limb extracellular matrix is mediated via heparan sulfate and fibroblast growth factor during limb regeneration in the axolotl (Ambystoma mexicanum). AB - Urodele amphibians are unique among adult vertebrates in their ability to regenerate complex body structures after traumatic injury. In salamander regeneration, the cells maintain a memory of their original position and use this positional information to recreate the missing pattern. We used an in vivo gain of-function assay to determine whether components of the extracellular matrix (ECM) have positional information required to induce formation of new limb pattern during regeneration. We discovered that salamander limb ECM has a position-specific ability to either inhibit regeneration or induce de novo limb structure, and that this difference is dependent on heparan sulfates that are associated with differential expression of heparan sulfate sulfotransferases. We also discovered that an artificial ECM containing only heparan sulfate was sufficient to induce de novo limb pattern in salamander limb regeneration. Finally, ECM from mouse limbs is capable of inducing limb pattern in axolotl blastemas in a position-specific, developmental-stage-specific, and heparan sulfate-dependent manner. This study demonstrates a mechanism for positional information in regeneration and establishes a crucial functional link between salamander regeneration and mammals. PMID- 27499875 TI - Skeletal callus formation is a nerve-independent regenerative response to limb amputation in mice and Xenopus. AB - To clarify the mechanism of limb regeneration that differs between mammals (non regenerative) and amphibians (regenerative), responses to limb amputation and the accessory limb inducible surgery (accessory limb model, ALM) were compared between mice and Xenopus, focusing on the events leading to blastema formation. In both animals, cartilaginous calluses were formed around the cut edge of bones after limb amputation. They not only are morphologically similar but show other similarities, such as growth driven by undifferentiated cell proliferation and macrophage-dependent and nerve-independent induction. It appears that amputation callus formation is a common nerve-independent regenerative response in mice and Xenopus. In contrast, the ALM revealed that the wound epithelium (WE) in Xenopus was innervated by many regenerating axons when a severed nerve ending was placed underneath it, whereas only a few axons were found within the WE in mice. Since nerves are involved in induction of the regeneration-permissive WE in amphibians, whether or not nerves can interact with the WE might be one of the key processes separating successful nerve-dependent blastema formation in Xenopus and failure in mice. PMID- 27499877 TI - Functional joint regeneration is achieved using reintegration mechanism in Xenopus laevis. AB - A functional joint requires integration of multiple tissues: the apposing skeletal elements should form an interlocking structure, and muscles should insert into skeletal tissues via tendons across the joint. Whereas newts can regenerate functional joints after amputation, Xenopus laevis regenerates a cartilaginous rod without joints, a "spike." Previously we reported that the reintegration mechanism between the remaining and regenerated tissues has a significant effect on regenerating joint morphogenesis during elbow joint regeneration in newt. Based on this insight into the importance of reintegration, we amputated frogs' limbs at the elbow joint and found that frogs could regenerate a functional elbow joint between the remaining tissues and regenerated spike. During regeneration, the regenerating cartilage was partially connected to the remaining articular cartilage to reform the interlocking structure of the elbow joint at the proximal end of the spike. Furthermore, the muscles of the remaining part inserted into the regenerated spike cartilage via tendons. This study might open up an avenue for analyzing molecular and cellular mechanisms of joint regeneration using Xenopus. PMID- 27499876 TI - Genome-wide analysis reveals conserved transcriptional responses downstream of resting potential change in Xenopus embryos, axolotl regeneration, and human mesenchymal cell differentiation. AB - Endogenous bioelectric signaling via changes in cellular resting potential (V mem) is a key regulator of patterning during regeneration and embryogenesis in numerous model systems. Depolarization of V mem has been functionally implicated in dedifferentiation, tumorigenesis, anatomical re-specification, and appendage regeneration. However, no unbiased analyses have been performed to understand genome-wide transcriptional responses to V mem change in vivo. Moreover, it is unknown which genes or gene networks represent conserved targets of bioelectrical signaling across different patterning contexts and species. Here, we use microarray analysis to comparatively analyze transcriptional responses to V mem depolarization. We compare the response of the transcriptome during embryogenesis (Xenopus development), regeneration (axolotl regeneration), and stem cell differentiation (human mesenchymal stem cells in culture) to identify common networks across model species that are associated with depolarization. Both subnetwork enrichment and PANTHER analyses identified a number of key genetic modules as targets of V mem change, and also revealed important (well-conserved) commonalities in bioelectric signal transduction, despite highly diverse experimental contexts and species. Depolarization regulates specific transcriptional networks across all three germ layers (ectoderm, mesoderm, and endoderm) such as cell differentiation and apoptosis, and this information will be used for developing mechanistic models of bioelectric regulation of patterning. Moreover, our analysis reveals that V mem change regulates transcripts related to important disease pathways such as cancer and neurodegeneration, which may represent novel targets for emerging electroceutical therapies. PMID- 27499878 TI - Analogous cellular contribution and healing mechanisms following digit amputation and phalangeal fracture in mice. AB - Regeneration of amputated structures is severely limited in humans and mice, with complete regeneration restricted to the distal portion of the terminal phalanx (P3). Here, we investigate the dynamic tissue repair response of the second phalangeal element (P2) post amputation in the adult mouse, and show that the repair response of the amputated bone is similar to the proximal P2 bone fragment in fracture healing. The regeneration-incompetent P2 amputation response is characterized by periosteal endochondral ossification resulting in the deposition of new trabecular bone, corresponding to a significant increase in bone volume; however, this response is not associated with bone lengthening. We show that cells of the periosteum respond to amputation and fracture by contributing both chondrocytes and osteoblasts to the endochondral ossification response. Based on our studies, we suggest that the amputation response represents an attempt at regeneration that ultimately fails due to the lack of a distal organizing influence that is present in fracture healing. PMID- 27499879 TI - Ear wound regeneration in the African spiny mouse Acomys cahirinus. AB - While regeneration occurs in a number of taxonomic groups across the Metazoa, there are very few reports of regeneration in mammals, which generally respond to wounding with fibrotic scarring rather than regeneration. A recent report described skin shedding, skin regeneration and extensive ear punch closure in two rodent species, Acomys kempi and Acomys percivali. We examined these striking results by testing the capacity for regeneration of a third species, Acomys cahirinus, and found a remarkable capacity to repair full thickness circular punches in the ear pinna. Four-millimeter-diameter wounds closed completely in 2 months in 100% of ear punches tested. Histology showed extensive formation of elastic cartilage, adipose tissue, dermis, epidermis and abundant hair follicles in the repaired region. Furthermore, we demonstrated abundant angiogenesis and unequivocal presence of both muscle and nerve fibers in the reconstituted region; in contrast, similar wounds in C57BL/6 mice simply healed the borders of the cut by fibrotic scarring. Our results confirm the regenerative capabilities of Acomys, and suggest this model merits further attention. PMID- 27499880 TI - Planarian brain regeneration as a model system for developmental neurotoxicology. AB - Freshwater planarians, famous for their regenerative prowess, have long been recognized as a valuable in vivo animal model to study the effects of chemical exposure. In this review, we summarize the current techniques and tools used in the literature to assess toxicity in the planarian system. We focus on the planarian's particular amenability for neurotoxicology and neuroregeneration studies, owing to the planarian's unique ability to regenerate a centralized nervous system. Zooming in from the organismal to the molecular level, we show that planarians offer a repertoire of morphological and behavioral readouts while also being amenable to mechanistic studies of compound toxicity. Finally, we discuss the open challenges and opportunities for planarian brain regeneration to become an important model system for modern toxicology. PMID- 27499882 TI - The relationship between growth and pattern formation. AB - Successful development depends on the creation of spatial gradients of transcription factors within developing fields, and images of graded distributions of gene products populate the pages of developmental biology journals. Therefore the challenge is to understand how the graded levels of intracellular transcription factors are generated across fields of cells. We propose that transcription factor gradients are generated as a result of an underlying gradient of cell cycle lengths. Very long cell cycles will permit accumulation of a high level of a gene product encoded by a large transcription unit, whereas shorter cell cycles will permit progressively fewer transcripts to be completed due to gating of transcription by the cell cycle. We also propose that the gradients of cell cycle lengths are generated by gradients of extracellular morphogens/growth factors. The model of cell cycle gated transcriptional regulation brings focus back to the functional role of morphogens as cell cycle regulators, and proposes a specific and testable mechanism by which morphogens, in their roles as growth factors (how they were originally discovered), also determine cell fate. PMID- 27499883 TI - Pilot study of a compassion meditation intervention in chronic pain. AB - BACKGROUND: The emergence of anger as an important predictor of chronic pain outcomes suggests that treatments that target anger may be particularly useful within the context of chronic pain. Eastern traditions prescribe compassion cultivation to treat persistent anger. Compassion cultivation has been shown to influence emotional processing and reduce negativity bias in the contexts of emotional and physical discomfort, thus suggesting it may be beneficial as a dual treatment for pain and anger. Our objective was to conduct a pilot study of a 9 week group compassion cultivation intervention in chronic pain to examine its effect on pain severity, anger, pain acceptance and pain-related interference. We also aimed to describe observer ratings provided by patients' significant others and secondary effects of the intervention. METHODS: Pilot clinical trial with repeated measures design that included a within-subjects wait-list control period. Twelve chronic pain patients completed the intervention (F= 10). Data were collected from patients at enrollment, treatment baseline and post treatment; participant significant others contributed data at the enrollment and post-treatment time points. RESULTS: In this predominantly female sample, patients had significantly reduced pain severity and anger and increased pain acceptance at post-treatment compared to treatment baseline. Significant other qualitative data corroborated patient reports for reductions in pain severity and anger. CONCLUSIONS: Compassion meditation may be a useful adjunctive treatment for reducing pain severity and anger, and for increasing chronic pain acceptance. Patient reported reductions in anger were corroborated by their significant others. The significant other corroborations offer a novel contribution to the literature and highlight the observable emotional and behavioral changes in the patient participants that occurred following the compassion intervention. Future studies may further examine how anger reductions impact relationships with self and others within the context of chronic pain. PMID- 27499884 TI - Concordance of In-Home "Smart" Scale Measurement with Body Weight Measured In Person. AB - OBJECTIVE: Newer "smart" scales that transmit participants' body weights directly to data collection centers offer the opportunity to simplify weight assessment in weight management research; however, little data exist on the concordance of these data compared to weights measured at in-person assessments. METHODS: We compared the weights of 58 participants (mean+/-SD BMI = 31.6+/-4.8, age = 52.1+/ 9.7 years, 86.2% White, 65.5% Female) measured by study staff at an in-person assessment visit to weights measured on the same day at home using BodyTrace "smart" scales. These measures occurred after 3 months of an internet-based weight management intervention. RESULTS: Weight (mean+/-SD) measured at the 3 month in-person assessment visit was 81.5+/-14.7kg compared to 80.4+/-14.5kg measured on the same day using in-home body weight scales; mean bias =1.1+/ 0.8kg, 95% limits of agreement = -0.5 to 2.6. Two outliers in the data suggest that there may be greater variability between measurements for participants weighing above 110 kg. CONCLUSION: Results suggest good concordance between the measurements and support the use of the BodyTrace smart scale in weight management research. Future trials using BodyTrace scales for outcome assessment should clearly define protocols for measurement and associated instructions to participants (e.g., instruct individuals to weigh at the same time of day, similarly clothed). Finally, measure concordance should be investigated in a group of individuals weighing more than 110kg. PMID- 27499885 TI - Relationship of Physical Activity and Healthy Eating with Mortality and Incident Heart Failure among Community-Dwelling Older Adults with Normal Body Mass Index. AB - AIMS: Normal body mass index (BMI) is associated with lower mortality and may be achieved by physical activity (PA), healthy eating (HE), or both. We examined the association of PA and HE with mortality and incident heart failure (HF) among 2040 community-dwelling older adults aged >= 65 years with baseline BMI 18.5 to 24.99 kg/m2 during 13 years of follow-up in Cardiovascular Health Study. METHODS AND RESULTS: Baseline PA was defined as >=500 weekly metabolic equivalent task minutes (MET-minutes) and HE as >=5 daily servings of vegetable and fruit intake. Participants were categorized into 4 groups: (1) PA-/HE- (n=384); (2) PA+/HE- (n=992); (3) PA-/HE+ (n=162); and (4) PA+/HE+ (n=502). Participants had a mean age of 74 (+/-6) years, mean BMI of 22.6 (+/-1.5) kg/m2, 61% were women, and 4% African American. Compared with PA-/HE-, age-sex-race-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality for PA-/HE+, PA+/HE-, and PA+/HE+ groups were 0.96 (0.76-1.21), 0.61 (0.52-0.71) and 0.62 (0.52-0.75), respectively. These associations remained unchanged after multivariable adjustment and were similar for cardiovascular and non cardiovascular mortalities. Respective demographic-adjusted HRs (95% Cis) for incident HF among 1954 participants without baseline HF were 1.21 (0.81-1.81), 0.71 (0.54-0.94) and 0.71 (0.51-0.98). These later associations lost significance after multivariable-adjustment. CONCLUSION: Among community-dwelling older adults with normal BMI, physical activity, regardless of healthy eating, was associated with lower risk of mortality and incident HF, but healthy eating had no similar protective association in this cohort. PMID- 27499881 TI - Physiological controls of large-scale patterning in planarian regeneration: a molecular and computational perspective on growth and form. AB - Planaria are complex metazoans that repair damage to their bodies and cease remodeling when a correct anatomy has been achieved. This model system offers a unique opportunity to understand how large-scale anatomical homeostasis emerges from the activities of individual cells. Much progress has been made on the molecular genetics of stem cell activity in planaria. However, recent data also indicate that the global pattern is regulated by physiological circuits composed of ionic and neurotransmitter signaling. Here, we overview the multi-scale problem of understanding pattern regulation in planaria, with specific focus on bioelectric signaling via ion channels and gap junctions (electrical synapses), and computational efforts to extract explanatory models from functional and molecular data on regeneration. We present a perspective that interprets results in this fascinating field using concepts from dynamical systems theory and computational neuroscience. Serving as a tractable nexus between genetic, physiological, and computational approaches to pattern regulation, planarian pattern homeostasis harbors many deep insights for regenerative medicine, evolutionary biology, and engineering. PMID- 27499886 TI - Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. AB - BACKGROUND: Bio-products from stem/progenitor cells, such as extracellular vesicles, are likely a new promising approach for reprogramming resident cells in both acute and chronic kidney disease. Forty CKD patients stage III and IV (eGFR 15-60 mg/ml) have been divided into two groups; twenty patients as treatment group "A" and twenty patients as a matching placebo group "B". Two doses of MSC derived extracellular vesicles had been administered to patients of group "A". Blood urea, serum creatinine, urinary albumin creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) have been used to assess kidney functions and TNF-alpha, TGF-beta1 and IL-10 have been used to assess the amelioration of the inflammatory immune activity. RESULTS: Participants in group A exhibited significant improvement of eGFR, serum creatinine level, blood urea and UACR. Patients of the treatment group "A" also exhibited significant increase in plasma levels of TGF-beta1, and IL-10 and significant decrease in plasma levels of TNF-alpha. Participants of the control group B did not show significant improvement in any of the previously mentioned parameters at any time point of the study period. CONCLUSION: Administration of cell-free cord-blood mesenchymal stem cells derived extracellular vesicles (CF-CB-MSCs-EVs) is safe and can ameliorate the inflammatory immune reaction and improve the overall kidney function in grade III-IV CKD patients. PMID- 27499888 TI - The Journal of Pathology: Clinical Research. A new step in the evolution of publishing in pathology. PMID- 27499887 TI - Superior absorption and retention properties of foam-film silver dressing versus other commercially available silver dressing. AB - BACKGROUND: The aim of this study is to investigate the physicochemical and structural properties of Medifoam(r)Silver and to compare with other commercially available silver-containing polyurethane (PU) foam dressing in vitro. METHODS: Surface and cross-section of four polyurethane foam dressings were assessed with field-emission scanning electron microscope. Thickness, density, tensile strength, elongation, absorption rate, absorption/retention capacity and water vapor transmission (WVT) were measured to compare physical properties of various dressing materials. RESULTS: Among four tested dressings, Medifoam(r)Silver has relatively uniform and smallest pore size in both surface and cross-section. In comparison of absorption properties with other dressing materials, Medifoam(r)Silver has rapid absorption rate, good absorption/retention capacity and good WVT value. CONCLUSIONS: The data further suggests that Medifoam(r)Silver is a promising candidate for wound healing management. PMID- 27499891 TI - Aurora A is a prognostic marker for breast cancer arising in BRCA2 mutation carriers. AB - Overexpression of the Aurora A kinase has been shown to have prognostic value in breast cancer. Previously, we showed a significant association between AURKA gene amplification and BRCA2 mutation in breast cancer. The aim of this study was to assess the prognostic impact of Aurora A overexpression on breast cancer arising in BRCA2 mutation carriers. Aurora A expression was evaluated by immunohistochemistry on breast tumour tissue microarrays from 107 BRCA2 999del5 mutation carriers and 284 of sporadic origin. Prognostic value of Aurora A nuclear staining was estimated in relation to clinical markers and adjuvant treatment, using multivariate Cox's proportional hazards ratio regression model. BRCA2 wild-type allele loss was measured by TaqMan in BRCA2 mutated tumour samples. All statistical tests were two sided. Multivariate analysis of breast cancer-specific survival, including proliferative markers and treatment, indicated independent prognostic value of Aurora A nuclear staining for BRCA2 mutation carriers (hazards ratio = 7.06; 95% confidence interval = 1.23-40.6; p = 0.028). Poor breast cancer-specific survival of BRCA2 mutation carriers was found to be significantly associated with combined Aurora A nuclear expression and BRCA2 wild type allele loss in tumours (p < 0.001). Multivariate analysis indicated independent prognostic value of both positive Aurora A nuclear staining (hazards ratio = 10.09; 95% confidence interval = 1.19-85.4, p = 0.034) and BRCA2 wild type allele loss (hazards ratio = 9.63; 95% confidence interval = 1.81-51.0, p = 0.008) for BRCA2 mutation carriers. Aurora A nuclear expression was found to be a significant prognostic marker for BRCA2 mutation carriers, independent of clinical parameters and adjuvant treatment. Our conclusion is that treatment benefits for BRCA2 mutation carriers and sporadic breast cancer patients with Aurora A positive tumours may be enhanced by giving attention to Aurora A targeted treatment. PMID- 27499889 TI - The molecular background of mucinous carcinoma beyond MUC2. AB - The increasing interest of the oncology community in tumour classification and prediction of outcome to targeted therapies has put emphasis on an improved identification of tumour types. Colorectal mucinous adenocarcinoma (MC) is a subtype that is characterized by the presence of abundant extracellular mucin that comprises at least 50% of the tumour volume and is found in 10-15% of colorectal cancer patients. MC development is poorly understood, however, the distinct clinical and pathological presentation of MC suggests a deviant development and molecular background. In this review we identify common molecular and genetic alterations in colorectal MC. MC is characterized by a high rate of MUC2 expression. Mutation rates in the therapeutically important RAS/RAF/MAPK and PI3K/AKT pathways are significantly higher in MC compared with non-mucinous adenocarcinoma. Furthermore, mucinous adenocarcinoma shows higher rates of microsatellite instability and is more frequently of the CpG island methylator phenotype. Although the majority of MCs arise from the large intestine, this subtype also develops in other organs, such as the stomach, pancreas, biliary tract, ovary, breast and lung. We compared findings from colorectal MC with tumour characteristics of MCs from other organs. In these organs, MCs show different mutation rates in the RAS/RAF/MAPK and PI3K/AKT pathways as well, but a common mucinous pathway cannot be identified. Identification of conditions and molecular aberrations that are associated with MC generates insight into the aetiology of this subtype and improves understanding of resistance to therapies. PMID- 27499890 TI - Performance of automated scoring of ER, PR, HER2, CK5/6 and EGFR in breast cancer tissue microarrays in the Breast Cancer Association Consortium. AB - Breast cancer risk factors and clinical outcomes vary by tumour marker expression. However, individual studies often lack the power required to assess these relationships, and large-scale analyses are limited by the need for high throughput, standardized scoring methods. To address these limitations, we assessed whether automated image analysis of immunohistochemically stained tissue microarrays can permit rapid, standardized scoring of tumour markers from multiple studies. Tissue microarray sections prepared in nine studies containing 20 263 cores from 8267 breast cancers stained for two nuclear (oestrogen receptor, progesterone receptor), two membranous (human epidermal growth factor receptor 2 and epidermal growth factor receptor) and one cytoplasmic (cytokeratin 5/6) marker were scanned as digital images. Automated algorithms were used to score markers in tumour cells using the Ariol system. We compared automated scores against visual reads, and their associations with breast cancer survival. Approximately 65-70% of tissue microarray cores were satisfactory for scoring. Among satisfactory cores, agreement between dichotomous automated and visual scores was highest for oestrogen receptor (Kappa = 0.76), followed by human epidermal growth factor receptor 2 (Kappa = 0.69) and progesterone receptor (Kappa = 0.67). Automated quantitative scores for these markers were associated with hazard ratios for breast cancer mortality in a dose-response manner. Considering visual scores of epidermal growth factor receptor or cytokeratin 5/6 as the reference, automated scoring achieved excellent negative predictive value (96-98%), but yielded many false positives (positive predictive value = 30-32%). For all markers, we observed substantial heterogeneity in automated scoring performance across tissue microarrays. Automated analysis is a potentially useful tool for large-scale, quantitative scoring of immunohistochemically stained tissue microarrays available in consortia. However, continued optimization, rigorous marker-specific quality control measures and standardization of tissue microarray designs, staining and scoring protocols is needed to enhance results. PMID- 27499892 TI - Differential expression of argininosuccinate synthetase in serous and non-serous ovarian carcinomas. AB - The current standard of care for epithelial ovarian cancer does not discriminate between different histologic subtypes (serous, clear cell, endometrioid and mucinous) despite the knowledge that ovarian carcinoma subtypes do not respond uniformly to conventional platinum/taxane-based chemotherapy. Exploiting addictions and vulnerabilities in cancers with distinguishable molecular features presents an opportunity to develop individualized therapies that may be more effective than the current 'one size fits all' approach. One such opportunity is arginine depletion therapy with pegylated arginine deiminase, which has shown promise in several cancer types that exhibit low levels of argininosuccinate synthetase including hepatocellular and prostate carcinoma and melanoma. Based on the high levels of argininosuccinate synthetase previously observed in ovarian cancers, these tumours have been considered unlikely candidates for arginine depletion therapy. However, argininosuccinate synthetase levels have not been evaluated in the individual histologic subtypes of ovarian carcinoma. The current study is the first to examine the expression of argininosuccinate synthetase at the mRNA and protein levels in large cohorts of primary and recurrent ovarian carcinomas and ovarian cancer cell lines. We show that the normal fallopian tube fimbria and the majority of primary high-grade and low-grade serous ovarian carcinomas express high levels of argininosuccinate synthetase, which tend to further increase in recurrent tumours. In contrast to the serous subtype, non serous ovarian carcinoma subtypes (clear cell, endometrioid and mucinous) frequently lack detectable argininosuccinate synthetase expression. The in vitro sensitivity of ovarian cancer cell lines to arginine depletion with pegylated arginine deiminase was inversely correlated with argininosuccinate synthetase expression. Our data suggest that the majority of serous ovarian carcinomas are not susceptible to therapeutic intervention with arginine deiminase while a subset of non-serous ovarian carcinoma subtypes are auxotrophic for arginine and should be considered for clinical trials with pegylated arginine deiminase. PMID- 27499893 TI - High CerS5 expression levels associate with reduced patient survival and transition from apoptotic to autophagy signalling pathways in colorectal cancer. AB - Ceramide synthase 5 is involved in the de novo synthesis of ceramide, a sphingolipid involved in cell death and proliferation. In this study, we investigated the role of ceramide synthase 5 in colorectal cancer by examining ceramide synthase 5 expression, clinico-pathological parameters and association with survival/death signalling pathways in cancer. Immunohistochemical analysis of CerS5 was performed on 102 colorectal cancer samples using tissue microarrays constructed from formalin-fixed and paraffin-embedded tissues. We found strong membranous ceramide synthase 5 staining in 57 of 102 (56%) colorectal cancers. A multivariate Cox regression analysis of ceramide synthase 5 expression adjusted for disease stage, differentiation and lymphovascular invasion revealed reduced 5 year overall survival (p = 0.001) and 5-year recurrence-free survival (p = 0.002), with hazard ratios of 4.712 and 4.322, respectively. The effect of ceramide synthase 5 expression on tumourigenic processes was further characterised by reverse phase protein array analysis. Reverse phase protein arrays were generated from laser capture microdissection-enriched carcinoma cells from 19 fresh-frozen colorectal cancer tissues. Measurements of phosphorylation and total levels of signalling proteins involved in apoptosis, autophagy and other cancer-related pathways revealed two distinct signalling networks; weak membranous ceramide synthase 5 intensity was associated with a proteomic network dominated by signalling proteins linked to apoptosis, whereas strong ceramide synthase 5 intensity was associated with a proteomic sub-network mostly composed of proteins linked to autophagy. In conclusion, high ceramide synthase 5 expression was found in colorectal cancer tissue and was associated with poorer patient outcomes. Our findings suggest that this may be mediated by a transition from apoptotic to autophagy signalling pathways in ceramide synthase 5 High expressing tumours, thus implicating ceramide synthase 5 in the progression of colorectal cancer. PMID- 27499894 TI - Novel association between microglia and stem cells in human gliomas: A contributor to tumour proliferation? AB - Brain tumour stem cells and microglia both promote the growth of astrocytomas, the commonest form of primary brain tumour, with recent emerging evidence that these cell types may interact in glioma models. It is unclear whether microglia and stem cells are associated in human gliomas. To investigate this question, we used the technique of tissue microarrays to perform a correlative study of a large number of tumour samples. We quantified immunostaining of human astrocytic tumour tissue microarrays (86 patients; World Health Organisation grade II-IV) for microglia Ionized calcium binding adaptor molecule 1 (Iba1) and CD68, and stem cell nestin, SOX2 and CD133. Ki67 was used to assess proliferation and GFAP for astrocytic differentiation. Immunoreactivity for both microglial markers and stem cell markers nestin and SOX2 significantly increased with increasing tumour grade. GFAP was higher in low grade astrocytomas. There was a positive correlation between: (i) both microglial markers and nestin and CD133, (ii) nestin and tumour cell proliferation Ki67 and (iii) both microglial markers and Ki67. SOX2 was not associated with microglia or tumour proliferation. To test the clinical relevance, we investigated the putative association of these markers with clinical outcomes. High expression for nestin and Iba1 correlated with significantly shorter survival times, and high expression for nestin, Iba1, CD68 and Ki67 was associated with faster tumour progression on univariate analysis. On multivariate analysis, nestin, CD133 and Ki67 remained significant predictors of poorer survival, after adjustment for other markers. These results confirm previous in vitro findings, demonstrating their functional relevance as a therapeutic target in humans. This is the first report of a novel correlation between microglia and stem cells that may drive human astrocytic tumour development. PMID- 27499895 TI - Metachronous pancreatic cancer originating from disseminated founder pancreatic intraductal neoplasias (PanINs). AB - Clonal populations originated from benign-looking 'founder cells' may spread widely within pancreas instead of being localized in situ before frank pancreatic ductal adenocarcinoma (PDA) can be detected. Metachronous PDA is not common event, and we here sought to define potent origin of multiple PDAs developed in a woman using advanced genetics technologies. Curative resection of pancreatic head tumour was performed; however, 'recurrent' lesions in the remnant pancreas were found 3.5 years later and total pancreatectomy was subsequently performed. The metachronous lesions were morphologically similar to the primary PDA. Using a next-generation sequencing and digital PCR, all three PDAs were shown to possess rare somatic mutations in KRAS (p.T58I & p.Q61H). Curiously, identical KRAS mutations were found in low-grade 'intraepithelial' lesions, which localized in normal area of the pancreas and one of them possessed p53 mutation, which was also found in the PDAs. The footprint of the tumour evolution marked by mutational profiling supports a human correlate to the mouse models of 'dissemination' occurring at the earliest stages of pancreatic neoplasia. PMID- 27499896 TI - Loss of ATRX and DAXX expression identifies poor prognosis for smooth muscle tumours of uncertain malignant potential and early stage uterine leiomyosarcoma. AB - Uterine smooth muscle tumours of uncertain malignant potential (STUMP) are diagnostically and clinically challenging. The alternative lengthening of telomeres (ALT) telomere maintenance mechanism is associated with poor survival in soft tissue leiomyosarcoma. Time to first recurrence and survival were known for 18 STUMP and 43 leiomyosarcomata (LMS). These were screened for ALT telomere maintenance by the presence of ALT-associated PML bodies (APBs) and for changes associated with the ALT phenotype, namely aberrant p53 expression, isocitrate dehydrogenase 1 mutation (R132H substitution) expression, mutant ATRX (alphathalassemia/mental retardation syndrome X-linked) expression and mutant DAXX (death-domain-associated protein) expression by immunohistochemistry (IHC). Overexpression of p16(INK4A) was examined immunohistologically in a subset of cases. Many of the tumours associated with death or recurrence demonstrated APBs commensurate with ALT telomere maintenance. However, all uterine STUMP (4/4), and vaginal STUMP (2/2) patients, and almost all LMS patients (88.4%, 23/26, including 90% (9/10) of stage 1 LMS cases), who had died of disease or who had recurrent disease, displayed loss of ATRX or DAXX expression. Loss of ATRX or DAXX expression identified poor prognosis (95% CI 2.1 to 40.8, p < 0.003), in the LMS group. Thus, loss of ATRX or DAXX expression in uterine smooth muscle tumours identifies a clinically aggressive molecular subtype of early stage LMS and when histopathological features are problematic such as in STUMP. As ATRX and DAXX IHC is readily performed in diagnostic laboratories these are potentially useful for routine histopathological classification and management. PMID- 27499897 TI - Clinical outcome in patients with peripherally-sited atypical lipomatous tumours and dedifferentiated liposarcoma. AB - The reported incidence of local recurrence of peripheral atypical lipomatous tumours is highly variable and is likely to reflect the different inclusion criteria of cases, and the design of previous studies. We aimed to study the incidence of local recurrence of 90 cases of atypical lipomatous tumours and an additional 18 cases of de novo dedifferentiated liposarcoma. All tumours were diagnosed on the basis of MDM2 amplification: all patients had their first treatment in the same specialist sarcoma unit and were followed for a minimum of 60 months. The tumours were diagnosed between 1997 and 2009 and followed until the end of 2014. Seventy cases (78%) of atypical lipomatous tumours were located in the thigh (mean size 195 mm on presentation). Eight atypical lipomatous tumours (8.9%) recurred locally, of which 50% recurred after 60 months. The only two tumours with intralesional excisions recurred. Seven of the eight recurrent tumours were detected by the patient by self-examination. One case recurred a second time as a dedifferentiated liposarcoma. Seventeen per cent of the de novo dedifferentiated liposarcomas recurred within 60 months of presentation. Extending the study period revealed that atypical lipomatous tumour could recur up to 40 years after the first surgery. Furthermore, of 26 tumours that recurred in the extended study, 27% recurred more than once, and three of the seven that recurred more than once transformed into a dedifferentiated liposarcoma. We recommend that, following post-operative wound care, patients with atypical lipomatous tumour are referred back to their general practitioner for follow up, but that in the event of a suspected recurrence they have rapid access back to the specialist unit using a 'supported discharge' scheme. In the event of an intralesional excision and if a lesion recurs, patients are followed in a specialist unit at regular intervals: whether MRI scanning is a valuable means of monitoring such patients is unclear and requires an evidence base. PMID- 27499899 TI - ReadMax-a novel reading and scoring approach for EGFR gene copy number to predict therapeutic benefit of erlotinib treatment in EGFR wild-type non-small-cell lung cancer. AB - EGFR mutation testing is now well established as a means of selecting the optimal first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). However, deciding on the correct treatment for EGFR wild-type NSCLC remains a challenge. EGFR fluorescence in-situ hybridization (FISH) testing of gene copy number has been a promising marker, but has provided mixed results despite attempts to standardize the reading and scoring process. The novel ReadMax reading and scoring system focuses on the most aberrant cells, to identify oncogene addiction, rather than taking a representative reading as in the Colorado method. The methodology was developed using historical samples from the TRUST and MERIT studies, followed by re-reading of the samples from the SATURN trial. Analysis of samples using the ReadMax methodology revealed that progression-free survival (PFS) and overall survival (OS) were improved in patients with ReadMax FISH-positive (RM FISH+) tumours, compared with those whose tumours were not RM FISH+: PFS hazard ratios (HRs) were 0.52 for RM FISH+ versus 0.93 for not RM FISH+; OS HRs were 0.69 and 0.92, respectively. For PFS, HR for RM FISH+ versus not RM FISH+ in the SATURN erlotinib group was 0.53 (p = 0.003). The PFS and OS results were also similar in the EGFR wild-type population (PFS HRs were 0.63 and 0.96; OS HRs were 0.61 and 0.84, respectively), although amplification of the EGFR gene in patients with EGFR wild-type disease was not found to be predictive of treatment outcomes, which was unexpected but not unprecedented. KRAS status was not found to affect outcomes. Further experience is required to refine the ReadMax methodology and fully establish its validity and robustness. In conclusion, the ReadMax scoring system to identify patients with EGFR FISH-positive NSCLC is a promising technique, which could improve treatment options and outcomes for patients with advanced NSCLC, in particular for EGFR wild-type tumours. PMID- 27499898 TI - Diagnostic value of H3F3A mutations in giant cell tumour of bone compared to osteoclast-rich mimics. AB - Driver mutations in the two histone 3.3 (H3.3) genes, H3F3A and H3F3B, were recently identified by whole genome sequencing in 95% of chondroblastoma (CB) and by targeted gene sequencing in 92% of giant cell tumour of bone (GCT). Given the high prevalence of these driver mutations, it may be possible to utilise these alterations as diagnostic adjuncts in clinical practice. Here, we explored the spectrum of H3.3 mutations in a wide range and large number of bone tumours (n = 412) to determine if these alterations could be used to distinguish GCT from other osteoclast-rich tumours such as aneurysmal bone cyst, nonossifying fibroma, giant cell granuloma, and osteoclast-rich malignant bone tumours and others. In addition, we explored the driver landscape of GCT through whole genome, exome and targeted sequencing (14 gene panel). We found that H3.3 mutations, namely mutations of glycine 34 in H3F3A, occur in 96% of GCT. We did not find additional driver mutations in GCT, including mutations in IDH1, IDH2, USP6, TP53. The genomes of GCT exhibited few somatic mutations, akin to the picture seen in CB. Overall our observations suggest that the presence of H3F3A p.Gly34 mutations does not entirely exclude malignancy in osteoclast-rich tumours. However, H3F3A p.Gly34 mutations appear to be an almost essential feature of GCT that will aid pathological evaluation of bone tumours, especially when confronted with small needle core biopsies. In the absence of H3F3A p.Gly34 mutations, a diagnosis of GCT should be made with caution. PMID- 27499900 TI - Cancer-testis antigens PRAME and NY-ESO-1 correlate with tumour grade and poor prognosis in myxoid liposarcoma. AB - Myxoid liposarcoma is the second most common liposarcoma. Although myxoid liposarcoma is relatively chemosensitive and thus a good candidate for chemotherapy, cases with relapsed or metastatic disease still have poor outcome. Here, we performed a gene microarray analysis to compare the gene expression profiles in six clinical myxoid liposarcoma samples and three normal adipose tissue samples, and to identify molecular biomarkers that would be useful as diagnostic markers or treatment targets in myxoid liposarcoma. This showed that the cancer-testis antigen PRAME was up-regulated in myxoid liposarcoma. We then performed immunohistochemical, western blotting and real-time polymerase chain reaction analyses to quantify the expression of PRAME and another cancer-testis antigen, NY-ESO-1, in clinical samples of myxoid liposarcoma (n = 93), dedifferentiated (n = 46), well-differentiated (n = 32) and pleomorphic liposarcomas (n = 14). Immunohistochemically, positivity for PRAME and NY-ESO-1 was observed in 84/93 (90%) and 83/93 (89%) of the myxoid liposarcomas, and in 20/46 (43%) and 3/46 (7%) of the dedifferentiated, 3/32 (9%) and 1/32 (3%) of the well-differentiated and 7/14 (50%) and 3/21 (21%) of the pleomorphic liposarcomas, respectively. High immunohistochemical expression of PRAME and/or NY-ESO-1 was significantly correlated with tumour diameter, the existence of tumour necrosis, a round-cell component of >5%, higher histological grade and advanced clinical stage. High PRAME and NY-ESO-1 expression correlated significantly with poor prognosis in a univariate analysis. The myxoid liposarcomas showed significantly higher protein and mRNA expression levels of PRAME and NY-ESO-1 (CTAG1B) than the other liposarcomas. In conclusion, PRAME and NY-ESO-1 (CTAG1B) were expressed in the vast majority of myxoid liposarcomas, and their high-level expression correlated with tumour grade and poor prognosis. Our results support the potential use of PRAME and NY-ESO-1 as ancillary parameters for differential diagnosis and as prognostic biomarkers, and indicate that the development of immunotherapy against these cancer-testis antigens in myxoid liposarcoma would be warranted. PMID- 27499901 TI - A 12-gene signature to distinguish colon cancer patients with better clinical outcome following treatment with 5-fluorouracil or FOLFIRI. AB - Currently, there is no marker in use in the clinical management of colon cancer to predict which patients will respond efficiently to 5-fluorouracil (5-FU), a common component of all cytotoxic therapies. Our aim was to develop and validate a multigene signature associated with clinical outcome from 5-FU therapy and to determine if it could be used to identify patients who might respond better to alternate treatments. Using a panel of 5-FU resistant and sensitive colon cancer cell lines, we identified 103 differentially expressed genes providing us with a 5-FU response signature. We refined this signature using a clinically relevant DNA microarray-based dataset of 359 formalin-fixed and paraffin-embedded (FFPE) colon cancer samples. We then validated the final signature in an external independent DNA microarray-based dataset of 316 stage III FFPE samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial. Finally, using a drug sensitivity database of 658 cell lines, we generated a list of drugs that could sensitize 5-FU resistant patients using our signature. We confirmed using the PETACC-3 dataset that the overall survival of subjects responding well to 5-FU did not improve with the addition of irinotecan (FOLFIRI; two-sided log-rank test p = 0.795). Conversely, patients who responded poorly to 5-FU based on our 12-gene signature were associated with better survival on FOLFIRI therapy (one-sided log-rank test p = 0.039). This new multigene signature is readily applicable to FFPE samples and provides a new tool to help manage treatment in stage III colon cancer. It also provides the first evidence that a subgroup of colon cancer patients can respond better to FOLFIRI than 5-FU treatment alone. PMID- 27499902 TI - In-depth molecular profiling of the biphasic components of uterine carcinosarcomas. AB - Uterine carcinosarcoma is a clinically aggressive malignancy composed of a mix of carcinomatous and sarcomatous elements. We performed targeted next-generation sequencing of 27 uterine cancer and sarcoma genes together with immunohistochemical analyses of selected proteins in 30 uterine carcinosarcomas. This included 13 cases in which the distinct carcinoma and sarcoma components were sequenced separately and 10 cases where the metastatic tumours were analysed in addition to the primary tumours. We identified non-synonymous somatic mutations in 90% of the cases, with 27 of 30 cases (90%) harbouring TP53 alterations. The PI3K pathway was the most commonly mutated signalling pathway with mutations identified in PIK3CA, PTEN, PIK3R1, and/or PIK3R2 in two-thirds of the cases. Mutations in FBXW7, PPP2R1A, ARID1A and KRAS were demonstrated in a minority of cases. In cases where the carcinomatous and sarcomatous components were separately analysed, most of the mutations identified were present in both components, indicating a common origin for the two components. Furthermore, the same TP53 alterations and/or PI3K pathway mutations seen in the primary tumours were also identified in the metastatic sites. Overall, carcinosarcomas exhibited heterogeneous molecular features that resemble the heterogeneity seen in endometrial carcinomas, with some showing endometrioid carcinoma-like and others showing serous carcinoma-like mutation profiles. While patients with serous-like tumours presented more frequently with advanced-stage disease compared to patients with endometrioid-like tumours, there was no statistical difference in outcome between the two groups. Our results provide insights into the oncogenesis of uterine carcinosarcoma and identify targetable mutations that represent early oncogenic events. The findings of the different molecular types of uterine carcinosarcoma that parallel the different molecular types in endometrial carcinoma may have future treatment implications with targeted therapies. PMID- 27499903 TI - Increased proliferation in atypical hyperplasia/endometrioid intraepithelial neoplasia of the endometrium with concurrent inactivation of ARID1A and PTEN tumour suppressors. AB - Uterine endometrioid carcinoma is the most common neoplastic disease in the female genital tract and develops from a common precursor lesion, atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN). Although the genomic landscape of endometrioid carcinoma has been recently revealed, the molecular alterations that contribute to tumour progression from AH/EIN to carcinoma remain to be elucidated. In this study, we used immunohistochemistry to determine if loss of expression of two of the most commonly mutated tumour suppressors in endometrioid carcinoma, PTEN and ARID1A, was associated with increased proliferation in AH/EIN. We found that 80 (70%) of 114 cases exhibited decreased or undetectable PTEN and 17 (15%) of 114 cases had focal loss of ARID1A staining. ARID1A loss was focal, while PTEN loss was diffuse, and all specimens with ARID1A loss had concurrent PTEN loss (p = 0.0003). Mapping the distribution of PTEN and ARID1A staining in the same specimens demonstrated that all AH/EIN areas with ARID1A loss were geographically nested within the areas of PTEN loss. A significant increase in the proliferative activity was observed in areas of AH/EIN with concurrent loss of PTEN and ARID1A compared to immediately adjacent AH/EIN areas showing only PTEN loss. In a cell culture system, co-silencing of ARID1A and PTEN in human endometrial epithelial cells increased cellular proliferation to a greater degree than silencing either ARID1A or PTEN alone. These results suggest an essential gatekeeper role for ARID1A that prevents PTEN inactivation from promoting cellular proliferation in the transition of pre cancerous lesions to uterine endometrioid carcinoma. PMID- 27499905 TI - Somatic mutation in PIK3CA is a late event in cervical carcinogenesis. AB - Somatic mutations in cervical intraepithelial neoplasia (CIN) are largely unknown. Here, we profiled 35 cervical carcinomas and 23 CIN grade 2/3 (CIN2/3) for mutations in 48 cancer-related genes using a Next Generation Sequencing-based cancer panel. PIK3CA exon 9 was the most frequently mutated locus in cervical carcinoma and the only mutated locus detected in CIN2/3. These PIK3CA exon 9 mutation findings were verified in a large, independent series (n = 647) covering all stages of cervical carcinogenesis using high resolution melting-guided Sanger sequencing. PIK3CA exon 9 mutation frequency was 37.1% (13/35; 95%CI 21.2-54.0%) in cervical carcinoma, and 2.4% (5/209; 95%CI 0.5-4.7%) in CIN3. No PIK3CA exon 9 mutations were detected in CIN2 (0/144), CIN1 (0/154) and normal cervix (0/105). In a third series of 46 CIN2/3 lesions from women with a known 5-year history of preceding high-risk human papillomavirus (hrHPV) infection, detection of PIK3CA exon 9 mutation was confined to 2 (5.4%; 95%CI 0.0-13.2%) CIN3 lesions with preceding hrHPV infection >=5 years, and was absent in those with a short duration (<5 years) of preceding hrHPV infection. In conclusion, somatic mutation in PIK3CA represents a late event during cervical carcinogenesis, detected in a substantial subset of cervical carcinoma, but only in a minority of CIN3. PMID- 27499904 TI - The pathology and pathobiology of bicuspid aortic valve: State of the art and novel research perspectives. AB - Bicuspid aortic valve is the most prevalent cardiac valvular malformation. It is associated with a high rate of long-term morbidity including development of calcific aortic valve disease, aortic regurgitation and concomitant thoracic aortic aneurysm and dissection. Recently, basic and translational studies have identified some key processes involved in the development of bicuspid aortic valve and its morbidity. The development of aortic valve disease and thoracic aortic aneurysm and dissection is the result of complex interactions between genotypes, environmental risk factors and specific haemodynamic conditions created by bicuspid aortic valve anatomy. Herein, we review the pathobiology of bicuspid aortic valve with a special emphasis on translational aspects of these basic findings. Important but unresolved problems in the pathology of bicuspid aortic valve and thoracic aortic aneurysm and dissection are discussed, along with the molecular processes involved. PMID- 27499906 TI - Biphasic components of sarcomatoid clear cell renal cell carcinomas are molecularly similar to each other, but distinct from, non-sarcomatoid renal carcinomas. AB - Sarcomatoid transformation, wherein an epithelioid carcinomatous tumour component coexists with a sarcomatoid histology, is a predictor of poor prognosis in clear cell renal cell carcinoma. Our understanding of sarcomatoid change has been hindered by the lack of molecular examination. Thus, we sought to characterize molecularly the biphasic epithelioid and sarcomatoid components of sarcomatoid clear cell renal cell carcinoma and compare them to non-sarcomatoid clear cell renal cell carcinoma. We examined the transcriptome of the epithelioid and sarcomatoid components of advanced stage sarcomatoid clear cell renal cell carcinoma (n=43) and non-sarcomatoid clear cell renal cell carcinoma (n=37) from independent discovery and validation cohorts using the cDNA microarray and RNA seq platforms. We analyzed DNA copy number profiles, generated using SNP arrays, from patients with sarcomatoid clear cell renal cell carcinoma (n=10) and advanced non-sarcomatoid clear cell renal cell carcinoma (n=155). The epithelioid and sarcomatoid components of sarcomatoid clear cell renal cell carcinoma had similar gene expression and DNA copy number signatures that were, however, distinct from those of high-grade, high-stage non-sarcomatoid clear cell renal cell carcinoma. Prognostic clear cell renal cell carcinoma gene expression profiles were shared by the biphasic components of sarcomatoid clear cell renal cell carcinoma and the sarcomatoid component showed a partial epithelial-to mesenchymal transition signature. Our genome-scale microarray-based transcript data were validated in an independent set of sarcomatoid and non-sarcomatoid clear cell renal cell carcinomas using RNA-seq. Sarcomatoid clear cell renal cell carcinoma is molecularly distinct from non-sarcomatoid clear cell renal cell carcinoma, with its genetic programming largely shared by its biphasic morphological components. These data explain why a low percentage of sarcomatoid histology augurs a poor prognosis; suggest the need to modify the pathological grading system and introduce the potential for candidate biomarkers to detect sarcomatoid change preoperatively without specifically sampling the histological sarcomatoid component. PMID- 27499907 TI - Classical pathology and mutational load of breast cancer - integration of two worlds. AB - Breast cancer is a complex molecular disease comprising several biological subtypes. However, daily routine diagnosis is still based on a small set of well characterized clinico-pathological variables. Here, we try to link the two worlds of surgical pathology and multilayered molecular profiling by analyzing the relationships between clinico-pathological phenotypes and mutational loads of breast cancer. We evaluated the number of mutated genes with somatic non-silent mutations in different subgroups of breast cancer based on clinico-pathological, including immunohistochemical and tumour characteristics. The analysis was performed for a cohort of 687 primary breast cancer patients with mutational profiling, gene expression and clinico-pathological data available from The Cancer Genome Atlas (TCGA) project. The number of mutated genes was strongly positively associated with higher tumour grade (p = 1.4e-14) and with the different immunohistochemical and PAM50 molecular subtypes of breast cancer (p = 1.4e-10 and p = 4.3e-10, respectively). We observed significant associations (|R| > 0.4) between the abundance of mutated genes and expression levels of genes related to proliferation in the overall cohort and hormone receptor positive cohort, including the Recurrence Score gene signature (e.g., MYBL2 and BIRC5). Specific mutated genes (TP53, NCOR1, NF1, PTPRD and RB1) were highly significantly associated with high loads of mutated genes. Multivariate analysis for overall survival (OS) revealed a worse survival for patients with high numbers of mutated genes (hazard ratio = 4.6, 95% CI: 1.0 - 20.0, p = 0.044). Here, we report a strong association of the number of mutated genes with immunohistochemical and PAM50 subtypes and tumour grade in breast cancer. We provide evidence that specific levels of the mutational load underlie different morphological and biological phenotypes, which collectively constitute the current basis of pathological diagnosis. Our study is a step towards genomics informed breast pathology and will provide a basis for future studies in this field bridging the gap between morphology, tumour biology and medical oncology. PMID- 27499908 TI - HMGA2 expression distinguishes between different types of postpubertal testicular germ cell tumour. AB - The group of postpubertal testicular germ cell tumours encompasses lesions with highly diverse differentiation - seminomas, embryonal carcinomas, yolk sac tumours, teratomas and choriocarcinomas. Heterogeneous differentiation is often present within individual tumours and the correct identification of the components is of clinical relevance. HMGA2 re-expression has been reported in many tumours, including testicular germ cell tumours. This is the first study investigating HMGA2 expression in a representative group of testicular germ cell tumours with the highly sensitive method of quantitative real-time PCR as well as with immunohistochemistry. The expression of HMGA2 and HPRT was measured using quantitative real-time PCR in 59 postpubertal testicular germ cell tumours. Thirty specimens contained only one type of tumour and 29 were mixed neoplasms. With the exception of choriocarcinomas, at least two pure specimens from each subgroup of testicular germ cell tumour were included. In order to validate the quantitative real-time PCR data and gather information about the localisation of the protein, additional immunohistochemical analysis with an antibody specific for HMGA2 was performed in 23 cases. Expression of HMGA2 in testicular germ cell tumours depended on the histological differentiation. Seminomas and embryonal carcinomas showed no or very little expression, whereas yolk sac tumours strongly expressed HMGA2 at the transcriptome as well as the protein level. In teratomas, the expression varied and in choriocarcinomas the expression was moderate. In part, these results contradict data from previous studies but HMGA2 seems to represent a novel marker to assist pathological subtyping of testicular germ cell tumours. The results indicate a critical role in yolk sac tumours and some forms of teratoma. PMID- 27499909 TI - Regulation of macroautophagy in amiodarone-induced pulmonary fibrosis. AB - Amiodarone (AD) is an iodinated benzofuran derivative, especially known for its antiarrhythmic properties. It exerts serious side-effects even in patients receiving low doses. AD is well-known to induce apoptosis of type II alveolar epithelial cells (AECII), a mechanism that has been suggested to play an important role in AD-induced lung fibrosis. The precise molecular mechanisms underlying this disease are, however, still unclear. Because of its amphiphilic nature, AD becomes enriched in the lysosomal compartments, affecting the general functions of these organelles. Hence, in this study, we aimed to assess the role of autophagy, a lysosome-dependent homeostasis mechanism, in driving AECII apoptosis in response to AD. In vitro, AD-treated MLE12 and primary AECII cells showed increased proSP-C and LC3B positive vacuolar structures and underwent LC3B dependent apoptosis. In addition, AD-induced autophagosome-lysosome fusion and increased autophagy flux were observed. In vivo, in C57BL/6 mice, LC3B was localised at the limiting membrane of lamellar bodies, which were closely connected to the autophagosomal structures in AECIIs. Our data suggest that AD causes activation of macroautophagy in AECIIs and extensive autophagy-dependent apoptosis of alveolar epithelial cells. Targeting the autophagy pathway may therefore represent an attractive treatment modality in AD-induced lung fibrosis. PMID- 27499910 TI - High expression of podoplanin in squamous cell carcinoma of the tongue occurs predominantly in patients <=40 years but does not correlate with tumour spread. AB - More than 30% of patients with squamous cell carcinoma (SCC) of the mobile tongue have clinically undetectable lymph node metastasis. Tumour cells can spread as single cells or collectively. A protein known to play a role in both processes is podoplanin, which is expressed in endothelial cells not only in lymph vessels but also in some aggressive tumours with high invasive and metastatic potential. Here we studied samples from 129 patients with primary SCC of the tongue for expression of podoplanin using immunohistochemistry. mRNA levels were analysed in another 27 cases of tongue SCC with adjacent clinically tumour-free tongue tissue and 14 tongue samples from healthy donors. Higher levels of podoplanin were seen in tumours compared to both normal tongue and clinically normal tongue in the tumour vicinity. No association was found between levels of podoplanin, presence of lymph node metastases or other clinical factors. Patients aged 40 or less were more likely to express high levels of podoplanin protein compared to older patients (p = 0.027). We conclude that levels of podoplanin in primary tongue SCCs are not associated with lymph node metastases. However, tongue SCCs arising in young patients (<=40 years of age) are more likely to express high levels of podoplanin than tongue SCCs that arise in the more elderly. The data suggest that podoplanin has a distinctive role in young patients, who are known to have a poor prognosis: these patients may, therefore, benefit from podoplanin inhibitory therapies. PMID- 27499911 TI - The molecular landscape of extraskeletal osteosarcoma: A clinicopathological and molecular biomarker study. AB - Extraskeletal osteosarcoma (ESOSA) is a rare soft tissue neoplasm representing <5% of osteosarcomas and <1% of all soft-tissue sarcomas. Herein, we investigate the clinicopathological and molecular features of ESOSA and explore potential parameters that may affect outcome. Thirty-two cases were retrieved and histomorphology was reviewed. Clinical history and follow-up were obtained through electronic record review. DNA from formalin-fixed paraffin-embedded (FFPE) tissue was extracted and processed from 27 cases. Genome-wide DNA copy number (CN) alterations and allelic imbalances were analyzed by single nucleotide polymorphism array using Affymetrix OncoScan FFPE Assay. Massive high-throughput deep parallel sequencing was performed using a customized panel targeting 410 cancer genes. Log rank, Fisher's exact test and Cox proportional hazards were used for statistical analysis. In this series of 32 patients (male n = 12, female n = 20), the average age was 66 years (19-93) and median follow up was 24 months (range 6-120 months). Frequent genomic alterations included CN losses in tumour suppressor genes including CDKN2A (70%), TP53 (56%) and RB1 (49%). Mutations affecting methylation/demethylation, chromatin remodeling and WNT/SHH pathways were identified in 40%, 27%, and 27%, respectively. PIK3CA and TERT promoter variant mutations were identified in 11% of the cases. Cases harbouring simultaneous TP53 and RB1 biallelic CN losses were associated with worse overall survival and local recurrence (p = 0.04, p = 0.02, respectively). CDKN2A losses and positive margins were also associated with worse overall survival (p = 0.002; p = 0.03, respectively). Our findings suggest that age above 60, positive margin status, simultaneous biallelic TP53 and RB1 losses and CDKN2A loss are associated with a worse outcome in ESOSA. Comparison between conventional paediatric osteosarcoma and ESOSA shows that, while both share genetic similarities, there are notable dissimilarities and mechanistic differences in the molecular pathways involved in ESOSA. PMID- 27499912 TI - The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer. AB - Giving strong prognostic information, T-cell infiltration is on the verge of becoming an additional component in the routine clinical setting for classification of colorectal cancer (CRC). With a view to further improving the tools for prognostic evaluation, we have studied how Th1 lymphocyte infiltration correlates with prognosis not only by quantity, but also by subsite, within CRCs with different molecular characteristics (microsatellite instability, CpG island methylator phenotype status, and BRAF and KRAS mutational status). We evaluated the Th1 marker T-bet by immunohistochemistry in 418 archival tumour tissue samples from patients who underwent surgical resection for CRC. We found that a high number of infiltrating Th1 lymphocytes is strongly associated with an improved prognosis in patients with CRC, irrespective of intratumoural subsite, and that both extent of infiltration and patient outcome differ according to molecular subgroup. In brief, microsatellite instability, CpG island methylator phenotype-high and BRAF mutated tumours showed increased infiltration of Th1 lymphocytes, and the most pronounced prognostic effect of Th1 infiltration was found in these tumours. Interestingly, BRAF mutated tumours were found to be more highly infiltrated by Th1 lymphocytes than BRAF wild-type tumours whereas the opposite was seen for KRAS mutated tumours. These differences could be explained at least partly by our finding that BRAF mutated, in contrast to KRAS mutated, CRC cell lines and tumour specimens expressed higher levels of the Th1-attracting chemokine CXCL10, and reduced levels of CCL22 and TGFB1, stimulating Th2/Treg recruitment and polarisation. In conclusion, the strong prognostic importance of Th1 lymphocyte infiltration in CRC was found at all subsites evaluated, and it remained significant in multivariable analyses, indicating that T-bet may be a valuable marker in the clinical setting. Our results also indicate that T-bet is of value when analysed in molecular subgroups of CRC, allowing identification of patients with especially poor prognosis who are in need of extended treatment. PMID- 27499913 TI - Genotyping confirms inheritance of the rare At(a-) type in a case of haemolytic disease of the newborn. AB - The At(a) blood group antigen (now AUG2 in the Augustine system) is a high frequency antigen with negative phenotype At(a-) found only in individuals of African ancestry. In a twin pregnancy, the fifth pregnancy in a woman of African origin, serological investigations confirmed that the mother was At(a-) and anti At(a) was detected. DNA samples were exome sequenced and alignment was performed to allow variant calling. It was confirmed that the single nucleotide polymorphism, rs45458701, within the SLC29A1 gene encoding the ENT1 protein, recently reported to be a basis of the At(a-) phenotype was also the basis of the phenotype in this family. The reagents for serological analysis required to identify the rare blood type present in this mother are held in only a few reference laboratories worldwide. This case highlights the utility of genetic methods in resolving complex investigations involving blood grouping and demonstrates that genotyping of variants associated with blood types present in specific ethnic groups may be the fastest method available for identification of the basis of fetomaternal incompatibilities. PMID- 27499914 TI - Nottingham Prognostic Index Plus: Validation of a clinical decision making tool in breast cancer in an independent series. AB - The Nottingham Prognostic Index Plus (NPI+) is a clinical decision making tool in breast cancer (BC) that aims to provide improved patient outcome stratification superior to the traditional NPI. This study aimed to validate the NPI+ in an independent series of BC. Eight hundred and eighty five primary early stage BC cases from Edinburgh were semi-quantitatively assessed for 10 biomarkers [Estrogen Receptor (ER), Progesterone Receptor (PgR), cytokeratin (CK) 5/6, CK7/8, epidermal growth factor receptor (EGFR), HER2, HER3, HER4, p53, and Mucin 1] using immunohistochemistry and classified into biological classes by fuzzy logic-derived algorithms previously developed in the Nottingham series. Subsequently, NPI+ Prognostic Groups (PGs) were assigned for each class using bespoke NPI-like formulae, previously developed in each NPI+ biological class of the Nottingham series, utilising clinicopathological parameters: number of positive nodes, pathological tumour size, stage, tubule formation, nuclear pleomorphism and mitotic counts. Biological classes and PGs were compared between the Edinburgh and Nottingham series using Cramer's V and their role in patient outcome prediction using Kaplan-Meier curves and tested using Log Rank. The NPI+ biomarker panel classified the Edinburgh series into seven biological classes similar to the Nottingham series (p > 0.01). The biological classes were significantly associated with patient outcome (p < 0.001). PGs were comparable in predicting patient outcome between series in Luminal A, Basal p53 altered, HER2+/ER+ tumours (p > 0.01). The good PGs were similarly validated in Luminal B, Basal p53 normal, HER2+/ER- tumours and the poor PG in the Luminal N class (p > 0.01). Due to small patient numbers assigned to the remaining PGs, Luminal N, Luminal B, Basal p53 normal and HER2+/ER- classes could not be validated. This study demonstrates the reproducibility of NPI+ and confirmed its prognostic value in an independent cohort of primary BC. Further validation in large randomised controlled trial material is warranted. PMID- 27499915 TI - FMNL2/FMNL3 formins are linked with oncogenic pathways and predict melanoma outcome. AB - While most early (stage I-II) melanomas are cured by surgery, recurrence is not uncommon. Prognostication by current clinicopathological parameters does not provide sufficient means for identifying patients who are at risk of developing metastases and in need of adjuvant therapy. Actin-regulating formins may account for invasive properties of cancer cells, including melanoma. Here, we studied formin-like protein 2 and 3 (FMNL2 and FMNL3) in melanoma by analysing their role in the invasive properties of melanoma cells and by evaluating whether FMNL2 expression is associated with melanoma outcome. Immunohistochemical characterization of FMNL2 in a cohort of 175 primary cutaneous stage I-II melanomas indicated that high FMNL2 reactivity correlates with poor outcome as evaluated by recurrence free survival (p < 0.0001) or disease specific survival (p < 0.0001). In multivariate analysis, Breslow's thickness (p < 0.05) and FMNL2 expression (p < 0.001) remained as independent prognostic factors. Cellular studies revealed that FMNL2 is a component of filopodia in many melanoma cell lines. Inhibition of either FMNL2 or the closely related FMNL3 affected the maintenance of melanoma cell morphology and reduced migration. Finally, inhibition of the BRAF, PI3K and MAPK oncogenic pathways markedly reduced expression of both FMNL2 and FMNL3 in melanoma cells. The results suggest a major role for FMNL2/FMNL3 formins in melanoma biology and raise the possibility that the novel targeted melanoma drugs may interfere with the cellular properties regulated by these formins. PMID- 27499916 TI - HR23b expression is a potential predictive biomarker for HDAC inhibitor treatment in mesenchymal tumours and is associated with response to vorinostat. AB - Histone deacetylases (HDAC) are key players in epigenetic regulation of gene expression and HDAC inhibitor (HDACi) treatment seems to be a promising anticancer therapy in many human tumours, including soft tissue sarcomas. HR23b has been shown to be a potential biomarker for sensitivity to HDACi therapy in cutaneous T-cell lymphoma and hepatocellular carcinoma. We aimed to evaluate HR23b as a candidate biomarker for HDACi response in sarcomas and gastrointestinal stromal tumours (GIST). Therefore, HR23b expression was analysed comprehensively by western blot in sarcoma and GIST cell lines covering all major clinically relevant subtypes. MTT assay and ApoTox-Glo(TM) Triplex assay were performed after treatment with vorinostat, belinostat, mocetinostat and entinostat. HR23b protein expression was measured under HDACi treatment. Furthermore, HR23b expression levels were immunohistochemically determined in a large set of 523 clinical samples from sarcoma and GIST patients. Western blot analyses showed that sarcomas differ significantly in their expression of HR23b protein. All HDACi were able to regulate proliferation and apoptosis in vitro. Sensitivity to vorinostat correlated significantly with HR23b protein expression. Immunohistochemical prevalence screening in clinical samples of relevant adult type tumours revealed that 12.5% of sarcomas (among them malignant peripheral nerve sheath tumours, pleomorphic liposarcomas, leiomyosarcomas, dedifferentiated liposarcomas, synovial sarcomas and angiosarcomas) and 23.2% of GIST show high HR23b expression. Therefore, HDACi have antiproliferative and proapoptotic effects in sarcomas depending on the expression level of HR23b. These findings suggest that HR23b represents a candidate biomarker for HDACi sensitivity in certain sarcoma types and in GIST. PMID- 27499917 TI - The pathological and biochemical identification of possible seed-lesions of transmitted transthyretin amyloidosis after domino liver transplantation. AB - The most serious issue in domino liver transplantation (DLT) using liver grafts from patients with transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) is the development of iatrogenic transmitted amyloidosis (de novo amyloidosis) in DLT-recipients. However, little is known regarding the mechanisms of the initial stage of amyloid formation in these recipients. We detected initial lesions (possible seed-lesions) of this iatrogenic amyloidosis in two recipients following liver grafting from FAP patients. Patient 1 underwent DLT at age 65 from an FAP patient with a Val30Met TTR variant and patient 2 received DLT from an FAP patient with a Val30Leu TTR variant at age 32. Patient 2 was started on diflunisal administration from 4 years after DLT. While neither patient had symptoms of FAP, small amyloid deposits were detected on the gastroduodenal mucosae 14 months and 12 years after DLT in patient 1 and patient 2, respectively. The amyloid was analyzed using a laser microdissection system and tandem mass spectrometry. Biochemical analysis indicated that the amyloid was composed mostly of variant TTR produced from the transplanted liver in both patients. In patient 1, wild-type TTR amyloid was detectable in the duodenal mucosa obtained 2 years after DLT. This is the first study to successfully capture the pathological and biochemical features of initial-stage amyloid lesions in DLT recipients. The findings clearly indicate that amyloid deposition can start by deposition of variant TTR followed by deposition of wild-type TTR, and blocking of amyloid seed formation from variant TTR may be a key to prevent or delay the development of DLT-associated amyloidosis. PMID- 27499918 TI - Gene expression analysis of biopsy samples reveals critical limitations of transcriptome-based molecular classifications of hepatocellular carcinoma. AB - Molecular classification of hepatocellular carcinomas (HCC) could guide patient stratification for personalized therapies targeting subclass-specific cancer 'driver pathways'. Currently, there are several transcriptome-based molecular classifications of HCC with different subclass numbers, ranging from two to six. They were established using resected tumours that introduce a selection bias towards patients without liver cirrhosis and with early stage HCCs. We generated and analyzed gene expression data from paired HCC and non-cancerous liver tissue biopsies from 60 patients as well as five normal liver samples. Unbiased consensus clustering of HCC biopsy profiles identified 3 robust classes. Class membership correlated with survival, tumour size and with Edmondson and Barcelona Clinical Liver Cancer (BCLC) stage. When focusing only on the gene expression of the HCC biopsies, we could validate previously reported classifications of HCC based on expression patterns of signature genes. However, the subclass-specific gene expression patterns were no longer preserved when the fold-change relative to the normal tissue was used. The majority of genes believed to be subclass specific turned out to be cancer-related genes differentially regulated in all HCC patients, with quantitative rather than qualitative differences between the molecular subclasses. With the exception of a subset of samples with a definitive beta-catenin gene signature, biological pathway analysis could not identify class specific pathways reflecting the activation of distinct oncogenic programs. In conclusion, we have found that gene expression profiling of HCC biopsies has limited potential to direct therapies that target specific driver pathways, but can identify subgroups of patients with different prognosis. PMID- 27499919 TI - Molecular classification of thyroid lesions by combined testing for miRNA gene expression and somatic gene alterations. AB - Multiple molecular markers contribute to the pathogenesis of thyroid cancer and can provide valuable information to improve disease diagnosis and patient management. We performed a comprehensive evaluation of miRNA gene expression in diverse thyroid lesions (n = 534) and developed predictive models for the classification of thyroid nodules, alone or in combination with genotyping. Expression profiling by reverse transcription-quantitative polymerase chain reaction in surgical specimens (n = 257) identified specific miRNAs differentially expressed in 17 histopathological categories. Eight supervised machine learning algorithms were trained to discriminate benign from malignant lesions and evaluated for accuracy and robustness. The selected models showed invariant area under the receiver operating characteristic curve (AUC) in cross validation (0.89), optimal AUC (0.94) in an independent set of preoperative thyroid nodule aspirates (n = 235), and classified 92% of benign lesions as low risk/negative and 92% of malignant lesions as high risk/positive. Surgical and preoperative specimens were further tested for the presence of 17 validated oncogenic gene alterations in the BRAF, RAS, RET or PAX8 genes. The miRNA-based classifiers complemented and significantly improved the diagnostic performance of the 17-mutation panel (p < 0.001 for McNemar's tests). In a subset of resected tissues (n = 54) and in an independent set of thyroid nodules with indeterminate cytology (n = 42), the optimized ThyraMIR Thyroid miRNA Classifier increased diagnostic sensitivity by 30-39% and correctly classified 100% of benign nodules negative by the 17-mutation panel. In contrast, testing with broad targeted next generation sequencing panels decreased diagnostic specificity by detecting additional mutations of unknown clinical significance in 19-39% of benign lesions. Our results demonstrate that, independent of mutational status, miRNA expression profiles are strongly associated with altered molecular pathways underlying thyroid tumorigenesis. Combined testing for miRNA gene expression and well-established somatic gene alterations is a novel diagnostic strategy that can improve the preoperative diagnosis and surgical management of patients with indeterminate thyroid nodules. PMID- 27499920 TI - Fluorescence imaging to localize head and neck squamous cell carcinoma for enhanced pathological assessment. AB - Accurately identifying close or positive margins in real-time permits re-excision during surgical procedures. Intraoperative assessment of margins via gross examination and frozen section is a widely used tool to assist the surgeon in achieving complete resection. While this methodology permits diagnosis of freshly resected tissue, the process is fraught with misinterpretation and sampling errors. During fluorescence-guided surgery, an exogenous fluorescent agent specific for the target disease is imaged in order to navigate the surgical excision. As this technique quickly advances into the clinic, we hypothesize that the disease-specific fluorescence inherently contained within the resected tissues can be used to guide histopathological assessment. To evaluate the feasibility of fluorescence-guided pathology, we evaluated head and neck squamous cell carcinoma tumour specimens and margins resected from animals and patients after systemic injection of cetuximab-IRDye800CW. In a preclinical model of luciferase-positive tumour resection using bioluminescence as the gold standard, fluorescence assessment determined by closed-field fluorescence imaging of fresh resected margins accurately predicted the presence of disease in 33/39 positive margins yielding an overall sensitivity of 85%, specificity of 95%, positive predictive value (PPV) of 94%, and a negative predictive value (NPV) of 87%, which was superior to both surgical assessment (54%, 61%, 57%, and 58%) and pathological assessment (49%, 95%, 91%, and 66%), respectively. When the power of the technique was evaluated using human-derived tumour tissues, as little as 0.5mg (1mm(3)) of tumour tissue was identified (tumour-to-background-ratio:5.2). When the sensitivity/specificity of fluorescence-guided pathology was determined using traditional histological assessment as the gold standard in human tissues obtained during fluorescence-guided surgery, the technique was highly accurate with a sensitivity of 91%, specificity of 85%, PPV of 81%, and NPV of 93% for 90 human-derived samples. This approach can be used as a companion to the pathologist, eliminating confounding factors while impacting surgical intervention and patient management. PMID- 27499922 TI - The molecular characteristics of colonic neoplasms in serrated polyposis: a systematic review and meta-analysis. AB - Serrated polyposis is a rare disorder characterised by the presence of multiple serrated polyps in the large intestine, and an increased personal and familial risk of colorectal cancer. Knowledge of the molecular characteristics of colonic lesions which develop in this syndrome is fragmented, making it difficult to understand the underlying genetic basis of this condition. We conducted a systematic review and meta-analysis of all studies which evaluated the molecular characteristics of colorectal neoplasms found in individuals with serrated polyposis. We identified 4561 potentially relevant studies, but due to a lack of consensus in the reporting of findings, only fourteen studies were able to be included in the meta-analysis. BRAF mutation was found in 73% (95% CI 65-80%) of serrated polyps, 0% (95% CI 0-3%) of conventional adenomas and 49% (95%CI 33-64%) of colorectal cancers. In contrast, KRAS mutation was present in 8% (95% CI 5 11%) of serrated polyps, 3% (95% CI 0-13%) of conventional adenomas and 6% (95% CI 0-13%) of colorectal cancers. Absence of MLH1 immunostaining was found in 3% (95% CI 0-10%) of serrated polyps and 53% (95% CI 36-71%) of colorectal cancers. Overall, microsatellite instability was found in 40% (95% CI 18-64%) of colorectal cancers arising in the setting of serrated polyposis. Our results indicate that diverse molecular pathways are likely to contribute to the increased predisposition for colorectal cancer in individuals with serrated polyposis. We also propose a set of minimum standards for the reporting of future research in serrated polyposis as this is a rare syndrome and collation of research findings from different centres will be essential to identify the molecular mechanisms involved in the pathogenesis of this condition. PMID- 27499921 TI - Inflammatory response in serrated precursor lesions of the colon classified according to WHO entities, clinical parameters and phenotype-genotype correlation. AB - Studies on traditional serrated adenoma (TSA) and sessile serrated adenoma with dysplasia (SSA-D) are rare due to the low frequency of these lesions, which are well defined by the latest WHO classification. However, introducing new morphological criteria such as intra-epithelial lymphocytes (IELs) might facilitate colorectal polyp diagnoses. Additionally, the phenotype-genotype correlation needs to be updated as the terminology has repeatedly changed. This study analysed 516 polyps, consisting of 118 classical adenomas (CAD), 116 hyperplastic polyps (HPP), 179 SSAs, 41 SSA-Ds, and 62 TSAs. The lesions were analysed in relation to the patients' clinical parameters including gender, age, localisation, and size. The inflammatory background of the polyps was quantified and BRAF and KRAS mutations as well as MLH1 and CDKN2A promoter methylation were assessed. In multivariate analyses, an increase in IELs was an independent and robust new criterion for the diagnosis of SSA-D (p < 0.001). Superficial erosions and acute neutrophil granulocytes led to reactive changes potentially resembling dysplasia. KRAS and BRAF mutations were associated with CAD/TSA and HPP/SSA, respectively. However, almost half of TSAs had a BRAF mutation and were KRAS wild type. CDKN2A seems to precede MLH1 hyper-methylation within the serrated carcinogenesis model. The genotyping of WHO-based entities - and especially SSA - has sharpened in comparison to previously published data. TSAs can be sub-grouped according to their mutation status. Of note, the higher number of IELs in SSA-D reflects their close relationship to colorectal cancers with micro-satellite instability. Therefore, IELs might represent a new diagnostic tool for SSA-D. PMID- 27499924 TI - Novel translational model of resolving inflammation triggered by UV-killed E. coli. AB - Whilst numerous studies investigating the aetiology of inflammatory diseases have been performed in rodents, the applicability of these data to human pathophysiology is frequently debated. Regardless of the strengths and weaknesses of rodent models in biomedical research, there is a need to develop models of experimental inflammation in humans. Here, we describe a self-resolving acute inflammatory response triggered by the intradermal injection of UV-killed Escherichia coli into the forearm of healthy volunteers. Cells and exudates were harvested from onset to resolution by applying negative pressure over the inflamed site. Onset was characterized by high blood flow, neutrophilia and peak levels of pro-inflammatory cytokines, whilst resolution showed a decline in blood blow, reduction in neutrophils, increase in monocytes/macrophages and waning of classic pro-inflammatory cytokine levels. An anti-inflammatory effect, defined as suppression of onset phase events, was demonstrated by administering naproxen, a conventional non-steroidal anti-inflammatory drug. In summary, this model of resolving acute inflammation is minimally invasive, highly tractable and allows simultaneous investigation of the vascular response, cellular trafficking and chemical mediator profile of onset and resolution phases of acute inflammation in humans. It can serve as a translational platform to provide mechanistic insights and to test the clinical efficacy of novel anti-inflammatory and pro-resolving drugs, and also as a tool in patients to explore inherent defects in resolution pathways. PMID- 27499923 TI - High-throughput automated scoring of Ki67 in breast cancer tissue microarrays from the Breast Cancer Association Consortium. AB - Automated methods are needed to facilitate high-throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large-scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performance in studies from the Breast Cancer Association Consortium. We utilized 166 TMAs containing 16,953 tumour cores representing 9,059 breast cancer cases, from 13 studies, with information on other clinical and pathological characteristics. TMAs were stained for Ki67 using standard immunohistochemical procedures, and scanned and digitized using the Ariol system. An automated algorithm was developed for the scoring of Ki67, and scores were compared to computer assisted visual (CAV) scores in a subset of 15 TMAs in a training set. We also assessed the correlation between automated Ki67 scores and other clinical and pathological characteristics. Overall, we observed good discriminatory accuracy (AUC = 85%) and good agreement (kappa = 0.64) between the automated and CAV scoring methods in the training set. The performance of the automated method varied by TMA (kappa range= 0.37-0.87) and study (kappa range = 0.39-0.69). The automated method performed better in satisfactory cores (kappa = 0.68) than suboptimal (kappa = 0.51) cores (p-value for comparison = 0.005); and among cores with higher total nuclei counted by the machine (4,000-4,500 cells: kappa = 0.78) than those with lower counts (50-500 cells: kappa = 0.41; p-value = 0.010). Among the 9,059 cases in this study, the correlations between automated Ki67 and clinical and pathological characteristics were found to be in the expected directions. Our findings indicate that automated scoring of Ki67 can be an efficient method to obtain good quality data across large numbers of TMAs from multicentre studies. However, robust algorithm development and rigorous pre- and post-analytical quality control procedures are necessary in order to ensure satisfactory performance. PMID- 27499925 TI - Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases: Identification of driver and passenger mutations. AB - The mutational profiles of primary colorectal cancers (CRCs) and corresponding ovarian metastases were compared. Using a custom-made next generation sequencing panel, 115 cancer-driving genes were analyzed in a cohort of 26 primary CRCs and 30 matching ovarian metastases (four with bilateral metastases). To obtain a complete overview of the mutational profile, low thresholds were used in bioinformatics analysis to prevent low frequency passenger mutations from being filtered out. A subset of variants was validated using Sanger and/or hydrolysis probe assays. The mutational landscape of CRC that metastasized to the ovary was not strikingly different from CRC in consecutive series. When comparing primary CRCs and their matching ovarian metastases, there was considerable overlap in the mutations of early affected genes. A subset of mutations demonstrated less overlap, presumably being passenger mutations. In particular, primary CRCs showed a substantially high number of passenger mutations. We also compared the primary CRCs and matching metastases for stratifying variants of six genes (KRAS, NRAS, BRAF, FBXW7, PTEN and PIK3CA) that select for established (EGFR directed) or future targeted therapies. In a total of 31 variants 12 were not found in either of the two locations. Tumours thus differed in the number of discordant variants between the primary tumours and matching metastases. Half of these discordant variants were definitive class 4/5 pathogenic variants. However, in terms of temporal heterogeneity, no clear relationship was observed between the number of discordant variants and the time interval between primary CRCs and the detection of ovarian metastases. This suggests that dormant metastases may be present from the early days of the primary tumours. PMID- 27499926 TI - Rapid and reliable diagnosis of Wilson disease using X-ray fluorescence. AB - Wilson's disease (WD) is a rare autosomal recessive disease due to mutations of the gene encoding the copper-transporter ATP7B. The diagnosis is hampered by the variability of symptoms induced by copper accumulation, the inconstancy of the pathognomonic signs and the absence of a reliable diagnostic test. We investigated the diagnostic potential of X-ray fluorescence (XRF) that allows quantitative analysis of multiple elements. Studies were performed on animal models using Wistar rats (n = 10) and Long Evans Cinnamon (LEC) rats (n = 11), and on human samples including normal livers (n = 10), alcohol cirrhosis (n = 8), haemochromatosis (n = 10), cholestasis (n = 6) and WD (n = 22). XRF experiments were first performed using synchrotron radiation to address the elemental composition at the cellular level. High-resolution mapping of tissue sections allowed measurement of the intensity and the distribution of copper, iron and zinc while preserving the morphology. Investigations were further conducted using a laboratory X-ray source for irradiating whole pieces of tissue. The sensitivity of XRF was highlighted by the discrimination of LEC rats from wild type even under a regimen using copper deficient food. XRF on whole formalin-fixed paraffin embedded needle biopsies allowed profiling of the elements in a few minutes. The intensity of copper related to iron and zinc significantly discriminated WD from other genetic or chronic liver diseases with 97.6% specificity and 100% sensitivity. This study established a definite diagnosis of Wilson's disease based on XRF. This rapid and versatile method can be easily implemented in a clinical setting. PMID- 27499927 TI - Increased MMP-7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia. AB - The molecular mechanisms underlying progressive liver fibrosis following surgical treatment of biliary atresia (BA) remain unclear. Our aim was to address hepatic gene and protein expression and serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) after successful portoenterostomy (PE), and relate them to histological signs of liver injury, clinical follow-up data and biochemical markers of hepatic function. LIver biopsies and serum samples were obtained from 25 children after successful PE at median age of 3.3 years. Serum MMP concentrations were determined by enzyme-linked immune sorbent assay. Hepatic gene expression of MMPs and TIMPs was analyzed using real-time reverse transcription PCR. Liver expression of MMP-7 and cytokeratin-7 was studied using immunohistochemistry. Despite effective clearance of biochemical and histological cholestasis following PE, BA patients showed increased hepatic gene expression of MMP-7 (29-fold, p < 0.001), MMP-2 (3.1-fold, p < 0.001), MMP-14 (1.7-fold, p = 0.007), and TIMP-1 (1.8-fold, p < 0.001), when compared to controls. Similar to a biliary epithelial marker cytokeratin-7, expression of MMP-7 localized in biliary epithelium of bile ducts and ductal proliferations and periportal hepatocytes and was increased (p < 0.001) in relation to controls. BA patients had 6-fold higher serum levels of MMP-7 (p < 0.001), which correlated positively with hepatic MMP-7 gene (r = 0.548, p = 0.007) and protein (r = 0.532, p = 0.007) expression. Patients showed a positive correlation between biliary MMP-7 expression and Metavir fibrosis stage (r = 0.605, p = 0.001) and portal fibrosis grade (r = 0.606, p = 0.001). Neither similarly increased MMP-7 expression nor correlation with liver fibrosis was observed in patients with intestinal failure-associated liver disease and comparable Metavir stage. In conclusion, our findings support an unique role of altered hepatic expression of MMP-7 in the progression of liver fibrosis after successful PE and introduce a potential therapeutic target to pharmacologically extend native liver survival by inhibiting MMP-7 hyperactivity. Serum MMP-7 may be a valuable postoperative prognostic tool in BA. PMID- 27499928 TI - Who's afraid of response bias? AB - Response bias (or criterion) contamination is insidious in studies of consciousness: that observers report they do not see a stimulus may not mean they have absolutely no subjective experience; they may be giving such reports in relative terms in the context of other stimuli. Bias-free signal detection theoretic measures provide an excellent method for avoiding response bias confounds, and many researchers correctly adopt this approach. However, here we discuss how a fixation on avoiding criterion effects can also be misleading and detrimental to fruitful inquiry. In a recent paper, Balsdon and Azzopardi (Absolute and relative blindsight. Consciousness and Cognition 2015; 32:79-91.) claimed that contamination by response bias led to flawed findings in a previous report of "relative blindsight". We argue that their criticisms are unfounded. They mistakenly assumed that others were trying (and failing) to apply their preferred methods to remove bias, when there was no such intention. They also dismissed meaningful findings because of their dependence on criterion, but such dismissal is problematic: many real effects necessarily depend on criterion. Unfortunately, these issues are technically tedious, and we discuss how they may have confused others to misapply psychophysical metrics and to draw questionable conclusions about the nature of TMS (transcranial magnetic stimulation)-induced blindsight. We conclude by discussing the conceptual importance of criterion effects in studies of conscious awareness: we need to treat them carefully, but not to avoid them without thinking. PMID- 27499929 TI - The signal processing architecture underlying subjective reports of sensory awareness. AB - What is the relationship between perceptual information processing and subjective perceptual experience? Empirical dissociations between stimulus identification performance and subjective reports of stimulus visibility are crucial for shedding light on this question. We replicated a finding that metacontrast masking can produce such a dissociation (Lau and Passingham, 2006), and report a novel finding that this paradigm can also dissociate stimulus identification performance from the efficacy with which visibility ratings predict task performance. We explored various hypotheses about the relationship between perceptual task performance and visibility rating by implementing them in computational models and using formal model comparison techniques to assess which ones best captured the unusual patterns in the data. The models fell into three broad categories: Single Channel models, which hold that task performance and visibility ratings are based on the same underlying source of information; Dual Channel models, which hold that there are two independent processing streams that differentially contribute to task performance and visibility rating; and Hierarchical models, which hold that a late processing stage generates visibility ratings by evaluating the quality of early perceptual processing. Taking into account the quality of data fitting and model complexity, we found that Hierarchical models perform best at capturing the observed behavioral dissociations. Because current theories of visual awareness map well onto these different model structures, a formal comparison between them is a powerful approach for arbitrating between the different theories. PMID- 27499930 TI - Strong correlation between lung ultrasound and chest computerized tomography imaging for the detection of acute lung injury/acute respiratory distress syndrome in rats. AB - BACKGROUND: Lung ultrasound (LUS) is a clinical imaging technique for diagnosing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In humans and several large animals, LUS demonstrates similar specificity and sensitivity to computerized tomography (CT) scanning. Current study evaluated the degree of agreement between LUS and CT imaging in characterizing ALI/ARDS in rats. METHODS: Thirty male Sprague-Dawley rats were imaged by LUS before randomization into three groups to receive intratracheal saline, 3 or 6 mg/kg LPS respectively (n=10). LUS and CT imaging was conducted 2 hours after instillation. Cross table analyses and kappa statistics were used to determine agreement levels between LUS and CT assessments of lung condition. RESULTS: Before instillation, rats presented with a largely A-pattern in LUS images, however, a significantly increase B-lines were observed in all groups after instillation and showed dose response to LPS or to saline. One rat treated with 6 mg/kg lipopolysaccharide (LPS) presented with lung consolidation. The agreement between the LUS and the CT in detecting the main characteristics of ALI/ARDS in rat was strong (r=0.758, P<0.01, k=0.737). CONCLUSIONS: In conclusion, LUS detects ALI/ARDS with high agreement with micro PET/CT scanning in a rat model, suggesting that LUS represents a positive refinement in rat ALI/ARDS disease models. PMID- 27499931 TI - Positive expression of protein chromosome 9 open reading frame 86 (C9orf86) correlated with poor prognosis in non-small cell lung cancer patients. AB - BACKGROUND: Chromosome 9 open reading frame 86 (C9orf86) is a novel subfamily of GTPases. Previous studies have implicated C9orf86 as a potential oncogene. METHODS: C9orf86 expression was detected in non-small cell lung cancer (NSCLC) cell lines and human bronchial epithelial (16HBE) cell lines by RT-PCR and western blotting. Immunohistochemistry (IHC) was used to detect 180 consecutive NSCLC specimens and 16 normal lung tissues. The correlation between C9orf86 expression and clinicopathological parameters was evaluated. Kaplan-Meier survival analysis and Cox hazards ratio models were used to estimate the effect of C9orf86 expression on survival. RESULTS: C9orf86 was expressed in the cytoplasm in 74 of 180 (41.11%) NSCLC specimens. In clinical pathology analysis, C9orf86 expression significantly correlated with lymph node metastasis and clinical stage significantly (P<0.05). Multivariable analysis confirmed that C9orf86 expression increased the risk of death after adjusting for other clinicopathological factors (P<0.01). Overall survival (OS) and disease-free survival (DFS) were significantly prolonged in the C9orf86 negative group compared to the C9orf86 positive group (P<0.001). Adjuvant chemotherapy prolonged OS and DFS in resected NSCLC patients with C9orf86 negative expression (P<0.001) but not C9orf86 positive. CONCLUSIONS: Positive expression of C9orf86 is an independent prognostic factor for NSCLC patients, and C9orf86 may serve as a prognostic biomarker for patients with NSCLC. PMID- 27499932 TI - Recognition of "aggressive" behavior in "indolent" ground glass opacity and mixed density lesions. AB - BACKGROUND: Radiologically characteristic ground-glass opacity (GGO) represents a special cohort of pulmonary adenocarcinomas that has been unanimously defined as biologically inert. Lymph node metastasis, however, occurs occasionally in these biologically "indolent" cancers. The incidence and underlying risk factors of nodal metastasis remain unknown. METHODS: All surgically removed GGO lesions between January 2008 and December 2014 were retrospectively reviewed from a single treatment institution. Pathologically-confirmed adenocarcinomas with systemic lymph node dissection or sampling were enrolled into the present study. All the lesions were classified into three groups according to the proportion of solid densities: group I, pure GGO; group II, 1% to 50%; and group III, 50% to 79%. Risk factor analysis of lymph node involvement was performed by multivariate logistic regression. RESULTS: Of the 867 patients eligible for this study, 553 (63.7%) presented as pure GGOs (Group I) and 314 (36.2%) were mixed GGOs, of which 160 (18.5%) were in group II and 154 (17.8%) in group III. Lymph node metastasis was confirmed in 25 patients, among these 25 cases, 11 (11/160) were group II and 14 (14/154) were group III; two of the 25 patients died from lung cancer metastases at their postoperative 23(rd) and 36(th) month, respectively. Statistical analysis revealed three predictors for lymph nodal metastasis: tumor size, preoperative serum carcinoembryonic antigen level and proportion of the mix density. CONCLUSIONS: A larger size, mixed GGOs with a higher proportion of solid component, and elevated serum CEA level were associated with a higher preference for nodal metastasis. PMID- 27499933 TI - A propensity matched comparison of effects between video assisted thoracoscopic single-port, two-port and three-port pulmonary resection on lung cancer. AB - BACKGROUND: To summarize our experiences of single-port, two-port vs. three-port VATS pulmonary resection for lung cancer patients. METHODS: Data of consecutive 1,553 patients who underwent video assisted thoracoscopic surgery (VATS) pulmonary resection for lung cancer in the Department of Thoracic Surgery of Cancer Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College between November 2014 and January 2016 were prospectively collected and analyzed. A propensity-matched analysis was used to compare the short-term outcomes of lung cancer patients who received VATS single-port, two-port and three-port pulmonary resection. RESULTS: There were 716 males and 837 females. The mean age was 58.90 years (range, 25-82 years) and the conversion rate was 2.7% (42/1,553) in this cohort. After propensity score matching, there were 207 patients in single-port and two-port group, and 680 patients in three-port group. Propensity-matched analysis demonstrated that there were no significant differences in duration of operation (129 vs. 131 min, P=0.689), intra-operative blood loss (63 vs. 70 mL, P=0.175), number of dissected lymph nodes (12 vs. 13, P=0.074), total hospital expense ($9,928 vs. $9,956, P=0.884) and cost of operation ($536 vs. $535, P=0.879) between VATS single-port, two-port and conventional three-port pulmonary resection groups. There was no significant difference in the complication rate between two groups (5.3% vs. 4.7%, P=0.220). However, compared with three-port group, patients who underwent single port and two-port experienced shorter postoperative length of stay (6.24 vs. 5.61 d, P=0.033), shorter duration of chest tube (4.92 vs. 4.25 d, P=0.008), and decreased volume of drainage (926 vs. 791 d, P=0.003). CONCLUSIONS: The short term outcomes between VATS single-port, two-port and conventional three-port groups for the surgical treatment of lung cancer were comparable. However, compared with three-port VATS pulmonary resection, single-port and two-port were associated with shorter postoperative length of stay, shorter duration of chest tube, and decreased volume of drainage. PMID- 27499934 TI - Prognostic factors in non-small cell lung cancer patients who received neoadjuvant therapy and curative resection. AB - BACKGROUND: Lung cancer is the leading cause of cancer deaths in the world, and more and more treatment modalities have been introduced in order to improve patients' survival. For patients with advanced non-small cell lung cancer (NSCLC), survival prognosis is poor and multimodality neoadjuvant therapies are given to improve patients' survival. However, the possibility of occult metastases may lead to discrepancy between clinical and pathologic staging and underestimation of the disease severity. This discrepancy could be the reason for poor survival prediction reported by previous studies which conducted their analysis from the point of view of clinical stage. The aim of this study was to analyze the relationship between clinico-pathologic factors and survival from the pathologic point of view and to try to identify survival prognostic factors. METHODS: From January 2005 to June 2011, 88 patients received neoadjuvant therapy because of initial locally advanced disease, followed by anatomic resection and mediastinal lymph node (LN) dissection. All their clinico-pathologic data were collected from a retrospective review of the medical records and subjected to further analysis. RESULTS: We found that total metastatic LN ratio (P=0.01) and tumor size (P=0.02) were predictive factors for disease free survival (DFS). We used these two prognostic factors to stratify all patients into four groups. Group 4 (tumor size <=5, total metastatic LN ratio <=0.065) had the best DFS curve, while the DFS curve progressively deteriorated across group 3 (tumor size <=5, total metastatic LN ratio >0.065), group 2 (tumor size >5, total metastatic LN ratio <=0.065) and group 1 (tumor size >5, total metastatic LN ratio >0.065). However, no definitive prognostic factor could be identified in this study. CONCLUSIONS: In conclusion, tumor size greater than 5 cm and total metastatic LN ratio greater than 0.065 could predict the DFS of patients with advanced NSCLC after multimodality therapies followed by surgical resection. Tumor size plays a more important role than total metastatic LN ratio in DFS. Moreover, patients identified with these factors need active post-operation surveillance and additional aggressive adjuvant therapies. PMID- 27499935 TI - Prognostic value of preoperative neutrophil-lymphocyte ratio is superior to platelet-lymphocyte ratio for survival in patients who underwent complete resection of thymic carcinoma. AB - BACKGROUND: Preoperative neutrophil-lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) have prognostic value in patients with various operable tumors. The aim of our study was to determine whether NLR and PLR are predictive of survival in thymic carcinoma patients after complete resection. METHODS: A total of seventy-nine patients who underwent complete resection of thymic carcinoma at our hospital between January 2005 and December 2015 were retrospectively enrolled. Differential leukocyte counts were collected before surgery, and the relationships of NLR, PLR, and other patient clinical variables with survival were estimated by Cox regression analysis and Kaplan-Meier survival analysis. RESULTS: Univariate analysis found that a high level of NLR was associated with lower disease-free survival (DFS) (HR: 3.385, 95% CI: 1.073 10.678, P=0.037) and lower overall survival (OS) (HR: 12.836, 95% CI: 1.615 101.990, P=0.016). The optimal NLR threshold of 4.1 could stratify the patients with high risk of recurrence or metastasis (P=0.026) and death (P=0.006). Meanwhile, the NLR value of >4.1 in those patients was associated with bigger tumor size (P=0.035) and more advanced Masaoka stages (P=0.040) compared with NLR <=4.1. However, the PLR and other variables were not significantly associated with survival in thymic carcinoma patients. CONCLUSIONS: The preoperative NLR of >4.1 was significantly associated with larger tumor size, more advanced Masaoka stages and reduced DFS and OS, but was not an independent predictor of survival in thymic carcinoma patients after complete resection. PMID- 27499936 TI - Cancer-related inflammation as predicting tool for treatment outcome in locally advanced and metastatic non-small cell lung cancer. AB - BACKGROUND: Lung cancer is the leading cause of cancer deaths and the non-small cell lung cancer (NSCLC) represents 80% of all cases. In most cases when diagnosed, it is in locally advanced or metastatic stage, when platinum based doublet chemotherapy is the established therapeutic option for majority of the patients. Predictive factors to filter the patients who will benefit the most from the chemotherapy are not clearly defined. Objective of this study was to explore predictive value of pre-treatment C-reactive protein (CRP), fibrinogen and their interaction, for the response to the frontline chemotherapy. METHODS: In this retrospective cohort study 170 patients with locally advanced and metastatic NSCLC were included. Relationship between baseline level of CRP and fibrinogen and response to the frontline chemotherapy was assessed. RESULTS: We found that pre-treatment CRP and fibrinogen values were statistically significantly correlated. Chemotherapy and CRP, fibrinogen, and their interaction were independently significantly associated with disease control rate at re evaluation. There was statistically significant difference in median pre treatment CRP level between the patients with disease control or progression at re-evaluation, 13.8 vs. 30.0 mg/L respectively, P=0.026. By Johnson-Neyman technique we found that in patients with initial fibrinogen value below 3.5 g/L, CRP level was significantly associated with disease control or progression of the disease. Above this fibrinogen value the association of CRP and disease control was lost. CONCLUSIONS: The findings from this study support the growing evidence of inflammation and cancer relationship, where elevated pre-treatment level of CRP has negative predictive significance on the NSCLC frontline chemotherapy response. PMID- 27499937 TI - Icotinib combined whole brain radiotherapy for patients with brain metastasis from lung adenocarcinoma harboring epidermal growth factor receptor mutation. AB - BACKGROUND: The brain is a metastatic organ that is most prone to lung adenocarcinoma (LAC). However, the prognosis of patients with brain metastasis remains very poor. In this study, we evaluated the efficacy of icotinib plus whole brain radiation therapy (WBRT) for treating patients with brain metastasis from epidermal growth factor receptor (EGFR)-mutated LAC. METHODS: All patients received standard WBRT administered to the whole brain in 30 Gy in 10 daily fractions. Each patient was also instructed to take 125 mg icotinib thrice per day beginning from the first day of the WBRT. After completing the WBRT, maintenance icotinib was administered until the disease progressed or intolerable adverse effects were observed. Cranial progression-free survival (CPFS) and overall survival (OS) times were the primary endpoints. RESULTS: A total of 43 patients were enrolled in this study. Two patients (4.7%) presented a complete response (CR), whereas 20 patients (46.5%) presented a partial response (PR). The median CPFS and OS times were 11.0 and 15.0 months, respectively. The one-year CPFS rate was 40.0% for the patients harboring EGFR exon 19 deletion and 16.7% for the patients with EGFR exon 21 L858R (P=0.027). CONCLUSIONS: The concurrent administration of icotinib and WBRT exhibited favorable effects on the patients with brain metastasis. EGFR exon 19 deletion was predictive of a long CPFS following icotinib plus WBRT. PMID- 27499938 TI - Ginsenoside Rg1 attenuates hypoxia and hypercapnia-induced vasoconstriction in isolated rat pulmonary arterial rings by reducing the expression of p38. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased pulmonary arteriolar resistance. Pulmonary vasoconstriction has been proved to play a significant role in PAH. We previously reported that Panax notoginseng saponins (PNS) might attenuate hypoxia and hypercapnia-induced pulmonary vasoconstriction (HHPV). METHODS: In the present study, our specific objective was to investigate the role of ginsenoside Rg1, a major component of PNS, in this process and the possible underlying mechanism. The second order pulmonary rings isolated from the Sprague-Dawley rats were treated with different dosage of ginsenoside Rg1 at 8, 40, or 100 mg/L respectively, both before and during the conditions of hypoxia and hypercapnia. Contractile force changes of the rings were detected. Furthermore, SB203580, the selective inhibitor for p38 activation was applied to the rings. Pulmonary arterial smooth muscle cells (PASMCs) were cultured under hypoxic and hypercapnic conditions, and ginsenoside Rg1 was administered to detect the changes induced by p38. RESULTS: Under the hypoxic and hypercapnic conditions, we observed a biphasic pulmonary artery contractile response to the second pulmonary artery rings. It is hypothesized that the observed attenuation of vasoconstriction and the production of vasodilation could have been induced by ginsenoside Rg1. This effect was significantly reinforced by SB203580 (P<0.05 or P<0.01). The expression of p38 in the PASMCs under hypoxic and hypercapnic conditions was significantly activated (P<0.05 or P<0.01) and the observed activation was attenuated by ginsenoside Rg1 (P<0.05 or P<0.01). CONCLUSIONS: Our findings strongly support the significant role of ginsenoside Rg1 in the inhibition of hypoxia and hypercapnia-induced vasoconstriction by the p38 pathway. PMID- 27499939 TI - Implications of the pulmonary artery to ascending aortic ratio in patients with relatively mild chronic obstructive pulmonary disease. AB - BACKGROUND: Identifying markers for predicting the course and outcome of chronic obstructive pulmonary disease (COPD) remains important. The relative pulmonary artery enlargement to aorta ratio (PA-A ratio), which is measured using computed tomography (CT), is a reported predictor for COPD exacerbation and mortality. However, little is known about the implications of the PA-A ratio in patients with mild COPD. METHODS: We investigated the utility of the PA-A ratio as a biomarker in patients with relatively mild COPD. A total of 131 patients with mild to moderate COPD [post-bronchodilator forced expiratory volume in 1 sec (FEV1)/forced vital capacity (FVC) 61.6+/-6.4, mean post-bronchodilator FEV1 83%+/-17.8% of predicted value] were selected from a Korean COPD cohort (from 2012 until the end of 2014) and analyzed retrospectively. We determined the correlation between the PA-A ratio and clinical parameters using a linear regression model. RESULTS: The COPD assessment test (P=0.04), FEV1 (P=0.03), and a history of exacerbation in the last year (P=0.03) were significant factors in the univariate linear regression analysis. Post-bronchodilator FEV1 was most significantly associated with the PA-A ratio in the multivariate analysis (P=0.01). CONCLUSIONS: The PA-A ratio evaluated by CT imaging was independently correlated with a representative pulmonary function factor (FEV1) in patients with relatively mild COPD. The results suggest that the PA-A ratio may be an important biomarker for clinical outcome in patients with mild COPD. PMID- 27499940 TI - Severity of coronary artery disease and retinal microvascular signs in patients with diagnosed versus undiagnosed diabetes: cross-sectional study. AB - BACKGROUND: There is increasing evidence that a considerable proportion of patients with diabetes remain undiagnosed and untreated, however, it is unclear whether this is associated with more severe coronary artery disease (CAD) and microvasculature changes compared with diagnosed patients. We assessed CAD extent and severity, along with changes to the retinal microvascular structure in participants with undiagnosed versus diagnosed type 2 diabetes. METHODS: Participants of the Australian Heart Eye Study were stratified into participants with previously diagnosed diabetes (n=489), undiagnosed diabetes (n=76) and no diabetes (n=1,112). Retinal vessel caliber was measured from digital retinal images. Extent and severity of CAD was assessed using Extent and Gensini scores from angiography findings, respectively. RESULTS: Participants with undiagnosed and diagnosed diabetes versus those with no diabetes (reference group) had increased odds of being in the highest quartile of Gensini scores, multivariate adjusted odds ratios (OR) =7.02 [95% confidence interval (CI), 2.04-24.1] and OR =2.76 (95% CI, 1.67-4.55), respectively. Participants with undiagnosed and diagnosed diabetes versus those with no diabetes also had increased odds of being in the highest quartile of Extent scores, multivariate adjusted OR =7.63 (95% CI, 2.15-27.10) and OR =3.72 (95% CI, 2.22-6.27), respectively. No significant differences were observed in retinal vessel caliber between participants with undiagnosed versus diagnosed diabetes. CONCLUSIONS: The present study demonstrated that participants with undiagnosed diabetes compared to those with previously diagnosed diabetes, had a stronger likelihood of having more severe and extensive CAD. However, retinal microvascular signs did not differ by diabetes status. PMID- 27499941 TI - The Aquamantys((r)) system improves haemostasis and pneumostasis in open decortication for thoracic empyema. AB - BACKGROUND: Decortication for thoracic empyema is associated with significant blood loss and prolonged postoperative air leak. We sought to assess the potential application of an irrigated-tip radiofrequency (RF) sealing device, in an attempt to reduce this morbidity. METHODS: Data for all patients undergoing open decortication (OD) for stage II thoracic empyema, using either conventional approach or facilitated by use of the Aquamantys((r)) device, at a single thoracic surgical unit between April 2010 and July 2014, were retrospectively analysed. Unpaired t-test and Fisher's exact test were used for statistical analysis. RESULTS: Thirty-three patients, aged 54+/-15 years (mean +/- SD), and with a Charlson comorbidity index of 2.5+/-1.9 were included. Preoperative and intraoperative characteristics, including surgical time, were similar in the conventional and Aquamantys((r)) groups. Patients in the Aquamantys group were less likely to require red cell transfusion (9/22 vs. 10/11 patients, P=0.024) and received lower volume transfusions [0.0 (2.0) vs. 3.0 (1.6) units (median, IQR), P<0.0001]; chest drain duration was shorter [3.0 (1.0) vs. 6.5 (6.8) days, P=0.006], as was length of postoperative hospital stay [6.0 (8.7) vs. 10.0 (4.6) days, P=0.031]. There was no demonstrable difference in mortality. CONCLUSIONS: Our data indicates that the use of irrigated tip RF ablation is safe and effective in improving pneumostasis and haemostasis in decortication for thoracic empyema; and that this translates to morbidity and logistical benefit. PMID- 27499942 TI - Liver failure in total artificial heart therapy. AB - BACKGROUND: Congestive hepatopathy (CH) and acute liver failure (ALF) are common among biventricular heart failure patients. We sought to evaluate the impact of total artificial heart (TAH) therapy on hepatic function and associated clinical outcomes. METHODS: A total of 31 patients received a Syncardia Total Artificial Heart. Preoperatively 17 patients exhibited normal liver function or mild hepatic derangements that were clinically insignificant and did not qualify as acute or chronic liver failure, 5 patients exhibited ALF and 9 various hepatic derangements owing to CH. Liver associated mortality and postoperative course of liver values were prospectively documented and retrospectively analyzed. RESULTS: Liver associated mortality in normal liver function, ALF and CH cases was 0%, 20% (P=0.03) and 44.4% (P=0.0008) respectively. 1/17 (5.8%) patients with a normal liver function developed an ALF, 4/5 (80%) patients with an ALF experienced a markedly improvement of hepatic function and 6/9 (66.6%) patients with CH a significant deterioration. CONCLUSIONS: TAH therapy results in recovery of hepatic function in ALF cases. Patients with CH prior to surgery form a high risk group with increased liver associated mortality. PMID- 27499943 TI - Clinical outcomes of cytoreductive surgery combined with intrapleural perfusion of hyperthermic chemotherapy in advanced lung adenocarcinoma with pleural dissemination. AB - BACKGROUND: This study aimed to investigate the safety and feasibility of intrapleural perfusion hyperthermic chemotherapy (IPHC) followed by cytoreductive surgery as a part of multimodal strategy for the treatment of advanced lung adenocarcinoma. METHODS: Medical records of advanced lung cancer patients with pleural dissemination who underwent surgical treatment between 2003 and 2013 were reviewed retrospectively. Enrolled patients were divided into a surgery group comprising patients who underwent surgery only and an IPHC group, which consisted of patients who underwent surgery combined with IPHC. RESULTS: A total of 33 patients were enrolled in this study. Twenty-three patients underwent IPHC after surgical resection, and 10 patients underwent surgical resection only. The complication rate of the IPHC group was estimated to be 34.8% (8 cases), none of which included postoperative mortality. The complication rate of the surgery group was 40.0% (4 cases), which included one postoperative mortality. The 6 month, 1-year, and 3-year overall survival rates for the IPHC group were 95.7%, 91.3% and 38.6%, respectively, while those of the surgery group were 80.0%, 80.0% and 37.5%. The 6-month, 1-year and 3-year progression-free survival rates for the IPHC group were 87.0%, 47.8% and 24.3%, while those of surgery group were 44.4%, 33.3% and 0.0%, respectively. There were significant differences in overall survival rates between two groups (P=0.045); however, progression-free survival was not different between the two groups. CONCLUSIONS: IPHC combined with cytoreductive surgery for advanced lung adenocarcinoma associated with pleural seeding could be performed safely and feasible. It would be part of multimodality therapy for certain category of advanced lung adenocarcinoma. However, the long term benefits for survival is uncertain. More extensive and precisely designed studies are warranted to further evaluate the effectiveness of IPHC. PMID- 27499944 TI - Pure ground-glass opacity on chest computed tomography: predictive factors for invasive adenocarcinoma. AB - BACKGROUND: Pure ground-glass opacity (GGO) on computed tomography (CT) is considered a diagnostic feature of noninvasive lung adenocarcinoma. However, pure GGO can sometimes be associated with invasive adenocarcinoma (IA). The purpose of this study was to determine the predictive factors for IA when pure GGO is present. METHODS: Between 2011 and 2014, 83 patients with persistent pure GGO on chest CT underwent surgical treatment for lung cancer. We compared the clinical, surgical, and pathological characteristics of non-IA with those of IA. RESULTS: A total of 66 patients (79.5%) were diagnosed with non-IA and 17 patients (20.5%) were diagnosed with IA. The mean axial diameter of the GGO lesions in IA was larger than that in non-IA (1.9 vs. 1.2 cm; P<0.001). The incidence of pleural retraction was higher in IA than in non-IA (76.5% vs. 15.2%; P<0.001). Multivariate logistic regression analysis identified GGO lesion size and the presence of pleural retraction as significant predictive factors for IA. CONCLUSIONS: Both preoperative GGO lesion size on CT and the computed-tomography or operative finding of pleural retraction are predictive factors for IA. In patients with these findings, curative lobectomy is preferable to limited resection. PMID- 27499945 TI - Clinical outcomes of infrarenal abdominal aortic aneurysms that underwent endovascular repair in a district general hospital. AB - BACKGROUND: The purpose of this study was to compare the outcomes of elective endovascular abdominal aortic aneurysm repair (EVAR) and ruptured abdominal aortic aneurysm (rAAA) in patients at a district general hospital. METHODS: A retrospective clinical study was conducted using data on 16 patients with elective abdominal aortic aneurysm (AAA) and nine patients with consecutive rAAA treated with EVAR from January 2010 to December 2014 in a district general hospital in Taiwan. RESULTS: The preoperative characteristics of the two groups are listed. Thirty-six percent (9/25) of the patients were referred from other hospitals that did not offer surgical services. The percentage of patients with rAAA that were transferred from other hospitals was 55.5% (5/9). The stay durations in the intensive care unit for elective EVAR cases were shorter than those for emergent EVAR (1.75+/-1 d elective vs. 10+/-13.37 d emergent; P<0.019). The hospitalization days (11.06+/-4.07 d elective vs. 21.89+/-18.36 d emergent; P<0.031), operative time (183.63+/-57.24 min elective vs. 227.11+/-59.92 min emergent; P<0.009), and blood loss volumes (115.63+/-80.41 mL elective vs. 422.22+/-276.26 mL emergent; P<0.005) are shown; statistics for use of Perclose ProGlide((r)) (7 cases elective vs. 0 case emergent; P<0.024) are compared. The overall 30-d mortality rate was 11.11% (1/9). CONCLUSIONS: The results confirm that EVAR surgery can be safely performed in a district general hospital with an integrated health care system. Using Perclose ProGlide((r)) for selected cases may reduce blood loss and operative time. PMID- 27499946 TI - Conservative management of empyema-complicated post-lobectomy bronchopleural fistulas: experience of consecutive 13 cases in 9 years. AB - BACKGROUND: Bronchopleural fistula (BPF) is an infrequent but life-threatening complication after lung surgery. Tentative closure of the fistula and irrigation have been the conventional treatments, but are also surgically challenging and associated with a considerable failure rate. This study reports on a conservative practice of this difficult issue, in aim to examine its outcomes. METHOD: All enrolled cases were handled consecutively from September 2006 to June 2015. The empyema was first properly drained till disseminated pneumonia controlled. After conducting lavage, tube drainage was gradually transited to postural drainage. During the follow-up, information on tube removal, fistula healing, and survival were recorded. RESULTS: Thirteen cases were enrolled, including 9 rights and 4 lefts. The primary diseases were lung cancer [10], lung abscess [1], organizing pneumonia [1], and aspergillosis [1]. Early fistula (<=30 days postoperatively) occurred in 8 cases and late fistula (>30 days postoperatively) in 5 cases. Two patients underwent debridement to ascertain complete drainage. Chest tubes retained from 7 to 114 days (mean 40.54+/-30.49 days) before removal. At follow up, we observed gradually narrowing-down of all residual cavities, and symptoms of fistula and empyema eventually disappeared in all patients. No complication or death occurred during the follow-up. CONCLUSIONS: Conservative management by a combination of tube and postural drainage provides an effective and safe treatment for empyema-complicated post-lobectomy BPFs. PMID- 27499947 TI - Clinicopathological and prognostic significance of Oct-4 expression in patients with non-small cell lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: Octamer-binding transcription factor 4 (Oct-4) has been identified to participate in the tumorigenicity and malignancy of non-small cell lung cancer (NSCLC). However, its definite prognostic roles in NSCLC still remain a debate. Therefore, we conducted this meta-analysis to evaluate the prognostic value of Oct-4 expression in NSCLC and its relationship to some major clinicopathological characteristics. METHODS: A comprehensive literature retrieval was performed in PubMed, EMBASE and the Web of Science to identify the full-text articles that met our eligibility criteria. Odds ratio (OR) with 95% confidence interval (CI) severed as the summarized statistics for clinicopathological assessments, and hazard ratio (HR) with 95% CI served as the summarized statistics for prognostic assessments. Q-test and I(2)-statistic were used to evaluate the level of heterogeneity. Potential publication bias was detected by both Begg's test and Egger's test. RESULTS: There were 16 retried articles with 1,363 NSCLC cases included into this meta-analysis. Oct-4 expression was found to be significantly associated with the unfavorable outcomes for differentiation degree (OR: 3.065; 95% CI: 1.568-5.957; P=0.001), TNM stage (OR: 3.695; 95% CI: 2.252-6.063; P<0.001) and lymphatic metastasis (OR: 2.372; 95% CI: 1.504-3.742; P<0.001), but not associated with the histological subtypes, gender, age and smoking status. Oct-4 expression was also significantly associated with the poor prognosis of NSCLC (HR: 3.030; 95% CI: 2.283-4.021; P<0.001). The prognostic roles of Oct-4 expression in NSCLC still remained statistically reliable in the subgroups stratified by statistical analysis, patients' origins, positively-stained sites and histological subtypes. CONCLUSIONS: Our meta-analysis indicates that Oct-4 can serve as a strong biomarker predicting the poor clinicopathological and prognostic characteristics of NSCLC. More high-quality studies based on a large sample size will be very helpful to further validate and modify our findings in the future. PMID- 27499948 TI - Long-term performance of the second-generation cobalt-chromium sirolimus-eluting stents in real-world clinical practice: 3-year clinical outcomes from the prospective multicenter FOCUS registry. AB - BACKGROUND: The short- and mid-term outcomes of the second-generation cobalt chromium sirolimus-eluting stent (CoCr-SES) in real-world patients had been reported previously, but the long-term performance remained unclear. The objective of this analysis was to evaluate the long-term safety and efficacy of the second-generation CoCr-SES from the FOCUS registry. METHODS: The FOCUS registry (ClinicalTrials.gov Identifier: NCT00868829) enrolled all-comers eligible to receive Firebird-2 CoCr-SES. Follow-up was continued to 3 years to evaluate long-term safety and effectiveness of the second-generation CoCr-SES in real-world practice. Results of the extended-use group and standard-use group are compared to explore performance of CoCr-SES in more severe patients with more complex lesions. RESULTS: The rate of 3-year MACE was 7.37%, consisting of 84 cases (1.78%) of cardiac death, 166 cases (3.52%) of MI and 98 cases (2.08%) of TVR. ARC definite/probable stent thrombosis happened in 34 (0.72%) patients, only 3 new cases (<0.1%) of very late stent thrombosis was reported in the third year. Meanwhile, the difference of MACE (7.77% vs. 6.06%; P=0.058), TLF (4.71% vs. 3.49%; P=0.085) and ARC definite/probable stent thrombosis (0.83% vs. 0.37%; P=0.116) between extended-use group and standard-use group showed no significance. CONCLUSIONS: The second-generation CoCr-SES was associated with continued low rates of 3-year MACE, TLF and stent thrombosis in a broad spectrum of patients. PMID- 27499949 TI - The relationship between preoperative serum cortisol level and the stability of plaque in carotid artery stenosis patients undergoing carotid endarterectomy. AB - BACKGROUND: Stability of plaque has been implicated as risk factor for stroke. Serum cortisol regulates lipoprotein metabolism and immune response, contributing to plaque stability in atherosclerosis. However, the relationship between serum cortisol and stability of carotid plaque has not been well characterized. We conducted a serology analysis to identify the relationship between serum cortisol and carotid plaque stability. METHODS: Between May 2013 to October 2015, 73 patients with carotid stenosis patients undergoing carotid endarterectomy (CEA) were enrolled in our study. Serum cortisol was analyzed at 8:00 AM in the morning before surgery via liquid chromatography tandem mass spectrometry. According to the classification made by the American Heart Association, hematoxylin-and-eosin staining was performed to divide these patients into either a stable or unstable group, according to the morphology of fibrous cap, lipid core and intima layer. A curve fitting method was used to identify the relationship between preoperative serum cortisol and stability of carotid plaque. Univariate and multivariate logistic regression analysis were used to identify carotid plaque stability associated serum cortisol. RESULTS: Curve fitting's result represents a U-shape characteristic. A total of 314.92 and 395.23 nmol/L were considered as the cut point for preoperative serum cortisol when trisected the patients. When adjusted for degree of stenosis, hyperlipemia, smoking and low-density lipoprotein (LDL), univariate and multivariate logistic regression analysis' results demonstrated that preoperative serum cortisol can significantly affect carotid plaque stability. The odds ratio values in multivariate logistic regression analysis for C reactive protein (CRP), white blood cell (WBC), interleukin-6 (IL-6) and preoperative serum cortisol level were 7.67 and 20.86 respectively. CONCLUSIONS: Preoperative serum cortisol was associated with stability of carotid plaque in patients undergoing CEA. Low or high levels of preoperative serum cortisol might be an adverse factor for carotid plaque stability. PMID- 27499950 TI - A 20-year study on treating childhood infective endocarditis with valve replacement in a single cardiac center in China. AB - BACKGROUND: Children with infective endocarditis (IE) have to undergo valve replacement instead of valve repair in China due to severe valve damage. The present study is to review our experience on surgical treatment of children with IE in reference to the incidence, pathologic status, diagnosis, surgical strategies and outcomes. METHODS: We reviewed 35 patients with a mean age of 13.7+/-2.2 years who were underwent valve replacement surgery for IE during the period from January 1993 to December 2013. Preoperative transthoracic echocardiographic (TTE) evaluation and transesophageal echocardiography during operation were performed in all patients. All the children underwent chart review and retrospective risk-hazard analysis. RESULTS: Among the patients surveyed congenital cardiac lesions were present in 15 (42.8%), rheumatic heart valve disease in 2 (5.7%) and previous heart surgery in 2 (5.7%). The median stay of intensive care unit was 6 days. Intraoperative findings showed that the endocarditis involved mostly the mitral and aortic valves (88.5%). Triple or quadruple valve involvement was found in one patient each. Ten-year freedom from IE-related death and re-intervention was 94.2% and 91.6%, respectively. CONCLUSIONS: Children undergoing surgery for IE frequently have advanced disease with embolic complications. Although valve replacement is not the primary option for pediatric IE, the rate of 5-year survival and freedom from re-operation was optimal prognostically. Pediatric physicians should pay attention to the common clinical features of IE so that the native valve is preserved well. PMID- 27499951 TI - A systematic review and meta-analysis-does chronic obstructive pulmonary disease predispose to bronchopleural fistula formation in patients undergoing lung cancer surgery? AB - BACKGROUND: we conducted this systematic meta-analysis to determine the association between chronic obstructive pulmonary disease (COPD) and risk of bronchopleural fistula (BPF) in patients undergoing lung cancer surgery. METHODS: Literature retrieval was performed in PubMed, Embase and the Web of Science to identify the full-text articles that met our eligibility criteria. Odds ratio (OR) with 95% confidence interval (CI) served as the summarized statistics. Q test and I(2)-statistic were used to evaluate the level of heterogeneity. Sensitivity analysis was performed to further examine the stability of pooled OR. Publication bias was detected by both Begg's test and Egger's test. RESULTS: Eight retrospective observational studies were included into this meta-analysis. The overall summarized OR was 2.03 (95% CI: 1.44-2.86; P<0.001), revealing that COPD was significantly associated with the risk of BPF after lung cancer surgery. In subgroup analysis, the relationship between COPD and BPF occurrence remained statistically prominent in the subgroups stratified by statistical analysis (univariate analysis, OR: 1.91; 95% CI: 1.35-2.69; P<0.001; multivariate analysis, OR: 3.18; 95% CI: 1.95-5.19; P<0.001), operative modes (pneumonectomy, OR: 2.11; 95% CI: 1.15-3.87; P=0.016) and in non-Asian populations (OR: 2.36; 95% CI: 1.18-4.73; P=0.016). No significant impact of COPD on BPF risk was observed in Asian patients (OR: 1.48; 95% CI: 0.85-2.57; P=0.16). No significant heterogeneity or publication bias was discovered across the included studies. CONCLUSIONS: Our meta-analysis indicates that COPD can significantly predispose to BPF formation in patients undergoing lung cancer surgery. Because some limitations still exist in this meta-analysis, our findings should be further verified and modified in the future. PMID- 27499952 TI - Mutations and expression of the NFE2L2/KEAP1/CUL3 pathway in Chinese patients with lung squamous cell carcinoma. AB - BACKGROUND: Recent studies have reported an abnormally high alteration rate in the nuclear factor erythroid 2-like 2 (NFE2L2)/kelch-like ECH-associated protein 1 (KEAP1)/cullin 3 (CUL3) pathway. But the status of this pathway in Chinese patients with lung squamous cell carcinoma (SqCC) has not been thoroughly studied, and there are many uncertainties regarding the expression of pathway intermediates. METHODS: cDNA sequencing and TaqMan qRT-PCR were carried out in paired cancer and adjacent normal samples obtained from 100 Chinese patients with lung SqCC. Immunohistochemical staining was performed in 50 other paraffin embedded specimens. RESULTS: We detected 47 mutations in 36 patients (36%), and 143 single nucleotide polymorphism (SNP) in 59 patients (59%), of which 41 mutations and 31 SNPs resulted in amino acid (AA) and possibly functional changes. By combining qRT-PCR and immunohistochemistry staining, we confirmed that the expression of NFE2L2 and KEAP1 were highly increased, while the expression of CUL3 was not significantly changed in lung SqCC samples from Chinese patients. CONCLUSIONS: Considering the frequent mutations and abnormal expression, the NFE2L2/KEAP1/CUL3 pathway may play an important role in the therapy of Chinese patients with lung SqCC. PMID- 27499953 TI - Role of plasma MicroRNAs in the early diagnosis of non-small-cell lung cancers: a case-control study. AB - BACKGROUND: Lung cancer is a leading cause of cancer death worldwide. Early diagnosis is essential for improvements of prognosis and survival of the patients. Altered expressions in many cancer types including lung cancer and stable existence in plasma make microRNAs (miRNAs) a group of potentially useful biomarkers for clinical assessments of patients with lung cancer. In this study, we evaluate the potential values of miRNAs as plasma biomarkers for early diagnosis in non-small-cell lung cancers (NSCLC) by comparing with other typical plasma biomarkers. METHODS: We analyzed the clinical and laboratory characteristics of 59 early-staged NSCLC (I-IIIA) patients and non-cancer controls by 1:1 matching age and gender from January 2012 to February 2014 in Xuanwu Hospital, Beijing, China. Peripheral blood samples from patients and controls before surgery were collected, and plasma was separated. Expression of ten miRNAs in the plasma of the patients and controls was detected by quantitative real-time polymerase chain reaction. Other typical markers, such as SCC, CEA, and CYFRA21-1 in plasma were also detected. The early diagnostic ability of miRNAs and other markers were evaluated by receiver-operating characteristic (ROC) curve analysis. The sensitivity, specificity, and area under the curve were calculated for the cut-off value. RESULTS: Plasma CYFRA21-1, miRNA 486 and miRNA-210 levels were significantly different in patients with NSCLC than those in controls (CYFRA21-1: 8.896+/-7.681 vs. 5.892+/-6.028, P=0.020; miR-486: 2.778+/-0.778 vs. 1.746+/-0.892, P<0.001; miR-210: 4.836+/-3.374 vs. 2.829+/ 2.503, P<0.001). Area under ROC curve of CYFRA21-1, miR-486 and miR-210 were 0.624 (sensitivity: 0.576, specificity: 0.797), 0.848 (sensitivity: 0.831, specificity: 0.780) and 0.751 (sensitivity: 0.746, specificity: 0.746), respectively. The optimal cut-off value of CYFRA21-1, miRNA-486 and miRNA-210 were 6.595, 1.988 and 3.341, respectively to discriminate patients from controls. Plasma markers combined diagnosis ability had the highest sensitivity: 0.983, but the specificity was low. miR-486, miR-210 and CYFRA21-1 combined diagnosis ability was the highest, and the AUC was 0.924 (sensitivity: 0.847; specificity: 0.728). CONCLUSIONS: The results suggest that miRNA-486 and miR-210 could be potential blood-based biomarkers for early diagnosis of NSCLC. miRNAs and other lab indexes may be combined to early diagnose NSCLC, which showed better ability of screening patients. PMID- 27499954 TI - Mediastinal transposition of the omentum reduces infection severity and pharmacy cost for patients undergoing esophagectomy. AB - BACKGROUND: The greater omentum has been found to be immunologically competent in protecting abdominal organs from inflammation. Anastomotic omentoplasty has been used and proven effective in preventing anastomotic leaks after an esophagectomy. However, pulmonary complications are still a substantial problem after an esophagectomy. This study investigated the benefits of mediastinal transposition of the omentum, a modification of the conventional omental wrapping technique, in controlling overall postoperative intrathoracic complications. METHODS: From January 2010 to March 2015, 208 consecutive patients receiving an open Ivor-Lewis esophagectomy at our institution were retrospectively reviewed. One hundred twenty-one patients with omentum mediastinal transposition were assigned to the transposition group and 87 patients without omental transposition were placed in the non-transposition group. The patients' demographics, postoperative short-term outcomes, and in-hospital cost were documented and analyzed. RESULTS: Mediastinal transposition of the omentum led to a shorter postoperative hospital stay (14 vs. 16 d, P=0.038) and a lower intrathoracic infection rate (30.6% vs. 48.3%, P=0.009). Intrathoracic infection was milder in the transposition group (P=0.005), though a non-significant was found in overall complications (P=0.071). The multivariate logistic regression analyses identified omentum mediastinal transposition (P=0.007, OR=0.415) as an independent protective factor for postoperative intrathoracic infection. The total in-hospital cost was comparable in both groups (P>0.05), whereas the pharmacy cost was lower in the transposition group than in the non-transposition group (Y21,668 vs. Y27,012, P=0.010). CONCLUSIONS: Mediastinal transposition of the omentum decreases the rate and severity of postoperative intrathoracic infection following an open Ivor-Lewis esophagectomy. This result in decreased pharmacy costs, rather than resulting in an increased economic burden sustained by surgical patients. PMID- 27499955 TI - Evaluation of a disease management program for COPD using propensity matched control group. AB - BACKGROUND: Disease management programs (DMPs) have proliferated recently as a means of improving the quality and efficiency of care for patients with chronic illness. These programs include education about disease, optimization of evidence based medications, information and support from case managers, and institution of self-management principles. Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in Singapore and worldwide. DMP aims to reduce mortality, hospitalizations, and average length of stay in such patients. This study assesses the outcomes of the DMP, comparing the propensity score matched DMP patients with controls. METHODS: DMP patients were compared with the controls, who were COPD patients fulfilling the DMP's inclusion criteria but not included in the program. Control patients were identified from Operations Data Store (ODS) database. The outcomes of interest were average length of stay, number of days admitted to hospital per 100 person days, readmission, and mortality rates per person year. The risk of death and readmission was estimated using Cox, and competing risk regression respectively. Propensity score was estimated to identify the predictors of DMP enrolment. DMP patients and controls were matched on their propensity score. RESULTS: There were 170 matched DMP patients and control patients having 287 and 207 hospitalizations respectively. Program patient had lower mortality than the controls (0.12 vs. 0.27 per person year); cumulative 1-year survival was 91% among program patient and 76% among the control patients. Readmission, and hospital days per 100 person-days was higher for the program patients (0.36 vs. 0.17 per person year), and (2.19 vs. 1.88 per person year) respectively. CONCLUSIONS: Participation in "DMP" was associated with lower all-cause mortality when compared to the controls. This survival gain in the program patients was paradoxically associated with an increase in readmission rate and total hospital days. PMID- 27499956 TI - Evaluation of the 7(th) edition of the UICC-AJCC tumor, node, metastasis classification for esophageal cancer in a Chinese cohort. AB - BACKGROUND: To assess and evaluate the prognostic value of the 7(th) edition of the Union for International Cancer Control-American Joint Committee on Cancer (UICC-AJCC) tumor, node, metastasis (TNM) staging system for Chinese patients with esophageal cancer in comparison with the 6(th) edition. METHODS: A retrospective review was performed on 766 consecutive esophageal cancer patients treated with esophagectomy between 2008 and 2012. Patients were staged according to the 6(th) and 7(th) editions for esophageal cancer respectively. Survival was calculated by the Kaplan-Meier method, and multivariate analysis was performed using Cox regression model. RESULTS: Overall 3-year survival rate was 59.5%. There were significant differences in 3-year survival rates among T stages both according to the 6(th) edition and the 7(th) edition (P<0.001). According to the 7(th) edition, the 3-year survival rates of N0 (75.4%), N1 (65.2%), N2 (39.7%) and N3 (27.3%) patients were significant differences (P<0.001). Kaplan-Meier curve revealed a good discriminatory ability from stage I to IV, except for stage IB, IIA and IIB in the 7(th) edition staging system. Based on the 7(th) edition, the degree of differentiation, tumor length and tumor location were not independent prognostic factors on multivariate analysis. The multivariate analyses suggested that pT-, pN-, pTNM-category were all the independent prognostic factors based on the 6(th) and 7(th) edition staging system. CONCLUSIONS: The 7(th) edition of AJCC TNM staging system of esophageal cancer should discriminate pT2-3N0M0 (stage IB, IIA and IIB) better when considering the esophageal squamous cell cancer patients. Therefore, to improve and optimize the AJCC TNM classification for Chinese patients with esophageal cancer, more considerations about the value of tumor grade and tumor location in pT2-3N0M0 esophageal squamous cell cancer should be taken in the next new TNM staging system. PMID- 27499957 TI - A potential role for VEGF in the diagnostic approach of pleural effusions. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) may play a role in pleural fluid formation, as it represents a potent inducer of capillary permeability. We aimed to investigate the diagnostic utility of VEGF levels in pleural fluid and serum in patients with pleural effusions with initially negative diagnostic work up. METHODS: Seventy-one patients with exudative lymphocytic pleural effusions undiagnosed after initial diagnostic work up were enrolled in this prospective study and their clinical course was followed up to 24 months. VEGF levels were measured in serum and pleural fluid by using immunoenzymometric assay. RESULTS: During the follow up period, in 43 patients the pleural effusion was eventually attributed to malignancy while in the rest 28 patients it was due to non malignant causes (benign and unknown origin). Patients with malignancy had significantly higher VEGF levels in pleural fluid compared to patients with non malignant effusions (1,506 vs. 588 pg/dL, P=0.0001), while no statistically significant difference was found in the VEGF serum levels between the two groups. CONCLUSIONS: Pleural VEGF levels may be helpful in identifying malignant pleural effusion (MPE) in patients with negative diagnostic work up at the initial assessment and help in selecting patients for more invasive procedures. PMID- 27499958 TI - Diagnostic performance of coronary computed tomography angiography versus exercise electrocardiography for coronary artery disease: a systematic review and meta-analysis. AB - BACKGROUND: Both coronary computed tomography angiography (CCTA) and exercise electrocardiography (ExECG) are non-invasive testing methods for the evaluation of coronary artery disease (CAD). However, there was controversy on the diagnostic performance of these methods due to the limited data in each single study. Therefore, we performed a meta-analysis to address these issues. METHODS: We searched PubMed and Embase databases up to May 22, 2015. Two authors identified eligible studies, extracted data and accessed quality. Pooled estimation of sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), summary receiver-operating characteristic curve (SROC) and the area under curve (AUC) of CCTA and ExECG for the diagnosis of CAD were calculated using Stata, Meta-Disc and Review Manager statistical software. RESULTS: Seven articles were included. Pooled sensitivity of CCTA and ExECG were 0.98 [95% confidence intervals (CIs): 0.95-0.99] and 0.66 (95% CIs: 0.59-0.72); pooled specificity of CCTA and ExECG were 0.84 (95% CIs: 0.81-0.87) and 0.75 (95% CIs: 0.71-0.79); pooled DOR of CCTA and ExECG were 110.24 (95% CIs: 35.07-346.55) and 6.28 (95% CIs: 2.06-19.13); and AUC of CCTA and ExECG were 0.9950+/-0.0046 and 0.7727+/-0.0638, respectively. There is no heterogeneity caused by threshold effect in CCTA or ExECG analysis. The Deeks' test showed no potential publication bias (P=0.17). CONCLUSIONS: CCTA has better diagnostic performance than ExECG in the evaluation of CAD, which can provide a better solution for the clinical problem of the diagnosis for CAD. PMID- 27499959 TI - Benefits of using omental pedicle flap over muscle flap for closure of open window thoracotomy. AB - BACKGROUND: Open window thoracotomy (OWT) as well as its closure are challenging. Transposition of omental pedicle and muscle flaps is often performed for OWT closure; however, the better technique among the two is unknown. The purpose of this series was to evaluate the outcomes of using both omental pedicle and muscle flaps for the aforementioned closure. METHODS: This was an observational retrospective cohort study on 27 consecutive patients who underwent OWT closure at a single institution between January 2005 and December 2014. The operation was performed using either omental pedicle or muscle flap with thoracoplasty. We compared both techniques in terms of the patient background [sex, age, body mass index (BMI) and C-reactive protein (CRP) before OWT and serum albumin levels before OWT closure], presence of methicillin-resistant Staphylococcus aureus (MRSA) infection, rate of bronchopleural fistula (BPF), duration of OWT, recurrence of local infection, morbidity, duration of indwelling drainage after operation, success, mortality and postoperative hospital stay. RESULTS: There were 9 (33.3%) omental pedicle flap procedures and 18 (66.7%) muscle flap procedures. The rate of local recurrence after closure of OWT was significantly higher with muscle flap than with omental pedicle flap (0% vs. 50.0%, P=0.012). The median duration of postoperative hospital stay was significantly shorter with omental pedicle flap than that with muscle flap (16.0 vs. 41.5 days, P=0.037). Mortality was observed in 2 patients (11.2%) in the muscle flap group and no patient in the omental pedicle flap group. Success rate was similar between the two groups (100% for omental pedicle flap vs. 83.3% for muscle flap). CONCLUSIONS: Omental pedicle flap was superior to muscle flap in terms of reducing local recurrence and shortening postoperative hospital stay. However, mortality, morbidity and success rates were not affected by the choice of flap. PMID- 27499960 TI - Association between NADPH oxidase (NOX) and lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: Lung cancer is a leading cause of death worldwide. Considerable studies have reported that NADPH oxidase (NOX) expression or activity may play an important role in the tumorigenesis of lung cancer. However, the results are inconsistent. Thus, a systematic review and meta-analysis were conducted in this study. METHODS: A systematic search of electronic databases was performed. Statistical analysis was performed using the Comprehensive Meta-Analysis software (Version 3). The pooled Hedges's g with 95% confidence intervals (95% CIs) or rate ratio with 95% CIs was adopted to assess the effect size. Fixed or random effect model was separately used based on the heterogeneity between the studies. RESULTS: A total of ten eligible studies were included in the current systematic review and overall meta-analysis showed that NOX/DUOX activity and mRNA were significantly in favor of lung cancer (Hedges's g =1.216, P=0.034). Suppression of NOX function by pharmacologic inhibitor or expression by siRNA resulted in significant inhibition of lung cancer cell invasion and migration in in vitro experiments (Hedges's g =2.422, P<0.001) and lung cancer formation in vivo studies (rate ratio =0.366, P=0.002). CONCLUSIONS: Findings of this systematic review indicate that NOX activity and expression is associated with tumorigenesis of lung cancer and inhibition of NOX function or mRNA expression significantly blocks lung cancer formation and invasion. Suppressing NOX up-regulation or interfering NOX function in tumor microenvironment may be one important approach to prevent oxidative-stress-related carcinogenesis in the lung. PMID- 27499961 TI - Transition to routine use of venoarterial extracorporeal oxygenation during lung transplantation could improve early outcomes. AB - BACKGROUND: The study objective was to compare the outcomes of intraoperative routine use of venoarterial (VA) extracorporeal membrane oxygenation (ECMO) versus selective use of cardiopulmonary bypass (CPB). METHODS: Between January 2010 and February 2013, 41 lung transplantations (LTx) were performed, and CPB was used as a primary cardiopulmonary support modality by selective basis (group A). Between March 2013 and December 2014, 41 LTx were performed, and ECMO was used routinely (group B). The two groups were compared retrospectively. RESULTS: The operative time was significantly longer in group A (group A, 458 min; group B, 420 min; P=0.041). Postoperatively, patients in group B had less fresh frozen plasma (FFP) transfusion (P=0.030). Complications were not different between the two groups. The 30- and 90-day survival rates were better in group B (30-day survival: group A, 75.6%; group B, 95.1%, P=0.012; 90-day survival: group A, 68.3%; group B, 87.8%, P=0.033). The 1-year survival showed better trends in group B, but it was not significant. Forced vital capacity (FVC) at 1, 3, and 6 months after LTx was better in group B than in group A (1 month: group A, 43.8%; group B, 52.9%, P=0.043; 3 months: group A, 45.5%; group B, 59.0%, P=0.005; 6 months: group A, 51.5%; group B, 65.2%, P=0.020). Forced expiratory volume in 1 second (FEV1) at 3 months after LTx was better in patients in group B than that in patient in group A (group A, 53.3%; group B, 67.5%, P=0.017). CONCLUSIONS: Routine use of ECMO during LTx could improve early outcome and postoperative lung function without increased extracorporeal-related complication such as vascular and neurologic complications. PMID- 27499962 TI - Factors influencing development and mortality of acute respiratory failure in hospitalized patient with active pulmonary tuberculosis: a 10-year retrospective review. AB - BACKGROUND: Pulmonary tuberculosis with acute respiratory failure is fatal and is a burden in the intensive care units and leads to mortality. This retrospective study identifies the factors influencing the development of pulmonary tuberculosis requiring mechanical ventilation (TBMV) and mortality in the hospitalized patients with pulmonary tuberculosis. METHODS: The medical records of hospitalized adult patients with pulmonary tuberculosis were retrospectively reviewed. Demographic data, clinical presentations, radiographic findings, biochemical tests, and clinical outcomes were collected. Data were compared by Student's t-test and Chi-square test between groups. Select variables that were statistically significant with P values <0.1 were introduced into a forward, stepwise, logistic regression model. Odds ratios (ORs) and their 95% confidence intervals (CIs) identified the independent influencing factors in the development of TBMV and mortality. RESULTS: Of 268 enrolled patients, 185 (69.0%) were male. The patients were equally divided between the TBMV and non-TBMV groups. The shorter duration of illness (OR, 0.99; 95% CI, 0.98-0.99), underlying disease of AIDS (OR, 14.55; 95% CI, 1.71-123.91), presentation of fever (OR, 2.11; 95% CI, 1.20-3.71) and dyspnea (OR, 3.51; 95% CI, 2.02-6.11), large amount of acid fast bacilli on sputum smear (OR, 3.76; 95% CI, 1.90-7.47), lower serum albumin level (OR, 0.39; 95% CI, 0.26-0.59), and delayed initiation of anti-tuberculosis agents (OR, 1.06; 95% CI, 1.00-1.12) were independent factors to develop TBMV. Male gender (OR, 2.16; 95% CI, 1.01-4.61), consolidation pattern on chest X-ray (OR, 2.41; 95% CI, 1.17-4.98), and lower serum albumin (OR, 0.39; 95% CI, 0.21-0.71) were correlated to mortality. CONCLUSIONS: The incidence and mortality rate of TBMV patients were high. Acute tuberculous pneumonia, underlying disease of AIDS, amount of acid fast bacilli, and delayed administration of anti-tuberculosis agents were independent risk factors to develop TBMV. Male gender, consolidation on chest X-ray, and low serum albumin were significantly related to mortality. PMID- 27499963 TI - The diagnostic utility and tendency of the soluble receptor for advanced glycation end products (sRAGE) in exudative pleural effusion. AB - BACKGROUND: The soluble receptor for advanced glycation end products (sRAGE) may have an inflammatory or homeostatic function in lung tissue. The aim of this study was to assess the usefulness of sRAGE as a diagnostic marker for exudative pleural effusions, which are common manifestations of a variety of diseases. METHODS: Patients with an undiagnosed pleural effusion were prospectively enrolled between January 2013 and January 2015. Samples of blood and pleural fluid were centrifuged and the supernatant stored at -70 degrees C. The levels of sRAGE in serum and pleural fluid were determined using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: In total 47 patients, 21 patients were diagnosed with a tuberculous effusion, and the groups diagnosed with parapneumonic or malignant effusions comprised 13 patients each. The serum sRAGE levels for tuberculosis were significantly elevated [median, 1,291 pg/mL; interquartile range (IQR), 948-1,711 pg/mL] when compared with those for both pneumonia (median, 794 pg/mL; IQR, 700-1,255 pg/mL) and lung cancer (median, 886 pg/mL; IQR, 722-1,285 pg/mL) (P=0.029). The pleural sRAGE levels for pneumonia (median, 1,763 pg/mL; IQR, 1,262-4,431 pg/mL) were lower than those for both tuberculosis (median, 5,081 pg/mL; IQR, 3,300-6,004 pg/mL) and lung cancer (median, 4,936 pg/mL; IQR, 3,282-7,018 pg/mL) (P=0.009) The receiver operating characteristic (ROC) curve analysis selected 896 pg/mL as the best cutoff value in the sRAGE serum level for tuberculosis [sensitivity, 86%; specificity 58%; area under the curve (AUC) =0.727, P=0.008]. For the pleural effusion sRAGE level, the ROC curve analysis selected 2,231 pg/mL as the best cutoff value for pneumonia (sensitivity, 91%; specificity, 62%, AUC =0.792, P=0.002). CONCLUSIONS: Among patients with exudative effusion, pleural and serum sRAGE measurements may be useful supportive diagnostic tools in the evaluation of ambiguous pleural effusion. Furthermore, the behavior of sRAGE in the serum and pleural fluid of various pulmonary diseases suggests that sRAGE may be linked to the chronic process of lung damage and inflammation rather than acute bacterial infection. PMID- 27499964 TI - Preoperative evaluation of stage T3, central-type non-small cell lung cancer with double sleeve lobectomy under complete video-assisted thoracoscopic surgery using spiral computed tomography post-processing techniques. AB - BACKGROUND: To investigate the estimated value of spiral computed tomography (CT) post-processing techniques in preoperative stage T3, central-type non-small cell lung cancer (NSCLC) with double sleeve lobectomy under complete video-assisted thoracoscopic surgery (c-VATS). METHODS: Preoperative clinical date and CT reconstructed data of 10 patients who underwent double sleeve lobectomy with upper lobe stage T3, central-type NSCLC were retrospectively analysed and compared to surgical pathological results and cross-sectional CT data. The diagnostic criterions of tumour invasion of pulmonary artery and bronchus were divided into five grades, which included estimation of upper lobe pulmonary arteries and bronchi (40 branches, respectively). RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of cross-sectional CT images of pulmonary artery tumour invasion were 78.57%, 58.33%, 81.48%, 53.85%, and 72.50%, respectively, while the respective values for CT reconstructed images were 93.55%, 87.50%, 96.67%, 70.00%, and 90.00%, showing statistical significance (chi(2)=4.021, P=0.045). Similarly, the evaluate, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of cross-sectional CT images of bronchial tumour invasion were 82.76%, 45.45%, 80.00%, 50.00%, and 72.50%, respectively, while the respective values for CT reconstructed images were 97.06%, 66.67%, 94.29%, 80.00%, 92.50%; these results were also statistically significant (chi(2)=5.541, P=0.019). CONCLUSIONS: The sensitivity, specificity, and diagnostic accuracy of the spiral CT post-processing techniques were better than cross-sectional CT images in estimating the extent of tumour invasion in the pulmonary arteries and bronchi of central-type NSCLC. CT post-processing techniques are essential tools in preoperative examination and operative method selection of central-type lung cancer with double sleeve lobectomy under c-VATS. PMID- 27499965 TI - Robotic-assisted thoracoscopic sleeve lobectomy for locally advanced lung cancer. AB - BACKGROUND: The Da Vinci robotic system has been used to enhance the surgeon's visualization and agility in lung cancer surgery, and thus facilitate refined dissection, knot tying and suturing. However, only a few case reports exist on performing a sleeve lobectomy with a robotic-assisted thoracoscopic surgery (RATS) technique. Here we describe our early experience performing RATS sleeve lobectomies. To our knowledge, this is the first study reporting a series of RATS sleeve lobectomies. METHODS: The six consecutive NSCLC patients who underwent a RATS sleeve lobectomy between November 2013 and July 2015 at the National Taiwan University Hospital were enrolled in this study. The lobectomies were all performed by the same surgeon using a three-arm robotic system with an additional utility incision made for assistance and specimen retrieval. RESULTS: Five patients were diagnosed with squamous cell carcinoma, while the sixth was diagnosed with a carcinoid tumor. The mean operation time was 436.7 [255-745] minutes. The mean postoperative intensive care unit (ICU) stay and hospital stay were 3.7 [1-11] and 11.3 [3-26] days, respectively. Two (33.3%; 2/6) morbidities were noted, including one pneumonia and one anastomosis stricture. There were no cases of mortality or of conversion to thoracotomy. CONCLUSIONS: Our experience performing a RATS sleeve lobectomy in the six patients demonstrated the feasibility of RATS in complex lung cancer surgeries. The three-dimensional vision and articulated joint instruments made robotic-assisted bronchial anastomosis easier under the endoscopic setting. Our experience suggests that RATS offers specific advantages with regard to accuracy and safety when performing sleeve lobectomies. PMID- 27499966 TI - Assessment of epidermal growth factor receptor mutation/copy number and K-ras mutation in esophageal cancer. AB - BACKGROUND: The molecular status of epidermal growth factor receptor (EGFR) in esophageal cancer has not been well elucidated. The purpose of the study was to investigate the prevalence of EGFR and K-ras mutation, and EGFR gene copy number status as well as its association with clinicopathologic characteristics, and also to identify the prognostic value of EGFR gene copy number in esophageal cancer. METHODS: EGFR mutation in exon 19/exon 21 and K-ras mutation in codon 12/codon 13 were detected by real-time PCR method, while EGFR gene copy number status was analyzed by fluorescent in situ hybridization (FISH). EGFR gene amplification and high polysomy were defined as high EGFR gene copy number status (FISH-positive), and all else were defined as low EGFR gene copy number status (FISH-negative). The relationship between EGFR gene copy number status and clinicpathologic characteristics was analyzed. Kaplan-Meier method and Cox proportional hazards regression model were employed to evaluate the effects of EGFR gene copy number status on the patients' survival. RESULTS: A total of 57 esophageal squamous cell carcinoma (ESCC) patients and 9 esophageal adenocarcinoma (EADC) patients were enrolled in the study. EGFR mutation was identified in one patient who was diagnosed as ESCC with stage IIIC disease. K ras mutation was identified in one patient who was diagnosed as EADC. In all, 34 of 66 (51.5%) samples were detected as FISH-positive, which includes 30 ESCC and 4 EADC tumor samples. The correlation analysis showed that FISH-positive was significantly associated with the tumor stage (P=0.019) and lymph node metastasis (P=0.005) in esophageal cancer patients, and FISH-positive was also significantly associated with the tumor stage (P=0.007) and lymph node metastasis (P=0.008) in ESCC patients. Cox regression analysis showed that high EGFR gene copy number was not a significant predictor of a poor outcome for esophageal cancer patients (P=0.251) or for ESCC patients (P=0.092), but esophageal cancer patients or ESCC patients with low EGFR gene copy number may have longer survival than those with high EGFR gene copy number according to the survival curve trends. CONCLUSIONS: The results indicated that EGFR or K-ras mutation was rare in esophageal cancer, but high EGFR gene copy number is frequent, and correlated with advanced pathologic stage and more number of the metastatic regional lymph nodes, especially in ESCC. In addition, high EGFR gene copy number is likely to have a deleterious effect on prognosis of esophageal cancer patients or ESCC patients, although no statistical significance was reached in the study. PMID- 27499967 TI - Surgery of colorectal cancer lung metastases: analysis of survival, recurrence and re-surgery. AB - BACKGROUND: Surgery is considered an effective therapeutic option for patients with lung metastasis (MTS) of colorectal cancer (CRC). The purpose of the study was to evaluate efficacy and feasibility of lung metastasectomy in CRC patients and to explore factors of prognostic relevance. METHODS: This is a retrospective study of patients operated for lung MTS of CRC from 2004 to 2012 in a single Institution. Overall survival (OS) was the primary endpoint. Secondary endpoints were progression free survival (PFS) in resection status R0 and OS in in patients submitted to re-resections. In order to evaluate prognostic factors, a multivariable Cox proportional hazard model was performed. RESULTS: One-hundred eighty-eight consecutive patients were included in the final analysis. The median follow-up (FU) was 45 months. The 5-year OS and PFS were 53% (95% CI: 44-60%) and 33% (95% CI: 25-42%), respectively. Two- and 5-year survival after re-resection were 79% (95% CI: 63-89%) and 49% (95% CI: 31-65%), respectively. Multivariate adjusted analysis showed that primary CRC pathological TNM stages (P=0.019), number of resected MTS >=5 (P=0.009) and lymph nodal involvement (P<0.0001) are independent predictors of poor prognosis. CONCLUSIONS: Patients operated and re operated for lung MTS from CRC cancers showed encouraging survival rates. Our results indicated that primary CRC stage, number of MTS and lymph nodal involvement are strong predictive factors. Prognosis after surgery remained comforting up to four resected MTS. Adjuvant chemotherapy seems to have a benefit on survival in patients affected by multiple metastases. Finally, according to the high rate of unidentified lymph node involvement in pre-operative setting, lymph node sampling should be advisable for a correct staging. PMID- 27499968 TI - Positive expression of miR-361-5p indicates better prognosis for breast cancer patients. AB - BACKGROUND: MicroRNA-361-5p (miR-361-5p) has been reported to be tumor suppressor in colorectal, gastric and prostate cancer, but as an oncogene in cervical cancer. No previous research has focused on the expression of miR-361-5p and its exact prognostic role in breast cancer (BC). METHODS: In this study, a tissue microarray (TMA)-based miRNA detection in situ hybridization (ISH) with LNA probe was used to detect miR-361-5p expression in 375 BC tissue. The expression level of miR-361-5p in BC and its potential prognostic value was investigated. RESULTS: Positive miR-361-5p staining was observed in 78.7% (N=295; 78.7% positive, 21.3% negative) in the 375 cases. The clinical outcome of patients with positive miR 361-5p expression [median disease-free survival (DFS) time 95.52 months] was significantly better than that of patients (median DFS time 82.33 months) with negative miR-361-5p expression (P=0.002). Moreover, the prognostic value of miR 361-5p was most significant among patients with triple-negative breast cancer (TNBC) for DFS (P=0.004). CONCLUSIONS: These results indicated that miR-361-5p expression is an independent predictive factor for better prognosis in BC. PMID- 27499969 TI - The value of esophagectomy surgical apgar score (eSAS) in predicting the risk of major morbidity after open esophagectomy. AB - BACKGROUND: Recently, surgical apgar score (SAS) has been reported to be strongly associated with major morbidity after major abdominal surgery. The aim of this study was to assess the value of esophagectomy SAS (eSAS) in predicting the risk of major morbidity after open esophagectomy in a high volume cancer center. METHODS: The data of all patients who admitted to intensive care unit (ICU) after open esophagectomy at Cancer Hospital of Chinese Academy of Medical Sciences & Peking Union Medical College from September 2008 through August 2010 was retrospectively collected and reviewed. Preoperative and perioperative variables were recorded and compared. The eSAS was calculated as the sum of the points of EBL, lowest MAP and lowest HR for each patient. Patients were divided into high risk (below the cutoff) and low-risk (above the cutoff) eSAS groups according to the cutoff score with optimal accuracy of eSAS for major morbidity. Univariable and multivariable regression analysis were used to define risk factors of the occurrence of major morbidity. RESULTS: Of 189 patients, 110 patients developed major morbidities (58.2%) and 30-day operative mortality was 5.8% (11/189). There were 156 high risk patients (eSAS <=7) and 33 low risk (eSAS >7) patients. Univariable analysis demonstrated that forced expiratory volume in one second of predicted (FEV1%) <=78% (44% vs. 61%, P=0.024), McKeown approach (22.7% vs. 7.6%, P=0.011), duration of operation longer than 230 minutes, intraoperative estimated blood loss (347+/-263 vs. 500+/-510 mL, P=0.015) and eSAS <=7 (62.2% vs. 90.0%, P=0.001) were predictive of major morbidity. Multivariable analysis demonstrated that FEV1% <=78% (OR, 2.493; 95% CI, 1.279-4.858, P=0.007) and eSAS <=7 (OR, 2.810; 95% CI, 1.105-7.144; P=0.030) were independent predictors of major morbidity after esophagectomy. Compared with patients who had eSAS >7, patients who had eSAS <=7 had longer hospital length of stay (25.39+/-14.36 vs. 32.22+/ 22.66 days, P=0.030). However, there were no significant differences in ICU length of stay, duration of mechanical ventilation, ICU death, 30-day death rate and in-hospital death rate between high risk and low risk patients. CONCLUSIONS: The eSAS score is predictive of major morbidity, and lower eSAS is associated with longer hospital length of stay in esophageal cancer patients after open esophagectomy. PMID- 27499970 TI - Visceral pleural invasion in lung adenocarcinoma <=3 cm with ground-glass opacity: a clinical, pathological and radiological study. AB - BACKGROUND: Visceral pleural invasion (VPI) had been demonstrated as an aggressive sign in non-small cell lung cancers (NSCLC). However, its incidence and clinical relevance in early lung cancer showing ground glass nodules (GGNs) has not been clarified. METHODS: All consecutive surgically treated patients with solitary GGNs between 2009 and 2013 were reviewed retrospectively. Inclusion criteria were defined as lesions <=3 cm with pleura abutting on computed tomography (CT) scan and pathologically confirmed NSCLC. RESULTS: Out of 156 enrolled patients, 38 had pathologically confirmed VPI. The incidence of VPI was 41.5% (27/65) if the tumor diameter was larger than 2.0 cm and 14.3% (13/91) if diameter was smaller than 2.0 cm (P<0.001). Further, the incidence was 17.4% (12/69) in pure GGNs and 32.2% (28/87) in part-solid GGNs (P=0.040). The tumor size and the nodule nodule-pleural relationship were significant predictors of positive VPI. In cases with pleural indentation, attachment, and closeness, the incidence was 38.1%, 25.5%, and 5.3%, respectively (P=0.001). All cases were PL0 and PL1, with no PL2 cases observed. CONCLUSIONS: Although VPI was visible in both pure/mix GGNs, it was more common in larger (>2 cm) GGNs. The radiographic findings of nodule abutment or a pleural tag did not reliably predict or exclude VPI. In patients with GGNs, a low rate of PL2 invasion may be observed. PMID- 27499971 TI - Comparison of robotic and video-assisted thoracic surgery for lung cancer: a propensity-matched analysis. AB - BACKGROUND: Reports of comparison between robotic and thoracoscopic surgery for lung cancer are limited, we aimed to compare the perioperative outcomes of robotic and thoracoscopic anatomic pulmonary resection for lung cancer. METHODS: A total of 184 patients with lung cancer underwent anatomic pulmonary resection by robotics or thoracoscopy. A propensity-matched analysis with incorporated preoperative variables was used to compare the perioperative outcomes between the two procedures. RESULTS: Overall, 71 patients underwent robotic pulmonary resection, including 64 lobectomies and 7 segmentectomies, while 113 patients underwent thoracoscopic lobectomy and segmentectomy. Propensity match produced 69 pairs. The mean length of postoperative stay (7.6+/-4.6 vs. 6.4+/-2.6 d, P=0.078), chest tube duration (5.3+/-3.7 vs. 4.4+/-1.7 d, P=0.056), number of lymph nodes retrieved (17.9+/-6.9 vs. 17.4+/-7.0, P=0.660), stations of lymph nodes resected (7.4+/-1.6 vs. 7.6+/-1.7, P=0.563), operative blood loss (53.9+/ 29.3 vs. 50.3+/-37.9 mL, P=0.531), morbidity rates (42.0% vs. 30.4%, P=0.157) were similar between the robotics and thoracoscopy. However, robotics was associated with higher cost ($12,067+/-1,610 vs. $8,328+/-1,004, P<0.001), and longer operative time (136+/-40 vs. 111+/-28 min, P<0.001). CONCLUSIONS: Robotics seems to have higher hospital costs and longer operative time, without superior advantages in morbidity rates and oncologic efficiency. Further prospective randomized clinical trials were needed to validate both of its short- and long term oncologic efficiency. PMID- 27499972 TI - Outcome of veno-venous extracorporeal membrane oxygenation use in acute respiratory distress syndrome after cardiac surgery with cardiopulmonary bypass. AB - BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CPB) is a known risk factor for acute respiratory distress syndrome (ARDS). We aimed to analyze the treatment outcome in patients who required veno-venous extracorporeal membrane oxygenation (VV-ECMO) for postcardiotomy ARDS despite other rescue modalities. METHODS: We retrospectively reviewed the outcomes in 13 patients (mean age, 54.7+/-5.9 years) who received VV-ECMO support for refractory ARDS after cardiac surgery between March 2013 and February 2016 at Severance Hospital, Yonsei University (Seoul, Korea). RESULTS: At the start of VV-ECMO, the average lung injury score was 3.0+/-0.2, and the Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score was -4+/-1.1. Although 7 patients initiated VV-ECMO support within 24 h from operation, the remaining 6 started at a median of 8.5 days (range, 5-16 days). Nine (69.3%) patients were successfully weaned from VV-ECMO. After a median follow-up duration of 14.5 months (range, 1.0 33.0 months) for survivors, the 1-year overall survival was 58.6%+/-14.4%. The differences in the overall survival from VV-ECMO according to the RESP score risk classes were borderline significant (100% in class III, 50%+/-25% in class IV, and 20%+/-17.9% in class V; P=0.088). CONCLUSIONS: VV-ECMO support can be a feasible rescue strategy for adult patients who develop refractory ARDS after a cardiac surgery. Additionally, the RESP score seems a valuable prognostic tool for post-ECMO survival outcome in this patient population as well. PMID- 27499973 TI - Efficacy of subpleural continuous infusion of local anesthetics after thoracoscopic pulmonary resection for primary lung cancer compared to intravenous patient-controlled analgesia. AB - BACKGROUND: This study compared the efficacy and side effects of intravenous patient-controlled analgesia (IV-PCA) with those of a subpleural continuous infusion of local anesthetic (ON-Q system) in patients undergoing thoracoscopic pulmonary resection for primary lung cancer. METHODS: We retrospectively reviewed 66 patients who underwent thoracoscopic pulmonary resection for primary lung cancer from January 2014 to August 2015 (36 in the IV-PCA group and 30 in the ON Q group). The numeric pain intensity scale (NPIS), additional IV injections for pain control, side effects, and early discontinuation of the pain control device were compared. RESULTS: There were no differences in the general characteristics of the two groups. The NPIS scores gradually decreased with time (P<0.001), but the two groups had differences in pattern of NPIS scores (P=0.111). There were no differences in the highest NPIS score during admission (4.75+/-2.35 vs. 5.27+/ 1.87, P=0.334) or the number of additional IV injections for pain control in the same period (0.72+/-0.94 for IV-PCA vs. 0.83+/-0.65 for ON-Q; P=0.575). Side effects such as nausea, dizziness, and drowsiness were significantly more frequent with IV-PCA (36.1% vs. 10.0%, P=0.014), and early discontinuation of the pain control device was more frequent in the IV-PCA group (33.3% vs. 6.7%, P=0.008). CONCLUSIONS: The ON-Q system was equivalent to the IV-PCA for postoperative pain control after thoracoscopic pulmonary resection for primary lung cancer, and it also had fewer effects and early discontinuations. PMID- 27499974 TI - Short-term effects of a vibrotactile neck-based treatment device for positional obstructive sleep apnea: preliminary data on tolerability and efficacy. AB - BACKGROUND: Positional supine obstructive sleep apnea syndrome (OSAS) characterizes a subgroup of patients suffering from OSAS. Several devices designed to limit supine position have been developed, but evidences of their efficacy and safety are lacking. It is unclear whether a neck-worn vibrating device could induce positional change in patients with positional OSAS. We evaluated the efficacy of a neck-worn device to induce supine avoidance positional feedback over a short-term trial in OSAS patients and its impact on sleep quality and polysomnographyc indexes. METHODS: Twenty patients with positional apneas/hypopneas were prospectively studied. Baseline characteristics of daytime somnolence and risk of sleep apnea were screened and the efficacy of a 3-day trial of supine-avoidance therapy by vibrotactile neck worn device assessed by reporting the self-perceived change in quality of sleep and performing cardio respiratory polysomnography. Comparison between baseline and treatment results was performed. RESULTS: The neck device produced a reduction in overall apnea hypopnea index (AHI) (mean AHI pre =16.8/h and post =4.4/h, P<0.0001), oxygen desaturation (pre =13.7/h and post =3.8/h, P<0.0001) and Respiratory Disturbance Indexes (RDI) (20.0/h vs. 5.2/h; P<0.0001).The time spent in supine position decreased from 62.1% to 33.7% of the total (P<0.001). However, the impact on the perceived quality of sleep was unpredictable. CONCLUSIONS: The neck position therapy device is effective in restricting supine sleep, improving AHI and related polysomnographic indexes. However, at least in a short-term trial, it seems unable to improve the patient's sleep quality. PMID- 27499975 TI - Urgent pulmonary lobectomy for blunt chest trauma: report of three cases without mortality. AB - BACKGROUND: The majority of patients with severe blunt chest trauma is successfully treated with supportive measures and thoracostomy tube; only few cases need urgent thoracotomy. Lung-sparing techniques are treatments of choice but major pulmonary resections are necessary in case of injuries involving hilar vessels or bronchi. Currently the mortality associated with pulmonary lobectomy performed for chest trauma is 40%. METHODS: Over a 2-year period [2013-2014], 210 patients with chest trauma were hospitalized at our Institution. Mechanism of injury was blunt in 204 (97.1%) patients and penetrating in 6 (2.9%). In 48 (22.8%) patients was necessary a ventilatory support and 37 (17.6%) patients were treated with thoracostomy tube. Nineteen (9%) patients needed urgent thoracotomy: 4 (1.9%) cases for penetrating injury and 15 (7.1%) cases for blunt trauma. Three (1.4%) patients treated with urgent thoracotomy required concomitant laparotomy for intra-abdominal injuries. The overall mortality rate was 1.4%. RESULTS: We report three cases of urgent lobectomies for chest trauma without mortality and with postoperative complete restoration of respiratory function. The anatomical lobectomies were performed for: massive hemothorax with bronchial disruption, expanding pulmonary hematoma with hypovolemic shock, and massive hemothorax in deep parenchymal laceration. CONCLUSIONS: Mortality rate after major pulmonary resections for trauma is very high and increases with the presence of multivisceral injuries, the severity of hypovolemic shock and extent of lung resection. Anterolateral thoracotomy was the approach employed in case of cardiac arrest. In hypovolemic patients a posterolateral incision with a double lumen intubation was performed. The absence of mortality in this series may be related to the prompt diagnosis, short operative time and absence of associated severe neurological or abdominal injuries. PMID- 27499976 TI - Uniportal video-assisted thoracoscopic lobectomy for lung cancer. AB - Great advances have been made in the multi-port video-assisted thoracoscopic surgery lobectomy in the recent two decades. However, only five years passed a more minimally surgery, namely uniportal video-assisted thoracoscopic lobectomy, was launched. Accumulating experience and exploration are being performed in most of the medical centres and hence we summarize the experience of uniportal video assisted thoracoscopic lobectomy in our operation group. PMID- 27499977 TI - Minimally invasive surgery for esophageal achalasia. AB - Esophageal achalasia is due to the esophagus of neuromuscular dysfunction caused by esophageal functional disease. Its main feature is the lack of esophageal peristalsis, the lower esophageal sphincter pressure and to reduce the swallow's relaxation response. Lower esophageal muscular dissection is one of the main ways to treat esophageal achalasia. At present, the period of muscular layer under the thoracoscope esophagus dissection is one of the treatment of esophageal achalasia. Combined with our experience in minimally invasive esophageal surgery, to improved incision and operation procedure, and adopts the model of the complete period of muscular layer under the thoracoscope esophagus dissection in the treatment of esophageal achalasia. PMID- 27499978 TI - Uniportal video-assisted thoracic surgery resection of small ground-glass opacities (GGOs) localized with CT-guided placement of microcoils and palpation. AB - Although uniportal video-assisted thoracic surgery (VATS) is becoming more popular, it's still very challenging to conduct a wedge resection of small pulmonary ground-glass opacities (GGOs), especially deeply situated subpleural GGOs, via uniportal VATS. We successfully performed thirteen uniportal VATS wedge resections through an approach that combines radiologically guided microcoil localization with palpation, and we encountered no complications related to the new approach. Based on our experience, a combination of CT-guided microcoil localization with palpation in uniportal VATS for deeply situated subpleural GGOs is a safe and effective procedure for accurate diag!nosis and resection of indeterminate GGOs. PMID- 27499979 TI - Clinical application of near-infrared thoracoscope with indocyanine green in video-assisted thoracoscopic bullectomy. AB - Failure to identify all the possible bullous lesions was considered an important reason for the higher recurrence rate after the VATS bullectomy. We applied the latest near-infrared (NIR) thoracoscope with indocyanine green (ICG) to detect bullous lesions for patients with spontaneous pneumothorax. Two male patients with spontaneous pneumothorax and poorly identified bullae intraoperatively were included in this pilot study. An NIR thoracoscope with two different doses of ICG injection (0.2 and 0.6 mg/kg) was used to detect bullous lesions during VATS bullectomy. Partial lung resections of the bullous lesions were performed under syncretic mode. Data was managed with ImageJ software. No procedure-related complications were observed. The fluorescent signal was detected in normal lung tissue 10.5 seconds (mean, 10-11 seconds) after the ICG bolus, and lasted up to 525 seconds (mean, 480-570 seconds). The bullous lesions showed an obviously decreased fluorescent densities comparing to adjacent normal tissue. At the dosage of 0.6 mg/kg, ICG emits sufficient fluorescence to demonstrate the precise border of bullae, with the max SBR of 6.32. All resected specimens were confirmed as bullous lesions microscopically. NIR thoracoscope with intravenous ICG is a safe, accurate and real-time method to detect bullous lesions of lung tissue difficult to be found under normal light in human subjects. TRIAL REGISTRATION: NCT02611245 (https://register.clinicaltrials.gov/). PMID- 27499980 TI - Surgery and pleuro-pulmonary tuberculosis: a scientific literature review. AB - Tuberculosis (TB) is still a major public health concern, mostly affecting resource-constrained settings and marginalized populations. The fight against the disease is hindered by the growing emergence of drug-resistant forms whose management can be rather challenging. Surgery may play an important role to support diagnosis and treatment of the most complex cases and improve their therapeutic outcome. We conducted a non-systematic review of the literature based on relevant keywords through PubMed database. Papers in English and Russian were included. The search was focused on five main areas of intervention as follows: (I) diagnosis of complicated cases; (II) elimination of contagious persisting cavities, despite appropriate chemotherapy; (III) treatment of destroyed lung; (V) resection of tuberculomas; (VI) treatment of tuberculous pleural empyema. Although specific practical guidelines concerning surgical indications and approaches are currently unavailable, a summary of the evidence emerged from the scientific literature was elaborated to help the clinician in the management of severely compromised TB patients. The decision to proceed to surgery is usually individualized and a careful assessment of the patient's risk profile is always recommended before performing any procedure in addition to appropriate chemotherapy. PMID- 27499981 TI - Tuberculous pleural effusion. AB - Although it is curable, tuberculosis remains one of the most frequent causes of pleural effusions on a global scale, especially in developing countries. Tuberculous pleural effusion (TPE) is one of the most common forms of extrapulmonary tuberculosis. TPE usually presents as an acute illness with fever, cough and pleuritic chest pain. The pleural fluid is an exudate that usually has predominantly lymphocytes. The gold standard for the diagnosis of TPE remains the detection of Mycobacterium tuberculosis in pleural fluid, or pleural biopsy specimens, either by microscopy and/or culture, or the histological demonstration of caseating granulomas in the pleura along with acid fast bacilli, Although adenosine deaminase and interferon-gamma in pleural fluid have been documented to be useful tests for the diagnosis of TPE. It can be accepted that in areas with high tuberculosis prevalence, the easiest way to establish the diagnosis of TPE in a patient with a lymphocytic pleural effusion is to generally demonstrate a adenosine deaminase level above 40 U/L. The recommended treatment for TPE is a regimen with isoniazid, rifampin, and pyrazinamide for two months followed by four months of two drugs, isoniazid and rifampin. PMID- 27499982 TI - Veno-arterial extracorporeal membrane oxygenation for cardiogenic shock due to myocarditis in adult patients. AB - Myocarditis is an inflammatory disease of the heart muscle with established histological, immunological and immunohistochemical diagnostic criteria. Different triggers could be advocated as possible etiologies of myocarditis such as viral and non-viral infections, medications, systemic autoimmune diseases and toxic reactions. The spectrum of clinical presentations of myocarditis is broad and varies from subclinical asymptomatic courses to refractory cardiogenic shock. The prognosis of patients with myocarditis depends mainly on the severity of clinical presentation. In particular, myocarditis patients developing cardiogenic shock refractory to optimal maximal medical treatment may benefit from the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as a temporary mechanical circulatory support (MCS). The aim of the present report is to offer a review of the most important articles of the literature showing the results of VA ECMO in the specific setting of cardiogenic shock due to myocarditis in adult patients. PMID- 27499983 TI - When size matters: changing opinion in the management of pleural space-the rise of small-bore pleural catheters. AB - Tube thoracostomy is usually the first step to treat several thoracic/pleural conditions such as pneumothorax, pleural effusions, haemothorax, haemo pneumothorax and empyema. Today, a wide range of drains is available, ranging from small to large bore ones. Indications for an appropriate selection remains yet matter of debate, especially regarding the use of small bore catheters. Through this paper, we aimed to retrace the improvements of drains through the years and to review the current clinical indications for chest drain placement in pleural/thoracic diseases, comparing the effectiveness of small-bore drains vs. large-bore ones. PMID- 27499984 TI - Post hoc ergo propter hoc. PMID- 27499985 TI - Free jejunum interposition as salvage surgery after cervical esophagus injury. AB - In rare cases when stomach could not be suitable for esophageal replacement, the jejunum should probably be suitable for esophageal reconstruction. However, the widespread prevalence of jejunal interposition is precluded because of its complexity. Here we present a case of a 74-year-old female who underwent free jejunal interposition as salvage surgery. In this case, cervical esophagus was injured during thyroidectomy. Nine months later, replacement of injured part of esophagus with free jejunum was performed. End-to-end and end-to-side anastomosis were used for esophagus-jejunum and vascular-to-vascular anastomosis respectively. This patient was discharged from hospital 15 days postoperatively. No severe postoperative complication happened. Only minor late operation complication (anastomotic stricture) occurred during 13 years of annual follow up. PMID- 27499986 TI - Partial anomalous venous drainage of the left upper lobe during a robot-assisted pulmonary resection. AB - Anomalies in pulmonary vasculature are rare; however, the knowledge of the anomal and potential physiological implications for a patient undergoing a thoracic surgery must be understood. We report a case of a 64-year-old female who had a robotic left upper lobectomy for an incidental pulmonary nodule and was found to have a partial anomalous pulmonary vein. We discuss the incidence of pulmonary vein anomalies, associated conditions, and surgical management in patients requiring thoracic surgery. PMID- 27499987 TI - Dissecting thoracic aortic aneurysm associated with tuberculous pleural effusion. AB - We present the case of thoracic aortic aneurysm associated with the tuberculous pleural effusion. An 82-year-old woman underwent emergency stent graft under a diagnosis of dissecting thoracic aortic aneurysm. Preoperative computed tomography revealed right pleural effusion supposed to the hemothorax caused by the dissecting aneurysm. But, the effusion was sanguineous color fluid and it was determined to result from pulmonary tuberculosis. The medical team was exposed to the pulmonary tuberculosis; fortunately no one became infected. Physicians should be aware of the possibility of an infected aortic aneurysm and prepare for pathogen transmission. PMID- 27499988 TI - Delayed aortic rupture resulting from postoperative superficial sternal wound infection. AB - While deep sternal wound infection (DSWI) after cardiac surgery is a significant contributor to patient morbidity and mortality, superficial sternal wound infection (SSWI) mostly has a benign course. We report a mortality case of aortic rupture resulting from SSWI after cardiac surgery. A 50-year-old male underwent an aortic valve replacement (AVR). Three months after the valve operation, he presented with severe dyspnea, which had never before been observed, and chest computed tomography revealed an ascending aortic rupture with large hematoma compressing the main pulmonary artery. We performed an emergent operation for aortic rupture that possibly originated from the SSWI. Postoperatively, the patient died of hypovolemic shock due to recurrent aortic rupture despite efforts to resuscitate him. PMID- 27499989 TI - Hypoxemia associated with right-side cardiac tumor: right atrial lymphoma with patent foramen ovale. AB - A 66-year-old man presented with acute type I respiratory failure, and was diagnosed to have a huge mass occupying the right atrium (RA) of the heart, with no evidence of pulmonary embolism. Intra-operative transesophageal echocardiogram identified a patent foramen ovale (PFO) with right-to-left shunt apart from a huge right atrial tumor arising from the atrioventricular groove. The tumor was debulked, and the patent foramen was closed. Patient had an uneventful recovery and WAS discharged on post-operative day 7. Pathology revealed diffuse large B cell lymphoma (DLBCL). The patient was further treated with adjuvant chemotherapy and remained well 1 year after surgery. This case illustrates the importance of meticulous echocardiographic examination to look for any intracardiac shunts in the case of hypoxemia associated with a right-sided cardiac tumor. We advocate surgery as the most important initial management to maximize survival, as it allows correction of any hemodynamic sequelae, and simultaneous attainment of definite histological diagnosis for guidance of adjuvant therapy. PMID- 27499990 TI - Simultaneous resection of left atrial myxoma and esophageal carcinoma via right thoraco-abdominal approach. AB - Concomitant occurrence of atrial myxoma and esophageal carcinoma is an extremely rare entity. Here we present two cases of synchronously suffered left atrial myxoma and esophageal carcinoma. Both patients underwent simultaneous resection of two tumors via the right thoraco-abdominal approach and recovered well. PMID- 27499991 TI - Dramatic response to anti-PD-1 therapy in a patient of squamous cell carcinoma of thymus with multiple lung metastases. AB - Immunotherapy directed at the programmed cell death-1 receptor (PD-1) or its ligand PD-L1 has demonstrated efficacy in some malignancies, such as metastatic melanoma and non-small-cell lung cancer (NSCLC). Compared with cytotoxic chemotherapy, radiotherapy or molecular targeted agent, it is an innovative way to treat malignancies with durable clinical responses and manageable adverse. We present a case of female patient with squamous cell carcinoma of thymus involving multiple lung metastases, who was successfully treated with anti-PD-1 monoclonal antibody, pembrolizumab. PMID- 27499992 TI - Exophiala pisciphila: a novel cause of allergic bronchopulmonary mycosis. AB - Allergic bronchopulmonary mycosis (ABPM) is a hypersensitivity reaction to fungal antigens, which may particularly plague uncontrolled asthmatics. Non-aspergillus fungal organisms may be implicated and may elicit a more severe immunologic response. Exophiala pisciphila, a marine organism, has not been reported as a culprit yet. However, this report indicates it may be implicated in unrelenting symptoms in a severe asthmatic patient who had become dependent on corticosteroids. Proper identification and adequate therapy of this organism led to complete resolution of respiratory symptoms, with adequate subsequent control of the asthma. ABPM may complicate asthma and lead to a lack of its control. Proper awareness, testing and treatment of non-aspergillus pulmonary mycosis is essential to proper asthma care and beneficial for its control. PMID- 27499993 TI - Exon 19 L747P mutation presented as a primary resistance to EGFR-TKI: a case report. AB - Active mutations of the EGFR gene have been proved to predict the activity of EGFR-TKI. The most common mutations are the exon 19 deletion and exon 21 point mutation, both of which are sensitive to EGFR-TKI. However, rare EGFR mutations or complex mutations still exist, and data of which are scarce and controversial. Their response to EGFR-TKI remains uncertain. We presented a patient diagnosed with stage IV lung adenocarcinoma who was found to have the EGFR mutation in exon 19 (L747P) before any treatment. The disease progressed 2 months after the chemotherapy containing cisplatin and pemetrexed, and erlotinib was administered, but there was no response found. This EGFR-TKI naive patient failed to achieve the desired effect with the therapy of EGFR-TKI. L747P may be associated with primary resistance to EGFR-TKI in this case. PMID- 27499994 TI - A 30-year-old female Behcet's disease patient with recurrent pleural and pericardial effusion and elevated adenosine deaminase levels: case report. AB - Behcet's disease is a systemic disease which may involve various organs. We describe a case of a patient diagnosed as pleuropericardial involvement of Behcet's disease. A 30-year-old woman visited our clinic presented with left pleuritic chest pain for s days. She had been diagnosed as Behcet's disease and admitted to our clinic due to pericardial and pleural effusion repeatedly in past two years. In the previous studies, effusion analysis revealed to be lympho dominant exudate with high adenosine deaminase level. Acid-fast bacilli (AFB) culture and polymerase chain reaction (PCR) for mycobacterial tuberculosis (M.TB) were negative in the pericardial tissue, and pathologic finding showed mild endothelitis with micro-thrombi formation in the lumen. The patient had been treated with antituberculous medication for a year. In the current admission, chest computed tomography (CT) again showed left pleural effusion without other significant lesion. Pleural fluid analysis was similar with the previous study. Video-assisted thoracoscopic pleural biopsy was performed to obtain the definite diagnosis. Pathology confirmed the diagnosis as pleuropericardial involvement of Behcet's disease, and we treated the patient with oral steroid in the out-patient department. Pleuropericardial involvement of Behcet's disease may mimic TB pleurisy or pericarditis due to high adenosine deaminase (ADA) level in effusion analysis. Clinicians should keep in mind that Behcet's disease may manifest as pleural or pericardial effusion, and pathologic confirmation could be helpful for the definite diagnosis. PMID- 27499995 TI - Acetaminophen to treat fever in intensive care unit patients with likely infection: a response from the author of the HEAT trial. PMID- 27499996 TI - Professor Wolfgang Oertel: research on Parkinson Disease-big step forward, more problems to research. PMID- 27499997 TI - Professor Gian Paolo Rossi: special hypertension patient-why blood pressure at night is higher than that in the daytime? PMID- 27499998 TI - Erratum to non-intubated combined with video-assisted thoracoscopic in carinal reconstruction. AB - [This corrects the article DOI: 10.21037/jtd.2016.01.58.]. PMID- 27499999 TI - Time to get real: critical and imperative change required in evidence evaluation. PMID- 27500000 TI - 2016 Respiratory Effectiveness Group Annual Summit Report-impact & influence of real-world respiratory evidence. PMID- 27500002 TI - Leveraging datasets and insisting on quality to address unmet research needs-the epidemiologists' dream. PMID- 27500001 TI - The role of primary care databases in developing asthma and allergy service delivery. PMID- 27500003 TI - Routine primary care data-the new crystal ball? PMID- 27500004 TI - Xanthomatous hypophysitis associated with autoimmune disease in an elderly patient: A rare case report. AB - BACKGROUND: Xanthomatous hypophysitis (XH) is an extremely rare form of primary hypophysitis characterized by infiltration of the pituitary gland by mixed types of inflammatory cells, including foamy cells, plasma cells, and small mature lymphocytes. XH manifests as varying degrees of hypopituitarism. Although several previous reports have denied a possible contribution of autoimmune mechanism, the exact pathogenesis of XH remains unclear. CASE DESCRIPTION: We describe the case of a 72-year-old woman with a history of rheumatoid arthritis and Sjogren's syndrome who presented with panhypopituitarism and diabetes insipidus. At the time of her visit, she also experienced relapsed rheumatoid arthritis and Sjogren's syndrome, manifesting as arthralgia. Magnetic resonance imaging (MRI) showed a multicystic mass in the sellar and suprasellar regions. In the course of steroid replacement therapy for hypocortisolism, the patient's arthralgia diminished, and MRI revealed shrinkage of the mass. XH was diagnosed histologically following a transsphenoidal endoscopic biopsy, and it was the oldest case of XH. CONCLUSION: To the best of our knowledge, this patient is the oldest of reported patients diagnosed with XH. Steroid therapy may be effective to XH temporarily. XH should be considered when diagnosing pituitary cystic lesions in elderly patients with autoimmune disease. PMID- 27500005 TI - Operative surgical nuances of modified extradural temporopolar approach with mini peeling of dura propria based on cadaveric anatomical study of lateral cavernous structures. AB - BACKGROUND: Extradural temporopolar approach (ETA) has been modified as less invasive manner and named as trans-superior orbital fissure (SOF) approach with mini-peeling technique. The present study discusses the operative nuances of this modified technique on the basis of cadaveric study of lateral cavernous structures. METHODS: In five consecutive cadaveric specimens, we performed an extradural anterior clinoidectomy with mini-peeling of the dura propria to expose the anterior clinoid process entirely. We also investigated the histological characteristics of the lateral cavernous sinus (CS) between the dura propria and periosteal dura at the SOF, foramen rotundum (FR), and foramen ovale (FO) levels, and of each trigeminal nerve division. RESULTS: Coronal histological examination of the lateral wall of the CS showed invagination of the dura propria and periosteal dura into the SOF. In contrast, no such invagination was observed at the levels of the FR and FO. This finding supports the technical rationale of the only skeletonization of the SOF for peeling of the dura propria but not FR. In addition, our modified ETA method needs only minimal dural incision between the SOF and FR where no cranial nerves are present. CONCLUSION: Our technical modification of ETA may be recommended for surgical treatment of paraclinoid lesions to reduce the risk of intraoperative neurovascular injury. PMID- 27500006 TI - Subarachnoid hemorrhage caused by an undifferentiated sarcoma of the sellar region. AB - BACKGROUND: It is rare for patients with pituitary apoplexy to exhibit concomitant subarachnoid hemorrhage (SAH). Only a handful of patients with pituitary apoplexy have developed such hemorrhagic complications, and histopathological examination revealed pituitary adenoma as the cause of SAH. CASE REPORT: A previously healthy 35-year-old woman was brought to our institution after complaining of severe headache and left monocular blindness. Brain computed tomography showed a diffuse SAH with a central low density. Subsequently, the brain magnetic resonance imaging revealed an intrasellar mass with heterogeneous contrast enhancement. The patient was presumptively diagnosed with SAH secondary to hemorrhagic pituitary adenoma and underwent transcranial surgery to remove both the tumor and subarachnoid clot. A histological evaluation of the surgical specimen revealed malignant cells with strong predilection for vascular invasion. Following immunohistochemical evaluation, the tumor was negative for the majority of tumor markers and was positive only for vimentin and p53; thus, a diagnosis of undifferentiated sarcoma was established. CONCLUSIONS: This case was informative in the respect that tumors other than pituitary adenoma should be included in the differential diagnosis of patients with pituitary apoplexy. PMID- 27500007 TI - Dural repair using autologous fat: Our experience and review of the literature. AB - BACKGROUND: Various materials have been proposed to obliterate dead spaces and to reconstruct dural defects during a neurosurgical approach. This study describes our technique of using the abdominal autologous fat graft and evaluates the complications and characteristics related to the use of this tissue during cranial procedures. METHODS: Autologous fat grafts were used in 296 patients with basicranial and convexity extraaxial tumors from April 2005 to January 2015. The adipose tissue was removed from the paraumbilical abdominal region and was transformed into a thin foil. When possible, a watertight suture was made between the dural or bone edge with a fat graft. We always used fibrin glue to reinforce the dural closure. RESULTS: Complications occurred between 2 days and 1 year following procedure. Cerebrospinal fluid leaks were found in 11 cases. No case of mortality, pseudomeningoceles, fistula, infections, bacterial meningitides, or lipoid meningitides was reported. No patient required removal of the graft. No adhesion was observed between the brain and the autologous fat. Other fat-related complications observed were 2 cases of fat necrosis in the abdomen and 2 cases of abdominal hemorrhage. CONCLUSION: The technique of harvesting and applying fat grafts is fairly simple, although it must be performed meticulously to be effective. Our experience has led us to believe that the use of fat grafts presents low morbidity and mortality. However, a neurosurgeon should never forget the possible late or early complications related to the use of fat grafts. PMID- 27500008 TI - Neurofibromatosis type 1 and Chiari type 1 malformation: A case report and literature review of a rare association. AB - BACKGROUND: The association between neurofibromatosis type 1 (NF-I) and Chiari I malformation (CMI) is rare, and not many studies are reported in the literature. Performing magnetic resonance imaging (MRI) in patients with NF-1 is essential because several cases of Chiari type I are completely asymptomatic. We emphasize the need for inclusion of Chiari I as diagnosis in association with NF-1. CASE DESCRIPTION: The patient was a 51-year-old black man who presented with complaints of pain and decreased motion and sensibility of his hands, wrists, and forearms, along with progressive dysarthria. Even though the computed tomography (CT) scan of the skull did not show changes, the MRI showed hydro/syringomyelia in the cervical spine area. Midline suboccipital craniectomy with total laminectomy of c1 and partial laminectomy of c2 was performed; tonsillectomy was also performed for cistern expansion because of intense thickening and obliteration of the obex by the cerebellar tonsils. Following treatment, the patient showed remission of symptoms. CONCLUSION: NF-1 in association with CMI is rare, and early diagnosis and surgical treatment are essential to slow down the myelopathy; although they prevent neurological damages, patients with NF-1 must remain under doctor's attention in case of association with CMI. Our literature review showed that symptoms can vary and include headache, gait disturbance, and sensory/motor diminution, until asymptomatic patients. Moreover, the incidence of NF-1 is considerably higher in CMI patients in comparison to the global incidence (8.6-11.8% and 0.775%, respectively). The surgical technique must be evaluated case by case according to the degree of cerebrospinal fluid obstruction. PMID- 27500009 TI - Creation of Interpretable Summary Measures in Displaying Results from Mixed effects Logit Models. AB - The authors of this article developed new approaches to present analytic results from mixed-effects binary logit models in longitudinal data analysis. We first described basic specifications of mixed-effects logit models, the derivation of the fixed and the random effects, and nonlinear predictions of the response probability and the corresponding standard errors. Particular attention was paid to the interpretability of the conventional odds ratio in the longitudinal setting. The authors contended that without information on averaging of the random effects for two population subgroups of interest, the regression coefficient of an explanatory variable and its antilog in mixed-effects binary logit models are not interpretable. We recommended the computation of the conditional effect and the conditional odds ratio to aid in displaying a covariate's effect on the longitudinal binary response. An empirical illustration was provided to demonstrate how to create interpretable summary measures for aiding in the interpretation of the results from mixed-effects logit models when analyzing binary longitudinal data. PMID- 27500010 TI - Codified Hashtags for Weather Warning on Twitter: an Italian Case Study. AB - INTRODUCTION: During emergencies increasing numbers of messages are shared through social media platforms becoming a primary source of information for lay people and emergency managers. For Twitter codified hashtagging is emerging as a practical way to coordinate messages during emergencies and quickly identify relevant information. This paper considers a case study on the use of codified hashtags concerning weather warning in Italy in three different regions. METHODS: From November 3rd to December 2nd 2014, tweets identified by the 3 codified hashtags #allertameteoTOS, #allertameteoLIG and #allertameteoPIE were retrieved, collecting a total of 35,558 tweets published by 7361 unique tweets authors, with the aim to assess if codified hashtags could represent an effective way to align formal and informal sources of information during weather related emergencies. An auxiliary R-package was built to lead the analytics used in this study. Authors performed a manual coding of users, hashtags and content of messages of all Twitter data considered. RESULTS: Content analysis showed that tweets were overwhelmingly related to situational updates, with a high percentage containing geo-location information. Communication patterns of different user types were discussed for the three contexts. In accordance with previous studies, individuals showed an active participation primarily functioning as information hub during the emergency. DISCUSSION: In the proposed cases codified hashtags have proven to be an effective tool to convey useful information on Twitter by formal and informal sources. Where institutions supported the use of the predefined hashtag in communication activities, like in Tuscany, messages were very focused, with more than 90% of tweets being situational updates. In this perspective, use of codified hashtags may potentially improve the performance of systems for automatic information retrieval and processing during disasters. PMID- 27500011 TI - Can Quantitative Muscle Strength and Functional Motor Ability Differentiate the Influence of Age and Corticosteroids in Ambulatory Boys with Duchenne Muscular Dystrophy? AB - BACKGROUND: In the absence of a curative treatment for Duchenne Muscular Dystrophy (DMD), corticosteroid therapy (prednisone, deflazacort) has been adopted as the standard of care, as it slows the progression of muscle weakness and enables longer retention of functional mobility. The ongoing development of novel pharmacological agents that target the genetic defect underlying DMD offer hope for a significant alteration in disease progression; however, substantiation of therapeutic efficacy has proved challenging. Identifying functional outcomes sensitive to the early, subtle changes in muscle function has confounded clinical trials. Additionally, the alterations in disease progression secondary to corticosteroid therapy are not well described making it difficult to ascertain the benefits of novel agents, often taken concurrently with corticosteroids. OBJECTIVE: The purpose of this study was to examine outcome responsiveness to corticosteroid therapy and age at the onset of a natural history study of ambulatory boys with DMD. METHODS: Eighty-five ambulatory boys with DMD (mean age 93 mo, range 49 to 180 mo) were recruited into this study. Fifty participants were on corticosteroid therapy, while 33 were corticosteroid naive at the baseline assessment. Within each treatment group boys were divided in two age groups, 4 to 7 years and 8 and greater years of age. The Biodex System 3 Pro isokinetic dynamometer was used to assess muscle strength. Motor skills were assessed using the upper two dimensions (standing/walking, running & jumping) of the Gross Motor Function Measure (GMFM 88) and Timed Motor Tests (TMTs) (10-meter run, sit to stand, supine to stand, climb 4-stairs). Two way analysis of variance and Pearson correlations were used for analysis. RESULTS: A main effect for age was seen in select lower extremity muscle groups (hip flexors, knee extensors and ankle dorsiflexors), standing dimension skills, and all TMTs with significantly greater weakness and loss of motor skill ability seen in the older age group regardless of treatment group. Interaction effects were seen for the walking, running, and jumping dimension of the GMFM with the naive boys scoring higher in the younger group and boys on corticosteroid therapy scoring higher in the older group. The TMT of climb 4-stairs demonstrated a significant treatment effect with the boys on corticosteroid therapy climbing stairs faster than those who were naive, regardless of age. Examination of individual items within the upper level GMFM dimensions revealed select motor skills are more informative of disease progression than others; indicating their potential to be sensitive indicators of alterations in disease progression and intervention efficacy. Analysis of the relationship between muscle group strength and motor skill performance revealed differences in use patterns in the corticosteroid versus naive boys. CONCLUSION: Significant muscle weakness is apparent in young boys with DMD regardless of corticosteroid treatment; however, older boys on corticosteroid therapy tend to have greater retention of muscle strength and motor skill ability than those who are naive. Quantification of muscle strength via isokinetic dynamometry is feasible and sensitive to the variable rates of disease progression in lower extremity muscle groups, but possibly most informative are the subtle changes in the performance characteristics of select motor skills. Further analysis of longitudinal data from this study will explore the influence of corticosteroid therapy on muscle strength and further clarify its impact on motor performance. PMID- 27500012 TI - Coping Strategies for Landslide and Flood Disasters: A Qualitative Study of Mt. Elgon Region, Uganda. AB - INTRODUCTION: The occurrence of landslides and floods in East Africa has increased over the past decades with enormous Public Health implications and massive alterations in the lives of those affected. In Uganda, the Elgon region is reported to have the highest occurrence of landslides and floods making this area vulnerable. This study aimed at understanding both coping strategies and the underlying causes of vulnerability to landslides and floods in the Mt. Elgon region. METHODS: We conducted a qualitative study in three districts of Bududa, Manafwa and Butalejja in the Mt. Elgon region in eastern Uganda. Six Focus Group Discussions (FGDs) and eight Key Informant Interviews (KIIs) were conducted. We used trained research assistants (moderator and note taker) to collect data. All discussions were audio taped, and were transcribed verbatim before analysis. We explored both coping strategies and underlying causes of vulnerability. Data were analysed using latent content analysis; through identifying codes from which basis categories were generated and grouped into themes. RESULTS: The positive coping strategies used to deal with landslides and floods included adoption of good farming methods, support from government and other partners, livelihood diversification and using indigenous knowledge in weather forecasting and preparedness. Relocation was identified as unsustainable because people often returned back to high risk areas. The key underlying causes of vulnerability were; poverty, population pressure making people move to high risk areas, unsatisfactory knowledge on disaster preparedness and, cultural beliefs affecting people's ability to cope. CONCLUSION: This study revealed that deep rooted links to poverty, culture and unsatisfactory knowledge on disaster preparedness were responsible for failure to overcome the effects to landslides and floods in disaster prone communities of Uganda. However, good farming practices and support from the government and implementation partners were shown to be effective in enabling the community to lessen the negative effects disasters. This calls for high impact innovative interventions focused in addressing these underlying causes as well as involvement of all stakeholders in scaling the effective coping strategies in order to build resilience in this community and other similarly affected areas. KEY WORDS: Coping, Underlying causes, Floods, Landslides, Mt. Elgon, Uganda. PMID- 27500013 TI - Effectiveness of Synchronized Noninvasive Ventilation to Prevent Intubation in Preterm Infants. AB - BACKGROUND: Noninvasive ventilation is being increasingly used on preterm infants to reduce ventilator lung injury and bronchopulmonary dysplasia. The aim of this study was to evaluate the effectiveness of synchronized nasal intermittent positive pressure ventilation (SNIPPV) to prevent intubation in premature infants. METHODS: Prospective observational study of SNIPPV use on preterm infants of less than 32 weeks' gestation. All patients were managed using a prospective protocol intended to reduce invasive mechanical ventilation (iMV) use. Previous respiratory status, as well as respiratory outcomes and possible secondary side effects were analyzed. RESULTS: SNIPPV was used on 78 patients: electively to support extubation on 25 ventilator-dependent patients and as a rescue therapy after nasal continuous positive airway pressure failure on 53 patients. For 92% of patients in the elective group and 66% in the rescue group, iMV was avoided over the following 72 hours. No adverse effects were detected, and all patients were in a stable condition even if intubation was eventually needed. CONCLUSIONS: The application of SNIPPV in place of or to remove mechanical ventilation avoids intubation in 74.4% of preterm infants with respiratory failure. No adverse effects were detected. PMID- 27500014 TI - Inadequate Processing of Decellularized Dermal Matrix Reduces Cell Viability In Vitro and Increases Apoptosis and Acute Inflammation In Vivo. AB - Decellularized tissue scaffolds are commonly used in the clinic because they can be used as substitutes for more traditional biomaterials, while imparting additional physiological effects. Nevertheless, reports of complications associated with their use are widespread and poorly understood. This study probes possible causes of these complications by examining cell viability and apoptosis in response to eluents from decellularized dermis. Using multiple sources of decellularized dermis, this study shows that typical decellularized scaffolds (prepared with commonly used laboratory techniques, as well as purchased from commercial sources) contain soluble components that are cytotoxic and that these components can be removed by extensive washes in cell culture media. In addition, this study demonstrates that these observed in vitro phenotypes correlate with increased apoptosis and acute inflammation when implanted subcutaneously in mice. PMID- 27500015 TI - Length and Dimensional Measurements at NIST. AB - This paper discusses the past, present, and future of length and dimensional measurements at NIST. It covers the evolution of the SI unit of length through its three definitions and the evolution of NBS-NIST dimensional measurement from early linescales and gage blocks to a future of atom-based dimensional standards. Current capabilities include dimensional measurements over a range of fourteen orders of magnitude. Uncertainties of measurements on different types of material artifacts range down to 7*10(-8) m at 1 m and 8 picometers (pm) at 300 pm. Current work deals with a broad range of areas of dimensional metrology. These include: large-scale coordinate systems; complex form; microform; surface finish; two-dimensional grids; optical, scanning-electron, atomic-force, and scanning tunneling microscopies; atomic-scale displacement; and atom-based artifacts. PMID- 27500016 TI - The Kilogram and Measurements of Mass and Force. AB - This paper describes the facilities, measurement capabilities, and ongoing research activities in the areas of mass and force at the National Institute of Standards and Technology (NIST). The first section of the paper is devoted to mass metrology and starts with a brief historical perspective on the developments that led to the current definition of the kilogram. An overview of mass measurement procedures is given with a brief discussion of current research on alternative materials for mass standards and surface profiles of the U.S. national prototype kilograms. A brief outlook into the future possible redefinition of the unit of mass based on fundamental principles is included. The second part of this paper focuses on the unit of force and describes the realization of the unit, measurement procedures, uncertainty in the realized force, facilities, and current efforts aimed at the realization of small forces. PMID- 27500017 TI - Primary Atomic Frequency Standards at NIST. AB - The development of atomic frequency standards at NIST is discussed and three of the key frequency-standard technologies of the current era are described. For each of these technologies, the most recent NIST implementation of the particular type of standard is described in greater detail. The best relative standard uncertainty achieved to date for a NIST frequency standard is 1.5*10(-15). The uncertainties of the most recent NIST standards are displayed relative to the uncertainties of atomic frequency standards of several other countries. PMID- 27500018 TI - The Ampere and Electrical Standards. AB - This paper describes some of the major contributions to metrology and physics made by the NIST Electricity Division, which has existed since 1901. It was one of the six original divisions of the National Bureau of Standards. The Electricity Division provides dc and low-frequency calibrations for industrial, scientific, and research organizations, and conducts research on topics related to electrical metrology and fundamental constants. The early work of the Electricity Division staff included the development of precision standards, such as Rosa and Thomas standard resistors and the ac-dc thermal converter. Research contributions helped define the early international system of measurement units and bring about the transition to absolute units based on fundamental principles and physical and dimensional measurements. NIST research has helped to develop and refine electrical standards using the quantum Hall effect and the Josephson effect, which are both based on quantum physics. Four projects covering a number of voltage and impedance measurements are described in detail. Several other areas of current research at NIST are described, including the use of the Internet for international compatibility in metrology, determination of the fine structure and Planck constants, and construction of the electronic kilogram. PMID- 27500019 TI - The Kelvin and Temperature Measurements. AB - The International Temperature Scale of 1990 (ITS-90) is defined from 0.65 K upwards to the highest temperature measurable by spectral radiation thermometry, the radiation thermometry being based on the Planck radiation law. When it was developed, the ITS-90 represented thermodynamic temperatures as closely as possible. Part I of this paper describes the realization of contact thermometry up to 1234.93 K, the temperature range in which the ITS-90 is defined in terms of calibration of thermometers at 15 fixed points and vapor pressure/temperature relations which are phase equilibrium states of pure substances. The realization is accomplished by using fixed-point devices, containing samples of the highest available purity, and suitable temperature-controlled environments. All components are constructed to achieve the defining equilibrium states of the samples for the calibration of thermometers. The high quality of the temperature realization and measurements is well documented. Various research efforts are described, including research to improve the uncertainty in thermodynamic temperatures by measuring the velocity of sound in gas up to 800 K, research in applying noise thermometry techniques, and research on thermocouples. Thermometer calibration services and high-purity samples and devices suitable for "on-site" thermometer calibration that are available to the thermometry community are described. Part II of the paper describes the realization of temperature above 1234.93 K for which the ITS-90 is defined in terms of the calibration of spectroradiometers using reference blackbody sources that are at the temperature of the equilibrium liquid-solid phase transition of pure silver, gold, or copper. The realization of temperature from absolute spectral or total radiometry over the temperature range from about 60 K to 3000 K is also described. The dissemination of the temperature scale using radiation thermometry from NIST to the customer is achieved by calibration of blackbody sources, tungsten-strip lamps, and pyrometers. As an example of the research efforts in absolute radiometry, which impacts the NIST spectral irradiance and radiance scales, results with filter radiometers and a high-temperature blackbody are summarized. PMID- 27500020 TI - The Candela and Photometric and Radiometric Measurements. AB - The national measurement system for photometric and radiometric quantities is presently based upon techniques that make these quantities traceable to a high accuracy cryogenic radiometer. The redefinition of the candela in 1979 provided the opportunity for national measurement laboratories to base their photometric measurements on optical detector technology rather than on the emission from high temperature blackbody optical sources. The ensuing technical developments of the past 20 years, including the significant improvements in cryogenic radiometer performance, have provided the opportunity to place the fundamental maintenance of photometric quantities upon absolute detector based technology as was allowed by the 1979 redefinition. Additionally, the development of improved photodetectors has had a significant impact on the methodology in most of the radiometric measurement areas. This paper will review the status of the NIST implementation of the technical changes mandated by the 1979 redefinition of the candela and its effect upon the maintenance and dissemination of optical radiation measurements. PMID- 27500022 TI - In Situ Burning of Oil Spills. AB - For more than a decade NIST conducted research to understand, measure and predict the important features of burning oil on water. Results of that research have been included in nationally recognized guidelines for approval of intentional burning. NIST measurements and predictions have played a major role in establishing in situ burning as a primary oil spill response method. Data are given for pool fire burning rates, smoke yield, smoke particulate size distribution, smoke aging, and polycyclic aromatic hydrocarbon content of the smoke for crude and fuel oil fires with effective diameters up to 17.2 m. New user-friendly software, ALOFT, was developed to quantify the large-scale features and trajectory of wind blown smoke plumes in the atmosphere and estimate the ground level smoke particulate concentrations. Predictions using the model were tested successfully against data from large-scale tests. ALOFT software is being used by oil spill response teams to help assess the potential impact of intentional burning. PMID- 27500021 TI - Materials Research With Neutrons at NIST. AB - The NIST Materials Science and Engineering Laboratory works with industry, standards bodies, universities, and other government laboratories to improve the nation's measurements and standards infrastructure for materials. An increasingly important component of this effort is carried out at the NIST Center for Neutron Research (NCNR), at present the most productive center of its kind in the United States. This article gives a brief historical account of the growth and activities of the Center with examples of its work in major materials research areas and describes the key role the Center can expect to play in future developments. PMID- 27500023 TI - Statistics and Measurements. AB - For more than 50 years, the Statistical Engineering Division (SED) has been instrumental in the success of a broad spectrum of metrology projects at NBS/NIST. This paper highlights fundamental contributions of NBS/NIST statisticians to statistics and to measurement science and technology. Published methods developed by SED staff, especially during the early years, endure as cornerstones of statistics not only in metrology and standards applications, but as data-analytic resources used across all disciplines. The history of statistics at NBS/NIST began with the formation of what is now the SED. Examples from the first five decades of the SED illustrate the critical role of the division in the successful resolution of a few of the highly visible, and sometimes controversial, statistical studies of national importance. A review of the history of major early publications of the division on statistical methods, design of experiments, and error analysis and uncertainty is followed by a survey of several thematic areas. The accompanying examples illustrate the importance of SED in the history of statistics, measurements and standards: calibration and measurement assurance, interlaboratory tests, development of measurement methods, Standard Reference Materials, statistical computing, and dissemination of measurement technology. A brief look forward sketches the expanding opportunity and demand for SED statisticians created by current trends in research and development at NIST. PMID- 27500024 TI - Mathematics and Measurement. AB - In this paper we describe the role that mathematics plays in measurement science at NIST. We first survey the history behind NIST's current work in this area, starting with the NBS Math Tables project of the 1930s. We then provide examples of more recent efforts in the application of mathematics to measurement science, including the solution of ill-posed inverse problems, characterization of the accuracy of software for micromagnetic modeling, and in the development and dissemination of mathematical reference data. Finally, we comment on emerging issues in measurement science to which mathematicians will devote their energies in coming years. PMID- 27500025 TI - NIST Mechanisms for Disseminating Measurements. AB - The national responsibilities assigned to the National Bureau of Standards (NBS) early in the last century for providing measurement assistance and service are carried out today by the four programs that comprise the National Institute of Standards and Technology (NIST) Office of Measurement Services (OMS). They are the Calibration Program (CP), the Standard Reference Materials Program (SRMP), the Standard Reference Data Program (SRDP), and the Weights and Measures Program (W&MP). Organized when the U.S. Congress changed the NBS name to NIST, the OMS facilitates access to the measurement and standards activities of NIST laboratories and programs through the dissemination of NIST products, data, and services. A brief historical introduction followed by a perspective of pivotal measurement developments from 1901 to the present and concluding with a look to the future of NIST measurement services in the next decade of the new millennium are presented for each OMS program. PMID- 27500026 TI - Information Technology Measurement and Testing Activities at NIST. AB - Our high technology society continues to rely more and more upon sophisticated measurements, technical standards, and associated testing activities. This was true for the industrial society of the 20th century and remains true for the information society of the 21st century. Over the last half of the 20th century, information technology (IT) has been a powerful agent of change in almost every sector of the economy. The complexity and rapidly changing nature of IT have presented unique technical challenges to the National Institute of Standards and Technology (NIST) and to the scientific measurement community in developing a sound measurement and testing infrastructure for IT. This measurement and testing infrastructure for the important non-physical and non-chemical properties associated with complex IT systems is still in an early stage of development. This paper explains key terms and concepts of IT metrology, briefly reviews the history of the National Bureau of Standards/National Institute of Standards and Technology (NBS/NIST) in the field of IT, and reviews NIST's current capabilities and work in measurement and testing for IT. It concludes with a look at what is likely to occur in the field of IT over the next ten years and what metrology roles NIST is likely to play. PMID- 27500027 TI - A Careful Consideration of the Calibration Concept. AB - This paper presents a detailed discussion of the technical aspects of the calibration process with emphasis on the definition of the measurand, the conditions under which the calibration results are valid, and the subsequent use of the calibration results in measurement uncertainty statements. The concepts of measurement uncertainty, error, systematic error, and reproducibility are also addressed as they pertain to the calibration process. PMID- 27500028 TI - The Development of Fluorescence Intensity Standards. AB - The use of fluorescence as an analytical technique has been growing over the last 20 years. A major factor in inhibiting more rapid growth has been the inability to make comparable fluorescence intensity measurements across laboratories. NIST recognizes the need to develop and provide primary fluorescence intensity standard (FIS) reference materials to the scientific and technical communities involved in these assays. The critical component of the effort will be the cooperation between the Federal laboratories, the manufacturers, and the technical personnel who will use the fluorescence intensity standards. We realize that the development and use of FIS will have to overcome many difficulties. However, as we outline in this article, the development of FIS is feasible. PMID- 27500029 TI - Concrete Mixing Methods and Concrete Mixers: State of the Art. AB - As for all materials, the performance of concrete is determined by its microstructure. Its microstructure is determined by its composition, its curing conditions, and also by the mixing method and mixer conditions used to process the concrete. This paper gives an overview of the various types of mixing methods and concrete mixers commercially available used by the concrete industry. There are two main types of mixers used: batch mixers and continuous mixers. Batch mixers are the most common. To determine the mixing method best suited for a specific application, factors to be considered include: location of the construction site (distance from the batching plant), the amount of concrete needed, the construction schedule (volume of concrete needed per hour), and the cost. Ultimately, the quality of the concrete produced determines its performance after placement. An important measure of the quality is the homogeneity of the material after mixing. This paper will review mixing methods in regards to the quality of the concrete produced. Some procedures used to determine the effectiveness of the mixing will be examined. PMID- 27500030 TI - Distribution of Link Distances in a Wireless Network. AB - The probability distribution is found for the link distance between two randomly positioned mobile radios in a wireless network for two representative deployment scenarios: (1) the mobile locations are uniformly distributed over a rectangular area and (2) the x and y coordinates of the mobile locations have Gaussian distributions. It is shown that the shapes of the link distance distributions for these scenarios are very similar when the width of the rectangular area in the first scenario is taken to be about three times the standard deviation of the location distribution in the second scenario. Thus the choice of mobile location distribution is not critical, but can be selected for the convenience of other aspects of the analysis or simulation of the mobile system. PMID- 27500031 TI - Information Model for Machine-Tool-Performance Tests. AB - This report specifies an information model of machine-tool-performance tests in the EXPRESS [1] language. The information model provides a mechanism for describing the properties and results of machine-tool-performance tests. The objective of the information model is a standardized, computer-interpretable representation that allows for efficient archiving and exchange of performance test data throughout the life cycle of the machine. The report also demonstrates the implementation of the information model using three different implementation methods. PMID- 27500032 TI - Global and Local Optimization Algorithms for Optimal Signal Set Design. AB - The problem of choosing an optimal signal set for non-Gaussian detection was reduced to a smooth inequality constrained mini-max nonlinear programming problem by Gockenbach and Kearsley. Here we consider the application of several optimization algorithms, both global and local, to this problem. The most promising results are obtained when special-purpose sequential quadratic programming (SQP) algorithms are embedded into stochastic global algorithms. PMID- 27500033 TI - Video Transmission for Third Generation Wireless Communication Systems. AB - This paper presents a twin-class unequal protected video transmission system over wireless channels. Video partitioning based on a separation of the Variable Length Coded (VLC) Discrete Cosine Transform (DCT) coefficients within each block is considered for constant bitrate transmission (CBR). In the splitting process the fraction of bits assigned to each of the two partitions is adjusted according to the requirements of the unequal error protection scheme employed. Subsequently, partitioning is applied to the ITU-T H.263 coding standard. As a transport vehicle, we have considered one of the leading third generation cellular radio standards known as WCDMA. A dual-priority transmission system is then invoked on the WCDMA system where the video data, after being broken into two streams, is unequally protected. We use a very simple error correction coding scheme for illustration and then propose more sophisticated forms of unequal protection of the digitized video signals. We show that this strategy results in a significantly higher quality of the reconstructed video data when it is transmitted over time-varying multipath fading channels. PMID- 27500034 TI - Treasure of the Past VI: Standard Potential of the Silver-Silver-Chloride Electrode from 0 degrees to 95 degrees C and the Thermodynamic Properties of Dilute Hydrochloric Acid Solutions. AB - From electromotive-force measurements of the cell without liquid junction: [Formula: see text]through the range 0 degrees to 95 degrees C, calculations have been made of (1) the standard potential of the silver-silver-chloride electrode, (2) the activity coefficient of hydrochloric acid in aqueous solutions from m (molality) =0 to m=0.1 and from 0 degrees to 90 degrees C, (3) the relative partial molal heat content of hydrochloric acid, and (4) the relative partial molal heat capacity of hydrochloric acid. The extrapolations were made by the method of least squares with the aid of punch-card techniques. Data from at least 24 cells were analyzed at each temperature, and 81 cells were studied at 25 degrees C. The value of the standard potential was found to be 0.22234 absolute volt at 25 degrees C, and the standard deviation was 0.02 millivolt at 0 degrees C, 0.01 millivolt at 25 degrees C, and 0.09 millivolt at 95 degrees C. The results from 0 degrees to 60 degrees C are compared with earlier determinations of the standard potential and other quantities derived from the electromotive force. PMID- 27500035 TI - Report on the Development of the Advanced Encryption Standard (AES). AB - In 1997, the National Institute of Standards and Technology (NIST) initiated a process to select a symmetric-key encryption algorithm to be used to protect sensitive (unclassified) Federal information in furtherance of NIST's statutory responsibilities. In 1998, NIST announced the acceptance of 15 candidate algorithms and requested the assistance of the cryptographic research community in analyzing the candidates. This analysis included an initial examination of the security and efficiency characteristics for each algorithm. NIST reviewed the results of this preliminary research and selected MARS, RCTM, Rijndael, Serpent and Twofish as finalists. Having reviewed further public analysis of the finalists, NIST has decided to propose Rijndael as the Advanced Encryption Standard (AES). The research results and rationale for this selection are documented in this report. PMID- 27500036 TI - Photocurrent Measurement of PC and PV HgCdTe Detectors. AB - Novel preamplifiers for working standard photoconductive (PC) and photovoltaic (PV) HgCdTe detectors have been developed to maintain the spectral responsivity scale of the National Institute of Standards and Technology (NIST) in the wavelength range of 5 MUm to 20 MUm. The linear PC mode preamplifier does not need any compensating source to zero the effect of the detector bias current for the preamplifier output. The impedance multiplication concept with a positive feedback buffer amplifier was analyzed and utilized in a bootstrap PV transimpedance amplifier to measure photocurrent of a 200 Omega shunt resistance photodiode with a maximum signal gain of 10(8) V/A. In spite of the high performance lock-in used as a second-stage signal-amplifier, the signal-to-noise ratio had to be optimized for the output of the photocurrent preamplifiers. Noise and drift were equalized for the output of the PV mode preamplifier. The signal gain errors were calculated to determine the signal frequency range where photocurrent-to-voltage conversion can be performed with very low uncertainties. For the design of both PC and PV detector preamplifiers, the most important gain equations are described. Measurement results on signal ranges and noise performance are discussed. PMID- 27500037 TI - Treasure of the Past VII: Measurement of the Thickness and Refractive Index of Very Thin Films and the Optical Properties of Surfaces by Ellipsometry. AB - The use of the ellipsometer for the measurement of the thickness and refractive index of very thin films is reviewed. The Poincare sphere representation of the state of polarization of light is developed and used to describe the reflection process. Details of the operation of the ellipsometer are examined critically. A computational method is presented by which the thickness of a film of known refractive index on a reflecting substrate of known optical constants may be calculated directly from the ellipsometer readings. A method for computing both the refractive index and thickness of an unknown film is also developed. These methods have been applied to the determination of the thickness of an adsorbed water layer on chromium ferrotype plates and on gold surfaces. In the former case the thickness was 23 to 27 A, and in the latter was 2 to 5 A. The measurement of the thickness and refractive index of barium fluoride films evaporated on chromium ferrotype surfaces is used as an illustration of the simultaneous determination of these two quantities. PMID- 27500038 TI - WORKSHOP ON TEXTURE IN ELECTRONIC APPLICATIONS Gaithersburg, MD October 10-11, 2000. PMID- 27500039 TI - Hysteresis and Related Error Mechanisms in the NIST Watt Balance Experiment. AB - The NIST watt balance experiment is being completely rebuilt after its 1998 determination of the Planck constant. That measurement yielded a result with an approximately 1*10(-7) relative standard uncertainty. Because the goal of the new incarnation of the experiment is a ten-fold decrease in uncertainty, it has been necessary to reexamine many sources of systematic error. Hysteresis effects account for a substantial portion of the projected uncertainty budget. They arise from mechanical, magnetic, and thermal sources. The new experiment incorporates several improvements in the apparatus to address these issues, including stiffer components for transferring the mass standard on and off the balance, better servo control of the balance, better pivot materials, and the incorporation of erasing techniques into the mass transfer servo system. We have carried out a series of tests of hysteresis sources on a separate system, and apply their results to the watt apparatus. The studies presented here suggest that our improvements can be expected to reduce hysteresis signals by at least a factor of 10-perhaps as much as a factor of 50-over the 1998 experiment. PMID- 27500040 TI - Comparison of Two Cryogenic Radiometers at NIST. AB - Two cryogenic radiometers from NIST, one from the Optical Technology Division and the other from the Optoelectronics Division, were compared at three visible laser wavelengths. For this comparison, each radiometer calibrated two photodiode trap detectors for spectral responsivity. The calibration values for the two trap detectors agreed within the expanded (k = 2) uncertainties. This paper describes the measurement and results of this comparison. PMID- 27500041 TI - Sources of Error in UV Radiation Measurements. AB - Increasing commercial, scientific, and technical applications involving ultraviolet (UV) radiation have led to the demand for improved understanding of the performance of instrumentation used to measure this radiation. There has been an effort by manufacturers of UV measuring devices (meters) to produce simple, optically filtered sensor systems to accomplish the varied measurement needs. We address common sources of measurement errors using these meters. The uncertainty in the calibration of the instrument depends on the response of the UV meter to the spectrum of the sources used and its similarity to the spectrum of the quantity to be measured. In addition, large errors can occur due to out-of-band, non-linear, and non-ideal geometric or spatial response of the UV meters. Finally, in many applications, how well the response of the UV meter approximates the presumed action spectrum needs to be understood for optimal use of the meters. PMID- 27500042 TI - Hysteresis in Transport Critical-Current Measurements of Oxide Superconductors. AB - We have investigated magnetic hysteresis in transport critical-current (I c) measurements of Ag-matrix (Bi,Pb)2Sr2Ca2Cu3O10- x (Bi-2223) and AgMg-matrix Bi2Sr2CaCu2O8+ x (Bi-2212) tapes. The effect of magnetic hysteresis on the measured critical current of high temperature superconductors is a very important consideration for every measurement procedure that involves more than one sweep of magnetic field, changes in field angle, or changes in temperature at a given field. The existence of this hysteresis is well known; however, the implications for a measurement standard or interlaboratory comparisons are often ignored and the measurements are often made in the most expedient way. A key finding is that I c at a given angle, determined by sweeping the angles in a given magnetic field, can be 17 % different from the I c determined after the angle was fixed in zero field and the magnet then ramped to the given field. Which value is correct is addressed in the context that the proper sequence of measurement conditions reflects the application conditions. The hysteresis in angle-sweep and temperature-sweep data is related to the hysteresis observed when the field is swept up and down at constant angle and temperature. The necessity of heating a specimen to near its transition temperature to reset it to an initial state between measurements at different angles and temperatures is discussed. PMID- 27500043 TI - Powder X-Ray Reference Patterns of Sr2RGaCu2O y (R = Pr, Nd, Sm, Eu, Gd, Dy, Ho, Er, Tm, and Y). AB - X-Ray Rietveld refinements were conducted on a series of eleven lanthanide phases, Sr2RGaCu2O y (2112 phase, R = Pr, Nd, Sm, Eu, Gd, Dy, Ho, Y, Er, Tm, and Yb) that are structurally related to the high T c superconductor Ba2YCu3O7 (213). In the 2112 structure, instead of square planar Cu-O chains, tetrahedral GaO4 chains were found to run in a zig-zag fashion along the diagonal of the basal 213 ab-direction. Reference powder patterns for these compounds were prepared by using the Rietveld decomposition technique. The unit cell volume of these compounds follows the expected trend of the lanthanide contraction. The lattice parameters range from a = 22.9694(3) A, b = 5.5587(2) A, and c = 5.44743(7) A for R = Pr, to a = 22.8059(2) A, b = 5.46031(5) A, and c = 5.37773(5) A for R = Yb. An electon diffraction study of the Sm- and Er-analogs showed characteristic diffuse streaks along the b-axis, suggesting some disorder within the GaO4 chains. PMID- 27500044 TI - Compressing Spin-Polarized (3)He With a Modified Diaphragm Pump. AB - Nuclear spin-polarized (3)He gas at pressures on the order of 100 kPa (1 bar) are required for several applications, such as neutron spin filters and magnetic resonance imaging. The metastability-exchange optical pumping (MEOP) method for polarizing (3)He gas can rapidly produce highly polarized gas, but the best results are obtained at much lower pressure (~0.1 kPa). We describe a compact compression apparatus for polarized gas that is based on a modified commercial diaphragm pump. The gas is polarized by MEOP at a typical pressure of 0.25 kPa (2.5 mbar), and compressed into a storage cell at a typical pressure of 100 kPa. In the storage cell, we have obtained 20 % to 35 % (3)He polarization using pure (3)He gas and 35 % to 50 % (3)He polarization using (3)He-(4)He mixtures. By maintaining the storage cell at liquid nitrogen temperature during compression, the density has been increased by a factor of four. PMID- 27500046 TI - Fraunhofer Diffraction Effects on Total Power for a Planckian Source. AB - An algorithm for computing diffraction effects on total power in the case of Fraunhofer diffraction by a circular lens or aperture is derived. The result for Fraunhofer diffraction of monochromatic radiation is well known, and this work reports the result for radiation from a Planckian source. The result obtained is valid at all temperatures. PMID- 27500045 TI - Treasure of the Past VIII: Molecular Basis of Flame Inhibition. AB - The role played by inorganic chemical additives in fire retardancy and flame inhibition is considered. Particular attention is given to the molecular level aspects of commercially important systems containing compounds of antimony, halogens, and phosphorus. The flame inhibiting function of metal containing additives is also discussed. PMID- 27500047 TI - Environmental Radiation Monitoring at NBS/NIST From 1960 Through 2000. AB - The program for monitoring the environment in and about the site of the National Bureau of Standards, now the National Institute of Standards and Technology, at its Gaithersburg, Maryland location began in 1960. The program includes measurements of radiation fields at the fence line of the site and of radionuclides in samples of soil, water, and biota taken within and around the site. A variety of instruments and equipment, processes and procedures, and measurement devices has been employed. To date, no measurement from the routine program has exhibited any result that could be attributed to any effluent or other effect of the radiological work conducted at the site; that includes the NIST Research Reactor, the now defunct Linear Electron Accelerator (LINAC) and other accelerators, radiochemistry, and sealed source operations. PMID- 27500048 TI - Vibrational Branching Ratios and Asymmetry Parameters in the Photoionization of CO2 in the Region Between 650 A and 840 A. AB - The vibrational branching ratios and asymmetry parameters for CO2 have been determined in the wavelength region of 650 A to near the ionization onset at about 840 A. The study was performed using synchrotron radiation from the Daresbury storage ring that was dispersed with a 5 m grating monochomator that afforded resolution of 0.1 A to 0.2 A. This resolution allowed the study of the branching ratios and asymmetry parameters with enough detail to see the changes in the parameters within the pronounced autoionization structure in CO2 in this wavelength region. While the electron spectrometer resolution was not sufficient to resolve the spin orbit and Renner-Teller splitting in the photoelectron spectra, we are able to fit the data with a model that identifies the major structure in terms of the symmetric stretch and elements of the asymmetric stretch and bending modes. A calculation of the expected relative vibrational excitations based upon the Franck-Condon principle clearly showed non-Franck Condon behavior in some of the vibrational-electronic transitions. PMID- 27500049 TI - Transfer Calibration Validation Tests on a Heat Flux Sensor in the 51 mm High Temperature Blackbody. AB - Facilities and techniques to characterize heat flux sensors are under development at the National Institute of Standards and Technology. As a part of this effort, a large aperture high-temperature blackbody was commissioned recently. The graphite tube blackbody, heated electrically, has a cavity diameter of 51 mm and can operate up to a maximum temperature of 2773 K. A closed-loop cooling system using a water-to-water heat exchanger cools electrodes and the outer reflecting shield. This paper describes the newly developed blackbody facility and the validation tests conducted using a reference standard Schmidt-Boelter heat flux sensor. The transfer calibration results obtained on the Schmidt-Boelter sensor agreed with the previous data within the experimental uncertainty limits. PMID- 27500050 TI - Precision Ultrasonic Wave Measurements With Simple Equipment. AB - We describe the design and construction of a relatively simple, inexpensive laser interferometer system for accurate measurements of ultrasonic surface displacement waveforms in reasonably friendly environments. We show how analysis of a single waveform can provide both the calibration constant required for absolute measurements and an estimate of the uncertainty of these measurements. We demonstrate the performance of this interferometer by measuring ultrasonic waveforms generated by a novel conical-element ultrasonic transducer. PMID- 27500051 TI - Studies of Excess Heat and Convection in a Water Calorimeter. AB - To explain a difference of 0.5 % between the absorbed-dose standards of the National Institute of Standards and Technology (NIST) and the National Research Council of Canada (NRCC), Seuntjens et al. suggest the fault lies with the NIST water calorimeter being operated at 22 degrees C and the method with which the measurements were made. Their calculations show that this difference is due to overprediction of temperature rises of six consecutive (60)Co radiation runs at NIST. However, the consecutive runs they refer to were merely preliminary measurements to determine the procedure for the NIST beam calibration. The beam calibration was determined from only two consecutive runs followed by water circulation to re-establish temperature equilibrium. This procedure was used for measurements on 77 days, with 32 runs per day. Convection external to the glass cylindrical detector assembly performed a beneficial role. It aided (along with conduction) in increasing the rate of excess heat transported away from the thin cylindrical wall. This decreased the rate of heat conducted toward the axially located thermistors. The other sources of excess heat are the: (1) non-water materials in the temperature probe, and (2) exothermic effect of the once distilled water external to the cylinder. Finite-element calculations were made to determine the separate and combined effects of the excess heat sources for the afterdrift. From this analysis, extrapolation of the measured afterdrifts of two consecutive runs to mid radiation leads to an estimated over-prediction of no more than about 0.1 %. Experimental measurements contradict the calculated results of Seuntjens et al. that convective motion (a plume) originates from the thermistors operated with an electrical power dissipation as low as 0.6 MUW, well below the measured threshold of 50 MUW. The method used for detecting a plume was sensitive enough to measure a convective plume (if it had started) down to about the 10 MUW power level. Measurements also contradict the NRCC calculations in predicting the behavior of the NIST afterdrifts. PMID- 27500052 TI - Treasure of the Past IX: Exposure Standardization of Iodine-125 Seeds Used for Brachytherapy. AB - A method for calibrating iodine-125 seeds in terms of exposure has been established. The standard free-air ionization chamber, used for measuring soft x rays, was chosen for the measurements. Arrays of four to six seeds were used to enhance the ionization-current-to-background-current ratio. Seeds from an array were measured individually in a re-entrant chamber. The quotient of the exposure rate for the array by the sum of the ionization currents in the re-entrant chamber is the calibration factor for the re-entrant chamber. Calibration factors were established for three types of iodine-125 seeds. The overall uncertainty for the seed exposure calibrations is less than 6%. PMID- 27500053 TI - NIST-ASME WORKSHOP ON UNCERTAINTY IN DIMENSIONAL MEASUREMENTS Gaithersburg, MD June 5-7, 2001. PMID- 27500054 TI - High Pressure X-Ray Crystallography With the Diamond Cell at NIST/NBS. AB - Scientists in the Crystallography Section at NIST/NBS made several outstanding contributions which greatly promoted the development and advancement of high pressure x-ray crystallography during the second-half of the 20th century. These milestone achievements or "firsts" included: (1) the invention of the lever-arm type diamond anvil cell (DAC) in 1958; (2) the development of DAC technology for powder x-ray diffraction at high pressure in 1960; (3) the introduction of DAC methodology for single crystal x-ray diffraction at high pressure in 1964; (4) the invention of the optical fluorescence ruby method of pressure measurement in 1971; and (5) the discovery of hydrostatic pressure-transmitting media useful to unprecedented pressures for that time. These achievements provided the spark that ignited the explosion of activity in high pressure research that occurred in laboratories throughout the world during the latter part of the 20th century. It is still going on, unabated, today. An estimated 5000 DACs were built during the last 40 years. PMID- 27500055 TI - Past and Present Crystallographic Work at the NBS/NIST Reactor. AB - Neutron diffraction at NBS/NIST started soon after the NBS reactor became operational in the summer of 1969. Since that time, literally hundreds of crystal structures have been determined and refined using single crystal and powder neutron diffraction data, collected with a variety of instruments. This work has been usually done in collaboration with other NBS/NIST divisions and/or universities and industrial laboratories. In parallel with the technical developments and the experimental work, also theoretical aspects of crystal geometry have been clarified, and significant improvements in the techniques of profile refinements have been made. It is therefore understandable that a comprehensive description of all the crystallographic studies carried out up to the present is impossible under the constraints of space and time imposed by a review of this type, and, in the following sections, we will limit ourselves to give, only a brief account of the topics which, in our opinion, represent the highlights of the work carried out at the reactor. PMID- 27500057 TI - Investigations of Zeolitic Materials at the NIST Center for Neutron Research. AB - Crystallographic studies of four zeolitic materials using neutron powder diffraction data are presented. In most cases, these projects benefited from the combined use of neutron and x-ray measurements. PMID- 27500056 TI - Magnetic Structure Determinations at NBS/NIST. AB - Magnetic neutron scattering plays a central role in determining and understanding the microscopic properties of a vast variety of magnetic systems, from the fundamental nature, symmetry, and dynamics of magnetically ordered materials to elucidating the magnetic characteristics essential in technological applications. From the early days of neutron scattering measurements at NBS/NIST, magnetic diffraction studies have been a central theme involving many universities, industrial and government labs from around the United States and worldwide. Such measurements have been used to determine the spatial arrangement and directions of the atomic magnetic moments, the atomic magnetization density of the individual atoms in the material, and the value of the ordered moments as a function of thermodynamic parameters such as temperature, pressure, and applied magnetic field. These types of measurements have been carried out on single crystals, powders, thin films, and artificially grown multilayers, and often the information collected can be obtained by no other experimental technique. This article presents, in an historical perspective, a few examples of work carried out at the NIST Center for Neutron Research (NCNR), and discusses the key role that the Center can expect to play in future magnetism research. PMID- 27500058 TI - Quasicrystals. AB - The discretely diffracting aperiodic crystals termed quasicrystals, discovered at NBS in the early 1980s, have led to much interdisciplinary activity involving mainly materials science, physics, mathematics, and crystallography. It led to a new understanding of how atoms can arrange themselves, the role of periodicity in nature, and has created a new branch of crystallography. PMID- 27500059 TI - Lattice Symmetry and Identification-The Fundamental Role of Reduced Cells in Materials Characterization. AB - In theory, physical crystals can be represented by idealized mathematical lattices. Under appropriate conditions, these representations can be used for a variety of purposes such as identifying, classifying, and understanding the physical properties of materials. Critical to these applications is the ability to construct a unique representation of the lattice. The vital link that enabled this theory to be realized in practice was provided by the 1970 paper on the determination of reduced cells. This seminal paper led to a mathematical approach to lattice analysis initially based on systematic reduction procedures and the use of standard cells. Subsequently, the process evolved to a matrix approach based on group theory and linear algebra that offered a more abstract and powerful way to look at lattices and their properties. Application of the reduced cell to both database work and laboratory research at NIST was immediately successful. Currently, this cell and/or procedures based on reduction are widely and routinely used by the general scientific community: (i) for calculating standard cells for the reporting of crystalline materials, (ii) for classifying materials, (iii) in crystallographic database work (iv) in routine x-ray and neutron diffractometry, and (v) in general crystallographic research. Especially important is its use in symmetry determination and in identification. The focus herein is on the role of the reduced cell in lattice symmetry determination. PMID- 27500060 TI - Electron Diffraction Using Transmission Electron Microscopy. AB - Electron diffraction via the transmission electron microscope is a powerful method for characterizing the structure of materials, including perfect crystals and defect structures. The advantages of electron diffraction over other methods, e.g., x-ray or neutron, arise from the extremely short wavelength (~2 pm), the strong atomic scattering, and the ability to examine tiny volumes of matter (~10 nm(3)). The NIST Materials Science and Engineering Laboratory has a history of discovery and characterization of new structures through electron diffraction, alone or in combination with other diffraction methods. This paper provides a survey of some of this work enabled through electron microscopy. PMID- 27500061 TI - JCPDS-ICDD Research Associateship (Cooperative Program with NBS/NIST). AB - The Research Associateship program of the Joint Committee on Powder Diffraction International Centre for Diffraction Data (JCPDS-ICDD, now known as the ICDD) at NBS/NIST was a long standing (over 35 years) successful industry-government cooperation. The main mission of the Associateship was to publish high quality x ray reference patterns to be included in the Powder Diffraction File (PDF). The PDF is a continuing compilation of patterns gathered from many sources, compiled and published by the ICDD. As a result of this collaboration, more than 1500 high quality powder diffraction patterns, which have had a significant impact on the scientific community, were reported. In addition, various research collaborations with NBS/NIST also led to the development of several standard reference materials (SRMs) for instrument calibration and quantitative analyses, and computer software for data collection, calibration, reduction, for the editorial process of powder pattern publication, analysis of powder data, and for quantitative analyses. This article summarizes information concerning the JCPDS-ICDD organization, the Powder Diffraction File (PDF), history and accomplishments of the JCPDS-ICDD Research Associateship. PMID- 27500062 TI - A Natural Bone Cement-A Laboratory Novelty Led to the Development of Revolutionary New Biomaterials. AB - Research on calcium phosphate chemistry at NIST led to the discovery of the worlds first self-hardening calcium phosphate cements (CPC) in 1987. Laboratory, animal, and clinical studies were conducted to develop CPC into clinically useful biomaterials. The combination of self-hardening capability and high biocompatibility makes CPC a unique material for repairing bone defects. Near perfect adaptation of the cement to the tissue surfaces in a defect, and a gradual resorption followed by new bone formation are some of the other distinctive advantages of this biomaterial. In 1996 a CPC, consisting of tetracalcium phosphate and dicalcium phosphate anhydrous, was approved by the Food and Drug Administration (FDA) for repairing cranial defects in humans, thus becoming the first material of its kind available for clinical use. This paper will review the course of the development, the physical and chemical properties, and clinical applications of CPC. PMID- 27500063 TI - Structures of Biological Minerals in Dental Research. AB - Structural features of some calcium phosphates of biological interest are described. Structure of hydroxyapatite (OHAp), considered as the prototype for the inorganic component of bones and teeth is discussed with respect to the kinds and locations of ionic substitutions. Octacalcium phosphate (OCP), is a probable precursor in biological mineralization. OCP has a layer type structure, with one layer quite similar to that of OHAp and the other, a hydrated layer consisting of more widely spaced Ca, and PO4 ions and the water molecules. The closeness of fit in the apatitic layers of OCP and OHAp accounts for the epitaxial, interlayered mixtures formed by these compounds and the in situ conversion of OCP to OHAp. Possible roles of OCP in biological mineralization are discussed. PMID- 27500064 TI - NIST Materials Properties Databases for Advanced Ceramics. AB - The NIST Ceramics Division maintains two databases on the physical, mechanical, thermal, and other properties of high temperature superconductors and structural ceramics. Crystallographic data are featured prominently among the physical property data and serve several important functions in the classification and evaluation of the property values. The scope of materials, properties, and data evaluation protocols are discussed for the two databases. PMID- 27500065 TI - Contributions of NIST/NBS Researchers to the Crystallography of Construction Materials. AB - For more than 100 years, the primary theme underlying the NBS/NIST staff contribution to the crystallography of building materials has been the development of an improved understanding of concrete materials performance. Over that time period, portland cement concrete has become one of the most important of our construction materials for roads, buildings, and other large municipal structures. At the beginning of the 20th century our understanding of portland cement composition, performance, use in concrete, and how the concrete performs in harsh environments was lacking. The efforts of NIST have served to advance construction materials science and technology through the combined efforts of experimental, field study, and theoretical computational materials science. One major achievement in the late 1920s, derived from studies on phase equilibria in cement clinker, allows calculation of potential cement clinker composition. Known as the Bogue calculation, this continues to be an essential tool in cement plant process control to this day. Additionally, contributions of NIST scientists to our knowledge of the chemistry and nature of cement hydration products have been crucial in our understanding of cement hydration and concrete durability. Today, computational materials science is a rapidly developing discipline, and NIST is developing tools incorporating predictive models aided by empirical studies. Examples include a computer-integrated knowledge system for prediction and optimization of performance and life-cycle cost of high performance concrete and the Virtual Cement and Concrete Testing Laboratory. Understanding the relationships between material and performance properties has not been confined only to portland cements. One of the longest running experiments at NIST, the stone test wall, has stood for over 50 years as one of the world's largest single collections of building stone, and is invaluable for studying weathering effects associated with stone mineralogy and texture. Standards development has also been promoted through participation on ASTM subcommittees on stone, cement, and concrete. The Cement and Concrete Reference Laboratory, established in 1929, continues to provide testing and training for outside laboratories and maintains a historical record of test data on construction materials. PMID- 27500066 TI - Crystallographic Texture in Ceramics and Metals. AB - Preferred crystallographic orientation, or texture, occurs almost universally, both in natural and man-made systems. Many components and devices in electronic and magnetic systems are fabricated from materials that have crystallographic texture. With the rapidly increasing use of thin film technology, where sharp axisymmetric crystallographic texture normal to the film plane is frequently observed, the occurrence and impact of texture are rising. Thin film applications in which the texture of the material plays a key role in determining properties and performance are broad: complex oxides in random access memory devices, ZnO thin film resonators for cell phone applications, metallic alloys in magnetic recording media, and Al and Cu interconnects in integrated circuits are but a few examples. Texture is established during the synthesis or post-synthesis heat treatment of a material and thus has a strong dependence upon processing history. Accurate measurement of texture is not simple and a variety of tools and approaches are being actively employed in texture studies. X-ray, neutron and electron diffraction based techniques are practiced around the world at varying levels of complexity with regard to equipment and analysis methods. Despite the well-documented existence of these varied approaches, many reported texture measurements on electronic materials are based solely on the relative intensities of conventional theta-2theta x-ray diffraction peaks, which typically yield inaccurate results. NIST has developed quantitative texture measurement techniques that employ equipment commonly available in most industrial and academic settings. A number of examples of texture measurement in ceramic and metal systems will be presented, taken from the historical development and application of these techniques at NIST over the past 7 years. PMID- 27500067 TI - Standard Reference Material (SRM 1990) For Single Crystal Diffractometer Alignment. AB - An international project was successfully completed which involved two major undertakings: (1) a round-robin to demonstrate the viability of the selected standard and (2) the certification of the lattice parameters of the SRM 1990, a Standard Reference Material((r)) for single crystal diffractometer alignment. This SRM is a set of ~3500 units of Cr-doped Al2O3, or ruby spheres [(0.420.011 mole fraction % Cr (expanded uncertainty)]. The round-robin consisted of determination of lattice parameters of a pair of crystals: the ruby sphere as a standard, and a zeolite reference to serve as an unknown. Fifty pairs of crystals were dispatched from Hauptman-Woodward Medical Research Institute to volunteers in x-ray laboratories world-wide. A total of 45 sets of data was received from 32 laboratories. The mean unit cell parameters of the ruby spheres was found to be a=4.7608 A+/-0.0062 A, and c=12.9979 A+/-0.020 A (95 % intervals of the laboratory means). The source of errors of outlier data was identified. The SRM project involved the certification of lattice parameters using four well-aligned single crystal diffractometers at (Bell Laboratories) Lucent Technologies and at NRC of Canada (39 ruby spheres), the quantification of the Cr content using a combined microprobe and SEM/EDS technique, and the evaluation of the mosaicity of the ruby spheres using a double-crystal spectrometry method. A confirmation of the lattice parameters was also conducted using a Guinier-Hagg camera. Systematic corrections of thermal expansion and refraction corrections were applied. These rubies- are rhombohedral, with space group [Formula: see text]. The certified mean unit cell parameters are a=4.76080+/-0.00029 A, and c=12.99568 A+/-0.00087 A (expanded uncertainty). These certified lattice parameters fall well within the results of those obtained from the international round-robin study. The Guinier Hagg transmission measurements on five samples of powdered rubies (a=4.7610 A+/ 0.0013 A, and c = 12.9954 A+/-0.0034 A) agreed well with the values obtained from the single crystal spheres. PMID- 27500068 TI - Phase Equilibria and Crystallography of Ceramic Oxides. AB - Research in phase equilibria and crystallography has been a tradition in the Ceramics Division at National Bureau of Standards/National Institute of Standatrds and Technology (NBS/NIST) since the early thirties. In the early years, effort was concentrated in areas of Portland cement, ceramic glazes and glasses, instrument bearings, and battery materials. In the past 40 years, a large portion of the work was related to electronic materials, including ferroelectrics, piezoelectrics, ionic conductors, dielectrics, microwave dielectrics, and high-temperature superconductors. As a result of the phase equilibria studies, many new compounds have been discovered. Some of these discoveries have had a significant impact on US industry. Structure determinations of these new phases have often been carried out as a joint effort among NBS/NIST colleagues and also with outside collaborators using both single crystal and neutron and x-ray powder diffraction techniques. All phase equilibria diagrams were included in Phase Diagrams for Ceramists, which are collaborative publications between The American Ceramic Society (ACerS) and NBS/NIST. All x-ray powder diffraction patterns have been included in the Powder Diffraction File (PDF). This article gives a brief account of the history of the development of the phase equilibria and crystallographic research on ceramic oxides in the Ceramics Division. Represented systems, particularly electronic materials, are highlighted. PMID- 27500069 TI - Towards Near Perfect Crystals With Only Well-Characterized Imperfections. AB - Throughout the past century NBS/NIST supported a great variety of research studies in crystallography where the aim was the highest attainable accuracy in measurements. While avoiding overlap with other papers in this volume, this article summarizes results from: 1) early work on crystallization as a method of purification, in contributions to sugar chemistry, and in solution growth of large crystals; 2) the NBS/ARPA Program of research on crystal growth and characterization; 3) the NBS Free-Radical Research Program; 4) the XRCD method as a direct path to relative atomic mass data and the fundamental physical constants; 5) the dynamical theory of x-ray diffraction; and 6) symmetry considerations such as are involved in the influence on crystals of mechanical stress or fields, and of point defect motion. PMID- 27500070 TI - National Institute of Standards and Technology Synchrotron Radiation Facilities for Materials Science. AB - Synchrotron Radiation Facilities, supported by the Materials Science and Engineering Laboratory of the National Institute of Standards and Technology, include beam stations at the National Synchrotron Light Source at Brookhaven National Laboratory and at the Advanced Photon Source at Argonne National Laboratory. The emphasis is on materials characterization at the microstructural and at the atomic and molecular levels, where NIST scientists, and researchers from industry, universities and government laboratories perform state-of-the-art x-ray measurements on a broad range of materials. PMID- 27500071 TI - Macromolecular Crystallography and Structural Biology Databases at NIST. AB - In the late 1970s, macromolecular crystallography at NIST began with collaboration between NIST and NIH to establish a single-crystal neutron diffractometer. This instrument was constructed and employed to solve a number of crystal structures: bovine ribonuclease A, bovine-ribonuclease-uridine vanadate complex, and porcine insulin. In the mid 1980s a Biomolecular Structure Group was created establishing NIST capabilities in biomolecular singe-crystal x-ray diffraction. The group worked on a variety of structural problems until joining the NIST/UMBI Center for Advanced Research in Biotechnology (CARB) in 1987. Crystallographic studies at CARB were then focused on protein engineering efforts that included among others chymosin, subtilisin BPN', interleukin 1beta, and glutathione S-transferase. Recently, the structural biology efforts have centered on enzymes in the chorismate metabolic pathways involved in amino acid biosynthesis and in structural genomics that involves determining the structures of "hypothetical" proteins to aid in assigning function. In addition to crystallographic studies, structural biology database activities began with the formal establishment of the Biological Macro-molecule Crystallization Database in 1989. Later, in 1997, NIST in partnership with Rutgers and UCSD formed the Research Collaboratory for Structural Bioinformatics that successfully acquired the Protein Data Bank. The NIST efforts in these activities have focused on data uniformity, establishing and maintaining the physical archive, and working with the NMR community. PMID- 27500072 TI - EAST syndrome: Clinical, pathophysiological, and genetic aspects of mutations in KCNJ10. AB - EAST syndrome is a recently described autosomal recessive disorder secondary to mutations in KCNJ10 (Kir4.1), a gene encoding a potassium channel expressed in the brain, eye, ear and kidney. This condition is characterized by 4 cardinal features; Epilepsy, Ataxia, Sensorineural deafness, and (a renal salt-wasting) Tubulopathy, hence the acronym EAST syndrome. Here we review reported clinical manifestations, in particular the neurological signs and symptoms which typically have the most impact on the quality of life of patients. In addition we review the pathophysiology and genetic aspects of the disease. So far 14 different KCNJ10 mutations have been published which either directly affect channel function or may lead to mislocalisation. Investigations of the pathophysiology may provide clues to potential treatments. PMID- 27500073 TI - SDF1-CXCR4 signaling: A new player involved in DiGeorge/22q11-deletion syndrome. AB - The DiGeorge/22q11-deletion syndrome (22q11DS), also known as velocardiofacial syndrome, is a congenital disease causing numerous structural and behavioral disorders, including cardiac outflow tract anomalies, craniofacial dysmorphogenesis, parathyroid and thymus hypoplasia, and mental disorders. It results from a unique chromosomal microdeletion on the 22q11.2 region in which the transcriptional activator TBX1 is decisive for the occurrence of the disease. During embryogenesis, Tbx1 is required for patterning of pharyngeal region giving rise to structures of the face, neck and chest. Genetic and developmental studies demonstrated that the severity and variability of the syndrome are determined by Tbx1 targets involved in pharyngeal neural crest cell migration and survival. Recently, we demonstrated that the chemokine Sdf1/Cxcl12 and its receptor Cxcr4 are genetically downstream of Tbx1 during pharyngeal development and that reduction of CXCR4 signaling results in defects which recapitulate the major morphological anomalies of 22q11DS, supporting the possibility of a pivotal role for the SDF1/CXCR4 axis in its etiology. PMID- 27500075 TI - Prosocial Behavior Mitigates the Negative Effects of Stress in Everyday Life. AB - Recent theories of stress reactivity posit that, when stressed, individuals tend to seek out opportunities to affiliate with and nurture others in order to prevent or mitigate the negative effects of stress. However, few studies have tested empirically the role of prosocial behavior in reducing negative emotional responses to stress. The current analyses used daily diary data to investigate whether engaging in prosocial behavior buffered the negative effects of naturally occurring stressors on emotional well-being. Results showed that on a given day, prosocial behavior moderated the effects of stress on positive affect, negative affect, and overall mental health. Findings suggest that affiliative behavior may be an important component of coping with stress, and indicate that engaging in prosocial behavior might be an effective strategy for reducing the impact of stress on emotional functioning. PMID- 27500074 TI - Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases. AB - We previously demonstrated elevated brain iron levels in myelinated structures and associated cells in a hemochromatosis Hfe (-/-) xTfr2 (mut) mouse model. This was accompanied by altered expression of a group of myelin-related genes, including a suite of genes causatively linked to the rare disease family 'neurodegeneration with brain iron accumulation' (NBIA). Expanded data mining and ontological analyses have now identified additional myelin-related transcriptome changes in response to brain iron loading. Concordance between the mouse transcriptome changes and human myelin-related gene expression networks in normal and NBIA basal ganglia testifies to potential clinical relevance. These analyses implicate, among others, genes linked to various rare central hypomyelinating leukodystrophies and peripheral neuropathies including Pelizaeus-Merzbacher-like disease and Charcot-Marie-Tooth disease as well as genes linked to other rare neurological diseases such as Niemann-Pick disease. The findings may help understand interrelationships of iron and myelin in more common conditions such as hemochromatosis, multiple sclerosis and various psychiatric disorders. PMID- 27500076 TI - Measuring Capacity for Resilience among Coastal Counties of the US Northern Gulf of Mexico Region. AB - Many have voiced concern about the long-term survival of coastal communities in the face of increasingly intense storms and sea level rise. In this study we select indicators of key theoretical concepts from the social-ecological resilience literature, aggregate those indicators into a resilience-capacity index, and calculate an index score for each of the 52 coastal counties of Louisiana, Texas, Mississippi, Alabama and Florida. Building upon Cutter's Social Vulnerability Index work [1], we use Factor Analysis to combine 43 variables measuring demographics, social capital, economic resources, local government actions, and environmental conditions within the counties. Then, we map the counties' scores to show the spatial distribution of resilience capacities. The counties identified as having the highest resilience capacities include the suburban areas near New Orleans, Louisiana and Tampa, Florida, and the growing beach-tourist communities of Alabama and central Florida. Also, we examine whether those counties more active in oil and gas development and production, part of the region's "energy coast", have greater capacity for resilience than other counties in the region. Correlation analyses between the resilience capacity index scores and two measures of oil and gas industry activity (total employment and number of business establishments within five industry categories) yielded no statistically significant associations. By aggregating a range of important contextual variables into a single index, the study demonstrates a useful approach for the more systematic examination and comparison of exposure, vulnerability and capacity for resilience among coastal communities. PMID- 27500077 TI - Rapid advance of two mountain glaciers in response to mine-related debris loading. AB - Rapid glacier advance is known to occur by a range of mechanisms. However, although large-scale debris loading has been proposed as a process for causing rapid terminus advance, it has rarely been observed. We use satellite remote sensing data to observe accelerated glacier terminus advance in response to massive supraglacial loading on two glaciers in Kyrgyzstan. Over a 15 year period, mining activity has led to the dumping of spoil of up to 180 m thick on large parts of these valley glaciers. We find that the termini of these glaciers advance by 1.2 and 3.2 km, respectively, at a rate of up to 350 m yr-1. Our analysis suggests that although enhanced basal sliding could be an important process, massive supraglacial loads have also caused enhanced internal ice deformation that would account for most, or all, of the glacier terminus advance. In addition, narrowing of the glacier valley and mining and dumping of ice alter the mass balance and flow regime of the glaciers. Although the scale of supraglacial loading is massive, this full-scale experiment provides insight into glacier flow acceleration response where small valley glaciers are impacted by very large volumes of landslide debris. PMID- 27500078 TI - Peer-assisted teaching student tutors as examiners in an orthopedic surgery OSCE station - pros and cons. AB - BACKGROUND: The OSCE (objective structured clinical examination) is composed of oral and practical examination in order to examine students' abilities to imply clinical examination techniques and to interact with patients. The examiners for this procedure can be either lecturers or peers. The aim of this work is to evaluate the peer-assisted teaching student tutors as examiners in an orthopedic surgery OSCE station. METHODS: We analyzed the OSCE data from 2013 to 2015. During this period over 300 medical students were examined each year. An evaluation was conducted at an orthopedic station and examined by peer students to assess the advantages and disadvantages of peer-assisted teaching student tutors as examiners. RESULTS: We have noticed that student peers are more flexible regarding their schedule and they have been well trained for OSCE. Concerning the economic aspects, student peers are clearly of major economic advantage. Disadvantages were not reported in our study probably because peers were well trained and the checklists are monitored regularly. CONCLUSION: Student peers in OSCE are of major advantage due to their flexible time schedule and relatively low costs. They must be well trained and the checklists are to be monitored regularly. Our study shows that peer tutor examiners conducted the examination as competent as lecture examiners. However, legal restrictions on the employment of students should be considered. PMID- 27500079 TI - Electrogenerated Chemiluminescence Reporting on Closed Bipolar Microelectrodes and the Influence of Electrode Size. AB - We report a fundamental study of the use of Ru(bpy)32+-based electrogenerated chemiluminescence (ECL) as an optical reporting system for the detection of redox active analyte on closed bipolar microelectrodes, focused on gaining an in-depth understanding of the correlation between ECL emission intensity and electrochemical current. We demonstrate the significant effect that the size of the anodic and cathodic poles has on the resulting ECL signal and show how this influences the quantitative detection of analyte on a closed bipolar electrode. By carefully designing the geometry of the bipolar electrode, the detection performance of the system can be tuned to different analyte concentration ranges. We show that through a simple voltammetric study of the individual reactions, one can understand the coupled bipolar behavior and accurately predict the ECL signal response to a range of analyte concentrations, enabling the accurate prediction of calibration curves. PMID- 27500080 TI - Human Papillomavirus (HPV) Infections and the Importance of HPV Vaccination. AB - HPV persistence is necessary for the development of anogenital cancer. Studies show that cervical and anal HPV infections in women and in men who have sex with men are common. Clearance of HPV infection is similarly common; few individuals show persistence unless they are HIV-infected. HIV strongly influences the development of cervical and anal cancer, as well as their pre-malignant counterparts. Women with cervical and vulvar HPV-associated lesions have higher rates of anal cancer than the general population. HPV also plays an important role in pathogenesis of head and neck cancers, particularly oropharyngeal cancer. Two commercially available HPV vaccines have been proven to be safe and efficacious against cervical HPV16/18 infections and associated precancerous lesions; one of these has also been shown to prevent HPV16/18-associated anal lesions. The FDA has also just approved a new nonavalent HPV vaccine. HPV vaccines will play an important role in prevention of HPV-associated cancers. PMID- 27500081 TI - A Role for Epigenetics in Broadening the Scope of Pediatric Care in the Prevention of Adolescent Smoking. AB - Adolescence presents a critical opportunity to support the development of healthy patterns of behavior and prevent future health problems. Unfortunately, there is not yet a well-developed prevention model that allows pediatricians to initiate and monitor prevention efforts for the substantial minority of individuals who engage in risky behavior during adolescence. We suggest that recently developed epigenetic technologies may provide a bridge to a new prevention paradigm in which pediatricians screen for indicated smoking prevention services. Specifically, since currently available tobacco use screening measures are insensitive to low levels of use, newly developed methylation based approaches may enhance the sensitivity of the initial screening for nascent smoking behavior as well monitoring of outcomes. We conclude that the incorporation of Next Gen screening technologies into standard pediatric evaluations may allow for more effective referral to prevention programming for tobacco use. In addition to the potential direct impact on long-term enhancement of health outcomes secondary to smoking prevention, well-established links between smoking and other risk behaviors suggest that expanded referral for nascent smoking may also create opportunities to address other risky adolescent behaviors, and so decrease several interrelated drivers of long-term health care costs. PMID- 27500082 TI - Raoultella ornithinolytica: An unusual pathogen for prosthetic joint infection. AB - We herein report the first case of a prosthetic joint infection caused by Raoultella ornithinolytica in an immunocompetent patient. The clinical outcome was favorable after a two-stage prosthetic exchange and a six-month course of antimicrobial therapy. PMID- 27500083 TI - Group G streptococcal myositis in a patient with myeloproliferative neoplasm. AB - While many cases of streptococcal infection are due to Lancefield groups A and B, there has been a rise in reported cases of infections due to group G streptococcus. We present a case of an individual with a hematologic malignancy who developed myositis secondary to group G streptococcus, with no clearly identifiable source of infection. The patient was managed with antibiotic therapy rather than surgical intervention due to high surgical risk related to severe thrombocytopenia. Targeted antibiotics initiated early in the course of disease may prevent the need for surgical intervention. Early diagnosis and treatment are critical to avoid the high morbidity and mortality of life-threatening infections caused by group G streptococcus. PMID- 27500084 TI - Neonatal encephalitis due to Chikungunya vertical transmission: First report in Brazil. AB - PURPOSE: To report the first case of Chikungunya encephalitis acquired in the perinatal period during the current outbreak in Brazil. METHODS: Case report. RESULTS: A male neonate with 3500 g developed macular erythematous rash, hypoactivity and fever progressing to generalized seizures. His mother had experienced a disseminated rash and fever before delivery. EEG showed diffuse slowing and cranial NMR was suggestive of encephalitis. Rt-PCR for Chikungunya virus (CHIKV) was positive in cerebrospinal fluid (CSF), blood, urine and saliva. The newborn was discharged home with neurological improvement. CONCLUSION: We report the first case of a perinatal CHIKV infection associated with a rapidly evolving encephalitis and an extensive dissemination of the virus as documented by positive rt-PCR results in CSF, blood, urine and saliva in the present outbreak in Brazil. In countries experiencing outbreaks of CHIKV infections, clinicians and neonatologists must be familiar with the possibility of the occurrence of neurologic complications and its possible consequences. PMID- 27500086 TI - A Mammary-type Myofibroblastoma of the Prostate: A Case Report. AB - We report the case of a 51-year-old gentleman presenting with obstructive and irritative urinary symptoms, found to have a large prostate mass on imaging. A radical prostatectomy was performed and pathological diagnosis revealed a 12 cm mammary-type myofibroblastoma replacing the entire prostate. Mammary-type myofibroblastoma is a rare lesion outside of the breast, and is considered benign. This is the first reported case of a mammary-type myofibroblastoma occurring in the prostate. PMID- 27500085 TI - Benign or Malignant? Two Case Reports of Gigantic Prostatic Cyst. AB - A 60-year-old male with a huge prostate cyst presented with obstruction symptom of urethra and intestinal tract. Complete excision of the cystic prostate failed as a result of the strong adherence and twice operations history, but we confirmed prostate adenocarcinoma and relieved his obstruction symptom. Case 2 was a 77-year-old male with an 8 cm cyst of which biopsy showed prostate cancer in local hospital. He was admitted 18 months later because of intestinal obstruction. Radical resection had a satisfied result of obstruction symptom and PSA. Here we summarized malignant characteristics of cystic lesions in prostate or surrounding structures and management. PMID- 27500087 TI - Endoscopic Management of Free Lying Migratory Orthopedic Screw in Bladder. AB - 75-year old gentleman presented with acute urinary retention. He had met with road traffic accident 15 years back and sustained pelvic fracture and bladder rupture, underwent bladder repair and open reduction and internal fixation of pubic symphsis. Imaging studies showed the free lying encrusted orthopedic screw in the bladder, which was removed per urethra using nephroscope. Migratory foreign bodies in the urinary bladder are rare. However there is a possibility of longstanding foreign bodies in adjacent structures to erode and perforate into the bladder. Inside the bladder these foreign bodies act as nidus for stone formation. PMID- 27500088 TI - Achieving better modulation of coronary atherosclerosis: its understanding, visualization and treatment. PMID- 27500089 TI - Therapeutic modulation of the natural history of coronary atherosclerosis: lessons learned from serial imaging studies. AB - Despite advances in risk prediction, preventive and therapeutic strategies, atherosclerotic cardiovascular disease remains a major public health challenge worldwide, carrying considerable morbidity, mortality and health economic burden. There continues to be a need to better understand the natural history of this disease to guide the development of more effective treatment, integral to which is the rapidly evolving field of coronary artery imaging. Various imaging modalities have been refined to enable detailed visualization of the pathological substrate of atherosclerosis, providing accurate and reproducible measures of coronary plaque burden and composition, including the presence of high-risk characteristics. The serial application of such techniques, including coronary computed tomography angiography (CTA), intravascular ultrasound (IVUS) and optical coherence tomography (OCT) have uncovered important insights into the progression of coronary plaque over time in patients with stable and unstable coronary artery disease (CAD), and its responsiveness to therapeutic interventions. Here we review the use of different imaging modalities for the surveillance of coronary atherosclerosis and the lessons they have provided about the modulation of CAD by both traditional and experimental therapies. PMID- 27500091 TI - Prediction of cardiovascular outcomes by imaging coronary atherosclerosis. AB - Over the last two decades, several invasive and non-invasive coronary atherosclerosis imaging modalities have emerged as predictors of cardiovascular outcomes in at-risk population. These modalities have demonstrated independent or incremental prognostic information over existing/standard risk stratification schemes, such as the Framingham risk score (FRS), by identifying characteristics of coronary artery diseases (CADs). In this review, we begin with discussing the importance of pre-test probability and quality of outcome measure, followed by specific findings of each modality in relation to prognosis. We focused on both short and long term prognostic aspects of coronary computed tomography (CT) (including coronary calcium score and coronary angiography) and magnetic resonance imaging as non-invasive tools, as well as invasive modalities including intravascular ultrasound (IVUS), optical coherence tomography (OCT), near infrared spectroscopy and Angioscopy. PMID- 27500092 TI - Noninvasive imaging modalities to visualize atherosclerotic plaques. AB - Atherosclerotic cardiovascular disease is becoming a major cause of death in the world due to global epidemic of diabetes and obesity. For the prevention of atherosclerotic cardiovascular disease, it is necessary to detect high-risk atherosclerotic plaques prior to events. Recent technological advances enable to visualize atherosclerotic plaques noninvasively. This ability of noninvasive imaging helps to refine cardiovascular risk assessment in various individuals, select optimal therapeutic strategy and evaluate the efficacy of medical therapies. In this review, we discuss the role of the currently available imaging modalities including computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography. Advantages and disadvantages of each noninvasive imaging modality will be also summarized. PMID- 27500090 TI - Stabilization of high-risk plaques. AB - The prevalence of atherosclerotic cardiovascular diseases (ASCVDs) is increasing globally and they have become the leading cause of death in most countries. Numerous experimental and clinical studies have been conducted to identify major risk factors and effective control strategies for ASCVDs. The development of imaging modalities with the ability to determine the plaque composition enables us to further identify high-risk plaque and evaluate the effectiveness of different treatment strategies. While intensive lipid-lowering by statins can stabilize or even regress plaque by various mechanisms, such as the reduction of lipid accumulation in a necrotic lipid core, the reduction of inflammation, and improvement of endothelial function, there are still considerable residual risks that need to be understood. We reviewed important findings regarding plaque vulnerability and some encouraging emerging approaches for plaque stabilization. PMID- 27500093 TI - Future imaging of atherosclerosis: molecular imaging of coronary atherosclerosis with (18)F positron emission tomography. AB - Atherosclerosis is characterized by the formation of complex atheroma lesions (plaques) in arteries that pose risk by their flow-limiting nature and propensity for rupture and thrombotic occlusion. It develops in the context of disturbances to lipid metabolism and immune response, with inflammation underpinning all stages of plaque formation, progression and rupture. As the primary disease process responsible for myocardial infarction, stroke and peripheral vascular disease, atherosclerosis is a leading cause of morbidity and mortality on a global scale. A precise understanding of its pathogenic mechanisms is therefore critically important. Integral to this is the role of vascular wall imaging. Over recent years, the rapidly evolving field of molecular imaging has begun to revolutionize our ability to image beyond just the anatomical substrate of vascular disease, and more dynamically assess its pathobiology. Nuclear imaging by positron emission tomography (PET) can target specific molecular and biological pathways involved in atherosclerosis, with the application of (18)Fluoride PET imaging being widely studied for its potential to identify plaques that are vulnerable or high risk. In this review, we discuss the emergence of (18)Fluoride PET as a promising modality for the assessment of coronary atherosclerosis, focusing on the strengths and limitations of the two main radionuclide tracers that have been investigated to date: 2-deoxy-2 ((18)F)fluoro-D-glucose ((18)F-FDG) and sodium (18)F-fluoride ((18)F-NaF). PMID- 27500094 TI - Characterization of coronary atherosclerosis by intravascular imaging modalities. AB - Coronary artery disease (CAD) is highly prevalent in Western countries and is associated with morbidity, mortality, and a significant economic burden. Despite the development of anti-atherosclerotic medical therapies, many patients still continue to suffer from coronary events. This residual risk indicates the need for better risk stratification and additional therapies to achieve more reductions in cardiovascular risk. Recent advances in imaging modalities have contributed to visualizing atherosclerotic plaques and defining lesion characteristics in vivo. This innovation has been applied to refining revascularization procedure, assessment of anti-atherosclerotic drug efficacy and the detection of high-risk plaques. As such, intravascular imaging plays an important role in further improvement of cardiovascular outcomes in patients with CAD. The current article reviews available intravascular imaging modalities with regard to its method, advantage and disadvantage. PMID- 27500095 TI - Imaging of coronary atherosclerosis in various susceptible groups. AB - Coronary artery disease (CAD) is the leading cause of death and disability worldwide. Atherosclerosis, which is the primary pathophysiologic mechanism for the development of plaque leading to CAD, is a multifactorial process resulting from a complex interplay between genetic susceptibility and various risk factors such as hypertension (HT), dyslipidaemia, diabetes mellitus (DM) and smoking. In addition, influences from other disease states such as chronic kidney disease (CKD), obesity and the metabolic syndrome as well as gender and ethnic diversity also contribute to the disease process. Insights from pathological observations and advances in cellular and molecular biology have helped us understand the process of plaque formation, progression and rupture leading to events. Several intravascular imaging techniques such as intravascular ultrasound (IVUS), Virtual histology IVUS (VH-IVUS) and optical coherence tomography (OCT) allow in vivo assessment of plaque burden, plaque morphology and response to therapy. In addition, non invasive assessment using coronary artery calcium (CAC) score allows risk stratification and plaque burden assessment whilst computed tomography coronary angiography (CTCA) allows evaluation of luminal stenosis, plaque characterisation and quantification. This review aims to summarise the results of invasive and non-invasive imaging studies of coronary atherosclerosis seen in various high-risk populations including DM, metabolic syndrome, obesity, CKD and, gender differences and ethnicity. Understanding the phenotype of plaques in various susceptible groups may allow potential development of personalised therapies. PMID- 27500096 TI - Pathology of coronary atherosclerosis and thrombosis. AB - The process of early atherosclerotic plaque progression is characterized by the development of pathologic intimal thickening (PIT) with lipid pool that may transform into the necrotic core to form fibroatheroma, where infiltration of foamy macrophages plays a crucial role. The expansion of the necrotic core is also attributable to intraplaque hemorrhage. Thin-cap fibroatheroma (TCFA) is characterized by a relatively large necrotic core with an overlying thin fibrous cap measuring <65 um typically containing numerous macrophages, and is considered to be the precursor lesion of plaque rupture which is the most common cause of coronary thrombosis. The second common cause of acute thrombosis is plaque erosion, while calcified nodules is known to be the least frequent cause of coronary thrombosis. Coronary thrombosis can occur without symptoms to form healed lesions, which contributes to an increase in plaque burden and luminal narrowing. The process of plaque progression is generally accompanied by the progression of calcification. An understanding of the histomorphological characteristics of coronary plaques should provide important insights into the pathogenesis, diagnosis, and treatment of atherosclerotic coronary disease for both basic and clinical researchers as well as for clinicians. PMID- 27500097 TI - Human beta-NGF gene transferred to cat corneal endothelial cells. AB - AIM: To transfect the cat corneal endothelial cells (CECs) with recombinant human beta-nerve growth factor gene adeno-associated virus (AAV-beta-NGF) and to observe the effect of the expressed beta-NGF protein on the proliferation activity of cat CECs. METHODS: The endothelium of cat cornea was torn under the microscope and rapidly cultivated in Dulbecco's modified Eagle's medium (DMEM) to form single layer CECs and the passage 2 endothelial cells were used in this experiment. The recombinant human AAV-beta-NGF was constructed. The recombinant human AAV-beta-NGF was transferred into cat CECs directly. Three groups were as following: normal CEC control group, CEC-AAV control group and recombinant CEC AAV-beta-NGF group. Forty-eight hours after transfection, the total RNA was extracted from the CEC by Trizol. The expression of the beta-NGF target gene detected by fluorescence quantitative polymerase chain reaction; proliferation activity of the transfected CEC detected at 48h by MTT assay; the percentage of G1 cells among CECs after transfect was detected by flow cytometry method (FCM); cell morphology was observed under inverted phase contrast microscope. RESULTS: The torn endothelium culture technique rapidly cultivated single layer cat corneal endothelial cells. The self-designed primers for the target gene and reference gene were efficient and special confirmed through electrophoresis analysis and DNA sequencing. Forty-eight hours after transfect, the human beta NGF gene mRNA detected by fluorescence quantitative polymerase chain reaction showed that there was no significant difference between normal CEC control group and CEC-AAV control group (P>0.05); there was significant difference between two control groups and recombinant CEC-AAV-beta-NGF group (P<0.05). MTT assay showed that transfect of recombinant AAV-beta-NGF promoted the proliferation activity of cat CEC, while there was no significant difference between normal CEC control group and CEC-AAV control group (P>0.05). FCM result showed that the percentage of G1cells in CEC-AAV-NGF group was 76.8% while that in normal CEC control group and CEC-AAV control group was 46.6% and 49.8%. CONCLUSION: Recombinant AAV-beta NGF promotes proliferation in cat CECs by expressing bioactive beta-NGF protein in high efficiency and suggests that its modulation can be used to treat vision loss secondary to corneal endothelial dysfunction. PMID- 27500098 TI - Anterior segment dysgenesis correlation with epithelial-mesenchymal transition in Smad4 knockout mice. AB - AIM: To explore the molecular mechanisms in lens development and the pathogenesis of Peters anomaly in Smad4 defective mice. METHODS: Le-Cre transgenic mouse line was employed to inactivate Smad4 in the surface ectoderm selectively. Pathological techniques were used to reveal the morphological changes of the anterior segment in Smad4 defective eye. Immunohistochemical staining was employed to observe the expression of E-cadherin, N-cadherin and alpha-SMA in anterior segment of Smad4 defective mice and control mice at embryonic (E) day 16.5. Real-time quantitative polymerase chain reaction (qPCR) was performed to detect the expression of Snail, Zeb1, Zeb2 and Twist2 in lens of Smad4 defective mice and control mice at E16.5. Statistical evaluations were performed using the unpaired Student's t-test (two-tailed) by SPSS 11.0 software. RESULTS: Conditional deletion of Smad4 on eye surface ectoderm resulted in corneal dysplasia, iridocorneal angle closure, corneolenticular adhesions and cataract resembling Peters anomaly. Loss of Smad4 function inhibited E-cadherin expression in the lens epithelium cells and corneal epithelium cells in Smad4 defective eye. Expression of N-cadherin was up-regulated in corneal epithelium and corneal stroma. Both E-cadherin and N-cadherin were down-regulated at the future trabecular meshwork region in mutant eye. The qPCR results showed that the expression of Twist2 was increased significantly in the mutant lens (P<0.01). CONCLUSION: Smad4 is essential to eye development and likely a candidate pathogenic gene to Peters anomaly by regulating epithelial-mesenchymal transition. Twist2 can be regulated by Smad4 and plays an essential role in lens development. PMID- 27500099 TI - Promotion on the differentiation of retinal Muller cells into retinal ganglion cells by Brn-3b. AB - AIM: To investigate the role of Brn-3b in differentiation process of stem cells derived from retinal Muller cells into the ganglion cell. METHODS: The passage culture method of Muller cells from retina of newborn Sprague Dawley rats was carried out by repeated incomplete pancreatic enzyme digestion method. The cells were detected by fluorescence-activated cell sorter (FACS), immunohistochemistry technology and reverse transcription-polymerase chain reaction (RT-PCR) to determine the purity. The third passage of cells was induced in the serum-free dedifferentiation medium. The expression of the specific markers Ki-67 and nestin of retinal stem cells was measured by RT-PCR and Western blot. The cell proliferation of retinal stem cells was detected by 5-ethynyl-2'-deoxyuridine (Edu) staining. The cells were randomly divided into 5 groups as follows: group A: Brn-3bsiRNA group; group B: Brn-3b control siRNA group; group C: pGC-Brn-3b green fluorescent protein (GFP) group; group D: pGC-GFP group; group E: control group (without any handling). The purified Muller cells were cultured for 3-7d, then, the percentage of ganglion cells was counted by immunofluorescence staining. RESULTS: FACS demonstrated the purity of retinal Muller cells was more 97.44%. A few spherical cell spheres appeared. Immunofluorescence staining showed that stem cells within the spheres were positive for retinal stem cell-specific markers nestin (red fluorescence, 92.94%+/-6.48%) and Ki-67 (green fluorescence, 85.96%+/-6.04%). Meanwhile, RT-PCR analysis showed cell spheres in the culture to have expressed a battery of transcripts characteristic of stem cells such as nestin and Ki-67, which were absent in the Muller cells. Western blot analysis further confirmed the expression of nestin and Ki-67 in the cell spheres but not in the Muller cells. Edu staining showed most of the nuclei within the cell spheres were stained red (82.80%+/-6.65%), suggesting the new cell spheres had the capacity for effective proliferation. The statistics result showed the difference between Brn-3bsiRNA group and Brn-3b control siRNA group or the control group was significant (F=15, P<0.05), while the difference between Brn-3b control siRNA group or the control group was not statistically significant (P>0.05). CONCLUSION: The repeated incomplete pancreatic enzyme digestion method is an efficient and practical method to purify retinal Muller cells. Retinal stem cells were successfully cloned in the dedifferentiational medium. Retinal Muller cells are accessible sources of retinal stem cells. Brn-3b is an important regulatory gene in stem cells differentiated into retinal ganglion cell. PMID- 27500100 TI - Promotion of axon regeneration and inhibition of astrocyte activation by alpha A crystallin on crushed optic nerve. AB - AIM: To explore the effects of alphaA-crystallin in astrocyte gliosis after optic nerve crush (ONC) and the mechanism of alpha-crystallin in neuroprotection and axon regeneration. METHODS: ONC was established on the Sprague-Dawley rat model and alphaA-crystallin (10(-4) g/L, 4 uL) was intravitreously injected into the rat model. Flash-visual evoked potential (F-VEP) was examined 14d after ONC, and the glial fibrillary acidic protein (GFAP) levels in the retina and crush site were analyzed 1, 3, 5, 7 and 14d after ONC by immunohistochemistry (IHC) and Western blot respectively. The levels of beta Tubulin (TUJ1), growth-associated membrane phosphoprotein-43 (GAP-43), chondroitin sulfate proteoglycans (CSPGs) and neurocan were also determined by IHC 14d after ONC. RESULTS: GFAP level in the retina and the optic nerve significantly increased 1d after ONC, and reached the peak level 7d post-ONC. Injection of alphaA-crystallin significantly decreased GFAP level in both the retina and the crush site 3d after ONC, and induced astrocytes architecture remodeling at the crush site. Quantification of retinal ganglion cell (RGC) axons indicated alphaA-crystallin markedly promoted axon regeneration in ONC rats and enhanced the regenerated axons penetrated into the glial scar. CSPGs and neurocan expression also decreased 14d after alphaA crystallin injection. The amplitude (N1-P1) and latency (P1) of F-VEP were also restored. CONCLUSION: Our results suggest alpha-crystallin promotes the axon regeneration of RGCs and suppresses the activation of astrocytes. PMID- 27500101 TI - Expression of microRNAs in fibroblast of pterygium. AB - AIM: To screen microRNAs (miRNAs) and set up target miRNAs in pterygium. METHODS: Primary fibroblasts were isolated from pterygium and Tenon's capsule and cultured. Immunocytochemical analysis and Western blotting were performed to confirm the culture of fibroblasts. In all, 1733 miRNAs were screened in the first step by using GeneChip((r)) miRNA3.0 Array. Specific miRNAs involved in the pathogenesis of pterygium were subsequently determined using the following criteria: 1) high reproducibility in a repetitive test; 2) base log value of >7.0 for both control and pterygial fibroblasts; and 3) log ratio of >1.0 between pterygial fibroblasts and control fibroblasts. RESULTS: Primary screening showed that 887/1733 miRNAs were up-regulated and 846/1733 miRNAs were down-regulated in pterygial fibroblasts compared with those in control fibroblasts. Of the 1733 miRNAs screened, 4 miRNAs, namely, miRNA-143a-3p, miRNA-181a-2-3p, miRNA-377-5p and miRNA-411a-5p, met the above-mentioned criteria. Primary screening showed that these 4 miRNAs were up-regulated in pterygial fibroblasts compared with control fibroblasts and that miRNA-143a-3p had the highest mean ratio compared with the miRNAs in control fibroblasts. CONCLUSION: miRNA-143a-3p, miRNA-181a-2 3p, miRNA-377-5p and miRNA-411a-5p are up-regulated in pterygial fibroblasts compared with control fibroblasts, suggesting their involvement in the pathogenesis of pterygium. PMID- 27500102 TI - Retraction Notice. AB - [This retracts the article DOI: 10.18240/ijo.2016.03.07.]. PMID- 27500103 TI - Comparison of corneal biomechanical properties in normal tension glaucoma patients with different visual field progression speed. AB - AIM: To compare the corneal biomechanical properties difference by ocular response analyzer (ORA) in normal tension glaucoma (NTG) patients with different visual field (VF) progression speed. METHODS: NTG patients with well-controlled Goldmann applanation tonometer (GAT) who routinely consulted Kitasato University Hospital Glaucoma Department between January 2010 and February 2014 were enrolled. GAT and ORA parameters including corneal compensated intraocular pressure (IOPcc), Goldmann estimated intraocular pressure (IOPg), corneal hysteresis (CH), corneal resistance factor (CRF) were recorded. VF was tested by Swedish interactive threshold algorithm (SITA)-standard 30-2 fields. All patients underwent VF measurement regularly and GAT did not exceed 15 mm Hg at any time during the 3y follow up. Patients were divided into four groups according to VF change over 3y, and ORA findings were compared between the upper 25(th) percentile group (slow progression group) and the lower 25(th) percentile group (rapid progression group). RESULTS: Eighty-two eyes of 56 patients were studied. There were 21 eyes (21 patients) each in rapid and slow progression groups respectively. GAT, IOPcc, IOPg, CH, CRF were 12.1+/-1.4 mm Hg, 15.8+/-1.8 mm Hg, 12.8+/-2.0 mm Hg, 8.4+/-1.1 mm Hg, 7.9+/-1.3 mm Hg respectively in rapid progression group and 11.5+/-1.3 mm Hg, 13.5+/-2.1 mm Hg, 11.2+/-1.6 mm Hg, 9.3+/ 1.1 mm Hg, 8.2+/-0.9 mm Hg respectively in slow progression group (P=0.214, <0.001, 0.007, 0.017, 0.413, respectively). In bivariate correlation analysis, IOPcc, IOPcc-GAT and CH were significant correlated with mDeltaMD (r=-0.292, 0.312, 0.228 respectively, P=0.008, 0.004, 0.039 respectively). CONCLUSION: Relatively rapid VF progression occurred in NTG patients whose IOPcc are rather high, CH are rather low and the difference between IOPcc and GAT are relatively large. Higher IOPcc and lower CH are associated with VF progression in NTG patients. This study suggests that GAT measures might underestimate the IOP in such patients. PMID- 27500104 TI - Diurnal changes in retinal nerve fiber layer thickness with obstructive sleep apnea/hypopnea syndrome. AB - AIM: To compare the retinal nerve fiber layer (RNFL) thickness in the morning and evening in Thai patients with varying degrees of obstructive sleep apnea/hypopnea syndrome (OSAHS). METHODS: In this cross-sectional study, potential OSAHS patients at Siriraj Hospital underwent polysomnography to determine the severity of OSAHS and an eye examination (including best corrected visual acuity, slit lamp examination, and Goldmann applanation tonometry). RNFL thickness was recorded once in the morning and once in the evening, using spectral domain optical coherence tomography. Thickness was expressed as an average and given for each quadrant. Patients with ocular or systemic diseases that might affect RNFL thickness were excluded. RESULTS: Forty-one eyes of 41 patients were classified into 4 OSAHS groups. The average and mean RNFL thickness in most of the four quadrants of the severe OSAHS group trended toward being less than those in the comparable quadrants of the other groups in both the morning and evening. In the moderate OSAHS group, the average RNFL thickness and temporal and superior quadrant thickness in the morning were significantly higher than in the evening (P=0.01, P=0.01, and P=0.03, respectively). In the severe OSAHS group, the inferior quadrant thickness in the morning was significantly higher than in the evening (P=0.03). CONCLUSION: The RNFL thickness in the morning was higher than in the evening in moderate OSAHS. PMID- 27500105 TI - Epidemiology and risk factors of retinoblastoma in Chongqing area. AB - AIM: To investigate the risk factors of retinoblastoma in Chongqing and offer the bases for scientific measures. METHODS: One hundred and thirty-three retinoblastoma patients were taken as case group, and 133 children were taken as control group in 1:1 ratio. The relevant factors were collected from a questionnaire survey which was made by our research group. First, Chi-square and t-test were used to discuss the various factors, and then the logistic regression analysis was made by statistics software SPSS17.0 based on the result of 266 people. RESULTS: Single factor analysis results showed the differences between the two groups were statistically significant (P<0.05) in 17 factors which were education level of their parents, occupation of their parents, exposure to harmful chemicals of their parents 6mo before pregnancy, the history of pelvic inflammatory disease of mother before pregnancy, childbearing history of their parents, pregnant age of their parents, the medication history of father 6 mo before pregnancy, living place of their parents, the pollution living place of mother, hobbies of their parents. Multivariate analysis showed that the living place of parents, mother who feed pets before pregnancy, and exposure to harmful chemicals of father before pregnancy were the independent risk factors of retinoblastoma (P<0.05). CONCLUSION: The living place of parents, mother who feed pets before pregnancy, exposure to harmful chemicals of father before pregnancy were the risk factors of retinoblastoma which affects the occurrence of retinoblastoma in a certain extent. PMID- 27500106 TI - Risk factors of rhegmatogenous retinal detachment associated with choroidal detachment in Chinese patients. AB - AIM: To comprehensively analyze the risk factors of rhegmatogenous retinal detachment (RRD) associated with choroidal detachment (CD). METHODS: A total of 265 eyes of 265 consecutive cases of RRD were retrospectively analyzed. All patients had systemic and ophthalmologic examination. CD was diagnosed by indirect ophthalmoscopy, B-scan ultrasonography, and ultrasound biomicroscope (UBM). Each parameter was compared between patients of RRD and rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD). Logistic regression analysis was used to determine the independent risk factors of CD. RESULTS: There were 52 eyes (19.62%) with CD. Pseudophakia was more commonly seen in RRDCD (21.15% vs 6.10%, P=0.002). Intraocular pressure (IOP) was lower (8.60+/ 3.62 vs 12.96+/-3.55, P<0.001), best-corrected visual acuity was worse [3.00 (2.00 to 3.00) vs 1.92 (1.22 to 3.00), P=0.001], and refractive error was more myopic [-4 (-9 to -2) vs -2 (-6 to 0), P=0.007] in RRDCD. Eyes with RRDCD had larger extent of retinal detachment (P=0.007). In RRDCD, 34.62% of eyes presented with multiple holes (P=0.044) and 25.00% with macular holes (P=0.012), compared with 20.66% and 14.08% in RRD. High myopia (P=0.039), low IOP (P=0.017), and larger extent of retinal detachment (P<0.001) were significant and independent risk factors for developing CD. CONCLUSION: For CD in RRD, related factors include BCVA, IOP, lens status, refractive error, extent of retinal detachment, number of holes, and macular hole. Larger extent of retinal detachment, high myopia, and low IOP are significant and independent risk factors. PMID- 27500107 TI - Predictive factors for postoperative visual function of primary chronic rhegmatogenous retinal detachment after scleral buckling. AB - AIM: To evaluate predictive factors for postoperative visual function of primary chronic rhegmatgenous retinal detachment (RRD) after sclera buckling (SB). METHODS: Totally 48 patients (51 eyes) with primary chronic RRD were included in this prospective interventional clinical cases study, which underwent SB alone from June 2008 to December 2014. Age, sex, symptoms duration, detached extension, retinal hole position, size, type, fovea on/off, proliferative vitreoretinopathy (PVR), posterior vitreous detachment (PVD), baseline best corrected visual acuity (BCVA), operative duration, follow up duration, final BCVA were measured. Pearson correlation analysis, Spearman correlation analysis and multivariate linear stepwise regression were used to confirm predictive factors for better final visual acuity. Student's t-test, Wilcoxon two-sample test, Chi-square test and logistic stepwise regression were used to confirm predictive factors for better vision improvement. RESULTS: Baseline BCVA was 0.8313+/-0.6911 logMAR and final BCVA was 0.4761+/-0.4956 logMAR. Primary surgical success rate was 92.16% (47/51). Correlation analyses revealed shorter symptoms duration (r=0.3850, P=0.0053), less detached area (r=0.5489, P<0.0001), fovea (r=0.4605, P=0.0007), no PVR (r=0.3138, P=0.0250), better baseline BCVA (r=0.7291, P<0.0001), shorter operative duration (r=0.3233, P=0.0207) and longer follow up (r=-0.3358, P=0.0160) were related with better final BCVA, while independent predictive factors were better baseline BCVA [partial R-square (PR(2))=0.5316, P<0.0001], shorter symptoms duration (PR(2)=0.0609, P=0.0101), longer follow up duration (PR(2)=0.0278, P=0.0477) and shorter operative duration (PR(2)=0.0338, P=0.0350). Patients with vision improvement took up 49.02% (25/51). Univariate and multivariate analyses both revealed predictive factors for better vision improvement were better baseline vision [odds ratio (OR) =50.369, P=0.0041] and longer follow up duration (OR=1.144, P=0.0067). CONCLUSION: Independent predictive factors for better visual outcome of primary chronic RRD after SB are better baseline BCVA, shorter symptoms duration, shorter operative duration and longer follow up duration, while independent predictive factors for better vision improvement after operation are better baseline vision and longer follow up duration. PMID- 27500108 TI - Effects of two different doses of intravitreal bevacizumab on subfoveal choroidal thickness and retinal vessel diameter in branch retinal vein occlusion. AB - AIM: To investigate the effects of two different doses of intravitreal bevacizumab on subfoveal choroidal thickness (SFChT) and retinal vessel diameter in patients with branch retinal vein occlusion. METHODS: An interventional, restrospective study of 41 eyes of 41 patients who had completed 12mo of follow up, divided into group 1 (1.25 mg of bevacizumab, 21 eyes of 21 patients) and group 2 (2.5 mg of bevacizumab, 20 eyes of 21 patients). Complete ophthalmic examination, fluorescein angiography, enhanced depth imaging optical coherence tomography and measurement of retinal vessel diameter with IVAN software were performed at baseline and follow-up. RESULTS: The SFChT changed from 279.1 (165 431) um at baseline to 277.0 (149-413) um at 12mo in group 1 (P=0.086), and from 301.4 (212-483) um to 300.3 (199-514) um in group 2 (P=0.076). The central retinal arteriolar equivalent (CRAE) changed from 128.8+/-11.2 um at baseline to 134.5+/-8.4 um at 12mo in group 1, and from 134.6+/-9.0 um to 131.4+/-12.7 um in group 2 (P=0.767). The central retinal venular equivalent (CRVE) changed from 204.1+/-24.4 um at baseline to 196.3+/-28.2 um at 12mo in group 1, and from 205.8+/-16.3 um to 194.8+/-18.2 um in group 2 (P=0.019). The mean central macular thickness (P<0.05) and average best-corrected visual acuity (BCVA; P<0.05) improved in both groups. CONCLUSION: Changes in the SFChT are not statistically significant and not different according to the doses of bevacizumab. The CRAE did not show significant change, however, the CRVE showed significant decrease regardless of the dose. PMID- 27500109 TI - Comparison of corneal flaps created by Wavelight FS200 and Intralase FS60 femtosecond lasers. AB - AIM: To assess and compare the morphology of corneal flaps created by the Wavelight FS200 and Intralase FS60 femtosecond lasers in laser in situ keratomileusis (LASIK). METHODS: Four hundred eyes of 200 patients were enrolled in this study and divided into Wavelight FS200 groups (200 eyes) and Intralase FS60 groups (200 eyes). Fourier-domain optical coherence tomography (RTVue OCT) was used to measure the corneal flap thickness of 36 specified measurements on each flap one week after surgery. Results were used to analyze the regularity, uniformity and accuracy of the two types of LASIK flaps. RESULTS: The mean thickness of corneal flap and central flap was 105.71+/-4.72 um and 105.39+/-4.50 um in Wavelight FS200 group and 109.78+/-11.42 um and 109.15 +/-11.59 um in Intralase FS60 group, respectively. The flaps made with the Wavelight FS200 femtosecond laser were thinner than those created by the Intralase FS60 femtosecond laser (P=0.000). Corneal flaps in the 2 groups were uniform and regular, showing an almost planar configuration. But the Wavelight FS200 group has more predictability and uniformity of flap creation. The mean deviation between achieved and attempted flap thickness was smaller in the Wavelight FS200 group than that in the Intralase FS60 group, which were 5.18+/-3.71 um and 8.68+/ 7.42 um respectively. The deviation of more than 20 um was 0.2% measurements in Wavelight FS200 group and 8.29% measurements in Intralase FS60 group. CONCLUSION: The morphologies of flaps created by Wavelight FS200 are more uniform and thinner than those created by Intralase FS60. PMID- 27500110 TI - Post-operative strabismus control and motor alignment for basic intermittent exotropia. AB - AIM: To assess strabismus control and motor ocular alignment for basic exotropia surgery at 5y follow-up. METHODS: The medical records of 80 consecutive patients aged less than 17 years of age, who underwent surgery for basic exotropia by a single surgeon between years 2000 to 2009 and completed a minimum of 5y follow-up post-operatively were reviewed. Pre- and post-operative characteristics were documented at 1wk, 6mo, 1, 3 and 5y follow-up. Subjects at 5-year follow-up were assigned to the success group if they had a post-operative angle of deviation within 10 prism diopters of exotropia or within 5 prism diopters of esotropia for distance on prism cover test, and had moderate to good strabismus control. The remaining subjects were assigned to the failure group. RESULTS: Post-operative surgical success at one week was 75%, which decreased to 41% at 5y follow-up. The success group was noted to have more patching pre-operatively (P=0.003). The duration of patching a day (P=0.020) and total duration of patching pre operatively (P=0.030) was higher in the success group. Surgical success at 1y (P=0.004) and 3y (P=0.002) were associated with higher surgical success at 5y follow-up. CONCLUSION: Post-operative motor alignment and strabismus control for basic exotropia surgery at 1y and beyond is associated with higher exotropia surgery success at 5-year follow-up. There is an association between pre operative patching and 5-year surgical success of basic intermittent exotropia surgery. PMID- 27500111 TI - Comparison of therapeutic effects of topical azithromycin solution and systemic doxycycline on posterior blepharitis. AB - AIM: To compare the effect of azithromycin drop and doxycycline capsule on treatment of posterior blepharitis. METHODS: Fifty patients (100 eyes) with moderate posterior blepharitis, randomly divided into two therapeutic groups; all the patients got warm eyelid compress and massage three times a day for 3wk. In addition the first group got azithromycin 1% drop, twice daily for 1wk and then one drop daily for 2wk. The second group got oral doxycycline 100 mg daily for 3wk. At the end of the research, patients' signs and symptoms were compared together. ANOVA, Chi-square and Mann-Whitney tests were used for statistical analysis. RESULTS: Topical therapy with azithromycin and oral therapy with doxycycline relieved signs and symptoms after 3wk. There were no significant differences between symptoms healing rate and foreign body sensation healing in these two groups (P>0.05). However, azithromycin drop was more effective in reduction of eye redness and doxycycline was more effective in meibomian glands plugging healing and reducing the corneal staining. CONCLUSION: Topical azithromycin could have similar effects as oral doxycycline on posterior blepharitis in improving subjective symptoms. However, doxycycline can reduce objective signs such as ocular surface staining and meibomian gland plugging more than azithromycin. PMID- 27500113 TI - Comparison of the efficacy of anti-VEGF monotherapy versus PDT and intravitreal anti-VEGF combination treatment in AMD: a Meta-analysis and systematic review. AB - AIM: To compare the effect of anti-vascular endothelial growth factor (VEGF) monotherapy versus photodynamic therapy (PDT) and anti-VEGF combination treatment in age-related macular degeneration (AMD). METHODS: A computerized online search was performed using PubMed, Web of Science and the Cochrane Library. Studies that compared anti-VEGF monotherapy with PDT and anti-VEGF combination treatment of AMD and were designed as randomized controlled trials were included. The means and standard deviations of the best-corrected visual acuity (BCVA), central retinal thickness (CRT), number of treatments and proportions of patients who gained BCVA >=15, 10, 5, or 0 letters at 12(th) month were extracted. A systematic review and Meta-analysis of the comparison of the two approaches was conducted using Review Manager 5.2. Subgroup. A sensitivity analysis was also performed. RESULTS: Eight studies were included. When the subgroup and sensitivity analysis was conducted, the results indicated that in the findings that included the monotherapy group and PDT (standard fluence, SF) group of Kaiser's study, the patients in the monotherapy group had a better BCVA compared with the combination group at 12(th) month in the PDT (SF) subgroup [weighted mean difference (WMD): 3.54; 95%CI: 0.36 to 6.73; P=0.03], and there were more patients who gained >=15 letters of BCVA in the monotherapy group compared with the combination group in the total result [odds ratio (OR): 1.41; 95%CI: 1.02 to 1.95; P=0.04]. The same conclusion was obtained in the total result that included the monotherapy group and PDT (reduced fluence, RF) group of Kaiser's study (OR: 1.56; 95%CI: 1.13 to 2.15; P=0.007). However, there were no significant differences in the other indexes between the two therapies. CONCLUSION: We found that anti-VEGF monotherapy is more effective on the recovery of visual acuity than combination therapy and more researches with lager sample size should be performed to study on the effect of the two therapy approaches on CRT and number of injections. PMID- 27500112 TI - Sub-threshold micro-pulse diode laser treatment in diabetic macular edema: A Meta analysis of randomized controlled trials. AB - AIM: To examine possible differences in clinical outcomes between sub-threshold micro-pulse diode laser photocoagulation (SDM) and traditional modified Early Treatment Diabetic Retinopathy Study (mETDRS) treatment protocol in diabetic macular edema (DME). METHODS: A comprehensive literature search using the Cochrane Collaboration methodology to identify RCTs comparing SDM with mETDRS for DME. The participants were type I or type II diabetes mellitus with clinically significant macular edema treated by SDM from previously reported randomized controlled trials (RCTs). The primary outcome measures were the changes in the best corrected visual acuity (BCVA) and the central macular thickness (CMT) as measured by optical coherence tomography (OCT). The secondary outcomes were the contrast sensitivity and the damages of the retina. RESULTS: Seven studies were identified and analyzed for comparing SDM (215 eyes) with mETDRS (210 eyes) for DME. There were no statistical differences in the BCVA after treatment between the SDM and mETDRS based on the follow-up: 3mo (MD, -0.02; 95% CI, -0.12 to 0.09; P=0.77), 6mo (MD, -0.02; 95% CI, -0.12 to 0.09; P=0.75), 12mo (MD, -0.05; 95% CI, -0.17 to 0.07; P=0.40). Likewise, there were no statistical differences in the CMT after treatment between the SDM and mETDRS in 3mo (MD, -9.92; 95% CI, -28.69 to 8.85; P=0.30), 6mo (MD, -11.37; 95% CI, -29.65 to 6.91; P=0.22), 12mo (MD, 8.44; 95% CI, -29.89 to 46.77; P=0.67). Three RCTs suggested that SDM laser results in good preservation of contrast sensitivity as mETDRS, in two different follow-up evaluations: 3mo (MD, 0.05; 95% CI, 0 to 0.09; P=0.04) and 6mo (MD, 0.02; 95% CI, -0.10 to 0.14; P=0.78). Two RCTs showed that the SDM laser treatment did less retinal damage than that mETDRS did (OR, 0.05; 95% CI, 0.02 to 0.13; P<0.01). CONCLUSION: SDM laser photocoagulation shows an equally good effect on visual acuity, contrast sensitivity, and reduction of DME as compared to conventional mETDRS protocol with less retinal damage. PMID- 27500114 TI - Metabolic syndrome risk factors and dry eye syndrome: a Meta-analysis. AB - AIM: To explore the relationship between metabolic risk factors and dry eye syndrome (DES). METHODS: Retrieved studies on the association of metabolic syndrome risk factors (hypertension, hyperglycemia, obesity, and hyperlipidemia) and DES were collected from PubMed, Web of Science, and the Cochrane Library in December 2015. Odds ratio (OR) with 95% confidence interval (CI) were pooled to evaluate the final relationship. Subgroup analyses were conducted according to diagnostic criteria of DES. RESULTS: Nine cross-sectional studies and three case control studies were included in this Meta-analysis. The pooled results showed that people with hypertension, hyperglycemia, and hyperlipidemia had a higher risk of suffering from DES (P<0.05), especially the typical DES symptoms. On the other hand, obesity did not increase the risk of DES. CONCLUSION: The present Meta-analysis suggests that all metabolic risk factors except obesity were risk factors for DES. PMID- 27500115 TI - Profitability analysis of a femtosecond laser system for cataract surgery using a fuzzy logic approach. AB - AIM: To define the financial and management conditions required to introduce a femtosecond laser system for cataract surgery in a clinic using a fuzzy logic approach. METHODS: In the simulation performed in the current study, the costs associated to the acquisition and use of a commercially available femtosecond laser platform for cataract surgery (VICTUS, TECHNOLAS Perfect Vision GmbH, Bausch & Lomb, Munich, Germany) during a period of 5y were considered. A sensitivity analysis was performed considering such costs and the countable amortization of the system during this 5y period. Furthermore, a fuzzy logic analysis was used to obtain an estimation of the money income associated to each femtosecond laser-assisted cataract surgery (G). RESULTS: According to the sensitivity analysis, the femtosecond laser system under evaluation can be profitable if 1400 cataract surgeries are performed per year and if each surgery can be invoiced more than $500. In contrast, the fuzzy logic analysis confirmed that the patient had to pay more per surgery, between $661.8 and $667.4 per surgery, without considering the cost of the intraocular lens (IOL). CONCLUSION: A profitability of femtosecond laser systems for cataract surgery can be obtained after a detailed financial analysis, especially in those centers with large volumes of patients. The cost of the surgery for patients should be adapted to the real flow of patients with the ability of paying a reasonable range of cost. PMID- 27500116 TI - Prevalences and causes of vision impairment in elderly Chinese: a socioeconomic perspective of a comparative report nested in Jiangsu Eye Study. AB - AIM: To survey the prevalence and causes of visual impairment/blindness among elderly Chinese from different socioeconomic status in community-based design. METHODS: Cluster-sampling randomly selected residents from Binhu and Funing District, two areas representing different socioeconomic levels in China with Binhu in an advanced status and Funing in less-developed area. The participants subjected to ophthalmic examination. The presenting visual acuity (PVA) and best corrected visual acuity (BCVA) were recorded. Visual impairment and blindness were defined according to World Health Organization criteria. The causes of visual impairment/blindness were identified by ophthalmic examination and/or questionnaire. The socioeconomic status included the per capita gross domestic product, numbers of hospital with ophthalmic service and the number of ophthalmologists per 1 million residents. RESULTS: We successfully included 12 867 participants form 2 areas in this study. The prevalence of PVA impairment (<20/63 to >=20/400) in the better eye was 5.4% in Binhu and 23.6% in Funing, while the prevalence of blindness (<20/400) was 0.9% in Binhu and 2.3% in Funing. With BCVA, the prevalence of visual impairment was 2.4% in Binhu and 6.4% in Funing, while the prevalence of blindness was 0.8% in Binhu and 1.6% in Funing. The participants with older age and female gender had higher prevalence in visual impairment and blindness. The highest prevalences of vision impairment and blindness evaluated by BCVA at >80y age group reached 20.4% and 6.3% respectively. The prevalences of vision impairment and blindness evaluated by BCVA were 3.5% and 1.0% in male and 5.0% and 1.3% in female. The above differences were statistically significant (P<0.05). The predominant causes of visual impairment and blindness were cataract, retinal disorders and uncorrected refractive error in both areas. The socioeconomic status was associated with visual impairment and blindness. CONCLUSION: This community-based study build a sufficient sample size for an ophthalmic survey. Our data show the disparities on socioeconomic development and genders in visual impairment and blindness in China. Special emphasis of ophthalmic service should be placed on females and less-developed area. PMID- 27500117 TI - Device interchangeability on anterior chamber depth and white-to-white measurements: a thorough literature review. AB - We have reviewed a set of recently published studies that compared the anterior chamber depth (ACD) and/or white-to-white (WTW) distance obtained by means of different measuring devices. Since some of those studies reached contradictory conclusions regarding device interchangeability, this review was carried out in attempting to clarify which clinical devices can or cannot be considered as interchangeable in clinical practice to measure ACD and/or WTW distance, among these devices: A-scan, ultrasound biomicroscopy, Orbscan and Orbscan II (Bausch&Lomb Surgical Inc., San Dimas, California, USA), Pentacam and Pentacam HR (Oculus, Wetzlar, Germany), Galilei (Ziemer, Switzerland), Visante optical coherence tomography (Visante OCT, Carl Zeiss Meditec Inc., Dublin, California, USA), IOLMaster (Carl Zeiss Meditec, Jena, Germany), and Lenstar LS 900/Biograph (Haag-Streit AG, Koeniz, Switzerland/Alcon Laboratories Inc., Ft Worth, Texas, USA). PMID- 27500119 TI - Comment on roles of tissue plasminogen activator and its inhibitor in proliferative diabetic retinopathy. PMID- 27500120 TI - Intensified intravitreal bevacizumab treatment regime for type 1 and 2 idiopathic macular telangiectasia. PMID- 27500121 TI - A surprising visual improvement following a prolonged 5-month retained subfoveal perfluorocarbon liquid. PMID- 27500118 TI - The effect of lens aging and cataract surgery on circadian rhythm. AB - Many organisms have evolved an approximately 24-hour circadian rhythm that allows them to achieve internal physiological homeostasis with external environment. Suprachiasmatic nucleus (SCN) is the central pacemaker of circadian rhythm, and its activity is entrained to the external light-dark cycle. The SCN controls circadian rhythm through regulating the synthesis of melatonin by pineal gland via a multisynaptic pathway. Light, especially short-wavelength blue light, is the most potent environmental time cue in circadian photoentrainment. Recently, the discovery of a novel type of retinal photoreceptors, intrinsically photosensitive retinal ganglion cells, sheds light on the mechanism of circadian photoentrainment and raises concerns about the effect of ocular diseases on circadian system. With age, light transmittance is significantly decreased due to the aging of crystalline lens, thus possibly resulting in progressive loss of circadian photoreception. In the current review, we summarize the circadian physiology, highlight the important role of light in circadian rhythm regulation, discuss about the correlation between age-related cataract and sleep disorders, and compare the effect of blue light- filtering intraocular lenses (IOLs) and ultraviolet only filtering IOLs on circadian rhythm. PMID- 27500122 TI - High sensitivity of diffusion tensor imaging in discriminating idiopathic demyelinating optic neuritis. PMID- 27500123 TI - Apocrine adenocarcinoma of the eyelid. PMID- 27500124 TI - All Hands on Deck: Nurses and Cancer Care Delivery in Women's Health. PMID- 27500125 TI - DNA Repair and Cytokines: TGF-beta, IL-6, and Thrombopoietin as Different Biomarkers of Radioresistance. AB - Double strand breaks (DSBs) induced by radiotherapy are highly cytotoxic lesions, leading to chromosomal aberrations and cell death. Ataxia-telangiectasia-mutated (ATM)-dependent DNA-damage response, non-homologous end joining, and homologous recombination pathways coordinately contribute to repairing DSBs in higher eukaryotes. It is known that the expression of DSB repair genes is increased in tumors, which is one of the main reasons for radioresistance. The inhibition of DSB repair pathways may be useful to increase tumor cell radiosensitivity and may target stem cell-like cancer cells, known to be the most radioresistant tumor components. Commonly overexpressed in neoplastic cells, cytokines confer radioresistance by promoting proliferation, survival, invasion, and angiogenesis. Unfortunately, tumor irradiation increases the expression of various cytokines displaying these effects, including transforming growth factor-beta and interleukin-6. Recently, the capabilities of these cytokines to support DNA repair pathways and the ATM-dependent DNA response have been demonstrated. Thrombopoietin, essential for megakaryopoiesis and very important for hematopoietic stem cell (HSC) homeostasis, has also been found to promote DNA repair in a highly selective manner. These findings reveal a novel mechanism underlying cytokine-related radioresistance, which may be clinically relevant. Therapies targeting specific cytokines may be used to improve radiosensitivity. Specific inhibitors may be chosen in consideration of different tumor microenvironments. Thrombopoietin may be useful in fending off irradiation induced loss of HSCs. PMID- 27500126 TI - Perspective of Postpartum Depression Theories: A Narrative Literature Review. AB - Postpartum depression is the most prevalent emotional problem during a women's lifespan. Untreated postpartum depression may lead to several consequences such as child, infant, fetal, and maternal effects. The main purpose of this article is to briefly describe different theoretical perspectives of postpartum depression. A literature search was conducted in Psych Info, PubMed, and Science Direct between 1950 and 2015. Additional articles and book chapters were referenced from these sources. Different theories were suggested for developing postpartum depression. Three theories, namely, biological, psychosocial, and evolutionary were discussed. One theory or combinations of psychosocial, biological, and evolutionary theories were considered for postpartum depression. The most important factor that makes clinicians' choice of intervention is their theoretical perspectives. Healthcare providers and physicians should help women to make informed choices regarding their treatment based on related theories. PMID- 27500127 TI - Comparative Study of Efficacy and Safety of Topical Squaric Acid Dibutylester and Diphenylcyclopropenone for the Treatment of Alopecia Areata. AB - BACKGROUND: Topical squaric acid dibutylester and diphenylcyclopropenone are still the most effective therapy for alopecia areata among widely available treatment options. Hence, it is important to know which one is more effective and safer between the two. AIMS: The aim of this study was to compare topical squaric acid dibutylester and diphenylcyclopropenone for the treatment of alopecia areata in terms of their efficacy and side effects. SUBJECTS AND METHODS: In the time period of January-March 2015, a total of 40 patients were selected for this study from the outpatient department of Rajendra Institute of Medical Sciences, Ranchi. After dropout of 16 patients, the remaining 24 patients were randomly divided into two groups; that is, group A for squaric acid dibutylester and group B for diphenylcyclopropenone. Each group received treatment for 6 months between March November 2015. Their efficacy and side effects were compared. STATISTICAL TEST: Unpaired student t-test was performed. P < 0.05 was considered to be significant and 95% confidence interval was also used to evaluate the efficacy. RESULTS: The mean values of percentage change in baseline severity of alopecia tool score for squaric acid dibutylester and diphenylcyclopropenone were 52.25 and 34.45, respectively. At 6 months, 95% confidence interval was 43.5-61% for group A and 25-44% for group B. In 58.33% of group A patients, A3 (50-74%) grade of improvement was observed, whereas in group B patients, it was 33.33%. A4 grade of improvement (75-99%) was also seen in 1 patient of group A. Minor side effects were seen in 2 patients of group A and 10 patients of group B. None of the group A patients showed major side effects, however, 2 patients suffered major side effects in group B. CONCLUSIONS: Between squaric acid dibutylester and diphenylcyclopropenone, squaric acid dibutylester is more efficacious. Further, frequencies of major and minor side effects are also lower than diphenylcyclopropenone. PMID- 27500128 TI - Cardiovascular Responses to an Isometric Handgrip Exercise in Females with Prehypertension. AB - BACKGROUND: Hypertensive individuals are known to exhibit greater increases in blood pressure during an isometric handgrip exercise (IHE) than their normotensive counterparts. AIM: This study tests the hypothesis that, compared to normotensive individuals, prehypertensive individuals exhibit an exaggerated response to IHE. MATERIALS AND METHODS: In this study, the effects of IHE were compared in matched prehypertensive vs. normotensive healthy African-American females. Six healthy young adult African-American female university students were screened in a physician's office for blood pressure in the range of prehypertension, systolic blood pressure (SBP) 120-139 mmHg and diastolic blood pressure (DBP) 80-89 mmHg. Six young adult African-American women were also recruited to serve as a healthy normotensive control group with SBP <=119 mmHg and DBP <=79 mmHg. Cardiovascular fitness was determined by peak oxygen uptake (VO2 peak) measured during a progressive exercise test. RESULTS: During the handgrip exercise, the prehypertensive group exhibited greater increases in SBP (from 139 +/- 6 to 205 +/- 11 mmHg, +48%) than the controls (from 132 +/- 3 to 145 +/- 3 mmHg, +10%); intergroup difference P < 0.001. The prehypertensive group also exhibited greater increases in DBP (from 77 +/- 2 to 112 +/- 5 mmHg, +46%) compared to the controls (from 72 +/- 3 to 78 +/- 4 mmHg, +8%); intergroup difference P < 0.001. The increase in systemic vascular resistance was also greater in the prehypertensive group (from 1713 +/- 91 to 2807 +/- 370 dyne.s.cm( 5), +64%) than in the controls (from 1668 +/- 80 to 1812 +/- 169 dyne.s.cm(-5), +9%); intergroup difference P < 0.05. CONCLUSION: These results suggest that blood pressure measurements performed during IHE may be a useful screening tool in evaluating prehypertensive individuals for antihypertensive treatments. PMID- 27500129 TI - Effect of Statins on the Mortality of Bacteremic Patients: A Systematic Review and Meta-analysis of Clinical Trials. AB - BACKGROUND: Statins modify inflammatory cell signaling during the immune response to infection. This has been considered as a pleotropic effect. Effects of statins in inflammatory conditions such as bacteremia have been found to be controversial. AIMS: We examined the effect of statins on the mortality of bacteremia patients. MATERIALS AND METHODS: Major databases were searched for the pertinent clinical trials. RESULTS: Six cohort studies comprising 7553 patients were included. Hospital mortality was lower (15.36% vs 22.28%) in patients on statin. CONCLUSIONS: There may be a potential role of statins in similar inflammatory and infective conditions. PMID- 27500130 TI - Acute Bowel Obstruction in a Giant Recurrent Right Bochdalek's Hernia: A Report of Complication on Both Sides of the Diaphragm. AB - CONTEXT: Diagnosis of congenital Bochdalek's hernia (BH) in adulthood is extremely rare and requires a fastidious surgical repair, the failure of which might result in a recurrence with severe complications. We report a rare case of a giant, right BH that recurred after surgical repair and was complicated with complete bowel obstruction. CASE REPORT: A 51-year-old Saudi male, with past surgical history of laparotomy that failed to repair BH, presented to the emergency room with severe abdominal pain, vomiting, and hypovolemic shock. Computerized tomography (CT) showed an unusual picture of closed-loop bowel obstruction above and below the diaphragm. We carried out laparotomy and thoracotomy that achieved lysis of adhesions, reduction of bowel, and repair of diaphragmatic defect. CONCLUSION: Acute presentation of complicated BH poses a formidable challenge because of its rarity and complexity. The preferred approach for elective repair of adult BH is debatable, where surgeons-guided by hernia type and biased by their experience-recommend either laparotomy or thoracotomy. Nevertheless, a complicated, giant, recurrent BH typically requires both laparotomy and thoracotomy. PMID- 27500131 TI - Acute Rhabdomyolysis Following Synthetic Cannabinoid Ingestion. AB - CONTEXT: Novel psychoactive substances, including synthetic cannabinoids, are becoming increasingly popular, with more patients being seen in the emergency room following acute ingestion. These substances have been associated with a wide range of adverse effects. However, identification of complications, clinical toxicity, and management remain challenging. CASE REPORT: We present the case of a young African-American male who developed severe agitation and bizarre behavior following acute K2 ingestion. Laboratory studies revealed markedly elevated serum creatine phosphokinase (CPK) with normal renal function. The patient was managed with aggressive intravenous (IV) fluid hydration and treatment of underlying psychiatric illness. CONCLUSION: We recommend the routine evaluation of renal function and CPK levels with early initiation of IV hydration among patients who present to the emergency department following acute ingestion of synthetic cannabinoids to identify potential complications early as well as institute early supportive therapy. PMID- 27500132 TI - Prosthetic Aortic Valve Endocarditis with Left Main Coronary Artery Embolism: A Case Report and Review of the Literature. AB - CONTEXT: Coronary embolization is potentially a fatal sequela of endocarditis. Although the primary cause of acute coronary syndrome is atherosclerotic disease, it is imperative to consider septic embolism as an etiological factor. CASE REPORT: Herein, we report a case of ventricular fibrillation and ST-segment depression myocardial infarction occurring in a patient who initially presented with fever and increased urinary frequency. Coronary angiography revealed new 99% occlusion of the left main coronary artery (LMCA). Transesophageal echocardiography showed bioprosthetic aortic valve with an abscess and vegetation. Histologic examination of the embolectomy specimen confirmed the presence of thrombus and Enterococcus faecalis bacteria. Subsequently, the patient was discharged to the skilled nursing facility in a stable condition where he completed 6 weeks of intravenous ampicillin. CONCLUSION: We present a rare case of LMCA embolism due to prosthetic valve endocarditis. The present report also highlights the diagnostic and therapeutic challenges associated with such patients. PMID- 27500133 TI - Electrochemical skin conductance to detect sudomotor dysfunction, peripheral neuropathy and the risk of foot ulceration among Saudi patients with diabetes mellitus. AB - BACKGROUND: Sudomotor dysfunction is manifested clinically as abnormal sweating leading to dryness of feet skin and increased risk of foot ulceration. The aim of this study was to test the performance of foot electrochemical skin conductance (ESC) to detect diabetic peripheral neuropathy and the risk of foot ulceration against traditional methods in Saudi patients with diabetes mellitus. METHODS: This cross-sectional study was conducted on 296 Saudi patients with diabetes mellitus. Painful neuropathic symptoms were evaluated using the neuropathy symptom score (NSS). The risk of foot ulceration and diabetic peripheral neuropathy were determined using the neuropathy disability score (NDS). Vibration perception threshold (VPT) was assessed using neurothesiometer. Neurophysiological assessment of the right and left sural, peroneal and tibial nerves was performed in 222 participants. Diabetic peripheral neuropathy was defined according to the definition of the American Academy of Neurology. ESC was measured with Sudoscan. RESULTS: Feet-ESC decreased as the scores of sensory and motor function tests increased. Feet-ESC decreased as the NSS, NDS and severity of diabetic peripheral neuropathy increased. Sensitivity of feet-ESC < 50MUS to detect diabetic peripheral neuropathy assessed by VPT >= 25 V, NDS >= 3, NDS >= 6 was 90.1, 61 and 63.8 % respectively and specificity 77, 85 and 81.9 % respectively. Sensitivity of feet-ESC < 70MUS to detect diabetic peripheral neuropathy assessed by VPT >= 25 V, NDS >= 3, NDS >= 6 was 100, 80.6 and 80.9 % respectively. Sensitivity and specificity of feet-ESC < 70MUS to detect confirmed diabetic peripheral neuropathy were 67.5 and 58.9 % respectively. CONCLUSION: Sudoscan a simple and objective tool can be used to detect diabetic peripheral neuropathy and the risk of foot ulceration among patients with diabetes mellitus. Prospective studies to confirm our results are warranted. PMID- 27500134 TI - Cancer Clocks Out for Lunch: Disruption of Circadian Rhythm and Metabolic Oscillation in Cancer. AB - Circadian rhythms are 24-h oscillations present in most eukaryotes and many prokaryotes that synchronize activity to the day-night cycle. They are an essential feature of organismal and cell physiology that coordinate many of the metabolic, biosynthetic, and signal transduction pathways studied in biology. The molecular mechanism of circadian rhythm is controlled both by signal transduction and gene transcription as well as by metabolic feedback. The role of circadian rhythm in cancer cell development and survival is still not well understood, but as will be discussed in this Review, accumulated research suggests that circadian rhythm may be altered or disrupted in many human cancers downstream of common oncogenic alterations. Thus, a complete understanding of the genetic and metabolic alterations in cancer must take potential circadian rhythm perturbations into account, as this disruption itself will influence how gene expression and metabolism are altered in the cancer cell compared to its non transformed neighbor. It will be important to better understand these circadian changes in both normal and cancer cell physiology to potentially design treatment modalities to exploit this insight. PMID- 27500135 TI - Adherence to a Mediterranean-Style Diet and Effects on Cognition in Adults: A Qualitative Evaluation and Systematic Review of Longitudinal and Prospective Trials. AB - The Mediterranean-style diet (MedDiet) involves substantial intake of fruits, vegetables, and fish, and a lower consumption of dairy, red meat, and sugars. Over the past 15 years, much empirical evidence supports the suggestion that a MedDiet may be beneficial with respect to reducing the incidence of cardiovascular disease, cancer, metabolic syndrome, and dementia. A number of cross-sectional studies that have examined the impact of MedDiet on cognition have yielded largely positive results. The objective of this review is to evaluate longitudinal and prospective trials to gain an understanding of how a MedDiet may impact cognitive processes over time. The included studies were aimed at improving cognition or minimizing of cognitive decline. Studies reviewed included assessments of dietary status using either a food frequency questionnaire or a food diary assessment. Eighteen articles meeting our inclusion criteria were subjected to systematic review. These revealed that higher adherence to a MedDiet is associated with slower rates of cognitive decline, reduced conversion to Alzheimer's disease, and improvements in cognitive function. The specific cognitive domains that were found to benefit with improved Mediterranean Diet Score were memory (delayed recognition, long-term, and working memory), executive function, and visual constructs. The current review has also considered a number of methodological issues in making recommendations for future research. The utilization of a dietary pattern, such as the MedDiet, will be essential as part of the armamentarium to maintain quality of life and reduce the potential social and economic burden of dementia. PMID- 27500136 TI - Response to Intravenous Allogeneic Equine Cord Blood-Derived Mesenchymal Stromal Cells Administered from Chilled or Frozen State in Serum and Protein-Free Media. AB - Equine mesenchymal stromal cells (MSC) are commonly transported, chilled or frozen, to veterinary clinics. These MSC must remain viable and minimally affected by culture, transport, or injection processes. The safety of two carrier solutions developed for optimal viability and excipient use were evaluated in ponies, with and without allogeneic cord blood-derived (CB) MSC. We hypothesized that neither the carrier solutions nor CB-MSC would elicit measurable changes in clinical, hematological, or biochemical parameters. In nine ponies (study 1), a bolus of HypoThermosol((r)) FRS (HTS-FRS), CryoStor((r)) CS10 (CS10), or saline was injected IV (n = 3/treatment). Study 2, following a 1-week washout period, 5 * 10(7) pooled allogeneic CB-MSCs were administered IV in HTS-FRS following 24 h simulated chilled transport. Study 3, following another 1-week washout period 5 * 10(7) pooled allogeneic CB-MSCs were administered IV in CS10 immediately after thawing. Nine ponies received CB-MSCs in study 2 and 3, and three ponies received the cell carrier media without cells. CB-MSCs were pooled in equal numbers from five unrelated donors. In all studies, ponies were monitored with physical examination, and blood collection for 7 days following injection. CD4 and CD8 lymphocyte populations were also evaluated in each blood sample. In all three studies, physical exam, complete blood cell count, serum biochemistry, and coagulation panel did not deviate from established normal ranges. Proportions of CD4(+) and CD8(+) lymphocytes increased at 168 h postinjection in CB-MSC treatment groups regardless of the carrier solution. Decreases in CD4(+/)CD8(+) double positive populations were observed at 24 and 72 h in CB-MSC-treated animals. There was no difference in viability between CB-MSCs suspended in HTS FRS and CS10. HTS-FRS and CS10 used for low volume excipient injection of MSC suspensions were not associated with short-term adverse reactions. HTS-FRS and CS10 both adequately maintain CB-MSC viability following hypothermic or frozen simulated transport, respectively. CB-MSCs do not elicit clinical abnormalities, but allogeneic stimulation of CD4(+) and CD8(+) lymphocyte populations may occur. Future studies should include in vitro or in vivo evaluation of cell-mediated or adaptive immunity to autologous, identical allogeneic, or MSC originating from additional unrelated individuals in order to better characterize this response. PMID- 27500138 TI - Techniques and innovations in liver surgery. PMID- 27500139 TI - How could we image the future in hepatic surgery. PMID- 27500140 TI - What has changed after the Morioka consensus conference 2014 on laparoscopic liver resection? AB - The 2(nd) International Consensus Conference on Laparoscopic Liver Resection (ICCLLR) was held 4(th)-6(th) October, 2014, in Morioka, Japan. The level of evidence appears to be low in the field of laparoscopic liver resection (LLR) to create strong recommendations. Therefore, an independent jury-based consensus model was applied to better define the current role of LLR and to develop internationally accepted recommendations. The three-day conference was very intense with full of insightful discussions on assessment of LLR and its future directions. The jury drew the statements based on the presentations and documents prepared by the expert. LLR is theoretically superior to open liver resection (OLR) because the laparoscope allows better exposure with a magnified view, and the pneumoperitoneum pressure reduces hepatic vein bleeding from the cut surface. During the ICCLLR, we shared these theoretical advantages in LLR and the conceptual change of liver resection. After the ICCLLR, a couple of important studies have been published to prove this theoretical superiority of LLR over OLR in short-term outcomes without deteriorating long-term outcomes. Another new concept was proposed at the ICCLLR: parenchyma sparing (limited) anatomical resection. Review of the literature supports anatomical resection with parenchyma sparing strategy for LLR irrespective of hepatocellular carcinoma (HCC) and colorectal liver metastasis (CRLM). Just after the ICCLLR, sensational news of clustered mortality after LLR was reported in the Japanese media and they impacted on daily practice of LLR in Japan. The most important message from the ICCLLR is to protect patients from this new surgical procedure. The ICCLLR recommended three actions for the protection of patients: (I) prospective reporting registry for transparency; (II) a difficulty scoring system to select patients; (III) creation of a formal structure of education. The online prospective registry system including items to calculate the difficulty score has been created in Japan after the ICCLLR for the safe development of LLR. PMID- 27500137 TI - Omnivores Going Astray: A Review and New Synthesis of Abnormal Behavior in Pigs and Laying Hens. AB - Pigs and poultry are by far the most omnivorous of the domesticated farm animals and it is in their nature to be highly explorative. In the barren production environments, this motivation to explore can be expressed as abnormal oral manipulation directed toward pen mates. Tail biting (TB) in pigs and feather pecking (FP) in laying hens are examples of unwanted behaviors that are detrimental to the welfare of the animals. The aim of this review is to draw these two seemingly similar abnormalities together in a common framework, in order to seek underlying mechanisms and principles. Both TB and FP are affected by the physical and social environment, but not all individuals in a group express these behaviors and individual genetic and neurobiological characteristics play an important role. By synthesizing what is known about environmental and individual influences, we suggest a novel possible mechanism, common for pigs and poultry, involving the brain-gut-microbiota axis. PMID- 27500141 TI - Laparoscopic hepatectomy versus open hepatectomy for colorectal cancer liver metastases: comparative study with propensity score matching. AB - BACKGROUND: The objective of this study was to compare the results of laparoscopic hepatectomy with those of open hepatectomy for colorectal cancer liver metastases (CCLM) using a propensity score matching (PSM) in two university hospital settings. METHODS: A patient in the laparoscopic approach (LA) surgery group was randomly matched with another patient in the open approach (OA) group using a 1:1 allocated ratio with the nearest estimated propensity score. No patients of the LA group were excluded for the matching. Matching criteria included age, gender, body mass index (BMI), American society anesthesiologists score, potential co-morbidities, hepatopathies, synchronous or metachronous lesions, size and number of CCLM, preoperative chemotherapy, minor or major liver resections. Intraoperative, postoperative data, and survival were compared in both groups. RESULTS: From January 2012 to January 2015, a total of 242 hepatectomies were consecutively performed, of which 119 for CCLM, namely 101 in the OA group (84.9%) and 18 in the LA group (15.1%). The conversion rate was 5.6% (n=1). The mortality rate was 1% in the OA group and 0% in the LA group. Prior to PSM, there was a statistically significant difference favorable to the LA group regarding operative time, blood loss, length of hospital stay and the rate of medical complications. After PSM, there was no difference regarding operative time or length of hospital stay. However, there was a trend towards less blood loss (P=0.066) and fewer medical complications (44.4% vs.16.7%, P=0.07). The R0 resection rate was 94.4% (n=17) in the two groups. In addition, there was no difference regarding overall survival (P=0.358) and recurrence-free survival [HR =0.99 (0.1-12.7); P=0.99]. CONCLUSIONS: Laparoscopic liver resections for CCLM seem to yield short- and long-term results, which are similar to open hepatectomies, and could well be considered an alternative to open surgery and become the gold standard in carefully selected patients. PMID- 27500143 TI - Robotic liver surgery: technical aspects and review of the literature. AB - Minimally invasive surgery for liver resections has a defined role and represents an accepted alternative to open techniques for selected cases. Robotic technology can overcome some of the disadvantages of the laparoscopic technique, mainly in the most complex cases. Precise dissection and microsuturing is possible, even in narrow operative fields, allowing for a better dissection of the hepatic hilum, fine lymphadenectomy, and biliary reconstruction even with small bile ducts and easier bleeding control. This technique has the potential to allow for a greater number of major resections and difficult segmentectomies to be performed in a minimally invasive fashion. The implementation of near-infrared fluorescence with indocyanine green (ICG) also allows for a more accurate recognition of vascular and biliary anatomy. The perspectives of this kind of virtually implemented imaging are very promising and may be reflected in better outcomes. The overall data present in current literature suggests that robotic liver resections are at least comparable to both open and laparoscopic surgery in terms of perioperative and postoperative outcomes. This article provides technical details of robotic liver resections and a review of the current literature. PMID- 27500142 TI - Short and long-term outcomes of laparoscopic compared to open liver resection for colorectal liver metastases. AB - BACKGROUND: Minimally invasive surgery (MIS) is now established as standard of care for a variety of gastrointestinal procedures for benign and malignant indications. However, due to concerns regarding superiority to open liver resection (OLR), the uptake of laparoscopic liver resection (LLR) has been slow. Data on long-term outcomes of LLR for colorectal liver metastases (CRLM) remain limited. We conducted a systematic review and meta-analysis of short and long term outcomes of LLR compared to OLR for CRLM. METHODS: Five electronic databases were systematically searched for studies comparing LLR and OLR for CRLM and reporting on survival outcomes. Two reviewers independently selected studies and extracted data. Primary outcomes were overall survival (OS) and recurrence free survival (RFS). Secondary outcomes were operative time, estimated blood loss, post-operative major morbidity, mortality, length of stay (LOS), and resection margins. RESULTS: Eight non-randomized studies (NRS) were included (n=2,017 total patients). Six were matched cohort studies. LLR reduced estimated blood loss [mean difference: -108.9; 95% confidence interval (CI), -214.0 to -3.7) and major morbidity [relative risk (RR): 0.68; 95% CI, 0.56-0.83], but not mortality. No difference was observed in operative time, LOS, resection margins, R0 resections, and recurrence. Survival data could not be pooled. No studies reported inferior survival with LLR. OS varied from 36% to 60% for LLR and 37% to 65% for OLR. RFS ranged from 14% to 30% for LLR and 22% to 38% for OLR. According to the grade classification, the strength of evidence was low to very low for all outcomes. The use of parenchymal sparing resections with LLR and OLR could not be assessed. CONCLUSIONS: Based on limited retrospective evidence, LLR offers reduced morbidity and blood loss compared to OLR for CRLM. Comparable oncologic outcomes can be achieved. Although LLR cannot be considered as standard of care for CRLM, it is beneficial for well-selected patients and lesions. Therefore, LLR should be part of the liver surgeon's armamentarium. PMID- 27500144 TI - Clinical application of indocyanine green-fluorescence imaging during hepatectomy. AB - In hepatobiliary surgery, the fluorescence and bile excretion of indocyanine green (ICG) can be used for real-time visualization of biological structure. Fluorescence cholangiography is used to obtain fluorescence images of the bile ducts following intrabiliary injection of 0.025-0.5 mg/mL ICG or intravenous injection of 2.5 mg ICG. Recently, the latter technique has been used in laparoscopic/robotic cholecystectomy. Intraoperative fluorescence imaging can be used to identify subcapsular hepatic tumors. Primary and secondary hepatic malignancy can be identified by intraoperative fluorescence imaging using preoperative intravenous injection of ICG through biliary excretion disorders that exist in cancerous tissues of hepatocellular carcinoma (HCC) and in non cancerous hepatic parenchyma around adenocarcinoma foci. Intraoperative fluorescence imaging may help detect tumors to be removed, especially during laparoscopic hepatectomy, in which visual inspection and palpation are limited, compared with open surgery. Fluorescence imaging can also be used to identify hepatic segments. Boundaries of hepatic segments can be visualized following injection of 0.25-2.5 mg/mL ICG into the portal veins or by intravenous injection of 2.5 mg ICG following closure of the proximal portal pedicle toward hepatic regions to be removed. These techniques enable identification of hepatic segments before hepatectomy and during parenchymal transection for anatomic resection. Advances in imaging systems will increase the use of fluorescence imaging as an intraoperative navigation tool that can enhance the safety and accuracy of open and laparoscopic/robotic hepatobiliary surgery. PMID- 27500145 TI - High intensity focused ultrasound (HIFU) applied to hepato-bilio-pancreatic and the digestive system-current state of the art and future perspectives. AB - BACKGROUND: High intensity focused ultrasound (HIFU) is emerging as a valid minimally-invasive image-guided treatment of malignancies. We aimed to review to current state of the art of HIFU therapy applied to the digestive system and discuss some promising avenues of the technology. METHODS: Pertinent studies were identified through PubMed and Embase search engines using the following keywords, combined in different ways: HIFU, esophagus, stomach, liver, pancreas, gallbladder, colon, rectum, and cancer. Experimental proof of the concept of endoluminal HIFU mucosa/submucosa ablation using a custom-made transducer has been obtained in vivo in the porcine model. RESULTS: Forty-four studies reported on the clinical use of HIFU to treat liver lesions, while 19 series were found on HIFU treatment of pancreatic cancers and four studies included patients suffering from both liver and pancreatic cancers, reporting on a total of 1,682 and 823 cases for liver and pancreas, respectively. Only very limited comparative prospective studies have been reported. CONCLUSIONS: Digestive system clinical applications of HIFU are limited to pancreatic and liver cancer. It is safe and well tolerated. The exact place in the hepatocellular carcinoma (HCC) management algorithm remains to be defined. HIFU seems to add clear survival advantages over trans arterial chemo embolization (TACE) alone and similar results when compared to radio frequency (RF). For pancreatic cancer, HIFU achieves consistent cancer related pain relief. Further research is warranted to improve targeting accuracy and efficacy monitoring. Furthermore, additional work is required to transfer this technology on appealing treatments such as endoscopic HIFU-based therapies. PMID- 27500146 TI - Laparoscopic Pringle maneuver: how we do it? AB - Laparoscopic liver resection (LLR) is technically possible with new devices which allow a relatively bloodless liver parenchymal transection. Despite, the main concern remains intraoperative hemorrhage. Currently, perioperative excessive blood loss during LLR is difficult to control with necessity of laparotomy conversion. Moreover, major blood loss requires transfusion and increases postoperative morbidity and mortality. When in-flow is limited by the hepatic pedicle clamping, it reduces intraoperative blood loss. The Pringle maneuver, first described in 1908, is the simplest method of inflow occlusion and currently can be achieved during LLR. The purpose of this note was to describe two different modalities of Pringle maneuver used by two different teams during LLR. PMID- 27500147 TI - Combined liver and extrahepatic bile duct resection for biliary invasion of colorectal metastasis: a case-cohort analysis and systematic review. AB - BACKGROUND: Colorectal liver metastases (CRLMs) with biliary invasion can be treated with a combined liver and extrahepatic bile duct resection. The aim of this study was to analyze outcomes of this procedure in a case-cohort analysis and systematic review. METHODS: Consecutive patients who underwent a major liver resection for CRLM between 2003 and 2013 were selected from a single center prospective database, comparing patients with and without biliary invasion. A specific and a general search strategy were used to identify relevant articles in the systematic review. RESULTS: Ten patients (13.2%) underwent combined liver and extrahepatic bile duct resection for CLRM with biliary invasion, among 76 patients included. An R0 resection was achieved in five of ten patients (50%); one of ten patients died postoperatively. Median overall survival was 19 months among patients with biliary invasion, versus 106 months among patients without biliary invasion (P=0.12). The systematic review yielded a large variability in 5 year survival after resection of CLRM with biliary invasion, ranging between 33 80%. CONCLUSIONS: Surgical resection of CLRM with central biliary invasion is feasible, but survival in these patients tends to be lower due to a high rate of non-radical resections. PMID- 27500149 TI - Twenty years of Milan criteria: the wicked flee though no one pursues. PMID- 27500148 TI - Nutrition assessment and its effect on various clinical variables among patients undergoing liver transplant. AB - BACKGROUND: Malnutrition is highly prevalent in patients undergoing liver transplantation and has been associated to various clinical variables and outcome of the surgery. METHODS: We recruited 54 adult patients undergoing living donor liver transplant (LT) as study sample. Nutrition assessment was performed by body mass index (BMI), BMI for ascites, albumin, subjective global assessment (SGA) and anthropometry [mid upper arm circumference (MUAC), mid arm muscle circumference (MAMC), and triceps skin-fold (TSF)], Hand Grip strength, and phase angle of the body. Prevalence and comparison of malnutrition was performed with various clinical variables: aetiology, Child Turcotte Pugh scores and model for end stage liver disease (ESLD) grades, degree of ascites, blood product usage, blood loss during the surgery, mortality, days [intensive care unit (ICU), Ventilator and Hospital], and Bio-impedance analysis [weight, fat mass, fat free mass (FFM), muscle mass and body fat%]. RESULTS: Assessment of nutrition status represents a major challenge because of complications like fluid retention, hypoalbuminemia and hypoproteinemia. Different nutrition assessment tools show great disparity in the level of malnutrition among ESLD patients. In the present study recipient nutrition status evaluation by different nutrition assessment tools used showed malnutrition ranging from 3.7% to 100%. BMI and anthropometric measurements showed lower prevalence of malnutrition than phase angle and SGA whereas hand grip strength showed 100% malnutrition. Agreement among nutrition assessment methods showed moderate agreement (kappa=0.444) of SGA with phase angle of the body. Malnutrition by different assessment tools was significantly associated to various clinical variables except MELD and days (ICU, Ventilator and Hospital). SGA was significantly (P<0.05) associated to majority of the clinical variables like aetiology, child Turcotte Pugh grades, degree of ascites, blood product usage, blood loss during the surgery, BIA (fat mass, FFM, muscle mass and body fat%). CONCLUSIONS: The different nutrition assessment tools showed great variability of results. SGA showed moderate agreement with phase angle of the body and was associated with various clinical and prognostic variables of liver transplantation. PMID- 27500150 TI - A totally laparoscopic associating liver partition and portal vein ligation for staged hepatectomy assisted with radiofrequency (radiofrequency assisted liver partition with portal vein ligation) for staged liver resection. AB - In order to induce liver hypertrophy to enable liver resection in patients with a small future liver remnant (FLR), various methods have been proposed in addition to portal vein embolisation (PVE). Most recently, the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) technique has gained significant international interest. This technique is limited by the high morbidity associated with an in situ liver splitting and the patient undergoing two open operations. We present the case of a variant ALPPS technique performed entirely laparoscopically with no major morbidity or mortality. An increased liver volume of 57.9% was seen after 14 days. This technique is feasible to perform and compares favourably to other ALPPS methods whilst gaining the advantages of laparoscopic surgery. PMID- 27500151 TI - Gastrointestinal stromal tumor as cause of hepatic mass. PMID- 27500152 TI - Evidence and pitfalls in diagnosis and prognostication of acute coronary syndrome. PMID- 27500153 TI - Predictive significance of detectable cardiac troponin I measured with a contemporary-sensitive assay in a real life experience. AB - BACKGROUND: Cardiac troponin (cTn) testing has reduced the likelihood of erroneous discharge of patients with acute coronary syndrome (ACS) from the emergency department (ED), but doubts remain about optimal clinical use. This study was planned for evaluating the predictive significance of cTn values between the limit of detection of the method and the 99th percentile in ED patients evaluated for suspected ACS. METHODS: In this retrospective study all hospital records of patients admitted over a 6-month period to the ED and with at least one cTnI value comprised between the limit of detection (0.01 ng/mL) and the 99th percentile of the assay (0.05 ng/mL) were analyzed. RESULTS: A total of 4,749 patients with cTnI value between 0.01-0.05 ng/mL were identified among 57,879 ED visits throughout the study period. Overall, 2,189 patients (46.1%) were discharged from the ED, 2,529 (53.25%) were admitted to the hospital and 31 (0.65%) died during ED stay. A total number of 289 patients out of 2,189 who were discharged (i.e., 13.2%) had additional ED visits within 30 days. Among these, 6 were diagnosed with ACS, representing 0.27% of patients discharged [negative predictive value (NPV) 0.997; 95% CI, 0.994-0.999] and 2.1% of those with second admission (NPV 0.979; 95% CI, 0.955-0.992). Only one of the 2,529 patients admitted to the hospital (i.e., 0.04%) developed an ACS during hospital stay. CONCLUSIONS: The results of our retrospective study suggest that the suitability of using a contemporary-sensitive cTnI immunoassay assay in the context of an appropriate protocol represents a safe and effective strategy for ruling in and ruling out ACS in patients presenting to the ED. PMID- 27500154 TI - Impact of gestational risk factors on maternal cardiovascular system. AB - BACKGROUND: Scarce evidence is available on the potential cardiovascular abnormalities associated with some common gestational complications. We aimed to analyze the potential maternal cardiac alterations related to gestational complications, including body mass index (BMI) >25 kg/m(2), gaining excessive weight, or developing antenatal depression. METHODS: The design of this study was a secondary analysis of a randomized controlled trial. Echocardiography was performed to assess cardiovascular indicators of maternal hemodynamic, cardiac remodeling and left ventricular (LV) function in 59 sedentary pregnant women at 20 and 34 weeks of gestation. RESULTS: Starting pregnancy with a BMI >25 kg/m(2), gaining excessive weight, and developing antenatal depression had no cardiovascular impact on maternal health (P value >0.002). Depressed women were more likely to exceed weight gain recommendations than non-depressed women (P value <0.002). CONCLUSIONS: The evaluated gestational complications seem not to induce cardiovascular alterations in hemodynamic, remodeling and LV function indicators. However, developing antenatal depression increases the risk of an excessive weight gain. This finding is potentially important because excessive weight gain during pregnancy associates with a higher risk of cardiovascular diseases (CVD) later in life. PMID- 27500155 TI - Red blood cell distribution width independently predicts medium-term mortality and major adverse cardiac events after an acute coronary syndrome. AB - BACKGROUND: The value of red blood cell distribution width (RDW), a simple and inexpensive measure of anisocytosis, has been associated with the outcome of many human chronic disorders. Therefore, this retrospective study was aimed to investigate whether RDW may be associated with medium-term mortality and major adverse cardiac events (MACE) after an acute coronary syndrome (ACS). METHODS: A total number of 979 patients diagnosed with ACS were enrolled from June 2014 to November 2014, and followed-up until June 2015. RESULTS: The RDW value in patients with 3-month MACE and in those who died was significantly higher than that of patients without 3-month MACE (13.3% vs. 14.0%; P<0.001) and those who were still alive at the end of follow-up (13.4% vs. 14.4%; P<0.001). In univariate analysis, RDW was found to be associated with 3-month MACE [odds ratio (OR), 1.70; 95% CI, 1.44-2.00, P<0.001]. In multivariate analysis, RDW remained independently associated with 3-month MACE (adjusted OR, 1.36; 95% CI, 1.19-1.55; P<0.001) and death (adjusted OR, 1.34; 95% CI, 1.05-1.71; P=0.020). The accuracy of RDW for predicting 3-month MACE was 0.67 (95% CI, 0.66-0.72; P<0.001). The most efficient discriminatory RDW value was 14.8%, which was associated with 3.8 (95% CI, 2.6-5.7; P<0.001) higher risk of 3-month MACE. Patients with RDW >14.8% exhibited a significantly short survival than those with RDW <=14.8% (331 vs. 465 days; P<0.001). CONCLUSIONS: The results of this study confirm that RDW may be a valuable, easy and inexpensive parameter for stratifying the medium-term risk in patients with ACS. PMID- 27500156 TI - Coronary computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR) imaging in the assessment of patients presenting with chest pain suspected for acute coronary syndrome. AB - Acute chest pain is an important clinical challenge and a major reason for presentation to the emergency department. Although multiple imaging techniques are available to assess patients with suspected acute coronary syndrome (ACS), considerable interest has been focused on the use of non-invasive imaging options as coronary computed tomography angiography (CCTA) and cardiac magnetic resonance (CMR). According to several recent evidences, CCTA has been shown to represent a useful tool to rapidly and accurately diagnose coronary artery disease (CAD) in patients with low to intermediate cardiovascular risk. CCTA examination has the unique ability to non-invasively depict the coronary anatomy, not only allowing visualization of the lumen of the arteries in order to detect severe stenosis or occlusion responsible of myocardial ischemia, but also allows the assessment of coronary artery wall by demonstrating the presence or absence of CAD. However, routine CCTA is not able to differentiate ischemic from non-ischemic chest pain in patients with known CAD and it does not provide any functional assessment of the heart. Conversely, CMR is considered the gold standard in the evaluation of morphology, function, viability and tissue characterization of the heart. CMR offers a wide range of tools for diagnosing myocardial infarction (MI) at least at the same time of the elevation of cardiac troponin values, differentiating infarct tissue and ischemic myocardium from normal myocardium or mimicking conditions, and distinguishing between new and old ischemic events. In high-risk patients, with acute and chronic manifestations of CAD, CMR may be preferable to CCTA, since it would allow detection, differential diagnosis, prognostic evaluation and management of MI. PMID- 27500157 TI - Epidemiology of coronary heart disease and acute coronary syndrome. AB - The aim of this review is to summarize the incidence, prevalence, trend in mortality, and general prognosis of coronary heart disease (CHD) and a related condition, acute coronary syndrome (ACS). Although CHD mortality has gradually declined over the last decades in western countries, this condition still causes about one-third of all deaths in people older than 35 years. This evidence, along with the fact that mortality from CHD is expected to continue increasing in developing countries, illustrates the need for implementing effective primary prevention approaches worldwide and identifying risk groups and areas for possible improvement. PMID- 27500158 TI - High-sensitivity cardiac troponin testing in routine practice: economic and organizational advantages. AB - Very seldom, if ever, a single laboratory test has provided such a paradigm shift in the managed care as cardiac troponin (cTn) testing. More than twenty years of improvements in test design and analytical features have contributed to revolutionize the clinical recommendations and guidelines, and the diagnosis of myocardial infarction (MI) is now highly dependent upon the kinetics of cTn within a suggestive clinical setting. Despite the advent of high-sensitivity cTn (HS-cTn) immunoassays has allowed a more accurate and timely diagnosis as well as a higher prognostic accuracy, the focus is now shifting on the most suitable algorithms and on a comprehensive approach to the clinical management of acute coronary syndrome (ACS). In this article we aim to discuss the implications of HS cTn testing for ruling out and ruling in ACS. In the latter instance, main improvements are related to ACS diagnosis in women, in whom this pathology is still often underdiagnosed or misdiagnosed. A quick and accurate rule out will also regarded as a great advantage from both an organizational and economic standpoint. The advantages that will stem from this new approach have been recently assessed, and shortening of repeated testing 1 or 2 h from conventional algorithms entailing blood sampling at 3 and 6 h seems attainable. The larger benefits will definitely occur in clinical settings where the actual diagnosis rate of MI among patients with suspect ACS is lower and, consequently, the negative predictive value (NPV) of HS-cTn is the highest. PMID- 27500159 TI - Prognostic biomarkers in acute coronary syndrome. AB - The acute coronary syndrome (ACS) is a leading cause of death around the globe. Beside a still high mortality rate, additional complications of ACS include arrhythmias, left ventricular mural thrombus, cardiac fibrosis, heart failure (HF), cardiogenic shock, mitral valve dysfunction, aneurysms, up to cardiac rupture. Despite many prognostic tools have been developed over the past decades, efforts are still ongoing to identify reliable and predictive biomarkers, which may help predict the prognosis of these patients and especially the risk of HF. Recent evidence suggests that the value of a discrete number of biomarkers of myocardial fibrosis, namely the soluble form of suppression of tumorigenicity 2 (sST2) and galectin-3 (GAL-3), may be predictive of HF and death in patients with ACS. Interestingly, the already promising predictive value of these biomarkers when measured alone was shown to be consistently magnified when combined with other and well-established cardiac biomarkers such natriuretic peptides and cardiac troponins. This article is hence aimed to review the current knowledge about cardiac biomarkers of fibrosis and adverse remodeling. PMID- 27500160 TI - Echocardiographic assessment of myocardial ischemia. AB - Over the last 60 years, echocardiography has emerged as a dominant and indispensable technique for the detection and assessment of coronary heart disease (CHD). In this review, we will describe and discuss this powerful tool of cardiology, especially in the hands of an experienced user, with a focus on myocardial ischemia. Technical development is still on-going, and various new ultrasound techniques have been established in the field of echocardiography in the last several years, including tissue Doppler imaging (TDI), contrast echocardiography, three-dimensional echocardiography (3DE), and speckle tracking echocardiography (i.e., strain/strain rate-echocardiography). High-end equipment with harmonic imaging, high frame rates and the opportunity to adjust mechanical indices has improved imaging quality. Like all new techniques, these techniques must first be subjected to comprehensive scientific assessment, and appropriate training that accounts for physical and physiological limits should be provided. These limits will constantly be redefined as echocardiographic techniques continue to change, which will present new challenges for the further development of ultrasound technology. PMID- 27500161 TI - The Popeye Domain Containing Genes and cAMP Signaling. AB - 3'-5'-cyclic adenosine monophosphate (cAMP) is a second messenger, which plays an important role in the heart. It is generated in response to activation of G protein-coupled receptors (GPCRs). Initially, it was thought that protein kinase A (PKA) exclusively mediates cAMP-induced cellular responses such as an increase in cardiac contractility, relaxation, and heart rate. With the identification of the exchange factor directly activated by cAMP (EPAC) and hyperpolarizing cyclic nucleotide-gated (HCN) channels as cAMP effector proteins it became clear that a protein network is involved in cAMP signaling. The Popeye domain containing (Popdc) genes encode yet another family of cAMP-binding proteins, which are prominently expressed in the heart. Loss-of-function mutations in mice are associated with cardiac arrhythmia and impaired skeletal muscle regeneration. Interestingly, the cardiac phenotype, which is present in both, Popdc1 and Popdc2 null mutants, is characterized by a stress-induced sinus bradycardia, suggesting that Popdc proteins participate in cAMP signaling in the sinuatrial node. The identification of the two-pore channel TREK-1 and Caveolin 3 as Popdc-interacting proteins represents a first step into understanding the mechanisms of heart rate modulation triggered by Popdc proteins. PMID- 27500162 TI - Cardiac-Restricted Expression of VCP/TER94 RNAi or Disease Alleles Perturbs Drosophila Heart Structure and Impairs Function. AB - Valosin-containing protein (VCP) is a highly conserved mechanoenzyme that helps maintain protein homeostasis in all cells and serves specialized functions in distinct cell types. In skeletal muscle, it is critical for myofibrillogenesis and atrophy. However, little is known about VCP's role(s) in the heart. Its functional diversity is determined by differential binding of distinct cofactors/adapters, which is likely disrupted during disease. VCP mutations cause multisystem proteinopathy (MSP), a pleiotropic degenerative disorder that involves inclusion body myopathy. MSP patients display progressive muscle weakness. They also exhibit cardiomyopathy and die from cardiac and respiratory failure, which are consistent with critical myocardial roles for the enzyme. Nonetheless, efficient models to interrogate VCP in cardiac muscle remain underdeveloped and poorly studied. Here, we investigated the significance of VCP and mutant VCP in the Drosophila heart. Cardiac-restricted RNAi-mediated knockdown of TER94, the Drosophila VCP homolog, severely perturbed myofibrillar organization and heart function in adult flies. Furthermore, expression of MSP disease-causing alleles engendered cardiomyopathy in adults and structural defects in embryonic hearts. Drosophila may therefore serve as a valuable model for examining role(s) of VCP in cardiogenesis and for identifying novel heart specific VCP interactions, which when disrupted via mutation, contribute to or elicit cardiac pathology. PMID- 27500163 TI - Investigating the Impact of Preparation Strategies on USMLE Step 1 Performance. AB - BACKGROUND: The USMLE Step 1 score helps differentiate applicants for competitive residency programs. Students frequently ask medical educators how to prepare for this high-stakes exam. Multiple resources exist such as books, training programs, and question banks. The purpose of this study is to provide medical educators with data on which resources correlate with higher exam scores. METHODS: 164 medical students at West Virginia University School of Medicine were given a survey following the completion of Step 1. The survey contained questions about resources used and exam date. De-identified data was paired with class quartile rankings and Step 1 scores. Average Step 1 scores were calculated for each resource and a student's t-test was used to compare between groups. Test dates were also broken into quintiles and average Step 1 scores were compared between groups. RESULTS: Students who used the USMLE World question bank had higher Step 1 scores (M=229, SE=1.4) compared to students who did not use this resource (M=215, SE=4.2). Commercial preparation courses were not associated with improved scores. The timing of when the exam was taken was also not associated with significant differences between scores. CONCLUSIONS: Interactive study options offer the best choice to improve USMLE Step 1 scores. PMID- 27500164 TI - Evaluation of the knowledge level of health violations in food production, distribution, sales centers and public places and their authorities investigating among the women of Bushehr city. AB - BACKGROUND: Women and mothers are the most important educational audience to convey health teachings. This study was aimed to evaluate the knowledge level of different types of health violations of food production, distribution, sale centers and public places; and authorities investigating the violations among women referring to health care centers in Bushehr. MATERIALS AND METHODS: In this descriptive-analytical study, which was done cross-sectionally, 600 women who were referred to health care centers affiliated to the Bushehr University of Medical Sciences was selected by convenience sampling. Two-part questionnaire was used to collect data: demographic information and a researcher-designed knowledge survey questionnaire consisted of 25 questions with Cronbach's alpha = 0.7. Data were analyzed with the software SPSS version 13; using Chi-square test and Phi and Cramer test. P <= 0.05 was considered to be statistically significant. RESULTS: The findings showed that 56.9% and 26.5% of women had good and moderate knowledge levels regarding health violations, while the general knowledge level of authorities investigating health violations were at the moderate level among 57.3% and at the good level among 15.3% of women. Overall, there was a significant relationship between education level and the women's knowledge level of health violations (P < 0.0001). The relationship between the women's education level and authorities investigating health violations was not significant (P = 0.073). CONCLUSION: Applying interventional methods of education in health violations to the women by health centers can elevate the level of health knowledge among them. PMID- 27500165 TI - Assessment of knowledge, attitude, and practice with regard to evidence-based dentistry among dental students in Isfahan University of Medical Sciences. AB - AIM: Evidence-based dentistry (EBD) is an approach to oral health that requires the application and examination of relevant scientific data related to the patient's oral health and his priorities. The aim of this study was to assess knowledge, attitude, and practice of dental students of Isfahan about EBD. MATERIALS AND METHODS: In this descriptive study, 168 dental students in 3 final years of their education who engaged in clinical practice by consensus sampling were recruited. For data collection, a validated questionnaire was used. The questionnaire was consisted of demographic questions and some questions about four issues: Knowledge of self-assess (KSA), evidence-based practice, actual knowledge and attitude about EBD. Data were analyzed with t-test, one-way ANOVA, Chi-square, and linear regression with SPSS 16. RESULTS: One hundred and thirty six students from 168 students were filled the questionnaire. The mean of KSA was 13 +/- 4.3, mean of usage of useful references in EBD was 16.9 +/- 7.6. One-third of students were studied their last article in last 6 months before. The mean of actual knowledge and attitude was 7.4 +/- 2.3 and 24 +/- 3.8, respectively. The relation between 4 main issues was significant (P < 0.05). CONCLUSION: By considering overall interest and positive attitude toward learning EBD in dental students, it is highly recommended that practical educational courses about EBD be planned by dental faculties. PMID- 27500166 TI - Factors affecting tea consumption pattern in an urban society in Isfahan, Iran. AB - OBJECTIVE: To determine the tea consumption pattern in an urban society in Isfahan. METHODS: A descriptive, cross-sectional survey was carried out using questioner among 664 households who were selected by two steps cluster sampling. A questionnaire was developed including demographic questions, information on the quantity of tea intake by every member of the family, tea type, and tea brand preference. RESULTS: The individuals who prioritized black tea as their 1(st) choice were 90.1% of the total surveyed community. The average amount of tea consumed was calculated as 1243 +/- 530 ml/day. The individuals who were between 36 and 45 and <15 years old were shown as the highest and the lowest tea consumers, respectively. Men significantly consumed more amount of tea than women did and married participants significantly used more amount of tea than singles (P < 0.05). The number of the family members, though, had no impact on tea consumption (P > 0.05). Brand preference of tea showed that the individuals who prioritized Ahmed brand as their 1(st) choice constituted 44% of the total participants. CONCLUSION: Tea consumption pattern in an Iranian sample is specific. Despite of the huge evidence on the green tea benefits, this type of tea has very low popularity and among the available black tea brands, the imported ones are the most preferred. PMID- 27500167 TI - The barriers to the application of the research findings from the nurses' perspective: A case study in a teaching hospital. AB - BACKGROUND: The application of the nursing research findings is one of the most important indicators of development in the nursing profession, which leads to providing efficient and effective patient care and improving the quality of nursing care. According the result of some studies, transferring the evidence based findings to the nurses' practice and education in the world has been slow and sometimes unsuccessful. This study aimed to investigate the most important barriers to the application of research findings from the nurses' perspective. MATERIALS AND METHODS: This cross-sectional study conducted on a sample of 210 nurses in a teaching hospital in Tehran in 2013. The data were collected using a researcher-made questionnaire consisted of two parts, including items about nurses' demographic characteristics and 30 items to identify the most important barriers to the application of research findings from the studied nurses' perspective. RESULTS: "The lack of sufficient time for reading the studies," "the lack of sufficient time to implement the new ideas," "the lack of adequate facilities to implement the ideas," "nurses' little interest in conducting studies," and "the lack of authority to change the methods and patterns of care" with, respectively, 85%, 84.6%, 83.8%, 83.4%, and 80.5% agreement with the existence of barriers were the most barriers to application of research findings from the studied nurses' perspective. CONCLUSION: The lack of time was the most important barrier to the use of research findings from the perspective of studied nurses. Therefore, some effective strategies should be used by hospital managers and health policy makers to overcome this barrier. Some of these strategies can be employing new personnel and hiring skilled and efficient human resources in order to decrease the workload of nurses, organizing the nurses' work shifts, providing right balance between patients and nurses in the wards, etc. PMID- 27500168 TI - Performance evaluation of Iranian cooling vest on the physiological indices in hot climatic chamber. AB - BACKGROUND: Heat stress is a threat to those who work in high temperatures. The purpose in this study was an examination of the cooling ability of Iranian phase change material (PCM) cold vest in hot and dry conditions in a climatic chamber. MATERIALS AND METHODS: This experimental study was implemented on 12 male students (age 23.7 +/- 2.8 years, weight 66.1 +/- 11.4 kg, and VO2 max 2.53 L/min) in 2013. The heat strain score index (HSSI), skin temperature and oral temperature, and heartbeat in two phases with and without cooling vest was measured during 30 min in a climatic chamber (temperature 38.8 +/- 1.3 degrees C humidity ratio 32.9 +/- 2.3%) and in two activity intensity of 2.4 and 4.8 km/h speed on the treadmill, and the data differences between groups "with" and "without" vest were tested by t-test and repeated measurement. The level of significance was considered as 0.05. RESULTS: The change in heartbeat at two activities, the oral temperature and heat strain score at 4.8 km/h, did not differ significantly between groups (with and without vest), as expected (P > 0.05). However, the change in skin temperature at two activities, oral temperature and heat strain score at 2.4 km/h, was significant between groups, as expected (P < 0.05). The average of skin temperature at 15(th) and 30(th) min during the experiment at two activities of 2.4 and 4.8 km/h was significant. CONCLUSION: The findings of the study indicated that using the Iranian PCM cold vest in hot and dry climate can affect the reduction of skin temperature, oral temperature, and HSSI in light activities. PMID- 27500169 TI - Acceptance and satisfaction of parents and students about a school-based dietary intervention in Isfahan, 2012-2013. AB - OBJECTIVE: Snacks play an important role in child health and nutritional status. Schools are considered as the preferred place to encourage healthy eating among children. The aim of this study was to evaluate the effect of buffet school-based intervention on acceptance and satisfaction of parents and students in Iran. MATERIALS AND METHODS: Primary school students (n = 1120, 68.83% girls) from first to third grade, with one of their parents, participated in this prospective field trial study conducted in Isfahan, Iran. The study was consisted of three phases; schools selection, kitchen selection, implementation including two different parts, getting order and distribution. We provided hot snacks as traditional and healthy fast food according to taste and food preferences of children. Acceptance and satisfaction of parents and students were evaluated via a researcher made questionnaire before and after the intervention in one-third of participants as a representative sample of students who ordered the snacks. RESULTS: Most of the students usually ate snack in the break-time at school, the eagerness of provided snacks was 98.8% and 63.6% in girls and boys, respectively. The most interesting tastes were Ashe Reshteh and Tahchin, (45.1% girls vs. 36.8% boys), while bean (among girls) and Ashe Jo (among boys) were ranked as the lowest. More than half of parents (66.7%) evaluated the price of snacks as "acceptable," showing their satisfaction. CONCLUSION: Results of this study indicate that school-based interventions accompanied with parental and principals' support is considered as a practical approach to promote healthful eating at an early age. Developing effective interventions for youth might, therefore, help to prevent unhealthy dietary choices becoming habitual. PMID- 27500170 TI - Students' perceptions on feedback module in pharmacology. AB - CONTEXT: Feedback is an integral part of formative assessment though underutilized in medical education. The objective of this study was to review our feedback module through students' perceptions. METHODOLOGY: We have developed a feedback module which is practiced by us for last 10 years for term ending examination that gives collective feedback to the whole class, followed by individual student-teacher interactions. Students were also exposed to 6-7 multiple choice questions (MCQs) based assessment during the course of pharmacology. Immediately after each MCQ test the answer keys is displayed along with an explanation. Two classes of students were requested to give their perceptions about the feedback by responding on Likert scale for the statements in the questionnaire. All the 206 students who volunteered for the study were enrolled in the study. Mann-Whitney test was used to calculate the difference in perceptions. RESULTS: Of 278 students of two classes, 206 responded (74%). Students' agreement varied from 93% to 98% for 5 items in the questionnaire for the feedback after term ending examinations. Perception of students attending one or more than one feedback session did not differ significantly. For MCQs, tests agreement was 91% to 98% for the 4 items. There was no significant difference between two classes in their perceptions regarding feedback practices (P < 0.05). CONCLUSION: Students gave a favorable opinion for our feedback module. In the medical colleges with a large number of students, this module is feasible for feedback in formative assessment in the form of written tests. PMID- 27500171 TI - Validation of a questionnaire to measure sexual health knowledge and understanding (Sexual Health Questionnaire) in Nepalese secondary school: A psychometric process. AB - BACKGROUND: School-based sex education has the potential to prevent unwanted pregnancy and to promote positive sexual health at the individual, family and community level. OBJECTIVES: To develop and validate a sexual health questionnaire to measure young peoples' sexual health knowledge and understanding (SHQ) in Nepalese secondary school. MATERIALS AND METHODS: Secondary school students (n = 259, male = 43.63%, female = 56.37%) and local experts (n = 9, male = 90%, female = 10%) were participated in this study. Evaluation processes were; content validity (>0.89), plausibility check (>95), item-total correlation (>0.3), factor loading (>0.4), principal component analysis (4 factors Kaiser's criterion), Chronbach's alpha (>0.65), face validity and internal consistency using test-retest reliability (P > 0.05). RESULTS: The principal component analysis revealed four factors to be extracted; sexual health norms and beliefs, source of sexual health information, sexual health knowledge and understanding, and level of sexual awareness. Kaiser-Meyer-Olkin (KMO) measure of sampling adequacy demonstrated that the patterns of correlations are relatively compact (>0.80). Chronbach's alpha for each factors were above the cut-off point (0.65). Face validity indicated that the questions were clear to the majority of the respondent. Moreover, there were no significant differences (P > 0.05) in the responses to the items at two time points at seven weeks later. CONCLUSIONS: The finding suggests that SHQ is a valid and reliable instrument to be used in schools to measure sexual health knowledge and understanding. Further analysis such as structured equation modelling (SEM) and confirmatory factor analysis could make the questionnaire more robust and applicable to the wider school population. PMID- 27500172 TI - Parental needs in infant's end-of-life and bereavement in NICU: A qualitative study. AB - BACKGROUND AND AIMS: Newborn death is an unexpected outcome for parents. Parents face with several needs in infant end-of-life. The health care team is responsible for meet these needs. This qualitative study aim was to explore of parental needs in infant end-of-life and bereavement. MATERIALS AND METHODS: For this qualitative study, 24 single semi-structure interviews were done. A qualitative content analysis method was used. Sampling conducted on purposeful with maximum variation in five Neonatal Intensive Care Unit (NICU) environments in Isfahan city. Inclusion criteria for nurses and doctors were having at least one experience of caring for an infant and their family at end-of-life. Inclusion criteria for parents and their families were having at least one infant at end-of life or had lost their infant for 6 months before in NICU. RESULTS: Data analysis uncovered two main themes. Family's support needs with two subthemes (family's support needs before infant's death and family's support needs after infant's death) and family's preparatory needs upon infant's death with two subthemes (management of the bad news of infant's death by treatment team and management of the bad news of infant's death by family). DISCUSSION: Mourning mother's need for her husband's presence by her side, getting hospitalized in a separate room, and management of infant's death news by father and family were among items rarely pointed out in other studies. Exploration of these needs cab be helpful for the health care team for providing care. PMID- 27500173 TI - Implementing clinical governance in Isfahan hospitals: Barriers and solutions, 2014. AB - INTRODUCTION: In the new approach, all health care providers have been obligated to maintain and improve the quality and have been accountable for it. One of the ways is the implementation of clinical governance (CG). More accurate understanding of its challenges can help to improve its performance. AIMS: In this study, barriers of CG implementation are investigated from the perspective of the hospitals involved. Besides, some solutions are suggested based on stakeholders' opinions. MATERIALS AND METHODS: This study used combined method (qualitative content analysis and questionnaire) in hospitals affiliated to Isfahan University of Medical Sciences in 2014. First, experts, and stakeholders talked about CG implementation obstacles in a semi-structured interview. Interviews were confirmed by the interviewee (double check). After analyzing the interviews using reduction coding the questionnaire was drawn up. The questionnaire "validity was confirmed by Cronbach's alpha (0/891)" and its reliability was obtained using experts confirmation. Data analyzing was performed using SPSS (18) software. RESULTS: According to results staffing and management factors were the main obstacles. After them, were factors related to organizational culture, infrastructure elements, information, sociocultural and then process factors. The learning barriers were in final rank. Thirty-four solutions was proposed by experts and divided into subset of eight major barriers. Most solutions were offered on modifying processes and minimal solutions about modifying of organizational culture, sociocultural, and educational factors. CONCLUSION: Removing the obstacles, especially management and human resource factors can be effective by facilitating and accelerating CG. Furthermore, use of experts and stakeholders opinions can help to remove CG barriers. PMID- 27500174 TI - The relationship between multi-dimensional self-compassion and fetal-maternal attachment in prenatal period in referred women to Mashhad Health Center. AB - BACKGROUND: Multi-dimensional self-compassion is one of the important factors predicting fetal-maternal attachment which vary among different cultures and countries. So the aim of this study was to determine the relationship between multi-dimensional, self-compassion, and fetal-maternal attachment in the prenatal period. SUBJECTS AND METHODS: This cross-sectional study was carried on 394 primigravida women to Mashhad Health Care Centers in with two stage sampling method (cluster-convenience) in the year 2014. Demographic/prenatal characteristics, multi-dimensional self-compassion (26Q) with five dimension (including self-kindness, self-judgment, common humanity, isolation items, mindfulness, over-identified), and fatal-maternal attachment (21Q) were completed by the participants. The statistical analysis was performed with various statistical tests such as Pearson correlation coefficient, t-test, one-way ANOVA, and linear regression using SPSS statistical software (version 14). RESULTS: Based on the findings, the mean (standard deviation) value for multi-dimensional self-compassion was 59.81 (6.4) and for fatal-maternal attachment was 81.63 (9.5). There was a positive correlation between fatal-maternal attachment and total self-compassion (P = 0.005, r = 0.30) and its dimension including self kindness (P = 0.003, r = 0.24), self-judgment (P = 0.001, r = 0.18), common humanity (P = 0.004, r = 0.28), isolation items (P = 0.006, r = 0.17), mindfulness (P = 0.002, r = 0.15), over-identified (P = 0.001, r = 0.15). CONCLUSIONS: There was a correlation between the multi-dimensional self compassion and fetal-maternal attachment in pregnant women. Hence, educating people like caregivers by community health midwives regarding psychological problems in during pregnancy can be effective in early diagnosing and identifying such disorders. PMID- 27500175 TI - Comparison of the effect of web-based, simulation-based, and conventional training on the accuracy of visual estimation of postpartum hemorrhage volume on midwifery students: A randomized clinical trial. AB - INTRODUCTION: Delay in diagnosis of bleeding can be due to underestimation of the actual amount of blood loss during delivery. Therefore, this research aimed to compare the efficacy of web-based, simulation-based, and conventional training on the accuracy of visual estimation of postpartum hemorrhage volume. MATERIALS AND METHODS: This three-group randomized clinical trial study was performed on 105 midwifery students in Mashhad School of Nursing and Midwifery in 2013. The samples were selected by the convenience method and were randomly divided into three groups of web-based, simulation-based, and conventional training. The three groups participated before and 1 week after the training course in eight station practical tests, then, the students of the web-based group were trained on-line for 1 week, the students of the simulation-based group were trained in the Clinical Skills Centre for 4 h, and the students of the conventional group were trained for 4 h presentation by researchers. The data gathering tool was a demographic questionnaire designed by the researchers and objective structured clinical examination. Data were analyzed by software version 11.5. RESULTS: The accuracy of visual estimation of postpartum hemorrhage volume after training increased significantly in the three groups at all stations (1, 2, 4, 5, 6 and 7 (P = 0.001), 8 (P = 0.027)) except station 3 (blood loss of 20 cc, P = 0.095), but the mean score of blood loss estimation after training did not significantly different between the three groups (P = 0.95). CONCLUSION: Training increased the accuracy of estimation of postpartum hemorrhage, but no significant difference was found among the three training groups. We can use web-based training as a substitute or supplement of training along with two other more common simulation and conventional methods. PMID- 27500176 TI - An investigation into the effect of health belief model-based education on healthcare behaviors of nursing staff in controlling nosocomial infections. AB - BACKGROUND: Health-care acquired infections are significant given the risks and costs they impose. All previous studies indicate a poor level of knowledge and performance among the nurses in hospital infections; as such, educating nurses can play an important role in infection control. This study aimed at evaluating the effects of the health belief model (HBM) in making nurses adopting health care behaviors needed to control nosocomial infections (Nis). MATERIALS AND METHODS: The participants of the study were 135 nurses from two hospitals in Mashhad, Iran. A self-administered questionnaire was used to collect data. The questionnaire consisted of seven parts. The intervention group received four 45 min educational programs, both in individual and collective forms. After a 2 month interval, a post-test was conducted to see whether any difference has been resulted. RESULTS: There was a significant relationship between knowledge (P = 0.001), perceived threat (P = 0.004), perceived benefits (P = 0.001), and practices (P = 0.001) in comparing to control and experimental groups after intervention. For the experimental and control groups, the most frequent cues to action at the preintervention stage were, respectively, related to the period of studying at university and in-service classes. CONCLUSION: According to this study, HBM-based education can increase knowledge, perceived threat, and perceived benefits of nurses. Additionally, it can reduce perceived barriers and improve the control of NIs among nurses. PMID- 27500177 TI - Determinants of complementary feeding practices among mothers of 6-24 months failure to thrive children based on behavioral analysis phase of PRECEDE model, Tehran. AB - BACKGROUND: This study intended to clarify the determining factors of complementary feeding practices among Tehran 6-24 months failure to thrive children in order to use the results for planning the interventions to reduce the possible adverse effects. MATERIALS AND METHODS: In this study, 132 mothers of three medical and health centers were chosen by random sampling among those centers operating under the supervision of south of Tehran District Health Center and study data were collected from them. A valid and reliable questionnaire as a data collection instrument developed based on behavioral analysis phase of PRECEDE model. Spearman and Pearson's correlation coefficient test were used to determine the statistical relationship between factors associated with complementary feeding practices among mothers. RESULTS: The mothers' knowledge was as follows: 0.8%, 20.4%, and 78.8% of them were good, medium, and poor, respectively. Mean scores for the mothers' performance in terms of supplementary feeding was 66.8. Pearson correlation indicated a positive and significant correlation between the mothers' performance with enabling and reinforcing factors, but there wasn't any significant relationship between the mothers' performance and knowledge about complementary feeding. CONCLUSIONS: According to the obtained results, reinforcing factors, and enabling factors are associated with the mothers' performance in terms of complementary feeding. Hence, attention to these issues is essential for better health interventions planning. PMID- 27500178 TI - Investigating the functionality of an OCT4-short response element in human induced pluripotent stem cells. AB - Pluripotent stem cells offer great therapeutic promise for personalized treatment platforms for numerous injuries, disorders, and diseases. Octamer-binding transcription factor 4 (OCT4) is a key regulatory gene maintaining pluripotency and self-renewal of mammalian cells. With site-specific integration for gene correction in cellular therapeutics, use of the OCT4 promoter may have advantages when expressing a suicide gene if pluripotency remains. However, the human OCT4 promoter region is 4 kb in size, limiting the capacity of therapeutic genes and other regulatory components for viral vectors, and decreasing the efficiency of homologous recombination. The purpose of this investigation was to characterize the functionality of a novel 967bp OCT4-short response element during pluripotency and to examine the OCT4 titer-dependent response during differentiation to human derivatives not expressing OCT4. Our findings demonstrate that the OCT4-short response element is active in pluripotency and this activity is in high correlation with transgene expression in vitro, and the OCT4-short response element is inactivated when pluripotent cells differentiate. These studies demonstrate that this shortened OCT4 regulatory element is functional and may be useful as part of an optimized safety component in a site specific gene transferring system that could be used as an efficient and clinically applicable safety platform for gene transfer in cellular therapeutics. PMID- 27500179 TI - Closing the Gender Gap: The Case for Gender-Specific Alcoholism Research. AB - As the number of women who use alcohol increases, so does the number of women who engage in alcohol abuse and develop alcohol dependence. The recent increased focus on women and gender differences in alcoholism research has largely come about following recognition that the face of alcoholism is changing, with alcoholism rates among men remaining stable and rising among women, particularly in younger women. As such, the need to understand gender differences in both acute and long-term effects of alcohol abuse has never been more critical. Gender differences in the long-term effects of chronic alcoholism on the brain and other systems are currently under debate, often with a focus on proclaiming whether men or women suffer the most impact. However, the story appears to be more complex than that. The issue of how alcoholism interacts with gender is complicated, as gender differences in many factors including alcohol metabolism, alcoholism progression, problematic drinking patterns, neurobiology, hormones, and psychiatric comorbidities will contribute to the differences in structural and functional outcomes observed experimentally across domains of inquiry. While women are now much more commonly included in studies of alcohol's effects on the brain, there remains a need for more explicit examinations of gender effects. PMID- 27500180 TI - Respiratory Cancer and Non-Malignant Respiratory Disease-Related Mortality among Older Construction Workers-Findings from the Health and Retirement Study. AB - OBJECTIVE: This study explored the risk of respiratory cancer and non-malignant respiratory disease (NMRD)-related mortality among older construction workers. METHODS: Analyzed data from the 1992-2010 RAND Health and Retirement Study (HRS) and the HRS National Death Index - Cause of Death file. About 25,183 workers aged 50 years and older were examined, including 5,447 decedents and 19,736 survivors, of which 1,460 reported their longest job was in construction. Multinomial logistic regression assessed the differences in mortality between workers' longest occupations, controlling for confounders. RESULTS: After adjusting for smoking and demographics, construction workers were almost twice as likely to die from respiratory cancer (OR = 1.65; CI: 1.10-2.47) or NMRD (OR = 1.73; CI: 1.16 2.58) compared to white-collar workers. CONCLUSIONS: This study adds to the growing evidence that respiratory cancer and NMRD are frequently associated with construction exposure. PMID- 27500181 TI - Amyloid-Beta Positron Emission Tomography Imaging of Alzheimer's Pathology in Parkinson's Disease Dementia. AB - BACKGROUND: Neuronal loss and alpha-synuclein (alpha-syn) pathology are diagnostic of PD in the appropriate clinical context. However, some PD patients have co-morbid Alzheimer's disease (AD) pathology on autopsy, including amyloid beta (Abeta) plaques and neurofibrillary tangles. Florbetapir(18F) is a PET ligand that detects Abeta pathology. We hypothesized that florbetapir(18F) imaging could detect Abeta pathology in Parkinson disease dementia (PDD) patients prior to death. OBJECTIVE: To determine the utility of florbetapir(18F) PET imaging in detecting Abeta pathology in patients with autopsy-confirmed PDD. METHODS: Five participants with PDD had florbetapir(18F) PET imaging prior to death as a part of a longitudinal research study of cognitive decline in PD. PET scans were evaluated by expert raters blinded to clinical and neuropathological information. At autopsy, all five participants underwent semi-quantitative assessments of regional Abeta and tau immunohistochemistry. RESULTS: All participants met neuropathological criteria for PD. Two had both positive florbetapir(18F) scans and Abeta-positive plaques in multiple brain regions. Regional florbetapir(18F) binding correlated with regional semi-quantitative Abeta pathology in these cases. Three cases had negative florbetapir(18F) scans. Two of these had significant tau pathology without Abeta pathology, consistent with progressive supranuclear palsy (PSP) in one case and argyrophilic grain disease (AGD) in the other. The last case had a low level of AD neuropathological change. CONCLUSIONS: Florbetapir(18F) Abeta imaging can detect the presence of Abeta neuropathology in patients with PDD. This imaging technique may aid the clinical evaluation of PDD patients to determine if cognitive decline is occurring in the setting of Abeta accumulation. PMID- 27500182 TI - Altered T-UCRs expression profile in the spinal cord of mice with neuropathic pain. AB - Spinal cord plays an important role in the transmission and modulation of nociceptive information. Global changes in gene expression in the spinal cord contribute to the induction and maintenance of neuropathic pain. Transcribed Ultraconserved Regions (T-UCRs), a novel class of long noncoding RNAs, can regulate gene expression at both transcriptional and post-transcriptional levels and are related to many human diseases such as cancer, Alzheimer's disease, and heart diseases. In this study, we screened abnormal T-UCRs expression in the spinal cord under spinal nerve ligation (SNL)-induced neuropathic pain condition. Microarray data showed the alternation of T-UCRs at the transcriptional level in the spinal cord 10 days after SNL. Among 78 altered T-UCRs, 23 T-UCRs were upregulated by more than 1.5-fold and 55 ones downregulated by less than 0.5-fold after SNL. Hierarchical cluster analysis of T-UCRs expression profiles showed the opposite expression pattern between SNL and sham-operated mice. The quantitative real-time reverse transcription polymerase chain reaction analysis further confirmed the expression patterns of uc.305, uc.189, uc.46, and uc.217 after SNL. The gene ontology annotation and signaling pathway analysis for the T-UCRs host genes indicated that differentially expressed T-UCRs were involved in several intracellular activities and signaling pathways, including Ephrin receptor activity, soluble NSF attachment protein receptor (SNARE) interactions in vesicular transport pathway, and WNT signaling pathway. Collectively, the current data suggest the possible role of T-UCR in the pathogenesis of neuropathic pain. T-UCRs may serve as a new kind of target for the treatment of neuropathic pain. PMID- 27500184 TI - In vitro Tumorsphere Formation Assays. AB - A tumorsphere is a solid, spherical formation developed from the proliferation of one cancer stem/progenitor cell. These tumorspheres (Figure 1a) are easily distinguishable from single or aggregated cells (Figure 1b) as the cells appear to become fused together and individual cells cannot be identified. Cells are grown in serum-free, non-adherent conditions in order to enrich the cancer stem/progenitor cell population as only cancer stem/progenitor cells can survive and proliferate in this environment. This assay can be used to estimate the percentage of cancer stem/progenitor cells present in a population of tumor cells. The size, which can vary from less than 50 micrometers to 250 micrometers, and number of tumorspheres formed can be used to characterize the cancer stem/progenitor cell population within a population of in vitro cultured cancer cells and within in vivo tumors (Lo et al., 2012; Liu et al., 2009). While several cell lines can be used for tumorsphere formation assay (e.g. primary mammary tumor cells from Her2/neu-transgenic mice, MCF7, BT474 and HCC1954), some cell lines may not form typical tumorsphere structures and may be difficult to count or classify definitively as tumorspheres. PMID- 27500185 TI - Isolation of Cancer Epithelial Cells from Mouse Mammary Tumors. AB - The isolation of cancer epithelial cells from mouse mammary tumor is accomplished by digestion of the solid tumor. Red blood cells and other contaminates are removed using several washing techniques such that primary epithelial cells can further enriched. This procedure yields primary tumor cells that can be used for in vitro tissue culture, fluorescence-activated cell sorting (FACS) and a wide variety of other experiments (Lo et al., 2012). PMID- 27500183 TI - The CRISPR/Cas9 system for gene editing and its potential application in pain research. AB - The CRISPR/Cas9 system is a research hotspot in genome editing and regulation. Currently, it is used in genomic silencing and knock-in experiments as well as transcriptional activation and repression. This versatile system consists of two components: a guide RNA (gRNA) and a Cas9 nuclease. Recognition of a genomic DNA target is mediated through base pairing with a 20-base gRNA. The latter further recruits the Cas9 endonuclease protein to the target site and creates double stranded breaks in the target DNA. Compared with traditional genome editing directed by DNA-binding protein domains, this short RNA-directed Cas9 endonuclease system is simple and easily programmable. Although this system may have off-target effects and in vivo delivery and immune challenges, researchers have employed this system in vivo to establish disease models, study specific gene functions under certain disease conditions, and correct genomic information for disease treatment. In regards to pain research, the CRISPR/Cas9 system may act as a novel tool in gene correction therapy for pain-associated hereditary diseases and may be a new approach for RNA-guided transcriptional activation or repression of pain-related genes. In addition, this system is also applied to loss-of-function mutations in pain-related genes and knockin of reporter genes or loxP tags at pain-related genomic loci. The CRISPR/Cas9 system will likely be carried out widely in both bench work and clinical settings in the pain field. PMID- 27500186 TI - In vitro Assay for Cytidine Deaminase Activity of APOBEC3 Protein. AB - Cytidine deaminases are enzymes that catalyze the removal of an amino group from cytidine, forming uridine. APOBEC3 (ApolipoproteinB mRNA editing enzyme, catalytic polypeptide like) proteins are cytidine deaminases that deaminate cytidines in polynucleotides (RNA/DNA), resulting in editing of their target substrates. Mammalian APOBEC3 proteins are an important element in cellular defenses against retrovirus replication, and this "restriction" of retroviral infections is partially due to the cytidine deaminase activity of the APOBEC3. The present protocol (Nair et al., 2014) describes the assay to detect the deaminase activity of mouse APOBEC3 protein, which targets cytidines present in TCC or TTC motifs in a single-stranded DNA substrate. In brief, the protein preparation to be assayed is incubated with a fluorophore-labeled oligodeoxynucleotide containing the deamination target motif (radiolabeled oligonucleotide substrates have also been successfully used by other groups). Cytidines in the oligonucleotide are deaminated to uridines; the addition of Uracil DNA Glycosylase (UDG) catalyzes the hydrolysis of the N-glycosylic bond between uracil and sugar, generating an abasic (AB) site in the oligonucleotide. Mild alkali treatment cleaves the substrate oligonucleotide at the AB site; cleaved products are resolved from uncleaved substrate by denaturing polyacrylamide gel electrophoresis and visualized on a fluorescence scanner. The protocol described here is mainly adapted from that described by Iwatani et al. (2006) with modifications. The assay can, of course, be used to detect the activity of other APOBEC3 deaminases targeting DNA substrates, using oligonucleotides containing the cytidine-containing target sequence for the deaminase. PMID- 27500187 TI - Primer Extension Reactions for the PCR- based alpha- complementation Assay. AB - The PCR- based- alpha- complementation assay is an effective technique to measure the fidelity of polymerases, especially RNA-dependent RNA polymerases (RDRP) and Reverse Transcriptases (RT). It has been successfully employed to determine the fidelity of the poliovirus polymerase 3D-pol (DeStefano, 2010) as well as the human immunodeficiency virus Reverse Transcriptase (HIV RT) (Achuthan et al., 2014). A major advantage of the assay is that since the PCR step is involved, even the low yield of products obtained after two rounds of low yield of RNA synthesis (for RDRP) or reverse transcription (for RT) can be measured using the assay. The assay also mimics the reverse transcription process, since both RNA- and DNA- directed RT synthesis steps are performed. We recently used this assay to show that the HIV RT, at physiologically relevant magnesium concentration, has accuracy in the same range as other reverse transcriptases (Achuthan et al., 2014). Here, we describe in detail how to prepare the inserts using the primer extension reactions. The prepared inserts are then processed further in the PCR- based- alpha- complementation assay. PMID- 27500188 TI - Telomere Dysfunction Induced Foci (TIF) Analysis. AB - Telomerase maintains telomeric DNA in eukaryotes during early developments, ~90% of cancer cells and some proliferative stem like cells. Telomeric repeats at the end of chromosomes are associated with the shelterin complex. This complex consists of TRF1, TRF2, Rap1, TIN2, TPP1, POT1 which protect DNA from being recognized as DNA double-stranded breaks. Critically short telomeres or impaired shelterin proteins can cause telomere dysfunction, which eventually induces DNA damage responses at the telomeres. DNA damage responses can be identified by antibodies to 53BP1, gammaH2AX, Rad17, ATM, and Mre11. DNA damage foci at uncapped telomeres are referred to as Telomere dysfunction-Induced Foci (TIFs) (de Lange, 2005; Takai et al., 2003). The TIF assay is based on the co localization detection of DNA damage by an antibody against DNA damage markers, such as gamma-H2AX, and telomeres using an antibody against one of the shelterin proteins such as TRF2 (Takai et al., 2003; de Lange, 2002; Karlseder et al., 1999). The method we describe here can be used in normal human and cancer cells. Other commonly used methods-Telomere Restriction Fragment (TRF) Analysis (Mender and Shay, 2015b) and Telomere Repeat Amplification Protocol (TRAP) (Mender and Shay, 2015a)- in telomere biology can be found by clicking on the indicated links. PMID- 27500189 TI - Telomere Restriction Fragment (TRF) Analysis. AB - While telomerase is expressed in ~90% of primary human tumors, most somatic tissue cells except transiently proliferating stem-like cells do not have detectable telomerase activity (Shay and Wright, 1996; Shay and Wright, 2001). Telomeres progressively shorten with each cell division in normal cells, including proliferating stem-like cells, due to the end replication (lagging strand synthesis) problem and other causes such as oxidative damage, therefore all somatic cells have limited cell proliferation capacity (Hayflick limit) (Hayflick and Moorhead, 1961; Olovnikov, 1973). The progressive telomere shortening eventually leads to growth arrest in normal cells, which is known as replicative senescence (Shay et al., 1991). Once telomerase is activated in cancer cells, telomere length is stabilized by the addition of TTAGGG repeats to the end of chromosomes, thus enabling the limitless continuation of cell division (Shay and Wright, 1996; Shay and Wright, 2001). Therefore, the link between aging and cancer can be partially explained by telomere biology. There are many rapid and convenient methods to study telomere biology such as Telomere Restriction Fragment (TRF), Telomere Repeat Amplification Protocol (TRAP) (Mender and Shay, 2015b) and Telomere dysfunction Induced Foci (TIF) analysis (Mender and Shay, 2015a). In this protocol paper we describe Telomere Restriction Fragment (TRF) analysis to determine average telomeric length of cells. Telomeric length can be indirectly measured by a technique called Telomere Restriction Fragment analysis (TRF). This technique is a modified Southern blot, which measures the heterogeneous range of telomere lengths in a cell population using the length distribution of the terminal restriction fragments (Harley et al., 1990; Ouellette et al., 2000). This method can be used in eukaryotic cells. The description below focuses on the measurement of human cancer cells telomere length. The principle of this method relies on the lack of restriction enzyme recognition sites within TTAGGG tandem telomeric repeats, therefore digestion of genomic DNA, not telomeric DNA, with a combination of 6 base restriction endonucleases reduces genomic DNA size to less than 800 bp. PMID- 27500190 TI - Data on greenhouse gases emission in condensate separation unit of a petrochemical company in Iran. AB - Since global warming due to greenhouse gas emissions is no respecter of geographical boundaries of countries, concerted mitigation activities such as Clean Development Mechanism (CDM), are suitable. In this mechanism, some developed countries can gain certified emission reduction credits from emission reduction actions undertaken in developing countries. Thus, the data of greenhouse gas emissions in developing countries would be informative for implementing of CDM. Herein, the data of greenhouse gas emissions of Bandar Imam Petrochemical Complex, one of the biggest petrochemical companies in the Middle East region is presented. The data was acquired using emission factor method and self-presented raw information of the Bandar Imam Petrochemical Complex. Overall, the data will be interesting for environmentalists, non-governmental organization (NGO), and developed countries to perform CDM. PMID- 27500191 TI - Processed data for CHMS 2007-2009: Bisphenol A, phthalates and lead and learning and behavioral problems in Canadian children 6-19 years of age. AB - This article presents processed data from an analysis of cross-sectional data from Cycle 1 of the Canadian Health Measures Survey (CHMS) to examine the potential association between urinary concentrations of BPA and phthalate metabolites and child learning and behavioral problems, considering important covariates such as gender, blood lead and environmental tobacco smoke (ETS). These processed data are related to the research on a subset of the children (Arbuckle et al., 2016) [1]. The Strengths and Difficulties Questionnaire (SDQ) outcomes of interest were emotional symptoms, hyperactivity/inattention, and a total difficulties SDQ score, with borderline and abnormal scores grouped together and compared with children with normal scores. Other outcomes studied included reported learning disability, ADD/ADHD (attention deficit disorder/attention deficit hyperactivity disorder) and use of psychotropic medications to treat behavioral disorders in the past month. Data are presented for all children 6-19 years of age combined. Weighted simple logistic regression estimates for important covariates of each of the outcomes from CHMS Cycle 1 children are reported. Odds ratios based on weighted multiple logistic regression estimates for urinary BPA and phthalate metabolites (including specific gravity as a covariate) and blood lead are presented for the reported outcomes ADD/ADHD, learning disability and psychotropic medications, as well as the SDQ outcomes emotional symptoms, hyperactivity/inattention and total difficulties. PMID- 27500192 TI - Standardized norm data for three self-report scales on egocentric and allocentric environmental spatial strategies. AB - Standardized norm data for three scales of a 19-item self-report measure on environmental spatial strategies are provided. This self-report measure comprises egocentric spatial strategies, an allocentric mental map strategy and knowledge of cardinal directions as three separate scales, "Validation of a 3-factor structure of spatial strategies and relations to possession and usage of navigational aids" (Munzer et al., 2016) [3]. The data are based on a large sample (N>4000) representative for the population in Germany. Standardized norm data for men and women in different age groups are provided through percentile ranks and T-values. PMID- 27500193 TI - Data on importance of hematopoietic cell derived Lipocalin 2 against gut inflammation. AB - The data herein is related to the research article entitled "Microbiota-inducible innate immune siderophore binding protein Lipocalin 2 is critical for intestinal homeostasis" (Singh et al., 2016) [1]. In the present article, we monitored dextran sodium sulfate (DSS)-induced colitis development upon Lipocalin 2 (Lcn2) neutralization, and examined the survival of Lcn2 deficient (Lcn2KO) mice and their WT littermates upon DSS challenge. To dissect the relative contribution of immune and non-immune cells-derived Lcn2 in mediating protection against gut inflammation, we generated respective bone marrow chimera and evaluated their susceptibility to IL-10 receptor neutralization-induced chronic colitis. Neutralization of Lcn2 in WT mice resulted in exacerbated DSS-induced colitis. Notably, mice lacking Lcn2 exhibited 100% mortality whereas only 20% mortality was observed in WT mice upon DSS challenge. Further, data from bone marrow chimera showed that immune cell-derived Lcn2 is the major contributor in conferring protection against colitis. PMID- 27500194 TI - Dataset exploited for the development and validation of automated cyanobacteria quantification algorithm, ACQUA. AB - The estimation and quantification of potentially toxic cyanobacteria in lakes and reservoirs are often used as a proxy of risk for water intended for human consumption and recreational activities. Here, we present data sets collected from three volcanic Italian lakes (Albano, Vico, Nemi) that present filamentous cyanobacteria strains at different environments. Presented data sets were used to estimate abundance and morphometric characteristics of potentially toxic cyanobacteria comparing manual Vs. automated estimation performed by ACQUA ("ACQUA: Automated Cyanobacterial Quantification Algorithm for toxic filamentous genera using spline curves, pattern recognition and machine learning" (Gandola et al., 2016) [1]). This strategy was used to assess the algorithm performance and to set up the denoising algorithm. Abundance and total length estimations were used for software development, to this aim we evaluated the efficiency of statistical tools and mathematical algorithms, here described. The image convolution with the Sobel filter has been chosen to denoise input images from background signals, then spline curves and least square method were used to parameterize detected filaments and to recombine crossing and interrupted sections aimed at performing precise abundances estimations and morphometric measurements. PMID- 27500195 TI - Characterisation data of simple sequence repeats of phages closely related to T7M. AB - Coliphages T7M and T3, Yersinia phage phiYeO3-12, and Salmonella phage phiSG-JL2 share high homology in genomic sequences. Simple sequence repeats (SSRs) are found in their genomes and variations of SSRs among these phages are observed. Analyses on regions of sequences in T7M and T3 genomes that are likely derived from phage recombination, as well as the counterparts in phiYeO3-12 and phiSG JL2, have been discussed by Lin in "Simple sequence repeat variations expedite phage divergence: mechanisms of indels and gene mutations" [1]. These regions are referred to as recombinant regions. The focus here is on SSRs in the whole genome and regions of sequences outside the recombinant regions, referred to as non recombinant regions. This article provides SSR counts, relative abundance, relative density, and GC contents in the complete genome and non-recombinant regions of these phages. SSR period sizes and motifs in the non-recombinant regions of phage genomes are plotted. Genomic sequence changes between T7M and T3 due to insertions, deletions, and substitutions are also illustrated. SSRs and nearby sequences of T7M in the non-recombinant regions are compared to the sequences of phiYeO3-12 and phiSG-JL2 in the corresponding positions. The sequence variations of SSRs due to vertical evolution are classified into four categories and tabulated: (1) insertion/deletion of SSR units, (2) expansion/contraction of SSRs without alteration of genome length, (3) changes of repeat motifs, and (4) generation/loss of repeats. PMID- 27500196 TI - The Future of Intravesical Drug Delivery for Non-Muscle Invasive Bladder Cancer. AB - Despite being the fifth most common cancer in the United States, minimal progress has been made in the treatment of bladder cancer in over a decade. Intravesical instillation of Bacillus Calmette-Guerin (BCG) for the treatment of non-muscle invasive bladder cancer (NMIBC) has been in use for over 30 years and remains the standard treatment in cases of intermediate and high risk disease. Despite the relative success of intravesical BCG, unmet needs in the treatment of NMIBC persist. These challenges include disease recurrence and progression even with treatment with BCG, as well as issues regarding its availability and patient tolerability. The inherent properties of the bladder pose the biggest obstacle to developing effective intravesical treatments for NMIBC. Current research is now focusing on methods to improve the delivery of intravesical therapies. The objective of this review is to discuss novel intravesical drug delivery systems and how they are addressing these challenges in the treatment of NMIBC. PMID- 27500197 TI - Systematic Review and Meta-Analysis on the Impact of Hexaminolevulinate- Versus White-Light Guided Transurethral Bladder Tumor Resection on Progression in Non Muscle Invasive Bladder Cancer. AB - Introduction: Although there is evidence that hexaminolevulinate (HAL)-based transurethral bladder tumor resection (TURBT) improves the detection of Ta-T1 non muscle-invasive bladder cancer (NMIBC) as well as carcinoma in situ there is uncertainty about its beneficial effects on progression. Material and Methods: A systematic literature search was conducted according to the PRISMA statement to identify studies reporting on HAL- vs. white-light (WL-) based TUR-BT in non muscle invasive bladder cancer between 2000 and 2016. A two-stage selection process was utilized to determine eligible studies. Of a total of 294 studies, 5 (4 randomized and one retrospective) were considered for final analysis. The primary objective was the rate of progression. Results: The median follow-up for patients treated with HAL- and WL-TURBT was 27.6 (1-55.1) and 28.9 (1-53) months, respectively. Of a total of 1301 patients, 644 underwent HAL- and 657 WL-based TURBT. Progression was reported in 44 of 644 patients (6.8%) with HAL- and 70 of 657 patients (10.7%) with WL-TURBT, respectively (median odds ratio: 1.64, 1.10 2.45 for HAL vs. WL; p = 0.01). Data on progression-free survival was reported in a single study with a trend towards improved survival for patients treated with HAL-TURBT (p = 0.05). Conclusions: In this meta-analysis the rate of progression was significantly lower in patients treated with HAL- vs. WL-based TURBT. These results support the initiation of randomized trials on HAL with progression as primary endpoint. PMID- 27500199 TI - The Relationship between Centralization of Care and Geographic Barriers to Cystectomy for Bladder Cancer. AB - Background: Centralization of cystectomy treatment for bladder cancer, while associated with improved outcomes, may impose geographic barriers to care. However, whether this effect may be counterbalanced by an increased number of high volume centers has not previously been explored. Objective: To characterize changes in geographic disparities to high volume cystectomy centers over time. Methods: Data on all inpatient admissions for cystectomy in New York State (NYS) from 1997-2011 was obtained from the Department of Health. Using these data, we classified hospitals according to cystectomy volume and measured patient distance traveled to a cystectomy center. Population weights, from the US Census, were used to describe changes in minimum travel distance to high- or very high-volume (HV/VHV) facilities across the NYS population. Results: Bladder cancer patients underwent cystectomies at 195 hospitals during the study period. In 1997-2001, eleven HV/VHV facilities accounted for 37.5% of all cystectomies, while sixteen HV/VHV hospitals accounted for 71.5% of all procedures during 2007-2011. Median distance traveled by cystectomy patients to all hospitals increased from 9.6 to 14.4 miles in 1997-2001 to 2007-2011, respectively. In the same time span, the median travel distance for the NYS population to a HV/VHV center decreased by 1.9 and 9.4 miles at the median and 75th percentile, respectively. Conclusions: Our findings demonstrate a complicated relationship between centralization and geographic access. While centralization has led to a decrease in overall access to cystectomy facilities, the process simultaneously improved access to high volume centers. PMID- 27500200 TI - Assessing Symptom Burden in Bladder Cancer: An Overview of Bladder Cancer Specific Health-Related Quality of Life Instruments. AB - Background: A key component to monitoring and investigating patient QOL is through patient reported health related quality of life (HRQOL) outcome measures. Many instruments have been used to assess HRQOL in bladder cancer and each instrument varies in its development, validation, the context of its usage in the literature and its applicability to certain disease states. Objective: In this review, we sought to summarize how clinicians and researchers should most appropriately utilize the available HRQOL instruments for bladder cancer. Methods: We performed a comprehensive literature search of each instrument used in bladder cancer, paying particular attention to the outcomes assessed. We used these outcomes to group the available instruments into categories best reflecting their optimal usage by stage of disease. Results: We found 5 instruments specific to bladder cancer, of which 3 are validated. Only one of the instruments (the EORTC-QLQ-NMIBC24) was involved in a randomized, prospective validation study. The most heavily used instruments are the EORTC-QLQ-BLM30 for muscle-invasive disease and the FACT-Bl which is used across all disease states. Of the 5 available instruments, 4 are automatically administered with general instruments, while the BCI lacks modularity, and requires co-administration with a generalized instrument. Conclusion: There are multiple strong instruments for use in gauging HRQOL in bladder cancer patients. We have divided these instruments into three categories which optimize their usage: instruments for use following NMIBC treatments (EORTC-QLQ-NMIBC24), instruments for use following radical cystectomy (FACT-Bl-Cys and EORTC-QLQ-BLM30) and more inclusive instruments not limited by treatment modality (BCI and FACT-Bl). PMID- 27500201 TI - Obesity and Outcomes in Patients with Metastatic Urothelial Carcinoma. AB - Background: Obesity has been associated with worse outcomes in patients with clinically localized urothelial cancer. However, this impact has not been evaluated in metastatic disease. Objective: To assess the impact of obesity on outcomes of patients with metastatic urothelial cancer. Methods: Data from 537 patients were aggregated from eight phase II and phase III clinical trials investigating first-line cisplatin-based combination therapy in metastatic urothelial cancer. Chemotherapy regimen, adverse events, treatment response, and survival outcomes were compared across body mass index (BMI) and body surface area (BSA) categories. Results: BMI was classified according to WHO criteria (<18.5 underweight, 18.5-24.99 normal weight, 25-29.99 overweight, >30 obese). BSA was classified as either below or greater than or equal to (average for this cohort (1.87 m2 for males and 1.66 m2 for females). There was no significant difference in number of chemotherapy cycles, adverse events, and response rate or survival outcomes (overall and progression-free) across BMI and BSA categories. There was no significant difference in adverse events across BMI categories, but the incidences of embolic events and renal failure were higher in patients with an average or higher BSA than those with a lower than average BSA (6.6% vs. 3.1% for renal failure p = 0.06; 5.9% vs. 2.7% for renal failure, p = 0.07). There was no significant difference in response rate or survival outcomes (overall and progression-free) amongst BMI and BSA categories. Conclusions: Obese patients with metastatic urothelial cancer on cisplatin-based therapies have similar response rates, survival outcomes, and tolerability of cisplatin-based therapy to non-obese patients. PMID- 27500202 TI - Elevated Derived Neutrophil-to-Lymphocyte Ratio Corresponds With Poor Outcome in Patients Undergoing Pre-Operative Chemotherapy in Muscle-Invasive Bladder Cancer. AB - Background: Platinum-based pre-operative chemotherapy (POC) for muscle-invasive bladder cancer (MIBC) increases the complete pathological response rate at cystectomy and improves overall survival. However, 60% of MIBC patients still has muscle-invasive disease at cystectomy despite POC. Therefore, accurate prediction of response to POC is an important clinical need. We hypothesized that an elevated neutrophil-to-lymphocyte ratio (NLR) corresponds with adverse outcome in patients undergoing POC and radical cystectomy. Objective: To explore the correlation between the NLR and outcome in MIBC patients treated by POC and radical cystectomy. Methods: In 123 MIBC patients (urothelial carcinoma) who were treated by platinum-based POC and radical cystectomy, the derived NLR (dNLR) was retrospectively calculated by dividing the neutrophil count by the difference between leukocytes and neutrophil counts, prior to the start of chemotherapy. The correlation of the dNLR with pathological response at cystectomy and survival was analyzed by logistic regression analysis or the Kaplan-Meier method. Results: The complete pathological response (ypT0N0Mx) rate was 28.5%, 8.9% obtained a partial response (ypTa/T1/TisN0Mx), and 62.6% were non-responders (stage >= ypT2 and/or N+). An elevated dNLR (>2.21) correlated with non-response to POC (OR 2.70, 95% confidence interval: 1.15-6.38, p = 0.02) but this effect was nullified when corrected for clinically node-positive disease and clinical T stage. Patients with an elevated dNLR had shorter progression-free and overall survival albeit non-significant (p = 0.42, and p = 0.45, respectively). Conclusions: An elevated dNLR corresponded with poor outcome in terms of survival and non-response to POC in MIBC patients undergoing radical surgery. However, after correction for well known prognostic factors, such as positive lymph node status at diagnostic imaging and clinical T stage, the correlation for the dNLR was nullified. Therefore, we conclude that the dNLR is insufficient to predict response to POC in this heterogeneous patient population. PMID- 27500203 TI - Clinical Trials Corner. PMID- 27500198 TI - A Systematic Review of the Diagnostic and Prognostic Value of Urinary Protein Biomarkers in Urothelial Bladder Cancer. AB - For over 80 years, cystoscopy has remained the gold-standard for detecting tumours of the urinary bladder. Since bladder tumours have a tendency to recur and progress, many patients are subjected to repeated cystoscopies during long term surveillance, with the procedure being both unpleasant for the patient and expensive for healthcare providers. The identification and validation of bladder tumour specific molecular markers in urine could enable tumour detection and reduce reliance on cystoscopy, and numerous classes of biomarkers have been studied. Proteins represent the most intensively studied class of biomolecule in this setting. As an aid to researchers searching for better urinary biomarkers, we report a comprehensive systematic review of the literature and a searchable database of proteins that have been investigated to date. Our objective was to classify these proteins as: 1) those with robustly characterised sensitivity and specificity for bladder cancer detection; 2) those that show potential but further investigation is required; 3) those unlikely to warrant further investigation; and 4) those investigated as prognostic markers. This work should help to prioritise certain biomarkers for rigorous validation, whilst preventing wasted effort on proteins that have shown no association whatsoever with the disease, or only modest biomarker performance despite large-scale efforts at validation. PMID- 27500204 TI - Beyond Cisplatin - I. PMID- 27500206 TI - NMR Signal Amplification by Reversible Exchange of Sulfur-Heterocyclic Compounds Found In Petroleum. AB - NMR hyperpolarization via Signal Amplification by Reversible Exchange (SABRE) was employed to investigate the feasibility of enhancing the NMR detection sensitivity of sulfur-heterocycles (specifically 2-methylthiophene and dibenzothiophenes), a family of compounds typically found in petroleum and refined petroleum products. SABRE hyperpolarization of sulfur-heterocycles (conducted in seconds) offers potential advantages of providing structural information about sulfur-containing contaminants in petroleum, thereby informing petroleum purification and refining to minimize sulfur content in refined products such as gasoline. Moreover, NMR spectroscopy sensitivity gains endowed by hyperpolarization potentially allows for performing structural assays using inexpensive, low-magnetic-field (ca. 1 T) high-resolution NMR spectrometers ideally suited for industrial applications in the field. PMID- 27500205 TI - Of Kindlins and Cancer. AB - Kindlins are 4.1-ezrin-ridixin-moesin (FERM) domain containing proteins. There are three kindlins in mammals, which share high sequence identity. Kindlin-1 is expressed primarily in epithelial cells, kindlin-2 is widely distributed and is particularly abundant in adherent cells, and kindlin-3 is expressed primarily in hematopoietic cells. These distributions are not exclusive; some cells express multiple kindlins, and transformed cells often exhibit aberrant expression, both in the isoforms and the levels of kindlins. Great interest in the kindlins has emerged from the recognition that they play major roles in controlling integrin function. In vitro studies, in vivo studies of mice deficient in kindlins, and studies of patients with genetic deficiencies of kindlins have clearly established that they regulate the capacity of integrins to mediate their functions. Kindlins are adaptor proteins; their function emanate from their interaction with binding partners, including the cytoplasmic tails of integrins and components of the actin cytoskeleton. The purpose of this review is to provide a brief overview of kindlin structure and function, a consideration of their binding partners, and then to focus on the relationship of each kindlin family member with cancer. In view of many correlations of kindlin expression levels and neoplasia and the known association of integrins with tumor progression and metastasis, we consider whether regulation of kindlins or their function would be attractive targets for treatment of cancer. PMID- 27500207 TI - An Open Letter to HHS Secretary Burwell on Ethically Increasing Organ Donation. PMID- 27500208 TI - Postrenal Transplant Human T-Cell Lymphotropic Virus Type I-Associated Myelopathy/Tropical Spastic Paraparesis: A Case Report and Review of the Literature. AB - We report a case of human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), in a 59 year-old, living donor, renal transplant recipient from Jamaica. The patient's renal transplant had been performed 11 years ago, and her organ donor was also from Jamaica. Pretransplant HTLV-I serologic status for both the donor and recipient was unknown. The prevalence of HTLV-I seropositivity in the United States and Europe is low, and HAM/TSP is a rare occurrence. The positive predictive value of HTLV-I screening in these regions is therefore, low. This has generated debate among transplant societies regarding universal screening for HTLV-I before solid organ transplantation. Very limited evidence is available for the prevention and treatment of this devastating condition. Our case highlights the importance of selected pretransplant screening for HTLV-I infection among organ donors and candidates from endemic areas. We feel such testing may aid in the early recognition of HAM/TSP and more timely initiation of treatment. PMID- 27500209 TI - Detection of Virus-Specific CD8+ T Cells With Cross-Reactivity Against Alloantigens: Potency and Flaws of Present Experimental Methods. AB - Virus-specific T cells have the intrinsic capacity to cross-react against allogeneic HLA antigens, a phenomenon known as heterologous immunity. In transplantation, these cells may contribute to the alloimmune response and negatively impact graft outcome. This study describes the various techniques that can be used to detect heterologous immune responses of virus-specific CD8(+) T cells against allogeneic HLA antigens. The strengths and weaknesses of the different approaches are discussed and illustrated by experimental data. METHODS: Mixed-lymphocyte reactions (MLRs) were performed to detect allo-HLA cross reactivity of virus-specific CD8(+) T cells in total peripheral blood mononuclear cells. T-cell lines and clones were generated to confirm allo-HLA cross reactivity by IFNgamma production and cytotoxicity. In addition, the conventional MLR protocol was adjusted by introducing a 3-day resting phase and subsequent short restimulation with alloantigen or viral peptide, whereupon the expression of IFNgamma, IL-2, CD107a, and CD137 was determined. RESULTS: The accuracy of conventional MLR is challenged by potential bystander activation. T-cell lines and clones can circumvent this issue, yet their generation is laborious and time consuming. Using the adjusted MLR and restimulation protocol, we found that only truly cross-reactive T cells responded to re-encounter of alloantigen and viral peptide, whereas bystander-activated cells did not. CONCLUSIONS: The introduction of a restimulation phase improved the accuracy of the MLR as a screening tool for the detection of allo-HLA cross-reactivity by virus-specific CD8(+) T cells at bulk level. For detailed characterization of cross-reactive cells, T-cell lines and clones remain the golden standard. PMID- 27500210 TI - Value of Magnetic Resonance Cholangiopancreatography in Assessment of Nonanastomotic Biliary Strictures After Liver Transplantation. AB - Nonanastomotic biliary strictures (NAS) remain a frequent complication after orthotopic liver transplantation (OLT). The aim of this study was to evaluate whether magnetic resonance cholangiopancreatography (MRCP) could be used to detect NAS and to grade the severity of biliary strictures. METHODS: In total, 58 patients after OLT from 2 Dutch transplantation centers in whom endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography and MRCP were performed within less than 6 months apart were included in the study. Of these patients, 41 had NAS and 17 were without NAS based on endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography and follow-up. Four radiologists-2 from each center-used an adapted validated classification-termed "Leiden Biliary Stricture Classification" "(LBSC)-to evaluate the MRCP examinations independently. In this classification, NAS severity is assessed in 4 hepatobiliary regions. Interobserver agreement of the severity score for each region was calculated with the kappa statistics. RESULTS: Optimal cutoff value of the LBSC to detect the presence of NAS with MRCP was calculated at 3 points or greater for all readers. Applying this cutoff sensitivity for each reader was greater than 90%, with a specificity of 50% to 82%, positive predictive value of 86% to 91%, and negative predictive value of 80% to 100%. The MRCP performance was better in evaluation of the intrahepatic than of the extrahepatic bile ducts. The additional value of MRCP for grading severity of NAS was limited. CONCLUSIONS: The MRCP with the LBSC is a reliable tool to detect or exclude NAS after OLT. Currently, MRCP cannot be used to reliably grade the severity of these strictures. PMID- 27500211 TI - The Cost and Utility of Renal Transplantation in Malaysia. AB - Kidney transplantation is the optimal therapy for the majority of patients with end-stage renal disease. However, the cost and health outcomes of transplantation have not been assessed in a middle-income nation with a low volume of transplantation, such as Malaysia. AIM AND METHODS: This study used microcosting methods to determine the cost and health outcomes of living and deceased donor kidney transplantation in adult and pediatric recipients. The perspective used was from the Ministry of Health Malaysia. Cost-effectiveness measures were cost per life year (LY) and cost per quality-adjusted LYs. The time horizon was the lifetime of the transplant recipient from transplant to death. RESULTS: Records of 206 KT recipients (118 adults and 88 children) were obtained for microcosting. In adults, discounted cost per LY was US $8609(Malaysian Ringgit [RM]29 482) and US $13 209(RM45 234) for living-donor kidney transplant (LKT) and deceased donor kidney transplant (DKT), respectively, whereas in children, it was US $10 485(RM35 905) and US $14 985(RM51 317), respectively. Cost per quality-adjusted LY in adults was US $8826 (RM30 224) for LKT and US $13 592(RM46 546) for DKT. Total lifetime discounted costs of adult transplants were US $119 702 (RM409 921) for LKT, US $147 152 (RM503 922) for DKT. Total costs for pediatric transplants were US $154 841(RM530 252) and US $159 313(RM545 566) for the 2 categories respectively. CONCLUSIONS: Both LKT and DKT are economically favorable for Malaysian adult and pediatric patients with ESRD and result in improvement in quality of life. PMID- 27500212 TI - Pyloroplasty for Refractory Diabetic Gastroparesis After Renal Transplantation. PMID- 27500213 TI - Cyclic Helix B Peptide in Preservation Solution and Autologous Blood Perfusate Ameliorates Ischemia-Reperfusion Injury in Isolated Porcine Kidneys. AB - There is a critical need to better preserve isolated organs before transplantation. We developed a novel nonerythropoiesis cyclic helix B peptide (CHBP) derived from erythropoietin, which has potent tissue protection and prolonged serum stability. The renoprotection and potential mechanism of CHBP were evaluated in a kidney preservation model. MATERIALS AND METHODS: Porcine kidneys (n = 5) subjected to 20-minute warm ischemia were retrieved and flushed with hyperosmolar citrate to mimic deceased donation. The kidneys and autologous blood +/- 10.56 nmol/L CHBP were placed in cold storage (CS) for 18 hours. These kidneys were then normothermically hemoreperfused for 3 hours using an isolated organ perfusion system. The renal function and structure, apoptosis, inflammation, and expression of caspase-3 and heat shock protein 70 (HSP70) were assessed. RESULTS: Cyclic helix B peptide significantly increased the renal blood flow, oxygen consumption, and urine output during reperfusion, but decreased serum potassium and renal tissue damage. Apoptotic cells were significantly decreased in the tubular areas, but increased in the lumens and interstitial areas in the post-CS and postreperfused kidneys, whereas myeloperoxidase+ cells were reduced. In addition, the expression of both caspase-3 precursor and active subunits was downregulated by CHBP in reperfused kidneys. However, HSP70 was upregulated in the post-CS and postreperfused kidneys treated with CHBP. CONCLUSIONS: Cyclic helix B peptide administered into preservation and reperfusion solutions ameliorated renal ischemia-reperfusion injury, which might be associated with decreased apoptosis, inflammation and caspase-3, but increased HSP70. This novel preservation approach using CHBP may be applied in a porcine kidney transplant model and potential human donor kidney preservation. PMID- 27500214 TI - A Safety and Efficacy Study of Medium-Dose Etoposide, Cyclophosphamide and Total Body Irradiation Conditioning Before Allogeneic Stem Cell Transplantation for Acute Lymphoblastic Leukemia. AB - Prognosis for adult patients with acute lymphoblastic leukemia (ALL) has been reported to be approximately 35% to 50%, even after allogeneic stem cell transplantation (allo-SCT). We previously reported retrospective analyses of a conditioning regimen of medium-dose etoposide, cyclophosphamide (CY), and total body irradiation (TBI) before allo-SCT for ALL. To prospectively analyze the efficacy of this conditioning regimen, we conducted a trial prospectively. METHODS: The eligibility criteria of this study were as follows: diagnosis of ALL, aged between 15 and 50 years, in complete remission, and first SCT from HLA serologically matched donor. The primary endpoint of this study was event-free survival at 1 year after SCT, and the events were defined as death and relapse. RESULTS: Fifty eligible patients were treated, and the median age of the patients was 33.5 years. Nineteen patients were Philadelphia chromosome-positive, and 47 were in first complete remission at SCT. All patients achieved neutrophil engraftment. Grade 3 to 4 acute graft-versus-host disease and extensive chronic graft-versus-host disease developed in 4 patients and 18 patients, respectively. No patient died within 100 days after SCT. One-year event-free survival was 76.0%, and 1-year overall survival was 80.0%. The cumulative incidences of relapse and non-relapse mortality at 1-year after SCT were 10.0% and 14.0%, respectively. CONCLUSIONS: Medium-dose etoposide + CY + TBI is an effective conditioning before allo-SCT for adult patients with ALL, enabling good disease control without an increase in nonrelapse mortality. A phase 3 trial comparing this regimen with the standard CY + TBI regimen for adult patients with ALL is warranted. PMID- 27500215 TI - Atypical Hemolytic Uremic Syndrome Recurrence after Renal Transplantation: C3 Glomerulonephritis as an Initial Presentation. AB - Risk for atypical hemolytic uremic syndrome (aHUS) recurrence after renal transplantation is low with an isolated membrane cofactor protein mutation (MCP). We report the case of a 32-year-old woman with a MCP who underwent kidney transplantation with a good evolution at 12 months. At 15 and 35 months, 2 episodes of thrombotic microangiopathy (TMA), after a miscarriage and a preeclampsia, were misinterpreted as triggered by tacrolimus. After each episode however serum creatinine returned to baseline. Five years after transplantation, she had a self-limited rhinosinusitis followed 3 weeks later by an oliguric renal failure. Her complement profile was normal. Graft biopsy showed C3 glomerulonephritis with no "humps" on electron microscopy. No significant renal function improvement followed methylprednisolone pulsing. A second biopsy showed severe acute TMA lesions with C3 glomerular deposits. Despite weekly eculizumab for 1 month, dialysis was resumed. A new workup identified the "at-risk" complement factor H haplotype. Thus, aHUS recurrence should be ruled out in aHUS patients considered at low recurrence risk when a TMA is found in graft biopsy. Prompt eculizumab therapy should be considered to avoid graft loss as aHUS recurrence can first present as a C3 glomerulonephritis. PMID- 27500216 TI - Rhodococcus equi Sepsis in a Renal Transplant Recipient: A Case Study. AB - Rhodococcus equi is an unusual cause of infection in humans, but has emerged as an opportunistic pathogen among immunocompromised patients. Primary pulmonary involvement is the most common clinical presentation, although the spectrum of disease is broad. Diagnosing R. equi infections remains challenging, both from clinical and microbiological view, and no standard treatment has been established. In this report, we present a detailed case of a 57-year-old male renal transplant recipient who developed R. equi bacteremia with a concomitant Pneumocystis jirovecii pneumonia. We describe the clinical features of R. equi infections, highlight the importance of an early diagnosis, and briefly review treatment options for this rare infection. PMID- 27500217 TI - Immunodiagnostic Tests' Predictive Values for Progression to Tuberculosis in Transplant Recipients: A Prospective Cohort Study. AB - BACKGROUND: Little is known about the predictive value for progression to tuberculosis (TB) of interferon-gamma release assays and how they compare with the tuberculin skin test (TST) in assessing the risk of TB infection in transplant recipients. METHODS: We screened 50 liver transplant (LT) and 26 hematopoietic stem cell transplant (HSCT) recipients with both QuantiFERON-TB Gold In-tube (QFT-GT) and TST and prospectively followed them for a median of 47 months without preventive chemoprophylaxis. RESULTS: In the LT cohort, 1 in 22 (4.5%) QFT-GT-positive patients developed posttransplant TB, compared with none of the QFT-GT-negative patients. In the HSCT cohort, none of the 7 QFT-GT positive patients developed TB, whereas 1 case (5.3%) progressed to active TB among the 19 QFT-GT-negative patients. Comparable results were obtained with the TST: in the LT group, 1 of 23 TST-positive and none of the 27 TST-negative patients developed TB; and in the HSCT group, none of the 8 TST-positive and one of the 18 TST-negative patients progressed to active TB. CONCLUSIONS: In this cohort of transplant recipients, the positive predictive value of QFT-GT for progression to active TB was low and comparable to that of TST. Although the risk of developing TB in patients with negative results at baseline is very low, some cases may still occur. PMID- 27500218 TI - Human Amnion-Derived Mesenchymal Stem Cell Transplantation Ameliorates Liver Fibrosis in Rats. AB - Mesenchymal stem cells (MSCs) are a valuable cell source in regenerative medicine. Recently, several studies have shown that MSCs can be easily isolated from human amnion. In this study, we investigated the therapeutic effect of transplantation of human amnion-derived MSCs (hAMSCs) in rats with liver fibrosis. METHODS: Liver fibrosis was induced by an intraperitoneal injection of 2 mL/kg of 50% carbon tetrachloride twice a week for 6 weeks. At 3 weeks, hAMSCs (1 * 10(6) cells) were transplanted intravenously. Rats were sacrificed at 7 weeks, and histological analyses and quantitative reverse-transcription polymerase chain reaction were performed. In vitro experiments were conducted to investigate the effect of hAMSCs on the activation of Kupffer cells. RESULTS: Transplantation of hAMSCs significantly reduced the fibrotic area, deposition of type-I collagen, the number of alpha-smooth muscle actin-positive hepatic stellate cells, and CD68-positive Kupffer cells in the livers. messenger RNA expression of alpha-smooth muscle actin and tissue inhibitor of metalloproteinase 1 was significantly decreased and the expression of matrix metalloproteinase-9 and hepatocyte growth factor was significantly increased in the liver of hAMSC treated rats. Transplantation of hAMSCs at 3 weeks plus 5 weeks did not have an additive effect. In vitro experiments demonstrated that Kupffer cell activation induced by lipopolysaccharide was significantly decreased by culturing with conditioned medium obtained from hAMSCs. CONCLUSIONS: Transplantation of hAMSCs provided significant improvement in a rat model of liver fibrosis, possibly through the inhibition of Kupffer cell and hepatic stellate cell activation. hAMSCs may be a potential new treatment for liver fibrosis. PMID- 27500219 TI - A Phased Desensitization Protocol With Rituximab and Bortezomib for Highly Sensitized Kidney Transplant Candidates. AB - Desensitization protocols comprising plasmapheresis, IVIGs, and rituximab and/or bortezomib have allowed for successful kidney transplantation in some highly HLA sensitized patients with end-stage renal disease. However, the optimal combination of these therapies and their proper timing remains entirely unknown. We propose a phased desensitization strategy using rituximab followed by bortezomib as a safer method. METHODS: Three sensitized kidney transplant candidates who could not be desensitized using our conventional protocol, which consists of a single rituximab dose combined with plasmapheresis, were enrolled in this study. When IgM(+) CD27(-) naive B cells reappeared but IgM(+) CD27(+) memory B cells remained undetectable in their peripheral blood, the patients were treated with 1 cycle of bortezomib followed by plasmapheresis. RESULTS: After bortezomib treatment, patients' donor-specific anti-HLA antibodies (DSA) values were decreased, and cross-match tests were consistently negative. All 3 patients underwent living donor kidney transplantation. They showed immediate renal function, and both DSA and non-DSA were undetectable during the observation period. Neither antibody-mediated rejection nor severe acute cellular rejection was encountered in these patients after transplantation. CONCLUSIONS: The present cases suggest that a phased use of rituximab and bortezomib can safely desensitize highly sensitized kidney transplant candidates. PMID- 27500220 TI - Functional Implications of Biochemical and Molecular Characteristics of Donation After Circulatory Death Livers. AB - In aggregate, livers donated after circulatory death (DCD) provide lower rates of graft and patient survival compared to brain dead donors (DBD). A method to identify DCD livers likely to perform well would lead to better decision-making regarding which livers to use and which to discard and is an important unmet clinical need. We hypothesized that the ischemic time between extubation and cold perfusion in the donor leads to immediate and unique biochemical and molecular changes that could be used to predict subsequent function. METHODS: Biopsies from normal perfused liver, immediately after cold perfusion during DCD or DBD liver procurement, and during subsequent cold storage were analyzed and compared. Biochemical analysis included adenosine triphosphate (ATP), adenosine diphosphate, adenosine monophosphate, hypoxanthine, xanthine, inosine, nicotinamide adenine dinucleotide, and flavin adenine dinucleotide. Levels of these metabolites were compared to peak posttransplant aspartate aminotransferase as a marker of ischemic injury. Molecular analysis was performed by transcriptional profiling using high throughput sequencing. RESULTS: Immediately after cold perfusion in the donor, biochemical analysis revealed lower levels of ATP and adenosine diphosphate in DCD versus DBD liver samples (P < 0.01 in both cases). The ATP levels showed high negative correlation with peak aspartate aminotransferase levels in recipients (P = 0.029). Four hundred seventy genes showed differential expression in DCD but not DBD samples immediately after cold perfusion compared with normal liver samples. Upregulated genes function in inflammation and immunity, whereas downregulated genes function in translation. During cold storage, samples were transcriptionally inactive with no consistent changes in messenger RNA expression. CONCLUSION: The ATP content of liver samples taken immediately postperfusion correlates with ischemic injury. Transcriptional profiling identifies biological process that may be relevant for enhancing function in DCD liver transplantation. Transcriptional inactivity of cold stored samples suggests messenger RNA levels over time are unlikely to provide prognostic data. PMID- 27500221 TI - Clostripain, the Missing Link in the Enzyme Blend for Efficient Human Islet Isolation. AB - Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential as they synergize with collagenase for effective pancreas digestion. The presence of tryptic-like activity has been implicated in efficient enzyme blends and the present study aimed to evaluate if addition of clostripain, an enzyme with tryptic-like activity, could improve efficacy of the islet isolation procedure. METHODS: Clostripain was added to the enzyme blend just before pancreas perfusion. Islets were isolated per standard method and numerous isolation parameters, islet quality control, and the number of isolations fulfilling standard transplantation criteria were evaluated. Two control organs per clostripain organ were chosen by blindly matching against body mass index, cold ischemia time, hemoglobin A1c, donor sex, and donor age. RESULTS: There were no differences in pancreas weight, dissection time, digestion time, harvest time, percent digested pancreas, or total pellet volume before islet purification between control or clostripain pancreases. Glucose-stimulated insulin release results were similar between groups. Total isolation islet equivalents, purified tissue volume and islet equivalents/g pancreas as well as fulfillment of transplantation criteria favored clostripain processed pancreases. CONCLUSIONS: The addition of clostripain to the enzyme blend soundly improved islet yields and transplantation rates. It gently aided pancreas digestion and maintained proper islet functionality. The addition of clostripain to the enzyme blend has now been implemented into standard isolation protocols at the isolation centers in Uppsala and in Oslo. PMID- 27500222 TI - Patterns of Immune Regulation in Rhesus Macaque and Human Families. AB - Naturally acquired immune regulation amongst family members can result in mutual regulation between living related renal transplant donor and recipients. Pretransplant bidirectional regulation predisposed to superior renal allograft outcome in a CAMPATH-1H protocol. We tested whether Rhesus macaques, a large animal model of choice for preclinical transplant studies, share these immunoregulatory properties. METHODS: Antigen-specific linked suppression was measured by trans vivo delayed-type hypersensitivity [tvDTH] response. Neutralizing antibodies to regulatory cytokines, IL-10, TGF-beta, and IL-35 were coinjected to ascertain the role of these cytokines in the regulatory response. RESULTS: Peripheral blood mononuclear cells (PBMC) of 116 Rhesus macaques in 50 families and 78 human subjects in 25 families were analyzed. Suppression of the recall response of 25% or greater was detected in 30 of 51 (59%) monkeys, and 25 of 36 (69%) human subjects when PBMC were coinjected with antigens of the mother, containing the noninherited maternal antigens. In 33% of Rhesus and 32% of human subjects, linked suppression was also seen when PBMC from the mother was assayed with antigens from offspring. Bidirectional regulation was also seen between greater than 50% of the major histocompatibility complex (MHC)-identical full siblings; subcellular antigens caused significant linked suppression in 7 of 10 (Rhesus) and 8 of 15 (human) cases, indicating the importance of familial minor H antigens. The lowest incidence of regulation was seen in MHC-1 haplotype mismatched siblings in both species. Linked suppression was most effectively reversed by antibodies that neutralized TGFbeta1, and the 2 subunits of IL-35 (Ebi3 and IL12p35). CONCLUSIONS: Rhesus macaques provide a suitable model for analyzing the impact of bidirectional regulation in living related donor recipient pairs. PMID- 27500223 TI - Sofosbuvir and Simeprevir Therapy for Recurrent Hepatitis C Infection After Liver Transplantation. AB - Antiviral therapy for recurrent hepatitis C in liver transplant recipients has been associated with low efficacy, poor tolerability, and drug-drug interactions. Recent approval of various hepatitis C direct-acting antivirals has resulted in improvement of these parameters. We evaluated the efficacy and safety of 12 week all-oral interferon- and ribavirin-free therapy with sofosbuvir and simeprevir. METHODS: Thirty-two genotype 1 liver transplant recipients with recurrent hepatitis C infection were retrospectively analyzed. All patients received 12 weeks of sofosbuvir 400 mg and simeprevir 150 mg orally daily. The primary endpoint was sustained virologic response 12 weeks after treatment. RESULTS: Sustained virologic response 12 weeks after treatment was achieved in 30 of 32 (94%; 95% confidence interval, 79-99%) patients. All patients enjoyed on treatment virological response. Both patients who relapsed were cirrhotic, previously treated with Q80K polymorphism. Significant improvements in alkaline phosphatase, albumin, alanine aminotransferase levels, and platelets were seen at 12-week post therapy. Treatment was well tolerated. No grade 3 or 4 adverse events were noted. Headache and fatigue were the most common complaints. CONCLUSION: Combination of sofosbuvir and simeprevir for 12 weeks resulted in 94% sustained virological response-12 rates in patients with hepatitis C genotype 1 and was well tolerated. PMID- 27500224 TI - Successful Combined Pancreas Fourth-Kidney Third and Pancreas Third-Kidney Second Transplantation: A Case Report. AB - Extremely few reports have been published on experience with multiple combined pancreas-kidney re-transplantation including long-term results. We here analyze our experience with two patients following successful combined pancreas fourth kidney third and pancreas third-kidney second transplantation. METHODS: Patient and graft survival as well as graft function and major complications were recorded. Patient 1 (women, 47 years) underwent combined pancreas fourth-kidney third transplantation after previous removal of the first and second renal and the second pancreatic grafts. Patient 2 (men, 51 years) underwent combined pancreas third-kidney second transplantation after nephrectomy of the first renal graft. Immunosuppression consisted of induction with alemtuzumab and maintenance with tacrolimus, mycophenolate mofetil/mycophenolic acid and steroids. RESULTS: After a follow-up of 44 and 49 months, respectively, both patients are doing well with stable graft function. Leukopenia, thrombocytopenia, bacterial sepsis, and chronic hepatitis C as major complications were controllable. CONCLUSIONS: Multiple pancreas-retransplantations combined with simultaneous renal transplantation are feasible. Meticulous immunosuppression, careful monitoring, and excellent patient adherence are of crucial importance. PMID- 27500225 TI - Kidneys From alpha1,3-Galactosyltransferase Knockout/Human Heme Oxygenase-1/Human A20 Transgenic Pigs Are Protected From Rejection During Ex Vivo Perfusion With Human Blood. AB - Multiple modifications of the porcine genome are required to prevent rejection after pig-to-primate xenotransplantation. Here, we produced pigs with a knockout of the alpha1,3-galactosyltransferase gene (GGTA1-KO) combined with transgenic expression of the human anti-apoptotic/anti-inflammatory molecules heme oxygenase 1 and A20, and investigated their xenoprotective properties. METHODS: The GGTA1 KO/human heme oxygenase-1 (hHO-1)/human A20 (hA20) transgenic pigs were produced in a stepwise approach using zinc finger nuclease vectors targeting the GGTA1 gene and a Sleeping Beauty vector coding for hA20. Two piglets were analyzed by quantitative reverse-transcription polymerase chain reaction, flow cytometry, and sequencing. The biological function of the genetic modifications was tested in a (51)Chromium release assay and by ex vivo kidney perfusions with human blood. RESULTS: Disruption of the GGTA1 gene by deletion of few basepairs was demonstrated in GGTA1-KO/hHO-1/hA20 transgenic pigs. The hHO-1 and hA20 mRNA expression was confirmed by quantitative reverse-transcription polymerase chain reaction. Ex vivo perfusion of 2 transgenic kidneys was feasible for the maximum experimental time of 240 minutes without symptoms of rejection. CONCLUSIONS: Results indicate that GGTA1-KO/hHO-1/hA20 transgenic pigs are a promising model to alleviate rejection and ischemia-reperfusion damage in porcine xenografts and could serve as a background for further genetic modifications toward the production of a donor pig that is clinically relevant for xenotransplantation. PMID- 27500226 TI - Medium-Term Renal Function in a Large Cohort of Stable Kidney Transplant Recipients Converted From Twice-Daily to Once-Daily Tacrolimus. AB - BACKGROUND: There is some evidence pointing toward better renal function in kidney transplant recipients (KTR) treated with once-daily tacrolimus (QD-TAC) vs. twice-daily tacrolimus (BID-TAC). METHODS: This is an extension study of a 1 year, single arm prospective study of stable KTR who were converted from BID-TAC to QD-TAC (4.9 +/- 4.0 years after transplantation) in Spanish routine clinical practice. Patient and graft survival, renal function, acute rejection episodes, and other analytic parameters were assessed at 24 and 36 months after conversion. RESULTS: A total of 1798 KTR were included in the extension study. Tacrolimus doses at 36 months were significantly lower compared to those at time of conversion (-0.2 mg/day; P = 0.023). Blood levels were lower than baseline during all the study (P < 0.001). Graft and patient survival at 3 years after conversion were 93.9% and 95.1%, respectively. Compared with baseline, the mean estimated glomerular filtration rate (eGFR) remained very stable at all timepoints (56.7 +/ 19.8 vs 58.1 +/- 24.6 mL/min per 1.73 m(2) at month 36; P = 0.623). Even when patients reinitiating dialysis were counted as eGFR = 0, the mean eGFR was very stable. In fact, a small but significant increase was observed at 36 months versus baseline (+0.1 mL/min per 1.73 m(2); P = 0.025). An increase in proteinuria was observed at 36 months versus baseline (+0.11 g/24 h; P < 0.001). Acute rejection rates were low during the study. CONCLUSIONS: Conversion from BID TAC to QD-TAC in a large cohort of stable KTR was safe and associated with a very stable renal function after 3 years. Comparative studies are warranted to assess the feasibility of such conversion. PMID- 27500228 TI - Skin Cancer in the Crosshairs: Highlights from the Biennial Scientific Retreat of International Transplant Skin Cancer Collaborative and Skin Care in Organ Transplant Recipients Europe. AB - The International Transplant Skin Cancer Collaborative (ITSCC) is an organization comprising of physicians; transplant surgeons and basic science research scientists dedicated in providing optimal care and ongoing research advancements in solid organ transplant recipients to improve patient outcome and quality of life. As medical advances occur, it is anticipated that the sheer number of solid organ transplantations occurring worldwide will continue to increase. The long term medication associated immunosuppression improves graft survival, but as a consequence, these individuals become increasingly susceptible to various cutaneous malignancies, lymphoproliferative disorders and infections. Squamous cell carcinoma is the most frequently encountered skin cancer and increases 65- to 250-fold [Jensen et al., Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40:177-186; Lindelof et al., Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000; 143:513-519]. However, the rates of basal cell carcinoma, Merkel cell carcinoma and melanoma also increase in organ transplant recipients leading to significant morbidity as well as mortality [Berg and Otley. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol. 2002; 47:1-20]. In October 2014, the International Transplant Skin Cancer Collaborative and its equivalent European counterpart, Skin Care in Organ Transplant Recipients Europe held its 10th biennial meeting in Essex, MA to discuss the clinical conundrums and the evolving research pertinent to the field. This meeting report provides a synthesis of all the clinical and research data presented at the 4-day meeting. PMID- 27500227 TI - HLA Associations and Risk of Posttransplant Lymphoproliferative Disorder in a Danish Population-Based Cohort. AB - BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a feared complication to organ transplantation, associated with substantial morbidity and inferior survival. Risk factors for PTLD include T cell-depleting induction therapy and primary infection or reactivation of Epstein-Barr virus. Possible associations between certain HLA types and the risk of developing PTLD have been reported by other investigators; however, results are conflicting. METHODS: We conducted a retrospective, population-based study on 4295 Danish solid organ transplant patients from the Scandiatransplant database. Having identified 93 PTLD patients in the cohort, we investigated the association of HLA types with PTLD, Epstein-Barr virus status and time to PTLD onset. The outcomes survival and PTLD were evaluated using Cox regression; mismatching, and the PTLD-specific mortality were evaluated in a competing risk analysis. RESULTS: Risk of PTLD was associated with male sex (odds ratio, 1.70; 95% confidence interval, 1.07-2.71), and, in women, HLA-DR13 conferred an increased risk (odds ratio, 3.22; 95% confidence interval, 1.41-7.31). In multivariate analysis, HLA-B45 and HLA-DR13 remained independent predictive factors of PTLD. Mismatching in the B locus was associated with a reduced risk of PTLD (P < 0.001). Overall survival was poor after a PTLD diagnosis and was significantly worse than that in the remaining transplant cohort (P < 0.001). CONCLUSIONS: Our data indicate risk-modifying HLA associations, which can be clinically useful after transplantation in personalized monitoring schemes. Given the strong linkage disequilibrium in the HLA region, the associations must be interpreted carefully. The large size, virtually complete ascertainment of cases and no loss to follow-up remain important strengths of the study. PMID- 27500229 TI - Hispanic/Latino Disparities in Living Donor Kidney Transplantation: Role of a Culturally Competent Transplant Program. AB - Hispanic Americans face disparities in access to kidney transplantation, particularly living donor kidney transplantation (LDKT). This study compared characteristics of LDKT recipients before and after implementing the Hispanic Kidney Transplant Program (HKTP) at Northwestern Medicines (NM) and other centers. METHODS: The NM HKTP, initiated in December 2006, delivers culturally and linguistically competent and congruent care. Program-specific data were used to compare the mean ratios of Hispanic to non-Hispanic white LDKTs between pre HKTP (2001-2006) and post-HKTP (2008-2013), and to compare the characteristics of NM's adult LDKT patients between pre-HKTP and post-HKTP. The same ratio was calculated for transplant centers in regions with a significant Hispanic population (>=25%) and performing in the top tertile of total LDKT volume in the pre-HKTP period. The number of Hispanic and non-Hispanic white patients added to the waiting list were compared between pre-HKTP (2001-2006) and post-HKTP (2008 2013) as a proxy for increased patient referrals and a pathway by which the HKTP may increase LDKTs. RESULTS: The ratio of Hispanic to non-Hispanic white LDKTs significantly increased by 70% after the implementation of NM's HKTP (pre-HKTP mean = 0.20, post-HKTP mean = 0.34; P= 0.001). None of the other transplant centers experienced a similar increase in their ratio of Hispanic to non-Hispanic white LDKTs. The NM waiting list additions grew by 91% among Hispanics, but grew only 4% for non-Hispanic whites. CONCLUSIONS: These data suggest that the development and implementation of a culturally congruent transplant program can positively affect Hispanic LDKT and thereby reduce Hispanics disparities in LDKT rates. Further studies are needed to prospectively evaluate the generalizability of implementing such culturally competent interventions at other transplant programs. PMID- 27500230 TI - Should We Exclude Live Donor Liver Transplantation for Liver Transplant Recipients Requiring Mechanical Ventilation and Intensive Care Unit Care? AB - Patients with acute and chronic liver disease often require admission to intensive care unit (ICU) and mechanical ventilation support before liver transplantation (LT). Rapid disease progression and high mortality on LT waiting lists makes live donor LT (LDLT) an attractive option for this patient population. METHODS: During 2000 to 2011, all ICU-bound and mechanically ventilated patients receiving an LDLT (n = 7) were compared to patients receiving a deceased donor LT (DDLT) (n = 38). RESULTS: Both groups were comparable regarding length of pretransplant ICU stay (DDLT: 2 [1-31] days vs LDLT: 2 [1-8] days; P = 0.2), days under mechanical ventilation (DDLT: 2 [1-31] days vs LDLT: 2 [1-5] days; P = 0.2), pretransplant dialysis (DDLT: 45% vs LDLT: 43%; P = 1) and model for end-stage liver disease score (DDLT: 33 +/- 8 vs LDLT: 33 +/- 10; P = 0.911). Live donors median evaluation time was 24 hours (18-561 hours). As expected, median time on waiting list was significantly lower in the LDLT group (DDLT: 13 [0-1704] days vs LDLT: 10 [1-33] days; P = 0.008). Incidence of postoperative complications was numerically, albeit not significantly higher in the DDLT versus LDLT (68% vs 29%; P = 0.08). No difference was detected between LDLT and DDLT patients regarding 1-year (DDLT: 76% vs LDLT: 85%), 3-year (DDLT: 68% vs LDLT: 85%), and 5-year (DDLT: 68% vs LDLT: 85%) graft and patient survivals (P = 0.41). No severe donor complication occurred after live donation. CONCLUSIONS: The LDLT may provide a faster access to transplantation and therefore, offers an alternative treatment option for critically ill patients requiring ICU care and mechanical ventilation support at the time of transplantation. PMID- 27500231 TI - Prediction of Long-term Renal Allograft Outcome By Early Urinary CXCL10 Chemokine Levels. AB - Predictive biomarkers for long-term renal allograft outcome could help to individualize follow-up strategies and therapeutic interventions. METHODS: We investigated the predictive value of urinary CXC chemokine ligand 10 (CXCL10) measured at different timepoints (ie, at 3 and 6 months, and mean of 3 and 6 months coined CXCL10-burden) for long-term allograft outcomes in 154 patients. The primary outcome was a composite graft endpoint of death-censored allograft loss and/or biopsy-proven rejection and/or decline of estimated glomerular filtration rate greater than 20% occurring beyond 6 months after transplantation. RESULTS: After a median follow-up of 6.6 years (interquartile range, 5.7-7.5 years) the endpoint was reached in 43/154 patients (28%). In a multivariable Cox regression model independent predictors were 6-month CXCL10 levels, the CXCL10 burden, HLA-mismatches, donor age and delayed graft function while previous (sub)clinical rejection, estimated glomerular filtration rate and proteinuria at 6 months, as well as 3-month CXCL10 levels were not. Time-dependent receiver operating characteristic analysis revealed an area under the curve of 0.68 (6 month CXCL10) and 0.67 (CXCL10-burden). Grouped by optimal cutoff, low 6-month CXCL10 (<0.70 ng/mmol) was associated with a 95% endpoint-free 5-year survival compared to 78% with high 6-month CXCL10 (P = 0.0007). Only 2 of 62 patients (3%) with low 6-month CXCL10 levels (<0.70 ng/mmol) experienced late rejection or graft loss due to rejection compared to 15 of 92 patients (16%) with high 6-month CXCL10 levels (P = 0.008). Similar results were obtained when patients were grouped according to CXCL10-burden (cutoff, 1.06 ng/mmol). CONCLUSIONS: Six-month urinary CXCL10 is an independent predictor for long-term graft outcome and thus might be a supplementary tool to tailor surveillance strategies and therapy. PMID- 27500232 TI - Laser Ablation Inductively Coupled Plasma Mass Spectrometry: An Emerging Technology for Multiparametric Analysis of Tissue Antigens. AB - New analytical techniques for multiparametric characterisation of individual cells are likely to reveal important information about the heterogeneity of immunological responses at the single-cell level. In this proof-of-principle study, laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) was applied to the problem of concurrently detecting 24 lineage and activation markers expressed by human leucocytes. This approach was sufficiently sensitive and specific to identify subpopulations of isolated T, B, and natural killer cells. Leucocyte subsets were also accurately detected within unfractionated peripheral blood mononuclear cells preparations. Accordingly, we judge LA-ICP-MS to be a suitable method for assessing expression of multiple tissue antigens in solid-phase biological specimens, such as tissue sections, cytospins, or cells grown on slides. These results augur well for future development of LA-ICP-MS based bioimaging instruments for general users. PMID- 27500233 TI - Subzero 12-hour Nonfreezing Cryopreservation of Porcine Heart in a Variable Magnetic Field. AB - BACKGROUND: A novel subzero nonfreezing heart preservation method has been developed. It uses a refrigerating device that generates a variable magnetic field, allowing the whole organ to be cooled simultaneously to a supercooled state without the use of cryoprotectant. As a fundamental experiment for heart preservation, we verified whether this novel method is able to suppress anaerobic metabolism and reduce damage in the hearts of large animals. METHODS: Twelve porcine hearts were collected and preserved for 12 hours using a simple immersion method. The hearts were divided into 2 groups: 6 underwent nonfreezing preservation at -3 degrees C in a variable magnetic field (subzero group), and 6 underwent conventional preservation at 4 degrees C (conventional group). The quantity of anaerobic metabolism and the degree of ultrastructural change in the 2 groups were evaluated and compared. RESULTS: The concentration of adenosine triphosphate in the myocardial tissue was significantly greater in the subzero group than in the conventional group (21.06+/-5.87 MUmol/g vs 5.96+/-3.41 MUmol/g; P < 0.05). The accumulated lactate concentration was significantly lower in the subzero group than in the conventional group (6.58+/-2.28 MUmol/g vs 11.15+/-3.74 MUmol/g; P < 0.05). The Flameng score, an index of ultrastructural changes to the mitochondria, was significantly lower in the subzero group than in the conventional group (1.28+/-0.40 vs 2.73+/-0.30; P < 0.05). CONCLUSIONS: Subzero nonfreezing preservation using a variable magnetic field resulted in a remarkable suppression of anaerobic metabolism and myocardial protection in porcine hearts. PMID- 27500234 TI - First Robotic-Assisted Dual Kidney Transplant: Surgical Technique and Report of a Case With 24-month Follow-up. AB - BACKGROUND: Open surgery is the gold standard procedure for kidney transplantation. There is a strong rationale for using minimally invasive surgery in patients with end-stage renal disease. A robotic-assisted dual kidney transplant was performed for the first time at our institution. METHODS: In August 2013, a 63-year-old man with end-stage renal disease and diabetes mellitus under pharmacological control received both kidneys from a 70-year-old marginal donor. Pretransplant donor biopsy demonstrated a bilateral Karpinski score greater than 5. The organs did not exhibit malformations and each had an artery and a vein. The procedure was carried out by a 7-port intraperitoneal approach using the da Vinci surgical system. The procedure was identical for the 2 kidneys except that mobilization of the sigmoid colon was required to introduce the left graft. The renal vessels were anastomosed to the left external iliac vessels. The novel aspect of the technique was the introduction of both grafts through a single, 7-cm upper midline incision. RESULTS: Total operative time was 400 minutes and blood loss was 120 mL. Both grafts immediately began functioning. There were no intraoperative or postoperative complications. The patient was discharged on the seventh postoperative day with normal renal function. At 24 months, he is well and does not require hemodialysis. CONCLUSIONS: Minimally invasive robotic-assisted technology is a promising technique that provides exceptional patient outcomes by reducing operative morbidity, immobilization, and time to recovery, while affording better esthetic results. Selected patients with multiple comorbidities benefit most. Grafts from marginal donors are an extremely valuable resource. PMID- 27500235 TI - The Role of Lysophosphatidic Acid on Airway Epithelial Cell Denudation in a Murine Heterotopic Tracheal Transplant Model. AB - BACKGROUND: Chronic rejection is the major leading cause of morbidity and mortality after lung transplantation. Obliterative bronchiolitis (OB), a fibroproliferative disorder of the small airways, is the main manifestation of chronic lung allograft rejection. However, there is currently no treatment for the disease. We hypothesized that lysophosphatidic acid (LPA) participates in the progression of OB. The aim of this study was to reveal the involvement of LPA on the lesion of OB. METHODS: Ki16198, an antagonist specifically for LPA1 and LPA3, was daily administered into the heterotopic tracheal transplant model mice at the day of transplantation. At days 10 and 28, the allografts were isolated and evaluated histologically. The messenger RNA levels of LPAR in microdissected mouse airway regions were assessed to reveal localization of lysophosphatidic acid receptors. The human airway epithelial cell was used to evaluate the mechanism of LPA-induced suppression of cell adhesion to the extracellular matrix (ECM). RESULTS: The administration of Ki16198 attenuated airway epithelial cell loss in the allograft at day 10. Messenger RNAs of LPA1 and LPA3 were detected in the airway epithelial cells of the mice. Lysophosphatidic acid inhibited the attachment of human airway epithelial cells to the ECM and induced cell detachment from the ECM, which was mediated by LPA1 and Rho-kinase pathway. However, Ki16198 did not prevent obliteration of allograft at day 28. CONCLUSIONS: The LPA signaling is involved in the status of epithelial cells by distinct contribution in 2 different phases of the OB lesion. This finding suggests a role of LPA in the pathogenesis of OB. PMID- 27500237 TI - Tacrolimus-Induced Salt Losing Nephropathy Resolved After Conversion to Everolimus. PMID- 27500236 TI - Renal Function in Kidney and Liver Transplant Recipients After A 130-km Road Cycling Race. AB - BACKGROUND: A few patients, after receiving solid organ transplantation, return to performing various sports and competitions; however, at present, data no study had evaluated the effects of endurance cycling races on their renal function. METHODS: Race times and short form (36) health survey questionnaires of 10 kidney transplant recipients (KTR) and 8 liver transplant recipients (LTR) transplanted recipients involved in a road cycling race (130 km) were compared with 35 healthy control subjects (HCS), also taking laboratory blood and urine tests the day before the race, at the end of the race, and 18 to 24 hours after competing. RESULTS: The 3 groups showed similar race times (KTR, 5 hours 59 minutes +/- 0 hours 39 minutes; LTR, 6 hours 20 minutes +/- 1 hour 11 minutes; HCS, 5 hours 40 minutes +/- 1 hour 28 minutes), similar short form (36) health survey scores, and similar trend of laboratory parameters which returned to baseline after 18 to 24 hours. After the race, there was an increase in creatinine (0.24 mg/dL; effect size [ES] = 0.78; P < 0.001), urea (22 mg/dL; ES = 1.42; P < 0.001), and a decrease of estimated glomerular filtration rate (-17 mL/min; ES = 0.85; P < 0.001). The increase of blood uric acid was more remarkable in HCS and KTR (2.3 mg/dL; ES = 1.39; P < 0.001). The KTR showed an increase of microalbuminuria (167.4 mg/L; ES = 1.20; P < 0.001) and proteinuria (175 mg/mL; ES = 0.97; P < 0.001) similar to LTR (microalbuminuria: 176.0 mg/L; ES = 1.26; P < 0.001; proteinuria: 213 mg/mL; ES = 1.18; P < 0.001), with high individual variability. The HCS had a nonsignificant increase of microalbuminuria (4.4 mg/L; ES = 0.03; P = 0.338) and proteinuria (59 mg/mL; ES = 0.33; P = 0.084). CONCLUSIONS: Selected and well-trained KTR and LTR patients can participate to an endurance cycling race showing final race times and temporary modifications of kidney function similar to those of HCS group, despite some differences related to baseline clinical conditions and pharmacological therapies. Patients involved in this study represent the upper limit of performance currently available for transplant recipients and cannot be considered representative of the entire transplanted population. PMID- 27500238 TI - Analysis of the Influence of HLA-A Matching Relative to HLA-B and -DR Matching on Heart Transplant Outcomes. AB - BACKGROUND: There are conflicting reports on the effect of donor-recipient HLA matching on outcomes in heart transplantation. The objective of this study was to investigate the effects of HLA-A matching relative to HLA-B and -DR matching on long-term survival in heart transplantation. METHODS: A total of 25 583 patients transplanted between 1988 and 2011 were identified from the International Society for Heart and Lung Transplantation registry. Transplants were divided into 2 donor-recipient matching groups: HLA-A-compatible (no HLA-A mismatches) and HLA-A incompatible (1-2 HLA-A mismatches). Primary outcome was all-cause mortality. Secondary outcomes were graft failure-, cardiovascular-, infection-, or malignancy-related deaths. RESULTS: The risk of all-cause mortality 15 years after transplantation was higher for HLA-A-compatible (vs HLA-A-incompatible) grafts in patients who had HLA-B-, HLA-DR-, or HLA-B,DR-incompatible grafts (P = 0.027, P = 0.007, and P = 0.002, respectively) but not in HLA-B- and/or HLA-DR compatible grafts. This was confirmed in multivariable Cox regression analysis where HLA-A compatibility (vs HLA-A incompatibility) was associated with higher mortality in transplants incompatible for HLA-DR or HLA-B and -DR (hazard ratio [HR], 1.59; 95% confidence interval [95% CI], 1.11-2.28; P = 0.012 and HR, 1.69; 95% CI, 1.17-2.43; P = 0.005, respectively). In multivariable analysis, the largest compromise in survival for HLA-A compatibility (vs HLA-incompatibility) was for chronic rejection in HLA-B- and -DR-incompatible grafts (HR, 1.91; 95% CI, 1.22-3.01; P = 0.005). CONCLUSIONS: Decreased long-term survival in heart transplantation was associated with HLA-A compatibility in HLA-B,DR-incompatible grafts. PMID- 27500239 TI - Indications and Outcomes in Liver Transplantation in Patients With Primary Sclerosing Cholangitis in Norway. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is 1 of the leading causes of liver transplantation (LTX) in Scandinavia, and an increasing number of PSC patients have been transplanted in Norway during the last 2 decades. This trend is partly attributable to the recently established practice in Norway of offering LTX to PSC patients with cholangiocellular dysplasia. Based on the controversy associated with this practice, we herein aimed to report the main features and outcomes of our LTX program in PSC. METHODS: The primary indication for LTX (quality of life/end-stage liver disease or suspected neoplasia) was retrospectively determined for 222 patients undergoing LTX for PSC or other autoimmune liver diseases (primary biliary cirrhosis/autoimmune hepatitis) with at least 5 years of follow-up. RESULTS: In PSC patients impaired quality of life (43.5%) and end-stage liver disease (38.4%) were the most frequent indications for LTX, whereas suspected neoplasia accounted for 18.1%. The proportion of PSC patients with manifest encephalopathy, variceal bleeding, or ascites declined over time. In patients with suspected neoplasia as the primary indication for LTX (n = 25), neoplasia was confirmed in the explanted liver in 20 patients (80%). Five-year survival rates for PSC patients transplanted between 2001 and 2009 were 91.9% for patients receiving LTX due to impaired quality of life or end-stage liver disease and 83.3% for suspected neoplasia. CONCLUSIONS: The PSC patients are increasingly listed for LTX at an earlier stage of their liver disease. In patients with suspected neoplasia before LTX, 5-year survival was acceptable, despite confirmation of neoplasia in 80% of the liver explants. PMID- 27500240 TI - Living Donor Liver Transplantation Using a Liver Graft With Congenital Intrahepatic Portosystemic Shunt. AB - Despite of recent development of imaging modalities, congenital intrahepatic portosystemic shunt (IPSS) is rarely diagnosed. Therefore, living donor liver transplantation using a liver graft with IPSS has not been previously published. MATERIALS AND METHODS: We report a 28-year-old male patient with end-stage liver disease secondary to Wilson disease. His 26-year-old brother was a potential living donor, who had an IPSS of 25 mm in diameter at segment 6 as shown by computed tomography. Liver function tests were normal, and blood ammonia concentration was in the upper limit of normal. RESULTS: Living donor liver transplantation was uneventfully performed. After surgery, a recipient liver function tests showed a quick recovery, and serum ammonia levels were consistently normal. Although thrombosis inside the IPSS was confirmed by computed tomography on postoperative day 21, this thrombosis disappeared at 3 months posttransplant with anticoagulants. Currently (12 months posttransplant), the patient has fully recovered, and the IPSS is still the same size. CONCLUSIONS: Based on our experience, liver allografts with IPSS can be accepted as potential liver allografts. PMID- 27500241 TI - Comparison of Neutral Proteases and Collagenase Class I as Essential Enzymes for Human Islet Isolation. AB - Efficient islet isolation requires synergistic interaction between collagenase class I (CI) and class II (CII). The CI degradation alters the ratio between CI and CII and is responsible for batch-to-batch variations. This study compares the role of neutral protease (NP) plus clostripain (CP) with CI as essential enzymes for human islet isolation. METHODS: Human islets were isolated using 4 different enzyme mixtures composed of CII plus either intact (CI-115) or degraded CI (CI 100). Blends were administered either with or without NP/CP. Purified islets were cultured for 3 to 4 days before islet quality assessment. RESULTS: Whereas using intact CI-115 without NP/CP did not significantly reduce islet yield (3429 +/- 631 vs 3087 +/- 970 islet equivalent/g, nonsignificant), administration of degraded CI-100 without NP/CP decreased islet yield from 3501 +/- 580 to 1312 +/- 244 islet equivalent/g (P < 0.01), doubled the amount of undigested tissue from 11.8 +/- 1.6 to 24.4 +/- 1.2% (P < 0.01) and triplicated the percentage of trapped islets from 7.7 +/- 2.8 to 22.5 +/- 3.6% (P < 0.05). Islet yield did not vary between supplemented CI-115 and CI-100, but was increased using CI-115 when NP/CP was omitted (P < 0.05). A trend toward higher viability and increased secretory insulin response was noted in both CI-100 and CI-115 when NP/CP was not added. CONCLUSIONS: This study suggests that NP/CP can compensate reduced CI activity. Future attempts to optimize enzyme blends should consider the possibility to increase the proportion of collagenase CI to reduce the need for potentially harmful NPs. PMID- 27500242 TI - Epstein-Barr Virus-Positive Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation: Pathogenesis, Clinical Manifestations, Diagnosis, and Management. AB - Posttransplant lymphoproliferative disease (PTLD) is a potentially fatal complication after (solid organ) transplantation, which is highly associated with Epstein-Barr virus (EBV). The EBV-specific cytotoxic T cell response that is essential in controlling the virus in healthy individuals is suppressed in transplant recipients using immunosuppressive drugs. A primary EBV infection in EBV-seronegative patients receiving an EBV-seropositive donor organ or a reactivation in those who are already latently infected pretransplantation can lead to uninhibited growth of EBV-infected B cells and subsequently to PTLD. Effective preventive strategies, such as vaccines and antiviral agents, are lacking. Because not every transplant recipient with increasing EBV viral load develops PTLD, it is hard to decide how intensively these patients should be monitored and how and when a preemptive intervention should take place. There is a need for other tools to help predict the development of PTLD in patients at risk to make timing and strategy of preemptive intervention easier and more reliable. The cornerstone of the treatment of patients with PTLD is restoring the host's immunity by reduction of immunosuppressive drug therapy. American and British guidelines recommend to add rituximab monotherapy or rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisolone, depending on histology and clinical characteristics. Although response to these therapies is good, toxicity is a problem, and PTLD still has a relatively high mortality rate. An evolving therapy, especially in PTLD occurring in allogeneic stem cell transplantation, is restoring the host's immune response with infusion of EBV-specific cytotoxic T cells. This may also play a role in the future in both prevention and treatment of PTLD in SOT. PMID- 27500243 TI - Reduced Transfusion During OLT by POC Coagulation Management and TEG Functional Fibrinogen: A Retrospective Observational Study. AB - Patients undergoing orthotopic liver transplantation are at high risk of bleeding complications. Several Authors have shown that thromboelastography (TEG)-based coagulation management and the administration of fibrinogen concentrate reduce the need for blood transfusion. METHODS: We conducted a single-center, retrospective cohort observational study (Modena Polyclinic, Italy) on 386 consecutive patients undergoing liver transplantation. We assessed the impact on resource consumption and patient survival after the introduction of a new TEG based transfusion algorithm, requiring also the introduction of the fibrinogen functional thromboelastography test and a maximum amplitude of functional fibrinogen thromboelastography transfusion cutoff (7 mm) to direct in administering fibrinogen (2012-2014, n = 118) compared with a purely TEG-based algorithm previously used (2005-2011, n = 268). RESULTS: After 2012, there was a significant decrease in the use of homologous blood (1502 +/- 1376 vs 794 +/- 717 mL, P < 0.001), fresh frozen plasma (537 +/- 798 vs 98 +/- 375 mL, P < 0.001), and platelets (158 +/- 280 vs 75 +/- 148 mL, P < 0.005), whereas the use of fibrinogen increased (0.1 +/- 0.5 vs 1.4 +/- 1.8 g, P < 0.001). There were no significant differences in 30-day and 6-month survival between the 2 groups. CONCLUSIONS: The implementation of a new coagulation management method featuring the addition of the fibrinogen functional thromboelastography test to the TEG test according to an algorithm which provides for the administration of fibrinogen has helped in reducing the need for transfusion in patients undergoing liver transplantation with no impact on their survival. PMID- 27500244 TI - Conservative Pancreas Graft Preservation at the Extreme. AB - Because of the value some patients place in remaining insulin-independent after pancreas transplantation, they may be reluctant to undergo graft pancreatectomy, even in the face of extreme complications, such as graft thrombosis and duodenal segment leak. Partly, for this reason, a variety of complex salvage techniques have been described to save the graft in such circumstances. We report a case of a series of extreme complications related to a leak from the duodenal segment after a simultaneous pancreas and kidney transplant. These included infected thrombosis of the inferior vena cava associated with a graft venous thrombosis and a retroperitoneal fistula. The patient retained graft function with insulin independence and repeatedly declined graft pancreatectomy against the advice of the transplant team. Conservative treatment with percutaneous drainage, antibiotics, and anticoagulation was eventually successful. This outcome is unique in our experience and may be instructive to teams caring for pancreas transplant recipients. PMID- 27500245 TI - Organ Donation Among Tiers of Health Workers: Expanding Resources to Optimize Organ Availability in a Developing Country. AB - The global increase in end organ failure but disproportional shortage of organ donation calls for attention. Expanding the organ pool by assessing and improving health workers' attitude at all levels of care may be a worthwhile initiative. METHODS: A questionnaire-based cross sectional study involving tertiary, secondary, and primary health institutions in Southwestern Nigeria was conducted. RESULTS: Age range was 18 to 62 (36.7 +/- 9.2) years. Only 13.5%, 11.7%, and 11.2% from primary, secondary, and tertiary health centers, respectively, would definitely donate despite high level of awareness (>90%) at each level of care. Participants from primary health care are of low income (P < 0.05), and this cohort is less likely to be aware of organ donation (P < 0.05). At each level of care, permission by religion to donate organs influenced positive attitudes (willingness to donate, readiness to counsel families of potential donors, and signing of organ donation cards) toward organ donation. Good knowledge of organ donation only significantly influenced readiness to counsel donors (P < 0.05) and not willingness to donate (P > 0.05). At each level of health care, young health care workers (P < 0.05) and women (P > 0.05) would be willing to donate, whereas men show positive attitude in signing of organ donor cards (P < 0.05) and counseling of families of potential donors (P > 0.05). CONCLUSIONS: Knowledge and willingness to donate organs among health care levels were not different. Considering the potential advantage of community placement of other tiers of health care (primary and secondary) in Nigeria, integrating them would be strategically beneficial to organ donation. PMID- 27500246 TI - Renal Transplantation From a Living Donor With a Horseshoe Kidney. PMID- 27500247 TI - Identifying Effective Enzyme Activity Targets for Recombinant Class I and Class II Collagenase for Successful Human Islet Isolation. AB - Isolation following a good manufacturing practice-compliant, human islet product requires development of a robust islet isolation procedure where effective limits of key reagents are known. The enzymes used for islet isolation are critical but little is known about the doses of class I and class II collagenase required for successful islet isolation. METHODS: We used a factorial approach to evaluate the effect of high and low target activities of recombinant class I (rC1) and class II (rC2) collagenase on human islet yield. Consequently, 4 different enzyme formulations with divergent C1:C2 collagenase mass ratios were assessed, each supplemented with the same dose of neutral protease. Both split pancreas and whole pancreas models were used to test enzyme targets (n = 20). Islet yield/g pancreas was compared with historical enzymes (n = 42). RESULTS: Varying the Wunsch (rC2) and collagen degradation activity (CDA, rC1) target dose, and consequently the C1:C2 mass ratio, had no significant effect on tissue digestion. Digestions using higher doses of Wunsch and CDA resulted in comparable islet yields to those obtained with 60% and 50% of those activities, respectively. Factorial analysis revealed no significant main effect of Wunsch activity or CDA for any parameter measured. Aggregate results from 4 different collagenase formulations gave 44% higher islet yield (>5000 islet equivalents/g) in the body/tail of the pancreas (n = 12) when compared with those from the same segment using a standard natural collagenase/protease mixture (n = 6). Additionally, islet yields greater than 5000 islet equivalents/g pancreas were also obtained in whole human pancreas. CONCLUSIONS: A broader C1:C2 ratio can be used for human islet isolation than has been used in the past. Recombinant collagenase is an effective replacement for the natural enzyme and we have determined that high islet yield can be obtained even with low doses of rC1:rC2, which is beneficial for the survival of islets. PMID- 27500248 TI - Successful Kidney and Lung Transplantation From a Deceased Donor With Blunt Abdominal Trauma and Intestinal Perforation. AB - The number of organ donors is limited by many contraindications for donation and poor quality of potential organ donors. Abdominal infection is a generally accepted contraindication for donation of abdominal organs. We present a 43-year old man with lethal brain injury, blunt abdominal trauma, and intestinal perforation. After withdrawal of life-sustaining treatment and circulatory arrest, a minilaparotomy confirmed abdominal contamination with intestinal content. After closure of the abdomen, organs were preserved with in situ preservation with an aortic cannula inserted via the femoral artery. Thereafter, the kidneys were procured via bilateral lumbotomy to reduce the risk of direct bacterial contamination; lungs were retrieved following a standard practice. There was no bacterial or fungal growth in the machine preservation fluid of both kidneys. All organs were successfully transplanted, without postoperative infection, and functioned well after 6 months. We hereby show that direct contamination of organs can be avoided with the use of in situ preservation and retroperitoneal procurement. Intestinal perforation is not an absolute contraindication for donation, although the risk of bacterial or fungal transmission has to be evaluated per case. PMID- 27500249 TI - Indicators to Identify Trafficking in Human Beings for the Purpose of Organ Removal. AB - This article presents indicators to support transplant professionals, judicial and law enforcement authorities and victim support workers with the identification of trafficking in persons for the purpose of organ removal. It outlines the legal and illegal service providers that facilitate trafficking in human beings for the purpose of organ removal and guides the reader through the following criminal process: recruitment, transport, entrance, documents, housing, transplant, aftercare, and finance. Identification of illegal transplant activities by transplant professionals can support police and judiciary with the investigation, disruption, and prosecuting of trafficking networks. PMID- 27500250 TI - Stimulating and Enhancing Partnerships Between Transplant Professionals and Law Enforcement: Recommendations. AB - To help combat trafficking in human beings for organ removal (THBOR), transplant professionals need to do more than carry out careful, multidisciplinary screening of potential living donors; they also need to communicate and collaborate with law enforcement professionals. This will involve transplant professionals educating investigators and prosecutors about transplant practices and in turn learning about THBOR and how it is prosecuted. Cases of illegal organ transplantation need to be detected at different levels. First, the victims of the crime itself need to be identified, especially when they present themselves for screening. Physicians have a collective responsibility to prevent exploitation of people, including THBOR victims. The second level involves the more difficult matter of making reports that involve transplant tourists who have returned home after receipt of an organ and need follow-up care. Besides counseling patients prospectively about the legal as well as medical risks in receiving a vended organ in a foreign transplant center, physicians treating such patients could have an obligation to report what has happened, if the government has established a mechanism that either allows reporting THBOR that does not include the identity of the patient or that treats patients as victims provided they cooperate in investigation and prosecution of the persons responsible for obtaining or implanting the organs. The third level of cooperation involves transplant professionals who participate in THBOR. Professional societies need to undertake programs to make physicians and nurses aware that their responsibility to protect their professions' reputation includes identifying members of their professions who depart from professional ethics. Doing so allows the local professional societies and state boards to discipline such violators. All 3 of these functions would be facilitated by the creation by an international body such as World Health Organization of a registry of patients who travel internationally to receive a legitimate organ transplant. PMID- 27500251 TI - Establishing Trafficking in Human Beings for the Purpose of Organ Removal and Improving Cross-Border Collaboration in Criminal Cases: Recommendations. AB - In this short summary report on the legal definition of trafficking in human beings for the purpose of organ removal and improving cross-border collaboration in criminal cases, challenges, and recommendations in the areas of defining the crime, criminal investigation and prosecution, and cross-border cooperation are made. These are the outcomes of a working group discussion during the writers' conference of the HOTT project, a European Union-funded project against trafficking in human beings for the purpose of organ removal. PMID- 27500252 TI - Protection of Human Beings Trafficked for the Purpose of Organ Removal: Recommendations. AB - This report presents a comprehensive set of recommendations for protection of human beings who are trafficked for the purpose of organ removal or are targeted for such trafficking. Developed by an interdisciplinary group of international experts under the auspices of the project Trafficking in Human Beings for the Purpose of Organ Removal (also known as the HOTT project), these recommendations are grounded in the view that an individual who parts with an organ for money within an illegal scheme is ipso facto a victim and that the crime of trafficking in human beings for the purpose of organ removal (THBOR) intersects with the crime of trafficking in organs. Consequently, the protection of victims should be a priority for all actors involved in antitrafficking activities: those combating organ-related crimes, such as health organizations and survivor support services, and those combating trafficking in human beings, such as the criminal justice sectors. Taking into account the special characteristics of THBOR, the authors identify 5 key stakeholders in the protection of human beings trafficked for organ removal or targeted for such trafficking: states, law enforcement agencies and judiciary, nongovernmental organizations working in the areas of human rights and antitrafficking, transplant centers and health professionals involved in transplant medicine, and oversight bodies. For each stakeholder, the authors identify key areas of concern and concrete measures to identify and protect the victims of THBOR. The aim of the recommendations is to contribute to the development of a nonlegislative response to THBOR, to promote the exchange of knowledge and best practices in the area of victim protection, and to facilitate the development of a policy-driven action plan for the protection of THBOR victims in the European Union and worldwide. PMID- 27500253 TI - Trafficking in Human Beings for the Purpose of Organ Removal and the Ethical and Legal Obligations of Healthcare Providers. AB - Physicians and other health care professionals seem well placed to play a role in the monitoring and, perhaps, in the curtailment of the trafficking in human beings for the purpose of organ removal. They serve as important sources of information for patients and may have access to information that can be used to gain a greater understanding of organ trafficking networks. However, well established legal and ethical obligations owed to their patients can create challenging policy tensions that can make it difficult to implement policy action at the level of the physician/patient. In this article, we explore the role-and legal and ethical obligations-of physicians at 3 key stages of patient interaction: the information phase, the pretransplant phase, and the posttransplant phase. Although policy challenges remain, physicians can still play a vital role by, for example, providing patients with a frank disclosure of the relevant risks and harms associated with the illegal organ trade and an honest account of the physician's own moral objections. They can also report colleagues involved in the illegal trade to an appropriate regulatory authority. Existing legal and ethical obligations likely prohibit physicians from reporting patients who have received an illegal organ. However, given the potential benefits that may accrue from the collection of more information about the illegal transactions, this is an area where legal reform should be considered. PMID- 27500254 TI - The Hague Recommendations: Improving Nonlegislative Responses to Trafficking in Human Beings for the Purpose of Organ Removal. AB - Over the years, the trade in human organs has become an object of international concern. Since the 1980s, antiorgan trade initiatives have mainly involved the strengthening of legislative responses. Little attention however is given to nonlegislative responses by law enforcement authorities. The HOTT project is a European Union-funded research project titled "trafficking in human beings for the purpose of organ removal." Its objectives are to increase knowledge, raise awareness, and improve the nonlegislative response to the crime. Its consortium organized a "Writers' Conference" in The Hague, The Netherlands at Europol's Headquarters where a group of 40 experts, consisting of transplant professionals, law enforcement officials, and policy makers, formulated recommendations to improve nonlegislative responses. These recommendations, presented hereafter, address the ethical and legal obligations of health care providers, the protection of persons trafficked for the purpose of organ removal, strengthening cross-border collaboration in criminal cases, and stimulating partnerships between transplant professionals and law enforcement. These recommendations offer ways in which transplant professionals can contribute to improving the nonlegislative response to trafficking in human beings for the purpose of organ removal. PMID- 27500255 TI - Early and Sustained Reduction in Donor-Specific Antibodies in Desensitized Living Donor Kidney Transplant Recipients: A 3-Year Prospective Study. AB - BACKGROUND: Desensitization with IVIG and rituximab allows acceptable graft survival in sensitized kidney transplant recipients with preexisting donor specific antibodies (DSAs) and a positive crossmatch. There is little published data reporting the durability of DSA removal in kidney transplant recipients treated with IVIG and rituximab. METHODS: We conducted a 3-year prospective DSA monitoring study in living donor kidney recipients with preexisting DSA to assess the durability of DSA removal after a perioperative protocol of IVIG and rituximab. All recipients had flow crossmatch titers less than 1:32. Data were analyzed using linear mixed effects models and Kaplan-Meier survival methods. RESULTS: The longitudinal database comprised 210 mean fluorescence intensity (MFI) determinations. Forty-two DSAs were identified in 29 patients. Pretreatment MFI averaged 4715 +/- 3962 (range, 947-20 129). At 1 month posttransplant, 18 patients (62%) had a complete response (MFI < 1000) and an additional 9 patients (31%) had a partial response (MFI reduced but >1000). There was a 46% reduction (P < 0.001) in DSA MFI at 1 month posttransplant that was sustained throughout the 3-year follow-up period and was observed for both class I and II DSAs regardless of pretreatment MFI levels. With a mean posttransplant follow-up of 1048 +/- 574 days, 3-year patient and graft survivals were 95% and 90%. Four patients (14%) had acute rejection between days 125 and 560. CONCLUSIONS: Desensitization with IVIG and rituximab results in early and sustained DSA removal over a 3-year posttransplant period in living donor kidney transplant recipients with pretransplant DSA and a positive crossmatch, excellent patient and graft survivals and a low incidence of acute rejection. PMID- 27500256 TI - A Preliminary Study Into the Significance of Intrarenal Reflux in BK Virus Nephropathy After Kidney Transplantation. AB - BACKGROUND: The BK virus typically colonizes the lower urinary tract and is the causative agent in BK virus nephropathy (BKVN), which can progress to allograft dysfunction and graft loss. Urinary reflux in kidney allografts is induced by vesicoureteral reflux or disturbances in intrarenal reflux (IRR), believed to be associated with BKVN. This study was designed to elucidate the relationship between BKVN and IRR. METHODS: We examined 30 renal transplant recipients histologically diagnosed with BKVN using anti-Simian virus 40 immunohistochemistry and 60 clinically matched control recipients. The BKVN patients were divided into stable (n = 12) and progressive (n = 18) groups according to allograft kidney function 1 year after diagnosis. Histological rejection scores according to the pathological classification of rejection in renal allografts (Banff classification), histological BKVN stages, and histological polyomavirus load levels (pvl) proposed by the Banff working group were evaluated. The IRR was quantified by histological reflux scores defined with retention and reflux of immunostained Tamm-Horsfall protein in renal tubules and glomeruli. RESULTS: Higher reflux scores were observed in the BKVN group compared with that in the control group. No differences in clinical parameters were observed between the BKVN and control groups. Reflux scores and pvl were significantly higher in the progressive group than in the stable BKVN group with no significant difference in BK stage observed between groups. Reflux scores were found to be significantly correlated with pvl. CONCLUSIONS: Our preliminary study suggested that IRR might be a predisposing and prognostic factor in BKVN. PMID- 27500257 TI - mTOR Inhibition: Reduced Insulin Secretion and Sensitivity in a Rat Model of Metabolic Syndrome. AB - BACKGROUND: Sirolimus (SRL) has been associated with new-onset diabetes mellitus after transplantation. The aim was to determine the effect of SRL on development of insulin resistance and beta -cell toxicity. METHODS: Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5, or 1.0 mg/kg) during 12 or 28 days. Intraperitoneal glucose tolerance test (IPGTT) was evaluated at days 0, 12, 28, and 45. Islet morphometry, beta-cell proliferation, and apoptosis were analyzed at 12 days. Islets were isolated to analyze insulin content, insulin secretion, and gene expression. RESULTS: After 12 days, SRL treatment only impaired IPGTT in a dose-dependent manner in OZR. Treatment prolongation induced increase of area under the curve of IPGTT in LZR and OZR; however, in contrast to OZR, LZR normalized glucose levels after 2 hours. The SRL reduced pancreas weight and islet proliferation in LZR and OZR as well as insulin content. Insulin secretion was only affected in OZR. Islets from OZR + SRL rats presented a downregulation of Neurod1, Pax4, and Ins2 gene. Genes related with insulin secretion remained unchanged or upregulated. CONCLUSIONS: In conditions that require adaptive beta -cell proliferation, SRL might reveal harmful effects by blocking beta -cell proliferation, insulin production and secretion. These effects disappeared when removing the therapy. PMID- 27500258 TI - Lowered Immune Cell Function in Liver Recipients Recovered From Posttransplant Lymphoproliferative Disease Who Developed Graft Tolerance. AB - Tolerance after treatment and recovery from posttransplant lymphoproliferative disease (PTLD) have been described but little is known about the immunology. The objective of this study is to evaluate the immunity of pediatric recipients who recovered from PTLD. MATERIALS AND METHODS: Pediatric recipients who recovered from PTLD after liver transplant and twice the number of recipients who never had PTLD were recruited. Their immune statuses were measured by ImmuKnow (measurement of adenosine 5-triphospate level produced CD4+ T helper cells), and the results were divided into 3 groups, "low" (<=225 ng/mL), "moderate" (226 to 524 ng/mL), and "high" (>=525 ng/mL). The results of both groups were compared and analyzed. RESULTS: Nine PTLD recipients and 20 non-PTLD recipients were recruited. There were no significant differences in terms of sex and age between the 2 groups. The majority of PTLD recipients (88.9%) had "low" immune status responses, and none of them had "high" responses. For non-PTLD recipients, more than half (55%) had "moderate" immune status responses. The median value of adenosine 5-triphospate levels was significantly lower in the PTLD group (119 ng/mL vs 380.5 ng/mL P = 0.014), and their trough immunosuppressant level was also lower (3.8 MUg/L vs 7.7 MUg/L; P = 0.004). None of the patients in either group had abnormal liver enzymes (aspartate aminotransferase/alanine aminotransferase) to suggest graft rejection. CONCLUSIONS: Patients who recovered from PTLD have a lower CD4 T-cell activity compared with those who have not suffered from PTLD. Under careful monitoring, their immunosuppressant levels can be kept at low levels to prevent recurrence of PTLD. PMID- 27500259 TI - Deep Vein Thrombosis and Pulmonary Embolism in Liver Transplant Patients: Risks and Prevention. AB - Deep vein thrombosis (DVT) and pulmonary embolism (PE) are surgical complications estimated to occur in 5% to 10% of patients. There are limited data regarding DVT/PE in the early postoperative period in liver transplant patients. The aim of this study is to determine risk factors that influence the incidence of DVT/PE and the effectiveness of prophylaxis. METHODS: We reviewed the records of 999 patients who underwent initial liver transplant between January 2000 and June 2012 at Henry Ford Hospital. In 2011, a standardized prophylactic regimen using subcutaneous (SQ) heparin was initiated. All patients that developed either upper/lower extremity DVT or PE within the first 30 days of transplant formed the cohort of this study. RESULTS: On multivariate analysis, only peripherally inserted central catheter (PICC) placement and SQ heparin were associated with DVT/PE. In patients receiving heparin, 3 (1.0%) had DVT/PE versus 25 (3.5%) who did not receive heparin (P = 0.03). Sixteen (6.9%) patients that had a PICC developed DVT/PE compared with 12 (1.6%) patients without a PICC (P < 0.001). In the heparin group, DVT/PE with PICC was reduced to 3 (3.0%) versus 13 (9.9%) in those with a PICC and did not receive heparin (P = 0.03). Mean time from transplant to DVT/PE diagnosis was 12.3 days. Length of hospitalization was significantly longer in patients who developed DVT/PE (18.5 vs 10.0 days, P < 0.001). CONCLUSIONS: In this study, we demonstrated that PICC placement significantly increases the likelihood of DVT/PE in liver transplant recipients. Prophylactic SQ heparin effectively reduced DVT/PE events in this patient population. PMID- 27500260 TI - Open-Label, Randomized Study of Transition From Tacrolimus to Sirolimus Immunosuppression in Renal Allograft Recipients. AB - Calcineurin inhibitor-associated nephrotoxicity and other adverse events have prompted efforts to minimize/eliminate calcineurin inhibitor use in kidney transplant recipients. METHODS: This open-label, randomized, multinational study evaluated the effect of planned transition from tacrolimus to sirolimus on kidney function in renal allograft recipients. Patients received tacrolimus-based immunosuppression and then were randomized 3 to 5 months posttransplantation to transition to sirolimus or continue tacrolimus. The primary end point was percentage of patients with 5 mL/min per 1.73 m(2) or greater improvement in estimated glomerular filtration rate from randomization to month 24. RESULTS: The on-therapy population included 195 patients (sirolimus, 86; tacrolimus, 109). No between-group difference was noted in percentage of patients with 5 mL/min per 1.73 m(2) or greater estimated glomerular filtration rate improvement (sirolimus, 34%; tacrolimus, 42%; P = 0.239) at month 24. Sirolimus patients had higher rates of biopsy-confirmed acute rejection (8% vs 2%; P = 0.02), treatment discontinuation attributed to adverse events (21% vs 3%; P < 0.001), and lower rates of squamous cell carcinoma of the skin (0% vs 5%; P = 0.012). CONCLUSIONS: Our findings suggest that renal function improvement at 24 months is similar for patients with early conversion to sirolimus after kidney transplantation versus those remaining on tacrolimus. PMID- 27500261 TI - Successful Management of Calciphylaxis in a Kidney Transplant Patient: Case Report. AB - Calciphylaxis is a rare and often fatal condition mostly associated with end stage renal disease. The pathophysiology remains elusive and treatment options are scarce. We present a rare case of severe calciphylaxis after kidney transplantation in a patient with persistent hyperparathyroidism. CASE DESCRIPTION: A 78-year-old man with a history of end-stage renal disease developed edema and ulcerations on both lower limbs 14 months after kidney transplantation while receiving an mammalian target of rapamycin inhibitor to manage polyoma virus-associated nephropathy. Skin biopsies taken from the ulcerations confirmed calciphylaxis. A multimodal treatment regimen combining medical (calcium-free phosphate binders, cinacalcet, paricalcitol, sodium thiosulfate, antibiotic treatment) and surgical treatments (debridement and autologous skin transplantation) ultimately resulted in successful wound healing. DISCUSSION: We describe a case of severe calciphylaxis in a nonuremic patient after kidney transplantation. Rapid diagnosis by skin biopsy and an aggressive multimodal therapy regimen followed by long-term oral sodium thiosulfate treatment were crucial factors for a favorable outcome. PMID- 27500262 TI - Well, I Wouldn't be Any Worse Off, Would I, Than I am Now? A Qualitative Study of Decision-Making, Hopes, and Realities of Adults With Type 1 Diabetes Undergoing Islet Cell Transplantation. AB - BACKGROUND: For selected individuals with type 1 diabetes, pancreatic islet transplantation (IT) prevents recurrent severe hypoglycemia and optimizes glycemia, although ongoing systemic immunosuppression is needed. Our aim was to explore candidates and recipients' expectations of transplantation, their experience of being on the waiting list, and (for recipients) the procedure and life posttransplant. METHODS: Cross-sectional qualitative research design using semistructured interviews with 16 adults (8 pretransplant, 8 posttransplant; from 4 UK centers (n = 13) and 1 Canadian center (n = 3)). Interviews were audio recorded, transcribed, and underwent inductive thematic analysis. RESULTS: Interviewees were aged (mean +/- SD) 52 +/- 10 years (range, 30-64); duration of diabetes, 36 +/- 9 years (range, 21-56); 12 (75%) were women. Narrative accounts centered on expectations, hopes, and realities; decision-making; waiting and uncertainty; the procedure, hospital stay, and follow-up. Expected benefits included fewer severe hypoglycemic episodes, reduced need for insulin, preventing onset/progression of complications and improved psychological well-being. These were realized for most, at least in the short term. Most interviewees described well-informed, shared decision-making with clinicians and family, and managing their expectations. Although life "on the list" could be stressful, and immunosuppressant side effects were severe, interviewees reported "no regrets." Posttransplant, interviewees experienced increased confidence, through freedom from hypoglycemia and regained glycemic control, which tempered any disappointment about continued reliance on insulin. Most viewed their transplant as a success, though several reflected upon setbacks and hidden hopes for becoming "insulin-free." CONCLUSIONS: Independently undertaken interviews demonstrated realistic and balanced expectations of IT and indicate how to optimize the process and support for future IT candidates. PMID- 27500264 TI - Outcomes of Living Donor Liver Transplantation Alone for Patients on Maintenance Renal Replacement Therapy in Japan: Results of a Nationwide Survey. AB - BACKGROUND: Because simultaneous liver and kidney transplantation has been limited as a standard practice because of a severe shortage of deceased donors in Japan, living donor (LD) liver transplantation alone (LTA) is indicated in most recipients with maintenance renal replacement therapy (MRRT). METHODS: A retrospective nationwide survey of LD LTA was performed for liver transplant patients on MRRT. The characteristics of donors and recipients, postoperative complications, survival rate, and causes of death were analyzed. RESULTS: In the adult cases (n = 28), the overall survival rate at 1 year and 5 years were 66.1% and 57.3%, respectively. When compared with those adults without MRRT (n = 237), it was significantly worse. In the 7 pediatric cases, the overall survival rate at 1 and 5 years were both 83.3%. Three adult recipients died of nonaneurysm cerebral hemorrhage after 1 year and 1 adult recipient died of acute heart failure after 7 months. In adult recipients with MRRT, graft weight versus standard liver volume, and duration and blood loss in LTA surgery were associated with poor outcomes after LD LTA. Multivariate analysis revealed that MRRT was highest hazard ratio on patient survival after LD LTA. CONCLUSIONS: Early post-LD LTA mortality was higher in patients with MRRT than in those without MRRT with characteristic causes. Smaller grafts for size and a complicated surgery were associated with poor outcome after LD LTA. Thus, LD LTA in adult patients on MRRT should be carefully treated with meticulous postoperative management and follow up. PMID- 27500263 TI - Kinetics of Alloantigen-Specific Regulatory CD4 T Cell Development and Tissue Distribution After Donor-Specific Transfusion and Costimulatory Blockade. AB - BACKGROUND: The influence of donor-side regulation toward recipient antigens on graft outcome is poorly understood. METHODS: Because this influence might be due in part to the accumulation of tissue-resident memory T cells in the donor organ, we used a standard murine tolerization model (donor-specific transfusion plus CD40L blockade) to determine the kinetics of development and peripheralization of allospecific regulatory T cell in lymphoid tissues and liver, a secondary lymphoid organ used in transplantation. RESULTS: We found that donor-specific transfusion and CD40L blockade leads to a progressive and sustained T regulatory allospecific response. The cytokines IL10, TGFbeta, and IL35 all contributed to the regulatory phenomenon as determined by trans vivo delayed hypersensitivity assay. Unexpectedly, an early and transient self-specific regulatory response was found as well. Using double reporter mice (forkhead box p 3 [Foxp3]-yellow fluorescent protein, Epstein-Barr virus-induced gene 3 [Ebi3]-TdTomRed), we found an increase in Foxp3+CD25+ regulatory T (Treg) cells paralleling the regulatory response. The Ebi3+ CD4 T cells (IL35-producing) were mainly classic Treg cells (Foxp3+CD25+), whereas TGFbeta+ CD4 T cells are mostly Foxp3-negative, suggesting 2 different CD4 Treg cell subsets. Liver-resident TGFbeta+ CD4 T cells appeared more rapidly than Ebi3-producing T cells, whereas at later timepoints, the Ebi3 response predominated both in lymphoid tissues and liver. CONCLUSIONS: The timing of appearance of donor organ resident Treg cell subsets should be considered in experiments testing the role of bidirectional regulation in transplant tolerance. PMID- 27500265 TI - Kidney Transplant Outcomes After Primary, Repeat and Kidney After Nonrenal Solid Organ Transplantation: A Single-Center Experience. AB - BACKGROUND: Improvements in renal allograft outcomes have permitted kidney transplantation after prior kidney allograft failure as well as after nonrenal solid organ transplantation. This study compares renal allograft outcomes in the 3 groups, that is, primary, repeat, and kidney after nonrenal solid organ transplantation, where transplant group was coded as a time-dependent variable. METHODS: We retrospectively reviewed registry data for kidney transplant recipients at University of Pittsburgh Medical Center from January 2000 to December 2011. We compared overall graft survival between the 3 groups using Cox regression modeling. We calculated 1-, 3-, and 5-year graft survival and half lives for each group where feasible. RESULTS: The study cohort (N = 2014) consisted of group A (primary kidney transplant, n = 1578, with 7923.2 years of follow-up time), group B (repeat kidney transplant, n = 314, with 1566.7 years of follow-up time) and group C (kidney post-nonrenal solid organ transplant, n = 176, with 844.8 years of follow-up time). Of the 1578 patients in the primary kidney transplant group, 74 later received a repeat transplant and thus also have follow-up counted in the repeat kidney transplant group. The median follow-up was 56, 53, and 55 months, respectively. The 5-year actuarial and death-censored graft survival was 68.69%, 68.79%, and 66.48% and 65.53%, 67.68%, and 62.92%, respectively (P = 0.70). There was no difference in overall graft survival in the Cox-adjusted analysis (group B: odds ratio, 1.02; 95% confidence interval, 0.84 1.26; P = 0.79; group C: odds ratio, 0.96; 95% confidence interval, 0.75-1.23; P = 0.76). CONCLUSIONS: The adjusted kidney graft survivals in the 3 groups were similar. PMID- 27500266 TI - Results of the TOP Study: Prospectively Randomized Multicenter Trial of an Ex Vivo Tacrolimus Rinse Before Transplantation in EDC Livers. AB - BACKGROUND: Organ shortage results in the transplantation of extended donor criteria (EDC) livers which is associated with increased ischemia-reperfusion injury (IRI). Experimental studies indicate that an organ rinse with the calcineurin inhibitor tacrolimus before implantation protects against IRI. The tacrolimus organ perfusion study was initiated to examine the effects of ex vivo tacrolimus perfusion on IRI in transplantation of EDC livers. METHODS: A prospective randomized multicenter trial comparing ex vivo perfusion of marginal liver grafts (>=2 EDC according to Eurotransplant manual) with tacrolimus (20 ng/mL) or histidine-tryptophane-ketoglutarate solution (control) was carried out at 5 German liver transplant centers (Munich Ludwig-Maximilians University, Berlin, Heidelberg, Mainz, Regensburg) between October 2011 and July 2013. Primary endpoint was the maximum alanine transaminase (ALT) level within 48 hours after transplantation. Secondary endpoints were aspartate transaminase (AST), prothrombine ratio, and graft-patient survival within an observation period of 1 week. After an interim analysis, the study was terminated by the scientific committee after the treatment of 24 patients (tacrolimus n = 11, Control n = 13). RESULTS: Tacrolimus rinse did not reduce postoperative ALT peaks compared with control (P = 0.207; tacrolimus: median, 812; range, 362-3403 vs control: median, 652; range, 147-2034). Moreover, ALT (P = 0.100), prothrombine ratio (P = 0.553), and bilirubin (P = 0.815) did not differ between the groups. AST was higher in patients treated with tacrolimus (P = 0.011). Survival was comparable in both groups (P > 0.05). CONCLUSIONS: Contrary to experimental findings, tacrolimus rinse failed to improve the primary endpoint of the study (ALT). Because 1 secondary endpoint (AST) was even higher in the intervention group, the study was terminated prematurely. Thus, tacrolimus rinse cannot be recommended in transplantation of EDC livers. PMID- 27500267 TI - Characterizing the Mechanistic Pathways of the Instant Blood-Mediated Inflammatory Reaction in Xenogeneic Neonatal Islet Cell Transplantation. AB - INTRODUCTION: The instant blood-mediated inflammatory reaction (IBMIR) causes major loss of islets after transplantation and consequently represents the initial barrier to survival of porcine neonatal islet cell clusters (NICC) after xenotransplantation. METHODS: This study used novel assays designed to characterize the various immunologic components responsible for xenogeneic IBMIR to identify initiators and investigate processes of IBMIR-associated coagulation, complement activation and neutrophil infiltration. The IBMIR was induced in vitro by exposing NICC to platelet-poor or platelet-rich human plasma or isolated neutrophils. RESULTS: We found that xenogeneic IBMIR was characterized by rapid, platelet-independent thrombin generation, with addition of platelets both accelerating and exacerbating this response. Platelet-independent complement activation was observed as early as 30 minutes after NICC exposure to plasma. However, membrane attack complex formation was not observed in NICC histopathology sections until after 60 minutes. We demonstrated for the first time that NICC-mediated complement activation was necessary for neutrophil activation in the xenogeneic IBMIR setting. Finally, using the Seahorse extracellular flux analyzer, we identified substantial loss of islet function (up to 40%) after IBMIR with surviving NICC showing evidence of mitochondrial damage. CONCLUSIONS: This study used novel assays to describe multiple key pathways by which xenogeneic IBMIR causes islet destruction, allowing further refinement of future interventions aimed at resolving the issue of IBMIR in xenotransplantation. PMID- 27500268 TI - Detecting Renal Allograft Inflammation Using Quantitative Urine Metabolomics and CXCL10. AB - BACKGROUND: The goal of this study was to characterize urinary metabolomics for the noninvasive detection of cellular inflammation and to determine if adding urinary chemokine ligand 10 (CXCL10) improves the overall diagnostic discrimination. METHODS: Urines (n = 137) were obtained before biopsy in 113 patients with no (n = 66), mild (borderline or subclinical; n = 58), or severe (clinical; n = 13) rejection from a prospective cohort of adult renal transplant patients (n = 113). Targeted, quantitative metabolomics was performed with direct flow injection tandem mass spectrometry using multiple reaction monitoring (ABI 4000 Q-Trap). Urine CXCL10 was measured by enzyme-linked immunosorbent assay. A projection on latent structures discriminant analysis was performed and validated using leave-one-out cross-validation, and an optimal 2-component model developed. Chemokine ligand 10 area under the curve (AUC) was determined and net reclassification index and integrated discrimination index analyses were performed. RESULTS: PLS2 demonstrated that urinary metabolites moderately discriminated the 3 groups (Cohen kappa, 0.601; 95% confidence interval [95% CI], 0.46-0.74; P < 0.001). Using binary classifiers, urinary metabolites and CXCL10 demonstrated an AUC of 0.81 (95% CI, 0.74-0.88) and 0.76 (95% CI, 0.68-0.84), respectively, and a combined AUC of 0.84 (95% CI, 0.78-0.91) for detecting alloimmune inflammation that was improved by net reclassification index and integrated discrimination index analyses. Urinary CXCL10 was the best univariate discriminator, followed by acylcarnitines and hexose. CONCLUSIONS: Urinary metabolomics can noninvasively discriminate noninflamed renal allografts from those with subclinical and clinical inflammation, and the addition of urine CXCL10 had a modest but significant effect on overall diagnostic performance. These data suggest that urinary metabolomics and CXCL10 may be useful for noninvasive monitoring of alloimmune inflammation in renal transplant patients. PMID- 27500270 TI - The Effect of Mycophenolate Mofetil on Early Wound Healing in a Rodent Model. AB - BACKGROUND: Immunosuppressant agents are inevitable for solid organ recipients, but may have a negative effect on wound healing that is difficult to measure because of clinical use of a polydrug regime. The evidence on mycophenolate mofetil (MMF) is scarce and contradictory. This study aims to investigate the effect of MMF administration on wound healing. METHODS: Ninety-six male Wistar rats divided into 4 groups underwent anastomotic construction in ileum and colon at day 0. Three groups received daily oral doses of 20 or 40 mg/kg MMF or saline (control group) from day 0 until the end of the experiment. Half of each group was analyzed after 3 days and half after 7 days. Another group started the medication 3 days after the laparotomy and was analyzed after 7 days, half of this group received 20 mg/kg and half 40 mg/kg MMF. Wound strength in anastomoses and in the abdominal wall was measured using bursting pressure, breaking strength, and histology. Trough levels were measured. RESULTS: Significant differences in wound strength were seen in ileum tissue after 3 days, which surprisingly showed a stronger anastomosis in the experimental groups. Bursting pressure as well as breaking strength was higher in the low-dose and high-dose MMF group compared with the control group. A negative effect was measured in abdominal wall tissue for the highest-dose group, which disappeared when the medication was delayed for 3 days. Histology showed poorer bridging of the submucosal layer and more polymorphonuclear cell infiltration in the ileum specimens of the control group compared with the treatment groups. CONCLUSIONS: As a single agent in a preclinical wound healing model in the rat, MMF has no negative effect on healing of bowel anastomoses but might have a negative effect on the healing of abdominal wall. PMID- 27500269 TI - Standardized Outcomes in Nephrology-Transplantation: A Global Initiative to Develop a Core Outcome Set for Trials in Kidney Transplantation. AB - BACKGROUND: Although advances in treatment have dramatically improved short-term graft survival and acute rejection in kidney transplant recipients, long-term graft outcomes have not substantially improved. Transplant recipients also have a considerably increased risk of cancer, cardiovascular disease, diabetes, and infection, which all contribute to appreciable morbidity and premature mortality. Many trials in kidney transplantation are short-term, frequently use unvalidated surrogate endpoints, outcomes of uncertain relevance to patients and clinicians, and do not consistently measure and report key outcomes like death, graft loss, graft function, and adverse effects of therapy. This diminishes the value of trials in supporting treatment decisions that require individual-level multiple tradeoffs between graft survival and the risk of side effects, adverse events, and mortality. The Standardized Outcomes in Nephrology-Transplantation initiative aims to develop a core outcome set for trials in kidney transplantation that is based on the shared priorities of all stakeholders. METHODS: This will include a systematic review to identify outcomes reported in randomized trials, a Delphi survey with an international multistakeholder panel (patients, caregivers, clinicians, researchers, policy makers, members from industry) to develop a consensus-based prioritized list of outcome domains and a consensus workshop to review and finalize the core outcome set for trials in kidney transplantation. CONCLUSIONS: Developing and implementing a core outcome set to be reported, at a minimum, in all kidney transplantation trials will improve the transparency, quality, and relevance of research; to enable kidney transplant recipients and their clinicians to make better-informed treatment decisions for improved patient outcomes. PMID- 27500271 TI - A Proposal for Early Dosing Regimens in Heart Transplant Patients Receiving Thymoglobulin and Calcineurin Inhibition. AB - There is currently no consensus regarding the dose or duration of rabbit antithymocyte globulin (rATG) induction in different types of heart transplant patients, or the timing and intensity of initial calcineurin inhibitor (CNI) therapy in rATG-treated individuals. Based on limited data and personal experience, the authors propose an approach to rATG dosing and initial CNI administration. Usually rATG is initiated immediately after exclusion of primary graft failure, although intraoperative initiation may be appropriate in specific cases. A total rATG dose of 4.5 to 7.5 mg/kg is advisable, tailored within that range according to immunologic risk and adjusted according to immune monitoring. Lower doses (eg, 3.0 mg/kg) of rATG can be used in patients at low immunological risk, or 1.5 to 2.5 mg/kg for patients with infection on mechanical circulatory support. The timing of CNI introduction is dictated by renal recovery, varying between day 3 and day 0 after heart transplantation, and the initial target exposure is influenced by immunological risk and presence of infection. Rabbit antithymocyte globulin and CNI dosing should not overlap except in high-risk cases. There is a clear need for more studies to define the optimal dosing regimens for rATG and early CNI exposure according to risk profile in heart transplantation. PMID- 27500272 TI - Successful Kidney Transplantation in Children With a Compromised Inferior Vena Cava. AB - BACKGROUND: Children with a compromised inferior vena cava (IVC) were previously considered unsuitable for kidney transplantation because of the technical difficulties and the increased risk of graft thrombosis secondary to inadequate renal venous outflow. METHODS: We conducted a retrospective study of 11 transplants in 9 patients with end-stage renal disease and thrombosed IVCs who received adult kidney allografts between 2000 and 2015. The mean age at transplantation was 7.5 +/- 3.5 years. A pretransplant diagnosis of the IVC thrombosis was made in 7 patients by magnetic resonance imaging and computerized tomography, whereas there were 2 instances of intraoperative discovery of the IVC thrombosis. RESULTS: In the early cases, a kidney was placed intraperitoneally at the right iliac fossa with a venous anastomosis to the patent segment of the suprarenal IVC. After 2008, however, 6 adult-sized kidneys were subsequently placed in the left orthotopic position. Venous drainage was attained to the infrahepatic IVC (n = 3), left native renal vein (n = 2), and ascending lumbar vein (n = 1). Moreover, a venous bypass was created between the graft and the splenic vein in 2 children who showed high return pressure after the vessel was declamped. The mean glomerular filtration rate of the functioning 8 grafts 1 year posttransplant was 73.4 +/- 20.4 mL/min per 1.73 m(2). Of note, 6 of the grafts have been functioning well, with a mean follow-up of 66 months. Both 1- and 5 year graft survival were 81.8%. CONCLUSIONS: Transplantation into the left orthotopic position and the revascularization methods are an effective set of surgical techniques that could potentially be adopted as safe and reliable transplant approaches in children with IVC thrombosis. PMID- 27500273 TI - Alemtuzumab as Antirejection Therapy: T Cell Repopulation and Cytokine Responsiveness. AB - BACKGROUND: Alemtuzumab induction therapy in kidney transplant patients results in T cell depletion followed by slow immune reconstitution of memory T cells with reduced immune functions. The kinetics and functional characteristics of T cell reconstitution when alemtuzumab is given during immune activation, ie, as antirejection therapy, are unknown. METHODS: Patients (n = 12) with glucocorticoid-resistant or severe vascular kidney transplant rejection were treated with alemtuzumab. Flow cytometric analysis was performed on whole blood to measure cell division by the marker Ki-67, and cytokine responsiveness by IL-2 mediated and IL-7-mediated phosphorylation of signal transducer and activator of transcription 5 of T cells before and during the first year after rejection therapy. RESULTS: At 1 year after alemtuzumab antirejection therapy, the total T cell population recovered to baseline level. Repopulation of CD4+ and CD8+ T cells was associated with increased percentages of Ki-67+ proliferating T cells (P < 0.05). In addition, both populations showed a phenotypic shift toward relatively more memory T cells (P < 0.01). At the functional level, IL-7 reactivity of CD4+ memory T cells was diminished, reflected by a decreased capacity to phosphorylate signal transducer and activator of transcription 5 during the first 6 months after alemtuzumab treatment (P < 0.05), whereas reactivity to IL-2 was preserved. CD8+ T cells were affected in terms of both IL 2 and IL-7 responses (both P < 0.05). After reconstitution, relatively more regulatory T cells were present, and a relatively high proportion of Ki-67+ T cells was observed. CONCLUSIONS: Preliminary data from this small series suggest that alemtuzumab antirejection therapy induces homeostatic proliferation of memory and regulatory T cells with diminished responsiveness to the homeostatic cytokine IL-7. IL-2 responsiveness was affected in repopulated CD8+ T cells. PMID- 27500274 TI - Highly sensitive sequencing reveals dynamic modifications and activities of small RNAs in mouse oocytes and early embryos. AB - Small RNAs play important roles in early embryonic development. However, their expression dynamics and modifications are poorly understood because of the scarcity of RNA that is obtainable for sequencing analysis. Using an improved deep sequencing method that requires as little as 10 ng of total RNA or 50 oocytes, we profile small RNAs in mouse oocytes and early embryos. We find that microRNA (miRNA) expression starts soon after fertilization, and the mature miRNAs carried into the zygote by sperm during fertilization are relatively rare compared to the oocyte miRNAs. Intriguingly, the zygotic miRNAs display a marked increase in 3' mono- and oligoadenylation in one- to two-cell embryos, which may protect the miRNAs from the massive degradation taking place during that time. Moreover, bioinformatics analyses show that the function of miRNA is suppressed from the oocyte to the two-cell stage and appears to be reactivated after the two cell stage to regulate genes important in embryonic development. Our study thus provides a highly sensitive profiling method and valuable data sets for further examination of small RNAs in early embryos. PMID- 27500275 TI - Spontaneous Preterm Delivery, Particularly with Reduced Fetal Growth, is Associated with DNA Hypomethylation of Tumor Related Genes. AB - BACKGROUND: Preterm delivery and sub-optimal fetal growth are associated with each other and affect both mother and infant. Our aim was to determine (i) whether there are detectable differences in DNA methylation between early and late gestation and (ii) whether changes in DNA methylation from entry are associated with spontaneous preterm delivery with and without reduced fetal growth. METHODS: We conducted a case-control study nested within a large prospective cohort. Gene specific methylation was measured by Methyl-Profiler PCR Array in a Human Breast Cancer Signature Panel of 24 genes from maternal peripheral leukocytes genomic DNA at entry and 3rd trimester (sampled at 16 and 30 weeks of gestation, respectively). Clonal bisulfite DNA sequencing was performed to confirm the changes in selected genes (CYP1B1, GADD45A and CXCL12). Multivariable analysis was used for data analysis. RESULTS: There was significantly decrease in DNA methylation in 15 of 24 genes during the 3rd trimester in cases of spontaneous preterm delivery (n=23) as compared to the controls (n=19) (p<0.05-p<0.01 for each gene). Similar results were observed by bisulfite sequencing for 3 genes. The change in DNA methylation between late and early gestation was significantly different in cases (overall decrease in methylation was -4.0 +/- 1.5%) compared to the controls (overall increase in methylation was 12.6 +/- 2.19%, p<0.0001). A graded pattern of DNA methylation was observed in 15 genes. Cases who delivered preterm with reduced fetal growth had the lowest level of methylation, cases delivering preterm without reduced fetal growth were next and term controls were highest in methylation (p for trend <0.05 to p<0.01 for each gene). Cases of preterm delivery also had significantly lower dietary choline intake. CONCLUSIONS: These data suggest that epigenetic modification is associated with an increased risk of spontaneous preterm delivery, spontaneous preterm delivery with reduced fetal growth in particular. PMID- 27500276 TI - Number of Primary Care Visits Associated with Screening for Cervical Dysplasia among Women with HIV Infection in Harris County, Texas, United States of America. AB - Studies indicate that women with HIV infection in the United States are inadequately screened for cervical dysplasia. However, few of these studies have included women in the southern United States, where HIV incidence is now concentrated. We performed a retrospective chart review of women with HIV infection in two HIV clinics in a large southern metropolitan area. To describe screening rates among women in care, only women with >=2 primary care clinic visits during 2007 were included. We used log-binomial regression to estimate prevalence ratios and 95% confidence intervals of screening and to identify demographic, behavioral, and care-related factors associated with screening. Only 52% (258/498) of women in our study were screened during the year; only 29% (8/28) of women with <=50 CD4 cells/mm3. Factors associated with increased screening in unadjusted analyses included increased number of primary care visits (p<0.001), higher CD4 cell count (p<0.001), younger age (p=0.006) and Hispanic compared to non-Hispanic ethnicity (p<0.001). In adjusted analyses, women with >=4 primary care visits were 21% more likely to be screened than women with <4 visits (adjusted prevalence ratio = 1.21; 95% confidence interval: 1.02-1.44). Women with CD4 cell counts <200 cells/mm3 were less likely to be screened than women with CD4 counts >=350 cells/mm3 (adjusted prevalence ratio: 0.77; 95% confidence interval: 0.59- 1.00). Rates of screening for cervical dysplasia were lower than those seen in similar care settings in other geographic areas in the United States. The number of HIV primary care visits, which has been associated with retention in care, was associated with screening prevalence. Interventions designed to improve retention in care may improve screening rates for cervical dysplasia as well. PMID- 27500277 TI - Tuning the selectivity and sensitivity of an OmpG nanopore sensor by adjusting ligand tether length. AB - We have previously shown that a biotin ligand tethered to the rim of an OmpG nanopore can be used to detect biotin-binding proteins. Here, we investigate the effect of the length of the polyethylene glycol tether on the nanopore's sensitivity and selectivity. When the tether length was increased from 2 to 45 ethylene repeats, sensitivity decreased substantially for a neutral protein streptavidin and slightly for a positively charged protein (avidin). In addition, we found that two distinct avidin binding conformations were possible when using a long tether. These conformations were sensitive to the salt concentration and applied voltage. Finally, a longer tether resulted in reduced sensitivity due to slower association for a monoclonal anti-biotin antibody. Our results highlight the importance of electrostatic, electroosmotic and electrophoretic forces on nanopore binding kinetics and sensor readout. PMID- 27500278 TI - Predictive Modeling for Comfortable Death Outcome Using Electronic Health Records. AB - Electronic health record (EHR) systems are used in healthcare industry to observe the progress of patients. With fast growth of the data, EHR data analysis has become a big data problem. Most EHRs are sparse and multi-dimensional datasets and mining them is a challenging task due to a number of reasons. In this paper, we have used a nursing EHR system to build predictive models to determine what factors impact death anxiety, a significant problem for the dying patients. Different existing modeling techniques have been used to develop coarse-grained as well as fine-grained models to predict patient outcomes. The coarse-grained models help in predicting the outcome at the end of each hospitalization, whereas fine-grained models help in predicting the outcome at the end of each shift, therefore providing a trajectory of predicted outcomes. Based on different modeling techniques, our results show significantly accurate predictions, due to relatively noise-free data. These models can help in determining effective treatments, lowering healthcare costs, and improving the quality of end-of-life (EOL) care. PMID- 27500279 TI - Program ACTIVE II: Design and Methods for a Multi-Center Community-Based Depression Treatment for Rural and Urban Adults with Type 2 Diabetes. AB - OBJECTIVE: Depression affects one in four adults with type 2 diabetes (T2DM) and is associated with worsened diabetes complications, increased health care costs and early mortality. Rural and low-income urban areas, including the Appalachian region, represent an epicenter of the T2DM epidemic. Program ACTIVE II is a comparative effectiveness treatment trial designed to test whether a combination of cognitive behavioral therapy (CBT) and community-based exercise (EXER) will offer greater improvements in diabetes and depression outcomes compared to individual treatment approaches and usual care (UC). The secondary aims are to assess changes in cardiovascular risk factors across groups and to conduct a cost effectiveness analysis of predicted incidence of cardiovascular complications across groups. METHODS: The study is a 2-by-2 factorial randomized controlled trial consisting of 4 treatment groups: CBT alone, EXER alone, combination of CBT and EXER, and UC. Adults with T2DM for > 1 year and who meet DSM-IVTR criteria for Major Depressive Disorder (MDD) are eligible to participate at two rural Appalachian sites (southeastern Ohio and West Virginia) and one urban site (Indianapolis). This type II behavioral translation study uses a community engaged research (CEnR) approach by incorporating community fitness centers and mental health practices as interventionists. CONCLUSIONS: This is the first study to evaluate the comparative effectiveness of combined CBT and exercise in the treatment of depression using community-based intervention delivery. This approach may serve as a national model for expanding depression treatment for patients with T2DM. PMID- 27500280 TI - Adenosine kinase deficiency with neurodevelopemental delay and recurrent hepatic dysfunction: A case report. AB - Hypermethioninemia may be benign, present as a nonspecific sign of nongenetic conditions such as liver failure and prematurity, or a severe, progressive inborn error of metabolism. Genetic causes of hypermethioninemia include mitochondrial depletion syndromes caused by mutations in the MPV17 and DGUOK genes and deficiencies of cystathionine beta-synthase, methionine adenosyltransferase types I and III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase, citrin, fumarylacetoacetate hydrolase, and adenosine kinase. Here we present a 3-year old girl with a history of poor feeding, irritability, respiratory infections, cholestasis, congenital heart disease, neurodevelopmental delay, hypotonia, sparse hair, facial dysmorphisms, liver dysfunction, severe hypermethioninemia and mild homocystinemia. Genetic analysis of the adenosine kinase (ADK) gene revealed a previously unreported variant (c.479-480 GA>TG) resulting in a stop codon (p.E160X) in ADK. A methionine-restricted diet normalized the liver function test results and improved her hypotonia. PMID- 27500281 TI - Interferons and HIV Infection: The Good, the Bad, and the Ugly. AB - Whether type I interferons (IFNs) hinder or facilitate HIV disease progression is controversial. Type I IFNs induce the production of restriction factors that protect against mucosal HIV/SIV acquisition and limit virus replication once systemic infection is established. However, type I IFNs also increase systemic immune activation, a predictor of poor CD4+ T-cell recovery and progression to AIDS, and facilitate production and recruitment of target CD4+ T cells. In addition, type I IFNs induce CD4+ T-cell apoptosis and limit antigen-specific CD4+ and CD8+ T-cell responses. The outcomes of type I IFN signaling may depend on the timing of IFN-stimulated gene upregulation relative to HIV exposure and infection, local versus systemic type I IFN-stimulated gene expression, and the subtype of type I IFN evaluated. To date, most interventional studies have evaluated IFNalpha2 administration largely in chronic HIV infection, and few have evaluated the effects on tissues or the HIV reservoir. Thus, whether the effect of type I IFN signaling on HIV disease is good, bad, or so complicated as to be ugly remains a topic of hot debate. PMID- 27500282 TI - Rosuvastatin Decreases Intestinal Fatty Acid Binding Protein (I-FABP), but Does Not Alter Zonulin or Lipopolysaccharide Binding Protein (LBP) Levels, in HIV Infected Subjects on Antiretroviral Therapy. AB - INTRODUCTION: Altered gastrointestinal (GI) barrier integrity and subsequent microbial translocation may contribute to immune activation in HIV infection. We have reported that rosuvastatin improved several markers of immune activation in HIV+ participants, but the effect of statin treatment on markers of GI barrier dysfunction is unknown. METHODS: SATURN-HIV is a randomized, double-blind, placebo-controlled trial assessing the effect of rosuvastatin (10mg/daily) on markers of cardiovascular disease, inflammation, and immune activation in ART treated patients. Gut-barrier integrity was assessed by the surrogate markers intestinal fatty acid binding protein (I-FABP), a marker of enterocyte death, and zonulin-1, a marker of gut epithelial cell function. Levels of lipopolysaccharide binding protein (LBP) were measured as a marker of microbial translocation. RESULTS: Rosuvastatin significantly reduced levels of I-FABP during the treatment period compared to the placebo. There was no effect of rosuvastatin treatment on levels of zonulin or LBP. Baseline levels of LBP were directly related to several markers of immune activation in samples from all participants, including soluble CD163, IP-10, VCAM-1, TNFR-II, and the proportion of CD4+ and CD8+ T cells expressing CD38 and HLA-DR. Many of these relationships, however, were not seen in the statin arm alone at baseline or over time, as inflammatory markers often decreased and LBP levels were unchanged. CONCLUSIONS: Forty-eight weeks of rosuvastatin treatment reduced levels of I-FABP, but did not affect levels of zonulin or LBP. The reduction in levels of inflammatory markers that we have reported with rosuvastatin treatment is likely mediated through other mechanisms not related to gut integrity or microbial translocation. PMID- 27500283 TI - Medicare and Private Insurance Variations in New Medical Technology: The Case of Drug Eluting Stents. AB - IMPORTANCE: Little is known about the geographic and hospital variations of the new medical technologies in Medicare. Even less is known about these variations for the privately insured. OBJECTIVE: To examine geographic and hospital variations in the diffusion of drug eluting stents, comparing Medicare and privately insured populations. DESIGN: Retrospective analyses of discharges from the State Inpatient Databases for 11 states (2004-2005) supplemented with data on hospital characteristics from the American Hospital Association Annual Survey. SETTING/PARTICIPANTS: Study sample included discharges with percutaneous coronary intervention (PCI) procedures that involved a cardiac stent. EXPOSURE: Insurance type: Medicare versus private insurance. MAIN OUTCOME: Use of a drug eluting stent during the PCI was our outcome variable. We estimated linear probability models at the discharge level that related our outcome variable to patient and hospital characteristics separately for Medicare and private insurance. To examine variations across hospital referral regions (HRRs) and across hospitals, our models included HRR and hospital indicators respectively. RESULTS: Our analysis included 390,649 records (237,991 Medicare, 152,658 private insurance). We found large HRR variations in the use of drug eluting stents in 2004 for both payer types, the year after drug eluting stents were approved (adjusted CoV: 0.35 (Medicare); 0.24 (Private Insurance)). We also found large hospital variations in 2004 (adjusted CoV: 0.32 (Medicare); 0.29 (Private Insurance)). Between 2004 and 2005, adjusted HRR and hospital variations decreased across both payer types, suggesting that practice styles converged as the drug eluting stents diffused and became more common. Finally, adjusted drug eluting stent rates were highly correlated both at the HRR and hospital level across payer types. CONCLUSION: Our findings are consistent with the hypothesis that private insurance closely follows the lead of Medicare in terms of medical technology coverage and reimbursement. PMID- 27500284 TI - Gender Differences in Community-acquired Meningitis in Adults: Clinical Presentations and Prognostic Factors. AB - Community-acquired meningitis is a serious disease that is associated with high morbidity and mortality. The purpose of this study was to investigate the gender differences involved with the clinical presentations of and prognostic factors for this disease. We conducted a retrospective study of 619 adults diagnosed with community-acquired meningitis in Houston, Texas, who were hospitalized between 2005 and 2010. Patients were categorized as male or female. Those who were evaluated to have a Glasgow Outcome Scale score of four or less were classified to have an adverse clinical outcome. Males consisted of 47.2% (292/619) of the total cohort, and more often presented with coexisting medical conditions, fever, abnormal microbiology results, and abnormalities on head computed tomography. Females more often presented with nuchal rigidity. On logistic regression, fever, CSF glucose <45 mg/dL, and an abnormal neurological examination were predictors of an adverse outcome in male patients, while age greater than 60 years and an abnormal neurological examination were associated with a poor prognosis in female patients. Thus, community-acquired meningitis in males differs significantly from females in regards to comorbidities, presenting symptoms and signs, abnormal laboratory and imaging analysis, and predictors of adverse clinical outcomes. PMID- 27500285 TI - Closing the Gap: Supporting Patients' Transition to Self-Management after Hospitalization. AB - Patients going home after a hospitalization face many challenges. This transition period exposes patients to unnecessary risks related to inadequate preparation prior to leaving the hospital, potentially leading to errors and patient harm. Although patients engaging in self-management have better health outcomes and increased self-efficacy, little is known about the processes in place to support and develop these skills for patients leaving the hospital. Through qualitative interviews and observations of 28 patients during and after their hospitalizations, we explore the challenges they face transitioning from hospital care to self-management. We identify three key elements in this process: knowledge, resources, and self-efficacy. We describe how both system and individual factors contribute to breakdowns leading to ineffective patient management. This work expands our understanding of the unique challenges faced by patients during this difficult transition and uncovers important design opportunities for supporting crucial yet unmet patient needs. PMID- 27500287 TI - Predictive Modeling for End-of-Life Pain Outcome using Electronic Health Records. AB - Electronic health record (EHR) systems are being widely used in the healthcare industry nowadays, mostly for monitoring the progress of the patients. EHR data analysis has become a big data problem as data is growing rapidly. Using a nursing EHR system, we built predictive models for determining what factors influence pain in end-of-life (EOL) patients. Utilizing different modeling techniques, we developed coarse-grained and fine-grained models to predict patient pain outcomes. The coarse-grained models help predict the outcome at the end of each hospitalization, whereas fine-grained models help predict the outcome at the end of each shift, thus providing a trajectory of predicted outcomes over the entire hospitalization. These models can help in determining effective treatments for individuals and groups of patients and support standardization of care where appropriate. Using these models may also lower the cost and increase the quality of end-of-life care. Results from these techniques show significantly accurate predictions. PMID- 27500286 TI - Preliminary Evidence for Effectiveness of Resourcefulness Training in Women Dementia Caregivers. AB - Nearly 10 million women in the U.S. are caregivers for an elder with dementia, which often produces overwhelming stress and adversely affects their health. Resourcefulness training (RT) may promote the caregiver's optimal health and continue in their caregiving role. This pilot trial of 138 women dementia caregivers examined the effectiveness of RT on perceived stress, depressive cognitions, and negative emotions over time. Caregivers were first randomized to RT or no RT and then further randomized into random versus choice conditions followed by assignment to the journal or recorder methods, thus creating eight groups. We examined differences on perceived stress, depressive cognitions, and negative emotions between groups: 1) RT versus no-RT, 2) choice versus random condition; and 3) journaling versus recording. Significant time by group interactions were found on stress (F=4.36, p<.05), depressive cognitions (F=10.93, p<.001), and negative emotions (F=20.48, p<.001) in the RT versus no RT group. No differences were found between the random versus choice conditions or the journaling versus recording methods for practicing the RT skills. The results provide evidence for the effectiveness of RT for decreasing stress, depressive cognitions, and negative emotions in women caregivers of elders with dementia. The findings also suggest the need for further examination of the effects of allowing caregivers to choose a method for practicing RT in larger samples if caregivers of elders with dementia. PMID- 27500288 TI - Capturing the transient species at the electrode-electrolyte interface by in situ dynamic molecular imaging. AB - In situ time-resolved identification of interfacial transient reaction species were captured using imaging mass spectrometry, leading to the discovery of more complex elementary electrode reactions and providing an unprecedented understanding of the reaction mechanism on the electrode surface and solid electrolyte interface using dynamic molecular imaging. PMID- 27500289 TI - Catalytic enantio- and diastereoselective Mannich reaction of alpha-substituted isocyanoacetates and ketimines. AB - The highly diastereo- and enantioselective Mannich addition/cyclisation reaction of alpha-substituted isocyanoacetate ester pronucleophiles and (hetero)aryl and alkyl methyl ketone-derived ketimines using a silver acetate and a cinchona derived amino phosphine binary catalyst system is reported. PMID- 27500290 TI - Enhancing alkaline hydrogen evolution reaction activity through Ni-Mn3O4 nanocomposites. AB - Developing efficient, stable and cost-effective electrocatalysts towards hydrogen production in alkaline environments is vital to improve energy efficiency for water splitting. In this work, we prepared Ni-Mn3O4 nanocomposites on Ni foam which exhibit an excellent hydrogen evolution reaction catalytic activity with a current density (j) of 10 mA cm(-2) at an overpotential (eta) of 91 mV and show good stability in an alkaline medium. PMID- 27500291 TI - Plasmonic coupling of dual gold nanoprobes for SERS imaging of sialic acids on living cells. AB - This work reports a benzoic group functionalized gold nanoflower as a bridge probe for both recognition of target sialic acids and assembly of poly(N acetylneuraminic acid) modified gold nanoparticles, which leads to plasmonic coupling of two kinds of gold nanoprobes in a single-core-multi-satellite nanostructure to produce a sensitive surface-enhanced Raman scattering (SERS) signal for the imaging of sialic acids on living cells. PMID- 27500292 TI - Pd-Catalyzed oxidative isomerization of propargylic acetates: highly efficient access to alpha-acetoxyenones via alkenyl Csp(2)-O bond-forming reductive elimination from Pd(IV). AB - A Pd(ii)/(iv)-catalyzed oxidative isomerization of propargylic acetates developed for the synthesis of polysubstituted alkenyl acetates is described. The reductive elimination of alkenyl Csp(2)-OAc bonds from Pd(IV) intermediates is achieved. Mechanistic studies indicate that the reaction mechanism consists of trans acetoxypalladation of a triple bond, isomerization, oxidative addition with PhI(OAc)2 and alkenyl C-OAc bond reductive elimination. PMID- 27500293 TI - Advances in levodopa therapy for Parkinson disease. PMID- 27500294 TI - [Comment on "Surgical ablation of atrial fibrillation during mitral-valve surgery"]. PMID- 27500295 TI - [Not Available]. PMID- 27500296 TI - [Not Available]. PMID- 27500297 TI - [Not Available]. PMID- 27500298 TI - Case report of aripiprazole in the treatment of adolescent stuttering. PMID- 27500299 TI - Author Response. PMID- 27500300 TI - Author Response. PMID- 27500302 TI - Never walk alone: reflecting on Hillsborough. PMID- 27500301 TI - Women's values and preferences and health state valuations for thromboprophylaxis during pregnancy: A cross-sectional interview. AB - BACKGROUND: Pregnant women with prior venous thromboembolism (VTE) are at risk of recurrence. Prophylaxis with low molecular weight heparin (LWMH) reduces that risk but is inconvenient, costly, and may be associated with increased risks of obstetrical bleeding. The views of pregnant women, crucial when making prophylaxis recommendations, are currently unknown. METHODS: Cross-sectional international multicenter study. We included women with a history of VTE who were either pregnant or planning pregnancy. We provided information regarding risk of VTE recurrence with and without LMWH and determined participant's willingness to receive LMWH prophylaxis through direct choice exercises, preference-elicitation (utilities) for health states (e.g. burden of LMWH prophylaxis), and a probability trade-off exercise. RESULTS: Of 123 women, more women at high risk than those at low risk of recurrence (86.4% vs. 60.0%; p = 0.003) chose to use LMWH. The median threshold reduction in VTE at which women were willing to accept use of LMWH, given a 16% risk of VTE without prophylaxis, was 3% (interquartile range: 1 to 6). Participants' evaluation of the relevant health states varied widely and was unrelated to their direct choices to use or not use LMWH. CONCLUSIONS: Although the majority of women with a previous VTE, pregnant or planning pregnancy choose to take LMWH during pregnancy, a minority -and in low risk women, a large minority- do not. Our results highlight the need for individualized shared decision-making (SDM) in the clinical encounter, and for guideline panels to make weak recommendations in favor of LMWH that make clear the need for SDM. PMID- 27500304 TI - The Perioperative Highway Code. SIGNS--Safety Initiative Group for National Sinage. PMID- 27500303 TI - Ambassador for patient safety and the promotion, protection and support of cardiac theatre staff. PMID- 27500305 TI - Equality issues. PMID- 27500306 TI - Large Scale Flow-Mediated Formation and Potential Applications of Surface Nanodroplets. AB - Microscopic droplets located on a solid substrate in contact with an immiscible liquid promise a broad range of applications in miniaturized analytical techniques, fabrication of antireflective coatings, high-resolution near-field imaging techniques, and many others. A simple method of producing oil nanodroplets with desirable morphology is a bottom-up approach called solvent exchange, where nanodroplets nucleate and grow, as a good solvent of oil is displaced by a poor solvent. In this work, we have achieved the production of surface nanodroplets over a large surface area on planar or curved surfaces, guided by the principles of the solvent exchange. The droplet size is uniform over the entire surface of a planar or curved substrate and tunable. The production rate is extremely high at 10(6) nanodroplets per second. This advance in the nanodroplet production provides a general platform for droplet-based applications. Here we demonstrate that the application of surface nanodroplets in microextraction of hydrophobic solute (dye) from its highly diluted aqueous solution and in situ detection of the dye in a simple process, and in fabrication of highly ordered array of microlens arrays and polymer-capped microstructures by simple processes. PMID- 27500307 TI - Hypoxic Preconditioning Improves the Therapeutic Potential of Aging Bone Marrow Mesenchymal Stem Cells in Streptozotocin-Induced Type-1 Diabetic Mice. AB - Insulin replacement is the current therapeutic option for type-1 diabetes. However, exogenous insulin cannot precisely represent the normal pattern of insulin secretion. Another therapeutic strategy is transplantation of pancreatic islets, but this is limited by immune rejection, intrinsic complications, and lack of donor availability. Stem cell therapy that results in the regeneration of insulin-producing cells represents an attractive choice. However, with advancing age, stem cells also undergo senescence, which leads to changes in the function of various cellular processes that result in a decrease in the regeneration potential of these aging stem cells. In this study, the effect of young and aging mesenchymal stem cells (MSCs) on the regeneration of pancreatic beta cells in streptozotocin (STZ)-induced type-1 diabetic mice was observed after hypoxic preconditioning. Hypoxia was chemically induced by 2, 4-dinitrophenol (DNP). Plasma insulin and glucose levels were measured at various time intervals, and pancreatic sections were analyzed histochemically. The effect of DNP was also analyzed on apoptosis of MSCs by flow cytometry and on gene expression of certain growth factors by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). We observed that hypoxic preconditioning caused changes in the gene expression levels of growth factors in both young and aging MSCs. Young MSCs showed significant regeneration potential compared with the aging cells in vivo. However, hypoxic preconditioning was able to improve the regeneration potential of aging MSCs. It is concluded from the present study that the regeneration potential of aging MSCs into pancreatic beta-cells can be enhanced by hypoxic preconditioning, which causes changes in the gene expression of certain growth factors. PMID- 27500308 TI - Photooxidation of Tryptophan and Tyrosine Residues in Human Serum Albumin Sensitized by Pterin: A Model for Globular Protein Photodamage in Skin. AB - Human serum albumin (HSA) is the most abundant protein in the circulatory system. Oxidized albumin was identified in the skin of patients suffering from vitiligo, a depigmentation disorder in which the protection against ultraviolet (UV) radiation fails because of the lack of melanin. Oxidized pterins, efficient photosensitizers under UV-A irradiation, accumulate in the skin affected by vitiligo. In this work, we have investigated the ability of pterin (Ptr), the parent compound of oxidized pterins, to induce structural and chemical changes in HSA under UV-A irradiation. Our results showed that Ptr is able to photoinduce oxidation of the protein in at least two amino acid residues: tryptophan (Trp) and tyrosine (Tyr). HSA undergoes oligomerization, yielding protein structures whose molecular weight increases with irradiation time. The protein cross linking, due to the formation of dimers of Tyr, does not significantly affect the secondary and tertiary structures of HSA. Trp is consumed in the photosensitized process, and N-formylkynurenine was identified as one of its oxidation products. The photosensitization of HSA takes place via a purely dynamic process, which involves the triplet excited state of Ptr. The results presented in this work suggest that protein photodamage mediated by endogenous photosensitizers can significantly contribute to the harmful effects of UV-A radiation on the human skin. PMID- 27500309 TI - Chemical composition and antimicrobial activity of fatty acid methyl ester of Quercus leucotrichophora fruits. AB - Natural fats and dietary oils are chief source of fatty acids and are well known to have antimicrobial activities against various microbes. The chemical composition and antimicrobial activities of fatty acids from fruits of white Oak (Quercus leucotrichophora) are yet unexplored and therefore the present study for the first time determines the fatty acid composition, and the antibacterial and antifungal activities of fatty acid methyl esters (FAME) of the white Oak plant found along the Himalayan region of Uttarakhand, India. The GCMS analysis revealed the presence of higher amount of saturated fatty acids than unsaturated fatty acids. FAME extract of fruits of Q. leucotrichophora demonstrated better antibacterial activity against Gram-positive bacteria than the Gram-negative bacteria. The present studies clearly establish the potential of the fruits of Q. leucotrichophora for use in soap, cosmetics and pharmaceutical industries. PMID- 27500310 TI - Using PacBio Long-Read High-Throughput Microbial Gene Amplicon Sequencing To Evaluate Infant Formula Safety. AB - Infant formula (IF) requires a strict microbiological standard because of the high vulnerability of infants to foodborne diseases. The current study used the PacBio single-molecule real-time (SMRT) sequencing platform to generate full length 16S rRNA-based bacterial microbiota profiles of 30 Chinese domestic and imported IF samples. A total of 600 species were identified, dominated by Streptococcus thermophilus, Lactococcus lactis, and Lactococcus piscium. Distinctive bacterial profiles were observed between the two sample groups, as confirmed with both principal coordinate analysis and multivariate analysis of variance. Moreover, the product whey protein nitrogen index (WPNI), representing the degree of preheating, negatively correlated with the relative abundances of the Bacillus genus. This study has demonstrated the application of the PacBio SMRT sequencing platform in assessing the bacterial contamination of IF products, which is of interest to the dairy industry for effective monitoring of microbial quality and safety during production. PMID- 27500311 TI - A Selective Galactose-Coumarin-Derived Galectin-3 Inhibitor Demonstrates Involvement of Galectin-3-glycan Interactions in a Pulmonary Fibrosis Model. AB - Synthesis of doubly 3-O-coumarylmethyl-substituted thiodigalactosides from bis-3 O-propargyl-thiodigalactoside resulted in highly selective and high affinity galectin-3 inhibitors. Mutant studies, structural analysis, and molecular modeling revealed that the coumaryl substituents stack onto arginine side chains. One inhibitor displayed efficacy in a murine model of bleomycin-induced lung fibrosis similar to that of a known nonselective galectin-1/galectin-3 inhibitor, which strongly suggests that blocking galectin-3 glycan recognition is an important antifibrotic drug target. PMID- 27500312 TI - Theoretical Modeling of the Chirality Discrimination of Enantiomers by Nanotubular Cyclic Peptides using Gas-Phase Photoelectron Spectroscopy: An ONIOM Spectroscopic Calculations. AB - In the present work, the chirality recognition of the enantiomers of a chiral molecule (1-phenyl-1-propanol) interacting with a nanotubular cyclic peptide (E type cyclic decapeptide) was investigated by their ionization in the gas phase, theoretically. The absolute energy difference between the interaction of the S- and R-enantiomer with the cyclic peptide, calculated at the M06-2X/6-311++G(d, p) level of theory, was 4.70 kcal.mol(-1). Two different schemes of "Our own N layered Integrated molecular Orbital and molecular Mechanics (ONIOM)" method such as (quantum mechanics (QM):molecular mechanics (MM)) and (QM:QM) were employed to study the effect of the interaction on the gas-phase ionization energies of the enantiomers and cyclic peptide, separately. The symmetry-adapted cluster/configuration interaction (SAC-CI) methodology was used for the calculation of the ionization energies. It was found that the difference between the interactions of R- and S-enantiomer with the cyclic peptide caused different changes in the photoelectron spectrum of each enantiomer so that these changes could be used for the chirality discrimination of the enantiomers in the gas phase. Similarly, the photoelectron spectrum of the cyclic peptide interacting with the R and S-enantiomer were calculated, separately, and it was observed that the difference in the interaction with the R- and S-enantiomer created different changes in the spectrum of cyclic peptide. Finally, it was shown that the difference in the interaction of cyclic peptide with the enantiomers of a chiral molecule in the gas phase can be used for the identification of enantiomers in the gas phase by the direct ionization. PMID- 27500314 TI - Octanuclear Heterobimetallic {Ni4Ln4} Assemblies Possessing Ln4 Square Grid [2 * 2] Motifs: Synthesis, Structure, and Magnetism. AB - Octanuclear heterobimetallic complexes, [Ln4Ni4(H3L)4(MU3-OH)4(MU2 OH)4]4Cl.xH2O.yCHCl3 (Dy(3+), x = 30.6, y = 2 (1); Tb(3+), x = 28, y = 0 (2) ; Gd(3+), x = 25.3, y = 0 (3); Ho(3+), x = 30.6, y = 3 (4)) (H5L = N1,N3-bis(6 formyl-2-(hydroxymethyl)-4-methylphenol)diethylenetriamine) are reported. These are assembled by the cumulative coordination action of four doubly deprotonated compartmental ligands, [H3L](2-), along with eight exogenous -OH ligands. Within the core of these complexes, four Ln(3+)'s are distributed to the four corners of a perfect square grid while four Ni(2+)'s are projected away from the plane of the Ln4 unit. Each of the four Ni(2+)'s possesses distorted octahedral geometry while all of the Ln(3+)'s are crystallographically equivalent and are present in an elongated square antiprism geometry. The magnetic properties of compound 3 are dominated by an easy-plane single-ion anisotropy of the Ni(2+) ions [DNi = 6.7(7) K] and dipolar interactions between Gd(3+) centers. Detailed ac magnetometry reveals the presence of distinct temperature-dependent out-of-phase signals for compounds 1 and 2, indicative of slow magnetic relaxation. Magnetochemical analysis of complex 1 implies the 3d and the 4f metal ions are engaged in ferromagnetic interactions with SMM behavior, while dc magnetometry of compound 2 is suggestive of an antiferromagnetic Ni-Tb spin-exchange with slow magnetic relaxation due to a field-induced level crossing. Compound 4 exhibits an easy plane single-ion anisotropy for the Ho(3+) ions and weak interactions between spin centers. PMID- 27500313 TI - Nucleophilic (Radio)Fluorination of alpha-Diazocarbonyl Compounds Enabled by Copper-Catalyzed H-F Insertion. AB - The copper-catalyzed H-F insertion into alpha-diazocarbonyl compounds is described using potassium fluoride (KF) and hexafluoroisopropanol. Access to complex alpha-fluorocarbonyl derivatives is achieved under mild conditions, and the method is readily adapted to radiofluorination with [(18)F]KF. This late stage strategy provides an attractive route to (18)F-labeled biomolecules. PMID- 27500315 TI - Current Resources for Evidence-Based Practice, September/October 2016. PMID- 27500316 TI - Thoracic dimples and dysmorphic features associated with a partial duplication and triplication of chromosome 12q24. PMID- 27500317 TI - Aminolevulinic Acid-Mediated Photodynamic Therapy Causes Cell Death in MG-63 Human Osteosarcoma Cells. AB - OBJECTIVE: The aim of this study was to test the efficacy of aminolevulinic acid mediated photodynamic therapy (PDT) against the human osteosarcoma cell line MG 63. BACKGROUND DATA: Osteosarcoma is the most common type of primary malignant bone tumor diagnosed in the United States among adolescents and children. Treatments for osteosarcoma often result in diminished limb use or amputation. Because ALA-mediated PDT exhibits dual specificity in the context of tumor killing, this therapy could represent a less invasive, but effective, treatment for this disease. MATERIALS AND METHODS: To assess ALA dark toxicity in MG-63 cells, cells were incubated with varying concentrations of ALA, and cell viability was determined by crystal violet assay. Protoporphyrin IX (PpIX) accumulation was assessed subsequent to ALA incubation at various concentrations using spectrofluorometry. Cell death subsequent to ALA-PDT was determined by illuminating cells at a wavelength of 635 nm at various light intensities subsequent to ALA incubation. Cell viability was assessed using the MTT assay. RESULTS: ALA dark toxicity was observed only at the highest concentrations of 2, 5, and 10 mM. Maximal PpIX concentration was observed at 0.5 and 1 mM ALA, subsequent to a 24-h incubation. Maximal cell death with minimal light toxicity was observed at 0.5 and 1 mM ALA after illumination with 0.6 and 3 J/cm(2) light. CONCLUSIONS: Collectively, our data indicate that ALA-PDT can result in the death of MG-64 human osteosarcoma cells in vitro. PMID- 27500318 TI - Angiogenic imbalance as a contributor to the pathophysiology of preeclampsia among black African women. AB - OBJECTIVE: The pathogenesis of preeclampsia remains unclear despite extensive research. Altered angiogenic balance has been hypothesized to play a significant role in the clinical manifestations of this syndrome. However this imbalance has not been investigated extensively among black African women. The aim of this study was to investigate the maternal levels of the angiogenic factors soluble vascular endothelial growth factor receptor 1 (sFLT1) and placental growth factor (PlGF) among black African women with preeclampsia. METHODS: A case control study was conducted in the Mthatha hospital complex in South Africa including 51 women with preeclampsia and 82 women with uncomplicated pregnancies. Blood samples were drawn from participants and serum was used to assess sFLT1, and PlGF levels quantified using specific enzyme linked immunosorbent assays. Non- parametric statistics were used for analysis. RESULTS: Black African women with preeclampsia were found to have significantly lower levels of PlGF (90.3 +/- 8.9 pg/ml versus 172.8 +/- 20.2 pg/ml; p < 0.01), higher sFLT1 (2087.3 +/- 200.1 pg/ml versus 1546.5 +/- 91.9 pg/ml; p < 0.01) and a higher sFLT1/PIGF ratio (66.8 +/- 18.7 versus 22.3 +/- 2.9; p < 0.01) compared to black African normotensive controls. CONCLUSION: The results support an altered angiogenic balance may contribute to the pathogenesis/pathophysiology of preeclampsia among black African women as reported in other populations. PMID- 27500319 TI - Testing the Efficacy of Pharmacological Agents in a Pericardial Target Delivery Model in the Swine. AB - To date, many pharmacological agents used to treat or prevent arrhythmias in open heart cases create undesired systemic side effects. For example, antiarrhythmic drugs administered intravenously can produce drops in systemic pressure in the already compromised cardiac patient. While performing open-heart procedures, surgeons will often either create a small port or form a pericardial cradle to create suitable fields for operation. This access yields opportunities for target pharmacological delivery (antiarrhythmic or ischemic preconditioning agents) directly to the myocardial tissue without undesired side effects. We have developed a swine model for testing pharmacological agents for target delivery within the pericardial fluid. While fully anesthetized, each animal was instrumented with a Swan-Ganz catheter as well as left and right ventricle pressure catheters, and pacing leads were placed in the right atrial appendage and the right ventricle. A medial sternotomy was then performed and a pericardial access cradle was created; a plunge pacing lead was placed in the left atrial appendage and a bipolar pacing lead was placed in the left ventricle. Utilizing a programmer and a cardiac mapping system, the refractory period of the atrioventricular node (AVN), atria and ventricles was determined. In addition, atrial fibrillation (AF) induction was produced utilizing a Grass stimulator and time in AF was observed. These measurements were performed prior to treatment, as well as 30 min and 60 min after pericardial treatment. Additional time points were added for selected studies. The heart was then cardiopleged and reanimated in a four chamber working mode. Pressure measurements and function were recorded for 1 hr after reanimation. This treatment strategy model allowed us to observe the effects of pharmacological agents that may decrease the incidence of cardiac arrhythmias and/or ischemic damage, during and after open-heart surgery. PMID- 27500320 TI - Genetic and Biochemical Approaches for In Vivo and In Vitro Assessment of Protein Oligomerization: The Ryanodine Receptor Case Study. AB - Oligomerization is often a structural requirement for proteins to accomplish their specific cellular function. For instance, tetramerization of the ryanodine receptor (RyR) is necessary for the formation of a functional Ca(2+) release channel pore. Here, we describe detailed protocols for the assessment of protein self-association, including yeast two-hybrid (Y2H), co-immunoprecipitation (co IP) and chemical cross-linking assays. In the Y2H system, protein self interaction is detected by beta-galactosidase assay in yeast co-expressing GAL4 bait and target fusions of the test protein. Protein self-interaction is further assessed by co-IP using HA- and cMyc-tagged fusions of the test protein co expressed in mammalian HEK293 cells. The precise stoichiometry of the protein homo-oligomer is examined by cross-linking and SDS-PAGE analysis following expression in HEK293 cells. Using these different but complementary techniques, we have consistently observed the self-association of the RyR N-terminal domain and demonstrated its intrinsic ability to form tetramers. These methods can be applied to protein-protein interaction and homo-oligomerization studies of other mammalian integral membrane proteins. PMID- 27500321 TI - Current Diagnosis and Management of Pelvic Fistulae in Women. AB - Pelvic fistulae are an abnormal communication among the genitourinary tract, the gastrointestinal tract, and the vagina or perineum. Genital tract fistulae have been described in the medical literature for the past several thousand years. Advancements in both the diagnosis and treatment of vaginal fistulae have been obtained over the past century as surgical interventions have become safer and surgical techniques have improved. The most common cause of fistulae worldwide is obstructed labor. In developed countries, fistulae most commonly occur after benign gynecologic surgery, but obstructed labor, malignancy, radiation exposure, and inflammatory bowel disease can also cause fistulae. Fistulae significantly affect quality of life. Diagnostic studies and radiologic imaging can help aid the diagnosis, but a thorough physical examination is the most important component in the evaluation and diagnosis of a fistula. Temporizing treatments are available to help ease patient suffering until surgical management can be performed. Surgical repairs can be performed using an abdominal, vaginal, or transanal approach. Although technically challenging, surgical repair is usually successful, but closure of the fistula tract does not guarantee continence of urine or feces, because there is often underlying damage to the bowel and bladder. PMID- 27500322 TI - Forceps, Simulation, and Social Media. PMID- 27500323 TI - Drilling Down on Maternal Mortality. PMID- 27500324 TI - What Is New in the Prevention of Preeclampsia?: Best Articles From the Past Year. AB - This month we focus on current research in prevention of preeclampsia. Dr. Norton discusses five recent publications, which are concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 27500325 TI - Connect the Dots-September 2016. PMID- 27500326 TI - Differences in Serum Human Chorionic Gonadotropin Rise in Early Pregnancy by Race and Value at Presentation. AB - OBJECTIVE: To assess whether variation in serum human chorionic gonadotropin (hCG) measures, used to assess early gestation viability, are associated with differences in clinical presentation and patient factors. METHOD: This retrospective cohort study included 285 women with first-trimester pain and bleeding and a pregnancy of unknown location for whom a normal intrauterine pregnancy was ultimately confirmed. Serial samples were collected at three U.S. sites and hCG changes were analyzed for differences by race, ethnicity, and clinical factors. A nonlinear, mixed-effects regression model was used assuming a random subject shift in the time axis. RESULTS: The hCG rise in symptomatic women with ongoing intrauterine pregnancy differs by patient factors and level at presentation. The 2-day minimum (first percentile) rise in hCG was faster when presenting hCG values were low and slower when presenting hCG value was high. African American women had a faster hCG rise (P<.001) compared with non-African American women. Variation in hCG curves was associated with prior miscarriage (P=.014), presentation of bleeding (P<.001), and pain (P=.002). For initial hCG values of less than 1,500, 1,500-3,000 and greater than 3,000 milli-international units/mL, the predicted 2-day minimal (first percentile) rise was 49%, 40%, and 33%, respectively. CONCLUSION: The rise of hCG levels in women with viable intrauterine pregnancies and symptoms of potential pregnancy failure varies significantly by initial value. Changes in hCG rise related to race should not affect clinical care. To limit interruption of a potential desired intrauterine pregnancy, a more conservative "cutoff" (slower rise) is needed when hCG values are high. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00194168. PMID- 27500327 TI - Unilateral Human Papillomavirus Infection and Cervical Dysplasia in a Patient With Two Cervices. AB - BACKGROUND: In a uterine didelphys with two cervices, cervical screening may not reveal the same abnormalities. CASE: We present a patient with a uterine didelphys with two cervices in a single vagina after resection of a longitudinal vaginal septum at age 12. She presented with abnormal Pap test results with the right and left cervices discordant from each other. Despite both cervices sharing stroma in the midline, her right cervix was negative for human papillomavirus (HPV) and dysplasia, while her left cervix was HPV positive with high-grade cervical dysplasia on an excisional specimen. CONCLUSION: Uterine didelphys with shared bilateral cervices will not necessarily share the same HPV status or have concordant dysplasia. PMID- 27500328 TI - Reverse Vesicouterine Fold Dissection for Laparoscopic Hysterectomy After Prior Cesarean Deliveries. AB - BACKGROUND: Cesarean delivery adhesions, during laparoscopic hysterectomy, can present surgical challenges, including distortion of anatomy, prolonged operating time, and inadvertent injury to nearby structures. TECHNIQUE: At the time of laparoscopic hysterectomy, in patients with significant adhesions from prior cesarean deliveries, we use a reverse inferior to superior vesicouterine fold dissection to mobilize the scarred bladder. We use this as an alternative to the commonly practiced technique of mobilizing the bladder in a superior to inferior fashion at the time of laparoscopic hysterectomy. EXPERIENCE: Fifty-two patients with a median age of 42.5 years are presented. Forty-eight patients were discharged within 3-6 hours postoperatively. Sixteen patients were discharged with Foley catheters, because they were unable to void within the protocol for a fast-track discharge. The catheters were removed between postoperative days 1 and 5. There were no gastrointestinal or genitourinary complications. One patient experienced a delayed vaginal cuff abscess and bleeding, which were managed conservatively. CONCLUSION: Reverse vesicouterine fold dissection is a useful alternative technique for laparoscopic hysterectomy in women with a history of prior cesarean deliveries. PMID- 27500330 TI - Disparities in Surgical Care Among Women With Endometrial Cancer. AB - OBJECTIVE: To analyze contemporary U.S. use of minimally invasive surgery for the treatment of endometrial cancer and associated inpatient complications and costs. METHODS: In this retrospective cohort study, the National Inpatient Sample database was analyzed in patients with nonmetastatic endometrial cancer who underwent hysterectomy during 2012-2013. Hierarchical multiple logistic regression and propensity score matching were used to compare complications among patients treated with open compared with minimally invasive hysterectomy surgery. Cost of care was also compared using generalized linear modeling. RESULTS: We identified 9,799 patients; 52.4% underwent open and 47.6% minimally invasive hysterectomy. Many patients (43.4%) were treated at low-volume hospitals (less than 10 endometrial cancer cases annually). Patients were less likely to undergo open surgery in high-volume compared with low-volume hospitals (51.8% compared with 58.1%, respectively; adjusted odds ratio [OR] 0.35, 95% confidence interval [CI] 0.13-0.94) and more likely to undergo open surgery in rural compared with urban teaching hospitals (75.6% compared with 51.1%, respectively; adjusted OR 14.34, 95% CI 9.66-21.27), government compared with nonprofit hospitals (61.3% compared with 51.1%, respectively; adjusted OR 1.66, 95% CI 1.15-2.39), and in patients of black (67.9%; OR 1.46, 95% CI 1.30-1.65) and "other" race (60.5%; adjusted OR 2.39, 95% CI 1.99-2.87) compared with white race (49.2%, referent). Open surgery was associated with increased perioperative complications (adjusted OR 2.80, 95% CI 2.48-3.17) and a $1,243 increase in cost per case compared with minimally invasive approaches (P<.001). Using minimally invasive surgery for 80% of study patients may have averted 2,733 complications and saved approximately $19 million. CONCLUSION: Most U.S. women with endometrial cancer continue to be treated with open hysterectomy surgery despite increased complication rates and financial costs associated with this approach. A disparity in endometrial cancer surgical care exists that is affected by patient race and hospital geography and cancer volumes. PMID- 27500329 TI - Second Curettage for Low-Risk Nonmetastatic Gestational Trophoblastic Neoplasia. AB - OBJECTIVE: To evaluate the efficacy and safety of second uterine curettage in lieu of chemotherapy for patients with low-risk, nonmetastatic gestational trophoblastic neoplasia (GTN) and to evaluate whether response to second curettage is independent of patient age, World Health Organization (WHO) risk score, registration human chorionic gonadotropin (hCG) level, lesion size, and depth of myometrial invasion measured on ultrasound examination. METHODS: This was a cooperative group multicenter prospective phase II study. Prestudy testing included quantitative hCG level, pelvic ultrasonography, and chest radiography. Patients were categorized according to WHO risk scoring criteria (low risk with a score of 0-6). RESULTS: Sixty-four women with newly diagnosed low-risk, nonmetastatic GTN were enrolled. Four patients were excluded. Twenty-four patients (40%) (lower 95% confidence limit 27.6%) were cured after second curettage. An additional two patients (3%) achieved a complete response but did not complete follow-up. Overall, 26 of 60 patients were able to avoid chemotherapy. Surgical failure was observed in 34 women (59%) and was more common in women 19 years old or younger or 40 years old or older. One case of grade 1 uterine perforation was successfully managed by observation. Four grade 1 and one grade 3 uterine hemorrhages were reported. New metastatic disease (lung) was identified in one of these women after second curettage. In three patients (surgical failures), the second curettage pathology was placental site trophoblastic tumor, and it was placental nodule in one additional patient. CONCLUSION: Second uterine curettage as initial treatment for low-risk, nonmetastatic GTN cures 40% of patients without significant morbidity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/, NCT00521118. PMID- 27500331 TI - Surgical Management of a Heterotopic Cesarean Scar Pregnancy With Preservation of an Intrauterine Pregnancy. AB - BACKGROUND: Spontaneously conceived heterotopic pregnancies are rare. A heterotopic cesarean scar pregnancy involves an intrauterine pregnancy and a second pregnancy in the cesarean scar. Treatment approaches include both medical and surgical management. We present a surgical approach to the treatment of a heterotopic cesarean scar pregnancy with preservation of an intrauterine gestation. CASE: A 29-year-old woman, gravida 4 para 1021, presented at 5 weeks of gestation with spotting. Ultrasonography revealed a heterotopic cesarean scar pregnancy. The patient underwent resection of the ectopic pregnancy through minilaparotomy in an attempt to conserve the intrauterine pregnancy. She subsequently delivered an early-term neonate. CONCLUSION: Laparotomy with resection of the ectopic pregnancy is an option for treatment of an early heterotopic cesarean scar pregnancy when the patient desires conservation of the intrauterine pregnancy. Excision was not associated with pregnancy complications. PMID- 27500332 TI - Atypical Endometrial Polyps and Concurrent Endometrial Cancer: A Systematic Review. AB - OBJECTIVE: To estimate the risk of concurrent endometrial cancer in nonpolypoid endometrium when atypia was diagnosed within an endometrial polyp. DATA SOURCES: MEDLINE, EMBASE, Web of Science, and ClinicalTrials.gov were searched for studies published between 1990 and January 2015 in which 1) women with atypical hyperplastic endometrial polyps underwent a consecutive hysterectomy; or 2) the natural behavior of endometrium with concurrent atypical endometrial polyps was evaluated. METHODS OF STUDY SELECTION: Studies were selected when at least one patient within each study was initially diagnosed with an atypical endometrial polyp for which follow-up pathology was available. RESULTS: Broad searches yielded 2,922 authentic citations, 307 met criteria for full-text evaluation, and 10 met inclusion criteria. Two authors independently reviewed articles and consensus was reached. The final selection included eight retrospective studies reporting on concurrent endometrial cancer in case of atypical endometrial polyps and two follow-up studies on patients conserving their uterus after hysteroscopic resection of atypical endometrial polyps. In total, 127 patients were included with an initial diagnosis of atypical endometrial hyperplasia within polyps. Meta analysis showed a pooled risk estimate of 5.6% (95% confidence interval [CI] 0.2 17.6%) on concurrent endometrial cancer after resection of an atypical endometrial polyp. CONCLUSION: The pooled risk estimate of 5.6% (95% CI 0.2 17.6%) on endometrial cancer when atypia is found within an endometrial polyp differs from the well-established risk of nonpolypoid atypical endometrial hyperplasia on endometrial cancer of up to 42%. This risk of endometrial cancer is important in the process of shared decision-making regarding follow-up and further treatment. PMID- 27500334 TI - Simulation Training for Forceps-Assisted Vaginal Delivery and Rates of Maternal Perineal Trauma. AB - OBJECTIVE: To evaluate the association of a forceps simulation training curriculum for obstetrics residents on rates of severe perineal lacerations after forceps deliveries. METHODS: This was a retrospective cohort study. We created a novel simulation curriculum for forceps-assisted vaginal delivery based on the best practices of local experts, and trained all residents beginning in 2013. We then retrospectively reviewed all forceps deliveries performed in the 2.5 years after initiation of the training and the 7.5 years before the training program. We identified patients who experienced a severe perineal laceration (third- or fourth-degree) and examined the relationship of resident training status and perineal laceration. Known risk factors for lacerations were identified and a multilevel multivariable model was created including these factors as well as resident training. RESULTS: During the study period, we identified 6,058 forceps assisted vaginal deliveries. We examined temporal trends in rates of forceps of severe perineal laceration. We identified a decrease in severe lacerations between 2005 and 2008, ending 5 years before the initiation of the training curriculum. These years were censored from the data, yielding a baseline observational period of 4,279 deliveries with no significant trend in laceration rate. Univariate analysis reveals a 22% reduction in severe perineal laceration (odds ratio [OR] 0.78; P=.005) among women delivered by residents who had completed forceps simulation training compared with women delivered by residents who had not. After adjusting for known maternal and delivery risk factors for perineal laceration, the magnitude of the reduction increased to 26% in the full data set model (OR 0.74; P=.002). CONCLUSION: A forceps simulation curriculum for obstetrics residents was associated with a significant reduction in severe perineal lacerations. PMID- 27500333 TI - Recent Increases in the U.S. Maternal Mortality Rate: Disentangling Trends From Measurement Issues. AB - OBJECTIVE: To develop methods for trend analysis of vital statistics maternal mortality data, taking into account changes in pregnancy question formats over time and between states, and to provide an overview of U.S. maternal mortality trends from 2000 to 2014. METHODS: This observational study analyzed vital statistics maternal mortality data from all U.S. states in relation to the format and year of adoption of the pregnancy question. Correction factors were developed to adjust data from before the standard pregnancy question was adopted to promote accurate trend analysis. Joinpoint regression was used to analyze trends for groups of states with similar pregnancy questions. RESULTS: The estimated maternal mortality rate (per 100,000 live births) for 48 states and Washington, DC (excluding California and Texas, analyzed separately) increased by 26.6%, from 18.8 in 2000 to 23.8 in 2014. California showed a declining trend, whereas Texas had a sudden increase in 2011-2012. Analysis of the measurement change suggests that U.S. rates in the early 2000s were higher than previously reported. CONCLUSION: Despite the United Nations Millennium Development Goal for a 75% reduction in maternal mortality by 2015, the estimated maternal mortality rate for 48 states and Washington, DC, increased from 2000 to 2014; the international trend was in the opposite direction. There is a need to redouble efforts to prevent maternal deaths and improve maternity care for the 4 million U.S. women giving birth each year. PMID- 27500335 TI - Association Between Western and Mediterranean Dietary Patterns and Mammographic Density. AB - OBJECTIVE: To examine the association between two dietary patterns (Western and Mediterranean), previously linked to breast cancer risk, and mammographic density. METHODS: This cross-sectional study included 3,584 women attending population-based breast cancer screening programs and recruited between October 7, 2007, and July 14, 2008 (participation rate 74.5%). Collected data included anthropometric measurements; demographic, obstetric, and gynecologic characteristics; family and personal health history; and diet in the preceding year. Mammographic density was blindly assessed by a single radiologist and classified into four categories: less than 10%, 10-25%, 25-50%, and greater than 50%. The association between adherence to either a Western or a Mediterranean dietary pattern and mammographic density was explored using multivariable ordinal logistic regression models with random center-specific intercepts. Models were adjusted for age, body mass index, parity, menopause, smoking, family history, hormonal treatment, and calorie and alcohol intake. Differences according to women's characteristics were tested including interaction terms. RESULTS: Women with a higher adherence to the Western dietary pattern were more likely to have high mammographic density (n=242 [27%]) than women with low adherence (n=169 [19%]) with a fully adjusted odds ratio (ORQ4vsQ1) of 1.25 (95% confidence interval [CI] 1.03-1.52). This association was confined to overweight-obese women (adjusted ORQ4vsQ1 [95% CI] 1.41 [1.13-1.76]). No association between Mediterranean dietary pattern and mammographic density was observed. CONCLUSION: The Western dietary pattern was associated with increased mammographic density among overweight-obese women. Our results might inform specific dietary recommendations for women with high mammographic density. PMID- 27500336 TI - Antenatal Corticosteroids for the Prevention of Respiratory Distress Syndrome in Premature Twins. AB - OBJECTIVE: To estimate whether antenatal corticosteroids before 34 weeks of gestation are associated with reduced incidence of respiratory distress syndrome (RDS) and composite neonatal morbidity in preterm twins. METHODS: This was a secondary analysis of a multicenter randomized trial for the prevention of preterm birth in multiple gestations. All liveborn, nonanomalous twins delivered between 24 0/7 and 36 6/7 weeks of gestation were included. Neonatal outcomes were compared between women who received antenatal corticosteroids and those who did not. The primary outcome was the incidence of RDS. The secondary outcome was the incidence of serious composite neonatal morbidity. Multivariable log Poisson regression with correlation adjustment between twins born to the same mother was performed for confounder control. Adjusted relative risks (RRs) are reported for study outcomes. Based on a post hoc power analysis, this study was powered to detect an RR less than 0.63 for RDS and greater than 1.43 for composite neonatal morbidity outcomes. RESULTS: A total of 432 women (850 neonates) were included. Only 300 (35%) neonates were born to women receiving antenatal corticosteroids. After multivariable regression, antenatal corticosteroids were not associated with a reduced incidence of RDS (81 [27%] compared with 92 [17%] neonates, adjusted RR 1.28, 95% confidence interval [CI] 0.97-1.71) or composite neonatal morbidity (87 [29%] compared with 108 [20%] neonates, adjusted RR 1.21, 95% CI 0.93-1.56). However, antenatal corticosteroids were associated with increased rates of neonatal intensive care unit admissions (235 [78%] compared with 322 [59%] neonates, adjusted RR 1.22, 95% CI 1.09-1.36) and mechanical ventilation (70 [23%] compared with 66 [12%] neonates, adjusted RR 1.52, 95% CI 1.12-2.09). Focusing analysis to newborns delivered before 34 weeks of gestation (n=311), 161 (52%) received antenatal corticosteroids. Similarly, no differences in the rate of RDS (66 [41%] compared with 68 [45%] neonates, adjusted RR 1.01, 95% CI 0.76 1.34) or composite neonatal morbidity (72 [45%] compared with 81 [54%] neonates, adjusted RR 0.95, 95% CI 0.74-1.22) were noted. CONCLUSION: In this cohort of preterm twins, antenatal corticosteroid administration was not associated with a reduced incidence of RDS and composite neonatal morbidity. PMID- 27500337 TI - Enhanced Recovery Implementation in Major Gynecologic Surgeries: Effect of Care Standardization. AB - OBJECTIVE: To examine implementing an enhanced recovery after surgery (ERAS) protocol for women undergoing major gynecologic surgery at an academic institution and compare surgical outcomes before and after implementation. METHODS: Two ERAS protocols were developed: a full pathway using regional anesthesia for open procedures and a light pathway without regional anesthesia for vaginal and minimally invasive procedures. Enhanced recovery after surgery pathways included extensive preoperative counseling, carbohydrate loading and oral fluids before surgery, multimodal analgesia with avoidance of intravenous opioids, intraoperative goal-directed fluid resuscitation, and immediate postoperative feeding and ambulation. A before-and-after study design was used to compare clinical outcomes, costs, and patient satisfaction. Complications and risk-adjusted length of stay were drawn from the American College of Surgeons' National Surgical Quality Improvement Program database. RESULTS: On the ERAS full protocol, 136 patients were compared with 211 historical controls and the median length of stay was reduced (2.0 compared with 3.0 days; P=.007) despite an increase in National Surgical Quality Improvement Program-predicted length of stay (2.5 compared with 2.0 days; P=.009). Reductions were seen in median intraoperative morphine equivalents (0.3 compared with 12.7 mg; P<.001), intraoperative (285 compared with 1,250 mL; P<.001) and total intravenous fluids (-917.5 compared with 1,410 mL; P<.001), immediate postoperative pain scores (3.7 compared with 5.0; P<.001), and total complications (21.3% compared with 40.2%; P=.004). On the ERAS light protocol, 249 patients were compared with 324 historical controls and demonstrated decreased intraoperative and postoperative morphine equivalents (0.0 compared with 13.0 mg; P<.001 and 15.0 compared with 23.6 mg; P<.001) and decreased intraoperative and overall net intravenous fluids (P<.001). Patient satisfaction scores showed a marked and significant improvement on focus questions regarding pain control, nurses keeping patients informed, and staff teamwork; 30-day total hospital costs were significantly decreased in both ERAS groups. CONCLUSION: Implementation of ERAS protocols in gynecologic surgery was associated with a substantial decrease in intravenous fluids and morphine administration coupled with reduction in length of stay for open procedures combined with improved patient satisfaction and decreased hospital costs. PMID- 27500338 TI - Polyethylene Glycol 3350 and Docusate Sodium Compared With Docusate Sodium Alone After Urogynecologic Surgery: A Randomized Controlled Trial. AB - OBJECTIVE: To compare time to first bowel movement and additional gastrointestinal outcomes between women receiving polyethylene glycol 3350 (PEG3350) and docusate sodium and docusate sodium alone after urogynecologic surgery. METHODS: Participants received twice-daily 100 mg docusate sodium and were randomized to daily 1) PEG3350 or 2) inert placebo for 5 days after urogynecologic surgery. They completed bowel diaries, Bristol stool scale, validated Patient Assessment of Constipation Symptom Questionnaire, and Patient Assessment of Constipation Quality-of-Life Questionnaire preoperatively and 1 week after surgery. Our primary outcome was time to first bowel movement after surgery. To detect a 1-day difference in time to first bowel movement (4 compared with 3 days), 63 participants were needed in each group. RESULTS: From September 2012 through March 2015, 145 women were randomized and 131 (90%) analyzed: 66 received PEG3350, and 65 received placebo. Polyethylene glycol 3350 did not significantly reduce time to first bowel movement after surgery compared with placebo (2.77 days [interquartile range 1.86-3.40] compared with 2.92 days [interquartile range 1.85-4.02] P=.25). Women in the PEG3350 group were less likely to take additional laxatives postoperatively, and the PEG3350 group was more adherent to the study drug regimen. Questionnaire scores, fecal incontinence, and urgency were similar between groups. CONCLUSION: In women taking routine docusate sodium after urogynecologic surgery, adding PEG3350 postoperatively did not reduce time to first bowel movement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01691742. PMID- 27500339 TI - Outcomes and Postoperative Complications After Hysterectomies Performed for Benign Compared With Malignant Indications. AB - OBJECTIVE: To compare complications and outcomes after hysterectomy for benign compared with malignant indications in the United States. METHODS: Women who underwent hysterectomy in the United States for either benign or malignant indications from January 2008 to December 2012 were retrospectively identified using the National Surgical Quality Improvement Program database. Patients were excluded if the procedure was not performed for primary gynecologic indications. Appropriate procedures were identified using Current Procedural Terminology and International Classification of Diseases, 9th Revision codes. Univariate and multivariable models for complication risk were estimated using logistic regression. RESULTS: We identified 59,525 eligible patients, with 49,331 (82.9%) hysterectomies performed for benign and 10,194 (17.1%) for malignant indications. All complications, including wound complications (2.5% benign compared with 5.5% malignant, P<.001), venous thromboembolism (0.33% compared with 1.7%, P<.001), urinary tract infection (2.7% compared with 3.2%, P=.009), sepsis (0.53% compared with 1.9%, P<.001), blood transfusion (2.6% compared with 11.5%, P<.001), death (0.02% compared with 0.10%, P<.001), unplanned readmission (1.8% compared with 4.5%, P<.001), and returns to the operating room (0.91% compared with 1.4%, P<.001), were significantly more common for malignant hysterectomies. The overall rate of complications for benign cases was 7.9% compared with a rate of 19.4% for malignant hysterectomy. The median operating time for laparoscopy in benign cases was significantly longer than for open or vaginal hysterectomy procedures (127 minutes compared with 105 or 94 minutes, respectively; P<.001). The median operating time in malignant cases was significantly longer than for benign cases (P<.001). CONCLUSION: Hysterectomies performed for gynecologic malignancies are associated with a more than twofold higher complication rate compared with those performed for benign conditions. Minimally invasive surgery is associated with a decreased complication rate compared with open surgery. These data can be used for patient counseling and surgical planning, determining physician and hospital costs of care, and considered when assigning value-based reimbursement. PMID- 27500340 TI - Higher Risk of Homicide Among Pregnant and Postpartum Females Aged 10-29 Years in Illinois, 2002-2011. AB - OBJECTIVE: To examine whether being pregnant or postpartum was associated with excess risk for homicide among females in Illinois and to describe the association between pregnancy status and homicide by race, ethnicity, and age group. METHODS: This is a retrospective, multicohort, ecologic study of females of reproductive age in Illinois between 2002 and 2011 using Illinois Department of Public Health maternal mortality data and vital records data. We compared pregnancy-associated homicides with live births using chi tests. Among maternal deaths in the state, we calculated mortality rates per 100,000 live births for homicide and other violent causes and the leading direct obstetric causes. We calculated aggregate, pregnancy-associated, and nonpregnancy associated homicide rates stratified by race or ethnicity and age group. RESULTS: There were 636 pregnancy-associated deaths in Illinois from 2002 to 2011. Of these, 82 (13%) were the result of homicide (5.0 [95% confidence interval (CI) 4.0-6.2]/100,000 live births). There were 931 homicides among females of reproductive age not associated with pregnancy (2.88 [95% CI 2.70-3.07]/100,000 population). More than half of the homicides were women aged 20-29 years (n=53 [64.6%]), non-Hispanic black women (n=43 [52.4%]), women residing in Cook County (n=47 [57.3%]), and unmarried women (n=57 [69.5%]). Pregnant and postpartum females aged 10-29 years were at twice the risk of homicide compared with their nonpregnant or postpartum counterparts (relative risk 2.20 [95% CI 1.70-2.85]). Non-Hispanic black and Hispanic females experienced higher rates of homicide than non-Hispanic white females irrespective of pregnancy or age. CONCLUSION: Although all violence against women must be addressed, we recommend that state maternal mortality review committees, in addition to reviewing deaths resulting from obstetric and clinical causes, should conduct in-depth reviews of pregnancy-associated homicides and other violent deaths. PMID- 27500341 TI - Association of Early Amniotomy After Foley Balloon Catheter Ripening and Duration of Nulliparous Labor Induction. AB - OBJECTIVE: To evaluate the association between early amniotomy after ripening with a Foley balloon catheter and duration of labor induction. METHODS: In this retrospective matched cohort study, 546 nulliparous women with a singleton viable gestation undergoing cervical ripening with a Foley balloon catheter were compared based on timing of amniotomy after catheter removal: early (defined as artificial rupture of membranes less than 1 hour after Foley removal) compared with no artificial rupture of membranes in the first hour. Women in the early amniotomy group were matched to women in the control group according to health care provider type, cervical examination after Foley removal, and indication for induction in a one-to-one ratio. Bivariable and multivariable analyses were performed to determine whether early amniotomy was associated with vaginal delivery within 24 hours and other adverse maternal and neonatal outcomes. Cox proportional hazard regression was used to compare time intervals from catheter removal to complete dilation and from catheter removal to delivery. RESULTS: In univariable analysis, the frequency of vaginal delivery within 24 hours of Foley placement was higher in women with early amniotomy (42.9% compared with 33.0%, P=.02). The median time intervals from Foley catheter removal to complete dilation (9.0 hours compared with 12.1 hours) and to delivery (10.6 hours compared with 13.8 hours) were also significantly shorter for women who underwent early amniotomy (P<.001 for both). There were no significant differences in any other adverse maternal or neonatal outcomes. In multivariable analysis, early amniotomy remained associated with higher odds of vaginal delivery within 24 hours and shorter times from catheter removal to complete dilation and to delivery. CONCLUSION: Early amniotomy after Foley balloon catheter removal is associated with shorter duration of labor induction among nulliparous women. PMID- 27500342 TI - Smoking Before and During Pregnancy Among Women Reporting Depression or Anxiety. AB - OBJECTIVE: To describe prepregnancy smoking, prenatal smoking, and prenatal cessation among women reporting and not reporting depression or anxiety. METHODS: We analyzed cross-sectional data from the 2009-2011 Pregnancy Risk Assessment Monitoring System, a population-based survey of women with live births (N=34,633). Smoking status was defined as self-reported prepregnancy smoking (during the 3 months before pregnancy), prenatal smoking (during the last 3 months of pregnancy), and prenatal cessation (no smoking by the last 3 months among prepregnancy smokers). Depression and anxiety status was self-reported of having either condition or both during the 3 months before pregnancy. We compared smoking prevalence by self-reported depression and anxiety status using chi tests and adjusted prevalence ratios. RESULTS: Overall, 16.9% of women in our sample reported depression, anxiety, or both during the 3 months before pregnancy. Compared with those who did not report, women who reported depression or anxiety had significantly higher prepregnancy (46.7% compared with 22.5%, P<.01) and prenatal smoking (27.5% compared with 10.5%, P<.01). A lower proportion of prepregnancy smokers who reported depression or anxiety quit smoking by the last 3 months of pregnancy than those who did not report (41.4% compared with 53.8%, P<.01). In adjusted analyses, women reporting depression or anxiety were 1.5 and 1.7 times more likely to smoke prepregnancy and prenatally, respectively, and less likely to quit smoking (adjusted prevalence ratio 0.86, 95% confidence interval 0.80-0.92). CONCLUSION: Women who reported depression, anxiety, or both were more likely to smoke before and during pregnancy and less likely to quit smoking during the prenatal period. Screening recommendations for perinatal depression and anxiety provide an opportunity to identify a subpopulation of women who may have a higher prevalence of smoking and to provide effective tobacco cessation interventions and mental health care. PMID- 27500343 TI - Accuracy of Home-Based Ultrasonographic Diagnosis of Obstetric Risk Factors by Primary-Level Health Care Workers in Rural Nepal. AB - OBJECTIVE: To assess the feasibility of ultrasonographic task shifting by estimating the accuracy at which primary-level health care workers can perform community-based third-trimester ultrasound diagnosis for selected obstetric risk factors in rural Nepal. METHODS: Three auxiliary nurse-midwives received two 1 week ultrasound trainings at Tribhuvan University Teaching Hospital in Kathmandu. At a study site in rural Nepal, pregnant women who were 32 weeks of gestation or greater were enrolled and received ultrasound examinations from the auxiliary nurse-midwives during home visits. Each auxiliary nurse-midwife screened for noncephalic presentation, multiple gestation, and placenta previa. Deidentified digital ultrasonograms were stored and uploaded onto an online server, where certified sonologists and ultrasonographers reviewed the images and made their own diagnoses for the three conditions. Accuracy of auxiliary nurse-midwife diagnoses was then calculated. RESULTS: A total of 804 women contributed to the analysis. Each auxiliary nurse-midwife's kappa statistic for diagnosis of noncephalic presentation was above 0.90 compared with the ultrasonogram reviewers. Sensitivity, specificity, and positive and negative predictive values were between 90% and 100% for all auxiliary nurse-midwives. For multiple gestation, the auxiliary nurse-midwives were in perfect agreement with both the ultrasonogram reviewers and maternal postpartum self-report. Two placenta previa cases were detected, and the ultrasonogram reviewers agreed with both. CONCLUSION: With limited training, primary-level health care workers in rural Nepal can accurately diagnose selected third-trimester obstetric risk factors using ultrasonography. PMID- 27500344 TI - Association of Recorded Estimated Fetal Weight and Cesarean Delivery in Attempted Vaginal Delivery at Term. AB - OBJECTIVE: To evaluate the association between documentation of estimated fetal weight, and its value, with cesarean delivery. METHODS: This was a secondary analysis of a multicenter observational cohort of 115,502 deliveries from 2008 to 2011. Data were abstracted by trained and certified study personnel. We included women at 37 weeks of gestation or greater attempting vaginal delivery with live, nonanomalous, singleton, vertex fetuses and no history of cesarean delivery. Rates and odds ratios (ORs) were calculated for women with ultrasonography or clinical estimated fetal weight compared with women without documentation of estimated fetal weight. Further subgroup analyses were performed for estimated fetal weight categories (less than 3,500, 3,500-3,999, and 4,000 g or greater) stratified by diabetic status. Multivariable analyses were performed to adjust for important potential confounding variables. RESULTS: We included 64,030 women. Cesarean delivery rates were 18.5% in the ultrasound estimated fetal weight group, 13.4% in the clinical estimated fetal weight group, and 11.7% in the no documented estimated fetal weight group (P<.001). After adjustment (including for birth weight), the adjusted OR of cesarean delivery was 1.44 (95% confidence interval [CI] 1.31-1.58, P<.001) for women with ultrasound estimated fetal weight and 1.08 for clinical estimated fetal weight (95% CI 1.01-1.15, P=.017) compared with women with no documented estimated fetal weight (referent). The highest estimates of fetal weight conveyed the greatest odds of cesarean delivery. When ultrasound estimated fetal weight was 4,000 g or greater, the adjusted OR was 2.15 (95% CI 1.55-2.98, P<.001) in women without diabetes and 9.00 (95% CI 3.65 22.17, P<.001) in women with diabetes compared to those with estimated fetal weight less than 3,500 g. CONCLUSION: In this contemporary cohort of women attempting vaginal delivery at term, documentation of estimated fetal weight (obtained clinically or, particularly, by ultrasonography) was associated with increased odds of cesarean delivery. This relationship was strongest at higher fetal weight estimates, even after controlling for the effects of birth weight and other factors associated with increased cesarean delivery risk. PMID- 27500345 TI - Obstetric Forceps: A Species on the Brink of Extinction. AB - Both resident training in the use of obstetric forceps and forceps deliveries are experiencing precipitous declines in the United States. Current minimum training requirements are insufficient to ensure competency in this skill. These trends bear striking similarities to observations regarding the decline and ultimate extinction of biologic species and portend the inevitable disappearance of this valuable skill from the obstetric armamentarium. Attempts by experienced teaching faculty to provide residents with experience in a few forceps deliveries are of little value and may do more harm than good. There would seem to be only two viable solutions to this dilemma: 1) abandon attempts to teach forceps and prepare residents for a real-world practice setting in which management of second stage labor does not include the availability forceps delivery; or 2) prioritize the development of high-fidelity simulation models in which fetal head size and attitude and pelvic size and architecture can be continuously varied to allow residents to obtain sufficient experience to know both how and when to proceed with forceps delivery. We believe this latter approach is the sole alternative to inevitable extinction of this species. PMID- 27500346 TI - Avoiding Inadequate Intrapartum Antibiotic Prophylaxis for Group B Streptococci. AB - OBJECTIVE: To estimate the frequency and reasons for inadequate group B streptococci (GBS) prophylaxis at our institution and to estimate what proportion of cases can be avoided with perfect protocol adherence. METHODS: This was a retrospective cohort study of neonates born to GBS-colonized women who received inadequate prophylaxis between April 30, 2013, and May 1, 2014. The maternal chart was analyzed to categorize each case as avoidable (adequate time on labor and delivery to receive antibiotics 4 hours before birth and beta-lactam antibiotic-eligible) or unavoidable and to determine whether a violation of the 2010 Centers for Disease Control and Prevention (CDC) protocol (delayed or incorrect antibiotics) occurred. RESULTS: A total of 197 of 488 (40.4%, 95% confidence interval 36.1-44.8%) newborns of group B-colonized women received inadequate prophylaxis. Of these, 157 cases (79.7%, 73.4-84.8%) were unavoidable and would have occurred even with perfect protocol adherence. The 40 (20.3%, 15.3 26.5%) avoidable cases due to protocol violations resulted from delayed antibiotic administration (first dose of antibiotics more than 1 hour after admission [median 9.33 hours, range 3.83-25 hours] in 25 patients; no antibiotics in four patients; total 29 patients, 72.5%) or incorrect antibiotic selection (11 patients, 27.5%). CONCLUSIONS: Forty percent of patients received inadequate prophylaxis, and four of five cases are unavoidable with our current labor management and the 2010 CDC guidelines. Timeliness and selection of antibiotics remain areas for improvement, but the overall effects on sepsis prevention will be modest. PMID- 27500347 TI - Salpingo-oophorectomy at the Time of Benign Hysterectomy: A Systematic Review. AB - OBJECTIVE: To compare the long-term risks associated with salpingo-oophorectomy with ovarian conservation at the time of benign hysterectomy. DATA SOURCES: MEDLINE, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials were searched from inception to January 30, 2015. We included prospective and retrospective comparative studies of women with benign hysterectomy who had either bilateral salpingo-oophorectomy (BSO) or conservation of one or both ovaries. METHODS OF STUDY SELECTION: Reviewers double-screened 5,568 citations and extracted eligible studies into customized forms. Twenty-six comparative studies met inclusion criteria. Studies were assessed for results, quality, and strength of evidence. TABULATION, INTEGRATION, AND RESULTS: Studies were extracted for participant, intervention, comparator, and outcomes data. When compared with hysterectomy with BSO, prevalence of reoperation and ovarian cancer was higher in women with ovarian conservation (ovarian cancer risk of 0.14-0.7% compared with 0.02-0.04% among those with BSO). Hysterectomy with BSO was associated with a lower incidence of breast and total cancer, but no difference in the incidence of cancer mortality was found when compared with ovarian conservation. All-cause mortality was higher in women younger than age 45 years at the time of BSO who were not treated with estrogen replacement therapy (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.04-1.92). Coronary heart disease (HR 1.26, 95% CI 1.04-1.54) and cardiovascular death were higher among women with BSO (HR 1.84, 95% CI 1.27-2.68), especially women younger than 45 years who were not treated with estrogen. Finally, there was an increase in the prevalence of dementia and Parkinson disease among women with BSO compared with conservation, especially in women younger than age 50 years. Clinical practice guidelines were devised based on these results. CONCLUSION: Bilateral salpingo-oophorectomy offers the advantage of effectively eliminating the risk of ovarian cancer and reoperation but can be detrimental to other aspects of health, especially among women younger than age 45 years. PMID- 27500348 TI - Group Prenatal Care Compared With Traditional Prenatal Care: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To estimate the effect of group prenatal care on perinatal outcomes compared with traditional prenatal care. DATA SOURCES: We searched MEDLINE through PubMed, EMBASE, Scopus, Cumulative Index of Nursing and Allied Health literature, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. METHODS OF STUDY SELECTION: We searched electronic databases for randomized controlled trials and observational studies comparing group care with traditional prenatal care. The primary outcome was preterm birth. Secondary outcomes were low birth weight, neonatal intensive care unit admission, and breastfeeding initiation. Heterogeneity was assessed using the Q test and I statistic. Pooled relative risks (RRs) and weighted mean differences were calculated using random-effects models. TABULATIONS, INTEGRATION, AND RESULTS: Four randomized controlled trials and 10 observational studies met inclusion criteria. The rate of preterm birth was not significantly different with group care compared with traditional care (11 studies: pooled rates 7.9% compared with 9.3%, pooled RR 0.87, 95% confidence interval [CI] 0.70 1.09). Group care was associated with a decreased rate of low birth weight overall (nine studies: pooled rate 7.5% group care compared with 9.5% traditional care; pooled RR 0.81, 95% CI 0.69-0.96), but not among randomized controlled trials (four studies: 7.9% group care compared with 8.7% traditional care, pooled RR 0.92, 95% CI 0.73-1.16). There were no significant differences in neonatal intensive care unit admission or breastfeeding initiation. CONCLUSION: Available data suggest that women who participate in group care have similar rates of preterm birth, neonatal intensive care unit admission, and breastfeeding. PMID- 27500349 TI - Risk Factors for Dyspareunia After First Childbirth. AB - OBJECTIVE: To investigate risk factors for dyspareunia among primiparous women. METHODS: This was a planned secondary analysis using data from the 1- and 6-month postpartum interviews of a prospective study of women who delivered their first neonate in Pennsylvania, 2009-2011. Participants who had resumed sexual intercourse by the 6-month interview (N=2,748) constituted the analytic sample. Women reporting a big or medium problem with painful intercourse at 6 months were categorized as having dyspareunia. Multivariable logistic regression was used to evaluate the effect of patient characteristics, obstetric and psychosocial factors, and breastfeeding on dyspareunia. RESULTS: There were 583 women (21.2%) who reported dyspareunia at 6 months postpartum. Nearly one third of those breastfeeding at 6 months reported dyspareunia (31.5%) compared with 12.7% of those not breastfeeding (adjusted odds ratio [OR] 2.89, 95% confidence interval [CI] 2.33-3.59, P<.001); 32.5% of those reporting a big or medium problem with perineal pain at 1 month reported dyspareunia at 6 months compared with 15.9% of those who did not (adjusted OR 2.45, 95% CI 1.93-3.10, P<.001); 28.3% of women who reported fatigue all or most of the time at 1 month reported dyspareunia at 6 months compared with 18.0% of those who reported fatigue less often (adjusted OR 1.60, 95% CI 1.30-1.98, P<.001); and 24.1% of those who scored in the upper third on the stress scale at 1 month reported dyspareunia at 6 months postpartum compared with 15.6% of those who scored in the lowest third (adjusted OR 1.55, 95% CI 1.18-2.02, P=.001). CONCLUSION: In this prospective cohort study, we identified specific risk factors for dyspareunia in primiparous women that can be discussed at the first postpartum visit, including breastfeeding, perineal pain, fatigue, and stress. PMID- 27500350 TI - Association of a Biweekly Research Workgroup With Enhanced Resident Research Productivity. AB - Almost all residency programs require a resident research project, yet teaching and mentoring of the required skills are often lacking. We established an every other-week gynecologic oncology research workgroup at our institution for obstetrics and gynecology faculty, fellows, and residents with the goal of increasing resident research education, involvement, and productivity. An informal, discussion-style format was adopted as a forum for brainstorming research ideas, formulating study protocols, and collaborating on institutional review board submissions. Additional aims included editorial feedback on abstracts and manuscripts as well as oral presentation preparation. The academic productivity of trainees mentored by the gynecologic oncology division was queried for 27 months before and 27 months after workgroup initiation, specifically assessing resident involvement in institutional review board submission, abstract presentation, and manuscript preparation. Institution of our workgroup was associated with a dramatic increase in resident research output, including manuscript preparation and presentations at national meetings. We describe our experience because it may benefit other residency programs wishing to improve both resident research education and productivity. PMID- 27500351 TI - Self-Administered Lidocaine Gel for Intrauterine Device Insertion in Nulliparous Women: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate self-administration of vaginal lidocaine gel to decrease pain with intrauterine device (IUD) insertion in nulliparous women. METHODS: In this randomized, double-blind, placebo-controlled trial, women self-administered 2% lidocaine or placebo vaginal gel 5 minutes before IUD insertion. The primary outcome was change in pain from baseline to IUD insertion on a 100-mm visual analog scale. We also assessed pain after speculum insertion, tenaculum placement, uterine sounding, and 5 minutes after IUD insertion. Secondary outcomes included patient acceptability, ease of IUD insertion, and need for pain medication for up to 7 days. RESULTS: From July 2012 to May 2013, 59 women were randomized; 30 received lidocaine gel and 29 placebo. Baseline demographics, including age, race, and body mass index, were similar. There was no difference in median change in pain during IUD insertion in women receiving lidocaine (61 mm [interquartile range 53-71]) compared with placebo (69 mm [interquartile range 63 80], P=.06). Women receiving lidocaine experienced less pain with tenaculum placement (32 mm [interquartile range 18-54]) compared with placebo (56 mm [interquartile range 26-75], P=.02). Most (76%) women were satisfied with their IUD insertion experience and 86% would probably or definitely recommend an IUD to a friend. Thirty-four percent of women required pain medication for at least 3 days after IUD insertion. CONCLUSION: For nulliparous women, self-administered vaginal lidocaine gel does not reduce pain with IUD insertion, but does decrease pain with tenaculum placement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01534520. PMID- 27500352 TI - Accuracy of Onsite Tests to Detect Asymptomatic Bacteriuria in Pregnancy: A Systematic Review and Meta-analysis. AB - OBJECTIVE: To estimate the accuracy of onsite tests to detect asymptomatic bacteriuria among pregnant women. DATA SOURCES: We searched MEDLINE, EMBASE, Web of Science, Scopus, and Latin-American Literature from inception until June 2015 without language restrictions. The ClinicalTrials.gov register database was screened to identify any recently completed studies. METHODS OF STUDY SELECTION: Two independent reviewers selected studies that recruited asymptomatic pregnant women to evaluate the accuracy of onsite tests in detecting the presence of bacteria in the urine using urine culture as a reference standard. TABULATION, INTEGRATION, AND RESULTS: Women's characteristics, study design, urine sample collection, and handling were extracted along with the test accuracy data. Where possible, we pooled the data using a bivariate, hierarchical random-effects model. Of 1,360 screened references, 27 articles (13,641 women) with test accuracy data on nine tests met the inclusion criteria. The most commonly evaluated test was urine dipstick. The pooled sensitivity and specificity of nitrites detected by dipstick to detect asymptomatic bacteriuria were 0.55 (95% confidence interval [CI] 0.42-0.67) and 0.99 (95% CI 0.98-0.99), respectively. The Griess test to detect nitrites had a sensitivity of 0.65 (95% CI 0.50-0.78) and specificity of 0.99 (95% CI 0.98-1.00). Dipslide with Gram staining had a pooled sensitivity of 0.86 (95% CI 0.80-0.91) and specificity of 0.97 (95% CI 0.93-0.99). CONCLUSION: The specificity of onsite tests is high; however, the sensitivity is not with the result that they will fail to detect a substantial number of cases of asymptomatic bacteriuria. CLINICAL TRIAL REGISTRATION: PROSPERO International prospective register of systematic reviews, http://www.crd.york.ac.uk/PROSPERO/, CRD42015027905. PMID- 27500353 TI - Optimal Lentivirus Production and Cell Culture Conditions Necessary to Successfully Transduce Primary Human Bronchial Epithelial Cells. AB - In vitro culture of primary human bronchial epithelial (HBE) cells using air liquid interface conditions provides a useful model to study the processes of airway cell differentiation and function. In the past few years, the use of lentiviral vectors for transgene delivery became common practice. While there are reports of transduction of fully differentiated airway epithelial cells with certain non-HIV pseudo-typed lentiviruses, the overall transduction efficiency is usually less than 15%. The protocol presented here provides a reliable and efficient method to produce lentiviruses and to transduce primary human bronchial epithelial cells. Using undifferentiated bronchial epithelial cells, transduction in bronchial epithelial growth media, while the cells attach, with a multiplicity of infection factor of 4 provides efficiencies close to 100%. This protocol describes, step-by-step, the preparation and concentration of high-titer lentiviral vectors and the transduction process. It discusses the experiments that determined the optimal culture conditions to achieve highly efficient transductions of primary human bronchial epithelial cells. PMID- 27500354 TI - FRET Imaging in Three-dimensional Hydrogels. AB - Imaging of Forster resonance energy transfer (FRET) is a powerful tool for examining cell biology in real-time. Studies utilizing FRET commonly employ two dimensional (2D) culture, which does not mimic the three-dimensional (3D) cellular microenvironment. A method to perform quenched emission FRET imaging using conventional widefield epifluorescence microscopy of cells within a 3D hydrogel environment is presented. Here an analysis method for ratiometric FRET probes that yields linear ratios over the probe activation range is described. Measurement of intracellular cyclic adenosine monophosphate (cAMP) levels is demonstrated in chondrocytes under forskolin stimulation using a probe for EPAC1 activation (ICUE1) and the ability to detect differences in cAMP signaling dependent on hydrogel material type, herein a photocrosslinking hydrogel (PC-gel, polyethylene glycol dimethacrylate) and a thermoresponsive hydrogel (TR-gel). Compared with 2D FRET methods, this method requires little additional work. Laboratories already utilizing FRET imaging in 2D can easily adopt this method to perform cellular studies in a 3D microenvironment. It can further be applied to high throughput drug screening in engineered 3D microtissues. Additionally, it is compatible with other forms of FRET imaging, such as anisotropy measurement and fluorescence lifetime imaging (FLIM), and with advanced microscopy platforms using confocal, pulsed, or modulated illumination. PMID- 27500355 TI - The Default Dilemma: Code Status Regardless of Medical Context. PMID- 27500356 TI - Probable glucometer interference caused by topical iodine solution test site preparation. AB - WHAT IS KNOWN AND OBJECTIVE: Use of disinfectants, such as alcohol prep pads, for test site preparation have demonstrated alterations in glucose readings. One case report details an overestimation of blood glucose (BG) readings when using Chemstrip bG and Visidex reagent test strips after cleaning test site with povidone-iodine swabs CASE SUMMARY: We present a case of a clinically relevant probable drug-device interaction between topical iodine and a point-of-care glucometer in a 28 year old pregnant woman of Chinese descent. In this case, the use of 10% povidone-iodine solution on the testing site before lancing likely resulted in variable and inaccurate BG readings, which was not reproduced when the patient used hand washing instead of iodine. WHAT IS NEW AND CONCLUSION: Our report expands on this prior knowledge by demonstrating that such an alteration associated with iodine can occur with modern electrochemical glucometers. In patients that have aberrant or variable BG readings, providers should investigate for improper testing technique. PMID- 27500357 TI - Hypoxia induces copper stable isotope fractionation in hepatocellular carcinoma, in a HIF-independent manner. AB - Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, with increasing incidence worldwide. The unrestrained proliferation of tumour cells leads to tumour hypoxia which in turn promotes cancer aggressiveness. While changes in the concentration of copper (Cu) have long been observed upon cancerization, we have recently reported that the isotopic composition of copper is also altered in several types of cancer. In particular, we showed that in hepatocellular carcinoma, tumour tissue contains heavier copper compared to the surrounding parenchyma. However, the reasons behind such isotopic signature remained elusive. Here we show that hypoxia causes heavy copper enrichment in several human cell lines. We also demonstrate that this effect of hypoxia is pH, HIF-1 and -2 independent. Our data identify a previously unrecognized cellular process associated with hypoxia, and suggests that in vivo tumour hypoxia determines copper isotope fractionation in HCC and other solid cancers. PMID- 27500358 TI - Loaded Ce-Ag organic-inorganic hybrids and their antibacterial activity. AB - There are requirements for surfaces with antibacterial properties in various technological fields. U-PEO hybrids with antibacterial properties were synthesized by the sol-gel process, incorporating combinations of cerium and silver salts at different silver molar fractions (0, 0.02, 0.05, 0.10, and 1) relative to the total amount of doped cations. The loaded hybrids were characterized by TGA, XRD, and Raman spectroscopy. Release tests were performed using UV-vis spectroscopy, and the antibacterial properties of the hybrids were studied in agar tests and turbidimetry assays. The nanostructural evolution of the hybrids during the release of the antibacterial agents was investigated by in situ SAXS. XRD results showed the presence of the AgCl crystalline phase in the loaded hybrids from a silver molar fraction of 0.05. Raman spectroscopy evidenced the interaction of silver cations with the polymeric part of the hybrid. SAXS results confirmed these interactions and showed that cerium species interacted with both organic and inorganic parts of the hybrids. The loaded U-PEO hybrids were found to release all the incorporated cerium in 1h, while the hybrid containing 100% of silver released only 78% of the incorporated silver. All the loaded hybrids displayed antibacterial activity against the Pseudomonas aeruginosa bacterium. The antibacterial activity was found to increase with silver molar fraction. Due to its high antibacterial activity and low silver molar fraction, the loaded hybrid with silver molar fraction of 0.10 seemed to be a good compromise between efficiency, esthetic transparency, and photostability. PMID- 27500359 TI - Multi-functional vesicles for cancer therapy: The ultimate magic bullet. AB - Delivering chemotherapy specifically, effectively and safely to tumor remains a significant challenge in recent years. Although cancer cells are more vulnerable than normal to the effect of anticancer agents, these drugs are non-selective and can cause injury to normal tissues. Different approaches i.e. passive, active and magnetic targeting, smart devices with appropriate stimuli-sensitive properties or drugs combinations, have been already proposed as single methods, contributing to minimize severe side effects and enhancing tumor-targeting efficacy. Often, the use of a single strategy is not sufficient, whereby multi-functional approach has been suggested as further evolution of traditional "magic bullet" proposed in the early 1900s by Paul Ehrlich. Among the macromolecular systems useful for targeted drug delivery, liposomes and niosomes are the most extensively studied and they own the most suitable characteristics to be converted in multi functional devices. Liposomes and niosomes are nanovesicles that contain amphiphilic molecules arranged in concentric bilayers, delimitating an aqueous core. These vesicular carriers are very versatile, since they can be differently designed and modified in such a way that they exhibit combinations of the following properties: longevity in blood, specific target to the tumor, respond to internal/external stimuli, promotion of drug intracellular delivery. This review will focus on the potential of multi-functional vesicular nanocarriers in cancer therapy, analizing each combination of targeting strategies, stimuli sensitivity and drug combinations and giving an exhaustive collection of recent investigations. Many multi-functional vesicular devices have shown great promise in clinical application, indicating broad potential as therapeutics in the near future, but more needs to be done. The development of more specific and efficient carriers for a personalized cancer therapy is the next challenge. PMID- 27500360 TI - Substrate-mediated delivery of gene complex nanoparticles via polydopamine coating for enhancing competitiveness of endothelial cells. AB - Substrate-mediated delivery of functional plasmid DNA (pDNA) has been proven to be a promising strategy to promote competitiveness of endothelial cells (ECs) over smooth muscle cells (SMCs), which is beneficial to inducing fast endothelialization of implanted vascular devices. Thus, it is of great importance to develop universal approaches with simplicity and easiness to immobilize DNA complex nanoparticles on substrates. In this study, the bioinspired polydopamine (PDA) coating was employed in immobilization of DNA complex nanoparticles, which were composed of protamine (PrS) and plasmid DNA encoding with hepatocyte growth factor (HGF-pDNA) gene. We demonstrated that the DNA complex nanoparticles can be successfully immobilized onto the PDA surface. Consequently, the HGF expression of both ECs and SMCs were significantly improved when they cultured on the DNA complex nanoparticles-immobilized substrates. Furthermore, EC proliferation was specifically promoted due to bioactivity of HGF, leading to an enhancement of EC competitiveness over SMCs. Our findings demonstrated the substrate-mediated functional gene nanoparticle delivery through PDA coating as a simple and efficient approach. It may hold great potential in the field of interventional cardiovascular implants. PMID- 27500361 TI - The Long-Term Follow-up and Support for Living Organ Donors: A Center-Based Initiative Founded on Developing a Community of Living Donors. AB - Transplant professionals recognize that the long-term follow-up of living organ donors is a priority, yet there has been no implemented solution to this problem. This critical gap is essential, because the transplant field is now emphasizing living donation as a means to address the organ shortage. We detail our living donor initiative, which sets several priorities we recognize as fundamental to persons who have donated organs at our transplant center. This intervention attempts to mitigate the donor and center factors that are known to contribute to the lack of long-term follow-up. Beyond that, our goals are aimed at providing ongoing engagement, wellness, clinical data accrual, laboratory follow-up, and social support for our living donors, in continuity. Our ultimate goal is to nurture the development of local living donor community networks by providing social engagement for current and past donors, which also serves as a platform for greater population education on the societal importance of living donation. This initiative is based on joint recognition by our transplant team and our hospital leadership that supporting the long-term welfare of living donors is essential to accomplishing the goal of expanding living donor transplantation. The transplant team and hospital missions are aligned, and both contribute resources to the initiative. PMID- 27500362 TI - Prevention of Heat Stress Adverse Effects in Rats by Bacillus subtilis Strain. AB - This study was designed to evaluate the protective effect of the Bacillus subtilis strain against complications related to heat stress. Thirty-two Sprague Dawley rats were used in this study. Animals were orally treated twice a day for two days with B. subtilis BSB3 strain or PBS. The next day after the last treatment, each group was divided and two experimental groups (one treated with PBS and one treated with B. subtilis) were placed at 45 (o)C for 25 min. Two control groups stayed for 25 min at room temperature. All rats were euthanized and different parameters were analyzed in all groups. Adverse effects of heat stress are registered by the decrease of villi height and total mucosal thickness in the intestinal epithelium; translocation of bacteria from the lumen; increased vesiculation of erythrocytes and elevation of the lipopolysaccharides (LPS) level in the blood. The protective efficacy of treatment is evaluated by prevention of these side effects. The protocol was set up for the oral treatment of rats with bacteria for prevention of heat stress complications, but this protocol can be modified and used for other routes of administration and for analysis of different compounds. PMID- 27500363 TI - Use of Rabbit Eyes in Pharmacokinetic Studies of Intraocular Drugs. AB - The intraocular route of drug administration enables the delivery of high concentrations of therapeutic drugs, while minimizing their systemic absorption. Several drugs are administered into the anterior chamber or vitreous, and the intraocular injection has been effective in curing various intraocular diseases. Rabbit eyes have been widely used for ophthalmic research, as the animal is easy to handle and economical compared to other mammals, and the size of a rabbit eye is similar to that of a human eye. Using a 30 G needle, drugs can be injected into the intracameral and intravitreal spaces of rabbit eyes. The eyeballs are then frozen until analysis, and can be divided into the aqueous humor, vitreous, and retina/choroid. The vitreous and retina/choroid samples can be homogenized and solubilized before analysis. Then, immunoassays can be performed to measure the concentrations of intraocular drugs in each compartment. Appropriate pharmacokinetic models can be used to calculate several parameters, such as the half-life and maximum concentration of the drug. Rabbit eyes can be a good model for pharmacokinetic studies of intraocular drugs. PMID- 27500364 TI - Compartmentalized dynamics of cytomegalovirus replication in treated congenital infection. AB - BACKGROUND: Cytomegalovirus (CMV) is the most prevalent congenital infection in developed countries. A significant number of infected infants develop long-term neurodevelopmental and hearing impairment irrespective of whether disease is detectable at birth. Studies of viral load and replication dynamics have informed the treatment of CMV in adult populations but no similar data exist in neonates. OBJECTIVES: To study CMV virus kinetics in different body fluids of babies treated for congenital infection. STUDY DESIGN: CMV virus load was sequentially analyzed in blood, urine and saliva in 17 babies treated for symptomatic congenital CMV infection. RESULTS: Virus was detectable in the urine and saliva of all babies at baseline but in only 15/17 in blood. At the end of 6 weeks of antiviral treatment CMV remained detectable in 9/14 blood samples, 9/12 urine samples and 4/7 salivary swabs. Median half-life (T1/2) of virus decline in blood was 2.4 days (IQR 1.9-3.3) and basic reproductive number (Ro) was 2.3. Although T1/2 values were similar in urine and saliva to those observed in blood, virus dynamics differed both during and after treatment. CONCLUSIONS: T1/2 and Ro in blood in this group of neonates were similar to values derived from studies of immunocompromised adults. The persistent viremia observed in treated neonates cannot therefore be adequately explained by the virus dynamics early in treatment. The different dynamics exhibited in blood and urine suggests that studying changes in distinct body compartments may assist in further understanding long-term manifestations of disease. PMID- 27500365 TI - Beta-HPV types in patients with head and neck pathology and in healthy subjects. AB - BACKGROUND: Human papillomaviruses (HPV) are a heterogeneous group of viruses classified into five genera. The beta-HPV type (beta-PV) infection is very common but mostly asymptomatic in immunocompetent individuals. However, beta-PVs play a role in Epidermodysplasia verruciformis and possibly in non-melanoma skin cancer. Head and neck cancer (HNC) is a common cancer type worldwide and high-risk alpha PV involvement in HNC has been extensively studied but beta-PV types have rarely been the focus of such studies. OBJECTIVES: To evaluate the prevalence of beta-PV types in HNC, subjects with non-malignant or potentially pre-malignant oral lesions, and healthy controls. STUDY DESIGN: The frequency of different beta-PVs in samples from oral (n=35) and oropharyngeal (n=35) cancer patients, gender- and age-matched healthy controls (n=70), and subjects with various non-malignant or potentially pre-malignant oral lesions (n=102) was assessed by a highly sensitive, bead-based, multiplex genotyping assay. RESULTS: Overall, 54.8% of all tested samples contained at least one beta-PV type. Even though the correlation between types found in lavage and tissue specimens from cancer patients was low, there was a large statistically significant difference between oropharyngeal cancer patients and matched controls for HPV5 (P=0.003; OR=15.58) and between both oral (P=0.026; OR=5.7) and oropharyngeal cancer patients (P=0.002; OR=25.5) and controls for HPV122. In addition, there was no correlation between the prevalence of alpha and beta-PVs in the study patients. CONCLUSION: The study provides new data on the prevalence of beta-PVs in HNC. HPV5 was found significantly associated with HNC as already observed by other studies. Additionally, the significant association of HPV122 with HNC might warrant further study as this type has not been extensively studied so far. PMID- 27500366 TI - Coronary stent thrombosis: what have we learned? PMID- 27500367 TI - Effect of appendicectomy on colonic inflammation and neoplasia in experimental ulcerative colitis. AB - BACKGROUND: Ulcerative colitis (UC) promotes cancer, and can be ameliorated by early appendicectomy for appendicitis. The aim of the study was to explore the effect of appendicectomy on colitis and colonic neoplasia in an animal model of colitis and a cohort of patients with UC. METHODS: Five-week old IL10/Nox1(DKO) mice with nascent colitis and 8-week-old IL10/Nox1(DKO) mice with established colitis underwent appendicectomy (for experimental appendicitis or no appendicitis) or sham laparotomy. The severity and extent of colitis was assessed by histopathological examination, and a clinical disease activity score was given. From a cohort of consecutive patients with UC who underwent colectomy, the prevalence of appendicectomy and pathological findings were collected from two institutional databases. RESULTS: Appendicectomy for appendicitis ameliorated experimental colitis in the mice; the effect was more pronounced in the 5-week old animals. Appendicectomy in the no-appendicitis group was associated with an increased rate of colonic high-grade dysplasia (HGD) or cancer compared with rates in sham and appendicitis groups (13 of 20 versus 0 of 20 and 0 of 20 respectively; P < 0.001). Fifteen of 232 patients who underwent colectomy for UC had previously had an appendicectomy, and nine of these had colonic cancer or HGD. Thirty (13.8 per cent) of 217 patients with the appendix in situ had colonic neoplastic lesions. Multivariable analysis showed that previous appendicectomy was associated with colorectal neoplasia (odds ratio 16.88, 95 per cent c.i. 3.32 to 112.69). CONCLUSION: Appendicectomy for experimental appendicitis ameliorated colitis. The risk of colorectal neoplasia appeared to increase following appendicectomy without induced appendicitis in a mouse model of colitis, and in patients with UC who had undergone appendicectomy. Surgical relevance Appendicectomy for appendicitis protects against UC. In this murine model of colitis, appendicectomy for experimental appendicitis protected against colitis, but appendicectomy without appendicitis promoted colorectal carcinogenesis. In patients with ulcerative colitis who underwent colectomy, absence of the appendix (proof of previous appendicectomy) in the resection specimen was independently associated with colorectal neoplasia. Although patients with UC and a history of appendicectomy represent a small subset, they may need closer monitoring for colorectal neoplasia. PMID- 27500368 TI - Honorary and ghost authorship in reports of randomised clinical trials in oncology. AB - BACKGROUND: The International Committee of Medical Journal Editors (ICMJE) has developed guidelines for responsible and accountable authorship. Few studies have assessed the frequency and nature of ghost and honorary authorship in publications of oncology trials. MATERIALS AND METHODS: Reports of randomised clinical trials evaluating systemic cancer therapy published from July 2010 to December 2012 in six high-impact journals were identified systematically. Ghost authorship was determined to be present in any scenario where investigators or statisticians listed in the protocol were not included as authors and not acknowledged in the report of the trial. The list of contributions for authors of published articles was recorded, and we defined an article as having an honorary author if any author did not meet all three criteria established by ICMJE in 1985. RESULTS: Two hundred publications were identified. For 61 articles, protocols with listed investigators were available, and 40 (66%) of these articles met our definition of ghost authorship. Medical writers were involved in 89 articles (45%), and assistance was acknowledged only in sponsored trials. Contributions of each author were provided in 195 articles, and 63 (33%) articles met our definition for honorary authorship. Funding source was not a predictor for either honorary or ghost authorship. Journal impact factor was positively associated with honorary authorship (odds ratio = 1.03; 95% confidence interval = 1.004-1.065; P = 0.03), but not with ghost authorship. CONCLUSION: Ghost and honorary authorship are prevalent in articles describing trials for systemic therapy of cancer. Guidelines should be enforced to improve transparency and accountability. PMID- 27500369 TI - International normalized ratio testing with a point-of-care coagulometer in 1 month-old infants: A comparison with Normotest. AB - INTRODUCTION: Early infants are at risk of vitamin K (VK) deficiency-associated bleeding unless they receive VK prophylaxis. A coagulation screening test might be necessary to detect prophylactic failure, but it is rarely conducted owing to the difficulty of blood sampling. CoaguChek XS is a portable, point-of-care (POC) coagulation analyzer that determines international normalized ratios (INRs) using only small volumes of blood. Although POC tests assessing INR have become widespread for adults, studies have not been performed in early infancy. This study aimed to determine the reference interval (RI) for INR for 1-month-old infants using the CoaguChek XS and to compare INRs with Normotest (NT) values to evaluate its efficacy as a VK deficiency screening test. MATERIALS AND METHODS: This study included 578 consecutive 1-month-old, healthy, term infants who underwent a 1-month health checkup. CoaguChek XS INRs and NT values were analyzed for each subject. RESULTS: The enrolled neonates were orally administered VK 6 12h and 4days after birth. An INR RI for 1-month-old infants was established using the CoaguChek XS (range of 0.9-1.1). On the other hand, the NT RI was 69% 130%. We observed a significant inverse correlation between INRs and NT values. CONCLUSIONS: Our study is the first to establish an INR RI using the CoaguChek XS for 1-month-old, healthy, term infants. CoaguChek XS INR was more convenient to test than NT. However, we could not demonstrate its efficacy as a VK deficiency screening test because no infant had an aberrant NT value or a bleeding disorder. PMID- 27500370 TI - Changes in hydration of the stratum corneum are the most suitable indicator to evaluate the irritation of surfactants on the skin. AB - BACKGROUND/PURPOSE: Irritancy levels of surfactants on human skin have not been clarified completely. The relationships between skin damage and changes of skin properties caused by various surfactants were investigated using non-invasive measurements. METHODS: Aqueous solutions of seven kinds of anionic, non-ionic, and amphoteric surfactants were exposed to the inside of forearm skin of 20 human subjects in two separate studies using the cup method. Hydration of the stratum corneum (SC), transepidermal water loss (TEWL), pH, skin surface roughness, and contents of the SC were measured before and after one exposure and after five and nine consecutive exposures to various surfactants. The discontinuation ratio of subjects for testing in each surfactant was determined by skin irritation symptoms and was defined as the degree of skin damage. RESULTS: Significant changes were observed only in hydration, TEWL, and natural moisturizing factors (NMF) content in the SC following surfactant exposure. A significant correlation was observed between the discontinuation ratio of each surfactant and the changes of hydration, TEWL, and NMF. Especially, the change of SC hydration showed an excellent correlation with the discontinuation ratio both for single (r = 0.942, P < 0.001) and for chronic exposures (r = 0.934, P < 0.001). CONCLUSION: Our results indicate that the change of hydration of the SC is equivalent to the skin damage caused by surfactants, and therefore is the most suitable indicator to evaluate the irritation of surfactants on the skin. PMID- 27500371 TI - Perspectives on Promoting Hospital Primary Vaginal Birth: A Qualitative Study. AB - BACKGROUND: One in three women will deliver by cesarean, a procedure that can be life saving, but which also carries short- and long-term risks. There is growing interest in preventing primary cesarean deliveries, while optimizing the health of the mother and infant. The primary aim of this study was to use participatory action strategies and ethnographic interview data collected from diverse stakeholders in birth (caregivers, women, policymakers) about facilitators and barriers to the achievement of primary vaginal birth in first-time mothers in hospital settings. The secondary aim was to use the findings to identify strategies to promote primary vaginal birth and future areas of research. METHODS: Individual and small group interviews were conducted with caregivers and policymakers (N = 79) and first-time mothers (N = 24) at a northeastern hospital. All interviews were audio-recorded, transcribed, and analyzed using Atlas.ti. RESULTS: Four broad themes were identified: 1) preparation for childbirth, 2) early labor management, 3) caregiver knowledge and practice style, and 4) birth environment (physical, cultural/emotional). The first two were closely linked from caregivers' perspectives. If the woman was not prepared for childbirth, it was perceived she would be more likely to present to the hospital in early labor. Once there, it was hard to prevent admission and interventions. A woman's knowledge and confidence were perceived as powerful mediators for vaginal birth. CONCLUSION: Caregivers and first-time mothers identified early labor management and childbirth preparation as important factors to promote primary vaginal birth in hospital settings. Both deserve further inquiry as potential strategies to decrease rising cesarean delivery rates. PMID- 27500372 TI - Spatial and temporal variation in artisanal catches of dolphinfish Coryphaena hippurus off north-eastern Brazil. AB - The sampling of fish from the artisanal fleet operating with surface lines off north-eastern Brazil was carried out between 1998 and 2000. Generalized linear models (GLMs) were used to standardize mean abundance indices using catch and fishing effort data on dolphinfish Coryphaena hippurus and to identify abundance trends in time and space, using 1215 surface line deployments. A standard relative abundance index (catch per unit effort, CPUE) was estimated for the most frequent vessels used in the sets, employing factors and coefficients generated in the GLMs. According to the models, C. hippurus catches are affected by the operating characteristics and power of different fishing vessels. These differences highlight the need for standardization of catch and effort data for artisanal fisheries. The highest mean abundance values for C. hippurus were off the state of Rio Grande do Norte, with an increasing tendency in areas with greater depths and more distant from the coast, reaching maximal values in areas whose depths range from 200 to 500 m. The highest mean abundance values occurred between April and June. The higher estimated abundance of C. hippurus in this period off the state of Rio Grande do Norte and within the 200-500 m depth range may be related to a migration pattern of food sources, as its main prey, the flying fish Hirundichthys affinis, uses floating algae as refuge and to deposit its pelagic eggs. PMID- 27500374 TI - Rearing the Fruit Fly Drosophila melanogaster Under Axenic and Gnotobiotic Conditions. AB - The influence of microbes on myriad animal traits and behaviors has been increasingly recognized in recent years. The fruit fly Drosophila melanogaster is a model for understanding microbial interactions with animal hosts, facilitated by approaches to rear large sample sizes of Drosophila under microorganism-free (axenic) conditions, or with defined microbial communities (gnotobiotic). This work outlines a method for collection of Drosophila embryos, hypochlorite dechorionation and sterilization, and transfer to sterile diet. Sterilized embryos are transferred to sterile diet in 50 ml centrifuge tubes, and developing larvae and adults remain free of any exogenous microbes until the vials are opened. Alternatively, flies with a defined microbiota can be reared by inoculating sterile diet and embryos with microbial species of interest. We describe the introduction of 4 bacterial species to establish a representative gnotobiotic microbiota in Drosophila. Finally, we describe approaches for confirming bacterial community composition, including testing if axenic Drosophila remain bacteria-free into adulthood. PMID- 27500375 TI - Observation of Enhanced Hole Extraction in Br Concentration Gradient Perovskite Materials. AB - Enhancing hole extraction inside the perovskite layer is the key factor for boosting photovoltaic performance. Realization of halide concentration gradient perovskite materials has been expected to exhibit rapid hole extraction due to the precise bandgap tuning. Moreover, a formation of Br-rich region on the tri iodide perovskite layer is expected to enhance moisture stability without a loss of current density. However, conventional synthetic techniques of perovskite materials such as the solution process have not achieved the realization of halide concentration gradient perovskite materials. In this report, we demonstrate the fabrication of Br concentration gradient mixed halide perovskite materials using a novel and facile halide conversion method based on vaporized hydrobromic acid. Accelerated hole extraction and enhanced lifetime due to Br gradient was verified by observing photoluminescence properties. Through the combination of secondary ion mass spectroscopy and transmission electron microscopy with energy-dispersive X-ray spectroscopy analysis, the diffusion behavior of Br ions in perovskite materials was investigated. The Br-gradient was found to be eventually converted into a homogeneous mixed halide layer after undergoing an intermixing process. Br-substituted perovskite solar cells exhibited a power conversion efficiency of 18.94% due to an increase in open circuit voltage from 1.08 to 1.11 V and an advance in fill-factor from 0.71 to 0.74. Long-term stability was also dramatically enhanced after the conversion process, i.e., the power conversion efficiency of the post-treated device has remained over 97% of the initial value under high humid conditions (40-90%) without any encapsulation for 4 weeks. PMID- 27500376 TI - TMPRSS2-ERG gene fusion is rare compared to PTEN deletions in stage T1a prostate cancer. AB - T1a prostate cancers (cancer found incidentally in transurethral resection, <5% of the tissue) are indolent tumors of the transition zone. The overexpression of ERG and the inactivation of PTEN have been shown to be important drivers of carcinogenesis in large series of prostate cancer, but the genetics of transition zone tumors have not been well characterized. We evaluated the status of ERG and PTEN in formalin-fixed paraffin-embedded tissue using immunohistochemical and FISH analysis in 54 T1a transition zone tumors. The protein expression of ERG was determined using a rabbit monoclonal antibody and nuclear staining was scored as positive or negative. The genomic status of ERG was determined using three colored FISH using an ERG-TMPRSS2 tri-color probe set. The protein expression of PTEN was determined using a rabbit monoclonal antibody and cytoplasmic, and nuclear staining was scored as positive or negative. The genomic status of PTEN was determined using dual color FISH with a PTEN probe and a CEP10 probe. We found ERG rearrangement in 2 of 54 tumors (4%), one with protein overexpression by immunohistochemistry. PTEN inactivation was seen in 13 of 54 tumors (24%). Nine of the 13 PTEN alleles were inactivated by hemizygous deletion. No homozygous PTEN deletion was observed. PTEN deletion and ERG rearrangement were mutually exclusive. ERG rearrangement was rare compared to peripheral zone tumors and to PTEN inactivation in T1a transition zone tumors. (c) 2016 Wiley Periodicals, Inc. PMID- 27500377 TI - Critical telomerase activity for uncontrolled cell growth. AB - The lengths of the telomere regions of chromosomes in a population of cells are modelled using a chemical master equation formalism, from which the evolution of the average number of cells of each telomere length is extracted. In particular, the role of the telomere-elongating enzyme telomerase on these dynamics is investigated. We show that for biologically relevant rates of cell birth and death, one finds a critical rate, R crit, of telomerase activity such that the total number of cells diverges. Further, R crit is similar in magnitude to the rates of mitosis and cell death. The possible relationship of this result to replicative immortality and its associated hallmark of cancer is discussed. PMID- 27500378 TI - Ionic-liquid-based dispersive liquid-liquid microextraction combined with magnetic solid-phase extraction for the determination of aflatoxins B1 , B2 , G1 , and G2 in animal feeds by high-performance liquid chromatography with fluorescence detection. AB - A novel two-step extraction technique combining ionic-liquid-based dispersive liquid-liquid microextraction with magnetic solid-phase extraction was developed for the preconcentration and separation of aflatoxins in animal feedstuffs before high-performance liquid chromatography coupled with fluorescence detection. In this work, ionic liquid 1-octyl-3-methylimidazolium hexafluorophosphate was used as the extractant in dispersive liquid-liquid microextraction, and hydrophobic pelargonic acid modified Fe3 O4 magnetic nanoparticles as an efficient adsorbent were applied to retrieve the aflatoxins-containing ionic liquid. Notably, the target of magnetic nanoparticles was the ionic liquid rather than the aflatoxins. Because of the rapid mass transfer associated with the dispersive liquid-liquid microextraction and magnetic solid phase steps, fast extraction could be achieved. The main parameters affecting the extraction recoveries of aflatoxins were investigated and optimized. Under the optimum conditions, vortexing at 2500 rpm for 1 min in the dispersive liquid-liquid microextraction and magnetic solid phase extraction and then desorption by sonication for 2 min with acetonitrile as eluent. The recoveries were 90.3-103.7% with relative standard deviations of 3.2 6.4%. Good linearity was observed with correlation coefficients ranged from 0.9986 to 0.9995. The detection limits were 0.632, 0.087, 0.422 and 0.146 ng/mL for aflatoxins B1 , B2, G1, and G2, respectively. The results were also compared with the pretreatment method carried out by conventional immunoaffinity columns. PMID- 27500379 TI - An innovative protocol for schwann cells extracellular matrix proteins extraction. AB - The evidence that extracellular matrix (ECM) components could represent new targets for drugs designed to approach degenerative disease, requires their analysis. Before the analysis, proteins should be extracted from ECM and solubilized. Currently, few protocols for ECM proteins extraction and solubilization are available in literature, and most of them are based mainly on the use of proteolytic enzymes, such as trypsin, which often lead to proteins damage. Moreover, no methods have been so far proposed to solubilize Schwann Cell ECM, which may represent an important target for the therapy of neurodegenerative disorders. In our study, we propose to solubilize SC ECM through the use of surfactants and urea. We compared our method of solubilization, with one of that proposed in literature for a general ECM, mainly based on the use of enzymes. We want to highlight the benefit of solubilizing SC ECM, avoiding the use of proteolytic enzymes. To compare the amount of proteins extracted with both methods, MicroBCA assay was used, while the quality of the proteins extracted was observed through the SDS-PAGE. The results obtained confirm a better solubilization of SC ECM proteins with the proposed protocol, both quantitatively and qualitatively, showing a higher concentration of proteins extracted and a better enrichment of protein fractions, if compared to the enzyme-based protocol. Our results show that SC ECM could be efficiently solubilized through the use of surfactant and urea, avoiding the use of enzyme-base methods. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3175-3180, 2016. PMID- 27500380 TI - Recent Advances in Doping of Molybdenum Disulfide: Industrial Applications and Future Prospects. AB - Owing to their excellent physical properties, atomically thin layers of molybdenum disulfide (MoS2 ) have recently attracted much attention due to their nonzero-gap property, exceptionally high electrical conductivity, good thermal stability, and excellent mechanical strength, etc. MoS2 -based devices exhibit great potential for applications in optoelectronics and energy harvesting. Here, a comprehensive review of various doping strategies is presented, including wet doping and dry doping of atomically crystalline MoS2 thin layers, and the progress made so far for their doping-based prospective applications is also discussed. Finally, several significant research issues for the prospects of doped-MoS2 in industry, as a guide for 2D material community, are also provided. PMID- 27500381 TI - Long-term outcome characteristics in mesial temporal lobe epilepsy with and without associated cortical dysplasia. AB - OBJECT: The intention of our study was to identify predictive characteristics for long-term seizure control and running down phenomenon after surgical treatment of pharmacoresistant mesiotemporal lobe epilepsy (mTLE) with and without associated cortical dysplasia. MATERIALS AND METHODS: Our study comprises a consecutive series of 458 patients who underwent surgical treatment for intractable mTLE at the Epilepsy Center Freiburg. Data evaluated included semiology, duration and frequency of seizures, results of presurgical diagnostics including video-EEG monitoring, MRI, PET and SPECT as well as postoperative seizure outcome. Results were evaluated forming two groups: Group A consisted of isolated mesiotemporal lesions. Group B comprised patients with mTLE and additional focal cortical dysplasia (FCD). Statistical evaluation was based on the Kaplan Meier survival analysis, using log-rank-tests and a multivariate regression model. Postoperative running down phenomenon was defined as seizure freedom after a period of gradual reduction of postoperative seizure frequency. This was compared to patients with ongoing epilepsy. RESULTS: Complete seizure freedom was achieved in 65.0% of investigated patients at 1year and in 56.5% at long-term follow-up of >=5 years after surgery. Corresponding results were 64.2% and 56.8% at 1 and >=5 years, respectively in group A and 66.4% and 56.0%, respectively in group B. Predictive for favorable postoperative outcome in the total group were younger age at surgery, shorter duration of epilepsy, absence of secondarily generalized tonic clonic seizures (SGTCS), presence of strictly ipsilateral temporal interictal epileptiform discharges (IEDs), complete resection of the lesion as well as absence of postoperative epileptiform activity and of early postoperative seizures. In subgroup analyses, patients of group A demonstrated longer postoperative seizure-free intervals with adolescent age at surgery, short duration of epilepsy before surgery and absence of SGTCS, whereas in patients of group B ipsilateral temporal seizure onset and strictly unilateral IEDs in EEG as well as complete resection were predictors for favorable seizure outcome. Furthermore, absence of early postoperative seizures and of spikes in EEG were predictive factors for long-term seizure-freedom in both subgroups. The running down phenomenon was found in 33 (7.2%) patients. None of the parameters evaluated demonstrated significant predictive power. Only late seizure onset and neoplastic lesions showed a trend for postoperative gradual seizure reduction in multivariate analyses. CONCLUSION: Depending on the presence or absence of focal cortical dysplasia in addition to mesiotemporal structural alterations, predictors of long-term seizure control differed regarding the relevant clinical and electrophysiological features. This is important for specific patient counseling in respective groups. PMID- 27500382 TI - Regression of fibrosis and portal hypertension in HCV-associated cirrhosis and sustained virologic response after interferon-free antiviral therapy. AB - It is still controversial, whether and to what amount cirrhosis and portal hypertension are reversible in patients with hepatitis C virus (HCV)-associated cirrhosis and sustained virologic response (SVR) after interferon-free antiviral therapy. In this study, we prospectively evaluated dynamics of liver and spleen stiffness in HCV-infected patients with advanced liver disease and SVR after interferon-free treatment. A total of 54 patients with HCV-associated cirrhosis and SVR were included. Liver and spleen stiffness was measured at therapy baseline (BL), end of treatment (EOT) and 24 weeks after EOT (FU24) by transient liver elastography (L-TE) as well as by acoustic radiation force impulse of the liver (L-ARFI) and spleen (S-ARFI), as well as biochemical, virologic and clinical data. Improvement of liver and spleen stiffness was found in 44 of 50 (88%), 31 of 54 (57%) and 25 of 54 (46%) of patients assessed by L-TE, L-ARFI and S-ARFI between baseline and FU24. Liver stiffness assessed by L-TE improved between BL [median (range), 32.5 (9.1-75) kPa] and EOT [median (range), 21.3 (6.7 73.5) kPa; (P<.0001)], and between BL and FU24 [median (range), 21.2 (5.4-70) kPa; (P<.0001)]. Liver stiffness assessed by L-ARFI improved between BL [median (range), 2.7 (1.2-4.1) m/s] and FU24 [median (range), 2.4 (1.2-3.9) m/s; P=.002), while spleen stiffness remained unchanged. Our data suggest that improvement of liver stiffness may be rather due to reduced necroinflammation and may be due to a less extent to regression of cirrhosis, as dynamics of liver stiffness improvement was more pronounced between BL and EOT than BL and FU24. PMID- 27500383 TI - The effects of Risk Factor-Targeted Lifestyle Counselling Intervention on working age stroke patients' adherence to lifestyle change. AB - INTRODUCTION: Since a history of stroke or transient ischaemic attack is a major risk factor for a recurrent event, lifestyle counselling during the hospital phase is an essential component of treatment and may increase the probability of lifestyle change. AIMS AND OBJECTIVES: To study the effect of risk factor targeted lifestyle counselling intervention on working-age stroke patients' adherence to lifestyle changes. DESIGN: A quasi-experimental, nonequivalent control group pretest-post-test design. METHODS: Stroke patients in an acute neurological unit were divided into a control group (n = 75) receiving standard counselling and an experimental group (n = 75) receiving risk factor-targeted counselling. Lifestyle data and clinical outcomes were collected at hospital between January 2010 and October 2011, while data on adherence to lifestyle changes 3, 6, and 12 months after discharge. RESULTS: The baseline lifestyle habits did not differ significantly other than in alcohol behaviour. Both groups increased their intake, but the intervention group to a lesser degree. However, the experimental group significantly lost their weight for the first 3 and 6 months; at 3 months reduction in cigarette consumption and at 6 months significant increases in smoking cessation were also achieved. All improved some of their lifestyle habits. Intervention was associated with support from nurses as well as from family and friends. Adherence scores were higher in the experimental group. CONCLUSION: Some short-term advantages in lifestyle habits due to the intervention were noted. Participants in both groups improved some of their lifestyle habits. PMID- 27500384 TI - Candidate egg case silk genes for the spider Argiope argentata from differential gene expression analyses. AB - Orb-web weaving spiders produce a variety of task-specific silks from specialized silk glands. The genetics underlying the synthesis of specific silk types are largely unknown, and transcriptome analysis could be a powerful approach for identifying candidate genes. However, de novo assembly and expression profiling of silk glands with RNA-sequencing (RNAseq) are problematic because the few known gene transcripts for silk proteins are extremely long and highly repetitive. To identify candidate genes for tubuliform (egg case) silk synthesis by the orb weaver Argiope argentata (Araneidae), we estimated transcript abundance using two sequencing methods: RNAseq reads from throughout the length of mRNA molecules, and 3' digital gene expression reads from the 3' region of mRNA molecules. Both analyses identified similar sets of genes as differentially expressed when comparing tubuliform and nonsilk gland tissue. However, incompletely assembled silk gene transcripts were identified as differentially expressed because of RNAseq read alignments to highly repetitive regions, confounding interpretation of RNAseq results. Homologues of egg case silk protein (ECP) genes were upregulated in tubuliform glands. This discovery is the first description of ECP homologues in an araneid. We also propose additional candidate genes involved in synthesis of tubuliform or other silk types. PMID- 27500385 TI - Characterization of tunnel mutants reveals a catalytic step in ammonia delivery by an aminoacyl-tRNA amidotransferase. AB - The Helicobacter pylori Asp-tRNA(A) (sn) /Glu-tRNA(G) (ln) amidotransferase (GatCAB) utilizes an uncommonly hydrophilic, ~ 40 A ammonia tunnel for ammonia/ammonium transport between isolated active sites. Hydrophilicity of this tunnel requires a distinct ammonia transport mechanism, which hypothetically occurs through a series of deprotonation and protonation steps. To explore the initiation of this relay mechanism, the highly conserved tunnel residue D185 (in the GatA subunit) was enzymatically and computationally investigated by comparing D185A, D185N, and D185E mutant enzymes to wild-type GatCAB. Our results indicate that D185 acts as an acid/base residue, participating directly in catalysis. To our knowledge, this is the first example of acid/base chemistry in a glutamine dependent amidotransferase ammonia tunnel. PMID- 27500386 TI - Adult mental health outcomes of child sexual abuse survivors born at extremely low birth weight. AB - The high prevalence of child sexual abuse (CSA) is concerning, particularly as survivors are at increased risk for multiple adverse outcomes, including poor mental health across the lifespan. Children born at an extremely low birth weight (ELBW; <1000g) and who experience CSA may be a group that is especially vulnerable to psychopathology later in life. However, no research has considered the mental health risks associated with being born at ELBW and experiencing CSA. In this study, we investigated the mental health of 179 ELBW survivors and 145 matched normal birth weight (NBW; >2500g) participants at ages 22-26 and 29-36. At age 22-26, CSA was associated with increased odds of clinically significant internalizing (OR=7.32, 95% CI: 2.31-23.23) and externalizing (OR=4.65, 95% CI: 1.11-19.51) problems among ELBW participants exposed to CSA compared to those who did not, though confidence intervals were wide. At age 29-36, CSA was linked to increased odds of any current (OR=3.43, 95% CI: 1.08-10.87) and lifetime (OR=7.09, 95% CI: 2.00-25.03) non-substance use psychiatric disorders, however, this did not hold after adjustment for covariates. Statistically significant differences in mental health outcomes were not observed in NBW participants exposed to CSA compared to NBW participants who were not exposed. Survivors of significant perinatal adversity who are also exposed to CSA may be at higher risk for psychopathology through the fourth decade of life. PMID- 27500387 TI - Parental absence, child victimization, and psychological well-being in rural China. AB - Using cross-sectional data regarding 793 rural children aged 10-16 in Sichuan Province of China, the present study examined the preceding-year rates of seven forms of child victimization (physical assault, property crime, peer/sibling victimization, child maltreatment, sexual victimization, witnessing family violence, and exposure to community violence) and poly-victimization, and found children's victimization experiences increased as the degree of parental absence increased (from the presence of two biological parents, to parental migration and parental separation and divorce). Elevated levels of depression were also found among left-behind children and children of separated or divorced parents, compared to children living with both biological parents; and child poly victimization added to the risk of child depression. Certain demographic characteristics (being a boy and younger) and parental factors were associated with child victimization in rural China. This study highlights the need for child protection in rural China, and in particular for parent-absent children. PMID- 27500388 TI - Modification of tumor cell exosome content by transfection with wt-p53 and microRNA-125b expressing plasmid DNA and its effect on macrophage polarization. AB - Exosomes are responsible for intercellular communication between tumor cells and others in the tumor microenvironment. These microvesicles promote oncogensis and can support towards metastasis by promoting a pro-tumorogenic environment. Modifying the exosomal content and exosome delivery are emerging novel cancer therapies. However, the clinical translation is limited due to feasibility of isolating and delivery of treated exosomes as well as an associated immune response in patients. In this study, we provide proof-of-concept for a novel treatment approach for manipulating exosomal content by genetic transfection of tumor cells using dual-targeted hyaluronic acid-based nanoparticles. Following transfection with plasmid DNA encoding for wild-type p53 (wt-p53) and microRNA 125b (miR-125b), we evaluate the transgene expression in the SK-LU-1 cells and in the secreted exosomes. Furthermore, along with modulation of wt-p53 and miR-125b expression, we also show that the exosomes (i.e., wt-p53/exo, miR-125b/exo and combination/exo) have a reprogramed global miRNA profile. The miRNAs in the exosomes were mainly related to the activation of genes associated with apoptosis as well as p53 signaling. More importantly, these altered miRNA levels in the exosomes could mediate macrophage repolarization towards a more pro inflammatory/antitumor M1 phenotype. However, further studies, especially in vivo studies, are warranted to assess the direct influence of such macrophage reprogramming on cancer cells and oncogenesis post-treatment. The current study provides a novel platform enabling the development of therapeutic strategies affecting not only the cancer cells but also the tumor microenvironment by utilizing the 'bystander effect' through genetic transfer with secreted exosomes. Such modification could also support antitumor environment leading to decreased oncogenesis. PMID- 27500389 TI - Value of 3-Tesla multiparametric magnetic resonance imaging and targeted biopsy for improved risk stratification in patients considered for active surveillance. AB - OBJECTIVE: To evaluate the role of multiparametric magnetic resonance imaging (mpMRI) of the prostate and transrectal ultrasonography guided biopsy (TRUS-Bx) with visual estimation in early risk stratification of patients with prostate cancer on active surveillance (AS). PATIENTS AND METHODS: Patients with low-risk, low-grade, localised prostate cancer were prospectively enrolled and submitted to a 3-T 16-channel cardiac surface coil mpMRI of the prostate and confirmatory biopsy (CBx), which included a standard biopsy (SBx) and visual estimation-guided TRUS-Bx. Cancer-suspicious regions were defined using Prostate Imaging Reporting and Data System (PI-RADS) scores. Reclassification occurred if CBx confirmed the presence of a Gleason score >=7, greater than three positive fragments, or >=50% involvement of any core. The performance of mpMRI for the prediction of CBx results was assessed. Univariate and multivariate logistic regressions were performed to study relationships between age, prostate-specific antigen (PSA) level, PSA density (PSAD), number of positive cores in the initial biopsy, and mpMRI grade on CBx reclassification. Our report is consistent with the Standards of Reporting for MRI-targeted Biopsy Studies (START) guidelines. RESULTS: In all, 105 patients were available for analysis in the study. From this cohort, 42 (40%) had PI-RADS 1, 2, or 3 lesions and 63 (60%) had only grade 4 or 5 lesions. Overall, 87 patients underwent visual estimation TRUS-Bx. Reclassification among patients with PI-RADS 1, 2, 3, 4, and 5 was 0%, 23.1%, 9.1%, 74.5%, and 100%, respectively. Overall, mpMRI sensitivity, specificity, positive predictive value, and negative predictive value for disease reclassification were 92.5%, 76%, 81%, and 90.5%, respectively. In the multivariate analysis, only PSAD and mpMRI remained significant for reclassification (P < 0.05). In the cross-tabulation, SBx would have missed 15 significant cases detected by targeted biopsy, but SBx did detect five cases of significant cancer not detected by targeted biopsy alone. CONCLUSION: Multiparametric magnetic resonance imaging is a significant tool for predicting cancer severity reclassification on CBx among AS candidates. The reclassification rate on CBx is particularly high in the group of patients who have PI-RADS grades 4 or 5 lesions. Despite the usefulness of visual-guided biopsy, it still remains highly recommended to retrieve standard fragments during CBx in order to avoid missing significant tumours. PMID- 27500390 TI - Optimal sequencing of postoperative radiotherapy and chemotherapy in IIIA-N2 non small cell lung cancer. PMID- 27500392 TI - Granulomatosis with polyangiitis-associated acute subglottic stenosis in a 13 year-old boy: a case report. AB - We present a case of a child with granulomatosis with polyangiitis, admitted with acute respiratory distress attributed to subglottic stenosis. The anesthetic management and potential complications are described. PMID- 27500391 TI - MR neurography for the evaluation of CIDP. AB - INTRODUCTION: To visualize peripheral nerves in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), we used MR imaging. We also quantified the volumes of the brachial and lumbar plexus and their nerve roots. METHODS: Thirteen patients with CIDP and 12 healthy volunteers were enrolled. Whole-body MR neurography based on diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) was performed. Peripheral nerve volumes were calculated from serial axial MR images. RESULTS: The peripheral nervous system was visualized with 3-dimensional reconstruction. Volumes ranged from 8.7 to 49.5 cm3 /m2 in the brachial plexus and nerve roots and from 10.2 to 53.5 cm3 /m2 in the lumbar plexus and nerve roots. Patients with CIDP had significantly larger volumes than controls (P < 0.05), and volume was positively correlated with disease duration. CONCLUSIONS: MR neurography and the measurement of peripheral nerve volume are useful for diagnosing and assessing CIDP. Muscle Nerve 55: 483-489, 2017. PMID- 27500393 TI - Graphene-based tunable terahertz plasmon-induced transparency metamaterial. AB - A novel terahertz plasmon induced transparency (PIT) metamaterial structure consisting of single-layered graphene microstructures was proposed and numerically studied in this study. A pronounced transparency peak was obtained in the transmission spectrum, which resulted from the destructive interference between the graphene dipole and monopole antennas. Further investigations have shown that the spectral location and lineshape of the transparency peak can be dynamically controlled by tuning the Fermi level in graphene. Since the monopole antennas in our designed structure exist in a continuous form, a more convenient method for tunablity is available by applying a gate voltage compared to those structures with discrete graphene patterns. This work may open up new avenues for designing tunable terahertz functional devices and slow light devices. PMID- 27500394 TI - Experience and outcomes for relatives of patients dying in the ICU: the CAESAR tool. PMID- 27500395 TI - Stigmatizing attitudes in nurses towards people with mental illness: a cross sectional study in primary settings in Finland. AB - WHAT IS KNOWN ON THE SUBJECT?: Stigma related to mental illnesses is a great burden on societies globally. Factors associated with nurses' attitudes towards people with mental illness in health-care settings are discrepant. Stigmatized attitudes among staff members towards patients with mental illness have widely been studied in various specialized health care contexts, but less often in primary health-care settings. WHAT THIS PAPER ADDS TO THE EXISTING KNOWLEDGE?: Nurses' attitudes towards people with mental illness in general were positive in primary care health settings. Younger nurses expressed feeling afraid of mentally ill patients. They not only lacked a feeling of safety around these patients but were also often of the opinion that people with mental illness should be segregated from the general population. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Systematic and continuous mental health on-the-job training for primary care nurses is recommended to strengthen the positive attitudes of young nurses towards patients. Young nurses especially should be prevented from developing stigmatized attitudes towards patients with mental problems and to ensure a skilled workforce for the future in this demanding area of health care. ABSTRACT: Introduction Despite the development of mental health services in many countries, nurses working in different health care specialties may still have concerns and negative attitudes towards people with mental illness. Aim To describe nurses' attitudes towards people with mental illness and examine factors associated with their attitudes in primary care health centres. Method The data were collected from nursing staff (N = 264, response rate 84%) in 15 primary care health centres in two Finnish cities (spring 2014) with a self-report questionnaire (Attribution Questionnaire-27, Corrigan 2003) and analysed by descriptive statistics and multiway covariance analysis. Results Nurses' attitudes towards people with mental illness were generally positive. The nurses mostly reported willingness to help and feelings of concern and sympathy towards these patients. However, younger nurses or those without additional mental health training expressed a fear of patients. Discussion Special attention should be paid to nursing education and on-the-job training to prevent young nurses from developing stigmatized attitudes towards patients. Implications for practice Higher confidence in nursing staff could ensure a skilled work force in areas of mental health in the future, prevent young nurses from developing a fear of patients at work and support positive attitudes towards patients with mental problems. PMID- 27500396 TI - Strong phylogeographic co-structure between the anther-smut fungus and its white campion host. AB - Although congruence between host and pathogen phylogenies has been extensively investigated, the congruence between host and pathogen genetic structures at the within-species level has received little attention. Using an unprecedented and comprehensive collection of associated plant-pathogen samples, we investigated the degree of congruence between the genetic structures across Europe of two evolutionary and ecological model organisms, the anther-smut pathogen Microbotryum lychnidis-dioicae and its host plant Silene latifolia. We demonstrated a significant and particularly strong level of host-pathogen co structure, with three main genetic clusters displaying highly similar spatial ranges in Western Europe, Eastern Europe and Italy, respectively. Correcting for the geographical component of genetic variation, significant correlations were still found between the genetic distances of anther-smut and host populations. Inoculation experiments suggested plant local adaptation, at the cluster level, for resistance to pathogens. These findings indicate that the pathogen remained isolated in the same fragmented southern refugia as its host plant during the last glaciation, and that little long-distance dispersal has occurred since the recolonization of Europe for either the plant or the pathogen, despite their known ability to travel across continents. This, together with the inoculation results, suggests that coevolutionary and competitive processes may be drivers of host-pathogen co-structure. PMID- 27500397 TI - To improve outcomes of gallbladder cancer we need to better understand it! PMID- 27500398 TI - Post-prophylaxis Toxoplasma chorioretinitis following donor-recipient mismatched liver transplantation. AB - Toxoplasmosis may be transferred by organ transplantation. The most common clinical presentation is with multisystem disease, although isolated ocular toxoplasmosis has been described. Many centers have suggested that universal use of co-trimoxazole prophylaxis obviates the need for specific Toxoplasma testing. We report a case of donor-acquired ocular toxoplasmosis after liver transplantation despite co-trimoxazole prophylaxis. The diagnosis was confirmed by Toxoplasma polymerase chain reaction assay in conjunction with seroconversion. The fact that the infection was donor acquired was confirmed by serological mismatch and the absence of sporozoite-specific antigen antibody in the recipient. PMID- 27500399 TI - Direct Acoustic Stimulation at the Lateral Canal: An Alternative Route to the Inner Ear? AB - Severe to profound mixed hearing loss is associated with hearing rehabilitation difficulties. Recently, promising results for speech understanding were obtained with a direct acoustic cochlear implant (DACI). The surgical implantation of a DACI with standard coupling through a stapedotomy can however be regarded as challenging. Therefore, in this experimental study, the feasibility of direct acoustic stimulation was investigated at an anatomically and surgically more accessible inner ear site. DACI stimulation of the intact, blue-lined and opened lateral semicircular canal (LC) was investigated and compared with standard oval window (OW) coupling. Additionally, stapes footplate fixation was induced. Round window (RW) velocity, as a measure of the performance of the device and its coupling efficiency, was determined in fresh-frozen human cadaver heads. Using single point laser Doppler vibrometry, RW velocity could reliably be measured in low and middle frequency range, and equivalent sound pressure level (LE) output was calculated. Results for the different conditions obtained in five heads were analyzed in subsequent frequency ranges. Comparing the difference in RW membrane velocity showed higher LE in the LC opened condition [mean: 103 equivalent dB SPL], than in LC intact or blue-lined conditions [63 and 74 equivalent dB SPL, respectively]. No difference was observed between the LC opened and the standard OW condition. Inducing stapes fixation, however, led to a difference in the low frequency range of LE compared to LC opened. In conclusion, this feasibility study showed promising results for direct acoustic stimulation at this specific anatomically and surgically more accessible inner ear site. Future studies are needed to address the impact of LC stimulation on cochlear micromechanics and on the vestibular system like dizziness and risks of hearing loss. PMID- 27500401 TI - Cellobiose dehydrogenase and chitosan-based lysozyme responsive materials for antimicrobial wound treatment. AB - The treatment of wound infection still constitutes a major threat in health care due to the increasing number of bacterial resistances and the difficulty of timely infection detection. Here, we present a smart antimicrobial system that is activated in case of infection based on elevated lysozyme activities. N-acetyl chitosan (degree of N-acetylation: 40%) was synthesized and hydrolysis by lysozyme in artificial wound fluid (AWF) was demonstrated. This resulted in the formation of N-acetylated chito oligosaccharides (COS) with a degree of polymerization of 2-5 units. The COS were shown to serve as substrate for cellobiose dehydrogenase (CDH) leading to the production of 1 mM antimicrobial hydrogen peroxide (H2 O2 ) after 24 h incubation at 37 degrees C in AWF. Growth inhibition was seen upon incubation of Escherichia coli and Staphylococcus aureus with this chitosan-CDH system over 8 h. This approach represents the first self regulating system for the infection responsive inhibition of bacterial growth in response to lysozyme as infection biomarker. Biotechnol. Bioeng. 2017;114: 416 422. (c) 2016 Wiley Periodicals, Inc. PMID- 27500400 TI - A MultiSite Gateway Toolkit for Rapid Cloning of Vertebrate Expression Constructs with Diverse Research Applications. AB - Recombination-based cloning is a quick and efficient way to generate expression vectors. Recent advancements have provided powerful recombinant DNA methods for molecular manipulations. Here, we describe a novel collection of three-fragment MultiSite Gateway cloning system-compatible vectors providing expanded molecular tools for vertebrate research. The components of this toolkit encompass a broad range of uses such as fluorescent imaging, dual gene expression, RNA interference, tandem affinity purification, chemically-inducible dimerization and lentiviral production. We demonstrate examples highlighting the utility of this toolkit for producing multi-component vertebrate expression vectors with diverse primary research applications. The vectors presented here are compatible with other Gateway toolkits and collections, facilitating the rapid generation of a broad range of innovative DNA constructs for biological research. PMID- 27500402 TI - Correction: Bayesian Multi-Trait Analysis Reveals a Useful Tool to Increase Oil Concentration and to Decrease Toxicity in Jatropha curcas L. AB - [This corrects the article DOI: 10.1371/journal.pone.0157038.]. PMID- 27500403 TI - A Complex System of Glacial Sub-Refugia Drives Endemic Freshwater Biodiversity on the Tibetan Plateau. AB - Although only relatively few freshwater invertebrate families are reported from the Tibetan Plateau, the degree of endemism may be high. Many endemic lineages occur within permafrost areas, raising questions about the existence of isolated intra-plateau glacial refugia. Moreover, if such refugia existed, it might be instructive to learn whether they were associated with lakes or with more dynamic ecosystems such as ponds, wetlands, or springs. To study these hypotheses, we used pulmonate snails of the plateau-wide distributed genus Radix as model group and the Lake Donggi Cona drainage system, located in the north-eastern part of the plateau, as model site. First, we performed plateau-wide phylogenetic analyses using mtDNA data to assess the overall relationships of Radix populations inhabiting the Lake Donggi Cona system for revealing refugial lineages. We then conducted regional phylogeographical analyses applying a combination of mtDNA and nuclear AFLP markers to infer the local structure and demographic history of the most abundant endemic Radix clade for identifying location and type of (sub-)refugia within the drainage system. Our phylogenetic analysis showed a high diversity of Radix lineages in the Lake Donggi Cona system. Subsequent phylogeographical analyses of the most abundant endemic clade indicated a habitat-related clustering of genotypes and several Late Pleistocene spatial/demographic expansion events. The most parsimonious explanation for these patterns would be a scenario of an intra-plateau glacial refugium in the Lake Donggi Cona drainage system, which might have consisted of isolated sub-refugia. Though the underlying processes remain unknown, an initial separation of lake and watershed populations could have been triggered by lake-level fluctuations before and during the Last Glacial Maximum. This study inferred the first intra-plateau refugium for freshwater animals on the Tibetan Plateau. It thus sheds new light on the evolutionary history of its endemic taxa and provides important insights into the complex refugial history of a high-altitude ecosystem. PMID- 27500404 TI - Comparison of Two New Robust Parameter Estimation Methods for the Power Function Distribution. AB - Estimation of any probability distribution parameters is vital because imprecise and biased estimates can be misleading. In this study, we investigate a flexible power function distribution and introduced new two methods such as, probability weighted moments, and generalized probability weighted methods for its parameters. We compare their results with L-moments, trimmed L-moments by a simulation study and a real data example based on performance measures such as, mean square error and total deviation. We concluded that all the methods perform well in the case of large sample size (n>30), however, the generalized probability weighted moment method performs better for small sample size. PMID- 27500405 TI - Combined GSTM1-Null, GSTT1-Active, GSTA1 Low-Activity and GSTP1-Variant Genotype Is Associated with Increased Risk of Clear Cell Renal Cell Carcinoma. AB - The aim of this study was to evaluate specific glutathione S-transferase (GST) gene variants as determinants of risk in patients with clear cell renal cell carcinoma (cRCC), independently or simultaneously with established RCC risk factors, as well as to discern whether phenotype changes reflect genotype associated risk. GSTA1, GSTM1, GSTP1 and GSTT1 genotypes were determined in 199 cRCC patients and 274 matched controls. Benzo(a)pyrene diolepoxide (BPDE)-DNA adducts were determined in DNA samples obtained from cRCC patients by ELISA method. Significant association between GST genotype and risk of cRCC development was found for the GSTM1-null and GSTP1-variant genotype (p = 0.02 and p<0.001, respectively). Furthermore, 22% of all recruited cRCC patients were carriers of combined GSTM1-null, GSTT1-active, GSTA1-low activity and GSTP1-variant genotype, exhibiting 9.32-fold elevated cRCC risk compared to the reference genotype combination (p = 0.04). Significant association between GST genotype and cRCC risk in smokers was found only for the GSTP1 genotype, while GSTM1-null/GSTP1 variant/GSTA1 low-activity genotype combination was present in 94% of smokers with cRCC, increasing the risk of cRCC up to 7.57 (p = 0.02). Furthermore, cRCC smokers with GSTM1-null genotype had significantly higher concentration of BPDE DNA adducts in comparison with GSTM1-active cRCC smokers (p = 0.05). GSTM1, GSTT1, GSTA1 and GSTP1 polymorphisms might be associated with the risk of cRCC, with special emphasis on GSTM1-null and GSTP1-variant genotypes. Combined GSTM1 null, GSTT1-active, GSTA1 low activity and GSTP1-variant genotypes might be considered as "risk-carrying genotype combination" in cRCC. PMID- 27500406 TI - Diminished KCC2 confounds synapse specificity of LTP during senescence. AB - The synapse specificity of long-term potentiation (LTP) ensures that no interference arises from inputs irrelevant to the memory to be encoded. In hippocampi of aged (21-28 months) mice, LTP was relayed to unstimulated synapses, blemishing its synapse specificity. Diminished levels of the K(+)/Cl(-) cotransporter KCC2 and a depolarizing GABAA receptor-mediated synaptic component following LTP were the most likely causes for the spreading of potentiation, unveiling mechanisms hindering information storage in the aged brain and identifying KCC2 as a potential target for intervention. PMID- 27500408 TI - Large-Scale Production of Cardiomyocytes from Human Pluripotent Stem Cells Using a Highly Reproducible Small Molecule-Based Differentiation Protocol. AB - Maximizing the benefit of human pluripotent stem cells (hPSCs) for research, disease modeling, pharmaceutical and clinical applications requires robust methods for the large-scale production of functional cell types, including cardiomyocytes. Here we demonstrate that the temporal manipulation of WNT, TGF beta, and SHH signaling pathways leads to highly efficient cardiomyocyte differentiation of single-cell passaged hPSC lines in both static suspension and stirred suspension bioreactor systems. Employing this strategy resulted in ~ 100% beating spheroids, consistently containing > 80% cardiac troponin T-positive cells after 15 days of culture, validated in multiple hPSC lines. We also report on a variation of this protocol for use with cell lines not currently adapted to single-cell passaging, the success of which has been verified in 42 hPSC lines. Cardiomyocytes generated using these protocols express lineage-specific markers and show expected electrophysiological functionalities. Our protocol presents a simple, efficient and robust platform for the large-scale production of human cardiomyocytes. PMID- 27500407 TI - Connectivity precedes function in the development of the visual word form area. AB - What determines the cortical location at which a given functionally specific region will arise in development? We tested the hypothesis that functionally specific regions develop in their characteristic locations because of pre existing differences in the extrinsic connectivity of that region to the rest of the brain. We exploited the visual word form area (VWFA) as a test case, scanning children with diffusion and functional imaging at age 5, before they learned to read, and at age 8, after they learned to read. We found the VWFA developed functionally in this interval and that its location in a particular child at age 8 could be predicted from that child's connectivity fingerprints (but not functional responses) at age 5. These results suggest that early connectivity instructs the functional development of the VWFA, possibly reflecting a general mechanism of cortical development. PMID- 27500409 TI - An Efficient Method to Obtain Dedifferentiated Fat Cells. AB - Tissue engineering and cell therapy hold great promise clinically. In this regard, multipotent cells, such as mesenchymal stem cells (MSCs), may be used therapeutically, in the near future, to restore function to damaged organs. Nevertheless, several technical issues, including the highly invasive procedure of isolating MSCs and the inefficiency surrounding their amplification, currently hamper the potential clinical use of these therapeutic modalities. Herein, we introduce a highly efficient method for the generation of dedifferentiated fat cells (DFAT), MSC-like cells. Interestingly, DFAT cells can be differentiated into several cell types including adipogenic, osteogenic, and chondrogenic cells. Although other groups have previously presented various methods for generating DFAT cells from mature adipose tissue, our method allows us to produce DFAT cells more efficiently. In this regard, we demonstrate that DFAT culture medium (DCM), supplemented with 20% FBS, is more effective in generating DFAT cells than DMEM, supplemented with 20% FBS. Additionally, the DFAT cells produced by our cell culture method can be redifferentiated into several tissue types. As such, a very interesting and useful model for the study of tissue dedifferentiation is presented. PMID- 27500411 TI - Comparison of Methods for Predicting the Compositional Dependence of the Density and Refractive Index of Organic-Aqueous Aerosols. AB - Representing the physicochemical properties of aerosol particles of complex composition is of crucial importance for understanding and predicting aerosol thermodynamic, kinetic, and optical properties and processes and for interpreting and comparing analysis methods. Here, we consider the representations of the density and refractive index of aqueous-organic aerosol with a particular focus on the dependence of these properties on relative humidity and water content, including an examination of the properties of solution aerosol droplets existing at supersaturated solute concentrations. Using bulk phase measurements of density and refractive index for typical organic aerosol components, we provide robust approaches for the estimation of these properties for aerosol at any intermediate composition between pure water and pure solute. Approximately 70 compounds are considered, including mono-, di- and tricarboxylic acids, alcohols, diols, nitriles, sulfoxides, amides, ethers, sugars, amino acids, aminium sulfates, and polyols. We conclude that the molar refraction mixing rule should be used to predict the refractive index of the solution using a density treatment that assumes ideal mixing or, preferably, a polynomial dependence on the square root of the mass fraction of solute, depending on the solubility limit of the organic component. Although the uncertainties in the density and refractive index predictions depend on the range of subsaturated compositional data available for each compound, typical errors for estimating the solution density and refractive index are less than +/-0.1% and +/-0.05%, respectively. Owing to the direct connection between molar refraction and the molecular polarizability, along with the availability of group contribution models for predicting molecular polarizability for organic species, our rigorous testing of the molar refraction mixing rule provides a route to predicting refractive indices for aqueous solutions containing organic molecules of arbitrary structure. PMID- 27500410 TI - Real-time X-ray Imaging of Lung Fluid Volumes in Neonatal Mouse Lung. AB - At birth, the lung undergoes a profound phenotypic switch from secretion to absorption, which allows for adaptation to breathing independently. Promoting and sustaining this phenotype is critically important in normal alveolar growth and gas exchange throughout life. Several in vitro studies have characterized the role of key regulatory proteins, signaling molecules, and steroid hormones that can influence the rate of lung fluid clearance. However, in vivo examinations must be performed to evaluate whether these regulatory factors play important physiological roles in regulating perinatal lung liquid absorption. As such, the utilization of real time X-ray imaging to determine perinatal lung fluid clearance, or pulmonary edema, represents a technological advancement in the field. Herein, we explain and illustrate an approach to assess the rate of alveolar lung fluid clearance and alveolar flooding in C57BL/6 mice at post natal day 10 using X-ray imaging and analysis. Successful implementation of this protocol requires prior approval from institutional animal care and use committees (IACUC), an in vivo small animal X-ray imaging system, and compatible molecular imaging software. PMID- 27500412 TI - Identification and Investigation of Novel Binding Fragments in the Fatty Acid Binding Protein 6 (FABP6). AB - Fatty acid binding protein 6 (FABP6) is a potential drug discovery target, which, if inhibited, may have a therapeutic benefit for the treatment of diabetes. Currently, there are no published inhibitors of FABP6, and with the target believed to be amenable to fragment-based drug discovery, a structurally enabled program was initiated. This program successfully identified fragment hits using the surface plasmon resonance (SPR) platform. Several hits were validated with SAR and were found to be displaced by the natural ligand taurocholate. We report the first crystal structure of human FABP6 in the unbound form, in complex with cholate, and with one of the key fragments. PMID- 27500413 TI - Adverse Childhood Experiences and Cervical Cancer Screening. AB - BACKGROUND: Adverse childhood experiences (ACEs) have been associated with an increased risk of a variety of diseases, including cancer. However, research has largely ignored how ACEs impact cancer screening, a potential intermediate outcome. As such, the present study examined the association between ACEs and ever and recent use of Papanicolaou (Pap) test, among women aged 21 and older. MATERIALS AND METHODS: Analyses used the 2009 Tennessee Behavioral Risk Factor Surveillance System (n = 1527) to model odds of ever and recently (within the last 3 years) engaging in Pap tests screening from nine different adversities. Bivariate and multivariate logistic regression models were run to accomplish this. RESULTS: In bivariate and multivariate models, living in a household in which adults treated each other violently increased odds of ever receiving a Pap test. In bivariate models, physical and sexual abuse was associated with decreased odds of receiving a recent Pap test. After accounting for confounders, only the latter association remained significant. CONCLUSIONS: Results highlight a potential mechanism by which early childhood experiences can impact the development of cervical cancer. Providers of care should consider modifications to their screening practices, including screening for child abuse, to better serve all women. PMID- 27500414 TI - Application of Free Energy Perturbation for the Design of BACE1 Inhibitors. AB - Novel spiroaminodihydropyrroles probing for optimized interactions at the P3 pocket of beta-secretase 1 (BACE1) were designed with the use of free energy perturbation (FEP) calculations. The resulting molecules showed pIC50 potencies in enzymatic BACE1 inhibition assays ranging from approximately 5 to 7. Good correlation was observed between the predicted activity from the FEP calculations and experimental activity. Simulations run with a default 5 ns approach delivered a mean unsigned error (MUE) between prediction and experiment of 0.58 and 0.91 kcal/mol for retrospective and prospective applications, respectively. With longer simulations of 10 and 20 ns, the MUE was in both cases 0.57 kcal/mol for the retrospective application, and 0.69 and 0.59 kcal/mol for the prospective application. Other considerations that impact the quality of the calculations are discussed. This work provides an example of the value of FEP as a computational tool for drug discovery. PMID- 27500415 TI - Hydrogenated Cagelike Titania Hollow Spherical Photocatalysts for Hydrogen Evolution under Simulated Solar Light Irradiation. AB - We synthesized the hydrogenated cagelike TiO2 hollow spheres through a facile sacrificial template method. After the hydrogenation treatment, the disordered surface layer and cagelike pores were generated on the shell of the hollow spheres. The spheres exhibit a high hydrogen evolution rate of 212.7 +/- 10.6 MUmol h(-1) (20 mg) under the simulated solar light irradiation, which is ~12 times higher than the hydrogenated TiO2 solid spheres and is ~9 times higher than the original TiO2 hollow spheres. The high activity results from the unique architectures and hydrogenation. Both the multiple reflection that was improved by the cagelike hollow structures and the red shift of the absorption edge that was induced by hydrogenation can enhance the ultraviolet and visible light absorption. In addition, the high concentration of oxygen vacancies, as well as the hydrogenated disordered surface layer, can improve the efficiency for migration and separation of generated charge carriers. PMID- 27500416 TI - Residue-specific Incorporation of Noncanonical Amino Acids into Model Proteins Using an Escherichia coli Cell-free Transcription-translation System. AB - The canonical set of amino acids leads to an exceptionally wide range of protein functionality. Nevertheless, the set of residues still imposes limitations on potential protein applications. The incorporation of noncanonical amino acids can enlarge this scope. There are two complementary approaches for the incorporation of noncanonical amino acids. For site-specific incorporation, in addition to the endogenous canonical translational machineries, an orthogonal aminoacyl-tRNA synthetase-tRNA pair must be provided that does not interact with the canonical ones. Consequently, a codon that is not assigned to a canonical amino acid, usually a stop codon, is also required. This genetic code expansion enables the incorporation of a noncanonical amino acid at a single, given site within the protein. The here presented work describes residue-specific incorporation where the genetic code is reassigned within the endogenous translational system. The translation machinery accepts the noncanonical amino acid as a surrogate to incorporate it at canonically prescribed locations, i.e., all occurrences of a canonical amino acid in the protein are replaced by the noncanonical one. The incorporation of noncanonical amino acids can change the protein structure, causing considerably modified physical and chemical properties. Noncanonical amino acid analogs often act as cell growth inhibitors for expression hosts since they modify endogenous proteins, limiting in vivo protein production. In vivo incorporation of toxic noncanonical amino acids into proteins remains particularly challenging. Here, a cell-free approach for a complete replacement of L-arginine by the noncanonical amino acid L-canavanine is presented. It circumvents the inherent difficulties of in vivo expression. Additionally, a protocol to prepare target proteins for mass spectral analysis is included. It is shown that L-lysine can be replaced by L-hydroxy-lysine, albeit with lower efficiency. In principle, any noncanonical amino acid analog can be incorporated using the presented method as long as the endogenous in vitro translation system recognizes it. PMID- 27500417 TI - HPLC-based Assay to Monitor Extracellular Nucleotide/Nucleoside Metabolism in Human Chronic Lymphocytic Leukemia Cells. AB - This method describes a sensitive, specific, reliable and reproducible reverse phase high-performance liquid chromatography (RP-HPLC) assay developed and validated for the quantification of extracellular purine nucleotides and nucleosides produced by purified chronic lymphocytic leukemia (CLL) cells under different culture conditions. The chromatographic separation of adenosine 5' monophosphate (AMP), adenosine (ADO) and inosine (INO) is performed at RT on a silica-based, reversed-phase column that is used for polar compound retention. The method includes a binary mobile phase, which consists of 7 mM ammonium acetate and acetonitrile with a flow rate of 1.00 ml/min. The eluates are monitored using a Photodiode Array UV detector set at 260 nm. A standard calibration curve is generated to calculate the equation for the analytical quantification of each purine compound. System control, data acquisition and analysis are then performed. Applying this protocol, AMP, INO and ADO elute at 7, 11 and 11.9 min, respectively, and the total run time for each sample is 20 min. This protocol may be applied to different cell types and cell lines (both suspension and adherent), using culture media as matrix. The advantages are easy and fast sample preparation and the requirement of a small amount of supernatant for analysis. Furthermore, the use of a serum-free medium allows skipping the protein precipitation step with acetonitrile that impacts the final concentration of purine compounds. One of the limitations of the method is the requirement of the equilibration column run before each single sample run, making the total run time of the experiment longer and preventing high throughput screening applications. PMID- 27500418 TI - New isocoumarin and stilbenoid derivatives from the tubers of Sparganium stoloniferum (Buch.-Ham.). AB - A new isocoumarin derivative 8,5'-dihydroxy-6'-methoxy-4-phenyl-5,2' oxidoisocoumarin (1) and a new stilbenoid derivative methyl 5-hydroxy-2-(2 hydroxyphenyl)benzofuran-4-carboxylate (2) together with nine known compounds (3 11) were isolated from the tubers of Sparganium stoloniferum Buch.-Ham.. Another stilbenoid derivative (3) and a xanthone (4) were identified as new natural products and compounds 5-10 were obtained for the first time from the genus Sparganium. All their structures were elucidated by comprehensive spectroscopic analysis and comparison with available literature information. PMID- 27500419 TI - Comparison of Light Penetration of Continuous Wave 810 nm and Superpulsed 904 nm Wavelength Light in Anesthetized Rats. AB - OBJECTIVE: The purpose of this study was to investigate light transmission of continuous wave (CW) 810 nm wavelength light and 904 nm wavelength superpulsed light through skin and gastrocnemius muscle and skin only using an anesthetized Sprague-Dawley rat model. MATERIALS AND METHODS: The hair was shaved from the left thigh region of the anesthetized rats and a detector, which measured fluence rate, was placed either in the fascial plane deep into the muscle or below the dermis. The laser probe was placed in contact with the surface of the skin and measurements were taken for 4, 5, 10, 15, and 20 min depending on the experiment. RESULTS: The initial fluence rate measurements through the muscle and skin demonstrated that if the 904 nm wavelength superpulsed laser was turned on for a minimum of 15 min, there was no increase in light penetration over time. With appropriate warm-up periods, both lasers had stable output powers, which were reflected in stable fluence rate measurements over 4 min. The percentages of light transmission (fluence rate) through muscle and skin were 7.42% (810 nm wavelength) and 4.01% (904 nm wavelength) and through skin were 24.63% (810 nm wavelength) and 19.94% (904 nm wavelength). These data prove that transmission of CW 810 nm wavelength light through muscle and skin and skin alone is greater than transmission of superpulsed 904 nm wavelength light. CONCLUSIONS: It has been previously reported that superpulsing 904 nm wavelength light increased depth of penetration over time due to photobleaching. Based on our data, the observed increase in light penetration over time was due to an insufficient warm-up period of the superpulsed laser. PMID- 27500420 TI - March 2016 (vol. 214, no. 3, pages 403-6). PMID- 27500421 TI - The Necessity of OCT-4 and CDX2 for Early Development and Gene Expression Involved in Differentiation of Inner Cell Mass and Trophectoderm Lineages in Bovine Embryos. AB - The functions of POU class 5 transcription factor 1 (Oct-4) and caudal-type homeobox 2 (Cdx2) in the differentiation of the murine inner cell mass (ICM) and trophectoderm (TE) have been described in detail. However, little is known about the roles of OCT-4 and CDX2 in preimplantation bovine embryos. To elucidate their functions during early development in bovine embryos, we performed OCT-4 and CDX2 downregulation using RNA interference. We injected OCT-4- or CDX2-specific short interfering RNAs (siRNAs) into bovine zygotes. The rate of blastocyst development of OCT-4-downregulated embryos was lower compared with uninjected or control siRNA-injected embryos. Gene expression analysis revealed decreased CDX2 and fibroblast growth factor 4 expression in OCT-4-downregulated embryos. CDX2 downregulated embryos developed to the blastocyst stage; however, in most cases, blastocoel formation was delayed. Gene expression analysis revealed decreased GATA3 expression and elevated NANOG expression in CDX2-downregulated embryos. In conclusion, OCT-4 and CDX2 are essential for early development and gene expression involved in differentiation of ICM and TE lineages in bovine embryos. PMID- 27500422 TI - Two Polymorphic Forms of a Six-Coordinate Mononuclear Cobalt(II) Complex with Easy-Plane Anisotropy: Structural Features, Theoretical Calculations, and Field Induced Slow Relaxation of the Magnetization. AB - A mononuclear cobalt(II) complex [Co(3,5-dnb)2(py)2(H2O)2] {3,5-Hdnb = 3,5 dinitrobenzoic acid; py = pyridine} was isolated in two polymorphs, in space groups C2/c (1) and P21/c (2). Single-crystal X-ray diffraction analyses reveal that 1 and 2 are not isostructural in spite of having equal formulas and ligand connectivity. In both structures, the Co(II) centers adopt octahedral {CoN2O4} geometries filled by pairs of mutually trans terminal 3,5-dnb, py, and water ligands. However, the structures of 1 and 2 disclose distinct packing patterns driven by strong intermolecular O-H...O hydrogen bonds, leading to their 0D->2D (1) or 0D->1D (2) extension. The resulting two-dimensional layers and one dimensional chains were topologically classified as the sql and 2C1 underlying nets, respectively. By means of DFT theoretical calculations, the energy variations between the polymorphs were estimated, and the binding energies associated with the noncovalent interactions observed in the crystal structures were also evaluated. The study of the direct-current magnetic properties, as well as ab initio calculations, reveal that both 1 and 2 present a strong easy-plane magnetic anisotropy (D > 0), which is larger for the latter polymorph (D is found to exhibit values between +58 and 117 cm(-1) depending on the method). Alternating current dynamic susceptibility measurements show that these polymorphs exhibit field-induced slow relaxation of the magnetization with Ueff values of 19.5 and 21.1 cm(-1) for 1 and 2, respectively. The analysis of the whole magnetic data allows the conclusion that the magnetization relaxation in these polymorphs mainly takes place through a virtual excited state (Raman process). It is worth noting that despite the notable difference between the supramolecular networks of 1 and 2, they exhibit almost identical magnetization dynamics. This fact suggests that the relaxation process is intramolecular in nature and that the virtual state involved in the two-phonon Raman process lies at a similar energy in polymorphs 1 and 2 (~20 cm(-1)). Interestingly, this value is recurrent in Co(II) single-ion magnets, even for those displaying different coordination number and geometry. PMID- 27500423 TI - Selective Harvesting of Marginating-hepatic Leukocytes. AB - Marginating-hepatic (MH) leukocytes (leukocytes adhering to the sinusoids of the liver), were shown to exhibit unique composition and characteristics compared to leukocytes of other immune compartments. Specifically, evidence suggests a distinct pro- and anti-inflammatory profile of the MH-leukocyte population and higher cytotoxicity of liver-specific NK cells (namely, pit cells) compared to circulating or splenic immunocytes in both mice and rats. The method presented herein enables selective harvesting of MH leukocytes by forced perfusion of the liver in mice and rats. In contrast to other methods used to extract liver leukocytes, including tissue grinding and biological degradation, this method exclusively yields leukocytes from the liver sinusoids, uncontaminated by cells from other liver compartments. In addition, the perfusion technique better preserves the integrity and the physiological milieu of MH leukocytes, sparing known physiological responses to tissue processing. As many circulating malignant cells and infected cells are detained while passing through the liver sinusoids, physically interacting with endothelial cells and resident leukocytes, the unique MH leukocyte population is strategically located to interact, identify, and react towards aberrant circulating cells. Thus, selective harvesting of MH-leukocytes and their study under various conditions may advance our understanding of the biological and clinical significance of MH leukocytes, specifically with respect to circulating aberrant cells and liver-related diseases and cancer metastases. PMID- 27500424 TI - Glycoproteomic Analysis of Malignant Ovarian Cancer Ascites Fluid Identifies Unusual Glycopeptides. AB - Ovarian cancer is a major cause of cancer mortality among women, largely due to late diagnosis of advanced metastatic disease. More extensive molecular analysis of metastatic ovarian cancer is needed to identify post-translational modifications of proteins, especially glycosylation that is particularly associated with metastatic disease to better understand the metastatic process and identify potential therapeutic targets. Glycoproteins in ascites fluid were enriched by affinity binding to lectins (ConA or WGA) and other affinity matrices. Separate glycomic, proteomic, and glycopeptide analyses were performed. Relative abundances of different N-glycan groups and proteins were identified from ascites fluids and a serum control. Levels of biomarkers CA125, MUC1, and fibronectin were also monitored in OC ascites samples by Western blot analysis. N Glycan analysis of ascites fluids showed the presence of large, highly fucosylated and sialylated complex and hybrid glycans, some of which were not observed in normal serum. OC ascites glycoproteins, haptoglobin, fibronectin, lumican, fibulin, hemopexin, ceruloplasmin, alpha-1-antitrypsin, and alpha-1 antichymotrypsin were more abundant in OC ascites or not present in serum control samples. Further glycopeptide analysis of OC ascites identified N- and O-glycans in clusterin, hemopexin, and fibulin glycopeptides, some of which are unusual and may be important in OC metastasis. PMID- 27500425 TI - Boronic Acid: A Bio-Inspired Strategy To Increase the Sensitivity and Selectivity of Fluorescent NADH Probe. AB - Fluorescent probes have emerged as an essential tool in the molecular recognition events in biological systems; however, due to the complex structures of certain biomolecules, it remains a challenge to design small-molecule fluorescent probes with high sensitivity and selectivity. Inspired by the enzyme-catalyzed reaction between biomolecule and probe, we present a novel combination-reaction two-step sensing strategy to improve sensitivity and selectivity. Based on this strategy, we successfully prepared a turn-on fluorescent reduced nicotinamide adenine dinucleotide (NADH) probe, in which boronic acid was introduced to bind with NADH and subsequently accelerate the sensing process. This probe shows remarkably improved sensitivity (detection limit: 0.084 MUM) and selectivity to NADH in the absence of any enzymes. In order to improve the practicality, the boronic acid was further modified to change the measurement conditions from alkalescent (pH 9.5) to physiological environment (pH 7.4). Utilizing these probes, we not only accurately quantified the NADH weight in a health care product but also evaluated intracellular NADH levels in live cell imaging. Thus, these bio-inspired fluorescent probes offer excellent tools for elucidating the roles of NADH in biological systems as well as a practical strategy to develop future sensitive and selective probes for complicated biomolecules. PMID- 27500426 TI - What should we consider when applying termination of resuscitation rules? PMID- 27500428 TI - Isolating Mesangiogenic Progenitor Cells (MPCs) from Human Bone Marrow. AB - In a research study aimed to isolate human bone marrow (hBM)-derived Mesenchymal Stromal Cells (MSCs) for clinical applications, we identified a novel cell population specifically selected for growth in human serum supplemented medium. These cells are characterized by morphological, phenotypic, and molecular features distinct from MSCs and we named them Mesodermal Progenitor Cells (MPCs). MPCs are round, with a thick highly refringent core region; they show strong, trypsin resistant adherence to plastic. Failure to expand MPCs directly revealed that they are slow in cycling. This is as also suggested by Ki-67 negativity. On the other hand, culturing MPCs in standard medium designed for MSC expansion, gave rise to a population of exponentially growing MSC-like cells. Besides showing mesenchymal differentiation capacity MPCs retained angiogenic potential, confirming their multiple lineage progenitor nature. Here we describe an optimized highly reproducible protocol to isolate and characterize hBM-MPCs by flow cytometry (CD73, CD90, CD31, and CD45), nestin expression, and F-actin organization. Protocols for mesengenic and angiogenic differentiation of MPCs are also provided. Here we also suggest a more appropriate nomenclature for these cells, which has been re-named as "Mesangiogenic Progenitor Cells". PMID- 27500427 TI - The Effectiveness and Long-Term Outcome of Conjunctivodacryocystorhinostomy With Frosted Jones Tubes. AB - PURPOSE: To describe success rates and long-term outcomes of conjunctivodacryocystorhinostomy (CDCR) with frosted Jones tubes (FJT) for epiphora with proximal outflow obstruction. METHODS: A retrospective chart review of all patients undergoing external and endoscopic CDCR with FJTs by one author (RAD) was performed between January 1, 2006 and November 1, 2014 at the Casey Eye Institute. Patient demographics, etiology of tearing, concurrent endonasal and eyelid procedures, and FJT size were recorded. After CDCR, follow-up time, tube size changes, tube position, and tearing status were noted. Exclusion criteria included follow up less than 6 months and/or prior CDCR. The study was IRB approved, HIPAA compliant, and adherent to the declaration of Helsinki. RESULTS: Forty-two eyes of 31 patients met the inclusion criteria, with the majority having epiphora from canalicular obstruction (31%) or flaccid canaliculi (31%). Average follow up was 1,088 days. Forty of 42 eyes, or 30 of 31 patients, had complete resolution of tearing after surgery. Twenty of 42 eyes required tube size changes, usually an increase in collar size (45%) and/or decrease in tube length (55%). Six of 42 FJTs were lost, one migrating outward, with an average time to loss between 61 and 1,122 days (mean 817 days). After collars larger than 4 mm became available, only one tube was lost. All epiphora resolved after repeat CDCR. The most common complication was intermittent irritation (17%) near the FJT that resolved after antibiotic-steroid drops and/or tube replacement/cleaning. CONCLUSION: CDCR with FJTs is highly effective in correcting epiphora, and well tolerated by the majority. PMID- 27500429 TI - Achieving High-Energy-High-Power Density in a Flexible Quasi-Solid-State Sodium Ion Capacitor. AB - Simultaneous integration of high-energy output with high-power delivery is a major challenge for electrochemical energy storage systems, limiting dual fine attributes on a device. We introduce a quasi-solid-state sodium ion capacitor (NIC) based on a battery type urchin-like Na2Ti3O7 anode and a capacitor type peanut shell derived carbon cathode, using a sodium ion conducting gel polymer as electrolyte, achieving high-energy-high-power characteristics in solid state. Energy densities can reach 111.2 Wh kg(-1) at power density of 800 W kg(-1), and 33.2 Wh kg(-1) at power density of 11200 W kg(-1), which are among the best reported state-of-the-art NICs. The designed device also exhibits long-term cycling stability over 3000 cycles with capacity retention ~86%. Furthermore, we demonstrate the assembly of a highly flexible quasi-solid-state NIC and it shows no obvious capacity loss under different bending conditions. PMID- 27500430 TI - Tenosynovitis of the Hand and Wrist: A Critical Analysis Review. AB - Trigger FingerTrigger finger is common in patients with diabetes.Corticosteroid injections are effective in about 60% to 92% of cases.Proximal interphalangeal joint contracture may occur in long-standing cases.The outcomes of open and percutaneous releases are similar; however, surgeons are split on preferences. Intersection SyndromeThe classic finding is crepitus with wrist motion at the distal one-third of the radial aspect of the forearm. Extensor Pollicis Longus (EPL) TenosynovitisCorticosteroid injections should be used with caution because of the potential for rupture.EPL tenosynovitis is very rare. de Quervain DisorderThis condition is common in postpartum women.A positive Finkelstein test is considered to be pathognomonic of de Quervain disorder, but care should be taken to differentiate this condition from thumb carpometacarpal arthritis.Corticosteroid injections are effective in about 80% of cases.Patients in whom corticosteroid injections fail to provide relief of symptoms frequently have a separate extensor pollicis brevis (EPB) compartment.The abductor pollicis longus (APL) tendon has multiple slips; care should be taken not to confuse one of these slips as the EPB.Traction on the APL pulls up the thumb metacarpal but not the thumb tip.Traction on the EPB extends the thumb metacarpophalangeal joint.Care should be taken to avoid injury to the sensory branch of the radial nerve. Fourth Compartment TenosynovitisThis uncommon condition is most often seen in patients with rheumatoid arthritis.The condition involves a large diffuse area, as opposed to the compact dorsal ganglion cyst. PMID- 27500431 TI - Blood Glucose Levels Following Intra-Articular Steroid Injections in Patients with Diabetes: A Systematic Review. AB - BACKGROUND: Parenterally administered steroids have been shown to affect the metabolism of glucose and to cause abnormal blood glucose levels in diabetic patients. These abnormal blood glucose levels in diabetic patients raise concerns that intra-articular steroid injections also may affect blood glucose levels. We performed a systematic review of studies examining the effect of intra-articular steroid injections on blood glucose levels in patients with diabetes mellitus. METHODS: A literature search of the PubMed, EMBASE, AMED, and CINAHL databases using all relevant keywords and phrases revealed 532 manuscripts. After the application of inclusion criteria, seven studies with a total of seventy-two patients were analyzed. RESULTS: All studies showed a rise in blood glucose levels following intra-articular steroid injection. Four of the seven studies showed a substantial increase in blood glucose. Peak values reached as high as 500 mg/dL. The peak increase in blood glucose did not occur immediately following intra-articular steroid injection, and in some cases it took several days to occur. In many patients, post-injection hyperglycemia occurred within twenty-four to seventy-two hours. CONCLUSION: Intra-articular steroid injections may cause hyperglycemia in patients with diabetes mellitus, and patients should be warned of this complication. Diabetic patients should be advised to regularly monitor their blood glucose levels for up to a week after injection and should seek medical advice if safe thresholds are breached. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 27500432 TI - Treatment of Head and Neck Injuries in the Helmeted Athlete. AB - Sport-related concussion treatment includes three major phases: initial evaluation at the time of the injury, treatment while the patient is symptomatic, and evaluation of the readiness for a gradual return to participation. Each concussion evaluation should include similar elements: assessment of symptoms, assessment of cognitive ability, assessment of coordination (of the eyes, upper extremities, and lower extremities), and assessment for additional injuries. The spine-boarding recommendations from the American College of Emergency Physicians, National Association of EMS Physicians, and National Athletic Trainers' Association have changed. These recommendations include both decreased use of spinal immobilization and removal of the helmet and shoulder pads prior to securing the athlete to the board when sufficient numbers of trained providers are present. Preseason training and pregame meetings or "medical time outs" should become standard practice for the sidelines medical team (including the athletic trainer, team physician, emergency response personnel, and possibly others). PMID- 27500433 TI - New Article Type for JBJS Reviews. PMID- 27500434 TI - Nonsteroidal Anti-Inflammatory Drugs and Bone-Healing: A Systematic Review of Research Quality. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are often avoided by orthopaedic surgeons because of their possible influence on bone-healing. This belief stems from multiple studies, in particular animal studies, that show delayed bone-healing or nonunions associated with NSAID exposure. The purpose of this review was to critically analyze the quality of published literature that evaluates the impact of NSAIDs on clinical bone-healing. METHODS: A MEDLINE and Embase search was conducted to identify all articles relating to bone and fracture-healing and the utilization of NSAIDs. All human studies, including review articles, were identified for further analysis. Non-English-language manuscripts and in vitro and animal studies were excluded. A total of twelve clinical articles and twenty-four literature reviews were selected for analysis. The quality of the clinical studies was assessed with a modified Coleman Methodology Score with emphasis on the NSAID utilization. Review articles were analyzed with regard to variability in the cited literature and final conclusions. RESULTS: The mean modified Coleman Methodology Score (and standard deviation) was significantly lower (p = 0.032) in clinical studies that demonstrated a negative effect of NSAIDs on bone-healing (40.0 +/- 14.3 points) compared with those that concluded that NSAIDs were safe (58.8 +/- 10.3 points). Review articles also demonstrated substantial variability in the number of cited clinical studies and overall conclusions. There were only two meta-analyses and twenty-two narrative reviews. The mean number (and standard deviation) of clinical studies cited was significantly greater (p = 0.008) for reviews that concluded that NSAIDs were safe (8.0 +/- 4.8) compared with those that recommended avoiding them (2.1 +/- 2.1). Unanimously, all reviews admitted to the need for prospective randomized controlled trials to help clarify the effects of NSAIDs on bone-healing. CONCLUSIONS: This systematic literature review highlights the great variability in the interpretation of the literature addressing the impact of NSAIDs on bone-healing. Unfortunately, there is no consensus regarding the safety of NSAIDs following orthopaedic procedures, and future studies should aim for appropriate methodological designs to help to clarify existing discrepancies to improve the quality of care for orthopaedic patients. CLINICAL RELEVANCE: This systematic review highlights the limitations in the current understanding of the effects of NSAIDs on bone healing. Thus, withholding these medications does not have any proven scientific benefit to patients and may even cause harm by increasing narcotic requirements in cases in which they could be beneficial for pain management. This review should encourage further basic science and clinical studies to clarify the risks and benefits of anti inflammatory medications in the postoperative period, with the aim of improving patient outcomes. PMID- 27500435 TI - Enhancement of Bone-Healing by Low-Intensity Pulsed Ultrasound: A Systematic Review. AB - BACKGROUND: Low-intensity pulsed ultrasound (LIPUS) is frequently used to enhance or to accelerate fracture-healing, but its clinical role and effectiveness as a treatment modality remain uncertain. We performed a systematic review and meta analysis of randomized controlled trials to determine the efficiency of LIPUS on bone-healing and/or fracture union, as well as on functional recovery. METHODS: The databases of PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science, and Embase were searched for trials concerning LIPUS stimulation and bone-healing or fracture repair, in any language, published from the inception of the database to January 2, 2015. Eligible studies were randomized controlled trials that enrolled patients with any type of fracture, delayed union, or nonunion and randomly assigned them to LIPUS treatment or a control group. Two reviewers independently agreed on eligibility, assessed methodological quality, and extracted outcome data. All relevant outcomes were pooled, and a meta-analysis was performed. RESULTS: Twenty-four unique randomized trials were selected for analysis after the search of all databases and the inclusion of one trial by the senior author. Time to radiographic fracture union was the most common primary outcome measure evaluated. After pooling the data concerning time to radiographic healing in the combined patient population (n = 429), LIPUS treatment resulted in a mean reduction in healing time of 39.8 days (95% confidence interval, 17.7 to 62.0 days; I = 94%). The most reduction in time to radiographic union by LIPUS treatment was seen in fractures with a long natural healing tendency. Three trials evaluating the time to return to work or active duty, as a surrogate for functional recovery, were unable to demonstrate a beneficial effect of LIPUS (n = 179). Evidence from two high-quality trials implied that LIPUS enhances fracture-healing through increased bone formation in cases of delayed and/or impaired bone-healing. The prevention of delayed union or nonunion by LIPUS treatment could not be demonstrated. CONCLUSIONS: LIPUS treatment effectively reduces the time to radiographic fracture union, but this does not directly result in a beneficial effect of accelerated functional recovery or the prevention of delayed union or nonunion. The increase in bone formation as a result of LIPUS treatment may provide a valuable tool in fracture repair, but it does not always lead to healing. Future studies should focus on reporting of a combination of subjective signs of clinical healing, functional recovery, and radiographic union to determine the effectiveness of LIPUS treatment in clinical fracture-healing. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 27500436 TI - Recurrent Cubital Tunnel Syndrome: A Critical Analysis Review. AB - Most patients (>90%) will have continued or recurrent symptoms after primary cubital tunnel release. Those patients with severe preoperative findings are at a higher risk of failure. Failed primary surgery may be due to diagnostic, technical, or biologic factors. Revision surgical interventions can provide relief, but there is no consensus on what is the optimal technique. The options for revision surgery include simple neurolysis, neurolysis with subcutaneous transposition, and neurolysis with submuscular transposition. Autogenous (vein) and non-autogenous nerve wraps may be placed around the nerve to prevent cicatrix reformation. PMID- 27500437 TI - Cost-effectiveness analysis of therapeutic options for chronic hepatitis C genotype 3 infected patients. AB - BACKGROUND: This study provides a cost-effectiveness analysis of therapeutic strategies for chronic hepatitis C genotype 3 infected patients in Spain. METHODS: A Markov model was designed to simulate the progression in a cohort of patients aged 50 years over a lifetime horizon. RESULTS: Sofosbuvir (SOF) plus peginterferon and ribavirin for 12 weeks was a cost-effective option when compared to standard of care (SoC) in the treatment of both 'moderate fibrosis' and 'cirrhotic' patients. Incremental cost-effectiveness ratios were ?35,276/QALY and ?18,374/QALY respectively. ICERs for SOF plus daclatasvir (DCV) regimens versus SoC were over the threshold limit considered, at ?56,178/QALY and ?77,378/QALY for 'moderate fibrosis' and 'cirrhotic' patients respectively. CONCLUSION: Addition of SOF to IFN-based regimens for genotype 3 was cost effective for both 'moderate fibrosis' and 'cirrhotic' patients. IFN-free options including SOF and DCV association required price reductions lower than the list prices to be considered cost-effective. PMID- 27500438 TI - All-inorganic perovskite CsPb(Br/I)3 nanorods for optoelectronic application. AB - Halide perovskites have attracted great attention in recent years as promising materials for optoelectronic devices, especially inorganic perovskites like CsPbX3 (X = I, Br, Cl). Herein, CsPb(Br/I)3 nanorods with a photoluminescence (PL) spectrum located at 610 nm have been obtained by a facile hot-injection method, and the UV-vis absorption spectrum further revealed that the bandgap absorption is around 1.98 eV. Furthermore, the photoelectric response of the CsPb(Br/I)3 nanorods showed a relatively short rise-time (0.68 s) and decay-time (0.66 s), and the on/off photocurrent ratio of the CsPb(Br/I)3 nanorod based photodetector was up to 10(3). PMID- 27500439 TI - On-line determination by small angle X-ray scattering of the shape of hen egg white lysozyme immediately following elution from a hydrophobic interaction chromatography column. AB - This study documents the use of an integrated approach, involving on-line hydrophobic interaction chromatography interfaced with Small Angle X-ray Scattering (HIC-SAXS) measurements, to monitor the conformational status of proteins immediately upon elution from a chromatographic column operated at different temperatures. Moreover, this approach provides an additional avenue to interrogate the changes in protein shape that may occur across the eluted chromatographic peak. To this end, radii of gyration were extrapolated from the Guinier approximation with the HIC-SAXS data, whilst pair distribution functions and bead model simulations were generated by using the indirect transform program GNOM and ab initio reconstruction with GASBOR to provide further insight into protein conformational changes that occur during hydrophobic interaction chromatography. PMID- 27500440 TI - Hyperglycemia and outcomes in patients with sepsis. PMID- 27500441 TI - Errata: Studies published in indexed journals on lawsuits for medicines in Brazil: a systematic review. AB - [This corrects the article DOI: 10.1590/0102-311X00219113.]. PMID- 27500442 TI - Ceritinib in second and further lines of therapy in advanced ALK mutant adenocarcinoma. PMID- 27500443 TI - Formation of Large Ag Clusters with Shells of Methane, Ethylene, and Acetylene in He Droplets. AB - Helium droplets were used to assemble composite metal-molecular clusters. Produced clusters have several hundreds of silver atoms in the core, immersed in a shell consisting of methane, ethylene, or acetylene molecules. The structure of the clusters was studied via infrared spectra of the C-H stretches of the hydrocarbon molecules. The spectra of the clusters containing methane and acetylene show two distinct features due to molecules on the interface with silver core and those in the volume of the neat molecular part of the clusters. The relative intensities of the peaks are in good agreement with the estimates based on the number of the captured particles. Experiments also suggest that selection rules for infrared transitions for molecules adsorbed on metal surfaces are also valid for silver clusters as small as 300 atoms. PMID- 27500444 TI - MicroRNAs are key regulators of hepatocellular carcinoma (HCC) cell dissemination what we learned from microRNA-494. PMID- 27500445 TI - Protocol for the Direct Conversion of Murine Embryonic Fibroblasts into Trophoblast Stem Cells. AB - Trophoblast stem cells (TSCs) arise as a consequence of the first cell fate decision in mammalian development. They can be cultured in vitro, retaining the ability to self-renew and to differentiate into all subtypes of the trophoblast lineage, equivalent to the in vivo stem cell population giving rise to the fetal portion of the placenta. Therefore, TSCs offer a unique model to study placental development and embryonic versus extra-embryonic cell fate decision in vitro. From the blastocyst stage onwards, a distinct epigenetic barrier consisting of DNA methylation and histone modifications tightly separates both lineages. Here, we describe a protocol to fully overcome this lineage barrier by transient over expression of trophoblast key regulators Tfap2c, Gata3, Eomes and Ets2 in murine embryonic fibroblasts. The induced trophoblast stem cells are able to self-renew and are almost identical to blastocyst derived trophoblast stem cells in terms of morphology, marker gene expression and methylation pattern. Functional in vitro and in vivo assays confirm that these cells are able to differentiate along the trophoblast lineage generating polyploid trophoblast giant cells and chimerizing the placenta when injected into blastocysts. The induction of trophoblast stem cells from somatic tissue opens new avenues to study genetic and epigenetic characteristics of this extra-embryonic lineage and offers the possibility to generate trophoblast stem cell lines without destroying the respective embryo. PMID- 27500446 TI - Development of an Algorithm to Perform a Comprehensive Study of Autonomic Dysreflexia in Animals with High Spinal Cord Injury Using a Telemetry Device. AB - Spinal cord injury (SCI) is a debilitating neurological condition characterized by somatic and autonomic dysfunctions. In particular, SCI above the mid-thoracic level can lead to a potentially life-threatening hypertensive condition called autonomic dysreflexia (AD) that is often triggered by noxious or non-noxious somatic or visceral stimuli below the level of injury. One of the most common triggers of AD is the distension of pelvic viscera, such as during bladder and bowel distension or evacuation. This protocol presents a novel pattern recognition algorithm developed for a JAVA platform software to study the fluctuations of cardiovascular parameters as well as the number, severity and duration of spontaneously occurring AD events. The software is able to apply a pattern recognition algorithm on hemodynamic data such as systolic blood pressure (SBP) and heart rate (HR) extracted from telemetry recordings of conscious and unrestrained animals before and after thoracic (T3) complete transection. With this software, hemodynamic parameters and episodes of AD are able to be detected and analyzed with minimal experimenter bias. PMID- 27500447 TI - Bracing the trunk and neck in young adults leads to a more aged-like gait. AB - Older individuals typically walk at slower speeds, with shorter step lengths, greater step widths and spend a larger proportion of the gait cycle in double stance. Changes in neck and trunk mobility may underlie some of the changes in walking seen with increasing age. Consequently, this study was designed to assess whether externally increasing trunk/neck stiffness in young adults leads to similar changes in gait pattern observed with aging. Twelve young adults (20-29 years), sixteen old adults (60-69 years) and fifteen older adults (70-79 years) walked across a 20' pressure sensitive GAITRite(c) instrumented walkway at their preferred speed. The young adults also walked under three bracing conditions: (1) Neck braced, (2) Trunk braced, and (3) Neck and Trunk braced. The results revealed that the old and older age groups walked significantly slower, with a shorter step length and with a narrower base of support (p's<0.05) compared to the young adults. In young adults, combined neck and trunk bracing led to reduced walking speed, shorter step length, wider base of support and a larger proportion of the gait cycle spent in double stance (p's<0.05). The walking speed and step length of older adults remained less than fully braced young adults (p's<0.05). Overall these results indicate that artificially stiffening the trunk and neck of young individuals leads to systematic gait changes similar to aging. Consequently, age-related changes in mobility of the neck and torso may in part contribute to the decrements in walking seen for older adults. PMID- 27500448 TI - Relationship between fluoride exposure and osteoclast markers during RANKL induced osteoclast differentiation. AB - Skeletal fluorosis is a metabolic bone disease caused by excessive accumulation of fluoride. Although the cause of this disease is known, the mechanism by which fluoride accumulates on the bone has not been clearly defined, thus there are no markers that can be used for screening skeletal fluorosis in epidemiology. In this study, osteoclasts were formed from bone marrow cells of C57BL/6 mice treated with macrophage colony stimulating factor and receptor activator of nuclear factor kappa-B ligand. The mRNA expression of tartrate-resistant acid phosphatase 5b (TRAP5b), osteoclast-associated receptor (OSCAR), calcitonin receptor (CTR), matrix metalloproteinase 9 (MMP9) and cathepsin K (CK) were detected using real-time PCR (RT-PCR). Results showed that fluoride between 0.5 and 8mg/l had no effect on osteoclast formation. However fluoride at 0.5mg/l level significantly decreased the activity of osteoclast bone resorption. Fluoride concentration was negatively correlated with the activity of osteoclast bone resorption. On day 5 of osteoclast differentiation maturity, MMP9 and CK mRNA expression were not only negatively correlated with fluoride concentration, but directly correlated with the activity of osteoclast bone resorption. TRAP5b, CTR and OSCAR mRNA expression were positively correlated with the number of osteoclast and they had no correlation with the activity of osteoclast bone resorption. Thus, it can be seen that MMP9 and CK may reflect the change of activity of bone resorption as well the degree of fluoride exposure. TRAP5b, CTR and OSCAR can represent the change of number of osteoclast formed. PMID- 27500449 TI - Advanced Compositional Analysis of Nanoparticle-polymer Composites Using Direct Fluorescence Imaging. AB - The fabrication of polymer-nanoparticle composites is extremely important in the development of many functional materials. Identifying the precise composition of these materials is essential, especially in the design of surface catalysts, where the surface concentration of the active component determines the activity of the material. Antimicrobial materials which utilize nanoparticles are a particular focus of this technology. Recently swell encapsulation has emerged as a technique for inserting antimicrobial nanoparticles into a host polymer matrix. Swell encapsulation provides the advantage of localizing the incorporation to the external surfaces of materials, which act as the active sites of these materials. However, quantification of this nanoparticle uptake is challenging. Previous studies explore the link between antimicrobial activity and surface concentration of the active component, but this is not directly visualized. Here we show a reliable method to monitor the incorporation of nanoparticles into a polymer host matrix via swell encapsulation. We show that the surface concentration of CdSe/ZnS nanoparticles can be accurately visualized through cross-sectional fluorescence imaging. Using this method, we can quantify the uptake of nanoparticles via swell encapsulation and measure the surface concentration of encapsulated particles, which is key in optimizing the activity of functional materials. PMID- 27500450 TI - Hand-held dynamometry strength measures for internal and external rotation demonstrate superior reliability, lower minimal detectable change and higher correlation to isokinetic dynamometry than externally-fixed dynamometry of the shoulder. AB - OBJECTIVES: To investigate inter and intra-rater reliability of hand held (HHD) and externally fixed (EFD) dynamometry for shoulder internal (IR) and external rotation (ER) strength and their correlation to isokinetic testing. DESIGN: Within participant, inter and intra-rater reliability study. PARTICIPANTS: Twenty active, healthy male and female participants underwent testing by two examiners. OUTCOME MEASURES: Intra-class coefficients (ICC), percentage standard error of measurement (%SEM), and percentage minimal detectable change (%MDC) were calculated for inter-rater, intra-day and intra-rater, inter-week reliability. Maximum and average of three repetitions were compared to the isokinetic results at three speeds (60 degrees /sec, 180 degrees /sec, 240 degrees /sec) for both concentric and eccentric contractions. RESULTS: Inter and intra-tester values demonstrated good to high agreement (HHD, ICC range = 0.89-0.97, %SEM = 4.80 8.60%, %MDC = 13.29-23.70%; EFD, ICC = 0.88-0.96, %SEM = 6.60-11.00%, %MDC = 18.40-30.04%). HHD and EFD showed moderate to very strong correlations to the isokinetic testing (HHD, r = 0.45-0.86; EFD, r = 0.49-0.83). CONCLUSIONS: The results of this study indicate that both EFD and HHD are suitable for clinical practice and research. Hand-held dynamometry is preferred due to its higher intra and inter-rater reliability and smaller MDC and lower SEM. PMID- 27500451 TI - Thulium Laser Resection Versus Plasmakinetic Resection of Prostates in the Treatment of Benign Prostate Hyperplasia: A Meta-Analysis. AB - OBJECTIVES: To compare the safety and efficacy of thulium laser resection of prostate (ThuRP) and plasmakinetic resection of prostate (PKRP) for benign prostate hyperplasia (BPH), we made this meta-analysis in regard of the two techniques. METHODS: A systematic search of PubMed, Web of Science, and China National Knowledge Infrastructure was performed up to October 1, 2015. Outcomes of interest assessing the two techniques included demographic and clinical characteristics, perioperative variables, follow-up data, and complications. RESULTS: Nine eligible trials evaluating ThuRP versus PKRP for BPH were identified, including six randomized controlled trials (RCTs) and three retrospective trials. ThuRP was associated with longer operation time (P < .001), shorter hospital stay (P < .001), irrigation (P = .02), and catheterization (P < .001) duration. Estimated blood loss (P = .005) and drop in hemoglobin level (P = .02) were significantly more in PKRP. Except quality of life score (P = .04), which was better in ThuRP, the postoperative data, including international prostate symptom score (P = .44), Qmax (P = .33), postvoid residual urine volume (P = .55), and the complications such as severe bleeding (P = .52), temporary urinary retention (P = .20), temporary urinary incontinence (P = .64), urinary tract infection (P = .83), and urethral stricture (P = .22), did not differ significantly. CONCLUSION: Our analysis showed that there was no significant difference in terms of efficacy between ThuRP and PKRP. Although ThuRP was associated with longer operation time, it possessed more safe capacity with less blood loss, shorter hospital stay, irrigation, and catheterization duration. More worldwide RCTs with long-term follow-up are still needed to support our conclusion. PMID- 27500452 TI - Decreased functional connectivity to posterior cingulate cortex in major depressive disorder. AB - The default mode network (DMN) and its interaction with other key networks such as the salience network and executive network are keys to understand psychiatric and neurological disorders including major depressive disorder (MDD). In this study, we combined independent component analysis and seed based connectivity analysis to study the posterior default mode network between 20 patients with MDD and 25 normal controls, as well as pre-treatment and post-treatment conditions of the patients. Both correlated and anti-correlated networks centered at the posterior cingulate cortex (PCC) were examined (PCC+ and PCC-). Our results showed aberrant functional connectivity of the PCC+ and PCC- networks between patients and normal controls. Specifically, normal controls exhibited significantly higher connectivity between the PCC and frontal/temporal regions for the PCC+ network and stronger connectivity strength between the PCC and the insula/middle frontal cortex for the PCC- network. The overall connectivity strength of the PCC+ and PCC- networks was also significantly lower in MDD. Because the PCC is a hub in the DMN that interacts with other networks, our result suggested a stronger interaction between the DMN and the salience network but a weak interaction between the DMN and the executive network in MDD. The treatment using sertraline did increase the functional connectivity strength, especially in the PCC+ network. Despite a large inter-subject variability in the overall connectivity strengths and change of the PCC network in response to the treatment, a high correlation between change of connectivity strength and the Hamilton depression score was observed for both the PCC+ and PCC- network. PMID- 27500454 TI - The use of beached bird surveys for marine plastic litter monitoring in Ireland. AB - Marine plastic litter has become a major threat to wildlife. Marine animals are highly susceptible to entanglement and ingestion of debris at sea. Governments all around the world are being urged to monitor litter sources and inputs, and to mitigate the impacts of marine litter, which is primarily composed of plastics. European policies, such as Oslo-Paris Convention (OSPAR) and Marine Strategy Framework Directive (MSFD) have adopted the monitoring of a seabird species, the Northern Fulmar (Fulmarus glacialis), as an environmental quality indicator through the analysis of stomach contents of beached Fulmar specimens. The aims of this research were to: firstly set a baseline investigation of multispecies of seabirds in Ireland affected by the ingestion of litter and, secondly to investigate the feasibility of using Fulmar and/or other potential species of seabird as an indicator for marine debris in Ireland through beached bird surveys. Within 30 months, 121 birds comprising 16 different species were collected and examined for the presence of litter. Of these, 27.3% (n = 33) comprising 12 different species were found to ingest litter, mainly plastics. The average mass of ingested litter was 0.141 g. Among 14 sampled Northern Fulmars, 13 (93%) had ingested plastic litter, all of them over the 0.1 g threshold used in OSPAR and MSFD policy target definitions. Results show that seabirds in Ireland are ingesting marine litter, as in many other countries in the world. Monitoring seabird litter ingestion has the potential to form part of a wider marine litter monitoring programme that can help to inform mitigation and management measures for marine litter. PMID- 27500453 TI - Lifetime use of cannabis from longitudinal assessments, cannabinoid receptor (CNR1) variation, and reduced volume of the right anterior cingulate. AB - Lifetime measures of cannabis use and co-occurring exposures were obtained from a longitudinal cohort followed an average of 13 years at the time they received a structural MRI scan. MRI scans were analyzed for 88 participants (mean age=25.9 years), 34 of whom were regular users of cannabis. Whole brain voxel based morphometry analyses (SPM8) were conducted using 50 voxel clusters at p=0.005. Controlling for age, familial risk, and gender, we found reduced volume in Regular Users compared to Non-Users, in the lingual gyrus, anterior cingulum (right and left), and the rolandic operculum (right). The right anterior cingulum reached family-wise error statistical significance at p=0.001, controlling for personal lifetime use of alcohol and cigarettes and any prenatal exposures. CNR1 haplotypes were formed from four CNR1 SNPs (rs806368, rs1049353, rs2023239, and rs6454674) and tested with level of cannabis exposure to assess their interactive effects on the lingual gyrus, cingulum (right and left) and rolandic operculum, regions showing cannabis exposure effects in the SPM8 analyses. These analyses used mixed model analyses (SPSS) to control for multiple potentially confounding variables. Level of cannabis exposure was associated with decreased volume of the right anterior cingulum and showed interaction effects with haplotype variation. PMID- 27500455 TI - Prevalence and risk factors of poor sleep quality among Inner Mongolia Medical University students: A cross-sectional survey. AB - Medical students face new challenges at the beginning of college life, such as being responsible for oneself, an unfamiliar environment, social obligations, and academic stress, all of which influence or even heavily change their sleep quality and life, leading to sleep-related problems to some degree. This study investigated the relationship between sleep quality and behavior among students at the Inner Mongolia Medical University in China. Self-administered questionnaires were used to collect information on sociodemographic characteristics and lifestyle habits. The Pittsburgh Sleep Quality Index was also used. A total of 6044 and 6085 students completed the questionnaires in 2011 and 2013. According to the index, 27.8% (1694) of students had poor sleep quality with major risk factors being poor academic performance and interpersonal relationships in 2013. Among others, regular exercise less than three times a week, skipping breakfast, and studying in higher grades were associated with poor sleep quality. These results will help university administrators understand the risk factors of poor sleep quality among students, which can be improved through individual efforts, and provide adequate counseling and systematic education to improve their behavior and lifestyle. PMID- 27500456 TI - Prevalence, correlates, psychiatric comorbidities, and suicidality in a community population with problematic Internet use. AB - We examined the prevalence, correlates, and psychiatric comorbidities of community-dwelling subjects with problematic Internet use (PIU). In an epidemiological survey of mental disorders among Korean adults conducted in 2006, 6510 subjects (aged 18-64 years) completed the Korean version of the Composite International Diagnostic Interview for DSM-IV psychiatric disorders; Diagnostic Interview Schedule exploring pathological gambling; Adult ADHD Self-Report Scale Version 1.1 Screener; questionnaire for sleep disturbances; and questionnaire for suicidal ideations, plans, and attempts. Young's Internet Addiction Test was administered to 3212 individuals who had used the Internet within one month before the interviews in order to identify problematic Internet users (cutoff >39). The prevalence of PIU was 9.3% in the general population of South Korea. Being male, younger, never married, or unemployed were all associated with increased risks of PIU. Significant positive associations were observed between PIU and nicotine use disorders, alcohol use disorders, mood disorders, anxiety disorders, somatoform disorders, pathological gambling, adult type ADHD symptoms, sleep disturbances, suicide ideas and suicide plans compare to subjects without PIU, after controlling for socio-demographic variables. These findings suggest that careful evaluation and management of such psychiatric disorders is needed for individuals with PIU. PMID- 27500457 TI - Bendamustine increases interleukin-10 secretion from B cells via p38 MAP kinase activation. AB - We investigated the effects of bendamustine on B cell functions and explored potential clinical applications of the drugs to autoimmune diseases. Proliferation of Ramos cells, a human B cell line, was significantly inhibited by 25-100MUM of bendamustine in a dose-dependent manner. Concordantly, IgM secretion from Ramos cells was significantly inhibited at these concentrations by up to 70%. Interestingly, however, the production and secretion of interleukin-10 (IL 10) were dramatically (at least >10-fold) increased by bendamustine at growth inhibitory concentrations. Exploration of the molecular mechanism of IL-10 production revealed that bendamustine enhanced the phosphorylation of p38 MAP kinase. Further, Sp1 was identified as a downstream transcription factor, and the inhibition of p38 MAP kinase and Sp1 with their inhibitors led to the abrogation of bendamustine-induced IL-10 production and the DNA binding of Sp1. Importantly, when PBMC from healthy donors were cultured with bendamustine at the concentration of 30MUM, under the stimulation with an anti-IgM antibody, an anti CD40 antibody, recombinant human IL-21 (rhIL-21) and recombinant human soluble BAFF (rhsBAFF), IL-10 production by B cells (CD20+CD4-CD8-CD14-) among peripheral blood mononuclear cell (PBMC) was significantly enhanced by adding bendamustine. These results collectively suggest that the p38 MAP kinase-Sp1 pathway plays a crucial role in bendamustine-induced IL-10 production by B cells. Our findings suggest a novel therapeutic possibility for autoimmune diseases through the upregulation of IL-10 which has an anti-inflammatory effects. PMID- 27500458 TI - Active hexose correlated compound modulates LPS-induced hypotension and gut injury in rats. AB - We hypothesized that AHCC; (Amino UP Chemical Co., Ltd., Sapporo, Japan), a mushroom mycelium extract obtained from liquid culture of Lentinula edodes, restores immune function in LPS-induced inflammation in the gut, especially when the nitric oxide signaling pathway is impaired. This is the first inter disciplinary proposal to identify molecular mechanisms involved in LPS-induced immune dysfunction in the gut in conscious animals treated or non-treated with AHCC, a promoter of immune support. Specifically, we have tested the effects of AHCC on LPS-induced deleterious effects on blood pressure and gut injury in conscious rats. The time course of biological markers of innate/acquired immune responses, and inflammation/oxidative stress is fully described in the present manuscript. Rats were randomly assigned into 3 groups (N=6 per group). Group 1 received 10% of AHCC in drinking water for 5days; Group 2 received lipopolysaccharide (LPS; Escherichia coli 0111:B4 purchased from Sigma) only at 20mg/kg IV; Group 3 received combined treatments (AHCC + LPS). LPS was administered at 20mg/kg IV, 5days following AHCC treatment. We have demonstrated that AHCC decreased the LPS-deleterious effects of blood pressure and also decreased inflammatory markers e.g., cytokines, nitric oxide and edema formation. Finally, AHCC diminished lymphocyte infiltration, restoring gut architecture. Because AHCC was administered prior to LPS, our results indicate the potential impact of AHCC's prophylactic effects on LPS inflammation. Consequently, additional experiments are warrant to assess its therapeutic effects in sepsis induced inflammation. PMID- 27500459 TI - Treatment with NAD(+) inhibited experimental autoimmune encephalomyelitis by activating AMPK/SIRT1 signaling pathway and modulating Th1/Th17 immune responses in mice. AB - Nicotinamide adenine dinucleotide (NAD(+)) plays vital roles in mitochondrial functions, cellular energy metabolism and calcium homeostasis. In this study, we investigated the effect of NAD(+) administration for the treatment of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. EAE, a classical animal model of multiple sclerosis (MS), was induced by subcutaneous injection of myelin oligodendrocyteglycoprotein (MOG). The mice were treated with 250mg/kg (body weight) NAD(+) in PBS administered intraperitoneally once daily. We observed that NAD(+) treatment could lessen the severity of EAE. Additionally, NAD(+) treatment attenuated pathological injuries of EAE mice. We also found that the AMP-activated protein kinase (AMPK)/silent mating-type information regulation 2 homolog 1(SIRT1) pathway was activated in the NAD(+)-treated mice and NAD(+) treatment suppressed pro-inflammatory T cell responses. Our findings demonstrated that NAD(+) could be an effective and promising agent to treat multiple sclerosis and its effects on other autoimmune diseases should be explored. PMID- 27500460 TI - Tertiary Element Interaction in HIV-1 TAR. AB - HIV-1 replication requires binding to occur between Trans-activation Response Element (TAR) RNA and the TAT protein. This TAR-TAT binding depends on the conformation of TAR, and therapeutic development has attempted to exploit this dynamic behavior. Here we simulate TAR dynamics in the context of mutations inhibiting TAR binding. We find that two tertiary elements, the apical loop and the bulge, can interact directly, and this interaction may be linked to the affinity of TAR for TAT. PMID- 27500461 TI - Development of a High-Affinity PET Radioligand for Imaging Cannabinoid Subtype 2 Receptor. AB - Cannabinoid receptors type 2 (CB2) represent a target with increasing importance for neuroimaging due to its upregulation under various pathological conditions. Encouraged by preliminary results obtained with [(11)C](Z)-N-(3-(2-methoxyethyl) 4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide ([(11)C]A-836339, [(11)C]1) in a mouse model of acute neuroinflammation (induced by lipopolysaccharide, LPS), we designed a library of fluorinated analogues aiming for an [(18)F]-labeled radiotracer with improved CB2 binding affinity and selectivity. Compound (Z)-N-(3-(4-fluorobutyl)-4,5-dimethylthiazol-2(3H)-ylidene) 2,2,3,3-tetramethyl-cyclopropanecarboxamide (29) was selected as the ligand with the highest CB2 affinity (Ki = 0.39 nM) and selectivity over those of CB1 (factor of 1000). [(18)F]29 was prepared starting from the bromo precursor (53). Specific binding was shown in vitro, whereas fast metabolism was observed in vivo in CD-1 mice. Animal PET revealed a brain uptake comparable to that of [(11)C]1. In the LPS-treated mice, a 20-30% higher uptake in brain was found in comparison to that in nontreated mice (n = 3, P < 0.05). PMID- 27500462 TI - Comparison Study of the Photoelectrochemical Activity of Carbon Nitride with Different Photoelectrode Configurations. AB - Polymeric carbon nitride (CN) has recently emerged as a novel metal-free semiconductor due to its unique electronic structure, wide availability, and promising applications in photoelectrochemical solar energy conversion. However, few works regarding CN photoelectrode optimization such as by minimization of unwanted grain boundary effects have been reported, which would greatly influence the photoelectrochemcial conversion efficiency. Herein, three general ways of preparing CN photoelectrode are presented and compared, including drop-casting of CN particles, or further blendeding with Nafion or PEDOT-PSS as the binder. In addition, the influences of CN particle sizes (0.5, 1.1, and 3.2 MUm) and the film thickness (i.e., the loading amount) to the overall photoelectrochemcial activity were also evaluated in detail. As a result, when PEDOT-PSS acted as binder, CN particles with size of 0.5 MUm and an optimal loading amount (2.4 mg/cm(2)) were adopted; the as-prepared CN photoelectrode had much superior photoelectrochemical activity than all other counterparts. Therefore, this study would pave the way for preparing CN photoelectrode of superior quality so as to promote CN materials to be better applied in solar fuel and sensing applications. PMID- 27500463 TI - Upper motor neuron evaluation in multiple sclerosis patients treated with Sativex(r). AB - BACKGROUND: Spasticity in multiple sclerosis (MS) results from an imbalance of inputs from descending pathways to the spinal motor circuits, as well as from a damage of the corticospinal tract (CST). OBJECTIVES: To assess CST impairment in MS patients with and without spasticity and to evaluate its evolution under Sativex(r) treatment. METHODS: Ten MS patients with spasticity ("cases") underwent clinical (EDSS, 9-hole Peg, Ashworth scale, Timed 25-Foot Walk, and NRS for spasticity), MRI (CST fractional anisotropy [FA]), and electrophysiological (central motor conduction time [CMCT] and H/M ratio) evaluations at baseline and after 12 months. We selected 20 MS patients without spasticity as control group at baseline. RESULTS: At baseline, cases showed a lower CST FA (0.492+/-0.045 vs 0.543+/-0.047; P=.01) and a higher CMCT (P=.001) compared to the control group. No correlations were found between clinical, electrophysiological, and MRI features. After 12 months, cases showed a decrease in non-prevalent degree of impairment (PDI) side FA (0.502+/-0.023 vs 0.516+/-0.033; P=.01) without differences for electrophysiological features compared to baseline. Treatment with Sativex(r) resulted in a reduction of NRS for spasticity (P=.01). CONCLUSIONS: We confirm the presence of CST impairment in MS patients with spasticity. We did not identify structural/electrophysiological correlates that could explain Sativex(r) clinical effect. PMID- 27500464 TI - Incidence and Burden of Wheezing Disorders, Eczema, and Rhinitis in Children: findings from the Born in Bradford Cohort. AB - BACKGROUND: Bradford city has high infant mortality and there is a major health concern in the community due to environmental pollution. The aim of the study was to investigate the incidence and burden of wheezing disorders, eczema, and rhinitis in children aged 3-7 years . METHODS: It is a prospective cohort study; the participants were 13 734 children from the Born in Bradford cohort. RESULTS: There were a total of 22.1% (95% Confidence Interval (CI) 21.4, 22.8%), 52.4% (95% CI 51.5%, 53.2%), and 19.3% (95% CI 18.6, 19.9%) incidence cases of wheezing disorders, eczema, and rhinitis respectively. A total of 37% (95% CI 36.2%, 37.8%), 19.5% (95% CI 18.9%, 20.2%,) and 5.9% (95% CI 5.5%, 6.3%) of the children were affected by only one, two, and three diseases respectively. Boys to girls incidence rate ratios for wheezing disorders, eczema, and rhinitis was 1.41 (95% CI 1.31, 1.51), 1.02 (95% CI 0.97, 1.07), and 1.18 (95% CI 1.09, 1.28) respectively. The respective incidence rate ratios of Pakistani to White British were 0.94 (95% CI 0.87, 1.02), 1.31 (95% CI 1.24, 1.39), and 2.03 (95% CI 1.83, 2.25) respectively. CONCLUSION: This study shows that the burden of wheezing disorders, eczema, and rhinitis in this cohort is higher than previously reported in earlier studies. In addition, it indicates that while boys are more likely to suffer from wheezing disorders, rhinitis, and multiple diseases than girls, Pakistani children are more likely to suffer from eczema, rhinitis, and multiple diseases than White British children. PMID- 27500465 TI - The Predictive Role of the Neutrophil/Lymphocyte Ratio in Survival with Multiple Myeloma: A Single Center Experience. AB - BACKGROUND: Recent studies have shown a positive correlation between tumor related immune response markers and the poor outcome in solid tumors. In this study, we aimed to investigate the neutrophil/lymphocyte ratio (NLR) in multiple myeloma. To the best of our knowledge, this would be the second report concerning this topic. METHODS: We retrospectively reviewed the data for 52 multiple myeloma patients. The patients were grouped using the baseline NLR as NLR <= 1.72 and NLR > 1.72 using receiver operating characteristic analysis to determine a cut off. We compared the two groups in terms of both the known prognostic factors of the myeloma and the overall survival (OS). RESULTS: Our study showed that NLR is associated with C-reactive protein and beta2 microglobulin (P = 0.02 and P = 0.001, respectively). The patients with NLR > 1.72 had significantly worse stages, performance status, and kidney functions. The whole group's OS was estimated as 35.1 months while the patients with lower NLR had better OS when compared with those with NLR > 1.72 (42.75 and 26.14 months, respectively, P: 0.04). CONCLUSION: Neutrophil/lymphocyte ratio, which is associated with stage, performance status, and kidney functions, can be used in daily practice as a predictor for survival in multiple myeloma. Simply adding NLR to the routine charts may enrich our data for larger studies. PMID- 27500466 TI - Photon Upconversion at Crystalline Organic-Organic Heterojunctions. AB - Triplet transfer across a surface-anchored metal-organic-framework heterojunction is demonstrated by the observation of triplet-triplet annihilation photon upconversion in a sensitizer-emitter heterostructure. Upconversion thresholds under 1 mW cm-2 are achieved. In the broader context, the double-electron exchange mechanism of triplet transfer indicates that the heterojunction quality is sufficient for electrons to move between layers in this solution-processed crystalline heterostructure. PMID- 27500467 TI - Correlation between the presence of degenerated inclusion-bearing cells in voided urine samples and the occurrence of polyomavirus infection. AB - OBJECTIVE: The purpose of the present, prospective, cohort study was to monitor urine cytology samples from recipients of renal transplants to search for the occurrence of decoy cells and degenerated inclusion-bearing cells with an aim to correlate the existence of these cells with molecular detection of polyomavirus BK (BKV) DNA in urine. MATERIAL AND METHODS: This study included patients who underwent renal transplantation. Patients had their urine tested quarterly, during the first year post-transplantation, for the presence of decoy cells and degenerated cells, as well as by quantitative determination of BKV load in the urine and plasma. RESULTS: Three hundred and sixty-one examinations were performed on 101 patients within 12 months of attendance. Urine cytology results were: 198 (54.9%) negative and 60 (16.6%) positive for the presence of viral cytopathic effects depending on the presence of BKV infection, 72 (19.9%) positive for the manifestation of degenerated cells and 31 (8.6%) unsatisfactory for analysis. There was a subtle tendency towards the presence of degenerated inclusion-bearing cells in cases in which the virus was detected in voided urine. However, the presence of degenerated cells exhibited a tendency to BKV positivity in months 3, 6 and 9 and, exclusively in month 12, this trend was statistically significant. CONCLUSIONS: There were not enough strong morphological and staining elements to state the origin of the degenerated cells or to describe the nature of the infection (viral or bacterial), given that these cells were undergoing an apoptotic process in post renal transplant patients. PMID- 27500468 TI - Melatonin as an antioxidant: under promises but over delivers. AB - Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes. In addition to these well-described actions, melatonin also reportedly chelates transition metals, which are involved in the Fenton/Haber Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its antiradical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment-resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age-related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet-to-be identified basic action(s) of this ancient molecule. PMID- 27500469 TI - Insurance status, health equity, and the cancer care continuum. PMID- 27500471 TI - Measurement of Survival Time in Brachionus Rotifers: Synchronization of Maternal Conditions. AB - Rotifers are microscopic cosmopolitan zooplankton used as models in ecotoxicological and aging studies due to their several advantages such as short lifespan, ease of culture, and parthenogenesis that enables clonal culture. However, caution is required when measuring their survival time as it is affected by maternal age and maternal feeding conditions. Here we provide a protocol for powerful and reproducible measurement of the survival time in Brachionus rotifers following a careful synchronization of culture conditions over several generations. Empirically, poor synchronization results in early mortality and a gradual decrease in survival rate, thus resulting in weak statistical power. Indeed, under such conditions, calorie restriction (CR) failed to significantly extend the lifespan of B. plicatilis although CR-induced longevity has been demonstrated with well-synchronized rotifer samples in past and present studies. This protocol is probably useful for other invertebrate models, including the fruitfly Drosophila melanogaster and the nematode Caenorhabditis elegans, because maternal age effects have also been reported in these species. PMID- 27500470 TI - The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques. AB - Although stable mixed-hematopoietic chimerism induces robust immune tolerance to solid organ allografts in mice, the translation of this strategy to large animal models and to patients has been challenging. We have previously shown that in MHC matched nonhuman primates (NHPs), a busulfan plus combined belatacept and anti CD154-based regimen could induce long-lived myeloid chimerism, but without T cell chimerism. In that setting, donor chimerism was eventually rejected, and tolerance to skin allografts was not achieved. Here, we describe an adaptation of this strategy, with the addition of low-dose total body irradiation to our conditioning regimen. This strategy has successfully induced multilineage hematopoietic chimerism in MHC-matched transplants that was stable for as long as 24 months posttransplant, the entire length of analysis. High-level T cell chimerism was achieved and associated with significant donor-specific prolongation of skin graft acceptance. However, we also observed significant infectious toxicities, prominently including cytomegalovirus (CMV) reactivation and end-organ disease in the setting of functional defects in anti-CMV T cell immunity. These results underscore the significant benefits that multilineage chimerism-induction approaches may represent to transplant patients as well as the inherent risks, and they emphasize the precision with which a clinically successful regimen will need to be formulated and then validated in NHP models. PMID- 27500472 TI - Loss of MiR-424-3p, not miR-424-5p, confers chemoresistance through targeting YAP1 in non-small cell lung cancer. AB - MiR-424 has been discovered to be involved in the chemoresistance of lung cancer. However, the underlying mechanism by which miR-424 played role in chemoresistance has been unknown. Here, in our study, to investigate the role of miR-424 in non small cell lung cancer (NSCLC), we have detected the expression of miR-424-3p and -5p in NSCLC tissues and paired normal control. Moreover, to explore the role of miR-424-3p in NSCLC cells, miR-424-3p and -5p were both re-expressed and knocked down using transient transfection with their respective mimics and inhibitors. Cell viability, migration, and invasion were evaluated using MTT, wound-healing and Transwell assays, respectively. It was found that down-regulation of miR-424 3p was pronouncedly associated with NSCLC progression and overall prognosis; and that both miR-424-3p and -5p were markedly capable of preventing the proliferation, migration, and invasion in NSCLC cells. Additionally, it is miR 424-3p but not miR-424-5p that enhances the chemo-sensitivity of NSCLC cells through targeting YAP1. Mechanistically, YAP1 was identified as down-stream target of miR-424-3p. Together, it was for the first time in our study found that it is loss of miR-424-3p not miR-424-5p that enables chemoresistance through targeting YAP1 in NSCLC, supporting that miR-424-3p could be used as therapeutic target in the curing of NSCLC with chemoresistance. (c) 2016 Wiley Periodicals, Inc. PMID- 27500473 TI - Instrumental Idiosyncrasies Affecting the Performance of Ultrafast Chiral and Achiral Sub/Supercritical Fluid Chromatography. AB - It is widely accepted that column technology is ahead of existing chromatographic instruments. The chromatographic output may not reflect the true picture of the peak profile inside the column. The instrumental optimization parameters become far more important when peaks elute in a few seconds. In this work, the low viscosity advantage of the supercritical/subcritical CO2 is coupled with the high efficiency of narrow particle size distribution silica. Using short efficient columns and high flow rates (up to 19 mL/min), separations on the order of a few seconds are demonstrated. In the domain of ultrafast supercritical fluid chromatography (SFC), unexpected results are seen which are absent in ultrafast liquid chromatography. These effects arise due to the compressible nature of the mobile phase and detector idiosyncrasies to eliminate back-pressure regulator noise. We demonstrate unusual connection tubing effects with 50, 75, 127, 254, and 500 MUm tubings and show the complex relation of dead time, retention time, efficiency, and optimum velocity with the tubing diameter (via column outlet pressure). Fourier analysis at different back-pressure regulator (BPR) settings shows that some instruments have very specific noise frequencies originating from the BPR, and those specific frequencies vanish under certain conditions. The performance of embedded digital filters, namely, moving average, numerically simulated low pass RC, and Gaussian kernels, is compared. This work also demonstrates, using a simple derivative test, that some instruments employ interpolation techniques while sampling at "true" low frequencies to avoid picking up high frequency noise. Researchers engaged in ultrafast chromatography need to be aware of the instrumental nuances and optimization procedures for achieving ultrafast chiral or achiral separations in SFC mode. PMID- 27500474 TI - [Forensic medical assessment of the cases of HIV infection and hemocontact viral hepatitis B and C during the period from 2011 till 2015 in different subjects of the Russian Federation]. AB - The annually increasing number of the patients presenting with HIV infection and hemocontact viral hepatitis is naturally accompanied by the growing number of deaths from these infectious pathologies. The objective of the present study was to analyze the results of forensic medical expertises of the cases of HIV infection and hemocontact viral hepatitis B and C during the period from 2011 till 2015 in different subjects of the Russian Federation. The data obtained confirm the tendency toward the further rise in the frequency of such cases in the practical work of forensic medical experts. Moreover, they indicate the necessity of registration of such cases in state forensic medical expertise organizations and open up the prospects for the development of the common approaches to the solution of the existing problems including the evaluation of the degree of the harm to human health. PMID- 27500475 TI - [The classification of the injuries inflicted to the human body by gunshots from the pneumatic weapons]. AB - The classification of the injuries inflicted to the human body by gunshots from the pneumatic weapons remains to be developed. The objective of the present work was to elaborate the classification of the injuries caused by gunshots from the pneumatic weapons based on the analysis of 98 expert CONCLUSION: and acts of forensic medical expertises (surveys) of living subjects (n=76) and corpses (n=22) affected by gunshots from the pneumatic weapons. These materials were collected from the bureaus of forensic medical expertise in different regions of the Ukraine during the period from 2006 till 2015. In addition, scientific publications concerned with the problem of interest were used along with the relevant explanatory and terminological dictionaries. The terminology and the conceptual framework proposed by the author in the earlier papers provided a basis for the development of the first standard classification of the injuries inflicted to the human body by gunshots from the pneumatic weapons categorized into 15 groups. It is believed that this classification will lay the foundation for the common approach of forensic medical experts to the examination and analysis of the data on the gunshots from the pneumatic weapons used to be found on the bodies of living subjects and the corpses. Moreover, it may be useful for the clinicians in their diagnostic and therapeutic practices and for the legal practitioners engaged in the quality assessment of the results of forensic medical expertises. It is recommended to present information about the gunshots from the pneumatic weapons in the accounting documents in a separate line. PMID- 27500476 TI - [The peculiar features of conducting comprehensive expertises of the injuries inflicted inside the passenger car compartment]. AB - The present article deals with the problem of forensic medical diagnostics of the injuries inflicted inside the passenger car compartment during motor vehicle accidents. The authors place special emphasis on the fact of a significant increase in the number of road traffic accidents (RTA) with such consequences throughout the world. The modern automobile industry pays much attention to the enhancement of the car safety features by significantly improving the design of passenger compartments. It accounts for a change in the traditional character of the injuries to both the driver and the passengers resulting from motor vehicle accidents. This, in turn, creates difficulties for the forensic medical experts as regards personality identification of the subjects who happened to be inside the car at the moment of the collision especially in the case of unascertainable circumstances of the accident and/or the involvement of several victims. The authors describe peculiarities of the injuries inflicted inside the passenger car compartment during road traffic accidents including such that result from bringing the driver and the passengers closer to the construction elements of the car (stage I), their direct contact with these elements (stage II), and subsequent displacement (stage III). PMID- 27500477 TI - [The forensic-medical characteristic of the injuries inflicted to a pedestrian in a road traffic accident by the vehicle in the side and front impact position]. AB - The objective of the present study was to distinguish between the separate phases of the car-to-pedestrian collision with the vehicle being in the side and front impact position. The secondary objective was to determine characteristics of injuries specific for the collisions of this type. The methods employed in the study included the analysis of archival materials and video sequence images. We propose to consider a special type of injury resulting from the car-to-pedestrian collision with the vehicle being in the side and front impact position and to distinguish its two varieties. One of them is caused by the vehicle hitting the pedestrian front laterally, the other arises from the oblique-transverse collision. Each type of collision produces injuries with highly specific characteristics. PMID- 27500478 TI - [The reconstruction of the occurrence circumstances from the analysis of blood stains with the use of the three-dimensional modeling technique]. AB - The present case study demonstrates the possibility of reconstruction of the occurrence circumstances by means of the three-dimensional modeling technique and of the application of this method for the solution of the problems facing forensic medical expertise. PMID- 27500479 TI - [The morphometric characteristics of the main structural components of renal nephrons in the white rats with experimentally induced acute and chronic alcohol intoxication]. AB - The objective of the present work was to study the morphometric characteristics of the main structural components of renal nephrons in the white rats with the experimentally induced acute and chronic alcohol intoxication. We undertook the morphometric examination of the structural elements of rat kidneys with the subsequent statistical analysis of the data obtained. The results of the study give evidence of the toxic action of ethanol on all structural components of the nephron in the case of both acute and chronic alcohol intoxication. The study revealed some specific features of the development of pathological process in the renal tissue structures at different stages of alcohol intoxication. The most pronounced morphological changes were observed in the renal proximal tubules and the least pronounced ones in the structure of the renal glomeruli. The earliest morphological changes become apparent in distal convoluted tubules of the nephron; in the case of persistent alcoholemia, they first develop in the renal corpuscles and thereafter in the distal proximal tubules. The maximum changes occur in the case of acute alcohol intoxication and between 2 weeks and 2 months of chronic intoxication; they become less conspicuous during a later period. PMID- 27500480 TI - [The peculiarities of preservation of the soft tissues and bone structures under the conditions of prolonged corpse deposition in the high-latitude cryolitic zone (the island Bely near the Kara Sea coast)]. AB - The objective of the present work was the primary forensic medical/medical criminalistic study of exhumed human remains with the determination of the main group characteristics for the purpose of evaluation of the degree of preservation of the soft tissues and bone structures under the conditions of prolonged corpse deposition in the high-latitude cryolitic zone. The materials available for the study consisted of the exhumed remains of 13 corpses. The author describes the transformed features of the soft tissues and bone structures. The former look like a grave wax. It is shown that the peculiar morphological features of the preserved soft tissues and bone structures depend on the burial depth and the characteristic natural factors of the high-latitude cryolitic zone. The main conditions influencing the state of the objects for the forensic medical expertise are considered including prescription of corpse burying, ground properties, freeze/thaw cycles, the influence of sea water, and microbiological factors. PMID- 27500481 TI - [Polymorphism of DNA nucleotide sequence as a source of enhancement of the discrimination potential of the STR-markers]. AB - The objective of the present pilot investigation was to reveal and to study polymorphism of nucleotide sequence in the alleles of STR loci of human autosomal DNA with special reference to the role of this phenomenon as a source of the differences between homonymous allelic variants. The secondary objection was to evaluate the possibility of using the data thus obtained for the enhancement of the informative value of the forensic medical genotyping of STR loci by means of identification of single nucleotide polymorphisms (SNP) for the purpose of extending their allelic spectrum. The methodological basis of the study was constituted by the comprehensive amplified fragment length polymorphism (AFLP) analysis and amplified fragment sequence polymorphisms (AFSP) analysis of DNA with the use of the PLEX-ID^TM analytical mass-spectrometry platform (Abbot Molecular, USA). The study has demonstrated that polymorphism of DNA nucleotide sequence can be regarded as the possible source of enhancement of the discriminating potential of STR markers. It means that the analysis of polymorphism of DNA nucleotide sequence for genotyping AFLP-type markers of chromosomal DNA can considerably increase the effectiveness of their application as individualizing markers for the purpose of molecular genetic expertises. PMID- 27500482 TI - [On the orientation of palmar whorl patterns]. AB - The objective of the present work was to study the palmar whorl patterns for the inclusion them in the scope of dermatoglyphic signs along with the arc and loop patterns having a well apparent structural organization. For the first time in the history of domestic dermatoglyphic studies, we described the structure of palmar whorl patterns (based on the palmar prints obtained from 555 subjects) with respect to the surrounding tri-radii. Moreover, the role of their radiants in the formation of node orientation was considered. The analysis of the variants of palmar whorl patterns encountered in the study sample provided a basis for the elaboration of the rule for determining their orientation. Specifically, the orientation of the palmar whorl patterns can be found from the direction of the embracing radiants as in the loop or complex patterns. PMID- 27500483 TI - [The specific features of the distribution of 4-metoxyhydroxybenzene in the organism of the warm-blooded animals suffering lethal intoxication]. AB - This work was designed to study the distribution of 4-metoxyhydroxybenzene in the organism of the omnivorous warm-blooded animals (rats) after the intragastric administration of this poisonous compound at a dose three-fold greater than the LD50 value. The administered 4-metoxyhydroxybenzene was isolated from the organs and blood of the experimental animals by exposing the biological tissues to acetone with subsequent purification on a silica gel L 40/100 mcm using a hexane:dioxane:propanol-2 (20:5:1) as the mobile phase. The identification and quantitation of 4-metoxyhydroxybenzene were carried out with the use of TLC, GC MS, and UF-spectrophotometry. It was shown that the administered 4 metoxyhydroxybenzene remained unmetabolized in the internal organs and blood of the poisoned experimental animals. The largest amounts of 4-metoxyhydroxybenzene were found in the stomach contents (2584,92+/-117,47), brain (59.49+/-6.05), contents of small intestines (28.21+/-3.77), and kidneys (26.13+/-1.64). PMID- 27500484 TI - [About the role of subjective factors in forensic expertise]. AB - The article examines the influence of subjective factors on the activities of a forensic expert. It is noted that to improve the objectivity and reliability of the findings of forensic experts is necessary to strictly observe the presumption of innocence, to develop guidelines for certain types of expertise, production of which is not carried out in the state forensic institutions, as well as carry out some other organizational and methodical activities. PMID- 27500485 TI - [Determination of the blood myoglobin levels for the purpose of forensic medical expertise: the methodological peculiarities and the prospects for the further use]. AB - The objective of the present work was to study the dependence of the blood myoglobin levels on the time of death, gender, and age of the subject, methods employed to analyze this protein, and the duration of storage of the biological materials after autopsy. Myoglobin levels were measured in cadaveric blood of the subjects who had died as a result of acute cardiovascular insufficiency and chronic coronary heart disease in the passive hemagglutination reaction with the use of the erythrocyte diagnosticum and in the immunoturbodimetric test combined with the fixed time method. It was shown that the blood myoglobin level depends on prescription of death coming, duration of storage of the biological materials, age and sex of the deceased subject. It is concluded that the immunoturbodimetric method is characterized by the higher accuracy and better reproducibility than the passive hemagglutination reaction with the use of the erythrocyte diagnosticum. PMID- 27500486 TI - [Demonstration of the impossibility of simultaneous Dupuytren and Destot fractures in the result of the car-pedestrian collision]. AB - This article reports the results of the commission forensic medical expertise undertaken to evaluate the possibility of severe injury to the ankle joint resulting from the road traffic accident as exemplified by the collision of a VAS 21043 car moving backward with a pedestrian. It was shown that the injury to the victim's right lower leg included the tear of the right crural deltoid ligament, the open communicated fracture of the lower third of fibular diaphysis with the displacement of the distal fragment, the lacerated wound in the lower third of the right leg, the rupture of distal tibiofibular synedesmosis, the closed communicated fracture of the posterior edge of the tibia without displacement, and outward subluxation of the right foot. According to the classification accepted in orthopedics , this variant of the injury to the ankle joint is a combination of the classical "complete" Dupuytren fracture and the Destot-type fracture. The analysis of the mechanism underlying formation of such injury has shown that it was a consequence of the indirect injurious action in the absence of the primary impact without the car running over the victim's leg. PMID- 27500487 TI - A randomized, controlled trial comparing skin health effects and comfort of two adult incontinence protective underwear. AB - BACKGROUND/PURPOSE: It is important to confirm product use effects on skin health for products intended for prolonged skin contact. This study compared experimental and marketed reference adult incontinence protective underwear. METHODS: Randomized, single-blind (examiner), parallel study evaluating skin health effects in predominantly obese incontinent women normally using protective underwear (approximately 20% Type II Diabetes). Subjects wore experimental or marketed reference protective underwear daily, 14 consecutive days. Visual skin grading, transepidermal water loss (TEWL) assessed before, after 1 and 2 weeks of product wear. Overall assessment of comfort assessed. RESULTS: Of the 122 subjects (60 experimental and 62 marketed reference), 22 were diabetic and 88 were postmenopausal. Under the conditions of this study, there were no statistically significant differences in overall change from baseline for visual grading and TEWL between the experimental product and the marketed reference product for all subjects. Changes from baseline for skin erythema and skin marking were generally small for both products for all subjects as well as for both diabetics and non-diabetics. There were no serious adverse events (AEs), and no withdrawals due to AEs. Overall comfort assessments of size and fit were 'just right,' and skin comfort in the leg, waist and crotch areas were 'comfortable' or 'very comfortable' for both products. CONCLUSIONS: In-use 14-day testing demonstrated few statistical differences between experimental product with unique odor neutralizing technology and currently marketed product for skin assessments and comfort. Both products were comfortable and well-tolerated. PMID- 27500488 TI - Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas. AB - Autonomous thyroid adenomas (ATAs) are a frequent cause of hyperthyroidism. Mutations in the genes encoding the TSH receptor (TSHR) or the Gs protein alpha subunit (GNAS) are found in approximately 70% of ATAs. The involvement of other genes and the pathogenesis of the remaining cases are presently unknown. Here, we performed whole-exome sequencing in 19 ATAs that were paired with normal DNA samples and identified a recurrent hot-spot mutation (c.1712A>G; p.Gln571Arg) in the enhancer of zeste homolog 1 (EZH1) gene, which codes for a catalytic subunit of the polycomb complex. Targeted screening in an independent cohort confirmed that this mutation occurs with high frequency (27%) in ATAs. EZH1 mutations were strongly associated with known (TSHR, GNAS) or presumed (adenylate cyclase 9 [ADCY9]) alterations in cAMP pathway genes. Furthermore, functional studies revealed that the p.Gln571Arg EZH1 mutation caused increased histone H3 trimethylation and increased proliferation of thyroid cells. In summary, this study revealed that a hot-spot mutation in EZH1 is the second most frequent genetic alteration in ATAs. The association between EZH1 and TSHR mutations suggests a 2-hit model for the pathogenesis of these tumors, whereby constitutive activation of the cAMP pathway and EZH1 mutations cooperate to induce the hyperproliferation of thyroid cells. PMID- 27500489 TI - Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity. AB - A rise in the occurrence of obesity has driven exploration of its underlying genetic basis and potential targets for intervention. GWAS studies have identified obesity susceptibility pathways involving several neuropeptides that control energy homeostasis, suggesting that variations in the genes that regulate food intake and energy expenditure may contribute to obesity. In this study, we identified 5 additional obesity loci, including a neuronal orphan GPCR called Gpr45, in a forward genetic screen of mutant mice generated by piggyBac insertional mutagenesis. Disruption of Gpr45 led to increased adiposity at the time of weaning and increases in body mass, fat content, glucose intolerance, and hepatic steatosis with advancing age. Mice with disruptions in Gpr45 also displayed a reduction in expression of the metabolic regulator POMC and less energy expenditure prior to the onset of obesity. Mechanistically, we determined that GPR45 regulates POMC expression via the JAK/STAT pathway in a cell autonomous manner. Consistent with this finding, intraventricular administration of melanotan-2, an analog of the POMC derivative alpha-MSH, suppressed adult obesity in Gpr45 mutants. These results reveal that GPR45 is a regulator of POMC signaling and energy expenditure, which suggests that it may be a potential intervention target to combat obesity. PMID- 27500490 TI - ZEB1 drives epithelial-to-mesenchymal transition in lung cancer. AB - Increased expression of zinc finger E-box binding homeobox 1 (ZEB1) is associated with tumor grade and metastasis in lung cancer, likely due to its role as a transcription factor in epithelial-to-mesenchymal transition (EMT). Here, we modeled malignant transformation in human bronchial epithelial cells (HBECs) and determined that EMT and ZEB1 expression are early, critical events in lung cancer pathogenesis. Specific oncogenic mutations in TP53 and KRAS were required for HBECs to engage EMT machinery in response to microenvironmental (serum/TGF-beta) or oncogenetic (MYC) factors. Both TGF-beta- and MYC-induced EMT required ZEB1, but engaged distinct TGF-beta-dependent and vitamin D receptor-dependent (VDR dependent) pathways, respectively. Functionally, we found that ZEB1 causally promotes malignant progression of HBECs and tumorigenicity, invasion, and metastases in non-small cell lung cancer (NSCLC) lines. Mechanistically, ZEB1 expression in HBECs directly repressed epithelial splicing regulatory protein 1 (ESRP1), leading to increased expression of a mesenchymal splice variant of CD44 and a more invasive phenotype. In addition, ZEB1 expression in early stage IB primary NSCLC correlated with tumor-node-metastasis stage. These findings indicate that ZEB1-induced EMT and associated molecular changes in ESRP1 and CD44 contribute to early pathogenesis and metastatic potential in established lung cancer. Moreover, TGF-beta and VDR signaling and CD44 splicing pathways associated with ZEB1 are potential EMT chemoprevention and therapeutic targets in NSCLC. PMID- 27500491 TI - MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling. AB - Intramuscular lipid accumulation is a common manifestation of chronic caloric excess and obesity that is strongly associated with insulin resistance. The mechanistic links between lipid accumulation in myocytes and insulin resistance are not completely understood. In this work, we used a high-throughput chemical biology screen to identify a small-molecule probe, SBI-477, that coordinately inhibited triacylglyceride (TAG) synthesis and enhanced basal glucose uptake in human skeletal myocytes. We then determined that SBI-477 stimulated insulin signaling by deactivating the transcription factor MondoA, leading to reduced expression of the insulin pathway suppressors thioredoxin-interacting protein (TXNIP) and arrestin domain-containing 4 (ARRDC4). Depleting MondoA in myocytes reproduced the effects of SBI-477 on glucose uptake and myocyte lipid accumulation. Furthermore, an analog of SBI-477 suppressed TXNIP expression, reduced muscle and liver TAG levels, enhanced insulin signaling, and improved glucose tolerance in mice fed a high-fat diet. These results identify a key role for MondoA-directed programs in the coordinated control of myocyte lipid balance and insulin signaling and suggest that this pathway may have potential as a therapeutic target for insulin resistance and lipotoxicity. PMID- 27500492 TI - Biallelic inactivation of REV7 is associated with Fanconi anemia. AB - Fanconi anemia (FA) is a recessive genetic disease characterized by congenital abnormalities, chromosome instability, progressive bone marrow failure (BMF), and a strong predisposition to cancer. Twenty FA genes have been identified, and the FANC proteins they encode cooperate in a common pathway that regulates DNA crosslink repair and replication fork stability. We identified a child with severe BMF who harbored biallelic inactivating mutations of the translesion DNA synthesis (TLS) gene REV7 (also known as MAD2L2), which encodes the mutant REV7 protein REV7-V85E. Patient-derived cells demonstrated an extended FA phenotype, which included increased chromosome breaks and G2/M accumulation upon exposure to DNA crosslinking agents, gammaH2AX and 53BP1 foci accumulation, and enhanced p53/p21 activation relative to cells derived from healthy patients. Expression of WT REV7 restored normal cellular and functional phenotypes in the patient's cells, and CRISPR/Cas9 inactivation of REV7 in a non-FA human cell line produced an FA phenotype. Finally, silencing Rev7 in primary hematopoietic cells impaired progenitor function, suggesting that the DNA repair defect underlies the development of BMF in FA. Taken together, our genetic and functional analyses identified REV7 as a previously undescribed FA gene, which we term FANCV. PMID- 27500493 TI - Mitochondrial calcium uptake underlies ROS generation during aminoglycoside induced hair cell death. AB - Exposure to aminoglycoside antibiotics can lead to the generation of toxic levels of reactive oxygen species (ROS) within mechanosensory hair cells of the inner ear that have been implicated in hearing and balance disorders. Better understanding of the origin of aminoglycoside-induced ROS could focus the development of therapies aimed at preventing this event. In this work, we used the zebrafish lateral line system to monitor the dynamic behavior of mitochondrial and cytoplasmic oxidation occurring within the same dying hair cell following exposure to aminoglycosides. The increased oxidation observed in both mitochondria and cytoplasm of dying hair cells was highly correlated with mitochondrial calcium uptake. Application of the mitochondrial uniporter inhibitor Ru360 reduced mitochondrial and cytoplasmic oxidation, suggesting that mitochondrial calcium drives ROS generation during aminoglycoside-induced hair cell death. Furthermore, targeting mitochondria with free radical scavengers conferred superior protection against aminoglycoside exposure compared with identical, untargeted scavengers. Our findings suggest that targeted therapies aimed at preventing mitochondrial oxidation have therapeutic potential to ameliorate the toxic effects of aminoglycoside exposure. PMID- 27500494 TI - Oxygen metabolism and barrier regulation in the intestinal mucosa. AB - Mucosal surfaces are lined by epithelial cells and provide an important barrier to the flux of antigens from the outside. This barrier is provided at a number of levels, including epithelial junctional complexes, mucus production, and mucosa derived antimicrobials. Tissue metabolism is central to the maintenance of homeostasis in the mucosa. In the intestine, for example, baseline pO2 levels are uniquely low due to counter-current blood flow and the presence of large numbers of bacteria. As such, hypoxia and HIF signaling predominates normal intestinal metabolism and barrier regulation during both homeostasis and active inflammation. Contributing factors that elicit important adaptive responses within the mucosa include the transcriptional regulation of tight junction proteins, metabolic regulation of barrier components, and changes in autophagic flux. Here, we review recent literature around the topic of hypoxia and barrier function in health and during disease. PMID- 27500497 TI - Homing is not for everyone: displaced cardinalfish find a new place to live. AB - It was tested whether the pajama cardinalfish Sphaeramia nematoptera (Apogonidae) could home by displacing individuals up to 250 m within and among isolated reefs. Contrary to expectations, only two of 37 (5.4%) displaced S. nematoptera returned home and another 16 (43.2%) were found to have joined other social groups and did not home after 26 months of observations; while over the same period, 94% of control S. nematoptera remained associated with home corals, demonstrating strong site attachment. Hence, while this species has the potential to return home, being able to do so may not be as critical as previously assumed. PMID- 27500495 TI - BRPF1 is essential for development of fetal hematopoietic stem cells. AB - Hematopoietic stem cells (HSCs) serve as a life-long reservoir for all blood cell types and are clinically useful for a variety of HSC transplantation-based therapies. Understanding the role of chromatin organization and regulation in HSC homeostasis may provide important insights into HSC development. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator that possesses 4 nucleosome-binding domains and activates 3 lysine acetyltransferases (KAT6A, KAT6B, and KAT7), suggesting that this protein has the potential to stimulate crosstalk between different chromatin modifications. Here, we investigated the function of BRPF1 in hematopoiesis by selectively deleting its gene in murine blood cells. Brpf1-deficient pups experienced early lethality due to acute bone marrow failure and aplastic anemia. The mutant bone marrow and fetal liver exhibited severe deficiency in HSCs and hematopoietic progenitors, along with elevated reactive oxygen species, senescence, and apoptosis. BRPF1 deficiency also reduced the expression of multipotency genes, including Slamf1, Mecom, Hoxa9, Hlf, Gfi1, Egr, and Gata3. Furthermore, BRPF1 was required for acetylation of histone H3 at lysine 23, a highly abundant but not well characterized epigenetic mark. These results identify an essential role of the multivalent chromatin regulator BRPF1 in definitive hematopoiesis and illuminate a potentially new avenue for studying epigenetic networks that govern HSC ontogeny. PMID- 27500496 TI - A colitogenic memory CD4+ T cell population mediates gastrointestinal graft versus-host disease. AB - Damage to the gastrointestinal tract is a major cause of morbidity and mortality in graft-versus-host disease (GVHD) and is attributable to T cell-mediated inflammation. In this work, we identified a unique CD4+ T cell population that constitutively expresses the beta2 integrin CD11c and displays a biased central memory phenotype and memory T cell transcriptional profile, innate-like properties, and increased expression of the gut-homing molecules alpha4beta7 and CCR9. Using several complementary murine GVHD models, we determined that adoptive transfer and early accumulation of beta2 integrin-expressing CD4+ T cells in the gastrointestinal tract initiated Th1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality. The pathogenic effect of this CD4+ T cell population critically depended on coexpression of the IL-23 receptor, which was required for maximal inflammatory effects. Non-Foxp3-expressing CD4+ T cells produced IL-10, which regulated colonic inflammation and attenuated lethality in the absence of functional CD4+Foxp3+ T cells. Thus, the coordinate expression of CD11c and the IL-23 receptor defines an IL-10-regulated, colitogenic memory CD4+ T cell subset that is poised to initiate inflammation when there is loss of tolerance and breakdown of mucosal barriers. PMID- 27500498 TI - Regulation of the vitamin D receptor by vitamin D lactam derivatives. AB - The active metabolite of vitamin D3 , 1alpha,25-dihydroxyvitamin D3 , acts as a ligand for the vitamin D receptor (VDR) and activates VDR-mediated gene expression. Recently, we characterized 1alpha,25-dihydroxyvitamin D3 -26,23 lactams (DLAMs), which mimic vitamin D3 metabolites, as noncalcemic VDR ligands that barely activate the receptor. In this study, we present structural insights onto the regulation of VDR function by DLAMs. X-ray crystallographic analysis revealed that DLAMs induced a large conformational change in the loop region between helices H6 and H7 in the VDR ligand-binding domain. Our structural analysis suggests that targeting of the loop region may be a new mode of VDR regulation. PMID- 27500499 TI - Technology-assisted self-testing and management of oral anticoagulation therapy: a qualitative patient-focused study. AB - BACKGROUND: Oral anticoagulation therapy requires regular blood testing to ensure therapeutic levels are maintained and excessive bleeding/clotting is avoided. Technology-assisted self-testing and management is seen as one of the key areas in which quality of care can be improved whilst reducing costs. Nevertheless, levels of patient engagement in self-testing and management remain low. To date, little research emphasis has been placed on understanding the patients' perspectives for low engagement. The typical approach adopted by healthcare providers is to provide patient education programmes, with the expectation that individual patients will change their behaviour and adopt new self-care strategies. However, if levels of patient engagement are to be increased, healthcare providers must also develop a better understanding of how their clinical service provision is perceived by patients and make adaptations. OBJECTIVE: To explore patient views, needs and expectations of an anticoagulation service and the self-testing and management services provided. METHODS: Interviews were conducted with 17 patients who currently engage in international normalised ratio (INR) self-testing and management. Thematic coding and analysis were carried out on the interview transcripts. RESULTS: Four high-level themes emerged from interviews: (i) role of clinic, (ii) motivations for self-testing, (iii) managing INR and (iv) trust. The clinic was seen as adding value in terms of specifying testing frequency, dosage profiles and calibrating equipment. Prompt communication from clinic to patient was also valued, although more personalised/real-time communication would help avoid feelings of isolation. Patients felt more in control as self-tester/managers and often took decisions about treatment adjustments themselves. However, some also manipulated their own test results to avoid 'unnecessary' interventions. CONCLUSIONS AND RECOMMENDATIONS: More personalised/real-time communication, pragmatic and collaborative patient-clinician partnerships and recognition of expert patient knowledge and expertise are needed if increased levels of engagement with self testing and management service provision is to be realised. PMID- 27500500 TI - Poly(polyol sebacate) Elastomers as Coatings for Metallic Coronary Stents. AB - Biocompatible polymeric coatings for metallic stents are desired, as currently used materials present limitations such as deformation during degradation and exponential loss of mechanical properties after implantation. These concerns, together with the present risks of the drug-eluting stents, namely, thrombosis and restenosis, require new materials to be studied. For this purpose, novel poly(polyol sebacate)-derived polymers are investigated as coatings for metallic stents. All pre-polymers reveal a low molecular weight between 3000 and 18 000 g mol-1 . The cured polymers range from flexible to more rigid, with E-modulus between 0.6 and 3.8 MPa. Their advantages include straightforward synthesis, biodegradability, easy processing through different scaffolding techniques, and easy transfer to industrial production. Furthermore, electrospraying and dip coating procedures are used as proof-of-concept to create coatings on metallic stents. Biocompatibility tests using adipose stem cells lead to promising results for the use of these materials as coatings for metallic coronary stents. PMID- 27500501 TI - Impact of Maternal Body Mass Index on Intrapartum and Neonatal Outcomes in Brisbane, Australia, 2007 to 2013. AB - BACKGROUND: The aim of this study was to evaluate the influence of maternal body mass index on intrapartum and neonatal outcomes at one of the largest maternity hospitals in Australia. METHODS: A retrospective cross-sectional study of 55,352 term singleton deliveries at the Mater Mothers' Hospital in Brisbane, Australia, was conducted. The study cohort was stratified into six groups based on the World Health Organization's body mass index classification. The normal body mass index category was the reference group for all comparisons. Multivariate logistic regression was used to examine the effect of maternal body mass index, adjusted for maternal age, ethnicity, parity, and preexisting conditions (e.g., diabetes mellitus and hypertension), on selected intrapartum and neonatal outcomes. RESULTS: Women in the overweight and Obese I, II, and III categories were more likely to have chronic or gestational hypertension/preeclampsia, and preexisting or gestational diabetes mellitus. They also had an increased risk for induction of labor, elective and emergency cesarean, and postpartum hemorrhage. Underweight women were less likely to require induction of labor and emergency cesarean. Infants born to women with increased body mass index were more likely to require neonatal resuscitation, neonatal intensive care unit admission, and have lower Apgar scores at 5 minutes. CONCLUSION: There is an increased risk of adverse intrapartum and neonatal outcomes for women who are overweight and obese, with the risks increasing with rising body mass index. Appropriately targeted weight management strategies and health education may yield improved maternal and perinatal outcomes if effectively implemented before pregnancy. These may particularly be of benefit in the teenage cohort that has yet to embark on pregnancy. PMID- 27500502 TI - Deadwood stocks increase with selective logging and large tree frequency in Gabon. AB - Deadwood is a major component of aboveground biomass (AGB) in tropical forests and is important as habitat and for nutrient cycling and carbon storage. With deforestation and degradation taking place throughout the tropics, improved understanding of the magnitude and spatial variation in deadwood is vital for the development of regional and global carbon budgets. However, this potentially important carbon pool is poorly quantified in Afrotropical forests and the regional drivers of deadwood stocks are unknown. In the first large-scale study of deadwood in Central Africa, we quantified stocks in 47 forest sites across Gabon and evaluated the effects of disturbance (logging), forest structure variables (live AGB, wood density, abundance of large trees), and abiotic variables (temperature, precipitation, seasonality). Average deadwood stocks (measured as necromass, the biomass of deadwood) were 65 Mg ha-1 or 23% of live AGB. Deadwood stocks varied spatially with disturbance and forest structure, but not abiotic variables. Deadwood stocks increased significantly with logging (+38 Mg ha-1 ) and the abundance of large trees (+2.4 Mg ha-1 for every tree >60 cm dbh). Gabon holds 0.74 Pg C, or 21% of total aboveground carbon in deadwood, a threefold increase over previous estimates. Importantly, deadwood densities in Gabon are comparable to those in the Neotropics and respond similarly to logging, but represent a lower proportion of live AGB (median of 18% in Gabon compared to 26% in the Neotropics). In forest carbon accounting, necromass is often assumed to be a constant proportion (9%) of biomass, but in humid tropical forests this ratio varies from 2% in undisturbed forest to 300% in logged forest. Because logging significantly increases the deadwood carbon pool, estimates of tropical forest carbon should at a minimum use different ratios for logged (mean of 30%) and unlogged forests (mean of 18%). PMID- 27500503 TI - Mechanistic Insights and Computational Design of Transition-Metal Catalysts for Hydrogenation and Dehydrogenation Reactions. AB - Catalytic hydrogenation and dehydrogenation reactions are fundamentally important in chemical synthesis and industrial processes, as well as potential applications in the storage and conversion of renewable energy. Modern computational quantum chemistry has already become a powerful tool in understanding the structures and properties of compounds and elucidating mechanistic insights of chemical reactions, and therefore, holds great promise in the design of new catalysts. Herein, we review our computational studies on the catalytic hydrogenation of carbon dioxide and small organic carbonyl compounds, and on the dehydrogenation of amine-borane and alcohols with an emphasis on elucidating reaction mechanisms and predicting new catalytic reactions, and in return provide some general ideas for the design of high-efficiency, low-cost transition-metal complexes for hydrogenation and dehydrogenation reactions. PMID- 27500504 TI - Synthesis of Silver(I) and Gold(I) Complexes Containing Enantiopure Pybox Ligands. First Assays on the Silver(I)-Catalyzed Asymmetric Addition of Alkynes to Imines. AB - Dinuclear complexes [Ag2(CF3SO3){(S,S)-(i)Pr-pybox}2][CF3SO3] (1), [Ag2(R pybox)2][X]2 [R-pybox = 2,6-bis[4-(S)-isopropyloxazolin-2-yl]pyridine (S,S)-(i)Pr pybox and X = PF6 (2) and BF4 (3); R-pybox = 2,6-bis[(3aS,8aR)-8,8a-dihydro-3aH indeno[1,2-d]oxazol-2-yl]pyridine (3aS,3a'S,8aR,8a'R)-indane-pybox and X = CF3SO3 (4)], [Ag2{(S,S)-(i)Pr-pybox}{(3aS,3a'S,8aR,8a'R)-indane-pybox}][CF3SO3]2 (5), and [Ag2(R-pybox)3][X]2 [R-pybox = (3aS,3a'S,8aR,8a'R)-indane-pybox and X = CF3SO3 (10), SF6 (11), and PF6 (12)] as well as mononuclear complexes [Ag(R pybox)2][X] [R-pybox = (S,S)-(i)Pr-pybox and X = SbF6 (6), PF6 (7), and BF4 (8); R-pybox = (3aS,3a'S,8aR,8a'R)-indane-pybox) and X = BF4 (9)] have been prepared by the reaction of the corresponding silver salts and pybox ligands using the appropriate molar ratio conditions. The first gold(I)/pybox complex [Au6Cl4{(S,S) (i)Pr-pybox}4][AuCl2]2 (13) has been synthesized by the reaction of [AuCl{S(CH3)2}] and (S,S)-(i)Pr-pybox (1:1 molar ratio) in acetonitrile. The structures of the dinuclear (1, 4, 5, 10, and 11) and mononuclear (6 and 9) silver complexes and the hexanuclear gold complex 13 have been determined by single-crystal X-ray diffraction analysis. These studies have been complemented with a solution-state study by NMR spectroscopy, which included structure elucidation, variable-temperature measurements, and diffusion studies using diffusion-ordered spectroscopy (DOSY; for complexes 1, 4, 10, and 12). Complexes 1, 2, 4, and 10 have been assayed as catalysts in the asymmetric addition of phenylacetylene to N-benzylideneaniline. PMID- 27500507 TI - Parents with mental illness - a qualitative study of identities and experiences with support services. AB - : WHAT IS KNOWN ON THE SUBJECT?: According to estimates more than half of adult mental health service users are parents, but their experiences are largely lacking from research literature. Parental mental illness can often be viewed from a risk perspective. Parents with mental illness and their families have unmet support needs. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Parents with mental illness want acknowledgement that they can be able and responsible. Many parents adopt an expert by experience identity. Fathers can feel their parental role is not recognized and mothers express fears of being judged if they discuss their illness. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Adult mental health services need to recognize and support parental role of service users. Joint care planning and family oriented care should be promoted. Professionals should take advantage of the knowledge of these parents and they could be more actively engaged in service development. ABSTRACT: Introduction Parental mental illness is often viewed from a risk perspective. Despite this, being a parent can be both valuable and motivating. Research literature lacks the perspective of mothers and fathers, who have experienced mental illness. Aim This study explores how parents with mental illness construct their identities as mothers and fathers and their experiences with health and social care services. Method Three focus groups with 19 participants were conducted in Finland and Scotland. Methods of discourse analysis have been used in to analyse the interview data. Results Adult service users want their parenting role recognized and supported. Parents have knowledge and skills which can be utilized and many have adopted an expert by experience identity. Discussion Being able to see oneself as a 'good' parent can be challenging but important. Parents may require support, but want to be included in the planning of their care. Services could make more use of the knowledge and skills parents and families have, and joint working could lessen parents' anxieties. Implications for practice Mental health practitioners are in a key position in providing more family centred, resource focused care. Service user expertise should be acknowledged in clinical practice. PMID- 27500505 TI - Rise and fall of vector infectivity during sequential strain displacements by mosquito-borne dengue virus. AB - Each of the four serotypes of mosquito-borne dengue virus (DENV-1-4) comprises multiple, genetically distinct strains. Competitive displacement between strains within a serotype is a common feature of DENV epidemiology and can trigger outbreaks of dengue disease. We investigated the mechanisms underlying two sequential displacements by DENV-3 strains in Sri Lanka that each coincided with abrupt increases in dengue haemorrhagic fever (DHF) incidence. First, the post DHF strain displaced the pre-DHF strain in the 1980s. We have previously shown that post-DHF is more infectious than pre-DHF for the major DENV vector, Aedes aegypti. Then, the ultra-DHF strain evolved in situ from post-DHF and displaced its ancestor in the 2000s. We predicted that ultra-DHF would be more infectious for Ae. aegypti than post-DHF but found that ultra-DHF infected a significantly lower percentage of mosquitoes than post-DHF. We therefore hypothesized that ultra-DHF had effected displacement by disseminating in Ae. aegypti more rapidly than post-DHF, but this was not borne out by a time course of mosquito infection. To elucidate the mechanisms that shape these virus-vector interactions, we tested the impact of RNA interference (RNAi), the principal mosquito defence against DENV, on replication of each of the three DENV strains. Replication of all strains was similar in mosquito cells with dysfunctional RNAi, but in cells with functional RNAi, replication of pre-DHF was significantly suppressed relative to the other two strains. Thus, differences in susceptibility to RNAi may account for the differences in mosquito infectivity between pre-DHF and post-DHF, but other mechanisms underlie the difference between post-DHF and ultra-DHF. PMID- 27500506 TI - Chemical composition and antimicrobial activity of Micromeria hedgei Rech. f. oil from Iran. AB - Micromeria hedgei belongs to the Lamiaceae family and is a rare endemic and endangered species that has been used in traditional medicine in Iran. In this regard, essential oil composition and antimicrobial activity of wild and cultivated M. hedgei was reported for the first time. Essential oils isolated via hydro distillation from the aerial parts of M. hedgei were analysed by a combination of capillary GC and GC-MS. The major constituents were geranial (18.04 and 22.68%), neral (13.81 and 15.99%), geraniol (13.15 and 10.74%), nerol (7.69 and 6.02%), E-caryophyllene (6.52-3.80%), carvacrol (6.20 and 5.27%), geranyl acetate (5.79 and 3.06%), caryophyllene oxide (4.73 and 3.88%), thymol (3.13 and 3.63%) and alpha-humulene (3.27 and 3.27%) in wild and cultivated M. hedgei. Antimicrobial activity of essential oils was investigated by disc diffusion method. Essential oil showed good antimicrobial activity against five medically important pathogens compared with standard antibiotics. PMID- 27500508 TI - A novel case presenting with an unusual ureteral diverticular lesion similar to adenomyomatous hyperplasia of the gallbladder. AB - We present the first case of an unusual ureteral diverticular lesion demonstrating similarities to adenomyomatous hyperplasia of the gallbladder. A 68 year-old asymptomatic Japanese man with high prostate-specific antigen levels was clinically evaluated. Left hydronephrosis and benign prostatic hyperplasia were detected. A bilateral retrograde pyelogram revealed that the upper and middle portions of the left ureter exhibited an irregular narrow lumen and some pooling of contrast material, which was compatible with ureteral pseudodiverticulosis. Although no malignant cells were seen on cytology, computed tomography detected a fusiform shaped lesion with a circumferential thick wall including multiple diverticulae. Left nephroureterectomy was performed because malignancy could not be ruled out. Pathology demonstrated that the ureteral lesion showed a localized thick wall consisting of multilocules and/or multicysts and a hyperplastic muscularis propria. The cysts were mostly seen in the muscularis propria or a deeper site. The inner layers of the cysts were lined with normal urothelium, and some cysts opened onto the mucosal surface, indicating that they were derived from invaginated mucosal epithelium. We believe that this lesion may be a novel form of diverticular disorder demonstrating similarities to adenomyomatous hyperplasia of the gallbladder. PMID- 27500509 TI - Pituitary Non-Functioning Adenoma Disclosed at 18F-Choline PET/CT to Investigate a Prostate Cancer Relapse. AB - We report the incidental finding of a pituitary macroadenoma on an F-choline PET/CT in a patient with recurrent prostate cancer. The pituitary gland was clearly enlarged and intensely FDG avid (SUVmax, 6.6). The diagnosis was confirmed by a subsequent contrast-enhanced MR evaluation, and the macroadenoma was classified as nonfunctioning on the basis of normality of the specific serum hormonal profile. A follow-up F-choline PET/CT scan performed after 6 months revealed stable dimension, and uptake of the pituitary macroadenoma patient deceased 1 month later. At autopsy, intracytoplasmic vesicles containing growth and prolactin hormones were observed at immunohistochemistry. PMID- 27500510 TI - Differences in Uptake of 18F-FDG and 11C-Choline in a Case of Acute Myeloid Leukemia. AB - A 26-year-old man had unilateral facial numbness. A brain MRI suggested possible brain metastases. F-FDG and C-choline PET/CT revealed multiple sites of abnormal activity in the body. However, C-choline PET/CT was more impressive than FDG PET/CT. Especially, the brain lesions revealed by MRI had only elevated C-choline uptake but had FDG uptake levels similar to adjacent brain. Acute myeloid leukemia was diagnosed after bone marrow biopsy. PMID- 27500511 TI - 68Ga DOTATATE PET/CT in Differentiated Thyroid Carcinoma With Fibular Metastasis and Mixed Response to Sorafenib. AB - We describe somatostatin receptor targeted imaging findings in a 56-year-old woman with elevated serum thyroglobulin and radioiodine negative DTC fibular metastasis. The fibular lesion was biopsy proven of poorly differentiated thyroid carcinoma and demonstrated high grade uptake on Tc-HYNIC-TOC scintigraphy. She opted for sorafenib therapy for progressively increasing fibular swelling and was started on 400 mg daily followed by dose escalation to 400 mg twice daily. At 17 months after sorafenib initiation, Ga DOTATATE PET/CT demonstrated necrosis of the fibular lesion; however, new lesions were documented in lower dorsal and lumbar vertebrae and skull, based upon which sorafenib withdrawal was contemplated. PMID- 27500513 TI - The Synthesis of Multisubstituted Pyrroles via a Copper-Catalyzed Tandem Three Component Reaction. AB - An unprecedented nucleophilic addition/cyclization/aromatization cascade of basic chemicals, i.e., aromatic alkenes/alkynes, trimethylsilyl cyanide and N,N disubstituted formamide, has been developed to give a series of multisubstituted pyrroles in moderate to good yields with high regioselectivities. This reaction not only reveals a new reaction mode for alpha-aminonitriles, but also provides a new and efficient cyclization pattern for the synthesis of multisubstituted pyrroles as well as their derivatives, which might facilitate related biological studies. PMID- 27500512 TI - Disease-specific scoring or generic scoring in ICU? PMID- 27500514 TI - Ronald W. Waynant, PhD (October 4, 1940-May 8, 2016). PMID- 27500515 TI - Self-Aggregating Deep Cavitand Acts as a Fluorescence Displacement Sensor for Lysine Methylation. AB - A dual-mode aggregative host:guest indicator displacement sensing system has been created for the detection of trimethylated peptides and determination of histone demethylase activity. The combination of selective recognition of suitably sized trimethylammonium salts and reversible lipophilic aggregation of the host:guest complex provides a unique quenching mechanism that is not only dependent on affinity for sensitivity but the lipophilicity of the indicator. In addition, aggregation can be controlled by the application of chaotropic anions in the mixture, allowing a second level of discrimination between hard lysine groups and softer trimethyllysines. PMID- 27500516 TI - Autoradiographic Measurements of [14C]-Iodoantipyrine in Rat Brain Following Central Post-Stroke Pain. AB - Approximately 8% of stroke patients present symptoms of central post-stroke pain (CPSP). CPSP is associated with allodynia and hypersensitivity to nociceptive stimuli. Although some studies have shown that neuropathic pain may involve the dorsolateral prefrontal cortex, rostral anterior cingulate cortex, amygdala, hippocampus, periaqueductal gray, rostral ventromedial medulla, and medial thalamus, the neural substrates and their connections that mediate CPSP remain unclear. [(14)C]-Iodoantipyrine (IAP) uptake can be measured to evaluate spontaneously active pain. It can be used to assess the activation of neural substrates that may be involved in CPSP in an animal model. The [(14)C]-IAP method in rats is less expensive to perform compared with other brain mapping techniques. The present [(14)C]-IAP protocol is used to measure the activation of neural substrates that are involved in CPSP that is induced by lesions of the ventral basal nucleus (VB) of the thalamus in a rodent model. PMID- 27500517 TI - Response to "Concerning the Article Entitled 'Judgment of Nasolabial Esthetics in Cleft Lip and Palate Is Not Influenced by Overall Facial Attractiveness'". PMID- 27500518 TI - Cleidocranial Dysplasia with 6p21.1-p12.3 Microdeletion: A Case Report and Literature Review. AB - OBJECTIVE: The aim of this article is to publish a literature review and report on a new case of cleidocranial dysplasia syndrome with 6p21.1-p12.3 microdeletion. DESIGN: A PubMed search using "cleidocranial dysplasia syndrome (CCD)" or "6p microdeletion" was performed. Articles with information relevant to our case were obtained for review. A new case of cleidocranial dysplasia syndrome is presented to describe and discuss clinical manifestations, pathogenesis, clinical progression of cleidocranial dysplasia syndrome, and management. RESULTS: There were 22 articles with reports of cleidocranial dysplasia syndrome or 6p microdeletion. Cleidocranial dysplasia syndrome, a rare genetic disorder, documented to have an autosomal dominant inheritance pattern and caused by caused by mutations of the transcription factor RUNX2. RUNX2 has been mapped to chromosome 6p21. The anomalies in cleidocranial dysplasia syndrome can involve not only the clavicle and skull but the entire skeleton because the membranous as well as endochondral bone formation may be affected. Upon follow-up, our patient was found to have global developmental delay. CONCLUSIONS: We report a near-term neonate with characteristic features of cleidocranial dysplasia and a 6p21.1 p12.3 microdeletion. Cleidocranial dysplasia syndrome is a rare autosomal dominant skeletal dysplasia. The mutation of the RUNX2 gene results in cleidocranial dysplasia syndrome. PMID- 27500519 TI - Cardiopulmonary dysfunction in patients with limb-girdle muscular dystrophy 2A. AB - INTRODUCTION: Little is known about the frequency of cardiopulmonary failure in limb-girdle muscular dystrophy type 2A (calpainopathy) patients, although some studies have reported severe cardiomyopathy or respiratory failure. METHODS: To clarify the frequency of cardiopulmonary dysfunction in this patient population, we retrospectively reviewed the respiratory and cardiac function of 43 patients with calpainopathy. RESULTS: Nine of the 43 patients had forced vital capacity (FVC) < 80%, and 3 used noninvasive positive pressure ventilation. Mean FVC was significantly lower in patients who were nonambulant and had normal creatine kinase levels. Only 1 patient had a prolonged QRS complex duration. Echocardiography revealed that 1 patient had very mild left ventricular dysfunction. CONCLUSIONS: These findings suggest that patients with calpainopathy may develop severe respiratory failure, but cardiac dysfunction is infrequent. Muscle Nerve 55: 465-469, 2017. PMID- 27500520 TI - The Eucalyptus linker histone variant EgH1.3 cooperates with the transcription factor EgMYB1 to control lignin biosynthesis during wood formation. AB - Wood, also called secondary xylem, is a specialized vascular tissue constituted by different cell types that undergo a differentiation process involving deposition of thick, lignified secondary cell walls. The mechanisms needed to control the extent of lignin deposition depending on the cell type and the differentiation stage are far from being fully understood. We found that the Eucalyptus transcription factor EgMYB1, which is known to repress lignin biosynthesis, interacts specifically with a linker histone variant, EgH1.3. This interaction enhances the repression of EgMYB1's target genes, strongly limiting the amount of lignin deposited in xylem cell walls. The expression profiles of EgMYB1 and EgH1.3 overlap in xylem cells at early stages of their differentiation as well as in mature parenchymatous xylem cells, which have no or only thin lignified secondary cell walls. This suggests that a complex between EgMYB1 and EgH1.3 integrates developmental signals to prevent premature or inappropriate lignification of secondary cell walls, providing a mechanism to fine-tune the differentiation of xylem cells in time and space. We also demonstrate a role for a linker histone variant in the regulation of a specific developmental process through interaction with a transcription factor, illustrating that plant linker histones have other functions beyond chromatin organization. PMID- 27500521 TI - Engineering Three-dimensional Epithelial Tissues Embedded within Extracellular Matrix. AB - The architecture of branched organs such as the lungs, kidneys, and mammary glands arises through the developmental process of branching morphogenesis, which is regulated by a variety of soluble and physical signals in the microenvironment. Described here is a method created to study the process of branching morphogenesis by forming engineered three-dimensional (3D) epithelial tissues of defined shape and size that are completely embedded within an extracellular matrix (ECM). This method enables the formation of arrays of identical tissues and enables the control of a variety of environmental factors, including tissue geometry, spacing, and ECM composition. This method can also be combined with widely used techniques such as traction force microscopy (TFM) to gain more information about the interactions between cells and their surrounding ECM. The protocol can be used to investigate a variety of cell and tissue processes beyond branching morphogenesis, including cancer invasion. PMID- 27500522 TI - Human Primary Trophoblast Cell Culture Model to Study the Protective Effects of Melatonin Against Hypoxia/reoxygenation-induced Disruption. AB - This protocol describes how villous cytotrophoblast cells are isolated from placentas at term by successive enzymatic digestions, followed by density centrifugation, media gradient isolation and immunomagnetic purification. As observed in vivo, mononucleated villous cytotrophoblast cells in primary culture differentiate into multinucleated syncytiotrophoblast cells after 72 hr. Compared to normoxia (8% O2), villous cytotrophoblast cells that undergo hypoxia/reoxygenation (0.5% / 8% O2) undergo increased oxidative stress and intrinsic apoptosis, similar to that observed in vivo in pregnancy complications such as preeclampsia, preterm birth, and intrauterine growth restriction. In this context, primary villous trophoblasts cultured under hypoxia/reoxygenation conditions represent a unique experimental system to better understand the mechanisms and signalling pathways that are altered in human placenta and facilitate the search for effective drugs that protect against certain pregnancy disorders. Human villous trophoblasts produce melatonin and express its synthesizing enzymes and receptors. Melatonin has been suggested as a treatment for preeclampsia and intrauterine growth restriction because of its protective antioxidant effects. In the primary villous cytotrophoblast cell model described in this paper, melatonin has no effect on trophoblast cells in normoxic state but restores the redox balance of syncytiotrophoblast cells disrupted by hypoxia/reoxygenation. Thus, human villous trophoblast cells in primary culture are an excellent approach to study the mechanisms behind the protective effects of melatonin on placental function during hypoxia/reoxygenation. PMID- 27500524 TI - Domestication history and geographical adaptation inferred from a SNP map of African rice. AB - African rice (Oryza glaberrima Steud.) is a cereal crop species closely related to Asian rice (Oryza sativa L.) but was independently domesticated in West Africa ~3,000 years ago. African rice is rarely grown outside sub-Saharan Africa but is of global interest because of its tolerance to abiotic stresses. Here we describe a map of 2.32 million SNPs of African rice from whole-genome resequencing of 93 landraces. Population genomic analysis shows a population bottleneck in this species that began ~13,000-15,000 years ago with effective population size reaching its minimum value ~3,500 years ago, suggesting a protracted period of population size reduction likely commencing with predomestication management and/or cultivation. Genome-wide association studies (GWAS) for six salt tolerance traits identify 11 significant loci, 4 of which are within ~300 kb of genomic regions that possess signatures of positive selection, suggesting adaptive geographical divergence for salt tolerance in this species. PMID- 27500525 TI - Nucleation of DNA repair factors by FOXA1 links DNA demethylation to transcriptional pioneering. AB - FOXA1 functions in epigenetic reprogramming and is described as a 'pioneer factor'. However, exactly how FOXA1 achieves these remarkable biological functions is not fully understood. Here we report that FOXA1 associates with DNA repair complexes and is required for genomic targeting of DNA polymerase beta (POLB) in human cells. Genome-wide DNA methylomes demonstrate that the FOXA1 DNA repair complex is functionally linked to DNA demethylation in a lineage-specific fashion. Depletion of FOXA1 results in localized reestablishment of methylation in a large portion of FOXA1-bound regions, and the regions with the most consistent hypermethylation exhibit the greatest loss of POLB and are represented by active promoters and enhancers. Consistently, overexpression of FOXA1 commits its binding sites to active DNA demethylation in a POLB-dependent manner. Finally, FOXA1-associated DNA demethylation is tightly coupled with estrogen receptor genomic targeting and estrogen responsiveness. Together, these results link FOXA1-associated DNA demethylation to transcriptional pioneering by FOXA1. PMID- 27500526 TI - Spatial-Temporal Study of Rab1b Dynamics and Function at the ER-Golgi Interface. AB - The GTPase Rab1b is involved in ER to Golgi transport, with multiple Rab1b effectors (located at ERES, VTCs and the Golgi complex) being required for its function. In this study, we performed live-cell dual-expression studies to analyze the dynamics of Rab1b and some effectors located at the ERES-Golgi interface. Rab1b occupied widely distributed mobile punctate and tubular structures, displaying a transient overlaps with its effectors and showing that these overlaps occurred at the same time in spatially distinct steps of ER to Golgi transport. In addition, we assessed Rab1b dynamics during cargo sorting by analyzing the concentration at ERES of a Golgi protein (SialT2-CFP) during Brefeldin A washout (BFA WO). Rab1b was associated to most of the ERES structures, but at different times during BFA WO, and recurrently SialT2-CFP was sorted in the ERES-Rab1b positive structures. Furthermore, we reveal for first time that Rab1b localization time at ERES depended on GBF1, a Rab1b effector that acts as the guanine nucleotide exchange factor of Arf1, and that Rab1b membrane association/dissociation dynamics at ERES was dependent on the GBF1 membrane association and activity, which strongly suggests that GBF1 activity modulates Rab1b membrane cycling dynamic. PMID- 27500523 TI - Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. AB - Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 * 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine. PMID- 27500527 TI - Correction: Analysis of Plasma Protein Concentrations and Enzyme Activities in Cattle within the Ex-Evacuation Zone of the Fukushima Daiichi Nuclear Plant Accident. AB - [This corrects the article DOI: 10.1371/journal.pone.0155069.]. PMID- 27500528 TI - Erratum to: "Metabolic Syndrome after Hematopoietic Cell Transplantation: At the Intersection of Treatment Toxicity and Immune Dysfunction" [Biol Blood Marrow Transplant 2016;22:1159-1166]. PMID- 27500530 TI - One-step microwave synthesis of N-doped hydroxyl-functionalized carbon dots with ultra-high fluorescence quantum yields. AB - A one-step microwave synthesis of N-doped hydroxyl-functionalized carbon dots (CDs) with ultra-high fluorescence quantum yields (QYs) of 99% is reported. These ultra-high QY CDs were synthesized using citric acid and amino compound containing hydroxyls like ethanolamine and tris(hydroxylmethyl)aminomethane. Amino and carboxyl moieties can form amides through dehydration condensation reactions, and these amides act as bridges between carboxyl and hydroxyl groups, and modify hydroxyl groups on the surface of the CDs. The entire reaction can be carried out within 5 min. When the molar ratio of reactants is 1 : 1, the hydroxyl and graphitic nitrogen content is the highest, and the synergy leads to a high ratio between the radiative transition rate and nonradiative transition rate as well as a high QY. The developed pathway to N-doped hydroxyl functionalized CDs can provide unambiguous and remarkable insights into the design of highly luminescent functionalized carbon dots, and expedite the applications of CDs. PMID- 27500529 TI - MDP: A Deinococcus Mn2+-Decapeptide Complex Protects Mice from Ionizing Radiation. AB - The radioprotective capacity of a rationally-designed Mn2+-decapeptide complex (MDP), based on Mn antioxidants in the bacterium Deinococcus radiodurans, was investigated in a mouse model of radiation injury. MDP was previously reported to be extraordinarily radioprotective of proteins in the setting of vaccine development. The peptide-component (DEHGTAVMLK) of MDP applied here was selected from a group of synthetic peptides screened in vitro for their ability to protect cultured human cells and purified enzymes from extreme damage caused by ionizing radiation (IR). We show that the peptides accumulated in Jurkat T-cells and protected them from 100 Gy. MDP preserved the activity of T4 DNA ligase exposed to 60,000 Gy. In vivo, MDP was nontoxic and protected B6D2F1/J (female) mice from acute radiation syndrome. All irradiated mice treated with MDP survived exposure to 9.5 Gy (LD70/30) in comparison to the untreated mice, which displayed 63% lethality after 30 days. Our results show that MDP provides early protection of white blood cells, and attenuates IR-induced damage to bone marrow and hematopoietic stem cells via G-CSF and GM-CSF modulation. Moreover, MDP mediated the immunomodulation of several cytokine concentrations in serum including G-CSF, GM-CSF, IL-3 and IL-10 during early recovery. Our results present the necessary prelude for future efforts towards clinical application of MDP as a promising IR countermeasure. Further investigation of MDP as a pre-exposure prophylactic and post-exposure therapeutic in radiotherapy and radiation emergencies is warranted. PMID- 27500531 TI - Genome Sequence of the Edible Cultivated Mushroom Lentinula edodes (Shiitake) Reveals Insights into Lignocellulose Degradation. AB - Lentinula edodes, one of the most popular, edible mushroom species with a high content of proteins and polysaccharides as well as unique aroma, is widely cultivated in many Asian countries, especially in China, Japan and Korea. As a white rot fungus with lignocellulose degradation ability, L. edodes has the potential for application in the utilization of agriculture straw resources. Here, we report its 41.8-Mb genome, encoding 14,889 predicted genes. Through a phylogenetic analysis with model species of fungi, the evolutionary divergence time of L. edodes and Gymnopus luxurians was estimated to be 39 MYA. The carbohydrate-active enzyme genes in L. edodes were compared with those of the other 25 fungal species, and 101 lignocellulolytic enzymes were identified in L. edodes, similar to other white rot fungi. Transcriptome analysis showed that the expression of genes encoding two cellulases and 16 transcription factor was up regulated when mycelia were cultivated for 120 minutes in cellulose medium versus glucose medium. Our results will foster a better understanding of the molecular mechanism of lignocellulose degradation and provide the basis for partial replacement of wood sawdust with agricultural wastes in L. edodes cultivation. PMID- 27500532 TI - Identification of Rare Bacterial Pathogens by 16S rRNA Gene Sequencing and MALDI TOF MS. AB - There are a number of rare and, therefore, insufficiently described bacterial pathogens which are reported to cause severe infections especially in immunocompromised patients. In most cases only few data, mostly published as case reports, are available which investigate the role of such pathogens as an infectious agent. Therefore, in order to clarify the pathogenic character of such microorganisms, it is necessary to conduct epidemiologic studies which include large numbers of these bacteria. The methods used in such a surveillance study have to meet the following criteria: the identification of the strains has to be accurate according to the valid nomenclature, they should be easy to handle (robustness), economical in routine diagnostics and they have to generate comparable results among different laboratories. Generally, there are three strategies for identifying bacterial strains in a routine setting: 1) phenotypic identification characterizing the biochemical and metabolic properties of the bacteria, 2) molecular techniques such as 16S rRNA gene sequencing and 3) mass spectrometry as a novel proteome based approach. Since mass spectrometry and molecular approaches are the most promising tools for identifying a large variety of bacterial species, these two methods are described. Advances, limitations and potential problems when using these techniques are discussed. PMID- 27500533 TI - Quantification of Boat Visitation Rates at Artificial and Natural Reefs in the Eastern Gulf of Mexico Using Acoustic Recorders. AB - Artificial reefs are commonly used as a management tool, in part to provide ecosystem services, including opportunities for recreational fishing and diving. Quantifying the use of artificial reefs by recreational boaters is essential for determining their value as ecosystem services. In this study, four artificial natural reef pairs in the eastern Gulf of Mexico (off western Florida) were investigated for boat visitation rates using autonomous acoustic recorders. Digital SpectroGram (DSG) recorders were used to collect sound files from April 2013 to March 2015. An automatic detection algorithm was used to identify boat noise in individual files using the harmonic peaks generated by boat engines, and by comparing the sound amplitude of each file with surrounding files. In all four pairs, visitation rates were significantly higher at the artificial reef than the natural reef. This increase in boat visitation was likely due to actual or perceived increased quality of fishing and diving at the artificial reefs, or to lack of knowledge of the presence or locations of the natural reefs. Inshore reefs (<15 m depth) had high variability in monthly visitation rates, which were generally highest in warmer months. However the seasonal signal was dampened on offshore reefs (>25 m depth). This study appears to be the first to use acoustic data to measure participant use of boating destinations, and highlights the utility of acoustic monitoring for the valuation of this important ecosystem service provided by artificial reefs. PMID- 27500534 TI - Correction: alpha-MSH Stimulates Glucose Uptake in Mouse Muscle and Phosphorylates Rab-GTPase-Activating Protein TBC1D1 Independently of AMPK. AB - [This corrects the article DOI: 10.1371/journal.pone.0157027.]. PMID- 27500535 TI - Early stage thymoma: is VATS the new standard of care? PMID- 27500536 TI - De novo mutations in genes of mediator complex causing syndromic intellectual disability: mediatorpathy or transcriptomopathy? AB - BACKGROUND: Mutations in the X-linked gene MED12 cause at least three different, but closely related, entities of syndromic intellectual disability. Recently, a new syndrome caused by MED13L deleterious variants has been described, which shows similar clinical manifestations including intellectual disability, hypotonia, and other congenital anomalies. METHODS: Genotyping of 1,256 genes related with neurodevelopment was performed by next-generation sequencing in three unrelated patients and their healthy parents. Clinically relevant findings were confirmed by conventional sequencing. RESULTS: Each patient showed one de novo variant not previously reported in the literature or databases. Two different missense variants were found in the MED12 or MED13L genes and one nonsense mutation was found in the MED13L gene. CONCLUSION: The phenotypic consequences of these mutations are closely related and/or have been previously reported in one or other gene. Additionally, MED12 and MED13L code for two closely related partners of the mediator kinase module. Consequently, we propose the concept of a common MED12/MED13L clinical spectrum, encompassing Opitz Kaveggia syndrome, Lujan-Fryns syndrome, Ohdo syndrome, MED13L haploinsufficiency syndrome, and others. PMID- 27500538 TI - Overlapping meta-analyses of bioresorbable vascular scaffolds versus everolimus eluting stents: bringing clarity or confusion? PMID- 27500539 TI - Comment on "Evaluation of Antiviral Therapy Performed after Curative Therapy in Patients with HBV-Related Hepatocellular Carcinoma: An Updated Meta-Analysis". PMID- 27500537 TI - What is the identity of fibroblast-pneumocyte factor? AB - Glucocorticoid induction of pulmonary surfactant involves a mesenchyme-derived protein first characterized in 1978 by Smith and termed fibroblast-pneumocyte factor (FPF). Despite a number of agents having been postulated as being FPF, its identity has remained obscure. In the past decade, three strong candidates for FPF have arisen. This review examines the evidence that keratinocyte growth factor (KGF), leptin or neuregulin-1beta (NRG-1beta) act as FPF or components of it. As with FPF production, glucocorticoids enhance the concentration of each of these agents in fibroblast-conditioned media. Moreover, each stimulates the synthesis of surfactant-associated phospholipids and proteins in type II pneumocytes. Further, some have unique activities, for example, KGF also minimizes lung injury through enhanced epithelial cell proliferation and NRG 1beta enhances surfactant phospholipid secretion and beta-adrenergic receptor activity in type II cells. However, even though these agents have attributes in common with FPF, it is inappropriate to specify any one of these agents as FPF. Rather, it appears that each contributes to separate mesenchymal-epithelial signaling mechanisms involved in different aspects of lung development. Given that the production of pulmonary surfactant is essential for postnatal survival, it is reasonable to suggest that several mechanisms independently regulate surfactant synthesis. PMID- 27500540 TI - Repair of Morgagni Hernia in Adults with Primary Closure and Mesh Placement: First Robotic Experience. AB - INTRODUCTION: Morgagni hernia (MH) is an uncommon type of diaphragmatic hernia, especially in adults. Laparoscopic or thorascopic approaches have been described in adults. There are few reported cases using the Da Vinci robot in children and no previously described cases in adults. We report our early experience and technique using the robotic approach for MH repair in adults and its potential advantages. METHOD: Robotic repair of MH was performed in 3 female patients. Four trocars were used to gain access to the abdomen. The hernia contents were reduced, the sac excised, and the defect closed primarily. A 4 * 6 inch bioabsorbable coating mesh was used in 2 patients and a biologic mesh in 1 for reinforcement. RESULTS: Robotic repair of MH was technically successful in all 3 patients. The average operative time was 199.3 minutes, and difficult hernia exposure in one case caused prolonged surgical time. There were no intraoperative complications. Additional interventions, including a repair of a transverse colon serosal tear during the reduction of hernia contents, occurred in 1 patient. Two of the 3 female patients were discharged on postoperative day 1, whereas the other patient was discharged on postoperative day 3. There were no postoperative complications. CONCLUSION: Robotic MH repair is an alternative minimally invasive approach for adults that allows for precise sac excision and primary tension-free repair with mesh reinforcement. PMID- 27500541 TI - Quorum sensing and other collective regenerative behavior in organ populations. AB - Stem cell and microenvironment molecular interactions have been studied in detail but regenerative behavior at the organ population level has remained unexplored. Organ renewal can occur continuously or in cyclic episodes. Progenitors may be distributed as one entity or compartmentalized into multiple units. Multiple units offer advantages as each unit can be regulated differently in different body regions or physiological stages, adapting animals to their niche with flexible functional forms. Using the hair paradigm, we show how periodic patterning can convert one morphogenetic field into many hair germs, how follicles can be renewed with different cycle times and phenotypes in a region specific manner, and how new properties, such as regenerative waves and quorum sensing, emerge to coordinate collective regenerative behavior. PMID- 27500542 TI - Development of microstructure and mechanical properties during annealing of a cold-swaged Co-Cr-Mo alloy rod. AB - In this study, we investigated the evolution of the microstructure and mechanical properties during annealing of a cold-swaged Ni-free Co-Cr-Mo alloy for biomedical applications. A Co-28Cr-6Mo-0.14N-0.05C (mass%) alloy rod was processed by cold swaging, with a reduction in area of 27.7%, and then annealed at 1173-1423K for various periods up to 6h. The duplex microstructure of the cold swaged rod consisted of a face-centered cubic gamma-matrix and hexagonal closed packed epsilon-martensite developed during cold swaging. This structure transformed nearly completely to the gamma-phase after annealing and many annealing twin boundaries were observed as a result of the heat treatment. A small amount of the epsilon-phase was identified in specimens annealed at 1173K. Growth of the gamma-grains occurred with increasing annealing time at temperatures >=1273K. Interestingly, the grain sizes remained almost unchanged at 1173K and a very fine grain size of approximately 8MUm was obtained. The precipitation that occurred during annealing was attributed to the limited grain coarsening during heat treatment. Consequently, the specimens treated at this temperature showed the highest tensile strength and lowest ductility among the specimens prepared. An elongation-to-failure value larger than 30% is sufficient for the proposed applications. The other specimens treated at higher temperatures possessed similar tensile properties and did not show any significant variations with different annealing times. Optimization of the present rod manufacturing process, including cold swaging and interval annealing heat treatment, is discussed. PMID- 27500543 TI - Kinetic Measurement and Real Time Visualization of Somatic Reprogramming. AB - Somatic reprogramming has enabled the conversion of adult cells to induced pluripotent stem cells (iPSC) from diverse genetic backgrounds and disease phenotypes. Recent advances have identified more efficient and safe methods for introduction of reprogramming factors. However, there are few tools to monitor and track the progression of reprogramming. Current methods for monitoring reprogramming rely on the qualitative inspection of morphology or staining with stem cell-specific dyes and antibodies. Tools to dissect the progression of iPSC generation can help better understand the process under different conditions from diverse cell sources. This study presents key approaches for kinetic measurement of reprogramming progression using flow cytometry as well as real-time monitoring via imaging. To measure the kinetics of reprogramming, flow analysis was performed at discrete time points using antibodies against positive and negative pluripotent stem cell markers. The combination of real-time visualization and flow analysis enables the quantitative study of reprogramming at different stages and provides a more accurate comparison of different systems and methods. Real time, image-based analysis was used for the continuous monitoring of fibroblasts as they are reprogrammed in a feeder-free medium system. The kinetics of colony formation was measured based on confluence in the phase contrast or fluorescence channels after staining with live alkaline phosphatase dye or antibodies against SSEA4 or TRA-1-60. The results indicated that measurement of confluence provides semi-quantitative metrics to monitor the progression of reprogramming. PMID- 27500544 TI - Odor threshold prediction by means of the Monte Carlo method. AB - A large set of organic compounds (n=906) has been used as a basis to build up a model for the odor threshold (mg/m(3)). The statistical characteristics of the best model are the following: n=523, r(2)=0.647, RMSE=1.18 (training set); n=191, r(2)=0.610, RMSE=1.03, (calibration set); and n=192, r(2)=0.686, RMSE=1.06 (validation set). A mechanistic interpretation of the model is presented as the lists of statistical promoters of the increase and decrease in the odor threshold. PMID- 27500545 TI - Preharvest ultraviolet-C irradiation: Influence on physicochemical parameters associated with strawberry fruit quality. AB - Postharvest ultraviolet-C (UV-C) hormesis has been shown effective for the treatment of the edible part of several horticultural crops such as strawberry fruit; however, there is a lack of information on its potential preharvest impact. In the present study three strawberry cultivars (Fragaria * ananassa Duch. 'Albion', 'Charlotte' and 'Seascape') were exposed to UV-C during two growth seasons for a period of three weeks. Treatment begins when the first flowers were wide open and fruits at commercial maturity were harvested within one week after UV treatment. The physicochemical quality parameters of the fruits harvested from the treated plants were compared to those of the fruits of the untreated control plants. Preharvest UV-C treatment tended to increase fruit firmness in all cultivars with significant differences declared only for 'Albion' and 'Seascape' in season 2. Fruits from treated plants were generally redder but a significant difference was observed only for cultivar 'Charlotte' in the second growing season. Other color attributes were not affected by UV-C, neither were organic acids, simple sugars, soluble solids content (SSC), titratable acidity (TA) and pH, although in most cases slight decreases were noticed. Cultivar and growing season were the factors that mostly influenced on the parameters under study. The present study show that cumulative preharvest UV-C treatment of 3.6 kJ m-2 did not adversely affected important strawberry quality parameters. PMID- 27500546 TI - Lithium Enolates Derived from Pyroglutaminol: Mechanism and Stereoselectivity of an Azaaldol Addition. AB - A lithium enolate derived from an acetonide-protected pyroglutaminol undergoes a highly selective azaaldol addition with (E)-N-phenyl-1-[2 (trifluoromethyl)phenyl]methanimine. The selectivity is sensitive to tetrahydrofuran (THF) concentration, temperature, and the presence of excess lithium diisopropylamide base. Rate studies show that the observable tetrasolvated dimeric enolate undergoes reversible deaggregation, with the reaction proceeding via a disolvated-monomer-based transition structure. Limited stereochemical erosion stems from the intervention of a trisolvated-monomer-based pathway, which is suppressed at low THF concentrations and elevated temperature. Endofacial selectivity observed with excess lithium diisopropylamide (LDA) is traced to an intermediate dianion formed by subsequent lithiation of the monomeric azaaldol adduct, which is characterized as both a dilithio form and a trilithio dianion-LDA mixed aggregate. PMID- 27500547 TI - Interleukin-6 gene polymorphisms correlate with the progression of nephropathy in Chinese patients with type 2 diabetes: A prospective cohort study. AB - AIMS: Interleukin-6 (IL-6), an inflammatory cytokine, is considered a candidate gene possibly involved in susceptibility to nephropathy in diabetes. This study aimed to examine whether IL-6 polymorphisms predict the progression of nephropathy in a prospective Chinese cohort of patients with type 2 diabetes. METHODS: A total of 568 type 2 diabetic patients with normoalbuminuria at baseline were followed up for a mean of 5.3+/-1.5years. Urinary albumin-to creatinine ratio (ACR) ?30mg/g in two consecutive urine tests were defined as progression to diabetic nephropathy (n=143). Five polymorphisms of IL-6 gene, rs1800795, rs1800796, rs1524107, rs2069837, and rs2069840, were genotyped. Cox proportional hazard models were used to estimate hazard ratio (HR) and 95% CI of progression to diabetic nephropathy under different genetic models. RESULTS: Almost all patients (99.6%) carried the rs1800795 GG homozygous genotypes. In the Cox proportional models adjusted for multiple covariates, the HR under recessive model was 2.02 for rs1800796 GG (vs. CC+CG, 95% CI: 1.08-3.75, p=0.027), 2.37 for rs2069837 GG (vs. AA+AG, 95% CI: 1.15-4.87, p=0.019), and 2.08 for rs1524107 CC (vs. TT+TC, 95% CI: 1.12-3.89, p=0.021). These associations remained significant for rs1800796 and rs1524107 after correction for multiple testing (alpha=0.017). Overall, our results suggest that rs1800796 GG and rs1524107 CC homozygous genotypes may confer a greater risk for development of nephropathy in type 2 diabetes. CONCLUSIONS: IL-6 gene polymorphisms rs1800796 and rs1524107 may serve as predictors of progression of nephropathy in Chinese patients with type 2 diabetes. PMID- 27500548 TI - The relationship between adipokines and the onset of type 2 diabetes in middle aged men: The PRIME study. AB - AIMS: Epidemiological evidence suggests that adipokines may be associated with the onset of type 2 diabetes, but the evidence to date is limited and inconclusive. This study examined the association between adiponectin and leptin and the subsequent diagnosis of type 2 diabetes in a UK population based cohort of non-diabetic middle-aged men. METHODS: Baseline serum levels of leptin and adiponectin were measured in 1839 non-diabetic men aged 50-60years who were participating in the prospective population-based PRIME study. Over a mean follow up of 14.7years, new cases of type 2 diabetes were determined from self-reported clinical information with subsequent validation by general practitioners. RESULTS: 151 Participants developed type 2 diabetes during follow-up. In Cox regression models adjusted for age, men in the top third of the leptin distribution were at increased risk (hazard ratio (HR) 4.27, 95% CI 2.67-6.83) and men in the top third of the adiponectin distribution at reduced risk (HR 0.24, 95% CI 0.14-0.42) relative to men in the bottom third. However, significance was lost for leptin after additional adjustment for BMI, waist to hip ratio, lifestyle factors and biological risk factors, including C-reactive protein (CRP). Further adjustment for HOMA-IR also resulted in loss of significance for adiponectin. CONCLUSIONS: This study provides evidence that adipokines are associated with men's future type 2 diabetes risk but not independently of other risk factors. PMID- 27500549 TI - Aspirin for primary prevention of cardiovascular disease in patients with diabetes: A meta-analysis. AB - AIMS: Aspirin use for primary prevention of cardiovascular disease (CVD) is controversial, especially in patients with diabetes. The objective of this meta analysis was to evaluate aspirin's safety and efficacy for primary prevention of CVD [fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, angina, transient ischemic attack (TIA), peripheral artery disease (PAD) and revascularization] in patients with diabetes. METHODS: A literature search was conducted using the terms cardiovascular disease, aspirin, diabetes mellitus to identify trials of patients with diabetes who received aspirin for primary prevention of CVD. Study sample size, and ischemic and bleeding events were extracted and analyzed using RevMan 5.2.7. RESULTS: In total, 6 studies (n=10,117) met criteria. Aspirin doses ranged from 100mg every other day to 650mg daily. Follow-up ranged from 3.6 to 10.1years. In patients with diabetes, there was no difference between aspirin and placebo with respect to the risk of all cause mortality (OR 0.93, 95% CI 0.81-1.06), or individual atherosclerotic events compared to placebo. There were no differences in bleeding (OR 2.53, 95% CI 0.77 8.34), GI bleeding (OR 2.14, 95% CI 0.63-7.33) or hemorrhagic stroke rates (OR 0.90, 0.34-2.33) between groups. CONCLUSIONS: It remains unclear whether aspirin may reduce the occurrence of a first atherosclerotic event or mortality in patients with diabetes. More research on this use of aspirin in patients with diabetes is required to supplement currently available research. PMID- 27500550 TI - Improved Computation of Protein-Protein Relative Binding Energies with the Nwat MMGBSA Method. AB - A MMGBSA variant (here referred to as Nwat-MMGBSA), based on the inclusion of a certain number of explicit water molecules (Nwat) during the calculations, has been tested on a set of 20 protein-protein complexes, using the correlation between predicted and experimental binding energy as the evaluation metric. Besides the Nwat parameter, the effect of the force field, the molecular dynamics simulation length, and the implicit solvent model used in the MMGBSA analysis have been also evaluated. We found that considering 30 interfacial water molecules improved the correlation between predicted and experimental binding energies by up to 30%, compared to the standard approach. Moreover, the correlation resulted in being rather sensitive to the force field and, to a minor extent, to the implicit solvent model and to the length of the MD simulation. PMID- 27500551 TI - Local heat application for perimenstrual pain and related syndromes. PMID- 27500552 TI - Development and community-based validation of eight item banks to assess mental health. AB - There is a need for precise but brief screening of mental health problems in a range of settings. The development of item banks to assess depression and anxiety has resulted in new adaptive and static screeners that accurately assess severity of symptoms. However, expansion to a wider array of mental health problems is required. The current study developed item banks for eight mental health problems: social anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, adult attention-deficit hyperactivity disorder, drug use, psychosis and suicidality. The item banks were calibrated in a population-based Australian adult sample (N=3175) by administering large item pools (45-75 items) and excluding items on the basis of local dependence or measurement non-invariance. Item Response Theory parameters were estimated for each item bank using a two-parameter graded response model. Each bank consisted of 19-47 items, demonstrating excellent fit and precision across a range of -1 to 3 standard deviations from the mean. No previous study has developed such a broad range of mental health item banks. The calibrated item banks will form the basis of a new system of static and adaptive measures to screen for a broad array of mental health problems in the community. PMID- 27500553 TI - Coralloid Co2P2O7 Nanocrystals Encapsulated by Thin Carbon Shells for Enhanced Electrochemical Water Oxidation. AB - Core-shell nanohybrids containing cheap inorganic nanocrystals and nanocarbon shells are promising electrocatalysts for water splitting or other renewable energy options. Despite that great progress has been achieved, biomimetic synthesis of metal phosphates@nanocarbon core-shell nanohybrids remains a challenge, and their use for electrocatalytic oxygen evolution reaction (OER) has not been explored. In this paper, novel nanohybrids composed of coralloid Co2P2O7 nanocrystal cores and thin porous nanocarbon shells are synthesized by combination of the structural merits of supramolecular polymer gels and a controllable thermal conversion technique, i.e., temperature programmable annealing of presynthesized supramolecular polymer gels that contain cobalt salt and phytic acid under a proper gas atmosphere. Electrocatalytic tests in alkaline solution show that such nanohybrids exhibit greatly enhanced electrocatalytic OER performance compared with that of Co2P2O7 nanostructure. At a current density of 10 mA cm(-2), their overpotential is 0.397 V, which is much lower than that of Co2P2O7 nanostructures, amorphous Co-Pi nanomaterials, Co(PO3)2 nanosheets, Pt/C, and some reported OER catalysts, and close to that of commercial IrO2. Most importantly, both of their current density at the overpotential over 0.40 V and durability are superior to those of IrO2 catalyst. As revealed by a series of spectroscopic and electrochemical analyses, their enhanced electrocatalytic performance results from the presence of thin porous nanocarbon shells, which not only improve interfacial electron penetration or transfer dynamics but also vary the coordination environment and increase the number of active 5-coordinated Co(2+) sites in Co2P2O7 cores. PMID- 27500554 TI - The ACE2 G8790A Polymorphism: Involvement in Type 2 Diabetes Mellitus Combined with Cerebral Stroke. AB - BACKGROUND: We aimed to investigate the correlations between ACE2 polymorphisms and type 2 diabetes mellitus (T2DM) combined with cerebral stroke (CS). METHODS: A total of 346 patients treated or hospitalized in our hospital were enrolled, including 181 cases without cerebrovascular complications (T2DM group) and 165 cases combined with CS (T2DM + CS group); 284 healthy individuals were selected as the control group. PCR-RFLP and ELISA were used to analyze ACE2 G8790A polymorphisms and serum ACE2 levels, respectively. RESULTS: Significant differences were observed in the genotype/allele frequency of ACE2 G8790A between the T2DM + CS and control groups, and the T2DM and T2DM + CS groups, and in the genotype frequency of ACE2 G8790A between the T2DM and the control groups. The A allele may increase the risk of T2DM combined with CS. The AA genotype may also increase the risk of T2DM combined with CS (OR = 3.733, 95%CI = 2.069-6.738; OR = 3.597, 95%CI = 1.884-6.867). Serum ACE2 levels showed statistically significant differences among the groups. Systolic pressure and diastolic pressure were protective factors of T2DM combined with CS. CONCLUSION: The ACE2 G8790A polymorphism in T2DM patients was correlated with CS, and the A allele might be a risk factor of T2DM combined with CS. PMID- 27500555 TI - Photosynthetic activity of vascular bundles in Plantago media leaves. AB - Photosynthetic processes in the leaf lamina and midribs of Plantago media were investigated using plants grown in high light (HL) or low light (LL) conditions. The fluorescence parameters, which indicate photochemical/photosynthetic activity, were different in HL and LL grown plants, but no major differences between lamina and midribs were found. An OJIP test (chlorophyll a fluorescence transient induction) of LL grown plants, indicative of the chloroplast electron transport chain, also showed both tissues to be similar. In HL plants, a partial blockage of electron flow between QA (the primary plastoquinone electron acceptor of PSII) and QB (the secondary plastoquinone acceptor of PSII) was found, and this was less visible in midribs. The effective dissipation of quantum energy per reaction center (DI0/RC) was similar in both tissues of HL grown plants, while in the midribs of LL leaves, this process seemed to be less effective. Measurements of 13C discrimination showed that the midrib tissues of LL and HL leaves effectively used beta-carboxylation products to accumulate their biomass. Thus, the well protected activity of electron transport in midribs with their limited capacity to fix CO2 from the air may indicate the involvement of this tissue in beta-carboxylation, transport or signaling. Carbon accumulated in roots showed a lower 13C discrimination value (more negative) than the values observed in lamina. This could indicate that roots are supplied with assimilates mostly during the light phase of the day cycle with intensive C3 photosynthesis. PMID- 27500556 TI - Metabolic acclimation of tetraploid and hexaploid wheats by cold stress-induced carbohydrate accumulation. AB - Metabolic acclimation of plants to cold stress may be of great importance for their growth, survival and crop productivity. The accumulation carbohydrates associated with cold tolerance (CT), transcript levels for genes encoding related enzymes along with damage indices were comparatively studied in three genotypes of bread and durum wheats differing in sensitivity. Two (Norstar, bread wheat and Gerdish, durum wheat) were tolerant and the other, SRN (durum wheat), was susceptible to cold stress. During cold stress (-5 degrees C for 24h), the contents of electrolyte leakage index (ELI) in Norstar and then Gerdish plants were lower than that of SRN plants, particularly in cold acclimated (CA) plants (4 degrees C for 14days), confirming lethal temperature 50 (LT50) under field conditions. Increased carbohydrate abundances in the cases of sucrose, glucose, fructose, hexose phosphates, fructan, raffinose, arabinose resulted in different intensities of oxidative stress in bread (Norstar) plants compared to durum plants (SRN and Gerdish) plants as well as in CA plants compared to non acclimated (NA) ones under cold, indicating metabolic/regulatory capacity along with a decrease in ELI content and enhanced defense activities. A significant decrease in these carbohydrates, particularly sucrose, under cold in NA plants showed an elevated level of cell damage (confirmed by ELI) compared to CA plants. On the other hand, an increase in hexose phosphates, particularly in NA plants, indicated sucrose degradation along with greater production of glucose and fructose compared to CA plants. Under such conditions, a significant increase in transcript levels of sucrose synthase and acidic invertase confirmed these results. Under cold, the high ABA-containing genotypes like Norstar and then Gerdish, which were obvious in CA plants, partly induced relative acclimation of cells for acquisition of CT compared to SRN. These results reveal an important role of carbohydrate metabolism in creating CT in durum wheats (particularly in Gerdish) as well as bread wheat with possible responsive components in metabolic and transcript levels. PMID- 27500558 TI - Molecular cloning of melatonin 3-hydroxylase and its production of cyclic 3 hydroxymelatonin in rice (Oryza sativa). AB - Melatonin is metabolized in animals to cyclic 3-hydroxymelatonin (3-OHM) not by an enzymatic pathway, but by interaction with hydroxyl radicals. The production of 3-OHM in animals suggests the possible presence of 3-OHM in plants. Prior to the identification of 3-OHM in plants, we directly cloned the corresponding gene(s) responsible for 3-OHM synthesis using Escherichia coli library strains expressing genes belonging to the 2-oxoglutarate-dependent dioxygenase (2-ODD) superfamily from rice. Three of 35 E. coli library strains supplemented with 1 mmol/L melatonin were found to produce 3-OHM in their extracellular medium, suggestive of three 2-ODD genes involved in 3-OHM production. The purified recombinant 2-ODD 11, 2-ODD 26, and 2-ODD 33 proteins were shown to catalyze the metabolism of melatonin to 3-OHM, with 2-ODD 11 showing the highest melatonin 3 hydroxylase (M3H) catalytic activity. Consistent with the presence of M3H genes, rice leaves supplemented with 5 mmol/L melatonin produced 3-OHM [233 MUg/g fresh weight (FW)], 2-hydroxymelatonin (21 MUg/g FW), and N1 -acetyl-N2 -formyl-5 methoxykynuramine (5 MUg/g FW). Three M3H transcripts were induced upon the treatment of rice leaves with cadmium followed by an increase in M3H enzyme activity. Cloning of M3H genes in plants has paved the way for the studies of melatonin in plants in terms of its multiple physiological roles. PMID- 27500559 TI - Prospective pilot study to detect dogs with non food-induced canine atopic dermatitis using Fourier transform infrared spectroscopy. AB - BACKGROUND: The diagnosis of canine atopic dermatitis (CAD) remains challenging due to the lack of a simple biomarker or metabolic profile. In human medicine, Fourier transform infrared spectroscopy (FTIR) is an analytical technique used for several diseases. It requires a small amount of sample and allows the identification of structural moieties of biomolecules on the basis of their infrared absorption, with limited sample pretreatment. HYPOTHESIS/OBJECTIVES: The aim of the study was to evaluate the diagnostic value of FTIR. ANIMALS: Three groups were tested: 21 dogs with non food-induced CAD (NFICAD), 16 dogs with inflammatory conditions of various origins but without allergic dermatoses (OD) and 10 healthy dogs (H). METHODS: Peripheral blood was collected and spectra were acquired with a FTIR spectrophotometer. A principal component analysis (PCA) was performed on the full wavenumber spectra (4000-600/cm), followed by a Fisher discriminant analysis (DA) to assess the differences between the three groups. RESULTS: The PCA followed by the DA of whole spectra showed significant differences between the three groups. These results suggest that by using the FTIR method, dogs with NFICAD can be differentiated from healthy dogs and dogs with nonallergic inflammation. There was no overlap between the spectral data of the three groups indicating that NFICAD dogs were correctly segregated from the H and OD groups. CONCLUSIONS: A study on a larger cohort including common pruritic skin diseases is necessary to confirm these initial results and the relevance of this diagnostic technique. PMID- 27500557 TI - A Novel Rodent Orthotopic Forelimb Transplantation Model That Allows for Reliable Assessment of Functional Recovery Resulting From Nerve Regeneration. AB - Improved nerve regeneration and functional outcomes would greatly enhance the utility of vascularized composite allotransplantation (VCA) such as hand and upper extremity transplantation. However, research aimed at achieving this goal has been limited by the lack of a functional VCA animal model. We have developed a novel rat midhumeral forelimb transplant model that allows for the characterization of upper extremity functional recovery following transplantation. At the final end point of 12 weeks, we found that animals with forelimb transplantation including median, ulnar and radial nerve coaptation demonstrated significantly improved grip strength and forelimb function as compared to forelimb transplantation without nerve approximation (grip strength: 1.71N +/- 0.57 vs. no appreciable recovery; IBB scale: 2.6 +/- 0.7? vs. 0.8 +/- 0.40; p = 0.0005), and similar recovery to nerve transection-and-repair only (grip strength: 1.71N +/- 0.57 vs. 2.03 +/- 0.42.6; IBB scale: 2.6 +/- 0.7 vs. 2.8 +/- 0.8; p = ns). Moreover, all forelimb transplant animals with nerve coaptation displayed robust axonal regeneration with myelination and reduced flexor muscle atrophy when compared to forelimb transplant animals without nerve coaptation. In conclusion, this is the first VCA small-animal model that allows for reliable and reproducible measurement of behavioral functional recovery in addition to histologic evaluation of nerve regeneration and graft reinnervation. PMID- 27500560 TI - Highly Stable, Functional Hairy Nanoparticles and Biopolymers from Wood Fibers: Towards Sustainable Nanotechnology. AB - Nanoparticles, as one of the key materials in nanotechnology and nanomedicine, have gained significant importance during the past decade. While metal-based nanoparticles are associated with synthetic and environmental hassles, cellulose introduces a green, sustainable alternative for nanoparticle synthesis. Here, we present the chemical synthesis and separation procedures to produce new classes of hairy nanoparticles (bearing both amorphous and crystalline regions) and biopolymers based on wood fibers. Through periodate oxidation of soft wood pulp, the glucose ring of cellulose is opened at the C2-C3 bond to form 2,3-dialdehyde groups. Further heating of the partially oxidized fibers (e.g., T = 80 degrees C) results in three products, namely fibrous oxidized cellulose, sterically stabilized nanocrystalline cellulose (SNCC), and dissolved dialdehyde modified cellulose (DAMC), which are well separated by intermittent centrifugation and co solvent addition. The partially oxidized fibers (without heating) were used as a highly reactive intermediate to react with chlorite for converting almost all aldehyde to carboxyl groups. Co-solvent precipitation and centrifugation resulted in electrosterically stabilized nanocrystalline cellulose (ENCC) and dicarboxylated cellulose (DCC). The aldehyde content of SNCC and consequently surface charge of ENCC (carboxyl content) were precisely controlled by controlling the periodate oxidation reaction time, resulting in highly stable nanoparticles bearing more than 7 mmol functional groups per gram of nanoparticles (e.g., as compared to conventional NCC bearing << 1 mmol functional group/g). Atomic force microscopy (AFM), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) attested to the rod-like morphology. Conductometric titration, Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), dynamic light scattering (DLS), electrokinetic-sonic amplitude (ESA) and acoustic attenuation spectroscopy shed light on the superior properties of these nanomaterials. PMID- 27500561 TI - Insurance status and disparities in disease presentation, treatment, and outcomes for men with germ cell tumors. AB - BACKGROUND: People aged 26 to 34 years represent the greatest proportion of the uninsured, and they have the highest incidence of testicular cancers. The aim of this study was to investigate the association between insurance status and cancer outcomes in men diagnosed with germ cell tumors. METHODS: The Surveillance, Epidemiology, and End Results database was used to identify 10,211 men diagnosed with germ cell gonadal neoplasms from 2007 to 2011. Associations between insurance status and characteristics at diagnosis and receipt of treatment were examined with log-binomial regression. The association between insurance status and mortality was assessed with Cox proportional hazards regression. RESULTS: Uninsured patients had an increased risk of metastatic disease at diagnosis (relative risk [RR], 1.26; 95% confidence interval [CI], 1.15-1.38) in comparison with insured patients, as did Medicaid patients (RR, 1.62; 95% CI, 1.51-1.74). Among men with metastatic disease, uninsured and Medicaid patients were more likely to be diagnosed with intermediate/poor-risk disease (RR for uninsured patients, 1.22; 95% CI, 1.04-1.44; RR for Medicaid patients, 1.39; 95% CI, 1.23 1.57) and were less likely to undergo lymph node dissection (RR for uninsured patients, 0.74; 95% CI, 0.57-0.94; RR for Medicaid patients, 0.76; 95% CI, 0.63 0.92) in comparison with insured patients. Men without insurance were more likely to die of their disease (hazard ratio [HR], 1.88; 95% CI, 1.29-2.75) in comparison with insured men, as were those with Medicaid (HR, 1.51; 95% CI, 1.08 2.10). CONCLUSIONS: Patients without insurance and patients with Medicaid have an increased risk of presenting with advanced disease and dying of the disease in comparison with those who have insurance. Future studies should examine whether implementation of the Patient Protection and Affordable Care Act reduces these disparities. Cancer 2016;122:3127-35. (c) 2016 American Cancer Society. PMID- 27500562 TI - A Vinylene-Bridged Perylenediimide-Based Polymeric Acceptor Enabling Efficient All-Polymer Solar Cells Processed under Ambient Conditions. AB - All-polymer solar cells with 7.57% power conversion efficiency are achieved via a new perylenediimide-based polymeric acceptor. Furthermore, the device processed in ambient air without encapsulation can still reach a high power conversion efficiency (PCE) of 7.49%, which is a significant economic advantage from an industrial processing perspective. These results represent the highest PCE achieved from perylenediimide-based polymers. PMID- 27500563 TI - Expanding our digital archives. PMID- 27500564 TI - Authors' reply. PMID- 27500565 TI - Kshitish Chandra Saha (January 1, 1930 - June 3, 2016). PMID- 27500566 TI - Fatty-acid biomarkers and tissue-specific turnover: validation from a controlled feeding study in juvenile Atlantic croaker Micropogonias undulatus. AB - Fatty-acid (FA) profiles of liver and muscle tissue from juvenile Atlantic croaker Micropogonias undulatus were examined over a 15 week diet-switch experiment to establish calibration coefficients (CC) and improve understanding of consumer-diet relationships for field applications. Essential FAs [docosahexaenoic acid (DHA), 22:6n-3 and eicosapentaenoic acid (EPA) , 20:5n-3] decreased and 18:2n-6 increased in tissues of M. undulatus fed diets with increasing proportions of terrestrial v. marine lipid sources. Non-linear models used to estimate the incorporation rate and days to saturation of per cent 18:2n 6 in tissues showed that livers incorporated 18:2n-6 faster than muscle, but the proportions of 18:2n-6 in muscle were higher. CCs were established to determine proportions of FA deposition in tissues relative to diet. Many CCs were consistent amongst diet treatments, despite growth and dietary differences. The CCs can be used to discern FA modification and retention within tissues and as tools for future quantitative estimates of diet histories. Incorporation rates and CCs of 18:2n-6 were applied to a sub-set of field samples of wild M. undulatus to understand habitat use and feeding ecology. Altogether, these results suggest that FAs provide a time-integrated measure of diet in aquatic food webs and are affected by tissue type, growth rate and the influence of mixed diets. PMID- 27500567 TI - Dynamics of gyrification in the human cerebral cortex during development. AB - This study quantitatively characterized cortical gyrus folding over human neocortical development by calculating the gyrification index (GI) in 22 human fetal specimens from 16 to 40 weeks with magnetic resonance imaging data. GI values remained constant at approximately 1.0 until the fetal specimens reached 500 g body weight and 200 mm crown-rump length (CRL), respectively, and then increased in correlation with the body weight and CRL. The rostrocaudal GI distribution in the cerebral cortex revealed a correspondence of GI peaks with indentations of early-generated primary sulci at 21 weeks of gestation and more frequently increased GI values in the parieto-occipital region than in the fronto temporal region at 31 and 40 weeks of gestation. These results provide a quantitative reference set for gyrification in normal human cortical development, which may help reveal the mechanism of neurodevelopmental disorders. PMID- 27500568 TI - Crystal structure of Arabidopsis thaliana calmodulin7 and insight into its mode of DNA binding. AB - Calmodulin (CaM) is a Ca(2+) sensor that participates in several cellular signaling cascades by interacting with various targets, including DNA. It has been shown that Arabidopsis thaliana CaM7 (AtCaM7) interacts with Z-box DNA and functions as a transcription factor [Kushwaha R et al. (2008) Plant Cell 20, 1747 1759; Abbas N et al. (2014) Plant Cell 26, 1036-1052]. The crystal structure of AtCaM7, and a model of the AtCAM7-Z-box complex suggest that Arg-127 determines the DNA-binding ability by forming crucial interactions with the guanine base. We validated the model using biolayer interferometry, which confirmed that AtCaM7 interacts with Z-box DNA with high affinity. In contrast, the AtCaM2/3/5 isoform does not show any binding, although it differs from AtCaM7 by only a single residue. PMID- 27500569 TI - [Department of Otorhinolaryngology of the I.P. Pavlov Saint-Peterburg First State Medical University]. AB - This article is designed to report the results of the analysis ofacademic, scientific, and clinical activities of the Department of Otorhinolaryngology of the I.P. Pavlov Saint-Peterburg First State Medical University. PMID- 27500570 TI - [The potential of cone beam computed tomography of the temporal bones in the patients presenting with otosclerosis]. AB - The objective of the present study was to analyze the potential of cone beam computed tomography of the temporal bones in the patients presenting with otosclerosis for the detection of surgically significant specific structural features of the labyrinth wall of the tympanic cavity. More than 400 tomograms of the temporal bones were obtained with the use of a cone beam tomographwere available for the investigation during the period from 2012 till 2016. The study was carried out in several steps, viz. the search for the optimal (for the given instrument) position of the patient, the experimental stage, the retrospective analysis of the tomograms and the comparison of the temporal bones of different types (pneumatic, mixed, and sclerotic) in individual patients, the comparison of the results of cone beam computed tomography (CBCT) with the intraoperative observations, and the modification of the algorithm for the analysis of temporal bone cone beam tomograms. The study included a total of 16 patients (15 women at the age from 32 to 56 years and one managed 58 years) presenting with the clinical diagnosis of otosclerosis. The results of the study were used to elaborate the algorithm for the analysis of cone beam tomograms of the temporal bones to be performed inthe stage by stage manner including the qualitative analysis of tomograms, evaluation of their quantitative parameters and additional characteristics to be taken into consideration when planning the surgical interventions on the labyrinth wall and the tympanic cavity as a preparation for the stapedoplastic treatment. The results of CBCT obtained in the present study were compared with the surgical observations. The diagnostic sensitivity and specificity of the method were estimated to be 100% and 83% respectively. It is concluded that cone beam computed tomography can be employed as a component of the diagnostic algorithm prior to the planning of surgical interventions onthe medial wall of the tympanic cavity and the assessment of dynamics of the clinical course of middle ear diseases. PMID- 27500571 TI - [The choice of parameters for the laser application in ENT surgery]. AB - The authors present the results and describe the methods of the experimental studies aimed at the evaluation of the biological effects of laser-assisted treatment of ENT pathologies at the wavelengths of 810 nm, 980 nm, and 1470 nm in comparison with the results obtained with the use of a radiofrequency scalpel in biological tissues having different optical and mechanical properties.Special emphasis is placed on the peculiarities of the action of laser irradiation and healing of radiation-induced wounds depending on the treatment regimens, viz. contact, remote, pulsed and continuous ones. The results of the analysis of the experience gained during the study and of the experimental findings provided a basis on which the main principles of the choice of the optimal parameters of the laser radiation action on the biological tissues have been formulated. PMID- 27500572 TI - [The damage to the trigeminal nerve associated with herpetic viral infection in otorhinolaryngology]. AB - Neurotropism of herpetic viral infection is attributable to a wide range of its clinical manifestations. Theobjective of the present study was to elucidate the specific features of the damage to the trigeminal nerve associated with this condition. A total of 36 patients presenting with trigeminal nerve neuropathycaused by type 1 herpes simplex infection and 21 patients with trigeminal nerve neuropathy due to Herpes zoster oticus infection were available for the examination and etiopathogenetic treatment. The traditional clinical methods used in the study were supplemented by virological diagnostics for the verification of herpetic infection and theelectroneurographic technique. The apparent clinical recovery was documented for 23 and 11 patients of the former and latter groups respectively. PMID- 27500573 TI - [The rationale for the conservative treatment of chronic tonsillitis in the patients of the older age groups by the "soft" therapy methods]. AB - The objective of the present study was to develop an efficient system for the treatment of chronic tonsillitis in the patients of advanced and middle age based on the application of polyvalent bacteriophages in the combination with the physical factors and herbal medicines. The study involved 65 patients (39 women and 276 men) at the age from 65 to 73 years presenting with chronic tonsillitis. The treatment included washing the tonsillar lacunae with herbal infusion consisting of a tetterwort (Choledoniummajus) extract. This procedure was followed by phonophoresiswith the use of the combined polyvalent bacteriophage preparation in the non-liquid formulation during 7-10 days. The effectiveness of such treatment was evaluated based on the results of clinical examination and the analysis of the subjective feelings reported by the patients. In addition, the rosette-forming function of lymphocytes was estimated and palatine tonsil microbiotas in different patients were compared. The effectiveness of therapy was estimated at 89.2%. The positive outcome of the proposed treatment was documented in 78.6% of the cases within 6 months after the onset of therapy. It is concluded that the treatment of chronic tonsillitis with bacteriophagal preparations and herbal infusions in combination with thetraditionallow-frequency ultrasound treatment is highly efficacious (favourable outcome in 78.6% of the patients of middle and advanced age) without the use of antibiotic medications. PMID- 27500574 TI - [Determination of the rational extent of laser-assisted resection for the treatment of paralytic laryngeal stenosis]. AB - The objective of the present study was to improve the procedures for extended and restricted laser-assisted laryngoplasty in the patients presenting withparalytic laryngeal stenosis and to evaluate the outcome of the surgical interventionsdiffering in extent. The study included 51 patients (47 women and 4 men) at the age varying from 18 to 78 years. Twenty five of these patients had a tracheostoma. The examination was focused on the detection of the following characteristics: vocal fold angle, body mass index, age, specific anatomical and physiological features of the larynx, clinically significant concomitant pathologies, engagement in voice and speech professional activities as well as the influence of paramedical factors. The resulting total score was calculated. The data obtained were used to rationally plan the laser-assisted resection (either extended or restricted)of the posterior third of a vocal fold. The total score of 6 or higher always implied the necessity of extended resection whereas the overall score of 3 and less was regarded as an indication for the tissue sparing surgery. The patients to whom the extended resection was prescribed had significantly higher physical health indices and the worse vocal function compared with the same parameters in the patients undergoing restricted resection. The spirometric characteristics of the patients in both groups were similar and either normal or slightly reduced. The characteristics of the psychic component of general health were not significantly different and corresponded to the internationally accepted normal values. It is concluded that the proposed treatment resulted in the favourable outcome in 49 of the 51 patients (96%). PMID- 27500575 TI - [The association of the severe clinical course of respiratory papillomatosis with certain HLA-DQ alleles]. AB - We undertook the analysis of genetic polymorphism of the HLADQA1 and DQB1 genes in the patients presenting with recurrent respiratory papillomatosis (n=21) with the use of the multiprimer polymerase chain reaction. The results of the study give evidence that the identification of DQ 2.5 and DQ 7.5 haplotypes encoded by the DQA1 *0501, DQB1 *0201, DQA1 *0505, and DQB1 *0301 alleles as well as the carriage of type 16 human papilloma virus (HPV) in combination with these haplotypes in the patients with recurrent respiratory papillomatosis can be used for the prognostication of the severity of this disease. PMID- 27500576 TI - [The low-invasive treatment of laryngotrachealstenoses]. AB - The objective of the present study was to evaluate the effectiveness and safety of balloonlaryngotracheoplasty for the treatment of laryngeal and tracheal stenosis We undertook the analysis of the case histories of the patients presenting withlaryngotracheal stenosis who had undergone balloonlaryngotracheoplasty during the period from October 2013 till February 2016. A total of 21 histories of the patients (6 men and 15 women) were available for the investigation. Most laryngotrachealstenoses that occurred in 18 (85.7%) patients were of the idiopathic, post-tracheotomy, and post-intubation types. Their most typical localization was the subfold part of the larynx and/or the upper third of the trachea (76.2%). The length of the stenotic lesions varied from 5 to 20 mm (76.2%) and corresponded to grade III if estimated based on the Cotton-Myer classification (81%). The number of the balloonlaryngotracheoplastic procedures ranged from 1 to 4 (a total of 36 operations). The interval between the consecutive interventions varied from 1.5 to 104 (mean 20) weeks. In 16 of the 36 cases, dilatation of the narrowed portion was followed by the 4 minute application of mitomycin C at a concentration of 0.4 mg/kg. No complications were documented during the surgical interventions and in the postoperative periods. The treatment was associated with a significant enhancement of the maximum expiratory flow rate from 2+/-1.13 l/s to 4.23+/-1.9 l/s (p=0.000). The duration of the follow up period varied from 1 to 105 (mean 36.2) weeks. Mitomycin C exerted nosignificant influence on the increment of the maximum expiratory flow rate (p=0.174). PMID- 27500577 TI - [The blockade of sphenopalatineganglionthrough the palatal approachin the present day rhinological practice]. AB - This article deals with the application of the sphenopalatine ganglion blockade in the present-day rhinological practice. The blockade is known to arrest the propagation of pain impulses from the nose and break the rhinocardiac reflex arc. Moreover, it is involved in bleeding control during nasal surgery. The method for the blockade via the palatal route using the modern equipment and imaging techniques is described. The objective of the present study was to evaluate the effectiveness and safety of the blockade of sphenopalatine ganglionthrough the palatal approach in the patients who had undergone septoplasty under general and local anesthesia. It included a total of 105 patients divided into two groups one of which was treated with the use ofblockade of sphenopalatineganglionin addition to conventional anesthesia while the patients of the other group were treated under traditional anesthesia alone. The results of the study confirm the effectiveness of blockade of sphenopalatineganglionthrough the palatal approach as a method for the treatment of postoperative syndrome, bleeding control during nasal surgery, and reduction of parasympathetic influence on the cardiac rhythm. PMID- 27500578 TI - [Endoscopic endonasal surgery of paranasal sinus osteomas]. AB - This article was designed to summarize the experience gained withendoscopic endonasal removal of paranasal sinus osteomas during the period from January 2013 till February 2016. In addition a review of the relevant literature is presented encompassing the publicationsthat provide information about etiology, pathogenesis, clinical picture, diagnostics, and treatment of bone tumours. The objective of the study was to enhance the effectiveness and safety of the surgical treatment of the patients presenting with paranasal sinus osteomas. A total of 81 cases of paranasal sinus osteoma were documented in the patients admitted to I.P. Pavlov Saint-Peterburg First State Medical Universityduring the period from January 2013 till February 2016. Forty nine of them were given the surgical endoscopic endonasal treatment with the removal of the neoplasm. The remaining 32 patients were included in the group for the further dynamic follow up. The authors report the data of morphological studies and the results of computed tomography performed in the pre- and postoperative periods with special reference to the potential for the use of the electromagnetic navigation station (an image-guidance system) that makes it possible to significantly reduce the risk of development of possible complications. In addition, the findings suggestive of the progressive tumour growth in the group of the patients under dynamic observation are discussed. PMID- 27500580 TI - [Differential diagnostics of the causes responsible for a cough in the pregnant women]. AB - The objective of the present study was to elucidate the causes responsible for a cough in the pregnant women. It involved 92 patients including 23 ones presenting with bronchial asthma and 69 having no manifestations of asthma in their medical histories but suffering from dry cough that started after the beginning of pregnancy. All the patients were given counseling by the otorhinolaryngology and pulmonology specialists. The degree of endoscopic manifestations of gastroesophageal reflux was estimated based on a scoring scale. The study revealed the correlation between cough duration and gestational age. The signs of reflux-induced changes in the larynx were documented in 91% cases among the patients with bronchial asthma and in 97% cases in the pregnant women having no bronchial pathology in their medical histories. The main cause behind the cough during pregnancy in women without bronchial pathology was sluggish bronchitis (7%), arising asthma (12%), gastroesophageal reflux (77%), and allergic rhinitis (4%). This conclusion was confirmed by the results of therapy. PMID- 27500579 TI - [Local cytokine therapy of inflammation of the rhinosinusotubal area]. AB - The objective of the present work was to elaborate a scheme for the effective combined treatment ofinflammation of the rhinosinusotubal area including the local administration of roncoleukin and cyclopheron without antibiotics. The study included 82 patients (27 men and 55 women) at the age from 25 to 55 years presenting with acute inflammation ofroncoleukin and cycloferon. They were divided into two groups. Group 1 was comprised of 39 patients dominated by those with the clinical picture of sinusitis whereas group 2 contained 43 patients in whom symptoms of catarrhal otitis media prevailed. The patients of both groups were treated by the local application of roncoleukin in combination with cycloferon inhalation, intranasal administration of decongestants and mucomodifiers. All the patients underwent, before and after the treatment, the microbiological study of the contents of the sinuses, impedancobarometry, 3D computed tomography, and measurement of the IgA, IgM, IgG, IgE, SIgA, IL-8, TNF alpha, and albumin levels in the blood sera and lavages. The study has demonstrated the difference between the local cytokine levels in the two groups of the patients. The clinical improvement was documented within 24 hours after the onset of therapy. 93.3% of the patients recovered by day 5. Three (3.7%) of them had to be prescribed antibiotic therapy for the lack of the desired effect of the cytokine treatment. It is concluded that the local application of ronkoleukin and cycloferon in combination with elimination therapy provides a tool for the efficient treatment of the patients suffering frominflammatory pathology of the rhinosinusotubalzone due to its stimulatory action on the immune system at the inflammation site mediated through the activation of the earlier formed targeted immune response, the promotion of the accelerated elimination of the causative factor, and the termination of the pathological process. PMID- 27500581 TI - [The systemic approach to the rehabilitation of the patients presenting with laryngeal cancer after the resection of the organ and laryngectomy with tracheoesophageal by-pass and endoprosthetics]. AB - The objective of the present study was to enhance the effectiveness of rehabilitation of the patients presenting with laryngeal cancer after the resection of the organ and laryngotomy with tracheoesophageal by-pass and endoprosthetics. Our experience in this field is based on the treatment of 102 patients. They were distributed by the nosological forms as follows: primary laryngeal cancer in 97 patients including T1NoMo - 8 (8.2%), T2NoMo - 63 (65%), T3NoMo - 18 (17.6%), T2N1Mo - 1 (0.9%), T4NoMo - 3 (2.9%), and T4N1M0 - 4 (3.9%), root of the tongue cancer spreading over the vestibular part of the larynx in one patient, laryngeal sarcoma in one patient, relapse of cancer following the full dose radiotherapy and organ-sparing surgery in 3 patients. Laryngeal resection was performed in 83 patients; 19 patients underwent laryngectomy with tracheoesophageal by-pass and endoprosthetics using a domestically manufactured voice prosthesis. The systemic approach to the rehabilitation of the patients and the use of the proposed treatment algorithm made it possible to restore the function of the larynx by means of organ-sparing surgery in 79 (95.1%) of the 83 patients. The vocal function in the patients following laryngectomy with tracheoesophageal by-pass and endoprosthetics was restored in 18 (94.7%) of the 19 patients. PMID- 27500582 TI - [Clinico-anamnestic diagnostics of chronic maxillary sinusitis associated with chlamydial infection]. AB - The present study included 201 adult patients presenting with exacerbation of chronic maxillary sinusitis. The presence of Chlamydia trachomatis and Chl. pneumoniae was verified by the direct immunofluorescencetechnique and polymerase chain reaction. The study material consisted of swipes und swabs from the mucous membrane of the middle nasal passage. The information from the patients was collected with the use of a questionnaire specially elaborated for the purpose of this study. The correlation relationships were established by means of gamma statistics. The method is based on the calculation of the integral index characterizing the risk of development of chlamydial infection using the scoring scale for the evaluation of the clinical and anamnestic characteristics of the patients. The assessment of the risk of chlamydial colonization by the anamnestic method makes it possible to enhance the effectiveness of clinical diagnostics of chlamydial infection and thereby provides a basis for the prescription of the adequate anti-chlamydial treatment facilitating reduction of the frequency of complications and preventing dissemination of the causative factor of the disease. Moreover, this approach creates the conditions for the targeted selection of the patients to be referred to the laboratory verification of Chlamydia. Highoperating performance and effectiveness characteristics of the clinic-anamnestic diagnostics make it a method of choice for the wide application in the clinical practice. PMID- 27500583 TI - [The anthropometric parameters of the external nose in a Kazakh population with particular reference to the planning of ethnic-specific rhinoplasty]. AB - The objective of the present study was to determine the anthropometric parameters of the external nose in a Kazakh population for the subsequent elaboration of the algorithms of and approaches to the planning of ethnic-specific rhinoplasty. The study included 500 ethnic Kazakhs (197 women and 303 men) at the age varying from 16 to 25 (mean 20.6+/-3.5) years. The following parameters were calculated; the height and the width of the nose, nasal index, lobular index, nasolabial angle, nasal projection index, projection and rotation of the tip of the nose. It was found that the nasal index in male and female Kazakhs was 80.8+/-0.53 and 79.4+/ 3.17 respectively which corresponds to mesorhinia and is more characteristic of the Europeoid race. The nasofrontalindex in men andwomen was 138.94+/-5.71 ad 130.1+/-8.25 degrees respectively. Rotation of the tip of the nose in men was 78.45+/-2.24 degrees in men and 73.92+/-4.32 degrees in women. Goode's nasal projection index was 57.25+/-4.36%. The nasal tip projection was estimated at 67.9+/-5.21 and 76.72+/-4.17 in men and women respectively. It is concluded based on the results of the present study that noses in Kazakh men and women have certain specific masculine and feminine anthropometric features making them different from the typical "Asiatic" noses because some of their proportions are more characteristic of the Europeoid race. The height of the nose in the Kazakhs is lowest among the three races. It indicates that the main concern as regards rhinoplasty in the Kazakh population is the dorsal augmentation. The present study provided the reference information on the parameters of the external nose in the Kazakh population that may be of value not only in terms of reconstructive and aesthetic rhinosurgery but also for the purpose of forensic medical and other expertises. PMID- 27500584 TI - The impact of knowledge and religion on organ donation as seen by immigrants in Sweden. AB - BACKGROUND: Transplantation of organs is one of the most successful medical advances of the past 60 years and transplantation is the treatment of choice for severe organ failure worldwide. Despite this situation, and the general acknowledgement of organ donation as a global priority, demand for organs outstrips supply in virtually every country in the world. AIM: The aim of the study was to elucidate factors that influence immigrant's decisions regarding organ donation. METHODS: Data were collected through three group interviews using open-ended questions and qualitative content analysis. 32 participants, 16 men and 16 women from Bosnia and Herzegovina, Somalia, Lebanon and Kosovo participated in focus group interviews (FGI). RESULTS: Analysis of the collected data resulted in two main categories: 'Information about organ donation' and 'Religious aspects of organ donation and a number of subcategories'. Some of the influencing factors concerning organ donation were mainly related to limited information from society as well as limited information from healthcare professionals. Religious aspects, fear and prejudices about organ donation were other factors that mentioned by participants as hamper regarding organ donation. CONCLUSION: In order to improve immigrants' attitude towards organ donation, information about this issue and identification of the hampering factors, particularly culturally related factors such as the religious aspect, is essential. In this context, different intervention studies are needed to increase monitories groups' attitude towards organ donations. PMID- 27500585 TI - Self-perceived taste disturbance: a 20-year prospective study of a Swedish 1942 birth cohort. AB - OBJECTIVES: The aim of this study was to assess the impact of dental care factors, general health factors and socio-economic factors on perceived taste disturbance (PTD) over time and to assess the stability of or change in PTD in a panel of individuals as they progressed from middle age (50 years) to early old age (70 years). MATERIALS AND METHODS: Data collection was conducted from a cohort study beginning in 1992, when the participants were 50 years old, and again 5, 10, 15 and 20 years later. Stability and change in PTD were described using cross-tabulation. Perceived taste disturbance over the 20-year survey period was modelled using the generalised estimating equation (GEE). RESULTS: The prevalence of PTD during a 5-year period found in this study ranged from 2.4 to 2.9%, the latter in individuals between 60 and 70 years of age. Women generally had PTD more often than men. The longitudinal analysis showed that problems with bad breath (OR = 3.6), blisters (OR = 3.4), burning mouth (OR = 3.4) and self perceived health (OR = 2.7) were the most important factors explaining PTD. CONCLUSIONS: This study showed that PTD does not increase between 50 and 70 years of age in ordinary community-living individuals. There were no long-term impacts on PTD over time from socio-economic factors, and over time, there were a limited number of factors contributing to the effect. Bad breath, blisters, burning mouth and self-perceived health are important factors for the dentist to discuss with the patient in the case of PTD. PMID- 27500586 TI - Integrated environmental monitoring and multivariate data analysis-A case study. AB - The present article describes integration of environmental monitoring and discharge data and interpretation using multivariate statistics, principal component analysis (PCA), and partial least squares (PLS) regression. The monitoring was carried out at the Peregrino oil field off the coast of Brazil. One sensor platform and 3 sediment traps were placed on the seabed. The sensors measured current speed and direction, turbidity, temperature, and conductivity. The sediment trap samples were used to determine suspended particulate matter that was characterized with respect to a number of chemical parameters (26 alkanes, 16 PAHs, N, C, calcium carbonate, and Ba). Data on discharges of drill cuttings and water-based drilling fluid were provided on a daily basis. The monitoring was carried out during 7 campaigns from June 2010 to October 2012, each lasting 2 to 3 months due to the capacity of the sediment traps. The data from the campaigns were preprocessed, combined, and interpreted using multivariate statistics. No systematic difference could be observed between campaigns or traps despite the fact that the first campaign was carried out before drilling, and 1 of 3 sediment traps was located in an area not expected to be influenced by the discharges. There was a strong covariation between suspended particulate matter and total N and organic C suggesting that the majority of the sediment samples had a natural and biogenic origin. Furthermore, the multivariate regression showed no correlation between discharges of drill cuttings and sediment trap or turbidity data taking current speed and direction into consideration. Because of this lack of correlation with discharges from the drilling location, a more detailed evaluation of chemical indicators providing information about origin was carried out in addition to numerical modeling of dispersion and deposition. The chemical indicators and the modeling of dispersion and deposition support the conclusions from the multivariate statistics. Integr Environ Assess Manag 2017;13:387-395. (c) 2016 SETAC. PMID- 27500587 TI - Mechanistic variables can enhance predictive models of endotherm distributions: the American pika under current, past, and future climates. AB - How climate constrains species' distributions through time and space is an important question in the context of conservation planning for climate change. Despite increasing awareness of the need to incorporate mechanism into species distribution models (SDMs), mechanistic modeling of endotherm distributions remains limited in this literature. Using the American pika (Ochotona princeps) as an example, we present a framework whereby mechanism can be incorporated into endotherm SDMs. Pika distribution has repeatedly been found to be constrained by warm temperatures, so we used Niche Mapper, a mechanistic heat-balance model, to convert macroclimate data to pika-specific surface activity time in summer across the western United States. We then explored the difference between using a macroclimate predictor (summer temperature) and using a mechanistic predictor (predicted surface activity time) in SDMs. Both approaches accurately predicted pika presences in current and past climate regimes. However, the activity models predicted 8-19% less habitat loss in response to annual temperature increases of ~3-5 degrees C predicted in the region by 2070, suggesting that pikas may be able to buffer some climate change effects through behavioral thermoregulation that can be captured by mechanistic modeling. Incorporating mechanism added value to the modeling by providing increased confidence in areas where different modeling approaches agreed and providing a range of outcomes in areas of disagreement. It also provided a more proximate variable relating animal distribution to climate, allowing investigations into how unique habitat characteristics and intraspecific phenotypic variation may allow pikas to exist in areas outside those predicted by generic SDMs. Only a small number of easily obtainable data are required to parameterize this mechanistic model for any endotherm, and its use can improve SDM predictions by explicitly modeling a widely applicable direct physiological effect: climate-imposed restrictions on activity. This more complete understanding is necessary to inform climate adaptation actions, management strategies, and conservation plans. PMID- 27500588 TI - Development of Nickel Hydrosilylation Catalysts. AB - In this account, our studies on nickel-catalyzed hydrosilylation reactions are described. A series of (salicylaldiminato)methylnickel complexes efficiently catalyze alkene hydrosilylation under ambient reaction conditions. Commercially available Ni(II) salts, Ni(acac)2 (acac = acetylacetonato) and its derivatives bis(hexafluoroacetylacetonato)nickel(II) and bis (2,2,6,6-tetramethyl-3,5 heptanedionato)nickel(II), also act as versatile hydrosilylation catalyst precursors in the presence of NaBHEt3 . These systems catalyze the hydrosilylation of various alkenes such as industrially important siloxy-, amino , and epoxy-substituted ones. The arene-supported cationic nickel allyl complexes also serve as good catalysts for alkene hydrosilylation at room temperature. These nickel complexes exhibit high selectivity towards the reaction using secondary hydrosilanes. Mechanistic studies based on experiments and DFT calculations support a novel mechanism, which includes a facile Si-H bond cleavage and a Si-C bond formation, assisted by the cooperative action of the allyl ligand. PMID- 27500589 TI - Selection for distinct gene expression properties favours the evolution of mutational robustness in gene regulatory networks. AB - Mutational robustness is a genotype's tendency to keep a phenotypic trait with little and few changes in the face of mutations. Mutational robustness is both ubiquitous and evolutionarily important as it affects in different ways the probability that new phenotypic variation arises. Understanding the origins of robustness is specially relevant for systems of development that are phylogenetically widespread and that construct phenotypic traits with a strong impact on fitness. Gene regulatory networks are examples of this class of systems. They comprise sets of genes that, through cross-regulation, build the gene activity patterns that define cellular responses, different tissues or distinct cell types. Several empirical observations, such as a greater robustness of wild-type phenotypes, suggest that stabilizing selection underlies the evolution of mutational robustness. However, the role of selection in the evolution of robustness is still under debate. Computer simulations of the dynamics and evolution of gene regulatory networks have shown that selection for any gene activity pattern that is steady and self-sustaining is sufficient to promote the evolution of mutational robustness. Here, I generalize this scenario using a computational model to show that selection for different aspects of a gene activity phenotype increases mutational robustness. Mutational robustness evolves even when selection favours properties that conflict with the stationarity of a gene activity pattern. The results that I present support an important role for stabilizing selection in the evolution of robustness in gene regulatory networks. PMID- 27500590 TI - Tuning the Rainbow: Systematic Modulation of Donor-Acceptor Systems through Donor Substituents and Solvent. AB - A series of donor-acceptor compounds is reported in which the energy of the triarylamine donor is systematically tuned through para substitution with electron-donating methoxy and electron-withdrawing cyano groups. The acceptor units investigated are benzothiadiazole (btd), dipyridophenazine (dppz), and its [ReCl(CO)3(dppz)] complex. The effect of modulating donor energy on the electronic and photophysical properties is investigated using (1)H NMR spectroscopy, DFT calculations, electrochemistry, electronic absorption and emission spectroscopies, ground state and resonance Raman spectroscopy, and transient absorption spectroscopy. Qualitative correlations between the donor energy and the properties of interest are obtained using Hammett sigma(+) constants. Methoxy and cyano groups are shown to destabilize and stabilize, respectively, the frontier molecular orbitals, with the HOMO affected more significantly than the LUMO, narrowing the HOMO-LUMO band gap as the substituent becomes more electron-donating-observable as a bathochromic shift in low-energy charge-transfer absorption bands. Charge-transfer emission bands are also dependent on the electron-donating/withdrawing nature of the substituent, and in combination with the highly solvatochromic nature of charge-transfer states, emission can be tuned to span the entire visible region. PMID- 27500591 TI - Evidence for and Against Genetic Predispositions to Acute and Chronic Altitude Illnesses. AB - MacInnis, Martin J., and Michael S. Koehle. Evidence for and against genetic predispositions to acute and chronic altitude illnesses. High Alt Med Biol. 17:281-293, 2016.-Humans exhibit marked variation in their responses to hypoxia, with susceptibility to acute and chronic altitude illnesses being a prominent and medically important example. Many have hypothesized that genetic differences are the cause of these variable responses to hypoxia; however, until recently, these hypotheses were based primarily on small (and sometimes anecdotal) reports pertaining to apparent differences in altitude illness susceptibility between populations, the notion that a history of altitude illness is indicative of subsequent risk, the heritability of hypoxia-related traits, and candidate gene association studies. In the past 5 years, the use of genomic techniques has helped bolster the claim that susceptibility to some altitude illnesses is likely the result of genetic variation. For each of the major altitude illnesses, we summarize and evaluate the evidence stemming from three important characteristics of a genetic trait: (1) individual susceptibility and repeatability across assessments, (2) biogeographical differences and familial aggregation, and (3) association(s) with genetic variants. Evidence to support a genetic basis for susceptibilities to acute mountain sickness (AMS) and high-altitude cerebral edema (HACE) is limited, owing partially to the subjective and unclear phenotype of AMS and the rarity and severity of HACE. In contrast, recent genomic studies have identified genes that influence susceptibility to high-altitude pulmonary edema, chronic mountain sickness, and high-altitude pulmonary hypertension. The collection of more individual, familial, and biogeographical susceptibility data should improve our understanding of the extent to which genetic variation contributes to altitude illness susceptibility, and genomic and molecular investigations have the potential to elucidate the mechanisms that underpin altitude illness susceptibility. PMID- 27500593 TI - Improving care planning and coordination for service users with medical co morbidity transitioning between tertiary medical and primary care services. AB - : WHAT IS KNOWN ON THE SUBJECT?: Mental health service users with medical co morbidity frequently experience difficulties accessing and receiving appropriate treatment in emergency departments. Service users frequently experience fragmented care planning and coordinating between tertiary medical and primary care services. Little is known about mental health nurses' perspectives about how to address these problems. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Emergency department clinicians' poor communication and negative attitudes have adverse effects on service users and the quality of care they receive. The findings contribute to the international evidence about mental health nurses' perspectives of service users feeling confused and frustrated in this situation, and improving coordination and continuity of care, facilitating transitions and increasing family and caregiver participation. Intervention studies are needed to evaluate if adoption of these measures leads to sustainable improvements in care planning and coordination, and how service users with medical co-morbidity are treated in emergency departments in particular. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Effective planning and coordination of care are essential to enable smooth transitions between tertiary medical (emergency departments in particular) and primary care services for service users with medical co-morbidity. Ongoing professional development education and support is needed for emergency department clinicians. There is also a need to develop an organized and systemic approach to improving service users' experience in emergency departments. ABSTRACT: Introduction Mental health service users with medical co-morbidity frequently experience difficulties accessing appropriate treatment in medical hospitals, and often there is poor collaboration within and between services. Little is known about mental health nurses' perspectives on how to address these problems. Aim To explore mental health nurses' perspectives of the experience of service users with medical co-morbidity in tertiary medical services, and to identify how to improve care planning and coordination for service users transitioning between tertiary medical and primary care services. Method Embedded within an experience based co-design study, focus group discussions were conducted with 17 emergency department nurses and other clinicians, in Melbourne, Australia. Results Three main themes were abstracted from the data: feeling confused and frustrated, enhancing service users' transition and experience and involving families and caregivers. Participants perceived the service user experience to be characterized by fear, confusion and a sense of not being listened to. They highlighted that service users' transition and experience could be enhanced by facilitating transitions and improving coordination and continuity of care. They also emphasized the need to increase family and caregiver participation. Conclusion Our findings contribute to knowledge about improving the way service users are treated in emergency departments and improving care planning and coordination; in particular, facilitating transitions, improving coordination and continuity of care and increasing family and caregiver participation. PMID- 27500592 TI - Molecular regulation and physiological functions of a novel FaHsfA2c cloned from tall fescue conferring plant tolerance to heat stress. AB - Heat stress transcription factors (HSFs) compose a large gene family, and different members play differential roles in regulating plant responses to abiotic stress. The objectives of this study were to identify and characterize an A2-type HSF, FaHsfA2c, in a cool-season perennial grass tall fescue (Festuca arundinacea Schreb.) for its association with heat tolerance and to determine the underlying physiological functions and regulatory mechanisms of FaHsfA2c imparting plant tolerance to heat stress. FaHsfA2c was localized in nucleus and exhibited a rapid transcriptional increase in leaves and roots during early phase of heat stress. Ectopic expression of FaHsfA2c improved basal and acquired thermotolerance in wild-type Arabidopsis and also restored heat-sensitive deficiency of hsfa2 mutant. Overexpression of FaHsfA2c in tall fescue enhanced plant tolerance to heat by triggering transcriptional regulation of heat protective gene expression, improving photosynthetic capacity and maintaining plant growth under heat stress. Our results indicated that FaHsfA2c acted as a positive regulator conferring thermotolerance improvement in Arabidopsis and tall fescue, and it could be potentially used as a candidate gene for genetic modification and molecular breeding to develop heat-tolerant cool-season grass species. PMID- 27500594 TI - Exploring the impact of gender inequities on the promotion of cardiovascular health of women in Pakistan. AB - Cardiovascular disease exerts an enormous burden on women's health. The intake of a healthy diet may reduce this burden. However, social norms and economic constraints are often factors that restrain women from paying attention to their diet. Underpinned by critical realism, this study explores how gender/sex influences decision-making regarding food consumption among women of low socioeconomic status (SES). The study was carried out at two cardiac facilities in Karachi, Pakistan, on 24 participants (male and female from different ethnic backgrounds), who had received health education. Using an interpretive descriptive approach, the study identified major barriers to a healthy diet: proscribed gender roles and lack of women's autonomy, power, male domination, and abusive behaviours. Cardiovascular risk and disease outcomes for the Pakistani women of low SES are likely to further escalate if individual and structural barriers are not reduced using multifactorial approaches. PMID- 27500595 TI - Lower prevalence and greater severity of asthma in hot and dry climate. AB - OBJECTIVE: To estimate asthma prevalence, severity, and associated factors in adolescents who live in a low relative humidity environment. METHODS: In this cross-sectional study, adolescents aged 13-14 years from the city of Petrolina located in the Brazilian semiarid region answered the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. The possible explanatory variables of the study were gender, family income, mother's education, smokers in the household, parental history of asthma, personal history of allergic rhinitis or atopic dermatitis, and physical activity level. Poisson regression analysis was used to assess the association between asthma and the explanatory variables. RESULTS: A total of 1591 adolescents participated in the study, of whom 49.7% were male. The prevalence of active asthma, severe asthma, and physician diagnosed asthma were 14.0%, 10.4%, and 17.8%, respectively. Adolescents with asthma missed more school days than their peers (33 vs. 22 days/year; p<0.03). Associated factors that remained significant after adjustment were history of asthma in parents (PR=2.65, p<0.001) and personal diagnosis of allergic rhinitis (PR=1.96, p<0.001) and/or atopic dermatitis (PR=2.18, p<0.001). CONCLUSION: Asthma prevalence in this low-humidity environment was lower, but more severe than those reported in other Brazilian cities. The dry climate might hamper disease control and this may have contributed to the higher school absenteeism observed. The association of asthma with allergic rhinitis and atopic dermatitis as well as a history of asthma in parents suggests that atopy is an important risk factor for asthma in this population. PMID- 27500596 TI - Steric and Electronic Effects of Bidentate Phosphine Ligands on Ruthenium(II) Catalyzed Hydrogenation of Carbon Dioxide. AB - The reactivity difference between the hydrogenation of CO2 catalyzed by various ruthenium bidentate phosphine complexes was explored by DFT. In addition to the ligand dmpe (Me2 PCH2 CH2 PMe2 ), which was studied experimentally previously, a more bulky diphosphine ligand, dmpp (Me2 PCH2 CH2 CH2 PMe2 ), together with a more electron-withdrawing diphosphine ligand, PN(Me) P (Me2 PCH2 N(Me) CH2 PMe2 ), have been studied theoretically to analyze the steric and electronic effects on these catalyzed reactions. Results show that all of the most favorable pathways for the hydrogenation of CO2 catalyzed by bidentate phosphine ruthenium dihydride complexes undergo three major steps: cis-trans isomerization of ruthenium dihydride complex, CO2 insertion into the Ru-H bond, and H2 insertion into the ruthenium formate ion. Of these steps, CO2 insertion into the Ru-H bond has the lowest barrier compared with the other two steps in each preferred pathway. For the hydrogenation of CO2 catalyzed by ruthenium complexes of dmpe and dmpp, cis-trans isomerization of ruthenium dihydride complex has a similar barrier to that of H2 insertion into the ruthenium formate ion. However, in the reaction catalyzed by the PN(Me) PRu complex, cis-trans isomerization of the ruthenium dihydride complex has a lower barrier than H2 insertion into the ruthenium formate ion. These results suggest that the steric effect caused by the change of the outer sphere of the diphosphine ligand on the reaction is not clear, although the electronic effect is significant to cis-trans isomerization and H2 insertion. This finding refreshes understanding of the mechanism and provides necessary insights for ligand design in transition-metal-catalyzed CO2 transformation. PMID- 27500597 TI - Is the Risk of Autism in Younger Siblings of Affected Children Moderated by Sex, Race/Ethnicity, or Gestational Age? AB - OBJECTIVE: To evaluate the recurrence risk of autism spectrum disorders (ASD) in younger siblings of affected children and determine how it is modified by race/ethnicity and sex. METHOD: Medical records of children born in a large health maintenance organization (Kaiser Permanent Southern California) hospitals from January 1, 2001, through December 31, 2010, and who remained in our system until 2 to 11 years of age were used to assess the risk of recurrence of ASD in younger siblings. Children born at <28 or >42 weeks gestation, multiple births, or those who were not active members for >=3 months were excluded. ASD diagnosis was ascertained from DSM-IV codes, and the magnitude of the association was estimated using adjusted relative risks (aRRs). RESULTS: Among eligible younger siblings, 592 (1.11%) had the diagnosis of ASD. The ASD rates were 11.30% and 0.92% for younger siblings of older affected and unaffected siblings, respectively (aRR: 14.27; 95% confidence interval, 11.41-17.83). This association remained after adjusting for potential confounding factors. Race/ethnicity- and gestational age-specific analyses revealed a positive association of similar magnitude across groups. Risk remained higher in younger boys than girls regardless of the sex of affected older siblings. CONCLUSION: The findings of this study suggest that the risk of ASD in younger siblings is higher if the older sibling has ASD. The risk of ASD in younger siblings of older affected siblings was comparable across gestational age at birth and child's race/ethnicity groups. However, risk remains higher for boys. This study contributes to a better understanding of the influence of race/ethnicity, sex, and gestational age at birth in identifying children at higher risk of ASD. PMID- 27500598 TI - Metal-Free Oxidative Radical Alkynylation/Ring Expansion Rearrangement of Alkenyl Cyclobutanols with Ethynylbenziodoxolones. AB - The first metal-free alkynylation/ring expansion cascade process of alkenyl cyclobutanols with ethynylbenziodoxolones has been developed. A variety of synthetically valuable beta-alkynylated cyclopentanones were prepared in moderate to good yields. Alkynyl cyclobutanols could also undergo this transformation, providing a new approach to substituted ene-yne-carbonyl compounds. PMID- 27500599 TI - Regional Intestinal Permeability in Dogs: Biopharmaceutical Aspects for Development of Oral Modified-Release Dosage Forms. AB - The development of oral modified-release (MR) dosage forms requires an active pharmaceutical ingredient (API) with a sufficiently high absorption rate in both the small and large intestine. Dogs are commonly used in preclinical evaluation of regional intestinal absorption and in the development of novel MR dosage forms. This study determined regional intestinal effective permeability (Peff) in dogs with the aim to improve regional Peff prediction in humans. Four model drugs, atenolol, enalaprilat, metoprolol, and ketoprofen, were intravenously and regionally dosed twice as a solution into the proximal small intestine (P-SI) and large intestine (LI) of three dogs with intestinal stomas. Based on plasma data from two separate study occasions for each dog, regional Peff values were calculated using a validated intestinal deconvolution method. The determined mean Peff values were 0.62, 0.14, 1.06, and 3.66 * 10(-4) cm/s in the P-SI, and 0.13, 0.02, 1.03, and 2.20 * 10(-4) cm/s in the LI, for atenolol, enalaprilat, metoprolol, and ketoprofen, respectively. The determined P-SI Peff values in dog were highly correlated (R(2) = 0.98) to the historically directly determined human jejunal Peff after a single-pass perfusion. The determined dog P-SI Peff values were also successfully implemented in GI-Sim to predict the risk for overestimation of LI absorption of low permeability drugs. We conclude that the dog intestinal stoma model is a useful preclinical tool for determination of regional intestinal permeability. Still, further studies are recommended to evaluate additional APIs, sources of variability, and formulation types, for more accurate determination of the dog model in the drug development process. PMID- 27500600 TI - Placental perfusion: interest and limits. PMID- 27500601 TI - Chemoenzymatic Synthesis and Receptor Binding of Mannose-6-Phosphate (M6P) Containing Glycoprotein Ligands Reveal Unusual Structural Requirements for M6P Receptor Recognition. AB - Mannose-6-phosphate (M6P)-terminated oligosaccharides are important signals for M6P-receptor-mediated targeting of newly synthesized hydrolases from Golgi to lysosomes, but the precise structural requirement for the M6P ligand-receptor recognition has not been fully understood due to the difficulties in obtaining homogeneous M6P-containing glycoproteins. We describe here a chemoenzymatic synthesis of homogeneous phosphoglycoproteins carrying natural M6P-containing N glycans. The method includes the chemical synthesis of glycan oxazolines with varied number and location of the M6P moieties and their transfer to the GlcNAc protein by an endoglycosynthase to provide homogeneous M6P-containing glycoproteins. Simultaneous attachment of two M6P-oligosaccahrides to a cyclic polypeptide was also accomplished to yield bivalent M6P-glycopeptides. Surface plasmon resonance binding studies reveal that a single M6P moiety located at the low alpha-1,3-branch of the oligomannose context is sufficient for a high affinity binding to receptor CI-MPR, while the presence of a M6P moiety at the alpha-1,6-branch is dispensable. In addition, a binding study with the bivalent cyclic and linear polypeptides reveals that a close proximity of two M6P oligosaccharide ligands is critical to achieve high affinity for the CI-MPR receptor. Taken together, the present study indicates that the location and valency of the M6P moieties and the right oligosaccharide context are all critical for high-affinity binding with the major M6P receptor. The chemoenzymatic method described here provides a new avenue for glycosylation remodeling of recombinant enzymes to enhance the uptake and delivery of enzymes to lysosomes in enzyme replacement therapy for the treatment of lysosomal storage diseases. PMID- 27500602 TI - Conscious and Non-conscious Representations of Emotional Faces in Asperger's Syndrome. AB - Several neuroimaging studies have suggested that the low spatial frequency content in an emotional face mainly activates the amygdala, pulvinar, and superior colliculus especially with fearful faces(1-3). These regions constitute the limbic structure in non-conscious perception of emotions and modulate cortical activity either directly or indirectly(2). In contrast, the conscious representation of emotions is more pronounced in the anterior cingulate, prefrontal cortex, and somatosensory cortex for directing voluntary attention to details in faces(3,4). Asperger's syndrome (AS)(5,6) represents an atypical mental disturbance that affects sensory, affective and communicative abilities, without interfering with normal linguistic skills and intellectual ability. Several studies have found that functional deficits in the neural circuitry important for facial emotion recognition can partly explain social communication failure in patients with AS(7-9). In order to clarify the interplay between conscious and non-conscious representations of emotional faces in AS, an EEG experimental protocol is designed with two tasks involving emotionality evaluation of either photograph or line-drawing faces. A pilot study is introduced for selecting face stimuli that minimize the differences in reaction times and scores assigned to facial emotions between the pretested patients with AS and IQ/gender-matched healthy controls. Information from the pretested patients was used to develop the scoring system used for the emotionality evaluation. Research into facial emotions and visual stimuli with different spatial frequency contents has reached discrepant findings depending on the demographic characteristics of participants and task demands(2). The experimental protocol is intended to clarify deficits in patients with AS in processing emotional faces when compared with healthy controls by controlling for factors unrelated to recognition of facial emotions, such as task difficulty, IQ and gender. PMID- 27500605 TI - No silver bullet: different soil handling techniques are useful for different research questions, exhibit differential type I and II error rates, and are sensitive to sampling intensity. PMID- 27500603 TI - Continuous Glucose Monitor Use and Accuracy in Hospitalized Patients. PMID- 27500604 TI - Evaluation of the Impact of Methicillin-Resistant Staphylococcus pseudintermedius Biofilm Formation on Antimicrobial Susceptibility. AB - OBJECTIVE: To compare the minimum inhibitory concentration (MIC) of four antimicrobials in planktonic vs. biofilm-associated Staphylococcus pseudintermedius. STUDY DESIGN: In vitro study. SAMPLE POPULATION: 78 isolates from dogs colonized or infected with methicillin-resistant S. pseudintermedius (MRSP, n=39) or methicillin-susceptible S. pseudintermedius (MSSP, n=39). METHODS: Agar dilution was used to determine the MIC of amikacin, cefazolin, enrofloxacin, and gentamicin for planktonic bacteria. A modified broth microdilution assay was used to assess the MIC of biofilm-associated bacteria. RESULTS: MIC were significantly higher in biofilm-associated vs. planktonic bacteria for all antimicrobials; amikacin (median MIC: biofilm >2,000 MUg/mL vs. planktonic 3 MUg/mL, P<.0001), cefazolin (>1,000 vs. 0.5 MUg/mL, P<.0001), enrofloxacin (>1,000 vs. 0.25 MUg/mL, P<.0001), and gentamicin (>1,000 vs. 0.3 MUg/mL, P<.001). For all antimicrobials, there were significant differences in planktonic MIC for MRSP and MSSP (all P<.0001) but no differences between biofilm MIC for MRSP and MSSP (P=.08-1.0). CONCLUSION: The MIC for biofilm-associated S. pseudintermedius are significantly higher than for planktonic bacteria. Standard methods for determining MIC are not appropriate for biofilm-associated infections. This must be considered when determining treatment regimens for infections that potentially involve biofilms, and further study of methods to control biofilm-associated infections is needed. PMID- 27500606 TI - Vascular Malformations and Associated Syndromes: The Role of the Orthopaedic Surgeon. PMID- 27500607 TI - Management of Osteoporotic Patients with Distal Radial Fractures. PMID- 27500608 TI - Hip Resection Arthroplasty. PMID- 27500609 TI - Cervical Traction for the Treatment of Spinal Injury and Deformity. PMID- 27500611 TI - Pediatric Critical Care Medicine: Accomplishments and Important New Initiatives. PMID- 27500610 TI - Visualization of HIV-1 Gag Binding to Giant Unilamellar Vesicle (GUV) Membranes. AB - The structural protein of HIV-1, Pr55(Gag) (or Gag), binds to the plasma membrane in cells during the virus assembly process. Membrane binding of Gag is an essential step for virus particle formation, since a defect in Gag membrane binding results in severe impairment of viral particle production. To gain mechanistic details of Gag-lipid membrane interactions, in vitro methods based on NMR, protein footprinting, surface plasmon resonance, liposome flotation centrifugation, or fluorescence lipid bead binding have been developed thus far. However, each of these in vitro methods has its limitations. To overcome some of these limitations and provide a complementary approach to the previously established methods, we developed an in vitro assay in which interactions between HIV-1 Gag and lipid membranes take place in a "cell-like" environment. In this assay, Gag binding to lipid membranes is visually analyzed using YFP-tagged Gag synthesized in a wheat germ-based in vitro translation system and GUVs prepared by an electroformation technique. Here we describe the background and the protocols to obtain myristoylated full-length Gag proteins and GUV membranes necessary for the assay and to detect Gag-GUV binding by microscopy. PMID- 27500612 TI - Multisite Tissue Oxygenation Monitoring Indicates Organ-Specific Flow Distribution and Oxygen Delivery Related to Low Cardiac Output in Preterm Infants With Clinical Sepsis. AB - OBJECTIVES: Cardiac output may be compromised in preterm infants with sepsis. Whether low cardiac output is associated with low tissue oxygen supply in these patients is unclear. The aim of the current study was to assess the association between cardiac output, assessed by echocardiography, and tissue oxygenation, measured with multisite near-infrared spectroscopy, in a cohort of preterm infants with clinical sepsis. DESIGN: Prospective observational cohort study. SETTING: Level III neonatal ICU. PATIENTS: Twenty-four preterm infants (gestational age < 32 wk) with clinical sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical and echocardiographic assessment of hemodynamics was performed within 48 hours of sepsis workup and repeated at least 24 hours later. We measured cerebral, renal, and intestinal tissue oxygen saturation using near infrared spectroscopy during an hour of stable measurements directly preceding or following echocardiography and calculated fractional tissue oxygen extraction in each tissue. We determined Spearman correlation coefficients between fractional tissue oxygen extraction and right ventricular output corrected for patent foramen ovale flow, left ventricular output corrected for ductus arteriosus flow, and superior vena cava flow. Right ventricular output corrected for patent foramen ovale and left ventricular output corrected for ductus arteriosus flow both correlated significantly with intestinal fractional tissue oxygen extraction (rho, -0.700; p = 0.036 and rho, -0.604; p = 0.029, respectively). In contrast, no significant correlations were found between cardiac output measurements and cerebral and renal fractional tissue oxygen extraction, respectively. Changes in cardiac output measurements were not associated with observed changes in fractional tissue oxygen extraction values. CONCLUSIONS: Right ventricular output corrected for patent foramen ovale and left ventricular output corrected for ductus arteriosus flow, indicators of systemic blood flow in preterm infants with shunts, were negatively associated with intestinal fractional tissue oxygen extraction, but not with renal and cerebral fractional tissue oxygen extraction. These findings suggest that during low output states due to clinical sepsis intestinal perfusion is most at risk. PMID- 27500613 TI - Targeted Temperature Management After Cardiac Arrest Due to Drowning: "Frequentist" and "Bayesian" Decision Making. PMID- 27500614 TI - How to Sustain Quality Improvements in Sedation Practice? PMID- 27500615 TI - Sepsis: From the Stone Age to Nowadays Without a Precise Definition. PMID- 27500616 TI - Critical Pertussis Among Infants-Many More Miles to Go! PMID- 27500617 TI - You Can Teach an Old Drug New Tricks-Aminophylline for Cardiac Surgery-Associated Acute Kidney Injury. PMID- 27500618 TI - Lies, Statistics, and ECMO Data Mining: Digging Dirt or Striking Gold? PMID- 27500619 TI - Tracheostomies and Long-Term Ventilation in Children: Are We Being Thoughtful and Consistent? PMID- 27500620 TI - Increasing Access to the Benefits of Palliative Care in the PICU. PMID- 27500621 TI - Lower Respiratory Tract Infections: Risks Are High in Early Childhood. PMID- 27500622 TI - Pediatric Acute Kidney Injury: The Fight of Inadequate Education Versus Inadequate Literature. PMID- 27500623 TI - Patient-Ventilator Asynchrony During Assisted Ventilation in Children: The Time to Rethink Our Knowledge. PMID- 27500624 TI - The authors reply. PMID- 27500625 TI - Strain Echocardiography in Pediatric Sepsis: Direct Guide to Hemodynamic Therapy in the Future? PMID- 27500626 TI - The authors reply. PMID- 27500627 TI - Use of Aminophylline to Prevent Acute Kidney Injury After Pediatric Cardiac Surgery. PMID- 27500628 TI - The authors reply. PMID- 27500629 TI - The Current State of the Diagnosis and Management of Acute Kidney Injury by Pediatric Critical Care Physicians. AB - OBJECTIVES: Increasingly prevalent in pediatric intensive care, acute kidney injury imparts significant short- and long-term consequences. Despite advances in acute kidney injury research, clinical outcomes are worsening. We surveyed pediatric critical care physicians to describe the current state of acute kidney injury diagnosis and management in critically ill children. DESIGN: Anonymous electronic questionnaire. PARTICIPANTS: Pediatric critical care physicians from academic centers, the Pediatric Acute Lung Injury and Sepsis Investigators network, and/or the pediatric branch of Society of Critical Care Medicine. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 201 surveys initiated, 170 surveys were more than 50% completed and included in our results. The majority of physicians (74%) diagnosed acute kidney injury using serum creatinine and urine output. Acute kidney injury guidelines or criteria were used routinely by 54% of physicians; Risk, Injury, Failure, Loss, and End stage criteria were the most commonly used. Awareness of any acute kidney injury guideline or definition was associated with five-fold higher odds of using any guideline (odds ratio, 5.22; 95% CI, 1.84-14.83) and four-fold higher odds of being dissatisfied with available acute kidney injury biomarkers (odds ratio, 4.88; 95% CI, 1.58-15.05). Less than half of respondents recognized the limitations of serum creatinine. Physicians unaware of the limitations of serum creatinine had two-fold higher odds of being unaware of newer biomarker availability (odds ratio, 2.34; 95% CI, 1.14-4.79). Novel biomarkers were available to 37.6% of physicians for routine use. Physicians with access to novel biomarkers more often practiced in larger (odds ratio, 3.09; 95% CI, 1.18-8.12) and Midwestern (odds ratio, 3.38; 95% CI, 1.47-7.78) institutions. More physicians with access to a novel biomarker reported satisfaction with current acute kidney injury diagnostics (66%) than physicians without access (48%); this finding approached significance (p = 0.07). CONCLUSIONS: Half of PICU attending physicians surveyed are not using recent acute kidney injury guidelines or diagnostic criteria in their practice. There is a positive association between awareness and clinical use of acute kidney injury guidelines. Serum creatinine and urine output are still the primary diagnostics; novel biomarkers are frequently unavailable. PMID- 27500630 TI - A Novel Behavioral Assay to Investigate Gustatory Responses of Individual, Freely moving Bumble Bees (Bombus terrestris). AB - Generalist pollinators like the buff-tailed bumble bee, Bombus terrestris, encounter both nutrients and toxins in the floral nectar they collect from flowering plants. Only a few studies have described the gustatory responses of bees toward toxins in food, and these experiments have mainly used the proboscis extension response on restrained honey bees. Here, a new behavioral assay is presented for measuring the feeding responses of freely-moving, individual worker bumble bees to nutrients and toxins. This assay measures the amount of solution ingested by each bumble bee and identifies how tastants in food influence the microstructure of the feeding behavior. The solutions are presented in a microcapillary tube to individual bumble bees that have been previously starved for 2-4 hr. The behavior is captured on digital video. The fine structure of the feeding behavior is analyzed by continuously scoring the position of the proboscis (mouthparts) from video recordings using event logging software. The position of the proboscis is defined by three different behavioral categories: (1) proboscis is extended and in contact with the solution, (2) proboscis is extended but not in contact with the solution and (3) proboscis is stowed under the head. Furthermore the speed of the proboscis retracting away from the solution is also estimated. In the present assay the volume of solution consumed, the number of feeding bouts, the duration of the feeding bouts and the speed of the proboscis retraction after the first contact is used to evaluate the phagostimulatory or the deterrent activity of the compounds tested. This new taste assay will allow researchers to measure how compounds found in nectar influence the feeding behavior of bees and will also be useful to pollination biologists, toxicologists and neuroethologists studying the bumble bee's taste system. PMID- 27500632 TI - The challenge of treating elderly coronary artery disease patients. PMID- 27500631 TI - Plasma cell differentiation is coupled to division-dependent DNA hypomethylation and gene regulation. AB - The epigenetic processes that regulate antibody-secreting plasma cells are not well understood. Here, analysis of plasma cell differentiation revealed DNA hypomethylation of 10% of CpG loci that were overrepresented at enhancers. Inhibition of DNA methylation enhanced plasma cell commitment in a cell-division dependent manner. Analysis of B cells differentiating in vivo stratified by cell division revealed a fivefold increase in mRNA transcription coupled to DNA hypomethylation. Demethylation occurred first at binding motifs for the transcription factors NF-kappaB and AP-1 and later at those for the transcription factors IRF and Oct-2 and was coincident with activation and differentiation gene expression programs in a cell-division-dependent manner. These data provide mechanistic insight into cell-division-coupled transcriptional and epigenetic reprogramming and suggest that DNA hypomethylation reflects the cis-regulatory history of plasma cell differentiation. PMID- 27500633 TI - Are Epiphytic Microbial Communities in the Carposphere of Ripening Grape Clusters (Vitis vinifera L.) Different between Conventional, Organic, and Biodynamic Grapes? AB - Using barcoded pyrosequencing fungal and bacterial communities associated with grape berry clusters (Vitis vinifera L.) obtained from conventional, organic and biodynamic vineyard plots were investigated in two subsequent years at different stages during berry ripening. The four most abundant operational taxonomic units (OTUs) based on fungal ITS data were Botrytis cinerea, Cladosporium spp., Aureobasidium pullulans and Alternaria alternata which represented 57% and 47% of the total reads in 2010 and 2011, respectively. Members of the genera Sphingomonas, Gluconobacter, Pseudomonas, Erwinia, and Massilia constituted 67% of the total number of bacterial 16S DNA reads in 2010 samples and 78% in 2011 samples. Viticultural management system had no significant effect on abundance of fungi or bacteria in both years and at all three sampling dates. Exceptions were A. alternata and Pseudomonas spp. which were more abundant in the carposphere of conventional compared to biodynamic berries, as well as Sphingomonas spp. which was significantly less abundant on conventional compared to organic berries at an early ripening stage in 2011. In general, there were no significant differences in fungal and bacterial diversity indices or richness evident between management systems. No distinct fungal or bacterial communities were associated with the different maturation stages or management systems, respectively. An exception was the last stage of berry maturation in 2011, where the Simpson diversity index was significantly higher for fungal communities on biodynamic compared to conventional grapes. Our study highlights the existence of complex and dynamic microbial communities in the grape cluster carposphere including both phytopathogenic and potentially antagonistic microorganisms that can have a significant impact on grape production. Such knowledge is particularly relevant for development, selection and application of effective control measures against economically important pathogens present in the grape carposphere. PMID- 27500634 TI - Hybridization between nanocavities for a polarimetric color sorter at the sub micron scale. AB - Metallic hole arrays have been recently used for color generation and filtering due to their reliability and color tunability. However, color generation is still limited to several microns. Understanding the interaction between the individual elements of the whole nanostructure may push the resolution to the sub-micron level. Herein, we study the hybridization between silver nanocavities in order to obtain active color generation at the micron scale. To do so, we use five identical triangular cavities which are separated by hundreds of nanometers from each other. By tuning either the distance between the cavities or the optical polarization state of the incoming field, the transmitted light through the cavities is actively enhanced at specific frequencies. Consequently, a rainbow of colors is observed from a sub-micron scale unit. The reason for this is that the metallic surface plays a vital role in the hybridization between the cavities and contributes to higher frequency modes. Cathodoluminescence measurements have confirmed this assumption and have revealed that these five triangular cavities act as a unified entity surrounded by the propagated surface plasmons. In such plasmonic structures, multi-color tuning can be accomplished and may open the possibility to improve color generation and high-quality pixel fabrication. PMID- 27500635 TI - Quantitation of Intra-peritoneal Ovarian Cancer Metastasis. AB - Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the United States. Mortality is due to diagnosis of 75% of women with late stage disease, when metastasis is already present. EOC is characterized by diffuse and widely disseminated intra-peritoneal metastasis. Cells shed from the primary tumor anchor in the mesothelium that lines the peritoneal cavity as well as in the omentum, resulting in multi-focal metastasis, often in the presence of peritoneal ascites. Efforts in our laboratory are directed at a more detailed understanding of factors that regulate EOC metastatic success. However, quantifying metastatic tumor burden represents a significant technical challenge due to the large number, small size and broad distribution of lesions throughout the peritoneum. Herein we describe a method for analysis of EOC metastasis using cells labeled with red fluorescent protein (RFP) coupled with in vivo multispectral imaging. Following intra-peritoneal injection of RFP-labelled tumor cells, mice are imaged weekly until time of sacrifice. At this time, the peritoneal cavity is surgically exposed and organs are imaged in situ. Dissected organs are then placed on a labeled transparent template and imaged ex vivo. Removal of tissue auto-fluorescence during image processing using multispectral unmixing enables accurate quantitation of relative tumor burden. This method has utility in a variety of applications including therapeutic studies to evaluate compounds that may inhibit metastasis and thereby improve overall survival. PMID- 27500636 TI - Virtual Hematoxylin and Eosin Transillumination Microscopy Using Epi-Fluorescence Imaging. AB - We derive a physically realistic model for the generation of virtual transillumination, white light microscopy images using epi-fluorescence measurements from thick, unsectioned tissue. We demonstrate this technique by generating virtual transillumination H&E images of unsectioned human breast tissue from epi-fluorescence multiphoton microscopy data. The virtual transillumination algorithm is shown to enable improved contrast and color accuracy compared with previous color mapping methods. Finally, we present an open source implementation of the algorithm in OpenGL, enabling real-time GPU based generation of virtual transillumination microscopy images using conventional fluorescence microscopy systems. PMID- 27500637 TI - Structural and functional basis of phospholipid oxygenase activity of bacterial lipoxygenase from Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa expresses a secreted LOX-isoform (PA-LOX, LoxA) capable of oxidizing polyenoic fatty acids to hydroperoxy derivatives. Here we report high level expression of this enzyme in E. coli and its structural and functional characterization. Recombinant PA-LOX oxygenates polyenoic fatty acids including eicosapentaenoic acid and docosahexaenoic acid to the corresponding (n-6)S hydroperoxy derivatives. This reaction involves abstraction of the proS-hydrogen from the n-8 bisallylic methylene. PA-LOX lacks major leukotriene synthase activity but converts 5S-HETE and 5S,6R/S-DiHETE to anti-inflammatory and pro resolving lipoxins. It also exhibits phospholipid oxygenase activity as indicated by the formation of a specific pattern of oxygenation products from different phospholipid subspecies. Multiple mutagenesis studies revealed that PA-LOX does not follow classical concepts explaining the reaction specificity of mammalian LOXs. The crystal structure of PA-LOX was solved with resolutions of up to 1.48A and its polypeptide chain is folded as single domain. The substrate-binding pocket consists of two fatty acid binding subcavities and lobby. Subcavity-1 contains the catalytic non-heme iron. A phosphatidylethanolamine molecule occupies the substrate-binding pocket and its sn1 fatty acid is located close to the catalytic non-heme iron. His377, His382, His555, Asn559 and the C-terminal Ile685 function as direct iron ligands and a water molecule (hydroxyl) completes the octahedral ligand sphere. Although the biological relevance of PA-LOX is still unknown its functional characteristics (lipoxin synthase activity) implicate this enzyme in a bacterial evasion strategy aimed at downregulating the hosts' immune system. PMID- 27500638 TI - Yeast Biodiversity in Vineyard Environments Is Increased by Human Intervention. AB - One hundred and five grape samples were collected during two consecutive years from 33 locations on seven oceanic islands of the Azores Archipelago. Grape samples were obtained from vineyards that were either abandoned or under regular cultivation involving common viticultural interventions, to evaluate the impact of regular human intervention on grape yeast biota diversity in vineyards. A total of 3150 yeast isolates were obtained and 23 yeast species were identified. The predominant species were Hanseniaspora uvarum, Pichia terricola, Starmerella bacillaris and Issatchenkia hanoiensis. The species Barnettozyma californica, Candida azymoides and Pichia cecembensis were reported in grapes or wine associated environments for the first time. A higher biodiversity was found in active vineyards where regular human intervention takes place (Shannon index: 1.89 and 1.53 in the first and second years, respectively) when compared to the abandoned ones (Shannon index: 0.76 and 0.31). This finding goes against the assumptions that human intervention can destroy biodiversity and lead to homogeneity in the environment. Biodiversity indices were considerably lower in the year with the heaviest rainfall. This study is the first to report on the grape yeast communities from several abandoned vineyards that have undergone no human intervention. PMID- 27500640 TI - Multiclass Classification for the Differential Diagnosis on the ADHD Subtypes Using Recursive Feature Elimination and Hierarchical Extreme Learning Machine: Structural MRI Study. AB - The classification of neuroimaging data for the diagnosis of certain brain diseases is one of the main research goals of the neuroscience and clinical communities. In this study, we performed multiclass classification using a hierarchical extreme learning machine (H-ELM) classifier. We compared the performance of this classifier with that of a support vector machine (SVM) and basic extreme learning machine (ELM) for cortical MRI data from attention deficit/hyperactivity disorder (ADHD) patients. We used 159 structural MRI images of children from the publicly available ADHD-200 MRI dataset. The data consisted of three types, namely, typically developing (TDC), ADHD-inattentive (ADHD-I), and ADHD-combined (ADHD-C). We carried out feature selection by using standard SVM-based recursive feature elimination (RFE-SVM) that enabled us to achieve good classification accuracy (60.78%). In this study, we found the RFE-SVM feature selection approach in combination with H-ELM to effectively enable the acquisition of high multiclass classification accuracy rates for structural neuroimaging data. In addition, we found that the most important features for classification were the surface area of the superior frontal lobe, and the cortical thickness, volume, and mean surface area of the whole cortex. PMID- 27500639 TI - HIV-1-Specific Antibody Response and Function after DNA Prime and Recombinant Adenovirus 5 Boost HIV Vaccine in HIV-Infected Subjects. AB - Little is known about the humoral immune response against DNA prime-recombinant adenovirus 5 (rAd5) boost HIV vaccine among HIV-infected patients on long-term suppressive antiretroviral therapy (ART). Previous studies emphasized cellular immune responses; however, current research suggests both cellular and humoral responses are likely required for a successful therapeutic vaccine. Thus, we aimed to understand antibody response and function induced by vaccination of ART treated HIV-1-infected patients with immune recovery. All subjects participated in EraMune 02, an open-label randomized clinical trial of ART intensification followed by a six plasmid DNA prime (envA, envB, envC, gagB, polB, nefB) and rAd5 boost HIV vaccine with matching inserts. Antibody binding levels were determined with a recently developed microarray approach. We also analyzed neutralization efficiency and antibody-dependent cellular cytotoxicity (ADCC). We found that the DNA prime-rAd5 boost vaccine induced a significant cross-clade HIV-specific antibody response, which correlated with antibody neutralization efficiency. However, despite the increase in antibody binding levels, the vaccine did not significantly stimulate neutralization or ADCC responses. This finding was also reflected by a lack of change in total CD4+ cell associated HIV DNA in those who received the vaccine. Our results have important implications for further therapeutic vaccine design and administration, especially in HIV-1 infected patients, as boosting of preexisting antibody responses are unlikely to lead to clearance of latent proviruses in the HIV reservoir. PMID- 27500642 TI - Simultaneous qualitative and quantitative analysis of 21 mycotoxins in Radix Paeoniae Alba by ultra-high performance liquid chromatography quadrupole linear ion trap mass spectrometry and QuEChERS for sample preparation. AB - A high-throughput method for simultaneous qualitative and quantitative analysis of 21 mycotoxins in Radix Paeoniae Alba (RPA) was developed by coupling the modified QuEChERS method with ultra-high performance liquid chromatography quadrupole linear ion trap mass spectrometry (UHPLC-QqLIT-MS). The 21 mycotoxins were extracted and cleaned up using QuEChERS-based procedure, then further separated on a C18 column and detected by a hybrid triple quadrupole linear ion trap mass spectrometer equipped with electrospray ionization source in the multiple reaction monitoring-information dependent acquisition-enhanced product ion (MRM-IDA-EPI) mode. Under this technique, 13 mycotoxins were detected using acetonitrile and water containing 0.1% formic acid as the mobile phase in positive mode while the other 8 mycotoxins were detected using acetonitrile and water containing 0.1% ammonia as the mobile phase in negative mode. The calibration curves of all analytes showed good linearity (r(2)>0.995) within test ranges. The limits of detection and quantification ranged from 0.031 to 5.4MUg/kg and 0.20 to 22MUg/kg, respectively. Additionally, recoveries were all above 75.3% with relative standard deviations within 15%. The method proposed herein with significant advantages including simple pretreatment, rapid determination as well as high sensitivity, accuracy and throughput would be a preferred candidate for the determination and quantification of multi-class mycotoxin contaminants in real samples. PMID- 27500641 TI - Potent Allosteric Dengue Virus NS5 Polymerase Inhibitors: Mechanism of Action and Resistance Profiling. AB - Flaviviruses comprise major emerging pathogens such as dengue virus (DENV) or Zika virus (ZIKV). The flavivirus RNA genome is replicated by the RNA-dependent RNA polymerase (RdRp) domain of non-structural protein 5 (NS5). This essential enzymatic activity renders the RdRp attractive for antiviral therapy. NS5 synthesizes viral RNA via a "de novo" initiation mechanism. Crystal structures of the flavivirus RdRp revealed a "closed" conformation reminiscent of a pre initiation state, with a well ordered priming loop that extrudes from the thumb subdomain into the dsRNA exit tunnel, close to the "GDD" active site. To-date, no allosteric pockets have been identified for the RdRp, and compound screening campaigns did not yield suitable drug candidates. Using fragment-based screening via X-ray crystallography, we found a fragment that bound to a pocket of the apo DENV RdRp close to its active site (termed "N pocket"). Structure-guided improvements yielded DENV pan-serotype inhibitors of the RdRp de novo initiation activity with nano-molar potency that also impeded elongation activity at micro molar concentrations. Inhibitors exhibited mixed inhibition kinetics with respect to competition with the RNA or GTP substrate. The best compounds have EC50 values of 1-2 MUM against all four DENV serotypes in cell culture assays. Genome sequencing of compound-resistant DENV replicons, identified amino acid changes that mapped to the N pocket. Since inhibitors bind at the thumb/palm interface of the RdRp, this class of compounds is proposed to hinder RdRp conformational changes during its transition from initiation to elongation. This is the first report of a class of pan-serotype and cell-active DENV RdRp inhibitors. Given the evolutionary conservation of residues lining the N pocket, these molecules offer insights to treat other serious conditions caused by flaviviruses. PMID- 27500643 TI - Development of a Monoclonal Antibody Against Porcine Circovirus2 Cap Protein. AB - Female BALB/c mice were immunized with a commercial PCV2 vaccine, and a monoclonal antibody (MAb) designated as 3H11 was achieved by hybridoma techniques. The MAb specifically reacted with Cap protein of PCV2, which has been identified by western blot. Immunoperoxidase monolayer assay results showed that 3H11 did not cross-react with PCV1-infected cells. Therefore, this work suggested that 3H11 could be a useful tool as a specific diagnostic reagent for PCV2 research. PMID- 27500644 TI - Activating Receptor Signals Drive Receptor Diversity in Developing Natural Killer Cells. AB - It has recently been appreciated that NK cells exhibit many features reminiscent of adaptive immune cells. Considerable heterogeneity exists with respect to the ligand specificity of individual NK cells and as such, a subset of NK cells can respond, expand, and differentiate into memory-like cells in a ligand-specific manner. MHC I-binding inhibitory receptors, including those belonging to the Ly49 and KIR families, are expressed in a variegated manner, which creates ligand specific diversity within the NK cell pool. However, how NK cells determine which inhibitory receptors to express on their cell surface during a narrow window of development is largely unknown. In this manuscript, we demonstrate that signals from activating receptors are critical for induction of Ly49 and KIR receptors during NK cell development; activating receptor-derived signals increased the probability of the Ly49 bidirectional Pro1 promoter to transcribe in the forward versus the reverse direction, leading to stable expression of Ly49 receptors in mature NK cells. Our data support a model where the balance of activating and inhibitory receptor signaling in NK cells selects for the induction of appropriate inhibitory receptors during development, which NK cells use to create a diverse pool of ligand-specific NK cells. PMID- 27500645 TI - Sex steroid-induced DNA methylation changes and inflammation response in prostate cancer. AB - BACKGROUND: Sex steroid hormones have been reported to induce inflammation causing dysregulation of cytokines in prostate cancer cells. However, the underlying epigenetic mechanism has not well been studied. The objective of this study was to evaluate the effect of sex steroid hormones on epigenetic DNA methylation changes in prostate cancer cells using a signature PCR methylation array panel that correspond to 96 genes with biological function in the human inflammatory and autoimmune signals in prostate cancer. Of the 96-gene panel, 32 genes showed at least 10% differentially methylation level in response to hormonal treatment when compared to untreated cells. Genes that were hypomethylated included CXCL12, CXCL5, CCL25, IL1F8, IL13RAI, STAT5A, CXCR4 and TLR5; and genes that were hypermethylated included ELA2, TOLLIP, LAG3, CD276 and MALT1. Quantitative RT-PCR analysis of select genes represented in a cytokine expression array panel showed inverse association between DNA methylation and gene expression for TOLLIP, CXCL5, CCL18 and IL5 genes and treatment of prostate cancer cells with 5'-aza-2'-deoxycytidine with or without trichostatin A induced up-regulation of TOLLIP expression. Further analysis of relative gene expression of matched prostate cancer tissues when compared to benign tissues from individual patients with prostate cancer showed increased and significant expression for CCL18 (2.6-fold; p<0.001), a modest yet significant increase in IL5 expression (1.17-fold; p=0.015), and a modest increase in CXCL5 expression (1.4-fold; p=0.25). In conclusion, our studies demonstrate that sex steroid hormones can induce aberrant gene expression via differential methylation changes in prostate carcinogenesis. PMID- 27500646 TI - Do arterial stiffness and wave reflections improve more with angiotensin receptor blockers than with other antihypertensive drug classes? PMID- 27500647 TI - Community-acquired pneumonia: the elusive quest for the best treatment strategy. PMID- 27500648 TI - Comment on "Use of Carnosine for Oxidative Stress Reduction in Different Pathologies". PMID- 27500649 TI - The genetics of kinship in remote human groups. AB - For fifteen years, part of the work of our research team has been focused on the study of parental links between individuals living hundreds or thousands of years ago, whose remains have been found in single graves or large funerary complexes. These studies have been undertaken using methods developed by forensic genetics to identify individuals, mainly based on the genotyping of autosomal STR (Short Tandem Repeats). Issues arose from this work, namely the limits of studying small numbers of subjects, originating from groups of finite sizes where kinships cannot be inferred a priori and for which reference allelic frequencies do not exist. Although ideal human populations are rare when undertaking such studies, the Yakuts of Eastern Siberia constitute a very advantageous model, with large numbers of small pastoral communities and well-preserved archaeological material. The study of kinship in the ancient Yakuts allowed us to highlight the difficulties in analysing genetic data from small ancient human groups and to develop a strategy to improve the accuracy of statistical computations. This work describes this strategy and possible solutions to the study of populations outside of the frame of reference of global meta-populations, due either to isolation, remoteness or antiquity. PMID- 27500650 TI - Analysis of uni and bi-parental markers in mixture samples: Lessons from the 22nd GHEP-ISFG Intercomparison Exercise. AB - Since 1992, the Spanish and Portuguese-Speaking Working Group of the ISFG (GHEP ISFG) has been organizing annual Intercomparison Exercises (IEs) coordinated by the Quality Service at the National Institute of Toxicology and Forensic Sciences (INTCF) from Madrid, aiming to provide proficiency tests for forensic DNA laboratories. Each annual exercise comprises a Basic (recently accredited under ISO/IEC 17043: 2010) and an Advanced Level, both including a kinship and a forensic module. Here, we show the results for both autosomal and sex-chromosomal STRs, and for mitochondrial DNA (mtDNA) in two samples included in the forensic modules, namely a mixture 2:1 (v/v) saliva/blood (M4) and a mixture 4:1 (v/v) saliva/semen (M8) out of the five items provided in the 2014 GHEP-ISFG IE. Discrepancies, other than typos or nomenclature errors (over the total allele calls), represented 6.5% (M4) and 4.7% (M8) for autosomal STRs, 15.4% (M4) and 7.8% (M8) for X-STRs, and 1.2% (M4) and 0.0% (M8) for Y-STRs. Drop-out and drop in alleles were the main cause of errors, with laboratories using different criteria regarding inclusion of minor peaks and stutter bands. Commonly used commercial kits yielded different results for a micro-variant detected at locus D12S391. In addition, the analysis of electropherograms revealed that the proportions of the contributors detected in the mixtures varied among the participants. In regards to mtDNA analysis, besides important discrepancies in reporting heteroplasmies, there was no agreement for the results of sample M4. Thus, while some laboratories documented a single control region haplotype, a few reported unexpected profiles (suggesting contamination problems). For M8, most laboratories detected only the haplotype corresponding to the saliva. Although the GHEP-ISFG has already a large experience in IEs, the present multi-centric study revealed challenges that still exist related to DNA mixtures interpretation. Overall, the results emphasize the need for further research and training actions in order to improve the analysis of mixtures among the forensic practitioners. PMID- 27500651 TI - Next generation sequencing of SNPs using the HID-Ion AmpliSeqTM Identity Panel on the Ion Torrent PGMTM platform. AB - The HID-Ion AmpliSeqTM Identity Panel (the HID Identity Panel) is designed to detect 124-plex single nucleotide polymorphisms (SNPs) with next generation sequencing (NGS) technology on the Ion Torrent PGMTM platform, including 90 individual identification SNPs (IISNPs) on autosomal chromosomes and 34 lineage informative SNPs (LISNPs) on Y chromosome. In this study, we evaluated performance for the HID Identity Panel to provide a reference for NGS-SNP application, focusing on locus strand balance, locus coverage balance, heterozygote balance, and background signals. Besides, several experiments were carried out to find out improvements and limitations of this panel, including studies of species specificity, repeatability and concordance, sensitivity, mixtures, case-type samples and degraded samples, population genetics and pedigrees following the Scientific Working Group on DNA Analysis Methods (SWGDAM) guidelines. In addition, Southern and Northern Chinese Han were investigated to assess applicability of this panel. Results showed this panel led to cross reactivity with primates to some extent but rarely with non-primate animals. Repeatable and concordant genotypes could be obtained in triplicate with one exception at rs7520386. Full profiles could be obtained from 100pg input DNA, but the optimal input DNA would be 1ng-200pg with 21 initial PCR cycles. A sample with >=20% minor contributor could be considered as a mixture by the number of homozygotes, and full profiles belonging to minor contributors could be detected between 9:1 and 1:9 mixtures with known reference profiles. Also, this assay could be used for case-type samples and degraded samples. For autosomal SNPs (A SNPs), FST across all 90loci was not significantly different between Southern and Northern Chinese Han or between male and female samples. All A-SNP loci were independent in Chinese Han population. Except for 18loci with He <0.4, most of the A-SNPs in the HID Identity Panel presented high polymorphisms. Forensic parameters were calculated as >99.999% for combined discrimination power (CDP), 0.999999724 for combined power of exclusion (CPE), 1.390*1011 for combined likelihood ratio (CLR) of trios, and 2.361*106 for CLR of motherless duos. For Y SNPs, a total of 8 haplotypes were observed with the value of 0.684 for haplotype diversity. As a whole, the HID Identity Panel is a well-performed, robust, reliable and high informative NGS-SNP assay and it can fully meet requirements for individual identification and paternity testing in forensic science. PMID- 27500652 TI - Evanescent Field Based Photoacoustics: Optical Property Evaluation at Surfaces. AB - Here, we present a protocol to estimate material and surface optical properties using the photoacoustic effect combined with total internal reflection. Optical property evaluation of thin films and the surfaces of bulk materials is an important step in understanding new optical material systems and their applications. The method presented can estimate thickness, refractive index, and use absorptive properties of materials for detection. This metrology system uses evanescent field-based photoacoustics (EFPA), a field of research based upon the interaction of an evanescent field with the photoacoustic effect. This interaction and its resulting family of techniques allow the technique to probe optical properties within a few hundred nanometers of the sample surface. This optical near field allows for the highly accurate estimation of material properties on the same scale as the field itself such as refractive index and film thickness. With the use of EFPA and its sub techniques such as total internal reflection photoacoustic spectroscopy (TIRPAS) and optical tunneling photoacoustic spectroscopy (OTPAS), it is possible to evaluate a material at the nanoscale in a consolidated instrument without the need for many instruments and experiments that may be cost prohibitive. PMID- 27500653 TI - How a high working memory capacity can increase proactive interference. AB - Previous findings suggested that a high working memory capacity (WMC) is potentially associated with a higher susceptibility to proactive interference (PI) if the latter is measured under high cognitive load. To explain such a finding, we propose to consider susceptibility to PI as a net effect of individual executive processes and the intrinsic potential for PI. With the latter, we refer to the amount of information that is activated at a given time and that has the potential to exert PI subsequently. In two studies deploying generalized linear mixed models, susceptibility to PI was modeled as the decline of performance over trials of a complex span task. The results revealed that a higher WMC was associated with a higher susceptibility to PI. Moreover, the number of stimuli recalled in one trial as a proxy variable for the intrinsic potential for PI negatively affected memory performance in the subsequent trial. PMID- 27500654 TI - Context-specific attentional sampling: Intentional control as a pre-requisite for contextual control. AB - Recent work suggests that environmental cues associated with previous attentional control settings can rapidly and involuntarily adjust attentional priorities. The current study tests predictions from adaptive-learning and memory-based theories of contextual control about the role of intentions for setting attentional priorities. To extend the empirical boundaries of contextual control phenomena, and to determine whether theoretical principles of contextual control are generalizable we used a novel bi-dimensional stimulus sampling task. Subjects viewed briefly presented arrays of letters and colors presented above or below fixation, and identified specific stimuli according to a dimensional (letter or color) and positional cue. Location was predictive of the cued dimension, but not the position or identity. In contrast to previous findings, contextual control failed to develop through automatic, adaptive-learning processes. Instead, previous experience with intentionally changing attentional sampling priorities between different contexts was required for contextual control to develop. PMID- 27500655 TI - Music chills: The eye pupil as a mirror to music's soul. AB - This study evaluated whether music-induced aesthetic "chill" responses, which typically correspond to peak emotional experiences, can be objectively monitored by degree of pupillary dilation. Participants listened to self-chosen songs versus control songs chosen by other participants. The experiment included an active condition where participants made key presses to indicate when experiencing chills and a passive condition (without key presses). Chills were reported more frequently for self-selected songs than control songs. Pupil diameter was concurrently measured by an eye-tracker while participants listened to each of the songs. Pupil size was larger within specific time-windows around the chill events, as monitored by key responses, than in comparison to pupil size observed during 'passive' song listening. In addition, there was a clear relationship between pupil diameter within the chills-related time-windows during both active and passive conditions, thus ruling out the possibility that chills related pupil dilations were an artifact of making a manual response. These findings strongly suggest that music chills can be visible in the moment-to moment changes in the size of pupillary responses and that a neuromodulatory role of the central norepinephrine system is thereby implicated in this phenomenon. PMID- 27500656 TI - Effective treatment via early cranioplasty for intractable contralateral subdural effusion after standard decompressive craniectomy in patients with severe traumatic brain injury. AB - OBJECTIVE: This study aimed to introduce an effective treatment for intractable contralateral subdural effusion after standard decompressive craniectomy in patients with severe traumatic brain injury (TBI) and to analyze the underlying mechanism. METHODS: A retrospective analysis was performed in 13 patients with severe traumatic craniocerebral injury showing complicated intractable contralateral subdural effusion after standard decompressive craniectomy, in whom satisfactory results were not obtained from treatments, including compression bandaging, head-down bed rest (HDBR), continuing lumbar drainage, and Ommaya catheter drainage. Among these patients, 6 underwent temporal muscle sticking, while 7 underwent early cranioplasty. The postoperative changes in the subdural effusion were observed. RESULTS: In the 6 patients who underwent temporal muscle sticking and the 7 who underwent early cranioplasty, the subdural effusion completely resolved or was significantly reduced within one month, and no recurrence was observed in the 6-month follow-up period. However, secondary bilateral cranioplasty was still necessary in the postoperative 3-6 months for the patients who underwent temporal muscle sticking. In the early cranioplasty group, there were three total operations, and the average length of stay (ALOS) was 76days. In the temporal muscle sticking group, there were four total operations, and the ALOS was 56.1days. A retrospective analysis of surgical pain showed that 100% of the patients in the first group experienced unacceptable suffering, while 14.3% of the patients in the second group experienced pain. CONCLUSION: Early cranioplasty is an effective, economical, and less painful treatment for intractable contralateral subdural effusion after standard decompressive craniectomy. PMID- 27500658 TI - Protocols for treating patients with end-stage renal disease: a survey of undergraduate dental programs. AB - RATIONALE/BACKGROUND: Approximately 14% of Americans are living with chronic kidney disease (CKD). The prevalence of end-stage renal disease (ESRD), the result of progressing CKD continues to rise by 21,000 per year. There are no updated, evidence-based antibiotic prophylaxis guidelines for patients with renal disease undergoing dental treatment. The most recent was a scientific statement from the American Heart Association (AHA) in 2003. Presented in three parts, the goal of the first part of this study is to determine the current protocol being used to treat renal patients at U.S. dental schools. METHODS AND MATERIALS: A 21 multiple-choice question survey was e-mailed to 58 clinic deans of accredited dental schools in the United States regarding renal treatment protocol details including antibiotic prophylaxis. RESULTS: Fifty-two percent of programs report having no established renal patient treatment protocol. For programs with a protocol, when using prophylactic antibiotics, 54% followed AHA protocol, whereas 62% used a modified protocol. CONCLUSION: There is a lack of consistent, established protocols among undergraduate dental programs. It is suggested that evidence-based guidelines for the safe treatment of patients be developed. PMID- 27500657 TI - PL-PatchSurfer2: Improved Local Surface Matching-Based Virtual Screening Method That Is Tolerant to Target and Ligand Structure Variation. AB - Virtual screening has become an indispensable procedure in drug discovery. Virtual screening methods can be classified into two categories: ligand-based and structure-based. While the former have advantages, including being quick to compute, in general they are relatively weak at discovering novel active compounds because they use known actives as references. On the other hand, structure-based methods have higher potential to find novel compounds because they directly predict the binding affinity of a ligand in a target binding pocket, albeit with substantially lower speed than ligand-based methods. Here we report a novel structure-based virtual screening method, PL-PatchSurfer2. In PL PatchSurfer2, protein and ligand surfaces are represented by a set of overlapping local patches, each of which is represented by three-dimensional Zernike descriptors (3DZDs). By means of 3DZDs, the shapes and physicochemical complementarities of local surface regions of a pocket surface and a ligand molecule can be concisely and effectively computed. Compared with the previous version of the program, the performance of PL-PatchSurfer2 is substantially improved by the addition of two more features, atom-based hydrophobicity and hydrogen-bond acceptors and donors. Benchmark studies showed that PL-PatchSurfer2 performed better than or comparable to popular existing methods. Particularly, PL PatchSurfer2 significantly outperformed existing methods when apo-form or template-based protein models were used for queries. The computational time of PL PatchSurfer2 is about 20 times shorter than those of conventional structure-based methods. The PL-PatchSurfer2 program is available at http://www.kiharalab.org/plps2/ . PMID- 27500659 TI - Detection, seroprevalence and antimicrobial resistance of Yersinia enterocolitica and Yersinia pseudotuberculosis in pig tonsils in Northern Italy. AB - Yersiniosis is the third most common reported zoonoses in Europe, with Y. enterocolitica and Y. pseudotuberculosis responsible for 98.66% and 0.94% of the confirmed human cases in 2013. From June 2013 to October 2014, 201 pigs at slaughter belonging to 67 batches were tested for Y. enterocolitica and Y. pseudotuberculosis in tonsils. Diaphragm muscle samples were tested for antibodies against Yersinia by a commercially available ELISA test. Y. enterocolitica 4/O:3 was detected in 55/201 pig tonsils (27.4%; 95% CI 23.1 37.1). The positive pigs came from 38/67 batches (56.7%) and were reared in 36/61 farms (59.0%). There was no statistical difference between farrow-to-finish and finishing farms. The mean count of Y. enterocolitica was 3.56+/-0.85log10CFU/g with a minimum of 2.0log10CFU/g and a maximum of 4.78log10CFU/g. Y. pseudotuberculosis was isolated from 4/201 pig tonsils (2.0%; 95% CI 0.0-4.5). Three isolates belonged to serotype O:3 and one to serotype O:1. The positive pigs belonged to 4/67 batches (6.0%) and came from finishing farms only. Y. pseudotuberculosis could be enumerated in one sample only (4.27log10CFU/g). The ELISA test demonstrated that 56.1% of the meat juice samples were positive for Yersinia antibodies. Serological positivity was found in 67.9% (36/53) of the Y. enterocolitica- and 75.0% (3/4) of the Y. pseudotuberculosis positive pigs. A significant association was found between serological results and the presence of Y. enterocolitica in tonsils (OR=1.97, p=0.044). All the Y. enterocolitica 4/O:3 isolates were susceptible to amoxicillin-clavulanic acid, gentamicin, ceftazidime, ertapenem and meropenem, 94.5% to cefotaxime, 89.1% to kanamycin and 78.2% to tetracycline. The highest resistance rates were observed for ampicillin (100%), sulphonamides (98.2%) and streptomycin (78.2%). Y. pseudotuberculosis strains were sensitive to all the antimicrobials tested, i.e. amoxicillin, amoxicillin/clavulanic acid, azithromycin, cephalothin, cefoxitin, ceftriaxone, ciprofloxacin, nalidixic acid, sulphonamide, tetracycline and ticarcillin. The study shows that Italian fattening pigs are frequently infected with human pathogenic Y. enterocolitica 4/O:3. Although the isolation rate is slightly lower than in other European countries, the serological test demonstrates that the infection is widespread among pig population. In fact, seroprevalence is similar to other EU countries. The detection of Y. pseudotuberculosis serotypes O:1 and O:3 in pig tonsils is of concern. Since tonsils may represent a contamination source for pig meat at slaughter, further studies regarding human infections by both microbial species are strongly recommended. PMID- 27500660 TI - Anxiety and quality of life after first-trimester termination of pregnancy: a prospective study. AB - INTRODUCTION: Possible effects of termination of pregnancy (TOP) on mental health are a matter of debate. MATERIAL AND METHODS: We assessed anxiety and quality of life during a one-year follow up after first-trimester TOP using the State-Trait Anxiety Inventory (STAI) Scale and EuroQoL Quality of Life Questionnaire (EQ-5D, EQ-VAS) in 742 women participating in a randomized controlled trial on early provision of intrauterine contraception. The measurements were performed before TOP, at 3 months and 1 year after TOP. Inclusion criteria were age >=18 years, residence in Helsinki, duration of gestation <12 weeks, non-medical indication for TOP, and approval of intrauterine contraception. The trial was registered with Clinical Trials [NCT01223521]. RESULTS: When compared with baseline, the overall anxiety level was significantly lower and quality of life higher at 3 months and at 1 year. Reduction of anxiety and improvement of quality of life was especially evident (p < 0.001) in the 58% of women reporting clinically relevant anxiety at baseline. High levels of anxiety at baseline, history of psychiatric morbidity and smoking predicted significantly greater risk of poorer quality of life and elevated level of anxiety during the follow up. CONCLUSIONS: TOP is associated with a significant overall reduction of anxiety and an improvement of quality of life among women undergoing it for non-medical indications. High baseline anxiety, history of psychiatric morbidity and smoking are risk factors of persistently high levels of anxiety and poor quality of life after an induced abortion. These data are important when designing and providing post-abortion care. PMID- 27500661 TI - Multimorbidity and mortality in older adults: A systematic review and meta analysis. AB - OBJECTIVE: To review literature and provide a pooled effect for the association between multimorbidity and mortality in older adults. METHODS: A systematic review was performed of articles held on the PUBMED database published up until January 2015. Studies which used different diseases and other conditions to define frailty, evaluated multimorbidity related only to mental health or which presented disease homogeneity were not included. A meta-analysis using random effect to obtain a pooled effect of multimorbidity on mortality in older adults was conducted only with studies which reported hazard ratio (HR). Stratified analysis and univariate meta-regression were performed to evaluate sources of heterogeneity. RESULTS: Out of 5806 identified articles, 26 were included in meta analysis. Overall, positive association between multimorbidity and mortality [HR: 1.44 (95%CI: 1.34; 1.55)] was detected. The number of morbidities was positively related to risk of death [HR: 1.20 (95%CI: 1.10; 1.30)]. Compared to individuals without multimorbidity, the risk of death was 1.73 (95%CI: 1.41; 2.13) and 2.72 (95%CI: 1.81; 4.08) for people with 2 or more and 3 or more morbidities, respectively. Heterogeneity between studies was high (96.5%). The sample, adjustment and follow-up modified the associations. Only nine estimates performed adjustment which included demographic, socioeconomic and behaviour variables. Disabilities appear to mediate the effect of multimorbidity on mortality. CONCLUSIONS: Multimorbidity was associated with an increase in risk of death. Multimorbidity measurement standardization is needed to produce more comparable estimates. Adjusted analysis which includes potential confounders might contribute to better understanding of causal relationships between multimorbidity and mortality. PMID- 27500662 TI - Growth and Tunable Surface Wettability of Vertical MoS2 Layers for Improved Hydrogen Evolution Reactions. AB - Layered materials, especially the transition metal dichalcogenides (TMDs), are of interest for a broad range of applications. Among the class of TMDs, molybdenum disulfide (MoS2) is perhaps the most studied because of its natural abundance and use in optoelectronics, energy storage and energy conversion applications. Understanding the fundamental structure-property relations is key for tailoring the enhancement in the above-mentioned applications. Here, we report a controlled powder vaporization synthesis of MoS2 flower-like structures consisting of vertically grown layers of MoS2 exhibiting exposed edges. This growth is readily achievable on multiple substrates, such as graphite, silicon, and silicon dioxide. The resulting MoS2 flowers are highly crystalline and stoichiometric. Further observations using contact angle indicate that MoS2 flowers exhibit the highest reported contact angle of ~160 +/- 10 degrees , making the material super hydrophobic. This surface wettability was further tuned by changing the edge chemistry of the MoS2 flowers using an ozone etching treatment. Hydrogen evolution reaction (HER) measurements indicate that the surface treated with UV ozone showed a reduction in the Tafel slope from 185 to 54 mV/dec, suggesting an increase in the amount of reactive surface to generate hydrogen. PMID- 27500663 TI - Predicting Financial Distress and Closure in Rural Hospitals. AB - PURPOSE: Annual rates of rural hospital closure have been increasing since 2010, and hospitals that close have poor financial performance relative to those that remain open. This study develops and validates a latent index of financial distress to forecast the probability of financial distress and closure within 2 years for rural hospitals. METHODS: Hospital and community characteristics are used to predict the risk of financial distress 2 years in the future. Financial and community data were drawn for 2,466 rural hospitals from 2000 through 2013. We tested and validated a model predicting a latent index of financial distress (FDI), measured by unprofitability, equity decline, insolvency, and closure. Using the predicted FDI score, hospitals are assigned to high, medium-high, medium-low, and low risk of financial distress for use by practitioners. FINDINGS: The FDI forecasts 8.01% of rural hospitals to be at high risk of financial distress in 2015, 16.3% as mid-high, 46.8% as mid-low, and 28.9% as low risk. The rate of closure for hospitals in the high-risk category is 4 times the rate in the mid-high category and 28 times that in the mid-low category. The ability of the FDI to discriminate hospitals experiencing financial distress is supported by a c-statistic of .74 in a validation sample. CONCLUSION: This methodology offers improved specificity and predictive power relative to existing measures of financial distress applied to rural hospitals. This risk assessment tool may inform programs at the federal, state, and local levels that provide funding or support to rural hospitals. PMID- 27500664 TI - Masting behaviour in a Mediterranean pine tree alters seed predator selection on reproductive output. AB - Context-dependency in species interactions is widespread and can produce concomitant patterns of context-dependent selection. Masting (synchronous production of large seed crops at irregular intervals by a plant population) has been shown to reduce seed predation through satiation (reduction in rates of seed predation with increasing seed cone output) and thus represents an important source of context-dependency in plant-animal interactions. However, the evolutionary consequences of such dynamics are not well understood. Here we describe masting behaviour in a Mediterranean model pine species (Pinus pinaster) and present a test of the effects of masting on selection by seed predators on reproductive output. We predicted that masting, by enhancing seed predator satiation, could in turn strengthen positive selection by seed predators for larger cone output. For this we collected six-year data (spanning one mast year and five non-mast years) on seed cone production and seed cone predation rates in a forest genetic trial composed by 116 P. pinaster genotypes. Following our prediction, we found stronger seed predator satiation during the masting year, which in turn led to stronger seed predator selection for increased cone production relative to non-masting years. These findings provide evidence that masting can alter the evolutionary outcome of plant-seed predator interactions. More broadly, our findings highlight that changes in consumer responses to resource abundance represent a widespread mechanism for predicting and understanding context dependency in plant-consumer evolutionary dynamics. PMID- 27500665 TI - A comparison of techniques for studying oogenesis in the European eel Anguilla anguilla. AB - A multi-technique approach was used to study the changes occurring in European eel Anguilla anguilla ovaries during hormonally-induced vitellogenesis. Aside from classic techniques used to monitor the vitellogenic process, such as ovary histology, fat content analysis, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and vitellogenin enzyme linked immunosorbent assay (ELISA), a new technique, Fourier-transform infrared (FT-IR) microspectroscopy, was used to analyse A. anguilla ovaries. The results from the different techniques provided different ways of approaching the same process. Although it is considered a time consuming approach, of all the employed techniques, histology provided the most direct evidences about vitellogenesis. SDS-PAGE and ELISA were also useful for studying vitellogenesis, whereas fat analysis cannot be used for this purpose. The FT-IR analysis provided a representative IR spectrum for each ovarian stage (previtellogenic stage, early vitellogenic stage, mid-vitellogenic stage and late vitellogenic stage), demonstrating that it is a valid method able to illustrate the distribution of the oocytes within the ovary slices. The chemical maps obtained confirmed changes in lipid concentrations and revealed their distribution within the oocytes at different maturational stages. When the results and the accuracy of the FT-IR analysis were compared with those of the traditional techniques commonly used to establish the vitellogenic stage, it became evident that FT-IR is a useful and reliable tool, with many advantages, including the fact that it requires little biological material, the costs involved are low, analysis times are short and last but not least, the fact that it offers the possibility of simultaneously analysing various biocomponents of the same oocyte. PMID- 27500667 TI - High-Performance Photovoltaic Polymers Employing Symmetry-Breaking Building Blocks. AB - Two 1D-2D asymmetric benzodithiophenes (BDTs) as donor building blocks are designed and synthesized, combining the advantages of both 1D and 2D symmetric BDTs. The photovoltaic properties of the asymmetric BDT-based polymers are improved greatly in comparison with corresponding symmetric BDT-based polymers. This work provides a new approach to design prospective organic optoelectronic materials employing the symmetry-breaking strategy. PMID- 27500666 TI - Impact of Massachusetts Health Reform on Inpatient Care Use: Was the Safety-Net Experience Different Than in the Non-Safety-Net? AB - OBJECTIVE: Most inpatient care for the uninsured and other vulnerable subpopulations occurs in safety-net hospitals. As insurance expansion increases the choice of hospitals for the previously uninsured, we examined if Massachusetts health reform was associated with shifts in the volume of inpatient care from safety-net to non-safety-net hospitals overall, or among other vulnerable sociodemographic (racial/ethnic minority, low socioeconomic status, high uninsured rate area) and clinical subpopulations (emergent status, diagnosis). DATA SOURCES/STUDY SETTING: Discharge records for adults discharged from all nonfederal acute care hospitals in Massachusetts, New Jersey, New York, and Pennsylvania 2004-2010. STUDY DESIGN: Using a difference-in-differences design, we compared pre-/post-reform changes in safety-net and non-safety-net hospital discharge outcomes in Massachusetts among adults 18-64 with corresponding changes in comparisons states with no reform, overall, and by subpopulations. PRINCIPAL FINDINGS: Reform was not associated with changes in inpatient care use at safety-net and non-safety-net hospitals across all discharges or in most subpopulations examined. CONCLUSIONS: Demand for inpatient care at safety-net hospitals may not decrease following insurance expansion. Whether this is due to other access barriers or patient preference needs to be explored. PMID- 27500668 TI - Influence of insurance status on survival of adults with glioblastoma multiforme: A population-based study. AB - BACKGROUND: To the authors' knowledge, the impact of insurance status on the survival time of patients with glioblastoma multiforme (GBM) has not been fully understood. The objective of the current study was to clarify the association between insurance status and survival of patients with GBM by analyzing population-based data. METHODS: The authors performed a cohort study using data from the Surveillance, Epidemiology, and End Results program. They included adult patients (aged >=18 years) with GBM as their primary diagnosis from the years 2007 to 2012. Patients without information regarding insurance status were excluded. A survival analysis between insurance status and GBM-related death was performed using an accelerated failure time model. Demographic and clinical variables were included to adjust for confounding effects. RESULTS: Among the 13,665 adult patients in the study cohort, 558 (4.1%) were uninsured, 1516 (11.1%) had Medicaid coverage, and 11,591 (84.8%) had non-Medicaid insurance. Compared with patients who were uninsured, insured patients were more likely to be older, female, white, married, and with a smaller tumor size at diagnosis. Accelerated failure time analysis demonstrated that older age (hazard ratio [HR], 1.04; P<.001), male sex (HR, 1.08; P<.001), large tumor size at the time of diagnosis (HR, 1.26; P<.001), uninsured status (HR, 1.14; P =.018), and Medicaid insurance (HR, 1.10; P =.006) were independent risk factors for shorter survival among patients with GBM, whereas radiotherapy (HR, 0.40; P<.001) and married status (HR, 0.86; P<.001) indicated a better outcome. The authors discovered an overall yearly progressive improvement in survival in patients with non-Medicaid insurance who were diagnosed from 2007 through 2011 (P =.015), but not in uninsured or Medicaid-insured patients. CONCLUSIONS: Variations existed in insurance status within the GBM population. Uninsured status and Medicaid insurance suggested shorter survival compared with non-Medicaid insurance among a population of patients with GBM. Cancer 2016;122:3157-65. (c) 2016 American Cancer Society. PMID- 27500669 TI - Jasmonate-mediated stomatal closure under elevated CO2 revealed by time-resolved metabolomics. AB - Foliar stomatal movements are critical for regulating plant water loss and gas exchange. Elevated carbon dioxide (CO2 ) levels are known to induce stomatal closure. However, the current knowledge on CO2 signal transduction in stomatal guard cells is limited. Here we report metabolomic responses of Brassica napus guard cells to elevated CO2 using three hyphenated metabolomics platforms: gas chromatography-mass spectrometry (MS); liquid chromatography (LC)-multiple reaction monitoring-MS; and ultra-high-performance LC-quadrupole time-of-flight MS. A total of 358 metabolites from guard cells were quantified in a time-course response to elevated CO2 level. Most metabolites increased under elevated CO2 , showing the most significant differences at 10 min. In addition, reactive oxygen species production increased and stomatal aperture decreased with time. Major alterations in flavonoid, organic acid, sugar, fatty acid, phenylpropanoid and amino acid metabolic pathways indicated changes in both primary and specialized metabolic pathways in guard cells. Most interestingly, the jasmonic acid (JA) biosynthesis pathway was significantly altered in the course of elevated CO2 treatment. Together with results obtained from JA biosynthesis and signaling mutants as well as CO2 signaling mutants, we discovered that CO2 -induced stomatal closure is mediated by JA signaling. PMID- 27500670 TI - An updated systematic review of epidemiological evidence on hormonal contraceptive methods and HIV acquisition in women. AB - OBJECTIVE AND DESIGN: Some studies suggest that specific hormonal contraceptive methods [particularly depot medroxyprogesterone acetate (DMPA)] may increase women's HIV acquisition risk. We updated a systematic review to incorporate recent epidemiological data. METHODS: We searched for articles published between 15 January 2014 and 15 January 2016 and hand-searched reference lists. We identified longitudinal studies comparing users of a specific hormonal contraceptive method against either nonusers of hormonal contraception or users of another specific hormonal contraceptive method. We added newly identified studies to those in the previous review, assessed study quality, created forest plots to display results, and conducted a meta-analysis for data on DMPA versus non-use of hormonal contraception. RESULTS: We identified 10 new reports of which five were considered 'unlikely to inform the primary question'. We focus on the other five reports, along with nine from the previous review, which were considered 'informative but with important limitations'. The preponderance of data for oral contraceptive pills, injectable norethisterone enanthate, and levonorgestrel implants do not suggest an association with HIV acquisition, though data for implants are limited. The new, higher quality studies on DMPA (or nondisaggregated injectables), which had mixed results in terms of statistical significance, had hazard ratios between 1.2 and 1.7, consistent with our meta analytic estimate for all higher quality studies of hazard ratio 1.4. CONCLUSION: Although confounding in these observational data cannot be excluded, new information increases concerns about DMPA and HIV acquisition risk in women. If the association is causal, the magnitude of effect is likely hazard ratio 1.5 or less. Data for other hormonal contraceptive methods, including norethisterone enanthate, are largely reassuring. PMID- 27500671 TI - A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging. AB - Age-related diseases are becoming increasingly prevalent and the burden continues to grow as our population ages. Effective treatments are necessary to lessen the impact of debilitating conditions but remain elusive in many cases. Only by understanding the causes and pathology of diseases associated with aging, can scientists begin to identify potential therapeutic targets and develop strategies for intervention. The most common age-related conditions are neurodegenerative disorders such as Parkinson's disease and blindness. Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Genome wide association studies have previously identified loci that are associated with increased susceptibility to this disease and identified two regions of interest: complement factor H (CFH) and the 10q26 locus, where the age-related maculopathy susceptibility 2 (ARMS2) and high-temperature requirement factor A1 (HtrA1) genes are located. CFH acts as a negative regulator of the alternative pathway (AP) of the complement system while HtrA1 is an extracellular serine protease. ARMS2 is located upstream of HtrA1 in the primate genome, although the gene is absent in mice. To study the effects of these genes, humanized knock-in mouse lines of Cfh and ARMS2, knockouts of Cfh, HtrA1, HtrA2, HtrA3 and HtrA4 as well as a conditional neural deletion of HtrA2 were generated. Of all the genetically engineered mice produced only mice lacking HtrA2, either systemically or in neural tissues, displayed clear phenotypes. In order to examine these mice thoroughly and systematically, an initial phenotyping schedule was established, consisting of a series of tests related to two main diseases of interest: AMD and Parkinson's. Genetically modified mice can be subjected to appropriate experiments to identify phenotypes that may be related to the associated diseases in humans. A phenotyping regimen with a mitochondrial focus is presented here alongside representative results from the tests of interest. PMID- 27500672 TI - [The application of the system of "reminder stickers" for the rehabilitation programs with the use of behavioural therapy for the patients presenting with anxiety disorders]. AB - This article was designed to report the results of research on the effectiveness of the new original "reminder stickers" technique proposed by the authors for the management of the patients undergoing rehabilitation based on behavioral therapy. The essence of this technique consists of providing the patients with systematic reminders of the need to implement skills aimed at coping with maladaptive sensations that accompany anxiety disorders. AIM: The objective of the present study was to evaluate the effectiveness of using the "reminder stickers" technique for the formation of stable responses to the correction of the target clinical symptoms. PATIENTS AND METHODS: The study involved 118 patients suffering from anxiety disorders allocated to two groups for comparison. Group 1 was comprised of the patients (n=76) given the reminders while group 2 contained those (n=42) not included in the system of "reminder stickers". The difference between the parameters of interest in the two groups was estimated with the use of Mann-Whitney and Kolmogorov-Smirnov tests. RESULTS: The analysis of diary records of the patients was used to evaluate the frequency of occurrence of maladaptive sensations that required the application of the appropriate behavioural skills and the frequency of the missed or delayed responses as well as the level of subjective satisfaction of the patients with the stability of the acquired skills. It was shown that the patients given "reminder stickers" significantly more frequently reported situations that required the application of the appropriate skills within the first week after the initiation of monitoring than the patients of group 2 (r<0,0001). The frequency of the missed or delayed responses in these patients was significantly lower than in group 2 (r<0,0001) whereas the degree of subjective satisfaction with the stability of the acquired skills was much higher (r<0,0001). These differences persisted during week 2 after the onset of monitoring when the frequency of maladaptive sensations that required the application of the previously formed behavioural skills of therapeutic significance in the patients given "reminder stickers" remained lower than in the patients to whom no such "remainders" were provided (r=0,001). The frequency of the missed or delayed responses in these patients decreased significantly in comparison with that in group 2 (r<0,0001),) while the degree of subjective satisfaction of the patients with the stability of the acquired skills further increased (r<0,0001). CONCLUSION: The results of the study indicate that inclusion of "reminder stickers" in the structure of cognitive-behavioral therapy at the stages of formation of the skills needed to cope with maladaptive sensations enhances the ability of the patients presenting with anxiety disorders to much more often timely identify situations that require the use of the appropriate behavioural skills and to apply them. It is concluded that the application of the original "reminder stickers" technique ensures an adequate response of the patients to maladaptive sensations that accompany anxiety disorders. PMID- 27500673 TI - [The analysis of compliance of pharmacotherapy of patients with myocardial infarction to the principles evidence-based medicine at the stage of rehabilitation in modern conditions]. AB - GOAL: Acute myocardial infarction is one of the causal factors of society and economic losses of companionship. Success in the treatment of acute myocardial infarction raises questions on the effective rehabilitation of the first places. New methods, clinical guidelines and standards have been introduced into clinical practice. However, the effectiveness of rehabilitation in the Russian Federation lower than developed countries. The present study was aimed to improve rehabilitation care to patients after acute myocardial infarction. Analysis of the effectiveness of rehabilitation and pharmacoepidemiological studies was conducted on the basis of a medical spa facility in 2006 and 2009. MATERIAL AND METHODS: Experts form and database were developed to achieve the objectives. Quantitative assessments were carried out on the basis of the developed quality indicators. We used pharmacoepidemiological and statistical methods in the study. RESULTS: Myocardial infarction was often combined with hypertension (73.8% and 61.9%) and chronic heart failure (87.6% and 85.8%). Patients had a high prevalence of risk factors: smoking (46.1% and 42.3%), overweight (53.8% and 67.2%), dyslipidemia (44.6% and 66.1%) in 2006 and 2009, respectively. Rehabilitation includes physical exercise, mineral baths, swimming pool. The average number of drugs of rehabilitation stage was 4,46+/-0,12 and 4,11+/-0,11. Beta-blockers are indicated for all patients after acute myocardial infarction, and they were prescribed in 86.1% and 90.1% of cases. Drugs affecting renin angiotensin system were in second place frequency of prescribing. These drugs are prescribed in 67.6% and 41.7% patients. The frequency of prescribing of statins increased by 5.8 times from 2006 to 2009 and reached 81.32%. CONCLUSION: Rehabilitation and pharmacotherapy in patients after acute myocardial infarction corresponds to the principle evidence-based medicine. However, the list of use drugs was narrow, and the doses were lower than recommended by current clinical guidelines. These facts may indicate a deficiency of awareness of doctors around the characteristics of drug usage. Standards of health - resort treatment and rehabilitation of patients after myocardial infarction is limited and their revision is required based on existing clinical guidelines and evidence-based medicine. PMID- 27500674 TI - [The systemic approach to the health protection in the workers of industrial enterprises]. AB - This paper presents the results of the systemic approach to the protection of health and prophylaxis of disability in the workers of industrial enterprises. The leading role in the technologies of rehabilitation (both short-term and long term one) is played by the natural and physical therapeutic factors. The priority in the implementation of the therapeutic and health-promoting measures is given to the treatment based on the spa and health resort facilities as well as the factory health centers. PMID- 27500675 TI - [The substantiation of the use of high-frequency intrapulmonary ventilation in the patients presenting with chronic obstructive pulmonary disease at the spa and health resort stage of rehabilitation]. AB - The importance of the development of the new methods for the rehabilitation of the patients presenting with chronic obstructive pulmonary disease under conditions of the spa and health resort-based treatment arises from the high prevalence and the progressive character of this disease, poor quality of the patients' life, great economic losses due to the reduction of the working capacity of the patients, and the high cost of COPD treatment. AIM: The objective of the present study was to substantiate the advisability of inclusion of high frequency intrapulmonary ventilation in the program of the therapeutic and rehabilitative treatment of the patients with COPD based at a spa and health resort facility. PATIENTS AND METHODS: The analysis of the results of examination and rehabilitative treatment included 49 patients treated at the "Belokurikha" health resort (14 women and 35 men presenting with stage 1 and 2 COPD). The patients were divided into two groups. The main one included 23 patients while the group of comparison consisted of 26 patients. Those of the main group were given the treatment that included the mineral water baths, inhalations, exercise therapy for the training of skeletal muscles, manual massage, high-frequency intrapulmonary ventilation, intake of extract maral root (Rhaponticum carthamoides) and the "Yantar antiox" (amber antiox) preparation. The patients of the comparison group received the same rehabilitative treatment but without high frequency intrapulmonary ventilation. The effectiveness of the rehabilitative measures was comprehensively estimated from the dynamics of the clinical data, indices of the inflammatory activity, the results of spirography and 6 minute walking test. RESULTS: It has been shown that the introduction of high-frequency intrapulmonary ventilation into the spa and health resort-based rehabilitative program facilitates the elimination of clinical manifestation of the disease, promotes recovery of the external respiration function due to sputum recruiting and stimulation of mucociliary clearance that in turn decreases the activity of the inflammatory processes. Simultaneously, the thoracic mobility and physical efficiency of the patients increased. The overall result of the treatment was the enhanced quality of rehabilitation of the patients suffering COPD within 14-16 days of their stay at the health resort with excellent tolerability of the proposed therapeutic modality. PMID- 27500676 TI - [Analysis of the effectiveness of the spa and health resort-based treatment of the patients presenting with broncho-pulmonary pathology at the southern coast of the Crimea depending on the period of flowering of Mediterranean Cypress (Cupressus sempervirens)]. AB - AIM: The objective of the present study was to evaluate the influence of pollen of Mediterranean Cypress (Cupressus sempervirens) on the effectiveness of the spa and health resort-based treatment (SHRT) of the patients with broncho-pulmonary pathology at the southern coast of the Crimea (SCC). MATERIAL AND METHODS: This article presents the results of the analysis of the data on 122 patients presenting with broncho-pulmonary pathology who received SHRT under the conditions of the Southern Coast of the Crimea. Fifty one (41.8%) of these patients suffered from chronic obstructive pulmonary disease and 71 (58.2%) ones had bronchial asthma. The whole group was comprised of 44 men (36.1%) and 78 women (63.9%). The average (median) age of the patients was 55.8 years. All the participants of the study underwent the comprehensive examination including the general medical and physical examination, complete blood count, the study of sputum cytology and immunological properties of blood including the standard characteristics, IgE and lysozyme levels), evaluation of the respiratory and locomotor (physical) functions with the use of the 6-minute walking test. RESULTS: The aeropollenological study of the aerial environment of the southern coast of the Crimea in the region of Yalta showed that the "bloom" of the Mediterranean Cypress occurs during the period from February till April inclusive. The highest concentrations of cypress pollen are observed in March and early April. The overall effectiveness of SHRT for the patients with broncho pulmonary pathology arriving for the treatment at the southern coast of the Crimea from other Crimean localities does not depend on the period of "flowering" (the presence of pollen in the air) of the Mediterranean Cypress. In these patients, the termination of the spa and health resort-based treatment during the "flowering" of the Mediterranean Cypress resulted in nothing more than a strained adaptive response manifested as the altered blood leukocyte count. Such reaction is considered to be a natural consequence of intake of antigenic substances into the human body. PMID- 27500677 TI - [The contingency of the therapeutic effectiveness with the peculiarities of the non-pharmacological treatment of the patients presenting with chronic cholecystitis]. AB - The elaboration of new technologies for the medical rehabilitation of the patients presenting with chronic cholecystitis in combination with chronic opisthorchiasis is a topical problem facing modern clinical gastroenterology. The application of up-to-date non-pharmacological therapeutic modalities, such as ultrahigh-frequency (UHF) therapy concomitantly with group chronophysiotherapy makes it possible to significantly improve the final outcome of the treatment. The results of clinical studies give evidence of the favourable influence of the combined chronorehabilitative treatment including UHF therapy on the characteristics of the functional state of the biliary-hepatic system and of the organism as a whole. The positive dynamics of these characteristics is suggestive of the high (up to 87,5%) therapeutic effectiveness of the proposed treatment. The investigations into the relationship between this effect and the peculiarities of the combined therapeutic modalities have demonstrated their correlation (chi2=104,13; p=0,0001; V-Kramer's coefficient =0,35) and showed that the use of combined chronorehabilitation including UHF therapy based on the application of phone resonance radiation guarantees (and is a predictor of) high therapeutic effect (percent concordance =95,6%; standard coefficient=2,13; p=0,001) of the treatment of the patients with chronic cholecystitis in combination with chronic opisthorchiasis. The statistical analysis of the results of application of the modern non-pharmacological therapeutic modalities and the chronobiological approach for the purpose of the combined treatment of patients presenting with chronic cholecystitis in combination with opisthorchiasis with the use of contingency table and logit regression, allowed not only to estimate the interdependence and interrelation between the characteristics of interest but also to reveal predictors of therapeutic effectiveness. These findings are of great practical importance since they can be used for the choice of therapeutic strategies for the management of this category of patients. PMID- 27500678 TI - [The prospects for the application of the natural and preformed therapeutic factors in the treatment of non-alcoholic fatty liver disease]. AB - Non-alcoholic fatty liver disease (NAFLD) is one of the most widespread diffuse liver pathologies among the patients over 40 years of age. The available algorithms for the pharmacological treatment of this disease do not always ensure the desirable results which makes their further development and improvement with the use of natural and preformed physical factors an important priority. AIM: The objective of the present study was to evaluate the effectiveness of the internal course of mineral waters of different balneological types and a bischofite aqueous solution for the treatment of the patients presenting with NAFLD. PATIENTS AND METHODS: A total of 120 patients with non-alcoholic fatty liver disease were examined and treated with the use of the anamnestic, clinical, biochemical and immunochemical methods as well as sonographic studies of the digestive system and the statistical analysis. RESULTS: The data on the effectiveness of the use of mineral waters of different balneological types and a bischofite aqueous solution in the treatment of NAFLD are presented. It is shown that the use of an aqueous solution of bischofite improves the clinical course of the underlying disease (p<0.05), concomitant diseases of the biliary tract (p<0.02) and irritable bowl syndrome complicated by constipation (p<0.003); also, it improves the functional state of the liver and the blood lipid profile (p<0.02) and significantly reduces insulin resistance (p<0.01), primarily due to the reduction of hyperinsulinemia (p<0.01). Using the mineral waters with the predominance of sulfates can improve the clinical course of liver diseases (p<0.01), biliary tract and intestines (p<0.02), normalize the functional state of the liver including that in the patients with non-alcoholic steatohepatitis (p<0.05,) significantly improve the blood lipid profile (p<0.02) due to the substantial improvement of disordered carbohydrate metabolism including that in the patients suffering from type 2 diabetes mellitus (p<0.05). The application of mineral waters with the elevated content of hydrocarbons improves the clinical course of NAFLD with the concomitant esophagogastroduodenal pathology (p<0.001) and simultaneously reduces the severity of insulin resistance due to the lowering of the level of hyperinsulinemia (p<0.001). Moreover, the mineral water-based therapy improves tolerance to carbohydrates, in the first place in the patients with type 2 diabetes mellitus (p<0.01), and restores the background lipid profile (p<0.05). CONCLUSION: The studies has demonstrated the high efficiency of the non pharmacological treatment resulting in the multifaceted and oppositely directional influence on the patients presenting with non-alcoholic fatty liver disease. The possibility of the differentiated application of mineral water and an aqueous solution of bischofite for the treatment of this pathology is confirmed depending on the stage of the disease, the severity of metabolic disorders, the presence of a concomitant pathology of the digestive system, type 2 diabetes mellitus, and hypertension. PMID- 27500680 TI - [The investigation of immunological effects of the new balneotherapeutic preparation glinofir used for the treatment of adjuvant arthritis]. AB - AIM: The objective of the present study was to investigate the influence of a course of application of the modified natural factors on the immunological mechanisms of regulation under experimental conditions with special reference to the application of the natural yellow clay, the clay from the Novo-Pyatigorsk quarry (the lake Tambokan) and of the new balneotherapeutic preparation glinofir based on this modified clay and designed for the treatment of adjuvant arthritis (AA). MATERIAL AND METHODS: The study of anti-inflammatory activity of the externally applied balneomedicines was carried out with the use of an animal model of adjuvant arthritis. The course of applications started 3 days prior to the initiation of AA and was terminated on the 24th day of the experimental disease. The action of three balneotherapeutic preparations (Tambukan mud, yellow clay, and modified clay in the form of Glinofir) was compared after they were heated to 42 degrees C and applied to the animals' limbs for 15-20 minutes every second and third days. The experiments were performed on Wistar rats (n=59) divided into five groups. Group 1 was comprised of 9 healthy animals that served as controls. The animals of group 2 (n=10) presented with untreated experimentally-induced adjuvant arthritis, those of Group 3 (n=10) had model AA treated by a course of application of the Tambukan mud. The animals of group 4 (n=10) had model AA and were treated by the application of the yellow clay and those of Group 5 (n=10) with model of AA received a course of application of the modified clay. RESULTS: On day 37 after the induction of adjuvant arthritis, the animals developed leukocytosis (white blood cell count in the blood was 1.5 times higher than in the control group) and alterations in the composition of the lymphocyte population, viz. B-lymphocytes increased 2-2.5 times (p<0,02) while T lymphocytes decreased (p<0,05). A course of glinofir application contributed to the restoration of the T-cytotoxic cell population (p<0,2) and influenced the regulation of pathological immune complexes (PIC) as confirmed the negative correlation between the PIC level and the absolute number of T-cytotoxic cells (r=-0,8, p<0,01). The chronic stage of AA was associated with a two-fold increase in the absorptive capacity of neutrophils. The treatment with the Tambukan mud and glinofir restored the phagocytic function of neutrophils and simultaneously reduced the blood leukocyte reaction. CONCLUSION: The anti-inflammatory action of the Tambukan mud and glinofir manifests itself in the unidirectional changes of dynamics of the characteristics of cellular and humoral immunity. PMID- 27500679 TI - [The application of the preformed physical factors for the combined treatment of the patients presenting with chronic vesiculitis]. AB - The problem of the development of the new efficient methods for the treatment of the patients presenting with chronic bacterial vesiculitis (CBV) is currently considered among the important priorities. AIM: The objective of the present study was to provide a scientifically sound substantiation for the application of sinusoidal modulated currents (SMC), magnetic fields, and laser radiation in the combined treatment of the patients with CBV. PATIENTS AND METHODS: A total of 121 patients presenting with chronic bacterial vesiculitis were examined and treated during the latent phase of the inflammatory process. They were randomly divided into three groups. Group 1 (main) was comprised of 40 patients treated, in addition to basal pharmacotherapy, by supravascular contact laser irradiation of the cubital vein area followed after 2-3 hours by the application of sinusoidal modulated currents to the pubosacral region. Group 2 included 41patents given, besides basal pharmacotherapy, laser therapy in the same regimen as in group 1 supplemented after 2-3 hours by abdominal magnetic therapy. Group 3 (control) received traditional pharmacotherapy in the combination with antibacterial and anti-inflammatory medicines. RESULTS: It was demonstrated that the patients of group 2 exhibited the most pronounced positive dynamics of the clinical signs and symptoms estimated from the total National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI) and of the characteristics of the quality of life evaluated based on the QLS scale. The patients of the two former groups experienced a more conspicuous decrease in the activity of the inflammatory process in seminal vesicles, restoration of their structural and anatomical features (as shown by the transrectal ultrasound study), improvement of testosterone metabolism, and normalization of the spermogram characteristics in comparison with controls. The analysis of the spermograms revealed the tendency toward the increase in the number of actively motile spermatozoa only in the patients of group 2. The combined treatment of the patients of the two former groups resulted in the decrease of the level of sex hormone-binding globulin and the increase of the free androgen index. CONCLUSION: The results of the study indicate that the application of the preformed physical factors for the treatment of the patients presenting with chronic bacterial vesiculitis enhances the effectiveness of pharmacotherapy and decreases both the frequency and the duration of relapses of the disease. PMID- 27500681 TI - [The natural therapeutic resources of Russia: the topical problems]. AB - Mineral water, therapeutic peloids, favorable landscape and climatic conditions make up the main basis for the creation and development of the health resort business. Mineral water and therapeutic peloids are mineral resources, their prospecting, discovery, exploration and stock assessment of the responsibility of the Geological Survey of the country while the exploration and practical exploitation of the natural medicinal resources is the prerogative of the users of subsurface resources. At present, there are over 1200 deposits of mineral waters as well as more than 260 sources of therapeutic peloids at the territory of the Russian Federation; the include almost all hydrochemical species and types known and exploited in the world's practice The overall picture of the distribution of the potential and developed deposits of mineral waters and therapeutic peloids of the territory of this country is highly non-uniform and depends on the extent of the economic development of different regions, their geographical and climatic conditions as well as the state and availability of the spa and health resort infrastructure. The natural therapeutic resources, territories suitable for the organization and realization of health promoting activities, setting up new spa and health resort facilities are highly vulnerable to any external impact. We possess the scientifically grounded and practice proven methods for the search, prospecting, practical development, and medical utilization of various natural therapeutic resources as well as technologies for their conservation, restoration, and protection from damages and overexploitation. The rational use and development of the territories promising for the extension of health resort business imply the necessity of the systemic approach in a consistent stage by stage manner based of the reliable prognoses. PMID- 27500682 TI - Key factors of scanning a plant virus with AFM in air and aqueous solution. AB - For tobacco mosaic virus (TMV) as a model virus, this article shows typical issues of scanning soft biological matter by atomic force microscopy (AFM). TMV adsorbed on chemically different flat surfaces, gold, mica, and APDMES functionalized silicon, is studied in air and aqueous environment. In air, the TMV particles arrangement shows some variety, depending on the substrate. The height of TMV is reduced to 13.7, 15.8, and 15.6 nm, for gold, APDMES, and mica, respectively while the width is about ~30 nm due to the influence of the tip radius. In aqueous solution, the surface charges of the virus and the solid support play an important role in the virus adsorption process. While deposition on negatively charged mica is favored only at low pH values, it is shown that positively charged APDMES functionalized silicon can be a suitable substrate to work with at neutral pHs. The effects of cantilever oscillation's free amplitude (A0 ) and the amplitude set-point (A) are also assessed here. While high A0 prompt reversible deformation of TMV in measurements performed in air, irreversible damage of the virus in liquid conditions (water) is observed using stiff cantilevers (0.35 N m-1 ) and high A0 (81 nm), leading to a 6 nm reduction in the height of TMV after the first scan. Finally, low values of the amplitude set-point (A/A0 = 0.3), which means applying higher forces to the sample, also brings the damage of TMV virus assemblies, reducing its monolayer roughness to 0.3 nm. Microsc. Res. Tech. 80:18-29, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27500683 TI - Complex Interaction Between Diphenylcyclopropenone and Immune Responses in Alopecia Areata. PMID- 27500684 TI - Renovation of Optically Active Phenanthrolines as Powerful Chiral Ligands for Versatile Asymmetric Metal Catalysis. AB - In the field of asymmetric synthesis, the development of new chiral ligands has been regarded as an attractive challenge for decades. Novel chiral ligands can often have a great impact on synthetic protocols. In this context, we are currently interested in the application of 1,10-phenanthroline (phen) as an entirely new class of chiral ligand. To handle this issue, we designed a chiral phen ligand that provides the N,N,O-tridentate coordination of the phen moiety and an additional phenolic hydroxyl group. As phen possesses greater coordination ability with various ions, our chiral phen ligand would be valuable as one of the "privileged" chiral ligands applied to a broad range of metal catalysts and new reactions. This account summarizes the results of the application of the chiral phen ligand to various kinds of metal catalysis. PMID- 27500685 TI - An uncommon cause of erythema nodosum. PMID- 27500686 TI - Steady-State Spectroscopic Analysis of Proton-Dependent Electron Transfer on Pyrazine-Appended Metal Dithiolenes [Ni(pdt)2], [Pd(pdt)2], and [Pt(pdt)2] (pdt = 2,3-Pyrazinedithiol). AB - We report the structural, electronic, and acid/base properties of a series of ML2 metal dithiolene complexes, where M = Ni, Pd, Pt and L = 2,3-pyrazinedithiol. These complexes are non-innocent and possess strong electronic coupling between ligands across the metal center. The electronic coupling can be readily quantified in the monoanionic mixed valence state using Marcus-Hush theory. Analysis of the intervalence charge transfer (IVCT) band reveals that that electronic coupling in the mixed valence state is 5800, 4500, and 5700 cm(-1) for the Ni, Pd, and Pt complexes, respectively. We then focus on their response to acid titration in the mixed valence state, which generates the asymmetrically protonated mixed valence mixed protonated state. For all three complexes, protonation results in severe attenuation of the electronic coupling, as measured by the IVCT band. We find nearly 5-fold decreases in electronic coupling for both Ni and Pt, while, for the Pd complex, the electronic coupling is reduced to the point that the IVCT band is no longer observable. We ascribe the reduction in electronic coupling to charge pinning induced by asymmetric protonation. The more severe reduction in coupling for the Pd complex is a result of greater energetic mismatch between ligand and metal orbitals, reflected in the smaller electronic coupling for the pure mixed valence state. This work demonstrates that the bridging metal center can be used to tune the electronic coupling in both the mixed valence and mixed valence mixed protonated states, as well as the magnitude of change of the electronic coupling that accompanies changes in protonation state. PMID- 27500688 TI - Maternal uniparental disomy for chromosome 6 in a patient with IUGR, ambiguous genitalia, and persistent mullerian structures. AB - Maternal uniparental disomy of chromosome 6 [upd(6)mat] is rare and has only been previously reported 13 times with the main associated phenotype being IUGR. We present a case of a male patient with isodisomy upd(6)mat resulting in severe IUGR and ambiguous genitalia, a phenotype not previously described in association with this chromosome finding. The patient initially presented prenatally with IUGR at 19 weeks gestation with placental dysfunction and ambiguous genitalia noted at 27 weeks. Postnatally, the patient had external genital abnormalities, the gonads were in the inguinal canal and there was a rudimentary appearing vagina and uterus. Karyotype is 46, XY and SNP array revealed maternal isodisomy of 171 Mb at 6p25.3q27 with no pathogenic copy number variants. To our best knowledge, this is the first case of an XY patient with upd(6)mat with IUGR and ambiguous genitalia, further supporting previous reports regarding an association between upd(6)mat and IUGR. This patient also presented with a disorder of sex development (46, XY DSD) with the sex chromosome being male and positive for the SRY gene, testicular gonadal sex and abnormal external and internal genitalia. (c) 2016 Wiley Periodicals, Inc. PMID- 27500687 TI - The functional effects of physical interactions involving cytochromes P450: putative mechanisms of action and the extent of these effects in biological membranes. AB - Cytochromes P450 represent a family of enzymes, which are responsible for the oxidative metabolism of a wide variety of xenobiotics. Although the mammalian P450s require interactions with their redox partners in order to function, more recently, P450 system proteins have been shown to exist as multi-protein complexes that include the formation of P450*P450 complexes. Evidence has shown that the metabolism of some substrates by a given P450 can be influenced by the specific interaction of the enzyme with other forms of P450. Detailed kinetic analysis of these reactions in vitro has shown that the P450-P450 interactions can alter metabolism by changing the ability of a P450 to bind to its cognate redox partner, NADPH-cytochrome P450 reductase; by altering substrate binding to the affected P450; and/or by changing the rate of a catalytic step of the reaction cycle. This review summarizes the known examples of P450-P450 interactions that have been shown in vitro to influence metabolism and categorizes them according to the mechanism(s) causing the effects. P450-P450 interactions have the potential to cause major changes in the metabolism and elimination of drugs in vivo. This review summarizes the evidence that the P450 P450 interactions influence metabolism in biological membranes and discusses the studies, which will provide further insight into the extent of these effects in the future. PMID- 27500689 TI - "This is a question we have to ask everyone": asking young people about self-harm and suicide. AB - : WHAT IS KNOWN ON THE SUBJECT?: An essential part of the mental health assessment is to evaluate the risk of harm to self. Fundamentally this involves asking directly about self-harming behaviour and suicidal thoughts or urges, but practitioners often find it difficult to open up these conversations. This evaluation of risk is particularly important as self-harm and suicidal thoughts are frequently found in young people who attend mental health services. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Young people are not always routinely asked directly about self-harm or suicidal thoughts when they are assessed. There are two ways that mental health practitioners introduce this topic: first, by building up to it by initially asking about general feelings, and second by stating that it is a requirement to ask everyone. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: These questions should not be avoided by mental health practitioners just because they are difficult. We offer suggestions as to how to ask questions about self-harm and suicide based on real-world practice. ABSTRACT: Introduction Questions about self-harm and suicide are essential in risk assessments with children and young people, yet little is known about how mental health practitioners do this. Aim The core aim was to examine how questions about self harm and suicidal ideation are asked in real-world practice. Method A qualitative design was employed to analyse 28 video-recorded naturally occurring mental health assessments in a child and adolescent mental health service. Data were analysed using conversation analysis (CA). Results In 13 cases young people were asked about self-harm and suicide, but 15 were not. Analysis revealed how practitioners asked these questions. Two main styles were revealed. First was an incremental approach, beginning with inquiries about emotions and behaviours, building to asking about self-harm and suicidal intent. Second was to externalize the question as being required by outside agencies. Discussion The study concluded that the design of risk questions to young people had implications for how open they were to engaging with the practitioner. Implications for practice The study has implications for training and practice for psychiatric nurses and other mental health practitioners in feeling more confident in communicating with young people about self-harm and suicidal ideation. PMID- 27500690 TI - Individual, social and environmental predictors of regular exercise among adults with type 2 diabetes and peripheral neuropathy in China. AB - The purpose of the study was to explore the individual, social and environmental factors influencing regular exercise on the basis of the theoretical framework of social ecological model among adults with type 2 diabetes and peripheral neuropathy. A total of 122 participants were chosen from Tianjin Metabolic Disease Hospital from November 2013 to May 2014. Information on exercise status and influencing factors was collected. Most participants took walking as the mode of exercise and exercised alone. Only 59.8% of participants were reported to carry out regular exercise. Logistic regression analysis suggested that being male, longer duration with diabetic peripheral neuropathy, higher self-efficacy for exercise and higher objective support were associated with regular exercise. Exercise status was clearly not ideal among adults with type 2 diabetes and peripheral neuropathy. The study highlighted the need to take measures to improve self-efficacy for exercise and social support in order to promote exercise participation among adults with type 2 diabetes and peripheral neuropathy. PMID- 27500691 TI - Synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage. AB - An efficient protocol for the synthesis of novel lupane triterpenoid-indazolone hybrids with oxime ester linkage has been developed from naturally accessible precursor betulin. For the first time a series of betulonic acid-indazolone hybrids have been synthesized via an acylation of corresponding 6,7-dihydro-1H indazol-4(5H)-one oximes with betulonic acid chloride. Diastereoselective reduction of the obtained betulonic acid conjugates with NaBH4 resulted in a formation of betulinic acid-indazolone hybrids in excellent yields. The configuration of the key compounds has been fully established by X-ray and 2D NMR analysis. PMID- 27500692 TI - Glucocorticoid receptor-mediated insulin-like growth factor-I transcriptional regulation in BeWo trophoblast cells before and after syncytialisation. AB - Prenatal exposure to excessive glucocorticoids (GCs) leads to intrauterine growth retardation and fetal programming of adult health and disease through deregulation of placental functions. Placental secretion of insulin-like growth factor-I (IGF-I) plays a critical role in the regulation of placental development and function. However, it remains elusive whether GCs affect placental functions through glucocorticoid receptor (GR)-mediated transcriptional regulation of IGF-I gene. In this study, human placental choriocarcinoma (BeWo) cells before and after syncytialization were used as cytotrophoblast and syncytiotrophoblast models, respectively, to explore the effects of dexamethasone (Dex) on transcriptional regulation of IGF-I gene at both stages. Dex significantly inhibited (P<0.05) cell proliferation in cytotrophoblasts and down-regulated amino acid transporter SLC7A5 in syncytiotrophoblasts. Concurrently, the abundance of IGF-I mRNA and its transcript variants, together with IGF-I level in culture media, were significantly reduced, in association with significantly enhanced (P<0.05) GR phosphorylation. GR antagonist RU486 was able to abolish all these effects. Two glucocorticoid response elements (GREs) were predicted in the promoter regions of IGF-I gene. GR binding to GRE1 was significantly enriched (P<0.05) in both cytotrophoblasts and syncytiotrophoblasts, but that to GRE2 was significantly diminished (P<0.05) in cytotrophoblasts but not in syncytiotrophoblasts, in response to Dex treatment. IGF-I supplementation completely rescued Dex-induced cell cycle arrest but not SLC7A5 down-regulation, indicating different regulatory mechanisms. Taken together, our results suggest that GR-mediated transcriptional regulation of IGF-I is involved in Dex-induced inhibition of placental cell proliferation and function. PMID- 27500693 TI - Using Kotter's Change Model for Implementing Bedside Handoff: A Quality Improvement Project. PMID- 27500694 TI - Alarm Fatigue: Use of an Evidence-Based Alarm Management Strategy. AB - The purpose of this article is to describe the impact of an evidence-based alarm management strategy on patient safety. An alarm management program reduced alarms up to 30%. Evaluation of patients on continuous cardiac monitoring showed a 3.5% decrease in census. This alarm management strategy has the potential to save $136 500 and 841 hours of registered nurses' time per year. No patient harm occurred during the 2-year project. PMID- 27500695 TI - Nurse-Driven Protocol to Reduce Indwelling Catheter Dwell Time: A Health Care Improvement Initiative. PMID- 27500696 TI - Stopping the Slide: How Hospital Bed Design Can Minimize Active and Passive Patient Migration. AB - Patient migration, or the amount of movement toward the foot of the bed, has been shown to significantly vary because of the mechanical design differences in hospital beds. Previously, the amount of migration was measured immediately following head-of-bed articulation in healthy subjects. This study not only evaluates how much migration occurs immediately after head-of-bed articulation but also measures additional migration during a standard 2-hour repositioning period in subjects with limited mobility. PMID- 27500697 TI - Improving Infusion Pump Safety Through Usability Testing. AB - With the recognition that the introduction of new technology causes changes in workflow and may introduce new errors to the system, usability testing was performed to provide data on nursing practice and interaction with infusion pump technology. Usability testing provides the opportunity to detect and analyze potentially dangerous problems with the design of infusion pumps that could cause or allow avoidable errors. This work will reduce preventable harm through the optimization of health care delivery. PMID- 27500698 TI - Development of Indicators to Measure Health Literate Discharge Practices. AB - Health literate discharge practices meet the health literacy needs of patients and families at the time of hospital discharge and are associated with improved patient outcomes and reduced readmission. A Delphi panel consisting of nurses, other health care providers, and researchers was used to develop a set of indicators of health literate discharge practices based on the practices of Project RED (Re-Engineered Discharge). These indicators can be used to measure and monitor the use of health literate discharge practices. PMID- 27500699 TI - Synthesis of Water-Soluble Deep-Cavity Cavitands. AB - An efficient, four-step synthesis of a range of water-soluble, deep-cavity cavitands is presented. Key to this approach are octahalide derivatives (4, X = Cl or Br) that allow a range of water-solubilizing groups to be added to the outer surface of the core host structure. In many cases, the conversion of the starting dodecol (1) resorcinarene to the different cavitands avoids any chromatographic procedures. PMID- 27500700 TI - Chronic rhinosinusitis: the rationale for current treatments. AB - INTRODUCTION: Chronic rhinosinusitis (CRS) is a broad clinical syndrome linked by mucosal inflammation. Primary treatment modalities are corticosteroids and antibiotics with surgery an option for failures, but the level of supporting evidence is generally low. The primary reason is that CRS is a symptom complex and not a specific disease. Areas covered: The primary treatment modalities for CRS are corticosteroids, antibiotics and surgery. Corticosteroids, which have very broad anti-inflammatory properties, also have the strongest evidence for efficacy. Antibiotics are likely effective in a subpopulation of patients but the various phenotypes and endotypes that make up CRS have thus far been poorly defined. Early surgery as well as biologics may also be more efficacious and cost effective in some phenotypes as well. Expert commentary: A better understanding of the inflammatory pathways that drive CRS will permit investigators to separate patient groups. This will allow for clinical trials that target specific subpopulations and more personalized therapy for CRS patients in the future. PMID- 27500701 TI - Psychoanalysis as a Philosophical Revolution: Freud's Divergence From the Philosophy of Kant, Schopenhauer, and Nietzsche. AB - In his classic, The Birth of Tragedy, Nietzsche described a philosophical worldview that has many similarities to Freudian metapsychology. This paper uses Freud's theories to analyze The Birth of Tragedy, discussing the similarities and differences between Nietzsche's philosophy and Freudian metapsychology. The author suggests that while psychoanalysis was born from the spirit of German philosophy, in that it based itself on a similar concept of the unconscious, Freud diverged from his predecessors to create a new worldview, based on the acceptance and integration of unconscious desire. This revolutionary theory provided a new approach to humanity's moral and existential issues. PMID- 27500702 TI - Obsessive States: Aesthetics, Erotism, and Fantasy. AB - Starting from his early writings, Freud devoted much thought to "obsessional neurosis" and continued developing this theme for more than thirty years. However, unlike the disorder hysteria, which in recent years has regained its honorable status in psychoanalytic literature, obsessional neurosis has been continually neglected and relegated to the fields of psychiatry and behavioral psychology, which emphasize the symptomatic and the overt. This process, by clinging to the objective aspects of obsessional neurosis and disassociating it from the instincts and from its historical sources, may itself be deemed obsessive. This paper suggests that obsessive processes should be viewed as structuring a distinct psychic state pertinent to analysis even when obsessive symptoms are not clearly present or apparent. Freud's conceptualizations thus become more flexibly and widely applicable, allowing the analyst once again to relate to the patient's inner world and to the original, implicit essence of obsession, relying less significantly on what is outwardly apparent. The paper will elaborate on three aspects of this "obsessive state": aesthetics, eroticism, and fantasy. Finally, the value of the notion of obsessive psychic states will be reassessed in the broader context of the role of sexuality in psychoanalytic theory. PMID- 27500703 TI - Zen Musings on Bion's "O" and "K". AB - The author defines Bion's use of "O" and "K" and discusses both from the radical nondualist realizational perspective available through the lens of Eihei Dogen's (1200-1253) Soto Zen Buddhist orientation. Fundamental differences in core foundational principles are discussed as well as similarities and their relevance to clinical practice. A case example exemplifies and explicates the abstract aspects of the discussion, which draws from Zen teaching stories, reference to Dogen's original writings, and the scholarly commentarial literature as well as from contemporary writers who integrate Zen Buddhist study and practice with Bion's psychoanalytic writings on theory and technique. PMID- 27500704 TI - Hermetic Narratives and False Analysis: A Unique Variant of the Mechanism of Identification With the Aggressor. AB - This paper focuses on a unique variant of the mechanism of identification with the aggressor. The term "hermetic narrative" refers to a condition in which the trauma victim creates a hermetically sealed narrative of witnessing, which becomes an addictive and subjugating object in itself, while obstructing natural processes of thinking. This paper examines the ways in which the hermetic narrative reconstructs victim-aggressor relations both within the individual and in the analytic relationship. It further discusses the risk of creating a "false analysis" that is based on a malignant cooperation of the analyst and patient with the internalized traumatic object. PMID- 27500705 TI - Converging Paradigms: A Reflection on Parallel Theoretical Developments in Psychoanalytic Metapsychology and Empirical Dream Research. AB - In the last decades one can perceive a striking parallelism between the shifting perspective of leading representatives of empirical dream research concerning their conceptualization of dreaming and the paradigm shift within clinically based psychoanalytic metapsychology with respect to its theory on the significance of dreaming. In metapsychology, dreaming becomes more and more a central metaphor of mental functioning in general. The theories of Klein, Bion, and Matte-Blanco can be considered as milestones of this paradigm shift. In empirical dream research, the competing theories of Hobson and of Solms respectively argued for and against the meaningfulness of the dream-work in the functioning of the mind. In the meantime, empirical data coming from various sources seemed to prove the significance of dream consciousness for the development and maintenance of adaptive waking consciousness. Metapsychological speculations and hypotheses based on empirical research data seem to point in the same direction, promising for contemporary psychoanalytic practice a more secure theoretical base. In this paper the author brings together these diverse theoretical developments and presents conclusions regarding psychoanalytic theory and technique, as well as proposing an outline of an empirical research plan for testing the specificity of psychoanalysis in developing dream formation. PMID- 27500706 TI - Listening to and Sharing of Self in Psychoanalytic Supervision: The Supervisor's Self-Perspective. AB - Just as the analyst's self-perspective is critical to effective analytic process, the supervisor's self-perspective is accordingly critical to effective supervision process. But the supervisor's self-perspective has received virtually no attention as a listening/experiencing perspective in the psychoanalytic supervision literature. In this paper, the author defines the supervisor's self perspective and considers five ways by which it contributes to an effective supervisory process: (1) sharing one's own impressions of/reactions to patients; (2) sharing personal disclosures about the supervisee-patient relationship; (3) sharing personal disclosures about the supervisee as a developing analytic therapist; (4) sharing personal disclosures about the supervisor-supervisee relationship; and (5) using one's own self-reflection as a check and balance for supervisory action. The supervisor's self-perspective provides the missing supervisory voice in the triadic complement of subject-other-self, has the potential to be eminently educative across the treatment/supervision dyads, and serves as a prototype for the supervisee's own development and use of analytic (or analyst) self-perspective. PMID- 27500710 TI - Proton radiotherapy for gynecologic neoplasms. AB - BACKGROUND: Proton beam therapy (PBT) is increasingly being used globally to treat a variety of malignancies. This is the first review assessing PBT for gynecologic neoplasms. Dose distribution to organs-at-risk (OARs), particularly bone marrow (BM), is addressed. Clinical outcomes and toxicity data are detailed. MATERIAL AND METHODS: Systematic searches of PubMed, EMBASE, abstracts from meetings of the American Society for Radiation Oncology, Particle Therapy Co Operative Group, and American Society of Clinical Oncology were conducted for publications. There were no restrictions on publication dates. Sixteen original investigations were identified and analyzed for this review. RESULTS: The available evidence for PBT in treating gynecologic cancers is of both low quantity and quality. The most studied scenarios for PBT include treatment of para-aortic lymph nodes, re-irradiation, and as an alternative to brachytherapy, and these also represent indications with the greatest opportunity for demonstrating as yet unproven toxicity reductions. Dosimetric studies have shown significantly decreased dose to OARs, such as the rectum, bladder, bowel, kidneys, BM, and femoral heads. This dose reduction to OARs with PBT is more pronounced within the low-dose volumes than the higher dose volumes, which radiobiologically could be expected to lower second malignancy rates. Clinical data, though no level 1 evidence, show appropriate stage-specific tumor control and outcomes with PBT treatment, along with low toxicity rates. CONCLUSION: The existing data, albeit limited, warrant and can help guide larger scale and higher quality studies addressing whether PBT could provide clinically meaningful differences in toxicities and outcomes in women with gynecologic neoplasms. PMID- 27500711 TI - Single-Molecule Observation of a Mechanically Activated Cis-to-Trans Cyclopropane Isomerization. AB - The mechanochemical activation of cis-gem-difluorocyclopropane (cis-gDFC) mechanophore in toluene was characterized with single-molecule force spectroscopy. Unlike previously reported behavior in methyl benzoate (MB), two transitions are observed in the force vs extension curves of cis-gDFC polymers in toluene. The first transition occurs at the same force of ~1300 pN observed previously in MB, but a second transition is observed at forces of ~1800 pN that reveal the partial formation of the trans-gDFC isomer. The behavior is attributed to competing reactions of the cis-gDFC at the 1300 pN plateau: addition of oxygen to a ring-opened diradicaloid intermediate, and isomerization of cis-gDFC to its trans isomer. PMID- 27500709 TI - How multiple episodes of exclusive breastfeeding impact estimates of exclusive breastfeeding duration: report from the eight-site MAL-ED birth cohort study. AB - The duration of exclusive breastfeeding (EBF) is often defined as the time from birth to the first non-breast milk food/liquid fed (EBFLONG), or it is estimated by calculating the proportion of women at a given infant age who EBF in the previous 24 h (EBFDHS). Others have measured the total days or personal prevalence of EBF (EBFPREV), recognizing that although non-EBF days may occur, EBF can be re-initiated for extended periods. We compared breastfeeding metrics in the MAL-ED study; infants' breastfeeding trajectories were characterized from enrollment (median 7 days, IQR: 4, 12) to 180 days at eight sites. During twice weekly surveillance, caretakers were queried about infant feeding the prior day. Overall, 101 833 visits and 356 764 child days of data were collected from 1957 infants. Median duration of EBFLONG was 33 days (95% CI: 32-36), compared to 49 days based on the EBFDHS. Median EBFPREV was 66 days (95% CI: 62-70). Differences were because of the return to EBF after a non-EBF period. The median number of returns to EBF was 2 (IQR: 1, 3). When mothers re-initiated EBF (second episode), infants gained an additional 18.8 days (SD: 25.1) of EBF, and gained 13.7 days (SD: 18.1) (third episode). In settings where women report short gaps in EBF, programmes should work with women to return to EBF. Interventions could positively influence the duration of these additional periods of EBF and their quantification should be considered in impact evaluation studies. (c) 2016 John Wiley & Sons Ltd. PMID- 27500712 TI - Enhancement of the Initial Growth Rate of Agricultural Plants by Using Static Magnetic Fields. AB - Electronic devices and high-voltage wires induce magnetic fields. A magnetic field of 1,300-2,500 Gauss (0.2 Tesla) was applied to Petri dishes containing seeds of Garden Balsam (Impatiens balsamina), Mizuna (Brassica rapa var. japonica), Komatsuna (Brassica rapa var. perviridis), and Mescluns (Lepidium sativum). We applied magnets under the culture dish. During the 4 days of application, we observed that the stem and root length increased. The group subjected to magnetic field treatment (n = 10) showed a 1.4 times faster rate of growth compared with the control group (n = 11) in a total of 8 days (p <0.0005). This rate is 20% higher than that reported in previous studies. The tubulin complex lines did not have connecting points, but connecting points occur upon the application of magnets. This shows complete difference from the control, which means abnormal arrangements. However, the exact cause remains unclear. These results of growth enhancement of applying magnets suggest that it is possible to enhance the growth rate, increase productivity, or control the speed of germination of plants by applying static magnetic fields. Also, magnetic fields can cause physiological changes in plant cells and can induce growth. Therefore, stimulation with a magnetic field can have possible effects that are similar to those of chemical fertilizers, which means that the use of fertilizers can be avoided. PMID- 27500713 TI - Improved Insulin Pharmacokinetics Using a Novel Microneedle Device for Intradermal Delivery in Patients with Type 2 Diabetes. AB - BACKGROUND: Currently available short-acting insulin analogs have slower absorption compared with endogenous insulin occasionally resulting in immediate postprandial hyperglycemia. Intradermal (ID) injection facilitates faster drug absorption and may result in improved insulin pharmacokinetics. METHODS: Seventeen patients with type 2 diabetes were included in this single-center, pilot, open-label crossover study. Patients received 0.2 U/kg Insulin aspart ID injections using a MicronJet (MJ) needle and subcutaneous (SC) injections, using a conventional needle in a crossover design. Thirteen patients were studied under fasting conditions and four before a standard meal test. The pharmacokinetic/pharmacodynamic (PK/PD) profile, as well as the safety and tolerability of injections, was compared. RESULTS: Fourteen patients completed the study per-protocol. ID versus SC injection demonstrated significantly shorter Tmax (median 35 vs. 87.5 min [P < 0.001]), while the Cmax did not significantly differ (median 80 vs. 55 MUU/mL [P = 0.085]). Median insulin area under the curve (AUC; 360 min) did not differ between the groups (9914 vs. 10,936 MUU/mL/min [p = 0.077]), yet 0-60 min insulin AUC was higher with ID versus SC injection (mean +/ SD 3821 +/- 1429 vs. 2534 +/- 737 MUU/mL/min [p = 0.01]) and 4-6 h AUC was lower with ID versus SC injection (mean +/- SD 2054 +/- 858 vs. 2929 +/- 1412 MUU/mL/min [p = 0.02]). The relative bioavailability of the ID versus the SC insulin (AUCID/AUCSC) was similar (median 0.91 [95% confidence interval 0.73 1.27]). CONCLUSIONS: ID insulin injection delivered through an MJ needle demonstrated superior PK profile compared with conventional SC administration, including shorter Tmax and higher early and lower late exposure in patients with type 2 diabetes. This may help achieve better insulin coverage of meals and lower postprandial glucose excursions. PMID- 27500714 TI - RAMA casein zymography: Time-saving and highly sensitive casein zymography for MMP7 and trypsin. AB - To detect metalloproteinase-7 (MMP7), zymography is conducted using a casein substrate and conventional CBB stain. It has disadvantages because it is time consuming and has low sensitivity. Previously, a sensitive method to detect MMP7 up to 30 pg was reported, however it required special substrates and complicated handlings. RAMA casein zymography described herein is rapid, sensitive, and reproducible. By applying high-sensitivity staining with low substrate conditions, the staining process is completed within 1 h and sensitivity was increased 100-fold. The method can detect 10 pg MMP7 by using commercially available casein without complicated handlings. Moreover, it increases detection sensitivity for trypsin. PMID- 27500715 TI - Treatment of Medial Collateral Ligament Injuries of the Elbow with Use of the "Tommy John" Operation: Indications and Results. PMID- 27500716 TI - Total Hip Replacement with Use of a Direct Anterior Approach: A Critical Analysis Review. PMID- 27500717 TI - Has the Promise Been Kept? PMID- 27500718 TI - Recombinant Human Bone Morphogenetic Protein-2 in Spine Surgery. PMID- 27500719 TI - Radiographic and Scintigraphic Evaluation of Bone Tumors and Diseases. PMID- 27500720 TI - A High-content In Vitro Pancreatic Islet beta-cell Replication Discovery Platform. AB - Loss of insulin-producing beta-cells is a central feature of diabetes. While a variety of potential replacement therapies are being explored, expansion of endogenous insulin-producing pancreatic islet beta-cells remains an attractive strategy. beta-cells have limited spontaneous regenerative activity; consequently, a crucial research effort is to develop a precise understanding of the molecular pathways that restrain beta-cell growth and to identify drugs capable of overcoming these restraints. Herein an automated high-content image based primary-cell screening method to identify beta-cell replication-promoting small molecules is presented. Several, limitations of prior methodologies are surmounted. First, use of primary islet cells rather than an immortalized cell line maximizes retention of in vivo growth restraints. Second, use of mixed composition islet-cell cultures rather than a beta-cell-line allows identification of both lineage-restricted and general growth stimulators. Third, the technique makes practical the use of primary islets, a limiting resource, through use of a 384-well format. Fourth, detrimental experimental variability associated with erratic islet culture quality is overcome through optimization of isolation, dispersion, plating and culture parameters. Fifth, the difficulties of accurately and consistently measuring the low basal replication rate of islet endocrine-cells are surmounted with optimized immunostaining parameters, automated data acquisition and data analysis; automation simultaneously enhances throughput and limits experimenter bias. Notable limitations of this assay are the use of dispersed islet cultures which disrupts islet architecture, the use of rodent rather than human islets and the inherent limitations of throughput and cost associated with the use of primary cells. Importantly, the strategy is easily adapted for human islet replication studies. This assay is well suited for investigating the mitogenic effect of substances on beta-cells and the molecular mechanisms that regulate beta-cell growth. PMID- 27500721 TI - Refractory Status Epilepticus in Children: Intention to Treat With Continuous Infusions of Midazolam and Pentobarbital. AB - OBJECTIVE: To describe pediatric patients with convulsive refractory status epilepticus in whom there is intention to use an IV anesthetic for seizure control. DESIGN: Two-year prospective observational study evaluating patients (age range, 1 mo to 21 yr) with refractory status epilepticus not responding to two antiepileptic drug classes and treated with continuous infusion of anesthetic agent. SETTING: Nine pediatric hospitals in the United States. PATIENTS: In a cohort of 111 patients with refractory status epilepticus (median age, 3.7 yr; 50% male), 54 (49%) underwent continuous infusion of anesthetic treatment. MAIN RESULTS: The median (interquartile range) ICU length of stay was 10 (3-20) days. Up to four "cycles" of serial anesthetic therapy were used, and seizure termination was achieved in 94% by the second cycle. Seizure duration in controlled patients was 5.9 (1.9-34) hours for the first cycle and longer when a second cycle was required (30 [4-120] hr; p = 0.048). Midazolam was the most frequent first-line anesthetic agent (78%); pentobarbital was the most frequently used second-line agent after midazolam failure (82%). An electroencephalographic endpoint was used in over half of the patients; higher midazolam dosing was used with a burst suppression endpoint. In midazolam nonresponders, transition to a second agent occurred after a median of 1 day. Most patients (94%) experienced seizure termination with these two therapies. CONCLUSIONS: Midazolam and pentobarbital remain the mainstay of continuous infusion therapy for refractory status epilepticus in the pediatric patient. The majority of patients experience seizure termination within a median of 30 hours. These data have implications for the design and feasibility of future intervention trials. That is, testing a new anesthetic anticonvulsant after failure of both midazolam and pentobarbital is unlikely to be feasible in a pediatric study, whereas a decision to test an alternative to pentobarbital, after midazolam failure, may be possible in a multicenter multinational study. PMID- 27500722 TI - Treatment of Pediatric Septic Shock With the Surviving Sepsis Campaign Guidelines and PICU Patient Outcomes. AB - OBJECTIVES: The Surviving Sepsis Campaign recommends rapid recognition and treatment of severe sepsis and septic shock. Few reports have evaluated the impact of these recommendations in pediatrics. We sought to determine if outcomes in patients who received initial care compliant with the Surviving Sepsis Campaign time goals differed from those treated more slowly. DESIGN: Single center retrospective cohort study. SETTING: Emergency department and PICU at an academic children's hospital. PATIENTS: Three hundred twenty-one patients treated for septic shock in the emergency department and admitted directly to the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The exposure was receipt of emergency department care compliant with the Surviving Sepsis Campaign recommendations (delivery of IV fluids, IV antibiotics, and vasoactive infusions within 1 hr of shock recognition). The primary outcome was development of new or progressive multiple organ dysfunction syndrome. Secondary outcomes included mortality, need for mechanical ventilation or vasoactive medications, and hospital and PICU length of stay. Of the 321 children studied, 117 received Surviving Sepsis Campaign compliant care in the emergency department and 204 did not. New or progressive multiple organ dysfunction syndrome developed in nine of the patients (7.7%) who received Surviving Sepsis Campaign compliant care and 25 (12.3%) who did not (p = 0.26). There were 17 deaths; overall mortality rate was 5%. There were no significant differences between groups in any of the secondary outcomes. Although only 36% of patients met the Surviving Sepsis Campaign guideline recommendation of bundled care within 1 hour of shock recognition, 75% of patients received the recommended interventions in less than 3 hours. CONCLUSIONS: Treatment for pediatric septic shock in compliance with the Surviving Sepsis Campaign recommendations was not associated with better outcomes compared with children whose initial therapies in the emergency department were administered more slowly. However, all patients were treated rapidly and we report low morbidity and mortality. This underscores the importance of rapid recognition and treatment of septic shock. PMID- 27500723 TI - Inotropic Therapy in Newborns, A Population-Based National Registry Study. AB - OBJECTIVE: To describe the use of inotropic drugs and the characteristics of neonates receiving such treatment in a national cohort of patients admitted to neonatal ICUs in Norway. DESIGN: A national registry study of patients included in the Norwegian Neonatal Network database 2009-2014. Demographic and treatment data, including the use of inotropic drugs (dopamine, dobutamine, epinephrine, norepinephrine, milrinone, and levosimendan) and outcomes, were retrieved and analyzed. SETTING: Neonatal ICUs in Norway. PATIENTS: All patients admitted to Norwegian neonatal ICUs 2009-2014 with a postmenstrual age of less than 310 days at admission, corresponding to a postnatal age of less than 28 days for a child born at term (n = 36 397). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Inotropic drugs were administered to 974 of 361,803 live born infants (0.27%) in the study period, representing 2.7% of the neonatal ICU patient population. The relative proportion of neonatal ICU patients receiving inotropes decreased with increasing gestational age, yet 41% of the patients receiving inotropes were born at term. Of note, 89.8% of treated patients received dopamine. Use of inotropes was particularly prevalent in patients with necrotizing enterocolitis (72.4%) and pulmonary hypertension (42.1%) and in patients with gestational age less than 28 weeks (28.2%). Inotropic treatment initiated in the first week of life (84.2%) was associated with birth asphyxia and pulmonary hypertension, whereas treatment initiated after the first week of life was associated with extremely preterm birth, neonatal surgery, neonatal sepsis, cardiac disease, and necrotizing enterocolitis. CONCLUSIONS: This comprehensive epidemiologic study indicates that less than 0.3% of newborns receive inotropic support in the neonatal period. Dopamine was the most commonly used drug. Relating inotrope use to clinical condition, gestational age, and postnatal age may be useful for clinicians and helpful in delineating relevant patient populations for future clinical trials. PMID- 27500724 TI - Defective proviruses rapidly accumulate during acute HIV-1 infection. AB - Although antiretroviral therapy (ART) suppresses viral replication to clinically undetectable levels, human immunodeficiency virus type 1 (HIV-1) persists in CD4(+) T cells in a latent form that is not targeted by the immune system or by ART. This latent reservoir is a major barrier to curing individuals of HIV-1 infection. Many individuals initiate ART during chronic infection, and in this setting, most proviruses are defective. However, the dynamics of the accumulation and the persistence of defective proviruses during acute HIV-1 infection are largely unknown. Here we show that defective proviruses accumulate rapidly within the first few weeks of infection to make up over 93% of all proviruses, regardless of how early ART is initiated. By using an unbiased method to amplify near-full-length proviral genomes from HIV-1-infected adults treated at different stages of infection, we demonstrate that early initiation of ART limits the size of the reservoir but does not profoundly affect the proviral landscape. This analysis allows us to revise our understanding of the composition of proviral populations and estimate the true reservoir size in individuals who were treated early versus late in infection. Additionally, we demonstrate that common assays for measuring the reservoir do not correlate with reservoir size, as determined by the number of genetically intact proviruses. These findings reveal hurdles that must be overcome to successfully analyze future HIV-1 cure strategies. PMID- 27500727 TI - Human Placental and Decidual Organ Cultures to Study Infections at the Maternal fetal Interface. AB - The placenta shows a large degree of interspecies anatomic variability. To best understand biology and pathophysiology of the human placenta, it is imperative to design experiments using human cells and tissues. An advantage of organ culture is maintenance of three-dimensional (3D) structural organization and extracellular matrix. The goal of the method described here is successful establishment of ex vivo human gestational tissue organ cultures and their healthy culture maintenance for 72-96 hr. The protocol details the immediate processing of research-consented, placental and decidual specimens fresh from the operating suite. These are abundant specimens that would otherwise be discarded. Detailed instructions on the sterile collection of these samples, including morphologic details on how to select appropriate tissues to establish 3D organ cultures, is provided. Placental villous and decidual tissues are microdissected into 2-3 mm(3) pieces and placed separately on matrix-lined transwell filters and cultured for several days. Villous and decidual organ cultures are well suited for the study of human host-pathogen interaction. As compared to other model organisms, these human cultures are particularly advantageous to examine mechanism of infection for pathogens that demonstrate variable patterns of host specificity. As an example, we demonstrate infection of placental and decidual organ cultures with the clinically relevant, facultative intracellular bacterial pathogen Listeria monocytogenes. PMID- 27500726 TI - Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma. AB - The protein kinase B-Raf proto-oncogene, serine/threonine kinase (BRAF) is an oncogenic driver and therapeutic target in melanoma. Inhibitors of BRAF (BRAFi) have shown high response rates and extended survival in patients with melanoma who bear tumors that express mutations encoding BRAF proteins mutant at Val600, but a vast majority of these patients develop drug resistance. Here we show that loss of stromal antigen 2 (STAG2) or STAG3, which encode subunits of the cohesin complex, in melanoma cells results in resistance to BRAFi. We identified loss-of function mutations in STAG2, as well as decreased expression of STAG2 or STAG3 proteins in several tumor samples from patients with acquired resistance to BRAFi and in BRAFi-resistant melanoma cell lines. Knockdown of STAG2 or STAG3 expression decreased sensitivity of BRAF(Val600Glu)-mutant melanoma cells and xenograft tumors to BRAFi. Loss of STAG2 inhibited CCCTC-binding-factor-mediated expression of dual specificity phosphatase 6 (DUSP6), leading to reactivation of mitogen-activated protein kinase (MAPK) signaling (via the MAPKs ERK1 and ERK2; hereafter referred to as ERK). Our studies unveil a previously unknown genetic mechanism of BRAFi resistance and provide new insights into the tumor suppressor function of STAG2 and STAG3. PMID- 27500725 TI - Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a potentially life-threatening autoimmune disease characterized by altered balance of activity between effector and regulatory CD4(+) T cells. The homeostasis of CD4(+) T cell subsets is regulated by interleukin (IL)-2, and reduced production of IL-2 by T cells is observed in individuals with SLE. Here we report that treatment with low-dose recombinant human IL-2 selectively modulated the abundance of regulatory T (Treg) cells, follicular helper T (TFH) cells and IL-17-producing helper T (TH17) cells, but not TH1 or TH2 cells, accompanied by marked reductions of disease activity in patients with SLE. PMID- 27500728 TI - Nanoengineering a library of metallic nanostructures using a single microfluidic reactor. AB - Microfluidic synthesis in a microfabricated reactor enables fast and facile synthesis of a wide library of metallic nanostructures: monometallic, bimetallic, anisotropic growth and heterostructures. Specific nanostructures are realized by selection of flow pattern and synthesis parameters. The technique is shown to have advantages over conventional batch technologies. Not only does it allow faster scalable synthesis, but also realization of nanostructures hitherto not reported such as Pt-Ru, Pt-Ni and Pt-Co nanodendrites, Pt-Pd heterostructures, Ag Pd core-shell NPs, Au-Pd nanodumbbells and Au-Pd nanosheets. PMID- 27500729 TI - Development of a Colloidal Gold-based Immunochromatographic Test Strip for Detection of Cetacean Myoglobin. AB - This protocol describes the development of a colloidal gold immunochromatographic test strip based on the sandwich format that can be used to differentiate the myoglobin (Mb) of cetaceans from that of seals and other animals. The strip provides rapid and on-the-spot screening for cetacean meat, thereby restraining its illegal trade and consumption. Two monoclonal antibodies (mAbs) with reactivity toward the Mb of cetaceans were developed. The amino acid sequences of Mb antigenic reactive regions from various animals were analyzed in order to design two synthetic peptides (a general peptide and a specific peptide) and thereafter raise the mAbs (subclass IgG1). The mAbs were selected from hybridomas screened by indirect ELISA, western blot and dot blot. CGF5H9 was specific to the Mbs of rabbits, dogs, pigs, cows, goats, and cetaceans while it showed weak to no affinity to the Mbs of chickens, tuna and seals. CSF1H13 can bind seals and cetaceans with strong affinity but showed no affinity to other animals. Cetacean samples from four families (Balaenopteridae, Delphinidae, Phocoenidae and Kogiidae) were used in this study, and the results indicated that these two mAbs have broad binding ability to Mbs from different cetaceans. These mAbs were applied on a sandwich-type colloidal gold immunochromatographic test strip. CGF5H9, which recognizes many species, was colloid gold-labeled and used as the detection antibody. CSF1H13, which was coated on the test zone, detected the presence of cetacean and seal Mbs. Muscle samples from tuna, chicken, seal, five species of terrestrial mammals and 15 species of cetaceans were tested in triplicate. All cetacean samples showed positive results and all the other samples showed negative results. PMID- 27500730 TI - Effect of Feed Form and Whole Grain Feeding on Gastrointestinal Weight and the Prevalence of Campylobacter jejuni in Broilers Orally Infected. AB - Two independent trials were carried out to evaluate the effect of feed form, whole wheat (WW) and oat hulls (OH) addition on gastrointestinal (GIT) weight and Campylobacter jejuni colonization in orally infected birds. In Trial 1, there were six treatments factorially arranged with two feed forms (mash vs pellets), and three levels of WW from 1-21/22-42d: 0/0, 7.5/15%, 15/30%. Broilers were allocated in cages (3 birds/cage, 12 cages/treatment). In Trial 2, there were three treatments: a mash diet, a mash diet including WW (7.5% from 1-21 and 15% from 22-42d), and a third treatment including also 5%OH. Broilers were allocated in floor pens (1 pen with 30 birds/treatment). At 14d, all broilers in Trial 1 or 3 broilers/pen in Trial 2 were orally challenged with 1.5 x 105 cfu of C. jejuni ST-45 /. In Trial 1, birds fed pelleted diets consumed 13.5% more feed, gained 31% more weight, and presented 12.9% better feed conversion for the whole trial (P<0.05). Pelleting decreased the relative weight of GIT and gizzard and increased the relative weight of proventriculus (P<0.05). Mash diets decreased pH in the gizzard (P<0.05). Inclusion of WW decreased the relative weight of proventriculus, increased gizzard weight, and reduced pH in the gizzard (P<0.05). At 21d of age, mash tended to reduce C. jejuni compared to pellets (7.85 vs 8.27 log10cfu/g; P = 0.091) and WW inclusion at 7.5/15% reduced C. jejuni colonization when compared to lower and higher inclusion (P<0.05). In Trial 2, birds fed T3 (WW+OH) showed 1.38 log10cfu/g less than birds fed Control diet (P<0.05). In conclusion, despite of the clear morphological changes in the GIT derived of FF and WW inclusion, no clear reductions in C. jejuni populations in the ceca were observed. However, WW and OH inclusion to mash diets significantly reduced cecal C. jejuni colonization at 42 days. PMID- 27500731 TI - Transgenic Suppression of AGAMOUS Genes in Apple Reduces Fertility and Increases Floral Attractiveness. AB - We investigated the ability of RNA interference (RNAi) directed against two co orthologs of AGAMOUS (AG) from Malus domestica (domestic apple, MdAG) to reduce the risks of invasiveness and provide genetic containment of transgenes, while also promoting the attractiveness of flowers for ornamental usage. Suppression of two MdAG-like genes, MdMADS15 and MdMADS22, led to the production of trees with highly showy, polypetalous flowers. These "double-flowers" had strongly reduced expression of both MdAG-like genes. Members of the two other clades within in the MdAG subfamily showed mild to moderate differences in gene expression, or were unchanged, with the level of suppression approximately proportional to the level of sequence identity between the gene analyzed and the RNAi fragment. The double flowers also exhibited reduced male and female fertility, had few viable pollen grains, a decreased number of stigmas, and produced few viable seeds after cross pollination. Despite these floral alterations, RNAi-AG trees with double-flowers set full-sized fruit. Suppression or mutation of apple AG-like genes appears to be a promising method for combining genetic containment with improved floral attractiveness. PMID- 27500732 TI - Analysis of the Enantioselective Effects of PCB95 in Zebrafish (Danio rerio) Embryos through Targeted Metabolomics by UPLC-MS/MS. AB - As persistent organic pollutants, polychlorinated biphenyls (PCBs) accumulate in the bodies of animals and humans, resulting in toxic effects on the reproductive, immune, nervous, and endocrine systems. The biological and toxicological characteristics of enantiomers of chiral PCBs may differ, but these enantioselective effects of PCBs have not been fully characterized. In this study, we performed metabolomics analysis, using ultra-high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to investigate the enantioselective toxic effects of PCB95 in zebrafish (Danio rerio) embryos after exposure to three dose levels of 0.1, 1, and 10 MUg/L for 72 h. Multivariate analysis directly reflected the metabolic perturbations caused by PCB95. The effects of (-)-PCB95 and (+)-PCB95 were more prominent than those of the racemate in zebrafish embryos. A total of 26 endogenous metabolites were selected as potential marker metabolites with variable importance at projection values larger than 1 and significant differences (p<0.05). These metabolites included amino acids, organic acids, nucleosides, betaine, and choline. The changes in these biomarkers were dependent on the enantiomer-specific structures of PCB95. Fifteen metabolic pathways were significantly affected, and several nervous and immune system-related metabolites were significantly validated after exposure. These metabolic changes indicated that the toxic effects of PCB95 may be associated with the interaction of PCB95 with the nervous and immune systems, thus resulting in disruption of energy metabolism and liver function. PMID- 27500733 TI - Disposition and Pharmacokinetics of a GalNAc3-Conjugated Antisense Oligonucleotide Targeting Human Lipoprotein (a) in Monkeys. AB - Triantennary N-acetyl galactosamine (GalNAc3)-conjugated antisense oligonucleotides (ASOs) have greatly improved potency due to receptor-mediated uptake into hepatocyte. The disposition and pharmacokinetics of ISIS 681257, a GalNAc3-conjugated ASO, were studied in monkeys. Following subcutaneous (SC) injection, ISIS 681257 was rapidly absorbed into the systemic circulation, with peak plasma levels observed within hours after dosing. After reaching Cmax, plasma concentrations rapidly declined in a multiexponential manner and were characterized by a dominant initial rapid distribution phase in which drug transferred to tissues from circulation, followed by a much slower terminal elimination phase (half-life of 4 weeks). Intact ISIS 681257 is the major full length oligonucleotide species in plasma (>=70%). In tissues, the conjugated GalNAc sugar moiety was rapidly metabolized, leaving the fully unconjugated form as the only full-length oligonucleotide detected at 48 h after dosing. Unconjugated ISIS 681257 cleared slowly from tissues with a half-life of 4 weeks. ISIS 681257 was highly bound to plasma proteins (>97% bound), which limited its urinary excretion. Disposition of ISIS 681257 in plasma and liver appeared nonlinear over the 1-40 mg/kg dose range studied. The plasma and liver tissue concentration data were well described by a population based mixed-effects modeling approach with Michaelis-Menten uptake from plasma to liver. Safety data from the study and the good exposure, as well as the extended half-life of the unconjugated ASO in the liver, support further development and less frequent dosing in Phase I clinical study. PMID- 27500734 TI - Potential beneficial impact of angiotensin receptor blockers on arterial stiffness in hypertension. PMID- 27500735 TI - Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis. AB - We investigated Brucella melitensis methionyl-tRNA-synthetase (BmMetRS) with molecular, structural and phenotypic methods to learn if BmMetRS is a promising target for brucellosis drug development. Recombinant BmMetRS was expressed, purified from wild type Brucella melitensis biovar Abortus 2308 strain ATCC/CRP #DD-156 and screened by a thermal melt assay against a focused library of one hundred previously classified methionyl-tRNA-synthetase inhibitors of the blood stage form of Trypanosoma brucei. Three compounds showed appreciable shift of denaturation temperature and were selected for further studies on inhibition of the recombinant enzyme activity and cell viability against wild type B. melitensis strain 16M. BmMetRS protein complexed with these three inhibitors resolved into three-dimensional crystal structures and was analyzed. All three selected methionyl-tRNA-synthetase compounds inhibit recombinant BmMetRS enzymatic functions in an aminoacylation assay at varying concentrations. Furthermore, growth inhibition of B. melitensis strain 16M by the compounds was shown. Inhibitor-BmMetRS crystal structure models were used to illustrate the molecular basis of the enzyme inhibition. Our current data suggests that BmMetRS is a promising target for brucellosis drug development. However, further studies are needed to optimize lead compound potency, efficacy and safety as well as determine the pharmacokinetics, optimal dosage, and duration for effective treatment. PMID- 27500736 TI - Riemerella anatipestifer M949_1360 Gene Functions on the Lipopolysaccharide Biosynthesis and Bacterial Virulence. AB - Riemerella anatipestifer causes septicemic and exudative diseases in poultry, resulting in major economic losses to the duck industry. Lipopolysaccharide (LPS), as an important virulence factor in Gram-negative bacteria, can be recognized by the immune system and plays a crucial role in many interactions between bacteria and animal hosts. In this study, we screened out one LPS defective mutant strain RADelta604 from a random transposon mutant library of R. anatipestifer serotype 1 strain CH3, which did not react with the anti-CH3 LPS monoclonal antibody 1C1 in an indirect enzyme-linked immunosorbent assay. Southern blot analysis confirmed that the genome of RADelta604 contained a single Tn4351 insert. Then, we found that the M949_1360 gene was inactivated by insertion of the transposon. Using silver staining and western blot analyses, we found that the LPS pattern of RADelta604 was defective, as compared with that of the wild-type (WT) strain CH3. The mutant strain RADelta604 showed no significant influence on bacterial growth, while bacterial counting and Live/dead BacLight Bacterial Viability staining revealed that bacterial viability was decreased, as compared with the WT strain CH3. In addition, the abilities of the mutant strain RADelta604 to adhere and invade Vero cells were significantly decreased. Animal studies revealed that the virulence of the mutant strain RADelta604 was decreased by more than 200-fold in a duck infection model, as compared with the WT strain CH3. Furthermore, immunization with live bacteria of the mutant strain RADelta604 protected 87.5% ducks from challenge with R. anatipestifer serotype 1 strain WJ4, indicating that the mutant strain RADelta604 could be used as a potential vaccine candidate in the future. PMID- 27500737 TI - The Mechanism for Type I Interferon Induction by Mycobacterium tuberculosis is Bacterial Strain-Dependent. AB - Type I interferons (including IFNalphabeta) are innate cytokines that may contribute to pathogenesis during Mycobacterium tuberculosis (Mtb) infection. To induce IFNbeta, Mtb must gain access to the host cytosol and trigger stimulator of interferon genes (STING) signaling. A recently proposed model suggests that Mtb triggers STING signaling through bacterial DNA binding cyclic GMP-AMP synthase (cGAS) in the cytosol. The aim of this study was to test the generalizability of this model using phylogenetically distinct strains of the Mtb complex (MTBC). We infected bone marrow derived macrophages with strains from MTBC Lineages 2, 4 and 6. We found that the Lineage 6 strain induced less IFNbeta, and that the Lineage 2 strain induced more IFNbeta, than the Lineage 4 strain. The strains did not differ in their access to the host cytosol and IFNbeta induction by each strain required both STING and cGAS. We also found that the three strains shed similar amounts of bacterial DNA. Interestingly, we found that the Lineage 6 strain was associated with less mitochondrial stress and less mitochondrial DNA (mtDNA) in the cytosol compared with the Lineage 4 strain. Treating macrophages with a mitochondria-specific antioxidant reduced cytosolic mtDNA and inhibited IFNbeta induction by the Lineage 2 and 4 strains. We also found that the Lineage 2 strain did not induce more mitochondrial stress than the Lineage 4 strain, suggesting that additional pathways contribute to higher IFNbeta induction. These results indicate that the mechanism for IFNbeta by Mtb is more complex than the established model suggests. We show that mitochondrial dynamics and mtDNA contribute to IFNbeta induction by Mtb. Moreover, we show that the contribution of mtDNA to the IFNbeta response varies by MTBC strain and that additional mechanisms exist for Mtb to induce IFNbeta. PMID- 27500739 TI - No recommendation of routine perioperative statin use for prevention of acute kidney injury in patients undergoing cardiac surgery. PMID- 27500740 TI - Microfluidic Pneumatic Cages: A Novel Approach for In-chip Crystal Trapping, Manipulation and Controlled Chemical Treatment. AB - The precise localization and controlled chemical treatment of structures on a surface are significant challenges for common laboratory technologies. Herein, we introduce a microfluidic-based technology, employing a double-layer microfluidic device, which can trap and localize in situ and ex situ synthesized structures on microfluidic channel surfaces. Crucially, we show how such a device can be used to conduct controlled chemical reactions onto on-chip trapped structures and we demonstrate how the synthetic pathway of a crystalline molecular material and its positioning inside a microfluidic channel can be precisely modified with this technology. This approach provides new opportunities for the controlled assembly of structures on surface and for their subsequent treatment. PMID- 27500738 TI - Drosophila Spidey/Kar Regulates Oenocyte Growth via PI3-Kinase Signaling. AB - Cell growth and proliferation depend upon many different aspects of lipid metabolism. One key signaling pathway that is utilized in many different anabolic contexts involves Phosphatidylinositide 3-kinase (PI3K) and its membrane lipid products, the Phosphatidylinositol (3,4,5)-trisphosphates. It remains unclear, however, which other branches of lipid metabolism interact with the PI3K signaling pathway. Here, we focus on specialized fat metabolizing cells in Drosophila called larval oenocytes. In the presence of dietary nutrients, oenocytes undergo PI3K-dependent cell growth and contain very few lipid droplets. In contrast, during starvation, oenocytes decrease PI3K signaling, shut down cell growth and accumulate abundant lipid droplets. We now show that PI3K in larval oenocytes, but not in fat body cells, functions to suppress lipid droplet accumulation. Several enzymes of fatty acid, triglyceride and hydrocarbon metabolism are required in oenocytes primarily for lipid droplet induction rather than for cell growth. In contrast, a very long chain fatty-acyl-CoA reductase (FarO) and a putative lipid dehydrogenase/reductase (Spidey, also known as Kar) not only promote lipid droplet induction but also inhibit oenocyte growth. In the case of Spidey/Kar, we show that the growth suppression mechanism involves inhibition of the PI3K signaling pathway upstream of Akt activity. Together, the findings in this study show how Spidey/Kar and FarO regulate the balance between the cell growth and lipid storage of larval oenocytes. PMID- 27500741 TI - An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway. AB - Persistent activation of signal transducer and activator of transcription 3 (STAT3) is associated with the progression of a range of tumors. In this report, we present the anticancer activity of 2-(1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3 yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5)undecane (CIMO) against breast cancer cells. We observed that CIMO suppresses the proliferation of both estrogen receptor-negative (ER-) (BT-549, MDA-MB-231) and estrogen receptor-positive (ER+) (MCF-7, and BT-474) breast cancer (BC) cells with IC50 of 3.05, 3.41, 4.12 and 4.19 uM, respectively, and without significantly affecting the viability of normal cells. CIMO was observed to mediate its anti-proliferative effect in ER- BC cells by inhibiting the phosphorylation of JAK2 and STAT3 proteins. Quantitative PCR analysis demonstrated that CIMO decreases the relative mRNA expression of genes that are involved in cell cycle progression (CCND1) and cell survival (BCL2, BCL-xL, BAD, CASP 3/7/9, and TP53). In addition, CIMO was observed to arrest BC cells at G0/G1 phase and of the cell cycle. Furthermore, CIMO suppressed BC cell migration and invasion with concordant regulation of genes involved in epithelial to mesechymal transition (CDH1, CDH2, OCLN and VIM). Thus, we report the utility of a synthetic azaspirane which targets the JAK-STAT pathway in ER- BC. PMID- 27500742 TI - Fast imaging of laboratory core floods using 3D compressed sensing RARE MRI. AB - Three-dimensional (3D) imaging of the fluid distributions within the rock is essential to enable the unambiguous interpretation of core flooding data. Magnetic resonance imaging (MRI) has been widely used to image fluid saturation in rock cores; however, conventional acquisition strategies are typically too slow to capture the dynamic nature of the displacement processes that are of interest. Using Compressed Sensing (CS), it is possible to reconstruct a near perfect image from significantly fewer measurements than was previously thought necessary, and this can result in a significant reduction in the image acquisition times. In the present study, a method using the Rapid Acquisition with Relaxation Enhancement (RARE) pulse sequence with CS to provide 3D images of the fluid saturation in rock core samples during laboratory core floods is demonstrated. An objective method using image quality metrics for the determination of the most suitable regularisation functional to be used in the CS reconstructions is reported. It is shown that for the present application, Total Variation outperforms the Haar and Daubechies3 wavelet families in terms of the agreement of their respective CS reconstructions with a fully-sampled reference image. Using the CS-RARE approach, 3D images of the fluid saturation in the rock core have been acquired in 16min. The CS-RARE technique has been applied to image the residual water saturation in the rock during a water-water displacement core flood. With a flow rate corresponding to an interstitial velocity of vi=1.89+/ 0.03ftday(-1), 0.1 pore volumes were injected over the course of each image acquisition, a four-fold reduction when compared to a fully-sampled RARE acquisition. Finally, the 3D CS-RARE technique has been used to image the drainage of dodecane into the water-saturated rock in which the dynamics of the coalescence of discrete clusters of the non-wetting phase are clearly observed. The enhancement in the temporal resolution that has been achieved using the CS RARE approach enables dynamic transport processes pertinent to laboratory core floods to be investigated in 3D on a time-scale and with a spatial resolution that, until now, has not been possible. PMID- 27500743 TI - Comment on "Surgically Resected Gall Bladder: Is Histopathology Needed for All?". PMID- 27500744 TI - Toward Accurate Modeling of the Effect of Ion-Pair Formation on Solute Redox Potential. AB - A scheme to model the dependence of a solute redox potential on the supporting electrolyte is proposed, and the results are compared to experimental observations and other reported theoretical models. An improved agreement with experiment is exhibited if the effect of the supporting electrolyte on the redox potential is modeled through a concentration change induced via ion pair formation with the salt, rather than by only considering the direct impact on the redox potential of the solute itself. To exemplify the approach, the scheme is applied to the concentration-dependent redox potential of select molecules proposed for nonaqueous flow batteries. However, the methodology is general and enables rational computational electrolyte design through tuning of the operating window of electrochemical systems by shifting the redox potential of its solutes; including potentially both salts as well as redox active molecules. PMID- 27500745 TI - Teaching to the test: developing an assessment tool for novice echocardiographers. PMID- 27500746 TI - Nucleophilic Difluoromethylenation of Ketones Using Diethyl (Difluoro(trimethylsilyl)methyl)phosphonate Mediated by 18-Crown-6 Ether/KOAc. AB - We report a general difluoromethylenation of various types of ketones using diethyl (difluoro(trimethylsilyl)methyl)phosphonate mediated by the combination of 18-crown-6 and KOAc. It provides facile access to structurally diverse beta hydroxy-alpha,alpha-difluorophosphonates as interesting targets for medicinal research. PMID- 27500747 TI - Significance of groundwater flux on contaminant concentration and mass discharge in the nonaqueous phase liquid (NAPL) contaminated zone. AB - Groundwater flowing through residual nonaqueous phase liquid (NAPL) source zone will cause NAPL dissolution and generate large contaminant plume. The use of contaminant mass discharge (CMD) measurements in addition to NAPL aqueous phase concentration to characterize site conditions and assess remediation performance is becoming popular. In this study, we developed new and generic numerical models to investigate the significance of groundwater flux temporal variations on the NAPL source dynamics. The developed models can accommodate any temporal variations of groundwater flux in the source zone. We examined the various features of groundwater flux using a few selected functional forms of linear increase/decrease, gradual smooth increase/decrease, and periodic fluctuations with a general trend. Groundwater flux temporal variations have more pronounced effects on the contaminant mass discharge dynamics than the aqueous concentration. If the groundwater flux initially increases, then the reduction in contaminant mass discharge (CMDR) vs. NAPL mass reduction (MR) relationship is mainly downward concave. If the groundwater flux initially decreases, then CMDR vs. MR relationship is mainly upward convex. If the groundwater flux variations are periodic, the CMDR vs. MR relationship tends to also have periodic variations ranging from upward convex to downward concave. Eventually, however, the CMDR vs. MR relationship approaches 1:1 when majority of the NAPL mass becomes depleted. PMID- 27500748 TI - Groundwater contamination in coastal urban areas: Anthropogenic pressure and natural attenuation processes. Example of Recife (PE State, NE Brazil). AB - In a context of increasing land use pressure (over-exploitation, surface-water contamination) and repeated droughts, identifying the processes affecting groundwater quality in coastal megacities of the tropical and arid countries will condition their long-term social and environmental sustainability. The present study focuses on the Brazilian Recife Metropolitan Region (RMR), which is a highly urbanized area (3,743,854 inhabitants in 2010) on the Atlantic coast located next to an estuarial zone and overlying a multi-layered sedimentary system featured by a variable sediment texture and organic content. It investigates the contamination and redox status patterns conditioning potential attenuation within the shallow aquifers that constitute the interface between the city and the strategic deeper semi-confined aquifers. These latter are increasingly exploited, leading to high drawdown in potenciometric levels of 20 30m and up to 70m in some high well density places, and potentially connected to the surface through leakage. From a multi-tracer approach (major ions, major gases, delta(11)B, delta(18)O-SO4, delta(34)S-SO4) carried out during two field campaigns in September 2012 and March 2013 (sampling of 19 wells and 3 surface waters), it has been possible to assess the contamination sources and the redox processes. The increasing trend for mineralization from inland to coastal and estuarial wells (from 119 to around 10,000MUS/cm) is at first attributed to water rock interactions combined with natural and human-induced potentiometric gradients. Secondly, along with this trend, one finds an environmental pressure gradient related to sewage and/or surface-channel network impacts (typically depleted delta(11)B within the range of 10-150/00) that are purveyors of chloride, nitrate, ammonium and sulfate. Nitrate, ammonium and sulfate (ranging from 0 to 1.70mmol/L, from 0 to 0,65mmol/L, from 0.03 to 3.91mmol/L respectively are also potentially produced or consumed through various redox processes (pyrite oxidation, denitrification, dissimilatory nitrate reduction to ammonium) within the system, as is apparent within a patchwork of biogeochemical reactors. Furthermore, intensive pumping in the coastal area with its high well density punctually leads to temporary well salinization ([Cl] reaching temporarily 79mmol/L). Our results, summarized as a conceptual scheme based on environmental conditions, is a suitable basis for implementing sustainable management in coastal sedimentary hydrosystems influenced by highly urbanized conditions. PMID- 27500749 TI - Effects of reservoir heterogeneity on scaling of effective mass transfer coefficient for solute transport. AB - Modeling transport process at large scale requires proper scale-up of subsurface heterogeneity and an understanding of its interaction with the underlying transport mechanisms. A technique based on volume averaging is applied to quantitatively assess the scaling characteristics of effective mass transfer coefficient in heterogeneous reservoir models. The effective mass transfer coefficient represents the combined contribution from diffusion and dispersion to the transport of non-reactive solute particles within a fluid phase. Although treatment of transport problems with the volume averaging technique has been published in the past, application to geological systems exhibiting realistic spatial variability remains a challenge. Previously, the authors developed a new procedure where results from a fine-scale numerical flow simulation reflecting the full physics of the transport process albeit over a sub-volume of the reservoir are integrated with the volume averaging technique to provide effective description of transport properties. The procedure is extended such that spatial averaging is performed at the local-heterogeneity scale. In this paper, the transport of a passive (non-reactive) solute is simulated on multiple reservoir models exhibiting different patterns of heterogeneities, and the scaling behavior of effective mass transfer coefficient (Keff) is examined and compared. One such set of models exhibit power-law (fractal) characteristics, and the variability of dispersion and Keff with scale is in good agreement with analytical expressions described in the literature. This work offers an insight into the impacts of heterogeneity on the scaling of effective transport parameters. A key finding is that spatial heterogeneity models with similar univariate and bivariate statistics may exhibit different scaling characteristics because of the influence of higher order statistics. More mixing is observed in the channelized models with higher-order continuity. It reinforces the notion that the flow response is influenced by the higher-order statistical description of heterogeneity. An important implication is that when scaling-up transport response from lab-scale results to the field scale, it is necessary to account for the scale-up of heterogeneity. Since the characteristics of higher-order multivariate distributions and large-scale heterogeneity are typically not captured in small scale experiments, a reservoir modeling framework that captures the uncertainty in heterogeneity description should be adopted. PMID- 27500750 TI - Dipeptide-Based Carbohydrate Receptors and Polymers for Glycopeptide Enrichment and Glycan Discrimination. AB - Glycoproteomics identifies and catalogs protein glycosylation and explores its impact on protein conformations and biofunctions. However, these studies are restricted by the bottleneck to enrich low-abundance glycopeptides from complex biosamples and the difficulties in analyzing glycan structures by mass spectrometry. Here, we report dipeptide as a simple but promising carbohydrate binding platform to tackle these problems. We build a hydropathy-index-based strategy for sequence optimization and screen out three optimal dipeptide sequences from 54 types of dipeptides. The optimized dipeptide-based homopolymers display excellent performance (e.g., selectivity up to ~70% for real biosamples and strong anti-interference capacity capable of resisting 1000-fold bovine serum albumin interference) in glycopeptide enrichment. Meanwhile, our polymers exhibit high-efficiency chromatographic separation toward oligosaccharides with different compositions, polymerization degrees and even their linkage isomers. This brings another attractive feature that our materials can discriminate subtly variable glycan structures of glycopeptides, especially, isomeric glycosidic linkages. These features provide a solid foundation to analyze the complex glycan structures and glycosites simultaneously, which will benefit future development of glycoproteomics and glycobiology. PMID- 27500751 TI - Stability analysis of switched cellular neural networks: A mode-dependent average dwell time approach. AB - This paper addresses the exponential stability of switched cellular neural networks by using the mode-dependent average dwell time (MDADT) approach. This method is quite different from the traditional average dwell time (ADT) method in permitting each subsystem to have its own average dwell time. Detailed investigations have been carried out for two cases. One is that all subsystems are stable and the other is that stable subsystems coexist with unstable subsystems. By employing Lyapunov functionals, linear matrix inequalities (LMIs), Jessen-type inequality, Wirtinger-based inequality, reciprocally convex approach, we derived some novel and less conservative conditions on exponential stability of the networks. Comparing to ADT, the proposed MDADT show that the minimal dwell time of each subsystem is smaller and the switched system stabilizes faster. The obtained results extend and improve some existing ones. Moreover, the validness and effectiveness of these results are demonstrated through numerical simulations. PMID- 27500752 TI - Long-Term Outcomes and Complications of Intracardiac Echocardiography-Assisted Patent Foramen Ovale Closure in 1,000 Consecutive Patients. AB - BACKGROUNDS: Long-term fate of patients submitted to patent foramen ovale (PFO) closure is still unclear. The aim of the study was to evaluate the incidence of atrial fibrillation (AF), aortic or atrial free wall erosion, device thrombosis (DT), new onset or worsening of mitral valve regurgitation (MVR), and recurrent cerebral ischemic events in the long-term follow up after intracardiac echocardiography (ICE)-aided PFO closure in a large population. METHODS: We reviewed the medical and instrumental data of 1,000 consecutive patients (mean age 47.3 +/- 17.1 years, females) prospectively enrolled in 2 centres over a 13 years period (February 1999-February 2012) for R-to-L shunt ICE-aided catheter based closure using different devices. RESULTS: Immediate success was 99.8%. Implanted devices were Amplatzer PFO Occluder in 463 patients (46.3%), Amplatzer ASD Cribriform Occluder in 420 patients (42.0%), Premere Occlusion System in 95 patients (9.5%), and Biostar Occluder in 22 patients (2.2%). On a mean follow-up of 12.3 +/- 0.6 years (minimum 4- maximum 17 years), permanent AF occurred in 0.5%, DT was apparent in 0.5%, new onset or worsening of MVR was observed in 0.2%, whereas recurrent cerebral ischemic events were 0.8%. Occlusion rate was 93.8%. No aortic or atrial free wall erosion has been observed. CONCLUSION: ICE aided closure of PFO using different devices, appeared very safe and effective on very long-term follow up with low incidence of erosion, DT, recurrent ischemic events, MVR new onset or worsening, and permanent AF. PMID- 27500753 TI - Use of antibiotics is associated with lower enterolactone plasma concentration. AB - SCOPE: High enterolactone levels may have health benefits in relation to risk of noncommunicable diseases. Enterolactone is produced by the colonic microbiota after intake of lignans and treatment with antimicrobials may result in altered enterolactone production. This study investigates the association between antibiotic use and enterolactone concentration. METHODS AND RESULTS: Using LC MS/MS, enterolactone concentrations were quantified in plasma samples from 2237 participants from the Diet, Cancer and Health cohort. The participants were healthy at enrollment, but were later diagnosed with cancer. At enrollment, participants had blood drawn and completed a food frequency questionnaire and lifestyle questionnaire. Antibiotic use was assessed as reimbursed antibiotic prescriptions up to 12 months before enrollment. Antibiotic use <=3 months before enrollment was associated with a 41% (Deltacrude : -41; 95% CI: -52, -28) lower enterolactone concentration in women and 12% in men (Deltacrude : -12; 95% CI: 31, 11), while antibiotic use >3-12 months before enrollment was associated with 26% lower enterolactone in women (Deltacrude : -26; 95% CI: -37, -14) and 14% in men (Deltacrude : -14; 95% CI: -28, 1). CONCLUSION: Use of antibiotics up to 12 months before enrollment was associated with lower plasma enterolactone levels, especially among women. PMID- 27500754 TI - Does intraspecific behavioural variation of pollinator species influence pollination? A quantitative study with hummingbirds and a Neotropical shrub. AB - Floral visitors differ in their efficacy as pollinators, and the impact of different pollinator species on pollen flow and plant reproduction has been frequently evaluated. In contrast, the impact of intraspecific behavioural changes on their efficacy as pollinators has seldom been quantified. We studied a self-incompatible shrub Palicourea rigida (Rubiaceae) and its hummingbird pollinators, which adjust their behaviour according to floral resource availability. Fluorescence microscopy was used to access pollen tube growth and incompatibility reaction in pistils after a single visit of territorial or intruder hummingbirds in two populations. To characterise the plant populations and possible differences in resource availability between areas we used a three term quadrat variance method to detect clusters of floral resources. Within species variation in foraging behaviour, but not species identity, affected pollinator efficacy. Effectively, hummingbirds intruding into territories deposited more compatible pollen grains on P. rigida stigmas than territory holders in both study areas. Additionally, territory holders deposited more incompatible than compatible pollen grains. Our results imply that intraspecific foraging behaviour variation has consequences for pollination success. Quantifying such variation and addressing the implications of intraspecific variability contribute to a better understanding of the dynamics and consequences of plant-pollinator interactions. PMID- 27500755 TI - Relationship between smoking and adverse outcomes in patients with atrial fibrillation: A meta-analysis and systematic review. AB - BACKGROUND: Several studies have investigated the impact of smoking on the prognosis of atrial fibrillation (AF), but the results remain controversial. We therefore aimed to estimate the association between smoking and adverse outcomes in patients with AF. METHODS: We systematically searched the Cochrane Library, PubMed, and Elsevier databases through May 2016 for studies regarding the association between smoking and adverse outcomes in AF patients. Risk ratios [RRs] and 95% confidence intervals [CIs] were abstracted and then pooled using a random-effects model. RESULTS: A total of 8 cohort studies with 87,373 participants were included in this meta-analysis. Among patients with AF, smoking was associated with increased risks of all-cause death (RR=1.82, 95% CI: 1.33 2.49, P=0.0002) and cardiovascular death (RR=1.54, 95% CI: 1.31-1.81, P<0.00001) but not stroke/thromboembolism (RR=1.19, 95% CI 0.97-1.46; P=0.10). In addition, smoking was associated with an increased risk of major bleeding (RR=1.93, 95% CI 1.08-3.47, P=0.03), even after adjustment for the antithrombotic treatment. CONCLUSIONS: The published literature demonstrates that smoking is not associated with the risk of stroke/thromboembolism but increases the risks of all-cause death and cardiovascular death in AF patients, as well as the risk of major bleeding in AF patients using anticoagulants. PMID- 27500756 TI - Marital status and living condition as predictors of mortality and readmissions among African Americans with heart failure. AB - Socioeconomic factors, including social support, may partially explain why African Americans (AA) have the highest prevalence of heart failure and with worse outcomes compared to other races. AA are more likely to be hospitalized and readmitted for heart failure and have higher mortality. The purpose of this study is to determine whether the social factors of marital status and living condition affect readmission rates and all-cause mortality following hospitalization for acute decompensated heart failure (ADHF) in AA patients. METHODS: Medical records from 611 AA admitted to Einstein Medical Center Philadelphia from January, 2011 to February, 2013 for ADHF were reviewed. Patient demographics including living condition (nursing home residents, living with family or living alone) and marital status (married or non-married -including single, divorced, separated and widowed) were correlated with all-cause mortality and readmission rates. RESULTS: In this cohort (53% male, mean age 65+/-15, mean ejection fraction 32+/-16%) 25% (n=152) of subjects were unmarried. Unmarried patients had significantly higher 30-day readmission rates (16% vs. 6% p=0.0002) and higher 1-year mortality (17% vs. 11% p=0.047) compared with married patients. Fifty percent (n=303) of subjects were living with family members, while 40% (n=242) and 11% (n=66) were living alone or in a nursing facility, respectively. Patients living with family members had significantly lower 30-day readmission rates when compared with those living alone or in a nursing facility (7% vs 21% vs. 18% p=<0.0001). Furthermore, they had the lowest 1-year mortality (14% vs 32% for nursing facility patients and 17% for those living alone (p=0.0007). After controlling for traditional risk factors (age, gender, body mass index, peak troponin I, left ventricular ejection fraction, B-type natriuretic peptide, hypertension, diabetes mellitus, hyperlipidemia, and coronary artery disease), being married was an indpendent predictor of 1-year mortality (OR 0.50 p=0.019) and living alone for 30-day readmission (OR 2.86 p=<0.001). CONCLUSION: The socioeconomic factors of marital status and living condition significantly correlated with mortality and 30-day readmission rate in AA heart failure patients. Specifically, being married and living with family independently predict lower mortality and fewer readmissions. Surprisingly, living in a nursing facility was associated with significantly higher mortality than living alone or with family. PMID- 27500757 TI - Retrograde revascularization of ostial left main CTO using internal mammary artery byepass graft: A case report. PMID- 27500758 TI - Acupuncture for heart failure: A systematic review of clinical studies. AB - BACKGROUND: Acupuncture has been used for treating heart failure mainly in combination with conventional treatments, but evidence for its effectiveness and safety has not been well established. Our aim was to review randomized controlled trials (RCTs) on acupuncture for heart failure and assess the clinical evidence. METHODS: Electronic databases such as Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and certain Chinese & Korean databases were searched until October 2015. The main outcomes assessed were mortality, New York Heart Association (NYHA) function classifications, and acupuncture-related adverse events. The details of acupuncture intervention were also investigated. RESULTS: Among 4107 publications, seven RCTs were included; most of them showed considerable methodological flaws. We could not conduct a meta-analysis because of the heterogeneity of the included studies. In one acute heart failure study, acupuncture shortened intensive care unit (ICU) stay by 2.2days (95% CI 1.26, 3.14) and reduced the risk ratio of re-admission to 0.53 (95% CI 0.28, 0.99). However, mortality was not affected. Hemodynamic parameters also showed improvement. Another study reported an improved left ventricular ejection fraction by 9.95% (95% CI 3.24, 16.66). In five chronic heart failure studies, acupuncture improved exercise capacity, quality of life, hemodynamic parameters, and time domain heart rate variability parameters. Acupuncture decreased NT-pro BNP levels by 292.20 (95% CI -567.36, -17.04). No adverse effects were reported. CONCLUSIONS: The effectiveness of acupuncture as a therapy for heart failure is currently inconclusive. Further large and rigorous clinical trials are needed to establish its clinical utility. PMID- 27500759 TI - Endovascular anatomic reconstruction of the iliac bifurcation with covered stentgrafts in sandwich-technique for the treatment of complex aorto-iliac aneurysms. AB - OBJECTIVE: Endovascular anatomic reconstruction of iliac artery bifurcation in aorto-iliac aneurysms using commercial stentgrafts in sandwich-technique by bilateral transfemoral approach. METHODS: 24 patients (mean 73.8+/-standard deviation 6.8years) with complex aorto-iliac aneurysms (AAA): n=17; diameter 64+/ 15 [48-100]mm; common-iliac-artery (CIA): n=27; 43+/-15 [30-87]mm; internal-iliac artery (IIA): n=14; 28+/-8 [15-43]mm) were prospectively enrolled for EVAR with preservation of the IIA (n=31; bi-lateral n=7). Maintenance of antegrade flow to IIA by iliac reconstruction was performed in sandwich-technique prior to EVAR. Follow-up of 15.0+/-10.8 [1-40]months included contrast-enhanced ultrasound and computed-tomography after 1week, 3, 6 and every 12months. RESULTS: Initial technical success for anatomic reconstruction of the iliac arteries in 31 instances was 100%. Primary patency of iliac neo-bifurcations was 90.9% (20/22) at 6months and 84.2% (16/19) at 1year. Postprocedural gutter-endoleaks type 1b were obvious in 6.5% (2/31) of cases, which disappeared 3months later. Aortic/iliac aneurysm-size after 1year decreased (>5mm) in 61.5% of patients. No aneurysm-size increase or late rupture occurred. CONCLUSIONS: Endovascular reconstruction of the iliac bifurcation with commercial standard stentgrafts is safe and effective. Transfemoral approach allows extension of distal landing zone for EVAR while preserving the internal iliac artery blood-flow, even in unfavorable iliac anatomy. PMID- 27500760 TI - Expanding the functional role of miRNAs in the establishment of permanent atrial fibrillation. PMID- 27500761 TI - Elevated fibroblast growth factor-23 and risk of cardiovascular disease or mortality in the general population: A meta-analysis. PMID- 27500762 TI - Pre-test probability of obstructive coronary stenosis in patients undergoing coronary CT angiography: Comparative performance of the modified diamond Forrester algorithm versus methods incorporating cardiovascular risk factors. AB - BACKGROUND: Current guidelines recommend the use of the Modified Diamond Forrester (MDF) method to assess the pre-test likelihood of obstructive coronary artery disease (CAD). We aimed to compare the performance of the MDF method with two contemporary algorithms derived from multicenter trials that additionally incorporate cardiovascular risk factors: the calculator-based 'CAD Consortium 2' method, and the integer-based CONFIRM score. METHODS: We assessed 1069 consecutive patients without known CAD undergoing coronary CT angiography (CCTA) for stable chest pain. Obstructive CAD was defined as the presence of coronary stenosis >=50% on 64-slice dual-source CT. The three methods were assessed for calibration, discrimination, net reclassification, and changes in proposed downstream testing based upon calculated pre-test likelihoods. RESULTS: The observed prevalence of obstructive CAD was 13.8% (n=147). Overestimations of the likelihood of obstructive CAD were 140.1%, 9.8%, and 18.8%, respectively, for the MDF, CAD Consortium 2 and CONFIRM methods. The CAD Consortium 2 showed greater discriminative power than the MDF method, with a C-statistic of 0.73 vs. 0.70 (p<0.001), while the CONFIRM score did not (C-statistic 0.71, p=0.492). Reclassification of pre-test likelihood using the 'CAD Consortium 2' or CONFIRM scores resulted in a net reclassification improvement of 0.19 and 0.18, respectively, which would change the diagnostic strategy in approximately half of the patients. CONCLUSIONS: Newer risk factor-encompassing models allow for a more precise estimation of pre-test probabilities of obstructive CAD than the guideline-recommended MDF method. Adoption of these scores may improve disease prediction and change the diagnostic pathway in a significant proportion of patients. PMID- 27500763 TI - Comparative safety and effectiveness of coronary computed tomography: Systematic review and meta-analysis including 11 randomized controlled trials and 19,957 patients. AB - BACKGROUND/OBJECTIVES: The clinical approach to suspected or established coronary artery disease (CAD) has been revolutionized in the last few decades by coronary computed tomography (coroCT). Yet, uncertainty persists on its comparative diagnostic and clinical effectiveness. We conducted a systematic review on randomized controlled trials (RCTs) of coroCT. METHODS: We searched RCTs in PubMed and The Cochrane Library, extracting as outcomes of interest long-term rates of death, myocardial infarction, revascularization, and invasive coronary angiography. Effects were estimated with risk ratios (RR) and 95% confidence intervals. RESULTS: A total of 11 trials were included, with 19,957 patients followed for a median of 6months. One trial focused on screening, 3 on stable CAD, and 7 on acute CAD. Meta-analysis showed that coroCT was associated with a trend toward fewer deaths or myocardial infarctions (RR=0.84 [0.70-1.01]) whereas no significant difference was found for the risk of death (RR=0.91 [0.71-1.18]). Conversely, the risk of myocardial infarction tended to be lower with coroCT at the overall analysis (RR=0.77 [0.59-1.02]), and this effect reached statistical significance in studies focusing on subjects with stable CAD (RR=0.69 [0.49 0.99]). These potential benefits were offset (or mediated) by a significant albeit modest increase in the need for invasive angiography (RR=1.36 [1.08 1.72]), and ensuing coronary revascularization (RR=1.76 [1.29-2.40]). CONCLUSIONS: According to the current evidence base, coroCT is associated with an increased usage of invasive angiography and coronary revascularization when compared to standard of care, with possible benefits on nonfatal myocardial infarction, but without significant benefits on death or the composite of death or myocardial infarction. PMID- 27500764 TI - A case of false positive cardiac troponin I in CANOMAD syndrome. PMID- 27500765 TI - Apelin-13 infusion salvages the peri-infarct region to preserve cardiac function after severe myocardial injury. AB - BACKGROUND: Apelin-13 (A13) regulates cardiac homeostasis. However, the effects and mechanism of A13 infusion after an acute myocardial injury (AMI) have not been elucidated. This study assesses the restorative effects and mechanism of A13 on the peri-infarct region in murine AMI model. METHODS: 51 FVB/N mice (12weeks, 30g) underwent AMI. A week following injury, continuous micro-pump infusion of A13 (0.5MUg/g/day) and saline was initiated for 4-week duration. Dual contrast MRI was conducted on weeks 1, 2, 3, and 5, consisting of delayed-enhanced and manganese-enhanced MRI. Four mice in each group were followed for an extended period of 4weeks without further infusion and underwent MRI scans on weeks 7 and 9. RESULTS: A13 infusion demonstrated preserved LVEF compared to saline from weeks 1 to 4 (21.9+/-3.2% to 23.1+/-1.7%* vs. 23.5+/-1.7% to 16.9+/-2.8%, *p=0.02), which persisted up to 9weeks post-MI (+1.4%* vs. -9.4%, *p=0.03). Mechanistically, dual contrast MRI demonstrated significant decrease in the peri infarct and scar % volume in A13 group from weeks 1 to 4 (15.1 to 7.4% and 34.3 to 25.1%, p=0.02, respectively). This was corroborated by significant increase in 5-ethynyl-2'-deoxyuridine (EdU(+)) cells by A13 vs. saline groups in the peri infarct region (16.5+/-3.1% vs. 8.1+/-1.6%; p=0.04), suggesting active cell mitosis. Finally, significantly enhanced mobilization of CD34(+) cells in the peripheral blood and up-regulation of APJ, fibrotic, and apoptotic genes in the peri-infarct region were found. CONCLUSIONS: A13 preserves cardiac performance by salvaging the peri-infarct region and may contribute to permanent restoration of the severely injured myocardium. PMID- 27500766 TI - Elevated levels of plasma transforming growth factor-beta1 in idiopathic and heritable pulmonary arterial hypertension. AB - BACKGROUND: Aberrant transforming growth factor (TGF)-beta signaling is involved in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate the predictive value of the upstream ligand of TGF-beta signaling (TGF-beta1) on long-term mortality and the clinical characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH) and heritable PAH (HPAH). METHODS AND RESULTS: Plasma TGF-beta1 levels were measured in 151 IPAH and 65 HPAH patients retrospectively enrolled between January 2008 and March 2013, and compared to 61 healthy subjects. Data for mortality over time were obtained from hospital databases and from telephone follow-ups. The main outcome was all-cause death. Plasma TGF-beta1 was significantly higher in IPAH/HPAH patients compared to control subjects (4.74 vs. 2.61ng/mL, respectively; P<0.001). Mean follow-up time was 3.4+/-1.8years, during which 86 patients died. ROC curves were utilized to determine TGF-beta1 cutoff values. Compared to patients with TGF-beta1 of <3.74ng/mL, heart function was significantly impaired (percentage of patients with WHO functional class III/IV, 51.4% vs. 65.5%, P=0.043) and mortality risk was elevated (P=0.009) for patients with TGF-beta1>3.74ng/mL. However, the difference in mortality rate between patients with higher and lower TGF-beta1 levels was only statistically significant for female patients (P=0.004), despite a similar trend for male patients. Multivariate analyses revealed that TGF-beta1 (HR after log transformation base of 10: 2.623; 95%CI: 1.228-5.603; P=0.013) emerged as the independent predictor for all-cause mortality. CONCLUSION: High circulating levels of TGF-beta1 were an independent predictor of a poor outcome for IPAH/HPAH patients. PMID- 27500767 TI - The Difference between the optical coherence tomography (OCT) findings of newly progressed coronary lesions in symptomatic and asymptomatic patients. AB - BACKGROUND: Generally, newly progressed coronary lesions (NPCLs) are considered to be composed of lipid-rich plaques. In case of vulnerable plaque rupture, they may quickly become culprit lesions responsible for acute coronary syndromes. METHODS: Between September 2011 and September 2015, 2034 patients underwent scheduled follow-up coronary angiography (CAG) after percutaneous coronary intervention (PCI) in Tsuchiya General Hospital. Patients with NPCLs found by CAG during the follow-up period were evaluated by optical coherence tomography (OCT). NPCLs were defined as the lesions with less than 50% diameter stenosis, which progressed to more than 75% diameter stenosis within 3years after the previous CAG. Patients with restenosis after PCI were excluded. We compared OCT findings of NPCLs between symptomatic and asymptomatic patients. RESULTS: The follow-up CAG showed NPCLs in 64 patients (3.2%). OCT revealed fibrous plaque in 42 patients (65.6%) and thin-cap fibroatheroma in one patient. Thirteen patients had chest symptoms for one month before CAG and the remaining 51 patients were asymptomatic. The prevalence of fibrous plaque and intimal disruption or plaque rupture were not significantly different between symptomatic and asymptomatic patients (61.5% vs. 66.7%, p=0.752 and 30.8% vs. 11.8%, p=0.213, respectively). However, thrombi were more frequently observed in symptomatic patients (61.5% vs. 13.7%, p<0.001). CONCLUSIONS: The majority of NPCLs found in asymptomatic patients at follow-up CAG were not vulnerable; however, those found in symptomatic patients might be vulnerable. In clinical practice, NPCLs found in asymptomatic patients should be evaluated for functional severity of stenosis in order to determine the need for coronary revascularization. PMID- 27500768 TI - Compensated Ferrimagnetic Tetragonal Heusler Thin Films for Antiferromagnetic Spintronics. AB - Fully compensated ferrimagnets with tetragonal crystal structure have the potential for large spin-polarization and strong out-of-plane magnetic anisotropy; hence, they are ideal candidates for high-density-memory applications. Tetragonal Heusler thin films with compensated magnetic state are realized by substitution of Pt in Mn3-x Ptx Ga. Furthermore, the bilayer formed from compensated/uncompensated Mn-Pt-Ga layers is utilized to accomplish exchange bias up to room temperature. PMID- 27500769 TI - [Postoperative applications of the fast track technology in patients with herniated intervertebral discs of the lumbosacral spine]. AB - TOPICALITY: The fast track technology means a complex of targeted measures involving rational preoperative preparation, minimally invasive surgery, regional anesthesia and short-acting anesthetics, and early postoperative rehabilitation. Elucidating the possibility of applying the fast track technology in neurosurgery, in particular in spinal surgery, is extremely topical. This is associated with the epidemiological data and the fact that minimally invasive techniques used in neurosurgery are highly expensive. AIM: The study objective was implementation of the fast track technology and subsequent analysis of its use after surgery in patients with herniated intervertebral discs of the lumbosacral spine. MATERIAL AND METHODS: The fast track technology following spinal surgery was implemented at the Clinical Hospital of the Presidential Administration of the Russian Federation and the Neurosurgical Department of the Clinical Hospital No 1 of the Presidential Administration of the Russian Federation using an algorithm of technology application. The study included 48 patients who underwent surgical treatment for herniated intervertebral discs of the lumbosacral spine between January and July 2015. RESULTS: An analysis of pain severity using the Visual Analog Scale demonstrated a slight decrease (10%) in a group of patients who were subjected to the fast track technology, at discharge and at 1 month after surgery; there was no difference in longer follow-up. An analysis of the functional status using the Oswestry index and Roland-Morris scale demonstrated that patients of the study group had faster and more efficient recovery and an improvement of the functional activity by 20% (p<0.05) compared to those in the control group. An analysis of patient-reported assessment of treatment quality revealed that indicators, such as awareness and pain control, in the study group were highest and amounted to 95% and higher. An analysis of the hospital stay duration showed a decrease in the number of bed-days in an integrated group by 39%, which saved 34 bed-days. CONCLUSION: The fast track technology reduces the degree of surgical aggression, increases surgery safety, and decreases the number of intraoperative complications and hospital stay duration. PMID- 27500770 TI - [Posterior decompression of the craniovertebral junction in children with Chiari malformation: a surgery extent issue]. AB - AIM: The study objective was to develop a rational approach for defining the extent of posterior decompression in children with Chiari 1 malformation. MATERIAL AND METHODS: Posterior decompression was performed in 76 children with Chiari 1 malformation, under 18 years of age, in the period between 2001 and 2015. Fifty two (68%) children had syringomyelia. Extradural decompression (EDD) was performed in 14 (18%) cases, extra-arachnoid duraplasty (EAD) in 21 (28%) cases, intra-arachnoid dissection and duraplasty in 21 (28%) cases, and foramen of Magendie stenting and duraplasty in 20 (26%) cases. RESULTS: Complications occurred in 15 (20%) patients, with one of them being fatal (case fatality rate, 1.3%). The complication rate was higher after (1) intra-arachnoid dissection (p=0.0009) and stenting (p=0.02). Re-operation was required in 8 (11%) patients. The overall rate of complications and re-operations was lowest after EAD (10%). CONCLUSION: EAD is the method of choice for Chiari 1 malformation in children. EDD can be adopted as a primary option, but it requires selection of relevant patients. Intra-arachnoid dissection, with/without stenting, is not advisable as a primary intervention, but may be inevitable in the re-operation case. PMID- 27500771 TI - [Venous compression as a cause of trigeminal neuralgia]. AB - AIM: The study objective was to verify venous compression as a cause of trigeminal neuralgia (TN) and to define the optimal surgical tactics for TN patients. MATERIAL AND METHODS: Four hundred twenty one patients were operated on for TN at the Neurosurgical Department of the City Hospital No2 from 1998 to 2015. Veins in the trigeminal nerve root entry zone, as a significant compression factor, were identified in 40 patients (9.5%). Intraoperative data, questionnaires, and self-assessment inventories were analyzed. Treatment outcomes were assessed using the Barrow Neurological Institute (BNI) scale. RESULTS: Patients with venous compression were divided into two groups. Eleven (27.5%) patients in the first group had isolated venous compression. The feature of microvascular decompression (MVD) in these patients was identification of all veins, vein mobilization, and, if possible, vein coagulation and resection. Resection of the vein along its course is a basic procedure to avoid recurrent neuralgia. The second group included 29 (72.5%) patients with a combination of venous and arterial compression. In these patients, a vein acted as an "assisting" compression factor: the vein changed the course of a compressing artery or nerve and exerted an additional compression effect on the nerve. The surgical tactics involved exploration of the trigeminal nerve root entry zone, arterial loop mobilization, and placement of a Teflon protector; venous vessels were coagulated and resected. The MVD efficacy was as follows: in group 1, 10 patients had a BNI score I-III, and 1 patient had a BNI score IV; in group II, 25 patients had a BNI score I-III, and 4 patients had a BNI score IV. CONCLUSION: Venous compression can play both independent and assisting roles in the TN genesis. When exploring the trigeminal nerve, examination of the proximal trigeminal nerve is of particular importance, with paying attention to veins that may be a compression factor. In the case of isolated venous compression, the MVD surgical technique has some peculiarities, in particular coagulation and resection of veins compressing the trigeminal nerve root entry zone. PMID- 27500772 TI - [Evaluation of short-term surgical outcomes in facial paralysis patients treated by trigeminal neurotization]. AB - The management of patients with facial nerve palsy is a challenge of modern neurosurgery. The study purpose was to evaluate the degree of facial nerve function recovery, following trigeminal neurotization. Trigeminal neurotization was performed in 23 patients within 1 to 10 months after the development of facial paralysis. In most cases, the cause of facial paralysis was surgery for space-occupying lesions of the cerebellopontine angle (95.6%). Outcomes of trigeminal neurotization were evaluated in 17 (73.9%) patients who were followed up for more than 6 months. In 16 (94.1%) patients, the facial nerve function was recovered to a House-Brackmann grade III-IV. Given the surgery RESULTS: we can say that trigeminal neurotization is one of the effective treatments for facial paralysis. In most cases, this technique has provided good outcomes without additional complications, which is important for this group of patients. PMID- 27500773 TI - [Mini-orbitozygomatic craniotomy in surgery for supratentorial aneurysms and tumors of the anterior and middle cranial fossae]. AB - Progress in microneurosurgical techniques, neuroanesthesiology, and intraoperative imaging enables surgery using small incisions and craniotomy, in accordance with the keyhole surgery concept. Supraorbital craniotomy is the most widespread minimally invasive approach. There are a number of supraorbital craniotomy modifications, regarding different soft tissue incisions and the extent of craniotomy. We present the first results of using mini-orbitozygomatic craniotomy for aneurysms of the anterior circle of Willis and space-occupying lesions of the anterior and middle cranial fossae performed through an eyebrow incision. MATERIAL AND METHODS: Forty five patients were operated on using mini orbitozygomatic (MOZ) craniotomy in the period between March 2014 and December 2015. Fifteen supratentorial aneurysms were clipped, and 30 space-occupying lesions were resected. Most patients had unruptured aneurysms (10 patients). Five patients had a history of SAH. The aneurysm localization was as follows: 8 anterior communicating artery aneurysms, 4 aneurysms of the internal carotid artery in the area of the posterior communicating artery orifice, and 3 ophthalmic aneurysms. The Hunt-Hess scale was used to evaluate the patients' condition, and the Fisher scale was used to quantify SAH volume. Surgery was performed 14 days after SAH, on average. Contrast-enhanced MRI of the brain was the diagnostic method of choice in a group of patients with space-occupying lesions within the anterior and middle cranial fossae. In some cases, patients underwent CT with reconstruction for assessment of the skull base bone structures. The mean age of patients was 58.3 years. RESULTS: All aneurysms were completely excluded from the cerebral blood flow. No serious complications and deaths in a group of aneurysm patients occurred. Complete tumor removal was performed in 28 patients. Two patients having pituitary macroadenomas with supra- and parasellar spread underwent subtotal resection due to adenoma invasion into the cavernous sinus. Mortality in this group was 3.3% (1 patient). Postoperative complications were evaluated after 2 weeks and 6 months. The postoperative cosmetic result after 3 and 6 months after surgery was assessed by patients as excellent. CONCLUSION: Mini-orbitozygomatic craniotomy is an alternative to classic approaches and can be assistive in surgery for skull base aneurysms and tumors. Selection of candidates for this keyhole surgery should be based on their critical assessment. PMID- 27500774 TI - [The paramedian supracerebellar transtentorial approach to the mediobasal temporal region]. AB - The mediobasal temporal region (MTR) is located near the brain stem and surrounded by the eloquent neurovascular structures. The supracerebellar transtentorial approach (STA) is safe access to the posterior MTR structures, however its use for resection of anterior MTR lesions still remains controversial. The article describes the technique and outcome of surgery for different MTR structures using STA. MATERIAL AND METHODS: The paramedian STA was used in 18 patients (13 females and 5 males) for 7 years. Ten patients presented with glial MTR tumors, 3 patients with cavernomas, 2 patients with arteriovenous malformations (AVMs), 2 patients with intraventricular meningiomas, and 1 patient with mesial temporal sclerosis. The patient age ranged from 19 to 57 years. In 10 cases, lesions were localized on the left. Epilepsy was the leading symptom in 14 cases. Patients underwent preoperative high-resolution MRI, electroencephalography video monitoring before and after surgery, intraoperative corticography (if necessary), and postoperative CT and MRI. RESULTS: Lesions were located in the anterior third of MTR in 5 patients, in the anterior and middle thirds in 2 patients, in the middle third in 5 patients, in the middle and posterior thirds in 2 patients, in the posterior third in 1 patient, in the anterior, middle, and posterior thirds in 1 patient, and in the ventricular triangle area in 2 patients. In all patients with intraventricular tumors, AVMs, and cavernous malformations and in 8 patients with glial MTR tumors, the lesions were totally resected. Two patients with intracerebral tumors underwent subtotal resection. A patient with intractable epilepsy and mesial temporal sclerosis underwent resection of the anterior two-thirds of the hippocampus and parahippocampal gyrus and, partially, amygdala using intraoperative corticography. There was no surgical mortality; 2 patients developed a transient neurological deficit, and 1 patient had a cerebellar hematoma that was successfully removed during surgery. CONCLUSION: STA enables resection of lesions localized in all parts of the MTR, without damage to the surrounding nerve and vascular structures. PMID- 27500775 TI - [Endoscopic transsphenoidal resection of pituitary adenomas invading the cavernous sinus]. AB - INTRODUCTION: Pituitary adenomas are benign growths that invade the cavernous sinus (CS) in 10-15% of cases. There are different types of microsurgical and endoscopic approaches enabling resection of tumors from the CS cavity that is a relatively small and hard to reach anatomical structure comprising eloquent neurovascular structures. MATERIAL AND METHODS: A study group included 97 patients with pituitary adenomas (PAs) invading the CS. PAs were resected using an endoscopic technique: adenomas were resected from the CS cavity through a standard endoscopic endonasal transsphenoidal approach in 62 cases; a lateral extended transsphenoidal endoscopic approach was used in 35 cases. A control group included patients with PAs spreading into the laterosellar region who were operated on using microsurgical extra-intradural (n=14) and transsphenoidal (n=149) approaches. In the study group, the degree of PA invasion into the CS cavity was determined using the Knosp scale. RESULTS: In the study group, total tumor resection was achieved in 49 (50.5%) cases, subtotal resection in 39 (40.2%) cases, and partial resection in 9 (9.3%) patients. In the case of visual disorders (n=70), vision improvement was achieved in 41.4% of cases. Vision deterioration was detected in 11.4% of cases; no vision changes were in 47.1% of cases. Patients (27.8%) who had not had visual impairments before surgery had no negative changes in vision in the postoperative period. The development/augmentation of oculomotor disorders in the study group occurred in 14 (14.4%) cases. In the study group, hormonal remission of the disease in patients with hormone-active PAs was in 26.7% of cases (n=12). There were no cases of nasal liquorrhea, meningitis, and death in the study group. CONCLUSION: Endoscopic endonasal transsphenoidal resection of PAs invading the CS is a more efficient and safer surgical technique compared to microsurgical techniques (transsphenoidal and extra-intradural approach). The lateral extended transsphenoidal endoscopic approach enables resection of PAs with massive invasion into the CS (Grade III and Grade IV, Knosp scale) and has less postoperative complications compared to the extra-intradural approach (p<0.05). PMID- 27500776 TI - [Intramedullary melanocytoma: a clinical case report and literature review]. AB - The paper describes a rare clinical case of intramedullary melanocytoma, provides a detailed description of a pathomorphological study, and addresses the issues of differential diagnosis and surgical treatment. PMID- 27500777 TI - [Cerebrospinal fluid shunt malfunction not associated with ventricular enlargement. A case report and literature review]. AB - Substantiation of the shunt failure diagnosis and subsequent consideration of indications for surgical elimination of the malfunction is a laborious and challenging process. Identification of a malfunction in doubtful cases requires, in addition to standard examinations, extra diagnostic procedures, which may delay making a decision for several weeks to several months. The article describes a case of mechanical CSF shunt malfunction (breakage and failure of a peritoneal catheter in a 7-year-old girl) with intracranial hypertension symptoms, but without typical enlargement of the brain ventricles. According to the medical history, congenital hydrocephalus in the child was accompanied by an inflammatory process of bacterial and viral etiology. The absence of brain ventricle enlargement was shown not to exclude a probability of shunt malfunction. In this case, a specific phenomenon, an intraparenchymatous cerebrospinal fluid "lake" surrounding a ventricular catheter, was observed. Shunting recovery did not lead to a significant reduction in the phenomenon size. Causes underlying this phenomenon require further investigation. PMID- 27500778 TI - [Treatment of patients with brain metastases]. PMID- 27500779 TI - DSM-5.1. PMID- 27500780 TI - Using fluorescence lifetime microscopy to study the subcellular localization of anthocyanins. AB - Anthocyanins are flavonoid pigments that accumulate in most seed plants. They are synthesized in the cytoplasm but accumulate inside the vacuoles. Anthocyanins are pigmented at the lower vacuolar pH, but in the cytoplasm they can be visualized based on their fluorescence properties. Thus, anthocyanins provide an ideal system for the development of new methods to investigate cytoplasmic pools and association with other molecular components. We have analyzed the fluorescence decay of anthocyanins by fluorescence lifetime imaging microscopy (FLIM), in both in vitro and in vivo conditions, using wild-type and mutant Arabidopsis thaliana seedlings. Within plant cells, the amplitude-weighted mean fluorescence lifetime (taum ) correlated with distinct subcellular localizations of anthocyanins. The vacuolar pool of anthocyanins exhibited shorter taum than the cytoplasmic pool. Consistently, lowering the pH of anthocyanins in solution shortened their fluorescence decay. We propose that FLIM is a useful tool for understanding the trafficking of anthocyanins and, potentially, for estimating vacuolar pH inside intact plant cells. PMID- 27500781 TI - Depressed-type submucosal invasive colorectal cancer in a patient with Lynch syndrome diagnosed using short-interval colonoscopy. AB - Although regular colonoscopy surveillance is recommended for patients with Lynch syndrome (LS) who underwent partial colectomy, the appropriate interval has not been determined. We report a case of colorectal cancer (CRC) detected by short interval surveillance colonoscopy (SC) in a patient with LS having a past history of partial colectomy. A 65-year-old man underwent sigmoidectomy for advanced CRC. His family history revealed that his two younger brothers had CRC in their twenties and thirties, respectively, and the patient met with the criteria in the Revised Bethesda Guidelines. After confirming the loss of MSH2 protein expression in the primary tumor, subsequent genetic testing showed germline mutation with a large deletion of exon 7-14 in the MSH2 gene, indicating a diagnosis of LS. After the diagnosis of LS, the patient underwent annual SC. Three years after the initial surgery, superficial submucosal invasive cancer was detected. Subsequently, SC after a 6-month interval revealed a deep submucosal invasive cancer (7 mm in diameter). Although additional surgery was recommended, considering his comorbidities, regular SC rather than colectomy was selected. Even shorter-interval SC carried out within a year is not sufficient to detect endoscopically resectable tumors in some high-risk LS cases. PMID- 27500783 TI - Myeloproliferative neoplasms: trends in incidence, prevalence and survival in Norway. AB - BACKGROUND: Polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) are clonal disorders collectively named as myeloproliferative neoplasms (MPN). Published data on epidemiology of MPN after the discovery of the JAK2 mutation and the 2008 WHO classifications are scarce. We aimed to study the incidence rates, prevalence and survival of MPN in Norway during the period 1993 2012. METHOD: We identified 2453 persons diagnosed with MPN from the Cancer Registry of Norway between 1993 and 2012. We report age-adjusted incidence rates, prevalence, relative survival and standardised mortality rates. RESULTS: The overall age-adjusted yearly incidence rate of PV increased from 0.4/105 to 0.7/105, ET increased from 0.3/105 to 1.0/105 and MF from 0.2/105 to 0.5/105. Prevalence of PV, ET and MF was 9.2, 8.6 and 3.0 per 105 inhabitants, respectively. The five-year relative survival (RS) of ET and PV was slightly reduced with no improvement. The five-year RS of MF was 58.1% (2008-2012). Standardised mortality rate (SMR) was 1.9 (95% CI 1.2 - 2.7). CONCLUSIONS: The incidence rates of ET, PV and MF doubled and tripled during the years 2007-2012 as compared to 1995-2006. This increment in incidence rates may be related to identification of the JAK2 mutation and the derived 2008 WHO guidelines for MPN. The RS was only slightly reduced in PV and ET, but was substantially reduced in MF. PMID- 27500782 TI - Autologous tendon-derived cell-seeded nanofibrous scaffolds improve rotator cuff repair in an age-dependent fashion. AB - Rotator cuff tendon tears are one of the most common shoulder pathologies, especially in the aging population. Due to a poor healing response and degenerative changes associated with aging, rotator cuff repair failure remains common. Although cell-based therapies to augment rotator cuff repair appear promising, it is unknown whether the success of such a therapy is age-dependent. We hypothesized that autologous cell therapy would improve tendon-to-bone healing across age groups, with autologous juvenile cells realizing the greatest benefit. In this study, juvenile, adult, and aged rats underwent bilateral supraspinatus tendon repair with augmentation of one shoulder with autologous tendon-derived cell-seeded polycaprolactone scaffolds. At 8 weeks, shoulders treated with cells in both juvenile and aged animals exhibited increased cellularity, increased collagen organization, and improved mechanical properties. No changes between treated and control limbs were seen in adult rats. These findings suggest that cell delivery during supraspinatus repair initiates earlier matrix remodeling in juvenile and aged animals. This may be due to the relative "equilibrium" of adult tendon tissue with regards to catabolic and anabolic processes, contrasted with actively growing juvenile tendons and degenerative aged tendons. This study demonstrates the potential for autologous cell-seeded scaffolds to improve repairs in both the juvenile and aged population. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1250-1257, 2017. PMID- 27500784 TI - Effects of QMix and ethylenediaminetetraacetic acid on decalcification and erosion of root canal dentin. AB - The aim of this study was to evaluate the effect of initial NaOCl on the decalcification and erosion ability of EDTA and QMix. Sixty-maxillary-incisors were bisected longitudinally and the tooth-halves were used. The experiment was conducted in two-sets. In set-I, 80-tooth halves were treated in the presence or absence of initial NaOCl and EDTA. In set-II, 40-tooth halves were immersed in NaOCl and QMix. After each treatment, calcium-ion release was determined with flame photometry. The erosion was imaged using SEM. Initial NaOCl led to concentration- and time-dependent increase in calcium removal effect of 17% EDTA (p < .05). The rate of calcium removal and root canal wall erosion was considerably more severe with the use of 5% NaOCl for 3 min (p < .05). QMix as a final solution showed less decalcification and erosion than 17% EDTA when used 5% NaOCl as an initial irrigant (p < .05). Optimizing the concentration and application time of NaOCl can decrease the decalcification effect of chelating agents. PMID- 27500785 TI - Pathways of protein and lipid receptor-mediated transcytosis in drug delivery. AB - INTRODUCTION: A critical factor for the efficacy of drugs is their availability at the site of interest. However, crossing endothelial and epithelial cell layers like the blood-brain barrier and the blood-intestinal barrier represents a major bottleneck for drug targeting. Coupling drugs to carriers that recognize endogenous receptors, which are then transported through cell layers by transcytosis, is a promising approach to overcome this bottleneck. Areas covered: This review focuses on the intracellular pathways of receptor-mediated transcytosis and their applicability for transcellular drug delivery. It gives an overview about transcytotic trafficking routes in epithelia and highlights the well-studied examples of immungobulin transcytosis and transferrin transcytosis. The current knowledge about the less understood transcytosis pathways in endothelia is also summarized and low-density lipoprotein transcytosis is described. In addition, transcytosis pathways that are based on glycosphingolipids and lectins as their receptors are presented. Expert opinion: Multiple transcellular drug delivery approaches based on proteinaceous receptors have been developed in recent years, whereas lectins that bind to glycosphingolipids emerge as promising alternative. Closer investigation of endogenous transcytosis mechanisms, especially in endothelia, will be a fruitful endeavor to devise more optimized carriers for transcytotic drug delivery. PMID- 27500786 TI - Morpho-histological and ultra architectural changes during early development of endangered golden mahseer Tor putitora. AB - Ultrastructural and histological changes in the embryonic and larval surface during ontogenesis of the endangered golden mahseer Tor putitora is studied here for the first time. Embryonic development was completed 91-92 h after fertilization at an ambient temperature of 23 degrees +/- 1 degrees C (mean +/- s.d.). The gastrula stage was characterized by presence of the Kupffer's vesicle, notochord, ectoderm and endoderm cells. Primordial germ cells were clearly identifiable from c. 55 h post-fertilization at the organogenesis stage. Mean total length of newly hatched larvae was 7.0 +/- 0.5 mm. Scanning electron microscopy of newly hatched larvae demonstrated vitelline arteries, microridged epithelial cells and mucous gland openings over much of the body surface. Eye, oral cavity, pharyngeal arches, heart, intestinal loop, prosencephalon, cephalic vesicle and nasal epithelium were clearly distinguished in 3 day old hatched individuals. In 6 day old individuals, caudal-fin rays and internal organs were evident. The dorsal fin became prominent at this stage and larvae began swimming at the surface. The reserved yolk material was totally absorbed 8-11 days after hatching and larvae began feeding exogenously. Tor putitora exhibited a longer early developmental period than other cyprinids reared at similar temperatures. PMID- 27500787 TI - Association of Interleukin 10 Gene Polymorphisms with Autoimmune Thyroid Disease: Meta-Analysis. AB - The aim of this study was to perform a meta-analysis of eligible studies and to derive a precise estimate of the association between interleukin 10 (IL10) polymorphisms and susceptibility to autoimmune thyroid disease (AITD). Meta analyses were conducted on the associations between AITD and the -1082 G/A (rs1800896), -819 C/T (rs1800871) and -592 C/A (rs1800872) polymorphisms in IL10, and the haplotype of these polymorphisms and AITD. A total of 2903 AITD patients and 3060 controls in 10 eligible studies were included in the meta-analysis. This meta-analysis showed significant associations between IL10 at the -1082 G allele and overall AITD (OR: 1.44, 95% CI 1.13-1.82, P = 0.003), but no association between the IL10 -592 C allele and the -819 C allele and AITD. Subgroup studies demonstrated significant associations between the -1082 G allele and susceptibility to Graves' disease. Ethnicity-specific meta-analysis revealed significant associations between the -1082 G allele and AITD susceptibility in Asian populations; however, in Middle Eastern populations, no association was evident. Meta-analysis of the IL10 haplotype revealed an association between the ATA haplotype and AITD (OR: 1.17, 95% CI 1.00-1.36, P = 0.04). Meta-analysis demonstrates that the IL10 polymorphisms are associated with susceptibility to AITD. PMID- 27500788 TI - Rural-Urban Differences in the Effect of Follow-Up Care on Postdischarge Outcomes. AB - OBJECTIVE: To assess rural-urban differences in quality of postdischarge care among Medicare beneficiaries, controlling for selection bias of postdischarge services. DATA SOURCES: The Medicare Current Beneficiary Survey (MCBS), Cost and Use Files from 2000 to 2010, the Area Resource File, Provider of Services File, and the Dartmouth Atlas of Health Care. STUDY DESIGN: Retrospective analysis of 30- and 60-day hospital readmission, emergency department (ED) use, and mortality using two-stage residual inclusion; receipt of 14-day follow-up care was the main independent variable. DATA EXTRACTION METHOD: We defined index admission from the MCBS as any admission without a previous admission within 60 days. PRINCIPAL FINDINGS: Noninstrumental variables estimation was the preferred estimation strategy. Fourteen-day follow-up care reduced the risk of readmission, ED use, and mortality. There were no rural- urban differences in the effect of 14-day follow-up care on readmission and mortality. Rural beneficiaries experienced a greater effect of 14-day follow-up care on reducing 30-day ED use compared to urban beneficiaries. CONCLUSIONS: Follow-up care reduces 30- and 60-day readmission, ED use, and mortality. Rural and urban Medicare beneficiaries experience similar beneficial effects of follow-up care on the outcomes. Policies that improve follow-up care in rural settings may be beneficial. PMID- 27500789 TI - CO2 Reduction Catalyzed by Nitrogenase: Pathways to Formate, Carbon Monoxide, and Methane. AB - The reduction of N2 to NH3 by Mo-dependent nitrogenase at its active-site metal cluster FeMo-cofactor utilizes reductive elimination of Fe-bound hydrides with obligatory loss of H2 to activate the enzyme for binding/reduction of N2. Earlier work showed that wild-type nitrogenase and a nitrogenase with amino acid substitutions in the MoFe protein near FeMo-cofactor can catalytically reduce CO2 by two or eight electrons/protons to carbon monoxide (CO) and methane (CH4) at low rates. Here, it is demonstrated that nitrogenase preferentially reduces CO2 by two electrons/protons to formate (HCOO(-)) at rates >10 times higher than rates of CO2 reduction to CO and CH4. Quantum mechanical calculations on the doubly reduced FeMo-cofactor with a Fe-bound hydride and S-bound proton (E2(2H) state) favor a direct reaction of CO2 with the hydride ("direct hydride transfer" reaction pathway), with facile hydride transfer to CO2 yielding formate. In contrast, a significant barrier is observed for reaction of Fe-bound CO2 with the hydride ("associative" reaction pathway), which leads to CO and CH4. Remarkably, in the direct hydride transfer pathway, the Fe-H behaves as a hydridic hydrogen, whereas in the associative pathway it acts as a protic hydrogen. MoFe proteins with amino acid substitutions near FeMo-cofactor (alpha-70(Val->Ala), alpha 195(His->Gln)) are found to significantly alter the distribution of products between formate and CO/CH4. PMID- 27500790 TI - A Protocol for the Production of Gliadin-cyanoacrylate Nanoparticles for Hydrophilic Coating. AB - This article presents a protocol for the production of protein-based nanoparticles that changes the hydrophobic surface to hydrophilic by a simple spray coating. These nanoparticles are produced by the polymerization reaction of alkyl cyanoacrylate on the surface of cereal protein (gliadin) molecules. Alkyl cyanoacrylate is a monomer that instantly polymerizes at RT when it is applied to the surface of materials. Its polymerization reaction is initiated by the trace amounts of weakly basic or nucleophilic species on the surface, including moisture. Once polymerized, the polymerized alkyl cyanoacrylates show a strong affinity with the object materials because nitrile groups are in the backbone of poly (alkyl cyanoacrylate). Proteins also work as initiator for this polymerization because they contain amine groups that can initiate the polymerization of cyanoacrylate. If aggregated protein is used as an initiator, protein aggregate is surrounded by the hydrophobic poly(alkyl cyanoacrylate) chains after the polymerization reaction of alkyl cyanoacrylate. By controlling the experimental condition, particles in the nanometer range are produced. The produced nanoparticles readily adsorb to the surface of most materials including glass, metals, plastics, wood, leather, and fabrics. When the surface of a material is sprayed with the produced nanoparticle suspension and rinsed with water, the micellar structure of nanoparticle changes its conformation, and the hydrophilic proteins are exposed to the air. As a result, the nanoparticle-coated surface changes to hydrophilic. PMID- 27500792 TI - Development and preliminary evaluation of culturally specific web-based intervention for parents of adolescents. AB - : WHAT IS KNOWN ON THE SUBJECT?: Problematic parent-child relationships have been identified as one of the main predictors of adolescents' mental health problems, but there are few existing interventions that address this issue. The format and delivery method of existing interventions for parents are relatively inaccessible for parents with full-time jobs and families living in rural areas. WHAT DOES THIS PAPER ADD TO EXISTING KNOWLEDGE?: The newly developed 'Stepping Stone' culturally specific web-based intervention, which is intended to help Korean parents of adolescents to acquire both knowledge and communication and conflict management skills, was found to be feasible and well-accepted by parents. This study enabled us to identify areas for improvement in the content and format of the intervention and strategies. This will potentially increase effect sizes for the outcome variables of parents' perception and behaviours. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: This web-based intervention could be delivered across diverse settings, such as schools and community mental health centers, to increase parents' knowledge of adolescent's mental health and allow for early detection of mental health problems. Mental health nurses working in schools may spend a significant amount of time addressing students' mental health issues; thus, this web-based intervention could be a useful resource to share with parents and children. In this way, the mental health nurses could facilitate parental engagement in the intervention and then help them to continue to apply and practice the knowledge and skills obtained through the program. ABSTRACT: Introduction There is a need for accessible, culturally specific web-based interventions to address parent-child relationships and adolescents' mental health. Aims This study developed and conducted a preliminary evaluation of a 4 week web-based intervention for parents of adolescents aged 11 to 16 years in Korea. Methods We used a two-group, repeated measures, quasi-experimental study design to assess the feasibility of developing and implementing a web-based intervention for parents. Descriptive statistics, chi-square and t tests, and mixed effect modeling were used for data analysis. Results The intervention and 1 month follow-up survey were completed by 47 parents in the intervention group and 46 parents in the attention control (AC) group. The intervention was found to be feasible and well-accepted by parents. Discussion This culturally specific web based intervention is a useful tool for knowledge dissemination among large numbers of parents. Areas for improvement in the content and format of the intervention and strategies to elicit significant parent-child interactions are provided. Implications for practice and conclusion The intervention could be disseminated in collaboration with mental health nurses working in schools to facilitate parents' participation. PMID- 27500791 TI - Highlights From the American Association of Pharmaceutical Scientists/ International Transporter Consortium Joint Workshop on Drug Transporters in Absorption, Distribution, Metabolism, and Excretion: From the Bench to the Bedside - Clinical Pharmacology Considerations. AB - The American Association of Pharmaceutical Scientists/International Transporter Consortium Joint Workshop on Drug Transporters in absorption, distribution, metabolism, and excretion was held with the objective of discussing innovative advances in transporter pharmacology. Specific topics included (i) transporters at the blood-brain barrier (BBB); (ii) emerging transport proteins; (iii) recent advances in achieving hepatoselectivity and optimizing clearance for organic anion-transporting polypeptide (OATP) substrates; (iv) utility of animal models for transporter studies; and (v) clinical correlation of transporter polymorphisms. Here, we present state-of-the-art highlights from this workshop in these key areas of focus. PMID- 27500793 TI - Pathogen and antimicrobial resistance profiles of culture-proven neonatal sepsis in Southwest China, 1990-2014. AB - AIM: Neonatal sepsis (NS) sustains high mortality and morbidity in China, but data on the epidemiology and antimicrobial resistance patterns of NS pathogens are limited. METHODS: The clinical features, aetiology and antimicrobial resistance of culture-proven NS were analysed over a period of 25 years in the metropolitan city of Chongqing in Southwest China. RESULTS: The occurrence rates of neonatal early-onset sepsis (EOS) were found to gradually decrease while late onset sepsis (LOS) was kept stable from 1990 to 2014. Although coagulase-negative staphylococcus (CoNS) sepsis accounted for most infections, the occurrence rates of CoNS sepsis gradually decreased, especially in EOS. Escherichia coli and Klebsiella were common Gram-negative bacteria. The occurrence rates of E. coli and Klebsiella remained stable in EOS; however, in LOS, those had increased mildly, especially from 2009 to 2014. Although a high-degree resistance to common first- and second-line antimicrobials was observed for the main causative pathogens of NS, the gentamicin-resistance rate declined gradually from the year 2003. Similarly, the ceftazidime-resistance rate of E. coli dropped gradually from the year 2007. CONCLUSIONS: The alarmingly high degree of antibiotic resistance calls for urgent evaluation and development of antibiotic policy and protocols for the treatment of NS. Clinicians should strictly control the antibiotics use, decrease invasive manipulations and shorten hospitalisation to prevent LOS. PMID- 27500794 TI - Current perspective on actinic keratosis: a review. AB - Actinic keratoses (AKs) are common, with prevalence in the U.S.A. estimated at almost 40 million in 2004 and annual costs of > $1 billion (U.S.D.). However, there is no universally accepted definition of AK and thus it is difficult to identify reliably. AKs are lesions of epidermal keratinocytic dysplasia that result from chronic sun exposure and have the ability to progress to invasive squamous cell carcinoma (SCC), but clinicians disagree about whether AKs are premalignant lesions, superficial SCCin situ or epiphenomena of chronically sun damaged skin. Yearly AK to SCC progression rates of 0.6% were reported in an elderly population with multiple prior keratinocyte carcinomas (KCs); and rates of spontaneous AK regression have been reported to be > 50%, but regressed lesions often reappear. As AKs have both cosmetic consequences and potential for malignant transformation, there are multiple reasons for treatment. There is no current agreement on the most efficacious treatment, but 5-fluorouracil has been shown to both prevent and treat AKs, and imiquimod and photodynamic therapy may have the best cosmetic outcomes. AKs may be treated to improve appearance and relieve symptoms, but the keratinocytic dysplasia that gives rise to malignancy, and sometimes appears as an AK, may be what actually threatens patient health. Thus, treatments should aim to decrease the risk of KC or facilitate KC diagnosis by reducing the potential for misidentification created when a KC appears in a field of AKs. Improved agreement among clinicians on AK definition may improve management. PMID- 27500795 TI - Environmental factors, life events, and trauma in the course of bipolar disorder. AB - The etiology and clinical course of bipolar disorder are considered to be determined by genetic and environmental factors. Although the kindling hypothesis emphasizes the impact of environmental factors on initial onset, their connection to the outcome and clinical course have been poorly established. Hence, there have been numerous research efforts to investigate the impact of environmental factors on the clinical course of illness. Our aim is to outline recent research on the impact of environmental determinants on the clinical course of bipolar disorder. We carried out a computer-aided search to find publications on an association between environmental factors, life events, and the clinical course of bipolar disorder. Publications in the reference lists of suitable papers have also been taken into consideration. We performed a narrative overview on all eligible publications. The available body of data supports an association between environmental factors and the clinical course of bipolar disorder. These factors comprise prenatal, early-life, and entire lifespan aspects. Given varying sample sizes and several methodological limitations, the reported quality and extent of the association between environmental factors and the clinical course of bipolar disorder should be interpreted with utmost caution. Systematic longitudinal long term follow-up trials are needed to obtain a clearer and more robust picture. PMID- 27500799 TI - A Route to the C,D,E Ring System of the Aspidosperma Alkaloids. AB - A short synthetic sequence leading to the formation of the C,D,E-ring subunit of the Aspidosperma alkaloids is reported. This route is based on a ring fragmentation/intramolecular azomethine ylide 1,3-dipolar cycloaddition reaction sequence that gives the desired tricyclic product as a single diastereomer. A gamma-amino-beta-hydroxy-alpha-diazo carbonyl compound is shown to fragment in the presence of a Lewis acid to give an iminium product that can be directly reduced to the corresponding amine. PMID- 27500800 TI - Hydroponics: A Versatile System to Study Nutrient Allocation and Plant Responses to Nutrient Availability and Exposure to Toxic Elements. AB - Hydroponic systems have been utilized as one of the standard methods for plant biology research and are also used in commercial production for several crops, including lettuce and tomato. Within the plant research community, numerous hydroponic systems have been designed to study plant responses to biotic and abiotic stresses. Here we present a hydroponic protocol that can be easily implemented in laboratories interested in pursuing studies on plant mineral nutrition. This protocol describes the hydroponic system set up in detail and the preparation of plant material for successful experiments. Most of the materials described in this protocol can be found outside scientific supply companies, making the set up for hydroponic experiments less expensive and convenient. The use of a hydroponic growth system is most advantageous in situations where the nutrient media need to be well controlled and when intact roots need to be harvested for downstream applications. We also demonstrate how nutrient concentrations can be modified to induce plant responses to both essential nutrients and toxic non-essential elements. PMID- 27500801 TI - Analgesic efficacy of equimolar 50% nitrous oxide/oxygen gas premix (Kalinox(r)) as compared with a 5% eutectic mixture of lidocaine/prilocaine (EMLA(r)) in chronic leg ulcer debridement. AB - Chronic foot and leg ulcers are a common health problem worldwide. A mainstay of chronic ulcer therapy is sharp mechanical wound debridement requiring potent analgesia. In this prospective, controlled, single-centre, crossover design study, patients were assigned to either the administration of topical analgesia with 5% lidocaine/prilocaine cream or the inhalation of an analgesic 50% N2 O/O2 gas premix. Primary outcome parameter was level of pain at maximum wound depth during debridement as measured by a visual analogue scale. Secondary outcomes included level of pain after debridement, overall duration of treatment session, duration and completeness of debridement, and the patient's subjective perception of analgesic quality during debridement. Pain level increased from 0.60/0.94 (first/second debridement; baseline) to 1.76/2.50 (debridement) with 5% lidocaine/prilocaine and from 1.00/1.35 (baseline) to 3.95/3.29 (debridement) with 50% N2 O/O2 gas premix. Patient satisfaction was 90.48%/94.44% (first/second debridement) with topical 5% lidocaine/prilocaine analgesia and 90.48%/76.47% with the inhalation of 50% N2 O/O2 gas premix. Debridement was completed in a significantly higher percentage of 85.71%/88.89% (first/second debridement) with 5% lidocaine/prilocaine than with 50% N2 O/O2 gas premix (42.86%/58.82%) (odds ratio 6.7; P = 0.001). This study provides sound evidence that analgesia with topically administered 5% lidocaine/prilocaine cream is superior to the use of inhaled 50% N2 O/O2 gas premix in chronic leg ulcer debridement. PMID- 27500802 TI - A Chemically Programmed Proximal Ligand Enhances the Catalytic Properties of a Heme Enzyme. AB - Enzymes rely on complex interactions between precisely positioned active site residues as a mechanism to compensate for the limited functionality contained within the genetic code. Heme enzymes provide a striking example of this complexity, whereby the electronic properties of reactive ferryl intermediates are finely tuned through hydrogen bonding interactions between proximal ligands and neighboring amino acids. Here, we show that introduction of a chemically programmed proximal Ndelta-methyl histidine (NMH) ligand into an engineered ascorbate peroxidase (APX2) overcomes the reliance on the conserved Asp-His hydrogen bonding interaction, leading to a catalytically modified enzyme (APX2 NMH), which is able to achieve a significantly higher number of turnovers compared with APX2 without compromising catalytic efficiency. Structural, spectroscopic and kinetic characterization of APX2 NMH and several active site variants provides valuable insights into the role of the Asp-His-Fe triad of heme peroxidases. More significantly, simplification of catalytic mechanisms through the incorporation of chemically optimized ligands may facilitate efforts to create and evolve new active site heme environments within proteins. PMID- 27500803 TI - Fabrication and electrokinetic motion of electrically anisotropic Janus droplets in microchannels. AB - This paper presents experimental investigations of the fabrication and the motion of electrically anisotropic Janus droplets in a microchannel under externally applied direct current (DC) electrical field. The fabrication method of the Janus droplets is presented first. To begin, oil droplets are coated uniformly with positively charged nanoparticles in the aluminum oxide nanoparticle suspension. The electrically anisotropic Janus droplets are formed when the nanoparticles are accumulated to one side of the droplets in response to externally applied DC electric field. The surface coverage of the Janus droplets by nanoparticles can be adjusted by controlling the concentration of the nanoparticle suspension. The flow fields around the Janus droplets moving in a microchannel were observed with tracing particles. Finally, the electrokinetic velocity of the Janus droplets in a microchannel was measured. The effects of the strength of the electrical field, the surface coverage of the Janus droplets by nanoparticles, the size of the droplets as well as the electrolyte concentration on the electrokinetic velocity of the Janus droplets were studied. PMID- 27500804 TI - Proton-Coupled Electron Transfer Reactions with Photometric Bases Reveal Free Energy Relationships for Proton Transfer. AB - The proton-coupled electron transfer (PCET) oxidation of p-aminophenol in acetonitrile was initiated via stopped-flow rapid-mixing and spectroscopically monitored. For oxidation by ferrocenium in the presence of 7 (dimethylamino)quinoline proton acceptors, both the electron transfer and proton transfer components could be optically monitored in the visible region; the decay of the ferrocenium absorbance is readily monitored (lambdamax = 620 nm), and the absorbance of the 2,4-substituted 7-(dimethylamino)quinoline derivatives (lambdamax = 370-392 nm) red-shifts substantially (ca. 70 nm) upon protonation. Spectral analysis revealed the reaction proceeds via a stepwise electron transfer proton transfer process, and modeling of the kinetics traces monitoring the ferrocenium and quinolinium signals provided rate constants for elementary proton and electron transfer steps. As the pKa values of the conjugate acids of the 2,4 R-7-(dimethylamino)quinoline derivatives employed were readily tuned by varying the substituents at the 2- and 4-positions of the quinoline backbone, the driving force for proton transfer was systematically varied. Proton transfer rate constants (kPT,2 = (1.5-7.5) * 10(8) M(-1) s(-1), kPT,4 = (0.55-3.0) * 10(7) M( 1) s(-1)) were found to correlate with the pKa of the conjugate acid of the proton acceptor, in agreement with anticipated free energy relationships for proton transfer processes in PCET reactions. PMID- 27500806 TI - Polariton condensates: Electrical spin switching. PMID- 27500805 TI - Design of efficient molecular organic light-emitting diodes by a high-throughput virtual screening and experimental approach. AB - Virtual screening is becoming a ground-breaking tool for molecular discovery due to the exponential growth of available computer time and constant improvement of simulation and machine learning techniques. We report an integrated organic functional material design process that incorporates theoretical insight, quantum chemistry, cheminformatics, machine learning, industrial expertise, organic synthesis, molecular characterization, device fabrication and optoelectronic testing. After exploring a search space of 1.6 million molecules and screening over 400,000 of them using time-dependent density functional theory, we identified thousands of promising novel organic light-emitting diode molecules across the visible spectrum. Our team collaboratively selected the best candidates from this set. The experimentally determined external quantum efficiencies for these synthesized candidates were as large as 22%. PMID- 27500807 TI - A sub-femtojoule electrical spin-switch based on optically trapped polariton condensates. AB - Practical challenges to extrapolating Moore's law favour alternatives to electrons as information carriers. Two promising candidates are spin-based and all-optical architectures, the former offering lower energy consumption, the latter superior signal transfer down to the level of chip-interconnects. Polaritons-spinor quasi-particles composed of semiconductor excitons and microcavity photons-directly couple exciton spins and photon polarizations, combining the advantages of both approaches. However, their implementation for spintronics has been hindered because polariton spins can be manipulated only optically or by strong magnetic fields. Here we use an external electric field to directly control the spin of a polariton condensate, bias-tuning the emission polarization. The nonlinear spin dynamics offers an alternative route to switching, allowing us to realize an electrical spin-switch exhibiting ultralow switching energies below 0.5 fJ. Our results lay the foundation for development of devices based on the electro-optical control of coherent spin ensembles on a chip. PMID- 27500810 TI - Top-down and bottom-up guidance in comprehension of schematic football diagrams. AB - Comprehension of a narrated diagram entail complex cognitive processing as learner is challenged to extract the orally evoked information. The present experiment examined the effects of 2 different forms of attention guidance - bottom-up and top-down - on comprehension performance, cognitive load investment, and motivation to learn, using a 2 * 2 mixed design with factors "Expertise" (Expert vs. Novice) and "Condition" (no-signal, circle, segment). The results revealed an expertise reversal effect indicating that the incorporation of visual signals in diagram is effective for novice learners but partially reverses and becomes ineffective for more experienced learners (even though they invested less mental effort and reported higher level of motivation in the segmented condition). The findings suggested that the effectiveness of instructional guidance depends heavily on levels of prior knowledge. PMID- 27500809 TI - The nanocomposite nature of bone drives its strength and damage resistance. AB - In human bone, an amorphous mineral serves as a precursor to the formation of a highly substituted nanocrystalline apatite. However, the precise role of this amorphous mineral remains unknown. Here, we show by using transmission electron microscopy that 100-300 nm amorphous calcium phosphate regions are present in the disordered phase of trabecular bone. Nanomechanical experiments on cylindrical samples, with diameters between 250 nm and 3,000 nm, of the bone's ordered and disordered phases revealed a transition from plastic deformation to brittle failure and at least a factor-of-2 higher strength in the smaller samples. We postulate that this transition in failure mechanism is caused by the suppression of extrafibrillar shearing in the smaller samples, and that the emergent smaller is-stronger size effect is related to the sample-size scaling of the distribution of flaws. Our findings should help in the understanding of the multi-scale nature of bone and provide insights into the biomineralization process. PMID- 27500808 TI - Detection and imaging of quorum sensing in Pseudomonas aeruginosa biofilm communities by surface-enhanced resonance Raman scattering. AB - Most bacteria in nature exist as biofilms, which support intercellular signalling processes such as quorum sensing (QS), a cell-to-cell communication mechanism that allows bacteria to monitor and respond to cell density and changes in the environment. As QS and biofilms are involved in the ability of bacteria to cause disease, there is a need for the development of methods for the non-invasive analysis of QS in natural bacterial populations. Here, by using surface-enhanced resonance Raman scattering spectroscopy, we report rationally designed nanostructured plasmonic substrates for the in situ, label-free detection of a QS signalling metabolite in growing Pseudomonas aeruginosa biofilms and microcolonies. The in situ, non-invasive plasmonic imaging of QS in biofilms provides a powerful analytical approach for studying intercellular communication on the basis of secreted molecules as signals. PMID- 27500812 TI - Role of Dual-Hormone Closed-Loop Delivery System in the Future. PMID- 27500813 TI - I. WORKING MEMORY CAPACITY IN CONTEXT: MODELING DYNAMIC PROCESSES OF BEHAVIOR, MEMORY, AND DEVELOPMENT. AB - Working memory is a vital cognitive skill that underlies a broad range of behaviors. Higher cognitive functions are reliably predicted by working memory measures from two domains: children's performance on complex span tasks, and infants' performance in looking paradigms. Despite the similar predictive power across these research areas, theories of working memory development have not connected these different task types and developmental periods. The current project takes a first step toward bridging this gap by presenting a process oriented theory, focusing on two tasks designed to assess visual working memory capacity in infants (the change-preference task) versus children and adults (the change detection task). Previous studies have shown inconsistent results, with capacity estimates increasing from one to four items during infancy, but only two to three items during early childhood. A probable source of this discrepancy is the different task structures used with each age group, but prior theories were not sufficiently specific to explain how performance relates across tasks. The current theory focuses on cognitive dynamics, that is, how memory representations are formed, maintained, and used within specific task contexts over development. This theory was formalized in a computational model to generate three predictions: 1) capacity estimates in the change-preference task should continue to increase beyond infancy; 2) capacity estimates should be higher in the change preference versus change detection task when tested within individuals; and 3) performance should correlate across tasks because both rely on the same underlying memory system. I also tested a fourth prediction, that development across tasks could be explained through increasing real-time stability, realized computationally as strengthening connectivity within the model. Results confirmed these predictions, supporting the cognitive dynamics account of performance and developmental changes in real-time stability. The monograph concludes with implications for understanding memory, behavior, and development in a broader range of cognitive development. PMID- 27500811 TI - Immune deficiency in chronic rhinosinusitis: screening and treatment. AB - INTRODUCTION: Chronic rhinosinusitis (CRS) is a prevalent disease with a high annual cost of treatment. Immune deficiencies are more common in individuals with CRS and should be especially considered in those patients who are refractory to medical and surgical therapy. Areas covered: We performed a literature search in PubMed of the terms "immunodeficiency" and "sinusitis" or "rhinosinusitis" from 2006 through March 2016. All abstracts were reviewed to determine if they pertained to human disease; relevant articles were evaluated in their entirety and included in this review. Expert commentary: CRS is a common disease; in those patients with frequent exacerbations or who are refractory to treatment, an immunodeficiency evaluation should be considered. Treatment includes vaccination, antibiotic therapy, immunoglobulin replacement and surgery. PMID- 27500814 TI - II. THE COGNITIVE DYNAMICS THEORY OF VISUAL WORKING MEMORY. PMID- 27500815 TI - III. EMPIRICAL TESTS OF PREDICTIONS COMPARING CAPACITY ESTIMATES ACROSS TASKS AND DEVELOPMENT. PMID- 27500816 TI - IV. MODEL SIMULATIONS TESTING THE REAL-TIME STABILITY HYPOTHESIS OF DEVELOPMENTAL CHANGES IN VISUAL WORKING MEMORY. PMID- 27500817 TI - V. NEW QUESTIONS AND REMAINING CHALLENGES TO ACCOUNT FOR DEVELOPMENTAL IMPROVEMENTS IN VISUAL WORKING MEMORY. PMID- 27500819 TI - EXPLORING THE POSSIBLE AND NECESSARY IN WORKING MEMORY DEVELOPMENT. AB - This commentary considers Vanessa Simmering's monograph on a dynamic-systems theoretical approach to understanding working memory development, with reference to the past, present, and future. In the section on the past, I attempt to provide a further historical context for the work, discussing from where it stemmed and how it is unique. In a second section, I contemplate the purpose of the present modeling. The aim of the monograph may be primarily to establish a simple possible account of development based on neural connection strength and dynamic principles; it should not be judged as a proposal of what is necessarily true. Finally, in the section on the future, I suggest some phenomena that dissociate performance levels from stability over time and, therefore, appear to require modifications of the theory. Several suggestions are made as to where further refinement of the modeling effort could lead. PMID- 27500820 TI - The impact of cognitive challenges in major depression: the role of the primary care physician. AB - Nearly 1 in 5 Americans will struggle with major depression in their lives; some will have recurring bouts. Recent psychiatric research has given new attention to the prevalence of cognitive deficits in major depression and the impact such deficits have on remission and overall life functioning. When depression is partially treated i.e., leaving residual symptoms, patients have higher rates of relapse and lower functional outcomes. Impaired cognitive functioning is a frequent residual symptom, persisting in about 45% of patients even when emotional symptoms have improved, and results in a disproportionate share of the functional impairment, particularly in the workplace. Patients with depression have disrupted circuitry in brain regions responsible for cognition and it is therefore important to screen depressed patients for cognitive as well as emotional symptoms. Cognitive dysfunction should be evaluated in every mood disordered patient with validated self-report scales such as the Patient Health Questionnaire-9 or the Beck Depression Inventory and objective measures of cognitive function are also very very useful. Two easily administered tests are the Trails B Test and the Digit Symbol Substitution Test. Each take less than two minutes and measure working memory, executive function, and processing speed and can track cognitive improvement in depressed patients. Treatment of cognitive dysfunction in major depression is complicated by the 'serotonin conundrum': SSRI's frequently do not treat to full remission, and can cause cognitive blunting-actually adding to cognitive problems. Based on recent data including results from a recently completed meta-analysis by McIntyre and colleagues, an evidence-based algorithm for treating cognitive symptoms in depression is presented. A hierarchy of antidepressants and augmentation strategies based on the best available evidence is discussed. In conclusion, cognitive symptoms in major depressive disorder have been recognized as a target of therapeutic improvement by the FDA and have become a focus of clinical importance. PMID- 27500821 TI - Facile synthesis of optical pH-sensitive molybdenum disulfide quantum dots. AB - An effective fabrication of MoS2 quantum dots (QDs) has been developed using alkali metal-intercalation and exfoliation. The obtained MoS2 QDs are monolayers with a uniform lateral size of 4.26 +/- 0.96 nm, which exhibit distinct blue fluorescence with a quantum yield of 2.28%, robust dispersibility, storage stability and pH dependent optical properties. PMID- 27500822 TI - beta1-Adrenergic receptor Arg389Gly polymorphism affects the antiarrhythmic efficacy of flecainide in patients with coadministration of beta-blockers. AB - OBJECTIVE: beta1-Adrenergic receptor (beta1-AR) stimulation modulates the antiarrhythmic activities of sodium channel blockers. The beta1-AR Gly389 variant shows a marked decrease in agonist-stimulated cyclic AMP production compared with that of the wild-type Arg389 in vitro. We investigated whether the Arg389Gly polymorphism affects the efficacy of flecainide, a typical sodium channel blocker, in patients with or without coadministration of beta-blockers. METHODS: The effects of the beta1-AR Arg389Gly polymorphism on the antiarrhythmic efficacy of flecainide were compared between with and without coadministered beta-blockers in 159 patients with supraventricular tachyarrhythmia. The antiarrhythmic efficacy of flecainide was assessed for at least 2 months by evaluating symptomatology, 12-lead ECGs, and Holter monitoring results. RESULTS: Genetic differences in the antiarrhythmic efficacy of flecainide were observed in patients with coadministration of beta-blockers. Tachyarrhythmia was well controlled in 60% of Arg389-homozygotes, 30% of Gly389-heterozygotes, and 0% of Gly389-homozygotes (P=0.001). In contrast, no difference in the antiarrhythmic efficacy was observed among the three genotypes in the patients without coadministration of beta-blockers (64, 70, and 60%, respectively). Heart rate in tachyarrhythmia in patients treated with flecainide was significantly higher in Gly389 carriers than in Arg389-homozygotes (P=0.013). CONCLUSION: The Gly389 polymorphism decreased the antiarrhythmic efficacy of flecainide when coadministered with beta-blockers. The results indicate that the Arg389Gly polymorphism may play an important role in predicting the efficacy of flecainide in patients with coadministration of beta-blockers. PMID- 27500824 TI - Electrochemical Etching and Characterization of Sharp Field Emission Points for Electron Impact Ionization. AB - A new variation of the drop-off method for fabricating field emission points by electrochemically etching tungsten rods in a NaOH solution is described. The results of studies in which the etching current and the molarity of the NaOH solution used in the etching process were varied are presented. The investigation of the geometry of the tips, by imaging them with a scanning electron microscope, and by operating them in field emission mode is also described. The field emission tips produced are intended to be used as an electron beam source for ion production via electron impact ionization of background gas or vapor in Penning trap mass spectrometry applications. PMID- 27500823 TI - Nephrotoxin Microinjection in Zebrafish to Model Acute Kidney Injury. AB - The kidneys are susceptible to harm from exposure to chemicals they filter from the bloodstream. This can lead to organ injury associated with a rapid decline in renal function and development of the clinical syndrome known as acute kidney injury (AKI). Pharmacological agents used to treat medical circumstances ranging from bacterial infection to cancer, when administered individually or in combination with other drugs, can initiate AKI. Zebrafish are a useful animal model to study the chemical effects on renal function in vivo, as they form an embryonic kidney comprised of nephron functional units that are conserved with higher vertebrates, including humans. Further, zebrafish can be utilized to perform genetic and chemical screens, which provide opportunities to elucidate the cellular and molecular facets of AKI and develop therapeutic strategies such as the identification of nephroprotective molecules. Here, we demonstrate how microinjection into the zebrafish embryo can be utilized as a paradigm for nephrotoxin studies. PMID- 27500825 TI - Diagnosis of Musculus Gastrocnemius Tightness - Key Factors for the Clinical Examination. AB - Common foot and ankle pathologies have been linked to isolated Musculus gastrocnemius tightness (MGT). Various examination techniques have been described to assess MGT. Still, a standardized examination procedure is missing. Literature argues for weightbearing examination but the degree of knee flexion needed to eliminate the restraining effect of the M. gastrocnemius on ankle dorsiflexion (ADF) is unknown. This manuscript investigates the effect of knee flexion on ankle dorsiflexion and provides a detailed description of a standardized examination protocol. Examination on 20 healthy individuals revealed, that 20 degrees of knee flexion is sufficient to fully eliminate the influence of the M. gastrocnemius on ADF. This builds the prerequisite for a standardized examination for MGT. Non-weightbearing and weightbearing examination of ADF has to be conducted with the knee fully extended and at least 20 degrees flexed. Two investigators should conduct non-weightbearing testing with the subject in supine position. In order to obtain reliable results, the axis of the fibula should be marked. One examiner can conduct weightbearing examination with the subject in lunge stance. Isolated MGT is present if ADF is impaired with the knee fully extended and knee flexion results in a significant ADF increase. The herein presented standardized examination is the prerequisite for future studies aiming at establishing norm values. PMID- 27500826 TI - Truncation and Mutation of a Transferrin Receptor Aptamer Enhances Binding Affinity. AB - Aptamers are proving their utility in a number of applications. However, to be easily functionalized, their structure needs to be simplified. Therefore, we sought to truncate a 50-nucleotide aptamer specific to the transferrin receptor to its smallest functional unit using rational engineering of the predicted two dimensional structure of the longer parent sequence. In addition, mutations were introduced into the binding loop to determine their effect on the selectivity of the aptamers. These base mutations enhanced the binding affinity of the aptamer, while retaining its specificity. The equilibrium dissociation constant (Kd) was reduced sixfold following the substitution of all four bases in the binding region. In addition, these aptamers were efficiently internalized into transferrin receptor-positive cells in a similar manner to the transferrin receptor antibody and demonstrated colocalization with this antibody. This study has shown that the smallest functional unit of this aptamer was 14 nucleotides. This small size will be advantageous for future applications, such as drug delivery or functionalization of other therapeutic modalities. PMID- 27500827 TI - Continuous electroencephalography in pediatric traumatic brain injury: Seizure characteristics and outcomes. AB - BACKGROUND: Traumatic brain injury (TBI) is a major cause of pediatric morbidity and mortality. Secondary injury that occurs as a result of a direct impact plays a crucial role in patient prognosis. The guidelines for the management of severe TBI target treatment of secondary injury. Posttraumatic seizure, one of the secondary injury sequelae, contributes to further damage to the injured brain. Continuous electroencephalography (cEEG) helps detect both clinical and subclinical seizure, which aids early detection and prompt treatment. OBJECTIVE: The aim of this study was to examine the relationship between cEEG findings in pediatric traumatic brain injury and neurocognitive/functional outcomes. METHODS: This study focuses on a subgroup of a larger prospective parent study that examined children admitted to a level-1 trauma hospital. The subgroup included sixteen children admitted to the pediatric intensive care unit (PICU) who received cEEG monitoring. Characteristics included demographics, cEEG reports, and antiseizure medication. We also examined outcome scores at the time of discharge and 4-6weeks postdischarge using the Glasgow Outcome Scale - Extended Pediatrics and center-based speech pathology neurocognitive/functional evaluation scores. RESULTS: Sixteen patients were included in this study. Patients with severe TBI made up the majority of those that received cEEG monitoring. Nonaccidental trauma was the most frequent TBI etiology (75%), and subdural hematoma was the most common lesion diagnosed by CT scan (75%). Fifteen patients received antiseizure medication, and levetiracetam was the medication of choice. Four patients (25%) developed seizures during PICU admission, and 3 patients had subclinical seizures that were detected by cEEG. One of these patients also had both a clinical and subclinical seizure. Nonaccidental trauma was an etiology of TBI in all patients with seizures. Characteristics of a nonreactive pattern, severe/burst suppression, and lack of sleep architecture, on cEEG, were associated with poor neurocognitive/functional outcome. CONCLUSION: Continuous electroencephalography demonstrated a pattern that associated seizures and poor outcomes in patients with moderate to severe traumatic brain injury, particularly in a subgroup of patients with nonaccidental trauma. Best practice should include institution-based TBI cEEG protocols, which may detect seizure activity early and promote outcomes. Future studies should include examination of individual cEEG characteristics to help improve outcomes in pediatric TBI. PMID- 27500828 TI - Stability and Biological Activity Evaluation of Chlorantraniliprole Solid Nanodispersions Prepared by High Pressure Homogenization. AB - Poorly water-soluble compounds are difficult to develop as pesticide products and face great challenges in water-based and environmentally friendly formulation development. In this study, high pressure homogenization combined with lyophilization was adopted to prepare the solid nanodispersions of chlorantraniliprole with poor solubility and high melting point. The mean particle sizes of the solid nanodispersions with different pesticide contents were all less than 75 nm, even when the content was up to 91.5%. For the 2.5% chlorantraniliprole solid nanodispersion with the mean particle size of 29 nm, the suspensibility and wetting time in water were 97.32% and 13 s, respectively. The re-dispersibility and wettability were superior to those of conventional water dispersible granules. The retention on the rice leaf of 18.7 mg/cm2 was 1.5 and 3 times that of commercial aqueous suspension concentrate and pure water. The bioassay result to diamondback moths indicated that the toxicity of the solid nanodispersion was 3.3 and 2.8 times that of technical and aqueous suspension concentrate, respectively. Moreover, the solid nanodispersion has the advantages of total avoidance of organic solvents, significant reduction of surfactants and feasibility of obtaining high concentration nanoformulations. The solid nanodispersion is an attractive candidate for improving pesticide solubility and efficacy, and its application in crop production will reduce both residues in food and environmental pollution of pesticide. PMID- 27500830 TI - Erratum: Immunodiagnostic Tests' Predictive Values for Progression to Tuberculosis in Transplant Recipients: A Prospective Cohort Study: Erratum. AB - [This corrects the article DOI: 10.1097/TXD.0000000000000520.]. PMID- 27500829 TI - The Discrete Emotions Questionnaire: A New Tool for Measuring State Self-Reported Emotions. AB - Several discrete emotions have broad theoretical and empirical importance, as shown by converging evidence from diverse areas of psychology, including facial displays, developmental behaviors, and neuroscience. However, the measurement of these states has not progressed along with theory, such that when researchers measure subjectively experienced emotions, they commonly rely on scales assessing broad dimensions of affect (positivity and negativity), rather than discrete emotions. The current manuscript presents four studies that validate a new instrument, the Discrete Emotions Questionnaire (DEQ), that is sensitive to eight distinct state emotions: anger, disgust, fear, anxiety, sadness, happiness, relaxation, and desire. Emotion theory supporting the importance of distinguishing these specific emotions is reviewed. PMID- 27500831 TI - Male Smokers' and Non-Smokers' Response Inhibition in Go/No-Go Tasks: Effect of Three Task Parameters. AB - Impaired response inhibition plays a major role in many addictive behaviors. However, in studies using go/no-go tasks, findings regarding the presence of response inhibition deficits in nicotine-dependent individuals are mixed. This might be due to differences between studies on a number of task parameters. Here we aimed to identify task conditions under which go/no-go task performance deficits can be observed in smokers and to characterize the nature of such deficits. Sixty-one male students (30 smokers, 31 non-smokers) performed a go/no go task while independently manipulating three task parameters: (1) percentage no go trials (50% or 25%), (2) stimulus presentation time (600 ms or 200 ms), and (3) nature of no-go stimuli (cigarette related or cigarette unrelated). Three measures, reaction time on go trials and percentage correct responses on go and no-go trials, served as performance indicators. Under 200-ms but not 600-ms stimulus presentation conditions, the smokers responded faster on go trials and made more errors on both go and no-go trials than the non-smokers did. These differences occurred irrespective of the percentage of no-go trials and nature of no-go stimuli. The accuracy differences disappeared after controlling for the response time differences, suggesting a strong speed-accuracy trade-off. This study contributes to unraveling the conditions under which smokers display impaired inhibition performance and helps to characterize the nature of this impairment. Under task conditions prompting fast responding, smokers are more prone to increase response speed and to make more errors than non-smokers. PMID- 27500832 TI - Re-interventions after TEVAR for type B aortic dissection: considerations for management and the need for further insight. PMID- 27500834 TI - Is the Combination of Insecticide and Mating Disruption Synergistic or Additive in Lightbrown Apple Moth, Epiphyas postvittana? AB - Pest suppression from combinations of tactics is fundamental to pest management and eradication. Interactions may occur among tactical combinations and affect suppression. The best case is synergistic, where suppression from a combination is greater than the sum of effects from single tactics (AB >> A+B). We explored how mating disruption and insecticide interacted at field scale, additively or synergistically. Use of a pheromone delivery formulation (SPLATTM) as either a mating disruption treatment (i.e. a two-component pheromone alone) or as a lure and kill treatment (i.e. the two-component pheromone plus a permethrin insecticide) was compared for efficacy against the lightbrown apple moth Epiphyas postvittana. Next, four point-source densities of the SPLATTM formulations were compared for communication disruption. Finally, the mating disruption and lure and kill treatments were applied with a broadcast insecticide. Population assessment used virgin female traps and synthetic pheromone in replicated 9-ha vineyard plots compared with untreated controls and insecticide-treated plots, to investigate interactions. Lure and kill and mating disruption provided equivalent suppression; no additional benefit accrued from including permethrin with the pheromone suggesting lack of contact. The highest point-source density tested (625/ha) was most effective. The insect growth regulator methoxyfenoxide applied by broadcast application lowered pest prevalence by 70% for the first ten weeks compared to pre-trial. Pheromone addition suppressed the pest further by an estimated 92.5%, for overall suppression of 97.7% from the treatment combination of insecticide plus mating disruption. This was close to that expected for an additive model of interactivity between insecticide and mating disruption (AB = A+B) estimated from plots with single tactics as 98% suppression in a combination. The results indicate the need to examine other tactical combinations to achieve the potential cost-efficiencies of synergistic interactions. PMID- 27500833 TI - Sirtuin-2 Regulates Sepsis Inflammation in ob/ob Mice. AB - OBJECTIVE: Obesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis. METHODS: Sepsis was induced using cecal ligation and puncture (CLP) in ob/ob mice. We measured microvascular inflammation in response to lipopolysaccharide/normal saline re-stimulation as a "second-hit" (marker of immune function) at different time points to track phases of sepsis in ob/ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 (RAW) cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese (DIO) mice with sepsis. RESULTS: We observed that the ob/ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob/ob mice during hypo inflammation. SIRT-2 inhibition in ob/ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFkappaBp65. CONCLUSION: SIRT-2 regulates microvascular inflammation in obese mice with sepsis and may provide a novel treatment target for obesity with sepsis. PMID- 27500835 TI - Retroviral Transduction of Bone Marrow Progenitor Cells to Generate T-cell Receptor Retrogenic Mice. AB - T cell receptor (TCR) signaling is essential in the development and differentiation of T cells in the thymus and periphery, respectively. The vast array of TCRs proves studying a specific antigenic response difficult. Therefore, TCR transgenic mice were made to study positive and negative selection in the thymus as well as peripheral T cell activation, proliferation and tolerance. However, relatively few TCR transgenic mice have been generated specific to any given antigen. Thus, studies involving TCRs of varying affinities for the same antigenic peptide have been lacking. The generation of a new TCR transgenic line can take six or more months. Additionally, any specific backcrosses can take an additional six months. In order to allow faster generation and screening of multiple TCRs, a protocol for retroviral transduction of bone marrow was established with stoichiometric expression of the TCRalpha and TCRbeta chains and the generation of retrogenic mice. Each retrogenic mouse is essentially a founder, virtually negating a founder effect, while the length of time to generate a TCR retrogenic is cut from six months to approximately six weeks. Here we present a rapid and flexible alternative to TCR transgenic mice that can be expressed on any chosen background with any particular TCR. PMID- 27500837 TI - [Not Available]. PMID- 27500838 TI - [Not Available]. PMID- 27500836 TI - Control of Oocyte Reawakening by Kit. AB - In mammals, females are born with finite numbers of oocytes stockpiled as primordial follicles. Oocytes are "reawakened" via an ovarian-intrinsic process that initiates their growth. The forkhead transcription factor Foxo3 controls reawakening downstream of PI3K-AKT signaling. However, the identity of the presumptive upstream cell surface receptor controlling the PI3K-AKT-Foxo3 axis has been questioned. Here we show that the receptor tyrosine kinase Kit controls reawakening. Oocyte-specific expression of a novel constitutively-active KitD818V allele resulted in female sterility and ovarian failure due to global oocyte reawakening. To confirm this result, we engineered a novel loss-of-function allele, KitL. Kit inactivation within oocytes also led to premature ovarian failure, albeit via a contrasting phenotype. Despite normal initial complements of primordial follicles, oocytes remained dormant with arrested oocyte maturation. Foxo3 protein localization in the nucleus versus cytoplasm explained both mutant phenotypes. These genetic studies provide formal genetic proof that Kit controls oocyte reawakening, focusing future investigations into the causes of primary ovarian insufficiency and ovarian aging. PMID- 27500839 TI - [Not Available]. PMID- 27500840 TI - [Not Available]. PMID- 27500841 TI - [Not Available]. PMID- 27500842 TI - [Not Available]. PMID- 27500843 TI - [Not Available]. PMID- 27500845 TI - [Not Available]. PMID- 27500844 TI - [Not Available]. PMID- 27500846 TI - [Not Available]. PMID- 27500847 TI - [Not Available]. PMID- 27500848 TI - [Not Available]. AB - The syndrome of overactive bladder (OAB) with the symptoms of frequency, urgency and nocturia is often seen. After the diagnosis has been made by careful exclusion of other conditions, there are different symptomatic treatment strategies available. These include drug treatment as well as minimally invasive local surgical treatments and treatments which intervene with the control of the bladder by modulating central nervous areas. Alternative methods such as acupuncture may help in individual cases; the placebo effect is high and there is a lack of controlled studies. PMID- 27500849 TI - [Physiotherapy in Women with Overactive Bladder]. AB - As regards treatment for overactive bladder, physiotherapeutic interventions can be seen as an alternative to drug treatment. Targeted pelvic floor and bladder training is used to decrease the number of voids and the incontinence episodes or to increase the average voided volume in women with overactive bladder (3 systematic reviews with evidence level 1/1a).An additional option to treat women with overactive bladder is to use functional electrical stimulation and magnetic stimulation.2 systematic reviews 1 2 and 2 RCTs 3 4 reveal a low level of evidence (2 studies with level 2/2b) for the use of electrical stimulation (transcutaneous, vaginal or transanal) to reduce incontinence episodes and the number of voids and to increase the average voided volume. The trial from Yamanishi et al. (2014) shows that magnetic stimulation has a positive effect 5. Further studies are needed to evaluate the benefit of conservative treatment procedures for overactive bladder. PMID- 27500850 TI - [Urethral Syndrome and Urethral Pain: Do we Treat People or Diagnoses?]. AB - The urethral syndrome with urethral pain and bladder voiding disorders is a diagnosis of exclusion. Possible aetiologies are diverse and include organic, functional and inflammatory pathologies of the urethra. Infections, inflammation of the paraurethral glands, spasms of the sphincter muscle and/or of the pelvic floor muscles, oestrogen deficiency, trauma, neuropathies, hypersensitivity and psychosomatic issues have been investigated as possible causes.Patients with urethral syndrome must be viewed, evaluated and treated holistically. They need a lot of time and attention during their evaluation and treatment. It is now well known that psychosocial aspects are involved in the development of many somatic conditions and may have a crucial impact on the course of a disease. This needs to be taken into consideration during the treatment process. PMID- 27500851 TI - [Not Available]. PMID- 27500852 TI - Chimeric antigen receptor (CAR)-directed adoptive immunotherapy: a new era in targeted cancer therapy. AB - As a result of the recent advances in molecular immunology, virology, genetics, and cell processing, chimeric antigen receptor (CAR)-directed cancer therapy has finally arrived for clinical application. CAR-directed adoptive immunotherapy represents a novel form of gene therapy, cellular therapy, and immunotherapy, a combination of three in one. Early phase clinical trial was reported in patients with refractory chronic lymphoid leukemia with 17p deletion. Accompanying the cytokine storm and tumor lysis syndrome was the shocking disappearance of the leukemia cells refractory to chemotherapy and monoclonal antibodies. CAR therapy was reproduced in both children and adults with refractory acute lymphoid leukemia. The CAR technology is being explored for solid tumor therapy, such as glioma. Close to 30 clinical trials are underway in the related fields (www.clinicaltrials.gov). Further improvement in gene targeting, cell expansion, delivery constructs (such as using Sleeping Beauty or Piggyback transposons) will undoubtedly enhance clinical utility. It is foreseeable that CAR-engineered T cell therapy will bring targeted cancer therapy into a new era. PMID- 27500853 TI - The role of danger-associated molecular patterns (DAMPs) in trauma and infections. PMID- 27500854 TI - Diffusion Monte Carlo Perspective on the Spin-State Energetics of [Fe(NCH)6](2.). AB - The energy difference between the high spin and the low spin state of the model compound [Fe(NCH)6](2+) is investigated by means of Diffusion Monte Carlo (DMC), where special attention is dedicated to analyzing the effect of the fix node approximation on the accuracy of the results. For this purpose, we compare several Slater-Jastrow and multireference Slater-Jastrow trial wave functions. We found that a Slater-Jastrow trial wave function constructed with the generalized Kohn-Sham orbitals from hybrid DFT represents the optimal choice. This is understood by observing that hybrid functionals account for the subtle balance between exchange and correlation effects and the respective orbitals accurately describe the ligand-metal hybridization as well as the charge reorganization accompanying the spin transition. Finally the DMC results are compared with those obtained by Hartree-Fock, DFT, CASSCF, and CASPT2. While there is no clear reference value for the high spin-low spin energy difference, DMC and high level CCSD(T) calculations agree within around 0.3 eV. PMID- 27500855 TI - Short-term effects of air temperature on plasma metabolite concentrations in patients undergoing cardiac catheterization. AB - BACKGROUND: Epidemiological studies have shown associations between air temperature and cardiovascular health outcomes. Metabolic dysregulation might also play a role in the development of cardiovascular disease. OBJECTIVES: To investigate short-term temperature effects on metabolites related to cardiovascular disease. METHODS: Concentrations of 45 acylcarnitines, 15 amino acids, ketone bodies and total free fatty acids were available in 2869 participants from the CATHeterization GENetics cohort recruited at the Duke University Cardiac Catheterization Clinic (Durham, NC) between 2001 and 2007. Ten metabolites were selected based on quality criteria and cluster analysis. Daily averages of meteorological variables were obtained from the North American Regional Reanalysis project. Immediate, lagged, and cumulative temperature effects on metabolite concentrations were analyzed using (piecewise) linear regression models. RESULTS: Linear temperature effects were found for glycine, C16-OH:C14:1-DC, and aspartic acid/asparagine. A 5 degrees C increase in temperature was associated with a 1.8% [95%-confidence interval: 0.3%; 3.3%] increase in glycine (5-day average), a 3.2% [0.1%; 6.3%] increase in C16-OH:C14:1 DC (lag of four days), and a -1.4% [-2.4%; -0.3%] decrease in aspartic acid/asparagine (lag of two days). Non-linear temperature effects were observed for alanine and total ketone bodies with breakpoint of 4 degrees C and 20 degrees C, respectively. Both a 5 degrees C decrease in temperature on colder days (<4 degrees C)and a 5 degrees C increase in temperature on warmer days (>=4 degrees C) were associated with a four day delayed increase in alanine by 6.6% [11.7; 1.8%] and 1.9% [0.3%; 3.4%], respectively. For ketone bodies we found immediate (0-day lag) increases of 4.2% [-0.5%; 9.1%] and 12.3% [0.1%; 26.0%] associated with 5 degrees C decreases on colder (<20 degrees C) days and 5 degrees C increases on warmer days (>=20 degrees C), respectively. CONCLUSIONS: We observed multiple effects of air temperature on metabolites several of which are reported to be involved in cardiovascular disease. Our findings might help to understand the link between air temperature and cardiovascular disease. PMID- 27500856 TI - Synthesis of N-(2-Hydroxyaryl)benzotriazoles via Metal-Free O-Arylation and N-O Bond Cleavage. AB - A metal-free method for synthesis of N-(2-hydroxyaryl)benzotriazoles via O arylation of N-hydroxybenzotriazoles with readily available diaryliodonium salts and sequential N-O bond cleavage under mild conditions has been developed. The [3,3]-rearrangement of N-O bond cleavage could take place on the N instead of C atom. The reaction was compatible with diverse functional groups and a new type of P,N-ligand was synthesized in three steps. PMID- 27500857 TI - Intercomparison NaI(Tl) and HPGe spectrometry to studies of natural radioactivity on geological samples. AB - In this study, in situ gamma spectra using NaI(Tl) detector have been compared with the laboratory measurements by using HPGe detector on geological samples. The results for measuring naturally occurring terrestrial gamma radiation of 40K and the decay series of 232Th and, 238U respectively of both detectors show a maximum deviation about 5%. The mass activities series from both detectors were checked for coherence using proficiency test procedure from the International Atomic Energy Agency. The reliability and precision pass for final scores for all the analytical determinations of are received "acceptable" for all radionuclides. PMID- 27500858 TI - Analysis of the accumulation and redistribution patterns of cesium in Vicia faba grown on contaminated soils. AB - The aim of this study was to investigate the relationship between cesium (Cs) contamination and plant growing stages in crops or vegetables grown on Cs contaminated soils. Vicia faba was grown on Cs-contaminated soils under pot culture conditions, and Cs uptake and bioaccumulation at various growing stages were then measured. The results showed that Cs uptake by V. faba was significantly greater on soils with a higher Cs content. As shown by the bioaccumulation factor (BCF), the highest transfer coefficient occurred when V. faba reached the maturation stage. Cs was easily transferred to young organs, especially seeds, with an average percentage of 9.60% in seeds during the maturation stage. This implies that Cs can be transferred to the human food chain at all growth stages of the plant, especially the last stages. Uptake rates of Cs remained stable during the generative growth phase of V. faba. This implies that the cultivation of varieties with short generative growth periods can reduce Cs accumulation in the edible parts of plants. PMID- 27500859 TI - Probiotics, gut microbiota, and their influence on host health and disease. AB - The gastrointestinal tract of mammals hosts a high and diverse number of different microorganisms, known as intestinal microbiota. Many probiotics were originally isolated from the gastrointestinal tract, and they were defined by the Food and Agriculture Organization of the United Nations (FAO)/WHO as "live microorganisms which when administered in adequate amounts confer a health benefit on the host." Probiotics exert their beneficial effects on the host through four main mechanisms: interference with potential pathogens, improvement of barrier function, immunomodulation and production of neurotransmitters, and their host targets vary from the resident microbiota to cellular components of the gut-brain axis. However, in spite of the wide array of beneficial mechanisms deployed by probiotic bacteria, relatively few effects have been supported by clinical data. In this regard, different probiotic strains have been effective in antibiotic-associated diarrhea or inflammatory bowel disease for instance. The aim of this review was to compile the molecular mechanisms underlying the beneficial effects of probiotics, mainly through their interaction with the intestinal microbiota and with the intestinal mucosa. The specific benefits discussed in this paper include among others those elicited directly through dietary modulation of the human gut microbiota. PMID- 27500860 TI - Multifunctional PLGA/Parylene C Coating for Implant Materials: An Integral Approach for Biointerface Optimization. AB - Functionalizing implant surfaces is critical for improving their performance. An integrated approach was employed to develop a multifunctional implant coating based on oxygen plasma-modified parylene C and drug-loaded, biodegradable poly(dl lactide-co-glycolide) (PLGA). The key functional attributes of the coating (i.e., anti-corrosion, biocompatible, anti-infection, and therapeutic) were thoroughly characterized at each fabrication step by spectroscopic, microscopic, and biologic methods and at different scales, ranging from molecular, through the nano- and microscales to the macroscopic scale. The chemistry of each layer was demonstrated separately, and their mutual affinity was shown to be indispensable for the development of versatile coatings for implant applications. PMID- 27500862 TI - Organ boundary NAC-domain transcription factors are implicated in the evolution of petal fusion. AB - : Research rationale: Evolution of fused petals (sympetaly) is considered to be an important innovation that has repeatedly led to increased pollination efficiency, resulting in accelerated rates of plant diversification. Although little is known about the underlying regulation of sympetaly, genetic pathways ancestrally involved in organ boundary establishment (e.g. CUP SHAPED COTYLEDON [CUC] 1-3 genes) are strong candidates. In sympetalous petunia, mutations in the CUC1/2-like orthologue NO APICAL MERISTEM (NAM) inhibit shoot apical meristem formation. Despite this, occasional 'escape shoots' develop flowers with extra petals and fused inter-floral whorl organs. Central methods: To To determine if petunia CUC-like genes regulate additional floral patterning, we used virus induced silencing (VIGS) following establishment of healthy shoot apices to re examine the role of NAM in petunia petal development, and uniquely characterise the CUC3 orthologue NH16. KEY RESULTS: Confirming previous results, we found that reduced floral NAM/NH16 expression caused increased petal-stamen and stamen carpel fusion, and often produced extra petals. However, further to previous results, all VIGS plants infected with NAM or NH16 constructs exhibited reduced fusion in the petal whorl compared to control plants. MAIN CONCLUSIONS: Together with previous data, our results demonstrate conservation of petunia CUC-like genes in establishing inter-floral whorl organ boundaries, as well as functional evolution to affect the fusion of petunia petals. PMID- 27500861 TI - Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders. AB - Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non-24-hour sleep-wake disorder (or non 24). However, three additional commercially available melatonin receptor agonists agomelatine, prolonged-release melatonin, and ramelteon-have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs. PMID- 27500863 TI - The impact of critical care transition programs on outcomes after intensive care unit (ICU) discharge: can we get there from here? PMID- 27500864 TI - Stretchable Multichannel Electromyography Sensor Array Covering Large Area for Controlling Home Electronics with Distinguishable Signals from Multiple Muscles. AB - Physiological signals provide important information for biomedical applications and, more recently, in the form of wearable electronics for active interactions between bodies and external environments. Multiple physiological sensors are often required to map distinct signals from multiple points over large areas for more diverse applications. In this paper, we present a reusable, multichannel, surface electromyography (EMG) sensor array that covers multiple muscles over relatively large areas, with compliant designs that provide different levels of stiffness for repetitive uses, without backing layers. Mechanical and electrical characteristics along with distinct measurements from different muscles demonstrate the feasibility of the concept. The results should be useful to actively control devices in the environment with one array of wearable sensors, as demonstrated with home electronics. PMID- 27500865 TI - Longitudinal clinical score prediction in Alzheimer's disease with soft-split sparse regression based random forest. AB - Alzheimer's disease (AD) is an irreversible neurodegenerative disease and affects a large population in the world. Cognitive scores at multiple time points can be reliably used to evaluate the progression of the disease clinically. In recent studies, machine learning techniques have shown promising results on the prediction of AD clinical scores. However, there are multiple limitations in the current models such as linearity assumption and missing data exclusion. Here, we present a nonlinear supervised sparse regression-based random forest (RF) framework to predict a variety of longitudinal AD clinical scores. Furthermore, we propose a soft-split technique to assign probabilistic paths to a test sample in RF for more accurate predictions. In order to benefit from the longitudinal scores in the study, unlike the previous studies that often removed the subjects with missing scores, we first estimate those missing scores with our proposed soft-split sparse regression-based RF and then utilize those estimated longitudinal scores at all the previous time points to predict the scores at the next time point. The experiment results demonstrate that our proposed method is superior to the traditional RF and outperforms other state-of-art regression models. Our method can also be extended to be a general regression framework to predict other disease scores. PMID- 27500866 TI - The presence of heterogeneous nuclear ribonucleoproteins in frontotemporal lobar degeneration with FUS-positive inclusions. AB - Frontotemporal lobar degeneration with fused in sarcoma-positive inclusions (FTLD FUS) is a disease with unknown cause. Transportin 1 is abundantly found in FUS positive inclusions and responsible for the nuclear import of the FET proteins of which FUS is a member. The presence of all FET proteins in pathological inclusions suggests a disturbance of transportin 1-mediated nuclear import. FUS also belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) protein family. We investigated whether hnRNP proteins are associated with FUS pathology implicating dysfunctional nuclear export in the pathogenesis of FTLD-FUS. hnRNP proteins were investigated in affected brain regions in FTLD-FUS using immunohistochemistry, biochemical analysis, and the expression analysis. We demonstrated the presence of several hnRNP proteins in pathological inclusions including neuronal cytoplasmic inclusions and dystrophic neurites. The biochemical analysis revealed a shift in the location of hnRNP A1 from the nucleus to the cytoplasm. The expression analysis revealed an increase in several hnRNP proteins in FTLD-FUS. These results implicate a wider dysregulation of movement between intracellular compartments, than mechanisms only affecting the nuclear import of FUS proteins. PMID- 27500869 TI - [Wernicke-Korsakoff syndrome]. AB - AIM: To study the diagnosis and treatment of non-alcoholic Wernicke-Korsakoff syndrome (WKS). MATERIAL AND METHODS: Eight patients (5 men and 3 women), mean age 38,9+/-1,4 years, with WKS developed due to acute gastrointestinal tract (GIT) disease (3 patients), the exacerbation of chronic GIT disease with malabsorption (2 patients) and after surgery on the upper GIT (3 patients) were included in the study. RESULTS: The disease manifested with consciousness disturbance, symptoms of ataxia, eye movement disorders and bulbar syndrome that developed after 24-48 h. Treatment resistant tonic-clonic seizures were developed in 1 patient. MRI revealed hyper intensive signals on T2-weighted images in the hypothalamus, mamillar bodies, brain stem, hippocampus as well as contrast accumulation in the mamillar bodies. Treatment with vitamin B complex (neurobion) and thiamine exerted a positive effect. CONCLUSION: Patients with GIT disease with malabsorption are at risk of WKS. Consciousness disturbance, symptoms of ataxia, eye movement disorders indicate the necessity of treatment with thiamine that allows to prevent the development of stable cognitive deficit. PMID- 27500870 TI - [The strategies for psychological self-control of seizures in patients with focal epilepsy]. AB - AIM: To investigate self-control strategies for epileptic seizures and their relationship to the individual coping-style in patients with focal epilepsy. MATERIAL AND METHODS: Twenty one adult patients with focal epilepsy were examined. Strategies for seizure control and coping-style were estimated with the CBES-SC and the Brief COPE scale, respectively. The control group consisted of 20 healthy individuals. RESULTS: 86% of patients tried to control their seizures. Most of the patients (33%) preferred to use behavioral self-management strategies, which reduced the consequences of seizure. Patients with the high self-control activity more often had adaptive problem-focused coping-style in comparison to the patients with the low self-control (p<0.01). CONCLUSION: The psychological coping-style modifying support can motivate patient to the wider use of strategies for seizure control and improve a psychosocial adjustment of the patient. PMID- 27500871 TI - [The cholinergic deficiency syndrome in patients with depressed consciousness after severe brain injury]. AB - AIM: To determine the clinical and electrophysiological (EEG) signs of cholinergic deficiency in the process of recovery of consciousness in patients with severe brain injury. MATERIAL AND METHODS: Thirty-seven people (24 men and 13 women, mean age 32+/-14 years) were studied. A comprehensive study included assessment of neurological status, mental activity, and EEG. RESULTS AND CONCLUSION: A set of neurological symptoms, including reduced muscle tone, autonomic disorders (dry mucous membranes and skin, tachycardia, hypotension, gastrointestinal tract), eye movement disorders, that were,in accordance with the literature, characteristicof the cholinergic deficiency syndrome was found. This syndrome was detected against the background of a comatose state, akinetic mutism and mutism with understanding of speech, disintegration of speech, disorientation and amnestic decline. EEG revealed stable over time (months) characteristic changes: slowing and asymmetric alpha activity, equivalent dipole sources of hippocampal and stem localization, persistent strengthening of intra-hemispheric coherent connections, especially on the left side. The regression of the cholinergic deficiency syndrome was accompanied by an increase of regularity, capacity and frequency of alpha-activity (from 7-8 to 9-10 Hz), prevalence of equivalent dipole sources in the hippocampus with their appearance in the occipital cortex, normalization of connections with right-brain coherence with the preservation of their pathologically high values on the left side. PMID- 27500872 TI - [Possibilities of treatment optimization in children and adolescents with epilepsy and disturbances of emotion and volition (disphoria)]. AB - AIM: To optimize the treatment of dysphoriain children and adolescents in regard to sex and disease severity. MATERIAL AND METHODS: Seventy children and adolescents (boys - 45, girls - 25), aged from 6 to 18 years, with different forms of epilepsy and emotion and dysphoric disturbances were studied using CPRS andGCIscales Depending on dysphoria severity, patients were stratified into three groups: mild (n=19 (27.1%), moderate (n=27 (38.6%)) and severe (n=24 (34.3%)). RESULTS AND CONCLUSION: Dysphoric disorders were significantly more prevalent in boys, hostility and aggression were characteristic of boys as well. These facts impactedtreatment options. Neuroleptics were more frequently used in boys (35.5%) compared to girls(16%).Mild dysphoria didn't require additional treatment besides AED in 78,4%. In 75% cases of moderate dysphoria,systemic treatment with neuroleptics for 6 months was necessary. One-time recommendations for neuroleptic treatment were made in all three groups with the prevalence in a groupof children with severe and moderate dysphoria. PMID- 27500873 TI - [A randomized single blind study of the efficacy of pregabalin in the treatment of opioid withdrawal syndrome]. AB - AIM: To study the efficacy and safety of pregabalin (lyrica) in the complex treatment of opioid withdrawal syndrome (OWS). MATERIAL AND METHODS: STUDY DESIGN: single-blind randomized symptom-triggered protocol with an active control. Thirty-four patients were randomly assigned to two groups. The first group (n=19) received up to 600 mg a day of pregabalin for six days along with symptomatic therapy (basic and symptom-triggered). The second group (n=15) received up to 600 micrograms of clonidine a day as the main treatment along with the same basic and symptomatic regimen. Opiate withdrawal severity, craving, sleep disturbance, anxiety and depression, as well as general clinical impressions and side-effects were assessed daily using internationally validated quantitative psychometric instruments. RESULTS: In the pregabalin group, 15 out of 19 (79%) patients completed treatment compared to 7 out of 15 (47%) patients in the clonidine group (p=0.05; Fisher exact test). There were no statistically significant differences between groups on any assessments of the severity of OWS (reduction of the severity of opiate withdrawal), perhaps because of the small sample size. In the pregabalin group, there were lower indicators of the severity of craving for opiates (p=0.05), anxiety (p=0.05) and depression (p<0.05), while patient-rated self-assessment of their general health condition was significantly better compared to the second group (p<0.05). There were no significant differences in the frequency of adverse events between the groups, though the better tolerability of treatment was noted in the pregabalin group. CONCLUSION: Treatment regimen of OWS with pregabalin is effective and safe and patients tolerate it better that leads to a higher detoxification completion rate (retention). PMID- 27500874 TI - [Treatment of chronic cerebral venous insufficiency: a study on an effect of L lysine aescinat]. AB - AIM: To study an effect of L-lysine aescinat on the dynamics of complaints, severity of neurological syndromes and parameters of cerebral blood flow estimated by transcranial doppler and duplex scanning in patients with chronic cerebral venous insufficiency (CCVI). MATERIAL AND METHODS: Eighty patients with ultrasound-confirmed CCVI were examined. The basic group included 40 patients who received two treatment courses (intravenous drop-by-drop/stream introductions of L-lysine aescinat in the dose of 5ml during 7 days in 2nd and 30th days of examination). The comparison group consisted of 40 patients. RESULTS AND CONCLUSION: Treatment with L-lysine aescinat led to the significant decrease in complaints and improved the scores on the scales used in the study. There was an improvement in the cerebral hemodynamics (an increase of hemodynamic reserve and normalization of the linear blood flow velocity in deep veins) in the patients with CCVI. The safe profile of L-lysine aescinat used in recommended doses was confirmed. PMID- 27500875 TI - [Linguistic adaptation of the Russian version of the Short-form McGill Pain Questionnaire-2]. AB - AIM: Linguistic adaptation of the Russian version of the Short-form McGill Pain Questionnaire-2 (SF-MPQ-2), which is conceptually equivalent to the original questionnaire. MATERIAL AND METHODS: The adaptation of the Russian version of SF MPQ-2 was performed in accordance to established rules in several stages by two independent translators with the development of a consensus Russian version and its back translation by two independent translators and development of a consensus English version. The final Russian SF-MPQ-2 version was then created. RESULTS AND CONCLUSION: The Russian version of the Short-form McGill Pain Questionnaire-2 (SF-MPQ-2-RU) was generated based on the established rules. This version was legally registered by the right holder - Mapi Research Trust and recommended for research in the Russian Federation. PMID- 27500876 TI - [An experimental in vitro study of antioxidant and antiradical properties of cytoflavin, vinpocetine, actovegin and ethylmethylhydroxypyridine succinate]. AB - AIM: To investigate experimentally in vitro the antioxidant and anti-radical activity of several drugs. MATERIAL AND METHODS: Antioxidant activity was assessed by induced luminol-dependent chemiluminescence (CL). An impact on the generation of reactive oxygen species (O2-, OH, 1D, H2O2, HClO) and their ability to inhibit the auto-oxidation of quercetin combined with the generation of superoxide radical anion were determined. Anti-radical activity was studied by the method of restoring a stable radical alpha-alpha-diphenyl-beta-picryl hydrazine (DPPH) molecule of the alleged anti-oxidant. RESULTS AND CONCLUSION: The many-sided action of the drugs on the products of free radicals generated in the in vitro experiments has been shown. Only cytoflavin has the highest total antioxidant and antiradical activity. Vinpocetine has demonstrated similar, but somewhat less pronounced, activity. Ethylmethylhydroxypyridine succinate and actovegin have shown only the nonspecific superoxide dismutase activity which was by times lower than that of cytoflavin and vinpocetine. PMID- 27500877 TI - [Structural variations of the genome in autistic spectrum disorders with intellectual disability]. AB - AIM: To analyze structural variations in the genome in children with autism and intellectual disability. MATERIAL AND METHODS: Using high-resolution karyotyping (AffymetrixCytoScan HD Array) and original bioinformatic technology, 200 children with autism and intellectual disability were studied. RESULTS AND CONCLUSION: Data on structural variations in the genome in children with autism and intellectual disability are provided. Causative genomic pathology (chromosome abnormalities and copy number variations - CNV) was determined in 97 cases (48.5%). Based on these RESULTS: 24 candidate genes for autism with intellectual disability were selected. In 16 cases (8%), the chromosome mosaicism manifested as aneuploidy of whole autosomes and sex chromosomes (gonosomes) was identified. In 87 children (43.5%), there were genomic variations, which are characteristic of the so-called "grey zone" of genetic pathology in mental illnesses. Bioinformatic analysis showed that these genomic variations had a pleiotropic effect on the phenotype. PMID- 27500878 TI - [An effect of quetiapine on the immune system of patients with schizophrenia]. AB - AIM: To study an effect of the atypical antipsychotic quetiapine on the immune system of patients with schizophrenia with account for treatment efficacy. MATERIAL AND METHODS: Quetiapine was administered to 27 patients diagnosed with residual schizophrenia (F20.5) for 6 weeks in dose 200-400 mg/day; dynamic of clinical symptoms was evaluated with PANSS i CGI scales before administration of quetiapine and by week 6 of the treatment. Along with clinical assessments, immune indices were determined. RESULTS: At the end of week 6 of treatment, statistically significant changes of PANSS psychopathological symptoms were noted. According to CGI scale, patients were divided into group 1 with high treatment efficacy (n=17) and group 2 with the low efficacy (n=10). Significant between-group differences before treatment were as follows: the decreased number of lymphocytes of CD3+- CD16+-phenotypes, increased number of HLADR+-lymphocytes and IgA level in group 2. The quetiapine therapy led to the positive dynamic of phagocytosis indices, CD16+-lymphocytes, decrease in the level of IgA. CONCLUSION: Possible predictors of treatment efficacy were found including the number of mature T (CD3+) lymphocytes, CD16+ natural killers, HLADR+ lymphocytes and IgA concentrations. PMID- 27500879 TI - [Significance of sleep deprivation in the development of local epilepsy from neuroplasticity opinion]. AB - AIM: Learning cycle "sleep-wake" is of great theoretical and practical importance because it allows to understand the general patterns of adaptive mechanisms of human interaction with the environment (neuroplasticity), violations of which are the basis of many diseases of the CNS, including epilepsy. MATERIAL AND METHODS: Complex clinical and electroencephalographic (video-EEG monitoring with mandatory recording of sleep) study was carried out before and after prolonged sleep deprivation (for at least 1 day) of 178 patients with locally due to epilepsy (LEi). 45 healthy volunteers were examined in the control group as well as the patients with epilepsy. The work was carried out to compare the results of clinical and neurological and electrophysiological studies during sleep deprivation (SD) in patients with LEi and in healthy individuals with neurohistological and electron microscopic patterns of changes in the brain of rats in an experiment with 48-hour SD. RESULTS AND CONCLUSION: Discovered in the CNS of rats after SD morphological changes such as pleyokoniya of mitochondria, damage in the blood-brain barrier, signs of exhaustion astrocytes, glial cells and the change of the nuclei of gliocytes and some neurons of the type of apoptosis and karyorrhexis and destruction of synapses reveal a violation of the fundamental mechanisms of neuroplasticity. The results allow us to consider the SD patients as a damaging factor for the central nervous system, provoking the development of epileptic seizures and epilepsy, and the SD in laboratory animals can be used as a model for further study of the mechanisms of neuroplasticity. In addition the findings greatly complement current understanding of the mechanisms of neuroplasticity and pathogenesis of epilepsy, and justify the need for the study of therapeutic efficacy of modulators of neuroplasticity (transcranial magnetic stimulation, ipidacrin etc.) in the complexe treatment of patients with the this specified profile. PMID- 27500880 TI - [A comparative analysis of multiple linear models of medical service satisfaction among inpatients with borderline disorders at first-time admission and rehospitalization]. AB - AIM: To find out the factors of satisfaction with psychiatric help in inpatients with neurotic and depressive disorders depending on the moment of satisfaction evaluation and patients' treatment experience. MATERIAL AND METHODS: The sample included 266 first-time admission inpatients (satisfaction was evaluated at the moment of discharge) and 134 rehospitalized inpatients (satisfaction with previous treatment was evaluated at the moment of discharge; satisfaction with current treatment was evaluated at the moment of rehospitalization). The survey was performed using a questionnaire designed for this study. Statistical analysis was performed using multiple regression. RESULTS AND CONCLUSION: Satisfaction with nursing care was the key factor of satisfaction at the moment of discharge among both groups of inpatients (first-time admission and rehospitalization). Psychiatrist's empathy was the 2nd factor by importance. The structure of factors of medical service satisfaction of these 2 groups was different. General satisfaction with psychiatrist's work was the key factor of satisfaction with medical service during previous hospitalization while nursing care was twice less important. In whole, there were major differences in the structure of factors of medical service satisfaction during previous and current hospitalizations. The shift of importance from nursing care to psychiatrist's work and other differences in the structure of factors of satisfaction of rehospitalized patients with medical services can be explained by belonging of medical services to credible goods - patient is able to evaluate results of treatment only some period after discharge. PMID- 27500881 TI - [Posterior reversible encephalopathy syndrome due to hypocalcemia: a description of a case and an analysis of a pathogenic role of electrolyte disturbances]. AB - Afemale patient with recurrent posterior reversible encephalopathy syndrome, severe hypocalcemia due to extirpation of the parathyroid glands is described. The disease was characterized by the acute development of headache, seizures, cognitive and behavioral disorders, mental confusion, transitory blood pressure increasing. The vasogenic edema in the posterior parts of the brain, detected by CT at the first exacerbation,was completely regressed. The residual neurological deficit and MRI changes remained after the recurrent exacerbations. Main clinical features of PRESare explained by hypocalcemia and accompanying electrolyte disturbances.The reported case shows the necessity to study blood electrolytes in patients with PRES to clarify their pathogenic role and the necessity of drug correction. PMID- 27500882 TI - Robust Underwater Oil-Repellent Material Inspired by Columnar Nacre. AB - Inspired by natural columnar nacre, artificial montmorillonite/hydroxyethyl cellulose columnar nacre-like materials with a site-specific layered structure in the interior and a hierarchical columnar structure on the surface are prepared. The materials exhibit improved tensile strength, good chemical stability in seawater, superior resistance to sand-grain impingement, and robust underwater low-adhesive superoleophobicity. PMID- 27500883 TI - Meningeal Ewing Sarcoma/Peripheral PNET: Clinicopathological, Immunohistochemical and FISH study of four cases. AB - Meningeal Ewing Sarcoma (ES)/peripheral primitive neuroectodermal tumor (pPNET) is a rare diagnostically challenging small round cell tumor in the CNS. This study investigates the clinical pathological features of four cases of this tumor from archives of 6 years in our hospital. Patients were within the median age of 21.5 years and male to female ratio was 1:1. The tumors distributed at the supra tentorial location, posterior fossa and lumbar vertebral canal, usually presenting as the dura-sited nodule or having close connection with the meninges within the cranium or vertebral canal. Histopathologically, small round undifferentiated tumor cells with hypercellularities, scant cytoplasm and inconspicuous nucleoli were observed, although some components such as atypical larger vesicular nuclei, prominent nucleoli of tumor cells, necrotic foci and mesenchymal collagen proliferation forming the lobular structure, were also appreciated. Immunohistochemally, tumor cells displayed membranous positivity of CD99 (4/4), nuclear positivity of FLI-1 (4/4) and NKX2.2 (4/4), negativity of EMA, GFAP and synaptophysin expression. The histochemical PAS staining showed weak positivity in one case. Fluorescence in situ hybridization (FISH) test using EWSR1 (22q12) dual color break apart rearrangement probe showed positive results in two cases. Results suggest that using a panel of immunohistochemical markers, including NKX2.2, CD99, FLI-1, EMA, GFAP and synaptophysin, combined with the supplementary EWSR1 FISH test, helps to define the diagnosis of meningeal ES/pPNET of CNS. PMID- 27500884 TI - Histone acetyltransferase general control non-repressed protein 5 (GCN5) affects the fatty acid composition of Arabidopsis thaliana seeds by acetylating fatty acid desaturase3 (FAD3). AB - Seed oils are important natural resources used in the processing and preparation of food. Histone modifications represent key epigenetic mechanisms that regulate gene expression, plant growth and development. However, histone modification events during fatty acid (FA) biosynthesis are not well understood. Here, we demonstrate that a mutation of the histone acetyltransferase GCN5 can decrease the ratio of alpha-linolenic acid (ALA) to linoleic acid (LA) in seed oil. Using RNA-Seq and ChIP assays, we identified FAD3, LACS2, LPP3 and PLAIIIbeta as the targets of GCN5. Notably, the GCN5-dependent H3K9/14 acetylation of FAD3 determined the expression levels of FAD3 in Arabidopsis thaliana seeds, and the ratio of ALA/LA in the gcn5 mutant was rescued to the wild-type levels through the overexpression of FAD3. The results of this study indicated that GCN5 modulated FA biosynthesis by affecting the acetylation levels of FAD3. We provide evidence that histone acetylation is involved in FA biosynthesis in Arabidopsis seeds and might contribute to the optimization of the nutritional structure of edible oils through epigenetic engineering. PMID- 27500885 TI - The initial repair response of articular cartilage after mechanically induced damage. AB - The regenerative potential of articular cartilage (AC) defects is limited and depends on defect size, biomechanical conditions, and age. Early events after overloading might be predictive for cartilage degeneration in the long term. Therefore, the present aim is to investigate the temporal response of cartilage to overloading at cell, matrix, and tissue level during the first period after mechanical overloading. In the present study, the effect of high loading (~8 MPa) at a high rate (~14 MPa/s) at day 0 during a 9 day period on collagen damage, gene expression, cell death, and biochemical composition in AC was investigated. A model system was developed which enabled culturing osteochondral explants after loading. Proteoglycan content was repeatedly monitored over time using MUCT, whereas other evaluations required destructive measurements. Changes in matrix related gene expressions indicated a degenerative response during the first 6 h after loading. After 24 h, this was restored and data suggested an initial repair response. Cell death and microscopic damage increased after 24 h following loading. These degradative changes were not restored within the 9 day culture period, and were accompanied by a slight loss of proteoglycans at the articular surface that extended into the middle zones. The combined findings indicate that high magnitude loading of articular cartilage at a high rate induces an initial damage that later initiates a healing response that can probably not be retained due to loss of cell viability. Consequently, the matrix cannot be restored in the short term. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1265-1273, 2017. PMID- 27500886 TI - Phosphorescent Molecular Butterflies with Controlled Potential-Energy Surfaces and Their Application as Luminescent Viscosity Sensor. AB - We report precise manipulation of the potential-energy surfaces (PESs) of a series of butterfly-like pyrazolate-bridged platinum binuclear complexes, by synthetic control of the electronic structure of the cyclometallating ligand and the steric bulkiness of the pyrazolate bridging ligand. Color tuning of dual emission from blue/red, to green/red and red/deep red were achieved for these phosphorescent molecular butterflies, which have two well-controlled energy minima on the PESs. The environmentally dependent photoluminescence of these molecular butterflies enabled their application as self-referenced luminescent viscosity sensor. PMID- 27500887 TI - Preclinical Assessment of Safety and Efficacy of Fluorescent Dye for Detecting Dermal Injuries (the injuries were both abrasions and incision) in a Murine Model. AB - Objective documentation of tears and abrasions to the external genitalia after sexual assault is an important part of the forensic examination. A 1% aqueous solution of toluidine blue (TB) dye is often used to highlight injury, but the dye can be difficult to see on dark skin. We evaluated a fluorescent dye for detecting injuries on all skin colors in a relevant preclinical murine model. We compared the ability of trained, blinded observers to detect unstained wounds and wounds stained with 1% fluorescein sodium (FL) and with TB. We also evaluated the cutaneous wound healing response after application of both dyes. The no-dye group had significantly fewer (p < 0.05) true-positive identifications compared to all the dye groups. No differences in effectiveness were detected between dye treatments. All groups exhibited statistically similar healing rates. These findings support the evaluation of fluorescein sodium in a future clinical study with human subjects. PMID- 27500888 TI - Implications of Variation in the Relationships between Beneficiary Characteristics and Medicare Advantage CAHPS Measures. AB - OBJECTIVE: To study how differences in quality score adjustments across Medicare Advantage contracts change comparisons for individuals and contracts. DATA SOURCES: Responses to the Medicare Advantage implementation of the Consumer Assessments of Healthcare Providers and Systems (CAHPS) survey from 2010 to 2014. STUDY DESIGN: We fit national-and state-level hierarchical models to predict CAHPS scores for individuals and contracts, adjusted for self-reported education, general health, and mental health. We allow the effects of these variables on quality measures to vary across contracts with a hierarchical model. DATA COLLECTION/EXTRACTION METHODS: We perform secondary data analysis. PRINCIPAL FINDINGS: For average consumers, standard adjustment is sufficient to represent variation in contract quality standardized to a common population. For people with characteristics far from average, personalized reporting using their characteristics and contract-specific coefficients can substantially change the expected quality measures across contracts. This effect is stronger when comparing among contracts within a state than across all contracts. CONCLUSIONS: Customized reporting may help consumers select the best Medicare Advantage plan, but policies should protect against unintended consequences. PMID- 27500890 TI - Intranodal palisaded myofibroblastoma - a rare case report and literature review. AB - Intranodal palisaded myofibroblastoma (IPM) is a benign mesenchymal neoplasm originating from smooth muscle cells and myofibroblasts. The inguinal region is the most common site of this rare tumor. As there are only about 89 such cases reported in the literature, the precise etiology and pathogenesis have yet to be explained adequately. It is characterized by spindle cells, amianthoid fibers, and by the proliferation of hemosiderin-containing histiocytes in the lymph node. A nodular lesion was excised from the inguinal region of a 47-year-old female patient with the clinical diagnosis of lymphoma and/or metastase. Macroscopic examination of a section of the lesion demonstrated a solid appearance. Microscopic examination revealed spindle-cell proliferation, amianthoid fibers, hemosiderin pigment, and extravasated erythrocytes. Nuclei of the spindle cells displayed a palisaded appearance. Compressed lymphoid tissue was observed around the lesion. Neoplastic cells were identified by the presence of vimentin, SMA, Cyclin D1, and beta-catenin. The Ki67 index was less than 1%. Histological examination confirmed the diagnosis of IPM. Although IPM is benign, it is frequently confused with metastatic lesions and lymphomas. PMID- 27500891 TI - Current trends in topical therapies for chronic rhinosinusitis: update and literature review. AB - INTRODUCTION: Chronic rhinosinusitis (CRS) affects millions of patients worldwide. The disease is multifactorial with influences including anatomic factors, immunological disturbances, and altered sinonasal microbiome. Although oral medications are effective in controlling some symptoms, they are associated with side effects and long-term use is not ideal. Thus, topical therapies have emerged as an alternative delivery method for localized, high-concentration medication with less side effects. Areas covered: This is a review of the various topical therapies available or under investigation for the management of CRS. Common medications such as saline, steroids, and antimicrobials will be discussed. Furthermore, additives including manuka honey, xylitol, surfactant, N chlorotaurine, Dead Sea salt, and sodium hyaluronate will be addressed. Innovations in topical therapies, such as drug-eluting biomaterials and photodynamic therapy, will also be reviewed. Expert opinion: Although topical therapies provide a high dose of active substance at the site of disease, their efficacy in CRS is not clear. Topical saline and intranasal steroids appear to consistently demonstrate therapeutic benefits. However, other topical medications require further investigation to determine long-term clinical efficacy and safety. A better understanding of their effects on the sinonasal mucociliary system is needed before they become the standard of care in CRS. PMID- 27500889 TI - Development of a Multicellular Three-dimensional Organotypic Model of the Human Intestinal Mucosa Grown Under Microgravity. AB - Because cells growing in a three-dimensional (3-D) environment have the potential to bridge many gaps of cell cultivation in 2-D environments (e.g., flasks or dishes). In fact, it is widely recognized that cells grown in flasks or dishes tend to de-differentiate and lose specialized features of the tissues from which they were derived. Currently, there are mainly two types of 3-D culture systems where the cells are seeded into scaffolds mimicking the native extracellular matrix (ECM): (a) static models and (b) models using bioreactors. The first breakthrough was the static 3-D models. 3-D models using bioreactors such as the rotating-wall-vessel (RWV) bioreactors are a more recent development. The original concept of the RWV bioreactors was developed at NASA's Johnson Space Center in the early 1990s and is believed to overcome the limitations of static models such as the development of hypoxic, necrotic cores. The RWV bioreactors might circumvent this problem by providing fluid dynamics that allow the efficient diffusion of nutrients and oxygen. These bioreactors consist of a rotator base that serves to support and rotate two different formats of culture vessels that differ by their aeration source type: (1) Slow Turning Lateral Vessels (STLVs) with a co-axial oxygenator in the center, or (2) High Aspect Ratio Vessels (HARVs) with oxygenation via a flat, silicone rubber gas transfer membrane. These vessels allow efficient gas transfer while avoiding bubble formation and consequent turbulence. These conditions result in laminar flow and minimal shear force that models reduced gravity (microgravity) inside the culture vessel. Here we describe the development of a multicellular 3-D organotypic model of the human intestinal mucosa composed of an intestinal epithelial cell line and primary human lymphocytes, endothelial cells and fibroblasts cultured under microgravity provided by the RWV bioreactor. PMID- 27500892 TI - Buccally impacted maxillary canines increase the likelihood of root separation in adjacent first premolars. AB - OBJECTIVE: To investigate the influence of maxillary impacted canines on the root morphology of adjacent premolars in a Chinese population. SUBJECTS AND METHODS: A sample of 370 Chinese subjects with maxillary canine impaction and 370 control subjects were collected in this study. CBCT data of all subjects were collected and analyzed. The prevalence of separate-rooted maxillary premolars was compared between subjects with and without impacted canines. Then, the prevalence of separate-rooted maxillary premolars was compared between subjects with buccal canine impaction (BIC) and those with palatal impaction (PIC). RESULTS: The prevalence of separate-rooted first premolars was significantly higher in the canine impaction group (P = 0.046), but the prevalence of separate-rooted second premolars was not different (P = 0.780). Furthermore, a significant higher prevalence of first premolar root separation was found on the impacted site in the BIC subgroup (P < 0.001), but not in the PIC subgroup (P = 0.508). Also, the prevalence of separate-rooted first premolars in the BIC subgroup was significantly higher than that of the control group (P = 0.008), but not so for the PIC subgroup (P = 0.097). CONCLUSIONS: Buccally impacted maxillary canines are associated with an increased prevalence of root separation in the adjacent maxillary first premolars. This is likely because that buccally impacted canines encroach on the space needed for root development of the first premolars. PMID- 27500893 TI - Appropriate fabrication method for vacuum-formed mouthguards. AB - AIM: The aim was to examine the influence of the heating temperature on the fabrication of vacuum-formed mouthguards. MATERIALS AND METHODS: Mouthguard sheets of 3.8 mm ethylene vinyl acetate were vacuum-formed on working models at three heating temperatures: 80, 100, and 120 degrees C. The thickness of the mouthguard was measured at the labial surface of the central incisor, and the buccal and occlusal surfaces of the first molar. Differences in the thickness of the mouthguards were analyzed by two-way analysis of variance. The fit of the mouthguard was examined at the central incisor and the first molar by measuring the distance between the mouthguard and the cervical margin of the working model. Differences in the distance between the mouthguard and the cervical margin according to the heating temperatures were analyzed by one-way analysis of variance. RESULTS: Mouthguard thickness varied among the measured regions of the central incisors and first molars (P < 0.01). The greatest thickness was found at the labial surface of the central incisor and the buccal surface of the first molar in mouthguards fabricated with heating temperature of 120 degrees C (P < 0.05). The best fit was obtained in mouthguards fabricated with heating temperature of 120 degrees C (P < 0.05). CONCLUSIONS: Heating the mouthguard sheet until the temperature reached 120 degrees C was the best fabrication method to maintain the thickness and to obtain proper fit. It is important to control the heating temperature when fabricating vacuum-formed mouthguards. PMID- 27500894 TI - Role of Clinical Pharmacology in the Development and Approval of Immunotherapies Targeting Immune Checkpoints. AB - Immune surveillance plays a critical role in preventing the development and progression of cancer. Immune modulators, such as interferon-gamma or interleukin 2, have been a part of the cancer treatment armament over the past few decades. However, new understandings regarding the role of the costimulatory and coinhibitory molecules associated with T-cells and antigen-presenting cells as well as tumor necrosis factor receptors and ligands have ushered the new era of immunotherapy for cancer treatment. We now know that primary cancer cells evade screening by the innate immune system, proliferate, and form metastases by upregulating immune inhibitory pathways referred to as immune checkpoints. The recent development of therapies that target immune checkpoints, such as cytotoxic T lymphocyte antigen 4, programmed cell death 1, programmed cell death ligand 1, indoleamine 2,3-dioxygenase, T-cell immunoglobulin and mucin domain 3, and lymphocyte activation gene 3 precisely target the immune system and give new hope for treating various types of cancer. In select marker-enriched populations, immunotherapies provide high response rates as well as durable responses in terms of progression-free survival and overall survival. Numerous factors, such as patient's immune system, the expression of targets on both immune and cancer cells, maintenance of an effective drug exposure, and tolerability to these agents may play a role in this unique observation. PMID- 27500895 TI - Half-century of Dental Public Health research: bibliometric analysis of world scientific trends. AB - OBJECTIVES: To describe the characteristics of Dental Public Health (DPH) scientific publications within core DPH journals over time and to compare DPH journals with DPH content from other journal types. METHODS: The Scopus database was used to identify DPH-relevant articles published from 1965 to 2014 in three core DPH journals (DPHJs) and from 2005 to 2014 in Dental Journals (DJs), Public Health (PHJs) and General Journals (GJs). To identify DPH-relevant articles, a search strategy with words about oral health and public health was applied to each group of journals. Research themes were created by grouping similar keywords to report changes in the focus of articles over time. The most productive journals, countries, institutions and authors were also estimated for each set of journals. RESULTS: In 2005-2014, 60 297 articles were identified, of which 2.7% in DPHJs, 10.4% from PHJs, 38.2% from GJs and 48.7% from DJs. DPH-relevant articles published in the core DPHJs, DJs and PHJs tended to share a strong emphasis on dental caries, healthcare/services research on children and adolescents. Over time, the focus in the DPHJs has increased towards health behaviour/promotion/education, quality of life and socioeconomic factors. In the last decade, those themes were more frequent in DPH journals than in the other groups. CONCLUSIONS: DPH research published in DPHJs had some unique features and greater focus on the themes of quality of life, socioeconomic factors and health behaviour/education/promotion than other groups of journals. PMID- 27500897 TI - The Microstructure of Cellulose Nanocrystal Aerogels as Revealed by Transmission Electron Microscope Tomography. AB - The microstructure of highly porous cellulose nanocrystal (CNC) aerogels is investigated via transmission electron microscope (TEM) tomography. The aerogels were fabricated by first supercritically drying a carboxylated CNC organogel and then coating via atomic layer deposition with a thin conformal layer of Al2O3 to protect the CNCs against prolonged electron beam exposure. A series of images was then acquired, reconstructed, and segmented in order to generate a three dimensional (3D) model of the aerogel. The model agrees well with theory and macroscopic measurements, indicating that a thin conformal inorganic coating enables TEM tomography as an analysis tool for microstructure characterization of CNC aerogels. The 3D model also reveals that the aerogels consist of randomly orientated CNCs that attach to one another primarily in three ways: end to end contact, "T" contact, and "X" contact. PMID- 27500896 TI - Combination of glycolic acid peel and topical 20% azelaic acid cream in melasma patients: efficacy and improvement in quality of life. AB - BACKGROUND: Glycolic acid (GA) peel is one of the most versatile agents in the treatment of melasma. GA peeling alone or in combination with topical hypopigmenting agents has shown encouraging results. However, there is paucity of controlled trial demonstrating the efficacy of glycolic peel in conjunction with topical azelaic acid (AA). We therefore sought to highlight the efficacy and safety of this combination in melasma. OBJECTIVE: To assess the clinical efficacy, safety and reduction in melasma quality of life (MELASQOL) scores on combining serial GA peels with topical 20% AA cream in epidermal melasma. MATERIALS AND METHOD: Sixty patients of epidermal melasma were enrolled for 24 weeks. Patients were divided into two groups: (1) Study group received serial GA peel every 3 weeks with twice daily 20% AA cream, and (2) control group received only 20% AA cream. Clinical improvement was assessed objectively using Melasma Area Severity Index (MASI). Melasma-related quality of life was measured by MELASQOL scale in both groups. Side effects were observed at each visit. RESULTS: The improvement in MASI and percentage decrease in MASI scoring were statistically significant 12 weeks onwards in study group as compared to control group. There was also a significant reduction in MELASQOL scores in study group as compared to control group after treatment. Minor reversible side effects were observed in both groups, which did not require cessation of therapy. CONCLUSION: GA peel enhances therapeutic efficacy of topical AA cream for treatment of melasma, with improvement in quality of life without serious side effects. PMID- 27500898 TI - National survey of nurse prescribing in mental health services; a follow-up 6 years on. AB - WHAT IS KNOWN ON THE SUBJECT?: Nurse prescribing allows nurses, after specific training, to prescribe medications under certain conditions. This article describes the third in a series of surveys of mental health services in England to understand how nurse prescribing is being used across the country. While there is research evidence that shows nurse prescribing to be as safe as prescribing by doctors and that service users typically find it at least as acceptable, there is a lack of detailed evidence about current forms of nurse prescribing practice specifically in mental health services. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: The survey found that the number of nurse prescribers has increased over the last few years. Nurse prescribers are increasingly prescribing in a form ('independent prescribing') that makes them independently responsible for prescribing decisions without working to a plan laid out by a doctor. Mental health organisations are increasingly planning in a systematic way how to identify, train and ensure good practice in nurse prescribing. This study demonstrates that growth in numbers of nurse prescribers can take place over an extended time period. The study demonstrates that the exact model of nurse prescribing will influence its applicability in different types of service. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Nurse prescribing is becoming increasingly common in mental health services, changing roles for nurses and the experience of services for service users. However, there is great variation between organisations in this regard. Research is needed regarding the outcomes and any risks of independent nurse prescribing specifically in mental health compared to medical prescribing. ABSTRACT: Introduction This paper reports the latest in a series of national surveys of nurse prescribing in mental health organizations in England. Aim To describe and understand changes and trends in the use of nurse prescribing nationally. Methods Postal survey to all 53 National Health Service Mental Health Trusts (publicly funded provider organizations); 75% responded (n = 40). Results Numbers of nurse prescribers (NPs) have grown significantly in the last 6 years, although remain a small percentage of the total Mental Health Nursing workforce. Most NPs are in community services, particularly community mental health teams and drug/alcohol services. Independent prescribing has now become the most common form of NP, replacing supplementary prescribing. Discussion Overall growth in numbers of NPs has continued, but remains marked by large variance in numbers between organizations. The study evidences that the particular form of nurse prescribing will influence its applicability in different clinical settings and that sustained increase over time in NP numbers is feasible at a national level, even with local variation in uptake. Implications for practice Nurse prescribing has become well embedded in many organizations although large-scale adoption may be hindered by the lack of a definitive evidence base as to outcomes compared with those from medical prescribing. PMID- 27500899 TI - Clusters of landscape characters as a way of communication in characterisation: A study from side, Turkey. AB - Landscape is the natural and cultural features of the environment. Characters are distinct recognisable patterns in the landscape that were comprised as a result of human and nature interactions. Landscape characters demonstrate precise features and values that exist in the current environment and provide information for those who use, manage, live in, benefit from and enjoy the landscape. The aim of this study was to interpret landscape characters with a common set of terminology and to evaluate clusters of characters and so to discuss how they can be used as a communicative tool in characterisation in the case of Side District in Turkish Mediterranean. Number of 35 landscape characters were analysed as variables with aesthetic, cultural, value, perceptual and natural features so to communicate between characters and landscapes. The study results demonstrated that clusters of landscape characters were divided into 3 character groups; mainly cultural, mainly cultural and a joint cluster of aesthetic, and perceptual and value aspects while spatial composition of landscape character groups was named and mapped as natural, rural, historical, urban and buffer. Aesthetic features were the most prominent elements as they combined in all sub-clusters giving the evidence that landscape is a visual construct. However, landscape characters which can be either outstanding or ordinary and their clusters provide exchange of information about relationship between man and nature, natural and cultural, objective and subjective for planners and managers, for public and professionals. Landscape characters become a body of message which ultimately offers a framework for planners and decision makers for both maintenance and protection of landscapes. PMID- 27500900 TI - Endometrial breakdown with sustained progesterone release involves NF-kappaB mediated functional progesterone withdrawal in a mouse implant model. AB - Irregular uterine bleeding is a major side effect of long-acting progestogen-only contraceptives in women, and is the primary reason women discontinue their use. In this study, a mouse model of endometrial breakdown was established using a subcutaneous progesterone implant to understand how irregular bleeding begins. Although progestogens sustained decidualization, endometrial breakdown was still observed in this model. We, therefore, hypothesized that endometrial breakdown might involve functional progesterone withdrawal. Using co-immunoprecipitation assays, we observed the constitutive activation of nuclear factor kappa-b (NF kappaB) p65 and its interaction with the progesterone receptor (PGR); moreover, transcriptional activity of the PGR was also repressed by NF-kappaB activity in primary mouse and human decidual stromal cells that mimic progesterone maintenance. Yet the ratio of PGR-B to PGR-A was not increased in the mouse model. In vivo comparison of endometrial breakdown induced by progesterone withdrawal to that seen during sustained progesterone exposure, in the presence of NF-kappaB inhibitors, revealed that NF-kappaB-mediated functional progesterone withdrawal is involved in endometrial breakdown in this implant model. These data prompt further studies to determine the homology of this functional progesterone withdrawal mechanism in human endometrium. Mol. Reprod. Dev. 83: 780-791, 2016 (c) 2016 Wiley Periodicals, Inc. PMID- 27500901 TI - Comparison of four validated psoriatic arthritis screening tools in diagnosing psoriatic arthritis in patients with psoriasis (COMPAQ Study). AB - BACKGROUND: Four validated psoriatic arthritis (PsA) screening tools are used for diagnosing PsA in patients with psoriasis. OBJECTIVES: To evaluate the sensitivity and specificity of the Toronto Psoriatic Arthritis Screen II (ToPAS II), the Psoriatic Arthritis Screening and Evaluation (PASE), the Psoriasis Epidemiology Screening Tool (PEST) and the Early Arthritis for Psoriatic Patients (EARP) questionnaires in diagnosing PsA in patients with psoriasis. METHODS: This was a noninterventional, cross-sectional study. In total, 302 patients with psoriasis completed all the questionnaires prior to rheumatological evaluation. Patients diagnosed as having a rheumatological disease were excluded. Characteristics of joint involvement in PsA were noted, but details of non-PsA rheumatological diseases were not captured. RESULTS: Of 302 patients with psoriasis, 45 (14.9%) had PsA, according to the Classification of Psoriatic Arthritis criteria; 27 (8.9%) had a ToPAS II score >= 8, suggestive of PsA; 36 (11.9%) had a PEST questionnaire score >= 3, suggestive of PsA; 50 (16.5%) had a PASE questionnaire score >= 44 (PASE 44), suggestive of PsA; 47 (15.5%) had a PASE score of 47 (PASE 47; used in development of the PASE questionnaire); and 72 (23.8%) patients had an EARP questionnaire score >= 3, suggestive of PsA. The sensitivities and specificities of EARP, PASE 44, PASE 47, PEST and ToPAS II were 91%, 80%, 76%, 53% and 44%, and 88%, 95%, 95%, 95% and 97%, respectively. CONCLUSIONS: EARP was found to have the best sensitivity; ToPAS II had the highest specificity. A major limitation of the study design was the exclusion of pre-existing rheumatological diseases. PMID- 27500902 TI - Trabecular architecture in the thumb of Pan and Homo: implications for investigating hand use, loading, and hand preference in the fossil record. AB - OBJECTIVES: Humans display an 85-95% cross-cultural right-hand bias in skilled tasks, which is considered a derived behavior because such a high frequency is not reported in wild non-human primates. Handedness is generally considered to be an evolutionary byproduct of selection for manual dexterity and augmented visuo cognitive capabilities within the context of complex stone tool manufacture/use. Testing this hypothesis requires an understanding of when appreciable levels of right dominant behavior entered the fossil record. Because bone remodels in vivo, skeletal asymmetries are thought to reflect greater mechanical loading on the dominant side, but incomplete preservation of external morphology and ambiguities about past loading environments complicate interpretations. We test if internal trabecular bone is capable of providing additional information by analyzing the thumb of Homo sapiens and Pan. MATERIALS AND METHODS: We assess trabecular structure at the distal head and proximal base of paired (left/right) first metacarpals using micro-CT scans of Homo sapiens (n = 14) and Pan (n = 9). Throughout each epiphysis we quantify average and local bone volume fraction (BV/TV), degree of anisotropy (DA), and elastic modulus (E) to address bone volume patterning and directional asymmetry. RESULTS: We find a right directional asymmetry in H. sapiens consistent with population-level handedness, but also report a left directional asymmetry in Pan that may be the result of postural and/or locomotor loading. CONCLUSION: We conclude that trabecular bone is capable of detecting right/left directional asymmetry, but suggest coupling studies of internal structure with analyses of other skeletal elements and cortical bone prior to applications in the fossil record. PMID- 27500904 TI - Microfluidic Buffer Exchange for Interference-free Micro/Nanoparticle Cell Engineering. AB - Engineering cells with active-ingredient-loaded micro/nanoparticles (NPs) is becoming an increasingly popular method to enhance native therapeutic properties, enable bio imaging and control cell phenotype. A critical yet inadequately addressed issue is the significant number of particles that remain unbound after cell labeling which cannot be readily removed by conventional centrifugation. This leads to an increase in bio imaging background noise and can impart transformative effects onto neighboring non-target cells. In this protocol, we present an inertial microfluidics-based buffer exchange strategy termed as Dean Flow Fractionation (DFF) to efficiently separate labeled cells from free NPs in a high throughput manner. The developed spiral microdevice facilitates continuous collection (>90% cell recovery) of purified cells (THP-1 and MSCs) suspended in new buffer solution, while achieving >95% depletion of unbound fluorescent dye or dye-loaded NPs (silica or PLGA). This single-step, size-based cell purification strategy enables high cell processing throughput (10(6) cells/min) and is highly useful for large-volume cell purification of micro/nanoparticle engineered cells to achieve interference-free clinical application. PMID- 27500903 TI - Fast Photochemical Oxidation of Proteins Maps the Topology of Intrinsic Membrane Proteins: Light-Harvesting Complex 2 in a Nanodisc. AB - Although membrane proteins are crucial participants in photosynthesis and other biological processes, many lack high-resolution structures. Prior to achieving a high-resolution structure, we are investigating whether MS-based footprinting can provide coarse-grained protein structure by following structural changes that occur upon ligand binding, pH change, and membrane binding. Our platform probes topology and conformation of membrane proteins by combining MS-based footprinting, specifically fast photochemical oxidation of proteins (FPOP), and lipid Nanodiscs, which are more similar to the native membrane environment than are the widely used detergent micelles. We describe here results that show a protein's outer membrane regions are more heavily footprinted by OH radicals whereas the regions spanning the lipid bilayer remain inert to the labeling. Nanodiscs generally exhibit more protection of membrane proteins compared to detergent micelles and less shielding to those protein residues that exist outside the membrane. The combination of immobilizing the protein in Nanodiscs and footprinting with FPOP is a feasible approach to map extra-membrane protein surfaces, even at the amino-acid level, and to illuminate intrinsic membrane protein topology. PMID- 27500905 TI - Conclusions of the II International and IV Spanish Hydration Congress. Toledo, Spain, 2nd-4th December, 2015. AB - Water is the major component of our organism representing about 60% of total body weight in adults and has to be obtained through the consumption of different foods and beverages as part of our diet. Water is an essential nutrient performing important functions, including transport of other nutrients, elimination of waste products, temperature regulation, lubrication and structural support. In this context, hydration through water has an essential role in health and wellness, which has been highly acknowledged in recent years among the health community experts such as nutritionists, dietitians, general practitioners, pharmacists, educators, as well as by physical activity and sport sciences experts and the general population. PMID- 27500906 TI - Age-Related Differences of Organism-Specific Peritonitis Rates: A Single-Center Experience. AB - Peritonitis remains an important cause of morbidity and mortality in peritoneal dialysis (PD) patients, but its incidence and the distribution of causative organisms vary widely between institutions and age groups. This study was performed to investigate the recent status and risk factors of PD-related peritonitis and to clarify differences between age groups. We retrospectively reviewed the medical records of 119 PD patients treated at our department between January 2002 and January 2013. We calculated both overall and organism-specific peritonitis rates and also analyzed risk factors. Sixty-three episodes of peritonitis occurred during 261.5 patient-years for an incident rate of 0.24 episodes/patient-year. Multivariate analysis showed that older age (>=65 years) and hypoalbuminemia (<3.0 g/dL) were associated with an increased risk of peritonitis (P = 0.035 and P = 0.029, respectively). In elderly patients (>=65 years old), the rate of peritonitis due to Gram-positive and Gram-negative bacteria was 0.17 and 0.08 episodes/patient-year, respectively, and Gram-positive peritonitis was markedly more frequent than in younger patients (<65 years old). In particular, there was a high frequency of Staphylococcus aureus peritonitis in elderly patients (0.09 episodes/patient-year) and it had a poor outcome. At our department, the risk of peritonitis was increased in older patients and patients with hypoalbuminemia. The distribution of causative organisms was markedly different between age groups and analysis of organism-specific peritonitis rates helped to identify current problems with our PD program. PMID- 27500907 TI - Accessing Three-Dimensional Crystals with Incorporated Guests through Metal Directed Coiled-Coil Peptide Assembly. AB - Obtaining three-dimensional (3D) protein and peptide crystals on demand requires a precisely orchestrated hierarchical assembly of biopolymer building blocks. In this work, we disclose a metal-ion-mediated strategy to assemble trimeric coiled coil peptides in a head-to-tail fashion into linear strands with interstrand interactions. This design led to hexagonal 3D peptide crystal formation within 30 min in the presence of divalent metal ions. The crystal morphology could be controlled by varying the metal ion/peptide ratio, resulting in hexagonal discs to rods. Diffraction studies elucidated the head-to-tail arrangement of the coiled-coil linear strands and their hexagonal, antiparallel packing within the crystal. Unsatisfied ligands at the hexagonal ends of the crystals were harnessed as a powerful means to direct His-tagged fluorophores to distinct locations within the crystals. Overall, the designed hierarchical assembly provides a facile means to obtain 3D peptide crystals and incorporate His-tag-based cargoes and may have potential use in drug delivery and sensor design. PMID- 27500908 TI - The Efficacy of Internal Family Systems Therapy in the Treatment of Depression Among Female College Students: A Pilot Study. AB - College women are vulnerable to depression due to developmental and transitional life changes. Early diagnosis and effective treatment is critically important. Empirical support exists for the effectiveness of select treatment options (i.e., antidepressant medication, cognitive-behavioral therapy [CBT], and interpersonal psychotherapy [IPT]), yet a significant percentage of those treated do not benefit. In this pilot study, Internal Family Systems (IFS) therapy was tested as an alternative approach. College women (N = 37) were randomly allocated to IFS treatment or treatment as usual (CBT or IPT). Results demonstrated a decline in depressive symptoms for both conditions and no significant differences in the magnitude or rate of change. The results provide preliminary evidence for the efficacy of IFS in the treatment of depressive symptoms. PMID- 27500909 TI - Selection of the Rotation Direction for a Camphor Disk Resulting from Chiral Asymmetry of a Water Chamber. AB - Self-motion of a camphor disk rotating inside a water chamber composed of two half-disks was investigated. The half-disks were joined along their diameter segments, and the distance between their midpoints (ds) was considered as the control parameter. Various types of camphor disk motions were observed depending on ds. When ds = 0, the chamber had a circular shape, so it was symmetric. A camphor disk showed either a clockwise (CW) or counterclockwise (CCW) rotation with the direction determined by its initial state. The symmetry of the chamber was broken for ds > 0. For moderate distances between the midpoints, a unidirectional orbital motion of the disk was observed. The preferred rotation direction was determined by the shape of the chamber, and it did not depend on the initial rotation direction. For yet larger ds, the unidirectional circular motion was no longer observed and the trajectory became irregular. A mathematical model coupling the camphor disk motion with the dynamics of the developed camphor molecular layer on water was constructed, and the numerical results were compared with the experimental results. The selection of motion type can be explained by considering the influence of camphor concentration on the disk trajectory through the surface tension gradient. PMID- 27500910 TI - Surfactant-Wrapped Multiwalled Carbon Nanotubes in Aquatic Systems: Surfactant Displacement in the Presence of Humic Acid. AB - Sodium dodecyl sulfate (SDS) facilitates multiwalled carbon nanotube (MWCNT) debundling and enhances nanotube stability in the aqueous environment by adsorbing on the nanotube surfaces, thereby increasing repulsive electrostatic forces and steric effects. The resulting SDS-wrapped MWCNTs are utilized in industrial applications and have been widely employed in environmental studies. In the present study, MWCNTs adsorbed SDS during ultrasonication to form stable MWCNTs suspensions. Desorption of SDS from MWCNTs surfaces was then investigated as a function of Suwannee River Humic Acid (SRHA) and background electrolyte concentrations. Due to hydrophobic effects and pi-pi interactions, MWCNTs exhibit higher affinity for SRHA than SDS. In the presence of SRHA, SDS adsorbed on MWCNTs was displaced. Cations (Na(+), Ca(2+)) decreased SDS desorption from MWCNTs due to charge screening effects. Interestingly, the presence of the divalent calcium cation facilitated multilayered SRHA adsorption on MWCNTs through bridging effects, while monovalent sodium reduced SRHA adsorption. Results of the present study suggest that properties of MWCNTs wrapped with commercial surfactants will be altered when these materials are released to surface waters and the surfactant coating will be displaced by natural organic matter (NOM). Changes on their surfaces will significantly affect MWCNTs fate in aquatic environments. PMID- 27500912 TI - Structural model of amyloid fibrils for amyloidogenic peptide from Bgl2p glucantransferase of S. cerevisiae cell wall and its modifying analog. New morphology of amyloid fibrils. AB - We performed a comparative study of the process of amyloid formation by short homologous peptides with a substitution of aspartate for glutamate in position 2 VDSWNVLVAG (AspNB) and VESWNVLVAG (GluNB) - with unblocked termini. Peptide AspNB (residues 166-175) corresponded to the predicted amyloidogenic region of the protein glucantransferase Bgl2 from the Saccharomyces cerevisiae cell wall. The process of amyloid formation was monitored by fluorescence spectroscopy (FS), electron microscopy (EM), tandem mass spectrometry (TMS), and X-ray diffraction (XD) methods. The experimental study at pH3.0 revealed formation of amyloid fibrils with similar morphology for both peptides. Moreover, we found that the morphology of fibrils made of untreated ammonia peptide is not mentioned in the literature. This morphology resembles snakes lying side by side in the form of a wave without intertwining. Irrespective of the way of the peptide preparation, the rate of fibril formation is higher for AspNB than for GluNB. However, preliminary treatment with ammonia highly affected fibril morphology especially for AspNB. Such treatment allowed us to obtain a lag period during the process of amyloid formation. It showed that the process was nucleation-dependent. With or without treatment, amyloid fibrils consisted of ring-like oligomers with the diameter of about 6nm packed either directly ring-to-ring or ring-on-ring with a slight shift. We also proposed the molecular structure of amyloid fibrils for two studied peptides. PMID- 27500913 TI - Does Reducing Basal Insulin During Ramadan Fasting by Children and Adolescents with Type 1 Diabetes Decrease the Risk of Symptomatic Hypoglycemia? AB - BACKGROUND: Ramadan fasting by patients with type 1 diabetes might predispose them to hypoglycemia. There are no data on the optimal way of adjusting basal insulin during fasting. We aim at studying whether reducing basal insulin during Ramadan reduces the frequency of symptomatic hypoglycemia. METHODS: We enrolled children and adolescents with type 1 diabetes who intended to fast during Ramadan. Logbooks were given to subjects to mark days fasted, symptomatic hypoglycemia, and dose of basal insulin on all days of Ramadan. Logbooks were examined. Glucometers and insulin pumps were downloaded. RESULTS: Seventy-five patients were enrolled. The age was 10.2-18.9 (14.5) years. Sixty-eight patients had results analyzed. Forty-one patients were on pumps, and 27 patients were on multiple daily injections (MDI). Mean HbA1c was 7.9 (1.2) and 8.4 (1.3) for the pump and the MDI, respectively (P = 0.007). Thirty-nine patients had hypoglycemia leading to breaking fast. The mean number of episodes of breaking fast was 3 (1 8). Thirty-five of the 68 patients had reduced basal insulin. The difference in the frequency of hypoglycemia in those who reduced/did not reduce insulin was not statistically significant (P > 0.10). Fifteen patients on MDI and 24 patients on pumps had at least one episode of breaking fast. Six and 18 of the patients on MDI and pumps, respectively, reduced basal insulin (P > 0.10). CONCLUSION: This is the first study examining the impact of reduction of basal insulin on hypoglycemia in adolescents. Reducing basal insulin during Ramadan fasting does not decrease the risk of symptomatic hypoglycemia. Use of the insulin pump does not appear to be different from MDI in the frequency of occurrence of hypoglycemia. PMID- 27500911 TI - Advances and challenges: dendritic cell vaccination strategies for glioblastoma. AB - INTRODUCTION: Glioblastoma is the most common primary brain tumor in adults and prognosis remains poor with a median survival of approximately 15-17 months. This review provides an overview of recent advances in the field of glioblastoma immunotherapy. Areas covered: Recent advances in dendritic cell vaccination immunotherapy are showing encouraging results in clinical trials and promise to extend patient survival. In this report we discuss current scientific knowledge regarding dendritic cell (DC) vaccines, including approaches to differentiating, priming, and injecting dendritic cells to achieve maximal anti-tumor efficacy in glioblastoma. These findings are compared to recently completed and currently ongoing glioblastoma clinical trials. Novel methods such as 'fastDCs' and vaccines targeting DCs in-vivo may offer more effective treatment when compared to traditional DC vaccines and have already entered the clinic. Expert commentary: Finally, we discuss the challenges of T-cell dysfunctions caused by glioblastoma immunosuppression and how they affect dendritic cell vaccinations approaches. PMID- 27500914 TI - Optimal prevention of transfusion-transmitted cytomegalovirus (TTCMV) infection by modern leukocyte reduction alone: CMV sero/antibody-negative donors needed only for leukocyte products. PMID- 27500915 TI - Enhancing blood safety in Africa: stepping forward. PMID- 27500916 TI - Dissecting the metabolic pathways controlling platelet survival in vivo: are our platelets what they eat? PMID- 27500917 TI - When visual inspection of the palpebral conjunctivae falls short .... PMID- 27500918 TI - Cancer-related microangiopathic hemolytic anemia. PMID- 27500920 TI - Mortality rates in major and subthreshold depression: 10-year follow-up of a Singaporean population cohort of older adults. AB - OBJECTIVES: To investigate the associations of major and subthreshold depression with all-cause, cardiovascular disease and stroke mortality, and the extent to which health behaviour, medical comorbidity and functional disability explained the associations. METHODS: A cohort of 1070 persons aged >=60 with Geriatric Mental State (GMS) diagnoses of major and subthreshold depression, and data on health behaviour (smoking, alcohol, physical activity) and physical comorbidity (hypertension, diabetes, cardiovascular disease, stroke, chronic pulmonary disease, multi-comorbidity and activity of daily living disability) at baseline (15 Feb 2003 - 30 Mar 2004) were followed up on mortality from 1 Jan 2005 to 31 Dec 2012. RESULTS: Major and subthreshold depression was present in 5.1% and 9.9% of the participants at baseline. The all-cause mortality HR adjusted for age, sex, ethnicity and marital status was 1.73 (95% CI, 1.11-2.67) for major depression and 1.38 (95% CI, 0.96-1.97) for subthreshold depression. In hierarchical models, the addition of health behaviour and especially physical comorbidity substantially reduced the HR estimates for all-cause mortality associated with major depression (HR=1.39, 95% CI, 0.89-2.18) and subthreshold depression (HR=0.94, 95% CI, 0.64-1.37). Controlling for the effects of all variables, only major depression was significantly associated with increased cardiovascular disease and stroke mortality (HR=2.10, 95% CI, 1.07-4.11). CONCLUSIONS: Both major and subthreshold depression were associated with increased mortality, largely due to hazardous behaviours and physical comorbidity. Only major depression per se was independently associated with excess cardiovascular disease and stroke mortality. PMID- 27500921 TI - Correction: A challenge for theranostics: is the optimal particle for therapy also optimal for diagnostics? AB - Correction for 'A challenge for theranostics: is the optimal particle for therapy also optimal for diagnostics?' by Tamar Dreifuss, et al., Nanoscale, 2015, 7, 15175-15184. PMID- 27500922 TI - A Method to Quantify Visual Information Processing in Children Using Eye Tracking. AB - Visual problems that occur early in life can have major impact on a child's development. Without verbal communication and only based on observational methods, it is difficult to make a quantitative assessment of a child's visual problems. This limits accurate diagnostics in children under the age of 4 years and in children with intellectual disabilities. Here we describe a quantitative method that overcomes these problems. The method uses a remote eye tracker and a four choice preferential looking paradigm to measure eye movement responses to different visual stimuli. The child sits without head support in front of a monitor with integrated infrared cameras. In one of four monitor quadrants a visual stimulus is presented. Each stimulus has a specific visual modality with respect to the background, e.g., form, motion, contrast or color. From the reflexive eye movement responses to these specific visual modalities, output parameters such as reaction times, fixation accuracy and fixation duration are calculated to quantify a child's viewing behavior. With this approach, the quality of visual information processing can be assessed without the use of communication. By comparing results with reference values obtained in typically developing children from 0-12 years, the method provides a characterization of visual information processing in visually impaired children. The quantitative information provided by this method can be advantageous for the field of clinical visual assessment and rehabilitation in multiple ways. The parameter values provide a good basis to: (i) characterize early visual capacities and consequently to enable early interventions; (ii) compare risk groups and follow visual development over time; and (iii), construct an individual visual profile for each child. PMID- 27500923 TI - Improved Heterojunction Quality in Cu2O-based Solar Cells Through the Optimization of Atmospheric Pressure Spatial Atomic Layer Deposited Zn1-xMgxO. AB - Atmospheric pressure spatial atomic layer deposition (AP-SALD) was used to deposit n-type ZnO and Zn1-xMgxO thin films onto p-type thermally oxidized Cu2O substrates outside vacuum at low temperature. The performance of photovoltaic devices featuring atmospherically fabricated ZnO/Cu2O heterojunction was dependent on the conditions of AP-SALD film deposition, namely, the substrate temperature and deposition time, as well as on the Cu2O substrate exposure to oxidizing agents prior to and during the ZnO deposition. Superficial Cu2O to CuO oxidation was identified as a limiting factor to heterojunction quality due to recombination at the ZnO/Cu2O interface. Optimization of AP-SALD conditions as well as keeping Cu2O away from air and moisture in order to minimize Cu2O surface oxidation led to improved device performance. A three-fold increase in the open circuit voltage (up to 0.65 V) and a two-fold increase in the short-circuit current density produced solar cells with a record 2.2% power conversion efficiency (PCE). This PCE is the highest reported for a Zn1-xMgxO/Cu2O heterojunction formed outside vacuum, which highlights atmospheric pressure spatial ALD as a promising technique for inexpensive and scalable fabrication of Cu2O-based photovoltaics. PMID- 27500924 TI - Laboratory Simulation of an Iron(II)-rich Precambrian Marine Upwelling System to Explore the Growth of Photosynthetic Bacteria. AB - A conventional concept for the deposition of some Precambrian Banded Iron Formations (BIF) proceeds on the assumption that ferrous iron [Fe(II)] upwelling from hydrothermal sources in the Precambrian ocean was oxidized by molecular oxygen [O2] produced by cyanobacteria. The oldest BIFs, deposited prior to the Great Oxidation Event (GOE) at about 2.4 billion years (Gy) ago, could have formed by direct oxidation of Fe(II) by anoxygenic photoferrotrophs under anoxic conditions. As a method for testing the geochemical and mineralogical patterns that develop under different biological scenarios, we designed a 40 cm long vertical flow-through column to simulate an anoxic Fe(II)-rich marine upwelling system representative of an ancient ocean on a lab scale. The cylinder was packed with a porous glass bead matrix to stabilize the geochemical gradients, and liquid samples for iron quantification could be taken throughout the water column. Dissolved oxygen was detected non-invasively via optodes from the outside. Results from biotic experiments that involved upwelling fluxes of Fe(II) from the bottom, a distinct light gradient from top, and cyanobacteria present in the water column, show clear evidence for the formation of Fe(III) mineral precipitates and development of a chemocline between Fe(II) and O2. This column allows us to test hypotheses for the formation of the BIFs by culturing cyanobacteria (and in the future photoferrotrophs) under simulated marine Precambrian conditions. Furthermore we hypothesize that our column concept allows for the simulation of various chemical and physical environments - including shallow marine or lacustrine sediments. PMID- 27500925 TI - Dieter C. Gruenert, PhD (1949-2016). PMID- 27500926 TI - Efficacy of Tumor-Targeting Salmonella A1-R on a Melanoma Patient-Derived Orthotopic Xenograft (PDOX) Nude-Mouse Model. AB - Tumor-targeting Salmonella enterica serovar Typhimurium A1-R (Salmonella A1-R) had strong efficacy on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. GFP-expressing Salmonella A1-R highly and selectively colonized the PDOX melanoma and significantly suppressed tumor growth (p = 0.021). The combination of Salmonella A1-R and cisplatinum (CDDP), both at low-dose, also significantly suppressed the growth of the melanoma PDOX (P = 0.001). Salmonella A1-R has future clinical potential for combination chemotherapy with CDDP of melanoma, a highly-recalcitrant cancer. PMID- 27500927 TI - Management of acute viral bronchiolitis in children: Evidence beyond guidelines. AB - Acute viral bronchiolitis is one of the leading causes of worldwide admission of children under 2 years of age during winter months. There is a lack of consensus regarding the clinical definition of acute viral bronchiolitis in children and hence the management varies across the globe. The purpose of this article is to review the epidemiology, etiology, risk factors, pathophysiology, clinical presentation, assessment and management of children with respiratory syncytial virus (RSV) bronchiolitis. The available evidence in the worldwide literature suggests that supportive and symptomatic management is still the mainstay of management in this condition. The key to reducing the morbidity and mortality in children with RSV bronchiolitis is through prevention of infection through immunoprophylaxis especially in high-risk children. PMID- 27500928 TI - Femur Window Chamber Model for In Vivo Cell Tracking in the Murine Bone Marrow. AB - Bone marrow is a complex organ that contains various hematopoietic and non hematopoietic cells. These cells are involved in many biological processes, including hematopoiesis, immune regulation and tumor regulation. Commonly used methods for understanding cellular actions in the bone marrow, such as histology and blood counts, provide static information rather than capturing the dynamic action of multiple cellular components in vivo. To complement the standard methods, a window chamber (WC)-based model was developed to enable serial in vivo imaging of cells and structures in the murine bone marrow. This protocol describes a surgical procedure for installing the WC in the femur, in order to facilitate long-term optical access to the femoral bone marrow. In particular, to demonstrate its experimental utility, this WC approach was used to image and track neutrophils within the vascular network of the femur, thereby providing a novel method to visualize and quantify immune cell trafficking and regulation in the bone marrow. This method can be applied to study various biological processes in the murine bone marrow, such as hematopoiesis, stem cell transplantation, and immune responses in pathological conditions, including cancer. PMID- 27500929 TI - In Vivo Cannulation Methods for Cardiomyocytes Isolation from Heart Disease Models. AB - Isolation of high quality cardiomyocytes is critically important for achieving successful experiments in many cellular and molecular cardiology studies. Methods for isolating cardiomyocytes from the murine heart generally are time-sensitive and experience-dependent, and often fail to produce high quality cells. Major technical difficulties can be related to the surgical procedures needed to explant the heart and to cannulate the vessel to mount onto the Langendorff system before in vitro reperfusion can begin. During this period, transient hypoxia and ischemia may damage the heart, resulting in low yield and poor quality of cells, especially for heart disease models that have fragile cells. We have developed novel in vivo cannulation methods to minimize hypoxia and ischemia, and fine-tuned the entire protocol to produce high quality ventricular myocytes. The high cell quality has been confirmed using important structural and functional criteria such as morphology, t-tubule structure, action potential morphology, Ca2+ signaling, responsiveness to beta-adrenergic agonist, and ability to have robust contraction under mechanically loaded condition. Together these assessments show the preservation of the cardiac excitation-contraction machinery in cells isolated using this technique. The in vivo cannulation method enables consistent isolation of high-quality cardiomyocytes, even from heart disease models that were notoriously difficult for cell isolation using traditional methods. PMID- 27500930 TI - Spectral Cytometry Has Unique Properties Allowing Multicolor Analysis of Cell Suspensions Isolated from Solid Tissues. AB - Flow cytometry, initially developed to analyze surface protein expression in hematopoietic cells, has increased in analytical complexity and is now widely used to identify cells from different tissues and organisms. As a consequence, data analysis became increasingly difficult due the need of large multi parametric compensation matrices and to the eventual auto-fluorescence frequently found in cell suspensions obtained from solid organs. In contrast with conventional flow cytometry that detects the emission peak of fluorochromes, spectral flow cytometry distinguishes the shapes of emission spectra along a large range of continuous wave lengths. The data is analyzed with an algorithm that replaces compensation matrices and treats auto-fluorescence as an independent parameter. Thus, spectral flow cytometry should be capable to discriminate fluorochromes with similar emission peaks and provide multi parametric analysis without compensation requirements. Here we show that spectral flow cytometry achieves a 21-parametric (19 fluorescent probes) characterization and deals with auto-fluorescent cells, providing high resolution of specifically fluorescence-labeled populations. Our results showed that spectral flow cytometry has advantages in the analysis of cell populations of tissues difficult to characterize in conventional flow cytometry, such as heart and intestine. Spectral flow cytometry thus combines the multi-parametric analytical capacity of the highest performing conventional flow cytometry without the requirement for compensation and enabling auto-fluorescence management. PMID- 27500931 TI - Evolution of diagnosis and clinical outcomes in acute aortic dissection: data from the International Registry of Acute Aortic Dissection. PMID- 27500932 TI - Racial/Ethnic Disparities in Measures of Self-reported Psychosocial States and Traits during Pregnancy. AB - Background The aim of this study was to determine whether racial/ethnic differences in psychosocial measures, independent of economic status, exist among a large population of pregnant nulliparas. Methods Between October 2010 and September 2013, nulliparous women at eight U.S. medical centers were followed longitudinally during pregnancy and completed validated instruments to quantify several psychosocial domains: Cohen Perceived Stress Scale, trait subscale of the Spielberger Anxiety Inventory, Connor-Davidson Resilience Scale, Multidimensional Scale of Perceived Social Support, Krieger Racism Scale, Edinburgh Postnatal Depression Scale, and the Pregnancy Experience Scale. Scores were stratified and compared by self-reported race, ethnicity, and income. Results Complete data were available for 8,128 of the 10,038 women enrolled in the study. For all measures, race and ethnicity were significantly associated (p < 0.001) with survey scores. Non-Hispanic black (NHB) women were most likely to score in the most unfavorable category for all measures, with the exception of the Pregnancy Experience Scale. The magnitude of these differences did not differ by income status (interaction, p > 0.05) except on the Krieger racism survey and the Edinburgh depression survey, which were exacerbated among NHB women with higher income (interaction, p < 0.001). Conclusion Significant racial/ethnic disparities, independent of income status, exist in psychosocial measures during pregnancy. PMID- 27500933 TI - Comparison of Respiratory Outcomes between Preterm Small-For-Gestational-Age and Appropriate-For-Gestational-Age Infants. AB - Objective This study aims to determine whether preterm infants who are small for gestational age (SGA) are more likely to have respiratory distress syndrome (RDS) compared with appropriate-for-gestational-age infants. Methods Secondary analysis of a multicenter trial evaluating magnesium for neuroprotection. Nonanomalous, singleton gestations delivered between 22 0/7 and 36 6/7 weeks were included. Large-for-gestational-age infants were excluded. We performed a nested case control study. Cases were infants with RDS; controls were infants without RDS. The sample size estimates revealed 779 subjects/group were needed to achieve a 80% power to demonstrate a 1/3 difference in RDS. We fit a multivariable logistic regression model to adjust for confounders. We assessed the association of SGA with RDS and a composite adverse respiratory and neonatal outcome. Results Overall, 947 cases and 920 controls were included. The groups differed by gestational age at delivery, antibiotic exposure, mode of delivery, infant gender, and birth weight. SGA was not associated with RDS (adjusted odds ratio [aOR]: 1.07, 95% confidence interval [CI]: 0.48-2.38) or the composite respiratory (aOR: 0.87, 95% CI: 0.37-2.04) or adverse neonatal outcome (aOR: 0.65, 95% CI: 0.27-1.54). RDS and the composite respiratory outcome were most associated with earlier gestational age at delivery, cesarean delivery, and male gender. Conclusion SGA is not associated with RDS or other adverse respiratory and neonatal composites. PMID- 27500934 TI - Beta Diversity in a Highly Heterogeneous Area: Disentangling Species and Taxonomic Dissimilarity for Terrestrial Vertebrates. AB - Quantifying differences in species composition among communities provides important information related to the distribution, conservation and management of biodiversity, especially when two components are recognized: dissimilarity due to turnover, and dissimilarity due to richness differences. The ecoregions in central Mexico, within the Mexican Transition Zone, have outstanding environmental heterogeneity and harbor huge biological richness, besides differences in the origin of the biota. Therefore, biodiversity studies in this area require the use of complementary measures to achieve appropriate information that may help in the design of conservation strategies. In this work we analyze the dissimilarity of terrestrial vertebrates, and the components of turnover and richness differences, among six ecoregions in the state of Hidalgo, central Mexico. We follow two approaches: one based on species level dissimilarity, and the second on taxonomic dissimilarity. We used databases from the project "Biodiversity in the state of Hidalgo". Our results indicate that species dissimilarity is higher than taxonomic dissimilarity, and that turnover contributes more than richness differences, both for species and taxonomic total dissimilarity. Moreover, total dissimilarity, turnover dissimilarity and the dissimilarity due to richness differences were positively related in the four vertebrate groups. Reptiles had the highest values of dissimilarity, followed by mammals, amphibians and birds. For reptiles, birds, and mammals, species turnover was the most important component, while richness differences had a higher contribution for amphibians. The highest values of dissimilarity occurred between environmentally contrasting ecoregions (i.e., tropical and temperate forests), which suggests that environmental heterogeneity and differences in the origin of biotas are key factors driving beta diversity of terrestrial vertebrates among ecoregions in this complex area. PMID- 27500935 TI - Disturbance in the Mucosa-Associated Commensal Bacteria Is Associated with the Exacerbation of Chronic Colitis by Repeated Psychological Stress; Is That the New Target of Probiotics? AB - Psychological stress can exacerbate inflammatory bowel disease. However, the mechanisms underlying how psychological stress affects gut inflammation remain unclear. Here, we focused on the relationship between changes in the microbial community of mucosa-associated commensal bacteria (MACB) and mucosal immune responses induced by chronic psychological stress in a murine model of ulcerative colitis. Furthermore, we examined the effect of probiotic treatment on exacerbated colitis and MACB composition changes induced by chronic psychological stress. Repeated water avoidance stress (rWAS) in B6-Tcra-/- mice severely exacerbated colitis, which was evaluated by both colorectal tissue weight and histological score of colitis. rWAS treatment increased mRNA expression of UCN2 and IFN-gamma in large intestinal lamina propria mononuclear cells (LI-LPMC). Interestingly, exacerbated colitis was associated with changes in the microbial community of MACB, specifically loss of bacterial species diversity and an increase in the component ratio of Clostridium, revealed by 16S rRNA gene amplicon analysis. Finally, the oral administration of a probiotic Lactobacillus strain was protective against the exacerbation of colitis and was associated with a change in the bacterial community of MACB in rWAS-exposed Tcra-/- mice. Taken together, these results suggested that loss of species diversity in MACB might play a key role in exacerbated colitis induced by chronic psychological stress. In addition, probiotic treatment may be used as a tool to preserve the diversity of bacterial species in MACB and alleviate gut inflammation induced by psychological stress. PMID- 27500940 TI - Application of a Dual-Hybrid Direct Random Phase Approximation to Water Clusters. AB - In water clusters, there is a delicate balance of van der Waals interactions and hydrogen bonds. Although semilocal and nonlocal density functional approximations have been recently routinely applied to water in various phases, the accurate description of hydrogen bonds remains a challenge. The most popular density functional approaches fail to predict the correct ordering of the energies of water clusters. To illustrate the required accuracy, the CCSD(T) complete basis set extrapolated dissociation energy difference between the two lowest energy hexamer structures is 0.06 kcal mol(-1) per monomer. In this work, we assessed interaction energies in neutral and ionic water clusters with various density functionals with or without van der Waals correction. Generally, van der Waals approximations play a significant role in clusters with increasing size, while hybrid functionals improve the description of hydrogen bonds. Despite these general trends, none of the tested density functional approximations with or without van der Waals correction and exact exchange mixing can lead to a uniform performance for neutral and ionic water clusters. The recently constructed dual hybrid dRPA75 approximation is a successful combination of exact and semilocal exchange, and nonlocal correlation in its energy, while utilizing a high fraction of exact exchange. We have shown that the dRPA75 method has a systematic error, which can be efficiently compensated for by the aug-cc-pVTZ basis set for small- and medium-sized water clusters. PMID- 27500936 TI - Wnt5a Signals through DVL1 to Repress Ribosomal DNA Transcription by RNA Polymerase I. AB - Ribosome biogenesis is essential for cell growth and proliferation and is commonly elevated in cancer. Accordingly, numerous oncogene and tumor suppressor signaling pathways target rRNA synthesis. In breast cancer, non-canonical Wnt signaling by Wnt5a has been reported to antagonize tumor growth. Here, we show that Wnt5a rapidly represses rDNA gene transcription in breast cancer cells and generates a chromatin state with reduced transcription of rDNA by RNA polymerase I (Pol I). These effects were specifically dependent on Dishevelled1 (DVL1), which accumulates in nucleolar organizer regions (NORs) and binds to rDNA regions of the chromosome. Upon DVL1 binding, the Pol I transcription activator and deacetylase Sirtuin 7 (SIRT7) releases from rDNA loci, concomitant with disassembly of Pol I transcription machinery at the rDNA promoter. These findings reveal that Wnt5a signals through DVL1 to suppress rRNA transcription. This provides a novel mechanism for how Wnt5a exerts tumor suppressive effects and why disruption of Wnt5a signaling enhances mammary tumor growth in vivo. PMID- 27500941 TI - Palladium-Catalyzed Oxidative Sulfenylation of Indoles and Related Electron-Rich Heteroarenes with Aryl Boronic Acids and Elemental Sulfur. AB - An efficient and convenient palladium-catalyzed C-H bond oxidative sulfenylation of indoles and related electron-rich heteroarenes with aryl boronic acids and elemental sulfur has been described. This procedure provides a useful and direct approach for the assembly of a wide range of structurally diverse 3 sulfenylheteroarenes with moderate to excellent yields from simple and readily available starting materials. Moreover, this synthetic protocol is suitable for N protected and unprotected indoles. Notably, the construction of two C-S bonds in one step was also achieved in this transformation. PMID- 27500942 TI - Gender and genetic contributions to weight identity among adolescents and young adults in the U.S. AB - In this paper, we investigate the possibility that genetic variation contributes to self-perceived weight status among adolescents and young adults in the U.S. Using samples of identical and fraternal twins across four waves of the National Longitudinal Study of Adolescent to Adult Health (Add Health) study, we calculate heritability estimates for objective body mass index (BMI) that are in line with previous estimates. We also show that perceived weight status is heritable (h(2) ~ 0.47) and most importantly that this trait continues to be heritable above and beyond objective BMI (h(2) ~ 0.25). We then demonstrate significant sex differences in the heritability of weight identity across the four waves of the study, where h(2)women = 0.39, 0.35, 0.40, and 0.50 for each wave, respectively, and h(2)men = 0.10, 0.10, 0.23, and 0.03. These results call for a deeper consideration of both identity and gender in genetics research. PMID- 27500943 TI - Do early life cognitive ability and self-regulation skills explain socio-economic inequalities in academic achievement? An effect decomposition analysis in UK and Australian cohorts. AB - Socio-economic inequalities in academic achievement emerge early in life and are observed across the globe. Cognitive ability and "non-cognitive" attributes (such as self-regulation) are the focus of many early years' interventions. Despite this, little research has compared the contributions of early cognitive and self regulation abilities as separate pathways to inequalities in academic achievement. We examined this in two nationally representative cohorts in the UK (Millennium Cohort Study, n = 11,168; 61% original cohort) and Australia (LSAC, n = 3028; 59% original cohort). An effect decomposition method was used to examine the pathways from socio-economic disadvantage (in infancy) to two academic outcomes: 'low' maths and literacy scores (based on bottom quintile) at age 7-9 years. Risk ratios (RRs, and bootstrap 95% confidence intervals) were estimated with binary regression for each pathway of interest: the 'direct effect' of socio economic disadvantage on academic achievement (not acting through self-regulation and cognitive ability in early childhood), and the 'indirect effects' of socio economic disadvantage acting via self-regulation and cognitive ability (separately). Analyses were adjusted for baseline and intermediate confounding. Children from less advantaged families were up to twice as likely to be in the lowest quintile of maths and literacy scores. Around two-thirds of this elevated risk was 'direct' and the majority of the remainder was mediated by early cognitive ability and not self-regulation. For example in LSAC: the RR for the direct pathway from socio-economic disadvantage to poor maths scores was 1.46 (95% CI: 1.17-1.79). The indirect effect of socio-economic disadvantage through cognitive ability (RR = 1.13 [1.06-1.22]) was larger than the indirect effect through self-regulation (1.05 [1.01-1.11]). Similar patterns were observed for both outcomes and in both cohorts. Policies to alleviate social inequality (e.g. child poverty reduction) remain important for closing the academic achievement gap. Early interventions to improve cognitive ability (rather than self regulation) also hold potential for reducing inequalities in children's academic outcomes. PMID- 27500944 TI - Development of Solution-Processed ZnO Nanorod Arrays Based Photodetectors and the Improvement of UV Photoresponse via AZO Seed Layers. AB - Designing a rational structure and developing an efficient fabrication technique for bottom-up devices offer a promising opportunity for achieving high performance devices. In this work, we studied how Al-doped ZnO (AZO) seed layer films influence the morphology and optical and electrical properties for ZnO aligned nanorod arrays (NRs) and then the performance of ZnO NRs based ultraviolet photodetectors (UV PDs) with Au/ZnO NRs Schottky junctions and p CuSCN/n-ZnO NRs heterojunctions. The PD with AZO thin film with 0.5 at. % Al doping (named as AZO (0.5%)) exhibited more excellent photoresponse properties than that with pristine ZnO and AZO (1%) thin films. This phenomenon can be ascribed to the good light transmission of the AZO layer, increased density of the NRs, and improved crystallinity of ZnO NRs. The PDs based on CuSCN/ZnO NRs heterojunctions showed good rectification characteristics in the dark and self powered UV photoresponse properties with excellent stability and reproducibility under low-intensity illumination conditions. A large responsivity located at 365 nm of 22.5 mA/W was achieved for the PD with AZO (0.5%) thin film without applied bias. The internal electric field originated from p-CuSCN/n-ZnO NRs heterojunctions can separate photogenerated carriers in ZnO NRs and drift toward the corresponding electrode. PMID- 27500945 TI - Modeling zero-modified count and semicontinuous data in health services research Part 1: background and overview. AB - Health services data often contain a high proportion of zeros. In studies examining patient hospitalization rates, for instance, many patients will have no hospitalizations, resulting in a count of zero. When the number of zeros is greater or less than expected under a standard count model, the data are said to be zero modified relative to the standard model. A similar phenomenon arises with semicontinuous data, which are characterized by a spike at zero followed by a continuous distribution with positive support. When analyzing zero-modified count and semicontinuous data, flexible mixture distributions are often needed to accommodate both the excess zeros and the typically skewed distribution of nonzero values. Various models have been introduced over the past three decades to accommodate such data, including hurdle models, zero-inflated models, and two part semicontinuous models. This tutorial describes recent modeling strategies for zero-modified count and semicontinuous data and highlights their role in health services research studies. Part 1 of the tutorial, presented here, provides a general overview of the topic. Part 2, appearing as a companion piece in this issue of Statistics in Medicine, discusses three case studies illustrating applications of the methods to health services research. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27500946 TI - Neon-Bearing Ammonium Metal Formates: Formation and Behaviour under Pressure. AB - The incorporation of noble gas atoms, in particular neon, into the pores of network structures is very challenging due to the weak interactions they experience with the network solid. Using high-pressure single-crystal X-ray diffraction, we demonstrate that neon atoms enter into the extended network of ammonium metal formates, thus forming compounds Nex [NH4 ][M(HCOO)3 ]. This phenomenon modifies the compressional and structural behaviours of the ammonium metal formates under pressure. The neon atoms can be clearly localised within the centre of [M(HCOO)3 ]5 cages and the total saturation of this site is achieved after ~1.5 GPa. We find that by using argon as the pressure-transmitting medium, the inclusion inside [NH4 ][M(HCOO)3 ] is inhibited due to the larger size of the argon. This study illustrates the size selectivity of [NH4 ][M(HCOO)3 ] compounds between neon and argon insertion under pressure, and the effect of inclusion on the high-pressure behaviour of neon-bearing ammonium metal formates. PMID- 27500948 TI - Dual-Template Synthesis of 2D Mesoporous Polypyrrole Nanosheets with Controlled Pore Size. AB - The first synergistic dual-template self-assembly approach is presented for bottom-up construction of 2D mesoporous polypyrrole nanosheets based on different supramolecular assemblies, which feature a double-layered architecture, controlled pore sizes, ultrathin thickness, and large surface area. The unique structure rends them with superior reversible discharge capability, rate performance, and stable cyclability when serving as the cathode materials for Na ion batteries. PMID- 27500947 TI - Plant peroxisomes: recent discoveries in functional complexity, organelle homeostasis, and morphological dynamics. AB - Peroxisomes are essential for life in plants. These organelles house a variety of metabolic processes that generate and inactivate reactive oxygen species. Our knowledge of pathways and mechanisms that depend on peroxisomes and their constituent enzymes continues to grow, and in this review we highlight recent advances in understanding the identity and biological functions of peroxisomal enzymes and metabolic processes. We also review how peroxisomal matrix and membrane proteins enter the organelle from their sites of synthesis. Peroxisome homeostasis is regulated by specific degradation mechanisms, and we discuss the contributions of specialized autophagy and a peroxisomal protease to the degradation of entire peroxisomes and peroxisomal enzymes that are damaged or superfluous. Finally, we review how peroxisomes can flexibly change their morphology to facilitate inter-organellar contacts. PMID- 27500949 TI - Phase 3, open-label, randomized study of the pharmacokinetics, efficacy and safety of ixekizumab following subcutaneous administration using a prefilled syringe or an autoinjector in patients with moderate-to-severe plaque psoriasis (UNCOVER-A). AB - BACKGROUND: The efficacy of ixekizumab, an anti-interleukin-17A (anti-IL-17A) monoclonal IgG4 antibody, was demonstrated in moderate-to-severe psoriasis patients when administered via prefilled syringe (PFS). OBJECTIVE: To evaluate the effect of two drug delivery devices on the pharmacokinetics (PK) of ixekizumab as well as efficacy and safety with both devices. METHODS: In the first 12 weeks of an open-label, phase 3 study, moderate-to-severe psoriasis patients were randomized to ixekizumab delivery via PFS or autoinjector device. Randomization was stratified by weight (<80 kg, 80-100 kg, >100 kg), injection assistance (yes/no) and injection site (arm, thigh or abdomen). Following a 160 mg initial dose at week 0, patients received subcutaneous 80-mg ixekizumab as a single injection every 2 weeks for 12 weeks. Blood samples were collected following the initial 160-mg dose on days 2, 4, 7, 10 and 14 for PK analysis. Primary PK parameters were maximum concentration (Cmax ) and area under the curve (AUC0-tlast ) where tlast is the time of last sample (14 days +/- 24 h). Efficacy was assessed by percent improvement on the Psoriasis Area and Severity Index (PASI) at week 12. Adverse event reporting, vital signs and clinical laboratory data were used to evaluate safety. RESULTS: Of 204 randomized patients, 192 were included in the PK analysis (PFS: 94; autoinjector: 98). The PFS and autoinjector showed similar geometric mean Cmax (90% CI) [15.0 MUg/mL (13.9-16.1) vs. 14.8 MUg/mL (13.8-15.9)] and geometric mean AUC0-tlast (90% CI) [157 MUg * day/mL (147 168) vs. 154 MUg * day/mL (144-165)]. When comparing Cmax and AUC0-tlast of the autoinjector to PFS, the geometric LS mean ratios were 0.97. At week 12, mean percent PASI improvement (via modified baseline observation carried forward) was similar with the PFS (89.3%) and autoinjector (86.9%). Both devices had safety results that were consistent with the known safety profile of ixekizumab. CONCLUSION: The PK, efficacy and safety of ixekizumab administered subcutaneously by PFS and autoinjector were similar. Clinicaltrials.gov number: NCT01777191 https://clinicaltrials.gov/ct2/show/NCT01777191. PMID- 27500950 TI - Sixty as the new forty: considerations on older related stem cell donors. AB - The era of reduced-intensity allogeneic stem cell transplantation, with its emphasis on older patients, has created new challenges in the management of what is now an older related stem cell donor population. These donors are now on average no less than 10 years older than in the mid-1990s. Donors over 70 years of age are no longer isolated or exceptional cases. They may still be considered eligible for donation but many of them, based on the older age and their medical history, may no longer fully qualify as 'healthy' or 'normal'. The older the donor, the more likely that hematologic abnormalities, comorbidities and treated malignancies will complicate the picture. Assessing the risk-benefit ratio for both donor and recipient can now be more challenging than ever. PMID- 27500951 TI - Left ventricular vascular and metabolic adaptations to high-intensity interval and moderate intensity continuous training: a randomized trial in healthy middle aged men. AB - KEY POINTS: High-intensity interval training (HIIT) has become popular, time sparing alternative to moderate intensity continuous training (MICT), although the cardiac vascular and metabolic effects of HIIT are incompletely known. We compared the effects of 2-week interventions with HIIT and MICT on myocardial perfusion and free fatty acid and glucose uptake. Insulin-stimulated myocardial glucose uptake was decreased by training without any significantly different response between the groups, whereas free fatty acid uptake remained unchanged. Adenosine-stimulated myocardial perfusion responded differently to the training modes (change in mean HIIT: -19%; MICT: +9%; P = 0.03 for interaction) and was correlated with myocardial glucose uptake for the entire dataset and especially after HIIT training. HIIT and MICT induce similar metabolic and functional changes in the heart, although myocardial vascular hyperaemic reactivity is impaired after HIIT, and this should be considered when prescribing very intense HIIT for previously untrained subjects. ABSTRACT: High-intensity interval training (HIIT) is a time-efficient way of obtaining the health benefits of exercise, although the cardiac effects of this training mode are incompletely known. We compared the effects of short-term HIIT and moderate intensity continuous training (MICT) interventions on myocardial perfusion and metabolism and cardiac function in healthy, sedentary, middle-aged men. Twenty-eight healthy, middle-aged men were randomized to either HIIT or MICT groups (n = 14 in both) and underwent six cycle ergometer training sessions within 2 weeks (HIIT session: 4-6 * 30 s all-out cycling/4 min recovery, MICT session 40-60 min at 60% VO2 peak ). Cardiac magnetic resonance imaging (CMRI) was performed to measure cardiac structure and function and positron emission tomography was used to measure myocardial perfusion at baseline and during adenosine stimulation, insulin-stimulated glucose uptake (MGU) and fasting free fatty acid uptake (MFFAU). End-diastolic and end-systolic volumes increased and ejection fraction slightly decreased with both training modes, although no other changes in CMRI were observed. MFFAU and basal myocardial perfusion remained unchanged. MGU was decreased by training (HIIT from 46.5 to 35.9; MICT from 47.4 to 44.4 mmol 100 g 1 min-1 , P = 0.007 for time, P = 0.11 for group * time). Adenosine-stimulated myocardial perfusion responded differently to the training modes (change in mean HIIT: -19%; MICT: +9%; P = 0.03 for group * time interaction). HIIT and MICT induce similar metabolic and functional changes in the heart, although myocardial vascular hyperaemic reactivity is impaired after HIIT. This should be taken into account when prescribing very intense HIIT for previously untrained subjects. PMID- 27500952 TI - Hair cortisol concentration and glycated hemoglobin in African American adults. AB - BACKGROUND: African Americans have higher diabetes prevalence compared to Whites. They also have elevated cortisol levels - indicating possible HPA axis dysregulation - which may raise blood glucose as part of the biological response to physiological and psychosocial stress. Little is known about chronic cortisol levels in African Americans, and even less about the role of chronically elevated cortisol in type 2 diabetes development in this racial group. PURPOSE: We used analysis of cortisol in hair to examine associations of long-term (~3months) cortisol levels with glycated hemoglobin (HbA1c) in a group of African American adults. In exploratory analyses, we also studied the relationship of hair dehydroepiandrosterone (DHEA) with HbA1c. METHOD: Participants were 61 community dwelling African American adults (85% female; mean age 54.30 years). The first 3cm of scalp-near hair were analyzed for cortisol and DHEA concentration using enzyme-linked immunoassay analysis. Glycated hemoglobin was assessed, and regression analyses predicting HbA1c from hair cortisol and DHEA were performed in the full sample and in a subsample of participants (n=20) meeting the National Institute of Diabetes and Digestive Kidney Disease (NIDDK) criteria for type 2 diabetes (HbA1c>=6.5%). RESULTS: In the full sample, HbA1c increased with hair cortisol level (beta=0.22, p=0.04, f(2)=0.10), independent of age, sex, chronic health conditions, diabetes medication use, exercise, and depressive symptoms. In the subsample of participants with an HbA1c>=6.5%, hair cortisol was also positively related to HbA1c (beta=0.45, p=0.04, f(2)=0.32), independent of diabetes medication use. Glycated hemoglobin was unrelated to hair DHEA in both the full sample and HbA1c>=6.5% subsample. CONCLUSION: Long-term HPA axis dysregulation in the form of elevated hair cortisol is associated with elevated HbA1c in African American adults. PMID- 27500953 TI - Prevalence of Frailty in Latin America and the Caribbean: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Countries in Latin America and the Caribbean (LAC) have experienced a rapid increase in their proportion of older people. This region is marked by a high prevalence of chronic diseases and disabilities among aging adults. Frailty appears in the context of LAC negatively affecting quality of life among many older people. AIM: To investigate the prevalence of frailty among community dwelling older people in LAC through a systematic review and meta-analysis. METHODS: A literature search was performed in indexed databases and in the grey literature. Studies investigating the prevalence of frailty with representative samples of community-dwelling older people in Latin America and the Caribbean were retrieved. Independent investigators carried out the study selection process and the data extraction. A meta-analysis and meta-regression were performed using STATA 11 software. The systematic review was registered at the International Prospective Register of Systematic Reviews under the number CRD42014015203. RESULTS: A total of 29 studies and 43,083 individuals were included in the systematic review. The prevalence of frailty was 19.6% (95% CI: 15.4-24.3%) in the investigated region, with a range of 7.7% to 42.6% in the studies reviewed. The year of data collection influenced the heterogeneity between the studies. CONCLUSION: Frailty is very common among older people in LAC. As a result, countries in the region need to adapt their health and social care systems to demands of an older population. PMID- 27500954 TI - Respiratory Syncytial Virus and Other Viral Infections among Children under Two Years Old in Southern Vietnam 2009-2010: Clinical Characteristics and Disease Severity. AB - BACKGROUND: Despite a high burden of respiratory syncytial virus (RSV) infections among children, data on demographic and clinical characteristics of RSV are scarce in low and middle income countries. This study aims to describe the viral etiologies, the demographic, epidemiological, and clinical characteristics of children under two years of age who were hospitalized with a lower respiratory tract infections (LRTI), focusing on RSV (prevalence, seasonality, subgroups, viral load) and its association with disease severity. METHODS: A prospective study among children under two years of age, hospitalized with LRTI was conducted in two referral pediatric hospitals in Ho Chi Minh City, Vietnam, from May 2009 to December 2010. Socio-demographic, clinical data and nasopharyngeal swabs were collected on enrolment and discharge. Multiplex real-time RT-PCR (13 viruses) and quantitative RSV RT-PCR were used to identify viral pathogens, RSV load and subgroups. RESULTS: Among 632 cases, 48% were RSV positive. RSV infections occurred at younger age than three other leading viral infections i.e rhinovirus (RV), metapneumovirus (MPV), parainfluenza virus (PIV-3) and were significantly more frequent in the first 6 months of life. Clinical severity score of RSV infection was significantly higher than PIV-3 but not for RV or MPV. In multivariate analysis, RV infection was significantly associated with severity while RSV infection was not. Among RSV infections, neither viral load nor viral co-infections were significantly associated with severity. Young age and having fever at admission were significantly associated with both RSV and LRTI severity. A shift in RSV subgroup predominance was observed during two consecutive rainy seasons but was not associated with severity. CONCLUSION: We report etiologies, the epidemiological and clinical characteristics of LRTI among hospitalized children under two years of age and risk factors of RSV and LRTI severity. PMID- 27500955 TI - Intracoronary Delivery of Mitochondria to the Ischemic Heart for Cardioprotection. AB - We have previously shown that transplantation of autologously derived, respiration-competent mitochondria by direct injection into the heart following transient ischemia and reperfusion enhances cell viability and contractile function. To increase the therapeutic potential of this approach, we investigated whether exogenous mitochondria can be effectively delivered through the coronary vasculature to protect the ischemic myocardium and studied the fate of these transplanted organelles in the heart. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and then reperfused for 10 minutes. Mitochondria were labeled with 18F-rhodamine 6G and iron oxide nanoparticles. The labeled mitochondria were either directly injected into the ischemic region or delivered by vascular perfusion through the coronary arteries at the onset of reperfusion. These hearts were used for positron emission tomography, microcomputed tomography, and magnetic resonance imaging with subsequent microscopic analyses of tissue sections to confirm the uptake and distribution of exogenous mitochondria. Injected mitochondria were localized near the site of delivery; while, vascular perfusion of mitochondria resulted in rapid and extensive dispersal throughout the heart. Both injected and perfused mitochondria were observed in interstitial spaces and were associated with blood vessels and cardiomyocytes. To determine the efficacy of vascular perfusion of mitochondria, an additional group of rabbit hearts were subjected to 30 minutes of regional ischemia and reperfused for 120 minutes. Immediately following regional ischemia, the hearts received unlabeled, autologous mitochondria delivered through the coronary arteries. Autologous mitochondria perfused through the coronary vasculature significantly decreased infarct size and significantly enhanced post ischemic myocardial function. In conclusion, the delivery of mitochondria through the coronary arteries resulted in their rapid integration and widespread distribution throughout the heart and provided cardioprotection from ischemia reperfusion injury. PMID- 27500956 TI - Uropathogenic Escherichia coli Releases Extracellular Vesicles That Are Associated with RNA. AB - BACKGROUND: Bacterium-to-host signalling during infection is a complex process involving proteins, lipids and other diffusible signals that manipulate host cell biology for pathogen survival. Bacteria also release membrane vesicles (MV) that can carry a cargo of effector molecules directly into host cells. Supported by recent publications, we hypothesised that these MVs also associate with RNA, which may be directly involved in the modulation of the host response to infection. METHODS AND RESULTS: Using the uropathogenic Escherichia coli (UPEC) strain 536, we have isolated MVs and found they carry a range of RNA species. Density gradient centrifugation further fractionated and characterised the MV preparation and confirmed that the isolated RNA was associated with the highest particle and protein containing fractions. Using a new approach, RNA-sequencing of libraries derived from three different 'size' RNA populations (<50nt, 50-200nt and 200nt+) isolated from MVs has enabled us to now report the first example of a complete bacterial MV-RNA profile. These data show that MVs carry rRNA, tRNAs, other small RNAs as well as full-length protein coding mRNAs. Confocal microscopy visualised the delivery of lipid labelled MVs into cultured bladder epithelial cells and showed their RNA cargo labelled with 5-EU (5-ethynyl uridine), was transported into the host cell cytoplasm and nucleus. MV RNA uptake by the cells was confirmed by droplet digital RT-PCR of csrC. It was estimated that 1% of MV RNA cargo is delivered into cultured cells. CONCLUSIONS: These data add to the growing evidence of pathogenic bacterial MV being associated a wide range of RNAs. It further raises the plausibility for MV-RNA-mediated cross-kingdom communication whereby they influence host cell function during the infection process. PMID- 27500958 TI - Mucin as a diagnostic clue in dermatopathology. AB - Mucins are high-molecular weight glycoproteins typically found in normal skin in small amounts. There are several reports regarding different types of cutaneous mucinosis. In this report, we discuss mucins in dermatopathology as a diagnostic clue of some well-known entities and some less frequent cutaneous diseases. We also emphasize mucin as a sign in the differential diagnosis between conditions that show histopathological overlap. Lastly, we discuss the locations and circumstances in which mucin could be considered almost normal or physiological. PMID- 27500957 TI - Human Rabies in China, 1960-2014: A Descriptive Epidemiological Study. AB - BACKGROUND: Rabies in China remains a public health problem. In 2014, nearly one thousand rabies-related deaths were reported while rabies geographic distribution has expanded for the recent years. This report used surveillance data to describe the epidemiological characteristics of human rabies in China including determining high-risk areas and seasonality to support national rabies prevention and control activities. METHODS: We analyzed the incidence and distribution of human rabies cases in mainland China using notifiable surveillance data from 1960 2014, which includes a detailed analysis of the recent years from 2004 to 2014. RESULTS: From 1960 to 2014, 120,913 human rabies cases were reported in mainland China. The highest number was recorded in 1981(0.7/100,000; 7037 cases), and in 2007(0.3/100,000; 3300 cases). A clear seasonal pattern has been observed with a peak in August (11.0% of total cases), Human rabies cases were reported in all provinces with a yearly average of 2198 from 1960 to 2014 in China, while the east and south regions were more seriously affected compared with other regions. From2004 to 2014, although the number of cases decreased by 65.2% since 2004 from 2651 to 924 cases, reported areas has paradoxically expanded from 162 prefectures to 200 prefectures and from southern to the central and northern provinces of China. Farmers accounted most of the cases (65.0%); 50-59 age group accounted for the highest proportion (20.5%), and cases are predominantly males with a male-to female ratio of 2.4:1 on average. CONCLUSIONS: Despite the overall steady decline of cases since the peak in 2007, the occurrence of cases in new areas and the spread trend were obvious in China in recent years. Further investigations and efforts are warranted in the areas have high rabies incidence to control rabies by interrupting transmission from dogs to humans and in the dog population. Furthermore, elimination of rabies should be eventually the ultimate goal for China. PMID- 27500959 TI - Cost of microbial larviciding for malaria control in rural Tanzania. AB - OBJECTIVE: Microbial larviciding may be a potential supplement to conventional malaria vector control measures, but scant information on its relative implementation costs and effectiveness, especially in rural areas, is an impediment to expanding its uptake. We perform a costing analysis of a seasonal microbial larviciding programme in rural Tanzania. METHODS: We evaluated the financial and economic costs from the perspective of the public provider of a 3 month, community-based larviciding intervention implemented in twelve villages in the Mvomero District of Tanzania in 2012-2013. Cost data were collected from financial reports and invoices and through discussion with programme administrators. Sensitivity analysis explored the robustness of our results to varying key parameters. RESULTS: Over the 2-year study period, approximately 6873 breeding sites were treated with larvicide. The average annual economic costs of the larviciding intervention in rural Tanzania are estimated at 2014 US$ 1.44 per person protected per year (pppy), US$ 6.18 per household and US$ 4481.88 per village, with the larvicide and staffing accounting for 14% and 58% of total costs, respectively. CONCLUSIONS: We found the costs pppy of implementing a seasonal larviciding programme in rural Tanzania to be comparable to the costs of other larviciding programmes in urban Tanzania and rural Kenya. Further research should evaluate the cost-effectiveness of larviciding relative to, and in combination with, other vector control strategies in rural settings. PMID- 27500960 TI - Anterior Perineal PlanE for ultra-low Anterior Resection of the rectum (APPEAR) technique: A systematic review. AB - INTRODUCTION: The Anterior Perineal PlanE for ultra-low Anterior Resection of the rectum (APPEAR) technique utilises a perineal incision to facilitate resection of the distal rectum. The aim of this study was to review use of the APPEAR technique, assessing patient selection, indications, complications and outcomes, both oncological and functional. MATERIALS AND METHODS: A systematic review was carried out to identify studies reporting outcomes following rectal resection via an anterior perineal incision, with no limits on year or language. All studies were included. Quality of studies was assessed using the methodological index for non-randomised studies (MINORS) score. RESULTS: Thirteen studies were identified from 1985 to 2013. 174 patients (102 male), ranging from 21 to 82 years, underwent surgery at eleven centres in seven countries. Maximum experience at one centre is 60 cases. 9 cases were performed for rectal dysplasia, 141 for rectal cancer; 96 resections were R0 (remaining 45 unstated). 14 cases were carried out laparoscopically. 30-day mortality was 2.3% (4 patients); there were 2 further deaths from systemic recurrence. Permanent stoma rate was 8/155 (5%). The most frequent complication was perineal or vaginal fistulation (26 patients): 6 underwent reoperation; 15 healed with conservative management; 5 required a permanent stoma. Functional outcomes were variably reported; median stool frequency was 3/24hrs with average Wexner scores of 5-5.5. CONCLUSION: In selected patients the APPEAR technique offers avoidance of permanent colostomy with good oncological outcomes. The majority of studies had short follow up periods and longer-term outcomes will need evaluation. PMID- 27500961 TI - Robot-assisted partial nephrectomy. AB - Partial nephrectomy is the standard treatment for small renal masses. Currently, it is commonly performed using minimally invasive approaches, including laparoscopic and robot-assisted techniques. The aim of the present review is to report the surgical technique of robot-assisted partial nephrectomy in full detail as well as available literature results. PMID- 27500962 TI - Massive and recurrent diverticular hemorrhage, risk factors and treatment. AB - AIM: Diverticular hemorrhage may be massive or recurrent, requiring surgical management. The aim of our study is to define risk factors that predict rebleeding or need for urgent operation in patients with diverticular hemorrhage. METHODS: Retrospective study was conducted on patients who were admitted for diverticular hemorrhage. Data pertaining to patient and bleeding characteristics, method of diagnosis, blood transfusion and type of operation were collected. Multivariate analysis model compared patients who experienced single bleeding episode with those with recurrent episodes, and patients who underwent surgery with those who did not. RESULTS: One hundred and four patients met the inclusion criteria. Thirty four patients experienced more than one bleeding episode. Ten patients needed surgery for recurrent bleeding. Five patients presented with hemodynamic instability, none of them required surgical treatment. Neither patients' comorbidity nor anticoagulant and antiaggregant treatments were associated with increased risk for recurrent hemorrhage. Diabetes mellitus was correlated with decreased risk for recurrent hemorrhage, OR = 0.21, (CI 95% (0.06 0.73)); p = 0.014. Independent risk factor for massive recurrent diverticular hemorrhage requiring surgery was right sided diverticulosis, OR = 4.6(CI 95% (2.1 19)); p = 0.006. CONCLUSIONS: Right colon diverticulosis rather than patient characteristics and medical treatment should prompt for aggressive management with lower threshold for surgical intervention. PMID- 27500963 TI - Cryoablation of small kidney tumors. AB - INTRODUCTION: Cryoablation (CA) has been broadly used mostly in the treatment of small renal masses (SRMs). The present review aims to define the current role of CA in the treatment of SRMs by assessing clinical indications and outcomes. METHOD: A comprehensive review on patient selection, procedural details, perioperative complications, and short/long-term oncological and functional outcomes was conducted. For each section, a take-home message was formulated with level of evidence (LoE) according to Cochrane collaboration. RESULTS: Age and comorbidity drive the choice of ablation in SRMs, although hospital setting also influences the decision. Technically in adequate CA or first post-CA control occurs in 3-5% of laparoscopic cryoablation (LCA) or percutaneous cryoablation (PCA) series. Meta-analysis does not evidence differences in the rate of residual tumor per person-year between the approaches (0.033 LCA vs. 0.046 PCA, p = 0.25). Perioperative complications (8-25%) are erratically reported. LCA has significantly lower likelihood of complications than minimally invasive partial nephrectomy (MIPN). Systematic reviews indicate 30-month local tumor progression rate of 8.5% for LCA in renal cell carcinoma but low metastatic progression (1 4.4%). Few LCA long-term follow-up series (mean/media 48-98 months) report recurrence-free survival (RFS) and cancer-specific survival (CSS) ranges of 80 100%. For PCA, Kaplan-Meier local disease-free survival (DFS) of 95.6% at 3-5 years [32] and 5-year overall survival and local RFS of 86.3% were reported. The decrease in renal function after CA is minimal, and the only risk factor associated is the basal estimated glomerular filtration rate (eGFR). CONCLUSION: LoE 3a/b confirms lower CA perioperative complication rate and higher local progression rate than those for MIPN. CA preserves postoperative renal functional, without any evidence of differences in mid-/long-term follow-up compared to nephron sparing surgery. PMID- 27500964 TI - Special considerations for the management of pediatric acute respiratory distress syndrome. AB - INTRODUCTION: Pediatric acute respiratory distress syndrome (ARDS) remains a diagnostic and therapeutic challenge with significant mortality and morbidity. There are limited data to guide identification and management. AREAS COVERED: The Pediatric Acute Lung Injury Consensus Conference recently proposed pediatric specific definitions for ARDS and management recommendations. In this review, we discuss aspects of pediatric ARDS that have received more attention over the past few years: high frequency oscillatory ventilation, administration of corticosteroids and functional outcomes. We conducted searches on PubMed, ClinicalKey and Google Scholar using medical subject heading terms and text words related to acute lung injury and ARDS. Expert commentary: The newly proposed definition for pediatric ARDS requires validation for efficacy in diagnosis and risk stratification. At present, there is insufficient evidence to support routine use of high frequency oscillatory ventilation or corticosteroids in pediatric ARDS. Further studies are required to determine the impact of pediatric ARDS on functional outcomes. PMID- 27500966 TI - New insights in the homotopic and heterotopic connectivity of the frontal portion of the human corpus callosum revealed by microdissection and diffusion tractography. AB - Extensive studies revealed that the human corpus callosum (CC) plays a crucial role in providing large-scale bi-hemispheric integration of sensory, motor and cognitive processing, especially within the frontal lobe. However, the literature lacks of conclusive data regarding the structural macroscopic connectivity of the frontal CC. In this study, a novel microdissection approach was adopted, to expose the frontal fibers of CC from the dorsum to the lateral cortex in eight hemispheres and in one entire brain. Post-mortem results were then combined with data from advanced constrained spherical deconvolution in 130 healthy subjects. We demonstrated as the frontal CC provides dense inter-hemispheric connections. In particular, we found three types of fronto-callosal fibers, having a dorso ventral organization. First, the dorso-medial CC fibers subserve homotopic connections between the homologous medial cortices of the superior frontal gyrus. Second, the ventro-lateral CC fibers subserve homotopic connections between lateral frontal cortices, including both the middle frontal gyrus and the inferior frontal gyrus, as well as heterotopic connections between the medial and lateral frontal cortices. Third, the ventro-striatal CC fibers connect the medial and lateral frontal cortices with the contralateral putamen and caudate nucleus. We also highlighted an intricate crossing of CC fibers with the main association pathways terminating in the lateral regions of the frontal lobes. This combined approach of ex vivo microdissection and in vivo diffusion tractography allowed demonstrating a previously unappreciated three-dimensional architecture of the anterior frontal CC, thus clarifying the functional role of the CC in mediating the inter-hemispheric connectivity. Hum Brain Mapp 37:4718-4735, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27500965 TI - Aging and peripheral lipopolysaccharide can modulate epigenetic regulators and decrease IL-1beta promoter DNA methylation in microglia. AB - In aged mice, peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes exaggerated neuroinflammation and prolonged sickness behavior due in part to microglial dysfunction. Epigenetic changes to DNA may play a role in microglial dysfunction; therefore, we sought to determine whether aged microglia displayed DNA hypomethylation of the interleukin-1 beta (IL-1beta) promoter and altered expression of epigenetic regulators. We further examined whether the demethylating agent 5-azacytidine induced IL-1beta expression in BV2 and primary microglia similar to microglia from aged mice. Novel findings indicated that aged mice had decreased methylation of the IL-1beta gene promoter in primary microglia basally or following systemic LPS that is associated with increased IL-1beta mRNA, intracellular IL-1beta production, as well as prolonged sickness behavior. Last, 5-azacytidine increased IL-1beta gene expression and decreased DNA methylation of BV2 and primary microglial cells similar to microglia from aged mice. Taken together, these data indicate that DNA methylation promotes heightened microglial activation in the aged brain. PMID- 27500967 TI - ALK gene rearranged lung adenocarcinomas: molecular genetics and morphology in cohort of patients from North India. AB - ALK gene rearrangement in the lung adenocarcinomas is the second most common (1.6 11.7% of NSCLC) targetable genomic change after EGFR mutations. However, the prevalence and clinicopathological features of ALK-rearranged lung adenocarcinomas from North India are lacking. A total of 240 cases of lung adenocarcinoma were screened for EGFR mutations and for ALK expression. Smoking status, TNM stage, and treatment response were recorded in all cases. Out of 240 cases screened, 37 cases were positive for EGFR mutations and 17 cases (7.08%) showed ALK positivity with immunohistochemistry and break-apart FISH. On excluding 37 EGFR mutation-positive cases, the incidence of ALK-positive adenocarcinoma appears to be higher (17/203 cases, 8.03%). Eight were men and nine were women with mean age of 51.7 years. Majority (62.5%) were non-smokers and had unresectable disease (70.6% stage IV, 17.6% IIIB). The morphological patterns noted were solid (12 cases), papillary (four cases), and micropapillary (one case). Signet ring (two cases) and clear cell change (one cases) were noted. Out of five patients who received crizotinib, three had partial response and two had stable disease. ALK-rearranged lung adenocarcinomas account for a minor proportion of NSCLC with prevalence similar to that reported in literature. However, as contrast to published data in our series, patients were in older age group and had solid and papillary pattern on morphology with an aggressive course. PMID- 27500968 TI - Role of gamma-glutamyl cyclotransferase as a therapeutic target for colorectal cancer based on the lentivirus-mediated system. AB - Human GGCT (gamma-glutamyl cyclotransferase) has been shown to be upregulated in most tumors, but its role in colorectal cancer (CRC) is poorly understood. Thus, CRC cell lines, including HCT116 and SW1116, were chosen to investigate the role of GGCT by constructing a GGCT silencing cells model using lentivirus-mediated RNA interference. The knockdown efficiency was confirmed by reverse transcription quantitative PCR and a western blot assay. Then, a set of biological functions of GGCT silencing on CRC cell was assessed by MTT, colony-formation assay, and flow cytometry analysis. Further, western blot and Pathscan intracellular signaling were used to detect intracellular signaling associated with cell growth and apoptosis induced by GGCT knockdown. In addition, the clinical chemotherapeutic drug 5-fluorouracil was used to investigate the impact of GGCT silencing on drug sensitivity by an Annexin V/7-AAD double-staining assay. The results of the analysis indicated that GGCT silencing significantly suppressed cell proliferation and arrested cell cycle at the G0/G1 phase by regulating the expression of p21, p27, and cyclin E. Moreover, GGCT silencing triggered the apoptosis of CRC cells by activating caspase-3 and cleaved poly-ADP-ribose polymerase pathways and downregulating the phosphorylation proline-rich Akt substrate of 40 kDa (PRAS40) expression levels. Furthermore, GGCT silencing combined with 5-fluorouracil treatment further induced the apoptotic rate of CRC cells. These findings suggest that GGCT may be a promising diagnostic and therapeutic target for CRC by activating the apoptotic pathway. PMID- 27500969 TI - Psychometric Properties of the Dutch Depression Stigma Scale (DSS) and Associations with Personal and Perceived Stigma in a Depressed and Community Sample. AB - BACKGROUND: Research on depression stigma is needed to gain more insight into the underlying construct and to reduce the level of stigma in the community. However, few validated measurements of depression stigma are available in the Netherlands. Therefore, this study first sought to examine the psychometric properties of the Dutch translation of the Depression Stigma Scale (DSS). Second, we examined which demographic (gender, age, education, partner status) and other variables (anxiety and knowledge of depression) are associated with personal and perceived stigma within these samples. METHODS: The study population consisted of an adult convenience sample (n = 253) (study 1) and a community adult sample with elevated depressive symptoms (n = 264) (study 2). Factor structure, internal consistency, and validity were assessed. The associations between stigma, demographic variables and anxiety level were examined with regression analyses. RESULTS: Confirmatory factor analysis supported the validity and internal consistency of the DSS personal stigma scale. Internal consistency was sufficient (Cronbach's alpha = .70 (study 1) and .77 (study 2)). The results regarding the perceived stigma scale revealed no clear factor structure. Regression analyses showed that personal stigma was higher in younger people, those with no experience with depression, and those with lower education. CONCLUSIONS: This study established the validity and internal consistency of the DSS personal scale in the Netherlands, in a community sample and in people with elevated depressive symptoms. However, additional research is needed to examine the factor structure of the DSS perceived scale and its use in other samples. PMID- 27500970 TI - Prophylactic Gentamicin Is Not Associated with Acute Kidney Injury in Patients with Open Fractures. AB - BACKGROUND: Data on antimicrobial prophylaxis for open fractures is limited, with many protocols based on expert recommendations. These protocols include aminoglycosides (AGs) for fractures with significant soft tissue injury, but these drugs are associated with acute kidney injury (AKI) in other settings; this risk has not been defined for open fracture prophylaxis. METHODS: We performed a retrospective study from May 2012 to October 2014 at our Level 1 trauma center. Patients with open fractures were evaluated for demographics, location/type of fracture, injury severity, and receipt of an AG. Outcomes included rates of AKI, infection, and mortality. RESULTS: There were 167 patients with open fractures during the study period (119 males, mean age 42 +/- 17 [standard deviation] years), with 80 (48%) receiving prophylactic gentamicin (AG+ group). The AG+ and AG- patients had similar fracture sites and Injury Severity Scores (ISSs) (12.6 +/- 9.9 AG+ vs. 15.9 +/- 13.2 AG-) but were more likely to have sustained blunt trauma (96% AG+ vs. 77%; p < 0.001) or received intravenous contrast medium <=48 h from admission (75% AG+ vs. 56% AG-; p = 0.01). Gentamicin was not associated with AKI (odds ratio [OR] 0.22; 95% confidence interval [CI] 0.020-2.44; p = 0.22), whereas hypotension on admission (OR 10.7; 95% CI 1.42-80.93; p = 0.02) and ISS (OR 1.1; 95% CI 1.01-1.20; p = 0.02) were both associated with AKI. Only four fracture site infections were identified, three in the AG+ group and one in the AG- group (3.8% vs. 1.1%; p = 0.27). The mortality rate was greater in the AG group (3.8% vs. 12.6%; p = 0.04). CONCLUSIONS: Prophylactic gentamicin is not associated with AKI, whereas hypotension on admission and higher ISS were. The use of nephrotoxic agents, including aminoglycosides, should be restricted in open fracture patients presenting with hypotension or a high ISS. PMID- 27500971 TI - Environmental variability and the evolution of the glucocorticoid receptor (Nr3c1) in African starlings. AB - One of the primary ways that organisms cope with environmental change is through regulation of the hypothalamo-pituitary-adrenal (HPA) axis, the neuroendocrine system that controls reactions to stress. Variation in genes regulating the HPA axis - particularly the glucocorticoid receptor - may facilitate adaptation to changing climatic conditions by altering expression. Here we examine signatures of selection on the glucocorticoid receptor gene (Nr3c1) in African starlings that inhabit a range of environments, including those with variable climatic conditions. To investigate potential adaptive mechanisms underlying the vertebrate stress response, we sequence the Nr3c1 gene in 27 species of African starlings. Although we find some evidence of positive selection, substitution rate is negatively correlated with variance in precipitation. This suggests climatic cycling in sub-Saharan Africa may have resulted in lower substitution rates to maintain a successful coping strategy. When environmental conditions fluctuate rapidly, variation in the strength of purifying selection can explain evolutionary rate variation. PMID- 27500972 TI - Development of an Insert Co-culture System of Two Cellular Types in the Absence of Cell-Cell Contact. AB - The role of secreted soluble factors in the modification of cellular responses is a recurrent theme in the study of all tissues and systems. In an attempt to make straightforward the very complex relationships between the several cellular subtypes that compose multicellular organisms, in vitro techniques have been developed to help researchers acquire a detailed understanding of single cell populations. One of these techniques uses inserts with a permeable membrane allowing secreted soluble factors to diffuse. Thus, a population of cells grown in inserts can be co-cultured in a well or dish containing a different cell type for evaluating cellular changes following paracrine signaling in the absence of cell-cell contact. Such insert co-culture systems offer various advantages over other co-culture techniques, namely bidirectional signaling, conserved cell polarity and population-specific detection of cellular changes. In addition to being utilized in the field of inflammation, cancer, angiogenesis and differentiation, these co-culture systems are of prime importance in the study of the intricate relationships that exist between the different cellular subtypes present in the central nervous system, particularly in the context of neuroinflammation. This article offers general methodological guidelines in order to set up an experiment in order to evaluating cellular changes mediated by secreted soluble factors using an insert co-culture system. Moreover, a specific protocol to measure the neuroinflammatory effects of cytokines secreted by lipopolysaccharide-activated N9 microglia on neuronal PC12 cells will be detailed, offering a concrete understanding of insert co-culture methodology. PMID- 27500973 TI - Modeling zero-modified count and semicontinuous data in health services research part 2: case studies. AB - This article is the second installment of a two-part tutorial on the analysis of zero-modified count and semicontinuous data. Part 1, which appears as a companion piece in this issue of Statistics in Medicine, provides a general background and overview of the topic, with particular emphasis on applications to health services research. Here, we present three case studies highlighting various approaches for the analysis of zero-modified data. The first case study describes methods for analyzing zero-inflated longitudinal count data. Case study 2 considers the use of hurdle models for the analysis of spatiotemporal count data. The third case study discusses an application of marginalized two-part models to the analysis of semicontinuous health expenditure data. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27500974 TI - Pathway-Dependent Post-assembly Modification of an Anthracene-Edged M(II)4L6 Tetrahedron. AB - Fe(II)4L6 tetrahedral cage 1 undergoes post-assembly modification (PAM) via a Diels-Alder cycloaddition of the anthracene panels of the cage with tetracyanoethylene (TCNE). The modified cage 2 possesses an enclosed cavity suitable for encapsulation of the fullerene C60, whereas original cage 1 forms a unique covalent adduct through a Diels-Alder cycloaddition of three of its anthracene ligands with C60. This adduct undergoes further PAM via reaction of the remaining three ligands with TCNE, enabling the isolation of two distinct products depending on the order of addition of C60 and TCNE. Modified cage 2 was also able to bind an anionic guest, [Co(C2B9H11)2](-), which was not encapsulated by the original cage, demonstrating the potential of PAM for tuning the binding properties of supramolecular hosts. PMID- 27500975 TI - Fabrication of Fully Solution Processed Inorganic Nanocrystal Photovoltaic Devices. AB - We demonstrate a method for the preparation of fully solution processed inorganic solar cells from a spin and spray coating deposition of nanocrystal inks. For the photoactive absorber layer, colloidal CdTe and CdSe nanocrystals (3-5 nm) are synthesized using an inert hot injection technique and cleaned with precipitations to remove excess starting reagents. Similarly, gold nanocrystals (3-5 nm) are synthesized under ambient conditions and dissolved in organic solvents. In addition, precursor solutions for transparent conductive indium tin oxide (ITO) films are prepared from solutions of indium and tin salts paired with a reactive oxidizer. Layer-by-layer, these solutions are deposited onto a glass substrate following annealing (200-400 degrees C) to build the nanocrystal solar cell (glass/ITO/CdSe/CdTe/Au). Pre-annealing ligand exchange is required for CdSe and CdTe nanocrystals where films are dipped in NH4Cl:methanol to replace long chain native ligands with small inorganic Cl(-) anions. NH4Cl(s) was found to act as a catalyst for the sintering reaction (as a non-toxic alternative to the conventional CdCl2(s) treatment) leading to grain growth (136+/-39 nm) during heating. The thickness and roughness of the prepared films are characterized with SEM and optical profilometry. FTIR is used to determine the degree of ligand exchange prior to sintering, and XRD is used to verify the crystallinity and phase of each material. UV/Vis spectra show high visible light transmission through the ITO layer and a red shift in the absorbance of the cadmium chalcogenide nanocrystals after thermal annealing. Current-voltage curves of completed devices are measured under simulated one sun illumination. Small differences in deposition techniques and reagents employed during ligand exchange have been shown to have a profound influence on the device properties. Here, we examine the effects of chemical (sintering and ligand exchange agents) and physical treatments (solution concentration, spray-pressure, annealing time and annealing temperature) on photovoltaic device performance. PMID- 27500976 TI - Cross-Correlated Relaxation of Dipolar Coupling and Chemical-Shift Anisotropy in Magic-Angle Spinning R1rho NMR Measurements: Application to Protein Backbone Dynamics Measurements. AB - Transverse relaxation rate measurements in magic-angle spinning solid-state nuclear magnetic resonance provide information about molecular motions occurring on nanosecond-to-millisecond (ns-ms) time scales. The measurement of heteronuclear ((13)C, (15)N) relaxation rate constants in the presence of a spin lock radiofrequency field (R1rho relaxation) provides access to such motions, and an increasing number of studies involving R1rho relaxation in proteins have been reported. However, two factors that influence the observed relaxation rate constants have so far been neglected, namely, (1) the role of CSA/dipolar cross correlated relaxation (CCR) and (2) the impact of fast proton spin flips (i.e., proton spin diffusion and relaxation). We show that CSA/D CCR in R1rho experiments is measurable and that the CCR rate constant depends on ns-ms motions; it can thus provide insight into dynamics. We find that proton spin diffusion attenuates this CCR due to its decoupling effect on the doublet components. For measurements of dynamics, the use of R1rho rate constants has practical advantages over the use of CCR rates, and this article reveals factors that have so far been disregarded and which are important for accurate measurements and interpretation. PMID- 27500977 TI - Population structure from NOS genes correlates with geographical differences in coronary incidence across Europe. AB - OBJECTIVES: The population analysis of cardiovascular risk and non-risk genetic variation can help to identify adaptive or random demographic processes that shaped coronary incidence variation across geography. MATERIAL AND METHODS: In this study, 114 single nucleotide polymorphisms and 17 tandem repeat polymorphisms from Nitric Oxide Synthases (NOS) regions were analyzed in 1686 individuals from 35 populations from Europe, North Africa, and the Middle East. NOS genes encode for key enzymes on nitric oxide availability, which is involved in several cardiovascular processes. These genetic variations were used to test for selection and to infer the population structure of NOS regions. Moreover, we tested whether the variation in the incidence of coronary events and in the levels of classical risk factors in 11 of these European populations could be explained by the population structure estimates. RESULTS: Our results supported, first, the absence of clear signs of selection for NOS genetic variants associated with cardiovascular diseases, and second, the presence of a continuous genetic pattern of variation across European and North African populations without a Mediterranean barrier for gene flow. Finally, population structure estimates from NOS regions are closely correlated with coronary event rates and classical risk parameters (explaining 39-98%) among European populations. CONCLUSION: Our results reinforce the hypothesis that genetic bases of cardiovascular diseases and associated complex phenotypes could be geographically shaped by random demographic processes. PMID- 27500978 TI - Midazolam-ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits. AB - OBJECTIVE: Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic gamma-aminobutyric acid A (GABAA ) receptors and externalization of N-methyl-d-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences. METHODS: A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits. RESULTS: Midazolam-ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate-midazolam or valproate-ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam-ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis, and MWM deficits. SIGNIFICANCE: This study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early midazolam-ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE. PMID- 27500979 TI - Catalyst-Free Difunctionalization of Activated Alkenes in Water: Efficient Synthesis of beta-Keto Sulfides and Sulfones. AB - Difunctionalization of activated alkenes, a powerful strategy in chemical synthesis, has been accomplished for direct synthesis of a series of beta-keto sulfides and beta-keto sulfones. The transformation, mediated by O2 , proceeds smoothly in water and without any catalyst. Prominent advantages of this method include mild reaction conditions, purification simplicity, and gram-scale synthesis, underlining the practical utility of this methodology. PMID- 27500980 TI - Porous Coordination Polymer Based on Bipyridinium Carboxylate Linkers with High and Reversible Ammonia Uptake. AB - The zwitterionic bipyridinium carboxylate ligand 1,1'-bis(4-carboxyphenyl)-4,4' bipyridinium (pc1) in the presence of cadmium chloride affords novel porous coordination polymers (PCPs): [Cd4(pc1)3Cl6].CdCl4.guest (1) crystallizing in the P31c space group. In the structure, [Cd4Cl6(CO2)6] building units are linked together by six pc1 ligands, leading to a 3D high-symmetrical network exhibiting hexagonal channels along the c axis. The walls of this PCP consist of cationic electron-acceptor bipyridinium units. The PCP 1 reversibly adsorbs H2O and CH3OH up to about 0.1 g/g at saturation showing the adsorption isotherms characteristic of a moderately hydrophilic sorbent. Adsorption of ammonia (NH3) follows a different pattern, reaching an exceptional uptake of 0.39 g/g (22.3 mmol/g) after the first adsorption cycle. Although the crystalline structure of 1 collapses after the first adsorption, the solid can be regenerated and maintains the capacity of 0.29 g/g (17 mmol/g) in the following cycles. We found that the high NH3 uptake is due to a combination of pore filling taking place below 150 h.Pa and chemisorption occurring at higher pressures. The latter process was shown to involve two phenomena: (i) coordination of NH3 molecules to Cd(2+) cations as follows from (113)Cd NMR and (ii) strong donor-acceptor interactions between NH3 molecules and pc1 ligands. PMID- 27500981 TI - Mitigation of Ventilator-induced Diaphragm Atrophy by Transvenous Phrenic Nerve Stimulation. AB - RATIONALE: Ventilator-induced diaphragm dysfunction is a significant contributor to weaning difficulty in ventilated critically ill patients. It has been hypothesized that electrically pacing the diaphragm during mechanical ventilation could reduce diaphragm dysfunction. OBJECTIVES: We tested a novel, central line catheter-based, transvenous phrenic nerve pacing therapy for protecting the diaphragm in sedated and ventilated pigs. METHODS: Eighteen Yorkshire pigs were studied. Six pigs were sedated and mechanically ventilated for 2.5 days with pacing on alternate breaths at intensities that reduced the ventilator pressure time product by 20-30%. Six matched subjects were similarly sedated and ventilated but were not paced. Six pigs served as never-ventilated, never-paced control animals. MEASUREMENTS AND MAIN RESULTS: Cumulative duration of pacing therapy ranged from 19.7 to 35.7 hours. Diaphragm thickness assessed by ultrasound and normalized to initial value showed a significant decline in ventilated-not paced but not in ventilated-paced subjects (0.84 [interquartile range (IQR), 0.78-0.89] vs. 1.10 [IQR, 1.02-1.24]; P = 0.001). Compared with control animals (24.6 MUm2/kg; IQR, 21.6-26.0), median myofiber cross-sectional areas normalized to weight and sarcomere length were significantly smaller in the ventilated-not paced (17.9 MUm2/kg; IQR, 15.3-23.7; P = 0.005) but not in the ventilated-paced group (24.9 MUm2/kg; IQR, 16.6-27.3; P = 0.351). After 60 hours of mechanical ventilation all six ventilated-paced subjects tolerated 8 minutes of intense phrenic stimulation, whereas three of six ventilated-not paced subjects did not (P = 0.055). There was a nonsignificant decrease in diaphragm tetanic force production over the experiment in the ventilated-paced and ventilated-not paced groups. CONCLUSIONS: These results suggest that early transvenous phrenic nerve pacing may mitigate ventilator-induced diaphragm dysfunction. PMID- 27500982 TI - Morphogenesis of the middle ear ossicles and spatial relationships with the external and inner ears during the embryonic period. AB - We describe the three-dimensional morphogenesis of the middle ear ossicles (MEOs) according to Carnegie stage (CS) in human embryos. Seventeen samples including 33 MEOs from CS18 to 23 were selected from the Kyoto Collection. The primordia of the MEOs and related structures were histologically observed and three dimensionally reconstructed from digital images. The timing of chondrogenesis was variable among structures. The stapes was recognizable as a vague condensation of the mesenchymal cells in all samples from CS18, whereas the malleus and incus were recognizable at CS19. Chondrogenesis of all MEOs was evident in all samples after CS21. The chondrocranium was recognizable in all samples by CS18, and the perichondrium border of the auricular cartilage and otic capsule was distinct in all samples at CS23. At CS19, the MEOs were positioned in the anterior to posterior direction, following the order malleus, incus, stapes, which adjusted gradually during development. The MEOs connected in all samples after CS22. The stapes was located close to the vestibular part of the inner ear, although the basal part was not differentiated into the "footplate" form, even at CS23. The handles of the malleus were close to the tubotympanic recess at CS23, but were distant from the external auditory meatus. Determining the timeline of the formation of MEOs and connection of the external and inner ears can be informative for understanding hearing loss caused by failure of this connection. These data may provide a useful standard for morphogenesis, and will contribute to distinguishing between normal and abnormal MEO development. Anat Rec, 299:1325 1337, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27500984 TI - The Editor recommends this issue's article to the reader: Adhesive systems for restoring primary teeth: a systematic review and meta-analysis of in vitro studies. PMID- 27500983 TI - Factor affecting happiness among nursing students in South Korea. AB - WHAT IS KNOWN ON THE SUBJECT?: Despite the increased interest in nursing students' happiness in South Korea, few studies have attempted to identify factors influencing their happiness. Therefore, nursing educators should consistently investigate the factors influencing happiness and develop strategies to improve happiness among Korean nursing students. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This study confirmed that there were positive correlations between grateful disposition, social support and happiness. In addition, grateful disposition and support from intimate people were identified as predictors of happiness in Korean nursing students. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Development of intervention programmes to help nursing students increase grateful disposition and support from intimate people may be helpful for improving happiness. These programmes can include activity, such as writing a gratitude journal, and extracurricular programmes, such as mentoring programmes between seniors and juniors and/or professor and student. ABSTRACT: Introduction Happiness is very important in the training and development of nursing students as future nurses. However, nursing students experience a high level of stress and low level of happiness in South Korea. Aim This study aimed to investigate factors that affect happiness among nursing students in South Korea. Method Data were collected from a total of 241 nursing enrolled in two 4-year baccalaureate nursing programmes in South Korea, using a self-administrated questionnaire. To identify predictors of happiness, stepwise regression analysis was conducted. Results The results indicated that grateful disposition and support from intimate people significantly predict happiness among Korean nursing students. These two factors accounted for 38.0% of the variance in happiness. Discussion This study indicated grateful disposition and support from intimate people as factors promoting happiness in nursing students. The findings highlight grateful disposition and support from intimate people as important factors when developing effective interventions that foster nursing students' happiness. PMID- 27500985 TI - Diagnostic accuracy of intracranial translucency in detecting spina bifida: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the diagnostic accuracy of intracranial translucency (IT) in the detection of spina bifida (SB) in the first trimester of pregnancy. METHODS: We included study assessing the accuracy of sonographic measurements of IT in a mid-sagittal view of the fetal face in prediction of SB in the first trimester of pregnancy. The primary outcome was the accuracy of IT in prediction of spina bifida. Summary estimates of sensitivity, specificity, positive and negative likelihood ratios (LR), and diagnostic odds ratio for the overall predictive accuracy of IT were computed. RESULTS: Nine studies (21 070 fetuses) were included in the analysis. IT was successfully assessed in the majority of fetuses 97.8% (95% CI 97.6-98.0). The diagnostic performance of IT in detecting SB was as follows: sensitivity: 53.5% (95% CI 42.4-64.3), specificity: 99.7% (95% CI 99.6-99.8), positive LR: 62.1 (95% CI 12.2-317), negative LR:0.55 (95% CI 0.45 0.68), and diagnostic odds ratio: 223 (95% CI 25-2039). CONCLUSIONS: Intracranial translucency had low diagnostic accuracy in prediction of open spina bifida, thus questioning its role as a screening marker for open SB in an unselected population. When looking at the individual study data, it appears that IT assessment for open SB prediction can be affected by a high rate of false positive results potentially leading to unnecessary parental anxiety. (c) 2016 John Wiley & Sons, Ltd. PMID- 27500986 TI - Normative reference values for the 20 m shuttle-run test in a population-based sample of school-aged youth in Bogota, Colombia: the FUPRECOL study. AB - OBJECTIVES: Our aim was to determine the normative reference values of cardiorespiratory fitness (CRF) and to establish the proportion of subjects with low CRF suggestive of future cardio-metabolic risk. METHODS: A total of 7244 children and adolescents attending public schools in Bogota, Colombia (55.7% girls; age range of 9-17.9 years) participated in this study. We expressed CRF performance as the nearest stage (minute) completed and the estimated peak oxygen consumption (VO2peak ). Smoothed percentile curves were calculated. In addition, we present the prevalence of low CRF after applying a correction factor to account for the impact of Bogota's altitude (2625 m over sea level) on CRF assessment, and we calculated the number of participants who fell below health related FITNESSGRAM cut-points for low CRF. RESULTS: Shuttles and VO2peak were higher in boys than in girls in all age groups. In boys, there were higher levels of performance with increasing age, with most gains between the ages of 13 and 17. The proportion of subjects with a low CRF, suggestive of future cardio metabolic risk (health risk FITNESSGRAM category) was 31.5% (28.2% for boys and 34.1% for girls; X2 P = .001). After applying a 1.11 altitude correction factor, the overall prevalence of low CRF was 11.5% (9.6% for boys and 13.1% for girls; X2 P = .001). CONCLUSIONS: Our results provide sex- and age-specific normative reference standards for the 20 m shuttle-run test and estimated VO2peak values in a large, population-based sample of schoolchildren from a large Latin-American city at high altitude. PMID- 27500987 TI - Extensive Necrotic Purpura in Levamisole-Adulterated Cocaine Abuse - A Case Report. AB - Levamisole, which is used as an adulterated compound of cocaine, is currently being seen year after year in cocaine intoxication. For a few cases in the last decade, necrotic purpura and neutropenia after levamisole/cocaine intoxication have been described in the medical community. Herein, we present an original case of levamisole intoxication of a 40-year-old woman who smoked heroin and cocaine few during a month. She rapidly presented an extensive necrotic purpura of the nose, cheeks and extremities (lower and upper), and immunologic reactions (positive anti-MPO and anti-HNE). Levamisole was detected on hairs with ultra high performance liquid chromatography and tandem mass spectrometry. The case reports also a probable cocaine supplier deceit, which bring pure drug for hospital investigation after the intoxication of his client. The intoxicated woman had survived with several skin and chronic pain complications. That case recalls the knowledge about levamisole with a short review of the forensic literature. PMID- 27500988 TI - Detection of RNA-binding Proteins by In Vitro RNA Pull-down in Adipocyte Culture. AB - RNA-binding proteins (RBPs) are emerging as a regulatory layer in the development and function of adipose. RBPs play a key role in the gene expression regulation at posttranscriptional levels by affecting the stability and translational efficiency of target mRNAs. RNA pull-down technique has been widely used to study RNA-protein interaction, which is necessary to elucidate the mechanism underlying RBPs' as well as long non-coding RNAs' (lncRNAs) function. However, the high lipid abundance in adipocytes poses a technical challenge in conducting this experiment. Here a detailed RNA pull-down protocol is optimized for primary adipocyte culture. An RNA fragment from androgen receptor's (AR) 3' untranslated region (3'UTR) containing an adenylate-uridylate-rich elementwas used as an example to demonstrate how to retrieve its RBP partner, HuR protein, from adipocyte lystate. The method described here can be applied to detect the interactions between RBPs and noncoding RNAs, as well as between RBPs and coding RNAs. PMID- 27500990 TI - Influence of Age and Pathology on Achilles Tendon Properties During a Single-leg Jump. AB - Prevalence of Achilles tendinopathy increases with age leading to a weaker tendon with predisposition to rupture. Conclusive evidence of the influence of age and pathology on Achilles tendon (AT) properties remains limited, as previous studies are based on standardized isometric conditions. The study investigates the influence of age and pathology on AT properties during single-leg vertical jump (SLVJ). 10 children (C), 10 asymptomatic adults (A), and 10 tendinopathic patients (T) were included. AT elongation [mm] from rest to maximal displacement during a SLVJ on a force-plate was sonographically assessed. AT compliance [mm/N]) and strain [%] was calculated by dividing elongation by peak ground reaction force [N] and length, respectively. One-way ANOVA followed by Bonferroni post-hoc correction (alpha=0.05) were used to compare C with A and A with T. AT elongation (p=0.004), compliance (p=0.001), and strain were found to be statistically significant higher in C (27+/-3 mm, 0.026+/-0.006 [mm/N], 13+/-2%) compared to A (21+/-4 mm, 0.017+/-0.005 [mm/N], 10+/-2%). No statistically significant differences (p>=0.05) was found between A and T (25+/-5 mm, 0.019+/ 0.004 [mm/N], 12+/-3%). During SLVJ, tendon responded differently in regards to age and pathology with children having the most compliant AT. Higher compliance found in healthy tendons might be considered as a protective factor against load related injuries. PMID- 27500989 TI - Regorafenib induced severe toxic hepatitis: characterization and discussion. AB - BACKGROUND: Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. MATERIAL AND METHODS: Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity. RESULTS: Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms, and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None of the patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 [rs3832043]) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy. CONCLUSION: This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of close liver tests monitoring during regorafenib treatment. PMID- 27500991 TI - A Model of First-responder Coping: An Approach/Avoidance Bifurcation. AB - The work of first responders is fraught with numerous stressors, ranging from potentially traumatic critical incidents to institutional strains. The severity and pervasiveness of these difficulties prompt a necessary consideration of the coping methods employed by first responders. The present study developed an empirical model of first-responder coping strategies, based upon a nationally representative survey sample of 6240 first responders. Participants were drawn from Swedish first responders in the following occupations: coast guard, customs control, military, emergency medical services, fire department and police services. In the final model, exposure to stress related to well-being through several indirect paths that in sum accounted for the original direct relationship between these constructs. These several indirect paths were classified theoretically as either approach or avoidance coping behaviours or subsequent health outcomes. In general, approach coping behaviours were related to better well-being; and avoidance was related to a decrease in the outcome. The size of the present sample, as well as the diverse nature of the included first responders, suggests that the resulting model may offer a unique insight into potentially adaptive pathways for first-responder coping. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27500992 TI - Illusory conjunctions in visual short-term memory: Individual differences in corpus callosum connectivity and splitting attention between the two hemifields. AB - Overloading the capacity of visual attention can result in mistakenly combining the various features of an object, that is, illusory conjunctions. We hypothesize that if the two hemispheres separately process visual information by splitting attention, connectivity of corpus callosum-a brain structure integrating the two hemispheres-would predict the degree of illusory conjunctions. In the current study, we assessed two types of illusory conjunctions using a memory-scanning paradigm; the features were either presented across the two opposite hemifields or within the same hemifield. Four objects, each with two visual features, were briefly presented together followed by a probe-recognition and a confidence rating for the recognition accuracy. MRI scans were also obtained. Results indicated that successful recollection during probe recognition was better for across hemifields conjunctions compared to within hemifield conjunctions, lending support to the bilateral advantage of the two hemispheres in visual short-term memory. Age-related differences regarding the underlying mechanisms of the bilateral advantage indicated greater reliance on recollection-based processing in young and on familiarity-based processing in old. Moreover, the integrity of the posterior corpus callosum was more predictive of opposite hemifield illusory conjunctions compared to within hemifield illusory conjunctions, even after controlling for age. That is, individuals with lesser posterior corpus callosum connectivity had better recognition for objects when their features were recombined from the opposite hemifields than from the same hemifield. This study is the first to investigate the role of the corpus callosum in splitting attention between versus within hemifields. PMID- 27500993 TI - Rupatadine: global safety evaluation in allergic rhinitis and urticaria. AB - INTRODUCTION: Rupatadine is a second-generation H1-antihistamine with dual affinity for histamine H1 and PAF receptors. Rupatadine is indicated for the treatment of allergic rhinitis and urticaria. AREAS COVERED: A Medline search was conducted to identify preclinical and clinical studies of rupatadine. This was supplemented with additional articles obtained from online sources. The focus of this review is on the safety profile of rupatadine. EXPERT OPINION: The review of these data indicates that rupatadine is highly selective for histamine H1 receptors, exhibits additional PAF antagonism in in vitro and in vivo studies, does not cross the blood-brain barrier, and has similar adverse events comparable with other second-generation antihistamines. Rupatadine is a safe and well tolerated drug in patients over 2 years old, with no central nervous system or cardiovascular effects and it can be taken with or without foods. PMID- 27500995 TI - New Onset of Chronic Diseases and Changes in Lifestyle Risk Factors Among Gulf War Veterans: A Longitudinal Comparison of High and Low Symptom Reporters. AB - OBJECTIVE: The aim of this study was to compare new chronic diseases onset and longitudinal changes in lifestyle risk factors between Gulf War veterans with different symptom reporting. METHODS: Data were collected from Gulf War veterans over two periods, and participants were grouped according to baseline symptom reporting. Logistic, nominal, and ordinal regressions were used for between-group comparisons. RESULTS: The veterans comprised low, moderate, and high symptom reporters. New onset of sleep apnea [odds ratio (OR) = 9.49; 95% confidence interval (CI) = 3.48 to 25.86], musculoskeletal (OR = 8.70; 95% CI = 4.17 to 18.17), psychological (OR = 5.36; 95% CI = 2.46 to 11.70), and cardiovascular (OR = 3.86; 95% CI = 1.33 to 11.23) conditions was elevated in high versus low symptom reporters. Although odds of obesity and alcohol use increased over time and smoking halved, the changes were similar across groups. CONCLUSIONS: These findings show increasing obesity and alcohol use, and indicate that high symptomatology among veterans may predict future disease onset. PMID- 27500994 TI - Shoulder arthritis secondary to rotator cuff tear: A reproducible murine model and histopathologic scoring system. AB - Untreated rotator cuff tears can progress to a distinct form of shoulder arthritis, and the mechanism of this progression is poorly understood. Biomechanical, molecular and genetic factors may be at play, and a reliable animal model is needed to enable further research. The purpose of this study was to create a reproducible model of posttraumatic shoulder arthritis in the mouse, and to develop a scoring system for this model to enable future research on interventions, the role of various gene products, and the development of therapies to alter the natural course of the disease. Forty-five mice underwent operative ligation of the rotator cuff tendons and were followed for 45 weeks following surgery, with free cage activity post-operatively. Mice were sacrificed at various intervals from 2 to 45 weeks post-injury and histopathologic scoring was developed and tested by blinded reviewers using both quantitative computational analysis of coronal sections of the shoulder joint and semi quantitative grading. The scoring system revealed a progressive, time-dependent set of tissue changes in the shoulder joint with features similar to human cuff tear arthropathy including acetabularization of the acromion and femoralization of the humeral head. This model establishes that osteoarthritis of the shoulder is distinct from osteoarthritis of the knee or hip, with different stages of degeneration and unique histopathologic features. Using the novel grading procedure and quantitative assessments presented here, future research using this model will enable investigators to test established and novel therapies and evaluate the role of inflammatory factors and gene products in shoulder arthritis. This study provides a reproducible mouse model of shoulder arthritis following isolated injury to the rotator cuff which elucidates characteristics of cuff tear arthropathy and provides a scoring system and venue for future research. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:506-514, 2017. PMID- 27500996 TI - Socioeconomic Differences in Cause-Specific Disability Retirement in Finland, 1988 to 2009. AB - OBJECTIVE: The major aim was to study socioeconomic inequalities in disability retirement due to different diagnostic causes over the period 1988 to 2009. METHODS: The register data are 11% sample of people aged 30 to 64 years and living in Finland in 1987 to 2007. Incidence rates were calculated for disability retirement due to different diseases during the follow-up period 1988 to 2009. RESULTS: The incidence of disability retirement decreased in each socioeconomic class from the early 1990s onward. Decreasing absolute socioeconomic inequalities in disability retirement due to any diagnostic cause and musculoskeletal diseases were seen in the period 1988 to 2009. Musculoskeletal diseases were the largest contributor to the overall socioeconomic inequalities in disability retirement throughout the whole study period. CONCLUSIONS: The contribution of musculoskeletal diseases to the overall socioeconomic inequalities has been large during the whole study period. PMID- 27500999 TI - Recognition, Compensation, and Prevention of Karoshi, or Death due to Overwork. PMID- 27501000 TI - Musculoskeletal Ultrasound Use Among Occupational Medicine Practitioners at the American Occupational Health Conference. PMID- 27501001 TI - Working Hours and Incident Cardiovascular Disease With Special Reference to Sleep Parameters. PMID- 27501002 TI - Response to Letter to the Editor. PMID- 27501003 TI - A Prospective Multicenter Randomized Controlled Study on Interleukin-6 Removal and Induction by a new Hemodialyzer With Improved Biocompatibility in Hemodialysis Patients: A Pilot Study. AB - We compared interleukin-6 (IL-6) removal and induction between conventional polysulfone (Con) and TORAYLIGHT NV (NV) dialyzers in hemodialysis patients. Twenty patients on Con with high IL-6 concentrations (2.7-8.5 pg/mL) were randomized to Con or NV group. Dialyzer performance was determined in NV group while patients were on Con and after being switched onto NV. Erythropoiesis stimulating agent (ESA) response index (ERI) was assessed every 4 months for one year. IL-6 clearance was comparable between Con and NV. IL-6 removal rates were comparable for the first 1 h, but were higher with NV for the entire session (P = 0.03). Before-to-during-dialysis IL-6 concentration ratios were lower with NV on the venous side after the session (P = 0.03). During the one-year study, hemoglobin was lower in Con group than in NV group at month 8 (P = 0.046). ERI decreased in NV and increased in Con group, with a significant difference between the groups (P = 0.002). NV and Con are comparable in removing IL-6 and both induce IL-6. However, the data suggest that NV induces less IL-6, which may reduce the risk of ESA hyporesponsiveness. PMID- 27501004 TI - Spatial variation in climate mediates gene flow across an island archipelago. AB - High levels of gene flow among partially isolated populations can overwhelm selection and limit local adaptation. This process, known as "gene swamping," can homogenize genetic diversity among populations and reduce the capacity of a species to withstand rapid environmental change. We studied brown anole lizards (Anolis sagrei) distributed across seven islands in The Bahamas. We used microsatellite markers to estimate gene flow among islands and then examined the correlation between thermal performance and island temperature. The thermal optimum for sprint performance was correlated with both mean and maximum island temperature, whereas performance breadth was not correlated with any measure of temperature variation. Gene flow between islands decreased as the difference between mean island temperatures increased, even when those islands were adjacent to one another. These data suggest that phenotypic variation is the result of either (1) local genetic adaptation with selection against immigrants maintaining variation in the thermal optimum, (2) irreversible forms of adaptive plasticity such that immigrants have reduced fitness, or (3) an interaction between fixed genetic differences and plasticity. In general, the patterns of gene flow we observed suggest that local thermal environments represent important ecological filters that can mediate gene flow on relatively fine geographic scales. PMID- 27501005 TI - Fast and Simplified Method for High Through-put Isolation of miRNA from Highly Purified High Density Lipoprotein. AB - Small non-coding RNAs (miRNAs) have been implicated in a variety of human diseases including metabolic syndromes. They may be utilized as biomarkers for diagnosis and prognosis or may serve as targets for drug development, respectively. Recently it has been shown that miRNAs are carried in lipoproteins, particularly high density lipoproteins (HDL) and are delivered to recipient cells for uptake. This raises the possibility that miRNAs play a critical and pivotal role in cellular and organ function via regulation of gene expression as well as messenger for cell-cell communications and crosstalk between organs. Current methods for miRNA isolation from purified HDL are impractical when utilizing small samples on a large scale. This is largely due to the time consuming and laborious methods used for lipoprotein isolation. We have developed a simplified approach to rapidly isolate purified HDL suitable for miRNA analysis from plasma samples. This method should facilitate investigations into the role of miRNAs in health and disease and in particular provide new insights into the variety of biological functions, outside of the reverse cholesterol transport, that have been ascribed to HDL. Also, the miRNA species which are present in HDL can provide valuable information of clinical biomarkers for diagnosis of various diseases. PMID- 27501006 TI - Dual benefits of renin-angiotensin-aldosterone blockade: lowering the blood pressure and de-stiffening the arteries. PMID- 27501007 TI - Antiviral therapy improves overall survival in hepatitis C virus-infected patients who develop diffuse large B-cell lymphoma. AB - Chronic Hepatitis C virus (HCV) infection is associated with increased incidence of non-Hodgkin lymphoma. Several studies have demonstrated regression of indolent lymphoma with antiviral therapy (AVT) alone. However, the role of AVT in HCV infected patients with diffuse large B-cell lymphoma (DLBCL) is unclear. We therefore analyzed AVT's impact on oncologic outcomes of HCV-infected patients (cases) who developed DLBCL. Cases seen at our institution (June 2004-May 2014) were matched with uninfected counterparts (controls) and then divided according to prior AVT consisting of interferon-based regimens. We studied 304 patients (76 cases and 228 controls). More cases than controls had extranodal (79% vs. 72%; p = 0.07) and upper gastrointestinal (GI; 42% vs. 24%; p = 0.004) involvement. Cases never given AVT had DLBCL more refractory to first-line chemotherapy than that in the controls (33% vs. 17%; p = 0.05) and exhibited a trend toward more progressive lymphoma at last examination compared to controls (50% vs. 32%; p = 0.09) or cases given AVT (50% vs. 27%; p = 0.06). Cases never given AVT had worse 5-year overall survival (OS) rates than did the controls (HR, 2.3 [95% CI, 1.01 5.3]; p = 0.04). Furthermore, AVT improved 5-year OS rates among cases in both univariate (median [Interquartile range]: 39 [26-56] vs. 16 [6-41] months, p = 0.02) and multivariate analyses (HR = 0.21 [95% CI, 0.06-0.69]; p = 0.01). This study highlights the negative impact of chronic HCV on survival of DLBCL patients and shows that treatment of HCV infection is associated with a better cancer response to chemotherapy and improves 5-year OS. PMID- 27501008 TI - To stop or continue aspirin before aortocoronary bypass operations-do we have enough evidence to adequately guide us? PMID- 27501009 TI - Commentary: Alexithymia, not autism, is associated with impaired interoception. PMID- 27501010 TI - Low-dose hyper-radiosensitivity in human hepatocellular HepG2 cells is associated with Cdc25C-mediated G2/M cell cycle checkpoint control. AB - PURPOSE: Although the significance of cell cycle checkpoints in overcoming low dose hyper-radiosensitivity (HRS) has been proposed, the underlying mechanism of HRS in human hepatocellular cells remains unclear. Therefore, the aim of this study was to characterize HRS inhuman hepatocellular HepG2 cells and to explore the molecular mechanism(s) mediating this response. MATERIALS AND METHODS: HepG2 cells were exposed to various single doses of gamma radiation (from 0 Gy to 4 Gy), and then were assayed at subsequent time-points. Survival curves were then generated using a linear-quadratic (LQ) equation and a modified induced repair model (MIRM). The percentage of cells in the G1, G2/M, and S phases of the cell cycle were also examined using propidium iodide (PI) staining and flow cytometry. Levels of total cell division cyclin 25C (Cdc25C) and phosphorylated Cdc25C were examined by Western blotting. RESULTS: Low-dose gamma radiation (<0.3 Gy) induced HRS in HepG2 cells, while doses of 0.3, 0.5, and 2.0 Gy gamma radiation significantly arrested HepG2 cells in the G2/M phase. While total Cdc25C levels remained unchanged after irradiation, levels of phosphorylated Cdc25C markedly increased 6, 16, and 24 h after treatment with 0.5 or 2.0 Gy radiation, and they peaked after 16 h. The latter observation is consistent with the G2/M arrest that was detected following irradiation. CONCLUSIONS: These findings indicate that low dose HRS in HepG2 cells may be associated with Cdc25C-mediated G2/M cell cycle checkpoint control. PMID- 27501011 TI - The Cross-Cultural Dementia Screening (CCD): A new neuropsychological screening instrument for dementia in elderly immigrants. AB - OBJECTIVE: Currently, approximately 3.9% of the European population are non-EU citizens, and a large part of these people are from "non-Western" societies, such as Turkey and Morocco. For various reasons, the incidence of dementia in this group is expected to increase. However, cognitive testing is challenging due to language barriers and low education and/or illiteracy. The newly developed Cross Cultural Dementia Screening (CCD) can be administered without an interpreter. It contains three subtests that assess memory, mental speed, and executive function. We hypothesized the CCD to be a culture-fair test that could discriminate between demented patients and cognitively healthy controls. METHOD: To test this hypothesis, 54 patients who had probable dementia were recruited via memory clinics. Controls (N = 1625) were recruited via their general practitioners. All patients and controls were aged 55 years and older and of six different self defined ethnicities (Dutch, Turkish, Moroccan-Arabic, Moroccan-Berber, Surinamese Creole, and Surinamese-Hindustani). Exclusion criteria included current or previous conditions that affect cognitive functioning. RESULTS: There were performance differences between the ethnic groups, but these disappeared after correcting for age and education differences between the groups, which supports our central hypothesis that the CCD is a culture-fair test. Receiver-operating characteristic (ROC) and logistic regression analyses showed that the CCD has high predictive validity for dementia (sensitivity: 85%; specificity: 89%). DISCUSSION: The CCD is a sensitive and culture-fair neuropsychological instrument for dementia screening in low-educated immigrant populations. PMID- 27501012 TI - Nanoindentation and finite element modelling of chitosan-alginate multilayer coated hydrogels. AB - Composite soft materials are used as compounds for determining the effects of mechanical cues on cell behavior and cell encapsulation and for controlling drug release. The appropriate composite soft materials are conventionally prepared by selective deposition of polymers at the surface of an ionic hydrogel. In the present study we address the impact of a mechanically stratified two-layer structure of these materials on their overall mechanical characterization by applying a combination of nanoindentation, confocal microscopy and finite element modelling. We prepare covalent cross-linked hydrogels based on acrylamide (AAM) and including an anionic group, and impregnate them using a multilayer deposition strategy of alternating exposure to cationic chitosan and anionic alginate. The thickness of the chitosan-alginate layer on the hydrogels was determined to be 0.4 +/- 0.05 MUm for 4 bilayers, and 0.7 +/- 0.1 MUm for the 8 bilayer deposition procedure employing a fluorescently labelled chitosan and confocal microscopy. The force-indentation data for the AAM gels were highly reproducible, whereas 77% and 50% of the force-indentation data were reproducible following the 4 and 8 bilayer deposition. The main trends in the reproducible force-distance data were found to yield an apparent increased Young's modulus after the deposition. Finite element modelling showed that adaption of a homogeneous Young's modulus for the specimens with deposited layers yields approximately three times too low stiffness compared to the estimate of the mechanical properties of the outer part in the two-layered mechanical model. The thickness of the multilayer region determined by confocal microscopy was used in the model. This study shows that the mechanical layered property needs to be included in the interpretation of the nanoindentation data when there is a significant mechanical contrast. PMID- 27501014 TI - Internal Morphology-Controllable Self-Assembly in Poly(Ionic Liquid) Nanoparticles. AB - Precise control of the interior and outer shapes of polymer nanoparticles has found broad interest in nanosciences, for example, in fundamental studies of their physical properties, colloidal behavior, and corresponding applications. Realizing such control below the 50 nm scale (i.e., a size scale close to individual polymer chains) requires accurate manipulation of polymerization techniques and a judicious choice of the chemical structure in monomers and/or polymers. Here, we constructed a series of well-defined sub-50 nm homopolymer nanoparticles with controllable shape and highly ordered, complex internal structures with sub-5 nm domain spacings, starting from 1-vinyl-1,2,4-triazolium type ionic liquids in a one-pot dispersion polymerization. With cryogenic electron microscopy and tomography, a morphological evolution of particle shape and interior at this extremely small size end, unusual for polymer colloids, was identified and investigated in detail. PMID- 27501013 TI - A candidate transacting modulator of fetal hemoglobin gene expression in the Arab Indian haplotype of sickle cell anemia. AB - Fetal hemoglobin (HbF) levels are higher in the Arab-Indian (AI) beta-globin gene haplotype of sickle cell anemia compared with African-origin haplotypes. To study genetic elements that effect HbF expression in the AI haplotype we completed whole genome sequencing in 14 Saudi AI haplotype sickle hemoglobin homozygotes seven selected for low HbF (8.2% +/- 1.3%) and seven selected for high HbF (23.5% +/- 2.6%). An intronic single nucleotide polymorphism (SNP) in ANTXR1, an anthrax toxin receptor (chromosome 2p13), was associated with HbF. These results were replicated in two independent Saudi AI haplotype cohorts of 120 and 139 patients, but not in 76 Saudi Benin haplotype, 894 African origin haplotype and 44 AI haplotype patients of Indian origin, suggesting that this association is effective only in the Saudi AI haplotype background. ANTXR1 variants explained 10% of the HbF variability compared with 8% for BCL11A. These two genes had independent, additive effects on HbF and together explained about 15% of HbF variability in Saudi AI sickle cell anemia patients. ANTXR1 was expressed at mRNA and protein levels in erythroid progenitors derived from induced pluripotent stem cells (iPSCs) and CD34+ cells. As CD34+ cells matured and their HbF decreased ANTXR1 expression increased; as iPSCs differentiated and their HbF increased, ANTXR1 expression decreased. Along with elements in cis to the HbF genes, ANTXR1 contributes to the variation in HbF in Saudi AI haplotype sickle cell anemia and is the first gene in trans to HBB that is associated with HbF only in carriers of the Saudi AI haplotype. Am. J. Hematol. 91:1118-1122, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27501015 TI - Pudendal Versus Caudal Block in Children Undergoing Hypospadias Surgery: A Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVES: Postoperative pain management after hypospadias surgery is often challenging. Caudal block is used for analgesia but has limitations. This study compares the analgesic efficiency of pudendal block with that of caudal block in pediatric patients undergoing hypospadias repair surgery. METHODS: This prospective, double-blind, randomized, controlled study enrolled 84 patients receiving pudendal block or caudal block before hypospadias surgery. In the pudendal group, the pudendal nerve was identified using a nerve stimulator, and the block consisted of 0.25% bupivacaine 0.5 mL/kg. In the caudal group, the caudal block used 0.2% bupivacaine 1 mL/kg. Our primary outcome was pain intensity within 24 hours postoperatively. The trial was registered at ClinicalTrials.gov (number: NCT02390388). RESULTS: For the primary outcome, patients in the pudendal group had lower postoperative pain intensity when compared with the caudal group (P < 0.001). Three patients in the pudendal group and all of the patients in the caudal group needed additional analgesia within 24 hours after the surgery (P < 0.001). The family satisfaction rate was significantly higher in the pudendal group (P < 0.001). CONCLUSIONS: For the pudendal group, the pain scores for the first 24 hours after the surgery were significantly lower and the duration of analgesia was longer. PMID- 27501016 TI - The Erector Spinae Plane Block: A Novel Analgesic Technique in Thoracic Neuropathic Pain. AB - Thoracic neuropathic pain is a debilitating condition that is often poorly responsive to oral and topical pharmacotherapy. The benefit of interventional nerve block procedures is unclear due to a paucity of evidence and the invasiveness of the described techniques. In this report, we describe a novel interfascial plane block, the erector spinae plane (ESP) block, and its successful application in 2 cases of severe neuropathic pain (the first resulting from metastatic disease of the ribs, and the second from malunion of multiple rib fractures). In both cases, the ESP block also produced an extensive multidermatomal sensory block. Anatomical and radiological investigation in fresh cadavers indicates that its likely site of action is at the dorsal and ventral rami of the thoracic spinal nerves. The ESP block holds promise as a simple and safe technique for thoracic analgesia in both chronic neuropathic pain as well as acute postsurgical or posttraumatic pain. PMID- 27501017 TI - Rosacea and gastrointestinal disorders: a population-based cohort study. AB - BACKGROUND: Rosacea is a common inflammatory facial skin condition. Recent genetic and epidemiological studies have suggested pathogenic links between rosacea and gastrointestinal disorders, but data are limited. OBJECTIVES: The objective was to investigate the association between rosacea and coeliac disease (CeD), Crohn disease (CD), ulcerative colitis (UC), Helicobacter pylori infection (HPI), small intestinal bacterial overgrowth (SIBO) and irritable bowel syndrome (IBS), respectively. METHODS: We performed a nationwide cohort study. A total of 49 475 patients with rosacea and 4 312 213 general population controls were identified using nationwide administrative registers. We established the prevalence of the aforementioned disorders, and used Cox regression analysis to obtain hazard ratios (HRs) of the risk of new-onset CeD, CD, UC, HPI, SIBO and IBS, respectively, in patients with rosacea. RESULTS: The prevalence of CeD, CD, UC, HPI, SIBO and IBS, respectively, was higher among patients with rosacea when compared with the control subjects. Adjusted HRs revealed significant associations between rosacea and CeD (HR 1.46, 1.11-1.93), CD (HR 1.45, 1.19 1.77), UC (HR 1.19, 1.02-1.39), and IBS (HR 1.34, 1.19-1.50), respectively, but not HPI (HR 1.04, 0.96-1.13) or SIBO (HR 0.71, 0.18-1.86). CONCLUSIONS: Rosacea is associated with certain gastrointestinal diseases, but the possible pathogenic link is unknown. Gastrointestinal complaints in patients with rosacea should warrant clinical suspicion of disease. PMID- 27501018 TI - MassARRAY determination of somatic oncogenic mutations in solid tumors: Moving forward to personalized medicine. AB - This article will review the impact of the recently developed MassARRAY technology on our understanding of cancer biology and treatment. Analysis of somatic mutations is a useful tool in selecting personalized therapy, and for predicting the outcome of many solid tumors. Here, we review the literature on the application of MassARRAY technology (Sequenom Hamburg, Germany) to determine the mutation profile of solid tumors from patients. We summarize the use of commercially available panels of mutations - such as OncoCartaTM or other combinations - and their concordance with results obtained by using other technologies, such as next generation sequencing. PMID- 27501019 TI - Bioluminescence-Based Tumor Quantification Method for Monitoring Tumor Progression and Treatment Effects in Mouse Lymphoma Models. AB - Although bioluminescence imaging (BLI) shows promise for monitoring tumor burden in animal models of cancer, these analyses remain mostly qualitative. Here we describe a method for bioluminescence imaging to obtain a semi-quantitative analysis of tumor burden and treatment response. This method is based on the calculation of a luminoscore, a value that allows comparisons of two animals from the same or different experiments. Current BLI instruments enable the calculation of this luminoscore, which relies mainly on the acquisition conditions (back and front acquisitions) and the drawing of the region of interest (manual markup around the mouse). Using two previously described mouse lymphoma models based on cell engraftment, we show that the luminoscore method can serve as a noninvasive way to verify successful tumor cell inoculation, monitor tumor burden, and evaluate the effects of in situ cancer treatment (CpG-DNA). Finally, we show that this method suits different experimental designs. We suggest that this method be used for early estimates of treatment response in preclinical small-animal studies. PMID- 27501020 TI - Quantifying Energy and Water Savings in the U.S. Residential Sector. AB - Stress on water and energy utilities, including natural resource depletion, infrastructure deterioration, and growing populations, threatens the ability to provide reliable and sustainable service. This study presents a demand-side management decision-making tool to evaluate energy and water efficiency opportunities at the residential level, including both direct and indirect consumption. The energy-water nexus accounts for indirect resource consumption, including water-for-energy and energy-for-water. We examine the relationship between water and energy in common household appliances and fixtures, comparing baseline appliances to ENERGY STAR or WaterSense appliances, using a cost abatement analysis for the average U.S. household, yielding a potential annual per household savings of 7600 kWh and 39 600 gallons, with most upgrades having negative abatement cost. We refine the national average cost abatement curves to understand regional relationships, specifically for the urban environments of Los Angeles, Chicago, and New York. Cost abatement curves display per unit cost savings related to overall direct and indirect energy and water efficiency, allowing utilities, policy makers, and homeowners to consider the relationship between energy and water when making decisions. Our research fills an important gap of the energy-water nexus in a residential unit and provides a decision making tool for policy initiatives. PMID- 27501021 TI - New definitions for septic shock-a roadmap for a better clinical outcome? PMID- 27501022 TI - Hemostatic Agents in Spine Surgery: A Critical Analysis Review. PMID- 27501023 TI - ACL Graft and Contralateral ACL Tear Risk within Ten Years Following Reconstruction: A Systematic Review. AB - BACKGROUND: Anterior cruciate ligament (ACL) graft tear and contralateral ACL injury have devastating effects on patient outcomes following ACL reconstruction. Long-term results after ACL reconstruction are being reported with greater frequency, allowing a detailed analysis of the long-term risk of failure. METHODS: A systematic review of prospective studies that recorded the risk of ACL graft rupture and contralateral ACL injury following primary ACL reconstruction was performed. All studies included intra-articular ACL reconstruction with modern techniques and patellar tendon or hamstring autograft with a minimum follow-up of ten years. RESULTS: Nine studies met the inclusion and exclusion criteria. The overall ACL graft rupture risk was 7.9% (211 ruptures in 2682 reconstructions) and ranged from 3.2% to 11.1% in the individual studies. The overall risk of ACL injury in the contralateral limb was 12.5% (335 injuries in 2682 reconstructions) and ranged from 0.6% to 22.7% in the individual studies. Among the seven homogeneous studies that were pooled, the overall risk of a contralateral ACL tear was 1.63 (95% confidence interval [CI]: 1.30 to 2.04) times that of a graft tear during the follow-up period. CONCLUSIONS: At a minimum follow-up time of ten years, the risk of contralateral ACL tear significantly exceeds the risk of ACL graft rupture. Further work is necessary to understand and potentially reduce this risk of graft and contralateral ACL tears. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 27501024 TI - Triangular Fibrocartilage Complex: An Anatomic Review. PMID- 27501025 TI - The Role of Patient Activation in Achieving Better Outcomes and Cost Effectiveness in Patient Care. PMID- 27501026 TI - Machine learning for large-scale wearable sensor data in Parkinson's disease: Concepts, promises, pitfalls, and futures. AB - For the treatment and monitoring of Parkinson's disease (PD) to be scientific, a key requirement is that measurement of disease stages and severity is quantitative, reliable, and repeatable. The last 50 years in PD research have been dominated by qualitative, subjective ratings obtained by human interpretation of the presentation of disease signs and symptoms at clinical visits. More recently, "wearable," sensor-based, quantitative, objective, and easy-to-use systems for quantifying PD signs for large numbers of participants over extended durations have been developed. This technology has the potential to significantly improve both clinical diagnosis and management in PD and the conduct of clinical studies. However, the large-scale, high-dimensional character of the data captured by these wearable sensors requires sophisticated signal processing and machine-learning algorithms to transform it into scientifically and clinically meaningful information. Such algorithms that "learn" from data have shown remarkable success in making accurate predictions for complex problems in which human skill has been required to date, but they are challenging to evaluate and apply without a basic understanding of the underlying logic on which they are based. This article contains a nontechnical tutorial review of relevant machine-learning algorithms, also describing their limitations and how these can be overcome. It discusses implications of this technology and a practical road map for realizing the full potential of this technology in PD research and practice. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27501027 TI - HKUST-1 as a Heterogeneous Catalyst for the Synthesis of Vanillin. AB - Vanillin (4-hydoxy-3-methoxybenzaldehyde) is the main component of the extract of vanilla bean. The natural vanilla scent is a mixture of approximately 200 different odorant compounds in addition to vanillin. The natural extraction of vanillin (from the orchid Vanilla planifolia, Vanilla tahitiensis and Vanilla pompon) represents only 1% of the worldwide production and since this process is expensive and very long, the rest of the production of vanillin is synthesized. Many biotechnological approaches can be used for the synthesis of vanillin from lignin, phenolic stilbenes, isoeugenol, eugenol, guaicol, etc., with the disadvantage of harming the environment since these processes use strong oxidizing agents and toxic solvents. Thus, eco-friendly alternatives on the production of vanillin are very desirable and thus, under current investigation. Porous coordination polymers (PCPs) are a new class of highly crystalline materials that recently have been used for catalysis. HKUST-1 (Cu3(BTC)2(H2O)3, BTC = 1,3,5-benzene-tricarboxylate) is a very well known PCP which has been extensively studied as a heterogeneous catalyst. Here, we report a synthetic strategy for the production of vanillin by the oxidation of trans-ferulic acid using HKUST-1 as a catalyst. PMID- 27501028 TI - Six-Step Syntheses of (-)-1-Deoxyaltronojirimycin and (+)-1-Deoxymannonojirimycin from N-Z-O-TBDPS-l-serinal. AB - Highly stereoselective six-step syntheses of (-)-1-deoxyaltronojirimycin (altro DNJ) and (+)-1-deoxymannojirimycin (manno-DNJ) from N-Cbz-O-TBDPS-l-serinal are described. Key transformations involve a two-step preparation of a functionalized dihydropyridin-3-one as a common intermediate followed by Luche reduction and dihydroxylation (for altro-DNJ). The same sequence employing an epoxidation/epoxide opening in place of dihydroxylation furnishes manno-DNJ. PMID- 27501029 TI - Interleukin (IL) 31 induces in cynomolgus monkeys a rapid and intense itch response that can be inhibited by an IL-31 neutralizing antibody. AB - BACKGROUND: Overexpression or administration of interleukin 31 (IL-31) has been shown to induce a profound itch response in mice and dogs. The chronic pruritus observed in mouse IL-31 transgenic mice results in the development of skin lesions and alopecia through excoriation from excessive scratching, a condition similar to that observed in patients with atopic dermatitis (AD). OBJECTIVE: To test whether IL-31 induces pruritus in non-human primates and, if so, whether treatment with an anti-IL-31 neutralizing monoclonal antibody (mAb) can block the response. METHODS: A series of studies was conducted in cynomolgus monkeys to evaluate the itch response to recombinant cynomolgus IL-31 (cIL-31) administration. Three routes of cIL-31 administration (intravenous, intradermal, and subcutaneous) were evaluated. Subcutaneous treatment with a humanized anti human IL-31 mAb cross-reactive to cIL-31 was subsequently tested for its ability to block the response to intradermal cIL-31 administration. RESULTS: Each route of cIL-31 delivery elicited a scratching response immediately after cIL-31 administration and lasted at least 3 h. Treatment with the IL-31 mAb inhibited the cIL-31-mediated scratching response in a dose-dependent manner. CONCLUSION: These results demonstrate that an IL-31 mAb can inhibit IL-31-mediated pruritus in vivo, and could be an effective therapy for pruritic skin conditions like AD where IL-31 upregulation may play a role. PMID- 27501030 TI - Biosorption of methylene blue from wastewater by an extraction residue of Salvia miltiorrhiza Bge. AB - Efforts were made in this study to using an extraction residue of Salvia mitiorrziza Bge (SM), a widely utilized traditional Chinese medicine, as an effective biosorbent of methylene blue from polluted water. Batch experiments were carried out with original and chemical modification, particle size, dosage, solution pH, contact time, and initial concentration of the dye. Experimental data fit Langmuir isotherm and pseudo-second order kinetic best compared to other models applied in the study. Characterization of adsorption was determined by FT IR, SEM and particle surface area measurement. The maximum monolayer biosorption capacity of raw SM is 100.0mg.g(-1). The citric acid and Na2CO3 modification can significantly enhance this value up to 161.29 and 178.57mg.g(-1), respectively. This investigation provides a novel approach for reutilizing the enormous quantity of Chinese herbal medicine wastes, which is significant since these dregs have brought out big environmental and heathy problems in the present China. PMID- 27501031 TI - Removal of volatile fatty acids and ammonia recovery from unstable anaerobic digesters with a microbial electrolysis cell. AB - Continuous assays with a microbial electrolysis cell (MEC) fed with digested pig slurry were performed to evaluate its stability and robustness to malfunction periods of an anaerobic digestion (AD) reactor and its feasibility as a strategy to recover ammonia. When performing punctual pulses of volatile fatty acids (VFA) in the anode compartment of the MEC, simulating a malfunction of the AD process, an increase in the current density was produced (up to 14 times, reaching values of 3500mAm(-2)) as a result of the added chemical oxygen demand (COD), especially when acetate was used. Furthermore, ammonium diffusion from the anode to the cathode compartment was enhanced and the removal efficiency achieved up to 60% during daily basis VFA pulses. An AD-MEC combined system has proven to be a robust and stable configuration to obtain a high quality effluent, with a lower organic and ammonium content. PMID- 27501032 TI - Production of bio-oil rich in acetic acid and phenol from fast pyrolysis of palm residues using a fluidized bed reactor: Influence of activated carbons. AB - In this study, palm residues were pyrolyzed in a bench-scale (3kg/h) fast pyrolysis plant equipped with a fluidized bed reactor and bio-oil separation system for the production of bio-oil rich in acetic acid and phenol. Pyrolysis experiments were performed to investigate the effects of reaction temperature and the types and amounts of activated carbon on the bio-oil composition. The maximum bio-oil yield obtained was approximately 47wt% at a reaction temperature of 515 degrees C. The main compounds produced from the bio-oils were acetic acid, hydroxyacetone, phenol, and phenolic compounds such as cresol, xylenol, and pyrocatechol. When coal-derived activated carbon was applied, the acetic acid and phenol yields in the bio-oils reached 21 and 19wt%, respectively. Finally, bio oils rich in acetic acid and phenol could be produced separately by using an in situ bio-oil separation system and activated carbon as an additive. PMID- 27501033 TI - Optimization of biohydrogen yield produced by bacterial consortia using residual glycerin from biodiesel production. AB - The aims of this study were to simplify the fermentation medium and to optimize the conditions of dark fermentation of residual glycerin to produce biohydrogen. It was possible to remove all micronutrients of fermentation medium and improve biohydrogen production by applying residual glycerin as feedstock. After statistical analysis of the following parameters pH, glycerin concentration and volatile suspended solids, the values of 5.5; 0.5g.L(-1) and 8.7g.L(-1), respectively, were defined as optimum condition for this process. It generated 2.44molH2/molglycerin, an expressive result when compared to previous results reported in literature and considering that theoretical yield of H2 from glycerol in dark fermentation process is 3molH2/molglycerol. This study allowed the improvement of yield and productivity by 68% and 67%, respectively. PMID- 27501034 TI - Investigation into the lignin decomposition mechanism by analysis of the pyrolysis product of Pinus radiata. AB - Lignin pyrolysis chemistry was investigated via the analysis of the products obtained from the fast pyrolysis of a pine wood at different temperatures. Methoxy phenols, such as guaiacols and eugenols, were produced mainly at 375 and 475 degrees C, while non-methoxy phenols, such as alkyl phenols and pyrocatechols were dominant at 525 and 575 degrees C. At 575 degrees C, aromatic hydrocarbons were formed together with larger amounts of light hydrocarbon gases. When the temperature was increased from 375 and 475 degrees C, the yield of pyrolytic lignin was increased, whereas its average molecular weight was decreased. At 525 degrees C, smaller molecular pyrolytic lignin with a maximum concentration of phenolic hydroxyl groups was produced due to the increased secondary cracking of the reaction intermediates. On the other hand, at 575 degrees C, larger molecular pyrolytic lignin with smaller amounts of phenolic hydroxyl groups was produced due to the increased condensation activity of the pyrolysis reaction intermediates. PMID- 27501035 TI - Carbon 13-Metabolic Flux Analysis derived constraint-based metabolic modelling of Clostridium acetobutylicum in stressed chemostat conditions. AB - The metabolism of butanol producing bacteria Clostridium acetobutylicum was studied in chemostat with glucose limited conditions, butanol stimulus, and as a reference cultivation. COnstraint-Based Reconstruction and Analysis (COBRA) was applied using additional constraints from (13)C Metabolic Flux Analysis ((13)C MFA) and experimental measurement results. A model consisting of 451 metabolites and 604 reactions was utilized in flux balance analysis (FBA). The stringency of the flux spaces considering different optimization objectives, i.e. growth rate maximization, ATP maintenance, and NADH/NADPH formation, for flux variance analysis (FVA) was studied in the different modelled conditions. Also a previously uncharacterized exopolysaccharide (EPS) produced by C. acetobutylicum was characterized on monosaccharide level. The major monosaccharide components of the EPS were 40n-% rhamnose, 34n-% glucose, 13n-% mannose, 10n-% galactose, and 2n-% arabinose. The EPS was studied to have butanol adsorbing property, 70(butanol)mg(EPS)g(-1) at 37 degrees C. PMID- 27501036 TI - Anchoring and promotion effects of metal oxides on silica supported catalytic gold nanoparticles. AB - The understanding of the interactions between the different components of supported metal doped gold catalysts is of crucial importance for selecting and designing efficient gold catalysts for reactions such as CO oxidation. To progress in this direction, a unique supported nano gold catalyst Au/SS was prepared, and three doped samples (Au/SS@M) were elaborated. The samples before and after test were characterized by Transmission Electron Microscopy (TEM) and X ray Photoelectron Spectroscopy (XPS). It is found that the doping metal species prefer to be located on the surface of gold nanoparticles and that a small amount of additional reductive metal leads to more efficient reaction. During the catalytic test, the nano-structure of the metal species transforms depending on its chemical nature. This study allows one to identify and address the contribution of each metal on the CO reaction in regard to oxidative species of gold, silica and dopants. Metal doping leads to different exposure of interface sites between Au and metal oxide, which is one of the key factors for the change of the catalytic activity. The metal oxides help the activation of oxygen by two actions: mobility inside the metal bulk and transfer of water species onto of gold nanoparticles. PMID- 27501037 TI - Ligand anchored poly(propyleneimine) dendrimers for brain targeting: Comparative in vitro and in vivo assessment. AB - The present investigation was aimed at developing various ligands-anchored dendrimers and comparing their brain targeting potential at one platform. Sialic acid (S), glucosamine (G) and concanavalin A (C) anchored poly(propyleneimine) (PPI) dendritic nanoconjugates were developed and evaluated for delivery of anti cancer drug, paclitaxel (PTX) to the brain. MTT assay on U373MG human astrocytoma cells indicated IC50 values of 0.40, 0.65, 0.95, 2.00 and 3.50MUM for PTX loaded SPPI, GPPI, CPPI, PPI formulations, and free PTX, respectively. The invivo pharmacokinetics and biodistribution studies in rats showed significantly higher accumulation of PTX in brain as compared to free PTX. The order of targeting potential of various ligands under investigation was found as sialic acid>glucosamine>concanavalin A. Thus, it can be concluded that sialic acid, glucosamine and Con A can be used as potential ligands to append PPI dendrimers for enhanced delivery of anticancer drugs to the brain for higher therapeutic outcome. PMID- 27501038 TI - 'Chocolate' silver nanoparticles: Synthesis, antibacterial activity and cytotoxicity. AB - HYPOTHESIS: Silver nanoparticles (AgNPs) have emerged as a powerful weapon against antibiotic resistant microorganisms. However, most conventional AgNPs syntheses require the use of hazardous chemicals and generate toxic organic waste. Hence, in recent year's, plant derived and biomolecule based synthetics have has gained much attention. Cacao has been used for years for its medicinal benefits and contains a powerful reducing agent - oxalic acid. We hypothesized that, due to the presence of oxalic acid, cacao extract is capable of reducing silver nitrate (AgNO3) to produce AgNPs. EXPERIMENTS: In this study, AgNPs were synthesized by using natural cacao extract as a reducing and stabilizing agent. The reaction temperature, time and reactant molarity were varied to optimize the synthesis yield. FINDINGS: UV-visible spectroscopy (UV-vis), dynamic light scattering (DLS) and transmission electron microscopy (TEM) characterization demonstrated that the synthesized AgNPs were spherical particles ranging in size from 35 to 42.5nm. The synthesized AgNPs showed significant antibacterial activity against clinically relevant pathogens such as Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis. Importantly, these green AgNPs are not cytotoxic to human dermal fibroblasts (HDFs) at concentrations below 32MUg/ml. We conclude that cacao-based synthesis is a reproducible and sustainable method for the generation of stable antimicrobial silver nanoparticles with low cytotoxicity to human cells. The AgNPs synthesized in this work have promising properties for applications in the biomedical field. PMID- 27501039 TI - Immobilization of invertase on chitosan coated gamma-Fe2O3 magnetic nanoparticles to facilitate magnetic separation. AB - Industrially important invertase enzyme was immobilized on chitosan coated sol gel derived gamma-Fe2O3 magnetic nanoparticles (MNPs) to enable it for repetitive use by magnetic separation. MNPs were characterized by X-ray diffraction (XRD), dynamic light scattering (DLS), field emission scanning electron microscope (FE SEM), Fourier transform infrared (FTIR) spectrometer and magnetic measurements. FTIR studies confirmed successful immobilization of invertase on MNPs. The ability to convert sucrose into invert syrup was enhanced in immobilized invertase compared to that of free enzyme. Further it was found that invertase immobilized on MNPs (IIMNPs) were more stable at varying pH and temperature conditions. Magnetic separation technique was successfully employed for reuse of the IIMNPs for 20 times without significant loss of activity. PMID- 27501040 TI - Novel g-C3N4/Ag2SO4 nanocomposites: Fast microwave-assisted preparation and enhanced photocatalytic performance towards degradation of organic pollutants under visible light. AB - Graphite carbon nitride (g-C3N4)/Ag2SO4 nanocomposites, as highly enhanced visible-light-driven photocatalysts, were prepared by a fast microwave-assisted method. The resulting g-C3N4/Ag2SO4 nanocomposites were characterized by X-ray diffraction, energy dispersive analysis of X-rays, scanning electron microscopy, transmission electron microscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy, and ultraviolet-visible diffuse reflectance spectroscopy techniques. Moreover, charge separation efficiency was studied by photoluminescence measurements. Photocatalytic activity of the g-C3N4/Ag2SO4 (40%) nanocomposite in degradation of rhodamine B, methylene blue, and fuchsine is about 6, 3.8, and 3.3-folds greater than that of the g-C3N4 under visible light illumination. Effect of microwave irradiation time, calcination temperature, and scavengers of the reactive species on the degradation reaction was also evaluated. The enhanced photocatalytic activity was mainly ascribed to the matching band energies of g-C3N4 and Ag2SO4 which leads to an improved separation of photogenerated electron-hole pairs. Finally, the optimized nanocomposite was recycled for five times without remarkable decrease of the photocatalytic activity. PMID- 27501041 TI - Filamentary superhydrophobic Teflon surfaces: Moderate apparent contact angle but superior air-retaining properties. AB - HYPOTHESIS: Micro-scale textured Teflon surfaces, resulting from plasma etching modification, show extremely high water contact angle values and fairly good resistance to water penetration when hit by water drops at medium-high speed. This behavior is more pronounced when these surfaces present denser and smaller micrometric reliefs. Tailoring the top of these reliefs with a structure which further stabilizes the air may further increase resistance to wetting (water penetration) under static and dynamic conditions. EXPERIMENTS: Conditions of the oxygen fed plasma were tuned in order to explore the possibility of obtaining differently topped structures on the surface of the polymer. Scanning Electron Microscopy (SEM) was used to explore topography and X-ray Photoelectron Spectroscopy (XPS) to assess chemical similarity of the modified surfaces. Beside the usual advancing and receding water contact angle (WCA) measurements, surfaces were subjected to high speed impacting drops and immersion in water. FINDINGS: At milder, i.e. shorter time and lower input power, plasma conditions formation of peculiar filaments is observed on the top of the sculpted reliefs. Filamentary topped surfaces result in a lower WCA than the spherical ones, appearing in this sense less superhydrophobic. However, these surfaces give rise to the formation of a more pronounced air layer when placed underwater. Further, when hit by water drops falling at medium/high speed, they show a higher resistance to water penetration and a sensitively lower surface-liquid contact time. The contact time is as low as previously observed only on heated solids. This behavior may be ascribed to the cavities formed beneath the filaments which, similarly with the salvinia leaf structures, require a surplus of pressure to be filled by water. Also, it suggests a different concept of superhydrophobicity, which cannot be expected on the basis of the conventional water contact angle characterization. PMID- 27501042 TI - Facile synthesis of birnessite-type manganese oxide nanoparticles as supercapacitor electrode materials. AB - Manganese oxides are environmentally benign supercapacitor electrode materials and, in particular, birnessite-type structure shows very promising electrochemical performance. In this work, nanostructured birnessite was facilely prepared by adding dropwise NH2OH.HCl to KMnO4 solution under ambient temperature and pressure. In order to fully exploit the potential of birnessite-type manganese oxide electrode materials, the effects of specific surface area, pore size, content of K(+), and manganese average oxidation state (Mn AOS) on their electrochemical performance were studied. The results showed that with the increase of NH2OH.HCl, the Mn AOS decreased and the corresponding pore sizes and specific surface area of birnessite increased. The synthesized nanostructured birnessite showed the highest specific capacitance of 245Fg(-1) at a current density of 0.1Ag(-1) within a potential range of 0-0.9V, and excellent cycle stability with a capacitance retention rate of 92% after 3000 cycles at a current density of 1.0Ag(-1). The present work implies that specific capacitance is mainly affected by specific surface area and pore volume, and provides a new method for the facile preparation of birnessite-type manganese oxide with excellent capacitive performance. PMID- 27501043 TI - Phase-field modelling of a miscible system in spinning droplet tensiometer. AB - The spinning drop tensiometry is used for measurements of surface tension coefficients, especially, when interfaces are characterised by low and ultra-low interfacial stresses. A droplet of lighter liquid is introduced into a rotating capillary that was initially saturated with another heavier liquid. The tube is subject to axial rotation that results in droplet's elongation along the tube's axis. The equilibrium shape of the droplet is used to determine the surface tension coefficient. In this work, the evolution of a slowly miscible droplet introduced into a spinning capillary is investigated. This technique is frequently employed for studies of the dynamics of miscible systems, even despite the fact that a strict equilibrium is never achieved in a mixture of fully miscible liquids. The numerical modelling of a miscible droplet is fulfilled on the basis of the phase-field (Cahn-Hilliard) approach. The numerical results are compared against the experimental data pursuing two objectives: (i) to verify the use of the phase-field approach as a consistent physics-based approach capable of accurate tracking of the short- and long-term evolution of miscible systems, and (ii) to estimate the values of the phenomenological parameters introduced within the phase-field approach, so making this approach a practical tool for modelling of thermohydrodynamic changes in miscible systems within various configurations. PMID- 27501044 TI - Early Differential Diagnosis of Rhino-Orbito-Cerebral Mucormycosis and Bacterial Orbital Cellulitis: Based on Computed Tomography Findings. AB - PURPOSE: To identify significant clinical and radiological findings that distinguish rhino-orbito-cerebral mucormycosis (ROCM) from bacterial orbital cellulitis (BOC). METHODS: This study was retrospective, multicenter, case control study that enrolled 34 cases; 14 cases were diagnosed with ROCM and 20 cases were diagnosed with BOC at three different tertiary hospitals between 2005 and 2013. The medical records of all 34 cases were reviewed. The initial clinical manifestations (eyelid swelling, ptosis, extraocular muscle [EOM] limitation, conjunctival injection, and chemosis) and computed tomography (CT) findings (sinus mucosal thickening, full opacification, and air-fluid level) of both diseases were compared. RESULTS: Patients with diabetes mellitus (DM) and hypertension (HTN) showed higher incidence rates of ROCM than BOC (DM: p < 0.001, HTN: p = 0.036). ROCM cases exhibited more frequent EOM limitation than cases with BOC (100.0% vs. 66.7%, p = 0.024) but less frequent eyelid swelling (35.7% vs. 90.0%, p = 0.002). However, the incidence rates of ptosis, conjunctival injection, and chemosis exhibited no differences between the diseases. Abnormal CT findings were observed in the sinuses of all patients with ROCM, whereas 12 patients with BOC had sinus abnormalities (100.0% vs. 60.0%, p = 0.011). Thickening of the sinus mucosa was more frequent in patients with ROCM than in those with BOC (92.9% vs. 45.0%, p = 0.009). No significant differences in full opacification or air-fluid level were detected between the groups. CONCLUSIONS: The differential diagnosis of ROCM and BOC is difficult. Nevertheless, physicians should consider ROCM when a patient with suspected orbital cellulitis presents with EOM limitation without swollen eyelids or thickening of the sinus mucosa on a CT scan. PMID- 27501045 TI - The Genomic Scrapheap Challenge; Extracting Relevant Data from Unmapped Whole Genome Sequencing Reads, Including Strain Specific Genomic Segments, in Rats. AB - Unmapped next-generation sequencing reads are typically ignored while they contain biologically relevant information. We systematically analyzed unmapped reads from whole genome sequencing of 33 inbred rat strains. High quality reads were selected and enriched for biologically relevant sequences; similarity-based analysis revealed clustering similar to previously reported phylogenetic trees. Our results demonstrate that on average 20% of all unmapped reads harbor sequences that can be used to improve reference genomes and generate hypotheses on potential genotype-phenotype relationships. Analysis pipelines would benefit from incorporating the described methods and reference genomes would benefit from inclusion of the genomic segments obtained through these efforts. PMID- 27501046 TI - VM Capacity-Aware Scheduling within Budget Constraints in IaaS Clouds. AB - Recently, cloud computing has drawn significant attention from both industry and academia, bringing unprecedented changes to computing and information technology. The infrastructure-as-a-Service (IaaS) model offers new abilities such as the elastic provisioning and relinquishing of computing resources in response to workload fluctuations. However, because the demand for resources dynamically changes over time, the provisioning of resources in a way that a given budget is efficiently utilized while maintaining a sufficing performance remains a key challenge. This paper addresses the problem of task scheduling and resource provisioning for a set of tasks running on IaaS clouds; it presents novel provisioning and scheduling algorithms capable of executing tasks within a given budget, while minimizing the slowdown due to the budget constraint. Our simulation study demonstrates a substantial reduction up to 70% in the overall task slowdown rate by the proposed algorithms. PMID- 27501047 TI - Cysteine and Aspartyl Proteases Contribute to Protein Digestion in the Gut of Freshwater Planaria. AB - Proteases perform numerous vital functions in flatworms, many of which are likely to be conserved throughout the phylum Platyhelminthes. Within this phylum are several parasitic worms that are often poorly characterized due to their complex life-cycles and lack of responsiveness to genetic manipulation. The flatworm Schmidtea mediterranea, or planaria, is an ideal model organism to study the complex role of protein digestion due to its simple life cycle and amenability to techniques like RNA interference (RNAi). In this study, we were interested in deconvoluting the digestive protease system that exists in the planarian gut. To do this, we developed an alcohol-induced regurgitation technique to enrich for the gut enzymes in S. mediterranea. Using a panel of fluorescent substrates, we show that this treatment produces a sharp increase in proteolytic activity. These enzymes have broad yet diverse substrate specificity profiles. Proteomic analysis of the gut contents revealed the presence of cysteine and metallo-proteases. However, treatment with class-specific inhibitors showed that aspartyl and cysteine proteases are responsible for the majority of protein digestion. Specific RNAi knockdown of the cathepsin B-like cysteine protease (SmedCB) reduced protein degradation in vivo. Immunohistochemistry and whole-mount in situ hybridization (WISH) confirmed that the full-length and active forms of SmedCB are found in secretory cells surrounding the planaria intestinal lumen. Finally, we show that the knockdown of SmedCB reduces the speed of tissue regeneration. Defining the roles of proteases in planaria can provide insight to functions of conserved proteases in parasitic flatworms, potentially uncovering drug targets in parasites. PMID- 27501048 TI - Pre-Transplant Cardiovascular Risk Factors Affect Kidney Allograft Survival: A Multi-Center Study in Korea. AB - BACKGROUND: Pre-transplant cardiovascular (CV) risk factors affect the development of CV events even after successful kidney transplantation (KT). However, the impact of pre-transplant CV risk factors on allograft failure (GF) has not been reported. METHODS AND FINDINGS: We analyzed the graft outcomes of 2,902 KT recipients who were enrolled in a multi-center cohort from 1997 to 2012. We calculated the pre-transplant CV risk scores based on the Framingham risk model using age, gender, total cholesterol level, smoking status, and history of hypertension. Vascular disease (a composite of ischemic heart disease, peripheral vascular disease, and cerebrovascular disease) was noted in 6.5% of the patients. During the median follow-up of 6.4 years, 286 (9.9%) patients had developed GF. In the multivariable-adjusted Cox proportional hazard model, pre-transplant vascular disease was associated with an increased risk of GF (HR 2.51; 95% CI 1.66-3.80). The HR for GF (comparing the highest with the lowest tertile regarding the pre-transplant CV risk scores) was 1.65 (95% CI 1.22-2.23). In the competing risk model, both pre-transplant vascular disease and CV risk score were independent risk factors for GF. Moreover, the addition of the CV risk score, the pre-transplant vascular disease, or both had a better predictability for GF compared to the traditional GF risk factors. CONCLUSIONS: In conclusion, both vascular disease and pre-transplant CV risk score were independently associated with GF in this multi-center study. Pre-transplant CV risk assessments could be useful in predicting GF in KT recipients. PMID- 27501049 TI - Migration and epithelial-to-mesenchymal transition of lung cancer can be targeted via translation initiation factors eIF4E and eIF4GI. AB - Metastasis underlies cancer morbidity and accounts for disease progression and significant death rates generally and in non-small cell lung cancer (NSCLC) particularly. Therefore, it is critically important to understand the molecular events that regulate metastasis. Accumulating data portray a central role for protein synthesis, particularly translation initiation (TI) factors eIF4E and eIF4G in tumorigenesis and patients' survival. We have published that eIF4E/eIF4GI activities and consequently NSCLC cell migration are modulated by bone-marrow mesenchymal stem cell secretomes, suggesting a role for TI in metastasis. Here, we aimed to expand our understanding of the TI factors significance to NSCLC characteristics, particularly epithelial-to-mesenchymal transition (EMT) and migration, supportive of metastasis. In a model of NSCLC cell lines (H1299, H460), we inhibited eIF4E/eIF4GI's expressions (siRNA, ribavirin) and assessed NSCLC cell lines' migration (scratch), differentiation (EMT, immunoblotting), and expression of select microRNAs (qPCR). Initially, we determined an overexpression of several TI factors (eIF4E, eIF4GI, eIF4B, and DHX29) and their respective targets in NSCLC compared with normal lung samples (70-350%?, P<0.05). Knockdown (KD) of eIF4E/eIF4GI in NSCLC cell lines (70%?, P<0.05) also manifested in decreased target levels (ERalpha, SMAD5, NFkB, CyclinD1, c-MYC, and HIF1alpha) (20-50%?, P<0.05). eIF4E/eIF4GI KD also attenuated cell migration (60-75%?, P<0.05), EMT promoters (15-90%?, P<0.05), and enhanced EMT suppressors (30-380%?, P<0.05). The importance of eIF4E KD to NSCLC phenotype was further corroborated with its inhibitor, ribavirin. Changes in expression of essential microRNAs implicated in NSCLC cell migration concluded the study (20-100%, P<0.05). In summary, targeting eIF4E/eIF4GI reduces migration and EMT, both essential for metastasis, thereby underscoring the potential of TI targeting in NSCLC therapy, especially the already clinically employed agents (ribavirin/4EGI). Comparison of these findings with previously reported effects of eIF4E/eIF4GI KD in multiple myeloma suggests a collective role for these TI factors in cancer progression. PMID- 27501050 TI - Ischemic post-conditioning attenuates acute lung injury induced by intestinal ischemia-reperfusion in mice: role of Nrf2. AB - Intestinal ischemic post-conditioning (IPo) protects against lung injury induced by intestinal ischemia-reperfusion (IIR) partly through promotion of expression and function of heme oxygenase-1 (HO-1). NF-E2-related factor-2 (Nrf2) is a key transcription factor that interacts with HO-1 and regulates antioxidant defense. However, the role of Nrf2 in IPo protection of IIR-induced pulmonary injury is not completely understood. Here we show that IPo significantly attenuated IIR induced lung injury and suppressed oxidative stress and systemic inflammatory responses. IPo also increased the expression of both Nrf2 and HO-1. Consistently, the beneficial effects of IPo were abolished by ATRA and Brusatol, potent inhibitors of Nrf2. Moreover, the Nrf2 agonist t-BHQ showed similar activity as IPo. Taken together, our data suggest that Nrf2 activity, along with HO-1, plays an important role in the protective effects of IPo against IIR-induced acute lung injury. PMID- 27501051 TI - Contrasting Patterns of rDNA Homogenization within the Zygosaccharomyces rouxii Species Complex. AB - Arrays of repetitive ribosomal DNA (rDNA) sequences are generally expected to evolve as a coherent family, where repeats within such a family are more similar to each other than to orthologs in related species. The continuous homogenization of repeats within individual genomes is a recombination process termed concerted evolution. Here, we investigated the extent and the direction of concerted evolution in 43 yeast strains of the Zygosaccharomyces rouxii species complex (Z. rouxii, Z. sapae, Z. mellis), by analyzing two portions of the 35S rDNA cistron, namely the D1/D2 domains at the 5' end of the 26S rRNA gene and the segment including the internal transcribed spacers (ITS) 1 and 2 (ITS regions). We demonstrate that intra-genomic rDNA sequence variation is unusually frequent in this clade and that rDNA arrays in single genomes consist of an intermixing of Z. rouxii, Z. sapae and Z. mellis-like sequences, putatively evolved by reticulate evolutionary events that involved repeated hybridization between lineages. The levels and distribution of sequence polymorphisms vary across rDNA repeats in different individuals, reflecting four patterns of rDNA evolution: I) rDNA repeats that are homogeneous within a genome but are chimeras derived from two parental lineages via recombination: Z. rouxii in the ITS region and Z. sapae in the D1/D2 region; II) intra-genomic rDNA repeats that retain polymorphisms only in ITS regions; III) rDNA repeats that vary only in their D1/D2 domains; IV) heterogeneous rDNA arrays that have both polymorphic ITS and D1/D2 regions. We argue that an ongoing process of homogenization following allodiplodization or incomplete lineage sorting gave rise to divergent evolutionary trajectories in different strains, depending upon temporal, structural and functional constraints. We discuss the consequences of these findings for Zygosaccharomyces species delineation and, more in general, for yeast barcoding. PMID- 27501052 TI - Convergence of visual and whisker responses in the primary somatosensory thalamus (ventral posterior medial region) of the mouse. AB - KEY POINTS: Using in vivo electrophysiology, we find that a subset of whisker responsive neurons in the ventral posterior medial region (VPM) respond to visual stimuli. These light-responsive neurons in the VPM are particularly sensitive to optic flow. Presentation of optic flow stimuli modulates the amplitude of concurrent whisker responses. Visual information reaches the VPM via a circuit encompassing the visual cortex. These data represent a new example of cross-modal integration in the primary sensory thalamus. ABSTRACT: Sensory signals reach the cortex via sense-specific thalamic nuclei. Here we report that neurons in the primary sensory thalamus of the mouse vibrissal system (the ventral posterior medial region; VPM) can be excited by visual as well as whisker stimuli. Using extracellular electrophysiological recordings from anaesthetized mice we first show that simple light steps can excite a subset of VPM neurons. We then test the ability of the VPM to respond to spatial patterns and show that many units are excited by visual motion in a direction-selective manner. Coherent movement of multiple objects (an artificial recreation of 'optic flow' that would usually occur during head rotations or body movements) best engages this visual motion response. We next show that, when co-applied with visual stimuli, the magnitude of responses to whisker deflections is highest in the presence of optic flow going in the opposite direction. Importantly, whisker response amplitude is also modulated by presentation of a movie recreating the mouse's visual experience during natural exploratory behaviour. We finally present functional and anatomical data indicating a functional connection (probably multisynaptic) from the primary visual cortex to VPM. These data provide a rare example of multisensory integration occurring at the level of the sensory thalamus, and provide evidence for dynamic regulation of whisker responses according to visual experience. PMID- 27501053 TI - Epidemiology and risk factors of uninvestigated dyspepsia, irritable bowel syndrome, and gastroesophageal reflux disease among students of Damascus University, Syria. AB - Uninvestigated dyspepsia (UD), irritable bowel syndrome (IBS), and gastroesophageal reflux disease (GERD) are common disorders universally. Many studies have assessed their epidemiological characteristics around the world. However, such information is not known for Syria. We aim to estimate the epidemiologic characteristics and possible risk factors for UD, IBS, and GERD among students at Damascus University, Damascus, Syria. A cross-sectional study was conducted in July-September 2015 at a campus of Damascus University. A total of 320 students were randomly asked to complete the survey. We used ROME III criteria to define UD and IBS, and Montreal definition for GERD. In total, 302 valid participants were included in the analysis. Prevalence for UD, IBS, and GERD was 25%, 17%, and 16%, respectively. Symptom overlap was present in 46 students (15%), with UD+IBS in 28 (9.3%), UD+GERD in 26 (8.6%), and IBS+GERD in 14 (4.6%) students. Eleven (3.6%) students had symptoms of UD+IBS+GERD. Each of these overlaps occurred more frequently than expected by chance. Significant risk factors included cigarettes smoking, waterpipe consumption, and body mass index <18.5kg/m2 for UD; female gender and three cups of coffee/d for IBS; and two cups of tea and one to five cigarettes/d for GERD. Risk factors for these disorders remain poorly characterized and need further investigations. PMID- 27501054 TI - Lack of genetic variation prevents adaptation at the geographic range margin in a damselfly. AB - What limits a species' distribution in the absence of physical barriers? Genetic load due to asymmetric gene flow and the absence of genetic variation due to lack of gene flow are hypothesized to constrain adaptation to novel environments in marginal populations, preventing range expansion. Here, we examined the genetic structure and geographic variation in morphological traits in two damselflies (Ischnura asiatica and I. senegalensis) along a latitudinal gradient in Japan, which is the distribution centre of I. asiatica and the northern limit of I. senegalensis. Genomewide genetic analyses found a loss of genetic diversity at the edge of distribution in I. senegalensis but consistently high diversity in I. asiatica. Gene flow was asymmetric in a south-north direction in both species. Although body size and wing loading showed decreasing latitudinal clines (smaller in north) in I. asiatica in Japan, increasing latitudinal clines (larger in north) in these phenotypic markers were observed in I. senegalensis, particularly near the northern boundary, which coincided well with the location where genetic diversity began a sharp decline. In ectothermic animals, increasing latitudinal cline in these traits was suggested to be established when they failed to adapt to thermal gradient. Therefore, our findings support the possibility that a lack of genetic variation rather than geneflow swamping is responsible for the constraint of adaptation at the margin of geographic distribution. PMID- 27501055 TI - In vitro study of the antibacterial effect of the bacteriophage T5 thermostable endolysin on Escherichia coli cells. AB - AIMS: This study aimed to evaluate lysis of Escherichia coli stationary cell cultures induced by the combined action of bacteriophage T5 endolysin (l-alanyl-d glutamate peptidase) and low doses of various cationic agents permeabilizing the outer membrane of Gram-negative bacteria (polymyxin B, gramicidin D, poly-l lysine, chlorhexidine and miramistin). METHODS AND RESULTS: The enzyme activity was assayed with the turbidimetric method. Antimicrobial activity was assessed through the number of colony-forming units (CFUs); the results of calculation were represented as logarithmic units. The optical microscopy examination of bacterial cells was conducted in the phase-contrast mode. The use of bacteriophage T5 endolysin in combination with polymyxin B (0.4 MUg ml-1 ) or chlorhexidine (0.5 MUg ml-1 ) made it possible to reduce the number of CFUs by five orders of magnitude; and in combination with poly-l-lysine (80 MUg ml-1 ) by four orders, as compared to control. The endolysin was found to be a thermostable protein: it retained ~65% of its initial activity after heating for 30 min at 90 degrees C. Examining the curves of its thermal denaturation revealed the half transition temperature to be 56.3 +/- 1.0 degrees C. Circular dichroism spectra showed that after recooling the protein restored up to 80% of its native structure. CONCLUSIONS: A substantial synergistic effect of the bacteriophage T5 endolysin and membrane-permeabilizing compounds was demonstrated. SIGNIFICANCE AND IMPACT OF THE STUDY: The study of thermal stability of the bacteriophage T5 endolysin and the quantified assessment of its antimicrobial activity have been done for the first time. The approach examined lays foundations for designing a two-component preparation which would effectively lyse cells of Gram-negative pathogens from outside. PMID- 27501056 TI - Digital palpation of the pilot balloon vs. continuous manometry for controlling the intracuff pressure in laryngeal mask airways. AB - This study compared two methods of controlling the intracuff pressure in laryngeal mask airways. One hundred and eighty patients were randomly assigned into two groups. In the first group (n = 90), after training, the intracuff pressure was controlled using digital palpation of the pilot balloon. In the second group (n = 90), continuous manometry was used to control the intracuff pressure. An upper pressure limit of 60 cmH2 O was set. The median (IQR [range]) intracuff pressure in the palpation group was 130 (125-130 [120-130]) cmH2 O compared with 29 (20-39 [5-60]) cmH2 O in the manometry group (p < 0.001). In the palpation group, 37% of patients experienced pharyngolaryngeal complications vs. 12% in the manometry group (p < 0.001). We conclude that the digital palpation technique is not a suitable alternative to manometry in controlling the intracuff pressure in laryngeal mask airways. PMID- 27501057 TI - The mathematics of random mutation and natural selection for multiple simultaneous selection pressures and the evolution of antimicrobial drug resistance. AB - The random mutation and natural selection phenomenon act in a mathematically predictable behavior, which when understood leads to approaches to reduce and prevent the failure of the use of these selection pressures when treating infections and cancers. The underlying principle to impair the random mutation and natural selection phenomenon is to use combination therapy, which forces the population to evolve to multiple selection pressures simultaneously that invoke the multiplication rule of probabilities simultaneously as well. Recently, it has been seen that combination therapy for the treatment of malaria has failed to prevent the emergence of drug-resistant variants. Using this empirical example and the principles of probability theory, the derivation of the equations describing this treatment failure is carried out. These equations give guidance as to how to use combination therapy for the treatment of cancers and infectious diseases and prevent the emergence of drug resistance. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27501058 TI - Biofuel cell operating on activated THP-1 cells: A fuel and substrate study. AB - It is known that electrochemical energy can be harvested from mammalian cells, more specifically from white blood cells (WBC). This study focuses on an improved biofuel cell operating on phorbol myristate acetate (PMA) activated THP-1 human monocytic cells. Electrochemical investigation showed strong evidence pointing towards hydrogen peroxide being the primary current source, confirming that the current originates from NADPH oxidase activity. Moreover, an adequate substrate for differentiation and activation of THP-1 cells was examined. ITO, gold, platinum and glass were tested and the amount of superoxide anion produced by NADPH oxidase was measured by spectrophotometry through WST-1 reduction at 450nm and used as an indicator of cellular activity and viability. These substrates were subsequently used in a conventional two-compartment biofuel cell where the power density output was recorded. The material showing the highest cell activity compared to the reference cell culture plate and the highest power output was ITO. Under our experimental conditions, a power density of 4.5MUW/cm2 was reached. To the best of our knowledge, this is a threefold higher power output than other leukocyte biofuel cells. PMID- 27501059 TI - The safety and efficacy of radium-223 dichloride for the treatment of advanced prostate cancer. AB - INTRODUCTION: A number of drugs have been shown to extend life expectancy in castration-resistant prostate cancer (CRPC). Skeletal related events (SREs) secondary to bone metastases cause significant morbidity for men with CRPC. The alpha-emitting radiopharmaceutical radium-223 dichloride has been shown to improve overall survival, time to symptomatic skeletal events (SSEs) and quality of life in CRPC. AREAS COVERED: The development of radium-223 from pre-clinical studies to the evidence of efficacy and safety from a phase 3 trial is discussed as well as its pharmacokinetics and metabolism. The integration of radium-223 into routine care for patients with advanced prostate cancer is included including a comparison with other agents in this setting. Expert commentary: The risk/benefit ratio for radium-223 is very similar to that of other agents used in the CRPC setting and is a treatment option for men unsuitable for cytotoxic chemotherapy because of comorbidities. The ALSYMPCA trial demonstrated an improvement in SSEs with radium-223. This is a clinically relevant end-point as not all radiologically-detected SREs are apparent to patients. The correct sequencing of the life-prolonging treatments available to men with CRPC is subject to debate. Radium-223 therapy should be considered before the development of visceral metastases. Drug-combination studies are underway. PMID- 27501060 TI - Efficacy and Safety of Bunium Persicum (Boiss) to Inactivate Protoscoleces during Hydatid Cyst Operations. AB - BACKGROUND: Current scolicidal agents, which have been used for inactivation of protoscoleces during surgical procedures, are associated with adverse side effects including sclerosing cholangitis. This investigation aimed to evaluate the scolicidal effects of Bunium persicum (Boiss) essential oil against protoscoleces of hydatid cysts and also its toxicity in a mice model. METHODS: Protoscoleces were aseptically aspirated from sheep livers having hydatid cysts. Various concentrations of the essential oil (3.125-50 mcL/mL) were used for 5-30 min. The viability of protoscoleces was confirmed using the eosin exclusion test (0.1% eosin staining). Further, 48 male NMRI mice were used to determine the acute and sub-acute toxicity of B. persicum essential oil. RESULTS: The obtained results revealed that the B. persicum essential oil at the concentrations of 25 and 50 mcL/mL after 5 min of exposure killed 100% protoscoleces. The mean mortality rate of protoscoleces after 10 min of exposure to the concentration of 12.5 mcL/mL was 100%. Lower concentrations (6.25 and 3.125 mcL/mL) of B. persicum essential oil, however, indicated a delayed protoscolicidal effects. The LD50 value of intra-peritoneal injection of the B. persicum essential oil was 1.96 mL/kg body wt. No significant difference (p > 0.05) was observed in the clinical chemistry and hematologic parameters after oral administrations of B. persicum essential oil at the doses 0.05, 0.1, 0.2, and 4 mL/kg for 14 d. CONCLUSION: Our findings demonstrated the potent scolicidal activity of B. persicum with no significant toxicity; it might be used as a natural scolicidal agent in hydatid cyst surgery. PMID- 27501061 TI - Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry. AB - The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the development of antibody drug conjugates (ADCs) and nanomedicine, fluorescent microscopy and systems chemistry. For many of these applications, specificity of the bioconjugation method used is of prime concern. The Michael addition of maleimides with cysteine(s) on the target proteins is highly selective and proceeds rapidly under mild conditions, making it one of the most popular methods for protein bioconjugation. We demonstrate here the modification of the only surface-accessible cysteine residue on yeast cytochrome c with a ruthenium(II) bisterpyridine maleimide. The protein bioconjugation is verified by gel electrophoresis and purified by aqueous-based fast protein liquid chromatography in 27% yield of isolated protein material. Structural characterization with MALDI TOF MS and UV-Vis is then used to verify that the bioconjugation is successful. The protocol shown here is easily applicable to other cysteine - maleimide coupling of proteins to other proteins, dyes, drugs or polymers. PMID- 27501062 TI - Long-term anti-endotoxin/E. coli efficacy in mice transfected with AAV2/1-muBPI25 -muFcgamma1. AB - Bactericidal/permeability increasing (BPI) is an antibiotic protein which kills Gram-negative bacteria and neutralizes endotoxin. We have previously developed a recombinant adeno-associated virus which contains human BPI amino acid residues 1 199 and Fc fragment of human IgG1 gene (AAV-hBPI-Fc) and shown that the recombinant virus can protect mice from lethal endotoxemia. However, whether AAV hBPI-Fc can be used in vivo for the long term remains unclear. To address this, we established an adeno-associated virus-containing mouse BPI and Fc fragment genes (muBPI-Fc) and compared antigenicity of these recombinant proteins in murine models. Immunohistochemistry showed the expression of both fusion proteins at injected sites. ELISA and Western blotting showed that the muBPI-Fc protein was detected in serum up to 8 weeks after injection, without generation of autoantibodies against muBPI-Fc. In contrast, expressed hBPI-Fc protein was only detected on the 2nd week, whereas the autoantibody against hBPI-Fc protein occurred in serum from the 4th week to the end of study. muBPI-Fc also reduced production of proinflammatory cytokines and protected mice from endotoxemia and bacteremia. Our data showed that AAV-muBPI-Fc has potential long-term efficacy as an anti-endotoxin and has anti-bacterial activity in mice, suggesting the potential clinical application of AAV-hBPI-Fc, such as in endotoxin shock. PMID- 27501063 TI - "Is voice a marker for Autism spectrum disorder? A systematic review and meta analysis". AB - Individuals with Autism Spectrum Disorder (ASD) tend to show distinctive, atypical acoustic patterns of speech. These behaviors affect social interactions and social development and could represent a non-invasive marker for ASD. We systematically reviewed the literature quantifying acoustic patterns in ASD. Search terms were: (prosody OR intonation OR inflection OR intensity OR pitch OR fundamental frequency OR speech rate OR voice quality OR acoustic) AND (autis* OR Asperger). Results were filtered to include only: empirical studies quantifying acoustic features of vocal production in ASD, with a sample size >2, and the inclusion of a neurotypical comparison group and/or correlations between acoustic measures and severity of clinical features. We identified 34 articles, including 30 univariate studies and 15 multivariate machine-learning studies. We performed meta-analyses of the univariate studies, identifying significant differences in mean pitch and pitch range between individuals with ASD and comparison participants (Cohen's d of 0.4-0.5 and discriminatory accuracy of about 61-64%). The multivariate studies reported higher accuracies than the univariate studies (63-96%). However, the methods used and the acoustic features investigated were too diverse for performing meta-analysis. We conclude that multivariate studies of acoustic patterns are a promising but yet unsystematic avenue for establishing ASD markers. We outline three recommendations for future studies: open data, open methods, and theory-driven research. Autism Res 2017, 10: 384-407. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 27501065 TI - Night shift work and other determinants of estradiol, testosterone, and dehydroepiandrosterone sulfate among middle-aged nurses and midwives. AB - OBJECTIVES: The aims of our study were to (i) investigate the association between rotating night shift work and blood concentrations of estradiol, testosterone and dehydroepiandrosterone sulfate (DHEAS) and (2) evaluate the role of their non occupational determinants. METHODS: A cross-sectional study was conducted on 345 premenopausal and 187 postmenopausal nurses and midwives (263 women working rotating night shifts and 269 women working during days). Data from in-person interviews were used, anthropometric measurements were performed, and body mass index (BMI) and waist- to-hip ratio were calculated. Morning blood and spot urine samples were collected. Multiple linear regression models were fitted with hormone concentrations as dependent variables, and night shift work characteristics and demographic, reproductive, lifestyle and anthropometric determinants as independent variables. Modification of the effect by chronotype was examined. RESULTS: Among postmenopausal women, we observed a statistically significant positive association between the total duration of night shift work >15 years and estradiol level (P<0.05 when compared to night work duration <5 years). Night shift work characteristics were significantly associated with estradiol among morning-type postmenopausal women. The well-established associations between hormones and their major determinants, such as age and BMI, were confirmed. CONCLUSIONS: The findings of our study imply that prolonged night shift work may be associated with increased estradiol levels among postmenopausal women, especially among the morning-type postmenopausal women. PMID- 27501066 TI - Free Energy Contribution Analysis Using Response Kernel Approximation: Insights into the Acylation Reaction of a Beta-Lactamase. AB - A widely applicable free energy contribution analysis (FECA) method based on the quantum mechanical/molecular mechanical (QM/MM) approximation using response kernel approaches has been proposed to investigate the influences of environmental residues and/or atoms in the QM region on the free energy profile. This method can evaluate atomic contributions to the free energy along the reaction path including polarization effects on the QM region within a dramatically reduced computational time. The rate-limiting step in the deactivation of the beta-lactam antibiotic cefalotin (CLS) by beta-lactamase was studied using this method. The experimentally observed activation barrier was successfully reproduced by free energy perturbation calculations along the optimized reaction path that involved activation by the carboxylate moiety in CLS. It was found that the free energy profile in the QM region was slightly higher than the isolated energy and that two residues, Lys67 and Lys315, as well as water molecules deeply influenced the QM atoms associated with the bond alternation reaction in the acyl-enzyme intermediate. These facts suggested that the surrounding residues are favorable for the reactant complex and prevent the intermediate from being too stabilized to proceed to the following deacylation reaction. We have demonstrated that the free energy contribution analysis should be a useful method to investigate enzyme catalysis and to facilitate intelligent molecular design. PMID- 27501067 TI - Nanoscale Electrochemistry of sp(2) Carbon Materials: From Graphite and Graphene to Carbon Nanotubes. AB - Carbon materials have a long history of use as electrodes in electrochemistry, from (bio)electroanalysis to applications in energy technologies, such as batteries and fuel cells. With the advent of new forms of nanocarbon, particularly, carbon nanotubes and graphene, carbon electrode materials have taken on even greater significance for electrochemical studies, both in their own right and as components and supports in an array of functional composites. With the increasing prominence of carbon nanomaterials in electrochemistry comes a need to critically evaluate the experimental framework from which a microscopic understanding of electrochemical processes is best developed. This Account advocates the use of emerging electrochemical imaging techniques and confined electrochemical cell formats that have considerable potential to reveal major new perspectives on the intrinsic electrochemical activity of carbon materials, with unprecedented detail and spatial resolution. These techniques allow particular features on a surface to be targeted and models of structure-activity to be developed and tested on a wide range of length scales and time scales. When high resolution electrochemical imaging data are combined with information from other microscopy and spectroscopy techniques applied to the same area of an electrode surface, in a correlative-electrochemical microscopy approach, highly resolved and unambiguous pictures of electrode activity are revealed that provide new views of the electrochemical properties of carbon materials. With a focus on major sp(2) carbon materials, graphite, graphene, and single walled carbon nanotubes (SWNTs), this Account summarizes recent advances that have changed understanding of interfacial electrochemistry at carbon electrodes including: (i) Unequivocal evidence for the high activity of the basal surface of highly oriented pyrolytic graphite (HOPG), which is at least as active as noble metal electrodes (e.g., platinum) for outer-sphere redox processes. (ii) Demonstration of the high activity of basal plane HOPG toward other reactions, with no requirement for catalysis by step edges or defects, as exemplified by studies of proton-coupled electron transfer, redox transformations of adsorbed molecules, surface functionalization via diazonium electrochemistry, and metal electrodeposition. (iii) Rationalization of the complex interplay of different factors that determine electrochemistry at graphene, including the source (mechanical exfoliation from graphite vs chemical vapor deposition), number of graphene layers, edges, electronic structure, redox couple, and electrode history effects. (iv) New methodologies that allow nanoscale electrochemistry of 1D materials (SWNTs) to be related to their electronic characteristics (metallic vs semiconductor SWNTs), size, and quality, with high resolution imaging revealing the high activity of SWNT sidewalls and the importance of defects for some electrocatalytic reactions (e.g., the oxygen reduction reaction). The experimental approaches highlighted for carbon electrodes are generally applicable to other electrode materials and set a new framework and course for the study of electrochemical and interfacial processes. PMID- 27501068 TI - Atomoxetine ameliorates nocturnal enuresis with subclinical attention deficit/hyperactivity disorder. AB - BACKGROUND: Recent studies have shown that incontinence and attention deficit/hyperactivity disorder (ADHD) coexist and there is an interaction between them. The treatment for nocturnal enuresis (NE) and ADHD, however, has not been established. METHODS: At the first visit to the outpatient clinic, physical examination and history taking were carried out in 265 new patients with NE. After excluding the possibility of comorbid ADHD and related disorders, patients with monosymptomatic NE (MNE) were treated with desmopressin and/or alarm, and those with non-monosymptomatic NE (NMNE) were treated with anti-cholinergics and/or alarm. This 12 week treatment did not work in 65 patients, and they were re-assessed for comorbid ADHD. A total of 24 were diagnosed with ADHD, and they were treated with atomoxetine (1.8 mg/kg/day) in addition to ongoing therapy for NE. RESULTS: After 8 weeks of atomoxetine, the average wet nights per months was significantly decreased: 18.5-4.6 in the MNE group (P = 0.001), and 22.1-12.4 in the NMNE group (P = 0.0251). Overall, atomoxetine was beneficial in 19 of 24 patients. CONCLUSIONS: Atomoxetine may be a suitable option for refractory NE with comorbid ADHD. PMID- 27501069 TI - Cytomegalovirus-Induced Hemophagocytic Lymphohistiocytosis in an Extreme Preterm Infant: Recognition and Therapy Leading to Recovery. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that can be triggered by cytomegalovirus, a relatively common infectious exposure to neonates. The clinical presentation is common to many acute illnesses seen in extreme premature infants; however, there are key clinical and laboratory findings that can lead to the diagnosis. PURPOSE: We present a case of an extreme premature infant of 25 weeks' gestation who developed cytomegalovirus-induced HLH. Using the current published protocols that are used in pediatric cancer can be adapted for use in a premature infant, which led to remission of HLH and eventual discharge from the neonatal intensive care unit. IMPLICATIONS FOR PRACTICE: There are published treatment protocols used in pediatric oncology that when initiated early can lead to favorable outcomes and remission in even the most fragile neonates. IMPLICATIONS FOR RESEARCH: Additional studies are needed on the pharmacokinetics, dosing, and side effects on medications used for treatment of HLH in preterm infants. Additional research is needed to improve the clinician's ability to reach the diagnosis as well as define treatment strategies that provide optimal outcomes. PMID- 27501070 TI - Establishment of the Relationship Between Fathers and Premature Infants in Neonatal Units. AB - BACKGROUND: Parents and their preterm infants (born between 32-37 weeks of gestation) are often overlooked by the healthcare system. And very little attention is given to the relationship parents develop with their infants in the neonatal unit (NNU). Specifically, very few studies focused on fathers and how they establish a relationship with their infants. However, we know that the father-infant relationship is extremely important for their future social development and more. PURPOSE: This article presents the results of a qualitative study of the establishment of the father-premature infant relationship in an NNU. METHODS/SEARCH STRATEGY: The study's theoretical framework was Bell's model of the parent-infant relationship, which encompasses discovery, physical proximity, communication, involvement, and emotional attachment. Ten fathers of premature infants (gestational age: 32-37 weeks) participated in 2 semistructured interviews (1 individual and 1 "in situ," ie, at the infant's bedside) during the first week following the premature birth. FINDINGS/RESULTS: The results confirm the emergence of different components of the relationship between fathers and their children from the first days of hospitalization in the NNU. The commitment component is the basis for the development of other components in the relationship with their children. Furthermore, involvement influences the deployment of emotional attachment, discovery, physical proximity, and communication toward premature infants. Similarly, the 5 themes of the model can be seen as forming a dynamic nexus in which each theme influences the others. IMPLICATIONS FOR PRACTICE: For neonatal nurses, this model of the early father child relationship helps the understanding of the deployment of that relationship according to 5 components. Similarly, it provides awareness of the experiences of fathers so that nurses can be better equipped to support and individualize interventions tailored to their specific needs, thus helping them develop and sustain the relationship with their children. IMPLICATIONS FOR RESEARCH: This study allows us to better understand fathers' experience regarding the establishment of the relationship to their premature infants born between 32 and 37 weeks of gestation. However, there is little understanding about the early paternal experience and more research on this dyad is necessary in neonatology. PMID- 27501071 TI - [Distal Pancreatectomy with Autologous Fibrin Sealant - Implementation of an Established Concept of Tissue Sealing in Pancreatic Surgery]. AB - Background: Postoperative pancreatic fistulas (POPF) remain a major concern after distal pancreatectomy. Irrespective of the technique to close the pancreatic remnant, pancreatic fistulas will occur in approximately 30 % of patients undergoing distal pancreatectomy. For the first time ever, autologous fibrin sealant (Vivostat(r)) was used to additionally seal the pancreatic remnant after a distal pancreatectomy. The aim was to analyse whether this changes the postoperative outcome. Patients/Material and Methods: In 2015, a technical case series was performed in 15 patients who underwent distal pancreatectomy. The pancreatic remnant was additionally sealed with autologous fibrin sealant (Vivostat(r)). Results: A postoperative pancreatic fistula (POPF) occurred in 5/15 patients (33 %). One patient had a POPF grade A (1/15, 6.7 %), whereas a POPF grade B occurred in 4/15 patients (26.7 %). 75 % (3/4) of the patients with a POPF grade B were sufficiently treated with antibiotics, whereas a CT-guided percutaneous drainage had to be placed only in one case. Conclusion: Autologous fibrin sealant is simple to apply and seems to be well tolerated. However, it does not seem to avoid the development of postoperative pancreatic fistulas after distal pancreatectomy. PMID- 27501072 TI - [Symptoms, Diagnostics, Treatment and Classification of 22 Patients with Postpancreatectomy Haemorrhage (PPH) in a Series of 400 Consecutive Pancreatic Head Resections and Pancreatectomies]. AB - Introduction: Postpancreatectomy haemorrhage (PPH) is a dangerous complication after pancreatic resection. Patients and Methods: From 2006 to 2015, 400 consecutive pancreatic head resections and pancreatectomies were performed and prospectively documented. This study analysed incidence, treatment and outcome of patients with PPH. Results: Incidence of PPH was 5.5 % (n = 22). PPH occurred in a median of eight days after pancreatic surgery with an equal frequency of symptoms being caused by gastrointestinal bleeding (n = 11) and abdominal bleeding (n = 11). Postoperative pancreatic fistulas (POPF) were significantly more frequent in case of PPH (45 % POPF in case of PPH vs. 20 % POPF in case of no PPH, p < 0.01). PPH was more frequent after pancreatogastrostomy (8/70; 11 %) than after pancreatojejunostomy (11/281; 4 %; p = 0.01). The majority of bleedings after pancreatogastrostomy came from the intragastric cut surface of the pancreas. During the first week, relaparotomy was significantly more frequent (n = 5; 56 %) than in late PPH (n = 1; 8 %; p = 0.01). In late PPH, interventions (angiography; n = 7, endoscopy; n = 4) were more frequent. In 16 severe cases, surgical/interventional bleeding control (n = 12) or relevant transfusions of more than 3 units of packed red blood cells (n = 4) were performed. Compared with the whole group, mortality was significantly increased in case of PPH (13.6 % in case of PPH vs. 3.7 % in case of no PPH; p = 0.03). Conclusion: PPH is an episodic and potentially life-threatening complication with an increased mortality rate, which is frequently associated with impaired healing of the pancreatic anastomosis. Diagnostic investigation and treatment of PPH requires an experienced surgical centre with a close cooperation with endoscopy and (interventional) radiology. PMID- 27501073 TI - [Prophylaxis of Recurrent Venous Leg Ulcer]. AB - Venous leg ulcer (VLU) counts among the most common chronic wounds in Europe. Treatment is lengthy, cumbersome and costly, and there is a high rate of recurrence. This review shows the measures that should be offered to every patient with healed VLU to permanently prevent recurrence. To prevent VLU in case of varicose veins, the progression of chronic venous insufficiency (CVI) has to be stopped. There is convincing evidence that the effective treatment of varicose veins reduces the recurrence rate in patients with VLU. In patients with post thrombotic syndrome (PTS), further thrombosis should be prevented through targeted prophylaxis of new thromboembolic events. The benefit of endovascular revascularization on the VLU recurrence rate in patients with post-thrombotic damage in the pelvic veins has not been proven in clinical studies. On the other hand, it has been clearly demonstrated in several studies that compression therapy is the basic procedure for the prevention of recurrent VLU in patients with varicose veins or PTS, regardless of whether other measures have been implemented or not. Good adherence in patients with compression therapy is more important than choosing the highest possible compression class. Future efforts for patients with VLU must aim to provide therapists with tools and treatment strategies to guide their patients and to increase patients' acceptance and understanding of the importance of self-management, in particular regarding compression therapy for the prevention of recurrent VLU. PMID- 27501074 TI - Purification of Native Complexes for Structural Study Using a Tandem Affinity Tag Method. AB - Affinity purification approaches have been successful in isolating native complexes for proteomic characterization. Structural heterogeneity and a degree of compositional heterogeneity of a complex do not usually impede progress in conducting such studies. In contrast, a complex intended for structural characterization should be purified in a state that is both compositionally and structurally homogeneous as well as at a higher concentration than required for proteomics. Recently, there have been significant advances in the application of electron microscopy for structure determination of large macromolecular complexes. This has heightened interest in approaches to purify native complexes of sufficient quality and quantity for structural determination by electron microscopy. The Tandem Affinity Purification (TAP) method has been optimized to extract and purify an 18-subunit, ~ 0.8 MDa ribonucleoprotein assembly from budding yeast (Saccharomyces cerevisiae) suitable for negative stain and electron cryo microscopy. Herein is detailed the modifications made to the TAP method, the rationale for making these changes, and the approaches taken to assay for a compositionally and structurally homogeneous complex. PMID- 27501075 TI - Systematic evaluation of circulating inflammatory markers for hepatocellular carcinoma. AB - BACKGROUNDS & AIMS: A number of circulating inflammatory factors are implicated in the pathogenesis and prognostication of hepatocellular carcinoma (HCC). We aim to evaluate the prognostication of multiple serum inflammatory factors simultaneously and develop an objective inflammatory score for HCC. METHODS: A prospective cohort of 555 patients with HCC with paired serum samples was accrued from 2009 to 2012. The blood levels of conventional inflammatory markers, namely C-reactive protein (CRP), albumin, neutrophils, lymphocytes and platelet, were determined, and 41 other exploratory markers were measured by a multiplex assay. The prognostication and interaction of markers were determined by univariate and multivarite analyses. RESULTS: The cohort was randomly divided into training cohort (n=139) and validation cohort (n=416). There were no differences in baseline characteristics between the two cohorts. In the training cohort, independent prognostic factors for overall survival included CRP (hazard ratio [HR] 1.107; P=.003), albumin (HR 0.953; P=.032) and interleukin-8 (HR=5.816; P<.001). We have modified the existing inflammation-based index (IBI) by adding serum interleukin-8 level. The modified IBI could stratify patients into four groups with distinct overall survival (P<.001). The results were also validated in the validation cohort. When compared with IBI and other conventional inflammatory markers, the modified IBI had better prognostic performance with higher c-index and homogeneity likelihood ratio chi-square. CONCLUSIONS: Among the conventional and exploratory circulating inflammatory markers, higher CRP, lower albumin and higher interleukin-8 were independent prognosticators. By combining these factors, a simple and accurate inflammatory index could be constructed. PMID- 27501076 TI - Beyond Taphonomy: Exploring Craniometric Variation Among Anatomical Material. AB - Anatomical crania are occasionally encountered in forensic anthropology laboratories when that material is mistaken for forensically significant human remains. Using craniometric analyses and statistical measures of sample homogeneity, we determine whether anatomical material can be described as a single, homogenous group or as a diverse mix of populations. Twenty-one interlandmark distances were collected from 85 anatomical preparations. Distance measures were calculated between all pairs using a pooled within-sample variance/covariance matrix and then subjected to a Defrise-Gussenhoven test between each paired distance to test whether each pair was drawn randomly from the same population. In the Defrise-Gussenhoven analysis, twenty-two percent (n = 66) of the 300 pairwise combinations were significant at the 0.05 level or below. The level of homogeneity suggests a majority of that material originated from the subcontinent of India or West Asia. Therefore, anatomical material can be viewed as a moderately homogenous group, but with a shared taphonomic history. PMID- 27501077 TI - Tactile massage as a nursing intervention in child and adolescent psychiatry: nurses' experiences. AB - : WHAT IS KNOWN ABOUT THE SUBJECT?: There is little research on the implementation of tactile massage in child and adolescent psychiatry that describes children's and adolescents' experiences and outcomes. There is also limited knowledge of providing tactile massage in child and adolescent psychiatry. WHAT DOES THIS PAPER ADD TO EXISTING KNOWLEDGE?: This paper describes 10 nurses' experiences of tactile massage as a nursing intervention in child and adolescent psychiatry. The nurses considered tactile massage a non-verbal nursing intervention that could complement other available treatments. It reveals their reflections on the impact of tactile massage on their nursing and on themselves as a person, including the belief that they had developed deepened self reflection and attentiveness. The nurses highlighted the importance of providing a trusting environment and collaborating with the children and adolescents. They both experienced and observed that tactile massage triggered various physical and mental processes in the children and adolescents, such as improvement in sleep disturbances, an ability to relax in body and mind and a deeper connectedness with their own bodies and feelings. The nurses described instructing next of kin in the use of tactile massage, which they believed could serve as a tool at home, mainly as a way for next of kin to help their children to relax, fall asleep more easily and to deepen connectedness. However, the nurses stressed the need to consider if it was appropriate or desired by the children and adolescents. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Tactile massage addresses the individual's emotional and physiological responses and could therefore bring holistic nursing to child and adolescent psychiatry. It could also help nurses in child and adolescent psychiatry to develop their attentiveness and sensitivity in acknowledging the needs of children and adolescents in psychiatric care. ABSTRACT: Introduction There is limited research on tactile massage in child and adolescent psychiatry and no studies investigating experiences of providing tactile massage in child and adolescent psychiatry were found. Aim The aim was therefore to describe nurses' experiences of providing tactile massage as a nursing intervention in child and adolescent psychiatry. Method Ten nurses trained in tactile massage and employed at five different child and adolescent psychiatry clinics in Sweden participated in a qualitative study. Semi-structured interviews were conducted, transcribed verbatim and analysed by qualitative content analysis. Results Three categories emerged from the analysis. 'Confirming body and mind', 'Building a trusting relationship' and 'Instructing next of kin in tactile massage'. Attentiveness to and respect for the integrity of the children and adolescents were essential for creating a trusting relationship with them. Tactile massage was found to trigger various physical and mental processes in the children and adolescents. The nurses reflected on the impact of tactile massage on their nursing and on themselves as a person, stating that it had led to the development of self-reflection and attentiveness. Implications for practice Tactile massage addresses the individual's emotional and physiological responses and could therefore bring holistic nursing to child and adolescent psychiatry. It might also enhance attentiveness and sensitivity on the part of child and adolescent psychiatry nurses when acknowledging the needs of children and adolescents in psychiatric care. PMID- 27501080 TI - Evaluating an Organizational-Level Occupational Health Intervention in a Combined Regression Discontinuity and Randomized Control Design. AB - Organizational-level occupational health interventions have great potential to improve employees' health and well-being. However, they often compare unfavourably to individual-level interventions. This calls for improving methods for designing, implementing and evaluating organizational interventions. This paper presents and discusses the regression discontinuity design because, like the randomized control trial, it is a strong summative experimental design, but it typically fits organizational-level interventions better. The paper explores advantages and disadvantages of a regression discontinuity design with an embedded randomized control trial. It provides an example from an intervention study focusing on reducing sickness absence in 196 preschools. The paper demonstrates that such a design fits the organizational context, because it allows management to focus on organizations or workgroups with the most salient problems. In addition, organizations may accept an embedded randomized design because the organizations or groups with most salient needs receive obligatory treatment as part of the regression discontinuity design. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27501079 TI - Applying Fluorescence Resonance Energy Transfer (FRET) to Examine Effector Translocation Efficiency by Coxiella burnetii during siRNA Silencing. AB - Coxiella burnetii, the causative agent of Q fever, is an intracellular pathogen that relies on a Type IV Dot/Icm Secretion System to establish a replicative niche. A cohort of effectors are translocated through this system into the host cell to manipulate host processes and allow the establishment of a unique lysosome-derived vacuole for replication. The method presented here involves the combination of two well-established techniques: specific gene silencing using siRNA and measurement of effector translocation using a FRET-based substrate that relies on beta-lactamase activity. Applying these two approaches, we can begin to understand the role of host factors in bacterial secretion system function and effector translocation. In this study we examined the role of Rab5A and Rab7A, both important regulators of the endocytic trafficking pathway. We demonstrate that silencing the expression of either protein results in a decrease in effector translocation efficiency. These methods can be easily modified to examine other intracellular and extracellular pathogens that also utilize secretion systems. In this way, a global picture of host factors involved in bacterial effector translocation may be revealed. PMID- 27501081 TI - Nickel-Catalyzed C-H Chalcogenation of Anilines. AB - The C-H thiolation of aniline derivatives was accomplished with a versatile nickel(II) catalyst under ligand-free conditions. The robust nature of the nickel catalysis system was reflected by the C-H thiolation with a good functional group tolerance and an ample scope, employing anilines possessing removable directing groups. The widely applicable nickel catalyst also allowed for aniline C-H selenylations, while mechanistic studies provided strong support that the rate determining step is the C-H activation. PMID- 27501078 TI - Role of Base Excision "Repair" Enzymes in Erasing Epigenetic Marks from DNA. AB - Base excision repair (BER) is one of several DNA repair pathways found in all three domains of life. BER counters the mutagenic and cytotoxic effects of damage that occurs continuously to the nitrogenous bases in DNA, and its critical role in maintaining genomic integrity is well established. However, BER also performs essential functions in processes other than DNA repair, where it acts on naturally modified bases in DNA. A prominent example is the central role of BER in mediating active DNA demethylation, a multistep process that erases the epigenetic mark 5-methylcytosine (5mC), and derivatives thereof, converting them back to cytosine. Herein, we review recent advances in the understanding of how BER mediates this critical component of epigenetic regulation in plants and animals. PMID- 27501082 TI - Phosphorus accumulates faster than nitrogen globally in freshwater ecosystems under anthropogenic impacts. AB - Combined effects of cumulative nutrient inputs and biogeochemical processes that occur in freshwater under anthropogenic eutrophication could lead to myriad shifts in nitrogen (N):phosphorus (P) stoichiometry in global freshwater ecosystems, but this is not yet well-assessed. Here we evaluated the characteristics of N and P stoichiometries in bodies of freshwater and their herbaceous macrophytes across human-impact levels, regions and periods. Freshwater and its macrophytes had higher N and P concentrations and lower N : P ratios in heavily than lightly human-impacted environments, further evidenced by spatiotemporal comparisons across eutrophication gradients. N and P concentrations in freshwater ecosystems were positively correlated and N : P was negatively correlated with population density in China. These results indicate a faster accumulation of P than N in human-impacted freshwater ecosystems, which could have large effects on the trophic webs and biogeochemical cycles of estuaries and coastal areas by freshwater loadings, and reinforce the importance of rehabilitating these ecosystems. PMID- 27501083 TI - A computational biomarker of idiopathic generalized epilepsy from resting state EEG. AB - Epilepsy is one of the most common serious neurologic conditions. It is characterized by the tendency to have recurrent seizures, which arise against a backdrop of apparently normal brain activity. At present, clinical diagnosis relies on the following: (1) case history, which can be unreliable; (2) observation of transient abnormal activity during electroencephalography (EEG), which may not be present during clinical evaluation; and (3) if diagnostic uncertainty occurs, undertaking prolonged monitoring in an attempt to observe EEG abnormalities, which is costly. Herein, we describe the discovery and validation of an epilepsy biomarker based on computational analysis of a short segment of resting-state (interictal) EEG. Our method utilizes a computer model of dynamic networks, where the network is inferred from the extent of synchrony between EEG channels (functional networks) and the normalized power spectrum of the clinical data. We optimize model parameters using a leave-one-out classification on a dataset comprising 30 people with idiopathic generalized epilepsy (IGE) and 38 normal controls. Applying this scheme to all 68 subjects we find 100% specificity at 56.7% sensitivity, and 100% sensitivity at 65.8% specificity. We believe this biomarker could readily provide additional support to the diagnostic process. PMID- 27501084 TI - A genotype-phenotype correlation study reveals that a non-coding RNA might be associated with cardiovascular anomalies in fetuses with WHS. PMID- 27501085 TI - Systematic review of paediatric studies of adverse drug reactions from pharmacovigilance databases. AB - OBJECTIVE: To perform a systematic review of studies describing paediatric adverse drug reactions (ADRs) conducted from national pharmacovigilance databases. METHODS: A systematic literature search of studies describing results for paediatric ADRs from national pharmacovigilance databases was performed. PubMed database, Embase and MEDLINE were searched up to March 2015. The descriptive studies included were analysed for country of origin, reporters, and ADR reporting rate, drugs, ADRs and number of fatalities. RESULTS: 20 studies were identified. Doctors were the largest group of reporters in all the studies, and with more consumer reports seen in USA. The studies ranged from 3 - 37 years. The highest ADR reporting rate was 1458 reports per year per million children in Cuba. Antibiotics and vaccines were the most frequently reported drugs, in almost all the studies. The most frequent ADRs were skin and nervous system disorders. The highest proportion of fatalities and serious reports was from North America. Drugs used for treating attention deficit hyperactivity disorders (ADHD) and isotretinoin were the most frequently reported drugs for ADRs in North America. CONCLUSIONS: There were geographical differences in drugs responsible for ADRs and their seriousness, especially in North America. Very few studies were conducted in Asia and Latin America, none were found from Africa. PMID- 27501086 TI - Wind- and Rain-Induced Vibrations Impose Different Selection Pressures on Multimodal Signaling. AB - The world is a noisy place, and animals have evolved a myriad of strategies to communicate in it. Animal communication signals are, however, often multimodal; their components can be processed by multiple sensory systems, and noise can thus affect signal components across different modalities. We studied the effect of environmental noise on multimodal communication in the tungara frog (Physalaemus pustulosus). Males communicate with rivals using airborne sounds combined with call-induced water ripples. We tested males under control as well as noisy conditions in which we mimicked rain- and wind-induced vibrations on the water surface. Males responded more strongly to a multimodal playback in which sound and ripples were combined, compared to a unimodal sound-only playback, but only in the absence of rain and wind. Under windy conditions, males decreased their response to the multimodal playback, suggesting that wind noise interferes with the detection of rival ripples. Under rainy conditions, males increased their response, irrespective of signal playback, suggesting that different noise sources can have different impacts on communication. Our findings show that noise in an additional sensory channel can affect multimodal signal perception and thereby drive signal evolution, but not always in the expected direction. PMID- 27501087 TI - Communication Value of Mistakes in Dark-Eyed Junco Song. AB - Sexual signals contain information on individual quality or motivation, and most explanations for their reliability are based on signal costs. A recent suggestion is that signaling mistakes, defined as deviations from typical signal design, provide cues on individual quality, contributing to reliable communication even when signal design is not costly. We describe several atypical song traits in dark-eyed juncos (Junco hyemalis) that may be mistakes during song production or development and occur in up to 6% of songs. These putative mistakes were more frequent in an urban versus a wildland population, and individuals differed in their frequency of mistakes. Some atypical signals were more frequent in younger males or were negatively related to paternity success, supporting the hypothesis that fewer mistakes indicate individual quality. We also discuss unexpected results, such as some atypical signals being more frequent in more ornamented males and in songs with lower performance demands. Song consistency (similarity across syllable renditions) was positively related to male age and paternity success; nonetheless, relations with paternity were stronger when looking at the most deviant syllable renditions, suggesting that the perceptual salience of large mistakes may mediate receiver responses to song consistency. Results indicate that signaling mistakes reveal relevant information to play a role in communication. PMID- 27501088 TI - Many Paths to a Common Destination: Morphological Differentiation of a Functionally Convergent Visual Signal. AB - Understanding the interacting outcomes of selection and historical contingency in shaping adaptive evolution remains a challenge in evolutionary biology. While selection can produce convergent outcomes when species occupy similar environments, the unique history of each species can also influence evolutionary trajectories and result in different phenotypic end points. The question is to what extent historical contingency places species on different adaptive pathways and, in turn, the extent to which we can predict evolutionary outcomes. Among lizards there are several distantly related genera that have independently evolved an elaborate extendible dewlap for territorial communication. We conducted a detailed morphological study and employed new phylogenetic comparative methods to investigate the evolution of the underlying hyoid that powers the extension of the dewlap. This analysis showed that there appear to have been multiple phenotypic pathways for evolving a functionally convergent dewlap. The biomechanical complexity that underlies this morphological structure implies that adaptation should have been constrained to a narrow phenotypic pathway. However, multiple adaptive solutions have been possible in apparent response to a common selection pressure. Thus, the phenotypic outcome that subsequently evolved in different genera seems to have been contingent on the history of the group in question. This blurs the distinction between convergent and historically contingent adaptation and suggests that adaptive phenotypic diversity can evolve without the need for divergent natural selection. PMID- 27501089 TI - Effects of Prior Contest Experience and Contest Outcome on Female Reproductive Decisions and Offspring Fitness. AB - Winning or losing a prior contest can influence the outcome of future contests, but it might also alter subsequent reproductive decisions. For example, losers may increase their investment in the current breeding attempt if losing a contest indicates limited prospects for future breeding. Using the burying beetle Nicrophorus vespilloides, we tested whether females adjust their prehatching and posthatching reproductive effort after winning or losing a contest with a same sex conspecific. Burying beetles breed on carcasses of small vertebrates for which there is fierce intrasexual competition. We found no evidence that winning or losing a contest influenced reproductive investment decisions in this species. Instead, we show that a female's prior contest experience (regardless of its outcome) influenced the amount of posthatching care provided, with downstream consequences for the female's reproductive output; both winners and losers spent more time provisioning food to their offspring and produced larger broods than females with no contest experience. We discuss the wider implications of our findings and present a conceptual model linking contest-mediated adjustments in parental investment to population-level processes. We propose that the frequency of intraspecific contests could both influence and be influenced by population dynamics in species where contest experience influences the size and/or number of offspring produced. PMID- 27501090 TI - How the Magnitude of Prey Genetic Variation Alters Predator-Prey Eco-Evolutionary Dynamics. AB - Evolution can alter the stability and dynamics of ecological communities; for example, prey evolution can drive cyclic dynamics in predator-prey systems that are not possible in the absence of evolution. However, it is unclear how the magnitude of additive genetic variation in the evolving species mediates those effects. In this study, I explore how the magnitude of prey additive genetic variation determines what effects prey evolution has on the dynamics and stability of predator-prey systems. I use linear stability analysis to decompose the stability of a general eco-evolutionary predator-prey model into components representing the stabilities of the ecological and evolutionary subsystems as well as the interactions between those subsystems. My results show that with low genetic variation, the cyclic dynamics and stability of the system are determined by the ecological subsystem. With increased genetic variation, disruptive selection always destabilizes stable communities, stabilizing selection can stabilize or destabilize communities, and prey evolution can alter predator-prey phase lags. Stability changes occur approximately when the magnitude of genetic variation balances the (in)stabilities of the ecological and evolutionary subsystems. I discuss the connections between my stability results and prior results from the theory of adaptive dynamics. PMID- 27501091 TI - Multiscale Evaluation of Thermal Dependence in the Glucocorticoid Response of Vertebrates. AB - Environmental temperature has profound effects on animal physiology, ecology, and evolution. Glucocorticoid (GC) hormones, through effects on phenotypic performance and life history, provide fundamental vertebrate physiological adaptations to environmental variation, yet we lack a comprehensive understanding of how temperature influences GC regulation in vertebrates. Using field studies and meta- and comparative phylogenetic analyses, we investigated how acute change and broadscale variation in temperature correlated with baseline and stress induced GC levels. Glucocorticoid levels were found to be temperature and taxon dependent, but generally, vertebrates exhibited strong positive correlations with acute changes in temperature. Furthermore, reptile baseline, bird baseline, and capture stress-induced GC levels to some extent covaried with broadscale environmental temperature. Thus, vertebrate GC function appears clearly thermally influenced. However, we caution that lack of detailed knowledge of thermal plasticity, heritability, and the basis for strong phylogenetic signal in GC responses limits our current understanding of the role of GC hormones in species' responses to current and future climate variation. PMID- 27501092 TI - Discovery of a Giant Chameleon-Like Lizard (Anolis) on Hispaniola and Its Significance to Understanding Replicated Adaptive Radiations. AB - We report a new chameleon-like Anolis species from Hispaniola that is ecomorphologically similar to congeners found only on Cuba. Lizards from both clades possess short limbs and a short tail and utilize relatively narrow perches, leading us to recognize a novel example of ecomorphological matching among islands in the well-known Greater Antillean anole radiation. This discovery supports the hypothesis that the assembly of island faunas can be substantially deterministic and highlights the continued potential for basic discovery to reveal new insights in well-studied groups. Restricted to a threatened band of midelevation transitional forest near the border of the Dominican Republic and Haiti, this new species appears to be highly endangered. PMID- 27501093 TI - Scale-Dependent Community Theory for Streams and Other Linear Habitats. AB - The maintenance of species diversity occurs at the regional scale but depends on interacting processes at the full range of lower scales. Although there is a long history of study of regional diversity as an emergent property, analyses of fully multiscale dynamics are rare. Here, we use scale transition theory for a quantitative analysis of multiscale diversity maintenance with continuous scales of dispersal and environmental variation in space and time. We develop our analysis with a model of a linear habitat, applicable to streams or coastlines, to provide a theoretical foundation for the long-standing interest in environmental variation and dispersal, including downstream drift. We find that the strength of regional coexistence is strongest when local densities and local environmental conditions are strongly correlated. Increasing dispersal and shortening environmental correlations weaken the strength of coexistence regionally and shift the dominant coexistence mechanism from fitness-density covariance to the spatial storage effect, while increasing local diversity. Analysis of the physical and biological determinants of these mechanisms improves understanding of traditional concepts of environmental filters, mass effects, and species sorting. Our results highlight the limitations of the binary distinction between local communities and a species pool and emphasize species coexistence as a problem of multiple scales in space and time. PMID- 27501094 TI - Tissue Specificity and Sex-Specific Regulatory Variation Permit the Evolution of Sex-Biased Gene Expression. AB - Genetic correlations between males and females are often thought to constrain the evolution of sexual dimorphism. However, sexually dimorphic traits and the underlying sexually dimorphic gene expression patterns are often rapidly evolving. We explore this apparent paradox by measuring the genetic correlation in gene expression between males and females (Cmf) across broad evolutionary timescales, using two RNA-sequencing data sets spanning multiple populations and multiple species. We find that unbiased genes have higher Cmf than sex-biased genes, consistent with intersexual genetic correlations constraining the evolution of sexual dimorphism. However, we found that highly sex-biased genes (both male and female biased) also had higher tissue specificity, and unbiased genes had greater expression breadth, suggesting that pleiotropy may constrain the breakdown of intersexual genetic correlations. Finally, we show that genes with high Cmf showed some degree of sex-specific changes in gene expression in males and females. Together, our results suggest that genetic correlations between males and females may be less important in constraining the evolution of sex-biased gene expression than pleiotropy. Sex-specific regulatory variation and tissue specificity may resolve the paradox of widespread sex bias within a largely shared genome. PMID- 27501095 TI - Complex heterochrony underlies the evolution of Caenorhabditis elegans hermaphrodite sex allocation. AB - Hermaphroditic organisms are key models in sex allocation research, yet the developmental processes by which hermaphrodite sex allocation can evolve remain largely unknown. Here we use experimental evolution of hermaphrodite-male (androdioecious) Caenorhabditis elegans populations to quantify the developmental changes underlying adaptive shifts in hermaphrodite sex allocation. We show that the experimental evolution of increased early-life self-fertility occurred through modification of a suite of developmental traits: increased self-sperm production, accelerated oogenesis and ovulation, and increased embryo retention. The experimental evolution of increased self-sperm production delayed entry into oogenesis-as expected, given the sequentially coupled production of self spermatogenesis and oogenesis. Surprisingly, however, delayed oogenesis onset did not delay reproductive maturity, nor did it trade-off with gamete or embryo size. Comparing developmental time dynamics of germline and soma indicates that the evolution of increased sperm production did not delay reproductive maturity due to a globally accelerated larval development during the period of self spermatogenesis. Overall, heterochrony in gametogenesis and soma can explain adaptive shifts in hermaphrodite sex allocation. PMID- 27501096 TI - Utility of the Department of Defense Serum Repository in Assessing Deployment Exposure. AB - OBJECTIVE: This paper describes why the research project was conducted in terms of demonstrating the utility of the Department of Defense Serum Repository in addressing deployment environmental exposures. METHODS: The history deployment exposure surveillance was reviewed and the rationale for developing validated biomarkers that were detected in sera in postdeployment samples and compared with nondeployed controls was described. The goal was to find validated biomarkers that are associated with both exposures and health outcomes. RESULTS: The articles in this supplement described novel serum biomarkers that were found to be associated with deployment exposures and weakly associated with some health outcomes. CONCLUSIONS: Future research must continue to validate the use of serum biomarkers when operational contingencies prevent the gold standard collection of real-time breathing zone samples in deployed service members. PMID- 27501097 TI - Assessing Health Outcomes After Environmental Exposures Associated With Open Pit Burning in Deployed US Service Members. AB - OBJECTIVE: This study assessed the long-term health impact of environmental exposures associated with open pit burning in deployed US service members. METHODS: Two hundred individuals deployed to Balad, Iraq, and Bagram, Afghanistan, with known exposure to open pits, were matched to 200 non-deployed service members. Both cohorts were observed for adverse health outcomes after returning from deployment. RESULTS: Slight increased risks were observed for respiratory diseases in the Bagram cohort (adj RR: 1.259), and for cardiovascular disease in the Balad cohort (adj RR: 1.072), but the findings were not significant. The combined deployed cohort showed lower risks for adverse health outcomes, suggesting a healthy deployer effect. CONCLUSIONS: In conclusion, this study did not find significantly increased risks for selected health outcomes after burn pit exposure during deployment among two deployed cohorts compared with a non-deployed cohort. PMID- 27501098 TI - Metabolic Pathways and Networks Associated With Tobacco Use in Military Personnel. AB - OBJECTIVE: The aim of this study is to use high-resolution metabolomics (HRM) to identify metabolic pathways and networks associated with tobacco use in military personnel. METHODS: Four hundred deidentified samples obtained from the Department of Defense Serum Repository were classified as tobacco users or nonusers according to cotinine content. HRM and bioinformatic methods were used to determine pathways and networks associated with classification. RESULTS: Eighty individuals were classified as tobacco users compared with 320 nonusers on the basis of cotinine levels at least 10 ng/mL. Alterations in lipid and xenobiotic metabolism, and diverse effects on amino acid, sialic acid, and purine and pyrimidine metabolism were observed. Importantly, network analysis showed broad effects on metabolic associations not simply linked to well-defined pathways. CONCLUSIONS: Tobacco use has complex metabolic effects that must be considered in evaluation of deployment-associated environmental exposures in military personnel. PMID- 27501099 TI - Deployment-Associated Exposure Surveillance With High-Resolution Metabolomics. AB - OBJECTIVE: The aim of this study was to assess the suitability of high-resolution metabolomics (HRM) for measure of internal exposure and effect biomarkers from deployment-related environmental hazards. METHODS: HRM provides extensive coverage of metabolism and data relevant to a broad spectrum of environmental exposures. This review briefly describes the analytic platform, workflow, and recent applications of HRM as a prototype environmental exposure surveillance system. RESULTS: Building upon techniques available for contemporary occupational medicine and exposure sciences, HRM methods are able to integrate external exposures, internal body burden of environmental agents, and relevant biological responses with health outcomes. CONCLUSIONS: Systematic analysis of existing Department of Defense Serum Repository samples will provide a high-quality, cross sectional reference dataset for deployment-associated exposures while at the same time establishing a foundation for precision medicine. PMID- 27501100 TI - Airborne Dioxins, Furans, and Polycyclic Aromatic Hydrocarbons Exposure to Military Personnel in Iraq. AB - OBJECTIVES: The objective of this study was to use ambient polycyclic aromatic hydrocarbon (PAH), polychlorinated dibenzo-p-dioxins (PCDD), and polychlorinated dibenzofurans (PCDF) concentrations measured at Joint Base Balad in Iraq in 2007 to identify the sources of these species and their spatial patterns. METHODS: The ratios of the measured species were compared with literature data for likely emission sources. Using the multiple site measurements on specific days, contour maps have been drawn using inverse distance weighting (IDW). RESULTS: These analyses suggest multiple sources, including the burn pit (primarily a source of PCDD/PCDFs), the transportation field (primarily as source of PAHs), and other sources of PAHs that include aircraft, space heating, and diesel power generation. CONCLUSIONS: The nature and locations of the sources were identified. PCDD/PCDFs were emitted by the burn pit. Multiple PAH sources exist across the base. PMID- 27501101 TI - Introduction to Department of Defense Research on Burn Pits, Biomarkers, and Health Outcomes Related to Deployment in Iraq and Afghanistan. AB - OBJECTIVE: This paper provides an overview of our study that was designed to assess the health impact of environmental exposures to open pit burning in deployed troops. METHODS: The rationale for the study and the structure of the research plan was laid out. An overview of each article in the supplement was provided. The cohort of deployed Service members was assessed for airborne exposure, relevant biomarkers, and health outcomes following deployment to Balad, Iraq, and/or Bagram, Afghanistan. RESULTS: Polycyclic aromatic hydrocarbon (PAH) exposures were elevated, and serum biomarkers were statistically different postdeployment. Associations were noted between PAHs and dioxins and microRNAs. Some health outcomes were evident in deployers compared with nondeployers. CONCLUSIONS: Future research will examine the associations between demographic variables, smoking status, biomarker levels, and related health outcomes. PMID- 27501102 TI - Source Apportionment of Airborne Dioxins, Furans, and Polycyclic Aromatic Hydrocarbons at a United States Forward Operating Air Base During the Iraq War. AB - OBJECTIVES: The objective was to apportion the sources of the ambient polycyclic aromatic hydrocarbon (PAH), polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran concentrations measured at Joint Base Balad in Iraq. METHODS: Positive matrix factorization (PMF) was applied to the data to obtain the chemical profiles and contribution time series of the PAHs, PCDDs, and PCDFs. Conditional probability function (CPF) analyses were performed to assess the source directionality relative to the monitoring sites. RESULTS: Three source types were identified and apportioned. The sources were: the burn pit, diesel vehicles and generators, and aircraft emissions. The CPF plots were consistent with the assigned source types. CONCLUSIONS: The PCDDs and PCDFs originated primarily from the burn pit. Higher molecular weight PAHs were associated with vehicle emissions while the aircraft emissions were enriched in low molecular weight PAHs. PMID- 27501103 TI - Environmental Air Sampling Near Burn Pit and Incinerator Operations at Bagram Airfield, Afghanistan. AB - OBJECTIVE: This study presents environmental air samples collected at a US military installation with a solid waste disposal facility (SWDF) containing a burn pit from 2005 through 2012 and compared these results with occupational (breathing zone) samples. METHODS: Particulate matter (PM) environmental samples were collected as part of the installation monitoring program. Service Members in four security positions were monitored for PM and acrolein occupational exposures. RESULTS: The highest recorded PM2.5 concentration occurred at the SWDF. A highly populated sampling site, the Bazaar site, had the highest mean PM10, with the SWDF following in second. Acrolein and respirable PM were considerably higher in the breathing zone samples than environmental samples. CONCLUSIONS: The diversity of results support the concept of a complex environment with multiple polluting sources and changing meteorological and operational conditions. PMID- 27501104 TI - Pilot Metabolome-Wide Association Study of Benzo(a)pyrene in Serum From Military Personnel. AB - OBJECTIVE: A pilot study was conducted to test the feasibility of using Department of Defense Serum Repository (DoDSR) samples to study health and exposure-related effects. METHODS: Thirty unidentified human serum samples were obtained from the DoDSR and analyzed for normal serum metabolites with high resolution mass spectrometry and serum levels of free benzo(a)pyrene (BaP) by gas chromatography-mass spectrometry. Metabolic associations with BaP were determined using a metabolome-wide association study (MWAS) and metabolic pathway enrichment. RESULTS: The serum analysis detected normal ranges of glucose, selected amino acids, fatty acids, and creatinine. Free BaP was detected in a broad concentration range. MWAS of BaP showed associations with lipids, fatty acids, and sulfur amino acid metabolic pathways. CONCLUSION: The results show that the DoDSR samples are of sufficient quality for chemical profiling of DoD personnel. PMID- 27501105 TI - High-Resolution Metabolomics Assessment of Military Personnel: Evaluating Analytical Strategies for Chemical Detection. AB - OBJECTIVE: The aim of this study was to maximize detection of serum metabolites with high-resolution metabolomics (HRM). METHODS: Department of Defense Serum Repository (DoDSR) samples were analyzed using ultrahigh resolution mass spectrometry with three complementary chromatographic phases and four ionization modes. Chemical coverage was evaluated by number of ions detected and accurate mass matches to a human metabolomics database. RESULTS: Individual HRM platforms provided accurate mass matches for up to 58% of the KEGG metabolite database. Combining two analytical methods increased matches to 72% and included metabolites in most major human metabolic pathways and chemical classes. Detection and feature quality varied by analytical configuration. CONCLUSIONS: Dual chromatography HRM with positive and negative electrospray ionization provides an effective generalized method for metabolic assessment of military personnel. PMID- 27501106 TI - Detection of Serum microRNAs From Department of Defense Serum Repository: Correlation With Cotinine, Cytokine, and Polycyclic Aromatic Hydrocarbon Levels. AB - OBJECTIVE: The aim of this study was to investigate whether serum samples from the Department of Defense Serum Repository (DoDSR) are of sufficient quality to detect microRNAs (miRNAs), cytokines, immunoglobulin E (IgE), and polycyclic aromatic hydrocarbons (PAHs). METHODS: MiRNAs were isolated and quantified by polymerase chain reaction (PCR) array. Cytokines and chemokines related to inflammation were measured using multiplex immunoassays. Cotinine and IgE were detected by enzyme-linked immunoassay (ELISA) and PAHs were detected by Liquid Chromatography/Mass Spectroscopy. RESULTS: We detected miRNAs, cytokines, IgE, and PAHs with high sensitivity. Eleven of 30 samples tested positive for cotinine suggesting tobacco exposure. Significant associations between serum cotinine, cytokine, IgE, PAHs, and miRNA were discovered. CONCLUSION: We successfully quantified over 200 potential biomarkers of occupational exposure from DoDSR samples. The stored serum samples were not affected by hemolysis and represent a powerful tool for biomarker discovery and analysis in retrospective studies. PMID- 27501107 TI - Polycyclic Aromatic Hydrocarbons and Polychlorinated Dibenzo-p Dioxins/Dibenzofurans in Microliter Samples of Human Serum as Exposure Indicators. AB - OBJECTIVE: The objectives were: 1) measure polycyclic aromatic hydrocarbons (PAHs), polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) in 100 MUL of human serum and 2) assess PAH and PCDD/PCDF as markers of burn pit exposures during military deployments. METHODS: PAHs and PCDDs/PCDFs were analyzed in 100 MUL serum samples collected pre- and post-deployment from 200 persons deployed to Iraq or Afghanistan (CASE); 200 persons not deployed (CONTROL) with gas chromatography/mass spectrometry. RESULTS: Naphthalene was found in ~83% of the samples and was statistically different between post deployment CASE personnel and pre-deployment. 1,2,3,4,6,7,8-Heptachlorodibenzo-p dioxin, Octachlorodibenzo-p-dioxin, 1,2,3,7,8,9-Hexachlorodibenzofuran, and 1,2,3,4,6,7,8-Heptachlorodibenzofuran were found in ~38% of samples. Concentrations were significantly different between CASE and CONTROL and between pre- and post-deployment samples. CONCLUSIONS: PAH and PCDD/PCDF in serum can serve as exposure markers and measurements in small volumes is feasible for quantifying exposure to burn pits. PMID- 27501108 TI - High-Resolution Metabolomics for Nutrition and Health Assessment of Armed Forces Personnel. AB - OBJECTIVE: The aim of this study was to test the utility of high-resolution metabolomics (HRM) for analysis of nutritional status and health indicators in military personnel. METHODS: Serum samples from 400 military personnel were obtained from the Department of Defense Serum Repository (DoDSR) and analyzed for metabolites related to nutrition and health status. Metabolic profile organization was studied using modulated modularity clustering (MMC). RESULTS: HRM provided quantitative measures of 61 metabolites across chemical classes for use as nutritional and clinical biomarkers. Levels were comparable to reported values except for arginine and glutamine, which were above and below reference ranges, respectively. MMC generated five clusters, three of which were associated and contained amino acids. The others contained lipids and mitochondria-related metabolites. CONCLUSIONS: HRM analysis of serum is suitable for real-time and/or retrospective evaluation of nutrition and health status of specific military cohorts. PMID- 27501109 TI - MicroRNAs as Novel Biomarkers of Deployment Status and Exposure to Polychlorinated Dibenzo-p-Dioxins/Dibenzofurans. AB - OBJECTIVE: To determine if service members deployed to locations with open air burn pits have different serum microRNA (miRNA) profiles after deployment compared with length-of-service matched, non-deployed individuals. We also tested for correlations between miRNA and serum levels of Polychlorinated Dibenzo-p Dioxins/Dibenzofurans (PCDD/PCDFs). METHODS: MiRNAs were isolated and quantified by PCR array. Groups were analyzed for differences in miRNA expression. Correlations between serum miRNA and PCDD/PCDFs were assessed with a linear regression model. RESULTS: Several miRNAs were differentially expressed after deployment and a partially overlapping set of miRNAs were identified between deployed and non-deployed individuals. Significant correlations between miRNAs and PCDD/PCDFs were identified. CONCLUSIONS: Serum miRNA levels show a link between deployment to locations with open burn pits and environmental exposures that can take place during deployment. PMID- 27501110 TI - MicroRNA Expression Profiling of the Armed Forces Health Surveillance Branch Cohort for Identification of "Enviro-miRs" Associated With Deployment-Based Environmental Exposure. AB - OBJECTIVE: The aim of this study was to identify serum microRNA (miRNA) biomarkers that indicate deployment-associated exposures in service members at military installations with open burn pits. Another objective was to determine detection rates of miRNAs in Department of Defense Serum Repository (DoDSR) samples with a high-throughput methodology. METHODS: Low-volume serum samples (n = 800) were profiled by miRNA-capture isolation, pre-amplification, and measurement by a quantitative PCR-based OpenArray platform. Normalized quantitative cycle values were used for differential expression analysis between groups. RESULTS: Assay specificity, dynamic range, reproducibility, and detection rates by OpenArray passed target desired specifications. Serum abundant miRNAs were consistently measured in study specimens. Four miRNAs were differentially expressed in the case deployment group subjects. CONCLUSIONS: miRNAs are suitable RNA species for biomarker discovery in the DoDSR serum specimens. Serum miRNAs are candidate biomarkers for deployment and environmental exposure in military service members. PMID- 27501111 TI - Piloting CenteringParenting in Two Alberta Public Health Well-Child Clinics. AB - OBJECTIVES: To pilot a group health service delivery model, CenteringParenting, for new parents, to assess its feasibility and impact on maternal and infant outcomes. DESIGN AND SAMPLE: Families attended six, 2-hr group sessions in their child's first year of life with three to seven other families. Health assessments, parent-led discussions, and vaccinations occurred within the group. MEASURES: Demographic, breastfeeding, vaccination, maternal psychosocial health, parenting, and satisfaction data were collected and compared to a representative cohort. RESULTS: Four groups ran in two clinics. Four to eight parent/infant dyads participated in each group, 24 total dyads. Most participating parents were mothers. Dyads in the group model received 12 hr of contact with Public Health over the year compared to 3 hr in the typical one-on-one model. Participants were younger, more likely to have lower levels of education, and lower household income than the comparison group. Parents reported improvements in parenting experiences following the program. At 4 months, all CenteringParenting babies were vaccinated compared to 95% of babies in the comparison group. CONCLUSIONS: The pilot was successfully completed. Additional research is required to examine the effectiveness of CenteringParenting. Data collected provide insight into potential primary outcomes of interest and informs larger, rigorously designed longitudinal studies. PMID- 27501112 TI - Herpes virus reactivation after initiation of interferon-free antiviral agents in HIV-HCV-coinfected subjects: a new immune restoration disease? AB - We report four HCV-HIV-coinfected patients who developed herpes zoster or muco cutaneous herpes virus disease shortly after starting interferon-free antiviral treatment for HCV. We suggest that in our patients the prompt clearance of HCV following direct-acting antivirals leads to a paradoxical effect on the innate and adaptive immune system mediating the reactivation of herpetic infection. PMID- 27501113 TI - Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells. AB - Ataxia telangiectasia and Rad3-related (ATR) proteins are sensors of DNA damage, which induces homologous recombination (HR)-dependent repair. ATR is a master regulator of DNA damage repair (DDR), signaling to control DNA replication, DNA repair and apoptosis. Therefore, the ATR pathway might be an attractive target for developing new drugs. This study was designed to investigate the antitumor effects of the ATR inhibitor, AZD6738 and its underlying mechanism in human breast cancer cells. Growth inhibitory effects of AZD6738 against human breast cancer cell lines were studied using a 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (methyl thiazolyl tetrazolium, MTT) assay. Cell cycle analysis, Western blotting, immunofluorescence and comet assays were also performed to elucidate underlying mechanisms of AZD6738 action. Anti proliferative and DDR inhibitory effects of AZD6738 were demonstrated in human breast cancer cell lines. Among 13 cell lines, the IC50 values of nine cell lines were less than 1 MUmol/L using MTT assay. Two cell lines, SK-BR-3 and BT-474, were chosen for further evaluation focused on human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells. Sensitive SK-BR-3 but not the less sensitive BT-474 breast cancer cells showed increased level of apoptosis and S phase arrest and reduced expression levels of phosphorylated check-point kinase 1 (CHK1) and other repair markers. Decreased functional CHK1 expression induced DNA damage accumulation due to HR inactivation. AZD6738 showed synergistic activity with cisplatin. Understanding the antitumor activity and mechanisms of AZD6738 in HER2-positive breast cancer cells creates the possibility for future clinical trials targeting DDR in HER2-positive breast cancer treatment. PMID- 27501114 TI - Automated Lipid Bilayer Membrane Formation Using a Polydimethylsiloxane Thin Film. AB - An artificial lipid bilayer, or black lipid membrane (BLM), is a powerful tool for studying ion channels and protein interactions, as well as for biosensor applications. However, conventional BLM formation techniques have several drawbacks and they often require specific expertise and laborious processes. In particular, conventional BLMs suffer from low formation success rates and inconsistent membrane formation time. Here, we demonstrate a storable and transportable BLM formation system with controlled thinning-out time and enhanced BLM formation rate by replacing conventionally used films (polytetrafluoroethylene, polyoxymethylene, polystyrene) to polydimethylsiloxane (PDMS). In this experiment, a porous-structured polymer such as PDMS thin film is used. In addition, as opposed to conventionally used solvents with low viscosity, the use of squalene permitted a controlled thinning-out time via slow solvent absorption by PDMS, prolonging membrane lifetime. In addition, by using a mixture of squalene and hexadecane, the freezing point of the lipid solution was increased (~16 degrees C), in addition, membrane precursors were produced that can be indefinitely stored and readily transported. These membrane precursors have reduced BLM formation time of < 1 hr and achieved a BLM formation rate of ~80%. Moreover, ion channel experiments with gramicidin A demonstrated the feasibility of the membrane system. PMID- 27501115 TI - High-sensitivity cardiac troponin testing for primary care: analytical assay considerations required before widespread implementation. PMID- 27501116 TI - Not all performance validity tests are created equal: The role of recollection and familiarity in the Test of Memory Malingering and Word Memory Test. AB - INTRODUCTION: The Test of Memory Malingering (TOMM) and the Word Memory Test (WMT) are both performance validity tests (PVTs) that use a two-alternative forced-choice (2AFC) recognition memory format. Several studies have reported that these tests are susceptible to cognitive impairment and that the WMT is more susceptible than the TOMM. The current study explored components of recognition memory (i.e., conscious recollection and familiarity) underlying the TOMM and WMT to identify factors that make them susceptible and resilient to cognitive impairment. METHOD: Fifty-four nonclinical undergraduate research participants were administered the TOMM and WMT while providing introspective judgments about their recognition memory using the remember/know/guess procedure. In addition, half of participants were administered dual-task interference, a manipulation intended to reduce recollection, during these tests, while the other half completed these tests without interference. Standard cutoffs on the TOMM and WMT were explored, as well as alternative cutoffs based on TOMM Trial 1 scores. RESULTS: The WMT was more impacted by dual-task interference than standard TOMM cutoff trials, while alternative TOMM cutoff trials were equally impacted by dual task interference relative to the WMT. Dual-task interference reduced recollection on these tests, but spared familiarity. Standard TOMM trials and the WMT were relatively comparable on levels of recollection, but familiarity contributed more to the TOMM than to the WMT. Alternative TOMM trials possessed lower familiarity and recollection than standard TOMM trials and lower recollection than the WMT. CONCLUSIONS: Reduced recollection places examinees at risk of failing the TOMM and WMT, while familiarity contributes to the relative resilience of the standard TOMM. Future development of 2AFC recognition memory PVTs should attempt to maximize the contribution of familiarity to their completion. PMID- 27501117 TI - Enhancing the Thermal Conductance of Polymer and Sapphire Interface via Self Assembled Monolayer. AB - Interfacial thermal conductance (ITC) receives enormous consideration because of its significance in determining thermal performance of hybrid materials, such as polymer based nanocomposites. In this study, the ITC between sapphire and polystyrene (PS) was systematically investigated by time domain thermoreflectance (TDTR) method. Silane based self-assembled monolayers (SAMs) with varying end groups, -NH2, -Cl, -SH and -H, were introduced into sapphire/PS interface, and their effects on ITC were investigated. The ITC was found to be enhanced up by a factor of 7 through functionalizing the sapphire surface with SAM, which ends with a chloride group (-Cl). The results show that the enhancement of the thermal transport across the SAM-functionalized interface comes from both strong covalent bonding between sapphire and silane-based SAM, and the high compatibility between the SAM and PS. Among the SAMs studied in this work, we found that the ITC almost linearly depends on solubility parameters, which could be the dominant factor influencing on the ITC compared with wettability and adhesion. The SAMs serve as an intermediate layer that bridges the sapphire and PS. Such a feature can be applied to ceramic-polymer immiscible interfaces by functionalizing the ceramic surface with molecules that are miscible with the polymer materials. This research provides guidance on the design of critical-heat transfer materials such as composites and nanofluids for thermal management. PMID- 27501118 TI - Multimodality therapy for locally-advanced thymic epithelial tumors: where are we now? PMID- 27501119 TI - Pulse modulated radiofrequency exposure influences cognitive performance. AB - PURPOSE: To investigate whether exposure to pulse modulated radiofrequency (PM RF) influences human cognitive performance, and whether it does so in a dose dependent manner. MATERIALS AND METHODS: Thirty-six healthy adults participated in a randomized, double-blind, counterbalanced provocation study. Cognitive performance was assessed using a visual discrimination task and a modified Sternberg working memory task, which were calibrated to individual performance levels in a preliminary testing session. An sXh920 planar exposure system was used to generate a 920 MHz GSM-like signal, providing three conditions (peak spatial SAR averaged over 10 g) of 0 W/kg (sham), 1 W/kg (low RF) and 2 W/kg (high RF). RESULTS: A significant decrease in reaction time (RT) in the Sternberg working memory task was found during exposure compared to sham. This effect was not dose-dependent. CONCLUSIONS: Cognitive performance was shown to be faster under PM RF conditions, relative to sham, in a working memory task. While the majority of the literature has not found effects of PM RF exposure on cognitive performance, it is possible that the methodological improvements employed in the present study increased sensitivity, and thus the ability to detect potential effects. PMID- 27501120 TI - Noninvasive Continuous Hemoglobin Monitoring in Combat Casualties: A Pilot Study. AB - OBJECTIVE: To describe the accuracy and precision of noninvasive hemoglobin measurement (SpHb) compared with laboratory or point-of-care Hb, and SpHb ability to trend in seriously injured casualties. METHODS: Observational study in a convenience sample of combat casualties undergoing resuscitation at two US military trauma hospitals in Afghanistan. SpHb was obtained using the Masimo Rainbow SET (Probe Rev E/Radical-7 Pulse CO-Oximeter v 7.6.2.1). Clinically indicated Hb was analyzed with a Coulter or iStat and compared with simultaneous SpHb values. RESULTS: Twenty-three patients were studied (ISS 20 +/- 9.8; age 29 +/- 9 years; male 97%; 100% intubated). Primary injury cause: improvised explosive device (67%) or gunshot (17%). There were 49 SpHb-Hb pairs (median 2 per subject). Bias: 0.3 +/- 1.6 g/dL (95% LOA -2.4, 3.4 g/dL). The SpHb-Hb difference < +/- 1 g/dL in 37% of pairs. Eighty-six percent of pairs changed in a similar direction. Using an absolute change in Hb of >1 g/dL, a concurrent absolute change in SpHb of >1 g/dL had a sensitivity: 61%, specificity 85%, positive predictive value: 80%, and a negative predictive value: 69%. The SpHb signal was present in 4643 of 6137 min monitored (76%). CONCLUSIONS: This was the first study to describe continuous SpHb in seriously injured combat casualties. Using a threshold of 1 g/dL previously specified in the literature, continuous SpHb is not precise enough to serve as sole transfusion trigger in trauma patients. Further research is needed to determine if it is useful for trending Hb changes or as an early indicator of deterioration in combat casualties. PMID- 27501121 TI - Is there an association between study size and reporting of study quality in dermatological clinical trials? A meta-epidemiological review. PMID- 27501122 TI - Outcomes of patients with renal monoclonal immunoglobulin deposition disease. AB - Recent reports suggest that deep hematologic responses to chemotherapy are associated with improved renal outcomes in monoclonal immunoglobulin deposition disease (MIDD). Here we describe the long term outcomes and identify prognostic factors after first line treatment of the largest reported series of patients with MIDD. Between March 1992 and December 2014, 88 patients with MIDD were seen at Mayo Clinic, MN. Renal responses were defined using criteria used for light chain amyloidosis (AL) or those used by the IMWG. Sixty-one (69%) patients had a GFR < 30 mL/min/1.73 m2 and 16 (18%) were on renal replacement therapy at diagnosis. The interval between albuminuria or elevation in creatinine and MIDD diagnosis was 12 months suggesting a delay in diagnosis. Thirty-seven patients (42%) had at least a hematologic CR/VGPR. Fifty-three (60%) received an autologous stem cell transplant (ASCT) or proteasome inhibitor (PI)-based treatments. Patients receiving ASCT or PI-based therapies were more likely to achieve at least a hematologic CR/VGPR compared to those receiving other therapies: 66% vs 2%, p < 0.0001. Patients that achieved a hematologic CR were more likely to achieve a renal response (53% vs 24%, p = 0.001). Five year overall and renal survival for the entire cohort was 67% and 57%, respectively. In multivariate analyses, a baseline GFR < 20 mL/min/1.73 m2 and a renal response (using AL or IMWG criteria) were independently predictive of progression to dialysis. This study confirms that deep hematologic responses, best achieved with ASCT or PI-based therapies, are a prerequisite to achieving renal responses. Am. J. Hematol. 91:1123-1128, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27501123 TI - Using Saccadometry with Deep Brain Stimulation to Study Normal and Pathological Brain Function. AB - The oculomotor system involves a large number of brain areas including parts of the basal ganglia, and various neurodegenerative diseases including Parkinson's and Huntington's can disrupt it. People with Parkinson's disease, for example, tend to have increased saccadic latencies. Consequently, the quantitative measurement of saccadic eye movements has received considerable attention as a potential biomarker for neurodegenerative conditions. A lot more can be learned about the brain in both health and disease by observing what happens to eye movements when the function of specific brain areas is perturbed. Deep brain stimulation is a surgical intervention used for the management of a range of neurological conditions including Parkinson's disease, in which stimulating electrodes are placed in specific brain areas including several sites in the basal ganglia. Eye movement measurements can then be made with the stimulator systems both off and on and the results compared. With suitable experimental design, this approach can be used to study the pathophysiology of the disease being treated, the mechanism by which DBS exerts it beneficial effects, and even aspects of normal neurophysiology. PMID- 27501124 TI - A Mouse Model of Retinal Ischemia-Reperfusion Injury Through Elevation of Intraocular Pressure. AB - Retinal ischemia-reperfusion (I/R) is a pathophysiological process contributing to cellular damage in multiple ocular conditions, including glaucoma, diabetic retinopathy, and retinal vascular occlusions. Rodent models of I/R injury are providing significant insights into mechanisms and treatment strategies for human I/R injury, especially with regard to neurodegenerative damage in the retinal neurovascular unit. Presented here is a protocol for inducing retinal I/R injury in mice through elevation of intraocular pressure (IOP). In this protocol, the ocular anterior chamber is cannulated with a needle, through which flows the drip of an elevated saline reservoir. Using this drip to raise IOP above systolic arterial blood pressure, a practitioner temporarily halts inner retinal blood flow (ischemia). When circulation is reinstated (reperfusion) by removal of the cannula, severe cellular damage ensues, resulting ultimately in retinal neurodegeneration. Recent studies demonstrate inflammation, vascular permeability, and capillary degeneration as additional elements of this model. Compared to alternative retinal I/R methodologies, such as retinal arterial ligation, retinal I/R injury by elevated IOP offers advantages in its anatomical specificity, experimental tractability, and technical accessibility, presenting itself as a valuable tool for examining neuronal pathogenesis and therapy in the retinal neurovascular unit. PMID- 27501125 TI - Separating and Recycling Plastic, Glass, and Gallium from Waste Solar Cell Modules by Nitrogen Pyrolysis and Vacuum Decomposition. AB - Many countries have gained benefits through the solar cells industry due to its high efficiency and nonpolluting power generation associated with solar energy. Accordingly, the market of solar cell modules is expanding rapidly in recent decade. However, how to environmentally friendly and effectively recycle waste solar cell modules is seldom concerned. Based on nitrogen pyrolysis and vacuum decomposition, this work can successfully recycle useful organic components, glass, and gallium from solar cell modules. The results were summarized as follows: (i) nitrogen pyrolysis process can effectively decompose plastic. Organic conversion rate approached 100% in the condition of 773 K, 30 min, and 0.5 L/min N2 flow rate. But, it should be noted that pyrolysis temperature should not exceed 773 K, and harmful products would be increased with the increasing of temperature, such as benzene and its derivatives by GC-MS measurement; (ii) separation principle, products analysis, and optimization of vacuum decomposition were discussed. Gallium can be well recycled under temperature of 1123 K, system pressure of 1 Pa and reaction time of 40 min. This technology is quite significant in accordance with the "Reduce, Reuse, and Recycle Principle" for solid waste, and provides an opportunity for sustainable development of photovoltaic industry. PMID- 27501126 TI - Inflammatory bowel disease: adherence to immunomodulators in a biological therapy era. AB - BACKGROUND: Combination therapy, with anti-tumor necrosis factor-alpha agents and immunomodulators, is the most effective option to induce and maintain remission in inflammatory bowel disease (IBD). Infliximab, with its administration features, determines particular conditions of adherence; the same is not possible with thiopurines. Nevertheless, research on adherence to these treatments is scarce. Nonadherence worsens the prognosis of IBD. AIM: (a) Assess adherence to immunomodulators and (b) determine therapeutic nonadherence predictors. PATIENTS AND METHODS: We included all IBD outpatients consecutively evaluated over a 6 month period in our center. Participants completed a study-specific questionnaire on IBD, IBD therapeutic adherence (Morisky Medication Adherence Scale-8-item), Therapeutics Complexity questionnaire, Beliefs about Medication questionnaire, and Hospital Anxiety and Depression Scale. RESULTS: A total of 112 patients under azathioprine were considered; 49.1% were also under anti-tumor necrosis factor alpha. Self-assessed questionnaire showed that 70.5% were adherent to immunosuppression. Similar adherence was found with and without infliximab (68.4% monotherapy vs. 72.7%-combination therapy; P=0.61). Nonintentional nonadherence was documented in 57.6%; 42.4% reported voluntary nonadherence. Nonadherence was higher in male patients [odds ratio (OR): 3.79; 95% confidence interval (CI): 1.2 11.95; P=0.023], younger patients (OR: 0.93; 95% CI: 0.87-0.98; P=0.01), nonsmokers (OR: 4.90; 95% CI: 1.22-19.73; P=0.025), and those who had depression (OR: 2.22; 95% CI: 1.36-3.62; P=0.001). Most of the IBD patients believed in the necessity of maintaining immunosuppression (86.7%), but 36.6% reported concerns about drugs. CONCLUSION: Nonadherence to thiopurines plays a significant role in IBD. Nonetheless, it does not increase with association with biological agents. Involuntary nonadherence is higher. Male sex, younger age, nonsmoker, and presence of depression were independent predictors of nonadherence to immunomodulators. More than one-third of IBD patients had concerns about drugs. Optimizing the discussion on patients' concerns to overcome perceptual barriers related to drugs may obviate the negative course of IBD related to nonadherence. PMID- 27501127 TI - Dexmedetomidine for the treatment of hyperactive delirium refractory to haloperidol in non-intubated patients. PMID- 27501128 TI - Neonatal hepatitis B vaccination impaired the behavior and neurogenesis of mice transiently in early adulthood. AB - The immune system plays a vital role in brain development. The hepatitis B vaccine (HBV) is administered to more than 70% of neonates worldwide. Whether this neonatal vaccination affects brain development is unknown. Newborn C57BL/6 mice were injected intraperitoneally with HBV or phosphate-buffered saline. HBV induced impaired behavioral performances and hippocampal long-term potentiation at 8 weeks (w) of age without influence at 4 or 12w. At 6w, there was decreased neurogenesis, M1 microglial activation and a neurotoxic profile of neuroimmune molecule expression [increased tumor necrosis factor-alpha and reduced interferon (IFN)-gamma, brain-derived neurotrophic factor and insulin-like growth factor-1] in the hippocampus of the HBV-vaccinated mice. In the serum, HBV induced significantly higher levels of interleukin (IL)-4, indicating a T helper (Th)-2 bias. Moreover, the serum IFN-gamma/IL-4 ratio was positively correlated with the levels of neurotrophins and neurogenesis in the hippocampus at the individual level. These findings suggest that neonatal HBV vaccination of mice results in neurobehavioral impairments in early adulthood by inducing a proinflammatory and low neurotrophic milieu in the hippocampus, which follows the HBV-induced systemic Th2 bias. PMID- 27501129 TI - Monoclonal gammopathy of cutaneous significance: review of a relevant concept. AB - Some dermatologic entities are strongly associated with the presence of a monoclonal gammopathy. They should be referred to as monoclonal gammopathy of cutaneous significance (MGCS). A short review of the main entities that fit into the spectrum of MGCS is provided. Amyloidosis, macroglobulinoderma and follicular hyperkeratotic spicules result from extravascular immunoglobulin or immunoglobulin-related protein deposition. Skin findings include papules and plaques, follicular spicules, purpura, haemorrhagic bullae, macroglossia and nail changes. The skin findings in cryoglobulinemia (CG) result from vascular immunoglobulin deposition, either as immune complexes within the vessel walls in mixed CG or within the lumina of small vessels in monoclonal CG. Mixed CG manifests as palpable purpura of leukocytoclastic vasculitis, and monoclonal CG as stellar and/or retiform purpura that can evolve into extensive skin necrosis. In some rare instances, immunoglobulins have a specific biological activity. This is, for example, the case when they bind lipoproteins that precipitate and induce hypocomplementemic xanthomas. Xanthoderma related to antiflavin activity of the monoclonal component or acquired angioedema related to anti-C1INH activity is other example. Abnormal cytokine secretion is the hallmark of some entities. High vascular endothelial growth factor levels correlate with some of the skin manifestations of the Polyneuropathy organomegaly endocrinopathy monoclonal component skin changes syndrome, such as hypertrichosis or the adenopathy and extensive skin patch overlying plasmacytoma syndrome. All the clinical manifestations of the Schnitzler syndrome are IL-1 mediated. In other MGCS, such as scleromyxedema, Clarkson syndrome, TEMPI syndrome, cutis laxa and the neutrophilic dermatoses, the link between the monoclocal component and the entity is clearly established, but not understood so far. PMID- 27501130 TI - Prediction of cardiovascular events with levels of proprotein convertase subtilisin/kexin type 9: A systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces atherogenic lipoproteins and could lead to reduction of cardiovascular (CV) events. However, it is unclear whether blood PCSK9 levels predict future CV events. We performed a meta-analysis of all longitudinal studies to determine the ability of PCSK9 levels to predict risk of future CV events. METHODS: A comprehensive search of electronic databases was conducted up to February 2016. Longitudinal studies that reported events or relative risk (RR) estimates with 95% confidence intervals (CI) were included. RESULTS: All 9 studies included (12,081 participants, mean follow-up 6.62 years) reported results on total CV events. The pooled RR of total CV events for an increase in baseline PCSK9 by 1 standard deviation (SD) was 1.098 (95% CI, 1.02-1.18), corresponding to a risk increase of 10% (Z = 2.43, p = 0.015). The pooled RR of total CV events for subjects categorized in the highest tertile of baseline PCSK9 was 1.228 (95% CI, 1.035-1.457), corresponding to a risk increase of 23% (Z = 2.35, p = 0.019). When pooled estimates were derived independently for low- and high-CV risk populations, baseline PCSK9 levels predicted total CV events only in apparently healthy subjects (RR = 1.13, 95% CI: 1.050-1.222, Z = 3.21, p = 0.001) and not in populations with established CV or renal disease (RR = 1.09, 95% CI: 0.961-1.23, Z = 1.33, p = 0.182). CONCLUSIONS: PCSK9 levels are modestly but significantly associated with increased risk of total CV events. These results suggest a predictive role of PCSK9 levels on CV health and support the possible clinical role of PCSK9 inhibitors. PMID- 27501131 TI - Computational Method for the Systematic Identification of Analog Series and Key Compounds Representing Series and Their Biological Activity Profiles. AB - A computational methodology is introduced for detecting all unique series of analogs in large compound data sets, regardless of chemical relationships between analogs. No prior knowledge of core structures or R-groups is required, which are automatically determined. The approach is based upon the generation of retrosynthetic matched molecular pairs and analog networks from which distinct series are isolated. The methodology was applied to systematically extract more than 17 000 distinct series from the ChEMBL database. For comparison, analog series were also isolated from screening compounds and drugs. Known biological activities were mapped to series from ChEMBL, and in more than 13 000 of these series, key compounds were identified that represented substitution sites of all analogs within a series and its complete activity profile. The analog series, key compounds, and activity profiles are made freely available as a resource for medicinal chemistry applications. PMID- 27501132 TI - Variance of essential tremor patients' time reproduction deficits. PMID- 27501133 TI - Understanding Internal Chirality Induction of Triarylsilyl Ethers Formed from Enantiopure Alcohols. AB - Chirality transmission from point chirality to helical chirality was explored using triarylsilyl ethers. Circular dichroism (CD) spectroscopy was employed to show that the alcohol stereocenter of silylated, enantiopure secondary alcohols can transmit chirality to the aryl groups on the silicon resulting in a higher population of one helical conformation over another. Cotton effects characteristic of the aryl groups organized into one preferred conformation were observed for all of the compounds examined, which included both triphenyl- and trinaphthylsilyl groups. Alcohols with an R configuration typically induced a PMP helical twist, while an S configuration induced a MPM helical twist. Molecular modeling combined with solid-state structures also gave evidence signifying that point chirality adjacent to triphenylsilyl groups could bias the conformation of the phenyl groups. This work helps in our understanding of the origin of selectivity in our silylation-based kinetic resolutions and a role the phenyl groups play in that selectivity. PMID- 27501134 TI - Antiarrhythmic drugs in out-of-hospital cardiac arrest-what does the Amiodarone, Lidocaine, or Placebo Study tell us? PMID- 27501135 TI - Effect of Al(3+) co-doping on the luminescence properties of Cu doped Na2SiF6. AB - Studies were carried out to assess the correlation between thermoluminescence (TL) and optically stimulated luminescence (OSL) of this phosphor. It was observed that the OSL and TL glow curve consists of a wide distribution of traps having different photo-ionization cross-sections, trap depths and frequency factors. In case of Al doped sample, some of the traps up to 200 degrees C are assumed to act as a source traps for the observance of OSL due to thermal transfer of charge carriers into the deep traps beyond 480 degrees C. This suggests that Al impurities play an important role in the thermal transfer OSL process. As most of the work on this phenomenon is done on natural materials (mainly quartz) in which aluminum is a natural impurity, this study will explain the role of Al in this phenomenon. PMID- 27501136 TI - Experience in production of (68)Ga-DOTA-NOC for clinical use under an Expanded Access IND. AB - [(68)Ga]Ga-DOTA-NOC was produced under an Expanded Access IND for 174 clinical PET/CT studies to evaluate patients with neuroendocrine tumors. Production employed either the TiO2-based Eckert & Ziegler (EZAG) (68)Ge/(68)Ga-generator (with fractionated elution), or the SiO2-based ITG (68)Ge/(68)Ga-generator. In both cases, [(68)Ga]Ga-DOTA-NOC was reliably produced, without pre-synthesis purification of the(68)Ga generator eluate, using readily-implemented manual synthesis procedures. [(68)Ga]Ga-DOTA-NOC radiochemical purity averaged 99.2+/ 0.4%. Administered (68)Ga dose averaged 181+/-22 MBq, and administered peptide mass averaged 43.2+/-5.2ug (n=47) and 23.9+/-5.7ug (n=127), respectively, using the EZAG and ITG generators. At dose expiration, (68)Ge breakthrough in the final product averaged 2.7*10(-7)% and 5.4*10(-5%) using the EZAG and ITG generators, respectively. PMID- 27501137 TI - Determination of HPGe peak efficiency for voluminous gamma-ray sources by using an effective solid angle method. AB - A code called EXVol has been developed to obtain the absolute peak efficiency for an extended or voluminous gamma-ray source. The method is based on the concept of effective solid angles. Several efficiency curves that have been determined semi empirically for voluminous sources are compared with the experimental values based on certified reference volume sources. To study the geometric and matrix effects, standard gamma-ray sources of several media, volumes and shapes were measured using HPGe detectors with three different efficiencies. For the n-type detector of 32% relative efficiency, the relative deviations are less than +/ 10%; this performance is similar to that of existing programs for similar purposes. The EXVol code is able to calculate the detection efficiency within approximately five minutes or less. Systematic errors based on EXVol input parameters, which are mainly due to the inherent uncertainty in the detector's characteristic dimensions provided by the vendor, are studied to obtain more accurate specifications of the detectors. PMID- 27501138 TI - Synthesis and evaluation of a (68)Ga labeled folic acid derivative for targeting folate receptors. AB - Present work evaluates the potential of a newly synthesized (68)Ga-NOTA-folic acid conjugate for PET imaging of tumors over-expressing folate receptors (FRs). NOTA-folic acid conjugate was synthesized and characterized. It was radiolabeled with (68)Ga in >= 95% radiolabeling yields. In vitro cell binding studies showed a maximum cell uptake of 1.7+/-0.4% per million KB cells which was completely blocked on addition of cold folic acid showing specificity towards the FRs. However, further studies in tumor xenografts are warranted in order to assess the potential of (68)Ga-folic acid complex for imaging tumors over-expressing FRs. PMID- 27501139 TI - Hydroxyapatite (HA) microparticles labeled with (32)P - A promising option in the radiation synovectomy for inflamed joints. AB - In the present article we describe a systematic approach pursued for the synthesis of (32)P-labeled hydroxyapatite (HA) microparticles (1-10um size range) using no carrier added (NCA) (32)P produced in a nuclear reactor and animal evaluation of its utility as an expected viable radiopharmaceutical for the treatment of pain intensive arthrosis. NCA (32)P was produced via the (32)S(n,p)(32)P route in nuclear reactor with high radionuclidic purity (99.95+/ 0.01%, n=5). Phosphorus-32-labeled hydroxyapatite microparticles (1-10um size range) were synthesized with high radiochemical purity (99.0+/-0.3% n=12) under optimized conditions and the formulation showed excellent in vitro stability in saline as well as in rat serum. Intra-articular administration of the radiolabeled particles in the knee joints of normal Wistar rats showed near complete retention of activity within the synovial cavity upto 1 month post administration. The radiochemical formulation thus demonstrated promising features as a radiopharmaceutical for treatment of arthritis with excellent logistic advantage for shipment to sites distant from the production facility thanks to the suitable nuclear decay properties of (32)P. PMID- 27501140 TI - ADHD and executive functioning deficits in OCD youths who hoard. AB - Hoarding is common among youth with obsessive compulsive disorder (OCD), with up to 26% of OCD youth exhibiting hoarding symptoms. Recent evidence from adult hoarding and OCD cohorts suggests that hoarding symptoms are associated with executive functioning deficits similar to those observed in subjects with attention deficit hyperactivity disorder (ADHD). However, while hoarding behavior often onsets during childhood, there is little information about executive function deficits and ADHD in affected children and adolescents. The study sample included 431 youths (ages 6-17 years) diagnosed with OCD who participated in the OCD Collaborative Genetics Study and the OCD Collaborative Genetics Association Study and completed a series of clinician-administered and parent report assessments, including diagnostic interviews and measures of executive functioning (Behavior Rating Inventory of Executive Functioning; BRIEF) and hoarding severity (Hoarding Rating Scale-Interview; HRS-I). 113 youths (26%) had clinically significant levels of hoarding compulsions. Youths with and without hoarding differed significantly on most executive functioning subdomains and composite indices as measured by the parent-rated BRIEF. Groups did not differ in the frequency of full DSM-IV ADHD diagnoses; however, the hoarding group had significantly greater number of inattention and hyperactivity symptoms compared to the non-hoarding group. In multivariate models, we found that overall BRIEF scores were related to hoarding severity, adjusting for age, gender and ADHD symptoms. These findings suggest an association between hoarding and executive functioning deficits in youths with OCD, and assessing executive functioning may be important for investigating the etiology and treatment of children and adolescents with hoarding and OCD. PMID- 27501141 TI - A population study of the association between sleep disturbance and suicidal behaviour in people with mental illness. AB - Limited representative research has considered the relationship between sleep disturbance and suicidal behaviour among people with mental illness. We investigated the relationship between sleep disturbance and suicidal behaviour across Part II interview of the National Comorbidity Survey Replication (NCSR). The associations between sleep disturbance and suicidal behaviour (thoughts, plans and attempts) were investigated using logistic and multinomial logistic regressions and stratified across six mental disorder groups (depression, anxiety, substance use disorders (SUD), eating disorders (ED), bipolar disorders (BD) and early life disorders). From 5701 participants (mean age 43.4 years 58% women), people with any mental disorder experiencing sleep disturbance were at increased odds of suicidal thoughts (odds ratio (OR): 2.5; 95% CI: 1.7, 3.6) and suicidal plans and attempts (OR: 5.7; 95% CI: 2.7, 11.9) adjusting for age, sex and income. People with BD (OR: 8.9; 95 CI: 2.1, 38.1), early life disorders (OR 6.98, 95% ci 2.48, 19.67), depression (OR 1.88, 95% CI 1.14, 3.11), anxiety (OR 1.90, 95% CI 1.28, 2.85) and SUD (2.60, 95% CI 1.23, 5.49) but not ED, were at increased odds of suicidal thoughts in the presence of sleep disturbance. Adjusting for anti-depressant intake attenuated the effect sizes by up to 20% but the associations remained significant. In conclusion, sleep disturbance is a potential risk factor for suicidal behaviours in people with mental illness. Monitoring and management of sleep disturbance in clinical practice might be an important strategy to mitigate suicidal behaviours in people with mental illness. PMID- 27501142 TI - Road accidents and business cycles in Spain. AB - This paper explores the causes behind the downturn in road accidents in Spain across the last decade. Possible causes are grouped into three categories: Institutional factors (a Penalty Point System, PPS, dating from 2006), technological factors (active safety and passive safety of vehicles), and macroeconomic factors (the Great recession starting in 2008, and an increase in fuel prices during the spring of 2008). The PPS has been blessed by incumbent authorities as responsible for the decline of road fatalities in Spain. Using cointegration techniques, the GDP growth rate, the fuel price, the PPS, and technological items embedded in motor vehicles appear to be statistically significantly related with accidents. Importantly, PPS is found to be significant in reducing fatal accidents. However, PPS is not significant for non-fatal accidents. In view of these results, we conclude that road accidents in Spain are very sensitive to the business cycle, and that the PPS influenced the severity (fatality) rather than the quantity of accidents in Spain. Importantly, technological items help explain a sizable fraction in accidents downturn, their effects dating back from the end of the nineties. PMID- 27501143 TI - Assessment of Methods for the Intracellular Blockade of GABAA Receptors. AB - Selective blockade of inhibitory synaptic transmission onto specific neurons is a useful tool for dissecting the excitatory and inhibitory synaptic components of ongoing network activity. To achieve this, intracellular recording with a patch solution capable of blocking GABAA receptors has advantages over other manipulations, such as pharmacological application of GABAergic antagonists or optogenetic inhibition of populations of interneurones, in that the majority of inhibitory transmission is unaffected and hence the remaining network activity preserved. Here, we assess three previously described methods to block inhibition: intracellular application of the molecules picrotoxin, 4,4'-dinitro stilbene-2,2'-disulphonic acid (DNDS) and 4,4'-diisothiocyanostilbene-2,2' disulphonic acid (DIDS). DNDS and picrotoxin were both found to be ineffective at blocking evoked, monosynaptic inhibitory postsynaptic currents (IPSCs) onto mouse CA1 pyramidal cells. An intracellular solution containing DIDS and caesium fluoride, but lacking nucleotides ATP and GTP, was effective at decreasing the amplitude of IPSCs. However, this effect was found to be independent of DIDS, and the absence of intracellular nucleotides, and was instead due to the presence of fluoride ions in this intracellular solution, which also blocked spontaneously occurring IPSCs during hippocampal sharp waves. Critically, intracellular fluoride ions also caused a decrease in both spontaneous and evoked excitatory synaptic currents and precluded the inclusion of nucleotides in the intracellular solution. Therefore, of the methods tested, only fluoride ions were effective for intracellular blockade of IPSCs but this approach has additional cellular effects reducing its selectivity and utility. PMID- 27501144 TI - Survey and Experimental Infection of Enteropathogenic Escherichia coli in Common Marmosets (Callithrix jacchus). AB - Common marmosets (Callithrix jacchus) are frequently used for biomedical research but can be afflicted with diarrhea-a serious and potentially lethal health problem. Enteropathogenic Escherichia coli (EPEC) is thought to be the causative pathogen of hemorrhagic typhlocolitis in common marmosets, but the actual incidence of the disease and the relationship between EPEC and hematochezia are unknown. This study investigated the prevalence of EPEC infection in common marmosets and the association between EPEC and hematochezia. A total of 230 stool or rectal swab samples were collected from 230 common marmosets (98 clinically healthy, 85 diarrhea, and 47 bloody stool samples) and tested by culture-based detection and PCR amplification of VT1, VT2, LT, ST, eae, and bfp genes. Healthy animals were divided into three groups (n = 4 each for high and low concentration groups and n = 2 as negative control), and those in the experimental groups were perorally inoculated with a 2-ml of suspension of EPEC R811 strain adjusted to 5 * 108 (high concentration) and 5 * 104 (low concentration) CFU/ ml. Two animals in each group were examined 3 and 14 days post-inoculation (DPI). EPEC was detected in 10 of 98 clinically healthy samples (10.2%), 17 of 85 diarrhea samples (20%), and all 47 bloody stool samples (100%), with a significant difference detected between presence of EPEC and sample status (P < 0.01). Acute hematochezia was observed in all animals of the high-concentration group but not in other groups at 1 or 2 DPI. A histopathological examination revealed the attachment of gram-negative bacilli to epithelial apical membranes and desquamated epithelial cells in the cecum of animals in the high-concentration group at 3 DPI. These findings suggest that EPEC is a causative agent of hemorrhagic typhlocolitis in common marmosets. PMID- 27501145 TI - Differential Assembly of Catalytic Interactions within the Conserved Active Sites of Two Ribozymes. AB - Molecular recognition is central to biology and a critical aspect of RNA function. Yet structured RNAs typically lack the preorganization needed for strong binding and precise positioning. A striking example is the group I ribozyme from Tetrahymena, which binds its guanosine substrate (G) orders of magnitude slower than diffusion. Binding of G is also thermodynamically coupled to binding of the oligonucleotide substrate (S) and further work has shown that the transition from E*G to E*S*G accompanies a conformational change that allows G to make the active site interactions required for catalysis. The group I ribozyme from Azoarcus has a similarly slow association rate but lacks the coupled binding observed for the Tetrahymena ribozyme. Here we test, using G analogs and metal ion rescue experiments, whether this absence of coupling arises from a higher degree of preorganization within the Azoarcus active site. Our results suggest that the Azoarcus ribozyme forms cognate catalytic metal ion interactions with G in the E*G complex, interactions that are absent in the Tetrahymena E*G complex. Thus, RNAs that share highly similar active site architectures and catalyze the same reactions can differ in the assembly of transition state interactions. More generally, an ability to readily access distinct local conformational states may have facilitated the evolutionary exploration needed to attain RNA machines that carry out complex, multi-step processes. PMID- 27501146 TI - Calculation of the Average Cost per Case of Dengue Fever in Mexico Using a Micro Costing Approach. AB - INTRODUCTION: The increasing burden of dengue fever (DF) in the Americas, and the current epidemic in previously unaffected countries, generate major costs for national healthcare systems. There is a need to quantify the average cost per DF case. In Mexico, few data are available on costs, despite DF being endemic in some areas. Extrapolations from studies in other countries may prove unreliable and are complicated by the two main Mexican healthcare systems (the Secretariat of Health [SS] and the Mexican Social Security Institute [IMSS]). The present study aimed to generate specific average DF cost-per-case data for Mexico using a micro-costing approach. METHODS: Expected medical costs associated with an ideal management protocol for DF (denoted 'ideal costs') were compared with the medical costs of current treatment practice (denoted 'real costs') in 2012. Real cost data were derived from chart review of DF cases and interviews with patients and key personnel from 64 selected hospitals and ambulatory care units in 16 states for IMSS and SS. In both institutions, ideal and real costs were estimated using the program, actions, activities, tasks, inputs (PAATI) approach, a micro-costing technique developed by us. RESULTS: Clinical pathways were obtained for 1,168 patients following review of 1,293 charts. Ideal and real costs for SS patients were US$165.72 and US$32.60, respectively, in the outpatient setting, and US$587.77 and US$490.93, respectively, in the hospital setting. For IMSS patients, ideal and real costs were US$337.50 and US$92.03, respectively, in the outpatient setting, and US$2,042.54 and US$1,644.69 in the hospital setting. CONCLUSIONS: The markedly higher ideal versus real costs may indicate deficiencies in the actual care of patients with DF. It may be necessary to derive better estimates with micro-costing techniques and compare the ideal protocol with current practice when calculating these costs, as patients do not always receive optimal care. PMID- 27501147 TI - Let's twist again: elasto-capillary assembly of parallel ribbons. AB - We show the self-assembly through twisting and bending of side by side ribbons under the action of capillary forces. Micro-ribbons made of silicon nitride are batch assembled at the wafer scale. We study their assembly as a function of their dimensions and separating distance. Model experiments are carried out at the macroscopic scale where the tension in ribbons can easily be tuned. The process is modeled considering the competition between capillary, elastic and tension forces. Theory shows a good agreement for macroscale assemblies, while the accuracy is within 30% at the micrometer scale. This simple self-assembly technique yields highly symmetric and controllable structures which could be used for batch fabrication of functional 3D micro-structures. PMID- 27501148 TI - Inter-Annual Variability of Area-Scaled Gaseous Carbon Emissions from Wetland Soils in the Liaohe Delta, China. AB - Global management of wetlands to suppress greenhouse gas (GHG) emissions, facilitate carbon (C) sequestration, and reduce atmospheric CO2 concentrations while simultaneously promoting agricultural gains is paramount. However, studies that relate variability in CO2 and CH4 emissions at large spatial scales are limited. We investigated three-year emissions of soil CO2 and CH4 from the primary wetland types of the Liaohe Delta, China, by focusing on a total wetland area of 3287 km2. One percent is Suaeda salsa, 24% is Phragmites australis, and 75% is rice. While S. salsa wetlands are under somewhat natural tidal influence, P. australis and rice are managed hydrologically for paper and food, respectively. Total C emissions from CO2 and CH4 from these wetland soils were 2.9 Tg C/year, ranging from 2.5 to 3.3 Tg C/year depending on the year assessed. Primary emissions were from CO2 (~98%). Photosynthetic uptake of CO2 would mitigate most of the soil CO2 emissions, but CH4 emissions would persist. Overall, CH4 fluxes were high when soil temperatures were >18 degrees C and pore water salinity <18 PSU. CH4 emissions from rice habitat alone in the Liaohe Delta represent 0.2% of CH4 carbon emissions globally from rice. With such a large area and interannual sensitivity in soil GHG fluxes, management practices in the Delta and similar wetlands around the world have the potential not only to influence local C budgeting, but also to influence global biogeochemical cycling. PMID- 27501149 TI - Minnelide/Triptolide Impairs Mitochondrial Function by Regulating SIRT3 in P53 Dependent Manner in Non-Small Cell Lung Cancer. AB - Minnelide/Triptolide (TL) has recently emerged as a potent anticancer drug in non small cell lung cancer (NSCLC). However, the precise mechanism of its action remains ambiguous. In this study, we elucidated the molecular basis for TL induced cell death in context to p53 status. Cell death was attributed to dysfunction of mitochondrial bioenergetics in p53-deficient cells, which was characterized by decreased mitochondrial respiration, steady-state ATP level and membrane potential, but augmented reactive oxygen species (ROS). Increased ROS production resulted in oxidative stress in TL-treated cells. This was exhibited by elevated nuclear levels of a redox-sensitive transcriptional factor, NF-E2 related factor-2 (NRF2), along with diminished cellular glutathione (GSH) content. We further demonstrated that in the absence of p53, TL blunted the expression of mitochondrial SIRT3 triggering increased acetylation of NDUAF9 and succinate dehydrogenase, components of complexes I and II of the electron transport chain (ETC). TL-mediated hyperacetylation of complexes I and II proteins and these complexes displayed decreased enzymatic activities. We also provide the evidence that P53 regulate steady-state level of SIRT3 through Proteasome-Pathway. Finally, forced overexpression of Sirt3, but not deacetylase deficient mutant of Sirt3 (H243Y), restored the deleterious effect of TL on p53 deficient cells by rescuing mitochondrial bioenergetics. On contrary, Sirt3 deficiency in the background of wild-type p53 triggered TL-induced mitochondrial impairment that echoed TL effect in p53-deficeint cells. These findings illustrate a novel mechanism by which TL exerts its potent effects on mitochondrial function and ultimately the viability of NSCLC tumor. PMID- 27501150 TI - Molecular modifiers reveal a mechanism of pathological crystal growth inhibition. AB - Crystalline materials are crucial to the function of living organisms, in the shells of molluscs, the matrix of bone, the teeth of sea urchins, and the exoskeletons of coccoliths. However, pathological biomineralization can be an undesirable crystallization process associated with human diseases. The crystal growth of biogenic, natural and synthetic materials may be regulated by the action of modifiers, most commonly inhibitors, which range from small ions and molecules to large macromolecules. Inhibitors adsorb on crystal surfaces and impede the addition of solute, thereby reducing the rate of growth. Complex inhibitor-crystal interactions in biomineralization are often not well elucidated. Here we show that two molecular inhibitors of calcium oxalate monohydrate crystallization--citrate and hydroxycitrate--exhibit a mechanism that differs from classical theory in that inhibitor adsorption on crystal surfaces induces dissolution of the crystal under specific conditions rather than a reduced rate of crystal growth. This phenomenon occurs even in supersaturated solutions where inhibitor concentration is three orders of magnitude less than that of the solute. The results of bulk crystallization, in situ atomic force microscopy, and density functional theory studies are qualitatively consistent with a hypothesis that inhibitor-crystal interactions impart localized strain to the crystal lattice and that oxalate and calcium ions are released into solution to alleviate this strain. Calcium oxalate monohydrate is the principal component of human kidney stones and citrate is an often-used therapy, but hydroxycitrate is not. For hydroxycitrate to function as a kidney stone treatment, it must be excreted in urine. We report that hydroxycitrate ingested by non-stone-forming humans at an often-recommended dose leads to substantial urinary excretion. In vitro assays using human urine reveal that the molecular modifier hydroxycitrate is as effective an inhibitor of nucleation of calcium oxalate monohydrate nucleation as is citrate. Our findings support exploration of the clinical potential of hydroxycitrate as an alternative treatment to citrate for kidney stones. PMID- 27501151 TI - Structural basis for the antifolding activity of a molecular chaperone. AB - Molecular chaperones act on non-native proteins in the cell to prevent their aggregation, premature folding or misfolding. Different chaperones often exert distinct effects, such as acceleration or delay of folding, on client proteins via mechanisms that are poorly understood. Here we report the solution structure of SecB, a chaperone that exhibits strong antifolding activity, in complex with alkaline phosphatase and maltose-binding protein captured in their unfolded states. SecB uses long hydrophobic grooves that run around its disk-like shape to recognize and bind to multiple hydrophobic segments across the length of non native proteins. The multivalent binding mode results in proteins wrapping around SecB. This unique complex architecture alters the kinetics of protein binding to SecB and confers strong antifolding activity on the chaperone. The data show how the different architectures of chaperones result in distinct binding modes with non-native proteins that ultimately define the activity of the chaperone. PMID- 27501152 TI - The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. AB - Ablation of the cellular prion protein PrP(C) leads to a chronic demyelinating polyneuropathy affecting Schwann cells. Neuron-restricted expression of PrP(C) prevents the disease, suggesting that PrP(C) acts in trans through an unidentified Schwann cell receptor. Here we show that the cAMP concentration in sciatic nerves from PrP(C)-deficient mice is reduced, suggesting that PrP(C) acts via a G protein-coupled receptor (GPCR). The amino-terminal flexible tail (residues 23-120) of PrP(C) triggered a concentration-dependent increase in cAMP in primary Schwann cells, in the Schwann cell line SW10, and in HEK293T cells overexpressing the GPCR Adgrg6 (also known as Gpr126). By contrast, naive HEK293T cells and HEK293T cells expressing several other GPCRs did not react to the flexible tail, and ablation of Gpr126 from SW10 cells abolished the flexible tail induced cAMP response. The flexible tail contains a polycationic cluster (KKRPKPG) similar to the GPRGKPG motif of the Gpr126 agonist type-IV collagen. A KKRPKPG-containing PrPC-derived peptide (FT(23-50)) sufficed to induce a Gpr126 dependent cAMP response in cells and mice, and improved myelination in hypomorphic gpr126 mutant zebrafish (Danio rerio). Substitution of the cationic residues with alanines abolished the biological activity of both FT(23-50) and the equivalent type-IV collagen peptide. We conclude that PrP(C) promotes myelin homeostasis through flexible tail-mediated Gpr126 agonism. As well as clarifying the physiological role of PrP(C), these observations are relevant to the pathogenesis of demyelinating polyneuropathies--common debilitating diseases for which there are limited therapeutic options. PMID- 27501154 TI - Faecal pollution along the southeastern coast of Florida and insight into the use of pepper mild mottle virus as an indicator. AB - AIMS: To identify faecal pollution along the southeastern Florida coast and determine the performance of a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) method for pepper mild mottle virus (PMMoV). METHODS AND RESULTS: In 2014, bimonthly surface water samples were collected from inlets, exposed to runoff and septic seepage, and coastal sites, exposed to ocean outfalls. Analysis of culturable enterococci and a suite of microbial source tracking (MST) markers (BacHum, CowM2, DogBact, HF183, HPyV, PMMoV) revealed faecal pollution, primarily of human origin, at all sites. Since PMMoV was detected more frequently than other MST markers, the process limits of quantification (undiluted to 10-2 dilution) and detection (10-2 dilution) for the RT-qPCR method were determined by seeding untreated wastewater into the coastal waters. Simulated quantitative microbial risk assessment, employing human norovirus as a reference pathogen, calculated a 0.286 median risk of gastrointestinal illness associated with the PMMoV limit of detection. CONCLUSIONS: All sites met the U.S. EPA recreational water criteria, despite detection of domestic wastewater-associated MST markers. PMMoV correlated only with human-associated MST markers. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated that PMMoV is an important domestic wastewater-associated marker that should be included in the MST toolbox; therefore, future studies should thoroughly investigate the health risks associated with its detection and quantification in environmental waters. PMID- 27501153 TI - Mitochondria-specific antioxidant supplementation does not influence endurance exercise training-induced adaptations in circulating angiogenic cells, skeletal muscle oxidative capacity or maximal oxygen uptake. AB - KEY POINTS: Reducing excessive oxidative stress, through chronic exercise or antioxidants, can decrease the negative effects induced by excessive amounts of oxidative stress. Transient increases in oxidative stress produced during acute exercise facilitate beneficial vascular training adaptations, but the effects of non-specific antioxidants on exercise training-induced vascular adaptations remain elusive. Circulating angiogenic cells (CACs) are an exercise-inducible subset of white blood cells that maintain vascular integrity. We investigated whether mitochondria-specific antioxidant (MitoQ) supplementation would affect the response to 3 weeks of endurance exercise training in CACs, muscle mitochondrial capacity and maximal oxygen uptake in young healthy men. We show that endurance exercise training increases multiple CAC types, an adaptation that is not altered by MitoQ supplementation. Additionally, MitoQ does not affect skeletal muscle or whole-body aerobic adaptations to exercise training. These results indicate that MitoQ supplementation neither enhances nor attenuates endurance training adaptations in young healthy men. ABSTRACT: Antioxidants have been shown to improve endothelial function and cardiovascular outcomes. However, the effects of antioxidants on exercise training-induced vascular adaptations remain elusive. General acting antioxidants combined with exercise have not impacted circulating angiogenic cells (CACs). We investigated whether mitochondria-specific antioxidant (MitoQ) supplementation would affect the response to 3 weeks of endurance exercise training on CD3+ , CD3+ /CD31+ , CD14+ /CD31+ , CD31+ , CD34+ /VEGFR2+ and CD62E+ peripheral blood mononuclear cells (PBMCs), muscle mitochondrial capacity, and maximal oxygen uptake (VO2 max ) in healthy men aged 22.1 +/- 0.7 years, with a body mass index of 26.9 +/- 0.9 kg m 2 , and 24.8 +/- 1.3% body fat. Analysis of main effects revealed that training induced 33, 105 and 285% increases in CD14+ /CD31+ , CD62E+ and CD34+ /VEGFR2+ CACs, respectively, and reduced CD3+ /CD31- PBMCs by 14%. There was no effect of MitoQ on CAC levels. Also independent of MitoQ supplementation, exercise training significantly increased quadriceps muscle mitochondrial capacity by 24% and VO2 max by roughly 7%. In conclusion, endurance exercise training induced increases in multiple CAC types, and this adaptation is not modified by MitoQ supplementation. Furthermore, we demonstrate that a mitochondrial-targeted antioxidant does not influence skeletal muscle or whole-body aerobic adaptations to exercise training. PMID- 27501155 TI - Cognitive decline in the elderly after surgery and anaesthesia: results from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. AB - Concerns have been raised about the effects on cognition of anaesthesia for surgery, especially in elderly people. We recorded cognitive decline in a cohort of 394 people (198 women) with median (IQR) age at recruitment of 72.6 (66.6 77.8) years, of whom 109 had moderate or major surgery during a median (IQR) follow-up of 4.1 (2.0-7.6) years. Cognitive decline was more rapid in people who on recruitment were: older, p = 0.0003; male, p = 0.027; had worse cognition, p < 0.0001; or carried the epsilon4 allele of apoliprotein E (APOEepsilon4), p = 0.008; and after an operation if cognitive impairment was already diagnosed, p = 0.0001. Cognitive decline appears to accelerate after surgery in elderly patients diagnosed with cognitive impairment, but not other elderly patients. PMID- 27501156 TI - Genetics of human origin and evolution: high-altitude adaptations. AB - High altitude, defined as elevations lying above 2500m sea level, challenges human survival and reproduction. This environment provides a natural experimental design wherein specific populations, Andeans, Ethiopians, and Tibetans, have lived in a chronic hypoxia state for millennia. These human groups have overcome the low ambient oxygen tension of high elevation via unique physiologic and genetic adaptations. Genomic studies have identified several genes that underlie high-altitude adaptive phenotypes, many of which are central components of the Hypoxia Inducible Factor (HIF) pathway. Further study of mechanisms governing the adaptive changes responsible for high-altitude adaptation will contribute to our understanding of the molecular basis of evolutionary change and assist in the functional annotation of the human genome. PMID- 27501157 TI - Antibacterial nanohydroxyapatite/polyurethane composite scaffolds with silver phosphate particles for bone regeneration. AB - Solving the issue of infection associated with implanted bone substitutes is one of the modern challenges of the biomedical engineering field. The purpose of this study was to develop a novel porous scaffold with sufficient antibacterial activity for bone repair or regeneration. Porous nanohydroxyapatite/polyurethane (n-HA/PU) composite scaffolds containing different amounts of silver phosphate particles were prepared through the in situ foaming method. Subsequently, their physicochemical properties, antibacterial abilities, and preliminary cytocompatibilities were evaluated. The results indicated that the porosity and mechanical properties of the n-HA/PU scaffolds incorporated with Ag3PO4 did not change significantly compared to n-HA/PU scaffold without Ag3PO4. The release of Ag(+) was time and concentration dependent, increasing with the immersion time and Ag3PO4 percentage in the scaffolds. A continuous Ag(+) release can last more than 3 weeks. The antibacterial tests and cytocompatibility evaluation revealed that n-HA/PU scaffolds with 3 wt% Ag3PO4 (n-HA/PU3) exhibit stronger antimicrobial effects as well as satisfactory cytocompatibility. The n-HA/PU3 scaffolds may hold great potential for application in the field of bone regeneration, especially for infection-associated bone defect repair. PMID- 27501158 TI - Comparison of drug dissolution profiles: a proposal based on tolerance limits. AB - Meaningful comparison of the dissolution profiles between the reference and test formulations of a drug is critical for assessing similarity between the two formulations, and for quality control purposes. Such a dissolution profile comparison is required by regulatory authorities, and the criteria used for this include the widely used difference factor f1 and a similarity factor f2 , recommended by the Food and Drug Administration . In spite of their extensive use in practice, the two factors have been heavily criticized on various grounds; the criticisms include ignoring sampling variability and ignoring the correlations across time points while using the criteria in practice. The goal of this article is to put f1 and f2 on a firm statistical footing by developing tolerance limits for the distributions of f1 and f2 , so that both the sampling variability and the correlations over time points are taken into account. Because f1 and f2 are defined in terms of sample mean dissolution profiles, they are not appropriate for comparing individual dissolution profiles. For the latter, we have considered similar criteria and have derived tolerance limits. Both parametric and nonparametric approaches are explored, and a bootstrap calibration is used to improve accuracy of the tolerance limits. Simulated coverage probabilities show that the method leads to accurate tolerance limits. Two examples are used to illustrate the methodology. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27501159 TI - Effects of JTV-519 on stretch-induced manifestations of mechanoelectric feedback. AB - JTV-519 is a 1,4-benzothiazepine derivative with multichannel effects that inhibits Ca2+ release from the sarcoplasmic reticulum and stabilizes the closed state of the ryanodine receptor, preventing myocardial damage and the induction of arrhythmias during Ca2+ overload. Mechanical stretch increases cellular Na+ inflow, activates the reverse mode of the Na+ /Ca2+ exchanger, and modifies Ca2+ handling and myocardial electrophysiology, favoring arrhythmogenesis. This study aims to determine whether JTV-519 modifies the stretch-induced manifestations of mechanoelectric feedback. The ventricular fibrillation (VF) modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts using epicardial multiple electrodes under control conditions (n=9) or during JTV-519 perfusion: 0.1 MUmol/L (n=9) and 1 MUmol/L (n=9). Spectral and mapping techniques were used to establish the baseline, stretch and post-stretch VF characteristics. JTV-519 slowed baseline VF and decreased activation complexity. These effects were dose-dependent (baseline VF dominant frequency: control=13.9+/-2.2 Hz; JTV 0.1 MUmol/L=11.1+/-1.1 Hz, P<.01; JTV 1 MUmol/L=6.6+/-1.1 Hz, P<.0001). The stretch-induced acceleration of VF (control=38.8%) was significantly reduced by JTV-519 0.1 MUmol/L (19.8%) and abolished by JTV 1 MUmol/L (-1.5%). During stretch, the VF activation complexity index was reduced in both JTV-519 series (control=1.60+/-0.15; JTV 0.1 MUmol/L=1.13+/-0.3, P<.0001; JTV 1 MUmol/L=0.57+/ 0.21, P<.0001), and was independently related to VF dominant frequency (R=.82; P<.0001). The fifth percentile of the VF activation intervals, conduction velocity and wavelength entered the multiple linear regression model using dominant frequency as the dependent variable (R=-.84; P<.0001). In conclusion, JTV-519 slowed and simplified the baseline VF activation patterns and abolished the stretch-induced manifestations of mechanoelectric feedback. PMID- 27501160 TI - Effectiveness of community-based exercise intervention programme in obese adults with metabolic syndrome. AB - AIMS AND OBJECTIVES: The objective of this study was to change the anthropometric, clinical, biochemical indicators and the rate of metabolic syndrome among obese adults in community. BACKGROUND: Obesity is an indicator of metabolic syndrome and cardiometabolic diseases. Obesity increases national health care expenditure in Taiwan. The high prevalence of obesity is not only a public health issue but also an economic problem. Changes in lifestyle can help to prevent metabolic syndrome for individuals with obesity. DESIGN: A randomised controlled trial was applied. METHODS: In this randomised controlled trial by location, 136 metabolically abnormal obese individuals were included. The related indicators with metabolic syndrome were measured at baseline and after six months. The experimental group participated in a six-month community-based programme including provided exercise environments, exercise skills and volunteers' reminding. The control group was only provided environment and skills. RESULTS: One hundred and thirty-one participants completed this trail. In comparison with the baseline, the intervention group showed a significant increase in high-density lipoprotein cholesterol (2.34 mg/dl), and decrease in body weight (1.09 kg), waist circumference (3.63 cm), systolic blood pressure (10.52 mmHg), diastolic blood pressure (5.21 mmHg), fasting blood glucose (5.84 mg/dl) and body mass index (0.74 kg/m(2) ). In the control group, significant decrease in body mass index and waist circumference were discovered. Compared to the changes between the two groups, the results showed there were significant differences in waist circumference, systolic blood pressure, diastolic blood pressure and high-density lipoprotein cholesterol. CONCLUSIONS: The community based intervention could help to improve high-density lipoprotein cholesterol, reduce body weight, body mass index, waist circumference, blood pressure and fasting blood glucose in metabolically abnormal obese. RELEVANCE TO CLINICAL PRACTICE: This community-based programme helped metabolically abnormal obese individuals become metabolically healthy. In the future, community nurses will work with village heads and volunteers. They can encourage residents in the communities to have healthy lifestyle. As a result, the goal of this programme will be successfully achieved with less time and effort. PMID- 27501161 TI - Childhood urinary tract infection caused by extended-spectrum beta-lactamase producing bacteria: Risk factors and empiric therapy. AB - BACKGROUND: This study investigated risk factors of childhood urinary tract infection (UTI) associated with extended-spectrum beta-lactamase (ESBL)-producing bacteria (ESBL-positive UTI) and evaluated antimicrobial resistance as well as empiric treatment of childhood UTI. METHODS: The records of children with positive urine culture between 1 January 2008 and 31 December 2012 were evaluated. Patients with positive urine culture for ESBL-producing bacteria were defined as the ESBL-positive group, whereas patients of the same gender and similar age with positive urine culture for non-ESBL-producing bacteria were defined as the ESBL-negative group. Each ESBL-positive patient was matched with two ESBL-negative patients. RESULTS: The ESBL-positive and negative groups consisted of 154 and 308 patients, respectively. Potential risk factors for ESBL positive UTI were identified as presence of underlying disease, clean intermittent catheterization (CIC), hospitalization, use of any antibiotic and history of infection in the last 3 months (P < 0.05). On logistic regression analysis, CIC, hospitalization and history of infection in the last 3 months were identified as independent risk factors. In the present study, 324 of 462 patients had empiric therapy. Empiric therapy was inappropriate in 90.3% of the ESBL positive group and in 4.5% of the ESBL-negative group. Resistance to nitrofurantoin was similar between groups (5.1% vs 1.2%, P = 0.072); resistance to amikacin was low in the ESBL-positive group (2.6%) and there was no resistance in the ESBL-negative group. CONCLUSIONS: Clean intermittent catheterization, hospitalization and history of infection in the last 3 months should be considered as risk factors for ESBL-positive UTI. The combination of ampicillin plus amikacin should be taken into consideration for empiric therapy in patients with acute pyelonephritis who have the risk factors for ESBL-positive UTI. Nitrofurantoin seems to be a logical choice for the empiric therapy of cystitis. PMID- 27501162 TI - Organizational justice and disability pension from all-causes, depression and musculoskeletal diseases: A Finnish cohort study of public sector employees. AB - OBJECTIVES: Work-related stress has been linked to increased risk of disability pensioning, but the association between perceived justice of managerial behavior and decision-making processes at the workplace (ie, organizational justice) and risk of disability pensioning remains unknown. We examined the associations of organizational justice and its relational and procedural components with all cause and diagnosis-specific disability pensions with repeated measures of justice. METHODS: Data from 24 895 employees responding to repeated surveys on organizational justice in 2000-2002 and 2004 were linked to the records of a national register for disability pensions from 2005-2011. Associations of long term organizational justice (average score from two surveys) with disability pensions were studied with Cox proportional hazard regression adjusted for demographics, socioeconomic status, baseline health and health risk behavior, stratified by sex. RESULTS: During a mean follow-up of 6.4 years, 1658 (7%) employees were granted disability pension (282 due to depression; 816 due to musculoskeletal diseases). Higher organizational justice was associated with a lower risk of disability pensioning [hazard ratio (HR) per one-unit increase in 5 point justice scale 0.87 (95% CI 0.81-0.94)]. For disability pension due to depression and musculoskeletal diseases, the corresponding HR were 0.77 (95% CI 0.65-0.91) and 0.87 (95% CI 0.79-0.97), respectively. Adjustment for job strain and effort-reward imbalance attenuated the HR by 20-80%. CONCLUSIONS: Supervisors' fair treatment of employees and fair decision-making in the organizations are associated with a decreased risk of disability pensioning from all-causes, depression and musculoskeletal diseases. These associations may be attributable to a wider range of favorable work characteristics. PMID- 27501163 TI - Sexism within anatomy as perceived by professional anatomists and in comparison with the perceptions of medical students. AB - Two hundred and eight professional anatomists responded to a questionnaire inviting them to address the possibility that social/gender factors hinder the dispassionate representation of anatomy. Ethical approval for the study was obtained from Cardiff University. The results of the survey provided comparisons with the attitudes of medical students that have previously been reported (Morgan et al., 2014). Although a few differences were discerned between females and males in our surveys and between anatomists and medical students, overall our findings suggest that, while both professional anatomists and medical students recognize the importance of gender issues and do not wish to associate with sexism, most are unaware of the possible negative aspects of sexism within anatomy. We recommend that teachers of anatomy should become more aware of the possibility of adverse effects on professional matters relating to equality and diversity issues. Clin. Anat. 29:892-910, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27501164 TI - Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures. AB - The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of IRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug-like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors. A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons. PMID- 27501165 TI - My Sister Myself: A Controlled Study of the Relationship Between Women with a Lifetime Diagnosis of Anorexia Nervosa and Their Sisters. AB - This study focused on the quality of the relationship between women with a lifetime anorexia nervosa (AN) diagnosis and their sisters, in the context of family functioning. Participants were 112 sister pairs including a woman with a lifetime diagnosis of AN, and 356 sister pairs with no history of an eating disorder. Participants completed the Sibling Relationship Questionnaire, Family Environment Scale and Eating Attitudes Test-26. We hypothesised that sister relationships would be less favourably assessed by women with an AN diagnosis than by their sisters, and less favourably assessed overall in the AN sister pairs than in the healthy sib-pair controls. These hypotheses were confirmed. Also, the AN sisters viewed the family as less cohesive and more conflicted than their non-affected sisters. For the AN sisters, there was an inverse relationship between level of current pathology and how favourably they viewed the sister relationship. Sister relationships may suffer during AN and improve as the pathology recedes. This would mean that the quality of sister relationships has clinical significance and may serve as an indicator of recovery. Copyright (c) 2016 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 27501166 TI - Residual Carcinoma In Situ at the Ductal Stump has a Negative Survival Effect: An Analysis of Early-stage Cholangiocarcinomas. AB - OBJECTIVE: The aim of the study was to evaluate whether carcinoma in situ (CIS) residue at the ductal stump affects the survival of patients undergoing resection for extrahepatic cholangiocarcinoma. BACKGROUND: Positive ductal margin with CIS has been treated as a tumor-free margin from a prognostic viewpoint because several studies have reported that residual CIS foci at the ductal stump do not affect survival after resection. METHODS: Patients who underwent resection for extrahepatic cholangiocarcinoma were retrospectively reviewed. The surgical margin status was histologically divided into negative (R0), positive with CIS (R1cis), and positive with invasive cancer (R1inv). The survival and incidence of local recurrence were compared among the groups. RESULTS: Of 684 consecutive resected patients, 172 patients with early-stage (pTis-2N0M0) cholangiocarcinoma (perihilar, n = 144; distal, n = 28) were analyzed. The cumulative incidence of local recurrence in R1cis patients was higher than R0 patients (32.8% vs 4.4% at 5 years, P < 0.001) and lower than R1inv patients (50.0% at 2 years, P = 0.012). The disease-specific survival for R1cis patients was worse than for R0 patients (35.1% vs 78.7% at 5 years, P = 0.005) and better than for R1inv patients (40.0% at 2 years, P = 0.002). The uni- and multivariate analyses identified the surgical margin status as an independent prognostic factor (R1cis vs R0, relative risk 2.39, P = 0.026; R1inv vs R0, RR 10.28, P < 0.001). CONCLUSION: R1cis increases the incidence of local recurrence and shortens postoperative survival in patients with early-stage cholangiocarcinoma, although this prognostic effect was less severe compared with R1inv. R1cis should be avoided as much as possible in surgery for early-stage cancer, although it may be allowed in advanced tumors. PMID- 27501167 TI - Reducing Non-Anastomotic Biliary Strictures in Donation After Circulatory Death Liver Transplantation: Cold Ischemia Time Matters! PMID- 27501168 TI - Effectiveness of Bariatric Surgery in the Remission of Type 2 Diabetes and Vascular Complications. PMID- 27501169 TI - Association Between Race and Postoperative Outcomes in a Universally Insured Population Versus Patients in the State of California. AB - OBJECTIVE: To compare disparities in postoperative outcomes for African Americans after surgical intervention in the universally insured military system, versus the civilian setting in California. BACKGROUND: Health reform proponents cite the reduction of disparities for African Americans and minorities as an expected benefit. The impact of universal health insurance on reducing surgical disparities for African Americans has not previously been examined. METHODS: We used Department of Defense health insurance (Tricare) data (2006-2010) to measure outcomes for African Americans as compared with Whites after 12 major surgical procedures across multiple specialties. The experience of African Americans in the Tricare system was compared with a similar cohort undergoing surgery in the state of California using the State Inpatient Database (2007-2011). RESULTS: No significant difference in postoperative complications [odds ratio (OR) 0.91; 95% confidence interval (CI) 0.81, 1.03] or mortality (OR 0.98; 95% CI 0.43, 2.25) were encountered between African Americans and Whites receiving surgery at hospitals administered by the Department of Defense. African Americans in California who were uninsured or on Medicaid had significantly increased odds of mortality (OR 4.76; 95% CI 2.82, 8.05), complications (OR 1.67; 95% CI 1.34, 2.08), failure to rescue (OR 2.72; 95% CI 1.25, 5.94), and readmission (OR 1.78; 95% CI 1.45, 2.19). CONCLUSIONS: In the equal access military healthcare system, African Americans have outcomes similar to Whites. Disparities were evident in California, especially among those without private insurance. These facts point toward the potential benefits of a federally administered system in which all patients are treated uniformly. PMID- 27501170 TI - Utility of Adjuvant Chemotherapy After Neoadjuvant Chemoradiation and Esophagectomy for Esophageal Cancer. AB - OBJECTIVE: To determine whether adjuvant chemotherapy (AC) after neoadjuvant chemoradiation and esophagectomy is associated with improved overall survival for patients with locally advanced esophageal cancer, and to evaluate how pathologic disease response to neoadjuvant treatment impacts this effect. BACKGROUND: Neoadjuvant chemoradiation is currently the preferred management approach for locoregional esophageal cancer. Although there is interest in the use of AC, the benefit of systemic therapy after neoadjuvant chemoradiation and esophagectomy is unclear. METHODS: Retrospective cohort study of patients with esophageal cancer treated with neoadjuvant chemoradiation and esophagectomy in the National Cancer Data Base (2006-2012). RESULTS: Among 3592 patients with esophageal cancer (84.7% adenocarcinoma, 15.2% squamous cell carcinoma), 335 (9.3%) were treated with AC. AC was not associated with a significantly lower risk of death among patients with no residual disease (ypT0N0) or residual non-nodal disease (ypT+N0). Among patients with residual nodal disease (ypTanyN+), AC was associated with a 30% lower risk of death in the overall cohort [hazard ratio (HR) 0.70, (0.57-0.85)] and among those with adenocarcinoma [HR 0.69 (0.57-0.85)]. Using a 90-day postoperative landmark, findings were similar. Among patients with postoperative length of stay <=10 days and no unplanned readmission, AC was associated with approximately 40% lower risk of death among patients with residual nodal disease [overall cohort, HR 0.63 (0.48-0.84); adenocarcinoma, HR 0.66 (0.49-0.88)]. CONCLUSIONS: AC after neoadjuvant chemoradiation and esophagectomy is associated with improved survival in patients with residual nodal disease. Our findings suggest AC may provide additional benefit for esophageal cancer patients, and merits further investigation. PMID- 27501171 TI - miR-221 Mediates Chemoresistance of Esophageal Adenocarcinoma by Direct Targeting of DKK2 Expression. AB - BACKGROUND: Chemoresistance is a main obstacle to effective esophageal cancer (EC) therapy. We hypothesize that altered expression of microRNAs (miRNAs) play a role in EC cancer progression and resistance to 5-fluorouracil (5-FU) based chemotherapeutic strategies. METHODS: Four pairs of esophageal adenocarcinoma (EAC) cell lines and corresponding 5-FU resistant variants were established. The expression levels of miRNAs previously shown to be involved in the general regulation of stem cell pathways were analyzed by qRT-PCR. The effects of selected miRNAs on proliferation, apoptosis, and chemosensitivity were evaluated both in vitro and in vivo. We identified a particular miRNA and analyzed its putative target genes in 14 pairs of human EC tumor specimens with surrounding normal tissue by qRT-PCR as well as Wnt pathway associated genes by immunohistochemistry in another 45 EAC tumor samples. RESULTS: MiR-221 was overexpressed in 5-FU resistant EC cell lines as well as in human EAC tissue. DKK2 was identified as a target gene for miR-221. Knockdown of miR-221 in 5-FU resistant cells resulted in reduced cell proliferation, increased apoptosis, restored chemosensitivity, and led to inactivation of the Wnt/beta-catenin pathway mediated by alteration in DKK2 expression. Moreover, miR-221 reduction resulted in alteration of EMT-associated genes such as E-cadherin and vimentin as well as significantly slower xenograft tumor growth in nude mice. RT profiler analysis identified a substantial dysregulation of 4 Wnt/beta-catenin signaling and chemoresistance target genes as a result of miR-221 modulation: CDH1, CD44, MYC, and ABCG2. CONCLUSION: MiR-221 controls 5-FU resistance of EC partly via modulation of Wnt/beta-catenin-EMT pathways by direct targeting of DKK2 expression. MiR-221 may serve as a prognostic marker and therapeutic target for patients with 5-FU resistant EAC. PMID- 27501172 TI - POST-TEXT III and IV Hepatoblastoma: Extended Hepatic Resection Avoids Liver Transplantation in Selected Cases. AB - OBJECTIVE: To analyze the outcome of hepatoblastoma (HB) patients presenting with post treatment extent of disease (POST-TEXT) stages III and IV after neoadjuvant chemotherapy. BACKGROUND: Primary liver transplantation has been advocated as surgical treatment for children with HB involving 3 or 4 sectors at diagnosis. However, in some cases, tumors seem resectable after chemotherapy through aggressive use of nontransplant surgical procedures. METHODS: Data of 27 HB patients were reviewed, undergoing extended liver resection for POST-TEXT III or IV tumors after chemotherapy between 1992 and 2015. Median follow-up was 58 months (range 9-188). RESULTS: Median age at surgery was 18.2 months (interquartile range 10.8-32.5). Staging of the children after chemotherapy revealed POST-TEXT III in 21 and POST-TEXT IV in 6 cases. In 2 children, the hepatic resection was performed under cardiopulmonary bypass because of extended vena cava thrombosis; in 2 patients, a simultaneous sternotomy was performed for resection of bilateral lung metastases. The 5-year overall survival rate was 80.7%. CONCLUSIONS: Aggressive surgical resection is a successful approach in some patients with POST-TEXT III and IV HB who otherwise would be candidates for liver transplantation. These children should undergo central review and should be surgically managed at centers of excellence for pediatric liver surgery. Despite challenging surgical procedures and complex clinical courses, the patients benefit from avoidance of morbidities of organ transplant. However, preparation of backup liver transplantation should be considered in selected cases. PMID- 27501173 TI - Seeing the Trees For the Forest: Rectal Cancer Intratumoral Heterogeneity. PMID- 27501174 TI - Primary Pancreatic Secretinoma: Further Evidence Supporting Secretin as a Diarrheogenic Hormone. AB - OBJECTIVES: To document the existence of primary pancreatic secretinoma in patients with watery diarrhea syndrome (WDS) and achlorhydria and establish secretin as a diarrheogenic hormone. BACKGROUND: Vasoactive intestinal peptide (VIP) has been widely accepted as the main mediator of WDS. However, in 1968, Zollinger et al reported 2 female patients with pancreatic neuroendocrine tumors, WDS, and achlorhydria. During surgery on the first, a 24-year-old patient, they noticed distended duodenum filled with fluid and a dilated gallbladder containing dilute bile with high bicarbonate concentration. After excision of the tumor, WDS ceased and gastric acid secretion returned. The second, a 47-year-old, patient's metastatic tumor extract given intravenously in dogs, produced significantly increased pancreatic and biliary fluid rich in bicarbonate. They suggested a secretin-like hormone of islet cell origin explains WDS and achlorhydria. These observations, however, predated radioimmunoassay, immunohistochemical staining, and other molecular studies. METHODS: The first patient's tumor tissue was investigated for secretin and VIP. Using both immunohistochemistry and laser microdissection and pressure catapulting technique for RNA isolation and subsequent reverse transcription polymerase chain reaction, the expression levels of secretin, and VIP were measured. RESULTS: Immunoreactive secretin and its mRNA were predominantly found in the tumor tissue whereas VIP and its mRNA were scarce. CONCLUSIONS: The findings strongly support that the WDS and achlorhydria in this patient may have been caused by secretin as originally proposed in 1968 and that secretin may act as a diarrheogenic hormone. PMID- 27501175 TI - Measuring the Value of a Clinical Practice Guideline for Children With Perforated Appendicitis. AB - OBJECTIVE: To determine the incremental cost-effectiveness of a clinical practice guideline (CPG) compared with "usual care" for treatment of perforated appendicitis in children. Secondary objective was to compare cost analyses using hospital accounting system data versus data in the Pediatric Health Information System (PHIS). BACKGROUND: Value-based surgical care (outcomes relative to costs) is frequently touted, but outcomes and costs are rarely measured together. METHODS: During an 18-month period, 122 children with perforated appendicitis at a tertiary referral children's hospital were treated using an evidence-based CPG. Clinical outcomes and costs for the CPG cohort were compared with patients in the 30-month period before CPG implementation (n = 191 children). RESULTS: With CPG directed care, intra-abdominal abscess rate decreased from 0.24 to 0.10 (adjusted risk ratio 0.44, 95% confidence interval [CI] 0.26-0.75). The rate of any adverse event decreased from 0.30 to 0.23 (adjusted risk ratio 0.82, 95% CI 0.58-1.17). Mean total hospital costs per patient (hospital accounting system) decreased from $16,466 to $10,528 (adjusted absolute difference-$5451, 95% CI -$7755 to -$3147), leading to estimated adjusted total savings of $665,022 during the study period. Costs obtained from the PHIS database also showed reduction with CPG-directed care (-$6669, 95% CI -$8949 to -$4389 per patient). In Bayesian cost effectiveness analyses, likelihood that CPG was the dominant strategy was 91%. CONCLUSIONS: An evidence-based CPG increased the value of surgical care for children with perforated appendicitis by improving outcomes and lowering costs. Hospital cost accounting data and pre-existing cost data within the PHIS database provided similar results. PMID- 27501177 TI - Reply to Letter: "Esophageal Cancer: Long-term Survival and Day of Surgery". PMID- 27501176 TI - Trajectory of Functional Recovery After Postoperative Delirium in Elective Surgery. AB - OBJECTIVE: To describe functional recovery after elective surgery and to determine whether improvements differ among individuals who develop delirium. BACKGROUND: No large studies of older adults have investigated whether delirium influences the trajectory of functional recovery after elective surgery. The prospective observational study assessed this association among 566 individuals aged 70 years and older. METHODS: Patients undergoing major elective surgery were assessed daily while in hospital for presence and severity of delirium using the Confusion Assessment Method, and their functional recovery was followed for 18 months thereafter. The Activities of Daily Living and Instrumental Activities of Daily Living Scales and the Physical Component Summary of the Short Form-12 were obtained before surgery and at 1, 2, 6, 12, and 18 months. A composite index (standard deviation 10, minimally clinically significant difference 2) derived from these scales was then analyzed using mixed-effects regression. RESULTS: Mean age was 77 years; 58% of participants were women and 24% developed postoperative delirium. Participants with delirium demonstrated lesser functional recovery than their counterparts without delirium; at 1 month, the covariate-adjusted mean difference on the physical function composite was -1.5 (95% confidence interval 3.3, -0.2). From 2 to 18 months, the corresponding difference was -1.8 (95% confidence interval -3.2, -0.3), an effect comparable with the minimally clinically significant difference. CONCLUSIONS: Delirium was associated with persistent and clinically meaningful impairment of functional recovery, to 18 months. Use of multifactorial preventive interventions for patients at high risk for delirium and tailored transitional care planning may help to maximize the functional benefits of elective surgery. PMID- 27501178 TI - Commentary on Hand Laterality and Acquired Ambidexterity in Surgical Training. PMID- 27501179 TI - A System to Create Stable Nanoparticle Aerosols from Nanopowders. AB - Nanoparticle aerosols released from nanopowders in workplaces are associated with human exposure and health risks. We developed a novel system, requiring minimal amounts of test materials (min. 200 mg), for studying powder aerosolization behavior and aerosol properties. The aerosolization procedure follows the concept of the fluidized-bed process, but occurs in the modified volume of a V-shaped aerosol generator. The airborne particle number concentration is adjustable by controlling the air flow rate. The system supplied stable aerosol generation rates and particle size distributions over long periods (0.5-2 hr and possibly longer), which are important, for example, to study aerosol behavior, but also for toxicological studies. Strict adherence to the operating procedures during the aerosolization experiments ensures the generation of reproducible test results. The critical steps in the standard protocol are the preparation of the material and setup, and the aerosolization operations themselves. The system can be used for experiments requiring stable aerosol concentrations and may also be an alternative method for testing dustiness. The controlled aerosolization made possible with this setup occurs using energy inputs (may be characterized by aerosolization air velocity) that are within the ranges commonly found in occupational environments where nanomaterial powders are handled. This setup and its operating protocol are thus helpful for human exposure and risk assessment. PMID- 27501180 TI - Disrupted-in-schizophrenia-1 as a broader link of glutamatergic transmission to schizophrenia impacts cerebral neurochemistry via the production of the 'gliotransmitter' d-serine, a NMDA receptor coagonist. AB - This Editorial highlights a study by Xia and coworkers in the current issue of the Journal of Neurochemistry, in which the authors reveal a possible mechanistic link between DISC1 (disrupted-in-schizophrenia-1), a genetic risk factor for schizophrenia, and N-methyl-d-aspartate receptor (NMDAR) that is also linked with schizophrenia. The authors show that perturbed communication between DISC1 and NMDARs represents a hidden perpetrator for abnormal dendritic and synaptic maturation. Read the highlighted article 'DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders' on page 518. PMID- 27501181 TI - Corrigendum. PMID- 27501182 TI - Type 2 Deiodinase Disruption in Astrocytes Results in Anxiety-Depressive-Like Behavior in Male Mice. AB - Millions of levothyroxine-treated hypothyroid patients complain of impaired cognition despite normal TSH serum levels. This could reflect abnormalities in the type 2 deiodinase (D2)-mediated T4-to-T3 conversion, given their much greater dependence on the D2 pathway for T3 production. T3 normally reaches the brain directly from the circulation or is produced locally by D2 in astrocytes. Here we report that mice with astrocyte-specific Dio2 inactivation (Astro-D2KO) have normal serum T3 but exhibit anxiety-depression-like behavior as found in open field and elevated plus maze studies and when tested for depression using the tail-suspension and the forced-swimming tests. Remarkably, 4 weeks of daily treadmill exercise sessions eliminated this phenotype. Microarray gene expression profiling of the Astro-D2KO hippocampi identified an enrichment of three gene sets related to inflammation and impoverishment of three gene sets related to mitochondrial function and response to oxidative stress. Despite normal neurogenesis, the Astro-D2KO hippocampi exhibited decreased expression of four of six known to be positively regulated genes by T3, ie, Mbp (~43%), Mag (~34%), Hr (~49%), and Aldh1a1 (~61%) and increased expression of 3 of 12 genes negatively regulated by T3, ie, Dgkg (~17%), Syce2 (~26%), and Col6a1 (~3-fold) by quantitative real-time PCR. Notably, in Astro-D2KO animals, there was also a reduction in mRNA levels of genes known to be affected in classical animal models of depression, ie, Bdnf (~18%), Ntf3 (~43%), Nmdar (~26%), and GR (~20%), which were also normalized by daily exercise sessions. These findings suggest that defects in Dio2 expression in the brain could result in mood and behavioral disorders. PMID- 27501183 TI - beta-Cell Glucagon-Like Peptide-1 Receptor Contributes to Improved Glucose Tolerance After Vertical Sleeve Gastrectomy. AB - Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible for this remain incompletely defined. Glucagon-like peptide-1 (GLP-1) is a gut hormone that contributes to the maintenance of glucose homeostasis and is elevated after VSG. VSG-induced increases in postprandial GLP-1 secretion have been proposed to contribute to the glucoregulatory benefits of VSG; however, previous work has been equivocal. In order to test the contribution of enhanced beta-cell GLP-1 receptor (GLP-1R) signaling we used a beta-cell-specific tamoxifen-inducible GLP-1R knockout mouse model. Male beta-cell-specific Glp-1r(beta-cell+/+) wild type (WT) and Glp 1r(beta-cell-/-) knockout (KO) littermates were placed on a high-fat diet for 6 weeks and then switched to high-fat diet supplemented with tamoxifen for the rest of the study. Mice underwent sham or VSG surgery after 2 weeks of tamoxifen diet and were fed ad libitum postoperatively. Mice underwent oral glucose tolerance testing at 3 weeks and were euthanized at 6 weeks after surgery. VSG reduced body weight and food intake independent of genotype. However, glucose tolerance was only improved in VSG WT compared with sham WT, whereas VSG KO had impaired glucose tolerance relative to VSG WT. Augmentation of glucose-stimulated insulin secretion during the oral glucose tolerance test was blunted in VSG KO compared with VSG WT. Therefore, our data suggest that enhanced beta-cell GLP-1R signaling contributes to improved glucose regulation after VSG by promoting increased glucose-stimulated insulin secretion. PMID- 27501185 TI - Vasoactive Intestinal Peptide Excites GnRH Neurons in Male and Female Mice. AB - A variety of external and internal factors modulate the activity of GnRH neurons to control fertility in mammals. A direct, vasoactive intestinal peptide (VIP) mediated input to GnRH neurons originating from the suprachiasmatic nucleus is thought to relay circadian information within this network. In the present study, we examined the effects of VIP on GnRH neuron activity in male and female mice at different stages of the estrous cycle. We carried out cell-attached recordings in slices from GnRH-green fluorescent protein mice and calcium imaging in slices from a mouse line expressing the genetically encoded calcium indicator GCaMP3 selectively in GnRH neurons. We show that 50%-80% of GnRH neurons increase their firing rate in response to bath-applied VIP (1nM-1000nM) in both male and female mice and that this is accompanied by a robust increase in intracellular calcium concentrations. This effect is mediated directly at the GnRH neuron likely through activation of high-affinity VIP receptors. Because suprachiasmatic nucleus-derived timing cues trigger the preovulatory surge only on the afternoon of proestrus in female mice, we examined the effects of VIP during the estrous cycle at different times of day. VIP responsiveness in GnRH neurons did not vary significantly in diestrous and proestrous mice before or around the time of the expected preovulatory surge. These results indicate that the majority of GnRH neurons in male and female mice express functional VIP receptors and that the effects of VIP on GnRH neurons do not alter across the estrous cycle. PMID- 27501184 TI - Chronically Increased Amino Acids Improve Insulin Secretion, Pancreatic Vascularity, and Islet Size in Growth-Restricted Fetal Sheep. AB - Placental insufficiency is associated with reduced supply of amino acids to the fetus and leads to intrauterine growth restriction (IUGR). IUGR fetuses are characterized by lower glucose-stimulated insulin secretion, smaller pancreatic islets with less beta-cells, and impaired pancreatic vascularity. To test whether supplemental amino acids infused into the IUGR fetus could improve these complications of IUGR we used acute (hours) and chronic (11 d) direct fetal amino acid infusions into a sheep model of placental insufficiency and IUGR near the end of gestation. IUGR fetuses had attenuated acute amino acid-stimulated insulin secretion compared with control fetuses. These results were confirmed in isolated IUGR pancreatic islets. After the chronic fetal amino acid infusion, fetal glucose-stimulated insulin secretion and islet size were restored to control values. These changes were associated with normalization of fetal pancreatic vascularity and higher fetal pancreatic vascular endothelial growth factor A protein concentrations. These results demonstrate that decreased fetal amino acid supply contributes to the pathogenesis of pancreatic islet defects in IUGR. Moreover, the results show that pancreatic islets in IUGR fetuses retain their ability to respond to increased amino acids near the end of gestation after chronic fetal growth restriction. PMID- 27501186 TI - The Circadian Timing System and Environmental Circadian Disruption: From Follicles to Fertility. AB - The internal or circadian timing system is deeply integrated in female reproductive physiology. Considerable details of rheostatic timing function in the neuroendocrine control of pituitary hormone secretion, adenohypophyseal hormone gene expression and secretion, gonadal steroid hormone biosynthesis and secretion, ovulation, implantation, and parturition have been reported. The molecular clock, an autonomous feedback loop oscillator of interacting transcriptional regulators, dictates the timing and amplitude of gene expression in each tissue of the female hypothalamic-pituitary-gonadal (HPG) axis. Although multiple targets of the molecular clock have been identified, many associated with critical physiological functions in the HPG axis, the full extent of clock driven gene expression and physiology in this critical system remains unknown. Environmental circadian disruption (ECD), the disturbance of temporal relationships within and between internal clocks (brain and periphery), and external timing cues (eg, light, nutrients, social cues) due to rotating/night shift work or transmeridian travel have been linked to reproductive dysfunction and subfertility. Moreover, ECD resulting from exposure to endocrine disrupting chemicals, environmental toxins, and/or irregular hormone levels during sexual development can also reduce fertility. Thus, perturbations that disturb clock function at the molecular, cellular or systemic level correlate with significant declines in female reproductive function. Here we briefly review the evidence for molecular clock function in each tissue of the female HPG axis (GnRH neuron, pituitary, uterus, oviduct, and ovary), describe the human epidemiological and animal data supporting the negative effects of ECD on fertility, and explore the potential for novel chronotherapeutics in women's health and fertility. PMID- 27501187 TI - Standard PK/PD concepts can be applied to determine a dosage regimen for a macrolide: the case of tulathromycin in the calf. AB - The pharmacokinetic (PK) profile of tulathromycin, administered to calves subcutaneously at the dosage of 2.5 mg/kg, was established in serum, inflamed (exudate), and noninflamed (transudate) fluids in a tissue cage model. The PK profile of tulathromycin was also established in pneumonic calves. For Mannheimia haemolytica and Pasteurella multocida, tulathromycin minimum inhibitory concentrations (MIC) were approximately 50 times lower in calf serum than in Mueller-Hinton broth. The breakpoint value of the PK/pharmacodynamic (PD) index (AUC(0-24 h) /MIC) to achieve a bactericidal effect was estimated from in vitro time-kill studies to be approximately 24 h for M. haemolytica and P. multocida. A population model was developed from healthy and pneumonic calves and, using Monte Carlo simulations, PK/PD cutoffs required for the development of antimicrobial susceptibility testing (AST) were determined. The population distributions of tulathromycin doses were established by Monte Carlo computation (MCC). The computation predicted a target attainment rate (TAR) for a tulathromycin dosage of 2.5 mg/kg of 66% for M. haemolytica and 87% for P. multocida. The findings indicate that free tulathromycin concentrations in serum suffice to explain the efficacy of single-dose tulathromycin in clinical use, and that a dosage regimen can be computed for tulathromycin using classical PK/PD concepts. PMID- 27501188 TI - Improved Swiss-rolling Technique for Intestinal Tissue Preparation for Immunohistochemical and Immunofluorescent Analyses. AB - Understanding the role of factors that regulate intestinal epithelial homeostasis and response to injury and regeneration is important. The current literature describes several different methodological approaches to obtain images of intestinal tissues for data validation. In this paper, we delineate a common protocol relating to the derivation and processing of mouse intestinal tissues. Proper fixation of intestinal tissues and Swiss-roll techniques that enhance intestinal epithelial morphology are discussed. Postresection processing and reorientation of embedded intestinal tissues are critical in obtaining paraffin embedded blocks that display intact intestinal structural features after sectioning. The Swiss-rolling technique helps in histological assessment of the complete intestinal or colonic sections examined. An ability to differentiate intestinal structural features can be vital in quantitative measurements of intestinal inflammation and tumorigenesis along the entire length. Finally, paraffin-embedded sections are ideal for robust processing using both immunohistochemical and immunofluorescent detection methods. Nonfluorescent immunohistochemical sections provide a vibrant image of the tissue detailing different cellular structural features but do not provide flexibility for intracellular co-localization experiments. Multiple fluorescent channels can be appropriately utilized with immunofluorescent detection for co-localization experiments, lending support to mechanistic studies. PMID- 27501189 TI - Validity and reliability of the Family Empowerment Scale for caregivers of adults with mental health issues. AB - : WHAT IS KNOWN ON THE SUBJECT?: Empowerment of family caregivers of adults with mental health issues has received increasing attention among mental health nurses in Japan and has been recognized as a new goal of family interventions. The Family Empowerment Scale (FES) was originally developed to measure the empowerment status of parents of children with emotional disorders. However, it was later applied to broader health issues. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: We developed a Japanese version of the FES for family caregivers of adults with mental health issues (FES-AMJ) and examined the validity and reliability among parents. Results showed that the FES-AMJ had acceptable concurrent validity and reliability; however, insufficient construct validity was found, especially for the subscale regarding the service system. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Further studies need to modify the scale. Clarification of ideal family empowerment status in the service system through discussion with mental health nurses and family caregivers may be important. ABSTRACT: Introduction The Family Empowerment Scale (FES) was originally developed for parents of children with emotional disorders. In Japan, family empowerment is gaining increasing attention and may be one goal of nursing interventions. Aim To develop a Japanese version of the FES for family caregivers of adults with mental health issues and to study the validity and reliability of this scale among parents. Method We translated the FES into Japanese and administered this self-report questionnaire to 275 parents. Results The multitrait scaling analysis revealed acceptable convergent validity and insufficient discriminant validity among all subscales. In particular, all items of the Service system subscale had insufficient discriminant and/or convergent validity. Each subscale significantly correlated with the indicator of empowerment. The intraclass correlation coefficients of each subscale were .855 .917. Cronbach's alpha of each factor ranged from .867 to .895. Discussion The Service system subscale may not linearly reflect family empowerment, and instead may depend on unclear roles of family caregivers of adults, disorder severity or insufficient services. Implications for practice Further studies need to modify the scale. Clarification of ideal family empowerment status in the service system through discussion with mental health nurses and family caregivers may be important. PMID- 27501190 TI - Whole genome sequence resource of Indian Zaprionus indianus. AB - This article documents the whole genome sequence information of the Indian Zaprionus indianus, a member of the fruit fly family Drosophilidae. The sequences were generated on an Illumina platform and reads and whole genome sequence submitted to NCBI to the SRA and BioProject databases, respectively. This is the first Indian Z. indianus whole genome (draft) submitted to the sequence repository with SRA reads. The details of methodology, assembly statistics and functional annotation are presented in this work. PMID- 27501191 TI - Placental Growth Measures in Relation to Birth Weight in a Latin American Population. AB - Introduction The placenta, translates how the fetus experiences the maternal environment and is a principal influence on birth weight (BW). Objective To explore the relationship between placental growth measures (PGMs) and BW in a public maternity hospital. Methods Observational retrospective study of 870 singleton live born infants at Hospital Maternidad Sarda, Universidad de Buenos Aires, Argentina, between January 2011 and August 2012 with complete data of PGMs. Details of history, clinical and obstetrical maternal data, labor and delivery and neonatal outcome data, including placental measures derived from the records, were evaluated. The following manual measurements of the placenta according to standard methods were performed: placental weight (PW, g), larger and smaller diameters (cm), eccentricity, width (cm), shape, area (cm(2)), BW/PW ratio (BPR) and PW/BW ratio (PBR), and efficiency. Associations between BW and PGMs were examined using multiple linear regression. Results Birth weight was correlated with placental weight (R(2) = 0.49, p < 0.001), whereas gestational age was moderately correlated with placental weight (R(2) = 0.64, p < 0.001). By gestational age, there was a positive trend for PW and BPR, but an inverse relationship with PBR (p < 0.001). Placental weight alone accounted for 49% of birth weight variability (p < 0,001), whereas all PGMs accounted for 52% (p < 0,001). Combined, PGMs, maternal characteristics (parity, pre-eclampsia, tobacco use), gestational age and gender explained 77.8% of BW variations (p < 0,001). Among preterm births, 59% of BW variances were accounted for by PGMs, compared with 44% at term. All placental measures except BPR were consistently higher in females than in males, which was also not significant. Indices of placental efficiency showed weakly clinical relevance. Conclusions Reliable measures of placental growth estimate 53.6% of BW variances and project this outcome to a greater degree in preterm births than at term. These findings would contribute to the understanding of the maternal-placental programming of chronic diseases. PMID- 27501192 TI - Organic Lasers: Recent Developments on Materials, Device Geometries, and Fabrication Techniques. AB - Organic dyes have been used as gain medium for lasers since the 1960s, long before the advent of today's organic electronic devices. Organic gain materials are highly attractive for lasing due to their chemical tunability and large stimulated emission cross section. While the traditional dye laser has been largely replaced by solid-state lasers, a number of new and miniaturized organic lasers have emerged that hold great potential for lab-on-chip applications, biointegration, low-cost sensing and related areas, which benefit from the unique properties of organic gain materials. On the fundamental level, these include high exciton binding energy, low refractive index (compared to inorganic semiconductors), and ease of spectral and chemical tuning. On a technological level, mechanical flexibility and compatibility with simple processing techniques such as printing, roll-to-roll, self-assembly, and soft-lithography are most relevant. Here, the authors provide a comprehensive review of the developments in the field over the past decade, discussing recent advances in organic gain materials, which are today often based on solid-state organic semiconductors, as well as optical feedback structures, and device fabrication. Recent efforts toward continuous wave operation and electrical pumping of solid-state organic lasers are reviewed, and new device concepts and emerging applications are summarized. PMID- 27501193 TI - Visualizing Motion Patterns in Acupuncture Manipulation. AB - Acupuncture manipulation varies widely among practitioners in clinical settings, and it is difficult to teach novice students how to perform acupuncture manipulation techniques skillfully. The Acupuncture Manipulation Education System (AMES) is an open source software system designed to enhance acupuncture manipulation skills using visual feedback. Using a phantom acupoint and motion sensor, our method for acupuncture manipulation training provides visual feedback regarding the actual movement of the student's acupuncture manipulation in addition to the optimal or intended movement, regardless of whether the manipulation skill is lifting, thrusting, or rotating. Our results show that students could enhance their manipulation skills by training using this method. This video shows the process of manufacturing phantom acupoints and discusses several issues that may require the attention of individuals interested in creating phantom acupoints or operating this system. PMID- 27501194 TI - Capturing the Active Ingredients of Multicomponent Participatory Organizational Stress Interventions Using an Adapted Study Design. AB - Adapted study designs use process evaluation to incorporate a measure of intervention exposure and create an artificial control and intervention groups. Taking into account exposure levels to interventions combines process and outcome evaluation and strengthens the design of the study when exposure levels cannot be controlled. This study includes longitudinal data (two assessments) with added process measures at time 2 gathered from three complex participatory intervention projects in Canada in a hospital and a university. Structural equation modelling was used to explore the specific working mechanisms of particular interventions on stress outcomes. Results showed that higher exposure to interventions aiming to modify tasks and working conditions reduced demands and improved social support, but not job control, which in turn, reduced psychological distress. Exposure to interventions aiming to improve relationships was not related to psychosocial risks. Most studies cannot explain how interventions produce their effects on outcomes, especially when there are multiple concurrent interventions delivered in several contexts. This study advances knowledge on process evaluation by using an adapted study design to capture the active ingredients of multicomponent interventions and suggesting some mechanisms by which the interventions produce their effects on stress outcomes. It provides an illustration of how to conduct process evaluation and relate exposure levels to observed outcomes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27501195 TI - A protein complex supports the production of Spo0A-P and plays additional roles for biofilms and the K-state in Bacillus subtilis. AB - Bacillus subtilis can enter three developmental pathways to form spores, biofilms or K-state cells. The K-state confers competence for transformation and antibiotic tolerance. Transition into each of these states requires a stable protein complex formed by YlbF, YmcA and YaaT. We have reported that this complex acts in sporulation by accelerating the phosphorylation of the response regulator Spo0A. Phosphorelay acceleration was also predicted to explain their involvement in biofilm formation and the K-state. This view has been challenged in the case of biofilms, by the suggestion that the three proteins act in association with the mRNA degradation protein RNaseY (Rny) to destabilize the sinR transcript. Here, we reaffirm the roles of the three proteins in supporting the phosphorylation of Spo0A for all three developmental pathways and show that in their absence sinR mRNA is not stabilized. We demonstrate that the three proteins also play unknown Spo0A-P-independent roles in the expression of biofilm matrix and in the production of ComK, the master transcription factor for competence. Finally, we show that domesticated strains of B. subtilis carry a mutation in sigH, which influences the expression kinetics of the early spore gene spoIIG, thereby increasing the penetrance of the ylbF, ymcA and yaaT sporulation phenotypes. PMID- 27501196 TI - Enhanced viral activity and dark CO2 fixation rates under oxygen depletion: the case study of the marine Lake Rogoznica. AB - Global change is determining the expansion of marine oxygen-depleted zones, which are hot spots of microbial-driven biogeochemical processes. However, information on the functioning of the microbial assemblages and the role of viruses in such low-oxygen systems remains largely unknown. Here, we used the marine Rogoznica Lake as a natural model to investigate the possible consequences of oxygen depletion on virus-prokaryote interactions and prokaryotic metabolism in pelagic and benthic ecosystems. We found higher bacterial and archaeal abundances in oxygen-depleted than in oxic conditions, associated with higher heterotrophic carbon production, enzymatic activities and dark inorganic carbon fixation (DCF) rates. The oxygen-depleted systems were also characterized by higher viral abundance, production and virus-induced prokaryotic mortality. The highest DCF relative contribution to the whole total C production (> 30%) was found in oxygen depleted systems, at the highest virus-induced prokaryotic mortality values (> 90%). Our results suggest that the higher rates of viral lysis in oxygen-depleted conditions can significantly enhance DCF by accelerating heterotrophic processes, organic matter cycling, and hence the supply of inorganic reduced compounds fuelling chemosynthesis. These findings suggest that the expansion of low-oxygen zones can trigger higher viral impacts on prokaryotic heterotrophic and chemoautotrophic metabolism, with cascading effects, neglected so far, on biogeochemical processes. PMID- 27501197 TI - Family-centered care in children with epilepsy: Evaluating the Measure of Processes of Care (MPOC-20). AB - OBJECTIVE: The objective was to test whether the five-domain structure of the Measure of Processes of Care (MPOC-20) was observed in a sample of children with epilepsy and, if not, to propose adaptations to improve its utility in this population. METHODS: Data came from the Health-Related Quality of Life in Children with Epilepsy Study (HERQULES)-a multicenter prospective cohort study (n = 374) following children 4-12 years of age for 2 years after diagnosis. Confirmatory factor analysis (CFA) tested the applicability of the five domains/factors in a sample of children with epilepsy approximately 6 months following diagnosis (n = 311). Goodness-of-fit statistics were used to examine sources of ill model fit, and modification indices guided the model modification process where there was strong theoretical rationale for changes. RESULTS: The five-factor model described by the originators of the MPOC-20 was found to be inadmissible in children with epilepsy, with four of the five factors demonstrating high correlations (r > 0.85). Upon merging the intercorrelated factors, a two-factor solution with a mediocre fit emerged (Root Mean Square Error of Approximation (RMSEA) = 0.080, Comparative Fit Index (CFI) = 0.902, Standardized Root Mean Square Residual (SRMR) = 0.060). Modification indices identified four items as the source of poor model fit. Removing these four items and reperforming the CFA resulted in an adequate model fit and a revised 16-item MPOC (RMSEA = 0.057, CFI = 0.958, SRMR = 0.036). The two factors are "Family/Care Provider Interaction" and "Providing Information." SIGNIFICANCE: Results suggest that the MPOC-16 better reflects family-centered care (FCC) in children with epilepsy than the original MPOC-20. The benefit of having fewer factors is that scoring is simpler and the interpretation of the results is easier. This was the first investigation of the factor structure of the MPOC-20 on a sample entirely composed of children with epilepsy. These results add to evidence that the factor structure (and how family-centered care is delivered and perceived) differs across treatment environments and treatment populations. PMID- 27501198 TI - Modified partial maxillary swing approach for myxofibrosarcoma in pterygopalatine fossa. AB - BACKGROUND: Extirpation of tumors arising in the pterygopalatine fossa is challenging because of its anatomic complexity. METHODS AND RESULTS: A 67-year old man was referred to our department with a diagnosis of a tumor in his left pterygoid fossa. An incisional biopsy through the canine fossa was diagnosed as myxofibrosarcoma. The upper part of the maxilla was swung laterally to remove the tumor while the hard plate was preserved. The defect was reconstructed using rectus abdominis musculocutaneous free and ipsilateral temporal. The postoperative course was uneventful, without facial palsy or mastication disorders. CONCLUSION: Our experience with this case suggests that the modified partial maxillary swing approach with preservation of the hard palate and orbital floor in combination with infratemporal and cervical approaches is useful for lesions in the pterygoid process without causing severe complications. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: E2519-E2522, 2016. PMID- 27501200 TI - Environment-dependent variation in selection on life history across small spatial scales. AB - Variation in life-history traits is ubiquitous, even though genetic variation is thought to be depleted by selection. One potential mechanism for the maintenance of trait variation is spatially variable selection. We explored spatial variation in selection in the field for a colonial marine invertebrate that shows phenotypic differences across a depth gradient of only 3 m. Our analysis included life-history traits relating to module size, colony growth, and phenology. Directional selection on colony growth varied in strength across depths, while module size was under directional selection at one depth but not the other. Differences in selection may explain some of the observed phenotypic differentiation among depths for one trait but not another: instead, selection should actually erode the differences observed for this trait. Our results suggest selection is not acting alone to maintain trait variation within and across environments in this system. PMID- 27501201 TI - Free anterolateral thigh flap and masseter nerve transfer for reconstruction of extensive periauricular defects: Surgical technique and clinical outcomes. AB - BACKGROUND: Radical tumor ablation in the periauricular area often results in extensive soft tissue defects, including facial nerve sacrifice, bone and/or dura defects. Reconstruction of these defects should aim at restoring facial reanimation, wound closure, and facial and neck contours. We present our experience using free anterolateral thigh flap (ALT) in combination with masseter nerve to facial nerve transfer in managing complex defects in the periauricular area. METHODS: Between 2011 and 2015 six patients underwent a combined procedure of ALT flap reconstruction and masseter nerve transfer, to reconstruct extensive, post tumor resection, periauricular defects. The ALT flap was customized according to the defect. For smile restoration, the masseter nerve was transferred to the buccal branch of the facial nerve. If the facial nerve stump was preserved, interposition of nerve grafts to the zygomatic and frontal branches was performed to provide separate eye closure. The outcomes were analyzed by assessing wound closure, contour deformity, symmetry of the face, and facial nerve function. RESULTS: There were no partial or total flap losses. Stable wound closure and adequate volume replacement in the neck was achieved in all cases, as well as good facial tonus and symmetry. The mean follow-up time of clinical outcomes was 16.8 months. Smile restoration was graded as good or excellent in four cases, moderate in one and fair in one. CONCLUSION: Extensive periauricular defects following oncologic resection could be adequately reconstructed in a combined procedure of free ALT flap and masseter nerve transfer to the facial nerve for smile restoration. PMID- 27501202 TI - Enhanced detection performance in electrosense through capacitive sensing. AB - Weakly electric fish emit an AC electric field into the water and use thousands of sensors on the skin to detect field perturbations due to surrounding objects. The fish's active electrosensory system allows them to navigate and hunt, using separate neural pathways and receptors for resistive and capacitive perturbations. We have previously developed a sensing method inspired by the weakly electric fish to detect resistive perturbations and now report on an extension of this system to detect capacitive perturbations as well. In our method, an external object is probed by an AC field over multiple frequencies. We present a quantitative framework that relates the response of a capacitive object at multiple frequencies to the object's composition and internal structure, and we validate this framework with an electrosense robot that implements our capacitive sensing method. We define a metric for comparing the electrosensory range of different underwater electrosense systems. For detecting non-conductive objects, we show that capacitive sensing performs better than resistive sensing by almost an order of magnitude using this measure, while for conductive objects there is a four-fold increase in performance. Capacitive sensing could therefore provide electric fish with extended sensing range for capacitive objects such as prey, and gives artificial electrolocation systems enhanced range for targets that are capacitive. PMID- 27501204 TI - Benzodiazepine dependence in subjects with alcohol use disorders: what prevalence? AB - OBJECTIVE: To our knowledge, no studies have been conducted in France on benzodiazepine (BZD) dependence among outpatients with alcohol use disorders (AUD). Some international studies have been conducted on the consumption of BZD in this specific population, but the comparisons among them are difficult. We aimed to assess the current prevalence of probable benzodiazepine and BZD-like hypnotics (Z-drugs) dependence among outpatients seeking treatment for AUD. METHODS: Participants were patients seeking treatment for AUD for the first time or repeating treatment after more than twelve months. Recruitment took place in seven addiction centres between January and December 2013 in the Nantes region (France). BZD/Z-drug dependence was assessed according to the DSM-IV diagnostic criteria for dependence. This information was gathered through a self-report questionnaire. RESULTS: Among the 1005 patients included in this study, 413 were BZD/Z-drug users (41.1%). Among the 413 patients, 217 were probably dependent on at least one substance, which represents 21.6% of the total population and 52.5% of BZD/Z-drug users. CONCLUSION: BZD/Z-drug dependence represents a public health concern. Prescribers should take the risks into account and keep treatment courses to a minimum. PMID- 27501203 TI - Immunosuppression With CD40 Costimulatory Blockade Plus Rapamycin for Simultaneous Islet-Kidney Transplantation in Nonhuman Primates. AB - The lack of a reliable immunosuppressive regimen that effectively suppresses both renal and islet allograft rejection without islet toxicity hampers a wider clinical application of simultaneous islet-kidney transplantation (SIK). Seven MHC-mismatched SIKs were performed in diabetic cynomolgus monkeys. Two recipients received rabbit antithymocyte globulin (ATG) induction followed by daily tacrolimus and rapamycin (ATG/Tac/Rapa), and five recipients were treated with anti-CD40 monoclonal antibody (mAb) and rapamycin (aCD40/Rapa). Anti-inflammatory therapy, including anti-interleukin-6 receptor mAb and anti-tumor necrosis factor alpha mAb, was given in both groups. The ATG/Tac/Rapa recipients failed to achieve long-term islet allograft survival (19 and 26 days) due to poor islet engraftment and cytomegalovirus pneumonia. In contrast, the aCD40/Rapa regimen provided long-term islet and kidney allograft survival (90, 94, >120, >120, and >120 days), with only one recipient developing evidence of allograft rejection. The aCD40/Rapa regimen was also tested in four kidney-alone transplant recipients. All four recipients achieved long-term renal allograft survival (100% at day 120), which was superior to renal allograft survival (62.9% at day 120) with triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids). The combination of anti-CD40 mAb and rapamycin is an effective and nontoxic immunosuppressive regimen that uses only clinically available agents for kidney and islet recipients. PMID- 27501205 TI - Reconsidering Empathy in Nursing Care. PMID- 27501206 TI - Men in Nursing: Intention, Intentionality, Caring, and Healing: Emphasis on the Results of a Grounded Theory Study. AB - The purpose of this article is to amplify the results section of a grounded theory study on how men in nursing view and experience intention, intentionality, caring, and healing. This is the second grounded theory study addressing intentionality in healing. The first study included a female population. The theory that was generated-Intentionality: The Matrix of Healing (IMH)-is examined with these new data. The results are compared with issues generally faced by men in nursing and how they described their beliefs and experiences with intentionality and healing. The theory (IMH) is supported; the importance of action in this cohort was an additional emphasis. This article provides an expanded view of men in nursing and their experiences as nurses and with intentionality, caring, and healing and has implications for the development of holistic nursing theory as well. PMID- 27501207 TI - Effect of Acupressure on Nausea-Vomiting in Patients With Acute Myeloblastic Leukemia. AB - The aim of this study was to assess the effect of acupressure, applied at P6 (Neiguan) acupuncture point, on chemotherapy-induced nausea and vomiting in patients with acute myeloblastic leukemia. This was a randomized controlled trial conducted on patients with myeloblastic leukemia. A total of 90 patients, who received the same chemotherapy regimen and antiemetic therapy, were included in the study as 30 patients in the control group, 30 patients in the band group, and 30 patients in the pressure group. Although acupressure was applied by placing wristbands at P6 acupuncture point of both wrists in patients of the band group for totally 4 days, acupressure was applied with the use of finger pressure in patients of the pressure group for totally 4 days. No intervention was made in patients of the control group other than the routine antiemetic therapy. The data of the study were collected by using a questionnaire and nausea-vomiting chart. Severity of nausea-vomiting was assessed by using the visual analog scale on this chart. It was determined that the acupressure band applied to the patients included in the study reduced number and severity of nausea-vomiting (P < .05); however, the acupressure applied with pressure did not affect number and severity of nausea-vomiting (P > .05). It was found that the acupressure band was effective for reducing the chemotherapy-induced nausea and vomiting. PMID- 27501208 TI - Incivility Across the Nursing Continuum. AB - Incivility affects nurses throughout education and practice; it directly affects patient safety as well as nurses' decisions to remain in academia and clinical practice. This article reviews the current literature on incivility and proposes the application of social learning theory to evidence-based strategies that can be implemented to combat incivility. PMID- 27501209 TI - Toward a Holistic Approach to Spiritual Health Care for People With Schizophrenia. AB - Medical and behavioral treatments are the predominant types of rehabilitation services for people with schizophrenia. Spirituality in people with schizophrenia remains poorly conceptualized, thereby limiting knowledge advancement in the area of spiritual health care services. To provide a framework for better clinical and research practices, we advocate a holistic approach to investigating spirituality and its application in spiritual health care services of people with schizophrenia. PMID- 27501210 TI - Effect of Support Group Intervention Applied to the Caregivers of Individuals With Heart Failure on Caregiver Outcomes. AB - This study was conducted to evaluate the effectiveness of support group intervention applied to the caregivers of individuals with heart failure on caregiver outcomes. Quasi-experimental research was conducted with 69 caregivers as control (n = 35) and intervention (n = 34) groups in the cardiology outpatient clinic of a university hospital. The intervention group participated in support group meetings structured according to the Neuman Systems Model, and the data were collected from both the intervention and control groups before the intervention and 3 and 6 months later. Caregivers in the intervention group had significantly lower burden scores compared with the control group in all subdimensions except objective personal care, in terms of the group * time interaction in a statistical way (P < .05). Caregivers in the intervention and control groups had similar scores of depression symptoms (P > .05). The burden of caregivers in the intervention group showed a statistically significant decrease compared with the preintervention in all dimensions at 3 months. Thus, it is suggested to extend the support group interventions for caregivers of patients with heart failure and conduct these interventions in a longer period. PMID- 27501211 TI - Effectiveness of Acupressure in Promoting Sleep Quality: A Systematic Review of Randomized Controlled Trials. AB - This review aimed to evaluate the effectiveness of acupressure in promoting sleep quality among adults. Study findings included in the review showed that acupressure significantly improved sleep quality compared with the control group, but no superior effect of acupressure was found compared with sham acupressure. PMID- 27501212 TI - Effect of Reflexology to Depressive Symptoms in Women With Overactive Bladder. AB - This study is to determine the effect of foot reflexology on the level of depression in women with OAB. Study findings included in the study showed foot reflexology as a part of OAB treatment relieved urinary and depressive symptoms and had a positive effect on quality of life. PMID- 27501213 TI - Allergic Rhinitis: A Proprietary Extract of Pinus pinaster Aiton (Pycnogenol) Is Found to Improve the Symptoms Associated With Allergic Rhinitis. PMID- 27501214 TI - Health Literacy and Its Influence on Self-care Potential. PMID- 27501215 TI - Detection of folate receptor-positive circulating tumor cells by ligand-targeted polymerase chain reaction in non-small cell lung cancer patients. PMID- 27501216 TI - Far-Field Super-resolution Detection of Plasmonic Near-Fields. AB - We demonstrate a far-field single molecule super-resolution method that maps plasmonic near-fields. The method is largely invariant to fluorescence quenching (arising from probe proximity to a metal), has reduced point-spread-function distortion compared to fluorescent dyes (arising from strong coupling to nanoscopic metallic features), and has a large dynamic range (of 2 orders of magnitude) allowing mapping of plasmonic field-enhancements regions. The method takes advantage of the sensitivity of quantum dot (QD) stochastic blinking to plasmonic near-fields. The modulation of the blinking characteristics thus provides an indirect measure of the local field strength. Since QD blinking can be monitored in the far-field, the method can measure localized plasmonic near fields at high throughput using a simple far-field optical setup. Using this method, propagation lengths and penetration depths were mapped-out for silver nanowires of different diameters and for different dielectric environments, with a spatial accuracy of ~15 nm. We initially use sparse sampling to ensure single molecule localization for accurate characterization of the plasmonic near-field with plans to increase density of emitters in further studies. The measured propagation lengths and penetration depths values agree well with Maxwell finite difference time-domain calculations and with published literature values. This method offers advantages such as low cost, high throughput, and superresolved mapping of localized plasmonic fields at high sensitivity and fidelity. PMID- 27501217 TI - SOx Tolerant Pt/TiO2 Catalysts for CO Oxidation and the Effect of TiO2 Supports on Catalytic Activity. AB - We developed a new technique for mitigating catalyst deactivation caused by SO2 in exhaust gases. A series of 0.1 wt %-Pt/TiO2 catalysts with different surface, crystal, and pore structures were prepared and tested for CO oxidation activity in the presence of SO2 and H2O. The order of the CO oxidation activity under the influence of SO2 was much different from that in the absence of SO2. Catalysts with a high ratio of larger pores exhibited higher catalytic activity under the influence of SO2 and H2O in the temperature range of 250-300 degrees C, whereas other parameters, such as BET surface area and crystal structure of the TiO2 support, had minor effects on the CO oxidation activity. The oxidation state of Pt differed significantly depending on the kind of TiO2 support. Some catalysts were less active without H2 reduction pretreatment due to the presence of oxidized Pt species. PMID- 27501218 TI - Depletion of Mouse Cells from Human Tumor Xenografts Significantly Improves Downstream Analysis of Target Cells. AB - The use of in vitro cell line models for cancer research has been a useful tool. However, it has been shown that these models fail to reliably mimic patient tumors in different assays(1). Human tumor xenografts represent the gold standard with respect to tumor biology, drug discovery, and metastasis research (2-4). Tumor xenografts can be derived from different types of material like tumor cell lines, tumor tissue from primary patient tumors(4) or serially transplanted tumors. When propagated in vivo, xenografted tissue is infiltrated and vascularized by cells of mouse origin. Multiple factors such as the tumor entity, the origin of xenografted material, growth rate and region of transplantation influence the composition and the amount of mouse cells present in tumor xenografts. However, even when these factors are kept constant, the degree of mouse cell contamination is highly variable. Contaminating mouse cells significantly impair downstream analyses of human tumor xenografts. As mouse fibroblasts show high plating efficacies and proliferation rates, they tend to overgrow cultures of human tumor cells, especially slowly proliferating subpopulations. Mouse cell derived DNA, mRNA, and protein components can bias downstream gene expression analysis, next-generation sequencing, as well as proteome analysis (5). To overcome these limitations, we have developed a fast and easy method to isolate untouched human tumor cells from xenografted tumor tissue. This procedure is based on the comprehensive depletion of cells of mouse origin by combining automated tissue dissociation with the benchtop tissue dissociator and magnetic cell sorting. Here, we demonstrate that human target cells can be can be obtained with purities higher than 96% within less than 20 min independent of the tumor type. PMID- 27501219 TI - Infertile men's needs and assessment of fertility care. AB - INTRODUCTION: Male infertility is potentially a severe, low-control stressor. There is limited knowledge of the expectations, needs, and assessment of fertility care among men with severe infertility. The aim of this study was to explore experience, expectations, needs, and assessment of fertility care among Danish men having severe male-factor infertility. METHODS: Semi-structured qualitative interview study with 10 men with very low sperm quality initiating intracytoplasmic sperm injection (ICSI) treatment at the Fertility Clinic, Copenhagen University Hospital, Hvidovre, Denmark. Five of the men participated in a follow-up interview after their first ICSI treatment. The data collection took place during November 2014 to May 2015. Data were analysed using qualitative content analysis. RESULTS: Two themes were found: 'The maze' and 'Desire for care'. It felt like an eternity for the men from the referral until treatment started. The men did not understand the process, and it was like being in a maze. The men saw fatherhood as something to strive for. They felt that they could not do what a man is supposed to do, and they felt pushed aside and that treatment focused on the women. The men appreciated the staff's kindness and professionalism but desired the staff to address emotional subjects too. CONCLUSION: The process from referral to treatment felt like a maze for these men. They needed the staff to give them the opportunity to speak of the psychosocial consequences of severe male-factor infertility. PMID- 27501220 TI - Direct and indirect effects of parenting practices on socio-moral approval of aggression in Polish young adults. Do all practices matter? AB - The purpose of this article was to determine the socialisation antecedents of socio-moral approval of aggression (SMAA). In Study 1, we assessed factorial structure and reliability of the SMAA with a sample of 355 students who reported on the extent to which they approved of six forms of aggressive behaviour and six justifications of aggression. Two-factor solutions were obtained with regard to forms and justifications of aggressive acts. Thus, approval of extreme and minor aggression was distinguished as well as legitimate and illegitimate justifications of aggression. In Study 2, we tested the path models of the socialisation antecedents that contributed to the high approval of minor and extreme aggressive acts as well as legitimate and illegitimate justifications of aggression. Data were collected from 173 undergraduate students. Path analyses showed that high levels of approval of extremely aggressive acts and of illegitimate justifications of aggression were preceded by a sequence of negative life events, beginning with frequent misbehaviour in childhood, corporal punishment used by parents and ending with delinquency in adolescence. The approval of minor aggression had little relation to socialisation factors apart from a detrimental effect of psychological aggression while approval of legitimate justifications of aggression had no socialisation antecedents. PMID- 27501221 TI - Modeling Myotonic Dystrophy 1 in C2C12 Myoblast Cells. AB - Myotonic dystrophy 1 (DM1) is a common form of muscular dystrophy. Although several animal models have been established for DM1, myoblast cell models are still important because they offer an efficient cellular alternative for studying cellular and molecular events. Though C2C12 myoblast cells have been widely used to study myogenesis, resistance to gene transfection, or viral transduction, hinders research in C2C12 cells. Here, we describe an optimized protocol that includes daily maintenance, transfection and transduction procedures to introduce genes into C2C12 myoblasts and the induction of myocyte differentiation. Collectively, these procedures enable best transfection/transduction efficiencies, as well as consistent differentiation outcomes. The protocol described in establishing DM1 myoblast cell models would benefit the study of myotonic dystrophy, as well as other muscular diseases. PMID- 27501222 TI - A Joint Leap into a Future of High-Quality Simulation Research-Standardizing the Reporting of Simulation Science. PMID- 27501224 TI - Cutaneous T-Cell Lymphoma. A hypothesis on disease pathophysiology involving deficiency in DNA repair. AB - Cutaneous T-cell lymphoma (CTCL) is a rare disease occurring in Europe among two persons per million per year. It affects men more often than women (2:1). It is primarily a skin disease. In about 20% of patients, it becomes fatal with tumours in the skin and spreading to lymph glands. Approximately 3% of patients show a leukemic form called Sezary's syndrome, where malignant cells are present in blood with accompanying erythrodermia. CTCL is a T-lymphocyte disease occurring late in life as the average age of patients is around 66 years in Europe, Japan and the US. This article focuses on cell lines and immune surveillance in CTCL, and especially the pronounced chromosomal instability. It leads to the hypothesis that chromosomal changes is the key event linked to DNA repair deficiencies, which in a subpopulation of T cells leads to CTCL development over years. PMID- 27501226 TI - Hypoxia-preconditioned allogeneic mesenchymal stem cells can be used for myocardial repair in non-human primates. PMID- 27501225 TI - Naming influences 9-month-olds' identification of discrete categories along a perceptual continuum. AB - A growing body of evidence documents that naming guides 9-month-old infants as they organize their visual experiences into categories. In particular, this evidence reveals that naming highlights categories when these are visually distinct. Here we advance this work in by introducing an anticipatory looking design to assess how naming influences infants' categorization of objects that vary along a perceptual continuum. We introduced 9-month-old infants (n = 48) to continua of novel creature-like objects. During the learning phase, infants had an opportunity to observe that objects from one end of the perceptual continuum moved to the left and objects from the other end moved to the right. What varied was how the objects were named. Infants in theone-name condition heard the same novel noun applied to all objects along the continuum; those in the two-name condition heard one name for objects from one end of the continuum and a second name for objects at the other end. At test, all infants viewed new objects from the same continuum. At issue was whether infants would anticipate the side to which the test objects would move and whether their expectations varied as a function of naming condition. Infants in the one-name condition formed a single overarching category and therefore searched for new test objects at either location; those in the two-name condition discerned two categories and therefore correctly anticipated the likely location of the test objects, whether these were close to the poles or to the center of the continuum. This provides the first evidence that by 9 months, naming supports both the number of categories infants impose along a perceptual continuum and the clarity of the category boundaries. PMID- 27501227 TI - HSV-Mediated Transgene Expression of Chimeric Constructs to Study Behavioral Function of GPCR Heteromers in Mice. AB - The heteromeric receptor complex between 5-HT2A and mGlu2 has been implicated in some of the behavioral phenotypes in mouse models of psychosis(1,2). Consequently, investigation of structural details of the interaction between 5 HT2A and mGlu2 affecting schizophrenia-related behaviors represents a powerful translational tool. As previously shown, the head-twitch response (HTR) in mice is elicited by hallucinogenic drugs and this behavioral response is absent in 5 HT2A knockout (KO) mice(3,4). Additionally, by conditionally expressing the 5 HT2A receptor only in cortex, it was demonstrated that 5-HT2A receptor-dependent signaling pathways on cortical pyramidal neurons are sufficient to elicit head twitch behavior in response to hallucinogenic drugs(3). Finally, it has been shown that the head-twitch behavioral response induced by the hallucinogens DOI and lysergic acid diethylamide (LSD) is significantly decreased in mGlu2-KO mice(5). These findings suggest that mGlu2 is at least in part necessary for the 5-HT2A receptor-dependent psychosis-like behavioral effects induced by LSD-like drugs. However, this does not provide evidence as to whether the 5-HT2A-mGlu2 receptor complex is necessary for this behavioral phenotype. To address this question, herpes simplex virus (HSV) constructs to express either mGlu2 or mGlu2DeltaTM4N (mGlu2/mGlu3 chimeric construct that does not form the 5-HT2A mGlu2 receptor complex) in the frontal cortex of mGlu2-KO mice were used to examine whether this GPCR heteromeric complex is needed for the behavioral effects induced by LSD-like drugs(6). PMID- 27501228 TI - Predicting the dynamic impact behaviour of spray droplets on flat plant surfaces. AB - The dynamic impact behaviour of water droplets on plant surfaces was investigated based on a multiphase computational fluid dynamics (CFD) model. The study was conducted using the Volume Of Fluid (VOF) approach. The static contact angle of water droplets on leaf surfaces of different plants (apple, pear, leek and cabbage) was measured and found to vary between 54.9 and 138.2 degrees . Impact experiments were conducted by monitoring the flow and impact characteristics of water droplets on leaves in still air with a high speed camera. Droplets were generated by an agricultural flat fan spray nozzle moving across the leaf at constant speed. The nozzle produced droplets with diameters ranging from 20.6 up to 550.8 MUm, and droplet velocity values near the impact between 0.03 and 13.2 m s(-1). The CFD model was capable of predicting the observed dynamic impact behaviour of droplets on the plant surfaces. The fate of the droplets after the impact process for adhesion, bouncing or splashing was accurately predicted for Weber numbers (We) in the range of 0.007 to 1096 and droplet Reynolds numbers (Re) between 5 to 8000. The process was highly dependent on the surface and droplet flow characteristics during the impact. Combinations of We, Re and Ohnesorge (Oh) numbers defined the droplet maximum spread factor, the number of secondary droplets generated as a result of the splashing process and the transition between the different impact outcomes. These criteria can then be used in field scale spray deposition and drift models to better understand agricultural spray operations. PMID- 27501230 TI - Stereoselective Construction of Spiro-Fused Tricyclic Frameworks by Sequential Reaction of Enynes, Imines, and Diazoalkenes with Rh(I) and Rh(II) Catalysts. AB - Stereoselective construction of spiro-fused tricyclic compounds from enynes having a tethered imine with diazoalkenes was achieved by Rh(I)- and Rh(II) catalyzed sequential reactions. This method consists of three reactions, i.e., Rh(I)-catalyzed cyclization of enynes with a tethered imine, Rh(II)-catalyzed cyclopropanation with diazoalkenes, and Cope rearrangement. Notably, the sequential reactions can be operated in one pot, in which Rh(I) and Rh(II) catalysts work in relay without any serious catalyst deactivation to afford the spirocycles in a stereoselective manner. PMID- 27501229 TI - Genomic Alteration in Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Inferred from Karyotyping, Molecular Cytogenetics, and Array Comparative Genomic Hybridization. AB - Genomic alteration in head and neck squamous cell carcinoma (HNSCC) was studied in two cell line pairs (HN30-HN31 and HN4-HN12) using conventional C-banding, multiplex fluorescence in situ hybridization (M-FISH), and array comparative genomic hybridization (array CGH). HN30 and HN4 were derived from primary lesions in the pharynx and base of tongue, respectively, and HN31 and HN12 were derived from lymph-node metastatic lesions belonging to the same patients. Gain of chromosome 1, 7, and 11 were shared in almost all cell lines. Hierarchical clustering revealed that HN31 was closely related to HN4, which shared eight chromosome alteration cases. Large C-positive heterochromatins were found in the centromeric region of chromosome 9 in HN31 and HN4, which suggests complex structural amplification of the repetitive sequence. Array CGH revealed amplification of 7p22.3p11.2, 8q11.23q12.1, and 14q32.33 in all cell lines involved with tumorigenesis and inflammation genes. The amplification of 2p21 (SIX3), 11p15.5 (H19), and 11q21q22.3 (MAML2, PGR, TRPC6, and MMP family) regions, and deletion of 9p23 (PTPRD) and 16q23.1 (WWOX) regions were identified in HN31 and HN12. Interestingly, partial loss of PTPRD (9p23) and WWOX (16q23.1) genes was identified in HN31 and HN12, and the level of gene expression tended to be the down-regulation of PTPRD, with no detectable expression of the WWOX gene. This suggests that the scarcity of PTPRD and WWOX genes might have played an important role in progression of HNSCC, and could be considered as a target for cancer therapy or a biomarker in molecular pathology. PMID- 27501231 TI - Event Recognition Based on Deep Learning in Chinese Texts. AB - Event recognition is the most fundamental and critical task in event-based natural language processing systems. Existing event recognition methods based on rules and shallow neural networks have certain limitations. For example, extracting features using methods based on rules is difficult; methods based on shallow neural networks converge too quickly to a local minimum, resulting in low recognition precision. To address these problems, we propose the Chinese emergency event recognition model based on deep learning (CEERM). Firstly, we use a word segmentation system to segment sentences. According to event elements labeled in the CEC 2.0 corpus, we classify words into five categories: trigger words, participants, objects, time and location. Each word is vectorized according to the following six feature layers: part of speech, dependency grammar, length, location, distance between trigger word and core word and trigger word frequency. We obtain deep semantic features of words by training a feature vector set using a deep belief network (DBN), then analyze those features in order to identify trigger words by means of a back propagation neural network. Extensive testing shows that the CEERM achieves excellent recognition performance, with a maximum F-measure value of 85.17%. Moreover, we propose the dynamic-supervised DBN, which adds supervised fine-tuning to a restricted Boltzmann machine layer by monitoring its training performance. Test analysis reveals that the new DBN improves recognition performance and effectively controls the training time. Although the F-measure increases to 88.11%, the training time increases by only 25.35%. PMID- 27501232 TI - Quality effects of using organogels in breakfast sausage. AB - Organogels made with canola oil, ethyl cellulose (EC; 8, 10, 12 and 14%), and sorbitan monostearate (SMS; 1.5, 3.0%) were used to replace pork fat in breakfast sausages. Some of the formulations with SMS matched the objective hardness (texture analyzer) of the pork fat control; however, sensory hardness was not so easily matched. Using canola oil by itself resulted in lower objective and subjective hardness values than the control. Sensory cohesiveness was not affected by the replacements, but springiness was lower in the treatments without SMS and some of the high EC treatments with SMS. Lightness of organogel treatments was lower than the control, but redness and yellowness values were not affected. Sensory juiciness and oiliness were in general lower in the organogel treatments. Overall, the study demonstrates the potential for the use of organogels in coarse ground meat products, as a means of improving the nutritional profile by replacing saturated fat with mono and poly unsaturated oils. PMID- 27501233 TI - Inter-laboratory assessment by trained panelists from France and the United Kingdom of beef cooked at two different end-point temperatures. AB - Eating quality of the same meat samples from different animal types cooked at two end-point cooking temperatures (55 degrees C and 74 degrees C) was evaluated by trained panels in France and the United Kingdom. Tenderness and juiciness scores were greater at 55 degrees C than at 74 degrees C, irrespective of the animal type and location of the panel. The UK panel, independently of animal type, gave greater scores for beef flavour (+7 to +24%, P<0.001) but lower scores for abnormal flavour (-10 to -17%, P<0.001) at 74 degrees C. Abnormal flavour score by the French panel was higher at 74 degrees C than at 55 degrees C (+26%, P<0.001). Irrespective of the data set, tenderness was correlated with juiciness and beef flavour. Overall, this study found that cooking beef at a lower temperature increased tenderness and juiciness, irrespective of the location of the panel. In contrast, cooking beef at higher temperatures increased beef flavour and decreased abnormal flavour for the UK panelists but increased abnormal flavour for the French panel. PMID- 27501234 TI - Quantification of soy protein using the isotope method (delta(13)C and delta(15)N) for commercial brands of beef hamburger. AB - Hamburgers (beef patties) may be adulterated through the overuse of protein extenders. Among vegetables, soy protein is the best substitute for animal protein. These ingredients help to reduce the cost of producing a final product, and they maximize profits for fraudulent industries. Moreover, the ingestion of soy or other non-meat proteins by allergic individuals may present a health risk. In addition, monitoring by supervisory bodies is hampered by a lack of appropriate analytical methodologies. Within this context, the aim of this study was to determine and quantify the levels of added soy protein by determination of (15)N and (13)C stable isotopes. A total of 100 beef hamburger samples from 10 commercial brands were analyzed. Only three samples of the G brand were within the standards set the Brazilian legislation. The remaining 97 samples from 10 commercial brands contained >4% soy protein; therefore, they are adulterated and not in compliance with the current legislation. PMID- 27501235 TI - Mice Expressing a "Hyper-Sensitive" Form of the Cannabinoid Receptor 1 (CB1) Are Neither Obese Nor Diabetic. AB - Multiple lines of evidence implicate the endocannabinoid signaling system in the modulation of metabolic disease. Genetic or pharmacological inactivation of CB1 in rodents leads to reduced body weight, resistance to diet-induced obesity, decreased intake of highly palatable food, and increased energy expenditure. Cannabinoid agonists stimulate feeding in rodents and increased levels of endocannabinoids can disrupt lipid metabolism. Therefore, the hypothesis that sustained endocannabinoid signaling can lead to obesity and diabetes was examined in this study using S426A/S430A mutant mice expressing a desensitization resistant CB1 receptor. These mice display exaggerated and prolonged responses to acute administration of phytocannabinoids, synthetic cannabinoids, and endocannabinoids. As a consequence these mice represent a novel model for determining the effect of enhanced endocannabinoid signaling on metabolic disease. S426A/S430A mutants consumed equivalent amounts of both high fat (45%) and low fat (10%) chow control diet compared to wild-type littermate controls. S426A/S430A mutants and wild-type mice fed either high or low fat control diet displayed similar fasting blood glucose levels and normal glucose clearance following a 2 g/kg glucose challenge. Furthermore, S426A/S430A mutants and wild type mice consumed similar amounts of chow following an overnight fast. While both THC and JZL195 significantly increased food intake two hours after injection, this increase was similar between the S426A/S430A mutant and wildtype control mice Our results indicate that S426A/S430A mutant mice expressing the desensitization-resistant form of CB1 do not exhibit differences in body weight, food intake, glucose homeostasis, or re-feeding following a fast. PMID- 27501236 TI - Paediatric primary cutaneous marginal zone B-cell lymphoma: does it differ from its adult counterpart? AB - BACKGROUND: Primary cutaneous marginal zone B-cell lymphoma (PCMZL) has rarely been reported in patients younger than 20 years. OBJECTIVES: To report our experience with PCMZL in the paediatric/adolescent age group. METHODS: Medical records of patients diagnosed with PCMZL before age 20 years and managed at two cutaneous lymphoma clinics in the U.S.A. and Israel from 1992 to 2015 were reviewed. RESULTS: The study group included 11 patients (six girls; median age 16 years, range 6-19.5); 10 had generalized/multifocal (T3) and one had regional/localized (T2) disease. Lesions were located on the limbs in all patients and the trunk in six; two had facial lesions. Staging in all but one was based on whole-body computed tomography or positron emission tomography. Initial management in most patients included nonradiation modalities: one patient with localized disease received intralesional steroids; six patients with multifocal disease received the following: topical/intralesional steroids (n = 3); excision (n = 2); 'watch and wait' (n = 1). No extracutaneous progression was noted during a median follow-up of 5.5 years (mean 7.5, range 0.5-14). At present, five patients are in complete remission. CONCLUSIONS: Based on our data (largest series in the literature with the longest follow-up), the clinicopathological presentation and course of PCMZL in the paediatric/adolescent age group are similar to those in adults. Given the indolent course and the long life expectancy of these young patients, the cumulative risk of imaging studies and the age-related potential toxicity of treatment, especially radiation, should be taken into consideration. PMID- 27501237 TI - Improving survival of patients with locally advanced non-small-cell cancer remains a challenge: comment to PROCLAIM. PMID- 27501238 TI - Sexual dysfunction in women with Parkinson's disease. AB - BACKGROUND: Sexual dysfunction in women with Parkinson's disease is poorly understood and research in this area is scarce. The objectives of this study were sexual function characterization in female Parkinson's disease patients, description of sexual dysfunctions, correlation with disease characteristics, and comparison with matched healthy controls. METHODS: Social and demographic data from consecutive female patients with Parkinson's disease and matched healthy controls were collected. The following instruments were used: UPDRS, the Hoehn and Yahr scale, the Beck Depression Inventory-II, the Female Sexual Function Index, and the Sexual Dysfunction Inventory. The only exclusion criterion was cognitive deterioration precluding comprehension of the study scope and its instruments. RESULTS: Of the 95 patients identified, 61 were included. Mean age was 66 years (range 40-89 years), and mean disease duration was seven years (range 1-18 years). Twenty-nine presented an akinetic-rigid syndrome, 25 tremoric disease, and, the remaining, a mixed type of disease. Mean "on" total/part III UPDRS scores were 46 +/- 15.0 and 31 +/- 8.9. Sexual dysfunction was present in 86.9% of patients and 79.0% of controls, according to the Female Sexual Function Index (p < .01), and in 57.4% of patients and 22.6% of controls, according to the Sexual Dysfunction Inventory (p < .001). Multivariate binary logistic regression identified age and depressive symptoms as positive predictors in the severity of sexual dysfunction. Disease duration, UPDRS part III score, Hoehn and Yahr stage, and antiparkinsonian medication did not show significant predictive value. CONCLUSIONS: Sexual dysfunction is more prevalent in women with Parkinson's disease than in controls and is predicted by older age and severity of depressive symptoms. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27501239 TI - The agar microdilution method - a new method for antimicrobial susceptibility testing for essential oils and plant extracts. AB - AIMS: To develop a new agar microdilution technique suitable for the assessment of the antimicrobial activity of natural plant products such as essential oils or plant extracts as well as to evaluate the antimicrobial effect of several essential oils and plant extracts. METHODS AND RESULTS: The proposed agar microdilution method was evolved on the basis of the CLSI agar dilution method, approved for conventional antimicrobials. However, this new method combines convenience and time/cost effectiveness typical for microtitre methods with the advantages of the agar dilution of hydrophobic or coloured substances. Different concentrations of the tested agents were added to Eppendorf tubes with molten Mueller-Hinton agar, vortexed and dispensed into the 96-well microplate in a small volume of 100 MUl per well which allows for rapid, easy and economical preparation of samples as well as providing a uniform and stable dispersion without separation of the oil-water phases which occurs in methods with liquid medium. Next, the agar microdilution plates were inoculated with four reference bacterial strains. The results of our study demonstrated that the minimal inhibitory concentrations (MICs) were successfully determined using the agar microdilution method even with hydrophobic essential oils or strongly coloured plant extracts. CONCLUSIONS: The new agar microdilution method avoids the problems associated with testing of water insoluble, oily or strongly coloured plant natural products. Moreover, it enables the reliable, cheap and easy MIC determination of such agents. SIGNIFICANCE AND IMPACT OF THE STUDY: In the era of increasing antibiotic resistance high hopes are associated with new drugs of plant origin. However, the lack of standardized and reliable testing methods for assessing antibacterial activity of plant natural products causes impediment to research into this area. This study demonstrated that the agar microdilution method can be used successfully for testing oily and coloured substances. PMID- 27501240 TI - Diffusion in Colocation Contact Networks: The Impact of Nodal Spatiotemporal Dynamics. AB - Temporal contact networks are studied to understand dynamic spreading phenomena such as communicable diseases or information dissemination. To establish how spatiotemporal dynamics of nodes impact spreading potential in colocation contact networks, we propose "inducement-shuffling" null models which break one or more correlations between times, locations and nodes. By reconfiguring the time and/or location of each node's presence in the network, these models induce alternative sets of colocation events giving rise to contact networks with varying spreading potential. This enables second-order causal reasoning about how correlations in nodes' spatiotemporal preferences not only lead to a given contact network but ultimately influence the network's spreading potential. We find the correlation between nodes and times to be the greatest impediment to spreading, while the correlation between times and locations slightly catalyzes spreading. Under each of the presented null models we measure both the number of contacts and infection prevalence as a function of time, with the surprising finding that the two have no direct causality. PMID- 27501241 TI - Establishment of 3D Co-Culture Models from Different Stages of Human Tongue Tumorigenesis: Utility in Understanding Neoplastic Progression. AB - To study multistep tumorigenesis process, there is a need of in-vitro 3D model simulating in-vivo tissue. Present study aimed to reconstitute in-vitro tissue models comprising various stages of neoplastic progression of tongue tumorigenesis and to evaluate the utility of these models to investigate the role of stromal fibroblasts in maintenance of desmosomal anchoring junctions using transmission electron microscopy. We reconstituted in-vitro models representing normal, dysplastic, and malignant tissues by seeding primary keratinocytes on either fibroblast embedded in collagen matrix or plain collagen matrix in growth factor-free medium. The findings of histomorphometry, immunohistochemistry, and electron microscopy analyses of the three types of 3D cultures showed that the stratified growth, cell proliferation, and differentiation were comparable between co-cultures and their respective native tissues; however, they largely differed in cultures grown without fibroblasts. The immunostaining intensity of proteins, viz., desmoplakin, desmoglein, and plakoglobin, was reduced as the disease stage increased in all co-cultures as observed in respective native tissues. Desmosome-like structures were identified using immunogold labeling in these cultures. Moreover, electron microscopic observations revealed that the desmosome number and their length were significantly reduced and intercellular spaces were increased in cultures grown without fibroblasts when compared with their co-culture counterparts. Our results showed that the major steps of tongue tumorigenesis can be reproduced in-vitro. Stromal fibroblasts play a role in regulation of epithelial thickness, cell proliferation, differentiation, and maintenance of desmosomalanchoring junctions in in-vitro grown tissues. The reconstituted co-culture models could help to answer various biological questions especially related to tongue tumorigenesis. PMID- 27501243 TI - New clinical criteria for septic shock: serum lactate level as new emerging vital sign. PMID- 27501242 TI - Stereological Analysis of Liver Biopsy Histology Sections as a Reference Standard for Validating Non-Invasive Liver Fat Fraction Measurements by MRI. AB - BACKGROUND AND AIMS: Validation of non-invasive methods of liver fat quantification requires a reference standard. However, using standard histopathology assessment of liver biopsies is problematical because of poor repeatability. We aimed to assess a stereological method of measuring volumetric liver fat fraction (VLFF) in liver biopsies and to use the method to validate a magnetic resonance imaging method for measurement of VLFF. METHODS: VLFFs were measured in 59 subjects (1) by three independent analysts using a stereological point counting technique combined with the Delesse principle on liver biopsy histological sections and (2) by three independent analysts using the HepaFat Scan(r) technique on magnetic resonance images of the liver. Bland Altman statistics and intraclass correlation (IC) were used to assess the repeatability of each method and the bias between the methods of liver fat fraction measurement. RESULTS: Inter-analyst repeatability coefficients for the stereology and HepaFat-Scan(r) methods were 8.2 (95% CI 7.7-8.8)% and 2.4 (95% CI 2.2-2.5)% VLFF respectively. IC coefficients were 0.86 (95% CI 0.69-0.93) and 0.990 (95% CI 0.985-0.994) respectively. Small biases (<=3.4%) were observable between two pairs of analysts using stereology while no significant biases were observable between any of the three pairs of analysts using HepaFat-Scan(r). A bias of 1.4+/ 0.5% VLFF was observed between the HepaFat-Scan(r) method and the stereological method. CONCLUSIONS: Repeatability of the stereological method is superior to the previously reported performance of assessment of hepatic steatosis by histopathologists and is a suitable reference standard for validating non invasive methods of measurement of VLFF. PMID- 27501244 TI - 2015 Philip S. Portoghese Medicinal Chemistry Lectureship. Curing Hepatitis C Virus Infection with Direct-Acting Antiviral Agents: The Arc of a Medicinal Chemistry Triumph. AB - The development of direct-acting antiviral agents that can cure a chronic hepatitis C virus (HCV) infection after 8-12 weeks of daily, well-tolerated therapy has revolutionized the treatment of this insidious disease. In this article, three of Bristol-Myers Squibb's HCV programs are summarized, each of which produced a clinical candidate: the NS3 protease inhibitor asunaprevir (64), marketed as Sunvepra, the NS5A replication complex inhibitor daclatasvir (117), marketed as Daklinza, and the allosteric NS5B polymerase inhibitor beclabuvir (142), which is in late stage clinical studies. A clinical study with 64 and 117 established for the first time that a chronic HCV infection could be cured by treatment with direct-acting antiviral agents alone in the absence of interferon. The development of small molecule HCV therapeutics, designed by medicinal chemists, has been hailed as "the arc of a medical triumph" but may equally well be described as "the arc of a medicinal chemistry triumph". PMID- 27501245 TI - Follicular CXCR5- expressing CD8(+) T cells curtail chronic viral infection. AB - During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV). These CXCR5(+) CD8(+) T cells were able to migrate into B-cell follicles, expressed lower levels of inhibitory receptors and exhibited more potent cytotoxicity than the CXCR5(-) [corrected] subset. Furthermore, we identified the Id2-E2A signalling axis as an important regulator of the generation of this subset. In patients with HIV, we also identified a virus-specific CXCR5(+) CD8(+) T-cell subset, and its number was inversely correlated with viral load. The CXCR5(+) subset showed greater therapeutic potential than the CXCR5(-) [corrected] subset when adoptively transferred to chronically infected mice, and exhibited synergistic reduction of viral load when combined with anti-PD-L1 treatment. This study defines a unique subset of exhausted CD8(+) T cells that has a pivotal role in the control of viral replication during chronic viral infection. PMID- 27501246 TI - Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness. AB - Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases. PMID- 27501247 TI - Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. AB - Germinal centres (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen-activated B cells proliferate, express high-affinity antibodies, promote antibody class switching, and yield B cell memory. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class, both cell-autonomous and extrinsic metabolic programming have emerged as modulators of T-cell-mediated immunity. Here we show in mice that GC light zones are hypoxic, and that low oxygen tension () alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low impairs antibody class switching to the pro-inflammatory IgG2c antibody isotype by limiting the expression of activation-induced cytosine deaminase (AID). Hypoxia induces HIF transcription factors by restricting the activity of prolyl hydroxyl dioxygenase enzymes, which hydroxylate HIF-1alpha and HIF-2alpha to destabilize HIF by binding the von Hippel-Landau tumour suppressor protein (pVHL). B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases antigen-specific GC B cells and undermines the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall antibody responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1 haploinsufficient B cells have reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity antibodies. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that the restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity. PMID- 27501248 TI - Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. AB - Chronic viral infections are characterized by a state of CD8+ T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8+ T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+ T cells. Here we identify a population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8+ T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8+ T-cell subset was characterized by a unique gene signature that was related to that of CD4+ T follicular helper (TFH) cells, CD8+ T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4+ TH1 cells and CD8+ terminal effectors. This CD8+ T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8+ T cells. These PD-1+CD8+ T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8+ T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8+ T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8+ T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer. PMID- 27501249 TI - Differential alpha-adrenergic modulation of rapid onset vasodilatation along resistance networks of skeletal muscle in old versus young mice. AB - KEY POINTS: Rapid onset vasodilatation (ROV) initiates functional hyperaemia upon skeletal muscle contraction and is attenuated during ageing via alpha adrenoreceptor (alphaAR) stimulation, but it is unknown where this effect predominates in resistance networks. In gluteus maximus muscles of young (4 months) and old (24 months) male C57BL/6 mice, tetanic contraction while observing feed arteries and arterioles initiated ROV, which increased with contraction duration, peaked later in upstream versus downstream vessel branches and was attenuated throughout networks with advanced age. With no effect on muscle force production, inhibiting alphaARs improved ROV in old mice while activating alphaARs attenuated ROV in young mice. Modulating ROV through alphaARs was greater in upstream feed arteries and arterioles compared to downstream arterioles, with alpha2 ARs more effective than alpha1 ARs. ROV is coordinated along resistance networks and modulated differentially between young and old mice via alphaARs; with advanced age, attenuated dilatation of upstream branches will restrict muscle blood flow. ABSTRACT: Rapid onset vasodilatation (ROV) in skeletal muscle is attenuated during advanced age via alpha-adrenoreceptor (alphaAR) activation, but it is unknown where such effects predominate in the resistance vasculature. Studying the gluteus maximus muscle (GM) of anaesthetized young (4 months) and old (24 months) male C57BL/6 mice, we tested the hypothesis that attenuation of ROV during advanced age is most effective in proximal branches of microvascular resistance networks. Diameters of a feed artery (FA) and first- (1A), second- (2A) and third- (3A) order arterioles were studied in response to single tetanic contractions (100 Hz, 100-1000 ms). ROV began within 1 s and peaked sooner in 2A and 3A (~3 s) than in 1A or FA (~4 s). Relative amplitudes of dilatation increased with contraction duration and with vessel branch order (FA<1A<2A<3A). In old mice, attenuation of ROV was greater in FA and 1A compared to 2A and 3A. With no effect on muscle force production, inhibiting alphaARs (phentolamine; 10-6 m) improved ROV in FA and 1A of old mice while subthreshold stimulation of alphaARs in young mice (noradrenaline; 10-9 m) depressed ROV most effectively in FA and 1A. In young mice, stimulating alpha1 ARs (phenylephrine; 10-7 m) and alpha2 ARs (UK 14304; 10-7 m) attenuated ROV primarily in FA. In old mice, inhibiting alpha2 ARs (rauwolscine; 10-7 m) restored ROV more effectively in FA and 1A than did inhibiting alpha1 ARs (prazosin; 10-8 m). We conclude that, with temporal and spatial coordination along resistance networks, attenuation of ROV with advanced age is most effective in proximal branches via constitutive activation of alpha2 ARs. PMID- 27501250 TI - Validation of a point-of-care prothrombin time test after cardiopulmonary bypass in cardiac surgery. AB - Point-of-care coagulation monitoring can be used for the guidance of haemostasis management. However, the influence of time on point-of-care prothrombin time testing following protamine administration after cardiopulmonary bypass has not been investigated. Bland-Altman and error grid analysis were used to analyse the level of agreement between prothrombin time measurements from point-of-care and laboratory tests before cardiopulmonary bypass, and then 3 min, 6 min and 10 min after protamine administration. Prothrombin times were expressed as International Normalised Ratios. While the point-of-care and laboratory prothrombin time measurements showed a high level of agreement before bypass, this agreement deteriorated following protamine administration to a mean (SD) bias of -0.22 (0.13) [limits of agreement 0.48-0.04]. Error grid analysis revealed that 35 (70%) of the paired values showed a clinically relevant discrepancy in international normalised ratio. At 3 min, 6 min and 10 min after cardiopulmonary bypass there is a clinical unacceptable discrepancy between the point-of-care and laboratory measurement of prothrombin time. PMID- 27501252 TI - Chronic and low exposure to a pharmaceutical cocktail induces mitochondrial dysfunction in liver and hyperglycemia: Differential responses between lean and obese mice. AB - Pharmaceuticals are found in the environment but the impact of this contamination on human and animal health is poorly known. The liver could be particularly targeted since a significant number of these drugs are hepatotoxic, in particular via oxidative stress and mitochondrial dysfunction. Notably, the latter events can also be observed in liver diseases linked to obesity, so that the obese liver might be more sensitive to drug toxicity. In this study, we determined the effects of a chronic exposure to low doses of pharmaceuticals in wild-type and obese mice, with a particular focus on mitochondrial function. To this end, wild type and ob/ob mice were exposed for 4 months to a cocktail of 11 pharmaceuticals provided in drinking water containing 0.01, 0.1, or 1 mg/L of each drug. At the end of the treatment, liver mitochondria were isolated and different parameters were measured. Chronic exposure to the pharmaceuticals reduced mitochondrial respiration driven by succinate and palmitoyl-l-carnitine in wild-type mice and increased antimycin-induced ROS production in ob/ob mice. Hyperglycemia and hepatic histological abnormalities were also observed in treated ob/ob mice. Investigations were also carried out in isolated liver mitochondria incubated with the mixture, or with each individual drug. The mitochondrial effects of the mixture were different from those observed in treated mice and could not be predicted from the results obtained with each drug. Because some of the 11 drugs included in our cocktail can be found in water at relatively high concentrations, our data could be relevant in environmental toxicology. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1375-1389, 2017. PMID- 27501253 TI - Downregulation of nucleophosmin expression inhibited proliferation and induced apoptosis in salivary gland adenoid cystic carcinoma. AB - BACKGROUND: This study aimed to explore the relationship between nucleophosmin (NPM1) and patient clinical characteristics. Moreover, we investigated the effect of NPM1 in tumor proliferation and apoptosis of salivary gland adenoid cystic carcinoma (SACC). MATERIALS AND METHODS: NPM1 expression was examined in 74 specimens of SACC and 31 non-cancerous epithelium adjacent to carcinoma (NCEAC) by immunohistochemistry (IHC). RNA interference technology was used to silence NPM1 expression in SACC cells. We used transwell culture assay, cell counting kit 8 tests, and colony formation assay to test the proliferation, cisplatin resistance, migration, and invasiveness of SACC cells. RESULTS: The nuclear and cytoplasmic expression of NPM1 in SACC tissue was overexpressed and was tightly linked to perineural invasion and lymph node metastasis. The downregulation of NPM1 inhibited proliferation and induced apoptosis in SACC cells. Knockdown of NPM1 expression had no effect on chemoresistance migration, or invasiveness. CONCLUSIONS: NPM1 may play an important role in tumor progress in SACC and is a potential biomarker for SACC. PMID- 27501254 TI - How coaching can play a key role in the development of nurse managers. AB - AIMS AND OBJECTIVES: The aim of this study was to explore empirically the role that coaching plays in the development of nurse managers in order to inform further research and policy makers about the potential utility and value of this means of development. BACKGROUND: There is evidence of the importance of the role of nurse managers who are first line managers of a team of nurses within any health sector. However, there appears to be little understanding of the United Kingdom wide scope of nurse manager development across the United Kingdom and the means to increase its effectiveness. At the same time, it appears that some nurse managers receive coaching to help in their development. DESIGN: This is a mixed methods study, using a pragmatist paradigm. METHODS: Data was gathered from a quantitative survey and qualitative interviews. This paper is reporting the results of the qualitative interviews only. Twenty-one qualitative interviews were undertaken with nurse managers, coaches and directors of nursing to draw out their own experiences of coaching for nurse managers. Thematic analysis framework was used for data interrogation, identifying new patterns and emerging themes. RESULTS: Themes that emerged from interviews include how nurse managers were introduced to coaching, how they balanced transitions, the role of reflection, the value of relationships and overlaps between clinical supervision, mentoring and coaching. CONCLUSIONS: Findings show that following coaching, nurse managers gained increased resilience, confidence and better coping mechanisms. This resulted in perceived improved team management and cohesion and appeared to lead to better quality of care for patients. RELEVANCE TO CLINICAL PRACTICE: This study suggests the importance of nurse managers accessing coaching, to enable transformational leadership of their teams of nurses. It suggests also the importance of organisations supporting a coaching culture, to ensure staff satisfaction, motivation and improved quality of patient care. PMID- 27501251 TI - Inhibition of Sodium Ion Channel Function with Truncated Forms of Batrachotoxin. AB - A novel family of small molecule inhibitors of voltage-gated sodium channels (NaVs) based on the structure of batrachotoxin (BTX), a well-known channel agonist, is described. Protein mutagenesis and electrophysiology experiments reveal the binding site as the inner pore region of the channel, analogous to BTX, alkaloid toxins, and local anesthetics. Homology modeling of the eukaryotic channel based on recent crystallographic analyses of bacterial NaVs suggests a mechanism of action for ion conduction block. PMID- 27501255 TI - The hidden symbols of the female anatomy in Michelangelo Buonarroti's ceiling in the Sistine Chapel. AB - A number of published articles have suggested that each element of Renaissance art contains an inner meaning. Some of these elements include the choice of theme and protagonists, faces selected for the characters, colors used, species of flowers and trees chosen, animals depicted, positions of the elements, posture of the characters and their gestures, juxtapositions in the scenes, and even the very scenario or landscape. All of these elements are thought to have hidden meanings. In this context, this manuscript presents a new hypothesis suggesting that Michelangelo Buonarroti (1475-1564) may have concealed symbols associated with female anatomy in the ceiling of the Sistine Chapel (painted 1508-1512) in Rome. Thus, this paper is useful to better understand the history of anatomy and corroborates recent descriptions that have suggested the possible existence of anatomic figures concealed in many of Michelangelo's works. Clin. Anat. 29:911 916, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27501256 TI - Trivariate mover-stayer counting process models for investigating joint damage in psoriatic arthritis. AB - In psoriatic arthritis, many patients do not develop permanent joint damage even after a prolonged follow-up. This has led several authors to consider the possibility of a subpopulation of stayers (those who do not have the propensity to experience the event of interest), as opposed to assuming the entire population consist of movers (those who have the propensity to experience the event of interest). In addition, it is recognised that the damaged joints process may act very differently across different joint areas, particularly the hands, feet and large joints. From a clinical perspective, interest lies in identifying possible relationships between the damaged joints processes in these joint areas for the movers and estimating the proportion of stayers in these joint areas, if they exist. For this purpose, this paper proposes a novel trivariate mover-stayer model consisting of mover-stayer truncated negative binomial margins, and patient level dynamic covariates and random effects in the models for the movers and stayers, respectively. The model is then extended to have a two-level mover stayer structure for its margins so that the nature of the stayer property can be investigated. A particularly attractive feature of the proposed models is that only an optimisation routine is required in their model fitting procedures. (c) 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID- 27501257 TI - Acquired palatal groove and delayed oral feeding in preterm infants. AB - BACKGROUND: Acquired palatal groove has been reported in the 1970s and 1980s, but its current incidence in Japanese newborns is unclear. The aims of this study were to determine the incidence of palatal groove in preterm infants and to evaluate whether this condition affects oral feeding ability. METHODS: We conducted a prospective observational study among very low-birthweight infants born at Takatsuki General Hospital, Osaka, between March and October in 2010. The shape of the hard palate was classified into three types: normal, narrow high arched palate, and palatal groove. RESULTS: Among the 37 enrolled infants, 14 (38%) had palatal groove. In particular, among the 29 infants with birthweight <1000 g, palatal groove was observed in 48% of these patients, and only 10% were normal. Infants with palatal groove were ventilated for considerably more days with oral endotracheal tube than those without palate groove, even after adjustment for gestational age, birthweight, and duration of oral duodenal tube placement (OR, 1.11). Establishment of oral feeding and disappearance of choking on milk were considerably delayed in infants with palatal groove. Transient oral feeding difficulty requiring thickened-feed intervention was observed only in infants with palatal groove; on multi-regression analysis this difficulty seemed to be induced by the palatal groove. CONCLUSIONS: Palatal groove formation induced by oral endotracheal intubation occurs with a high frequency in preterm infants, and this is likely to affect oral feeding ability. PMID- 27501259 TI - Viruses and the Diversity of Cell Death. AB - Cell death is a common outcome of virus infection. In some cases, cell death curbs virus replication. In others, cell death enhances virus dissemination and contributes to tissue injury, exacerbating viral disease. Three forms of cell death are observed following virus infection-apoptosis, necroptosis, and pyroptosis. In this review, I describe the core machinery needed for each of these forms of cell death. Using representative viruses, I highlight how distinct stages of virus replication initiate signaling pathways that elicit these forms of cell death. I also discuss viral strategies to overcome the deleterious effects of cell death on virus propagation and the consequences of cell death for host physiology. PMID- 27501260 TI - Integrins as Herpesvirus Receptors and Mediators of the Host Signalosome. AB - The repertoire of herpesvirus receptors consists of nonintegrin and integrin molecules. Integrins interact with the conserved glycoproteins gH/gL or gB. This interaction is a conserved biology across the Herpesviridae family, likely directed to promote virus entry and endocytosis. Herpesviruses exploit this interaction to execute a range of critical functions that include (a) relocation of nonintegrin receptors (e.g., herpes simplex virus nectin1 and Kaposi's sarcoma associated herpesvirus EphA2), or association with nonintegrin receptors (i.e., human cytomegalovirus EGFR), to dictate species-specific entry pathways; (b) activation of multiple signaling pathways (e.g., Ca2+ release, c-Src, FAK, MAPK, and PI3K); and (c) association with Rho GTPases, tyrosine kinase receptors, Toll like receptors, which result in cytoskeletal remodeling, differential cell type targeting, and innate responses. In turn, integrins can be modulated by viral proteins (e.g., Epstein-Barr virus LMPs) to favor spread of transformed cells. We propose that herpesviruses evolved a multipartite entry system to allow interaction with multiple receptors, including integrins, required for their sophisticated life cycle. PMID- 27501258 TI - Human Cytomegalovirus Latency: Approaching the Gordian Knot. AB - Herpesviruses have evolved exquisite virus-host interactions that co-opt or evade a number of host pathways to enable the viruses to persist. Persistence of human cytomegalovirus (CMV), the prototypical betaherpesvirus, is particularly complex in the host organism. Depending on host physiology and the cell types infected, CMV persistence comprises latent, chronic, and productive states that may occur concurrently. Viral latency is a central strategy by which herpesviruses ensure their lifelong persistence. Although much remains to be defined about the virus host interactions important to CMV latency, it is clear that checkpoints composed of viral and cellular factors exist to either maintain a latent state or initiate productive replication in response to host cues. CMV offers a rich platform for defining the virus-host interactions and understanding the host biology important to viral latency. This review describes current understanding of the virus-host interactions that contribute to viral latency and reactivation. PMID- 27501262 TI - A Cap-to-Tail Guide to mRNA Translation Strategies in Virus-Infected Cells. AB - Although viruses require cellular functions to replicate, their absolute dependence upon the host translation machinery to produce polypeptides indispensable for their reproduction is most conspicuous. Despite their incredible diversity, the mRNAs produced by all viruses must engage cellular ribosomes. This has proven to be anything but a passive process and has revealed a remarkable array of tactics for rapidly subverting control over and dominating cellular regulatory pathways that influence translation initiation, elongation, and termination. Besides enforcing viral mRNA translation, these processes profoundly impact host cell-intrinsic immune defenses at the ready to deny foreign mRNA access to ribosomes and block protein synthesis. Finally, genome size constraints have driven the evolution of resourceful strategies for maximizing viral coding capacity. Here, we review the amazing strategies that work to regulate translation in virus-infected cells, highlighting both virus specific tactics and the tremendous insight they provide into fundamental translational control mechanisms in health and disease. PMID- 27501261 TI - Properties and Functions of the Dengue Virus Capsid Protein. AB - Dengue virus affects hundreds of millions of people each year around the world, causing a tremendous social and economic impact on affected countries. The aim of this review is to summarize our current knowledge of the functions, structure, and interactions of the viral capsid protein. The primary role of capsid is to package the viral genome. There are two processes linked to this function: the recruitment of the viral RNA during assembly and the release of the genome during infection. Although particle assembly takes place on endoplasmic reticulum membranes, capsid localizes in nucleoli and lipid droplets. Why capsid accumulates in these locations during infection remains unknown. In this review, we describe available data and discuss new ideas on dengue virus capsid functions and interactions. We believe that a deeper understanding of how the capsid protein works during infection will create opportunities for novel antiviral strategies, which are urgently needed to control dengue virus infections. PMID- 27501263 TI - Polyomavirus Persistence. AB - Mammalian polyomaviruses are characterized by establishing persistent infections in healthy hosts and generally causing clinical disease only in hosts whose immune systems are compromised. Despite the fact that these viruses were discovered decades ago, our knowledge of the mechanisms that govern viral persistence and reactivation is limited. Whereas mouse polyomavirus has been studied in a fair amount of detail, our understanding of the human viruses in particular is mostly inferred from experiments aimed at addressing other questions. In this review, we summarize the state of our current knowledge, draw conclusions when possible, and suggest areas that are in need of further study. PMID- 27501266 TI - Bioactive gold(i) complexes with 4-mercaptoproline derivatives. AB - Unprecedented gold(i) bioconjugates bearing non-proteinogenic amino acid 4 mercaptoproline species as bioorganic ligands have been prepared. Firstly, the synthesis of Boc-Pro(SH)-OMe (1) has been accomplished by standard procedures. The subsequent reaction of 1 with [AuCl(PR3)] gives complexes Boc-Pro(SAuPR3)-OMe (PR3 = PPh3 (2), PPh2Py (3)). Starting from complex 2 several structural modifications have been performed, in addition to the incorporation of a different phosphine in 3, such as the formation of the acid Boc-Pro(SAuPPh3)-OH (4), the synthesis of a dipeptide derivative by coupling the amino acid glycine tert-butyl ester Boc-Pro(SAuPPh3)-Gly-O(t)Bu (5), or the coordination of another gold phosphine fragment to the sulfur atom as in [Boc-Pro(SAuPPh3)2-OMe]OTf (6). The cytotoxic activity in vitro of these complexes has been evaluated against three different tumor human cell lines, A549 (lung carcinoma), Jurkat (T-cell leukaemia) and MiaPaca2 (pancreatic carcinoma). All the complexes displayed excellent cytotoxic activity with IC50 values in the low MUM range and even in the nM range in some cases. Structure-Activity Relationships (SAR) observed from this family of complexes opens the possibility of designing more potent and selective promising gold(i) anticancer agents. PMID- 27501265 TI - Determination of Biofilm Initiation on Virus-infected Cells by Bacteria and Fungi. AB - The study of polymicrobial interactions across the taxonomic kingdoms that include fungi, bacteria and virus have not been previously examined with respect to how viral members of the microbiome affect subsequent microbe interactions with these virus-infected host cells. The co-habitation of virus with bacteria and fungi is principally present on the mucosal surfaces of the oral cavity and genital tract. Mucosal cells, particularly those with persistent chronic or persistent latent viral infections, could have a significant impact on members of the microbiome through virus alteration in number and type of receptors expressed. Modification in host cell membrane architecture would result in altered ability of subsequent members of the normal flora and opportunistic pathogens to initiate the first step in biofilm formation, i.e., adherence. This study describes a method for quantitation and visual examination of HSV's effect on the initiation of biofilm formation (adherence) of S. aureus and C. albicans. PMID- 27501264 TI - Genomic Analysis of Viral Outbreaks. AB - Genomic analysis is a powerful tool for understanding viral disease outbreaks. Sequencing of viral samples is now easier and cheaper than ever before and can supplement epidemiological methods by providing nucleotide-level resolution of outbreak-causing pathogens. In this review, we describe methods used to answer crucial questions about outbreaks, such as how they began and how a disease is transmitted. More specifically, we explain current techniques for viral sequencing, phylogenetic analysis, transmission reconstruction, and evolutionary investigation of viral pathogens. By detailing the ways in which genomic data can help us understand viral disease outbreaks, we aim to provide a resource that will facilitate the response to future outbreaks. PMID- 27501267 TI - The effect of rumen ciliates on chitinolytic activity, chitin content and the number of fungal zoospores in the rumen fluid of sheep. AB - The objective of this study was to investigate the effect of selected protozoa on the degradation and concentration of chitin and the numbers of fungal zoospores in the rumen fluid of sheep. Three adult ewes were fed a hay-concentrate diet, defaunated, then monofaunated with Entodinium caudatum or Diploplastron affine alone and refaunated with natural rumen fauna. The average density of the protozoa population varied from 6.1 . 10(4) (D. affine) to 42.2 . 10(4) cells/ml rumen fluid (natural rumen fauna). The inoculation of protozoa in the rumen of defaunated sheep increased the total activity of chitinolytic enzymes from 2.9 to 3.6 MUmol N-acetylglucosamine/g dry matter (DM) of rumen fluid per min, the chitin concentration from 6.3 to 7.2 mg/g DM of rumen fluid and the number of fungal zoospores from 8.1 to 10.9 . 10(5) cells/ml rumen fluid. All examined indices showed diurnal variations. Ciliate population density was highest immediately prior to feeding and lowest at 4 h thereafter. The opposite effects were observed for the numbers of fungal zoospores, the chitin concentration and chitinolytic activity. Furthermore, it was found that chitin from zoospores may account for up to 95% of total microbial chitin in the rumen fluid of sheep. In summary, the examined ciliate species showed the ability of chitin degradation as well as a positive influence on the development of the ruminal fungal population. PMID- 27501268 TI - Temporal increase in thymocyte negative selection parallels enhanced thymic SIRPalpha+ DC function. AB - Dysregulation of negative selection contributes to T-cell-mediated autoimmunity, such as type 1 diabetes. The events regulating thymic negative selection, however, are ill defined. Work by our group and others suggest that negative selection is inefficient early in ontogeny and increases with age. This study examines temporal changes in negative selection and the thymic DC compartment. Peptide-induced thymocyte deletion in vivo was reduced in newborn versus 4-week old NOD mice, despite a similar sensitivity of the respective thymocytes to apoptosis induction. The temporal increase in negative selection corresponded with an elevated capacity of thymic antigen-presenting cells to stimulate T cells, along with altered subset composition and function of resident DC. The frequency of signal regulatory protein alpha+ (SIRPalpha+ ) and plasmacytoid DCs was increased concomitant with a decrease in CD8alpha+ DC in 4-week-old NOD thymi. Importantly, 4-week-old versus newborn thymic SIRPalpha+ DC exhibited increased antigen processing and presentation via the MHC class II but not class I pathway, coupled with an enhanced T-cell stimulatory capacity not seen in thymic plasmacytoid DC and CD8alpha+ DC. These findings indicate that the efficiency of thymic DC-mediated negative selection is limited early after birth, and increases with age paralleling expansion of functionally superior thymic SIRPalpha+ DC. PMID- 27501269 TI - Psychosocial Well-being of Siblings of Adolescents with Anorexia Nervosa. AB - OBJECTIVE: Anorexia nervosa (AN) is often first diagnosed in the adolescent years. The treatment with the greatest evidence during this time is family-based treatment (FBT). In FBT, siblings are expected to attend treatment sessions; however, sibling well-being during this time has not been well researched. This study aimed to explore sibling well-being when the ill child was initially diagnosed with AN and after FBT had been completed. METHOD: Eighty-five parents and 55 siblings of adolescents with AN completed the Strengths and Difficulties Questionnaire at diagnosis. In addition, 88 parents and 46 siblings completed the Strengths and Difficulties Questionnaire after finishing treatment. RESULTS: Mothers and fathers reported siblings to have lower levels of conduct problems in comparison with population norms. Mothers also reported lower levels of prosocial behaviours. Siblings reported higher levels of emotional difficulties and hyperactivity in comparison with their peers. There were no differences in reported psychosocial well-being of siblings between diagnosis and following FBT. CONCLUSIONS: Siblings of adolescents with AN have poorer psychosocial adjustment than their peers, both before and after FBT. Clinicians and parents are encouraged to be aware of sibling difficulties and seek additional support if required. Copyright (c) 2016 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 27501270 TI - Palliative care for patients with hematological malignancies: Time for a new model. PMID- 27501271 TI - CML patients show sperm alterations at diagnosis that are not improved with imatinib treatment. PMID- 27501272 TI - Similarity in G matrix structure among natural populations of Arabidopsis lyrata. AB - Understanding the stability of the G matrix in natural populations is fundamental for predicting evolutionary trajectories; yet, the extent of its spatial variation and how this impacts responses to selection remain open questions. With a nested paternal half-sib crossing design and plants grown in a field experiment, we examined differences in the genetic architecture of flowering time, floral display, and plant size among four Scandinavian populations of Arabidopsis lyrata. Using a multivariate Bayesian framework, we compared the size, shape, and orientation of G matrices and assessed their potential to facilitate or constrain trait evolution. Flowering time, floral display and rosette size varied among populations and significant additive genetic variation within populations indicated potential to evolve in response to selection. Yet, some characters, including flowering start and number of flowers, may not evolve independently because of genetic correlations. Using a multivariate framework, we found few differences in the genetic architecture of traits among populations. G matrices varied mostly in size rather than shape or orientation. Differences in multivariate responses to selection predicted from differences in G were small, suggesting overall matrix similarity and shared constraints to trait evolution among populations. PMID- 27501273 TI - Preparation and Antiproliferative Activity of Liposomes Containing a Combination of Cisplatin and Procainamide Hydrochloride. AB - We have previously reported the enhancement of the antiproliferative and apoptotic activities of cis-diamminedichloroplatinum(II) (DDP) when it is coadministered with a class I antiarrhythmic drug procainamide hydrochloride (PA). Here, we determined the antiproliferative activity of DDP, either in solution or loaded in liposomes, in the presence of PA, in the bulk solution, or directly embedded in liposomes together with DDP. Our results show that PA potentiates the activity of DDP-liposomes and that this effect is maintained at least in some of the investigated cell types when both drugs were mixed and loaded together into liposomes. PMID- 27501274 TI - Engineering a Prototypic P-type ATPase Listeria monocytogenes Ca(2+)-ATPase 1 for Single-Molecule FRET Studies. AB - Approximately 30% of the ATP generated in the living cell is utilized by P-type ATPase primary active transporters to generate and maintain electrochemical gradients across biological membranes. P-type ATPases undergo large conformational changes during their functional cycle to couple ATP hydrolysis in the cytoplasmic domains to ion transport across the membrane. The Ca(2+)-ATPase from Listeria monocytogenes, LMCA1, was found to be a suitable model of P-type ATPases and was engineered to facilitate single-molecule FRET studies of transport-related structural changes. Mutational analyses of the endogenous cysteine residues in LMCA1 were performed to reduce background labeling without compromising activity. Pairs of cysteines were introduced into the optimized low reactivity background, and labeled with maleimide derivatives of Cy3 and Cy5 resulting in site-specifically double-labeled protein with moderate activity. Ensemble and confocal single-molecule FRET studies revealed changes in FRET distribution related to structural changes during the transport cycle, consistent with those observed by X-ray crystallography for the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA). Notably, the cytosolic headpiece of LMCA1 was found to be distinctly more compact in the E1 state than in the E2 state. Thus, the established experimental system should allow future real-time FRET studies of the structural dynamics of LMCA1 as a representative P-type ATPase. PMID- 27501275 TI - Kidney Intragraft Homing of De Novo Donor-Specific HLA Antibodies Is an Essential Step of Antibody-Mediated Damage but Not Per Se Predictive of Graft Loss. AB - Donor-specific HLA antibody (DSA)-mediated graft injury is the major cause of kidney loss. Among DSA characteristics, graft homing has been suggested as an indicator of severe tissue damage. We analyzed the role of de novo DSA (dnDSA) graft homing on kidney transplantation outcome. Graft biopsy specimens and parallel sera from 48 nonsensitized pediatric kidney recipients were analyzed. Serum samples and eluates from graft biopsy specimens were tested for the presence of dnDSAs with flow bead technology. Intragraft dnDSAs (gDSAs) were never detected in the absence of serum dnDSAs (sDSAs), whereas in the presence of sDSAs, gDSAs were demonstrated in 72% of biopsy specimens. A significantly higher homing capability was expressed by class II sDSAs endowed with high mean fluorescence intensity and C3d- and/or C1q-fixing properties. In patients with available sequential biopsy specimens, we detected gDSAs before the appearance of antibody-mediated rejection. In sDSA-positive patients, gDSA positivity did not allow stratification for antibody-mediated graft lesions and graft loss. However, a consistent detection of skewed unique DSA specificities was observed over time within the graft, likely responsible for the damage. Our results indicate that gDSAs could represent an instrumental tool to identify, among sDSAs, clinically relevant antibody specificities requiring monitoring and possibly guiding patient management. PMID- 27501277 TI - Challenges faced by international nurses when migrating: an integrative literature review. AB - AIM: Results from this literature review were used to identify the challenges faced by international nurses in their host countries following migration. BACKGROUND: The increasing strain of nursing shortages in the healthcare system has led to the recruitment of international nurses among many countries. However, following migration, international nurses are faced with challenges that may result in poor integration with their host countries. METHODS: Using Cooper's five stages for integrative research reviews, a literature search was conducted across seven databases using a PRISMA search strategy. Additional manual searches were also conducted on the end-references of the retrieved articles. The authors then independently reviewed the selected articles using the Joanna Briggs Institute appraisal form to extract and generate the themes for the review. FINDINGS: Twenty-four articles were selected for the review. The themes generated included: (i) difficulty orientating; (ii) a longing for what is missing; (iii) professional development and devaluing; (iv) communication barriers; (v) discrimination and marginalization; (vi) personal and professional differences; and (vii) a meaningful support system. IMPLICATIONS FOR POLICY AND PRACTICE: By identifying the challenges faced by international nurses, interventions that ensure equal treatment (e.g. multifaceted transition programmes and culturally sensitive 'buddy' systems) can be implemented to help international nurses adapt to their new environments. Adequate communication can be achieved by encouraging international nurses to speak English and learn the colloquial language and non verbal behaviours used by native nurses. CONCLUSION: With good integration international nurses may be able to reach their full career potential as professional nurses in their host countries. The adaptation process is a dynamic process that requires effort from both international and native nurses. Thus, any strategies that are developed and implemented must be multifaceted. PMID- 27501276 TI - Quantification of Neural Ethanol and Acetaldehyde Using Headspace GC-MS. AB - BACKGROUND: There is controversy regarding the active agent responsible for alcohol addiction. The theory that ethanol (EtOH) itself was the agent in alcohol drinking behavior was widely accepted until acetaldehyde (AcH) was found in the brain. The importance of AcH formation in the brain is still subject to speculation due to the lack of a method to accurately assay the AcH levels directly. A highly sensitive gas chromatography mass spectrometry (GC-MS) method to reliably determine AcH concentration with certainty is needed to address whether neural AcH is indeed responsible for increased alcohol consumption. METHODS: A headspace gas chromatograph coupled to selected-ion monitoring MS was utilized to develop a quantitative assay for AcH and EtOH. Our GC-MS approach was carried out using a Bruker Scion 436-GC SQ MS. RESULTS: Our approach yields limits of detection of AcH in the nanomolar range and limits of quantification in the low micromolar range. Our linear calibration includes 5 concentrations with a least-square regression greater than 0.99 for both AcH and EtOH. Tissue analyses using this method revealed the capacity to quantify EtOH and AcH in blood, brain, and liver tissue from mice. CONCLUSIONS: By allowing quantification of very low concentrations, this method may be used to examine the formation of EtOH metabolites, specifically AcH, in murine brain tissue in alcohol research. PMID- 27501278 TI - The Dynamic Integrated Evaluation Model (DIEM): Achieving Sustainability in Organizational Intervention through a Participatory Evaluation Approach. AB - Recently, there have been calls to develop ways of using a participatory approach when conducting interventions, including evaluating the process and context to improve and adapt the intervention as it evolves over time. The need to integrate interventions into daily organizational practices, thereby increasing the likelihood of successful implementation and sustainable changes, has also been highlighted. We propose an evaluation model-the Dynamic Integrated Evaluation Model (DIEM)-that takes this into consideration. In the model, evaluation is fitted into a co-created iterative intervention process, in which the intervention activities can be continuously adapted based on collected data. By explicitly integrating process and context factors, DIEM also considers the dynamic sustainability of the intervention over time. It emphasizes the practical value of these evaluations for organizations, as well as the importance of their rigorousness for research purposes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27501279 TI - TRUST trial: BAY 86-6150 use in haemophilia with inhibitors and assessment for immunogenicity. AB - INTRODUCTION: The most serious and challenging complication of haemophilia treatment is development of inhibitors to replacement factors VIII or IX. Innovative therapies currently being explored for patients with haemophilia and inhibitors include BAY 86-6150, a modified recombinant activated factor VII (FVIIa). Immunogenicity remains a substantial barrier in this endeavour. AIM: To present safety and efficacy results of the BAY 86-6150 study in patients with inhibitors and report detailed analysis of epitope mapping in a patient who developed anti-BAY 86-6150 antibodies. METHODS: Patients aged 12-62 years with moderate or severe haemophilia A or B were eligible for the phase 3 TRUST trial if they had a history of high-titre inhibitors. Four escalating doses of BAY 86 6150 (6.5, 20, 50, 90 MUg kg-1 ) were planned with >=10 patients per dose level. Bleeding episodes were treated with BAY 86-6150. Development of anti-BAY 86-6150 antibodies was considered a serious adverse event. RESULTS: TRUST was discontinued after one patient in the 6.5-MUg kg-1 cohort developed anti-BAY 86 6150 neutralizing antibodies following three exposures. The anti-BAY 86-6150 antibodies cross-reacted with and neutralized wild-type FVIIa (WT-FVIIa). Post hoc epitope mapping using peripheral blood mononuclear cells from the responding patient found that none of the 14 peptides unique to BAY 86-6150 were recognized by the patient's T cells, but strong responses were detected against 2 WT-FVIIa peptides. CONCLUSION: In the single patient with haemophilia A who developed anti BAY 86-6150 antibodies, results of T-cell epitope mapping indicated BAY 86-6150 was no more immunogenic than WT-FVIIa. PMID- 27501280 TI - Features and Outcome of Autonomous Thyroid Nodules in Children: 31 Consecutive Patients Seen at a Single Center. AB - CONTEXT: Most thyroid nodules are benign and their accurate identification can avoid unnecessary procedures. In adult patients, documentation of nodule autonomy is accepted as reassurance of benign histology and as justification to forgo biopsy or thyroidectomy. In contrast, the negative predictive value of nodule autonomy in children is uncertain. Some recent publications recommend surgical resection as initial management, but few address the degree of TSH suppression or the specific scintigraphic criteria used to diagnose autonomy. OBJECTIVE: The objective of the study was to study the presenting features and cancer risk of children with autonomous nodules. DESIGN AND SETTING: Medical records of all 31 children diagnosed with autonomous nodules at our center from 2003 to 2014 were retrospectively reviewed. PATIENTS AND RESULTS: All children met full diagnostic criteria for autonomous nodules, defined by both autonomous 123I uptake into the nodule and the suppression of uptake in the normal thyroid parenchyma on scintigraphy performed during hypothyrotropinemia. The median age of presentation was 15 years (range 3-18 y) with a female to male ratio of 15:1. Fifty-eight percent of patients had solitary nodules and 42% had multiple nodules. The median size of each patient's largest autonomous nodule was 39 mm (range 18-67 mm). Most of the children in this series (68%) had diagnostic biopsies and/or operative pathology of their largest autonomous nodule, which showed benign cytology or histology in all cases. CONCLUSIONS: In this pediatric series, the cancer rate observed in biopsied or resected autonomous nodules was 0%. Whereas larger studies are needed to confirm our findings, these results agree with earlier reports suggesting that thyroid cancer is rare in rigorously defined autonomous nodules and support that conservative management may be offered to selected children who meet strict diagnostic criteria for autonomous nodules, deferring definitive therapies until adulthood when the risks of thyroidectomy and 131I ablation are lower. PMID- 27501281 TI - Circulating and Adipose Levels of Adipokines Associated With Insulin Sensitivity in Nonobese Subjects With Type 2 Diabetes. AB - CONTEXT: The adipokines chemerin, dipeptidyl peptidase 4, and adiponectin influence insulin sensitivity. Whether their circulating levels and adipose secretion are altered in nonobese individuals with type 2 diabetes mellitus (T2DM) is unknown. OBJECTIVE: The objective of this study was to investigate SC adipose secretion and serum levels of the three adipokines in relation to T2DM features. DESIGN: Fourteen nonobese T2DM and 13 healthy men were investigated. Insulin sensitivity and glucose control were assessed by hyperinsulinemic euglycemic clamp, homeostasis model assessment, and glycated hemoglobin. MAIN OUTCOME MEASURE: Association of circulating and adipose-secreted adipokines with fat cell volume and insulin sensitivity was measured. PARTICIPANTS: Volunteers in an outpatient academic clinic participated. RESULTS: Although adipose secretion was similar between the groups, serum chemerin was higher (70 +/- 10 vs 50 +/- 1 ng/ml; P = .005), adiponectin lower (4.7 +/- 1.3 vs 6.8 +/- 2.2 MUg/ml; P = .005), and dipeptidyl peptidase 4 unaltered in T2DM. Serum adiponectin (r = 0.53; P = .005) and chemerin (r = -0.42; P = .03) correlated with adipose secreted levels. Secreted and circulating chemerin correlated positively with adipocyte volume (r > 0.40; P < .05), whereas serum adiponectin correlated negatively with this measure (r = -0.61; P = .001). Adiponectin serum half-life was decreased in T2DM (168 +/- 24 vs 186 +/- 18 minutes; P = .029) and correlated negatively with glycated hemoglobin (r = -0.45; P = .03) and adipocyte volume (r = -0.56; P < .003). Serum adiponectin (r = 0.57; P = .017) and chemerin (r = -0.52; P = .03) associated with clamp measures independently of T2DM diagnosis. CONCLUSIONS: In nonobese men, circulating adiponectin and chemerin levels are altered in T2DM without changes in adipose secretion. Adipocyte volume is important for variations in serum chemerin and adiponectin and for serum clearance of adiponectin. In T2DM, poor glucose control also plays a role for adiponectin clearance. PMID- 27501283 TI - Partial Loss of Function of the GHRH Receptor Leads to Mild Growth Hormone Deficiency. AB - OBJECTIVE: Recessive mutations in GHRHR are associated with severe isolated growth hormone deficiency (IGHD), with a final height in untreated patients of 130 cm +/- 10 cm (-7.2 +/- 1.6 SDS; males) and 114 +/- 0.7 cm (-8.3 +/- 0.1 SDS; females). DESIGN: We hypothesized that a consanguineous Pakistani family with IGHD in three siblings (two males, one female) would have mutations in GH1 or GHRHR. RESULTS: Two novel homozygous missense variants [c.11G>A (p.R4Q), c.236C>T (p.P79L)] at conserved residues were identified in all three siblings. Both were absent from control databases, aside from pR4Q appearing once in heterozygous form in the Exome Aggregation Consortium Browser. The brothers were diagnosed with GH deficiency at 9.8 and 6.0 years (height SDS: -2.24 and -1.23, respectively), with a peak GH of 2.9 MUg/liter with low IGF-1/IGF binding protein 3. Their sister presented at 16 years with classic GH deficiency (peak GH <0.1 MUg/liter, IGF-1 <3.3 mmol/liter) and attained an untreated near-adult height of 144 cm (-3.0 SDS); the tallest untreated patient with GHRHR mutations reported. An unrelated Pakistani female IGHD patient was also compound homozygous. All patients had a small anterior pituitary on magnetic resonance imaging. Functional analysis revealed a 50% reduction in maximal cAMP response to stimulation with GHRH by the p.R4Q/p.P79L double mutant receptor, with a 100-fold increase in EC50. CONCLUSION: We report the first coexistence of two novel compound homozygous GHRHR variants in two unrelated pedigrees associated with a partial loss of function. Surprisingly, the patients have a relatively mild IGHD phenotype. Analysis revealed that the pP79L mutation is associated with the compromise in function, with the residual partial activity explaining the mild phenotype. PMID- 27501282 TI - Fibroblast Growth Factor 23 and Cause-Specific Mortality in the General Population: The Northern Manhattan Study. AB - CONTEXT: An elevated fibroblast growth factor (FGF) 23 is an independent risk factor for cardiovascular disease and mortality in patients with kidney disease. The relationship between FGF23 and cause-specific mortality in the general population is unknown. OBJECTIVE: To investigate the association of elevated FGF23 with the risk of cause-specific mortality in a racially and ethnically diverse urban general population. DESIGN, SETTING, PARTICIPANTS: The Northern Manhattan Study is a population-based prospective cohort study. Residents who were > 39 years old and had no history of stroke were enrolled between 1993 and 2001. Participants with available blood samples for baseline FGF23 testing were included in the current study (n = 2525). MAIN OUTCOME MEASURES: Cause-specific death events. RESULTS: A total of 1198 deaths (474 vascular, 612 nonvascular, 112 unknown cause) occurred during a median follow-up of 14 years. Compared to participants in the lowest FGF23 quintile, those in the highest quintile had a 2.07-fold higher risk (95% confidence interval [CI], 1.45, 2.94) of vascular death and a 1.64-fold higher risk (95% CI, 1.22, 2.20) of nonvascular death in fully adjusted models. Higher FGF23 was independently associated with increased risk of mortality due to cancer, but only in Hispanic participants (hazard ratio per 1 unit increase in ln FGF23 of 1.87; 95% CI, 1.40, 2.50; P for interaction = .01). CONCLUSIONS: Elevated FGF23 was independently associated with increased risk of vascular and nonvascular mortality in a diverse general population and with increased risk of cancer death specifically in Hispanic individuals. PMID- 27501284 TI - Histamine elimination from the cerebrospinal fluid across the blood-cerebrospinal fluid barrier: involvement of plasma membrane monoamine transporter (PMAT/SLC29A4). AB - The elimination of histamine, an excitatory neurotransmitter, from the brain/CSF across the blood-brain barrier and blood-CSF barrier (BCSFB) was investigated using Wistar rats, which were anesthetized with pentobarbital sodium. An in vivo intracerebral microinjection study suggested that there was only partial efflux of [3 H]histamine from the rat brain across the blood-brain barrier. The [3 H]histamine elimination clearance from the rat CSF was 3.8-fold greater than that of a CSF bulk flow marker, and the elimination of [3 H]histamine was significantly inhibited by the co-administration of unlabeled histamine, suggesting the involvement of a carrier-mediated process in histamine elimination from the CSF. The uptake study of [3 H]histamine by the isolated rat choroid plexus revealed histamine elimination from the CSF across the BCSFB. The [3 H]histamine uptake by TR-CSFB3 cells, a model cell line for the BCSFB, exhibited temperature-dependent and saturable kinetics, suggesting the involvement of carrier-mediated transport of histamine at the BCSFB. In the inhibition study, [3 H]histamine uptake by TR-CSFB3 cells was significantly inhibited by substrates and/or inhibitors of plasma membrane monoamine transporter (PMAT/SLC29A4), but not affected by substrates of organic cation transporters. These results suggest the elimination of histamine from the CSF via plasma membrane monoamine transporter at the BCSFB. PMID- 27501285 TI - Implementation of a Coherent Anti-Stokes Raman Scattering (CARS) System on a Ti:Sapphire and OPO Laser Based Standard Laser Scanning Microscope. AB - Laser scanning microscopes combining a femtosecond Ti:sapphire laser and an optical parametric oscillator (OPO) to duplicate the laser line have become available for biologists. These systems are primarily designed for multi-channel two-photon fluorescence microscopy. However, without any modification, complementary non-linear optical microscopy such as second-harmonic generation (SHG) or third harmonic generation (THG) can also be performed with this set-up, allowing label-free imaging of structured molecules or aqueous medium-lipid interfaces. These techniques are well suited for in-vivo observation, but are limited in chemical specificity. Chemically selective imaging can be obtained from inherent vibration signals based on Raman scattering. Confocal Raman microscopy provides 3D spatial resolution, but it requires high average power and long acquisition time. To overcome these difficulties, recent advances in laser technology have permitted the development of nonlinear optical vibrational microscopy, in particular coherent anti-Stokes Raman scattering (CARS). CARS microscopy has therefore emerged as a powerful tool for biological and live cell imaging, by chemically mapping lipids (via C-H stretch vibration), water (via O-H stretch vibrations), proteins or DNA. In this work, we describe the implementation of the CARS technique on a standard OPO-coupled multiphoton laser scanning microscope. It is based on the in-time synchronization of the two laser lines by adjusting the length of one of the laser beam path. We present a step-by step implementation of this technique on an existing multiphoton system. A basic background in experimental optics is helpful and the presented system does not require expensive supplementary equipment. We also illustrate CARS imaging obtained on myelin sheaths of sciatic nerve of rodent, and we show that this imaging can be performed simultaneously with other nonlinear optical imaging, such as standard two-photon fluorescence technique and second-harmonic generation. PMID- 27501286 TI - Effects of Moderators on Physical Training Programs: A Bayesian Approach. AB - Vetter, RE, Yu, H, and Foose, AK. Effects of moderators on physical training programs: a Bayesian approach. J Strength Cond Res 31(7): 1868-1878, 2017 Creating an optimal physical training program is an important focus in sport and exercise research. The purpose of this research was to examine how different moderators (age, ability level, training weeks, training frequencies, and intensity) impacted the physiological outcomes of specific exercise training programs (muscular strength, speed, power, and cardiorespiratory) using the Bayesian method. A Bayesian approach uses flexible frameworks to determine the pattern of outcomes. This Bayesian analysis combined data generated by 34 previous studies from 1984 to 2015 to improve estimates of effects; these studies rendered 312 cases. The analyses for age were strong in cardiorespiratory and speed but less in power and muscular strength. Ability level was not a predictor of outcomes in each of the 4 areas. Training weeks contributed to power and cardiorespiratory, but not for speed, whereas for strength the effect size (ES) increased only up to the 16th week. Training frequency was a nonsignificant predictor of ES; most of the included studies within this analysis used only training frequencies of 2 or 3 days. Training intensity clearly contributed to the ES. The pattern of influence for intensity level in strength was greatest between 55 and 80%, in power it increased at 65% and continued in a positive linear pattern, in cardiorespiratory it increased up to 65% and then plateaued, and for speed no inferences could be made. PMID- 27501287 TI - Watershed Planning within a Quantitative Scenario Analysis Framework. AB - There is a critical need for tools and methodologies capable of managing aquatic systems within heavily impacted watersheds. Current efforts often fall short as a result of an inability to quantify and predict complex cumulative effects of current and future land use scenarios at relevant spatial scales. The goal of this manuscript is to provide methods for conducting a targeted watershed assessment that enables resource managers to produce landscape-based cumulative effects models for use within a scenario analysis management framework. Sites are first selected for inclusion within the watershed assessment by identifying sites that fall along independent gradients and combinations of known stressors. Field and laboratory techniques are then used to obtain data on the physical, chemical, and biological effects of multiple land use activities. Multiple linear regression analysis is then used to produce landscape-based cumulative effects models for predicting aquatic conditions. Lastly, methods for incorporating cumulative effects models within a scenario analysis framework for guiding management and regulatory decisions (e.g., permitting and mitigation) within actively developing watersheds are discussed and demonstrated for 2 sub watersheds within the mountaintop mining region of central Appalachia. The watershed assessment and management approach provided herein enables resource managers to facilitate economic and development activity while protecting aquatic resources and producing opportunity for net ecological benefits through targeted remediation. PMID- 27501288 TI - Buckling of a holey column. AB - We report the results from a combined experimental and numerical investigation of buckling in a novel variant of an elastic column under axial load. We find that including a regular line of centred holes in the column can prevent conventional, global, lateral buckling. Instead, the local microstructure introduced by the holes allows the column to buckle in an entirely different, internal, mode in which the holes are compressed in alternate directions, but the column maintains the lateral reflection symmetry about its centreline. The internal buckling mode can be accommodated within a smaller external space than the global one; and it is the preferred buckling mode over an intermediate range of column lengths for sufficiently large holes. For very short or sufficiently long columns a modification of the classical, global, lateral buckling is dominant. PMID- 27501289 TI - Transparent and Flexible Self-Charging Power Film and Its Application in a Sliding Unlock System in Touchpad Technology. AB - Portable and wearable personal electronics and smart security systems are accelerating the development of transparent, flexible, and thin-film electronic devices. Here, we report a transparent and flexible self-charging power film (SCPF) that functions either as a power generator integrated with an energy storage unit or as a self-powered information input matrix. The SCPF possesses the capability of harvesting mechanical energy from finger motions, based on the coupling between the contact electrification and electrostatic induction effects, and meanwhile storing the generated energy. Under the fast finger sliding, the film can be charged from 0 to 2.5 V within 2094 s and discharge at 1 MUA for approximately 1630 s. Furthermore, the film is able to identify personal characteristics during a sliding motion by recording the electric signals related to the person's individual bioelectricity, applied pressing force, sliding speed, and so on, which shows its potential applications in security systems in touchpad technology. PMID- 27501291 TI - A severe case of X-linked ichthyosis showing palmar hyperlinearity without FLG mutations. PMID- 27501290 TI - Sequencing postoperative radiotherapy and adjuvant chemotherapy in non-small cell lung cancer: unanswered questions on the not evidence-based approach. AB - This editorial comments on the study by Lee et al. which reported on the use of postoperative radiotherapy (PORT) as first strategy after resection of stage IIIA pN2 non-small cell lung cancer (NSCLC). After completion of PORT, 41% of patients received postoperative chemotherapy (POCT). The five-year overall survival (OS) was significantly higher in patients treated with PORT and POCT than in patients treated with PORT alone. Authors concluded that PORT used as first postoperative strategy does not compromise a benefit of POCT and its implementation should be further studied. We discuss the pros and cons of using PORT before POCT for stage IIIA-pN2 NSCLC. Some radiobiological data support earlier use of PORT, however, caution should be paid to not to unnecessarily delay or omit POCT because of its demonstrated survival benefit. Concurrent postoperative radio-chemotherapy could be an attractive approach, but we still have very limited clinical data on its use in this indication. PMID- 27501292 TI - Protocol of Electrochemical Test and Characterization of Aprotic Li-O2 Battery. AB - We demonstrate a method for electrochemical testing of an aprotic Li-O2 battery. An aprotic Li-O2 battery is made of a Li-metal anode, an aprotic electrolyte, and an O2-breathing cathode. The aprotic electrolyte is a solution of lithium salt with aprotic solvent; and porous carbon is commonly used as the cathode substrate. To improve the performance, an electrocatalyst is deposited onto the porous carbon substrate by certain deposition methods, such as atomic layer deposition (ALD) and wet-chemistry reaction. The as-prepared cathode materials are characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray absorption near edge structure (XANES). A Swagelok type cell, sealed in a glass chamber filled with pure O2, is used for the electrochemical test on a battery test system. The cells are tested under either capacity-controlled mode or voltage controlled mode. The reaction products are investigated by electron microscopy, X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), attenuated total reflection Fourier transform infrared (ATR FTIR) spectroscopy, and Raman spectroscopy to study the possible pathway of oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). This protocol demonstrates a systematic and efficient arrangement of routine tests of the aprotic Li-O2 battery, including the electrochemical test and characterization of battery materials. PMID- 27501293 TI - Ibudilast for the treatment of multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) characterized by inflammatory demyelination and progressive axonal loss. Clinically, this is manifest as relapsing and remitting neurological symptoms and progressive accumulation of disability. Ibudilast is a nonselective phosphodiesterase inhibitor which works by blocking the cleavage of cyclic adenosine monophosphate (cAMP). It has been found to have anti-inflammatory and neuroprotective properties in animal studies and in-vitro studies; it is currently being studied in progressive MS. AREAS COVERED: This article reviews various studies looking at ibudilast as a potential therapy for MS. It summarizes prior and current clinical trials of ibudilast in MS as well as its pharmacology. EXPERT OPINION: Although ibudilast has not been found to decrease the focal inflammatory activity in relapsing MS, it was shown to have an effect on preserving brain volume and disability progression. Ibudilast may have a role in the treatment of progressive MS phenotypes. PMID- 27501294 TI - Genetic Basis of Nonsyndromic Sensorineural Hearing Loss in the Sub-Saharan African Island Population of Sao Tome and Principe: The Role of the DFNB1 Locus? AB - Hearing loss (HL) is a common condition with both genetic and environmental causes, and it greatly impacts global health. The prevalence of HL is reportedly higher in developing countries such as the Sub-Saharan African island of Sao Tome and Principe, where the deaf community is estimated to be less than 1% of the population. We investigated the role of the DFNB1 locus (GJB2 and GJB6 genes) in the etiology of nonsyndromic sensorineural hearing loss (NSSHL) in Sao Tome and Principe. A sample of 316 individuals, comprising 136 NSSHL patients (92 bilateral, 44 unilateral) and 180 controls, underwent a clinical and audiological examination. Sequencing of the GJB2 coding region and testing for the (GJB6 D13S1830) and del(GJB6-D13S1854) GJB6 deletions were performed. A total of 311 out of 316 individuals were successfully analyzed regarding the GJB2 and GJB6 genetic variations, respectively. The frequency of the GJB2 coding mutations in patients and controls was low. Some of those coding mutations are the most commonly found in Eurasian and Mediterranean populations and have also been identified in Portugal. None of the GJB6 deletions was present. The presence of certain coding variants in Sao Tome and Principe suggests a non-Sub-Saharan genetic influx and supports the previously reported genetic influx from European (mainly Portuguese) ancestors. In summary, DFNB1 locus does not appear to be a major contributor to NSSHL in Sao Tome and Principe. However, the presence of both pathogenic and likely pathogenic mutations in GJB2 suggests that GJB2 related NSSHL might still occur in this population, warranting further research on GJB2 testing in NSSHL cases. PMID- 27501295 TI - Can Peripheral MicroRNA Expression Data Serve as Epigenomic (Upstream) Biomarkers of Alzheimer's Disease? AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. However, biomarkers that require testing in the brain tissue pose a formidable practical barrier to AD diagnostic innovation. MicroRNAs (miRNAs) are responsible for control of gene expression at the posttranscriptional level and are essential for the function of neuronal networks and neuronal survival. miRNA expression can impact the regulation of APP (amyloid beta A4 precursor protein), PSEN1 (presenilin 1), PSEN2 (presenilin 2), and BACE1 (beta-secretase 1) genes in the brain that were previously implicated in AD pathophysiology. Little is known, however, on the extent to which peripheral tissue (e.g., whole blood) miRNA variation might offer clinical predictive value for AD. Moreover, few studies have examined multiple peripheral miRNA expression data at the same time. We report here, to the best of our knowledge, the first whole-blood-based and parallel study of seven miRNAs (hsa-miR-9-5p, hsa-miR-29a 3p, hsa-miR-106a-5p, hsa-miR-106b-5p, hsa-miR-107, hsa-miR-125a-3p, and hsa-miR 125b-5p) in relation to AD susceptibility. Notably, these miRNAs are situated "upstream" to the genes implicated in AD. We measured the whole-blood miRNA expression by a real-time polymerase chain reaction in a large study sample (n = 281), comprising patients with AD (n = 172) and healthy controls (n = 109). A reduction in whole-blood expression of hsa-miR-9-5p, hsa-miR-106a-5p, hsa-miR 106b-5p, and hsa-miR-107 was significantly associated with an increased risk of AD (p < 0.05). Notably, after receiver operating characteristics curve analyses, hsa-miR-106a-5p displayed, as a predictor variable, 93% specificity and 68% sensitivity. On the other hand, the expression of hsa-miR-29a-3p, hsa-miR-125a 3p, and hsa-miR-125b-5p was not significantly different between patients and controls (p > 0.05). In conclusion, these observations warrant replication in larger samples while making a contribution to translational research, precision medicine, and biomarker literatures, by expanding the current efforts for AD diagnostic innovation to the realm of epigenomic pathways such as miRNA expression variation among patients. PMID- 27501296 TI - Deciphering Cell-to-Cell Communication in Acquisition of Cancer Traits: Extracellular Membrane Vesicles Are Regulators of Tissue Biomechanics. AB - Deciphering the role of cell-to-cell communication in acquisition of cancer traits such as metastasis is one of the key challenges of integrative biology and clinical oncology. In this context, extracellular vesicles (EVs) are important vectors in cell-to-cell communication and serve as conduits in the transfer of cellular constituents required for cell function and for the establishment of cellular phenotypes. In the case of malignancy, they have been shown to support the acquisition of common traits defined as constituting the hallmarks of cancer. Cellular biophysics has contributed to our understanding of some of these central traits with changes in tissue biomechanics reflective of cell state. Indeed, much is known about stiffness of the tissue scaffold in the context of cell invasion and migration. This article advances this knowledge frontier by showing for the first time that EVs are mediators of tissue biomechanical properties and, importantly, demonstrates a link between the acquisition of cancer multidrug resistance and increased tissue stiffness of the malignant mass. The methodology used in the study employed optical coherence elastography and atomic force microscopy on breast cancer cell monolayers and tumor spheroids. Specifically, we show here that the acquired changes in tissue stiffness can be attributed to the intracellular transfer of a protein complex comprising ezrin, radixin, moesin, CD44, and P-glycoprotein. This has important implications in facilitating mechano transduced signaling cascades that regulate the acquisition of cancer traits, such as invasion and metastasis. Finally, this study also introduces novel targets and strategies for diagnostic and therapeutic innovation in oncology, with a view to prevention of metastatic spread and personalized medicine in cancer treatment. PMID- 27501297 TI - A Causal Network Analysis of the Fatty Acid Metabolome in African-Americans Reveals a Critical Role for Palmitoleate and Margarate. AB - Fatty acids are important sources of energy and possible predictors and etiologic factors in many common complex pathologies such as cardiovascular disease, diabetes, and certain forms of cancers. While fatty acids are thought to covary with each other, their underlying causal networks have not been fully elucidated. This study reports the identification and analysis of a statistical causal network among 15 mostly long-chain fatty acids. In an African-American population sample and using the Genome granularity-Directed Acyclic Graph (GDAG) algorithm, we determined directions or causal relationships in the fatty acid metabolome. A directed causal network was constructed that revealed 29 significant edges among the 15 nodes (p < 0.001). We report that two fatty acid metabolites, palmitoleate and margarate, which originate from dietary intake, together influence every other fatty acid in the network. On the other hand, despite its high connectivity, dihomo-linoleate did not appear to play an important role over the whole fatty acid network. These findings collectively suggest possible strategic entry points for new treatments or preventive modalities against diseases affected by fatty acid metabolites such as cardiovascular disease, diabetes, and obesity. Further studies examining the embedded substructure of the fatty acid metabolite networks in independent population samples would be timely and warranted as we move toward novel postgenomic diagnostics and therapeutics. PMID- 27501299 TI - Second-generation anaplastic lymphoma kinase inhibitors: revolutionary or evolutionary? PMID- 27501300 TI - Nanoimprint of a 3D structure on an optical fiber for light wavefront manipulation. AB - Integration of complex photonic structures onto optical fiber facets enables powerful platforms with unprecedented optical functionalities. Conventional nanofabrication technologies, however, do not permit viable integration of complex photonic devices onto optical fibers owing to their low throughput and high cost. In this paper we report the fabrication of a three-dimensional structure achieved by direct nanoimprint lithography on the facet of an optical fiber. Nanoimprint processes and tools were specifically developed to enable a high lithographic accuracy and coaxial alignment of the optical device with respect to the fiber core. To demonstrate the capability of this new approach, a 3D beam splitter has been designed, imprinted and optically characterized. Scanning electron microscopy and optical measurements confirmed the good lithographic capabilities of the proposed approach as well as the desired optical performance of the imprinted structure. The inexpensive solution presented here should enable advancements in areas such as integrated optics and sensing, achieving enhanced portability and versatility of fiber optic components. PMID- 27501301 TI - Low Night Temperature Affects the Phloem Ultrastructure of Lateral Branches and Raffinose Family Oligosaccharide (RFO) Accumulation in RFO-Transporting Plant Melon (Cucumismelo L.) during Fruit Expansion. AB - Due to the importance and complexity of photo assimilate transport in raffinose family oligosaccharide (RFO)-transporting plants such as melon, it is important to study the features of the transport structure (phloem) particularly of the lateral branches connecting the source leaves and the sink fruits, and its responses to environmental challenges. Currently, it is unclear to what extents the cold environmental temperature stress would alter the phloem ultrastructure and RFO accumulation in RFO-transporting plants. In this study, we firstly utilized electron microscopy to investigate the changes in the phloem ultrastructure of lateral branches and RFO accumulation in melons after being subjected to low night temperatures (12 degrees C and 9 degrees C). The results demonstrated that exposure to 9 degrees C and 12 degrees C altered the ultrastructure of the phloem, with the effect of 9 degrees C being more obvious. The most obvious change was the appearance of plasma membrane invaginations in 99% companion cells and intermediary cells. In addition, phloem parenchyma cells contained chloroplasts with increased amounts of starch grains, sparse cytoplasm and reduced numbers of mitochondria. In the intermediary cells, the volume of cytoplasm was reduced by 50%, and the central vacuole was present. Moreover, the treatment at 9 degrees C during the night led to RFO accumulation in the vascular bundles of the lateral branches and fruit carpopodiums. These ultrastructural changes of the transport structure (phloem) following the treatment at 9 degrees C represented adaptive responses of melons to low temperature stresses. Future studies are required to examine whether these responses may affect phloem transport. PMID- 27501302 TI - The Critical Role of Early Dengue Surveillance and Limitations of Clinical Reporting - Implications for Non-Endemic Countries. AB - The increasing dengue burden and epidemic severity worldwide have highlighted the need to improve surveillance. In non-endemic areas such as Taiwan, where outbreaks start mostly with imported cases from Southeast Asia, a closer examination of surveillance dynamics to detect cases early is necessary. To evaluate problems with dengue surveillance and investigate the involvement of different factors at various epidemic stages, we investigated 632 laboratory confirmed indigenous dengue cases in Kaohsiung City, Taiwan during 2009-2010. The estimated sensitivity of clinical surveillance was 82.4% (521/632). Initially, the modified serological surveillance (targeting only the contacts of laboratory confirmed dengue cases) identified clinically unrecognized afebrile cases in younger patients who visited private clinics and accounted for 30.4% (35/115) of the early-stage cases. Multivariate regression indicated that hospital/medical center visits [Adjusted Odds Ratio (aOR): 11.6, 95% confidence interval (CI): 6.3 21.4], middle epidemic stage [aOR: 2.4 (1.2-4.7)], fever [aOR: 2.3 (2.3-12.9)], and musculo-articular pain [aOR: 1.9 (1.05-3.3)] were significantly associated with clinical reporting. However, cases with pruritus/rash [aOR: 0.47 (0.26 0.83)] and diarrhea [aOR: 0.47 (0.26-0.85)] were underreported. In conclusion, multiple factors contributed to dengue surveillance problems. To prevent a large scale epidemic and minimize severe dengue cases, there is a need for integrated surveillance incorporating entomological, clinical, serological, and virological surveillance systems to detect early cases, followed by immediate prevention and control measures and continuous evaluation to ensure effectiveness. This effort will be particularly important for an arbovirus, such as Zika virus, with a high asymptomatic infection ratio. For dengue- non-endemic countries, we recommend serological surveillance be implemented in areas with high Aedes mosquito indices or many breeding sites. Syndromic surveillance, spatial analysis and monitoring changes in epidemiological characteristics using a geographical information system, as well as epidemic prediction models involving epidemiological, meteorological and environmental variables will be helpful for early risk communication to increase awareness. PMID- 27501303 TI - Analysis of Brain Mitochondria Using Serial Block-Face Scanning Electron Microscopy. AB - Human brain is a high energy consuming organ that mainly relies on glucose as a fuel source. Glucose is catabolized by brain mitochondria via glycolysis, tri carboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) pathways to produce cellular energy in the form of adenosine triphosphate (ATP). Impairment of mitochondrial ATP production causes mitochondrial disorders, which present clinically with prominent neurological and myopathic symptoms. Mitochondrial defects are also present in neurodevelopmental disorders (e.g. autism spectrum disorder) and neurodegenerative disorders (e.g. amyotrophic lateral sclerosis, Alzheimer's and Parkinson's diseases). Thus, there is an increased interest in the field for performing 3D analysis of mitochondrial morphology, structure and distribution under both healthy and disease states. The brain mitochondrial morphology is extremely diverse, with some mitochondria especially those in the synaptic region being in the range of <200 nm diameter, which is below the resolution limit of traditional light microscopy. Expressing a mitochondrially targeted green fluorescent protein (GFP) in the brain significantly enhances the organellar detection by confocal microscopy. However, it does not overcome the constraints on the sensitivity of detection of relatively small sized mitochondria without oversaturating the images of large sized mitochondria. While serial transmission electron microscopy has been successfully used to characterize mitochondria at the neuronal synapse, this technique is extremely time-consuming especially when comparing multiple samples. The serial block-face scanning electron microscopy (SBFSEM) technique involves an automated process of sectioning, imaging blocks of tissue and data acquisition. Here, we provide a protocol to perform SBFSEM of a defined region from rodent brain to rapidly reconstruct and visualize mitochondrial morphology. This technique could also be used to provide accurate information on mitochondrial number, volume, size and distribution in a defined brain region. Since the obtained image resolution is high (typically under 10 nm) any gross mitochondrial morphological defects may also be detected. PMID- 27501304 TI - Preoperative analgesics for additional pain relief in children and adolescents having dental treatment. AB - BACKGROUND: Fear of dental pain is a major barrier to treatment for children who need dental care. The use of preoperative analgesics has the potential to reduce postoperative discomfort and intraoperative pain. We reviewed the available evidence to determine whether further research is warranted and to inform the development of prescribing guidelines. This is an update of a Cochrane review published in 2012. OBJECTIVES: To assess the effects of preoperative analgesics for intraoperative or postoperative pain relief (or both) in children and adolescents undergoing dental treatment without general anaesthesia or sedation. SEARCH METHODS: We searched the following electronic databases: Cochrane Oral Health's Trials Register (to 5 January 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2015, Issue 12), MEDLINE via OVID (1946 to 5 January 2016), EMBASE via OVID (1980 to 5 January 2016), LILACS via BIREME (1982 to 5 January 2016) and the ISI Web of Science (1945 to 5 January 2016). We searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials to 5 January 2016. There were no restrictions regarding language or date of publication in the searches of the electronic databases. We handsearched several specialist journals dating from 2000 to 2011.We checked the reference lists of all eligible trials for additional studies. We contacted specialists in the field for any unpublished data. SELECTION CRITERIA: Randomised controlled clinical trials of analgesics given before dental treatment versus placebo or no analgesics in children and adolescents up to 17 years of age. We excluded children and adolescents having dental treatment under sedation (including nitrous oxide/oxygen) or general anaesthesia. DATA COLLECTION AND ANALYSIS: Two review authors assessed titles and abstracts of the articles obtained from the searches for eligibility, undertook data extraction and assessed the risk of bias in the included studies. We assessed the quality of the evidence using GRADE criteria. MAIN RESULTS: We included five trials in the review, with 190 participants in total. We did not identify any new studies for inclusion from the updated search in January 2016.Three trials were related to dental treatment, i.e. restorative and extraction treatments; two trials related to orthodontic treatment. We did not judge any of the included trials to be at low risk of bias.Three of the included trials compared paracetamol with placebo, only two of which provided data for analysis (presence or absence of parent-reported postoperative pain behaviour). Meta-analysis of the two trials gave arisk ratio (RR) for postoperative pain of 0.81 (95% confidence interval (CI) 0.53 to 1.22; two trials, 100 participants; P = 0.31), which showed no evidence of a benefit in taking paracetamol preoperatively (52% reporting pain in the placebo group versus 42% in the paracetamol group). One of these trials was at unclear risk of bias, and the other was at high risk. The quality of the evidence is low. One study did not have any adverse events; the other two trials did not mention adverse events.Four of the included trials compared ibuprofen with placebo. Three of these trials provided useable data. One trial reported no statistical difference in postoperative pain experienced by the ibuprofen group and the control group for children undergoing dental treatment. We pooled the data from the other two trials, which included participants who were having orthodontic separator replacement without a general anaesthetic, to determine the effect of preoperative ibuprofen on the severity of postoperative pain. There was a statistically significant mean difference in severity of postoperative pain of 13.44 (95% CI -23.01 to -3.88; two trials, 85 participants; P = 0.006) on a visual analogue scale (0 to 100), which indicated a probable benefit for preoperative ibuprofen before this orthodontic procedure. However, both trials were at high risk of bias. The quality of the evidence is low. Only one of the trials reported adverse events (one participant from the ibuprofen group and one from the placebo group reporting a lip or cheek biting injury). AUTHORS' CONCLUSIONS: From the available evidence, we cannot determine whether or not preoperative analgesics are of benefit in paediatric dentistry for procedures under local anaesthetic. There is probably a benefit in using preoperative analgesics prior to orthodontic separator placement. The quality of the evidence is low. Further randomised clinical trials should be completed with appropriate sample sizes and well defined outcome measures. PMID- 27501305 TI - New Methyloceanibacter diversity from North Sea sediments includes methanotroph containing solely the soluble methane monooxygenase. AB - Marine methylotrophs play a key role in the global carbon cycle by metabolizing reduced one-carbon compounds that are found in high concentrations in marine environments. Genome, physiology and diversity studies have been greatly facilitated by the numerous model organisms brought into culture. However, the availability of marine representatives remains poor. Here, we report the isolation of four novel species from North Sea sediment enrichments closely related to the Alphaproteobacterium Methyloceanibacter caenitepidi. Each of the newly isolated Methyloceanibacter species exhibited a clear genome sequence divergence which was reflected in physiological differences. Notably one strain R 67174 was capable of oxidizing methane as sole source of carbon and energy using solely a soluble methane monooxygenase and represents the first marine Alphaproteobacterial methanotroph brought into culture. Differences in maximum cell density of >1.5 orders of magnitude were observed. Furthermore, three strains were capable of producing nitrous oxide from nitrate. Together, these findings highlight the metabolic and physiologic variability within closely related Methyloceanibacter species and provide a new understanding of the physiological basis of marine methylotrophy. PMID- 27501306 TI - NONSULFATED SULFAKININ CHANGES METABOLIC PARAMETERS OF INSECT FAT BODY MITOCHONDRIA. AB - We investigated the effect of neuropeptide, the nonsulfated sulfakinin (SK) Zopat SK-1 (pETSDDYGHLRFa) on the mitochondrial oxidative metabolism in the Zophobas atratus larval fat body. Mitochondria were isolated from beetle fat bodies 2 and 24 h after hormone injection. The administration of 20 pmol of Zopat-SK-1 to feeding larvae led to decreased mitochondrial oxidative activities in larval fat body. Diminished activities of citrate synthase and the cytochrome pathway, that is, nonphosphorylating and phosphorylating respiration during succinate oxidation, were observed. However, the effect of Zopat-SK-1 was more pronounced in fat body of insects after 24 h since hormone application. In hormone-treated larval fat bodies, mitochondrial respiration was decreased at the level of respiratory chain and the TCA cycle as well as at the level of mitochondrial biogenesis, as indicated by decreased activities of mitochondrial marker enzymes in fat body homogenates. The inhibition of succinate oxidation may indicate the role of Zopat-SK-1 in the regulation of mitochondrial complex II activity. Moreover, decreased respiratory chain activity was accompanied by the reduced activity of mitochondrial energy-dissipating pathway, uncoupling protein 4. The observed decrease in mitochondrial oxidative metabolism may reflect the Zopat-SK 1-induced reduction in the metabolic rate of larval fat body linked to actual energetic demands of animal. PMID- 27501307 TI - Mass-Dependent and -Independent Fractionation of Mercury Isotope during Gas-Phase Oxidation of Elemental Mercury Vapor by Atomic Cl and Br. AB - This study presents the first measurement of Hg stable isotope fractionation during gas-phase oxidation of Hg(0) vapor by halogen atoms (Cl(*), Br(*)) in the laboratory at 750 +/- 1 Torr and 298 +/- 3 K. Using a relative rate technique, the rate coefficients for Hg(0)+Cl(*) and Hg(0)+Br(*) reactions are determined to be (1.8 +/- 0.5) * 10(-11) and (1.6 +/- 0.8) * 10(-12) cm(3) molecule(-1) s(-1), respectively. Results show that heavier isotopes are preferentially enriched in the remaining Hg(0) during Cl(*) initiated oxidation, whereas being enriched in the product during oxidation by Br(*). The fractionation factors for (202)Hg/(198)Hg during the Cl(*) and Br(*) initiated oxidations are alpha(202/198) = 0.99941 +/- 0.00006 (2sigma) and 1.00074 +/- 0.00014 (2sigma), respectively. A Delta(199)Hg/Delta(201)Hg ratio of 1.64 +/- 0.30 (2sigma) during oxidation of Hg(0) by Br atoms suggests that Hg-MIF is introduced by the nuclear volume effect (NVE). In contrast, the Hg(0) + Cl(*) reaction produces a Delta(199)Hg/Delta(201)Hg-slope of 1.89 +/- 0.18 (2sigma), which in addition to a high degree of odd-mass-number isotope MIF suggests impacts from MIF effects other than NVE. This reaction also exhibits significant MIF of (200)Hg (Delta(200)Hg, up to -0.170/00 in the reactant) and is the first physicochemical process identified to trigger (200)Hg anomalies that are frequently detected in atmospheric samples. PMID- 27501308 TI - Mitochondrial genome erosion and the evolution of sex. PMID- 27501309 TI - Specific and sustainable bioelectro-reduction of carbon dioxide to formate on a novel enzymatic cathode. AB - To specifically convert waste CO2 into renewable chemicals, enzymatic electrosynthesis (EES) of formate from CO2 reduction was investigated in a bioelectrochemical system (BES). A novel cathode with immobilized enzyme and electropolymerized mediator-regenerator was fabricated for such bioelectrocatalytic EES. Formate dehydrogenase from Candida boidinii (CbFDH) was set as a new model enzyme in BES. Modified Nafion micelles with appropriate pore size were found to be suitable for immobilization of CbFDH and protection of its enzymatic activity and lifetime at optimal pH of 6.0. The enzymatic electrosynthesis activity of immobilized CbFDH was characterized systematically. Quite a small overpotential was required in the bioelectrochemical EES reaction. A two-electron transfer process was confirmed in the CbFDH-catalyzed reduction of bicarbonate to formate. With electro-polymerized neutral red (PolyNR) as a NADH (mediator)-regenerator, efficient formate production could be achieved at a maximum rate of 159.89 mg L(-1) h(-1) under poised potential of -0.80 V (vs. SHE). The immobilized CbFDH and electropolymerized PolyNR on an enzymatic cathode contributed greatly to sustainable EES, giving energy-rich formate as the only catalysis product. PMID- 27501310 TI - Effects of Ni/Fe bimetallic nanoparticles on phytotoxicity and translocation of polybrominated diphenyl ethers in contaminated soil. AB - In vivo studies of the interactions of polybrominated diphenyl ethers (PBDEs) in plants have generally focused on uptake, translocation, metabolism and accumulation, but there were limited reports about the phytotoxicity and translocation of PBDEs in contaminated soil with the effects of nanoparticles. In this study, the effects of Ni/Fe bimetallic nanoparticles on translocation of polybrominated diphenyl ethers (PBDEs) in contaminated soil and its phytotoxicity to Chinese cabbage were investigated by soil culture experiments. The results showed that the plant biomass, germination rate, and shoot and root lengths of treated soil (S-5) increased by 0.0044 g, 15%, and 5 and 6 mm, respectively, compared with untreated soil (S-2B). The average Ni and Fe contents of the edible parts(stem and leaf) of the S-5 sample, which contained 0.03 g/g Ni/Fe and 10 mg/kg BDE209, were measured at 1.71 and 184 mg/kg, respectively. The superoxide dismutase, peroxidase and catalase activities in the S-5 sample decreased by 12%, 6.1% and 5.9%, respectively, while compared with the S-2B sample. In all treatments, the contents of BDE209 and the total PBDEs in sample S-5 were lowest, suggesting that the fresh Ni/Fe nanoparticles had higher toxicity than that of the aged nanoparticles. And the lower brominated PBDEs (tri-to nona-) were detected in samples, indicating uptake, debromination and/or metabolism of PBDEs existed in plants. The phytotoxicity and translocation of BDE209 in the contaminated soil decreased as a result of the effects of the Ni/Fe bimetallic nanoparticles. PMID- 27501311 TI - Herbicides interfere with antigrazer defenses in Scenedesmus obliquus. AB - The extensive application of herbicides has led to a serious threat of herbicide contamination to aquatic ecosystem. Herbicide exposure affects aquatic communities not only by exerting toxicity on single species but also by changing interspecific interactions. This study investigated the antigrazer defenses of the common green alga Scenedesmus obliquus against different herbicides [glyphosate, 2,4-dichlorophenoxyacetic acid (2,4-D), and atrazine] at various concentrations (0-2.0 mg L(-1)). In the presence of grazer (Daphnia)-derived cues, S. obliquus populations without herbicides formed high proportions of multicelled (e.g., four- and eight-celled) colonies. This result confirms that S. obliquus exhibits a morphological defense against grazing risk. At the low concentration range of 0.002-0.02 mg L(-1), the three herbicides exerted no influence on the growth and photosynthetic efficiency of S. obliquus, and multicelled colonies showed constant proportions. At the high concentration range of 0.20-2.0 mg L(-1), atrazine significantly inhibited the algal growth and photosynthesis whereas glyphosate or 2,4-D did not. Nonetheless, these levels of glyphosate or 2,4-D remarkably decreased the proportion of multicelled colonies, with reduced numbers of cells per particle in Daphnia filtrate-treated population. No eight-celled colony was formed after treatment with atrazine at 0.20-2.0 mg L(-1) despite the addition of Daphnia filtrate. These results suggest that herbicide exposure impairs antigrazer colonial morphs in phytoplankton although it is not sufficient to hamper algal growth. This phenomenon can increase the risk of predation by herbivores, thereby disrupting the inducible phytoplankton community. Furthermore, the predator-prey interactions between herbivores and phytoplankton can be potentially changed more seriously than previously considered. PMID- 27501312 TI - Pesticide residues in drinking water and associated risk to consumers in Ethiopia. AB - Access to safe and reliable drinking water is vital for a healthy population. However, surface water may be contaminated with pesticides because of the nearby agricultural areas as well as from household application. Water samples were collected from water sources in Jimma zone and Addis Ababa, Ethiopia. The extraction and clean up of the samples were undertaken using liquid-solid and liquid-liquid methods. Human exposure was assessed by calculating the estimated daily intake (EDI) of pesticides in water and compared with the acceptable daily intake (ADI) and the acute reference dose (ARfD). The mean concentrations of 2,4 D, malathion, diazinon and fenpropimorph were 1.59-13.90 MUg/l and 0.11-138 ug/l in Jimma and Addis Ababa water sources, respectively. The residue level of some of the pesticides were above the European drinking water guide line values, which is an indication of an illegal use of pesticides in the study areas. Concerning human health risk estimation, there was no acute risk (EDI < ARfD). However, chronic risks to human health were observed from exposure to diazinon and fenpropimorph (EDI > ADI) for Jimma and Addis Ababa populations, respectively. A comprehensive monitoring is required to reduce the level of pesticide residues in the water and to minimize particularly the long term human health risks. PMID- 27501313 TI - Biomimetic Ant-Nest Electrode Structures for High Sulfur Ratio Lithium-Sulfur Batteries. AB - The lithium-sulfur (Li-S) rechargeable battery has the benefit of high gravimetric energy density and low cost. Significant research currently focuses on increasing the sulfur loading and sulfur/inactive-materials ratio, to improve life and capacity. Inspired by nature's ant-nest structure, this research results in a novel Li-S electrode that is designed to meet both goals. With only three simple manufacturing-friendly steps, which include slurry ball-milling, doctor blade-based laminate casting, and the use of the sacrificial method with water to dissolve away table salt, the ant-nest design has been successfully recreated in an Li-S electrode. The efficient capabilities of the ant-nest structure are adopted to facilitate fast ion transportation, sustain polysulfide dissolution, and assist efficient precipitation. High cycling stability in the Li-S batteries, for practical applications, has been achieved with up to 3 mg.cm(-2) sulfur loading. Li-S electrodes with up to a 85% sulfur ratio have also been achieved for the efficient design of this novel ant-nest structure. PMID- 27501314 TI - Efficacy and Safety of Beclomethasone Dipropionate versus 5-Aminosalicylic Acid in the Treatment of Ulcerative Colitis: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Ulcerative colitis (UC) is a chronic and remitting inflammatory disease that is characterized by chronic idiopathic inflammation of the colon and bloody diarrhea. Currently drug treatment is the main intervention for patients with mild to moderate UC. Mesalazine (5-ASA) and beclomethasone dipropionate (BDP) have been widely used for the treatment of UC and have yielded satisfactory results. This study compared the effectiveness of 5-ASA and BDP in the treatment of UC. METHODS: The PubMed, Medline, SinoMed, Embase, and Cochrane Librinary databases were searched for eligible studies. Data were extracted by two of the coauthors independently and were analyzed using RevMan statistical software, version 5.3. Weighted mean differences (WMDs), odds ratios (ORs), and 95% confidence intervals (CIs) were calculated. Cochrane Collaboration's Risk of Bias Tool was used to assess the risk of bias. RESULTS: Seven randomized controlled trials that compared BDP with 5-ASA in treating UC were identified as eligible. The methodological quality of the trials ranged from low to moderate. A pooled analysis of effectiveness based on the Disease Activity Index (DAI) or other assessment method after treatment revealed that in the treatment of UC, there are no obvious differences between BDP and 5-ASA in inducing remission and clinical improvement (OR = 0.76, 95% CI = 0.56-1.03, P = 0.08). The total numbers of adverse events associated with BDP and 5-ASA treatments for UC were similar (OR = 1.21, 95% CI = 0.71-2.09, P = 0.48). The safety profiles for these two drugs are good. According to subgroup-analysis, we found no obvious differences of clinical efficacy between BDP and 5-ASA no matter oral or enema administration was used in the treatment of UC. A sensitivity analysis demonstrated the stability of the pooled results. CONCLUSION: During induction treatment of mild to moderate UC, there is no obvious difference between the two groups with respect to remission and clinical improvement. Given that the upper confidence limit for the OR barely exceeds 1.0 and that the p-value is close to 0.05 for this primary efficacy outcome as well as that the horizontal block lies to the left of the vertical line, it indicates that the clinical efficacy of BDP may be better than 5-ASA. However, taking into account that BDP has the risk of hypothalamic-pituitary adrenal axis (HPA) suppression, 5-ASA has a potential advantage of safety in the treatment of mild to moderate UC. PMID- 27501315 TI - DNA condensation in one dimension. AB - DNA can be programmed to assemble into a variety of shapes and patterns on the nanoscale and can act as a template for hybrid nanostructures such as conducting wires, protein arrays and field-effect transistors. Current DNA nanostructures are typically in the sub-micrometre range, limited by the sequence space and length of the assembled strands. Here we show that on a patterned biochip, DNA chains collapse into one-dimensional (1D) fibres that are 20 nm wide and around 70 um long, each comprising approximately 35 co-aligned chains at its cross section. Electron beam writing on a photocleavable monolayer was used to immobilize and pattern the DNA molecules, which condense into 1D bundles in the presence of spermidine. DNA condensation can propagate and split at junctions, cross gaps and create domain walls between counterpropagating fronts. This system is inherently adept at solving probabilistic problems and was used to find the possible paths through a maze and to evaluate stochastic switching circuits. This technique could be used to propagate biological or ionic signals in combination with sequence-specific DNA nanotechnology or for gene expression in cell-free DNA compartments. PMID- 27501316 TI - Integrated optical addressing of an ion qubit. AB - The long coherence times and strong Coulomb interactions afforded by trapped ion qubits have enabled realizations of the necessary primitives for quantum information processing and the highest-fidelity quantum operations in any qubit to date. Although light delivery to each individual ion in a system is essential for general quantum manipulations and readout, experiments so far have employed optical systems that are cumbersome to scale to even a few tens of qubits. Here we demonstrate lithographically defined nanophotonic waveguide devices for light routing and ion addressing that are fully integrated within a surface-electrode ion trap chip. Ion qubits are addressed at multiple locations via focusing grating couplers emitting through openings in the trap electrodes to ions trapped 50 MUm above the chip; using this light, we perform quantum coherent operations on the optical qubit transition in individual 88Sr+ ions. The grating focuses the beam to a diffraction-limited spot near the ion position with 2 MUm 1/e2 radius along the trap axis, and we measure crosstalk errors between 10-2 and 4 * 10-4 at distances 7.5-15 MUm from the beam centre. Owing to the scalability of the planar fabrication technique employed, together with the tight focusing and stable alignment afforded by the integration of the optics within the trap chip, this approach presents a path to creating the optical systems required for large-scale trapped-ion quantum information processing. PMID- 27501317 TI - Ultrafast growth of single-crystal graphene assisted by a continuous oxygen supply. AB - Graphene has a range of unique physical properties and could be of use in the development of a variety of electronic, photonic and photovoltaic devices. For most applications, large-area high-quality graphene films are required and chemical vapour deposition (CVD) synthesis of graphene on copper surfaces has been of particular interest due to its simplicity and cost effectiveness. However, the rates of growth for graphene by CVD on copper are less than 0.4 MUm s-1, and therefore the synthesis of large, single-crystal graphene domains takes at least a few hours. Here, we show that single-crystal graphene can be grown on copper foils with a growth rate of 60 MUm s-1. Our high growth rate is achieved by placing the copper foil above an oxide substrate with a gap of ~15 MUm between them. The oxide substrate provides a continuous supply of oxygen to the surface of the copper catalyst during the CVD growth, which significantly lowers the energy barrier to the decomposition of the carbon feedstock and increases the growth rate. With this approach, we are able to grow single-crystal graphene domains with a lateral size of 0.3 mm in just 5 s. PMID- 27501319 TI - Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) as a Biomarker in the Mouse Model of Experimental Autoimmune Myocarditis (EAM). AB - Vascular cell adhesion molecule-1 (VCAM-1) is strongly upregulated in hearts of mice with coxsackie virus-induced as well as in patients with viral infection triggered dilated cardiomyopathy. Nevertheless, the role of its soluble form as a biomarker in inflammatory heart diseases remains unclear. Therefore, we investigated whether plasma levels of soluble VCAM-1 (sVCAM-1) directly correlated with disease activity and progression of cardiac dysfunction in the mouse model of experimental autoimmune myocarditis (EAM). EAM was induced by immunization of BALB/c mice with heart-specific myosin-alpha heavy chain peptide together with complete Freund's adjuvant. ELISA revealed strong expression of cardiac VCAM-1 (cVCAM-1) throughout the course of EAM in immunized mice compared to control animals. Furthermore, sVCAM-1 was elevated in the plasma of immunized compared to control mice at acute and chronic stages of the disease. sVCAM-1 did not correlate with the degree of acute cardiac inflammation analyzed by histology or cardiac cytokine expression investigated by ELISA. Nevertheless, heart to body weight ratio correlated significantly with sVCAM-1 at chronic stages of EAM. Cardiac systolic dysfunction studied with positron emission tomography indicated a weak relationship with sVCAM-1 at the chronic stage of the disease. Our data provide evidence that plasma levels of sVCAM-1 are elevated throughout all stages of the disease but showed no strong correlation with the severity of EAM. PMID- 27501318 TI - Fast and Specific Assessment of the Halogenating Peroxidase Activity in Leukocyte enriched Blood Samples. AB - In this paper a protocol for the quick and standardized enrichment of leukocytes from small whole blood samples is described. This procedure is based on the hypotonic lysis of erythrocytes and can be applied to human samples as well as to blood of non-human origin. The small initial sample volume of about 50 to 100 ul makes this method applicable to recurrent blood sampling from small laboratory animals. Moreover, leukocyte enrichment is achieved within minutes and with low material efforts regarding chemicals and instrumentation, making this method applicable in multiple laboratory environments. Standardized purification of leukocytes is combined with a highly selective staining method to evaluate halogenating peroxidase activity of the heme peroxidases, myeloperoxidase (MPO) and eosinophil peroxidase (EPO), i.e., the formation of hypochlorous and hypobromous acid (HOCl and HOBr). While MPO is strongly expressed in neutrophils, the most abundant immune cell type in human blood as well as in monocytes, the related enzyme EPO is exclusively expressed in eosinophils. The halogenating activity of these enzymes is addressed by using the almost HOCl- and HOBr specific dye aminophenyl fluorescein (APF) and the primary peroxidase substrate hydrogen peroxide. Upon subsequent flow cytometry analysis all peroxidase positive cells (neutrophils, monocytes, eosinophils) are distinguishable and their halogenating peroxidase activity can be quantified. Since APF staining may be combined with the application of cell surface markers, this protocol can be extended to specifically address leukocyte sub-fractions. The method is applicable to detect HOCl and HOBr production both in human and in rodent leukocytes. Given the widely and diversely discussed immunological role of these enzymatic products in chronic inflammatory diseases, this protocol may contribute to a better understanding of the immunological relevance of leukocyte-derived heme peroxidases. PMID- 27501320 TI - Temporal Patterns in the Abundance of a Critically Endangered Marsupial Relates to Disturbance by Roads and Agriculture. AB - The aim of this study was to investigate how landscape disturbance associated with roads, agriculture and forestry influenced temporal patterns in woylie (Bettongia penicillata) abundance before, during and after periods of rapid population change. Data were collected from an area of approximately 140,000 ha of forest within the Upper Warren region in south-western Australia. Woylie abundance was measured using cage trapping at 22 grid and five transect locations with varying degrees of landscape disturbance between 1994 and 2012. We found evidence that the distribution and abundance of woylies over time appears to be related to the degree of fragmentation by roads and proximity to agriculture. Sites furthest from agriculture supported a greater abundance of woylies and had slower rates of population decline. Sites with fewer roads had a greater abundance of woylies generally and a greater rate of increase in abundance after the implementation of invasive predator control. The results of this study suggest that landscape disturbance is less important at peak population densities, but during times of environmental and population change, sites less dissected by roads and agriculture better support woylie populations. This may be due to the role these factors play in increasing the vulnerability of woylies to introduced predators, population fragmentation, weed species invasion, mortality from road collisions or a reduction in available habitat. Strategies that reduce the impact of disturbance on woylie populations could include the rationalisation of forest tracks and consolidation of contiguous habitat through the acquisition of private property. Reducing the impact of disturbance in the Upper Warren region could improve the resilience of this critically important woylie population during future environmental change. PMID- 27501321 TI - Immunoproteasomes and immunotherapy-a smoking gun for lung cancer? AB - Lung cancer is the second most prevalent cancer in both women and men with some 221,200 new cases and 158,040 deaths reported in 2015. Almost 90% of these are non-small cell lung cancer (NSCLC) and these patients have a very poor prognosis. Recently a new treatment option for NSCLC appeared that strongly improved treatment responses-immunotherapy. Here we review the various forms of immunotherapy and how immune modification of proteasomes in lung cancer may support the immune system in controlling NSCLC. These immunoproteasomes then support recognition of NSCLC and may act as a biomarker for selecting responding patients to immunotherapy. PMID- 27501322 TI - High-risk neuroblastoma: challenges in management in low- and middle-income countries. PMID- 27501323 TI - Moving Parkinson care to the home. AB - In many ways, the care of individuals with Parkinson disease does not meet their needs. Despite the documented benefits of receiving care from clinicians with Parkinson disease expertise, many patients (if not most) do not. Moreover, current care models frequently require older individuals with impaired mobility, cognition, and driving ability to be driven by overburdened caregivers to large, complex urban medical centers. Moving care to the patient's home would make Parkinson disease care more patient-centered. Demographic factors, including aging populations, and social factors, such as the splintering of the extended family, will increase the need for home-based care. Technological advances, especially the ability to assess and deliver care remotely, will enable the transition of care back to the home. However, despite its promise, this next generation of home-based care will have to overcome barriers, including outdated insurance models and a technological divide. Once these barriers are addressed, home-based care will increase access to high quality care for the growing number of individuals with Parkinson disease. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27501324 TI - Selection of Reference Genes for Expression Study in Pulp and Seeds of Theobroma grandiflorum (Willd. ex Spreng.) Schum. AB - Cupuassu (Theobroma grandiflorum [Willd. ex Spreng.] Schum) is a species of high economic importance in Brazil with great potential at international level due to the multiple uses of both its seeds and pulp in the industry of sweets and cosmetics. For this reason, the cupuassu breeding program focused on the selection of genotypes with high pulp and seed quality-selection associated with the understanding of the mechanisms involved in fruit formation. Gene expression is one of the most used approaches related to such understanding. In this sense, quantitative real-time PCR (qPCR) is a powerful tool, since it rapidly and reliably quantifies gene expression levels across different experimental conditions. The analysis by qPCR and the correct interpretation of data depend on signal normalization using reference genes, i.e. genes presenting a uniform pattern of expression in the analyzed samples. Here, we selected and analyzed the expression of five genes from cupuassu (ACP, ACT, GAPDH, MDH, TUB) to be used as candidates for reference genes on pulp and seed of young, maturing and mature cupuassu fruits. The evaluation of the gene expression stability was obtained using the NormFinder, geNorm and BestKeeper programs. In general, our results indicated that the GAPDH and MDH genes constituted the best combination as reference genes to analyze the expression of cupuassu samples. To our knowledge, this is the first report of reference gene definition in cupuassu, and these results will support subsequent analysis related to gene expression studies in cupuassu plants subjected to different biotic or abiotic conditions as well as serve as a tool for diversity analysis based on pulp and seed quality. PMID- 27501325 TI - Metabolic resuscitation in sepsis: a necessary step beyond the hemodynamic? AB - Despite the advances made in monitoring and treatment of sepsis and septic shock, many septic patients ultimately develop multiple organ dysfunction (MODS) and die, suggesting that other players are involved in the pathophysiology of this syndrome. Mitochondrial dysfunction occurs early in sepsis and has a central role in MODS development. MODS severity and recovery of mitochondrial function have been associated with survival. In recent clinical and experimental investigations, mitochondrion-target therapy for sepsis and septic shock has been suggested to reduce MODS severity and mortality. This intervention, which might be named "metabolic resuscitation", would lead to improved mitochondrial activity afforded by pharmacological and nutritional agents. Of particular interest in this therapeutic strategy is thiamine, a water-soluble vitamin that plays an essential role in cellular energy metabolism. Critical illness associated with hypermetabolic states may predispose susceptible individuals to the development of thiamine deficiency, which is not usually identified by clinicians as a source of lactic acidosis. The protective effects of thiamine on mitochondrial function may justify supplementation in septic patients at risk of deficiency. Perspectives of supplementation with other micronutrients (ascorbic acid, tocopherol, selenium and zinc) and potential metabolic resuscitators [coenzyme Q10 (CoQ10), cytochrome oxidase (CytOx), L-carnitine, melatonin] to target sepsis induced mitochondrial dysfunction are also emerging. Metabolic resuscitation may probably be a safe and effective strategy in the treatment of septic shock in the future. However, until then, preliminary investigations should be replicated in further researches for confirmation. Better identification of groups of patients presumed to benefit clinically by a certain intervention directed to "mitochondrial resuscitation" are expected to increase driven by genomics and metabolomics. PMID- 27501326 TI - The presence of respiratory disorders in individuals with low back pain: A systematic review. AB - BACKGROUND: Inspiratory muscles, such as the diaphragm, play a key role in both respiration and spinal control. Therefore, diaphragm dysfunctions are often related to low back pain (LBP). However, few is known on the association between the presence of LBP and the presence of respiratory disorders (RD). OBJECTIVES: To perform a systematic review on the relation between RD and LBP. STUDY DESIGN: Systematic review. METHODS: Two reviewers searched on PubMed/MEDLINE for studies concerning LBP and RD, from 1950 up to January 2016. The search string consisted of the following key words: low back pain, dyspnea, respiratory problems, lung diseases, comorbidity, pulmonary disease, chronic obstructive, smoking, asthma, allergy, sinusitis, respiratory tract infection and hyperventilation. The aim was to evaluate a potential correlation, co-occurrence or causality between RD and LBP. RESULTS: A total of 16 articles were included. A significant correlation between the presence of LBP and the presence of RD such as dyspnea, asthma, different forms of allergy, and respiratory infections was found. No correlation was found between Chronic Obstructive Pulmonary Disease (COPD) and LBP, and no articles were found on the correlation between hyperventilation and LBP. CONCLUSIONS: This is the first study providing an overview of the literature on the relation between LBP and RD. Immunological, biomechanical, psychosocial and socio-economic factors might explain this correlation. Smoking is likely to contribute. Future studies must reveal the causative relationship. LEVEL OF EVIDENCE: Therapy, level 2a. PMID- 27501327 TI - Thin-Section Computed Tomography Manifestations During Convalescence and Long Term Follow-Up of Patients with Severe Acute Respiratory Syndrome (SARS). AB - BACKGROUND SARS is not only an acute disease, but also leads to long-term impaired lung diffusing capacity in some survivors. However, there is a paucity of data regarding long-term CT findings in survivors after SARS. The aim of this study was to assess the changes in lung function and lung thin-section computed tomography (CT) features in patients recovering from severe acute respiratory syndrome (SARS), especially the dynamic changes in ground-glass opacity (GGO). MATERIAL AND METHODS Clinical and radiological data from 11 patients with SARS were collected. The serial follow-up thin-section CTs were evaluated at 3, 6, and 84 months after SARS presentation. The distribution and predominant thin-section CT findings of lesions were evaluated. RESULTS The extent of the lesions on the CT scans of the 11 patients decreased at 6 and 84 months compared to 3 months. The number of segments involved on 84-month follow-up CTs was less than those at 6 months (P<0.05). The predominant thin-section CT manifestation at 84 months (intralobular and interlobular septal thickening) was different than that at 6 months, at which GGO was predominant. CONCLUSIONS During convalescence after SARS, GGO and intralobular and interlobular septal thickening were the main thin section CT manifestation. Intralobular and interlobular septal thickening predominated over GGO at 84 months. PMID- 27501328 TI - Graphene-Fe3 O4 as a magnetic solid-phase extraction sorbent coupled to capillary electrophoresis for the determination of sulfonamides in milk. AB - Graphene-Fe3 O4 nanoparticles were prepared using one-step solvothermal method and characterized by X-ray diffraction, FTIR spectroscopy, scanning electron microscopy, and vibrating sample magnetometry. The results demonstrated that Fe3 O4 nanoparticles were homogeneously anchored on graphene nanosheets. The as synthesized graphene-Fe3 O4 nanoparticles were employed as sorbent for magnetic solid-phase extraction of sulfonamides in milk prior to capillary electrophoresis analysis. The optimal capillary electrophoresis conditions were as follows: 60 mmol/L Na2 HPO4 containing 2 mmol/L ethylenediaminetetraacetic acid disodium salt and 24% v/v methanol as running buffer, separation voltage of 14 kV, and detection wavelength of 270 nm. The parameters affecting extraction efficiency including desorption solution, the amount of graphene-Fe3 O4 nanoparticles, extraction time, and sample pH were investigated in detail. Under the optimal conditions, good linearity (5-200 MUg/L) with correlation coefficients >=0.9910 was obtained. The limits of detection were 0.89-2.31 MUg/L. The relative standard deviations for intraday and interday analyses were 4.9-8.5 and 4.0-9.0%, respectively. The proposed method was successfully applied to the analysis of sulfonamides in milk samples with recoveries ranging from 62.7 to 104.8% and relative standard deviations less than 10.2%. PMID- 27501329 TI - Nuclear GSK3beta promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22. AB - Emerging evidence has shown that GSK3beta plays oncogenic roles in multiple tumour types; however, the underlying mechanisms remain largely unknown. Here, we show that nuclear GSK3beta is responsible for the accumulation of the histone demethylase KDM1A and critically regulates histone H3K4 methylation during tumorigenesis. GSK3beta phosphorylates KDM1A Ser683 upon priming phosphorylation of KDM1A Ser687 by CK1alpha. Phosphorylation of KDM1A induces its binding with and deubiquitylation by USP22, leading to KDM1A stabilization. GSK3beta- and USP22-dependent KDM1A stabilization is required for the demethylation of histone H3K4, thereby repressing BMP2, CDKN1A and GATA6 transcription, which results in cancer stem cell self-renewal and glioblastoma tumorigenesis. In human glioblastoma specimens, KDM1A levels are correlated with nuclear GSK3beta and USP22 levels. Furthermore, a GSK3 inhibitor, tideglusib, sensitizes tumour xenografts to chemotherapy in mice via KDM1A downregulation and improves survival. Our findings demonstrate that nuclear GSK3beta- and USP22-mediated KDM1A stabilization is essential for glioblastoma tumorigenesis. PMID- 27501330 TI - Early polysensitization is associated with allergic multimorbidity in PARIS birth cohort infants. AB - BACKGROUND: Profiles of allergic sensitization are poorly documented in infancy. Relations between early sensitization and allergic morbidity need to be clarified. METHODS: This study dealt with children involved in the Pollution and Asthma Risk: an Infant Study (PARIS), a population-based prospective birth cohort. Allergic sensitization to twelve food and four inhalant allergens was assessed at 18 months and defined by a specific immunoglobulin E (IgE) level >=0.35 kUA /l. Health data were collected by standardized questionnaires at 2 and 6 years. Early allergic profiles were identified by an unsupervised cluster analysis based on health data at 2 years and IgE measurements. Profiles were compared with regard to allergic morbidity and multimorbidity at 6 years. RESULTS: Sensitization to any allergen concerned 13.6% of infants. By cluster analysis, 1525 infants were grouped into three profiles: 89.2% not or rarely sensitized (only 3.7% of sensitized), 9.2% mainly sensitized to one or few allergens (45.2% of monosensitized and 45.9% of paucisensitized) and 1.6% all polysensitized. The prevalence of doctor-diagnosed asthma, rhinitis, eczema, food allergy and multimorbidity at 2 years increased from profile one to profile three (p-trend <0.001). At 6 years, symptoms of current asthma, rhinitis, eczema and multimorbidity were significantly more frequent in the last two profiles. CONCLUSIONS: This study highlights, as early as 18 months of age, three profiles of increasing severity with regard to allergic sensitization and diseases. These profiles also differ in terms of allergic morbidity at 6 years. Early sensitization can predict allergic multimorbidity in childhood, and in the case of early polysensitization, multimorbidity is more frequent as soon as infancy. PMID- 27501332 TI - Psychophysical Tracking Method to Measure Taste Preferences in Children and Adults. AB - The Monell two-series, forced-choice, paired-comparison tracking method provides a reliable measure of sweet taste preferences from childhood to adulthood. The method, which is identical for children, adolescents, and adults, is of short duration (< 15 min), does not rely on sustained attention or place demands on memory (which would yield spurious age differences), and minimizes the impact of language development, making this method amenable to the cognitive limitations of pediatric populations. In this whole-mouth tasting method, subjects are asked to taste (without swallowing) pairs of solutions of different sucrose concentrations and to point to the solution they prefer. Each subsequent pair contains the participant's preceding preferred concentration and an adjacent stimulus concentration. The procedure continues until the subject chooses either a given concentration of sucrose when paired with both a higher and a lower concentration, or the highest or lowest concentration two consecutive times. Subjects are prevented from reaching response criteria on the basis of first or second position bias by the two-series design of the method, which counterbalances the order of solution presentation within each pair between the series (the weaker concentration is presented first in Series 1, second in Series 2). The geometric mean of the two sucrose concentrations chosen in Series 1 and 2 is an estimate of the participant's most preferred level of sucrose. Sucrose preference as determined with this laboratory-based measure has been shown to be associated with preference for sugars in foods and beverages and with taste receptor genotype, family history of alcoholism, and race/ethnicity, as well as depressive symptomatology among pediatric populations. The method has real-world relevance and has been applied to determine most preferred level of other tastes (e.g., salt), making it a valuable psychophysical tool. PMID- 27501331 TI - Peperomin E reactivates silenced tumor suppressor genes in lung cancer cells by inhibition of DNA methyltransferase. AB - Advanced lung cancer has poor prognosis owing to its low sensitivity to current chemotherapy agents. Therefore, discovery of new therapeutic agents is urgently needed. In this study, we investigated the antitumor effects of peperomin E, a secolignan isolated from Peperomia dindygulensis, a frequently used Chinese folk medicine for lung cancer treatment. The results indicate that peperomin E has antiproliferative effects, promoting apoptosis and cell cycle arrest in non-small cell lung cancer (NSCLC) cell lines in a dose-dependent manner, while showing lower toxicity against normal human lung epidermal cells. Peperomin E inhibited tumor growth in A549 xenograft BALB/c nude mice without significant secondary adverse effects, indicating that it may be safely used to treat NSCLC. Furthermore, the mechanisms underlying the anticancer effects of peperomin E have been investigated. Using an in silico target fishing method, we observed that peperomin E directly interacts with the active domain of DNA methyltransferase 1 (DNMT1), potentially affecting its genome methylation activity. Subsequent experiments verified that peperomin E decreased DNMT1 activity and expression, thereby decreasing global methylation and reactivating the epigenetically silenced tumor suppressor genes including RASSF1A, APC, RUNX3, and p16INK4, which in turn activates their mediated pro-apoptotic and cell cycle regulatory signaling pathways in lung cancer cells. The observations herein report for the first time that peperomin E is a potential chemotherapeutic agent for NSCLC. The anticancer effects of peperomin E may be partly attributable to its ability to demethylate and reactivate methylation-silenced tumor suppressor genes through direct inhibition of the activity and expression of DNMT1. PMID- 27501333 TI - Preoperative navigated transcranial magnetic stimulation in patients with motor eloquent lesions with emphasis on metastasis. AB - Navigated transcranial magnetic stimulation (nTMS) is a frequently used, non invasive method to map the motor cortex. It is of great value in the preoperative workup of patients that suffer from motor eloquent brain lesions. Here, we present a single-center experience using preoperative nTMS in cortical motor eloquent lesions with emphasis on metastasis. All patients that underwent preoperative nTMS between June 2013 and January 2016 were evaluated. A total of 61 patients underwent nTMS before undergoing surgery for a motor eloquent brain lesion. Patients suffered from cerebral metastasis (23), glioblastoma (16), high grade glioma WHO III (4), low grade glioma WHO II (4), lymphoma (2), meningioma (8), cavernous hemangioma (3), or arteriovenous malformation (1). Thirty patients (49.2%) presented with a preoperative motor deficit. One week after surgery, paresis had resolved or improved in 56.7% of the patients. Out of the patients with postoperative paresis, 89.5% experienced an improvement of motor status at follow-up. All metastatic lesions were completely resected compared to 78.9% of non-metastatic lesions (P = 0.02). Only 4.3% of patients with a metastatic lesion, but 26.3% of patients with a non-metastatic lesion experienced deterioration of motor function after surgery (P = 0.04). Preoperative nTMS is suitable for mapping of a variety of motor eloquent brain lesions resulting in favorable neurological outcome. Particularly in metastatic motor eloquent lesion, motor function appears to be preserved after surgery. Clin. Anat. 29:925-931, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27501335 TI - Highly efficient phosphorescent materials based on Ir(iii) complexes-grafted on a polyhedral oligomeric silsesquioxane core. AB - A new iridium(iii) complex containing a coumarin derivative as the cyclometalated ligand (L) and a carbazole-functionalized beta-diketonate (Cz-acac-allyl) as the ancillary ligand, namely, Ir(iii) bis(3-(pyridin-2-yl)coumarinato-N,C(4))(1-(9 butyl-9H-carbazol-3-yl)hept-6-ene-1,3-dionato-O,O) [Ir(L)2(Cz-acac-allyl)], was firstly synthesized as the emissive iridium(iii) complex. Then three new phosphorescent polyhedral oligomeric silsesquioxane (POSS) materials, consisting of the emissive Ir(iii) complex and carbazole moieties covalently attached to a polyhedral oligomeric silsesquioxane (POSS) core were successfully synthesized by hydrosilylation reaction in the presence of platinum(0)-1,3-divinyl-1,1,3,3 tetramethyldisiloxane (Pt-dvs) as the catalyst. These phosphorescent POSS materials offer many advantages including amorphous properties, good thermal stabilities, and good solubility in common solvents, and high purity via column chromatography. The photoluminescence spectra of the POSS materials in solution and in the solid state indicate a reduction in the degrees of interactions among the Ir(iii) complex units and concentration quenching due to the bulky POSS core. Solution processed light-emitting devices based on these phosphorescent POSS materials exhibit a maximum external quantum efficiency (EQE) of 9.77%. PMID- 27501334 TI - Endocannabinoid signaling enhances visual responses through modulation of intracellular chloride levels in retinal ganglion cells. AB - Type 1 cannabinoid receptors (CB1Rs) are widely expressed in the vertebrate retina, but the role of endocannabinoids in vision is not fully understood. Here, we identified a novel mechanism underlying a CB1R-mediated increase in retinal ganglion cell (RGC) intrinsic excitability acting through AMPK-dependent inhibition of NKCC1 activity. Clomeleon imaging and patch clamp recordings revealed that inhibition of NKCC1 downstream of CB1R activation reduces intracellular Cl(-) levels in RGCs, hyperpolarizing the resting membrane potential. We confirmed that such hyperpolarization enhances RGC action potential firing in response to subsequent depolarization, consistent with the increased intrinsic excitability of RGCs observed with CB1R activation. Using a dot avoidance assay in freely swimming Xenopus tadpoles, we demonstrate that CB1R activation markedly improves visual contrast sensitivity under low-light conditions. These results highlight a role for endocannabinoids in vision and present a novel mechanism for cannabinoid modulation of neuronal activity through Cl(-) regulation. PMID- 27501336 TI - Nonbacterial Thrombotic Endocarditis: Pathogenesis, Diagnosis, and Management. AB - Nonbacterial thrombotic endocarditis (NBTE), formerly known as marantic endocarditis, is a potentially overlooked condition that involves the formation of sterile, fibrin vegetations on heart valve leaflets. Often confused with classic infective endocarditis during its early stages, NBTE can lead to valvular dysfunction, heart failure, and systemic embolization when unchecked. The pathogenesis is not entirely clear but involves a preexisting hypercoagulable state. Diagnosis requires ruling out infection and establishing the presence of valvular vegetations using echocardiography. Therapy for NBTE includes treating the underlying disease, systemic anticoagulation and surgical intervention. PMID- 27501337 TI - Standardising anaesthesia for hip fracture surgery. PMID- 27501338 TI - Combination gemcitabine/cisplatin therapy and ERCC1 expression for resected pancreatic adenocarcinoma: Results of a Phase II prospective trial. AB - BACKGROUND: Standard adjuvant treatment for pancreatic adenocarcinoma (PDAC) is gemcitabine [Gem(CONKO-001: Gem vs. placebo DFS:13.4 vs. 6.7 mo; P < 0.001; OS:22.8 vs. 20.2 mo; P = 0.01)]. Addition of cisplatin (Cis) to Gem has resulted in increased PFS for advanced and metastatic disease, which may be predicted by low expression of excision repair cross-complementing group-1 (ERCC1), the key enzyme in nucleotide excision repair. This Phase II prospective trial assesses outcomes of patients treated with adjuvant Gem/Cis, stratifying results by tumor ERCC1 expression. METHODS: Patients with resected PDAC were enrolled (2010-2013) and received Gem(1,000 mg/m(2) )/Cis(50 mg/m(2) ). Tumor ERCC1 expression was evaluated by immunohistochemistry and dichotomized into low or high expression. Primary outcomes were recurrence-free and overall survival (RFS/OS). RESULTS: Of 22 pts, 16(73%) were Stage IIB, 5(23%) Stage IIA, and 1(4%) Stage IA. Grade 3/4 toxicity occurred in 13 pts (59%); neutropenia was most common (n = 9;41%). Median follow-up was 37.5 months. Median RFS was 16.7 mo; OS was 35.5 mo. Low ERCC1 (n = 15;75%) compared to high ERCC1 (n = 5;25%) was not associated with improved RFS (12.4 vs. 16.7 mo; P = 0.68) or OS (Median not reached vs. 21.6 mo; P = 0.22). CONCLUSIONS: Adjuvant Gem/Cis is feasible in patients with resected pancreatic adenocarcinoma. RFS and OS for Gem/Cis appear promising compared to historic control. Tumor ERCC1 expression can be reliably evaluated, and low expression is present in most patients. J. Surg. Oncol. 2016;114:336-341. (c) 2016 Wiley Periodicals, Inc. PMID- 27501339 TI - Bisphosphonate use and the risk of endometrial cancer: a meta-analysis of observational studies. AB - BACKGROUND: The association of bisphosphonate use and the risk of endometrial cancer is still unclear. No meta-analysis was conducted to review the evidence concerning this topic. METHODS: Relevant studies were identified through PubMed and EMBASE and the Cochrane Library databases. The adjusted relative risk (RR) or odds ratios were determined using a fixed effects or random effects model, depending on the overall heterogeneity. RESULTS: Seven studies, including four cohort studies and three case-control studies, met the method criteria and were included. The random effects model showed a significant reduction in the risk association between bisphosphonate use and endometrial cancer incidence (RR 0.75, 95%CI 0.60-0.94, p = 0.064, I2 = 49.6%). A significantly protective effect was observed with the use of bisphosphonate for more than 1 year, and we found a statistically significant risk reduction with the use of bisphosphonate for more than 1 to 3 years (RR 0.58, 95%CI 0.47-0.72) and for more than 3 years (RR 0.44, 95%CI 0.28-0.70). However, with the use of bisphosphonate for less than 1 year (RR 0.92, 95%CI 0.64-1.34), we found no protective effect against endometrial cancer. CONCLUSIONS: We found that the use of bisphosphonate was significantly associated with a 25% risk reduction in the incidence of endometrial cancer in the overall analysis. Furthermore, the use of bisphosphonate for more than 1 year but not less than 1 year may have a more beneficial effect on endometrial cancer risk. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27501340 TI - Region of Nipah virus C protein responsible for shuttling between the cytoplasm and nucleus. AB - Nipah virus (NiV) causes severe encephalitis in humans, with high mortality. NiV nonstructural C protein (NiV-C) is essential for its pathogenicity, but its functions are unclear. In this study, we focused on NiV-C trafficking in cells and found that it localizes predominantly in the cytoplasm but partly in the nucleus. An analysis of NiV-C mutants showed that amino acids 2, 21-24 and 110 139 of NiV-C are important for its localization in the cytoplasm. Inhibitor treatment indicates that the nuclear export determinant is not a classical CRM1 dependent nuclear export signal. We also determined that amino acids 60-75 and 72 75 were important for nuclear localization of NiV-C. Furthermore, NiV-C mutants that had lost their capacity for nuclear localization inhibited the interferon (IFN) response more strongly than complete NiV-C. These results indicate that the IFN-antagonist activity of NiV-C occurs in the cytoplasm. PMID- 27501341 TI - Label-free fluorescent enzymatic assay of citrate synthase by CoA-Au(I) co ordination polymer and its application in a multi-enzyme logic gate cascade. AB - Citrate synthase (CS) is one of the key metabolic enzymes in the Krebs tricarboxylic acid (TCA) cycle. It regulates energy generation in mitochondrial respiration by catalysing the reaction between oxaloacetic acid (OAA) and acetyl coenzyme A (Ac-CoA) to generate citrate and coenzyme A (CoA). CS has been shown to be a biomarker of neurological diseases and various kinds of cancers. Here, a label-free fluorescent assay has been developed for homogeneously detecting CS and its inhibitor based on the in situ generation of CoA-Au(I) co-ordination polymer (CP) and the fluorescence signal-on by SYBR Green II-stained CoA-Au(I) CP. Because of the unique property of the CoA-Au(I) CP, this CS activity assay method could achieve excellent selectivity and sensitivity, with a linear range from 0.0033 U/MUL to 0.264 U/MUL and a limit of detection to be 0.00165 U/MUL. Meanwhile, this assay method has advantages of being facile and cost effective with quick detection. Moreover, based on this method, a biomimetic logic system was established by rationally exploiting the cascade enzymatic interactions in TCA cycle for chemical information processing. In the TCA cycle-derived logic system, an AND-AND-AND-cascaded gate was rigorously operated step by step in one pot, and is outputted by a label-free fluorescent signal with visualized readout. PMID- 27501342 TI - Activatable molecular MRI nanoprobe for tumor cell imaging based on gadolinium oxide and iron oxide nanoparticle. AB - Activatable molecular MRI nanoprobe for intracellular GSH sensing was designed. As an alternative to "always on" nanoprobe, activatable imaging nanoprobes which are designed to amplify or boost imaging signals only in response to the targets have attracted more and more attention. In this paper, we designed a novel activatable molecular magnetic resonance imaging (MRI) nanoprobe for tumor cell recognization based on a MRI signal variation induced by the distance change between T1 and T2 contrast agents (CAs) in the presence of glutathione (GSH). To achieve this aim, carboxyl group functionalized iron oxide nanoparticles (Fe3O4 NPs) and polyethylene glycol-coated gadolinium oxide (PEG-Gd2O3) NPs as T2 and T1 MRI CA were connected by cystamine which contains a disulfide linkage. Transmission electron microscopic (TEM), X-ray photoelectron spectroscopy (XPS), energy dispersive spectrometer (EDS), fourier transform infrared spectroscopy (FT IR), mass spectra and (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) were introduced for their characterizations. The formation of Fe3O4-cystamine Gd2O3 (Fe3O4-SS-Gd2O3) nanocomplex resulted in a quenched T1 signal due to the near proximity of PEG-Gd2O3 NPs to Fe3O4 NPs and a "light-up" T1 signal with the cleavage of disulfide bond in the presence of GSH. These results provide not only an easy way to realize MRI of tumor cells based on the overexpressed intracellular GSH level, but also a new insight for the design of activatable MRI nanoprobe. PMID- 27501343 TI - Biomechanical comparison of sinus floor elevation and alternative treatment methods for dental implant placement. AB - OBJECTIVE: In this study, we compared the success of sinus lifting and alternative treatment methods in applying dental implants in cases lacking adequate bone due to pneumatization of the maxillary sinus. METHODS: In a computer environment, 3D models were created using computerized tomography data from a patient. Additionally, implants and abutments were scanned at the macroscopic level, and the resulting images were transferred to the 3D models. Five different models were examined: a control model, lateral sinus lifting (LSL), short dental implant placement (SIP), tilted implant placement (TIP) and distal prosthetic cantilever (DC) use. Vertical and oblique forces were applied in each model. The compression, tension and von Mises stresses in each model were analyzed by implementing a finite element analysis method. RESULTS: In our study, the LSL method was observed to be the closest to the control model. The TIP model showed high stress values under conditions of oblique forces but showed successful results under conditions of vertical forces, and the opposite results were observed in the SIP model. The DC model provided the least successful results among all models. CONCLUSIONS: Based on the results of this study, the LSL method should be the first choice among treatment options. Considering its successful results under conditions of oblique forces, the SIP method may be preferable to the TIP method. In contrast, every effort should be made to avoid the use of DCs. PMID- 27501344 TI - Older persons' experiences of what influences their vitality - a study of 65- and 75-year-olds in Finland and Sweden. AB - Throughout the world, life expectancy has noticeably increased during the past decade, and health promotive initiatives for older persons will therefore become ever more important. During the past few years, interest in what constitutes the source of health for human beings has markedly increased in health science research. An interesting and relatively unresearched domain is what provides older persons the strength and energy to look forward and what positively or negatively influences older persons' vitality. The aim of the study was to explore and describe older persons' vitality and their subjective experiences of what influences their vitality, despite disease and suffering. The study has an explorative and descriptive design. A comprehensive questionnaire including two open-ended questions about vitality was sent to 4927 older persons aged 65 and 75, and a total of 2579 responded to the open-ended questions. Qualitative content analyses were used. A safe and confirming communion, meaningful activities, an optimal state of health and an inner strength were important sources of vitality. Ageing that includes illness or a restricted life, happenings in the world and in one's close environment that threaten inner meaningfulness, and mental burdens that give rise to a feeling of hopelessness or depression decrease vitality. Vitality is an important health resource for 65- and 75-year-olds in that it influences a person's longing for life, love and meaning. Accordingly, it is of fundamental importance that Registered Nurses and other healthcare personnel strengthen older persons' vitality during the ageing process. By taking into consideration that which positively vs. negatively affects the vitality of each unique person, healthcare personnel can strengthen each older person's health resources and attempt to minimise and limit what negatively influences said person's vitality. PMID- 27501346 TI - Discovery of a novel HLA-DRB1*09 variant, HLA-DRB1*09:28, in a Taiwanese individual. AB - One nucleotide substitution at residue 332 of HLA-DRB1*09:01:02 results in a novel allele, HLA-DRB1*09:28. PMID- 27501345 TI - Selective Enhancement of Dopamine Release in the Ventral Pallidum of Methamphetamine-Sensitized Mice. AB - Drugs of abuse induce sensitization, which is defined as enhanced response to additional drug following a period of withdrawal. Sensitization occurs in both humans and animal models of drug reinforcement and contributes substantially to the addictive nature of drugs of abuse, because it is thought to represent enhanced motivational wanting for drug. The ventral pallidum, a key member of the reward pathway, contributes to behaviors associated with reward, such as sensitization. Dopamine inputs to the ventral pallidum have not been directly characterized. Here we provide anatomical, neurochemical, and behavioral evidence demonstrating that dopamine terminals in the ventral pallidum contribute to reward in mice. We report subregional differences in dopamine release, measured by ex vivo fast-scan cyclic voltammetry: rostral ventral pallidum exhibits increased dopamine release and uptake compared with caudal ventral pallidum, which is correlated with tissue expression of dopaminergic proteins. We then subjected mice to a methamphetamine-sensitization protocol to investigate the contribution of dopaminergic projections to the region in reward related behavior. Methamphetamine-sensitized animals displayed a 508% and 307% increase in baseline dopamine release in the rostral and caudal ventral pallidum, respectively. Augmented dopamine release in the rostral ventral pallidum was significantly correlated with sensitized locomotor activity. Moreover, this presynaptic dopaminergic plasticity occurred only in the ventral pallidum and not in the ventral or dorsal striatum, suggesting that dopamine release in the ventral pallidum may be integrally important to drug-induced sensitization. PMID- 27501347 TI - Microwave-assisted cleavage of Alloc and Allyl Ester protecting groups in solid phase peptide synthesis. AB - Orthogonal protection of amino acid side chains in solid phase peptide synthesis allows for selective deprotection of side chains and the formation of cyclic peptides on resin. Cyclizations are useful as they may improve the activity of the peptide or improve the metabolic stability of peptides in vivo. One cyclization method often used is the formation of a lactam bridge between an amine and a carboxylic acid. It is desirable to perform the cyclization on resin as opposed to in solution to avoid unwanted side reactions; therefore, a common strategy is to use -Alloc and -OAllyl protecting groups as they are compatible with Fmoc solid phase peptide synthesis conditions. Alloc and -OAllyl may be removed using Pd(PPh3 )4 and phenylsilane in DMF. This method can be problematic as the reaction is most often performed at room temperature under argon gas. It is not usually done at higher temperatures because of the fear of poisoning the palladium catalyst. As a result, the reaction is long and reagent-intensive. Herein, we report the development of a method in which the -Alloc/-OAllyl groups are removed using a microwave synthesizer under atmospheric conditions. The reaction is much faster, allowing for the removal of the protecting groups before the catalyst is oxidized, as well as being less reagent-intensive. This method of deprotection was tested using a variety of amino acid sequences and side chain protecting groups, and it was found that after two 5-min deprotections at 38 degrees C, all -Alloc and -OAllyl groups were removed with >98% purity. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27501348 TI - Cobalt(II) complexes of sparfloxacin: Characterization, structure, antimicrobial activity and interaction with DNA and albumins. AB - The cobalt(II) complexes with the quinolone sparfloxacin (Hsf) in the absence or presence of the nitrogen-donor heterocyclic ligands 2,2'-bipyridine (bipy), 1,10 phenanthroline (phen) or 2,2'-bipyridylamine (bipyam) were prepared and characterized physicochemically and spectroscopically. The crystal structures of complexes [Co(sf)2(bipy)]?3MeOH?2H2O and [Co(sf)2(phen)]?4MeOH were determined by X-ray crystallography. The antimicrobial activity of the complexes was tested against four different microorganisms (Escherichia coli, Xanthomonas campestris, Staphylococcus aureus and Bacillus subtilis) and was found similar or higher than that of free Hsf. The binding of the complexes to calf-thymus DNA was monitored by UV-vis spectroscopy and DNA-viscosity measurements and indirectly by competitive studies with ethidium bromide; intercalation is suggested as the most possible interaction mode. Fluorescence emission spectroscopy was used to evaluate the interaction of the complexes with human or bovine serum albumin and the corresponding binding constants were determined. PMID- 27501349 TI - TbLOK1/ATOM19 is a novel subunit of the noncanonical mitochondrial outer membrane protein translocase of Trypanosoma brucei. AB - TbLOK1 has previously been characterized as a trypanosomatid-specific mitochondrial outer membrane protein whose ablation caused a collapse of the mitochondrial network, disruption of the membrane potential and loss of mitochondrial DNA. Here we show that ablation of TbLOK1 primarily abolishes mitochondrial protein import, both in vivo and in vitro. Co-immunprecipitations together with blue native gel analysis demonstrate that TbLOK1 is a stable and stoichiometric component of the archaic protein translocase of the outer membrane (ATOM), the highly diverged functional analogue of the TOM complex in other organisms. Furthermore, we show that TbLOK1 together with the other ATOM subunits forms a complex functional network where ablation of individual subunits either causes degradation of a specific set of other subunits or their exclusion from the ATOM complex. In summary these results establish that TbLOK1 is an essential novel subunit of the ATOM complex and thus that its primary molecular function is linked to mitochondrial protein import across the outer membrane. The previously described phenotypes can all be explained as consequences of the lack of mitochondrial protein import. We therefore suggest that in line with the nomenclature of the ATOM complex subunits, TbLOK1 should be renamed to ATOM19. PMID- 27501350 TI - Costs of resistance and correlational selection in the multiple-herbivore community of Solanum carolinense. PMID- 27501353 TI - Response to the Article "Multi-Ethnic Attitudes Toward Physician-Assisted Death in California and Hawai'i:" Selection of Respondents Creates Fatally Flawed Study. PMID- 27501352 TI - Eculizumab Therapy for Chronic Antibody-Mediated Injury in Kidney Transplant Recipients: A Pilot Randomized Controlled Trial. AB - We hypothesized that de novo donor-specific antibody (DSA) causes complement dependent endothelial cell injury in kidney transplants, as assessed by expression of endothelial cell-associated transcripts (ENDATs), that may be attenuated through complement inhibition. In total, 15 participants (five control, 10 treatment) with DSA and deteriorating renal function were enrolled. The treatment group received 6 mo of eculizumab followed by 6 mo of observation, whereas controls were observed. The primary end point was percentage change in estimated GFR (eGFR) trajectory over the treatment period. The treatment group had an improved eGFR trajectory versus control, based on our predetermined two sided 0.10 significance level (p = 0.09). Within-subject analysis of treated participants at 6-mo intervals did not show significant change (p = 0.60). Modeling C1q status showed that C1q-positive patients had significantly higher mean eGFR than patients with negative C1q (p = 0.04). Biopsies revealed elevated renal ENDATs in most participants, but ENDATs were not reduced with complement inhibition. Our data suggest that eculizumab treatment may stabilize kidney function in patients with chronic persistent DSA based on our pilot a priori significance threshold. ENDAT expression predicative of acute humoral injury is not reduced with complement inhibition in this chronic setting. Further studies will be necessary to determine which patients may benefit from eculizumab. PMID- 27501351 TI - Divergence in Ubiquitin Interaction and Catalysis among the Ubiquitin-Specific Protease Family Deubiquitinating Enzymes. AB - Deubiquitinating enzymes (DUBs) are responsible for reversing mono- and polyubiquitination of proteins and play essential roles in numerous cellular processes. Close to 100 human DUBs have been identified and are classified into five families, with the ubiquitin-specific protease (USP) family being the largest (>50 members). The binding of ubiquitin (Ub) to USP is strikingly different from that observed for the DUBs in the ubiquitin C-terminal hydrolase (UCH) and ovarian tumor domain protease (OTU) families. We generated a panel of mutant ubiquitins and used them to probe the ubiquitin's interaction with a number of USPs. Our results revealed a remarkable divergence of USP-Ub interactions among the USP catalytic domains. Our double-mutant cycle analysis targeting the ubiquitin residues located in the tip, the central body, and the tail of ubiquitin also demonstrated different crosstalk among the USP-Ub interactions. This work uncovered intriguing divergence in the ubiquitin-binding mode in the USP family DUBs and raised the possibility of targeting the ubiquitin binding hot spots on USPs for selective inhibition of USPs by small molecule antagonists. PMID- 27501354 TI - FTY720P inhibits hepatic Na(+)-K(+) ATPase via S1PR2 and PGE2. AB - Sphingosine-1-phosphate (S1P) was found previously to inhibit Na(+)-K(+) ATPase in HepG2 cells. Whether fingolimod (FTY720), a S1P receptor (S1PR) agonist, similarly inhibits the ATPase is a question that needs to be addressed. The aim of this work was to study the effect of FTY720P, the active form of the drug, on the activity of Na(+)-K(+) ATPase in HepG2 cells and determine its mechanism of action. The activity of the ATPase was assayed by measuring the amount of inorganic phosphate liberated in the presence and the absence of ouabain. FTY720 P (7.5 nmol/L, 15 min) significantly reduced the activity of the ATPase. This effect disappeared completely in the presence of JTE-013, which is a specific blocker of sphingosine-1-phosphate receptor 2 (S1PR2), as well as in the presence of calphostin and indomethacin, which are inhibitors of protein kinase C (PKC) and COX-2, respectively. The effect of FTY720P was mimicked by prostaglandin E2 (PGE2) and PMA, but abrogated by NF-kappaB inhibition. When NF-kappaB was inhibited, the effect of exogenous PGE2 still appeared, but that of PMA did not manifest, suggesting that NF-kappaB is upstream of PGE2 and downstream of PKC. It was concluded that FTY720P activates via S1PR2, PKC, and NF-kappaB. The latter induces PGE2 generation and inhibits Na(+)-K(+) ATPase. PMID- 27501355 TI - A Simple Dewar/Cryostat for Thermally Equilibrating Samples at Known Temperatures for Accurate Cryogenic Luminescence Measurements. AB - The design and operation of a simple liquid nitrogen Dewar/cryostat apparatus based upon a small fused silica optical Dewar, a thermocouple assembly, and a CCD spectrograph are described. The experiments for which this Dewar/cryostat is designed require fast sample loading, fast sample freezing, fast alignment of the sample, accurate and stable sample temperatures, and small size and portability of the Dewar/cryostat cryogenic unit. When coupled with the fast data acquisition rates of the CCD spectrograph, this Dewar/cryostat is capable of supporting cryogenic luminescence spectroscopic measurements on luminescent samples at a series of known, stable temperatures in the 77-300 K range. A temperature dependent study of the oxygen quenching of luminescence in a rhodium(III) transition metal complex is presented as an example of the type of investigation possible with this Dewar/cryostat. In the context of this apparatus, a stable temperature for cryogenic spectroscopy means a luminescent sample that is thermally equilibrated with either liquid nitrogen or gaseous nitrogen at a known measureable temperature that does not vary (DeltaT < 0.1 K) during the short time scale (~1-10 sec) of the spectroscopic measurement by the CCD. The Dewar/cryostat works by taking advantage of the positive thermal gradient dT/dh that develops above liquid nitrogen level in the Dewar where h is the height of the sample above the liquid nitrogen level. The slow evaporation of the liquid nitrogen results in a slow increase in h over several hours and a consequent slow increase in the sample temperature T over this time period. A quickly acquired luminescence spectrum effectively catches the sample at a constant, thermally equilibrated temperature. PMID- 27501357 TI - Are We All in the Same Boat? The Role of Perceptual Distance in Organizational Health Interventions. AB - The study investigates how agreement between leaders' and their team's perceptions influence intervention outcomes in a leadership-training intervention aimed at improving organizational learning. Agreement, i.e. perceptual distance was calculated for the organizational learning dimensions at baseline. Changes in the dimensions from pre-intervention to post-intervention were evaluated using polynomial regression analysis with response surface analysis. The general pattern of the results indicated that the organizational learning improved when leaders and their teams agreed on the level of organizational learning prior to the intervention. The improvement was greatest when the leader's and the team's perceptions at baseline were aligned and high rather than aligned and low. The least beneficial scenario was when the leader's perceptions were higher than the team's perceptions. These results give insights into the importance of comparing leaders' and their team's perceptions in intervention research. Polynomial regression analyses with response surface methodology allow three-dimensional examination of relationship between two predictor variables and an outcome. This contributes with knowledge on how combination of predictor variables may affect outcome and allows studies of potential non-linearity relating to the outcome. Future studies could use these methods in process evaluation of interventions. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27501356 TI - Neural Correlates and Connectivity Underlying Stress-Related Impulse Control Difficulties in Alcoholism. AB - BACKGROUND: Stress triggers impulsive and addictive behaviors, and alcoholism has been frequently associated with increased stress sensitivity and impulse control problems. However, neural correlates underlying the link between alcoholism and impulsivity in the context of stress in patients with alcohol use disorders (AUD) have not been well studied. METHODS: This study investigated neural correlates and connectivity patterns associated with impulse control difficulties in abstinent AUD patients. Using functional magnetic resonance imaging, brain responses of 37 AUD inpatients, and 37 demographically matched healthy controls were examined during brief individualized imagery trials of stress, alcohol cue, and neutral-relaxing conditions. Stress-related impulsivity was measured using a subscale score of impulse control problems from Difficulties in Emotion Regulation Scale. RESULTS: Impulse control difficulties in AUD patients were significantly associated with hypo-active response to stress in the ventromedial prefrontal cortex (VmPFC), right caudate, and left lateral PFC (LPFC) compared to the neutral condition (p < 0.01, whole-brain corrected). These regions were used as seed regions to further examine the connectivity patterns with other brain regions. With the VmPFC seed, AUD patients showed reduced connectivity with the anterior cingulate cortex compared to controls, which are core regions of emotion regulation, suggesting AUD patients' decreased ability to modulate emotional response under distressed state. With the right caudate seed, patients showed increased connectivity with the right motor cortex, suggesting increased tendency toward habitually driven behaviors. With the left LPFC seed, decreased connectivity with the dorsomedial PFC (DmPFC), but increased connectivity with sensory and motor cortices were found in AUD patients compared to controls (p < 0.05, whole-brain corrected). Reduced connectivity between the left LPFC and DmPFC was further associated with increased stress-induced anxiety in AUD patients (p < 0.05, with adjusted Bonferroni correction). CONCLUSIONS: Hypo active response to stress and altered connectivity in key emotion regulatory regions may account for greater stress-related impulse control problems in alcoholism. PMID- 27501358 TI - Potential Corticomotor Plasticity in Those with and without Chronic Ankle Instability. AB - INTRODUCTION: Quantifying corticomotor alterations is important to understand the neurophysiological mechanisms that likely contribute to the neuromuscular control deficits observed in patients with chronic ankle instability (CAI). Corticomotor output mapping provides further insight into the changes within the motor cortex and identifies potential changes in the area of the motor cortex associated with selected muscles. Therefore, this investigation compared the corticomotor map output for the fibularis longus (FL) muscle in patients with and without CAI. METHODS: Eighteen CAI patients and 16 healthy controls (HC) volunteered. Transcranial magnetic stimulation was used to map the motor cortex's representation of the FL. The normalized average of three motor evoked potentials at 100% of active motor threshold intensity was recorded for each scalp site on a 6 * 6 cm grid. Corticomotor output map was compared between groups through 1) the size of the corticomotor map area, 2) the volume of the corticomotor map, and 3) the location of cortical representation. Independent t-tests were used to assess group differences in each mapping outcome variable. Cohen's d effect sizes along with 95% confidence intervals were calculated using the pooled SD values. RESULTS: CAI patients exhibited less map volume (P = 0.018, CAI = 8.2 +/- 3.2 cm mV vs HC = 11.3 +/- 3.9 cm mV) and map area (P = 0.046, CAI = 12.8 +/- 6.0 cm vs HC: 17.4 +/- 6.9 cm) compared with HC. CONCLUSIONS: The smaller map area and volume suggest a more concentrated area of neurons communicating with the FL muscle in patients with CAI. Consequently, motor cortical cells on the border of the FL excitation area are less committed to the proper function of the FL muscle and may be recruited by other surrounding areas. This may explain altered movement strategies that lead to ankle reinjury. PMID- 27501359 TI - Lower Extremity Stiffness Changes after Concussion in Collegiate Football Players. AB - PURPOSE: Recent research indicates that a concussion increases the risk of musculoskeletal injury. Neuromuscular changes after concussion might contribute to the increased risk of injury. Many studies have examined gait postconcussion, but few studies have examined more demanding tasks. This study compared changes in stiffness across the lower extremity, a measure of neuromuscular function, during a jump-landing task in athletes with a concussion (CONC) to uninjured athletes (UNINJ). METHODS: Division I football players (13 CONC and 26 UNINJ) were tested pre- and postseason. A motion capture system recorded subjects jumping on one limb from a 25.4-cm step onto a force plate. Hip, knee, and ankle joint stiffness were calculated from initial contact to peak joint flexion using the regression line slopes of the joint moment versus the joint angle plots. Leg stiffness was (peak vertical ground reaction force [PVGRF]/lower extremity vertical displacement) from initial contact to peak vertical ground reaction force. All stiffness values were normalized to body weight. Values from both limbs were averaged. General linear models compared group (CONC, UNINJ) differences in the changes of pre- and postseason stiffness values. RESULTS: Average time from concussion to postseason testing was 49.9 d. The CONC group showed an increase in hip stiffness (P = 0.03), a decrease in knee (P = 0.03) and leg stiffness (P = 0.03), but no change in ankle stiffness (P = 0.65) from pre- to postseason. CONCLUSION: Lower extremity stiffness is altered after concussion, which could contribute to an increased risk of lower extremity injury. These data provide further evidence of altered neuromuscular function after concussion. PMID- 27501360 TI - High-Speed Cycling Intervention Improves Rate-Dependent Mobility in Older Adults. AB - PURPOSE: The aim was to determine the feasibility of a 6-wk speed-based exercise program that could be used to initiate new exercise behaviors and to improve rapid movement in older adults approaching frailty. METHODS: The intervention group included 14 older adults (3 males and 11 females; mean +/- SD, age = 70 +/- 7.6 yr, height = 1.6 +/- 0.11 m, mass = 76.8 +/- 12.0 kg, body mass index = 27.7 +/- 4.7 kg.m). The control group included 12 older adults (6 males and 6 females; mean +/- SD, age = 69.2 +/- 6.9 yr, height = 1.7 +/- 0.09 m, mass = 78.2 +/- 10.9 kg, body mass index = 25.3 +/- 2.7 kg.m). Subjects included active older adults, including regular exercisers, but none were engaged in sports or exercises with an emphasis on speed (e.g., cycling spin classes or tennis). Stationary recumbent cycling was selected to minimize fall risk, and low pedaling resistance reduced musculoskeletal and cardiovascular load. Two weekly 30-min exercise sessions consisted of interval training in which subjects pedaled at preferred cadence and performed ten 20-s fast cadence intervals separated by 40 s of active recovery at preferred cadence. RESULTS: Significant group-time interactions (P < 0.05) supported a 2-s improvement in the timed up and go test and a 34% improvement in rapid isometric knee extension contractions in the exercise group but not in controls. Central neural adaptations are suggested because this lower extremity exercise program also elicited significant improvements in the untrained upper extremities of the exercise group (elbow extension rate of force development scaling factor and Nine-Hole Peg Test, P < 0.05). CONCLUSION: These results demonstrate that a relatively low dose of speed-based exercise can improve neuromuscular function and tests of mobility in older adults. Such a program serves as a sensible precursor to subsequent, more vigorous training or as an adjunct to a program where a velocity emphasis is lacking. PMID- 27501361 TI - The Effect of Age on the VO2max Response to High-Intensity Interval Training. AB - PURPOSE: High-intensity interval training (HIIT) is documented to yield effective improvements in the cardiovascular system and be an excellent strategy for healthy aging. However, it is not determined how age may affect the training response of key components of aerobic endurance. METHODS: We recruited 72 males (mean +/- SD, weight = 84.9 +/- 12.9 kg, height = 180.4 +/- 5.8 cm) and 22 females (weight = 76.0 +/- 17.2 kg, height = 171.2 +/- 6.7 cm) from 20 to 70+ yr with a training status typical for their age group and divided them into six decade cohorts. The participants followed supervised training with a targeted intensity of 90%-95% of maximal HR (HRmax) three times a week for 8 wk. RESULTS: After HIIT, all age groups increased (P < 0.001-P = 0.004) maximal oxygen consumption (VO2max) with 0.39 +/- 0.20 (20-29 yr), 0.28 +/- 0.21 (30-39 yr), 0.36 +/- 0.08 (40-49 yr), 0.34 +/- 0.27 (50-59 yr), 0.33 +/- 0.23 (60-69 yr), and 0.34 +/- 0.14 (70+ yr) L.min, respectively. These 9%-13% improvements were not significantly different between the age groups. In contrast to age, the percentage improvements after HIIT were inversely associated with baseline training status (r = 0.66, P < 0.001). HRmax was not altered within the respective age cohorts, but the two oldest cohorts exhibited a tendency (P = 0.07) to increase HRmax in contrast to a training-induced decrease in the younger cohorts. CONCLUSION: In healthy individuals with an aerobic capacity typical for what is observed in the population, the training response is likely not affected by age in a short-term training intervention but may rather be affected by the initial training status. These findings imply that individuals across age all have a great potential for cardiovascular improvements, and that HIIT may be used as an excellent strategy for healthy aging. PMID- 27501362 TI - Delivery of Therapeutic siRNA to the CNS Using Cationic and Anionic Liposomes. AB - Prion diseases result from the misfolding of the normal, cellular prion protein (PrP(C)) to an abnormal protease resistant isomer called PrP(Res). The emergence of prion diseases in wildlife populations and their increasing threat to human health has led to increased efforts to find a treatment for these diseases. Recent studies have found numerous anti-prion compounds that can either inhibit the infectious PrP(Res) isomer or down regulate the normal cellular prion protein. However, most of these compounds do not cross the blood brain barrier to effectively inhibit PrP(Res) formation in brain tissue, do not specifically target neuronal PrP(C), and are often too toxic to use in animal or human subjects. We investigated whether siRNA delivered intravascularly and targeted towards neuronal PrP(C) is a safer and more effective anti-prion compound. This report outlines a protocol to produce two siRNA liposomal delivery vehicles, and to package and deliver PrP siRNA to neuronal cells. The two liposomal delivery vehicles are 1) complexed-siRNA liposome formulation using cationic liposomes (LSPCs), and 2) encapsulated-siRNA liposome formulation using cationic or anionic liposomes (PALETS). For the LSPCs, negatively charged siRNA is electrostatically bound to the cationic liposome. A positively charged peptide (RVG-9r [rabies virus glycoprotein]) is added to the complex, which specifically targets the liposome-siRNA-peptide complexes (LSPCs) across the blood brain barrier (BBB) to acetylcholine expressing neurons in the central nervous system (CNS). For the PALETS (peptide addressed liposome encapsulated therapeutic siRNA), the cationic and anionic lipids were rehydrated by the PrP siRNA. This procedure results in encapsulation of the siRNA within the cationic or anionic liposomes. Again, the RVG-9r neuropeptide was bound to the liposomes to target the siRNA/liposome complexes to the CNS. Using these formulations, we have successfully delivered PrP siRNA to AchR-expressing neurons, and decreased the PrP(C) expression of neurons in the CNS. PMID- 27501363 TI - Amyloid beta attenuates metabotropic zinc sensing receptor, mZnR/GPR39, dependent Ca2+ , ERK1/2 and Clusterin signaling in neurons. AB - A hallmark of Alzheimer's disease is accumulation of amyloid beta (Abeta) deposits, which are associated with neuronal dysfunction, spine loss, and impaired Ca2+ homeostasis. Amyloid beta (Abeta) binds to and is aggregated by Zn2+ , a metal released from synaptic glutamatergic vesicles during neuronal activity. Synaptically released Zn2+ activates a metabotropic Gq-coupled Zn2+ sensing receptor, mZnR/GPR39, and induces Ca2+ -signaling in post-synaptic neurons. We examined if Abeta, as a Zn2+ binding protein, regulates neuronal Zn2+ -signaling mediated by mZnR/GPR39 using SHSY-5Y cells and cortical neurons from GPR39 wild-type and knockout mice. Following acute or chronic treatment with Abeta neuronal Zn2+ -dependent Ca2+ release via mZnR/GPR39 is significantly reduced. This impairment is overcome when excess Zn2+ is applied, suggesting that impaired Ca2+ -signaling results from Abeta binding of Zn2+ . The Zn2+ -dependent mZnR/GPR39 activation triggers phosphorylation of extracellular regulated kinase and up-regulates expression of the chaperone protein clusterin (Clu). Importantly, neuronal Zn2+ -dependent extracellular regulated kinase1/2 phosphorylation and up-regulation of Clu are attenuated by silencing mZnR/GPR39 as well as by Abeta treatment. In contrast, Zn2+ -dependent AKT phosphorylation is not mediated by mZnR/GPR39 and is not attenuated by Abeta treatment. Thus, Zn2+ signaling via mZnR/GPR39 is distinctively disrupted by a critical pathological component of Alzheimer's disease. Synaptically released Zn2+ activates a Zn2+ -sensing receptor, mZnR/GPR39, and induces Ca2+ -signaling, followed by ERK1/2 MAPK activation and up-regulation of clusterin. Amyloid beta (Abeta) binds to Zn2+ thus forming oligomers that are a hallmark of Alzheimer's disease. We show that Abeta attenuates Zn2+ -dependent Ca2+ -responses, abolishes ERK1/2 activation and down-regulates clusterin expression. Thus, Zn2+ signaling via mZnR/GPR39 is disrupted by Abeta, a critical pathological component of Alzheimer's disease. PMID- 27501364 TI - The influence of intercalating perfluorohexane into lipid shells on nano and microbubble stability. AB - Microbubbles are potential diagnostic and therapeutic agents. In vivo stability is important as the bubbles are required to survive multiple passages through the heart and lungs to allow targeting and delivery. Here we have systematically varied key parameters affecting microbubble lifetime to significantly increase in vivo stability. Whilst shell and core composition are found to have an important role in improving microbubble stability, we show that inclusion of small quantities of C6F14 in the microbubble bolus significantly improves microbubble lifetime. Our results indicate that C6F14 inserts into the lipid shell, decreasing surface tension to 19 mN m(-1), and increasing shell resistance, in addition to saturating the surrounding medium. Surface area isotherms suggest that C6F14 incorporates into the acyl chain region of the lipid at a high molar ratio, indicating ~2 perfluorocarbon molecules per 5 lipid molecules. The resulting microbubble boluses exhibit a higher in vivo image intensity compared to commercial compositions, as well as longer lifetimes. PMID- 27501365 TI - Compositional Analysis of Asymmetric and Symmetric Dimethylated H3R2 Using Liquid Chromatography-Tandem Mass Spectrometry-Based Targeted Proteomics. AB - Protein arginine methylation is one of the common post-translational modifications in cellular processes. To date, two isomeric forms of dimethylated arginine have been identified: asymmetric N(G),N(G)-dimethylarginine (aDMA), and symmetric N(G),N'(G)-dimethylarginine (sDMA). Evidence indicated that these isomers can coexist and have different or even opposite functions, with aDMA and sDMA forms of arginine 2 on histone H3 (i.e., H3R2me2a and H3R2me2s) being an example. Thus, specific detection and quantification of each isomeric form is important. Current methods are capable of predicting and detecting thousands of methylarginine sites in proteins, whereas differentiation and stoichiometric measurement of dimethylated protein isomers are still challenging. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)-based targeted proteomics has emerged as a promising technique for site-specific quantification of protein methylation using enzymatic peptides as surrogates of target proteins. However, it should be pointed out that a routine targeted proteomics strategy cannot easily distinguish sDMA- and aDMA-containing surrogate peptides due to their common nature. The estimated amount should be considered as the sum of both arginine dimethylated isomers. In this study, compositional analysis based on a linear algebra algorithm as an add-on to targeted proteomics was employed to quantify H3R2me2a and H3R2me2s (i.e., surrogate peptides of AR(me2a)TK(me1/2)QT and AR(me2s)TK(me1/2)QT). To achieve this simultaneous quantification, a targeted proteomics assay was developed and validated for each isomer first. With the slope and intercept of their calibration curves for each multiple reaction monitoring (MRM) transition, linear algebraic equations were derived. Using a series of mock mixtures consisting of isomers in varying concentrations, the reliability of the method was confirmed. Finally, the H3R2 dimethylation status was analyzed in normal MCF-10A cells, parental drug-sensitive MCF-7/WT cancer cells, and drug-resistant MCF-7/ADR cancer cells. Dimethylated H3R2 was also monitored in MCF-7/WT cells with the treatment of doxorubicin (DOX) for confirmation. PMID- 27501366 TI - Generalized Valence Bond Description of Chalcogen-Nitrogen Compounds. III. Why the NO-OH and NS-OH Bonds Are So Different. AB - Crabtree et al. recently reported the microwave spectrum of nitrosyl-O-hydroxide (trans-NOOH), an isomer of nitrous acid, and found that this molecule has the longest O-O bond ever observed: 1.9149 A +/- 0.0005 A. This is in marked contrast to the structure of the valence isoelectronic trans-NSOH molecule, which has a normal NS-OH bond length and strength. Generalized valence bond calculations show that the long bond in trans-NOOH is the result of a weak through-pair interaction that singlet couples the spins of the electrons in singly occupied orbitals on the hydroxyl radical and nitrogen atom, an interaction that is enhanced by the intervening lone pair of the oxygen atom in NO. The NS-OH bond is the result of the formation of a stable recoupled pair bond dyad, which accounts for both its length and strength. PMID- 27501367 TI - Sensitivity of breeding values for carcass traits of meat-type quail to changes in dietary (methionine + cystine):lysine ratio using reaction norm models. AB - Our objective was to evaluate changes in breeding values for carcass traits of two meat-type quail (Coturnix coturnix) strains (LF1 and LF2) to changes in the dietary (methionine + cystine):lysine ([Met + Cys]:Lys) ratio due to genotype by environment (G * E) interaction via reaction norm. A total of 7000 records of carcass weight and yield were used for analyses. During the initial phase (from hatching to day 21), five diets with increasing (Met + Cys):Lys ratios (0.61, 0.66, 0.71, 0.76 and 0.81), containing 26.1% crude protein and 2900 kcal ME/kg, were evaluated. Analyses were performed using random regression models that included linear functions of sex (fixed effect) and breeding value (random effect) for carcass weight and yield, without and with heterogeneous residual variance adjustment. Both fixed and random effects were modelled using Legendre polynomials of second order. Genetic variance and heritability estimates were affected by both (Met + Cys):Lys ratio and strain. We observed that a G * E interaction was present, with changes in the breeding value ranking. Therefore, genetic evaluation for carcass traits should be performed under the same (Met + Cys):Lys ratio in which quails are raised. PMID- 27501368 TI - Inhibitor development in two cousins receiving full-length factor VIII (FVIII) and FVIII-Fc fusion protein. PMID- 27501369 TI - Development and Validation of the Chinese Triarchic Psychopathy Measure. AB - The nature of psychopathy is not well understood in East Asian cultures, partially due to a lack of an established measurement of this important construct. This study developed and validated a Chinese-language version of the Triarchic Psychopathy Measure (TriPM) based on Patrick et al.'s (2009) triarchic model of psychopathy. Study 1 described the translation of the Chinese TriPM and demonstrated that the Chinese version of the TriPM is equivalent to the original English version in linguistic meaning. Study 2 examined the construct validity of the Chinese TriPM in a Chinese student sample. The TriPM evinced acceptable reliability and promising validity. Moreover, cross-cultural equivalence was examined by relative associations for the TriPM with the Levenson Self-Report Psychopathy Scale across the Chinese sample and a comparable United States student sample. Results revealed that the test bias in the strength of associations, regression intercepts, and slopes was mostly absent across the two samples. PMID- 27501370 TI - Percutaneous Hepatic Perfusion (PHP) with Melphalan as a Treatment for Unresectable Metastases Confined to the Liver. AB - Unresectable liver metastases of colorectal cancer can be treated with systemic chemotherapy, aiming to limit the disease, extend survival or turn unresectable metastases into resectable ones. Some patients however, suffer from side effects or progression under systemic treatment. For patients with metastasized uveal melanoma there are no standard systemic therapy options. For patients without extrahepatic disease, isolated liver perfusion (IHP) may enable local disease control with limited systemic side effects. Previously, this was performed during open surgery with satisfying results, but morbidity and mortality related to the open procedure, prohibited a widespread application. Therefore, percutaneous hepatic perfusion (PHP) with simultaneous chemofiltration was developed. Besides decreasing morbidity and mortality, this procedure can be repeated, hopefully leading to a higher response rate and improved survival (by local control of disease). During PHP, catheters are placed in the proper hepatic artery, to infuse the chemotherapeutic agent, and in the inferior caval vein to aspirate the chemosaturated blood returning through the hepatic veins. The caval vein catheter is a double balloon catheter that prohibits leakage into the systemic circulation. The blood returning from the hepatic veins is aspirated through the catheter fenestrations and then perfused through an extra-corporeal filtration system. After filtration, the blood is returned to the patient by a third catheter in the right internal jugular vein. During PHP a high dose of melphalan is infused into the liver, which is toxic and would lead to life threatening complications when administered systemically. Because of the significant hemodynamic instability resulting from the combination of caval vein occlusion and chemofiltration, hemodynamic monitoring and hemodynamic support is of paramount importance during this complex procedure. PMID- 27501371 TI - Bioresorbable scaffold-the holy grail of percutaneous coronary intervention: fact or myth? PMID- 27501372 TI - Single- and dual-wavelength photodetectors with MgZnO/ZnO metal-semiconductor metal structure by varying the bias voltage. AB - By varying the bias voltage of an Mg x Zn1-x O/ZnO metal-semiconductor-metal photodetector (MSM-PDs), the detection wavelength can be modulated from a single to a dual wavelength. A long-wavelength band response is caused by the ZnO absorption and a short-wavelength band response is caused by Mg x Zn1-x O. At a 0 V bias voltage, the photogenerated electrons in ZnO are confined to the Mg x Zn1 x O/ZnO interface, arising from the piezoelectric polarization. The accumulated electrons hop the Mg x Zn1-x O layer through the assistance of defects; however, the photogenerated electrons in Mg x Zn1-x O cannot cross over the large barrier height at the Au/MgZnO interface, resulting in a single-wavelength photodetector with a long-wavelength band (345-400 nm) having a peak wavelength of 370 nm. By increasing the bias voltage to 1-2 V, the barrier height is lowered, enabling the photogenerated electrons in Mg x Zn1-x O to easily cross over the low barrier height, leading to dual-wavelength photodetectors having peak wavelengths of 370 and 340 nm. On further increasing the bias voltage beyond 2 V, the photogenerated electrons in ZnO sink deeply in the hollow at the Mg x Zn1-x O/ZnO interface owing to the large applied voltage. These electrons are effectively confined at the Mg x Zn1-x O/ZnO interface, which retards the tunneling of the photogenerated electrons in ZnO through the Mg x Zn1-x O layer; hence the MSM-PDs revert back to single wavelength photodetectors; however, the detection wavelength is different from that of the MSM-PDs biased at 0 V. Instead of having a long-wavelength band (345-400 nm), the MSM-PDs demonstrate a short-wavelength band (320-345 nm) at a 3 V bias voltage. PMID- 27501373 TI - Thiophene-Fused pi-Systems from Diarylacetylenes and Elemental Sulfur. AB - A simple yet effective method for the formation of thiophene-fused pi-systems is reported. When arylethynyl-substituted polycyclic arenes were heated in DMF in the presence of elemental sulfur, the corresponding thiophene-fused polycyclic arenes were obtained via cleavage of the ortho-C-H bond. Thus, arylethynylated naphthalenes, fluoranthenes, pyrenes, corannulenes, chrysenes, and benzo[c]naphtho[2,1-p]chrysenes were effectively converted into the corresponding thiophene-fused pi-systems. Apart from polycyclic hydrocarbons, thiophene derivatives are also susceptible to this reaction. The practical utility of this reaction is demonstrated by preparations on the decagram scale, one-pot two-step reaction sequences, and multiple thiophene annulations. PMID- 27501375 TI - Long-term preclinical magnetic resonance imaging alterations in sporadic Creutzfeldt-Jakob disease. AB - An asymptomatic 74-year-old woman, on follow-up for a carotid body tumor, showed magnetic resonance imaging (MRI) focal restricted diffusion confined to the left temporal and occipital cortices. Thirteen months later, diffusion-weighted images revealed a bilateral cortical ribbon sign involving all lobes. After 1 month, the patient developed gait instability and cognitive decline rapidly evolving to severe dementia and death within 3 months. Prion protein gene sequence, molecular, and neuropathological studies confirmed the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 subtype. Here we show the kinetics of MRI changes and prion spreading in preclinical sCJD MM1. Ann Neurol 2016;80:629-632. PMID- 27501374 TI - Promising therapies for treatment of nonalcoholic steatohepatitis. AB - INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) has become the most common etiology for abnormal aminotransferase levels and chronic liver disease. Its growing prevalence is largely linked to the presence of metabolic syndrome, particularly diabetes and insulin resistance. It is estimated that 60-80% of the type 2 diabetic population has NAFLD. NAFLD encompasses a range of conditions ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). A subset of patients with hepatic steatosis progress to NASH, while 15-20% of patients with NASH develop cirrhosis. This progression is thought to be multifactorial, and there are currently no FDA-approved medications for the treatment of NASH. AREAS COVERED: We review drugs currently in Phase II and III clinical trials for treatment of NAFLD and NASH, including their mechanisms of action, relationship to the pathophysiology of NASH, and rationale for their development. EXPERT OPINION: The treatment of NASH is complex and necessitates targeting a number of different pathways. Combination therapy, preferably tailored toward the disease stage and severity, will be needed to achieve maximum therapeutic effect. With multiple agents currently being developed, there may soon be an ability to effectively slow or even reverse the disease process in many NAFLD/NASH patients. PMID- 27501376 TI - From Planar to Cage in 15 Easy Steps: Resolving the C60H21F9(-) -> C60(-) Transformation by Ion Mobility Mass Spectrometry. AB - A combination of mass spectrometry, collision-induced dissociation, ion mobility mass spectrometry (IM-MS), and density functional theory (DFT) has been used to study the evolution of anionic species generated by laser-desorption of the near planar, fluorinated polycyclic aromatic hydrocarbon (PAH), C60H21F9 (s). The dominant decay process for isolated, thermally activated C60H21F9(-) species comprises a sequence of multiple regioselective cyclodehydrofluorination and cyclodehydrogenation reactions (eliminating HF and H2, respectively, while forming additional pentagons and/or hexagons). The DFT calculations allow us to set narrow bounds on the structures of the resulting fragment ions by fitting structural models to experimentally determined collision cross sections. These show that the transformation of the precursor anion proceeds via a series of intermediate structures characterized by increasing curvature, ultimately leading to the closed-shell fullerene cage C60(-) as preprogrammed by the precursor structure. PMID- 27501377 TI - Only when all contribute their firewood can they build up a big fire. PMID- 27501379 TI - Endoscopic scoring indices for evaluation of disease activity in Crohn's disease. AB - BACKGROUND: Endoscopic assessment of mucosal disease activity is widely used to determine eligibility and response to therapy in clinical trials of treatment for Crohn's disease. However, the operating properties of the currently available endoscopic indices remain unclear. OBJECTIVES: A systematic review was undertaken to evaluate the development and operating characteristics of the Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Scale for Crohn's Disease (SES-CD). SEARCH METHODS: Electronic searches of the MEDLINE (1966 to December 2015), EMBASE (1980 to December 2015), and Cochrane CENTRAL Register of Controlled Trials (Issue 12, 2015) databases were supplemented by manual reviews of reference listings and conference proceedings (Digestive Disease Week, United European Gastroenterology Week, European Crohn's and Colitis Organization). SELECTION CRITERIA: Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated either or both the CDEIS or SES-CD in patients with Crohn's disease was considered for inclusion. Eligible participants were adult patients (> 16 years), diagnosed with Crohn's disease using conventional clinical, radiographic, and endoscopic criteria. DATA COLLECTION AND ANALYSIS: Two authors (RK, JKM) independently reviewed the titles and abstracts of the studies identified from the literature search. The full texts of potentially relevant citations were reviewed for inclusion and the study investigators were contacted to clarify any unclear data. Any disagreements were resolved by discussion and consensus with a third author. A standardized form was used to assess eligibility of trials for inclusion in the study and for data extraction.Two authors independently extracted and recorded data (RK, SAN). The number of patients enrolled; number of patients per treatment arm; patient characteristics including age and gender distribution; endoscopic index; and outcomes such as intra-rater reliability, inter-rater reliability responsiveness, validity, feasibility, construct validity, and criterion validity were recorded for each trial. MAIN RESULTS: Forty-three reports of 30 studies fulfilled the inclusion criteria.For the SES-CD, inter-rater reliability was assessed in four studies. In the development study for the SES-CD (Daperno 2004), the overall ICC (0.9815, 95% CI 0.9705 to 0.9884) and the kappa for the regions is high; however the paired raters were in the same room which introduces the potential for bias.For the CDEIS, inter-rater reliability was assessed in six studies. Daperno 2014 reported that the ICC for the CDEIS was 0.985 (95% CI 0.939-1.000) for average measures of video score and was 0.835 (95% CI 0.540-0.995) for single measures of video score.With respect to validity, correlation between the CDEIS and clinical measures, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), was also reported. The estimates of correlation with CRP were r = 0.521 (Sipponen 2010b), r = 0.553 (Sipponen 2008a) and r = 0.608 (Sipponen 2008c). For the SES-CD, the corresponding values for correlation with CRP ranged from r = 0.46 (Jones 2008) to r = 0.68 (Green 2011).Responsiveness data for the CDEIS were available in nine studies. Seven studies demonstrated statistically significant decreases in the CDEIS score after administration of a treatment of known efficacy. Minimal responsiveness data were available for the SES-CD. Sipponen 2010a and Sipponen 2010b demonstrated statistically significant changes in the SES-CD score after subjects were administered a treatment of known efficacy.No studies were identified that explicitly evaluated the feasibility for either the SES-CD or the CDEIS. The SES-CD requires fewer calculations and may therefore be easier to use than the CDEIS. AUTHORS' CONCLUSIONS: Although they are used in clinical trials, the CDEIS and SES-CD remain incompletely validated. Future research is required to determine the operating properties and to define the optimal index. PMID- 27501378 TI - Targeted Therapy for Acute Autoimmune Myocarditis with Nano-Sized Liposomal FK506 in Rats. AB - Immunosuppressive agents are used for the treatment of immune-mediated myocarditis; however, the need to develop a more effective therapeutic approach remains. Nano-sized liposomes may accumulate in and selectively deliver drugs to an inflammatory lesion with enhanced vascular permeability. The aims of this study were to investigate the distribution of liposomal FK506, an immunosuppressive drug encapsulated within liposomes, and the drug's effects on cardiac function in a rat experimental autoimmune myocarditis (EAM) model. We prepared polyethylene glycol-modified liposomal FK506 (mean diameter: 109.5 +/- 4.4 nm). We induced EAM by immunization with porcine myosin and assessed the tissue distribution of the nano-sized beads and liposomal FK506 in this model. After liposomal or free FK506 was administered on days 14 and 17 after immunization, the cytokine expression in the rat hearts along with the histological findings and hemodynamic parameters were determined on day 21. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent labeled nano-sized beads had accumulated in myocarditic but not normal hearts on day 14 after immunization and thereafter. Compared to the administration of free FK506, FK506 levels were increased in both the plasma and hearts of EAM rats when liposomal FK506 was administered. The administration of liposomal FK506 markedly suppressed the expression of cytokines, such as interferon-gamma and tumor necrosis factor-alpha, and reduced inflammation and fibrosis in the myocardium on day 21 compared to free FK506. The administration of liposomal FK506 also markedly ameliorated cardiac dysfunction on day 21 compared to free FK506. Nano sized liposomes may be a promising drug delivery system for targeting myocarditic hearts with cardioprotective agents. PMID- 27501380 TI - What distinguishes cyanobacteria able to revive after desiccation from those that cannot: the genome aspect. AB - Filamentous cyanobacteria are the main founders and primary producers in biological desert soil crusts (BSCs) and are likely equipped to cope with one of the harshest environmental conditions on earth including daily hydration/dehydration cycles, high irradiance and extreme temperatures. Here, we resolved and report on the genome sequence of Leptolyngbya ohadii, an important constituent of the BSC. Comparative genomics identified a set of genes present in desiccation-tolerant but not in dehydration-sensitive cyanobacteria. RT qPCR analyses showed that the transcript abundance of many of them is upregulated during desiccation in L. ohadii. In addition, we identified genes where the orthologs detected in desiccation-tolerant cyanobacteria differs substantially from that found in desiccation-sensitive cells. We present two examples, treS and fbpA (encoding trehalose synthase and fructose 1,6-bisphosphate aldolase respectively) where, in addition to the orthologs present in the desiccation sensitive strains, the resistant cyanobacteria also possess genes with different predicted structures. We show that in both cases the two orthologs are transcribed during controlled dehydration of L. ohadii and discuss the genetic basis for the acclimation of cyanobacteria to the desiccation conditions in desert BSC. PMID- 27501381 TI - Observing Mitotic Division and Dynamics in a Live Zebrafish Embryo. AB - Mitosis is critical for organismal growth and differentiation. The process is highly dynamic and requires ordered events to accomplish proper chromatin condensation, microtubule-kinetochore attachment, chromosome segregation, and cytokinesis in a small time frame. Errors in the delicate process can result in human disease, including birth defects and cancer. Traditional approaches investigating human mitotic disease states often rely on cell culture systems, which lack the natural physiology and developmental/tissue-specific context advantageous when studying human disease. This protocol overcomes many obstacles by providing a way to visualize, with high resolution, chromosome dynamics in a vertebrate system, the zebrafish. This protocol will detail an approach that can be used to obtain dynamic images of dividing cells, which include: in vitro transcription, zebrafish breeding/collecting, embryo embedding, and time-lapse imaging. Optimization and modifications of this protocol are also explored. Using H2A.F/Z-EGFP (labels chromatin) and mCherry-CAAX (labels cell membrane) mRNA injected embryos, mitosis in AB wild-type, auroraB(hi1045) (,) and esco2(hi2865) mutant zebrafish is visualized. High resolution live imaging in zebrafish allows one to observe multiple mitoses to statistically quantify mitotic defects and timing of mitotic progression. In addition, observation of qualitative aspects that define improper mitotic processes (i.e., congression defects, missegregation of chromosomes, etc.) and improper chromosomal outcomes (i.e., aneuploidy, polyploidy, micronuclei, etc.) are observed. This assay can be applied to the observation of tissue differentiation/development and is amenable to the use of mutant zebrafish and pharmacological agents. Visualization of how defects in mitosis lead to cancer and developmental disorders will greatly enhance understanding of the pathogenesis of disease. PMID- 27501383 TI - A purely predatory relationship... Really? PMID- 27501382 TI - Design and implementation of embedded 8-channel receive-only arrays for whole brain MRI and fMRI of conscious awake marmosets. AB - PURPOSE: The common marmoset (Callithrix jacchus) is a New World primate of increasing interest to neuroscience and in translational brain research. The present work describes the design and implementation of individualized 8-channel receive-only radiofrequency (RF) coil arrays that provide whole-brain coverage and allow anatomical and functional MRI experiments in conscious, awake marmosets. METHODS: The coil arrays were designed with their elements embedded inside individualized restraint helmets. The size, geometry, and arrangement of the coil elements were optimized to allow whole-brain coverage. Coil-to-coil decoupling was achieved by a combination of geometric decoupling and low input impedance preamplifiers. The performance of the embedded arrays was compared against that of one 8-channel receive-only array built to fit the external surface of the helmets. RESULTS: Three individualized helmets with embedded coil arrays were built for three marmosets. Whole-brain coverage was achieved with high sensitivity extending over the entire cortex. Visual stimulation of conscious awake marmosets elicited robust BOLD fMRI responses in both primary and higher order visual areas of the occipitotemporal cortex. CONCLUSION: The high sensitivity provided by embedded receive-only coil arrays allows both anatomical and functional MRI data to be obtained with high spatial resolution in conscious, awake marmosets. Magn Reson Med 78:387-398, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27501384 TI - Evaluation of Nitrous Oxide Emission from Sulfide- and Sulfur-Based Autotrophic Denitrification Processes. AB - Recent studies have shown that sulfide- and sulfur-based autotrophic denitrification (AD) processes play an important role in contributing to nitrous oxide (N2O) production and emissions. However, N2O production is not recognized in the current AD models, limiting their ability to predict N2O accumulation during AD. In this work, a mathematical model is developed to describe N2O dynamics during sulfide- and sulfur-based AD processes for the first time. The model is successfully calibrated and validated using N2O data from two independent experimental systems with sulfide or sulfur as electron donors for AD. The model satisfactorily describes nitrogen reductions, sulfide/sulfur oxidation, and N2O accumulation in both systems. Modeling results revealed substantial N2O accumulation due to the relatively low N2O reduction rate during both sulfide- and sulfur-based AD processes. Application of the model to simulate long-term operations of activated sludge systems performing sulfide- and sulfur based AD processes indicates longer sludge retention time reduced N2O emission. For sulfide-based AD process, higher initial S/N ratio also decreased N2O emission but with a higher operational cost. This model can be a useful tool to support process operation optimization for N2O mitigation during AD with sulfide or sulfur as electron donor. PMID- 27501385 TI - A linguistic comparison between auditory verbal hallucinations in patients with a psychotic disorder and in nonpsychotic individuals: Not just what the voices say, but how they say it. AB - BACKGROUND: Auditory verbal hallucinations (AVH) in psychotic patients are associated with activation of right hemisphere language areas, although this hemisphere is non-dominant in most people. Language generated in the right hemisphere can be observed in aphasia patients with left hemisphere damage. It is called "automatic speech", characterized by low syntactic complexity and negative emotional valence. AVH in nonpsychotic individuals, by contrast, predominantly have a neutral or positive emotional content and may be less dependent on right hemisphere activity. We hypothesize that right hemisphere language characteristics can be observed in the language of AVH, differentiating psychotic from nonpsychotic individuals. METHOD: 17 patients with a psychotic disorder and 19 nonpsychotic individuals were instructed to repeat their AVH verbatim directly upon hearing them. Responses were recorded, transcribed and analyzed for total words, mean length of utterance, proportion of grammatical utterances, proportion of negations, literal and thematic perseverations, abuses, type-token ratio, embeddings, verb complexity, noun-verb ratio, and open-closed class ratio. RESULTS: Linguistic features of AVH overall differed between groups F(13,24)=3.920, p=0.002; Pillai's Trace 0.680. AVH of psychotic patients compared with AVH of nonpsychotic individuals had a shorter mean length of utterance, lower verb complexity, and more verbal abuses and perseverations (all p<0.05). Other features were similar between groups. CONCLUSION: AVH of psychotic patients showed lower syntactic complexity and higher levels of repetition and abuses than AVH of nonpsychotic individuals. These differences are in line with a stronger involvement of the right hemisphere in the origination of AVH in patients than in nonpsychotic voice hearers. PMID- 27501386 TI - How language flows when movements don't: An automated analysis of spontaneous discourse in Parkinson's disease. AB - To assess the impact of Parkinson's disease (PD) on spontaneous discourse, we conducted computerized analyses of brief monologues produced by 51 patients and 50 controls. We explored differences in semantic fields (via latent semantic analysis), grammatical choices (using part-of-speech tagging), and word-level repetitions (with graph embedding tools). Although overall output was quantitatively similar between groups, patients relied less heavily on action related concepts and used more subordinate structures. Also, a classification tool operating on grammatical patterns identified monologues as pertaining to patients or controls with 75% accuracy. Finally, while the incidence of dysfluent word repetitions was similar between groups, it allowed inferring the patients' level of motor impairment with 77% accuracy. Our results highlight the relevance of studying naturalistic discourse features to tap the integrity of neural (and, particularly, motor) networks, beyond the possibilities of standard token-level instruments. PMID- 27501387 TI - Current Welfare Problems Facing Horses in Great Britain as Identified by Equine Stakeholders. AB - Despite growing concerns about the welfare of horses in Great Britain (GB) there has been little surveillance of the welfare status of the horse population. Consequently we have limited knowledge of the range of welfare problems experienced by horses in GB and the situations in which poor welfare occurs. Thirty-one in-depth interviews were conducted with a cross -section of equine stakeholders, in order to explore their perceptions of the welfare problems faced by horses in GB. Welfare problems relating to health, management and riding and training were identified, including horses being under or over weight, stabling 24 hours a day and the inappropriate use of training aids. The interviewees also discussed broader contexts in which they perceived that welfare was compromised. The most commonly discussed context was where horses are kept in unsuitable environments, for example environments with poor grazing. The racing industry and travellers horses were identified as areas of the industry where horse welfare was particularly vulnerable to compromise. Lack of knowledge and financial constraints were perceived to be the root cause of poor welfare by many interviewees. The findings give insight into the range of welfare problems that may be faced by horses in GB, the contexts in which these may occur and their possible causes. Many of the problems identified by the interviewees have undergone limited scientific investigation pointing to areas where further research is likely to be necessary for welfare improvement. The large number of issues identified suggests that some form of prioritisation may be necessary to target research and resources effectively. PMID- 27501388 TI - Detailed Observation of Multiphoton Emission Enhancement from a Single Colloidal Quantum Dot Using a Silver-Coated AFM Tip. AB - The enhancement of multiphoton emission from a single colloidal nanocrystal quantum dot (NQD) interacting with a plasmonic nanostructure was investigated using a silver-coated atomic force microscopy tip (AgTip) as the plasmonic nanostructure. Using the AgTip, which exhibited a well-defined localized surface plasmon (LSP) resonance band, we controlled the spectral overlap and the distance between the single NQD and the AgTip. The emission behavior of the single NQD when approaching the AgTip at the nanometer scale was measured using off resonance (405 nm) and resonance (465 nm) excitation of the LSP. We directly observed the conversion of the single-photon emission from a single NQD to multiphoton emission with reduction of the emission lifetime at both excitation wavelengths as the NQD-AgTip distance decreased, whereas a decrease and increase in the emission intensity were observed at 405 and 465 nm excitation, respectively. By combining theoretical analysis and the numerical simulation of the AgTip, we deduced that the enhancement of the multiphoton emission was caused by the quenching of the single-exciton state due to the energy transfer from the NQD to the AgTip and that the emission intensity was increased by enhancement of the excitation rate due to the electric field of the LSP on the AgTip. These results provide evidence that the photon statistics and the photon flux from the single NQD can be manipulated by the plasmonic nanostructure through control of the spectral overlap and the distance. PMID- 27501389 TI - Is Transthyretin a Regulator of Ubc9 SUMOylation? AB - Ageing and mutations of transthyretin (TTR), the thyroid hormones and retinol transporting protein lead to amyloidosis by destabilizing the structure of TTR. Because protein structure is regulated through posttranslational modifications, we investigated the Small Ubiquitin-like Modifier (SUMO)ylation of TTR. We chose the widely used Ubc9 fusion-directed SUMOylation system, which is based on a fusion of the SUMOylation substrate of interest with Ubc9, a sole SUMO conjugating enzyme. Surprisingly, despite our presumptions, we found that Ubc9 fused to TTR was SUMOylated at a unique set of lysine residues. Three unknown SUMOylation sites of Ubc9-K154, K18 and K65-were revealed by mass spectrometry (MS). The previously reported SUMOylation at K49 of Ubc9 was also observed. SUMOylation of the lysine residues of TTR fused to Ubc9 was hardly detectable. However, non-fused TTR was SUMOylated via trans-SUMOylation by Ubc9 fused to TTR. Interestingly, mutating the catalytic residue of Ubc9 fused to TTR did not result in complete loss of the SUMOylation signal, suggesting that Ubc9 linked to TTR is directly cross-SUMOylated by the SUMO-activating enzyme E1. Ubc9, TTR or fusion proteins composed of TTR and Ubc9 specifically affected the global SUMOylation of cellular proteins. TTR or Ubc9 alone increased global SUMOylation, whereas concomitant presence of TTR and Ubc9 did not further increase the amount of high molecular weight (HMW) SUMO conjugates. Our data suggest that TTR may influence the SUMOylation of Ubc9, thereby altering signalling pathways in the cell. PMID- 27501390 TI - Cattle Immunized with a Recombinant Subunit Vaccine Formulation Exhibits a Trend towards Protection against Histophilus somni Bacterial Challenge. AB - Histophilosis, a mucosal and septicemic infection of cattle is caused by the Gram negative pathogen Histophilus somni (H. somni). As existing vaccines against H. somni infection have shown to be of limited efficacy, we used a reverse vaccinology approach to identify new vaccine candidates. Three groups (B, C, D) of cattle were immunized with subunit vaccines and a control group (group A) was vaccinated with adjuvant alone. All four groups were challenged with H. somni. The results demonstrate that there was no significant difference in clinical signs, joint lesions, weight change or rectal temperature between any of the vaccinated groups (B,C,D) vs the control group A. However, the trend to protection was greatest for group C vaccinates. The group C vaccine was a pool of six recombinant proteins. Serum antibody responses determined using ELISA showed significantly higher titers for group C, with P values ranging from < 0.0148 to < 0.0002, than group A. Even though serum antibody titers in group B (5 out of 6 antigens) and group D were significantly higher compared to group A, they exerted less of a trend towards protection. In conclusion, the vaccine used in group C exhibits a trend towards protective immunity in cattle and would be a good candidate for further analysis to determine which proteins were responsible for the trend towards protection. PMID- 27501391 TI - Assessment of Cortical Dysfunction in Patients with Intermittent Exotropia: An fMRI Study. AB - Neural imaging studies have found the connection between strabismus and brain cortex. However, the pathological mechanisms of intermittent exotropia are still not fully understood. In the present study, changes of binocular fusion related cortices in intermittent exotropia were investigated with blood oxygen level dependent functional magnetic resonance imaging. Activated cortices induced by fusion stimulus were found to be distributed in several regions such as bilateral middle occipital gyrus, bilateral middle temporal gyrus, left superior parietal lobule and so on. Compared with normal subjects, the increased activation intensity was observed in bilateral superior parietal lobule and inferior parietal lobule in subjects with intermittent exotropia. These findings indicate that binocular fusion involves a complicated brain network including several regions. And cortical activities of bilateral superior parietal lobule and inferior parietal lobule compensate for the binocular fusion dysfunction in intermittent exotropia. PMID- 27501392 TI - Microemulsions as Potential Carriers of Nisin: Effect of Composition on Structure and Efficacy. AB - Water-in-oil (W/O) microemulsions based on either refined olive oil (ROO) or sunflower oil (SO), distilled monoglycerides (DMG), and ethanol were used as nisin carriers in order to ensure its effectiveness as a biopreservative. This work presents experimental evidence on the effects of ethanol concentration, hydration, the nature of oil, and the addition of nisin on the nanostructure of the proposed inverse microemulsions as revealed by electrical conductivity measurements, dynamic light scattering (DLS), small angle X-ray scattering (SAXS), and electron paramagnetic resonance (EPR) spectroscopy. Modeling of representative SAXS profiles was applied to gain further insight into the effects of ethanol and solubilized water content on the inverse swollen micelles' size and morphology. With increasing ethanol content, the overall size of the inverse micelles decreased, whereas hydration resulted in an increase in the micellar size due to the penetration of water into the hydrophilic core of the inverse swollen micelles (hydration-induced swelling behavior). The dynamic properties of the surfactant monolayer were also affected by the nature of the used vegetable oil, the ethanol content, and the presence of the bioactive molecule, as evidenced by EPR spin probing experiments. According to simulation on the experimental spectra, two populations of spin probes at different polarities were revealed. The antimicrobial effect of the encapsulated nisin was evaluated using the well diffusion assay (WDA) technique against Lactococccus lactis. It was found that this encapsulated bacteriocin induced an inhibition of the microorganism growth. The effect was more pronounced at higher ethanol concentrations, but no significant difference was observed between the two used vegetable oils (ROO and SO). PMID- 27501393 TI - Regulation of Nutritional Metabolism in Transition Dairy Cows: Energy Homeostasis and Health in Response to Post-Ruminal Choline and Methionine. AB - This study investigated the effects of rumen-protected methionine (RPM) and rumen protected choline (RPC) on energy balance, postpartum lactation performance, antioxidant capacity and immune response in transition dairy cows. Forty-eight multiparous transition cows were matched and divided into four groups: control, 15 g/d RPC, 15 g/d RPM or 15 g/d RPC + 15 g/d RPM. Diet samples were collected daily before feeding, and blood samples were collected weekly from the jugular vein before morning feeding from 21 days prepartum to 21 days postpartum. Postpartum dry matter intake (DMI) was increased by both additives (P < 0.05), and energy balance values in supplemented cows were improved after parturition (P < 0.05). Both RPC and RPM decreased the plasma concentrations of non-esterified fatty acids (NEFA), beta-hydroxybutyric acid (BHBA), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (P < 0.05), but increased the plasma levels of glucose, very-low-density lipoprotein (VLDL) and apolipoprotein B100 (ApoB 100, P < 0.05). The supplements improved milk production (P < 0.05), and increased (P < 0.05) or tended to increase (0.05 < P < 0.10) the contents of milk fat and protein. The post-ruminal choline and methionine elevated the blood antioxidant status, as indicated by total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-Px) activity and the vitamin E concentration (P < 0.05), and reduced the plasma malondialdehyde (MDA) level (P < 0.05). Furthermore, RPM and RPC elevated the plasma interleukin 2 (IL-2) concentration and the CD4+/CD8+ T lymphocyte ratio in peripheral blood (P < 0.05). Alternatively, the levels of tumor necrosis factor-alpha (TNF-alpha) and IL-6 were decreased by RPM and RPC (P < 0.05). Overall, the regulatory responses of RPC and RPM were highly correlated with time and were more effective in the postpartum cows. The results demonstrated that dietary supplementation with RPC and RPM promoted energy balance by increasing postpartal DMI and regulating hepatic lipid metabolism, improved postpartum lactation performance and enhanced antioxidant capacity and immune function of transition dairy cows. PMID- 27501394 TI - Comparison of methods using paraffin-embedded tissues and exfoliated cervical cells to evaluate human papillomavirus genotype attribution. AB - Monitoring the attribution of human papillomavirus (HPV) genotypes to cervical precancerous lesions is essential in assessing the efficacy of HPV vaccines. To resolve the lack of studies comparing the HPV genotyping procedures used to estimate HPV genotype attribution, we undertook a retrospective cross-sectional study to determine the appropriate genotyping procedures for evaluating the potential efficacy of HPV vaccines. Three procedures, including two different genotyping methods, Clinichip HPV test (C-Chip) and modified GP5+/6+ PCR coupled to fluorescent bead sorter detection (MGP), using exfoliated cervical cells (C Chip and C-MGP, respectively) or formalin-fixed paraffin-embedded tissues (F MGP), were compared. The overall agreement in detecting high-risk HPV was 88.5 92.1% among the three procedures, and genotype-specific agreement was 83.9-100% for all pairwise comparisons. In cervical intraepithelial neoplasia grade 2/3 specimens, HPV16/18 attribution estimated with the hierarchical attribution method was consistent among the procedures: 52.3% (45/86) for C-Chip, 54.7% (47/86) for C-MGP, and 52.3% (45/86) for F-MGP (P = 0.81). HPV16/18/31/33/45/52/58 hierarchical attribution was 88.4% (76/86) with C-Chip, 86.0% (74/86) with C-MGP, and 83.7% (72/86) with F-MGP (P = 0.49). In cervical intraepithelial neoplasia grade 3 specimens, the corresponding hierarchical attribution was 96.4% (53/55) with C-Chip, 89.1% (49/55) with C-MGP, and 94.5% (52/55) with F-MGP (P = 0.27). Although F-MGP is theoretically a reliable method for determining HPV genotype attribution, it is acceptable to use C-Chip or C MGP, coupled to the hierarchical attribution formula to correct the bias of multiple infections. These approaches using exfoliated cervical cells are practical for monitoring the efficacy of HPV vaccines. PMID- 27501395 TI - A hybrid polyketide-nonribosomal peptide in nematodes that promotes larval survival. AB - Polyketides and nonribosomal peptides are two important types of natural products that are produced by many species of bacteria and fungi but are exceedingly rare in metazoans. Here, we elucidate the structure of a hybrid polyketide nonribosomal peptide from Caenorhabditis elegans that is produced in the canal associated neurons (CANs) and promotes survival during starvation-induced larval arrest. Our results uncover a novel mechanism by which animals respond to nutrient fluctuations to extend survival. PMID- 27501396 TI - FRET binding antenna reports spatiotemporal dynamics of GDI-Cdc42 GTPase interactions. AB - Guanine-nucleotide dissociation inhibitors (GDIs) are negative regulators of Rho family GTPases that sequester the GTPases away from the membrane. Here we ask how GDI-Cdc42 interaction regulates localized Cdc42 activation for cell motility. The sensitivity of cells to overexpression of Rho family pathway components led us to a new biosensor, GDI.Cdc42 FLARE, in which Cdc42 is modified with a fluorescence resonance energy transfer (FRET) 'binding antenna' that selectively reports Cdc42 binding to endogenous GDIs. Similar antennae could also report GDI-Rac1 and GDI RhoA interaction. Through computational multiplexing and simultaneous imaging, we determined the spatiotemporal dynamics of GDI-Cdc42 interaction and Cdc42 activation during cell protrusion and retraction. This revealed remarkably tight coordination of GTPase release and activation on a time scale of 10 s, suggesting that GDI-Cdc42 interactions are a critical component of the spatiotemporal regulation of Cdc42 activity, and not merely a mechanism for global sequestration of an inactivated pool of signaling molecules. PMID- 27501398 TI - Intracerebroventricular and Intravascular Injection of Viral Particles and Fluorescent Microbeads into the Neonatal Brain. AB - In the study on the pathogenesis of viral encephalitis, the infection method is critical. The first of the two main infectious routes to the brain is the hematogenous route, which involves infection of the endothelial cells and pericytes of the brain. The second is the intracerebroventricular (ICV) route. Once within the central nervous system (CNS), viruses may spread to the subarachnoid space, meninges, and choroid plexus via the cerebrospinal fluid. In experimental models, the earliest stages of CNS viral distribution are not well characterized, and it is unclear whether only certain cells are initially infected. Here, we have analyzed the distribution of cytomegalovirus (CMV) particles during the acute phase of infection, termed primary viremia, following ICV or intravascular (IV) injection into the neonatal mouse brain. In the ICV injection model, 5 ul of murine CMV (MCMV) or fluorescent microbeads were injected into the lateral ventricle at the midpoint between the ear and eye using a 10-ul syringe with a 27 G needle. In the IV injection model, a 1-ml syringe with a 35 G needle was used. A transilluminator was used to visualize the superficial temporal (facial) vein of the neonatal mouse. We infused 50 ul of MCMV or fluorescent microbeads into the superficial temporal vein. Brains were harvested at different time points post-injection. MCMV genomes were detected using the in situ hybridization method. Fluorescent microbeads or green fluorescent protein expressing recombinant MCMV particles were observed by fluorescent microscopy. These techniques can be applied to many other pathogens to investigate the pathogenesis of encephalitis. PMID- 27501397 TI - Inhibiting androgen receptor nuclear entry in castration-resistant prostate cancer. AB - Clinical resistance to the second-generation antiandrogen enzalutamide in castration-resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights an unmet medical need for next-generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide) and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was determined that the AR-CB complex was not recruited to AR-regulated promoters and, like apo AR, remains sequestered in the cytoplasm, bound to heat shock proteins. Thus, we have identified third-generation AR antagonists whose unique mechanism of action suggests that they may have therapeutic potential in CRPC. PMID- 27501399 TI - Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation contraction Coupling. AB - Heart failure and cardiac arrhythmias are the leading causes of mortality and morbidity worldwide. However, the mechanism of pathogenesis and myocardial malfunction in the diseased heart remains to be fully clarified. Recent compelling evidence demonstrates that changes in the myofilament Ca(2+) sensitivity affect intracellular Ca(2+) homeostasis and ion channel activities in cardiac myocytes, the essential mechanisms responsible for the cardiac action potential and contraction in healthy and diseased hearts. Indeed, activities of ion channels and transporters underlying cardiac action potentials (e.g., Na(+), Ca(2+) and K(+) channels and the Na(+)-Ca(2+) exchanger) and intracellular Ca(2+) handling proteins (e.g., ryanodine receptors and Ca(2+)-ATPase in sarcoplasmic reticulum (SERCA2a) or phospholamban and its phosphorylation) are conventionally measured to evaluate the fundamental mechanisms of cardiac excitation-contraction (E-C) coupling. Both electrical activities in the membrane and intracellular Ca(2+) changes are the trigger signals of E-C coupling, whereas myofilament is the functional unit of contraction and relaxation, and myofilament Ca(2+) sensitivity is imperative in the implementation of myofibril performance. Nevertheless, few studies incorporate myofilament Ca(2+) sensitivity into the functional analysis of the myocardium unless it is the focus of the study. Here, we describe a protocol that measures sarcomere shortening/re-lengthening and the intracellular Ca(2+) level using Fura-2 AM (ratiometric detection) and evaluate the changes of myofilament Ca(2+) sensitivity in cardiac myocytes from rat hearts. The main aim is to emphasize that myofilament Ca(2+) sensitivity should be taken into consideration in E-C coupling for mechanistic analysis. Comprehensive investigation of ion channels, ion transporters, intracellular Ca(2+) handling, and myofilament Ca(2+) sensitivity that underlie myocyte contractility in healthy and diseased hearts will provide valuable information for designing more effective strategies of translational and therapeutic value. PMID- 27501400 TI - Transgressive phenotypes and generalist pollination in the floral evolution of Nicotiana polyploids. AB - Polyploidy is an important driving force in angiosperm evolution, and much research has focused on genetic, epigenetic and transcriptomic responses to allopolyploidy. Nicotiana is an excellent system in which to study allopolyploidy because half of the species are allotetraploids of different ages, allowing us to examine the trajectory of floral evolution over time. Here, we study the effects of allopolyploidy on floral morphology in Nicotiana, using corolla tube measurements and geometric morphometrics to quantify petal shape. We show that polyploid morphological divergence from the intermediate phenotype expected (based on progenitor morphology) increases with time for floral limb shape and tube length, and that most polyploids are distinct or transgressive in at least one trait. In addition, we show that polyploids tend to evolve shorter and wider corolla tubes, suggesting that allopolyploidy could provide an escape from specialist pollination via reversion to more generalist pollination strategies. PMID- 27501401 TI - Incidence and outcomes of bloodstream infections among hematopoietic cell transplant recipients from species commonly reported to be in over-the-counter probiotic formulations. AB - BACKGROUND: Probiotic supplementation has been promoted for numerous health conditions; however, safety in immunosuppressed patients is unknown. We evaluated bloodstream infections (BSIs) caused by common probiotic organisms in hematopoietic cell transplant recipients. METHODS: All blood culture (BC) results from a cohort of hematopoietic cell transplant recipients transplanted at Fred Hutchinson Cancer Research Center in Seattle, Washington, between 2002 and 2011 were reviewed. Patients with at least 1 positive BC for common probiotic organisms (Lactobacillus species, Bifidobacterium species, Streptococcus thermophilus, and Saccharomyces species) within 1 year post hematopoietic cell transplantation (HCT) were considered cases. Data were collected from center databases, which contain archived laboratory data, patient demographics, and clinical summaries. RESULTS: A total of 19/3796 (0.5%) patients developed a BSI from one of these organisms within 1 year post HCT; no Bifidobacterium species or S. thermophilus were identified. Cases had a median age of 49 years (interquartile range [IQR]: 39-53), and the majority were allogeneic hematopoietic cell transplant recipients (14/19, 74%). Most positive BCs were Lactobacillus species (18/19) and occurred at a median of 84 days (IQR: 34-127) post transplant. The incidence rate of Lactobacillus bacteremia was 1.62 cases per 100,000 patient-days; the highest rate occurred within 100 days post transplant (3.3 per 100,000 patient-days). Eight patients (44%) were diagnosed with acute graft-versus-host disease of the gut prior to the development of bacteremia. No mortality was attributable to any of these infections. CONCLUSION: Organisms frequently incorporated in available over-the-counter probiotics are infrequent causes of bacteremia after HCT. Studies evaluating the use of probiotics among high-risk patients are needed. PMID- 27501402 TI - A possible interaction between periostin and CD163+ skin-resident macrophages in pemphigus vulgaris and bullous pemphigoid. AB - Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are autoimmune blistering diseases, and substantial numbers of CD163+ tissue-associated macrophages (TAMs) are detected in both diseases. PV and BP possess different subsets of helper T cells, suggesting that the cytokine profiles of PV and BP might be different. The purpose of this study was to investigate the microenvironment of lesional skin and serum of PV and BP patients, focusing on the immunomodulatory factors related to TAMs, such as periostin (POSTN), chemokines, cytokines and matrix metalloproteinases (MMPs). We first performed immunohistological staining of POSTN in PV and BP lesions. POSTN was prominent in the superficial dermis in both PV and BP lesions. Next, to validate the activation of CD163+ TAMs in PV and BP patients, we examined the serum levels of soluble (s)CD163. The serum sCD163 levels in PV and BP patients are significantly higher than in healthy controls. To further elucidate the molecular mechanisms of the effects of POSTN on CD163+ TAMs in PV and BP, we examined chemokines, MMPs and cytokines selected by DNA microarray database. The serum CXCL5 levels from PV patients are significantly higher than those in BP patients and healthy controls. The IL-36gamma expression on infiltrating macrophages was prominent only in the lesional skin of PV, while the MMP12 deposition was detected in both PV and BP lesions. Our results shed light on the novel pathogenesis of PV through CD163+ TAMs. PMID- 27501403 TI - Mitral valve repair for moderate ischemic mitral regurgitation. PMID- 27501404 TI - Use of computer-aided holographic models improves performance in a cadaver dissection-based course in gross anatomy. AB - A compelling, innovative approach to teaching gross anatomy is the use of computer-aided holographic models. They allow for clean, time-saving dissection, manipulation of structures and appreciation of anatomical relationships, and potential elimination of the need for cadavers. The present study tests the hypothesis that using holographic models improves mastery of anatomical information. First-year medical students were taught gross anatomy using the dissection of donor cadavers, manipulation of digitized 3-dimensional holographic renderings, and examination of plastinated specimens. The effectiveness of these approaches was assessed by comparing students' performance on identification questions on cadavers (qC), holographic models (qH), and plastinated specimens (qP). Students in the top quintile of the class performed strongly on qC, qH, and qP. In contrast, performance by students in the bottom quintile was uneven; they scored best on qH. Performance on the qP was relatively non-discriminating. Students in the top quintile scored higher on the biological sciences section of the Medical College Admission Test (MCAT) than students in the lowest quintile, whereas students in the lowest quintile had higher scores on the verbal section of their MCATs. The availability of different approaches for presenting gross anatomy improves the success of students in mastering the material, particularly for students struggling with the information. The use of holographic models apparently reaches students who may be challenged to learn the material using traditional approaches. This may be linked to potentially predictive information gleaned through performance on the MCAT. Clin. Anat. 29:917-924, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27501405 TI - Complex vein graft intervention after double-valve transcatheter aortic valve replacement. PMID- 27501406 TI - Evolution of nonculprit coronary atherosclerotic plaques assessed by serial virtual histology intravascular ultrasound in patients with ST-segment elevation myocardial infarction and chronic total occlusion. AB - OBJECTIVE: The pathophysiology and natural course of coronary nonculprit plaques remain unclear. We investigated whether the short-term natural course of nonculprit plaques differs between ST-segment elevation myocardial infarction (STEMI) and chronic total occlusion (CTO) patients. METHODS: We performed serial virtual histology intravascular ultrasound on nonculprit plaques in 26 STEMI and 11 CTO lesions at baseline and the 6-month follow-up. RESULTS: At baseline, more lesions in the STEMI group were virtual histology intravascular ultrasound derived thin-cap fibroatheromas (TCFA; 76.9 vs. 18.1%, P=0.002). During the follow-up period, the plaque composition changed dynamically in the STEMI group (fibrofatty: 9.8+/-1.9 to 17.3+/-2.9%, P=0.030; dense calcium: 12.7+/-1.8 to 8.1+/-1.7%, P=0.026; necrotic core: 21.1+/-1.8 to 15.4+/-2.2%, P=0.052), with a consistent plaque size. In the CTO group, the plaque composition and plaque size remained consistent without a significant change. Also, more lesions in the STEMI group remained as or progressed to TCFA, compared with the CTO group (67 vs. 11%, P=0.089). Factors associated with a persistent TCFA or with a new development of TCFA were a large necrotic core volume index and the diagnosis of STEMI, whereas new statin usage was a protective factor. CONCLUSION: Nonculprit lesions in STEMI patients were more unstable at the baseline compared with those in CTO patients. During follow-up, nonculprit lesions in STEMI and CTO patients showed a distinct pattern of change; the former were stabilized in plaque composition, whereas the latter remained consistent. The diagnosis of STEMI and a large necrotic core volume were predictors of evolution to a TCFA, and new statin usage was a protective factor. PMID- 27501407 TI - Experimental Investigation of Secondary Flow Structures Downstream of a Model Type IV Stent Failure in a 180 degrees Curved Artery Test Section. AB - The arterial network in the human vasculature comprises of ubiquitously present blood vessels with complex geometries (branches, curvatures and tortuosity). Secondary flow structures are vortical flow patterns that occur in curved arteries due to the combined action of centrifugal forces, adverse pressure gradients and inflow characteristics. Such flow morphologies are greatly affected by pulsatility and multiple harmonics of physiological inflow conditions and vary greatly in size-strength-shape characteristics compared to non-physiological (steady and oscillatory) flows (1 - 7). Secondary flow structures may ultimately influence the wall shear stress and exposure time of blood-borne particles toward progression of atherosclerosis, restenosis, sensitization of platelets and thrombosis (4 - 6, 8 - 13). Therefore, the ability to detect and characterize these structures under laboratory-controlled conditions is precursor to further clinical investigations. A common surgical treatment to atherosclerosis is stent implantation, to open up stenosed arteries for unobstructed blood flow. But the concomitant flow perturbations due to stent installations result in multi-scale secondary flow morphologies (4 - 6). Progressively higher order complexities such as asymmetry and loss in coherence can be induced by ensuing stent failures vis-a vis those under unperturbed flows (5). These stent failures have been classified as "Types I-to-IV" based on failure considerations and clinical severity (14). This study presents a protocol for the experimental investigation of the complex secondary flow structures due to complete transverse stent fracture and linear displacement of fractured parts ("Type IV") in a curved artery model. The experimental method involves the implementation of particle image velocimetry (2C 2D PIV) techniques with an archetypal carotid artery inflow waveform, a refractive index matched blood-analog working fluid for phase-averaged measurements (15 - 18). Quantitative identification of secondary flow structures was achieved using concepts of flow physics, critical point theory and a novel wavelet transform algorithm applied to experimental PIV data (5, 6, 19 - 26). PMID- 27501408 TI - Double Gene Targeting Multiplex Polymerase Chain Reaction-Restriction Fragment Length Polymorphism Assay Discriminates Beef, Buffalo, and Pork Substitution in Frankfurter Products. AB - Beef, buffalo, and pork adulteration in the food chain is an emerging and sensitive issue. Current molecular techniques to authenticate these species depend on polymerase chain reaction (PCR) assays involving long and single targets which break down under natural decomposition and/or processing treatments. This novel multiplex polymerase chain reaction-restriction fragment length polymorphism assay targeted two different gene sites for each of the bovine, buffalo, and porcine materials. This authentication ensured better security, first through a complementation approach because it is highly unlikely that both sites will be missing under compromised states, and second through molecular fingerprints. Mitochondrial cytochrome b and ND5 genes were targeted, and all targets (73, 90, 106, 120, 138, and 146 bp) were stable under extreme boiling and autoclaving treatments. Target specificity and authenticity were ensured through cross-amplification reaction and restriction digestion of PCR products with AluI, EciI, FatI, and CviKI-1 enzymes. A survey of Malaysian frankfurter products revealed rampant substitution of beef with buffalo but purity in porcine materials. PMID- 27501409 TI - Simulator evaluation of a prototype device to reduce medication errors in anaesthesia. AB - We undertook a randomised control led trial to evaluate the effect of a prototype device which attaches to the intravenous drug administration port, and allows injection of intravenous drugs only after the user scans the barcode on the syringe label. This requires two steps: first, that the correct drug label is generated; and second, that the syringe-with-label is scanned before administration. Ten anaesthetists, who were unaware of the primary outcome being measured, administered general anaesthesia for two simulated standardised cases each without and with our prototype (control and intervention, respectively). The primary outcome measured was compliance with a safe drug administration procedure (defined as a two-step procedure where, step one is scanning a drug ampoule to print a label for a syringe and step two is scanning of the labelled syringe before administering it intravenously). A total of 182 intravenous drug administrations occurred in the study (91 in each group). We found that the use of our prototype increased safe drug administration behaviour in experienced anaesthetists; 33 (36.3% [95% CI 26-47%]) vs. 91 (100% [95% CI 96-100%]) in the control and intervention groups, respectively (p = 0.0001). PMID- 27501410 TI - Development of an adverse events reporting form for Korean folk medicine. AB - PURPOSE: We developed an adverse events (AEs) reporting form for Korean folk medicine. METHODS: The first version of the form was developed and tested in the clinical setting for spontaneous reporting of AEs. Additional revisions to the reporting form were made based on collected data and expert input. RESULTS: We developed an AEs reporting form for Korean folk medicine. The items of this form were based on patient information, folk medicine properties, and AEs. For causality assessment, folk medicine properties such as classification, common and vernacular names, scientific name, part used, harvesting time, storage conditions, purchasing route, product licensing, prescription, persons with similar exposure, any remnant of raw natural products collected from the patient, and cautions or contraindications were added. CONCLUSIONS: This is the first reporting form for AEs that incorporates important characteristics of Korean folk medicine. This form would have an important role in reporting adverse events for Korean folk medicine. (c) 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd. PMID- 27501411 TI - Capillary electrophoresis in a fused-silica capillary with surface roughness gradient. AB - The electro-osmotic flow, a significant factor in capillary electrophoretic separations, is very sensitive to small changes in structure and surface roughness of the inner surface of fused silica capillary. Besides a number of negative effects, the electro-osmotic flow can also have a positive effect on the separation. An example could be fused silica capillaries with homogenous surface roughness along their entire separation length as produced by etching with supercritical water. Different strains of methicillin-resistant and methicillin susceptible Staphylococcus aureus were separated on that type of capillaries. In the present study, fused-silica capillaries with a gradient of surface roughness were prepared and their basic behavior was studied in capillary zone electrophoresis with UV-visible detection. First the influence of the electro osmotic flow on the peak shape of a marker of electro-osmotic flow, thiourea, has been discussed. An antifungal agent, hydrophobic amphotericin B, and a protein marker, albumin, have been used as model analytes. A significant narrowing of the detected zones of the examined analytes was achieved in supercritical-water treated capillaries as compared to the electrophoretic separation in smooth capillaries. Minimum detectable amounts of 5 ng/mL amphotericin B and 5 MUg/mL albumin were reached with this method. PMID- 27501412 TI - Towards a systems-level understanding of development in the marine annelid Platynereis dumerilii. AB - Platynereis dumerilii is a segmented marine worm from the phylum Annelida, a member of the Lophotrochozoans. Platynereis is easily maintained in the lab and exhibits a highly stereotypic development through spiral cleavage with a small, transparent, free-swimming larva highly suitable for microscopy studies. A protocol for embryo microinjection in Platynereis has enabled several genetic tools to be developed, paving the way for functional studies. Recent Platynereis studies have provided insights into the function of several signaling pathways in development. Platynereis has also proven a useful model system for comparative evolutionary developmental studies, allowing the formation of new hypotheses on the evolution of neuroendocrine signaling, body patterning, and organ development. Combining existing large datasets of spatial gene expression mapping, cell lineage mapping, and neuronal circuits with functional analyses of developmental genes represents a promising approach for future studies aiming at a systems-level understanding of development in Platynereis. PMID- 27501413 TI - miR-346 promotes migration and invasion of nasopharyngeal carcinoma cells via targeting BRMS1. AB - The aim of this study is to determine the expression and roles of miR-346 in nasopharyngeal carcinoma (NPC). We showed that miR-346 was upregulated in NPC tissues compared with adjacent non-tumorous nasopharyngeal tissues. Inhibition of miR-346 significantly attenuated the migration and invasion of NPC cells. Luciferase reporter assay showed that miR-346 targeted the 3'-untranslated region (3'-UTR) of breast cancer metastasis suppressor 1 (BRMS1). Overexpression of miR 346 suppressed the endogenous expression of BRMS1 in NPC cells. There was a significant negative correlation between miR-346 and BRMS1 protein expression in NPC tissues (r = -0.372, P = 0.008). Rescue experiments demonstrated that overexpression of BRMS1 lacking the 3'-UTR impaired the invasiveness of NPC cells transfected with miR-346 mimic. Taken together, miR-346 shows the ability to promote the migration and invasion of nasopharyngeal cancer cells via targeting BRMS1 and represents a potential therapeutic target for NPC. PMID- 27501414 TI - SNPing SCNA regulatory elements gives a CRISPR view of genetic susceptibility in Parkinson's disease. PMID- 27501415 TI - Synthesis, Antibacterial, and Anticancer Evaluation of Novel Spiramycin-Like Conjugates Containing C(5) Triazole Arm. AB - Huisgen cycloaddition allowed obtaining of novel triazole-bridged antibiotics (6 16) with the reconstructed C(5) arm of spiramycin. (1)H-(1)H NOESY couplings indicated the structure of novel derivatives in solution and demonstrated that the rebuilt C(5) arm is slightly differently oriented relative to the aglycone part if compared to that of spiramycin (1). Combined analysis of biological data together with experimentally determined lipophilicity (clogP) and solubility show the importance of the chemical nature of the newly introduced triazole C(5) arm in the presence of attractive antibacterial and anticancer potency. The most cytotoxic active triazole conjugates having a hydrophobic and bulky C(5) arm showed higher selectivity toward cancer cell lines (HeLa, KB, MCF-7, Hep-G2, and U87) relative to HDF normal cells than that of the parent spiramycin. Our studies have demonstrated that the aldehyde group is not crucial for the presence of interesting antibacterial [MIC(S. pneumoniae) ~ 1.2 MUM] and anticancer [IC50(HepG2) ~ 6 MUM] properties of 16-membered lactone macrolides based on spiramycin's aglycone. PMID- 27501417 TI - Structural design approaches for creating fat droplet and starch granule mimetics. AB - This article focuses on hydrogel-based strategies for creating reduced calorie foods with desirable physicochemical, sensory, and nutritional properties. Initially, the role of fat droplets and starch granules in foods is discussed, and then different methods for fabricating hydrogel beads are reviewed, including phase separation, antisolvent precipitation, injection, and emulsion template methods. Finally, the potential application of hydrogel beads as fat droplet and starch granule replacements is discussed. There is still a need for large-scale, high-throughout, and economical methods of fabricating hydrogel beads suitable for utilization within the food industry. PMID- 27501416 TI - Genome-wide analysis suggests divergent evolution of lipid phosphotases/phosphotransferase genes in plants. AB - Genes of the LPPT (lipid phosphatase/phosphotransferase) family play important roles in lipid phosphorous transfer and triacylglycerol accumulation in plants. To provide overviews of the plant LPPT family and their overall relationships, here we carried out genome-wide identifications and analyses of plant LPPT family members. A total of 643 putative LPPT genes were identified from 48 sequenced plant genomes, among which 205 genes from 14 plants were chosen for further analyses. Plant LPPT genes belonged to three distinctive groups, namely the LPT (lipid phosphotransfease), LPP (lipid phosphatase), and pLPP (plastidic lipid phosphotransfease) groups. Genes of the LPT group could be further partitioned into three groups, two of which were only identified in terrestrial plants. Genes in the LPP and pLPP groups experienced duplications in early stages of plant evolution. Among 17 Zea mays LPPT genes, divergence of temporal-spatial expression patterns was revealed based on microarray data analysis. Peptide sequences of plant LPPT genes harbored different conserved motifs. A test of Branch Model versus One-ratio Model did not support significant selective pressures acting on different groups of LPPT genes, although quite different nonsynonymous evolutionary rates and selective pressures were observed. The complete picture of the plant LPPT family provided here should facilitate further investigations of plant LPPT genes and offer a better understanding of lipid biosynthesis in plants. PMID- 27501418 TI - Division of Responsibility. PMID- 27501419 TI - Determination of pholcodine in syrups and human plasma using the chemiluminescence system of tris(1,10 phenanthroline)ruthenium(II) and acidic Ce(IV). AB - Pholcodine is an opiate derivative drug which is widely used in pediatric medicine. In this study, a chemiluminescence (CL) method is described that determines pholcodine in human plasma and syrup samples. This method is based on the fact that pholcodine can greatly enhance the weak CL emission of reaction between tris(1,10 phenanthroline)ruthenium(II), Ru(phen)32+ , and acidic Ce(IV). The CL mechanism is described in detail using UV-vis light, fluorescence and CL spectra. Effects of chemical variables were investigated and under optimum conditions, CL intensity was proportional to the pholcodine concentration over the range 4.0 * 10-8 to 8.0 * 10-6 mol L-1 . The limit of detection (LOD) (S/N = 3) was 2.5 * 10-8 mol L-1 . Percent of relative standard deviations (%RSD) for 3.0 * 10-7 and 3.0 * 10-6 mol L-1 of pholcodine was 2.9 and 4.0%, respectively. Effects of common ingredients were investigated and the method was applied successfully to the determination of pholcodine in syrup samples and human plasma. PMID- 27501420 TI - Hyperglycemia in septic patients: an essential stress survival response in all, a robust marker for risk stratification in some, to be messed with in none. PMID- 27501422 TI - A SWAT model validation of nested-scale contemporaneous stream flow, suspended sediment and nutrients from a multiple-land-use watershed of the central USA. AB - There is an ongoing need to validate the accuracy of predictive model simulated pollutant yields, particularly from multiple-land-use (i.e. forested, agricultural, and urban) watersheds. However, there are seldom sufficient observed data sets available that supply requisite spatial and temporal resolution and coupled multi-parameter constituents for rigorous model performance assessment. Four years of hydroclimate and water quality data were used to validate SWAT model estimates of monthly stream flow, suspended sediment, total phosphorus, nitrate, nitrite, ammonium, and total inorganic nitrogen from 5 nested-scale gauging sites located in a multiple-land-use watershed of the central USA. The uncalibrated SWAT model satisfactorily simulated monthly stream flow with Nash-Sutcliffe efficiency (NSE) values ranging from 0.50 near the headwaters, to 0.75 near the watershed outlet. However, the uncalibrated model did not accurately simulate monthly sediment, total phosphorus, nitrate, nitrite, ammonium, and total inorganic nitrogen with NSE values<0.05. Calibrating the SWAT model to multiple gauging sites within the watershed improved estimates of monthly stream flow (NSE=0.83), sediment (NSE=0.78), total phosphorus (NSE=0.81), nitrate (NSE=0.90), and total inorganic nitrogen (NSE=0.86). However, NSE values were <-0.16 for nitrite and ammonium estimates. Additionally, model performance decreased for sediment, nitrate, and total inorganic nitrogen during the validation period with NSE values<0.62, 0.52, and 0.36, respectively. Results highlight the benefits of calibrating the SWAT model to multiple gauging sites and provide guidance to SWAT model (or similar models) users wishing to improve model performance at multiple scales. PMID- 27501421 TI - Moss and lichen biomonitoring of atmospheric mercury: A review. AB - Long-range transport and residence time of elemental Hg (Hg degrees ) in air promote global dispersion and deposition in remote ecosystems. Many biotic and abiotic factors contribute to the photoreduction and phytovolatilization of Hg from terrestrial ecosystems, and the assessment of deposition and volatilization fluxes is very challenging. Mosses and lichens are widespread in nature and constitute the dominant vegetation in alpine and polar ecosystems. This review surveys the results of Hg biomonitoring with cryptogams in areas with different Hg sources and deposition processes. Lichen and moss ecophysiology, and factors affecting Hg uptake and bioaccumulation are discussed. Although some laboratory experiments indicate a linear accumulation of Hg in cryptogams exposed to Hg degrees , without any significant release, in nature the Hg accumulated in cryptogams is in a dynamic equilibrium with Hg in air and decreases when organisms are transplanted to clean environments. Mercury concentrations in mosses and lichens have often been used to estimate concentrations and deposition fluxes of atmospheric Hg; however, Hg degrees exchanges between cryptogams and air, and the time necessary for mosses and lichens to equilibrate elemental composition with changing atmospheric chemistry, preclude reliable estimates. Biological processes of Hg uptake and exchange with air cannot be reproduced by mechanical collectors, and comparisons between Hg concentrations in biomonitors and those in atmospheric deposition are scarcely reliable. However, the Hg biomonitoring with mosses and lichens is easy and cheap and allows to locate "hot spots" of natural or anthropogenic emissions and to assess spatio-temporal changes in Hg deposition patterns. Climate change is affecting the global Hg cycle through the melting of sea-ice in coastal Polar Regions, and modifying Hg sequestration in mountain ecosystems. Despite limitations, large-scale monitoring of Hg with mosses and lichens may be used as a tool to evaluate the impact of global processes in remote ecosystems. PMID- 27501423 TI - Removal of trace level amounts of twelve sulfonamides from drinking water by UV activated peroxymonosulfate. AB - Trace levels of residual antibiotics in drinking water may threaten public health and become a serious problem in modern society. In this work, we investigated the degradation of twelve sulfonamides (SAs) at environmentally relevant trace level concentrations by three different methods: ultraviolet (UV) photolysis, peroxymonosulfate (PMS) oxidation, and UV-activated PMS (UV/PMS). Sulfaguanidine, sulfadiazine, sulfamerazine, sulfamethazine, sulfathiazole, sulfamethoxydiazine, and sulfadimethoxine were be effectively removed by direct UV photolysis and PMS oxidation. However, sulfanilamide, sulfamethizole, sulfamethoxazole, sulfisoxazole, and sulfachloropyridazine were not completely degraded, despite prolonging the UV irradiation time to 30min or increasing the PMS concentration to 5.0mg.L-1. UV/PMS provided more thorough elimination of SAs, as demonstrated by the complete removal of 200ng.L-1 of all SAs within 5min at an initial PMS concentration of 1.0mg.L-1. UV/PMS promoted SA decomposition more efficiently than UV photolysis or PMS oxidation alone. Bicarbonate concentration and pH had a negligible effect on SA degradation by UV/PMS. However, humic acid retarded the process. Removal of 200ng.L-1 of each SA from a sample of sand-filtered effluent from a drinking water treatment plant (DWTPs) was quickly and completely achieved by UV/PMS. Meanwhile, about 41% of the total organic carbon (TOC) was eliminated. Scavenging experiments showed that sulfate radical (SO4-) was the predominant species involved in the degradation. It is concluded that UV/PMS is a rapid and efficient method for removing trace-level SAs from drinking water. PMID- 27501424 TI - Effects of biocide treatments on the biofilm community in Domitilla's catacombs in Rome. AB - Different types of biofilms are widespread on lithic faces of the Catacombs of Domitilla (Rome, Italy) due to the favorable microclimatic conditions (temperature, high RH% and low irradiance). The biofilm, once established, becomes particularly dangerous due to the coverage of valuable surfaces causing spoilage, softening of materials and mineral precipitation. It is common practice to treat these surfaces with biocides in order to eradicate the microorganisms present. The aim of the present research was to compare the changes occurring to the microbial community present in the biofilm in one site of the Catacombs of Domitilla (CD15) before and after a biocide treatment (a mixture of quaternary ammonium compounds and octylisothiazolone, OIT), applied for a one month period. A multistep approach was followed, based on microscopy, cultural methods and molecular techniques (f-ITS and 16S rDNA sequencing), for the phenotypic and genetic analysis of the culturable microbial population. Our results highlighted that the biocide treatments had little effect against cyanobacteria, while the bacterial population increased in numbers but changed drastically in terms of diversity. In fact, some bacteria proliferate at the expense of the organic matter released by dead microorganisms as demonstrated by laboratory tests. Further, our data describe how the microbial interaction can have different responses depending on the favorable conditions for one kind of microorganism in respect to the others. This study exemplifies the real risks of applying biocide treatments on complex microbial communities and pinpoints the necessity of subjecting treatments to monitoring and reassessment. Moreover, the work showed the potential of bacteria isolated after the treatment for use, under controlled conditions, in combatting unwanted microbial growth in that they possess a positive tropism toward stressed microorganisms and high hydrolytic enzymatic activity against cell components (e.g. cellulose, chitin and pectin). A tentative protocol is proposed. PMID- 27501425 TI - Multi-matrix quantification and risk assessment of pesticides in the longest river of the Iberian peninsula. AB - The distribution of pesticides in dissolved aqueous phase (DAP), suspended particulate matter (SPM) and Scrobicularia plana soft tissues from the Tagus River estuary was determined to evaluate the chemicals pollution status and their hazard potential in this area. Samples were collected in 6 campaigns (December 2012-October 2013), from 3 strategical sites, and analysed via different extraction procedures followed by gas chromatography tandem mass spectrometry (GC MS/MS) determination. The contamination profile among matrices (DAP, SPM, and soft tissue from bivalves (STB)) was marked by average concentrations of 345ng/L, 0.51mg/kg, and 0.02mg/kg, respectively, with several samples above the 2013/39/EU Directive of environmental quality standards (EQS); no differences were observed between sex. A wider range of pesticides was present in STB (n=53) than in SPM (n=36) and DAP (n=19) matrices. Sediment-water partition coefficient, bioaccumulation factor in both DAP and SPM fraction were estimated ranging between 2.5 and 4.4 and 0.008-2799, respectively. The spatial distribution of most pesticides and physicochemical parameters were consistent, indicating a pollution pattern primarily near the Trancao River mouth. Due to the presence of the target compounds, calculated risk quotients pointed out potential hazards for aquatic organisms, mainly to invertebrates. The estimated average daily intake, theoretical maximum daily intake, and hazard quotient of the studied pesticides via bivalve ingestion-indicated no risk for human health, although it is important to note possible biomagnification processes that may happen along the estuarine food-chain. PMID- 27501426 TI - Biodegradation and detoxification of naphthenic acids in oil sands process affected waters. AB - After oil sands process affected water (OSPW) was treated in a continuous flow biofilm reactor, about 40% of the organic compounds in the acid extractable fraction (AEF) including naphthenic acids (NAs) were degraded resulting in a reduction of 73% in the Microtox acute toxicity and of 22% in the yeast estrogenic assay. Using effect directed analysis, treated and untreated OSPW were fractionated by solid phase extraction and the fractions with the largest decrease in toxicity and estrogenicity were selected for analysis by electrospray ionization combined with linear ion trap and a high-resolution Orbitrap mass spectrometer (negative ion mode). The aim of this study was to determine whether compositional changes between the untreated and treated fractions provide insight related to biodegradation and detoxification of NAs. The O2S, O3S and O4S compounds were either not major contributors of toxicity or estrogenicity or the more toxic or estrogenic ones were biodegraded. The O3- and O4-NAs seem to be more readily metabolized than O2NAs and their degradation would contribute to detoxification. The decrease in acute toxicity may be associated with the degradation of C12 and C13 bicyclic and C12-C14 tricyclic NAs while the decrease in estrogenicity may be linked to the degradation of C16 O2-NAs with double bond equivalents (DBE)=5 and 6, C16 and 17 O2-NAs with DBE=7, and C19-O2-NAs with DBE=8. The residual acute toxicity may be caused by recalcitrant components and/or degradation products such as the O2 bicyclic and tricyclic NAs, particularly the C14 and C15 bicyclic and C14-C16 tricyclic NAs as well as the polycyclic aromatic NAs (DBE>=5 compounds). The decrease in estrogenicity may be linked to the degradation of the O3 and O4 oxidized NAs while much of the residual estrogenicity may be due to the recalcitrant polycyclic aromatic O2-NAs. Hence, treatment to further detoxify OSPW should target these compounds. PMID- 27501427 TI - The phosphorus release pathways and their mechanisms driven by organic carbon and nitrogen in sediments of eutrophic shallow lakes. AB - To reveal phosphorus (P) release pathways from sediment and their mechanisms induced by organic matter enrichment, 116 sampling sites (including surface water and sediment) in 29 shallow lakes with different eutrophic degrees in Wuhan city, China, were investigated from July 2011 to November 2011. Empirical relationship and structural equation model indicated that the decomposition of total organic matter (TOM), including proteins (PRT), carbo-hydrates (CHO) and lipids (especially PRT) mediated by extracellular enzymes, accelerated the formation of anaerobic status. On the other hand, coupled nitrification-denitrification caused by ammonium (NH4+-N) accumulation due to PRT decomposition further aggravated anaerobic status and nitrate removal in terms of the increase of dehydrogenase activity (DHA). As a consequence, ferric iron was reduced to ferrous iron and soluble reactive phosphorus (SRP) was released from iron-bound phosphorus (Fe(OOH)~P) in sediments. In addition, extracellular alkaline phosphatase can be induced by organic carbon and nitrogen on condition that the input of nitrogen (N) and carbon (C) exceeded by far that of P. Taken together, enrichment of N and C can result in P release through the formation of anaerobic status and alkaline phosphatase production. Hence, we indicated that a close coupling existed among C, N and P cycles. PMID- 27501428 TI - Measurement of rare isotopologues of nitrous oxide by high-resolution multi collector mass spectrometry. AB - RATIONALE: Bulk and position-specific stable isotope characterization of nitrous oxide represents one of the most powerful tools for identifying its environmental sources and sinks. Constraining (14) N(15) N(18) O and (15) N(14) N(18) O will add two new dimensions to our ability to uniquely fingerprint N2 O sources. METHODS: We describe a technique to measure six singly and doubly substituted isotopic variants of N2 O, constraining the values of delta(15) N, delta(18) O, ?(17) O, (15) N site preference, and the clumped isotopomers (14) N(15) N(18) O and (15) N(14) N(18) O. The technique uses a Thermo MAT 253 Ultra, a high resolution multi-collector gas source isotope ratio mass spectrometer. It requires 8-10 hours per sample and ~10 micromoles or more of pure N2 O. RESULTS: We demonstrate the precision and accuracy of these measurements by analyzing N2 O brought to equilibrium in its position-specific and clumped isotopic composition by heating in the presence of a catalyst. Finally, an illustrative analysis of biogenic N2 O from a denitrifying bacterium suggests that its clumped isotopic composition is controlled by kinetic isotope effects in N2 O production. CONCLUSIONS: We developed a method for measuring six isotopic variants of N2 O and tested it with analyses of biogenic N2 O. The added isotopic constraints provided by these measurements will enhance our ability to apportion N2 O sources. PMID- 27501429 TI - Compound-specific bromine isotope ratio analysis using gas chromatography/quadrupole mass spectrometry. AB - RATIONALE: Brominated organic compounds (BOCs) are common persistent toxic pollutants. Compound-specific stable bromine isotope ratio analysis is one of the potential approaches for investigating BOC transformations in the environment. In the present study, we demonstrate that precise bromine isotope analysis of BOCs can be successfully performed by gas chromatography/quadrupole mass spectrometry (GC/qMS) systems that are widely available in analytical laboratories. METHODS: Optimization and validation of the GC/qMS method were performed by analysis of bromoform, 3-bromophenol and 4-bromotoluene. In addition, comparison of the results obtained by GC/qMS and GC/multi-collector inductively coupled plasma mass spectrometry (MC-ICPMS) for 1,2-dibromoethane and 3-bromophenol samples with different bromine isotope composition was carried out to evaluate the analytical performance of the developed method. RESULTS: Precisions in the range 0.2-0.30/00 were attained for sample amounts in the range of tens to thousands pmol. Good correlation between the results obtained by GC/qMS and GC/MC-ICPMS for laboratory standard materials (1,2-dibromoethane and 3-bromophenol) (regression coefficient R(2) > 0.98) was achieved. CONCLUSIONS: The GC/qMS method for bromine isotope analysis shows a good performance and can be applied routinely for studying transformations of BOCs. Due to the observed dependence of the measured isotope ratios on the amount of the analyte and the calculation scheme applied, normalization of the results versus appropriate standards is required for source attribution applications. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27501431 TI - Red deer bone and antler collagen are not isotopically equivalent in carbon and nitrogen. AB - RATIONALE: Bone and antler collagen delta(13) C and delta(15) N values are often assumed to be equivalent when measured in palaeodietary, palaeoclimate and palaeocological studies. Although compositionally similar, bone grows slowly and is remodelled whereas antler growth is rapid and remodelling does not occur. These different patterns of growth could result in isotopic difference within antler and between the two tissue types. Here we test whether red deer (Cervus elaphus) bone and antler delta(13) C and delta(15) N values are equivalent, and whether intra-antler isotopic values are uniform. METHODS: Bone and antler were isotopically analysed from six stags that lived in a temperate maritime climate on the Isle of Rum, Scotland. Multiple antlers from different years were sampled per individual, together with a single bone sample per individual. Up to 12 samples were taken along the length of each antler (total of 25 antlers, 259 samples) so that a chronological record of the isotopic composition during antler growth could be obtained. Collagen was extracted and its delta(13) C and delta(15) N values were measured by continuous-flow isotope ratio mass spectrometry. RESULTS: Intra-antler collagen isotope signatures vary, and show that not all antlers from an individual or a growth year are equivalent in carbon and nitrogen isotopic ratios. delta(15) N values typically increase with distance along antler length, but no overall trend is observed in delta(13) C values. An isotopic offset is visible between bone and antler, with bone delta(13) C and delta(15) N values being higher in most cases. CONCLUSIONS: Bone and antler collagen delta(13) C and delta(15) N values are not isotopically equivalent and are therefore not directly comparable in palaeodietary, palaeoclimate and palaeocological studies. Bone and antler collagen isotopic differences probably relate to differential metabolic processes during the formation of the two tissues. Intra- and inter-antler isotopic variations probably reflect the isotopic composition of an individual's diet rather than physiological parameters, and may have the potential to provide high-resolution individual specific information in modern and ancient cervid populations. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27501430 TI - Measurement of the accurate mass of a 50 MDa infectious virus. AB - RATIONALE: Bacteriophage P22 is believed to contain a total of 521 copies of 9 different proteins and a 41,724 base pair genome. Despite its enormous size and complexity, phage P22 can be electrosprayed, and it remains intact in ultra-high vacuum where its molar mass distribution has been measured. METHODS: Phage P22 virions were generated by complementation in Salmonella enterica and purified. They were transferred into 100 mM ammonium acetate and then electrosprayed. The masses of individual virions were determined using charge detection mass spectrometry. RESULTS: The stoichiometry of the protein components of phage P22 is sufficiently well known that the theoretical molar mass can be determined to within a narrow range. The measured average molar mass of phage P22, 52,180 +/- 59 kDa, is consistent with the theoretical molar mass and supports the proposed stoichiometry of the components. The intrinsic width of the phage P22 mass distribution can be accounted for by the distribution of DNA packaged by the headful mechanism. CONCLUSIONS: At over 50 MDa, phage P22 is the largest object with a well-defined molar mass to be analyzed by mass spectrometry. The narrow measured mass distribution indicates that the virions survive the transition into the gas phase intact. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27501432 TI - Resonance ejection mass scan using dipole excitation with a non-integer frequency ratio in a digital linear ion trap mass spectrometer. PMID- 27501433 TI - Synthesis of Wavelength-shifting DNA Hybridization Probes by Using Photostable Cyanine Dyes. AB - In this protocol, we demonstrate a method for the synthesis of 2'-alkyne modified deoxyribonucleic acid (DNA) strands by automated solid phase synthesis using standard phosphoramidite chemistry. Oligonucleotides are post-synthetically labeled by two new photostable cyanine dyes using copper-catalyzed click chemistry. The synthesis of both donor and acceptor dye is described and is performed in three consecutive steps. With the DNA as the surrounding architecture, these two dyes undergo an energy transfer when they are brought into close proximity by hybridization. Therefore, annealing of two single stranded DNA strands is visualized by a change of fluorescence color. This color change is characterized by fluorescence spectroscopy but can also be directly observed by using a handheld ultraviolet (UV) lamp. The concept of a dual fluorescence color readout makes these oligonucleotide probes excellent tools for molecular imaging especially when the described photostable dyes are used. Thereby, photobleaching of the imaging probes is prevented, and biological processes can be observed in real time for a longer time period. PMID- 27501434 TI - Practitioner Review: Psychological treatments for children and adolescents with conduct disorder problems - a systematic review and meta-analysis. AB - BACKGROUND: This meta-analysis evaluates the efficacy of nonpharmacological treatments for conduct disorder (CD) problems in children and adolescents, based on child, parent and teacher report. METHODS: PubMed, PsycINFO and EMBASE were searched for peer-reviewed articles published between January 1970 and March 2015. Main inclusion criteria were nonpharmacological treatment, participants younger than 18 years, clinical CD problems/diagnosis, randomized controlled trials and inclusion of at least one CD problem-related outcome. Treatment efficacy is expressed in effect sizes (ESs) calculated for each rater (parent, teacher, self and blinded observer). RESULTS: Of 1,549 articles retrieved, 17 (published between June 2004 and January 2014) describing 19 interventions met the inclusion criteria. All studies used psychological treatments; only three studies included a blinded observer to rate CD problems. Most studies were of very poor to fair quality. ESs were significant but small for parent-reported outcomes (0.36, 95% CI = 0.27-0.47), teacher-reported outcomes (0.26, 95% CI = 0.12-0.49) and blinded observer outcomes (0.26, 95% CI = 0.06-0.47), and they were nonsignificant for self-reported outcomes (-0.01, 95% CI = -0.25 to 0.23). Comorbidity, gender, age, number of sessions, duration, intervention type, setting, medication use or dropout percentage did not influence the effect of treatment. CONCLUSIONS: Psychological treatments have a small effect in reducing parent-, teacher- and observer-rated CD problems in children and adolescents with clinical CD problems/diagnosis. There is not enough evidence to support one specific psychological treatment over another. Future studies should investigate the influence of participant characteristics (e.g. age of CD onset), use more homogeneous outcome measures and allow better evaluation of study quality. Many reports failed to provide detailed information to allow optimization of psychological treatment strategies. PMID- 27501435 TI - Does interim 18F-FDG-PET response-adapted therapy really benefit advanced-stage Hodgkin lymphoma patients? PMID- 27501436 TI - Activity concentration measurements using a conjugate gradient (Siemens xSPECT) reconstruction algorithm in SPECT/CT. AB - The interest in quantitative single photon emission computer tomography (SPECT) shows potential in a number of clinical applications and now several vendors are providing software and hardware solutions to allow 'SUV-SPECT' to mirror metrics used in PET imaging. This brief technical report assesses the accuracy of activity concentration measurements using a new algorithm 'xSPECT' from Siemens Healthcare. SPECT/CT data were acquired from a uniform cylinder with 5, 10, 15 and 20 s/projection and NEMA image quality phantom with 25 s/projection. The NEMA phantom had hot spheres filled with an 8 : 1 activity concentration relative to the background compartment. Reconstructions were performed using parameters defined by manufacturer presets available with the algorithm. The accuracy of activity concentration measurements was assessed. A dose calibrator-camera cross calibration factor (CCF) was derived from the uniform phantom data. In uniform phantom images, a positive bias was observed, ranging from ~6% in the lower count images to ~4% in the higher-count images. On the basis of the higher-count data, a CCF of 0.96 was derived. As expected, considerable negative bias was measured in the NEMA spheres using region mean values whereas positive bias was measured in the four largest NEMA spheres. Nonmonotonically increasing recovery curves for the hot spheres suggested the presence of Gibbs edge enhancement from resolution modelling. Sufficiently accurate activity concentration measurements can easily be measured on images reconstructed with the xSPECT algorithm without a CCF. However, the use of a CCF is likely to improve accuracy further. A manual conversion of voxel values into SUV should be possible, provided that the patient weight, injected activity and time between injection and imaging are all known accurately. PMID- 27501437 TI - Controlling Molecular Ordering in Aqueous Conducting Polymers Using Ionic Liquids. AB - The molecular ordering of aqueous conducting polymers is controlled using a rational method. By introducing various ionic liquids, which have designed electrostatic interactions to PEDOT:PSS solutions, the evolution of the molecular ordering of the PEDOT is manipulated. Consequently, highly ordered nanostructures are achieved with a reduced pi-pi stacking distance of ~3.38 A and, thus, a maximum sigmadc of ~2100 S cm-1 . PMID- 27501438 TI - Cognitive behavioural therapy (CBT), third-wave CBT and interpersonal therapy (IPT) based interventions for preventing depression in children and adolescents. AB - BACKGROUND: Depression is common in young people. It has a marked negative impact and is associated with self-harm and suicide. Preventing its onset would be an important advance in public health. This is an update of a Cochrane review that was last updated in 2011. OBJECTIVES: To determine whether evidence-based psychological interventions (including cognitive behavioural therapy (CBT), interpersonal therapy (IPT) and third wave CBT)) are effective in preventing the onset of depressive disorder in children and adolescents. SEARCH METHODS: We searched the specialised register of the Cochrane Common Mental Disorders Group (CCMDCTR to 11 September 2015), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). We searched conference abstracts and reference lists of included trials and reviews, and contacted experts in the field. SELECTION CRITERIA: We included randomised controlled trials of an evidence-based psychological prevention programme compared with any comparison control for young people aged 5 to 19 years, who did not currently meet diagnostic criteria for depression. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion and rated their risk of bias. We adjusted sample sizes to take account of cluster designs and multiple comparisons. We contacted trial authors for additional information where needed. We assessed the quality of evidence for the primary outcomes using GRADE. MAIN RESULTS: We included 83 trials in this review. The majority of trials (67) were carried out in school settings with eight in colleges or universities, four in clinical settings, three in the community and four in mixed settings. Twenty-nine trials were carried out in unselected populations and 53 in targeted populations.For the primary outcome of depression diagnosis at medium-term follow-up (up to 12 months), there were 32 trials with 5965 participants and the risk of having a diagnosis of depression was reduced for participants receiving an intervention compared to those receiving no intervention (risk difference (RD) -0.03, 95% confidence interval (CI) -0.05 to 0.01; P value = 0.01). We rated this evidence as moderate quality according to the GRADE criteria. There were 70 trials (73 trial arms) with 13,829 participants that contributed to the analysis for the primary outcome of depression symptoms (self-rated) at the post-intervention time point, with results showing a small but statistically significant effect (standardised mean difference (SMD) -0.21, 95% CI -0.27 to -0.15; P value < 0.0001). This effect persisted to the short-term assessment point (up to three months) (SMD -0.31, 95% CI -0.45 to -0.17; P value < 0.0001; 16 studies; 1558 participants) and medium-term (4 to 12 months) assessment point (SMD -0.12, 95% CI -0.18 to -0.05; P value = 0.0002; 53 studies; 11,913 participants); however, the effect was no longer evident at the long-term follow-up. We rated this evidence as low to moderate quality according to the GRADE criteria.The evidence from this review is unclear with regard to whether the type of population modified the overall effects; there was statistically significant moderation of the overall effect for depression symptoms (P value = 0.0002), but not for depressive disorder (P value = 0.08). For trials implemented in universal populations there was no effect for depression diagnosis (RD -0.01, 95% CI -0.03 to 0.01) and a small effect for depression symptoms (SMD -0.11, 95% CI -0.17 to -0.05). For trials implemented in targeted populations there was a statistically significantly beneficial effect of intervention (depression diagnosis RD -0.04, 95% CI -0.07 to -0.01; depression symptoms SMD -0.32, 95% CI 0.42 to -0.23). Of note were the lack of attention placebo-controlled trials in targeted populations (none for depression diagnosis and four for depression symptoms). Among trials implemented in universal populations a number used an attention placebo comparison in which the intervention consistently showed no effect. AUTHORS' CONCLUSIONS: Overall the results show small positive benefits of depression prevention, for both the primary outcomes of self-rated depressive symptoms post-intervention and depression diagnosis up to 12 months (but not beyond). Estimates of numbers needed to treat to benefit (NNTB = 11) compare well with other public health interventions. However, the evidence was of moderate to low quality using the GRADE framework and the results were heterogeneous. Prevention programmes delivered to universal populations showed a sobering lack of effect when compared with an attention placebo control. Interventions delivered to targeted populations, particularly those selected on the basis of depression symptoms, had larger effect sizes, but these seldom used an attention placebo comparison and there are practical difficulties inherent in the implementation of targeted programmes. We conclude that there is still not enough evidence to support the implementation of depression prevention programmes.Future research should focus on current gaps in our knowledge. Given the relative lack of evidence for universal interventions compared with attention placebo controls and the poor results from well-conducted effectiveness trials of universal interventions, in our opinion any future such trials should test a depression prevention programme in an indicated targeted population using a credible attention placebo comparison group. Depressive disorder as the primary outcome should be measured over the longer term, as well as clinician-rated depression. Such a trial should consider scalability as well as the potential for the intervention to do harm. PMID- 27501439 TI - Beneficial effects of live and dead Salmonella-based vector strain on the course of colitis in mice. AB - : Dysbiosis of intestinal microbiota and hyperactive immune responses seem to be crucial for the uncontrolled inflammation in inflammatory bowel diseases (IBD). Modulation of the microbiome and immune stimulation of the intestinal epithelium were suggested as therapeutic approaches. In this study, live attenuated and dead bacterial cells of Salmonella Typhimurium SL7207 - a widely used bacterial vector for gene therapy were administered in DSS-induced colitis in mice. C57BL/6 mice were divided into four groups. The first group received pure water (CTRL). The other three groups received 2% dextran sulphate sodium (DSS) to induce colitis. Two DSS groups were treated with live attenuated (DSS live) or inactivated (DSS dead) Salmonella by gastric gavage. Intake of 2% DSS caused weight loss in all DSS groups compared to control mice with some improvement in DSS live group on the last day of the experiment. Significantly longer colon and improved stool consistency were reported in DSS live group, but not DSS dead group, when compared with DSS. Significant enlargement of spleens was observed only in DSS and DSS dead groups compared to control. Significant differences in stool consistency, colon length and spleen enlargement were observed between DSS live and DSS dead groups with beneficial effects of live bacteria. Interestingly, significant decrease in myeloperoxidase activity was detected in both, DSS live and DSS dead groups compared to the DSS group. On the basis of these results, progression of colitis seems to be beneficially influenced not only by live attenuated but to some extent also by inactivated Salmonella Typhimurium SL7207. Our results provide evidence that Salmonella-based gene therapy vectors are able to positively alter gut homeostasis during DSS-induced colitis. SIGNIFICANCE AND IMPACT OF THE STUDY: Restoration of gut homeostasis has a great importance in IBD. Here, we tested the nonspecific effect of the strain Salmonella Typhimurium SL7207 on the course of colitis to find out whether the potential effect would be mediated by activity of live bacterial cells or by bacterial structures that are also present in dead bacteria. Live bacterial therapy of colitis showed a beneficial effect on clinical signs as well as on macroscopic and inflammatory markers of colitis. On the other hand, therapy with dead bacteria showed inconsistent effects, negative in most clinical outcomes, positive especially in myeloperoxidase activity. Our data indicate that the beneficial effect of bacterial gene therapy vectors carrying therapeutic genes might be, at least partially, caused by the bacterial vector instead of the therapeutic gene. PMID- 27501440 TI - Survey of the anti-factor IX immunoglobulin profiles in patients with hemophilia B using a fluorescence-based immunoassay. AB - : Essentials Studies characterizing neutralizing antibodies (inhibitors) in hemophilia B (HB) are lacking. The current study describes anti-factor (F) IX antibody profiles in 37 patients who have HB. Anti-FIX IgG4 levels exhibited a strong positive correlation with Nijmegen-Bethesda results. These data will help to more clearly define, predict, and treat alloantibody formation in HB. SUMMARY: Background Hemophilia B (HB) is an inherited bleeding disorder caused by the absence or dysfunction of coagulation factor IX (FIX). A subset of patients who have HB develop neutralizing alloantibodies (inhibitors) against FIX after infusion therapy. HB prevalence and the proportion of patients who develop inhibitors are much lower than those for hemophilia A (HA), which makes studies of inhibitors in patients with HB challenging due to the limited availability of samples. As a result, there is a knowledge gap regarding HB inhibitors. Objective Evaluate the largest group of patients with inhibitor-positive HB studied to date to assess the relationship between anti-FIX antibody profiles and inhibitor formation. Methods A fluorescence immunoassay was used to detect anti-FIX antibodies in plasma samples from 37 patients with HB. Results Assessments of antibody profiles showed that anti-FIX IgG1-4 , IgA, and IgE were detected significantly more often in patients with a positive Nijmegen-Bethesda assay (NBA). All NBA-positive samples were positive for IgG4 . Anti-FIX IgG4 demonstrated a strong correlation with the NBA, while correlations were significant, yet more moderate, for anti-FIX IgG1-2 and IgA. Conclusions The anti FIX antibody profile in HB patients who develop inhibitors is diverse and correlates well with the NBA across immunoglobulin (sub)class, and anti-FIX IgG4 is particularly relevant to functional inhibition. The anti-FIX fluorescence immunoassay may serve as a useful tool to confirm the presence of antibodies in patients who have low positive NBA results and to more clearly define, predict, and treat alloantibody formation against FIX. PMID- 27501442 TI - An improved non-Cartesian partially parallel imaging by exploiting artificial sparsity. AB - PURPOSE: To improve the performance of non-Cartesian partially parallel imaging (PPI) by exploiting artificial sparsity, the generalized autocalibrating partially parallel acquisitions (GRAPPA) operator for wider band lines (GROWL) is taken as a specific example for explanation. THEORY: This work is based on the GRAPPA-like PPI having an improved performance when the to-be-reconstructed image is sparse in the image domain. METHODS: A systematic scheme is proposed to artificially generate the sparse image for non-Cartesian trajectory. Using GROWL as a specific non-Cartesian PPI method, artificial sparsity-enhanced GROWL (ARTS GROWL) is used to demonstrate the efficiency of the proposed scheme. The ARTS GROWL consists of three steps: 1) generating synthetic k-space data corresponding to an image with smaller support, that is, artificial sparsity; 2) applying GROWL to the synthetic k-space data from previous step; and 3) recovering the final image from the reconstruction with the processed data. RESULTS: For simulation and in vivo data, the experiments demonstrate that the proposed ARTS-GROWL significantly reduces the reconstruction errors compared with the conventional GROWL technique for the tested acceleration factors. CONCLUSION: Taking ARTS GROWL, for instance, experimental results indicate that artificial sparsity improved the signal-to-noise ratio and normalized root-mean-square error of non Cartesian PPI. Magn Reson Med 78:271-279, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27501441 TI - Tau and spectraplakins promote synapse formation and maintenance through Jun kinase and neuronal trafficking. AB - The mechanisms regulating synapse numbers during development and ageing are essential for normal brain function and closely linked to brain disorders including dementias. Using Drosophila, we demonstrate roles of the microtubule associated protein Tau in regulating synapse numbers, thus unravelling an important cellular requirement of normal Tau. In this context, we find that Tau displays a strong functional overlap with microtubule-binding spectraplakins, establishing new links between two different neurodegenerative factors. Tau and the spectraplakin Short Stop act upstream of a three-step regulatory cascade ensuring adequate delivery of synaptic proteins. This cascade involves microtubule stability as the initial trigger, JNK signalling as the central mediator, and kinesin-3 mediated axonal transport as the key effector. This cascade acts during development (synapse formation) and ageing (synapse maintenance) alike. Therefore, our findings suggest novel explanations for intellectual disability in Tau deficient individuals, as well as early synapse loss in dementias including Alzheimer's disease. PMID- 27501443 TI - Unconscious Affective Responses to Food. AB - Affective or hedonic responses to food are crucial for humans, both advantageously (e.g., enhancing survival) and disadvantageously (e.g., promoting overeating and lifestyle-related disease). Although previous psychological studies have reported evidence of unconscious cognitive and behavioral processing related to food, it remains unknown whether affective reactions to food can be triggered unconsciously and its relationship with daily eating behaviors. We investigated these issues by using the subliminal affective priming paradigm. Photographs of food or corresponding mosaic images were presented in the peripheral visual field for 33 ms. Target photos of faces with emotionally neutral expressions were then presented, and participants rated their preferences for the faces. Eating behaviors were also assessed using questionnaires. The food images, relative to the mosaics, increased participants' preference for subsequent target faces. Furthermore, the difference in the preference induced by food versus mosaic images was positively correlated with the tendency to engage in external eating. These results suggest that unconscious affective reactions are elicited by the sight of food and that these responses contribute to daily eating behaviors related to overeating. PMID- 27501444 TI - Cellular and Molecular Mechanisms of MT1-MMP-Dependent Cancer Cell Invasion. AB - Metastasis is responsible for most cancer-associated deaths. Accumulating evidence based on 3D migration models has revealed a diversity of invasive migratory schemes reflecting the plasticity of tumor cells to switch between proteolytic and nonproteolytic modes of invasion. Yet, initial stages of localized regional tumor dissemination require proteolytic remodeling of the extracellular matrix to overcome tissue barriers. Recent data indicate that surface-exposed membrane type 1-matrix metalloproteinase (MT1-MMP), belonging to a group of membrane-anchored MMPs, plays a central role in pericellular matrix degradation during basement membrane and interstitial tissue transmigration programs. In addition, a large body of work indicates that MT1-MMP is targeted to specialized actin-rich cell protrusions termed invadopodia, which are responsible for matrix degradation. This review describes the multistep assembly of actin based invadopodia in molecular details. Mechanisms underlying MT1-MMP traffic to invadopodia through endocytosis/recycling cycles, which are key to the invasive program of carcinoma cells, are discussed. PMID- 27501445 TI - Cell Competition: Mechanisms and Physiological Roles. AB - Cell-competitive interactions are widespread in nature and determine the outcome of a vast variety of biological processes. A particular class of competitive interactions takes place when alterations in intrinsic cellular properties are sensed nonautonomously by comparison between neighboring cells, resulting in the selective elimination of one cell population. This type of cell competition was first described four decades ago in developing epithelia of Drosophila. In the last 15 years, further molecular and cellular analyses have provided essential knowledge about the mechanisms, universality, and physiological relevance of cell competition. The two main phenomena triggering cell competition are alterations in cellular metabolic status and alterations in epithelial apico-basal polarity, while other reported pathways are less characterized. Cell competition plays essential roles in quality control, homeostasis, and repair of developing and adult tissues, and depending on the context, it may function as a tumor suppressing or tumor-promoting mechanism. PMID- 27501446 TI - Transcriptional Control of Developmental Cell Behaviors. AB - Tissue-specific transcription regulators emerged as key developmental control genes, which operate in the context of complex gene regulatory networks (GRNs) to coordinate progressive cell fate specification and tissue morphogenesis. We discuss how GRNs control the individual cell behaviors underlying complex morphogenetic events. Cell behaviors classically range from mesenchymal cell motility to cell shape changes in epithelial sheets. These behaviors emerge from the tissue-specific, multiscale integration of the local activities of universal and pleiotropic effectors, which underlie modular subcellular processes including cytoskeletal dynamics, cell-cell and cell-matrix adhesion, signaling, polarity, and vesicle trafficking. Extrinsic cues and intrinsic cell competence determine the subcellular spatiotemporal patterns of effector activities. GRNs influence most subcellular activities by controlling only a fraction of the effector-coding genes, which we argue is enriched in effectors involved in reading and processing the extrinsic cues to contextualize intrinsic subcellular processes and canalize developmental cell behaviors. The properties of the transcription-cell behavior interface have profound implications for evolution and disease. PMID- 27501447 TI - Focal Adhesion-Independent Cell Migration. AB - Cell migration is central to a multitude of physiological processes, including embryonic development, immune surveillance, and wound healing, and deregulated migration is key to cancer dissemination. Decades of investigations have uncovered many of the molecular and physical mechanisms underlying cell migration. Together with protrusion extension and cell body retraction, adhesion to the substrate via specific focal adhesion points has long been considered an essential step in cell migration. Although this is true for cells moving on two dimensional substrates, recent studies have demonstrated that focal adhesions are not required for cells moving in three dimensions, in which confinement is sufficient to maintain a cell in contact with its substrate. Here, we review the investigations that have led to challenging the requirement of specific adhesions for migration, discuss the physical mechanisms proposed for cell body translocation during focal adhesion-independent migration, and highlight the remaining open questions for the future. PMID- 27501448 TI - Genotypes, Networks, Phenotypes: Moving Toward Plant Systems Genetics. AB - One of the central goals in biology is to understand how and how much of the phenotype of an organism is encoded in its genome. Although many genes that are crucial for organismal processes have been identified, much less is known about the genetic bases underlying quantitative phenotypic differences in natural populations. We discuss the fundamental gap between the large body of knowledge generated over the past decades by experimental genetics in the laboratory and what is needed to understand the genotype-to-phenotype problem on a broader scale. We argue that systems genetics, a combination of systems biology and the study of natural variation using quantitative genetics, will help to address this problem. We present major advances in these two mostly disconnected areas that have increased our understanding of the developmental processes of flowering time control and root growth. We conclude by illustrating and discussing the efforts that have been made toward systems genetics specifically in plants. PMID- 27501449 TI - The Lysosome as a Regulatory Hub. AB - The lysosome has long been viewed as the recycling center of the cell. However, recent discoveries have challenged this simple view and have established a central role of the lysosome in nutrient-dependent signal transduction. The degradative role of the lysosome and its newly discovered signaling functions are not in conflict but rather cooperate extensively to mediate fundamental cellular activities such as nutrient sensing, metabolic adaptation, and quality control of proteins and organelles. Moreover, lysosome-based signaling and degradation are subject to reciprocal regulation. Transcriptional programs of increasing complexity control the biogenesis, composition, and abundance of lysosomes and fine-tune their activity to match the evolving needs of the cell. Alterations in these essential activities are, not surprisingly, central to the pathophysiology of an ever-expanding spectrum of conditions, including storage disorders, neurodegenerative diseases, and cancer. Thus, unraveling the functions of this fascinating organelle will contribute to our understanding of the fundamental logic of metabolic organization and will point to novel therapeutic avenues in several human diseases. PMID- 27501450 TI - Signaling and Polarized Communication Across the T Cell Immunological Synapse. AB - T cells express a somatically recombined antigen receptor (alphabetaTCR) that is calibrated during development to respond to changes in peptides displayed by major histocompatibility complex proteins (pMHC) on the surface of antigen presenting cells (APC). A key characteristic of pMHC for adaptive immunity is the ability to sample internal states of cells and tissues to sensitively detect changes associated with infection, cell derangement, or tissue injury. Physical T cell-APC contact sets up an axis for polarization of TCR, adhesion molecules, kinases, cytoskeletal elements, and organelles inherent in this mode of juxtacrine signaling. The discovery of further lateral organization of the TCR and adhesion molecules into radially symmetric compartments, the immunological synapse, revealed an intersecting plane of symmetry and potential for regulated symmetry breaking to control duration of T cell-APC interactions. In addition to organizing signaling machinery, the immunological synapse directs the polarized transport and secretion of cytokines and cytolytic agents across the synaptic cleft and is a site for the generation and exocytic release of bioactive microvesicles that can functionally affect recipient APC and other cells in the environment. This machinery is coopted by retroviruses, and human immune deficiency virus-1 may even use antigen-specific synapses for infection of healthy T cells. Here, we discuss recent advances in the molecular and cell biological mechanisms of immunological synapse assembly and signaling and its role in intercellular communication across the synaptic cleft. PMID- 27501451 TI - The Heidelberg Screen for Pattern Mutants of Drosophila: A Personal Account. AB - In large-scale mutagenesis screens performed in 1979-1980 at the EMBL in Heidelberg, we isolated mutations affecting the pattern or structure of the larval cuticle in Drosophila. The 600 mutants we characterized could be assigned to 120 genes and represent the majority of such genes in the genome. These mutants subsequently provided a rich resource for understanding many fundamental developmental processes, such as the transcriptional hierarchies controlling segmentation, the establishment of cell states by signaling pathways, and the differentiation of epithelial cells. Most of the Heidelberg genes are now molecularly known, and many of them are conserved in other animals, including humans. Although the screens were initially driven entirely by curiosity, the mutants now serve as models for many human diseases. In this review, we describe the rationale of the screening procedures and provide a classification of the genes on the basis of their initial phenotypes and the subsequent molecular analyses. PMID- 27501452 TI - Fluorophore-binding RNA aptamers and their applications. AB - Why image RNA? Of all the biological molecules, RNA exhibits the most diverse range of functions. Evidence suggests that transcription produces a wide range of noncoding RNAs (ncRNAs), both short (e.g., siRNAs, miRNAs) and long (e.g., telomeric RNAs) that regulate many aspects of gene expression, including the epigenetic processes that underlie cell fate determination, polarization, and morphogenesis. All these functions are realized through the exquisite temporal and spatial control of RNA expression levels and the stability of specific RNAs within well-defined sub-cellular compartments. Given the central importance of RNA in dictating cell behavior via gene-related functions, there is a great demand for RNA imaging methods so as to determine the composition of the cellular 'transcriptome' and to acquire a complete spatial-temporal profile of RNA localization. Recent advances in fluorophore-binding RNA aptamers promise to provide exactly this knowledge, which can ultimately advance our understanding of cell function and behavior in conditions of health and disease, and in response to external stimuli. WIREs RNA 2016, 7:843-851. doi: 10.1002/wrna.1383 For further resources related to this article, please visit the WIREs website. PMID- 27501453 TI - Characterizing the Developmental Trajectory of Sirolimus Clearance in Neonates and Infants. AB - Sirolimus is increasingly being used in neonates and infants, but the mechanistic basis of age-dependent changes in sirolimus disposition has not been fully addressed yet. In order to characterize the age-dependent changes, serial sirolimus clearance (CL) estimates in individual young pediatric patients were collected and analyzed by population modeling analysis. In addition, sirolimus metabolite formation was also investigated to further substantiate the corresponding age-dependent change in CYP3A activity. The increasing pattern over time of allometrically size-normalized sirolimus CL estimates vs. age was well described by a sigmoidal Emax model. This age-dependent increase was also observed within each individual patient over a 4-year study period. CYP3A dependent sirolimus metabolite formation changed in a similar fashion. This study clearly demonstrates the rapid increase of sirolimus CL over time in neonates and infants, indicating the developmental change. This developmental pattern can be explained by a parallel increase in CYP3A metabolic activity. PMID- 27501454 TI - The Swedish P-CAT: modification and exploration of psychometric properties of two different versions. AB - The aim of this study was to further investigate the psychometric properties (with focus on construct validity and scale function) of the Swedish version of the Person-centred Care Assessment Tool (P-CAT) in a sample consisting of staff working in elderly care units (N = 142). The aim was also to further develop and psychometrically test a modified, noncontext-specific version of the instrument (mP-CAT) in a sample consisting of staff working in primary health care or within home care for older people (N = 182). Principal component analysis with varimax rotation initially suggested a three-factor solution for the P-CAT, explaining 55.96% of variance. Item 13 solely represented one factor wherefore this solution was rejected. A final 2-factor solution, without item 13, had a cumulative explained variance of 50.03%. All communalities were satisfactory (>0.3), and alpha values for both first factor (items 1-6, 11) and second factor (items 7-10, 12) were found to be acceptable. Principal component analysis with varimax rotation suggested a final 2-factor solution for the mP-CAT explaining 46.15% of the total variance with communalities ranging from 0.263 to 0.712. Cronbach's alpha for both factors was found to be acceptable (>0.7). This study suggests a 2 factor structure for the P-CAT and an exclusion of item 13. The results indicated that the modified noncontext-specific version, mP-CAT, seems to be a valid measure. Further psychometric testing of the mP-CAT is however needed in order to establish the instrument's validity and reliability in various contexts. PMID- 27501455 TI - Human Organotypic Lung Tumor Models: Suitable For Preclinical 18F-FDG PET Imaging. AB - Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and -testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. Human lung tumor cells cultured on the scaffold formed cluster and exhibited an up-regulation of the carcinoma-associated marker mucin1 as well as a reduced proliferation rate compared to respective 2D culture. Additionally, employing functional imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) these tumor cell cluster could be detected and tracked over time. This approach allowed monitoring of a targeted tyrosine kinase inhibitor treatment in the in vitro lung tumor model non-destructively. Surprisingly, FDG-PET assessment of single tumor cell cluster on the same scaffold exhibited differences in their response to therapy, indicating heterogeneity in the lung tumor model. In conclusion, our complex lung tumor test system features important characteristics of tumors and its microenvironment and allows monitoring of tumor growth and -metabolism in combination with functional imaging. In longitudinal studies, new therapeutic approaches and their long-term effects can be evaluated to adapt treatment regimes in future. PMID- 27501456 TI - Etiological Subgroups of Small-for-Gestational-Age: Differential Neurodevelopmental Outcomes. AB - OBJECTIVES: It remains unclear why substantial variations in neurodevelopmental outcomes exist within small-for-gestational-age (SGA) children. We prospectively compared 5-y neurodevelopmental outcomes across SGA etiological subgroups. METHODS: Children born SGA (N = 1050) from U.S. Early Childhood Longitudinal Study-Birth Cohort (2001-2007) was divided into etiological subgroups by each of 7 well-established prenatal risk factors. We fit linear regression models to compare 5-y reading, math, gross motor and fine motor scores across SGA subgroups, adjusting for socio-demographic confounders. RESULTS: Compared to singleton SGA subgroup, multiple-birth SGA subgroup had lower mean reading (adjusted mean difference, -4.08 [95% confidence interval, -6.10, -2.06]) and math (-2.22 [-3.61, -0.84]) scores. These disadvantages in reading and math existed only among multiple-birth SGA subgroup without ovulation stimulation (reading, -4.50 [-6.64, -2.36]; math, -2.91 [-4.37, -1.44]), but not among those with ovulation stimulation (reading, -2.33 [-6.24, 1.57]; math 0.63 [-1.86, 3.12]). Compared to singleton SGA subgroup without maternal smoking and inadequate gestational weight gain, singleton SGA subgroup with co-occurrence of maternal smoking and inadequate gestational weight gain (GWG) had lower mean reading (-4.81 [-8.50, -1.12]) and math (-2.95 [-5.51, -0.38]) scores. These differences were not mediated by Apgar score. CONCLUSIONS: Multiple-birth SGA subgroups (vs. singleton SGA) or singleton SGA subgroup with co-occurrence of smoking and inadequate GWG (vs. singleton SGA subgroup without maternal smoking and inadequate gestational weight gain) have poorer cognitive development up to 5 y. PMID- 27501457 TI - Cel5I, a SLH-Containing Glycoside Hydrolase: Characterization and Investigation on Its Role in Ruminiclostridium cellulolyticum. AB - Ruminiclostridium cellulolyticum (Clostridium cellulolyticum) is a mesophilic cellulolytic anaerobic bacterium that produces a multi-enzymatic system composed of cellulosomes and non-cellulosomal enzymes to degrade plant cell wall polysaccharides. We characterized one of the non-cellulosomal enzymes, Cel5I, composed of a Family-5 Glycoside Hydrolase catalytic module (GH5), a tandem of Family-17 and -28 Carbohydrate Binding Modules (CBM), and three S-layer homologous (SLH) modules, where the latter are expected to anchor the protein on the cell surface. Cel5I is the only putative endoglucanase targeting the cell surface as well as the only putative protein in R. cellulolyticum containing CBM17 and/or CBM28 modules. We characterized different recombinant structural variants from Cel5I. We showed that Cel5I has an affinity for insoluble cellulosic substrates through its CBMs, that it is the most active endoglucanase on crystalline cellulose of R. cellulolyticum characterized to date and mostly localized in the cell envelope of R. cellulolyticum. Its role in vivo was analyzed using a R. cellulolyticum cel5I mutant strain. Absence of Cel5I in the cell envelope did not lead to a significant variation of the phenotype compared to the wild type strain. Neither in terms of cell binding to cellulose, nor for its growth on crystalline cellulose, thus indicating that the protein has a rather subtle role in tested conditions. Cel5I might be more important in a natural environment, at low concentration of degradable glucose polymers, where its role might be to generate higher concentration of short cellodextrins close to the cell surface, facilitating their uptake or for signalization purpose. PMID- 27501458 TI - Serological Evidence of Lyssaviruses among Bats on Southwestern Indian Ocean Islands. AB - We provide serological evidence of lyssavirus circulation among bats on southwestern Indian Ocean (SWIO) islands. A total of 572 bats belonging to 22 species were collected on Anjouan, Mayotte, La Reunion, Mauritius, Mahe and Madagascar and screened by the Rapid Fluorescent Focus Inhibition Test for the presence of neutralising antibodies against the two main rabies related lyssaviruses circulating on the African continent: Duvenhage lyssavirus (DUVV) and Lagos bat lyssavirus (LBV), representing phylogroups I and II, respectively. A total of 97 and 42 sera were able to neutralise DUVV and LBV, respectively. No serum neutralised both DUVV and LBV but most DUVV-seropositive bats (n = 32/220) also neutralised European bat lyssavirus 1 (EBLV-1) but not Rabies lyssavirus (RABV), the prototypic lyssavirus of phylogroup I. These results highlight that lyssaviruses belonging to phylogroups I and II circulate in regional bat populations and that the putative phylogroup I lyssavirus is antigenically closer to DUVV and EBLV-1 than to RABV. Variation between bat species, roost sites and bioclimatic regions were observed. All brain samples tested by RT-PCR specific for lyssavirus RNA were negative. PMID- 27501459 TI - Racial-Ethnic Disparities in Opioid Prescriptions at Emergency Department Visits for Conditions Commonly Associated with Prescription Drug Abuse. AB - Prescription drug abuse is a growing problem nationally. In an effort to curb this problem, emergency physicians might rely on subjective cues such as race ethnicity, often unknowingly, when prescribing opioids for pain-related complaints, especially for conditions that are often associated with drug-seeking behavior. Previous studies that examined racial-ethnic disparities in opioid dispensing at emergency departments (EDs) did not differentiate between prescriptions at discharge and drug administration in the ED. We examined racial ethnic disparities in opioid prescription at ED visits for pain-related complaints often associated with drug-seeking behavior and contrasted them with conditions objectively associated with pain. We hypothesized a priori that racial ethnic disparities will be present among opioid prescriptions for conditions associated with non-medical use, but not for objective pain-related conditions. Using data from the National Hospital Ambulatory Medical Care Survey for 5 years (2007-2011), the odds of opioid prescription during ED visits made by non-elderly adults aged 18-65 for 'non-definitive' conditions (toothache, back pain and abdominal pain) or 'definitive' conditions (long-bone fracture and kidney stones) were modeled. Opioid prescription at discharge and opioid administration at the ED were the primary outcomes. We found significant racial-ethnic disparities, with non-Hispanic Blacks being less likely (adjusted odds ratio ranging from 0.56 0.67, p-value < 0.05) to receive opioid prescription at discharge during ED visits for back pain and abdominal pain, but not for toothache, fractures and kidney stones, compared to non-Hispanic whites after adjusting for other covariates. Differential prescription of opioids by race-ethnicity could lead to widening of existing disparities in health, and may have implications for disproportionate burden of opioid abuse among whites. The findings have important implications for medical provider education to include sensitization exercises towards their inherent biases, to enable them to consciously avoid these biases from defining their practice behavior. PMID- 27501460 TI - Functional requirements of cellular differentiation: lessons from Bacillus subtilis. AB - Successful execution of differentiation programs requires cells to assess multitudes of internal and external cues and respond with appropriate gene expression programs. Here, we review how Bacillus subtilis sporulation network deals with these tasks focusing on the lessons generalizable to other systems. With feedforward loops controlling both production and activation of downstream transcriptional regulators, cells achieve ultrasensitive threshold-like responses. The arrangement of sporulation network genes on the chromosome and transcriptional feedback loops allow coordination of sporulation decision with DNA-replication. Furthermore, to assess the starvation conditions without sensing specific metabolites, cells respond to changes in their growth rates with increased activity of sporulation master regulator. These design features of the sporulation network enable cells to robustly decide between vegetative growth and sporulation. PMID- 27501461 TI - An up-date on Giardia and giardiasis. AB - Giardia intestinalis is a non-invasive protozoan parasite infecting the upper small intestine causing acute, watery diarrhea or giardiasis in 280 million people annually. Asymptomatic infections are equally common and recent data have suggested that infections even can be protective against other diarrheal diseases. Most symptomatic infections resolve spontaneously but infections can lead to chronic disease and treatment failures are becoming more common world wide. Giardia infections can also result in irritable bowel syndrome (IBS) and food allergies after resolution. Until recently not much was known about the mechanism of giardiasis or the cause of post-giardiasis syndromes and treatment failures, but here we will describe the recent progress in these areas. PMID- 27501463 TI - Hydroxypropyl-beta-CD vs. its alpha-homologue for a 3D modified polyrotaxane network formation and properties: the relationship between modified CD and polymer revealed through comparison. AB - The threading mechanism of the hydroxypropyl-cyclodextrin (Hy-CD)/tetrahedron like poly(ethylene glycol) (tetra-PEG) based host-guest complex and the relationship between Hy-CD and poly(ethylene oxide) (PEO) in the three dimensional modified polyrotaxane (PR) formed by the complex were revealed through the comparison between Hy-beta-CD/tetra-PEG and Hy-alpha-CD/tetra-PEG based systems from the macroscopic material view to the microscopic molecular view. The complexation between Hy-CD and tetra-PEG in water experiences a threading-dethreading-rethreading process which is controlled by the intermolecular interaction intensity or molecular hindrance depending on the feed ratio of Hy-CD to tetra-PEG. In the 3D modified PR, the methyl group of the Hy part on one Hy-CD can insert into the cavity of the adjacent Hy-CD and interacts with both the interior surface of the cavity and the PEO segment within the cavity if the cavity of Hy-CD is large enough. The threaded Hy-CD in the PR straightens the chain of PEO and suppresses the segment motion of the PEO. With the decrease of the cavity size of Hy-CD, the degree of suppression on the segment motion of PEO increases. Hy-CD threaded on the PEO chain can also deform when the 3D modified PR is compressed, and the degree of deformation increases with the increase of the cavity size of Hy-CD. These results of the modified CD/PEG based complex system set it apart from the unmodified CD/PEG based one, and reveal the structure-property relationship of this new type of Hy-CD/tetra PEG based 3D modified PR material. PMID- 27501462 TI - Epitaxial Growth of Perovskite Strontium Titanate on Germanium via Atomic Layer Deposition. AB - Atomic layer deposition (ALD) is a commercially utilized deposition method for electronic materials. ALD growth of thin films offers thickness control and conformality by taking advantage of self-limiting reactions between vapor-phase precursors and the growing film. Perovskite oxides present potential for next generation electronic materials, but to-date have mostly been deposited by physical methods. This work outlines a method for depositing SrTiO3 (STO) on germanium using ALD. Germanium has higher carrier mobilities than silicon and therefore offers an alternative semiconductor material with faster device operation. This method takes advantage of the instability of germanium's native oxide by using thermal deoxidation to clean and reconstruct the Ge (001) surface to the 2*1 structure. 2-nm thick, amorphous STO is then deposited by ALD. The STO film is annealed under ultra-high vacuum and crystallizes on the reconstructed Ge surface. Reflection high-energy electron diffraction (RHEED) is used during this annealing step to monitor the STO crystallization. The thin, crystalline layer of STO acts as a template for subsequent growth of STO that is crystalline as-grown, as confirmed by RHEED. In situ X-ray photoelectron spectroscopy is used to verify film stoichiometry before and after the annealing step, as well as after subsequent STO growth. This procedure provides framework for additional perovskite oxides to be deposited on semiconductors via chemical methods in addition to the integration of more sophisticated heterostructures already achievable by physical methods. PMID- 27501464 TI - Templated Synthesis of Uniform Perovskite Nanowire Arrays. AB - While the chemical composition of semiconducting metal halide perovskites can be precisely controlled in thin films for photovoltaic devices, the synthesis of perovskite nanostructures with tunable dimensions and composition has not been realized. Here, we describe the templated synthesis of uniform perovskite nanowires with controlled diameter (50-200 nm). Importantly, by providing three examples (CH3NH3PbI3, CH3NH3PbBr3, and Cs2SnI6), we show that this process is composition general and results in oriented nanowire arrays on transparent conductive substrates. PMID- 27501465 TI - An integrative theory-driven framework for evaluating travel training programs. AB - Since the 1970s, travel training programs, which provide a short-term training to people with disabilities and older people to teach them independent travel skills required to use fixed-route transportation, have spread across the United States. But the authors note that currently, there is no integrative framework for evaluating the training programs, although it is crucial for improving program implementation and developing knowledge and theories related to travel training. Therefore, this research aims to build an integrative theory-driven evaluation framework of the programs on the basis of prior studies on travel training and the literature on program evaluation and learning and training theories. The framework considers (1) a wide range of key elements related to the delivery systems and outcomes of travel training; (2) diverse stakeholders that engage in designing, operating, and assessing travel training; and (3) the short-term, intermediate, and long-term outcomes of the programs. Based on the framework, the authors develop a flexible logic model for travel training programs to help scholars and practitioners design and conduct actual evaluation studies. Thus, this research is expected to make theoretical and practical contributions to theory-driven program evaluation and travel training programs. PMID- 27501466 TI - Lessons learned while building a trauma-informed public behavioral health system in the City of Philadelphia. AB - Exposure to traumatic experiences among youth is a serious public health concern. A trauma-informed public behavioral health system that emphasizes core principles such as understanding trauma, promoting safety, supporting consumer autonomy, sharing power, and ensuring cultural competence, is needed to support traumatized youth and the providers who work with them. This article describes a case study of the creation and evaluation of a trauma-informed publicly funded behavioral health system for children and adolescents in the City of Philadelphia (the Philadelphia Alliance for Child Trauma Services; PACTS) using the Exploration, Preparation, Implementation, and Sustainment (EPIS) as a guiding framework. We describe our evaluation of this effort with an emphasis on implementation determinants and outcomes. Implementation determinants include inner context factors, specifically therapist knowledge and attitudes (N=114) towards evidence based practices. Implementation outcomes include rate of PTSD diagnoses in agencies over time, number of youth receiving TF-CBT over time, and penetration (i.e., number of youth receiving TF-CBT divided by the number of youth screening positive on trauma screening). We describe lessons learned from our experiences building a trauma-informed public behavioral health system in the hopes that this case study can guide other similar efforts. PMID- 27501469 TI - Length distributions of Au-catalyzed and In-catalyzed InAs nanowires. AB - We present experimental data on the length distributions of InAs nanowires grown by chemical beam epitaxy with Au catalyst nanoparticles obtained by thermal dewetting of Au film, Au colloidal nanoparticles and In droplets. Poissonian length distributions are observed in the first case. Au colloidal nanoparticles produce broader and asymmetric length distributions of InAs nanowires. However, the distributions can be strongly narrowed by removing the high temperature annealing step. The length distributions for the In-catalyzed growth are instead very broad. We develop a generic model that is capable of describing the observed behaviors by accounting for both the incubation time for nanowire growth and secondary nucleation of In droplets. These results allow us to formulate some general recipes for obtaining more uniform length distributions of III-V nanowires. PMID- 27501467 TI - High-Density Lipoprotein Biogenesis: Defining the Domains Involved in Human Apolipoprotein A-I Lipidation. AB - The first step in removing cholesterol from a cell is the ATP-binding cassette transporter 1 (ABCA1)-driven transfer of cholesterol to lipid-free or lipid-poor apolipoprotein A-I (apoA-I), which yields cholesterol-rich nascent high-density lipoprotein (nHDL) that then matures in plasma to spherical, cholesteryl ester rich HDL. However, lipid-free apoA-I has a three-dimensional (3D) conformation that is significantly different from that of lipidated apoA-I on nHDL. By comparing the lipid-free apoA-I 3D conformation of apoA-I to that of 9-14 nm diameter nHDL, we formulated the hypothetical helical domain transitions that might drive particle formation. To test the hypothesis, ten apoA-I mutants were prepared that contained two strategically placed cysteines several of which could form intramolecular disulfide bonds and others that could not form these bonds. Mass spectrometry was used to identify amino acid sequence and intramolecular disulfide bond formation. Recombinant HDL (rHDL) formation was assessed with this group of apoA-I mutants. ABCA1-driven nHDL formation was measured in four mutants and wild-type apoA-I. The mutants contained cysteine substitutions in one of three regions: the N-terminus, amino acids 34 and 55 (E34C to S55C), central domain amino acids 104 and 162 (F104C to H162C), and the C-terminus, amino acids 200 and 233 (L200C to L233C). Mutants were studied in the locked form, with an intramolecular disulfide bond present, or unlocked form, with the cysteine thiol blocked by alkylation. Only small amounts of rHDL or nHDL were formed upon locking the central domain. We conclude that both the N- and C-terminal ends assist in the initial steps in lipid acquisition, but that opening of the central domain was essential for particle formation. PMID- 27501470 TI - The Novel Application of Genomic Profiling Assays to Shorten Inactive Status for Potential Kidney Transplant Recipients With Breast Cancer. AB - The concern about cancer recurrence has traditionally resulted in delaying kidney transplantation for 2-5 years after a cancer diagnosis in patients who are otherwise eligible for transplant. This period of inactive status to observe the tumor biology can result in significant morbidity and decreased quality of life for patients with end-stage renal disease (ESRD). We reported the novel application of genomic profiling assays in breast cancer to identify low-risk cancers in two patients with ESRD who were able to have the mandatory inactive status eliminated prior to kidney transplantation. PMID- 27501468 TI - MicroRNAs 29b and 181a down-regulate the expression of the norepinephrine transporter and glucocorticoid receptors in PC12 cells. AB - MicroRNAs are short non-coding RNAs that provide global regulation of gene expression at the post-transcriptional level. Such regulation has been found to play a role in stress-induced epigenetic responses in the brain. The norepinephrine transporter (NET) and glucocorticoid receptors are closely related to the homeostatic integration and regulation after stress. Our previous studies demonstrated that NET mRNA and protein levels in rats are regulated by chronic stress and by administration of corticosterone, which is mediated through glucocorticoid receptors. Whether miRNAs are intermediaries in the regulation of these proteins remains to be elucidated. This study was undertaken to determine possible regulatory effects of miRNAs on the expression of NET and glucocorticoid receptors in the noradrenergic neuronal cell line. Using computational target prediction, we identified several candidate miRNAs potentially targeting NET and glucocorticoid receptors. Western blot results showed that over-expression of miR 181a and miR-29b significantly repressed protein levels of NET, which is accompanied by a reduced [3 H] norepinephrine uptake, and glucocorticoid receptors in PC12 cells. Luciferase reporter assays verified that both miR-181a and miR-29b bind the 3'UTR of mRNA of NET and glucocorticoid receptors. Furthermore, exposure of PC12 cells to corticosterone markedly reduced the endogenous levels of miR-29b, which was not reversed by the application of glucocorticoid receptor antagonist mifepristone. These observations indicate that miR-181a and miR-29b can function as the negative regulators of NET and glucocorticoid receptor translation in vitro. This regulatory effect may be related to stress-induced up-regulation of the noradrenergic phenotype, a phenomenon observed in stress models and depressive patients. This study demonstrated that miR-29b and miR-181a, two short non-coding RNAs that provide global regulation of gene expression, markedly repressed protein levels of norepinephrine (NE) transporter and glucocorticoid receptor (GR), as well as NE uptake by binding the 3'UTR of their mRNAs in PC12 cells. Also, exposure of cells to corticosterone significantly reduced miR-29b levels through a GR-independent way. PMID- 27501471 TI - Long-Term Follow-Up of Isolated Epicardial Left Ventricular Lead Implant Using a Minithoracotomy Approach for Cardiac Resynchronization Therapy. AB - BACKGROUND: Transvenous left ventricular (LV) lead placement for cardiac resynchronization therapy is unsuccessful in 5-10% of reported cases. These patients may benefit from isolated surgical placement of an epicardial LV lead via minithoracotomy approach. AIM: To evaluate the success of this approach at long-term follow-up. METHODS: Retrospective evaluation of all consecutive patients undergoing isolated epicardial LV lead placement after failed transvenous attempt over a 6-year period. Data collected on baseline parameters, procedural details, and outcome at follow-up (hospital stay, complications, mortality, and clinical response). RESULTS: Forty-two patients underwent epicardial lead implant. Five died within 1 year (11.9%): two (4.8%) died within 30-days post op (one from intraoperative hemorrhage, the other from multiple organ failure); 39 (95.1%) were admitted to the high dependency unit and transferred to the ward <24 hours. Median hospital stay was 3.4 +/- 1.9 days. The overall complication rate was 17.5% (n = 7): 15.0% (n = 6) short term and 2.5% (n = 1) long term; these included three (7.5%) LV noncapture events all treated with reprogramming. There were two (5.0%) wound infections requiring oral antibiotics and two (5.0%) device infections requiring intravenous antibiotics (one had device resiting, the other developed septic shock requiring intensive care admission). Assessment of clinical response was possible in 34 (81.0%) at follow up: 21 (61.8%) were responders and 13 (28.2%) nonresponders with no significant differences between these groups; no clinical predictors of response were identified. CONCLUSION: Isolated epicardial LV lead implant using minithoracotomy is relatively safe and effective at successful LV pacing. Response rate and postoperative recovery at long-term follow-up are reasonable in these high-risk patients. PMID- 27501472 TI - Resonantly Enhanced Second-Harmonic Generation Using III-V Semiconductor All Dielectric Metasurfaces. AB - Nonlinear optical phenomena in nanostructured materials have been challenging our perceptions of nonlinear optical processes that have been explored since the invention of lasers. For example, the ability to control optical field confinement, enhancement, and scattering almost independently allows nonlinear frequency conversion efficiencies to be enhanced by many orders of magnitude compared to bulk materials. Also, the subwavelength length scale renders phase matching issues irrelevant. Compared with plasmonic nanostructures, dielectric resonator metamaterials show great promise for enhanced nonlinear optical processes due to their larger mode volumes. Here, we present, for the first time, resonantly enhanced second-harmonic generation (SHG) using gallium arsenide (GaAs) based dielectric metasurfaces. Using arrays of cylindrical resonators we observe SHG enhancement factors as large as 10(4) relative to unpatterned GaAs. At the magnetic dipole resonance, we measure an absolute nonlinear conversion efficiency of ~2 * 10(-5) with ~3.4 GW/cm(2) pump intensity. The polarization properties of the SHG reveal that both bulk and surface nonlinearities play important roles in the observed nonlinear process. PMID- 27501473 TI - Admission hyperglycemia in sepsis is associated with poor outcomes: where do we go from here? PMID- 27501474 TI - Outcomes with frontline nilotinib treatment in Turkish patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase. AB - OBJECTIVE: Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with chronic myeloid leukemia in chronic phase (CML-CP). This study was the first prospective evaluation of the efficacy and safety of nilotinib in Turkish patients with newly diagnosed CML-CP. The primary endpoint of the study was the rate of major molecular response (MMR; BCR-ABL1 <= 0.1% on the International Scale [BCR-ABL1(IS)]) by 12 months. METHODS: Patients with newly diagnosed CML-CP were treated with nilotinib 300 mg twice daily. This analysis was based on the first 12 months of follow-up in a 24-month study. RESULTS AND CONCLUSIONS: Of 112 patients enrolled, 66.1% (80% CI, 59.7-72.0%) achieved MMR and 22.3% achieved a deep molecular response of MR(4.5) (BCR ABL1(IS) <= 0.0032%) by 12 months. During the first year of treatment, 1 patient progressed to blast crisis and 2 patients died. Safety results were consistent with previous studies. Most adverse events (AEs) were grade 1/2. Most frequently reported nonhematologic AEs of any grade were elevations in bilirubin, alanine aminotransferase, and triglycerides. These results support the use of nilotinib 300 mg twice daily as a standard-of-care treatment option for patients with newly diagnosed CML-CP. PMID- 27501475 TI - Comparative performance of oral midazolam clearance and plasma 4beta hydroxycholesterol to explain interindividual variability in tacrolimus clearance. AB - AIMS: We compared the CYP3A4 metrics weight-corrected midazolam apparent oral clearance (MDZ Cl/F/W) and plasma 4beta-hydroxycholesterol/cholesterol (4beta OHC/C) as they relate to tacrolimus (TAC) Cl/F/W in renal transplant recipients. METHODS: For a cohort of 147 patients, 8 h area under the curve (AUC) values for TAC and oral MDZ were calculated besides measurement of 4beta-OHC/C. A subgroup of 70 patients additionally underwent intravenous erythromycin breath test (EBT) and were administered the intravenous MDZ probe. All patients were genotyped for common polymorphisms in CYP3A4, CYP3A5 and P450 oxidoreductase, among others. RESULTS: MDZ Cl/F/W, 4beta-OHC/C/W, EBT and TAC Cl/F/W were all moderately correlated (r = 0.262-0.505). Neither MDZ Cl/F/W nor 4beta-OHC/C/W explained variability in TAC Cl/F/W in CYP3A5 expressors (n = 29). For CYP3A5 non expressors (n = 118), factors explaining variability in TAC Cl/F/W in a MDZ-based model were MDZ Cl/F/W (R2 = 0.201), haematocrit (R2 = 0.139), TAC formulation (R2 = 0.107) and age (R2 = 0.032; total R2 = 0.479). In the 4beta-OHC/C/W based model, predictors were 4beta-OHC/C/W (R2 = 0.196), haematocrit (R2 = 0.059) and age (R2 = 0.057; total R2 = 0.312). When genotype information was ignored, predictors of TAC Cl/F/W in the whole cohort were 4beta-OHC/C/W (R2 = 0.167), MDZ Cl/F/W (R2 = 0.045); Tac QD formulation (R2 = 0.036), and haematocrit (R2 = 0.032; total R2 = 0.315). 4beta-OHC/C/W, but not MDZ Cl/F/W, was higher in CYP3A5 expressors because it was higher in CYP3A4*1b carriers, which were almost all CYP3A5 expressors. CONCLUSIONS: A MDZ-based model explained more variability in TAC clearance in CYP3A5 non-expressors. However, 4beta OHC/C/W was superior in a model in which no genotype information was available, likely because 4beta-OHC/C/W was influenced by the CYP3A4*1b polymorphism. PMID- 27501476 TI - Crystal structures of SIRT3 reveal that the alpha2-alpha3 loop and alpha3-helix affect the interaction with long-chain acyl lysine. AB - SIRT1-7 play important roles in many biological processes and age-related diseases. In addition to a NAD(+) -dependent deacetylase activity, they can catalyze several other reactions, including the hydrolysis of long-chain fatty acyl lysine. To study the binding modes of sirtuins to long-chain acyl lysines, we solved the crystal structures of SIRT3 bound to either a H3K9-myristoylated- or a H3K9-palmitoylated peptide. Interaction of SIRT3 with the palmitoyl group led to unfolding of the alpha3-helix. The myristoyl and palmitoyl groups bind to the C-pocket and an allosteric site near the alpha3-helix, respectively. We found that the residues preceding the alpha3-helix determine the size of the C-pocket. The flexibility of the alpha2-alpha3 loop and the plasticity of the alpha3-helix affect the interaction with long-chain acyl lysine. PMID- 27501477 TI - Inhibitor development after liver transplantation in congenital factor VII deficiency. AB - Congenital factor VII (FVII) deficiency is the commonest type of the rare bleeding disorders. Very few cases of congenital FVII deficiency developed inhibitor and liver transplant is considered as definitive treatment. In the literature, twelve patients with congenital FVII deficiency developed inhibitors. Two had spontaneous resolution of inhibitors and one did not respond to high dose recombinant factor VIIa (rFVIIa) and died. Regarding liver transplant in congenital FVII patients, seven patients underwent liver transplant with good prognosis. We report a 5-year-old girl with confirmed severe congenital FVII deficiency since neonatal period. She suffered from recurrent intracranial bleeding despite rFVIIa replacement. After auxiliary liver transplant at the age of 4, she continued to show persistent deranged clotting profile and was found to have inhibitor towards FVII. Interestingly, she was still responsive to rFVIIa replacement. PMID- 27501478 TI - Perioperative complications and outcomes in children with cerebral palsy undergoing scoliosis surgery. AB - INTRODUCTION: Neuromuscular scoliosis is a known risk factor for postoperative complications after corrective spine surgery. Few studies have looked at the preoperative factors affecting postoperative complications in children with cerebral palsy. AIM: The aim of this study was to examine the factors that might influence postoperative course in patients with cerebral palsy undergoing spine surgery for scoliosis. METHODS: Nineteen case notes of children with cerebral palsy who had spine surgery (2008-2014) were reviewed retrospectively. Preoperative comorbidities and postoperative complications were noted and complications were classified as major and minor. RESULTS: Thirteen out of 19 (68.4%) patients had two or more systemic comorbidities. Most common comorbidities included reflux and seizure disorder. Nine patients (49%) had at least one major complication. About 5/19 patients had respiratory complications requiring ventilation and 4/19 had massive blood loss. A higher incidence of postoperative major complication was recorded in the group with two systemic comorbidities as compared to those with less than two systemic comorbidities (47% vs 16%). Both patients who had a single-stage anterior release and posterior fixation had a major complication. CONCLUSION: Presence of two or more comorbidities and thoracotomy are risk factors for perioperative complications in children with cerebral palsy undergoing surgery for scoliosis correction. PMID- 27501479 TI - Unique Three-Dimensional InP Nanopore Arrays for Improved Photoelectrochemical Hydrogen Production. AB - Ordered three-dimensional (3D) nanostructure arrays hold promise for high performance energy harvesting and storage devices. Here, we report the fabrication of InP nanopore arrays (NPs) in unique 3D architectures with excellent light trapping characteristic and large surface areas for use as highly active photoelectrodes in photoelectrochemical (PEC) hydrogen evolution devices. The ordered 3D NPs were scalably synthesized by a facile two-step etching process of (1) anodic etching of InP in neutral 3 M NaCl electrolytes to realize nanoporous structures and (2) wet chemical etching in HCl/H3PO4 (volume ratio of 1:3) solutions for removing the remaining top irregular layer. Importantly, we demonstrated that the use of neutral electrolyte of NaCl instead of other solutions, such as HCl, in anodic etching of InP can significantly passivate the surface states of 3D NPs. As a result, the maximum photoconversion efficiency obtained with ~15.7 MUm thick 3D NPs was 0.95%, which was 7.3 and 1.4 times higher than that of planar and 2D NPs. Electrochemical impedance spectroscopy and photoluminescence analyses further clarified that the improved PEC performance was attributed to the enhanced charge transfer across 3D NPs/electrolyte interfaces, the improved charge separation at 3D NPs/electrolyte junction, and the increased PEC active surface areas with our unique 3D NP arrays. PMID- 27501480 TI - The impact of personalisation on people from Chinese backgrounds: qualitative accounts of social care experience. AB - The limited research that considers people from black and minority ethnic communities' experiences of personalisation tends to focus on personal budgets rather than personalisation per se. This article provides an opportunity to hear the voices of people from Chinese backgrounds and their experiences of personalisation. The study used individual semi-structured interviews and focus groups to collect data from physically disabled people from Chinese backgrounds who lived in England, were aged between 18 and 70, and received social care. Data were analysed using an iterative and thematic approach, with early analysis informing the subsequent analytical rounds. The findings reveal that personalisation has the potential to transform the lives of people from Chinese backgrounds, especially when tailored support is available for people to understand and access personal budgets and put them to creative use. However, the impact of personalisation is barely evident because few eligible individuals access personal budgets or participate in co-production. This is related to a lack of encouragement for service users to become genuine partners in understanding, designing, commissioning and accessing a diverse range of social care services to meet their cultural and social care needs. PMID- 27501481 TI - Admission hyperglycemia and outcome in ICU patients with sepsis. PMID- 27501482 TI - Robust anti-nociceptive effects of monoacylglycerol lipase inhibition in a model of osteoarthritis pain. AB - BACKGROUND AND PURPOSE: Chronic pain is often a symptom of knee osteoarthritis (OA) for which current analgesics are either inadequate or are associated with serious side effects. The endocannabinoid system may offer alternative targets for pain relief. We evaluated the effects of a potent and selective monoacylglycerol (MAG) lipase inhibitor (MJN110) on OA pain behaviour, spinal mechanisms of action and joint histopathology in the rat. EXPERIMENTAL APPROACH: Intra-articular injection of monosodium iodoacetate (MIA) models OA pain and mimics clinical joint pathology. Effects of MJN110 on MIA-induced weight-bearing asymmetry and lowered paw withdrawal thresholds (PWTs), changes in spinal gene expression and brain levels of relevant lipids were determined. KEY RESULTS: Acute MJN110 (5 mg.kg-1 ) significantly reversed MIA-induced weight-bearing asymmetry (MIA/vehicle: 68 +/- 6 g; MIA/MJN110: 35 +/- 4 g) and lowered ipsilateral PWTs (MIA/vehicle: 7 +/- 0.8 g; MIA/MJN110: 11 +/- 0.6 g), via both CB1 and CB2 receptors. Repeated treatment with MJN110 (5 mg.kg-1 ) resulted in anti-nociceptive tolerance. A lower dose of MJN110 (1 mg.kg-1 ) acutely inhibited pain behaviour, which was maintained for 1 week of repeated administration but had no effect on joint histology. MJN110 significantly inhibited expression of membrane-associated PGE synthase-1 in the ipsilateral dorsal horn of the spinal cord of MIA rats, compared with vehicle-treated MIA rats. Both doses of MJN110 significantly elevated brain levels of the endocannabinoid 2 arachidonoylglycerol. CONCLUSIONS AND IMPLICATIONS: Our data support further assessment of the therapeutic potential of MAG lipase inhibitors for the treatment of OA pain. PMID- 27501483 TI - Stigmatization toward irritable bowel syndrome and inflammatory bowel disease in an online cohort. AB - BACKGROUND: Stigma is associated with many negative health outcomes. Research has examined perceived and internalized stigma in individuals with irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), but less has been done to evaluate levels of enacted stigma associated with these conditions. The aim of this study was to evaluate the presence of enacted stigma toward IBS and IBD in the general population compared to an adult-onset asthma (AOA) control group. METHODS: Participants were recruited via social media and a research-dedicated website and completed all measures online. Participants were randomized to one of six clinical vignettes: (i) IBD male, (ii) IBD female, (iii) IBS male, (iv) IBS female, (v) AOA male, or (vi) AOA female. Participants read the assigned vignette and then completed measures of emotional empathy, level of familiarity, and enacted stigma. KEY RESULTS: Participants reported higher levels of enacted stigma toward IBS compared to both IBD and AOA. No differences in stigma were found between IBD and AOA. Higher levels of familiarity were most strongly correlated with reduced IBD-related stigma, with weaker but still significant correlations between level of familiarity and IBS and AOA. Higher levels of emotional empathy were associated with reduced stigma for IBD, IBS, and AOA. CONCLUSIONS & INFERENCES: Individuals with IBS experience greater levels of enacted stigma compared to IBD and AOA. This finding is consistent with previous research that has shown greater levels of perceived and internalized stigma in IBS compared to IBD. PMID- 27501485 TI - One step effective removal of Congo Red in chitosan nanoparticles by encapsulation. AB - Chitosan nanoparticles (CNPs) were prepared with ionotropic gelation between chitosan and tripolyphosphate for the removal of Congo Red. The production of chitosan nanoparticles and the dye removal process was carried out in one-step. The removal efficiency of Congo Red by encapsulation within chitosan from the aqueous solution and its storage stability are examined at different pH values. The influence of some parameters such as the initial dye concentration, pH value of the dye solution, electrolyte concentration, tripolyphosphate concentration, mixing time and speed on the encapsulation is examined. Congo Red removal efficiency and encapsulation capacity of chitosan nanoparticles were determined as above 98% and 5107mg Congo Red/g chitosan, respectively. PMID- 27501486 TI - Etchant-based design of gold tip apexes for plasmon-enhanced Raman spectromicroscopy. AB - In this paper, we gain insight into the design and optimization of plasmonic (metallic) tips prepared with dc-pulsed voltage electrochemical etching gold wires, provided that, a duty cycle is self-tuned. Physically, it means that etching electrolyte attacks the gold wire equally for all pulse lengths, regardless of its surface shape. Etchant effect on the reproducibility of a curvature radius of the tip apex is demonstrated. It means that the gold conical tips can be designed chemically with a choice of proper etchant electrolyte. It is suggested to use a microtomed binary polymer blend consisting of polyamide and low density polyethylene, as a calibration grating, for optimizing and standardizing tip-enhanced Raman scattering performance. PMID- 27501487 TI - Geriatric periodontology: how the need to care for the aging population can influence the future of the dental profession. AB - The world's population is aging, and it has been estimated that by 2050, the number of people 65 years of age and older will reach 1.5 billion. The aging population will be affected by noncommunicable chronic diseases, including diabetes mellitus, cardiovascular disease and cognitive impairment. This important demographic shift includes a reduction in tooth loss/edentulism, particularly in older adults of the developed countries in North America, western Europe and north-east Asia. Therefore, in the future, dental providers will be required to care for an expanded number of older adults who have retained teeth and are medically complex. As the linkage of oral disease and systemic disease has focused on the relationship of periodontitis and noncommunicable chronic diseases, a broad review of 'geriatric periodontology' is both timely and important. This volume of Periodontology 2000 covers a range of subjects under this heading. Included are the demographics of an aging world; the effect of aging on stem cell function in the periodontium; the periodontal microbiota associated with aging; the host response in the periodontium of aging individuals; an analysis of the prevalence of periodontitis in the USA on a national, state-wide and community basis; differentiation of physiologic oral aging from disease; treatment of periodontal disease in older adults; implant therapy for older patients; oral disease and the frailty syndrome; the relationship of tooth loss to longevity and life expectancy; and the relationship of periodontal disease to noncommunicable chronic diseases. Although 'geriatric dentistry' is not a recognized specialty in dentistry, and 'geriatric periodontology' is a descriptive title, the subject of this volume of Periodontology 2000 is critical to the future of clinical dentistry, dental public health and dental research. Any comprehensive focus on older patients can only be accomplished with an emphasis on interprofessional education and practice. If embraced, this shift will allow the dental profession to be more closely aligned with the larger health-care environment, and can improve both oral health and health outcomes for patients seen in the dental office. PMID- 27501488 TI - The aging population: demographics and the biology of aging. AB - Epidemiologic studies show that 11% of the world's population is over 60 years of age; this is projected to increase, by 2050, to 22% of the population. Oral aging is a current focus of several organizations including the Federation Dentaire Internationale, the World Health Organization and the American and Japanese Dental Associations. In their Tokyo Declaration, the Japanese Association identified the elderly population as one of its main target groups. One of the WHO goals is for each person to retain more than 20 teeth by age 80, despite the fact that the prevalence of periodontal disease is continuously rising as the population is aging. Every species has its own characteristic lifespan, which is determined by its evolutionary history and is modified by multiple diverse factors, including biological mechanisms. In humans, the gradual accumulation of products of cellular metabolism and extensive DNA damage contribute to the aging process. Aging is thought to be associated with a low-grade inflammatory phenotype in mammals, called 'inflammaging', and is the result of autophagic capacity impairing so-called 'housekeeping activities' in the cells, resulting in protein aggregation, mitochondrial dysfunction and oxidative stress. Delayed stem cell proliferation, associated with aging, may impact the maintenance and survival of a living being, but excessive proliferation could also result in depleted reserves of stem cells. Studies are needed to address the association of delayed cell proliferation and wound healing with the onset of periodontal diseases and response to treatment. The effects of systemic diseases, medications, psychological effects and decreased interest or ability in performing oral-hygiene practices are thought to result in periodontal diseases, and ultimately in tooth loss, in aged individuals. Together with an aging population comes a responsibility for 'healthy' and 'successful' aging. This article describes the changing global demographic profile and the effects of an aging society on the prevalence and incidence of periodontal diseases. We review the definitions of normal and successful aging, the principles of geriatric medicine and the highlights of biological aging at cellular, tissue and systems levels. PMID- 27501489 TI - From restoration to regeneration: periodontal aging and opportunities for therapeutic intervention. AB - With the march of time our bodies start to wear out: eyesight fades, skin loses its elasticity, teeth and bones become more brittle and injuries heal more slowly. These universal features of aging can be traced back to our stem cells. Aging has a profound effect on stem cells: DNA mutations naturally accumulate over time and our bodies have evolved highly specialized mechanisms to remove these damaged cells. Whilst obviously beneficial, this repair mechanism also reduces the pool of available stem cells and this, in turn, has a dramatic effect on tissue homeostasis and on our rate of healing. Simply put: fewer stem cells means a decline in tissue function and slower healing. Despite this seemingly intractable situation, research over the past decade now demonstrates that some of the effects of aging are reversible. Nobel prize-winning research demonstrates that old cells can become young again, and lessons learned from these experiments in-a-dish are now being translated into human therapies. Scientists and clinicians around the world are identifying and characterizing methods to activate stem cells to reinvigorate the body's natural regenerative process. If this research in dental regenerative medicine pans out, the end result will be tissue homeostasis and healing back to the levels we appreciated when we were young. PMID- 27501491 TI - Aging, inflammation, immunity and periodontal disease. AB - The increased prevalence and severity of periodontal disease have long been associated with aging, such that this oral condition affects the majority of the adult population over 50 years of age. Although the immune system is a critical component for maintaining health, aging can be characterized by quantitative and qualitative modifications of the immune system. This process, termed 'immunosenescence', is a progressive modification of the immune system that leads to greater susceptibility to infections, neoplasia and autoimmunity, presumably reflecting the prolonged antigenic stimulation and/or stress responses that occur across the lifespan. Interestingly, the global reduction in the host capability to respond effectively to these challenges is coupled with a progressive increase in the general proinflammatory status, termed 'inflammaging'. Consistent with the definition of immunosenescence, it has been suggested that the cumulative effect of prolonged exposure of the periodontium to microbial challenge is, at least in part, a contributor to the effects of aging on these tissues. Thus, it has also been hypothesized that alterations in the function of resident immune and nonimmune cells of the periodontium contribute to the expression of inflammaging in periodontal disease. Although the majority of aging research has focused on the adaptive immune response, it is becoming increasingly clear that the innate immune compartment is also highly affected by aging. Thus, the phenomenon of immunosenescence and inflammaging, expressed as age-associated changes within the periodontium, needs to be more fully understood in this era of precision and personalized medicine and dentistry. PMID- 27501490 TI - The subgingival periodontal microbiota of the aging mouth. AB - Different mechanisms have been hypothesized to explain the increase in prevalence and severity of periodontitis in older adults, including shifts in the periodontal microbiota. However, the actual impact of aging on the composition of subgingival biofilms remains unclear. In the present article, we provide an overview of the composition of the subgingival biofilm in older adults and the potential effects of age on the oral microbiome. In particular, this review covers the following topics: (i) the oral microbiota of an aging mouth; (ii) the effects of age and time on the human oral microbiome; (iii) the potential impact of inflammaging and immunosenescence in the host-oral microbiota interactions; and (iv) the relationship of the aging oral microbiota and Alzheimer's disease. Finally, we present analyses of data compiled from large clinical studies that evaluated the subgingival microbiota of periodontally healthy subjects and patients with periodontitis from a wide age spectrum (20-83 years of age). PMID- 27501492 TI - Periodontitis prevalence in adults >= 65 years of age, in the USA. AB - The older adult population is growing rapidly in the USA and it is expected that by 2040 the number of adults >= 65 years of age will have increased by about 50%. With the growth of this subpopulation, oral health status, and periodontal status in particular, becomes important in the quest to maintain an adequate quality of life. Poor oral health can have a major impact, leading to tooth loss, pain and discomfort, and may prevent older adults from chewing food properly, often leading to poor nutrition. Periodontitis is monitored in the USA at the national level as part of the Healthy People 2020 initiative. In this report, we provide estimates of the overall burden of periodontitis among adults >= 65 years of age and after stratification according to sociodemographic factors, modifiable risk factors (such as smoking status), the presence of other systemic conditions (such as diabetes) and access to dental care. We also estimated the burden of periodontitis within this age group at the state and local levels. Data from the National Health and Nutrition Examination Survey 2009/2010 and 2011/2012 cycles were analyzed. Periodontal measures from both survey cycles were based on a full mouth periodontal examination. Nineteen per cent of adults in this subpopulation were edentulous. The mean age was 73 years, 7% were current smokers, 8% lived below the 100% Federal Poverty Level and < 40% had seen a dentist in the past year. Almost two-thirds (62.3%) had one or more sites with >= 5 mm of clinical attachment loss and almost half had at least one site with probing pocket depth of >= 4 mm. We estimated the lowest prevalence of periodontitis in Utah (62.3%) and New Hampshire (62.6%) and the highest in New Mexico, Hawaii, and the District of Columbia each with a prevalence of higher than 70%. Overall, periodontitis is highly prevalent in this subpopulation, with two-thirds of dentate older adults affected at any geographic level. These findings provide an opportunity to determine how the overall health-care management of older adults should consider the improvement of their oral health conditions. Many older adults do not have dental insurance and are also likely to have some chronic conditions, which can adversely affect their oral health. PMID- 27501493 TI - The aging mouth: differentiating normal aging from disease. AB - Aging is the physiologic change that occurs over time. In humans, this change occurs at different rates and are related to lifestyle, environment and genetics. It can be challenging to differentiate normal aging from disease. In the oral cavity, with increasing age the teeth demonstrate wearing of the enamel, chipping and fracture lines, and a darker color. The pulp chamber and canals are reduced in size as a result of the deposition of secondary dentin. Coronal or root caries, however, represent disease. A limited amount of periodontal attachment loss occurs in association with aging, usually manifesting as recession on the buccal surface of teeth. Severe periodontitis occurs in 10.5-12% of the population, with the peak incidence being observed at 35-40 years of age. Changes to the mucosal tissue that occur with age include reduced wound-healing capacity. However, environmental factors, such as smoking, dramatically increase the risk of mucosal pathology. Reduced salivary gland function is often seen in association with medication usage, as well as with disorders such as diabetes mellitus. Both medication use and chronic disorders are more common in older adults. Masticatory function is of particular importance for older adults. Maintenance of a nutritionally complete diet is important for avoiding sarcopenia and the frailty syndrome. Successful oral aging is associated with adequate function and comfort. A reduced, but functional, dentition of 20 teeth in occlusion has been proposed as a measure of successful oral aging. Healthy oral aging is important to healthy aging from both biological and social perspectives. PMID- 27501494 TI - Treatment of periodontal disease in older adults. AB - Within the next 40 years the number of older adults worldwide will more than double. This will impact periodontal treatment needs and presents a challenge to health-care providers and governments worldwide, as severe periodontitis has been reported to be the sixth most prevalent medical condition in the world. Older adults (>= 80 years of age) who receive regular dental care retain more teeth than those who do not receive such care, but routine general dental care for these individuals is not sufficient to prevent the progression of periodontitis with the same degree of success as in younger individuals. There is a paucity of data on the efficacy of different periodontal therapies for older individuals. However, considering the higher prevalence of chronic medical conditions seen in older adults, it cannot be assumed that periodontal therapy will yield the same degree of success seen in younger individuals. Furthermore, medications can influence the status of the periodontium and the delivery of periodontal care. As an example, anticoagulant drugs are common among older patients and may be a contraindication to certain treatments. Newer anticoagulants will, however, facilitate surgical intervention in older patients. Furthermore, prescription medications taken for chronic conditions, such as osteoporosis and cardiovascular diseases, can affect the periodontium in a variety of ways. In summary, consideration of socio-economic factors, general health status and multiple-drug therapies will, in the future, be an important part of the management of periodontitis in older adults. PMID- 27501495 TI - Implants for the aged patient: biological, clinical and sociological considerations. AB - Until recently, age, particularly old age, was considered a contraindication to the placement of dental implants. However, this was based largely on anecdotal dogma rather than on empirical information. This review considers the biological, clinical and socio-economic implications of implants placed in the aged population. Aging has been shown to have an influence on the biological aspects of soft- and hard-tissue wound healing and tissue remodeling, which may influence the establishment and maintenance of implant integration. However, information to date indicates that age should not be an a priori contraindication for implant placement and there is good evidence to indicate that dental implants can be placed successfully in the elderly with good clinical and socio-economic outcomes. PMID- 27501496 TI - Oral health and the frailty syndrome. AB - The frailty syndrome is an ever-growing area of study among older adults because of its association with an increased risk of falls, hospitalization, institutionalization, dependency and mortality. Frailty is neither a disease nor a disability but is better understood as a medical syndrome of multisystem dysregulation that results in a diminished ability to overcome everyday stressors. The prevalence of frailty in any given population can vary widely, in part because of the way in which it is defined and measured, but in general it is higher among women and in those with advanced age and declining health. Whilst it is largely understood that older adults will differ biologically, psychologically and socially, and that each of these domains can impact oral health, we are only beginning to investigate how the mouth is affected in frailty. Given that both hard and soft structures contribute to oral health and disease status among older adults with varying degrees of impairment and disability, frailty adds yet another dimension to be considered. This paper will discuss how frailty can influence and be influenced by oral disorders, as well as the potential relationship to oral neglect and the resultant consequences among this vulnerable population. PMID- 27501497 TI - Tooth loss as a predictor of shortened longevity: exploring the hypothesis. AB - Many factors contribute to human tooth loss, including oral hygiene practices, trauma, smoking, health status, socio-economic status and individual preferences. Loss of teeth impairs quality-of-life measures, including the eating of most foods that require full masticatory function. A recent study of centenarians found that at age 65-74 years, those who lived to be 100 had a lower rate of edentulism than did younger members of their birth cohort at ages 65-74 years. Oral health was consistent with compression of morbidity toward the end of life. This article explores the hypothesis that factors associated with oral disease and noncommunicable diseases may increase the risk of tooth loss and lead to diminished longevity as a result of multifactorial interactions. It specifically addresses two critical questions. The first is: 'Can we conclude that the number of teeth in aging humans can affect longevity and life expectancy?' The answer is yes. The second is: 'Is tooth loss a predictor of shortened longevity?' Again, the answer is yes. Edentulism and partial edentulism are discussed as a disability, and how the philosophy/belief systems of dental providers and patients toward retaining teeth influences the outcome of tooth loss is also examined. Osteoporosis and cognitive impairment provide examples of modifying risk factors. PMID- 27501498 TI - Oral inflammation and infection, and chronic medical diseases: implications for the elderly. AB - Oral diseases, such as caries and periodontitis, not only have local effects on the dentition and on tooth-supporting tissues but also may impact a number of systemic conditions. Emerging evidence suggests that poor oral health influences the initiation and/or progression of diseases such as atherosclerosis (with sequelae including myocardial infarction and stoke), diabetes mellitus and neurodegenerative diseases (such as Alzheimer's disease, rheumatoid arthritis and others). Aspiration of oropharyngeal (including periodontal) bacteria causes pneumonia, especially in hospitalized patients and the elderly, and may influence the course of chronic obstructive pulmonary disease. This article addresses several pertinent aspects related to the medical implications of periodontal disease in the elderly. There is moderate evidence that improved oral hygiene may help prevent aspiration pneumonia in high-risk patients. For other medical conditions, because of the absence of well-designed randomized clinical trials in elderly patients, no specific guidance can be provided regarding oral hygiene or periodontal interventions that enhance the medical management of older adults. PMID- 27501499 TI - Biopeptides with antioxidant and anti-inflammatory potential in the prevention and treatment of diabesity disease. AB - Diabesity is the leading cause of modern, chronic disease. In 2012, diabetes killed 1.2 million people worldwide and its global prevalence exceeded 347 million people, and it is expected that it will increase to 540 million by 2030. Because of this health imperative, it is also linked to increasing obesity. The role of the inflammatory process and oxidative stress in the pathophysiology of these diseases is widely documented. This paper review, using data from major databases, the role of biopeptides with antioxidant and anti-inflammatory activity as a potential aid for the prevention and treatment of diabesity, since the mechanisms of action mentioned directly affect oxidative stress and the characteristic imbalance of the inflammatory process of this disease. Some of these studies have demonstrated beneficial results in relation to oxidative stress and proinflammatory markers. However, the role of biopeptides, in relation to oxidative stress and inflammatory biomarkers, remains unclear and represents a potentially fruitful area for further research in the health area. PMID- 27501500 TI - Evaluation of the anti-diarrheal activity of the hydromethanolic root extract of Rhus tripartita (Ucria) (Anacardiacae). AB - INTRODUCTION: Rhus tripartita (Anacardiacae) is a plant which is traditionally used for the treatment of ulcer and diarrhea in Tunisia. However, the scientific basis for this usage has not been well established. The core aim of the present study is to evaluate the antidiarrheal activity of Rhus tripartita root methanolic extract (RRE). MATERIAL AND METHODS: The antidiarrheal activity of RRE oral doses (50, 100, 200 and 300mg/kg) was evaluated using the castor oil-induced diarrhea, the intestinal fluid emptying method and the normal intestinal transit test. The antibacterial activity was tested against four pathogenic bacteria using two methods. The RRE was also phytochemical studied. RESULTS: Diarrhea experiments showed a protective effect of the RRE which produced a significant (p<0.05) and dose-dependent reduction of all the diarrhea parameters. It delayed the onset of diarrhea, produced a significant decrease in the frequency of defecation and the diarrhea score severity and decreased the volume of intestinal fluid induced by castor oil as well as the propulsion intestinal transit. The effect of the extract at the highest dose (300mg/kg) was similar to that of loperamide, the standard anti-diarrheal drug (10mg/kg). The anti-bacterial activity test showed that RRE exhibited a great inhibition activity against four pathogenic bacteria strains (Esherichia coli, Salmonella typhimurium, Salmonella argenosa, Staphylococcus aureus). Oral administration of the extract up to 3g/kg did not produce any acute toxicity in rats. The preliminary phytochemical screening of the RRE revealed the presence of flavonoids, tannins, and polyphenols. CONCLUSION: Results showed that RRE at 300mg/kg possesses the highest anti-diarrheal activity possibly mediated by the inhibitory effects on gastrointestinal propulsion and intestinal fluid accumulation. PMID- 27501501 TI - The Urtica dioica extract enhances sensitivity of paclitaxel drug to MDA-MB-468 breast cancer cells. AB - INTRODUCTION: Due to the chemo resistant nature of cancer cells and adverse effects of current therapies, researchers are looking for the most efficient therapeutic approach which has the lowest side effects and the highest toxicity on cancer cells. The aim of the present study was to investigate the synergic effect of Urtica dioica extract in combination with paclitaxel on cell death and invasion of human breast cancer MDA-MB-468 cell line. MATERIALS AND METHODS: To determine the cytotoxic effects of Urtica dioica extract with paclitaxel, MTT assay was performed. The scratch test was exploited to assess the effects of Urtica dioica, Paclitaxel alone and combination on migration of cancer cells. The expression levels of snail-1, ZEB1, ZEB2, twist, Cdc2, cyclin B1 and Wee1 genes were quantified using qRT-PCR and western blot performed for snail-1expression. The effects of plant extract, Paclitaxel alone and combination on different phases of cell cycle was analyzed using flow cytometry. RESULTS: Results of MTT assay showed that Urtica dioica significantly destroyed cancer cells. Interestingly, Concurrent use of Urtica dioica extract with paclitaxel resulted in decreased IC50 dose of paclitaxel. Moreover, findings of scratch assay exhibited the inhibitory effects of Urtica dioica, Paclitaxel alone and combination on migration of MDA-MB-468 cell line. Our findings also demonstrated that the extract substantially decreased the Snail-1 and related gene expression. Ultimately, Cell cycle arrest occurred at G2/M phase post-treatment by deregulating Cdc2 and wee1. CONCLUSIONS: Our results demonstrated that the dichloromethane extract of Urtica dioica inhibit cell growth and migration. Also, Urtica dioica extract substantially increased sensitivity of breast cancer cells to paclitaxel. Therefore, it can be used as a potential candidate for treatment of breast cancer with paclitaxel. PMID- 27501502 TI - MiR-622 functions as a tumor suppressor and directly targets E2F1 in human esophageal squamous cell carcinoma. AB - PURPOSE: MicroRNA-622 has been proven down-regulated in many human malignancies and correlated with tumor progression. However, its role in esophageal squamous cell carcinoma (ESCC) is still unclear. The aim of this study was to explore the expression and function of miR-622 in ESCC. METHODS: Using quantitative RT-PCR, we detected miR-622 expression in ESCC cell lines and primary tumor tissues. The association of miR-622 expression with clinicopathological factors and prognosis was also analyzed. Then, the effects of miR-622 on the biological behavior of ESCC cells were investigated. At last, the potential regulatory function of miR 622 on E2F1 expression was confirmed. RESULTS: miR-622 was found to be down regulated in ESCC tissues and cell lines. Decreased miR-622 expression was closely correlated with aggressive clinicopathological features and poor overall survival. Multivariate regression analysis corroborated that low level of miR-622 expression was an independent unfavourable prognostic factor for patients with ESCC. Up-regulation of miR-622 could significantly reduce ESCC cell proliferation, enhance cell apoptosis, and impair cell invasion and migration in vitro, while down-regulation of miR-622 showed opposite effects. Further, E2F1 was confirmed as a direct target of miR-622 by using Luciferase Reporter Assay. CONCLUSIONS: These findings indicate that miR-622 may act as a tumor suppressor in ESCC and would serve as a potential therapy target for this disease. PMID- 27501503 TI - Shedding light on the gray zone. PMID- 27501504 TI - Effect of metronidazole use on tacrolimus concentrations in transplant patients treated for Clostridium difficile. AB - BACKGROUND: Two case reports suggest that metronidazole treatment for Clostridium difficile infections (CDI) increases tacrolimus (TAC) trough levels. The primary objective of this study was to determine the clinical significance of this potential interaction in transplant patients receiving CDI treatment. Currently, no robust literature exists to estimate a magnitude of pharmacokinetic interaction between metronidazole and TAC. METHODS: In this retrospective study, the effects of CDI and metronidazole treatment on TAC levels in 52 adult solid organ transplant patients were investigated. The primary outcome was to determine the difference in dose-normalized TAC levels between baseline and symptom resolution in patients treated with metronidazole or vancomycin. The secondary outcome was to determine the difference in dose-normalized TAC levels at baseline and CDI diagnosis. RESULTS: The average change in log-transformed dose-normalized TAC levels from baseline to symptom resolution was 0.99 for metronidazole (n = 35) and 1.04 for vancomycin (n = 17) treatment. The mean difference between the groups was 0.96 (95% confidence interval: 0.74-1.24). No significant difference was found between dose-normalized TAC levels at CDI diagnosis and baseline (P = 0.37). CONCLUSION: CDI treatment with metronidazole was not associated with a >30% increase in TAC levels compared with vancomycin. Both treatment groups required TAC dose adjustments to maintain goal TAC levels and those treated with metronidazole did not require a significantly greater dose adjustment. PMID- 27501505 TI - Randomised phase III study of S-1 alone versus S-1 plus lentinan for unresectable or recurrent gastric cancer (JFMC36-0701). AB - BACKGROUND: Lentinan (LNT) is a purified beta-1, 3-glucan that augments immune responses. The present study was conducted to assess the efficacy of LNT in combination with S-1 as a first-line treatment for unresectable or recurrent gastric cancer. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive S-1 alone or S-1 plus LNT. The primary end-point was overall survival (OS). Secondary end-points were time-to-treatment failure (TTF), overall response rate (ORR), safety, quality of life (QOL), and biomarker. The percentages of LNT binding monocytes in peripheral blood prior to treatment were analysed for the biomarker assessment. RESULTS: One hundred and fifty-four and 155 patients were randomly assigned to receive S-1 alone or S-1 plus LNT, respectively. The median OS was 13.8 and 9.9 months (P = 0.208), the median TTF was 4.3 and 2.6 months (P < 0.001), the ORR was 22.3% and 18.7% for the S-1 and S-1 plus LNT groups, respectively. The incidences of haematologic and non-haematologic adverse events were similar, and no significant changes in QOL scores were observed during the treatment in both groups. In a subpopulation of patients with LNT-binding monocytes >=2%, patients who received more than two cycles of chemotherapy showed a longer survival time in the S-1 plus LNT group. CONCLUSIONS: OS did not improve and TTF was significantly worse in the S-1 plus LNT group as compared with the S 1-only group. This study showed no efficacy of LNT when combined with S-1 treatment in patients with unresectable or recurrent gastric cancer. CLINICAL TRIAL REGISTRATION ID NUMBER: UMIN 000000574. PMID- 27501506 TI - Systemic review: Radiation therapy alone in medical non-operable endometrial carcinoma. AB - BACKGROUND AND PURPOSE: Radiotherapy is a good option for inoperable and frail patients diagnosed with endometrial cancer. Because of the lack of large multicentre trials, a systematic review was performed in an attempt to get an overview on the feasibility and efficacy of this specific approach. MATERIALS AND METHODS: We performed a bibliographic search for articles in English or French which were published in PubMed from the start of this database in January 1969 to identify publications on radiation therapy (RT) as single treatment for localised non-operable carcinoma of the endometrium. The review was completed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULTS: Twenty-five reports containing 2694 patients treated with RT as single treatment were identified that fulfilled the selection criteria. Disease-specific survival (DSS) at 5 years was reported for a cohort of 1322 (49.1%) patients. The combined DSS for this group of patients was 78.5% (range: 68.4-92%; 95% confidence interval: 74.5-82.5). External beam radiation therapy (EBRT) combined with brachytherapy (BT) was used in 1278 patients (47.4%), BT alone in 1383 patients (51.3%), and EBRT alone in 33 patients (1.2%). The average occurrence of grade III or worse late toxicity was 3.7% for EBRT + BT, 2.8% for BT alone, and 1.2% for EBRT alone. CONCLUSIONS: RT is in terms of disease control and toxicity, an acceptable option for non-surgical candidate patients. Prospective multicentre randomised or observational trials are needed to validate these results. PMID- 27501507 TI - Combined low-dose ipilimumab and pembrolizumab after sequential ipilimumab and pembrolizumab failure in advanced melanoma. AB - With the wide use of anti-PD-1 therapy, an increasing number of patients progress under treatment. Combined immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies induces higher response rates as first-line treatment in comparison to single agent therapy, however, with substantial toxicity since the combination of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) induced 55% grade 3/4 treatment related adverse events and treatment discontinuation rates of 39%. In this case series, we investigated the efficacy and toxicity of the combined immunotherapy with low-dose ipilimumab (1 mg/kg) plus pembrolizumab (2 mg/kg) in patients with metastatic melanoma with progressive disease under sequential monotherapy with both agents. All patients had received at least three lines of treatment, 78% of patients were M1c, and 67% had brain metastases. Stable disease was observed in 3 out of 9 patients with a median overall survival of 8 months after double checkpoint inhibition. No treatment-related grade 3/4 adverse events occurred, and none of the patients needed to discontinue the treatment due to toxicity. Further trials are needed to investigate combined immunotherapy as rescue treatment in heavily pretreated melanoma patients to find optimal dosage in regard to outcome and toxicity. PMID- 27501508 TI - LVAD implantation following repair of acute postmyocardial infarction ventricular septal defect. AB - Ventricular septal defect (VSD) is a life-threatening complication of myocardial infarction (MI). Mortality is highest if VSD repair occurs within seven days following MI. We report a case of post-MI VSD stabilized with peripheral veno arterial extracorporeal membrane oxygenation (VA-ECMO) followed by patch repair and implantation of a durable left ventricular assist device (LVAD). PMID- 27501509 TI - Electrochemical Characterization of Ultrathin Cross-Linked Metal Nanoparticle Films. AB - Here we report the preparation, characterization, and electrochemical study of conductive, ultrathin films of cross-linked metal nanoparticles (NPs). Nanoporous films ranging from 40 to 200 nm in thickness composed of gold and platinum NPs of ~5 nm were fabricated via a powerful layer-by-layer spin coating process. This process allows preparation of uniform NP films as large as 2 * 2 cm(2) with precise control over thickness, structure, and electrochemical and electrocatalytic properties. Gold, platinum, and bimetallic NP films were fabricated and characterized using cyclic voltammetry, scanning electron microscopy, and conductance measurements. Their electrocatalytic activity toward the oxygen reduction reaction (ORR) was investigated. Our results show that the electrochemical activity of such NP films is initially hindered by the presence of dense thiolate cross-linking ligands. Both electrochemical cycling and oxygen plasma cleaning are effective means in restoring their electrochemical activity. Gold NP films have higher electric conductivity than platinum possibly due to more uniform film structure and closer particle-particle distance. The electrochemical and electrocatalytic performance of platinum NP films can be greatly enhanced by the incorporation of gold NPs. This work focuses on electrochemical characterization of cross-linked NP films and demonstrates several unique properties. These include quick and easy preparation, ultrathin and uniform film thickness, tunable structure and composition, and transferability to many other substrates. PMID- 27501510 TI - Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus. AB - AIM: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral glucagon receptor antagonist, LGD 6972, in healthy subjects and subjects with type 2 diabetes (T2DM). METHODS: In the single ascending dose study, LGD-6972 (2-480 mg) was administered to healthy subjects (n = 48) and T2DM subjects (n = 8). In the multiple ascending dose study, healthy subjects (n = 12) received a dose of 15 mg LGD-6972 and T2DM subjects (n = 36) received doses of 5, 10 or 15 mg of LGD-6972 daily for 14 days. RESULTS: LGD-6972 had linear plasma pharmacokinetics consistent with once-daily dosing that was comparable in healthy and T2DM subjects. Dose-dependent decreases in fasting plasma glucose were observed in all groups with a maximum of 3.15 mmol/L (56.8 mg/dL) on day 14 in T2DM subjects. LGD-6972 also reduced plasma glucose in the postprandial state. Dose-dependent increases in fasting plasma glucagon were observed, but glucagon levels decreased and insulin levels increased after an oral glucose load in T2DM subjects. LGD-6972 was well tolerated at the doses tested without dose-related or clinically meaningful changes in clinical laboratory parameters. No subject experienced hypoglycaemia. CONCLUSION: Inhibition of glucagon action by LGD-6972 was associated with decreases in glucose in both healthy and T2DM subjects, the magnitude of which was sufficient to predict improvement in glycaemic control with longer treatment duration in T2DM patients. The safety and pharmacological profile of LGD-6972 after 14 days of dosing supports continued clinical development. PMID- 27501511 TI - Preparation and application of a coated-fiber needle extraction device. AB - In this study, a needle-trap device with fibers coated with a molecularly imprinted polymer was developed for separation. A number of heat-resistant Zylon filaments were longitudinally packed into a glass capillary, followed by coating with a molecularly imprinted polymer. Then, the molecularly imprinted polymer coating was copolymerized and anchored onto the surface of the fibers. The bundle of synthetic fibers coated with the molecularly imprinted polymer was packed into a 21G stainless-steel needle and served as an extraction medium. The coated-fiber needle extraction device was used to extract volatile organic compounds from paints and gasoline effectively. Subsequently, the extracted volatile organic compounds were analyzed by gas chromatography. Calibration curves of gaseous benzene, toluene, ethylbenzene, and o-xylene in the concentration range of 1-250 MUg/L were obtained to evaluate the method, acceptable linearity was attended with correlation coefficients above 0.998. The limit of detection of benzene, toluene, ethylbenzene, and o-xylene was 11-20 ng/L using the coated-fiber needle trap device. The relative standard deviation of needle-to-needle repeatability was less than 8% with an extraction time of 20 min. The loss rates after storage for 3 and 7 days at room temperature were less than 30%. PMID- 27501512 TI - Thymomectomy in early stage thymomas-case closed? PMID- 27501513 TI - Removal of Ozone by Carbon Nanotubes/Quartz Fiber Film. AB - Ozone is recognized as a harmful gaseous pollutant, which can lead to severe human health problems. In this study, carbon nanotubes (CNTs) were tested as a new approach for ozone removal. The CNTs/quartz fiber film was fabricated through growth of CNTs upon pure quartz fiber using chemical vapor deposition method. Ozone conversion efficiency of the CNTs/quartz fiber film was tested for 10 h and compared with that of quartz film, activated carbon (AC), and a potassium iodide (KI) solution under the same conditions. The pressure resistance of these materials under different airflow rates was also measured. The results showed that the CNTs/quartz fiber film had better ozone conversion efficiency but also higher pressure resistance than AC and the KI solution of the same weight. The ozone removal performance of the CNTs/quartz fiber film was comparable with AC at 20 times more weight. The CNTs played a dominant role in ozone removal by the CNTs/quartz fiber film. Its high ozone conversion efficiency, lightweight and free-standing properties make the CNTs/quartz fiber film applicable to ozone removal. Further investigation should be focused on reducing pressure resistance and studying the CNT mechanism for removing ozone. PMID- 27501514 TI - Interleukin-32 levels in gingival crevicular fluid and saliva of patients with chronic periodontitis after periodontal treatment. AB - BACKGROUND AND OBJECTIVE: The cytokine, interleukin (IL)-32, is a relatively new discovery. However, it is very powerful for stimulating tumor necrosis factor alpha (TNF-alpha) under inflammatory conditions. The objective of this research was to explore fluctuations in the levels of TNF-alpha, IL-32 and IL-10, in both saliva and gingival crevicular fluid. The focus was on measurements taken before and after clinical treatment of chronic periodontitis. MATERIAL AND METHODS: For the purposes of the study, a total of 27 patients with chronic periodontitis and 27 controls (periodontally healthy) were recruited. Important clinical periodontal criteria were established before and 4 wk after the start of the research. The chronic periodontitis group was given an initial form of periodontal care. Samples of saliva and gingival crevicular fluid were collected exactly 4 wk preceding and 4 wk following the care. The levels of IL-10, IL-32 and TNF-alpha present in saliva and gingival crevicular fluid were recorded via the use of an ELISA. RESULTS: At baseline, the levels of TNF-alpha and IL-32 in the gingival crevicular fluid and saliva were significantly higher among patients in the chronic periodontitis group than among patients in the control group (p < 0.05). On the other hand, at baseline the levels of IL-10 were significantly lower in the gingival crevicular fluid and saliva of the chronic periodontitis group than the control group (p < 0.05). A significantly positive link was found between the TNF-alpha and IL-32 levels in the two study groups (p < 0.05). After treatment, the levels of TNF-alpha and IL-32 in saliva and gingival crevicular fluid were significantly lower in the chronic periodontitis group when compared with the baseline readings. However, the levels of IL-10 were significantly higher (p < 0.05). CONCLUSION: Ultimately, the level of IL-32 present in saliva and gingival crevicular fluid might be useful as an indicator of the condition and the expectations for its treatment and care. According to the results of the research, the proinflammatory impact of IL-32 could potentially be linked to the intensity and progression of periodontitis. PMID- 27501515 TI - BOLD quantified renal pO2 is sensitive to pharmacological challenges in rats. AB - PURPOSE: Blood oxygen level-dependent (BOLD) MRI has been effectively used to monitor changes in renal oxygenation. However, R2* (or T2*) is not specific to blood oxygenation and is dependent on other factors. This study investigates the use of a statistical model that takes these factors into account and maps BOLD MRI measurements to blood pO2. METHODS: Spin echo and gradient echo images were obtained in six Sprague-Dawley rats and R2 and R2* maps were computed. Measurements were made at baseline, post-nitric oxide synthase inhibitor (L NAME), and post-furosemide administration. A simulation of each region was performed to map R2' (computed as R2*-R2) to blood pO2. RESULTS: At baseline, blood pO2 in the outer medulla was 30.5 +/- 1.2 mmHg and 51.9 +/- 5.2 mmHg in the cortex, in agreement with previous invasive studies. Blood pO2 was found to decrease within the outer medulla following L-NAME (P < 0.05) and increase after furosemide (P < 0.05). Blood pO2 in the cortex increased following furosemide (P < 0.05). CONCLUSIONS: Model-derived blood pO2 is sensitive to pharmacological challenges, and baseline pO2 is comparable to literature values. Reporting pO2 instead of R2* could lead to a greater clinical impact of renal BOLD MRI and facilitate the identification of hypoxic regions. Magn Reson Med 78:297-302, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27501516 TI - Beyond the Billboard: The Facebook-Based Application, Donor, and Its Guided Approach to Facilitating Living Organ Donation. AB - Living donor solicitation can raise ethical concerns, regardless of the medium used: newspaper, television, pulpit, billboard or Internet. Moving the search for a living donor into the social media realm introduces the risk of unguided and coercive patient narratives as well as decoupling or even total absence of information that could aid the consent process. The Facebook application (app) for living donors, called Donor (restricted to patient use), aims to address these concerns in several ways: (i) by directing the patient's initial appeal to friends and family; (ii) by guiding the patient's narrative; and (iii) by providing a library of clinical, ethical and regulatory information that informs the consent process. In this paper, we explored these features and contrasted them with billboard solicitation activities and current independent social media efforts. We concluded that the proactive ethical design of the Donor app is a permissible way to help satisfy the shortfall of deceased donor livers and kidneys. PMID- 27501518 TI - Pyrethroid resistance is associated with a kdr-type mutation (L1014F) in the potato tuber moth Tecia solanivora. AB - BACKGROUND: The Guatemalan potato tuber moth, Tecia solanivora, has been the most important pest species in Hispanico-American potato fields since its first record on potatoes in 1956 in Guatemala. This insect pest has been spreading to other parts of the world, including the Canary Islands in Europe. Tuber moth control relies heavily on the use of insecticides, including pyrethroids. Here, we assessed the likelihood of control failures and performed concentration-response bioassays in five Colombian strains of T. solanivora to evaluate their susceptibilities to the pyrethroid permethrin. RESULTS: Evidence of control failures was observed in four strains tested, which exhibited moderate resistance levels (i.e. ranging from 5.4- to 24.4-fold). However, no spatial dependence was observed between the permethrin LC50 values and the geographic distances among the tuber moth strains. In order to evaluate whether permethrin resistance was mediated by potential mutations in the para-type sodium channels of T. solanivora, the IIS4-IIS6 region of the para gene was PCR amplified and sequenced from the five strains tested. As demonstrated across a range of different arthropod species that exhibited knockdown resistance (kdr), we observed a single point substitution (L1014F) at high frequencies in the para gene of all four resistant strains. CONCLUSION: This is the first identification of a target-site alteration-based resistance in the Guatemalan potato tuber moth T. solanivora, which is widespread and exhibits high frequencies among geographically distant strains, indicating that pyrethroids are probably becoming ineffective for the control of this pest species. (c) 2016 Society of Chemical Industry. PMID- 27501517 TI - Invasive species' leaf traits and dissimilarity from natives shape their impact on nitrogen cycling: a meta-analysis. AB - Many exotic species have little apparent impact on ecosystem processes, whereas others have dramatic consequences for human and ecosystem health. There is growing evidence that invasions foster eutrophication. We need to identify species that are harmful and systems that are vulnerable to anticipate these consequences. Species' traits may provide the necessary insights. We conducted a global meta-analysis to determine whether plant leaf and litter functional traits, and particularly leaf and litter nitrogen (N) content and carbon: nitrogen (C : N) ratio, explain variation in invasive species' impacts on soil N cycling. Dissimilarity in leaf and litter traits among invaded and noninvaded plant communities control the magnitude and direction of invasion impacts on N cycling. Invasions that caused the greatest increases in soil inorganic N and mineralization rates had a much greater litter N content and lower litter C : N in the invaded than the reference community. Trait dissimilarities were better predictors than the trait values of invasive species alone. Quantifying baseline community tissue traits, in addition to those of the invasive species, is critical to understanding the impacts of invasion on soil N cycling. PMID- 27501519 TI - Putative RopGAPs impact division plane selection and interact with kinesin-12 POK1. AB - Cell shape is defined by the surrounding cell walls in plants. Thus, spatial control over cell division planes and cell expansion polarity are essential to maintain cell morphology. In eukaryotes, cell polarity and expansion are controlled by Rho GTPase signalling, regulating cytoskeletal reorganization and vesicle trafficking(1). However, until now, Rho signalling was not implicated in mitotic events in plants. Here, we report a pair of putative Rho GTPase activating proteins (RhoGAPs) that interact with the mitosis-specific kinesin-12 POK1, a core component of the cortical division zone/site (CDZ/CDS) that is required for division plane maintenance in Arabidopsis(2-4). The designated pleckstrin homology GAPs (PHGAPs) are cytoplasmic and plasma membrane associated in interphase, but during mitosis they additionally localize to the CDZ/CDS in a POK-dependent manner. In contrast to pok1 pok2 mutants, phgap1 phgap2 double mutants show moderate cell wall positioning defects as a consequence of inaccurate positioning of the cortical division zone marker POK1. We conclude that loss of PHGAP function interferes with division plane selection in proliferative cell divisions. PMID- 27501520 TI - Assessment of endothelial damage and cardiac injury in a mouse model mimicking thrombotic thrombocytopenic purpura. AB - : Essentials Endothelial injury is thought to be a key event in thrombotic thrombocytopenic purpura (TTP). Endothelial and cardiac damages were assessed in a model of TTP using ADAMTS-13 knockout mice. Damages of cardiac perfusion and function were associated with nitric oxide pathway alteration. Endothelial dysfunction constitutes a critical event in TTP development and cardiac injury. SUMMARY: Background Cardiac alterations represent a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). Endothelial injury remains poorly defined, but seems to be a key initiating event leading to the formation of platelet-rich thrombi in TTP patients. Objectives To assess the changes in endothelial function and the induced cardiac damage in a mouse model of TTP. Patients/methods We used an animal model in which TTP-like symptoms are triggered by injection of 2000 units kg-1 of recombinant von Willebrand factor in ADAMTS-13 knockout mice. Results These mice developed TTP-like symptoms, i.e. severe thrombocytopenia, schistocytosis, and anemia. On day 2, magnetic resonance imaging demonstrated a decrease in left ventricular perfusion associated with alteration of left ventricular ejection fraction, fractional shortening, and cardiac output, suggesting early systolic dysfunction. This was associated with decrease in endothelium-mediated relaxation responses to acetylcholine in mesenteric and coronary arteries, demonstrating severe early endothelial dysfunction. In parallel, we showed decreased cardiac expression of endothelial nitric oxide (NO) synthase and increased expression of antioxidant enzymes, suggesting alteration of the NO pathway. At this time, cardiac immunohistochemistry revealed an increase in the expression of VCAM-1 and E selectin. Conclusion This study provides evidence that the heart is a sensitive target organ in TTP, and shows, for the first time, strong mesenteric and coronary endothelial dysfunction in an induced-TTP model. The mechanisms incriminated are the occurrence of a pro-oxidant state, and proadhesive and proinflammatory phenotypes. This previously largely unrecognized vascular dysfunction may represent an important contributor to the systemic organ failure occurring in TTP. PMID- 27501521 TI - Analysis of biophysical and functional consequences of tropomyosin-fluorescent protein fusions. AB - The dynamic nature of actin polymers is modulated to facilitate a diverse range of cellular processes. These dynamic properties are determined by different isoforms of tropomyosin which are recruited to distinct subpopulations of actin polymers to differentially regulate their functional properties. This makes tropomyosin an attractive target for labelling discrete actin populations. We have assessed the effect of different fluorescent labelling strategies for this protein. Although tropomyosin-fluorescent fusions decorate actin in vivo, they are either nonfunctional or perturb regulation of actin nucleation and cell cycle timings. Thus, conclusions and physiological relevance should be carefully evaluated when using tropomyosin fusions. PMID- 27501522 TI - Measuring glycated haemoglobin in women with gestational diabetes mellitus: How useful is it? AB - BACKGROUND: Glycated haemoglobin (HbA1c) is an important tool for assessing glycaemic status in patients with diabetes, but its usefulness in gestational diabetes mellitus (GDM), is unclear. AIMS: The aim of this study is to evaluate whether HbA1c in women with GDM is valuable in predicting adverse pregnancy outcomes. MATERIALS AND METHODS: A retrospective review of women with GDM who had HbA1c measured at diagnosis of GDM (GHb-diag) and at 36 weeks gestation (GHb-36 weeks) was conducted. The association between HbA1c and various pregnancy outcomes was assessed RESULTS: Among 1244 women with GDM in our cohort, both GHb diag and GHb-36 weeks were independent predictors for large-for-gestation (LGA) babies (OR 1.06, P = 0.005 and OR 1.06, P = 0.002, respectively) and neonatal hypoglycaemia (OR 1.10, P < 0.001 and OR 1.09, P < 0.001, respectively). Women with HbA1c >= 5.4% (35 mmol/mol) at diagnosis had significantly greater risk for LGA (15.3% vs 8.2%, P < 0.001) and neonatal hypoglycaemia (42.2% vs 23.6%, P < 0.001) than those below this cut-off. The difference between GHb-diag and GHb-36 weeks was small and improvement in HbA1c by 36 weeks was not associated with better pregnancy outcomes. CONCLUSION: We showed that measurement of HbA1c, either at the time of diagnosis of GDM or toward the end of pregnancy, were both associated with adverse pregnancy outcomes. Women with elevated HbA1c (>5.4% or 35 mmol/mol) at diagnosis of GDM should be monitored closely during pregnancy. However, there is not enough evidence to suggest that repeating HbA1c toward the end of pregnancy will provide additional information in predicting adverse pregnancy outcomes. PMID- 27501523 TI - Cytoplasmic expression of beta-catenin is an independent predictor of progression of conventional renal cell carcinoma: a simple immunostaining score. AB - AIMS: The aims of this study were to investigate the potential of beta-catenin as a biomarker for predicting cancer-specific survival, and to find a reproducible mode of evaluation of immunohistochemistry. METHODS AND RESULTS: beta-Catenin expression was analysed by immunohistochemistry in a cohort of 488 patients with conventional renal cell carcinoma (RCC) operated on between 2000 and 2010. The association between beta-catenin expression and cancer-specific survival was assessed with univariate and multivariate Cox regression models in relation to conventional clinical pathological prognostic factors, and by Kaplan-Meier survival analysis with the log rank test. The univariate Cox regression model revealed an association of cytoplasmic beta-catenin positivity and pathological variables with cancer-specific death. The multivariate Cox regression model analysis of tumours without metastatic disease at the first presentation identified the T-classification (P < 0.001) and cytoplasmic beta-catenin positivity as risk factors for postoperative tumour progression. Specifically, cytoplasmic beta-catenin expression was an independent factor indicating an unfavourable prognosis, with a four-fold higher risk of cancer-specific death (relative risk 4.017; 95% confidence interval 2.489-6.482; P < 0.001). The median survival time for patients with tumours showing cytoplasmic accumulation of beta catenin was 48 months, whereas the overall survival time was 166 months. CONCLUSIONS: Cytoplasmic beta-catenin expression is an independent prognostic factor for conventional RCC, and may help to identify patients with a high risk of cancer-specific death and to direct optimized active surveillance or adjuvant therapy. PMID- 27501524 TI - Physicians' identification of the need for palliative care in people with intellectual disabilities. AB - BACKGROUND: A growing number of people with intellectual disabilities (ID) is suffering from life-threatening chronic illnesses and is therefore in need for palliative care. AIMS: We aimed to explore how the need for palliative care is recognized in people with ID. METHODS AND PROCEDURES: We conducted a semi structured interview study among 10 ID-physicians in the Netherlands. OUTCOMES AND RESULTS: Identification of people with ID in need for palliative care mostly results from a process in which multiple signals from different information sources converge and lead to a growing awareness. As a result, ID-physicians do not expect people to return to their prior level of health or functioning, but rather expect an irreversible decline leading to death. The presence, stage and prognosis of the disease, physician-patient interaction, and communication with proxies who provide contextual information are factors influencing the process. CONCLUSIONS AND IMPLICATIONS: Distinctive for a population of people with ID are the frequent diagnostic uncertainty in people with ID, the patients' communicational abilities and the reliance of ID-physicians on close proxies. We argue for a proactive attitude of physicians regarding care and support of people with ID with palliative care needs. PMID- 27501525 TI - Progress and challenges in diagnosis of dysferlinopathy. AB - Dysferlin-deficient limb girdle muscular dystrophy type 2B, distal Miyoshi myopathy, and other less frequent phenotypes are a group of recessive disorders called dysferlinopathies. They are characterized by wide clinical heterogeneity. To diagnose dysferlinopathy, a clinical neuromuscular workup, including electrophysiological and muscle imaging investigations, is essential to support subsequent laboratory testing. Increased serum creatine kinase levels, distal or proximal muscle weakness, and myalgia with onset in the second or third decades are the main clinical features of the disease. In muscle biopsies, severe dysferlin deficiency by immunoblot or its abnormal localization by immunohistochemistry are the gold standard, as they have a high diagnostic value. Dysferlin testing on monocytes is a valuable alternative to muscle immunoblotting. Molecular techniques for gene mutation detection, such as next generation sequencing, have improved the genetic diagnosis, which is crucial for treatment and genetic counselling. Muscle Nerve 54: 821-835, 2016. PMID- 27501526 TI - High plasticity reversible resistive switching in heteroepitaxial metal/CeO2-x /Nb:SrTiO3/Ti/Pt structures. AB - We report on the characterization of resistive switching devices based on epitaxial CeO2 thin films as a functional material. CeO2 epitaxial thin films were grown by the pulsed laser deposition technique on conductive substrates. Platinum and titanium nitride top electrodes (TE) were successively deposited. Very good performances, in terms of resistivity switching and multilevel operation capability, were obtained using the Pt TE. The dependence of the low resistance and high resistance state on the TE material and on the CeO2 film thickness were explained. The electrical characteristics of these heterostructures make them promising as synapse for neuromorphic computation, but suggest also their use with multi-valued digital systems or multibit memory cells. PMID- 27501527 TI - Complex effects of dyslexia risk factors account for ADHD traits: evidence from two independent samples. AB - BACKGROUND: Developmental dyslexia (DD) and attention deficit/hyperactivity disorder (ADHD) are among the most common neurodevelopmental disorders, whose etiology involves multiple risk factors. DD and ADHD co-occur in the same individuals much more often than would be expected by chance. Several studies have found significant bivariate heritability, and specific genes associated with either DD or ADHD have been investigated for association in the other disorder. Moreover, there are likely to be gene-by-gene and gene-by-environment interaction effects (G * G and G * E, respectively) underlying the comorbidity between DD and ADHD. We investigated the pleiotropic effects of 19 SNPs spanning five DD genes (DYX1C1, DCDC2, KIAA0319, ROBO1, and GRIN2B) and seven DD environmental factors (smoke, miscarriage, birth weight, breastfeeding, parental age, socioeconomic status, and parental education) for main, either (a) genetic or (b) environmental, (c) G * G, and (d) G * E upon inattention and hyperactivity/impulsivity. We then attempted replication of these findings in an independent twin cohort. METHODS: Marker-trait association was analyzed by implementing the Quantitative Transmission Disequilibrium Test (QTDT). Environmental associations were tested by partial correlations. G * G were investigated by a general linear model equation and a family-based association test. G * E were analyzed through a general test for G * E in sib pair-based association analysis of quantitative traits. RESULTS: DCDC2-rs793862 was associated with hyperactivity/impulsivity via G * G (KIAA0319) and G * E (miscarriage). Smoke was significantly correlated with hyperactivity/impulsivity. We replicated the DCDC2 * KIAA0319 interaction upon hyperactivity/impulsivity in the twin cohort. CONCLUSIONS: DD genetic (DCDC2) and environmental factors (smoke and miscarriage) underlie ADHD traits supporting a potential pleiotropic effect. PMID- 27501528 TI - Successful multivessel percutaneous coronary intervention for acute coronary syndrome in a HIV-positive severe haemophiliac. PMID- 27501529 TI - The two sides of creatinine: both as bad as each other? PMID- 27501530 TI - Development and pilot testing of an educational intervention for parents, caregivers and teachers of children with verbal communication disabilities in Mexico. AB - The purpose of this study was to implement and test an educational intervention aimed at training parents/caregivers and teachers in strategies to support children with verbal communication disabilities (VCDs). We carried out a descriptive observational research conducted in two phases during 2013-2014: a mixed-method diagnosis and intervention development. We used convenience sampling to select the parents/caregivers and teachers of first-to-third graders with VCDs across four public elementary schools in a suburban community in central Mexico. Diagnosis was based on questionnaires conducted with parents/caregivers (n = 38) and teachers (n = 16). The instruments focused not only on the respondents' socioeconomic characteristics and general knowledge about VCDs but also included open questions (24/42) about their common practices and support for children with VCDs. The intervention was built on data collected through the questionnaires, and was designed according to the Integral Intervention Model framework based on the ecosystemic approach. Participants were parents/caregivers and teachers of children with VCDs. Main results showed that the participants were trained in various support techniques, they gained knowledge about VCDs and changed their perception of their own ability to help children with language impairments. As an important upshot of the intervention, communication and networking among parents/caregivers and teachers increased. The main strengths of this research reside in its solid theoretical foundation and the fact that intervention design was based on the specific needs of the target group. In as much as the public health problem of VCDs in Mexico has barely been studied and has received minimal official support, it is essential to engage additional social actors, stakeholders and decision-makers in the implementation of permanent actions. Our study emphasises the importance of recognising this form of health impairment as a social responsibility and not as an individual family problem. PMID- 27501531 TI - The remaining core: a fresh look at religiosity trends in Great Britain. AB - In recent years, there has been a growing argument that the end product of secularization may not be a disappearance of all things religious, but rather a polarization between a larger secular group in society and smaller religiously fervent and active communities. Yet, there has been little empirical testing of this theory in contexts of advanced secularization. The aim of this paper is to fill this gap by studying individual belief and religiosity trends over the past four decades in Great Britain, searching specifically for evidence of the population splitting more and more between religious 'nones' removed from all forms of religion, and actively religious individuals characterized by strong beliefs and favourable to the public involvement of religion. Analysing descriptive statistics from the 1983-2012 BSAs as well as more detailed models from the 1991, 1998 and 2008 BSAs, we find growing differences in levels of beliefs and attitudes towards public religion between the increasing proportions of unaffiliated and, in recent years and among younger cohorts, more stable proportions of religiously committed individuals. The remaining religiously committed generally have stronger beliefs and more favourable views towards religious leaders influencing politics in 2008 compared with 1991, and the unaffiliated, less favourable views towards public religion. PMID- 27501532 TI - Effect of auriculopalpebral nerve block on Schirmer tear test I values in normal horses. AB - OBJECTIVE: To compare Schirmer tear test I (STTI) values collected in normal horses with and without an auriculopalpebral nerve block. PROCEDURE: Schirmer tear test I values were measured in 20 clinically normal horses (38 eyes) with a median age of 12 years. The order of eyes tested was randomized. Within 24-48 h, at the same time of day, tear measurements were collected again after administration of an auriculopalpebral nerve block. Each block was performed a minimum of 5 min prior to each STT I. A repeated-measures model was used to analyze differences between STT I values in eyes with and without nerve blocks incorporating within horse correlation between eyes. The mixed-model included fixed factors of treatment and eye and a random intercept for each horse. An unstructured covariance structure was used. RESULTS: On average, STT I values measured in eyes after auriculopalpebral nerve blocks were 0.55 mm/min greater than those without nerve blocks. This difference was not statistically significant (P = 0.5268). CONCLUSIONS: There was no effect of auriculopalpebral nerve block on STT I values in normal horses. PMID- 27501533 TI - Considerations about the Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) trial. PMID- 27501534 TI - Antihypertensive agents and arterial stiffness. PMID- 27501535 TI - Cryomicroscopy provides structural snapshots of influenza virus membrane fusion. AB - The lipid-enveloped influenza virus enters host cells during infection by binding cell-surface receptors and, after receptor-mediated endocytosis, fusing with the membrane of the endosome and delivering the viral genome and transcription machinery into the host cell. These events are mediated by the hemagglutinin (HA) surface glycoprotein. At the low pH of the endosome, an irreversible conformational change in the HA, including the exposure of the hydrophobic fusion peptide, activates membrane fusion. Here we used electron cryomicroscopy and cryotomography to image the fusion of influenza virus with target membranes at low pH. We visualized structural intermediates of HA and their interactions with membranes during the course of membrane fusion as well as ultrastructural changes in the virus that accompany membrane fusion. Our observations are relevant to a wide range of protein-mediated membrane-fusion processes and demonstrate how dynamic membrane events may be studied by cryomicroscopy. PMID- 27501537 TI - FALL-RELATED ACTIVITIES OF DAILY LIVING AND BEHAVIOUR DISTURBANCES IN DEMENTIA. AB - The purpose of this study is to clarify the activities of daily living and behaviour disturbances related to inpatients and outpatients with dementia experiencing falls. Patients diagnosed with dementia belonging to 18 facilities which consented to the study were subjected. The study involved "whether or not the patient has fallen in the past 12 months", "Barthel Index (B.I)", and "Dementia Behaviour Disturbance Scale (DBD)" and other data from 325 people in 18 facilities who had been diagnosed with dementia. The ratio of subjects who had fallen to those who had not was 113:212. The results of multiple logistic regression analysis showed that the study items related to falls including the DBD item of "making unwarranted accusations" had an OR = 1.445, 95% CI (1.133 1.843), the DBD item of "refusing to eat" had an OR = 0.699, 95% CI (0.521- 0.938), the B.I item of "feeding" had OR = 1.115, 95% CI (1.032-1.204) and the B.I item of "bathing" had OR = 0.782, 95% CI (0.671-0.912). Integral characteristics of dementia patients who have fallen are assumed to be making unwarranted accusations, having a low rate of refusing to eat, being able to eat alone and requiring attention when bathing. PMID- 27501536 TI - One-way membrane trafficking of SOS in receptor-triggered Ras activation. AB - SOS is a key activator of the small GTPase Ras. In cells, SOS-Ras signaling is thought to be initiated predominantly by membrane recruitment of SOS via the adaptor Grb2 and balanced by rapidly reversible Grb2-SOS binding kinetics. However, SOS has multiple protein and lipid interactions that provide linkage to the membrane. In reconstituted-membrane experiments, these Grb2-independent interactions were sufficient to retain human SOS on the membrane for many minutes, during which a single SOS molecule could processively activate thousands of Ras molecules. These observations raised questions concerning how receptors maintain control of SOS in cells and how membrane-recruited SOS is ultimately released. We addressed these questions in quantitative assays of reconstituted SOS-deficient chicken B-cell signaling systems combined with single-molecule measurements in supported membranes. These studies revealed an essentially one way trafficking process in which membrane-recruited SOS remains trapped on the membrane and continuously activates Ras until being actively removed via endocytosis. PMID- 27501538 TI - PHYSIOLOGICAL STRAIN AMONG WOMEN POTATO CULTIVATORS IN WEST BENGAL, INDIA. AB - The present study was aimed to evaluate physiological strain among women cultivators engaged in potato cultivation. The cross-sectional descriptive study was conducted on 150 women participants in different districts of West Bengal State, India. The physiological strain was evaluated by working heart rate, blood lactate and oxygen consumption. The average working heart rate was 109.97 +/- 9.94 beats/min when all tasks were considered together. According to the working heart rate, oxygen consumption and energy cost, the potato cultivation job was categorized as a moderate work category. Whereas, according to cardiovascular stress index (CSI), all tasks of potato cultivation were categorized into a stressful category. The more experienced workers were more productive than their less experienced counterparts, and this increased productivity appeared to be a combination of greater efficiency and greater physical exertion. Stepwise multiple linear regression analyses revealed that work pace and work experience had significant association with all the indices of physiological strain. Work pace had strongest significant impact on these indices even after controlling the effect of age, work experience and efficiency. It was concluded that during performing potato cultivation tasks the workers had a great extent of physiological strain. PMID- 27501539 TI - PULMONARY FUNCTION STUDIES IN FEMALE SINGERS OF KOLKATA, INDIA. AB - Singing performance is based on the efficiency of the respiratory system. The present study was aimed to evaluate the results of pulmonary function tests (PFTs) in female singers of Kolkata, India and to compare the data with their sedentary counterparts from India and abroad. The study was also aimed to propose prediction norms for PFTs in both the groups. Fifty-six female singers and fifty two female non-singers (control group) with similar socioeconomic backgrounds were randomly sampled from the Rabindrabharati University, Kolkata. Pulmonary function tests were conducted by an Expirograph and the peak expiratory flow rate (PEFR) was measured by Wright's peak flow meter. PFTs were significantly higher in singers than in their control group. The correlation matrix depicted a significant relationship of physical parameters (age, body height and body weight) with vital capacity (VC), forced vital capacity (FVC), forced expiratoty volume in 1 second (FEV1) and PEFR in both groups. Regression equations were computed to predict PFTs from physical parameters and duration of invovlement in singing training. The results indicated that female singers of Kolkata had higher lung capacity than their non-singer counterparts probably because of their regular practice and training of singing that required imperative effort of the respiratory system. PMID- 27501540 TI - SEX DIFFERENCES IN THE EFFECTS OF DIVERSE SOUNDS ON HEART RATE VARIABILITY. AB - With the goal of facilitating the creation of relaxing sound environments in stressful places, such as offices, we examined differences in the heart rate fluctuations of men and women induced by different sounds. Twenty-three healthy students (13 males and 10 females) aged between 18 and 23 listened to seven different sounds while we collected electrocardiogram data. We extracted the high frequency component (HF) and low frequency component (LF) of the signals using the wavelet method, and calculated LF/HF. We found no statistically significant differences between males and females in the frequency distribution of a no change group, increased group, and decreased group for any sound. However, certain sounds had somewhat similar patterns for men and women for all three groups. Additionally, the pairs of experimental sounds with highly similar effects on individuals were different for men and women. PMID- 27501541 TI - [Editorial]. PMID- 27501542 TI - [Prof. Dr. Gunnar Stollberg. 1 October 1945 Berlin, 25 March 2014 Berlin]. PMID- 27501543 TI - [Main topic: Patient history in hospital, sanatorium and hospital]. PMID- 27501544 TI - [An interest group in the Haina Hospital against the anatomic dissection. Actors and their protest readiness against organizational expectations]. AB - Between 1839 and 1853 several petitions have been addressed by inmates of the Haina hospital (Hesse, Germany) in order to save them from being transferred to the Anatomical Institute of the University of Marburg for post mortem dissection. In 1855, exemptions were granted in certain cases. Initially, the petitioners' strategies of argumentation and procedure have been analysed; then--referring to the application being sent in December 1847 and signed by 30 persons--the focus goes to the formation of this group and their opportunities for action. As a result it can be stated that inmates being physically ill or impaired or with impeded visual sensory perception tried to withstand unsuitable restrictions of their liberty of action as well as their personal rights induced by the routines of every-day hospital life. Guiltless for depending on public assistance they were not willing to accept unjustified curtailing of their personal and moral integrity. The attempts of being saved from anatomical dissection are part of the inmates' self-assertion. PMID- 27501545 TI - [Private charity - public health service. Comparison between British and German birthing centers of the 18th century]. AB - In the eighteenth century, lying-in hospitals were founded in many European towns and cities. The way in which these institutions were financed differed greatly across Europe. In the UK, most of them were "charities" and relied on donations from wealthy benefactors, whereas on the continent they were usually funded by "public" money, be it from the state or local communities. The paper focuses on British charities and German hospitals, and explores the corollaries of the mode of financing. In the eighteenth century, a market emerged in Britain where numerous charities with different aims competed for donations from the well-to do. For attracting benefactors, a charity had to convince potential donors that its clientele and purpose were particularly deserving, and that it used the money donated in a cost-efficient way. In Germany, it was mainly bureaucrats and governments who had to be persuaded, but public opinion did matter as well. In British lying-in charities, the main donors acted as governors, and benefactors could recommend persons for being admitted. In publicly funded German hospitals, the medical directors had much more power. In the competitive market, in which British charities acted, out-patient dispensaries (policlinics) became increasingly important, since they could argue that they were more cost-efficient and had lower mortality. In Germany, however, hospitals remained the dominant type of assistance in this field, in spite of the criticism they received. The different sources of finance appear to have been one of the reasons for this divergence. Teaching was the main purpose of most German lying-in hospitals. They either trained medical students or midwife apprentices or both. Since the patients served as teaching objects, all women were welcomed, and in fact most patients were single mothers. By contrast, most of the British institutions admitted only married women, because donors did not wish to encourage immorality. The charities staged the relation between donors and patients as a personal patron-client bond. PMID- 27501546 TI - [Women's complaint leadership in the Causa Kleinwachter. A contribution to patient history of the Innsbruck maternity hospital]. AB - On the basis of the Innsbruck Maternity Clinic this paper deals with the individual and collective worlds of experience of obstetric patients. However, not only the patient's view on the proceedings in this specific medical space is being reconstructed, also the prevailing conventions surrounding the treatment of pregnant, parturient and puerperal patients serving as clinical material in obstetric research and education are critically scrutinised. At the centre of this paper stands Dr. Ludwig Kleinwachter's period of duty, who acted as professor for obstetrics and gynaecology in Innsbruck between 1877 and 1881. During this period numerous conflicts regarding the treatment of patients are documented. Concerned about the good reputation of the Maternity Clinic, the Tyrolean State Committee, as the Clinic's provider, tried to solve the crisis. The existing letters of complaint and protocols do not only give a voice to the women concerned, but also to the medical professions as well as the local political representatives involved. PMID- 27501547 TI - [Power and everyday life in a lunatic asylum environment - a case example from Glasgow at the beginning of the 20th century]. AB - In this article the focus of analysis lies on power relations in everyday life in one of Glasgow's Pauper Lunatic Asylums at the turn of the twentieth century. Taking a sample of patient case files I examine the daily processes of negotiation between inmates and their relatives, physicians, attendants and nurses as well as the poor law administration. Some cases especially exemplify the complex relationships between the actors. They show which opportunities and boundaries existed for "power brokering" for the more powerless. At the same time these cases illustrate the formal and practical limits of enforcement by doctors and nursing staff. Without turning a blind eve to hierarchies and power imbalances the analysis shows that even in settings like "total institutions" power remains volatile. Even there the more powerful actors have to actualize, seize and prevail on a regular basis. PMID- 27501548 TI - [Insanity, life crises and longing for a "real life". On the discussion of deviant behavior and mental disorders in psychiatry of the 19th and 20th century]. AB - On insanity, life crises and the longing for a "right life". A contribution to the discussion on the deviant behavior and mental disorders in the psychiatry of the 19th and 20th centuries using the example of patient stories. History of psychiatry, understood as social and cultural history, provides the framework for this micro-historical article. Using the example of three patients treated in Wuerttemberg or Baden psychiatric asylums between 1875 and 1912, the article focuses on the critical analysis of types of asylums, their practices of admissions, therapies and power relations between patients and staff. Ways of thinking and acting, subjective experiences and emotions are exemplified by patient records, personal testimonials and contemporary publications again by patients and staff. The article examines options of patients to influence the institutional daily asylum routine against the background of its complexity and dynamics. Borders, manipulations, malingering and querulous paranoia are at stake here. Furthermore, the article reflects various forms of social interaction with the power regulating therapeutic and disciplinary aspects against the backdrop of the "canons of rules" of the asylum as well as the contemporary political and legal framework. PMID- 27501549 TI - Introduction. PMID- 27501550 TI - Records of "Infirmity": Dis/ability and Life Writing in 16th-Century Germany. PMID- 27501551 TI - Disablement as Disability? Public Welfare and the Disabled Poor in Early Modern Germany. PMID- 27501552 TI - A Life in Darkness--Coping with Blindness in Rural Society about 1800 in Hesse. PMID- 27501553 TI - Disability in the Early Modern Society: or How to Read "Against the Grain" and "Fill in Gaps". PMID- 27501554 TI - [Preliminary remarks]. PMID- 27501555 TI - [Over 70 years after "Action T4": a new memorial at the site of murder of the sick in Brandenburg/Havel]. PMID- 27501556 TI - [Artifact discoveries in Hartheim and their significance for memorial site development]. PMID- 27501557 TI - [What means "resistance" against National Socialism "euthanasia" crime]. PMID- 27501558 TI - [Impressions and memories of the educational trip to Florence for the 19th Symposium "The art of healing and healing art in buildings and pictures from the 9th to 12th October 2013]. PMID- 27501559 TI - [Hospital in the picture - pictures of hospitals in Italian art between 1385 and 1529]. PMID- 27501561 TI - [Hospitals in the Islamic world]. PMID- 27501560 TI - [Hospitals and patients in Tuscany during the Renaissance]. PMID- 27501562 TI - [Surgery and art]. PMID- 27501563 TI - [10 years of art in DRK Clinics Berlin/Westend - what happens next?]. PMID- 27501564 TI - [20th Symposium of the German Society for Hospital History from 10th to 12th October 2014 in Munster (Westfalen)-- - introduction]. PMID- 27501565 TI - [An appreciation of the services of the honorary chairman Axel Hinrich Murken. 30 years chairman of the German Society of Hospital History 1979 to 2009 and editor of the Historia Hospitalium 1972 to 2010]. PMID- 27501566 TI - [Giving the hospital a place in history. 50 years German Society of Hospital History. A retrospect of half a century (1964 -2014)]. PMID- 27501567 TI - [Responsibilities and goals of hospital history. A personal retrospect from the viewpoint of a hospital architect and historian]. PMID- 27501568 TI - [Organization and administration. 11 years as managing board member of the German Society of Hospital History e. V. (2003 - 2014)]. PMID- 27501569 TI - [The Herrlinger case: a controversy of ethics in anatomy and medical history]. PMID- 27501570 TI - [Between continuity and new beginning. On the development of university medical history in postwar Germany]. PMID- 27501571 TI - [History and responsibility: comments on the cross section field GTE (history, theory and ethics) in the medical curriculum]. PMID- 27501572 TI - [For the poor, sick and pilgrims. Late middle ages welfare policy in the city of Munster]. PMID- 27501573 TI - Forms of Protection for Historic Hospitals. PMID- 27501574 TI - [The district Weinheim nursing home in national socialism]. PMID- 27501575 TI - [Success or failure? Surgical robot from the historical perspective]. PMID- 27501576 TI - [Iron bedsteads. On the history of the hospital bed (1700 - 1900)]. PMID- 27501577 TI - [The Nicolai Hospital. Study of the leprosorium in the middle ages of Luneburg (1251-1530)]. PMID- 27501578 TI - EDITORIAL. PMID- 27501579 TI - THE ART OF MEDICINE. PMID- 27501580 TI - CLIMATE CHANGE AND HEALTH: A FEBRILE PLANET. PMID- 27501581 TI - BROKEN FACES OF WAR THE QUEENS HOSPITAL, SIDCUP, 1917-1925. PMID- 27501582 TI - HEALTH CARE IN AUSTERITY FROM THE FALKLANDS TO AFGHANISTAN AND BEYOND. PMID- 27501583 TI - IN 2014 CAN WE PREVENT DEMENTIA? PMID- 27501584 TI - GYNAECOLOGICAL CANCER: GREAT PROGRESS FROM MY HEROES BUT IS IT TIME FOR A PARADIGM SHIFT? PMID- 27501585 TI - MEDICINE, WAR AND CAPTIVITY: SOUTHEAST ASIA 1941-1945. PMID- 27501586 TI - ON CRUSADERS ANCIENT AND MODERN THE ORDER OF ST JOHN. PMID- 27501587 TI - LORD MORAN AND WINSTON CHURCHILL DID THE PRCP HELP TO WIN THE WAR. PMID- 27501588 TI - BARIATRIC SURGERY--BELIEF, BIOLOGY OR BEHAVIOUR. PMID- 27501589 TI - HISTORY DOWN THE DRAIN. PMID- 27501590 TI - Sleepless in America: Burning the Candle at Both Ends? At What Cost? PMID- 27501591 TI - Osteonecrosis of the Jaw in Patients Receiving Bone-Targeted Therapies: An Overview--Part I. AB - Urologic patients receiving bone-targeted therapies are at risk of developing osteonecrosis of the jaw (ONJ). ONJ has historically been associated with bisphosphonate therapy. More recently, RANK-Ligand inhibitors (denosumab) have also been used to reduce the risk of skeletal-related events in patients who have advanced cancers with bone metastases. More than 65% of men with metastatic prostate cancer and nearly 75% of women with metastatic breast cancer are affected by bone metastases. The literature has described ONJ associated with bisphosphonate therapy as bisphosphonate-related osteonecrosis of the jaw (BRONJ). However, with evidence also linking the use of RANK-Ligand inhibitors with osteonecrosis of the jaw, we advocate use of the term "anti-bone resorption therapy-related osteonecrosis of the jaw" (ABRT-ONJ). The term "medication related osteonecrosis of the jaw" (MRONJ) is now becoming more widespread. There is not a universally accepted definition of ABRT-ONJ, which may have hindered recognition and reporting of the condition. In Part I of this article, a review of current knowledge around the etiology of ABRT-ONJ and incidence data are provided. In Part II, we provide an audit of ONJ in a nurse consultant-led bone support clinic. In the article, we refer to zoledronic acid because this is the bisphosphonate of choice for use in men with prostate cancer in the United Kingdom. PMID- 27501592 TI - Retrospective Audit: Does Prior Assessment by Oral and Maxillofacial Surgeons Reduce the Risk of Osteonecrosis of The Jaw in Patients Receiving Bone-Targeted Therapies for Metastatic Cancers to the Skeleton?--Part II. AB - Men who receive bone-targeted therapy for metastatic prostate cancer are at increased risk of osteonecrosis of the jaw (ONJ). Development of ONJ has been associated with the administration of bone-targeted therapies in association with other risk factors. ONJ can be distressing for a patient because it can cause pain, risk of jaw fracture, body image disturbance, difficultly eating, and difficulty maintaining good oral hygiene. The aim of this article is to report results of an audit of prior assessment by oral and maxillofacial surgeons (OMFS) before initiation of bone-targeted therapies and whether it may reduce the risk of ONJ in patients receiving bone-targeted therapies for advanced cancers. PMID- 27501593 TI - Cycling Versus Continuous Mode In Neuromodulator Programming: A Crossover, Randomized, Controlled Trial. AB - This is a randomized, controlled, blind, crossover trial comparing cycling versus continuous programming of a sacral neuromodulator in women diagnosed with overactive bladder (OAB). At 6 months, treatment order significantly affected Overactive Bladder Questionnaire - Short Form (OABq-SF) symptom scores. The cycling followed by continuous stimulation group had superior OABq-SF scores (p > 0.02). PMID- 27501594 TI - Preoperative Nutritional Status and The Impact on Radical Cystectomy Recovery: An International Comparative Study. AB - In radical cystectomy, under-nutrition is common and has detrimental physiological and clinical effects, which can lead to increased complications and prolonged recovery. This article compares measurements and outcomes across continents in this patient population with advanced bladder cancer. The association of preoperative nutritional risk, nutritional status, and length of stay is equal across continents, and the results promote increased clinical awareness that women at severe risk should be identified preoperatively. PMID- 27501595 TI - Decision-Making in Prostate Cancer: Active Surveillance Over Other Treatment Options. AB - A qualitative-descriptive study of four patients with prostate cancer used the Cognitive-Social Health Information Processing framework to understand how and why men diagnosed with prostate cancer choose active surveillance over other treatment options. In accordance with the literature, it was found that the surgeon or general practitioner's recommendation was the most influential factor when patients are making a treatment decision. PMID- 27501596 TI - Application to the Evidence Base: Decision-Making in Prostate Cancer: Active Surveillance over Other Treatment Options. PMID- 27501598 TI - Comparison of Spraying and Nebulized Lidocaine in Patients Undergoing Esophago Gastro-Duodenoscopy: A Randomized Trial. AB - OBJECTIVE: Esophago-gastro-duodenoscopy (EGD) was performed under the topical anesthesia of the pharynx. However spraying lidocaine was found to be an annoying maneuver to patients, while nebulized lidocaine appeared to efficiently suppress gags and cough reflexes in airway anesthesia. This study aimed to compare the effectiveness of spraying and nebulized lidocaine for patients undergoing EGD. MATERIAL AND METHOD: A total of 110 patients undergoing elective EGD, with a history of neither lidocaine intolerance nor irritable airways due to smoking, chronic obstructive pulmonary disease (COPD), upper respiratory infection, asthma, cardiac and pulmonary diseases and allergy to lidocaine were included. All patients were randomized into two groups: A- where 5 puffs (10 mg/puff) of spraying lidocaine were administered four times at 5-minute intervals, up to a total dose of 200 mg, and B-where 250 mg of nebulized lidocaine was administered via a nebulization kit with an oxygen face mask of 7 LPM for 15 minutes prior to the commencement of EGD. The procedure was performed by the same board-certified endoscopist The co-researcher who was blinded to the lidocaine administration technique assessed the ease of esophageal instrumentation as either difficult, poor; fair or excellent. Both the endoscopist and the patients expressed their satisfaction by using the numerical rating scale. RESULTS: The endoscopist expressed her satisfaction with instrumentation, which showed significant difference between group A and group B as 84.8 +/- 8.3 and 79.2 +/- 11.2, respectively. The co-researcher also found that group A patients responded to the ease of esophageal instrumentation better than those in group B. However nebulized lidocaine had significant advantages over spraying lidocaine, with better acceptance in patients undergoing EGD. CONCLUSION: The endoscopist expressed her approval of spraying lidocaine for taking less time to start the procedure, ease for instrumentation, less gag reflex during the procedure, less presence of hypersecretion, and smooth operation. However participants favored nebulized lidocaine administration. PMID- 27501597 TI - A Randomized Placebo-Controlled Trial of Oral Ramosetron for Prevention of Post Operative Nausea and Vomiting after Intrathecal Morphine in Patients Undergoing Gynecological Surgery. AB - BACKGROUND: The incidence of postoperative nausea and vomiting (PONV) after intrathecal morphine is high. Ramosetron is a 5-HT3 antagonist that has been shown to reduce PONV in general anesthesia. The objective of this study was to evaluate the efficacy of Ramosetron in preventing PONV MATERIAL AND METHOD: 165 patients undergoing elective gynecological surgery under spinal anesthesia were randomly allocated to two groups: the Ramosetron group (0.1 mg orally, n = 82), and the placebo group (oral corn starch, n = 83). The incidence of PONV severity of nausea and use of rescue antiemetic during the first 24 hour after surgery were evaluated. RESULTS: The incidence of PONV was significantly lower in the Ramosetron group compared with the placebo group (24.4% vs. 44.6%, number needed to treat (NNT) = 5.0). The severity of nausea was significantly lower in the Ramosetron group compared with the placebo group (20.7% vs. 39.8%, NNT = 6.0) in the 24 hour period. CONCLUSION: Oral Ramosetron 0.1 mg was more effective than placebo in PONV prevention and reduced the incidence of moderate to severe nausea after intrathecal morphine in the first 24 hour after gynecological surgery. PMID- 27501599 TI - The Efficacy of Two Oxygen Therapy Devices (Nasal Cannula vs. Simple Mask) for Preventing Hypoxemia after General Anesthesia: A Randomized Controlled Non Inferiority Trial of 500 Patients. AB - OBJECTIVE: To compare the efficacy of two oxygen devices (nasal cannula and mask) and two flows for preventing hypoxemia in post anesthesia care unit (PACU). MATERIAL AND METHOD: Five hundred (18-70 year old) patients were enrolled into a randomized, controlled non-inferiority trial at Sirirai Hospital, Mahidol University from May 2013 to December 2014. They received oxygen therapy after general anesthesia according to their groups by computer-generated randomization. Group I received oxygen nasal cannula 4 liters per minute and group II received oxygen mask 5 liters per minute. Both methods gave comparable FiO2 (FiO2 = 0.35). Inclusion criteria were elective surgery, American Society of Anesthesiologist (ASA) physical status 1-3. Exclusion criteria were unstable pulmonary disease, BMI > 35 kg/m2, baseline SpO2 < 94%, myopathy, alteration of consciousness, and nasal problems. The high-risk operations for post operative hypoxemia were excluded The efficacy of two oxygen devices and flows were compared in term of preventing hypoxemia in PACU. RESULTS: Five hundred patients were analyzed (249 patients in the cannula group and 251 patients in the mask group). They were comparable in demographics and operations. At PACU, none of 500 patients had SpO2 < 94% (non-inferiority trial, 95% CI-0.0152, 0.0152). They were mildly sedated or fully awake and had no respiratory complications. CONCLUSION: In low risk patients undergoing low risk operations, both nasal cannula or simple mask with FiO2 = 0.35 are equally effective for preventing hypoxemia in PACU. PMID- 27501600 TI - Appropriateness of Broad Spectrum Antibiotics for Severe Sepsis and Septic Shock in the Emergency Department. AB - OBJECTIVE: Determine the appropriateness of broad-spectrum antibiotics applied in severe sepsis and septic shock in an emergency room and its impact on the survival rate. MATERIAL AND METHOD: This was a prospective observational study in an emergency room setting at a tertiary care facility where early goal-directed therapy (EGDT) was applied for resuscitation of severe septic and septic shock patients. The data recorded were the initial vital signs, SAP II score, time of EGDT goals achieved (ScvO2> 70), time of antibiotics initiated, type of antibiotics used, organisms that were identified, source of infection, initial and final diagnosis, and outcome of treatment. The student's t-test and Mann Whitney U test were used to compare survival rates between appropriate and inappropriate antibiotics used. RESULTS: Seventy-eight newly diagnosed severe septic and septic shock cases were treated per the EGDT protocol. There were 41 (52.6%) male and 37 (47.4) female patients. The organisms were identified by hemoculture in 28 cases, 18 (64.3%) cases were gram-negative, seven (25.0%) cases were gram-positive, and three (10.7%) were mixed organisms. The five most common sites of infection were 30 (38.5%) cases of lung infection, 18 (23.1%) cases of bacteremia, 16 (20.5%) of gastrointestinal tract infection, 15 (19.2%) cases were genito-urinary tract infection, and six (7.7%) were skin and soft tissue infection. The mean SAP II score was 44.2 +/- 15.4 and the mean time to initiate antibiotics was 59 +/- 50 minute. Fifty-five cases (70.5%) were classified as appropriate antibiotics group, 31 (56.4%) of the 55 cases survived, while only nine (39.1%) of the 23 cases in the inappropriate group survived. This was not statistically significant. CONCLUSION: The most common sources of infection of septic patients were lung infection, bacteremia, gastrointestinal tract infection, genito-urinary tract infection, and skin and soft tissue infection. The hemocultures were positive in 58.9% of the cases and the common organisms were E. coli, K. pneumonia, S. aureus, and S. pneumoniae. The immunocompromised, multiple co-morbid and prolonged intubated patients should receive antibiotics to cover ESBL-producing E. coli, P. aeruginosa, and A. baumannii. PMID- 27501601 TI - The Performance of the Neck Circumference for a Difficult Laryngoscopy in Obese Patients. AB - BACKGROUND AND OBJECTIVE: There is conflicting evidence as to whether neck circumference (NC) is related to a difficult laryngoscopy in obese patients. The objectives of this study were to determine the performance of the NC in defining a difficult laryngoscopy, and to identify factors predicting a difficult laryngoscopy among those obese patients. MATERIAL AND METHOD: This prospective study was conducted in adult patients with a body mass index (BM) of greater or equal to 30 kg/m2 who underwent conventional endotracheal intubation. Preoperative NC, the modified Mallampati test (MMT), the thyromental distance (TM) and the sternomental distance (SM) were measured. A difficult laryngoscopy was defined as a Cormack-Lehane laryngoscopic view of grade III or IV. RESULTS: Five hundred patients (366 females; 134 males), with a mean BMI of 34.3 +/- 4.6 kg/m2 (minimum = 30.0 kg/m2, and maximum = 68.4 kg/m2) and who had elective surgery planned, were enrolled. The incidence of a difficult laryngoscopy was 7.2%. The overall performance of the NC using the area under the receiver operating characteristic curves of a difficult laryngoscopy was 0.574, with a 95% confidence interval (CI) of 0.53 to 0.618. The optimal cutoff point of the NC for a difficult laryngoscopy was 37.1 centimeters. It provided sensitivity and specificity of 75.5% (95% CI 57.8, 87.9) and 42.5% (95% CI 37.9, 47.2). The positive and negative predictive values were 9.2% and 95.6%. After multivariate analysis, factors affecting a difficult laryngoscopy were high grades of MMT (odds ratio (OR) 2.23, 95% CI 1.10, 4.50) and NC/TM (OR 1.78, 95% CI 1.15, 2.74). CONCLUSION: The NC per se was not a good predictor of a difficult laryngoscopy. However the ratio of the NC to the TM and the MMT were factors predicting a difficult laryngoscopy in obese patients. PMID- 27501602 TI - Prevalence and Characteristics of Abnormal Pre-Operative Chest X-Rays in Patients Undergoing Elective Surgery. AB - OBJECTIVE: To determine the prevalence of pre-operative abnormal chest x-rays (CX Rs) in patients undergoing elective surgery, and to describe the management of the patients with abnormal CXRs. In addition, we question whether the healthy patients aged more than 45 years really needs pre-operative chest radiographs. MATERIAL AND METHOD: Patients undergoing elective surgery between June 2013 and May 2014 were recruited, and medical records were retrospectively reviewed. RESULTS: Data for 960 patients was included CX Rs were abnormal in 485 patients (50.5%), with cardiomegaly being the most common abnormality. Among patients who had pre-operative abnormal CXRs, 91 patients (18.8%) required consultation or other investigation pre-operatively, and three patients (0.6%) had their treatment plans altered. Comparing between age groups, there was no different of abnormal results (p-value = 0.606). CONCLUSION: Prevalence of pre-operative abnormal CXRs was high; however, the abnormalities seldom led to changes in case management. PMID- 27501603 TI - Development of New Lemon-Lime Flavored Beverage for OGTT: Acceptability and Reproducibility. AB - BACKGROUND: The oral glucose tolerance test (OGTT) is essential procedure in both screening and diagnosis of impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and diabetes mellitus (DM), but it is not easy to perform because of intense sweetness of the 75-g glucose test beverage causing abdominal discomfort post-testing. Therefore, the new formula of non-carbonated lemon-lime flavored beverage was developed to increase its palatability and better compliance. OBJECTIVE: To develop a new non-carbonated lemon-lime flavored beverage to replace the standard beverage for OGTT Subsequently, the diagnostic value and acceptability between the new formula and the traditional 75-g OGTT formula were compared in healthy subjects. MATERIAL AND METHOD: The new lemon lime flavored formula was developed to replace the standard beverage for OGTT by adding 1,000 milligram of citric acid and 0.03 gram of lime flavor to 75 gram of anhydrous glucose to a final volume of 300 ml. The study was conducted in 30 healthy subjects who underwent the traditional 75-gram OGTT test and the new formula of OGTT beverage one week later, or vice versa, to access acceptability, indices markers of insulin secretion, and insulin sensitivity. Palatability was determined by rating on a 9-point Hedonic Scale. RESULTS: Thirty healthy subjects (15 females) with the age of 33.2 +/- 7.5 years and body mass index of 22.9 +/- 3.5 kg/m2 were enrolled. No significant difference was found between plasma glucose in 0, 30, 60, 90, and 120 minutes, insulin level (0 and 120 minutes) and four insulin surrogate markers in both traditional 75-gram OGTT and new formula of lemon-lime flavored OGTT beverage. The overall satisfaction score of the new formula OGTT was better when compared with the scores of the traditional OGTT (7.1 +/- 1.8 vs. 4.7 +/- 2.0). Only one subject complained about abdominal discomfort in both episode of OGTT CONCLUSION: The modified lemon-lime flavored beverage for OGTT demonstrated better acceptance in the subjects without difference in plasma glucose values and OGTT derived parameters responses to OGTT in comparison to the traditional formula. PMID- 27501604 TI - Comparing the Success Rate of Radial Artery Cannulation under Ultrasound Guidance and Palpation Technique in Adults. AB - BACKGROUND: Previous studies have shown ultrasound guidance (USG)for arterial cannulation being advantageous compared to palpation technique, but little is known about its performance by novices. OBJECTIVE: This study was to compare the utility of USG radial artery cannulation with palpation technique in terms of success rate, real-time to placement, number of attempts and complications. MATERIAL AND METHOD: After IRB approval, a randomized prospective study was performed November 2009-October 2010. Ten third-year residents, having performed USG vascular catheterization as yet less than 3 times, were coached on the pork phantom during a workshop for real time ultrasound-guided vascular access. For the study patients were randomized to US-guided technique (US-group) and palpation (P-group); ten patients for each resident. RESULTS: One hundred adult patients undergoing neurosurgery were enrolled. There were no statistically significant differences between US-group vs. P-group in success rate (78% vs. 82%; p = 0.62), time to success (60 (12.8, 547.0) vs. 52 (6.9, 639.0) sec; p = 0.22), and number of attempts (1 (1, 4) vs. 1 (1, 3); p = 0.79). Most common complication was puncture hematoma (US-group 26% vs. P-group 24%; p = 0.82). Success was defined as no change in catheterization site, performer and technique. CONCLUSION: Regarding success rate, attended time, or number of attempts for radial arterial cannulation, we did not find any benefit of ultrasound guidance compared to palpation technique. Our findings were not in accordance to other trials. However, we have to consider operators in our study being in experienced in ultrasound-guided procedures but not in palpation techniques. PMID- 27501605 TI - Severe Venous Air Embolism Related to Positioning in Posterior Cranial Fossa Surgery in Siriraj Hospital. AB - BACKGROUND: Posterior cranial fossa surgery is commonly performed under sitting and horizontal position in our institution. Venous air embolism is a potentially serious complication of neurosurgery especially in the sitting position. OBJECTIVE: We aim to compare the incidence of severe venous air embolism and other complications of both positions. MATERIAL AND METHOD: A retrospective analysis of medical record was performed in 192 patients undergoing posterior cranial fossa craniotomy from January 2010 to December 2013. Data collected from the records included demographic profile, patient position, hemodynamic changes, venous air embolism (VAE), blood loss/transfusion, duration of surgery, postoperative complications, duration of ICU stay, and postoperative discharge status. The definition of severe air embolism was identified as suspected VAE with decreased systolic blood pressure greater than 20%. RESULTS: There were 92 patients in sitting position (SP) group and 100 patients in horizontal position (HP) group. The incidence of severe venous air embolism was signficantly higher in SP group compared with HP group (41.3% vs. 11.0%, p<0. 001). SP group had more complications than HP group in both central nervous system (71% vs. 34.0%, p = 0.001), and cardiovascular system (17% vs. 6%, p = 0.001). Although postoperative ventilator time in SP group was less than HP group (1.24 vs. 1.60 days, p = 0.029), ICU and hospital stay were not different in either group. CONCLUSION: The incidence of severe venous air embolism detected by end tidal CO2 was significantly higher in SP group. However, 11% of HP group were suspected of severe air embolism. PMID- 27501606 TI - Incidence of Abnormal Preoperative Blood Testing and Postoperative Complication in Appendectomy Patients in Siriraj Hospital. AB - BACKGROUND: A cute appendicitis is a common emergency surgical problem. Pre operative complete blood count and urinalysis are used for supporting diagnosis. Blood chemistry is also requested for patient's status evaluation despite limited evidence of its cost-effectiveness. OBJECTIVE: The primary objective was to determine the incidence of abnormal pre-operative blood chemistry result. The secondary objectives were the relationship between preoperative abnormal blood chemistry and postoperative complication and to find the risk factors of abnormal blood chemistry. MATERIAL AND METHOD: 450 patients underwent emergency appendectomy at Siriraj Hospital from January 1st, 2012 to March 31st, 2014 were included in this retrospective descriptive study. Demographic data, blood chemistry test result and postoperative complication were recorded. The incidence of abnormal blood chemistry results was reported. Relationship between abnormal laboratory results, postoperative complications and predisposing factors were analyzed. RESULTS: The incidence of abnormal pre-operative serum BUN, creatinine, sodium, potassium, bicarbonate and chloride were 19.1%, 35.4%, 26%, 24%, 32.9% and 24.3%, respectively. Abnormal blood chemistry results were not associated with postoperative complications. However ASA physical status equal or more than 3 and duration of symptoms > 48 hours are significantly associated with postoperative complications (adjusted OR 2.91, 95% CI 1.04-8.13, p-value = 0.041 and adjusted OR 2.78, 95% CI 1.24-6.25, p-value = 0.013, respectively). The predisposing factors of abnormal blood chemistry are ASA physical status equal or more than 3 (adjusted odd ratio 4.27, 95% CI 1.25-14.65, p-value = 0.021) and duration of symptoms > 48 hours (adjusted odd ratio 1.79, 95% CI 1.01-3.20, p value = 0.047). CONCLUSION: There was no association between abnormal blood chemistry result and postoperative complication. Preoperative blood chemistry should be tested only if indicated. PMID- 27501607 TI - Anesthetic Management for Esophageal Stent Placement in an Endoscopy Unit Outside Operating Room. AB - BACKGROUND: Esophageal stent placement is a minimally invasive procedure for treatment of esophageal strictures that cannot be treated with surgical procedure. It requires some forms of anesthesia. This procedure could be performed in the operating room and in the endoscopy unit. OBJECTIVE: The study is aimed to report and evaluate the choices and techniques, drugs used and complications of anesthesia in the patients undergoing esophageal stent placement procedure in an endoscopy unit outside the operating room in a developing country. MATERIAL AND METHOD: Retrospectively analyzed the patients on whom esophageal stent placement had been performed during the period of January, 2010 to December, 2012 in Siriraj Hospital in Thailand. The patients' characteristics, pre-anesthetic problems, anesthetic techniques, drugs, duration of anesthesia, and anesthesia-related complications were assessed and summarized by using descriptive statistics. RESULTS: During the study period, there were 48 procedures. Mean age 63.7 +/- 13.4 years. The majority of them was male (72.9%) and classified in ASA physical status II (52.1%). Mean duration of anesthesia was 60.6 +/- 36.1 minutes. Most common pre-anesthetic problems were hematologic disease (64.6%), electrolyte imbalance (50.0%), respiratory disease (31.3%) and hypertension (29.2%). General anesthesia with endotracheal tube (64.6%) was the main anesthetic technique. The mainly used sedoanalgesic agents were propofol, fentanyl and midazolam. The most common neuromuscular blocking drugs were succinylcholine and atracurium. Additionally, sevoflurane was the most inhalation agent. The overall anesthesia-related complication rate was 35.4%. Hypotension (31.3%) was the most frequent anesthetic complication. CONCLUSION: All of the esophageal stent placement procedures, general anesthesia and intravenous sedation techniques could be performed effectively in the appropriate patients. However, clinical signs should be carefully observed and the anesthetic personnel had to optimize the patient's condition for safety and beware of complications. PMID- 27501608 TI - Effectiveness of Postoperative Epidural Analgesia for Thoracic and Abdominal Surgery in Siriraj Hospital. AB - BACKGROUND: Epidural analgesia is the recommended analgesic technique in patients having surgery with moderate to severe postoperative pain. Inadequate pain control in patients receiving epidural analgesia frequently occurred in clinical practice but the number of the success rate or the failure rate have not been reported in our university hospital. OBJECTIVE: The aim of the prospective descriptive study is to examine various data related to and evaluate the effectiveness of the postoperative epidural analgesia in Siriraj Hospital, a university hospital in Thailand. MATERIAL AND METHOD: Patients scheduled to have elective thoracic or abdominal surgery under general anesthesia combined with epidural analgesia from December 2014 to October 2015 were enrolled in this study. Three hundred and sixty-four patients were finally analyzed. All data about demographics, surgery, epidural techniques, postoperative pain scores at rest and on movement, and postoperative complications were collected RESULTS: The number of patients having acceptable postoperative pain score at rest at all time period was 51.4%, (95% CI 46.3-56.5). Fifty patients (13.7%) in this group needed intravenous rescue medication for breakthrough pain. The incidence of severe postoperative pain at rest during running of epidural medication was 24.5% (95% CI 20.3-29.1). One hundred patients (27.5%) experienced postoperative nausea and vomiting; and 28 patients (7.7%) had episodes of hypotension. The incidences of accidental dural puncture and post-dural puncture headache were 1.36% and 0.8%, respectively. CONCLUSION: Inadequate postoperative analgesia with epidural technique occurred in up to 50% of patients in this study in which the rescue pain medication was necessary. In-depth analysis to identify associated factors to improve the effectiveness of postoperative epidural analgesia should be further investigated. PMID- 27501609 TI - Pain after Major Craniotomy in a University Hospital: A Prospective Cohort Study. AB - BACKGROUND: Pain after major craniotomy has been believed to be less severe than the other operations. OBJECTIVE: To determine the incidence and risk factors of moderate to severe pain after major craniotomy. MATERIAL AND METHOD: This is a prospective observational study in a neurosurgical intensive care unit and wards of a university, tertiary hospital. After institutional IRB approval, patients undergoing major craniotomy during May 2011-August 2012 were interviewed preoperatively and 24 and 48 hours postoperatively. Demographic data, preoperative anxiety scores, operative data and postoperative pain characteristics were recorded. RESULTS: Two hundred and eighty patients completed the study. The incidence of moderate to severe pain was 75%. Mean pain score during 24 and 48 hours were 5.5 +/- 2.7 and 3.5 +/- 2.6, respectively. Univariate analysis identified age under 45 years and perioperative steroid therapy as predictors of moderate to severe postoperative pain. Using multivariate analysis, only age under 45 years was a significant risk factor. Patients' satisfaction scores were good in both mild and moderate to severe pain groups (9.49 +/- 1.08 and 8.37 +/- 1.76). During postoperative period, almost all of the patients received intravenous opioid and oral acetaminophen for pain treatment. No respiratory depression occurred, but postoperative nausea and vomiting occurred in 51.7% and pruritus in 23.6%. CONCLUSION: Incidence of pain after craniotomy was high especially in younger age group, which is not in accordance with all similar reports. However we believe pain management after major craniotomy in our hospital requires improvement. PMID- 27501610 TI - Postoperative Pain Management and the Risk Factors in Major Operation: A Baseline Study of Acute Pain Service, Siriraj Hospital. AB - BACKGROUND: Acute pain service (APS) has been set up at Siriraj Hospital with the aim of providing postoperative pain management for patients receiving anesthetic pain control and other complicated cases undergoing major operations. OBJECTIVE: To identify the incidence of moderate to severe postoperative pain and its risk factors. To describe the techniques used and adverse effects in patients under APS care. MATERIAL AND METHOD: A prospective study in 340 surgical patients under APS care from January to September 2008 was performed. Data were obtained from medical records and patients' answers during 48 hours postoperatively. RESULTS: The incidences of postoperative pain scores 4-10 at 24 and 48 hours were 28.8% and 7.4%, with median pain intensity (0-10, [interquartile range]) of 2.5 [1.0 4.0] and 1.0 [0.0-2.0], respectively. The risk factors related to pain score 4-10 included analgesic intake for > 2 consecutive weeks prior to operation, type of surgery with severe degree of pain and age 65 years (odds ratios [95% CI] of 7.12 [1.92, 26.44], 6.17 [1.37, 27.77], and 1.87 [1.07, 3.29], respectively). Of the patients, 67.9% received epidural block for postoperative analgesia. The incidences of nausea/vomiting and itching that needed treatment were 12.4% and 9.4%, respectively. CONCLUSION: Risk factors that should be concerned were age <= 65 years, pre-operative prolonged analgesic use and surgeries with expected severe degree of pain. PMID- 27501611 TI - Psychometric Validity and Reliability of the Thai Version of the Neuropathic Pain Symptom Inventory. AB - OBJECTIVE: The aim of this study was to evaluate validity and reliability of the Thai version of the Neuropathic Pain Symptom Inventory (NPSI-T) in Thai patients with neuropathic pain. Although the Thai version of Neuropathic Pain Symptom Inventory (NPSI-T) has been linguistically validated, the tool has to be psychometrically validated before applying to neuropathic pain patients in daily practice. MATERIAL AND METHOD: Forty Thai patients with diagnosis of neuropathic pain were enrolled to the study and were evaluated by visual analog scale (VAS), the Thai version of Neuropathic Pain Diagnostic Questionnaire (DN4-T) and NPSI-T questionnaires. Four hours later the patients were asked to perform retest NPSI-T and to evaluate the understanding of each NPSI-T question. RESULTS: The total score of NPSI-T questionnaire was statistically correlated to visual analog scale (VAS) (Spearman's correlation coefficient = 0.599, p < 0.001) and neuropathic pain diagnostic questionnaire (DN4-T) (Spearman's correlation coefficient = 0.695, p < 0.001). The reliability was determined by Intraclass correlation coefficient (ICC), an excellent interobserver agreement (ICC > 0.8) and good agreement (ICC 0.6-0.8) were presented in 30% and 70% of the questionnaire, respectively. CONCLUSION: The study demonstrated validity and reliability of the NPSI-T for assessing the neuropathic pain in Thai patients. PMID- 27501612 TI - Effective Pain Management for Inpatients at Siriraj Hospital: A Retrospective Study. AB - BACKGROUND AND OBJECTIVE: The prevalence of severe cancer and non-cancer pain among in patients has been reported at rates ranging from 15% to 36%. We examined the effectiveness of the pain management provided to inpatients by the Siriraj Pain Clinic. MATERIAL AND METHOD: A retrospective chart review was conducted among inpatients who had consulted the clinic between January 2013 and December 2014. Patients with a numeric pain rating scale (NRS) 4 on the day of consultation, those discharged within seven days, and postoperative patients were excluded. Successful pain control was defined as NRS <= 4 within seven days of the initial consultation. RESULTS: We identified 352 eligible patients, of which 231 (65.4%) had cancer pain. Only 42.6% achieved successful pain control. An absence of psychological problems (odds ratio (OR) 2.1, 95% confidence interval (CI) 1.1-4.2; p = 0.010); an initial NRS < 7 (OR 1.9, 95% CI 1.2-3.0; p = 0.008); the use of either a non-steroidal anti-inflammatory drugs (NSAIDs) or a Coxibs (OR 2.3, 95% CI 1.3-3.9; p = 0.017), and abdominal pain (OR 2.7, 95% CI 1.5-4.7; p =0.008) were factors associated with successful pain control. CONCLUSION: Adequate pain control was achieved in less than half of the inpatients in our institution. Psychological disturbance and severe pain predicted unsatisfactory pain control. PMID- 27501613 TI - Assessment of Pain Severity after Radiofrequency Ablation in Patients with Hepatocellular Carcinoma. AB - OBJECTIVE: To find the incidence of moderate to severe pain after percutaneous radiofrequency ablation (RFA) in patients with hepatocellular carcinoma and to identify the factors affecting unwanted pain scores. MATERIAL AND METHOD: This prospective study was conducted on patients who underwent percutaneous radiofrequency ablation under intravenous sedation and local anesthesia. The pain scores were obtained from 18 to 24 hours after the procedure. Moderate to severe pain was defined as a value of 4 or more on the Numeric Rating Scale (NRS). Data on patients' factors, tumor characteristics, procedural factors, anesthetic management, postoperative treatment and perioperative complication was collected RESULTS: A total of 190 patients were enrolled, comprised of 134 men (70.5%) and 56 women (29.5%). The mean age of the patients was 63.3 +/- 11.1 years. The incidence of moderate to severe pain on movement (an NRS value equal to or greater than 4) was 11.6% (22 out of 190 patients). A univariate analysis revealed that two factors--patients with multiple tumors (more than two tumors), and an ablation time of greater than 30 minutes--seemed to be related to an NRS equal to or greater than 4. Nevertheless, after entering those two factors into a multiple regression model, neither factor was associated with the moderate to severe pain scores. CONCLUSION: The incidence of undesired pain scores after percutaneous radiofrequency ablation in our institution was around 10%, and the rate of complication was very low. PMID- 27501614 TI - Femoral Nerve Block versus Intra-Articular Infiltration: A Preliminary Study of Analgesic Effects and Quadriceps Strength in Patients Undergoing Arthroscopic Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Adequate analgesia and early rehabilitation is necessary for arthroscopic anterior cruciate ligament reconstruction (A CLR) surgery. OBJECTIVE: To compare analgesia and quadriceps strength after femoral nerve block (FNB) with intra-articular infiltration (IA) using 0.25% bupivacaine for ACLR with patella tendon graft. MATERIAL AND METHOD: Forty patients were randomized to receive FNB under ultrasound guidance with 20 mL of bupivacaine or IA with 15 mL of bupivacaine into the knee joint and 5 mL infiltrated along the incision sites including portal sites at the end of surgery. All patients received intravenous ketorolac at wound closure. Data regarding demographic, time to first pain, time to first morphine requirement, morphine usage, pain scores and quadriceps strength were recorded. RESULTS: Significant difference in quadriceps strength was shown. Ninety percent of patients in Group IA and fifty-five percent of patients in Group FNB had good ability to extend knee at 24 hours after surgery (p = 0.013). No differences were found in demographic data, time to first pain, time to first morphine requirement, post operative pain scores and morphine consumption, CONCLUSION: The preliminary results demonstrated that IA has an effect on quadriceps strength less than FNB while provide comparable postoperative analgesia after patellar tendon graft ACLR. PMID- 27501615 TI - Incidence of Delayed Recovery from Femoral Nerve Block in Total Knee Arthroplasty. AB - OBJECTIVE: Femoral nerve block has been proven as an effective analgesia for total knee arthroplasty (TKA). Delayed recovery from nerve block can result in serious complication during postoperative period. This prospective, single center, observational study investigated the incidence in delayed recovery from femoral nerve block more than 24 hours postoperatively. MATERIAL AND METHOD: Two hundred and forty patients with femoral nerve block as part of anesthesia plan for elective unilateral TKA were recruited into study. Participants were assessed for sensory or motor impairment lasting longer than 24 hours post operation. Factors associated with delayed recovery from femoral nerve block were analyzed. RESULTS: Five patients (incidence = 2.08%) reported sensory or motor impairment more than 24 hours post operation. All of the patients could ambulate within 4 days post operation without permanent nerve injury or serious complication. Higher dose of local anesthetic agent using for femoral nerve block showed association with the delayed recovery (p-value = 0.01). CONCLUSION: This study demonstrated 2.08% incidence in delayed recovery from femoral nerve block. High concentration and dose of local anesthetic agent may lead to fall during early ambulatory period. PMID- 27501616 TI - Onset Time of 2% Lidocaine and 0.5% Bupivacaine Mixture versus 0.5% Bupivacaine Alone using Ultrasound and Double Nerve Stimulation for Infraclavicular Brachial Plexus Anesthesia in ESRD Patients Undergoing Arteriovenous Fistula Creation. AB - OBJECTIVE: To reduce the onset of 0.5% bupivacaine by adding 2% lidocaine with 0.5% bupivacaine for ultrasound-guided and double stimulation technique at musculocutaneous and radial nerve for infraclavicular brachial plexus block. DESIGN: Prospective randomized double-blinded, controlled trial study. MATERIAL AND METHOD: 90 patients undergoing creation of arteriovenous fistula under ultrasound-guided infraclavicular brachial plexus block were randomized into 2 groups. Gr B (46 patients) received 0.5% bupivacaine 30 mL and Gr BL (44 patients) received mixture of 0.5% bupivacaine 20 mL and 2% lidocaine 10 mL. The onset of sensory block were assessed by response to pinprick (grading: 0 = no sensation, 1 = hypoesthesia, and 2 = normal sensation). Rescue analgesia during the operation, duration of sensory and motor blockade were recorded. Surgeon and patient satisfactions are also evaluated using 6-point scale (0 = dissatisfied to 5 = very satisfied). RESULTS: There were no significant difference in the onset time of either group. Duration of sensory and motor block was not different. Surgeons' and patients' satisfaction were also not significantly different between the groups. CONCLUSION: Mixing 2% lidocaine with 0.5% bupivacaine to the final concentration of 0.67%for lidocaine and 0.33% for bupivacaine does not reduce the onset of ultrasound-guided infraclavicular brachial plexus block. PMID- 27501617 TI - The Success of MRI without Sedations in 6-15 Years Old Pediatric Patients after Watching MRI Introductory Video. AB - High-quality imaging is important for effective diagnosis and treatment in pediatrics. In order to obtain such high-quality image, the patient has to be still during the scan, which may or may not require sedation depending on each patient's condition. This study, conducted at Siriraj Hospital in Bangkok, Thailand, focused on patient factors that influence success of radiologic procedures for patients without sedation. The participants were children aged between 6 to 15 years old. Participants and parents were asked to watch a 5 minute MRI introductory video, which was specially designed for children. Participants would then make decision whether they needed sedation or not. Fifty five patients were included in this study. There were 37 patients agreed with non sedation technique. Ninety-four percent of children (35/37) who decided to proceed without sedation, were able to complete their MRI sessions. Factors identified from this study that determined success in MRI without sedation in 6 15 years old patients were children at aged 11-15 years and children who had previous exposure to MRI without need of sedation/anesthesia. There was no anesthetic complication in sedation group. PMID- 27501618 TI - Anesthetic Techniques and Incidence of Complications in Fetoscopic Surgery. AB - BACKGROUND: Nowadays, fetoscopic surgery has been accepted to be a procedure to correct numerous congenital anomalies. This operation can be successfully done under general, regional or local anesthesia with sedation. Incidence of complications from anesthesia in fetoscopic surgery has not been reported in Thailand. OBJECTIVE: To describe anesthetic techniques and incidence of complications in fetoscopic surgery. MATERIAL AND METHOD: Data of 152 pregnant women undergoing fetoscopic surgery in a single university hospital was retrospectively chart reviewed from June 2005 to November 2015. Patient characteristics, choices of anesthesia, medication used, intraoperative data and complications were collected. RESULTS: During the study period, spinal anesthesia was the most popular technique used in fetoscopic surgery (71%). Other anesthetic techniques used were general anesthesia with endotracheal tube (GA) (20.5%), epidural anesthesia (1.3%), combined spinal and epidural anesthesia (0.7%), failed spinal anesthesia converting to GA (2.6%) and local anesthesia with sedation (3.9%). Most frequent anesthetic-related complication was maternal hypotension which occurs in 115 out of 152 patients (75.6%). All of 5 cases (3.3%) of postoperative pulmonary edema received SA. Fetal death after operation was 25 in 152 records (16.4%). None of patients received GA experienced desaturation, pulmonary aspiration, failed intubation or pulmonary edema. CONCLUSION: Spinal anesthesia (SA) is the most frequent technique used for fetoscopy, and hypotension is the most common complication. Since pulmonary edema was also found, judicious perioperative fluid management should be implemented to prevent postoperative pulmonary edema. PMID- 27501619 TI - Reference Values for Umbilical Cord Blood Gases of Newborns Delivered by Elective Cesarean Section. AB - BACKGROUND: Umbilical cord blood gas values are better indicators of perinatal asphyxia than Apgar scores. Many studies have reported normal ranges of umbilical cord blood gases, which vary greatly due to many factors. This study aimed to establish the reference values of umbilical cord blood gases of normal cesarean newborns in a university hospital setting. MATERIAL AND METHOD: Blood samples from the umbilical artery and vein were collected from 160 newborns delivered by elective cesarean section. The indications for caesarean section were not due to fetal distress, intrauterine growth retardation, or non-reassuring fetal heart rate. The blood samples were collected immediately after birth in the operating room and then sent for blood-gas analysis. The blood-gas values were statistically analyzed and reported. RESULTS: The cord blood collected from 160 newborns was analyzed in this study. Seventy-eight percent (115) of the parturients were hypotensive before delivery. All Apgar scores at one and five minutes after delivery were at least 7. The calculated reference range of the umbilical arterial pH was 7.18-7.42, of pO2was 6.43-29.43 mmHg, of pCO2was 33.44 66.56 mmHg, and of HCO3was 15.60-30.70 mEq/L. The reference range obtained for the umbilical venous pH was 7.28-7.44,for pO2was 13.97-37.13 mmHg, for pCO2was 30.70-57.0 mmHg, and for HCO3was 18.50-29.90 mEq/L. CONCLUSION: The study determined normal reference values as a result of umbilical cord blood gas analyses. PMID- 27501620 TI - 50th Year Anniversary of Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, Mahidol University. AB - Department of Anesthesiology, Faculty of Medicine Siriraj Hospital, has started to be a formal anesthesia division, divided from division of Surgery in 1965; hence our 50th year anniversary in 2015. Research is now a priority and mandatory mission, according to the vision of Mahidol University. Second mission is to teach and train, and we produce the highest number of states-of-the-art anesthesiologists and anesthetic nurses each year Curriculum and training are being continuously improved. From a small unit, now it is one of the largest departments and extends the service, our third mission, to more than only in the operating theaters. We look after pre-anesthesia assessment, inside and outside operating room anesthesia, post-operative pain relief Intensive Care Unit, and chronic pain management. The number of patients and their diseases increase; so do the complexities of surgeries. There are tremendous changes in drugs and equipment. There is the fourth mission on administration, IT and resource management. And the fifth mission which is corporate social responsibility. However, we still believe that compassion, responsibility and integrity are most important. We have taught and tried to live by the teaching of HRH the King's Father. And these will contribute to our progress and shine in the next 50 years. PMID- 27501621 TI - Quality of Anesthesia Care in a University Hospital in Thailand. AB - BACKGROUND: Service quality is an important factor, which value differs between the patient's satisfaction and expectation. The patient's expectations are important factors for development. This service quality is a key part for improvement of our anesthesia service. In general, an improvement in service design and delivery helps to achieve higher levels of the service quality. OBJECTIVE: To evaluate the level of patient's expectation, patient's satisfaction and the quality of anesthesia care in a university hospital in Thailand MATERIAL AND METHOD: The patient satisfaction questionnaire, developed from service quality criteria and patient satisfaction questionnaire (PSQ-18), was applied to evaluate 467 in patients 24-72 hours after anesthesia care. The patients'expectation was also assessed A proportional stratified randomized allocation was done. The questionnaire consisted of three dimensions; 1) structure: reliability & empathy, 2) process: assurance & tangible and 3) result: responsiveness. Data expectation and satisfaction were analyzed with mean, standard deviation, t-test, ANOVA and normalized gain for the quality of anesthesia care. RESULTS: The patient's satisfaction in our anesthesia care is relatively high. The mean patient's satisfaction score is significantly higher than the mean patient's expectation in all dimensions. This study indicated that an anesthesia service in our hospital was a high quality service in the inpatient aspects. CONCLUSION: Patient's expectation and satisfaction with anesthesia services in our setting was relatively high. Although most patients never had been any expectation regarding anesthesia service, the information and the involvement in decision- making were the most requirements of the adult inpatients. PMID- 27501622 TI - Development of An Assessment Test for An Anesthetic Machine. AB - OBJECTIVE: The study is aimed to develop and assess the quality of an evaluation form used to evaluate the nurse anesthetic trainees' skills in undertaking a pre use check of an anesthetic machine. MATERIAL AND METHOD: An evaluation form comprising 25 items was developed, informed by the guidelines published by national anesthesiologist societies and refined to reflect the anesthetic machine used in our institution. The item-checking included the cylinder supplies and medical gas pipelines, vaporizer back bar, ventilator anesthetic breathing system, scavenging system and emergency back-up equipment. The authors sought the opinions of five experienced anesthetic trainers to judge the validity of the content. The authors measured its inter-rater reliability when used by two achievement scores evaluating the performance of 36 nurse anesthetic trainees undertaking 15-minute anesthetic machine checks and test-retest the reliability correlation scores between the two performances in the seven days interval. RESULTS: The five experienced anesthesiologists agreed that the evaluation form accurately reflected the objectives of anesthetic machine checking, equating to an index of congruency of 1.00. The inter-rater reliability of the independent assessors scoring was 0.977 (p = 0.01) and the test-retest reliability was 0.883 (p = 0.01). CONCLUSION: An evaluation form proved to be a reliable and effective tool for assessing the anesthetic nurse trainees' checking of an anesthetic machine before the use. This evaluation form was brief clear and practical to use, and should help to improve anesthetic nurse education and the patient safety. PMID- 27501623 TI - A Contemporary Clinical Assessment of Historical Findings of a 14,000 Year Old Tooth. AB - A recent publication in Nature--Scientific Reports identified a 14,000-year-old tooth that apparently had undergone a dental procedure to remove dental caries. This report is well detailed and focused on the discovery of what appeared to be dental caries manipulation in the Late Upper Palaeolithic Era in a human specimen (Villabruna) from a burial site in Northern Italy. Modern technology was used to assess this finding and provide a reasonable explanation based on specific enamel chipping observed in the uppermost mesial margin of the tooth cavity. While details of the discovery were based primarily on the tooth cavity that was identified and the specific characteristics it displayed, upon review of the report other observations not reported or assessed may suggest additional considerations for contemporary dentistry. The purpose of this article is to attempt to provide a plausible clinical perspective on these additional observation and assessments along with identifying questions as to the importance of these conclusions. PMID- 27501624 TI - The Brisbane Dental Hospital Building: "The Palace" An Era Ends. AB - Constitutional, educational, humanitarian and political considerations underpinned the design and construction of the Brisbane Dental Hospital Building, often colloquially referred to as "The Palace." The Queensland Heritage Council's listing of the Brisbane Dental Hospital Building on The Queensland Heritage Register in 1999 confirms the cultural significance of Nowland's architectural signature, the historical importance of the Wickham Park precinct and prior students' connection with the building. Influences on decisions determining the location, grand design and timing of construction of the Brisbane Dental Hospital Building emanated from a far bigger and largely unrecorded political picture. The authors argue that the political context in two tiers of government, the timing and nature of the proposal, town planning issues, the exigencies of the caries epidemic and Forgan Smith's post-Depression economic reconstruction across Queensland underpinned the project. Hanlon's personal attributes and disdain for the autonomy of the dental profession, together with his desire to reform dental education and to establish statewide government-administred dental clinics, were also relevant. Accordingly, the BDHD portrayed aspiration, purpose, symbolism, and vision. This paper, essentially an integration of dental and mainstream history, assembles and analyzes hitherto scattered and unpublished evidence to fill a gap in the current literature. PMID- 27501625 TI - Dental Trade Cards XLIII. PMID- 27501627 TI - Creating and Maintaining a Culture of Safety--Our Role. PMID- 27501626 TI - Promoting Resilience Among Patients with End Stage Renal Disease. PMID- 27501628 TI - Contrasting Perceptions of Home Dialysis Therapies Among In-Center and Home Dialysis Staff. AB - Home dialysis offers many advantages over in-center dialysis, but peritoneal dialysis and home hemodialysis are infrequently used. To better understand why, a survey of dialysis healthcare professionals (N = 273) in the United States was conducted to assess their knowledge, perceptions, and beliefs about home dialysis modalities. Most survey respondents demonstrated a lack of knowledge about home dialysis and perceived many barriers to home therapy, which may affect patient modality choice; however, 90% of respondents stated they would choose home dialysis for themselves if they required dialysis. Additional staff education may help reduce misperceptions, address knowledge gaps, and subsequently, increase use of home modalities. PMID- 27501629 TI - Improving the Care of Patients with Chronic Kidney Disease Using Group Visits: A Pilot Study to Reflect an Emphasis on the Patients Rather Than the Disease. AB - This two-group, repeated-measures experimental study assessed the efficacy of a nurse practitioner-facilitated chronic kidney disease (CKD) group visit (GV) model versus usual nephrology care for patients with Stage 4 CKD. The study enrolled patients from two sites of an outpatient nephrology practice (n = 30) and randomized subjects to usual care (n = 14) or to the GV model (n = 16). Data regarding CKD knowledge, self-efficacy/disease self-management, and physiologic measures were collected at baseline, 6 months, and 9 months. Satisfaction was obtained at 6 months and 9 months. Usual nephrology office visit components were maintained during six monthly GVs, with group discussions of CKD-related topies. Results indicated a statistical improvement in CKD knowledge for both groups (F[1.498, 34.446] = 6.363, p = 0.008). An upward trend in mean scores for self management subscales and self-efficacy scores was demonstrated in the GV patients, with no improvement found in the usual care group. Twenty-six of 30 patients completed the study, with 92% attendance in the GV group. GV satisfaction was high. PMID- 27501630 TI - Non-Biological Barriers to Referral and the Pre-Kidney Transplant Evaluation Among African Americans in the United States: A Systematic Review. AB - African Americans face a disproportionate burden related to the incidence of end stage renal disease. A literature search was conducted for research articles published between 2006-2015 to synthesize current literature related to non biological barriers to early stages of the pre-kidney transplant continuum for African Americans in the United States. Twenty-four articles were included in the final sample. Eleven barriers were identified. Barriers were categorized as socioeconomic-based barriers, culture-based barriers, and knowledge-based barriers. Resources to develop educational interventions for both patients and providers may help reduce existing barriers. PMID- 27501631 TI - Experiences of Patients on Outpatient Hemodialysis Therapy Who Are Anticipating a Transplant. AB - The person with kidney failure may experience many lifestyle disruptions that initiate distressing responses. This article reports on the results of a phenomenological study that explored the experiences of patients with kidney failure who were receiving outpatient hemodialysis therapy and who were either on the transplant list or in the process of being assessed to get on the transplant list. The participants described the existential distress they endured as a result of living with this disease and treatment; however, the participants' descriptions of distress were different than the psychological perspective of emotional distress depicted in the existing research. The information provided in this article can enhance nurses' ability to recognize and respond more appropriately to the distressing moods experienced by patients with kidney failure on outpatient hemodialysis. PMID- 27501632 TI - Home Dialysis Modalities: Educational Barriers to Utilization. AB - In the United States, an increasing number of individuals are being diagnosed with end stage renal disease requiring renal replacement therapy. Home dialysis modalities are an available option in lieu of in-center hemodialysis therapy for these individuals, but are vastly underutilized in the U.S. for multiple reasons. Both healthcare providers and individuals requiring renal replacement therapy are frequently unaware these modalities are an available alternative to in-center hemodialysis and of the potential benefits related to home modality use. Lack of healthcare provider and patient education regarding home modalities is a primary factor related to underutilization. PMID- 27501633 TI - The Nephrology Clinical Research Nurse Role: Potential Role Conflicts. AB - Clinical research nursing is becoming more visible to nephrology professionals. As more nephrology practices and units are participating in clinical trials, clinical research nursing is gaining interest as a career niche among nephrology nurses. This unique specialty requires that nephrology clinical nurse nurses (CRNs) reconcile the roles of nurse as caregiver and nurse as researcher, which may result in a role conflict. Nephrology nurses should be aware that they may experience this role conflict when transitioning from patient care to a position as a clinical research nurse. These nurses can rely on the American Nurses Association's Code of Ethics for Nurses and the Oncology Nursing Society's Oncology Clinical Trials Nurse Competencies to help reconcile the potential role conflict. PMID- 27501634 TI - Living with a Change in Dialysis Modalities: A Case Study. AB - Nephrology nurses play a major role in every aspect of caring for patients on dialysis. It is always challenging to witness patients and families struggling through dialysis modality changes coupled with end-of-life decisions. Open discussions and care provided by an interdisciplinary team approach provides the foundational structure for quality care necessary for this population. In the case of Mr. T., a dialysis modality change was a necessary change in his life. The FNP PCP played a significant role in coordinating his care to achieve the desired outcomes and ensure there was a coordinated team approach. PMID- 27501635 TI - The Role of Nephrology Nurses in the Selection of the Peritoneal Dialysis Catheter and Exit Site Location. PMID- 27501636 TI - Social Work's Grand Challenges: Mobilizing the Profession. PMID- 27501637 TI - Mechanisms of Familial Influence on Reentry among Formerly Incarcerated Latino Men. AB - In the United States more than 10,000 people are released from state and federal prisons every week and often reenter the communities in which they were arrested. Formerly incarcerated individuals face considerable challenges to securing employment and housing. Subsequently, approximately two-thirds of former prisoners are rearrested within three years of their release. Latino men represent the fastest growing ethnic group of prisoners in the United States with unique cultural and social needs during the reentry process. The present study examined the role of the family in the reentry process through in-depth interviews (N = 16) with formerly incarcerated Latino men (FILM). The authors sought to identify familial processes specific to Latino men with potential to affect engagement and participation in reentry programs. Findings suggest that family mechanisms of social control and social support influence FILM's reentry. Social work practitioners who work with this growing population can engage familial processes to prevent recidivism and promote desistance. PMID- 27501638 TI - Social Work-Business Sector Collaboration in Pursuit of Economic Justice. AB - This article examines social workers' perceptions, experiences, and prospects regarding working in the business sector after participating in an MSW field practicum with a local microlending program. Social workers' insights suggest that cross-sector collaboration leads to vast opportunities not only for the populations served by the collaborative efforts, but also for social work as a profession. However, several challenges are evealed, including social workers' unfamiliarity with business operations, the business sector's narrow understanding of social workers' roles, and divisions between participants in interprofessional collaboration. This article calls for enhancing the role of social work to maximize its impact on economic development through further research and tangible cross-sector projects. PMID- 27501639 TI - Promoting Young People's Participation: Exploring Social Work's Contribution to the Literature. AB - In the National Association of Social Workers' Code of Ethics, social workers are called on to promote meaningful involvement in decision making among vulnerable populations. The ethical imperatives and social justice implications associated with unequal participation suggest that the field of social work is uniquely situated to lead research and practice in the area of youth civic engagement. This article examines the current state of the social work literature regarding how young people participate civically. Authors identified 113 articles on this topic published over the past decade in journals with a large presence in social work or by social work authors. They present the findings of their exploratory research, with a focus on describing where this research is being published, the range of research foci, and the terms used to describe this work. Increased attention to promoting youth civic engagement is needed in the profession's core journals. Based on the analysis of this literature, they recommend moving toward a cohesive body of social work scholarship that includes increased collaboration among scholars, more unified terms and language, increased range of research foci and methodologies, and more rigorous and comparative testing of strategies by which youths participate civically. PMID- 27501640 TI - The Affordable Care Act, Substance Use Disorders, and Low-Income Clients: Implications for Social Work. AB - Social workers are leaders in the substance abuse services field and may often work in substance use disorder (SUD) education, prevention, assessment, treatment, or resource coordination and case management roles. As the Patient Protection and Affordable Care Act (ACA) (2010) drives changes in the fields of health and behavioral health, social workers have an opportunity to lead structural changes at the micro and macro levels that will have a positive impact on low-income clients with SUDs. In this article, authors examine the current state of SUDs and health care access, the impact of the ACA on the field, and implications for social work practice and education. Social workers should seek specialized education and credentialing in SUD services, know how to help clients apply for health care coverage, and advocate for integrated substance abuse treatment and health care programs and an expansion of Medicaid in their local communities. Social workers are well positioned to be a voice for clients to ensure that the current structural changes result in a better, integrated system of care that is able to respond to the needs of low-income clients with SUDs. PMID- 27501641 TI - Out-of-School Suspensions of Black Youths: Culture, Ability, Disability, Gender, and Perspective. AB - Racial disproportionality in out-of-school suspensions is a persistent social justice issue in public schools. This article examines out-of-school suspensions of four black youths from the perspectives of the youths, their caregivers, and educators. The case involving David, a 14-year-old African American with a learning disability, illustrates the challenges of students experiencing the intersection of disability and race. The case involving George, a 14-year-old Liberian immigrant, illustrates how parents and teachers may form alliances around shared goals and values despite profound cultural differences in understanding of youths' misbehavior. The case involving Nina, a 12-year-old African American, illustrates how educators' failure to consider the context of her misbehaviors as responses to sexual harassment, along with their subsequent harsh punishment and failure to protect her, led to her disengagement from school. The case involving Craig, a 16-year-old African American, provides a glimpse into how the use of criminal justice language to refer to youths' misbehaviors can support the development of a criminalized self- and social identity. These cases illustrate the diversity of black students--including ability, disability, culture, and gender--and how events surrounding suspensions are interpreted by students, caregivers, and educators. Understanding such diversity will undergird implementation of effective alternatives to suspensions. PMID- 27501642 TI - Feminist Social Work: Practice and Theory of Practice. AB - Although feminist social work has been practiced in Israel since the 1970s, little has been written about it. This qualitative study aims to fill this gap by documenting and conceptualizing feminist theory of practice and actual practice based on interviews with 12 feminist social workers. Findings reveal that the interviewees perceive feminist practice as significantly different from traditional social work practice based on four analytical principles: (1) gender analysis, (2) awareness of power relations, (3) analysis of welfare services as structures of oppression, and (4) utilization of feminist language, as well as 10 principles of action. The principles are discussed in the context of feminist social work in Israel and in light of feminist principles described in international literature. PMID- 27501644 TI - Taking a Timeout to Ensure Well-Being: Social Work Involvement in College Sports. PMID- 27501643 TI - Toward Complete Inclusion: Lesbian, Gay, Bisexual, and Transgender Military Service Members after Repeal of Don't Ask, Don't Tell. AB - The 2010 repeal of Don't Ask, Don't Tell (DADT) is one example of how U.S. public policy has shifted toward greater inclusion of lesbian, gay, and bisexual (LGB) individuals. The repeal of DADT reversed the practice of discharging LGB service members on the basis of sexual identity. LGB service members may now serve their country without fear of direct repercussions stemming from sexual identity. Though it is a statutory step toward parity, DADT repeal does not address a number of cultural and institutional inequities that continue to hinder full inclusion of sexual minority service members. Notably, as discussed in this article, DADT largely ignores issues facing the transgender population. This study examines remaining inequities and their ramifications for lesbian, gay, bisexual, and transgender service members and their families. The article concludes with practice and policy recommendations for culturally competent social work practice with military service members across the sexual identity spectrum. PMID- 27501645 TI - The Social Worker, Psychotropic Medication, and Right to Refuse. PMID- 27501646 TI - Agency in Vulnerable Families: A Critical Response to Goh. PMID- 27501647 TI - On Combat Anesthesia. PMID- 27501648 TI - Response. PMID- 27501649 TI - Hazardous Intraoperative Behaviors: What's at Risk?. PMID- 27501650 TI - Effects of a 30-mL Epidural Normal Saline Bolus on Time to Full Motor Recovery in Parturients Who Received Patient-Controlled Epidural Analgesia With 0.125% Bupivacaine With 2 ug/mL of Fentanyl. AB - Previous research suggests that an epidural bolus of 30 mL of normal saline after vaginal delivery may decrease the time for recovery from motor block. A double blind, randomized controlled study was conducted in 46 parturients to determine if a 30-mL normal saline bolus or sham administered via epidural approach after delivery reduces the time to full motor recovery and the time to 2-dermatome regression. No significant difference was found in time to full motor recovery (saline group 83.18 +/- 54 minutes vs control group 100.23 +/- 48 minutes, P = .27) or time to 2-dermatome sensory regression (saline group 29.32 +/- 16.35 minutes vs control group 36.14 +/- 14.39 minutes, P = .15). Results suggest no advantage to the administration of a saline bolus after delivery to hasten the motor recovery in parturients. A post hoc power analysis suggested a sample size of 204 subjects would have been needed to show a difference for this dilute local anesthetic regimen. There were no complications to the technique, which suggests that it is safe to perform, but the difference in recovery (approximately 17 minutes) from a dilute local anesthetic dose may not be clinically significant. PMID- 27501651 TI - Venous Thromboembolism Prophylaxis in Plastic Surgery: A Literature Review. AB - Venous thromboembolism (VTE) is a major health concern because it increases morbidity and mortality after a surgical procedure. A number of well-defined, evidence-based guidelines are available delineating suitable use of prophylaxis to prevent deep vein thrombosis and pulmonary embolism. Despite the available literature, there are clear gaps between recommendations and clinical practice, affecting the incidence of VTE. Plastic surgeons underuse the substantiated literature and risk stratification tools that are available to decrease the incidence of VTE in the office-based surgical setting because of fear of bleeding or hematoma complications postoperatively. Venous thromboembolism creates an economic burden on both the patient and the healthcare system. The intent of this literature review is to determine existing VTE risk using assessment models available to aid in the implementation of protocols for VTE prevention, specifically for high-risk cosmetic surgical patients in office-based settings. PMID- 27501652 TI - The Jehovah's Witness Population: Considerations for Preoperative Optimization of Hemoglobin. AB - Most members of the Jehovah's Witness community refuse blood transfusions, and there are variations in what alternatives they will accept depending on their personal decisions. To provide culturally competent care, healthcare providers need to be knowledgeable about substitutions for blood administration as well as the risks and benefits of available alternatives so that they can inform their patients. It has been recognized in the literature that preoperative optimization of hemoglobin levels with alternative treatment modalities through a multidisciplinary approach can improve clinical outcomes in patients who refuse blood products. The purpose of this article is to illuminate the current beliefs of Jehovah's Witnesses regarding receiving blood products, discuss ethical and legal considerations for the nurse anesthetist, discuss the risks of blood transfusions, and examine transfusion alternatives. Finally, this article considers a multidisciplinary approach to the optimization of preoperative hemoglobin levels. PMID- 27501653 TI - Anesthetic Considerations of Stiff-Person Syndrome: A Case Report. AB - Stiff-person syndrome (SPS) is a neurologic disorder characterized by painful involuntary episodes of severe muscle rigidity affecting the axial muscles and extremities. Although the etiology of SPS is unknown, it is suspected to involve the synthesis of gamma-aminobutyric acid (GABA). Symptoms of SPS are precipitated by sudden unexpected movements, noises, and stress. Additionally, SPS has been linked with various autoimmune disorders, including diabetes mellitus, thyroid disease, pernicious anemia, and certain cancers. Because of the effect of SPS and SPS medications, inhalational agents and neuromuscular blockers have the potential to cause prolonged hypotonia following anesthesia, resulting in respiratory failure despite full reversal of neuromuscular blockade. In documented case reports, the outcomes of using general anesthesia with inhalational agents and neuromuscular blockers in patients with SPS varied. This case report highlights the anesthetic management of a 56-year-old woman with diagnosed SPS undergoing a hemicolectomy for a colon mass using total intravenous anesthesia. PMID- 27501654 TI - Preventive Dorzolamide-Timolol for Rising Intraocular Pressure During Steep Trendelenburg Position Surgery. AB - The study purpose was to evaluate preventive use of dorzolamide-timolol ophthalmic solution (Cosopt) during laparoscopic surgery with the patient in steep Trendelenburg (ST) position. Periorbital swelling, venous congestion, and elevated intraocular pressure (IOP) may produce low ocular perfusion. Prompt IOP reduction is important because 30- to 40-minute episodes of acute IOP elevations can result in retinal ganglion cell dysfunction. Dorzolamide-timolol ophthalmic drops reduce IOP and may ameliorate this effect. A double-blind randomized experimental study was conducted to test the effect of dorzolamide-timolol on IOP elevation during laparoscopic surgeries in ST position. Patients were randomly assigned to receive dorzolamide-timolol treatment or balanced salt solution following anesthesia induction. The IOP levels were measured at baseline and 30 minutes intervals throughout surgery. The generalized estimating equations model was used to analyze treatment and time effects and treatment by time interactions. Ninety patients were recruited, with 46 receiving dorzolamide timolol treatment and 44 receiving balanced salt solution. Statistical analysis revealed significant treatment and time effects and treatment-time interactions on IOP. Patients' IOP was significantly lower in the treatment group than controls (P < .05 to P < .001). Treatment effects were medium to strong. Prophylactic therapy with dorzolamide-timolol significantly reduced IOP of surgical patients during ST positioning. PMID- 27501655 TI - Unknown Pseudocholinesterase Deficiency in a Patient Undergoing TIVA with Planned Motor Evoked Potential Monitoring: A Case Report. AB - Pseudocholinesterase abnormalities are a genetic cause of aberrant metabolism of the depolarizing muscle relaxant succinylcholine. This article examines a case where succinylcholine was chosen to facilitate intubation due to its ultra short duration and the request of the surgeon to monitor motor evoked potentials. Following succinylcholine administration the neurophysiologist was unable to obtain motor evoked potentials. This case study highlights the intraoperative and postoperative management of an elderly patient with an unknown pseudocholinesterase deficiency. PMID- 27501656 TI - Tranexamic Acid in Anesthetic Management of Surgical Procedures. AB - Blood loss during surgical procedures poses a grave risk to the patient, but transfusion is costly and associated with adverse outcomes. Antifibrinolytics, however, offer an economical and effective means of decreasing blood loss associated with surgical procedures. Tranexamic acid (TXA) is an antifibrinolytic that blocks lysine-binding sites of fibrinogen and fibrin, preventing the breakdown of existing clots. This journal course reviews extensive research demonstrating that antifibrinolytics such as TXA decrease blood loss and in some studies reduce allogeneic transfusion requirements. In addition, this journal course addresses concerns that use of antifibrinolytics increases embolic events, reviews research that demonstrates TXA does not increase the incidence of vascular occlusive events, and describes methods of TXA use in cardiac and orthopedic surgical procedures, neurosurgery, and obstetrics. The Certified Registered Nurse Anesthetist should consider the possibility, on a case-by-case basis, of using TXA in surgical procedures to reduce blood loss with minimal adverse effects. PMID- 27501657 TI - [Laudatio on the prize of the Pflegezeitschrift 2015]. PMID- 27501658 TI - [Respectful communication in the nursing team]. PMID- 27501659 TI - [Nursing requires continuous language change. PMID- 27501660 TI - [Nursing must retain its own language]. PMID- 27501661 TI - [No time - when pressure and stress increasingly dominate thinking, speaking and nursing care]. PMID- 27501662 TI - ["But we only just want what's best for you!" - Subtle forms of coercion in nursing]. PMID- 27501663 TI - [The language of youth in nursing]. PMID- 27501664 TI - [Psychological verbal communication in (psychiatric) nursing]. PMID- 27501665 TI - [Foreign nursing staff: quality assurance by reliable language tests]. PMID- 27501666 TI - [Eliminating minute nursing]. PMID- 27501667 TI - [Transcultural nursing: how different cultural concepts can influence your nursing practice]. PMID- 27501668 TI - [Nursing anamnesis in theory and practice]. PMID- 27501669 TI - [Supporting parents in neonatology]. PMID- 27501670 TI - [Individual conflict resolution outside the confines of the legal system]. PMID- 27501671 TI - [Clarifying the goals of the research and selecting information sources]. PMID- 27501672 TI - [The intuitive interview]. PMID- 27501673 TI - [Nursing documentation disengaged from bureaucracy in ambulatory nursing services]. PMID- 27501674 TI - [The project expert standards@work]. PMID- 27501675 TI - [The Role of Hydrogen Sulfide in Acute Liver Injury Induced by Traumatic Stress in Rats]. AB - OBJECTIVE: To explore the role of hydrogen sulfide (H2S) in acute liver injury induced by crushing hind limbs of rats. METHODS: The rats were randomly divided into the following groups: control, crushing, H2S donor sodium hydrosulfide (NaHS) + crushing, H2S inhibitor propargylglycine (PAG) + crushing group. The acute liver injury model was established by 'crushing the hind limbs of rats with standard weight. Rats were sacrificed at 30 min and 120 min after the crush. The activities of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured by colorimetric method, and the content of H2S in plasma and the contents of malondialdehyde (MDA), protein carbonyl, glutathione (GSH) in the liver and the activity of H2S generating enzyme (cystathionine y-lyase, CSE) were determined by chemical method. The expression of CSE mRNA in liver was detected by RT-PCR. RESULTS: For crush injury group, the levels of AST and ALT in serum, MDA and protein carbonyl in liver increased. The levels of GSH, CSE, CSE mRNA in liver and H2S in serum decreased. The administration of NaHS before limbs crush could attenuate the changes of liver injury, but the pre-treatment with PAG could exacerbate the changes. CONCLUSION: The decrease of H2S production could involve in mediating the acute liver injury induced by traumatic stress in rats. PMID- 27501676 TI - [Comparison of Postmortem MSCT and Autopsy Findings in Traffic Accident Victims]. AB - OBJECTIVE: To explore the application value of postmortem multi-slice spiral computed tomography (MSCT) by observing and analyzing the injury features in the traffic accident victims. METHODS: Ten traffic accident victims were scanned with whole body MSCT. The systemic autopsy was subsequently performed to compare with the results of MSCT. The advantages and disadvantages of autopsy and MSCT for obtaining the information of traffic accident injuries were then analyzed. RESULTS: MSCT could reveal 3D shape of fractures clearly and detect air accumulation in different positions of the body, which showed the obvious advantages compared with autopsy. However, the resolution of MSCT was limited compared to the detection of organ and soft tissue injuries. CONCLUSION: A combination of MSCT and autopsy is the best way for determining the manner and the cause of death in traffic fatality victims. PMID- 27501677 TI - [Relationship between Injury Time and Expressions of EPO and Its Receptors in Rats Brain after Cerebral Injury]. AB - OBJECTIVE: To explore the relationship between injury age and expressions of erythropoietin (EPO) and its receptor EPOR in the brain tissue of rats after cerebral injury. METHODS: Seventy-two rats were randomly divided into control group (36 rats) and cerebral injury group (36 rats). The rats were sacrificed at 1, 2, 4, 8, 12, 24 h after cerebral injury (6 rats at each time point) and the brain tissues were extracted. The expressions of mRNA and protein of EPO and EPOR at different time points were detected by real-time fluorescent quantitative PCR and Western bloting. RESULTS: The expressions of EPO and EPOR increased within 24 h after injury. The expressions of mRNA and protein of EPO were related to the injury age, and the correlations were 0.875, 0.911, respectively (P < 0.05). The expressions of mRNA and protein of EPOR were related to the injury age, and the correlation coefficients were 0.936, 0.905, respectively (P < 0.05). CONCLUSION: The expressions of EPO and EPOR increase gradually in the early stage of the rat's cerebral injury, which are associated with the injury age and could be a useful value for estimating injury age. PMID- 27501678 TI - [Expression of PTEN in Myocardial Tissue in Coronary Heart Disease]. AB - OBJECTIVE: To observe the expression of phosphatase and tensin homology deleted on chromosome ten (PTEN) in myocardial tissue in patients with coronary heart disease, and explore the relevance between the expression of PTEN and the occurrence and development of coronary heart disease. METHODS: A total of 16 death cases with pathological diagnosis of coronary heart disease were collected as experimental group, and 19 cases without myocardial lesions were selected as control group. The expression of PTEN protein and its mRNA were detected by immunohistochemistry and real-time fluorescence quantitative PCR respectively. The correlation between the expression of PTEN and the pathogenesis of coronary heart disease was analyzed. RESULTS: The expression of PTEN protein in myocardium in cases with coronary heart disease was significantly lower compared with the control group (P < 0.05). There was no statistical difference of the expression of PTEN mRNA between experimental and control group (P > 0.05). CONCLUSION: PTEN may be involved in the occurrence and development of coronary heart disease. PMID- 27501679 TI - [Relationship between Body Height and Craniofacial Lines Measured by CT in Southwest Han Males]. AB - OBJECTIVE: To establish regression model between craniofacial lines and body height by measuring craniofacial lines in Southwest Han males using CT and to accumulate data for the study of forensic anthropology. METHODS: Head CT data of 273 Han males in Southwest were collected and 7 craniofacial lines were determined. Multiplanar reconstruction and volume rendering were performed by image post-processing software and the selected lines were measured. The relationship between each measuring indicator and body height was analyzed using SPSS 21.0 software. The regression equation of body height estimation was established and 50 samples were selected again and put into the mathematics models to verify its accuracy. RESULTS: The linear regression equations of 7 lines were established (P < 0.05). The correlation coefficients of the unary linear regression equations were 0.190-0.439 and the standard errors of the estimate (SEE) were 4.597-5.023 cm. The correlation coefficients of the multiple linear regression equation were 0.494-0.524 and the SEE were 4.418-4.458 cm. The return tests showed that the highest +/- 1SEE accuracy of the multiple regression equation: y = 83.959+3.589 x6+2.573 x2, were 30%; and the highest +/- 2SEE accuracy of the multiple regression equation: y = 72.646+3.316 x6+1.586 x2+1.553 x4+2.211 x3, were 92%. CONCLUSION: There is significant linear correlation between 7 selected lines and the stature in this study, and the plural linear regression equation established could be applied for estimating the stature of Southwest Han males. PMID- 27501680 TI - [Personality Change due to Brain Trauma Caused by Traffic Accidents and Its Assessment of Psychiatric Impairment]. AB - OBJECTIVE: To explore the main performance of personality change in people with mild psychiatric impairments which due to the brain trauma caused by traffic accidents and its value in assessment of psychiatric impairment. METHODS: The condition of personality change of patients with traumatic brain injury caused by traffic accident was evaluated by the Scale of Personality Change Post-traumatic Brain Injury (SPCPTBI). Furthermore, the correlation between the personality change and the degrees of traumatic brain injury and psychiatric impairment were explored. Results In 271 samples, 239 (88.2%) with personality changes. Among these 239 samples, 178 (65.7%), 46 (17.0%), 15 (5.5%) with mild, moderate and severe personality changes, respectively. The ratio based on the extent of personality changes to the degree of brain trauma was not significant (P > 0.05), but the total score difference between the groups was significant (P < 0.05). There was no statistical significance between the medium and high severity brain trauma groups. The higher degree of personality changes, the higher rank of mental disabilities. The total score difference of the scale of personality change among the different mild psychiatric impairment group was significant (P<0.05). The difference between other psychiatric impairment levels had statistical significance (P < 0.05) except level 7 and 8. CONCLUSION: The occurrence of personality change due to traumatic brain injury caused by traffic accident was high. Correlations exist between the personality change and the degree of psychiatric impairment. Personality change due to brain trauma caused by traffic accident can be assessed effectively by means of SPCPTBI, and the correlation between the total score and the extent of traumatic brain injury can be found. PMID- 27501681 TI - [Application of the Peak Area Ratio of STR Loci to Amelogenin Locus in the Estimation of DNA Degradation]. AB - OBJECTIVE: To explore the change rules of peak area ratio of STR loci to Amelogenin (AMEL) locus (STR/AMEL), a sex-determining gene in DNA degradation, and to evaluate the application of STR/AMEL value in the estimation of DNA degradation degree. METHODS: DNA was extracted from iliopsoas, and the variations of STR/AMEL value (Penta E/AMEL, Penta D/AMEL, FGA/AMEL) were analyzed after the artificial degradation was made by DNase I, and the changes of these three ratios of the iliopsoas naturally degraded in an outdoor environment were also analyzed. The regression curves were analyzed using the periods of DNA degradation and outside the body as the independent variable (x) and the STR/AMEL value as the dependent variable (y) and three curve equations under two conditions were established. RESULTS: Both under the conditions of artificial and natural degradation, STR/AMEL value had a negative relationship with the degradation time. The relationship between STR/AMEL and degradation time can be well simulated by the cubic function. R2 was over 0.99 under controlled degradation condition and over 0.86 under natural degradation condition. CONCLUSION: The STR/AMEL value (Penta E/AMEL, Penta D/AMEL, FGA/AMEL) is negatively related with the DNA degradation degree, which follows mathematical regression models strictly, and it might be applied to evaluate the DNA degradation degree. PMID- 27501682 TI - [Establishment and Verification of 6-color Fluorescent-labeled Rapid PCR Amplification System]. AB - OBJECTIVE: To establish the rapid PCR amplification program and system and to verify the technical indexes. METHODS: PCR multiplex and capillary electrophoresis detection of 24 autosomal STR loci and one Y-STR loci using the 6 color fluorescence marking technology, as well as A melogenin and Y-InDel. Meanwhile, sensitivity, specificity, identity, stability, mixing and a batch of sample tests were investigated, and the genotype of various routine samples and degraded, exfoliated cell samples were observed. RESULTS: The sensitivity of the system was 0.062 5 ng. In addition, the genotype could be detected accurately only around 65 min via rapid amplification. The species-specificity was high and the genotyping of all kinds of dry blood specimens of filter paper and mixed, degraded, exfoliated cell samples were accurate. CONCLUSION: The rapid amplification system can significantly improve the detection rate, and obtain accurate and stable genotyping results, which may be important implications for the establishment of STR database and study on population genetics and forensic identification. PMID- 27501683 TI - Biomonitoring of 33 Elements in Blood and Urine Samples from Coastal Populations in Sanmen County of Zhejiang Province. AB - OBJECTIVE: To determine the normal reference values of 33 elements, Ag, Al, As, Au, B, Ba, Be, Ca, Cd, Co, Cr, Cs, Cu, Fe, Ga, Hg, Li, Mg, Mn, Mo, Ni, Pb, Rb, Sb, Se, Sr, Th, Ti, Tl, U, V, Zn and Zr, in the blood and urine samples from the general population in Sanmen County of Zhejiang province, a typical coastal area of eastern China. METHODS: The 33 elements in 272 blood and 300 urine samples were determined by inductively coupled plasma-mass spectrometry (ICP-MS). The normality test of data was conducted using SPSS 17.0 Statistics. The data was compared with other reports. RESULTS: The normal reference values of the 33 elements in the blood and urine samples from the general population in Sanmen County were obtained, which of some elements were found to be similar with other reports, such as Co, Cu, Mn and Sr, while As, Cd, Hg and Pb were generally found to be higher than those previously reported. There was a wide variation between the reports from different countries in blood Ba. CONCLUSION: The normal reference values of the 33 elements in the blood and urine samples from the general population in Sanmen County are established, and successfully applied to two poisoning cases. PMID- 27501684 TI - [A Retrospective Analysis of 88 Solved Intentional Homicide Cases]. AB - OBJECTIVE: To summarize the key points, difficulties and relevant practical experiences for analyzing the scene of solved intentional homicide cases. METHODS: The data of 88 solved intentional homicide cases in a county from 2004 to 2013 were collected and the retrospective analysis was performed. RESULTS: The number of local female victims obviously higher than non-local female victims and the number of non-local suspects is obviously higher than local suspects. The number of Male suspects showed higher compared with the female. Most of them were temporary workers, unemployment or farmers with less education backgrounds. The main causes of victims' death were mechanical injury or asphyxia. The murders were acquaintances in most intentional homicide cases. The motive of the stranger murders was commonly money. The murder behavior types of homicide cases were related with people, money and sexual assault. Camouflage and guilty behavior showed the most significance. CONCLUSION: The accurate identification of suspects is one of the most important task in forensic investigation and reflects the importance of the criminal scene analysis for intentional homicide cases. It also provides the direction of future research. PMID- 27501685 TI - [Comparison of Different Pretreatment Methods for DNA Extraction from Teeth]. AB - OBJECTIVE: To compare the concentration of teeth DNA extracted by three different pretreatment methods and to explore a simple, economical and practical pretreatment method with high concentration of extracted DNA from teeth. METHODS: A total number of 21 molars were collected from 7 corpses. The pretreatment of 3 molars from each individual was randomly performed by tooth crumb method, ball milling method and liquid nitrogen milling method and 50 mg tooth crumb was weight and DNA was extracted by AutoMate Express forensic DNA extraction system. Subsequently, the concentration of DNA and corresponding STR genotyping of three methods were compared. RESULTS: The DNA concentration extracted by tooth crumb method, ball-milling method and liquid nitrogen milling method was 0.055 6-1.989 1 ng/MUL, 0.036 6-1.175 6 ng/MUL and 0.037 8-1.249 0 ng/MUL, respectively. The DNA concentration obtained by tooth crumb method was higher (P < 0.05) and the success rate of STR genotyping was high. CONCLUSION: Combined with AutoMate Express forensic DNA extraction system, tooth crumb method is an efficient and feasible method to extract DNA from teeth, which can be applied in forensic practice. PMID- 27501686 TI - [New Progress of MALDI-TOF-IMS in the Study of Proteomics]. AB - Matrix-assisted laser desorption/ionization time-of-flight imaging mass spectrometry (MALDI-TOF-IMS) has been a classical technique for studying proteomics in present and a tool for analyzing the distribution of proteins and small molecules within biological tissue sections. MALDI-TOF-IMS can analyze multiple unknown compounds in biological tissue sections simultaneously through a single measurement which can obtain molecule imaging of the tissue while maintaining the integrity of cellular and molecules in tissue. In recent years, imaging mass spectrometry technique develops relatively quickly in all biomedical domain. This paper based on the relevant data and reviews the present developing level of MALDI-TOF-IMS, the principle of imaging mass spectrometry, methology and the prospect in forensic pathology. PMID- 27501687 TI - [Research Progress of circRNA and Its Significance in Forensic Science]. AB - RNA has received more attention in the field of forensic medicine and the development of the new biological markers based on RNA shows great significance in the analysis of complex cases. circular RNA (circRNA) is a kind of non-coding RNA which is widely reported recently. Although the regulatory mechanisms of generation and expression are not fully clear, the existing research indicates that circRNA has important biological functions. CircRNA has a cell-type-specific expression with great stability and a high expression level, which makes it meaningful in forensic applications potentially. In this paper, the research progress, the generation and regulation of circRNA as well as its biological characteristics and functions are summarized, which will provide references for related studies and forensic applications. PMID- 27501688 TI - Development of a fast and low-cost qPCR assay for diagnosis of acute gas pharyngitis. AB - BACKGROUND: Group A streptococci (GAS) are the most common bacterial cause of acute pharyngitis and account for 15-30 % of cases of acute pharyngitis in children and 5-10 % of cases in adults. In this study, a real-time quantitative PCR (qPCR) based GAS detection assay in pharyngeal swab specimens was developed. METHODS: The qPCR assay was compared with the gold standard bacterial culture and a rapid antigen detection test (RADT) to evaluate its clinical performance in 687 patients. The analytical sensitivity of the assay was 240 cfu/swab. Forty-five different potential cross-reacting organisms did not react with the test. Four different laboratories for the reproducibility studies were in 100 % (60/60) agreement for the contrived GAS positive and negative swab samples. RESULTS: The relative sensitivities of the RADT and the qPCR test were 55.9 and 100 %; and the relative specificities were 100 and 96.3 %, respectively. Duration of the total assay for 24 samples including pre-analytical processing and analysis changed between 42 and 55 min depending on the type of qPCR instrument used. A simple DNA extraction method and a low qPCR volume made the developed assay an economical alternative for the GAS detection. CONCLUSION: We showed that the developed qPCR test is rapid, cheap, sensitive and specific and therefore can be used to replace both antigen detection and culture for diagnosis of acute GAS pharyngitis. PMID- 27501689 TI - Is psychometrics science? PMID- 27501690 TI - Construction of high-resolution genetic maps of Zoysia matrella (L.) Merrill and applications to comparative genomic analysis and QTL mapping of resistance to fall armyworm. AB - BACKGROUND: Zoysia matrella, widely used in lawns and sports fields, is of great economic and ecological value. Z. matrella is an allotetraploid species (2n = 4x = 40) in the genus zoysia under the subfamily Chloridoideae. Despite its ecological impacts and economic importance, the subfamily Chloridoideae has received little attention in genomics studies. As a result, limited genetic and genomic information are available for this subfamily, which have impeded progress in understanding evolutionary history of grasses in this important lineage. The lack of a high-resolution genetic map has hampered efforts to improve zoysiagrass using molecular genetic tools. RESULTS: We used restriction site-associated DNA sequencing (RADSeq) approach and a segregating population developed from the cross between Z. matrella cultivars 'Diamond' and 'Cavalier' to construct high resolution genetic maps of Z. matrella. The genetic map of Diamond consists of 2,375 Single Nucleotide Polymorphism (SNP) markers mapped on 20 linkage groups (LGs) with a total length of 1754.48 cM and an average distance between adjacent markers at 0.74 cM. The genetic map of Cavalier contains 3,563 SNP markers on 20 LGs, covering 1824.92 cM, with an average distance between adjacent markers at 0.51 cM. A higher level of genome collinearity between Z. matrella and rice than that between Z. matrella and sorghum was revealed by comparative genomic analysis. Pairwise comparison revealed that two independent nested chromosome fusion events occurred after Z. matrella and sorghum split from a common ancestor. The high-resolution linkage maps were applied into mapping QTLs associated with fall armyworm (FAW) resistance and six loci located on LGs 8 and 20 were detected to be significantly associated with FAW resistance. CONCLUSION: The high-resolution linkage maps provide anchor points for comparative genomics analysis between Z. matrella and other grass species. Our comparative genomic analysis suggested that the chromosome number reduction from 12 to 10 had occurred independently via a single-step in the subfamilies Chloridoideae and Panicoideae. The high-resolution genetic maps provide an essential framework for mapping QTLs associated with economically and agronomically important traits. The major QTLs mapped on LG8 of the Cavalier map provide a starting point for cloning FAW resistance genes and further studies for a better understanding of FAW resistance in zoysiagrass. PMID- 27501691 TI - Effects of procurement practices on quality of medical device or service received: a qualitative study comparing countries. AB - BACKGROUND: We know little about how procurement of a high-risk medical device (HRMD) affects clinical practice and outcomes. In health systems in high-income countries, and specifically those that maintain a national arthroplasty registry, procurement decisions are frequently guided by long-term clinical results, with the goal of ensuring at least standard quality of HRMDs. But in countries like Mexico, decision-making is often dominated by lowest acquisition price. We set out to study the impact of procurement for orthopaedic HRMDs on clinical procedures and outcomes. METHODS: We based our qualitative study on 59 in-depth interviews with stakeholders from Mexico, Switzerland, Germany, and UK: orthopaedic specialists, government officials, other experts, and social security system managers or administrators. We took a healthcare delivery approach to capturing and comparing factors that affected the regulations of HRMDs and procurement processes, and to understanding connections between procurement and clinical practice. RESULTS: Our findings demonstrate for procurement processes that the three European countries compared to Mexico don't have similar concerns with regards to their procurement processes. Deficiencies of procurement regulations and practices identified from representatives in Mexico were almost absent in European countries. We identified three areas of deficiency: 1) HRMD regulations based on insufficiently robust clinical evidence (mainly noted by European countries); 2) Follow-up on Health Technology Assessments is inadequate (noted by Mexico) and methodology not always good enough (noted by European countries); and, 3) Lowest-acquisition price often guides procurement decisions and thus may not align with needs of clinical procedures (noted by Mexico and some European countries). CONCLUSIONS: Procurement processes for orthopaedic HRMDs may have an impact on clinical procedures and outcomes. A favourable approach is one where orthopaedic specialists are parties to the procurement process, and post-market surveillance data informs decision-making. Actors in the procurement process can improve their impact on clinical procedures and outcomes by developing specific strategies that better align the needs of both, procurement and clinical procedures. PMID- 27501692 TI - Intravascular ultrasound for transcatheter paravalvular leak closure. AB - Transcatheter closure of paravalvular leaks requires precise assessment of the location, size, and shape of the defect. Transesophageal echocardiography plays an important role in this process. We encountered a case of a paravalvular leak at the aortic position after aortic and mitral valve replacement. It was impossible to detect the precise location of the paravalvular leak with transesophageal echocardiography because of an acoustic shadow from the mitral mechanical valve. Intraoperative use of intravascular ultrasound was useful for determining the morphology of the defect and evaluating the procedure during the operation. PMID- 27501693 TI - Surgical decision making for revascularization of chronically occluded right coronary artery. AB - OBJECTIVE: Chronic totally occluded right coronary artery (CTO-RCA) often poses a problem in decision making for/against bypass grafting due to the lack of standardized indication criteria. The aim of the study was to investigate whether qualitative angiograms can be useful in decision making for/against surgical revascularization of CTO-RCA. METHODS: A retrospective cohort study was conducted with 69 patients who underwent elective CABG procedure, including single graft to the RCA. The distal run-off of the bypassed RCA was measured intraoperatively using the ultrasonic transit-time method. As a primary endpoint of the study, the flow values were analysed in regard to diameter of the recipient artery. As a secondary endpoint, the correlations between the regional and global LV function, Rentrop grading, type of collateral pathway, number of donor sources, comorbidity, and the graft flow and the diameter of the recipient artery were investigated using uni- and multi-variate regression analyses. RESULTS: In general, the flow values correlated significantly with the diameter of the recipient artery. Significantly lower flow (p < 0.0001) and diameter values (p < 0.05) were found in hypo/akinetic and infarcted area reflecting functionality of the CTO-RCA territory. CONCLUSIONS: The qualitative angiograms combined with regional wall motion studies can be useful in decision making for revascularization of CTO-RCA. Revascularization of akinetic/infarcted CTO-RCA territory is associated with lower graft flows even in patients presented with high Rentrop class and high degree of collaterality, suggesting necessity of viability tests prior to bypass surgery. PMID- 27501696 TI - Clinical severity in forecasting platelet to lymphocyte ratio in Crimean-Congo hemorrhagic fever patients. AB - Crimean-Congo hemorrhagic fever (CCHF) is a life-threatening disease that develops as a result of infection by a member of the Nairovirus genus of the Bunyaviridae family, and its initial symptoms are not specific. In patients with severe clinical progression, in particular, the neutrophil rate is high, whereas lymphocyte and monocyte levels are low. A total of 149 patients, in whom the diagnosis was confirmed with reverse transcriptase PCR, were included in the study. In order to compare patient clinical progression severity, we divided the patients into two groups. For group 1, Cevik's severity score was used. The patients who had a platelet/lymphocyte ratio (PLR) <41 constituted group 2. Of 149 patients, 20 (13.4 %) were determined as group 1 (Cevik's classification) and 38 (25.5 %) were determined as group 2 (PLR <41). Of 11 deaths, 4 (36.4 %) patients were from group 1 and 7 (63.6 %) were from group 2. This is the first study to our knowledge to analyse the relationship between severity and PLR in patients with CCHF. PLR is a simple laboratory test that can aid in determining the prognosis of individuals with this disease. PMID- 27501695 TI - Development of an annually updated Japanese national clinical database for chest surgery in 2014. AB - OBJECTIVES: A national clinical database (NCD) adopted an "Internet-based collection" in 2011. An NCD specializing in chest surgery was launched based on the NCD system in 2014. The system was linked to the board certification as the second level in the hierarchy of the specialty of chest surgery and accreditation of educational institutions for chest surgery. Here, we report the status of the NCD for chest surgery in 2014 and clarified its registration rate and its accuracy. METHODS: Chest surgeries undertaken in Japan since January 1st, 2014 until the end of the same year were registered through an Internet-based system until April 8th, 2015. The registration rate was compared with the annual survey conducted by the Japanese Association for Thoracic Surgery (JATS) from 2011 to 2014. The rate of accurate inputting was measured by an Internet-based audit in reference to 563 anonymous operative notes of patients presented by 106 chest surgeons at the time of renewal for board certification for chest surgery. RESULTS: A total of 88,112 chest-surgical procedures were registered from 1000 chest surgery units (CSUs). Distribution of procedures by thoracic disease was almost identical to that of the annual survey conducted by JATS. However, the NCD had 4260 more registered procedures compared with the annual survey. The Internet based audit showed that inter-rater agreement between Internet-based data and operative notes in any item was >94 %. CONCLUSIONS: The NCD system can sustainably provide important and up-to-date information relating to preoperative status, oncology, and best practice for chest surgery in Japan. PMID- 27501694 TI - Optimal temperature management in aortic arch operations. AB - Hypothermic circulatory arrest is a critical component of aortic arch procedures, without which these operations could not be safely performed. Despite the use of hypothermia as a protective adjunct for organ preservation, aortic arch surgery remains complex and is associated with numerous complications despite years of surgical advancement. Deep hypothermic circulatory arrest affords the surgeon a safe period of time to perform the arch reconstruction, but this interruption of perfusion comes at a high clinical cost: stroke, paraplegia, and organ dysfunction are all potential-associated complications. Retrograde cerebral perfusion was subsequently developed as a technique to improve upon the rates of neurologic dysfunction, but was done with only modest success. Selective antegrade cerebral perfusion, on the other hand, has consistently been shown to be an effective form of cerebral protection over deep hypothermia alone, even during extended periods of circulatory arrest. A primary disadvantage of using deep hypothermic circulatory arrest is the prolonged bypass times required for cooling and rewarming which adds significantly to the morbidity associated with these procedures, especially coagulopathic bleeding and organ dysfunction. In an effort to mitigate this problem, the degree of hypothermia at the time of the initial circulatory arrest has more recently been reduced in multiple centers across the globe. This technique of moderate hypothermic circulatory arrest in combination with adjunctive brain perfusion techniques has been shown to be safe when performing aortic arch operations. In this review, we will discuss the evolution of these protection strategies as well as their relative strengths and weaknesses. PMID- 27501697 TI - Validation of T1 and T2 algorithms for quantitative MRI: performance by a vendor independent software. AB - BACKGROUND: Determination of the relaxation time constants T1 and T2 with quantitative magnetic resonance imaging is increasingly used for both research and clinical practice. Recently, groups have been formed within the Society of Cardiovascular Magnetic Resonance to address issues with relaxometry. However, so far they have avoided specific recommendations on methodology due to lack of consensus and current evolving research. Standardised widely available software may simplify this process. The purpose of the current study was to develop and validate vendor-independent T1 and T2 mapping modules and implement those in the versatile and widespread software Segment, freely available for research and FDA approved for clinical applications. RESULTS: The T1 and T2 mapping modules were developed and validated in phantoms at 1.5 T and 3 T with reference standard values calculated from reference pulse sequences using the Nelder-Mead Simplex optimisation method. The proposed modules support current commonly available MRI pulse sequences and both 2- and 3-parameter curve fitting. Images acquired in patients using three major vendors showed vendor-independence. Bias and variability showed high agreement with T1 and T2 reference standards for T1 (range 214-1752 ms) and T2 (range 45-338 ms), respectively. CONCLUSIONS: The developed and validated T1 and T2 mapping and quantification modules generated relaxation maps from current commonly used MRI sequences and multiple signal models. Patient applications showed usability for three major vendors. PMID- 27501698 TI - A Prospective Examination of the Relations Between Emotional Abuse and Anxiety: Moderation by Distress Tolerance. AB - Anxiety, the most common and impairing psychological problem experienced by youth, is associated with numerous individual and environmental factors. Two such factors include childhood emotional abuse (CEA) and low distress tolerance (DT). The current study aimed to understand how CEA and low DT impacted anxiety symptoms measured annually across 5 years among a community sample of youth. We hypothesized DT would moderate the relationship between CEA and anxiety, such that youth with higher levels of CEA and lower levels of DT would have elevated anxiety over time. Community youth (N = 244) were annually assessed across 5 years using the Revised Child Anxiety and Depression Scale, Childhood Trauma Questionnaire, and Behavioral Indicator of Resiliency to Distress. Higher CEA at baseline was associated with higher anxiety at baseline, higher anxiety at each annual assessment, and with greater overall decreases in anxiety over time. Lower DT was associated with higher anxiety at baseline, but did not predict changes in anxiety over time. Baseline DT significantly moderated the relationship between baseline CEA and anxiety, such that youth with both higher CEA and lower DT had the highest anxiety at each annual assessment. Youth with lower DT and higher CEA scores had the highest level of anxiety symptoms across time. PMID- 27501699 TI - A unique method for estimating the reliability learning curve of optic nerve sheath diameter ultrasound measurement. AB - BACKGROUND: Optic nerve sheath diameter (ONSD) measurement using ultrasound has been proposed as a rapid, non-invasive, point of care technique to estimate intra cranial pressure (ICP). Ultrasonic measurement of the optic nerve sheath can be quite challenging and there is limited literature surrounding learning curves for this technique. We attempted to develop a method to estimate the reliability learning curve for ONSD measurement utilizing a unique definition of reliability: a plateau in within-subject variability with unchanged between-subject variability. METHODS: As part of a previously published study, a single operator measured the ONSD in 120 healthy volunteers over a 6-month period. Utilizing the assumption that the four measurements made on each subject during this study should be equal, the relationship of within-subject variance was described using a quadratic-plateau model as assessed by segmental polynomial (knot) regression. RESULTS: Segmental polynomial (knot) regression revealed a plateau in within subject variance after the 21st subject. However, there was no difference in overall mean values [3.69 vs 3.68 mm (p = 0.884)] or between-subject variance [14.49 vs 11.92 (p = 0.54)] above or below this cutoff. CONCLUSIONS: This study suggests a significant finite learning curve associated with ONSD measurements. It also offers a unique method of calculating the learning curve associated with ONSD measurement. PMID- 27501700 TI - Lung ultrasound in internal medicine: training and clinical practice. AB - BACKGROUND: Lung ultrasound (LUS) represents an emerging technique for bedside chest imaging in different clinical settings. A standardized approach allows the diagnosis, the quantification, and the follow-up of different conditions for which acute respiratory failure is the main clinical presentation. The aim of this study was to test what skill targets could be achieved in LUS, with a short training course offered to 19 Medical Doctors attending the certification board school in Internal Medicine at the University of Verona, Italy. METHODS: The training course (theoretical and practical) consisted of 9 h subdivided in 4 days. Each trainee examined three healthy volunteers during the first day that was also the day of the theoretical lessons. Moreover, they examined nine patients per day (a total of 27 patients). Trainees were tested in the recognition of the basic signs in LUS, the managing of the Bedside Lung Ultrasound Evaluation (the BLUE protocol), and the recognition of the broad clinical scenarios recognized by the LUS. Kappa statistic was used to calculate the inter-observer agreement (trainees/tutor). RESULTS: Twenty-seven patients were examined by the 19 trainees (ten trainees had previous limited experience in general ultrasound). The agreement among the trainees and the tutor in the recognition of the LUS basic signs and in the recognition of the BLUE protocol profiles ranged from "fair" to "excellent". In particular, the agreement among the trainees and the tutor in the final LUS diagnosis was "excellent" for the recognition of the interstitial syndrome and the pleural effusion, "substantial" for the recognition of the normal lung, and "moderate" for the recognition of consolidation and pneumothorax. LUS outcome gave useful information and drove change in therapy in 16 patients. It affected immediate management in nine patients. The concordance between the previous X chest ray and LUS was observed in 21 patients. CONCLUSIONS: A short training in LUS provided good proficiency in the recognition only of the main signs of the BLUE protocol, but allowed a correct LUS diagnosis in the Internal Medicine most frequent clinical settings of acute respiratory failure. This study supports incorporating LUS into Internal Medicine fellowship training programs. PMID- 27501701 TI - Orthogeriatric co-management improves the outcome of long-term care residents with fragility fractures. AB - BACKGROUND: Fragility fractures are a major health care problem worldwide. Both hip and non-hip fractures are associated with excess mortality in the years following the fracture. Residents of long-term nursing homes represent a special high-risk group for poor outcomes. Orthogeriatric co-management models of care have shown in multiple studies to have medical as well as economic advantages, but their impact on this high-risk group has not been well studied. OBJECTIVE: We studied the outcome of long-term care residents with hip and non-hip fractures admitted to a geriatric fracture center. METHODS: The study design is a single center, prospective cohort study at a level-I trauma center in Austria running a geriatric fracture center. The cohort included all fragility fracture patients aged over 70 admitted from a long-term care residence from May 2009 to November 2011. The data set consisted of 265 patients; the mean age was 86.8 +/- 6.7 years, and 80 % were female. The mean follow-up after the index fracture was 789 days, with a range from 1 to 1842 days. Basic clinical and demographic data were collected at hospital admission. Functional status and mobility were assessed during follow-up at 3, 6, and 12 months. Additional outcome data regarding readmissions for new fractures were obtained from the hospital information database; mortality was crosschecked with the death registry from the governmental institute of epidemiology. RESULTS: 187 (70.6 %) patients died during the follow-up period, with 78 patients (29.4 %) dying in the first year. The mean life expectancy after the index fracture was 527 (+/-431) days. Differences in mortality rates between hip and non-hip fracture patients were not statistically significant. Compared to reported mortality rates in the literature, hip fracture patients in this orthogeriatric-comanaged cohort had a significantly reduced one-year mortality [OR of 0.57 (95 % CI 0.31-0.85)]. After adjustment for confounders, only older age (OR 1.091; p = 0.013; CI 1.019-1.169) and a lower Parker Mobility Scale (PMS) (OR 0.737; p = 0.022; CI 0.568-0.957) remained as independent predictors. During follow-up, 62 patients (23.4 %) sustained at least one subsequent fracture, and 10 patients (3.4 %) experienced multiple fractures; 29 patients (10.9 %) experienced an additional fracture within the first year. Nearly, half (47.1 %) regained their pre-fracture mobility based on the PMS. CONCLUSION: Despite the generally poor outcomes for fragility fracture patients residing in long-term care facilities, orthogeriatric co management appears to improve the outcome of high-risk fragility fracture patients. One-year mortality was 29.4 % in this cohort, significantly lower than in comparable trials. Orthogeriatric co-management may also have positive impacts on both functional outcome and the risk of subsequent fractures. PMID- 27501702 TI - Better satisfaction of patients operated on anterior cruciate ligament reconstruction in outpatient setting. A prospective comparative monocentric study of 60 cases. AB - INTRODUCTION: The purpose of this study was to compare satisfaction, clinical scores, and complications of patients operated on anterior cruciate ligament reconstruction (ACLR) in outpatient setting compared to patients operated in the conventional hospitalization. PATIENTS AND METHODS: This prospective non randomized study compared 30 patients (mean age 31 +/- 9 years) operated on outpatient setting for an isolated ACLR matched 1:1 according to age, gender, body mass index, delay to surgery, and preoperative clinical score (IKDC) to 30 patients operated for an ACLR in our conventional hospitalization department during the same period. All the patients were operated on by the same surgeon. The same technique of anterior cruciate ligament reconstruction with using four bundles semitendinosus and cage fixation was used. The same anaesthesiologic protocol and perioperative cares were used in all patients. Patients' satisfaction was assed using five questions about the course of surgery and hospitalization and a four-level satisfaction questionnaire (excellent, good, fair, and poor). Clinical scores (IKDC and KOOS) were compared preoperatively and at 1 year. Readmission within 30 day and complications at 1 year were compared in both groups. RESULTS: Satisfaction was significantly better in the group of day case surgery and more patients of the group day-case surgery recommended this modality of treatment (29 against 24; p = 0.04). The IKDC score improved in the two groups (day-case group from 64 +/- 17 to 86 +/- 7; p < 0.001; conventional hospitalization from 60 +/- 21 to 85 +/- 10; p < 0.001), but no significant difference between two groups was found at 1 year (p = 0.86). No readmission was necessary in the two groups, but two revisions were needed in the group of the conventional hospitalization. CONCLUSIONS: Results of our study showed that patients operated on day-case surgery for an isolated ACLR presented a higher rate of satisfaction compared to patients operated in the conventional hospitalization with comparable clinical results at 1 year. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 27501703 TI - Significant differences in femoral torsion values depending on the CT measurement technique. AB - INTRODUCTION: This study compared the feasibility of six different CT-based measurement techniques for establishing an indication for derotational osteotomy in the cases of patellar instability or femoral fracture. MATERIALS AND METHODS: CT scans of 52 single human cadaver femora were measured using six different torsion measurement techniques (described by Waidelich, Murphy, and Yoshioka on transverse images and Hernandez, Jarrett, and Yoshioka on oblique images). All measurements were performed by four observers twice to assess intraobserver and interobserver agreement. The intraclass correlation coefficient (ICC), ANOVA, and Bonferroni post hoc test were used for the statistical analysis. RESULTS: Significant differences (P < 0.001) between the values for femoral torsion were observed with all techniques except Yoshioka's techniques on transverse and oblique slices (P = 1.000) (transverse images: Waidelich 22.4 degrees +/- 6.8 degrees , Murphy 17.5 degrees +/- 7.0 degrees , Yoshioka 13.4 degrees +/- 6.9 degrees ; oblique images: Hernandez 11.4 degrees +/- 7.4 degrees , Jarrett 14.9 degrees +/- 7.5 degrees , Yoshioka oblique 13.4 degrees +/- 7.1 degrees ). Intraobserver and interobserver agreement showed a high level of reproducibility (ICC 0.877-0.986; mean 0.8 degrees -2.9 degrees ) for all techniques, with the greatest difference being observed with Hernandez's technique (11.4 degrees /10 degrees ). CONCLUSIONS: Femoral torsion values depend on the measurement technique. When derotational osteotomy is being considered, it is essential to use different threshold values depending on the measurement technique. PMID- 27501704 TI - Management of shoulder instability: the current state of treatment among German orthopaedic surgeons. AB - INTRODUCTION: The aim of this study was to evaluate the current state of treatment in traumatic anterior shoulder dislocation in Germany and to detect changes over the last 12 years. METHODS: Seven hundred ninety-six trauma and/or orthopaedic departments were found in the German hospital directory 2012. The websites of each department were searched for the email address of the responsible shoulder surgeon (if applicable) or the head of the department. Seven hundred forty-six email addresses were found, and emails with the request to participate in an online survey were sent in January 2013. Six hundred seventy five emails probably reached the correct addressee. Seventy-one emails were rejected, and no contact could be made. One-hundred ninety-one (28 %) participated in the study. The data were compared to similar data from a survey on shoulder dislocation performed in the same department and published in 2001. RESULTS: After the first-time traumatic shoulder dislocation in patients aged younger than 30 years participating in sports, 14 % of the participants would prefer conservative treatment, 83 % arthroscopic, and 3 % open surgery. When surgery was indicated, arthroscopic Bankart repair was the treatment of choice for 93 % of the participants. In 2001, 27 % had indicated conservative treatment after the first-time shoulder dislocation in active patients younger than 30 years. When surgery was indicated, 66 % had performed arthroscopic and 34 % open stabilization. For the standard arthroscopic Bankart repair without concomitant injuries, 41 % of the participants use two and 54 % three suture anchors. Knotless anchors were preferred by 72 %. In the case of glenoid bone loss greater than 25 %, only 46 % perform a procedure for glenoid bone augmentation. Fifteen percent of the participants always recommended immobilization in external rotation after traumatic first-time shoulder dislocation. CONCLUSIONS: The majority of participants recommend arthroscopic Bankart repair with two or three suture anchors in young persons with the first-time dislocations. Compared to 2001 less recommend conservative treatment, complex "open" surgical procedures are no longer used. The knowledge that a Bankart procedure likely fails in significant glenoid bone loss is not implemented in the clinical practice. Thus, there is a need to educate surgeons on this topic. PMID- 27501705 TI - One-year development of QOL following orthopaedic polytrauma: a prospective observational cohort study of 53 patients. AB - INTRODUCTION: Most studies of polytrauma examined highly mixed patient groups. The objective of the present study was to report the development of patient reported quality of life (QOL), in a patient group with musculoskeletal polytrauma, excluding patients with major thoracic, abdominal, and brain injuries. MATERIALS AND METHODS: The study design was a 1-year cohort follow-up study. Recordings of injury severity were measured with the ISS and NISS. Patient reported QOL was measured with the questionnaires Eq5d-5L and SF-36 and compared to age-matched reference populations. Moreover, patients return to work status was measured. Data were collected prospectively at discharge, 3, 6, and 12 months. RESULTS: 53 patients were included. The mean age was 42.3 years, ranging from 17 to 78 years. Twelve months after trauma admission, the mean Eq5d-5L index was 0.601 (95 % CI 0.546-0.657). A progressive increasing Eq5d-5L index and SF-36 PCS was observed between the discharge and the 12-month follow-up (p < 0.001). The development in QOL from 6 to 12 months almost shows identically scores. Throughout the study period, patients reported significant worse QOL compared with the established reference population. 32 % of patients have resumed earlier employment status at 1-year follow-up. CONCLUSIONS: Throughout the 12-month observational period, patients reported worse QOL compared to the age-matched reference population. The development of QOL from 6- to 12-month time points almost showed identically scores with only little improvement. At the end of 1 year follow-up, 32 % of patients had resumed prior employment status. PMID- 27501706 TI - Effect of Laminin on Neurotrophic Factors Expression in Schwann-Like Cells Induced from Human Adipose-Derived Stem Cells In Vitro. AB - The Schwann-like cells can be considered as promising in stem cell therapies, at least in experimental models. Human adipose-derived stem cells (ADSCs) are induced into Schwann-like cells (SC-like cells) and are cultured on either a plastic surface or laminin-coated plates. The findings here reveal that laminin is a critical component in extracellular matrix (ECM) of SC-like cells at in vitro. The survival rate of SC-like cells on a laminin matrix are measured through MTT assay and it is found that this rate is significantly higher than that of the cells grown on a plastic surface (P < 0.05). Schwann cell markers and the myelinogenic ability of SC-like cells at the presence versus absence of laminin are assessed through immunocytochemistry. The analysis of GFAP/S100beta and S100beta/MBP markers indicate that laminin can increase the differentiated rate and myelinogenic potential of SC-like cells. The expression levels of SCs markers, myelin basic proteins (MBP), and neurotrophic factors in two conditions are analyzed by real-time reverse transcription polymerase chain reaction (RT PCR). The findings here demonstrated that gene expression of SCs markers, MBP, and brain-derived neurotrophic factors (BDNF) increase significantly on laminin compared to plastic surface (P < 0.01). In contrast, the nerve growth factor (NGF) expression is downregulated significantly on laminin-coated plates (P < 0.05). The obtained data suggest that production of neurotrophic factors in SC like cell in presence of laminin can induce appropriate microenvironment for nerve repair in neurodegenerative diseases. PMID- 27501707 TI - Dihydromyricetin Ameliorates 3NP-induced Behavioral Deficits and Striatal Injury in Rats. AB - Oxidative stress is closely involved in neurodegenerative diseases. The present study aimed to examine the effect of anti-oxidant DHM (dihydromyricetin) on 3NP (3-nitropropionic acid) -induced behavioral deficits of experimental rats and striatal histopathological injury by using behavioral, imaging, biochemistry, histochemistry and molecular biology technologies. The experimental results showed that both motor dysfunctions and learning and memory impairments induced by 3NP were significantly reduced after DHM treatment. 3NP-induced striatal metabolic abnormality was also remarkably improved by DHM treatment, showed as the increased glucose metabolism in PET/CT scan, decreased MDA (malondialdehyde) and increased SOD (superoxide dismutase) activity in enzyme histochemical staining. In addition, the cell apoptosis was evidently detected in the striatum of the 3NP group, while in the 3NP + DHM group, the number of apoptotic cells was remarkably reduced. 3NP treatment obviously induced down-regulation of Bcl-2, and up-regulations of Bax and Cleaved Caspase-3, while these changes were significantly reversed by DHM treatment. The present results suggested that DHM showed its protective effect by anti-oxidant and anti-apoptosis mechanisms. PMID- 27501708 TI - Nipple Preservation in Breast Cancer Associated with Nipple Discharge. AB - BACKGROUND: Breast carcinoma presented with nipple discharge is a rare condition. There is theoretical concern about preserving nipple in these patients since the risk of nipple-areolar complex involvement may be greater, but not many studies in the literature have addressed on this issue. The aim of the current study was to determine the incidence and outcome of nipple preservation in breast cancer associated with nipple discharge. METHODS: Medical records of patients who were diagnosed to have breast carcinoma and presented with nipple discharge from May 2009 to October 2014 were retrospectively reviewed. RESULTS: Sixty patients presented with nipple discharge were diagnosed with breast cancer, which represent 3.8 % of all patients who underwent breast cancer surgery in our unit during the study period. Forty-six patients (76.7 %) had nipple discharge as their only symptom, while the rest also presented with breast mass clinically or radiologically. All patients had mammogram and ultrasound performed, and 53.3 and 63.3 % respectively showed suspicious findings. Forty-one out of 46 (89.1 %) nipple discharge cytology were inadequate or benign. Thirty-two microdochectomy were performed. Routine frozen section was utilized intra-operatively to ensure clear margins. The most common histology was ductal carcinoma in situ (DCIS) (n = 29, 48.3 %), followed by DCIS with invasive ductal carcinoma (n = 23, 38.3 %). Regarding treatment, 26 patients (43.3 %) had nipple preserved, including 21 breast conservative surgery and five nipple-sparing mastectomies. Overall, no local or systemic recurrence was observed at a median follow-up of 27 months. Ten out of 34 (29.4 %) mastectomy specimens showed NAC involvement on pathology. By comparing patients with NAC preserved to patients with NAC removed, no significant preoperative predictors were identified. CONCLUSION: Breast carcinoma patients who present with nipple discharge usually have early-stage cancer. Presence of nipple discharge is not equivalent to NAC involvement. Nipple preservation can be oncologically safe if negative margins are ascertained. PMID- 27501709 TI - The Role of Troponin in Blunt Cardiac Injury After Multiple Trauma in Humans. AB - BACKGROUND: The incidence of cardiac injury in immediate fatalities after blunt trauma remains underestimated, and reliable diagnostic strategies are still missing. Furthermore, clinical data concerning heart-specific troponin serum levels, injury severity score (ISS), catecholamine treatment and survival of patients on admission to the hospital have rarely been interrelated so far. Therefore, the object of the present study was to identify predictive parameters for mortality in the context of blunt cardiac injury. METHODS: This retrospective observational study included 173 severely injured patients with an ISS >=25 admitted to the University Hospital of Ulm, a level 1 trauma center, during 2009 2013 . Furthermore, 83 blunt trauma victims who died before hospital admission were subjected to postmortem examination at the Institute of Legal Medicine, University of Ulm, during 2009-2014. ISS, cardiac injury and associated thoracic injuries were determined in both groups. Furthermore, in the hospitalized patients, serum troponin and IL-6 levels were measured. RESULTS: Macroscopic heart injury was observed in 18 % of the patients who died at the scene and only in 1 % of the patients admitted to the hospital, indicating that macroscopic heart injury is associated with an immediate life-threatening condition. Troponin levels were elevated in 43 % of the patients after admission to the hospital. Moreover, troponin serum concentrations were significantly higher in patients treated with norepinephrine (26.4 +/- 4 ng/l) and in non-survivors (84.9 +/- 22.8 ng/l) compared to patients without catecholamines and survivors, respectively. CONCLUSIONS: Macroscopic heart injury was 20 times more frequent in non-survivors than in survivors. Serum troponin levels correlated with mortality after multiple injury and therefore may represent a valuable prognostic marker in trauma patients. PMID- 27501710 TI - Pancreatic Duct Holder and Mucosa Squeeze-out Technique for Duct-to-Mucosa Pancreatojejunostomy After Pancreatoduodenectomy: Propensity Score Matching Analysis. AB - BACKGROUND: Duct-to-mucosa pancreatojejunostomy after pancreatoduodenectomy can be technically difficult, particularly in cases with a non-dilated pancreatic duct. We devised a novel procedure employing a pancreatic duct holder and mucosa squeeze-out technique facilitating duct-to-mucosa anastomosis. We compared the perioperative outcomes of pancreatoduodenectomy with duct-to-mucosa pancreatojejunostomy between the novel and conventional procedures. METHODS: Our pancreatic holder has a cone-shaped tip with a slit. The holder can expand the pancreatic duct and provides a good surgical field for anastomosis. A small incision for anastomosis is made on the jejunum, while the jejunum is grasped around the incision. Then, the jejunal mucosa becomes squeezed-out and everted. This mucosa squeeze-out technique facilitates suturing the full thickness of the jejunum. Propensity score matching yielded 113 cases each undergoing the novel and the conventional procedure, among 308 cases receiving pancreatoduodenectomy with duct-to-mucosa pancreatojejunostomy. RESULTS: The overall morbidity rate was significantly lower in the novel procedure group. The pancreatic fistula (ISGPF grade B/C) rate was significantly lower in the novel (5 %) than in the conventional (13 %) procedure group. For cases with a non-dilated pancreatic duct (<=3 mm), the rate was significantly lower in the novel (10 %) than in the conventional procedure group (24 %). Multivariate analysis identified a non dilated pancreatic duct, soft pancreas, and the conventional procedure as factors independently predicting the complication of pancreatic fistula formation. CONCLUSIONS: Our novel procedure facilitates duct-to-mucosa pancreatojejunostomy and decreases the pancreatic fistula rate. This procedure is simple, rational, and useful for achieving anastomosis, particularly in cases with a non-dilated pancreatic duct. PMID- 27501711 TI - [Dermatoscopy without a dermatoscope]. PMID- 27501712 TI - [Maculonodular lesion on the back of a 66-year-old man]. PMID- 27501713 TI - Review: Therapeutic Targeting of HMGB1 in Stroke. AB - High mobility group box-1 (HMGB1) is a nuclear protein that is expressed in almost all eukaryotic cells. In the nucleus, it maintains nuclear homeostasis and promotes gene transcription. HMGB1 can be passively released into the extracellular milieu after cell necrosis or actively secreted by activated immune cells. HMGB1 has several receptors such as Toll-like receptor 2, Toll-like receptor 4, and the receptor for advanced glycation end products. After brain injury, HMGB1 is released early from neural cells and contributes to the initial stages of the inflammatory response. However, surprisingly, HMGB1 can mediate beneficial effects during the course of stroke recovery. The biphasic biological property of extracellular HMGB1 may be related to the redox modifications of its cysteine residues. This review discusses the emerging roles of HMGB1 in several stroke models, as well as its potential role as a therapeutic target for stroke patients. PMID- 27501714 TI - Water-soluble Complex of Curcumin with Cyclodextrins: Enhanced Physical Properties For Ocular Drug Delivery. AB - BACKGROUND: Curcumin, a natural hydrophobic polyphenol, has been reported to have diverse pharmacological activities. Previous studies have evaluated its efficacy using both oral and transdermal dosage forms. However, two major obstacles-poor aqueous solubility and low stability-severely limited its pharmaceutical use. OBJECTIVE: The main objective of this study was to prepare curcumin eye drops that provided sustained release to allow for once daily application in retinitis pigmentosa. METHOD: To achieve our goal, curcumin was complexed with beta cyclodextrin and hydroxypropyl-beta- cyclodextrin in two molar ratios (1:1 and 1:2) using co-solvent, co-solvent with sonication and freezedrying filtration methods. A total of 12 complexes were prepared, then characterized using differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, solubility assessment and in vitro release studies. RESULTS: An improvement in curcumin aqueous solubility relative to pure curcumin was achieved for all 12 complexes. However, the freeze drying filtration method was superior to all other methods because it produced highly water-soluble drug-CD complexes. Based on our stability analyses, pH 6.8 phosphate buffer containing 1% Tween 80 was selected as the release medium for in vitro release studies because curcumin exhibited high stability in this medium. Our F11 formulation provided sustained release of the drug for more than 96 h with a maximum amount released of drug (21.77+/-0.26 MUg/ml). Our in vitro release data also showed that release of drug from curcumin-CDs inclusion complexes followed a Higuchi non-Fickian diffusion mechanism. CONCLUSION: Based on these results, F11 was formulated as eye drops, which provide a promising once daily novel topical delivery of this naturally derived phytochemical. PMID- 27501715 TI - Novel Drug Delivery System for Dermal Uptake of Etofenamate: Semisolid SLN Dispersion. AB - BACKGROUND: Semisolid SLNs are novel strategy for dermal drug administration instead of incorporating the SLN dispersions into conventional semisolids. Etofenamate loaded semisolid SLNs were successfully prepared and in vitro characterization of formulations were performed in our previous study. The present study is an attempt to evaluate the dermal behavior of the semisolid SLNs selected on the basis of previous research and investigate the properties in terms of the convenience for topical applications. OBJECTIVE: The objective of this study is to evaluate the skin penetration characteristics of semisolid SLN formulations. The occlusive and mechanical properties of semisolid SLNs were also evaluated because of their impression on the dermal behavior of the formulations. METHOD: The occlusive properties were investigated by in vitro occlusion test. Texture analysis was performed to define the hardness, compressibility, adhesiveness, cohesiveness and elasticity of the formulations. Rat skin was chosen to evaluate the ex vivo penetration of etofenamate loaded semisolid SLNs and commercial gel product. Coumarin-6 was used to visualize the dermal distribution of the semisolid SLN formulations. For monitorizing the penetration of coumarin-6 into the skin samples Confocal Laser Scanning Microscopy was employed. RESULTS: The occlusive and mechanical properties of C1 coded semisolid SLN formulation were found more favorable in comparison with P1. The cumulative etofenamate amount in skin samples was found to be 39.88 +/- 1.50 MUg/cm2 for C1 and 30.56 +/- 2.10 MUg/cm2 for P1 coded formulations. According to CLSM images, greater fluorescence intensities and deeper skin penetrations were obtained with both of the semisolid SLNs in comparison to plain Carbopol gel. CONCLUSION: It can be concluded that the semisolid SLNs are promising alternative dermal drug delivery systems to the conventional dosage forms. PMID- 27501716 TI - Drug Delivery From Hydrogels: A General Framework for the Release Modeling. AB - The controlled delivery of drugs, including siRNAs, can be effectively obtained using Hydrogel- Based Drugs Delivery Systems (HB-DDSs). Successful design of HB DDSs requires the knowledge of the mechanisms that influence drug release. The modeling of the physical phenomena involved could help in the development and optimization of HB-DDS, sensibly reducing the time and costs required by a trial and-error procedures. The modeling is rather complex because of the presence of several, synergistic and competing, transport phenomena. In this work a general framework useful for modeling the HB-DDS has been derived and it is proposed, coupling and homogenizing the literature models. It is shown that all of them can be traced back to two different approaches: multiphasic models and multicomponent mixture models. In the first one the hydrogel is seen as constituted by different phases, the behavior of each one being described by their own mass and momentum conservation equations. In the second approach, the hydrogel is considered as made of one phase composed by several components. PMID- 27501717 TI - Current Therapeutic Drugs Against Cerebral Vasospasm after Subarachnoid Hemorrhage: A Comprehensive Review of Basic and Clinical Studies. AB - BACKGROUND: Cerebral vasospasm (CVS) is well known as a major complication in subarachnoid hemorrhage (SAH) patients, and research has long been focused on improving morbidity and mortality. As CVS commonly develops from day 4 to day 14 after SAH onset, SAH patients require therapies with drugs for preventing CVS after surgical treatment for the source of hemorrhage, mostly ruptured intracranial aneurysms. It is thought that the pathogenesis of CVS is initiated by prolonged smooth muscle contraction, and the subsequent hypoperfusion and cytotoxic responses induce cerebral ischemia. Although therapeutic investigations have historically focused on morphological improvement, the improvement of outcome is limited by the reversal of arterial narrowing. Therefore, it might be important to look back at evidence from long-lasting studies of CVS and to determine a highroad to effective drugs, including combination therapy. OBJECTIVE: In this review, we introduce current candidate beneficial drugs against CVS in clinical SAH, including nimodipine and other Ca2+ channel antagonists, magnesium sulfate, clazosentan, statins, cilostazol, eicosapentaenoic acid, fasudil hydrochloride, milrinone, and edaravone, all of which have been frequently studied in recent years. PMID- 27501718 TI - A draft genome of the brown alga, Cladosiphon okamuranus, S-strain: a platform for future studies of 'mozuku' biology. AB - The brown alga, Cladosiphon okamuranus (Okinawa mozuku), is economically one of the most important edible seaweeds, and is cultivated for market primarily in Okinawa, Japan. C. okamuranus constitutes a significant source of fucoidan, which has various physiological and biological activities. To facilitate studies of seaweed biology, we decoded the draft genome of C. okamuranus S-strain. The genome size of C. okamuranus was estimated as ~140 Mbp, smaller than genomes of two other brown algae, Ectocarpus siliculosus and Saccharina japonica Sequencing with ~100* coverage yielded an assembly of 541 scaffolds with N50 = 416 kbp. Together with transcriptomic data, we estimated that the C. okamuranus genome contains 13,640 protein-coding genes, approximately 94% of which have been confirmed with corresponding mRNAs. Comparisons with the E. siliculosus genome identified a set of C. okamuranus genes that encode enzymes involved in biosynthetic pathways for sulfated fucans and alginate biosynthesis. In addition, we identified C. okamuranus genes for enzymes involved in phlorotannin biosynthesis. The present decoding of the Cladosiphon okamuranus genome provides a platform for future studies of mozuku biology. PMID- 27501720 TI - Caregiver characteristics and bereavement needs: Findings from a population study. AB - BACKGROUND: Globally, most care for people with life-limiting illnesses is provided by informal caregivers. Identifying characteristics of caregivers that may have unmet needs and negative outcomes can help provide better support to facilitate adjustment. AIM: We compared characteristics, expressed unmet needs and outcomes for spousal caregivers, with other caregivers at the end of life, by gender and age. DESIGN: The South Australian Health Omnibus is an annual, random, face-to-face, cross-sectional survey wherein respondents are asked about end-of life care. SETTING/PARTICIPANTS: Participants were aged over 15 years, resided in households in South Australia and had someone close to them die from a terminal illness in the last 5 years. RESULTS: Of the 1540 respondents who provided hands on care for someone close at the end of life, 155 were widows/widowers. Bereaved spousal caregivers were more likely to be older, female, better educated, have lower incomes, less full-time work, English as second language, sought help with grief and provided more day-to-day care for longer periods. Spousal caregivers were less likely to be willing to take on caregiving again, less able to 'move on' with life and needed greater emotional support and information about illness and services. The only difference between widows and widowers was older age of spouse in women. Younger spousal caregivers perceived greater unmet emotional needs and were significantly less likely to be able to 'move on'. CONCLUSION: Spousal caregivers are different from other caregivers, with more intense needs that are not fully met. These have implications for bereavement, health and social services. PMID- 27501719 TI - Biomechanics and Physiology of Uphill and Downhill Running. AB - Most running studies have considered level running (LR), yet the regulation of locomotor behaviour during uphill (UR) and downhill (DR) running is fundamental to increase our understanding of human locomotion. The purpose of this article was to review the existing literature regarding biomechanical, neuromuscular and physiological adaptations during graded running. Relative to LR, UR is characterized by a higher step frequency, increased internal mechanical work, shorter swing/aerial phase duration, and greater duty factor, while DR is characterized by increased aerial time, reduced step frequency and decreased duty factor. Grade also modifies foot strike patterns, with a progressive adoption of a mid- to fore-foot strike pattern during UR, and rear-foot strike patterns during DR. In UR, lower limb muscles perform a higher net mechanical work compared to LR and DR to increase the body's potential energy. In DR, energy dissipation is generally prevalent compared to energy generation. The increased demands for work as running incline increases are met by an increase in power output at all joints, particularly the hip. This implies that UR requires greater muscular activity compared to LR and DR. Energy cost of running (C r) linearly increases with positive slope but C r of DR decreases until a minimum slope is reached at -20 %, after which C r increases again. The effects of slope on biomechanics, muscle contraction patterns and physiological responses have important implications for injury prevention and success of athletes engaged in graded running competitions. PMID- 27501721 TI - Is Sedentary Lifestyle Associated With Testicular Function? A Cross-Sectional Study of 1,210 Men. AB - Based on cross-sectional data on 1,210 healthy young Danish men, we investigated whether sedentary lifestyle was associated with testicular function (semen quality and reproductive hormones) independent of physical activity. The men were invited to participate in the study between 2008 and 2012, when they attended a compulsory medical examination to determine their fitness for military service. Information on sedentary behavior (television watching and computer time) and physical activity was obtained by questionnaire. The men had a physical examination, delivered a semen sample, and had a blood sample drawn. Time spent watching television, but not time sitting in front of a computer, was associated with lower sperm counts. Men who watched television more than 5 hours/day had an adjusted sperm concentration of 37 million/mL (95% confidence interval (CI): 30, 44) versus 52 million/mL (95% CI: 43, 62) among men who did not watch television; total sperm counts in those 2 groups were 104 million (95% CI: 84, 126) and 158 million (95% CI: 130, 189), respectively. Furthermore, an increase in follicle stimulating hormone and decreases in testosterone and the testosterone/luteinizing hormone ratio were detected in men watching many hours of television. Self-rated physical fitness, but not time spent on physical activity, was positively associated with sperm counts. PMID- 27501722 TI - Erratum to: Serum B cell-activating factor (BAFF) level in connective tissue disease associated interstitial lung disease. PMID- 27501723 TI - Erratum to: Conformational changes and translocation of tissue-transglutaminase to the plasma membranes: role in cancer cell migration. PMID- 27501724 TI - Iterative development of Vegethon: a theory-based mobile app intervention to increase vegetable consumption. AB - BACKGROUND: Mobile technology may serve as a cost-effective and scalable tool for delivering behavioral nutrition interventions. This research sought to iteratively develop a theory-driven mobile app, Vegethon, to increase vegetable consumption. METHODS: Development of Vegethon followed phases outlined by the IDEAS framework: 1) empathize with users (qualitative interviews, n = 18); 2) specify target behavior; 3) ground in behavioral theory; 4) ideate implementation strategies; 5) prototype potential products; 6) gather user feedback (qualitative interviews, n = 14; questionnaire, n = 41); 7) build minimum viable product; and 8) pilot potential efficacy and usability (pilot RCT, n = 17). Findings from each phase informed subsequent phases. The target population that informed intervention development was 18-50 years of age, had BMIs of 28-40 kg/m(2), and lived in the geographical area surrounding Stanford University. A full description of the final version of Vegethon is included in the paper. RESULTS: Qualitative findings that shaped initial intervention conception were: participants' interests in accountability without judgment; their desire for simple and efficient dietary self-monitoring; and the importance of planning meals in advance. Qualitative findings identified during intervention refinement were the need for a focus on vegetable self-monitoring; inclusion of vegetable challenges; simplification of features; advice and inspiration for eating vegetables; reminder notifications; and peer comparison. Pilot RCT findings suggested the initial efficacy, acceptance, and feasibility of the intervention. The final version of Vegethon enabled easy self-monitoring of vegetable consumption and included a range of features designed to engage the user (e.g., surprise challenges; leaderboard; weekly reports). Vegethon was coded for its inclusion of 18 behavior change techniques (BCTs) (e.g., goal setting; feedback; social comparison; prompts/cues; framing/reframing; identity). CONCLUSIONS: Vegethon is a theory-based, user-informed mobile intervention that was systematically developed using the IDEAS framework. Vegethon targets increased vegetable consumption among overweight adults and is currently being evaluated in a randomized controlled efficacy trial. TRIAL REGISTRATION: Clinical Trials.gov: NCT01826591. PMID- 27501726 TI - The safety of laparoscopic sleeve gastrectomy among diabetic patients. AB - AIMS: Laparoscopic sleeve gastrectomy (LSG) is a commonly performed bariatric procedure. Although bariatric surgery is becoming increasingly recognized as a treatment option for diabetes, there remain concerns about the operative risks faced by diabetic patients. This study's objective was to determine the safety of bariatric surgery in diabetic patients, specifically the type 2 diabetic (T2DM) population. METHODS: Patients over 18 years of age with a body mass index (BMI) >= 35 kg/m2 who underwent LSG in 2012 in the ACS-NSQIP database were identified. Emergency cases were excluded from analysis. Data included patient demographics, comorbidities, length of stay, and 30-day complications. The primary outcome was 30-day overall complication rate, and secondary outcomes included major complications and reoperation rates. RESULTS: There were 6399 LSG in the NSQIP database in 2012. Three hundred and twenty-two patients were excluded for BMI < 35, and 15 cases were deemed emergencies and excluded. Of the 6062 LSG who met the study criteria, 4726 (78 %) of patients were non-diabetic, 941 (15.5 %) had T2DM, and 395 (6.5 %) had T1DM. T2DM patients were more likely to be male (28.9 vs. 19.3 %, p < 0.001), were older (47.6 years vs. 42.5 years, p < 0.001), and had a higher BMI (46.4 vs. 45.7 kg/m2, p = 0.027) compared with non-diabetics. The overall 30-day complication rate did not differ between groups (6.5 % T2DM vs. 5.6 % non-diabetic, p = 0.292). After controlling for possible confounders, T2DM remained at no increased risk of 30-day complications (OR 1.16, 95 % CI 0.87 1.55, p = 0.301). In sub-analyses of specific complications, T2DM had a slightly higher rate of blood transfusions (1.8 vs. 1.0 %, p = 0.037). Other postoperative complications did not differ between groups. The 30-day complication rate for type 1 diabetics was greater than for T2DM (9.9 vs. 6.5 %, p = 0.031) and non diabetics (9.9 vs. 5.6 %, p < 0.001). CONCLUSION: Laparoscopic sleeve gastrectomy is a safe procedure for type 2 diabetics with regard to early postoperative complications. PMID- 27501727 TI - A hands-free region-of-interest selection interface for solo surgery with a wide angle endoscope: preclinical proof of concept. AB - BACKGROUND: A hands-free region-of-interest (ROI) selection interface is proposed for solo surgery using a wide-angle endoscope. A wide-angle endoscope provides images with a larger field of view than a conventional endoscope. With an appropriate selection interface for a ROI, surgeons can also obtain a detailed local view as if they moved a conventional endoscope in a specific position and direction. METHODS: To manipulate the endoscope without releasing the surgical instrument in hand, a mini-camera is attached to the instrument, and the images taken by the attached camera are analyzed. When a surgeon moves the instrument, the instrument orientation is calculated by an image processing. Surgeons can select the ROI with this instrument movement after switching from 'task mode' to 'selection mode.' The accelerated KAZE algorithm is used to track the features of the camera images once the instrument is moved. Both the wide-angle and detailed local views are displayed simultaneously, and a surgeon can move the local view area by moving the mini-camera attached to the surgical instrument. RESULTS: Local view selection for a solo surgery was performed without releasing the instrument. The accuracy of camera pose estimation was not significantly different between camera resolutions, but it was significantly different between background camera images with different numbers of features (P < 0.01). The success rate of ROI selection diminished as the number of separated regions increased. However, separated regions up to 12 with a region size of 160 * 160 pixels were selected with no failure. Surgical tasks on a phantom model and a cadaver were attempted to verify the feasibility in a clinical environment. CONCLUSIONS: Hands-free endoscope manipulation without releasing the instruments in hand was achieved. The proposed method requires only a small, low-cost camera and an image processing. The technique enables surgeons to perform solo surgeries without a camera assistant. PMID- 27501728 TI - A novel methodology for in vivo endoscopic phenotyping of colorectal cancer based on real-time analysis of the mucosal lipidome: a prospective observational study of the iKnife. AB - BACKGROUND: This pilot study assessed the diagnostic accuracy of rapid evaporative ionization mass spectrometry (REIMS) in colorectal cancer (CRC) and colonic adenomas. METHODS: Patients undergoing elective surgical resection for CRC were recruited at St. Mary's Hospital London and The Royal Marsden Hospital, UK. Ex vivo analysis was performed using a standard electrosurgery handpiece with aspiration of the electrosurgical aerosol to a Xevo G2-S iKnife QTof mass spectrometer (Waters Corporation). Histological examination was performed for validation purposes. Multivariate analysis was performed using principal component analysis and linear discriminant analysis in Matlab 2015a (Mathworks, Natick, MA). A modified REIMS endoscopic snare was developed (Medwork) and used prospectively in five patients to assess its feasibility during hot snare polypectomy. RESULTS: Twenty-eight patients were recruited (12 males, median age 71, range 35-89). REIMS was able to reliably distinguish between cancer and normal adjacent mucosa (NAM) (AUC 0.96) and between NAM and adenoma (AUC 0.99). It had an overall accuracy of 94.4 % for the detection of cancer versus adenoma and an adenoma sensitivity of 78.6 % and specificity of 97.3 % (AUC 0.99) versus cancer. Long-chain phosphatidylserines (e.g., PS 22:0) and bacterial phosphatidylglycerols were over-expressed on cancer samples, while NAM was defined by raised plasmalogens and triacylglycerols expression and adenomas demonstrated an over-expression of ceramides. REIMS was able to classify samples according to tumor differentiation, tumor budding, lymphovascular invasion, extramural vascular invasion and lymph node micrometastases (AUC's 0.88, 0.87, 0.83, 0.81 and 0.81, respectively). During endoscopic deployment, colonoscopic REIMS was able to detect target lipid species such as ceramides during hot snare polypectomy. CONCLUSION: REIMS demonstrates high diagnostic accuracy for tumor type and for established histological features of poor prognostic outcome in CRC based on a multivariate analysis of the mucosal lipidome. REIMS could augment endoscopic and imaging technologies for precision phenotyping of colorectal cancer. PMID- 27501725 TI - Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications. AB - Strongly associated with tobacco use, heavy alcohol consumption, and with high risk human papillomavirus (HPV) infection, head and neck squamous cell carcinoma (HNSCC) is a frequently lethal, heterogeneous disease whose pathogenesis is a multistep and multifactorial process involving genetic and epigenetic events. The majority of HNSCC patients present with locoregional advanced stage disease and are treated with combined modality strategies that can markedly impair quality of life and elicit unpredictable results. A large fraction of those who undergo locoregional treatment and achieve a complete response later develop locoregional recurrences or second field tumors. Biomarkers that are thus able to stratify risk and enable clinicians to tailor treatment plans and to personalize post therapeutic surveillance strategies are highly desirable. To date, only HPV status is considered a reliable independent predictor of treatment response and survival in patients with HNSCC arising from the oropharyngeal site. Recent studies suggest that telomere attrition, which may be an early event in human carcinogenesis, and telomerase activation, which is detected in up to 90 % of malignancies, could be potential markers of cancer risk and disease outcome. This review examines the current state of knowledge on and discusses the implications linked to telomere dysfunction and telomerase activation in the development and clinical outcome of HNSCC. PMID- 27501730 TI - Endoscopic control of enterocutaneous fistula by dual intussuscepting stent technique. AB - INTRODUCTION: Large high-output enterocutaneous fistulas pose great difficulties, especially in the setting of recent surgery and compromised skin integrity. METHODS: This video demonstrates a new technique of endoscopic control of enterocutaneous fistula by using two covered overlapping stents. In brief, the two stents are each inserted endoscopically, one proximal, and the other distal to the fistula with 2 cm of each stent protruding cutaneously. Following this, the proximal stent is crimped and intussuscepted into the distal stent with an adequate overlap. A prolene suture is passed through the anterior wall of both stents to prevent migration. The two stents used were evolution esophageal stents 10 cm long, fully covered, double-flared with non-flared and flared diameters being 20 and 25 mm, respectively (product number EVO-FC-20-25-10-E, Cook Medical, Bloomington, IN, USA). RESULTS: The patient featured in this video developed a high-output enterocutaneous fistula proximal to a loop ileostomy, which was created following a small bowel leak after a curative surgery for bladder cancer. Using the technique featured in this video (schematic depicted in Fig. 1), the patient was nutritionally optimized with oral feeds from albumin of 0.9-3.4 g/dl within 2 months despite prior failure to achieve nutrition optimization and adequate skin protection with combination of oral and/or parenteral nutrition. Three months after stenting, following nutritional optimization and improvement of skin coverage, definitive procedure consisted of uncomplicated fistula resection with primary stapled side-to-side functional end-to-end anastomosis. The stents were not completely incorporated into the mucosa and were rather easily pulled through the residual fistula opening just prior to the surgery. Only minimal fibrosis was noted and less than 20 cm of involved small bowel needed to be resected. Had the fistula have closed completely, the options would have included (1) proceeding to bowel resection with removal of the stents regardless of closure, or (2) cutting the securing prolene stitch and observation. Considering the placement of the stents in mid-small bowel, their endoscopic retrieval would have been difficult unless they were to migrate into the colon. CONCLUSIONS: Although a prior attempt at managing an enterocutaneous fistula with a stent deployed through a colostomy site was previously reported [1], there is no published account of bridging an enterocutaneous fistula with overlapping endoscopic stents through the fistula itself. This video serves as a proof of concept for temporizing enterocutaneous fistulas with endoscopic stenting. PMID- 27501729 TI - Mucosal perforation during laparoscopic surgery for achalasia: impact of preoperative pneumatic balloon dilation. AB - BACKGROUND: Controversy remains whether preoperative pneumatic balloon dilation (PBD) influences the surgical outcome of laparoscopic esophagocardiomyotomy in patients with esophageal achalasia. The aim of this study was to evaluate whether preoperative PBD represents a risk factor for surgical complications and affects the symptomatic and/or functional outcomes of laparoscopic Heller myotomy with Dor fundoplication (LHD). METHODS: A retrospective chart review was conducted on a prospectively compiled surgical database of 103 consecutive patients with esophageal achalasia who underwent LHD from November 1994 to September 2014. The following data were compared between the patients with preoperative PBD (PBD group; n = 26) and without PBD (non-PBD group; n = 77): (1) patients' demographics: age, gender, body mass index, duration of symptoms, maximum transverse diameter of esophagus; (2) operative findings: operating time, blood loss, intraoperative complications; (3) postoperative course: complications, clinical symptoms, postoperative treatment; and (4) esophageal functional tests: preoperative and postoperative manometric data and postoperative profile of 24-h esophageal pH monitoring. RESULTS: (1) No significant differences were observed in the patients' demographics. (2) Operative findings were similar between the two groups; however, the incidence of mucosal perforation was significantly higher in the PBD group (n = 8; 30.7 %) compared to the non-PBD group (n = 6; 7.7 %) (p = 0.005). (3) Postoperative complications were not encountered in either group. The differences were not significant for postoperative clinical symptoms, the incidence of gastroesophageal reflux disease, or necessity of postoperative treatments. (4) Lower esophageal sphincter pressure was effectively reduced in both groups, and no differences were observed in manometric data or 24-h pH monitoring profiles between the two groups. Multivariate logistic regression analysis showed that preoperative PBD and the maximum transverse diameter of esophagus were significantly associated with intraoperative mucosal perforation. CONCLUSIONS: Although postoperative outcomes were not affected, additional caution is recommended in identifying intraoperative mucosal perforation in patients with preoperative PBD when performing LHD. PMID- 27501731 TI - Drawing sounds: representing tones and chords spatially. AB - Research on the crossmodal correspondences has revealed that seemingly unrelated perceptual information can be matched across the senses in a manner that is consistent across individuals. An interesting extension of this line of research is to study how sensory information biases action. In the present study, we investigated whether different sounds (i.e. tones and piano chords) would bias participants' hand movements in a free movement task. Right-handed participants were instructed to move a computer mouse in order to represent three tones and two chords. They also had to rate each sound in terms of three visual analogue scales (slow-fast, unpleasant-pleasant, and weak-strong). The results demonstrate that tones and chords influence hand movements, with higher-(lower-)pitched sounds giving rise to a significant bias towards upper (lower) locations in space. These results are discussed in terms of the literature on forward models, embodied cognition, crossmodal correspondences, and mental imagery. Potential applications sports and rehabilitation are discussed briefly. PMID- 27501732 TI - Vibrotactile cuing revisited to reveal a possible challenge to sensorimotor adaptation. AB - Motor responses to unexpected external perturbations require the adjustment of the motor commands driving the ongoing activity. Strategies can be learned with practice to compensate for these unpredictable perturbations (e.g., externally induced slips and trips). It has been hypothesized that response improvements reflect the adaptation of motor commands through updates of an internal model. This hypothesis may be nuanced when a pre-existing motor response could be used. In that case, since a relatively adequate response is known, only the timing of the command needs to be determined. If so, then it could be inferred that the timing of movement initiation and the specific sequence of motor commands can be dissociated. Previously, we quantified the benefits of cuing vs. learning on recovery motor responses resulting from a trip induced by the abrupt stop of one side of a split belt treadmill. Trip occurrence was randomized within a series of strides. Two groups of young adults participated to two distinct experiments (learning, cuing). In the learning experiment, trip recovery improved progressively from the 4th to the 8th trial to reach an "adapted response". In the cuing experiment, trip recovery was immediate (from 1st trial). Expanding from these results, the aim of the present work was to differentiate the processes underlying the generation of motor compensation strategies in response to an external perturbation under time uncertainty. A supplementary analysis revealed that "cued" responses were kinematically similar to the "adapted response" and remained invariant regardless of cue lead time (250, 500 ms before trip) and application location of the cue (arm, trunk, lower leg). It is posited that all responses (cued and non-cued) are the expression of a pre-existing motor program derived from life experiences. Here, the cue significantly reduces time uncertainty and adaptation consists primarily in resolving time uncertainty based on the trial-by-trial learning of the stochastic property of trip occurrence in order to reduce the response delay. Hence, response time delay and motor program parameters appear to stem from two distinct processes. PMID- 27501733 TI - Adolescents', mothers', and fathers' reports of adherence across adolescence and their relation to HbA1c and daily blood glucose. AB - This study examined what is measured by adolescents', mothers', and fathers' reports of adolescents' adherence to the type 1 diabetes regimen and how such reports relate to HbA1c and daily blood glucose. Two-hundred fifty-two adolescents (M age = 12.49 at baseline), mothers, and 188 fathers completed an adapted Self-Care Inventory (LaGreca et al. in Child Health Care 19(3):132-139, 1990) every 6 months for 2.5 years, HbA1c was gathered from medical records, and daily number of blood glucose tests (BGT) and blood glucose mean (BGM) were obtained from glucose meters at one time point. A multitrait-multimethod approach decomposing adherence indicated that fathers' reports reflected a stable perception across time, mothers' reports a shared view within the family that varied with HbA1c across time, and adolescents' reports a unique view. Fathers' and mothers' reports were related to HbA1c; adolescents' reports were not, but were uniquely associated with BGT. Family members' adherence reports capture different information across time, with implications for measuring adherence and for family processes. PMID- 27501734 TI - Fatalism and hypertension prevalence, awareness, treatment and control in US Hispanics/Latinos: results from HCHS/SOL Sociocultural Ancillary Study. AB - Compared with non-Hispanic whites, US Hispanics/Latinos display similar hypertension prevalence, but lower awareness, treatment, and control. Sociocultural factors may affect these patterns. Fatalism, the belief that health is predetermined by fate, relates to poorer adoption of risk reducing health behaviors. We examined the association of fatalism with hypertension prevalence, awareness, treatment, and control among 5313 Hispanics/Latinos, ages 18-74, who were enrolled from four US communities in the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study. After accounting for socioeconomic status and acculturation in logistic regression analyses, higher fatalism was associated with increased odds of hypertension (OR 1.14, 95 % CI 1.02, 1.28). This association was non-significant when diabetes and other health related covariates were statistically adjusted. Fatalism was not associated with hypertension awareness, treatment, or control. Findings suggest that the association of fatalism with hypertension may be due largely to its association with SES, acculturation, or related health conditions. PMID- 27501735 TI - Towards valid 'serious non-fatal injury' indicators for international comparisons based on probability of admission estimates. AB - BACKGROUND: Governments wish to compare their performance in preventing serious injury. International comparisons based on hospital inpatient records are typically contaminated by variations in health services utilisation. To reduce these effects, a serious injury case definition has been proposed based on diagnoses with a high probability of inpatient admission (PrA). The aim of this paper was to identify diagnoses with estimated high PrA for selected developed countries. METHODS: The study population was injured persons of all ages who attended emergency department (ED) for their injury in regions of Canada, Denmark, Greece, Spain and the USA. International Classification of Diseases (ICD)-9 or ICD-10 4-digit/character injury diagnosis-specific ED attendance and inpatient admission counts were provided, based on a common protocol. Diagnosis specific and region-specific PrAs with 95% CIs were calculated. RESULTS: The results confirmed that femoral fractures have high PrA across all countries studied. Strong evidence for high PrA also exists for fracture of base of skull with cerebral laceration and contusion; intracranial haemorrhage; open fracture of radius, ulna, tibia and fibula; pneumohaemothorax and injury to the liver and spleen. Slightly weaker evidence exists for cerebellar or brain stem laceration; closed fracture of the tibia and fibula; open and closed fracture of the ankle; haemothorax and injury to the heart and lung. CONCLUSIONS: Using a large study size, we identified injury diagnoses with high estimated PrAs. These diagnoses can be used as the basis for more valid international comparisons of life threatening injury, based on hospital discharge data, for countries with well developed healthcare and data collection systems. PMID- 27501736 TI - Protective effect of porcine placenta in a menopausal ovariectomized mouse. PMID- 27501737 TI - Nocturnal hypoxia in obese-related obstructive sleep apnea as a putative trigger of oxidative stress in pediatric NAFLD progression. PMID- 27501739 TI - Propolis: a potential natural product to fight Candida species infections. AB - AIM: To evaluate the effect of propolis against Candida species planktonic cells and its counterpart's biofilms. MATERIALS & METHODS: The MIC values, time-kill curves and filamentation form inhibition were determined in Candida planktonic cells. The effect of propolis on Candida biofilms was assessed through quantification of CFUs. RESULTS: MIC values, ranging from 220 to 880 ug/ml, demonstrated higher efficiency on C. albicans and C. parapsilosis than on C. tropicalis cells. In addition, propolis was able to prevent Candida species biofilm's formation and eradicate their mature biofilms, coupled with a significant reduction on C. tropicalis and C. albicans filamentation. CONCLUSION: Propolis is an inhibitor of Candida virulence factors and represents an innovative alternative to fight candidiasis. PMID- 27501740 TI - Retracted: Aetiology and clinical profile of children with 46, XY differences of sex development at an Indian referral centre. AB - Retraction: 'Aetiology and clinical profile of children with 46, XY differences of sex development at an Indian referral centre' by Vasundhera Chauhan, Rima Dada, Vandana Jain The above article, published online on 8 August 2016 in Wiley Online Library (http://wileyonlinelibrary.com), has been retracted by agreement between the authors, the Journal Editors-in-Chief, Wolf-Bernhard Schill and Ralf Henkel, and Blackwell Verlag GmbH. The retraction has been agreed as the result of an unresolved dispute between the first author and a colleague research fellow due to the inclusion of data from patients who were simultaneously enrolled in two studies being conducted separately by the two parties. Reference Chauhan, V., Dada, R. and Jain, V. (2016), Aetiology and clinical profile of children with 46, XY differences of sex development at an Indian referral centre. Andrologia. doi:10.1111/and.12663. PMID- 27501738 TI - Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Oxidative stress is proposed as a central mediator in NAFLD pathogenesis, but the specific trigger for reactive oxygen species generation has not been clearly delineated. In addition, emerging evidence shows that obesity related obstructive sleep apnea (OSA) and nocturnal hypoxia are associated with NAFLD progression in adults. The aim of this study was to determine if OSA/nocturnal hypoxia-induced oxidative stress promotes the progression of pediatric NAFLD. METHODS: Subjects with biopsy proven NAFLD and lean controls were studied. Subjects underwent polysomnograms, liver histology scoring, laboratory testing, urine F(2)-isoprostanes (measure of lipid peroxidation) and 4 hydroxynonenal liver immunohistochemistry (in situ hepatic lipid peroxidation). RESULTS: We studied 36 adolescents with NAFLD and 14 lean controls. The OSA/hypoxia group (69% of NAFLD subjects) had more severe fibrosis (64% stage 0 2; 36% stage 3) than those without OSA/hypoxia (100% stage 0-2), p=0.03. Higher F(2)-isoprostanes correlated with apnea/hypoxia index (r=0.39, p=0.03), % time SaO2 <90% (r=0.56, p=0.0008) and inversely with SaO2 nadir (r=-0.46, p=0.008). OSA/hypoxia was most severe in subjects with the greatest 4HNE staining (p=0.03). Increasing F(2)-isoprostanes(r=0.32, p=0.04) and 4HNE hepatic staining (r=0.47, p=0.007) were associated with worsening steatosis. Greater oxidative stress occurred in subjects with definite NASH as measured by F(2)-isoprostanes (p=0.06) and hepatic 4HNE (p=0.03) compared to those with borderline/not NASH. CONCLUSIONS: These data support the role of nocturnal hypoxia as a trigger for localized hepatic oxidative stress, an important factor associated with the progression of NASH and hepatic fibrosis in obese pediatric patients. LAY SUMMARY: Obstructive sleep apnea and low nighttime oxygen are associated with NAFLD progression in adults. In this study, we show that adolescents with NAFLD who have OSA and low oxygen have significant scar tissue in their livers. NAFLD subjects affected by OSA and low oxygen have a greater imbalance between the production of free radicals and their body's ability to counteract their harmful effects than subjects without OSA and low oxygen. This study shows that low oxygen levels may be an important trigger in the progression of pediatric NASH. PMID- 27501741 TI - Hollow silica nanospheres coated with insoluble calcium salts for pH-responsive sustained release of anticancer drugs. AB - Hollow silica nanospheres coated with biocompatible and pH-sensitive inorganic insoluble calcium salts including calcium carbonate and hydroxyapatite have been successfully prepared. The results indicate that the nanospheres can efficiently load doxorubicin and release it in a pH-responsive and sustained manner, and improve the treatment efficacy significantly. PMID- 27501742 TI - Cu(i)-Catalyzed oxidative homo-coupling of thiazoline-4-carboxylates: synthesis of 4,4'-bithiazoline derivatives. AB - Cu(i)-Catalyzed oxidative homo-coupling of thiazoline-4-carboxylates with good functional group tolerance has been developed. The methodology presented an efficient method to directly construct vicinal carbon-hetero quaternary centers existing in numerous functional molecules and could be applied to the synthesis of 4,4'-bithiazoles which are difficult to prepare by direct C-H activation. PMID- 27501743 TI - Aging Reduces an ERRalpha-Directed Mitochondrial Glutaminase Expression Suppressing Glutamine Anaplerosis and Osteogenic Differentiation of Mesenchymal Stem Cells. AB - Aging deteriorates osteogenic capacity of mesenchymal stem/stromal cells (MSCs), contributing to imbalanced bone remodeling and osteoporosis. Glutaminase (Gls) catabolizes glutamine into glutamate at the first step of mitochondrial glutamine (Gln)-dependent anaplerosis which is essential for MSCs upon osteogenic differentiation. Estrogen-related receptor alpha (ERRalpha) regulates genes required for mitochondrial function. Here, we found that ERRalpha and Gls are upregulated by osteogenic induction in human MSCs (hMSCs). In contrast, osteogenic differentiation capacity and glutamine consumption of MSCs, as well as ERRalpha, Gls and osteogenic marker genes are significantly reduced with age. We demonstrated that ERRalpha binds to response elements on Gls promoter and affects glutamine anaplerosis through transcriptional induction of Gls. Conversely, mTOR inhibitor rapamycin, ERRalpha inverse agonist compound 29 or Gls inhibitor BPTES leads to reduced Gln anaplerosis and deteriorated osteogenic differentiation of hMSCs. Importantly, overexpression of ERRalpha or Gls restored impairment by these inhibitors. Finally, we proved that compensated ERRalpha or Gls expression indeed potentiated Gln anaplerosis and osteogenic capability of elderly mice MSCs in vitro. Together, we establish that Gls is a novel ERRalpha target gene and ERRalpha/Gls signaling pathway plays an important role in osteogenic differentiation of MSCs, providing new sights into novel regenerative therapeutics development. Our findings suggest that restoring age-related mitochondrial Gln-dependent anaplerosis may be beneficial for degenerative bone disorders such as osteoporosis. Stem Cells 2017;35:411-424. PMID- 27501745 TI - New details of the neural architecture of the salmonid adipose fin. AB - The adipose fin of salmonids, once widely regarded as vestigial and lacking in function, was shown to be important to swimming efficiency in juvenile brown trout Salmo trutta. Examination with confocal microscopy of adipose fins of S. trutta stained with various antibodies targeting the nervous system revealed several large nerves entering the fin and anastomosing throughout its length. The branching nerves form a plexus with specific patterns of fine terminal branches in the leading and trailing edges. A network of astrocyte-like cells (ALCs) that is linked through cell processes to nerves and structural collagen reacted positively with antibodies to glial cells. No other fish fins, including other adipose fins, have been shown to exhibit this type of neural architecture. Many vertebrate mechanoreceptors rely on collagen deformation to stimulate responses in afferent nerves; similarly, the adipose fin also may function as a mechanosensor, where passive mechanical deflection by water currents stimulates afferent nerves. PMID- 27501746 TI - A network meta-analysis of the relative efficacy of treatments for actinic keratosis of the face or scalp in Europe: response to comments from Prof Dirschka. PMID- 27501744 TI - Microbial transformation of contraceptive drug etonogestrel into new metabolites with Cunninghamella blakesleeana and Cunninghamella echinulata. AB - Biotransformation of a steroidal contraceptive drug, etonogestrel (1), (13-ethyl 17beta-hydroxy-11-methylene-18,19-dinor-17alpha-pregn-4-en-20-yn-3-one) was investigated with Cunninghamella blakesleeana and C. echinulata. Five metabolites 2-6 were obtained on incubation of 1 with Cunninghamella blakesleeana, and three metabolites, 2, 4, and 6 were isolated from the transformation of 1 with C. echinulata. Among them, metabolites 2-4 were identified as new compounds. Their structures were deduced as 6beta-hydroxy-11,22-epoxy-etonogestrel (2), 11,22 epoxy-etonogestrel (3), 10beta-hydroxy-etonogestrel (4), 6beta-hydroxy etonogestrel (5), and 14alpha-hydroxy-etonogestrel (6). Compounds 1-6 were evaluated for various biological activities. Interestingly, compound 5 was found to be active against beta-glucuronidase enzyme with IC50 value of 13.97+/ 0.12MUM, in comparison to standard compound, d-saccharic acid 1,4-lactone (IC50=45.75+/-2.16MUM). Intestinal bacteria produce beta-glucuronidase. Increased activity of beta-glucuronidase is responsible for the hydrolyses of glucuronic acid conjugates of estrogen and other toxic substances in the colon, which plays a key role in the etiology of colon cancer. Inhibition of beta-glucoronidase enzyme therefore has a therapeutic significance. Compounds 1-6 were also found to be non cytotoxic against 3T3 mouse fibroblast cell lines. PMID- 27501747 TI - Reply to Letter to the Editor regarding "Management of the exposed total knee prosthesis, a six-year review". PMID- 27501748 TI - Self-propelled swimming simulations of bio-inspired smart structures. AB - This paper presents self-propelled swimming simulations of a foldable structure, whose folded configuration is a box. For self-locomotion through water the structure unfolds and undulates. To guide the design of the structure and understand how it should undulate to achieve either highest speed or maximize efficiency during locomotion, several kinematic parameters were systematically varied in the simulations: the wave type (standing wave versus traveling wave), the smoothness of undulations (smooth undulations versus undulations of rigid links), the mode of undulations (carangiform: mackerel-like versus anguilliform: eel-like undulations), and the maximum amplitude of undulations. We show that the swimmers with standing wave are slow and inefficient because they are not able to produce thrust using the added-mass mechanism. Among the tested types of undulation at low Reynolds number (Re) regime of [Formula: see text] (Strouhal number of about 1.0), structures that employ carangiform undulations can swim faster, whereas anguilliform swimmers are more economic, i.e., using less power they can swim a longer distance. Another finding of our simulations is that structures which are made of rigid links are typically less efficient (lower propulsive and power efficiencies and also lower swimming speed) compared with smoothly undulating ones because a higher added-mass force is generated by smooth undulations. The wake of all the swimmers bifurcated at the low Re regime because of the higher lateral relative to the axial velocity (high Strouhal number) that advects the vortices laterally creating a double row of vortices in the wake. In addition, we show that the wake cannot be used to predict the performance of the swimmers because the net force in each cycle is zero for self-propelled bodies and the pressure term is not negligible compared to the other terms. PMID- 27501749 TI - Nanolithography using Bessel Beams of Extreme Ultraviolet Wavelength. AB - Bessel beams are nondiffracting light beams with large depth-of-focus and self healing properties, making them suitable as a serial beam writing tool over surfaces with arbitrary topography. This property breaks the inherent resolution vs. depth-of-focus tradeoff of photolithography. One approach for their formation is to use circularly symmetric diffraction gratings. Such a ring grating was designed and fabricated for the extreme ultraviolet (EUV) wavelength of 13.5 nm, a candidate wavelength for future industrial lithography. Exposure of the aerial images showed that a Bessel beam with an approximately 1 mm long z-invariant central core of 223 nm diameter had been achieved, in good agreement with theory. Arbitrary patterns were written using the Bessel spot, demonstrating possible future application of Bessel beams for serial beam writing. Lithographic marks of ~30 nm size were also observed using a high resolution Bessel beam. PMID- 27501750 TI - Themed Issue on "Metallodrugs: Activation, Targeting, and Delivery". PMID- 27501751 TI - Crystal structure of EstSRT1, a family VIII carboxylesterase displaying hydrolytic activity toward oxyimino cephalosporins. AB - EstSRT1 is a family VIII carboxylesterase that hydrolyzes oxyimino third- and fourth-generation cephalosporins, first-generation cephalosporins and ester substrates. According to the crystal structure of EstSRT1 (2.0-A resolution), this protein contains a large alpha/beta domain and a small alpha-helical domain and harbors three catalytic residues (Ser71, Lys74, and Tyr160) in the cavity at the domain interface, similarly to other family VIII carboxylesterases. Comparison of the structures of EstSRT1 and EstU1, a family VIII carboxylesterase with no hydrolytic activity toward bulky oxyimino cephalosporins, revealed that EstSRT1 has a smaller active site, despite its extended substrate range. The B factors of the active site segments that could potentially contact with the oxyimino groups and the R2 side chains of oxyimino cephalosporins are higher in EstSRT1 than in EstU1, thus suggesting the role of the active site's structural flexibility in the extension of EstSRT1's substrate spectrum. PMID- 27501752 TI - BAT3 negatively regulates lipopolysaccharide-induced NF-kappaB signaling through TRAF6. AB - TNF receptor-associated factor 6 (TRAF6) plays a critical role in NF-kappaB and mitogen-activated protein kinase (MAPK) signaling pathways, both of which mediate macrophage activation in response to pathogen-associated molecular patterns such as bacterial endotoxin, lipopolysaccharides (LPS). In this study, we investigated whether HLA-B associated transcript-3 (BAT3) regulates LPS-induced macrophage activation. BAT3 physically interacted with TRAF6 in macrophages, and this interaction was enhanced in the cells after LPS treatment. Furthermore, BAT3 inhibited the homo-oligomerization of TRAF6 as well as the interaction between TRAF6 and its downstream kinase transforming growth factor beta-activated kinase 1 (TAK1), thereby suppressing TRAF6-mediated signaling events. Intriguingly, TRAF6 mediated ubiquitination of BAT3 and this ubiquitination was crucial for its inhibitory effect on TRAF6-mediated signaling. Depletion of BAT3 by RNA interference resulted in enhancement of LPS-induced activation of the NF-kappaB signaling with increasing expression levels of pro-inflammatory cytokines. These findings suggest that BAT3 functions as the negative regulator of LPS-induced macrophage activation. PMID- 27501753 TI - Ablation of aldehyde reductase aggravates carbon tetrachloride-induced acute hepatic injury involving oxidative stress and endoplasmic reticulum stress. AB - Aldehyde reductase (Akr1a) has been reported to be involved in the biosynthesis of ascorbic acid (AsA) in the mouse liver. Because Akr1a is expressed at high levels in the liver, we aimed to investigate the role of Akr1a in liver homeostasis by employing a carbon tetrachloride (CCl4)-induced hepatotoxicity model. Akr1a-deficient (Akr1a(-/-)) and wild-type (WT) mice were injected intraperitoneally with CCl4 and the extent of hepatic injury in the acute phase was assessed. Liver damage was heavier in the Akr1a(-/-) mice than in the WT mice. Furthermore, severe hepatic steatosis was observed in the livers of Akr1a( /-) mice compared to WT mice and was restored to the levels in WT mice by AsA supplementation. Since the presence or absence of AsA had no effect on the decrease in CYP2E1 activity after the CCl4 treatment, it appears that AsA plays a role in the process after the bioactivation of CCl4. Biomarkers for oxidative stress and ER stress were markedly increased in the livers of Akr1a(-/-) mice and were effectively suppressed by AsA supplementation. Based on these collective results, we conclude that Akr1a exerts a protective effect against CCl4-induced hepatic steatosis by replenishing AsA via its antioxidative properties. PMID- 27501754 TI - Chronic reactive oxygen species exposure inhibits glucose uptake and causes insulin resistance in C2C12 myotubes. AB - Reactive oxygen species (ROS) is an important regulator in cellular signaling transduction, and many previous studies have indicated that acute ROS stimulation improves insulin sensitivity in skeletal muscle. In the study, we found that chronic ROS treatment caused serious insulin resistance in C2C12 myotubes. Glucose uptake and consumption assay indicated that pretreatment with 80 MUM H2O2 for 2 h inhibited insulin-stimulated glucose uptake in C2C12 myotubes, and the reason for it, is that chronic H2O2 treatment decreased insulin-induced glucose transporter 4 (GLUT4) translocation from cell plasma to cell membrane. Moreover, Akt2 phosphorylation depended on insulin was reduced in C2C12 myotubes of chronic H2O2 treatment. Together, this study provides further demonstration that chronic ROS stress is associated with insulin resistance of skeletal muscle in the progression of type 2 diabetes. PMID- 27501755 TI - A novel role for the nuclear localization signal in regulating hnRNP K protein stability in vivo. AB - hnRNP K is a highly conserved nucleocytoplasmic shuttling protein, which associates with RNAs through synergistic binding via its three KH domains. hnRNP K is required for proper nuclear export and translational control of its mRNA targets, and these processes are controlled by hnRNP K's movement between subcellular compartments. Whereas the nuclear export and localization of hnRNP K that is associated with mRNP complexes has been well studied, the trafficking of hnRNP K that is unbound to mRNA has yet to be elucidated. To that end, we expressed an EGFP-tagged RNA binding-defective form of hnRNP K in intact Xenopus embryos, and found it was rapidly degraded in vivo. Deleting hnRNP K's nuclear localization signal (NLS), which contains two prospective ubiquitination sites, rescued the protein from degradation. These data demonstrate a novel activity for the NLS of hnRNP K in regulating the protein's stability in vivo when it is unbound to nucleic acids. PMID- 27501756 TI - Long noncoding RNA XIST acts as an oncogene in non-small cell lung cancer by epigenetically repressing KLF2 expression. AB - Recently, long noncoding RNAs (lncRNAs) have been identified as critical regulators in numerous types of cancers, including non-small cell lung cancer (NSCLC). X inactivate-specific transcript (XIST) has been found to be up regulated and acts as an oncogene in gastric cancer and hepatocellular carcinoma, but little is known about its expression pattern, biological function and underlying mechanism in NSCLC. Here, we identified XIST as an oncogenic lncRNA by driving tumorigenesis in NSCLC. We found that XIST is over-expressed in NSCLC, and its increased level is associated with shorter survival and poorer prognosis. Knockdown of XIST impaired NSCLC cells proliferation, migration and invasion in vitro, and repressed the tumorigenicity of NSCLC cells in vivo. Mechanistically, RNA immune-precipitation (RIP) and RNA pull-down experiment demonstrated that XIST could simultaneously interact with EZH2 to suppress transcription of its potential target KLF2. Additionally, rescue experiments revealed that XIST's oncogenic functions were partly depending on silencing KLF2 expression. Collectively, our findings expound how XIST over-expression endows an oncogenic function in NSCLC. PMID- 27501757 TI - Downregulation of miR-17-92a cluster promotes autophagy induction in response to celastrol treatment in prostate cancer cells. AB - Celastrol has potential application for the treatment of prostate cancer. However it causes autophagy as a protective response in prostate and other types of cancers, thus unveiling the underlying mechanisms may benefit its future application. In the present study, we demonstrate that the miR-17-92a cluster plays a negative role in celastrol induced-autophagy. Dissection of miR-17-92a cluster revealed the role of miR-17 seed family (miR-20a and miR-17) in autophagy inhibition in the context of prostate cancer cells. Autophagy-related gene ATG7 was validated as a target of miR-17 seed family by dual-luciferase assay and qPCR. Celastrol induced autophagy was inhibited by miR-20a or miR-17, while the inhibitory effects were rescued in the presence of pcDNA-ATG7 lacking 3' UTR, demonstrating that these two members target ATG7 to inhibit celastrol-induced autophagy. As celastrol degrades androgen receptor (AR), a key transcription factor in prostate cancer cells, we further investigated whether AR affected miR 17-92a expression in prostate cancer cells. AR binding sites were found in the promoter and two introns of miR-17-92a. In addition, higher expression levels of miR-17-92a were observed in AR positive cells compared with AR negative cells. Ectopic expression of AR could enhance the expression of miR-17-92a cluster in AR negative prostate cancer cells while knockdown of AR decreased miR-17-92a expression in AR-positive cells, demonstrating the regulation of AR on miR-17-92a transcription. In summary, our results demonstrate that celastrol downregulates AR and its target miR-17-92a, leading to autophagy induction in prostate cancer cells. PMID- 27501758 TI - Nuclear factor Y regulates ancient budgerigar hepadnavirus core promoter activity. AB - Endogenous viral elements (EVE) in animal genomes are the fossil records of ancient viruses and provide invaluable information on the origin and evolution of extant viruses. Extant hepadnaviruses include avihepadnaviruses of birds and orthohepadnaviruses of mammals. The core promoter (Cp) of hepadnaviruses is vital for viral gene expression and replication. We previously identified in the budgerigar genome two EVEs that contain the full-length genome of an ancient budgerigar hepadnavirus (eBHBV1 and eBHBV2). Here, we found eBHBV1 Cp and eBHBV2 Cp were active in several human and chicken cell lines. A region from nt -85 to 11 in eBHBV1 Cp was critical for the promoter activity. Bioinformatic analysis revealed a putative binding site of nuclear factor Y (NF-Y), a ubiquitous transcription factor, at nt -64 to -50 in eBHBV1 Cp. The NF-Y core binding site (ATTGG, nt -58 to -54) was essential for eBHBV1 Cp activity. The same results were obtained with eBHBV2 Cp and duck hepatitis B virus Cp. The subunit A of NF-Y (NF-YA) was recruited via the NF-Y core binding site to eBHBV1 Cp and upregulated the promoter activity. Finally, the NF-Y core binding site is conserved in the Cps of all the extant avihepadnaviruses but not of orthohepadnaviruses. Interestingly, a putative and functionally important NF-Y core binding site is located at nt -21 to -17 in the Cp of human hepatitis B virus. In conclusion, our findings have pinpointed an evolutionary conserved and functionally critical NF-Y binding element in the Cps of avihepadnaviruses. PMID- 27501759 TI - Potential mechanisms underlying ectodermal differentiation of Wharton's jelly mesenchymal stem cells. AB - Wharton's jelly mesenchymal stem cells (WJMSCs) are being increasingly recognized for their ectodermal differentiation potential. Previously, we demonstrated that when WJMSC were seeded onto an acellular matrix material derived from Wharton's jelly and cultured in osteogenic induction media, generated CK19 positive cells and hair-like structures indicative of ectodermal differentiation of WJMSCs. In this manuscript, we examine the underlying mechanism behind this observation using a variety of microscopy and molecular biology techniques such as western blotting and qPCR. We demonstrate that these hair-like structures are associated with live cells that are positive for epithelial and mesenchymal markers such as cytokeratin-19 and alpha-smooth muscle actin, respectively. We also show that up regulation of beta-catenin and noggin, along with the expression of TGF-beta and SMAD and inhibition of BMP4 could be the mechanism behind this ectodermal differentiation and hair-like structure formation. PMID- 27501760 TI - Direct induction of hepatocyte-like cells from immortalized human bone marrow mesenchymal stem cells by overexpression of HNF4alpha. AB - Hepatocytes from human bone marrow-derived mesenchymal stem cells (hBM-MSCs) are expected to be a useful source for cell transplantation. However, relatively low efficiency and repeatability of hepatic differentiation of human BM-MSCs remains an obstacle for clinical translation. Hepatocyte nuclear factor 4 alpha (HNF4alpha), a critical transcription factor, plays an essential role in the entire process of liver development. In this study, immortalized hBM-MSCs, UE7T 13 cells were transduced with a lentiviral vector containing HNF4alpha. The typical fibroblast-like morphology of the MSCs changed, and polygonal, epithelioid cells grew out after HNF4alpha transduction. In hepatocyte culture medium, HNF4alpha-transduced MSCs (E7-hHNF4alpha cells) strongly expressed the albumin (ALB), CYP2B6, alpha-1 antitrypsin (AAT), and FOXA2 mRNA and exhibited morphology markedly similar to that of mature hepatocytes. The E7-hHNF4alpha cells showed hepatic functions such as Indocyanine green (ICG) uptake and release, glycogen storage, urea production and ALB secretion. Approximately 28% of E7-hHNF4alpha cells expressed both ALB and AAT. Furthermore, these E7 hHNF4alpha cells via superior mesenteric vein (SMV) injection expressed human ALB in mouse chronic injured liver. In conclusion, this study represents a novel strategy by directly inducing hepatocyte-like cells from MSCs. PMID- 27501761 TI - Photochemical Copper Coating on 3D Printed Thermoplastics. AB - 3D printing using thermoplastics has become very popular in recent years, however, it is challenging to provide a metal coating on 3D objects without using specialized and expensive tools. Herein, a novel acrylic paint containing malachite for coating on 3D printed objects is introduced, which can be transformed to copper via one-step laser treatment. The malachite containing pigment can be used as a commercial acrylic paint, which can be brushed onto 3D printed objects. The material properties and photochemical transformation processes have been comprehensively studied. The underlying physics of the photochemical synthesis of copper was characterized using density functional theory calculations. After laser treatment, the surface coating of the 3D printed objects was transformed to copper, which was experimentally characterized by XRD. 3D printed prototypes, including model of the Statue of Liberty covered with a copper surface coating and a robotic hand with copper interconnections, are demonstrated using this painting method. This composite material can provide a novel solution for coating metals on 3D printed objects. The photochemical reduction analysis indicates that the copper rust in malachite form can be remotely and photo-chemically reduced to pure copper with sufficient photon energy. PMID- 27501762 TI - A Versatile and Scalable Approach toward Robust Superhydrophobic Porous Materials with Excellent Absorbency and Flame Retardancy. AB - The frequent oil spillages and the industrial discharge of organic contaminants have not only created severe environmental and ecological crises, but also cause a risk of fire and explosion. These environmental and safety issues emphasize the urgent need for materials that possess superior sorption capability and less flammability and thus can effectively and safely clean up the floating oils and water-insoluble organic compounds. Here we present the successful hydrophobic modification of the flame retardant melamine sponge with a commercial fluorosilicone, by using a facile one-step solvent-free approach and demonstrate that the resultant superhydrophobic sponge not only exhibits extraordinary absorption efficiency (including high capacity, superior selectivity, good recyclability, and simple recycling routes), but also retains excellent flame retardancy and robust stability. In comparison to conventional methods, which usually utilize massive organic solvents, the present approach does not involve any complicated process or sophisticated equipment nor generates any waste liquids, and thus is a more labor-saving, environment-friendly, energy-efficient and cost-effective strategy for the hydrophobic modification. Taking into account the critical role of hydrophobic porous materials, especially in the field of environmental remediation, the approach presented herein would be highly valuable for environmental remediation and industrial applications. PMID- 27501763 TI - Metabolism and excretion of 1-hydroxymethylpyrene, the proximate metabolite of the carcinogen 1-methylpyrene, in rats. AB - 1-Methylpyrene, an alkylated polycyclic aromatic hydrocarbon and environmental carcinogen, is activated by side-chain hydroxylation to 1-hydroxymethylpyrene (1 HMP) and subsequent sulfo conjugation to the DNA-reactive 1-sulfooxymethylpyrene. In addition to the bioactivation, processes of metabolic detoxification and transport greatly influence the genotoxicity of 1-methylpyrene. For a better understanding of 1-HMP detoxification in vivo we studied urinary and fecal metabolites in rats following intraperitoneal doses of 19.3mg 1-HMP/kg body weight (5 rats) or the same dose containing 200MUCi [(14)C]1-HMP/kg body weight (2 rats). After 48h, 48.0% (rat 1) and 29.1% (rat 2) of the radioactivity was recovered as 1-HMP in the feces. Six major metabolites were observed by UV and on line radioactivity detection in urine samples and feces after HPLC separation. The compounds were characterized by mass spectrometry, (1)H NMR and (1)H-(1)H COSY NMR spectroscopy, which allowed assigning tentative molecular structures. Two prominent metabolites, 1-pyrene carboxylic acid (M-6) and the acyl glucuronide of 1-pyrene carboxylic acid (M-5) accounted for 17.7% (rat 1) and 25.2% (rat 2) of the overall radioactive dose. Further, we detected the acyl glucuronide of 6-hydroxy-1-pyrene carboxylic acid (M-1) and 8-sulfooxy-1-pyrene carboxylic acid (M-3) together with two regioisomers of M-3 (M-2 and M-4) differing in position of the sulfate group at the pyrene ring. In urine samples, the radioactivity of 1-pyrene carboxylic acid and its five derivatives amounted to 32.4% (rat 1) or 45.5% (rat 2) of the total [(14)C]1-HMP dose. PMID- 27501764 TI - Taurine zinc solid dispersions enhance bile-incubated L02 cell viability and improve liver function by inhibiting ERK2 and JNK phosphorylation during cholestasis. AB - Dietary intakes of taurine and zinc are associated with decreased risk of liver disease. In this study, solid dispersions (SDs) of a taurine zinc complex on hepatic injury were examined in vitro using the immortalized human hepatocyte cell line L02 and in a rat model of bile duct ligation. Sham-operated and bile duct ligated Sprague-Dawley rats were treated with the vehicle alone or taurine zinc (40, 80, 160mg/kg) for 17days. Bile duct ligation significantly increased blood lipid levels, and promoted hepatocyte apoptosis, inflammation and compensatory biliary proliferation. In vitro, incubation with bile significantly reduced L02 cell viability; this effect was significantly attenuated by pretreatment with SP600125 (a JNK inhibitor) and enhanced when co-incubated with taurine zinc SDs. In vivo, administration of taurine zinc SDs decreased serum alanine aminotransferase and aspartate aminotransferase activities in a dose dependent manner and attenuated the increases in serum total bilirubin, total cholesterol and low density lipoprotein cholesterol levels after bile duct ligation. Additionally, taurine zinc SDs downregulated the expression of interleukin-1beta and inhibited the phosphorylation of Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase2 (ERK2) in the liver after bile duct ligation. Moreover, taurine zinc SDs had more potent blood lipid regulatory and anti-apoptotic effects than the physical mixture of taurine and zinc acetate. Therefore, we speculate that taurine zinc SDs protect liver function at least in part via a mechanism linked to reduce phosphorylation of JNK and ERK2, which suppresses inflammation, apoptosis and cholangiocyte proliferation during cholestasis. PMID- 27501765 TI - Differences in the action of lower and higher chlorinated polychlorinated naphthalene (PCN) congeners on estrogen dependent breast cancer cell line viability and apoptosis, and its correlation with Ahr and CYP1A1 expression. AB - There are data showing that exposition to PCNs mixture increased incidence of gastrointestinal and respiratory neoplasms, but data regarding incidence of hormone-dependent cancer so far not shown. The objective was to determine if exposure to single lower and higher chlorinated PCN congeners is associated with altered proliferation and apoptosis of estrogen dependent breast cancer cells, and whether such effects are related to induction of AhR and CYP1A1 protein expression. MCF-7 cells were exposed to PCN 34, 39, 42, 46, 48, 52, 53, 54, 66, 67, 70, 71, 73 and 74 at concentrations of 100-10,000pg/ml. We evaluated the action of these PCN congeners on cell proliferation, DNA fragmentation and caspase-8,-9 activity. AhR and CYP1A1 protein expression and CYP1A1 activity was evaluated at a concentration of 1000pg/ml. An opposite action of tri- to tetraCNs than of penta-to heptaCNs on cell proliferation and apoptosis was evident. Tetra PCNs increased cell proliferation, but had no effect on DNA fragmentation nor caspase activity. Fast induction of CYP1A1 protein expression under the influence of lower chlorinated PCNs suggests faster metabolism and a possible stimulatory action of locally formed metabolites on cell proliferation. None of the higher chlorinated PCNs affected cell proliferation but all higher chlorinated PCNs increased caspase-8 activity, and hexa PCNs also increased caspase-9 activity. The rapid activation of the Ah receptor and CYP1A1 protein expression by higher chlorinated PCNs point to their toxicity; however, it is not sufficient for potential carcinogenicity. Action of lower chlorinated naphthalenes metabolites should be explored. PMID- 27501766 TI - MicroRNAs as key mediators of hepatic detoxification. AB - MicroRNAs (miRNAs) are a class of short noncoding RNAs that modulate gene expression at both transcriptional and post-transcriptional levels. Many studies have extensively revealed the significance of miRNAs in mediating liver development and diseases. However, their role in hepatic detoxification processes has been explored only recently. In this review, we summarized the up-to-date knowledge about miRNA dependent regulation of enzymes involved in all three phases of the drugs and xenobiotics detoxification process. We also discussed the role of miRNA in regulating some upstream nuclear receptors involving gene expression of enzymes for detoxification process in liver. The toxicological significance of miRNAs in liver diseases and future research perspectives are finally presented. PMID- 27501768 TI - Improvement of outcomes for TP53 carriers. PMID- 27501767 TI - Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. AB - BACKGROUND: The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1.04; 97.5% repeated CI [RCI] -infinity to 1.69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer. METHODS: In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR >=1.33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340. FINDINGS: Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30.2 months (95% CI 25.6-32.6 months) versus 26.1 months (22.3-29.0), respectively. The stratified HR was 1.02 (97.5% RCI -infinity to 1.26; repeated p=0.0070), indicating non-inferiority. The unstratified Cox model (HR 1.13 [97.5% RCI infinity to 1.39]; repeated p=0.061) did not support the primary analysis. Intent to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group. INTERPRETATION: Bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles. FUNDING: Roche. PMID- 27501769 TI - Is there room for bevacizumab in metastatic breast cancer? PMID- 27501770 TI - Biochemical and imaging surveillance in germline TP53 mutation carriers with Li Fraumeni syndrome: 11 year follow-up of a prospective observational study. AB - BACKGROUND: Carriers of a germline TP53 pathogenic variant have a substantial lifetime risk of developing cancer. In 2011, we did a prospective observational study of members of families who chose to either undergo a comprehensive surveillance protocol for individuals with Li-Fraumeni syndrome or not. We sought to update our assessment of and modify the surveillance protocol, so in this study we report both longer follow-up of these patients and additional patients who underwent surveillance, as well as update the originally presented surveillance protocol. METHODS: A clinical surveillance protocol using physical examination and frequent biochemical and imaging studies (consisting of whole body MRI, brain MRI, breast MRI, mammography, abdominal and pelvic ultrasound, and colonoscopy) was introduced at three tertiary care centres in Canada and the USA on Jan 1, 2004, for carriers of TP53 pathogenic variants. After confirmation of TP53 mutation, participants either chose to undergo surveillance or chose not to undergo surveillance. Patients could cross over between groups at any time. The primary outcome measure was detection of asymptomatic tumours by surveillance investigations. The secondary outcome measure was 5 year overall survival established from a tumour diagnosed symptomatically (in the non-surveillance group) versus one diagnosed by surveillance. We completed survival analyses using an as-treated approach. FINDINGS: Between Jan 1, 2004, and July 1, 2015, we identified 89 carriers of TP53 pathogenic variants in 39 unrelated families, of whom 40 (45%) agreed to surveillance and 49 (55%) declined surveillance. 19 (21%) patients crossed over from the non-surveillance to the surveillance group, giving a total of 59 (66%) individuals undergoing surveillance for a median of 32 months (IQR 12-87). 40 asymptomatic tumours have been detected in 19 (32%) of 59 patients who underwent surveillance. Two additional cancers were diagnosed between surveillance assessments (false negatives) and two biopsied lesions were non-neoplastic entities on pathological review (false positives). Among the 49 individuals who initially declined surveillance, 61 symptomatic tumours were diagnosed in 43 (88%) patients. 21 (49%) of the 43 individuals not on surveillance who developed cancer were alive compared with 16 (84%) of the 19 individuals undergoing surveillance who developed cancer (p=0.012) after a median follow-up of 46 months (IQR 22-72) for those not on surveillance and 38 months (12-86) for those on surveillance. 5 year overall survival was 88.8% (95% CI 78.7 100) in the surveillance group and 59.6% (47.2-75.2) in the non-surveillance group (p=0.0132). INTERPRETATION: Our findings show that long-term compliance with a comprehensive surveillance protocol for early tumour detection in individuals with pathogenic TP53 variants is feasible and that early tumour detection through surveillance is associated with improved long-term survival. Incorporation of this approach into clinical management of these patients should be considered. FUNDING: Canadian Institutes for Heath Research, Canadian Cancer Society, Terry Fox Research Institute, SickKids Foundation, and Soccer for Hope Foundation. PMID- 27501771 TI - Differences in metabolic biomarkers in the blood and gene expression profiles of peripheral blood mononuclear cells among normal weight, mildly obese and moderately obese subjects. AB - We compared metabolic biomarkers in the blood and peripheral blood mononuclear cell (PBMC) gene expression profiles among normal weight (BMI, 18.5-23 kg/m2), mildly obese (BMI, 25-27.5 kg/m2) and moderately obese Korean adult men (BMI, 27.5-30 kg/m2). High leptin, lipids (except LDL- and HDL-cholesterol) and apoB levels and low adiponectin and HDL-cholesterol levels were present in the plasma of both mildly and moderately obese subjects. Circulating levels of inflammatory cytokines and markers of insulin resistance, oxidative stress and liver damage were altered in moderately obese subjects but not in mildly obese subjects. PBMC transcriptome data showed enrichment of pathways involved in energy metabolism, insulin resistance, bone metabolism, cancer, inflammation and fibrosis in both mildly and moderately obese subjects. Signalling pathways involved in oxidative phosphorylation, TAG synthesis, carbohydrate metabolism and insulin production; mammalian target of rapamycin, forkhead box O, ras-proximate-1, RAS and transforming growth factor-beta signalling; as well as extracellular matrix receptor interaction were enriched only in moderately obese subjects, indicating that changes in PBMC gene expression profiles, according to metabolic disturbances, were associated with the development and/or aggravation of obesity. In particular, fourteen and fifteen genes differentially expressed only in mildly obese subjects and in both mildly and moderately obese subjects, respectively, could be used as early or stable biomarkers for diagnosing and treating obesity associated metabolic disturbance. We characterised BMI-associated metabolic and molecular biomarkers in the blood and provided clues about potential blood-based targets for preventing or treating obesity-related complications. PMID- 27501772 TI - Plasma Inflammatory Cytokine IL-4, IL-8, IL-10, and TNF-alpha Levels Correlate with Pulmonary Function in Patients with Asthma-Chronic Obstructive Pulmonary Disease (COPD) Overlap Syndrome. AB - BACKGROUND The aim of this study was to investigate the plasma inflammatory cytokine levels and their correlations with pulmonary function in patients with asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS). MATERIAL AND METHODS Between January 2013 and December 2014, a total of 96 patients with asthma, acute exacerbation of chronic obstructive pulmonary disease (AECOPD), or ACOS were enrolled, and 35 healthy people were included as a control group. Fasting plasma interleukin (IL)-4, IL-8, IL-10, and tumor necrosis factor alpha (TNF-alpha) levels were detected using enzyme-linked immunosorbent assay (ELISA). Correlations between the plasma inflammatory cytokine levels and forced expiratory volume in 1 second (FEV1), FEV1/predicted value ratio (FEV1%pred), and FEV1/forced vital capacity (FVC) were analyzed. RESULTS IL-4 and IL-8 levels showed statistically significant differences among the 3 groups of patients (both P<0.001); IL-4 level was significantly lower, while IL-8 level was significantly higher in the AECOPD group and ACOS group than those in the asthma group (all P<0.05). IL-10 level and TNF-alpha level were significantly different among the 3 patient groups (both P<0.001). IL-10 level was significantly different between each of the 2 groups (all P<0.001). TNF-alpha level in the asthma group was higher than in the AECOPD group and ACOS group (both P<0.001). IL-4 and IL-10 were positively and IL-8 and TNF-alpha were negatively related with FEV1, FEV1%pred, and FEV1/FVC. CONCLUSIONS Plasma levels of inflammatory cytokines IL 4, IL-8, IL-10, and TNF-alpha are related with severity of airway diseases and could be potential markers for the evaluation of asthma, COPD, and ACOS. PMID- 27501773 TI - Thyroid hormones are essential to preserve non-proliferative cells of adult neurogenesis of the dentate gyrus. AB - Thyroid hormones (THs) regulate adult hippocampal neurogenesis, a process that involves both cell populations that dynamically switch between pools of proliferative and quiescent cells, and cells that definitely leave the cell cycle to maturate into granular neurons. This investigation was carried out to determine the role of THs on the mitotic activity of specific proliferative cell populations and the preservation of non-proliferative cells participating in the neurogenic process of the dentate gyrus (DG) of the hippocampus. Hypothyroidism was induced in male adult Wistar rats with methimazole for 28days. We quantified the total number of proliferative cells (BrdU+), proliferative type 1 (BrdU+/GFAP+), and 2b and 3 (BrdU+/DCX+) cells. Early non-proliferative cells (BrdU-/DCX+ cells lacking dendritic process), postmitotic neuroblasts (Tuj 1+ cells lacking dendritic process), and immature granular neurons (IGN; DCX+ or Tuj 1+ and the presence of dendritic processes into granular or molecular layer) were also included. The evidence showed that the proliferation of Type 1, 2b and 3 cells is not modified by hypothyroidism. In contrast, hypothyroidism reduced the number of early non-proliferative cells and also leads to a decrement in the number of IGN. Our results show that proliferative cells of the DG are not sensitive to thyroid perturbations. However, THs are essential to preserve cell populations that leave the cell cycle in the DG of the hippocampus. PMID- 27501774 TI - Genome-Wide Transcriptome and Binding Sites Analyses Identify Early FOX Expressions for Enhancing Cardiomyogenesis Efficiency of hESC Cultures. AB - The differentiation efficiency of human embryonic stem cells (hESCs) into heart muscle cells (cardiomyocytes) is highly sensitive to culture conditions. To elucidate the regulatory mechanisms involved, we investigated hESCs grown on three distinct culture platforms: feeder-free Matrigel, mouse embryonic fibroblast feeders, and Matrigel replated on feeders. At the outset, we profiled and quantified their differentiation efficiency, transcriptome, transcription factor binding sites and DNA-methylation. Subsequent genome-wide analyses allowed us to reconstruct the relevant interactome, thereby forming the regulatory basis for implicating the contrasting differentiation efficiency of the culture conditions. We hypothesized that the parental expressions of FOXC1, FOXD1 and FOXQ1 transcription factors (TFs) are correlative with eventual cardiomyogenic outcome. Through WNT induction of the FOX TFs, we observed the co-activation of WNT3 and EOMES which are potent inducers of mesoderm differentiation. The result strengthened our hypothesis on the regulatory role of the FOX TFs in enhancing mesoderm differentiation capacity of hESCs. Importantly, the final proportions of cells expressing cardiac markers were directly correlated to the strength of FOX inductions within 72 hours after initiation of differentiation across different cell lines and protocols. Thus, we affirmed the relationship between early FOX TF expressions and cardiomyogenesis efficiency. PMID- 27501775 TI - Inhibition of Mycobacterium tuberculosis dihydrodipicolinate synthase by alpha ketopimelic acid and its other structural analogues. AB - The Mycobacterium tuberculosis dihydrodipicolinate synthase (Mtb-dapA) is an essential gene. Mtb-DapA catalyzes the aldol condensation between pyruvate and L aspartate-beta-semialdehyde (ASA) to yield dihydrodipicolinate. In this work we tested the inhibitory effects of structural analogues of pyruvate on recombinant Mtb-DapA (Mtb-rDapA) using a coupled assay with recombinant dihydrodipicolinate reductase (Mtb-rDapB). Alpha-ketopimelic acid (alpha-KPA) showed maximum inhibition of 88% and IC50 of 21 MUM in the presence of pyruvate (500 MUM) and ASA (400 MUM). Competition experiments with pyruvate and ASA revealed competition of alpha-KPA with pyruvate. Liquid chromatography-mass spectrometry (LC-MS) data with multiple reaction monitoring (MRM) showed that the relative abundance peak of final product, 2,3,4,5-tetrahydrodipicolinate, was decreased by 50%. Thermal shift assays showed 1 degrees C Tm shift of Mtb-rDapA upon binding alpha-KPA. The 2.4 A crystal structure of Mtb-rDapA-alpha-KPA complex showed the interaction of critical residues at the active site with alpha-KPA. Molecular dynamics simulations over 500 ns of pyruvate docked to Mtb-DapA and of alpha-KPA-bound Mtb rDapA revealed formation of hydrogen bonds with pyruvate throughout in contrast to alpha-KPA. Molecular descriptors analysis showed that ligands with polar surface area of 91.7 A(2) are likely inhibitors. In summary, alpha-hydroxypimelic acid and other analogues could be explored further as inhibitors of Mtb-DapA. PMID- 27501776 TI - Radiation-induced changes in intestinal and tissue-nonspecific alkaline phosphatase: implications for recovery after radiation therapy. AB - BACKGROUND: Exogenous replacement of depleted enterocyte intestinal alkaline phosphatase (IAP) decreases intestinal injury in models of colitis. We determined whether radiation-induced intestinal injury could be mitigated by oral IAP supplementation and the impact on tissue-nonspecific AP. METHODS: WAG/RjjCmcr rats (n = 5 per group) received lower hemibody irradiation (13 Gy) followed by daily gavage with phosphate-buffered saline or IAP (40 U/kg/d) for 4 days. Real time polymerase chain reaction, AP activity, and microbiota analysis were performed on intestine. Lipopolysaccharide and cytokine analysis was performed on serum. Data were expressed as a mean +/- SEM with P greater than .05 considered significant. RESULTS: Intestine of irradiated animals demonstrates lower hemibody irradiation and is associated with upregulation of tissue-nonspecific AP, downregulation of IAP, decreased AP activity, and altered composition of the intestinal microbiome. CONCLUSIONS: Supplemental IAP after radiation may be beneficial in mitigating intestinal radiation syndrome as evidenced by improved histologic injury, decreased acute intestinal inflammation, and normalization of intestinal microbiome. PMID- 27501777 TI - High-Density Protein Loading on Hierarchically Porous Layered Double Hydroxide Composites with a Rational Mesostructure. AB - Hierarchically porous biocompatible Mg-Al-Cl-type layered double hydroxide (LDH) composites containing aluminum hydroxide (Alhy) have been prepared using a phase separation process. The sol-gel synthesis allows for the hierarchical pores of the LDH-Alhy composites to be tuned, leading to a high specific solid surface area per unit volume available for high-molecular-weight protein adsorptions. A linear relationship between the effective surface area, SEFF, and loading capacity of a model protein, bovine serum albumin (BSA), is established following successful control of the structure of the LDH-Alhy composite. The threshold of the mean pore diameter, Dpm, above which BSA is effectively adsorbed on the surface of LDH-Alhy composites, is deduced as 20 nm. In particular, LDH-Alhy composite aerogels obtained via supercritical drying exhibit an extremely high capacity for protein loading (996 mg/g) as a result of a large mean mesopore diameter (>30 nm). The protein loading on LDH-Alhy is >14 times that of a reference LDH material (70 mg/g) prepared via a standard procedure. Importantly, BSA molecules pre-adsorbed on porous composites were successfully released on soaking in ionic solutions (HPO4(2-) and Cl(-) aqueous). The superior capability of the biocompatible LDH materials for loading, encapsulation, and releasing large quantities of proteins was clearly demonstrated. PMID- 27501778 TI - Larvicidal activity of natural and modified triterpenoids against Aedes aegypti (Diptera: Culicidae). AB - BACKGROUND: Insecticide resistance to commonly used substances demands new molecules for the chemical control of the dengue vector Aedes aegypti. Because natural product sources have been an alternative to obtain larvicidal compounds, the aim of this study was to evaluate the triterpenoids betulinic (BA) and ursolic (UA) acids and their semi-synthetic derivatives against larval Ae. aegypti. BA, UA, ten derivatives modified at the C-3 position and a positive control (diflubenzuron) were evaluated. Larvicidal assays were carried out with early fourth-instar larvae, and mortality was observed between 48 and 96 h. Doses from 200 to 10 ppm were used to calculate lethal concentrations (LCs). RESULTS: Natural compounds, i.e. UA and BA, had the lowest LCs (LC50 of 112 and 142 ppm respectively), except for the modified compound 2b (LC50 of 130 ppm). Larvicidal activity increased significantly from 48 to 96 h for all the compounds evaluated, ranging from 20 to 50% after 48 h and from 48 to 76% after 96 h. Some derivatives, e.g. 2a and 2d, had up to a three-fold larvicidal activity increase from 48 to 96 h. CONCLUSION: BA, UA and their derivatives showed larvicidal activity against Ae. aegypti larvae, increasing significantly from 48 to 96 h. The presence of a hydroxyl group is essential for larvicidal potential in these triterpenoids. (c) 2016 Society of Chemical Industry. PMID- 27501779 TI - Target-controlled gating liposome "off-on" cascade amplification for sensitive and accurate detection of phospholipase D in breast cancer cells with a low background signal. AB - Here we developed a simple, sensitive and accurate PLD detection method based on a target-controlled gating liposome (TCGL) "off-on" cascade amplified strategy and personal glucose meters (PGMs). It showed excellent sensitivity with a detection limit of 0.005 U L(-1) and well performed PLD activity analysis in breast cancer cells and inhibitor drug screening. PMID- 27501780 TI - Protein phosphatase 5 mediates corticosteroid insensitivity in airway smooth muscle in patients with severe asthma. AB - BACKGROUND: The mechanisms driving glucocorticoid (GC) insensitivity in patients with severe asthma are still unknown. Recent evidence suggests the existence of GC-insensitive pathways in airway smooth muscle (ASM) caused by a defect in GC receptor (GRalpha) function. We examined whether other mechanisms could potentially explain the reduced sensitivity of ASM cells to GC in severe asthmatics. METHODS: Airway smooth muscle cells from healthy and severe asthmatic subjects were treated with TNF-alpha and responses to corticosteroids in both cohorts were compared by ELISA, immunoblot, immunohistochemistry and real-time PCR. Immunohistochemistry and flow cytometry assays were used to assess the expression of the protein phosphatase PP5 in endobronchial biopsies and ASM cells. RESULTS: The production of CCL11 and CCL5 by TNF-alpha was insensitive to both fluticasone and dexamethasone in ASM cells from severe asthmatic compared to that in healthy subjects. Fluticasone-induced GRalpha nuclear translocation, phosphorylation at serine 211 and expression of GC-induced leucine zipper (GILZ) were significantly reduced in ASM cells from severe asthmatics compared to responses in healthy subjects. Levels of PP5 were increased in ASM cells from severe asthmatics and PP5 knockdown using siRNA restored fluticasone repressive action on chemokine production and its ability to induce GRalpha nuclear translocation and GRE-dependent GILZ expression. In vivo PP5 expression was also increased in the ASM bundles in endobronchial biopsies in severe asthmatics. CONCLUSIONS: PP5-dependent impairment of GRalpha function represents a novel mechanism driving GC insensitivity in ASM in severe asthma. PMID- 27501783 TI - Nutrition Transition and Obesity Among Teenagers and Young Adults in South Asia. AB - INTRODUCTION: Obesity among teenagers/adolescents and young adults is associated with significant adverse short and longer-term effects on health. To date, no narrative reviews have evaluated nutrition transition and its contribution to the obesity epidemic among adolescents and young adults in the South Asian (SA) region. METHOD: Data were retrieved by a four-stage systematic search process. A search of the online Pub- Med/Medline, SciVerse Scopus and Web of Science databases was performed. The age groups were defined as follows; teenage:13-19 years, adolescence:10-18 years and young adult:19-24 years. RESULTS: Among teenagers/adolescents, the prevalence of overweight ranged from 11.0% (Sri Lanka) to 19.0% (India), while obesity ranged from 2.4% (Sri Lanka) to 11.0% (Pakistan). In young adults, prevalence of overweight ranged between 7.9% (Nepal) to 15.0% (Pakistan), while obesity showed a much wider variation (0.005%[Nepal] - 22.8%[India]). Nutritional risk factors associated with overweight/ obesity among SAs of this age group included reduced fruit and vegetable consumption, a total vegetarian diet, consumption of fast food and soft drinks, and skipping breakfast. Other contributing factors identified were: adding extra salt to meals, eating meals outside of the home, frequently visiting restaurants and eating while watching television. Daily milk/yoghurt consumption and a family supper have shown a protective effect against overweight/obesity. CONCLUSION: Overweight and obesity are common amongst teenagers/adolescents and young adults of the SA region. Several food types and habits were identified as being associated with overweight/ obesity in this population. Identifying common protective and contributory factors is very important for the development of a shared regional preventive strategy. PMID- 27501782 TI - Transplantation of Human Placenta-Derived Mesenchymal Stem Cells Alleviates Critical Limb Ischemia in Diabetic Nude Rats. AB - Neovasculogenesis induced by stem cell therapy is an innovative approach to improve critical limb ischemia (CLI) in diabetes. Mesenchymal stem cells (MSCs) are ideal candidates due to their angiogenic and immunomodulatory features. The aim of this study is to determine the therapeutic effects of human placenta derived MSCs (P-MSCs) on diabetic CLI, with or without exogenous insulin administration, and the underlying mechanism of any effect. A series of in vitro experiments were performed to assess the stemness and vasculogenic activity of P MSCs. P-MSCs were intramuscularly injected at two different doses with and without the administration of insulin. The efficacy of P-MSC transplantation was evaluated by ischemia damage score, ambulatory score, laser Doppler perfusion image (LDPI), capillary, and vascular density. In vivo imaging was applied to track the implanted P-MSCs. In vivo differentiation and in situ secretion of angiogenic cytokines were determined. In vitro experimental outcomes showed the differentiation potential and potent paracrine effect of P-MSCs. P-MSCs survived in vivo for at least 3 weeks and led to the acceleration of ischemia recovery, due to newly formed capillaries, increased arterioles, and secretion of various proangiogenic factors. P-MSCs participate in angiogenesis and vascularization directly through differentiation and cytokine expression. PMID- 27501781 TI - Association of variations in HLA class II and other loci with susceptibility to EGFR-mutated lung adenocarcinoma. AB - Lung adenocarcinoma driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Here we investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA class II at 6p21.32 (rs2179920; P =5.1 * 10(-17), per-allele OR=1.36) and 6p21.1 (FOXP4) (rs2495239; P=3.9 * 10(-9), per-allele OR=1.19) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma. This study indicates that multiple genetic factors underlie the risk of lung adenocarcinomas with EGFR mutations. PMID- 27501784 TI - Dietary Fats and Oils in India. AB - BACKGROUND: India is undergoing rapid nutrition transition concurrent with an increase in obesity, metabolic syndrome, and type 2 diabetes (T2DM). There is a shift from a healthy traditional home-cooked high-fiber, low-fat, low-calorie diet, towards increasing consumption of packaged, ready-to-eat foods which are calorie-dense and contain refined carbohydrates, high fat, salt and sugar; and less fiber. Although fats and oils have been an integral part of our diets, there is a change in the pattern of consumption, in terms of both quality and quantity. METHODS: A literature search was conducted using the terms "fats, oil consumption in India, effects of vegetable oils, obesity and T2DM in Indians" in the medical search database PubMed (National Library of Medicine, Bethesda, MD, USA) from 1966 to June 2016. A manual search of the relevant quoted references was also carried out from the retrieved articles. Data have also been taken from nutritional surveys in India and worldwide, websites and published documents of the World Health Organization, the Food and Agricultural Organization, National Sample Survey Organization and websites of industries related to oil production. CONCLUSION: Increasing use of saturated fat, low intake of n-3 poly unsaturated fatty acids and increase in trans-fatty acids, along with increasing intake of dietary sugars has been noted in India. Most importantly, traditional false beliefs and unawareness about health effects of oils continues to be prevalent. Aggressive public health awareness programs coupled with governmental action and guidelines tailored for Indian population are required, to promote less consumption of fats and oils, use of healthy oils and fats, decreased intake of saturated fats and trans fatty acids, and increase intake of n-3 Poly-unsaturated fatty acids and mono-unsaturated fatty acids. PMID- 27501785 TI - Overdiagnosis, medicalisation and social justice: commentary on Carter et al (2016) 'A definition and ethical evaluation of overdiagnosis'. PMID- 27501786 TI - Back to the bedside? Making clinical decisions in patients with prolonged unconsciousness. AB - In 1993, the UK High Court decided that Tony Bland was unaware of himself and his environment, had no interest in medical treatment and allowed withdrawal of treatment. Subsequently, the court has reviewed all cases of stopping feeding and hydration in people with a prolonged disorder of consciousness. Their focus has been on determining whether the person is in the permanent vegetative state, because this avoids considering what is in a person's Best Interests. Consequently, much resource is spent distinguishing the vegetative state from the minimally conscious state and often clinical decisions are delayed or not made because of the requirement to go to court. In this paper, I argue that the neurophysiological basis of consciousness is unknown, and one cannot test whether the necessary structures are functioning. Unconscious people have responsiveness which varies; they may even have brief behaviours suggestive of awareness. No single clinical sign or investigation nor assessment battery can prove the presence (or absence) of consciousness or its permanence. The diagnosis of consciousness is clinical. Furthermore, awareness varies across a spectrum. There is no separate vegetative state. People simply have very limited or absent awareness. Even if there were such a state, it cannot be identified. The ethical and legal issues associated with decisions on treatment of unconscious people are no different from similar decisions in other patients. All decisions should be taken within the Best Interests framework and process. There should be no requirement to take any particular decision to court in this patient group. PMID- 27501787 TI - Casting the net too wide on overdiagnosis: benefits, burdens and non-harmful disease. PMID- 27501788 TI - Why do parents decline newborn intramuscular vitamin K prophylaxis? AB - OBJECTIVE: To explore the influencing factors and reasoning of parents who opt out of intramuscular vitamin K prophylaxis for their newborn. DESIGN: We conducted a qualitative study with 15 families from the Otago/Southland region of New Zealand. Semistructured interviews explored their choice to opt out of intramuscular vitamin K prophylaxis and thematic analysis was used to elucidate themes that captured important aspects of this parental decision-making process. RESULTS: Parents opt out of intramuscular vitamin K for a variety of reasons. These were clustered into three main themes: parents' beliefs and values (philosophy and spirituality), concerns about their child's welfare (pain and potential side effects) and external influencing factors (family, friends, media and health professionals). As part of a wider family hesitancy towards medical intervention, the majority of parents also raised concerns regarding other perinatal or childhood interventions. CONCLUSION: Many factors influence parental decision making and lead to a decision to opt out of newborn intramuscular vitamin K prophylaxis. Due to strong parallels with other common childhood interventions, these findings have relevance for vitamin K prophylaxis and for other healthcare interventions in childhood. PMID- 27501789 TI - Challenges in diagnosis and management of giant solitary fibrous tumour of pleura: a case report. AB - BACKGROUND: Majority of patients with solitary fibrous tumours of the pleura (SFTP) are asymptomatic. Acute presentation with symptoms resulting from mass effect due to rapid expansion of tumour size has not been reported before. CASE PRESENTATION: This report chronicles the case of a giant SFTP in a 76-year-old lady who presented with acute onset of haemoptysis, left-sided pleuritic chest pain and hoarseness of voice. Her chest radiograph showed a large left upper hemithorax mass with an ipsilateral effusion. Computed tomography (CT) scan of the thorax confirmed the presence of a pleural-based mass lesion in the left apex measuring 9.7 cm with close apposition to the aortic arch. The mass demonstrated neovascularization and there was also presence of a moderate-sized heterogeneous appearing left pleural effusion. Thoracocentesis yielded deeply haemoserous pleural fluid with a pleural aspirate hematocrit closely approaching that of peripheral blood hematocrit and alongside a 2 unit decrease in haemoglobin, was indicative of a haemothorax. Repeat CT 10 days from initial presentation showed reduction in size of the left apical mass as well as resolution of the left effusion. This was consistent with the occurrence of an intra-tumoural bleed resulting in rapid increase in the size of the SFTP, causing rupture of superficial blood vessels on the tumour surface (haemothorax) and consequential compression of the lung parenchyma (haemoptysis) and left recurrent laryngeal nerve (hoarseness of voice). The patient eventually underwent an uneventful surgical resection. CONCLUSION: A benign SFTP can present acutely with compressive symptoms as a result of spontaneous intra-tumoural bleed causing sudden increase in its size. It is important to allow temporal regression of these acute changes before deciding on surgical resectability. PMID- 27501790 TI - Assessment of prison life of persons with disability in Ghana. AB - BACKGROUND: Persons with Disabilities (PWDs) are a unique group that are often overlooked in many developing countries due to systemic weaknesses, lack of political commitment and inadequate support from government and non-governmental agencies. The population of these individuals is however steadily on the increase and currently corresponds to 15 % of the world population. Although much data exist on lifestyle and conditions of prisoners with disabilities in the western world, scanty information is available in Africa. In Ghana, there is insufficient data on the occurrence and social characteristics of prisoners with disabilities. The purpose of this current study was therefore to identify the occurrence, types and causes of disabilities among prisoners serving sentences in Ghanaian prisons. METHODS: This study was a descriptive cross-sectional survey conducted in the Male and Female Regional Prisons in Kumasi, Sunyani and the Nsawam Medium Security Prison, from November to December 2011. PWDs were selected by prisons officers and interviewed using structured questionnaires on variables such as socio-demographic characteristics, causes of disabilities and accessibility to recreational facilities. Ethical approval was obtained from the security services and the Committee of Human Research Publications and Ethics (CHRPE) of the School of Medical Sciences, Kwame Nkrumah University of Science and Technology (KNUST). RESULTS: We screened 6114 records of prisoners of which 1852 (30.3 %) were from the Kumasi Central Prisons, 3483 (57 %) from the Nsawam Medium Security and 779 (12.8 %) from the Sunyani Central Prisons. A total of 99 PWDs were identified with the commonest disability being physical, followed by visual, hearing, speech, mental and albinism. Most of the disabilities were caused by trauma (68.8 %) followed by infection (16.7 %), and drug related mental disabilities (6.3 %). Fifty (50.5 %) out of the 99 PWDs were not provided with assistive devices although they admitted the need for such. CONCLUSION: The present study has demonstrated the occurrence and conditions of PWDs in Ghanaian prisons. Major stakeholders including government agencies and other organisations could develop policies that would improve the conditions and livelihood of prisoners with disabilities in Ghana. PMID- 27501792 TI - Counter-clockwise vortical blood flow in the main pulmonary artery in a patient with patent ductus arteriosus with pulmonary arterial hypertension: a cardiac magnetic resonance imaging case report. AB - BACKGROUND: In patients with pulmonary hypertension (PH), duration of vortical blood flow along the main pulmonary artery enables estimation of the mean pulmonary arterial pressure (mPAP) non-invasively. It remains to date not known, if this method is applicable in patients with pulmonary arterial hypertension (PAH) and abnormal aortic-to-pulmonary shunting. CASE PRESENTATION: The present case analyzes the effect of a patent ductus arteriosus (PDA) on pulmonary artery flow patterns in PAH (mPAP from right heart catheterization, 75 mmHg). PH associated vortical blood flow, which is typically observed rotating in a clockwise direction when viewed in right ventricular outflow tract orientation, was found nested in PDA left-to-right shunting. Even though rotating counter clockwise, duration of vortical flow translated into correct non-invasive mPAP estimate. CONCLUSIONS: This case indicates that PH-associated vortex rotation is not restricted to clockwise direction, and that vortex-based estimation of elevated mPAP might also be feasible in patients with PAH and PDA. PMID- 27501791 TI - Transcriptome analysis of seed dormancy after rinsing and chilling in ornamental peaches (Prunus persica (L.) Batsch). AB - BACKGROUND: Ornamental peaches cv. 'Yaguchi' (Prunus persica (L.) Batsch) can be propagated via seeds. The establishment of efficient seed treatments for early germination and seedling growth is required to shorten nursery and breeding periods. It is important, therefore, to identify potential candidate genes responsible for the effects of rinsing and chilling on seed germination. We hypothesized that longer rinsing combined with chilling of seeds can alter the genes expression in related to dormancy and then raise the germination rate in the peach. To date, most molecular studies in peaches have involved structural genomics, and few transcriptome studies of seed germination have been conducted. In this study, we investigated the function of key seed dormancy-related genes using next-generation sequencing to profile the transcriptomes involved in seed dormancy in peaches. De novo assembly and analysis of the transcriptome identified differentially expressed and unique genes present in this fruit. RESULTS: De novo RNA-sequencing of peach was performed using the Illumina Miseq 2000 system. Paired-end sequence from mRNAs generated high quality sequence reads (9,049,964, 10,026,362 and 10,101,918 reads) from 'Yaguchi' peach seeds before rinsed (BR) and after rinsed for 2 or 7 days with a chilling period of 4 weeks (termed 2D4W and 7D4W), respectively. The germination rate of 7D4W was significantly higher than that of 2D4W. In total, we obtained 51,366 unique sequences. Differential expression analysis identified 7752, 8469 and 506 differentially expressed genes from BR vs 2D4W, BR vs 7D4W and 2D4W vs 7D4W libraries respectively, filtered based on p-value and an adjusted false discovery rate of less than 0.05. This study identified genes associated with the rinsing and chilling process that included those associated with phytohormones, the stress response and transcription factors. 7D4W treatment downregulated genes involved in ABA synthesis, catabolism and signaling pathways, which eventually suppressed abscisic acid activity and consequently promoted germination and seedling growth. Stress response genes were also downregulated by the 7D4W treatment, suggesting that this treatment released seeds from endodormancy. Transcription factors were upregulated by the BR and 2D4W treatment, suggesting that they play important roles in maintaining seed dormancy. CONCLUSIONS: This work indicated that longer rinsing combined with chilling affects gene expression and germination rate, and identified potential candidate genes responsible for dormancy progression in seeds of 'Yaguchi' peach. The results could be used to develop breeding programs and will aid future functional genomic research in peaches and other fruit trees. PMID- 27501793 TI - Pazolimus: pazopanib plus sirolimus following progression on pazopanib, a retrospective case series analysis. AB - BACKGROUND: To explore the activity of pazopanib (P) + sirolimus (S) in patients who progressed after previous clinical benefit on pazopanib. METHODS: Eight patients with progressing metastatic high grade soft tissue sarcoma (STS) whose disease advanced on P following a response duration of at least 4 months were offered re-challenge of P supplemented by off-label S and a single patient with progressing metastatic chondrosarcoma was offered the combination as compassionate treatment. Patients were treated in two centers: Hadassah Medical Center and Tel Aviv Medical Center. Patients received oral P 200-600 mg once a day supplemented by S 3-4 mg taken separately, 12 h after the P dose. RESULTS: Patients received treatment from December 2012 to February 2016. Four progressed on the combination and their treatment was terminated. Two patients were undergoing treatment when data was summarized. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: one partial response (PR), four stable disease (SD), and four progressive disease (PD), corresponding to five PR and four PD on the Choi criteria. Median progression free survival was 5.5 months (range 4-17). CONCLUSIONS: Our series showed that the combination of P + S has activity in STS patients selected by previous response to P and in a patient with chondrosarcoma, suggesting this can serve as a mechanism to reverse resistance to P and extend the chemotherapy-free window. PMID- 27501795 TI - Reply to Letter to Editor: Management of Suprahepatic Inferior Vena Cava Obstruction. PMID- 27501796 TI - 23 Lung Metastases Treated by Radiofrequency Ablation Over 10 Years in a Single Patient: Successful Oncological Outcome of a Metastatic Cancer Without Altered Respiratory Function. AB - An 82-year-old man, who was diagnosed in 2002 with an oncocytic (Hurthle cell) thyroid carcinoma, was initially treated by local surgery and was refractory to radioiodine treatment. The patient had successive secondary recurrences from 2006 onwards. Metastases were suspected due to an elevation of thyroglobulin in serum. Hypermetabolic nodules were targeted using FDG PET as well as CT-guided radiofrequency ablations. Thyroglobulin levels decreased following each procedure. 10 years later, tolerance and efficacy are excellent; 23 lung metastases have been treated during 11 sessions without current relapse. Respiratory function and quality of life are not altered. This report illustrates how radiofrequency ablation can be efficiently integrated into the long-term management of poorly aggressive oligometastatic cancer, in combination with other local and/or systemic therapies. PMID- 27501797 TI - Regarding "Amplatzer Vascular Plugs Versus Coils for Embolization of Pulmonary Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia". PMID- 27501798 TI - Management of Suprahepatic Inferior Vena Cava Obstruction. PMID- 27501799 TI - Patient factors associated with initiation of behavioral weight loss treatment: a prospective observational study in an integrated care setting. AB - Low enrollment in behavioral weight loss treatments limits their impact. We aimed to identify factors associated with treatment initiation. The participants were outpatients (n = 198) at Veterans Affairs (VA) healthcare facilities who were referred to a free VA-based behavioral weight loss treatment. Participants were assessed on psychosocial factors potentially relevant to treatment initiation. Subsequent treatment initiation was determined via medical record review. Study participants were 77 % male, 60 % African American, and 54 % initiated treatment. In multivariable analyses, treatment initiation was associated with being single, higher anxiety, and patients' perceptions that referring provider supported their weight autonomy. Endorsement of treatment barriers was not associated with treatment initiation. Treatments offering in-person sessions and mood management components were rated as more preferred. Initiation of behavioral weight loss treatments may increase if patients believe that providers respect their weight control autonomy and if healthcare organizations offer treatments that match patients' preferences. PMID- 27501801 TI - Erratum to: Transitional Progenitors during Vertebrate Retinogenesis. PMID- 27501800 TI - [Chronic low back pain and psychological comorbidity : A review]. AB - BACKGROUND: Back pain is a common, disabling problem in Germany. Previous research has evaluated associations between low back pain (LBP), depression, and fear. OBJECTIVES: The results should provide ideas of how to optimize preventive measures, give guidelines for rehabilitation of patients with LBP, and to develop new therapies. MATERIALS AND METHODS: A systematic review of the literature including primary publications and meta-analyses using set search criteria in PubMed was performed. A meta-analysis was then done. RESULTS: In all, 34 studies met the inclusion and quality criteria, whereby 14 studies were included in the meta-analysis. In the literature, significantly different depression scores were reported for people with LBP compared to a healthy control group. The pain perception in persons with LBP is associated with depression and fear. The correlation between depression and pain perception was highly significant in 5 studies (p < 0.01) and significant in 8 studies (p < 0.05). Fear and pain perception were highly significant in 4 studies (highly significant, p < 0.01) and significant in 3 studies (p < 0.05); 5 studies had no significant results. The studies were very heterogeneous. CONCLUSIONS: The results can improve the understanding of the complexity of LBP perception and its therapy. The generalization of the results is limited. To cover the correlation of psychosocial and lifestyle factors and pain perception of LBP, further research is required. To obtain a clearer picture of pain perception in persons with LBP, standardized pain assessment would be beneficial. In addition, we recommend that future studies follow standardized procedures to allow greater comparability. PMID- 27501802 TI - Dodecafluoropentane Improves Neurological Function Following Anterior Ischemic Stroke. AB - Dodecafluoropentane emulsion (DDFPe), an advanced oxygen transport drug, given IV at 90-min intervals maintains viability in the penumbra during cerebral ischemia in the standard rabbit anterior stroke model (STND). This study investigated shortened dosage schedules of DDFPe in nonstandard posterior (NSTND) strokes following occlusions of the posterior cerebral arteries. DDFPe given at shortened schedules of 30 or 60-min injection intervals will reduce neurological deficits, percent stroke volume (%SV), and serum glutamate levels in NSTND ischemic strokes. New Zealand White rabbits (N = 26) were randomly placed into three groups: A (n = 9) controls given saline injections every 60 min, B (n = 9) 2 % DDFPe given IV every 30 min, and C (n = 8) DDFPe every 60 min. Injections began 1 h after embolization. Groups were subdivided into STND and NSTND based on angiographically verified embolization of the cerebral arteries. Neurological assessments and blood samples were done at 0.5-1-h intervals. Rabbits were euthanized at 7 h following embolization. Stained brain slices were measured for %SV. The 30 and 60-min subgroups did not differ and were combined as DDFPe-STND or DDFPe-NSTND groups. In the DDFPe-STND stroke group, the %SV, neurological assessment scores (NAS), and serum glutamate were decreased vs. STND controls (p = 0.0016, 0.008, and 0.016, respectively). In the DDFPe-NSTND stroke group, %SV, NAS, and serum glutamate did not differ statistically compared to NSTND controls (p = 0.82, 0.097, and 0.06, respectively). More frequent dosage schedules provided no additional improvement. In anterior strokes, DDFPe improves recovery but not in the more severe NSTND strokes. PMID- 27501803 TI - Gene Polymorphisms for Both Auto-antigen and Immune-Modulating Proteins Are Associated with the Susceptibility of Autoimmune Myasthenia Gravis. AB - Myasthenia gravis (MG) is an antibody-mediated autoimmune disease against antigens at the neuromuscular junction. Both genetic and environmental factors contribute to the susceptibility of MG. We undertook a case-control study to explore the contribution of genes of the auto-antigen and immune-modulating proteins in the pathogenesis of MG. We enrolled 389 adult MG patients and 487 healthy controls. Eighteen SNPs were selected from genes of cholinergic receptor nicotinic alpha 1 (CHRNA1), autoimmune regulator (AIRE), cytotoxic T lymphocyte associated protein 4 (CTLA-4), protein tyrosine phosphatase nonreceptor type 22 (PTPN22), and interleukin-10 (IL-10). Rs16862847 and rs2229957 in CHRNA1, rs3761389 in AIRE, and rs733618 in CTLA-4 were significantly associated with MG, with the highest association in SNPs of CHRNA1. Carrier of rs16862847 G allele was found to be an independent risk factor in predicting high-level acetylcholine receptor (AChR) antibodies (P = 0.003, OR = 10.296). Genetic interaction analysis revealed a synergistic effect of CHRNA1 (rs16862847), AIRE (rs3761389), and CTLA 4 (rs733618) in the susceptibility of MG (P < 0.0001, OR = 1.95). These findings highlight the role of auto-antigen gene (CHRNA1) in the autoimmune reactions against AChR and reveal synergistic contribution of genes of both auto-antigen and immune-regulating proteins (AIRE and CTLA-4) in the pathogenesis of MG. PMID- 27501804 TI - Mitochondrion-Mediated Apoptosis Induced by Acrylamide is Regulated by a Balance Between Nrf2 Antioxidant and MAPK Signaling Pathways in PC12 Cells. AB - Acrylamide (ACR) is a potent toxin that affects the human nervous system. However, the underlying mechanism of ACR neurotoxicity remains poorly understood. In the present study, we investigated whether ACR induces mitochondrion-dependent apoptosis and the involved signaling pathways in PC12 cells. ACR exposure activated the mitochondrial apoptotic pathway in PC12 cells and triggered the up regulation of Bax/Bcl-2 ratio, excessive release of cytochrome c, cleavage of capase-9 and caspase-3, depolarization of the mitochondrial membrane, structural damages to the mitochondria, and compaction of nuclear heterochromatin. ACR induced oxidative stress was also observed based on distinct increase in cellular reactive oxygen species (ROS) and malondialdehyde (MDA), and significant decrease in glutathione (GSH). Mitogen-activated protein kinases (MAPK) signaling including extracellular signal-regulated protein kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 were phosphorylated by ROS overproduction in PC12 cells in a time-and dose-dependent manner. ACR promoted the translocation of nuclear factor E2-related factor 2 (Nrf2) from the cytosol to the nucleus, thereby enhancing the expression of downstream gamma-glutamyl-cysteine synthetase (gamma GCS). The regulation of Nrf2 activation by MAPK pathways was confirmed by the blockade of MAPK pathways. The suppression of JNK and p38 pathways showed a protective effect on ACR-induced mitochondrial dysfunction and apoptosis. Nrf2 knockdown further enhanced MDA production and reduced GSH generation induced by ACR. These results suggest that MAPK and Nrf2 signaling pathways contribute to mitochondrion-mediated apoptosis induced by ACR in PC12 cells. PMID- 27501805 TI - Distinct Hippocampal Expression Profiles of Long Non-coding RNAs in an Alzheimer's Disease Model. AB - Alzheimer's disease (AD), the most prevalent form of dementia worldwide, is a complex neurodegenerative disease characterized by the progressive loss of memory and other cognitive functions. The pathogenesis of AD is not yet completely understood. Although long non-coding RNAs (lncRNAs) have recently been shown to play a role in AD pathogenesis, the specific influences of lncRNAs in AD remain largely unknown; in particular, hippocampal lncRNA expression profiles in AD rats are lacking. In this study, microarray analysis was performed to investigate the hippocampal expression patterns of dysregulated lncRNAs in a rat model of AD. A total of 315 lncRNAs and 311 mRNAs were found to be significantly dysregulated in the AD model (>=2.0 fold, p < 0.05). Then, quantitative real-time PCR was used to validate the expression of selected lncRNAs and mRNAs. Bioinformatics tools and databases were employed to explore the potential lncRNA functions. This is the first study to comprehensively identify dysregulated hippocampal lncRNAs in AD and to demonstrate the involvement of different lncRNA expression patterns in the hippocampal pathogenesis of AD. This information will enable further research on the pathogenesis of AD and facilitate the development of novel AD therapeutics targeting lncRNAs. PMID- 27501806 TI - Si/PEDOT:PSS Hybrid Solar Cells with Advanced Antireflection and Back Surface Field Designs. AB - Molybdenum oxide (MoO3) is one of most suitable antireflection (AR) layers for silicon/poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (Si/ PEDOT: PSS) hybrid solar cells due to its well-matched refractive index (2.1). A simulation model was employed to predict the optical characteristics of Si/ PEDOT: PSS hybrid solar cells with the MoO3 layers as antireflection coatings (ARCs), as well as to analyze the loss in current density. By adding an optimum thickness of a 34-nm-thick ARC of MoO3 on the front side and an effective rear back surface field (BSF) of phosphorus-diffused N (+) layer at the rear side, the hybrid cells displayed higher light response in the visible and near infrared regions, boosting a short-circuit current density (J sc) up to 28.7 mA/cm(2). The average power conversion efficiency (PCE) of the Si/ PEDOT: PSS hybrid solar cells was thus increased up to 11.90 %, greater than the value of 9.23 % for the reference devices. PMID- 27501807 TI - Teen Dating Violence, Sexual Harassment, and Bullying Among Middle School Students: Examining Mediation and Moderated Mediation by Gender. AB - This longitudinal study tested whether sexual harassment perpetration mediates the relationship between bullying perpetration and teen dating violence (TDV) perpetration and tested moderated mediation by assessing whether the developmental pathway varies by gender among middle school-aged youth. Although TDV has been associated with bullying and sexual harassment, the developmental relationship among all three behaviors has rarely been examined, especially by gender. The data were collected from one cohort of seventh grade middle school students (N = 612) from four schools. Students were surveyed every 6 months during seventh and eighth grades for a total of four waves of data collection. Structural equation modeling (SEM) was conducted to address the study aims, consisting of three stages: measurement models, mediation, and moderated mediation (otherwise known as Contrast of Mediated Effects). Results indicate no evidence of mediation. However, in the overall model, bullying and sexual harassment both emerged as significant predictors of TDV at a later time point. Among girls, only bullying significantly predicted TDV at a later time point, and, among boys, only sexual harassment significantly predicted TDV at a later time point. Prevention programs that target bullying and sexual harassment perpetration may reduce later perpetration of TDV. Further research is needed to disentangle the temporal relationships between these aggressive behaviors among youth. PMID- 27501808 TI - It's not just the big kids: both high and low BMI impact bracing success for adolescent idiopathic scoliosis. AB - PURPOSE: Bracing is a common treatment for patients with adolescent idiopathic scoliosis (AIS) and is recommended for most skeletally immature patients with a curve of 25-45 degrees in order to prevent or delay curve progression. The aim of this study was to determine at which body habitus orthotic management for AIS becomes less effective. We hypothesize that overweight children are more likely to fail brace treatment. METHODS: This was a retrospective cohort study involving consecutive patients with AIS treated with a thoracolumbosacral orthosis at a large pediatric tertiary care center. Patients were divided into three groups based on BMI: (1) high-BMI group (BMI >85th percentile); (2) low-BMI group (BMI <20th percentile); (3) mid-BMI group (BMI 20th-85th percentile). Successful orthotic treatment was defined as an increase in the primary curve of <5 degrees , prevention of progression past 45 degrees , and avoidance of surgery. RESULTS: The study cohort comprised 182 patients with a mean age of 12.5 years at brace prescription and a mean follow-up of 2 years. Compared to the mid-BMI group, high and low-BMI patients were significantly more likely to fail orthotic management. The association between high-BMI and orthotic failure disappeared when compliance and in-brace correction were taken into account, but the association between low BMI and each poor outcome remained significant. CONCLUSIONS: Based on our results, children on either end of the BMI spectrum are more likely to fail brace treatment for scoliosis than their mid-BMI counterparts. In high-BMI patients, this appears to be in large part attributable to an inadequacy of in-brace curve correction as well as to poorer brace compliance, while a low BMI appears to be an independent risk factor for brace failure. PMID- 27501809 TI - Decreased PD-1 positive blood follicular helper T cells in patients with psoriasis. AB - Follicular helper T (Tfh) cells are recently characterized subset of helper T cells, which are initially found in the germinal centers of B cell follicles. The major role of Tfh cells is helping B cell activation and antibody production during humoral immunity. Recently, blood Tfh cells were shown to be associated with autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigoid and psoriasis. There is only one study which investigated Tfh cells in psoriasis patients. Therefore, in this study, we evaluated and analyzed blood Tfh cells in Korean patients with psoriasis. A total of 28 psoriasis patients and 16 healthy controls were enrolled. The frequency and absolute number of CXCR5(+)PD-1(+) Tfh cells were decreased in patients with psoriasis compared to healthy controls. CD4(+)CXCR5(+) T cells and CXCR5(+)ICOS(+) Tfh cells did not show differences. The frequency and absolute number of CXCR5(+)PD-1(+) Tfh cells in psoriasis patients negatively correlated with erythrocyte sedimentation rate and positively correlated with disease duration. The absolute number of CXCR5(+)ICOS(+) Tfh cells also showed positive correlation with disease duration. However, the subpopulations of Tfh cells did not correlate with Psoriasis Area and Severity Index. Serum interleukin-21 level was significantly increased in psoriasis patients compared to healthy controls, however, its level did not correlate with clinical and experimental parameters of psoriasis patients. These findings suggest the decreased function of Tfh cells in psoriasis, which could result in attenuated B cell immune responses in the pathogenesis of psoriasis. However, further investigations are necessary to confirm the function of Tfh cells in psoriasis vulgaris. PMID- 27501810 TI - Ethnicity, Sex Work, and Incident HIV/STI Among Transgender Women in New York City: A Three Year Prospective Study. AB - In conjunction with a 3-year prospective study of 199 transgender women from the New York City Area, we attempted to better understand why non-Whites are much more likely than Whites to become HIV infected. We first assessed associations of ethnicity with sex work, sexual risk behavior for HIV, and biologically determined HIV/STI, and then assessed the extent to which these ethnic differences are explained by socioeconomic factors, immigration status, and sexual orientation. Statistical techniques included generalized estimating equations and Cox proportional hazards. As expected, compared to Whites, Blacks and Hispanics were more involved in the sex trade, more likely to report unprotected receptive anal intercourse, and as a result, more likely to become HIV/STI infected. All of these associations were mediated by androphilia, and to a lesser extent androphilia/gynephilia. Sexual orientation is a significant but little recognized factors associated with new cases of HIV/STI among transgender women of color. PMID- 27501812 TI - [Transcatheter aortic valve implantation and internal carotid artery stenting in a 74-year-old female patient]. AB - This article presents the case of a combined intervention for transcatheter aortic valve implantation (TAVI) and stenting of the internal carotid artery. Due to severe aortic stenosis and a subacute infarction in the middle cerebral artery territory, with neurological instability while hypotensive and cardiac failure while hypertensive, it was decided to carry out the intervention as a single combined procedure. An open surgical intervention was decided against because of the high peri-interventional mortality risk. The intervention was complication free but a slight subarachnoid hemorrhage occurred in the postinterventional period. It was unclear if the bleeding was the result of cerebral hyperperfusion poststenting, if bleeding in an ischemic region was favored by post-TAVI hyperemia and whether the outcome would have been better with two separate interventions. PMID- 27501811 TI - Shifting the HIV Training and Research Paradigm to Address Disparities in HIV Outcomes. AB - Tailored programs to diversify the pool of HIV/AIDS investigators and provide sufficient training and support for minority investigators to compete successfully are uncommon in the US and abroad. This paper encourages a shift in the HIV/AIDS training and research paradigm to effectively train and mentor Latino researchers in the US, Latin America and the Caribbean. We suggest three strategies to accomplish this: (1) coaching senior administrative and academic staff of HIV/AIDS training programs on the needs, values, and experiences unique to Latino investigators; (2) encouraging mentors to be receptive to a different set of research questions and approaches that Latino researchers offer due to their life experiences and perspectives; and (3) creating a virtual infrastructure to share resources and tackle challenges faced by minority researchers. Shifts in the research paradigm to include, retain, and promote Latino HIV/AIDS researchers will benefit the scientific process and the patients and communities who await the promise of HIV/AIDS research. PMID- 27501815 TI - Latitudinal Gradients in Induced and Constitutive Resistance against Herbivores. AB - Plants are hypothesized to evolve increased defense against herbivores at lower latitudes, but an increasing number of studies report evidence that contradicts this hypothesis. Few studies have examined the evolution of constitutive and induced resistance along latitudinal gradients. When induction is not considered, underlying patterns of latitudinal clines in resistance can be obscured because plant resistance represents a combination of induced and constitutive resistance, which may show contrasting patterns with latitude. Here, we asked if there are latitudinal gradients in constitutive versus induced resistance by using genotypes of Oenothera biennis (Onagraceae) sampled along an 18 degrees latitudinal gradient. We conducted two bioassay experiments to compare the resistance of plant genotypes against one generalist (Spodoptera exigua) and one specialist (Acanthoscelidius acephalus) herbivore. These insects were assayed on: i) undamaged control plants, ii) plants that had been induced with jasmonic acid, and iii) plants induced with herbivore damage. Additionally, we examined latitudinal gradients of constitutive and induced chemical resistance by measuring the concentrations of total phenolics, the concentration of oxidized phenolics, and the percentage of phenolics that were oxidized. Spodoptera exigua showed lower performance on plants from lower latitudes, whereas A. acephalus showed no latitudinal pattern. Constitutive total phenolics were greater in plants from lower latitudes, but induced plants showed higher total phenolics at higher latitudes. Oxidative activity was greatest at higher latitudes regardless of induction. Overall, both latitude and induction have an impact on different metrics of plant resistance to herbivory. Further studies should consider the effect of induction and herbivore specialization more explicitly, which may help to resolve the controversy in latitudinal gradients in herbivory and defense. PMID- 27501814 TI - Sex and Aggregation-Sex Pheromones of Cerambycid Beetles: Basic Science and Practical Applications. AB - Research since 2004 has shown that the use of volatile attractants and pheromones is widespread in the large beetle family Cerambycidae, with pheromones now identified from more than 100 species, and likely pheromones for many more. The pheromones identified to date from species in the subfamilies Cerambycinae, Spondylidinae, and Lamiinae are all male-produced aggregation-sex pheromones that attract both sexes, whereas all known examples for species in the subfamilies Prioninae and Lepturinae are female-produced sex pheromones that attract only males. Here, we summarize the chemistry of the known pheromones, and the optimal methods for their collection, analysis, and synthesis. Attraction of cerambycids to host plant volatiles, interactions between their pheromones and host plant volatiles, and the implications of pheromone chemistry for invasion biology are discussed. We also describe optimized traps, lures, and operational parameters for practical applications of the pheromones in detection, sampling, and management of cerambycids. PMID- 27501816 TI - Iranian homograft heart valves: assessment of durability and late outcome. AB - Durability and the rate of complications of homograft heart valves, adjusted for patient-related contributors and surgical techniques, rely mainly on the quality of allografts which in turn are mirrored in the donor characteristics and most importantly recovery and processing procedures. Aimed to assess the quality, a study was conducted to figure out the durability and late outcome following homograft replacement with valved conduits procured by the Iranian Tissue Bank. Retrospectively, the pre-implantation, perioperative and follow-up data of 400 non-consecutive recipients of cryopreserved heart valves (222 pulmonary and 178 aortic) from 2006 to 2015 were collected and analyzed in terms of variables reflecting late outcome including adverse events and durability. In the context of durability, the event of interest was defined as the need for homograft replacement and homograft-related death. The mean follow-up time (SD) of study entrants (male/female ratio, 1.4) was 49.8 (36.3) months. Median age at the time of implantation was 11 years. Total 10-years mortality was 21 % (84/400), including 66.7 % early (30-days mortality: 56/84) and 33.3 % late (28/84). Overall late complication rate was 2 %. Median survival time was 120 months (95 % CI 83.3-156.6). The pulmonary valves appeared to be more durable (P value <0.001) and survival probabilities in small sized grafts were lower (P value 0.008). One , five-, and ten-year graft survival was 82, 76 and 73 %, respectively. The evidences suggest that the homografts function satisfactory with low rate of late complications; nevertheless, more emphasis should be given to make long-term durability comparable. PMID- 27501813 TI - DNA Methylation and Urological Cancer, a Step Towards Personalized Medicine: Current and Future Prospects. AB - Urologic malignancies are some of the commonest tumors often curable when diagnosed at early stage. However, accurate diagnostic markers and faithful predictors of prognosis are needed to avoid over-diagnosis leading to overtreatment. Many promising exploratory studies have identified epigenetic markers in urinary malignancies based on DNA methylation, histone modification and non-coding ribonucleic acid (ncRNA) expression that epigenetically regulate gene expression. We review and discuss the current state of development and the future potential of epigenetic biomarkers for more accurate and less invasive detection of urological cancer, tumor recurrence and progression of disease serving to establish diagnosis and monitor treatment efficacies. The specific clinical implications of such methylation tests on therapeutic decisions and patient outcome and current limitations are also discussed. PMID- 27501818 TI - The Central Nervous System and Bone Metabolism: An Evolving Story. AB - Our understanding of the control of skeletal metabolism has undergone a dynamic shift in the last two decades, primarily driven by our understanding of energy metabolism. Evidence demonstrating that leptin not only influences bone cells directly, but that it also plays a pivotal role in controlling bone mass centrally, opened up an investigative process that has changed the way in which skeletal metabolism is now perceived. Other central regulators of bone metabolism have since been identified including neuropeptide Y (NPY), serotonin, endocannabinoids, cocaine- and amphetamine-regulated transcript (CART), adiponectin, melatonin and neuromedin U, controlling osteoblast and osteoclast differentiation, proliferation and function. The sympathetic nervous system was originally identified as the predominant efferent pathway mediating central signalling to control skeleton metabolism, in part regulated through circadian genes. More recent evidence points to a role of the parasympathetic nervous system in the control of skeletal metabolism either through muscarinic influence of sympathetic nerves in the brain or directly via nicotinic receptors on osteoclasts, thus providing evidence for broader autonomic skeletal regulation. Sensory innervation of bone has also received focus again widening our understanding of the complex neuronal regulation of bone mass. Whilst scientific advance in this field of bone metabolism has been rapid, progress is still required to understand how these model systems work in relation to the multiple confounders influencing skeletal metabolism, and the relative balance in these neuronal systems required for skeletal growth and development in childhood and maintaining skeletal integrity in adulthood. PMID- 27501817 TI - Laser-Sintered Constructs with Bio-inspired Porosity and Surface Micro/Nano Roughness Enhance Mesenchymal Stem Cell Differentiation and Matrix Mineralization In Vitro. AB - Direct metal laser sintering can produce porous Ti-6Al-4V orthopedic and dental implants. The process requires reduced resources and time and can provide greater structural control than machine manufacturing. Implants in bone are colonized by mesenchymal stem cells (MSCs), which can differentiate into osteoblasts and contribute to osseointegration. This study examined osteoblast differentiation and matrix mineralization of human MSCs cultured on laser-sintered Ti-6Al-4V constructs with varying porosity and at different time scales. 2D solid disks and low, medium and high porosity (LP, MP, and HP) 3D constructs based on a human trabecular bone template were laser sintered from Ti-6Al-4V powder and further processed to have micro- and nanoscale roughness. hMSCs exhibited greater osteoblastic differentiation and local factor production on all 3D porous constructs compared to 2D surfaces, which was sustained for 9 days without use of exogenous factors. hMSCs cultured for 8 weeks on MP constructs in osteogenic medium (OM), OM supplemented with BMP2 or collagen-coated MP constructs in OM exhibited bone-like extracellular matrix mineralization. Use of bio-inspired porosity for the 3D architecture of additively manufactured Ti-6Al-4V enhanced osteogenic differentiation of hMSCs beyond surface roughness alone. This study suggests that a 3D architecture may enhance the osseointegration of orthopedic and dental implants in vivo. PMID- 27501819 TI - The Role of Tumor Necrosis Factor Alpha and TNF Superfamily Members in Bone Damage in Patients with End-Stage Chronic Obstructive Lung Disease Prior to Lung Transplantation. AB - A disequilibrium of tumor necrosis superfamily (TNF) members, including the serum osteoprotegerin, soluble receptor activator of nuclear factor-kappaB ligand, soluble TNF-related apoptosis-inducing ligand and TNF-alpha, was associated with the occurrence of a reduced skeletal mass and osteoporosis in male patients with end-stage chronic obstructive pulmonary disease (COPD). The purpose of this study was to explore the associations between serum biomarkers of tumor necrosis factor (TNF) superfamily and body and bone compositions in end-stage COPD males. Pulmonary function, T-score at the lumbar spine and femoral neck, lean mass, serum osteoprotegerin (OPG), soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), TNF-alpha and its receptors (sTNFR-I, sTNFR-II) and soluble TNF related apoptosis-inducing ligand (sTRAIL) levels were evaluated in 48 male patients with end-stage COPD and 36 healthy male volunteers. OPG was lower in male COPD patients than in control subjects, whereas sRANKL, TNF-alpha and its receptors were higher. The serum sTRAIL level showed a tendency to increase compared with that of healthy subjects (P = 0.062). Serum OPG showed a positive correlation with bone density. In contrast, serum TNF-alpha, sRANKL and sTRAIL were inversely associated with pretransplant bone density. We have noted the appearance of statistically significant inverse relationships between lean mass values and TNF-alpha, sTNFR-I and II and sRANKL levels in male COPD patients. Moreover, there was a negative correlation between sTRAIL levels with airway obstruction (P = 0.005) and hypercapnia (P = 0.042) in advanced COPD patients. Through a multiple linear regression analysis, our study revealed that a disequilibrium of TNF family members was strongly associated with the occurrence of a reduced skeletal mass and osteoporosis. These results provide further evidence that abnormal levels of TNF superfamily molecules may cause not only a decrease in BMD, but also lower muscle mass in end-stage COPD. PMID- 27501820 TI - The association of parental education with childhood undernutrition in low- and middle-income countries: comparing the role of paternal and maternal education. AB - Background: Most existing research on the association of parental education with childhood undernutrition focuses on maternal education and often ignores paternal education. We systematically investigate differences in maternal and paternal education and their association with childhood undernutrition. Methods: One hundred and eighty Demographic and Health Surveys from 62 countries performed between 1990 and 2014 were analysed. We used linear-probability models to predict childhood undernutrition prevalences, measured as stunting, underweight and wasting, for all combinations of maternal and paternal attainment in school. Models were adjusted for demographic and socio-economic covariates for the child, mother and household, country-level fixed effects and clustering. Additional specifications adjust for local area characteristics instead of country fixed effects. Results: Both higher maternal and paternal education levels are associated with lower childhood undernutrition. In regressions adjusted for child age and sex as well as country-level fixed effects, the association is stronger for maternal education than for paternal education when their combined level of education is held constant. In the fully adjusted models, the observed differences in predicted undernutrition prevalences are strongly attenuated, suggesting a similar importance of maternal and paternal education. These findings are confirmed by the analysis of composite schooling indicators. Conclusions: We find that paternal education is similarly important for reducing childhood undernutrition as maternal education and should therefore receive increased attention in the literature. PMID- 27501821 TI - Transfemoral transcatheter aortic-valve replacement should be preferred over surgery in most intermediate-risk patients. PMID- 27501822 TI - Controlling the half-metallicity of Heusler/Si(1 1 1) interfaces by a monolayer of Si-Co-Si. AB - By using first-principles calculations we show that the spin-polarization reverses its sign at atomically abrupt interfaces between the half-metallic Co2(Fe,Mn)(Al,Si) and Si(1 1 1). This unfavourable spin-electronic configuration at the Fermi-level can be completely removed by introducing a Si-Co-Si monolayer at the interface. In addition, this interfacial monolayer shifts the Fermi-level from the valence band edge close to the conduction band edge of Si. We show that such a layer is energetically favourable to exist at the interface. This was further confirmed by direct observations of CoSi2 nano-islands at the interface, by employing atomic resolution scanning transmission electron microscopy. PMID- 27501823 TI - The dietary effect of milk sphingomyelin on the lipid metabolism of obese/diabetic KK-A(y) mice and wild-type C57BL/6J mice. AB - Purified milk sphingomyelin (SM) was obtained from lipid concentrated butter serum (LC-BS) by successive separations involving solvent fractionation, selective saponification, and silicic acid column chromatography. The SM obtained was given to obese/diabetic KK-A(y) mice and wild-type C57BL/6J mice. SM supplementation significantly increased fecal lipids paralleled with a decrease in non-HDL cholesterol levels in the serum and neutral lipids and in cholesterol levels in the livers of KK-A(y) mice. The reduction of liver lipid levels also resulted in a decrease in the total fatty acid content of the KK-A(y) mice livers, while n-3 fatty acids derived from the conversion of alpha-linolenic acid (18:3n-3) increased due to SM supplementation. In contrast to the KK-A(y) mice, little change in the serum and liver lipids was observed in wild-type C57BL/6J mice. The present study suggests that SM may be effective only in subjects with metabolic disorders. PMID- 27501824 TI - A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines. AB - A metal-free hydrogenation of 3-substituted 2H-1,4-benzoxazines has been successfully realized with 2.5 mol% of B(C6F5)3 as a catalyst to furnish a variety of 3,4-dihydro-2H-1,4-benzoxazines in 93-99% yields. Up to 42% ee was also achieved for the asymmetric hydrogenation with the use of a chiral diene and HB(C6F5)2. PMID- 27501826 TI - Organizing Exposure Data Is Beyond Conceptualization. PMID- 27501825 TI - Analyte-directed formation of emissive excimers for the selective detection of polyamines. AB - A convenient and selective method for the sensing of polyamines, which are important biomarkers for cancers, has been developed. The fluorescence light-up mechanism utilizes the analyte-induced formation of emissive excimers of a sulfonated probe. Detection is achieved in aqueous media and artificial urine samples, as indicated by an excellent fluorescence turn-on signal with a large spectral shift. PMID- 27501827 TI - Foldable Thermoelectric Materials: Improvement of the Thermoelectric Performance of Directly Spun CNT Webs by Individual Control of Electrical and Thermal Conductivity. AB - We suggest the fabrication of foldable thermoelectric (TE) materials by embedding conducting polymers into Au-doped CNT webs. The CNT bundles, which are interconnected by a direct spinning method to form 3D networks without interfacial contact resistance, provide both high electrical conductivity and high carrier mobility. The ZT value of the spun CNT web is significantly enhanced through two simple processes. Decorating the porous CNT webs with Au nanoparticles increases the electrical conductivity, resulting in an optimal ZT of 0.163, which represents a more than 2-fold improvement compared to the ZT of pristine CNT webs (0.079). After decoration, polyaniline (PANI) is integrated into the Au-doped CNT webs both to improve the Seebeck coefficient by an energy filtering effect and to decrease the thermal conductivity by the phonon scattering effect. This leads to a ZT of 0.203, which is one of the highest ZT values reported for organic TE materials. Moreover, Au-doped CNT/PANI web is ultralightweight, free-standing, thermally stable, and mechanically robust, which makes it a viable candidate for a hybrid TE conversion device for wearable electronics. When a 20 K temperature gradient is applied to the TE module consisting of seven p-n couples, 1.74 MUW of power is generated. PMID- 27501828 TI - An overview of the bacterial contribution to Crohn disease pathogenesis. AB - Crohn disease (CD) is a chronic inflammatory condition primarily affecting the gastro-intestinal tract and is characterized by reduced bacterial diversity. The exact cause of disease is unknown; however, evidence suggests that several components, including microbiota, may contribute to the underlying pathology and disease development. Perturbation of the host-microbe commensal relationship is considered the main driving force of tissue destruction and pathological changes seen in CD. Several putative bacterial pathogens including species from Mycobacterium, Campylobacter and Helicobacter are postulated in the aetiology of CD. However, to date, no strong evidence supports a single bacterium contributing overall to CD pathogenesis. Alternatively, dysbiosis or bacterial imbalance is more widely accepted as a leading factor in the disrupted host-immune system cross-talk resulting in subsequent intestinal inflammation. Depletion of symbiont microbes including Firmicutes, Bifidobacterium and Clostridia, in conjunction with an increase in pathobiont microbes from Bacteroidetes and Enterobacteria, is a striking feature observed in CD. No single factor has been identified as driving this dysbiosis, although diet, antibiotic exposure and possible early life events in presence of underlying genetic susceptibility may contribute. The aim of this review is to highlight the current accumulating literature on the proposed role of bacteria in the pathogenesis of CD. PMID- 27501829 TI - Understanding the pathophysiology of the human TB lung granuloma using in vitro granuloma models. AB - Tuberculosis remains a major human health threat that infects one in three individuals worldwide. Infection with Mycobacterium tuberculosis is a standoff between host and bacteria in the formation of a granuloma. This review will introduce a variety of bacterial and host factors that impact individual granuloma fates. The authors describe advances in the development of in vitro granuloma models, current evidence surrounding infection and granuloma development, and the applicability of existing in vitro models in the study of human disease. In vitro models of infection help improve our understanding of pathophysiology and allow for the discovery of other potential models of study. PMID- 27501830 TI - CXCR4 Overexpression in Human Adipose Tissue-Derived Stem Cells Improves Homing and Engraftment in an Animal Limb Ischemia Model. AB - We investigated the effects of transplantation of CXCR4-overexpressing adipose tissue-derived stem cells (ADSCs) into a mouse diabetic hindlimb ischemia model on homing and engraftment as early as 48 h after transplant. CXCR4-overexpressing ADSCs were intramuscularly or intravenously injected into diabetic mice with hindlimb ischemia. After 48 h, muscle tissues in the femur and tibia were collected, and the CXCR4 expression pattern was analyzed by immunofluorescence staining. The homing and engraftment of transplanted CXCR4-overexpressing ADSCs into the ischemic area were significantly increased, and intravenous (systemic) injection resulted in the more effective delivery of stem cells to the target site 48 h posttransplantation. Furthermore, CXCR4-overexpressing ADSCs more efficiently contributed to long-term engraftment and muscle tissue regeneration than normal ADSCs in a limb ischemia model. In addition, the homing and engraftment of ADSCs were correlated with the CXCR4 transfection efficiency. These results demonstrated that enhanced CXCR4 signaling could significantly improve the early homing and engraftment of ADSCs into ischemic areas as well as the long-term engraftment and ultimate muscle tissue regeneration. PMID- 27501831 TI - TREM2 p.H157Y Variant and the Risk of Alzheimer's Disease: A Meta-Analysis Involving 14,510 Subjects. AB - We recently revealed that p.H157Y (rs2234255), a rare coding variant of triggering receptor expressed on myeloid cells 2 gene (TREM2), was associated with Alzheimer's disease (AD) susceptibility in Han Chinese. Contrastingly, although p.H157Y was previously identified in both AD cases and controls by several sequencing studies, no association of this variant with disease susceptibility was reported. To gain a credible conclusion on the association between p.H157Y and AD risk, a meta-analysis involving 7,102 cases and 7,408 controls was conducted. Our results indicated that p.H157Y was associated with an increased risk of AD (OR=3.65, 95% CI: 1.61-8.28; P=0.002), further establishing TREM2 as an important susceptibility gene for this disease. PMID- 27501832 TI - Mesenchymal Stem Cell Secretome: A Potential Tool for the Prevention of Muscle Degenerative Changes Associated With Chronic Rotator Cuff Tears. AB - BACKGROUND: Massive rotator cuff tears (MRCTs) are usually chronic lesions with pronounced degenerative changes, where advanced fatty degeneration and atrophy can make the tear irreparable. Human mesenchymal stem cells (hMSCs) secrete a range of growth factors and vesicular systems, known as secretome, that mediates regenerative processes in tissues undergoing degeneration. PURPOSE: To study the effect of hMSC secretome on muscular degenerative changes and shoulder function on a rat MRCT model. STUDY DESIGN: Controlled laboratory study. METHODS: A bilateral 2-tendon (supraspinatus and infraspinatus) section was performed to create an MRCT in a rat model. Forty-four Wistar-Han rats were randomly assigned to 6 groups: control group (sham surgery), lesion control group (MRCT), and 4 treated-lesion groups according to the site and periodicity of hMSC secretome injection: single local injection, multiple local injections, single systemic injection, and multiple systemic injections. Forelimb function was analyzed with the staircase test. Atrophy and fatty degeneration of the muscle were evaluated at 8 and 16 weeks after injury. A proteomic analysis was conducted to identify the molecules present in the hMSC secretome that can be associated with muscular degeneration prevention. RESULTS: When untreated for 8 weeks, the MRCT rats exhibited a significantly higher fat content (0.73% +/- 0.19%) compared with rats treated with a single local injection (0.21% +/- 0.04%; P < .01) or multiple systemic injections (0.25% +/- 0.10%; P < .05) of hMSC secretome. At 16 weeks after injury, a protective effect of the secretome in the multiple systemic injections (0.62% +/- 0.14%; P < .001), single local injection (0.76% +/- 0.17%; P < .001), and multiple local injections (1.35% +/- 0.21%; P < .05) was observed when compared with the untreated MRCT group (2.51% +/- 0.42%). Regarding muscle atrophy, 8 weeks after injury, only the single local injection group (0.0993% +/- 0.0036%) presented a significantly higher muscle mass than that of the untreated MRCT group (0.0794% +/- 0.0047%; P < .05). Finally, the proteomic analysis revealed the presence of important proteins with muscle regeneration, namely, pigment epithelium-derived factor and follistatin. CONCLUSION: The study data suggest that hMSC secretome effectively decreases the fatty degeneration and atrophy of the rotator cuff muscles. CLINICAL RELEVANCE: We describe a new approach for decreasing the characteristic muscle degeneration associated with chronic rotator cuff tears. This strategy is particularly important for patients whose tendon healing after later surgical repair could be compromised by the progressing degenerative changes. In addition, both precise intramuscular local injection and multiple systemic secretome injections have been shown to be promising delivery forms for preventing muscle degeneration. PMID- 27501833 TI - Influence of the Heel-to-Toe Drop of Standard Cushioned Running Shoes on Injury Risk in Leisure-Time Runners: A Randomized Controlled Trial With 6-Month Follow up. AB - BACKGROUND: Modern running shoes are available in a wide range of heel-to-toe drops (ie, the height difference between the forward and rear parts of the inside of the shoe). While shoe drop has been shown to influence strike pattern, its effect on injury risk has never been investigated. Therefore, the reasons for such variety in this parameter are unclear. PURPOSE: The first aim of this study was to determine whether the drop of standard cushioned running shoes influences running injury risk. The secondary aim was to investigate whether recent running regularity modifies the relationship between shoe drop and injury risk. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Leisure-time runners (N = 553) were observed for 6 months after having received a pair of shoes with a heel-to-toe drop of 10 mm (D10), 6 mm (D6), or 0 mm (D0). All participants reported their running activities and injuries (time-loss definition, at least 1 day) in an electronic system. Cox regression analyses were used to compare injury risk between the 3 groups based on hazard rate ratios (HRs) and their 95% CIs. A stratified analysis was conducted to evaluate the effect of shoe drop in occasional runners (<6 months of weekly practice over the previous 12 months) versus regular runners (>=6 months). RESULTS: The overall injury risk was not different among the participants who had received the D6 (HR, 1.30; 95% CI, 0.86-1.98) or D0 (HR, 1.17; 95% CI, 0.76-1.80) versions compared with the D10 shoes. After stratification according to running regularity, low drop shoes (D6 and D0) were found to be associated with a lower injury risk in occasional runners (HR, 0.48; 95% CI, 0.23-0.98), whereas these shoes were associated with a higher injury risk in regular runners (HR, 1.67; 95% CI, 1.07 2.62). CONCLUSION: Overall, injury risk was not modified by the drop of standard cushioned running shoes. However, low-drop shoes could be more hazardous for regular runners, while these shoes seem to be preferable for occasional runners to limit injury risk. PMID- 27501834 TI - The Combined Use of Losartan and Muscle-Derived Stem Cells Significantly Improves the Functional Recovery of Muscle in a Young Mouse Model of Contusion Injuries. AB - BACKGROUND: Although muscle injuries tend to heal uneventfully in most cases, incomplete functional recovery commonly occurs as a result of scar tissue formation at the site of injury, even after treatment with muscle-derived stem cells (MDSCs). HYPOTHESIS: The transplantation of MDSCs in the presence of a transforming growth factor beta1 (TGF-beta1) antagonist (losartan) would result in decreased scar tissue formation and enhance muscle regeneration after contusion injuries in a mouse model. STUDY DESIGN: Controlled laboratory study. METHODS: An animal model of muscle contusion was developed using the tibialis anterior muscle in 48 healthy mice at 8 to 10 weeks of age. After sustaining muscle contusion injuries, the mice were divided into 4 groups: (1) saline injection group (control group; n = 15), (2) MDSC transplantation group (MDSC group; n = 15), (3) MDSC transplantation plus oral losartan group (MDSC/losartan group; n = 15), and (4) healthy uninjured group (healthy group; n = 3). Losartan was administrated systemically beginning 3 days after injury and continued until the designated endpoint (1, 2, or 4 weeks after injury). MDSCs were transplanted 4 days after injury. Muscle regeneration and fibrotic scar formation were evaluated by histology, and the expression of follistatin, MyoD, Smad7, and Smad2/3 were analyzed by immunohistochemistry and reverse transcription polymerase chain reaction analysis. Functional recovery was measured via electrical stimulation of the peroneal nerve. RESULTS: When compared with MDSC transplantation alone, MDSC/losartan treatment resulted in significantly decreased scar formation, an increase in the number of regenerating myofibers, and improved functional recovery after muscle contusions. In support of these findings, the expression levels of Smad7 and MyoD were significantly increased in the group treated with both MDSCs and losartan. CONCLUSION: When compared with MDSCs alone, the simultaneous treatment of muscle contusions with MDSCs and losartan significantly reduced scar formation, increased the number of regenerating myofibers, and improved the functional recovery of muscle; these effects were caused, at least in part, by the losartan-mediated upregulation of Smad7 and MyoD. Increased levels of Smad7 and MyoD together reduced the deposition of scar tissue (via the inhibition of TGF-beta1 by Smad7) and committed the transplanted MDSCs toward a myogenic lineage (via Smad7-regulated MyoD expression). CLINICAL RELEVANCE: The study findings contribute to the development of biological treatments to accelerate and improve the quality of muscle healing after injury. PMID- 27501835 TI - Arthroscopic Bankart Repair Versus Open Bristow-Latarjet for Shoulder Instability: A Matched-Pair Multicenter Study Focused on Return to Sport. AB - BACKGROUND: The arthroscopic Bankart repair and open Bristow-Latarjet procedure are the 2 most commonly used techniques to treat recurrent shoulder instability. PURPOSE: To compare in a case control-matched manner the 2 techniques, with particular emphasis on return to sport after surgery. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A study was conducted in 2 hospitals matching 60 patients with posttraumatic recurrent anterior shoulder instability with a minimum follow-up of 2 years (30 patients treated with arthroscopic Bankart procedure and 30 treated with open Bristow-Latarjet procedure). Patients with severe glenoid bone loss and revision surgeries were excluded. In one hospital, patients were treated with arthroscopic Bankart repair using anchors; in the other, patients underwent the Bristow-Latarjet procedure. Patients were matched according to age at surgery, type and level of sport practiced before shoulder instability (Degree of Shoulder Involvement in Sports [DOSIS] scale), and number of dislocations. The primary outcomes were return to sport (Subjective Patient Outcome for Return to Sports [SPORTS] score), rate of recurrent instability, Oxford Shoulder Instability Score (OSIS), Subjective Shoulder Value (SSV), Western Ontario Shoulder Instability Index (WOSI), and range of motion (ROM). RESULTS: After a mean follow-up of 5.3 years (range, 2-9 years), patients who underwent arthroscopic Bankart repair obtained better results in terms of return to sport (SPORTS score: 8 vs 6; P = .02) and ROM in the throwing position (86 degrees vs 79 degrees ; P = .01), and they reported better subjective perception of the shoulder (SSV: 86% vs 75%; P = .02). No differences were detectable using the OSIS or WOSI. The rate of recurrent instability was not statistically different between the 2 groups (Bankart repair 10% vs Bristow-Latarjet 0%; P = .25), although the study may have been underpowered to detect a clinically important difference in this parameter. The multiple regression analysis showed that the independent variables associated with return to sport were preoperative DOSIS scale, type of surgery, and recurrent dislocations after surgery. Patients who played sports with high upper extremity involvement (eg, swimming, rugby, martial arts) at a competitive level (DOSIS scale 9 or 10) had a lower level of return to sport with both repair techniques. CONCLUSION: Arthroscopic stabilization using anchors provided better return to sport and subjective perception of the shoulder compared with the open Bristow-Latarjet procedure in the population studied. Recurrence may be higher in the arthroscopic Bankart group; further study is needed on this point. PMID- 27501836 TI - Lower Limb Length Discrepancy After High Tibial Osteotomy: Prospective Randomized Controlled Trial of Lateral Closing Versus Medial Opening Wedge Osteotomy. AB - BACKGROUND: High tibial osteotomy (HTO) produces valgus limb alignment, and this change can affect lower limb length. PURPOSE: To compare the change in lower limb length and the discrepancy compared with the contralateral limb after unilateral lateral closing wedge HTO (CWHTO) and medial opening wedge HTO (OWHTO). STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: In this study, 30 knees undergoing unilateral CWHTO and 30 knees undergoing unilateral OWHTO for medial compartmental osteoarthritis were analyzed with 1-year follow up. The tibial length, lower limb length, and lower limb length discrepancy were measured preoperatively and 1 year postoperatively. The patients' subjective sensation of, and discomfort due to, the lower limb length discrepancy were recorded 1 year postoperatively. Univariate and multivariate linear regression analyses were conducted to identify predictors related to the change in lower limb length. RESULTS: The mean lengths of the tibia and lower limb increased significantly after OWHTO (5.2 +/- 3.7 and 7.6 +/- 2.1 mm, respectively; P < .001). The mean tibial length decreased significantly after CWHTO (-6.0 +/- 2.1 mm; P < .001); however, the mean lower limb length change was not significant ( 0.8 +/- 2.5 mm; P = .073). The mean lower limb length discrepancy increased significantly after OWHTO (-0.5 +/- 0.7 to 7.2 +/- 2.1 mm; P < .001) but not after CWHTO (-0.7 +/- 0.6 to -1.0 +/- 2.5 mm; P = .539). A significantly greater proportion of patients in the OWHTO group were aware of (70% vs 20%, respectively; P = .002), and uncomfortable because of (37% vs 7%, respectively; P = .010), the lower limb length discrepancy compared with those in the CWHTO group. The strongest predictor of a change in lower limb length was the wedge length in the OWHTO group and the preoperative hip-knee-ankle angle in the CWHTO group. CONCLUSION: The lower limb length change and discrepancy were significant after unilateral OWHTO, whereas they were negligible after unilateral CWHTO. CWHTO was more beneficial in cases of unilateral HTO to minimize the discrepancy of lower limb length rather than OWHTO, particularly in knees requiring a large correction. REGISTRATION: Clinical Trials Registry Platform (protocol number KCT00001684). PMID- 27501837 TI - Factors responsible for poor sleep quality in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Sleep disturbance is a common complaint in patients with chronic obstructive lung disease (COPD). However, the factors resulting in sleep disturbance remain unclear. This retrospective, observational, multicenter study aimed to identify the factors associated with sleep disturbance in patients with COPD. METHODS: The study was a retrospective, observational, and multicenter research. Data including age, sex, body mass index, smoking status, COPD inhaler prescribed, clinical symptoms, pulmonary function tests, medical history of comorbidities, and questionnaires were collected. Parameters including demographics, symptoms, medication, severity, functional classification, and comorbidities were correlated with sleep quality scores. RESULTS: Among 377 patients with COPD, 200 (53 %) patients experienced poor sleep quality (Pittsburg Sleep Quality Index scores > 5). A significant difference in sleep quality, as measured by PSQI scores, was noted between groups based on the 2011 Global Initiatives for Chronic Obstructive Lung Disease (GOLD) classification system. The most common sleep disturbances included "getting up to use the bathroom" (70.3 %), "wake up at night or early morning" (40.3 %), and "cough and snore loudly at night" (15.9 %). The use of inhaled corticosteroids, the presence of wheezing, COPD Assessment Test (CAT) scores, and Modified Medical Research Council (mMRC) dyspnea scale scores positively correlated with poor sleep quality (odds ratio: 1.51, 1.66, 1.09, and 1.30, respectively). Upon multivariate analysis, the CAT score was an independent factor for poor sleep quality in these patients. With the exception of sleep problem items, based on the CAT questionnaire, phlegm was significantly higher in COPD patients with poor sleep quality. CONCLUSIONS: Poor sleep quality is common among patients with COPD and symptoms including wheeze, phlegm, and inhaled corticosteroid use may contribute to poor sleep quality. The CAT score is a good indicator of poor sleep quality in patients with COPD. PMID- 27501838 TI - Transcriptome profiling of drought responsive noncoding RNAs and their target genes in rice. AB - BACKGROUND: Plant transcriptome profiling has provided a tool for understanding the mechanisms by which plants respond to stress conditions. Analysis of genome wide transcriptome will provides a useful dataset of drought responsive noncoding RNAs and their candidate target genes that may be involved in drought stress responses. RESULTS: Here RNA-seq analyses of leaves from drought stressed rice plants was performed, producing differential expression profiles of noncoding RNAs. We found that the transcript levels of 66 miRNAs changed significantly in response to drought conditions and that they were negatively correlated with putative target genes during the treatments. The negative correlations were further validated by qRT-PCR using total RNAs from both drought-treated leaves and various tissues at different developmental stages. The drought responsive miRNA/target pairs were confirmed by the presence of decay intermediates generated by miRNA-guided cleavages in Parallel Analysis of RNA Ends (PARE) libraries. We observed that the precursor miR171f produced two different mature miRNAs, miR171f-5p and miR171f-3p with 4 candidate target genes, the former of which was responsive to drought conditions. We found that the expression levels of the miR171f precursor negatively correlated with those of one candidate target gene, but not with the others, suggesting that miR171f-5p was drought-responsive, with Os03g0828701-00 being a likely target. Pre-miRNA expression profiling indicated that miR171f is involved in the progression of rice root development and growth, as well as the response to drought stress. Ninety-eight lncRNAs were also identified, together with their corresponding antisense transcripts, some of which were responsive to drought conditions. CONCLUSIONS: We identified rice noncoding RNAs (66 miRNAs and 98 lncRNAs), whose expression was highly regulated by drought stress conditions, and whose transcript levels negatively correlated with putative target genes. PMID- 27501839 TI - Healthcare Outbreaks Associated With Dental Unit Water Systems: Strong Scientific Evidence of Minimal Risk. PMID- 27501840 TI - Reply to Petti. PMID- 27501841 TI - The Spectrum of Serious Infections Among Patients Receiving Immune Checkpoint Blockade for the Treatment of Melanoma. AB - The risk of infection among patients receiving immune checkpoint blockade is unknown. We retrospectively reviewed medical records of 740 patients with melanoma who received immune checkpoint blockers. Serious infection occurred in 54 patients (7.3%). The main risk factors were receipt of corticosteroids and/or infliximab. PMID- 27501843 TI - Hospitalizations in Immigrants and Nonimmigrants Diagnosed With Chronic Hepatitis C Infection in Quebec. AB - BACKGROUND: Rates of hospitalization due to chronic hepatitis C virus (HCV) are increasing in Canada and the United States. A large proportion of immigrants originate from countries with intermediate to high HCV prevalence but are not screened for HCV post-arrival and may therefore have increased risks of liver related complications and hospitalization. METHODS: We conducted a retrospective cohort study of reported HCV cases in Quebec, Canada, from 1998 to 2007 that were linked to administrative health databases. Outcomes included all-cause and liver related hospitalizations and in-hospital days in immigrants compared with nonimmigrants adjusted for age, sex, and comorbidities. RESULTS: We identified 20 139 HCV cases; 9% (N = 1821) were immigrants. At diagnosis, immigrants were older (47.6 vs 43.2 years) and more likely to have hepatocellular carcinoma (HCC; 0.93% vs 0.31%), while nonimmigrants were 2- to 10-fold more likely to have substance use-related comorbidities. Mean time to HCV diagnosis after arrival was 9.8 years. Nonimmigrants had higher rates of all-cause hospitalization (adjusted rate ratio [95% confidence interval], 1.42 [1.35-1.47]), driven by mental illness and injury and/or poisoning. Unadjusted liver-related hospitalization rates were similar between cohorts. After adjustment, immigrant status was associated with lower rates of liver-related hospitalization (0.68 [.53-.88]). CONCLUSIONS: Higher burden of all-cause hospitalization in nonimmigrants likely reflects more prevalent behavioral comorbidities. Similar liver-related hospitalization rates appear to be driven by older age in immigrants who were more likely to have HCC at diagnosis possibly reflecting delayed HCV diagnosis. These findings suggest that earlier screening and treatment in immigrants could play an important role in preventing HCV complications in this population. PMID- 27501844 TI - Macracanthorhynchus ingens Infection in an 18-Month-Old Child in Florida: A Case Report and Review of Acanthocephaliasis in Humans. AB - A case of acanthocephaliasis in an 18-month-old child caused by Macracanthorhynchus ingens is reported from Florida. This represents only the third documented case of this species in a human host. An overview of human cases of acanthocephaliasis in the literature is presented, along with a review of the biology, clinical manifestations and pathology in the human host, morphology, and diagnosis. PMID- 27501845 TI - The Epigenetic Regulator HDAC1 Modulates Transcription of a Core Cardiogenic Program in Human Cardiac Mesenchymal Stromal Cells Through a p53-Dependent Mechanism. AB - Histone deacetylase (HDAC) regulation is an essential process in myogenic differentiation. Inhibitors targeting the activity of specific HDAC family members have been shown to enhance the cardiogenic differentiation capacity of discrete progenitor cell types; a key property of donor cell populations contributing to their afforded benefits in cardiac cell therapy applications. The influence of HDAC inhibition on cardiac-derived mesenchymal stromal cell (CMC) transdifferentiation or the role of specific HDAC family members in dictating cardiovascular cell lineage specification has not been investigated. In the current study, the consequences of HDAC inhibition on patient-derived CMC proliferation, cardiogenic program activation, and cardiovascular differentiation/cell lineage specification were investigated using pharmacologic and genetic targeting approaches. Here, CMCs exposed to the pan-HDAC inhibitor sodium butyrate exhibited induction of a cardiogenic transcriptional program and heightened expression of myocyte and endothelial lineage-specific markers when coaxed to differentiate in vitro. Further, shRNA knockdown screens revealed CMCs depleted of HDAC1 to promote the induction of a cardiogenic transcriptional program characterized by enhanced expression of cardiomyogenic- and vasculogenic specific markers, a finding which depended on and correlated with enhanced acetylation and stabilization of p53. Cardiogenic gene activation and elevated p53 expression levels observed in HDAC1-depleted CMCs were associated with improved aptitude to assume a cardiomyogenic/vasculogenic cell-like fate in vitro. These results suggest that HDAC1 depletion-induced p53 expression alters CMC cell fate decisions and identify HDAC1 as a potential exploitable target to facilitate CMC-mediated myocardial repair in ischemic cardiomyopathy. Stem Cells 2016;34:2916-2929. PMID- 27501842 TI - Epidemiology and Impact of Campylobacter Infection in Children in 8 Low-Resource Settings: Results From the MAL-ED Study. AB - BACKGROUND: Enteropathogen infections have been associated with enteric dysfunction and impaired growth in children in low-resource settings. In a multisite birth cohort study (MAL-ED), we describe the epidemiology and impact of Campylobacter infection in the first 2 years of life. METHODS: Children were actively followed up until 24 months of age. Diarrheal and nondiarrheal stool samples were collected and tested by enzyme immunoassay for Campylobacter Stool and blood samples were assayed for markers of intestinal permeability and inflammation. RESULTS: A total of 1892 children had 7601 diarrheal and 26 267 nondiarrheal stool samples tested for Campylobacter We describe a high prevalence of infection, with most children (n = 1606; 84.9%) having a Campylobacter positive stool sample by 1 year of age. Factors associated with a reduced risk of Campylobacter detection included exclusive breastfeeding (risk ratio, 0.57; 95% confidence interval, .47-.67), treatment of drinking water (0.76; 0.70-0.83), access to an improved latrine (0.89; 0.82-0.97), and recent macrolide antibiotic use (0.68; 0.63-0.74). A high Campylobacter burden was associated with a lower length-for-age Z score at 24 months (-1.82; 95% confidence interval, -1.94 to 1.70) compared with a low burden (-1.49; -1.60 to -1.38). This association was robust to confounders and consistent across sites. Campylobacter infection was also associated with increased intestinal permeability and intestinal and systemic inflammation. CONCLUSIONS: Campylobacter was prevalent across diverse settings and associated with growth shortfalls. Promotion of exclusive breastfeeding, drinking water treatment, improved latrines, and targeted antibiotic treatment may reduce the burden of Campylobacter infection and improve growth in children in these settings. PMID- 27501846 TI - Nanoroughened adhesion-based capture of circulating tumor cells with heterogeneous expression and metastatic characteristics. AB - BACKGROUND: Circulating tumor cells (CTCs) have shown prognostic relevance in many cancer types. However, the majority of current CTC capture methods rely on positive selection techniques that require a priori knowledge about the surface protein expression of disseminated CTCs, which are known to be a dynamic population. METHODS: We developed a microfluidic CTC capture chip that incorporated a nanoroughened glass substrate for capturing CTCs from blood samples. Our CTC capture chip utilized the differential adhesion preference of cancer cells to nanoroughened etched glass surfaces as compared to normal blood cells and thus did not depend on the physical size or surface protein expression of CTCs. RESULTS: The microfluidic CTC capture chip was able to achieve a superior capture yield for both epithelial cell adhesion molecule positive (EpCAM+) and EpCAM- cancer cells in blood samples. Additionally, the microfluidic CTC chip captured CTCs undergoing transforming growth factor beta-induced epithelial-to-mesenchymal transition (TGF-beta-induced EMT) with dynamically down regulated EpCAM expression. In a mouse model of human breast cancer using EpCAM positive and negative cell lines, the number of CTCs captured correlated positively with the size of the primary tumor and was independent of their EpCAM expression. Furthermore, in a syngeneic mouse model of lung cancer using cell lines with differential metastasis capability, CTCs were captured from all mice with detectable primary tumors independent of the cell lines' metastatic ability. CONCLUSIONS: The microfluidic CTC capture chip using a novel nanoroughened glass substrate is broadly applicable to capturing heterogeneous CTC populations of clinical interest independent of their surface marker expression and metastatic propensity. We were able to capture CTCs from a non-metastatic lung cancer model, demonstrating the potential of the chip to collect the entirety of CTC populations including subgroups of distinct biological and phenotypical properties. Further exploration of the biological potential of metastatic and presumably non-metastatic CTCs captured using the microfluidic chip will yield insights into their relevant differences and their effects on tumor progression and cancer outcomes. PMID- 27501847 TI - The secondary coordination sphere and axial ligand effects on oxygen reduction reaction by iron porphyrins: a DFT computational study. AB - Oxygen reduction reaction (ORR) catalyzed by a bio-inspired iron porphyrin bearing a hanging carboxylic acid group over the porphyrin ring, and a tethered axial imidazole ligand was studied by DFT calculations. BP86 free energy calculations of the redox potentials and pK a's of reaction components involved in the proton coupled electron transfer (PCET) reactions of the ferric-hydroxo and -superoxo complexes were performed based on Born-Haber thermodynamic cycle in conjunction with a continuum solvation model. The comparison was made with iron porphyrins that lack either in the hanging acid group or axial ligand, suggesting that H-bond interaction between the carboxylic acid and iron-bound hydroxo, aquo, superoxo, and peroxo ligands (de)stabilizes the Fe-O bonding, resulting in the increase in the reduction potential of the ferric complexes. The axial ligand interaction with the imidazole raises the affinity of the iron-bound superoxo and peroxo ligands for proton. In addition, a low-spin end-on ferric-hydroperoxo intermediate, a key precursor for O-O cleavage, can be stabilized in the presence of axial ligation. Thus, selective and efficient ORR of iron porphyrin can be achieved with the aid of the secondary coordination sphere and axial ligand interactions. PMID- 27501848 TI - Comparison of Clinical Results Following the Use of Drug-Eluting Balloons for a Bare-Metal Stent and Drug-Eluting Stent Instent Restenosis. AB - BACKGROUND: Drug-eluting balloons (DEBs) have emerged as a potential alternative to current treatments of instent restenosis (ISR). The study aims to investigate the clinical outcomes of a DEB angioplasty to treat bare-metal stent (BMS) ISR and drug-eluting stent (DES) ISR at 1-year clinical follow-up period. METHODS: Between November 2011 and December 2014, 312 patients were diagnosed with coronary artery ISR at our hospital. A total of 426 coronary ISR lesions were treated with DEBs. The clinical outcomes, including target lesion revascularization (TLR), myocardial infarction, stroke, cardiovascular mortality, and all-cause mortality were compared between the BMS-ISR group and DES-ISR group. Propensity score matched analysis was used to minimize bias. RESULTS: The average age of the patients was 64.99 +/- 10.35 years, and 76.9% of the patients were male. After multivariate Cox regression analyses about 1-year recurrent restenosis in DES-ISR group, only end stage renal disease (ESRD) (P = 0.047) and previous DEB failure (P < 0.001) were identified with significant difference. After propensity score matched analysis, the bias of baseline characteristics showed no significant difference. The DES-ISR group experienced more myocardial infarctions (2.8% vs 8.3%, P = 0.075), more TLR (8.1% vs 15.4%, P = 0.051), especially at nonostial lesion (5.7% vs 14.9%, P = 0.030) than the BMS-ISR group. Higher incidence of major cardiac cerebral adverse events happened in the DES-ISR group. (11.7% vs 22.1 %, P = 0.038) CONCLUSION: During the 1-year follow-up period, DEBs angioplasty for BMS-ISR had better clinical outcomes and less TLR than DES-ISR. ESRD and previous DEB failure were associated to TLR in DES-ISR group. PMID- 27501849 TI - Calibration of parameters for cardiovascular models with application to arterial growth. AB - We present a computational framework for the calibration of parameters describing cardiovascular models with a focus on the application of growth of abdominal aortic aneurysms (AAA). The growth rate in this sort of pathology is considered a critical parameter in the risk management and is an essential indicator for the assessment of surveillance intervals. Parameters describing growth of AAAs are not measurable directly and need to be estimated from available data often given by medical imaging technologies. Registration procedures often applied in standard workflows of parameter identification to extract the image encoded information are a source of significant systematic error. The concept of surface currents provides means to effectively avoid this source of errors by establishing a mathematical framework to compare surface information, directly accessible from image data. By utilizing this concept it is possible to inversely estimate growth parameters using sophisticated numerical models of AAAs from measurements available as surface information. In this work we present a framework to obtain spatial distributions of parameters governing growth of arterial tissue, and we show how the use of surface currents can significantly improve the results. We further present the application to patient specific follow-up data resulting in a spatial map of volumetric growth rates enabling, for the first time, prediction of further AAA expansion. PMID- 27501850 TI - Programmed cell death-1 blockade enhances response to stereotactic radiation in an orthotopic murine model of hepatocellular carcinoma. AB - AIM: Small, solitary hepatocellular carcinoma is curable with stereotactic radiation or other methods of tumor ablation, however, regional and systemic tumor recurrence occurs in over 70% of patients. Here we describe the ability of immunoradiotherapy to induce an antitumor immune response and delay the growth of tumors in immunocompetent mice. METHODS: A syngeneic hepatocellular carcinoma cell line (Hep-55.1c) was injected directly into the livers of C57BL/6 mice using ultrasound guidance, then tumors were treated with stereotactic radiation using a Small Animal Radiation Research Platform with computed tomography guidance. RESULTS: Delivery of three doses of 250 MUg anti-programmed cell death protein-1 (alphaPD-1) antibody concurrently with 30 Gy stereotactic body radiation therapy in three fractions reduced the growth rate of tumors and improved survival (P < 0.05). Combined treatment was associated with increased CD8+ cytotoxic T cells in the tumor; depletion of CD8 T cells eliminated the efficacy of combined treatment. Combined treatment also induced expression of programmed cell death-1 ligand expression on tumor-infiltrating macrophages, and the tumors grew rapidly after alphaPD-1 treatment was discontinued. CONCLUSIONS: Tumor response to stereotactic radiation can be augmented by concurrent treatment with alphaPD-1. The efficacy of this combination therapy was transient, however, and treatment induced markers of adaptive immune resistance. These data are promising, but also indicate that mechanisms of immune resistance will need to be durably overcome for this combination to generate lasting immunity to protect against tumor recurrence. PMID- 27501851 TI - Impact of treatment duration of neoadjuvant FIRINOX in patients with borderline resectable pancreatic cancer: a pilot trial. AB - PURPOSE: The aim of this pilot study is to confirm the safety and efficacy of neoadjuvant therapy and also treatment duration efficacy using modified FOLFIRINOX for patients with borderline resectable pancreatic cancer (BRPC). METHODS: The study is a prospective multicenter pilot trial conducted on patients with BRPC. Intervention for clinical trials: Modified FOLFIRINOX (without bolus 5 FU and LV, also decreased the dose of irinotecan; FIRINOX) was given to the first five patients in the 4-cycle group of the regimen and next five patients in the 8 cycle group. The primary end point was the toxicity of the therapy and one of the secondary end points were the optimal duration. RESULTS: The overall rate of grade 3 and 4 events was 80 %: 3 patients (60 %) in the four-cycle group and five patients (100 %) in the eight-cycle group had grade 3 or 4 adverse events. There was no incidence of serious adverse effect such as febrile neutropenia, sepsis, liver abscess or uncontrollable diarrhea. There was no clinically relevant morbidity presented in patients who underwent surgery. R0 rates by intention to treat were 60.0 % in the four-cycle group and 40 % in the eight-cycle group (P = 0.999). The histopathologic treatment effect based on the Evans grade revealed grade I (n = 1), IIa (n = 3) in the four-cycle group and grade I (n = 2), IIa (n = 1) in the eight-cycle group. CONCLUSIONS: FIRINOX therapy was feasible and safe for strictly selected patients with BRPC. Four cycles of FIRINOX would be sufficient for patients with BRPC as neoadjuvant therapy. PMID- 27501852 TI - Repositioning organohalogen drugs: a case study for identification of potent B Raf V600E inhibitors via docking and bioassay. AB - Drug repositioning has been attracting increasingly attention for its advantages of reducing costs and risks. Statistics showed that around one quarter of the marketed drugs are organohalogens. However, no study has been reported, to the best of our knowledge, to aim at efficiently repositioning organohalogen drugs, which may be attributed to the lack of accurate halogen bonding scoring function. Here, we present a study to show that two organohalogen drugs were successfully repositioned as potent B-Raf V600E inhibitors via molecular docking with halogen bonding scoring function, namely D(3)DOCKxb developed in our lab, and bioassay. After virtual screening by D(3)DOCKxb against the database CMC (Comprehensive Medicinal Chemistry), 3 organohalogen drugs that were predicted to form strong halogen bonding with B-Raf V600E were purchased and tested with ELISA-based assay. In the end, 2 of them, rafoxanide and closantel, were identified as potent inhibitors with IC50 values of 0.07 MUM and 1.90 MUM, respectively, which are comparable to that of vemurafenib (IC50: 0.17 MUM), a marketed drug targeting B Raf V600E. Single point mutagenesis experiments confirmed the conformations predicted by D(3)DOCKxb. And comparison experiment revealed that halogen bonding scoring function is essential for repositioning those drugs with heavy halogen atoms in their molecular structures. PMID- 27501854 TI - Mild Palladium Catalyzed ortho C-H Bond Functionalizations of Aniline Derivatives. AB - This account collects the developments and transformations which avoid the utilization of harsh reaction conditions in the field of palladium catalyzed, ortho-directed C-H activation of aniline derivatives from the first attempts to up-to-date results, including the results of our research laboratory. The discussed functionalizations performed under mild conditions include acylation, olefination, arylation, alkylation, alkoxylation reactions. Beside the optimization studies and the synthetic applications mechanistic investigations are also presented. PMID- 27501853 TI - Pilot Trial of Intravenous Lipid Emulsion Treatment for Severe Nifedipine-Induced Shock. AB - Animal studies and human case reports show promise in using lipid rescue to treat refractory calcium channel antagonist toxicity. However, the majority of research and clinical experience has focused on non-dihydropyridine agents. Thus, we sought to investigate the value of lipid emulsion (ILE) therapy for dihydropyridine-induced shock. This IACUC-approved study utilized seven swine that were sedated with alpha-chloralose, mechanically ventilated, and instrumented for drug delivery and hemodynamic measures. After stabilization and basal measures, nifedipine (0.01875 mg/kg/min) was infused until imminent cardiac arrest (seizure, end tidal CO2 < 10 mmHg, bradydysrhythmia, or pulseless electrical activity). Animals then received a 7 mL/kg bolus of 20% lipid emulsion via central catheter. Lipid circulation was visually confirmed by the presence of fat in peripheral arterial blood. Hemodynamics were continuously monitored until 10 min after lipid bolus. Surviving animals were euthanized. Pre- and post-lipid treatment parameters were analyzed using the Wilxocon signed rank test (p <0.05 significant). Nifedipine toxicity was characterized by vasodilatory hypotension, impaired vascular contractility, and tachycardia with terminal bradycardia. The median time to imminent cardiac arrest from start of nifedipine infusion was 218 min. Lipid treatment did not improve hemodynamics or restore circulation in any animal. There was no benefit from lipid rescue in this model of nifedipine toxicity. Further study of ILE for dihydropyridine toxicity is warranted but initial animal model results are not promising. PMID- 27501855 TI - Environmental selection of planktonic methanogens in permafrost thaw ponds. AB - The warming and thermal erosion of ice-containing permafrost results in thaw ponds that are strong emitters of methane to the atmosphere. Here we examined methanogens and other Archaea, in two types of thaw ponds that are formed by the collapse of either permafrost peat mounds (palsas) or mineral soil mounds (lithalsas) in subarctic Quebec, Canada. Using high-throughput sequencing of a hypervariable region of 16S rRNA, we determined the taxonomic structure and diversity of archaeal communities in near-bottom water samples, and analyzed the mcrA gene transcripts from two sites. The ponds at all sites were well stratified, with hypoxic or anoxic bottom waters. Their archaeal communities were dominated by Euryarchaeota, specifically taxa in the methanogenic orders Methanomicrobiales and Methanosarcinales, indicating a potentially active community of planktonic methanogens. The order Methanomicrobiales accounted for most of the mcrA transcripts in the two ponds. The Archaeal communities differed significantly between the lithalsa and palsa ponds, with higher alpha diversity in the organic-rich palsa ponds, and pronounced differences in community structure. These results indicate the widespread occurrence of planktonic, methane-producing Archaea in thaw ponds, with environmental selection of taxa according to permafrost landscape type. PMID- 27501856 TI - Can we improve the therapy of Clostridium difficile infection in elderly patients? AB - BACKGROUND: Clostridium difficile infection (CDI) is becoming a serious problem predominantly in geriatric patients, who are a significant risk group. The goal of this study was to evaluate the risk factors for mortality in CDI patients and to construct a binary logistic regression model that describes the probability of mortality in geriatric patients suffering from CDI. METHODS: In this retrospective study, we evaluated a group of 235 patients over 65 years of age with confirmed diagnoses of CDI, hospitalized at the Department of Internal Medicine, Geriatrics and General Practice, Brno, from January 2008 to December 2013. The examined group comprised 148 women (63 %) and 87 men (37 %). For the diagnosis of CDI, confirmation of A and B toxins in the patients' stool or an autopsy confirmation was crucial. RESULTS: The impact of antibiotic therapy on the increased incidence of CDI was clearly confirmed in our study group when examining patients' histories. Other risk factors included cerebrovascular disease, dementia, the presence of pressure ulcers, and immobility. Our new model consisted of a combination of the following parameters: the number of antibiotics used (from patients' history), nutritional status (Mini Nutritional Assessment short-form test), presence of pressure ulcers, and occurrence of fever. CONCLUSION: Our logistic regression model may predict mortality in geriatric patients suffering from CDI. This could help improve the therapeutic process. PMID- 27501857 TI - Tuning the Drug Loading and Release of DNA-Assembled Gold-Nanorod Superstructures. AB - The use of DNA to assemble inorganic nanoparticles into superstructures is an emerging strategy to build non-toxic delivery vehicles for targeting diseases in the body. The impact of the core-satellite nanosystem design in mediating drug storage, drug release (via heat), and killing of HeLa cells in culture is investigated. PMID- 27501858 TI - Helicity-dependent photocurrent induced by the in-plane transverse electric current in an InAs quantum well. AB - We report the observation of a new type of helicity-dependent photocurrent induced by an in-plane transverse direct electric current in an InAs quantum well. The amplitude of the photocurrent depends linearly on the transverse current. Moreover, the observed incident azimuth-angle dependence of this photocurrent is different from that induced by the circular photogalvanic effect. This new photocurrent appears as a result of an asymmetrical carrier distribution in both the conduction and valence bands induced by the transverse current. The photoexcited carrier density created by interband transition processes is thus modulated and leads to the observed new azimuth-angle dependence. The observed efficient generation of the helicity-dependent photocurrent offers an effective approach to manipulate electron spins in two-dimensional semiconductor systems with the added advantage of electrical control of the spin-related photocurrent in spintronic applications. PMID- 27501859 TI - The acceptability of three vaccine injections given to infants during a single clinic visit in South Africa. AB - BACKGROUND: The Expanded Programme on Immunisation (EPI) has increased the number of antigens and injections administered at one visit. There are concerns that more injections at a single immunisation visit could decrease vaccination coverage. We assessed the acceptability and acceptance of three vaccine injections at a single immunisation visit by caregivers and vaccinators in South Africa. METHODS: A mixed methods exploratory study of caregivers and vaccinators at clinics in two provinces of South Africa was conducted. Quantitative and qualitative data were collected using questionnaires as well as observations of the administration of three-injection vaccination sessions. RESULTS: The sample comprised 229 caregivers and 98 vaccinators. Caregivers were satisfied with the vaccinators' care (97 %) and their infants receiving immunisation injections (93 %). However, many caregivers, (86 %) also felt that three or more injections were excessive at one visit. Caregivers had limited knowledge of actual vaccines provided, and reasons for three injections. Although vaccinators recognised the importance of informing caregivers about vaccination, they only did this sometimes. Overall, acceptance of three injections was high, with 97 % of caregivers expressing willingness to bring their infant for three injections again in future visits despite concerns about the pain and discomfort that the infant experienced. Many (55 %) vaccinators expressed concern about giving three injections in one immunisation visit. However, in 122 (95 %) observed three injection vaccination sessions, the vaccinators administered all required vaccinations for that visit. The remaining seven vaccinations were not completed because of vaccine stock-outs. CONCLUSIONS: We found high acceptance by caregivers and vaccinators of three injections. Caregivers' poor understanding of reasons for three injections resulted from limited information sharing by vaccinators for caregivers. Acceptability of three injections may be improved through enhanced vaccinator-caregiver communication, and improved management of infants' pain. Vaccinator training should include evidence-informed ways of communicating with caregivers and reducing injection pain. Strategies to improve acceptance and acceptability of three injections should be rigorously evaluated as part of EPI's expansion in resource-limited countries. PMID- 27501860 TI - 2-(Maleimidomethyl)-1,3-Dioxanes (MD): a Serum-Stable Self-hydrolysable Hydrophilic Alternative to Classical Maleimide Conjugation. AB - The vast majority of antibody-drug conjugates (ADC) are prepared through amine-to thiol conjugation. To date, N-Succinimidyl-4-(maleimidomethyl) cyclohexanecarboxylate (SMCC) has been one of the most frequently applied reagents for the preparation of ADC and other functional conjugates. However, SMCC-based conjugates suffer from limited stability in blood circulation and from a hydrophobic character of the linker, which may give rise to major pharmacokinetic implications. To address this issue, we have developed a heterobifunctional analogue of a SMCC reagent, i.e., sodium 4-(maleimidomethyl) 1,3-dioxane-5-carbonyl)oxy)-2,3,5,6- tetrafluorobenzenesulfonate (MDTF) for amine to-thiol conjugation. By replacing the cyclohexyl ring in the SMCC structure with the 1,3-dioxane, we increased the hydrophilicity of the linker. A FRET probe based on MD linker was prepared and showed superior stability compared to the MCC linker in human plasma, as well as in a variety of aqueous buffers. A detailed investigation demonstrated an accelerated succinimide ring opening for MD linker, resulting in stabilized conjugates. Finally, the MDTF reagent was applied for the preparation of serum stable antibody-dye conjugate. PMID- 27501861 TI - A la Peche aux Moules. AB - In a recent manuscript, Goff and collaborators (Metzger et al. 2016) reported data arguing for the spread of contagious cancer cells among different species of shellfish. Although horizontal transmission of cancer cells has been observed in a few cases in higher organisms, it appears to be rather frequent among molluscs. Recent evidence supports the concept of inter-species horizontal infectious transmission of cancer cells both in molluscs but also in mammals, including humans. PMID- 27501862 TI - Asthma-COPD overlap syndrome (ACOS) vs 'pure' COPD: a distinct phenotype? AB - BACKGROUND: Some studies suggest that asthma-COPD overlap syndrome (ACOS) is associated with worse outcomes than chronic obstructive pulmonary disease (COPD). The goal of this study was to further explore the clinical characteristics and survival of patients with ACOS identified in a real-life cohort of patients with COPD. METHODS: Data from the French COPD cohort 'INITIATIVES BronchoPneumopathie Chronique Obstructive' (n = 998 patients) were analyzed to assess the frequency of ACOS defined as a physician diagnosis of asthma before the age of 40 years and to analyze its impact. Univariate analyses were performed to assess the relationship between ACOS and sociodemographic characteristics, risk factors (smoking, occupational exposure, atopic diseases), symptoms (chronic bronchitis, dyspnea-modified Medical Research Council scale and baseline dyspnea index), quality of life (QoL), mood disorders, exacerbations, comorbidities, lung function, prescribed treatment, and survival. RESULTS: ACOS was diagnosed in 129 patients (13%). In multivariate analyses, ACOS was associated negatively with cumulative smoking (odds ratio [OR]: 0.992; 95% CI 0.984-1.000 per pack-year) and positively with obesity: OR: 1.97 [1.22-3.16], history of atopic disease (hay fever: OR: 5.50 [3.42-9.00] and atopic dermatitis: OR 3.76 [2.14-6.61]), and drug use (LABA + ICS: 1.86 [1.27-2.74], antileukotrienes 4.83 [1.63-14.34], theophylline: 2.46 [1.23-4.91], and oral corticosteroids: [2.99;.1.26-7.08]). No independent association was found with dyspnea, QoL, exacerbations, and mortality. CONCLUSIONS: Compared to 'pure' COPD patients, patients with ACOS exhibit lower cumulative smoking, suffer more from obesity and atopic diseases, and use more asthma treatments. Disease severity (dyspnea, QoL, exacerbations, comorbidities) and prognosis (mortality) are not different from 'pure' COPD patients. PMID- 27501863 TI - Burden of atrial fibrillation: a retrospective review of patients presenting to acute medical services. AB - BACKGROUND: Atrial fibrillation (AF) is a major risk factor for stroke and is associated with increased stroke severity and greater morbidity and mortality. Anticoagulation is highly effective for preventing episodes of thromboembolism but remains under-utilised. AIMS: The aim of this review was to estimate the short-term risk of thromboembolic events in patients presenting with an acute medical illness, to assess rates of anticoagulation in eligible patients with AF and to describe physician decisions when prescribing anticoagulation in a hospital setting. METHODS: A retrospective cohort analysis of patients with AF presenting to acute medical services at Wellington Regional Hospital between 1 January 2012 and 31 December 2012 was performed. RESULTS: A total of 751 patient presentations with AF was identified; 613 unique patient encounters were eligible for analysis, and 38.8% of patients with a CHA2 DS2 -VASc score >=2 were discharged after anticoagulation. The mean CHA2 DS2 -VASc score was 4.03 (SD = 1.94). The CHA2 DS2 -VASc score was not associated with being started on anticoagulation, odds ratio 1.16 (95% confidence interval = 0.83-1.61), P = 0.38, but age by decade older was associated with a reduced likelihood of being started on anticoagulation, odds ratio 0.61 (95% confidence interval = 0.41-0.89), P = 0.01. In untreated patients with a CHA2 DS2 -VASc score >=2, the most frequently documented reasons not to initiate anticoagulation were decision deferred to the primary care physician, 15.6%; fall risk or frailty, 7.2%; and high bleeding risk, 6.6%. However, no reason was documented in 56.9%. The thromboembolic rate in patients discharged without anticoagulation within 3 months of presentation to acute medical services was 7/330 (2.1%). CONCLUSION: Anticoagulation for stroke prevention in AF remains under-utilised in eligible patients presenting to acute medical services at a tertiary-level hospital. PMID- 27501864 TI - Iron intakes and status of 2-year-old children in the Cork BASELINE Birth Cohort Study. AB - Young children are at risk of iron deficiency and subsequent anaemia, resulting in long-term consequences for cognitive, motor and behavioural development. This study aimed to describe the iron intakes, status and determinants of status in 2 year-old children. Data were collected prospectively in the mother-child Cork BASELINE Birth Cohort Study from 15 weeks' gestation throughout early childhood. At the 24-month assessment, serum ferritin, haemoglobin and mean corpuscular volume were measured, and food/nutrient intake data were collected using a 2-day weighed food diary. Iron status was assessed in 729 children (median [IQR] age: 2.1 [2.1, 2.2] years) and 468 completed a food diary. From the food diary, mean (SD) iron intakes were 6.8 (2.6) mg/day and 30% had intakes < UK Estimated Average Requirement (5.3 mg/day). Using WHO definitions, iron deficiency was observed in 4.6% (n = 31) and iron deficiency anaemia in five children (1.0%). Following an iron series workup, five more children were diagnosed with iron deficiency anaemia. Twenty-one per cent had ferritin concentrations <15 ug/L. Inadequate iron intakes (OR [95% CI]: 1.94 [1.09, 3.48]) and unmodified cows' milk intakes >= 400 mL/day (1.95 [1.07, 3.56]) increased the risk of low iron status. Iron-fortified formula consumption was associated with decreased risk (0.21 [0.11, 0.41] P < 0.05). In this, the largest study in toddlers in Europe, a lower prevalence of low iron status was observed than in previous reports. Compliance with dietary recommendations to limit cows' milk intakes in young children and consumption of iron-fortified products appears to have contributed to improved iron status at two years. PMID- 27501866 TI - Isolation, identification and characterisation of ballan wrasse Labrus bergylta plasma pigment. AB - This study confirmed that observations of blue-green colouration in plasma fractions of the ballan wrasse Labrus bergylta were caused by the linear tetra pyrrole biliverdin and that the molecule was of the physiologically relevant IXalpha isomer. Accumulation appears driven by chromogenic association with an unknown protein moiety which precludes enzymatic reduction and would suggest active management. It was demonstrated that the pigment did not fluctuate relative to ontogeny, or indeed binary gender in the species of interest, but mobilisation and depletion in the subset of individuals undergoing sex change at the time of study supports a potential association with gender inversion processes. It is of note that although biliverdin does have some effect on external colouration, the evidence is indicative that crypsis is a supplementary function thus other factors must be considered. PMID- 27501867 TI - A tale of loss of privilege, resilience and change: the impact of the economic crisis on physicians and medical services in Portugal. AB - That the current economic crisis is having an impact on population health and healthcare utilisation across Europe is fairly established; how national health systems and markets are reacting is however still poorly understood. Drawing from the economic literature we conducted 21 interviews with physicians, policy-makers and healthcare managers in Portugal, to explore their perceptions on the impact of the crisis on the country's market medical services, on physicians' motivation, and the ensuing coping strategies. Interviews were recorded, transcribed and analysed using NVivo software. We show that despite the crisis, few physicians reported considering leaving the public sector and the country, and very diverse coping strategies are emerging, depending on the respective employment institutions and seniority. In spite of the changes in patient case mix, demand for medical services may not have necessarily increased, having shifted from public to private, with many highlighting the contribution of the current crisis in consolidating the private sector. In order to maintain their pre-crisis living standards amidst deteriorating salaries and increasing controls, hospital physicians have resorted to strategies such as shifting hours to the private, and primary care ones to anticipating their retirement. Migration was reported to be an option only for the younger and older doctors. Our study suggests the existence of resilience among Portuguese physicians and in the country's market for medical services, which, if corroborated by further research, will need to be taken into account by national health policies. PMID- 27501865 TI - Changes in total plasma and serum N-glycome composition and patient-controlled analgesia after major abdominal surgery. AB - Systemic inflammation participates to the complex healing process occurring after major surgery, thus directly affecting the surgical outcome and patient recovery. Total plasma N-glycome might be an indicator of inflammation after major surgery, as well as an anti-inflammatory therapy response marker, since protein glycosylation plays an essential role in the inflammatory cascade. Therefore, we assessed the effects of surgery on the total plasma N-glycome and the association with self-administration of postoperative morphine in two cohorts of patients that underwent major abdominal surgery. We found that plasma N-glycome undergoes significant changes one day after surgery and intensifies one day later, thus indicating a systemic physiological response. In particular, we observed the increase of bisialylated biantennary glycan, A2G2S[3,6]2, 12 hours after surgery, which progressively increased until 48 postoperative hours. Most changes occurred 24 hours after surgery with the decrease of most core-fucosylated biantennary structures, as well as the increase in sialylated tetraantennary and FA3G3S[3,3,3]3 structures. Moreover, we observed a progressive increase of sialylated triantennary and tetraantennary structures two days after surgery, with a concomitant decrease of the structures containing bisecting N acetylglucosamine along with bi- and trisialylated triantennary glycans. We did not find any statistically significant association between morphine consumption and plasma N-glycome. PMID- 27501869 TI - Comparative analysis of in vitro characteristics of fresh and frozen-thawed urethral and epididymal spermatozoa from cats (Felis domesticus). AB - The first aim of this study was to provide a comprehensive analysis of structural and functional features of spermatozoa in semen collected from the same cat by two methods: urethral catheterization and epididymis slicing. The second aim was to assess if feline urethral (CT) and epididymal (EP) spermatozoa undergo the same changes during cryopreservation and to compare the postthaw characteristics of spermatozoa collected by the two methods. In the first phase, CT and EP semen were collected from 20 cats, and sperm motility, viability, morphology, computer assisted sperm analysis (CASA) parameters, membrane and acrosome integrity, mitochondrial potential, lipid peroxidation, and chromatin status were assessed. In the second phase, both types of semen collected from 10 cats were cryopreserved, thawed, and the same sperm parameters were assessed as in fresh semen. Fresh CT spermatozoa (phase I) showed higher (P < 0.05) motility (subjective: median 75.0% vs. 62.5%; by CASA: mean +/- SD 60.2 +/- 10.7% vs. 43.1 +/- 16.7%), morphology (mean +/- SD, 57.5 +/- 9.6% vs. 45.2 +/- 15.9%), and membrane integrity (median live: 89.2% vs. 79.8%). Other parameters were not different between CT and EP spermatozoa. After cryopreservation (phase II), spermatozoa from both types of semen did not differ significantly, except for lipid peroxidation of live sperm cells (median CT: 3.5%, EP: 1.7%, P < 0.05). Urethral and EP spermatozoa showed a similar, significant drop in motility (CT to 18.6 +/- 10.3% and EP to 21.6 +/- 12.1%, P < 0.05), progressive motility (CT to 6.8 +/- 5.9% and EP to 8.3 +/- 8.8%, P < 0.05), and rapid movement (from 34.3 +/- 20.6% to 8.5 +/- 7.0% in CT and from 26.0 +/- 14.7% to 10.1 +/- 10.4% in EP, P < 0.05), whereas other motion characteristics assessed by CASA were not affected (P > 0.05). The strongest change after cryopreservation was noted in high mitochondrial potential (median CT: 1.3%, EP: 2.2%). Although cryopreservation increased acrosome damage and lipid peroxidation, the level of these changes in the population of live sperm cells remained low (median acrosome damage: CT: 3.3%, EP: 4.5%, lipid peroxidation CT: 3.5%, EP: 1.7%). Cryopreservation did not affect chromatin structure (median percent DNA fragmentation index, CT: 3.3%, EP: 2.3%). In this study, we confirmed that urethral catheterization for collection of semen allows the retrieval of spermatozoa with quality equally good as in those obtained by epididymal slicing. Spermatozoa from both types of semen collected showed similar characteristics after freezing/thawing so both types can be used for semen banking. PMID- 27501868 TI - Local adaptation of a bacterium is as important as its presence in structuring a natural microbial community. AB - Local adaptation of a species can affect community composition, yet the importance of local adaptation compared with species presence per se is unknown. Here we determine how a compost bacterial community exposed to elevated temperature changes over 2 months as a result of the presence of a focal bacterium, Pseudomonas fluorescens SBW25, that had been pre-adapted or not to the compost for 48 days. The effect of local adaptation on community composition is as great as the effect of species presence per se, with these results robust to the presence of an additional strong selection pressure: an SBW25-specific virus. These findings suggest that evolution occurring over ecological time scales can be a key driver of the structure of natural microbial communities, particularly in situations where some species have an evolutionary head start following large perturbations, such as exposure to antibiotics or crop planting and harvesting. PMID- 27501870 TI - Reproductive performance of Japanese Black cattle: Association with herd size, season, and parity in commercial cow-calf operations. AB - The Japanese Black is the most common breed of beef cattle in Japan. However, only limited data are available on the associations of season, parity, and herd size with reproductive performance in Japanese Black cattle. Therefore, the objective of the present study was to determine the associations of these factors with reproductive performance parameters, such as the calving to first service interval (CFSI) and first service conception rate in Japanese Black cattle. Data were collected from 34,763 calvings in 13,186 animals from 826 commercial cow calf operations in the Miyazaki prefecture, which is located on the south eastern coast of Kyushu, Japan. This region has a temperate climate with warm humid summers and cold winters. All cattle were reared intensively, and the animals were housed in free stalls throughout their lives. The mean number of cows per farm was 18 (range, 1-454). All animals were bred by artificial insemination. Herds were classified into three groups based on size: small (<=10 cows), intermediate (11-50 cows), and large (>=51 cows). The mean (+/-SD) parity, CFSI, and the first service conception rate were 4.9 +/- 2.9, 80.0 +/- 46.2 days, and 53.5 +/- 49.9%, respectively. Cows that calved in the spring (March to May) and winter (December to February) had the longest CFSI (P < 0.05). The CFSI in first parity cows was shorter than in cows at parity 7 or higher (P < 0.05). Cows in large herds had an approximately 10 days shorter mean CFSI than those in small herds (P < 0.05). Cows inseminated in the winter or spring had an approximately 5% points lesser first-service conception rate (FSCR) than those inseminated during the summer (June to August) or autumn (September to November; P < 0.05). As parity increased from 1 to 9, FSCR decreased from 60.0% to 43.1% (P < 0.05). Cows in small herds had a lesser FSCR than those in intermediate and large herds (P < 0.05). In summary, decreased reproductive performance in intensively reared Japanese Black cattle was associated with calving and artificial insemination during the winter and spring, greater parity, and small herd size. PMID- 27501871 TI - Complexities of follicle deviation during selection of a dominant follicle in Bos taurus heifers. AB - Follicle deviation during a follicular wave is a continuation in growth rate of the dominant follicle (F1) and decreased growth rate of the largest subordinate follicle (F2). The reliability of using an F1 of 8.5 mm to represent the beginning of expected deviation for experimental purposes during waves 1 and 2 (n = 26 per wave) was studied daily in heifers. Each wave was subgrouped as follows: standard subgroup (F1 larger than F2 for 2 days preceding deviation and F2 > 7.0 mm on the day of deviation), undersized subgroup (F2 did not attain 7.0 mm by the day of deviation), and switched subgroup (F2 larger than F1 at least once on the 2 days before or on the day of deviation). For each wave, mean differences in diameter between F1 and F2 changed abruptly at expected deviation in the standard subgroup but began 1 day before expected deviation in the undersized and switched subgroups. Concentrations of FSH in the wave-stimulating FSH surge and an increase in LH centered on expected deviation did not differ among subgroups. Results for each wave indicated that (1) expected deviation (F1, 8.5 mm) was a reliable representation of actual deviation in the standard subgroup but not in the undersized and switched subgroups; (2) concentrations of the gonadotropins normalized to expected deviation were similar among the three subgroups, indicating that the day of deviation was related to diameter of F1 and not F2; and (3) defining an expected day of deviation for experimental use should consider both diameter of F1 and the characteristics of deviation. PMID- 27501872 TI - The effect of ovine oocyte vitrification on expression of subset of genes involved in epigenetic modifications during oocyte maturation and early embryo development. AB - Apart from ultrastructural damages in oocytes subjected to cryopreservation procedures, little is known about the status of epigenetic modification and chromatin remodeling in vitrified oocytes. In present study, the expression patterns of eight genes involved in epigenetic modification (HAT1, HDAC1, SUV39H1, DNMT1, and DNMT3b), chromatin remodeling (HMGN3a and SMARCAL1), and transcription (STAT3), were investigated in fresh and vitrified germinal vesicle and metaphase II oocytes and their resulting embryos at 2 to 7 cells, 8 to 16 cells, morula, and blastocyst stages. The mRNA relative abundance was quantified by reverse transcriptase real-time polymerase chain reaction, as fold change relative to the value obtained for fresh germinal vesicle oocytes. Vitrified oocytes showed lower cleavage (38.1% vs. 95.5%, P < 0.001) and development to blastocyst (8.2% vs. 50.8%, P < 0.001) compared with controls. In both fresh and vitrified groups, the genes expressions in oocytes were lower than cleaving embryos, with an exception of HMGN3a. Compared with fresh derived embryos, in vitrified groups, the overall expressions of HMGN3a and HDAC1 were decreased, whereas the expressions of STAT3, SMARCAL1, and DNMT3B were increased. Altogether, despite some differences in expression pattern of some genes, the overall pattern of increase and/or decrease in gene expression was almost the same in most of the genes studied between vitrified and fresh groups. Thus, apart from some mismatch in pattern of genes expression in a number of cases, the difference in magnitude and/or primacy and recency in reaching to the maximum expression, in association to embryonic genome activation, between fresh and vitrified groups, might be the reason for the lower developmental competence of vitrified-warmed oocytes compared with fresh ones. PMID- 27501873 TI - Identification of the pregnancy-associated glycoprotein family (PAGs) and some aspects of placenta development in the European moose (Alces alces L.). AB - This study describes the identification and a broad-based characterization of the pregnancy-associated glycoprotein (PAG) genes expressed in the synepitheliochorial placenta of the Alces alces (Aa; N = 51). We used: (1) both size measurements (cm) of various Aa embryos/fetuses (crown-rump length) and placentomes (PLCs); (2) PCR, Southern and sequencing; (3) Western-blot for total placental glycoproteins; (4) deglycosylation of total cotyledonary proteins; and (5) double heterologous IHC for cellular immune-localization of the PAGs as pregnancy advanced (50-200 days post coitum). The crown-rump length and PLC size measurements permitted a novel pattern estimation of various pregnancy stages in wild Aa. The PLC number varied (5-21) and was the greatest at the mid and late stages of gestation in females bearing singletons or twins. The genomic existence of the identified PAG-like family was named AaPAG-L. Amplicon profiles of the AaPAG-L varied in the number and length (118-2000 bp). Southern with porcine cDNA probes confirmed specificity and revealed dominant AaPAG-L amplicons in males and females. Nucleotide sequences of the AaPAG-L amplicons shared 86.27% homology with the bovine PAG1 (bPAG1) gene. Amino acid AaPAG sequences revealed in silico 88.23% to 100% homology with the bPAG1 precursor. Western-blots revealed a dominant mature 55 kDa AaPAG fraction, and the major ~48 kDa glycosylated form that was deglycosylated to ~44 kDa. The AaPAG-Ls was immuno-localized to mono- and bi-nucleated trophectodermal cells (TRD-chorionic epithelium), where signal intensity resembled intense TRD proliferation within developing PLCs as pregnancy advanced. This is the first study identifying the AaPAG-L family in the largest representative among the Cervidae. PMID- 27501874 TI - Impact of photon cross section uncertainties on Monte Carlo-determined depth-dose distributions. AB - This work studies the impact of systematic uncertainties associated to interaction cross sections on depth dose curves determined by Monte Carlo simulations. The corresponding sensitivity factors are quantified by changing cross sections by a given amount and determining the variation in the dose. The influence of total and partial photon cross sections is addressed. Partial cross sections for Compton and Rayleigh scattering, photo-electric effect, and pair production have been accounted for. The PENELOPE code was used in all simulations. It was found that photon cross section sensitivity factors depend on depth. In addition, they are positive and negative for depths below and above an equilibrium depth, respectively. At this depth, sensitivity factors are null. The equilibrium depths found in this work agree very well with the mean free path of the corresponding incident photon energy. Using the sensitivity factors reported here, it is possible to estimate the impact of photon cross section uncertainties on the uncertainty of Monte Carlo-determined depth dose curves. PMID- 27501875 TI - Iterative image reconstruction using modified non-local means filtering for limited-angle computed tomography. AB - PURPOSE: Limited-angle CT imaging is an effective technique to reduce radiation. However, existing image reconstruction methods can effectively reduce streak artifacts but fail to suppress those artifacts around edges due to incomplete projection data. Thus, a modified NLM (mNLM) based reconstruction method is proposed. METHODS: Since the artifacts around edges mainly exist in local position, it is possible to restore the true pixels in artifacts using pixels located in artifacts-free regions. In each iteration, mNLM is performed on image reconstructed by ART followed by positivity constraint. To solve the problem caused by ART-mNLM that there is undesirable information that may appear in the image, ART-TV is then utilized in the following iterative process after ART-mNLM iterates for a number of iterations. The proposed algorithm is named as ART mNLM/TV. RESULTS: Simulation experiments are performed to validate the feasibility of algorithm. When the scanning range is [0, 150 degrees ], our algorithm outperforms the ART-NLM and ART-TV with more than 40% and 29% improvement in terms of SNR and with more than 58% and 49% reduction in terms of MAE. Consistently, reconstructed images from real projection data also demonstrate the effectiveness of presented algorithm. CONCLUSION: This paper uses mNLM which benefits from redundancy of information across the whole image, to recover the true value of pixels in artifacts region by utilizing pixels from artifact-free regions, and artifacts around the edges can be mitigated effectively. Experiments show that the proposed ART-mNLM/TV is able to achieve better performances compared to traditional methods. PMID- 27501876 TI - Molten thermoplastic dripping behavior induced by flame spread over wire insulation under overload currents. AB - The dripping behavior of the molten thermoplastic insulation of copper wire, induced by flame spread under overload currents, was investigated for a better understanding of energized electrical wire fires. Three types of sample wire, with the same polyethylene insulation thickness and different core diameters, were used in this study. First, overload current effects on the transient one dimensional wire temperature profile were predicted using simplified theoretical analysis; the heating process and equilibrium temperature were obtained. Second, experiments on the melting characteristics were conducted in a laboratory environment, including drop formation and frequency, falling speed, and combustion on the steel base. Third, a relationship between molten mass loss and volume variation was proposed to evaluate the dripping time and frequency. A strong current was a prerequisite for the wire dripping behavior and the averaged dripping frequency was found to be proportional to the square of the current based on the theoretical and experimental results. Finally, the influence of dripping behavior on the flame propagation along the energized electrical wire was discussed. The flame width, bright flame height and flame spreading velocity presented different behaviors. PMID- 27501877 TI - Decolorization of azo dye by peroxymonosulfate activated by carbon nanotube: Radical versus non-radical mechanism. AB - Carbon nanotube (CNT) has been shown to effectively activate peroxymonosulfate (PMS) to remove contaminants, whereas controversial activation mechanisms (radical vs non-radical mechanism) were previously proposed. Here we report that radical-induced decolorization of acid orange 7 (AO7) dominated in the CNT activated PMS system, but non-radical mechanism was also involved at high Cl- concentration. CNT exhibited high activity in activating PMS to decolorize AO7. The decolorization rate of AO7 increased with increasing PMS dosages and CNT loadings, rising temperature and higher pH. Radical quenching and photoluminescence techniques confirmed the decolorization of AO7 in the CNT/PMS system was caused by the radical oxidation, which dominantly took place on the surface of CNT, rather than the bulk solution. The presence of Cl- exhibited a dual effect on AO7 decolorization. Low concentration of Cl- slightly inhibited AO7 decolorization, but further raising the concentration to above 0.1M significantly accelerated its decolorizaition. Cl- was confirmed to react with PMS to generate HClO, which effectively bleached AO7 through non-radical process rather than radical process. The decolorization of AO7 induced from the non radical process exhibited different degradation products and less mineralization in comparison to that derived from radical process. PMID- 27501878 TI - An Eco-tank system containing microbes and different aquatic plant species for the bioremediation of N,N-dimethylformamide polluted river waters. AB - An Eco-tank system of 10m was designed to simulate the natural river. It consisted of five tanks sequentially connected containing microbes, biofilm carriers and four species of floating aquatic plants. The purification performance of the system for N,N-dimethylformamide (DMF) polluted river water was evaluated by operating in continuous mode. DMF was completely removed in Tanks 1 and 2 at influent DMF concentrations between 75.42 and 161.05mg L-1. The NH4+-N concentration increased in Tank 1, followed by a gradual decrease in Tanks 2-5. Removal of NH4+-N was enhanced by aeration. The average effluent NH4+-N concentration of Tank 5 decreased to a minimum of 0.89mg L-1, corresponding to a decrease of 84.8% when compared with that before aeration. TN concentration did not decrease significantly as expected after inoculation with denitrifying bacteria. The average effluent TN concentration of the system was determined to be 4.58mg L-1, still unable to satisfy the Class V standard for surface water environmental quality. The results of this study demonstrated that the Eco-tank system is an efficient process in removing DMF, TOC, and NH4+-N from DMF polluted river water. However, if possible, alternative technologies should be adopted for controlling the effluent TN concentration. PMID- 27501879 TI - pH-dependent degradation of p-nitrophenol by sulfidated nanoscale zerovalent iron under aerobic or anoxic conditions. AB - Sulfidated nanoscale zerovalent iron (S-NZVI) is attracting considerable attention due to its easy production and high reactivity to pollutants. We studied the reactivity of optimized S-NZVI (Fe/S molar ratio 6.9), comparing with pristine nanoscale zerovalent iron (NZVI), at various pH solutions (6.77-9.11) towards p-nitrophenol (PNP) under aerobic and anoxic conditions. Studies showed that the optimized extent of sulfidation could utterly enhance PNP degradation compared to NZVI. Batch experiments indicated that in anoxic S-NZVI systems the degradation rate constant increased with increasing pH up to 7.60, and then declined. However, in aerobic S-NZVI, and in anoxic or aerobic NZVI systems, it decreased as pH increased. It was manifested that anoxic S-NZVI systems preferred to weaker alkaline solutions, whereas aerobic S-NZVI systems performed better in acidic solutions. The highest TOC removal efficiency of PNP (17.59%) was achieved in the aerobic S-NZVI system at pH 6.77, revealing that oxygen improved the degradation of PNP by excessive amounts of hydroxyl radicals in slightly acidic conditions, and the TOC removal efficiency was supposed to be further improved in moderate acidic solutions. Acetic acid, a nontoxic ring opening by-product, confirms that the S-NZVI system could be a promising process for industrial wastewater containing sulfide ions. PMID- 27501880 TI - Integrated biodepuration of pesticide-contaminated wastewaters from the fruit packaging industry using biobeds: Bioaugmentation, risk assessment and optimized management. AB - Wastewaters from fruit-packaging plants contain high loads of toxic and persistent pesticides and should be treated on site. We evaluated the depuration performance of five pilot biobeds against those effluents. In addition we tested bioaugmentation with bacterial inocula as a strategy for optimization of their depuration capacity. Finally we determined the composition and functional dynamics of the microbial community via q-PCR. Practical issues were also addressed including the risk associated with the direct environmental disposal of biobed-treated effluents and decontamination methods for the spent packing material. Biobeds showed high depuration capacity (>99.5%) against all pesticides with bioaugmentation maximizing their depuration performance against the persistent fungicide thiabendazole (TBZ). This was followed by a significant increase in the abundance of bacteria, fungi and of catabolic genes of aromatic compounds catA and pcaH. Bioaugmentation was the most potent decontamination method for spent packing material with composting being an effective alternative. Risk assessment based on practical scenarios (pome and citrus fruit-packaging plants) and the depuration performance of the pilot biobeds showed that discharge of the treated effluents into an 0.1-ha disposal site did not entail an environmental risk, except for TBZ-containing effluents where a larger disposal area (0.2ha) or bioaugmentation alleviated the risk. PMID- 27501881 TI - Morphology and concentration of smoke from fluorinated ethylene propylene wire insulation in microgravity under forced airflow. AB - The production of smoke particles from the jet bursting flame caused by overheating fluorinated ethylene propylene (FEP) wire insulations was investigated. Experiments examining the morphology and volume fraction of the fractal smoke particle aggregates with forced airflow were conducted in a 3.5s drop tower. Gravity level and forced flow were shown to have significant hydrodynamic effects on the pathlines and fractal aggregation of the smoke particles, thus the residence time-dependent flame shape, particle size and concentration have obvious changes. For cases in still air, compared with normal gravity, the jet flame in microgravity has a spherical shape, the mean primary particle and aggregate gyration radius are bigger due to longer residence time, but the fractal dimension maintains at about 1.79, similar to that in the normal gravity level; the calculated smoke volume fraction is also bigger. For cases with force flow in microgravity, the mean primary particle diameter, the mean aggregate gyration radius, and soot volume fraction all decrease with increasing forced flow due to decreasing residence time. PMID- 27501882 TI - Coupling electrokinetics with microbial biodegradation enhances the removal of cycloparaffinic hydrocarbons in soils. AB - An innovative approach that couples electrokinetics with microbial degradation to breakdown cycloparaffinic hydrocarbons in soils is described. Soils were spiked with cyclododecane, used as a model pollutant, at approximately 1000mgkg-1. A mixture of petroleum-utilizing bacteria was added to achieve about 106-107 CFUg 1. Then, three treatments were applied for 25 days: (1) no electric field, control; (2) a constant voltage gradient of 1.3Vcm-1 in one direction; and (3) the same electric field, but with periodical switching of polarity. The degradation pathway of cyclododecane was not changed by the electric field, but the dynamic processes were remarkably enhanced, especially when the electric field was periodically switched. After 25 days, 79.9% and 87.0% of the cyclododecane was degraded in tests 2 and 3, respectively; both much higher than the 61.5% degraded in test 1. Analysis of the intermediate products strongly indicated that the competitive advantage of the electric field was the increase in ring-breaking of cyclododecane, resulting in greater concentrations of linear substances that were more susceptible to microbial attack, that is, beta oxidation. The conditions near the cathode were more favorable for the growth and metabolism of microorganisms, which also enhanced beta-oxidation of the linear alkanoic acids. Therefore, when the electric field polarity was periodically switched, the functions of both the anode and cathode electrodes were applied across the whole soil cell, further increasing the degradation efficiency. PMID- 27501883 TI - Simultaneous biological-photocatalytic treatment with strain CDS-8 and TiO2 for chlorothalonil removal from liquid and soil. AB - In this study, a novel chlorothalonil (CTN) degrading bacterial strain CDS-8, identified as Pseudomonas sp., was combined with photocatalyst titanium dioxide (TiO2) for the CTN degradation in liquid and soil. After 7day incubation, 90.73% of CTN was removed from mineral salt medium (MSM) by CDS-8 with the optimal condition at pH 7.0 and 30 degrees C. Single biodegradation or photocatalytic degradation could not degrade CTN completely, and many toxic and persistent intermediate metabolites remained. However, simultaneous biological photocatalytic treatments could markedly remove CTN and reduce the chemical oxygen demand (COD) which could not be removed by single biodegradation or photocatalytic degradation. In MSM, treatment with CDS-8/40mgL-1 TiO2 showed the highest COD removal rate (84.10%). Furthermore, combined CDS-8/TiO2 treatments could effectively degrade CTN in soil. In treatments with CDS-8/20mgkg-1 TiO2 of soil, the maximum CTN removal rate reached 97.55% in turned soils. However, with CDS-8/40mgkg-1 TiO2 of soil, the maximum CTN removal rate (94.94%) was found in static soil. In general, the combined biological-photocatalytic treatments provided a promising alternative candidate for the remediation of CTN contaminated sites. PMID- 27501884 TI - Assessment of the parenchymal blood volume by C-arm computed tomography for radioembolization dosimetry. AB - PURPOSE: Aim of the study was to evaluate the impact of parenchymal blood volume (PBV) C-arm CT in transarterial radioembolization (TARE) planning procedure regarding the appropriateness of segmental blood supply from selective catheter positions defined by angiographic images compared to PBV mapsto determine the influence of changed target volumes on dose calculation. MATERIAL AND METHODS: A total of 22 consecutive patients (median age, 62 years) underwent a TARE planning procedure were included in this retrospective study. Selective angiograms and selective PBV C-arm CT (right and left liver lobe) were evaluated in a blinded fashion, regarding segmental hepatic artery variants. Volumetry of target volume and dosimetry of glass and resin microspheres were performed. RESULTS: Classification of segment IV and segment I to the corresponding target vascular bed supply was correct in 91.0% (20/22) and 86.4% (19/22) for angiography and C arm CT, respectively. Except one case, all other liver segments were classified properly to the left and right hepatic arterial supply. Based on the mismatch of the angiographic and the C-arm CT approach, changes of target volume were evident in 27.3% of patients, resulting in a mean mismatch volume of 90+/-54ml (range, 51 198ml) and a percentage of dose differences of 14.2+/-11.8% and 12.6+/-10.6% for the right and 12.5+/-8.5% and 11.1+/-7.8% for the left liver lobe in glass and resin microspheres, respectively. CONCLUSION: The C-arm CT approach is superior to the angiographic determination of vascular supply of specific liver segments for dosimetry before radioembolization. Especially for unexperienced interventional radiologists or for a complex anatomy, C-arm CT improves individualized dosimetry concepts. PMID- 27501885 TI - First pass perfusion imaging to improve the assessment of left ventricular thrombus following a myocardial infarction. AB - PURPOSE: To assess whether a first-pass perfusion sequence (FPP) improved the detection of left ventricular thrombus (LVT). MATERIALS AND METHODS: Three hundred and twenty-nine patients with a first STEMI were prospectively included to undergo cardiac magnetic resonance (CMR) at baseline and after a 3-month follow-up. A CMR delayed analysis was performed by three blinded examiners (2 CMR experts and 1 novice) according to a two-step reading protocol. First, an analysis was performed on cine CMR and late gadolinium enhancement (routine stage). Then, the FPP stage was performed following initial protocol along with a FPP sequence. RESULTS: LVT was found in 31 out of a total of 638 (4.9%) CMR scans, affecting 30 (9.1%) individuals. All were located in the left ventricular apex. The FPP stage improved significantly the LVT diagnosis for all readers, in 10 and 13 cases (32% and 42%) of LVT suspicion for the experts and 16 cases (41%) for the novice. Respectively 1, 2 and 6 LVT were not detected during the routine stage by the CMR experts and the novice. For the novice, the FPP stage improved diagnosis sensitivity from 78.1 to 91.2%. CONCLUSIONS: The prevalence of LVT following a myocardial infarction reached 9.1% and increased with the reading of FPP sequence. The FPP stage improved expert diagnostic certitude and the novice's abilities to reach expert level. PMID- 27501886 TI - Diffusion tensor imaging of the hippocampus in chronic cigarette smokers. AB - PURPOSE: Previous studies have demonstrated neuronal dis-integrity in chronic smokers using diffusion tensor imaging (DTI). However, assessment of hippocampal DTI has not been performed in this group. The purpose of this study was to investigate the hippocampal integrity in chronic smokers and non-smokers and to compare this to memory performance. METHODS: We used in vivo DTI to measure the differences in hippocampal integrity between 88 chronic smoker and 88 non-smoking subjects. DTI was performed on a 3T scanner. We administered a verbal learning test to assess new verbal learning capabilities. The immediate recall (IR) was administered immediately after test procedure and delayed recall (DR) after 15min. RESULTS: Mean values of fractional anisotropy (FA) for non-smokers and smokers were 0.46 and 0.40, respectively (p<0.05). Mean IR word number for non smokers and smokers was 11.6, 9.04, respectively (p<0.05). The mean word number of DR for non-smokers and smokers was 10.2, 7.2, respectively (p<0.05). CONCLUSIONS: This is the first study of hippocampal DTI assessment in the chronic smokers. We found that decreased hippocampal FA associated with neuronal dis integrity and worse memory performance in chronic smokers than non-smokers. We also found a low positive correlation hippocampal FA values with memory performance in nonsmoking group. PMID- 27501887 TI - Comparison between dynamic susceptibility contrast magnetic resonance imaging and arterial spin labeling techniques in distinguishing malignant from benign brain tumors. AB - OBJECTIVES: The purpose of this study was to preliminarily compare unenhanced arterial spin-labeled (ASL) imaging, dynamic susceptibility contrast-enhanced cerebral blood volume (DSCE-CBV) magnetic resonance imaging (MRI) for evaluation of tumor perfusion in patients with brain tumors. MATERIALS AND METHODS: A total of 27 patients with brain tumors were examined in 1,5T MRI. Single phase and multiphase ASL, DSCE-CBV examinations were assessed by both qualitative and quantitative analysis for the detection of malignancy. Imaging results were correlated with a histopathology or follow-up. RESULTS: Based on 31 studies in 27 patients with brain tumors, the visual inspection sensitivities for ASL and dynamic DSC perfusion imaging were 88% and 94%, respectively, with 100% specificity for both. On qualitative evaluation, sensitivities for ASL and DSC perfusion imaging perfusions were 88% and 94%, respectively, with 100% specificity for both. The highest sensitivity values for quantitative ASL imaging were obtained using a normalized cut-off ratio of 1.65, resulting in sensitivity of 94% for ASL imaging and cut-off ratio of 1.95 and sensitivity 94% for DSCE-CBV imaging. CONCLUSION: The present study revealed similar sensitivity and specificity for both multhiphase ASL and DSC MRI. Thus, we suggest that ASL perfusion can be used in daily clinical practice. PMID- 27501888 TI - Adding 3D automated breast ultrasound to mammography screening in women with heterogeneously and extremely dense breasts: Report from a hospital-based, high volume, single-center breast cancer screening program. AB - PURPOSE: The aim of this study was to evaluate the impact of the 3D automated breast ultrasound (3D ABUS) when added to full field digital screening mammography (FFDSM), on breast cancer detection and recall rates in asymptomatic women with dense breasts examined in a high-volume breast cancer screening mammography center. METHODS AND MATERIAL: 1668 asymptomatic women, age 40-74 years, with heterogeneously dense parenchyma (ACR3) or extremely dense breast (ACR4) were included in the study. FFDSM was performed using standard craniocaudal (CC) and mediolateral oblique (MLO) views followed by anteroposterior (AP); lateral (LAT) and medial (MED) acquisitions of 3D ABUS in both breasts. All mammograms were double read by two dedicated breast radiologists. The 3D ABUS was read by the first radiologist immediately after reading the mammograms. The second reader looked at the 3D ABUS only if there was a need for consensus discussion because of unclear or abnormal mammograms or 3D ABUS. RESULTS: The combined FFDSM and 3D ABUS generated a total of 6.6 cancers per 1000 women screened (95% CI: 3.0, 10.2; p<0.001) compared with 4.2 cancers per 1000 women screened (95% CI) for FFDSM alone. The difference in yield was an additional 2.4 detected cancers per 1000 women screened (95% CI: 0.6, 4.8; p<0.001). The corresponding recall rate per 1000 women screened was 13.8 (95% CI: 9.0, 19.8) for FFDSM alone and 22.8 for combined FFDSM and ABUS (95% CI: 16.2, 30.0), yielding a difference of an additional 9.0 recalls per 1000 women screened (95% CI: 3.0, 15.0; p=0.004). CONCLUSION: The addition of 3D ABUS to FFDSM in women with ACR3 or ACR4 breast density significantly improved invasive breast cancer detection rate with an acceptable recall increase. PMID- 27501889 TI - Changes in brain magnetic resonance imaging patterns for preterm infants after introduction of a magnetic resonance-compatible incubator coil system: 5-year experience at a single institution. AB - OBJECTIVE: To evaluate the changes in using patterns of brain magnetic resonance imaging (MRI) in preterm infants after introduction of a MR-compatible incubator coil system. MATERIALS AND METHODS: Brain MRIs for preterm infants with the MR compatible incubator coil from March 2010 to July 2014 (n=154, group A) were compared with MRIs prior to the introduction of the incubator coil, from March 2005 to February 2010 (n=65, group B). Clinical data, MRI findings, acquisition time, and incidence of adverse events during the study were retrospectively reviewed. For the qualitative analysis of the examinations, the presence of motion artefact, spatial resolution, and overall image quality were assessed. Signal uniformity of each sequence was evaluated for a quantitative comparison. RESULTS: Comparing with group B, Group A was significantly younger (36+3 vs. 38+3 weeks, p<0.001), had a significantly lower body weight (2006.6 and 2390.3g respectively; p<0.001) at the time of MRI, and had shorter time interval (54.3+/ 2.6 vs. 70.5+/-4.4days, p=0.002) between birth and examination. Abnormal findings were noted more frequently in group A (n=100, 65%) than in B (n=24, 37%. p=0.001) with a significantly higher incidence of diffusion restriction (n=21, 13.6% vs. n=4, 6.2%, p=0.034). Mean image acquisition time was significantly shorter in group A (21.4+/-4.5 vs. 25.4+/-5.5min, p<0.001) with significant lower adverse events during MRI (n=26, 40 vs. n=6, 3.9%, p<0.001). Group A exhibited significantly less motion artefact, better spatial resolution, and better overall image quality with decreased signal variation than group B (all p<0.001). CONCLUSION: Application of the MR-compatible incubator for preterm brain MRI evaluation is safer and provides more timely evaluation of preterm infants with better image quality. PMID- 27501890 TI - Reducing CT radiation exposure with organ effective modulation: A retrospective clinical study. AB - OBJECTIVE: To evaluate the effect of Organ Effective Modulation (OEM) on objective and subjective image quality as well as the radiation dose needed for thoracoabdominal computed tomography (CT). METHOD: This retrospective study included 196 consecutive patients who were referred to our institution for enhanced thoracoabdominal CT on a specific scanner. Patients were divided into two groups: those for whom OEM was used and those for whom it was not used. For the non-OEM group, the tube current was controlled with an angular-longitudinal modulation technique. All CT examinations were performed with adaptive iterative dose reduction with 3D processing (AIDR-3D). The radiation dose was compared between the two groups. Objective image noise was measured in several regions at the thoracic and abdominal level. Subjective image quality was assessed by two radiologists for image noise, artifacts, sharpness, and overall diagnostic acceptability at the chest, abdomen, and pelvis. RESULTS: The CTDIvol was 8.3% lower in the OEM group and high-BMI patients tended to have higher dose reductions. Image noise was not significantly different at the thoracic level, except for the ventral air space, which showed more noise in the OEM group. At the abdominal level, the OEM group showed less noise in every region, only demonstrating a significant difference in the posterior segment of the right hepatic lobe. Subjective image quality assessment indicated more artifacts in the thoracic ventral air space in the OEM group, whereas all other items including the overall diagnostic acceptability showed no statistical differences between the two groups. CONCLUSION: OEM can reduce the radiation dose by approximately 8% without affecting the diagnostic acceptability of the image compared to angular longitudinal modulation, especially in patients with a high BMI. PMID- 27501891 TI - Dual-energy CT to estimate clinical severity of chronic thromboembolic pulmonary hypertension: Comparison with invasive right heart catheterization. AB - PURPOSE: To evaluate whether the extent of perfusion defects assessed by examining lung perfused blood volume (PBV) images is a stronger estimator of the clinical severity of chronic thromboembolic pulmonary hypertension (CTEPH) compared with other computed tomography (CT) findings and noninvasive parameters. MATERIALS AND METHODS: We analyzed 46 consecutive patients (10 men, 36 women) with CTEPH who underwent both dual-energy CT and right-heart catheter (RHC) examinations. Lung PBV images were acquired using a second-generation dual-source CT scanner. Two radiologists independently scored the extent of perfusion defects in each lung segment employing the following criteria: 0, no defect, 1, defect in <50% of a segment, 2, defect in >=50% of a segment. Each lung PBV score was defined as the sum of the scores of 18 segments. In addition, all of the following were recorded: 6-min walk distance (6MWD), brain natriuretic peptide (BNP) level, and RHC hemodynamic parameters including pulmonary artery pressure (PAP), right ventricular pressure (RVP), cardiac output (CO), the cardiac index (CI), and pulmonary vascular resistance (PVR). Bootstrapped weighted kappa values with 95% confidence intervals (CIs) were calculated to evaluate the level of interobserver agreement. Correlations between lung PBV scores and other parameters were evaluated by calculating Spearman's rho correlation coefficients. Multivariable linear regression analyses (using a stepwise method) were employed to identify useful estimators of mean PAP and PVR among CT, BNP, and 6MWD parameters. A p value<0.05 was considered to reflect statistical significance. RESULTS: Interobserver agreement in terms of the scoring of perfusion defects was excellent (kappa=0.88, 95% CIs: 0.85, 0.91). The lung PBV score was significantly correlated with the PAP (mean, rho=0.48; systolic, rho=0.47; diastolic, rho=0.39), PVR (rho=0.47), and RVP (rho=0.48) (all p values<0.01). Multivariable linear regression analyses showed that only the lung PBV score was significantly associated with both the mean PAP (coefficient, 0.84, p<0.01) and the PVR (coefficient, 28.83, p<0.01). CONCLUSION: The lung PBV score is a useful and noninvasive estimator of clinical CTEPH severity, especially in comparison with the mean PAP and PVR, which currently serve as the gold standards for the management of CTEPH . PMID- 27501892 TI - Decrease of pulmonary blood flow detected by phase contrast MRI is correlated with a decrease in lung volume and increase of lung fibrosis area determined by computed tomography in interstitial lung disease. AB - PURPOSE: Lung volume and pulmonary blood flow decrease in patients with interstitial lung disease (ILD). The purpose of this study was to assess the relationship between pulmonary blood flow and lung volume in ILD patients. METHODS: This research was approved by the institutional review board. Twenty seven patients (9 men, 18 women; mean age, 59 years; range, 24-79 years) with ILD were included. Blood flow was assessed in the pulmonary trunk and the left and right pulmonary arteries by phase contrast magnetic resonance imaging (MRI). Lung volume and the computed tomography (CT) visual score that indicates the severity of ILD were assessed on the left and right sides by thin-section CT scanning. Lung volume was automatically measured by lung analysis software (VINCENT Ver. 4). The CT visual score was measured by averaging the proportion of abnormal lung area at five anatomic levels. Pearson's correlation coefficient was used to determine the relationship between pulmonary blood flow and lung volume. RESULTS: Pulmonary blood flow showed a significant correlation with lung volume (both: r=0.52, p=0.006; left: r=0.61, p=0.001; right: r=0.54, p=0.004) and CT visual score (both: r=-0.39, p=0.04; left: r=-0.48, p=0.01; right: r=-0.38, p=0.04). Partial correlation analysis, controlled for age, height and weight, showed a significant correlation between pulmonary blood flow and lung volume (both: r=0.43, p=0.03; left: r=0.55, p=0.005; right: r=0.48, p=0.01) and CT visual score (both: r=-0.58, p=0.003; left: r=-0.51, p=0.01; right: r=-0.64, p=0.001). CONCLUSION: In ILD, reduced pulmonary blood flow is associated with reduced lung volume and increased abnormal lung area. PMID- 27501893 TI - Shear wave elastography and parathyroid adenoma: A new tool for diagnosing parathyroid adenomas. AB - OBJECTIVES: This study prospectively determines the shear wave elastography characteristics of parathyroid adenomas using virtual touch imaging quantification, a non-invasive ultrasound based shear wave elastography method. METHODS: This prospective study examined 57 consecutive patients with biochemically proven primary hyperparathyroidism and solitary parathyroid adenoma identified by ultrasound and confirmed by at least one of the following: surgical resection, positive Technetium-99m Sestamibi Scintigraphy (MIBI) scan, or fine needle aspiration biopsy with positive PTH washout (performed only in MIBI negative patients). Vascularity and shear wave elastography were performed for all patients. Parathyroid adenoma stiffness was measured as shear wave velocity in meters per second. RESULTS: The median (range) pre-surgical value for PTH and calcium were 58pg/mL (19, 427) and 10.8mg/dL (9.5, 12.1), respectively. 37 patients had positive MIBI scan. 20 patients had negative MIBI scan but diagnosis was confirmed with positive PTH washout. 42 patients underwent parathyroidectomy, and an adenoma was confirmed in all. The median (range) shear wave velocity for all parathyroid adenomas enrolled in this study was 2.02m/s (1.53, 2.50). The median (range) shear wave velocity for thyroid tissue was 2.77m/s (1.89, 3.70). The shear wave velocity of the adenomas was independent of adenoma size, serum parathyroid hormone concentration, or plasma parathyroid hormone concentration. CONCLUSIONS: Tissue elasticity of parathyroid adenoma is significantly lower than thyroid tissue. B-mode features and distinct vascularity pattern are helpful tools in diagnosing parathyroid adenoma with ultrasound. Shear wave elastography may provide valuable information in diagnosing parathyroid adenoma. PMID- 27501894 TI - Pleural irregularities and mediastinal pleural involvement in early stages of malignant pleural mesothelioma and benign asbestos pleural effusion. AB - OBJECTIVE: To elucidate differences in the level and localization of pleural irregularities in early malignant pleural mesothelioma (eMPM) and benign asbestos pleural effusion (BAPE) using CT. STUDY DESIGN: Retrospective assessment of CT findings of consecutive patients with BAPE at a single centre and patients with eMPM reported in Japanese vital statistics. METHODOLOGY: Thirty-six patients with confirmed diagnoses of BAPE and sixty-six patients with confirmed diagnoses of eMPM (mesothelioma stages T1 or T2) were included. Informed consent, CT scans, and clinical and pathologic details were obtained for all patients and were reviewed by one radiologist, two pathologists, and two pulmonologists. Asbestosis, pleural plaque, rounded atelectasis, and diffuse pleural thickening were assessed in all patients. RESULTS: Prevalence of asbestosis, pleural plaque, rounded atelectasis, and diffuse pleural thickening was significantly higher in the BAPE group. Low-level irregularity was more common in the BAPE group (p<0.001), whereas high-level irregularity, mediastinal localization, and interlobar fissure were more prevalent in the eMPM group (p<0.001). Interlobar pleural irregularity was not observed in any patients in the BAPE group, although 55% of patients in the eMPM group showed interlobar pleural irregularity. Mediastinal pleural involvement was observed in 74% of patients in the eMPM group and had a positive predictive value of 89%. CONCLUSION: This study demonstrates that the level and localization of plural irregularities significantly differed between patients with BAPE and eMPM. Large-scale prospective studies are needed to fully establish the diagnostic utility of such differences. PMID- 27501895 TI - Morphologic and functional abnormalities in patients with Ebstein's anomaly with cardiac magnetic resonance imaging: Correlation with tricuspid regurgitation. AB - PURPOSE: The aim of this study was to assess the correlations of functional and dimensional parameters with the severity of tricuspid regurgitation in patients with Ebstein's anomaly (EA) by using cardiac magnetic resonance (CMR) imaging. MATERIALS AND METHODS: Thirty-three patients with EA without previous cardiac surgery and 25 normal individuals were recruited and underwent both cardiac MR imaging and preoperative transthoracic echocardiography. The left ventricular (LV) functional parameters and dimensions of the right ventricle (RV) and LV were measured using 3.0-T cardiac MR imaging. Tricuspid regurgitation severity grading was estimated by echocardiography. The functional and dimensional parameters were compared between EA patients and controls using independent sample t-tests. Spearman's rank correlation was used to determine the correlations between the functional and dimensional parameters and tricuspid regurgitation. Receiver operating characteristic (ROC) analysis was used to predict tricuspid regurgitation severity using individual functional and dimensional parameters. RESULTS: Statistical analysis revealed significant differences in the functional and dimensional parameters between EA patients and controls. Within the EA group, tricuspid valve regurgitation negatively correlated well with the left ventricular ejection fraction (LVEF) (r=-0.558, p=0.001). The ratio of the right ventricular (functional right ventricle) end-diastolic dimension to the left ventricle end-diastolic dimension (RVEDD/LVEDD) in EA patients also correlated well with the severity of tricuspid valve regurgitation (r=0.492, p=0.004). Moreover, ROC analysis revealed that high sensitivity and specificity were obtained for predicting the severity of tricuspid valve regurgitation with LVEF (78.3%, 90.0%) and RVEDD/LVEDD (78.3%, 94.3%). CONCLUSION: In EA patients, the left and right ventricular functional and dimensional parameters from MRI correlated well with tricuspid regurgitation, which helped predict the severity of EA. PMID- 27501896 TI - Quantification of lung perfusion blood volume (lung PBV) by dual-energy CT in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after balloon pulmonary angioplasty (BPA): Preliminary results. AB - OBJECTIVES: Balloon pulmonary angioplasty (BPA) is a treatment option for patients with chronic thromboembolic pulmonary hypertension (CTEPH). Its effect on pulmonary perfusion has not been quantified; we examined the clinical significance of pulmonary blood volume (PBV) using dual-energy computed tomography (DECT) in patients with CTEPH undergoing BPA. METHODS: In this retrospective study of 16 BPAs in eight female patients with CTEPH, we evaluated both-lung (n=16), right- or left-lung (n=32), and three right- or left-segment (upper, middle, and lower) (n=96) PBVs before and after BPA, using DECT. We evaluated the relationships between improvement in lung PBV and pulmonary artery (PA) pressure (PAP), cardiac index (CI), pulmonary vascular resistance (PVR), and 6-min walking distance. We measured PA enhancement (PAenh) on DECT images and calculated lung PBV/PAenh to adjust timing. RESULTS: Pre- and post-BPA 6-segment lung PBV/PAenh were 0.067+/-0.021 and 0.077+/-0.019, respectively, in the treated segment (p<0.0001). There were significant positive correlations between pre- to post-BPA improvements in both-lung PBV/PAenh and PAP (R=0.69, p=0.005), PVR (R=0.56, p=0.03), and 6-min walking distance (R=0.67, p=0.01). CONCLUSIONS: Improved PBV after BPA, reflecting increased lung perfusion, was positively correlated with PAP, PVR, and 6-min walking distance. Lung PBV may be an indicator of BPA treatment effect. PMID- 27501897 TI - Automatic segmentation of abdominal organs and adipose tissue compartments in water-fat MRI: Application to weight-loss in obesity. AB - PURPOSE: To develop a fully automatic algorithm for abdominal organs and adipose tissue compartments segmentation and to assess organ and adipose tissue volume changes in longitudinal water-fat magnetic resonance imaging (MRI) data. MATERIALS AND METHODS: Axial two-point Dixon images were acquired in 20 obese women (age range 24-65, BMI 34.9+/-3.8kg/m(2)) before and after a four-week calorie restriction. Abdominal organs, subcutaneous adipose tissue (SAT) compartments (abdominal, anterior, posterior), SAT regions along the feet-head direction and regional visceral adipose tissue (VAT) were assessed by a fully automatic algorithm using morphological operations and a multi-atlas-based segmentation method. RESULTS: The accuracy of organ segmentation represented by Dice coefficients ranged from 0.672+/-0.155 for the pancreas to 0.943+/-0.023 for the liver. Abdominal SAT changes were significantly greater in the posterior than the anterior SAT compartment (-11.4%+/-5.1% versus -9.5%+/-6.3%, p<0.001). The loss of VAT that was not located around any organ (-16.1%+/-8.9%) was significantly greater than the loss of VAT 5cm around liver, left and right kidney, spleen, and pancreas (p<0.05). CONCLUSION: The presented fully automatic algorithm showed good performance in abdominal adipose tissue and organ segmentation, and allowed the detection of SAT and VAT subcompartments changes during weight loss. PMID- 27501898 TI - Pancreatic cysts: What imaging characteristics are associated with development of pancreatic ductal adenocarcinoma? AB - PURPOSE: To assess relationship between pancreatic cysts (PC) and pancreatic ductal adenocarcinoma (PDAC) and to compare imaging features of PC in subjects who develop PDAC and those who do not. MATERIAL AND METHODS: This case-control IRB-approved HIPAA-compliant study included patients with PDAC (cases) and lung cancer (controls), diagnosed between 1/1/05-1/1/14. The most recent abdominal CT/MR of each patient done >6months prior to cancer diagnosis date was reviewed by radiologist blinded to case/control status. Presence of PC, number and size of largest PC, presence of main pancreatic duct (MPD) dilatation (MPD >3mm) were recorded. Simple PC was defined as lack of calcifications, septations and enhancement. Logistic regression models with binary outcome of PDAC were constructed. RESULTS: There were 88 cases and 273 controls with mean ages of 69.6 years (+/-10.3) and 69.8 years (+/-12.0), respectively (p=0.864). PC were present in 21.6% (19/88) cases and in 9.2% (25/273) controls (p=0.002). The OR of PC for development of PDAC was 2.83, adjusting for age, sex and race (p=0.001). Mean PC size was 14.8mm (+/-8.7) in cases and 7.6mm (+/-8.0) in controls (p=0.007). PC were solitary in 6 (31.6%) of 19 cases and 21 (84.0%) of 25 controls (p=0.001). There was no significant difference in proportions of simple cysts or MPD dilatation between cases and controls. Multiple PC had 8.2 times increased odds of PDAC compared with solitary PC, adjusting for cyst size (p=0.007). CONCLUSION: Multiple PC are associated with 8.2 times higher odds of PDAC compared with solitary PC. PMID- 27501899 TI - Radiation exposure levels of routine SPECT/CT imaging protocols. AB - AIMS: To assess incremental and total patient exposure from clinical SPECT/CT imaging by means of effective dose estimations with regards to different protocols and SPECT/CT systems. MATERIALS AND METHODS: Consecutive patient exposure levels were documented prospectively from SPECT/CT operations at three European imaging centers. Documentation included the volume-weighted computed tomography (CT) dose index, the CT dose length product (DLP) and the amount of applied radiopharmaceutical. SPECT/CT examinations were categorized regionally into head, neck, myocardium, thorax, abdomen, extremities and whole-body. Effective dose from the CT (EDCT) was estimated from the DLP using gender specific conversion factors. EDSPECT was estimated from the injected activity levels and corresponding conversion factors (ICRP 106). RESULTS: This study included 678 SPECT/CT examinations. EDCT per indication and EDSPECT per tracer ranged from 0.01mSv to 7.4mSv and from 1.1mSv to 12.2mSv, respectively. In general, EDSPECT contributed most to overall patient exposure. Total EDSPECT/CT averaged across all protocol categories was 6.7mSv. CONCLUSION: Total patient exposure from clinical SPECT/CT is 7mSv on average. Individual dose levels vary with the clinical indication and on-site protocol parameters. PMID- 27501900 TI - Value of ultra-low-dose chest CT with iterative reconstruction for selected emergency room patients with acute dyspnea. AB - OBJECTIVE: To compare the diagnostic confidence between low-dose computed tomography (LDCT) and ultra-low-dose CT (ULDCT) of the chest on a single source CT system (SSCT) for patients with acute dyspnoea. MATERIALS AND METHODS: One hundred thirty-three consecutive dyspnoeic patients referred from the emergency room (ER) were selected to undergo two sequential non-enhanced chest CT acquisitions: LDCT first acquisition (100kVp and 60mAs), followed by ULDCT (100kVp+/-20 and 10mAs). Images were reconstructed with sinogram affirmed reconstruction (SAFIRE). Objective and subjective image quality assessments were made. Two radiologists evaluated subjective image quality and the level of diagnostic confidence as certain or uncertain. RESULTS: The mean effective doses (ED) were 1.164+/-0.403 and 0.182+/-0.028mSv for LDCT and ULDCT, respectively. Objective image quality improved significantly on lung images of ULDCT compared with LDCT (p<0.05). Subjective image quality was rated excellent/good in 90% of patients with BMI=25kg/m(2) for ULDCT. The level of diagnostic confidence was "certain" in all cases for both radiologists with excellent inter-observer agreement (k=1). CONCLUSION: Chest ULDCT with SAFIRE on a SSCT allows a high level diagnostic confidence for the evaluation of selected acute dyspnoeic patients. PMID- 27501901 TI - Does motion affect liver stiffness estimates in shear wave elastography? Phantom and clinical study. AB - This study was undertaken to evaluate the impact of free-breathing (FB) vs. Apnea on Shear-wave elastography (SWE) measurements. Quantitative liver-stiffness measurements were obtained during FB and Apnea for 97 patients with various body morphologies and liver textures. Quality indexes of FB and Apnea elasticity maps (percentage of non-filling (PNF), temporal (TV) and spatial (SV) variabilities) were computed. SWE measurements were also obtained from an homogeneous phantom at rest and during a mechanically-induced motion. Liver-stiffness values estimated from FB and Apnea acquisitions were correlated, particularly for homogeneous livers (r=0.76, P<0.001) and favorable body-morphologies (r=0.68, P<0.001). However FB values were consistently 20-25% lower than Apnea ones (P<0.001). FB also systematically resulted in degradation of TV (P<0.005) and PNF (P<0.001) compared to Apnea but had no impact on SV. With the phantom, no differences between SWE measurements at rest and during motion were observed. Apnea and FB measurements are highly correlated, although FB data quality is degraded compared to Apnea and estimated stiffness in FB is systematically lower than in Apnea. These discrepancies between rest and motion states were observed for patients but not for phantom data, suggesting that patient breath-holding impacts liver stiffness. PMID- 27501902 TI - Quantitative apparent diffusion coefficient measurement obtained by 3.0Tesla MRI as a potential noninvasive marker of tumor aggressiveness in breast cancer. AB - PURPOSE: To assess the association between apparent diffusion coefficient (ADC), and histological prognostic parameters in malignant breast lesions. The ability of ADC to identify lesions with the presence of Lymphovascular invasion (LVI) in breast carcinoma was also examined. MATERIALS AND METHODS: This HIPAA-compliant retrospective study consisted of 212 consecutive patients with known cancers who underwent 3.0T MRI between January 2011 and 2013. In this study, a total of 126 malignant lesions in 114 women, who had undergone DWI (b-values of 0 and 1000s/mm(2)) in addition to diagnostic MRI, were included. Patients with less than 0.8cm lesions, or those who underwent neoadjuvant chemotherapy or suboptimal DW images were excluded. Classical prognostic factors [lesion size, histopathological type and grade, lymph node (LN) status and lymphovascular invasion (LVI)], molecular prognostic markers [estrogen receptor (ER), progesterone receptor (PR) and human epidermal grow factor receptor 2 (HER2)] were reviewed and recorded. A region of interest (ROI) was drawn within the lesions to measure ADC values. Statistical analyses were performed by the Wilcoxon rank sum test (statistical significance at P<0.05). Adjusted p values from multiple comparison analysis were also calculated. RESULTS: This study demonstrates an inverse correlation between ADC and LVI in malignant lesions and the ability of ADC to identify aggressiveness in lesions with positive LVI. Tumor size, grade, ER, PR, HER2 and lymph node status did not impact tumor ADC value. However, tumors with LVI showed significantly lower ADC values when compared to tumors without LVI, regardless of the enhancement type, histological grade, histological type, and LN status. CONCLUSION: Our study shows that ADC could be a potential clinical adjunct in the evaluation of prognostic factors related to malignant lesion aggressiveness such as LVI. PMID- 27501903 TI - Prediction for rupture risk of carotid artery plaques: A comparative study of 3D GSM and CAS system. AB - PURPOSE: The study aimed to explore whether GSM based on 3D-ultrasound could predict rupture of carotid plaques and to quantitatively evaluate the vulnerability of carotid plaques. MATERIALS AND METHODS: 22 Patients with carotid plaques enrolled received 3D-US and 3.0T MRI examinations with intervals less than 48h. Images from two modalities were compared plane by plane. Based on the MRI analysis of plaques tissue compositions, images were divided into 4 groups: fibrous group, lipid core group, calcification group and hybrid group. GSM differences among groups were analyzed and 95% CI was calculated. Based on CAS(carotid atherosclerosis score)system, MRI images were divided into low risk group, medium-low risk group, medium-high risk group and high risk group. GSM differences were compared among groups and 95% CI was calculated. The correlation between GSM and LRNC% (lipid-rich necrotic core%) was analyzed in medium-high risk group and high risk group. Coefficient of variation(CoV) was used to compare the reproducibility of GSM in calcification group and lipid core group. RESULTS: A total of 164 images were matched between 3D-US and MRI. In the classification of plaque tissue composition, GSM was the highest in calcification group (n=29, 95%CI: 57.28-70.38) with a significant difference from other groups, whereas the lowest in lipid core group (n=78, 95% CI:41.79-49.36), but with no significance compared with the fibrous group and hybrid group. In CAS system, GSM was the lowest in high risk group (n=19, 95% CI: 26.44-36.56) and there were significant differences among each group (p<0.05). In high risk group and medium-high risk group, GSM was negatively correlated with lipid core ratio (r=-0.46, p=0.003). CoV of GSM in the calcification group(10.87%) was better than in lipid core group(13.02%), both of them were acceptable. CONCLUSION: GSM obtained by 3D-US VPQ could evaluate the plaque vulnerability and be served as a new promising method to predict plaque rupture. PMID- 27501904 TI - Performance of adaptive iterative dose reduction 3D integrated with automatic tube current modulation in radiation dose and image noise reduction compared with filtered-back projection for 80-kVp abdominal CT: Anthropomorphic phantom and patient study. AB - OBJECTIVES: Evaluate the performance of Adaptive Iterative Dose Reduction 3D (AIDR 3D) and compare with filtered-back projection (FBP) regarding radiation dosage and image quality for an 80-kVp abdominal CT. MATERIALS AND METHODS: An abdominal phantom underwent four CT acquisitions and reconstruction algorithms (FBP; AIDR 3D mild, standard and strong). Sixty-three patients underwent unenhanced liver CT with FBP and standard level AIDR 3D. Further post-acquisition reconstruction with strong level AIDR 3D was made. Patients were divided into two groups (< and ?29cm) based on the abdominal effective diameter (Deff) at T12 level. Quantitative (attenuation, noise, and signal-to-noise ratio) and qualitative (image quality, noise, sharpness, and artifact) analysis by two readers were assessed and the interobserver agreement was calculated. RESULTS: Strong level AIDR 3D reduced radiation dose by 72% in the phantom and 47.1% in the patient study compared with FBP. There was no difference in mean attenuations. Image noise was the lowest and signal-to-noise ratio the highest using strong level AIDR 3D in both patient groups. For Deff<29cm, image sharpness of FBP was significantly different from those of AIDR 3D (P<0.05). For Deff ?29cm, image quality of AIDR 3D was significantly more favorable than FBP (P<0.05). Interobserver agreement was substantial. CONCLUSIONS: Integrated AIDR 3D allows for an automatic reduction in radiation dose and maintenance of image quality compared with FBP. Using AIDR 3D reconstruction, patients with larger abdomen circumference could be imaged at 80kVp. PMID- 27501905 TI - Modified MR defecography without rectal filling in obstructed defecation syndrome: Initial experience. AB - OBJECTIVE: To evaluate the role of dynamic MR defecography before rectal filling in detecting occult anterior compartment prolapse in patients with obstructed defecation. METHODS: This prospective study was approved by the ethics committee. Seventy six females with obstructed defecation underwent dynamic MR defecography before and after rectal filling. Pre-rectal and post-rectal filling sequences were interpreted separately by two radiologists on two different settings with a time interval of one week. Statistical analysis was performed using Wilcoxon's matched-pairs signed rank test and t-test for matched pairs; differences were considered statistically significant at p<0.05. RESULTS: Fifty eight females of 76 showed additional anterior compartment derangement, with 27 diagnosed only in pre-rectal filling sequence (27/58=46.55%). Following rectal filling detected cystocele in 27 patients was not identified in 14 cases and downgraded in 13. Similarly, detected uterine prolapse in 17 patients was not visualized in 14 patients and downgraded in 3. Furthermore, rectocele was identified in 7 cases before gel enema, additional 32 detected after rectal filling. Significant statistical difference in the detection of both cystocele (p=0.0001) and uterine prolapse (p=0.0013) was identified in the non-filled sequence. CONCLUSION: Pelvic floor imaging before rectal filling is significantly better for detection of anterior compartment prolapse. PMID- 27501906 TI - Tobacco as platform for a commercial production of cyanophycin. AB - Cyanophycin (CP) is a proteinogenic polymer that can be substituted for petroleum in the production of plastic compounds and can also serve as a source of valuable dietary supplements. However, because there is no economically feasible system for large-scale industrial production, its application is limited. In order to develop a low-input system, CP-synthesis was established in the two commercial Nicotiana tabacum (N. tabacum) cultivars 'Badischer Geudertheimer' (BG) and 'Virginia Golta' (VG), by introducing the cyanophycin-synthetase gene from Thermosynecchococcus elongatus BP-1 (CphATe) either via crossbreeding with transgenic N. tabacum cv. Petit Havana SR1 (PH) T2 individual 51-3-2 or by agrobacterium-mediated transformation. Both in F1 hybrids (max. 9.4% CP/DW) and T0 transformants (max. 8.8% CP/DW), a substantial increase in CP content was achieved in leaf tissue, compared to a maximum of 1.7% CP/DW in PH T0 transformants of Huhns et al. (2008). In BG CP, yields were homogenous and there was no substantial difference in the variation of the CP content between primary transformants (T0), clones of T0 individuals, T1 siblings and F1 siblings of hybrids. Therefore, BG meets the requirements for establishing a master seed bank for continuous and reliable CP-production. In addition, it was shown that the polymer is not only stable in planta but also during silage, which simplifies storage of the harvest prior to isolation of CP. PMID- 27501907 TI - A two-stage cognitive theory of the positive symptoms of psychosis. Highlighting the role of lowered decision thresholds. AB - OBJECTIVES: We outline a two-stage heuristic account for the pathogenesis of the positive symptoms of psychosis. METHODS: A narrative review on the empirical evidence of the liberal acceptance (LA) account of positive symptoms is presented. HYPOTHESIS: At the heart of our theory is the idea that psychosis is characterized by a lowered decision threshold, which results in the premature acceptance of hypotheses that a nonpsychotic individual would reject. Once the hypothesis is judged as valid, counterevidence is not sought anymore due to a bias against disconfirmatory evidence as well as confirmation biases, consolidating the false hypothesis. As a result of LA, confidence in errors is enhanced relative to controls. Subjective probabilities are initially low for hypotheses in individuals with delusions, and delusional ideas at stage 1 (belief formation) are often fragile. In the course of the second stage (belief maintenance), fleeting delusional ideas evolve into fixed false beliefs, particularly if the delusional idea is congruent with the emotional state and provides "meaning". LA may also contribute to hallucinations through a misattribution of (partially) normal sensory phenomena. Interventions such as metacognitive training that aim to "plant the seeds of doubt" decrease positive symptoms by encouraging individuals to seek more information and to attenuate confidence. The effect of antipsychotic medication is explained by its doubt inducing properties. LIMITATIONS: The model needs to be confirmed by longitudinal designs that allow an examination of causal relationships. Evidence is currently weak for hallucinations. CONCLUSIONS: The theory may account for positive symptoms in a subgroup of patients. Future directions are outlined. PMID- 27501908 TI - Phytosterol structured algae oil nanoemulsions and powders: improving antioxidant and flavor properties. AB - Algae oil, enriched with omega-3 long-chain polyunsaturated fatty acids (omega-3 LC-PUFA), is known for its health benefits. However, protection against lipid oxidation as well as masking of unpleasant fishy malodors in algae oil enriched foods is a big challenge to achieve. In this study, we firstly achieved a one-pot ultrasound emulsification strategy (alternative heating-homogenization) to prepare phytosterol structured thermosensitive algae oil-in-water nanoemulsion stabilized by quillaja saponin. After spray drying, the resulting algae oil powders from the structured nanoemulsion templates exhibit an excellent reconstructed behavior, even after 30 d of storage. Furthermore, an enhanced oxidative stability was obtained by reducing both the primary and secondary oxidation products through formulation with beta-sitosterol and gamma-oryzanol, which are natural antioxidants. Following the results of headspace volatiles using dynamic headspace-gas chromatography-mass spectrometry (DHS-GC-MS), it was clear that the structured algae oil-loaded nanoemulsion and powder had lower levels of fishy off-flavour (e.g., (Z)-heptenal, decanal, ethanone, and hexadecenoic acid), whereas the control emulsion and oil powder without structure performed worse. This study demonstrated that the structure from phytosterols is an effective strategy to minimize the fishy off-flavour and maximize oxidative stability of both algae oil nanoemulsions and spray-dried powders, and opens up the possibility of formulation design in polyunsaturated oil encapsulates as novel delivery systems to apply in functional foods and beverages. PMID- 27501909 TI - Oleanolic acid-NO donor-platinum(II) trihybrid molecules: Targeting cytotoxicity on hepatoma cells with combined action mode and good safety. AB - By taking advantage of good affinity of oleanolic acid (OA) to the bile acid transporter, a series of hybrid compounds from oleanolic acid (OA) or OA-nitric oxide (NO) donor derivative coordinating to platinum(II) complexes were designed and synthesized. As expected, complexes 1c and 1d showed selective cytotoxicity to hepatoma carcinoma cells (e.g. HepG2, SMMC-7721, BEL-7402 cells) rather than other tumor cells. Interestingly, they had only a weak toxicity to normal hepatic cells (e.g. LO2 cells). Mechanism studies revealed that 1c could effectively bind to the ligand domain of the farnesoid X receptor and maintain the normal function of liver cells. Furthermore, the NO donor moiety could moderately release cytotoxic NO and finally enhance the cytotoxic effect, while the cytotoxicity of the corresponding complexes was decreased when the cells were pretreated with NO scavenger. Additionally, the agarose gel electrophoresis revealed that the Pt(II) part could also offer DNA binding activity, suggesting the complexes possess a combined action mode which may help to overcome the resistance of cisplatin. The flow cytometry studies found that 1c caused tumor apoptosis and blocked cell cycle progression in the G2 phase. PMID- 27501910 TI - Assessing the physiological relevance of alternate architectures of the p7 protein of hepatitis C virus in different environments. AB - The viroporin p7 of the hepatitis C virus forms multimeric channels eligible for ion transport across the endoplasmic reticulum membrane. Currently the subject of many studies and discussion, the molecular assembly of the ion channel and the structural characteristics of the p7 monomer are not yet fully understood. Structural investigation of p7 has been carried out only in detergent environments, making the interpretation of the experimental results somewhat questionable. Here, we analyze by means of molecular dynamics simulations the structure of the p7 monomer as a function of its sequence, initial conformation and environment. We investigate the conductance properties of three models of a hexameric p7 ion channel by examining ion translocation in a pure lipid bilayer. It is noteworthy that although none of the models reflects the experimentally observed trend to conduct preferentially cations, we were able to identify the position and orientation of titratable acidic or basic residues playing a crucial role in ion selectivity and in the overall conductance of the channel. In addition, too compact a packing of the monomers leads to channel collapse rather than formation of a reasonable pore, amenable to ion translocation. The present findings are envisioned to help assess the physiological relevance of p7 ion channel models consisting of multimeric structures obtained in non-native environments. PMID- 27501911 TI - Arylazolyl(azinyl)thioacetanilides. Part 20: Discovery of novel purinylthioacetanilides derivatives as potent HIV-1 NNRTIs via a structure-based bioisosterism approach. AB - By means of structure-based bioisosterism approach, a series of novel purinylthioacetanilide derivatives were designed, synthesized and evaluated as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the tested compounds were found to be active against wild-type (WT) HIV-1(IIIB) with EC50 in the range of 0.78-4.46MUM. Among them, LAD-8 displayed the most potent anti-HIV activity (EC50=0.78MUM, SI=24). In addition, LBD-6 showed moderate activity against L100I mutant (EC50=5.64MUM) and double mutant strain RES056 (EC50=22.24MUM). Preliminary structure-activity relationships (SARs) were discussed in detail. Molecular modeling study was used to predict the optimal conformation in the NNRTI binding site, which may play a guiding role in further rational optimization. PMID- 27501912 TI - Origins of regioselectivity in 1,3-dipolar cycloadditions of nitrile oxides with alkynylboronates. AB - Density functional theory (M06-2X) studies of the regioselectivity of 1,3-dipolar cycloaddition reactions of benzo and mesitonitrile oxides with alkynyl pinacol and MIDA boronates are reported. Calculated relative free energies of activation reproduce the experimentally observed product ratios. The electronic energies of activation are found to be mainly controlled by distortion energies required to achieve the transition states. Both electronic and steric effects influence regioselectivities. PMID- 27501913 TI - Occupying a flat subpocket in a tRNA-modifying enzyme with ordered or disordered side chains: Favorable or unfavorable for binding? AB - Small-molecule ligands binding with partial disorder or enhanced residual mobility are usually assumed as unfavorable with respect to their binding properties. Considering thermodynamics, disorder or residual mobility is entropically favorable and contributes to the Gibbs energy of binding. In the present study, we analyzed a series of congeneric ligands inhibiting the tRNA modifying enzyme TGT. Attached to the parent lin-benzoguanine scaffold, substituents in position 2 accommodate in a flat solvent-exposed pocket and exhibit varying degree of residual mobility. This is indicated in the crystal structures by enhanced B-factors, reduced occupancies, or distributions over split conformers. MD simulations of the complexes suggest an even larger scatter over several conformational families. Introduction of a terminal acidic group fixes the substituent by a salt-bridge to an Arg residue. Overall, all substituted derivatives show the same affinity underpinning that neither order nor disorder is a determinant factor for binding affinity. The additional salt bridge remains strongly solvent-exposed and thus does not contribute to affinity. MD suggests temporary fluctuation of this contact. PMID- 27501914 TI - Depression risk in patients with late-onset rheumatoid arthritis in Germany. AB - GOAL: The goal of this study was to determine the prevalence of depression and its risk factors in patients with late-onset rheumatoid arthritis (RA) treated in German primary care practices. METHODS: Longitudinal data from general practices (n=1072) throughout Germany were analyzed. Individuals initially diagnosed with RA (2009-2013) were identified, and 7301 patients were included and matched (1:1) to 7301 controls. The primary outcome measure was the initial diagnosis of depression within 5 years after the index date in patients with and without RA. Cox proportional hazards models were used to adjust for confounders. RESULTS: The mean age was 72.2 years (SD: 7.6 years). A total of 34.9 % of patients were men. Depression diagnoses were present in 22.0 % of the RA group and 14.3 % of the control group after a 5-year follow-up period (p < 0.001). In the multivariate regression model, RA was a strong risk factor for the development of depression (HR: 1.55, p < 0.001). There was significant interaction of RA and diagnosed inflammatory polyarthropathies (IP) (RA*IP interaction: p < 0.001). Furthermore, dementia, cancer, osteoporosis, hypertension, and diabetes were associated with a higher risk of developing depression (p values <0.001). CONCLUSION: The risk of depression is significantly higher in patients with late-onset RA than in patients without RA for subjects treated in primary care practices in Germany. RA patients should be screened routinely for depression in order to ensure improved treatment and management. PMID- 27501917 TI - The influence of the electronic specific heat on swift heavy ion irradiation simulations of silicon. AB - The swift heavy ion (SHI) irradiation of materials is often modelled using the two-temperature model. While the model has been successful in describing SHI damage in metals, it fails to account for the presence of a bandgap in semiconductors and insulators. Here we explore the potential to overcome this limitation by explicitly incorporating the influence of the bandgap in the parameterisation of the electronic specific heat for Si. The specific heat as a function of electronic temperature is calculated using finite temperature density functional theory with three different exchange correlation functionals, each with a characteristic bandgap. These electronic temperature dependent specific heats are employed with two-temperature molecular dynamics to model ion track creation in Si. The results obtained using a specific heat derived from density functional theory showed dramatically reduced defect creation compared to models that used the free electron gas specific heat. As a consequence, the track radii are smaller and in much better agreement with experimental observations. We also observe a correlation between the width of the band gap and the track radius, arising due to the variation in the temperature dependence of the electronic specific heat. PMID- 27501915 TI - The Role of Molecular Diagnostics in the Management of Patients with Gliomas. AB - OPINION STATEMENT: The revised World Health Organization (WHO) classification of tumors of the central nervous system of 2016 combines biology-driven molecular marker diagnostics with classical histological cancer diagnosis. Reclassification of gliomas by molecular similarity beyond histological boundaries improves outcome prediction and will increasingly guide treatment decisions. This change in paradigms implies more personalized and eventually more efficient therapeutic approaches, but the era of molecular targeted therapies for gliomas is yet at its onset. Promising results of molecularly targeted therapies in genetically less complex gliomas with circumscribed growth such as subependymal giant cell astrocytoma or pilocytic astrocytoma support further development of molecularly targeted therapies. In diffuse gliomas, several molecular markers that predict benefit from alkylating agent chemotherapy have been identified in recent years. For example, co-deletion of chromosome arms 1p and 19q predicts benefit from polychemotherapy with procarbazine, CCNU (lomustine), and vincristine (PCV) in patients with anaplastic oligodendroglioma, and the presence of 1p/19q co deletion was integrated as a defining feature of oligodendroglial tumors in the revised WHO classification. However, the tremendous increase in knowledge of molecular drivers of diffuse gliomas on genomic, epigenetic, and gene expression levels has not yet translated into effective molecular targeted therapies. Multiple reasons account for the failure of early clinical trials of molecularly targeted therapies in diffuse gliomas, including the lack of molecular entry controls as well as pharmacokinetic and pharmacodynamics issues, but the key challenge of specifically targeting the molecular backbone of diffuse gliomas is probably extensive clonal heterogeneity. A more profound understanding of clonal selection, alternative activation of oncogenic signaling pathways, and genomic instability is warranted to identify effective combination treatments and ultimately improve survival. PMID- 27501916 TI - Helminth-Tuberculosis Co-infection: An Immunologic Perspective. AB - Over 2 billion people worldwide are infected with helminths (worms). Similarly, infection with Mycobacterium tuberculosis (Mtb) occurs in over a third of the world's population, often with a great degree of geographical overlap with helminth infection. Interestingly, the responses induced by the extracellular helminths and those induced by the intracellular Mtb are often mutually antagonistic and, as a consequence, can result in impaired (or cross-regulated) host responses to either of the infecting pathogens. In this review, we outline the nature of the immune responses induced by infections with helminths and tuberculosis (TB) and then provide data from both experimental models and human studies that illustrate how the immune response engendered by helminth parasites modulates Mtb-specific responses in helminth-TB coinfection. PMID- 27501918 TI - Characterisation of a novel, high affinity and selective alphavbeta6 integrin RGD mimetic radioligand. AB - The alpha-v beta-6 (alphavbeta6) integrin has been identified as playing a key role in the activation of transforming growth factor-beta (TGFbeta) that is hypothesised to be pivotal in the development of cancer and fibrotic diseases. Therefore, the alphavbeta6 integrin is an attractive therapeutic target for these debilitating diseases and a drug discovery programme to identify small molecule alphavbeta6 selective arginyl-glycinyl-aspartic acid (RGD)-mimetics was initiated within GlaxoSmithKline. The primary aim of this study was to pharmacologically characterise the binding to alphavbeta6 of a novel clinical candidate, compound 1, using a radiolabelled form. Radioligand binding studies were completed with [(3)H]compound 1 against the human and mouse soluble protein forms of alphavbeta6 to determine accurate affinity estimates and binding kinetics. The selectivity of compound 1 for the RGD integrin family was also determined using saturation binding studies (alphavbeta1, alphavbeta3, alphavbeta5, alphavbeta8, alpha5beta1 and alpha8beta1 integrins) and fibrinogen-induced platelet aggregation (alphaIIbbeta3 integrin). In addition, the relationship between divalent metal cation type and concentration and alphavbeta6 RGD site binding was also investigated. Compound 1 has been demonstrated to bind with extremely high affinity and selectivity for the alphavbeta6 integrin and has the potential as a clinical tool and therapeutic for investigating the role of alphavbeta6 in a range of disease states both pre-clinically and clinically. In addition, this is the first study that has successfully applied radioligand binding to the RGD integrin field to accurately determine the affinity and selectivity profile of a small molecule RGD-mimetic. PMID- 27501919 TI - Dehydroepiandrosterone-induced changes in mitochondrial proteins contribute to phenotypic alterations in hepatoma cells. AB - Dehydroepiandrosterone (DHEA)-induced growth arrest of hepatoma cells is associated with metabolic disturbance. Our previous study has suggested that DHEA may cause cellular energy drain. It is possible that mitochondrial dysfunction may be mechanistically implicated in DHEA-induced changes in cellular phenotype. Treatment of SK-Hep-1 cells with DHEA caused significant reduction in proliferation, colony formation, and growth in semi-solid medium. Such changes in cellular phenotype were associated with mitochondrial depolarization, increase in mitochondrial mass, and decrease in respiratory activity. Level of reactive oxygen species (ROS) increased in DHEA-treated cells. To explore the mechanistic aspect of DHEA-induced mitochondrial dysfunction, we employed SILAC approach to study the changes in the mitoproteome of SK-Hep-1 cells after DHEA treatment. Respiratory chain complex proteins such as NDUFB8 and SDHB were differentially expressed. Of mitochondrial proteins with altered expression, FAST kinase domain containing protein 2 (FASTKD2) showed significantly reduced expression. Exogenous expression of FASTKD2 in SK-Hep-1 cells increased their resistance to growth inhibitory effect of DHEA, though it alone did not affect cell growth. FASTKD2 expression partially reversed the effect of DHEA on mitochondria, and reduced DHEA-induced ROS generation. Our results suggest that DHEA induces changes in mitochondrial proteins and respiratory activity, and contributes to growth arrest. FASTKD2 may be an important regulator of mitochondrial physiology, and represent a downstream target for DHEA. PMID- 27501920 TI - Kinetic binding and activation profiles of endogenous tachykinins targeting the NK1 receptor. AB - Ligand-receptor binding kinetics (i.e. association and dissociation rates) are emerging as important parameters for drug efficacy in vivo. Awareness of the kinetic behavior of endogenous ligands is pivotal, as drugs often have to compete with those. The binding kinetics of neurokinin 1 (NK1) receptor antagonists have been widely investigated while binding kinetics of endogenous tachykinins have hardly been reported, if at all. Therefore, the aim of this research was to investigate the binding kinetics of endogenous tachykinins and derivatives thereof and their role in the activation of the NK1 receptor. We determined the binding kinetics of seven tachykinins targeting the NK1 receptor. Dissociation rate constants (koff) ranged from 0.026+/-0.0029min-1 (Sar9,Met(O2)11-SP) to 0.21+/-0.015min-1 (septide). Association rate constants (kon) were more diverse: substance P (SP) associated the fastest with a kon value of 0.24+/-0.046nM-1min-1 while neurokinin A (NKA) had the slowest association rate constant of 0.001+/ 0.0002nM-1min-1. Kinetic binding parameters were highly correlated with potency and maximal response values determined in label-free impedance-based experiments on U-251 MG cells. Our research demonstrates large variations in binding kinetics of tachykinins which correlate to receptor activation. These findings provide new insights into the ligand-receptor interactions of tachykinins and underline the importance of measuring binding kinetics of both drug candidates and competing endogenous ligands. PMID- 27501921 TI - Hybrid agent-based model for quantitative in-silico cell-free protein synthesis. AB - An advanced vision of the mRNA translation is presented through a hybrid modeling approach. The dynamics of the polysome formation was investigated by computer simulation that combined agent-based model and fine-grained Markov chain representation of the chemical kinetics. This approach allowed for the investigation of the polysome dynamics under non-steady-state and non-continuum conditions. The model is validated by the quantitative comparison of the simulation results and Luciferase protein production in cell-free system, as well as by testing of the hypothesis regarding the two possible mechanisms of the Edeine antibiotic. Calculation of the Hurst exponent demonstrated a relationship between the microscopic properties of amino acid elongation and the fractal dimension of the translation duration time series. The temporal properties of the amino acid elongation have indicated an anti-persistent behavior under low mRNA occupancy and evinced the appearance of long range interactions within the mRNA ribosome system for high ribosome density. The dynamic and temporal characteristics of the polysomal system presented here can have a direct impact on the studies of the co-translation protein folding and provide a validated platform for cell-free system studies. PMID- 27501922 TI - New Evidence That Nonlinear Source-Filter Coupling Affects Harmonic Intensity and fo Stability During Instances of Harmonics Crossing Formants. AB - The traditional source-filter theory of voice production describes a linear relationship between the source (glottal flow pulse) and the filter (vocal tract). Such a linear relationship does not allow for nor explain how changes in the filter may impact the stability and regularity of the source. The objective of this experiment was to examine what effect unpredictable changes to vocal tract dimensions could have on fo stability and individual harmonic intensities in situations in which low frequency harmonics cross formants in a fundamental frequency glide. To determine these effects, eight human subjects (five male, three female) were recorded producing fo glides while their vocal tracts were artificially lengthened by a section of vinyl tubing inserted into the mouth. It was hypothesized that if the source and filter operated as a purely linear system, harmonic intensities would increase and decrease at nearly the same rates as they passed through a formant bandwidth, resulting in a relatively symmetric peak on an intensity-time contour. Additionally, fo stability should not be predictably perturbed by formant/harmonic crossings in a linear system. Acoustic analysis of these recordings, however, revealed that harmonic intensity peaks were asymmetric in 76% of cases, and that 85% of fo instabilities aligned with a crossing of one of the first four harmonics with the first three formants. These results provide further evidence that nonlinear dynamics in the source-filter relationship can impact fo stability as well as harmonic intensities as harmonics cross through formant bandwidths. PMID- 27501923 TI - Voice in Friedreich Ataxia. AB - BACKGROUND: Friedreich Ataxia (FRDA) is the most common hereditary ataxia, with dysarthria as one of its key clinical signs. OBJECTIVE: To describe the voice profile of individuals with FRDA to inform outcome marker development and goals of speech therapy. METHODS: Thirty-six individuals with FRDA and 30 age-matched controls provided sustained vowel and connected speech samples. Speech and voice samples were analyzed acoustically using the Analysis of Dysphonia in Speech and Voice program and perceptually using the Consensus Auditory-Perceptual Evaluation of Voice form. Correlations between dysphonia and overall dysarthria severity, demographic, clinical, and genetic information were explored. RESULTS: Individuals with FRDA presented with mild dysphonia characterized by hoarseness (combined roughness and breathiness), increased strain, and altered pitch variability (increased in vowel productions; slightly decreased on reading samples). Acoustically, individuals with FRDA had significantly higher scores on the Cepstral Spectral Index of Dysphonia during vowel production. A combination of perceptual and acoustic measures of dysphonia used in this study was quite effective in categorizing the FRDA versus control participants, with >80% overall accuracy. CONCLUSIONS: Although dysphonia severity in FRDA did not correlate significantly with overall disease severity, speaking rate and syllabic duration significantly correlated with age at disease onset and disease duration, and also have an effect on listener perception of dysphonia. The relationship between dysphonia and dysarthria in FRDA suggests that reducing overall dysphonia severity via therapeutic techniques that improve phonatory stability and increase speaking rate is a viable target for speech therapy. PMID- 27501924 TI - Expression, purification and characterization of GAPDH-ChSase ABC I from Proteus vulgaris in Escherichia coli. AB - Chondroitinases (ChSases) are a family of polysaccharide lyases that can depolymerize high molecular weight chondroitin sulfate (CS) and dermatan sulfate (DS). In this study, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which is stably expressed in different cells like normal cells and cancer cells and the expression is relatively insensitive to experimental conditions, was expressed as a fusion protein with ChSase ABC I. Results showed that the expression level and enzyme activity of GAPDH-ChSase ABC I were about 2.2 and 3.0 times higher than those of ChSase ABC I. By optimization of fermentation conditions, higher productivity of ChSase ABC I was achieved as 880 +/- 61 IU/g wet cell weight compared with the reported ones. The optimal temperature and pH of GAPDH-ChSase ABC I were 40 degrees C and 7.5, respectively. GAPDH-ChSase ABC I had a kcat/Km of 131 +/- 4.1 L/MUmol s and the catalytic efficiency was decreased as compared to ChSase ABC I. The relative activity of GAPDH-ChSase ABC I remained 89% after being incubated at 30 degrees C for 180 min and the thermostability of ChSase ABC I was enhanced by GAPDH when it was incubated at 30, 35, 40 and 45 degrees C. PMID- 27501925 TI - Health Sector Reform: Time to Introspect. PMID- 27501926 TI - Chlamydia trachomatis infection and HPV/Chlamydia trachomatis co-infection among HPV-vaccinated young women at the beginning of their sexual activity. AB - PURPOSE: This study investigated the prevalence of Chlamydia trachomatis infection, co-infection with Human Papillomavirus (HPV) and associated risk factors in a cohort of sexually active young women enrolled in an ongoing trial on HPV vaccination at the European Institute of Oncology (IEO, Milan, Italy). METHODS: Cervical samples were collected from 591 girls (median age 18.8 years) at the beginning of their sexual activity. At the time of sample collection, 354 women had not yet been vaccinated, and 237 women had been vaccinated for at least 12 months. All samples were analyzed through a molecular assay for the detection of C. trachomatis infection. Demographic, behavioral risk factors and high-risk HPV (HR-HPV) status were investigated. RESULTS: The prevalence of C. trachomatis infection was 4.9 % and HPV/C. trachomatis co-infection rate was 1.5 %. The exact analysis has not underlined statistical significance for the variables considered, except for the infection with HR-HPV (p < 0.001). The prevalence of C. trachomatis infection among women who had not been immunized and those already vaccinated was similar (5.6 vs 3.8 %). However, the rate of HPV/C. trachomatis co infection was twice as high in unvaccinated women (2 %) compared to vaccinated women (0.8 %). CONCLUSIONS: Over 16 % of young women had at least one of the two STIs investigated. The risk of C. trachomatis infection was higher in HR-HPV infected compared to HR-HPV uninfected young women. The rate of co-infection was halved in HPV-vaccinated compared to unvaccinated women. This study underlines that HPV vaccination can confer benefits also in terms of co-infections prevention, leading to a decreased risk of developing cervical malignancies. PMID- 27501927 TI - Induction of labor: does indication matter? AB - PURPOSE: Labor induction is performed in 20 % of pregnancies. However, the impact of the indications for induction on its failure rate has hardly been investigated. We aimed to evaluate the association of indications for labor induction with failure rate. METHODS: Background and delivery-related data were retrospectively collected for all women with a viable term singleton pregnancy, who underwent labor induction with a PGE2 vaginal insert in 2013-2014. Reasons for induction were categorized as maternal indications, hypertensive disorders, premature rupture of membranes, and fetal indications. Induction failure was defined as Bishop score <=7 at 24 h after PGE2 administration, cesarean delivery due to latent phase dystocia or removal of the insert due to non-reassuring fetal heart rate followed by emergency cesarean delivery. Outcome measures were rate of induction failure (primary) and rate of cesarean delivery (secondary). RESULTS: The cohort included 1066 women. Those who failed induction (n = 213, 20 %) were more likely to be nulliparous (69.5 vs. 45.7 %, p < 0.0001), older (31 vs. 30 years, p = 0.047), and at an earlier gestational age (39.4 vs. 40.0 weeks, p < 0.0001). Among nulliparous women, maternal indications were significantly associated with induction failure (aOR 2.52, 95 % CI 1.28-4.95, p = 0.007) and cesarean delivery (aOR 2.36, 95 % CI 0.40-2.29, p = 0.019). Among multiparous women, hypertensive disorders (aOR 7.26, 95 % CI 1.89-27.87, p = 0.004) and maternal indications (aOR 4.22, 95 %CI 1.14-15.58, p = 0.031) were significantly associated with induction failure but not cesarean delivery. CONCLUSIONS: The indication for induction of labor may impact its failure rate. PMID- 27501928 TI - Impact of combined hormonal contraceptives on vessels functionality. AB - PURPOSE: To evaluate the dynamic and static retinal vascular functionality in young females using combined hormonal contraceptive (CHC). METHODS: Thirty-eight consecutive young female subjects were enrolled in this study between January 2015 and December 2015. Subjects were divided in two groups: CHC group, defined as CHC use for >=6 months, and control group, defined as no current and prior CHC use. Participants underwent a dynamic and static retinal vessel analysis using the Dynamic Vessel Analyzer (DVA, Imedos, Jena, Germany). RESULTS: Seventeen subjects continuously took CHC for 54.6 +/- 29.3 months, while 21 subjects belonged to control group. No difference was found between the CHC and control groups for age (p = 0.1), smoking status (p = 0.6), and systolic (p = 0.3) and diastolic (p = 0.1) blood pressure. With regard to dynamic analysis, women taking CHC exhibited a marked significant vasoconstriction following flicker stimulation in comparison with control group (-2.43 +/- 2.5 vs 0.63 +/- 2.1, respectively; p = 0.0002). No significant difference was observed between groups for mean arterial (p = 0.2) and venous dilatations (p = 0.3), arteriovenous ratio (p = 0.09), central retinal artery equivalent (p = 0.4), and central retinal venous equivalent (p = 0.5). CONCLUSIONS: CHC may affect vessel reactivity to flicker light by increasing arteries constriction. This may reflect systemic changes in vascular functionality in subjects using CHC. Moreover, CHC should be considered as a confounding bias in studies involving DVA. PMID- 27501929 TI - Premature rupture of the membranes at term: time to reevaluate the management. AB - PURPOSE: To compare maternal and neonatal outcomes in induced vs. expectant management of term PROM. METHODS: This retrospective study included patients with term PROM. A total of 325 were enrolled: 213 managed expectantly and 112 induced at admission and matched according to gestational age. Expectant management group patients were allowed to defer labour induction up to 48 h. Primary outcome measures were maternal or foetal signs of infection (chorioamnionitis, early neonatal sepsis or postpartum endometritis) and prolonged maternal hospitalization. Secondary outcome was caesarean delivery rate. RESULTS: All group characteristics were comparable except that expectant management included more nulliparous women. Women managed expectantly had a higher rate of prolonged hospitalization [15 (7 %) vs. 2 (1.8 %); P = 0.043] as an indication of maternal complications, compared to induction management. They also had a higher rate of caesarean delivery [34 (16.4 %) vs. 8 (7.1 %), respectively; P = 0.024]. Adjustment for parity did not change the results. Early neonatal outcomes were similar between groups. CONCLUSIONS: Expectant management increases the likelihood of caesarean delivery and prolonged maternal hospitalization. This should be considered when advising patients with term PROM regarding labour induction. PMID- 27501930 TI - The Impact of Electronic Health Records on Risk Management of Information Systems in Australian Residential Aged Care Homes. AB - To obtain indications of the influence of electronic health records (EHR) in managing risks and meeting information system accreditation standard in Australian residential aged care (RAC) homes. The hypothesis to be tested is that the RAC homes using EHR have better performance in meeting information system standards in aged care accreditation than their counterparts only using paper records for information management. Content analysis of aged care accreditation reports from the Aged Care Standards and Accreditation Agency produced between April 2011 and December 2013. Items identified included types of information systems, compliance with accreditation standards, and indicators of failure to meet an expected outcome for information systems. The Chi-square test was used to identify difference between the RAC homes that used EHR systems and those that used paper records in not meeting aged care accreditation standards. 1,031 (37.4%) of 2,754 RAC homes had adopted EHR systems. Although the proportion of homes that met all accreditation standards was significantly higher for those with EHR than for homes with paper records, only 13 RAC homes did not meet one or more expected outcomes. 12 used paper records and nine of these failed the expected outcome for information systems. The overall contribution of EHR to meeting aged care accreditation standard in Australia was very small. Risk indicators for not meeting information system standard were no access to accurate and appropriate information, failure in monitoring mechanisms, not reporting clinical incidents, insufficient recording of residents' clinical changes, not providing accurate care plans, and communication processes failure. The study has provided indications that use of EHR provides small, yet significant advantages for RAC homes in Australia in managing risks for information management and in meeting accreditation requirements. The implication of the study for introducing technology innovation in RAC in Australia is discussed. PMID- 27501931 TI - Diversity of helminth parasites in aquatic invertebrate hosts in Latin America: how much do we know? AB - Helminths in aquatic invertebrate hosts have been overlooked in comparison with vertebrate hosts. Therefore, the known diversity, ecology and distribution of these host-parasite systems are very limited in terms of their taxonomic diversity, habitat and geographic regions. In this study we examined the published literature on helminth parasites of aquatic invertebrates from Latin America and the Caribbean (LAC) to identify the state of the knowledge in the region and to identify patterns of helminth diversity. Results showed that 67% of the literature is from Argentina, Mexico and Brazil. We found records for 772 host-parasite associations. Most records relate to medically or economically important hosts. Molluscs were the most studied host group with 377 helminth records (80% trematodes). The lymnaeids and planorbids were the most studied molluscs across LAC. Arthropods were the second most studied host group with 78 helminth records (trematodes 38%, cestodes 24% and nematodes 20%), with shrimps and crabs being the most studied hosts. Host species with the largest number of helminth taxa were those with a larger sampling effort through time, usually in a small country region. No large geographical-scale studies were identified. In general, the knowledge is still too scarce to allow any zoogeographical or helminth diversity generalization, as most hosts have been studied locally and the studies on invertebrate hosts in LAC are substantially uneven among countries. PMID- 27501932 TI - Dynamically Arranging Gold Nanoparticles on DNA Origami for Molecular Logic Gates. AB - In molecular engineering, DNA molecules have been extensively studied owing to their capacity for accurate structural control and complex programmability. Recent studies have shown that the versatility and predictability of DNA origami make it an excellent platform for constructing nanodevices. In this study, we developed a strand-displacing strategy to selectively and dynamically release specific gold nanoparticles (AuNPs) on a rectangular DNA origami. A set of DNA logic gates ("OR", "AND", and "three-input majority gate") were established based on this strategy, in which computing results were identified by disassembly between the AuNPs and DNA origami. The computing results were detected using experimental approaches such as gel electrophoresis and transmission electron microscopy (TEM). This method can be used to assemble more complex nanosystems and may have potential applications for molecular engineering. PMID- 27501934 TI - Authors' Response: Health Benefits/Hazards Associated with Companion Animal Exposure Might be Endpoint-and-Animal Specific. PMID- 27501935 TI - Cetrimide-induced oral mucositis: an unusual adverse drug reaction. PMID- 27501933 TI - Meta-Analysis of BDNF Levels in Autism. AB - Brain-derived neurotrophic factor (BDNF) centrally mediates growth, differentiation and survival of neurons, and the synaptic plasticity that underlies learning and memory. Recent meta-analyses have reported significantly lower peripheral BDNF among individuals with schizophrenia, bipolar disorder, and depression, compared with controls. To evaluate the role of BDNF in autism, and to compare autism to psychotic-affective disorders with regard to BDNF, we conducted a meta-analysis of BDNF levels in autism. Inclusion criteria were met by 15 studies, which included 1242 participants. The meta-analysis estimated a significant summary effect size of 0.33 (95 % CI 0.21-0.45, P < 0.001), suggesting higher BDNF in autism than in controls. The studies showed notable heterogeneity, but no evidence of publication biases. Higher peripheral BDNF in autism is concordant with several neurological and psychological theories on the causes and symptoms of this condition, and it contrasts notably with the lower levels of BDNF found in schizophrenia, bipolar disorder, and depression. PMID- 27501937 TI - Increasing severity of traumatic brain injury is associated with an increased risk of subsequent headache or migraine: a retrospective cohort study of U.S. active duty service members, 2006-2015. AB - Traumatic brain injury (TBI) is a common injury in the U.S. Compared to the general population, military service members can be at increased risk for TBI because of the nature of their work. Sequelae of TBI, such as headache or migraine, can lead to military duty limitations or separation from service. To determine whether the severity of TBI is associated with the risk of these sequelae, this 2006-2015 retrospective cohort study compared the incidence of diagnosed headache or migraine among all service members with a first-time mild or moderate/severe TBI (N=111,018) against a matched sample without any history of TBI. Risk increased according to the severity of TBI. Compared to service members without TBI, those who sustained a mild TBI were 3.99 times more likely to have a headache or migraine, and those with a moderate/severe TBI were 8.89 times more likely. Patients, medical providers, and military leaders can use these results to guide care after a TBI. Early identification of those at higher risk of these sequelae could improve medical management and reduce disability. PMID- 27501936 TI - A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy. AB - In many cancers early intervention involves surgical resection of small localised tumour masses. Inadequate resection leads to recurrence whereas overzealous treatment can lead to organ damage. This work describes production of a HER2 targeting antibody Fab fragment dual conjugated to achieve both real time near infrared fluorescent imaging and photodynamic therapy. The use of fluorescence emission from a NIR-dye could be used to guide resection of tumour bulk, for example during endoscopic diagnosis for oesophago-gastric adenocarcinoma, this would then be followed by activation of the photodynamic therapeutic agent to destroy untreated localised areas of cancer infiltration and tumour infiltrated lymph nodes. This theranostic agent was prepared from the Fab fragment of trastuzumab initially by functional disulfide re-bridging and site-specific click reaction of a NIR-dye. This was followed by further reaction with a novel pre activated form of the photosensitiser chlorin e6 with the exposed fragments' lysine residues. Specific binding of the theranostic agent was observed in vitro with a HER2 positive cell line and cellular near-infrared fluorescence was observed with flow cytometry. Specific photo-activity of the conjugates when exposed to laser light was observed with HER2 positive but not HER2 negative cell lines in vitro, this selectivity was not seen with the unconjugated drug. This theranostic agent demonstrates that two different photo-active functions can be coupled to the same antibody fragment with little interference to their independent activities. PMID- 27501938 TI - Use of complementary health approaches at military treatment facilities, active component, U.S. Armed Forces, 2010-2015. AB - Survey-based research has demonstrated the increasing use and acceptance of complementary and alternative medicine (CAM) in general and military populations. This report summarizes the use of three CAM procedures (chiropractic/osteopathic manipulation, acupuncture, and biofeedback) among active component service members from 2010 through 2015. Findings document a marked increase in the use of chiropractic/osteopathic manipulation and acupuncture procedures since 2010. The majority of the 240 military installations in this analysis provided chiropractic/osteopathic manipulation; more than three-quarters provided acupuncture; and approximately one-third provided biofeedback procedures. "Other and unspecified disorders of the back" was the most frequent condition for which chiropractic/osteopathic manipulation and acupuncture were used. "Non-allopathic lesions not elsewhere classified" was the second most frequent diagnosis during chiropractic/osteopathic manipulation-related visits. The second and third most frequent diagnoses during acupuncture-related visits were "acute and chronic pain" and "adjustment reaction," respectively. "Adjustment reaction" was the second most frequent diagnosis associated with biofeedback. Continued research is needed to gain a better understanding of why military personnel are using CAM and the role these procedures play in their health care. PMID- 27501939 TI - Incident diagnoses of cancers in the active component and cancer-related deaths in the active and reserve components, U.S. Armed Forces, 2005-2014. AB - Cancer is the second leading cause of death in the U.S., surpassed only by heart disease. It is estimated that approximately one of every four deaths in the U.S. is due to cancer. Between 2005 and 2014 among active component service members in the U.S. military, crude incidence rates of most cancer diagnoses have remained relatively stable. During this period, 8,973 active component members were diagnosed with at least one of the cancers of interest and no specific increasing or decreasing trends were evident. Cancers accounted for 1,054 deaths of service members on active duty during the 10-year surveillance period; this included 727 service members in the active component and 327 in the reserve component. PMID- 27501940 TI - Group-based educational interventions in 11-16-year-olds can be effective in supporting suboptimal diabetes control. PMID- 27501941 TI - Using antibiotics responsibly: are we there yet? AB - Problems of antibiotic access and excess coexist in the world today and are compounded by rising rates of antibiotic resistance. We introduce two dimensions of responsibility to this context: responsible individual practices and a broad societal obligation centered on sustainability. Acting on these responsibilities requires recognizing the potential tensions between an individual optimum for antibiotic use and the societal optimum. We relate the tragedy of the commons metaphor to this situation to illustrate the complexity involved, and we draw on real-world experiences in Uganda, India, China and France. We conclude that we must form a global stewardship of antibiotics that can link access, innovation and conservation efforts across countries to ensure sustainable access to effective antibiotics for all who need them. PMID- 27501942 TI - Regulatory Divergence among Beta-Keratin Genes during Bird Evolution. AB - Feathers, which are mainly composed of alpha- and beta-keratins, are highly diversified, largely owing to duplication and diversification of beta-keratin genes during bird evolution. However, little is known about the regulatory changes that contributed to the expressional diversification of beta-keratin genes. To address this issue, we studied transcriptomes from five different parts of chicken contour and flight feathers. From these transcriptomes we inferred beta-keratin enriched co-expression modules of genes and predicted transcription factors (TFs) of beta-keratin genes. In total, we predicted 262 TF-target gene relationships in which 56 TFs regulate 91 beta-keratin genes; we validated 14 of them by in vitro tests. A dual criterion of TF enrichment and "TF-target gene" expression correlation identified 26 TFs as the major regulators of beta-keratin genes. According to our predictions, the ancestral scale and claw beta-keratin genes have common and unique regulators, whereas most feather beta-keratin genes show chromosome-wise regulation, distinct from scale and claw beta-keratin genes. Thus, after expansion from the beta-keratin gene on Chr7 to other chromosomes, which still shares a TF with scale and claw beta-keratin genes, most feather beta keratin genes have recruited distinct or chromosome-specific regulators. Moreover, our data showed correlated gene expression profiles, positive or negative, between predicted TFs and their target genes over the five studied feather regions. Therefore, regulatory divergences among feather beta-keratin genes have contributed to structural differences among different parts of feathers. Our study sheds light on how feather beta-keratin genes have diverged in regulation from scale and claw beta-keratin genes and among themselves. PMID- 27501943 TI - Membrane Proteins Are Dramatically Less Conserved than Water-Soluble Proteins across the Tree of Life. AB - Membrane proteins are crucial in transport, signaling, bioenergetics, catalysis, and as drug targets. Here, we show that membrane proteins have dramatically fewer detectable orthologs than water-soluble proteins, less than half in most species analyzed. This sparse distribution could reflect rapid divergence or gene loss. We find that both mechanisms operate. First, membrane proteins evolve faster than water-soluble proteins, particularly in their exterior-facing portions. Second, we demonstrate that predicted ancestral membrane proteins are preferentially lost compared with water-soluble proteins in closely related species of archaea and bacteria. These patterns are consistent across the whole tree of life, and in each of the three domains of archaea, bacteria, and eukaryotes. Our findings point to a fundamental evolutionary principle: membrane proteins evolve faster due to stronger adaptive selection in changing environments, whereas cytosolic proteins are under more stringent purifying selection in the homeostatic interior of the cell. This effect should be strongest in prokaryotes, weaker in unicellular eukaryotes (with intracellular membranes), and weakest in multicellular eukaryotes (with extracellular homeostasis). We demonstrate that this is indeed the case. Similarly, we show that extracellular water-soluble proteins exhibit an even stronger pattern of low homology than membrane proteins. These striking differences in conservation of membrane proteins versus water soluble proteins have important implications for evolution and medicine. PMID- 27501944 TI - Novel Ciliate Genetic Code Variants Including the Reassignment of All Three Stop Codons to Sense Codons in Condylostoma magnum. AB - mRNA translation in many ciliates utilizes variant genetic codes where stop codons are reassigned to specify amino acids. To characterize the repertoire of ciliate genetic codes, we analyzed ciliate transcriptomes from marine environments. Using codon substitution frequencies in ciliate protein-coding genes and their orthologs, we inferred the genetic codes of 24 ciliate species. Nine did not match genetic code tables currently assigned by NCBI. Surprisingly, we identified a novel genetic code where all three standard stop codons (TAA, TAG, and TGA) specify amino acids in Condylostoma magnum We provide evidence suggesting that the functions of these codons in C. magnum depend on their location within mRNA. They are decoded as amino acids at internal positions, but specify translation termination when in close proximity to an mRNA 3' end. The frequency of stop codons in protein coding sequences of closely related Climacostomum virens suggests that it may represent a transitory state. PMID- 27501946 TI - Is it true that plant-derived polyphenols are always beneficial for the human? In vitro study on Leonurus cardiaca extract properties in the context of the pathogenesis of Staphylococcus aureus infections. AB - The aim of the study was to determine whether Leonurus cardiaca L. herb extract (LCE) used at subinhibitory concentration modifies the characteristics of Staphylococcus aureus, which is important in the pathogenesis of invasive infections originating from the bloodstream, in a way favourable for the human host. Polyphenol-rich LCE, a common ingredient in pharmaceutical products used for various cardiovascular and nervous system disorders, had shown interesting antibacterial and antibiofilm properties in our previous studies. Our current findings indicate that the following S. aureus characteristics decreased, depending on the LCE concentration: (i) formation of aggregates in plasma, (ii) adherence to a fibrin-coated surface, (iii) staphylocoagulase-dependent plasma clotting, (iv) bacterial survival in whole human blood in an ex vivo model, (v) expression of cell surface protein A and (vi) synthesis of alpha-toxin. However, staphylococcal tolerance to exogenous hydrogen peroxide was enhanced after pre incubation with LCE, possibly due to the increased activity of bacterial antioxidant enzymes, a possibility confirmed by the higher production of superoxide dismutase and slightly higher production of catalase. The use of LCE at sub-MIC in in vitro and ex vivo models resulted in the weakening of some important staphylococcal immunoprotective attributes but the strengthening of such virulence factors as those responsible for oxidative stress tolerance. Some of these results and the fact that LCE has direct anticoagulant properties, reflected in a reduced thrombin-dependent fibrinogen polymerization rate, suggest a risk of adverse effects, which could be important in the context of S. aureus survival in the host. PMID- 27501945 TI - Survival and Evolution of a Large Multidrug Resistance Plasmid in New Clinical Bacterial Hosts. AB - Large conjugative plasmids are important drivers of bacterial evolution and contribute significantly to the dissemination of antibiotic resistance. Although plasmid borne multidrug resistance is recognized as one of the main challenges in modern medicine, the adaptive forces shaping the evolution of these plasmids within pathogenic hosts are poorly understood. Here we study plasmid-host adaptations following transfer of a 73 kb conjugative multidrug resistance plasmid to naive clinical isolates of Klebsiella pneumoniae and Escherichia coli. We use experimental evolution, mathematical modelling and population sequencing to show that the long-term persistence and molecular integrity of the plasmid is highly influenced by multiple factors within a 25 kb plasmid region constituting a host-dependent burden. In the E. coli hosts investigated here, improved plasmid stability readily evolves via IS26 mediated deletions of costly regions from the plasmid backbone, effectively expanding the host-range of the plasmid. Although these adaptations were also beneficial to plasmid persistence in a naive K. pneumoniae host, they were never observed in this species, indicating that differential evolvability can limit opportunities of plasmid adaptation. While insertion sequences are well known to supply plasmids with adaptive traits, our findings suggest that they also play an important role in plasmid evolution by maintaining the plasticity necessary to alleviate plasmid-host constrains. Further, the observed evolutionary strategy consistently followed by all evolved E. coli lineages exposes a trade-off between horizontal and vertical transmission that may ultimately limit the dissemination potential of clinical multidrug resistance plasmids in these hosts. PMID- 27501947 TI - Fetal Tissues Tested for Microbial Sterility by Culture- and PCR-Based Methods Can be Safely Used in Clinics. AB - Cell preparations to be used in clinical practice must be free of infectious agents. Safety concerns are especially elevated upon the use of human fetal tissues, which are otherwise highly advantageous in cell therapy. We demonstrate that treating fetal samples with antibiotic, extensive washing, and homogenization prior to cryoconservation efficiently removes microbes in general. Screening a large collection by an automatic culture system showed that 89.2% fetal tissue samples were sterile, while contamination was detected in 10.8% samples. Liver and chorion were contaminated more than the brain, kidney, lung, and soft tissues. Broad-range PCR from the bacterial 16s rRNA gene was adopted as a confirmatory assay; however, the concordance between the culture-based and PCR assays was weak. Taxonomic identification was done for contaminated samples by bacteriological methods and sequencing 16s rRNA PCR products. The two approaches revealed different spectra of taxonomic groups sharing only Lactobacillus, the most frequently found genus. In addition, other representatives of vaginal microbiota were detected by culture-based identification, while PCR product sequencing has also revealed a subset of nosocomial microorganisms. Importantly, species known to cause sepsis were identified by both techniques, arguing for their indispensability and mutual complementarity. We suggest that most contaminations are taken up during collection of fetal material rather than originating from an in utero infection. In conclusion, a rigorous microbiological control by culture and PCR is a prerequisite for safe clinical use of fetal tissue suspensions. PMID- 27501948 TI - Commentary: Histaminergic Drugs Could be Novel Targets for Neuroprotection in CNS Disorders. PMID- 27501949 TI - Conference Report: 14th International Congress on Amino Acids, Peptides and Proteins, Vienna, Austria, August 3-7, 2015. PMID- 27501950 TI - Editorial (Thematic Issue: Old Facts and New Perspectives to Face Alzheimer's Dementia. Focus on Non Neuronal Participants to Neurodegeneration). PMID- 27501953 TI - Immediate implant placement and provisionalization in the aesthetic zone using a flapless or a flap-involving approach: a randomized controlled trial. AB - AIM: We conducted a randomized controlled trial to compare the effect of flapless (FLS) or flap-involving (F) immediate placement and provisionalization of single tooth implants in the aesthetic zone. MATERIALS AND METHODS: Thirty-nine patients were randomized following extraction of a non-restorable tooth to a FLS or F group. All implants were immediately placed and provisionalized. We monitored prospectively changes in the peri-implant mucosal margin, the interproximal bone and buccal horizontal ridge at 3, 6 and 12 months. RESULTS: At 3 months post surgery, the mean +/- SD [median (interquartile range)] mesiobuccal peri-implant gingival margin recession from the pre-surgical soft tissue position amounted to 0.11 +/- 0.32 mm [0 (0, 0.5)] in the FLS treatment arm versus 0.43 +/- 37 mm [0.5 (0, 0.5)] in the F treatment arm (p = 0.02); corresponding values at the distobuccal surface were 0.11 +/- 32 mm [0 (0, 0)] in the FLS arm versus 0.48 +/- 0.44 mm [0.5 (0, 1)] in the F arm (p = 0.01). No other significant differences in soft or hard tissue remodelling between the treatment arms were observed at 3, 6 or 12 months. CONCLUSIONS: Flapless and a flap-involving immediate implant placement and provisionalization in the aesthetic zone resulted in comparable remodelling of the peri-implant mucosa, interproximal bone and buccal ridge at 6 and 12 months. PMID- 27501952 TI - S100B Mediates Stemness of Ovarian Cancer Stem-Like Cells Through Inhibiting p53. AB - S100B is one of the members of the S100 protein family and is involved in the progression of a variety of cancers. Ovarian cancer is driven by cancer stem-like cells (CSLCs) that are involved in tumorigenesis, metastasis, chemo-resistance and relapse. We then hypothesized that S100B might exert pro-tumor effects by regulating ovarian CSLCs stemness, a key characteristic of CSLCs. First, we observed the high expression of S100B in ovarian cancer specimens when compared to that in normal ovary. The S100B upregulation associated with more advanced tumor stages, poorer differentiation and poorer survival. In addition, elevated S100B expression correlated with increased expression of stem cell markers including CD133, Nanog and Oct4. Then, we found that S100B was preferentially expressed in CD133+ ovarian CSLCs derived from both ovarian cancer cell lines and primary tumors of patients. More importantly, we revealed that S100B knockdown suppressed the in vitro self-renewal and in vivo tumorigenicity of ovarian CSLCs and decreased their expression of stem cell markers. S100B ectopic expression endowed non-CSLCs with stemness, which has been demonstrated with both in vitro and in vivo experiments. Mechanically, we demonstrated that the underlying mechanism of S100B-mediated effects on CSLCs stemness was not dependent on its binding with a receptor for advanced glycation end products (RAGE), but might be through intracellular regulation, through the inhibition of p53 expression and phosphorylation. In conclusion, our results elucidate the importance of S100B in maintenance of ovarian CSLCs stemness, which might provide a promising therapeutic target for ovarian cancer. Stem Cells 2017;35:325-336. PMID- 27501951 TI - Cytosolic phospholipase A2 contributes to innate immune defense against Candida albicans lung infection. AB - BACKGROUND: The lung is exposed to airborne fungal spores, and fungi that colonize the oral cavity such as Candida albicans, but does not develop disease to opportunistic fungal pathogens unless the immune system is compromised. The Group IVA cytosolic phospholipase A2 (cPLA2alpha) is activated in response to Candida albicans infection resulting in the release of arachidonic acid for eicosanoid production. Although eicosanoids such as prostaglandins and leukotrienes modulate inflammation and immune responses, the role of cPLA2alpha and eicosanoids in regulating C. albicans lung infection is not understood. METHODS: The responses of cPLA2alpha(+/+) and cPLA2alpha(-/-) Balb/c mice to intratracheal instillation of C. albicans were compared. After challenge, we evaluated weight loss, organ fungal burden, and the recruitment of cells and the levels of cytokines and eicosanoids in bronchoalveolar lavage fluid. The ability of macrophages and neutrophils from cPLA2alpha(+/+) and cPLA2alpha(-/-) mice to recognize and kill C. albicans was also compared. RESULTS: After C. albicans instillation, cPLA2alpha(+/+) mice recovered a modest weight loss by 48 h and completely cleared fungi from the lung by 12 h with no dissemination to the kidneys. In cPLA2alpha(-/-) mice, weight loss continued for 72 h, C. albicans was not completely cleared from the lung and disseminated to the kidneys. cPLA2alpha( /-) mice exhibited greater signs of inflammation including higher neutrophil influx, and elevated levels of albumin and pro-inflammatory cytokines/chemokines (IL1alpha, IL1beta, TNFalpha, IL6, CSF2, CXCL1, CCL20) in bronchoalveolar lavage fluid. The amounts of cysteinyl leukotrienes, thromboxane B2 and prostaglandin E2 were significantly lower in bronchoalveolar lavage fluid from C. albicans infected cPLA2alpha(-/-) mice compared to cPLA2alpha(+/+) mice. Alveolar macrophages and neutrophils from uninfected cPLA2alpha(-/-) mice exhibited less killing of C. albicans in vitro than cells from cPLA2alpha(+/+) mice. In addition alveolar macrophages from cPLA2alpha(-/-) mice isolated 6 h after instillation of GFP-C. albicans contained fewer internalized fungi than cPLA2alpha(+/+) macrophages. CONCLUSIONS: The results demonstrate that cPLA2alpha contributes to immune surveillance and host defense in the lung to prevent infection by the commensal fungus C. albicans and to dampen inflammation. PMID- 27501954 TI - Bibliometric analysis of rheumatology research in the Arab countries. AB - BACKGROUND: The Arab world has seen an increase in the burden of musculoskeletal diseases. No bibliometric studies have characterized rheumatology research in the Arab world. This study evaluates the productivity and impact of rheumatology research in the Arab world. METHODS: We searched the Web of Science Core Collection for rheumatology publications, from 1976 to 2014, for each of the Arab League (AL) countries, North America, Europe and Asia. For the AL countries, the overall trend of publications and citations was analyzed, while considering the paper type and collaborations. RESULTS: The AL countries published 944 rheumatology papers over the period studied. The number of publications increased by a factor of 2.77 (95 % CI, 2.75-2.78) each decade, and citations increased by a factor of 2.36 (95 % CI, 0.96-5.82). The absolute number of papers included in the top-10 rheumatology journals remained constant but the proportion decreased. Papers involving collaboration among AL countries were found to increase over time. CONCLUSIONS: Overall, the AL countries lag in research productivity and impact compared to other regions. Three countries are responsible for the majority of publications, while four countries receive the majority of citations. PMID- 27501955 TI - Determination of GP88 (progranulin) expression in breast tumor biopsies improves the risk predictive value of the Nottingham Prognostic Index. AB - BACKGROUND: The Nottingham Prognostic Index (NPI), which combines numerical values for nodal status, tumor size and histological grade, is used in the standard of care to provide predictive value information on post-surgery survival for patients with primary breast cancer. Attempts to improve the performance of the NPI algorithm have been carried out by testing the inclusion of other biomarker expression and morphological features such as vascular invasion. In the present study, we investigated whether expression of the autocrine growth and survival factor GP88 (progranulin), known to be overexpressed in breast cancer, would improve NPI's predictive value. METHODS: We examined by immunohistochemistry (IHC) the GP88 expression in 508 cases of estrogen receptor positive invasive ductal carcinoma with known clinical outcomes and for which NPI had been determined. GP88 IHC expression was scored by two board certified pathologists and classified into two score groups of GP88 <3+ (0, 1+, 2+) and GP88 = 3+. The correlation between GP88 scoring, NPI and disease-free (DFS) or overall survival (OS) outcomes was then examined by Kaplan-Meier analysis, Cox proportional Hazard (CPH) ratio and Pearson's X (2) test. RESULTS: Kaplan-Meier survival graphs of cases categorized by their NPI scores (<3.4, 3.4-5.4, >5.4) and GP88 expression showed that for patients within the same NPI subgroup, patients having tumors with a high GP88 expression (GP88 IHC score of 3+) had a worse DFS than patients with tumors that had a low GP88 expression (GP88 IHC score <3+). When adjusted for NPI, high GP88 score was significantly associated with recurrence with a hazard ratio of 3.30 (95 % CI 2.12 to 5.14). CONCLUSIONS: The data suggest that the determination of GP88 tumor expression at time of diagnosis for early stage breast cancer patients can provide additional survival information to that provided by NPI alone and thus may be useful for risk management of patients diagnosed with breast cancer. PMID- 27501956 TI - The leishmanicidal activity of oleuropein is selectively regulated through inflammation- and oxidative stress-related genes. AB - BACKGROUND: Much research effort has been focused on investigating new compounds derived from low-cost sources, such as natural products, for treating leishmaniasis. Oleuropein derived from numerous plants, particularly from the olive tree, Olea europaea L. (Oleaceae), is a biophenol with many biological activities. Our previous findings showed that oleuropein exhibits leishmanicidal effects against three Leishmania spp. in vitro, and minimizes the parasite burden in L. donovani-infected BALB/c mice. The aim of the present study is to investigate the possible mechanism(s) that mediate this leishmanicidal activity. METHODS: We determined the efficacy of oleuropein in elevating ROS and NO production in L. donovani-infected J774A.1 macrophages and in explanted splenocytes and hepatocytes obtained from L. donovani-infected BALB/c mice. We also assessed the expression of genes that are related to inflammation, T-cell polarization and antioxidant defense, in splenocytes. Finally, we determined the ratios of specific IgG2a/IgG1 antibodies and DTH reactions in L. donovani infected BALB/c mice treated with oleuropein. RESULTS: Oleuropein was able to elevate ROS production in both in vitro and in vivo models of visceral leishmaniasis and raised NO production in ex vivo cultures of splenocytes and hepatocytes. The extensive oxidative stress found in oleuropein-treated mice was obviated by the upregulation of the host's antioxidant enzyme (mGCLC) and the simultaneous downregulation of the corresponding enzyme of the parasite (LdGCLC). Moreover, oleuropein was able to mount a significant Th1 polarization characterized by the expression of immune genes (IL-12beta, IL-10, TGF-beta1, IFN gamma) and transcription factors (Tbx21 and GATA3). Moreover, this immunomodulatory effect was also correlated with an inhibitory effect on IL-1beta gene expression, rather than with the expression of IL-1alpha, IL-1rn and TNF alpha. Furthermore, oleuropein-treated BALB/c mice mounted a delayed-type hypersensitivity (DTH) response and an elevated Leishmania-specific IgG2a/IgG1 ratio that clearly demonstrated an in vivo protective mechanism. CONCLUSION: The ability of Oleuropein to promote a Th1 type immune response in L. donovani infected BALB/c mice points towards the candidacy of this bioactive compound as an immunomodulatory agent that may complement therapeutic approaches to leishmaniasis. PMID- 27501957 TI - Preclinical anaylses of [18F]cEFQ as a PET tracer for imaging metabotropic glutamate receptor type 1 (mGluR1). AB - Metabotropic glutamate receptor type 1 (mGluR1) is related with various neurological and psychiatric diseases, such as anxiety, depression, epilepsy, Parkinson's disease, and neuropathic pain. Hence, mGluR1 is an important target for drug development and imaging. We synthesized [18F]cEFQ (3-ethyl-2 [18F]fluoroquinolin-6-yl cis-(4-methoxycyclohexyl)methanone) as a PET tracer for selective mGluR1 imaging and evaluated its properties in rodents. A chloroquinoline precursor was labeled by a nucleophilic substitution reaction, and the resulting [18F]cEFQ was obtained with high radiochemical purity (>99%) and specific activity (63-246 GBq/umol). The log D value was 3.24, and the initial brain uptake at 10 min was over 4% of injected dose per gram in BALB/c mice. According to PET/CT and autoradiography in SD rats, [18F]cEFQ showed wide distribution in the whole brain and the highest uptake in the cerebellum. Pre treatment with unlabeled cEFQ or the mGluR1-specific antagonist JNJ16259685 blocked the uptake of [18F]cEFQ. However, the uptake was not blocked by pre treatment with the mGluR5-specific antagonist ABP688. The trans isomer [18F]tEFQ did not show high uptake in the mGluR1-rich region. [18F]cEFQ was straightforwardly prepared using a chloro-derivative precursor. Its feasibility as a specific and selective PET agent for imaging mGluR1 was proved by in vitro and in vivo experiments using rodents. PMID- 27501958 TI - Bone tissue response to experimental zirconia implants. AB - OBJECTIVES: This study seeks to assess the bone tissue response at experimental zirconia implants in comparison with titanium implants by means of descriptive histology and histomorphometry in a dog model. MATERIALS AND METHODS: Experimental zirconia implants with three different surface roughnesses (Z1 < Z2 < Z3) and conventional sandblasted large grit and acid-etched titanium implants were inserted bilaterally in the lower jaws of nine beagle dogs. Tissue biopsies were obtained after 3 and 14 days and 10 weeks of transmucosal healing. The tissue response was investigated by assessing new, old, and total bone-to-implant contact (nBIC, oBIC, and tBIC). RESULTS: After 3 days, histological specimens of all groups showed an intimate contact between the implant threads and pristine bone (tBIC: Ti 42.3 % > Z2 30.1 % > Z3 28.9 % > Z1 25.1 %, p > 0.05, unpaired t test, respectively). A provisional matrix was evident at all implant surfaces. At 14 days, percentages of BIC increased in all groups (tBIC: Ti 62.1 % > Z3 69.2 % < Z2 44.4 % > Z1 42.3 %; nBIC: Z3 58.9 % > Ti 52.2 % > Z2 35.1 % > Z1 32.5 %). Two implants, one of group Z1 and one of group Z2, were lost. At 10 weeks, 13 of 18 zirconia implants were lost, equally distributed between all three surface modifications. The remaining implants revealed increased BIC values (tBIC: Z3 69.5 % > Ti 58.5 % > Z1 49.7 % > Z2 37.1 %; nBIC: Z3 57.2 % > Ti 46.5 % > Z1 32.3 % > Z2 29.3 %). Histomorphometrical analysis showed comparable mean BIC values in all groups at all healing periods without showing statistical differences (p > 0.05, unpaired t test, respectively). CONCLUSION: The bone tissue response throughout the healing periods was characterized by a constant bone remodeling accompanied by resorption of old bone in favor of new bone formation at both titanium and zirconia implants. Surface roughness had a positive effect on BIC, although not showing statistical significance. Due to the poor survival rate, the experimental zirconia implants investigated may not be suitable for clinical use. CLINICAL RELEVANCE: Zirconia has been introduced as an alternative biomaterial for dental implants. A profound knowledge about the bone tissue response at zirconia implant surfaces is necessary as it plays an important role for proper osseointegration and long-term stability. PMID- 27501959 TI - Risk factors associated with early mortality in patients with multiple myeloma who were treated upfront with a novel agents containing regimen. AB - BACKGROUND: Although the introduction of novel agents improved the survival outcomes in patients with multiple myeloma (MM), some patients died within one year (early mortality, EM) following diagnosis. In this study, we evaluated the EM rate, and investigated the risk factors associated with EM in MM patients. METHODS: Retrospective data from 542 patients who were initially treated with a novel agent-containing regimen were analyzed. RESULTS: The median overall survival (OS) for the entire cohort was 56.5 months. The median OS in the 2010 2014 group was longer than in the 2002-2009 group (59.2 months vs. 49.1 months, P = 0.054). The rate of EM was 13.8 %, and the most common causes of EM were infection and comorbidity. In multivariate analysis, the age-adjusted Charlson comorbidity index (ACCI >= 4), low body mass index (BMI < 20 kg/m(2)), thrombocytopenia, and renal failure were significantly associated with EM. The presence of none, 1, or >= 2 factors was associated with a 4.1 %, 14.3 %, or 27.4 % risk of EM (P < 0.001), respectively. The median OS times were significantly different depending on the presence of factors associated with EM (P < 0.001). CONCLUSIONS: In conclusion, the ACCI (>= 4), low BMI, thrombocytopenia and renal failure were strong predictors for EM in the novel agent era. The results of this study will help to identify patients at high risk for EM, and may be helpful to more accurately predict prognosis of MM patients in the novel-agent era. PMID- 27501961 TI - Beyond the Drama: the Beautiful Life in News Feeds on Cancer. AB - Facebook is one of the main communication tools in the world nowadays. In Brazil, it is used for almost half of the population. Knowing what is conveyed about cancer by this social network can be an important step for the development of efficient health communication strategies. We evaluate Facebook user's comments on pages about cancer; verify if there is a pattern of public awareness on the disease and compare it with results from other studies. Three pages about cancer on Facebook were selected among those with more followers in Brazil. For 6 months, from January to June 2014, all posts were selected and evaluated, and we created eight categories. On each page, the categories that generated most comments were elected for the second analysis. The behavior of empowered citizens by new communication tools is the target of this study. Similarities and differences between 12,926 comments coming from 1243 posts in three different Facebook pages on cancer were analyzed. Four new categories were identified: "religion," "positive," "negative," and "information." Despite the differences among the three pages selected for this study, we observed the predominance of positive speeches associated with religious terms. Following public perceptions on cancer is an important step for the development of efficient health communication strategies. PMID- 27501960 TI - Pregnancy and multiple sclerosis: from molecular mechanisms to clinical application. AB - Translational research generally refers to a "bench to bedside" approach where basic science discoveries in models move to clinical trials in humans. However, a "bedside to bench to bedside" approach may be more promising with respect to clinical relevance, since it starts with a clinical observation that can serve as a research paradigm to elucidate mechanisms and translate them back into novel therapeutic approaches. The effect of pregnancy on human autoimmune disorders in general, and multiple sclerosis (MS) in particular, serves as an intriguing example of how this can be used to understand disease pathobiology and discover new therapeutic targets. Disease activity in MS undergoes pronounced shifts in the time before, during, and after pregnancy. The most well-known and established example is a reduction in relapse rates in the last trimester by 70-80 %. However, disease activity reappears in the first few months after delivery, temporarily overshooting pre-pregnancy levels. This phenomenon has since its first description served as a model for investigating novel treatment options in animal models and has cumulated in successful phase 2a and 2b trials in female MS patients. However, recently, a number of other clinical observations have been made that might be similarly suitable to offer additional insights into pathobiological mechanisms of MS activity, progression, and possibly even incidence. Here, we outline the various changes in the clinical course of MS that have been described in relation to pregnancy, both short term and long term, and discuss how these may inform the development of novel treatments for autoimmune diseases. PMID- 27501962 TI - Material deprivation and health: a longitudinal study. AB - BACKGROUND: Does material deprivation affect the consequences of ill health? Answering this question requires that we move beyond the effects of income. Longitudinal data on material deprivation, longstanding illness and limiting longstanding illness enables investigations of the effects of material deprivation on risk of limiting longstanding illness. This study investigates whether a shift from affording to not affording a car predicts the probability of limiting longstanding ill (LLSI). METHODS: The 2008-2011 longitudinal panel of Statistics on Income, Social Inclusion and Living Conditions (EU-SILC) is utilised. Longitudinal fixed effects logit models are applied, using LLSI as dependent variable. Transition from affording a car to not affording a car is used as a proxy for material deprivation. All models are controlled for whether the person becomes longstanding ill (LSI) as well as other time-variant covariates that could affect the results. RESULTS: The analysis shows a statistically significant increased odds ratio of LLSI when individuals no longer can afford a car, after controlling for confounders and LSI in the previous year (1.129, CI = 1.022-1.248). However, when restricting the sample to observations where respondents report longstanding illness the results are no longer significant (1.032, CI = 0.910-1.171). CONCLUSION: The results indicate an individual level effect of material deprivation on LLSI, suggesting that material resources can affect the consequences of ill health. PMID- 27501963 TI - Orthokeratinized Odontogenic Cyst with an Associated Keratocystic Odontogenic Tumor Component and Ghost Cell Keratinization and Calcifications in a Patient with Gardner Syndrome. AB - Gardner syndrome (GS) is caused by mutations in the APC and besides adenomatous colorectal polyps includes such manifestations as osteomas, epidermoid cysts (ECs) and occasionally multiple pilomatricomas. More than 50 % of ECs in patients with GS exhibit pilomatricoma-like ghost cell keratinization. The latter may be explained by the fact that the development of both GS and pilomatricoma is driven by activation of the Wnt/beta-catenin signaling pathway. A 62-year-old, Caucasian male with history of GS presented with a unilocular, mixed radiopaque/radiolucent mandibular lesion causing divergence and external root resorption of involved teeth. Histopathologically, the lesion was composed of two cystic components, an orthokeratinized odontogenic cyst (OOC) and a smaller one with characteristics of keratocystic odontogenic tumor (KCOT) featuring, focally, ghost cells and an epithelial morule-like structure. Dystrophic calcifications essentially similar to those seen in pilomatricomas were observed in the fibrous connective tissue wall. The KCOT and OOC epithelia revealed strong and diffuse cytokeratin (AE1/AE3) and beta-catenin immunoreactivity. CD10 positive immunostaining was seen in the keratin and superficial spinous cell layers in both OOC and KCOT. The intraepithelial and mural ghost cells showed a cytokeratin (+), beta-catenin and CD10 (-) immunophenotype. The diagnosis of OOC with ghost cell calcifications in association with KCOT was rendered. The patient was lost to follow-up. Although a coincidental co-existence cannot be excluded, ghost cell calcifications mimicking pilomatricoma-like changes in an unusual odontogenic cyst combining OOC and KCOT features as seen in this patient with GS may be explained by the common molecular mechanisms underlying the pathogenesis of cutaneous pilomatricomas and GS. PMID- 27501964 TI - MASCC/ESMO Antiemetic Guidelines: Introduction to the 2016 guideline update. PMID- 27501965 TI - 2016 Updated MASCC/ESMO consensus recommendations: Emetic risk classification and evaluation of the emetogenicity of antineoplastic agents. AB - PURPOSE: Employing the same framework as in previous guideline updates, antineoplastic agents were classified into four emetic risk categories. The classification of the emetogenic level of new antineoplastic agents, especially for the oral drugs, represents an increasing challenge. Accurate reporting of emetogenicity of new antineoplastic agents in the absence of preventive antiemetic treatment is rarely available. METHODS: A systematic search was conducted for drugs approved after 2009 until June 2015 using EMBASE and PubMed. The search term was "drug name." The restrictions were language (English records only), date (2009 to 2015), and level of evidence ("clinical trial"). RESULTS: From January 2009 to June 2015, 42 new antineoplastic agents were identified and a systematic search was conducted to identify relevant studies to help define emetic risk levels. The reported incidence of vomiting varied across studies for many agents, but there was adequate evidence to allow 41 of the 42 new antineoplastic agents to be classified according to emetogenic risk. No highly emetogenic agents were identified. Seven moderately emetogenic agents, 26 low emetogenic, agents and eight minimal emetogenic agents were identified and classified accordingly. The MASCC/ESMO update committee also recommended reclassification of the combination of an anthracycline and cyclophosphamide (AC) as highly emetogenic. CONCLUSION: Despite several limitations, we have attempted to provide a reasonable approximation of the emetic risk associated with new antineoplastic agents through a comprehensive search of the available literature. Hopefully by the next update, more precise information on emetic risk will have been collected during new agent development process. PMID- 27501966 TI - Efficacy and safety of lipegfilgrastim compared with placebo in patients with non small cell lung cancer receiving chemotherapy: post hoc analysis of elderly versus younger patients. AB - PURPOSE: Lipegfilgrastim, a glycoPEGylated recombinant granulocyte colony stimulating factor (G-CSF), reduces neutropenia duration and febrile neutropenia (FN) incidence in patients with cancer receiving myelosuppressive chemotherapy. A phase 3 trial of lipegfilgrastim was conducted in patients with advanced non small cell lung cancer (NSCLC) receiving cisplatin/etoposide (which produces mild to-moderate myelosuppression). Because patients aged >65 years are at higher risk for FN versus younger patients, this post hoc analysis compared outcomes in elderly (>65 years) versus younger participants in this trial. METHODS: Patients were randomized 2:1 to receive a once-per-cycle single subcutaneous injection of lipegfilgrastim 6 mg or placebo, with up to 4 cycles of every-3-week cisplatin (day 1) and etoposide (days 1-3). The primary end point was FN incidence during cycle 1. Outcomes were compared across treatment groups and by age groups (<=65 and >65 years). RESULTS: For patients aged <=65 years, FN incidence during cycle 1 was similar in the lipegfilgrastim and placebo groups (3.0 vs 3.2 %, respectively), whereas for elderly patients, there was a reduction in FN incidence with lipegfilgrastim (0 vs 13.3 %, respectively). In both age subgroups, lipegfilgrastim showed a propensity to reduce the incidence and duration of severe neutropenia, time to absolute neutrophil count (ANC) recovery, and depth of ANC nadir. Adverse events were generally similar between groups. CONCLUSIONS: This analysis suggests that in patients with a higher FN risk, such as the elderly patients of this study, lipegfilgrastim reduces not only the duration of severe neutropenia but also the incidence of FN. PMID- 27501967 TI - The influence hydrogen atom addition has on charge switching during motion of the metal atom in endohedral Ca@C60H4 isomers. AB - Density functional theory has been applied in a study of charge transfer between an endohedral calcium atom and the fullerene cage in Ca@C60H4 and [Ca@C60H4](+) isomers. Previous calculations on Ca@C60 have shown that the motion of calcium within a fullerene is accompanied by large changes in electron density on the carbon cage. Based on this observation, it has been proposed that a tethered endohedral fullerene might form the bases of a nanoswitch. Through the addition of hydrogen atoms to one hemisphere of the cage it is shown that, when compared with Ca@C60, asymmetric and significantly reduced energy barriers can be generated with respect to motion of the calcium atom. It is proposed that hydrogen atom addition to a fullerene might offer a route for creating a bi stable nanoswitch that can be fine-tuned through the selection of an appropriate isomer and number of atoms attached to the cage of an endohedral fullerene.This article is part of the themed issue 'Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene'. PMID- 27501968 TI - The Stone-Wales transformation: from fullerenes to graphite, from radiation damage to heat capacity. AB - The Stone-Wales (SW) transformation, or carbon-bond rotation, has been fundamental to understanding fullerene growth and stability, and ab initio calculations show it to be a high-energy process. The nature and topology of the fullerene energy landscape shows how the Ih-C60 must be the final product, if SW transformations are fast enough, and various mechanisms for their catalysis have been proposed. We review SW transformations in fullerenes and then discuss the analogous transformation in graphite, where they form the Dienes defect, originally posited to be a transition state in the direct exchange of a bonded atom pair. On the basis of density functional theory calculations in the local density approximation, we propose that non-equilibrium concentrations of the Dienes defect arising from displacing radiation are rapidly healed by point defects and that equilibrium concentrations of Dienes defects are responsible for the divergent ultra-high-temperature heat capacity of graphite.This article is part of the themed issue 'Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene'. PMID- 27501970 TI - Super-atom molecular orbital excited states of fullerenes. AB - Super-atom molecular orbitals are orbitals that form diffuse hydrogenic excited electronic states of fullerenes with their electron density centred at the centre of the hollow carbon cage and a significant electron density inside the cage. This is a consequence of the high symmetry and hollow structure of the molecules and distinguishes them from typical low-lying molecular Rydberg states. This review summarizes the current experimental and theoretical studies related to these exotic excited electronic states with emphasis on femtosecond photoelectron spectroscopy experiments on gas-phase fullerenes.This article is part of the themed issue 'Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene'. PMID- 27501969 TI - Two-dimensional inorganic analogues of graphene: transition metal dichalcogenides. AB - The discovery of graphene marks a major event in the physics and chemistry of materials. The amazing properties of this two-dimensional (2D) material have prompted research on other 2D layered materials, of which layered transition metal dichalcogenides (TMDCs) are important members. Single-layer and few-layer TMDCs have been synthesized and characterized. They possess a wide range of properties many of which have not been known hitherto. A typical example of such materials is MoS2 In this article, we briefly present various aspects of layered analogues of graphene as exemplified by TMDCs. The discussion includes not only synthesis and characterization, but also various properties and phenomena exhibited by the TMDCs.This article is part of the themed issue 'Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene'. PMID- 27501971 TI - Unconventional high-Tc superconductivity in fullerides. AB - A3C60 molecular superconductors share a common electronic phase diagram with unconventional high-temperature superconductors such as the cuprates: superconductivity emerges from an antiferromagnetic strongly correlated Mott insulating state upon tuning a parameter such as pressure (bandwidth control) accompanied by a dome-shaped dependence of the critical temperature, Tc However, unlike atom-based superconductors, the parent state from which superconductivity emerges solely by changing an electronic parameter-the overlap between the outer wave functions of the constituent molecules-is controlled by the C60 (3-) molecular electronic structure via the on-molecule Jahn-Teller effect influence of molecular geometry and spin state. Destruction of the parent Mott-Jahn-Teller state through chemical or physical pressurization yields an unconventional Jahn Teller metal, where quasi-localized and itinerant electron behaviours coexist. Localized features gradually disappear with lattice contraction and conventional Fermi liquid behaviour is recovered. The nature of the underlying (correlated versus weak-coupling Bardeen-Cooper-Schrieffer theory) s-wave superconducting states mirrors the unconventional/conventional metal dichotomy: the highest superconducting critical temperature occurs at the crossover between Jahn-Teller and Fermi liquid metal when the Jahn-Teller distortion melts.This article is part of the themed issue 'Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene'. PMID- 27501972 TI - Fullerene ion chemistry: a journey of discovery and achievement. AB - An account is provided of the extraordinary features of buckminster fullerene cations and their chemistry that we discovered in our Ion Chemistry Laboratory at York University (Canada) during a 'golden' period of research in the early 1990s, just after C60 powder became available. We identified new chemical ways of C60 ionization and tracked novel chemistry of C60 (n+) as a function of charge state (n=1-3) with some 50 different reagent molecules. We found that multiple charges enhance reaction rates and diversify reaction products and mechanisms. Strong electrostatic interactions with reagent molecules were seen to reduce barriers to carbon surface bonding and charge-separation reactions, while intramolecular Coulomb repulsion appeared to localize charge on the surface or the substituent and so influence higher order chemistry, including 'spindle', 'star', 'fuzzy ball', 'ball-and-chain' and dimer ion formation. We introduced the notion of 'apparent' gas-phase acidity with measurements of proton-transfer reactions of multiply charged fullerene cations. We also explored the attachment of atomic metal cations to C60 and their subsequent reactions. All these findings were applied to the possible chemistry of fullerene cations in the interstellar medium with a focus on multiply charged fullerene ion formation and the intervention of fullerene cations in fullerene derivatization and molecular synthesis, with a view to their possible future detection.This article is part of the themed issue 'Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene'. PMID- 27501973 TI - Another big discovery-metallofullerenes. AB - Several days after the first experimental observation of the 'magic number' soccerball-shaped C60 in a laser-vaporized cluster beam mass spectrum by Kroto and co-workers (Heath et al 1985 J. Am. Chem. Soc. 107, 7779-7780. (doi:10.1021/ja00311a102)) they also found a magic number feature owing to La@C60 in a mass spectrum prepared by laser vaporization of a LaCl3-impregnated graphite rod. With the advent of macroscopic synthesis and the following successful separation and purification of metallofullerenes, both experimental and theoretical studies of metallofullerenes have developed quite rapidly to date so as to elucidate their structural, electronic, magnetic and transport properties. Furthermore, a bottom-up closed network growth mechanism has experimentally been shown to play a crucial role in generating various types of metallofullerenes.This article is part of the themed issue 'Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene'. PMID- 27501974 TI - Fullerene and nanotube growth: new insights using first principles and molecular dynamics. AB - Shortly after the discovery of fullerenes, many researchers pointed out that carbon nanotubes could be considered as elongated fullerenes. However, the detailed formation mechanism for both structures has been a topic of debate for several years, and consequently it has been difficult to draw a clear connection between the two systems. While the synthesis conditions appear to be different for both fullerenes and nanotubes, here, we demonstrate that it is highly likely that, at an initial growth stage, single-walled carbon nanotubes begin to grow from a hemisphere-like fullerene cap. More importantly, by analysing the minimum energy path, it is shown that the insertion of C2 fragments drives the transformation of this fullerene cap into an elongated structure that leads to the formation of very short carbon nanotubes.This article is part of the themed issue 'Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene'. PMID- 27501975 TI - Ab initio infrared vibrational modes for neutral and charged small fullerenes (C20, C24, C26, C28, C30 and C60). AB - We calculate the infrared (IR) absorption spectra using DFT B3LYP(6-311G) for a range of small closed-cage fullerenes, Cn, n=20, 24, 26, 28, 30 and 60, in both neutral and multiple positive and negative charge states. The results are of use, notably, for direct comparison with observed IR absorption in the interstellar medium. Frequencies fall typically into two ranges, with C-C stretch modes around 1100-1500 cm(-1) (6.7-9.1 MUm) and fullerene-specific radial motion associated with under-coordinated carbon at pentagonal sites in the range 600-800 cm(-1) (12.5-16.7 MUm). Notably, negatively charged fullerenes show significantly stronger absorption intensities than neutral species. The results suggest that small cage fullerenes, and notably metallic endofullerenes, may be responsible for many of the unassigned interstellar IR spectral lines.This article is part of the themed issue 'Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene'. PMID- 27501976 TI - Pathway to the identification of C60+ in diffuse interstellar clouds. AB - The origin of the attenuation of starlight in diffuse clouds in interstellar space at specific wavelengths ranging from the visible to the near-infrared has been unknown since the first astronomical observations around a century ago. The absorption features, termed the diffuse interstellar bands, have subsequently been the subject of much research. Earlier this year four of these interstellar bands were shown to be due to the absorption by cold, gas phase [Formula: see text] molecules. This discovery provides the first answer to the problem of the diffuse interstellar bands and leads naturally to fascinating questions regarding the role of fullerenes and derivatives in interstellar chemistry. Here, we review the identification process placing special emphasis on the laboratory studies which have enabled spectroscopic measurement of large cations cooled to temperatures prevailing in the interstellar medium.This article is part of the themed issue 'Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene'. PMID- 27501977 TI - Professor Sir Harry Kroto (1939-2016). PMID- 27501978 TI - Fullerenes: past, present and future, celebrating the 30th anniversary of Buckminster Fullerene. PMID- 27501979 TI - Morphology and Photoluminescence of HfO2Obtained by Microwave-Hydrothermal. AB - In this letter, we report on the obtention of hafnium oxide (HfO2) nanostructures by the microwave-hydrothermal method. These nanostructures were analyzed by X-ray diffraction (XRD), field-emission gum scanning electron microscopy (FEG-SEM), transmission electron microscopy (TEM), energy dispersive X-ray spectrometry (EDXS), ultraviolet-visible (UV-vis) spectroscopy, and photoluminescence (PL) measurements. XRD patterns confirmed that this material crystallizes in a monoclinic structure. FEG-SEM and TEM micrographs indicated that the rice-like morphologies were formed due to an increase in the effective collisions between the nanoparticles during the MH processing. The EDXS spectrum was used to verify the chemical compositional of this oxide. UV-vis spectrum revealed that this material have an indirect optical band gap. When excited with 488 nm wavelength at room temperature, the HfO2nanostructures exhibited only one broad PL band with a maximum at around 548 nm (green emission). PMID- 27501980 TI - Role of the ganSPQAB Operon in Degradation of Galactan by Bacillus subtilis. AB - Bacillus subtilis possesses different enzymes for the utilization of plant cell wall polysaccharides. This includes a gene cluster containing galactan degradation genes (ganA and ganB), two transporter component genes (ganQ and ganP), and the sugar-binding lipoprotein-encoding gene ganS (previously known as cycB). These genes form an operon that is regulated by GanR. The degradation of galactan by B. subtilis begins with the activity of extracellular GanB. GanB is an endo-beta-1,4-galactanase and is a member of glycoside hydrolase (GH) family 53. This enzyme was active on high-molecular-weight arabinose-free galactan and mainly produced galactotetraose as well as galactotriose and galactobiose. These galacto-oligosaccharides may enter the cell via the GanQP transmembrane proteins of the galactan ABC transporter. The specificity of the galactan ABC transporter depends on the sugar-binding lipoprotein, GanS. Purified GanS was shown to bind galactotetraose and galactotriose using thermal shift assay. The energy for this transport is provided by MsmX, an ATP-binding protein. The transported galacto oligosaccharides are further degraded by GanA. GanA is a beta-galactosidase that belongs to GH family 42. The GanA enzyme was able to hydrolyze short-chain beta 1,4-galacto-oligosaccharides as well as synthetic beta-galactopyranosides into galactose. Thermal shift assay as well as electrophoretic mobility shift assay demonstrated that galactobiose is the inducer of the galactan operon regulated by GanR. DNase I footprinting revealed that the GanR protein binds to an operator overlapping the -35 box of the sigma(A)-type promoter of Pgan, which is located upstream of ganS IMPORTANCE: Bacillus subtilis is a Gram-positive soil bacterium that utilizes different types of carbohydrates, such as pectin, as carbon sources. So far, most of the pectin degradation systems and enzymes have been thoroughly studied in B. subtilis Nevertheless, the B. subtilis utilization system of galactan, which is found as the side chain of the rhamnogalacturonan type I complex in pectin, has remained partially studied. Here, we investigated the galactan utilization system consisting of the ganSPQAB operon and its regulator ganR This study improves our knowledge of the carbohydrate degradation systems of B. subtilis, especially the pectin degradation systems. Moreover, the galactan-degrading enzymes may be exploited for the production of galacto oligosaccharides, which are used as prebiotic substances in the food industry. PMID- 27501981 TI - Transcriptomic and Phenotypic Analysis Reveals New Functions for the Tat Pathway in Yersinia pseudotuberculosis. AB - The twin-arginine translocation (Tat) system mediates the secretion of folded proteins that are identified via an N-terminal signal peptide in bacteria, plants, and archaea. Tat systems are associated with virulence in many bacterial pathogens, and our previous studies revealed that Tat-deficient Yersinia pseudotuberculosis was severely attenuated for virulence. Aiming to identify Tat dependent pathways and phenotypes of relevance for in vivo infection, we analyzed the global transcriptome of parental and DeltatatC mutant strains of Y. pseudotuberculosis during exponential and stationary growth at 26 degrees C and 37 degrees C. The most significant changes in the transcriptome of the DeltatatC mutant were seen at 26 degrees C during stationary-phase growth, and these included the altered expression of genes related to virulence, stress responses, and metabolism. Subsequent phenotypic analysis based on these transcriptome changes revealed several novel Tat-dependent phenotypes, including decreased YadA expression, impaired growth under iron-limited and high-copper conditions, as well as acidic pH and SDS. Several functionally related Tat substrates were also verified to contribute to these phenotypes. Interestingly, the phenotypic defects observed in the Tat-deficient strain were generally more pronounced than those in mutants lacking the Tat substrate predicted to contribute to that specific function. Altogether, this provides new insight into the impact of Tat deficiency on in vivo fitness and survival/replication of Y. pseudotuberculosis during infection. IMPORTANCE: In addition to its established role in mediating the secretion of housekeeping enzymes, the Tat system has been recognized as being involved in infection. In some clinically relevant bacteria, such as Pseudomonas spp., several key virulence determinants can readily be identified among the Tat substrates. In enteropathogens, such as Yersinia spp., there are no obvious virulence determinants among the Tat substrates. Tat mutants show no growth defect in vitro but are highly attenuated in in vivo This makes Tat an attractive target for the development of novel antimicrobials. Therefore, it is important to establish the causes of the attenuation. Here, we show that the attenuation is likely due to synergistic effects of different Tat-dependent phenotypes that each contributes to lowered in vivo fitness. PMID- 27501982 TI - A Synonymous Mutation Upstream of the Gene Encoding a Weak-Link Enzyme Causes an Ultrasensitive Response in Growth Rate. AB - When microbes are faced with an environmental challenge or opportunity, preexisting enzymes with promiscuous secondary activities can be recruited to provide newly important functions. Mutations that increase the efficiency of a new activity often compromise the original activity, resulting in an inefficient bifunctional enzyme. We have investigated the mechanisms by which growth of Escherichia coli can be improved when fitness is limited by such an enzyme, E383A ProA (ProA*). ProA* can serve the functions of both ProA (required for synthesis of proline) and ArgC (required for synthesis of arginine), albeit poorly. We identified four genetic changes that improve the growth rate by up to 6.2-fold. Two point mutations in the promoter of the proBA* operon increase expression of the entire operon. Massive amplification of a genomic segment around the proBA* operon also increases expression of the entire operon. Finally, a synonymous point mutation in the coding region of proB creates a new promoter for proA* This synonymous mutation increases the level of ProA* by 2-fold but increases the growth rate by 5-fold, an ultrasensitive response likely arising from competition between two substrates for the active site of the inefficient bifunctional ProA*. IMPORTANCE: The high-impact synonymous mutation we discovered in proB is remarkable for two reasons. First, most polar effects documented in the literature are detrimental. This finding demonstrates that polar effect mutations can have strongly beneficial effects, especially when an organism is facing a difficult environmental challenge for which it is poorly adapted. Furthermore, the consequence of the synonymous mutation in proB is a 2-fold increase in the level of ProA* but a disproportionately large 5.1-fold increase in growth rate. While ultrasensitive responses are often found in signaling networks and genetic circuits, an ultrasensitive response to an adaptive mutation has not been previously reported. PMID- 27501984 TI - AraC-Type Regulator Rbf Controls the Staphylococcus epidermidis Biofilm Phenotype by Negatively Regulating the icaADBC Repressor SarR. AB - : Regulation of icaADBC-encoded polysaccharide intercellular adhesin (PIA)/poly-N acetylglucosasmine (PNAG) production in staphylococci plays an important role in biofilm-associated medical-device-related infections. Here, we report that the AraC-type transcriptional regulator Rbf activates icaADBC operon transcription and PIA production in Staphylococcus epidermidis Purified recombinant Rbf did not bind to the ica operon promoter region in electrophoretic mobility shift assays (EMSAs), indicating that Rbf regulates ica transcription indirectly. To identify the putative transcription factor(s) involved in Rbf-mediated icaADBC regulation, the ability of recombinant Rbf to interact with the promoter sequences of known icaADBC regulators was investigated. Recombinant Rbf bound to the sarR promoter and not the sarX, sarA, sarZ, spx, and srrA promoters. Reverse transcription (RT) PCR demonstrated that Rbf acts as a repressor of sarR transcription. PIA expression and biofilm production were restored to wild-type levels in an rbf sarR double mutant grown in brain heart infusion (BHI) medium supplemented with NaCl, which is known to activate the ica locus, but not in BHI medium alone. RT PCR further demonstrated that although Rbf does not bind the sarX promoter, it nevertheless exerted a negative effect on sarX expression. Apparently, direct downregulation of the SarR repressor by Rbf has a dominant effect over indirect repression of the SarX activator by Rbf in the control of S. epidermidis PIA production and biofilm formation. IMPORTANCE: The importance of Staphylococcus epidermidis as an opportunistic pathogen in hospital patients with implanted medical devices derives largely from its capacity to form biofilm. Expression of the icaADBC-encoded extracellular polysaccharide is the predominant biofilm mechanism in S. epidermidis clinical isolates and is tightly regulated. Here, we report that the transcriptional regulator Rbf promotes icaADBC expression by negatively regulating expression of sarR, which encodes an ica operon repressor. Furthermore, Rbf indirectly represses the ica operon activator, SarX. The data reveal complicated interplay between Rbf and two Sar family proteins in fine tuning regulation of the biofilm phenotype and indicate that in the hierarchy of biofilm regulators, IcaR is dominant over the Rbf-SarR-SarX axis. PMID- 27501983 TI - Lipogenesis and Redox Balance in Nitrogen-Fixing Pea Bacteroids. AB - Within legume root nodules, rhizobia differentiate into bacteroids that oxidize host-derived dicarboxylic acids, which is assumed to occur via the tricarboxylic acid (TCA) cycle to generate NAD(P)H for reduction of N2 Metabolic flux analysis of laboratory-grown Rhizobium leguminosarum showed that the flux from [(13)C]succinate was consistent with respiration of an obligate aerobe growing on a TCA cycle intermediate as the sole carbon source. However, the instability of fragile pea bacteroids prevented their steady-state labeling under N2-fixing conditions. Therefore, comparative metabolomic profiling was used to compare free living R. leguminosarum with pea bacteroids. While the TCA cycle was shown to be essential for maximal rates of N2 fixation, levels of pyruvate (5.5-fold reduced), acetyl coenzyme A (acetyl-CoA; 50-fold reduced), free coenzyme A (33 fold reduced), and citrate (4.5-fold reduced) were much lower in bacteroids. Instead of completely oxidizing acetyl-CoA, pea bacteroids channel it into both lipid and the lipid-like polymer poly-beta-hydroxybutyrate (PHB), the latter via a type III PHB synthase that is active only in bacteroids. Lipogenesis may be a fundamental requirement of the redox poise of electron donation to N2 in all legume nodules. Direct reduction by NAD(P)H of the likely electron donors for nitrogenase, such as ferredoxin, is inconsistent with their redox potentials. Instead, bacteroids must balance the production of NAD(P)H from oxidation of acetyl-CoA in the TCA cycle with its storage in PHB and lipids. IMPORTANCE: Biological nitrogen fixation by symbiotic bacteria (rhizobia) in legume root nodules is an energy-expensive process. Within legume root nodules, rhizobia differentiate into bacteroids that oxidize host-derived dicarboxylic acids, which is assumed to occur via the TCA cycle to generate NAD(P)H for reduction of N2 However, direct reduction of the likely electron donors for nitrogenase, such as ferredoxin, is inconsistent with their redox potentials. Instead, bacteroids must balance oxidation of plant-derived dicarboxylates in the TCA cycle with lipid synthesis. Pea bacteroids channel acetyl-CoA into both lipid and the lipid-like polymer poly-beta-hydroxybutyrate, the latter via a type II PHB synthase. Lipogenesis is likely to be a fundamental requirement of the redox poise of electron donation to N2 in all legume nodules. PMID- 27501985 TI - Evidence that Oxidative Stress Induces spxA2 Transcription in Bacillus anthracis Sterne through a Mechanism Requiring SpxA1 and Positive Autoregulation. AB - : Bacillus anthracis possesses two paralogs of the transcriptional regulator, Spx. SpxA1 and SpxA2 interact with RNA polymerase (RNAP) to activate the transcription of genes implicated in the prevention and alleviation of oxidative protein damage. The spxA2 gene is highly upregulated in infected macrophages, but how this is achieved is unknown. Previous studies have shown that the spxA2 gene was under negative control by the Rrf2 family repressor protein, SaiR, whose activity is sensitive to oxidative stress. These studies also suggested that spxA2 was under positive autoregulation. In the present study, we show by in vivo and in vitro analyses that spxA2 is under direct autoregulation but is also dependent on the SpxA1 paralogous protein. The deletion of either spxA1 or spxA2 reduced the diamide-inducible expression of an spxA2-lacZ construct. In vitro transcription reactions using purified B. anthracis RNAP showed that SpxA1 and SpxA2 protein stimulates transcription from a DNA fragment containing the spxA2 promoter. Ectopically positioned spxA2-lacZ fusion requires both SpxA1 and SpxA2 for expression, but the requirement for SpxA1 is partially overcome when saiR is deleted. Electrophoretic mobility shift assays showed that SpxA1 and SpxA2 enhance the affinity of RNAP for spxA2 promoter DNA and that this activity is sensitive to reductant. We hypothesize that the previously observed upregulation of spxA2 in the oxidative environment of the macrophage is at least partly due to SpxA1-mediated SaiR repressor inactivation and the positive autoregulation of spxA2 transcription. IMPORTANCE: Regulators of transcription initiation are known to govern the expression of genes required for virulence in pathogenic bacterial species. Members of the Spx family of transcription factors function in control of genes required for virulence and viability in low-GC Gram-positive bacteria. In Bacillus anthracis, the spxA2 gene is highly induced in infected macrophages, which suggests an important role in the control of virulence gene expression during the anthrax disease state. We provide evidence that elevated concentrations of oxidized, active SpxA2 result from an autoregulatory positive feedback loop driving spxA2 transcription. PMID- 27501987 TI - Developmental profile of select immune cells in mice infected with Trichinella spiralis during the intestinal phase. AB - Trichinella spiralis can cause immunosuppression during the intestinal phase of early infection. However, changes in the peripheral blood during T. spiralis early infection remain unclear. Here, select immune cells in mice infected with 500 muscle larvae (ML) of T. spiralis during the intestinal phase of infection were studied. First, the recovery rates of the intestinal worms and female fecundity were determined, and the results showed that the intestinal worms were completely eliminated at 17 days post-infection (dpi) and that large numbers of new-born larvae (NBL) were generated from 5 to 9dpi. Using flow cytometry, it was shown that the number of CD4+ T cells and CD8+ T cells increased over the entire intestinal phase, except on 7dpi when CD4+ T cells decreased significantly compared to the control groups. Although both CD4+ and CD8+ T cells increased, CD8+ T cells increased more than CD4+ T cells, leading to a lower CD4+/CD8+ ratio compared to the control group. Subsequently, a depression of the proliferative response of T cells to concanavalin A (Con A) was noticed at 7 and 11dpi. Although the proliferative response of B cells to LPS was enhanced, the number of B cells from mouse peripheral blood stimulated by T. spiralis antigens showed no differences with the control group prior to 11dpi. The expression of CD14 on monocyte-macrophages decreased during the same period, which meant that the antigen-presenting response was reduced in the immune system of the infected mice. Moreover, the alternatively activated macrophages were induced in T. spiralis early infection. These data provide a better understanding of the development of the intestinal immune response in mice infected with T. spiralis. PMID- 27501986 TI - Stochastic anomaly of methylome but persistent SRY hypermethylation in disorder of sex development in canine somatic cell nuclear transfer. AB - Somatic cell nuclear transfer (SCNT) provides an excellent model for studying epigenomic reprogramming during mammalian development. We mapped the whole genome and whole methylome for potential anomalies of mutations or epimutations in SCNT generated dogs with XY chromosomal sex but complete gonadal dysgenesis, which is classified as 78, XY disorder of sex development (DSD). Whole genome sequencing revealed no potential genomic variations that could explain the pathogenesis of DSD. However, extensive but stochastic anomalies of genome-wide DNA methylation were discovered in these SCNT DSD dogs. Persistent abnormal hypermethylation of the SRY gene was observed together with its down-regulated mRNA and protein expression. Failure of SRY expression due to hypermethylation was further correlated with silencing of a serial of testis determining genes, including SOX9, SF1, SOX8, AMH and DMRT1 in an early embryonic development stage at E34 in the XY(DSD) gonad, and high activation of the female specific genes, including FOXL2, RSPO1, CYP19A1, WNT4, ERalpha and ERbeta, after one postnatal year in the ovotestis. Our results demonstrate that incomplete demethylation on the SRY gene is the driving cause of XY(DSD) in these XY DSD dogs, indicating a central role of epigenetic regulation in sex determination. PMID- 27501988 TI - The roles of supernatant of macrophage treated by excretory-secretory products from muscle larvae of Trichinella spiralis on the differentiation of C2C12 myoblasts. AB - The excretory-secretory products (ESPs) released by the muscle-larvae (ML) stage of Trichinella spiralis have been suggested to be involved in nurse cell formation. However, the molecular mechanisms by which ML-ESPs modulate nurse cell formation remain unclear. Macrophages exert either beneficial or deleterious effects on tissue repair, depending on their activation/polarization state. They are crucial for skeletal muscle repair, notably, via their actions on myogenic precursor cells. However, these interactions during T. spiralis infection have not been characterized. In the present study, the ability of conditioned medium (CM) from J774A.1 macrophages treated with ML-ESPs to influence the differentiation of murine myoblasts, and the mechanisms of this influence, were investigated in vitro. The results showed that the expression of Myogenic Regulatory Factors (MRFs) MyoD and myogenin, myosin heavy chain (MyHC), and the p21 cyclin-dependent kinase inhibitor were reduced in CM treated cells compared to their expression in the control group. These findings indicated that CM inhibited myoblast differentiation. Conversely, CM promoted myoblast proliferation and increased cyclin D1 levels. Taken together, results of our study suggested that CM can indirectly influence myoblast differentiation and proliferation, which provides a new method for the elucidation of the complex mechanisms involved in cell-parasite and cell-cell interactions during T. spiralis infection. PMID- 27501989 TI - On the feasibility of the Chevron Notch Beam method to measure fracture toughness of fine-grained zirconia ceramics. AB - OBJECTIVE: The fracture toughness determination of fine-grained zirconia ceramics using the chevron notched beam method (CNB) was investigated to assess the feasibility of this method for quality assurance and material characterization. METHODS: CNB tests were performed using four different yttria-stabilized zirconia ceramics under various testing modes and conditions, including displacement controlled and load-rate-controlled four point bending to assess the influence of slow crack growth and identify most suitable test parameters. For comparison, tests using single-edge V-notch beams (SEVNB) were conducted. RESULTS: It was observed that the CNB method yields well-reproducible results. However, slow crack growth effects significantly affect the measured KIC values, especially when slow loading rates are used. To minimize the effect of slow crack growth, the application of high loading rates is recommended. SIGNIFICANCE: Despite a certain effort needed for setting up a sample preparation routine, the CNB method is considered to be very useful for measuring and controlling the fracture toughness of zirconia ceramics. PMID- 27501990 TI - Hierarchical PEG-Based 3D Patterns Grafting from Polymer Substrate by Surface Initiated Visible Light Photolithography. AB - The precise construction of a hierarchical complex pattern on substrates is required for numerous applications. Here, a strategy to fabricate well-defined hierarchical three dimensional (3D) patterns on polymer substrate is developed. This technique, which combines photolithography and visible light-induced surface initiated living graft crosslinking polymerization (VSLGCP), can effectively graft 3D patterns onto polymer substrate with high fidelity and controllable height. Owing to the living nature of VSLGCP, hierarchical 3D patterns can be prepared when a sequential living graft crosslinking process is performed on the first formed patterns. As a proof-of-concept, a reactive two layer 3D pattern with a morphology of lateral stripe on vertical stripe is prepared and employed to separately immobilize model biomolecules, e.g., biotin and IgG. This two component pattern can specifically interact with corresponding target proteins successfully, indicating that this strategy has potential applications in the fabrication of polymer-based multicomponent biomolecule microarrays. PMID- 27501991 TI - Computer-assisted versus traditional freehand technique in fibular free flap mandibular reconstruction: a morphological comparative study. AB - The purpose of the study was to compare the accuracy of computer-assisted surgery (CAS) and the traditional freehand technique for fibular free flap mandibular reconstruction as well as to evaluate the accuracy of the CAS planning. The medical records of 18 patients who underwent mandibular reconstruction with fibular free flap were reviewed. The CAS group (n = 7) benefited from virtual surgical planning and custom patient-specific plates and surgical cutting guides. The Control group (n = 11) was treated by conventional surgery. Morphometric comparison was done by calculating the differences in specific linear and angular parameters on pre- and postoperative CT-scans for both groups by using ProPlan CMF(r) software. Symmetry was also assessed by calculating the ratio of the affected versus the nonaffected side. In the CAS group, planned and postoperative CT-scans were compared to evaluate accuracy. The morphometric comparison showed no statistically significant differences between the groups except for the axial angle on the nonaffected side (mean difference 1.0 degrees in the CAS group versus 2.9 degrees in the Control group; p = 0.03). Ratios of the affected side over the nonaffected side showed no differences between the two groups. In the CAS group, the accuracy assessment showed a mean distance deviation of 2.3 mm for mandibular osteotomies and 1.9 mm for fibular osteotomies. Our results indicated that CAS and the conventional freehand techniques were comparable in their ability to provide a satisfactory morphological fibular free flap mandibular reconstruction. Moreover, the accuracy of the CAS technique was within the range reported in the literature. PMID- 27501992 TI - Erratum to: Comparison of acyclovir and famciclovir for the treatment of Bell's palsy. PMID- 27501993 TI - Bowl-shaped Troger's bases and their recognition properties. AB - The tris-Troger's bases (TBs) are electron-rich fluorescent concave receptors due to the incorporation of naphthalene or triphenylene moieties (calix-1 and calix 2). The structures of the TBs were studied using SXRD to reveal the propensity to bind nitroaromatics. Titration with explosive-related nitro-compounds suggests that the TBs may be used for sensing explosives. PMID- 27501994 TI - Maximizing the benefits and minimizing the risks of intervention programs to address micronutrient malnutrition: symposium report. AB - Interventions to address micronutrient deficiencies have large potential to reduce the related disease and economic burden. However, the potential risks of excessive micronutrient intakes are often not well determined. During the Global Summit on Food Fortification, 9-11 September 2015, in Arusha, a symposium was organized on micronutrient risk-benefit assessments. Using case studies on folic acid, iodine and vitamin A, the presenters discussed how to maximize the benefits and minimize the risks of intervention programs to address micronutrient malnutrition. Pre-implementation assessment of dietary intake, and/or biomarkers of micronutrient exposure, status and morbidity/mortality is critical in identifying the population segments at risk of inadequate and excessive intake. Dietary intake models allow to predict the effect of micronutrient interventions and their combinations, e.g. fortified food and supplements, on the proportion of the population with intakes below adequate and above safe thresholds. Continuous monitoring of micronutrient intake and biomarkers is critical to identify whether the target population is actually reached, whether subgroups receive excessive amounts, and inform program adjustments. However, the relation between regular high intake and adverse health consequences is neither well understood for many micronutrients, nor do biomarkers exist that can detect them. More accurate and reliable biomarkers predictive of micronutrient exposure, status and function are needed to ensure effective and safe intake ranges for vulnerable population groups such as young children and pregnant women. Modelling tools that integrate information on program coverage, dietary intake distribution and biomarkers will further enable program makers to design effective, efficient and safe programs. PMID- 27501996 TI - Reduced Intramolecular Twisting Improves the Performance of 3D Molecular Acceptors in Non-Fullerene Organic Solar Cells. AB - A small-molecular acceptor, tetraphenylpyrazine-perylenediimide tetramer (TPPz PDI4 ), which has a reduced extent of intramolecular twisting compared to two other small-molecular acceptors is designed. Benefiting from the lowest extent of intramolecular twisting, TPPz-PDI4 exhibits the highest aggregation tendency and electron mobility, and therefore achieves a highest power conversion efficiency of 7.1%. PMID- 27501997 TI - p-Hydroxylcinnamaldehyde induces the differentiation of oesophageal carcinoma cells via the cAMP-RhoA-MAPK signalling pathway. AB - p-Hydroxylcinnamaldehyde (CMSP) has been identified as an inhibitor of the growth of various cancer cells. However, its function in oesophageal squamous cell carcinoma (ESCC) and the underlying mechanism remain unclear. The aim of the present study was to characterize the differentiation effects of CMSP, as well as its mechanism in the differentiation of ESCC Kyse30 and TE-13 cells. The function of CMSP in the viability, colony formation, migration and invasion of Kyse30 and TE-13 cells was determined by MTS, colony-formation, wound healing and transwell assays. Western blotting and pull-down assays were used to investigate the effect of CMSP on the expression level of malignant markers of ESCC, as well as the activity of MAPKs, RhoA and GTP-RhoA in Kyse30 and TE-13 cells. We found that CMSP could inhibit proliferation and migration and induce Kyse30 and TE-13 cell differentiation, characterized by dendrite-like outgrowth, decreased expression of tumour-associated antigens, as well as the decreased expression of malignant markers. Furthermore, increased cAMP, p-P38 and decreased activities of ERK, JNK and GTP-RhoA, were detected after treatment with CMSP. These results indicated that CMSP induced the differentiation of Kyse30 and TE-13 cells through mediating the cAMP-RhoA-MAPK axis, which might provide new potential strategies for ESCC treatment. PMID- 27501998 TI - Treatment of heparin-induced thrombocytopenia before and after the implementation of a hemostatic and antithrombotic stewardship program. AB - In October 2013, we implemented a hemostatic and antithrombotic (HAT) stewardship program with the primary focus of ensuring appropriate use of intravenous direct thrombin inhibitors (DTI) in patients with heparin-induced thrombocytopenia (HIT). We sought to compare the duration and cost of DTI therapy for the management of HIT before and after implementation of the HAT stewardship program. Following institutional review board approval, we conducted a single center, retrospective chart review of all patients with a suspected diagnosis of HIT as assessed by an anti-heparin-PF4 enzyme-linked immunosorbent assay 6 months pre HAT and post-HAT implementation. Patients were excluded if they were initiated on a DTI at an outside hospital, had a prior episode of HIT, or received mechanical circulatory support. Clinical characteristics, including demographics, comorbidities, medications, laboratory values, clinical and safety outcomes, length of stay, and mortality, were collected. A total of 592 patients were included; 333 patients were evaluated pre-HAT, while 259 patients were evaluated post-HAT. The mean duration of DTI treatment was significantly decreased in the post-HAT cohort (6.64 vs 5.17 days, p = 0.01), primarily driven by decreased duration of use for patients with suspected HIT (4.07 vs 2.86 days, p = 0.01). The HAT Stewardship program demonstrated a total decrease in annual costs associated with the diagnosis and management of HIT of $248,500. Our results indicate that the implementation of the HAT stewardship program had a significant impact on reducing the duration and costs of DTI therapy and the costs of laboratory evaluations in the management of HIT at our institution. PMID- 27501999 TI - Additive prognostic value of left ventricular ejection fraction to the TIMI risk score for in-hospital and long-term mortality in patients with ST segment elevation myocardial infarction. AB - To investigate whether the addition of left ventricular ejection fraction (LVEF) to the TIMI risk score enhances the prediction of in-hospital and long-term death in ST segment elevation myocardial infarction (STEMI) patients. 673 patients with STEMI were divided into three groups based on TIMI risk score for STEMI: low-risk group (TIMI <=3, n = 213), moderate-risk group (TIMI 4-6, n = 285), and high-risk group (TIMI >=7, n = 175). The predictive value was evaluated using the receiver operating characteristic. Multivariate logistic regression was used to determine risk predictors. The rates of in-hospital death (0.5 vs 3.2 vs 10.3 %, p < 0.001) and major adverse cardiovascular events (14.6 vs 22.5 vs 40.6 %, p < 0.001) were significantly higher in high-risk group. Multivariate analysis showed that TIMI risk score (OR 1.24, 95 % CI 1.04-1.48, P = 0.015) and LVEF (OR 3.85, 95 % CI 1.58-10.43, P = 0.004) were independent predictors of in-hospital death. LVEF had good predictive value for in-hospital death (AUC: 0.838 vs 0.803, p = 0.571) or 1 year death (AUC: 0.743 vs 0.728, p = 0.775), which was similar to TIMI risk score. When compared with the TIMI risk score alone, the addition of LVEF was associated with significant improvements in predicting in-hospital (AUC: 0.854 vs 0.803, p = 0.033) or 1-year death (AUC: 0.763 vs 0.728, p = 0.016). The addition of LVEF to TIMI risk score enhanced net reclassification improvement (0.864 for in-hospital death, p < 0.001; 0.510 for 1-year death, p < 0.001). LVEF was associated with in-hospital and long-term mortality in STEMI patients and had additive prognostic value to TIMI risk score. PMID- 27502000 TI - A new approach to regression analysis of censored competing-risks data. AB - An approximate likelihood approach is developed for regression analysis of censored competing-risks data. This approach models directly the cumulative incidence function, instead of the cause-specific hazard function, in terms of explanatory covariates under a proportional subdistribution hazards assumption. It uses a self-consistent iterative procedure to maximize an approximate semiparametric likelihood function, leading to an asymptotically normal and efficient estimator of the vector of regression parameters. Simulation studies demonstrate its advantages over previous methods. PMID- 27502001 TI - Natriuretic peptide levels taken following unplanned admission to a cardiology department predict the duration of hospitalization. AB - AIMS: Natriuretic peptide (NP) levels are routinely employed as useful diagnostic and prognostic tools in the evaluation of patients with heart failure (HF). As hospitalization is the major consumer of healthcare resources, the prognostic power of admission NPs with regard to the duration of hospitalization deserves further investigation. METHODS AND RESULTS: We assessed retrospectively the association between NP values sampled shortly following unplanned admission and the duration of hospitalization in 2978 patients admitted to a cardiology department. Duration of hospitalization (hours) and survival were determined by interrogation of the electronic medical records system. Associations with peptide levels were estimated using regression models and receiver operating characteristic (ROC) analysis. The results demonstrate a significant positive relationship between NP levels and the duration of hospitalization, after adjusting for age (P < 0.001). The median duration of hospitalization for the lowest BNP and NT-proBNP quintiles were 80 and 97 h, respectively, vs. 224.5 and 236 h for the highest quintiles. Using cut-off levels of 115 pmol/L for BNP and 390 pmol/L for NT-proBNP, the peptides have a positive predictive value of 78% and 85% for a stay >4 days. During follow-up, NP levels were strongly predictive of all-cause mortality. CONCLUSION: The results quantify the strong relationship between NP levels taken following an unplanned admission to a cardiology department and the duration of hospitalization. This information permits improved identification of a patient population likely to require a prolonged hospital stay and consume more healthcare resources. Such patients may require a more aggressive diagnostic, treatment, and management strategy. PMID- 27502002 TI - [Lung carcinoma screening]. PMID- 27502003 TI - [Prerequisites for a successful lung cancer screening program]. AB - The American national lung cancer screening trial (NLST) has provided the first confirmation of a reduction in lung cancer mortality by using low-dose multislice computed tomography (MSCT). Preliminary evaluations of smaller European trials could not confirm such a reduction. The final evaluation of the larger Dutch Belgian NELSON trial and five other European trials are expected within the next 1-2 years. The results of the completed rounds of screening in all these studies indicate that the margin between a positive and a negative benefit-to-harm balance will be narrow. In such a scenario it will be crucial to optimize the definition of the target population for screening as a high-risk group for lung cancer, the quality of screening in terms of high sensitivity and specificity as well as high quality treatment and an effective ongoing control of program quality. Not all healthcare systems are suitable to fulfill these prerequisites. PMID- 27502005 TI - [(18)F-FDG PET/CT: Image-guided surveillance in advanced head and neck cancer as an alternative to neck dissection]. PMID- 27502004 TI - [Early recognition of lung cancer in workers occupationally exposed to asbestos]. AB - Despite the fact that working with asbestos and placing it on the market have been banned in Germany since 1993 according to the Ordinance on Hazardous Substances, asbestos-related diseases of the lungs and pleura are still the leading cause of death in occupational diseases. The maximum industrial usage of asbestos was reached in former West Germany in the late 1970s and in former East Germany the late 1980s. Occupational diseases, mainly mesotheliomas and lung cancer emerging now are thus caused by asbestos exposure which occurred 30-40 years earlier. It is known that the combination of smoking and asbestos exposure results in a superadditive increase in the risk to develop lung cancer. No suitable screening methods for early detection of malignant mesothelioma are currently available and the therapeutic options are still very limited; however, the national lung screening trial (NLST) has shown for the first time that by employing low-dose computed tomography (LDCT) in heavy smokers, lung cancer mortality can be significantly reduced. According to current knowledge the resulting survival benefits far outweigh the potential risks involved in the diagnostic work-up of suspicious lesions. These results in association with the recommendations of international medical societies and organizations were pivotal as the German statutory accident insurance (DGUV) decided to provide LDCT as a special occupational medical examination for workers previously exposed to asbestos and with a particularly high risk for developing lung cancer. PMID- 27502006 TI - Modeling the mechanics of axonal fiber tracts using the embedded finite element method. AB - A subject-specific human head finite element model with embedded axonal fiber tractography obtained from diffusion tensor imaging was developed. The axonal fiber tractography finite element model was coupled with the volumetric elements in the head model using the embedded element method. This technique enables the calculation of axonal strains and real-time tracking of the mechanical response of the axonal fiber tracts. The coupled model was then verified using pressure and relative displacement-based (between skull and brain) experimental studies and was employed to analyze a head impact, demonstrating the applicability of this method in studying axonal injury. Following this, a comparison study of different injury criteria was performed. This model was used to determine the influence of impact direction on the extent of the axonal injury. The results suggested that the lateral impact loading is more dangerous compared to loading in the sagittal plane, a finding in agreement with previous studies. Through this analysis, we demonstrated the viability of the embedded element method as an alternative numerical approach for studying axonal injury in patient-specific human head models. PMID- 27502008 TI - Scientific Abstracts of the 13th Congress of the European Academy of Paediatric Dentistry (EAPD). PMID- 27502007 TI - Down-regulation of Irf8 by Lyz2-cre/loxP accelerates osteoclast differentiation in vitro. AB - Interferon regulatory factor 8 (Irf8) is a transcription factor that negatively regulates osteoclast differentiation and Irf8 global knockout (Irf8 -/-) mice have been shown to have reduced bone volume resulting from increased osteoclast numbers. However, detailed analysis of the functions of Irf8 in osteoclast precursors with a monocyte/macrophage linage is difficult, because the population and properties of hematopoietic cells in Irf8 -/- mice are severely altered. Therefore, to clearly elucidate the functions of Irf8 during osteoclastogenesis, we established myeloid cell-specific Irf8 conditional knockout (Irf8 fl/fl ;Lyz2 cre/+) mice. We found that trabecular bone volume in the Irf8 fl/fl ;Lyz2 cre/+ mice was not significantly affected, while exposure to M-CSF and RANKL significantly increased TRAP activity in vitro in osteoclasts that underwent osteoclastogenesis from bone marrow-derived macrophages (BMMs) induced from bone marrow cells (BMCs) of those mice by addition of M-CSF. Our results also showed that expression of Irf8 mRNA and protein in BMMs obtained from Irf8 fl/fl ;Lyz2 cre/+ mice and cultured with M-CSF was reduced. These findings predicted that Lyz2/Lyz2-cre expression is induced when BMCs differentiate into BMMs in cultures with M-CSF. In osteoclast differentiation cultures, Lyz2 was gradually increased by M-CSF during the first 3 days of culture, then rapidly decreased by the addition of RANKL with M-CSF during the next 3 days. Furthermore, BMCs differentiated into osteoclasts while maintaining a low level of Lyz2 expression when cultured simultaneously with both M-CSF and RANKL from the initiation of culture. These findings suggest that Lyz2-cre expression is induced along with differentiation to BMMs by BMCs obtained from Irf8 fl/fl ;Lyz2 cre/+ mice and cultured with M-CSF. In addition, Irf8 was down-regulated by activation of the cre/loxP recombination system in BMMs and osteoclastogenesis was accelerated. Based on our results, we propose the existence in vivo of a new lineage of osteoclast precursors among BMCs, which differentiate into osteoclasts without up regulation of Lyz2 expression. PMID- 27502009 TI - Hemorrhage is the most common cause of neonatal mortality in patients with sacrococcygeal teratoma. AB - BACKGROUND: A small percentage of neonates with sacrococcygeal teratoma die shortly after birth from hemorrhagic complications. The incidence of and risk factors associated with hemorrhagic mortality are unknown. In this multicenter study we determined the incidence of early death in neonates born with SCT and evaluated potential risk factors for hemorrhagic mortality. METHODS: 235 children with SCT treated from 1970 to 2010 in the Netherlands were retrospectively included. The following candidate risk factors for hemorrhagic mortality were examined: sex, prematurity, Altman type, tumor volume, tumor histology, necessity of emergency operation and time of diagnosis. RESULTS: Eighteen patients (7.7%) died at a median age of 163.5days (range 1.7-973days). Nine patients died of a malignancy. Nine others (3.8%) died postnatally (age 1-27days), six even within two days after birth. In seven of these nine patients death was related to tumor hemorrhage and/or circulatory failure. Risk factors for hemorrhagic mortality were prematurity, tumor volume>1000cm3 and performance of an emergency operation. CONCLUSIONS: Hemorrhagic mortality of neonates with SCT is relatively high (3.8%) representing almost 70% of the overall mortality in the neonatal period. High output cardiac failure, internal tumor hemorrhage and perioperative bleeding were the most common causes of early death and were all strongly associated with larger tumor sizes. LEVEL-OF-EVIDENCE RATING: II (Retrospective study). PMID- 27502010 TI - Multiple orifices and cholangiography with a "fire-like" appearance after Kasai hepatoportoenterostomy for biliary atresia. AB - A 21-year-old female underwent a Kasai hepatoportoenterostomy with Roux-en-Y reconstruction for typeIII biliary atresia at age 63 days. At the age of 19 years, she developed cholangitis and CT scan revealed hepatolithiasis. She presented for treatment of the intrahepatic stone and the hepatportoenterostomy was directly visualized with double-balloon endoscopy (DBE). Endoscopic findings showed multiple intrahepatic bile ducts open to the jejunum through multiple orifices. Cholangiography showed narrowing of intrahepatic bile duct branches with a "fire-like" appearance. These findings have not been previously reported, since endoscopic approaches to patients with a hepaticojejunostomy were limited. DBE was useful to directly visualize the anastomosis in a patient status-post the Kasai operation for biliary atresia with a Rouxen-Y reconstruction. PMID- 27502011 TI - Pharmacokinetic model of florfenicol in turbot (Scophthalmus maximus): establishment of optimal dosage and administration in medicated feed. AB - The pharmacokinetics of florfenicol (FF) in turbot (Scophthalmus maximus) was studied after single intravenous (10 mg kg-1 ) and oral (100 mg kg-1 ) administration. The plasma concentration-time data of florfenicol were described by an open one-compartment model. The elimination half-life (t1/2 ) was estimated to be 21.0 h, and the total body clearance, Cl, was determined as 0.028 L kg h-1 . The apparent volume distribution (Vd ) was calculated to be 0.86 L kg-1 and the mean residence time (MRTiv ) was 30.2 h. Following oral administration, the maximum plasma concentration (Cmax ) of 55.4 MUg mL-1 was reached at 12 h (Tmax ). The absorption constant (ka ) was 0.158 h-1 . The bioavailability was estimated to be 57.1%. The low bioavailability observed at higher doses was explained by the saturation of the mechanisms of absorption. The drug absorption process was limited by its inherent low solubility, which limited the amount of available FF absorbed in the gastrointestinal tract. Based on the pharmacokinetic data, an optimal dosing schedule for FF administration is hereby provided. Based on the minimum inhibitory concentration found for susceptible strains of Aeromonas salmonicida, oral FF administration of first, an initial dose of 30 mg FF kg-1 , followed by 6 maintenance doses at 18 mg kg-1 /daily could be effective against furunculosis in turbot. PMID- 27502012 TI - Adaptation and memory in innate immunity. PMID- 27502013 TI - Promotion of formyl peptide receptor 1-mediated neutrophil chemotactic migration by antimicrobial peptides isolated from the centipede Scolopendra subspinipes mutilans. AB - We investigated the effects of two antimicrobial peptides (AMPs) isolated from Scolopendra subspinipes mutilans on neutrophil activity. Stimulation of mouse neutrophils with the two AMPs elicited chemotactic migration of the cells in a pertussis toxin-sensitive manner. The two AMPs also stimulated activation of ERK and Akt, which contribute to chemotactic migration of neutrophils. We found that AMP-stimulated neutrophil chemotaxis was blocked by a formyl peptide receptor (FPR) 1 antagonist (cyclosporin H); moreover the two AMPs stimulated the chemotactic migration of FPR1-expressing RBL-2H3 cells but not of vector expressing RBL-2H3 cells. We also found that the two AMPs stimulate neutrophil migration in vivo, and that this effect is blocked in FPR1-deficient mice. Taken together, our results suggest that the two AMPs stimulate neutrophils, leading to chemotactic migration through FPR1, and the two AMPs will be useful for the study of FPR1 signaling and neutrophil activation. [BMB Reports 2016; 49(9): 520-525]. PMID- 27502014 TI - The cellular basis of dendrite pathology in neurodegenerative diseases. AB - One of the characteristics of the neurons that distinguishes them from other cells is their complex and polarized structure consisting of dendrites, cell body, and axon. The complexity and diversity of dendrites are particularly well recognized, and accumulating evidences suggest that the alterations in the dendrite structure are associated with many neurodegenerative diseases. Given the importance of the proper dendritic structures for neuronal functions, the dendrite pathology appears to have crucial contribution to the pathogenesis of neurodegenerative diseases. Nonetheless, the cellular and molecular basis of dendritic changes in the neurodegenerative diseases remains largely elusive. Previous studies in normal condition have revealed that several cellular components, such as local cytoskeletal structures and organelles located locally in dendrites, play crucial roles in dendrite growth. By reviewing what has been unveiled to date regarding dendrite growth in terms of these local cellular components, we aim to provide an insight to categorize the potential cellular basis that can be applied to the dendrite pathology manifested in many neurodegenerative diseases. [BMB Reports 2017; 50(1): 5-11]. PMID- 27502015 TI - Databases and tools for constructing signal transduction networks in cancer. AB - Traditionally, biologists have devoted their careers to studying individual biological entities of their own interest, partly due to lack of available data regarding that entity. Large, highthroughput data, too complex for conventional processing methods (i.e., "big data"), has accumulated in cancer biology, which is freely available in public data repositories. Such challenges urge biologists to inspect their biological entities of interest using novel approaches, firstly including repository data retrieval. Essentially, these revolutionary changes demand new interpretations of huge datasets at a systems-level, by so called "systems biology". One of the representative applications of systems biology is to generate a biological network from high-throughput big data, providing a global map of molecular events associated with specific phenotype changes. In this review, we introduce the repositories of cancer big data and cutting-edge systems biology tools for network generation, and improved identification of therapeutic targets. [BMB Reports 2017; 50(1): 12-19]. PMID- 27502016 TI - Meis: New friends of Pax. AB - The generation of neuronal diversity in the mammalian brain is a multistep process, beginning with the regional patterning of neural stem- and progenitor cell domains, the commitment of these cells toward a general neuronal fate, followed by the selection of a particular neuronal subtype and the differentiation of postmitotic neurons. Each of these steps as well as the transitions between them require precisely controlled changes in transcriptional programs. Although a large number of transcription factors are known to regulate neurogenesis in the embryonic and adult central nervous system, the sheer number of neuronal cell types in the brain and the complexity of the cellular processes that accompany their production suggest that transcription factors act cooperatively to control individual steps in neurogenesis. In fact, combinatorial regulation by sets of transcription factors has emerged as a versatile mode to control cell fate specification. Here, I discuss our recent finding that members of the MEIS-subfamily of TALE-transcription factors, originally identified as HOX cofactors in non-neural tissues, function in concert with PAX-proteins in the regulation of cell fate specification and neuronal differentiation in the embryonic and adult brain. PMID- 27502017 TI - Force sensitivity of multilayer graphene optomechanical devices. AB - Mechanical resonators based on low-dimensional materials are promising for force and mass sensing experiments. The force sensitivity in these ultra-light resonators is often limited by the imprecision in the measurement of the vibrations, the fluctuations of the mechanical resonant frequency and the heating induced by the measurement. Here, we strongly couple multilayer graphene resonators to superconducting cavities in order to achieve a displacement sensitivity of 1.3 fm Hz(-1/2). This coupling also allows us to damp the resonator to an average phonon occupation of 7.2. Our best force sensitivity, 390 zN Hz(-1/2) with a bandwidth of 200 Hz, is achieved by balancing measurement imprecision, optomechanical damping, and measurement-induced heating. Our results hold promise for studying the quantum capacitance of graphene, its magnetization, and the electron and nuclear spins of molecules adsorbed on its surface. PMID- 27502018 TI - Ginsenoside Rg3, a Gating Modifier of EAG Family K+ Channels. AB - Ginsenoside 20(S)-Rg3 (Rg3) is a steroid glycoside that induces human ether-a-go go-related gene type 1 (hERG1, Kv11.1) channels to activate at more negative potentials and to deactivate more slowly than normal. However, it is unknown whether this action is unique to hERG1 channels. Here we compare and contrast the mechanisms of actions of Rg3 on hERG1 with three other members of the ether-a-go go (EAG) K(+) channel gene family, including EAG1 (Kv10.1), ERG3 (Kv11.3), and ELK1 (Kv12.1). All four channel types were heterologously expressed in Xenopus laevis oocytes, and K(+) currents were measured using the two-microelectrode voltage-clamp technique. At a maximally effective concentration, Rg3 shifted the half-point of voltage-dependent activation of currents by -14 mV for ERG1 (EC50 = 414 nM), -20 mV for ERG3 (EC50 = 374 nM), -28 mV for EAG1 (EC50 = 1.18 MUM), and more than -100 mV for ELK1 (EC50 = 197 nM) channels. Rg3 also induced slowing of ERG1, ERG3, and ELK1 channel deactivation and accelerated the rate of EAG1 channel activation. A Markov model was developed to simulate gating and the effects of Rg3 on the voltage dependence of activation of hELK1 channels. Understanding the mechanism underlying the action of Rg3 may facilitate the development of more potent and selective EAG family channel activators as therapies for cardiovascular and neural disorders. PMID- 27502019 TI - Electrolyte Cations Binding with Extracellular Polymeric Substances Enhanced Microcystis Aggregation: Implication for Microcystis Bloom Formation in Eutrophic Freshwater Lakes. AB - The hydrodynamic and structural properties of Microcystis extracellular polymeric substances (EPS) in electrolytes with different valences and ionic strengths were investigated via using dynamic light scattering, the fluorescence excitation emission matrix coupled with parallel factor (EEM-PARAFAC) analysis, two dimensional correlation spectroscopy (2D-COS), and cryogenic transmission electron microscopy (Cryo-TEM). The hydrodynamic diameters of EPS colloids exhibited no variation for monovalent NaCl but a substantial increase for divalent CaCl2 and MgCl2. However, the negative electrophoretic mobilities for all complexes indicated that charge neutralization would not be the main mechanism for EPS aggregation. Application of EEM-PARAFAC and 2D-Fourier transform infrared (FTIR)-COS revealed obvious electrolyte binding potential with both fluorescent phenolic and aromatic compounds and nonfluorescent polysaccharides. The complexation model showed that divalent Ca(2+) and Mg(2+) exhibited a strong binding capability with phenolic -OH, aromatic C?C, and polysaccharide C-O groups, while the monovalent electrolyte exhibited negligible association with these groups. Such a strong complexation can bridge each individual biomolecule together to form EPS aggregates and Microcystis colonies, as supported by in situ Cryo-TEM and light microscope observation, respectively. Given the increased concentration in natural ecosystems, electrolyte cations, especially divalent cations, would play increased roles in Microcystis bloom formation and thus should be considered. PMID- 27502020 TI - Alveolar bone grafting with simultaneous cleft lip rhinoplasty. AB - BACKGROUND: Optimal timing for cleft lip rhinoplasty is controversial. Definitive rhinoplasty is deferred until facial skeletal growth is completed. Intermediate rhinoplasty is performed after stabilization of the grafted alveolar bone, because the grafted bone tends to be absorbed over several months postoperatively, distorting the nasal profile. Here, we report our experience with simultaneous rhinoplasty during alveolar bone grafting for indicated patients, describe our surgical technique that ensures long-term bone graft survival, and report graft take rates and nasal profile changes. METHODS: This retrospective chart review included a total of 54 patients; 44 underwent alveolar bone grafting only, and 10 underwent simultaneous cleft lip rhinoplasty. All surgeries were conducted with a judicious mucosal incision for tensionless wound closure. Bone graft take was evaluated with dental radiographs by the Bergland classification. Further, nasal aesthetic outcome was evaluated with medical photographs, based on nostril height and width and alar base width. RESULTS: In total, 96.3% of clefts showed graft success with Type I (66.7%) or Type II (27.8%) classifications; only 3.7% of clefts showed unfavorable results classified as Type III, and no clefts showed Type IV failure. The nasal shape was flatter with a decreased nostril height and increased nostril width after alveolar bone grafting, while nostril height was increased and nostril width was decreased in patients who underwent simultaneous rhinoplasty. CONCLUSION: With surgical techniques ensuring alveolar bone graft survival, simultaneous cleft lip rhinoplasty can result in nasal aesthetic improvement for patients with severe nasal deformities, decreasing the number of operations. PMID- 27502021 TI - Abstracts from National Young Researchers' Forum on Materials Science and Technology, XIII AIMAT National Congress, National Biomaterial Congress - SIB, July 2016, Ischia, Italy. PMID- 27502022 TI - SCCmec-associated psm-mec mRNA promotes Staphylococcus epidermidis biofilm formation. AB - Biofilm formation is considered the major pathogenic mechanism of Staphylococcus epidermidis-associated nosocomial infections. Reports have shown that SCCmec associated psm-mec regulated methicillin-resistant Staphylococcus aureus virulence and biofilm formation. However, the role of psm-mec in S. epidermidis remains unclear. To this purpose, we analysed 165 clinical isolates of S. epidermidis to study the distribution, mutation and expression of psm-mec and the relationship between this gene and biofilm formation. Next, we constructed three psm-mec deletion mutants, one psm-mec transgene expression strain (p221) and two psm-mec point mutant strains (pM, pAG) to explore its effects on S. epidermidis biofilm formation. Then, the amount of biofilm formation, extracellular DNA (eDNA) and Triton X-100-induced autolysis of the constructed strains was measured. Results of psm-mec deletion and transgene expression showed that the gene regulated S. epidermidis biofilm formation. Compared with the control strains, the ability to form biofilm, Triton X-100-induced autolysis and the amount of eDNA increased in the p221 strain and the two psm-mec mutants pM and pAG expressed psm-mec mRNA without its protein, whereas no differences were observed among the three constructed strains, illustrating that psm-mec mRNA promoted S. epidermidis biofilm formation through up-regulation of bacterial autolysis and the release of eDNA. Our results reveal that acquisition of psm-mec promotes S. epidermidis biofilm formation. PMID- 27502023 TI - Citricoccus lacusdiani sp. nov., an actinobacterium promoting Microcystis growth with limited soluble phosphorus. AB - A novel actinobacterium, designated strain JXJ CY 21T, was isolated from the culture mass of Microcystis sp. FACHB-905 collected from Lake Dianchi, South-west China. Polyphasic taxonomic study revealed that the isolate should be a member of the genus Citricoccus. Comparison of the 16S rRNA gene sequence of strain JXJ CY 21T with the available sequences in the GenBank database showed that the strain is closely related to Citricoccus zhacaiensis FS24T (97.8 % similarity), Citricoccus parietis 02-Je-010T (97.7 %), Citricoccus terreus V3M1T (97.6 %), Citricoccus nitrophenolicus PNP1T (97.2 %), Citricoccus alkalitolerans YIM 70010T (97.2 %) and Citricoccus muralis 4-0T (97.0 %). The DNA-DNA hybridization values between strain JXJ CY 21T and the related type strains C. zhacaiensis FS24T and C. parietis 02-Je-010T were 16.0 +/- 2.6 and 5.4 +/- 1.7 %, respectively. The peptidoglycan in the cell wall was A4alpha type containing lysine-glutamic acid glycine. The major respiratory menaquinone was found to be MK-8 (H2) (98.5 %), while the major cellular fatty acids (>10 %) were anteiso-C15:0, iso-C16:0, iso C15:0 and iso-C14:0. The polar lipids detected were diphosphatidylglycerol, phosphatidylinositol, phosphatidylglycerol, an unidentified phospholipid and an unidentified glycolipid. The DNA G + C content was determined to be 62.7 mol%. Strain JXJ CY 21T can solubilize both insoluble inorganic and organic phosphates up to 24.7 and 1.7 mg/l respectively. This property of the novel actinobacterium acts as a modulator for enhancement of growth of Microcystis sp. FACHB-905 in the lake ecosystem where the amount of soluble phosphate is limited. On the basis of the above taxonomic data, strain JXJ CY 21T represents a novel species of the genus Citricoccus, for which the name Citricoccus lacusdiani sp. nov. is proposed. The type strain is JXJ CY 21T (=KCTC 29653T = DSM 29160T). PMID- 27502024 TI - Occlusive bandaging of wounds with decreased circulation promotes growth of anaerobic bacteria and necrosis: case report. AB - BACKGROUND: Topical occlusive/semi-occlusive dressings that induce a damp and trapped environment are widely used in wound treatment. Subjecting the wound with impaired circulation to such trapped/air-free environment potentiates the growth of anaerobic bacteria and risk for serious infection. CASE PRESENTATION: We present a case of previously healthy Swedish male that had a muscle contusion after heavy trauma that induced impaired circulation. The application of an occlusive bandage to the post-traumatic wound on the patient resulted in a poly microbial anaerobic infection and necrosis. These complications were treated successfully with antibiotics and open dressing of the wound. CONCLUSION: The pathophysiology of difficult- to- treat ulcers should be reviewed by the physician and occlusive dressing should be avoided when treating wounds with impaired circulation. PMID- 27502026 TI - Modeling size controlled nanoparticle precipitation with the co-solvency method by spinodal decomposition. AB - The co-solvency method is a method for the size controlled preparation of nanoparticles like polymersomes, where a poor co-solvent is mixed into a homogeneous copolymer solution to trigger precipitation of the polymer. The size of the resulting particles is determined by the rate of co-solvent addition. We use the Cahn-Hilliard equation with a Flory-Huggins free energy model to describe the precipitation of a polymer under changing solvent quality by applying a time dependent Flory-Huggins interaction parameter. The analysis focuses on the characteristic size R of polymer aggregates that form during the initial spinodal decomposition stage, and especially on how R depends on the rate s of solvent quality change. Both numerical results and a perturbation analysis predict a power law dependence R~s(-1/6), which is in agreement with power laws for the final particle sizes that have been reported from experiments and molecular dynamics simulations. Hence, our model results suggest that the nanoparticle size in size-controlled precipitation is essentially determined during the spinodal decomposition stage. PMID- 27502025 TI - TALEN-based generation of a cynomolgus monkey disease model for human microcephaly. AB - Gene editing in non-human primates may lead to valuable models for exploring the etiologies and therapeutic strategies of genetically based neurological disorders in humans. However, a monkey model of neurological disorders that closely mimics pathological and behavioral deficits in humans has not yet been successfully generated. Microcephalin 1 (MCPH1) is implicated in the evolution of the human brain, and MCPH1 mutation causes microcephaly accompanied by mental retardation. Here we generated a cynomolgus monkey (Macaca fascicularis) carrying biallelic MCPH1 mutations using transcription activator-like effector nucleases. The monkey recapitulated most of the important clinical features observed in patients, including marked reductions in head circumference, premature chromosome condensation (PCC), hypoplasia of the corpus callosum and upper limb spasticity. Moreover, overexpression of MCPH1 in mutated dermal fibroblasts rescued the PCC syndrome. This monkey model may help us elucidate the role of MCPH1 in the pathogenesis of human microcephaly and better understand the function of this protein in the evolution of primate brain size. PMID- 27502027 TI - Discriminative stimulus properties of 1.25mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors. AB - The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug discrimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT2A inverse agonist M100907 and the two preferential D4/5-HT2/alpha1 receptor antagonists Lu 37-114 ((S)-1-(3-(2-(4-(1H indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4 (1H-indol-5-yl)piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one). Partial substitution occurred with the D4 receptor antagonist Lu 38-012 and the alpha1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT2C, 5-HT6 muscarinic, histamine H1, and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT2A inverse agonism and D4 receptor antagonism mediate the discriminative stimulus properties of 1.25mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus. PMID- 27502028 TI - Grey matter density decreases as well as increases in patients with classic galactosemia: A voxel-based morphometry study. AB - Brain impairments have been observed in patients with classic galactosemia, an inherited metabolic disorder resulting in a particular neuro-cognitive profile. Neuroimaging studies showed abnormalities such as diffuse white mater (WM) abnormalities and grey matter (GM) atrophy. Our current study analysed grey matter density using voxel-based morphometry (VBM) and compared the brains of eight adolescent patients with classic galactosemia with eight healthy gender- and aged-matched controls. GM density differences were found in several regions. Decreased GM density was found in the patients in the bilateral putamen and bilateral occipital cortex. Increased GM density in the patients, on the other hand, was found in the bilateral inferior frontal and medial prefrontal cortex. The anatomical profile of the abnormalities is in line with the neuro-cognitive profile of patients with classic galactosemia, including motor dysfunction, speech and language difficulties and higher order cognitive problems. Less favourable GM densities in patients (either increased or decreased compared to controls) correlated with younger age, a worse visual working memory performance, and an older age at initiation of the galactose-restricted diet. To conclude, this explorative study is the first to analyse the GM using VBM in this population, and demonstrates a mixed profile of both increased and decreased GM density in these patients. PMID- 27502029 TI - Behavioral evidence for the interaction between cannabinoids and Catha edulis F. (Khat) in mice. AB - Several studies have shown the existence of an interaction between the endocannabinoid system and some drugs of abuse, such as opioids, nicotine, alcohol, and cocaine. For instance, the endocannabinoid system has long been known to play a role in the underlying mechanisms of drug reward and dependence. The aim of this study was to evaluate the possible existence of an interaction between the endocannabinoid system and khat after acute administration. Behavioral interactions of khat extract with cannabinoids were assessed. To this effect, mice were randomly divided into different groups (vehicle, khat extract, khat and WIN55,212-2, a cannabinoid agonist, khat extract and cannabinoid antagonists, AM251 & AM630) and their behavioral responses were evaluated in activity monitor, elevated plus maze and Y-maze tests. These tests were used to determine changes in locomotor activity, anxiety-like behavior, and working memory. Khat and WIN55,212-2 demonstrated differential responses in these tests, but co-administration of these agents invariably increased the measured parameters, which were reversed by the cannabinoid receptor antagonists used. The data collectively indicate that there is an interaction between khat and the endocannabinoid system, which most likely involves the cannabinoid receptors or a common mechanism separately activated by the two agents. PMID- 27502030 TI - Change in atmospheric deposition during last half century and its impact on lichen community structure in Eastern Himalaya. AB - Climatic fluctuations largely affects species turnover and cause major shifts of terrestrial ecosystem. In the present study the five decade old herbarium specimens of lichens were compared with recent collection from Darjeeling district with respect to elements, PAHs accumulation and carbon isotope composition (delta(13)C) to explore the changes in climatic conditions and its impact on lichen flora. The delta(13)C has increased in recent specimens which is in contrast to the assumption that anthropogenic emission leads to delta(13)C depletion in air and increased carbon discrimination in flora. Study clearly demonstrated an increase in anthropogenic pollution and drastic decrease in precipitation while temperature showed abrupt changes during the past five decades resulting in significant change in lichen community structure. The Usneoid and Pertusorioid communities increased, while Physcioid and Cyanophycean decreased, drastically. Lobarian abolished from the study area, however, Calcicoid has been introduced in the recent past. Probably, post-industrial revolution, the abrupt changes in the environment has influenced CO2 diffusion and/C fixation of (lower) plants either as an adaptation strategy or due to toxicity of pollutants. Thus, the short term studies (<=5 decades) might reflect recent micro-environmental condition and lichen community structure can be used as model to study the global climate change. PMID- 27502031 TI - Heart failure following cancer treatment: characteristics, survival and mortality of a linked health data analysis. AB - BACKGROUND: Cardiotoxicity resulting in heart failure is a devastating complication of cancer therapy. A patient may survive cancer only to develop heart failure (HF), which has a higher mortality rate than some cancers. AIM: This study aimed to describe the characteristics and outcomes of HF in patients with blood or breast cancer after chemotherapy treatment. METHODS: Queensland Cancer Registry, Death Registry and Hospital Administration records were linked (1996-2009). Patients were categorised as those with an index HF admission (that occurred after cancer diagnosis) and those without an index HF admission (non HF). RESULTS: A total of 15 987 patients was included, and 1062 (6.6%) had an index HF admission. Median age of HF patients was 67 years (interquartile range 58-75) versus 54 years (interquartile range 44-64) for non-HF patients. More men than women developed HF (48.6% vs 29.5%), and a greater proportion in the HF group had haematological cancer (83.1%) compared with breast cancer (16.9%). After covariate adjustment, HF patients had increased mortality risk compared with non-HF patients (hazard ratios 1.67 (95% confidence interval, 1.54-1.81)), and 47% of the index HF admission occurred within 1 year from cancer diagnosis and 70% within 3 years. CONCLUSION: Cancer treatment may place patients at a greater risk of developing HF. The onset of HF occurred soon after chemotherapy, and those who developed HF had a greater mortality risk. PMID- 27502032 TI - Cardiovascular and Skeletal-related Events Following Localized Prostate Cancer Treatment: Role of Surgery, Radiotherapy, and Androgen Deprivation. AB - OBJECTIVE: To examine the impact of androgen deprivation therapy (ADT) and primary treatment modality on cardiovascular and skeletal-related events and to investigate potential effect modification in a contemporary cohort of patients treated for clinically localized prostate cancer. SUBJECTS AND METHODS: We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results-Medicare linked databases for men aged 65-79 years who underwent radical prostatectomy or radiotherapy for cT1 or cT2 prostate cancer from 2000 to 2008. We categorized treatment according to primary therapy and receipt of ADT. We described the cumulative incidence of cardiovascular and skeletal-related events. RESULTS: Among 60,156 men, 14,403 underwent surgery and 45,753 underwent radiotherapy. Median follow-up was 6.0 years. After adjusting for baseline differences, treatments with radiotherapy (adjusted hazard ratios [aHR] 1.16 1.28, P <.0001-.04) and ADT (aHR 1.18-1.32, P <.0001-.008) were each independently associated with increased risk of coronary heart disease, sudden cardiac death, fracture, and fracture requiring hospitalization. Radiotherapy was associated with an increased risk of myocardial infarction (aHR 1.20, P = .02), whereas ADT was not (P = .5). We did not identify a significant statistical interaction between primary and hormonal treatment. CONCLUSION: Care for cardiovascular and skeletal-related events is an important part of the survivorship phase for a significant proportion of patients with localized prostate cancer. Increasing use of ADT for patients with localized disease undergoing radiotherapy and the observed higher prevalence of these events in these patients should be considered when discussing the risks and benefits of treatment for localized prostate cancer and when formulating a survivorship plan. PMID- 27502034 TI - Tunable High-Field Magnetization in Strongly Exchange-Coupled Freestanding Co/CoO Core/Shell Coaxial Nanowires. AB - The exchange bias properties of Co/CoO coaxial core/shell nanowires were investigated with cooling and applied fields perpendicular to the wire axis. This configuration leads to unexpected exchange-bias effects. First, the magnetization value at high fields is found to depend on the field-cooling conditions. This effect arises from the competition between the magnetic anisotropy and the Zeeman energies for cooling fields perpendicular to the wire axis. This allows imprinting predefined magnetization states to the antiferromagnetic (AFM) shell, as corroborated by micromagnetic simulations. Second, the system exhibits a high field magnetic irreversibility, leading to open hysteresis loops attributed to the AFM easy axis reorientation during the reversal (effect similar to athermal training). A distinct way to manipulate the high-field magnetization in exchange biased systems, beyond the archetypical effects, was thus experimentally and theoretically demonstrated. PMID- 27502033 TI - An Important Mimic of Inguinal Hernia. AB - Spermatic cord malignancy is a rare and challenging diagnosis, often misdiagnosed as an inguinal hernia or cord lipoma. In these images, we show a 61-year-old male for whom laparoscopic repair of clinically diagnosed hernia was attempted. Laparoscopy revealed closed internal ring without hernia. Imaging showed large paratesticular mass; radical inguinal excision of testicle, cord, and mass was performed. Pathology showed mixed low-grade and high-grade sarcoma. Liposarcoma should be considered in cases of unusual inguinal mass; appropriate imaging can guide surgical approach and optimize outcomes. PMID- 27502035 TI - beta-arrestins regulate gonadotropin receptor-mediated cell proliferation and apoptosis by controlling different FSHR or LHCGR intracellular signaling in the hGL5 cell line. AB - Gonadotropin signaling classically involves proliferative, steroidogenic and apoptotic stimuli. In this study, we used the human granulosa cell line hGL5 to demonstrate how follicle-stimulating hormone (FSH) and luteinizing hormone (LH) differently control proliferative or apoptotic signals, revealing novel intrinsic properties of their receptors (FSHR, LHCGR). We found that, in this tumor-like cell line, the expression of endogenous FSHR and LHCGR is serum-dependent, but both receptors were unable to activate the canonical cAMP/PKA pathway upon gonadotropin stimulation, failing to produce cAMP, progesterone and G protein coupled receptor (GPCR)-mediated apoptosis in vitro. Conversely, ligand treatment resulted in FSHR- and LHCGR-mediated ERK1/2 phosphorylation and cell proliferation due to receptor coupling to beta-arrestins. The inactive cAMP/PKA pathway was unlocked by siRNA-mediated knock-down of beta-arrestin 1 and 2, leading to progesterone synthesis and apoptosis. Surprisingly, FSH, but not LH treatment accelerated the cAMP/PKA-mediated apoptosis after beta-arrestin silencing, an effect which could be reproduced by overexpressing the FSHR, but not the LHCGR. This work demonstrates that the expression of FSHR and LHCGR can be induced in hGL5 cells but that the FSHR-dependent cAMP/PKA pathway is constitutively silenced, possibly to protect cells from FSHR-cAMP-PKA-induced apoptosis. Also, we revealed previously unrecognized features intrinsic to the two structurally similar gonadotropin receptors, oppositely resulting in the regulation of life and death signals in vitro. PMID- 27502036 TI - LH and FSH promote migration and invasion properties of a breast cancer cell line through regulatory actions on the actin cytoskeleton. AB - Reproductive hormones influence breast cancer development and progression. While the actions of sex steroids in this setting are established, tentative evidence suggests that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) may also play a role, yet this remains elusive. We here identify that T-47D breast cancer cells express functional receptors for FSH and LH, and that these hormones regulate breast cancer cell motility and invasion through the control of the actin cytoskeleton and the formation of cortical actin aggregates and focal adhesion complexes. Such actions are mediated by the cytoskeletal controllers Moesin and focal adhesion kinase (FAK). Moesin is recruited rapidly by FSH and LH through a signaling cascade requiring the G protein Galpha13 and the Rho associated kinase, ROCK-2. FSH and LH activate FAK via a Galphai/beta and c-Src dependent signaling cascade. Both cascades involve signaling to phosphatidylinositol-3 kinase and Akt. FSH and LH receptors and the related signaling intermediates are necessary for the actions of gonadotrophins on breast cancer cell cytoskeletal rearrangement, migration and invasion. These findings provide original information on the actions of gonadotrophins on breast cancer cells and may have clinical implications for the use of drugs that modulate gonadotrophins in breast cancer patients. PMID- 27502037 TI - Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and Kallmann syndrome. AB - The genetic basis is unknown for ~60% of normosmic hypogonadotropic hypogonadism (nHH)/Kallmann syndrome (KS). DNAs from (17 male and 31 female) nHH/KS patients were analyzed by targeted next generation sequencing (NGS) of 261 genes involved in hypothalamic, pituitary, and/or olfactory pathways, or suggested by chromosome rearrangements. Selected variants were subjected to Sanger DNA sequencing, the gold standard. The frequency of Sanger-confirmed variants was determined using the ExAC database. Variants were classified as likely pathogenic (frameshift, nonsense, and splice site) or predicted pathogenic (nonsynonymous missense). Two novel FGFR1 mutations were identified, as were 18 new candidate genes including: AMN1, CCKBR, CRY1, CXCR4, FGF13, GAP43, GLI3, JAG1, NOS1, MASTL, NOTCH1, NRP2, PALM2, PDE3A, PLEKHA5, RD3, and TRAPPC9, and TSPAN11. Digenic and trigenic variants were found in 8/48 (16.7%) and 1/48 (2.1%) patients, respectively. NGS with confirmation by Sanger sequencing resulted in the identification of new causative FGFR1 gene mutations and suggested 18 new candidate genes in nHH/KS. PMID- 27502038 TI - Dilated cavum septi pellucidi in fetuses with microdeletion 22q11. AB - OBJECTIVES: The cavum septi pellucidi (CSP) is an easily recognizable landmark in the fetal brain. CSP disappears after birth to form the septum pellucidum. Children with microdeletion 22q11 (del. 22q11) were, however, reported to have a persistent dilated CSP. This study was designed to examine whether the CSP is dilated in fetuses with del.22q11. METHODS: This was a case-control study where the CSP width was measured in normal fetuses from 16 to 34 weeks and in fetuses with del. 22q11. CSP width was correlated to the biparietal diameter (BPD). Reference curves were constructed, and z-scores calculated. RESULTS: Cavum septi pellucidi width in 260 normal fetuses showed a linear correlation with BPD. The study group consisted of 37 fetuses with del. 22q11. In 25/37 (67.5%) of fetuses with del. 22q11, the CSP was enlarged with a mean z-score of 2.64 (p < 0.0001). Fetuses with a BPD > 50 mm (>22 weeks of gestation) had a dilated CSP in 85.7% (24/28). CONCLUSIONS: The CSP is a structure routinely evaluated in screening ultrasound. A wide CSP is found in second trimester fetuses with del. 22q11. A dilated CSP may be an important sonographic marker for the presence of del. 22q11 along with conotruncal malformations and thymic hypoplasia. (c) 2016 John Wiley & Sons, Ltd. PMID- 27502039 TI - Fascin Is Critical for the Maintenance of Breast Cancer Stem Cell Pool Predominantly via the Activation of the Notch Self-Renewal Pathway. AB - An emerging dogma shows that tumors are initiated and maintained by a subpopulation of cancer cells that hijack some stem cell features and thus referred to as "cancer stem cells" (CSCs). The exact mechanism that regulates the maintenance of CSC pool remains largely unknown. Fascin is an actin-bundling protein that we have previously demonstrated to be a major regulator of breast cancer chemoresistance and metastasis, two cardinal features of CSCs. Here, we manipulated fascin expression in breast cancer cell lines and used several in vitro and in vivo approaches to examine the relationship between fascin expression and breast CSCs. Fascin knockdown significantly reduced stem cell-like phenotype (CD44hi /CD24lo and ALDH+ ) and reversal of epithelial to mesenchymal transition. Interestingly, expression of the embryonic stem cell transcriptional factors (Oct4, Nanog, Sox2, and Klf4) was significantly reduced when fascin expression was down-regulated. Functionally, fascin-knockdown cells were less competent in forming colonies and tumorspheres, consistent with lower basal self renewal activity and higher susceptibility to chemotherapy. Fascin effect on CSC chemoresistance and self-renewability was associated with Notch signaling. Activation of Notch induced the relevant downstream targets predominantly in the fascin-positive cells. Limiting-dilution xenotransplantation assay showed higher frequency of tumor-initiating cells in the fascin-positive group. Collectively, our data demonstrated fascin as a critical regulator of breast CSC pool at least partially via activation of the Notch self-renewal signaling pathway and modification of the expression embryonic transcriptional factors. Targeting fascin may halt CSCs and thus presents a novel therapeutic approach for effective treatment of breast cancer. Stem Cells 2016;34:2799-2813 Video Highlight: https://youtu.be/GxS4fJ_Ow-o. PMID- 27502040 TI - Tetracycline marks visible in Baltic cod Gadus morhua otoliths stored for 40 years. AB - Baltic cod Gadus morhua otoliths marked with oxytetracycline (OTC) in 1974-1975 had been sectioned and the sections stored in paper envelopes at room temperature in dry, dark conditions. After 40 years of storage, the historic OTC marks were still clearly visible showing that OTC is suitable for long-term chemical marking of otoliths. They were, however, noticeably paler than marks in recently recaptured and archived Baltic G. morhua otoliths, chemically tagged with tetracycline at similar dosage to the historic otoliths. PMID- 27502041 TI - Identification of nontuberculous mycobacteria in MGIT by matrix-assisted laser desorption/ionization mass spectrometry. AB - AIM: The performance of Bruker Biotyper matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) in identifying species of nontuberculous mycobacteria (NTM) in flagged Mycobacteria Growth Indicator Tubes (MGIT)s is unclear. MATERIALS & METHODS: A total of 92 sequential MGIT-positive nontuberculous mycobacteria isolates, including Mycobacterium intracellulare, M. abscessus complex, M. avium complex and M. avium, were used to compare the performance of the MALDI-TOF MS for species-level identification with that of the BluePoint MycoID plus kit and final identification. RESULTS: A total of 44 (47.8%) and 80 (87.0%) isolates were correctly identified to the species level by the MALDI-TOF MS and BluePoint MycoID plus kit, respectively. CONCLUSION: The procedure of MALDI-TOF MS in MGITs inoculated with clinical specimens is needed to be further optimized. PMID- 27502042 TI - Three-Dimensional Transthoracic Echocardiography in the Comprehensive Evaluation of Right and Left Heart Chamber Remodeling Following Percutaneous Mitral Valve Repair. AB - BACKGROUND: Percutaneous mitral valve repair (PMVR) is an alternative treatment in patients with significant mitral regurgitation (MR) who are denied surgery. Although in surgical patients, outcomes have been related both to acute hemodynamic favorable results and to positive cardiac remodeling in the midterm, in the case of PMVR the effect on cardiac chamber remodeling has never been extensively studied. The aims of this study were (1) to evaluate the short- and mid-term remodeling induced by PMVR on cardiac chamber volume using two- and three-dimensional (3D) transthoracic echocardiographic (TTE) imaging and (2) to assess changes in left ventricular (LV) shape on the basis of 3D TTE data. METHODS: Patients undergoing PMVR were prospectively enrolled. Two-dimensional and 3D TTE data sets acquired at baseline, and at 30 days and 6 months after PMVR were analyzed to assess LV and right ventricular (RV) volumes and ejection fraction and left atrial and right atrial volumes. Moreover, 3D endocardial surfaces were extracted to compute 3D shape indexes of LV sphericity and conicity at end-diastole and end-systole. RESULTS: Six of the 64 enrolled patients did not reach follow-up and were excluded. The analysis was feasible in all 58 patients considered (26 with functional MR and 32 [55%] with degenerative MR). PMVR resulted in significant reduction of MR and in favorable remodeling: (1) effective PMVR was mainly associated with decreased LV loading, (2) PMVR-related reverse remodeling was observed in patients with degenerative MR and those with functional MR at 30 days and continued at 6-month follow-up, (3) favorable remodeling in LV shape from abnormally spherical to more normal conical took place in both groups after PMVR, and (4) RV volumes and systolic function were preserved after PMVR. CONCLUSIONS: A comprehensive two-dimensional and 3D TTE analysis allows investigation from a double perspective (volume and morphology) of the entity and modality of changes following PMVR. In high-risk patients undergoing PMVR, postprocedural heart remodeling involves all cardiac chambers, occurs in the short term, and further improves at midterm follow-up. PMID- 27502043 TI - Two angiotensin-converting enzyme-inhibitory peptides from almond protein and the protective action on vascular endothelial function. AB - This study aimed to discover and prepare novel angiotensin converting enzyme (ACE) inhibitory peptides from almond protein and further evaluate the effect on endothelial function of human umbilical vascular endothelial cells (HUVECs). Almond protein was hydrolyzed using a two-stage alcalase-protamex hydrolysis process, and the hydrolysates were subjected to a series of separations, ultrafiltration, gel filtration chromatography, and reversed-phased preparative chromatography, to obtain the active peptides. Seven ACE inhibitory fractions with the molecular weight below 1.5 kDa were isolated and prepared, and two purified ACE inhibitory peptides with the IC50 values of 67.52 +/- 0.05 and 43.18 +/- 0.07 MUg mL(-1), were identified as Met-His-Thr-Asp-Asp and Gln-His-Thr-Asp Asp, respectively. Then the effect of two ACE inhibitory peptides on the endothelial function of HUVECs was evaluated. Results showed that the two potent ACE inhibitory peptides significantly regulated the release of nitric oxide and endothelin in HUVECs. These results suggest that almond peptides have potential as an antihypertensive nutraceuticals or a functional food ingredient. PMID- 27502044 TI - Energies and densities of electrons confined in elliptical and ellipsoidal quantum dots. AB - We consider a droplet of electrons confined within an external harmonic potential well of elliptical or ellipsoidal shape, a geometry commonly encountered in work with semiconductor quantum dots and other nanoscale or mesoscale structures. For droplet sizes exceeding the effective Bohr radius, the dominant contribution to average system parameters in the Thomas-Fermi approximation comes from the potential energy terms, which allows us to derive expressions describing the electron droplet's shape and dimensions, its density, total and capacitive energy, and chemical potential. The analytical results are in very good agreement with experimental data and numerical calculations, and make it possible to follow the dependence of the properties of the system on its parameters (the total number of electrons, the axial ratios and curvatures of the confinement potential, and the dielectric constant of the material). An interesting feature is that the eccentricity of the electron droplet is not the same as that of its confining potential well. PMID- 27502045 TI - A new lizard malaria parasite Plasmodium intabazwe n. sp. (Apicomplexa: Haemospororida: Plasmodiidae) in the Afromontane Pseudocordylus melanotus (Sauria: Cordylidae) with a review of African saurian malaria parasites. AB - BACKGROUND: Saurian malaria parasites are diverse apicomplexan blood parasites including the family Plasmodiidae Mesnil, 1903, and have been studied since the early 1900s. Currently, at least 27 species of Plasmodium are recorded in African lizards, and to date only two species, Plasmodium zonuriae (Pienaar, 1962) and Plasmodium cordyli Telford, 1987, have been reported from the African endemic family Cordylidae. This paper presents a description of a new malaria parasite in a cordylid lizard and provides a phylogenetic hypothesis for saurian Plasmodium species from South Africa. Furthermore, it provides a tabular review of the Plasmodium species that to date have been formally described infecting species of African lizards. METHODS: Blood samples were collected from 77 specimens of Pseudocordylus melanotus (A. Smith, 1838) from Platberg reserve in the Eastern Free State, and two specimens of Cordylus vittifer (Reichenow, 1887) from the Roodewalshoek conservancy in Mpumalanga (South Africa). Blood smears were Giemsa stained, screened for haematozoa, specifically saurian malaria parasites, parasite stages were photographed and measured. A small volume was also preserved for TEM studies. Plasmodium and Haemoproteus primer sets, with a nested polymerase chain reaction (PCR) protocol, were employed to target a fragment of the cytochrome-b (cyt-b) gene region. Resulting sequences of the saurian Plasmodium species' isolates were compared with each other and to other known Plasmodium spp. sequences in the GenBank database. RESULTS: The presence of P. zonuriae in both specimens of the type lizard host C. vittifer was confirmed using morphological characteristics, which subsequently allowed for the species' molecular characterisation. Of the 77 P. melanotus, 44 were parasitised by a Plasmodium species, which when compared morphologically to other African saurian Plasmodium spp. and molecularly to P. zonuriae, supported its description as a new species Plasmodium intabazwe n. sp. CONCLUSIONS: This is the first morphological and molecular account of Plasmodium species within the African endemic family Cordylidae from South Africa. The study highlights the need for molecular analysis of other cordylid Plasmodium species within Africa. Future studies should also include elucidating of the life-cycles of these species, thus promoting the use of both morphological and molecular characteristics in species descriptions of saurian malaria parasites. PMID- 27502046 TI - Cerebral responses to local and global auditory novelty under general anesthesia. AB - Primate brains can detect a variety of unexpected deviations in auditory sequences. The local-global paradigm dissociates two hierarchical levels of auditory predictive coding by examining the brain responses to first-order (local) and second-order (global) sequence violations. Using the macaque model, we previously demonstrated that, in the awake state, local violations cause focal auditory responses while global violations activate a brain circuit comprising prefrontal, parietal and cingulate cortices. Here we used the same local-global auditory paradigm to clarify the encoding of the hierarchical auditory regularities in anesthetized monkeys and compared their brain responses to those obtained in the awake state as measured with fMRI. Both, propofol, a GABAA agonist, and ketamine, an NMDA-antagonist, left intact or even enhanced the cortical response to auditory inputs. The local effect vanished during propofol anesthesia and shifted spatially during ketamine anesthesia compared with wakefulness. Under increasing levels of propofol, we observed a progressive disorganization of the global effect in prefrontal, parietal and cingulate cortices and its complete suppression under ketamine anesthesia. Anesthesia also suppressed thalamic activations to the global effect. These results suggest that anesthesia preserves initial auditory processing, but disturbs both short-term and long-term auditory predictive coding mechanisms. The disorganization of auditory novelty processing under anesthesia relates to a loss of thalamic responses to novelty and to a disruption of higher-order functional cortical networks in parietal, prefrontal and cingular cortices. PMID- 27502047 TI - Calibrated bold fMRI with an optimized ASL-BOLD dual-acquisition sequence. AB - Calibrated fMRI techniques estimate task-induced changes in the cerebral metabolic rate of oxygen (CMRO2) based on simultaneous measurements of cerebral blood flow (CBF) and blood-oxygen-level-dependent (BOLD) signal changes evoked by stimulation. To determine the calibration factor M (corresponding to the maximum possible BOLD signal increase), BOLD signal and CBF are measured in response to a gas breathing challenge (usually CO2 or O2). Here we describe an ASL dual acquisition sequence that combines a background-suppressed 3D-GRASE readout with 2D multi-slice EPI. The concatenation of these two imaging sequences allowed separate optimization of the acquisition for CBF and BOLD data. The dual acquisition sequence was validated by comparison to an ASL sequence with a dual echo EPI readout, using a visual fMRI paradigm. Results showed a 3-fold increase in temporal signal-to-noise ratio (tSNR) of the ASL time-series data while BOLD tSNR was similar to that obtained with the dual-echo sequence. The longer TR of the proposed dual-acquisition sequence, however, resulted in slightly lower T scores (by 30%) in the BOLD activation maps. Further, the potential of the dual acquisition sequence for M-mapping on the basis of a hypercapnia gas breathing challenge and for quantification of CMRO2 changes in response to a motor activation task was assessed. In five subjects, an average gray matter M-value of 8.71+/-1.03 and fractional changes of CMRO2 of 12.5+/-5% were found. The new sequence remedies the deficiencies of prior combined BOLD-ASL acquisition strategies by substantially enhancing perfusion tSNR, which is essential for accurate BOLD calibration. PMID- 27502049 TI - Regional homogeneity of intrinsic brain activity correlates with auditory-motor processing of vocal pitch errors. AB - It has been well documented that speakers produce rapid compensatory vocal adjustments for errors they perceive in their auditory feedback. The fact that they differ greatly in the degree to which they compensate for perceived errors, however, has received much less attention. The present study investigated whether intrinsic brain activity during resting can predict an individual's behavioral and cortical responses in compensating for pitch-shifted auditory feedback during vocalization. This relationship was investigated by correlating the regional homogeneity (ReHo) of resting-state fMRI signals with the vocal compensation and event-related potentials (N1 and P2) in response to pitch shifts of -200 and -500 cents. Behaviorally, the magnitudes of vocal compensation were significantly correlated with the ReHo values in the right supplementary motor area (SMA) for both -200 and -500 cents, the right primary motor cortex (M1) for -200 cents, and the left premotor cortex (PMC) for -500 cents. For both pitch shift sizes, there were significant correlations between ReHo and N1 amplitude in the left inferior frontal gyrus (IFG), right superior temporal gyrus (STG), bilateral M1, and left SMA. Significant correlations between ReHo and P2 amplitude were observed in the bilateral IFG, right STG, left SMA and M1 for -200 and -500 cents, the left PMC for -200 cents, and the right SMA for -500 cents. These findings provide the first evidence that regional homogeneity of intrinsic brain activity can predict behavioral and cortical responses in compensating for pitch errors in voice auditory feedback. PMID- 27502050 TI - Diabetes in Rats Is Cured by Islet Transplantation...But Only During Daytime. PMID- 27502048 TI - Ten problems and solutions when predicting individual outcome from lesion site after stroke. AB - In this paper, we consider solutions to ten of the challenges faced when trying to predict an individual's functional outcome after stroke on the basis of lesion site. A primary goal is to find lesion-outcome associations that are consistently observed in large populations of stroke patients because consistent associations maximise confidence in future individualised predictions. To understand and control multiple sources of inter-patient variability, we need to systematically investigate each contributing factor and how each factor depends on other factors. This requires very large cohorts of patients, who differ from one another in typical and measurable ways, including lesion site, lesion size, functional outcome and time post stroke (weeks to decades). These multivariate investigations are complex, particularly when the contributions of different variables interact with one another. Machine learning algorithms can help to identify the most influential variables and indicate dependencies between different factors. Multivariate lesion analyses are needed to understand how the effect of damage to one brain region depends on damage or preservation in other brain regions. Such data-led investigations can reveal predictive relationships between lesion site and outcome. However, to understand and improve the predictions we need explanatory models of the neural networks and degenerate pathways that support functions of interest. This will entail integrating the results of lesion analyses with those from functional imaging (fMRI, MEG), transcranial magnetic stimulation (TMS) and diffusor tensor imaging (DTI) studies of healthy participants and patients. PMID- 27502051 TI - Investigating the association between photosynthetic efficiency and generation of biophotoelectricity in autotrophic microbial fuel cells. AB - Microbial fuel cells operating with autotrophic microorganisms are known as biophotovoltaic devices. It represents a great opportunity for environmentally friendly power generation using the energy of the sunlight. The efficiency of electricity generation in this novel system is however low. This is partially reflected by the poor understanding of the bioelectrochemical mechanisms behind the electron transfer from these microorganisms to the electrode surface. In this work, we propose a combination of electrochemical and fluorescence techniques, giving emphasis to the pulse amplitude modulation fluorescence. The combination of these two techniques allow us to obtain information that can assist in understanding the electrical response obtained from the generation of electricity through the intrinsic properties related to the photosynthetic efficiency that can be obtained from the fluorescence emitted. These were achieved quantitatively by means of observed changes in four photosynthetic parameters with the bioanode generating electricity. These are the maximum quantum yield (Fv/Fm), alpha (alpha), light saturation coefficient (Ek) and maximum rate of electron transfer (rETRm). The relationship between the increases in the current density collected by the bioanode to the decrease of the rETRm values in the photosynthetic pathway for the two microorganisms was also discussed. PMID- 27502052 TI - Dimerization of Arginyl-tRNA Synthetase by Free Heme Drives Its Inactivation in Plasmodium falciparum. AB - Excess cellular heme is toxic, and malaria parasites regulate its levels during hemoglobin digestion. Aminoacyl-tRNA synthetases are ubiquitous enzymes, and of these, arginyl-tRNA synthetase (RRS) is unique as its enzymatic product of charged tRNA is required for protein synthesis and degradation. We show that Plasmodium falciparum arginyl-tRNA synthetase (PfRRS) is an active, cytosolic, and monomeric enzyme. Its high-resolution crystal structure highlights critical structural differences with the human enzyme. We further show that hemin binds to and inhibits the aminoacylation activity of PfRRS. Hemin induces a dimeric form of PfRRS that is thus rendered enzymatically dead as it is unable to recognize its cognate tRNA(arg). Excessive hemin in chloroquine-treated malaria parasites results in significantly reduced charged tRNA(arg) levels, thus suggesting deceleration of protein synthesis. These data together suggest that the inhibition of Plasmodium falciparum arginyl-tRNA synthetase can now be synergized with existing antimalarials for more potent drug cocktails against malaria parasites. PMID- 27502053 TI - Wholesome Nutrition: an example for a sustainable diet. AB - 'Wholesome Nutrition' is a concept of sustainable nutrition that was developed at the University of Giessen in the 1980s. In this concept, health and the ecologic, economic, social and cultural dimensions of nutrition are equally important. In 1992 at the UN-Conference on Environment and Development in Rio de Janeiro the definition of 'Sustainable Development' comprised the dimensions environment, economy and society. Additionally to these three 'classical' dimensions of sustainability, we included 'health' as the fourth dimension because nutrition has far reaching effects on human health. The fifth dimension, 'culture', became part of the sustainability dialogue since many years; the respective cultural background influences food habits. Presently, mankind has to cope with huge global challenges such as poverty and food insecurity in low-income countries as well as climate change. Therefore the objective is to identify prospects for actions to respond to these global challenges. The concept of 'Sustainable Nutrition' analyses the food supply chain at all stages from input-production and primary production to processing, distribution, preparation, consumption and waste disposal. The present analysis leads to the following seven principles: preference of plant-based foods, organic foods, regional and seasonal products, preference of minimally processed foods, Fair Trade products, resource-saving housekeeping and enjoyable eating culture. This concept is based on holistic thinking and has the potential to reduce the global challenges in the field of nutrition. Scientists, stakeholders, multipliers and consumers are asked to consider environmental, economic, social and cultural aspects in addition to the biological (health) aspects. PMID- 27502055 TI - Ephemeral ecological speciation and the latitudinal biodiversity gradient. AB - The richness of biodiversity in the tropics compared to high-latitude parts of the world forms one of the most globally conspicuous patterns in biology, and yet few hypotheses aim to explain this phenomenon in terms of explicit microevolutionary mechanisms of speciation and extinction. We link population genetic processes of selection and adaptation to speciation and extinction by way of their interaction with environmental factors to drive global scale macroecological patterns. High-latitude regions are both cradle and grave with respect to species diversification. In particular, we point to a conceptual equivalence of "environmental harshness" and "hard selection" as eco-evolutionary drivers of local adaptation and ecological speciation. By describing how ecological speciation likely occurs more readily at high latitudes, with such nascent species especially prone to extinction by fusion, we derive the ephemeral ecological speciation hypothesis as an integrative mechanistic explanation for latitudinal gradients in species turnover and the net accumulation of biodiversity. PMID- 27502054 TI - Pilot clinical observations between food and drug seeking derived from fifty cases attending an eating disorder clinic. AB - Background The reward deficiency syndrome hypothesis posits that genes are responsible for reward dependence and related behaviors. There is evidence that both bulimia and anorexia nervosa, especially in women, have been linked to a lifetime history of substance use disorder (SUD). There are difficulties in accepting food as an addiction similar to drugs; however, increasingly neuroimaging studies favor such an assertion. Case presentations We are reporting the evidence of comorbidity of eating disorders with SUD found within these case presentations. We show 50 case reports derived from two independent treatment centers in Florida that suggest the commonality between food and drug addictions. In an attempt to provide data from this cohort, many participants did not adequately respond to our questionnaire. Discussion We propose that dopamine agonist therapy may be of common benefit. Failure in the past may reside in too powerful D2 agonist activity leading to D2 receptor downregulation, while the new methodology may cause a reduction of "dopamine resistance" by inducing "dopamine homeostasis." While this is not a definitive study, it does provide some additional clinical evidence that these two addictions are not mutually exclusive. Conclusion Certainly, it is our position that there is an overlap between food- and drug-seeking behavior. We propose that the studies focused on an effort to produce natural activation of dopaminergic reward circuitry as a type of common therapy may certainly be reasonable. Additional research is warranted. PMID- 27502056 TI - Comparison of the compatible solute pool of two slightly halophilic planctomycetes species, Gimesia maris and Rubinisphaera brasiliensis. AB - Gimesia maris and Rubinisphaera brasiliensis are slightly halophilic representatives of the deep-branching phylum Planctomycetes. For osmoadaptation both species accumulated alpha-glutamate, sucrose, ectoine and hydroxyectoine. A major role was found for ectoine, hydroxyectoine as well as sucrose under hyper osmotic shock conditions. Nevertheless, the levels of sucrose were up-regulated by the increased salinity levels and also by low nitrogen availability. Additionally, G. maris accumulated glucosylglycerate (GG) as major solute specifically under low nitrogen levels, which prompted us to analyse the transcript abundance of two homologues genes known for the biosynthesis of GG, namely glucosyl-3-phosphoglycerate synthase (GpgS) and glucosyl-3 phosphoglycerate phosphatase (GpgP). By qPCR using a suitable reference gene selected in this study, the transcript abundance of the biosynthetic genes was quantified in G. maris cells under hyper-osmotic shock or under low nitrogen conditions. The gpgS gene was induced under nitrogen-limiting conditions suggesting that GG synthesis is regulated primarily at the transcription level. Moreover, the expression of a gene coding for a putative sucrose-phosphorylase (Spase) located upstream the gpgS and gpgP genes was up-regulated, predicting a metabolic role of Spase probably related to GG synthesis. PMID- 27502057 TI - Periodontal conditions and incidence of new cardiovascular events among patients with coronary vascular disease. AB - AIM: We wanted to investigate whether periodontal conditions and/or oral care habits are associated with new cardiovascular events among patients with coronary vascular disease (CVD). MATERIALS AND METHODS: In this longitudinal cohort study, 1002 inpatients with CVD were included. They were examined regarding prevalence of severe periodontitis, bleeding upon probing (BOP), number of missing teeth and oral care habits. The combined endpoint was defined as myocardial infarction, stroke/transient ischaemic attack, cardiovascular death and death caused by stroke. Survival analyses were carried out after a 3-year follow-up period. Hazard ratios (HRs) were adjusted for known cardiac risk factors using Cox regression. RESULTS: Nine hundred and fifty-three patients completed the 3-year follow-up. The overall incidence of the combined endpoint was 16.4%. Significant HRs for BOP (HR = 2, 95% CI: 1.2-3.3), severe tooth loss (HR = 1.8, 95% CI: 1.3 2.5), brushing teeth more than once a day (HR = 0.6, 95% CI: 0.5-1.0) and use of floss/inter-dental brushes (HR = 0.5, 95% CI: 0.3-0.9) were evaluated only in univariate but not in multivariate survival analyses. Patients with severe periodontitis achieved the combined endpoint more often (18.9% versus 14.2%), but the result was not statistically significant after both univariate and multivariate survival analyses. CONCLUSIONS: Periodontal conditions and oral care habits are not independent indicators for further adverse events in patients with CVD. PMID- 27502058 TI - Anthracycline-Associated T1 Mapping Characteristics Are Elevated Independent of the Presence of Cardiovascular Comorbidities in Cancer Survivors. AB - BACKGROUND: Cardiovascular magnetic resonance T1 mapping characteristics are elevated in adult cancer survivors; however, it remains unknown whether these elevations are related to age or presence of coincident cardiovascular comorbidities. METHODS AND RESULTS: We performed blinded cardiovascular magnetic resonance analyses of left ventricular T1 and extracellular volume (ECV) fraction in 327 individuals (65% women, aged 64+/-12 years). Thirty-seven individuals had breast cancer or a hematologic malignancy but had not yet initiated their treatment, and 54 cancer survivors who received either anthracycline-based (n=37) or nonanthracycline-based (n=17) chemotherapy 2.8+/-1.3 years earlier were compared with 236 cancer-free participants. Multivariable analyses were performed to determine the association between T1/ECV measures and variables associated with myocardial fibrosis. Age-adjusted native T1 was elevated pre- (1058+/-7 ms) and post- (1040+/-7 ms) receipt of anthracycline chemotherapy versus comparators (965+/-3 ms; P<0.0001 for both). Age-adjusted ECV, a marker of myocardial fibrosis, was elevated in anthracycline-treated cancer participants (30.4+/-0.7%) compared with either pretreatment cancer (27.8+/-0.7%; P<0.01) or cancer-free comparators (26.9+/-0.2%; P<0.0001). T1 and ECV of nonanthracycline survivors were no different than pretreatment survivors (P=0.17 and P=0.16, respectively). Native T1 and ECV remained elevated in cancer survivors after accounting for demographics (including age), myocardial fibrosis risk factors, and left ventricular ejection fraction or myocardial mass index (P<0.0001 for all). CONCLUSIONS: Three years after anthracycline-based chemotherapy, elevations in myocardial T1 and ECV occur independent of underlying cancer or cardiovascular comorbidities, suggesting that imaging biomarkers of interstitial fibrosis in cancer survivors are related to prior receipt of a potentially cardiotoxic cancer treatment regimen. PMID- 27502059 TI - Moderate Physical Activity in Healthy Adults Is Associated With Cardiac Remodeling. AB - BACKGROUND: Cardiac mass and volumes are often elevated in athletes, but it is not known whether moderate physical activity is also associated with cardiac dilatation and hypertrophy in a healthy adult population. METHODS AND RESULTS: In total, 1096 adults (54% female, median age 39 years) without cardiovascular disease or cardiomyopathy-associated genetic variants underwent cardiac magnetic resonance imaging to determine biventricular volumes and function. Physical activity was assessed using a validated activity questionnaire. The relationship between cardiac parameters and activity was assessed using multiple linear regression adjusting for age, sex, race, and systolic blood pressure. Logistic regression was performed to determine the effect of activity on the likelihood of subjects having cardiac dilatation or hypertrophy according to standard cardiac magnetic resonance normal ranges. Increasing physical activity was associated with greater left ventricular (LV) mass (beta=0.23; P<0.0001) and elevated LV and right ventricular volumes (LV: beta=0.26, P<0.0001; right ventricular: beta=0.26, P<0.0001). Physical activity had a larger effect on cardiac parameters than systolic blood pressure (0.06<=beta<=0.21) and a similar effect to age ( 0.20<=beta<=-0.31). Increasing physical activity was a risk factor for meeting imaging criteria for LV hypertrophy (adjusted odds ratio 2.1; P<0.0001), LV dilatation (adjusted odds ratio 2.2; P<0.0001), and right ventricular dilatation (adjusted odds ratio 2.2; P<0.0001). CONCLUSIONS: Exercise-related cardiac remodeling is not confined to athletes, and there is a risk of overdiagnosing cardiac dilatation or hypertrophy in a proportion of active, healthy adults. PMID- 27502061 TI - Detection of Myocarditis With Molecular Echo Imaging: Another Potential Application for the Phosphatidyl Serine Microbubble. PMID- 27502060 TI - Noninvasive Contrast-Enhanced Ultrasound Molecular Imaging Detects Myocardial Inflammatory Response in Autoimmune Myocarditis. AB - BACKGROUND: Cardiac tests for diagnosing myocarditis lack sensitivity or specificity. We hypothesized that contrast-enhanced ultrasound molecular imaging could detect myocardial inflammation and the recruitment of specific cellular subsets of the inflammatory response in murine myocarditis. METHODS AND RESULTS: Microbubbles (MB) bearing antibodies targeting lymphocyte CD4 (MBCD4), endothelial P-selectin (MBPSel), or isotype control antibody (MBIso) and MB with a negative electric charge for targeting of leukocytes (MBLc) were prepared. Attachment of MBCD4 was validated in vitro using murine spleen CD4+ T cells. Twenty-eight mice were studied after the induction of autoimmune myocarditis by immunization with alpha-myosin-peptide; 20 mice served as controls. Contrast enhanced ultrasound molecular imaging of the heart was performed. Left ventricular function was assessed by conventional and deformation echocardiography, and myocarditis severity graded on histology. Animals were grouped into no myocarditis, moderate myocarditis, and severe myocarditis. In vitro, attachment of MBCD4 to CD4+ T cells was significantly greater than of MBIso. Of the left ventricular ejection fraction or strain and strain rate readouts, only longitudinal strain was significantly different from control animals in severe myocarditis. In contrast, contrast-enhanced ultrasound molecular imaging showed increased signals for all targeted MB versus MBIso both in moderate and severe myocarditis, and MBCD4 signal correlated with CD4+ T lymphocyte infiltration in the myocardium. CONCLUSIONS: Contrast-enhanced ultrasound molecular imaging can detect endothelial inflammation and leukocyte infiltration in myocarditis in the absence of a detectable decline in left ventricular performance by functional imaging. In particular, imaging of CD4+ T cells involved in autoimmune responses could be helpful in diagnosing myocarditis. PMID- 27502062 TI - Exercise-Induced Cardiac Remodeling: Competitive Athletes Are Just the Tip of the Iceberg. PMID- 27502063 TI - Anthracycline Cardiotoxicity: How Do We Move From Diagnosis to Prediction? PMID- 27502064 TI - Streptococcus dysgalactiae subsp. equisimilis Isolated From Infections in Dogs and Humans: Are Current Subspecies Identification Criteria accurate? AB - Streptococcus dysgalactiae is a pyogenic species pathogenic both for humans and animals. Until recently, it has been considered an exclusive animal pathogen causing infections in wild as well as domestic animals. Currently, human infections are being reported with increasing frequency, and their clinical picture is often similar to the ones caused by Streptococcus pyogenes. Due to the fact that S. dysgalactiae is a heterogeneous species, it was divided into two subspecies: S. dysgalactiae subsp. equisimilis (SDSE) and S. dysgalactiae subsp. dysgalactiae (SDSD). The first differentiation criterion, described in 1996, was based on strain isolation source. Currently applied criteria, published in 1998, are based on hemolysis type and Lancefield group classification. In this study, we compared subspecies identification results for 36 strains isolated from clinical cases both in humans and animals. Species differentiation was based on two previously described criteria as well as MALDI-TOF and genetic analyses: RISA and 16S rRNA genes sequencing. Antimicrobial susceptibility profiles were also determined according to CLSI guidelines. The results presented in our study suggest that the subspecies differentiation criteria previously described in the above two literature positions seem to be inaccurate in analyzed group of strains, the hemolysis type on blood agar, and Lancefield classification should not be here longer considered as criteria in subspecies identification. The antimicrobial susceptibility tests indicate emerging of multiresistant human SDSE strains resistant also to vancomycin, linezolid and tigecycline, which might pose a substantial problem in treatment. PMID- 27502065 TI - Evaluation of a Commercial Real-Time PCR Kit for the Detection of Mycobacterium avium subspecies paratuberculosis in Milk. AB - There are several commercial test kits for Mycobacterium avium subspecies paratuberculosis (MAP) detection, each with different advantages, disadvantages, and applications. In the present study, a real-time PCR kit targeting the unique transposon sequence ISMAP02 was evaluated. The analytical sensitivity was determined using the type strain ATCC 19698, and the specificity was validated by testing fifteen MAP isolates, thirteen non-MAP Mycobacterium isolates, and eight non-Mycobacterium isolates. Six spiking experiments were performed using raw milk and reconstituted infant milk artificially contaminated with dilutions containing 10(0)-10(5) MAP cells mL(-1). Sensitivity and specificity were at 100 %. The detection probabilities in raw milk and reconstituted infant milk for the samples (containing 1.4 * 10(1) and 1.7 * 10(1) MAP cell 50 mL(-1)) were 16.6 and 91.6 %, respectively. Thus, the tested kit yielded satisfying results to detect MAP in milk. PMID- 27502066 TI - Spirosoma fluminis sp. nov., a Gamma-Radiation Resistant Bacterium Isolated from Sediment of the Han River in South Korea. AB - A Gram-negative, long rod-shaped, and yellowish bacterium, designated as strain 15J17T(T), was isolated from sediment of the Han River in South Korea after exposure to 3 kGy of gamma radiation. The strain was catalase- and oxidase positive and showed resistance to gamma radiation-D10 value (i.e., the dose required to reduce the bacterial population by 10-fold) of >4 kGy. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that the strain belonged to the genus Spirosoma and showed moderate degrees of sequence similarity with related species (90.6-93.5 %). Chemotaxonomic data revealed that the strain contained summed feature 3 (C16:1 omega7c/C16:1 omega6c), C16:1 omega5c, C16:0, C18:0, and C15:0 iso as the major fatty acids; phosphatidylethanolamine, an unidentified aminophospholipid, and an unidentified polar lipid as the major polar lipids; and menaquinone-7 (MK-7) as the major quinone. The genomic DNA G+C content of the new strain was 48.3 mol%. Based on these data, type strain 15J17T(T) (=KCTC 52198(T) = JCM 31409(T)) should be classified as representing a new species, for which we propose the name Spirosoma fluminis sp. nov. PMID- 27502067 TI - Creating a family through connection websites and events: ethical and social issues. AB - Over the years, connection websites and speed dating events have increasingly attracted singles and couples who cannot have a child in the 'traditional' way. These initiatives bring together candidate gamete providers and recipients with the promise of offering more freedom of choice than fertility centres or sperm banks currently do. Depending on the level of contact desired, the role of the gamete provider may range from not being involved at all to sharing full parental rights and obligations. In this paper, we take a look at the ethical and social issues that emerge with these new forms of family arrangements. We suggest that, although the private arrangements promote greater autonomy and control for all parties involved, risks and questionable assumptions are also at play. In particular, risks involve insufficient screening of the involved donor or co parent, particularly in terms of motives and psychological characteristics. One must also be wary of the risk of unregulated commercialization and, more importantly, of disappointments and legal conflicts caused by unclear or changing expectations. We also warn for the risk of reinforcing heterosexist and genetic norms of parenting and valid family building. PMID- 27502068 TI - Anti-Mullerian hormone for prediction of ovarian response in Chinese infertile women undergoing IVF/ICSI cycles: a prospective, multi-centre, observational study. AB - This study explored the correlation between serum anti-Mullerian hormone (AMH) concentration and the number of retrieved oocytes after ovarian stimulation in Chinese infertile women undergoing assisted reproductive technology treatment and AMH cut-off values predicting low and high ovarian response. This was a prospective, multi-centre, observational study. A total of 615 subjects were included in nine assisted reproductive centres in China for outcome analysis. Subjects received assisted reproductive technology treatment and used recombinant human FSH (r-HFSH) or r-HFSH plus recombinant LH (rLH) for ovarian stimulation according to conventional treatment regimens. The main outcome variables were correlations between AMH and the number of retrieved oocytes and the cut-off values of AMH predicting low and high ovarian response. Serum AMH concentration was positively correlated with the number of oocytes retrieved in Chinese infertile women treated with IVF/intracytoplasmic sperm injection (ICSI) (Pearson correlation coefficient = 0.4754, P < 0.0001). The optimal AMH cut-off value was 2.6 ng/ml (sensitivity: 81.28%, specificity: 59.51%) in predicting high and normal response, and 1.1 ng/ml (sensitivity: 52.27%, specificity: 87.23%) in predicting low and normal response. In conclusion, serum AMH concentration can be used as a biomarker to predict ovarian response in Chinese infertile women treated with assisted reproductive technology. PMID- 27502070 TI - Erratum to: The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b+ Ly6Chi cells to tumor tissue reduces tumor growth. PMID- 27502071 TI - Perceived discrimination and self-rated health in Canada: an exploratory study. AB - BACKGROUND: Our objective was to explore whether the link between discrimination and self-rated health status differed as a function of discrimination type, including discrimination based on ethnicity/culture, race, physical appearance (other than skin colour), religion, age, and disability. METHODS: A sample of 19,422 men and women aged 15 and older was included in this study. A multivariate logistic regression analysis was used to measure the association between perceived discrimination types and self-reported health status defined as excellent/good versus fair/poor. RESULTS: The prevalence of experiencing any discrimination in the past five years was higher among those who rated their health as fair or poor (21.8 %) compared to those who rated their health as excellent or good (14.5 %, p < 0.0001). After controlling for all other covariates, there was a positive association between poorer self-rated health and two of the six specific discrimination variables entered into the model: perceived discrimination based on physical appearance (other than skin colour) (OR = 1.79, 95 % CI: 1.24, 2.58) and perceived discrimination based on a having a disability (OR = 1.59, 95 % CI: 1.04, 2.41). CONCLUSIONS: Our main findings indicate that perceived discrimination based on physical appearance and disability may have an adverse impact on health. The results highlight the need for a comprehensive approach to improving health outcomes that should include policies that are targeted against specific types of discrimination. PMID- 27502069 TI - EGFR and SYNE2 are associated with p21 expression and SYNE2 variants predict post operative clinical outcomes in HBV-related hepatocellular carcinoma. AB - This study was to explore the association between gene variants and p21 expression and investigate the TP53-independent p21 regulation in hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) patients from Guangxi by genome-wide association study. 426 HBV-related HCC patients were enrolled. Results showed that, after quality control, a total of 21,643 SNPs were identified in 107 p21 positive and 298 p21 negative patients. The variants of epidermal growth factor receptor (EGFR; rs2227983 and rs6950826) and spectrin repeat containing, nuclear envelope 2 (SYNE2; rs8010699, rs4027405 and rs1890908) were associated with p21 expression. Moreover the haplotype block (rs2227983 and rs6950826, r(2) = 0.378) in EGFR and the haplotype block in SYNE2 (rs8010699 was in strong LD with rs4027405 and rs1890908 (r(2) = 0.91 and 0.70, respectively)) were identified, and the haplotype A-G of EGFR and haplotype G-A-A of SYNE2 were significantly associated with p21 expression (P < 0.01). rs4027405 and rs1890908 were significantly associated with overall survival, and patients with AG/GG genotypes of SYNE2 gene had a worse overall survival (P = 0.001, P = 0.002). Our findings indicate that variants of EGFR and SYNE2 play an important role in p21 regulation and are associated with the clinical outcome of HBV-related HCC in a TP53-indenpdent manner. PMID- 27502072 TI - Outcome and late effects among acute myeloid leukemia survivors: a nationwide population-based study. AB - BACKGROUND: Understanding of pathogenesis and treatment for acute myeloid leukemia (AML) is growing. However, studies regarding the outcomes and late effects among AML survivors are relatively limited. METHODS: This nationwide population-based study used medical records from the Taiwanese National Health Insurance Research Database. A total of 3356 AML patients diagnosed from 2000 to 2008 were analyzed. The physiological and psychological morbidities in AML survivors were compared to those identified from a normal population. This study also compared late effects among AML survivors treated by intensive chemotherapy alone and allogeneic hematopoietic stem cell transplantation (allo-HSCT). RESULTS: The incidence of AML in Taiwan has increased from 1.07 per 100,000 persons in 2000 to 2.17 per 100,000 persons in 2008 (p < 0.0001). With the median overall survival (OS) time of 0.98 years, 25.0 % of AML patients in this study cohort received best supportive care alone. Compared to the normal population, AML survivors had higher rates of hypertension (hazard ratio [HR] 1.69; 95 % confidence interval [CI] 1.18-2.42; p < 0.01), cardiovascular disease (HR 2.53; 95 % CI 1.39-4.61; p < 0.01), diabetes (HR 2.27; 95 % CI 1.48-3.48; p < 0.001), and psychological disorders (HR 1.45; 95 % CI 1.04-2.04; p < 0.05). Although patients undergoing allo-HSCT had a better OS than did patients treated with intensive chemotherapy alone (median not reached vs. 1.53 years; p < 0.0001), diabetes was found more often among allo-HSCT recipients than among patients receiving intensive chemotherapy only (HR 2.93; 95 % CI 1.21-7.08; p < 0.05). CONCLUSION: Regular physical and psychological surveillance of AML survivors is needed especially for those receiving allo-HSCT. PMID- 27502075 TI - Dermoscopic findings in pigmented Bowen's disease of the lip. PMID- 27502074 TI - Fabrication of Unique Magnetic Bionanocomposite for Highly Efficient Removal of Hexavalent Chromium from Water. AB - Biotreatment of hexavalent chromium has attracted widespread interest due to its cost effective and environmental friendliness. However, the difficult separation of biomass from aqueous solution and the slow hexavalent chromium bioreduction rate are bottlenecks for biotechnology application. In this approach, a core shell structured functional polymer coated magnetic nanocomposite was prepared for enriching the hexavalent chromium. Then the nanocomposite was connected to the bacteria via amines on bacterial (Bacillus subtilis ATCC-6633) surface. Under optimal conditions, a series of experiments were launched to degrade hexavalent chromium from the aqueous solution using the as-prepared bionanocomposite. Results showed that B. subtilis@Fe3O4@mSiO2@MANHE (BFSM) can degrade hexavalent chromium from the water more effectively (a respectable degradation efficiency of about 94%) when compared with pristine B. subtilis and Fe3O4@mSiO2@MANHE (FSM). Moreover, the BFSM could be separated from the wastewater by magnetic separation technology conveniently due to the Fe3O4 core of FSM. These results indicate that the application of BFSM is a promising strategy for effective treating wastewater containing hexavalent chromium. PMID- 27502073 TI - Extending the Minority Stress Model to Incorporate HIV-Positive Gay and Bisexual Men's Experiences: a Longitudinal Examination of Mental Health and Sexual Risk Behavior. AB - BACKGROUND: Minority stress theory represents the most plausible conceptual framework for explaining health disparities for gay and bisexual men (GBM). However, little focus has been given to including the unique stressors experienced by HIV-positive GBM. PURPOSE: We explored the role of HIV-related stress within a minority stress model of mental health and condomless anal sex. METHODS: Longitudinal data were collected on a diverse convenience sample of 138 highly sexually active, HIV-positive GBM in NYC regarding sexual minority (internalized homonegativity and gay-related rejection sensitivity) and HIV related stressors (internalized HIV stigma and HIV-related rejection sensitivity), emotion dysregulation, mental health (symptoms of depression, anxiety, sexual compulsivity, and hypersexuality), and sexual behavior (condomless anal sex with all male partners and with serodiscordant male partners). RESULTS: Across both sexual minority and HIV-related stressors, internalized stigma was significantly associated with mental health and sexual behavior outcomes while rejection sensitivity was not. Moreover, path analyses revealed that emotion dysregulation mediated the influence of both forms of internalized stigma on symptoms of depression/anxiety and sexual compulsivity/hypersexuality as well as serodiscordant condomless anal sex. CONCLUSIONS: We identified two targets of behavioral interventions that may lead to improvements in mental health and reductions in sexual transmission risk behaviors-maladaptive cognitions underlying negative self-schemas and difficulties with emotion regulation. Techniques for cognitive restructuring and emotion regulation may be particularly useful in the development of interventions that are sensitive to the needs of this population while also highlighting the important role that structural interventions can have in preventing these disparities for future generations. PMID- 27502076 TI - Cell-based phenotypic screening of mast cell degranulation unveils kinetic perturbations of agents targeting phosphorylation. AB - Mast cells play an essential role in initiating allergic diseases. The activation of mast cells are controlled by a complicated signal network of reversible phosphorylation, and finding the key regulators involved in this network has been the focus of the pharmaceutical industry. In this work, we used a method named Time-dependent cell responding profile (TCRP) to track the process of mast cell degranulation under various perturbations caused by agents targeting phosphorylation. To test the feasibility of this high-throughput cell-based phenotypic screening method, a variety of biological techniques were used. We further screened 145 inhibitors and clustered them based on the similarities of their TCRPs. Stat3 phosphorylation has been widely reported as a key step in mast cell degranulation. Interestingly, our TCRP results showed that a Stat3 inhibitor JSI124 did not inhibit degranulation like other Stat3 inhibitors, such as Stattic, clearly inhibited degranulation. Regular endpoint assays demonstrated that the distinctive TCRP of JSI124 potentially correlated with the ability to induce apoptosis. Consequently, different agents possibly have disparate functions, which can be conveniently detected by TCRP. From this perspective, our TCRP screening method is reliable and sensitive when it comes to discovering and selecting novel compounds for new drug developments. PMID- 27502077 TI - Correction: Selective and broad spectrum amphiphilic small molecules to combat bacterial resistance and eradicate biofilms. AB - Correction for 'Selective and broad spectrum amphiphilic small molecules to combat bacterial resistance and eradicate biofilms' by Jiaul Hoque et al., Chem. Commun., 2015, 51, 13670-13673. PMID- 27502078 TI - Acute myocardial infarction. AB - Acute myocardial infarction has traditionally been divided into ST elevation or non-ST elevation myocardial infarction; however, therapies are similar between the two, and the overall management of acute myocardial infarction can be reviewed for simplicity. Acute myocardial infarction remains a leading cause of morbidity and mortality worldwide, despite substantial improvements in prognosis over the past decade. The progress is a result of several major trends, including improvements in risk stratification, more widespread use of an invasive strategy, implementation of care delivery systems prioritising immediate revascularisation through percutaneous coronary intervention (or fibrinolysis), advances in antiplatelet agents and anticoagulants, and greater use of secondary prevention strategies such as statins. This seminar discusses the important topics of the pathophysiology, epidemiological trends, and modern management of acute myocardial infarction, focusing on the recent advances in reperfusion strategies and pharmacological treatment approaches. PMID- 27502079 TI - Synthesis, Characterization, and Microwave Absorption Property of the SnO2Nanowire/Paraffin Composites. AB - In this article, SnO2nanowires (NWs) have been prepared and their microwave absorption properties have been investigated in detail. Complex permittivity and permeability of the SnO2NWs/paraffin composites have been measured in a frequency range of 0.1-18 GHz, and the measured results are compared with that calculated from effective medium theory. The value of maximum reflection loss for the composites with 20 vol.% SnO2NWs is approximately -32.5 dB at 14 GHz with a thickness of 5.0 mm. PMID- 27502080 TI - Validity of body adiposity index in predicting body fat in Brazilians adults. AB - OBJECTIVES: The aim of this study was to compare various methods of assessing body compositions with body adiposity index (BAI) and to identify the validity of BAI as a predictor of body fat in Brazilian adults. METHODS: This study included 706 individuals (average age 37.3 years, SD = 12.1). Anthropometric data included percent body fat obtained by skinfold thicknesses, bioelectrical impedance analysis and DXA. Body mass index (BMI), waist/hip ratio, and BAI were calculated. The correlation between variables was assessed by Pearson's correlation coefficient, and the Bland-Altman and Kaplan Meier graphic approaches were used to verify the agreement between BAI and DXA. RESULTS: There was a strong correlation between BAI and BMI (r = 0.84 in men and r = 0.86 in women, P < .001), waist circumference (r = 0.77 in men and r = 0.75 in women, P < .001) percent fat by skinfold thicknesses (r = 0.71 in men and r = 0.71 in women, P < .001) and by DXA (r = 0.72 in men and r = 0.78 in women, P < .001). The Bland Altman approach showed an overestimation of BAI in males and an underestimation in women using DXA as the reference method. The agreement between BAI and DXA through the Kaplan-Meier analysis was 41%. CONCLUSIONS: It was found that BAI does not replace other measurements of body fat, but compared with more complex methods can be an alternative for estimating the body fat in the absence of these methods. PMID- 27502081 TI - Highly Efficient Interfaces in Nanocomposites Based on Polyethylene and ZnO Nano/Hierarchical Particles: A Novel Approach toward Ultralow Electrical Conductivity Insulations. AB - Polyethylene nanocomposites based on functionalized ZnO nano/hierarchical particles with highly effective interfacial surface area are presented, for the next generation of ultralow transmission-loss high-voltage DC insulating materials. PMID- 27502082 TI - Relationship between type 1 metabotropic glutamate receptors and cerebellar ataxia. AB - Imaging of type 1 metabotropic glutamate receptor (mGluR1) has recently become possible using positron emission tomography (PET). We aimed to examine the relationship between mGluR1 and cerebellar ataxia. Families with spinocerebellar ataxia type 19/22 (SCA19/22) and SCA6, six patients with sporadic SCA, and 26 healthy subjects underwent PET using an mGluR1 radiotracer. Volumes-of-interest were placed on the anterior and posterior lobes and vermis. The binding potential (BPND) was calculated to estimate mGluR1 availability. A partial volume correction was applied to the BPND values. The Scale for the Assessment and Rating of Ataxia (SARA) score were measured. In each patient with SCA19/22 and SCA6, the anterior lobe showed the highest decrease rates in the BPND values, compared with healthy subjects. In the families with SCA19/22 and SCA6, the disease durations and SARA scores were shorter and lower, respectively, in the offspring, compared with the parents. However, the offspring paradoxically showed lower BPND values, especially in the anterior lobe, compared with the parents. The patients with sporadic SCA showed significantly lower BPND values in all subregions than healthy subjects. The BPND values significantly correlated with the SARA scores in all participants. In conclusion, these results showed a decrease in mGluR1 availability in patients with hereditary and sporadic SCA, a correlation between mGluR1 availability and degree of cerebellar ataxia, and paradoxical findings in two families. These results suggest the potential use of mGluR1 imaging as a specific biomarker of cerebellar ataxia. PMID- 27502083 TI - A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism. AB - Defects in the respiratory chain or mitochondrial ATP synthase (complex V) result in mitochondrial dysfunction that is an important cause of inherited neurological disease. Two of the subunits of complex V are encoded by MT-ATP6 and MT-ATP8 in the mitochondrial genome. Pathogenic mutations in MT-ATP6 are associated with the Leigh syndrome, the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP), as well as with non-classical phenotypes, while MT-ATP8 is less frequently mutated in patients with mitochondrial disease. We investigated two adult siblings presenting with features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, sensorineural hearing impairment, and hypergonadotropic hypogonadism. As the phenotype was suggestive of mitochondrial disease, mitochondrial DNA was sequenced and a novel heteroplasmic mutation m.8561C>G in the overlapping region of the MT-ATP6 and MT-ATP8 was found. The mutation changed amino acids in both subunits. Mutation heteroplasmy correlated with the disease phenotype in five family members. An additional assembly intermediate of complex V and increased amount of subcomplex F1 were observed in myoblasts of the two patients, but the total amount of complex V was unaffected. Furthermore, intracellular ATP concentration was lower in patient myoblasts indicating defective energy production. We suggest that the m.8561C>G mutation in MT-ATP6/8 is pathogenic, leads biochemically to impaired assembly and decreased ATP production of complex V, and results clinically in a phenotype with the core features of cerebellar ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism. PMID- 27502084 TI - Sir William Withey Gull (1816-1890). PMID- 27502085 TI - Diagnostic accuracy of nerve ultrasound in hereditary and sporadic non-entrapment neuropathies. AB - The objective of this study is to compare the diagnostic accuracy of nerve ultrasound (US) and nerve conduction studies (NCS) for acquired non-entrapment peripheral neuropathies (PNP) and hereditary motor and sensory neuropathies (HMSN) in a routine clinical setting. The methods are based on a single-center, prospective, examiner-blinded cross-sectional study on three subject groups of healthy controls, PNP (both enrolled by a consecutive recruitment strategy), and HMSN patients (convenience sample). A clinical reference standard based on the neuropathy impairment (NIS) and neuropathy symptoms scores (NSS) was used for PNP as the external validation criterion. Diagnostic accuracy was assessed by receiver-operating curve (ROC) analyses of single-nerve measurements and logit models. Of a total of 676 consecutively screened subjects, 107 (15.8 %) were recruited, of which 36 (33.6 %) had a PNP. HMSN group consisted of 53 subjects (30 subjects (56.6 %) with genetic confirmation). AUCs of best diagnostic logit models to distinguish between controls and PNP patients were 0.86 for US and 0.97 for NCS corresponding to an equivalent specificity [US 93 % (95 % CI: 83-98 %), NCS 89 % (95 % CI: 78-95 %)], but inferior sensitivity of US [US 56 % (95 % CI: 35-74 %), NCS 97 % (95 % CI: 84-100 %)]. For differentiation between PNP and HMSN, both methods had equivalent AUCs of 0.95 corresponding to similar sensitivities/specificities. Simpler diagnostic models based on measurement protocols feasible for clinical routine revealed similar diagnostic accuracies. US has an inferior sensitivity than NCS for acquired PNP, but comparable specificity. For identification of HMSN in a PNP population, US and NCS show comparable performance. PMID- 27502086 TI - Spinocerebellar ataxia type 3 in Israel: phenotype and genotype of a Jew Yemenite subpopulation. AB - Spinocerebellar ataxia type 3 is an autosomal dominant ataxia with various phenotypes affecting Jews of Yemenite origin in Israel. Clinical and family pedigrees data of 125 Yemenite Jewish patients were collected in our clinic. All examined patients underwent a detailed neurological and bedside vestibular examination. Cytosine-adenine-guanine repeats size in the Ataxin-3 gene was measured, and patients with expanded cytosine-adenine-guanine repeats >44 were diagnosed genetically as having spinocerebellar ataxia type 3. We estimated a disease prevalence rate of about 29/100,000 in Jew of Yemenite descendents living in Israel. We were able to group patients into 17 families. Mean age of onset was 44 years. 74 % of our population expressed neurological signs compatible with sub phenotype III, i.e., ataxia and polyneuropathy. Vestibulo-ocular reflex deficit detected on bedside examination was found in 90 % of the patients. The mean number of cytosine-adenine-guanine repeats in the Ataxin-3 gene of the diseased allele was 67 (range 55-76). Age of onset was inversely correlated with the number of cytosine-adenine-guanine repeats (r = -0.7) and was significantly earlier among male patients. Though the mean number of cytosine-adenine-guanine repeats was not larger in the offspring, their age of onset was significantly earlier than that of their parents. In addition, paternal offspring expressed the disease significantly earlier than maternal offspring. Signs and stages of disease seem to progress slower during the first 10-15 years of the disease and faster afterward. A high disease prevalence rate in our Yemenite Jewish subpopulation is similar to that found in other isolated populations in other countries. Vestibulo-ocular reflex deficit detected on bedside examination should be added as part of the phenotype of Yemenite Jewish patients. Our clinical and genetic findings are in partial agreement with other spinocerebellar ataxia type 3 population studies and are relevant to patient management and the design of further studies. PMID- 27502087 TI - Bilateral nevus comedonicus of the eyelids associated with bladder cancer and successful treatment with topical tretinoin. PMID- 27502088 TI - Influence of alterations in heart rate on left ventricular echocardiographic measurements in healthy cats. AB - Objectives The purpose of this study was to evaluate the effect of sudden alterations in heart rate (HR) on left ventricular (LV) wall thickness and dimensions determined by echocardiography in healthy cats. Methods Six experimental cats were used. All cats were anaesthetised and HR was controlled with right atrial pacing. The interventricular septum and left ventricular free wall thickness at end diastole (IVSd and LVFWd, respectively), left ventricular end-diastolic and end-systolic diameter (LVIDd and LVIDs, respectively) and shortening fraction (FS) of each cat were assessed using echocardiography at pacing rates of 120, 130, 140, 150, 160, 170 and 180 ppm. Results There were significant relationships between HR and IVSd, LVFWd, LVIDd, LVIDs and FS. As the HR increased, LV wall thickness increased and chamber dimensions got smaller in a linear fashion. The maximum and minimum differences in wall thickness between 120 ppm and 180 ppm were 2.0 mm and 0.7 mm in single measurements, respectively. Conclusions and relevance LV wall thickness and dimensions were significantly influenced by alterations in HR. PMID- 27502089 TI - Molecular characterisation of parvoviruses from domestic cats reveals emergence of newer variants in India. AB - Objectives The present study was undertaken to characterise the viral polypeptide 2 (VP2) gene of parvovirus from domestic cats in India. Methods The faecal samples from diarrhoeic/healthy domestic cats were collected from different geographical regions of India for screening by PCR assay followed by sequence analysis of the VP2 gene. Results Canine parvovirus (CPV)/feline panleukopenia virus (FPV) infections were found in 12 (11.3%) of 106 faecal samples tested. Two new CPV-2a (297Ala and Asn426) and three FPV strains were identified by VP2 gene analysis. Several unique and existing amino acid mutations were found, suggesting continuous evolution and emergence of newer variants. The phylogenetic analysis of the CPV sequences revealed that the two new CPV-2a strains from Mumbai (MC8) and Puducherry (P15) were clustered together in a single clade but had evolved independently and were ancestrally related to Chinese CPV-2a isolates. The FPV sequences (T-C-6 and T-C-1) from Thrissur, Kerala, formed a different clade (FPV clade) and were closely related to each other and had an ancestral relationship with an FPV isolate from the USA. Another FPV isolate from Goa (GC1) was positioned in the same clade but had evolved independently. Conclusions and relevance Detection of CPV in both diarrhoeic/healthy cats and the occurrence of FPV infection in a vaccinated cat provide new insights into parvovirus infections in cats in India. PMID- 27502090 TI - Full-Term Small-for-Gestational-Age Newborns in the U.S.: Characteristics, Trends, and Morbidity. AB - Objectives The magnitude, characteristics, and morbidity of term (>=37 weeks gestation) newborns that are small-for-gestational-age (SGA) in the U.S. are underexplored. We sought to examine characteristics and trends for SGA-coded term newborns in the U.S. Methods Data were obtained from the Nationwide Inpatient Sample, a nationally representative database of hospital stays in the U.S. from 2002 to 2011. Term, singleton newborns with SGA codes were identified and examined over the study period. Demographic characteristics were compared for term newborns according to presence of SGA codes using chi2 tests. Odds ratios (OR) were calculated to compare morbidities between the two groups, adjusting for relevant demographic and clinical variables. Results In 2011, 15 per 1000 term newborns in the U.S. were coded as SGA, a 29.9 % increase since 2002. Compared with other term newborns, SGA term newborns were significantly (p < 0.05) more likely to be female, receive public insurance, and reside in lower income zip codes. Comorbidities, including perinatal complications, metabolic disorders, central nervous system diseases, infection, and neonatal abstinence syndrome were more common among SGA-coded term newborns. These newborns also had higher odds of in-hospital death (OR = 3.0 95 % confidence interval: 2.0, 4.4), longer mean length of stay (3.7 vs. 2.3 days, p < 0.001), and higher mean hospital charges ($12,621 vs. $5012, p < 0.001). Conclusions for practice Term newborns coded as SGA have higher morbidity, mortality, and incur higher hospital charges than other term newborns. More research is needed to understand causes of SGA so its incidence and effects can be reduced. PMID- 27502091 TI - Treatment of Childhood Acute Lymphoblastic Leukemia: Prognostic Factors and Clinical Advances. AB - While the majority of children and adolescents with newly diagnosed childhood acute lymphoblastic leukemia (ALL) will be cured, as many as 20 % of patients will experience relapse. On current treatment regimens, the intensity of upfront treatment is stratified based upon prognostic factors with the aim of improving cure rates (for those at the highest risk of relapse) and minimizing treatment related morbidity (for lower-risk patients). Here we review advances in the understanding of prognostic factors and their application. We also highlight novel treatment approaches aimed at improving outcomes in childhood ALL. PMID- 27502093 TI - Editors' Notes. PMID- 27502094 TI - Setting the Stage: The Intersection of Leadership and Assessment. AB - This chapter provides an overview of leadership and assessment and addresses the complexity of assessing leadership. PMID- 27502092 TI - Improving Prognostic Modeling in Myelodysplastic Syndromes. AB - Myelodysplastic syndromes (MDSs) are a heterogeneous group of disorders characterized by the accumulation of complex genetic alterations that drive disease pathogenesis and outcome. Several prognostic models have been developed over the last two decades to risk stratify patients with MDS. These models mainly used clinical variables including blast percentage, cytopenias, cytogenetics, transfusion dependency, and age. Recently, somatic mutations in specific genes have been shown to impact overall survival in MDS and can be incorporated into established prognostic models to improve their predictive abilities. Here, we review the advantages and disadvantages of established prognostic models in MDS and the impact of emerging data regarding the incorporation of somatic mutations in risk stratification. PMID- 27502095 TI - Developing a Comprehensive Assessment Plan. AB - This chapter provides practical advice for developing a comprehensive assessment plan. Two examples from institutions that have created both individual and program-level assessment plans for leadership programs are shared. PMID- 27502096 TI - Exploring the Language of Leadership Learning and Education. AB - This chapter examines the importance of language in the emerging field of leadership, especially when establishing and maintaining partnerships and when designing pedagogical practices for leadership learning. PMID- 27502097 TI - Assessing Student Leadership Competency Development. AB - Many mission statements include language focusing on the institutional commitment to develop student leaders who will affect their communities and professions upon graduation. This chapter explores how institutions can ensure that elements of the experience are factors in a student's leadership development. PMID- 27502098 TI - Assessing Leadership Using National Assessment Tools. AB - Determining the appropriate use of national or multicampus leadership assessments requires careful consideration of program goals and resources. This chapter explores quantitative dimensions of assessing leadership. PMID- 27502099 TI - Carts Before Horses? Remembering the Primacy of the Student's Experience in Student Learning. AB - This chapter makes a case for employing qualitative methodologies in the assessment of student leadership programs. Frameworks for reflective practice are discussed. PMID- 27502100 TI - Leadership Assessment from an Institutional Approach. AB - This chapter provides information about linking undergraduates' leadership development assessment to institutional student learning outcomes illustrated by a case example at the University of Minnesota. PMID- 27502102 TI - [Not Available]. PMID- 27502101 TI - Breast pumps as an incentive for breastfeeding: a mixed methods study of acceptability. AB - Increasing breastfeeding rates would improve maternal and child health, but multiple barriers to breastfeeding persist. Breast pump provision has been used as an incentive for breastfeeding, although effectiveness is unclear. Women's use of breast pumps is increasing and a high proportion of mothers express breastmilk. No research has yet reported women's and health professionals' perspectives on breast pumps as an incentive for breastfeeding. In the Benefits of Incentives for Breastfeeding and Smoking cessation in pregnancy (BIBS) study, mixed methods research explored women's and professionals' views of breast pumps as an incentive for breastfeeding. A survey of health professionals across Scotland and North West England measured agreement with 'a breast pump costing around L40 provided for free on the NHS' as an incentive strategy. Qualitative interviews and focus groups were conducted in two UK regions with a total of 68 participants (pregnant women, new mothers, and their significant others and health professionals) and thematic analysis undertaken. The survey of 497 health professionals found net agreement of 67.8% (337/497) with the breast pump incentive strategy, with no predictors of agreement shown by a multiple ordered logistic regression model. Qualitative research found interrelated themes of the 'appeal and value of breast pumps', 'sharing the load', 'perceived benefits', 'perceived risks' and issues related to 'timing'. Qualitative participants expressed mixed views on the acceptability of breast pumps as an incentive for breastfeeding. Understanding the mechanisms of action for pump type, timing and additional support required for effectiveness is required to underpin trials of breast pump provision as an incentive for improving breastfeeding outcomes. (c) 2016 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd. PMID- 27502103 TI - Bosentan as Adjunctive Therapy for Persistent Pulmonary Hypertension of the Newborn: Results of the Randomized Multicenter Placebo-Controlled Exploratory Trial. AB - OBJECTIVE: To evaluate the efficacy, safety, and pharmacokinetics of the endothelin receptor antagonist bosentan as adjunctive therapy for neonates with persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: This was a phase 3, multicenter, randomized, placebo-controlled exploratory trial (FUTURE 4). Eligible patients were >34 weeks gestation, <7 days old, receiving inhaled nitric oxide (iNO) treatment (>=4 hours), and had persistent respiratory failure (oxygenation index [OI] >=12). After 2:1 randomization, bosentan 2 mg/kg or placebo was given by nasogastric tube twice daily for >=48 hours and up to 1 day after iNO weaning. RESULTS: Twenty-one neonates received a study drug (13 bosentan, 8 placebo). Compared with the placebo group, the group treated with bosentan had a higher median baseline OI and greater need for vasoactive agents. One treatment failure (need for extracorporeal membrane oxygenation) occurred in the group treated with bosentan. The time to weaning from iNO or mechanical ventilation was not different between the groups. Bosentan was well tolerated and did not adversely affect systemic blood pressure or hepatic transaminase levels. Anemia and edema were more frequent in patients receiving bosentan. Blood concentrations of bosentan were low and variable on day 1, and achieved steady state on day 5. CONCLUSION: Adjunctive bosentan was well tolerated, but did not improve oxygenation or other outcomes in our patients with PPHN. This effect may be related to delayed absorption of bosentan on treatment initiation in critically ill neonates or to more severe illness of the neonates who received bosentan. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01389856. PMID- 27502104 TI - Clinical Presentation of Pediatric Patients at Risk for Sudden Cardiac Arrest. AB - OBJECTIVES: To identify the clinical presentation of children and adolescents affected by 1 of 4 cardiac conditions predisposing to sudden cardiac arrest: hypertrophic cardiomyopathy, long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and anomalous origin of the left coronary artery from the right sinus of Valsalva (ALCA-R). STUDY DESIGN: This was a retrospective review of newly diagnosed pediatric patients with hypertrophic cardiomyopathy, LQTS, CPVT, and ALCA-R referred for cardiac evaluation at 6 US centers from 2008 to 2014. RESULTS: A total of 450 patients (257 male/193 female; median age 10.1 years [3.6-13.8 years, 25th-75th percentiles]) were enrolled. Patient age was <=13 years for 70.4% of the cohort (n = 317). Sudden cardiac arrest was the initial presentation in 7%; others were referred on the basis of abnormal or suspicious family history, personal symptoms, or physical findings. Patients with LQTS and hypertrophic cardiomyopathy were referred most commonly because of family history concerns. ALCA-R was most likely to have abnormal signs or symptoms (eg, exercise chest pain, syncope, or sudden cardiac arrest). Patients with CPVT had a high incidence of syncope and the greatest incidence of sudden cardiac arrest (45%); 77% exhibited exercise syncope or sudden cardiac arrest. This study demonstrated that suspicious or known family history plays a role in identification of many patients ultimately affected by 1 of the 3 genetic disorders (hypertrophic cardiomyopathy, LQTS, CPVT). CONCLUSION: Important patient and family history and physical examination findings may allow medical providers to identify many pediatric patients affected by 4 cardiac disorders predisposing to sudden cardiac arrest. PMID- 27502105 TI - Social Emotional Factors Increase Risk of Postpartum Depression in Mothers of Preterm Infants. AB - OBJECTIVE: To examine the association of maternal mental health, perceptions of readiness at neonatal intensive care unit (NICU) discharge, and social risk factors with depressive symptoms 1 month postdischarge in mothers of early (<32 weeks), moderate (32-33 weeks), and late (34-36 weeks) preterm infants. A secondary objective was to compare depressive symptoms among mothers in all preterm groups. STUDY DESIGN: Mothers (n = 734) of preterm infants cared for >5 days in the NICU and participating in a Transition Home Program completed the Fragile Infant Parent Readiness Evaluation prior to discharge for perceptions of NICU staff support, infant well-being, maternal well-being (emotional readiness/competency), and maternal comfort (worry about infant). Mental health history and social risk factors were obtained. At 1 month postdischarge the Edinburgh Postnatal Depression Scale was administered. Group comparisons and logistic regression analyses were run to predict possible depression (Edinburgh Postnatal Depression Scale >=10). RESULTS: Mothers of early, moderate, and late preterm infants reported similar rates of possible depression (20%, 22%, and 18%, respectively) 1 month after NICU discharge. History of mental health disorder, decreased perception of maternal well-being, decreased maternal comfort regarding infant, and decreased perception of family cohesion were associated with possible depression at 1 month postdischarge. CONCLUSIONS: Mothers with a previous mental health disorder and experiencing negative perceptions of self and infant at NICU discharge were at increased risk for depressive symptomatology 1 month postdischarge regardless of infant gestational age. Comprehensive mental health assessment prior to discharge is essential to identify women at risk and provide appropriate referral. PMID- 27502106 TI - Comparative analyses within Gyrodactylus (Platyhelminthes: Monogenea) mitochondrial genomes and conserved polymerase chain reaction primers for gyrodactylid mitochondrial DNA. AB - In this study, we describe the complete mitochondrial genomes of Gyrodactylus brachymystacis and Gyrodactylus parvae infecting rainbow trout (Oncorhynchus mykiss) and the invasive topmouth gudgeon (Pseudorasbora parva), respectively. The two circular genomes have a common genome organization found in other Gyrodactylus species. Comparative analyses of mitochondrial genomes from six Gyrodactylus species were carried out to determine base composition, codon usage, transfer RNA and ribosomal RNA genes, major non-coding regions, and nucleotide diversity within the genus. We also provide the first universal models of the secondary structures of rrnS and rrnL for this group thereby promoting utilization of these genetic markers. Universal primers provided herein can be used to obtain more mitochondrial information for pathogen identification and may reveal different levels of molecular phylogenetic inferences for this lineage. PMID- 27502107 TI - A simultaneous assessment metric for MAb quantity and glycan quality. AB - As a critical quality attribute, glycosylation represents an important consideration when analyzing the success of a glycoprotein production process. Though critical, glycosylation is not the only measure of culture success; other factors, including culture size, maintenance, and productivity, are also critical. A new metric was developed to address both product quality, as measured through glycosylation, and product quantity, as measured through product concentration. A monoclonal antibody Chinese hamster ovary cell culture model system was used to assess this metric across various media formulations. In a model test system, the metric discriminated that some media supplements had a net positive impact on productivity and glycosylation, while others had a net negative impact on productivity and glycosylation. PMID- 27502108 TI - Role of anthropometric factors, self-perception, and diet on weight misperception among young adolescents: a cross-sectional study. AB - PURPOSE: Adolescence overweight and obesity have increased considerably, and the misperception of their weight status could reduce the efficiency of intervention programs. The aim of this study was to evaluate the prevalence rate of misperception and to assess the relationship between weight perception and anthropometric parameters, self-perception, physical activity, and adherence to the Mediterranean diet. METHODS: A total of 1643 young adolescents (11-16 years old) were surveyed in a cross-sectional investigation during two scholastic years (period October-May of 2012-2013 and 2013-2014) in 15 secondary schools of Sicily, southern Italy. Data on demographic information, anthropometric characteristics (bioelectrical impedance), physical activity level, The Children and Youth Physical Self-Perception Profile, weight perception, and dietary habits (KIDMED) were collected. RESULTS: Misperception was found in the 27.6 % of the young adolescents, and boys were more likely to underestimate their weight status, while girls had a high percentage of overestimation. The strong association with weight misperception was with socioeconomic status, waist circumference, physical activities, and physical self-worth. Moreover, a good adherence to the Mediterranean diet was inversely associated with both overestimation and underestimation in both boys and girls. CONCLUSION: These findings highlight that almost one-third of the participants had a weight misperception that was associated with several anthropometric, social, and lifestyle factors. Future intervention to prevent overweight and obesity should consider not only gender-specific differences, but also parental SES, perception, and satisfaction of body weight status. PMID- 27502109 TI - Implementation of Methodology for Quality Improvement in Pediatric Cardiac Catheterization: A Multi-center Initiative by the Congenital Cardiac Catheterization Project on Outcomes-Quality Improvement (C3PO-QI). AB - The Congenital Cardiac Catheterization Project on Outcomes (C3PO) launched in 2007 as a multi-center collaborative to establish standardized and comparable metrics for pediatric cardiac catheterization procedures. The limitations of larger registries at the time led to the development of the next phase in 2013, C3PO-Quality Improvement (C3PO-QI), focusing on instituting QI initiatives within the field. The objective of this manuscript is to provide a detailed overview of C3PO-QI and report data on case characteristics and outcome metrics being explored. C3PO-QI was designed to cultivate institutional collaboration during implementation of its initiatives. A database and website were developed to support data entry and on-demand reporting. The registry prospectively captures pediatric cardiac catheterization data among 15 hospitals. The present study includes case demographic data (n) and quality metric reporting by case type, age, and radiation dose variables. This dataset includes 13,135 cases entered into the database between 1/1/2014 and 12/31/2015. Interventional cases make up the highest percentage by case mix distribution (48 %), and patients <1 years make up the highest percentage by age distribution (26 %). The ratio of diagnostic and interventional procedures performed changes by age group. Application of QI metric shows all procedure types surpassing metric goals. Large volume data collection, such as in C3PO-QI, allows for meaningful interpretation of data. C3PO-QI is uniquely poised to deliver fast-paced changes in the field. Although the project initiatives are specific to pediatric cardiac catheterization, the implementation of the project and utilization of real-time reporting is generalizable to other specialties and multi-center collaboratives. PMID- 27502111 TI - Evaluation of site-specific tactics using bifenazate and Neoseiulus californicus for management of Tetranychus urticae (Acari: Tetranychidae) in strawberries. AB - Greenhouse and field experiments were conducted to evaluate the effectiveness of site-specific tactics for management of the twospotted spider mite, Tetranychus urticae Koch, a major pest of greenhouse and field-grown strawberries (Fragaria x ananassa Duchesne). Two site-specific (spot) treatments, the miticide bifenazate (Acramite((r))) and the predatory mite Neoseiulus californicus McGregor, were compared with whole-plot treatments of bifenazate or N. californicus to determine whether T. urticae could be effectively managed in field-grown strawberry using only site-specific tactics. Additionally, the cost of site-specific tactics was compared with whole-plot treatments to determine the economic value of using site specific management tactics for T. urticae in strawberries. In the greenhouse, all treatments equivalently reduced the number of T. urticae below control. In the field during the 2011-2012 season, more T. urticae eggs and motiles were in the whole-plot treatments of both N. californicus and bifenazate in the mid season and late season, respectively, compared with the spot treatments. With the exception of site-specific N. californicus during the 2011-2012 field season, there were no differences in marketable yields between plots with site-specific treatments and whole-plot management. An economic analysis demonstrated a significant cost savings (75.3 %) with site-specific treatments of N. californicus compared with whole-plot application of N. californicus. Similarly, a 24.7 % reduction in cost was achieved in using site-specific bifenazate compared with whole-plot application of bifenazate. The findings indicate that site-specific treatments with N. californicus and bifenazate are competitive alternatives to whole-field application for T. urticae management in strawberries. PMID- 27502110 TI - Synergistic effects of baicalein with cefotaxime against Klebsiella pneumoniae through inhibiting CTX-M-1 gene expression. AB - BACKGROUND: Generation of extended- spectrum beta- lactamases is one of the major mechanisms by which clinical Klebsiella pneumoniae develop resistance to antibiotics. Combined antibiotics prove to be a relatively effective method of controlling such resistant strains. Some of Chinese herbal active ingredients are known to have synergistic antibacterial effects. This study is aimed to investigate synergistic effects of Chinese herbal active ingredients with cefotaxime on the extended- spectrum beta- lactamase positive strains of Klebsiella pneumoniae, and to analyze mechanism of synergistic action, providing experimental evidence for clinical application of antimicrobial drugs. RESULTS: For total sixteen strains including fifteen strains of cefotaxime resistant K. pneumoniae and one extended- spectrum beta- lactamase positive standard strain, the synergy rates of cefotaxime with baicalein, matrine, and clavulanic acid were 56.3 %, 0 %, and 100 %, respectively. The fractional inhibitory concentration index of combined baicalein and cefotaxime was correlated with the percentage decrease of cefotaxime MIC of all the strains (r = -0.78, p <0.01). In the group of synergy baicalein and cefotaxime, the transcribed mRNA level of CTX-M-1 after treatment of baicalein was decreased significantly (p <0.05). Moreover, the CTX-M 1 mRNA expression percentage inhibition (100 %, 5/5) was significantly higher than non- synergy group (25 %, 1/4) (p <0.05). CONCLUSIONS: Our study demonstrated that baicalein exhibited synergistic activity when combined with cefotaxime against some of extended- spectrum beta- lactamases positive K. pneumoniae strains by inhibiting CTX-M-1 mRNA expression. However, no direct bactericidal or bacteriostatic activity was involved in the synergistic action. Baicalein seems to be a promising novel effective synergistic antimicrobial agent. PMID- 27502112 TI - Glyphosate sub-lethal toxicity to non-target organisms occurring in Jatropha curcas plantations in Brazil. AB - Weed management in physic nut plantations has generally been performed by spraying the herbicide glyphosate. However, the effects of glyphosate on non target organisms present in the crop system are unknown. Here, we evaluated the toxicity of glyphosate (Roundup Transorb((r))) against the pest species Polyphagotarsonemus latus (Acari: Tarsonemidae) and Tetranychus bastosi (Acari: Tetranychidae) which can be exposed by drift. These mites are considered pests of the physic nut; however, they can also feed and reside on weeds associated with the crop, serving as food sources for predatory mites. When subjected to residue (by ingestion of sap of treated plants), and direct contact to glyphosate, P. latus reproduction was affected but T. bastosi was affected only by the residual effect. Although the herbicide caused a reduction in the number of eggs laid by the females of both pest mites, it is suggested that sublethal effects of glyphosate stimulates oviposition of P. latus and T. bastosi: both species displayed higher reproductive rates when exposed to 0.36 kg ha(-1) of the herbicide. We conclude that glyphosate negatively affects the arthropod herbivores studied and we discuss possible implications on their biological control in Jatropha curcas plantations. PMID- 27502114 TI - Suboral fork: a newly discerned gnathosomal structure from the proboscis of eriophyoid mites (Acari, Eriophyoidea). AB - The infracapitulum of eriophyoid mites comprises a cone-like basal infracapitulum, containing a pharynx, and a distal infracapitulum, forming a proboscis ensheathing a bunch of stylets. A well-developed basal labral section was observed in all studied specimens. A newly discerned structure, the suboral fork, situated in the ventral part of the proboscis was discovered. It is larger in diptilomiopids and Nalepella and notably smaller in eriophyids and phytoptids. This structure presumably determines the site of piercing and functions in a similar way to the pressure foot of a sewing machine which controls the movements of a needle. In diptilomiopids the suboral fork might have an additional function: it is a stopper which prevents the proboscis from further penetrating into plant tissues. It is possible that the suboral fork is homologous with the labium of early derivative acariform mites. The proboscis might be a fusion product of the infracapitular lateral lips, malapophyses and the labium. The proboscis serves as a feeding structure in eriophyoids; two ways of sucking plant cell sap, depending on shapes of proboscis and labrum, are hypothesized. Further work is needed to draw conclusions on homologies and the function of all gnathosomal structures in eriophyoids. PMID- 27502113 TI - Detection and localization of Solitalea-like and Cardinium bacteria in three Acarus siro populations (Astigmata: Acaridae). AB - Bacteria associated with mites influence their fitness, nutrition and reproduction. Previously, we found Solitalea-like (Sphingobacteriales) and Candidatus Cardinium (Cytophagales) bacteria in the stored product mite Acarus siro L. by cloning and using pyrosequencing. In this study, taxon-specific primers targeting 16S rRNA gene were used to detect and quantify the bacteria in mites and eggs of three A. siro populations. The specific probes for fluorescent in situ hybridization (FISH) were used to localize Solitalea-like and Cardinium bacteria in mite bodies. The population growth as an indirect estimator of fitness was used to describe the mite-bacteria interactions on (1) control diet; (2) rifampicin supplemented diet; (3) tetracycline supplemented diet; (4) rifampicin pretreated mites; (5) tetracycline pretreated mites. Solitalea-like 16S rRNA gene sequences from A. siro formed a separate cluster together with sequences from Tyrophagus putrescentiae. qPCR analysis indicated that number of Solitalea-like bacteria 16S rRNA gene copies was ca. 100* higher than that of Cardinium and the numbers differed between populations. FISH analysis localized Solitalea-like bacteria in the parenchymal tissues, mesodeum and food bolus of larvae, nymphs and adults. Solitalea-like, but not Cardinium bacteria were detected by taxon-specific primers in mites and eggs of all three investigated populations. None of the antibiotic treatments eliminated Solitalea-like bacteria in the A. siro populations tested. Rifampicin pretreatment significantly decreased the population growth. The numbers of Solitalea-like bacteria did not correlate with the population growth as a fitness indicator. This study demonstrated that A. siro can host Solitalea-like bacteria either alone or together with Cardinium. We suggest that Solitalea-like bacteria are shared by vertical transfer in A. siro populations. PMID- 27502115 TI - Editorial (Thematic Issue: What's Behind the Sex Gap in Cardiovascular Mortality?). PMID- 27502116 TI - A high titre of autoantibody at onset does not predict pancreatic beta-cell fate. PMID- 27502117 TI - Type A personality is not associated with poor glycaemic control: Data from cross sectional and longitudinal surveys of people with type 1 or type 2 diabetes. PMID- 27502120 TI - Editorial note. PMID- 27502118 TI - Aromatase inhibition remodels the clonal architecture of estrogen-receptor positive breast cancers. AB - Resistance to oestrogen-deprivation therapy is common in oestrogen-receptor positive (ER+) breast cancer. To better understand the contributions of tumour heterogeneity and evolution to resistance, here we perform comprehensive genomic characterization of 22 primary tumours sampled before and after 4 months of neoadjuvant aromatase inhibitor (NAI) treatment. Comparing whole-genome sequencing of tumour/normal pairs from the two time points, with coincident tumour RNA sequencing, reveals widespread spatial and temporal heterogeneity, with marked remodelling of the clonal landscape in response to NAI. Two cases have genomic evidence of two independent tumours, most obviously an ER- 'collision tumour', which was only detected after NAI treatment of baseline ER+ disease. Many mutations are newly detected or enriched post treatment, including two ligand-binding domain mutations in ESR1. The observed clonal complexity of the ER+ breast cancer genome suggests that precision medicine approaches based on genomic analysis of a single specimen are likely insufficient to capture all clinically significant information. PMID- 27502119 TI - Study design of PANGAEA 2.0, a non-interventional study on RRMS patients to be switched to fingolimod. AB - BACKGROUND: The therapeutic options for patients with Multiple Sclerosis (MS) have steadily increased due to the approval of new substances that now supplement traditional first-line agents, demanding a paradigm shift in the assessment of disease activity and treatment response in clinical routine. Here, we report the study design of PANGAEA 2.0 (Post-Authorization Non-interventional GermAn treatment benefit study of GilEnyA in MS patients), a non-interventional study in patients with relapsing-remitting MS (RRMS) identify patients with disease activity and monitor their disease course after treatment switch to fingolimod (Gilenya(r)), an oral medication approved for patients with highly active RRMS. METHOD/DESIGN: In the first phase of the PANGAEA 2.0 study the disease activity status of patients receiving a disease-modifying therapy (DMT) is evaluated in order to identify patients at risk of disease progression. This evaluation is based on outcome parameters for both clinical disease activity and magnetic resonance imaging (MRI), and subclinical measures, describing disease activity from the physician's and the patient's perspective. In the second phase of the study, 1500 RRMS patients identified as being non-responders and switched to fingolimod (oral, 0.5 mg/daily) are followed-up for 3 years. Data on relapse activity, disability progression, MRI lesions, and brain volume loss will be assessed in accordance to 'no evidence of disease activity-4' (NEDA-4). The modified Rio score, currently validated for the evaluation of treatment response to interferons, will be used to evaluate the treatment response to fingolimod. The MS management software MSDS3D will guide physicians through the complex processes of diagnosis and treatment. A sub-study further analyzes the benefits of a standardized quantitative evaluation of routine MRI scans by a central reading facility. PANGAEA 2.0 is being conducted between June 2015 and December 2019 in 350 neurological practices and centers in Germany, including 100 centers participating in the sub-study. DISCUSSION: PANGAEA 2.0 will not only evaluate the long-term benefit of a treatment change to fingolimod but also the applicability of new concepts of data acquisition, assessment of MS disease activity and evaluation of treatment response for the in clinical routine. TRIAL REGISTRATION: BfArM6532; Trial Registration Date: 20/05/2015. PMID- 27502122 TI - Freedom from long DAPT signals the demise of the bare-metal stent. PMID- 27502121 TI - Regional and ethnic differences among patients with heart failure in Asia: the Asian sudden cardiac death in heart failure registry. AB - AIMS: To characterize regional and ethnic differences in heart failure (HF) across Asia. METHODS AND RESULTS: We prospectively studied 5276 patients with stable HF and reduced ejection fraction (<=40%) from 11 Asian regions (China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Taiwan, and Thailand). Mean age was 59.6 +/- 13.1 years, 78.2% were men, and mean body mass index was 24.9 +/- 5.1 kg/m2. Majority (64%) of patients had two or more comorbid conditions such as hypertension (51.9%), coronary artery disease (CAD, 50.2%), or diabetes (40.4%). The prevalence of CAD was highest in Southeast Asians (58.8 vs. 38.2% in Northeast Asians). Compared with Chinese ethnicity, Malays (adjusted odds ratio [OR] 1.97, 95% CI 1.63-2.38) and Indians (OR 1.44, 95% CI 1.24-1.68) had higher odds of CAD, whereas Koreans (OR 0.38, 95% CI 0.29 0.50) and Japanese (OR 0.44, 95% CI 0.36-0.55) had lower odds. The prevalence of hypertension and diabetes was highest in Southeast Asians (64.2 and 49.3%, respectively) and high-income regions (59.7 and 46.2%, respectively). There was significant interaction between ethnicity and region, where the adjusted odds were 3.95 (95% CI 2.51-6.21) for hypertension and 4.91 (95% CI 3.07-7.87) for diabetes among Indians from high- vs. low-income regions; and 2.60 (95% CI 1.66 4.06) for hypertension and 2.62 (95% CI 1.73-3.97) for diabetes among Malays from high- vs. low-income regions. CONCLUSIONS: These first prospective multi-national data from Asia highlight the significant heterogeneity among Asian patients with stable HF, and the important influence of both ethnicity and regional income level on patient characteristics. CLINICALTRIALSGOV IDENTIFIER: NCT01633398. PMID- 27502123 TI - Frontotemporal dementia: from molecular mechanisms to therapy. AB - Frontotemporal dementia (FTD) is a heterogeneous clinical syndrome characterized by frontotemporal lobar degeneration (FTLD). Neuropathologically, FTLD is characterized by abnormal protein deposits and almost all cases can now be classified into three major molecular subgroups based on specific accumulating proteins with the most common being FTLD-tau and FTLD-TDP (accounting for ~40% and 50%, respectively) and FTLD-FET (accounting for ~5-10%). In this special issue, the molecular and genetic basics as well as clinical approaches and therapeutics are reviewed in a series of articles. This article is part of the Frontotemporal Dementia special issue. PMID- 27502124 TI - Prion-like propagation as a pathogenic principle in frontotemporal dementia. AB - Frontotemporal dementia is a devastating neurodegenerative disease causing stark alterations in personality and language. Characterized by severe atrophy of the frontal and temporal brain lobes, frontotemporal dementia (FTD) shows extreme heterogeneity in clinical presentation, genetic causes, and pathological findings. Like most neurodegenerative diseases, the initial symptoms of FTD are subtle, but increase in severity over time, as the disease progresses. Clinical progression is paralleled by exacerbation of pathological findings and the involvement of broader brain regions, which currently lack mechanistic explanation. Yet, a flurry of studies indicate that protein aggregates accumulating in neurodegenerative diseases can act as propagating entities, amplifying their pathogenic conformation, in a way similar to infectious prions. In this prion-centric view, FTD can be divided into three subtypes, TDP-43 or FUS proteinopathy and tauopathy. Here, we review the current evidence that FTD-linked pathology propagates in a prion-like manner and discuss the implications of these findings for disease progression and heterogeneity. Frontotemporal dementia (FTD) is a progressive neurodegenerative disease causing severe personality dysfunctions, characterized by profound heterogeneity. Accumulation of tau, TDP 43 or FUS cytoplasmic aggregates characterize molecularly distinct and non overlapping FTD subtypes. Here, we discuss the current evidence suggesting that prion-like propagation and cell-to-cell spread of each of these cytoplasmic aggregates may underlie disease progression and heterogeneity. This article is part of the Frontotemporal Dementia special issue. PMID- 27502125 TI - Advances in neuroimaging in frontotemporal dementia. AB - Frontotemporal dementia (FTD) is a clinically and neuroanatomically heterogeneous neurodegenerative disorder with multiple underlying genetic and pathological causes. Whilst initial neuroimaging studies highlighted the presence of frontal and temporal lobe atrophy or hypometabolism as the unifying feature in patients with FTD, more detailed studies have revealed diverse patterns across individuals, with variable frontal or temporal predominance, differing degrees of asymmetry, and the involvement of other cortical areas including the insula and cingulate, as well as subcortical structures such as the basal ganglia and thalamus. Recent advances in novel imaging modalities including diffusion tensor imaging, resting-state functional magnetic resonance imaging and molecular positron emission tomography imaging allow the possibility of investigating alterations in structural and functional connectivity and the visualisation of pathological protein deposition. This review will cover the major imaging modalities currently used in research and clinical practice, focusing on the key insights they have provided into FTD, including the onset and evolution of pathological changes and also importantly their utility as biomarkers for disease detection and staging, differential diagnosis and measurement of disease progression. Validating neuroimaging biomarkers that are able to accomplish these tasks will be crucial for the ultimate goal of powering upcoming clinical trials by correctly stratifying patient enrolment and providing sensitive markers for evaluating the effects and efficacy of disease-modifying therapies. This review describes the key insights provided by research into the major neuroimaging modalities currently used in research and clinical practice, including what they tell us about the onset and evolution of FTD and how they may be used as biomarkers for disease detection and staging, differential diagnosis and measurement of disease progression. This article is part of the Frontotemporal Dementia special issue. PMID- 27502127 TI - [Future directions of cardiovascular surgery in China]. AB - The cardiovascular surgery in China has achieved great progress both on scale and technology though development over the past thirty years. However, the technical predominance of cardiovascular surgery in therapies for some diseases has been weakened, along with developments of new drugs and interventional technology. Besides, the change of doctor-patient relationship result from internet medical information service and less attraction of cardiovascular surgery discipline to talents bring certain challenge to the development of cardiovascular surgery. Currently, cardiovascular surgeons should practice the "patient first" principle, carry out individual customized treatment and precision therapy, absorb the advantages of other subjects like intervention and imaging in order to achieve technological breakthroughs, create new treatment technologies and models with smaller trauma and better outcome, establish heart team to provide patient oriented treatment. Besides, cardiovascular surgeons should improve knowledge system by learning related technology and science, become hybrid doctors of research. Cardiovascular surgeons should pay high attention to critical effect of research on the disciplinary development, carry out question and demand oriented clinical studies, change the medical practice by virtue of research achievements, direct the treatment for cardiovascular diseases, and finally provide better health service and rebuild the predominance of cardiovascular surgery. PMID- 27502126 TI - Sequence capture using RAD probes clarifies phylogenetic relationships and species boundaries in Primula sect. Auricula. AB - Species-rich evolutionary radiations are a common feature of mountain floras worldwide. However, the frequent lack of phylogenetic resolution in species-rich alpine plant groups hampers progress towards clarifying the causes of diversification in mountains. In this study, we use the largest plant group endemic to the European Alpine system, Primula sect. Auricula, as a model system. We employ a newly developed next-generation-sequencing protocol, involving sequence capture with RAD probes, and map reads to the reference genome of Primula veris to obtain DNA matrices with thousands of SNPs. We use these data rich matrices to infer phylogenetic relationships in Primula sect. Auricula and examine species delimitations in two taxonomically difficult subgroups: the clades formed by the close relatives of P. auricula and P. pedemontana, respectively. Our molecular dataset enables us to resolve most phylogenetic relationships in the group with strong support, and in particular to infer four well-supported clades within sect. Auricula. Our results support existing species delimitations for P. auricula, P. lutea, and P. subpyrenaica, while they suggest that the group formed by P. pedemontana and close relatives might need taxonomic revision. Finally, we discuss preliminary implications of these findings on the biogeographic history of Primula sect. Auricula. PMID- 27502128 TI - [Standardize the endovascular treatment for arteriosclerosis obliterans]. AB - Endovascular therapy has become the first-line strategy for most peripheral artery disease cases. Currently, many guidelines recommend endovascular therapy as the first choice for arteriosclerosis obliterans. Recently, drug-eluting stent and drug-coated balloon are available. The clinical outcomes have been greatly improved with the evolution of devices. However, the long-term outcomes of endovascular therapy for arteriosclerosis obliterans are still not satisfied. Many centers treat arteriosclerosis obliterans using endovascular therapy in appropriately. In this editorial, an evidence-based approach and some strategies will be discussed to standardize the endovascular treatment and improve the result of endovascular therapy for arteriosclerosis obliterans. PMID- 27502129 TI - [Transcatheter aortic valve replacement: the new era, new opportunity and new challenge of cardiac surgery]. AB - Conventional surgical aortic valve replacement is still the current "gold standard" in treatment of aortic valve disease, but part of the high-risk elder patients couldn't tolerate the surgical trauma. Now those people could receive timely and effective treatment with the application of transcatheter aortic valve replacement, and the related guidelines have been published in recent years. With its wide use in recent 10 years, different implantation systems, such as SAPIEN, CoreValve, Lotus, ACURATE neo, have been gradually improved and provened in several large clinical trials. Transfemoral, transapical and transaortic approaches are approved for the access and used according to different indications. Bleeding, vascular events, III grade atrioventricular block, coronary obstruction, valve malpositioning, valve degeneration are the major complications for this skill, but would be overcome with the improvement of the system. The transcather aortic valve replacement brings not only the opportunity to develop new treatment protocols, but the challenge for cardiac surgeons to learn new skills to control. PMID- 27502130 TI - [Thought on the techniques of totally thoracoscopic cardiac surgery]. AB - Minimally invasive surgery has become the guiding principle of the entire surgical treatment. In last 16 years, totally thoracoscopic cardiac surgery (TTCS) has developed rapidly, and achieved good results. However, there are obvious differences between the basic surgical techniques of TTCS and of conventional cardiac surgery. At present, there is still lack of standard and in sufficient evidence in the surgical techniques of TTCS. It requires professional and standardized training and evidence-based research on TTCS, including indication selection and procedure standardization, to improve the therapy level of TTCS further. PMID- 27502131 TI - [Analysis of endovascular treatment strategies on in-stent restenosis of femoropopliteal artery lesions]. AB - Over the last few years, the treatment of complex femoropopliteal lesions led to the increasing use of stents in this challenging anatomical area. Whereas in stent restenosis remains the Achilles' heel of stenting this segment, and leads to recurrent ischemia and repeated interventions. A majority of endovascular techniques have been evaluated to repair this complication, including plain balloon angioplasty, new stent deployment, cutting balloons but without satisfactory mid- and long-term results. More recently debulking and drug-eluting devices have been applied in femoropopliteal in-stent restenosis with promising results. And relining with a stent graft or drug-eluting stent of femoropopliteal in-stent restenosis can be considered in cases of stent fracture as this strategy has showed relatively optimal outcomes. The aim of this article is to analyze the evidence of those endovascular techniques for the treatment of femoropopliteal in stent restenosis. PMID- 27502132 TI - [Clinical experience of 2 543 cases of congenital heart diseases undergoing totally thoracoscopic cardiac surgery in a single center]. AB - OBJECTIVE: To summarize the experience of totally thoracoscopic cardiac surgical (TTCS) at congenital heart diseases (CHD) treatment. METHODS: From April 2000 to March 2016, 2 543 patients with CHD underwent TTCS in Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, including 957 male and 1 586 female patients. The age ranged from 0.5 to 66.0 years with a mean age of (21+/-18) years. The body weight ranged from 6 to 118 kg with a mean of (49+/-30) kg. Patients were diagnosed with echocardiography or transesophagel echocardiography as complex or complicated CHD which was unsuitable for percutaneous procedure. Surgical procedures were performed through 3 holes inserted at the right chest wall, and catheters were placed in the right femoral artery and vein to set up cardiopulmonary bypass.The ascending aorta was cross-clamped with long tailor-made forceps and the myocardium was protected by coronary perfusion with cold crystalloid(blood)cardioplegia. There were 787 cases (from January 2013 to December 2015) were selected to compare with 710 cases underwent conventional thoracotomy over the same period. Statistical analysis was performed by t test, t' test, rank-sum test, chi(2) test and Fisher exact test, respectively. RESULTS: The total death rate and the major complication rate of the operation were 0.35% (9/2 543) and 2.28% (58/2 543), respectively. All patients were followed up 1 to 190 months and the average follow-up time was (75+/-34) months. No residual shunt or obvious mitral/tricuspid regurgitation was observed, and the patients gained better cardiac function as level I to II (New York Heart Association classification). There was no significant difference in aorta clamp time, ICU stay, hospital cost, and surgical fatality rate between 787 patients underwent TTCS and 710 conventional thoracotomy. The cardiopulmonary bypass time ((31+/-20) minuets vs. (40+/-17) minuets, t'=9.407, P=0.001), operation time ((91+/-27) minuets vs. ( 102+/-64) minuets, t'=4.251, P=0.000), hospital stay ((5.3+/-2.2) d vs. (13.0+/-4.0) d, t'=45.463, P=0.000), postoperative drainage (M(QR): 33(17) ml vs. 121(53) ml, T=2.632, P=0.000) and major complications (7/787 vs. 23/710, chi(2)=10.49, P=0.001) were significantly reduced and no sternal deformation occurrence (0 vs. 192/710, chi(2)=244.10, P=0.000) in TTCS group. While the cost was higher in TTCS group ((24 000+/-400) yuan vs. (20 000+/-400) yuan, t=19.320, P=0.000). CONCLUSION: TTCS is feasible, safe, and minimal invasive for patients with CHD, resulting in quick recovery and good median-long term outcomes. PMID- 27502133 TI - [Transapical transcatheter aortic valve replacement for high risk elderly patients with predominant aortic incompetence]. AB - OBJECTIVES: To introduce the application of the J-ValveTM system in elderly patients with predominant aortic incompetence without significant valve calcification, and to evaluate its feasibility. METHODS: From April 2014 to July 2015, 33 cases of transapical implantation of J-ValveTM were performed in Department of Cardiac Surgery, Zhongshan Hospital, Fudan University. Sixteen of these patients were diagnosed as predominant aortic incompetence without significant valve calcification. There were 11 male and 5 female patients aged from 61 to 84 years, with a mean age of (76+/-6) years. All patients had symptoms of left ventricular dysfunction for at least 3 months. They were considered to be prohibitive for surgical valve replacement (logistic European system for cardiac operative risk evaluation: 22.2% to 44.4%, mean 27%+/-6% after evaluation by an interdisciplinary heart team. The J-ValveTM system was applied in transapical transcatheter aortic valve replacement for patients. The multi-slice CT was performed before discharge. Clinical evaluation including patients' history, symptoms and New York Heart Association classification and echocardiogram evaluation were performed before discharge, 1(st) month, 3(th) month and 12(th) month after the operation respectively. RESULTS: Implantations were successful in all patients. One patient died from moderate paravalvular leak which led to multi organ failure during the hospital stay. The mean time of postoperative hospital stay of the other 15 patients was (6.1+/-1.3) days. The 15 patients were followed by 174 to 410 days, with a median time of 188 days. Only two patients had trivial prosthetic valve incompetence, the other 13 patients had no prosthetic valve incompetence; two patients had no paravavular leak and the other 13 patients had paravavular leak of no more than moderate grade. There were no major complication or mortality during the follow-up. CONCLUSIONS: The transapical implantation of the J-ValveTM system in high risk elderly patients with predominant aortic incompetence is feasible.The early postoperative outcome is satisfactory. PMID- 27502134 TI - [Comparison of anterolateral minithoracotomy versus partial upper hemisternotomy in aortic valve replacement]. AB - OBJECTIVE: To compare the results of aortic valve replacement through anterolateral minithoracotomy (RT) and partial upper hemisternotomy (PS) approaches. METHODS: This was a retrospective, observational, cohort study of collected data on 297 patients undergoing isolated primary aortic valve replacement between July 2009 and March 2016 at Department of Cardiovascular Surgery, Zhongshan Hospital, Fudan University. There were 174 male and 123 female patients, aging from 15 to 73 years with a mean age of (51+/-13) years. Of these, 132 were performed through right RT and 165 through PS. Outcomes of the two groups were compared by t test, t' test, rank-sum test and chi(2) test, respectively. RESULTS: The overall in-hospital mortality was 1.7% (5/297), with no difference between the 2 groups (3.0%, 4/132 vs. 0.6%, 1/165, P=0.175 ). Patients in the RT group had longer cardiopulmonary bypass ((92+/-27) minutes vs. (76+/-18) minutes, t'=5.848, P=0.000)and crossclamping ((56+/-21) minutes vs. (43+/-12) minutes, t'=6.333, P=0.000)times. Three patients in the RT group and two patients required intraoperative conversion. Patients by way of RT was associated with a lower incidence of blood transfusions (20.4% vs. 39.4%, chi(2)=12.303, P=0.001) and less drainage (250 (307) ml vs. 570 (370) ml, Z=8.161, P=0.000). In addition, patients in RT group had a shorter postoperative length of stay (5(4) days vs. 9(10) days, Z=4.548, P=0.000). CONCLUSIONS: Aortic valve replacement via RT and PS are both safe and feasible. The approach through PS is associated with better exposure, more extensive indication for surgery, and more suitable to heart centers which intend to carry out miminally invasive aortic valve replacement. While, for an experienced surgeon, the approach through right RT is worthy of clinical selective application for patients concern more about good cosmetic result, and patients have faster recovery by avoid sternotomy through RT approach. PMID- 27502135 TI - [Clinical experience of 60 patients underwent three-dimensional video assisted thoracoscopic mitral valvuloplasty]. AB - OBJECTIVE: To summarize the clinical experience of 60 patients underwent three dimensional video assisted thoracoscopic mitral valvuloplasty. METHODS: Sixty patients were enrolled retrospectively from March 2014 to January 2016 in Department of Cardiacvascular Surgery, Guangdong Cardiovascular Institute. They underwent three-dimensional video assisted thoracoscopic mitral valvuloplasty. There were 37 male and 23 female patients. The range of age was 15 to 78 years (the median age was 47 years). The techniques of mitral valvuloplasty included chordae tendineae transplantation (53 patients), annuloplasty (58 patients), posterior leaflet resection (13 patients), anterior leaflet resection (2 patients), commissure resection (1 patient). Their information from charts were collected. The follow-up time was lasting 3 to 25 months by telephone or outpatient department interview. The data was analyzed via paired t test or Wilcoxon signed-rank test. RESULTS: Conversions to mitral valve replacement were performed for two patients. No patients underwent thoracotomy. The operation time was (213+/-37) minutes, cardiopulmonary bypass time was (129+/-31) minutes, aortic cross clamping time was (81+/-21) minutes. Postoperative hospital stay was (7+/-3) days. During follow-up period, there were no re-operation and no death. Mitral regurgitation level and New York Heart Association class were both improved (Z=-6.286, P=0.000, Z=-6.237, P=0.000), respectively. Besides, there was also no new atrial fibrillation patients. CONCLUSIONS: Not only does three dimensional video assisted thoracoscopic mitral valvuloplasty maintain the advantages of 2-Dimensional thoracoscopy, but also have the similar view of median thoracotomy. This technique showed promising clinical value in the future. PMID- 27502136 TI - [Clinical outcome of totally thoracoscopic cardiac surgery for mitral valve replacement: a series of 634 cases]. AB - OBJECTIVE: To summarize the clinical outcome of totally thoracoscopic cardiac surgery for mitral valve replacement. METHODS: Clinical data of 634 cases undergoing totally thoracoscopic cardiac surgery for mitral valve replacement from May 2004 to February 2016 in Department of Thoracoscopic Cardiacsurgery, Shanghai Yodak Cardiothoracic Hospital was analyzed retrospectively. There were 292 male and 342 female patients, aged from 17 to 68 years with a mean of (45+/ 13) years. All the 634 patients had moderate-severe mitral valve stenosis and (or) incompetence, 263 patients had moderate-severe tricuspid valve incompetence, 356 patients had atrial fibrillation, 46 patients had left atrium thrombosis. Cardiopulmonary bypass was established with right femoral artery and a single 2 stage venus cannula in the right atrium. The ascending aorta was cross-clamped and the myocardium was protected by coronary perfusion with cold crystalloid cardioplegia. Totally thoracoscopic mitral valve replacement were performed. RESULTS: Thirteen cases had incision expanded and 8 cases had conversions to sternotomy. Cardiopulmonary bypass and aortic cross-clamp time were (89+/-18) minutes and (51+/-12) minutes, respectively. Operation time was (3.1+/-1.2) hours. Mechanical ventilation time and intensive care unit stay were (17+/-6) hours and (27+/-8) hours, respectively. Postoperation drainage quantity was (390+/-70) ml. The hospital days was (9.2+/-2.1) days. There were 5 cases in hospital deaths. Postoperative complications occurred in 42 cases (6.6%), including 18 cases of right hemoneumothorax, 12 cases of reoperation for bleeding, 3 cases of perivalvular leakage (reoperation was done in 1 patient), 3 cases of low cardiac output syndrome, 2 cases of acute renal failure, 2 cases of inferior vena cava injury, 1 case of right femoral artery thrombosis and liver injury, respectively. The mean duration of follow-up was (58+/-9) months in 608 cases, with a follow-up rate of 96.7% (608/629). Three patients had died during the period of follow-up caused by congestive heart failure (2 patients) and stroke (1 patient). Late complication among 605 survivors were 37 cases, including 32 cases of moderate tricuspid valve insufficiency, 3 cases of stroke, 1 case of perivalvular leakage and infective endocarditis, respectively.There was no reoperation during the period of follow-up. CONCLUSION: Totally thoracoscopic cardiac surgery for mitral valve replacement is safe and effective, with unique superiority and clinical feasible. PMID- 27502137 TI - [Clinical application of modified minimally cardiopulmonary bypass: compared with conventional cardiopulmonary bypass]. AB - OBJECTIVE: To evaluate the safety and effects on blood transfusion of modified minimally cardiopulmonary bypass (CPB). METHODS: From April 2013 to February 2016, 1 103 elective cardiac surgery cases in National Center for Cardiovascular Diseases China, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College were prospectively enrolled in the study. Patients undergoing modified minimally CPB were assigned to mini-CPB group (n=553), the others undergoing conventional CPB were assigned to conventional group (n=550). In mini-CPB group, oxygenator with integrated arterial filter, modified minimized circuit, mini-cardioplegia and vacuum assisted venous drainage(VAVD) were used. In conventional group, conventional CPB was composed with conventional oxygenator from the same manufactory, conventional circuit and 1?4 blood cardioplegia. Analysis was performed with t test, t' test, Wilcoxon rank-sum test, chi(2) test, and Fisher exact test. RESULTS: No CPB accidents and peri-operative stroke were observed. There was no statistical difference in postoperative mechanical ventilation time, length of ICU stay, postoperative complications and mortality between the two groups. The incidence of erythrocyte transfusion (13.7% vs. 27.6%, chi(2)=32.458, P=0.000) and the incidence of ultrafilter (11.0% vs. 33.7%, chi(2)=76.019, P=0.000) were lower in the mini-CPB group. Postoperative hematocrit (M(QR): 32.9 (5.7) vs. 32.2 (5.7), Z=3.403, P=0.001) and 12-hour chest drainage ((228+/-154) ml vs.(260+/-197) ml, t'=3.004, P=0.003) of mini-CPB were imporved compared with conventional group. CONCLUSIONS: Modified minimally CPB is safe. It might reduce erythrocyte transfusion for adult cardiac surgery, warranting widely adoption. PMID- 27502139 TI - [The value of postoperative C-reactive protein in predictive diagnosis of postoperative intra-abdominal septic complications for patients with Crohn disease]. AB - OBJECTIVE: To analyze the value of postoperative C-reactive protein (CRP) in predictive diagnosis of postoperative intra-abdominal septic complications (IASC) for patients with Crohn disease (CD). METHODS: Clinical data of patients with CD received intestinal resection and anastomosis surgery at Research Institute of General Surgery, Jinling Hospital from January 2011 to January 2015 were analyzed. Patients were divided into two groups by whether suffer from IASC 1 month after surgery, including IASC group and no-IASC group. Propensity score matching method was used to match the general clinical data. A total of 54 patients were analyzed, including IASC 17 cases, no-IASC 37 cases. Postoperative CRP at 1-day and 3-day were compared between the two groups using t test. Receiver operator characteristic (ROC) cure was used to analyze the value of postoperative CRP in predictive diagnosis of IASC. RESULTS: IASC group had higher levels of CRP at 1-day ((78+/-13) mg/L vs. (54+/-19) mg/L, t=4.633, P=0.000) and 3-day ((103+/-19) mg/L vs. (69+/-21) mg/L, t=5.859, P=0.000) after surgery than no-IASC group. ROC analysis showed that the CRP 3-day after surgery cut-off point value of 81.45 mg/L, as used for the predictive diagnosis of IASC, provided a sensitivity of 94.1%, a specificity of 82.9%, an area under the curve of 0.90, better than CRP 1-day after surgery. CONCLUSION: Postoperative CRP can be used as a predictive diagnosis of IASC for CD patients received intestinal resection and anastomosis surgery. PMID- 27502138 TI - [Drug coated balloon with paclitaxel for the treatment of symptomatic peripheral artery disease: early and midterm results]. AB - OBJECTIVE: To evaluate the safety and efficacy of the drug coated balloon (DCB) with paclitaxel in patients with symptomatic peripheral artery disease (PAD). METHODS: The clinical data of 18 patients, who were diagnosed as PAD and treated with DCB from October 2013 to June 2014 in Department of Vascular Surgery, People's Liberation Army General Hospital, were retrospectively analyzed.Thirteen male and 5 female patients were in the series, the mean age of the patients was (65+/-7) years, and the Rutherford's categories were level 3 to 5. Patients were followed up at 3- and 6-month postoperative. The main efficacy end point were late lumen loss(LLL), rate of restenosis and clinically driven target lesion revascularization (TLR). Meanwhile, the clinical events were recorded. RESULTS: Mean lesion length, the percentage of total occlusions and the percentage of in stent restenosis were (138+/-91) mm, 9/18 and 2/18, respectively. Rate of technical success was 18/18. At 6-month postoperative, LLL, rate of restenosis and TLR were (0.1+/-0.9) mm, 2/14 and 0, respectively. There was no deaths or no amputations. CONCLUSION: DCB with paclitaxel is safe in patients with PAD, and associated with reductions in LLL, restenosis and clinically driven TLR 6-month postoperative. PMID- 27502140 TI - [Reconstruct abdominal aortic branch arteries totally by endovascular repair in complex aortic aneurysms: a single-centre experience]. AB - OBJECTIVE: To report experiences and results of complex aortic aneurysms involving the visceral arteries treating by total endovascular repair. METHODS: Seventy cases of thoracoabdominal aortic lesions treating by total endovascular repair in Department of Vascular Surgery, People's Liberation Army General Hospital from January 2011 to December 2014 were retrospectively analyzed. There were 47 cases underwent chimney technique, 6 underwent sandwich technique, 15 underwent fenestration technique and 2 underwent branched stent grafts technique. RESULTS: The average follow-up time was 21 months, range from 3 to 47 months. Completion angiography showed that typeI endoleak of chimney, sandwich, fenestration and branched stent grafts group were 9/47, 5/6, 2/15 and 0, respectively. While at 30-day typeI endoleak reduced to 7/47, 2/6, 0 and 0. During follow-up, there were 3 target vessel stents occlusion in chimney group, the patency rate of target vessel stent was 95.1% (58/61). In sandwich, fenestration and branched stent grafts group, all the target vessel stents kept patent. CONCLUSION: In this study, chimney, sandwich, fenestration and branched stent grafts techniques show good short-term and midterm results, the long-term effects still need further studies. PMID- 27502141 TI - [The relationship between preoperative renal failure and severe postoperative hypoxemia of patients received surgical procedures for Stanford A aortic dissection]. AB - OBJECTIVE: To study the relationship between renal failure and severe postoperative hypoxemia of patients received surgical procedure for Stanford A aortic dissection. METHODS: Clinical data of 411 consecutive patients from January 2014 to April 2015, who received surgical procedure for Stanford A aortic dissection in Department of Cardiovascular Surgery of Beijing Anzhen Hospital, were collected retrospectively. The appearance of severe postoperative hypoxemia was recorded in all the cases. All the data about potential prognostic factors was put into the database and analyzed by univariate and multivariate Logistic regression respectively. RESULTS: Severe postoperative hypoxemia (PO2/FiO2<100 mmHg, 1 mmHg=0.133 kPa) happened on 69 cases within 48 hours after procedures, with the incidence rate of 17.1%. Both univariate and multivariate Logistic regression indicated the influence that preoperative creatinine clearance rate had on severe postoperative hypoxemia showed no statistical significance. However, the influence of preoperative serum creatinine showed statistical significance (OR=1.009, 95%CI: 1.000 to 1.018, P=0.048). CONCLUSIONS: The preoperative creatinine clearance rate of patients has no direct relationship with severe postoperative hypoxemia. But the preoperative serum creatinine could be regarded as an independent predictor of severe postoperative hypoxemia. PMID- 27502142 TI - [Effect of prostate volume on the peripheral nerve block anesthesia in prostate biopsy]. AB - OBJECTIVE: To evaluate the anesthetic efficacy of periprostatic nerve block in transrectal ultrasound(TRUS) guided biopsy on different prostate volume. METHODS: A total of 568 patients received prostate biopsy in Department of Urology, Subei People's Hospital from May 2013 to September 2015 were retrospectively studied. All patients were divided into local anesthesia group and nerve block group according to different way of anesthesia. Then each group was divided into four subgroups(20-40 ml, >40-60 ml, >60-100 ml and >100 ml subgroups) according to different prostate volume range. After being anaesthetized successfully, patients in two groups underwent prostate biopsy, visual analogue scale(VAS) scores, visual numeric scale(VNS)scores and complications were recorded and analyzed. At inter-group and intra-group in local anesthesia group and nerve block group, Mann Whitney U test of non-parametric analysis and single factor variance analysis were used to compare the VAS scores and the VNS scores respectively, and chi square test was used to compare the rates of complication. RESULTS: The VAS scores of four subgroups: local anesthesia group: 1.9+/-0.9, 2.8+/-1.5, 3.8+/-2.3 and 5.3+/-2.5; nerve block group: 1.5+/-0.7, 2.0+/-0.8, 2.9+/-1.7 and 4.2+/-2.0. The VNS scores: local anesthesia group: 3.4+/-0.6, 2.9+/-0.6, 2.7+/-0.5 and 1.6+/ 0.7; nerve block group: 3.7+/-0.5, 3.3+/-0.4, 3.0+/-0.8 and 2.0+/-0.7. The VAS scores and the VNS scores had significant differences (Z=-3.637-98.253, all P<0.05) at inter-group or intra-group level. For the complication rates of operation, hematuria, blood, urinary retention were significant differences (F=1.347-15.402, all P<0.05) at intra-group level. But there were no significant differences at inter-group level(P>0.05). CONCLUSION: Compared with local anesthesia, ultrasound guided prostate peripheral nerve block anesthesia has great analgesic effect and high safety, but for patients with a large prostate volumethe analgesic effect is inefficiency. PMID- 27502143 TI - IgG subclass co-expression brings harmony to the quartet model of murine IgG function. AB - A model of murine IgG function is presented in which the co-expression of the IgG subclasses is a central feature, class switching occurs before the commencement of somatic hypermutation, and there is little switching between subclasses. It is named the quartet model to emphasize the harmony that comes from the simultaneous presence of the four subclasses. In this model, IgG3 and IgG2b antibodies are particularly important early in the response, when T-cell help may be limiting. IgG3 initiates inflammation through complement fixation, whereas IgG2b provides early FcgammaR-mediated effector functions. As T-cell help strengthens, IgG2a antibodies increase the power of the response, whereas IgG1 production helps limit the inflammatory drive and limits immunopathology. The model highlights the fact that murine IgG subclasses function quite differently to human IgG subclasses. This allows them to serve the special immunological needs of a species that is vulnerable because of its small size. PMID- 27502145 TI - Making a mes: A transcription factor-microRNA pair governs the size of the midbrain and the dopaminergic progenitor pool. AB - Canonical Wnt signaling is critical for midbrain dopaminergic progenitor specification, proliferation, and neurogenesis. Yet mechanisms that control Wnt signaling remain to be fully elucidated. Wnt1 is a key ligand in the embryonic midbrain, and directs proliferation, survival, specification and neurogenesis. In a recent study, we reveal that the transcription factor Lmx1b promotes Wnt1/Wnt signaling, and dopaminergic progenitor expansion, consistent with earlier studies. Additionally, Lmx1b drives expression of a non-coding RNA called Rmst, which harbors miR135a2 in its last intron. miR135a2 in turn targets Lmx1b as well as several Wnt pathway targets. Conditional overexpression of miR135a2 in the midbrain, particularly during an early time, results in a decreased dopaminergic progenitor pool, and less dopaminergic neurons, consistent with decreased Wnt signaling. We propose a model in which Lmx1b and miR135a2 influence levels of Wnt1 and Wnt signaling, and expansion of the dopaminergic progenitor pool. Further loss of function experiments and biochemical validation of targets will be critical to verify this model. Wnt agonists have recently been utilized for programming stem cells toward a dopaminergic fate in vitro, highlighting the importance of agents that modulate the Wnt pathway. PMID- 27502144 TI - Effects of transmission-blocking vaccines simultaneously targeting pre- and post fertilization antigens in the rodent malaria parasite Plasmodium yoelii. AB - BACKGROUND: Transmission-blocking vaccine (TBV) is a promising strategy for interrupting the malaria transmission cycle. Current TBV candidates include both pre- and post-fertilization antigens expressed during sexual development of the malaria parasites. METHODS: We tested whether a TBV design combining two sexual stage antigens has better transmission-blocking activity. Using the rodent malaria model Plasmodium yoelii, we pursued a DNA vaccination strategy with genes encoding the gametocyte antigen Pys48/45 and the major ookinete surface protein Pys25. RESULTS: Immunization of mice with DNA constructs expression either Pys48/45 or Pys25 elicited strong antibody responses, which specifically recognized a ~45 and ~25 kDa protein from gametocyte and ookinete lysates, respectively. Immune sera from mice immunized with DNA constructs expressing Pys48/45 and Pys25 individually and in combination displayed evident transmission blocking activity in in vitro ookinete culture and direct mosquito feeding experiments. With both assays, the Pys25 sera had higher transmission-blocking activity than the Pys48/45 sera. Intriguingly, compared with the immunization with the individual DNA vaccines, immunization with both DNA constructs produced lower antibody responses against individual antigens. The resultant immune sera from the composite vaccination had significantly lower transmission-blocking activity than those from Pys25 DNA immunization group, albeit the activity was substantially higher than that from the Pys48 DNA vaccination group. CONCLUSIONS: This result suggested that vaccination with the two DNA constructs did not achieve a synergistic effect, but rather caused interference in inducing antigen specific antibody responses. This result has important implications for future design of composite vaccines targeting different sexual antigens. PMID- 27502146 TI - Applications of Polymers as Pharmaceutical Excipients in Solid Oral Dosage Forms. AB - Over the last few decades, polymers have been extensively used as pharmaceutical excipients in drug delivery systems. Pharmaceutical polymers evolved from being simply used as gelatin shells comprising capsule to offering great formulation advantages including enabling controlled/slow release and specific targeting of drugs to the site(s) of action (the "magic bullets" concept), hence hold a significant clinical promise. Oral administration of solid dosage forms (e.g., tablets and capsules) is the most common and convenient route of drug administration. When formulating challenging molecules into solid oral dosage forms, polymeric pharmaceutical excipients permit masking undesired physicochemical properties of drugs and consequently, altering their pharmacokinetic profiles to improve the therapeutic effect. As a result, the number of synthetic and natural polymers available commercially as pharmaceutical excipients has increased dramatically, offering potential solutions to various difficulties. For instance, the different polymers may allow increased solubility, swellability, viscosity, biodegradability, advanced coatings, pH dependency, mucodhesion, and inhibition of crystallization. The aim of this article is to provide a wide angle prospect of the different uses of pharmaceutical polymers in solid oral dosage forms. The various types of polymeric excipients are presented, and their distinctive role in oral drug delivery is emphasized. The comprehensive know-how provided in this article may allow scientists to use these polymeric excipients rationally, to fully exploit their different features and potential influence on drug delivery, with the overall aim of making better drug products. PMID- 27502147 TI - 5-(2-Aminopropyl)benzofuran and phenazepam demonstrate the possibility of dependence by increasing dopamine levels in the brain. AB - Although 5-(2-aminopropyl)benzofuran (5-APB) and 7-bromo-5-(2-chlorophenyl)-1,3 dihydro-2H-1,4-benzodiazepin-2-one (phenazepam) are being used as recreational drugs, research on their dependence liability or mechanisms of action is lacking. The present study aimed to evaluate the behavioral effects and dependence liability of these drugs using conditioned place preference and self administration paradigms in rodents. Additionally, biochemical techniques were used to assess the substance-induced alterations in synaptosome-released dopamine. While both of the tested substances elicited increases in conditioned place preference and dopamine, neither of them facilitated self-administration, suggesting that 5-APB and phenazepam have rewarding effects, rather than reinforcing effects. PMID- 27502148 TI - Cutting edge issues in autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) is a severe liver disease affecting all age groups worldwide. Novel basic and clinical aspects of AIH, addressed at a Monothematic Conference in London in September 2015, are highlighted in this review. The diagnosis of AIH relies upon detection of characteristic autoantibodies, hypergammaglobulinemia, and interface hepatitis on liver histology. The International Autoimmune Hepatitis Group (IAIHG) has devised diagnostic scoring systems to help in comparative studies and clinical practice. AIH arises in a genetically predisposed host, when yet unknown triggers - such an encounter with a pathogen - lead to a T cell-mediated immune response targeting liver autoantigens. This immune response is inadequately controlled because regulatory mechanisms are impaired. The mainstay of treatment for AIH is immunosuppression, which should be instituted as soon as the diagnosis is made. Standard treatment regimens include relatively high doses of predniso(lo)ne, which are tapered gradually as azathioprine is introduced. Recent guidelines have described newer treatment regimens and have tightened the goal of therapy to complete normalization of biochemical, serological and histological parameters. Mycophenolate mofetil, calcineurin inhibitors, mTOR inhibitors and biological agents are potential salvage therapies, but should be reserved for selected non responsive patients and administered only in experienced centers. Liver transplantation is a life-saving option for those patients who progress to end stage liver disease. Further dissection of cellular and molecular pathways involved in AIH pathogenesis is likely to lead to the discovery of novel, tailored and better tolerated therapies. PMID- 27502149 TI - Retrospective evaluation of 211 patients with maxillofacial reconstruction using parietal bone graft for implants insertion. AB - PURPOSE: For a century, autologous bone grafts have been used in maxillofacial reconstruction. The ideal bone harvest site and grafting procedure remains a point of contention in regards to obtaining optimal long-term results with sufficient bone quantity and density without serious complications. More recently, confronted with growing patient requests and biomaterials development, maxillofacial surgeons and dentists have been considering these issues as they relate to pre-implant surgery. This study sought to evaluate implant success rate and complications following pre-implant surgery with parietal bone grafting. MATERIALS AND METHODS: A retrospective study was carried out on patients who underwent maxillofacial reconstruction of different sites (symphysis, mandibular corpus, maxillary sinus and premaxilla) for the purpose of implant insertion. RESULTS: 311 procedures in 211 patients were included. The implant osseointegration rate was around 95%. Clinical follow-up ranged from 10 months to 11 years. A secondary procedure was performed in 6.1% of cases and we noted no serious complications at the harvest site. DISCUSSION: With good revascularization and osseointegration of the graft, the use of parietal bone leads to an implant success rate similar to that seen in the literature. Moreover, the use of this material results in few infections and low bone resorption provided there is strict immobilization of the graft and no tension on the soft tissue sutures. CONCLUSION: Parietal bone grafts technique possess the required qualities for the success of implant surgery, offering results at least as interesting as others using autogenous bone and with no serious complications on donor site. PMID- 27502151 TI - Comparative cytotoxic and genotoxic effects of permethrin and its nanometric form on human erythrocytes and lymphocytes in vitro. AB - The research on the novel pesticides such as nanopesticides has become inevitable to control the mosquito population. Nanopermethrin (NP), one of such kind was formulated in pesticide loaded oil-in-water (o/w) microemulsion by rapid evaporation. Even though NP possess improved efficacy against the target pests, the toxicological investigation on the human or mammalian system remains unexplored. So, the present study focused on a comparative investigation of the cytotoxic and genotoxic effects of NP in vitro and its commercial parental bulk form of permethrin (BP) on human peripheral erythrocyte/lymphocyte by erythrocyte morphology analysis, cell viability assay, and cytokinesis-block micronucleus (CBMN) assay. The NP and BP concentrations (10, 25, 50 and 100 MUg/ml) interacted with human blood cells, and the morphological changes were observed using a phase contrast microscope. The drastic increase of echinocyte was observed at 24, 48 and 72 h treatment as compared with the control. The cell viability studies have shown the significant decrease with increase in NP and BP concentration. CBMN study showed a series correlation in the number of micronuclei, bridge, bud, trinucleated and tetranucleated when interacted with different levels of NP and BP, as comparative to control *p < 0.05, **p < 0.001, ***p < 0.0001. PMID- 27502150 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin suppress AChE activity in NGF treated PC12 cells. AB - PC12 is a well studied cell model for neuronal differentiation. AChE is also considered as a marker for neuronal differentiation. In this study, we detected the change of AChE activity during the NGF induced differentiation of PC 12 cells, and targeted on the ratio of the activity of AChE on the cell surface, and found that NGF mainly increased the intracellular AChE activity. Dioxin is a kind of persistent organic pollutants which have extreme impact on human health and widely distributed all over the world. Recently, AChE was reported as a target of the toxicity of dioxin. Here we investigated the effect of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) on AChE activity in the PC12 cells, and found that at the later stage of differentiation, TCDD could decrease the AChE activity. This down regulation might not related to transcriptional regulation. PMID- 27502152 TI - 25-hydroxyvitamin D in malignant pleural disease: a prospective cohort study. AB - INTRODUCTION: Growing evidence suggests a role of vitamin D in various cancers but the significance of vitamin D in malignant pleural disease remains unexplored. We sought to investigate the concentration and diagnostic role of 25 hydroxyvitamin D (25(OH)D) in malignant pleural effusions. MATERIALS AND METHODS: Prospective study of consecutive treatment-naive patients with a new diagnosis of pleural effusion. RESULTS: Seventy-eight patients were studied, 45 of whom had malignant pleural effusions. Concentration of 25(OH)D in pleural fluid was significantly higher than serum in both malignant (15.2 ng/mL (9.7, 25.6) versus 10.2 ng/mL (6.4, 17.7), P < .001) and benign (11.4 ng/mL (8.4, 23.6) versus 7.9 (5.9, 16.1), P < .001) pleural disease. Pleural fluid 25(OH)D was almost significantly higher in exudates compared to transudates (P = .050) but it did not differ significantly between malignant and benign effusions (P = .217) and it was not diagnostic for malignant pleural disease (area under the ROC curve .58, 95% CI .45-.71). CONCLUSIONS: In subjects with unselected pleural effusions, 25(OH)D in pleural fluid was not diagnostic for malignant pleural disease. The novel finding of convincingly and consistently higher 25(OH)D in pleural fluid than serum suggests a role for vitamin D in pleural disease and merits further research. PMID- 27502154 TI - Role of block copolymer adsorption versus bimodal grafting on nanoparticle self assembly in polymer nanocomposites. AB - We compare the self-assembly of silica nanoparticles (NPs) with physically adsorbed polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) copolymers (BCP) against NPs with grafted bimodal (BM) brushes comprised of long, sparsely grafted PS chains and a short dense carpet of P2VP chains. As with grafted NPs, the dispersion state of the BCP NPs can be facilely tuned in PS matrices by varying the PS coverage on the NP surface or by changes in the ratio of the PS graft to matrix chain lengths. Surprisingly, the BCP NPs are remarkably better dispersed than the NPs tethered with bimodal brushes at comparable PS grafting densities. We postulate that this difference arises because of two factors inherent in the synthesis of the NPs: In the case of the BCP NPs the adsorption process is analogous to the chains being "grafted to" the NP surface, while the BM case corresponds to "grafting from" the surface. We have shown that the "grafted from" protocol yields patchy NPs even if the graft points are uniformly placed on each particle. This phenomenon, which is caused by chain conformation fluctuations, is exacerbated by the distribution function associated with the (small) number of grafts per particle. In contrast, in the case of BCP adsorption, each NP is more uniformly coated by a P2VP monolayer driven by the strongly favorable P2VP-silica interactions. Since each P2VP block is connected to a PS chain we conjecture that these adsorbed systems are closer to the limit of spatially uniform sparse brush coverage than the chemically grafted case. We finally show that the better NP dispersion resulting from BCP adsorption leads to larger mechanical reinforcement than those achieved with BM particles. These results emphasize that physical adsorption of BCPs is a simple, effective and practically promising strategy to direct NP dispersion in a chemically unfavorable polymer matrix. PMID- 27502153 TI - Motivating factors and barriers towards exercise in severe mental illness: a systematic review and meta-analysis. AB - Exercise can improve clinical outcomes in people with severe mental illness (SMI). However, this population typically engages in low levels of physical activity with poor adherence to exercise interventions. Understanding the motivating factors and barriers towards exercise for people with SMI would help to maximize exercise participation. A search of major electronic databases was conducted from inception until May 2016. Quantitative studies providing proportional data on the motivating factors and/or barriers towards exercise among patients with SMI were eligible. Random-effects meta-analyses were undertaken to calculate proportional data and 95% confidence intervals (CI) for motivating factors and barriers toward exercise. From 1468 studies, 12 independent studies of 6431 psychiatric patients were eligible for inclusion. Meta-analyses showed that 91% of people with SMI endorsed 'improving health' as a reason for exercise (N = 6, n = 790, 95% CI 80-94). Among specific aspects of health and well-being, the most common motivations were 'losing weight' (83% of patients), 'improving mood' (81%) and 'reducing stress' (78%). However, low mood and stress were also identified as the most prevalent barriers towards exercise (61% of patients), followed by 'lack of support' (50%). Many of the desirable outcomes of exercise for people with SMI, such as mood improvement, stress reduction and increased energy, are inversely related to the barriers of depression, stress and fatigue which frequently restrict their participation in exercise. Providing patients with professional support to identify and achieve their exercise goals may enable them to overcome psychological barriers, and maintain motivation towards regular physical activity. PMID- 27502155 TI - Natural and synthetic peptides with antifungal activity. AB - In recent years, the increase of invasive fungal infections and the emergence of antifungal resistance stressed the need for new antifungal drugs. Peptides have shown to be good candidates for the development of alternative antimicrobial agents through high-throughput screening, and subsequent optimization according to a rational approach. This review presents a brief overview on antifungal natural peptides of different sources (animals, plants, micro-organisms), peptide fragments derived by proteolytic cleavage of precursor physiological proteins (cryptides), synthetic unnatural peptides and peptide derivatives. Antifungal peptides are schematically reported based on their structure, antifungal spectrum and reported effects. Natural or synthetic peptides and their modified derivatives may represent the basis for new compounds active against fungal infections. PMID- 27502156 TI - Forizymes - functionalised artificial forisomes as a platform for the production and immobilisation of single enzymes and multi-enzyme complexes. AB - The immobilisation of enzymes plays an important role in many applications, including biosensors that require enzyme activity, stability and recyclability in order to function efficiently. Here we show that forisomes (plant-derived mechanoproteins) can be functionalised with enzymes by translational fusion, leading to the assembly of structures designated as forizymes. When forizymes are expressed in the yeast Saccharomyces cerevisiae, the enzymes are immobilised by the self-assembly of forisome subunits to form well-structured protein bodies. We used glucose-6-phosphate dehydrogenase (G6PDH) and hexokinase 2 (HXK2) as model enzymes for the one-step production and purification of catalytically active forizymes. These structures retain the typical stimulus-response reaction of the forisome and the enzyme remains active even after multiple assay cycles, which we demonstrated using G6PDH forizymes as an example. We also achieved the co incorporation of both HXK2 and G6PDH in a single forizyme, facilitating a two step reaction cascade that was 30% faster than the coupled reaction using the corresponding enzymes on different forizymes or in solution. Our novel forizyme immobilisation technique therefore not only combines the sensory properties of forisome proteins with the catalytic properties of enzymes but also allows the development of multi-enzyme complexes for incorporation into technical devices. PMID- 27502157 TI - Evolution of a Protein Interaction Domain Family by Tuning Conformational Flexibility. AB - Conformational flexibility allows proteins to adopt multiple functionally important conformations but can also lead to nonfunctional structures. We analyzed the dynamic behavior of the enzyme guanylate kinase as it evolved into the GK protein interaction domain (GKPID) to investigate the role of flexibility in the evolution of new protein functions. We found that the ancestral enzyme is very flexible, allowing it to adopt open conformations that can bind nucleotide and closed ones that enable catalysis of phosphotransfer from ATP to GMP. Historical mutations that converted the GK from an enzyme to a protein interaction domain dramatically reduce flexibility, predominantly by inhibiting rotations of the protein backbone that are coupled to the global closing motion. Removing flexibility prevents adoption of conformations that cannot fit the protein partner in the binding site. Our results highlight the importance of mutations that optimize protein conformational flexibility with function during evolution. PMID- 27502158 TI - Cardiorespiratory fitness as a predictor of intestinal microbial diversity and distinct metagenomic functions. AB - BACKGROUND: Reduced microbial diversity in human intestines has been implicated in various conditions such as diabetes, colorectal cancer, and inflammatory bowel disease. The role of physical fitness in the context of human intestinal microbiota is currently not known. We used high-throughput sequencing to analyze fecal microbiota of 39 healthy participants with similar age, BMI, and diets but with varying cardiorespiratory fitness levels. Fecal short-chain fatty acids were analyzed using gas chromatography. RESULTS: We showed that peak oxygen uptake (VO2peak), the gold standard measure of cardiorespiratory fitness, can account for more than 20 % of the variation in taxonomic richness, after accounting for all other factors, including diet. While VO2peak did not explain variation in beta diversity, it did play a significant role in explaining variation in the microbiomes' predicted metagenomic functions, aligning positively with genes related to bacterial chemotaxis, motility, and fatty acid biosynthesis. These predicted functions were supported by measured increases in production of fecal butyrate, a short-chain fatty acid associated with improved gut health, amongst physically fit participants. We also identified increased abundances of key butyrate-producing taxa (Clostridiales, Roseburia, Lachnospiraceae, and Erysipelotrichaceae) amongst these individuals, which likely contributed to the observed increases in butyrate levels. CONCLUSIONS: Results from this study show that cardiorespiratory fitness is correlated with increased microbial diversity in healthy humans and that the associated changes are anchored around a set of functional cores rather than specific taxa. The microbial profiles of fit individuals favor the production of butyrate. As increased microbiota diversity and butyrate production is associated with overall host health, our findings warrant the use of exercise prescription as an adjuvant therapy in combating dysbiosis-associated diseases. PMID- 27502159 TI - Acetate ions enhance load and stability of doxorubicin onto PEGylated nanodiamond for selective tumor intracellular controlled release and therapy. AB - A successful drug delivery device for cancer chemotherapy should ideally be able to load drugs highly, bring the drug preferentially into tumor cells and reduce its distribution in normal tissue to enhance therapeutic efficacy. To this purpose, a novel protocol for DOX-loaded PEGylated nanodiamond (ND-PEG-DOX/NaAc, NPDA) was fabricated using sodium acetate medium. The NPDA nanoparticles exhibited a maximum loading efficiency (99 wt%) with ultra-low drug leakage (7 wt%). Examination by confocal microscope and flow cytometer showed that the NPDA uptake by cells was time-dependent, with a slow and sustained drug release from the lysosomes at a low pH. Also, when CHO (a normal cell) and MCF-7 (a cancer cell) were treated with NPDA, the results demonstrated that NPDA preferentially accumulated much more in tumor cells than in normal cells, which implied that NPDA has the ability to selectively kill tumor cells. In addition, NPDA can inhibit the migration and proliferation of tumor cells and change the cell cycle compared to the free drug. Outcomes from this work suggest that NPDA would be a promising drug delivery platform and the preparation of such a drug delivery system will also have implications in improving the biomedical applications of smart nanodiamond carriers. PMID- 27502160 TI - Nanostructured Tendon-Derived Scaffolds for Enhanced Bone Regeneration by Human Adipose-Derived Stem Cells. AB - Decellularized matrix-based scaffolds can induce enhanced tissue regeneration due to their biochemical, biophysical, and mechanical similarity to native tissues. In this study, we report a nanostructured decellularized tendon scaffold with aligned, nanofibrous structures to enhance osteogenic differentiation and in vivo bone formation of human adipose-derived stem cells (hADSCs). Using a bioskiving method, we prepared decellularized tendon scaffolds from tissue slices of bovine Achilles and neck tendons with or without fixation, and investigated the effects on physical and mechanical properties of decellularized tendon scaffolds, based on the types and concentrations of cross-linking agents. In general, we found that decellularized tendon scaffolds without fixative treatments were more effective in inducing osteogenic differentiation and mineralization of hADSCs in vitro. When non-cross-linked decellularized tendon scaffolds were applied together with hydroxyapatite for hADSC transplantation in critical-sized bone defects, they promoted bone-specific collagen deposition and mineralized bone formation 4 and 8 weeks after hADSC transplantation, compared to conventional collagen type I scaffolds. Interestingly, stacking of decellularized tendon scaffolds cultured with osteogenically committed hADSCs and those containing human cord blood-derived endothelial progenitor cells (hEPCs) induced vascularized bone regeneration in the defects 8 weeks after transplantation. Our study suggests that biomimetic nanostructured scaffolds made of decellularized tissue matrices can serve as functional tissue-engineering scaffolds for enhanced osteogenesis of stem cells. PMID- 27502161 TI - School performance for children with cleft lip and palate: a population-based study. AB - BACKGROUND: Educational attainment is important in shaping young people's life prospects. To investigate whether being born with orofacial cleft (OFC) affects school performance, we compared school test results between children born with and without OFC. METHODS: Using record-linked datasets, we conducted a population based cohort study of children liveborn in Western Australia 1980-2010 with a diagnosis of OFC on the Register of Developmental Anomalies, and a random sample of 6603 children born without OFC. We compared odds ratios for meeting national minimum standards in five domains (reading, numeracy, writing, spelling, grammar and punctuation), and adjusted OR (aOR) for children with cleft lip only (CLO), cleft lip and palate (CL + P) and cleft palate only (CPO) for each domain. RESULTS: Results from two testing programs (WALNA and NAPLAN) were available for 3238 (89%) children expected to participate. Most met the national minimum standards. Compared with children without OFC, children with CPO were less likely to meet minimum standards for NAPLAN reading (aOR 0.57 [95%CI 0.34, 0.96]) grammar and punctuation (aOR 0.49 [95%CI 0.32, 0.76]), WALNA writing (aOR 0.66 [95%CI 0.47, 0.92]), and WALNA and NAPLAN numeracy (aOR 0.64 [95%CI 0.43, 0.95] and aOR 0.47 [95%CI 0.28, 0.82]), respectively. Children with CL + P had significantly lower odds for reaching the spelling standard in NAPLAN tests (aOR 0.52 [95%CI 0.29, 0.94]). Children with CLO had similar odds for reaching all minimum standards. CONCLUSION: Children born with OFC, particularly children with CPO, should be monitored to identify learning difficulties early, to enable intervention to maximize school attainment. PMID- 27502162 TI - Identifying the Leading Edge of Exceptionally Long Contaminant Plumes. PMID- 27502163 TI - Ribosomal protein L18aB is required for both male gametophyte function and embryo development in Arabidopsis. AB - Ribosomal proteins are involved in numerous essential cell activities in plants. However, the regulatory role in specific plant developmental processes has not yet been fully elucidated. Here we identified the new ribosomal protein L18aB, which is specifically involved in sexual reproduction and plays a critical role in male gametophyte development and embryo pattern formation. In rpl18aB mutant plants, the mature pollen grains can germinate normally, but their competitiveness for growing in the style is significantly reduced. More interestingly, RPL18aB is required in early embryogenesis. rpl18aB embryos displayed irregular cell division orientations in the early pro-embryo and arrested at the globular stage with possible, secondary pattern formation defects. Further investigations revealed that the polar transportation of auxin is disturbed in the rpl18aB mutant embryos, which may explain the observed failure in embryo pattern formation. The cell type-specific complementation of RPL18aB in rpl18aB was not able to recover the phenotype, indicating that RPL18aB may play an essential role in early cell fate determination. This work unravels a novel role in embryo development for a ribosomal protein, and provides insight into regulatory mechanism of early embryogenesis. PMID- 27502164 TI - Downregulation of miR-3940-5p promotes T-cell activity by targeting the cytokine receptor IL-2R gamma on human cutaneous T-cell lines. AB - Vitiligo is a common established depigmentation skin disease characterized by the presence of activated T lymphocytes anti melanocytes within the skin. T-cell immunity mainly mediates the destruction of melanocytes and is one of the main mechanisms involved in the pathogenesis of non-segmental vitiligo. Our previous study had identified several differentially expressed miRNAs and found that the expression of miR-3940-5p was downregulated in vitiligo patients. According to the research findings, we hypothesized that the novel miRNA plays a potential role on human cutaneous T lymphocytes in the action mechanism of immune imbalance in vitiligo. PMID- 27502165 TI - Dock10 regulates CD23 expression and sustains B-cell lymphopoiesis in secondary lymphoid tissue. AB - Dock10, a guanine nucleotide exchange factor for the Rho GTPases Rac1 and Cdc42, affects cell morphology, membrane protrusive activity, and cell movement. Dock10 is prominently expressed in lymphoid tissue and upregulated by IL-4 in B cells. To investigate the physiological role of Dock10, WT mice and Dock10 KO mice were used. KO mice showed decreased numbers of B cells in spleen, both follicular B cells and marginal zone B cells, and in peripheral blood, but not in bone marrow. The antiapoptotic effect of IL-4 in vitro, the migratory response to CXCL13 or CCL21 in vitro, and the whole genome expression profile were intact in spleen B cells from KO mice. CD23, the low-affinity receptor for immunoglobulin E, was overexpressed on follicular B cells from KO mice, suggesting that Dock10 negatively regulates membrane CD23 expression. Negative regulation of CD23 expression by Dock10 could play a role in B cell maturation and function. PMID- 27502166 TI - Impact of cartilage graft size on success of tympanoplasty. AB - INTRODUCTION: In the last decade, there has been an increasing use of cartilage grafts in the primary repair of tympanic membrane perforations. The major advantages of cartilage are its stiffness and its very low metabolic requirements, which make it particularly suitable for difficult conditions, such as subtotal perforations, adhesive otitis and reoperation. OBJECTIVE: To analyze the impact of different perforation sizes requiring different sizes of cartilage on the anatomical and functional outcome after tympanoplasty. METHODS: Through this prospective non-controlled, non-randomized study, 50 patients underwent cartilage type 1 tympanoplasty (20 females and 30 males), with a mean age of 19.3+/-9.8 years. According to size of perforation, patients were subdivided into three groups, Group I had perforation >50% of tympanic membrane area, in Group II patients the perforations were 25-50% of tympanic membrane area, and in Group III the perforations were <=25% of tympanic membrane. All patients had pre and postoperative Pure Tone Average and Air Bone Gap frequencies (0.5, 1, 2, 4kHz). All patients were followed up at least 12 months after operation. RESULTS: The anatomical success rate among all patients was 92%, all groups showed statistical significant improvement between pre and postoperative air bone gap, no significant correlation between size of cartilage graft and degree of air bone gap improvement was noticed among the three groups. CONCLUSION: Size of a cartilage graft has no impact on degree of hearing improvement or anatomical success rate after tympanoplasty. PMID- 27502167 TI - Desulfation of cell surface HSPG is an effective strategy for the treatment of gallbladder carcinoma. AB - Cell surface heparan sulfate proteoglycan (HSPG) is a group of critical glycoproteins that mediates signal transduction. Sulfated HSPG can mediate the activation of a variety of cell growth factor signal pathway to promote the progression of gallbladder carcinoma (GBC). This study analyzed 527 clinical GBC specimens and confirmed that the HSPG sulfation level was significantly higher in GBC tissues than in gallbladder mucosa (GBM) tissues. The high HSPG sulfation level was closely associated with poor differentiation, local metastasis, and advanced clinical stage of GBC; it was also associated with the shortening of disease-free survival (DFS) and overall survival (OS) and influenced the outcome of chemotherapy or radio-chemotherapy in patients with GBC recurrence. Inhibition of HSPG sulfation on the GBC cell surface using human sulfatase 1 (hSulf-1) significantly reduced the phosphorylation levels of growth factor receptors and signaling protein kinases in GBC cells, decreased cell responses to growth factors, and inhibited cell proliferation and migration abilities. In a nude mouse model with GBC xenografts, we observed that the xenograft tumor growth was suppressed and the phosphorylation levels of signaling proteins were downregulated, together with decreased expression of Ki67 and reduced sensitivity to bFGF (basic fibroblast growth factor) induction after inhibition of HSPG sulfation. Our study demonstrated that a high HSPG sulfation endows GBC with high malignant biological behaviors and a poor prognosis. Desulfation of cell surface HSPG can inhibit the kinase activities of a variety of signaling proteins, hinder the cell response to growth factors, and effectively inhibit the malignant biological behaviors of GBC cells. PMID- 27502169 TI - The modular approach enables a fully ab initio simulation of the contacts between 3D and 2D materials. AB - Up to now, the electrical properties of the contacts between 3D metals and 2D materials have never been computed at a fully ab initio level due to the huge number of atomic orbitals involved in a current path from an electrode to a pristine 2D material. As a result, there are still numerous open questions and controversial theories on the electrical properties of systems with 3D/2D interfaces-for example, the current path and the contact length scalability. Our work provides a first-principles solution to this long-standing problem with the use of the modular approach, a method which rigorously combines a Green function formalism with the density functional theory (DFT) for this particular contact type. The modular approach is a general approach valid for any 3D/2D contact. As an example, we apply it to the most investigated among 3D/2D contacts metal/graphene contacts-and show its abilities and consistency by comparison with existing experimental data. As it is applicable to any 3D/2D interface, the modular approach allows the engineering of 3D/2D contacts with the pre-defined electrical properties. PMID- 27502168 TI - The efficient elimination of solid tumor cells by EGFR-specific and HER2-specific scFv-SNAP fusion proteins conjugated to benzylguanine-modified auristatin F. AB - Antibody-drug conjugates (ADCs) combine the potency of cytotoxic drugs with the specificity of monoclonal antibodies (mAbs). Most ADCs are currently generated by the nonspecific conjugation of drug-linker reagents to certain amino acid residues in mAbs, resulting in a heterogeneous product. To overcome this limitation and prepare ADCs with a defined stoichiometry, we use SNAP-tag technology as an alternative conjugation strategy. This allows the site-specific conjugation of O(6)-benzylguanine (BG)-modified small molecules to SNAP-tag fusion proteins. To demonstrate the suitability of this system for the preparation of novel recombinant ADCs, here we conjugated SNAP-tagged single chain antibody fragments (scFvs) to a BG-modified version of auristatin F (AURIF). We used two scFv-SNAP fusion proteins targeting members of the epidermal growth factor receptor (EGFR) family that are frequently overexpressed in breast cancer. The conjugation of BG-AURIF to EGFR-specific 425(scFv)-SNAP and HER2 specific alphaHER2(scFv)-SNAP resulted in two potent recombinant ADCs that specifically killed breast cancer cell lines by inducing apoptosis when applied at nanomolar concentrations. These data confirm that SNAP-tag technology is a promising tool for the generation of novel recombinant ADCs. PMID- 27502170 TI - Normal saline versus lower-chloride solutions for kidney transplantation. AB - BACKGROUND: The ideal intravenous fluid for kidney transplantation has not been defined, despite the common use of normal saline during the peri-operative period. The high chloride content of normal saline is associated with an increased risk of hyperchloraemic metabolic acidosis, which may in turn increase the risk of hyperkalaemia and delayed graft function. Balanced electrolyte solutions have a lower chloride content which may decrease this risk and avoid the need for dialysis due to hyperkalaemia in the immediate post-transplant period. Randomised controlled trials (RCTs) addressing this issue have used biochemical outcomes to compare fluids and have been underpowered to address patient-centred outcomes such as delayed graft function. OBJECTIVES: To examine the effect of lower-chloride solutions versus normal saline on delayed graft function, hyperkalaemia and acid-base status in kidney transplant recipients. SEARCH METHODS: We searched the Cochrane Kidney and Transplant's Specialised Register to 26 November 2015 through contact with the Information Specialist using search terms relevant to this review. SELECTION CRITERIA: RCTs of kidney transplant recipients that compared peri-operative intravenous lower-chloride solutions to normal saline were included. DATA COLLECTION AND ANALYSIS: Two independent investigators assessed studies for eligibility and risk of bias. Data from individual studies were extracted using standardised forms and pooled according to a published protocol. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: Six studies (477 participants) were included in the review. All participants were adult kidney transplant recipients and 70% of participants underwent live-donor kidney transplantation. The overall risk of bias was low for selection bias and unclear for remaining domains. There was no difference in the risk of delayed graft function (3 studies, 298 participants: RR 1.03, 95% CI 0.62 to 1.70) or hyperkalaemia (2 studies, 199 participants: RR 0.48, 95% CI 0.04 to 6.10) for participants who received balanced electrolyte solutions compared to normal saline. Intraoperative balanced electrolyte solutions compared to normal saline were associated with higher blood pH (3 studies, 193 participants: MD 0.07, 95% CI 0.05 to 0.09), higher serum bicarbonate (3 studies, 215 participants: MD 3.02 mEq/L, 95% CI 2.00 to 4.05) and lower serum chloride (3 studies, 215 participants: MD -9.93 mmol/L, 95% CI -19.96 to 0.11). There were four cases of graft loss in the normal saline group and one in the balanced electrolyte solution group, and four cases of acute rejection in the normal saline group compared to two cases in the balanced electrolyte solution group. AUTHORS' CONCLUSIONS: Balanced electrolyte solutions are associated with less hyperchloraemic metabolic acidosis compared to normal saline, however it remains uncertain whether lower-chloride solutions lead to improved graft outcomes compared to normal saline. PMID- 27502171 TI - Targeted and untargeted profiling of alkaloids in herbal extracts using online solid-phase extraction and high-resolution mass spectrometry (Q-Orbitrap). AB - The biological activity of alkaloids (ALKs) and the different content of these natural products in herbs and plants have made them an attractive field for chemical studies. A screening method automatically combining online solid-phase purification and concentration of samples with analysis using ultra-high performance liquid chromatography coupled with a hybrid quadrupole orbitrap mass spectrometer was developed and is reported in this paper. The proposed quantification method was validated for 35 ALKs with reference to pure analytical standards. A further 48 ALKs were identified on the basis of their accurate mass and characterised for chromatographic retention time and fragmentation profile, following their confirmation in extracts of herbs already well documented in the literature. More than 250 other untargeted ALKs were also tentatively identified using literature information, such as exact mass and isotopic pattern. The mass spectrometer operated in positive ion mode and mass spectra were acquired, with full MS-data-dependent MS/MS analysis (full MS-dd MS/MS) at a resolution of 140 000. The method was linear up to an ALK concentration of 1000/3000 ug l(-1) , with R(2) always >0.99 and limits of detection ranging between 0.04 and 10 ug l( 1) . Accuracy, expressed as the recovery relative error, had a median value of 7.4%, and precision (relative standard deviation %) was generally lower than 10% throughout the quantitation range. The proposed method was then used to investigate the targeted and untargeted ALK profile of a selection of 18 alpine herbal plants, establishing that pyrrolizidine, pyrrolidine and piperidine ALKs were the most well represented. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27502172 TI - Fibpredictor: a computational method for rapid prediction of amyloid fibril structures. AB - Amyloid fibrils are important in diseases such as Alzheimer's disease and Parkinson's disease, and are also a common instability in peptide and protein drug products. Despite their importance, experimental structures of amyloid fibrils in atomistic detail are rare. To address this limitation, we have developed a novel, rapid computational method to predict amyloid fibril structures (Fibpredictor). The method combines beta-sheet model building, beta sheet replication, and symmetry operations with side-chain prediction and statistical scoring functions. When applied to nine amyloid fibrils with experimentally determined structures, the method predicted the correct structures of amyloid fibrils and enriched those among the top-ranked structures. These models can be used as the initial heuristic structures for more complicated computational studies. Fibpredictor is available at http://nanohub.org/resources/fibpredictor . PMID- 27502173 TI - Biliary Polyunsaturated Fatty Acids and Telocytes in Gallstone Disease. AB - It has been reported that intake of omega-3 polyunsaturated fatty acids (PUFAs) reduces the risk of coronary heart disease. It also influences bile composition, decreasing biliary cholesterol saturation in the bile of patients with gallstones. In addition to bile composition disturbances, gallbladder hypomotility must be a cofactor in the pathogenesis of cholelithiasis, as it leads to the prolonged nucleation phase. Our current knowledge about gallbladder motility has been enhanced by the study of a population of newly described interstitial (stromal) cells-telocytes (TCs). The purpose of this study was to determine whether TC loss, reported by our team recently, might be related to bile lithogenicity, expressed as cholesterol saturation index or the difference in biliary PUFA profiles in patients who suffer from cholecystolithiasis and those not affected by this disease. We determined biliary lipid composition including the fatty acid composition of the phospholipid species in bile. Thus, we investigated whether differences in biliary fatty acid profiles (omega-3 PUFA and omega-6 PUFA) in gallbladder bile may influence its lithogenicity and the quantity of TCs within the gallbladder wall. We conclude that the altered PUFA concentrations in the gallbladder bile, with elevation of omega-6 PUFA, constitute important factors influencing TC density in the gallbladder wall, being one of the possible pathophysiological components for the gallstone disease development. This study established that altered bile composition in patients with cholelithiasis may influence TC quantity within the gallbladder muscle, and we concluded that reduction in TC number may be a consequence of the supersaturated bile toxicity, while some other bile components (omega-3 PUFA, glycocholic, and taurocholic acids) may exert protective effects on TC and thus possibly influence the mechanisms regulating gallbladder and extrahepatic bile duct motility. Thus, omega-3 PUFA may represent a possible option to prevent formation of cholesterol gallstones. PMID- 27502174 TI - Marseillevirus in lymphoma: a giant in the lymph node. AB - The family Marseilleviridae is a new clade of giant viruses whose original member, marseillevirus, was described in 2009. These viruses were isolated using Acanthamoeba spp primarily from the environment. Subsequently, a close relative of marseillevirus was isolated from the faeces of a healthy young man, and others were detected in blood samples of blood donors and recipients and in a child with lymph node adenitis. In this Grand Round we describe the detection of marseillevirus by PCR, fluorescence in-situ hybridisation, direct immunofluorescence, and immunohistochemistry in the lymph node of a 30-year-old woman diagnosed with Hodgkin's lymphoma, together with IgG antibodies to marseillevirus. A link with viruses and bacteria has been reported for many lymphomas. We review the literature describing these associations, the criteria used to consider a causal association, and the underlying mechanisms of lymphomagenesis. Our observations suggest that consideration should be given to marseillevirus infections as an additional viral cause or consequence of Hodgkin's lymphoma, and that this hypothesis should be tested further. PMID- 27502175 TI - Thalassiella azotovora gen. nov., sp. nov., a New Member of the Family Kineosporiaceae Isolated from Sea Water in South Korea. AB - A gram-positive, nonmotile, rod-shaped, nonflagellated, aerobic bacterium, designated strain DSD2(T) was isolated from a seawater sample from Sadong wharf, Ulleung-Island, South Korea. Strain DSD2(T) was found to be able to grow at pH ranging from 6 to 11 (optimum 7-8), 0-7 % (w/v) NaCl (optimum 0 %), at 10-42 degrees C (optimum 37 degrees C). 16S rRNA gene sequence analysis revealed that strain DSD2(T) was 95.8 % similar to the type strain of Kineosporia rhamnosa KACC 15195(T), 95.8 % similar to Angustibacter aerolatus KACC 15527(T), and 95.5 % similar to Kineococcus xinjiangensis KCTC 19474(T) as its closest relatives. A neighbor-joining phylogenetic tree based on the 16S rRNA gene sequence showed that strain DSD2(T) related to Micrococcineae and Kineosporiineae suborder clade. The major polar lipids were phosphoglycolipids and phospholipids. Strain DSD2(T) was found to contain MK-8 (H2) and MK-9 (H4) as the predominant menaquinone and iso-C16:0 as the major fatty acid. The isolate contained meso-diaminopimelic acid (meso-A2pm) with alanine, glutamic acid, and glycine as the diagnostic diamino acid. The DNA G+C content of strain DSD2(T) was 73.2 mol%. On the basis of phylogenetic, biochemical, chemotaxonomic, and other physiological characteristics, strain DSD2(T) is assigned to a novel species of a novel genus within the suborder Kineosporiineae and the name Thalassiella azotovora gen nov., sp. nov., is proposed. The type strain is DSD2(T) (= KCTC 39634(T) = JCM 31134(T)). PMID- 27502176 TI - Magnesium-Calcite Crystal Formation Mediated by the Thermophilic Bacterium Geobacillus thermoglucosidasius Requires Calcium and Endospores. AB - Fresh Geobacillus thermoglucosidasius cells grown on soybean-casein digest nutrient agar were inoculated as a parent colony 1 cm in diameter on the surface of an agar gel containing acetate and calcium ions (calcite-promoting hydrogel) and incubated at 60 degrees C for 4 days, after which magnesium-calcite single crystals of 50-130 um in size formed within the parent colony. Addition of EDTA, polyacrylic acid or N,N-dicyclohexylcarbodiimide to the calcite-forming hydrogel inhibited the parent colony from forming magnesium-calcite crystals. Inoculation of G. thermoglucosidasius on calcite-forming hydrogel containing 5 uM cadmium and 20 uM zinc resulted in a decrease in the sporulation rate from 55 to 7-8 %. Magnesium-calcite synthesis decreased relative to the sporulation rate. G. thermoglucosidasius exhibited higher adsorption/absorbance of calcium than other Geobacillus sp. that do not mediate calcite formation and higher levels of magnesium accumulation. Calcium ions contained in the calcite-promoting hydrogel and magnesium ions concentrated in G. thermoglucosidasius cells serve as the elements for magnesium-calcite synthesis. The observed decreases in sporulation rate and magnesium-calcite formation support the hypothesis that endospores act as nuclei for the synthesis of magnesium-calcite single crystals. PMID- 27502177 TI - Homogenised daily lake surface water temperature data generated from multiple satellite sensors: A long-term case study of a large sub-Alpine lake. AB - Availability of remotely sensed multi-spectral images since the 1980's, which cover three decades of voluminous data could help researchers to study the changing dynamics of bio-physical characteristics of land and water. In this study, we introduce a new methodology to develop homogenised Lake Surface Water Temperature (LSWT) from multiple polar orbiting satellites. Precisely, we developed homogenised 1 km daily LSWT maps covering the last 30 years (1986 to 2015) combining data from 13 satellites. We used a split-window technique to derive LSWT from brightness temperatures and a modified diurnal temperature cycle model to homogenise data which were acquired between 8:00 to 17:00 UTC. Gaps in the temporal LSWT data due to the presence of clouds were filled by applying Harmonic ANalysis of Time Series (HANTS). The satellite derived LSWT maps were validated based on long-term monthly in-situ bulk temperature measurements in Lake Garda, the largest lake in Italy. We found the satellite derived homogenised LSWT being significantly correlated to in-situ data. The new LSWT time series showed a significant annual rate of increase of 0.020 degrees C yr(-1) (*P < 0.05), and of 0.036 degrees C yr(-1) (***P < 0.001) during summer. PMID- 27502178 TI - Nanometal Skin of Plasmonic Heterostructures for Highly Efficient Near-Field Scattering Probes. AB - In this work, atomic force microscopy probes are functionalized by virtue of self assembling monolayers of block copolymer (BCP) micelles loaded either with clusters of silver nanoparticles or bimetallic heterostructures consisting of mixed species of silver and gold nanoparticles. The resulting self-organized patterns allow coating the tips with a sort of nanometal skin made of geometrically confined nanoislands. This approach favors the reproducible engineering and tuning of the plasmonic properties of the resulting structured tip by varying the nanometal loading of the micelles. The newly conceived tips are applied for experiments of tip-enhanced Raman scattering (TERS) spectroscopy and scattering-type scanning near-field optical microscopy (s-SNOM). TERS and s SNOM probe characterizations on several standard Raman analytes and patterned nanostructures demonstrate excellent enhancement factor with the possibility of fast scanning and spatial resolution <12 nm. In fact, each metal nanoisland consists of a multiscale heterostructure that favors large scattering and near field amplification. Then, we verify the tips to allow challenging nongap-TER spectroscopy on thick biosamples. Our approach introduces a synergistic chemical functionalization of the tips for versatile inclusion and delivery of plasmonic nanoparticles at the tip apex, which may promote the tuning of the plasmonic properties, a large enhancement, and the possibility of adding new degrees of freedom for tip functionalization. PMID- 27502179 TI - The genetics of an early Neolithic pastoralist from the Zagros, Iran. AB - The agricultural transition profoundly changed human societies. We sequenced and analysed the first genome (1.39x) of an early Neolithic woman from Ganj Dareh, in the Zagros Mountains of Iran, a site with early evidence for an economy based on goat herding, ca. 10,000 BP. We show that Western Iran was inhabited by a population genetically most similar to hunter-gatherers from the Caucasus, but distinct from the Neolithic Anatolian people who later brought food production into Europe. The inhabitants of Ganj Dareh made little direct genetic contribution to modern European populations, suggesting those of the Central Zagros were somewhat isolated from other populations of the Fertile Crescent. Runs of homozygosity are of a similar length to those from Neolithic farmers, and shorter than those of Caucasus and Western Hunter-Gatherers, suggesting that the inhabitants of Ganj Dareh did not undergo the large population bottleneck suffered by their northern neighbours. While some degree of cultural diffusion between Anatolia, Western Iran and other neighbouring regions is possible, the genetic dissimilarity between early Anatolian farmers and the inhabitants of Ganj Dareh supports a model in which Neolithic societies in these areas were distinct. PMID- 27502182 TI - Plasma cell cheilitis successfully treated with topical calcineurin inhibitors. PMID- 27502180 TI - Imaging-genomics reveals driving pathways of MRI derived volumetric tumor phenotype features in Glioblastoma. AB - BACKGROUND: Glioblastoma (GBM) tumors exhibit strong phenotypic differences that can be quantified using magnetic resonance imaging (MRI), but the underlying biological drivers of these imaging phenotypes remain largely unknown. An Imaging Genomics analysis was performed to reveal the mechanistic associations between MRI derived quantitative volumetric tumor phenotype features and molecular pathways. METHODS: One hundred fourty one patients with presurgery MRI and survival data were included in our analysis. Volumetric features were defined, including the necrotic core (NE), contrast-enhancement (CE), abnormal tumor volume assessed by post-contrast T1w (tumor bulk or TB), tumor-associated edema based on T2-FLAIR (ED), and total tumor volume (TV), as well as ratios of these tumor components. Based on gene expression where available (n = 91), pathway associations were assessed using a preranked gene set enrichment analysis. These results were put into context of molecular subtypes in GBM and prognostication. RESULTS: Volumetric features were significantly associated with diverse sets of biological processes (FDR < 0.05). While NE and TB were enriched for immune response pathways and apoptosis, CE was associated with signal transduction and protein folding processes. ED was mainly enriched for homeostasis and cell cycling pathways. ED was also the strongest predictor of molecular GBM subtypes (AUC = 0.61). CE was the strongest predictor of overall survival (C-index = 0.6; Noether test, p = 4x10(-4)). CONCLUSION: GBM volumetric features extracted from MRI are significantly enriched for information about the biological state of a tumor that impacts patient outcomes. Clinical decision-support systems could exploit this information to develop personalized treatment strategies on the basis of noninvasive imaging. PMID- 27502183 TI - Assessment of physico-chemical characteristics of water in Tamilnadu. AB - Water is an important component to human life. The major aims of the present work are to assess the quality of the ground water and its impact in Villupuram District of Tamilnadu. The present study focus to bring an awareness among the people about the quality of ground water by taking water samples from various locations for Physico - Chemical analysis of the ground water. This analysis result was compared with the WHO, ICMR, USPH and European standards of drinking water quality parameters with the following water quality parameters namely pH, Electrical conductivity, Cl, , Na, K, Ca , Mg, Total dissolved solids, Total hardness, Dissolved oxygen, Fluoride etc. Various chemical methods have been employed to investigate the extent level of pollution in ground water. PMID- 27502184 TI - Translating an early childhood obesity prevention program for local community implementation: a case study of the Melbourne InFANT Program. AB - BACKGROUND: While there is a growing interest in the field of research translation, there are few published examples of public health interventions that have been effectively scaled up and implemented in the community. This paper provides a case study of the community-wide implementation of the Melbourne Infant, Feeding, Activity and Nutrition Trial (InFANT), an obesity prevention program for parents with infants aged 3-18 months. The study explored key factors influencing the translation of the Program into routine practice and the respective role of policy makers, researchers and implementers. METHODS: Case studies were conducted of five of the eight prevention areas in Victoria, Australia who implemented the Program. Cases were selected on the basis of having implemented the Program for 6 months or more. Data were collected from January to June 2015 and included 18 individual interviews, one focus group and observation of two meetings. A total of 28 individuals, including research staff (n = 4), policy makers (n = 2) and implementers (n = 22), contributed to the data collected. Thematic analysis was conducted using cross case comparisons and key themes were verified through member checking. RESULTS: Key facilitators of implementation included availability of a pre-packaged evidence based program addressing a community need, along with support and training provided by research staff to local implementers. Partnerships between researchers and policy makers facilitated initial program adoption, while local partnerships supported community implementation. Community partnerships were facilitated by local coordinators through alignment of program goals with existing policies and services. Workforce capacity for program delivery and administration was a challenge, largely overcome by embedding the Program into existing roles. Adapting the Program to fit local circumstance was critical for feasible and sustainable delivery, however balancing this with program fidelity was a critical issue. The lack of ongoing funding to support translation activities was a barrier for researchers continued involvement in community implementation. CONCLUSION: Policy makers, researchers and practitioners have important and complementary roles to play in supporting the translation of effective research interventions into practice. New avenues need to be explored to strengthen partnerships between researchers and end users to support the integration of effective public health research interventions into practice. PMID- 27502185 TI - The superior fault tolerance of artificial neural network training with a fault/noise injection-based genetic algorithm. AB - Artificial neural networks (ANNs) are powerful computational tools that are designed to replicate the human brain and adopted to solve a variety of problems in many different fields. Fault tolerance (FT), an important property of ANNs, ensures their reliability when significant portions of a network are lost. In this paper, a fault/noise injection-based (FIB) genetic algorithm (GA) is proposed to construct fault-tolerant ANNs. The FT performance of an FIB-GA was compared with that of a common genetic algorithm, the back-propagation algorithm, and the modification of weights algorithm. The FIB-GA showed a slower fitting speed when solving the exclusive OR (XOR) problem and the overlapping classification problem, but it significantly reduced the errors in cases of single or multiple faults in ANN weights or nodes. Further analysis revealed that the fit weights showed no correlation with the fitting errors in the ANNs constructed with the FIB-GA, suggesting a relatively even distribution of the various fitting parameters. In contrast, the output weights in the training of ANNs implemented with the use the other three algorithms demonstrated a positive correlation with the errors. Our findings therefore indicate that a combination of the fault/noise injection-based method and a GA is capable of introducing FT to ANNs and imply that the distributed ANNs demonstrate superior FT performance. PMID- 27502186 TI - On the ground in Western Africa: from the outbreak to the elapse of Ebola. PMID- 27502187 TI - The emerging roles of the DDX41 protein in immunity and diseases. AB - RNA helicases are involved in almost every aspect of RNA, from transcription to RNA decay. DExD/H-box helicases comprise the largest SF2 helicase superfamily, which are characterized by two conserved RecA-like domains. In recent years, an increasing number of unexpected functions of these proteins have been discovered. They play important roles not only in innate immune response but also in diseases like cancers and chronic hepatitis C. In this review, we summarize the recent literatures on one member of the SF2 superfamily, the DEAD-box protein DDX41. After bacterial or viral infection, DNA or cyclic-di-GMP is released to cells. After phosphorylation of Tyr414 by BTK kinase, DDX41 will act as a sensor to recognize the invaders, followed by induction of type I interferons (IFN). After the immune response, DDX41 is degraded by the E3 ligase TRIM21, using Lys9 and Lys115 of DDX41 as the ubiquitination sites. Besides the roles in innate immunity, DDX41 is also related to diseases. An increasing number of both inherited and acquired mutations in DDX41 gene are identified from myelodysplastic syndrome and/or acute myeloid leukemia (MDS/AML) patients. The review focuses on DDX41, as well as its homolog Abstrakt in Drosophila, which is important for survival at all stages throughout the life cycle of the fly. PMID- 27502188 TI - Rab1A mediates proinsulin to insulin conversion in beta-cells by maintaining Golgi stability through interactions with golgin-84. PMID- 27502189 TI - Dual red imaging (novel advanced endoscopy) can increase visibility and can predict the depth in diagnosing esophageal varices. AB - BACKGROUND: Dual red imaging (DRI) is a new technology that can increase the visibility of deeper veins compared with narrow band imaging (NBI). As esophageal varices (EVs) are a vascular disease occurring in the submucosal layer, their visibility might be increased by DRI. We prospectively clarified whether the visibility of EVs with red color sign (RCS) can be increased by DRI, and clarified the relation between the visibility scores and the obtained endoscopic ultrasound (EUS) images. METHODS: Forty patients were enrolled. The visibility of the EVs on DRI and NBI endoscopic images was evaluated by five observers in a blinded manner and was compared with a white light image (bad, 0; equal, 1; good, 2). The diameter of the lumen and the depth of the EVs and RCS from the epithelium were measured by EUS. The relation between the visibility scores and the EUS findings was investigated. RESULTS: The DRI scores were 1.66 +/- 0.34 for the EV substance and 1.79 +/- 0.28 for the RCS, whereas the NBI scores were 0.68 +/- 0.38 and 0.41 +/- 0.28, respectively. A significant negative correlation was found between the depth and the visibility score (r = -0.505, p = 0.001 for EVs; r = -0.458, p = 0.003 for RCS). CONCLUSIONS: DRI increased the visibility of the EVs and RCS. The visibility of the EVs or RCS in the shallower position was more enhanced by DRI. Visual recognition of the changing degrees of visibility by DRI enables the prediction of the depth of EVs. PMID- 27502190 TI - AvaR2, a pseudo gamma-butyrolactone receptor homologue from Streptomyces avermitilis, is a pleiotropic repressor of avermectin and avenolide biosynthesis and cell growth. AB - Avermectins produced by Streptomyces avermitilis are effective anthelmintic agents. The autoregulatory signalling molecule that triggers avermectin biosynthesis is a novel butenolide-type molecule, avenolide, rather than common gamma-butyrolactones (GBLs). We identified AvaR2, a pseudo GBL receptor homologue, as an important repressor of avermectin and avenolide biosynthesis and cell growth. AvaR2 directly repressed transcription of aveR (the ave cluster situated activator gene), aco (a key gene for avenolide biosynthesis), its own gene (avaR2) and two other GBL receptor homologous genes (avaR1 and avaR3) by binding to their promoter regions. The aveR promoter had the highest affinity for AvaR2. A consensus 18 bp ARE (autoregulatory element)-like sequence was found in the AvaR2-binding regions of these five target genes. Eleven novel AvaR2 targets were identified, including genes involved in primary metabolism, ribosomal protein synthesis, and stress responses. AvaR2 bound and responded to endogenous avenolide and exogenous antibiotics jadomycin B (JadB) and aminoglycosides to modulate its DNA-binding activity. Our findings help to clarify the roles of pseudo GBL receptors as pleiotropic regulators and as receptors for new type autoregulator and exogenous antibiotic signal. A pseudo GBL receptor-mediated antibiotic signalling transduction system may be a common strategy that facilitates Streptomyces interspecies communication and survival in complex environments. PMID- 27502191 TI - High-dose ustekinumab for the treatment of severe, recalcitrant pyoderma gangrenosum. PMID- 27502192 TI - Solvothermal Synthesis, Structure and Optical Property of Nanosized CoSb3 Skutterudite. AB - Binary skutterudite CoSb3 nanoparticles were synthesized by solvothermal method. The nanostructuring of CoSb3 material was achieved by the inclusion of various kinds of additives. X-ray diffraction examination indicated the formation of the cubic phase of CoSb3. Structural analysis by transmission electron microscopy analysis further confirmed the formation of crystalline CoSb3 nanoparticles with high purity. With the assistance of additives, CoSb3 nanoparticles with size as small as 10 nm were obtained. The effect of the nanostructure of CoSb3 on the UV visible absorption and luminescence was studied. The nanosized CoSb3 skutterudite may find application in developing thermoelectric devices with better efficiency. PMID- 27502193 TI - Erratum to: One-Step UV-Induced Synthesis of Polypyrrole/Ag Nanocomposites at the Water/Ionic Liquid Interface. PMID- 27502194 TI - An anatomical study of the orbital floor in relation to the infraorbital groove: implications of predisposition to orbital floor fracture site. AB - PURPOSE: To examine the anatomy of the orbital floor in relation to the infraorbital groove. METHODS: Twenty-two Japanese cadavers aged 86.9 +/- 6.0 years at death were used. We examined whether the bony overhang on the infraorbital nerve extending laterally was connected to the segment medial to the infraorbital groove. The bone thicknesses at 1, 2, and 3 mm anterior to the junction between the infraorbital groove and the inferior orbital fissure were measured along the groove. We examined the angle between the infraorbital groove and the orbital floor, both at the medial and lateral margins, at the thinnest point in the above three measurement points. We used the measurement values examined in the left orbits to prevent doubling the number of the orbits. RESULTS: The bony overhang was not connected to the medial segment in 19 (86.4 %) orbits. The thickness at the thinnest point was thinner in the medial portion (1.02 +/- 1.20 mm) than in the lateral portion (2.60 +/- 1.82 mm; p = 0.001). The angle between the medial margin and the orbital floor was obtuse (156.5 degrees +/- 12.3 degrees ), compared with that of the lateral margin (104.0 degrees +/- 17.0 degrees ; p < 0.001). CONCLUSIONS: The results of this study imply that the medial portion has an anatomical weakness and few supportive structures. Although these findings were obtained only from Japanese cadavers, there may be associated with frequent occurrences of an orbital floor fracture just medial to the infraorbital groove. PMID- 27502195 TI - Practice of ultrasound-guided central venous catheter technique by the French intensivists: a survey from the BoReal study group. AB - BACKGROUND: The ultrasound (US)-guided technique has been recommended for central venous catheter (CVC) placement in critical care. However, several surveys have shown that the majority of physicians continue to perform landmark procedures. In our region, we have implemented special courses to promote the use of US with formal training and simulators. Ultrasound machines have also been installed in almost every ICU in our area. We designed a survey to investigate whether the training program established for years and the widespread of ultrasound devices in the ICU of our region will be associated with a high rate of physicians performing US procedures. METHODS: A survey comprising 14 questions was designed to elicit information on training in US techniques, the use of US for CVC placement, reasons for nonuse of US and their opinion concerning the need to teach the landmark technique to residents. This survey was electronically sent to every physician of the BoReal study group (32 ICUs located in the North West of France). RESULTS: We received 190 responses (response rate 66 %) including 34 % of residents. Only 11 % of respondents reported the absence of training in the US technique, and 3 % reported they did not have access to an ultrasound machine. A total of 68 % declared "always" (18 %) or "almost always" (50 %) using US to guide CVC placement. Our results are better than those of previous surveys. The main reasons why physicians did not use the US technique were that they thought that US guidance was unnecessary (36 %) or because the ultrasound machine was not immediately available (33 %). Ninety-one percentages think that the landmark technique should still be taught to the residents. A higher proportion of residents compared to seniors declared that they always or almost always used the US technique. CONCLUSION: Training in ultrasound techniques and the widespread availability of ultrasound machines in ICUs seem to improve the rate of US procedures. However, despite strong scientific evidence a proportion of physicians continue to consider the landmark technique as an alternative to US. Training and education are potentially still the best ways to overcome such barriers or conviction. PMID- 27502197 TI - Women's Use of Health Care in the First 2 Years Postpartum: Occurrence and Correlates. AB - Objectives We sought to determine rates and correlates of accessing health care in the 2 years following delivery among women at an urban academic medical center. Methods We used electronic medical records, discharge, and billing data to determine the occurrence of primary care, other non-primary outpatient care, emergency department visits, and inpatient admissions among women delivering at a single medical center who had a known primary care affiliation to that medical center over a 5 year period. We explored sociodemographic, clinical, and health care-related factors as correlates of care, using bivariate and multivariable modeling. Results Of 6216 women studied, most (91 %) had had at least one health care visit in the window between 2 months and 2 years postpartum (the "late postpartum period"). The majority (81 %) had had a primary care visit. Factors associated with use of health care in this period included a chronic medical condition diagnosed prior to pregnancy (adjusted odds ratio (AOR) 1.42, 95 % CI [1.19, 1.71]), prenatal care received in an urban community health center (AOR 1.35 [1.06, 1.73]), having received obstetric (AOR 1.90 [1.51, 2.37]), primary (AOR 2.30 [1.68, 3.23]), or other non-primary outpatient care (AOR 2.35 [1.72, 3.39]) in the first 2 months postpartum, and living closer to the hospital [AOR for residence >17.8 miles from the medical center (AOR 0.74 [0.61, 0.90])]. Having had an obstetrical complication did not increase the likelihood of receipt of care during this window. Conclusions for Practice Among women already enrolled in a primary care practice at our medical center, health care utilization in the late postpartum period is high, but not universal. Understanding the characteristics of women who return for health care during this window, and where they are seen, can improve transitions of care across the life course and can provide opportunities for important and consistent interconception and well-woman messaging. PMID- 27502196 TI - Polymyxin-B hemoperfusion in septic patients: analysis of a multicenter registry. AB - BACKGROUND: In 2010, the EUPHAS 2 collaborative group created a registry with the purpose of recording data from critically ill patients suffering from severe sepsis and septic shock treated with polymyxin-B hemoperfusion (PMX-HP) for endotoxin removal. The aim of the registry was to verify the application of PMX HP in the daily clinical practice. METHODS: The EUPHAS 2 registry involved 57 centers between January 2010 and December 2014, collecting retrospective data of 357 patients (297 in Europe and 60 in Asia) suffering from severe sepsis and septic shock caused by proved or suspected infection related to Gram negative bacteria. All patients received atleast one cycle of extracorporeal endotoxin removal by PMX-HP. RESULTS: Septic shock was diagnosed in 305 (85.4 %) patients. The most common source of infection was abdominal (44.0 %) followed by pulmonary (17.6 %). Gram negative bacteria represented 60.6 % of the pathogens responsible of infection. After 72 h from the first cycle of PMX-HP, some of the SOFA score components significantly improved with respect to baseline: cardiovascular (2.16 +/- 1.77 from 3.32 +/- 1.29, p < 0.0001), respiratory (1.95 +/- 0.95 from 2.40 +/ 1.06, p < 0.001) and renal (1.84 +/- 1.77 from 2.23 +/- 1.62, p = 0.013). Overall 28-day survival rate was 54.5 % (60.4 % in abdominal and 47.5 % in pulmonary infection). Patients with abdominal infection treated with PMX-HP within 24 h from the diagnosis of septic shock had a 28-day survival rate of 64.5 %. Patients showing a significantly cardiovascular improvement after PMX-HP had a 28-survival rate of 75 % in comparison to the 39 % of patients who did not (p < 0.001). Cox regression analysis found the variation of cardiovascular, respiratory and coagulation SOFA to be independent covariates for 28-day survival. In European patients were observed a higher 28-day (58.8 vs. 34.5 %, p = 0.003), ICU (59 vs. 36.7 %, p = 0.006) and hospital survival rate (53.2 vs. 35 %, p = 0.02) than in Asian patients. However, the two populations were highly heterogeneous in terms of source of infection and severity scores at admission. CONCLUSION: The EUPHAS 2 is the largest registry conducted outside Japan on the clinical use of PMX-HP in septic patients. Data analysis confirmed the feasibility of PMX-HP to treat septic patients in daily clinical practice, showing clinical benefits associated with endotoxin removal without significant adverse events related to the extracorporeal technique. PMID- 27502198 TI - The Ohio Gestational Diabetes Postpartum Care Learning Collaborative: Development of a Quality Improvement Initiative to Improve Systems of Care for Women. AB - Objectives To improve clinical practice and increase postpartum visit Type 2 diabetes mellitus (T2DM) screening rates in women with a history of gestational diabetes mellitus (GDM). Methods We recruited clinical sites with at least half of pregnant patients enrolled in Medicaid to participate in an 18-month quality improvement (QI) project. To support clinical practice changes, we developed provider and patient toolkits with educational and clinical practice resources. Clinical subject-matter experts facilitated a learning network to train sites and promote discussion and learning among sites. Sites submitted data from patient chart reviews monthly for key measures that we used to provide rapid-cycle feedback. Providers were surveyed at completion regarding toolkit usefulness and satisfaction. Results Of fifteen practices recruited, twelve remained actively engaged. We disseminated more than 70 provider and 2345 patient toolkits. Documented delivery of patient education improved for timely GDM prenatal screening, reduction of future T2DM risk, smoking cessation, and family planning. Sites reported toolkits were useful and easy to use. Of women for whom postpartum data were available, 67 % had a documented postpartum visit and 33 % had a postpartum T2DM screen. Lack of information sharing between prenatal and postpartum care providers was are barriers to provision and documentation of care. Conclusions for Practice QI and toolkit resources may improve the quality of prenatal education. However, postpartum care did not reach optimal levels. Future work should focus on strategies to support coordination of care between obstetrical and primary care providers. PMID- 27502199 TI - Advancing MCH Interdisciplinary/Interprofessional Leadership Training and Practice Through a Learning Collaborative. AB - Purpose The Interdisciplinary Leadership Learning Collaborative (ILLC), under the sponsorship of AUCD and the Maternal and Child Health Bureau, brought together six teams, composed of 14 MCHB and UCEDD training programs to enhance their leadership training. Description Using adult learning principles, interactive training methods, and skill-focused learning, the ILLC built upon the evidence based Interdisciplinary Leadership Development Program of the University of North Carolina at Chapel Hill. The program began with a 4-day on-site intensive and then continued through monthly conference calls, a mid-term on-site workshop, and a summary virtual workshop to present programmatic accomplishments and share plans for sustainability. Coaching/consultation for the teams around particular challenges was also part of the program. Assessment All teams reported enhancements in intentional leadership training, threading of leadership concepts across clinical, didactic, and workshop settings, and new collaborative partnerships for leadership training. Teams also identified a number of strategies to increase sustainability of their intentional leadership training efforts. Conclusion for Practice The learning collaborative is a productive model to address the growing need for interdisciplinary MCH leaders. PMID- 27502200 TI - A rapid marker ordering approach for high-density genetic linkage maps in experimental autotetraploid populations using multidimensional scaling. AB - KEY MESSAGE: The paper proposes and validates a robust method for rapid construction of high-density linkage maps suitable for autotetraploid species. Modern genotyping techniques are producing increasingly high numbers of genetic markers that can be scored in experimental populations of plants and animals. Ordering these markers to form a reliable linkage map is computationally challenging. There is a wide literature on this topic, but most has focussed on populations derived from diploid, homozygous parents. The challenge of ordering markers in an autotetraploid population has received little attention, and there is currently no method that runs sufficiently rapidly to investigate the effects of omitting problematic markers on map order in larger datasets. Here, we have explored the use of multidimensional scaling (MDS) to order markers from a cross between autotetraploid parents, using simulated data with 74-152 markers on a linkage group and also experimental data from a potato population. We compared different functions of the recombination fraction and LOD score to form the MDS stress function and found that an LOD2 weighting generally performed well, including when missing values and genotyping errors are present. We conclude that an initial analysis using unconstrained MDS gives a rapid method to detect and remove problematic markers, and that a subsequent analysis using either constrained MDS or principal curve analysis gives reliable marker orders. The latter approach is also particularly rapid, taking less than 10 s on a set of 258 markers compared to 6 days for the JoinMap software. This MDS approach could also be applied to experimental populations of diploid species. PMID- 27502201 TI - Stigma and Mental Health: A Proposal for Next Steps. PMID- 27502202 TI - Comparison of chemical compositions in air particulate matter during summer and winter in Beijing, China. AB - The development of industry in Beijing, the capital of China, particularly in last decades, has caused severe environmental pollution including particulate matter (PM), dust-haze, and photochemical smog, which has already caused considerable harm to local ecological environment. Thus, in this study, air particle samples were continuously collected in August and December, 2014. And elements (Si, Al, V, Cr, Mn, Fe, Ni, Cu, Zn, Mo, Cd, Ba, Pb and Ti) and ions ([Formula: see text], [Formula: see text], F-, Cl-, Na+, K+, Mg2+, Ca2+ and [Formula: see text]) were analyzed by inductively coupled plasma mass spectrometer and ion chromatography. According to seasonal changes, discuss the various pollution situations in order to find possible particulate matter sources and then propose appropriate control strategies to local government. The results indicated serious PM and metallic pollution in some sampling days, especially in December. Chemical Mass Balance model revealed central heating activities, road dust and vehicles contribute as main sources, account for 5.84-32.05 % differently to the summer and winter air pollution in 2014. PMID- 27502203 TI - Aboveground Epichloe coenophiala-Grass Associations Do Not Affect Belowground Fungal Symbionts or Associated Plant, Soil Parameters. AB - Cool season grasses host multiple fungal symbionts, such as aboveground Epichloe endophytes and belowground arbuscular mycorrhizal fungi (AMF) and dark septate endophytes (DSEs). Asexual Epichloe endophytes can influence root colonization by AMF, but the type of interaction-whether antagonistic or beneficial-varies. In Schedonorus arundinaceus (tall fescue), Epichloe coenophiala can negatively affect AMF, which may impact soil properties and ecosystem function. Within field plots of S. arundinaceus that were either E. coenophiala-free (E-), infected with the common, mammal-toxic E. coenophiala strain (CTE+), or infected with one of two novel, non-toxic strains (AR542 NTE+ and AR584 NTE+), we hypothesized that (1) CTE+ would decrease AMF and DSE colonization rates and reduce soil extraradical AMF hyphae compared to E- or NTE+, and (2) this would lead to E- and NTE+ plots having greater water stable soil aggregates and C than CTE+. E. coenophiala presence and strain did not significantly alter AMF or DSE colonization, nor did it affect extraradical AMF hypha length, soil aggregates, or aggregate-associated C and N. Soil extraradical AMF hypha length negatively correlated with root AMF colonization. Our results contrast with previous demonstrations that E. coenophiala symbiosis inhibits belowground AMF communities. In our mesic, relatively nutrient-rich grassland, E. coenophiala symbiosis did not antagonize belowground symbionts, regardless of strain. Manipulating E. coenophiala strains within S. arundinaceus may not significantly alter AMF communities and nutrient cycling, yet we must further explore these relationships under different soils and environmental conditions given that symbiont interactions can be important in determining ecosystem response to global change. PMID- 27502204 TI - Obstructive sleep apnea is associated with visit-to-visit variability in low density lipoprotein-cholesterol in patients with coronary artery disease. AB - PURPOSE: Visit-to-visit variability in low-density lipoprotein-cholesterol (LDL C) was found to be a novel predictor of adverse cardiac events. Obstructive sleep apnea (OSA), an emerging cardiovascular risk factor, is characterized by sympathetic activation and increased oxidative stress which are regulators of LDL C metabolism. We hypothesized that OSA was associated with LDL-C variability. METHODS: We prospectively recruited 190 patients with coronary artery disease for an overnight sleep study. Statin was prescribed upon discharge for 186 patients. Serum LDL-C levels were measured at clinic every 3 to 6 months. Severity of OSA (on the basis of apnea-hypopnea index (AHI)) was correlated with visit-to-visit LDL-C variability (on the basis of variation independent of mean (VIM)) in outpatient clinic. RESULTS: The mean AHI was 21.9 +/- 18.9. Using an AHI cut-off of 5-14.9, 15-29.9, and >=30, the prevalence of mild, moderate, and severe OSA was 26.3, 18.9, and 27.4 %, respectively. After 53.2 +/- 25.3 months, LDL-C was recorded over 8.1 +/- 4.2 measurements. VIM positively correlated with AHI (Pearson's r = 0.183, p = 0.016), but not body mass index, baseline and mean follow-up LDL-C levels, and number of LDL-C measurements. In multiple linear regression analysis, AHI remained an independent predictor of VIM after adjusting for diabetes mellitus and hyperlipidemia. A 10-unit rise in AHI led to a 3.8 % increase in VIM (95 % CI 0.1 to 7.4 %; p = 0.044). CONCLUSION: This is the first study to show the independent correlation between OSA severity and visit-to-visit LDL-C variability. Our finding contributes to the understanding of the vasculopathic effects of OSA. PMID- 27502205 TI - Meta-analysis of all-cause and cardiovascular mortality in obstructive sleep apnea with or without continuous positive airway pressure treatment. AB - PURPOSE: The associations between obstructive sleep apnea (OSA) and all-cause and cardiovascular mortality are well established but are not entirely consistent. To accurately evaluate these associations as well as the therapeutic effects of continuous positive airway pressure (CPAP), we conducted a comprehensive meta analysis of all eligible cohort studies. METHODS: Electronic literature databases (i.e., PubMed and Embase) were searched for relevant studies published before January 2016 that evaluated the associations between OSA and all-cause or cardiovascular mortality. Random-effect models were used to calculate the pooled hazard ratio (HR) and corresponding 95 % confidence intervals (CIs) for categorical risk estimates. The therapeutic effects of CPAP treatment for all cause and cardiovascular mortality in OSA were examined through the meta analysis. RESULTS: The 27 cohort studies included in the meta-analysis included 3,162,083 participants. Compared to the control group, the pooled HR of all-cause mortality was 1.19 (95 % CI, 0.86-1.65) for mild OSA, 1.28 (0.96-1.69) for moderate OSA, and 2.13 (1.68-2.68) for severe OSA. The pooled HR of cardiovascular mortality was 1.24 (0.53-2.55) for mild OSA, 2.05 (0.57-5.47) for moderate OSA, and 2.73 (1.94-3.85) for severe OSA. All-cause mortality (HR 0.66; 0.59-0.73) and cardiovascular mortality (HR 0.37; 0.16-0.54) were significantly lower in CPAP-treated than in untreated patients. There were no differences in cardiovascular mortality in CPAP-treated OSA patients vs. normal control subjects (HR 0.82; 0.52-1.29). CONCLUSIONS: Greater attention should be paid to severe OSA, as it is an independent predictor for risk for all-cause and cardiovascular mortality. CPAP is an effective treatment that reduces risk of mortality. PMID- 27502206 TI - Microbial functional genes enriched in the Xiangjiang River sediments with heavy metal contamination. AB - BACKGROUND: Xiangjiang River (Hunan, China) has been contaminated with heavy metal for several decades by surrounding factories. However, little is known about the influence of a gradient of heavy metal contamination on the diversity, structure of microbial functional gene in sediment. To deeply understand the impact of heavy metal contamination on microbial community, a comprehensive functional gene array (GeoChip 5.0) has been used to study the functional genes structure, composition, diversity and metabolic potential of microbial community from three heavy metal polluted sites of Xiangjiang River. RESULTS: A total of 25595 functional genes involved in different biogeochemical processes have been detected in three sites, and different diversities and structures of microbial functional genes were observed. The analysis of gene overlapping, unique genes, and various diversity indices indicated a significant correlation between the level of heavy metal contamination and the functional diversity. Plentiful resistant genes related to various metal were detected, such as copper, arsenic, chromium and mercury. The results indicated a significantly higher abundance of genes involved in metal resistance including sulfate reduction genes (dsr) in studied site with most serious heavy metal contamination, such as cueo, mer, metc, merb, tehb and terc gene. With regard to the relationship between the environmental variables and microbial functional structure, S, Cu, Cd, Hg and Cr were the dominating factor shaping the microbial distribution pattern in three sites. CONCLUSIONS: This study suggests that high level of heavy metal contamination resulted in higher functional diversity and the abundance of metal resistant genes. These variation therefore significantly contribute to the resistance, resilience and stability of the microbial community subjected to the gradient of heavy metals contaminant in Xiangjiang River. PMID- 27502207 TI - Amelotin gene expression is temporarily being upregulated at the initiation of apoptosis induced by TGFbeta1 in mouse gingival epithelial cells. AB - Amelotin (AMTN) is expressed and secreted by ameloblasts in the maturation stage of amelogenesis and persist with low levels in the junctional epithelium (JE) of erupted teeth. The purpose of this study is to investigate the transcriptional regulation of the AMTN gene by transforming growth factor beta1 (TGFbeta1) in gingival epithelial (GE1) cells in the apoptosis phase. Apoptosis was evaluated by the fragmentation of chromosomal DNA and TUNEL staining. A real-time PCR was carried out to examine the AMTN mRNA levels induced by TGFbeta1 and Smad3 overexpression. Transient transfection analyses were completed using the various lengths of mouse AMTN gene promoter constructs with or without TGFbeta1. Chromatin immunoprecipitation (ChIP) assays were performed to investigate the Smad3 bindings to the AMTN gene promoter by TGFbeta1. TGFbeta1-induced apoptosis in GE1 cells were detected at 24 and 48 h by DNA fragmentation and TUNEL staining. AMTN mRNA levels increased at 6 h and reached maximum at 24 h in GE1 cells. Luciferase activities of the mouse AMTN gene promoter constructs were induced by TGFbeta1. The results of the ChIP assays showed that there was an increase in Smad3 binding to Smad-binding element (SBE)#1 and SBE#2 after stimulation by TGFbeta1. Immunohistochemical localization of AMTN was detected in the JE, and the AMTN protein levels in Smad3-deficient mice were decreased compared with wild-type mice. AMTN mRNA levels were induced at the initiation of apoptosis by TGFbeta1, which mediated through the Smad3 bindings to SBEs in the mouse AMTN gene promoter. PMID- 27502208 TI - Novel SAHA analogues inhibit HDACs, induce apoptosis and modulate the expression of microRNAs in hepatocellular carcinoma. AB - In eukaryotes, transcriptional regulation occurs via chromatin remodeling, mainly through post translational modifications of histones that package DNA into structural units. Histone deacetylases (HDACs) are enzymes that play important role in various biological processes by repressing gene expression. Suberoylanilide hydroxamic acid (SAHA) is a known HDAC inhibitor that showed significant anti cancer activity by relieving gene silencing against hematologic and solid tumors. We have designed and synthesized a series of SAHA analogs C1-C4 and performed biological studies to elucidate its anti-cancer effects. It is observed that SAHA analogs significantly inhibited cell proliferation and induced apoptosis in hepatocellular carcinoma (HCC) cell lines HepG2 and SK-HEP-1. These analogs also showed non-toxic activity towards primary human hepatocytes, which describes its tumor specificity. SAHA analogs exhibited strong HDAC inhibition, which is 2-3 fold higher compared to SAHA. Moreover, these molecules induced hyper acetylation of histone H3 at various positions on the lysine residue. Further, it is observed that SAHA analogs are strong inducers of apoptosis, as they regulated the expression of various proteins involved in both extrinsic and intrinsic pathways. Interestingly, SAHA analogs induced upregulation of tumor suppressor miRNAs by activating its biogenesis pathway. Further, it is confirmed by microRNA (miRNA) prediction tools that these miRNAs are capable of targeting various anti-apoptotic genes. Based on these findings we conclude that SAHA analogs could be strong HDAC inhibitors with promising apoptosis inducing nature in HCC. PMID- 27502209 TI - Assessing Computational Fractional Flow Reserve From Optical Coherence Tomography in Patients With Intermediate Coronary Stenosis in the Left Anterior Descending Artery. AB - BACKGROUND: Intravascular optical coherence tomography (OCT) imaging provides limited information on the functional assessment of coronary stenosis. We evaluated a new approach to OCT image-based computation modeling, which can be used to estimate the fractional flow reserve (FFR) in patients with intermediate coronary stenosis. METHODS AND RESULTS: Ninety-two patients with intermediate diameter stenosis in the left anterior descending artery underwent both FFR measurement with pressure wires and OCT examination. Using the OCT data, a computational fluid dynamics algorithm was used to calculate the computational FFR (FFROCT). The diagnostic performance of the FFROCT was assessed based on the pressure wire-based FFR. The median FFR and FFROCT values were 0.86 (0.79-0.89) and 0.89 (0.82-0.94), respectively. The average diameter stenosis in quantitative coronary angiography and area stenosis in OCT were 58.1+/-13.4% and 67.5+/-13.5%, respectively. The FFROCT was better correlated to the FFR than were the anatomic variables (r=0.72; P<0.001 versus r=0.46; P<0.001 for minimal luminal diameter on quantitative coronary angiography or r=0.57; P<0.001 for minimal lumen area on OCT). When functionally significant stenosis was defined as an FFR cutoff value of <=0.8, FFROCT resulted in 88.0% accuracy, 68.7% sensitivity, and 95.6% specificity. The positive and negative predictive values were 84.2% and 89.0%, respectively. CONCLUSIONS: The computation of FFROCT enables assessment not only of anatomic information, but also of the functional significance of intermediate stenosis. This measurement may be a useful approach for the simultaneous evaluation of the functional and anatomic severity of coronary stenosis. PMID- 27502210 TI - Letter by Saad et al Regarding Article, "Outcomes With Intravascular Ultrasound Guided Stent Implantation: A Meta-Analysis of Randomized Trials in the Era of Drug-Eluting Stents". PMID- 27502211 TI - Response by Elgendy et al to Letter Regarding Article, "Outcomes With Intravascular Ultrasound-Guided Stent Implantation: A Meta-Analysis of Randomized Trials in the Era of Drug-Fluting Stents". PMID- 27502212 TI - Women in Interventional Cardiology: Small Numbers, Big Impact. PMID- 27502213 TI - A qualitative review of implementer perceptions of the national community-level malaria surveillance system in Southern Province, Zambia. AB - BACKGROUND: Parts of Zambia with very low malaria parasite prevalence and high coverage of vector control interventions are targeted for malaria elimination through a series of interventions including reactive case detection (RCD) at community level. When a symptomatic individual presenting to a community health worker (CHW) or government clinic is diagnostically confirmed as an incident malaria case an RCD response is initiated. This consists of a CHW screening the community around the incident case with rapid diagnostic tests (RDT) and treating positive cases with artemether-lumefantrine (AL, CoartemTM) in accordance with national policy. Since its inception in 2011, Zambia's RCD programme has relied on anecdotal feedback from staff to identify issues and possible solutions. In 2014, a systematic qualitative programme review was conducted to determine perceptions around malaria rates, incentives, operational challenges and solutions according to CHWs, their supervisors and district-level managers. METHODS: A criterion-based sampling framework based on training regime and performance level was used to select nine rural health posts in four districts of Southern Province. Twenty-two staff interviews were completed to produce English or bilingual (CiTonga or Silozi + English) verbatim transcripts, which were then analysed using thematic framework analysis. RESULTS: CHWs, their supervisors and district-level managers strongly credited the system with improving access to malaria services and significantly reducing the number of cases in their area. The main implementation barriers included access (e.g., lack of rain gear, broken bicycles), insufficient number of CHWs for programme coverage, communication (e.g. difficulties maintaining cell phones and "talk time" to transmit data by phone), and inconsistent supply chain (e.g., inadequate numbers of RDT kits and anti-malarial drugs to test and treat uncomplicated cases). CONCLUSIONS: This review highlights the importance of a community surveillance system like RCD in shaping Zambia's malaria elimination campaign by identifying community-based infections that might otherwise remain undetected. At this stage the system must ensure it can meet growing public demand by providing CHWs the tools and materials they need to consistently carry out their work and expand programme reach to more isolated communities. Results from this review will be used to plan programme scale-up into other parts of Zambia. PMID- 27502214 TI - Understanding the double burden of malnutrition in food insecure households in Brazil. AB - Household food insecurity (HFI) has been associated with both obesity among mothers and undernutrition among children. However, this association has not been well investigated in mother/child pairs living in the same household. The objective of this study was to examine the relationship of coexistence of maternal overweight and child stunting with HFI in Brazil. We conducted secondary data analyses of the 2006 Brazilian National Demographic and Health Survey. We analyzed the nutritional status of 4299 pairs of 15-49-year-olds mothers and their children under 5 years of age. The double burden of malnutrition (DBM) was defined as the presence of an overweight mother and a stunted child in the same household. HFI was measured with the Brazilian HFI Measurement Scale. The association between DBM and HFI was examined with hierarchical multivariable logistic regression analyses. Severe HFI was associated with DBM after adjusting for macroeconomic and household level socio-economic and demographic variables (Adjusted OR: 2.65 - CI: 1.17-8.53). Findings suggest that policies and programmes targeting HFI are needed to prevent the coexistence of child chronic undernutrition and maternal overweight/obesity in the same household. These investments are likely to be highly cost-effective as stunting has been identified as one of the major risk factors for poor child development and adult overweight/obesity and a strong risk factor for the development of costly chronic diseases including type 2 diabetes and cardiovascular disease. PMID- 27502215 TI - Spindle-cell rhabdomyosarcoma of the thumb: Rare site, rare tumor in a child. AB - Spindle-cell rhabdomyosarcoma (RMS) is a relatively recently recognized favorable variant of embryonal RMS occurring mainly in the paratesticular and head and neck regions. Cytological reports of spindle-cell RMS have been sparse in the literature and the awareness of its cytological features is not very wide among cytopathologists. A 2-year-old girl was brought to clinical attention for a progressively enlarging swelling of right thumb. Imaging studies showed it to be a soft-tissue tumor in the subcutaneous region. Fine-needle aspiration yielded moderately cellular smears composed of small, round cells and few spindle cells with tapered cytoplasm. A cytological impression of RMS was rendered, which was later confirmed as spindle-cell RMS on excision biopsy. Spindle-cell RMS, a favorable prognostic variant of embryonal RMS, should be considered in the cytologic diagnosis of soft-tissue tumors with round cell and spindle cell morphology. This is especially true for tumors occurring in hitherto unreported sites. Diagn. Cytopathol. 2016;44:1094-1097. (c) 2016 Wiley Periodicals, Inc. PMID- 27502216 TI - Disorganized Amygdala Networks in Conduct-Disordered Juvenile Offenders With Callous-Unemotional Traits. AB - BACKGROUND: The developmental trajectory of psychopathy seemingly begins early in life and includes the presence of callous-unemotional (CU) traits (e.g., deficient emotional reactivity, callousness) in conduct-disordered (CD) youth. Though subregion-specific anomalies in amygdala function have been suggested in CU pathophysiology among antisocial populations, system-level studies of CU traits have typically examined the amygdala as a unitary structure. Hence, nothing is yet known of how amygdala subregional network function may contribute to callous-unemotionality in severely antisocial people. METHODS: We addressed this important issue by uniquely examining the intrinsic functional connectivity of basolateral amygdala (BLA) and centromedial amygdala (CMA) networks across three matched groups of juveniles: CD offenders with CU traits (CD/CU+; n = 25), CD offenders without CU traits (CD/CU-; n = 25), and healthy control subjects (n = 24). We additionally examined whether perturbed amygdala subregional connectivity coincides with altered volume and shape of the amygdaloid complex. RESULTS: Relative to CD/CU- and healthy control youths, CD/CU+ youths showed abnormally increased BLA connectivity with a cluster that included both dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices, along with posterior cingulate, sensory associative, and striatal regions. In contrast, compared with CD/CU- and healthy control youths, CD/CU+ youths showed diminished CMA connectivity with ventromedial/orbitofrontal regions. Critically, these connectivity changes coincided with local hypotrophy of BLA and CMA subregions (without being statistically correlated) and were associated to more severe CU symptoms. CONCLUSIONS: These findings provide unique insights into a putative mechanism for perturbed attention-emotion interactions, which could bias salience processing and associative learning in youth with CD/CU+. PMID- 27502217 TI - Representing genetic variation with synthetic DNA standards. AB - The identification of genetic variation with next-generation sequencing is confounded by the complexity of the human genome sequence and by biases that arise during library preparation, sequencing and analysis. We have developed a set of synthetic DNA standards, termed 'sequins', that emulate human genetic features and constitute qualitative and quantitative spike-in controls for genome sequencing. Sequencing reads derived from sequins align exclusively to an artificial in silico reference chromosome, rather than the human reference genome, which allows them them to be partitioned for parallel analysis. Here we use this approach to represent common and clinically relevant genetic variation, ranging from single nucleotide variants to large structural rearrangements and copy-number variation. We validate the design and performance of sequin standards by comparison to examples in the NA12878 reference genome, and we demonstrate their utility during the detection and quantification of variants. We provide sequins as a standardized, quantitative resource against which human genetic variation can be measured and diagnostic performance assessed. PMID- 27502218 TI - Spliced synthetic genes as internal controls in RNA sequencing experiments. AB - RNA sequencing (RNA-seq) can be used to assemble spliced isoforms, quantify expressed genes and provide a global profile of the transcriptome. However, the size and diversity of the transcriptome, the wide dynamic range in gene expression and inherent technical biases confound RNA-seq analysis. We have developed a set of spike-in RNA standards, termed 'sequins' (sequencing spike ins), that represent full-length spliced mRNA isoforms. Sequins have an entirely artificial sequence with no homology to natural reference genomes, but they align to gene loci encoded on an artificial in silico chromosome. The combination of multiple sequins across a range of concentrations emulates alternative splicing and differential gene expression, and it provides scaling factors for normalization between samples. We demonstrate the use of sequins in RNA-seq experiments to measure sample-specific biases and determine the limits of reliable transcript assembly and quantification in accompanying human RNA samples. In addition, we have designed a complementary set of sequins that represent fusion genes arising from rearrangements of the in silico chromosome to aid in cancer diagnosis. RNA sequins provide a qualitative and quantitative reference with which to navigate the complexity of the human transcriptome. PMID- 27502219 TI - Africa's jungle and the arch: Of elephants and CHIMPS. PMID- 27502220 TI - "Foot and Ankle Surgery" is awarded its first impact factor. PMID- 27502221 TI - Does external fixation result in superior ankle function than open reduction internal fixation in the management of adult distal tibial plafond fractures? AB - BACKGROUND: Traditionally distal tibial plafond fractures were managed with open reduction internal fixation however, high complication rates have prompted the use of external fixation as an alternative. No definitive review has been conducted and the issue of superior treatment method remains contentious. This review assesses the comparative effectiveness of both with regards ankle function. METHOD: A search strategy was formulated with keywords ensuring full use of Medical Subject Headings terms for maximum sensitivity with Boolean combinations. Multiple databases were used. RESULTS: All papers had limitations, hence results and conclusions must be considered conservatively. Paper-1 demonstrated an association between ORIF and superior ankle function (P<0.05). Papers-2 and -3 demonstrated no significant difference (P>0.05) between treatment techniques. CONCLUSIONS: Neither method can yet be widely advocated as superior with the treatment method chosen remaining primarily on surgeon preference and experience. This review highlights the requirement for further, high-quality research in this area. PMID- 27502222 TI - Short term results of the Mobility Total Ankle System: Clinical and radiographic outcome. AB - BACKGROUND: Ankle arthroplasty is increasingly used to reduce pain and improve or maintain joint mobility in end-stage ankle arthritis. The aim of this study was to assess the clinical and radiographic short term results of the Mobility prosthesis. METHODS: Complications, secondary operations, failures and the survival rate were retrospectively examined in 67 primary Mobility total ankle arthroplasties. Prosthesis alignment was measured and patient reported outcomes were assessed with the use of questionnaires. RESULTS: There were two intraoperative and 13 postoperative complications, requiring seven reoperations. Failure occurred in three cases, with a survival of 95% after 61 months. Clinical scores improved after surgery and alignment was correct in 93% of the tibial and 93% of the talar components. CONCLUSION: Despite few intraoperative complications and satisfactory clinical and radiological outcome, the incidence of postoperative complications, reoperations and failure indicate the importance of further development and research in the field of ankle arthroplasty. PMID- 27502223 TI - Comparison of modern locked plating and antiglide plating for fixation of osteoporotic distal fibular fractures. AB - BACKGROUND: Fractures in osteoporotic patients can be difficult to treat because of poor bone quality and inability to gain screw purchase. The purpose of this study is to compare modern lateral periarticular distal fibula locked plating to antiglide plating in the setting of an osteoporotic, unstable distal fibula fracture. METHODS: AO/OTA 44-B2 distal fibula fractures were created in sixteen paired fresh frozen cadaveric ankles and fixed with a lateral locking plate and an independent lag screw or an antiglide plate with a lag screw through the plate. The specimens underwent stiffness, cyclic loading, and load to failure testing. The energy absorbed until failure, torque to failure, construct stiffness, angle at failure, and energy at failure was recorded. RESULTS: The lateral locking construct had a higher torque to failure (p=0.02) and construct stiffness (p=0.04). The locking construct showed a trend toward increased angle at failure, but did not reach statistical significance (p=0.07). Seven of the eight lateral locking plate specimens failed through the distal locking screws, while the antiglide plating construct failed with pullout of the distal screws and displacement of the fracture in six of the eight specimens. CONCLUSION: In our study, the newly designed distal fibula periarticular locking plate with increased distal fixation is biomechanically stronger than a non-locking one third tubular plate applied in antiglide fashion for the treatment of AO/OTA 44 B2 osteoporotic distal fibula fractures. LEVEL OF EVIDENCE: V: This is an ex-vivo study performed on cadavers and is not a study performed on live patients. Therefore, this is considered Level V evidence. PMID- 27502224 TI - Is arthroscopic assisted percutaneous screw fixation as good as open reduction and internal fixation for the treatment of displaced intra-articular calcaneal fractures? AB - BACKGROUND: This study compares the outcomes of calcaneal fracture surgery after open reduction internal fixation and plating (ORIF) versus arthroscopic assisted percutaneous screw fixation (APSF). METHODS: Group I (N=12) underwent ORIF. Group II (N=15) underwent APSF. Anthropometric data, pre and post-operative stay, complications and duration off work were recorded in this retrospective case cohort study. Radiographs were analyzed for Bohler's, Gissane's angle and Sanders' classification. AOFAS Hindfoot and SF 36 scores were collected at final follow-up. RESULTS: Anthropometric data, Bohler's and Gissane's angles, AOFAS and SF 36 scores were not significantly different. Pre-operative duration was 12.3 days in ORIF and 6.9 days in APSF. Post-operative duration was 7.3 days vs 3.8 days. Duration off work was 6.2 months vs 2.9 months. CONCLUSION: The APSF group was able to have surgery earlier, go home faster, and return to work earlier. This study was not powered to demonstrate a difference in wound complication rates. PMID- 27502225 TI - Randomised comparison of two skin preparation methods in foot and ankle surgery. AB - BACKGROUND: Foot and ankle surgery has an increased incidence of post-operative surgical site infections. The aim of this study was to examine the efficacy and efficiency of an alternative method of surgical site preparation for foot and ankle surgery. METHOD: Fifty-one volunteers were recruited for this study which compared standard gauze painting using 2% chlorhexidine with 70% alcohol to immersion of the foot and ankle in a non-sterile bag filled with 60mL of the same solution and rubbing all skin surfaces (bag immersion method). Each method was applied to different feet of each volunteer in a randomised order. Commercially available impression agar slides were used to measure bacteria colony-forming unit (CFU) counts from four areas of each foot after allowing the preparation to dry. Outcomes included CFU count and preparation time. RESULT: There was no difference between the methods in terms of CFU count (0 total CFU vs. 1). Preparation time was significantly shorter for the bag immersion method (63.98s vs. 67.98s). Two-side 90% confidence intervals (2.03-6.00) for the difference in means of preparation time demonstrated equivalence using a margin of +/-20%. CONCLUSIONS: The bag immersion method is a valid alternative, equivalent in preparation timing and the elimination of transient skin flora when using 2% Chlorhexidine with 70% alcohol. PMID- 27502226 TI - 5 year retrospective follow-up of new cases of Charcot neuroarthropathy-A single centre experience. AB - BACKGROUND: Few data describe the natural history of Charcot neuroarthropathy treated with a total contact plaster cast (TCC). METHODS: A 5 year retrospective analysis of 50 patients presenting with an acute CN, Assessing time to clinical resolution into appropriate footwear and assessing if initial immobilisation device influenced resolution time. RESULTS: During the study period 42 patients (84%) of patients went into remission, 2 died during their treatment, 4 had major amputations, in 2 patients treatment was ongoing. 36 patients were treated with combination offloading devices, 6 were treated with one modality only. Median time to resolution for patients initially treated with a TCC was not significantly shorter than for those treated with a removable below knee boot. 34.9% required re-casting due to clinical deterioration in the removable device. CONCLUSIONS: More precise measures of resolution of CN are needed to assess the impact of initial treatment modality on time to resolution. PMID- 27502227 TI - Modified Chevron osteotomy for hallux valgus deformity in female athletes. A 2 year follow-up study. AB - BACKGROUND: Hallux valgus is an increasingly common deformity in young female athletes that constricts their daily athletic activities and influences foot cosmesis. The aim of this study was to evaluate the outcome of modified Chevron osteotomy for hallux valgus deformity in this specific population. METHODS: Forty two cases of modified Chevron osteotomies were carried out in 33 patients with mild to moderate hallux valgus deformity. Each participant was evaluated for AOFAS score, pain, range of motion, cosmetic and radiological outcome. RESULTS: Mean AOFAS score improved to 96.3 (p<0.001) while the mean range of motion of the metatarsophalangeal joint was maintained (p=0.138). The cosmetic result was excellent/good in 40 cases (95%). Mean metatarsophalangeal and intermetatarsal angles were decreased from 29.8 degrees and 14.2 degrees preoperatively to 12.2 degrees and 8.1 degrees postoperatively (p<0.001 and p<0.036), respectively. CONCLUSIONS: Modified Chevron osteotomy could offer substantial correction of hallux valgus deformity in young female athletes, with excellent clinical outcome. PMID- 27502228 TI - Posterior ankle and hindfoot endoscopy: A cadaveric study. AB - BACKGROUND: The list of indications of posterior ankle endoscopy is expanding and includes various soft tissue and bony pathologies of the posterior ankle. Some of the indications, e.g. release of frozen ankle, debridement of posteromedial soft tissue impingement of the ankle and debridement or fixation of the posteromedial osteochondral lesion of the talus, require approach to the posterior ankle medial to the flexor hallucis longus tendon. The purpose of this study was to assess the risk of injury to the posterior tibial neurovascular bundle during posterior ankle endoscopy. METHODS: Fourteen fresh frozen foot and ankle specimens were used. A metal rod was inserted into the posteromedial, posterolateral and modified posteromedial portals and touched the medial border of the posterolateral talar tubercle and the posteromedial corner of the ankle mortise in turn. The neurovascular bundle and FHL tendon were examined for any kink. RESULTS: The neurovascular bundle was kinked in all specimens (100%) with the rod at the posteromedial corner of the ankle mortise through the posteromedial portal and was kinked in 11 specimens (79%) with the rod through the modified posteromedial portal. The neurovascular bundle was kinked in 1 specimen (7%) with the rod through the posterolateral portal. CONCLUSIONS: The neurovascular bundle was at risk during instrumentation of the posteromedial ankle through the posteromedial portal but was safe through the posterolateral portal. PMID- 27502229 TI - A critical evaluation of venous thromboembolism risk assessment models used in patients with lower limb cast immobilisation. AB - BACKGROUND: There is a recognised link between lower limb cast immobilisation and the development of venous thromboembolism (VTE). Our aim was to assess the diagnostic accuracy of risk assessment models (RAMs) applicable to this patient group. This has not been done before. METHODS: A literature and guideline review identified five RAMs. They were used to retrospectively risk assess a consecutive series of patients who were diagnosed with symptomatic VTE following lower limb injury treated with a cast (Group I). A case-matched cohort who did not suffer symptomatic VTE (Group II) was also retrospectively risk assessed. The RAMs' diagnostic performance indicators were calculated. RESULTS: Groups I and II consisted of 21 patients each. There was no significant difference in the mean age or total number of VTE risk factors between Groups I and II (p=.957 and p=.878 respectively). The Plymouth (2010) RAM achieved the highest accuracy (54.8%). CONCLUSIONS: Each RAM demonstrated significant limitations. Two displayed very limited clinical utility. Three recommended chemical thromboprophylaxis to all patients because they weighted lower limb immobilisation as an absolute risk factor for the development of VTE. Cast immobilisation should not be considered an absolute risk factor when risk assessing patients who all have casts. Prospective evaluation with a larger patient cohort is required. PMID- 27502230 TI - Interosseous membrane window size for tibialis posterior tendon transfer Geometrical and MRI analysis. AB - BACKGROUND: Tibialis posterior (TP) tendon transfer through the interosseous membrane is commonly performed in Charcot-Marie-Tooth disease. In order to avoid entrapment of this tendon, no clear recommendation relative to the interosseous membrane (IOM) incision size has been made. OBJECTIVE: Analyze the TP size at the transfer level and therefore determine the most adequate IOM window size to avoid muscle entrapment. METHODS: Eleven lower extremity magnetic resonances were analyzed. TP muscle measurements were made in axial views, obtaining the medial lateral and antero-posterior diameter at various distances from the medial malleolus tip. The distance from the posterior to anterior compartment was also measured. These measurements were applied to a mathematical model to predict the IOM window size necessary to allow an ample TP passage in an oblique direction. RESULTS: The average tendon diameter (confidence-interval) at 15cm proximal to the medial malleolus tip was 19.47mm (17.47-21.48). The deep posterior compartment to anterior compartment distance was 10.97mm (9.03-12.90). Using a mathematical model, the estimated IOM window size ranges from 4.2 to 4.9cm. CONCLUSION: The IOM window size is of utmost importance in trans-membrane TP transfers, given that if equal or smaller than the transposed tendon oblique diameter, a high entrapment risk exists. A membrane window of 5cm or 2.5 times the size of the tendon diameter should be performed in order to theoretically diminish this complication. PMID- 27502231 TI - Talolisthesis in end stage ankle arthrosis. AB - BACKGROUND: Sagittal displacement in patients with end stage ankle arthritis has been described as the tibiotalar ratio (TTR). Yet the incidence, distribution and predictive factors of talolisthesis are unknown. METHODS: The radiographs of 470 cases of ankle arthritis were compared with a control group of 49 normal ankles. The TTR was measured for both groups. Additional co-variables included the anterior and lateral distal tibial angles, and talar tilt. RESULTS: The mean TTR in the arthritis cohort was 34.8+9.12 compared to the normal group of 34.1+2.62. Twenty-eight percent of the ankles had anterior displacement and twenty-eight percent had posterior talolisthesis, while forty-four percent had normal tibiotalar alignment. Multivariate linear regression revealed significant predictors of anterior distal tibial angle (p<0.0001) and talar tilt (p=0.0007) for abnormal TTR. CONCLUSION: Sagittal displacement is common in end stage ankle arthritis and is affected by ligamentous laxity and joint morphology. PMID- 27502232 TI - Talonavicular joint arthroscopic portals: A cadaveric study of feasibility and safety. AB - BACKGROUND: The objectives of the study were to evaluate the safety of hypothetical arthroscopic portals from talonavicular joint and to evaluate their reproducibility and enforceability. METHODS: 19 cadaveric feet were marked and four arthroscopic portals were made (medial, dorsomedial, dorsolateral and lateral). The specimens were dissected in layers and the distances between neurovascular structures and the trocars were measured. RESULTS: Medial and dorsomedial portals were in average 8.3 and 8.7, respectively, to the saphenous vein and nerve. Dorsolateral portal was in average 8.1mm to the deep peroneal nerve and dorsalis pedis artery, and 9.1mm to the medial dorsal cutaneous branch of the superficial peroneal nerve. Lateral portal was in average 12.3mm to the intermediate dorsal cutaneous branch of the superficial peroneal nerve. CONCLUSION: Tested portals shown to have a good safety margin for the foot neurovascular deep dorsal structures and an acceptable safety margin for the superficial neurovascular structures. PMID- 27502233 TI - Syndesmosis preserving osteotomy of the fibula for access to the lateral talar dome. AB - BACKGROUND: Open surgical access to the postero-lateral talar dome for the treatment of osteochondral lesions is challenging, often requiring a segmental osteotomy of the fibula (fibular window) and division of the anterior inferior tibiofibular ligament (AITFL) or a fibular osteotomy with division of the AITFL and the anterior talofibular ligament (ATFL) (fibular door). Alternatively, to preserve the tibiofibular syndesmosis both the fibula and the lateral tibial plafond can be osteotomised to expose the entire lateral talar dome. All of these techniques involve extensive surgical exposures and a significant amount of internal fixation of the osteotomy to achieve surgical access. METHODS: A trapezoidal fibular osteotomy which hinges on the AITFL thus preserving the syndesmotic and lateral ligamentous complex was developed to permit perpendicular access to the lateral talar dome. The remaining posterior column of fibula allows keying in of the osteotomy requiring minimal internal fixation. RESULTS: A 43 year old male with a displaced osteochondral fracture of the superolateral talar dome underwent the osteotomy to provide perpendicular fixation with two Herbert's screws. The osteotomy was reduced and fixed with a single 3.5mm lag screw. At 3 month follow up the osteotomy had healed both clinically and radiographically. CONCLUSIONS: Our technique utilizes a novel trapezoidal fibular osteotomy with preservation of key syndesmotic and ligamentous structures and requires minimal internal fixation. PMID- 27502234 TI - Letter to the editor on "A standard shoelace prevents equinus posturing of the ankle during circular external fixation of the tibia". PMID- 27502235 TI - Response to: "Re: Standard shoelace prevents equinus posturing of the ankle during circular external fixation of the tibia". Manuscript 14-00002. PMID- 27502236 TI - Conversion of ankle autofusion to total ankle replacement using the Salto XT revision prosthesis. AB - Few reports in the literature have described the conversion of a surgically fused ankle to a total ankle replacement. The takedown of an autofusion and conversion to a prosthesis has not been described. We report the case of a patient with severe rheumatoid arthritis with an ankle autofusion fixed in equinus and severe talonavicular arthritis that was converted to ankle replacement using the Salto XT revision system. We describe the reasons why the decision was made to perform total ankle arthroplasty while concomitantly fusing the talonavicular joint, and discuss the rationale of the various surgical treatment options considered. We describe the clinical and radiographic outcomes achieved in this case. At 12 months post-operatively the patient reported significant reduction of pain, increased FAOS scores and had increased ankle range of motion. PMID- 27502237 TI - Poncet's disease (tubercular rheumatism) with primary involvement of the foot - A case report. AB - We present a rare case with primary tubercular involvement of the foot, accomapanied by a reactionary (aseptic) effusion in the knee. The diagnosis was delayed due to unusual presentation and also because of failure to elicit a detailed history. Incision and drainage of the foot abscess and antitubercular drug therapy resulted in satisfactory control of tubercular infection. Polyarticular presentation may not always signify active tubercular focus in every joint; it may reflect reactive synovitis known as Poncet's disease, which resolves with multidrug antitubercular therapy.A multidispilinary approach should be adopted and chest physicians, rheumatologists and orthopaedic surgeons should work in close association to correctly diagnose and treatthis condition. PMID- 27502238 TI - Hereditary Heterozygous C2 Deficiency: Variable Clinical and Serological Manifestations Among Three Sisters. AB - The causal link between inherited complement deficiencies and systemic lupus erythematosus (SLE) has been well established, although it remains a rare cause of the disease. We present the case of three biological sisters with hereditary heterozygous C2 deficiency, but who differ widely in their clinical and serological manifestations. Patient 1 is 25 years old and was diagnosed with SLE at the age of 12. Further testing revealed positive ANA and anti-dsDNA, antiphospholipid syndrome (APS) and decreased C2, C3 and C4 levels. Patients 2 and 3 are 21-year-old dizygotic twins. Both have positive ANA and antiphospholipid (APL) antibodies, and decreased C2 and C4 levels. We present a case of familial heterozygous C2 deficiency with different disease phenotypes. The presence of positive APL antibodies in all 3 patients is significant, as this association has been rarely described. The variable clinical and serological manifestations among our patients further reflect the complex and multifactorial nature of SLE. PMID- 27502240 TI - Quantity Distortion Effect in Consumers' Perception of Different Volumes and Weights of Money: A Pilot Study. AB - Consumers tend to misunderstand the physical value of cash money by adopting improper anchors for their judgments (e.g., banknote size and shape, currency denominations, etc.). In a pilot study carried out on a sample of 242 participants (n = 116 men; M age = 29.6 year, SD = 10.8), a quantity distortion effect was demonstrated by evaluating consumers' misperceptions of different monetary quantities, either in terms of volume or weight, using banknotes of the same denomination (?50). A threshold value was found, for both volume (?876,324) and weight (?371,779), above (below) which consumers tend to overrate (underrate) monetary amounts. The theoretical and operative implications are discussed. PMID- 27502239 TI - Non-invasive real-time biopsy of intracranial lesions using short time expanded circulating tumor cells on glass slide: report of two cases. AB - BACKGROUND: Circulating Tumor Cells (CTCs) are promising biomarkers for monitoring solid cancer and were used to monitor brain tumors. Here we report two cases in which, for the first time, CTCs were used in cytological diagnostic evaluation to discriminate a space-occupying lesion of the brain. CASE PRESENTATION: Two cases of focal intracranial lesions, unclassified for diagnosis, untreated and apparently symptomatic, were examined after high contrast resolution Magnetic Resonance Imaging and/or Computed Tomography scans. CTCs were seeded on chamber slides and short-time expanded under the optimized conditions as we previously reported. The first case was a focal lesion localized in the parietal-occipital area in a 67-year-old woman. The second case was a 31 year-old man with an expansive intracerebral lesion localized in the left peri trigonal area. Both patients underwent excisional biopsy. Histopathological evaluation of the biopsy confirmed the previous cytological diagnoses, and the analysis of the clinical outcomes retrospectively validated both diagnoses. CONCLUSIONS: The cases here reported illustrate the potential for using expanded CTCs as non-invasive, real-time biopsy. Moreover, non-invasive real-time biopsy can represent an alternative diagnostic tool to be used when a functional area of the brain is at risk of injury from excisional biopsy procedures. PMID- 27502241 TI - Force Irregularity Following Maximal Effort: The After-Peak Reduction. AB - Irregularities in force output are present throughout human movement and can impair task performance. We investigated the presence of a large force discontinuity (after-peak reduction, APR) that appeared immediately following peak in maximal effort ramp contractions performed with the thumb adductor and ankle dorsiflexor muscles in 25 young adult participants (76% males, 24% females; M age 24.4 years, SD = 7.1). The after-peak reduction displayed similar parameters in both muscle groups with comparable drops in force during the after peak reduction minima (thumb adductor: 27.5 +/- 7.5% maximal voluntary contraction; ankle dorsiflexor: 25.8 +/- 6.2% maximal voluntary contraction). A trend for the presence of fewer after-peak reductions with successive ramp trials was observed, suggesting a learning effect. Further investigation should explore underlying neural mechanisms contributing to the after-peak reduction. PMID- 27502242 TI - Attentional Focus in Motor Learning, the Feldenkrais Method, and Mindful Movement. AB - The present paper discusses attentional focus in motor learning and performance from the point of view of mindful movement practices, taking as a starting point the Feldenkrais method. It is argued that earlier criticism of the Feldenkrais method (and thereby implicitly of mindful movement practices more generally) because of allegedly inappropriate attentional focus turns out to be unfounded in light of recent developments in the study of motor learning and performance. Conversely, the examples of the Feldenkrais method and Ki-Aikido are used to illustrate how both Western and Eastern (martial arts derived) mindful movement practices might benefit sports psychology. PMID- 27502243 TI - Postural Control During Cascade Ball Juggling: Effects of Expertise and Base of Support. AB - Cascade ball juggling is a complex perceptual motor skill which requires efficient postural stabilization. The aim of this study was to investigate effects of experience (expert and intermediate groups) and foot distance (wide and narrow stances) on body sway of jugglers during three ball cascade juggling. A total of 10 expert jugglers and 11 intermediate jugglers participated in this study. Participants stood barefoot on the force plate (some participants wore a gaze tracking system), with feet maintained in wide and narrow conditions and performed three 40-seconds trials of the three-ball juggling task. Dependent variables were sway mean velocity, amplitude, mean frequency, number of ball cycles, fixation number, mean duration and its variability, and area of gaze displacement. Two-way analyses of variance with factors for group and condition were conducted. Experts' body sway was characterized by lower velocity and smaller amplitude as compared to intermediate group. Interestingly, the more challenging (narrow) basis of support caused significant attenuation in body sway only for the intermediate group. These data suggest that expertise in cascade juggling was associated with refined postural control. PMID- 27502244 TI - Competitive Performance Correlates of Mental Toughness in Tennis: A Preliminary Analysis. AB - This study investigated relationships between mental toughness and measures of competitive performance in tennis. Forty-three male (N = 25) and female (N = 18) players (M age = 13.6 years, SD = 2.4) completed the mental toughness inventory, and the point-by-point outcomes recorded during a competitive tennis match (singles) were used to generate performance indices for each athlete. The results indicated that mental toughness was associated with several, but not all, macro, micro, and critical moment performance indices. The findings suggest mental toughness may contribute to successful performance during tennis competition, although the importance of the construct appears to depend depend on specific match situations. Future mental toughness research should consider a range of factors related to sport performance, including athletes' and opponents' physical, technical, and tactical abilities. PMID- 27502245 TI - Cartilage inflammation and degeneration is enhanced by pro-inflammatory (M1) macrophages in vitro, but not inhibited directly by anti-inflammatory (M2) macrophages. AB - OBJECTIVE: Macrophages play a crucial role in the progression of osteoarthritis (OA). Their phenotype may range from pro-inflammatory to anti-inflammatory. The aim of this study was to evaluate the direct effects of macrophage subtypes on cartilage by culturing macrophage conditioned medium (MCM) on human articular cartilage. DESIGN: Human OA cartilage explants were cultured with MCM of pro inflammatory M(IFNgamma+TNFalpha), or anti-inflammatory M(IL-4) or M(IL-10) human monocyte-derived macrophages. To assess effects of anti-inflammatory macrophages, the cartilage was cultured with a combination of MCM phenotypes as well as pre stimulated with IFNgamma+TNFalpha cartilage before culture with MCM. The reactions of the explants were assessed by gene expression, nitric oxide (NO) production and release of glycosaminoglycans (GAGs). RESULTS: M(IFNgamma+TNFalpha) MCM affected OA cartilage by upregulation of IL1B (Interleukin 1beta), IL6, MMP13 (Matrix Metalloproteinase-13) and ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin Motifs-5), while inhibiting ACAN (aggrecan) and COL2A1 (collagen type II). M(IL-10) upregulated IL1B and Suppressor of cytokine signaling 1 (SOCS1). NO production and GAG release by the cartilage was increased when cultured with M(IFNgamma+TNFalpha) MCM. M(IL-4) and M(IL-10) did not inhibit the effects of M(IFNgamma+TNFalpha) MCM of neither phenotype affected IFNgamma+TNFalpha pre-stimulated cartilage, in which an inflammatory gene response was deliberately induced. CONCLUSION: M(IFNgamma+TNFalpha) macrophages have a prominent direct effect on OA cartilage, while M(IL-4) and M(IL-10) do not inhibit the effects of M(IFNgamma+TNFalpha), or IFNgamma+TNFalpha induced inflammation of the cartilage. Therapies aiming at inhibiting cartilage degeneration may take this into account by directing suppression of pro-inflammatory macrophages or stimulation of anti-inflammatory macrophages. PMID- 27502246 TI - Rift Valley fever vector diversity and impact of meteorological and environmental factors on Culex pipiens dynamics in the Okavango Delta, Botswana. AB - BACKGROUND: In Northern Botswana, rural communities, livestock, wildlife and large numbers of mosquitoes cohabitate around permanent waters of the Okavango Delta. As in other regions of sub-Saharan Africa, Rift Valley Fever (RVF) virus is known to circulate in that area among wild and domestic animals. However, the diversity and composition of potential RVF mosquito vectors in that area are unknown as well as the climatic and ecological drivers susceptible to affect their population dynamics. METHODS: Using net traps baited with carbon dioxide, monthly mosquito catches were implemented over four sites surrounding cattle corrals at the northwestern border of the Okavango Delta between 2011 and 2012. The collected mosquito species were identified and analysed for the presence of RVF virus by molecular methods. In addition, a mechanistic model was developed to assess the qualitative influence of meteorological and environmental factors such as temperature, rainfall and flooding levels, on the population dynamics of the most abundant species detected (Culex pipiens). RESULTS: More than 25,000 mosquitoes from 32 different species were captured with an overabundance of Cx. pipiens (69,39 %), followed by Mansonia uniformis (20,67 %) and a very low detection of Aedes spp. (0.51 %). No RVF virus was detected in our mosquito pooled samples. The model fitted well the Cx. pipiens catching results (rho = 0.94, P = 0.017). The spatial distribution of its abundance was well represented when using local rainfall and flooding measures (rho = 1, P = 0.083). The global population dynamics were mainly influenced by temperature, but both rainfall and flooding presented a significant influence. The best and worst suitable periods for mosquito abundance were around March to May and June to October, respectively. CONCLUSIONS: Our study provides the first available data on the presence of potential RVF vectors that could contribute to the maintenance and dissemination of RVF virus in the Okavango Delta. Our model allowed us to understand the dynamics of Cx. pipiens, the most abundant vector identified in this area. Potential predictions of peaks in abundance of this vector could allow the identification of the most suitable periods for disease occurrence and provide recommendations for vectorial and disease surveillance and control strategies. PMID- 27502247 TI - MR perfusion-weighted imaging in the evaluation of high-grade gliomas after treatment: a systematic review and meta-analysis. AB - BACKGROUND: Distinction between tumor and treatment related changes is crucial for clinical management of patients with high-grade gliomas. Our purpose was to evaluate whether dynamic susceptibility contrast-enhanced (DSC) and dynamic contrast enhanced (DCE) perfusion-weighted imaging (PWI) metrics can effectively differentiate between recurrent tumor and posttreatment changes within the enhancing signal abnormality on conventional MRI. METHODS: A comprehensive literature search was performed for studies evaluating PWI-based differentiation of recurrent tumor and posttreatment changes in patients with high-grade gliomas (World Health Organization grades III and IV). Only studies published in the "temozolomide era" beginning in 2005 were included. Summary estimates of diagnostic accuracy were obtained by using a random-effects model. RESULTS: Of 1581 abstracts screened, 28 articles were included. The pooled sensitivities and specificities of each study's best performing parameter were 90% and 88% (95% CI: 0.85-0.94; 0.83-0.92) and 89% and 85% (95% CI: 0.78-0.96; 0.77-0.91) for DSC and DCE, respectively. The pooled sensitivities and specificities for detecting tumor recurrence using the 2 most commonly evaluated parameters, mean relative cerebral blood volume (rCBV) (threshold range, 0.9-2.15) and maximum rCBV (threshold range, 1.49-3.1), were 88% and 88% (95% CI: 0.81-0.94; 0.78-0.95) and 93% and 76% (95% CI: 0.86-0.98; 0.66-0.85), respectively. CONCLUSIONS: PWI-derived thresholds separating viable tumor from treatment changes demonstrate relatively good accuracy in individual studies. However, because of significant variability in optimal reported thresholds and other limitations in the existing body of literature, further investigation and standardization is needed before implementing any particular quantitative PWI strategy across institutions. PMID- 27502248 TI - Radiogenomics to characterize regional genetic heterogeneity in glioblastoma. AB - BACKGROUND: Glioblastoma (GBM) exhibits profound intratumoral genetic heterogeneity. Each tumor comprises multiple genetically distinct clonal populations with different therapeutic sensitivities. This has implications for targeted therapy and genetically informed paradigms. Contrast-enhanced (CE)-MRI and conventional sampling techniques have failed to resolve this heterogeneity, particularly for nonenhancing tumor populations. This study explores the feasibility of using multiparametric MRI and texture analysis to characterize regional genetic heterogeneity throughout MRI-enhancing and nonenhancing tumor segments. METHODS: We collected multiple image-guided biopsies from primary GBM patients throughout regions of enhancement (ENH) and nonenhancing parenchyma (so called brain-around-tumor, [BAT]). For each biopsy, we analyzed DNA copy number variants for core GBM driver genes reported by The Cancer Genome Atlas. We co registered biopsy locations with MRI and texture maps to correlate regional genetic status with spatially matched imaging measurements. We also built multivariate predictive decision-tree models for each GBM driver gene and validated accuracies using leave-one-out-cross-validation (LOOCV). RESULTS: We collected 48 biopsies (13 tumors) and identified significant imaging correlations (univariate analysis) for 6 driver genes: EGFR, PDGFRA, PTEN, CDKN2A, RB1, and TP53. Predictive model accuracies (on LOOCV) varied by driver gene of interest. Highest accuracies were observed for PDGFRA (77.1%), EGFR (75%), CDKN2A (87.5%), and RB1 (87.5%), while lowest accuracy was observed in TP53 (37.5%). Models for 4 driver genes (EGFR, RB1, CDKN2A, and PTEN) showed higher accuracy in BAT samples (n = 16) compared with those from ENH segments (n = 32). CONCLUSION: MRI and texture analysis can help characterize regional genetic heterogeneity, which offers potential diagnostic value under the paradigm of individualized oncology. PMID- 27502249 TI - Ruxolitinib in steroid refractory graft-vs.-host disease: a case report. AB - BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative in a variety of hematological malignancies. Graft-vs.-host disease (GvHD) remains a life-threatening complication. Standard treatment is high-dose (HD) corticosteroids. Steroid-refractory (SR) GvHD is associated with poor prognosis. At present, second-line treatment is ill-defined and includes a number of agents. Novel insights into the pathophysiology of acute GvHD (aGvHD) highlight the relevant role of the host inflammatory response governed by several kinase families, including Janus kinases (JAK)1/2. Ruxolitinib, a JAK1/2 inhibitor approved for intermediate-2/high-risk myelofibrosis, was recently employed in SR-GvHD with encouraging overall response rates. Clinical experience however remains limited. CASE PRESENTATION: A 51-year-old male with refractory anemia with excess blast type-2 underwent a myeloablative allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine, methotrexate, and thymoglobulin. CD34(+) cells/kg infused were 8.69 * 10(6) kg. On day 29, the patient developed overall grade IV aGvHD with biopsy proven stage IV gastrointestinal (GI) GvHD refractory to HD corticosteroids. Patient conditions rapidly deteriorated and became critical despite the addition of mycophenolate mofetil and budesonide. On day 33, Ruxolitinib was started, and on day 39 the patient clinical conditions gradually improved. Complete resolution of aGvHD was also confirmed by histology on day 54. CONCLUSIONS: At 5 months from HSCT, the patient is well and in continuous hematological complete remission without flare of GvHD. Ruxolitinib was discontinued on day 156. Ruxolitinib is feasible and effective in SR-aGvHD though large prospective clinical trials are warranted. PMID- 27502251 TI - Dermatologic Jottings I: George Orwell's Animal Farm Has Arrived. PMID- 27502250 TI - Glycemic variability evaluated by continuous glucose monitoring system is associated with the 10-y cardiovascular risk of diabetic patients with well controlled HbA1c. AB - BACKGROUND: The present study aimed to identify the relationship between glycemic variability (GV) and the 10-y risk of cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) patients with good glycemic control. METHODS: Two hundred forty consecutive T2DM patients (HbA1c<=7.0%) without CVD were included to calculate the 10-y CVD risk by Framingham risk score (FRS), and divided into 3 groups: low-risk group (FRS<=10%), intermediate-risk group (>10%, <=20%) and high risk group (>20%). Inter-group differences of GV were determined by comparing the SD of blood glucose (SDBG), mean amplitudes of glycemic excursion (MAGE), and mean of daily differences (MODD) gathered from 72-h continuous glucose monitoring system. RESULTS: The levels of SDBG and MAGE significantly increased along with the raises of 10-y CVD risk of T2DM patients (p<0.01). FRS was positively correlated with age, systolic blood pressure, SDBG and MAGE (r=0.717, 0.525, 0.509 and 0.485 respectively, p<0.01), while negatively correlated with the level of HDL-C (r=-0.348, p<0.01). Furthermore, multivariate logistic regression analysis confirmed that increased MAGE [OR: 1.623(1.198-2.316), p<0.001] and patients with high urine albumin excretion rates [OR: 1.743(1.247-2.793), p<0.001] were independent predictors for high 10-y CVD risk. CONCLUSION: GV predicts independently the 10-y CVD risk of T2DM patients with well-controlled HbA1c. PMID- 27502252 TI - Erectile Dysfunction in Dermatology: It's Not As Hard As You Think. PMID- 27502253 TI - Characteristics of Eccrine Tumors in a Tertiary Institution: A 5-Year Retrospective Study. AB - Eccrine tumors are adnexal tumors with a varied clinical presentation and wide histological spectrum. This study aims to consolidate data on the clinical characteristics of eccrine tumors to help improve clinical acumen and management of such tumors. Histopathological records from January 2008 to December 2012 were retrieved. Clinical characteristics of the tumor including site, appearance, symptoms, color, duration prior to presentation, and clinical and histological diagnosis were recorded. Eighty-four patients with eccrine tumors were identified, with seven main types of tumors recognized-hidradenoma (33.3%), poroma (29.8%), mixed tumors (14.3%), spiradenoma (8.3%), porocarcinoma (6.7%), eccrine adenoma (3.6%), and syringoma (3.6%). A total of 50% of mixed tumors were misdiagnosed as epidermal cysts. Eccrine tumors have a wide array of clinical presentations and are often clinically misdiagnosed as cysts. Recognizing certain clinical features may aid in the diagnosis, but, if in doubt, a biopsy should be performed. PMID- 27502254 TI - Clinical Efficacy and Safety of a Monopolar Radiofrequency Device With Comfort Pulse Technology for the Treatment of Facial and Neck Laxity in Men. AB - The objective of this study was to demonstrate the efficacy and safety of a monopolar radiofrequency treatment for facial and neck laxity in men. Twelve men received one treatment of the face and upper portion of the neck using an RF system with comfort pulsed technology. Standardized photographs were taken at baseline and at 1, 3, and 6 months of follow-up. Study investigators evaluated facial and neck laxity at baseline and all follow-up visits using the Fasil Laxity Scale. Patents and investigators assessed skin texture and overall appearance using the Quartile Improvement Scale. Average improvement in treated areas was statistically significant at 1-month (P<.01), 3-month (P=.02), and 6 month (P=.05) follow-up visits compared with baseline. Investigators rated greatest improvement in skin texture and overall appearance (mild to moderate) at the 3-month follow-up. Patient assessments demonstrated moderate improvement in skin laxity, skin texture, and overall appearance maintained out to 6 months after treatment. A total of 64% of patients were satisfied to very satisfied with treatment at the 6-month follow-up. One RF treatment of the face and neck yielded 20% reduction in facial laxity 1 month after treatment, with maintained improvement out to 6 months (15% reduction). PMID- 27502255 TI - What Is Vitamin D3 and Its Potential Use in Dermatology? AB - There are many clinical studies that show the importance of vitamin D in multiple skin disorders. Understanding the molecular elements of cathelicidin expression might lead to new treatments and help explain mechanisms of current therapies. Overall, current data are generating many questions and expectations and require larger trials to confirm the therapeutic use of vitamin D3 supplementation. Vitamin D now represents a vast and promising field of research to dermatologists. PMID- 27502257 TI - Oral Mucosal Lesions: Miscellaneous-Part III. AB - Oral mucosal lesions are a common occurrence in dermatology. In part III of this series, the authors discuss the epidemiology and etiopathology of these lesions, including clinical classifications, modifying factors, and incriminating agents. PMID- 27502258 TI - A Leopard Can't Change Its Spots, but a Melanocyte Can! False-Negative MART-1 Staining. PMID- 27502259 TI - JUBLIA (Efinaconazole): An Update. PMID- 27502260 TI - Adult-Onset Still Disease Is on the Move. PMID- 27502261 TI - Dermatology in a Bygone Era: Part II. PMID- 27502262 TI - Lymphangioma Circumscriptum of the Vulva. PMID- 27502263 TI - A Souvenir From France: Acrodermatitis Chronica Atrophicans Presenting in the United States. AB - A 70-year-old man was referred by his rheumatologist to our dermatology clinic for evaluation of dermatitis on his right arm that appeared 3 months earlier. The skin lesion was asymptomatic and the patient denied current systemic symptoms, including fever, chills, and joint pain; however, 10 months prior to this presentation he experienced arthritis in the left knee. At that time, Borrelia serology revealed positive IgG (6.07; <0.8 negative, 0.8 to 0.99 borderline, >=1 positive) and negative IgM titers. The patient had not received treatment for Lyme disease in the past. He was referred to rheumatology for evaluation of possible Lyme disease but did not follow up until 10 months later. The arthritis has since resolved. He travels frequently to France and recalls multiple tick bites during these trips. PMID- 27502264 TI - Porokeratotic Adnexal Ostial Nevus-Report of a Case With Unusual Clinical and Histologic Features. AB - An 11-year-old Tanzanian girl presented with diffuse verrucous lesions of varying morphology, scarring alopecia, and keloid scars over the face with a predilection for the ears. Physical examination revealed dark keratoderma and patches of hypopigmentation near the midline of the dorsal trunk (Figure 1a). Her forearms were densely covered by verrucous lesions with the exception of a clear linear patch on the dorsal aspect of the left forearm (Figure 1b). The perioral area was notable for white spires projecting from verrucous papules (Figure 1c) while the oral mucosa and teeth appeared normal on visual examination. The rest of her body, including the palms and soles, was covered by patchy, scaly lesions of varying severity. PMID- 27502265 TI - Four Diseases, Two Associations, One Patient: A Case of Frontal Fibrosing Alopecia, Lichen Planus Pigmentosus, Acne Rosacea, and Morbihan Disease. AB - A 77-year-old woman born in the Dominican Republic presented with fullness of the glabella and medial eyebrows for 1 year followed by alopecia of the lateral eyebrows and frontal hairline. She stated that although she had a high hairline at baseline, it had receded in the past year. She had also noted central scalp hair thinning that started 6 years earlier. She denied all styling practices that used traction or chemical processes, although she admitted to hair dye and blow dryer use. She reported "acne" in the central face for decades and darkening of the skin on the lateral face for several years. Her medical history included hypertension, hyperlipidemia, hypothyroidism, benign paroxysmal positional vertigo, and treated breast ductal hyperplasia. Her medications were metoprolol, amlodipine, aspirin, levothyroxine, omeprazole, pravastatin, and meclizine; she denied starting any new medications within the past 2 years. Her family history was notable for androgenic pattern alopecia in a brother and a high hairline in her father. Review of systems was negative except for knee arthralgias and seasonal allergic rhinitis. PMID- 27502266 TI - Epidermal Nevus Presenting in a Pediatric Patient With Pallister-Killian Syndrome. AB - A six-year-old boy with Pallister-Killian syndrome (PKS) presented to the clinic with extensive lesions on his body (Figure 1). The patient was not born with the lesions but began developing them on the head and neck, extending to his lower extremities, at 2 years of age. These lesions had been evaluated by his primary care physician and were previously treated with desonide and ketoconazole cream with little improvement. PMID- 27502267 TI - Penile Granuloma Annulare. AB - A 50-year-old man presented to the genitourinary medicine clinic with a 3-year history of skin-colored circular papules over the shaft and glans of the penis. There were multiple lesions that were initially small, around 0.3 cm in diameter, and gradually enlarged. Physical examination revealed five nodules over the glans and shaft of the penis, with the largest lesion measuring 3*1 cm over the lateral aspect of the shaft (Figure 1). There were no similar lesions elsewhere. There was no lymphadenopathy and the rest of the examination was unremarkable. The patient complained of discomfort during sexual intercourse but the lesions were otherwise asymptomatic and nontender. There was no history of trauma to the area and no dermatological history. He had had the same sexual partner for the past 22 years, no significant medical history, and was not taking any medication. He was a smoker with a 32-pack-year history. His family history did not include any dermatological diseases. His father was diagnosed with type II diabetes at 65 years of age and his mother had hypertension since age 60 years. He had consulted his general practitioner regarding the penile eruption a year earlier and was treated for a presumed fungal infection with clotrimazole cream for 1 month with no effect. Results from genitourinary investigations for sexually transmitted diseases including syphilis were all negative. PMID- 27502268 TI - Scrotodynia: Diagnostic and Therapeutic Challenge. AB - Case 1 A 35-year-old married man presented with diffuse burning of the scrotum for 6 months' duration that was aggravated by sitting and wearing tight-fitting undergarments. He reported a history of sexual exposure 6 months prior, after which the complaint started. Clinical examination of the scrotal skin, testis, epididymis, penis, and perianal area did not reveal any abnormality. Rectal examination was performed to rule out chronic proctitis. Investigations were performed to exclude sexually transmitted infections. Ultrasonography of the abdomen and pelvis was ordered to rule out organic cause. The patient experienced guilt from the exposure because he was married, and therefore was referred to the psychiatrist to rule out psychological problems. A diagnosis of major depressive disorder was made. He was started on amitriptyline 25 mg and was gradually increased to 50 mg. The patient showed gradual improvement in symptoms after 3 weeks of follow-up. PMID- 27502269 TI - Facial Blanching After Cosmetic Botulinum Toxin Injection: Case Series. AB - Case 1 A 32-year-old woman was treated for the first time with onabotulinumtoxinA (BoNT), receiving 10 units in her forehead and 20 units in her glabella. She reported no history of skin disease and had a very active lifestyle. She first noticed blanching while doing a group workout and a friend inquired if she had "hives" on her forehead (Figure 1). She continued to note the blanching during workouts 5 months after injection. Each episode lasted 30 minutes to 2 hours. There were no associated symptoms with the blanching other than minor embarrassment. Given her active lifestyle and frequent blanching, she has elected not to receive further injections. PMID- 27502270 TI - microRNA regulation of neural precursor self-renewal and differentiation. AB - During early stages of development of the vertebrate central nervous system, neural precursors divide symmetrically to produce new precursors, thereby expanding the precursor population. During middle stages of neural development, precursors switch to an asymmetric division pattern whereby each mitosis produces one new precursor and one cell that differentiates as a neuron or glial cell. At late stages of development, most precursors stop dividing and terminally differentiate. Par complex proteins are associated with the apical membrane of neural precursors and promote precursor self-renewal. How Par proteins are down regulated to bring precursor self-renewal to an end has not been known. Our investigations of zebrafish neural development revealed that the microRNA miR-219 negatively regulates apical Par proteins, thereby promoting cessation of neural precursor division and driving terminal differentiation. PMID- 27502271 TI - RNA-sequencing of the sturgeon Acipenser baeri provides insights into expression dynamics of morphogenic differentiation and developmental regulatory genes in early versus late developmental stages. AB - BACKGROUND: Acipenser baeri, one of the critically endangered animals on the verge of extinction, is a key species for evolutionary, developmental, physiology and conservation studies and a standout amongst the most important food products worldwide. Though the transcriptome of the early development of A. baeri has been published recently, the transcriptome changes occurring in the transition from embryonic to late stages are still unknown. The aim of this work was to analyze the transcriptomes of embryonic and post-embryonic stages of A. baeri and identify differentially expressed genes (DEGs) and their expression patterns using mRNA collected from specimens at big yolk plug, wide neural plate and 64 day old sturgeon developmental stages for RNA-Seq. RESULTS: The paired-end sequencing of the transcriptome of samples of A. baeri collected at two early (big yolk plug (T1, 32 h after fertilization) and wide neural plate formation (T2, 45 h after fertilization)) and one late (T22, 64 day old sturgeon) developmental stages using Illumina Hiseq2000 platform generated 64039846, 64635214 and 75293762 clean paired-end reads for T1, T2 and T22, respectively. After quality control, the sequencing reads were de novo assembled to generate a set of 149,265 unigenes with N50 value of 1277 bp. Functional annotation indicated that a substantial number of these unigenes had significant similarity with proteins in public databases. Differential expression profiling allowed the identification of 2789, 12,819 and 10,824 DEGs from the respective T1 vs. T2, T1 vs. T22 and T2 vs. T22 comparisons. High correlation of DEGs' features was recorded among early stages while significant divergences were observed when comparing the late stage with early stages. GO and KEGG enrichment analyses revealed the biological processes, cellular component, molecular functions and metabolic pathways associated with identified DEGs. The qRT-PCR performed for candidate genes in specimens confirmed the validity of the RNA-seq data. CONCLUSIONS: This study presents, for the first time, an extensive overview of RNA-Seq based characterization of the early and post-embryonic developmental transcriptomes of A. baeri and provided 149,265 gene sequences that will be potentially valuable for future molecular and genetic studies in A. baeri. PMID- 27502272 TI - Thresholds and timing of pre-operative thrombocytosis and ovarian cancer survival: analysis of laboratory measures from electronic medical records. AB - BACKGROUND: Thrombocytosis has been associated with poor ovarian cancer prognosis. However, comparisons of thresholds to define thrombocytosis and evaluation of relevant timing of platelet measurement has not been previously conducted. METHODS: We selected Tumor Registry confirmed ovarian, primary peritoneal, and fallopian tube cancer cases diagnosed between 1995-2013 from the Vanderbilt University Medical Center. Laboratory measured platelet values from electronic medical records (EMR) were used to determine thrombocytosis at three thresholds: a platelet count greater than 350, 400, or 450 * 10(9)/liter. Timing was evaluated with 5 intervals: on the date of diagnosis, and up to 1, 2, 4, and 8 weeks prior to the date of diagnosis. Cox regression was used to calculate hazard ratios (HR) and confidence intervals (CI) for association with overall survival; adjustment included age, stage, grade, and histologic subtype of disease. RESULTS: Pre-diagnosis platelet measures were available for 136, 241, 280, 297, and 304 cases in the five intervals. The prevalence of thrombocytosis decreased with increasing thresholds and was generally consistent across the five time intervals, ranging from 44.8-53.2 %, 31.6-39.4 %, and 19.9-26.1 % across the three thresholds. Associations with higher grade and stage of disease gained significance as the threshold increased. With the exception of the lowest threshold on the date of diagnosis (HR350: 1.55, 95 % CI: 0.97-2.47), all other survival associations were significant, with the highest reaching twice the risk of death for thrombocytosis on the date of diagnosis (HR400: 2.01, 95 % CI: 1.25 3.23). CONCLUSIONS: Our EMR approach yielded associations comparable to published findings from medical record abstraction approaches. In addition, our results indicate that lower thrombocytosis thresholds and platelet measures up to 8 weeks before diagnosis may inform ovarian cancer characteristics and prognosis. PMID- 27502274 TI - Molecular Basis for the Protein Recognition Specificity of the Dynein Light Chain DYNLT1/Tctex1: CHARACTERIZATION OF THE INTERACTION WITH ACTIVIN RECEPTOR IIB. AB - It has been suggested that DYNLT1, a dynein light chain known to bind to various cellular and viral proteins, can function both as a molecular clamp and as a microtubule-cargo adapter. Recent data have shown that the DYNLT1 homodimer binds to two dynein intermediate chains to subsequently link cargo proteins such as the guanine nucleotide exchange factor Lfc or the small GTPases RagA and Rab3D. Although over 20 DYNLT1-interacting proteins have been reported, the exact sequence requirements that enable their association to the canonical binding groove or to the secondary site within the DYNLT1 surface are unknown. We describe herein the sequence recognition properties of the hydrophobic groove of DYNLT1 known to accommodate dynein intermediate chain. Using a pepscan approach, we have substituted each amino acid within the interacting peptide for all 20 natural amino acids and identified novel binding sequences. Our data led us to propose activin receptor IIB as a novel DYNLT1 ligand and suggest that DYNLT1 functions as a molecular dimerization engine bringing together two receptor monomers in the cytoplasmic side of the membrane. In addition, we provide evidence regarding a dual binding mode adopted by certain interacting partners such as Lfc or the parathyroid hormone receptor. Finally, we have used NMR spectroscopy to obtain the solution structure of human DYNLT1 forming a complex with dynein intermediate chain of ~74 kDa; it is the first mammalian structure available. PMID- 27502273 TI - The Human Ether-a-go-go-related Gene (hERG) Potassium Channel Represents an Unusual Target for Protease-mediated Damage. AB - The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Dysfunction of hERG causes long QT syndrome and sudden death, which occur in patients with cardiac ischemia. Cardiac ischemia is also associated with activation, up-regulation, and secretion of various proteolytic enzymes. Here, using whole-cell patch clamp and Western blotting analysis, we demonstrate that the hERG/IKr channel was selectively cleaved by the serine protease, proteinase K (PK). Using molecular biology techniques including making a chimeric channel between protease-sensitive hERG and insensitive human ether-a-go-go (hEAG), as well as application of the scorpion toxin BeKm-1, we identified that the S5-pore linker of hERG is the target domain for proteinase K cleavage. To investigate the physiological relevance of the unique susceptibility of hERG to proteases, we show that cardiac ischemia in a rabbit model was associated with a reduction in mature ERG expression and an increase in the expression of several proteases, including calpain. Using cell biology approaches, we found that calpain-1 was actively released into the extracellular milieu and cleaved hERG at the S5-pore linker. Using protease cleavage-predicting software and site-directed mutagenesis, we identified that calpain-1 cleaves hERG at position Gly-603 in the S5-pore linker of hERG. Clarification of protease mediated damage of hERG extends our understanding of hERG regulation. Damage of hERG mediated by proteases such as calpain may contribute to ischemia-associated QT prolongation and sudden cardiac death. PMID- 27502275 TI - Interdomain Conformational Changes Provide Allosteric Regulation en Route to Chorismate. AB - Multifunctional proteins play a variety of roles in metabolism. Here, we examine the catalytic function of the combined 3-deoxy-d-arabino heptulosonate-7 phosphate synthase (DAH7PS) and chorismate mutase (CM) from Geobacillus sp. DAH7PS operates at the start of the biosynthetic pathway for aromatic metabolites, whereas CM operates in a dedicated branch of the pathway for the biosynthesis of amino acids tyrosine and phenylalanine. In line with sequence predictions, the two catalytic functions are located in distinct domains, and these two activities can be separated and retain functionality. For the full length protein, prephenate, the product of the CM reaction, acts as an allosteric inhibitor for the DAH7PS. The crystal structure of the full-length protein with prephenate bound and the accompanying small angle x-ray scattering data reveal the molecular mechanism of the allostery. Prephenate binding results in the tighter association between the dimeric CM domains and the tetrameric DAH7PS, occluding the active site and therefore disrupting DAH7PS function. Acquisition of a physical gating mechanism to control catalytic function through gene fusion appears to be a general mechanism for providing allostery for this enzyme. PMID- 27502276 TI - The Effect of Cellular Stress on T and B Cell Memory Pathways in Immunized and Unimmunized BALB/c Mice. AB - Immunological memory is a fundamental function of vaccination. The antigenic breakdown products of the vaccine may not persist, and undefined tonic stimulation has been proposed to maintain the specific memory. We have suggested that cellular stress agents to which the immune cells are constantly exposed may be responsible for tonic stimulation. Here we have studied four stress agents: sodium arsenite, an oxidative agent; Gramicidin, eliciting K(+) efflux and calcium influx; dithiocarbamate, a metal ionophore; and aluminum hydroxide (alum), an immunological adjuvant. The aims of this study are to extend these investigations to T and B cell responses of unimmunized and ovalbumin (OVA) immunized BALB/c mice, and furthermore, to ascertain whether stress is involved in optimal expression of memory B cells, as demonstrated in CD4(+) T cells. Examination of the homeostatic pathway defined by IL-15/IL-15R (IL-15 receptor) interaction and the inflammasome pathway defined by the IL-1-IL-1R interaction between dendritic cells (DC) and CD4(+) T cells suggests that both pathways are involved in the development of optimal expression of CD4(+)CD45RO(+) memory T cells in unimmunized and OVA-immunized BALB/c mice. Furthermore, significant direct correlation was found between CD4(+)CD44(+) memory T cells and both IL-15 of the homeostatic and IL-1beta of the inflammasome pathways. However, CD19(+)CD27(+) memory B cells in vivo seem to utilize only the IL-15/IL-15R homeostatic pathway, although the proliferative responses are enhanced by the stress agents. Altogether, stress agents may up-regulate unimmunized and OVA immunized CD4(+)CD44(+) memory T cells by the homeostatic and inflammasome pathways. However, the CD19(+)CD27(+) memory B cells utilize only the homeostatic pathway. PMID- 27502277 TI - An ATP Binding Cassette Transporter Mediates the Uptake of alpha-(1,6)-Linked Dietary Oligosaccharides in Bifidobacterium and Correlates with Competitive Growth on These Substrates. AB - The molecular details and impact of oligosaccharide uptake by distinct human gut microbiota (HGM) are currently not well understood. Non-digestible dietary galacto- and gluco-alpha-(1,6)-oligosaccharides from legumes and starch, respectively, are preferentially fermented by mainly bifidobacteria and lactobacilli in the human gut. Here we show that the solute binding protein (BlG16BP) associated with an ATP binding cassette (ABC) transporter from the probiotic Bifidobacterium animalis subsp. lactis Bl-04 binds alpha-(1,6)-linked glucosides and galactosides of varying size, linkage, and monosaccharide composition with preference for the trisaccharides raffinose and panose. This preference is also reflected in the alpha-(1,6)-galactoside uptake profile of the bacterium. Structures of BlG16BP in complex with raffinose and panose revealed the basis for the remarkable ligand binding plasticity of BlG16BP, which recognizes the non-reducing alpha-(1,6)-diglycoside in its ligands. BlG16BP homologues occur predominantly in bifidobacteria and a few Firmicutes but lack in other HGMs. Among seven bifidobacterial taxa, only those possessing this transporter displayed growth on alpha-(1,6)-glycosides. Competition assays revealed that the dominant HGM commensal Bacteroides ovatus was out-competed by B. animalis subsp. lactis Bl-04 in mixed cultures growing on raffinose, the preferred ligand for the BlG16BP. By comparison, B. ovatus mono-cultures grew very efficiently on this trisaccharide. These findings suggest that the ABC mediated uptake of raffinose provides an important competitive advantage, particularly against dominant Bacteroides that lack glycan-specific ABC transporters. This novel insight highlights the role of glycan transport in defining the metabolic specialization of gut bacteria. PMID- 27502278 TI - Outer Membrane Proteins Derived from Non-cyanobacterial Lineage Cover the Peptidoglycan of Cyanophora paradoxa Cyanelles and Serve as a Cyanelle Diffusion Channel. AB - The cyanelle is a primitive chloroplast that contains a peptidoglycan layer between its inner and outer membranes. Despite the fact that the envelope structure of the cyanelle is reminiscent of Gram-negative bacteria, the Cyanophora paradoxa genome appears to lack genes encoding homologs of putative peptidoglycan-associated outer membrane proteins and outer membrane channels. These are key components of Gram-negative bacterial membranes, maintaining structural stability and regulating permeability of outer membrane, respectively. Here, we discovered and characterized two dominant peptidoglycan-associated outer membrane proteins of the cyanelle (~2 * 10(6) molecules per cyanelle). We named these proteins CppF and CppS (cyanelle peptidoglycan-associated proteins). They are homologous to each other and function as a diffusion channel that allows the permeation of compounds with Mr <1,000 as revealed by permeability measurements using proteoliposomes reconstituted with purified CppS and CppF. Unexpectedly, amino acid sequence analysis revealed no evolutionary linkage to cyanobacteria, showing only a moderate similarity to cell surface proteins of bacteria belonging to Planctomycetes phylum. Our findings suggest that the C. paradoxa cyanelle adopted non-cyanobacterial lineage proteins as its main outer membrane components, providing a physical link with the underlying peptidoglycan layer and functioning as a diffusion route for various small substances across the outer membrane. PMID- 27502279 TI - Structures of Exopolysaccharides Involved in Receptor-mediated Perception of Mesorhizobium loti by Lotus japonicus. AB - In the symbiosis formed between Mesorhizobium loti strain R7A and Lotus japonicus Gifu, rhizobial exopolysaccharide (EPS) plays an important role in infection thread formation. Mutants of strain R7A affected in early exopolysaccharide biosynthetic steps form nitrogen-fixing nodules on L. japonicus Gifu after a delay, whereas mutants affected in mid or late biosynthetic steps induce uninfected nodule primordia. Recently, it was shown that a plant receptor-like kinase, EPR3, binds low molecular mass exopolysaccharide from strain R7A to regulate bacterial passage through the plant's epidermal cell layer (Kawaharada, Y., Kelly, S., Nielsen, M. W., Hjuler, C. T., Gysel, K., Muszynski, A., Carlson, R. W., Thygesen, M. B., Sandal, N., Asmussen, M. H., Vinther, M., Andersen, S. U., Krusell, L., Thirup, S., Jensen, K. J., et al. (2015) Nature 523, 308-312). In this work, we define the structure of both high and low molecular mass exopolysaccharide from R7A. The low molecular mass exopolysaccharide produced by R7A is a monomer unit of the acetylated octasaccharide with the structure (2,3/3 OAc)beta-d-RibfA-(1->4)-alpha-d-GlcpA-(1->4)-beta-d-Glcp-(1->6)-(3OAc)beta-d-Glcp (1->6)-*[(2OAc)beta-d-Glcp-(1->4)-(2/3OAc)beta-d-Glcp-(1->4)-beta-d-Glcp-(1->3) beta-d-Galp]. We propose it is a biosynthetic constituent of high molecular mass EPS polymer. Every new repeating unit is attached via its reducing-end beta-d Galp to C-4 of the fourth glucose (asterisked above) of the octasaccharide, forming a branch. The O-acetylation occurs on the four glycosyl residues in a non stoichiometric ratio, and each octasaccharide subunit is on average substituted with three O-acetyl groups. The availability of these structures will facilitate studies of EPR3 receptor binding of symbiotically compatible and incompatible EPS and the positive or negative consequences on infection by the M. loti exo mutants synthesizing such EPS variants. PMID- 27502280 TI - Tuning the Transcriptional Response to Hypoxia by Inhibiting Hypoxia-inducible Factor (HIF) Prolyl and Asparaginyl Hydroxylases. AB - The hypoxia-inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an alpha/beta-heterodimeric transcription factor that regulates the expression of hundreds of genes in a tissue context-dependent manner. The major hypoxia-sensing component of the HIF system involves oxygen dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (factor-inhibiting HIF (FIH)). PHD catalysis regulates HIFalpha levels, and FIH catalysis regulates HIF activity. How differences in HIFalpha hydroxylation status relate to variations in the induction of specific HIF target gene transcription is unknown. We report studies using small molecule HIF hydroxylase inhibitors that investigate the extent to which HIF target gene expression is induced by PHD or FIH inhibition. The results reveal substantial differences in the role of prolyl and asparaginyl hydroxylation in regulating hypoxia-responsive genes in cells. PHD inhibitors with different structural scaffolds behave similarly. Under the tested conditions, a broad-spectrum 2-oxoglutarate dioxygenase inhibitor is a better mimic of the overall transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in the transcriptional induction of a subset of genes not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable. PMID- 27502281 TI - MicroRNA-223-5p and -3p Cooperatively Suppress Necroptosis in Ischemic/Reperfused Hearts. AB - Recent studies have shown that myocardial ischemia/reperfusion (I/R)-induced necrosis can be controlled by multiple genes. In this study, we observed that both strands (5p and 3p) of miR-223 were remarkably dysregulated in mouse hearts upon I/R. Precursor miR-223 (pre-miR-223) transgenic mouse hearts exhibited better recovery of contractile performance over reperfusion period and lesser degree of myocardial necrosis than wild type hearts upon ex vivo and in vivo myocardial ischemia. Conversely, pre-miR-223 knock-out (KO) mouse hearts displayed opposite effects. Furthermore, we found that the RIP1/RIP3/MLKL necroptotic pathway and inflammatory response were suppressed in transgenic hearts, whereas they were activated in pre-miR-223 KO hearts upon I/R compared with wild type controls. Accordingly, treatment of pre-miR-223 KO mice with necrostatin-1s, a potent necroptosis inhibitor, significantly decreased I/R triggered cardiac necroptosis, infarction size, and dysfunction. Mechanistically, we identified two critical cell death receptors, TNFR1 and DR6, as direct targets of miR-223-5p, whereas miR-223-3p directly suppressed the expression of NLRP3 and IkappaB kinase alpha, two important mediators known to be involved in I/R-induced inflammation and cell necroptosis. Our findings indicate that miR-223-5p/-3p duplex works together and cooperatively inhibits I/R-induced cardiac necroptosis at multiple layers. Thus, pre-miR-223 may constitute a new therapeutic agent for the treatment of ischemic heart disease. PMID- 27502282 TI - Functional Annotation of a Presumed Nitronate Monoxygenase Reveals a New Class of NADH:Quinone Reductases. AB - The protein PA1024 from Pseudomonas aeruginosa PAO1 is currently classified as 2 nitropropane dioxygenase, the previous name for nitronate monooxygenase in the GenBankTM and PDB databases, but the enzyme was not kinetically characterized. In this study, PA1024 was purified to high levels, and the enzymatic activity was investigated by spectroscopic and polarographic techniques. Purified PA1024 did not exhibit nitronate monooxygenase activity; however, it displayed NADH:quinone reductase and a small NADH:oxidase activity. The enzyme preferred NADH to NADPH as a reducing substrate. PA1024 could reduce a broad spectrum of quinone substrates via a Ping Pong Bi Bi steady-state kinetic mechanism, generating the corresponding hydroquinones. The reductive half-reaction with NADH showed a kred value of 24 s-1 and an apparent Kd value estimated in the low micromolar range. The enzyme was not able to reduce the azo dye methyl red, routinely used in the kinetic characterization of azoreductases. Finally, we revisited and modified the existing six conserved motifs of PA1024, which define a new class of NADH:quinone reductases and are present in more than 490 hypothetical proteins in the GenBankTM, the vast majority of which are currently misannotated as nitronate monooxygenase. PMID- 27502283 TI - Rice Endosperm Starch Phosphorylase (Pho1) Assembles with Disproportionating Enzyme (Dpe1) to Form a Protein Complex That Enhances Synthesis of Malto oligosaccharides. AB - Starch synthesis in cereal grain endosperm is dependent on the concerted actions of many enzymes. The starch plastidial phosphorylase (Pho1) plays an important role in the initiation of starch synthesis and in the maturation of starch granule in developing rice seeds. Prior evidence has suggested that the rice enzyme, OsPho1, may have a physical/functional interaction with other starch biosynthetic enzymes. Pulldown experiments showed that OsPho1 as well as OsPho1 devoid of its L80 region, a peptide unique to higher plant phosphorylases, captures disproportionating enzyme (OsDpe1). Interaction of the latter enzyme form with OsDpe1 indicates that the putative regulatory L80 is not responsible for multienzyme assembly. This heterotypic enzyme complex, determined at a molar ratio of 1:1, was validated by reciprocal co-immunoprecipitation studies of native seed proteins and by co-elution chromatographic and co-migration electrophoretic patterns of these enzymes in rice seed extracts. The OsPho1 OsDpe1 complex utilized a broader range of substrates for enhanced synthesis of larger maltooligosaccharides than each individual enzyme and significantly elevated the substrate affinities of OsPho1 at 30 degrees C. Moreover, the assembly with OsDpe1 enables OsPho1 to utilize products of transglycosylation reactions involving G1 and G3, sugars that it cannot catalyze directly. PMID- 27502284 TI - Result of randomized control trial to increase breast health awareness among young females in Malaysia. AB - BACKGROUND: Breast cancer is the most common cancer and the second principal cause of cancer deaths in women worldwide as well as in Malaysia. Breast self examination (BSE) has a role in raising breast cancer awareness among women and educational programs play an important role in breast cancer preventive behavior. The aim of this study is to develop, implement and evaluate the effectiveness of Breast Health Awareness program based on health belief model on knowledge of breast cancer and breast-selfexamination and BSE practice among female students in Malaysia. METHODS: A single-blind randomized controlled trial was carried out among 370 female undergraduate students from January 2011 to April 2012 in two selected public universities in Malaysia. Participants were randomized to either the intervention group or the control group. The educational program was delivered to the intervention group. The outcome measures were assessed at baseline, 6, and 12 months after implementing the health educational program. Chi square, independent samples t-test and two-way repeated measures ANOVA (GLM) were conducted in the course of the data analyses. RESULTS: Mean scores of knowledge on breast cancer (p<0.003), knowledge on breast self examination (p<0.001), benefits of BSE (p<0.00), barrier of BSE (0.01) and confidence of BSE practice (p<0.00) in the intervention group had significant differences in comparison with those of the control group 6 and 12 months after the intervention. Also, among those who never practiced BSE at baseline, frequency of BSE practice increased 6 and 12 months after the intervention (p<0.05). CONCLUSION: The Breast Health Awareness program based on health the belief model had a positive effect on knowledge of breast cancer and breast self-examination and practice of BSE among females in Malaysia. TRIAL REGISTRATION: The ANZCTR clinical trial registry ( ACTRN12616000831482 ), retrospectively registered on Jun 23, 2016 in ANZCTR.org.au. PMID- 27502285 TI - Three new sesquiterpenoids from agarwood of Aquilaria crassna. AB - Three new sesquiterpenoids (1-3), together with two known ones were isolated from the EtOAc extract of agarwood originating from Aquilaria crassna. The new compounds were elucidated on the basis of spectroscopic techniques (UV, IR, MS, 1D and 2D NMR). Compounds 1-5 were isolated from agarwood of A. crassna for the first time. In the acetylcholinesterase inhibition experiment of 2-5, compound 3 showed acetylcholinesterase inhibition activity (IR 42.9+/-0.6%). Compound 5 expressed antibacterial activities against Staphylococcus aureus and Ralstonia solanacearum with diameter of the inhibition zones of 12.35+/-0.11mm and 16.90+/ 0.09mm, respectively. PMID- 27502286 TI - Morphology, Clinicopathologic Correlations, and Mechanisms in Heart Valve Health and Disease. AB - The clinical and pathological features of the most frequent intrinsic structural diseases that affect the heart valves are well established, but heart valve disease mechanisms are poorly understood, and effective treatment options are evolving. Major advances in the understanding of the structure, function and biology of native valves and the pathobiology, biomaterials and biomedical engineering, and the clinical management of valvular heart disease have occurred over the past several decades. This communication reviews contemporary considerations relative to the pathology of valvular heart disease, including (1) clinical significance and epidemiology of valvular heart disease; (2) functional and dynamic valvular macro-, micro- and ultrastructure; (3) causes, morphology and mechanisms of human valvular heart disease; and (4) pathologic considerations in valve replacement, repair and, potentially, regeneration of the heart valves. PMID- 27502287 TI - Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection. AB - BACKGROUND: DCV-TRIO, a fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies. METHODS: In this phase 3 study, DCV-TRIO for 12 weeks and daclatasvir plus asunaprevir (DUAL) for 24 weeks were studied in Japanese patients infected with HCV genotype 1 (99 % genotype 1b). RESULTS: SVR12 rates >=95 % were achieved in both treatment-naive (N = 152) and interferon-experienced (N = 65) cohorts treated with DCV-TRIO for 12 weeks and were comparable across patient subgroups, including patients aged >=65 years and those with cirrhosis. DUAL recipients (N = 75) had an SVR12 rate of 87 %. In the absence of baseline resistance-associated polymorphisms at positions NS5A-Y93H or -L31, SVR12 rates were 98 % with DCV-TRIO or DUAL. Among genotype 1b-infected patients with baseline Y93H or L31 polymorphisms, 35/38 (92 %) DCV-TRIO recipients, and 7/16 (44 %) DUAL recipients achieved SVR12. Adverse events, mostly liver related, led to treatment discontinuation in 10 % of DCV TRIO recipients. In this group, SVR12 was achieved by 3/9 patients who discontinued before Week 4 and by 12/12 patients who completed >=4 weeks of DCV TRIO. Treatment-related serious adverse events occurred in 4 and 3 % of DCV-TRIO and DUAL recipients, respectively. Seven patients (9 %) discontinued DUAL due to adverse events. No deaths occurred. CONCLUSION: SVR12 was achieved by 96 % of Japanese patients with HCV genotype 1 infection after 12 weeks of treatment with the DCV-TRIO regimen. DCV-TRIO and DUAL exhibited comparable safety profiles. PMID- 27502289 TI - Erratum to: Concentric Multiple Rings by Droplet Epitaxy: Fabrication and Study of the Morphological Anisotropy. PMID- 27502288 TI - Sphingolipids as targets for treatment of fungal infections. AB - Invasive fungal infections have significantly increased in the last few decades. Three classes of drugs are commonly used to treat these infections: polyenes, azoles and echinocandins. Unfortunately each of these drugs has drawbacks; polyenes are toxic, resistance against azoles is emerging and echinocandins have narrow spectrum of activity. Thus, the development of new antifungals is urgently needed. In this context, fungal sphingolipids have emerged as a potential target for new antifungals, because their biosynthesis in fungi is structurally different than in mammals. Besides, some fungal sphingolipids play an important role in the regulation of virulence in a variety of fungi. This review aims to highlight the diverse strategies that could be used to block the synthesis or/and function of fungal sphingolipids. PMID- 27502291 TI - Another piece in the puzzle of bicuspid aortic valve syndrome. PMID- 27502290 TI - Identification of patients at risk for renal impairment after living donor kidney transplantation. AB - PURPOSE: Outcome after living donor kidney transplantation is highly relevant, since recipient and donor were exposed to notable harm. Reliable identification of risk factors is necessary. METHODS: Three hundred sixty-six living donor kidney transplants were included in this observational retrospective study. Relevant risk factors for renal impairment 1 year after transplantation and delayed graft function were identified with univariable and multivariable binary logistic regression and ordinal regression analysis. RESULTS: Eighty-four patients (26.6 %) suffered from renal impairment KDIGO stage >=4 1 year post transplant; median estimated glomerular filtration rate was 35.3 ml/min. In multivariable ordinal regression, male recipient sex (p < 0.001), recipient body mass index (p = 0.006), donor age (p = 0.002) and high percentages of panel reactive antibodies (p = 0.021) were revealed as independent risk factors for higher KDIGO stages. After adjustment for post-transplant data, recipient male sex (p < 0.001), donor age (p = 0.026) and decreased early renal function at the first post-transplant outpatient visit (p < 0.001) were identified as independent risk factors. Delayed graft function was independently associated with long stay on the waiting list (p = 0.011), high donor body mass index (p = 0.043), prolonged warm ischemic time (p = 0.016) and the presence of preformed donor specific antibodies (p = 0.043). CONCLUSIONS: Broadening the donor pool with non blood related donors seems to be legitimate, although with respect to careful medical selection, since donor age in combination with male recipient sex were shown to be risk factors for decreased graft function. Warm ischemic time and waiting time need to be kept as short as possible to avoid delayed graft function. Transplantation across HLA and ABO borders did not affect outcome significantly. PMID- 27502292 TI - The high-risk criteria low-attenuation plaque <60 HU and the napkin-ring sign are the most powerful predictors of MACE: a long-term follow-up study. AB - Aims: To assess the prognostic value of coronary CT angiography (CTA) for prediction of major adverse cardiac events (MACE) over a long-term follow-up period. Methods and Results: A total of 1469 low-to-intermediate-risk patients (65.9 years; 44.2% females) were included in our prospective cohort study. CTA was evaluated for (i) stenosis severity (minimal <10%; mild <50%; moderate 50 70%; severe >70%), (ii) plaque types (calcified, mixed dominantly calcified, mixed dominantly non-calcified, non-calcified), and (iii) high-risk plaque criteria [low-attenuation plaque (LAP) quantified by HU, napkin-ring (NR) sign, spotty calcification <3 mm, and remodelling index (RI)]. Over a follow-up of mean 7.8 years, MACE rate was 41 (2.8%) and 0% in patients with negative CTA. MACE rate increased along with stenosis severity by CTA (from 1.3 to 7.8%) (P < 0.001) and was higher in T3/T4 plaques than in T2/T1 (7.8 vs. 1.9%; P < 0.0001). LAP density was lower (35.2 HU +/- 32 vs. 108.8 HU +/- 53) (P < 0.001) and both NR sign prevalence with n = 26 (63.4%) vs. n = 40 (28%) and LAP <30, <60, and <90 HU prevalence with 46.3-78% vs. 2.4-7% were higher in the MACE group (P < 0.001). On univariate and unadjusted multivariable proportional Hazards model, LAP <60 HU and NR were the strongest MACE predictors (HR 4.96; 95% CI: 2.0-12.2 and HR 3.85; 95% CI: 1.7-8.6) (P < 0.0001), while spotty calcification (HR 2.2; 95% CI: 1.1 4.3, P < 0.001), stenosis severity, and plaque type (HR 1.5; 95% CI: 1.1-2.3 and HR 1.7; 95% CI: 1.1-2.6) (P < 0.001) were less powerful. After adjusting for risk factors, CTA stenosis severity, and plaque type, LAP <60 HU and the NR sign remained significant (P < 0.001), while the effect of NR sign was even enhancing. HRP criteria were independent predictors from other risk factors. Conclusion: Prognosis is excellent over a long-term period if CTA is negative and worsening with an increasing non-calcifying plaque component. LAP <60 HU and NR sign are the most powerful MACE predictors. PMID- 27502293 TI - Quantitative assessment of the entire right ventricle from one acoustic window: an attractive approach. AB - Aims: The aim of this prospective study was to evaluate the feasibility and establish normal values of functional right ventricle (RV) parameters as assessed in our four, long-axis view RV model using iRotate echocardiography. Furthermore, we evaluated the potential use of this model in patients with abnormally loaded RVs. Method and results: One hundred and fifty-five healthy subjects aged 20-72 years (>=28 subjects per decile) were prospectively recruited. We used non dedicated RV speckle-tracking software to test the feasibility and to establish normal range values of peak systolic global longitudinal RV strain (RV-GLS) from the RV free-walls (septum was excluded). Also normal range values for: dimensions, tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular peak systolic velocity (TDI-S') were established. The feasibility of RV GLS was 88, 84, and 62%, respectively, in the lateral, inferior, and anterior free wall. Mean RV-GLS normal values were -24.5 +/- 4.9% for lateral wall and 25.4 +/- 5.0% for anterior wall. Mean RV-GLS in the inferior wall was -23.2 +/- 4.4% in the aortic (Ao) view and -20.7 +/- 5.0% in the coronal (CV) view. The feasibility of mean RV-GLS was 100% in the anterior, lateral, and inferior walls in abnormally dilated RVs. Conclusion: The feasibility of all RV parameters assessed in the four-view iRotate model is good to excellent. Normal values for RV dimension and function of the anterior, inferior, and lateral RV walls have been established. Further studies and dedicated RV speckle-tracking software are warranted to discover the full potential of this new technique. PMID- 27502294 TI - Predicting outcomes after percutaneous mitral balloon valvotomy: the impact of left ventricular strain imaging. AB - Aims: This study aimed (1) to evaluate the impact of preprocedural two dimensional speckle-tracking echocardiography (2D-STE) on long-term outcome after successful percutaneous mitral balloon valvotomy (PMBV) in patients with mitral stenosis (MS) and (2) to determine whether 2D-STE detects underlying diastolic dysfunction as defined by invasive haemodynamic study. Methods and Results: Sixty four consecutive MS patients with preserved left ventricular ejection fraction (LVEF >=50%) and who underwent successfully PMBV were studied. Successful immediate result was defined as post-procedural mitral valve area >=1.5 cm2 and <=2/4 mitral regurgitation by catheterization. During a follow-up of 4.2 +/- 3.0 years, there were 7 deaths (11%) and 21 late mitral valve reintervention (33%). Univariate predictors of death were global longitudinal strain (GLS), age, LVEF, and pre- and post-procedural pulmonary artery pressures. In the multivariate Cox model, GLS was the strongest predictor of death [hazard ratio (HR) (95% CI), 1.45 (1.07-2.04); P= 0.01]. For the composite endpoint, GLS and post-procedural left atrial pressure (LAP) were univariate predictors of death or reintervention. At multivariable analysis, GLS and post-procedural LAP remained in the final model with strong trend towards significance [GLS HR (95% CI), 1.17 (0.99-1.37); P= 0.056]. There was no correlation between diastolic dysfunction identified at catheterization and standard echocardiographic and 2D-STE indexes, even after adjustments for age, left ventricular mass, effective arterial elastance (afterload), and end-diastolic volume indexes (preload). Conclusion: GLS is a powerful predictor of long-term outcome after successful PMBV and provides incremental prognostic value over traditional parameters. Echocardiographic diagnosis of concomitant diastolic dysfunction in MS patients remains elusive. PMID- 27502295 TI - The additive prognostic value of coronary flow velocity reserve during exercise echocardiography. AB - Aims: The aim of the study was to assess the additive prognostic value of coronary flow velocity reserve (CFVR) alongside wall motion analysis during exercise echocardiography in patients with known or suspected coronary artery disease (CAD). Methods and results: In a prospective, single-centre, observational study, we evaluated 689 patients (449 males; 56 + 9 years) who underwent supine bicycle stress echo (ESE) with CFVR evaluation of the left anterior descending artery (LAD) by Doppler. ESE was positive for regional wall motion abnormalities in 359 (52%) patients. Mean CFVR was 1.9 +/- 0.8. During a median follow-up of 36.6 months, there were 200 patients with major adverse cardiac events (MACE): 15 deaths, 17 non-fatal myocardial infarctions [11 of them also had percutaneous coronary intervention with stenting (PCI) or/and coronary artery bypass graft surgery (CABG)] and 179 patients underwent revascularization. The 37 months' event-free survival showed the best outcome for those patients with negative ESE by wall motion criteria and normal CFVR, and the worst outcome for patients with positive ESE by wall motion and abnormal CVFR (99 vs. 42%, P < 0.0001). At multivariable analysis, CFVR in LAD (OR 0.53, 95% CI 0.35-0.79, P < 0.0001), positivity for regional wall motion abnormalities during testing (OR 0.10, 95% CI 0.04-0.25, P < 0.000), previous PCI (OR 0.38, 95% CI 0.16-0.90, P < 0.003), male sex (OR 0.44, 95% CI 0.27-0.71, P < 0.0009), and heart rate reached during exercise (OR 0.98, 95% CI 0.96-0.99, P < 0.02) were independent prognostic predictors of MACE. Conclusion: In patients with known or suspected CAD, exercise stress tests measuring wall motion criteria and CFVR are additive and complementary for the identification of patients at risk of experiencing major adverse events. PMID- 27502296 TI - Robust phase retrieval for high resolution edge illumination x-ray phase-contrast computed tomography in non-ideal environments. AB - Edge illumination x-ray phase contrast tomography is a recently developed imaging technique which enables three-dimensional visualisation of low-absorbing materials. Dedicated phase retrieval algorithms can provide separate computed tomography (CT) maps of sample absorption, refraction and scattering properties. In this paper we propose a novel "modified local retrieval" method which is capable of accurately retrieving sample properties in a range of realistic, non ideal imaging environments. These include system misalignment, defects in the used optical elements and system geometry variations over time due to vibrations or temperature fluctuations. System instabilities were analysed, modelled and incorporated into a simulation study. As a result, an additional modification was introduced to the retrieval procedure to account for changes in the imaging system over time, as well as local variations over the field of view. The performance of the proposed method was evaluated in comparison to a previously used "global retrieval" method by applying both approaches to experimental CT data of a rat's heart acquired in a non-ideal environment. The use of the proposed method resulted in the removal of major artefacts, leading to a significant improvement in image quality. This method will therefore enable acquiring high-resolution, reliable CT data of large samples in realistic settings. PMID- 27502298 TI - Non-Alzheimer Dementias. PMID- 27502297 TI - beta-Defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis. AB - BACKGROUND: IL-17A is a key driver of human autoimmune diseases, particularly psoriasis. OBJECTIVE: We sought to determine the role of IL-17A in psoriasis pathogenesis and to identify a robust and measurable biomarker of IL-17A-driven pathology. METHODS: We studied 8 healthy subjects and 8 patients with psoriasis before and after administration of secukinumab, a fully human anti-IL-17A mAb, and used a combination of classical techniques and a novel skin microperfusion assay to evaluate the expression of 170 proteins in blood, nonlesional skin, and lesional skin. For validation, we also tested stored sera from 601 patients with a variety of autoimmune diseases. RESULTS: IL-17A was specifically expressed in lesional compared with nonlesional psoriatic skin (9.8 vs 0.8 pg/mL, P < .001). Proteomic and gene transcription analyses revealed dysregulated antimicrobial peptides, proinflammatory cytokines, and neutrophil chemoattractants, levels of which returned to normal after treatment with secukinumab. beta-Defensin 2 (BD-2) was identified as a biomarker of IL-17A-driven pathology by comparing protein expression in patients with psoriasis versus that in healthy subjects (5746 vs 82 pg/mL in serum, P < .0001; 2747 vs <218 pg/mL in dermis, P < .001), responsiveness to secukinumab therapy, and synergistic induction by IL-17A and TNF-alpha in epidermal keratinocytes. In a validation set of sera from 601 patients with autoimmune diseases thought to be IL-17A driven, we found that BD-2 levels are most highly increased in patients with psoriatic skin lesions, and in patients with psoriasis, BD-2 levels correlated well with IL-17A levels (r = 0.70, n = 199, P < .001) and Psoriasis Area and Severity Index scores (r = 0.53, n = 281, P < .001). CONCLUSION: IL-17A is a primary driver of skin pathology in patients with psoriasis, and serum BD-2 is an easily measurable biomarker of IL 17A-driven skin pathology. PMID- 27502299 TI - Revisiting DLB Diagnosis: A Consideration of Prodromal DLB and of the Diagnostic Overlap With Alzheimer Disease. AB - Efforts to clinically diagnose cases having dementia with Lewy bodies (DLB) identify those with a characteristic clinical syndrome (probable DLB) at the expense of missing an equal, if not greater, number of cases who have atypical presentations thought to be associated with coexisting Alzheimer pathologies. This article argues that further efforts should now be made to characterize this atypical group that constitutes cases previously identified postmortem as the Lewy body variant of Alzheimer disease (AD) or as AD with Lewy bodies. Since such fine distinction is unlikely to be achieved on clinical grounds alone, this new diagnostic category will require robust biomarker validation. Turning to a consideration of early/prodromal diagnosis of both typical and atypical DLB cases, it is suggested that there will be at least 3 prototypical forms-a mild cognitive impairment variant, associated with early visuoperceptual and attentional deficits; a delirium onset DLB with provoked or spontaneous delirium as the presenting features; and a psychiatric disorder DLB with its primary presentation as a late-onset affective disorder or psychosis. PMID- 27502300 TI - Imaging in Dementia With Lewy Bodies: An Overview. AB - Dementia with Lewy bodies (DLB) while common in older age can present a diagnostic challenge to clinicians and is often misdiagnosed as Alzheimer disease (AD). Imaging studies have improved our understanding of the neurobiological changes in DLB during life and how they differ from AD. This has led to significant advances in the development of new techniques, such as dopaminergic imaging, which can aid the clinical diagnosis. Other functional imaging methods also show promise in helping to assess the influence of differing pathologies in DLB, most notably, AD-related and vascular pathology during life. This article will provide an overview of the main imaging findings in DLB. PMID- 27502301 TI - Parkinson Disease and Dementia. AB - Dementia is a frequent complication of Parkinson disease (PD) with a yearly incidence of around 10% of patients with PD. Lewy body pathology is the most important factor in the development of Parkinson disease dementia (PDD) and there is evidence for a synergistic effect with beta-amyloid. The clinical phenotype in PDD extends beyond the dysexecutive syndrome that is often present in early PD and encompasses deficits in recognition memory, attention, and visual perception. Sleep disturbances, hallucinations, neuroleptic sensitivity, and fluctuations are often present. This review provides an update on current knowledge of PDD including aspects of epidemiology, pathology, clinical presentation, management, and prognosis. PMID- 27502302 TI - Frontotemporal Dementia: An Updated Clinician's Guide. AB - Today, frontotemporal dementia (FTD) remains one of the most common forms of early-onset dementia, that is, before the age of 65, thus posing several diagnostic challenges to clinicians since symptoms are often mistaken for psychiatric or neurological diseases causing a delay in correct diagnosis, and the majority of patients with FTD present with symptoms at ages between 50 and 60. Genetic components are established risk factors for FTD, but the influence of lifestyle, comorbidity, and environmental factors on the risk of FTD is still unclear. Approximately 40% of individuals with FTD have a family history of dementia but less than 10% have a clear autosomal dominant pattern of inheritance. Lack of insight is often an early clue to FTD. A tailored treatment option at an early phase can mitigate suffering and improve patients' and caregivers' quality of life. PMID- 27502303 TI - Update on Vascular Dementia. AB - Vascular dementia (VaD) is a major contributor to the dementia syndrome and is described as having problems with reasoning, planning, judgment, and memory caused by impaired blood flow to the brain and damage to the blood vessels resulting from events such as stroke. There are a variety of etiologies that contribute to the development of vascular cognitive impairment and VaD, and these are often associated with other dementia-related pathologies such as Alzheimer disease. The diagnosis of VaD is difficult due to the number and types of lesions and their locations in the brain. Factors that increase the risk of vascular diseases such as stroke, high blood pressure, high cholesterol, and smoking also raise the risk of VaD. Therefore, controlling these risk factors can help lower the chances of developing VaD. This update describes the subtypes of VaD, with details of their complex presentation, associated pathological lesions, and issues with diagnosis, prevention, and treatment. PMID- 27502304 TI - Erratum to: Therapeutic dilemmas in Hashimoto's encephalopathy. PMID- 27502305 TI - Overexpression of Antimicrobial, Anticancer, and Transmembrane Peptides in Escherichia coli through a Calmodulin-Peptide Fusion System. AB - In recent years, the increasing number of antibiotic-resistant bacteria has become a serious health concern. Antimicrobial peptides (AMPs) are an important component of the innate immune system of most organisms. A better understanding of their structures and mechanisms of action would lead to the design of more potent and safer AMPs as alternatives for current antibiotics. For detailed investigations, effective recombinant production which allows the facile modification of the amino acid sequence, the introduction of unnatural amino acids, and labeling with stable isotopes for nuclear magnetic resonance (NMR) studies is desired. Several expression strategies have been introduced in previous reports; however, their effectiveness has been limited to a select few AMPs. Here, we have studied calmodulin (CaM) as a more universal carrier protein to express many types of AMPs in E. coli. We have discovered that the unique architecture of CaM, consisting of two independent target binding domains with malleable methionine-rich interaction surfaces, can accommodate numerous amino acid sequences containing basic and hydrophobic residues. This effectively masks the toxic antimicrobial activities of many amphipathic AMPs and protects them from degradation during expression and purification. Here, we demonstrate the expression of various AMPs using a CaM-fusion expression system, including melittin, fowlicidin-1, tritrpticin, indolicidin, puroindoline A peptide, magainin II F5W, lactoferrampin B, MIP3alpha51-70, and human beta-defensin 3 (HBD 3), the latter requiring three disulfide bonds for proper folding. In addition, our approach was extended to the transmembrane domain of the cell adhesion protein l-selectin. We propose the use of the CaM-fusion system as a universal approach to express many cationic amphipathic peptides that are normally toxic and would kill the bacterial host cells. PMID- 27502306 TI - Curcumin attenuates osteogenic differentiation and calcification of rat vascular smooth muscle cells. AB - Vascular calcification has been considered as a biological process resembling bone formation involving osteogenic differentiation. It is a major risk factor for cardiovascular morbidity and mortality. Previous studies have shown the protective effects of curcumin on cardiovascular diseases. However, whether curcumin has effects on osteogenic differentiation and calcification of vascular smooth muscle cells (VSMCs) has not been reported. In the present study, we used an in vitro model of VSMC calcification to investigate the role of curcumin in the progression of rat VSMC calcification. Curcumin treatment significantly reduced calcification of VSMCs in a dose-dependent manner, detected by alizarin red staining and calcium content assay. Similarly, ALP activity and expression of bone-related molecules including Runx2, BMP2, and Osterix were also decreased in VSMCs treated with curcumin. In addition, flow cytometry analysis and caspase-3 activity assay revealed that curcumin treatment significantly suppressed apoptosis of VSMCs, which plays an important role during vascular calcification. Furthermore, we found that pro-apoptotic molecules including p-JNK and Bax were up-regulated in VSMCs treated with calcifying medium, but they were reduced in VSMCs after curcumin treatment. However, curcumin treatment has no effect on expression of NF-kappaB p65. Taken together, these findings suggest that curcumin attenuates apoptosis and calcification of VSMCs, presumably via inhibition of JNK/Bax signaling pathway. PMID- 27502307 TI - Randomized trial assessing the safety and efficacy of sitagliptin in Chinese patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea alone or combined with metformin. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a significant burden in China, where approximately 114 million patients have been diagnosed with diabetes. Chinese patients present with prominent beta-cell failure, with resulting deficiency in insulin secretion, particularly early phase insulin secretion leading to postprandial hyperglycemia. Sitagliptin, a selective once-daily oral dipeptidyl peptidase-4 inhibitor, has been shown to improve glycemic control as monotherapy and in combination with other antihyperglycemic agents, including sulfonylureas and metformin. METHODS: This was a multicenter randomized double blind placebo-controlled study conducted in China. The study assessed the safety and efficacy of the addition of sitagliptin 100 mg once daily versus placebo on changes from baseline at Week 24 in HbA1c, fasting plasma glucose (FPG) and 2-h post-meal glucose (PMG). Patients were aged 18-79 years, had T2DM with inadequate glycemic control, and were taking a sulfonylurea, with or without metformin. RESULTS: After 24 weeks, sitagliptin reduced HbA1c, FPG, and 2-h PMG significantly more than placebo (between-treatment differences: -0.61 %, -16.8 mg/dL, and -32.9 mg/dL, respectively; P < 0.001 for all). The addition of sitagliptin was generally well tolerated, with a comparable incidence of adverse events and drug-related adverse events in both treatment groups. The sitagliptin group had a higher incidence of symptomatic hypoglycemia than the placebo group (25/248 [10.1 %] vs 13/249 [5.2 %], respectively; P = 0.042). CONCLUSIONS: Sitagliptin 100 mg once daily significantly improved glycemic control in Chinese patients with T2DM who had inadequate glycemic control with sulfonylurea, with or without metformin therapy. The addition of sitagliptin was generally well tolerated. (clinicaltrials.gov: NCT01590771). PMID- 27502308 TI - USING EXPERT OPINION IN HEALTH TECHNOLOGY ASSESSMENT: A GUIDELINE REVIEW. AB - OBJECTIVES: External experts can be consulted at different stages of an HTA. When using vague information sources, it is particularly important to plan, analyze, and report the information processing in a standardized and transparent way. Our objective was to search and analyze recommendations regarding where and how to include expert data in HTA. METHODS: We performed a systematic database search and screened the Internet pages of seventy-seven HTA organizations for guidelines, recommendations, and methods papers that address the inclusion of experts in HTA. Relevant documents were downloaded, and information was extracted in a standard form. Results were merged in tables and narrative evidence synthesis. RESULTS: From twenty-two HTA organizations, we included forty-two documents that consider the use of expert opinion in HTA. Nearly all documents mention experts in the step of preparation of the evidence report. Six documents address their role for priority setting of topics, fifteen for scoping, twelve for the appraisal of evidence and results, another twelve documents mention experts when considering the dissemination of HTA results. During the assessment step, experts are most often asked to amend the literature search or to provide expertise for special data analyses. Another issue for external experts is to appraise the HTA results and refer them back to a clinical and social context. Little is reported on methods of expert elicitation when their input substitutes study data. CONCLUSIONS: Despite existing recommendations on the use of expert opinion in HTA, common standards for elicitation are scarce in HTA guidelines. PMID- 27502309 TI - Metabolic Surgery Enters the T2DM Treatment Algorithm. AB - A Joint Statement endorsed by 45 international organizations, clinicians, and researchers indicating when to recommend or consider metabolic surgery in type 2 diabetes mellitus (T2DM) treatment has been recently published. These new guidelines, resulting from the Second Diabetes Surgery Summit (DSS-II), represent the most radical change in T2DM management of the past few decades. PMID- 27502310 TI - Typing concordance between PowerPlex(r) Fusion and GlobalFiler(r) based on 1501 Japanese individuals and the causes of typing discrepancies. PMID- 27502311 TI - Duration of oral tetracycline-class antibiotic therapy and use of topical retinoids for the treatment of acne among general practitioners (GP): A retrospective cohort study. AB - BACKGROUND: Guidelines recommend limiting the duration of oral antibiotic therapy in acne to 3 to 6 months and prescribing concomitant topical retinoids for all patients. OBJECTIVE: We sought to evaluate the duration of therapy with oral tetracyclines and the use of topical retinoids among patients with acne treated primarily by general practitioners in the United Kingdom. METHODS: We conducted a retrospective cohort study using the Health Improvement Network database. RESULTS: The mean duration of therapy was 175.1 days. Of antibiotic courses, 62% were not associated with a topical retinoid; 29% exceeded 6 months in duration. If all regions were to achieve uses similar to the region with the shortest mean duration of therapy, approximately 3.3 million antibiotic days per year could be avoided in the United Kingdom. LIMITATIONS: The Health Improvement Network does not include information on acne severity and clinical outcomes. CONCLUSIONS: Prescribing behavior for oral antibiotics in the treatment of acne among general practitioners is not aligned with current guideline recommendations. Increasing the use of topical retinoids and considering alternative agents to oral antibiotics when appropriate represent opportunities to reduce antibiotic exposure and associated complications such as antibiotic resistance and to improve outcomes in patients treated for acne. PMID- 27502312 TI - Imaging mass spectrometry assists in the classification of diagnostically challenging atypical Spitzoid neoplasms. AB - BACKGROUND: Previously, using imaging mass spectrometry (IMS), we discovered proteomic differences between Spitz nevi and Spitzoid melanomas. OBJECTIVE: We sought to determine whether IMS can assist in the classification of diagnostically challenging atypical Spitzoid neoplasms (ASN), to compare and correlate the IMS and histopathological diagnoses with clinical behavior. METHODS: We conducted a retrospective collaborative study involving centers from 11 countries and 11 US institutions analyzing 102 ASNs by IMS. Patients were divided into clinical groups 1 to 4 representing best to worst clinical behavior. The association among IMS findings, histopathological diagnoses, and clinical groups was assessed. RESULTS: There was a strong association between a diagnosis of Spitzoid melanoma by IMS and lesions categorized as clinical groups 2, 3, and 4 (recurrence of disease, metastases, or death) compared with clinical group 1 (no recurrence or metastasis beyond a sentinel node) (P < .0001). Older age and greater tumor thickness were strongly associated with poorer outcome (P = .01). CONCLUSIONS: IMS diagnosis of ASN better predicted clinical outcome than histopathology. Diagnosis of Spitzoid melanoma by IMS was strongly associated with aggressive clinical behavior. IMS analysis using a proteomic signature may improve the diagnosis and prediction of outcome/risk stratification for patients with ASN. PMID- 27502314 TI - Polydiacetylenyl beta-cyclodextrin based smart vesicles for colorimetric assay of arginine and lysine. AB - Selective visualization of arginine and lysine has been explored among 20 amino acids using the hybrid conjugate of beta-cyclodextrin (beta-CD) and polydiacetylene (PDA). The mono pentacosa-10,12-diynyl aminomethyl group was successfully coupled to either the primary or the secondary face of beta-CD, where mono-6-amino-6-deoxy-beta-CD or mono-3-amino-3-deoxy-beta-CD reacted with the N-hydroxysuccinimide ester of 10,12-pentacosadiynoic acid. In this combinatorial system, the cylindrical beta-cyclodextrin functions as a channel for the introduction of the cationic amino acids to the artificial membrane. The membrane perturbation and aggregation by the target amino acids could be exclusively visualized as a blue to red color change based on the responsive polydiacetylene domain. These interesting findings demonstrated that the developed beta-CD conjugated PDA system may offer a new method of cell penetrating mechanism, a promising vector system, as well as impact the production industry of arginine or lysine. PMID- 27502315 TI - Usefulness of peripheral arterial signs in the evaluation of aortic regurgitation. AB - BACKGROUND: Early diagnosis and optimal timing of surgical repair for chronic aortic regurgitation (AR) are topics of interest, because left ventricular compensation delays the clinical signs of the early stages of left ventricular dysfunction. Various physical signs have been described as indicators of chronic AR, but AR screening can be difficult depending on the proficiency of primary care providers. The recent use of the cardio-ankle vascular index (CAVI) measurement to assess peripheral atherosclerosis may detect AR objectively and simply because its arterial pulse wave configuration is closely related to the physical signs of AR. METHODS: CAVI measurements include pulse pressure (PP), the difference in blood pressures between upper and lower limbs (ABD), ankle-brachial index (ABI), ejection time (ET), and upstroke time (UT). We evaluated the differences in CAVI parameters between AR group and age-matched control group, the relationships between CAVI parameters and the echocardiographic semi quantitative measurements of AR severity such as left ventricular dimensions (Dd, Ds) and vena contracta (VC), and between the changes in CAVI parameters before and after aortic valve replacement. RESULTS: ABD, PP, ET, ankle systolic pressure and ABI in the AR group were significantly higher than that in the control group. Brachial diastolic pressure and CAVI in the AR group were significantly lower than that in the control group. UT was lower than that in the control group (p=0.05). PP did not correlate with the semi-quantitative AR severity, but ABD was correlated with Dd, Ds, and VC and was negatively correlated with UT. The exaggerated ABD, PP, ET, and ABI were moderated after surgery. CONCLUSIONS: CAVI parameters could be useful in the screening and serial follow-up of AR patients. PMID- 27502316 TI - Safety and efficacy of direct oral anticoagulants over warfarin in Japanese patients with acute venous thromboembolism: A meta-analysis. AB - BACKGROUND: Direct oral anticoagulants (DOACs) have been developed as alternatives to conventional therapy with warfarin for the treatment of acute venous thromboembolism (VTE) events. The safety and efficacy of DOACs in Japanese patients with acute VTE has been investigated in small trials or subgroups from global randomized controlled trials (RCTs). METHODS AND RESULTS: We conducted a systematic review and meta-analysis of RCTs, to compare the safety and efficacy of DOACs to those of conventional therapy in Japanese patients with acute VTE. Published research was systematically searched for RCTs that compared DOAC to conventional therapy in Japanese patients with acute VTE. Random-effects models were used to pool safety and efficacy data across RCTs. Three studies, including 386 patients, were identified. Patients randomized to DOAC had a decreased risk for all bleeding [risk ratio (RR) 0.69, 95% confidential interval (CI) 0.50 0.95], without any significant differences in recurrent VTE (RR 0.84, 95% CI 0.29 2.43) and recurrent VTE/all-cause death (RR 0.60, 95% CI 0.23-1.56). CONCLUSION: DOACs offer clinical benefit over conventional therapy in Japanese patients with acute VTE, showing a significant difference in their bleeding profile. PMID- 27502317 TI - Adaptive evolution of virus-sensing toll-like receptor 8 in bats. AB - Recently, bats have gained attention as potential reservoir hosts for emerging zoonotic single-stranded (ssRNA) viruses that may prove fatal for humans and other mammals. It has been hypothesized that some features of their innate immune system may enable bats to trigger an efficient early immune response. Toll-like receptors (TLRs) represent a first line defense within the innate immune system and lie directly at the host-pathogen interface in targeting specific microbe molecular patterns. However, the direction and strength of selection acting on TLRs are largely unknown for bats. Here, we studied the selection on viral ssRNA sensing TLR8 based on sequence data of 21 bat species. The major part (63 %) of the TLR8 gene evolved under purifying selection, likely due to functional constraints. We also found evidence for persistent positive selection acting on specific amino acid sites (7 %), especially when compared to viral TLR evolution of other mammals. All of these putatively positively selected codons were located in the ligand-binding ectodomain, some coincidenced or were in close proximity to functional sites, as suggested by the crystallographic structure of the human TLR8. This might contribute to the inter-species variation in the ability to recognize molecular patterns of viruses. TLR8 evolution within bats revealed that branches leading to ancestral and recent lineages evolved under episodic positive selection, indicating selective selection pressures in restricted bat lineages. Altogether, we found that the TLR8 displays extensive sequence variation within bats and that unique features separate them from humans and other mammals. PMID- 27502313 TI - Clinical outcomes and response of patients applying topical therapy for pyoderma gangrenosum: A prospective cohort study. AB - BACKGROUND: Pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. OBJECTIVE: We sought to estimate the effectiveness of topical therapies in the treatment of patients with PG. METHODS: This was a prospective cohort study of UK secondary care patients with a clinical diagnosis of PG that was suitable for topical treatment (recruited between July 2009 and June 2012). Participants received topical therapy after normal clinical practice (primarily topical corticosteroids [classes I-III] and tacrolimus 0.03% or 0.1%). The primary outcome was speed of healing at 6 weeks. Secondary outcomes included the following: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality of life; treatment failure; and recurrence. RESULTS: Sixty-six patients (22-85 years of age) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28 of 66 (43.8%) ulcers healed by 6 months. The median time to healing was 145 days (95% confidence interval, 96 days to infinity). Initial ulcer size was a significant predictor of time to healing (hazard ratio, 0.94 [95% confidence interval, 0.88-1.00); P = .043). Four patients (15%) had a recurrence. LIMITATIONS: Our study did not include a randomized comparator. CONCLUSION: Topical therapy is potentially an effective first-line treatment for PG that avoids the possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone. PMID- 27502319 TI - Emergent spin-valley-orbital physics by spontaneous parity breaking. AB - The spin-orbit coupling in the absence of spatial inversion symmetry plays an important role in realizing intriguing electronic states in solids, such as topological insulators and unconventional superconductivity. Usually, the inversion symmetry breaking is inherent in the lattice structures, and hence, it is not easy to control these interesting properties by external parameters. We here theoretically investigate the possibility of generating the spin-orbital entanglement by spontaneous electronic ordering caused by electron correlations. In particular, we focus on the centrosymmetric lattices with local asymmetry at the lattice sites, e.g. zigzag, honeycomb, and diamond structures. In such systems, conventional staggered orders, such as charge order and antiferromagnetic order, break the inversion symmetry and activate the antisymmetric spin-orbit coupling, which is hidden in a sublattice-dependent form in the paramagnetic state. Considering a minimal two-orbital model on a honeycomb structure, we scrutinize the explicit form of the antisymmetric spin-orbit coupling for all the possible staggered charge, spin, orbital, and spin-orbital orders. We show that the complete table is useful for understanding of spin valley-orbital physics, such as spin and valley splitting in the electronic band structure and generalized magnetoelectric responses in not only spin but also orbital and spin-orbital channels, reflecting in peculiar magnetic, elastic, and optical properties in solids. PMID- 27502320 TI - Erratum to: KSC-N: Clustering of Hierarchical Time Profile Data. PMID- 27502321 TI - Midrefractive Dielectric Modulator for Broadband Unidirectional Scattering and Effective Radiative Tailoring in the Visible Region. AB - Nanoantennas have found many applications in ultrasmall sensors, single-molecule detection, and all-optical communication. Conventional nanoantennas are based on noble-metal plasmonic structures, but suffer from large ohmic loss and only possess dipolar plasmon modes. This has driven an intense search for all dielectric materials beyond noble metals. Here, we propose midrefractive nanospheres as a novel all-dielectric material to realize broadband unidirectional radiation and effective radiative tailoring in the visible region. Midrefractive all-dielectric materials such as boron nanospheres possess broad and overlapping electric and magnetic dipole modes. The internal interaction between these two modes can route the radiation almost on the one side covering the whole visible range. Unlike the elaborate design in plasmonic nanostructures to obtain strong coupled broad and narrow modes, the bright mode in boron nanospheres is intrinsic, independent, and easily coupled with adjacent narrow modes. So the strong interaction in boron-based heterodimer is able to realize an independent and precise tailoring of the radiant and subradiant states by simply changing the particle sizes, respectively. Our findings imply midrefractivity materials like boron are excellent building blocks to support electromagnetic coupling operation in nanoscale devices, which will lead to a variety of emerging applications such as nanoantennas with directing exciton emission, ultrasensitive nanosensors, or even potential new construction of photonic metamaterials. PMID- 27502318 TI - Donor-unrestricted T cells in the human CD1 system. AB - The CD1 and MHC systems are specialized for lipid and peptide display, respectively. Here, we review evidence showing how cellular CD1a, CD1b, CD1c, and CD1d proteins capture and display many cellular lipids to T cell receptors (TCRs). Increasing evidence shows that CD1-reactive T cells operate outside two classical immunogenetic concepts derived from the MHC paradigm. First, because CD1 proteins are non-polymorphic in human populations, T cell responses are not restricted to the donor's genetic background. Second, the simplified population genetics of CD1 antigen-presenting molecules can lead to simplified patterns of TCR usage. As contrasted with donor-restricted patterns of MHC-TCR interaction, the donor-unrestricted nature of CD1-TCR interactions raises the prospect that lipid agonists and antagonists of T cells could be developed. PMID- 27502322 TI - In-Depth Characterization and Validation of Human Urine Metabolomes Reveal Novel Metabolic Signatures of Lower Urinary Tract Symptoms. AB - Lower urinary tract symptoms (LUTS) are a range of irritative or obstructive symptoms that commonly afflict aging population. The diagnosis is mostly based on patient-reported symptoms, and current medication often fails to completely eliminate these symptoms. There is a pressing need for objective non-invasive approaches to measure symptoms and understand disease mechanisms. We developed an in-depth workflow combining urine metabolomics analysis and machine learning bioinformatics to characterize metabolic alterations and support objective diagnosis of LUTS. Machine learning feature selection and statistical tests were combined to identify candidate biomarkers, which were statistically validated with leave-one-patient-out cross-validation and absolutely quantified by selected reaction monitoring assay. Receiver operating characteristic analysis showed highly-accurate prediction power of candidate biomarkers to stratify patients into disease or non-diseased categories. The key metabolites and pathways may be possibly correlated with smooth muscle tone changes, increased collagen content, and inflammation, which have been identified as potential contributors to urinary dysfunction in humans and rodents. Periurethral tissue staining revealed a significant increase in collagen content and tissue stiffness in men with LUTS. Together, our study provides the first characterization and validation of LUTS urinary metabolites and pathways to support the future development of a urine based diagnostic test for LUTS. PMID- 27502323 TI - A Cost-Effectiveness Analysis of Using the JBR.10-Based 15-Gene Expression Signature to Guide Adjuvant Chemotherapy in Early Stage Non-Small-Cell Lung Cancer. AB - BACKGROUND: Adjuvant chemotherapy (ACT) improved survival in the NCIC Clinical Trials Group JBR.10 trial of resected stage IB/II non-small-cell lung cancer. A prognostic 15-gene expression signature was developed, which may also predict for benefit from ACT. An exploratory economic analysis was conducted to assess the potential cost-effectiveness of using the 15-gene signature in guiding ACT decisions. METHODS: A decision analytic model was populated by study patients with quantitative reverse transcription polymerase chain reaction tumor profiling, current costs, and quality-adjusted survival. Analysis was performed over the 6-year follow-up from the perspective of the Canadian public health care system in 2015 Canadian dollars (discounted 5%/year). Incremental cost effectiveness and cost-utility ratios were determined for ACT versus observation using clinical stage, gene signature, or a combined approach to select treatment. RESULTS: The mean survival gain of ACT versus observation was higher using the gene signature (1.86 years) compared with clinical stage (1.28 years). Although more costly, ACT guided by the gene signature remained cost-effective at $10,421/life-year gained (95% confidence interval [CI], $466-$19,568 Canadian), comparable to stage-directed selection ($7081/life-year gained; 95% CI, -$2370 to $14,721; P = .52). Incremental cost-utility ratios were $13,452/quality-adjusted life-year (95% CI, $373-$31,949) and $9194/quality-adjusted life-year (95% CI, $4104 to $23,952), respectively (P = .53). Comparing the standard and test-and treat approaches, use of the gene signature did not significantly alter survival compared with the standard strategy, but it reduced the ACT rate by 25%. CONCLUSION: If validated, the use of the 15-gene expression signature to select patients for ACT may increase the survival gain of treatment in patients with high-risk stage IB/II non-small-cell lung cancer, while avoiding toxicities in low-risk patients. PMID- 27502324 TI - Graphene-mediated microfluidic transport and nebulization via high frequency Rayleigh wave substrate excitation. AB - The deposition of a thin graphene film atop a chip scale piezoelectric substrate on which surface acoustic waves are excited is observed to enhance its performance for fluid transport and manipulation considerably, which can be exploited to achieve further efficiency gains in these devices. Such gains can then enable complete integration and miniaturization for true portability for a variety of microfluidic applications across drug delivery, biosensing and point of-care diagnostics, among others, where field-use, point-of-collection or point of-care functionality is desired. In addition to a first demonstration of vibration-induced molecular transport in graphene films, we show that the coupling of the surface acoustic wave gives rise to antisymmetric Lamb waves in the film which enhance molecular diffusion and hence the flow through the interstitial layers that make up the film. Above a critical input power, the strong substrate vibration displacement can also force the molecules out of the graphene film to form a thin fluid layer, which subsequently destabilizes and breaks up to form a mist of micron dimension aerosol droplets. We provide physical insight into this coupling through a simple numerical model, verified through experiments, and show several-fold improvement in the rate of fluid transport through the film, and up to 55% enhancement in the rate of fluid atomization from the film using this simple method. PMID- 27502325 TI - Investigating the potential role of non-vls genes on linear plasmid 28-1 in virulence and persistence by Borrelia burgdorferi. AB - BACKGROUND: The lp28-1 plasmid is required for persistent infection by the Lyme disease spirochete, Borrelia burgdorferi. Mutational studies on this plasmid have shown that the vls locus is important for antigenic variation of the VlsE lipoprotein that leads to immune evasion and persistence. However, it is still unknown whether the vls system is the only genetic locus on this plasmid necessary for long-term infection, and thus the potential role of non-vls genes on lp28-1 in virulence and persistence is yet to be fully determined. Despite extensive mutational analyses, two lp28-1 regions containing the ORFs bbf19 - bbf22 and bbf27 - bbf30 have not yet been mutated in their entirety. RESULTS: In this study, we set out to establish if these unstudied regions of lp28-1 play a role in spirochete persistence. Results show that the generated mutants were fully infectious in immunocompetent mice, and were able to persist for 91 days following infection. Following this finding, ospC expression by these mutants was determined, as it has been reported that spirochetes lacking lp28-1 fail to downregulate expression of this lipoprotein leading to immune clearance. Data presented here failed to show a definitive difference in ospC expression levels during host infection when the mutants were compared to the wild type. CONCLUSIONS: Overall, the results strongly suggest that non-vls genes residing on lp28-1 do not play a role in spirochete persistence during infection of the mammalian host, and that the regions under study are likely not involved in the regulation of ospC expression. In conjunction with previous studies involving mutation of non-vls loci on lp28-1, these findings suggest that the vls locus is likely the sole genetic element on this plasmid responsible for immune evasion and persistence exhibited by the Lyme disease pathogen. PMID- 27502327 TI - Treatment for avascular necrosis of bone in people with sickle cell disease. AB - BACKGROUND: Avascular necrosis of bone is a frequent and severe complication of sickle cell disease and its treatment is not standardised. This is an update of a previously published Cochrane Review. OBJECTIVES: To determine the impact of any surgical procedure compared with other surgical interventions or non-surgical procedures, on avascular necrosis of bone in people with sickle cell disease in terms of efficacy and safety. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Additional trials were sought from the reference lists of papers identified by the search strategy.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 27 May 2016. SELECTION CRITERIA: Randomized clinical trials comparing specific therapies for avascular necrosis of bone in people with sickle cell disease. DATA COLLECTION AND ANALYSIS: Each author independently extracted data and assessed trial quality. Since only one trial was identified, meta-analysis was not possible. MAIN RESULTS: One trial (46 participants) was eligible for inclusion. After randomization eight participants were withdrawn, mainly because they declined to participate in the trial. Data were analysed for 38 participants at the end of the trial. After a mean follow up of three years, hip core decompression and physical therapy did not show clinical improvement when compared with physical therapy alone using the score from the original trial (an improvement of 18.1 points for those treated with intervention therapy versus an improvement of 15.7 points with control therapy). There was no significant statistical difference between groups regarding major complications (hip pain, risk ratio 0.95 (95% confidence interval 0.56 to 1.60; vaso-occlusive crises, risk ratio 1.14 (95% confidence interval 0.72 to 1.80; very low quality of evidence); and acute chest syndrome, risk ratio 1.06 (95% confidence interval 0.44 to 2.56; very low quality of evidence)). This trial did not report results on mortality or quality of life. AUTHORS' CONCLUSIONS: We found no evidence that adding hip core decompression to physical therapy achieves clinical improvement in people with sickle cell disease with avascular necrosis of bone compared to physical therapy alone. However, we highlight that our conclusion is based on one trial with high attrition rates. Further randomized controlled trials are necessary to evaluate the role of hip-core depression for this clinical condition. Endpoints should focus on participants' subjective experience (e.g. quality of life and pain) as well as more objective 'time-to-event' measures (e.g. mortality, survival, hip longevity). The availability of participants to allow adequate trial power will be a key consideration for endpoint choice. PMID- 27502326 TI - A Randomized, Double-blind, Multicenter, Phase III Study to Evaluate the Efficacy and Safety of Fimasartan/Amlodipine Combined Therapy Versus Fimasartan Monotherapy in Patients With Essential Hypertension Unresponsive to Fimasartan Monotherapy. AB - PURPOSE: The goal of this study was to evaluate whether the blood pressure lowering efficacy of fimasartan/amlodipine combination therapy was superior to that of fimasartan monotherapy after 8 weeks of treatment in patients with hypertension who had failed to respond adequately to fimasartan monotherapy. METHODS: This trial was a randomized, double-blind, multicenter, Phase III clinical study. Patients who failed to respond after 4 weeks of treatment with 60 mg daily of fimasartan (sitting systolic blood pressure [SiSBP]) >=140 mm Hg) were randomized to receive either daily fimasartan 60 mg or fimasartan/amlodipine 60 mg/10 mg. The primary efficacy end point was the change in SiSBP from baseline to week 8. Secondary end points included the change in SiSBP from baseline to week 4, the changes in sitting diastolic blood pressure from baseline to weeks 4 and 8, and the response rate (SiSBP <140 mm Hg or decrease in SiSBP >=20 mm Hg) or control rate (SiSBP <140 mm Hg) at week 8. Treatment-emergent adverse events were also assessed. FINDINGS: Of 143 patients randomized to treatment, 137 patients who had available efficacy data were analyzed. The mean age of patients was 59.1 (8.9) years, and 100 (73.0%) were male. Baseline SiSBP and sitting diastolic blood pressure were 150.6 (9.2) mm Hg and 91.7 (8.6) mm Hg, respectively. In the fimasartan/amlodipine combination group, a greater reduction in SiSBP from baseline to week 8 was observed compared with the fimasartan group (7.8 [13.3] mm Hg in the fimasartan group vs 20.5 [14.6] mm Hg in the fimasartan/amlodipine group; P < 0.0001). This reduction was observed after 4 weeks. The mean SiSBP changes from baseline to week 4 were 8.1 (15.8) mm Hg in the fimasartan group and 20.1 (14.7) mm Hg in the fimasartan/amlodipine group (P < 0.0001). At week 8, the response rate was significantly higher in the fimasartan/amlodipine (82.1%) group than in the fimasartan (32.9%) group (P < 0.0001). The control rate at week 8 was also higher in the fimasartan/amlodipine (79.1%) group than in the fimasartan (31.4%) group (P < 0.0001). Adverse drug reactions were observed in 9 patients (6.3%), with no significant differences between treatment groups. There were no serious adverse events associated with the study drugs. IMPLICATIONS: Fimasartan/amlodipine combination therapy exhibited superior efficacy in reducing blood pressure, with no increase in adverse drug reactions, compared with fimasartan monotherapy. ClinicalTrials.gov identifier: NCT02152306. PMID- 27502329 TI - Pacing-Induced Cardiomyopathy: "It's Tough to Make Predictions, Especially About the Future"*. PMID- 27502328 TI - Metabolic and diffusional limitations of photosynthesis in fluctuating irradiance in Arabidopsis thaliana. AB - A better understanding of the metabolic and diffusional limitations of photosynthesis in fluctuating irradiance can help identify targets for improving crop yields. We used different genotypes of Arabidopsis thaliana to characterise the importance of Rubisco activase (Rca), stomatal conductance (gs), non photochemical quenching of chlorophyll fluorescence (NPQ) and sucrose phosphate synthase (SPS) on photosynthesis in fluctuating irradiance. Leaf gas exchange and chlorophyll fluorescence were measured in leaves exposed to stepwise increases and decreases in irradiance. rwt43, which has a constitutively active Rubisco enzyme in different irradiance intensities (except in darkness), showed faster increases than the wildtype, Colombia-0, in photosynthesis rates after step increases in irradiance. rca-2, having decreased Rca concentration, showed lower rates of increase. In aba2-1, high gs increased the rate of change after stepwise irradiance increases, while in C24, low gs tended to decrease it. Differences in rates of change between Colombia-0 and plants with low levels of NPQ (npq1-2, npq4-1) or SPS (spsa1) were negligible. In Colombia-0, the regulation of Rubisco activation and of gs were therefore limiting for photosynthesis in fluctuating irradiance, while levels of NPQ or SPS were not. This suggests Rca and gs as targets for improvement of photosynthesis of plants in fluctuating irradiance. PMID- 27502332 TI - Fundamental literature and hot topics on rural left-behind children in China: a bibliometric analysis. AB - BACKGROUND: Recently, the literature on rural left-behind children in China has rapidly grown. However, no comprehensive review of the status of knowledge on the issue exists. METHODS: A co-cited network map of 327 studies (covering 1998 through 2014) drawn from the Chinese Social Studies Citation Index database was analysed. RESULTS: Using visualization software, the results identified three fundamental studies on the issue and four hot topics: interventions, deviant behaviours, mental health and family childrearing strategies. The analysis found that knowledge on this topic could be furthered by (1) focusing on protective factors and (2) integrating disciplines by standardizing concepts and measures. CONCLUSIONS: These study's results are an important reference for the development of theories, practices and policies regarding rural left-behind children in China. PMID- 27502333 TI - Two cases of disseminated superficial actinic porokeratosis treated with daylight mediated photodynamic therapy. PMID- 27502334 TI - Advances in Controlled Drug Delivery for Treatment of Osteoporosis. AB - Osteoporosis, which is characterized by resorption of bone exceeding formation, remains a significant human health concern, and the impact of this condition will only increase with the "graying" of the worldwide population. This review focuses on current and emerging approaches for delivering therapeutic agents to restore bone remodeling homeostasis. Well-known antiresorptive and anabolic agents, such as estrogen, estrogen analogs, bisphosphonates, calcitonin, and parathyroid hormone, along with newer modulators and antibodies, are primarily administered orally, intravenously, or subcutaneously. Although these treatments can be effective, continuing problems include patient noncompliance and adverse systemic or remote-site effects. Controlled drug delivery via polymeric, targeted, and active release systems extends drug half-life by shielding against premature degradation and improves bioavailability while also providing prolonged, sustained, or intermittent release at therapeutic doses to more effectively treat osteoporosis and associated fracture risk. PMID- 27502336 TI - Pre-NELA vs NELA - has anything changed, or is it just an audit exercise? AB - BACKGROUND Following evidence suggestive of high mortality following emergency laparotomies, the National Emergency Laparotomy Audit (NELA) was set up, highlighting key standards in emergency service provision. Our aim was to compare our NHS trust's adherence to these recommendations immediately prior to, and following, the launch of NELA, and to compare patient outcome. METHODS This was a retrospective study of patients who underwent an emergency laparotomy over the course of 6 months - 3 months either side of the initiation of NELA. RESULTS There were 44 patients before the initiation of NELA (pre-NELA, PN group) and 55 in the first 3 months of NELA (N group). We saw a significant increase in the proportion of patients whose decision to operate was made by the consultant: 75.0% in the PN group vs 100% in N group (subsequent data presented in this order) (P < 0.001). The presence of a consultant surgeon (75.0% vs 83.6%, P = 0.321) and anaesthetist (100.0% vs 90.9%, P = 0.064) in theatres were comparable in both groups. Risk stratification based on Portsmouth Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (P POSSUM) score showed no difference in high-risk patients in both groups (47.7% vs 36.4%, P = 0.306). With the NELA initiative, however, significantly more patients were admitted directly from theatres to the critical care unit, when compared with the pre-NELA period (9.1% vs 27.3%, P = 0.038). This also reflected a significant reduction in unexpected escalation to a higher level of care during this period (10.0% vs 0%, P = 0.036). Significantly more patients had uneventful recovery in the NELA period (52.3 vs 76.4%, P = 0.018), although there was no difference in 30-day mortality between the groups (2.3% vs 7.3%, P = 0.378). CONCLUSIONS This study demonstrated a greater degree of consultant involvement in the decision to operate during NELA. More high-risk patients have been identified preoperatively with diligent risk assessment and, hence, have been proactively admitted to critical care units following laparotomy, which may account for the significant reduction in unexpected escalation to level 2 or level 3 care and thus in overall better patient outcomes. PMID- 27502335 TI - Does smoking influence the physical activity and lung cancer relation? A systematic review and meta-analysis. AB - Research suggests an inverse association between physical activity and lung cancer. However, whether the relation is modified by degree of smoking adjustment has not been summarized. We conducted a meta-analysis of physical activity and lung cancer focusing on evaluating whether smoking status and the degree of smoking adjustment influenced the association. Comparing high versus low physical activity levels from 25 observational studies yielded a lung cancer summary relative risk (RR) of 0.79 [95 % confidence interval (CI) = 0.72-0.87], with RRs of 0.87 (95 % CI = 0.80-0.94) for cohort studies and 0.57 (95 % CI = 0.46-0.71) for case-control studies. In further analyses restricted to cohort studies, physical activity was inversely related to lung cancer among former smokers (RR = 0.68, 95 % CI = 0.51-0.90) and current smokers (RR = 0.80, 95 % CI = 0.70-0.90), whereas the association was null among never smokers (RR = 1.05, 95 % CI = 0.78 1.40, p interaction = 0.26). The degree of smoking adjustment did not modify the association (p interaction = 0.73). Physical activity was unrelated to lung cancer among never smokers but it was inversely associated with lung cancer among former and current smokers. Although the physical activity and lung cancer relation was not modified by smoking status or degree of smoking adjustment, residual confounding by smoking remains a possible explanation for the relations observed. PMID- 27502337 TI - Prediction of histological stage based on cystoscopic appearances of newly diagnosed bladder tumours. AB - INTRODUCTION In the 75-80% of urothelial bladder cancers (UBC) presenting as non muscle invasive bladder cancer (NMIBC), transurethral resection of bladder tumour (TURBT) is the key treatment and staging procedure. In the 20-25% of patients with muscle invasive bladder cancer (MIBC), further cross-sectional imaging is required to complete the staging process before considering radical treatment. Given the adverse effects of ionising radiation, clinicians identify patients believed to have MIBC, and so requiring further imaging pre-TURBT, at the tumour histology/stage based on the tumour's visual characteristics. There is minimal evidence describing the accuracy of such predictions in newly-diagnosed patients. METHODS Over a 6-year period, a database of patients undergoing resection of newly-diagnosed bladder lesions in a single UK centre was prospectively established. Predictions based on histology were simultaneously recorded, and the accuracy of these predictions of histology/stage subsequently assessed. RESULTS One hundred and twenty two (73.1%) patients with histologically confirmed NMIBC had predictions recorded versus 45 (26.9%) patients with MIBC. Visual assessment predictions of MIBC had a sensitivity of 88.9% (95% confidence interval [CI] 76.5%-95.2%) and a specificity of 91.0% (95% CI 84.6%-94.9%), giving a positive predictive value of 78.4% (95% CI 65.4%-87.5%) and a negative predictive value of 95.7% (95% CI 90.3%-98.1%). CONCLUSIONS We find that visual assessment is accurate in predicting the presence of MIBC. This supports the practice of stratifying patients at the time of initial cystoscopy for those requiring further radiological staging pre-TURBT. PMID- 27502338 TI - The right colic artery: An anatomical demonstration and its relevance in the laparoscopic era. AB - INTRODUCTION Hemicolectomies are not tailored in right-sided colon cancer resections, despite significant variation in the incidence and origin of the right colic artery (RCA). Early evidence suggests that removal of the relevant lymphovascular package and associated cancer as part of complete mesocolic excision (CME), rather than the entire right colon, may produce better outcomes. Advancing laparoscopic techniques are making this possible, and so it is increasingly important to more precisely define the anatomy of the RCA. METHODS To demonstrate the incidence and variation of the RCA, 25 formalin embalmed cadavers were dissected. Consent to dissection and photography was obtained under Human Tissue Act regulations. RESULTS Eleven female and 14 male cadavers (mean age 79.7 years, range 41-95 years) were included. The RCA originated from the right branch of the middle colic artery in nine cadavers (36%), while it arose from the superior mesenteric artery in eight cases (32%) and from the ileocolic or root of the middle colic artery in a smaller number of specimens. The RCA was absent in two individuals. CONCLUSIONS The RCA arises from the right branch of the middle colic artery in a considerable number of cases. The literature to date does not reflect the precision of anatomical understanding required for CME; hence, a new definition for the right colic vessel is proposed. PMID- 27502339 TI - The evolution of intraoperative conversion in video assisted thoracoscopic lobectomy. AB - INTRODUCTION Unplanned conversion to thoracotomy remains a major concern in video assisted thoracoscopic surgery (VATS) lobectomy. This study aimed to investigate the development of a VATS lobectomy programme over a five-year period, with a focus on the causes and consequences of unplanned conversions. METHODS A single centre retrospective review was performed of patients who underwent complete anatomical lung resection initiated by VATS between January 2010 and April 2015. RESULTS In total, 1,270 patients underwent a lobectomy in the study period and 684 (53.9%) of these were commenced thoracoscopically. There were 75 cases (10.9%) with unplanned conversion. The proportion of lobectomies started as VATS was significantly higher in the second half of the study period (2010-2012: 277/713 [38.8%], 2013-2015: 407/557 [73.1%], p<0.001). The conversion rate dropped initially from 20.4% (11/54) in 2010 to 9.9% (15/151) in 2013 and then remained consistently under 10% until 2015. Conversions were most commonly secondary to vascular injury (26/75, 34.7%). Patients undergoing unplanned conversion had a longer length of stay than VATS completed patients (9 vs 6 days, p<0.001). There was a higher incidence of respiratory failure (10/75 [14.1%] vs 23/607 [3.8%], p<0.001) and 30-day mortality (7/75 [9.3%] vs 6/607 [1.0%], p=0.003) in patients with unplanned conversion than in those with completed VATS. CONCLUSIONS As our VATS lobectomy programme developed, the unplanned conversion rate dropped initially and then remained constant at approximately 10%. With increasing unit experience, it is both safe and technically possible to complete the majority of lobectomy procedures thoracoscopically. PMID- 27502340 TI - Abdominal fat ratio - a novel parameter for predicting conversion in laparoscopic colorectal surgery. AB - INTRODUCTION Laparoscopic surgery has become the standard for colorectal cancer resection in the UK but it can be technically challenging in patients who are obese. Patients whose body fat is mainly inside the abdominal cavity are more challenging than those whose fat is mainly outside the abdominal cavity. Abdominal fat ratio (AFR) is a simple parameter proposed by the authors to aid identification of this subgroup. MATERIALS AND METHODS All 195 patients who underwent elective, laparoscopic colorectal cancer resections from March 2010 to November 2013 were included in the study. For patients who were obese (body mass index greater than 30), preoperative staging computed tomography was used to determine AFR. This was assessed by two different, blinded observers and compared with conversion rate. RESULTS Of the 195 patients, 58 (29.7%) fell into the obese group and 137 (70.3%) into the non-obese group. The median AFR of the obese group that were converted to open surgery was significantly higher at 5.9 compared with those completed laparoscopically (3.3, P = 0.0001, Mann-Whitney). There was no significant difference in conversion rate when looking at body mass index, tumour site or size. DISCUSSION Previous studies have found body mass index, age, gender, previous abdominal surgery, site and locally advanced tumours to be associated with an increased risk of conversion. This study adds AFR to the list of risk factors. CONCLUSION AFR is a simple, reproducible parameter which can help to predict conversion risk in obese patients undergoing colorectal cancer resection. PMID- 27502341 TI - An unusual diaphragmatic hernia with gastric perforation and sub-acute presentation. AB - Gastric perforation into the thoracic cavity through a diaphragmatic hernia is rare but, when it occurs, patients present in severe distress, with mortality approaching 50%. We present a unique case in which a fibrotic reaction between the stomach and the parietal pleura led to a subacute presentation upon perforation. The extra time that this afforded led to more effective multidisciplinary team management and ultimately an excellent outcome for the patient. PMID- 27502342 TI - Non-steroidal anti-inflammatory drug-induced diaphragm disease: an uncommon cause of small bowel obstruction. AB - Surgeons frequently deal with small bowel obstruction. However, small bowel obstruction caused by non-steroidal anti-inflammatory drug (NSAID)-induced diaphragm disease is very rare. The diagnosis is challenging, as symptoms are often non-specific and radiological studies remain inconclusive. We present a case of a 63-year-old man who, after an extensive diagnostic work-up and small bowel resection for obstructive symptoms, was finally diagnosed with NSAID induced diaphragm disease as confirmed by histology. An unusual aspect of this case is that the patient stopped using NSAIDs after he was diagnosed with a gastric ulcer 2-years previously. This suggests that NSAID-induced diaphragms of the small bowel take some time to develop and underlines the importance of careful history taking. PMID- 27502343 TI - Giant cell aortitis in treatment-naive human immunodeficiency virus and hepatitis C coinfection. AB - Giant cell arteritis is a common form of vasculitis, although involvement of the aorta is unusual. There is no established association between giant cell aortitis and human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection. We present the case of a 46-year-old female coinfected with HIV and HCV who had never received antiretroviral therapy and developed symptoms of deteriorating shortness of breath on exertion. Investigations demonstrated aortic root and ascending aorta dilatation, along with severe aortic valve regurgitation, for which the patient underwent valve-sparing aortic root replacement (a David procedure). Histopathology confirmed giant cell aortitis. PMID- 27502344 TI - Management of joint dislocations of the lower limb in Larsen syndrome: practical approach. AB - INTRODUCTION Larsen syndrome is an autosomal-dominant osteochondrodysplasia characterised by large joint dislocations and craniofacial anomalies. CASE HISTORY We present a rare case of Larsen syndrome with bilateral dislocated hips and knees and severe clubfeet at 7-year follow-up. We undertook bilateral open reduction of both hips at age 8 months. This procedure was preceded by open reduction and left-knee V-Y quadricepsplasty at age 4 months following a failed trial of closed reduction of the left knee. Both feet had a severe deformity (Pirani score of 5.5 and 6.0) and were treated using the Ponseti method, but the left foot relapsed at 24 months and required posteromedial release. CONCLUSIONS We tried to address the difficult questions on the timing and sequence of surgical interventions by treating clubfeet and dislocated knees early using Ponseti casts which included the knees. Open reduction of hips was done later, and further interventions were guided by functional needs. PMID- 27502345 TI - Supra-aural gossypiboma: case report of a retained textile surgical sponge in an unusual location. AB - Gossypiboma or retained surgical sponge is an infrequently encountered surgical complication, more so in the head and neck region. A literature search did not reveal a previously reported case of retained or concealed surgical sponge after microscopic ear surgery. We present a unique and previously unreported case of a 25-year-old male who presented with a cystic swelling in the right supra-aural region 5 months post-modified radical mastoidectomy of the right ear. Surgical excision of the swelling revealed a retained surgical sponge. We emphasise the importance of counting surgical sponges after every surgical step to minimise the incidence of such retained surgical items. PMID- 27502346 TI - Peritoneal encapsulation; a rare cause of bowel obstruction. AB - Peritoneal encapsulation is a rare congenital cause of bowel obstruction in children. We present the case of a 12-year-old male with severe dehydration and recurrent episodes of vomiting. This pathology should be considered in cases of bowel obstruction with a virgin abdomen. PMID- 27502347 TI - A rare case of primary epithelioid angiosarcoma of the ureter. AB - Angiosarcoma is an extremely rare vascular malignancy with a 1-year survival rate of 50%, regardless of tumour origin. Distant metastases are common and occur in the lungs, bone, lymph nodes and soft tissues. The majority of patients with angiosarcoma present with localised disease, although 25-45% have distant metastases at presentation. There are few reported cases of angiosarcomas of the bladder and we report the second case in the literature of primary angiosarcoma of the ureter. We suggest that, in atypical manifestations of suspected urothelial malignancy, the multidisciplinary team considers the possibility of rarer, aggressive tumours early. This may influence clinical decision making towards offering radical treatments earlier, before it is too late to do so owing to aggressive oncological behaviour. PMID- 27502348 TI - Sexual Orientation Self-Presentation Among Bisexual-Identified Women and Men: Patterns and Predictors. AB - Writing on the experiences of bisexual-identified people has highlighted the potential complexity of the ongoing process of deciding when and how to present one's sexual orientation identity to others (Rust, 2002). The two studies presented here were designed to contribute basic knowledge regarding self presentation of sexual orientation among bisexual people. In Study 1, bisexual participants (N = 147) were less likely than their lesbian and gay (LG) peers (N = 191) to present their actual orientation to others, and more likely to present themselves as having a sexual orientation different from their actual orientation. These sexual orientation differences were explained by gender of romantic partner and uncertainty about one's sexual orientation. Sexual orientation differences also emerged in links between self-presentation and outness level. For example, bisexual participants who presented themselves as LG had relatively high everyday outness levels; in contrast, LG participants who presented themselves as bisexual had relatively low everyday outness levels. In Study 2, 240 bisexual women and men indicated their levels of outness as a sexual minority person (potentially including identification as gay, lesbian, queer) and specifically as bisexual. Outness was higher with respect to status as a sexual minority compared to status as bisexual; the magnitude of this difference was predicted by gender of romantic partner and uncertainty about one's sexual orientation. Moreover, even controlling for outness as a sexual minority person, well-being was predicted by outness as bisexual to family members. PMID- 27502349 TI - Moving Transgender Care Forward within Public Health Organizations: Inclusion of Facial Feminizing Surgery in the Swedish National Treatment Recommendations. PMID- 27502350 TI - Female Sexual Function Index Short Version: A MsFLASH Item Response Analysis. AB - The Female Sexual Function Index (FSFI) is a psychometrically sound and popular 19-item self-report measure, but its length may preclude its use in studies with multiple outcome measures, especially when sexual function is not a primary endpoint. Only one attempt has been made to create a shorter scale, resulting in the Italian FSFI-6, later translated into Spanish and Korean without further psychometric analysis. Our study evaluated whether a subset of items on the 19 item English-language FSFI would perform as well as the full-length FSFI in peri- and postmenopausal women. We used baseline data from 898 peri- and postmenopausal women recruited from multiple communities, ages 42-62 years, and enrolled in randomized controlled trials for vasomotor symptom management. Goals were to (1) create a psychometrically sound, shorter version of the FSFI for use in peri- and postmenopausal women as a continuous measure and (2) compare it to the Italian FSFI-6. Results indicated that a 9-item scale provided more information than the FSFI-6 across a spectrum of sexual functioning, was able to capture sample variability, and showed sufficient range without floor or ceiling effects. All but one of the items from the Italian 6-item version were included in the 9-item version. Most omitted FSFI items focused on frequency of events or experiences. When assessment of sexual function is a secondary endpoint and subject burden related to questionnaire length is a priority, the 9-item FSFI may provide important information about sexual function in English-speaking peri- and postmenopausal women. PMID- 27502351 TI - Views and Experiences of Malaysian Family Medicine Trainees of Female Sexual Dysfunction. AB - Sociocultural factors have been shown to be important influencers of sexual health and sexuality. Hence, the aim of our study was to explore the views and experiences of family medicine trainees regarding female sexual dysfunction (FSD) with a focus on the barriers and facilitators towards the initiation of conversation on this topic. A qualitative study design involving semi-structured focus group discussions (FGDs) was conducted with 19 family medicine trainees in Malaysia. The conceptual framework used was based on the Theory of Planned Behavior. Thematic approach was used to analyze the data. Participants perceived FSD as being uncommon and unimportant. According to our participants, patients often presented with indirect complaints, and doctors were not proactive in asking about FSD. Three main barriers were identified: doctor factors, perceived patient factors, and system factors. Lack of confidence, knowledge, experience, time, and embarrassment were the key barriers identified at the doctors' level. Lack of awareness, among patients regarding FSD, and local cultural and religious norms were the perceived patient barriers. System barriers were lack of time and privacy. Various facilitators, such as continuous medical education and public forums, were suggested as means to encourage family medicine trainees to initiate discussion on sexual matters during consultations. In conclusion, family medicine trainees found it difficult to initiate conversation on FSD with patients. Interventions to encourage conversation on FSD should target this and other identified barriers. PMID- 27502353 TI - Electroclinical phenotypes and outcomes in TBC1D24-related epilepsy. AB - TBC1D24 is a newly recognized gene in which variations lead to variable clinical phenotypes including drug-resistant epilepsy. We report four patients with novel variants of TBC1D24 demonstrating drug-resistant focal epilepsy, developmental delays, and head growth deceleration. All patients had seizure semiologies consisting of prolonged, unilateral, focal clonic activity of the arm, leg or face, in addition to generalized clonic or myoclonic seizures. Ictal EEG characteristics included epilepsia partialis continua, epilepsy of infancy with migrating focal seizures, and other focal seizures with indiscrete interictal ictal transitions. Two seemingly unrelated Navajo patients with identical variations experienced super-refractory status epilepticus at 9 months of age, with one achieving resolution with ketogenic diet therapy. Our series suggests that TBC1D24-related epilepsy can manifest with hypotonia, developmental delays, and a variety of focal-onset seizures prone to electroclinical dissociation. PMID- 27502354 TI - Electron ionization mass spectrometric fragmentation and multiple reaction monitoring quantification of trimethylsilyl derivatives of cucurbic acid and its 6,7-stereoisomers. AB - RATIONALE: Isomeric cucurbic acids derive from the reduction of the keto group of jasmonic acids. These growth regulators are natural constituents of various higher plants and fungi. Elucidation of electron ionization mass spectrometry (EIMS) fragmentation pathways of the trimethylsilyl (TMS) derivatives of the different stereoisomers is essential for their characterization and quantification in natural samples. METHODS: EIMS fragmentation pathways of TMS derivatives of isomeric cucurbic acids and methyl cucurbates were investigated. These pathways were deduced by: (i) low-energy collision-induced dissociation (CID) gas chromatography/tandem mass spectrometry (GC/MS/MS), (ii) accurate mass measurement, and (iii) deuterium labelling. RESULTS: CID-MS/MS analyses, accurate mass measurement and deuterium labelling allowed us to elucidate EIMS fragmentations of TMS derivatives of several isomeric cucurbic acids and methyl cucurbates and to propose some specific fragment ions useful in addition to chromatographic retention times to characterize individual stereoisomers. As an application of some of the described fragmentations, isomeric cucurbic acids were characterized and quantified in multiple reaction monitoring (MRM) mode in different natural samples. CONCLUSIONS: The EIMS fragmentations of TMS derivatives of isomeric cucurbic acids appear to be distinct when the ether and ester groups are in the cis or trans positions, allowing for an easy differentiation of individual stereoisomers in natural samples. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27502355 TI - The effect of experimental osteoporosis on bone regeneration: Part 1, histology findings. AB - OBJECTIVES: To histologically define the healing events occurring in calvarial critical size defects (CSDs) following treatment with a collagen barrier for guided bone regeneration (GBR) and a particulate graft in healthy and osteoporotic conditions. MATERIAL AND METHODS: Thirty-six 10-month-old, female, Wistar rats were used in this study. Half of them were ovariectomized (OVX) and fed with a low-calcium diet to induce an osteoporotic-like status. In each animal of both groups, two 5-mm CSDs were created, one in the centre of each parietal bone, and they were treated with a deproteinized bovine bone mineral (DBBM) particulate graft and a bi-layer collagen membrane. Six OVX and six healthy control rats were randomly euthanized at 7, 14 and 30 days. One defect per animal was randomly processed for decalcified histology. Three central sections were used for qualitative histology and histomorphometric analysis. RESULTS: No significant difference in terms of percentage of newly formed bone was detected between the two groups at the different healing periods. However, a trend towards less bone formation and of poorer quality, expressed as reduced bone maturation, was detected in the OVX animals at 30 days. DISCUSSION: According to this study, GBR with a collagen barrier and a DBBM graft can be successfully obtained also in osteoporotic-like conditions. Future studies considering longer healing periods and controlling for the confounding factors arising from the use of a particulate graft are needed to confirm these data. PMID- 27502356 TI - Dynamically Tuning the Up-conversion Luminescence of Er(3+)/Yb(3+) Co-doped Sodium Niobate Nano-crystals through Magnetic Field. AB - In this work, we show here that the up-conversion luminescence of NaNbO3:Er(3+)/Yb(3+) nano-materials can be modulated by magnetic field and a enhancement of up-conversion intensities by a factor of about 2 for Er(3+):(4)S3/2 -> (4)I15/2 obtained at 30 T and about 5.4 for Er(3+):(4)F9/2 -> (4)I15/2 obtained at 20 T. The increased up-conversion luminescence are mainly interpreted in terms of the enhanced non-radiation transition from (4)I11/2 to (4)I13/2 of Er(3+) ions and the spin-orbital coupling (that is "mixing" effect) in crystal field by an external magnetic field. Meanwhile, we observed continuously spectra broadening with growing the magnetic field intensity, which is ascribed to the "mixing" effect induced by magnetic field and the difference of g factor of sub-bands. This bi-functional material with controllable optical magnetic interactions has various potential applications, such as optical detection of magnetic field, etc. PMID- 27502358 TI - Analytical relationships for prediction of the mechanical properties of additively manufactured porous biomaterials. AB - Recent developments in additive manufacturing techniques have motivated an increasing number of researchers to study regular porous biomaterials that are based on repeating unit cells. The physical and mechanical properties of such porous biomaterials have therefore received increasing attention during recent years. One of the areas that have revived is analytical study of the mechanical behavior of regular porous biomaterials with the aim of deriving analytical relationships that could predict the relative density and mechanical properties of porous biomaterials, given the design and dimensions of their repeating unit cells. In this article, we review the analytical relationships that have been presented in the literature for predicting the relative density, elastic modulus, Poisson's ratio, yield stress, and buckling limit of regular porous structures based on various types of unit cells. The reviewed analytical relationships are used to compare the mechanical properties of porous biomaterials based on different types of unit cells. The major areas where the analytical relationships have improved during the recent years are discussed and suggestions are made for future research directions. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3164-3174, 2016. PMID- 27502360 TI - Immunotherapy: Here or there, PD-L1 can be anywhere. PMID- 27502361 TI - Driving factors of dinoflagellate cyst distribution in surface sediments of a Mediterranean lagoon with limited access to the sea. AB - Seasonal distribution of dinoflagellate cysts were studied at five surface sediment study stations in Ghar El Melh Lagoon (GML) (Tunisia) in relation to physicochemical parameters and phytoplankton abundance in the water column. At least sixteen dinocyst types were identified, dominated mainly by Protoperidinium spp., Scrippsiella trochoidea complex, Lingulodinum machaerophorum, Alexandrium spp. and Gymnodinium spp., along with many round brown cysts. Cyst abundance ranged from 0 to 229g-1 dry sediment. No significant differences in cyst distribution were found among stations, though a significant variation was observed among seasons with cyst dominance in autumn. No significant variation was found between cyst abundance and the different abiotic factors monitored, neither in the water column (physicochemical parameters) nor in the sediment (% H2O). Low dinocyst abundance was consistent with the dominance of non-cyst forming dinoflagellates in the GML water column. PMID- 27502362 TI - Fundao Dam collapse: Oceanic dispersion of River Doce after the greatest Brazilian environmental accident. AB - On 5 November 2015, the Fundao tailings dam collapsed and its content first reached River Doce and then the Atlantic Ocean by 22 November. This study focuses on the oceanic time and space patterns of river discharge dispersion. By using an ocean model together with nLw(555) and RGB images from MODIS sensors, the river plume was followed for 2months after the arrival of the tailings at the ocean. The results show the huge effect of this accident and reveal that riverine waters may have dispersed hundreds of kilometres, reaching regions as far as the shelf in front of the city of Rio de Janeiro. The movement of the freshwater was essentially to the south in accordance with the seasonal wind regime. Episodic frontal systems, leading to wind reversion, and oceanic mesoscale features contribute to the offshore dispersion of the plume. The region more often in contact with the riverine waters was located at the inner shelf between the river mouth and the city of Vitoria, turning to the outer shelf and shelf break at lower latitudes. PMID- 27502363 TI - Culture supernatants of cervical cancer cells induce an M2 phenotypic profile in THP-1 macrophages. AB - Patients with cervical cancer (CxCa) typically present an infiltrate of tumor associated macrophages, which is associated with a poor prognosis. We found that CxCa cell lines (HeLa, SiHa, and C-33A) secreted factors involved in regulating tumor growth including IL-6, IL-4, PDGFAA, HGF, VEGF, ANG-2, and TGF-beta3. We assessed the effects of culture supernatants from these cell lines on macrophages derived from the THP-1 cell line. Macrophages treated with culture supernatants from CxCa cells developed an M2-like phenotype with expression of CD163, low nitric oxide release, and high secretion of IL-6, PDGFAA, HGF, ANG-2, and VEGF. The macrophages continued to produce PDGFAA, PDGFBB, and VEGF 48h after the CxCa cell culture supernatants were removed. The induction of M2 macrophages in vivo favors tumor growth, angiogenesis, tissue remodeling, and metastasis. These results demonstrated that factors secreted by CxCa cells induced a stable M2 phenotype in THP-1 macrophages. PMID- 27502359 TI - Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing? AB - The prevalence of obesity, of type 2 diabetes mellitus (T2DM), and of cancer are all increasing globally. The relationships between these diseases are complex, and thus difficult to elucidate; nevertheless, evidence supports the hypothesis that obesity increases the risks of both T2DM and certain cancers. Further complexity arises from controversial evidence that specific drugs used in the treatment of T2DM increase or decrease cancer risk or influence cancer prognosis. Herein, we review the current evidence from studies that have addressed these relationships, and summarize the methodological challenges that are frequently encountered in such research. We also outline the physiology that links obesity, T2DM, and neoplasia. Finally, we outline the practical principles relevant to the increasingly common challenge of managing patients who have been diagnosed with both diabetes and cancer. PMID- 27502364 TI - Phosphatidylcholine as a metabolic cue for determining B cell fate and function. AB - In activated B cells, increased production of phosphatidylcholine (PtdCho), the most abundant cellular phospholipid, is handled primarily by the CDP-choline pathway. B cell-specific deletion of CTP:phosphocholine cytidylyltransferase alpha (CCTalpha), the rate-limiting enzyme in the CDP-choline pathway, led to augmented IgM secretion and reduced IgG production, suggesting that PtdCho synthesis is required for germinal center reactions. To specifically assess whether PtdCho influences B cell fate during germinal center responses, we examined immune responses in mice whereby PtdCho synthesis is disrupted in B cells that have undergone class switch recombination to IgG1 (referred to as either Cgamma1wt/wt, Cgamma1Cre/wt or Cgamma1Cre/Cre based on Cre copy number). Serum IgG1 was markedly reduced in naive Cgamma1Cre/wt and Cgamma1Cre/Cre mice, while levels of IgM and other IgG subclasses were similar between Cgamma1Cre/wt and Cgamma1wt/wt control mice. Serum IgG2b titers were notably reduced and IgG3 titers were increased in Cgamma1Cre/Cre mice compared with controls. Following immunization with T cell-dependent antigen NP-KLH, control mice generated high titer IgG anti-NP while IgG anti-NP titers were markedly reduced in both immunized Cgamma1Cre/wt and Cgamma1Cre/Cre mice. Correspondingly, the frequency of NP-specific IgG antibody-secreting cells was also reduced in spleens and bone marrow of Cgamma1Cre/wt and Cgamma. 1Cre/Cre mice compared to control mice. Interestingly, though antigen-specific IgM B cells were comparable between Cgamma1Cre/wt, Cgamma1Cre/Cre and control mice, the frequency and number of IgG1 NP-specific B cells was reduced only in Cgamma1Cre/Cre mice. These data indicate that PtdCho is required for the generation of both germinal center-derived B cells and antibody-secreting cells. Further, the reduction in class-switched ASC but not B cells in Cgamma1Cre/wt mice suggests that ASC have a greater demand for PtdCho compared to germinal center B cells. PMID- 27502365 TI - Whipple's arthritis. AB - Whipple's disease is a chronic systemic infection that is due to the bacterial agent Tropheryma whipplei and can be cured by appropriate antibiotic therapy. The typical patient is a middle-aged man. Rheumatologists are in a prime position to handle Whipple's disease. The classical presentation combines weight loss and diarrhea, preceded in three-quarters of patients by a distinctive pattern of joint manifestations that run an intermittent course, at least initially. The mean time from joint symptom onset to the diagnosis of Whipple's disease is 6 years. Either oligoarthritis or chronic polyarthritis with negative tests for rheumatoid factors (RFs) develops. If the diagnosis is missed, progression to chronic septic destructive polyarthritis may occur. Spondyloarthritis has also been reported, as well as a few cases of diskitis or, even more rarely, of hypertrophic osteoarthropathy. In most patients with the classical form of Whipple's disease, periodic acid-Schiff (PAS) staining of duodenal and jejunal biopsies shows macrophagic inclusions that contain bacteria. However, the involvement of the bowel may be undetectable clinically or, less often, histologically, and even PCR testing of bowel biopsies may be negative. Therefore, when nothing points to bowel disease, rheumatologists should consider T. whipplei infection in middle-aged men with unexplained intermittent oligoarthritis. PCR testing allows the detection of T. whipplei genetic material in joint fluid, saliva, and feces. This test is now a first-line diagnostic investigation, although T. whipplei is a rare cause of unexplained RF-negative oligoarthritis or polyarthritis in males. PCR testing can provide an early diagnosis before the development of severe systemic complications, which are still fatal in some cases. PMID- 27502366 TI - Individual and structural environmental influences on utilization of iron and folic acid supplementation among pregnant women in Harare, Zimbabwe. AB - Micronutrient deficiencies are prevalent among Zimbabweans with serious health and social implications. Due to a lack of a national micronutrient food fortification policy, the Zimbabwe Ministry of Health and Child Care established a policy for the prevention of maternal micronutrient deficiencies, which centres on pregnant women receiving daily iron and folic acid (IFA) at their first antenatal care visit and throughout pregnancy. Despite these efforts, utilization of IFA supplementation in pregnancy in Zimbabwe is low. This study aimed to understand the experiences and knowledge of IFA supplementation among pregnant women and healthcare workers in Harare, Zimbabwe, and the influence of health service and social environments on utilization. Semi-structured in-depth interviews were conducted in Shona and English, with pregnant women (n = 24) and healthcare workers (n = 14) providing direct antenatal care services to pregnant women in two high-density community clinics. Data were analysed thematically using NVivo 10. Influences on utilization were at the individual and structural environmental levels. Reasons for low utilization of IFA supplementation included forgetting to take IFA, side effects, misconceptions about IFA, limited access to nutrition information, delayed entry or non-uptake of antenatal care and social norms of pregnant women for IFA supplementation. Utilization was enhanced by knowledge of risks and benefits of supplementation, fear of negative health complications with non-utilization, family support and healthcare worker recommendation for supplementation. Study findings can inform approaches to strengthen micronutrient supplementation utilization to improve the micronutrient status of pregnant women to decrease maternal mortality and improve overall maternal and child health in Zimbabwe. (c) 2016 John Wiley & Sons Ltd. PMID- 27502367 TI - Interval Appendectomy: Finding the Breaking Point for Cost-Effectiveness. AB - BACKGROUND: Patients with phlegmonous appendicitis can be managed nonoperatively, yet debate continues about the need for interval appendectomy (IA), given the low risk of recurrence or neoplasm. We sought to determine for which patient age interval appendectomy is cost-effective. METHODS: Using TreeAge software, a cost effectiveness model was developed. Two strategies were compared, IA and no interval appendectomy (NIA). Interval appendectomy patients were modeled with probability of benign pathology, cancer or inflammatory bowel disease, and possible operative complications. Patients with NIA were modeled with the probability of recurrence. The probability of malignancy or inflammatory bowel disease developing, or death occurring during a lifetime, was modeled. Base case scenarios at 18, 35, and 50 years old were completed using a Monte Carlo microsimulation. Probabilistic sensitivity analysis was completed using 2 dimensional sample as a Monte Carlo microsimulation to account for variability for patients 18 to 60 years old. Probabilities of complications developing, pathologic diagnosis requiring additional management, and state utility were extracted from published data. Costs were collected from the Centers for Medicare and Medicaid Services and utility was quality-adjusted life years (QALY). RESULTS: For an 18-year-old patient, IA costs $9,417.22 with a gain of 16.59 QALYs compared with NIA, which costs $11,613.57 with a gain of 16.52 QALYs. For a 35-year-old, IA costs $8,989.16 with 9.1 QALYs gained. No interval appendectomy costs $6,614.61 and 9.09 QALYs gained. For the 35-year-old patient, the interval cost-effectiveness ratio comparing NIA with IA is $237,455/QALY. As patient age increases, the interval cost-effectiveness ratio increases. Using a willingness to-pay threshold of $50,000/QALY, IA remains cost-effective until the patient is 33 years old. CONCLUSIONS: Interval appendectomy should be considered in patients younger than 34 years of age. PMID- 27502368 TI - Physician-Owned Surgical Hospitals Outperform Other Hospitals in Medicare Value Based Purchasing Program. AB - BACKGROUND: The Hospital Value-Based Purchasing Program measures value of care provided by participating Medicare hospitals and creates financial incentives for quality improvement and fosters increased transparency. Limited information is available comparing hospital performance across health care business models. STUDY DESIGN: The 2015 Hospital Value-Based Purchasing Program results were used to examine hospital performance by business model. General linear modeling assessed differences in mean total performance score, hospital case mix index, and differences after adjustment for differences in hospital case mix index. RESULTS: Of 3,089 hospitals with total performance scores, categories of representative health care business models included 104 physician-owned surgical hospitals, 111 University HealthSystem Consortium, 14 US News & World Report Honor Roll hospitals, 33 Kaiser Permanente, and 124 Pioneer accountable care organization affiliated hospitals. Estimated mean total performance scores for physician-owned surgical hospitals (64.4; 95% CI, 61.83-66.38) and Kaiser Permanente (60.79; 95% CI, 56.56-65.03) were significantly higher compared with all remaining hospitals, and University HealthSystem Consortium members (36.8; 95% CI, 34.51-39.17) performed below the mean (p < 0.0001). Significant differences in mean hospital case mix index included physician-owned surgical hospitals (mean 2.32; p < 0.0001), US News & World Report honorees (mean 2.24; p = 0.0140), and University HealthSystem Consortium members (mean 1.99; p < 0.0001), and Kaiser Permanente hospitals had lower case mix value (mean 1.54; p < 0.0001). Re-estimation of total performance scores did not change the original results after adjustment for differences in hospital case mix index. CONCLUSIONS: The Hospital Value-Based Purchasing Program revealed superior hospital performance associated with business model. Closer inspection of high-value hospitals can guide value improvement and policy-making decisions for all Medicare Value-Based Purchasing Program Hospitals. PMID- 27502370 TI - Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor. AB - BACKGROUND: Prostaglandin E2 (PGE2) EP receptors EP3 and EP4 signal via decreased and increased cAMP production, respectively. Previously, we reported that cardiomyocyte-specific EP4 knockout mice develop dilated cardiomyopathy with reduced ejection fraction. Thus, we hypothesized that PGE2 increases contractility via EP4 but decreases contractility via EP3. METHODS AND RESULTS: The effects of PGE2 and the EP1/EP3 agonist sulprostone on contractility were examined in the mouse Langendorff preparation and in adult mouse cardiomyocytes. Isolated hearts of adult male C57Bl/6 mice were perfused with PGE2 (10(-6) M) or sulprostone (10(-6) M) and compared with vehicle. Both PGE2 and sulprostone decreased +dp/dt (P<0.01) and left ventricular developed pressure (P<0.001) with reversal by an EP3 antagonist. In contrast, the EP4 agonist had the opposite effect. Adult mouse cardiomyocytes contractility was also reduced after treatment with either PGE2 or sulprostone for 10 minutes. We then examined the acute effects of PGE2, sulprostone, and the EP4 agonist on expression of phosphorylated phospholamban and sarcoendoplasmic reticulum Ca(2+)-ATPase 2a in adult mouse cardiomyocytes using Western blot. Treatment with either PGE2 or sulprostone decreased expression of phosphorylated phospholamban corrected to total phospholamban, whereas treatment with the EP4 agonist had the opposite effect. Sarcoendoplasmic reticulum Ca(2+)-ATPase 2a expression was unaffected. Finally, we examined the effect of these compounds in vivo using pressure-volume loops. Both PGE2 and sulprostone decreased +dp/dt, whereas the EP4 agonist increased +dp/dt. CONCLUSIONS: Contractility is reduced via the EP3 receptor but increased via EP4. These effects may be mediated through changes in phospholamban phosphorylation and has relevance to detrimental effects of inflammation. PMID- 27502369 TI - Postnatal Loss of Kindlin-2 Leads to Progressive Heart Failure. AB - BACKGROUND: The striated muscle costamere, a multiprotein complex at the boundary between the sarcomere and the sarcolemma, plays an integral role in maintaining striated muscle structure and function. Multiple costamere-associated proteins, such as integrins and integrin-interacting proteins, have been identified and shown to play an increasingly important role in the pathogenesis of human cardiomyopathy. Kindlin-2 is an adaptor protein that binds to the integrin beta cytoplasmic tail to promote integrin activation. Genetic deficiency of Kindlin-2 results in embryonic lethality, and knockdown of the Kindlin-2 homolog in Caenorhabditis elegans and Danio rerio suggests that it has an essential role in integrin function and normal muscle structure and function. The precise role of Kindlin-2 in the mammalian cardiac myocyte remains to be determined. METHODS AND RESULTS: The current studies were designed to investigate the role of Kindlin-2 in the mammalian heart. We generated a series of cardiac myocyte-specific Kindlin 2 knockout mice with excision of the Kindlin-2 gene in either developing or adult cardiac myocytes. We found that mice lacking Kindlin-2 in the early developing heart are embryonic lethal. We demonstrate that deletion of Kindlin-2 at late gestation or in adult cardiac myocytes resulted in heart failure and premature death, which were associated with enlargement of the heart and extensive fibrosis. In addition, integrin beta1D protein expression was significantly downregulated in the adult heart. CONCLUSIONS: Kindlin-2 is required to maintain integrin beta1D protein stability. Postnatal loss of Kindlin-2 from cardiac myocytes leads to progressive heart failure, showing the importance of costameric proteins like Kindlin-2 for homeostasis of normal heart function. PMID- 27502371 TI - Savannahs of Asia: antiquity, biogeography, and an uncertain future. AB - The savannahs of Asia remain locally unrecognized as distinctive ecosystems, and continue to be viewed as degraded forests or seasonally dry tropical forests. These colonial-era legacies are problematic, because they fail to recognize the unique diversity of Asian savannahs and the critical roles of fire and herbivory in maintaining ecosystem health and diversity. In this review, we show that: the palaeo-historical evidence suggests that the savannahs of Asia have existed for at least 1 million years, long before widespread landscape modification by humans; savannah regions across Asia have levels of C4 grass endemism and diversity that are consistent with area-based expectations for non-Asian savannahs; there are at least three distinct Asian savannah communities, namely deciduous broadleaf savannahs, deciduous fine-leafed and spiny savannahs and evergreen pine savannahs, with distinct functional ecologies consistent with fire and herbivory-driven community assembly. Via an analysis of savannah climate domains on other continents, we map the potential extent of savannahs across Asia. We find that the climates of African savannahs provide the closest analogues for those of Asian deciduous savannahs, but that Asian pine savannahs occur in climates different to any of the savannahs in the southern continents. Finally, we review major threats to the persistence of savannahs in Asia, including the mismanagement of fire and herbivory, alien woody encroachment, afforestation policies and future climate uncertainty associated with the changing Asian monsoon. Research agendas that target these issues are urgently needed to manage and conserve these ecosystems.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502372 TI - Clarifying the confusion: old-growth savannahs and tropical ecosystem degradation. AB - Ancient tropical grassy biomes are often misrecognized as severely degraded forests. I trace this confusion to several factors, with roots in the nineteenth century, including misinterpretations of the nature of fire in savannahs, attempts to reconcile savannah ecology with Clementsian succession, use of physiognomic (structural) definitions of savannah and development of tropical degradation frameworks focused solely on forests. Towards clarity, I present two models that conceptualize the drivers of ecosystem degradation as operating in both savannahs and forests. These models highlight how human-induced environmental changes create ecosystems with superficially similar physiognomies but radically different conservation values. Given the limitation of physiognomy to differentiate savannahs from severely degraded forests, I present an alternative approach based on floristic composition. Data from eastern lowland Bolivia show that old-growth savannahs can be reliably distinguished by eight grass species and that species identity influences ecosystem flammability. I recommend that scientists incorporate savannahs in tropical degradation frameworks alongside forests, and that savannah be qualified as old-growth savannah in reference to ancient grassy biomes or derived savannah in reference to deforestation. These conceptual advances will require attention not only to tree cover, but also to savannah herbaceous plant species and their ecologies.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502373 TI - Many shades of green: the dynamic tropical forest-savannah transition zones. AB - The forest-savannah transition is the most widespread ecotone in tropical areas, separating two of the most productive terrestrial ecosystems. Here, we review current understanding of the factors that shape this transition, and how it may change under various drivers of local or global change. At broadest scales, the location of the transition is shaped by water availability, mediated strongly at local scales by fire regimes, herbivory pressure and spatial variation in soil properties. The frequently dynamic nature of this transition suggests that forest and savannah can exist as alternative stable states, maintained and separated by fire-grass feedbacks and tree shade-fire suppression feedback. However, this theory is still contested and the relative contributions of the main biotic and abiotic drivers and their interactions are yet not fully understood. These drivers interplay with a wide range of ecological processes and attributes at the global, continental, regional and local scales. The evolutionary history of the biotic and abiotic drivers and processes plays an important role in the current distributions of these transitions as well as in their species composition and ecosystem functioning. This ecotone can be sensitive to shifts in climate and other driving factors, but is also potentially stabilized by negative feedback processes. There is abundant evidence that these transitions are shifting under contemporary global and local changes, but the direction of shift varies according to region. However, it still remains uncertain how these transitions will respond to rapid and multi-faceted ongoing current changes, and how increasing human influence will interact with these shifts.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502374 TI - Competing consumers: contrasting the patterns and impacts of fire and mammalian herbivory in Africa. AB - Fire and herbivory are the two consumers of above-ground biomass globally. They have contrasting impacts as they differ in terms of selectivity and temporal occurrence. Here, we integrate continental-scale data on fire and herbivory in Africa to explore (i) how environmental drivers constrain these two consumers and (ii) the degree to which each consumer affects the other. Environments conducive to mammalian herbivory are not necessarily the same as those conducive to fire, although their spheres of influence do overlap-especially in grassy ecosystems which are known for their frequent fires and abundance of large mammalian herbivores. Interactions between fire and herbivory can be competitive, facultative or antagonistic, and we explore this with reference to the potential for alternative ecosystem states. Although fire removes orders of magnitude more biomass than herbivory their methane emissions are very similar, and in the past, herbivores probably emitted more methane than fire. We contrast the type of herbivory and fire in different ecosystems to define 'consumer-realms'.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502375 TI - Reforestation or conservation? The attributes of old growth grasslands in South Africa. AB - Deforestation as a result of burning and land conversion in the tropics and subtropics has been widely studied and active restoration of forests has been widely promoted. Besides other benefits, reforestation can sequester carbon thereby reducing CO2 emissions to the atmosphere. However, before grasslands are targeted for 'reforestation', it is necessary to distinguish whether they are ancient natural grasslands or secondary vegetation colonizing deforested areas. Here we report the results of a study comparing primary grasslands in South Africa with 4-40 year old secondary grasslands recovering from afforestation with Pinus species. Primary grasslands had significantly higher plant species richness overall, especially of forb species. Ground cover of primary grasslands was more evenly distributed among species than secondary grasslands which tended to mono dominance. Forbs with underground storage organs (USOs) were common in primary grasslands but conspicuously absent in the recovering systems. Comparison of secondary grasslands of different ages (up to 40 years) showed negligible recovery of the original species composition. Three key features distinguish old growth primary from secondary grasslands: total and forb species numbers, evenness of species contributions to cover and the presence of USOs. Old growth grasslands also differed in their fire response, showing significant post-burn resprouting and fire-stimulated flowering in contrast to secondary grasslands. Though similar contrasting attributes of ancient and secondary grasslands have been reported in South America, more studies are needed to explore their generality in other geographical regions.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502376 TI - The future distribution of the savannah biome: model-based and biogeographic contingency. AB - The extent of the savannah biome is expected to be profoundly altered by climatic change and increasing atmospheric CO2 concentrations. Contrasting projections are given when using different modelling approaches to estimate future distributions. Furthermore, biogeographic variation within savannahs in plant function and structure is expected to lead to divergent responses to global change. Hence the use of a single model with a single savannah tree type will likely lead to biased projections. Here we compare and contrast projections of South American, African and Australian savannah distributions from the physiologically based Thornley transport resistance statistical distribution model (TTR-SDM)-and three versions of a dynamic vegetation model (DVM) designed and parametrized separately for specific continents. We show that attempting to extrapolate any continent specific model globally biases projections. By 2070, all DVMs generally project a decrease in the extent of savannahs at their boundary with forests, whereas the TTR-SDM projects a decrease in savannahs at their boundary with aridlands and grasslands. This difference is driven by forest and woodland expansion in response to rising atmospheric CO2 concentrations in DVMs, unaccounted for by the TTR-SDM. We suggest that the most suitable models of the savannah biome for future development are individual-based dynamic vegetation models designed for specific biogeographic regions.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502377 TI - Ecosystem services from southern African woodlands and their future under global change. AB - Miombo and mopane woodlands are the dominant land cover in southern Africa. Ecosystem services from these woodlands support the livelihoods of 100 M rural people and 50 M urban dwellers, and others beyond the region. Provisioning services contribute $9 +/- 2 billion yr(-1) to rural livelihoods; 76% of energy used in the region is derived from woodlands; and traded woodfuels have an annual value of $780 M. Woodlands support much of the region's agriculture through transfers of nutrients to fields and shifting cultivation. Woodlands store 18-24 PgC carbon, and harbour a unique and diverse flora and fauna that provides spiritual succour and attracts tourists. Longstanding processes that will impact service provision are the expansion of croplands (0.1 M km(2); 2000-2014), harvesting of woodfuels (93 M tonnes yr(-1)) and changing access arrangements. Novel, exogenous changes include large-scale land acquisitions (0.07 M km(2); 2000-2015), climate change and rising CO2 The net ecological response to these changes is poorly constrained, as they act in different directions, and differentially on trees and grasses, leading to uncertainty in future service provision. Land-use change and socio-political dynamics are likely to be dominant forces of change in the short term, but important land-use dynamics remain unquantified.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502378 TI - Woody encroachment and its consequences on hydrological processes in the savannah. AB - Woody encroachment due to changes in climate or in the disturbance regimes (fire and herbivory) has been observed throughout the savannah biome over the last century with ecological, hydrological and socioeconomic consequences. We assessed changes in tree density and basal area and estimated changes in rain interception by the canopies across a 5-year period over a biomass gradient in Cerrado vegetation protected from fire. We modelled throughfall, stemflow and net rainfall on the basis of tree basal area (TBA). Tree density increased by an average annual rate of 6.7%, basal area at 5.7% and rain interception by the canopies at 0.6% of the gross rainfall. Independent of the vegetation structure, we found a robust relationship of 0.9% less rainfall reaching the ground as TBA increases by 1 m(2) ha(-1) Increases in tree biomass with woody encroachment may potentially result in less water available for uptake by plants and to recharge rivers and groundwater reserves. Given that water is a seasonally scarce resource in all savannahs, woody encroachment may threaten the ecosystem services related to water resources.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502380 TI - Charcoal production in the Mopane woodlands of Mozambique: what are the trade offs with other ecosystem services? AB - African woodlands form a major part of the tropical grassy biome and support the livelihoods of millions of rural and urban people. Charcoal production in particular is a major economic activity, but its impact on other ecosystem services is little studied. To address this, our study collected biophysical and social datasets, which were combined in ecological production functions, to assess ecosystem service provision and its change under different charcoal production scenarios in Gaza Province, southern Mozambique. We found that villages with longer histories of charcoal production had experienced declines in wood suitable for charcoal, firewood and construction, and tended to have lower perceived availabilities of these services. Scenarios of future charcoal impacts indicated that firewood and woody construction services were likely to trade-off with charcoal production. However, even under the most extreme charcoal scenario, these services were not completely lost. Other provisioning services, such as wild food, medicinal plants and grass, were largely unaffected by charcoal production. To reduce the future impacts of charcoal production, producers must avoid increased intensification of charcoal extraction by avoiding the expansion of species and sizes of trees used for charcoal production. This is a major challenge to land managers and policymakers in the area.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502379 TI - The spatial distribution of African savannah herbivores: species associations and habitat occupancy in a landscape context. AB - Herbivores play an important role in determining the structure and function of tropical savannahs. Here, we (i) outline a framework for how interactions among large mammalian herbivores, carnivores and environmental variation influence herbivore habitat occupancy in tropical savannahs. We then (ii) use a Bayesian hierarchical model to analyse camera trap data to quantify spatial patterns of habitat occupancy for lions and eight common ungulates of varying body size across an approximately 1100 km(2) landscape in the Serengeti ecosystem. Our results reveal strong positive associations among herbivores at the scale of the entire landscape. Lions were positively associated with migratory ungulates but negatively associated with residents. Herbivore habitat occupancy differed with body size and migratory strategy: large-bodied migrants, at less risk of predation and able to tolerate lower quality food, were associated with high NDVI, while smaller residents, constrained to higher quality forage, avoided these areas. Small herbivores were strongly associated with fires, likely due to the subsequent high-quality regrowth, while larger herbivores avoided burned areas. Body mass was strongly related to herbivore habitat use, with larger species more strongly associated with riverine and woodlands than smaller species. Large-bodied migrants displayed diffuse habitat occupancy, whereas smaller species demonstrated fine-scale occupancy reflecting use of smaller patches of high-quality habitat. Our results demonstrate the emergence of strong positive spatial associations among a diverse group of savannah herbivores, while highlighting species-specific habitat selection strongly determined by herbivore body size.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502381 TI - Reconciling agriculture, carbon and biodiversity in a savannah transformation frontier. AB - Rapidly rising populations and likely increases in incomes in sub-Saharan Africa make tens of millions of hectares of cropland expansion nearly inevitable, even with large increases in crop yields. Much of that expansion is likely to occur in higher rainfall savannas, with substantial costs to biodiversity and carbon storage. Zambia presents an acute example of this challenge, with an expected tripling of population by 2050, good potential to expand maize and soya bean production, and large areas of relatively undisturbed miombo woodland and associated habitat types of high biodiversity value. Here, we present a new model designed to explore the potential for targeting agricultural expansion in ways that achieve quantitatively optimal trade-offs between competing economic and environmental objectives: total converted land area (the reciprocal of potential yield); carbon loss, biodiversity loss and transportation costs. To allow different interests to find potential compromises, users can apply varying weights to examine the effects of their subjective preferences on the spatial allocation of new cropland and its costs. We find that small compromises from the objective to convert the highest yielding areas permit large savings in transportation costs, and the carbon and biodiversity impacts resulting from savannah conversion. For example, transferring just 30% of weight from a yield maximizing objective equally between carbon and biodiversity protection objectives would increase total cropland area by just 2.7%, but result in avoided costs of 27-47% for carbon, biodiversity and transportation. Compromise solutions tend to focus agricultural expansion along existing transportation corridors and in already disturbed areas. Used appropriately, this type of model could help countries find agricultural expansion alternatives and related infrastructure and land use policies that help achieve production targets while helping to conserve Africa's rapidly transforming savannahs.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502382 TI - The underestimated biodiversity of tropical grassy biomes. AB - For decades, there has been enormous scientific interest in tropical savannahs and grasslands, fuelled by the recognition that they are a dynamic and potentially unstable biome, requiring periodic disturbance for their maintenance. However, that scientific interest has not translated into widespread appreciation of, and concern about threats to, their biodiversity. In terms of biodiversity, grassy biomes are considered poor cousins of the other dominant biome of the tropics-forests. Simple notions of grassy biomes being species-poor cannot be supported; for some key taxa, such as vascular plants, this may be valid, but for others it is not. Here, we use an analysis of existing data to demonstrate that high-rainfall tropical grassy biomes (TGBs) have vertebrate species richness comparable with that of forests, despite having lower plant diversity. The Neotropics stand out in terms of both overall vertebrate species richness and number of range-restricted vertebrate species in TGBs. Given high rates of land cover conversion in Neotropical grassy biomes, they should be a high priority for conservation and greater inclusion in protected areas. Fire needs to be actively maintained in these systems, and in many cases re-introduced after decades of inappropriate fire exclusion. The relative intactness of TGBs in Africa and Australia make them the least vulnerable to biodiversity loss in the immediate future. We argue that, like forests, TGBs should be recognized as a critical-but increasingly threatened-store of global biodiversity.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502383 TI - Understanding patterns of land-cover change in the Brazilian Cerrado from 2000 to 2015. AB - Clearing tropical vegetation impacts biodiversity, the provision of ecosystem services, and thus ultimately human welfare. We quantified changes in land cover from 2000 to 2015 across the Cerrado biome of northern Minas Gerais state, Brazil. We assessed the potential biophysical and socio-economic drivers of the loss of Cerrado, natural regeneration and net cover change at the municipality level. Further, we evaluated correlations between these land change variables and indicators of human welfare. We detected extensive land-cover changes in the study area, with the conversion of 23 446 km(2) and the natural regeneration of 13 926 km(2), resulting in a net loss of 9520 km(2) The annual net loss (-1.2% per year) of the cover of Cerrado is higher than that reported for the whole biome in similar periods. We argue that environmental and economic variables interact to underpin rates of conversion of Cerrado, most severely affecting more humid Cerrado lowlands. While rates of Cerrado regeneration are important for conservation strategies of the remaining biome, their integrity must be investigated given the likelihood of encroachment. Given the high frequency of land abandonment in tropical regions, secondary vegetation is fundamental to maintain biodiversity and ecosystem services. Finally, the impacts of Cerrado conversion on human welfare likely vary from local to regional scales, making it difficult to elaborate land-use policies based solely on socio-economic indicators.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502384 TI - Woody encroachment over 70 years in South African savannahs: overgrazing, global change or extinction aftershock? AB - Woody encroachment in 'open' biomes like grasslands and savannahs is occurring globally. Both local and global drivers, including elevated CO2, have been implicated in these increases. The relative importance of different processes is unresolved as there are few multi-site, multi-land-use evaluations of woody plant encroachment. We measured 70 years of woody cover changes over a 1020 km(2) area covering four land uses (commercial ranching, conservation with elephants, conservation without elephants and communal rangelands) across a rainfall gradient in South African savannahs. Different directions of woody cover change would be expected for each different land use, unless a global factor is causing the increases. Woody cover change was measured between 1940 and 2010 using the aerial photo record. Detection of woody cover from each aerial photograph was automated using eCognitions' Object-based image analysis (OBIA). Woody cover doubled in all land uses across the rainfall gradient, except in conservation areas with elephants in low-rainfall savannahs. Woody cover in 2010 in low rainfall savannahs frequently exceeded the maximum woody cover threshold predicted for African savannahs. The results indicate that a global factor, of which elevated CO2 is the likely candidate, may be driving encroachment. Elephants in low-rainfall savannahs prevent encroachment and localized megafaunal extinction is a probable additional cause of encroachment.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502386 TI - Correction to 'The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occludin recovery in experimental colitis'. PMID- 27502385 TI - Tropical grassy biomes: linking ecology, human use and conservation. AB - Tropical grassy biomes (TGBs) are changing rapidly the world over through a coalescence of high rates of land-use change, global change and altered disturbance regimes that maintain the ecosystem structure and function of these biomes. Our theme issue brings together the latest research examining the characterization, complex ecology, drivers of change, and human use and ecosystem services of TGBs. Recent advances in ecology and evolution have facilitated a new perspective on these biomes. However, there continues to be controversies over their classification and state dynamics that demonstrate critical data and knowledge gaps in our quantitative understanding of these geographically dispersed regions. We highlight an urgent need to improve ecological understanding in order to effectively predict the sensitivity and resilience of TGBs under future scenarios of global change. With human reliance on TGBs increasing and their propensity for change, ecological and evolutionary understanding of these biomes is central to the dual goals of sustaining their ecological integrity and the diverse services these landscapes provide to millions of people.This article is part of the themed issue 'Tropical grassy biomes: linking ecology, human use and conservation'. PMID- 27502388 TI - Synthesis and Applications of Nanoflowers. AB - BACKGROUND: Recent advances in nanotechnology make novel shapes of nanostructured materials with novel physicochemical properties. Different kinds of materials including carbon, metals, alloys, metal oxides, conducting polymers, metal chalcogenides, pnictides and fluorides have been synthesized with small size of <100 nm with shapes resembled to the natural flowers. The objective of this review is to provide a broad overview of the synthesis strategies, effects of different parameters on the morphology of nanoflowers, and their applications. METHODS: A comprehensive search to assess the current evidence for the synthesis routs of nanoflowers and applications was conducted. 487 studies became selected and the quality of papers were appraised and categorized according to type of nanomaterials. Within each section, the nanomaterials addressed specifically. In addition, recent patents were reviewed in a separate section. RESULTS: The nanoflowers exhibited unique properties which were utilized in the design of efficient applications. These nanostructures can be processed with different methods. The configuration of flower-like nanostructures can be controlled by altering experimental parameters, such as the precursor's ratio, temperature and reaction time. Despite the huge efforts to control and understand the growth mechanism of these nanostructures, some fundamental phenomena are still not well understood. Investigation of the fundamental effects of size and morphology on their properties is required in order to better apply these nanostructured materials. CONCLUSION: The nanoflowers with interesting properties can be used in the design of future devices with various applications. The existence of different routes to synthesis nanoflowers and their unique properties confirm the importance promoted awareness of potential benefits of nanoflowers in different applications. The reviewed patents emphasized the importance of these nanostructures. Therefore, research efforts based on nanoflowers are dynamic and applicable in various fields. PMID- 27502387 TI - Bi-insular cortical involvement in anti-NMDA-receptor encephalitis - a case report. AB - BACKGROUND: Anti-NMDA-receptor encephalitis is an immune-mediated inflammatory disorder of the central nervous system. Brain MRI is unremarkable in at least 50% of patients and highly variable in the remaining patients with signal abnormalities in different brain regions. Only scarce reports exist on other imaging modalities. CASE PRESENTATION: A 31-year-old woman sub-acutely developed psychosis, behavioural changes, amnesia, alternating states of agitation and mutism, fever and epileptic seizures. Clinically suspected diagnosis of anti-NMDA receptor encephalitis was confirmed by the detection of anti-NMDA receptor antibodies in CSF and serum. During the acute phase, brain MRI abnormalities were found in both insular cortices and hippocampi, whereas F(18)-FDG-PET showed hypermetabolism bilaterally in insular and prefrontal cortex. After resection of the underlying ovarian teratoma and with multimodal immunotherapy the patient substantially improved reaching a modified Rankin Scale score of 2 after 3 months. At follow-up, both hippocampi were still affected on MRI, whereas insular cortex appeared normal; however, both regions showed prominent glucose hypometabolism. CONCLUSIONS: Here, we report bi-insular cortical abnormalities on MRI and F(18)-FDG-PET in a patient with anti-NMDA-receptor encephalitis during the acute phase and after clinical improvement. PMID- 27502389 TI - Lymphatic Delivery of Anti-HIV Drug Nanoparticles. AB - BACKGROUND: HIV infection persists for a longer time in AIDS patient compared to many other viral diseases. This is mainly because the HIV resides maximally in lymphatic system mainly the lymph nodes. Most of the present anti-HIV drugs have very poor bioavailability at lymphatic tissue. Hence, pharmaceutical scientists have made many efforts to formulate anti-HIV drugs for targeting lymphatic system. The exploration of nanoparticulate drug delivery systems have been popularly investigated for lymphatic targeting and for improving therapeutic efficacy. METHODS: An electronic search was undertaken to review the recent publications and patents from the available resources on nanoformulations of anti HIV drugs for lymphatic delivery. RESULTS: Various carrier systems such as liposomes, polymeric nanoparticles, solid-lipid nanoparticles, nanostructured lipid carriers, polymeric micelles, dendrimers, and nanocrystals have been tried for lymphatic targeting. These nanoparticles are widely studied as passive targeting carriers for lymphatic systems. There is dearth of active targeting for anti-HIV drugs. The studies on surface modified nanoparticles have shown promising results for lymphatic targeting. CONCLUSION: One of the reasons for low success rate in targeting the lymphatic tissue is poor-understanding of pharmacokinetic interactions of novel delivery systems in disease pathology. Apart from this, there are several hurdles in biological screening models and clinical trials. These issues should never be neglected in developing newer targeted delivery systems for treatment of AIDS. PMID- 27502390 TI - Nanocarriers as Tools in Delivering Active Compounds for Immune System Related Pathologies. AB - BACKGROUND: Immune system related pathologies affect an increasing number of patients every year, having potentially lethal consequences and requiring expensive and difficult tolerated treatments. This area of pathologies offers an excellent potential for the development of innovative solutions such as nanoformulations; this review aims to describe the main categories of nanostructured drug delivery platforms that have been developed in order to achieve a more effective, low toxic treatment in autoimmune pathologies. METHODS: We conducted a systematic search of peer-reviewed original studies focusing on nanoformulations suitable for use against autoimmune disorders. Each study was evaluated by at least two reviewers who applied inclusion and exclusion criteria in order to establish the quality of the research reported in the selected papers. The systematic screening of the literature also identified the most recent patents issued in the field of inflammatory/autoimmune diseases which were included in the current paper. RESULTS: One hundred ninety-seven bibliographic titles were included in the review of which fifty-three recently published patents. Twenty-one papers were selected to define the interaction between nanoformulations and the immune system triggering either immunosuppression or immunostimulation. Thirty-seven papers outlined the characteristics of liposomal formulations that have been reported as treatment for several autoimmune diseases including multiple sclerosis. Twentythree articles provided data on the main lipid nanoparticles of the first and second generation which may include physiological lipids with low cytotoxicity. Gold nanoparticles were described by thirteen papers which highlighted the advantages of the new hybrid organic inorganic nanoparticles vs. the classical ionic gold compounds. Polymeric nanoformulations were the subject of fifty-nine papers that described their preparation as well as various advantages in the treatment of inflammatory disorders; dendrimers and polymeric micelles were included in the study. Thirty three studies were selected to outline the benefits provided by the use of cyclodextrins as carriers for active drugs. The review also identified the possibility of producing combined nanoformulations (e.g. polymer/cyclodextrin, liposome/polymer) thus achieving superior therapeutic results. CONCLUSION: Nanoformulations offer multiple advantages over the classical pharmaceutical formulations, the main ones being the precise targeted therapy with small doses of active drugs, longer circulating time in the bloodstream, and high loading capacity for diagnostic and therapeutic molecules; moreover, the nanoparticles may be functionalized in order to act as nanotheranostics within the larger frame of personalized medicine. PMID- 27502391 TI - The Advanced Aluminum Nitride Synthesis Methods and Its Applications: Patent Review. AB - BACKGROUND: High purity nanosized aluminum nitride synthesis is a current issue for both industry and science. However, there is no up-to-date review considering the major issues and the technical solutions for different methods. This review aims to investigate the advanced methods of aluminum nitride synthesis and its development tendencies. Also the aluminum nitride application patents and prospects for development of the branch have been considered. METHODS: The patent search on "aluminum nitride synthesis" has been carried out. The research activity has been analyzed. Special attention has been paid to the patenting geography and the leading researchers in aluminum nitride synthesis. RESULTS: Aluminum nitride synthesis methods have been divided into 6 main groups, the most studied approaches are carbothermal reduction (88 patents) and direct nitridation (107 patents). The current issues for each group have been analyzed; the main trends are purification of the final product and nanopowder synthesis. The leading researchers in aluminum nitride synthesis have represented 5 countries, namely: Japan, China, Russia, South Korea and USA. The main aluminum nitride application spheres are electronics (59,1 percent of applications) and new materials manufacturing (30,9 percent). CONCLUSION: The review deals with the state of the art data in nanosized aluminum nitride synthesis, the major issues and the technical solutions for different synthesis methods. It gives a full understanding of the development tendencies and of the current leaders in the sphere. PMID- 27502392 TI - Effect of Gold/Amine Nanoparticles on Polyaniline Electrochemical Sensitivity to Formaldehyde. AB - BACKGROUND: Nanoparticles have a promising potential in electrochemical sensitivity. Polyaniline (PANI) received significant attention in the latest years owing to its high conductivity and excellent electrochemical stability. This research aims to study the effect of gold nanoparticles capped octadecyl amine (Au/ODA) on polyaniline emeraldine salt (ES) electrochemical sensitivity to formaldehyde (FA) using DPV technique. Furthermore, ES and Au-ODA/ES have been applied for the first time in sensing FA. Few relevant patents to the topic have been reviewed and cited in this article. METHODS: Emeraldine salt (ES) was prepared by doping the prepared emeraldine base (EB) powder with dodecylbenzene sulfonic acid (DBSA) at a ratio of 1:2 W/W. Then ES-DBSA was dissolved in chloroform solution and added to Au/ODA nanoparticles solution to obtain Au/ES DBSA nanocomposite. FA sensors were prepared by depositing a film from ESDBSA or Au/ES-DBSA on a working electrode and the potential was measured at FA different concentrations in Electrochemical cell kit. RESULTS: FTIR and XRD confirmed the structure of ES-DBSA and Au/ES-DBSA. The obtained results reveal that the ESDBSA nanosensor is an efficient sensor because it can recognize the low levels of FA starting from 0.06 ppm. The recorded electrochemical oxidation current shows a linear direct relationship between the produced current and FA concentration in case of ES-DBSA nanoparticles while it illustrates a fluctuating signal with lower sensitivity in the case of the novel prepared nanocomposites (Au/ES-DBSA). This may be due to the gold capping agent (ODA), which in turn could inhibit the role of DBSA and decrease the conductivity of the nanocomposite. CONCLUSION: Herein we described the application of ES-DBSA and Au/ES-DBSA nanocomposite for the first time as a novel, facile, and cheap method for electrochemical sensitive detection of formaldehyde. The gold capping agent ODA hinders the ES-DBSA conductivity through interaction with the DBSA sulfo group. PMID- 27502393 TI - Effective Strategies for Achieving Scope of Practice Reform in Pennsylvania. AB - BACKGROUND: Current regulatory impediments prohibit advanced practice registered nurses from practicing to their full capacity. PURPOSE: To examine the process of successful removal of scope of practice barriers in Pennsylvania under the Rx4PA legislation introduced in 2007. METHOD: We used qualitative research techniques, including purposeful sampling of participants. Twelve stakeholder informed interviews were conducted between October 2013 and May 2014. Participants were closely involved with the development of the Rx4PA legislation. Thematic content analysis was performed to analyze our interviews. DISCUSSION: Interviews identified overarching themes, including the importance of leveraging years of grass roots advocacy, identifying political allies, and recognizing mutually beneficial compromises. CONCLUSIONS: The combination of timing, careful political maneuvering, and compromise were key to scope of practice reform in Pennsylvania and may be useful strategies for other states seeking similar practice changes. PMID- 27502394 TI - Vaccination of rabbits with immunodominant antigens from Sarcoptes scabiei induced high levels of humoral responses and pro-inflammatory cytokines but confers limited protection. AB - BACKGROUND: Vaccination is an attractive ecological alternative to the use of acaricides for parasite control. However, effective anti-parasite vaccines against sarcoptic mange have not yet been developed. The purpose of this study was first to identify Sarcoptes scabiei immunodominant antigens and second to evaluate them as vaccine candidates in a rabbit/S. scabiei var. cuniculi model. METHODS: The S. scabiei Sslambda15 immunodominant antigen was selected by immunoscreening of a S. scabiei var. hominis cDNA. The full-length cDNA was sequenced and cloned into the pGEX vector and the recombinant protein expressed in BL21 (DE3) cells and purified. A vaccination trial was performed consisting of a test group (n = 8) immunised with recAgs (a mix of two recombinant antigens, Sslambda15 and the previously described Sslambda20?B3) and a control group (n = 8) immunised with PBS. All analyses were performed with R Statistical Environment with alpha set at 0.050. RESULTS: The full-length open reading frame of the 1,821 nt cloned cDNA encodes a 64 kDa polypeptide, the sequence of which had 96 % identity with a hypothetical protein of S. scabiei. Sslambda15 was localised by immunostaining of skin sections in the tegument surrounding the mouthparts and the coxa in the legs of mites. Rabbit immunisation with recAgs induced high levels of specific IgG (P < 0.010) and increased levels of total IgEs. However, no significant clinical protection against S. scabiei challenge was detected. Unexpectedly, the group immunised with the recAgs mix had significantly higher lesion scores (P = 0.050) although lower mean mite densities than those observed in the control group. These results might indicate that the lesions in the recAgs group were due not only to the mites density but also to an exacerbated immunological response after challenge, which is in agreement with the specific high levels of pro-inflammatory cytokines (IL-1 and TNFalpha) detected after challenge in this group. CONCLUSIONS: The selected antigens delivered as recombinant proteins had no clinical protective efficacy against S. scabiei infestation although immunisation reduced mite density. However, these results pave the way for future studies on alternative production systems, adjuvants, delivery methods and combinations of antigens in order to manage stimulation of clinical protective immune responses. PMID- 27502395 TI - Correlation between invasion mode and the histologic risk assessment model in oral squamous cell carcinoma. AB - PURPOSE: The histologic risk assessment (HRA) model was proposed to assess clinical outcome of oral squamous cell carcinomas (SCCs), and its prognostic value has been confirmed in several studies, but its underlying molecular mechanisms has not been fully investigated. The objective of this study was to evaluate the association between immunohistochemical invasion mode of head and neck SCC and the HRA grading system. METHODS: The HRA model consisting of risk scores (RSs), based on perineural invasion (PI), lymphocytic infiltration (LI), and worst pattern of invasion (WPOI), was used for grading 80 samples of head and neck SCC, followed by immunohistochemical staining with antibodies against E cadherin, N-cadherin, and podoplanin. The two major invasion modes were considered as epithelial-mesenchymal-transition (EMT) and collective cell invasion (CCI) with profiles of E-cadherin-/N-cadherin+/podoplanin- and E cadherin+/N-cadherin-/podoplanin+, respectively. All other immunohistochemical profiles were classified as partial/incomplete EMT. Statistical analysis was performed by Kruskal-Wallis and Mann-Whitney U tests (P < 0.05). RESULTS: Invasion pattern was significantly different among the three RSs (P = 0.01) and across the different scores of LI (P = 0.03) but not perineural invasion (PNI) (P = 0.07) and WPOI (P = 0.70). CONCLUSIONS: Based on our results, it seems that there is a difference in EMT, CCI, and partial/incomplete EMT among the variables of the HRA model which might help clarify its functioning system. PMID- 27502396 TI - uPAR enhances malignant potential of triple-negative breast cancer by directly interacting with uPA and IGF1R. AB - BACKGROUND: Due to lack of a targeted therapy for the triple-negative breast cancer (TNBC) patients, it is important to explore this aggressive breast cancer type in more detail and to establish novel therapeutic approaches. TNBC is defined negative for the protein expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). One prominent feature of this cancer type is the frequent overexpression of major components of the urokinase-type plasminogen activator system (uPAS) including uPA, its receptor uPAR and the inhibitor PAI-1, which may be valuable as therapeutic targets. METHODS: Direct interactions of uPAR with interactors were demonstrated by immunoprecipitations and proximity ligation assays. For stable knockdowns of target proteins, lentiviral vectors were used and the effects were analysed by immunoblottings and using in vitro cell viability, migration and invasion assays. Immunohistochemical and statistical analyses of biomarkers and clinical parameters were conducted in a TNBC cohort (n = 174). RESULTS: Direct tumour-promoting interactions of uPAR with uPA and the insulin-like growth factor receptor 1 (IGF1R) were shown in TNBC cells and these interactions were significantly reduced (p = 0.001) when uPAR was downregulated. The combined knockdown of uPAR and uPA or IGF1R additively and significantly reduced cell viability, migration and invasion of the model cell lines. In TNBC tissue, the complexes formed by uPAR with uPA or with IGF1R significantly correlated with the histological grade (p = 0.0019) as well as with cathepsin B and D (p <= 0.0001) that are implicated in cell invasion and metastasis. CONCLUSIONS: Our outcomes show that not only overexpressed biomarkers promote tumourigenesis, but rather their interactions further potentiate tumour progression. This study emphasises the potential of combined approaches targeting uPAR and its interactors with regard to an improved therapy of TNBC. PMID- 27502397 TI - Violacein induces death of RAS-mutated metastatic melanoma by impairing autophagy process. AB - Treatment of metastatic melanoma still remains a challenge, since in advanced stage it is refractory to conventional treatments. Most patients with melanoma have either B-RAF or N-RAS mutations, and these oncogenes lead to activation of the RAS-RAF-MEK-ERK and AKT signal pathway, keeping active the proliferation and survival pathways in the cell. Therefore, the identification of small molecules that block metastatic cell proliferation and induce cell death is needed. Violacein, a pigment produced by Chromobacterium violaceum found in Amazon River, has been used by our group as a biotool for scrutinizing signaling pathways associated with proliferation, survival, aggressiveness, and resistance of cancer cells. In the present study, we demonstrate that violacein diminished the viability of RAS- and RAF-mutated melanoma cells (IC50 value ~500 nM), and more important, this effect was not abolished after treatment medium removal. Furthermore, violacein was able to reduce significantly the invasion capacity of metastatic melanoma cells in 3D culture. In the molecular context, we have shown for the first time that violacein causes a strong drop on histone deacetylase 6 expression, a proliferating activator, in melanoma cells. Besides, an inhibition of AXL and AKT was detected. All these molecular events propitiate an inhibition of autophagy, and consequently, melanoma cell death by apoptosis. PMID- 27502398 TI - In vitro and in vivo effects of hemodilution on kaolin-based activated clotting time predicted heparin requirement using a heparin dose-response technique. AB - PURPOSE: The heparin dose-response (HDR) technique is based on activated clotting time (ACT) response to a fixed-dose heparin bolus, which varies substantially among patients. It is unclear, however, whether hemodilution-associated reductions in coagulation and anticoagulation factors affect the HDR slope. METHODS: For in vitro hemodilution, aliquots of whole blood from healthy volunteers were diluted 9:1 and 8:2 v/v with normal saline. For in vivo hemodilution, a prospective observational study was performed on 46 patients who underwent elective cardiovascular surgery with or without cardiopulmonary bypass. HDR slope, antithrombin (AT) activity, complete blood count, and other coagulation parameters were compared after induction of anesthesia and after hemodilution with 500 ml of intravenous fluid. RESULTS: In vitro 10 and 20 % hemodilution significantly increased the HDR slope relative to baseline, reducing the heparin requirement. Hemodilution of heparinized samples significantly prolonged ACT, whereas there was no significant change in non-heparinized blood. The percent changes in fibrinogen and AT activity were significantly greater at 20 % than those of the other coagulation variables. In vivo, hemodilution significantly increased the HDR slope and reduced heparin requirement. The percent change in fibrinogen due to hemodilution was significantly greater than the change in AT activity. Target ACTs of 300 and 450 s were not achieved in 83.3 and 53.8 % of patients, respectively. CONCLUSION: In vitro and in vivo hemodilution significantly increased the HDR slope and reduced the requirement for heparin. In vitro, the HDR slope did not change in parallel but became steeper, depending on the degree of hemodilution. PMID- 27502399 TI - Size doesn't matter in the heat shock response. AB - Heat shock factor 1 (Hsf1) is a transcription factor that is often described as the master regulator of the heat shock response in all eukaryotes. However, due to its essentiality in yeast, Hsf1's contribution to the transcriptome under basal and heat shock conditions has never been directly determined. Using a chemical genetics approach that allowed rapid Hsf1 inactivation, my colleagues and I have recently shown that the bulk of the heat shock response is Hsf1 independent. Rather than inducing genes responsible for carrying out the various cellular processes required for adaptation to thermal stress, Hsf1 controls a dedicated set of chaperone protein genes devoted to restoring protein-folding homeostasis. The limited scope of the Hsf1 regulon belies its outsize importance in cellular fitness. PMID- 27502400 TI - Morbidity and mortality rates after emergency abdominal surgery: an analysis of 4346 patients scheduled for emergency laparotomy or laparoscopy. AB - PURPOSE: Emergency abdominal surgery results in a high rate of post-operative complications and death. There are limited data describing the emergency surgical population in details. We aimed to give a detailed analyses of complications and mortality in a consecutive group of patients undergoing acute abdominal surgery over a 4-year period. METHODS: This observational study was conducted between 2009 and 2013 at Copenhagen University Hospital Herlev, Denmark. All patients scheduled for emergency laparotomy or laparoscopy were included. Pre-, intra-, and post-operative data were collected from medical records. Complications were registered according to the Clavien-Dindo classification. Cox regression analysis was performed to identify risk factors for mortality. RESULTS: A total of 4,346 patients underwent emergency surgery, of whom 14 % had surgical complications and 23 % medical complications. The overall 30-day mortality was 8 % with 50 % of those in this group over 80 years of age. The 30-day mortality rates were 0.8 % (95 % CI 0.5-1.1) and 17 % (95 % CI 15.5-18.9), respectively, for the laparoscopy and the laparotomy groups. The overall death rate within 24 h of surgery was 21 %. Several risk factors for 30- and 90-day mortality were identified: age, ASA >=3 (American Society of Anaesthesiologists physical status classification), performance score (Zubroed/WHOclassification), cirrhosis of the liver, chronic nephropathy, several medical conditions, and malignancy. CONCLUSION: Almost one in five patients died after emergency laparotomy, of whom one in five died within 24 h of surgery. Predictors for poor outcome were identified. PMID- 27502402 TI - Endovascular treatment of previously clipped aneurysms: continued evolution of hybrid neurosurgery. AB - BACKGROUND/OBJECTIVE: The optimal management of residual or recurrent clipped aneurysms is infrequently addressed in the literature. METHODS: We reviewed our endovascular database from January 1998 to May 2016 to identify patients with clipped aneurysms undergoing subsequent endovascular treatment, evaluating treatment approach, and clinical and angiographic outcomes. RESULTS: 60 patients underwent endovascular treatment of residual/recurrent clipped aneurysms; 7 rebled prior to endovascular therapy. Treatment was via coiling alone (n=25, 42%), stent assisted coiling (n=15, 25%), balloon assisted coiling (n=8, 13%), flow diversion (n=8, 13%), stenting alone (n=3, 5%), or flow diversion with coiling (n=1, 2%). The procedural permanent neurological morbidity and mortality rates were 3% and 2%, respectively. Over a clinical follow-up of 253.4 patient years (median 3.9 years), there was one rebleed in a patient who had declined further treatment. For 43 patients with at least 1 month of digital subtraction angiographic follow-up (median 3.4 years), complete aneurysm occlusion was seen in 79% of cases. Neck remnants were observed in 14%, and stable small dome remnants were observed in 7% of cases. In a subgroup of 18 patients with 'clip induced' narrow neck aneurysms, all domes were initially coil occluded (Raymond 1 or 2); there was no permanent procedural morbidity and no aneurysms required retreatment or recanalized over a median follow-up of 3.9 years. CONCLUSIONS: Endovascular treatment of residual or recurrent clipped aneurysms is an excellent treatment approach in well selected patients; 'clip induced' narrow neck aneurysms fare particularly well after treatment both angiographically and clinically. PMID- 27502401 TI - Canalization of gene expression is a major signature of regulatory cold adaptation in temperate Drosophila melanogaster. AB - BACKGROUND: Transcriptome analysis may provide means to investigate the underlying genetic causes of shared and divergent phenotypes in different populations and help to identify potential targets of adaptive evolution. Applying RNA sequencing to whole male Drosophila melanogaster from the ancestral tropical African environment and a very recently colonized cold-temperate European environment at both standard laboratory conditions and following a cold shock, we seek to uncover the transcriptional basis of cold adaptation. RESULTS: In both the ancestral and the derived populations, the predominant characteristic of the cold shock response is the swift and massive upregulation of heat shock proteins and other chaperones. Although we find ~25 % of the genome to be differentially expressed following a cold shock, only relatively few genes (n = 16) are up- or down-regulated in a population-specific way. Intriguingly, 14 of these 16 genes show a greater degree of differential expression in the African population. Likewise, there is an excess of genes with particularly strong cold induced changes in expression in Africa on a genome-wide scale. CONCLUSIONS: The analysis of the transcriptional cold shock response most prominently reveals an upregulation of components of a general stress response, which is conserved over many taxa and triggered by a plethora of stressors. Despite the overall response being fairly similar in both populations, there is a definite excess of genes with a strong cold-induced fold-change in Africa. This is consistent with a detrimental deregulation or an overshooting stress response. Thus, the canalization of European gene expression might be responsible for the increased cold tolerance of European flies. PMID- 27502403 TI - Endovascular treatment for AIS with underlying ICAD. AB - BACKGROUND: Acute large vessel occlusion (LVO) can result from thromboemboli or underlying intracranial atherosclerotic disease (ICAD). Although the technique for revascularization differs significantly for these two lesions (simple thrombectomy for thromboemboli and balloon angioplasty and stenting for ICAD), the underlying etiology is often unknown in acute ischemic stroke (AIS). OBJECTIVE: To evaluate whether procedural complications, revascularization rates, and functional outcomes differ among patients with LVO from ICAD or thromboembolism. METHODS: A retrospective review of thrombectomy cases from 2008 to 2015 was carried out for cases of AIS due to underlying ICAD. Thirty-six patients were identified. A chart and imaging review was performed to determine revascularization rates, periprocedural complications, and functional outcomes. Patients with ICAD and acute LVO were compared with those with underlying thromboemboli. RESULTS: Among patients with ICAD and LVO, mean National Institutes of Health Stroke Scale (NIHSS) score on admission was 12.9+/-8.5, revascularization (Thrombolysis In Cerebral Infarction, TICI >=2b) was achieved in 22/34 (64.7%) patients, 11% had postprocedural intracerebral hemorrhage (PH2), and 14/33 (42.4%) had achieved a modified Rankin Scale (mRS) score of 0-2 at the 3-month follow-up. Compared with patients without underlying ICAD, there was no difference in NIHSS on presentation, or in the postprocedural complication rate. However, procedure times for ICAD were longer (98.5+/-59.8 vs 37.1+/-34.2 min), there was significant difference in successful revascularization rate between the groups (p=0.001), and a trend towards difference in functional outcome at 3 months (p=0.07). CONCLUSIONS: Despite AIS with underlying ICAD requiring a more complex, technically demanding recanalization strategy than traditional thromboembolic AIS, it appears safe, and good outcomes are obtainable. PMID- 27502404 TI - Biological Effects of Drug-Free Alginate Beads Cross-Linked by Copper Ions Prepared Using External Ionotropic Gelation. AB - External ionotropic gelation offers a unique possibility to entrap multivalent ions in a polymer structure. The aim of this experimental study was to prepare new drug-free sodium alginate (ALG) particles cross-linked by Cu2+ ions and to investigate their technological parameters (particle size, sphericity, surface topology, swelling capacity, copper content, release of Cu2+ ions, mucoadhesivity) and biological activity (cytotoxicity and efficiency against the most common vaginal pathogens-Herpes simplex, Escherichia coli, Candida albicans) with respect to potential vaginal administration. Beads prepared from NaALG dispersions (3 or 4%) were cross-linked by Cu2+ ions (0.5 or 1.0 M CuCl2) using external ionotropic gelation. Prepared mucoadhesive beads with particle size over 1000 MUm exhibited sufficient sphericity (all ?0.89) and copper content (214.8 249.07 g/kg), which increased with concentration of polymer and hardening solution. Dissolution behaviour was characterized by extended burst effect, followed by 2 h of copper release. The efficiency of all samples against the most common vaginal pathogens was observed at cytotoxic Cu2+ concentrations. Anti-HSV activity was demonstrated at a Cu2+ concentration of 546 mg/L. Antibacterial activity of beads (expressed as minimum inhibition concentration, MIC) was influenced mainly by the rate of Cu2+ release which was controlled by the extent of swelling capacity. Lower MIC values were found for E. coli in comparison with C. albicans. Sample ALG-3_1.0 exhibited the fastest copper release and was proved to be the most effective against both bacteria. This could be a result of its lower polymer concentration in combination with smaller particle size and thus larger surface area. PMID- 27502405 TI - Improved Method for Solid Lipid Nanoparticle Preparation Based on Hot Microemulsions: Preparation, Characterization, Cytotoxicity, and Hemocompatibility Evaluation. AB - The ease of application and no requirement of extra energy input make the microemulsion method favorable for solid lipid nanoparticles (SLNs) production. Very limited data are available to date on preparation of SLNs from pre-screened microemulsion phase diagrams. The purpose of this study was to investigate the microemulsion formation area with solid lipids using hot ternary phase diagrams at elevated temperatures and to use selected microemulsions for SLN production. Also, we aimed to characterize obtained SLNs in terms of physicochemical properties, in vitro cell toxicity, and hemolysis. Phase diagrams of solid lipids were screened at elevated temperatures and oil-in-water microemulsion regions were determined. Microemulsions were selected, and SLNs were produced by modification of the microemulsion dilution method and characterized in terms of visual appearance, turbidity, particle size, and zeta potential. Cytotoxicity of nanoparticles was tested on L929 mouse skin fibroblast cells. Hemolytic potential was assessed in vitro using freshly isolated erythrocytes. The phase diagram screening and the modified hot microemulsion dilution method enabled production of SLNs with particle size below 100 nm. We found evidence that the solid lipids in the SLNs produced by the new method remain in supercooled liquid state. Nanoparticles prepared by the new method exhibit lower toxicity on L929 cells and have lower hemolytic potential than the formulations prepared by direct mixing of the components. The method can be used to prepare SLNs with controllable composition and small particle size below 100 nm. These SLNs are low toxic and can be used for drug delivery purposes. PMID- 27502406 TI - Growth Factor-Loaded Nano-niosomal Gel Formulation and Characterization. AB - Controlled delivery of signaling factors could be a great approach in the tissue engineering field. Nano-niosomal drug delivery systems offer numerous advantages for this purpose. The present study reports the formulation and evaluation of a growth factor (GF)-loaded nano-niosome-hydrogel composite for GF delivery to modulate cell behavior. Niosomes were prepared, using span 60 surfactant with cholesterol (CH) in diethyl ether solvent, by reverse-phase evaporation technique. Basic fibroblast growth factor (bFGF) and bovine serum albumin (BSA) were loaded simultaneously and the final suspension was embedded into agarose hydrogel. Particle size, vesicle morphology, protein entrapment efficiency (EE), and release profile were measured by dynamic light scattering (DLS) nanoparticle size analyzer, transmission electron microscopy (TEM) and NanoDrop spectrophotometry methods, respectively. The release and performance of bFGF were revealed via human umbilical vein endothelial cell (HUVEC) proliferation using microscopy imaging and MTT assay. Nano-niosomes had an average particle size of 232 nm and had encapsulated 58% of the total proteins present in the suspension. bFGF-BSA-loaded niosomal gel considerably enhanced HUVEC proliferation. This GF loaded niosomal hydrogel could be a potent material in many biomedical applications including the induction of angiogenesis in tissue engineering. PMID- 27502407 TI - Development of Microemulsion Delivery System of Essential Oil from Zingiber cassumunar Roxb. Rhizome for Improvement of Stability and Anti-Inflammatory Activity. AB - The present study aims to investigate the major constituents of the essential oil from Zingiber cassumunar rhizome (EO) and to develop microemulsions with enhanced chemical stability and anti-inflammatory activity of EO. The major constituents of EO were terpinen-4-ol (40.5 +/- 6.6%) and sabinene (17.4 +/- 1.4%) as determined by gas chromatography-mass spectrometry. These compounds were responsible for the anti-inflammatory activities of EO. Sabinene and terpinen-4 ol significantly reduced nuclear factor-kappa B (NF-kB) expression by 47 +/- 5 and 78 +/- 8%, respectively (p < 0.001) and significantly reduced the interleukin 6 (IL-6) secretion levels to 64 +/- 4% (p < 0.05) and 50 +/- 1% (p < 0.001), respectively. EO microemulsions, developed using the system of EO/Tween 20 and propylene glycol (2:1)/water, showed the internal droplet size in the range of 211.5 +/- 63.3 to 366.7 +/- 77.8 nm. Both EO and EO microemulsions were shown to be safe for human use since there was no apparent toxic effect on human peripheral blood mononuclear cells. Interestingly, EO microemulsion could significantly protect sabinene from the evaporation after heating-cooling stability test, which leads to a good stability and high efficacy. Moreover, EO microemulsions significantly enhanced the anti-inflammatory effect comparing to the native EO. Therefore, microemulsions were attractive delivery system for natural anti-inflammatory compounds since they could enhance both efficacy and stability of EO. PMID- 27502408 TI - Electronic data capture on athletes' pre-participation health and in-competition injury and illness at major sports championships: An extended usability study in Athletics. AB - This study set out to identify factors critical for the usability of electronic data collection in association with championships in individual sports. A qualitative analysis of electronic data collection system usability for collection of data on pre-participation health from athletes and in-competition injury and illness from team physicians was performed during the 2013 European Athletics Indoor Championships. A total of 15 athletes and team physicians participated. Athletes were found to experience few problems interacting with the electronic data collection system, but reported concerns about having to reflect on injury and illness before competitions and the medical terminology used. Team physicians encountered problems when first navigating through the module for clinical reporting, but they were not subjected to motivational problems. We conclude that athletes' motivation to self-report health data and the design of the human-computer interface for team physicians are key issues for the usability of electronic data collection systems in association with championships in individual sports. PMID- 27502409 TI - Neonatal encephalocardiomyopathy caused by mutations in VARS2. AB - VARS2 encodes a mitochondrial aminoacyl-tRNA-synthetase. Mutations in VARS2 have recently been identified as a cause of mitochondrial encephalomyopathy in three individuals. However, clinical information remained scarce. Exome sequencing lead us to identify compound heterozygous pathogenic VARS2 variants in a boy presenting with severe lactic acidosis, hypertrophic cardiomyopathy, epilepsy, and abnormalities on brain imaging including hypoplasia of corpus callosum and cerebellum as well as a massive lactate peak on MR-spectroscopy. Studies in patient-derived fibroblasts confirmed the functional relevance of the identified VARS2 variants. Our report expands the phenotypic spectrum associated with this rare mitochondrial defect, in that VARS2 deficiency may also cause severe neonatal presentations with cardiac involvement and structural brain abnormalities. PMID- 27502411 TI - Use of food labels by adolescents to make healthier choices on snacks: a cross sectional study from Sri Lanka. AB - BACKGROUND: Unhealthy snacking is commonly seen among adolescents. Therefore, use of food labels is promoted for making healthier choices on packaged snacks. This study was conducted to assess the use of food labels in making choices on packaged snack and its associated factors among adolescents. METHODS: A cross sectional study was conducted in 2012 among 542 Grade 12 students in Sri Lanka. Eight classes were selected as 'clusters' for the study (two classes each from two schools that were selected randomly from each list of 'Girls only' and 'Boys only' schools in Colombo district). A self-administered questionnaire assessed their socio-demography, snacking behaviour, attitudes and nutrition knowledge related to food labels. Adolescents' use of labels was assessed by three practices (label reading frequency, attention paid to label contents and correct interpretation of six hypothetical labels of snacks). Based on total scores obtained for the three practices, 'satisfactory' (score >=75(th) percentile mark) and 'unsatisfactory' (score <75(th) percentile mark) label users were identified. Using SPSS, associations were assessed at 0.05 significance level using Chi square-test. RESULTS: Of the participants, 51 % were males; 61 % spent their pocket money at least once/week on packaged snacks; predominantly on biscuits (85 %) and cola-drinks (77 %) and 88 % selected snacks on their own. The majority (74.5 %) was frequent ('always' or 'most often') label readers with female predominance (p < 0.05). Over 74 % paid attention frequently to the brand name (75 %), price (85 %) and nutrition panel (81 %). Over 64 % were able to select the better food label when given a choice between two snacks, although some did it for reasons such as attractive label (63 %). The majority (84 %) had good knowledge (obtaining more than the 75(th) percentile mark) on interpreting labels. Although not statistically significant, 'unsatisfactory' label use was higher among males (73 %), purchasing power (70.4 %) and unhealthy snacking behaviour (73 %). In contrast, among the marketing strategies, identifying known brands (73.2 %) and imported products (75.8 %) as 'good' products were significantly associated with 'unsatisfactory' label use (p < 0.05). CONCLUSIONS: Despite having good knowledge and positive attitudes, food label use is unsatisfactory among adolescents. Skills in reading labels should be addressed in the 'School canteen policy' in Sri Lanka. PMID- 27502410 TI - The serum zinc concentration as a potential biological marker in patients with major depressive disorder. AB - Despite many clinical trials assessing the role of zinc in major depressive disorder (MDD), the conclusions still remain ambiguous. The aim of the present clinical study was to determine and comparison the zinc concentration in the blood of MDD patients (active stage or remission) and healthy volunteers (controls), as well as to discuss its potential clinical usefulness as a biomarker of the disease. In this study 69 patients with current depressive episode, 45 patients in remission and 50 controls were enrolled. The zinc concentration was measured by electrothermal atomic absorption spectrometry (ET AAS). The obtained results revealed, that the zinc concentration in depressed phase were statistically lower than in the healthy volunteers [0.89 vs. 1.06 mg/L, respectively], while the zinc level in patients achieve remission was not significantly different from the controls [1.07 vs. 1.06 mg/L, respectively]. Additionally, among the patients achieve remission a significant differences in zinc concentration between group with and without presence of drug-resistance in the previous episode of depression were observed. Also, patients in remission demonstrated correlation between zinc level and the average number of depressive episodes in the last year. Serum zinc concentration was not dependent on atypical features of depression, presence of psychotic symptoms or melancholic syndrome, age, age of onset or duration of disease, number of episodes in the life time, duration of the episode/remission and severity of depression measured by the Hamilton Rating Scale for Depression (HDRS), and the Montgomery-Asberg Depression Rating Scale (MADRS). Concluding, our findings confirm the correlation between zinc deficit present in the depressive episode, and are consistent with the majority of previous studies. These results may also indicate that serum zinc concentration might be considered as a potential biological marker of MDD. PMID- 27502412 TI - Accumulation of Copper in Gill, Liver, Spleen, Kidney and Muscle Tissues of Clarias gariepinus Exposed to the Metal Singly and in Mixture with Chitosan. AB - Accumulation of copper (Cu), applied singly and in mixture with chitosan (CT), in gill, liver, spleen, kidney and muscle tissues of Clarias gariepinus was studied after exposing the fish to no Cu (control), 5 ppm Cu, 5 ppm Cu + 75 ppm CT mixture over 1, 7 and 15 days. Metal levels in tissues were determined using an ICP-AES spectrophotometer. No mortality was observed during the experiments. Highest accumulation of Cu was observed in liver while lowest accumulation was observed in muscle tissue. Exposure to Cu-CT mixture decreased Cu accumulation in liver at all exposure periods and in kidney on the 15th day compared to Cu alone. Exposure to Cu alone and Cu-CT mixture had no effect on Cu accumulation in spleen or muscle tissue. Copper accumulation increased in gill tissue compared to control when exposed to Cu alone at all exposure periods, and exposure to the Cu CT mixture significantly increased Cu accumulation in this tissue at all exposure periods compared to Cu alone. PMID- 27502413 TI - High-frequency rTMS on leg motor area in the early phase of stroke. AB - Although repetitive transcranial magnetic stimulation (rTMS) for upper limb motor area in stroke patients is beneficial, it has been poorly investigated in rTMS for leg motor area. Furthermore, no study has examined the usefulness of rTMS for leg motor area in patients in the early phase of stroke. Twenty-one patients with a hemispheric stroke lesion in the early phase were randomly assigned into two groups: the high-frequency (HF)-rTMS group [N = 11] and the sham stimulation group [N = 10]. Patients received rTMS for 5 consecutive days, beginning 10.9 +/- 6.6 days on average after the onset. Brunnstrom Recovery Stages (BRS) for the lower limbs and the Ability for Basic Movement Scale Revised (ABMS II) were assessed before and after the intervention. The improvement in BRS for the lower limbs was significant after the intervention in the HF-rTMS group. Although both the HF-rTMS and sham stimulation groups had significant improvements in ABMS II scores, the extent of improvement in the AMBS II was significantly greater in the HF-rTMS group than in the sham stimulation group. Application of HF-rTMS over the bilateral leg motor areas has potential to be a new rehabilitation therapy for patients in the acute phase of stroke. PMID- 27502414 TI - Recent advances on halohydrin dehalogenases-from enzyme identification to novel biocatalytic applications. AB - Halohydrin dehalogenases are industrially relevant enzymes that catalyze the reversible dehalogenation of vicinal haloalcohols with formation of the corresponding epoxides. In the reverse reaction, also other negatively charged nucleophiles such as azide, cyanide, or nitrite are accepted besides halides to open the epoxide ring. Thus, novel C-N, C-C, or C-O bonds can be formed by halohydrin dehalogenases, which makes them attractive biocatalysts for the production of various beta-substituted alcohols. Despite the fact that only five individual halohydrin dehalogenase enzyme sequences have been known until recently enabling their heterologous production, a large number of different biocatalytic applications have been reported using these enzymes. The recent characterization of specific sequence motifs has facilitated the identification of novel halohydrin dehalogenase sequences available in public databases and has largely increased the number of recombinantly available enzymes. These will help to extend the biocatalytic repertoire of this enzyme family and to foster novel biotechnological applications and developments in the future. This review gives a general overview on the halohydrin dehalogenase enzyme family and their biochemical properties and further focuses on recent developments in halohydrin dehalogenase biocatalysis and protein engineering. PMID- 27502415 TI - Antimicrobial properties and death-inducing mechanisms of saccharomycin, a biocide secreted by Saccharomyces cerevisiae. AB - We recently found that Saccharomyces cerevisiae (strain CCMI 885) secretes antimicrobial peptides (AMPs) derived from the glycolytic enzyme glyceraldehyde 3 phosphate dehydrogenase (GAPDH) that are active against various wine-related yeast and bacteria. Here, we show that several other S. cerevisiae strains also secrete natural biocide fractions during alcoholic fermentation, although at different levels, which correlates with the antagonistic effect exerted against non-Saccharomyces yeasts. We, therefore, term this biocide saccharomycin. The native AMPs were purified by gel-filtration chromatography and its antimicrobial activity was compared to that exhibited by chemically synthesized analogues (AMP1 and AMP2/3). Results show that the antimicrobial activity of the native AMPs is significantly higher than that of the synthetic analogues (AMP1 and AMP2/3), but a conjugated action of the two synthetic peptides is observed. Moreover, while the natural AMPs are active at pH 3.5, the synthetic peptides are not, since they are anionic and cannot dissolve at this acidic pH. These findings suggest that the molecular structure of the native biocide probably involves the formation of aggregates of several peptides that render them soluble under acidic conditions. The death mechanisms induced by the AMPs were also evaluated by means of epifluorescence microscopy-based methods. Sensitive yeast cells treated with the synthetic AMPs show cell membrane disruption, apoptotic molecular markers, and internalization of the AMPs. In conclusion, our work shows that saccharomycin is a natural biocide secreted by S. cerevisiae whose activity depends on the conjugated action of GAPDH-derived peptides. This study also reveals that S. cerevisiae secretes GAPDH-derived peptides as a strategy to combat other microbial species during alcoholic fermentations. PMID- 27502416 TI - Influence of cAMP receptor protein (CRP) on bacterial virulence and transcriptional regulation of allS by CRP in Klebsiella pneumoniae. AB - cAMP receptor protein (CRP) is one of the most important transcriptional regulators, which can regulate large quantities of operons in different bacteria. The gene allS was well-known as allantoin-utilizing capability and involving in bacterial virulence in Klebsiella pneumoniae (K. pneumoniae). The specific DNA recognition motif of transcription regulator CRP was found in allS promoter region. Therefore, this study is aimed to investigate the function of CRP on virulence and its transcriptional regulation mechanism to gene allS in K. pneumoniae. The wild-type (WT) K. pneumoniae NTUH-2044, crp knockout (Kp Deltacrp) and the complemented knockout (KpC-Deltacrp) strains were used to determine the function of crp gene. The lacZ fusion, qRT-PCR, electrophoretic mobility shift and DNase I footprinting assays were performed to study the transcriptional regulation of CRP on allS. The result showed a decreased virulence in crp knockout strain. Complement through supplementing crp fragment in expression plasmid partially restore virulence of knockout bacteria. The CRP could bind to the allS promoter-proximal region and the binding site was further refined to be located from 60bp to 94bp upstream of the allS promoter. Based on these results, we proposed that CRP is an essential virulence regulator and knock out of crp gene will result in reduced virulence in K. pneumoniae. In the meantime, the transcription of gene allS is positively regulated by CRP via directly binding to upstream of allS promoter. PMID- 27502417 TI - Intrinsic HER4/4ICD transcriptional activation domains are required for STAT5A activated gene expression. AB - The epidermal growth factor receptor family member HER4 undergoes proteolytic processing at the cell surface to release the HER4 intracellular domain (4ICD) nuclear protein. Interestingly, 4ICD directly interacts with STAT5 and functions as an obligate STAT5 nuclear chaperone. Once in the nucleus 4ICD binds with STAT5 at STAT5 target genes, dramatically potentiating STAT5 transcriptional activation. These observations raise the possibility that 4ICD directly coactivates STAT5 gene expression. Using both yeast and mammalian transactivation reporter assays, we performed truncations of 4ICD fused to a GAL4 DNA binding domain and identified two independent 4ICD transactivation domains located between residues 1022 and 1090 (TAD1) and 1192 and 1225 (TAD2). The ability of the 4ICD DNA binding domain fusions to transactivate reporter gene expression required deletion of the intrinsic tyrosine kinase domain. In addition, we identified the 4ICD carboxyl terminal TVV residues, a PDZ domain binding motif (PDZ-DBM), as a potent transcriptional repressor. The transactivation activity of the HER4 carboxyl terminal domain lacking the tyrosine kinase (CTD) was significantly lower than similar EGFR or HER2 CTD. However, deletion of the HER4 CTD PDZ-DBM enhanced HER4 CTD transactivation to levels equivalent to the EGFR and HER2 CTDs. To determine if 4ICD TAD1 and TAD2 have a physiologically relevant role in STAT5 transactivation, we coexpressed 4ICD or 4ICD lacking TAD2 or both TAD1 and TAD2 with STAT5 in a luciferase reporter assay. Our results demonstrate that each 4ICD TAD contributes additively to STAT5A transactivation and the ability of STAT5A to transactivate the beta-casein promoter requires the 4ICD TADs. Taken together, published data and our current results demonstrate that both 4ICD nuclear chaperone and intrinsic coactivation activities are essential for STAT5 regulated gene expression. PMID- 27502418 TI - Identification of AaCASPS7, an effector caspase in Aedes albopictus. AB - Aedes albopictus mosquito is a vector of various arboviruses and is becoming a significant threat to public health due to its rapid global expansion. Several reports suggest that apoptosis could be a factor limiting arbovirus infection in mosquitoes. Thus, it is significant to identify apoptosis pathway and study the correlation between apoptosis and virus infection in mosquitoes. Apoptosis is a type of programmed cell death that plays a vital role in immunity, development, and tissue homeostasis. Caspases are a family of conserved proteases playing important roles in apoptosis. In this study, we identified Aedes albopictus AaCASPS7, a caspase shared high identity with dipteran insect drICE orthologs. Phylogenetic analysis showed the closest relative of AaCASPS7 was Aedes aegypti AeCASPS7. AaCASPS7 displayed several features that were typical of an effector caspase and showed significant activity to effector caspase substrates. Aacasps7 transcripts were expressed ubiquitously in developmental and adult stages in Aedes albopictus mosquitoes. Transient expression of AaCASPS7 induced caspase dependent apoptosis in C6/36 cells. Taken together the above data, this study identified a novel caspase, AaCASPS7, which might function as an apoptotic caspase. Further study the function of AaCASPS7 would facilitate better understanding the apoptotic mechanism in Aedes albopictus mosquito. PMID- 27502419 TI - Response of the JAK-STAT signaling pathway to oxygen deprivation in the red eared slider turtle, Trachemys scripta elegans. AB - The red-eared slider turtle, Trachemys scripta elegans, is a model organism commonly used to study the environmental stress of anoxia. It exhibits multiple biochemical adaptations to ensure its survival during the winter months where quantities of oxygen are largely depleted. We proposed that JAK-STAT signaling would display stress responsive regulation to mediate the survival of the red eared slider turtle, Trachemys scripta elegans, during anoxic stress. Importantly, the JAK-STAT signaling pathway is involved in transmitting extracellular signals to the nucleus resulting in the expression of select genes that aid cell survival and growth. Immunoblotting was used to compare the relative phosphorylation levels of JAK proteins, STAT proteins, and two of its inhibitors, SOCS and PIAS, in response to anoxia. A clear activation of the JAK STAT pathway was observed in the liver tissue while no significant changes were found in the skeletal muscle. To further support our findings we also found an increase in mRNA transcripts of downstream targets of STATs, namely bcl-xL and bcl-2, using PCR analysis in the liver tissues. These findings suggest an important role for the JAK-STAT pathway in exhibiting natural anoxia tolerance by the red-eared slider turtle. PMID- 27502421 TI - Novel cellulose-collagen blend biofibers prepared from an amine/salt solvent system. AB - Cellulose/collagen biofibers were produced from ethylene diamine/potassium thiocyanate binary solvent system, with methanol as a coagulant. The dynamic viscosity of the solutions decreased with the gradual increase in the collagen content up to 40%. The elemental analysis showed incorporation of collagen into cellulose matrix, thereby demonstrating some degree of interaction with the cellulose matrix. The chemical and thermal analysis further revealed an intermolecular interaction between cellulose and the protein and improved thermal stability, respectively. Furthermore, the electron microscopy images mostly exhibited fibrillar morphology with no visible phase separation, indicating compatibility between the two phases. Moreover, biofibers containing higher cellulose content showed higher crystallinity, tensile, and birefringence properties of the composite fibers. PMID- 27502422 TI - Transubstantiating commercial mushroom market with ultrasonically ultrasized mushroom powders showcasing higher bioactivity. AB - Mushrooms that have been restricted to fresh markets have now entered commercial and pharmaceutical markets. However, not much research has been targeted on testing the efficiency of these commercialized mushroom powders or capsules. For the first time, efforts were made to study the bioactive properties and antimicrobial properties of four predominant mushroom capsules available for commercial purposes. Then, these commercial mushroom powders were downsized to ultrasized fine powders by sonication and then their properties were compared against the commercialized ones. The results indicated that the bioactive properties and the antioxidant properties of these powders when used as marketed capsules was very less. It was following ultrasonication assisted size reduction that the cumulative bioactivity related properties got accelerated. Micro size reduction of the mushroom powders lead to significant enhancement of antiviral properties compared to antibacterial and antifungal properties. This work demonstrates that commercialization of mushroom as powders could realize higher impact through sonication assisted ultrasizing and even nanosizing. PMID- 27502424 TI - Risk Factors and Outcome Analysis in Children with Carbon Monoxide Poisoning. AB - BACKGROUND: Carbon monoxide (CO) poisoning is one of the common causes of poisoning in patients and can result in significant morbidity and mortality. However, few studies have focused on the pediatric group. METHODS: We retrospectively reviewed children (age < 18 years) with CO poisoning from nonfire accidents at a tertiary medical center in Taiwan from 2002 to 2010. We analyzed the patients' characteristics, management, and outcome; compared the data of patients who received hyperbaric oxygen (HBO) to those who received normobaric oxygen (NBO) therapy; and identified the ri0sk factors for patients who developed delayed neurological sequelae (DNS) or permanent neurological sequelae (PNS). RESULTS: A total of 81 children were enrolled. The annual case number increased from five cases in 2002 to 20 in 2010, particularly during the cold months (December to February). The most common source of exposure was an indoor heating system (54.3%). The most common presenting symptoms were vomiting (32.1%) and consciousness changes (30.9%). HBO treatment tended to be administered to patients with a higher initial COHb (%) (p < 0.001), an initial Glasgow coma scale change (p < 0.001), and admission to the hospital (p = 0.002). After multivariate analysis, treatment in the intensive care unit because of prolonged loss of consciousness (p = 0.002) was the only independent risk factor for patients with DNS; only rescue by a ventilator (p < 0.001) was an independent risk factor for patients with PNS. In comparison to the NBO therapy, HBO treatment did not show benefit or harm to patients according to the incidence of inducing DNS or PNS after multivariate analysis. CONCLUSION: For those with treatment in the intensive care unit because of prolonged loss of consciousness and rescue by a ventilator, special attention should be given and follow-up should be performed to determine whether DNS or PNS occurs, particularly epilepsy and cognitive deficits. PMID- 27502420 TI - Nuclear retinoid receptors and pregnancy: placental transfer, functions, and pharmacological aspects. AB - Animal models of vitamin A (retinol) deficiency have highlighted its crucial role in reproduction and placentation, whereas an excess of retinoids (structurally or functionally related entities) can cause toxic and teratogenic effects in the embryo and foetus, especially in the first trimester of human pregnancy. Knock out experimental strategies-targeting retinoid nuclear receptors RARs and RXRs have confirmed that the effects of vitamin A are mediated by retinoic acid (especially all-trans retinoic acid) and that this vitamin is essential for the developmental process. All these data show that the vitamin A pathway and metabolism are as important for the well-being of the foetus, as they are for that of the adult. Accordingly, during this last decade, extensive research on retinoid metabolism has yielded detailed knowledge on all the actors in this pathway, spurring the development of antagonists and agonists for therapeutic and research applications. Natural and synthetic retinoids are currently used in clinical practice, most often on the skin for the treatment of acne, and as anti oncogenic agents in acute promyelocytic leukaemia. However, because of the toxicity and teratogenicity of retinoids during pregnancy, their pharmacological use needs a sound knowledge of their metabolism, molecular aspects, placental transfer, and action. PMID- 27502426 TI - A PROCESS OF PRIORITIZING TOPICS FOR HEALTH TECHNOLOGY ASSESSMENT IN KAZAKHSTAN. AB - OBJECTIVES: The aim of this study was to develop criteria for the prioritization of topics for health technology assessment (HTA) in the healthcare system of Kazakhstan. METHODS: Initial proposals for criteria were suggested through consultation with Ministry of Health (MoH) policy areas. These were refined through a workshop attended by HTA department staff, persons from medical universities and research institutes, and MoH policy makers. The workshop included discussion on methods used in international HTA practice. Opinions of participants on selection of criteria from those specified in a review of prioritization processes were used to define a list for inclusion in an instrument for routine use. A scoring system was established in later discussion. RESULTS: Selected criteria for HTA prioritization were burden of disease, availability of alternative technology, clinical effectiveness, economic efficiency, budget impact, and ethical, legal, and/or psychosocial aspects. For each criterion, a health technology under consideration is given a score from 3 (High) to 1 (Low). The total score determines whether the technology is of high to medium priority or of low priority. Determination of priorities for assessment, using the instrument, should be carried out by an expert group appointed by the MoH. The process was applied in 2014 to a selection of topics, and three health technologies were chosen for full assessments. CONCLUSIONS: Criteria for prioritization have evolved with development of the HTA program in Kazakhstan. A method for HTA prioritization has been developed that is easy to apply, requires comparatively few resources, and is compatible with processes required by the MoH. PMID- 27502425 TI - Olfactory perception of chemically diverse molecules. AB - BACKGROUND: Understanding the relationship between a stimulus and how it is perceived reveals fundamental principles about the mechanisms of sensory perception. While this stimulus-percept problem is mostly understood for color vision and tone perception, it is not currently possible to predict how a given molecule smells. While there has been some progress in predicting the pleasantness and intensity of an odorant, perceptual data for a larger number of diverse molecules are needed to improve current predictions. Towards this goal, we tested the olfactory perception of 480 structurally and perceptually diverse molecules at two concentrations using a panel of 55 healthy human subjects. RESULTS: For each stimulus, we collected data on perceived intensity, pleasantness, and familiarity. In addition, subjects were asked to apply 20 semantic odor quality descriptors to these stimuli, and were offered the option to describe the smell in their own words. Using this dataset, we replicated several previous correlations between molecular features of the stimulus and olfactory perception. The number of sulfur atoms in a molecule was correlated with the odor quality descriptors "garlic," "fish," and "decayed," and large and structurally complex molecules were perceived to be more pleasant. We discovered a number of correlations in intensity perception between molecules. We show that familiarity had a strong effect on the ability of subjects to describe a smell. Many subjects used commercial products to describe familiar odorants, highlighting the role of prior experience in verbal reports of olfactory perception. Nonspecific descriptors like "chemical" were applied frequently to unfamiliar odorants, and unfamiliar odorants were generally rated as neither pleasant nor unpleasant. CONCLUSIONS: We present a very large psychophysical dataset and use this to correlate molecular features of a stimulus to olfactory percept. Our work reveals robust correlations between molecular features and perceptual qualities, and highlights the dominant role of familiarity and experience in assigning verbal descriptors to odorants. PMID- 27502427 TI - Abnormal auditory pattern perception in schizophrenia. AB - Mismatch negativity (MMN) in response to deviation from physical sound parameters (e.g., pitch, duration) is reduced in individuals with long-term schizophrenia (Sz), suggesting deficits in deviance detection. However, MMN can appear at several time intervals as part of deviance detection. Understanding which part of the processing stream is abnormal in Sz is crucial for understanding MMN pathophysiology. We measured MMN to complex pattern deviants, which have been shown to produce multiple MMNs in healthy controls (HC). Both simple and complex MMNs were recorded from 27 Sz and 27 matched HC. For simple MMN, pitch- and duration-deviants were presented among frequent standard tones. For complex MMN, patterns of five single tones were repeatedly presented, with the occasional deviant group of tones containing an extra sixth tone. Sz showed smaller pitch MMN (p=0.009, ~110ms) and duration MMN (p=0.030, ~170ms) than healthy controls. For complex MMN, there were two deviance-related negativities. The first (~150ms) was not significantly different between HC and SZ. The second was significantly reduced in Sz (p=0.011, ~400ms). The topography of the late complex MMN was consistent with generators in anterior temporal cortex. Worse late MMN in Sz was associated with increased emotional withdrawal, poor attention, lack of spontaneity/conversation, and increased preoccupation. Late MMN blunting in schizophrenia suggests a deficit in later stages of deviance processing. Correlations with negative symptoms measures are preliminary, but suggest that abnormal complex auditory perceptual processes may compound higher-order cognitive and social deficits in the disorder. PMID- 27502428 TI - Targeted Anterior Gland Focal Therapy-a Novel Treatment Option for a Better Defined Disease. AB - The goal of focal therapy is to achieve long-term oncological control by eradicating only the clinically significant focus/foci of cancer within the prostate, while preserving erectile function and continence. Anterior prostate cancers may have a PZ or TZ origin and share commonalities in location and biology. While anterior prostate cancers previously constituted a diagnostic blind spot in the prostate and were often not detected or discovered late, with the rapid dissemination of advanced imaging and biopsy techniques, they can now be identified at an earlier, organ-confined stage due to MR imaging and targeted biopsies. Due to their anterior location, they represent a therapeutic target that allows for thorough ablation of the cancer focus/foci with an adequate margin while remaining far from the neurovascular bundles bilaterally. However, the TZ origin cancers are mostly anterior to the distal urethra close to the apex and the striated sphincter. Men having early stage anterior cancers may represent good candidates to achieve a balance between oncological control and functional preservation with focal therapy. Thus, this class of tumor based on location, along with the proposed treatment, represents a novel form of targeted image guided therapy. PMID- 27502430 TI - Rescuing neuronal cell death by RAIDD- and PIDD- derived peptides and its implications for therapeutic intervention in neurodegenerative diseases. AB - Caspase-2 is known to be involved in oxidative-stress mediated neuronal cell death. In this study, we demonstrated that rotenone-induced neuronal cell death is mediated by caspase-2 activation via PIDDosome formation. Our newly designed TAT-fused peptides, which contains wild-type helix number3 (H3) from RAIDD and PIDD, blocked the PIDDosome formation in vitro. Furthermore, peptides inhibited rotenone-induced caspase-2-dependent apoptosis in neuronal cells. These results suggest that PIDD- or RAIDD-targeted peptides might be effective at protecting against rotenone-induced neurotoxicity. Our peptides are novel neuronal cell apoptosis inhibitors that might serve as a prototype for development of drugs for the treatment of neurodegenerative diseases. PMID- 27502431 TI - Intensity-modulated radiotherapy for early glottic cancer: transition to a new standard of care? AB - For decades, the standard of care for radiation treatment of early larynx cancers has been conventional treatment using opposed lateral fields encompassing the larynx and overlying neck structures, including the adjacent carotid arteries. While intensity-modulated radiotherapy (IMRT) has replaced conventional radiotherapy for all other head/neck cancer situations, the use of IMRT to treat early glottic cancers remains controversial. The article reviews the published experience with IMRT for this clinical situation and provides a detailed review of the literature on radiation-induced carotid toxicity and how it might apply to the controversy. Finally, we discuss whether the radiation oncology community should transition to IMRT as a new standard of care for the treatment of early glottic cancers. PMID- 27502429 TI - Genetics of Male Infertility. AB - While 7 % of the men are infertile, currently, a genetic etiology is identified in less than 25 % of those men, and 30 % of the infertile men lack a definitive diagnosis, falling in the "idiopathic infertility" category. Advances in genetics and epigenetics have led to several proposed mechanisms for male infertility. These advances may result in new diagnostic tools, treatment approaches, and better counseling with regard to treatment options and prognosis. In this review, we focus on clinical aspects of male infertility and the role of genetics in elucidating etiologies and the potential of treatments. PMID- 27502432 TI - Long-term effectiveness and safety of once-daily, single-entity, extended-release hydrocodone in patients of >=75 years of age with moderate to severe nonmalignant and nonneuropathic pain. AB - In elderly (>=75 years) individuals, age-associated physiologic changes and a higher prevalence of comorbidities, polypharmacy, and increased susceptibility to medication-induced side effects complicate pain management. Hysingla(r) ER (HYD) is a once-daily, single-entity, extended-release hydrocodone formulation approved for the treatment of chronic pain that is insufficiently controlled by alternative treatments. In this post-hoc analysis of a previously reported study, the effectiveness and safety of HYD for the treatment of moderate-to-severe chronic pain among the elderly (>=75 years) for a 52-week duration was investigated. HYD dose administered during the maintenance period-remained relatively stable and provided clinically meaningful decreases in mean "pain over the last 24 h" and pain interference scores. Patients achieved pain control without additional non-study opioid use at the end of the study. Adverse events were typical of opioids. In summary, HYD provided clinically meaningful reduction of pain scores in elderly patients that were maintained over a 52-week period. PMID- 27502433 TI - Effect of long-term combined application of organic and inorganic fertilizers on soil nematode communities within aggregates. AB - A long-term fertilization experiment was conducted to examine the effects of different fertilization practices on nematode community composition within aggregates in a wheat-maize rotation system. The study was a randomized complete block design with three replicates. The experiment involved the following four treatments: no fertilizer, inorganic N, P and K fertilizer (NPK), NPK plus manure (NPKM) and NPK plus maize straw (NPKS). Soil samples were taken at 0-20 cm depth during the wheat harvest stage. Based on our results, NPKS contributed to soil aggregation and moisture retention, with a positive effect on soil total nitrogen accumulation, particularly within small macroaggregates (0.25-1 mm) and microaggregates (<0.25 mm). The C/N ratio was correlated to the distribution of the soil nematode community. Both manure application and straw incorporation increased the nematode functional metabolic footprints within all aggregates. Additionally, the functional metabolic footprints decreased with a decline in aggregate size. The accumulation of total nitrogen within <1 mm aggregates under NPKS might play a key role in maintaining the survival of soil nematodes. In our study, both crop straw incorporation and inorganic fertilizer application effectively improved soil physicochemical properties and were also beneficial for nematode survival within small aggregate size fractions. PMID- 27502434 TI - Partial redundancy and functional specialization of E-class SEPALLATA genes in an early-diverging eudicot. AB - Plant MADS-box genes have duplicated extensively, allegedly contributing to the immense diversity of floral form in angiosperms. In Arabidopsis thaliana (a core eudicot model plant), four SEPALLATA (SEP) genes comprise the E-class from the extended ABCE model of flower development. They are redundantly involved in the development of the four types of floral organs (sepals, petals, stamens and carpels) and in floral meristem determinacy. E-class genes have been examined in other core eudicots and monocots, but have been less investigated in non-core eudicots. Our goal was to functionally characterize the E-class genes in the early-diverging eudicot Thalictrum thalictroides (Ranunculaceae), whose flowers are apetalous. We identified four SEP orthologs, which when placed in a phylogenetic context, resulted from a major gene duplication event before the origin of angiosperms and a subsequent duplication at the origin of the Ranunculales. We used Virus-Induced Gene Silencing (VIGS) to down-regulate the three expressed paralogs individually and in combination to investigate their function and to determine the degree of conservation versus divergence of this important plant transcription factor. All loci were partially redundant in sepal and stamen identity and in promoting petaloidy of sepals, yet the SEP3 ortholog had a more pronounced role in carpel identity and development. The two other paralogs appear to have subfunctionalized in their cadastral roles to keep the boundaries between either sepal and stamen zones or stamen and carpel zones. Double knockdowns had enhanced phenotypes and the triple knockdown had an even more severe phenotype that included partial to complete homeotic conversion of stamens and carpels to sepaloid organs and green sepals, highlighting a role of E class genes in petaloidy of sepals in this species. While no floral meristem determinacy defects were observed, this could be due to residual amounts of gene expression in the VIGS experiments being sufficient to perform this function or to the masking role of a redundant gene. PMID- 27502435 TI - Functional constraints on SoxE proteins in neural crest development: The importance of differential expression for evolution of protein activity. AB - Vertebrate SoxE genes (Sox8, 9, and 10) are key regulators of neural crest cell (NCC) development. These genes arose by duplication from a single SoxE gene in the vertebrate ancestor. Although SoxE paralogs are coexpressed early in NCC development, later, Sox9 is restricted to skeletogenic lineages in the head, and Sox10 to non-skeletogenic NCC in the trunk and head. When this subfunctionalization evolved and its possible role in the evolution of the neural crest are unknown. Sea lampreys are basal vertebrates that also possess three SoxE genes, while only a single SoxE is present in the cephalochordate amphioxus. In order to address the functional divergence of SoxE genes, and to determine if differences in their biochemical functions may be linked to changes in neural crest developmental potential, we examined the ability of lamprey and amphioxus SoxE genes to regulate differentiation of NCC derivatives in zebrafish colourless (cls) mutants lacking expression of sox10. Our findings suggest that the proto vertebrate SoxE gene possessed both melanogenic and neurogenic capabilities prior to SoxE gene duplication. Following the agnathan-gnathostome split, lamprey SoxE1 and SoxE3 largely lost their melanogenic and/or enteric neurogenic properties, while gnathostome SoxE paralogs have retained functional conservation. We posit that this difference in protein subfunctionalization is a direct consequence of the independent regulation of SoxE paralog expression between the two lineages. Specifically, we propose that the overlapping expression of gnathostome SoxE paralogs in early neural crest largely constrained the function of gnathostome SoxE proteins. In contrast, the largely non-overlapping expression of lamprey SoxE paralogs allowed them to specialize with regard to their DNA-binding and/or protein interaction properties. Restriction of developmental potential among cranial and trunk neural crest in lampreys may be related to constraints on SoxE activity among duplicates, but such specialization does not appear to have occurred in gnathostomes. This highlights an important difference in the evolution of SoxE activity between these two divergent vertebrate lineages and provides insights for understanding how cell fate restriction in different NCC populations may be dependent on subfunctionalization among SoxE duplicates. PMID- 27502436 TI - Increased avidity for Dpp/BMP2 maintains the proliferation of progenitors-like cells in the Drosophila eye. AB - During organ development, the progenitor state is transient, and depends on specific combinations of transcription factors and extracellular signals. Not surprisingly, abnormal maintenance of progenitor transcription factors may lead to tissue overgrowth, and the concurrence of signals from the local environment is often critical to trigger this overgrowth. Therefore, identifying specific combinations of transcription factors/signals promoting -or opposing- proliferation in progenitors is essential to understand normal development and disease. We have investigated this issue using the Drosophila eye as model. Transcription factors hth and tsh are transiently expressed in eye progenitors causing the expansion of the progenitor pool. However, if their co-expression is maintained experimentally, cell proliferation continues and differentiation is halted. Here we show that Hth+Tsh-induced tissue overgrowth requires the BMP2 Dpp and the abnormal hyperactivation of its pathway. Rather than using autocrine Dpp expression, Hth+Tsh cells increase their avidity for Dpp, produced locally, by upregulating extracellular matrix components. During normal development, Dpp represses hth and tsh ensuring that the progenitor state is transient. However, cells in which Hth+Tsh expression is forcibly maintained use Dpp to enhance their proliferation. PMID- 27502437 TI - Quality of life in patients with skin tumors: the mediator role of body image and social support. AB - OBJECTIVE: This study analyzed the relationships between illness representations, psychological morbidity, family stress, and quality of life and whether these variables were mediated by body image and social support. METHODS: The sample consisted of 106 patients with skin tumors, who answered the following measures: Dermatology Life Quality Index, Illness Perception Questionnaire-Brief, Medical Outcomes Study Social Support Survey, Index of Family Relations, Hospital Anxiety and Depression Scales, and the Body Image Scale. RESULTS: Patients with poor quality of life showed more threatening cognitive and emotional illness representations, less perceived social support, higher psychological morbidity, and higher concern with body image. Body image mediated the relationship between cognitive and comprehension illness representations, family stress, psychological morbidity, and quality of life. Social support mediated the relationship between family stress/psychological morbidity and quality of life. CONCLUSIONS: Psychological intervention should focus on body image and social support, particularly in patients with melanoma, less disease duration, tumors in the face, head or neck, in an active professional status, and with lower education. PMID- 27502438 TI - Microfluidic blood plasma separation for medical diagnostics: is it worth it? AB - Circulating biomarkers are on the verge of becoming powerful diagnostic tools for various human diseases. However, the complex sample composition makes it difficult to detect biomarkers directly from blood at the bench or at the point of-care. Blood cells are often a source of variability of the biomarker signal. While the interference of hemoglobin is a long known source of variability, the release of nucleic acids and other cellular components from hemocytes is a new concern for measurement and detection of circulating extracellular markers. Research into miniaturised blood plasma separation has been thriving in the last 10 years (2006-2016). Most point-of-care systems need microscale blood plasma separation, but developed solutions differ in complexity and sample volume range. But could blood plasma separation be avoided completely? This focused review weights the advantages and limits of miniaturised blood plasma separation and highlights the most interesting advances in direct capture as well as smart blood plasma separation. PMID- 27502439 TI - Expression patterns of Ikaros family members during positive selection and lineage commitment of human thymocytes. AB - The Ikaros family of transcription factors is essential for normal T-cell development, but their expression pattern in human thymocytes remains poorly defined. Our goal is to determine how protein levels of Ikaros, Helios and Aiolos change as human thymocytes progress through the positive selection and lineage commitment stages. To accomplish this goal, we used multi-parameter flow cytometry to define the populations in which positive selection and lineage commitment are most likely to occur. After human thymocytes express CD3 and receive positive selection signals, the cells down-regulate expression of CD4 to become transitional single-positive (TSP) CD8+ thymocytes. At this stage, there was a transient increase in the Ikaros, Helios and Aiolos protein levels. After the TSP CD8+ developmental stage, some thymocytes re-express CD4 and become CD3hi double-positive thymocytes before down-regulating CD8 to become mature single positive CD4+ thymocytes. Except for regulatory T cells, Helios protein levels declined and Aiolos protein levels transiently increased during CD4+ T-cell maturation. For thymocytes progressing toward the CD8+ T-cell lineage, TSP CD8+ thymocytes increase their expression of CD3 and maintain high levels of Aiolos protein as the cells complete their maturation. In summary, we defined the TSP CD8+ developmental stage in human T-cell development and propose that this stage is where CD4/CD8 lineage commitment occurs. Ikaros, Helios and Aiolos each undergo a transient increase in protein levels at the TSP stage before diverging in their expression patterns at later stages. PMID- 27502440 TI - Pro-arrhythmogenic effects of CACNA1C G1911R mutation in human ventricular tachycardia: insights from cardiac multi-scale models. AB - Mutations in the CACNA1C gene are associated with ventricular tachycardia (VT). Although the CACNA1C mutations were well identified in patients with cardiac arrhythmias, mechanisms by which cardiac arrhythmias are generated in such genetic mutation conditions remain unclear. In this study, we identified a novel mechanism of VT resulted from enhanced repolarization dispersion which is a key factor for arrhythmias in the CACNA1C G1911R mutation using multi-scale computational models of the human ventricle. The increased calcium influx in the mutation prolonged action potential duration (APD), produced steepened action potential duration restitution (APDR) curves as well as augmented membrane potential differences among different cell types during repolarization, increasing transmural dispersion of repolarization (DOR) and the spatial and temporal heterogeneity of cardiac electrical activities. Consequentially, the vulnerability to unidirectional conduction block in response to a premature stimulus increased at tissue level in the G1911R mutation. The increased functional repolarization dispersion anchored reentrant excitation waves in tissue and organ models, facilitating the initiation and maintenance of VT due to less meandering rotor tip. Thus, the increased repolarization dispersion caused by the G1911R mutation is a primary factor that may primarily contribute to the genesis of cardiac arrhythmias in Timothy Syndrome. PMID- 27502442 TI - Effects of Carbon Content on the Electrochemical Performances of MoS2-C Nanocomposites for Li-Ion Batteries. AB - Molybdenum disulfide is popular for rechargeable batteries, especially in Li-ion batteries, because of its layered structure and relatively high specific capacity. In this paper, we report MoS2-C nanocomposites that are synthesized by a hydrothermal process, and their use as anode material for Li-ion batteries. Ascorbic acid is used as the carbon source, and the carbon contents can be tuned from 2.5 wt % to 16.2 wt %. With increasing of carbon content, the morphology of MoS2-C nanocomposites changes from nanoflowers to nanospheres, and the particle size is decreased from 200 to 60 nm. This change is caused by the chemical complex interaction of ascorbic acid. The MoS2-C nanocomposite with 8.4 wt % C features a high capacity of 970 mAh g(-1) and sustains a capacity retention ratio of nearly 100% after 100 cycles. When the current increases to 1000 mA g(-1), the capacity still reaches 730 mAh g(-1). The above manifests that the carbon coating layer does not only accelerate the charge transfer kinetics to supply quick discharging and charging, but also hold the integrity of the electrode materials as evidenced by the long cycling stability. Therefore, MoS2-based nanocomposites could be used as commercial anode materials in Li-ion batteries. PMID- 27502441 TI - MicroRNA-21 Mediates Angiotensin II-Induced Liver Fibrosis by Activating NLRP3 Inflammasome/IL-1beta Axis via Targeting Smad7 and Spry1. AB - AIMS: Angiotensin II (AngII), a vasoconstrictive peptide of the renin-angiotensin system (RAS), promotes hepatic fibrogenesis and induces microRNA-21(mir-21) expression. Angiotensin-(1-7) [Ang-(1-7)] is a peptide of the RAS, which attenuates liver fibrosis. Recently, it was reported that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome participated in liver fibrosis. However, it remains unclear how mir-21 mediates AngII-induced NLRP3 inflammasome activation. We investigate the role of AngII-induced mir-21 in the regulation of NLRP3 inflammasome/IL-1beta axis in liver fibrosis. RESULTS: In vivo, circulating mir-21 was upregulated in patients with liver fibrosis and was positively correlated with liver fibrosis and oxidation. Treatment with Ang-(1-7) inhibited mir-21, NLRP3 inflammasome, and liver fibrosis after bile duct ligation (BDL) or AngII infusion. Inhibition of mir-21 suppressed the Smad7/Smad2/3/NOX4, Spry1/ERK/NF-kappaB pathway, NLRP3 inflammasome, and liver fibrosis induced by AngII infusion. In vitro, AngII upregulated mir-21 expression via targeting Smad7 and Spry1 in primary hepatic stellate cells (HSCs). In contrast, Ang-(1-7) suppressed mir-21 expression and oxidation induced by AngII. Overexpression of mir-21 promoted oxidation, and collagen production enhanced the effect of AngII on NLRP3 inflammasome activation via the Spry1/ERK/NF-kappaB, Smad7/Smad2/3/NOX4 pathways. However, downregulation of mir-21 exerted the opposite effects. Innovation and Conclusions: Mir-21 mediates AngII-activated NLRP3 inflammasome and resultant HSC activation via targeting Spry1 and Smad7. Ang-(1-7) protected against BDL or AngII infusion-induced hepatic fibrosis and inhibited mir-21 expression. Antioxid. Redox Signal. 27, 1-20. PMID- 27502443 TI - Tacrolimus induced dermatophyte infection overlying a plaque morphea. PMID- 27502445 TI - High-efficiency sono-solar-induced degradation of organic dye by the piezophototronic/photocatalytic coupling effect of FeS/ZnO nanoarrays. AB - Highly-efficient sono-solar-induced degradation of organic dye by the piezophototronic/photocatalytic coupling effect of FeS/ZnO nanoarrays was achieved. A steel screen was used as the substrate for supporting FeS/ZnO nanoarrays, and the nanoarrays were vertically and uniformly grown on the substrate via a wet-chemical route. Under ultrasonic and solar irradiation, FeS/ZnO nanoarrays have high sono-photocatalytic activity for degrading methylene blue in water. The photogenerated carriers can be separated by a piezoelectric field and a built-in electric field, resulting in a low recombination rate and high photocatalytic efficiency. The piezophototronic and photocatalytic effects were coupled together. The experimental/theoretical data indicate that this novel wastewater treatment can co-use mechanical and solar energy in nature, and so is a promising technology for environment improvement. PMID- 27502444 TI - Breaking through the strength-ductility trade-off dilemma in an Al-Si-based casting alloy. AB - Al-Si-based casting alloys have a great potential in various industrial applications. Common strengthening strategies on these alloys are accompanied inevitably by sacrifice of ductility, known as strength-ductility trade-off dilemma. Here, we report a simple route by combining rapid solidification (RS) with a post-solidification heat treatment (PHT), i.e. a RS + PHT route, to break through this dilemma using a commercial Al-Si-based casting alloy (A356 alloy) as an example. It is shown that yield strength and elongation to failure of the RS + PHT processed alloy are elevated simultaneously by increasing the cooling rate upon RS, which are not influenced by subsequent T6 heat treatment. Breaking through the dilemma is attributed to the hierarchical microstructure formed by the RS + PHT route, i.e. highly dispersed nanoscale Si particles in Al dendrites and nanoscale Al particles decorated in eutectic Si. Simplicity of the RS + PHT route makes it being suitable for industrial scaling production. The strategy of engineering microstructures offers a general pathway in tailoring mechanical properties of other Al-Si-based alloys. Moreover, the remarkably enhanced ductility of A356 alloy not only permits strengthening further the material by work hardening but also enables possibly conventional solid-state forming of the material, thus extending the applications of such an alloy. PMID- 27502446 TI - Sultiame revisited: treatment of refractory absence seizures. AB - Sultiame is recommended for the treatment of benign epilepsy of childhood with centrotemporal spikes, electrical status epilepticus during slow-wave sleep, as well as other genetic (idiopathic) focal epilepsies. Sultiame is not traditionally considered a treatment choice for idiopathic generalised epilepsy, and it does not appear on the list of drugs recommended for treatment of absence seizures. We report the efficacy of sultiame in treating three children with drug resistant absence seizures and discuss the potential use of sultiame beyond the idiopathic focal epilepsies. PMID- 27502448 TI - Structural derivation of lipid A from Cronobacter sakazakii using tandem mass spectrometry. AB - RATIONALE: Cronobacter sakazakii is a Gram-negative opportunistic pathogen that can cause necrotizing enterocolitis, bacteremia, and meningitis. Lipid A, the glycolipid membrane anchor of lipopolysaccharide (LPS), is a potential virulence factor for C. sakazakii. Given the potential importance of this molecule in infection and virulence, structural characterization of lipid A was carried out. METHODS: The structural characterization of lipid A extracted from C. sakazakii was performed using electrospray ionization and collision-induced dissociation in a linear ion trap mass spectrometer. Specifically, for detailed structural characterization, hierarchical tandem mass spectrometry was performed on the dominant ions present in the precursor ion mass spectra. By comparing the C. sakazakii fragmentation pathways to those of the known structure of E. coli lipid A, a structure of C. sakazakii lipid A was derived. RESULTS: The precursor ion at m/z 1796 from C. sakazakii is produced from a lipid A molecule where the acyl chains between the 2'b (C14) and 3'b (C12) positions are reversed as compared to E. coli lipid A. Additionally, the precursor ion at m/z 1824 from C. sakazakii corresponds to an E. coli structure with the same acyl chain at the 2'b position (C14), but a longer acyl chain (C14) at the 3'b position versus m/z 1796. CONCLUSIONS: Two lipid A structures were derived for the C. sakazakii ions at m/z 1796 and 1824. They differed in composition at the 2'b and 3'b acyl chain substituents, which may be a result of differences in substrate specificity of the two lipid A acyl chain transferases: LpxL and LpxM. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27502449 TI - Preexisting cognitive impairment in intracerebral hemorrhage. AB - OBJECTIVES: Preexisting cognitive impairment is a predictor of cognitive decline after ischemic stroke, but evidence in intracerebral hemorrhage (ICH) is limited. We aimed to determine the prevalence of premorbid cognitive impairment in patients with ICH. MATERIALS AND METHODS: We included patients with acute ICH. Pre-ICH cognitive impairment was determined based on the results of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) that uses information from close relatives. Patients were assessed as having been cognitively impaired with an IQCODE score of >=3.44; an IQCODE >=4.00 indicated pre-ICH dementia. CT and MRI images were reviewed to determine the extent of white matter lesions and to measure the radial width of the temporal horn as marker of brain atrophy. We investigated differences of cardiovascular risk factors and imaging data between patients with and without pre-ICH cognitive impairment using correlation analyses, uni- and multivariable regression models. Functional neurological state was assessed using the modified Rankin Scale (mRS). The mRS was dichotomized at the level of 3, and a premorbid mRS of 0-2 was considered as functional independency. RESULTS: Among the 89 participants, median age was 70 years (interquartile range 58-78) and 52 (58.4%) were male. IQCODE indicated pre-ICH cognitive impairment in 18.0% (16 of 89), and 83.1% were functionally independent before ICH. Cognitive impairment was associated with a premorbid mRS>=3 (chi squared test, P=0.009). In multivariable analysis, prior stroke/transient ischemic attack (OR 18.29, 95%-CI 1.945-172.033, P=.011) and hematoma volume (OR 0.90, 95%-CI 0.812-0.991, P=.033) were independently associated with pre-ICH cognitive impairment. CONCLUSIONS: In conclusion, cognitive impairment frequently precedes ICH. A higher frequency of cerebrovascular events suggests a role of vascular processes in the development of cognitive impairment before ICH. PMID- 27502450 TI - Spontaneous Reversion of Mild Cognitive Impairment to Normal Cognition: A Systematic Review of Literature and Meta-Analysis. AB - OBJECTIVES: The issue of subjects with mild cognitive impairment (MCI) reverting to normal cognition (NC) has to date been taken in limited consideration, and no conclusive data are available on the rate of reversion. We aimed at systematically reviewing available longitudinal studies on MCI and meta-analyzing data with the purpose of estimating the proportion of subjects reverting to NC. DESIGN: We performed a systematic bibliographic search on PubMed, the Cochrane Library, and the ISI Web of Science databases. We included in the review all longitudinal studies on MCI published from 1999 up to November 2015. Only studies with a longitudinal design, a follow-up >=2 years, enrolling subjects with MCI, and reporting the number or the percentage of subjects reverting to NC were included. Data extraction was performed independently by 2 authors. The methodological quality of studies was also assessed by 2 independent authors using the QUIPS tool. RESULTS: Twenty-five studies were included. The quality of evidence was found to be moderate. We observed an overall 18% (95% CI 14-22) reversion rate from MCI to NC. Results from the metaregression showed a significant association between effect size and study setting. In particular, estimates significantly varied according to study setting, with an 8% (95% CI 4 11) reversion rate in clinical-based studies and a 25% (95% CI 19-30) rate in population-based studies. The frequency of reversion from MCI to NC further increased to 26% when considering only studies of better quality. Only a few studies were designed to specifically investigate the reversion from MCI to NC, thus relevant information on this topic was frequently missing. CONCLUSION: Our data confirm that reversion to normality is a common outcome in subjects with MCI, thus leading to recommend a more balanced view when approaching the construct of MCI both in a clinical and in a research setting. PMID- 27502451 TI - Subclinical Mood and Cognition Impairments and Blood Pressure Control in a Large Cohort of Elderly Hypertensives. AB - BACKGROUND: Blood pressure (BP) control in the elderly is often limited by poor compliance with prescribed regimen. Both can be influenced by clinical cognitive or mood impairments; however, the impact of subclinical alterations of cognition or mood remains unknown. OBJECTIVES: To assess the relation between cognition, mood, and BP control in treated older hypertensive patients. DESIGN: Cross sectional association study. SETTING: Predefined substudy to the POLFOKUS nationwide survey investigating the correlates of poor BP control in patients randomly drawn from primary and specialist practices across Poland. PARTICIPANTS: 1988 outpatients >=65 years of age treated for hypertension for at least 1 year. MEASUREMENTS: BP was mean of at least 2 office measurements. We assessed adherence to antihypertensive medications using a questionnaire and performed screening tests for cognitive deficits [Abbreviated Mental Test Score (AMTS)] and mood disorders [Geriatric Depression Scale (GDS)]. In all patients, we used a unified (BP <140/90 mm Hg) and in >=80 years old a unified or age-specific (<150 mm Hg systolic BP) definition of BP control. We fitted logistic regression models to assess the probability of poor BP control in association with cognitive and mood disturbances. RESULTS: The mean [standard deviation (SD)] age of 1988 (65.6% women) patients was 73.9 (6.0) years (19.3% >=80 years old). Cognitive and mood impairments were observed in 8.0% and 37.2%, respectively. Mean systolic and diastolic BP were 141.8 (16.4) and 83.6 (9.5) mm Hg, respectively. According to age-stratified and unified definition of proper BP control, goal BP was achieved in 65.4% and 38.5% patients >=80 years of age, respectively. In younger patients, the control reached 46%. Globally, 66% patients adhered to antihypertensive medications. Poor compliance was related to cognitive and mood impairments. When unified goal was applied, there was a 15.0% higher risk of finding poor BP control per 1 score lost in AMTS and an 8.0% increase per 1 score gained in GDS (all P < .001). CONCLUSION: Poorer BP control is related to subclinical worsening of cognition and mood, which supports widespread use of the Comprehensive Geriatric Assessment even in apparently self-dependent older patients with hypertension. PMID- 27502452 TI - Ten-year hard and soft tissue results of a pilot double-blinded randomized controlled trial on immediately loaded post-extractive implants using platform switching concept. AB - AIM: To evaluate the 10-year post-loading radiological and esthetic outcomes of implants inserted in post-extraction sites and restored with or without platform switching protocol. MATERIAL AND METHODS: Twenty-two patients were scheduled for maxillary post-extractive implant, using a 13 mm in length and 5.5 mm in diameter implant (Global, Sweden & Martina, Padua, Italy). They randomly received definitive restorations using platform-switching concept (abutment 3.8 mm in diameter: test group) or standard restoration (abutment 5.5 mm in diameter: control group). Outcome measures were survival rates of implants and prostheses, peri-implant marginal bone loss and periodontal indices 10 years after prosthetic loading. Moreover, esthetic parameters including soft tissue buccal peri-implant mucosal levels (REC) and mesial and distal papilla height (PH) were taken at definitive restoration, 2 and 10 years thereafter. RESULTS: Nineteen implants were analyzed after 10 years of follow-up. No implants nor prostheses failed. The postoperative radiographs demonstrated an overall mean bone loss of 0.18 +/- 0.14 mm in the test group and of 0.80 +/- 0.40 mm in the control group (P = 0.00108). Test group showed 0.23 +/- 0.51 mm of REC gain and PH was of 0.21 +/- 0.33 mm on average. On the other side, the control group presented a REC = -0.59 +/- 0.80 mm with PH = -1.12 +/- 0.55 mm, demonstrating a slight continuous soft tissue shrinkage during the entire follow-up. The mean values were statistically significant different between test and control group for both REC gain (P = 0.01174) and PH (P = 0.0009). CONCLUSIONS: With the limitations of this study, immediate single implant restorations rehabilitated with platform-switching protocol may provide peri-implant alveolar bone-level stability and avoid continuous soft tissue shrinkage after 10 years of prosthetic loading compared to a platform-matching restoration. Further studies involving larger sample sizes are required to confirm these preliminary results. PMID- 27502453 TI - Beyond the known functions of the CCR4-NOT complex in gene expression regulatory mechanisms: New structural insights to unravel CCR4-NOT mRNA processing machinery. AB - Large protein assemblies are usually the effectors of major cellular processes. The intricate cell homeostasis network is divided into numerous interconnected pathways, each controlled by a set of protein machines. One of these master regulators is the CCR4-NOT complex, which ultimately controls protein expression levels. This multisubunit complex assembles around a scaffold platform, which enables a wide variety of well-studied functions from mRNA synthesis to transcript decay, as well as other tasks still being identified. Solving the structure of the entire CCR4-NOT complex will help to define the distribution of its functions. The recently published three-dimensional reconstruction of the complex, in combination with the known crystal structures of some of the components, has begun to address this. Methodological improvements in structural biology, especially in cryoelectron microscopy, encourage further structural and protein-protein interaction studies, which will advance our comprehension of the gene expression machinery. PMID- 27502454 TI - Plasmonic nanoparticles tuned thermal sensitive photonic polymer for biomimetic chameleon. AB - Among many thermo-photochromic materials, the color-changing behavior caused by temperature and light is usually lack of a full color response. And the study on visible light-stimuli chromic response is rarely reported. Here, we proposed a strategy to design a thermo-photochromic chameleon biomimetic material consisting of photonic poly(N-isopropylacrylamide-co-methacrylic acid) copolymer and plasmonic nanoparticles which has a vivid color change triggered by temperature and light like chameleons. We make use of the plasmonic nanoparticles like gold nanoparticles and silver nanoparticles to increase the sensitivity of the responsive behavior and control the lower critical solution temperature of the thermosensitive films by tuning the polymer chain conformation transition. Finally, it is possible that this film would have colorimetric responses to the entire VIS spectrum by the addition of different plasmonic nanoparticles to tune the plasmonic excitation wavelength. As a result, this method provides a potential use in new biosensors, military and many other aspects. PMID- 27502455 TI - A self-sufficient system for removal of synthetic dye by coupling of spore displayed triphenylmethane reductase and glucose 1-dehydrogenase. AB - Biodegradation of triphenylmethane dyes by microorganisms is hampered by the transport barrier imposed by cell membranes. On the other hand, cell-free systems using enzyme-based biodegradation strategy are costly. Therefore, an efficient and inexpensive approach circumventing these problems is highly desirable. Here, we constructed a self-sufficient system for synthetic dye removal by coupling of spore surface-displayed triphenylmethane reductase (TMR) and glucose 1 dehydrogenase (GDH) for the first time. Display of both TMR and GDH significantly enhanced their stability under conditions of extreme pH and temperature. These engineered spores also exhibited more robust long-term stability than their purified counterparts. Furthermore, we observed that a high ratio of spore displayed GDH is necessary for high dye degradation efficiency. These results indicate that this continuous dye removal system with cofactor regeneration offers a promising solution for dye biodegradation applications. PMID- 27502456 TI - Particle- and gas-phase PAHs toxicity equivalency quantity emitted by a non-road diesel engine with non-thermal plasma technology. AB - Polycyclic aromatic hydrocarbon (PAH) toxicity equivalency quantity (TEQ, denoted by benzo(a)pyrene equivalent (BaPeq) concentration) is more meaningful when evaluating the influence of non-road diesel engines PAH toxicity on environment. Particle- and gas-phase PAH BaPeq concentrations were calculated based on gas chromatography-mass spectrometer (GC-MS) results and toxic equivalency factors. A non-thermal plasma (NTP) reactor was applied to a non-road diesel engine to decrease PAH TEQ content. Only the gas-phase Nap BaPeq concentration increased slightly with the action of NTP at three different generator power outputs. BaP dominated the BaPeq concentration for 15 samples with, and without NTP except in the gas-phase at 4 kW. Almost all medium molecular weight (MMW) and high molecular weight (HMW) PAH TEQs increased for particle- and gas-phases at 3 kW power output compared to 2 kW without the use of NTP. Particle-phase Nap, Acp, and AcPy (low molecular weight, LMW) TEQ were under detection at 3 and 4 kW, while gas-phase BkF, IND, DBA, and BghiP (HMW) concentrations were below the limits of detection. The most abundant PAH TEQ compounds were MMW and HMW PAHs for gas- and particle-phase while they were BaA, CHR, BbF, BaP, and IND for PM aggregation. The total BaPeq emission factors were 15.1, 141.4, and 46.5 MUg m( 3) at three engine loads, respectively. Significant BaPeq concentration percentage reduction was obtained (more than 80 and 60 %) with the use of NTP for particle- and gas-phases. A high TEQ content was observed for PM aggregation (38.8, 98.4, and 50.0 MUg kg(-1)) which may have caused secondary PAH toxicity emissions. With the action of NTP, the breakup of MMW and HMW into LMW PAHs led to reduction of some PAH concentrations. PMID- 27502457 TI - Aseptic hydroponics to assess rhamnolipid-Cd and rhamnolipid-Zn bioavailability for sunflower (Helianthus annuus): a phytoextraction mechanism study. AB - The availability of cadmium (Cd) and zinc (Zn) to sunflower (Helianthus annuus) was investigated in rhamnolipid- and ethylenediaminetetraacetic acid (EDTA) buffered solutions in order to evaluate the influence of aqueous speciation of the metals on their uptake by the plant, in relation to predictions of uptake by the free ion activity model (FIAM). Free metal ion activity was estimated using the chemical equilibrium program MINTEQ or measured by Donnan dialysis. The uptake of Cd followed the FIAM for the EDTA-buffered solution at EDTA concentrations below 0.4 MUM; for the rhamnolipid-buffered solution, the uptake of both metals in roots was not markedly affected by increasing rhamnolipid concentrations in solution. This suggests rhamnolipid enhanced metal accumulation in plant roots (per unit free metal in solution) possibly through formation and uptake of lipophilic complexes. The addition of normal Ca concentrations (low millimetre range) to the rhamnolipid uptake solutions reduced Cd accumulation in shoots by inhibiting Cd translocation, whereas it significantly increased Zn accumulation in shoots. This study confirms that although rhamnolipid could enhance accumulation of Cd in plants roots at low Ca supply, it is not suitable for Cd phytoextraction in contaminated soil environments where Ca concentrations in soil solution are orders of magnitude greater than those of Cd. PMID- 27502458 TI - Evaluating the dynamical characteristics of particle matter emissions in an open ore yard with industrial operation activities. AB - A study to investigate the dynamical characteristics of particle matter emissions in a working open yard is conducted in Caofeidian Port of Hebei Province, China. The average diurnal concentrations of the total suspended particulate (TSP) matter and respirable particulate matter (PM10 and PM5) are monitored during the field measurement campaign. Sampling is performed at a regular interval at 8 monitoring stations in the yard with normal industrial activities. The average TSP, PM10 and PM5 concentrations range from 285 to 568, 198 to 423 and 189 to 330 MUg.m-3 in the yard, respectively. The linear regression correlation coefficient of TSP/PM10 and TSP/PM5 is 0.95+/-0.01 and 0.88+/-0.02, respectively.By using the Spearman correlation method, the wind speed and relative humidity are both weakly correlated with the PM10 and PM5 concentrations according to the measurements. In addition, industrial operation activities, such as vehicular traffic in the yard and the loading time of stackers, are significantly positively correlated with the PM concentration. Using the multivariate regression method, the main parameters influencing the TSP concentration variations are integratedly analysed. The traffic volume is found to be a significant predictor of TSP concentration variation, with the smallest P value (P<0.05).To understand the dynamical characteristics of particle emissions in the yard, the emissions from the truck transports, that is, from unpaved haul roads and from the loading process, are established. Then, the dynamical emission factor (EFD) based on the industrial activities in the yard is proposed. The dynamical emissions average 5.25x105 kg.year-1 and EFD is evaluated to be 0.29 kg.(ton.day)-1 during the measurement period. These outcomes have meaningful implications not only for understanding the dynamical characteristics of particle emissions in the working stockyard but also for implementing effective control measures at appropriate sites in the harbour area. PMID- 27502459 TI - Thermodynamic entropy of organic oxidation in the water environment: experimental evaluation compared to semi-empirical calculation. AB - Residual organic matters in the secondary effluent are usually less biodegradable in terms of the total organic carbon content, and when discharged into a receiving water body, their further decomposition most likely mainly occurs due to chemical oxidation. Using this scenario, a semi-empirical method was previously developed to calculate the thermodynamic entropy of organic oxidation to quantitatively evaluate the impact of organic discharge on the water environment. In this study, the relationship between the entropy increase (DeltaSC) and excess organic mass (DeltaTOC) was experimentally verified via combustion heat measurement using typical organic chemicals and mixtures. For individual organic chemicals, a linear relationship was detected between DeltaSC and DeltaTOC with the same proportionality coefficient, 54.0 kJ/g, determined in the previous semi-empirical relationship. For the organic mixtures, a linear relationship was also identified; however, the proportionality coefficient was 69.2 kJ/g, indicating an approximately 28 % increase in the oxidation heat required to decompose the same organic mass. This increase in energy can likely be attributed to the synergistic effects of hydrogen bonding, hydrophobic interactions, pi-pi interactions, and van der Waals interactions between functional groups of different organic compounds. Intermolecular interactions may result in 17-32 % more dissociation energy for organic mixtures compared to the organic components' chemical structures. Because organics discharged into a water body are always a mixture of organic compounds, the proportionality coefficient obtained using organic mixtures should be adopted to modify the previously proposed semi-empirical equation. PMID- 27502460 TI - Catalytic ozonation of sulfamethoxazole by composite iron-manganese silicate oxide: cooperation mechanism between adsorption and catalytic reaction. AB - A systematic investigation of the cooperation mechanism between adsorption and catalytic reaction during the catalytic ozonation of sulfamethoxazole (SMX) by composite iron-manganese silicate oxide (FMSO) was carried out in this work. Results showed that the total organic carbon (TOC) removal increased significantly from 27 % (sole-ozonation) to 79.8 % (FMSO catalytic ozonation). The presence of FMSO in the ozonation process effectively enhanced the ozone utilization efficiency and accelerated the transformation of ozone into hydroxyl radicals. The latter result was verified by the indirect method, using NaHSO3 as the reductor, and the direct electron spin resonance (ESR) determination technology. The adsorption of SMX on FMSO was minimal (1.8 %). However, ozone rapidly converted SMX into various intermediates, which was exhibited by the much higher adsorption affinity on the surface of FMSO than that of SMX. The accumulation of various intermediates on the FMSO surface also increased their contact probability with the .OH radicals generated by the ozone decomposition. The continuous interaction of intermediates with .OH radicals could further promote the benign cycling of the release of adsorption sites and the succeeding adsorption/decomposition of ozone and intermediates on FMSO. This could be another reason for the higher and faster TOC removal rate. PMID- 27502461 TI - The significance of cell-related challenges in the clinical application of tissue engineering. AB - Tissue engineering is increasingly being recognized as a new approach that could alleviate the burden of tissue damage currently managed with transplants or synthetic devices. Making this novel approach available in the future for patients who would potentially benefit is largely dependent on understanding and addressing all those factors that impede the translation of this technology to the clinic. Cell-associated factors in particular raise many challenges, including those related to cell sources, up- and downstream techniques, preservation, and the creation of in vitro microenvironments that enable cells to grow and function as far as possible as they would in vivo. This article highlights the main confounding issues associated with cells in tissue engineering and how these issues may hinder the advancement of therapeutic tissue engineering. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3157-3163, 2016. PMID- 27502462 TI - 55-Year-Old Woman With Recurrent Syncope. PMID- 27502463 TI - Murder Liability for Prescribing Opioids: A Way Forward? PMID- 27502464 TI - 46-Year-Old Man With Jaundice and Hypoxemia. PMID- 27502465 TI - Survival predictors in patients with prostate adenocarcinoma with hormonal blockade. AB - Ki-67 index and clinical-pathological factors such as the Gleason score and the presence of neuroendocrine differentiation have been used for predicting survival in patients with prostate cancer. We examined prostate tissue from 45 patients with advanced prostate cancer who were treated with maximal androgen blockade and analysed their cancer-specific survival (CSS). We assessed the Gleason index, performed an immunohistochemical analysis of Ki-67 (MIB-1) and determined the presence of neuroendocrine differentiation (chromogranin A). A survival study was conducted using Kaplan-Meier curves (log-rank test) and a Cox regression analysis. Twenty-four patients (53.3%) died from the disease, with a mean follow up of 68.7+/-7.7 months (56.6% CSS at 5 years and 31.8% at 10 years). In the univariate analysis, survival was associated with an interquartile distribution of Ki-67 (0-5, 6-12%, 13-25%, >25%; log-rank, p=0.01), Gleason 5 (total index 9 10; log-rank, p=0.002) and the presence of metastases during the diagnosis (M1; log-rank, p=0.004) but not to cT category (T3-T4; log-rank, p=0.26) or neuroendocrine differentiation (immunohistochemically positive tumour cell nests; log-rank, p=0.46). The multivariate analysis revealed that a Ki-67 index <=12% (HR, 0.22; p=0.0009) and the absence of metastases (M0) during diagnosis (HR, 0.17; p=0.0002) were protective factors in this population. In conclusion, Ki-67 proliferation index and the lack of metastases at diagnosis predict CSS in patients with advanced prostate cancer who undergo hormonal blockade. Neuroendocrine differentiation in tumour tissue had no prognostic value in this study. PMID- 27502466 TI - Cutaneous syncytial myoepithelioma:: Clinico-pathological features and differential diagnosis. AB - Cutaneous syncytial myoepithelioma (CSM) is a very rare tumor belonging to the spectrum of skin myoepithelial lesions. CSM usually affects the upper extremities of young to middle aged patients and is characterized by peculiar morphological and immunohistochemical features. Unlike classic myoepithelioma, CSM is composed by a densely packed proliferation of spindled to histiocytoid cells, which are variably positive for EMA, S100, SMA, and frequently negative for cytokeratins and GFAP. The peculiar histopathology and the extreme rarity of such lesion (less than 40 cases reported in the literature) can make the diagnosis of CSM a true challenge. In the present case, we report the clinico-pathological features of a primary CSM occurring in a 38 year-old Caucasian man. The differential diagnoses of such lesion are also briefly discussed. PMID- 27502468 TI - IL-22/IL-22R1 signaling regulates the pathophysiology of chronic rhinosinusitis with nasal polyps via alteration of MUC1 expression. AB - BACKGROUND: IL-22 is an IL-10-family cytokine that regulates chronic inflammation. We investigated the role of IL-22 and its receptor, IL-22R1, in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: IL 22 and IL-22R1 protein and mRNA expression in NP and in uncinate tissues (UT) from CRS and non-CRS patients was examined using immunohistochemistry and real time PCR, respectively. Dispersed NP and UT cells were cultured with the Staphylococcus aureus exotoxins, staphylococcal enterotoxin B and alpha-toxin, following which exotoxin-induced IL-22 levels and their association with clinicopathological factors were analyzed. Effects of IL-22 on MUC1 expression and cytokine release in NP cells were also determined. RESULTS: IL-22 and IL-22R1 in NP were mainly expressed in infiltrating inflammatory cells and in epithelial cells, respectively. IL-22 mRNA levels in NP were significantly higher than those in UTs from non-CRS patients whereas IL-22R1 levels were conversely lower in NPs. NP cells produced substantial amounts of IL-22 in response to exotoxins. Exotoxin induced IL-22 production by NP cells significantly and negatively correlated with the degree of local eosinophilia and postoperative computed tomography (CT) score, whereas conversely it positively correlated with the forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) ratio. IL-22 significantly enhanced MUC1 mRNA expression in NP cells. IL-22-induced MUC1 mRNA levels were significantly and positively correlated with IL-22R1 mRNA levels in NPs. CONCLUSIONS: These data suggest that imbalance of IL-22/IL-22R1 signaling regulates the pathogenesis of CRSwNP, including local eosinophilia, via alteration of MUC1 expression. PMID- 27502469 TI - Validation of an algorithm to predict reulceration in amputation patients with diabetes. AB - The aim of this article was to assess the ability to predict reulceration in people with diabetes and a history of minor amputation according to the formula proposed by Miller et al. A retrospective study was performed on 156 consecutive records of patients with a recent history of simple or multiple forefoot amputation. The sample was divided according to Miller's formula into patients at low risk of reulceration and those at high risk; those were further divided into two subgroups according to whether or not the first segment of the forefoot had been amputated. Forty-eight (47.1%) individuals suffered forefoot reulceration, showing a median reulceration-free survival time of 8 months [interquartile range (IR) 3.6-14.8]. Nephropathy (P = 0.005) and Miller's formula (P = 0.028) were risk factors for reulceration-free survival time in the univariate analysis. The pattern relating to the first segment amputated [hazard ratio (HR) 2.853; P = 0.004; 95% confidence interval (CI) 1.391-5.849] and nephropathy (HR 2.468; P = 0.004; 95% CI 1.328-4.587) showed a significant hazard ratio in the multivariate Cox model. Participants with first segment amputation and one other amputation showed an association with the probability of reulceration in comparison with any other specific type of minor amputation. PMID- 27502470 TI - The relative contributions of store-operated and voltage-gated Ca2+ channels to the control of Ca2+ oscillations in airway smooth muscle. AB - KEY POINTS: Agonist-dependent oscillations in the concentration of free cytosolic calcium are a vital mechanism for the control of airway smooth muscle contraction and thus are a critical factor in airway hyper-responsiveness. Using a mathematical model, closely tied to experimental work, we show that the oscillations in membrane potential accompanying the calcium oscillations have no significant effect on the properties of the calcium oscillations. In addition, the model shows that calcium entry through store-operated calcium channels is critical for calcium oscillations, but calcium entry through voltage-gated channels has much less effect. The model predicts that voltage-gated channels are less important than store-operated channels in the control of airway smooth muscle tone. ABSTRACT: Airway smooth muscle contraction is typically the key mechanism underlying airway hyper-responsiveness, and the strength of muscle contraction is determined by the frequency of oscillations of intracellular calcium (Ca2+ ) concentration. In airway smooth muscle cells, these Ca2+ oscillations are caused by cyclic Ca2+ release from the sarcoplasmic reticulum, although Ca2+ influx via plasma membrane channels is also necessary to sustain the oscillations over longer times. To assess the relative contributions of store operated and voltage-gated Ca2+ channels to this Ca2+ influx, we generated a comprehensive mathematical model, based on experimental Ca2+ measurements in mouse precision-cut lung slices, to simulate Ca2+ oscillations and changes in membrane potential. Agonist-induced Ca2+ oscillations are accompanied by oscillations in membrane potential, although the membrane potential oscillations are too small to generate large Ca2+ currents through voltage-gated Ca2+ channels, and thus have little effect on the Ca2+ oscillations. Ca2+ entry through voltage-gated channels only becomes important when the cell is depolarized (e.g. by a high external K+ concentration). As a result, agonist induced Ca2+ oscillations are critically dependent on Ca2+ entry through store operated channels but do not depend strongly on Ca2+ entry though voltage-gated channels. PMID- 27502471 TI - PARL: The mitochondrial rhomboid protease. AB - The rhomboid family comprises evolutionary conserved intramembrane proteases involved in a wide spectrum of biologically relevant activities. A mitochondrion localized rhomboid, called PARL in mammals, and conserved in yeast and Drosophila as RBD1/PCP1 and rho-7, respectively, plays an indispensable role in cell homeostasis as illustrated by the severe phenotypes caused by its genetic ablation in the various investigated species. Although several substrates of PARL have been proposed to explain these phenotypes, there remains a lot of controversy in this important area of research. We review here the putative functions and substrates of PARL and its orthologues in different species, highlighting areas of uncertainty, and discuss its potential involvement in some prevalent diseases such as type II diabetes and Parkinson's disease. PMID- 27502472 TI - Attention-deficit hyperactivity disorder in adults: a systematic review and meta analysis of genetic, pharmacogenetic and biochemical studies. PMID- 27502473 TI - All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class. AB - Autoantibodies of the IgG class against N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) were first described in anti-NMDAR encephalitis and seen as disease indicators. Recent work on together over 5000 individuals challenged this exclusive view by showing age-dependently up to >20% NMDAR1-autoantibody seroprevalence with comparable immunoglobulin class and titer distribution across health and disease. The key question therefore is to understand the properties of these autoantibodies, also in healthy carriers, in order to assess secondary complications and possible contributions to neuropsychiatric disease. Here, we believe we provide for human NMDAR1-autoantibodies the first comprehensive analysis of their target epitopes and functionality. We selected sera of representative carriers, healthy or diagnosed with very diverse conditions, that is, schizophrenia, age-related disorders like hypertension and diabetes, or anti NMDAR encephalitis. We show that all positive sera investigated, regardless of source (ill or healthy donor) and immunoglobulin class, provoked NMDAR1 internalization in human-induced pluripotent stem cell-derived neurons and reduction of glutamate-evoked currents in NR1-1b/NR2A-expressing Xenopus oocytes. They displayed frequently polyclonal/polyspecific epitope recognition in the extracellular or intracellular NMDAR1 domains and some additionally in NR2A. We conclude that all circulating NMDAR1-autoantibodies have pathogenic potential regarding the whole spectrum of neuronal NMDAR-mediated effects upon access to the brain in situations of increased blood-brain-barrier permeability. PMID- 27502474 TI - Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia. AB - This corrects the article DOI: 10.1038/mp.2016.97. PMID- 27502476 TI - Exome-sequencing in a large population-based study reveals a rare Asn396Ser variant in the LIPG gene associated with depressive symptoms. PMID- 27502477 TI - Towards natural language question generation for the validation of ontologies and mappings. AB - BACKGROUND: The increasing number of open-access ontologies and their key role in several applications such as decision-support systems highlight the importance of their validation. Human expertise is crucial for the validation of ontologies from a domain point-of-view. However, the growing number of ontologies and their fast evolution over time make manual validation challenging. METHODS: We propose a novel semi-automatic approach based on the generation of natural language (NL) questions to support the validation of ontologies and their evolution. The proposed approach includes the automatic generation, factorization and ordering of NL questions from medical ontologies. The final validation and correction is performed by submitting these questions to domain experts and automatically analyzing their feedback. We also propose a second approach for the validation of mappings impacted by ontology changes. The method exploits the context of the changes to propose correction alternatives presented as Multiple Choice Questions. RESULTS: This research provides a question optimization strategy to maximize the validation of ontology entities with a reduced number of questions. We evaluate our approach for the validation of three medical ontologies. We also evaluate the feasibility and efficiency of our mappings validation approach in the context of ontology evolution. These experiments are performed with different versions of SNOMED-CT and ICD9. CONCLUSIONS: The obtained experimental results suggest the feasibility and adequacy of our approach to support the validation of interconnected and evolving ontologies. Results also suggest that taking into account RDFS and OWL entailment helps reducing the number of questions and validation time. The application of our approach to validate mapping evolution also shows the difficulty of adapting mapping evolution over time and highlights the importance of semi-automatic validation. PMID- 27502475 TI - mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions. AB - Cognitive deficits in psychiatric and age-related disorders generally involve dysfunction of the dorsolateral prefrontal cortex (dlPFC), but there are few treatments for these debilitating symptoms. Group II metabotropic glutamate receptors (mGluR2/3), which couple to Gi/Go, have been a focus of therapeutics based on rodent research, where mGluR2/3 have been shown to reduce axonal glutamate release and increase glial glutamate uptake. However, this strategy has had mixed results in patients, and understanding mGluR2/3 mechanisms in primates will help guide therapeutic interventions. The current study examined mGluR2/3 localization and actions in the primate dlPFC layer III circuits underlying working memory, where the persistent firing of 'Delay cells' is mediated by N methyl-d-aspartate receptors and weakened by cAMP-PKA-potassium channel signaling in dendritic spines. Immunoelectron microscopy identified postsynaptic mGluR2/3 in the spines, in addition to the traditional presynaptic and astrocytic locations. In vivo iontophoretic application of the mGluR2/3 agonists (2R, 4R) APDC or LY379268 onto dlPFC Delay cells produced an inverted-U effect on working memory representation, with enhanced neuronal firing following low doses of mGluR2/3 agonists. The enhancing effects were reversed by an mGluR2/3 antagonist or by activating cAMP signaling, consistent with mGluR2/3 inhibiting postsynaptic cAMP signaling in spines. Systemic administration of these agonists to monkeys performing a working memory task also produced an inverted-U dose-response, where low doses improved performance but higher doses, similar to clinical trials, had mixed effects. Our data suggest that low doses of mGluR2/3 stimulation may have therapeutic effects through unexpected postsynaptic actions in dlPFC, strengthening synaptic connections and improving cognitive function. PMID- 27502478 TI - Precursors of age-related macular degeneration: associations with vitamin A and interaction with CFHY402H in the Inter99 Eye Study. AB - PURPOSE: To investigate associations of very early age-related macular degeneration (AMD) with daily intake of vitamin A, beta-carotene, vitamin E, vitamin C, zinc and copper and interactions with AMD-associated polymorphisms in complement factor H (CFHY402H) and ARMS2/LOC387715. METHODS: Cross-sectional study of 848 subjects aged 30-60 years from the Inter99 Eye Study. Daily intake of vitamins and minerals was estimated from a 198-item food frequency questionnaire. Digital fundus photographs were recorded in red-free illumination and graded for macular drusen >63 MUm and numerous (>20) small hard macular drusen as a mean of both eyes. RESULTS: Higher intake of vitamin A increased the risk of having macular drusen >63 MUm with odds ratio = 1.82 (CI95 1.02-3.24, p = 0.042) comparing participants in the highest quartile of vitamin A intake with participants in the lowest quartile, adjusted for recruitment group, age and sex. There was a significant interaction with CFHY402H (p = 0.038). Among 504 participants with CFHY402H, the relative risk of having macular drusen >63 MUm was increased in participants in the highest quartile of vitamin A intake (odds ratio = 2.58; CI95 1.16-5.73, p = 0.020) and in the second highest quartile (odds ratio = 3.27; CI95 1.50-7.13, p = 0.0029) compared with the lowest quartile. Further adjusting for total fat intake, energy intake, plasma cholesterol, body mass index (BMI), smoking, alcohol intake, education and physical activity strengthened the association. CONCLUSIONS: In this cross-sectional study, a higher intake of vitamin A increased the risk of macular drusen >63 MUm in subjects with CFHY402H. The study supports that vitamin A may be a risk factor for early AMD. PMID- 27502479 TI - A Simplified, Langendorff-Free Method for Concomitant Isolation of Viable Cardiac Myocytes and Nonmyocytes From the Adult Mouse Heart. AB - RATIONALE: Cardiovascular disease represents a global pandemic. The advent of and recent advances in mouse genomics, epigenomics, and transgenics offer ever greater potential for powerful avenues of research. However, progress is often constrained by unique complexities associated with the isolation of viable myocytes from the adult mouse heart. Current protocols rely on retrograde aortic perfusion using specialized Langendorff apparatus, which poses considerable logistical and technical barriers to researchers and demands extensive training investment. OBJECTIVE: To identify and optimize a convenient, alternative approach, allowing the robust isolation and culture of adult mouse cardiac myocytes using only common surgical and laboratory equipment. METHODS AND RESULTS: Cardiac myocytes were isolated with yields comparable to those in published Langendorff-based methods, using direct needle perfusion of the LV ex vivo and without requirement for heparin injection. Isolated myocytes can be cultured antibiotic free, with retained organized contractile and mitochondrial morphology, transcriptional signatures, calcium handling, responses to hypoxia, neurohormonal stimulation, and electric pacing, and are amenable to patch clamp and adenoviral gene transfer techniques. Furthermore, the methodology permits concurrent isolation, separation, and coculture of myocyte and nonmyocyte cardiac populations. CONCLUSIONS: We present a novel, simplified method, demonstrating concomitant isolation of viable cardiac myocytes and nonmyocytes from the same adult mouse heart. We anticipate that this new approach will expand and accelerate innovative research in the field of cardiac biology. PMID- 27502480 TI - A school-based health promotion programme to increase help-seeking for substance use and mental health problems: study protocol for a randomised controlled trial. AB - BACKGROUND: Adolescence is a high-risk time for the development of mental health and substance use problems. However, fewer than one in four 16-24 year-olds with a current disorder access health services, with those experiencing a substance use disorder being the least likely to seek professional help. Research indicates that young people are keeping their problems to themselves or alternatively, turning to peers or trusted adults in their lives for help. These help-seeking preferences highlight the need to build the mental health literacy of adolescents, to ensure that they know when and how to assist themselves and their peers to access support. The MAKINGtheLINK intervention aims to introduce these skills to adolescents within a classroom environment. METHODS/DESIGN: This is a cluster randomised controlled trial (RCT) with schools as clusters and individual students as participants from 22 secondary schools in Victoria, Australia. Schools will be randomly assigned to either the MAKINGtheLINK intervention group or the waitlist control group. All students will complete a self-report questionnaire at baseline, immediately post intervention and 6 and 12 months post baseline. The primary outcome to be assessed is increased help-seeking behaviour (from both formal and informal sources) for alcohol and mental health issues, measured at 12 months post baseline. DISCUSSION: The findings from this research will provide evidence on the effectiveness of the MAKINGtheLINK intervention for teaching school students how to overcome prominent barriers associated with seeking help, as well as how to effectively support their peers. If deemed effective, the MAKINGtheLINK programme will be the first evidence-informed resource that is able to address critical gaps in the knowledge and behaviour of adolescents in relation to help-seeking. It could, therefore, be a valuable resource that could be readily implemented by classroom teachers. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12613000235707 . Registered on 27 February 2013. PMID- 27502481 TI - Sox2: A multitasking networker. AB - The transcription factor Sox2 is best known as a pluripotency factor in stem and precursor cells and its expression generally correlates with an undifferentiated state. Proposed modes of action include those as classical transcription factor and pre-patterning factor with influence on histone modifications and chromatin structure. Recently, we provided the first detailed analysis of Sox2 expression and function during development of oligodendrocytes, the myelin-forming cells of the CNS. Surprisingly, we found evidence for a role of Sox2 as differentiation factor and found it to act through modulation of microRNA levels. Thus, we add new facets to the functional repertoire of Sox2 and throw light on the networking activity of this multitasking developmental regulator. PMID- 27502482 TI - A case of lymphomatosis cerebri mimicking inflammatory diseases. AB - BACKGROUND: Lymphomatosis cerebri (LC) is a rare subtype of primary central nervous system malignant lymphoma. The typical features of this disease exhibited on magnetic resonance imaging (MRI) without contrast enhancement are similar to those observed with diffuse leukoencephalopathy, mimicking white matter disorders such as encephalitis. Clinical features and examination findings that are suggestive of inflammatory diseases may indeed confound the diagnosis of LC. CASE PRESENTATION: A 66-year-old woman with continuous fever over a two-month period developed left hemiparesis despite presenting in an alert state with normal cognitive function. Sampling tests showed autoantibodies in the serum and inflammatory changes in the cerebrospinal fluid. The results from an MRI demonstrated multiple non-enhanced brain lesions in the splenium of the corpus callosum and deep white matter. Single photon emission computed tomography revealed increases in blood flow in the basal ganglia, thalamus and brainstem. No systemic malignancies were found. The patient was suspected of having a diagnosis of nonvasculitic autoimmune inflammatory meningoencephalitis and treated with intravenous methylprednisolone pulse therapy. Her fever transiently dropped to within the normal range. However, she had a sudden seizure and a second MRI exhibited infiltrative lesions gradually extending throughout the whole brain. We performed a brain biopsy, and LC was histologically diagnosed. The patient received whole-brain radiation therapy, which diminished the fever and seizures. The patient died one year after the initial onset of fever. CONCLUSIONS: The present case yields an important consideration that brain neoplasms, especially LC, cannot be ruled out, even in cases with clinical characteristics and examinations consistent with inflammatory diseases. Careful follow-up and histological study are vital for the correct diagnosis of LC. PMID- 27502483 TI - RECQ5 helicase promotes resolution of conflicts between replication and transcription in human cells. AB - Collisions between replication and transcription machineries represent a significant source of genomic instability. RECQ5 DNA helicase binds to RNA polymerase (RNAP) II during transcription elongation and suppresses transcription associated genomic instability. Here, we show that RECQ5 also associates with RNAPI and enforces the stability of ribosomal DNA arrays. We demonstrate that RECQ5 associates with transcription complexes in DNA replication foci and counteracts replication fork stalling in RNAPI- and RNAPII-transcribed genes, suggesting that RECQ5 exerts its genome-stabilizing effect by acting at sites of replication-transcription collisions. Moreover, RECQ5-deficient cells accumulate RAD18 foci and BRCA1-dependent RAD51 foci that are both formed at sites of interference between replication and transcription and likely represent unresolved replication intermediates. Finally, we provide evidence for a novel mechanism of resolution of replication-transcription collisions wherein the interaction between RECQ5 and proliferating cell nuclear antigen (PCNA) promotes RAD18-dependent PCNA ubiquitination and the helicase activity of RECQ5 promotes the processing of replication intermediates. PMID- 27502484 TI - TMX1 determines cancer cell metabolism as a thiol-based modulator of ER mitochondria Ca2+ flux. AB - The flux of Ca(2+) from the endoplasmic reticulum (ER) to mitochondria regulates mitochondria metabolism. Within tumor tissue, mitochondria metabolism is frequently repressed, leading to chemotherapy resistance and increased growth of the tumor mass. Therefore, altered ER-mitochondria Ca(2+) flux could be a cancer hallmark, but only a few regulatory proteins of this mechanism are currently known. One candidate is the redox-sensitive oxidoreductase TMX1 that is enriched on the mitochondria-associated membrane (MAM), the site of ER-mitochondria Ca(2+) flux. Our findings demonstrate that cancer cells with low TMX1 exhibit increased ER Ca(2+), accelerated cytosolic Ca(2+) clearance, and reduced Ca(2+) transfer to mitochondria. Thus, low levels of TMX1 reduce ER-mitochondria contacts, shift bioenergetics away from mitochondria, and accelerate tumor growth. For its role in intracellular ER-mitochondria Ca(2+) flux, TMX1 requires its thioredoxin motif and palmitoylation to target to the MAM. As a thiol-based tumor suppressor, TMX1 increases mitochondrial ATP production and apoptosis progression. PMID- 27502485 TI - A disulfide bond in the TIM23 complex is crucial for voltage gating and mitochondrial protein import. AB - Tim17 is a central, membrane-embedded subunit of the mitochondrial protein import machinery. In this study, we show that Tim17 contains a pair of highly conserved cysteine residues that form a structural disulfide bond exposed to the intermembrane space (IMS). This disulfide bond is critical for efficient protein translocation through the TIM23 complex and for dynamic gating of its preprotein conducting channel. The disulfide bond in Tim17 is formed during insertion of the protein into the inner membrane. Whereas the import of Tim17 depends on the binding to the IMS protein Mia40, the oxidoreductase activity of Mia40 is surprisingly dispensable for Tim17 oxidation. Our observations suggest that Tim17 can be directly oxidized by the sulfhydryl oxidase Erv1. Thus, import and oxidation of Tim17 are mediated by the mitochondrial disulfide relay, though the mechanism by which the disulfide bond in Tim17 is formed differs considerably from that of soluble IMS proteins. PMID- 27502486 TI - A Toll receptor-FoxO pathway represses Pavarotti/MKLP1 to promote microtubule dynamics in motoneurons. AB - FoxO proteins are evolutionarily conserved regulators of neuronal structure and function, yet the neuron-specific pathways within which they act are poorly understood. To elucidate neuronal FoxO function in Drosophila melanogaster, we first screened for FoxO's upstream regulators and downstream effectors. On the upstream side, we present genetic and molecular pathway analyses indicating that the Toll-6 receptor, the Toll/interleukin-1 receptor domain adaptor dSARM, and FoxO function in a linear pathway. On the downstream side, we find that Toll-6 FoxO signaling represses the mitotic kinesin Pavarotti/MKLP1 (Pav-KLP), which itself attenuates microtubule (MT) dynamics. We next probed in vivo functions for this novel pathway and found that it is essential for axon transport and structural plasticity in motoneurons. We demonstrate that elevated expression of Pav-KLP underlies transport and plasticity phenotypes in pathway mutants, indicating that Toll-6-FoxO signaling promotes MT dynamics by limiting Pav-KLP expression. In addition to uncovering a novel molecular pathway, our work reveals an unexpected function for dynamic MTs in enabling rapid activity-dependent structural plasticity. PMID- 27502487 TI - ERK signaling promotes cell motility by inducing the localization of myosin 1E to lamellipodial tips. AB - Signaling by extracellular signal-regulated kinase (ERK) plays an essential role in the induction of cell motility, but the precise mechanism underlying such regulation has remained elusive. We recently identified SH3P2 as a negative regulator of cell motility whose function is inhibited by p90 ribosomal S6 kinase (RSK)-mediated phosphorylation downstream of ERK. We here show that myosin 1E (Myo1E) is a binding partner of SH3P2 and that the interaction of the two proteins in the cytosol prevents the localization of Myo1E to the plasma membrane. Serum-induced phosphorylation of SH3P2 at Ser(202) by RSK results in dissociation of Myo1E from SH3P2 in the cytosol and the subsequent localization of Myo1E to the tips of lamellipodia mediated by binding of its TH2 domain to F actin. This translocation of Myo1E is essential for lamellipodium extension and consequent cell migration. The ERK signaling pathway thus promotes cell motility through regulation of the subcellular localization of Myo1E. PMID- 27502488 TI - Mitochondrial protein import: An unexpected disulfide bond. AB - Most mitochondrial proteins are imported through the TIM23 translocation channel, the structure and molecular nature of which are still unclear. In this issue, Ramesh et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201602074) show that the TIM23 subunit Tim17 contains a disulfide bond that is crucial for protein translocation and channel gating. PMID- 27502489 TI - VPS35 binds farnesylated N-Ras in the cytosol to regulate N-Ras trafficking. AB - Ras guanosine triphosphatases (GTPases) regulate signaling pathways only when associated with cellular membranes through their C-terminal prenylated regions. Ras proteins move between membrane compartments in part via diffusion-limited, fluid phase transfer through the cytosol, suggesting that chaperones sequester the polyisoprene lipid from the aqueous environment. In this study, we analyze the nature of the pool of endogenous Ras proteins found in the cytosol. The majority of the pool consists of farnesylated, but not palmitoylated, N-Ras that is associated with a high molecular weight (HMW) complex. Affinity purification and mass spectrographic identification revealed that among the proteins found in the HMW fraction is VPS35, a latent cytosolic component of the retromer coat. VPS35 bound to N-Ras in a farnesyl-dependent, but neither palmitoyl- nor guanosine triphosphate (GTP)-dependent, fashion. Silencing VPS35 increased N Ras's association with cytoplasmic vesicles, diminished GTP loading of Ras, and inhibited mitogen-activated protein kinase signaling and growth of N-Ras dependent melanoma cells. PMID- 27502490 TI - Systemically and cutaneously distributed ectoparasiticides: a review of the efficacy against ticks and fleas on dogs. AB - Acaricidal (tick) and insecticidal (flea) efficacy of systemically and cutaneously distributed ectoparasiticide products for dogs are compared based on permethrin and fluralaner as representative molecules. Results of efficacy studies against fleas and ticks are reviewed that show generally good to excellent results. Both externally and systemically distributed treatments have benefits and weaknesses in potentially preventing pathogen transmission by these arthropod vectors.Four general properties are considered related to the goal of providing optimal reduction in the risk of vector-borne pathogen transmission. These are: 1. Owner adherence to the recommended treatment protocol; 2. Rapid onset of activity following administration; 3. Uniform efficacy over all areas of the treated dog at risk for parasite attachment; 4. Maintenance of high efficacy throughout the retreatment interval. In considering these four factors, a systemically distributed acaricide can offer an option that is at least as effective as a cutaneously administered acaricide with regard to the overall goal of reducing the risk of vector-borne pathogen transmission. PMID- 27502491 TI - Factors associated with needle sharing among people who inject drugs in Yunnan, China: a combined network and regression analysis. AB - BACKGROUND: Network analyses have been widely utilized to evaluate large datasets, but have not yet been used to explore factors associated with risk behaviours. In combination with traditional regression analysis, network analyses may provide useful information and highlight key factors for reducing needle sharing behaviours among people who inject drugs (PWID). METHODS: Sociodemographic data, and information on injection behaviour and sexual practices were collected from a cross-sectional survey that was conducted with PWID in five prefectures of Yunnan province, China. A combination of logistic regression and correlation network analyses were used to explore key factors for reducing needle-sharing behaviours among PWID. RESULTS: In a total of 1 049 PWID, 37.5 % had a history of needle or syringe sharing. The logistic analysis showed that Zhaotong, Qujing, Dehong, or Lincang residents, diazepam use, longer injection duration, needle reuse, and infection with HIV, viral hepatitis, tuberculosis and/or malaria were independently associated with needle sharing. The correlation network analyses showed that, compared to PWID who had never shared needles, PWID who did share needles would achieve harm reduction goals faster and more permanently. HIV serostatus and marital status were found to be closely associated with other risk factors. By combining regression analyses with network analyses, it was shown that PWID who are HIV seropositive will be an ideal target group for harm reduction programs. CONCLUSION: Needle-sharing behaviours are common among PWID in Yunnan, and harm reduction programs may help PWID who are HIV seropositive reduce risk behaviours and prevent blood borne diseases. PMID- 27502492 TI - Antiangiogenic and antihepatocellular carcinoma activities of the Juniperus chinensis extract. AB - BACKGROUND: To identify a novel therapeutic agent for hepatocellular carcinoma (HCC), for which no promising therapeutic agent exists, we screened a panel of plants and found that Juniperus chinensis exhibited potential antiangiogenic and anti-HCC activities. We further investigated the antiangiogenic and anti-HCC effects of the active ingredient of J. chinensis extract, CBT-143-S-F6F7, both in vitro and in vivo. METHODS: A tube formation assay conducted using human umbilical vein endothelial cells (HUVECs) was first performed to identify the active ingredient of CBT-143-S-F6F7. A series of angiogenesis studies, including HUVEC migration, Matrigel plug, and chorioallantoic membrane (CAM) assays, were then performed to confirm the effects of CBT-143-S-F6F7 on angiogenesis. The effects of CBT-143-S-F6F7 on tumor growth were investigated using a subcutaneous and orthotopic mouse model of HCC. In vitro studies were performed to investigate the effects of CBT-143-S-F6F7 on the cell cycle and apoptosis in HCC cells. Moreover, protein arrays for angiogenesis and apoptosis were used to discover biomarkers that may be influenced by CBT-143-S-F6F7. Finally, nuclear magnetic resonance analysis was conducted to identify the compounds of CBT-143-S-F6F7. RESULTS: CBT-143-S-F6F7 showed significantly antiangiogenic activity in various assays, including HUVEC tube formation and migration, CAM, and Matrigel plug assays. In in vivo studies, gavage with CBT-143-S-F6F7 significantly repressed subcutaneous Huh7 tumor growth in severe combined immunodeficient (SCID) mice, and prolonged the survival of orthotopic Huh7 tumor-bearing SCID mice (a 40 % increase in median survival duration compared with the vehicle-treated mice). Immunohistochemical staining of subcutaneous Huh7 tumors in CBT-143-S-F6F7 treated mice showed a significantly decrease in the cell cycle regulatory protein cyclin D1, cellular proliferation marker Ki-67, and endothelial marker CD31. CBT 143-S-F6F7 caused arrest of the G2/M phase and induced Huh7 cell apoptosis, possibly contributing to the inhibition of HCC tumors. Protein array analysis revealed that several angiogenic and antiapoptotic factors were suppressed in CBT 143-S-F6F7-treated Huh7 cells. Finally, five compounds from CBT-143-S-F6F7 were identified. CONCLUSIONS: According to these results, we report for the first time the antiangiogenic and anti-HCC activities of CBT-143-S-F6F7, the active fractional extract of J. chinensis. We believe that CBT-143-S-F6F7 warrants further evaluation as a new anti-HCC drug. PMID- 27502493 TI - Evaluation of long-term surgical site occurrences in ventral hernia repair: implications of preoperative site independent MRSA infection. AB - PURPOSE: Previous work demonstrated that prior MRSA infection [MRSA(+)] is associated with 30-day surgical site infection (SSI) following ventral hernia repair (VHR). We aimed to determine the impact of MRSA(+) on long-term wound outcomes after VHR. PARTICIPANTS: A retrospective cohort study was performed at a tertiary center between July 11, 2005, and May 18, 2012, of patients undergoing elective VHR with class I wounds. Patients with documented preoperative MRSA infection at any site (urinary, bloodstream, SSI, etc.) were considered MRSA(+). Primary outcome was 2-year surgical site occurrence (SSO), defined as SSI, cellulitis, necrosis, nonhealing wound, seroma, hematoma, dehiscence, or fistula. SSOs were subdivided into those that required procedural intervention (SSOPI) and those that did not. RESULTS: Among 632 patients, 46 % were female with average age 53 +/- 13 years. There were 368 SSOs in 193 patients (31 %); an SSOPI occurred in 9.8 % (n = 62). The most common SSOs were cellulitis (91/632), seroma (91/632), and serous drainage (58/632). The rate of 2-year SSO was higher with MRSA(+) compared to those without (46 vs. 29 %, p = 0.023), attributed to increased soft tissue necrosis, purulent drainage, serous drainage, cellulitis, and fistula. In multivariable analysis, MRSA(+) was not associated with 2-year SSO (HR 1.5, 95 % CI 0.91-2.55, p = 0.113); factors associated with SSO included obesity, immunosuppression, mesh repair, and operative times. CONCLUSIONS: This study is the first to evaluate long-term SSOs and SSOPIs after VHR, highlighting the importance of long-term follow-up. Though not independently associated with SSOs, MRSA(+) may be a marker of hernia complexity. PMID- 27502494 TI - Changes in posterior corneal elevations after combined transepithelial photorefractive keratectomy and accelerated corneal collagen cross-linking: retrospective, comparative observational case series. AB - BACKGROUND: To compare the changes in anterior and posterior corneal elevations after combined transepithelial photorefractive keratectomy (PRK) and accelerated corneal collagen cross-linking (CXL) and after PRK. METHODS: Medical records of 82 eyes of 44 patients undergoing either combined transepithelial PRK and CXL (PRK-CXL group) or transepithelial PRK (PRK group) were examined retrospectively. Changes in anterior and posterior corneal elevations were calculated by fitting an 8.0-mm diameter best-fit sphere and best-fit toric ellipsoid (BFTE) to the corneal shape with a fixed eccentricity of 0.4 using Scheimpflug tomography (Pentacam HR; Oculus Optikgerate GmbH, Wetzlar, Germany) preoperatively and 6 months postoperatively. RESULTS: In anterior corneal elevation, both groups demonstrated a similar trend of a forward displacement of peripheral anterior corneal surface and a backward displacement of central anterior corneal surface. In posterior corneal elevation, a forward displacement of peripheral posterior corneal surface was induced in both groups, along with a backward displacement of central posterior corneal surface, regardless of the calculation method. The magnitudes of displacement of peripheral and central posterior corneal surfaces were significantly smaller in the PRK-CXL group than in the PRK group. Moreover, the PRK-CXL group showed a backward displacement of posterior corneal surface at maximum corneal elevations when the BFTE was used as the reference surface. CONCLUSIONS: Transepithelial PRK combined with prophylactic CXL significantly reduced the magnitudes of displacement of peripheral and central posterior corneal surfaces, with the radius of the BFTE was set to 8.0-mm on the Scheimpflug tomography system. PMID- 27502495 TI - Systematic Literature Review of DPP-4 Inhibitors in Patients with Type 2 Diabetes Mellitus and Renal Impairment. AB - INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the management of patients with type 2 diabetes mellitus (T2DM) and renal impairment (RI). A systematic literature review was performed to compare the efficacy and safety of DPP-4 inhibitors in patients with T2DM and RI. METHODS: We searched EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials (cut-off, June 2015) to identify >=12-week, randomized, placebo-controlled trials on DPP-4 inhibitors in >=50 patients with T2DM and RI. Outcomes of interest included change in glycated hemoglobin (HbA1c), overall safety, and incidence of hypoglycemic events (HEs). RESULTS: Seven trials of <=52-54 weeks duration were retrieved, which included one study each on vildagliptin, saxagliptin, and sitagliptin, two on linagliptin, and the remaining two were extension studies of vildagliptin and saxagliptin. Majority of patients were on insulin at baseline (53-86%), except in the sitagliptin study, where approximately 11% received insulin during the placebo-controlled phase. After 52 weeks, vildagliptin and saxagliptin reduced HbA1c levels by 0.6-0.7% (baseline 7.8-8.4%) versus placebo in the overall population. HbA1c reductions were similar at weeks 12 and 52. In the 12-week, placebo-controlled phase, sitagliptin and linagliptin reduced mean HbA1c by approximately 0.4% (baseline 7.7-8.1%) versus placebo. Rates of HEs with DPP-4 inhibitors were not significantly different versus placebo in any study. Rates of adverse events (AEs) and changes involving renal function were similar in the active- and placebo-treated groups. CONCLUSION: These results suggest that DPP-4 inhibitors have the potential to improve glycemic control in patients with RI without increasing the risk of HEs or overall AEs. FUNDING: Novartis Pharma AG. PMID- 27502496 TI - Effective Utilization of Oral Hypoglycemic Agents to Achieve Individualized HbA1c Targets in Patients with Type 2 Diabetes Mellitus. AB - Type 2 diabetes is a progressive condition that may require the combination of three oral treatments to achieve optimal glycemic management to prevent microvascular and macrovascular complications whilst minimizing the risk of acute complications and side effects or adverse reactions to treatments. With the widening availability of treatment options and increasing importance of individualized treatment pathways, including personalized HbA1c targets, this article will explore the mode of action of currently available oral treatments, factors to consider when individualizing HbA1c targets, the relevance of estimated glomerular filtration rate assessment, and the importance of reviewing the clinical impact of all treatment decisions. PMID- 27502497 TI - Accuracy of patient-specific template-guided vs. free-hand fluoroscopically controlled pedicle screw placement in the thoracic and lumbar spine: a randomized cadaveric study. AB - PURPOSE: Dorsal spinal instrumentation with pedicle screw constructs is considered the gold standard for numerous spinal pathologies. Screw misplacement is biomechanically disadvantageous and may create severe complications. The aim of this study was to assess the accuracy of patient-specific template-guided pedicle screw placement in the thoracic and lumbar spine compared to the free hand technique with fluoroscopy. METHODS: Patient-specific targeting guides were used for pedicle screw placement from Th2-L5 in three cadaveric specimens by three surgeons with different experience levels. Instrumentation for each side and level was randomized (template-guided vs. free-hand). Accuracy was assessed by computed tomography (CT), considering perforations of <2 mm as acceptable (safe zone). Time efficiency, radiation exposure and dependencies on surgical experience were compared between the two techniques. RESULTS: 96 screws were inserted with an equal distribution of 48 screws (50 %) in each group. 58 % (n = 28) of template-guided (without fluoroscopy) vs. 44 % (n = 21) of free-hand screws (with fluoroscopy) were fully contained within the pedicle (p = 0.153). 97.9 % (n = 47) of template-guided vs. 81.3 % (n = 39) of free-hand screws were within the 2 mm safe zone (p = 0.008). The mean time for instrumentation per level was 01:14 +/- 00:37 for the template-guided vs. 01:40 +/- 00:59 min for the free-hand technique (p = 0.013), respectively. Increased radiation exposure was highly associated with lesser experience of the surgeon with the free-hand technique. CONCLUSIONS: In a cadaver model, template-guided pedicle screw placement is faster considering intraoperative instrumentation time, has a higher accuracy particularly in the thoracic spine and creates less intraoperative radiation exposure compared to the free-hand technique. PMID- 27502499 TI - The Epidemiology of Staphylococcus aureus and Panton-Valentine Leucocidin (pvl) in Central Australia, 2006-2010. AB - BACKGROUND: The Central Australian Indigenous population has a high incidence of Staphylococcus aureus bacteremia (SAB) but little is known about the local molecular epidemiology. METHODS: Prospective observational study of bacteremic and nasal colonizing S.aureus isolates between June 2006 to June 2010. All isolates underwent single nucleotide polymorphism (SNP) genotyping and testing for the presence of the Panton-Valentine Leucocidin (pvl) gene. RESULTS: Invasive isolates (n = 97) were predominantly ST93 (26.6 %) and pvl positive (54.3 %), which was associated with skin and soft tissue infections (OR 4.35, 95 % CI 1.16, 16.31). Non-multiresistant MRSA accounted for 31.9 % of bacteremic samples and showed a trend to being healthcare associated (OR 2.16, 95 % CI 0.86, 5.40). Non invasive isolates (n = 54) were rarely ST93 (1.9 %) or pvl positive (7.4 %). CONCLUSIONS: In Central Australia, ST93 was the dominant S.aureus clone, and was frequently pvl positive and associated with an aggressive clinical phenotype. Whether non-nasal carriage is more important with invasive clones or whether colonization occurs only transiently remains to be elucidated. PMID- 27502500 TI - Epidemiological study of adult-onset Still's disease using a Japanese administrative database. AB - Adult-onset Still's disease (AOSD) is a rare disease, and large epidemiological studies of this disease are limited. Furthermore, it has been difficult to show the incidence and characteristics of severe AOSD complications due to the rarity of this disease. The aim of our study was to describe the demographics of AOSD and the incidence and characteristics of severe complications. Using a large Japanese administrative database, we identified hospitalized patients with AOSD and described the demographics. We also calculated the incidence of severe complications (i.e., macrophage activation syndrome [MAS] and disseminated intravascular coagulation [DIC]) and in-hospital mortality in AOSD patients, and then analyzed the age-controlled difference between men and women. We identified 513 patients with AOSD (mean age: 53.1 years; women 64.1 %). According to the age distribution, there was no distinct peak age. The thirties and the sixties were relatively large age groups. There were 76 patients of AOSD with MAS or DIC observed in this study. The incidence of severe complications was 14.8 %, 95 % CI [11.9, 18.2]. Women were more likely to have severe complications than men after controlling for age (odds ratio: 2.07; [1.14, 3.73]; p = 0.014). AOSD does not predominantly affect young adults in our study population. Elderly AOSD patients can be observed more than before due to global population aging. Severe complications are more likely to occur in women than in men. PMID- 27502501 TI - Clinical and Pathological Significance of ER Stress Marker (BiP/GRP78 and PERK) Expression in Malignant Melanoma. AB - Glucose-regulated protein of 78 kD (GRP78) also referred to as immunoglobulin heavy chain binding protein (BiP/GRP78) plays an important role in the endoplasmic reticulum (ER) stress. The level of BiP/GRP78 is highly elevated in various human cancers. The purpose of this study is to examine the prognostic significance of BiP/GRP78 expression in patients with malignant melanoma. A total of 133 malignant melanoma patients were analyzed, and tumor specimens were stained by immunohistochemistry for BiP/GRP78, PKR-like endoplasmic reticulum kinase (PERK), Ki-67, p53 and microvessel density (MVD) determined by CD34. BiP/GRP78 and PERK were highly expressed in 40 % (53/133) and 78 % (104/133), respectively. BiP/GRP78 disclosed a significant relationship with PERK expression, thickness, T factor, N factor, disease staging, cell proliferation (Ki-67) and MVD (CD34). By multivariate analysis, the high expression of BiP/GRP78 was identified as an independent prognostic factor for predicting poor survival against malignant melanoma. The increased BiP/GRP78 expression was clarified as an independent prognostic marker for predicting worse outcome. ER stress marker, BiP/GRP78 could be a powerful molecular target for the treatment of malignant melanoma. PMID- 27502502 TI - Risk Factors for Cryptococcal Meningitis: A Single United States Center Experience. AB - Cryptococcal meningitis carries a high mortality. Further understanding of immune suppression factors associated with neuroinvasive infection will improve risk stratification and enhance early diagnosis and treatment with antifungal therapy. The aim of the study was to corroborate established or find novel clinical predictors for cryptococcal meningitis. We performed a matched case-control study of Cryptococcus infection in immunocompromised patients with or without cryptococcal meningitis. Data of all patients with a diagnosis of cryptococcal disease were collected at University of Colorado Hospital between 2000 and 2015 (n = 51). Thirty patients were diagnosed with cryptococcal meningitis. We built a logistic regression model for risk factors associated with cryptococcal meningitis. The single-predictor univariate model found that a positive blood culture, positive serum cryptococcal antigen, current malignancy, and headaches were significantly associated with cryptococcal meningitis (p = 0.02). In the adjusted multivariate model, central nervous system disease was significantly associated with a diagnosis of HIV infection (OR 24.45, 95 % CI 1.62-350.37; p = 0.022) and a positive serum cryptococcal antigen test (OR 42.92, 95 % CI 3.26 555.55; p = 0.0055). In patients with HIV infection or a positive serum cryptococcal antigen, the pretest probability of neuroinvasive Cryptococcus infection is increased and an aggressive diagnostic evaluation should be conducted to exclude infection and consider empiric therapy. PMID- 27502503 TI - New Antifungal Agents and New Formulations Against Dermatophytes. AB - A variety of oral and topical antifungal agents are available for the treatment of superficial fungal infections caused by dermatophytes. This review builds on the antifungal therapy update published in this journal for the first special issue on Dermatophytosis (Gupta and Cooper 2008;166:353-67). Since 2008, there have not been additions to the oral antifungal armamentarium, with terbinafine, itraconazole, and fluconazole still in widespread use, albeit for generally more severe or recalcitrant infections. Griseofulvin is used in the treatment of tinea capitis. Oral ketoconazole has fallen out of favor in many jurisdictions due to risks of hepatotoxicity. Topical antifungals, applied once or twice daily, are the primary treatment for tinea pedis, tinea corporis/tinea cruris, and mild cases of tinea unguium. Newer topical antifungal agents introduced include the azoles, efinaconazole, luliconazole, and sertaconazole, and the oxaborole, tavaborole. Research is focused on developing formulations of existing topical antifungals that utilize novel delivery systems in order to enhance treatment efficacy and compliance. PMID- 27502504 TI - Genetic Predictors of Susceptibility to Dermatophytoses. AB - Countless observational studies conducted over the last century reveal that dermatophytes infect humans of every age, race, gender, and socioeconomic status with strikingly high rates. The curious disparity in dermatophyte infection patterns observed within and between populations has led countless investigators to explore whether genetics underlie a susceptibility to, or confer protection against, dermatophyte infections. This paper examines the data that offer a link between genetics and dermatophytoses and discusses the underlying mechanisms that support these observations. PMID- 27502505 TI - Evaluation of Daily Physical Activity (DPA) policy implementation in Ontario: surveys of elementary school administrators and teachers. AB - BACKGROUND: School-based structured opportunities for physical activity can provide health-related benefits to children and youth, and contribute to international guidelines recommending 60 min of moderate-to-vigorous physical activity (MVPA) per day. In 2005, the Ministry of Education in Ontario, Canada, released the Daily Physical Activity (DPA) policy requiring school boards to "ensure that all elementary students, including students with special needs, have a minimum of twenty minutes of sustained MVPA each school day during instructional time". This paper reports on the first provincial study evaluating implementation fidelity to the DPA policy in Ontario elementary schools and classrooms. Using an adapted conceptual framework, the study also examined associations between implementation of DPA and a number of predictors in each of these respective settings. METHODS: Separate cross-sectional online surveys were conducted in 2014 with Ontario elementary school administrators and classroom teachers, based on a representative random sample of schools and classrooms. An implementation fidelity score was developed based on six required components of the DPA policy. Other survey items measured potential predictors of implementation at the school and classroom levels. Descriptive analyses included frequency distributions of implementation fidelity and predictor variables. Bivariate analyses examining associations between implementation and predictors included binary logistic regression for school level data and generalized linear mixed models for classroom level data, in order to adjust for school-level clustering effects. RESULTS: Among administrators, 61.4 % reported implementation fidelity to the policy at the school level, while 50.0 % of teachers reported fidelity at the classroom level. Several factors were found to be significantly associated with implementation fidelity in both school and classroom settings including: awareness of policy requirements; scheduling; monitoring; use of resources and supports; perception that the policy is realistic and achievable; and specific barriers to implementation. CONCLUSIONS: Findings from the surveys indicate incomplete policy implementation and a number of factors significantly associated with implementation fidelity. The results indicate a number of important implications for policy, practice and further research, including the need for additional research to monitor implementation and its predictors, and assess the impacts of study recommendations and subsequent outcomes of a reinvigorated DPA moving forward. PMID- 27502507 TI - Critical illness polyneuropathy and myopathy 20 years later. No man's land? No, it is our land! PMID- 27502506 TI - The highly expressed 5'isomiR of hsa-miR-140-3p contributes to the tumor suppressive effects of miR-140 by reducing breast cancer proliferation and migration. AB - BACKGROUND: miRNAs are small noncoding RNA molecules that play an important role in post-transcriptional regulation of gene expression. Length and/or sequence variants of the same miRNA are termed isomiRs. While most isomiRs are functionally redundant compared to their canonical counterparts, the so-called 5'isomiRs exhibit a shifted 5' end and therefore a shifted seed sequence resulting in a different target spectrum. However, not much is known about the functional relevance of these isoforms. RESULTS: Analysis of miRNA-seq data from breast cancer cell lines identified six pairs of highly expressed miRNAs and associated 5'isomiRs. Among them, hsa-miR-140-3p was of particular interest because its 5'isomiR showed higher expression compared to the canonical miRNA annotated in miRbase. This miRNA has previously been shown to control stemness of breast cancer cells. miRNAseq data of breast cancer patients (TCGA dataset) showed that both the canonical hsa-miR-140-3p and its 5'isomiR-140-3p were highly expressed in patients' tumors compared to normal breast tissue. In the current work, we present the functional characterization of 5'isomiR-140-3p and the cellular phenotypes associated with its overexpression in MCF10A, MDA-MB-468 and MDA-MB-231 cell lines in comparison to the canonical hsa-miR-140-3p. Contrary to the effect of the canonical hsa-miR-140-3p, overexpression of the 5'isomiR-140-3p led to a decrease in cell viability. The latter observation was supported by cell cycle analysis, where the 5'isomiR-140-3p but not the hsa-miR-140-3p caused cell cycle arrest in G0/G1-phase. Additionally, 5'ismoiR-140-3p overexpression was found to cause a decrease in cell migration in the three cell lines. We identified three novel direct target genes of the 5'isomiR-140-3p; COL4A1, ITGA6 and MARCKSL1. Finally, we have shown that knocking down these genes partially phenocopied the effects of the 5'isomiR-140-4p overexpression, where COL4A1 and ITGA6 knockdown led to reduced cell viability and cell cycle arrest, while MARCKSL1 knockdown resulted in a decrease in the migratory potential of cells. CONCLUSIONS: In summary, this work presents evidence that there is functional synergy between the canonical hsa-miR-140-3p and the newly identified 5'isomiR 140-3p in suppressing growth and progression of breast cancer by simultaneously targeting genes related to differentiation, proliferation, and migration. PMID- 27502508 TI - Increased risk for secondary infections in trauma patients with viral reactivation. PMID- 27502509 TI - Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis. AB - Rheumatoid arthritis is an autoimmune disease that is characterized by chronic inflammation and destruction of joints. Netrin-1, a chemorepulsant, laminin-like matrix protein, promotes inflammation by preventing macrophage egress from inflamed sites and is required for osteoclast differentiation. We asked whether blockade of Netrin-1 or its receptors [Unc5b and DCC (deleted in colorectal carcinoma)] may be useful therapeutic targets for treatment of inflammatory arthritis. Arthritis was induced in 8-wk-old C57Bl/6 mice by intraperitoneal injection of K/BxN serum. Murine monoclonal antibodies against Netrin-1, Unc5b, or DCC (10 ug/mouse) were injected weekly for 4 wk (n = 10). Paw swelling and thickness were assessed and following euthanasia 2-4 wk after serum transfer, paws were prepared for micro-computed tomography and histology. Paw inflammation was maximal 2 wk after injection. Anti-Netrin-1 or anti-Unc5b, but not anti-DCC, antibodies significantly reduced paw inflammation (clinical score: 9.8 +/- 0.8, 10.4 +/- 0.9, and 13.5 +/- 0.5, respectively vs 16 +/- 0 for control; P < 0.001). Micro-computed tomography showed bony erosions in untreated or anti-DCC-treated mice, whereas there were no erosions in anti-Netrin-1/anti-Unc5b-treated-animals. Tartrate-resistant acid phosphatase staining demonstrated a marked decrease in osteoclasts in anti-Netrin-1/anti-Unc5b-treated animals. Immunofluorescence staining revealed a decrease in cathepsin K+ and CD68+ cells in anti-Netrin 1/anti-Unc5b-treated animals. Blockade of Netrin-1/Unc5b by monoclonal antibodies prevents bone destruction and reduces the severity of K/BxN serum transfer induced arthritis. Netrin-1 may be a novel therapeutic target for treatment of inflammatory bone destruction.-Mediero, A., Wilder, T., Ramkhelawon, B., Moore, K. J., Cronstein, B. N. Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis. PMID- 27502510 TI - The great recession, youth unemployment and inequalities in psychological health complaints in adolescents: a multilevel study in 31 countries. AB - OBJECTIVES: Little is known about the impact of recessions on young people's socioeconomic inequalities in health. This study investigates the impact of the economic recession in terms of youth unemployment on socioeconomic inequalities in psychological health complaints among adolescents across Europe and North America. METHODS: Data from the WHO collaborative 'Health Behaviour in School aged Children' (HBSC) study were collected in 2005/06 (N = 160,830) and 2009/10 (N = 166,590) in 31 European and North American countries. Logistic multilevel models were used to assess the contribution of youth unemployment in 2009/10 (enduring recession) and the change in youth unemployment (2005-2010) to adolescent psychological health complaints and socioeconomic inequalities in complaints in 2009/10. RESULTS: Youth unemployment during the recession is positively related to psychological health complaints, but not to inequalities in complaints. Changes in youth unemployment (2005-2010) were not associated with adolescents' psychological health complaints, whereas greater inequalities in complaints were found in countries with greater increases in youth unemployment. CONCLUSIONS: This study highlights the need to tackle the impact of increasing unemployment on adolescent health and health inequalities during economic recessions. PMID- 27502511 TI - Competition in the healthcare sector: a missing dimension. PMID- 27502512 TI - Gain-of-Function Research: Ethical Analysis. AB - Gain-of-function (GOF) research involves experimentation that aims or is expected to (and/or, perhaps, actually does) increase the transmissibility and/or virulence of pathogens. Such research, when conducted by responsible scientists, usually aims to improve understanding of disease causing agents, their interaction with human hosts, and/or their potential to cause pandemics. The ultimate objective of such research is to better inform public health and preparedness efforts and/or development of medical countermeasures. Despite these important potential benefits, GOF research (GOFR) can pose risks regarding biosecurity and biosafety. In 2014 the administration of US President Barack Obama called for a "pause" on funding (and relevant research with existing US Government funding) of GOF experiments involving influenza, SARS, and MERS viruses in particular. With announcement of this pause, the US Government launched a "deliberative process" regarding risks and benefits of GOFR to inform future funding decisions-and the US National Science Advisory Board for Biosecurity (NSABB) was tasked with making recommendations to the US Government on this matter. As part of this deliberative process the National Institutes of Health commissioned this Ethical Analysis White Paper, requesting that it provide (1) review and summary of ethical literature on GOFR, (2) identification and analysis of existing ethical and decision-making frameworks relevant to (i) the evaluation of risks and benefits of GOFR, (ii) decision-making about the conduct of GOF studies, and (iii) the development of US policy regarding GOFR (especially with respect to funding of GOFR), and (3) development of an ethical and decision making framework that may be considered by NSABB when analyzing information provided by GOFR risk-benefit assessment, and when crafting its final recommendations (especially regarding policy decisions about funding of GOFR in particular). The ethical and decision-making framework ultimately developed is based on the idea that there are numerous ethically relevant dimensions upon which any given case of GOFR can fare better or worse (as opposed to there being necessary conditions that are either satisfied or not satisfied, where all must be satisfied in order for a given case of GOFR to be considered ethically acceptable): research imperative, proportionality, minimization of risks, manageability of risks, justice, good governance (i.e., democracy), evidence, and international outlook and engagement. Rather than drawing a sharp bright line between GOFR studies that are ethically acceptable and those that are ethically unacceptable, this framework is designed to indicate where any given study would fall on an ethical spectrum-where imaginable cases of GOFR might range from those that are most ethically acceptable (perhaps even ethically praiseworthy or ethically obligatory), at one end of the spectrum, to those that are most ethically problematic or unacceptable (and thus should not be funded, or conducted), at the other. The aim should be that any GOFR pursued (and/or funded) should be as far as possible towards the former end of the spectrum. PMID- 27502513 TI - A Breastfeeding Quality Improvement Project in Rural Primary Care. AB - BACKGROUND: Breastfeeding is the gold standard nutrition for infants, and more than three-fourths of US mother-infant couplets initiate breastfeeding at birth. However, breastfeeding rates plummet after hospital discharge, when mother-infant couplets enter primary care. This quality improvement project examined the effect of a primary care intervention on breastfeeding rates from the newborn visit through the 4-month visit. OBJECTIVE: The overall aim of this evidence-based quality improvement project was to increase breastfeeding rates by refining the care provided to a diverse patient population with historically low breastfeeding rates. METHODS: Two independent groups of mother-infant couplets, a pre implementation (N = 43) and a post-implementation (N = 45), were longitudinally evaluated on breastfeeding rates at the newborn, 1-month, 2-month, and 4-month well-child visits for exclusive, partial, and any breastfeeding rates. Relationships for the 2 groups were compared using 2-sample t tests, chi-square, and Fisher exact tests. RESULTS: Post-implementation rates for any breastfeeding progressively increased at each timepoint. Exclusive breastfeeding increased 40.98% at the 1-month visit, 27.4% at the 2-month visit, and 139% at the 4-month visit. CONCLUSION: The implementation of an evidence-based breastfeeding-friendly office protocol in a rural low breastfeeding rate primary care setting was associated with increased breastfeeding rates. PMID- 27502514 TI - Community Rates of Breastfeeding Initiation. AB - BACKGROUND: Breastfeeding initiation rates vary considerably across racial and ethnic groups, maternal age, and education level, yet there are limited data concerning the influence of geography on community rates of breastfeeding initiation. OBJECTIVE: This study aimed to describe how community rates of breastfeeding initiation vary in geographic space, highlighting "hot spots" and "cool spots" of initiation and exploring the potential connections between race, socioeconomic status, and urbanization levels on these patterns. METHODS: Birth certificate data from the Kentucky Department of Health for 2004-2010 were combined with county-level geographic base files, Census 2010 demographic and socioeconomic data, and Rural-Urban Continuum Codes to conduct a spatial statistical analysis of community rates of breastfeeding initiation. RESULTS: Between 2004 and 2010, the average rate of breastfeeding initiation for Kentucky increased from 43.84% to 49.22%. Simultaneously, the number of counties identified as breastfeeding initiation hot spots also increased, displaying a systematic geographic pattern in doing so. Cool spots of breastfeeding initiation persisted in rural, Appalachian Kentucky. Spatial regression results suggested that unemployment, income, race, education, location, and the availability of International Board Certified Lactation Consultants are connected to breastfeeding initiation. CONCLUSION: Not only do spatial analytics facilitate the identification of breastfeeding initiation hot spots and cool spots, but they can be used to better understand the landscape of breastfeeding initiation and help target breastfeeding education and/or support efforts. PMID- 27502519 TI - Skeletal Muscle Differentiation on a Chip Shows Human Donor Mesoangioblasts' Efficiency in Restoring Dystrophin in a Duchenne Muscular Dystrophy Model. AB - : : Restoration of the protein dystrophin on muscle membrane is the goal of many research lines aimed at curing Duchenne muscular dystrophy (DMD). Results of ongoing preclinical and clinical trials suggest that partial restoration of dystrophin might be sufficient to significantly reduce muscle damage. Different myogenic progenitors are candidates for cell therapy of muscular dystrophies, but only satellite cells and pericytes have already entered clinical experimentation. This study aimed to provide in vitro quantitative evidence of the ability of mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from DMD patients, using a microengineered model. We designed an ad hoc experimental strategy to miniaturize on a chip the standard process of muscle regeneration independent of variables such as inflammation and fibrosis. It is based on the coculture, at different ratios, of human dystrophin-positive myogenic progenitors and dystrophin-negative myoblasts in a substrate with muscle-like physiological stiffness and cell micropatterns. Results showed that both healthy myoblasts and mesoangioblasts restored dystrophin expression in DMD myotubes. However, mesoangioblasts showed unexpected efficiency with respect to myoblasts in dystrophin production in terms of the amount of protein produced (40% vs. 15%) and length of the dystrophin membrane domain (210-240 um vs. 40-70 um). These results show that our microscaled in vitro model of human DMD skeletal muscle validated previous in vivo preclinical work and may be used to predict efficacy of new methods aimed at enhancing dystrophin accumulation and distribution before they are tested in vivo, reducing time, costs, and variability of clinical experimentation. SIGNIFICANCE: This study aimed to provide in vitro quantitative evidence of the ability of human mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from patients with Duchenne muscular dystrophy (DMD), using a microengineered model. An ad hoc experimental strategy was designed to miniaturize on a chip the standard process of muscle regeneration independent of variables such as inflammation and fibrosis. This microscaled in vitro model, which validated previous in vivo preclinical work, revealed that mesoangioblasts showed unexpected efficiency as compared with myoblasts in dystrophin production. Consequently, this model may be used to predict efficacy of new drugs or therapies aimed at enhancing dystrophin accumulation and distribution before they are tested in vivo. PMID- 27502520 TI - Characterization of hydrocarbons in aerosols at a Mediterranean city with a high density of palm groves. AB - Samples of PM1 and PM10 were collected for 1 year at an urban background station in the city of Elche (southeastern Spain) and analyzed to determine the content of n-alkanes and polycyclic aromatic hydrocarbons (PAHs). A few samples were also gathered at a second sampling point established at one of the several palm tree gardens of the city in order to evaluate the influence of biogenic emissions on the urban levels of n-alkanes. Diagnostic parameters obtained for aliphatic hydrocarbons (carbon maximum number (C max), carbon preference index (CPI), and wax n-alkane content (%WNA)) revealed a higher contribution of biogenic n-alkanes in PM10 than in PM1. Moreover, the values of %WNA indicated that the levels of n alkanes in Elche were more affected by emissions from terrestrial vegetation than in other urban areas, particularly in the palm tree grove location (%WNA = 29 for PM10). PAH diagnostic ratios pointed to traffic as the main anthropogenic source of hydrocarbons in Elche, with predominance of diesel versus gasoline vehicle emissions. The average levels of total PAHs (~1 ng m(-3)) were noticeably lower than the values registered at other urban areas in Europe, most likely because emissions from other sources are scarce. Both aliphatic and aromatic hydrocarbons showed higher levels in the cold season due to the lower atmospheric dispersion conditions, the increase in traffic exhaust emissions, and the lower ambient temperatures that reduce the evaporation of semivolatile species. PMID- 27502521 TI - A multi-temporal analysis for change assessment and estimation of algal bloom in Sambhar Lake, Rajasthan, India. AB - Sambhar Lake in Rajasthan, India is the major inland salt water lake producing salt for centuries. The present study addresses the monitoring changes in and around the lake and its consequent effect on the lake water ecology. For this, satellite images of the years 1976, 1981, 1997, and 2013 are analyzed for land use land cover classes. Significant reduction in the water body is observed in contrast with the increase in salt pan around the periphery of lake and wetland classes. Further, the extent of water body and algae in the lake are delineated as per normalized difference water index and normalized difference vegetation index. Rainfall data do not indicate any major change in the pattern, but drastic decrease in the extent of water body and significant increase in algal bloom are serious concerns for the lake's existence. This may be due to surrounding anthropogenic activities and construction of check dams and anicuts in the lake catchment which curtail the runoff into the lake and provide favorable growth of algae. Sambhar Lake, being declared as a wetland according to the Ramsar Convention, is necessary to protect and conserve the ecological importance of the lake through sustainable planning and management. PMID- 27502522 TI - Polycyclic aromatic hydrocarbons in urban green spaces of Beijing: concentration, spatial distribution and risk assessment. AB - A comprehensive investigation of the levels, spatial distribution of polycyclic aromatic hydrocarbons (PAHs) in urban green space soils of Beijing, China, was conducted, and the potential human health risks associated with the levels observed were addressed. The objective of this study was to determine concentration, spatial distribution, and health risk of 15 PAHs in 121 surface soil (0-5 cm) samples collected from four types of green space, such as park green space (PGS), roadside green space (RDS), residential green space (RGS), and attached green space (AGS). Results showed that the highest concentrations of 15 PAHs was in soils of RDS, followed by RGS, PGS, and AGS. The level of PAHs pollution was seriously and mainly distributed in the central and southwest of the city. Incremental lifetime cancer risks (ILCRs) associated with exposures to PAHs in soil was calculated separately for children and adults under normal and extreme conditions. The results showed that ILCRs for urban green space soil of Beijing were low under normal conditions. But individual samples are seriously polluted, and its potential health risks cannot be ignored. PMID- 27502523 TI - Offline solid-phase extraction for preconcentration of pharmaceuticals and personal care products in environmental water and their simultaneous determination using the reversed phase high-performance liquid chromatography method. AB - The present study reports a precise and simple offline solid-phase extraction (SPE) coupled with reversed-phase high-performance liquid chromatography (RP HPLC) method for the simultaneous determination of five representative and commonly present pharmaceuticals and personal care products (PPCPs), a new class of emerging pollutants in the aquatic environment. The target list of analytes including ciprofloxacin, acetaminophen, caffeine benzophenone and irgasan were separated by a simple HPLC method. The column used was a reversed-phase C18 column, and the mobile phase was 1 % acetic acid and methanol (20:80 v/v) under isocratic conditions, at a flow rate of 1 mL min(-1). The analytes were separated and detected within 15 min using the photodiode array detector (PDA). The linearity of the calibration curves were obtained with correlation coefficients 0.98-0.99.The limit of detection (LOD), limit of quantification (LOQ), precision, accuracy and ruggedness demonstrated the reproducibility, specificity and sensitivity of the developed method. Prior to the analysis, the SPE was performed using a C18 cartridge to preconcentrate the targeted analytes from the environmental water samples. The developed method was applied to evaluate and fingerprint PPCPs in sewage collected from a residential engineering college campus, polluted water bodies such as Nag river and Pili river and the influent and effluent samples from a sewage treatment plant (STP) situated at Nagpur city, in the peak summer season. This method is useful for estimation of pollutants present in microquantities in the surface water bodies and treated sewage as compared to nanolevel pollutants detected by mass spectrometry (MS) detectors. PMID- 27502524 TI - Are Saudi medical students aware of middle east respiratory syndrome coronavirus during an outbreak? AB - Recently, an outbreak of MERS-CoV occurred in King Abdulaziz Medical City (KAMC), Riyadh. This outbreak contributed to the students at the King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) becoming more involved in promoting health awareness in their communities. This was a cross-sectional study that evaluated students in the clinical phase of medical school. The data were collected by an online questionnaire. The measurements were obtained using a researcher-administered and a self-reported questionnaire that had been previously validated. A p-value of less than 0.05 was considered statistically significant. One hundred and thirty-six students participated and showed good awareness regarding the clinical aspects of MERS, such as etiology, diagnosis, management, and prevention. However, 76% of the students were not aware of the mortality rate. Conversely, this study uncovered a low level of awareness in the basic sciences. Interestingly, fifth year medical students were more familiar with the incubation period than final year students (p-value <0.05). Regarding gender differences, more female students were knowledgeable about the incubation period and the possible asymptomatic presentation of the disease than male students (p-value <0.05). However, male students were more aware of the diagnostic tests for MERS than their female counterparts. Medical students were knowledgeable about the clinical aspects of MERS but were lacking background awareness in the basic sciences. PMID- 27502525 TI - Police officers gunned down while protecting vaccination workers in Pakistan. PMID- 27502526 TI - Prevalence and risk factors for viral blipping in chronic hepatitis B patients treated with nucleos (t) ide analogues. AB - The clinical relevance of viral blipping during nucleos (t) ide analogue (NA) treatment is unclear in chronic hepatitis B (CHB). We investigated the prevalence, risk factors and clinical outcomes for those with viral blipping during NA treatment. A retrospective cohort study investigated consecutively treated CHB patients from May 2008 to February 2015 on the NAs such as entecavir (ETV), tenofovir (TDF) and lamivudine (LAM). Included patients were previously treatment naive. Viral blipping was defined as serum HBV DNA >20 IU/mL on one occasion, and not >200 IU/mL, with subsequent measurement returning to undetectable levels, that is <20 IU/mL. A total of 242 treatment-compliant CHB patients were included with 44 (18.2%) experiencing viral blipping. In multivariable Cox regression, Asian race (HR=7.40, 95% CI 1.01-54.29, P<.049), LAM therapy (vs ETV/TDF, HR=2.53, 95% CI 1.29-4.95, P<.007), higher creatinine (per SD, HR=1.47, 95% CI 1.21-1.79, P<.001), HBeAg positivity (HR=2.68, 95% CI 1.39-5.03, P<.003) and longer time to achieve undetectable HBV DNA (per month, HR=1.05, 95% CI 1.02-1.08, P=.001) were associated with an increased risk of viral blipping. Viral blipping did not show any significant association with viral breakthrough, HBsAg loss, ALT flares or disease progression. Viral blipping is a frequent event during NA therapy; however, it did not lead to any clinically significant outcomes. Thus, it may not require more frequent blood work and patient visits in clinical practice. PMID- 27502527 TI - Delirium in elderly patients: association with educational attainment. AB - OBJECTIVE: Among cognitive reserve markers, educational attainment is the most widely studied, with several studies establishing a strong association with risk of dementia. However, it has not yet been fully examined in delirium. This study aims to analyse the relationship between educational attainment and delirium. METHODS: The study included elderly hospitalised patients admitted (>=48 h) into an intermediate care unit (IMCU) of Intensive Care Medicine Service. Exclusion criteria were as follows: Glasgow Coma Scale (total<=11), blindness/deafness, inability to communicate or to speak Portuguese. The European Portuguese Version of the Confusion Assessment Method (CAM) was used for delirium assessment. RESULTS: The final sample (n=157) had a mean age of 78.8 (SD=7.6) the majority being female (52.2%), married (51.5%) and with low educational level (49%). According to CAM, 21% of the patients had delirium. The delirium group presented the fewest years of education (median 1 vs. 4), with statistical significance (p=0.003). Delirium was more frequent among male patients [odds ratio (OR) 0.32; 95% confidence interval (CI) 0.12-0.86; p=0.023], as well as those patients with lower education (OR 0.76; 95% CI 0.62-0.95; p=0.016), and with respiratory disease (OR 3.35; 95% CI 1.20-9.33; p=0.020), after controlling for age and medication. CONCLUSION: Similar to previous studies, these findings point to a negative correlation between education and delirium. This study appears as an attempt to contribute to the knowledge about the role of cognitive reserve in risk of delirium, particularly because is the first one that has been carried out in an IMCU, with lower educated elderly patients. Further studies are needed to clarify this relationship considering other markers (e.g. cognitive activities), which can contribute to the definition of preventive strategies. PMID- 27502528 TI - Weight gain in insulin-treated patients by body mass index category at treatment initiation: new evidence from real-world data in patients with type 2 diabetes. AB - AIMS: To evaluate, in patients with type 2 diabetes (T2DM) treated with insulin, the extent of weight gain over 2 years of insulin treatment, and the dynamics of weight gain in relation to glycaemic achievements over time according to adiposity levels at insulin initiation. MATERIALS AND METHODS: Patients with T2DM (n = 155 917), who commenced insulin therapy and continued it for at least 6 months, were selected from a large database of electronic medical records in the USA. Longitudinal changes in body weight and glycated haemoglobin (HbA1c) according to body mass index (BMI) category were estimated. RESULTS: Patients had a mean age of 59 years, a mean HbA1c level of 9.5%, and a mean BMI of 35 kg/m2 at insulin initiation. The HbA1c levels at insulin initiation were significantly lower (9.2-9.4%) in the obese patients than in patients with normal body weight (10.0%); however, the proportions of patients with HbA1c >7.5% or >8.0% were similar across the BMI categories. The adjusted weight gain fell progressively with increasing baseline BMI category over 6, 12 and 24 months (p < .01). The adjusted changes in HbA1c were similar across BMI categories. A 1% decrease in HbA1c was associated with progressively less weight gain as pretreatment BMI rose, ranging from a 1.24 kg gain in those with a BMI <25 kg/m2 to a 0.32 kg loss in those with a BMI > 40 kg/m2 . CONCLUSIONS: During 24 months of insulin treatment, obese patients gained significantly less body weight than normal weight and overweight patients, while achieving clinically similar glycaemic benefits. These data provide reassurance with regard to the use of insulin in obese patients. PMID- 27502529 TI - Significance Testing Needs a Taxonomy: Or How the Fisher, Neyman-Pearson Controversy Resulted in the Inferential Tail Wagging the Measurement Dog. AB - Accurate measurement and a cutoff probability with inferential statistics are not wholly compatible. Fisher understood this when he developed the F test to deal with measurement variability and to make judgments on manipulations that may be worth further study. Neyman and Pearson focused on modeled distributions whose parameters were highly determined and concluded that inferential judgments following an F test could be made with accuracy because the distribution parameters were determined. Neyman and Pearson's approach in the application of statistical analyses using alpha and beta error rates has played a dominant role guiding inferential judgments, appropriately in highly determined situations and inappropriately in scientific exploration. Fisher tried to explain the different situations, but, in part due to some obscure wording, generated a long standing dispute that currently has left the importance of Fisher's p < .05 criteria not fully understood and a general endorsement of the Neyman and Pearson error rate approach. Problems were compounded with power calculations based on effect sizes following significant results entering into exploratory science. To understand in a practical sense when each approach should be used, a dimension reflecting varying levels of certainty or knowledge of population distributions is presented. The dimension provides a taxonomy of statistical situations and appropriate approaches by delineating four zones that represent how well the underlying population of interest is defined ranging from exploratory situations to highly determined populations. PMID- 27502530 TI - The Taxonic Latent Structure and Taxometrics in Forensic Mental Health. AB - Recently, researchers in the field of forensic mental health have attempted to address the technical, empirical question of whether important clinical problems, such as psychopathy or malingering, constitute taxa (i.e., discrete conditions). In this paper, we provide a detailed elucidation of the foundational logic of the quantitative methods employed to answer this question, focusing on the taxometric procedures developed by Paul Meehl and colleagues. We attempt to demonstrate that research on taxonicity is hampered by (a) researchers' unfamiliarity with or misunderstanding of the logic underlying latent variable technologies and (b) the fundamental incapacity of Meehlian procedures to provide a test of taxonicity. We conclude by discussing the utility of taxometric procedures to research in forensic mental health and, more broadly, in the field of applied psychological measurement. PMID- 27502531 TI - Males Perform Better in Identifying Voices During Menstruation Than Females: A Pilot Study. AB - The objective of the present study is to investigate gender differences in the ability to identify females' voice during menstruation. In Study 1, 55 male participants (M age = 19.6 years, SD = 1.0) were asked to listen to vocal samples from women during both ovulation and menstruation and to identify which recordings featured menstruating women. The results showed that the accuracy of men's responses (M = 56.73%, SD = 0.21) was significantly higher than 50%. In Study 2, 118 female students (M age = 19.4 years, SD = 1.6) completed the same task. The results indicated that the accuracy of women's performance was nearly 50%. These preliminary findings suggest that men are better able to identify women's voices during menstruation than women. Future work could consider several significant variables for the purpose of validating the results. PMID- 27502532 TI - A Brief Exploratory Report of Coping Strategies Among Police Recruits During Academy Training. AB - Few longitudinal studies have investigated the use of coping strategies among police recruits. This study investigated perceived life and work stressors, appraisal, and coping over a seven-month police recruit academy training program. Participants were 81 police recruits who completed the Ways of Coping Questionnaire at three time points approximately three months apart. The average age of the recruits was 27.6 years (SD = 5.1, range 20-51). Separate repeated measures analyses of variance were conducted to examine coping scores. Statistically significant decreases, although small, were observed in reported emotion-focused, problem-focused, and seeking social support coping strategies. Results suggested that as police recruits undergo academy training, they rely on fewer coping strategies to deal with life and work stress. More longitudinal studies are needed that assess the methods police recruits utilize to manage stress during academy training. Such results can inform stress management interventions. PMID- 27502533 TI - Impact of the DSM-V Attention Deficit Hyperactivity Disorder Criteria for Diagnosing Children With High IQ. AB - This study compared the number of attention deficit hyperactivity disorder (ADHD) cases defined by Diagnostic and Statistical Manual (DSM)-IV versus DSM-V criterion in children who have learning or behavioral problems with high IQ. The medical records of children <=15 years of age who presented with learning or behavioral problems and underwent a Wechsler Intelligence Scale for Children (WISC)-III IQ test at the Pediatric Outpatient Clinic unit between 2010 and 2015 were reviewed. Information on DSM-IV and DSM-V criteria for ADHD were derived from computer-based medical records. Twenty-eight children who had learning or behavioral problems were identified to have a full-scale IQ >=120. Sixteen of these high-IQ children met the DSM-IV criteria diagnosis for ADHD. Applying the extension of the age-of-onset criterion from 7 to 12 years in DSM-V led to an increase of three cases, all of which were the inattentive type ADHD. Including the pervasive developmental disorder criterion led to an increase of one case. The total number of ADHD cases also increased from 16 to 20 in this group. The data supported the hypothesis that applying the extension of the age-of-onset ADHD criterion and enabling the diagnosis of children with pervasive developmental disorders will increase the number of ADHD diagnoses among children with high IQ. PMID- 27502534 TI - Effect of Acute Emotional Stress on Proteomic Profile of Selected Brain Areas and Lysosomal Proteolysis in Rats with Different Behavioral Activity. AB - We compared proteome profiles of selected brain areas (cortex, amygdala, hippocampus, and reticular formation) and measured cathepsins B and D activity in liver lysosomal fraction in rats with different behavioral activity under conditions of emotional stress. In passive rats, the expression of some proteins in various brain regions was changed and baseline cathepsin B activity was higher than in active animals. Taken together, the results attest to differences in the adaptive response formation in rats, depending on behavioral features. PMID- 27502535 TI - Effect of Afobazole and Betaine on Cognitive Disorders in the Offspring of Rats with Streptozotocin-Induced Diabetes and Their Relationship with DNA Damage. AB - Cognitive activity in 60-day-old offspring of rats (intrauterine development in experimental streptozotocin-induced diabetes) was studied on the model of food seeking behavior under conditions of free choice in a 6-arm maze. The formation of the food-procuring skill was significantly delayed, which attests to impairment of cognitive functions in these animals. Peroral administration of afobazole (10 and 50 mg/kg) and betaine (50 and 100 mg/kg) significantly and dose dependently alleviated this disorder. Correlation analysis of the data on delayed formation of a food-procuring skill and results of DNA comet attests to a strong relationship between DNA damage in cells of the embryo and placenta during intrauterine development and cognitive dysfunction in the postnatal offspring of animals with streptozotocin-induced diabetes. PMID- 27502536 TI - Antitumor Effects of JAK3 Inhibitor on the Model of Transplantable Lewis Lung Carcinoma and Mechanisms of Their Development. AB - Mice with Lewis lung carcinoma were used to study the antitumor and antimetastatic effects of JAK3 inhibitor. The study revealed no effect of JAK3 inhibitor on the growth of primary tumor node, but found a pronounced inhibition of hematogenous spread of the pathologic process into the lungs. In vitro blockade of JAK3 in cultured Lewis lung carcinoma produced no effect on the count of the stem tumor cells and stimulated functions of committed elements. In addition, blockade of JAK3 significantly elevated maturation index of the tumor tissue. PMID- 27502537 TI - Enzyme Changes in the Offspring of Female Rats due to Long-Term Administration of Cyclic AMP and Insulin before Pregnancy. AB - We studied the effects of insulin and cAMP on the offspring of female rats after daily treatment with these substances over 4 weeks. In adult offspring from cAMP treated females, activities of pyruvate kinase and glucose-6-phosphate dehydrogenase decreased in the liver and brain and activities of NADP-dependent malate dehydrogenase and 6-phosphogluconate dehydrogenase decreased in the liver. In the offspring of insulin-treated females, we observed only activation of glucose-6-phosphate dehydrogenase and malate dehydrogenase in the liver and only in females. Enzyme activity probably correlates with their content, as no changes in their kinetic properties were observed under these conditions. Long-term hormone treatment before pregnancy can affect the expression of genes for some enzymes in the offspring due to transmission of epigenetic signals by the ovum. However, further studies are required to confirm this mechanism. PMID- 27502538 TI - Evidence of Echocardiography Validity in Model Experiments on Small Animals. AB - Dynamic echocardiographic monitoring in rats subjected to forced alcoholization showed the formation of disorders in intracardiac hemodynamics characteristic of ethanol cardiomyopathy formed by the end of 24-week continuous ethanol consumption. The results of echocardiographic monitoring were confirmed by histological and morphometric studies demonstrating fatty infiltration of the myocardium pathognomonic for this condition and bifocal dilatation of cardiac ventricles. These results persuasively demonstrate that echocardiographic studies on small animals are valid and can be used for search for cardiotropic drugs and studies of the mechanisms of their activities. PMID- 27502539 TI - Studying the General Toxicity and Cumulative Properties of a Radiopharmaceutical Nanocolloid, (99m)Tc-Al2O3. AB - We studied toxicity of a new Russian radiopharmaceutical Nanocolloid, (99m)Tc Al2O3. Tests for acute toxicity showed that this agent belongs to a class of moderate-toxicity substances and does not have cumulative properties. The evaluation of subchronic toxicity after subcutaneous injection of this product to rats (0.04, 0.2, and 0.4 ml/kg) and rabbits (0.02 and 0.2 ml/kg) for 7 days did not reveal changes in the general state, temperature, body weight, indices of the peripheral blood and bone marrow, functions of the heart, liver, kidneys, and nervous system, and morphological characteristics of the internal organs in animals. The drug does not produce a local irritant effect. PMID- 27502540 TI - Investigation of anti-asthmatic potential of Kanakasava in ovalbumin-induced bronchial asthma and airway inflammation in rats. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: Kanakasava is an Indian traditional Ayurvedic formulation containing Datura (Datura metel), Vasaca (Adhatoda vasica), Dhataki (Woodfordia fruticosa) and Grape (Vitis vinifera) extracts as major constituents and used to treat pulmonary diseases including coughing, breathing difficulty and asthma. The present study was designed to assess the safety and therapeutic efficacy of Kanakasava against ovalbumin-induced bronchial asthma and related airway inflammation in rats due to lack of evidence based therapeutic efficacy data. MATERIAL AND METHODS: Male wistar rats were sensitized with allergen (ovalbumin, 40mg/rat+aluminum hydroxide, 2.0mg/rat) and treated orally with standard dexamethasone (2.5mg/kg, b.w.) or Kanakasava (1.23 and 2.46ml/kg, b.w.) from day 1 to day 28. Inflammatory markers, including cell counts and cytokines such as interleukins (IL-4, IL-5, IL-1beta), tumor necrosis factor (TNF-alpha), leukotriene (LTD-4), immunoglobulin (IgE), nitric oxide and nitrite levels in both blood and broncheo alveolar lavaged fluid (BALF) were analyzed. Abdominal mesentery was studied histologically for mast cell degranulation, whereas lung functions were investigated by spirometer. Method was also developed to quantify gallic acid and ethyl gallate content in Kanakasava by HPTLC for its quality control. RESULTS: None of the rats exhibited mortality and Kanakasava was found to be safe at the tested doses. Treatment with Kanakasava significantly (P<0.01) reversed elevated levels of IgE, cytokines, nitrites and influx of eosinophils and neutrophils in blood and BALF. These findings were further supported by the significant improvement in lung functions (P<0.01) and suppression (P<0.01) of degranulation of mast cells. The content of gallic acid and ethyl gallate in Kanakasava was found to be 1.94% and 0.98%, respectively. CONCLUSION: These findings demonstrated the preventive effect of Kanakasava in allergen induced model of asthma providing scientific basis for its traditional use in Ayurveda, since long time. PMID- 27502541 TI - Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors. AB - Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacologic inhibition of COT should be a valid approach to therapeutically intervene in the pathogenesis of macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report the discovery and chemical optimization of a novel series of COT kinase inhibitors, with unprecedented nanomolar potency for the inhibition of TNFalpha. Pharmacological profiling in vivo revealed a high metabolism of these compounds in rats which was demonstrated to be predominantly attributed to aldehyde oxidase. Due to the very low activity of hepatic AO in the dog, the selected candidate 32 displayed significant blood exposure in dogs which resulted in a clear prevention of inflammation-driven lameness. Taken together, the described compounds both potently and selectively inhibit COT kinase in primary human cells and ameliorate inflammatory pathologies in vivo, supporting the notion that COT is an appropriate therapeutic target for inflammatory diseases. PMID- 27502542 TI - Calpains are involved in asexual and sexual development, cell wall integrity and pathogenicity of the rice blast fungus. AB - Calpains are ubiquitous and well-conserved proteins that belong to the calcium dependent, non-lysosomal cysteine protease family. In this study, 8 putative calpains were identified using Pfam domain analysis and BlastP searches in M. oryzae. Three single gene deletion mutants (DeltaMocapn7, DeltaMocapn9 and DeltaMocapn14) and two double gene deletion mutants (DeltaMocapn4DeltaMocapn7 and DeltaMocapn9DeltaMocapn7) were obtained using the high-throughput gene knockout system. The calpain disruption mutants showed defects in colony characteristics, conidiation, sexual reproduction and cell wall integrity. The mycelia of the DeltaMocapn7, DeltaMocapn4DeltaMocapn7 and DeltaMocapn9DeltaMocapn7 mutants showed reduced pathogenicity on rice and barley. PMID- 27502543 TI - Computer simulations of a new toroidal-cylindrical ion trap mass analyzer. AB - RATIONALE: A novel toroidal-cylindrical ion trap (TCIT) design is introduced based on a compact dual ion trap system that comprises an outer toroidal ion trap (T-trap) and an inner cylindrical ion trap (CIT). These two traps have specific but different functions that can improve the performance of tandem mass analysis operation. METHODS: The TCIT is studied by using a simulated mass spectrometer platform that is mainly based on SIMION modeling and extensive data processing. This platform combines different functions, such as simulation of ion motion and field calculations, as well as acquisition of a simulated mass spectrum. RESULTS: The main steps of the MS operation, including the full scan process, the mass selective ejection of the ions in the T-trap, and the capture of the injected precursor ions in the CIT, are realized using the abovementioned platform. In addition, the simulated design is optimized for improved mass analysis performance. CONCLUSIONS: For the outer T-trap, when the outside surface of the inner cylindrical electrode is modified to include a circular arc with appropriate radius, the ion ejection efficiency that is directed into the CIT could be significantly enhanced. In the case of the inner CIT, the ion capture efficiency could be improved to more than 90% with geometry optimization. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27502545 TI - Evaluation of VDR gene polymorphisms in Trypanosoma cruzi infection and chronic Chagasic cardiomyopathy. AB - Vitamin D is an important modulator of the immune response. It acts over several immune cell types where the Vitamin D receptor (VDR) is expressed. Due to the high relevance of this signaling pathway, several studies have investigated the possible influence of genes involved in the metabolism of Vitamin D and its receptor in different human diseases. Here, we analyzed whether four single nucleotide polymorphisms of the VDR gene (rs731236, rs7975232, rs1544410 and rs2228570) are involved in the susceptibility to infection by Trypanosoma cruzi and/or to chronic Chagas cardiomyopathy (CCC) in a Colombian endemic population for this parasite. Our results showed that the rs2228570*A allele is associated with CCC development (P = 4.46E-03, OR = 1.51). In summary, the data presented in this report suggest that variation within the VDR gene may affect the immune response against T. cruzi, increasing the probability of cardiac complications in infected individuals. PMID- 27502546 TI - Evolution of Insulator-Metal Phase Transitions in Epitaxial Tungsten Oxide Films during Electrolyte-Gating. AB - An interface between an oxide and an electrolyte gives rise to various processes as exemplified by electrostatic charge accumulation/depletion and electrochemical reactions such as intercalation/decalation under electric field. Here we directly compare typical device operations of those in electric double layer transistor geometry by adopting A-site vacant perovskite WO3 epitaxial thin films as a channel material and two different electrolytes as gating agent. In situ measurements of X-ray diffraction and channel resistance performed during the gating revealed that in both the cases WO3 thin film reaches a new metallic state through multiple phase transitions, accompanied by the change in out-of-plane lattice constant. Electrons are electrostatically accumulated from the interface side with an ionic liquid, while alkaline metal ions are more uniformly intercalated into the film with a polymer electrolyte. We systematically demonstrate this difference in the electrostatic and electrochemical processes, by comparing doped carrier density, lattice deformation behavior, and time constant of the phase transitions. PMID- 27502547 TI - Transplantation: GoCAR - on the road to reduced allograft loss. PMID- 27502548 TI - Contemporary evidence for robot-assisted radical cystectomy for treating bladder cancer. AB - Robot-assisted radical cystectomy (RARC) is an evolving technique for the treatment of muscle-invasive bladder cancer (MIBC); however, its effectiveness compared with open radical cystectomy (ORC) - the established modality - is debated. Six specific areas of evidence are critically important for supporting the continuing use of RARC for MIBC, including technical aspects of surgery, perioperative outcomes, complications, oncological outcomes, functional outcomes, and financial costs. Considerable progress has been made regarding these aspects and data show that RARC replicates the technical benchmarks of ORC in terms of success of cystectomy, lymph node dissection, and urinary diversion, and could offer advantages over the more-established technique. Despite some clear benefits of RARC (such as reduced blood loss) other perioperative outcomes, including duration of inpatient stay and 30-90 day complication rates, seem to be similar to those of ORC. Current data on oncological and functional outcomes are promising, but robust data from prospective studies will help determine the indications for use of RARC for treating MIBC in the future. PMID- 27502549 TI - Kidney cancer: Open gates for oxaliplatin. PMID- 27502550 TI - Prostate cancer: Focal laser ablation improves short-term outcomes. PMID- 27502551 TI - Panels of chemically-modified heparin polysaccharides and natural heparan sulfate saccharides both exhibit differences in binding to Slit and Robo, as well as variation between protein binding and cellular activity. AB - Heparin/heparan sulfate (HS) glycosaminoglycans are required for Slit-Robo cellular responses. Evidence exists for interactions between each combination of Slit, Robo and heparin/HS and for formation of a ternary complex. Heparin/HS are complex mixtures displaying extensive structural diversity. The relevance of this diversity has been studied to a limited extent using a few select chemically modified heparins as models of HS diversity. Here we extend these studies by parallel screening of structurally diverse panels of eight chemically-modified heparin polysaccharides and numerous natural HS oligosaccharide chromatographic fractions for binding to both Drosophila Slit and Robo N-terminal domains and for activation of a chick retina axon response to the Slit fragment. Both the polysaccharides and oligosaccharide fractions displayed variability in binding and cellular activity that could not be attributed solely to increasing sulfation, extending evidence for the importance of structural diversity to natural HS as well as model modified heparins. They also displayed differences in their interactions with Slit compared to Robo, with Robo preferring compounds with higher sulfation. Furthermore, the patterns of cellular activity across compounds were different to those for binding to each protein, suggesting that biological outcomes are selectively determined in a subtle manner that does not simply reflect the sum of the separate interactions of heparin/HS with Slit and Robo. PMID- 27502552 TI - Oral sildenafil as a treatment option for lymphatic malformations in PIK3CA related tissue overgrowth syndromes. AB - Patients with extensive lymphatic malformations associated with tissue overgrowth syndromes (such as Klippel-Trenaunay syndrome and CLOVES) often pose a therapeutic challenge for physicians. In recent years, it has been suggested that oral sildenafil therapy might be used to treat congenital lymphatic malformations. However, this possible new therapy has not yet been used in patients with lymphatic malformations associated with tissue overgrowth syndromes. A 30-year-old man with extensive capillary-lymphatic malformations of the right leg and thorax, and a tissue overgrowth syndrome caused by a somatic mutation in the PIK3CA gene, was treated with oral sildenafil due to symptoms of pain, dyspnea, and functional impairment. Several weeks after the start of the treatment, the patient reported softening of the lymphatic malformation and a significant improvement of his symptoms and physical condition. So far, sildenafil is still considered a last resort in the treatment of complex treatment-resistant lymphatic malformations. With this case report, we demonstrate that sildenafil could also be an alternative treatment option for lymphatic malformations in patients with syndromes belonging to the PIK3CA related overgrowth spectrum. PMID- 27502553 TI - Closed-state inactivation involving an internal gate in Kv4.1 channels modulates pore blockade by intracellular quaternary ammonium ions. AB - Voltage-gated K(+) (Kv) channel activation depends on interactions between voltage sensors and an intracellular activation gate that controls access to a central pore cavity. Here, we hypothesize that this gate is additionally responsible for closed-state inactivation (CSI) in Kv4.x channels. These Kv channels undergo CSI by a mechanism that is still poorly understood. To test the hypothesis, we deduced the state of the Kv4.1 channel intracellular gate by exploiting the trap-door paradigm of pore blockade by internally applied quaternary ammonium (QA) ions exhibiting slow blocking kinetics and high-affinity for a blocking site. We found that inactivation gating seemingly traps benzyl tributylammonium (bTBuA) when it enters the central pore cavity in the open state. However, bTBuA fails to block inactivated Kv4.1 channels, suggesting gated access involving an internal gate. In contrast, bTBuA blockade of a Shaker Kv channel that undergoes open-state P/C-type inactivation exhibits fast onset and recovery inconsistent with bTBuA trapping. Furthermore, the inactivated Shaker Kv channel is readily blocked by bTBuA. We conclude that Kv4.1 closed-state inactivation modulates pore blockade by QA ions in a manner that depends on the state of the internal activation gate. PMID- 27502554 TI - Complementary mechanisms create direction selectivity in the fly. AB - How neurons become sensitive to the direction of visual motion represents a classic example of neural computation. Two alternative mechanisms have been discussed in the literature so far: preferred direction enhancement, by which responses are amplified when stimuli move along the preferred direction of the cell, and null direction suppression, where one signal inhibits the response to the subsequent one when stimuli move along the opposite, i.e. null direction. Along the processing chain in the Drosophila optic lobe, directional responses first appear in T4 and T5 cells. Visually stimulating sequences of individual columns in the optic lobe with a telescope while recording from single T4 neurons, we find both mechanisms at work implemented in different sub-regions of the receptive field. This finding explains the high degree of directional selectivity found already in the fly's primary motion-sensing neurons and marks an important step in our understanding of elementary motion detection. PMID- 27502555 TI - Conserved functional antagonism of CELF and MBNL proteins controls stem cell specific alternative splicing in planarians. AB - In contrast to transcriptional regulation, the function of alternative splicing (AS) in stem cells is poorly understood. In mammals, MBNL proteins negatively regulate an exon program specific of embryonic stem cells; however, little is known about the in vivo significance of this regulation. We studied AS in a powerful in vivo model for stem cell biology, the planarian Schmidtea mediterranea. We discover a conserved AS program comprising hundreds of alternative exons, microexons and introns that is differentially regulated in planarian stem cells, and comprehensively identify its regulators. We show that functional antagonism between CELF and MBNL factors directly controls stem cell specific AS in planarians, placing the origin of this regulatory mechanism at the base of Bilaterians. Knockdown of CELF or MBNL factors lead to abnormal regenerative capacities by affecting self-renewal and differentiation sets of genes, respectively. These results highlight the importance of AS interactions in stem cell regulation across metazoans. PMID- 27502556 TI - Physical association between a novel plasma-membrane structure and centrosome orients cell division. AB - In the last mitotic division of the epidermal lineage in the ascidian embryo, the cells divide stereotypically along the anterior-posterior axis. During interphase, we found that a unique membrane structure invaginates from the posterior to the centre of the cell, in a microtubule-dependent manner. The invagination projects toward centrioles on the apical side of the nucleus and associates with one of them. Further, a cilium forms on the posterior side of the cell and its basal body remains associated with the invagination. A laser ablation experiment suggests that the invagination is under tensile force and promotes the posterior positioning of the centrosome. Finally, we showed that the orientation of the invaginations is coupled with the polarized dynamics of centrosome movements and the orientation of cell division. Based on these findings, we propose a model whereby this novel membrane structure orchestrates centrosome positioning and thus the orientation of cell division axis. PMID- 27502558 TI - Cellular fingers take hold. AB - Invaginations in the membranes of embryonic cells appear to orient cell division in sea squirts. PMID- 27502557 TI - Impact of HIV co-infection on the evolution and transmission of multidrug resistant tuberculosis. AB - The tuberculosis (TB) epidemic is fueled by a parallel Human Immunodeficiency Virus (HIV) epidemic, but it remains unclear to what extent the HIV epidemic has been a driver for drug resistance in Mycobacterium tuberculosis (Mtb). Here we assess the impact of HIV co-infection on the emergence of resistance and transmission of Mtb in the largest outbreak of multidrug-resistant TB in South America to date. By combining Bayesian evolutionary analyses and the reconstruction of transmission networks utilizing a new model optimized for TB, we find that HIV co-infection does not significantly affect the transmissibility or the mutation rate of Mtb within patients and was not associated with increased emergence of resistance within patients. Our results indicate that the HIV epidemic serves as an amplifier of TB outbreaks by providing a reservoir of susceptible hosts, but that HIV co-infection is not a direct driver for the emergence and transmission of resistant strains. PMID- 27502559 TI - Effective antigen presentation to helper T cells by human eosinophils. AB - Although eosinophils are inflammatory cells, there is increasing attention on their immunomodulatory roles. For example, murine eosinophils can present antigen to CD4+ T helper (Th) cells, but it remains unclear whether human eosinophils also have this ability. This study determined whether human eosinophils present a range of antigens, including allergens, to activate Th cells, and characterized their expression of MHC class II and co-stimulatory molecules required for effective presentation. Human peripheral blood eosinophils purified from non allergic donors were pulsed with the antigens house dust mite extract (HDM), Timothy Grass extract (TG) or Mycobacterium tuberculosis purified protein derivative (PPD), before co-culture with autologous CD4+ Th cells. Proliferative and cytokine responses were measured, with eosinophil expression of HLA-DR/DP/DQ and the co-stimulatory molecules CD40, CD80 and CD86 determined by flow cytometry. Eosinophils pulsed with HDM, TG or PPD drove Th cell proliferation, with the response strength dependent on antigen concentration. The cytokine responses varied with donor and antigen, and were not biased towards any particular Th subset, often including combinations of pro- and anti-inflammatory cytokines. Eosinophils up-regulated surface expression of HLA-DR/DP/DQ, CD80, CD86 and CD40 in culture, increases that were sustained over 5 days when incubated with antigens, including HDM, or the major allergens it contains, Der p I or Der p II. Human eosinophils can, therefore, act as effective antigen presenting cells to stimulate varied Th cell responses against a panel of antigens including HDM, TG or PPD, an ability that may help to determine the development of allergic disease. PMID- 27502560 TI - Endothelial Progenitor Cells as Shuttle of Anticancer Agents. AB - Cell therapies are treatments in which stem or progenitor cells are stimulated to differentiate into specialized cells able to home to and repair damaged tissues. After their discovery, endothelial progenitor cells (EPCs) stimulated worldwide interest as possible vehicles to perform autologous cell therapy of tumors. Taking into account the tumor-homing properties of EPCs, two different approaches to control cancer progression have been pursued by combining cell-based therapy with gene therapy or with nanomedicine. The first approach is based on the possibility of engineering EPCs to express different transgenes, and the second is based on the capacity of EPCs to take up nanomaterials. Here we review the most important progress covering the following issues: the characterization of bona fide endothelial progenitor cells, their role in tumor vascularization and metastasis, and preclinical data about their use in cell-based tumor therapy, considering antiangiogenic, suicide, immune-stimulating, and oncolytic virus gene therapy. The mixed approach of EPC cell therapy and nanomedicine is discussed in terms of plasmonic-dependent thermoablation and molecular imaging. PMID- 27502561 TI - Oncologist, patient, and companion questions during pretreatment consultations about adjuvant cancer treatment: a shared decision-making perspective. AB - OBJECTIVES: To assess the occurrence of questions that foster shared decision making, in particular cancer patients' understanding of treatment decisions and oncologists' understanding of patients' priorities, during consultations in which preference-sensitive decisions are discussed. Specifically, (a) regarding patient understanding, do oncologists ask about patients' preexisting knowledge, information preferences, and understanding and do patients and companions ask about the disease and treatment, and (b) regarding patient priorities, do oncologists ask about patients' treatment- and decision-related preferences and do patients and companions ask about the decision? METHODS: Audiotaped pretreatment consultations of 100 cancer patients with 32 oncologists about (neo)adjuvant treatment were coded and analyzed to document question type, topic, and initiative. RESULTS: The oncologists ascertained prior knowledge in 50 patients, asked 24 patients about preferred (probability) information, and invited questions from 56 patients. The oncologists asked 32 patients about treatment preferences and/or for consent. Respectively, one-third and one-fifth of patients and companions asked about treatment benefits compared with three quarters of them who asked about treatment harms and/or procedures. CONCLUSIONS: It would be helpful to patients if oncologists more often assessed patients' existing knowledge to tailor their information provision. Also, patients could receive treatment recommendations that better fit their personal situation if oncologists collected information on patients' views about treatments. Moreover, by educating patients to ask about treatment alternatives, benefits, and harms, patients may gain a better understanding of the choice they have. PMID- 27502562 TI - Prevalence of bacterial resistance within an eco-agricultural system in Hangzhou, China. AB - The wide use of antibiotics in the animal husbandry and the relevant sustainable industries may promote the emergence of antibiotic-resistant bacteria (ARB), which constitutes a growing threat to human health. The objective of this study was to determine the abundance and diversity of sulfonamide- and tetracycline resistant bacteria within an eco-agricultural system (EAS) in Hangzhou, China. We investigated samples at every link in the EAS, from livestock manure, to biogas residues and biogas slurry, to vegetable and ryegrass fields, to a fish pond. A combination of culture-based and 16S rRNA gene-based sequencing method was used in this study. Within the studied system, the average rate of bacterial resistance to sulfonamide (46.19 %) was much higher than that of tetracycline (8.51 %) (p < 0.01). There were 224 isolates that were enumerated and sequenced, 108 of which were identified to species level. The genera comprising the sulfamethoxazole-resistant (SMXr) bacteria were generally different from those of tetracycline-resistant (TCr) bacteria. Staphylococcus and Acinetobacter were the most dominant genera of SMXr bacteria (19.30 % of the total resistant bacteria) and TCr bacteria (14.04 % of the total resistant bacteria), respectively. Several strains of resistant opportunistic pathogens (e.g., Pantoea agglomerans) were detected in edible vegetable samples, which may exert a potential threat to both pig production and human health. In general, this study indicates that the EAS is an important reservoir of antibiotic-resistant bacteria, some of which may be pathogenic. PMID- 27502563 TI - Periphyton: an important regulator in optimizing soil phosphorus bioavailability in paddy fields. AB - Periphyton is ubiquitous in paddy field, but its importance in influencing the bioavailability of phosphorus (P) in paddy soil has been rarely recognized. A paddy field was simulated in a greenhouse to investigate how periphyton influences P bioavailability in paddy soil. Results showed that periphyton colonizing on paddy soil greatly reduced P content in paddy floodwater but increased P bioavailability of paddy soil. Specifically, all the contents of water-soluble P (WSP), readily desorbable P (RDP), algal-available P (AAP), and NaHCO3-extractable P (Olsen-P) in paddy soil increased to an extent compared to the control (without periphyton) after fertilization. In particular, Olsen-P was the most increased P species, up to 216 mg kg-1 after fertilization, accounting for nearly 60 % of total phosphorus (TP) in soil. The paddy periphyton captured P up to 1.4 mg g-1 with Ca-P as the dominant P fraction and can be a potential crop fertilizer. These findings indicated that the presence of periphyton in paddy field benefited in improving P bioavailability for crops. This study provides valuable insights into the roles of periphyton in P bioavailability and migration in a paddy ecosystem and technical support for P regulation. PMID- 27502565 TI - Comparative study of different carbon-supported Fe2O3-Pt catalysts for oxygen reduction reaction. AB - One of the challenges in electrocatalysis is the adequate dispersion of the catalyst on an appropriate porous support matrix, being up to now the most commonly used the carbon-based supports. To overcome this challenge, carbon supports must first be functionalized to guide the catalyst's nucleation, thereby, improving the dispersion and allowing the use of smaller amount of the catalyst material to achieve a higher electrochemically active surface area. This study present the effect of functionalized Vulcan carbon XC72 (FVC) and functionalized Black Pearl carbon (FBPC) as supports on the catalytic activity of decorated Fe2O3 with Pt. Both carbons were functionalized with HNO3 and subsequently treated with ethanolamine. Fe2O3 nanoparticles were synthesized by chemical reduction and decorated with platinum by epitaxial growth. Pt and Fe2O3 structural phases were identified by XRD and XPS; the Pt content was measured by XPS, and results showed to a high Pt content in Fe2O3-Pt/FBPC. TEM micrographs reveal nanoparticles with an average size of 2 nm in both supported catalysts. The Fe2O3-Pt/FVC catalyst presents the highest specific activity and mass activity, 0.21 mA cm-2Pt and 140 mA mgPt-1, respectively, associated to the appropriate distribution of platinum on the Fe2O3 nanoparticles. PMID- 27502564 TI - Biochar enhances the cadmium tolerance in spinach (Spinacia oleracea) through modification of Cd uptake and physiological and biochemical attributes. AB - Cadmium (Cd) has no known role in plant biology and is toxic to plants and animals. The Cd mainly accumulated in agricultural soils through anthropogenic activities, such as sewage water irrigation and phosphorus fertilization. Biochar (BC) has been proposed as an amendment to reduce metal toxicity in plants. The objective of this study was to evaluate the role of BC (cotton stick at a rate of 0, 3, and 5 %) on Cd uptake and the photosynthetic, physiological, and biochemical responses of spinach (Spinacia oleracea) grown in Cd-spiked soil (0, 25, 50, 75, and 100 mg Cd kg-1 soil). The results showed that Cd toxicity decreased growth, photosynthetic pigments, gas exchange characteristics, and amino acid and protein contents in 52-day-old spinach seedlings. The Cd treatments increased the concentrations of Cd, sugar, ascorbic acid, and malondialdehyde (MDA) in plants. The application of BC ameliorated the harmful effects of Cd in spinach plants. Under Cd stress, BC application increased the growth, photosynthesis, and protein contents and decreased Cd concentrations and MDA contents in plants. The maximum BC-mediated increase in dry biomass was about 25 % with 5 % BC application in control plants. It is concluded that BC could ameliorate Cd toxic effects in spinach through changing the physiological and biochemical attributes under Cd stress. PMID- 27502566 TI - Photocatalytic performance of electrospun CNT/TiO2 nanofibers in a simulated air purifier under visible light irradiation. AB - The photocatalytic treatment of gaseous benzene under visible light irradiation was developed using electrospun carbon nanotube/titanium dioxide (CNT/TiO2) nanofibers as visible light active photocatalysts. The CNT/TiO2 nanofibers were fabricated by electrospinning CNT/poly(vinyl pyrrolidone) (PVP) solution followed by the removal of PVP by calcination at 450 degrees C. The molar ratio of CNT/TiO2 was fixed at 0.05:1 by weight, and the quantity of CNT/TiO2 loaded in PVP solution varied between 30 and 60 % wt. CNT/TiO2 nanofibers have high specific surface area (116 m2/g), significantly higher than that of TiO2 nanofibers (44 m2/g). The photocatalytic performance of the CNT/TiO2 nanofibers was investigated by decolorization of 1 * 10-5 M methylene blue (MB) dye (in water solution) and degradation of 100 ppm gaseous benzene under visible light irradiation. The 50-CNT/TiO2 nanofibers (calcined CNT/TiO2 nanofibers fabricated from a spinning solution of 50 % wt CNT/TiO2 based on PVP) had higher MB degradation efficiency (58 %) than did other CNT/TiO2 nanofibers and pristine TiO2 nanofibers (15 %) under visible light irradiation. The photocatalytic degradation of gaseous benzene under visible light irradiation on filters made of 50-CNT/TiO2 nanofibers was carried out in a simulated air purifier system. Similar to MB results, the degradation efficiency of gaseous benzene by 50 CNT/TiO2 nanofibers (52 %) was higher than by other CNT/TiO2 nanofibers and pristine TiO2 nanofibers (18 %). The synergistic effects of the larger surface area and lower band gap energy of CNT/TiO2 nanofibers were presented as strong adsorption ability and greater visible light adsorption. The CNT/TiO2 nanofiber prepared in this study has potential for use in air purifiers to improve air treatment efficiency with less energy. PMID- 27502567 TI - Use of mixed solid waste as a soil amendment for saline-sodic soil remediation and oat seedling growth improvement. AB - Soil salinization has become a worldwide problem that imposes restrictions on crop production and food quality. This study utilizes a soil column experiment to address the potential of using mixed solid waste (vinegar residue, fly ash, and sewage sludge) as soil amendment to ameliorate saline-sodic soil and enhance crop growth. Mixed solid waste with vinegar residue content ranging from 60-90 %, sewage sludge of 8.7-30 %, and fly ash of 1.3-10 % was added to saline-sodic soil (electrical conductivity (EC1:5) = 1.83 dS m-1, sodium adsorption ratio (SAR1:5) = 129.3 (mmolc L-1)1/2, pH = 9.73) at rates of 0 (control), 130, 260, and 650 kg ha-1. Results showed that the application of waste amendment significantly reduced SAR, while increasing soil soluble K+, Ca2+, and Mg2+, at a dose of 650 kg ha-1. The wet stability of macro-aggregates (>1 mm) was improved 90.7-133.7 % when the application rate of amendment was greater than 260 kg ha-1. The application of this amendment significantly reduced soil pH. Germination rates and plant heights of oats were improved with the increasing rate of application. There was a positive correlation between the percentage of vinegar residue and the K/Na ratio in the soil solutions and roots. These findings suggest that applying a mixed waste amendment (vinegar residue, fly ash, and sewage sludge) could be a cost-effective method for the reclamation of saline-sodic soil and the improvement of the growth of salt-tolerant plants. PMID- 27502568 TI - Biosynthesised magnetic iron nanoparticles for sludge dewatering via Fenton process. AB - The magnetic iron nanoparticles (MFeNp) were biosynthesised using the extract of Cinnamomum tamala (bay leaf) and examined for its efficacy on sludge dewatering. The characteristics of MFeNp were studied using scanning electron microscope (SEM), transmission electron microscopy (TEM), x-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and x-ray photoelectron spectrometer (XPS) techniques. The presence of polyphenolic compounds were confirmed by FTIR and XPS analysis. The reduction in capillary suction time (CST) (71.36 to 16.5 s) and specific resistance to filtration (SRF) (53.71 * 1011 to 1.47 * 1011 m/kg) values have indicated that the use of Fenton nanocatalyst enhanced the sludge dewaterability. The differential scanning calorimetry (DSC) analysis has shown that the mass of bound water in the treated sludge was decreased significantly from 1.45 to 0.92 kg H2O/kg DS. The breakdown of extracellular polymeric substances (EPS) by the MFeNp leads to the significant reduction in proteins, polysaccharides, water content and heavy metals. The optimisation using response surface modelling (RSM) have shown that the maximum removal efficiency of water from the sludge was 85.9 % when the optimum pH (3) MFeNp dosage (50 mg/g DS) and H2O2 dosage (500 mg/g DS) were maintained. The experimental results and the statistical optimisation have suggested that MFeNp can be used as a potential nanocatalyst for the sludge dewaterability and hence it can be used for the agricultural purpose. Graphical abstract Schematic representation of sludge dewatering process. PMID- 27502569 TI - Human CD8+ T cells mediate protective immunity induced by a human malaria vaccine in human immune system mice. AB - A number of studies have shown that CD8+ T cells mediate protective anti-malaria immunity in a mouse model. However, whether human CD8+ T cells play a role in protection against malaria remains unknown. We recently established human immune system (HIS) mice harboring functional human CD8+ T cells (HIS-CD8 mice) by transduction with HLA-A*0201 and certain human cytokines using recombinant adeno associated virus-based gene transfer technologies. These HIS-CD8 mice mount a potent, antigen-specific HLA-A*0201-restricted human CD8+ T-cell response upon immunization with a recombinant adenovirus expressing a human malaria antigen, the Plasmodium falciparum circumsporozoite protein (PfCSP), termed AdPfCSP. In the present study, we challenged AdPfCSP-immunized HIS-CD8 mice with transgenic Plasmodium berghei sporozoites expressing full-length PfCSP and found that AdPfCSP-immunized (but not naive) mice were protected against subsequent malaria challenge. The level of the HLA-A*0201-restricted, PfCSP-specific human CD8+ T cell response was closely correlated with the level of malaria protection. Furthermore, depletion of human CD8+ T cells from AdPfCSP-immunized HIS-CD8 mice almost completely abolished the anti-malaria immune response. Taken together, our data show that human CD8+ T cells mediate protective anti-malaria immunity in vivo. PMID- 27502571 TI - Radiative neutron capture as a counting technique at pulsed spallation neutron sources: a review of current progress. AB - Neutron scattering techniques are attracting an increasing interest from scientists in various research fields, ranging from physics and chemistry to biology and archaeometry. The success of these neutron scattering applications is stimulated by the development of higher performance instrumentation. The development of new techniques and concepts, including radiative capture based neutron detection, is therefore a key issue to be addressed. Radiative capture based neutron detectors utilize the emission of prompt gamma rays after neutron absorption in a suitable isotope and the detection of those gammas by a photon counter. They can be used as simple counters in the thermal region and (simultaneously) as energy selector and counters for neutrons in the eV energy region. Several years of extensive development have made eV neutron spectrometers operating in the so-called resonance detector spectrometer (RDS) configuration outperform their conventional counterparts. In fact, the VESUVIO spectrometer, a flagship instrument at ISIS serving a continuous user programme for eV inelastic neutron spectroscopy measurements, is operating in the RDS configuration since 2007. In this review, we discuss the physical mechanism underlying the RDS configuration and the development of associated instrumentation. A few successful neutron scattering experiments that utilize the radiative capture counting techniques will be presented together with the potential of this technique for thermal neutron diffraction measurements. We also outline possible improvements and future perspectives for radiative capture based neutron detectors in neutron scattering application at pulsed neutron sources. PMID- 27502570 TI - Live-vaccinia virus encapsulation in pH-sensitive polymer increases safety of a reservoir-targeted Lyme disease vaccine by targeting gastrointestinal release. AB - The incidence of Lyme disease has continued to rise despite attempts to control its spread. Vaccination of zoonotic reservoirs of human pathogens has been successfully used to decrease the incidence of rabies in raccoons and foxes. We have previously reported on the efficacy of a vaccinia virus vectored vaccine to reduce carriage of Borrelia burgdorferi in reservoir mice and ticks. One potential drawback to vaccinia virus vectored vaccines is the risk of accidental infection of humans. To reduce this risk, we developed a process to encapsulate vaccinia virus with a pH-sensitive polymer that inactivates the virus until it is ingested and dissolved by stomach acids. We demonstrate that the vaccine is inactive both in vitro and in vivo until it is released from the polymer. Once released from the polymer by contact with an acidic pH solution, the virus regains infectivity. Vaccination with coated vaccinia virus confers protection against B. burgdorferi infection and reduction in acquisition of the pathogen by naive feeding ticks. PMID- 27502572 TI - Thymic E4bp4 gene transcription is up-regulated in the chicken during experimental peritonitis modified by the season-related lighting conditions. AB - Immunity, like other vertebrate processes, undergoes the diurnal and seasonal rhythmicity generated and synchronized by the endogenous clock. In the present study a transcription of the selected clock genes was evaluated in the chicken thymus to verify its supposed role as a peripheral clock and to check its relation with the seasonality of immune function. Chickens kept from hatch in the season-related lighting conditions (LD 16:8 in summer vs 8:16 in winter) and in a controlled temperature were exposed to the experimental peritonitis elicited by i.p. thioglycollate injection. Previously described seasonality of the inflammatory response has been confirmed and the diurnal rhythms of a core clock gene Per3 and its repressor E4bp4 in the thymus has been evidenced. E4bp4 transcription was up-regulated in inflamed chickens while that of Per3 appeared independent of the locally induced inflammation. Our results suggest an interconnecting role of E4BP4 between molecular clock and immunity in the chicken. PMID- 27502573 TI - Application of diffusion-weighted imaging and dynamic susceptibility contrast perfusion-weighted imaging for ganglioglioma in adults: Comparison study with oligodendroglioma. AB - BACKGROUND AND PURPOSE: To evaluate diffusion-weighted imaging (DWI) and dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) of ganglioglioma (GG) compared with oligodendroglioma (ODG). MATERIALS AND METHODS: We enrolled 36 patients with histopathologically confirmed GG (12 patients) or ODG (24 patients). The volumetric analyses of normalized ADC (nADC) and normalized CBV (nCBV) maps, tumor volume, and ratio of enhancing portion compared to the tumor volume were performed. The microvessel area (MVA) was analyzed by staining with the CD34 monoclonal antibody. RESULTS: GGs occurred more frequently in the temporal lobe than in the frontal lobe. GGs showed a smaller tumor volume, and higher ratio of enhancing portion per tumor volume than ODGs (P=.002, and P=.010, respectively). GGs also showed lower nADC values (1.055+/-0.063 vs 1.204+/-0.030, P=.021) and higher nCBV values (0.777+/-0.032 vs 0.514+/-0.025, P<.001) than ODGs. Among the parameters in the multivariate model, nCBV was the most significant factor for differentiating GGs and ODGs (P<.0001). GGs showed significantly higher MVAs than ODGs (0.48+/-0.09 vs 0.24+/-0.04, P=.025). CONCLUSION: Our results suggest that GGs tend to have relatively smaller tumor volume with higher ratio of enhancing portions, lower nADC values, and higher nCBV values than ODGs. Among these parameters, measurement of nCBV, which is correlated with a higher MVA measurement in GGs, can be the most useful tool for differentiating GGs from ODGs. PMID- 27502574 TI - Tracking successive Wallerian degenerations in a relapsing-remitting multiple sclerosis patient. PMID- 27502575 TI - Role of intratumoral flow void signs in the differential diagnosis of intracranial solitary fibrous tumors and meningiomas. AB - BACKGROUND AND OBJECTIVE: An absence of signal on magnetic resonance (MR) images caused by blood or cerebral spinal fluid flow is known as a flow void, and may be related to intracranial tumors such as intracranial solitary fibrous tumor (SFT) or meningioma. However, the differential diagnosis of these neoplasms based on flow void configuration is controversial. This study investigated common intratumoral flow void patterns for differentiating intracranial SFT from meningioma. METHODS: From May 2008 to May 2015, 14 patients (10 men, 4 women; 14 63y) received a pathologic diagnosis of primary intracranial SFT, and in 85 patients (23 men, 62 women; 20-76y) a pathologic diagnosis of meningioma was made. Intratumoral flow void signs were retrospectively observed on MR images of all these patients and classified by radiologists blinded to the pathology findings. Statistical significance was established by chi-squared tests. RESULTS: In intracranial SFT patients, the sunburst flow void was detected in 1 case (7.1%) and the serpentine in 13 cases (92.9%). In meningioma patients, the sunburst flow void was detected in 82 cases (96.5%) and the serpentine in 3 cases (3.5%). The differences in the prevalence of the flow void types between the 2 groups were significant (chi(2)=64.348; P<0.01). CONCLUSION: Intracranial SFTs on MR images were more likely to show a serpentine than a sunburst flow void, while the sunburst pattern was far more typical of meningioma. Thus, the pattern of the intratumoral flow void sign may be a useful tool to assist in differentiating these tumors. PMID- 27502576 TI - Endovascular treatment of intracranial aneurysms with Barricade coils: Feasibility, procedural safety, and immediate postoperative anatomical results. AB - BACKGROUND AND PURPOSE: The safety of bare platinum coils has been widely described in the literature. This study aimed to report the first series of intracranial aneurysms treated with Barricade bare platinum coils with a comprehensive evaluation of their procedural safety and postprocedural anatomical results. METHODS: Patients with intracranial aneurysms treated between October 2013 and December 2015 by simple coiling or balloon-assisted coiling with Barricade coils (Blockade Medical, Irvine, California, USA) were prospectively included in a database and retrospectively studied. For all included patients, the patient and aneurysm characteristics, procedural complications, technical issues, postoperative anatomical results, and one-month clinical outcome (modified Rankin Scale) were evaluated by an independent interventional neuroradiologist. RESULTS: Eighty-eight patients harboring 97 aneurysms were included. Procedural complications and technical issues were encountered in 17 and 5 patients (19.3 and 5.7%, respectively), but clinical worsening in only 2 patients (2.2%). There was no treatment-related mortality. After one month, morbidity (mRS>=1) was observed in 19 patients (21.8%), 17 related to subarachnoid hemorrhage (SAH) in patients with ruptured aneurysms (19.4%) and 2 related to thromboembolic events in patients with unruptured aneurysms (2.3%). Nine patients initially presenting with a ruptured aneurysm were deceased at 1 month as a consequence of SAH (10.2%). Adequate occlusion was observed postoperatively in 94.8% of the aneurysms (complete occlusion in 81.4% and residual neck in 13.4%). CONCLUSION: Endovascular treatment of intracranial aneurysms with Barricade coils is feasible and the demonstrated overall safety results are within the ranges found in the literature for other coils. Immediate anatomical results are satisfying. PMID- 27502577 TI - Serum amyloid A1 is induced by UV irradiation and detected by toll-like receptor 4 to causes skin inflammation. PMID- 27502579 TI - Clinical and subjective evaluation of implants in patients with hypodontia: a two year observation study. AB - BACKGROUND: Hypodontia compromises appearance and function and is challenging to manage clinically. OBJECTIVES: To assess the impact of implant retained crowns on quality of life of patients and to determine clinical performance of implant retained crowns in these patients. METHODS: In a 24-month prospective observation study, patients with non-syndromic mild hypodontia manifested with missing teeth in the anterior maxilla were included. Pre-treatment screening included a clinical and radiographic examination and completion of an OHIP-20. Narrow neck SLActive TiZr implants (Roxolid(r) , Straumann AG, Switzerland) were provided and restored with single unit crowns. Implant stability was recorded at time of placement and abutment connection. Standardized radiographs were recorded at time of surgery, abutment connection and 12- and 24-month follow-up visits, and distance between implant shoulder and first bone contact was measured. Oral health-related quality of life was calculated using OHIP-20 scores at 12- and 24 month visits compared with pre-treatment scores. Pink (PES) and white (WES) aesthetic scores were used to objectively assess aesthetic outcome of treatment. RESULTS: Twenty implants were placed in 12 patients (seven females, five males; mean [SD] age 19.33 [2.37] years). There was a significant improvement in oral health-related quality of life following treatment (P = 0.026), and the effect size of this change was 1.17 indicating a large clinically meaningful change. Mean PES and WES scores were high, indicated a satisfactory aesthetic outcome at 24 months. Crestal bone-level changes were considered small. CONCLUSION: Favourable clinical outcomes were observed. Implant retained crowns had a large and clinically meaningful impact on quality of life of patients with hypodontia. PMID- 27502578 TI - Bisphenol A Exposure May Induce Hepatic Lipid Accumulation via Reprogramming the DNA Methylation Patterns of Genes Involved in Lipid Metabolism. AB - Accumulating evidence suggests a role of bisphenol A (BPA) in metabolic disorders. However, the underlying mechanism is still unclear. Using a mouse BPA exposure model, we investigated the effects of long-term BPA exposure on lipid metabolism and the underlying mechanisms. The male mice exposed to BPA (0.5 MUg BPA /kg/day, a human relevant dose) for 10 months exhibited significant hepatic accumulation of triglycerides and cholesterol. The liver cells from the BPA exposed mice showed significantly increased expression levels of the genes related to lipid synthesis. These liver cells showed decreased DNA methylation levels of Srebf1 and Srebf2, and increased expression levels of Srebf1 and Srebf2 that may upregulate the genes related to lipid synthesis. The expression levels of DNA methyltransferases were decreased in BPA-exposed mouse liver. Hepa1-6 cell line treated with BPA showed decreased expression levels of DNA methyltransferases and increased expression levels of genes involved in lipid synthesis. DNA methyltransferase knockdown in Hepa1-6 led to hypo-methylation and increased expression levels of genes involved in lipid synthesis. Our results suggest that long-term BPA exposure could induce hepatic lipid accumulation, which may be due to the epigenetic reprogramming of the genes involved in lipid metabolism, such as the alterations of DNA methylation patterns. PMID- 27502580 TI - Extremely heat tolerant photo-symbiosis in a shallow marine benthic foraminifera. AB - Bleaching, the loss of algal symbionts, occurs in marine photosymbiotic organisms at water temperatures minimally exceeding average summer SST (sea surface temperatures). Pre-adaptation allows organisms to persist under warmer conditions, providing the tolerance can be carried to new habitats. Here we provide evidence for the existence of such adaptation in the benthic foraminifera Pararotalia calcariformata. This species occurs at a thermally polluted site in the Mediterranean, where water temperatures reach a maxima daily average of 36 degrees C during the summer. To test whether this occurrence represents a widespread adaptation, we conducted manipulative experiments exposing this species from an unpolluted site to elevated temperatures (20-42 degrees C). It was kept in co-culture with the more thermally sensitive foraminifera Amphistegina lobifera in two experiments (20-36 degrees C). Reduced photosynthetic activity in A. lobifera occurred at 32 degrees C whereas photochemical stress in P. calcariformata was first observed during exposure to 36 degrees C. Pararotalia calcariformata survived all treatment conditions and grew under 36 degrees C. The photosymbiosis in P. calcariformata is unusually thermally tolerant. These observations imply that marine eukaryote-eukaryote photosymbiosis can respond to elevated temperatures by drawing on a pool of naturally occurring pre-adaptations. It also provides a perspective on the massive occurrence of symbiont-bearing foraminifera in the early Cenozoic hothouse climate. PMID- 27502581 TI - Prognostic factors for long-term infliximab treatment in Crohn's disease patients: a 20-year single centre experience. AB - BACKGROUND: The long-term efficacy of infliximab in patients with Crohn's disease is suboptimal. AIM: To study prognostic factors for real-life long-term effcacy of infliximab in Crohn's disease. METHODS: All consecutive Crohn's disease patients treated with infliximab at a tertiary centre were retrospectively analysed. Only patients who received scheduled infliximab maintenance treatment were considered. Patient- and disease-related factors were used to identify independent predictors of infliximab failure-free survival using Cox proportional hazards regression. RESULTS: Of 1031 patients with Crohn's disease, 261 were eligible for inclusion. Median time on infliximab was 2.4 [IQR 1.4-4.7] years, and 65 (24.9%) patients experienced infliximab failure. Estimated 5-year infliximab failure-free survival was 65.9% (95% CI 58.3-73.5). Multivariate Cox regression identified disease duration >=1 year (HR 2.5 (95% CI 1.2-5.2), P = 0.02), L1 disease location [HR 2.0 (1.1-3.5), P = 0.02], prior anti-TNF use [HR 2.3 (1.1-4.8), P = 0.03], haemoglobin <13.5 g/dL [HR 2.3 (1.2-4.4), P = 0.02], not using therapeutic drug monitoring [HR 8.0 (4.1-15.6), P = 1 * 10(-9) ], and first dose optimisation within first year [HR 3.7 (2.1-6.6), P = 5 * 10(-6) ] as independent predictors of infliximab failure-free survival. Stratifying patients into risk groups resulted in estimated 3-year infliximab failure-free survival rates ranging from 95.3% (94.2-96.4) to 26.3% (8.6-44.0) depending on the number of risk factors (P = 8 * 10(-13) ). CONCLUSIONS: This study identified several easy to obtain predictors of infliximab failure in patients with Crohn's disease, and these are in line with previous reports. Those with a high-risk profile for infliximab failure in whom infliximab initiation is considered, should be treated as early as possible making use of therapeutic drug monitoring. PMID- 27502582 TI - Evaluation of two doses of etoricoxib, a COX-2 selective non-steroidal anti inflammatory drug (NSAID), in the treatment of Rheumatoid Arthritis in a double blind, randomized controlled trial. AB - BACKGROUND: Treatment with non-steroidal anti-inflammatory drugs (NSAID) is a common component of treatment regimens for rheumatoid arthritis (RA). Etoricoxib is a COX-2 selective NSAID that has demonstrated efficacy in the treatment of RA at a dose of 90 mg. The current study further evaluated the efficacy of etoricoxib 60 mg and 90 mg in RA patients with active disease. METHODS: This was a 2-part, double-blind, placebo-controlled study in RA (NCT01208181). Patients were required to have a diagnosis of RA (according to ARA 1987 revised classification criteria) and were to demonstrate symptom flare upon discontinuation of previous NSAID treatment prior to randomization. Part I was a 6-week, placebo-controlled period to assess the efficacy of etoricoxib 90 mg and etoricoxib 60 mg, each compared to placebo, as well as to each other. Part II was a 6-week period to evaluate the potential benefit of dose escalation from etoricoxib 60 mg to etoricoxib 90 mg after 6 weeks exposure to etoricoxib 60 mg in Part I compared to maintaining a steady dose of etoricoxib 60 mg throughout Parts I and II. Primary endpoints were Disease Activity Score evaluating 28 joints and C reactive protein level (DAS28-CRP) index and Patient Global Assessment of Pain (Pain) score (0-100 mm VAS) after 6 weeks of treatment in Part I. Adverse events were monitored throughout the study. RESULTS: In total, 1404 patients were randomized in a 2:7:7:8 ratio; 1228 patients completed Part I and 713 patients continued to Part II. Both etoricoxib doses were superior to placebo on both primary efficacy endpoints (p = 0.004 for 60 mg and p = 0.034 for 90 mg for DAS28-CRP; p < 0.001 for both doses for PGAP) in Part I. Further in Part I, etoricoxib 90 mg was not significantly different from 60 mg for DAS28-CRP, but did demonstrate a small, but statistically significant decrease in baseline PGAP score vs. 60 mg (p = 0.019). In Part II, there was no significant decrease in PGAP score after increasing to 90 mg in subjects with inadequate pain relief on 60 mg as compared to subjects who stayed on 60 mg. The incidence of AEs and SAEs were similar between etoricoxib 60 mg and 90 mg in both Part I and II. CONCLUSION: Both etoricoxib 90 mg and 60 mg are superior to placebo in relieving the symptoms of RA. Etoricoxib 90 mg vs 60 mg resulted in a statistically significant, though small, improvement in PGAP score, but not DAS28-CRP. Dose escalation from 60 mg to 90 mg in pain inadequate responders did not significantly improve efficacy. These results confirm the efficacy and tolerability of etoricoxib 90mg in patients with RA. In addition, this study demonstrated that etoricoxib 60 mg is also efficacious and well-tolerated in RA. CLINICAL TRIAL REGISTRATION: NCT01208181 (registered September 22, 2010). PMID- 27502583 TI - Long-Term Effects of an Internet-Mediated Pedometer-Based Walking Program for Chronic Obstructive Pulmonary Disease: Randomized Controlled Trial. AB - BACKGROUND: Regular physical activity (PA) is recommended for persons with chronic obstructive pulmonary disease (COPD). Interventions that promote PA and sustain long-term adherence to PA are needed. OBJECTIVE: We examined the effects of an Internet-mediated, pedometer-based walking intervention, called Taking Healthy Steps, at 12 months. METHODS: Veterans with COPD (N=239) were randomized in a 2:1 ratio to the intervention or wait-list control. During the first 4 months, participants in the intervention group were instructed to wear the pedometer every day, upload daily step counts at least once a week, and were provided access to a website with four key components: individualized goal setting, iterative feedback, educational and motivational content, and an online community forum. The subsequent 8-month maintenance phase was the same except that participants no longer received new educational content. Participants randomized to the wait-list control group were instructed to wear the pedometer, but they did not receive step-count goals or instructions to increase PA. The primary outcome was health-related quality of life (HRQL) assessed by the St George's Respiratory Questionnaire Total Score (SGRQ-TS); the secondary outcome was daily step count. Linear mixed-effect models assessed the effect of intervention over time. One participant was excluded from the analysis because he was an outlier. Within the intervention group, we assessed pedometer adherence and website engagement by examining percent of days with valid step-count data, number of log-ins to the website each month, use of the online community forum, and responses to a structured survey. RESULTS: Participants were 93.7% male (223/238) with a mean age of 67 (SD 9) years. At 12 months, there were no significant between-group differences in SGRQ-TS or daily step count. Between group difference in daily step count was maximal and statistically significant at month 4 (P<.001), but approached zero in months 8-12. Within the intervention group, mean 76.7% (SD 29.5) of 366 days had valid step-count data, which decreased over the months of study (P<.001). Mean number of log-ins to the website each month also significantly decreased over the months of study (P<.001). The online community forum was used at least once during the study by 83.8% (129/154) of participants. Responses to questions assessing participants' goal commitment and intervention engagement were not significantly different at 12 months compared to 4 months. CONCLUSIONS: An Internet-mediated, pedometer based PA intervention, although efficacious at 4 months, does not maintain improvements in HRQL and daily step counts at 12 months. Waning pedometer adherence and website engagement by the intervention group were observed. Future efforts should focus on improving features of PA interventions to promote long term behavior change and sustain engagement in PA. CLINICALTRIAL: Clinicaltrials.gov NCT01102777; https://clinicaltrials.gov/ct2/show/NCT01102777 (Archived by WebCite at http://www.webcitation.org/6iyNP9KUC). PMID- 27502585 TI - Using AberOWL for fast and scalable reasoning over BioPortal ontologies. AB - BACKGROUND: Reasoning over biomedical ontologies using their OWL semantics has traditionally been a challenging task due to the high theoretical complexity of OWL-based automated reasoning. As a consequence, ontology repositories, as well as most other tools utilizing ontologies, either provide access to ontologies without use of automated reasoning, or limit the number of ontologies for which automated reasoning-based access is provided. METHODS: We apply the AberOWL infrastructure to provide automated reasoning-based access to all accessible and consistent ontologies in BioPortal (368 ontologies). We perform an extensive performance evaluation to determine query times, both for queries of different complexity and for queries that are performed in parallel over the ontologies. RESULTS AND CONCLUSIONS: We demonstrate that, with the exception of a few ontologies, even complex and parallel queries can now be answered in milliseconds, therefore allowing automated reasoning to be used on a large scale, to run in parallel, and with rapid response times. PMID- 27502584 TI - MicroRNA-203 mimics age-related aortic smooth muscle dysfunction of cytoskeletal pathways. AB - Increased aortic stiffness is a biomarker for subsequent adverse cardiovascular events. We have previously reported that vascular smooth muscle Src-dependent cytoskeletal remodelling, which contributes to aortic plasticity, is impaired with ageing. Here, we use a multi-scale approach to determine the molecular mechanisms behind defective Src-dependent signalling in an aged C57BL/6 male mouse model. Increased aortic stiffness, as measured in vivo by pulse wave velocity, was found to have a comparable time course to that in humans. Bioinformatic analyses predicted several miRs to regulate Src-dependent cytoskeletal remodelling. qRT-PCR was used to determine the relative levels of predicted miRs in aortas and, notably, the expression of miR-203 increased almost twofold in aged aorta. Increased miR-203 expression was associated with a decrease in both mRNA and protein expression of Src, caveolin-1 and paxillin in aged aorta. Probing with phospho-specific antibodies confirmed that overexpression of miR-203 significantly attenuated Src and extracellular signal regulated kinase (ERK) signalling, which we have previously found to regulate vascular smooth muscle stiffness. In addition, transfection of miR-203 into aortic tissue from young mice increased phenylephrine-induced aortic stiffness ex vivo, mimicking the aged phenotype. Upstream of miR-203, we found that DNA methyltransferases (DNMT) 1, 3a, and 3b are also significantly decreased in the aged mouse aorta and that DNMT inhibition significantly increases miR-203 expression. Thus, the age-induced increase in miR-203 may be caused by epigenetic promoter hypomethylation in the aorta. These findings indicate that miR-203 promotes a re-programming of Src/ERK signalling pathways in vascular smooth muscle, impairing the regulation of stiffness in aged aorta. PMID- 27502586 TI - EFFECTS: an expanded access program of everolimus for patients with subependymal giant cell astrocytoma associated with tuberous sclerosis complex. AB - BACKGROUND: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to be effective and safe in the treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC). The Everolimus For Fast Expanded aCcess in TSC SEGA (EFFECTS) study was designed to provide everolimus access to patients with SEGA associated with TSC and to mainly assess the safety and also efficacy of everolimus in a real-world setting. METHODS: EFFECTS was a phase 3b, open-label, noncomparative, multicenter, expanded access study. Eligible patients were >= 3 years of age, with a definite diagnosis of TSC, and with at least one SEGA lesion identified by MRI or CT scan. Patients received once daily everolimus (dose adjusted to attain a trough level of 5-15 ng/mL). Safety evaluation was the primary objective and included collection of adverse events (AEs) and serious AEs, with their severity and relationship to everolimus. Efficacy evaluation, which was the secondary objective, was based on the best overall response as per medical judgment. RESULTS: Of the 120 patients enrolled, 100 (83.3%) completed the study. Median age of patients was 11 years (range, 1-47). Median daily dose of everolimus was 5.82 mg (range, 2.0-11.8). Median duration of exposure was 56.5 weeks (range, 0.3 130). The overall incidence of AEs was 74.2%. Aphthous stomatitis (18 [15.0%]), pyrexia (18 [15.0%]), bronchitis (11 [9.2%]), and stomatitis (10 [8.3%]) were the most common AEs reported. Overall, 25 patients had grade 3 AEs; most frequent was stomatitis (4 [3.3%]). Grade 4 AEs were reported in three (2.5%) patients. A total of 62 (51.7%) patients had suspected drug-related AEs, of which 15 (12.5%) were of grade 3 or 4. In eight (6.7%) patients, AEs led to drug discontinuation. With regard to efficacy, 81 (67.5%) patients had a partial response, 35 (29.2%) had a stable disease, and one (0.8%) had progressive disease. The response was unknown in three (2.5%) patients. CONCLUSION: This study confirms the acceptable safety profile of everolimus in patients with SEGA associated with TSC in a real world setting. The results further support the efficacy of everolimus in the treatment of SEGA associated with TSC. (EudraCT: 2010-022583-13). PMID- 27502587 TI - Copper induces hepatocyte injury due to the endoplasmic reticulum stress in cultured cells and patients with Wilson disease. AB - Copper is an essential trace element, however, excess copper is harmful to human health. Excess copper-derived oxidants contribute to the progression of Wilson disease, and oxidative stress induces accumulation of abnormal proteins. It is known that the endoplasmic reticulum (ER) plays an important role in proper protein folding, and that accumulation of misfolded proteins disturbs ER homeostasis resulting in ER stress. However, copper-induced ER homeostasis disturbance has not been fully clarified. We treated human hepatoma cell line (Huh7) and immortalized-human hepatocyte cell line (OUMS29) with copper and chemical chaperones, including 4-phenylbutyrate and ursodeoxycholic acid. We examined copper-induced oxidative stress, ER stress and apoptosis by immunofluorescence microscopy and immunoblot analyses. Furthermore, we examined the effects of copper on carcinogenesis. Excess copper induced not only oxidative stress but also ER stress. Furthermore, excess copper induced DNA damage and reduced cell proliferation. Chemical chaperones reduced this copper-induced hepatotoxicity. Excess copper induced hepatotoxicity via ER stress. We also confirmed the abnormality of ultra-structure of the ER of hepatocytes in patients with Wilson disease. These findings show that ER stress plays a pivotal role in Wilson disease, and suggests that chemical chaperones may have beneficial effects in the treatment of Wilson disease. PMID- 27502588 TI - Inhibition of hydrogen sulfide on the proliferation of vascular smooth muscle cells involved in the modulation of calcium sensing receptor in high homocysteine. AB - Hyperhomocysteinemia induces the proliferation of vascular smooth muscle cells (VSMCs). Hydrogen sulfide (H2S) inhibits the phenotype switch of VSMCs and calcium-sensing receptor (CaSR) regulated the production of endogenous H2S. However, whether CaSR inhibits the proliferation of VSMCs by regulating the endogenous cystathionine-gamma-lyase (CSE, a major enzyme that produces H2S) pathway in high homocysteine (HHcy) has not been previously investigated. The intracellular calcium concentration, the concentration of H2S, the cell viability, the proliferation and the expression of proteins of cultured VSMCs from rat thoracic aortas were measured, respectively. The results showed that the [Ca(2+)]i and the expression of p-CaMK and CSE increased upon treatment with CaSR agonist. In HHcy, the H2S concentration decrease, the proliferation and migration rate increased, the expression of Cyclin D1, PCNA, Osteopontin and p-Erk1/2 increased while the alpha-SM actin, P21(Cip/WAK-1) and Calponin decreased. The CaSR agonist or exogenous H2S significantly reversed the changes of VSMCs caused by HHcy. In conclusion, our results demonstrated that CaSR regulate the endogenous CSE/H2S is related to the PLC-IP3 receptor and CaM signal pathways which inhibit the proliferation of VSMCs, and the latter is involved in the Erk1/2 dependent signal pathway in high homocysteine. PMID- 27502589 TI - ACEMg-mediated hearing preservation in cochlear implant patients receiving different electrode lengths (PROHEARING): study protocol for a randomized controlled trial. AB - BACKGROUND: The indications for a cochlear implant (CI) have been extended to include patients with some residual hearing. Shorter and thinner atraumatic electrodes have been designed to preserve the residual hearing in the implanted ear. However, the insertion of the electrode array into the cochlea, with potential mechanical trauma and the presence of this foreign body inside the cochlea, may lead to free radical formation and reduced blood perfusion of the cochlea which can result in the loss of residual hearing. METHODS/DESIGN: In this single-center, randomized, placebo-controlled, double-blind phase II clinical trial the effect of free radical scavengers and a vasodilator on the residual hearing of 140 CI patients will be evaluated. The formulation is composed of beta carotene (vitamin A), ascorbic acid (vitamin C), dl-alpha-tocopherol acetate (vitamin E) and the vasodilator magnesium (Mg), or ACEMg. Medication is administered twice daily per os for approximately 3 months. The primary measure is based upon the reduction in postoperative low-frequency air-conducted pure tone thresholds compared to preoperative thresholds in ACEMg-treated patients compared to those of a placebo group. Additionally, the effect of different electrode lengths (20, 24 and 28 mm) is analyzed. Study visits are scheduled 2 days before surgery, at first fitting, which is the adjustment and start of stimulation via CI 4 weeks after surgery and 3, 6, 9 and 12 months after first fitting. The primary endpoint is the air-conduction hearing loss at 500 Hz 3 months after first fitting. Additionally, speech recognition tests, hearing aid benefit in the implanted ear and electrophysiological measurements of implant function are assessed. Since this is a blinded clinical trial and recruitment is still ongoing, data continue to accrue and we cannot yet analyze the outcome of the ACEMg treatment. DISCUSSION: There is an unfulfilled need for new strategies to preserve acoustic hearing in CI patients. This study will provide first-in-man data on ACEMg-mediated protection of residual hearing in CI patients. Performing all surgeries and patient follow-up at one study site improves consistency in diagnosis and therapy and less variability in surgery, audiological test techniques and fitting. This approach will allow investigation of the influence of ACEMg on residual hearing in CI patients. TRIAL REGISTRATION: The German Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM) application number 4039192, was registered on 6 December 2013 with protocol amendment version 3.0 from 19 August 2014. EudraCT number: 2012-005002-22 . PMID- 27502590 TI - Using the Theoretical Domains Framework (TDF) to understand adherence to multiple evidence-based indicators in primary care: a qualitative study. AB - BACKGROUND: There are recognised gaps between evidence and practice in general practice, a setting posing particular implementation challenges. We earlier screened clinical guideline recommendations to derive a set of 'high-impact' indicators based upon criteria including potential for significant patient benefit, scope for improved practice and amenability to measurement using routinely collected data. Here, we explore health professionals' perceived determinants of adherence to these indicators, examining the degree to which determinants were indicator-specific or potentially generalisable across indicators. METHODS: We interviewed 60 general practitioners, practice nurses and practice managers in West Yorkshire, the UK, about adherence to four indicators: avoidance of risky prescribing; treatment targets in type 2 diabetes; blood pressure targets in treated hypertension; and anticoagulation in atrial fibrillation. Interview questions drew upon the Theoretical Domains Framework (TDF). Data were analysed using framework analysis. RESULTS: Professional role and identity and environmental context and resources featured prominently across all indicators whilst the importance of other domains, for example, beliefs about consequences, social influences and knowledge varied across indicators. We identified five meta-themes representing more general organisational and contextual factors common to all indicators. CONCLUSIONS: The TDF helped elicit a wide range of reported determinants of adherence to 'high-impact' indicators in primary care. It was more difficult to pinpoint which determinants, if targeted by an implementation strategy, would maximise change. The meta-themes broadly underline the need to align the design of interventions targeting general practices with higher level supports and broader contextual considerations. However, our findings suggest that it is feasible to develop interventions to promote the uptake of different evidence-based indicators which share common features whilst also including content-specific adaptations. PMID- 27502592 TI - Facial movement disorder and dopamine imaging in a patient with amphetamine abuse. PMID- 27502593 TI - Switching the poles in sexual and reproductive health research: implementing a research capacity-strengthening network in West and North Africa. AB - Health research capacities have been improved in Africa but still remain weak as compared to other regions of the World. To strengthen these research capacities, international collaboration and networking for knowledge and capacity transfer are needed. In this commentary, we present the Network for Scientific Support in the field of Sexual and Reproductive Health in West and North Africa, its priority research topics and discuss its implementation process. Established in January 2014, the Network aims at generating human rights and gender-based research fully carried out and driven by South based institutions. It is composed of 12 institutions including the Institute of Tropical Medicine of Antwerp (Belgium) and 11 institutions from eight Francophone West and North African countries. The key areas of interest of this network are health policies analysis and health system research in family planning, HIV prevention among vulnerable groups, quality of care and breast cancers. Since it started, seventeen research proposals based on locally relevant research questions have been developed. Among the seventeen proposals, eleven have been implemented. Several research institutions enhanced linkages with local representations of international partners such as UNFPA. The network is committed to strengthening methodological research capacities and soft skills such as fundraising, advocacy and leadership. Such competencies are strongly needed for developing an effective South-based leadership in Sexual and Reproductive Health research, and for achieving the Sustainable Development Goals. PMID- 27502591 TI - Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline. AB - PURPOSE: To provide guidance to clinicians regarding the use of neoadjuvant chemotherapy and interval cytoreduction among women with stage IIIC or IV epithelial ovarian cancer. METHODS: The Society of Gynecologic Oncology and the American Society of Clinical Oncology convened an Expert Panel and conducted a systematic review of the literature. RESULTS: Four phase III clinical trials form the primary evidence base for the recommendations. The published studies suggest that for selected women with stage IIIC or IV epithelial ovarian cancer, neoadjuvant chemotherapy and interval cytoreduction are noninferior to primary cytoreduction and adjuvant chemotherapy with respect to overall and progression free survival and are associated with less perioperative morbidity and mortality. RECOMMENDATIONS: All women with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy. The primary clinical evaluation should include a CT of the abdomen and pelvis, and chest imaging (CT preferred). Women with a high perioperative risk profile or a low likelihood of achieving cytoreduction to < 1 cm of residual disease (ideally to no visible disease) should receive neoadjuvant chemotherapy. Women who are fit for primary cytoreductive surgery, and with potentially resectable disease, may receive either neoadjuvant chemotherapy or primary cytoreductive surgery. However, primary cytoreductive surgery is preferred if there is a high likelihood of achieving cytoreduction to < 1 cm (ideally to no visible disease) with acceptable morbidity. Before neoadjuvant chemotherapy is delivered, all patients should have confirmation of an invasive ovarian, fallopian tube, or peritoneal cancer. Additional information is available at www.asco.org/NACT-ovarian-guideline and www.asco.org/guidelineswiki. PMID- 27502594 TI - Significance of EZH2 expression in canine mammary tumors. AB - BACKGROUND: Current studies report that aberrations in epigenetic regulators or chromatin modifications are related to tumor development and maintenance. EZH2 (Enhancer of zeste homolog 2) is one of the catalytic subunits of Polycomb repressive complex 2, a crucial epigenetic regulator. EZH2 has a master regulatory function in such processes as cell proliferation, stem cell differentiation, and early embryogenesis. In humans, EZH2 is linked to oncogenic function in several carcinomas, including breast cancer, and dysregulation of EZH2 has been particularly associated with loss of differentiation and the development of poorly differentiated breast cancer. In our present study, we were interested in determining whether EZH2 is increased in canine mammary tumors, which show similarities to human breast cancer. RESULTS: Investigation of the expression of EZH2 in canine mammary tumors revealed that EZH2 protein was overexpressed in canine mammary carcinomas, as in human breast cancer. In addition, the immunohistochemical expression level of EZH2 was associated with the degree of malignancy in canine mammary carcinoma. This is the first report to describe EZH2 expression in canine mammary tumors. CONCLUSIONS: Because the expression of EZH2 was similar in canine mammary carcinoma and human breast cancer, spontaneous canine mammary tumors may be a suitable model for studying EZH2 and treatment development. PMID- 27502595 TI - Cryptosporidium parvum rhomboid1 has an activity in microneme protein CpGP900 cleavage. AB - BACKGROUND: Apicomplexan parasites actively release transmembrane (TM) adhesive proteins involved in host cell attachment and invasion. Rhomboids, a family of intramembrane serine proteases, cleave these secreted adhesive proteins within their TM domains as an essential step in completing the invasion process. In Cryptosporidium parvum, the activity of rhomboids in cleaving microneme proteins (MICs) has not been reported. In the present study, the interaction between C. parvum rhomboids (CpROM1 and CpROM4) and C. parvum microneme proteins (CpGP900 and CpTRAP-C1) was investigated using yeast two-hybrid assay and co immunoprecipitation assays. RESULTS: Our study demonstrated that CpROM1 protein could interact with CpGP900 protein in co-transformed AH109 yeasts. Analysis of these proteins in co-transfected mammalian cells showed that the cleavage product of the CpGP900 protein was detected in the co-transfected cells. As control, CpGP900 only was transfected into cells and no cleavage was observed. The results suggested that CpGP900 protein was the substrate of CpROM1. Moreover, CpROM1 and CpROM4 could not cleave CpTRAP-C1 protein, which is the substrate of T. gondii rhomboid 2. CONCLUSIONS: Our results showed that CpROM1 is an active protease that is involved in microneme protein CpGP900 cleavage, which lay the foundation for further research on the mechanisms of C. parvum invasion. PMID- 27502596 TI - The development of an automatically produced cholangiography procedure using the reconstruction of portal-phase multidetector-row computed tomography images: preliminary experience. AB - PURPOSE: Fusion angiography using reconstructed multidetector-row computed tomography (MDCT) images, and cholangiography using reconstructed images from MDCT with a cholangiographic agent include an anatomical gap due to the different periods of MDCT scanning. To conquer such gaps, we attempted to develop a cholangiography procedure that automatically reconstructs a cholangiogram from portal-phase MDCT images. METHODS: The automatically produced cholangiography procedure utilized an original software program that was developed by the Graduate School of Information Science, Nagoya University. This program structured 5 candidate biliary tracts, and automatically selected one as the candidate for cholangiography. The clinical value of the automatically produced cholangiography procedure was estimated based on a comparison with manually produced cholangiography. RESULTS: Automatically produced cholangiograms were reconstructed for 20 patients who underwent MDCT scanning before biliary drainage for distal biliary obstruction. The procedure showed the ability to extract the 5 main biliary branches and the 21 subsegmental biliary branches in 55 and 25 % of the cases, respectively. The extent of aberrant connections and aberrant extractions outside the biliary tract was acceptable. Among all of the cholangiograms, 5 were clinically applied with no correction, 8 were applied with modest improvements, and 3 produced a correct cholangiography before automatic selection. CONCLUSIONS: Although our procedure requires further improvement based on the analysis of additional patient data, it may represent an alternative to direct cholangiography in the future. PMID- 27502597 TI - Severe tricuspid regurgitation after mitral valve surgery: the risk factors and results of the aggressive application of prophylactic tricuspid valve repair. AB - PURPOSE: This study aimed to examine the risk factors for severe postoperative tricuspid regurgitation (TR) in patients undergoing mitral valve surgery. We also studied the effects of prophylactic tricuspid valve repair (TVR) on severe postoperative TR. METHODS: We retrospectively studied 125 patients without severe TR who underwent mitral valve surgery from 1987 to 2006. Patients did not undergo TVR before 1998 (the early period, n = 54). In 1998 (the late period, n = 71), patients with a preoperative tricuspid annular diameter of >=35 mm underwent TVR using an annuloplasty ring (n = 52). RESULTS: In the analysis of the early period, the rates of freedom from severe TR at 10 and 20 years after surgery were 76 and 59 %, respectively. A multivariate analysis identified moderate preoperative TR as a significant risk factor for severe TR. In the late period, none of the 52 patients who underwent TVR developed severe TR. However, 4/19 patients who did not undergo TVR developed severe TR, and all of these four patients had a preoperative tricuspid annular diameter of <=35 mm. CONCLUSIONS: Moderate preoperative TR is a significant risk factor for severe postoperative TR in patients undergoing mitral valve surgery. The aggressive application of TVR can prevent severe postoperative TR; however, tricuspid annular dilatation might not be a good indicator for TVR. PMID- 27502598 TI - Clinical factors that affect the outcomes after anatomical versus non-anatomical resection for hepatocellular carcinoma. AB - PURPOSE: For hepatocellular carcinoma (HCC), the superiority of anatomical resection (AR) over non-anatomical resection (NR) is still controversial. In this study, we assessed the potential benefits of AR for HCC. METHODS: We enrolled 173 consecutive patients with HCC who underwent hepatectomy in our hospital from August 2003 to May 2013 and compared the outcomes for the AR group (n = 125) with those for the NR group (n = 48). RESULTS: The median observational period was 790 days. The 1- and 2-year overall survival (OS) rates were 92.1 and 85.8 %, respectively; the 1- and 2-year disease-free survival (DFS) rates were 78.2 and 63.0 %, respectively. The AR and NR groups did not significantly differ in the OS or DFS. However, the 2-year DFS was significantly better for the AR group than the NR group among HCV patients (68.2 vs. 32.2 %; P = 0.004) and patients with alpha-fetoprotein (AFP) within the normal range (<20 ng/ml; 76.7 vs. 60.9 %; P = 0.031), total bilirubin <0.8 mg/dl (70.8 vs. 47.0 %; P = 0.034), and tumors 2-5 cm in diameter (82.0 vs. 62.5 %; P = 0.025). CONCLUSIONS: If a patient is HCV negative, has low AFP, low total bilirubin, or a tumor diameter of 2-5 cm, AR is recommended. PMID- 27502599 TI - Risk factors to predict drug-resistant pathogens in hemodialysis-associated pneumonia. AB - BACKGROUND: After the concept of healthcare associated pneumonia (HCAP) was introduced in 2005 by the American Thoracic Society/Infectious Disease Society of America (ATS/IDSA), pneumonia in hemodialysis patients has been classified as HCAP. Even though there are several risk factors and scoring systems of drug resistant pathogens (DRPs) in HCAP, the risk factors for DRPs in hemodialysis associated pneumonia are unclear. METHODS: Patients who were admitted to our tertiary care hospital from January 2005 to December 2010 were screened by a discharge diagnosis of pneumonia. Patients were enrolled if they fulfilled the definition of HCAP according to the 2005 ATS/IDSA guidelines. RESULTS: A total of 530 subjects were diagnosed with HCAP, of whom 48 (9.1 %) received regular hemodialysis (HD group) and the other 482 did not (non-HD group). The most common pathogens in HD group were Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus (MRSA). There was a similar distribution of Gram-negative bacilli infections between the two groups except for Haemophilus influenzae and Citrobacter species. The incidence of DRPs was not significantly different between the two groups (HD vs. non-HD, 35.4 vs. 39.2 %, p = 0.607). Wound care, severe pneumonia and an age of more than 70 years were significant risk factors for DRPs. The area under the operating cure of predicting DRPs was 0.727 (0.575 0.879, p = 0.01). CONCLUSION: P. aeruginosa and MRSA were the most important pathogens in hemodialysis-associated pneumonia. Wound care, severe pneumonia and old age were significant risk factors for DRPs. PMID- 27502600 TI - The clinical utility of serum IL-35 in patients with polymyositis and dermatomyositis. AB - The objectives of this study are to assess the levels of serum Interleukin-35 (IL 35) in patients with idiopathic inflammatory myopathies (IIMs) and to evaluate the association between IL-35 levels and IIM-related features. Serum IL-35 was detected in 76 patients with dermatomyositis (DM), 28 patients with polymyositis (PM), 98 disease controls (40 rheumatoid arthritis (RA), 34 systemic lupus erythematosus (SLE), 12 systemic sclerosis (SSc), and 12 sjogren syndrome (SS)), and 43 healthy controls by ELISA. Follow-up was conducted on 34 patients. Serum IL-35 was higher in myositis (PM/DM) patients than in healthy controls (median 76.6 pg/ml [interquartile range (IQR) 57.9-136.2] vs. 29.9 pg/ml (IQR 21.9-65.5), P < 0.001) and disease controls. Serum IL-35 in IIM patients negatively correlated with disease duration moderately (r = -0.35, P < 0.01). Patients with dysphagia had higher IL-35 than those without (median149.35 pg/ml (IQR 87.97 267.32) vs. 70.72 pg/ml (IQR 54.49-123.42), P = 0.001). Cross-sectional correlation analysis showed a weak positive correlation between serum IL-35 and CK (r = 0.293, P = 0.003), moderate positive correlation with erythrocyte sedimentation rate (ESR) (r = 0.304, P = 0.002), serum ferritin (SF) (r = 0.467, P = 0.001) and LDH levels (r = 0.401, P < 0.001). Additionally, serum IL-35 was higher in patients who were positive for anti-HMGCR (median 292.04 pg/ml (IQR 67.9-442.86) vs. 74.66 pg/ml (IQR 57.24-131.32), P = 0.038) and anti-SRP antibody (median 130.33 pg/ml (IQR 88.04-481.28) vs. 73.06 pg/ml (IQR 56.78-134.28), P = 0.009) than in negative patients, respectively. Follow-up study showed that changes in IL-35 levels after treatment correlated with changes in MYOACT scores moderately (r = 0.375, P = 0.029). These data indicate that increased serum IL-35 could act as a disease activity marker and as a risk factor for esophageal involvement in IIM. IL-35 may participate in the pathophysiological processes of IIM, but it still needs further study to confirm. PMID- 27502601 TI - DPP-4 inhibitors in diabetic complications: role of DPP-4 beyond glucose control. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are an emerging class of antidiabetic drugs that constitutes approximately fifty percent of the market share of the oral hypoglycemic drugs. Its mechanism of action for lowering blood glucose is essentially via inhibition of the rapid degradation of incretin hormones, such as glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP), thus the plasma concentration of GLP-1 increases, which promotes insulin secretion from the pancreatic beta cells and suppresses glucagon secretion from the alpha cells. In addition to the direct actions on the pancreas, GLP-1 exhibits diverse actions on different tissues through its action on GLP-1 receptor, which is expressed ubiquitously. Moreover, DPP-4 has multiple substrates besides GLP-1 and GIP, including cytokines, chemokines, neuropeptides, and growth factors, which are involved in many pathophysiological conditions. Recently, it was suggested that DPP-4 is a new adipokine secreted from the adipose tissue, which plays an important role in the regulation of the endocrine function in obesity-associated type 2 diabetes. Consequently, DPP-4 inhibitors have been reported to exhibit cytoprotective functions against various diabetic complications affecting the liver, heart, kidneys, retina, and neurons. This review outlines the current understanding of the effect of DPP-4 inhibitors on the complications associated with type 2 diabetes, such as liver steatosis and inflammation, dysfunction of the adipose tissue and pancreas, cardiovascular diseases, nephropathy, and neuropathy in preclinical and clinical studies. PMID- 27502602 TI - Papaya CpERF9 acts as a transcriptional repressor of cell-wall-modifying genes CpPME1/2 and CpPG5 involved in fruit ripening. AB - KEY MESSAGE: CpERF9 controls papaya fruit ripening through transcriptional repression of cell-wall-modifying genes CpPME1/2 and CpPG5 by directly binding to their promoters. Papaya fruit ripening is an intricate and highly coordinated developmental process which is controlled by the action of ethylene and expression of numerous ethylene-responsive genes. Ethylene response factors (ERFs) representing the last regulators of ethylene-signaling pathway determine the specificities of ethylene response. However, knowledge concerning the transcriptional controlling mechanism of ERF-mediated papaya fruit ripening is limited. In the present work, a gene-encoding AP2/ERF protein with two ERF associated amphiphilic repression (EAR) motifs, named CpERF9, was characterized from papaya fruit. CpERF9 was found to localize in nucleus, and possess transcriptional repression ability. CpERF9 expression steadily decreased during papaya fruit ripening, while several genes encoding pectin methylesterases (PMEs) and polygalacturonases (PGs), such as CpPME1/2 and CpPG5, were gradually increased, paralleling the decline of fruit firmness. Electrophoretic mobility shift assay (EMSA) demonstrated a specific binding of CpERF9 to promoters of CpPME1/2 and CpPG5, via the GCC-box motif. Transient expression of CpERF9 in tobacco repressed CpPME1/2 and CpPG5 promoter activities, which was depended on two EAR motifs of CpERF9 protein. Taken together, these findings suggest that papaya CpERF9 may act as a transcriptional repressor of several cell-wall modifying genes, such as CpPME1/2 and CpPG5, via directly binding to their promoters. PMID- 27502603 TI - Do perfusion and diffusion MRI predict glioblastoma relapse sites following chemoradiation? AB - To assess the value of T2* dynamic-susceptibility contrast MRI (DSC-MRI) and diffusion-weighted imaging (DWI) to predict the glioblastoma relapse sites after chemoradiation. From a cohort of 44 patients, primarily treated with radiotherapy (60 Gy) and concomitant temozolomide for glioblastoma, who were included in the reference arm of a prospective clinical trial (NCT01507506), 15 patients relapsed and their imaging data were analyzed. All patients underwent anatomical MRI, DSC MRI and DWI before radiotherapy and every 2 months thereafter until relapse. Voxels within the sites of relapse were correlated with their perfusion and/or diffusion abnormality (PDA) pretreatment status after rigid co-registration. The relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were used as biomarkers. Several PDA areas were thresholded: hyperperfused voxels using a 1.75 fixed rCBV threshold (HPt); hypoperfused (hPg) and hyperperfused (HPg) voxels using a histogram-based Gaussian method; diffusion-restricted voxels (DRg); and HPg voxels with diffusion restriction (HPg&DRg). Two sets of voxels (2,459,483 and 2,073,880) were analyzed according to these thresholding methods. Positive predictive values (PPV) of PDA voxels were low (between 9.5 and 31.9 %). The best PPV was obtained with HPg&DRg voxels within the FLAIR hyperintensity, as 18.3 % of voxels without initial PDA were within relapse sites, versus 31.9 % with initial PDA (p < 0.0001). This prospective study suggests that DSC and/or DWI-MRI do not predict the glioblastoma relapse sites. However, further investigations with new methodological approaches are needed to better understand the role of these modalities in the prediction of glioblastoma relapse sites. PMID- 27502604 TI - Young systemic factors as a medicine for age-related neurodegenerative diseases. AB - It is widely known that neurogenesis, brain function and cognition decline with aging. Increasing evidence suggests that cerebrovascular dysfunction is a major cause of cognitive impairment in the elderly but is also involved in age-related neurodegenerative diseases. Finding ways and molecules that reverse this process and ameliorate age- and disease-related cognitive impairment by targeting vascular and neurogenic deterioration would be of great therapeutic value. In Katsimpardi et al. we reported that young blood has a dual beneficial effect in the aged brain by restoring age-related decline in neurogenesis as well as inducing a striking remodeling of the aged vasculature and restoring blood flow to youthful levels. Additionally, we identified a youthful systemic factor, GDF11 that recapitulates these beneficial effects of young blood. We believe that the identification of young systemic factors that can rejuvenate the aged brain opens new roads to therapeutic intervention for neurodegenerative diseases by targeting both neural stem cells and neurogenesis as well as at the vasculature. PMID- 27502605 TI - Accreditation for centers of sarcoma surgery. AB - Soft-tissue sarcomas (STS) are a heterogeneous group of neoplasms which may be subclassified into over 70 specific histologies and may be distributed throughout the body. Approximately one-half arises in the extremities and one-third arises in the abdomen, pelvis, and retroperitoneum. The diversity and rarity of sarcomas combined with the quite large number of affected patients are factors which underline of the importance of networking in diagnosis, therapy, and research dealing with rare cancers. The expertise of the treating center is one of the most significant factors affecting survival in STS. The optimal treatment of locally recurrent disease is to prevent it; aggressive multidisciplinary treatment of the primary disease is thus required, as adjuvant therapies cannot compensate for inadequate surgery. Treatment within specialized multidisciplinary teams (MDTs) is crucial; a body of expertise in all the areas of diagnosis and treatment is required to manage STS appropriately. Conformity to approved treatment guidelines is improved when patients are treated by an MDT in a reference centre. Traditionally, peer-reviewed literature has discussed the surgical management of STS based on the site of origin. While the site of origin remains an important consideration, it has become increasingly clear that surgery must also be tailored to specific sarcoma histology to more accurately reflect tumor biology and pattern of recurrence. All sarcoma operations, included retroperitoneal surgery, should be performed in specialized centres to ensure optimal outcomes. PMID- 27502606 TI - Treatment of branch-duct intraductal papillary mucinous neoplasms of the pancreas: state of the art. AB - The diagnosis of branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) has been dramatically increased. BD-IPMNs are frequently discovered as incidental findings in asymptomatic individuals, mainly in elderly patients. An accurate evaluation of BD-IPMNs with high-resolution imaging techniques and endoscopic ultrasound is necessary. Patients with high-risk stigmata (HRS, obstructive jaundice, enhanced solid component) should undergo resection. Patients with worrisome features (WF, cyst size >=3 cm, thickened enhanced cyst walls, non enhanced mural nodules, and clinical acute pancreatitis) may undergo either a strict surveillance based on patients' characteristics (age, comorbidities) or surgical resection. Non-operative management is indicated for BD-IPMNs without HRS and WF. Patients with BD-IPMN who do not undergo resection may develop malignant change over time as well as IPMN-distinct pancreatic cancer. However, non-operative management of BD-IPMNs lacking WF and HRS is safe and the risk of malignant degeneration seems relatively low. The optimal surveillance protocol is currently unclear. PMID- 27502607 TI - Echinocandin B biosynthesis: a biosynthetic cluster from Aspergillus nidulans NRRL 8112 and reassembly of the subclusters Ecd and Hty from Aspergillus pachycristatus NRRL 11440 reveals a single coherent gene cluster. AB - BACKGROUND: Echinocandins are nonribosomal lipopeptides produced by ascommycete fungi. Due to their strong inhibitory effect on fungal cell wall biosynthesis and lack of human toxicity, they have been developed to an important class of antifungal drugs. Since 2012, the biosynthetic gene clusters of most of the main echinocandin variants have been characterized. Especially the comparison of the clusters allows a deeper insight for the biosynthesis of these complex structures. RESULTS: In the genome of the echinocandin B producer Aspergillus nidulans NRRL 8112 we have identified a gene cluster (Ani) that encodes echinocandin biosynthesis. Sequence analyses showed that Ani is clearly delimited from the genomic context and forms a monophyletic lineage with the other echinocandin gene clusters. Importantly, we found that the disjunct genomic location of the echinocandin B gene cluster in A. pachycristatus NRRL 11440 on two separate subclusters, Ecd and Hty, at two loci was likely an artifact of genome misassembly in the absence of a reference sequence. We show that both sequences can be aligned resulting a single cluster with a gene arrangement collinear compared to other clusters of Aspergillus section Nidulantes. The reassembled gene cluster (Ecd/Hty) is identical to a putative gene cluster (AE) that was previously deposited at the NCBI as a sequence from A. delacroxii NRRL 3860. PCR amplification of a part of the gene cluster resulted a sequence that was very similar (97 % identity), but not identical to that of AE. CONCLUSIONS: The Echinocandin B biosynthetic cluster from A. nidulans NRRL 8112 (Ani) is particularly similar to that of A. pachycristatus NRRL 11440 (Ecd/Hty). Ecd/Hty was originally reported as two disjunct sub-clusters Ecd and Hty, but is in fact a continuous sequence with the same gene order as in Ani. According to sequences of PCR products amplified from genomic DNA, the echinocandin B producer A. delacroxii NRRL 3860 is closely related to A. pachycristatus NRRL 11440. A PCR product from the gene cluster was very similar, but clearly distinct from the sequence published for A. delacroxii NRRL 3860 at the NCBI (No. AB720074). As the NCBI entry is virtually identical with the re-assembled Ecd/Hty cluster, it is likely that it originates from A. pachycristatus NRRL 11440 rather than A. delacroxii NRRL 3860. PMID- 27502609 TI - Extracorporeal membrane oxygenation in burn patients with refractory acute respiratory distress syndrome leads to 28 % 90-day survival. PMID- 27502610 TI - Editor's Note. PMID- 27502608 TI - GDF11 Protects against Endothelial Injury and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice. AB - Growth differentiation factor 11 (GDF11) reduces cardiac hypertrophy, improves cerebral vasculature and enhances neurogenesis in ageing mice. Higher growth differentiation factor 11/8 (GDF11/8) is associated with lower risk of cardiovascular events in humans. Here, we showed that adeno-associated viruses GDF11 and recombinant GDF11 protein improve endothelial dysfunction, decrease endothelial apoptosis, and reduce inflammation, consequently decrease atherosclerotic plaques area in apolipoprotein E-/- mice. Moreover, adeno associated viruses-GDF11 and recombinant GDF11 stabilize atherosclerotic plaques by selectively decreasing in macrophages and T lymphocytes, while increasing in collagen and vascular smooth muscle cells within plaques. In addition, GDF11 inhibit palmitic acid-induced endothelial apoptosis and ameliorate palmitic acid induced inflammatory response in RAW264.7 macrophages in vitro. Mechanistically, GDF11 activates the TGF-beta/Smad2/3, AMPK/endothelial nitricoxide synthase (eNOS) while suppresses JNK and NF-kappaB pathways. In humans, circulating GDF11/8 is positively associated with flow-mediated endothelium-dependent dilation in overweight subjects. We concluded that adeno-associated viruses-GDF11 and recombinant GDF11 protect against endothelial injury and reduce atherosclerosis in apolipoprotein E-/- mice, thus may be providing a novel approach to the treatment of atherosclerosis. PMID- 27502611 TI - Compassionate Care Through the Centuries: Highlights in Nursing History. PMID- 27502612 TI - "Endeavoring to Carry On Their Work": The National Debate Over Midwives and Its Impact in Rhode Island, 1890-1940. AB - This article analyzes the national discourse over "the problem" of midwifery in medical literature and examines the impact of this dialogue on Rhode Island from 1890 to 1940. Doctors did not speak as a monolithic bloc on this "problem": some blamed midwives while others impugned poorly trained physicians. This debate led to curricula reform and to state laws to regulate midwifery. The attempt to eliminate midwives in the 1910s failed because of a shortage of trained obstetricians, and because of cultural barriers between immigrant and mainstream communities. A decrease in immigration, an increase in trained obstetricians, the growing notion of midwives as relics of an outdated past, and the emergence of insurance plans to cover "modern" hospital births led to a decline in midwifery. PMID- 27502613 TI - "A Powerful Protector of the Japanese People": The History of the Japanese Hospital in Steveston, British Columbia, Canada,1896-1942. AB - From 1896 to 1942, a Japanese hospital operated in the village of Steveston, British Columbia, Canada. For the first 4 years, Japanese Methodist missionaries utilized a small mission building as a makeshift hospital, until a larger institution was constructed by the local Japanese Fishermen's Association in 1900. The hospital operated until the Japanese internment, after the attack on Pearl Harbor during World War II. This study offers important commentary about the relationships between health, hospitals, and race in British Columbia during a period of increased immigration and economic upheaval. From the unique perspective of Japanese leaders, this study provides new insight about how Japanese populations negotiated hospital care, despite a context of severe racial discrimination. Japanese populations utilized Christianization, fishing expertise, and hospital work to garner more equitable access to opportunities and resources. This study demonstrates that in addition to providing medical treatment, training grounds for health-care workers, and safe refuge for the sick, hospitals played a significant role in confronting broader racialized inequities in Canada's past. PMID- 27502614 TI - Confectionery Care: The Child as a Category of Historical Analysis. PMID- 27502616 TI - "Mother: Here's the Aspirin Tablet That 'Fits' Your Child's Needs"-"Candy" Aspirin and Children, 1947-1960. PMID- 27502618 TI - Media Reviews. PMID- 27502617 TI - Playing Doctor, Playing Nurse: Perspectives on the Origins of the Toy Doctor and Nurse Kits. PMID- 27502619 TI - Use of customised pressure-guided elastic bandages to improve efficacy of compression bandaging for venous ulcers. AB - Compression bandaging is a major treatment of chronic venous ulcers. Its efficacy depends on the applied pressure, which is dependent on the skill of the individual applying the bandage. To improve the quality of bandaging by reducing the variability in compression bandage interface pressures, we changed elastic bandages into a customised version by marking them with circular ink stamps, applied when the stretch achieves an interface pressure between 35 and 45 mmHg. Repeated applications by 20 residents of the customised bandage and non-marked bandage to one smaller and one larger leg were evaluated by measuring the sub bandage pressure. The results demonstrated that the target pressure range is more often attained with the customised bandage compared with the non-marked bandage. The customised bandage improved the efficacy of compression bandaging for venous ulcers, with optimal sub-bandage pressure. PMID- 27502620 TI - Mathematical analysis of the sodium sensitivity of the human histamine H3 receptor. AB - PURPOSE: It was shown by several experimental studies that some G protein coupled receptors (GPCR) are sensitive to sodium ions. Furthermore, mutagenesis studies or the determination of crystal structures of the adenosine A2A or delta-opioid receptor revealed an allosteric Na(+) binding pocket near to the highly conserved Asp(2.50). Within a previous study, the influence of NaCl concentration onto the steady-state GTPase activity at the human histamine H3 receptor (hH3R) in presence of the endogenous histamine or the inverse agonist thioperamide was analyzed. The purpose of the present study was to examine and quantify the Na(+) sensitivity of hH3R on a molecular level. METHODS: To achieve this, we developed a set of equations, describing constitutive activity and the different ligand receptor equilibria in absence or presence of sodium ions. Furthermore, in order to gain a better understanding of the ligand- and Na(+)-binding to hH3R on molecular level, we performed molecular dynamic (MD) simulations. RESULTS: The analysis of the previously determined experimental steady-state GTPase data with the set of equations presented within this study, reveals that thioperamide binds into the orthosteric binding pocket of the hH3R in absence or presence of a Na(+) in its allosteric binding site. However, the data suggest that thioperamide binds preferentially into the hH3R in absence of a sodium ion in its allosteric site. These experimental results were supported by MD simulations of thioperamide in the binding pocket of the inactive hH3R. Furthermore, the MD simulations revealed two different binding modes for thioperamide in presence or absence of a Na(+) in its allosteric site. CONCLUSION: The mathematical model presented within this study describes the experimental data regarding the Na(+)-sensitivity of hH3R in an excellent manner. Although the present study is focused onto the Na(+) sensitivity of the hH3R, the resulting equations, describing Na(+)- and ligand binding to a GPCR, can be used for all other ion-sensitive GPCRs. PMID- 27502622 TI - Arab Journal of Gastroenterology: A rising star. PMID- 27502621 TI - In silico evaluation of gadofosveset pharmacokinetics in different population groups using the Simcyp(r) simulator platform. AB - PURPOSE: Gadofosveset is a Gd-based contrast agent used for magnetic resonance imaging (MRI). Gadolinium kinetic distribution models are implemented in T1 weighted dynamic contrast-enhanced perfusion MRI for characterization of lesion sites in the body. Physiology changes in a disease state potentially can influence the pharmacokinetics of drugs and to this respect modify the distribution properties of contrast agents. This work focuses on the in silico modelling of pharmacokinetic properties of gadofosveset in different population groups through the application of physiologically-based pharmacokinetic models (PBPK) embedded in Simcyp(r) population pharmacokinetics platform. METHODS: Physicochemical and pharmacokinetic properties of gadofosveset were introduced into Simcyp(r) simulator platform and a min-PBPK model was applied. In silico clinical trials were generated simulating the administration of the recommended dose for the contrast agent (i.v., 30 mg/kg) in population cohorts of healthy volunteers, obese, renal and liver impairment, and in a generated virtual oncology population. Results were evaluated regarding basic pharmacokinetic parameters of Cmax, AUC and systemic CL and differences were assessed through ANOVA and estimation of ratio of geometric mean between healthy volunteers and the other population groups. RESULTS: Simcyp(r) predicted a mean Cmax = 551.60 mg/l, a mean AUC = 4079.12 mg/L*h and a mean systemic CL = 0.56 L/h for the virtual population of healthy volunteers. Obese population showed a modulation in Cmax and CL, attributed to increased administered dose. In renal and liver impairment cohorts a significant modulation in Cmax, AUC and CL of gadofosveset is predicted. Oncology population exhibited statistical significant differences regarding AUC when compared with healthy volunteers. CONCLUSIONS: This work employed Simcyp(r) population pharmacokinetics platform in order to compute gadofosveset's pharmacokinetic profiles through PBPK models and in silico clinical trials and evaluate possible differences between population groups. The approach showed promising results that could provide new insights regarding administration of contrast agents in special population cohorts. In silico pharmacokinetics could further be used for evaluating of possible toxicity, interpretation of MRI PK image maps and development of novel contrast agents. PMID- 27502623 TI - Radial head button holing: a cause of irreducible anterior radial head dislocation. AB - "Buttonholing" of the radial head through the anterior joint capsule is a known cause of irreducible anterior radial head dislocation associated with Monteggia injuries in pediatric patients. To the best of our knowledge, no report has described an injury consisting of buttonholing of the radial head through the annular ligament and a simultaneous radial head fracture in an adolescent. In the present case, the radiographic findings were a radial head fracture with anterior dislocation and lack of the anterior fat pad sign. Magnetic resonance imaging (MRI) clearly demonstrated anterior dislocation of the fractured radial head through the torn annular ligament. The anterior joint capsule and proximal portion of the annular ligament were interposed between the radial head and capitellum, preventing closed reduction of the radial head. Familiarity with this condition and imaging findings will aid clinicians to make a proper diagnosis and fast decision to perform an open reduction. PMID- 27502624 TI - Glenoid avulsion of the glenohumeral ligament (GAGL): a case report and review of the anatomy. AB - Shoulder dislocations are frequently seen in the general population and can be a cause of instability. Instability can lead to debilitating symptoms and morbidity as a result of progressive damage to the shoulder. Anterior shoulder dislocations are the most frequent type of dislocations and have been studied extensively with MRI. The soft tissue Bankart lesion is the most well-known entity associated with anterior instability; however, additional structural lesions arising from traumatic events have been described in recent literature which also predispose to anterior shoulder instability. One of these lesions, the glenoid avulsion of the glenohumeral ligament (GAGL), involves avulsion of the inferior glenohumeral ligament from the glenoid and involves separation from an intact labrum. In contrast to the Bankart lesion, there has been limited discussion of the GAGL lesion in the literature and very few imaging examples. We report a case of a GAGL diagnosed on MRI and confirmed with arthroscopy. It is discussed in the context of the anatomy of the inferior glenohumeral ligament and the imaging findings. PMID- 27502626 TI - Real-life experience with intravitreal ocriplasmin on vitreomacular traction and full-thickness macular holes. PMID- 27502625 TI - Short- and midterm reproducibility of marrow fat measurements using mDixon imaging in healthy postmenopausal women. AB - OBJECTIVE: We tested the short- and midterm reproducibility of vertebral marrow fat fraction (FF) measurements using mDixon imaging. MATERIALS AND METHODS: Thirty postmenopausal women underwent mDixon scans to obtain L1-4 FF from three slices per vertebra by two independent observers (session 1). Measurements were repeated after 6 weeks (session 2) and 6 months (session 3). The mean FF for three regions of interest per vertebra was calculated. The coefficients of variation (CVs) were calculated for each participant and imaging session, and the intraclass correlation coefficients (ICCs) were calculated to assess interobserver and intersession agreements. RESULTS: There were no significant differences in FF measurements among the three slices, imaging sessions or observers. The mean intrasubject CV for FF measurement reproducibility was 1.94 %. The interobserver agreement for the average FF value was excellent (ICC >=0.945 for each session). The ICC for intersession agreement was excellent (ICC >=0.955 between sessions). The mean intersession CV was lower within a short-term interval (2.97 %) than within sessions 1 and 3 (4.80 %) or sessions 3 and 2 (4.44 %). The overall mean CV for the reproducibility of FF measured with mDixon imaging over the short- and midterm was 4.09 % (95 % CI, 3.79-4.40 %). CONCLUSION: mDixon is a reproducible method for FF quantification over short- and midterm intervals up to 6 months in healthy postmenopausal women. Our results also provide data by which a power analysis can be optimized when designing studies involving the use of FF derived from similar mDixon sequences. PMID- 27502627 TI - Cancer burden in four countries of the Middle East Cancer Consortium (Cyprus; Jordan; Israel; Izmir (Turkey)) with comparison to the United States surveillance; epidemiology and end results program. AB - It is important that population-based cancer registries provide accurate and reliable data for public health purposes. These data are essential data for planning of cancer control and prevention. In this study, we examined cancer incidence rates (year 2005-2010) in four MECC registries (Cyprus, Jordan, Israel, Izmir (Turkey)) and compared with the rates in the US. The overall age standardized incidence rates for males were highest in the US followed by Israeli Jews, Izmir (Turkey), Cyprus, Israeli Arabs, and lowest in Jordan. In women the rates of cancer of all sites were also highest in US women followed by Israeli Jews, Cyprus, Israeli Arabs, Izmir (Turkey), and lowest in Jordan. It is of interest that although site-specific cancer rates differ between the countries studied, prostate, lung and colorectal cancers are within the five most common cancers males in all countries studied. In females, breast colorectal and endometrium cancers are three of the five most common cancers in females in all countries studied. The results presented in this paper can have implications for opportunities in cancer control and prevention in these countries. Future studies on individual cancer sites with highest rates in these Countries are currently underway. PMID- 27502628 TI - Investigation of Nucleation Mechanism and Tapering Observed in ZnO Nanowire Growth by Carbothermal Reduction Technique. AB - ZnO nanowire nucleation mechanism and initial stages of nanowire growth using the carbothermal reduction technique are studied confirming the involvement of the catalyst at the tip in the growth process. Role of the Au catalyst is further confirmed when the tapering observed in the nanowires can be explained by the change in the shape of the catalyst causing a variation of the contact area at the liquid-solid interface of the nanowires. The rate of decrease in nanowire diameter with length on the average is found to be 0.36 nm/s and this rate is larger near the base. Variation in the ZnO nanowire diameter with length is further explained on the basis of the rate at which Zn atoms are supplied as well as the droplet stability at the high flow rates and temperature. Further, saw tooth faceting is noticed in tapered nanowires, and the formation is analyzed crystallographically. PMID- 27502629 TI - Oral Delivery of DMAB-Modified Docetaxel-Loaded PLGA-TPGS Nanoparticles for Cancer Chemotherapy. AB - Three types of nanoparticle formulation from biodegradable PLGA-TPGS random copolymer were developed in this research for oral administration of anticancer drugs, which include DMAB-modified PLGA nanoparticles, unmodified PLGA-TPGS nanoparticles and DMAB-modified PLGA-TPGS nanoparticles. Firstly, the PLGA-TPGS random copolymer was synthesized and characterized. DMAB was used to increase retention time at the cell surface, thus increasing the chances of particle uptake and improving oral drug bioavailability. Nanoparticles were found to be of spherical shape with an average particle diameter of around 250 nm. The surface charge of PLGA-TPGS nanoparticles was changed to positive after DMAB modification. The results also showed that the DMAB-modified PLGA-TPGS nanoparticles have significantly higher level of the cellular uptake than that of DMAB-modified PLGA nanoparticles and unmodified PLGA-TPGS nanoparticles. In vitro, cytotoxicity experiment showed advantages of the DMAB-modified PLGA-TPGS nanoparticle formulation over commercial Taxotere((r)) in terms of cytotoxicity against MCF-7 cells. In conclusion, oral chemotherapy by DMAB-modified PLGA-TPGS nanoparticle formulation is an attractive and promising treatment option for patients. PMID- 27502630 TI - Optical Properties of GaSb Nanofibers. AB - Amorphous GaSb nanofibers were obtained by ion beam irradiation of bulk GaSb single-crystal wafers, resulting in fibers with diameters of ~20 nm. The Raman spectra and photoluminescence (PL) of the ion irradiation-induced nanofibers before and after annealing were studied. Results show that the Raman intensity of the GaSb LO phonon mode decreased after ion beam irradiation as a result of the formation of the amorphous nanofibers. A new mode is observed at ~155 cm(-1) both from the unannealed and annealed GaSb nanofiber samples related to the A1g mode of Sb-Sb bond vibration. Room temperature PL measurements of the annealed nanofibers present a wide feature band at ~1.4-1.6 eV. The room temperature PL properties of the irradiated samples presents a large blue shift compared to bulk GaSb. Annealed nanofibers and annealed nanofibers with Au nanodots present two different PL peaks (400 and 540 nm), both of which may originate from Ga or O vacancies in GaO. The enhanced PL and new band characteristics in nanostructured GaSb suggest that the nanostructured fibers may have unique applications in optoelectronic devices. PMID- 27502631 TI - Sensitivity of Dielectric Properties to Wear Process on Carbon Nanofiber/High Density Polyethylene Composites. AB - We examined the correlation of wear effects with dielectric properties of carbon nanofibers (CNFs; untreated and organosilane-treated)-reinforced high-density polyethylene (HDPE) composites. Wear testing for the nanocomposites over up to 120 h was carried out, and then, dielectric permittivity and dielectric loss factor of the polymer composites with the increased wear time were studied. Scanning electron microscope and optical microscope observations were made to analyze the microstructure features of the nanocomposites. The results reveal that there exist approximate linear relationships of permittivity with wear coefficient for the nanocomposites. Composites containing silanized CNFs with the sufficiently thick coating exhibited high wear resistance. The change in permittivity was more sensitive to the increased wear coefficient for the nanocomposites with lower wear resistance. This work provides potential for further research on the application of dielectric signals to detect the effects of wear process on lifetime of polymeric materials. PMID- 27502632 TI - Biocompatibility of Graphene Oxide. AB - Herein, we report the effects of graphene oxides on human fibroblast cells and mice with the aim of investigating graphene oxides' biocompatibility. The graphene oxides were prepared by the modified Hummers method and characterized by high-resolution transmission electron microscope and atomic force microscopy. The human fibroblast cells were cultured with different doses of graphene oxides for day 1 to day 5. Thirty mice divided into three test groups (low, middle, high dose) and one control group were injected with 0.1, 0.25, and 0.4 mg graphene oxides, respectively, and were raised for 1 day, 7 days, and 30 days, respectively. Results showed that the water-soluble graphene oxides were successfully prepared; graphene oxides with dose less than 20 MUg/mL did not exhibit toxicity to human fibroblast cells, and the dose of more than 50 MUg/mL exhibits obvious cytotoxicity such as decreasing cell adhesion, inducing cell apoptosis, entering into lysosomes, mitochondrion, endoplasm, and cell nucleus. Graphene oxides under low dose (0.1 mg) and middle dose (0.25 mg) did not exhibit obvious toxicity to mice and under high dose (0.4 mg) exhibited chronic toxicity, such as 4/9 mice death and lung granuloma formation, mainly located in lung, liver, spleen, and kidney, almost could not be cleaned by kidney. In conclusion, graphene oxides exhibit dose-dependent toxicity to cells and animals, such as inducing cell apoptosis and lung granuloma formation, and cannot be cleaned by kidney. When graphene oxides are explored for in vivo applications in animal or human body, its biocompatibility must be considered. PMID- 27502633 TI - Interaction of Water-Soluble CdTe Quantum Dots with Bovine Serum Albumin. AB - Semiconductor nanoparticles (quantum dots) are promising fluorescent markers, but it is very little known about interaction of quantum dots with biological molecules. In this study, interaction of CdTe quantum dots coated with thioglycolic acid (TGA) with bovine serum albumin was investigated. Steady state spectroscopy, atomic force microscopy, electron microscopy and dynamic light scattering methods were used. It was explored how bovine serum albumin affects stability and spectral properties of quantum dots in aqueous media. CdTe-TGA quantum dots in aqueous solution appeared to be not stable and precipitated. Interaction with bovine serum albumin significantly enhanced stability and photoluminescence quantum yield of quantum dots and prevented quantum dots from aggregating. PMID- 27502634 TI - Assessment of Influence of Magnetic Forces on Aggregation of Zero-valent Iron Nanoparticles. AB - Aggregation of zero-valent nanoparticles in groundwater is influenced by several physical phenomena. The article shortly introduces preceding works in modeling of aggregation of small particles including influence of sedimentation, velocity profile of water, heat fluctuations, and surface electric charge. A brief description of inclusion of magnetic forces into the model of aggregation follows. Rate of influence of the magnetic forces on the aggregation depends on the magnitude of magnetization of the particles, radius of nanoparticles, size of the aggregates, and their concentration in the solution. Presented results show that the magnetic forces have significant influence on aggregation especially of the smallest iron particles. PMID- 27502635 TI - In situ-Directed Growth of Organic Nanofibers and Nanoflakes: Electrical and Morphological Properties. AB - Organic nanostructures made from organic molecules such as para-hexaphenylene (p 6P) could form nanoscale components in future electronic and optoelectronic devices. However, the integration of such fragile nanostructures with the necessary interface circuitry such as metal electrodes for electrical connection continues to be a significant hindrance toward their large-scale implementation. Here, we demonstrate in situ-directed growth of such organic nanostructures between pre-fabricated contacts, which are source-drain gold electrodes on a transistor platform (bottom-gate) on silicon dioxide patterned by a combination of optical lithography and electron beam lithography. The dimensions of the gold electrodes strongly influence the morphology of the resulting structures leading to notably different electrical properties. The ability to control such nanofiber or nanoflake growth opens the possibility for large-scale optoelectronic device fabrication. PMID- 27502636 TI - Arc Discharge Synthesis and Photoluminescence of 3D Feather-like AlN Nanostructures. AB - A complex three-dimensional (3D) feather-like AlN nanostructure was synthesized by a direct reaction of high-purity Al granules with nitrogen using an arc discharge method. By adjusting the discharge time, a coral-like nanostructure, which evolved from the feather-like nanostructure, has also been observed. The novel 3D feather-like AlN nanostructure has a hierarchical dendritic structure, which means that the angle between the trunk stem and its branch is always about 30 degrees in any part of the structure. The fine branches on the surface of the feather-like nanostructure have shown a uniform fish scale shape, which are about 100 nm long, 10 nm thick and several tens of nanometers in width. An alternate growth model has been proposed to explain the novel nanostructure. The spectrum of the feather-like products shows a strong blue emission band centered at 438 nm (2.84 eV), which indicates their potential application as blue light-emitting diodes. PMID- 27502637 TI - Perpendicular Magnetic Anisotropy in FePt Patterned Media Employing a CrV Seed Layer. AB - A thin FePt film was deposited onto a CrV seed layer at 400 degrees C and showed a high coercivity (~3,400 Oe) and high magnetization (900-1,000 emu/cm(3)) characteristic of L 10 phase. However, the magnetic properties of patterned media fabricated from the film stack were degraded due to the Ar-ion bombardment. We employed a deposition-last process, in which FePt film deposited at room temperature underwent lift-off and post-annealing processes, to avoid the exposure of FePt to Ar plasma. A patterned medium with 100-nm nano-columns showed an out-of-plane coercivity fivefold larger than its in-plane counterpart and a remanent magnetization comparable to saturation magnetization in the out-of-plane direction, indicating a high perpendicular anisotropy. These results demonstrate the high perpendicular anisotropy in FePt patterned media using a Cr-based compound seed layer for the first time and suggest that ultra-high-density magnetic recording media can be achieved using this optimized top-down approach. PMID- 27502638 TI - In situ Precursor-Template Route to Semi-Ordered NaNbO3 Nanobelt Arrays. AB - We exploited a precursor-template route to chemically synthesize NaNbO3 nanobelt arrays. Na7(H3O)Nb6O19.14H2O nanobelt precursor was firstly prepared via a hydrothermal synthetic route using Nb foil. The aspect ratio of the precursor is controllable facilely depending on the concentration of NaOH aqueous solution. The precursor was calcined in air to yield single-crystalline monoclinic NaNbO3 nanobelt arrays. The proposed scheme for NaNbO3 nanobelt formation starting from Nb metal may be extended to the chemical fabrication of more niobate arrays. PMID- 27502639 TI - Intestine-Specific, Oral Delivery of Captopril/Montmorillonite: Formulation and Release Kinetics. AB - The intercalation of captopril (CP) into the interlayers of montmorillonite (MMT) affords an intestine-selective drug delivery system that has a captopril-loading capacity of up to ca. 14 %w/w and which exhibits near-zero-order release kinetics. PMID- 27502640 TI - Biofabrication of Anisotropic Gold Nanotriangles Using Extract of Endophytic Aspergillus clavatus as a Dual Functional Reductant and Stabilizer. AB - Biosynthesis of metal and semiconductor nanoparticles using microorganisms has emerged as a more eco-friendly, simpler and reproducible alternative to the chemical synthesis, allowing the generation of rare forms such as nanotriangles and prisms. Here, we report the endophytic fungus Aspergillus clavatus, isolated from surface sterilized stem tissues of Azadirachta indica A. Juss., when incubated with an aqueous solution of chloroaurate ions produces a diverse mixture of intracellular gold nanoparticles (AuNPs), especially nanotriangles (GNT) in the size range from 20 to 35 nm. These structures (GNT) are of special interest since they possess distinct plasmonic features in the visible and IR regions, which equipped them with unique physical and optical properties exploitable in vital applications such as optics, electronics, catalysis and biomedicine. The reaction process was simple and convenient to handle and was monitored using ultraviolet-visible spectroscopy (UV-vis). The morphology and crystalline nature of the GNTs were determined from transmission electron microscopy (TEM), atomic force spectroscopy (AFM) and X-ray diffraction (XRD) spectroscopy. This proposed mechanistic principal might serve as a set of design rule for the synthesis of anisotropic nanostructures with desired architecture and can be amenable for the large scale commercial production and technical applications. PMID- 27502642 TI - Design and Fabrication of Fiber-Optic Nanoprobes for Optical Sensing. AB - This paper describes the design and fabrication of fiber-optic nanoprobes developed for optical detection in single living cells. It is critical to fabricate probes with well-controlled nanoapertures for optimized spatial resolution and optical transmission. The detection sensitivity of fiber-optic nanoprobe depends mainly on the extremely small excitation volume that is determined by the aperture sizes and penetration depths. We investigate the angle dependence of the aperture in shadow evaporation of the metal coating onto the tip wall. It was found that nanoaperture diameters of approximately 50 nm can be achieved using a 25 degrees tilt angle. On the other hand, the aperture size is sensitive to the subtle change of the metal evaporation angle and could be blocked by irregular metal grains. Through focused ion beam (FIB) milling, optical nanoprobes with well-defined aperture size as small as 200 nm can be obtained. Finally, we illustrate the use of the nanoprobes by detecting a fluorescent species, benzo[a]pyrene tetrol (BPT), in single living cells. A quantitative estimation of the numbers of BPT molecules detected using fiber optic nanoprobes for BPT solutions shows that the limit of detection was approximately 100 molecules. PMID- 27502641 TI - Silver and Gold Nanoparticles Alter Cathepsin Activity In vitro. AB - Nanomaterials are being incorporated into many biological applications for use as therapeutics, sensors, or labels. Silver nanomaterials are being utilized for biological implants and wound dressings as an antiviral material, whereas gold nanomaterials are being used as biological labels or sensors due to their surface properties and biocompatibility. Cytotoxicity data of these materials are becoming more prevalent; however, little research has been performed to understand how the introduction of these materials into cells affects cellular processes. Here, we demonstrate the impact that silver and gold nanoparticles have on cathepsin activity in vitro. Cathepsins are important cellular proteases that are imperative for proper immune system function. We have selected to examine gold and silver nanoparticles due to the increased use of these materials in biological applications. This manuscript depicts how both of these types of nanomaterials affect cathepsin activity, which could impact the host's immune system and its ability to respond to pathogens. Cathepsin B activity decreases in a dose-dependent manner with all nanoparticles tested. Alternatively, the impact of nanoparticles on cathepsin L activity depends greatly on the type and size of the material. PMID- 27502643 TI - Biomagnetic of Apatite-Coated Cobalt Ferrite: A Core-Shell Particle for Protein Adsorption and pH-Controlled Release. AB - Magnetic nanoparticle composite with a cobalt ferrite (CoFe2O4, (CF)) core and an apatite (Ap) coating was synthesized using a biomineralization process in which a modified simulated body fluid (1.5SBF) solution is the source of the calcium phosphate for the apatite formation. The core-shell structure formed after the citric acid-stabilized cobalt ferrite (CFCA) particles were incubated in the 1.5 SBF solution for 1 week. The mean particle size of CFCA-Ap is about 750 nm. A saturation magnetization of 15.56 emug(-1) and a coercivity of 1808.5 Oe were observed for the CFCA-Ap obtained. Bovine serum albumin (BSA) was used as the model protein to study the adsorption and release of the proteins by the CFCA-Ap particles. The protein adsorption by the CFCA-Ap particles followed a more typical Freundlich than Langmuir adsorption isotherm. The BSA release as a function of time became less rapid as the CFCA-Ap particles were immersed in higher pH solution, thus indicating that the BSA release is dependent on the local pH. PMID- 27502644 TI - Quantum Dot Infrared Photodetectors: Photoresponse Enhancement Due to Potential Barriers. AB - Potential barriers around quantum dots (QDs) play a key role in kinetics of photoelectrons. These barriers are always created, when electrons from dopants outside QDs fill the dots. Potential barriers suppress the capture processes of photoelectrons and increase the photoresponse. To directly investigate the effect of potential barriers on photoelectron kinetics, we fabricated several QD structures with different positions of dopants and various levels of doping. The potential barriers as a function of doping and dopant positions have been determined using nextnano(3) software. We experimentally investigated the photoresponse to IR radiation as a function of the radiation frequency and voltage bias. We also measured the dark current in these QD structures. Our investigations show that the photoresponse increases ~30 times as the height of potential barriers changes from 30 to 130 meV. PMID- 27502646 TI - Organic-Inorganic Nanostructure Architecture via Directly Capping Fullerenes onto Quantum Dots. AB - A new form of fullerene-capped CdSe nanoparticles (PCBA-capped CdSe NPs), using carboxylate ligands with [60]fullerene capping groups that provides an effective synthetic methodology to attach fullerenes noncovalently to CdSe, is presented for usage in nanotechnology and photoelectric fields. Interestingly, either the internal charge transfer or the energy transfer in the hybrid material contributes to photoluminescence (PL) quenching of the CdSe moieties. PMID- 27502645 TI - Biomimetic Synthesis of Gelatin Polypeptide-Assisted Noble-Metal Nanoparticles and Their Interaction Study. AB - Herein, the generation of gold, silver, and silver-gold (Ag-Au) bimetallic nanoparticles was carried out in collagen (gelatin) solution. It first showed that the major ingredient in gelatin polypeptide, glutamic acid, acted as reducing agent to biomimetically synthesize noble metal nanoparticles at 80 degrees C. The size of nanoparticles can be controlled not only by the mass ratio of gelatin to gold ion but also by pH of gelatin solution. Interaction between noble-metal nanoparticles and polypeptide has been investigated by TEM, UV visible, fluorescence spectroscopy, and HNMR. This study testified that the degradation of gelatin protein could not alter the morphology of nanoparticles, but it made nanoparticles aggregated clusters array (opposing three-dimensional alpha-helix folding structure) into isolated nanoparticles stabilized by gelatin residues. This is a promising merit of gelatin to apply in the synthesis of nanoparticles. Therefore, gelatin protein is an excellent template for biomimetic synthesis of noble metal/bimetallic nanoparticle growth to form nanometer-sized device. PMID- 27502647 TI - Facile Synthesis of Amine-Functionalized Eu(3+)-Doped La(OH)3 Nanophosphors for Bioimaging. AB - Here, we report a straightforward synthesis process to produce colloidal Eu(3+) activated nanophosphors (NPs) for use as bioimaging probes. In this procedure, poly(ethylene glycol) serves as a high-boiling point solvent allowing for nanoscale particle formation as well as a convenient medium for solvent exchange and subsequent surface modification. The La(OH)3:Eu(3+) NPs produced by this process were ~3.5 nm in diameter as determined by transmission electron microscopy. The NP surface was coated with aminopropyltriethoxysilane to provide chemical functionality for attachment of biological ligands, improve chemical stability and prevent surface quenching of luminescent centers. Photoluminescence spectroscopy of the NPs displayed emission peaks at 597 and 615 nm (lambdaex = 280 nm). The red emission, due to (5)D0 -> (7)F1 and (5)D0 -> (7)F2 transitions, was linear with concentration as observed by imaging with a conventional bioimaging system. To demonstrate the feasibility of these NPs to serve as optical probes in biological applications, an in vitro experiment was performed with HeLa cells. NP emission was observed in the cells by fluorescence microscopy. In addition, the NPs displayed no cytotoxicity over the course of a 48-h MTT cell viability assay. These results suggest that La(OH)3:Eu(3+) NPs possess the potential to serve as a luminescent bioimaging probe. PMID- 27502648 TI - Fabrication of Nickel Nanostructure Arrays Via a Modified Nanosphere Lithography. AB - In this paper, we present a modified nanosphere lithographic scheme that is based on the self-assembly and electroforming techniques. The scheme was demonstrated to fabricate a nickel template of ordered nanobowl arrays together with a nickel nanostructure array-patterned glass substrate. The hemispherical nanobowls exhibit uniform sizes and smooth interior surfaces, and the shallow nanobowls with a flat bottom on the glass substrate are interconnected as a net structure with uniform thickness. A multiphysics model based on the level set method (LSM) was built up to understand this fabricating process by tracking the interface between the growing nickel and the electrolyte. The fabricated nickel nanobowl template can be used as a mold of long lifetime in soft lithography due to the high strength of nickel. The nanostructure-patterned glass substrate can be used in optical and magnetic devices due to their shape effects. This fabrication scheme can also be extended to a wide range of metals and alloys. PMID- 27502649 TI - The MoS2 Nanotubes with Defect-Controlled Electric Properties. AB - We describe a two-step synthesis of pure multiwall MoS2 nanotubes with a high degree of homogeneity in size. The Mo6S4I6 nanowires grown directly from elements under temperature gradient conditions in hedgehog-like assemblies were used as precursor material. Transformation in argon-H2S/H2 mixture leads to the MoS2 nanotubes still grouped in hedgehog-like morphology. The described method enables a large-scale production of MoS2 nanotubes and their size control. X-ray diffraction, optical absorption and Raman spectroscopy, scanning electron microscopy with wave dispersive analysis, and transmission electron microscopy were used to characterize the starting Mo6S4I6 nanowires and the MoS2 nanotubes. The unit cell parameters of the Mo6S4I6 phase are proposed. Blue shift in optical absorbance and metallic behavior of MoS2 nanotubes in two-probe measurement are explained by a high defect concentration. PMID- 27502650 TI - Role of Surface Area, Primary Particle Size, and Crystal Phase on Titanium Dioxide Nanoparticle Dispersion Properties. AB - Characterizing nanoparticle dispersions and understanding the effect of parameters that alter dispersion properties are important for both environmental applications and toxicity investigations. The role of particle surface area, primary particle size, and crystal phase on TiO2 nanoparticle dispersion properties is reported. Hydrodynamic size, zeta potential, and isoelectric point (IEP) of ten laboratory synthesized TiO2 samples, and one commercial Degussa TiO2 sample (P25) dispersed in different solutions were characterized. Solution ionic strength and pH affect titania dispersion properties. The effect of monovalent (NaCl) and divalent (MgCl2) inert electrolytes on dispersion properties was quantified through their contribution to ionic strength. Increasing titania particle surface area resulted in a decrease in solution pH. At fixed pH, increasing the particle surface area enhanced the collision frequency between particles and led to a higher degree of agglomeration. In addition to the synthesis method, TiO2 isoelectric point was found to be dependent on particle size. As anatase TiO2 primary particle size increased from 6 nm to 104 nm, its IEP decreased from 6.0 to 3.8 that also results in changes in dispersion zeta potential and hydrodynamic size. In contrast to particle size, TiO2 nanoparticle IEP was found to be insensitive to particle crystal structure. PMID- 27502651 TI - Effect of Topological Defects on Buckling Behavior of Single-walled Carbon Nanotube. AB - Molecular dynamic simulation method has been employed to consider the critical buckling force, pressure, and strain of pristine and defected single-walled carbon nanotube (SWCNT) under axial compression. Effects of length, radius, chirality, Stone-Wales (SW) defect, and single vacancy (SV) defect on buckling behavior of SWCNTs have been studied. Obtained results indicate that axial stability of SWCNT reduces significantly due to topological defects. Critical buckling strain is more susceptible to defects than critical buckling force. Both SW and SV defects decrease the buckling mode of SWCNT. Comparative approach of this study leads to more reliable design of nanostructures. PMID- 27502652 TI - Novel Strategy to Fabricate PLA/Au Nanocomposites as an Efficient Drug Carrier for Human Leukemia Cells in Vitro. AB - Poly (lactic acid) (PLA) polymer has the promising applications in the biomedical field because of its biodegradability and safe elimination. In this study, we have explored the bio-application of new nanocomposites composed with PLA nanofibers and Au nanoparticles as the potential drug carrier for an efficient drug delivery in target cancer cells. The results demonstrated that the anticancer drug daunorubicin could be efficiently self-assembled on the surface of PLA/Au nanocomposites and the synergistic enhancement of PLA/Au nanocomposites conjugated with daunorubicin into drug-sensitive K562 and drug-resistant leukemia K562/AO2 cells could be obviously observed by MTT assay and confocal fluorescence microscopy studies. These observations suggest that the new nanocomposites could readily induce daunorubicin to accumulate and uptake in target leukemia cells and increase the drug's cytotoxicity. Especially, the PLA/Au nanocomposites could significantly facilitate the cellular drug absorbtion of daunorubicin into drug resistant K562/AO2 cells and efficiently inhibit the cancer cell proliferation. This raised the possibility to utilize the PLA/Au nanocomposites as a new effective additive agent to inhibit the drug resistance and thus as a novel strategy to sensitively track the respective cancer cells. PMID- 27502653 TI - Efficient Performance of Electrostatic Spray-Deposited TiO2 Blocking Layers in Dye-Sensitized Solar Cells after Swift Heavy Ion Beam Irradiation. AB - A compact TiO2 layer (~1.1 MUm) prepared by electrostatic spray deposition (ESD) and swift heavy ion beam (SHI) irradiation using oxygen ions onto a fluorinated tin oxide (FTO) conducting substrate showed enhancement of photovoltaic performance in dye-sensitized solar cells (DSSCs). The short circuit current density (Jsc = 12.2 mA cm(-2)) of DSSCs was found to increase significantly when an ESD technique was applied for fabrication of the TiO2 blocking layer, compared to a conventional spin-coated layer (Jsc = 8.9 mA cm(-2)). When SHI irradiation of oxygen ions of fluence 1 * 10(13) ions/cm(2) was carried out on the ESD TiO2, it was found that the energy conversion efficiency improved mainly due to the increase in open circuit voltage of DSSCs. This increased energy conversion efficiency seems to be associated with improved electronic energy transfer by increasing the densification of the blocking layer and improving the adhesion between the blocking layer and the FTO substrate. The adhesion results from instantaneous local melting of the TiO2 particles. An increase in the electron transport from the blocking layer may also retard the electron recombination process due to the oxidized species present in the electrolyte. These findings from novel treatments using ESD and SHI irradiation techniques may provide a new tool to improve the photovoltaic performance of DSSCs. PMID- 27502654 TI - One-Pot Synthesis of Biocompatible CdSe/CdS Quantum Dots and Their Applications as Fluorescent Biological Labels. AB - We developed a novel one-pot polyol approach for the synthesis of biocompatible CdSe quantum dots (QDs) using poly(acrylic acid) (PAA) as a capping ligand at 240 degrees C. The morphological and structural characterization confirmed the formation of biocompatible and monodisperse CdSe QDs with several nanometers in size. The encapsulation of CdS thin layers on the surface of CdSe QDs (CdSe/CdS core-shell QDs) was used for passivating the defect emission (650 nm) and enhancing the fluorescent quantum yields up to 30% of band-to-band emission (530 600 nm). Moreover, the PL emission peak of CdSe/CdS core-shell QDs could be tuned from 530 to 600 nm by the size of CdSe core. The as-prepared CdSe/CdS core-shell QDs with small size, well water solubility, good monodispersity, and bright PL emission showed high performance as fluorescent cell labels in vitro. The viability of QDs-labeled 293T cells was evaluated using a 3-(4,5-dimethylthiazol) 2-diphenyltertrazolium bromide (MTT) assay. The results showed the satisfactory (>80%) biocompatibility of as-synthesized PAA-capped QDs at the Cd concentration of 15 MUg/ml. PMID- 27502655 TI - Role of Temperature in the Growth of Silver Nanoparticles Through a Synergetic Reduction Approach. AB - This study presents the role of reaction temperature in the formation and growth of silver nanoparticles through a synergetic reduction approach using two or three reducing agents simultaneously. By this approach, the shape-/size controlled silver nanoparticles (plates and spheres) can be generated under mild conditions. It was found that the reaction temperature could play a key role in particle growth and shape/size control, especially for silver nanoplates. These nanoplates could exhibit an intensive surface plasmon resonance in the wavelength range of 700-1,400 nm in the UV-vis spectrum depending upon their shapes and sizes, which make them useful for optical applications, such as optical probes, ionic sensing, and biochemical sensors. A detailed analysis conducted in this study clearly shows that the reaction temperature can greatly influence reaction rate, and hence the particle characteristics. The findings would be useful for optimization of experimental parameters for shape-controlled synthesis of other metallic nanoparticles (e.g., Au, Cu, Pt, and Pd) with desirable functional properties. PMID- 27502656 TI - Characterization of Films with Thickness Less than 10 nm by Sensitivity-Enhanced Atomic Force Acoustic Microscopy. AB - We present a method for characterizing ultrathin films using sensitivity-enhanced atomic force acoustic microscopy, where a concentrated-mass cantilever having a flat tip was used as a sensitive oscillator. Evaluation was aimed at 6-nm-thick and 10-nm-thick diamond-like carbon (DLC) films deposited, using different methods, on a hard disk for the effective Young's modulus defined as E/(1 - nu(2)), where E is the Young's modulus, and nu is the Poisson's ratio. The resonant frequency of the cantilever was affected not only by the film's elasticity but also by the substrate even at an indentation depth of about 0.6 nm. The substrate effect was removed by employing a theoretical formula on the indentation of a layered half-space, together with a hard disk without DLC coating. The moduli of the 6-nm-thick and 10-nm-thick DLC films were 392 and 345 GPa, respectively. The error analysis showed the standard deviation less than 5% in the moduli. PMID- 27502657 TI - Large-scale Synthesis of beta-SiC Nanochains and Their Raman/Photoluminescence Properties. AB - Although the SiC/SiO2 nanochain heterojunction has been synthesized, the chained homogeneous nanostructure of SiC has not been reported before. Herein, the novel beta-SiC nanochains are synthesized assisted by the AAO template. The characterized results demonstrate that the nanostructures are constructed by spheres of 25-30 nm and conjoint wires of 15-20 nm in diameters. Raman and photoluminescence measurements are used to explore the unique optical properties. A speed-alternating vapor-solid (SA-VS) growth mechanism is proposed to interpret the formation of this typical nanochains. The achieved nanochains enrich the species of one-dimensional (1D) nanostructures and may hold great potential applications in nanotechnology. PMID- 27502658 TI - beta-Phase Morphology in Ordered Poly(9,9-dioctylfluorene) Nanopillars by Template Wetting Method. AB - An efficient method based in template wetting is applied for fabrication of ordered Poly(9,9-dioctylfluorene) (PFO) nanopillars with beta-phase morphology. In this process, nanoporous alumina obtained by anodization process is used as template. PFO nanostructures are prepared under ambient conditions via infiltration of the polymeric solution into the pores of the alumina with an average pore diameter of 225 nm and a pore depth of 500 nm. The geometric features of the resulting structures are characterized with environmental scanning electron microscopy (ESEM), luminescence fluorimeter (PL) and micro MU-X ray diffractometer (MU-XRD). The characterization demonstrates the beta-phase of the PFO in the nanopillars fabricated. Furthermore, the PFO nanopillars are characterized by Raman spectroscopy to study the polymer conformation. These ordered nanostructures can be used in optoelectronic applications such as polymer light-emitting diodes, sensors and organic solar cells. PMID- 27502659 TI - Thermal Effects and Small Signal Modulation of 1.3-MUm InAs/GaAs Self-Assembled Quantum-Dot Lasers. AB - We investigate the influence of thermal effects on the high-speed performance of 1.3-MUm InAs/GaAs quantum-dot lasers in a wide temperature range (5-50 degrees C). Ridge waveguide devices with 1.1 mm cavity length exhibit small signal modulation bandwidths of 7.51 GHz at 5 degrees C and 3.98 GHz at 50 degrees C. Temperature-dependent K-factor, differential gain, and gain compression factor are studied. While the intrinsic damping-limited modulation bandwidth is as high as 23 GHz, the actual modulation bandwidth is limited by carrier thermalization under continuous wave operation. Saturation of the resonance frequency was found to be the result of thermal reduction in the differential gain, which may originate from carrier thermalization. PMID- 27502660 TI - Flexible Dye-Sensitized Solar Cell Based on Vertical ZnO Nanowire Arrays. AB - Flexible dye-sensitized solar cells are fabricated using vertically aligned ZnO nanowire arrays that are transferred onto ITO-coated poly(ethylene terephthalate) substrates using a simple peel-off process. The solar cells demonstrate an energy conversion efficiency of 0.44% with good bending tolerance. This technique paves a new route for building large-scale cost-effective flexible photovoltaic and optoelectronic devices. PMID- 27502661 TI - A High Diffusive Model for Nanomaterials. AB - Considerable attention is today devoted to the engineering of films widely used in photocatalytic, solar energy converters, photochemical and photoelectrochemical cells, dye-sensitized solar cells (DSSCs), to optimize electronic time response following photogeneration. However, the precise nature of transport processes in these systems has remained unresolved. To investigate such aspects of carrier dynamics, we have suggested a model for the calculation of correlation functions, expressed as the Fourier transform of the frequency dependent complex conductivity sigma(omega). Results are presented for the velocity correlation functions, the mean square deviation of position and the diffusion coefficient in systems, like TiO2 and doped Si, of large interest in present devices. Fast diffusion occurs in short time intervals of the order of few collision times. Consequences for efficiency of this fast response are discussed in relation to nanostructured devices. PMID- 27502662 TI - Investigation on the Plasma-Induced Emission Properties of Large Area Carbon Nanotube Array Cathodes with Different Morphologies. AB - Large area well-aligned carbon nanotube (CNT) arrays with different morphologies were synthesized by using a chemical vapor deposition. The plasma-induced emission properties of CNT array cathodes with different morphologies were investigated. The ratio of CNT height to CNT-to-CNT distance has considerable effects on their plasma-induced emission properties. As the ratio increases, emission currents of CNT array cathodes decrease due to screening effects. Under the pulse electric field of about 6 V/MUm, high-intensity electron beams of 170 180 A/cm(2) were emitted from the surface plasma. The production mechanism of the high-intensity electron beams emitted from the CNT arrays was plasma-induced emission. Moreover, the distribution of the electron beams was in situ characterized by the light emission from the surface plasma. PMID- 27502663 TI - Nano-Floating Gate Memory Devices Composed of ZnO Thin-Film Transistors on Flexible Plastics. AB - Nano-floating gate memory devices were fabricated on a flexible plastic substrate by a low-temperature fabrication process. The memory characteristics of ZnO-based thin-film transistors with Al nanoparticles embedded in the gate oxides were investigated in this study. Their electron mobility was found to be 0.18 cm(2)/V.s and their on/off ratio was in the range of 10(4)-10(5). The threshold voltages of the programmed and erased states were negligibly changed up to 10(3) cycles. The flexibility, memory properties, and low-temperature fabrication of the nano-floating gate memory devices described herein suggest that they have potential applications for future flexible integrated electronics. PMID- 27502664 TI - The Investigation of Intermediate Stage of Template Etching with Metal Droplets by Wetting Angle Analysis on (001) GaAs Surface. AB - In this work, we study metal droplets on a semiconductor surface that are the initial stage for both droplet epitaxy and local droplet etching. The distributions of droplet geometrical parameters such as height, radius and volume help to understand the droplet formation that strongly influences subsequent nanohole etching. To investigate the etching and intermixing processes, we offer a new method of wetting angle analysis. The aspect ratio that is defined as the ratio of the height to radius was used as an estimation of wetting angle which depends on the droplet material. The investigation of the wetting angle and the estimation of indium content revealed significant materials intermixing during the deposition time. AFM measurements reveal the presence of two droplet groups that is in agreement with nanohole investigations. To explain this observation, we consider arsenic evaporation and consequent change in the initial substrate. On the basis of our analysis, we suggest the model of droplet evolution and the formation of two droplet groups. PMID- 27502665 TI - Trapping Iron Oxide into Hollow Gold Nanoparticles. AB - Synthesis of the core/shell-structured Fe3O4/Au nanoparticles by trapping Fe3O4 inside hollow Au nanoparticles is described. The produced composite nanoparticles are strongly magnetic with their surface plasmon resonance peaks in the near infrared region (wavelength from 700 to 800 nm), combining desirable magnetic and plasmonic properties into one nanoparticle. They are particularly suitable for in vivo diagnostic and therapeutic applications. The intact Au surface provides convenient anchorage sites for attachment of targeting molecules, and the particles can be activated by both near infrared lights and magnetic fields. As more and more hollow nanoparticles become available, this synthetic method would find general applications in the fabrication of core-shell multifunctional nanostructures. PMID- 27502666 TI - Single Walled Carbon Nanotubes Exhibit Dual-Phase Regulation to Exposed Arabidopsis Mesophyll Cells. AB - Herein we are the first to report that single-walled carbon nanotubes (SWCNTs) exhibit dual-phase regulation to Arabidopsis mesophyll cells exposed to different concentration of SWCNTs. The mesophyll protoplasts were prepared by enzyme digestion, and incubated with 15, 25, 50, 100 MUg/ml SWCNTs for 48 h, and then were observed by optical microscopy and transmission electron microscopy, the reactive oxygen species (ROS) generation was measured. Partial protoplasts were stained with propidium iodide and 4'-6- diamidino-2-phenylindole, partial protoplasts were incubated with fluorescein isothiocyanate-labeled SWCNTs, and observed by fluorescence microscopy. Results showed that SWCNTs could traverse both the plant cell wall and cell membrane, with less than or equal to 50 MUg/ml in the culture medium, SWCNTs stimulated plant cells to grow out trichome clusters on their surface, with more than 50 MUg/ml SWCNTs in the culture medium, SWCNTs exhibited obvious toxic effects to the protoplasts such as increasing generation of ROS, inducing changes of protoplast morphology, changing green leaves into yellow, and inducing protoplast cells' necrosis and apoptosis. In conclusion, single walled carbon nanotubes can get through Arabidopsis mesophyll cell wall and membrane, and exhibit dose-dependent dual-phase regulation to Arabidopsis mesophyll protoplasts such as low dose stimulating cell growth, and high dose inducing cells' ROS generation, necrosis or apoptosis. PMID- 27502667 TI - A Novel Way for Synthesizing Phosphorus-Doped Zno Nanowires. AB - We developed a novel approach to synthesize phosphorus (P)-doped ZnO nanowires by directly decomposing zinc phosphate powder. The samples were demonstrated to be P doped ZnO nanowires by using scanning electron microscopy, high-resolution transmission electron microscopy, X-ray diffraction spectra, X-ray photoelectron spectroscopy, energy dispersive spectrum, Raman spectra and photoluminescence measurements. The chemical state of P was investigated by electron energy loss spectroscopy (EELS) analyses in individual ZnO nanowires. P was found to substitute at oxygen sites (PO), with the presence of anti-site P on Zn sites (PZn). P-doped ZnO nanowires were high resistance and the related P-doping mechanism was discussed by combining EELS results with electrical measurements, structure characterization and photoluminescence measurements. Our method provides an efficient way of synthesizing P-doped ZnO nanowires and the results help to understand the P-doping mechanism. PMID- 27502669 TI - Highly Efficient Method for Preparing Homogeneous and Stable Colloids Containing Graphene Oxide. AB - Phase transfer method has been developed for preparing homogeneous and stable graphene oxide colloids. Graphene oxide nanosheets (GONs) were successfully transferred from water to n-octane after modification by oleylamine. Corrugation and scrolling exist dominantly in the modified GONs. GONs were single layered with the maximum solubility in n-octane up to 3.82 mg mL(-1). Oleylamine molecules chemically attach onto the GONs. Compared with traditional strategies, the phase transfer method has the features of simplicity and high efficiency. PMID- 27502668 TI - Observation of Coalescence Process of Silver Nanospheres During Shape Transformation to Nanoprisms. AB - In this report, we observed the growth mechanism and the shape transformation from spherical nanoparticles (diameter ~6 nm) to triangular nanoprisms (bisector length ~100 nm). We used a simple direct chemical reduction method and provided evidences for the growth of silver nanoprisms via a coalescence process. Unlike previous reports, our method does not rely upon light, heat, or strong oxidant for the shape transformation. This transformation could be launched by fine tuning the pH value of the silver colloidal solution. Based on our extensive examination using transmission electron microscopy, we propose a non-point initiated growth mechanism, which is a combination of coalescence and dissolution recrystallization process during the growth of silver nanoprisms. PMID- 27502670 TI - Dielectric Relaxation of La-Doped Zirconia Caused by Annealing Ambient. AB - La-doped zirconia films, deposited by ALD at 300 degrees C, were found to be amorphous with dielectric constants (k-values) up to 19. A tetragonal or cubic phase was induced by post-deposition annealing (PDA) at 900 degrees C in both nitrogen and air. Higher k-values (~32) were measured following PDA in air, but not after PDA in nitrogen. However, a significant dielectric relaxation was observed in the air-annealed film, and this is attributed to the formation of nano-crystallites. The relaxation behavior was modeled using the Curie-von Schweidler (CS) and Havriliak-Negami (HN) relationships. The k-value of the as deposited films clearly shows a mixed CS and HN dependence on frequency. The CS dependence vanished after annealing in air, while the HN dependence disappeared after annealing in nitrogen. PMID- 27502671 TI - Nanospiral Formation by Droplet Drying: One Molecule at a Time. AB - We have created nanospirals by self-assembly during droplet evaporation. The nanospirals, 60-70 nm in diameter, formed when solvent mixtures of methanol and m cresol were used. In contrast, spin coating using only methanol as the solvent produced epitaxial films of stripe nanopatterns and using only m-cresol disordered structure. Due to the disparity in vapor pressure between the two solvents, droplets of m-cresol solution remaining on the substrate serve as templates for the self-assembly of carboxylic acid molecules, which in turn allows the visualization of solution droplet evaporation one molecule at a time. PMID- 27502672 TI - Determination of InN/Diamond Heterojunction Band Offset by X-ray Photoelectron Spectroscopy. AB - Diamond is not only a free standing highly transparent window but also a promising carrier confinement layer for InN based devices, yet little is known of the band offsets in InN/diamond system. X-ray photoelectron spectroscopy was used to measure the energy discontinuity in the valence band offset (VBO) of InN/diamond heterostructure. The value of VBO was determined to be 0.39 +/- 0.08 eV and a type-I heterojunction with a conduction band offset (CBO) of 4.42 +/- 0.08 eV was obtained. The accurate determination of VBO and CBO is important for the application of III-N alloys based electronic devices. PMID- 27502673 TI - Enhanced Specificity of Multiplex Polymerase Chain Reaction via CdTe Quantum Dots. AB - Nanoparticles were recently reported to be able to improve both efficiency and specificity in polymerase chain reaction (PCR). Here, CdTe QDs were introduced into multi-PCR systems. It was found that an appropriate concentration of CdTe QDs could enhance the performance of multi-PCR by reducing the formation of nonspecific products in the complex system, but an excessive amount of CdTe QDs could suppress the PCR. The effects of QDs on PCR can be reversed by increasing the polymerase concentration or by adding bovine serum albumin (BSA). The mechanisms underlying these effects were also discussed. The results indicated that CdTe QDs could be used to optimize the amplification products of the PCR, especially in the multi-PCR system with different primers annealing temperatures, which is of great significance for molecular diagnosis. PMID- 27502674 TI - Giant Persistent Photoconductivity of the WO3 Nanowires in Vacuum Condition. AB - A giant persistent photoconductivity (PPC) phenomenon has been observed in vacuum condition based on a single WO3 nanowire and presents some interesting results in the experiments. With the decay time lasting for 1 * 10(4) s, no obvious current change can be found in vacuum, and a decreasing current can be only observed in air condition. When the WO3 nanowires were coated with 200 nm SiO2 layer, the photoresponse almost disappeared. And the high bias and high electric field effect could not reduce the current in vacuum condition. These results show that the photoconductivity of WO3 nanowires is mainly related to the oxygen adsorption and desorption, and the semiconductor photoconductivity properties are very weak. The giant PPC effect in vacuum condition was caused by the absence of oxygen molecular. And the thermal effect combining with oxygen re-adsorption can reduce the intensity of PPC. PMID- 27502675 TI - Radial Corrugations of Multi-Walled Carbon Nanotubes Driven by Inter-Wall Nonbonding Interactions. AB - We perform large-scale quasi-continuum simulations to determine the stable cross sectional configurations of free-standing multi-walled carbon nanotubes (MWCNTs). We show that at an inter-wall spacing larger than the equilibrium distance set by the inter-wall van der Waals (vdW) interactions, the initial circular cross sections of the MWCNTs are transformed into symmetric polygonal shapes or asymmetric water-drop-like shapes. Our simulations also show that removing several innermost walls causes even more drastic cross-sectional polygonization of the MWCNTs. The predicted cross-sectional configurations agree with prior experimental observations. We attribute the radial corrugations to the compressive stresses induced by the excessive inter-wall vdW energy release of the MWCNTs. The stable cross-sectional configurations provide fundamental guidance to the design of single MWCNT-based devices and shed lights on the mechanical control of electrical properties. PMID- 27502676 TI - Atomic Force Microscopy Study of Protein-Protein Interactions in the Cytochrome CYP11A1 (P450scc)-Containing Steroid Hydroxylase System. AB - Atomic force microscopy (AFM) and photon correlation spectroscopy (PCS) were used for monitoring of the procedure for cytochrome CYP11A1 monomerization in solution without phospholipids. It was shown that the incubation of 100 MUM CYP11A1 with 12% Emulgen 913 in 50 mM KP, pH 7.4, for 10 min at T = 22 degrees C leads to dissociation of hemoprotein aggregates to monomers with the monomerization degree of (82 +/- 4)%. Following the monomerization procedure, CYP11A1 remained functionally active. AFM was employed to detect and visualize the isolated proteins as well as complexes formed between the components of the cytochrome CYP11A1-dependent steroid hydroxylase system. Both Ad and AdR were present in solution as monomers. The typical heights of the monomeric AdR, Ad and CYP11A1 images were measured by AFM and were found to correspond to the sizes 1.6 +/- 0.2 nm, 1.0 +/- 0.2 nm and 1.8 +/- 0.2 nm, respectively. The binary Ad/AdR and AdR/CYP11A1mon complexes with the heights 2.2 +/- 0.2 nm and 2.8 +/- 0.2 nm, respectively, were registered by use of AFM. The Ad/CYP11A1mon complex formation reaction was kinetically characterized based on optical biosensor data. In addition, the ternary AdR/Ad/CYP11A1 complexes with a typical height of 4 +/- 1 nm were AFM registered. PMID- 27502677 TI - The Microscopic Origin of Residual Stress for Flat Self-Actuating Piezoelectric Cantilevers. AB - In this study, flat piezoelectric microcantilevers were fabricated under low stress Pb(Zr0.52Ti0.48)O3 (PZT) film conditions. They were analyzed using the Raman spectrum and wafer curvature methods. Based on the residual stress analysis, we found that a thickness of 1 MUm was critical, since stress relaxation starts to occur at greater thicknesses, due to surface roughening. The (111) preferred orientation started to decrease when the film thickness was greater than 1 MUm. The d33 value was closely related to the stress relaxation associated with the preferred orientation changes. We examined the harmonic response at different PZT cantilever lengths and obtained a 9.4-MUm tip displacement at 3 Vp-p at 1 kHz. These analyses can provide a platform for the reliable operation of piezoelectric microdevices, potentially nanodevice when one needs to have simultaneous control of the residual stress and the piezoelectric properties. PMID- 27502679 TI - Synthesis and Thermoelectric Properties of Bi2Se3 Nanostructures. AB - Bismuth selenide (Bi2Se3) nanostructures were synthesized via solvothermal method. The crystallinity of the as-synthesized sample has been analyzed by X-ray diffraction, which shows the formation of rhombohedral Bi2Se3. Electron microscopy examination indicates that the Bi2Se3 nanoparticles have hexagonal flake-like shape. The effect of the synthesis temperature on the morphology of the Bi2Se3 nanostructures has also been investigated. It is found that the particle size increases with the synthesis temperature. Thermoelectric properties of the Bi2Se3 nanostructures were also measured, and the maximum value of dimensionless figure of merit (ZT) of 0.096 was obtained at 523 K. PMID- 27502678 TI - Anisotropic Confinement, Electronic Coupling and Strain Induced Effects Detected by Valence-Band Anisotropy in Self-Assembled Quantum Dots. AB - A method to determine the effects of the geometry and lateral ordering on the electronic properties of an array of one-dimensional self-assembled quantum dots is discussed. A model that takes into account the valence-band anisotropic effective masses and strain effects must be used to describe the behavior of the photoluminescence emission, proposed as a clean tool for the characterization of dot anisotropy and/or inter-dot coupling. Under special growth conditions, such as substrate temperature and Arsenic background, 1D chains of In0.4Ga0.6 As quantum dots were grown by molecular beam epitaxy. Grazing-incidence X-ray diffraction measurements directly evidence the strong strain anisotropy due to the formation of quantum dot chains, probed by polarization-resolved low temperature photoluminescence. The results are in fair good agreement with the proposed model. PMID- 27502680 TI - Template-free Synthesis of One-dimensional Cobalt Nanostructures by Hydrazine Reduction Route. AB - One-dimensional cobalt nanostructures with large aspect ratio up to 450 have been prepared via a template-free hydrazine reduction route under external magnetic field assistance. The morphology and properties of cobalt nanostructures were characterized by scanning electron microscopy, X-ray diffractometer, and vibrating sample magnetometer. The roles of the reaction conditions such as temperature, concentration, and pH value on morphology and magnetic properties of fabricated Co nanostructures were investigated. This work presents a simple, low cost, environment-friendly, and large-scale production approach to fabricate one dimensional magnetic Co materials. The resulting materials may have potential applications in nanodevice, catalytic agent, and magnetic recording. PMID- 27502681 TI - Formation of Nanopits in Si Capping Layers on SiGe Quantum Dots. AB - In-situ annealing at a high temperature of 640 degrees C was performed for a low temperature grown Si capping layer, which was grown at 300 degrees C on SiGe self assembled quantum dots with a thickness of 50 nm. Square nanopits, with a depth of about 8 nm and boundaries along <110>, are formed in the Si capping layer after annealing. Cross-sectional transmission electron microscopy observation shows that each nanopit is located right over one dot with one to one correspondence. The detailed migration of Si atoms for the nanopit formation is revealed by in-situ annealing at a low temperature of 540 degrees C. The final well-defined profiles of the nanopits indicate that both strain energy and surface energy play roles during the nanopit formation, and the nanopits are stable at 640 degrees C. A subsequent growth of Ge on the nanopit-patterned surface results in the formation of SiGe quantum dot molecules around the nanopits. PMID- 27502682 TI - In Situ Synthesis of Reduced Graphene Oxide and Gold Nanocomposites for Nanoelectronics and Biosensing. AB - In this study, an in situ chemical synthesis approach has been developed to prepare graphene-Au nanocomposites from chemically reduced graphene oxide (rGO) in aqueous media. UV-Vis absorption, atomic force microscopy, scanning electron microscopy, transmission electron microscopy, and Raman spectroscopy were used to demonstrate the successful attachment of Au nanoparticles to graphene sheets. Configured as field-effect transistors (FETs), the as-synthesized single-layered rGO-Au nanocomposites exhibit higher hole mobility and conductance when compared to the rGO sheets, promising its applications in nanoelectronics. Furthermore, we demonstrate that the rGO-Au FETs are able to label-freely detect DNA hybridization with high sensitivity, indicating its potentials in nanoelectronic biosensing. PMID- 27502683 TI - Conductance of Graphene Nanoribbon Junctions and the Tight Binding Model. AB - Planar carbon-based electronic devices, including metal/semiconductor junctions, transistors and interconnects, can now be formed from patterned sheets of graphene. Most simulations of charge transport within graphene-based electronic devices assume an energy band structure based on a nearest-neighbour tight binding analysis. In this paper, the energy band structure and conductance of graphene nanoribbons and metal/semiconductor junctions are obtained using a third nearest-neighbour tight binding analysis in conjunction with an efficient nonequilibrium Green's function formalism. We find significant differences in both the energy band structure and conductance obtained with the two approximations. PMID- 27502684 TI - Effect of MWCNTs on Gastric Emptying in Mice. AB - After making model of gastric functional disorder (FD), part of model mice were injected intravenously (i.v.) with oxide multi-walled carbon nanotubes (oMWCNTs) to investigate effect of carbon nanotubes on gastric emptying. The results showed that NO content in stomach, compared with model group, was decreased significantly and close to normal level post-injection with oMWCNTs (500 and 800 MUg/mouse). In contrast to FD or normal groups, the content of acetylcholine (Ach) in stomach was increased obviously in injection group with 500 or 800 MUg/mouse of oMWCNTs. The kinetic curve of emptying was fitted to calculate gastric motility factor k; the results showed that the k of injection group was much higher than FD and normal. In other words, the gastric motility of FD mice was enhanced via injection with oMWCNTs. In certain dosage, oMWCNTs could improve gastric emptying and motility. PMID- 27502685 TI - Morphology and Microstructure of As-Synthesized Anodic TiO2 Nanotube Arrays. AB - The as-grown structure of electrochemically synthesized titania nanotube arrays is investigated by scanning electron microscope (SEM) in combination with transmission electron microscope (TEM) as well as X-ray diffraction (XRD). The analysis reveals a preferred growth direction of the nanotubes relative to the substrate surface and the well control on the nanotube arrays morphology. The crystal structure of the anatase phase is detected and exists in the tube walls without any thermal treatment, which makes it possible to realize the application of as-formed TiO2 nanotubes avoiding the degradation of the nanotube structures when sintering. In addition, a new growth, layered model of the anodic TiO2 nanotubes is presented to obtain further understanding of the growth mechanism. PMID- 27502686 TI - n-Type Doping of Vapor-Liquid-Solid Grown GaAs Nanowires. AB - In this letter, n-type doping of GaAs nanowires grown by metal-organic vapor phase epitaxy in the vapor-liquid-solid growth mode on (111)B GaAs substrates is reported. A low growth temperature of 400 degrees C is adjusted in order to exclude shell growth. The impact of doping precursors on the morphology of GaAs nanowires was investigated. Tetraethyl tin as doping precursor enables heavily n type doped GaAs nanowires in a relatively small process window while no doping effect could be found for ditertiarybutylsilane. Electrical measurements carried out on single nanowires reveal an axially non-uniform doping profile. Within a number of wires from the same run, the donor concentrations ND of GaAs nanowires are found to vary from 7 * 10(17) cm(-3) to 2 * 10(18) cm(-3). The n-type conductivity is proven by the transfer characteristics of fabricated nanowire metal-insulator-semiconductor field-effect transistor devices. PMID- 27502687 TI - Mathematical modelling of the degradation behaviour of biodegradable metals. AB - A mathematical model for the biodegradation of magnesium is developed in this study to inspect the corrosion behaviour of biodegradable implants. The aim of this study was to provide a suitable framework for the assessment of the corrosion rate of magnesium which includes the process of formation/dissolution of the protective film. The model is intended to aid the design of implants with suitable geometries. The level-set method is used to follow the changing geometry of the implants during the corrosion process. A system of partial differential equations is formulated based on the physical and chemical processes that occur at the implant-medium boundary in order to simulate the effect of the formation of a protective film on the degradation rate. The experimental data from the literature on the corrosion of a high-purity magnesium sample immersed in simulated body fluid is used to calibrate the model. The model is then used to predict the degradation behaviour of a porous orthopaedic implant. The model successfully reproduces the precipitation of the corrosion products on the magnesium surface and the effect on the degradation rate. It can be used to simulate the implant degradation and the formation of the corrosion products on the surface of biodegradable magnesium implants with complex geometries. PMID- 27502688 TI - Regulation of autophagy by mitochondrial phospholipids in health and diseases. AB - Autophagy is an evolutionarily conserved mechanism that maintains nutrient homeostasis by degrading protein aggregates and damaged organelles. Autophagy is reduced in aging, which is implicated in the pathogenesis of aging-related diseases, including cancers, obesity, type 2 diabetes, cardiovascular diseases, and neurodegenerative diseases. Mitochondria-derived phospholipids cardiolipin, phosphatidylethanolamine, and phosphatidylglycerol are critical throughout the autophagic process, from initiation and phagophore formation to elongation and fusion with endolysosomal vesicles. Cardiolipin is also required for mitochondrial fusion and fission, an important step in isolating dysfunctional mitochondria for mitophagy. Furthermore, genetic screen in yeast has identified a surprising role for cardiolipin in regulating lysosomal function. Phosphatidylethanolamine plays a pivotal role in supporting the autophagic process, including autophagosome elongation as part of lipidated Atg8/LC3. An emerging role for phosphatidylglycerol in AMPK and mTORC1 signaling as well as mitochondrial fission may provide the first glimpse into the function of phosphatidylglycerol apart from being a precursor for cardiolipin. This review examines the effects of manipulating phospholipids on autophagy and mitophagy in health and diseases, as well as current limitations in the field. This article is part of a Special Issue entitled: Lipids of Mitochondria edited by Guenther Daum. PMID- 27502689 TI - Factors associated with poor adherence to antiviral treatment for hepatitis B. AB - Antiviral therapy for hepatitis B is effective and reduces the risk of progression to cirrhosis and liver cancer but is often required for an indefinite duration. Treatment adherence is important to prevent the development of resistance and optimize outcomes. Pharmacy adherence measures can be used to assess treatment adherence, with the medication possession ratio being less susceptible to bias than physician- or self-reported adherence. The aim of this study was to measure adherence in public hospital outpatients over a 3-year period and to examine factors associated with nonadherence. A retrospective study of pharmacy records of patients dispensed antiviral therapy for hepatitis B from four major hospitals in Melbourne between 2010 and 2013. Hospital record numbers were linked with and de-identified demographic information including age, sex, Indigenous status, country of birth, interpreter requirement, spoken language and postcode of residence. The medication possession ratio was the outcome measure with poor adherence defined <.90. Univariate logistic regression and multivariate logistic regression were performed to examine associations with nonadherence. Records of 1026 patients were included in the analysis. Twenty per cent of all participants met the definition of poor adherence. Significant factors affecting adherence included age <35 years (P=.002), hospital site and treatment by multiple doctors within shorter time periods. This is the largest study examining detailed factors associated with adherence to hepatitis B treatment. Understanding poor adherence in clinical settings, and the factors associated with lower adherence, is important to inform efforts towards promoting treatment adherence for hepatitis B. PMID- 27502690 TI - Promotion of couples' voluntary HIV counseling and testing: a comparison of influence networks in Rwanda and Zambia. AB - BACKGROUND: Many African adults do not know that partners in steady or cohabiting relationships can have different HIV test results. Despite WHO recommendations for couples' voluntary counseling and testing (CVCT), fewer than 10 % of couples have been jointly tested and counseled. We examine the roles and interactions of influential network leaders (INLs) and influential network agents (INAs) in promoting CVCT in Kigali, Rwanda and Lusaka, Zambia. METHODS: INLs were identified in the faith-based, non-governmental, private, and health sectors. Each INL recruited and mentored several INAs who promoted CVCT. INLs and INAs were interviewed about demographic characteristics, promotional efforts, and working relationships. We also surveyed CVCT clients about sources of CVCT information. RESULTS: In Zambia, 53 INAs and 31 INLs were surveyed. In Rwanda, 33 INAs and 27 INLs were surveyed. Most (75 %-90 %) INAs believed that INL support was necessary for their promotional work. Zambian INLs reported being more engaged with their INAs than Rwandan INLs, with 58 % of Zambian INLs reporting that they gave a lot of support to their INAs versus 39 % in Rwanda. INAs in both Rwanda and Zambia reported promoting CVCT via group forums (77 %-97 %) and speaking to a community leader about CVCT (79 %-88 %) in the past month. More Rwandan INAs and INLs reported previous joint or individual HIV testing compared with their Zambian counterparts, of which more than half had not been tested. In Zambia and Rwanda, 1271 and 3895 CVCT clients were surveyed, respectively. Hearing about CVCT from INAs during one-on-one promotions was the most frequent source of information reported by clients in Zambia (71 %). In contrast, Rwandan couples who tested were more likely to have heard about CVCT from a previously tested couple (59 %). CONCLUSIONS: CVCT has long been endorsed for HIV prevention but few couples have been reached. Influential social networks can successfully promote evidence-based HIV prevention in Africa. Support from more senior INLs and group presentations leveraged INAs' one-on-one promotions. The INL/INA model was effective in promoting couples to seek joint HIV testing and counseling and may have broader application to other sub-Saharan African countries to sustainably increase CVCT uptake. PMID- 27502691 TI - Cognitive leisure activities and future risk of cognitive impairment and dementia: systematic review and meta-analysis. AB - BACKGROUND: As life expectancies continue to rise, modifiable lifestyle factors that may prevent cognitive decline and dementia in later life become increasingly important in order to maintain quality of life in old age. METHODS: Five meta analyses were conducted on data from papers identified in a systematic review. Studies were grouped according to outcomes (dementia, cognitive impairment including amnestic Mild Cognitive Impairment (aMCI), Mild Cognitive Impairment (MCI), and cognitive decline) and output (risk (RR), odds (OR), or hazard ratios (HR)). RESULTS: Nineteen studies met our inclusion criteria and quality assessments. Four of five meta-analyses showed significant associations between participation in cognitive leisure activities and reduced risk of cognitive impairment (OR = 0.69, 95% CI: 0.56-0.85) and dementia (HR = 0.58, 95% CI: 0.46 0.74; RR = 0.61, 95% CI: 0.42-0.90; OR = 0.78, 95% CI: 0.67-0.90). However, one pooled analysis of cognitive impairment studies did not reach significance (HR = 0.85, 95% CI: 0.71-1.02). Mentally stimulating leisure activities were significantly associated with later life cognition (beta = 0.11, p = 0.05), better memory (beta = 0.20, 95% CI: 0.11-0.29), speed of processing (beta = 0.37, 95% CI: 0.29-0.45), and executive functioning (beta = 0.23, 95% CI: 0.15-0.29), and less decline in overall cognition (beta = -0.23, p < 0.01), language (beta = 0.11, p < 0.05), and executive functioning (beta = -0.13, p < 0.05). Activities were also shown to reduce rate of cognitive decline (estimate = 0.03, SE = 0.01, p = 0.00). CONCLUSIONS: There is increasing evidence that participation in cognitively stimulating leisure activities may contribute to a reduction of risk of dementia and cognitive impairment in later life. Promoting involvement in such activities across lifespan could be an important focus for primary prevention strategies for governments and health services. PMID- 27502692 TI - Preference in time of insulin injection in type 2 diabetic patients treated with once-daily long-acting insulin analog. PMID- 27502693 TI - Fine mapping and genetic association analysis of Net2, the causative D-genome locus of low temperature-induced hybrid necrosis in interspecific crosses between tetraploid wheat and Aegilops tauschii. AB - Hybrid necrosis has been observed in many interspecific hybrids from crosses between tetraploid wheat and the wheat D-genome donor Aegilops tauschii. Type II necrosis is a kind of hybrid incompatibility that is specifically characterized by low-temperature induction and growth suppression. Two complementary genes, Net1 on the AB genome and Net2 on the D genome, putatively control type II necrosis in ABD triploids and synthetic hexaploid wheat. Toward map-based cloning of Net2, a fine map around the Net2 region on 2DS was constructed in this study. Using the draft genome sequence of Ae. tauschii and the physical map of the barley genome, the Net2 locus was mapped within a 0.6 cM interval between two closely linked markers. Although local chromosomal rearrangements were observed in the Net2-corresponding region between the barley/Brachypodium and Ae. tauschii genomes, the two closely linked markers were significantly associated with type II necrosis in Ae. tauschii. These results suggest that these markers will aid efficient selection of Net2 non-carrier individuals from the Ae. tauschii population and intraspecific progeny, and could help with introgression of agriculturally important genes from Ae. tauschii to common wheat. PMID- 27502694 TI - Mycoplasma genitalium macrolide resistance in Stockholm, Sweden. AB - OBJECTIVES: Mycoplasma genitalium is an important cause of STI in men and women. Worldwide evidence suggests a reduction in efficacy of azithromycin treatment due to the prevalence of macrolide resistant M. genitalium. The aim of this study was to describe the prevalence of macrolide resistance in patients with a positive test for M. genitalium within our setting. METHODS: Two STI clinics in Stockholm offered tests for M. genitalium as part of a routine care pathway. Positive specimens were analysed for macrolide resistance mediating mutations by sequencing. RESULTS: During the study period, 171 (7.5%) of 2276 patients had a positive M. genitalium test; 7% of women and 8% of men. Macrolide resistance was detected in 31 (18%) of the M. genitalium positive; treatment with azithromycin within the previous 6 months was strongly associated with macrolide resistance. CONCLUSIONS: The prevalence of macrolide resistance was lower in Sweden than in other Northern European settings. We hypothesise that this observation may be due to use of doxycycline as primary treatment of Chlamydia trachomatis. The efficacy of empirical treatment is challenged by azithromycin resistant M. genitalium. Clinically available and enhanced diagnostics targeting this pathogen are urgently required. We suggest a test of cure 3-4 weeks after start of azithromycin therapy since macrolide resistance develop during treatment. PMID- 27502695 TI - STAT3-mediated TLR2/4 pathway upregulation in an IFN-gamma-induced Chlamydia trachomatis persistent infection model. AB - Inflammatory pathological injury caused by Chlamydia trachomatis persistent infection could lead to a variety of urogenital tract diseases. By comparing the cytokine production and PRR (pattern recognition receptor) expression between cell models with acute or persistent C. trachomatis infection, our data supported that persistent infection of C. trachomatis led to abnormal activation of toll like receptor (TLR)2/4 signaling pathway and elevated IL-1alpha and IL-6 production, which was mediated by signal transducer and activator of transcription3 (STAT3). Studying the effects of abnormal activation of TLR signaling pathway in the cells with C. trachomatis persistent infection could provide new hints for chronic infection treatment and an important experimental basis for understanding the pathogenesis of C. trachomatis persistent infection. PMID- 27502697 TI - Imaginaries of nuclear energy in the Portuguese parliament: Between promise, risk, and democracy. AB - This article explores the evolution of the nuclear energy debate and its associated controversies in the Portuguese parliament. The analysis focuses on the dictatorial regime of the New State (from the beginning of the nuclear program in 1951 until the 1974 revolution) and on the democratic period (post 1974). Portugal, as an exporting country of uranium minerals, significantly invested in the development of a national capacity in nuclear research, but never developed an endogenous nuclear power infrastructure. Through the analysis of parliamentary debates, this article characterizes the dynamic evolution of the Portuguese sociotechnical imaginary on nuclear energy and technology interlinked with ambivalent representations, including the promise of nuclear energy as key for the constitution of a technological Nation or as prompting new sociotechnical risks. PMID- 27502696 TI - Intravenous adenovirus expressing a multi-specific, single-domain antibody neutralizing TcdA and TcdB protects mice from Clostridium difficile infection. AB - Clostridium difficile infection (CDI) is the most common cause of antibiotic associated diarrhea and colitis in developed countries. The disease is mainly mediated via two major exotoxins TcdA and TcdB secreted by the bacterium. We have previously developed a novel, potently neutralizing, tetravalent and bispecific heavy-chain-only single domain (VHH) antibody to both TcdA and TcdB (designated as ABA) that reverses fulminant CDI in mice. Since ABA has a short serum half life, in this study a replication-deficient recombinant adenovirus expressing ABA was generated and the long-lasting expression of functional ABA was demonstrated in vitro and in vivo Mice transduced with one dose of the adenovirus displayed high levels of serum ABA for more than1 month and were fully protected against systemic toxin challenges. More importantly, the ABA delivered by the adenovirus protected mice from both primary and recurrent CDI. Thus, replication-deficient adenoviral vector may be used to deliver neutralizing antibodies against the toxins in order to prevent CDI and recurrence. PMID- 27502698 TI - Radial simultaneous multi-slice CAIPI for ungated myocardial perfusion. AB - OBJECTIVE: Simultaneous multi-slice (SMS) imaging is a slice acceleration technique that acquires multiple slices in the same time as a single slice. Radial controlled aliasing in parallel imaging results in higher acceleration (radial CAIPIRINHA or CAIPI) is a promising SMS method with less severe slice aliasing artifacts as compared to its Cartesian counterpart. Here we use radial CAIPI with data undersampling and constrained reconstruction to improve the utility of ungated cardiac perfusion acquisitions. We test the proposed framework with a traditional saturation recovery fast low-angle shot (turboFLASH) sequence and also without saturation recovery as a steady-state spoiled gradient echo (SPGR) sequence on animal and human studies. METHODS: Simulations and phantom studies were performed for both the turboFLASH and the SPGR radial CAIPI methods. Ungated undersampled golden ratio radial CAIPI data with saturation recovery were acquired in 8 dogs and 2 human subjects. The CAIPI data without saturation pulses were acquired in 4 human subjects. For both methods, slice acceleration factors of two and three were used. A new spatio-temporal reconstruction using total variation and patch-based low rank constraints was used to jointly reconstruct the multi-slice multi-coil images. RESULTS: Phantom scans and computer simulations showed that ungated SPGR generally provides better contrast to noise ratio (CNR) than the saturation recovery sequence if the saturation recovery time is less than 100ms. Both of the ungated radial CAIPI methods demonstrated promising image quality in terms of preserving dynamics of the contrast agent and maintaining anatomical structures, even with three slices acquired simultaneously. CONCLUSION: Ungated simultaneous multi-slice acquisitions with either a saturation recovery turboFLASH sequence or a steady-state gradient echo SPGR sequence are feasible and provide increased slice coverage without loss of temporal resolution. Compared with a sensitivity encoding (SENSE) SMS reconstruction, the constrained reconstruction method provides better image quality for undersampled radial CAIPI data. PMID- 27502699 TI - Anticompulsive Activity of a New Pyrazolo[C]Pyridine Derivative GIZh-72 under Conditions of Unpredictable Chronic Mild Stress. AB - Anticompulsive activity of a novel compound GIZh-72 (4,6-dimethyl-2-(4 chlorphenyl)-2,3-dihydro-1H-pyrazolo[4,3-C]Pyridine-3-on, chloral hydrate) in a dose of 20 mg/kg (single, subchronic, and chronic administration) in comparison with fluvoxamine (25 mg/kg) was studied in the marble burying test in the model of unpredictable chronic mild stress on BALB/c mice. GIZh-72 produced an anticompulsive effect that increased with increasing treatment duration under stress conditions in contrast to fluvoxamine that induced inversion of this effect after long-term administration. Neuroleptic activity of GIZh-72 in doses of 20 and 40 mg/kg was studied on the model of apomorphine-induced climbing in C57Bl/6 mice. In contrast to haloperidol (0.5 mg/kg), GIZh-72 exhibited no neuroleptic properties. Our results indicate that GIZh-72 holds much promise for pharmacotherapy of obsessive-compulsive disorder. PMID- 27502700 TI - Optimization of Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for Duration of Action, as an Inhaled Therapy for Lung Remodeling in Pulmonary Arterial Hypertension. AB - A series of potent PDGFR inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after i.t. dosing. Compound 25 shows 24 h occupancy of the PDGFR kinase domain, after a single i.t. dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro:in vivo correlations which link duration of action in vivo with low permeability and high basicity and demonstrate that nonspecific binding to lung tissue increases with lipophilicity. PMID- 27502702 TI - Circulating microRNA-1290 as a novel diagnostic and prognostic biomarker in human colorectal cancer. AB - BACKGROUND: Circulating microRNAs (miRNAs) are attracting major interest as potential non-invasive biomarkers for colorectal cancer (CRC). This study aimed to identify a novel serum miRNA biomarker for the early detection and/or evaluating prognosis of CRC patients. PATIENTS AND METHODS: Comprehensive miRNA array analysis was carried out using serum samples from patients with colorectal neoplasia and healthy controls. Next, to verify whether the candidate miRNA possessed a secretory potential, we screened miRNA expression levels in culture medium from 2 CRC cell lines, followed by serum analysis from 12 stage IV CRC, 12 adenoma, and 12 control subjects. Thereafter, we validated expression of candidate miRNAs in 179 primary CRC tissues, as well as serum samples from an independent cohort of 211 CRCs, 56 adenomas, and 57 control subjects. RESULTS: Through microarray analysis, we identified significantly higher levels of miRNA 1290 (miR-1290) in serum from patients with colorectal adenomas and cancers. We verified miR-1290 overexpression in serum of CRC patients in a training cohort. In the validation cohort, serum miR-1290 levels were significantly up-regulated in patients with colorectal adenomas (P < 0.0001) and cancers (P < 0.0001). Serum miR-1290 levels could robustly distinguish adenoma [area under the curve (AUC) = 0.718] and CRC patients (AUC = 0.830) from normal subjects. High miR-1290 expression in serum and tissue was significantly associated with tumor aggressiveness and poor prognosis. Moreover, serum miR-1290 levels were an independent prognostic factor [hazard ratio (HR) = 4.51; 95% confidence interval (CI) = 1.23-23.69; P = 0.0096] and an independent predictor for tumor recurrence (hazard ratio = 3.92; 95% confidence interval = 1.11-25.14; P = 0.032) in CRC. CONCLUSIONS: Serum miR-1290 is a novel biomarker for early detection, recurrence, and prognosis in CRC. PMID- 27502701 TI - Selection of an early biomarker for vascular normalization using dynamic contrast enhanced ultrasonography to predict outcomes of metastatic patients treated with bevacizumab. AB - BACKGROUND: Dynamic contrast-enhanced ultrasonography (DCE-US) has been used for evaluation of tumor response to antiangiogenic treatments. The objective of this study was to assess the link between DCE-US data obtained during the first week of treatment and subsequent tumor progression. PATIENTS AND METHODS: Patients treated with antiangiogenic therapies were included in a multicentric prospective study from 2007 to 2010. DCE-US examinations were available at baseline and at day 7. For each examination, a 3 min perfusion curve was recorded just after injection of a contrast agent. Each perfusion curve was modeled with seven parameters. We analyzed the correlation between criteria measured up to day 7 on freedom from progression (FFP). The impact was assessed globally, according to tumor localization and to type of treatment. RESULTS: The median follow-up was 20 months. The mean transit time (MTT) evaluated at day 7 was the only criterion significantly associated with FFP (P = 0.002). The cut-off point maximizing the difference between FFP curves was 12 s. Patients with at least a 12 s MTT had a better FFP. The results according to tumor type were significantly heterogeneous: the impact of MTT on FFP was more marked for breast cancer (P = 0.004) and for colon cancer (P = 0.025) than for other tumor types. Similarly, the differences in FFP according to MTT at day 7 were marked (P = 0.004) in patients receiving bevacizumab. CONCLUSION: The MTT evaluated with DCE-US at day 7 is significantly correlated to FFP of patients treated with bevacizumab. This criterion might be linked to vascular normalization. AFSSAPS NO: 2007-A00399-44. PMID- 27502703 TI - Improved survival with dose-escalated radiotherapy in stage III non-small-cell lung cancer: analysis of the National Cancer Database. AB - BACKGROUND: Concurrent chemoradiation is the standard of care in non-operable stage III non-small-cell lung cancer (NSCLC). Data have suggested a benefit of dose escalation; however, results from the randomized dose-escalation trial RTOG 0617 revealed a lower survival rate with high-dose radiation. To evaluate the impact of dose escalation on overall survival (OS) in stage III NSCLC treated with chemoradiotherapy outside the controlled setting of a randomized trial, we carried out an observational, population-based investigation of the National Cancer Database (NCDB). PATIENTS AND METHODS: A total of 33 566 patients with stage III NSCLC treated with chemoradiation from 2004 to 2012 and radiation doses between 59.4 and 85 Gy were included. The primary end point was OS, with median survival calculated via Kaplan-Meier. Univariate, multivariable and propensity score matching analyses were carried out. RESULTS: Patients were stratified by dose with median OS of: 18.8, 19.8 and 21.6 months for cohorts receiving 59.4-60, 61-69 and >=70 Gy, respectively (P < 0.001). Granular dose analyses were carried out demonstrating increased OS with increasing radiation dose: median survival of 18.8, 21.1, 22.0 and 21.0 months for 59.4-60, 66, 70 and >=71 Gy, respectively. While 66, 70 and >=71 Gy resulted in increased OS in comparison with 59.4-60 Gy, no significant difference in OS was observed when comparing 66 with >=71 Gy (P = 0.38). CONCLUSIONS: Dose escalation above 60 Gy was associated with improved OS in this cohort of stage III NSCLC patients treated with chemoradiotherapy. A plateau of benefit was observed, with no additional improvement in OS with increased dose (>=71 Gy) compared with 66-70 Gy. With evidence suggesting worse OS and quality of life with increased dose, these data support investigation of the role of intermediate-dose radiation, and in the absence of randomized evidence, may be leveraged to justify utilization of intermediate-dose radiation. PMID- 27502704 TI - Distinct subclonal tumour responses to therapy revealed by circulating cell-free DNA. AB - BACKGROUND: The application of precision medicine in oncology requires in-depth characterisation of a patient's tumours and the dynamics of their responses to treatment. PATIENTS AND METHODS: We used next-generation sequencing of circulating cell-free DNA (cfDNA) to monitor the response of a KIT p.L576P-mutant metastatic vaginal mucosal melanoma to sequential targeted, immuno- and chemotherapy. RESULTS: Despite a KIT mutation, the response to imatinib was mixed. Unfortunately, tumours were not accessible for molecular analysis. To study the mechanism underlying the mixed clinical response, we carried out whole exome sequencing and targeted longitudinal analysis of cfDNA. This revealed two tumour subclones; one with a KIT mutation that responded to imatinib and a second KIT-wild-type subclone that did not respond to imatinib. Notably, the subclones also responded differently to immunotherapy. However, both subclones responded to carboplatin/paclitaxel, and although the KIT-wild-type subclone progressed after chemotherapy, it responded to subsequent re-administration of paclitaxel. CONCLUSION: We show that cfDNA can reveal tumour evolution and subclonal responses to therapy even when biopsies are not available. PMID- 27502705 TI - Establishing a complementary diagnostic for anti-PD-1 immune checkpoint inhibitor therapy. PMID- 27502706 TI - The clinical dilemma of grade 3 follicular lymphoma. PMID- 27502707 TI - Is the Gleason score the driver for the treatment decision-making of patients with castration-resistant prostate cancer in the new era of the anti-androgenic therapies? PMID- 27502708 TI - Phase II study of MLN8237 (Alisertib) in advanced/metastatic sarcoma. AB - BACKGROUND: Aurora kinase A (AURKA) is commonly overexpressed in sarcoma. The inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel oral adenosine triphosphate-competitive AURKA inhibitor. PATIENTS AND METHODS: This Cancer Therapy Evaluation Program-sponsored phase II study of alisertib was conducted through the Alliance for Clinical Trials in Oncology (A091102). Patients were enrolled into histology-defined cohorts: (i) liposarcoma, (ii) leiomyosarcoma, (iii) undifferentiated sarcoma, (iv) malignant peripheral nerve sheath tumor, or (v) other. Treatment was alisertib 50 mg PO b.i.d. d1-d7 every 21 days. The primary end point was response rate; progression-free survival (PFS) was secondary. One response in the first 9 patients expanded enrollment in a cohort to 24 using a Simon two-stage design. RESULTS: Seventy-two patients were enrolled at 24 sites [12 LPS, 10 LMS, 11 US, 10 malignant peripheral nerve sheath tumor (MPNST), 29 Other]. The median age was 55 years; 54% were male; 58%/38%/4% were ECOG PS 0/1/2. One PR expanded enrollment to the second stage in the other sarcoma cohort. The histology-specific cohorts ceased at the first stage. There were two confirmed PRs in the other cohort (both angiosarcoma) and one unconfirmed PR in dedifferentiated chondrosarcoma. Twelve-week PFS was 73% (LPS), 44% (LMS), 36% (US), 60% (MPNST), and 38% (Other). Grade 3-4 adverse events: oral mucositis (12%), anemia (14%), platelet count decreased (14%), leukopenia (22%), and neutropenia (42%). CONCLUSIONS: Alisertib was well tolerated. Occasional responses, yet prolonged stable disease, were observed. Although failing to meet the primary RR end point, PFS was promising. TRIAL REGISTRATION ID: NCT01653028. PMID- 27502709 TI - Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. AB - BACKGROUND: The dynamics of PD-L1 expression may limit its use as a tissue-based predictive biomarker. We sought to expand our understanding of the dynamics of PD L1 expression and tumor-infiltrating lymphocytes (TILs) in patients with lung cancer-related brain metastases. EXPERIMENTAL DESIGN: Paired primary lung cancers and brain metastases were identified and assessed for PD-L1 and CD3 expression by immunohistochemistry. Lesions with 5% or greater PD-L1 expression were considered positive. Agreement statistics and the chi(2) or Fisher's exact test were used for analysis. RESULTS: We analyzed 146 paired lesions from 73 cases. There was disagreement of tumor cell PD-L1 expression in 10 cases (14%, kappa = 0.71), and disagreement of TIL PD-L1 expression in 19 cases (26%, kappa = 0.38). Most paired lesions with discordant tumor cell expression of PD-L1 were obtained 6 or more months apart. When specimens were categorized using a proposed tumor microenvironment categorization scheme based on PD-L1 expression and TILs, there were significant changes in the classifications because many of the brain metastases lacked either PD-L1 expression, tumor lymphocyte infiltration or both even when they were present in the primary lung cancer specimens (P = 0.009). CONCLUSIONS: We identified that there are significant differences between the tumor microenvironment of paired primary lung cancers and brain metastases. When physicians decide to treat patients with lung cancer with a PD-1 or PD-L1 inhibitor, they must do so in the context of the spatial and temporal heterogeneity of the tumor microenvironment. PMID- 27502710 TI - Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). AB - BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 uM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade >=2 (38% versus 23%, P < 0.001) and grade >=3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767). PMID- 27502711 TI - Statistical controversies in clinical research: should schedules of tumor size assessments be changed? AB - BACKGROUND: Time to progression (TTP) is often used as a primary end point in phase II clinical trials. Since the actual date of nadir and progression is never known, most calculated TTP are overestimated. This study evaluates the imprecision on the estimate of TTP under two hypothetical tumor kinetic settings and various assessment schedules. DESIGN: A two-component tumor growth model was used to account for treatment effect assuming exponential decay for tumor shrinkage and linear growth for progression. Evolution of tumor burden (TB) was modelized according to two scenarios using either a cytotoxic or a cytostatic agent and several assessment schedules. TB, nadir, progression and TTP were simulated for each visit schedule. RESULTS: For cytotoxic agents, our model predicted response at 1.5 weeks, a TB at nadir of 40.2 mm (starting from 100 mm) occurring at 6.7 weeks and true progression at 11.2 weeks with a TB of 48.2 mm. For cytostatic agents, our model predicted no response, a TB at nadir of 77 mm occurring at 9.2 weeks and true progression at 19.4 weeks with a TB of 92 mm. Depending on the assessment schedule, estimated TTP was increased from 0.8 to 36.8 weeks and from 0.6 to 28.6 weeks when compared with the true TTP and varied from 5.2% to 298% and from 1.66 to 109.58% when compared with the true TB at progression for cytotoxic and cytostatic agents, respectively. Our model further shows that for cytotoxic agents, evaluation of TB every 6 weeks is optimal to capture the true nadir, the time to nadir, the true progression and the true TTP, whereas for cytostatic agents, this evaluation is optimal every 10 weeks. CONCLUSIONS: Our results emphasize the importance to estimate the effects of tested drugs on tumor shrinkage before design any phase II clinical trials to choose optimal TB evaluation's timing. PMID- 27502713 TI - Reply to the letter to the editor 'Epstein-Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin, histone deacetylase (HDAC) inhibitors when combined with a proteasome inhibitor are safe and effective in patients with extranodal natural killer/T-cell lymphoma' by Tan et al. PMID- 27502712 TI - Prospective assessment of a gene signature potentially predictive of clinical benefit in metastatic melanoma patients following MAGE-A3 immunotherapeutic (PREDICT). AB - BACKGROUND: Genomic profiling of tumor tissue may aid in identifying predictive or prognostic gene signatures (GS) in some cancers. Retrospective gene expression profiling of melanoma and non-small-cell lung cancer led to the characterization of a GS associated with clinical benefit, including improved overall survival (OS), following immunization with the MAGE-A3 immunotherapeutic. The goal of the present study was to prospectively evaluate the predictive value of the previously characterized GS. PATIENTS AND METHODS: An open-label prospective phase II trial ('PREDICT') in patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma. RESULTS: Of 123 subjects who received the MAGE-A3 immunotherapeutic, 71 (58.7%) displayed the predictive GS (GS+). The 1-year OS rate was 83.1%/83.3% in the GS+/GS- populations. The rate of progression-free survival at 12 months was 5.8%/4.1% in GS+/GS- patients. The median time-to treatment failure was 2.7/2.4 months (GS+/GS-). There was one complete response (GS-) and two partial responses (GS+). The MAGE-A3 immunotherapeutic was similarly immunogenic in both populations and had a clinically acceptable safety profile. CONCLUSION: Treatment of patients with MAGE-A3-positive unresectable stage IIIB-C/IV-M1a melanoma with the MAGE-A3 immunotherapeutic demonstrated an overall 1-year OS rate of 83.5%. GS- and GS+ patients had similar 1-year OS rates, indicating that in this study, GS was not predictive of outcome. Unexpectedly, the objective response rate was lower in this study than in other studies carried out in the same setting with the MAGE-A3 immunotherapeutic. Investigation of a GS to predict clinical benefit to adjuvant MAGE-A3 immunotherapeutic treatment is ongoing in another melanoma study.This study is registered at www.clinicatrials.gov NCT00942162. PMID- 27502714 TI - Tolerability of immune checkpoint inhibition cancer therapy in a cardiac transplant patient. PMID- 27502715 TI - Sustained response to salvage therapy for dabrafenib-resistant metastatic Langerhans cell sarcoma. PMID- 27502716 TI - The obese endometrial cancer patient: how do we effectively improve morbidity and mortality in this patient population? AB - The relationship between obesity, metabolic syndrome, and endometrial cancer has been established and accepted for decades. However, despite this understanding, endometrial cancer patients continue to die of their obesity-related comorbidities such as cardiovascular disease and diabetes. Furthermore, studies show that gynecologic oncologists, general obstetrician/gynecologists, and bariatric specialists do not appropriately address obesity as a risk factor for cancer and also do not provide appropriate counseling on weight loss and lifestyle modification during screening, diagnosis, and follow-up for endometrial cancer. Given the increasing numbers of obese women both in the United States as well as globally, it is imperative that this risk be addressed and mitigated during patient interactions. Therefore, this article reviews the literature on obesity, metabolic syndrome, and endometrial cancer, as well as the literature on causes of death in endometrial cancer patients. Given the increased cardiovascular and all-cause mortality, we provide a number of methods to address obesity as a risk factor for cancer during patient visits. These methods include self-directed diet and exercise, supervised diet and exercise programs, medical management with insulin-sensitizing agents and statins, as well as bariatric surgery in extreme cases. Furthermore, we also encourage collaboration between general obstetrician/gynecologists, gynecologic oncologists, and bariatric specialists in the care of obese endometrial cancer patients to ensure that they not only survive their diagnosis, but also go on to live long, healthy lives. PMID- 27502717 TI - Tumor-related leukocytosis is associated with poor radiation response and clinical outcome in uterine cervical cancer patients. AB - BACKGROUND: To evaluate response to radiation and clinical outcome of uterine cervical cancer patients with tumor-related leukocytosis (TRL) at initial diagnosis and during definitive radiotherapy. PATIENTS AND METHODS: We retrospectively analyzed 2456 patients with stage IA-IVA uterine cervical cancer who received definitive radiotherapy with (37.4%) or without (62.6%) platinum based chemotherapy between 1986 and 2012. TRL was defined as two or more occurrences of leukocytosis over 9000/MUl at the time of diagnosis and during the course of treatment. Locoregional failure-free survival (LFFS) and overall survival (OS) were compared between patients with or without TRL. RESULTS: The median age of all patients was 55 years, and the median follow-up time was 65.1 months. TRL was observed in 398 patients (16%) at initial diagnosis; TRL (+) patients were younger and had larger tumors, advanced stage, and more frequent lymph node metastases (all P < 0.05). TRL (+) patients showed a significantly lower rate of complete remission than TRL (-) patients (89.9% versus 96.3%, respectively, P = 0.042). Ten-year LFFS and OS for all patients were 84% and 78%, respectively. LFFS and OS were significantly lower in TRL (+) patients than TRL ( ) patients (10-year LFFS: 69% versus 87% respectively, P < 0.001; 10-year OS: 63% versus 81% respectively P < 0.001). After propensity score matching, LFFS and OS rates in TRL (+) patients remained significantly lower than for TRL (-) patients; this significant difference was also observed on multivariate analysis. Twenty six percent of patients with locoregional failure (n = 345) were TRL (+) and had significantly poorer median OS (6 versus 12 months, P = 0.001). CONCLUSION: This study reveals the aggressive nature of cervical cancer with TRL and its poor response to radiation therapy. Given the unfavorable prognosis and higher probability of treatment failure, optimal diagnostic and therapeutic approaches and careful monitoring for early detection of recurrence should be considered for these patients. PMID- 27502718 TI - Utilisation of the ESMO-MCBS in practice of HTA. PMID- 27502719 TI - Possible determinants of VSL#3 probiotic failure in preventing gastrointestinal adverse events associated with dacomitinib in patients with advanced non-small cell lung cancer enrolled in ARCHER-1042 trial. PMID- 27502720 TI - Reply to the letter to the editor 'the clinical dilemma of grade 3 follicular lymphoma' by Sorigue et al. PMID- 27502721 TI - Higher rate of severe toxicities in obese patients receiving dose-dense (dd) chemotherapy according to unadjusted body surface area: results of the prospectively randomized GAIN study. AB - BACKGROUND: In routine clinical practice, chemotherapy doses are frequently capped at a body surface area (BSA) of 2.0 m2 or adjusted to an ideal weight for obese patients due to safety reasons. MATERIALS AND METHODS: Between August 2004 and July 2008, a total of 3023 patients were enrolled in the GAIN study, a randomized phase III adjuvant trial, comparing two types of dose-dense (dd) regimen [epirubicin, docetaxel and cyclophosphamide (iddETC) versus epirubicin and cyclophosphamide (EC) followed by docetaxel (T) plus capecitabine (X)]. We retrospectively evaluated a total of 555 patients with a BMI of >=30 for safety and outcome. RESULTS: Eighteen percent of all patients were obese: 31% of those received chemotherapy according to an unadjusted BSA. For the remaining patients, BSA was adjusted to ideal weight or was capped at 2.0 m2. A total of 15% of obese patients receiving full (unadjusted) dose of chemotherapy versus 6% of obese patients with an adjusted BSA experienced febrile neutropenia (P = 0.003) and 9% versus 3% high-grade thrombopenia (P = 0.002). Overall, 17% versus 10% had a thromboembolic event (P = 0.017), which was high grade in 13% versus 6%, respectively (P = 0.019), and 3% versus 0.3% high-grade hot flushes (P = 0.013). Dizziness (5% versus 11%; P = 0.016), diarrhea (19% versus 27%; P = 0.033) and an increase in serum creatinine (7% versus 14%; P = 0.019) were higher in the adjusted group. However, no differences in disease-free survival (DFS) and overall survival (OS) were observed between non-obese patients, obese patients receiving full-dose chemotherapy or according to an adjusted BSA [5-year DFS 81% (confidence interval 79% to 83%) versus 82% (75% to 87%) versus 81% (76% to 84%); P = 0.761; 5-year OS 90% (88% to 91%) versus 86% (80% to 91%) versus 88% (84% to 91%); P = 0.143]. CONCLUSION: Obese patients receiving dd chemotherapy according to their real BSA have a higher risk of developing severe toxicities without influencing survival. Therefore, a dose adjustment of intense dd chemotherapy should be carried out to avoid life-threatening complications. PMID- 27502722 TI - Toward the molecular dissection of peritoneal pseudomyxoma. AB - BACKGROUND: Outcome of pseudomyxoma peritonei (PMP) after cytoreductive surgery (CRS) and hypertermic intraperitoneal chemotherapy (HIPEC) is heterogeneous even after adjusting for clinico-pathological prognostic variables. The identification of additional prognostic or even predictive biomarkers is an unmet clinical need. PATIENTS AND METHODS: Forty patients with mucinous appendiceal tumors and PMP were clinically eligible and had evaluable tumor samples obtained after CRS and HIPEC. We carried out next-generations sequencing (NGS) of 50 gene's hotspot regions contained in the Hotspot Cancer Panel v2 using the Ion Torrent Personal Genome Machine platform (Life Technologies). RESULTS: KRAS and GNAS mutations were found in 72% and 52%, and their allelic frequency was below 10% in 55% and 43% of samples, respectively. KRAS and GNAS mutations were associated with worse progression-free survival (PFS) at univariate analysis (P = 0.006 and 0.011, respectively). At multivariate analysis, only KRAS mutations were independently associated with PFS (P = 0.012); GNAS mutations were not-being significantly associated with other poor prognostic features such as incomplete cytoreduction or KRAS mutations. Validation of results was carried out in an independent bi institutional cohort of 25 patients and the prognostic effect of KRAS mutations was again confirmed in the multivariate model (P = 0.029). NGS approach allowed the discovery of other potentially druggable mutations such as those in PI3K, AKT, LKB1, FGFR3 and PDGFRA. CONCLUSIONS: Given the homogeneity of this series and the sensitivity of NGS in this low-cellularity tumor, we demonstrated for the first time a poor prognostic role of KRAS mutations. PMID- 27502723 TI - Fertility-sparing surgery in epithelial ovarian cancer: a systematic review of oncological issues. AB - Since the last two decades, the feasibility of fertility-sparing surgery (FSS) in early-stage epithelial ovarian cancer (EOC) has been explored by several teams and is reconsidered in this systematic review undertaken using the PRISMA guidelines. Borderline ovarian tumours and non-EOCs were excluded. This review comprises 1150 patients and 139 relapsing patients reported by 21 teams. This conservative treatment can be safely carried out for stage IA and IC grade 1 and 2 disease and stage IC1 according to the new FIGO staging system. Nevertheless, the number of patients reported with grade 2 disease is too small to definitively confirm whether FSS is safe in this subgroup. For patients with 'less favourable' prognostic factors (grade 3 or stage IC3 disease), the safety of FSS could not be confirmed, but patients should be informed that radical treatment probably may not necessarily improve their oncological outcome, because the poorest survival observed could be related to the natural history of the disease itself and not specifically to the use of conservative therapy. FSS could probably be considered in stage I clear-cell tumours but should remain contraindicated for stage II/III disease (whatever the histologic subtype). As the disease stage and the histologic data (tumour type and grade) are crucial to patient selection for this treatment, this implies careful and mandatory complete surgical staging surgery in this context and a pathological analysis (or review) of the tumour by an expert pathologist. PMID- 27502724 TI - Long-term outcomes of accelerated BEP (bleomycin, etoposide, cisplatin) for advanced germ cell tumours: updated analysis of an Australian multicentre phase II trial by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). PMID- 27502726 TI - Predictors of chemotherapy efficacy in non-small-cell lung cancer: a challenging landscape. AB - BACKGROUND: Conventional cytotoxic chemotherapy (CCC) is the backbone of non small-cell lung cancer (NSCLC) treatment since decades and still represents a key element of the therapeutic armamentarium. Contrary to molecularly targeted therapies and immune therapies, for which predictive biomarkers of activity have been actively looked for and developed in parallel to the drug development process ('companion biomarkers'), no patient selection biomarker is currently available for CCC, precluding customizing treatment. MATERIALS AND METHODS: We reviewed preclinical and clinical studies that assessed potential predictive biomarkers of CCC used in NSCLC (platinum, antimetabolites, topoisomerase inhibitors, and spindle poisons). Biomarker evaluation method, analytical validity, and robustness are described and challenged for each biomarker. RESULTS: The best-validated predictive biomarkers for efficacy are currently ERCC1, RRM1, and TS for platinum agents, gemcitabine and pemetrexed, respectively. Other potential biomarkers include hENT1 for gemcitabine, class III beta-tubulin for spindle poisons, TOP2A expression and CEP17 duplication (mostly studied for predicting anthracyclines efficacy) whose applicability concerning etoposide would deserve further evaluation. However, none of these biomarkers has till now been validated prospectively in an appropriately designed and powered randomised trial, and none of them is currently ready for implementation in routine clinical practice. CONCLUSION: The search for predictive biomarkers to CCC has been proven challenging. If a plethora of biomarkers have been evaluated either in the preclinical or in the clinical setting, none of them is ready for clinical implementation yet. Considering that most mechanisms of resistance or sensitivity to CCC are multifactorial, a combinatorial approach might be relevant and further efforts are required. PMID- 27502725 TI - Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. AB - BACKGROUND: The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61-0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients with HER2 negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety. RESULTS: Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68-1.05) or OS (HR = 0.96, 95% CI 0.76 1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected. CONCLUSIONS: In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life. CLINICALTRIALSGOV: NCT01250379. PMID- 27502727 TI - Searching for aurora in the night of sarcoma phase II trials: isn't it time to move to second gear? PMID- 27502728 TI - Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer. AB - BACKGROUND: T-cell infiltration in tumors has been used as a prognostic tool in non-small-cell lung cancer (NSCLC). However, the influence of smoking habit and histological type on tumor-infiltrating lymphocytes (TILs) in NSCLC remains unclear. PATIENTS AND METHODS: We evaluated the prognostic significance of TILs (CD4+, CD8+, CD20+, and FOXP3+) according to histological type and smoking habit using automatic immunohistochemical staining and cell counting in 218 patients with NSCLC. RESULTS: In multivariate survival analyses of clinical, pathological, and immunological factors, a high ratio of FOXP3+ to CD4+ T cells (FOXP3/CD4) [hazard ratio (HR): 4.46, P < 0.01 for overall survival (OS); HR: 1.96, P < 0.05 for recurrence-free survival (RFS)] and a low accumulation of CD20+ B cells (HR: 2.45, P = 0.09 for OS; HR: 2.86, P < 0.01 for RFS) were identified as worse prognostic factors in patients with adenocarcinoma (AD). In non-AD, a low number of CD8+ T cells were correlated with an unfavorable outcome (HR: 7.69, P < 0.01 for OS; HR: 3.57, P < 0.02 for RFS). Regarding smoking habit in AD, a high FOXP3/CD4 ratio was poorly prognostic with a smoking history (HR: 5.21, P < 0.01 for OS; HR: 2.38, P < 0.03 for RFS), whereas a low accumulation of CD20+ B cells (HR: 4.54, P = 0.03 for OS; HR: 2.94, P < 0.01 for RFS) was confirmed as an unfavorable factor in non-smokers with AD. CONCLUSIONS: A low number of CD8+ T cells in non-AD, a high FOXP3/CD4 ratio in smokers with AD, and a low number of CD20+ B cells in non-smokers with AD were identified as independent unfavorable prognostic factors in resected NSCLC. Evaluating the influence of histological type and smoking habit on the immunological environment may lead to the establishment of immunological diagnosis and appropriate individualized immunotherapy for NSCLC. PMID- 27502729 TI - Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). AB - BACKGROUND: Sequential administration of anthracycline and taxane is the current standard of care adjuvant regimen for node-positive early breast cancer. Due to long-term toxicity concerns, anthracycline-free regimens have been developed. We compared a sequential dose-dense anthracycline and taxane regimen with the anthracycline-free regimen of docetaxel and cyclophosphamide. PATIENTS AND METHODS: In this randomized, non-inferiority, phase III trial, women with HER2 negative invasive breast cancer and at least one positive axillary lymph node were randomized to receive either epirubicin (75 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and cyclophosphamide (500 mg/m(2)) every 2 weeks for four cycles, followed by four cycles of docetaxel (75 mg/m(2)) every 2 weeks with prophylactic G-CSF support (FEC -> D) or docetaxel (75 mg/m(2)) and cyclophosphamide (600 mg/m(2)) every 21 days for six cycles (TC). The primary end point of the study was the 3-year disease-free survival (DFS) rate. RESULTS: Six hundred and fifty women were randomized to either FEC -> D (n = 326) or TC (n = 324). After a median follow-up of 46 and 47 months, the 3-year DFS rate was 89.5% and 91.1% for the FEC -> D and TC arm, respectively (hazard ratio = 1.147, 95% confidence interval 0.716-1.839, P = 0.568). Grade 3-4 neutropenia was higher in the TC arm (32.4% versus 10.5%, P = 0.0001). The incidence of neutropenic fever was low (<1%). Nausea, vomiting, hand-foot syndrome and fatigue (grade 3-4) were more common with FEC -> D. Acute cardiotoxicity was rare (1 event in each group). There were no toxic deaths. CONCLUSIONS: This trial did not clearly demonstrate that TC is non-inferior to dose-dense FEC -> D. However, 3-year DFS rates were excellent in both arms for women with node-positive, HER2-negative early breast cancer. CLINICALTRIALSGOV: NCT01985724. PMID- 27502730 TI - High power laser-driven ceramic phosphor plate for outstanding efficient white light conversion in application of automotive lighting. AB - We report on Y3Al5O12: Ce(3+) ceramic phosphor plate (CPP) using nano phosphor for high power laser diode (LD) application for white light in automotive lighting. The prepared CPP shows improved luminous properties as a function of Ce(3+) concentration. The luminous properties of the Y3Al5O12: Ce(3+) CPP nano phosphor are improved when compared to the Y3Al5O12: Ce(3+) CPP with bulk phosphor, and hence, the luminous emittance, luminous flux, and conversion efficiency are improved. The Y3Al5O12: Ce(3+) CPP with an optimal Ce(3+) content of 0.5 mol % shows 2733 lm/mm(2) value under high power blue radiant flux density of 19.1 W/mm(2). The results indicate that Y3Al5O12: Ce(3+) CPP using nano phosphor can serve as a potential material for solid-state laser lighting in automotive applications. PMID- 27502731 TI - Water vapor delta(2) H, delta(18) O and delta(17) O measurements using an off axis integrated cavity output spectrometer - sensitivity to water vapor concentration, delta value and averaging-time. AB - RATIONALE: High-precision analysis of atmospheric water vapor isotope compositions, especially delta(17) O values, can be used to improve our understanding of multiple hydrological and meteorological processes (e.g., differentiate equilibrium or kinetic fractionation). This study focused on assessing, for the first time, how the accuracy and precision of vapor delta(17) O laser spectroscopy measurements depend on vapor concentration, delta range, and averaging-time. METHODS: A Triple Water Vapor Isotope Analyzer (T-WVIA) was used to evaluate the accuracy and precision of delta(2) H, delta(18) O and delta(17) O measurements. The sensitivity of accuracy and precision to water vapor concentration was evaluated using two international standards (GISP and SLAP2). The sensitivity of precision to delta value was evaluated using four working standards spanning a large delta range. The sensitivity of precision to averaging time was assessed by measuring one standard continuously for 24 hours. RESULTS: Overall, the accuracy and precision of the delta(2) H, delta(18) O and delta(17) O measurements were high. Across all vapor concentrations, the accuracy of delta(2) H, delta(18) O and delta(17) O observations ranged from 0.100/00 to 1.840/00, 0.080/00 to 0.860/00 and 0.060/00 to 0.620/00, respectively, and the precision ranged from 0.0990/00 to 0.4300/00, 0.0090/00 to 0.0800/00 and 0.0220/00 to 0.0540/00, respectively. The accuracy and precision of all isotope measurements were sensitive to concentration, with the higher accuracy and precision generally observed under moderate vapor concentrations (i.e., 10000 15000 ppm) for all isotopes. The precision was also sensitive to the range of delta values, although the effect was not as large compared with the sensitivity to concentration. The precision was much less sensitive to averaging-time than the concentration and delta range effects. CONCLUSIONS: The accuracy and precision performance of the T-WVIA depend on concentration but depend less on the delta value and averaging-time. The instrument can simultaneously and continuously measure delta(2) H, delta(18) O and delta(17) O values in water vapor, opening a new window to better understand ecological, hydrological and meteorological processes. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27502732 TI - Novel Poly(3-hydroxybutyrate-g-vinyl alcohol) Polyurethane Scaffold for Tissue Engineering. AB - The design of new synthetic grafted poly(3-hydroxybutyrate) as composite 3D scaffolds is a convenient alternative for tissue engineering applications. The chemically modified poly(3-hydroxybutyrate) is receiving increasing attention for use as biomimetic copolymers for cell growth. As of yet, these copolymers cannot be used efficiently because of the lack of good mechanical properties. Here, we address this challenge, preparing a composite-scaffold of grafted poly(3 hydroxybutyrate) polyurethane for the first time. However, it is unclear if the composite structure and morphology can also offer a biological application. We obtained the polyurethane by mixing a polyester hydroxylated resin with polyisocyanate and the modified polyhydroxyalkanoates. The results show that the poly(3-hydroxybutyrate) grafted with poly(vinyl alcohol) can be successfully used as a chain extender to form a chemically-crosslinked thermosetting polymer. Furthermore, we show a proposal for the mechanism of the polyurethane synthesis, the analysis of its morphology and the ability of the scaffolds for growing mammalian cells. We demonstrated that astrocytes isolated from mouse cerebellum, and HEK293 can be cultured in the prepared material, and express efficiently fluorescent proteins by adenoviral transduction. We also tested the metabolism of Ca(2+) to obtain evidence of the biological activity. PMID- 27502733 TI - Intestinal infection at onset of mycophenolic acid-associated chronic diarrhea in kidney transplant recipients. AB - BACKGROUND: Chronic diarrhea after kidney transplantation is often attributed to mycophenolic acid (MPA) toxicity. We hypothesize that intestinal infections contribute to the pathogenesis of chronic MPA-associated diarrhea. METHODS: In this retrospective study, all patients (n = 726) receiving a kidney transplant between 2000 and 2010 at the University Hospital Zurich were followed until July 2014 for occurrence of chronic diarrhea (>=4 weeks). Infectious triggers at diarrhea onset were assessed by reviewing medical history, stool microbiology, and histology of colon biopsies. RESULTS: In 46 patients (6.3% of the cohort), a total of 51 episodes of chronic diarrhea during MPA treatment were documented. The diarrhea episodes were often severe, as confirmed by significant weight loss. The cumulative incidence of chronic diarrhea was uniformly distributed throughout the post-transplant period, with 2.0%, 5.1%, and 9.6% at 1, 5, and 10 years, respectively. Evidence was found for intestinal infection at diarrhea onset in 38 episodes (74.5%). Occurrence of diarrhea onset showed a seasonal distribution with peaks in April and October/November. Specific antimicrobial treatment alone was associated with a 19% resolution rate only, whereas combination with dose reduction of MPA or switch from mycophenolate mofetil to enteric-coated mycophenolate sodium resulted in a 22.7% and 76.5% resolution rate, respectively. Change to an MPA-free regimen was associated with a 100% resolution rate. CONCLUSION: These results provide first evidence for a contribution of intestinal infections in chronic post-transplant diarrhea associated with MPA treatment. PMID- 27502735 TI - Pd Nanoparticles Decorated N-Doped Graphene Quantum Dots@N-Doped Carbon Hollow Nanospheres with High Electrochemical Sensing Performance in Cancer Detection. AB - The development of carbon based hollow-structured nanospheres (HNSs) materials has stimulated growing interest due to their controllable structure, high specific surface area, large void space, enhanced mass transport, and good biocompatibility. The incorporation of functional nanomaterials into their core and/or shell opens new horizons in designing functionalized HNSs for a wider spectrum of promising applications. In this work, we report a new type of functionalized HNSs based on Pd nanoparticles (NPs) decorated double shell structured N-doped graphene quantum dots (NGQDs)@N-doped carbon (NC) HNSs, with ultrafine Pd NPs and "nanozyme" NGQDs as dual signal-amplifying nanoprobes, and explore their promising application as a highly efficient electrocatalyst in electrochemical sensing of a newly emerging biomarker, i.e., hydrogen peroxide (H2O2), for cancer detection. Due to the synergistic effect of the robust and conductive HNS supports and catalytically active Pd NPs and NGQD in facilitating electron transfer, the NGQD@NC@Pd HNS hybrid material exhibits high electrocatalytic activity toward the direct reduction of H2O2 and can promote the electrochemical reduction reaction of H2O2 at a favorable potential of 0 V, which effectively restrains the redox of most electroactive species in physiological samples and eliminates interference signals. The resultant electrochemical H2O2 biosensor based hybrid HNSs materials demonstrates attractive performance, including low detection limit down to nanomole level, short response time within 2 s, as well as high sensitivity, reproducibility, selectivity, and stability, and have been used in real-time tracking of trace amounts of H2O2 secreted from different living cancer cells in a normal state and treated with chemotherapy and radiotherapy. PMID- 27502736 TI - Identification of IL6 as a susceptibility gene for major depressive disorder. AB - Our previous work implied that interleukin 6 (IL6) may be a biological marker for major depressive disorder (MDD). In this study, we performed a comprehensive genetic study to determine the association between the gene encoding IL6 (IL6) and MDD in Han Chinese. There were 50 drug-naive MDD patients and 50 healthy controls undergoing an mRNA expression study. A sample of 772 patients with MDD and 759 healthy controls were used for genetic analysis. Next, we performed an eQTL analysis to identify whether risk SNP(s) is associated with IL6 expression in brain. Our results showed that patients with MDD have higher levels of IL6 than healthy controls (P = 0.008). The SNP rs1800797 has a significant association with MDD (P = 0.01) in a dominant model. The eQTL analysis showed a marginally significant association between the rs1800797 and IL6 expression in the frontal cortex (P = 0.087). Our preliminary findings are suggestive of an association between rs1800797 and the risk of MDD. Further investigations are required to evaluate this association in larger samples to increase statistical power, and to examine the correlation between rs1800797 and IL6 methylation patterns. PMID- 27502737 TI - Predictors of duration of abiraterone acetate in men with castration-resistant prostate cancer. AB - BACKGROUND: Androgen receptor signaling remains important in castration-resistant prostate cancer (CRPC) as demonstrated by the efficacy of abiraterone acetate (henceforth abiraterone) in phase III trials. Given that heterogeneous patient responses are observed, we sought to identify clinical factors associated with duration of abiraterone. METHODS: We retrospectively identified patients with CRPC treated with abiraterone in our database. Patient characteristics and types and duration of prostate cancer (PC) therapies were analyzed. These parameters were analyzed with duration of abiraterone in univariate and multivariable analyses. RESULTS: We identified 161 patients who had received abiraterone. All had received primary androgen-deprivation therapy (ADT), 86% prior secondary hormone therapy (SHT) and 33% prior chemotherapy. The median duration of primary ADT was 23 months, duration of SHT (excluding abiraterone) was 17 months and duration of chemotherapy was 8 months. We demonstrated that lower PSA at abiraterone initiation, longer primary ADT duration, no prior ketoconazole, no prior chemotherapy and longer chemotherapy duration were associated with a longer duration on abiraterone in univariate analysis. In multivariable analysis, duration of primary ADT (duration of abiraterone 9 versus 13 months for ?12 versus >12 months, P=0.03) and no use of prior chemotherapy (duration of abiraterone 16 versus 7 months for no versus yes prior chemotherapy, P<0.01) were associated with duration of abiraterone. CONCLUSIONS: Several clinical parameters, including type and duration of prior therapy, are predictive of responsiveness to abiraterone. These parameters are logical and correlate with smaller disease burden or less exposure to PC therapies. This information can help physicians counsel patients about the potential durability of efficacy of abiraterone. Identifying predictive biomarkers that inform patient selection for therapy is critical to optimizing treatment outcomes. PMID- 27502738 TI - Morbidity and mortality after surgery for lower urinary tract symptoms: a study of 95 577 cases from a nationwide German health insurance database. AB - BACKGROUND: Little real-world data is available on the comparison of different methods in surgery for lower urinary tract symptoms due to benign prostatic obstruction in terms of complications. The objective was to evaluate the proportions of TURP, open prostatectomy (OP) and laser-based surgical approaches over time and to analyse the effect of approach on complication rates. METHODS: Using data of the German local healthcare funds (Allgemeine Ortskrankenkassen (AOK)), we identified 95 577 cases with a primary diagnosis of hyperplasia of prostate who received TURP, laser vaporisation (LVP), laser enucleation (LEP) of the prostate or OP between 2008 and 2013. Univariable logistic regression was used to analyse proportions of surgical approach over time, and the effect of surgical method on outcomes was analysed by means of multivariable logistic regression. RESULTS: The proportion of TURP decreased from 83.4% in 2008 to 78.7% in 2013 (P<0.001). Relative to TURP and adjusting for age, co-morbidities, AOK hospital volume, year of surgery and antithrombotic medication, OP had increased mortality (odds ratio (OR) 1.47, P<0.05), transfusions (OR 5.20, P<0.001) and adverse events (OR 2.17, P<0.001), and lower re-interventions for bleeding (OR 0.75, P<0.001) and long-term re-interventions (OR 0.55, P<0.001). LVP carried a lower risk of transfusions (OR 0.57, P<0.001) and re-interventions for bleeding (OR 0.76, P<0.001), but a higher risk of long-term re-interventions (OR 1.43, P<0.001). LEP had increased re-interventions for bleeding (OR 1.35, P<0.01). Complications were also dependent on age and co-morbidity. Limitations include the lack of clinical information and functional results. CONCLUSIONS: OP has the greatest risks of complication despite a low re-intervention rate. LVP demonstrated favourable results for transfusion and bleeding, but increased long term re-interventions compared with TURP, while LEP showed increased re interventions for bleeding. Findings support a careful indication and choice of method for surgery for LUTS, taking age and co-morbidities into account. PMID- 27502739 TI - Tumor features and survival after radical prostatectomy among antidiabetic drug users. AB - BACKGROUND: To evaluate the association between use of metformin and other antidiabetic drugs with tumor characteristics and survival in surgically managed prostate cancer (PCa) patients. METHODS: The study population included 1314 men who underwent radical prostatectomy at the Tampere University Hospital during 1995-2009. Causes of deaths were collected from the Finnish Cancer Registry. Individual-level data on medication use during 1995-2009 was obtained from national prescription database. Fasting blood glucose and hemoglobin A1c values during the study period were gathered from hospital district database. Gleason grade and pathological stage were compared by drug use before surgery and separately by metformin usage. Risk of biochemical recurrence, all-cause death and PCa-specific death were calculated using Cox proportional hazard regression with adjustment for age, tumor characteristics, glycemic control and use of other drug groups. RESULTS: High-grade tumors were more common among antidiabetic drug users (P=0.032), including metformin users (P=0.012). Despite this, no difference in PSA levels was observed. Men who had used antidiabetic drugs before surgery had an increased risk of Gleason 7-10 disease (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.04-3.23). The risk of high-grade PCa was higher among metformin users compared with other antidiabetic drug users (OR 3.11, 95% CI 1.16 8.33). During the median follow-up of 8.6 years after surgery, 551 men had biochemical recurrence and 244 died, 32 owing to PCa. Generally, no association with risk of disease recurrence was observed. Risk of death was increased by preoperative use of antidiabetic drugs (hazard ratio 1.81 95% CI 1.03-3.19), but no survival associations for postoperative use of antidiabetic drugs or metformin were observed. CONCLUSION: Diabetic men have more high-grade PCa at lower PSA levels, but that does not have a clear impact on disease-specific survival in the short term even when glycemic control is being considered. PMID- 27502740 TI - The concordance between the volume hotspot and the grade hotspot: a 3-D reconstructive model using the pathology outputs from the PROMIS trial. PMID- 27502741 TI - The contribution of the citrate pathway to oxidative stress in Down syndrome. AB - Inflammatory conditions and oxidative stress have a crucial role in Down syndrome (DS). Emerging studies have also reported an altered lipid profile in the early stages of DS. Our previous works demonstrate that citrate pathway activation is required for oxygen radical production during inflammation. Here, we find up regulation of the citrate pathway and down-regulation of carnitine/acylcarnitine carrier and carnitine palmitoyl-transferase 1 genes in cells from children with DS. Interestingly, when the citrate pathway is inhibited, we observe a reduction in oxygen radicals as well as in lipid peroxidation levels. Our preliminary findings provide evidence for a citrate pathway dysregulation, which could be related to some phenotypic traits of people with DS. PMID- 27502742 TI - A circuit motif in the zebrafish hindbrain for a two alternative behavioral choice to turn left or right. AB - Animals collect sensory information from the world and make adaptive choices about how to respond to it. Here, we reveal a network motif in the brain for one of the most fundamental behavioral choices made by bilaterally symmetric animals: whether to respond to a sensory stimulus by moving to the left or to the right. We define network connectivity in the hindbrain important for the lateralized escape behavior of zebrafish and then test the role of neurons by using laser ablations and behavioral studies. Key inhibitory neurons in the circuit lie in a column of morphologically similar cells that is one of a series of such columns that form a developmental and functional ground plan for building hindbrain networks. Repetition within the columns of the network motif we defined may therefore lie at the foundation of other lateralized behavioral choices. PMID- 27502743 TI - Breslow density is a novel prognostic feature in cutaneous malignant melanoma. AB - AIMS: In 1970, Breslow described his eponymously named thickness measurement. No one has sought to enhance the Breslow thickness (BT). The aim of this study was to demonstrate a proof of concept that the density of melanoma cells at the position where the BT is measured is a morphological prognostic biomarker, which we name the Breslow density (BD). The hypothesis was that the BD has prognostic value for overall survival (OS) and is independent of the BT. METHODS AND RESULTS: We analysed 100 cutaneous melanomas, and followed REMARK guidelines. The BD was the estimated percentage dermal area occupied by melanoma cells in a specified location. The BT and BD had a strong correlation (P = 2.1 * 10-11 ) but, despite this, they were independent prognostic factors for OS in Cox regression [BD hazard ratio (HR) 1.03, P = 0.001849; and BT HR 1.09, P = 0.000146]. This was corroborated by an independent effect on melanoma-specific survival. We assessed whether the BT and BD could be combined into a Breslow score. A prognostic index based on Cox regression coefficients was used, and this showed a marginal improvement in predicted 5-year survival as compared with the BT alone (area under the curve of 94.8% versus 96.7%). CONCLUSIONS: We show a proof of concept that the BD represents a novel morphological prognostic biomarker that is independent of the BT, and that there is potential to combine these into a Breslow score. Larger studies are needed to validate the BD, but the simplicity of this biomarker makes it a strong candidate for translation to clinical practice. PMID- 27502744 TI - Real-world implementation of electronic patient-reported outcomes in outpatient pediatric cancer care. AB - OBJECTIVE: The KLIK method is an online tool that monitors and discusses electronic patient-reported outcomes (ePROs), which has been shown to enhance outcomes. This study aimed (1) to determine the fidelity (ie, extent to which used as intended) of the KLIK method as implemented in outpatient pediatric cancer care and (2) to study health care professional (HCP)-reported barriers and facilitators for implementation. METHODS: Two hundred five children with newly diagnosed cancer (enrollment rate 85%) participated. At 1 (T1), 3 (T2), and 6 (T3) months after diagnosis, patients (8-18 years) or parents (of patients 0-7 years) completed health-related quality of life (HRQoL) questionnaires, which were transformed into an ePROfile and discussed by their HCP during consultations. Fidelity was determined by the following: percentage of website registrations, HRQoL questionnaires completed, and ePROfiles discussed. Implementation determinants were assessed with HCPs after the final T3 with the Measurement Instrument for Determinants of Innovations. RESULTS: Depending on the time point (T1-T3), fidelity was 86% to 89% for website registration, 66-85% for completed HRQoL questionnaires, and 56% to 62% for ePROfile discussion. Barriers were mainly related to organizational issues (eg, organizational change) and less frequently to users (eg, motivation to comply) or the intervention (compatibility). Facilitators were related to the user (eg, positive outcome expectations) and intervention (simplicity) but not to the organization. CONCLUSIONS: When implementing ePROs in outpatient pediatric oncology practice, HCPs report determinants that influence ePRO integration. To improve implementation and outcomes, tailored organizational (eg, formal ratification by management and time) and specific local (eg, individualized assessments) strategies should be developed to achieve optimal ePRO discussion. PMID- 27502745 TI - Promiscuous Pathogenicity Islands and Phylogeny of Pathogenic Streptomyces spp. AB - Approximately 10 Streptomyces species cause disease on underground plant structures. The most economically important of these is potato scab, and the most studied of these pathogens is Streptomyces scabiei (syn. S. scabies). The main pathogenicity determinant of scab-causing Streptomyces species is a nitrated diketopiperazine, known as thaxtomin A (ThxA). In the pathogenic species Streptomyces turgidiscabies, ThxA biosynthetic genes reside on a mobile pathogenicity island (PAI). However, the mobilization of PAIs in other Streptomyces species remains uncharacterized. Here, we investigated the mobilization of the PAI of S. scabiei 87-22. Based on whole genome sequences, we inferred the evolutionary relationships of pathogenic Streptomyces species and discovered that Streptomyces sp. strain 96-12, a novel pathogenic species isolated from potatoes in Egypt, was phylogenetically grouped with nonpathogenic species rather than with known pathogenic species. We also found that Streptomyces sp. strain 96-12 contains a PAI that is almost identical to the PAI in S. scabiei 87-22, despite significant differences in their genome sequences. This suggested direct or indirect in vivo mobilization of the PAI between S. scabiei and nonpathogenic Streptomyces species. To test whether the S. scabiei 87 22 PAI could, indeed, be mobilized, S. scabiei 87-22 deletion mutants containing antibiotic resistance markers in the PAI were mated with Streptomyces diastatochromogenes, a nonpathogenic species. The PAI of S. scabiei was site specifically inserted into the aviX1 gene of S. diastatochromogenes and conferred pathogenicity in radish seedling assays. Our results demonstrated that S. scabiei, the earliest described Streptomyces pathogen, could be the source of a PAI responsible for the emergence of novel pathogenic species. PMID- 27502746 TI - Concentrations of 226Ra, 232Th and 40K in industrial kaolinized granite. AB - Activity concentrations of 226Ra, 232Th and 40K in 120 kaolinized granite samples imported in Serbia from the Motajica mine, Bosnia and Herzegovina, were measured. The 226Ra concentration ranged from 61 to 319 Bq kg-1, the 232Th from 44 to 272 Bq kg-1, and the 40K from 590 to 1470 Bq kg-1. The frequency distribution of 40K concentrations was near-Gaussian, where those of 226Ra and 232Th were right skewed. In 6 samples, the gamma index, I, was higher than 2, which exceeds the exemption dose criterion (0.3 mSv y-1). The absorbed dose rate and annual effective doses for workers in the ceramic industries in Serbia who worked with kaolinized granite were below levels of concern. PMID- 27502747 TI - 210Po and 210Pb disequilibrium at the PN section in the East China Sea. AB - Lead-210 and 210Po have been widely used as tracers for quantifying particulate scavenging in the upper layer of the oceanic water column. In this study, we investigated the 210Po/210Pb disequilibrium in the water column of the PN section in the East China Sea (ECS) during autumn 2013. In most of the water column, a deficiency of 210Po was observed with respect to its parent nuclide 210Pb (i.e., a 210Po/210Pb activity ratio < 1.0). The (210Po/210Pb)dissolved, (210Po/210Pb)particulate and (210Po/210Pb)total activity ratios ranged from 0.29 to 0.71 (average: 0.53 +/- 0.13, n = 27), 0.31 to 1.42 (average: 0.70 +/- 0.27, n = 27) and 0.22 to 0.62 (average: 0.50 +/- 0.12, n = 27), respectively. The distribution coefficients (Kd) of 210Po and 210Pb were 12.1* 104 ml g-1 and 8.8* 104 ml g-1, with an average (210Po/210Pb) total activity ratio of (0.50 +/- 0.12, n = 27). However, over the continental shelf, planktonic detritus and fecal pellets appear to be the main carriers for 210Po, which preferentially scavenges 210Po and produces a lower (210Po/210Pb) total activity ratio (0.49 +/- 0.12, n = 22) with a Kd for 210Po of 13.8* 104 ml g-1 in the water column. The variations in the fractionation factor (1.48 +/- 0.66) of 210Po/210Pb reveal distinct differences between the distribution and scavenging of 210Po and 210Pb by particulate matter in different marine environments: in the estuarine zone (a high turbidity area), terrigenous suspended particulate matter scavenges 210Pb from the water column, while in areas dominated by biogenic particular matter, 210Po is preferentially scavenged from the water column. Using the 210Po/210Pb disequilibrium in the water column, we estimated the removal fluxes of POC from the upper waters downward to be 25.0 mg C m-2 d-1, comparable to those in other marginal seas. Moreover, a decreasing trend of POC removal fluxes was observed with increasing distance offshore. PMID- 27502750 TI - The contributions of resting state and task-based functional connectivity studies to our understanding of adolescent brain network maturation. AB - This review summarizes functional magnetic resonance imaging (fMRI) research done over the past decade that examined changes in the function and organization of brain networks across human adolescence. Its over-arching goal is to highlight how both resting state functional connectivity (rs-fcMRI) and task-based functional connectivity (t-fcMRI) have jointly contributed - albeit in different ways - to our understanding of the scope and types of network organization changes that occur from puberty until young adulthood. These two approaches generally have tested different types of hypotheses using different analysis techniques. This has hampered the convergence of findings. Although much has been learned about system-wide changes to adolescents' neural network organization, if both rs-fcMRI and t-fcMRI approaches draw upon each other's methodology and ask broader questions, it will produce a more detailed connectome-informed theory of adolescent neurodevelopment to guide physiological, clinical, and other lines of research. PMID- 27502748 TI - Electronic approaches to restoration of sight. AB - Retinal prostheses are a promising means for restoring sight to patients blinded by the gradual atrophy of photoreceptors due to retinal degeneration. They are designed to reintroduce information into the visual system by electrically stimulating surviving neurons in the retina. This review outlines the concepts and technologies behind two major approaches to retinal prosthetics: epiretinal and subretinal. We describe how the visual system responds to electrical stimulation. We highlight major differences between direct encoding of the retinal output with epiretinal stimulation, and network-mediated response with subretinal stimulation. We summarize results of pre-clinical evaluation of prosthetic visual functions in- and ex vivo, as well as the outcomes of current clinical trials of various retinal implants. We also briefly review alternative, non-electronic, approaches to restoration of sight to the blind, and conclude by suggesting some perspectives for future advancement in the field. PMID- 27502749 TI - Neurocognitive functioning in euthymic patients with bipolar disorder and unaffected relatives: A review of the literature. AB - BACKGROUND: Neurocognitive deficits are present in bipolar disorder (BD) patients and their unaffected (nonbipolar) relatives, but it is not clear which domains are most often impaired and the extent of the impairment resulting from shared genetic factors. In this literature review, we address these issues and identify specific neurocognitive tasks most sensitive to cognitive deficits in patients and unaffected relatives. METHOD: We conducted a systematic review in Web of Science, PubMed/Medline and PsycINFO databases. RESULTS: Fifty-one articles assessing cognitive functioning in BD patients (23 studies) and unaffected relatives (28 studies) were examined. Patients and, less so, relatives show impairments in attention, processing speed, verbal learning/memory, and verbal fluency. CONCLUSION: Studies were more likely to find impairment in patients than relatives, suggesting that some neurocognitive deficits may be a result of the illness itself and/or its treatment. However, small sample sizes, differences among relatives studied (e.g., relatedness, diagnostic status, age), and differences in assessment instruments may contribute to inconsistencies in reported neurocognitive performance among relatives. Additional studies addressing these issues are needed. PMID- 27502751 TI - The dlt genes play a role in antimicrobial tolerance of Streptococcus mutans biofilms. AB - Microbial biofilms are tolerant to antibiotic treatment and therefore cause problematic infections. Knowledge about the molecular mechanisms underlying biofilm-associated antimicrobial tolerance will aid the development of antibiofilm drugs. Screening of a Streptococcus mutans transposon mutant library for genes that are important for biofilm-associated antimicrobial tolerance provided evidence that the dlt genes play a role in the tolerance of S. mutans biofilms towards gentamicin. The minimum bactericidal concentration for biofilm cells (MBC-B) for a dltA transposon mutant was eight-fold lower than that of the wild-type. The minimum bactericidal concentration for planktonic cells (MBC-P) was only slightly reduced, indicating that the mechanism involved in the observed antimicrobial tolerance has a predominant role specifically in biofilms. Experiments with a knockout dltA mutant and complemented strain confirmed that the dlt genes in S. mutans play a role in biofilm-associated tolerance to gentamicin. Confocal laser scanning microscopy analyses of biofilms grown on glass slides showed that the dltA mutant produced roughly the same amount of biofilm as the wild-type, indicating that the reduced antimicrobial tolerance of the dltA mutant is not due to a defect in biofilm formation. The products of the dlt genes have been shown to mediate alanylation of teichoic acids, and in accordance the dltA mutant showed a more negatively charged surface than the wild type, which likely is an important factor in the reduced tolerance of the dltA mutant biofilms towards the positively charged gentamicin. PMID- 27502752 TI - Ten key points for the appropriate use of antibiotics in hospitalised patients: a consensus from the Antimicrobial Stewardship and Resistance Working Groups of the International Society of Chemotherapy. AB - The Antibiotic Stewardship and Resistance Working Groups of the International Society for Chemotherapy propose ten key points for the appropriate use of antibiotics in hospital settings. (i) Get appropriate microbiological samples before antibiotic administration and carefully interpret the results: in the absence of clinical signs of infection, colonisation rarely requires antimicrobial treatment. (ii) Avoid the use of antibiotics to 'treat' fever: use them to treat infections, and investigate the root cause of fever prior to starting treatment. (iii) Start empirical antibiotic treatment after taking cultures, tailoring it to the site of infection, risk factors for multidrug resistant bacteria, and the local microbiology and susceptibility patterns. (iv) Prescribe drugs at their optimal dosing and for an appropriate duration, adapted to each clinical situation and patient characteristics. (v) Use antibiotic combinations only where the current evidence suggests some benefit. (vi) When possible, avoid antibiotics with a higher likelihood of promoting drug resistance or hospital-acquired infections, or use them only as a last resort. (vii) Drain the infected foci quickly and remove all potentially or proven infected devices: control the infection source. (viii) Always try to de-escalate/streamline antibiotic treatment according to the clinical situation and the microbiological results. (ix) Stop unnecessarily prescribed antibiotics once the absence of infection is likely. And (x) Do not work alone: set up local teams with an infectious diseases specialist, clinical microbiologist, hospital pharmacist, infection control practitioner or hospital epidemiologist, and comply with hospital antibiotic policies and guidelines. PMID- 27502753 TI - Retrospective survey of the efficacy of mandatory implementation of the Essential Medicine Policy in the primary healthcare setting in China: failure to promote the rational use of antibiotics in clinics. AB - The objective of this study was to understand the impact of implementation of the Essential Medicine Policy (EMP) on the rational use of antibiotics in primary medical institutions in China. A retrospective survey was conducted in 39 primary medical institutions to compare the efficacy of EMP in rational antibiotic use. All institutions completed the survey 1 year before and 1 year after implementation of the EMP. In particular, antibiotic use and its rationality were closely examined. The institutions mainly dealt with common diseases, especially non-infectious chronic diseases. Antibiotic usage was very inappropriate both before and after EMP implementation. Before and after EMP implementation, respectively, the median outpatient cost was US$6.34 and US$5.05, 52.50% (2005/3819) and 53.41% (1865/3492) of the outpatient prescriptions contained antibiotics, and 76.23% (1132/1485) and 78.83% (1106/1403) of inpatients were administered antibiotics. In addition, 98.38% (425/432) and 97.52% (512/525) of surgical inpatients were administered antibiotics, respectively, and 80.76% (638/790) and 75.19% (503/669) of patients with a cold were prescribed antibiotics, respectively. The most commonly used antibiotics were broad-spectrum and injectable agents, including cephalosporins, fluoroquinolones and penicillins. This profile showed little change following implementation of the EMP. In conclusion, inappropriate antibiotic use is a serious problem in primary medical institutions in China. Whilst enforcing the EMP reduced the cost of medical services, it had little effect on promoting the rational use of antibiotics. PMID- 27502755 TI - [Atypical scurvy associated with anorexia nervosa]. AB - INTRODUCTION: Scurvy, or "Barlow's disease", is a widely described disease involving cutaneous and mucosal lesions resulting from vitamin C deficiency. Herein, we report a case of scurvy in a 48-year-old woman that was unusual in its atypical cutaneous-mucosal presentation as well as its association with anorexia nervosa. PATIENTS AND METHODS: A 48-year-old woman treated for depression for several years was admitted to hospital for her impaired general state of health. Over the last year, she had presented palmoplantar rash and episodes of perimalleolar oedema. The clinical examination showed the patient to have wasting syndrome, with a BMI of 11.9kg/m2, lower-limb oedema, palmoplantar fissures, geographic tongue, telogen effluvium and purpuric petechiae on her right knee. However, no gingival bleeding was noted and there was no loss of tooth enamel. The remainder of the clinical examination was normal. Blood tests revealed extremely low vitamin C levels without any other associated deficiencies, as well as laboratory signs of cytolysis and anicteric cholestasis without inflammatory syndrome. The diagnosis of anorexia nervosa was made by psychiatrists, despite the unusual age of onset. Favorable clinical outcome was rapidly achieved via a one-month course of vitamin C supplements at a daily dose of 1g. DISCUSSION: The absence of classical buccal-dental symptoms and the presence of keratotic dermatosis with fissures and ulcers on the hands and feet are atypical in scurvy; however, this diagnosis was confirmed by the existence of purpura evoking capillary fragility, the patient's drastically low vitamin C level and the rapid subsidence of symptoms following treatment with oral vitamin C alone. Anorexia nervosa was doubtless the cause of deficiency. This situation is rare and a systematic review of the literature in Medline via PubMed showed that only three reports of scurvy associated with mental anorexia have been published since 1975. PMID- 27502754 TI - [Reversible posterior leukoencephalopathy syndrome in a patient presenting granulomatosis with polyangiitis]. AB - BACKGROUND: Reversible posterior leukoencephalopathy syndrome (RPLS) is characterised by clinical neurological features of sudden onset and brain MRI findings such as T2/Flair white matter hyperintensities. RPLS can occur in autoimmune diseases, and rarely in systemic vasculitis. We report a case of RPLS in a woman presenting granulomatosis with polyangiitis (Wegener's granulomatosis). PATIENTS AND METHODS: A 22-year-old female patient was treated with methylprednisolone pulses for granulomatosis with polyangiitis and neurological impairment. A few hours after the second pulse, the patient had seizures, blindness and confusion associated with high blood pressure and acute renal failure. MRI revealed a high-intensity area on T2-Flair weighted images of the occipital-temporal lobes. The patient was treated with antiepileptic and antihypertensive medications, oral steroids and cyclophosphamide; the clinical and radiological findings proved reversible over the ensuing days. DISCUSSION: The occurrence of RPLS in systemic vasculitis is rare. Six cases of RPLS associated with granulomatosis and polyangiitis have been reported. It appears important to screen for high blood pressure in patients recently treated with corticosteroids for vasculitis as this condition may represent a precipitating factor for RPLS. PMID- 27502757 TI - Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety/depression. AB - Antidepressants increase hippocampal neurogenesis by activating the glucocorticoid receptor (GR), but excessive GR activation impairs hippocampal neurogenesis, suggesting that normal GR function is crucial for hippocampal neurogenesis. Baicalin was reported to regulate the expression of GR and facilitate hippocampal neurogenesis, but the underlying molecular mechanisms are still unknown. In this study, we used the chronic corticosterone (CORT)-induced mouse model of anxiety/depression to assess antidepressant-like effects of baicalin and illuminate possible molecular mechanisms by which baicalin affects GR-mediated hippocampal neurogenesis. We found that oral administration of baicalin (40, 80 or 160 mg/kg) for 4 weeks alleviated several chronic CORT induced anxiety/depression-like behaviors. Baicalin also increased Ki-67- and DCX positive cells to restore chronic CORT-induced suppression of hippocampal neurogenesis. Moreover, baicalin normalized the chronic CORT-induced decrease in GR protein levels, the increase in GR nuclear translocation and the increase in GR phosphorylation at Ser203 and Ser211. Finally, chronic CORT exposure increased the level of FK506-binding protein 51 (FKBP5) and of phosphorylated serum- and glucocorticoid-inducible kinase 1 (SGK1) at Ser422 and Thr256, whereas baicalin normalized these changes. Together, our findings suggest that baicalin improves anxiety/depression-like behaviors and promotes hippocampal neurogenesis. We propose that baicalin may normalize GR function through SGK1- and FKBP5-mediated GR phosphorylation. PMID- 27502756 TI - 'Atherothrombosis-associated microRNAs in Antiphospholipid syndrome and Systemic Lupus Erythematosus patients'. AB - MicroRNAs markedly affect the immune system, and have a relevant role in CVD and autoimmune diseases. Yet, no study has analyzed their involvement in atherothrombosis related to APS and SLE patients. This study intended to: 1) identify and characterize microRNAs linked to CVD in APS and SLE; 2) assess the effects of specific autoantibodies. Six microRNAs, involved in atherothrombosis development, were quantified in purified leukocytes from 23 APS and 64 SLE patients, and 56 healthy donors. Levels of microRNAs in neutrophils were lower in APS and SLE than in healthy donors. Gene and protein expression of miRNA biogenesis-related molecules were also reduced. Accordingly, more than 75% of identified miRNAs by miRNA profiling were underexpressed. In monocytes, miR124a and -125a were low, while miR-146a and miR-155 appeared elevated. Altered microRNAs' expression was linked to autoimmunity, thrombosis, early atherosclerosis, and oxidative stress in both pathologies. In vitro treatment of neutrophils, monocytes, and ECs with aPL-IgG or anti-dsDNA-IgG antibodies deregulated microRNAs expression, and decreased miRNA biogenesis-related proteins. Monocyte transfections with pre-miR-124a and/or -125a caused reduction in atherothrombosis-related target molecules. In conclusion, microRNA biogenesis, significantly altered in neutrophils of APS and SLE patients, is associated to their atherothrombotic status, further modulated by specific autoantibodies. PMID- 27502758 TI - Environment-wide association study to identify factors associated with hematocrit: evidence from the Guangzhou Biobank Cohort Study. AB - PURPOSE: In randomized controlled trials reducing high hematocrit (Hct) in patients with polycythemia vera protects against cardiovascular disease (CVD) events, whereas increasing Hct in anemia patients causes CVD events. Hct is influenced by environmental and lifestyle factors. Given limited knowledge concerning the drivers of Hct, we took an agnostic approach to identify drivers of Hct. METHODS: We used an environment-wide association study to identify environmental and lifestyle factors associated with Hct in 20443 older Chinese adults (mean age = 62.7 years) from the Guangzhou Biobank Cohort Study. We evaluated the role of 25 nutrients, 40 environmental contaminants, two metals (only available for 10405 participants), and six lifestyle factors in relation to Hct, adjusted for sex, age, recruitment phase, and socioeconomic position. RESULTS: In a mutually adjusted model vitamin A, serum calcium, serum magnesium, and alcohol use were associated with higher Hct, whereas physical activity was associated with lower Hct. CONCLUSIONS: Despite the difficulty of ascertaining causality, finding both expected (vitamin A and physical inactivity) and novel factors (serum calcium, serum magnesium and alcohol use) strongly associated with Hct illustrates the utility of environment-wide association study to generate hypotheses regarding the potential contribution of modifiable exposures to CVD. PMID- 27502759 TI - Internet Mindfulness Meditation Intervention for the General Public: Pilot Randomized Controlled Trial. AB - BACKGROUND: Mindfulness meditation interventions improve a variety of health conditions and quality of life, are inexpensive, easy to implement, have minimal if any side effects, and engage patients to take an active role in their treatment. However, the group format can be an obstacle for many to take structured meditation programs. Internet Mindfulness Meditation Intervention (IMMI) is a program that could make mindfulness meditation accessible to all people who want and need to receive it. However, the feasibility, acceptability, and ability of IMMI to increase meditation practice have yet to be evaluated. OBJECTIVES: The primary objectives of this pilot randomized controlled study were to (1) evaluate the feasibility and acceptability of IMMIs in the general population and (2) to evaluate IMMI's ability to change meditation practice behavior. The secondary objective was to collect preliminary data on health outcomes. METHODS: Potential participants were recruited from online and offline sources. In a randomized controlled trial, participants were allocated to IMMI or Access to Guided Meditation arm. IMMI included a 1-hour Web-based training session weekly for 6 weeks along with daily home practice guided meditations between sessions. The Access to Guided Meditation arm included a handout on mindfulness meditation and access to the same guided meditation practices that the IMMI participants received, but not the 1-hour Web-based training sessions. The study activities occurred through the participants' own computer and Internet connection and with research-assistant telephone and email contact. Feasibility and acceptability were measured with enrollment and completion rates and participant satisfaction. The ability of IMMI to modify behavior and increase meditation practice was measured by objective adherence of daily meditation practice via Web-based forms. Self-report questionnaires of quality of life, self efficacy, depression symptoms, sleep disturbance, perceived stress, and mindfulness were completed before and after the intervention period via Web-based surveys. RESULTS: We enrolled 44 adults were enrolled and 31 adults completed all study activities. There were no group differences on demographics or important variables at baseline. Participants rated the IMMI arm higher than the Access to Guided Meditation arm on Client Satisfaction Questionnaire. IMMI was able to increase home practice behavior significantly compared to the Access to Guided Meditation arm: days practiced (P=.05), total minutes (P=.01), and average minutes (P=.05). As expected, there were no significant differences on health outcomes. CONCLUSIONS: In conclusion, IMMI was found to be feasible and acceptable. The IMMI arm had increased daily meditation practice compared with the Access to Guided Meditation control group. More interaction through staff and/or through built-in email or text reminders may increase daily practice even more. Future studies will examine IMMI's efficacy at improving health outcomes in the general population and also compare it directly to the well-studied mindfulness-based group interventions to evaluate relative efficacy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02655835; http://clinicaltrials.gov/ct2/show/NCT02655835 (Archived by WebCite at http://www.webcitation/ 6jUDuQsG2). PMID- 27502760 TI - Improving conceptual and procedural knowledge: The impact of instructional content within a mathematics lesson. AB - BACKGROUND: Students, parents, teachers, and theorists often advocate for direct instruction on both concepts and procedures, but some theorists suggest that including instruction on procedures in combination with concepts may limit learning opportunities and student understanding. AIMS: This study evaluated the effect of instruction on a math concept and procedure within the same lesson relative to a comparable amount of instruction on the concept alone. Direct instruction was provided before or after solving problems to evaluate whether the type of instruction interacted with the timing of instruction within a lesson. SAMPLE: We worked with 180 second-grade children in the United States. METHODS: In a randomized experiment, children received a classroom lesson on mathematical equivalence in one of four conditions that varied in instruction type (conceptual or combined conceptual and procedural) and in instruction order (instruction before or after solving problems). RESULTS: Children who received two iterations of conceptual instruction had better retention of conceptual and procedural knowledge than children who received both conceptual and procedural instruction in the same lesson. Order of instruction did not impact outcomes. CONCLUSIONS: Findings suggest that within a single lesson, spending more time on conceptual instruction may be more beneficial than time spent teaching a procedure when the goal is to promote more robust understanding of target concepts and procedures. PMID- 27502761 TI - Determinants of patient satisfaction and their willingness to return after primary total hip replacement: a cross-sectional study. AB - BACKGROUND: Surveys of patient satisfaction and their willingness to return can be used for the optimization of processes, improving their quality, and increasing the satisfaction and loyalty in customers. This study looked at the factors significantly associated with patient satisfaction after primary total hip replacement (THR), and which affect the patients' willingness to return to the same hospital for future treatment, even when unrelated to their THR. METHODS: Data for the study was collected by written survey from 810 patients of 43 hospitals following their THR. Satisfaction and willingness to return were measured using a validated, multidimensional questionnaire, primarily based on six-point scales, which were then evaluated together with routine hospital data, according to bivariate and multivariate analyses. RESULTS: The bivariate analysis showed a strong correlation between satisfaction or willingness to return and the health condition before hospitalization as well as the perceived length of stay. In contrast, the patient's gender and the number of inpatient cases in a hospital with THR had no influence. The binary logistic regression analyses identified three predictors associated with overall satisfaction and seven predictors associated with willingness to return. The strongest factor for both dependent variables was the perceived length of stay, and the weakest factor for satisfaction was the treatment outcome. CONCLUSIONS: Overall, with all of the medical and service-related issues considered, high levels of satisfaction were reached. Despite the high satisfaction scores, probable causes for declining the willingness to return were identified. The results provide incentives for hospitals and medical professionals to attain a high satisfaction levels in their THR patients. PMID- 27502762 TI - Engaging members and partner organizations in translating a nursing science agenda. PMID- 27502763 TI - Human milk and breastfeeding: An intervention to mitigate toxic stress. AB - The American Academy of Nursing has identified toxic stress in childhood as a health policy concern of high priority. Adult diseases (e.g., obesity, diabetes, hypertension and cardiovascular disease) should be viewed as developmental disorders that begin early in life that could be reduced with the alleviation of toxic stress in childhood. The provision of human milk/breastfeeding is an evidence-based intervention that may hold the greatest potential to mitigate the effects of toxic stress from the moment of birth. Assisting families to make an informed choice to initiate and continue breastfeeding from birth has the potential to address both the disparity in the quality of nutrition provided infants and the economic stress experienced by families who purchase formula. The Expert Panel on Breastfeeding endorses initiatives to improve the initiation, duration, and exclusivity of breastfeeding to mitigate the effects of toxic stress in this call to action for research to build the evidence to support these critical relationships. PMID- 27502764 TI - How fast will the registered nurse workforce grow through 2030? Projections in nine regions of the country. AB - BACKGROUND: After an unprecedented increase in nursing school enrollment and graduates in the past 10 years, projected shortages of nurses have been erased at a national level. However, nursing markets are local, and an uneven distribution of health care providers of all types is a longstanding feature of health care in the United States. PURPOSE: The purpose of this study was to understand how the outlook for future registered nurse (RN) supply varies regionally across the United States. METHODS: We apply our nursing supply model to the nine U.S. Census Divisions to produce separate supply forecasts for each region. DISCUSSION: We find dramatic differences in expected future growth of the nursing workforce across U.S. regions. These range from zero expected growth in the number of RNs per capita in New England and in the Pacific regions between 2015 and 2030 to 40% growth in the East South Central region (Mississippi, Alabama, Tennessee, Kentucky) and in the West South Central region (Texas, Oklahoma, Arkansas, Louisiana). CONCLUSION: Assuming growth in the demand for RNs per population, some regions of the United States are expected to face shortfalls in their nursing workforce if recent trends do not change. PMID- 27502766 TI - Mitochondrial STAT3 is negatively regulated by SOCS3 and upregulated after spinal cord injury. AB - Suppressor of cytokine signaling-3 (SOCS3) expression is induced by the Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. SOCS3 then acts as a feedback inhibitor of JAK-STAT signaling. Previous studies have shown that knocking down SOCS3 in spinal cord neurons with Lentiviral delivery of SOCS3-targeting shRNA (shSOCS3) increased spinal cord injury (SCI)-induced tyrosine phosphorylation of STAT3 (P-STAT3 Tyr), which in part contributed to decreased neuronal death and demyelination as well as enhanced dendritic regeneration and protection of neuronal morphology after SCI. However, the role of serine phosphorylation of STAT3 (P-STAT3 Ser) is in large part undetermined. Our purposes of this study were to evaluate the expression patterns of P-STAT3 Ser and to explore the possible role of SOCS3 in the regulation of P-STAT3 Ser expression. Immunoblot analyses demonstrated that Oncostatin M (OSM), a member of the interleukin-6 (IL-6) cytokine family, induced both P-STAT3 Tyr and P-STAT3 Ser in SH-SY5Y cells. Subcellular fractionation further revealed that P-STAT3 Ser was localized in mitochondria. Overexpression of SOCS3 with a Lentivirus-mediated approach in SH-SY5Y cells inhibited OSM induced P-STAT3 Ser in both cytosol and mitochondria fractions. In contrast, OSM induced P-STAT3 Ser was further upregulated in both cytosol and mitochondria when SOCS3 was knocked down by Lentivirus-delivered shSOCS3. Using a rat T8 spinal cord complete transection model, we found that SCI induced upregulation of P STAT3 Ser in the mitochondria of macrophages/microglia and neurons both rostral and caudal to the injury site of spinal cord. Collectively, these results suggest that SOCS3 regulation of STAT3 signaling plays critical roles in stress conditions. PMID- 27502767 TI - Baicalin suppresses NLRP3 inflammasome and nuclear factor-kappa B (NF-kappaB) signaling during Haemophilus parasuis infection. AB - Haemophilus parasuis (H. parasuis) is the causative agent of Glasser's disease, a severe membrane inflammation disorder. Previously we showed that Baicalin (BA) possesses anti-inflammatory effects via the NLRP3 inflammatory pathway in an LPS challenged piglet model. However, whether BA has anti-inflammatory effects upon H. parasuis infection is still unclear. This study investigated the anti inflammatory effects and mechanisms of BA on H. parasuis-induced inflammatory responses via the NF-kappaB and NLRP3 inflammasome pathway in piglet mononuclear phagocytes (PMNP). Our data demonstrate that PMNP, when infected with H. parasuis, induced ROS (reactive oxygen species) production, promoted apoptosis, and initiated transcription expression of IL-6, IL-8, IL-10, PGE2, COX-2 and TNF alpha via the NF-kappaB signaling pathway, and IL-1beta and IL-18 via the NLRP3 inflammasome signaling pathway. Moreover, when BA was administrated, we observed a reduction in ROS production, suppression of apoptosis, and inhibition of the activation of NF-kappaB and NLRP3 inflammasome signaling pathway in PMNP treated with H. parasuis. To our best knowledge, this is the first example that uses piglet primary immune cells for an H. parasuis infection study. Our data strongly suggest that BA can reverse the inflammatory effect initiated by H. parasuis and possesses significant immunosuppression activity, which represents a promising therapeutic agent in the treatment of H. parasuis infection. PMID- 27502768 TI - Infant feeding and health-related quality of life in healthy Chinese infants: results from a prospective, observational cohort study. AB - BACKGROUND: Infant feeding regimens, including breastfeeding, formula-feeding, or a combination of the two, may influence infant health-related quality of life (HRQOL). However, few studies have examined this association. METHODS: This prospective cohort study assessed HRQOL in relation to three parent-selected feeding regimens: exclusively breastfed (n = 136), exclusively study formula-fed (n = 140), and mixed-fed with study formula and breast milk (n = 151). Healthy Chinese infants were enrolled at their first normally scheduled well infant clinic visit at age 42 days (study day 1). Parents independently chose their infants' feeding regimens prior to recruitment into the study, with infants in the formula and mixed-fed groups already consuming an infant formula enriched with alpha-lactalbumin and increased sn-2 palmitate and oligofructose. The Infant and Toddler Quality of Life Questionnaire, which includes six infant-focused and three parent-focused concepts, was used to assess HRQOL at day 1 and at a follow up visit 48 days later. Scores for each concept ranged from 0 to 100. Parent quality of life (assessed using the Mental Component Summary score of the SF-12v2 Health Survey) was included in the ANCOVA model to adjust for its potential effect on parent's perception of infant HRQOL. RESULTS: HRQOL concept scores were high in all three study groups at both visits (mean scores 71-95). Day 1 HRQOL scores were not significantly different between groups. At day 48, 5 of 9 HRQOL scores were not significantly different between groups. However, scores for Temperament and Moods, General Health Perceptions and Parent Impact-Time were slightly but statistically significantly lower in the formula-fed group (mean scores 75-86; all p <= 0.01) compared to the breastfed (78-90) and mixed-fed (77 91) groups. Day 48 Parent Impact-Emotional scores were also significantly lower by a small margin (4 points; p = 0.003) in the formula-fed group compared with the breastfed group. CONCLUSIONS: HRQOL was high in this population of healthy infants, with only a few small differences in HRQOL concept scores observed between breastfed, formula-fed and mixed-fed infants. These results indicate favorable physical, mental, and social well-being in these infants and parents. Assessment of infant HRQOL is therefore feasible and provides valuable insight into parental perceptions of their child's health and well-being. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01370967 . PMID- 27502770 TI - Implementing shared decision-making: consider all the consequences. AB - BACKGROUND: The ethical argument that shared decision-making is "the right" thing to do, however laudable, is unlikely to change how healthcare is organized, just as evidence alone will be an insufficient factor: practice change is governed by factors such as cost, profit margin, quality, and efficiency. It is helpful, therefore, when evaluating new approaches such as shared decision-making to conceptualize potential consequences in a way that is broad, long-term, and as relevant as possible to multiple stakeholders. Yet, so far, evaluation metrics for shared decision-making have been mostly focused on short-term outcomes, such as cognitive or affective consequences in patients. The goal of this article is to hypothesize a wider set of consequences, that apply over an extended time horizon, and include outcomes at interactional, team, organizational and system levels, and to call for future research to study these possible consequences. MAIN ARGUMENT: To date, many more studies have evaluated patient decision aids rather than other approaches to shared decision-making, and the outcomes measured have typically been focused on short-term cognitive and affective outcomes, for example knowledge and decisional conflict. From a clinicians perspective, the shared decision-making process could be viewed as either intrinsically rewarding and protective, or burdensome and impractical, yet studies have not focused on the impact on professionals, either positive or negative. At interactional levels, group, team, and microsystem, the potential long-term consequences could include the development of a culture where deliberation and collaboration are regarded as guiding principles, where patients are coached to assess the value of interventions, to trade-off benefits versus harms, and assess their burdens-in short, to new social norms in the clinical workplace. At organizational levels, consistent shared decision-making might boost patient experience evaluations and lead to fewer complaints and legal challenges. In the long-term, shared decision making might lead to changes in resource utilization, perhaps to reductions in cost, and to modification of workforce composition. Despite the gradual shift to value-based payment, some organizations, motivated by continued income derived from achieving high volumes of procedures and contacts, will see this as a negative consequence. CONCLUSION: We suggest that a broader conceptualization and measurement of shared decision-making would provide a more substantive evidence base to guide implementation. We outline a framework which illustrates a hypothesized set of proximal, distal, and distant consequences that might occur if collaboration and deliberation could be achieved routinely, proposing that well-informed preference-based patient decisions might lead to safer, more cost effective healthcare, which in turn might result in reduced utilization rates and improved health outcomes. PMID- 27502769 TI - The Post-Anaesthesia N-acetylcysteine Cognitive Evaluation (PANACEA) trial: study protocol for a randomised controlled trial. AB - BACKGROUND: Some degree of cognitive decline after surgery occurs in as many as one quarter of elderly surgical patients, and this decline is associated with increased morbidity and mortality. Cognition may be affected across a range of domains, including memory, psychomotor skills, and executive function. Whilst the exact mechanisms of cognitive change after surgery are not precisely known, oxidative stress and subsequent neuroinflammation have been implicated. N acetylcysteine (NAC) acts via multiple interrelated mechanisms to influence oxidative homeostasis, neuronal transmission, and inflammation. NAC has been shown to reduce oxidative stress and inflammation in both human and animal models. There is clinical evidence to suggest that NAC may be beneficial in preventing the cognitive decline associated with both acute physiological insults and dementia-related disorders. To date, no trials have examined perioperative NAC as a potential moderator of postoperative cognitive changes in the noncardiac surgery setting. METHODS AND DESIGN: This is a single-centre, randomised, double blind, placebo-controlled clinical trial, with a between-group, repeated measures, longitudinal design. The study will recruit 370 noncardiac surgical patients at the University Hospital Geelong, aged 60 years or older. Participants are randomly assigned to receive either NAC or placebo (1:1 ratio), and groups are stratified by age and surgery type. Participants undergo a series of neuropsychological tests prior to surgery, 7 days, 3 months, and 12 months post surgery. It is hypothesised that the perioperative administration of NAC will reduce the degree of postoperative cognitive changes at early and long-term follow-up, as measured by changes on individual measures of the neurocognitive battery, when compared with placebo. Serum samples are taken on the day of surgery and on day 2 post surgery to quantitate any changes in levels of biomarkers of inflammation and oxidative stress. DISCUSSION: The PANACEA trial aims to examine the potential efficacy of perioperative NAC to reduce the severity of postoperative cognitive dysfunction in an elderly, noncardiac surgery population. This is an entirely novel approach to the prevention of postoperative cognitive dysfunction and will have high impact and translatable outcomes if NAC is found to be beneficial. TRIAL REGISTRATION: The PANACEA trial has been registered with the Therapeutic Goods Administration, and the Australian New Zealand Clinical Trials Registry: ACTRN12614000411640 ; registered on 15 April 2014. PMID- 27502771 TI - Metabolic host responses to malarial infection during the intraerythrocytic developmental cycle. AB - BACKGROUND: The malarial parasite Plasmodium falciparum undergoes a complex life cycle, including an intraerythrocytic developmental cycle, during which it is metabolically dependent on the infected human red blood cell (RBC). To describe whole cell metabolic activity within both P. falciparum and RBCs during the asexual reproduction phase of the intraerythrocytic developmental cycle, we developed an integrated host-parasite metabolic modeling framework driven by time dependent gene expression data. RESULTS: We validated the model by reproducing the experimentally determined 1) stage-specific production of biomass components and their precursors in the parasite and 2) metabolite concentration changes in the medium of P. falciparum-infected RBC cultures. The model allowed us to explore time- and strain-dependent P. falciparum metabolism and hypothesize how host cell metabolism alters in response to malarial infection. Specifically, the metabolic analysis showed that uninfected RBCs that coexist with infected cells in the same culture decrease their production of 2,3-bisphosphoglycerate, an oxygen-carrying regulator, reducing the ability of hemoglobin in these cells to release oxygen. Furthermore, in response to parasite-induced oxidative stress, infected RBCs downgraded their glycolytic flux by using the pentose phosphate pathway and secreting ribulose-5-phosphate. This mechanism links individually observed experimental phenomena, such as glycolytic inhibition and ribulose-5 phosphate secretion, to the oxidative stress response. CONCLUSIONS: Although the metabolic model does not incorporate regulatory mechanisms per se, alterations in gene expression levels caused by regulatory mechanisms are manifested in the model as altered metabolic states. This provides the model the capability to capture complex multicellular host-pathogen metabolic interactions of the infected RBC culture. The system-level analysis revealed complex relationships such as how the parasite can reduce oxygen release in uninfected cells in the presence of infected RBCs as well as the role of different metabolic pathways involved in the oxidative stress response of infected RBCs. PMID- 27502772 TI - Stimulation and quantification of Babesia divergens gametocytogenesis. AB - BACKGROUND: Babesia divergens is the most common blood parasite in Europe causing babesiosis, a tick-borne malaria-like disease. Despite an increasing focus on B. divergens, especially regarding veterinary and human medicine, the sexual development of Babesia is poorly understood. Development of Babesia sexual stages in the host blood (gametocytes) plays a decisive role in parasite acquisition by the tick vector. However, the exact mechanism of gametocytogenesis is still unexplained. METHODS: Babesia divergens gametocytes are characterized by expression of bdccp1, bdccp2 and bdccp3 genes. Using previously described sequences of bdccp1, bdccp2 and bdccp3, we have established a quantitative real time PCR (qRT-PCR) assay for detection and assessment of the efficiency of B. divergens gametocytes production in bovine blood. We analysed fluctuations in expression of bdccp genes during cultivation in vitro, as well as in cultures treated with different drugs and stimuli. RESULTS: We demonstrated that all B. divergens clonal lines tested, originally derived from naturally infected cows, exhibited sexual stages. Furthermore, sexual commitment was stimulated during continuous growth of the cultures, by addition of specific stress-inducing drugs or by alternating cultivation conditions. Expression of bdccp genes was greatly reduced or even lost after long-term cultivation, suggesting possible problems in the artificial infections of ticks in feeding assays in vitro. CONCLUSIONS: Our research provides insight into sexual development of B. divergens and may facilitate the development of transmission models in vitro, enabling a more detailed understanding of Babesia-tick interactions. PMID- 27502773 TI - Using complexity theory to develop a student-directed interprofessional learning activity for 1220 healthcare students. AB - BACKGROUND: More and better interprofessional practice is predicated to be necessary to deliver good care to the patients of the future. However, universities struggle to create authentic learning activities that enable students to experience the dynamic interprofessional interactions common in healthcare and that can accommodate large interprofessional student cohorts. We investigated a large-scale mandatory interprofessional learning (IPL) activity for health professional students designed to promote social learning. METHODS: A mixed methods research approach determined feasibility, acceptability and the extent to which student IPL outcomes were met. We developed an IPL activity founded in complexity theory to prepare students for future practice by engaging them in a self-directed (self-organised) learning activity with a diverse team, whose assessable products would be emergent creations. Complicated but authentic clinical cases (n = 12) were developed to challenge student teams (n = 5 or 6). Assessment consisted of a written management plan (academically marked) and a five-minute video (peer marked) designed to assess creative collaboration as well as provide evidence of integrated collective knowledge; the cohesive patient centred management plan. RESULTS: All students (including the disciplines of diagnostic radiology, exercise physiology, medicine, nursing, occupational therapy, pharmacy, physiotherapy and speech pathology), completed all tasks successfully. Of the 26 % of students who completed the evaluation survey, 70 % agreed or strongly agreed that the IPL activity was worthwhile, and 87 % agreed or strongly agreed that their case study was relevant. Thematic analysis found overarching themes of engagement and collaboration-in-action suggesting that the IPL activity enabled students to achieve the intended learning objectives. Students recognised the contribution of others and described negotiation, collaboration and creation of new collective knowledge after working together on the complicated patient case studies. The novel video assessment was challenging to many students and contextual issues limited engagement for some disciplines. CONCLUSIONS: We demonstrated the feasibility and acceptability of a large scale IPL activity where design of cases, format and assessment tasks was founded in complexity theory. This theoretically based design enabled students to achieve complex IPL outcomes relevant to future practice. Future research could establish the psychometric properties of assessments of student performance in large-scale IPL events. PMID- 27502774 TI - Pericardial effusion and cardiac tamponade after ventriculoperitoneal shunt placement: a case report. AB - Insertion of a ventriculoperitoneal shunt is a common neurosurgical procedure in both adult and paediatric patients. It is one of the most important treatments in cases of hydrocephalus; however, there is a wide range of complications: the most common complication being a shunt infection, and examples of rare complications are shunt migrations and cardiac tamponade. Several reports of distal ventriculoperitoneal shunt migration in different sites, including chest, right ventricle, pulmonary artery, bowel and scrotum were published. But pericardial effusion with cardiac tamponade and its relationship to distal ventriculoperitoneal shunt migration into the pericardial sac has never been reported. PMID- 27502775 TI - Maximum surgical resection and adjuvant intensity-modulated radiotherapy with simultaneous integrated boost for skull base chordoma. AB - BACKGROUND: Local recurrence is common after surgical resection of clivus chordoma. We report the results of maximum surgical resection followed by intensity-modulated radiotherapy with simultaneous integrated boost (IMRT-SIB). METHODS: We reviewed 14 consecutive clivus chordoma cases undergoing postoperative IMRT-SIB using the institutional protocol between 2005 and 2013. Total and near-total resections were achieved in 11 patients (78.6 %), partial in 2 patients (14.3 %), and 1 patient (7.1 %) received RT for recurrent tumor after total resection. Gross residual or the high-risk area defined the planning target volume (PTV)1; PTV2 was the postoperative tumor bed plus a 3-5-mm margin, and PTV3 was PTV2 plus a 5-10 mm margin. A moderate hypofractionation schedule was used: doses to PTV1, PTV2 and PTV3 were 3.9 Gy, 3.15 Gy and 2.8 Gy through 15 fractions for the first two patients, and the rest received 2.5 Gy, 2.2 Gy and 1.8 Gy through 25 fractions. The biologically equivalent dose in 2-Gy fractions (EQD2) was 65-68 Gy for PTV1, 52-56 Gy for PTV2, and 44.3-44.8 Gy for PTV3. RESULTS: Median follow-up was 41 months. Eight patients were free of disease for median 42.5 months (range 23-91 months), four patients had stable disease for median 60.5 months (range 39-113 months), and 1 patient showed partial response for 38 months after RT. Local progression was seen in one patient who received EQD2 67.8 Gy after partial resection. Estimated 5-year progression-free and overall survival rates were 92.9 %. Surgery improved the neurologic deficit in six patients, and IMRT-SIB was well tolerated without lasting toxicity. CONCLUSION: Our experience suggests that maximum resection and high-dose IMRT-SIB can achieve local control without significant morbidities. PMID- 27502776 TI - Evaluation of a demand-creation intervention for couples' HIV testing services among married or cohabiting individuals in Rakai, Uganda: a cluster-randomized intervention trial. AB - BACKGROUND: Uptake of couples' HIV counseling and testing (couples' HCT) services remains largely low in most settings. We report the effect of a demand-creation intervention trial on couples' HCT uptake among married or cohabiting individuals who had never received couples' HCT. METHODS: This was a cluster-randomized intervention trial implemented in three study regions with differing HIV prevalence levels (range: 9-43 %) in Rakai district, southwestern Uganda, between February and September 2014. We randomly assigned six clusters (1:1) to receive the intervention or serve as the comparison arm using computer-generated random numbers. In the intervention clusters, individuals attended small group, couple and male-focused interactive sessions, reinforced with testimonies from 'expert couples', and received invitation coupons to test together with their partners at designated health facilities. In the comparison clusters, participants attended general adult health education sessions but received no invitation coupons. The primary outcome was couples' HCT uptake, measured 12 months post-baseline. Baseline data were collected between November 2013 and February 2014 while follow up data were collected between March and April 2015. We conducted intention-to treat analysis using a mixed effects Poisson regression model to assess for differences in couples' HCT uptake between the intervention and comparison clusters. Data analysis was conducted using STATA statistical software, version 14.1. RESULTS: Of 2135 married or cohabiting individuals interviewed at baseline, 42 % (n = 846) had ever received couples' HCT. Of those who had never received couples' HCT (n = 1,174), 697 were interviewed in the intervention clusters while 477 were interviewed in the comparison clusters. 73.6 % (n = 513) of those interviewed in the intervention and 82.6 % (n = 394) of those interviewed in the comparison cluster were interviewed at follow-up. Of those interviewed, 72.3 % (n = 371) in the intervention and 65.2 % (n = 257) in the comparison clusters received HCT. Couples' HCT uptake was higher in the intervention than in the comparison clusters (20.3 % versus 13.7 %; adjusted prevalence ratio (aPR) = 1.43, 95 % CI: 1.02, 2.01, P = 0.04). CONCLUSION: Our findings show that a small group, couple and male-focused, demand-creation intervention reinforced with testimonies from 'expert couples', improved uptake of couples' HCT in this rural setting. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02492061 . Date of registration: June 14, 2015. PMID- 27502777 TI - Heart involvement in systemic lupus erythematosus: a systemic review and meta analysis. AB - Cardiovascular diseases are one of the most important causes of the disability and mortality in patients with systemic lupus erythematosus (SLE). The present study examined the cardiac abnormalities in patients with SLE by echocardiography. Case-control studies were obtained by searching PubMed MEDLINE, Embase, and MD Consult. Systemic review and meta-analysis were performed to assess the cardiac abnormalities based on the changes in the echocardiography in patients with SLE. Twenty-two studies including 1117 SLE patients and 901 healthy controls were enrolled into this study. We found that patients with SLE developed the pericardial effusion (odds ratio (OR) (95 % confidence interval (CI)) 30.52 (9.70-96.02); p < 0.00001) and the combined valvular alterations (OR (95 %CI) 11.08 (6.98-17.59); p < 0.00001). In addition, SLE patients also exhibited an increase in the left atrial diameter (LAD) (WMD-weighted mean difference (95 %CI) 0.18 (0.06-0.29); p = 0.002), the left ventricular internal diameter in diastole (LVDd) (WMD (95 %CI) 0.07 (0.02-0.12); p = 0.01), and the left ventricular mass index (LVMI) (WMD (95 %CI) 5.69 (2.69-8.69); p = 0.0002). In contrast, the left ventricular systolic function (WMD (95 %CI) -1.22 (-1.69 to -0.75); p < 0.00001) and diastolic function including E/A ratio and E/E' ratio (WMD (95 % CI) -0.13 ( 0.24 to -0.01); p = 0.04; WMD (95 % CI) 1.71 (0.43 to 2.99); p = 0.009) were decreased in SLE patients. Patients with SLE are associated with significant alterations in cardiac structure and function as demonstrated by echocardiography. Data from this study suggest that echocardiographic assessment should be considered as a part of routine examinations for SLE patients clinically. PMID- 27502778 TI - Aortic aneurysm associated with rheumatoid arthritis: a population-based cross sectional study. AB - There is substantial evidence that aortic aneurysm (AA) may be a manifestation of several systemic rheumatic disorders. However, only several studies have assessed the association between rheumatoid arthritis (RA) and AA. The aim of this study was to evaluate the incidence of AA in RA patients in a case-control study. A retrospective case-control study was performed utilizing the database of Clalit Health Services (CHS), a large healthcare provider organization in Israel. Data available from the CHS database included age, sex, socioeconomic status (SES), and diagnoses of chronic diseases, including AA. Patients over the age of 20 years who were diagnosed with RA ("cases") were compared with a sample of age- and gender-matched enrollees without RA ("controls") regarding the prevalence of AA. Chi-square and t tests were used for univariate analysis, and a logistic regression model was used for multivariate analysis. The study included 11,782 RA patients and 57,973 age- and gender-matched controls. The proportion of AA was significantly higher in RA patients (0.72 %) compared to the control group 0.49 % (odds ratio (OR) 1.48, 95 %; confidence interval (CI) 1.15-1.88; p = 0.002). A multivariate analysis that evaluated covariates associated with AA revealed an independent association of AA and RA after adjustment for different factors including age, gender, SES, and smoking status (OR 1.406, 95 %; CI 1.094-1.789; p = 0.006). Our study has demonstrated that AA is more prevalent in patients with RA in comparison with general population. Future large randomized studies are important to identify cardiovascular- and disease-related risk factors for AA formation in RA patients. PMID- 27502779 TI - Hormone receptor status of contralateral breast cancers: analysis of data from the US SEER population-based registries. AB - BACKGROUND: Women diagnosed with breast cancer display higher propensity to develop second primary cancer in the contralateral breast (CBC). Identification of patients with increased risk of CBC and understanding relationships between hormone receptor (HR) statuses of the first and second breast cancers is desirable for endocrine-based prevention strategies. METHODS: Using 1992-2012 data from 13 SEER registries, the risk of developing CBC was determined as ratio of observed and expected second breast cancers (SIR). Association between HR statuses was examined by exploratory data analysis and multivariable logistic regression. RESULTS: Women with ER-positive and ER-negative breast cancers have increased risk of developing CBC with SIR values 2.09 (CI 95 = 1.97-2.21) and 2.40 (CI 95 = 2.18-2.63), respectively. ER statuses of the CBC are moderately positively associated. In metachronous CBC, most cases with ER-positive first cancers had ER-positive second breast cancers (81.6 %; CI 95 = 80.2-82.9 %); however, considerable proportion of cases with ER-negative first cancers had ER positive second cancers (48.8 %; CI 95 = 46.2-51.4 %). CONCLUSIONS: Some women with ER-negative breast cancers may benefit from endocrine-based prevention of ER positive CBC. PMID- 27502780 TI - Erratum: Revealing the mechanism of passive transport in lipid bilayers via phonon-mediated nanometre-scale density fluctuations. PMID- 27502781 TI - Operationalising resilience in longitudinal studies: a systematic review of methodological approaches. AB - Over the life course, we are invariably faced with some form of adversity. The process of positively adapting to adverse events is known as 'resilience'. Despite the acknowledgement of 2 common components of resilience, that is, adversity and positive adaptation, no consensus operational definition has been agreed. Resilience operationalisations have been reviewed in a cross-sectional context; however, a review of longitudinal methods of operationalising resilience has not been conducted. The present study conducts a systematic review across Scopus and Web of Science capturing studies of ageing that posited operational definitions of resilience in longitudinal studies of ageing. Thirty-six studies met inclusion criteria. Non-acute events, for example, cancer, were the most common form of adversity identified and psychological components, for example, the absence of depression, the most common forms of positive adaptation. Of the included studies, 4 used psychometrically driven methods, that is, repeated administration of established resilience metrics, 9 used definition-driven methods, that is, a priori establishment of resilience components and criteria, and 23 used data-driven methods, that is, techniques that identify resilient individuals using latent variable models. Acknowledging the strengths and limitations of each operationalisation is integral to the appropriate application of these methods to life course and longitudinal resilience research. PMID- 27502782 TI - Periodontitis is an independent risk indicator for atherosclerotic cardiovascular diseases among 60 174 participants in a large dental school in the Netherlands. AB - BACKGROUND: The association between periodontitis and atherosclerotic cardiovascular diseases (ACVD) has been established in some modestly sized studies (<10 000). Rarely, however, periodontitis has been studied directly; often tooth loss or self-reported periodontitis has been used as a proxy measure for periodontitis. Our aim is to investigate the adjusted association between periodontitis and ACVD among all individuals registered in a large dental school in the Netherlands (Academic Centre for Dentistry Amsterdam (ACTA)). METHODS: Anonymised data were extracted from the electronic health records for all registered patients aged >35 years (period 1998-2013). A participant was recorded as having periodontitis based on diagnostic and treatment codes. Any affirmative answer for cerebrovascular accidents, angina pectoris and/or myocardial infarction labelled a participant as having ACVD. Other risk factors for ACVD, notably age, sex, smoking, diabetes, hypertension, hypercholesterolaemia and social economic status, were also extracted. Logistic regression analyses were used to evaluate the adjusted associations between periodontitis and ACVD. RESULTS: 60 174 individuals were identified; 4.7% of the periodontitis participants (455/9730) and 1.9% of the non-periodontitis participants (962/50 444) reported ACVD; periodontitis showed a significant association with ACVD (OR 2.52; 95% CI 2.3 to 2.8). After adjustment for the confounders, periodontitis remained independently associated with ACVD (OR 1.59; 95% CI 1.39 to 1.81). With subsequent stratification for age and sex, periodontitis remained independently associated with ACVD. CONCLUSIONS: This cross-sectional analysis of a large cohort in the Netherlands of 60 174 participants shows the independent association of periodontitis with ACVD. PMID- 27502783 TI - Multi-site phospho-regulation of proneural transcription factors controls proliferation versus differentiation in development and reprogramming. AB - During development of the nervous system, it is essential to co-ordinate the processes of proliferation and differentiation. Basic helix-loop-helix transcription factors play a central role in controlling neuronal differentiation and maturation as well as being components of the combinatorial code that determines neuronal identity. We have recently shown that the ability of the proneural proteins Ngn2 and Ascl1 to drive neuronal differentiation is inhibited by cyclin dependent kinase-mediated multi-site phosphorylation. This limits downstream target promoter dwell time, thus demonstrating a direct mechanistic regulatory link between the cell cycle and differentiation machinery.Proneural proteins are key components of transcription factor cocktails that can bring about the direct reprogramming of human fibroblasts into neurons. Building on our observations demonstrating that phospho-mutant proneural proteins show an enhanced ability to drive neuronal differentiation in vivo, we see that replacing wild-type with phospho-mutant proneural proteins in fibroblast reprogramming cocktails significantly enhances the axonal outgrowth, branching and electrophysiological maturity of the neurons generated. A model is presented here that can explain the enhanced ability of dephosphorylated proneural proteins to drive neuronal differentiation, and some unanswered questions in this emerging area are highlighted. PMID- 27502784 TI - Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma. AB - The average survival time for patients with recurrent glioblastoma is between 5 and 9 months. Phase I and II trials have shown a modest survival benefit with combination temozolomide and other chemotherapeutics. We conducted a phase I trial of dose-escalating temozolomide with bevacizumab and the proteasome inhibitor bortezomib for patients with recurrent disease. Three groups of three patients were scheduled to receive daily doses of temozolomide at 25, 50, and 75 mg/m2. Fixed doses of bortezomib and bevacizumab were given at standard intervals. Patients were monitored for dose-limiting toxicities (DLT) to determine the maximum-tolerated dose (MTD) of temozolomide with this regimen. No DLT were seen in the first two groups (25 and 50 mg/m2 temozolomide). One patient in the 75 mg/m2 group experienced a grade 4 elevation of ALT and three more patients were accrued for a total of six patients at that dose level. No other DLT occurred, thus making 75 mg/m2 the MTD. Progression-free survival was 3.27 months for all patients and mean overall survival was 20.75 months. The MTD of temozolomide was 75 mg/m2 in combination with bevacizumab and bortezomib for recurrent glioblastoma. Only one patient experienced a severe (Grade 4) elevation of ALT. This study will provide the framework for further studies to elicit effectiveness and better determine a safety profile for this drug combination. PMID- 27502785 TI - Postoperative surveillance of pediatric cerebellar pilocytic astrocytoma. AB - The purpose of this study was to identify the optimal frequency and duration of magnetic resonance imaging follow-up in children who had gross totally resected cerebellar pilocytic astrocytomas (CPAs). Our hypothesis was that following two MR examinations, separated by at least 3 months, showing no evidence of tumor, gross totally resected CPAs did not recur and no further imaging follow-up was necessary. Retrospective review of Neuro-Oncology database from 1/2000 to 7/2013 yielded 53 patients with CPAs that had preoperative imaging and >2 years post operative imaging follow-up available. Pilocytic astrocytomas with brainstem involvement and patients with neurofibromatosis type I were excluded. Preoperative tumor volumes were calculated. The dates and reports of the examinations were tabulated. The median number of follow-up examinations was 9 over a median follow-up time of 6.05 years (2.07-12.28 years). Two consecutive MR examinations over at least a 3 month span demonstrated the smallest negative likelihood ratio of future recurrence (0.15). There was no association of recurrence with preoperative tumor volume. Among the 35 patients with gross total resection of their tumor and greater than two negative follow-up examinations, one recurrence (2.9 %) was identified, occurring 6.4 years after initial resection. Gross totally resected pediatric CPAs can recur, but this is exceedingly rare. Frequent surveillance (every 3-6 months) is suggested in patients with CPAs until absence of tumor is concluded on imaging and documented on two consecutive studies spaced at least 3 months apart. The likelihood of recurrence thereafter is low. PMID- 27502786 TI - Use of Antiepileptic Drugs During Pregnancy: Evolving Concepts. AB - Although prenatal exposure to antiepileptic drugs (AEDs) is known to impart relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. As the number of AED prescriptions has dramatically increased in reproductive-aged women with a variety of neuropsychiatric indications, the evolving concepts learned from studies in women with epilepsy can be applied to a much larger group of pregnant women to improve child outcomes while maintaining maternal disease control. In addition to careful selection of the type of medication, the amount of fetal exposure at conception and in the first trimester probably matters across all AEDs. Some AED polytherapy regimens are not associated with a higher risk of malformations, although other outcomes have not yet been formally studied. The individual woman's drug target concentration should be established preconception and maintained during pregnancy, to prevent seizure worsening. Substantial pharmacokinetic changes occur with many of the medications during pregnancy and postpartum, and interindividual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine fetal growth, obstetric complications, and neonatal complications. Breastfeeding can provide additional neurodevelopmental benefit and should be an option for women on AEDs. Knowledge of these key principles enhances our ability to make treatment recommendations with resultant improved maternal and child outcomes. Additional prospective studies are needed to further define the risk benefit ratio across a variety of medications, dosing strategies, and neuropsychiatric disorders. PMID- 27502789 TI - Posterior subtenon injection of triamcinolone acetonide for pseudophakic cystoid macular oedema. PMID- 27502787 TI - Modeling central metabolism and energy biosynthesis across microbial life. AB - BACKGROUND: Automatically generated bacterial metabolic models, and even some curated models, lack accuracy in predicting energy yields due to poor representation of key pathways in energy biosynthesis and the electron transport chain (ETC). Further compounding the problem, complex interlinking pathways in genome-scale metabolic models, and the need for extensive gapfilling to support complex biomass reactions, often results in predicting unrealistic yields or unrealistic physiological flux profiles. RESULTS: To overcome this challenge, we developed methods and tools ( http://coremodels.mcs.anl.gov ) to build high quality core metabolic models (CMM) representing accurate energy biosynthesis based on a well studied, phylogenetically diverse set of model organisms. We compare these models to explore the variability of core pathways across all microbial life, and by analyzing the ability of our core models to synthesize ATP and essential biomass precursors, we evaluate the extent to which the core metabolic pathways and functional ETCs are known for all microbes. 6,600 (80 %) of our models were found to have some type of aerobic ETC, whereas 5,100 (62 %) have an anaerobic ETC, and 1,279 (15 %) do not have any ETC. Using our manually curated ETC and energy biosynthesis pathways with no gapfilling at all, we predict accurate ATP yields for nearly 5586 (70 %) of the models under aerobic and anaerobic growth conditions. This study revealed gaps in our knowledge of the central pathways that result in 2,495 (30 %) CMMs being unable to produce ATP under any of the tested conditions. We then established a methodology for the systematic identification and correction of inconsistent annotations using core metabolic models coupled with phylogenetic analysis. CONCLUSIONS: We predict accurate energy yields based on our improved annotations in energy biosynthesis pathways and the implementation of diverse ETC reactions across the microbial tree of life. We highlighted missing annotations that were essential to energy biosynthesis in our models. We examine the diversity of these pathways across all microbial life and enable the scientific community to explore the analyses generated from this large-scale analysis of over 8000 microbial genomes. PMID- 27502788 TI - Inadequate pre-operative glycaemic control in patients with diabetes mellitus adversely influences functional recovery after total knee arthroplasty : Patients with impaired glycaemic control exhibit poorer functional outcomes at 1-year post arthroplasty. AB - PURPOSE: Whilst inadequate glycaemic control is associated with an increase in perioperative complications following total knee arthroplasty, the impact of glycaemic control in this at-risk patient group remains ill-defined. Identification of at-risk patients would allow targeted pre-operative glycaemic control intervention. METHODS: One hundred consecutive patients with a diagnosis of diabetes mellitus and one hundred age, sex and BMI matched patients without diabetes undergoing total knee arthroplasty in a single institution were analysed between 2008 and 2013. Inadequate glycaemic control was defined as having an HbA1c of greater than 64 mmol/mol (8.0 % NGSP) measured within the 3 months before surgery. Patient demographics, diabetes management and complications of diabetes were recorded and used as explanatory variables to deliver a generalised linear model. This allows for relationships to be defined between change in patient-reported function (SF-36, WOMAC) and these explanatory variables. RESULTS: The patient group with concomitant diabetes exhibited smaller improvements in WOMAC and SF-36 physical component summary at 1 year after knee arthroplasty. This effect was most pronounced in the subset of patients with inadequate glycaemic control recorded in the early pre-operative period. CONCLUSION: Patients with diabetes, particularly those with inadequate glycaemic control, exhibit less improvement at 1 year following knee arthroplasty than patients without diabetes mellitus. Clinical focus on modulating this factor in this at-risk group is warranted. LEVEL OF EVIDENCE: III. PMID- 27502790 TI - Desmoid fibromatosis: MRI features of response to systemic therapy. AB - OBJECTIVE: Imaging criteria for measuring the response of desmoid fibromatosis to systemic therapy are not well established. We evaluated a series of patients with desmoids who underwent systemic therapy to document magnetic resonance imaging (MRI) features associated with a positive clinical response. MATERIALS AND METHODS: This Institutional Review Board-approved retrospective study included 23 patients (mean age 40.5) with 29 extra-abdominal tumors. Therapeutic regimens included cytotoxic chemotherapy (n = 19), targeted therapy (n = 3), and nonsteroid anti-inflammatory drugs (NSAIDS; n = 1). Clinical effects were categorized as progressive disease, stable, or partial response. Maximum tumor dimension (Dmax), approximate tumor volume (VTumor), and quantitative tumor T2 hyperintensity and contrast enhancement (relative to muscle) for pre- and post treatment MRIs were compared. RESULTS: Three lesions progressed, 5 lesions were stable, whereas 21 showed a clinical response. Dmax decreased more in responders (mean -11.0 %) than in stable/progressive lesions (mean -3.6 and 0 % respectively, p = 0.28, ANOVA); by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 27 out of 29 lesions were "stable," including the 3 progressive lesions. In responders, VTumor change averaged -29.4 %, but -19.2 % and +32.5 % in stable and progressive lesions respectively (p = 0.002, ANOVA); by 3D criteria 14 out of 29 lesions showed a partial response. T2 hyperintensity decreased by 50 54 % in partial response/stable disease, but only by 10 % in progressive lesions (p = 0.049, t test). Changes in contrast enhancement ranged from -23 % to 0 %, but were not statistically significant among response groups (p = 0.37). Change in T2 hyperintensity showed a positive correlation with volumetric change (r = 0.40). CONCLUSION: Decreases in volume and T2 hyperintensity reflect the positive response of desmoid fibromatosis to systemic therapy; RECIST 1.1 criteria are not sensitive to clinically determined tumor response. PMID- 27502792 TI - Landmarks of the Frankfort horizontal plane : Reliability in a three-dimensional Cartesian coordinate system. AB - OBJECTIVES: The goal was to investigate whether the three-dimensional (3D) reliability of the landmarks defining the Frankfort horizontal plane (FH) can be enhanced by reducing variance with the help of nearby anatomical structures. METHODS: Twenty multislice computed tomography (MSCT) datasets of evidently symmetrical patients (11 female and 9 male patients, 6.1-16 years old) were selected from 695 datasets archived at our department. In the 3D reconstructions, we located the anthropometric landmarks orbitale and porion, then these were modified with the help of frontomalare temporale, radiculare and the most anterior border of the left and right external acoustic pore. The resultant orbitale* and porion* reference points for the Frankfort horizontal plane were then compared to the original landmarks. Statistical analysis was performed. RESULTS: The superior reliability in the sagittal y-axis and in the transversal x axis of the new reference points was confirmed. Based on the covariance matrices, the mean maximum standard deviation (square root of the maximum eigenvalue) in the direction of maximum variance was reduced from 0.77/0.94 mm to 0.47/0.48 mm for left/right orbitale, and similar reductions from 0.85/0.92 mm to 0.29/0.30 mm were noted for left/right porion (p < 0.001 for all four points). Vertical reliability did not improve further. CONCLUSIONS: The modifications significantly reduced the variance of the orbitale and porion landmarks, thus, clearly increasing the three-dimensional reliability. Hence these optimized reference points are better suited to construct the FH, which arguably is an important spatial reference plane in orthodontics. PMID- 27502791 TI - Growth, metabolic markers, and cognition in 8-year old children born prematurely, follow-up of a randomized controlled trial with essential fatty acids. AB - The study is a follow-up of a randomized, double-blinded, placebo-controlled trial of supplementation with docosahexaenoic acid (DHA) and arachidonic acid (AA) to 129 very low birth weight (VLBW; birth weight <1500 g) infants fed human milk. The main hypothesis was that supplementation would affect growth, metabolic markers, and cognitive function. The secondary aim was to describe predictors of metabolic markers and cognitive status at follow-up. Ninety-eight children met for 8-year follow-up with anthropometric measures, blood biomarkers, and cognitive testing. The intervention group had significantly lower insulin-like growth factor-1 (IGF-1) at 8 years, whereas no differences in growth or intelligence quotient (IQ) were found. For the total cohort, weight gain during first year of life was neither associated with BMI, metabolic markers, nor IQ at follow-up. Blood DHA at 8 years was positively associated with IQ. CONCLUSIONS: The study is the first long-term follow-up of a randomized controlled trial with essential fatty acids investigating growth, metabolic factors, and IQ. IGF-1 levels were significantly lower in the intervention group at 8 years. First-year growth was not associated with BMI, metabolic markers, or IQ at follow-up. Current DHA status was a significant predictor of higher IQ at follow-up. WHAT IS KNOWN: * Preterm children have increased risk of lower intelligence quotient (IQ), reduced growth, and abnormal metabolic status. * Early intake of docosahexaenoic acid (DHA) and arachidonic acid (AA), as well as early growth pattern, may influence both IQ and metabolic status. What is New: * Early intervention with DHA and AA led to reduced insulin-like growth factor-1 in blood at 8 years of age. * Weight gain during first year of life was neither associated with impaired metabolic markers nor improved IQ at follow-up. * Current DHA status was a significant predictor of higher IQ at 8 years, also when maternal education and birth weight were included in the model. PMID- 27502793 TI - Phototherapy for Pityriasis Lichenoides in the Pediatric Population: A Review of the Published Literature. AB - BACKGROUND: Pityriasis lichenoides (PL) is a dermatologic disorder that manifests in either the acute (pityriasis lichenoides et varioliformis acuta) or the chronic form (pityriasis lichenoides chronica, also known as parapsoriasis chronica). Traditional first-line therapy consists of corticosteroids or antibiotics; however, these treatments are often accompanied with multiple side effects and may be ineffective. OBJECTIVE: The goal of this study was to review the use of phototherapy for treating PL in the pediatric population. MATERIALS AND METHODS: We performed a systematic review of the literature in the National Library of Medicine's PubMed database and the SCOPUS database discussing phototherapy for treatment of PL in the pediatric population. The following search terms were used: 'pityriasis lichenoides', 'pityriasis lichenoides chronica', 'pityriasis lichenoides et varioliformis acuta', and 'febrile ulceronecrotic Mucha-Habermann disease'. RESULTS: The systematic search and screening of articles resulted in 14 articles including a total of 64 patients with PL treated with phototherapy. Three different modalities were utilized, with five studies using broadband ultraviolet B (BB-UVB) radiation, nine studies utilizing narrowband UVB (NB-UVB), and two studies employing psoralen with ultraviolet A (PUVA) therapy. Overall, the use of BB-UVB had an initial clearance rate of 89.6 % with 23.1 % recurrence, whereas NB-UVB cleared 73 % of the lesions with no recurrence, and PUVA therapy initially cleared 83 % of the lesions with 60 % recurrence. The side-effect profiles were similar and revealed limited toxicity. CONCLUSION: Phototherapy shows promising results and a favorable side effect profile in the treatment of PL. Ultimately, large randomized controlled trials are needed to determine optimal treatments. PMID- 27502794 TI - Relief from anxiety using complementary therapies in the perioperative period: A principle-based concept analysis. AB - AIMS AND OBJECTIVES: To analyze and clarify the concept of providing relief from anxiety using complementary therapies in the perioperative period utilizing the epistemological, pragmatic, linguistic and logical principles of a principle based concept analysis to examine the state of the science. BACKGROUND: The majority of patients scheduled for surgery experience anxiety in the perioperative period. Anxiety has the potential to limit a patient's ability to participate in his or her care throughout their hospitalization. Although medications are the conventional medical treatment for anxiety in the perioperative period, the addition of a complementary therapy could be an effective holistic approach to providing relief from anxiety. DESIGN: Principle based concept analysis. METHODS: In 2015, strategic literature searches of CINHAL and PUBMED using keywords were performed. Fifty-six full text articles were assessed for eligibility. RESULTS: Twelve studies were used in the final analysis to clarify the concept of relief from anxiety using complementary therapies in the perioperative period. CONCLUSION: This analysis has clarified the maturity and boundaries, within the four principles of a principle-based concept analysis, of the concept of relief from anxiety using complementary therapies in the perioperative period. A greater understanding of relief from anxiety using complimentary therapies in the perioperative period as an adjunct to conventional medicine will allow perioperative nurses and anesthesia providers to modify and specify the plan of care for their surgical patients. The use of complementary therapies for relief in the perioperative period appears to be an area of promising research and treatment for patients, families and providers. PMID- 27502795 TI - Effects of Muslims praying (Salat) on EEG gamma activity. AB - This study investigates the difference of mean gamma EEG power between actual and mimic Salat practices in twenty healthy Muslim subjects. In the actual Salat practice, the participants were asked to recite and performing the physical steps in all four stages of Salat; whereas in the mimic Salat practice, they were instructed to perform only the physical steps without recitation. The gamma power during actual Salat was statistically higher than during mimic Salat in the frontal and parietal regions in all stages. In the actual Salat practice, the left hemisphere exhibited significantly higher mean gamma power in all cerebral regions and all stages, except the central-parietal region in the sitting position, and the frontal area in the bowing position. Increased gamma power during Salat, possibly related to an increase in cognitive and attentional processing, supports the concept of Salat as a focus attention meditation. PMID- 27502796 TI - Clinical nurses' perceptions of the opportunities for using complementary therapies in Iranian clinical settings: A qualitative study. AB - Nurses need to use complementary therapies in their clinical practice in order to fulfill community's needs. There are potential opportunities for using complementary therapies in different clinical settings. This study was done to explore nurses' perceptions of these opportunities in Iranian clinical settings. In this qualitative study, sampling was done purposively and ended after reaching data saturation. Semi-structured interviews were done with fifteen nurses. The data were analyzed via the conventional content analysis approach. The participants' perceptions fell into three main categories of 'consumer demand', 'environmental potentials', and 'optimal official regulations' from which, the main theme of 'A potentially-supportive environment' was abstracted. The context of Iranian clinical settings is appropriate for using complementary therapies in nursing practice. A potentially-supportive environment automatically directs nurses towards using such therapies. These findings can be used by nursing managers to integrate complementary therapies into nursing practice. PMID- 27502798 TI - Bending without breaking: A narrative review of trauma-sensitive yoga for women with PTSD. AB - OBJECTIVE: The purpose of this review is to evaluate the peer-reviewed empirical evidence on the use of Trauma-Sensitive Yoga (TSY) for the treatment of women with post-traumatic stress disorder (PTSD): specifically interpersonal trauma such as intimate partner violence. To date, no such review has been conducted. METHODS: Articles meeting study inclusionary criteria were identified through electronic database searches. A total of five studies (N = 5) were selected and reviewed. These studies included two randomized controlled trials (RCT), one follow-up of an RCT, one quasi-experimental study, and one qualitative study. RESULTS: There is tentative evidence to support the efficacy of TSY in reducing PTSD, depression, and anxiety symptomatology for women with PTSD; there is also tentative evidence confirming the feasibility of implementing TSY as an adjunctive mental health intervention, particularly for individuals who are non responsive to cognitive-based psychotherapies. The qualitative findings speak to a number of benefits of yoga practice stimulated by TSY participation centering on the phenomenon of peaceful embodiment. CONCLUSIONS: Replication of these results using larger and more diverse samples and rigorous study designs by independent researchers would add credibility to these findings and contribute to the growing body of knowledge on TSY. Additionally, there is a dearth of studies on this nascent form of therapeutic yoga. Therefore, further research is needed to explore the potential efficacy of TSY with other types of trauma, populations, and settings. PMID- 27502797 TI - Massage therapy research review. AB - In this review, massage therapy has been shown to have beneficial effects on varying conditions including prenatal depression, preterm infants, full-term infants, autism, skin conditions, pain syndromes including arthritis and fibromyalgia, hypertension, autoimmune conditions including asthma and multiple sclerosis, immune conditions including HIV and breast cancer and aging problems including Parkinson's and dementia. Although many of the studies have involved comparisons between massage therapy and standard treatment control groups, several have compared different forms of massage (e.g. Swedish versus Thai massage), and different active therapies such as massage versus exercise. Typically, the massage therapy groups have experienced more positive effects than the control or comparison groups. This may relate to the massage therapy providing more stimulation of pressure receptors, in turn enhancing vagal activity and reducing cortisol levels. Some of the researchers have assessed physical, physiological and biochemical effects, although most have relied exclusively on self-report measures. Despite these methodological problems and the dearth of research from the U.S., the massage therapy profession has grown significantly and massage therapy is increasingly practiced in traditional medical settings, highlighting the need for more rigorous research. PMID- 27502799 TI - Health literacy screening of patients attending a student-led osteopathy clinic: A pilot investigation. AB - Adequate levels of health literacy (HL) are required for patients to access appropriate health services and develop an understanding of the options for managing their healthcare needs. There is limited literature on HL of patients seeking care for a musculoskeletal complaint. The present study sought to screen the HL of patients presenting to an Australian osteopathy student-led clinic using a single screening question 'Are you confident completing medical forms?'. Less than 10% of patients attending the clinic were considered to have below adequate levels of HL using this question, consistent with other work in Australian populations. Logistic regression analysis identified that the most significant demographic variables associated with lower HL were patients who did not speak English at home, those with lower education levels, and those who were less satisfied with their life. Evaluation of a patients' HL may assist practitioners to improve patient education and management strategies. PMID- 27502800 TI - Investigating the effect of rose essential oil in patients with primary dysmenorrhea. AB - OBJECTIVE: This study aimed to evaluate the effects of rose essential oil on primary dysmenorrhea. METHODS: One hundred patients were randomly divided into two groups; Group D received diclofenac sodium (75 mg/im) and Group A administered diclofenac sodium with aromatherapy (2% rose essential oil). The visual analog scale (VAS) scores in all subjects at baseline, 10th min, and 30th min were recorded. RESULTS: When the two groups were compared before and after the treatment, there were significant decreases in VAS values at the 10 min and 30 min compared to baseline values in both groups (p < 0.001). However, the 30th min mean VAS value in Group D was higher than in Group A (p = 0.019). CONCLUSION: The present study suggests that aromatherapy with rose essential oil, which is a nonpharmacologic treatment method, as an adjuvant to conventional treatment methods may be beneficial for pain relief in individuals with primary dysmenorrhea. PMID- 27502801 TI - Yoga reduces perceived stress and exhaustion levels in healthy elderly individuals. AB - This study investigated whether a 7-week yoga intervention could improve physical function, perceived stress, and mental/emotional wellness in elderly participants. METHODS: 8 participants (66.5 +/- 0.3 years) attended 2 60-min Hatha yoga sessions/week for 7 weeks, and performed pre- and post-intervention assessments. Balance was assessed using a 5-test battery. Flexibility was measured by sit-and-reach and shoulder flexibility tests. Functional mobility tests included 8-ft up-and-go, 5 chair stands, and 4-m walk. Participants completed SF-12, exhaustion level, and Perceived Stress Scale (PSS) questionnaires. RESULTS: SF-12 Mental Component Summary scores, exhaustion levels, and PSS scores improved post-intervention. No differences were found for physical function measures. CONCLUSIONS: Yoga participation can improve mental/emotional wellness, exhaustion levels, and stress levels in elderly individuals, even without measurable improvements in physical function. Clinicians and health practitioners who work with the elderly should consider yoga as a potential therapeutic modality for improving important aspects of quality of life in this population. PMID- 27502802 TI - Welcoming max: Increasing pediatric provider knowledge of service dogs. AB - Service dogs have been used in the adult population for decades. Recently, there has been a diversification in types of service dogs, specifically for the pediatric population. Although guide dogs and mobility dogs are accepted in society, autism assistance dogs, seizure alert and response dogs and diabetic alert dogs are relatively new. As pediatric service dogs attract more attention, pediatric providers need to be prepared to answer parental inquires regarding service dog use. The pediatric provider is well equipped to identify children who could benefit from a service dog intervention and should be able to make a referral to a reputable service dog provider. This article presents guidance on appropriate patient selection, making a service dog referral, and risks and benefits involved. Pediatric providers are ideally positioned to be leaders in implementing this evolving new assistive technology that can help to alleviate pediatric disabilities for both the patient and family. PMID- 27502803 TI - Training postural control and sitting in children with cerebral palsy: Kinesio taping vs. neuromuscular electrical stimulation. AB - OBJECTIVE: To elucidate the effects of Kinesio Taping (KT) in addition to neurodevelopmental therapy (NDT) on posture and sitting, and to compare the effects of KT and neuromuscular electrical stimulation (NMES). MATERIALS-METHODS: Seventy-five children were randomized into control, KT, and NMES groups. NDT was applied to all children 4 times a week for 4 weeks. In addition, KT and NMES were applied to KT and NMES groups, respectively. Sitting subset of Gross Motor Function Measure (GMFM) and kyphosis levels of the groups were analyzed by two way mixed ANOVA. RESULTS: GMFM and kyphosis values improved significantly in all groups (all p < 0.01), yet change levels were more prominent in the KT and NMES groups than the control group. Moreover, NMES group showed better improvement. CONCLUSION: KT or NMES application for four weeks in addition to NDT is effective on improving kyphosis and sitting. Besides, NMES is more effective than KT. PMID- 27502804 TI - Glycemic reductions following water- and land-based exercise in patients with type 2 diabetes mellitus. AB - PURPOSE: To assess the acute glucose responses to the first sessions of three mesocycles of water- and land-based aerobic exercise. METHODS: The water-based exercise group (WBE, n = 14; 54.1 +/- 9.1 years) performed deep water walking and/or running, while the land-based exercise group (LBE, n = 11; 60.1 +/- 7.3 years) performed walking and/or running on athletic track. In the first mesocycle, patients trained at 85-90% of their anaerobic threshold (AT) for 35 min, progressing to 90-95% of the AT in the second mesocycle, and 95-100% of the AT in the last mesocycle. Capillary glucose was assessed before and immediately after the first session of each mesocycle. RESULTS: There was glycemic reduction (p < 0.001) in all sessions, with relative reductions of 19%, 29% and 24% for the WBE and 24%, 29% and 27% for the LBE in the mesocycles 1, 2 and 3, respectively. There were no found differences between groups and between mesocycles. CONCLUSIONS: The acute response of blood glucose to aerobic training between 85 and 100% of the heart rate of AT is effective and independent of the environment in which it is performed. Clinical trial reg. no. NCT01956357, clinicaltrials.gov. PMID- 27502805 TI - The effect of foot reflexology applied to women aged between 40 and 60 on vasomotor complaints and quality of life. AB - PURPOSE: This study aims to identify the effects of foot reflexology applied to women on their vasomotor complaints and quality of life. METHODS: A randomised controlled study was conducted with 120 women. The experimental group received foot reflexology treatment, while the control group received nonspecific foot massage. RESULTS: The mean scores for hot flashes, sweats, and night sweats, were lower in the reflexology group than the control group after the practice; and the difference between the groups was statistically significant (p < 0.001). The mean scores for the sub-groups of the MENQOL demonstrated improvements in both groups after the application (p < 0.001). As for the sexual domain, there was a significant improvement in the reflexology group (p < 0.05), but no improvements were found in the control group (p > 0.05). CONCLUSION: Results showed that reflexology might be effective in decreasing vasomotor problems and increasing quality of life in women in the menopausal period. PMID- 27502806 TI - TENS and heat therapy for pain relief and quality of life improvement in individuals with primary dysmenorrhea: A systematic review. AB - The present systematic review aimed to synthesize evidence for the effectiveness of TENS and heat therapy interventions from randomized trials. Six relevant databases were searched for studies on TENS and heat therapy for primary dysmenorrhea. Menstrual pain intensity and quality of life were the primary and secondary outcomes respectively. The search yielded 46 citations from which six studies on TENS and three studies on heat therapy were systematically reviewed. On the PEDRO quality scale, the trials methodological quality was 4.8 out of 10 for TENS and 6.3 out of 10 for heat therapy. TENS and heat therapy both showed evidence of pain reduction, but no study included quality of life as an outcome. Meta-analysis was not possible due to substantial heterogeneity in included studies. TENS and heat therapy show potential as adjunct remedies in the management of primary dysmenorrhea, but rigorous high quality trials are still needed to made conclusive recommendation. PMID- 27502807 TI - Massage as adjuvant therapy in the management of post-cesarean pain and anxiety: A randomized clinical trial. AB - OBJECTIVE: The present study was conducted to determine the effect of massage on post-cesarean pain and anxiety. METHODS: The present single-blind clinical trial was conducted on 156 primiparous women undergone elective cesarean section. The participants were randomly divided into three groups, including a hand and foot massage group, a foot massage group and a control group (n = 52 per group). The patients' intensity of pain, vital signs and anxiety level were measured before, immediately after and 90 min after the massage. RESULTS: A significant reduction was observed in the intensity of pain immediately and 90 min after massage (P < 0.001). Moreover, changes in some of the physiological parameters, including blood pressure and respiration rate, were significant after massage (P < 0.001); however, this change was not significant for pulse rate. A significant reduction was also observed in the level of anxiety (P < 0.001) and a significant increase in the frequency of breastfeeding (P < 0.001) after massage. CONCLUSION: As an effective nursing intervention presenting no side-effects, hand and foot massage can be helpful in the management of postoperative pain and stress. PMID- 27502808 TI - Birth ball or heat therapy? A randomized controlled trial to compare the effectiveness of birth ball usage with sacrum-perineal heat therapy in labor pain management. AB - OBJECTIVE: Labor pain and its management is a major concern for childbearing women, their families and health care providers. This study aimed to investigate the effects of two non-pharmacological methods such as birth ball and heat therapy on labor pain relief. MATERIAL & METHODS: This randomized control trial was undertaken on 90 primiparous women aged 18-35 years old who were randomly assigned to two intervention (birth ball and heat) and control groups. The pain score was recorded by using Visual Analogue Scale (VAS) before the intervention and every 30 min in three groups until cervical dilatation reached 8 cm. RESULTS: The mean pain severity score in the heat therapy group was less than that of in control group at 60 and 90 min after intervention (p < 0.05). In addition there were significantly differences between the pain scores in the birth ball group after all three investigated times in comparison to control group. CONCLUSION: Both heat therapy and birth ball can use as inexpensive complementary and low risk treatment for labor pain. PMID- 27502809 TI - Use and interest in complementary and alternative medicine among college students seeking healthcare at a university campus student health center. AB - BACKGROUND: There is growing data on complementary and alternative medicine (CAM) preferences among college students. While several studies have focused on undergraduate students, there is limited data on graduate students. MATERIALS AND METHODS: Cross sectional analysis of undergraduate and graduate students seeking medical care at the University of California Irvine's Student Health Center (SHC). The survey assessed previous CAM use and preferences for future CAM use and education. RESULTS: The majority (67.0%) had used CAM within the last year, 27.0% would use CAM for their current health condition, and 51.9% would consider CAM for their current health condition if they were more knowledgeable. Most respondents desired more CAM education and indicated that they would try CAM modalities if covered under insurance. CONCLUSION: Most college students requested more knowledge to assist in their decisions to use CAM. These findings provide insight for health centers on the preferences of college student patients. PMID- 27502810 TI - Efficacy of rehabilitation with Tai Ji Quan in an Italian cohort of patients with Fibromyalgia Syndrome. AB - BACKGROUND: Fibromyalgia Syndrome (FMS) is characterized by musculoskeletal pain, muscle tenderness leading to disability, impaired quality of life (QoL), fatigue and it is accompanied by sleep disorders and psychological distress. Mind body therapies (MBT), such as Tai Ji Quan (TJQ), use different techniques to facilitate the ability of the mind to influence disease characteristics and symptoms. Some studies showed that TJQ, in patients with rheumatic diseases, particularly FMS, improved QoL, disability and psychological distress. OBJECTIVES: To evaluate the efficacy of TJQ on disability, QoL, fatigue, sleep and psychological distress in an Italian cohort of FMS patients. METHODS: We enrolled 44 FMS patients: 22 patients (Experimental Group) participated to a course of Tai Ji Quan style of (2/week for 16 weeks); 22 patients (Control Group) participated to an educational course about FMS (2/week for 16 weeks). At baseline (T0) and at the end of treatment (T1), patients were assessed for disability [Fibromyalgia Impact Questionnaire (FIQ), Health Assessment Questionnaire (HAQ)], Quality of Life [Short-Form 36 (SF36)], fatigue [Functional Assessment of Chronic Illness-Fatigue (FACIT-F)], pain [Widespread Pain Index (WPI)], tenderness [Tender Points (TP)], Sleep Quality [Pittsburgh Sleep Quality Index (PSQI)] and mood disorders [Hospital Anxiety and Depression Scale (HADS)]. RESULTS: At T1 versus T0, patients of the Experimental Group showed a significant improvement in FIQ, FACIT, SF36 (Summary Physical Index, Physical activity, physical role, bodily pain, general health, vitality, emotional role limitations), in WPI, TP, PSQI (total, sleep duration, and sleep disturbance) and HADS (total score and anxiety subscale), while Patients in the Control Group did not improve in any parameter. CONCLUSIONS: In FMS patients TJQ, if performed by an expert physiotherapist, should be regarded as an effective rehabilitation method. PMID- 27502811 TI - Perceived relaxation as a function of restorative yoga combined with Reiki for cancer survivors. AB - AIMS & OBJECTIVES: Twenty-six cancer survivor volunteers participated in a study of the efficacy of perceived relaxation after performing restorative yoga combined with Reiki. RESULTS: Subjects scoring high ratings of Meaning and Peace in life demonstrated greater perception of depth of relaxation. A comparison of subjects receiving concurrent Reiki (19) and restorative yoga with those who only received restorative yoga (7) showed that Reiki subjects experienced greater perceived depth of relaxation than subjects who were not afforded the Reiki intervention. Non-Reiki participants also showed more difficulty overcoming intrusive fearful thoughts than the Reiki group. CONCLUSIONS: Clinical implications suggest that patients should be screened and treated for trauma-like symptoms including intrusive thoughts linked to anxiety and depression before referral to complementary programs that offer meditative or relaxation interventions. PMID- 27502813 TI - Topical honey for the treatment of diabetic foot ulcer: A systematic review. AB - Topical honey has been used for the treatment of wound since ancient time. But the medical evidence proving it is limited. Hence a systematic review was planned. An exhaustive literature search was done in PUBMED, COCHRANE, GOOGLE using 'topical honey', 'diabetic foot ulcer', 'chronic wounds' as key words. Literature search showed total of five clinical trials and about ten observational studies in various part of world. Out of five clinical trials three concluded that honey dressing is better than conventional dressing, all the clinical trials proved safety of honey for the treatment of diabetic foot ulcer. Observational studies included total of 320 patients which also showed safety of honey but efficacy cannot be considered from observational studies. This review showed that honey dressing is safer for treatment of diabetic foot ulcer but there is insufficient good quality data to realistically conclude on the efficacy of honey on diabetic foot ulcers. PMID- 27502812 TI - Effects of a chair-yoga exercises on stress hormone levels, daily life activities, falls and physical fitness in institutionalized older adults. AB - The aim of this study was to assess the changes mediated by exercise on activities of daily life and falls, physical fitness, salivary cortisol and alpha amylase in older adults living in social and health care givers centers. METHODS: Sample consisted in 35 women (83.81 +/- 6.6 years old) were divided into two groups: chair-yoga exercises group (CY, n = 20) and control group (CG, n = 15). All subjects were evaluated before and after 14-weeks. CY was involved in exercise classes two times per week, while the GC did not participate in any exercise. RESULTS: Fear of falling decreased in both groups, cortisol increased and alpha-amylase decreased in the CG. No significant changes occurred in physical fitness outcomes. CONCLUSION: CY practice was able to maintain the physical fitness scores and stress hormone levels, but was not able to improve the subject's perception on the ability to perform the instrumental activities of daily life. PMID- 27502814 TI - Therapeutic Touch((r)) in a geriatric Palliative Care Unit - A retrospective review. AB - Complementary therapies are increasingly used in palliative care as an adjunct to the standard management of symptoms to achieve an overall well-being for patients with malignant and non-malignant terminal illnesses. A Therapeutic Touch Program was introduced to a geriatric Palliative Care Unit (PCU) in October 2010 with two volunteer Therapeutic Touch Practitioners providing treatment. OBJECTIVE: To conduct a retrospective review of Therapeutic Touch services provided to patients in an in-patient geriatric palliative care unit in order to understand their responses to Therapeutic Touch. METHODS: A retrospective medical chart review was conducted on both patients who received Therapeutic Touch as well as a random selection of patients who did not receive Therapeutic Touch from October 2010 June 2013. Client characteristics and the Therapeutic Touch Practitioners' observations of the patients' response to treatment were collected and analyzed. RESULTS: Patients who did not receive Therapeutic Touch tended to have lower admitting Palliative Performance Scale scores, shorter length of stay and were older. Based on a sample of responses provided by patients and observed by the Therapeutic Touch practitioner, the majority of patients receiving treatment achieved a state of relaxation or sleep. CONCLUSIONS: This retrospective chart review suggests that implementation of a TT program for an inpatient geriatric Palliative Care Unit is feasible, and appears to be safe, and well-tolerated. Moreover, patient responses, as recorded in the Therapeutic Touch practitioners' session notes, suggest beneficial effects of Therapeutic Touch for a significant number of participants with no evidence of negative sequelae. Therefore, the use of TT in this difficult setting appears to have potential value as an adjunct or complementary therapy to help patients relax. PMID- 27502815 TI - The effect of foot reflexology and back massage on hemodialysis patients' fatigue and sleep quality. AB - OBJECTIVE: The aim of this study is to examine the effectiveness of foot reflexology and back massage on optimizing the sleep quality and reducing the fatigue of hemodialysis patients. METHODS: The study includes 105 volunteer patients who were registered at a private dialysis clinic and were receiving hemodialysis treatment. Foot reflexology and back massage were administered to the patients two times a week for four weeks. The Visual Analogue Scale for Fatigue and the Pittsburg Sleep Quality Index were used to collect data. RESULTS: The differences between the pretest and posttest score averages of the patients on the Visual Analogue Scale for Fatigue and the Pittsburg Sleep Quality Index were statistically significant (p < 0.001). CONCLUSION: Foot reflexology and back massage were shown to improve the sleep quality and reduce the fatigue of hemodialysis patients. Compared to back massage, foot reflexology was determined to be more effective. PMID- 27502816 TI - Yoga research review. AB - This paper is a review of empirical studies, review and meta-analysis publications on yoga from the last few years. The review includes demographics/prevalence of yoga as a practice, bibliometric analyses of the yoga publications and the use of yoga for physical fitness and cognitive function. Most of the studies reviewed here involve yoga effects on psychiatric and medical conditions. These include pregnancy, prenatal and postpartum depression; stress, PTSD, anxiety, and obesity; cardiovascular conditions including hypertension; pain syndromes including arthritis, headaches and low back pain; autoimmune conditions including asthma, type II diabetes and multiple sclerosis; immune conditions including HIV and breast cancer; and aging problems including balance, osteoporosis and Parkinson's. The methods and results of those studies are briefly summarized along with their limitations and suggestions for future research. Basically yoga has been more effective than control and waitlist control conditions, although not always more effective than treatment comparison groups such as other forms of exercise. More randomized controlled studies are needed in which yoga is compared to active exercise groups. Having established the physical and mental health benefits of yoga makes it ethically questionable to assign participants to inactive control groups. Shorter sessions should be investigated for cost-effectiveness and for daily practice. Multiple physical and physiological measures need to be added to the self-report research protocols and potential underlying mechanisms need to be further explored. In the interim, the studies reviewed here highlight the therapeutic effects of yoga, a practice that could come to be called yoga therapy. PMID- 27502817 TI - Systemic acupuncture in patients with faecal incontinence. AB - CONTEXT: Faecal incontinence is defined as the involuntary loss of intestinal contents (whether faeces or gas). Although it is not frequently reported, it does cause physical and psychological distress. Traditional Chinese medicine believes that the healthy human body is originally in a state of balanced energy (Qi) between Yin and Yang, and all disorders that occur in the body are explained by disruptions in this energy balance. Acupuncture is a valuable therapy and is used as a therapeutic approach for the treatment of pelvic floor dysfunction. Data regarding faecal incontinence and acupuncture is scarce. This research describes the efficacy of using acupuncture in patients with faecal incontinence. PATIENTS AND METHODS: Eighteen adults (2 men and 16 women) underwent acupuncture therapy with traditional acupuncture needles for 10 weeks. Before and after treatment, all patients completed a Fecal Incontinence Quality of Life (FIQL) survey and the incontinence intensity was assessed using a visual analogue scale. RESULTS: After 10 sessions of acupuncture, all patients reported an improvement, and the vast majority of patients showed statistically significant improvements in both tests. CONCLUSION: Therefore, evidence now shows that acupuncture can improve the quality of life of patients undergoing faecal incontinence treatment. PMID- 27502818 TI - Pregnant women and health professional's perceptions of complementary alternative medicine, and participation in a randomised controlled trial of acupressure for labour onset. AB - Feasibility randomised controlled trials of complementary medicine are important to evaluate acceptability and practicality. This study examined participants' and health professionals' perceptions of CAM and participation in a feasibility RCT of acupressure for labour onset. METHODS: A qualitative study incorporated within an RCT. Data were collected from postnatal women via questionnaires and health professionals via focus groups. RESULTS: Four themes emerged from the women's views: "Using CAM to start labour", "Feeling empowered through action", "Desiring randomisation to acupressure group", and "Welcoming the opportunity to assist in research". Five themes emerged from the health professionals' views: "Personal awareness and attitudes towards CAM"; "Supporting and empowering women"; "Complements the wellness model of pregnancy and childbirth"; "Need for evidenced based practice"; and "Randomisation 'doing it on the sly'". CONCLUSIONS: Themes from the groups were similar. The study protocol will be refined with a placebo group to improve equipoise with a powered RCT planned. PMID- 27502819 TI - The therapeutic impacts of environmental design interventions on wellness in clinical settings: A narrative review. AB - PURPOSE: The aim of this review is to document the role of physical environmental factors in clinical environments and their impact on patients and staff wellness with a particular focus on physical and mental healthcare. METHODS: Data sources comprised relevant English language articles and the results of literature search of ISI Web of Knowledge, PubMed, Scopus, ProQuest Central, MEDLINE, and Google. RESULTS: Incorporating physical environmental factors into hospital design can facilitate better user satisfaction, efficiency and organisational outcomes. Many of the design interventions convey positive distractions for patients and staff, in terms of views of pleasant outside vistas, soothing sound, artwork and music. CONCLUSIONS: Well-designed physical settings play an important role in the healing process of patients in health care facilities. The challenge then is to fully understand that role in the ecological context of health care. Other contributors are possible and should be explored in further research. PMID- 27502820 TI - The effect of auricular acupressure on nausea and vomiting caused by chemotherapy among breast cancer patients. AB - OBJECTIVE: The aim of this study was to determine the effect of auricular acupressure in relieving nausea and vomiting among the women who received chemotherapy. METHODS: 48 women suffering from Breast Cancer and receiving chemotherapy were recruited for the study. The patients were randomly assigned into two groups of experiment and control. In the initial phase of chemotherapy, the experimental group received standard medications to control nausea and vomiting and auricular acupressure for five days. Meanwhile, the control group received only the standard medications. RESULTS: The use of auricular acupressure led to the decrease in the number and intensity of nausea and vomiting in both the acute and delayed phases in experimental group which were significantly lower than the control group (P = 0/001). CONCLUSIONS: It is suggested that nurses use this pressure technique as a complementary treatment, non - pharmacological, inexpensive, non-invasive approach for the relief of chemotherapy-induced nausea and vomiting. PMID- 27502821 TI - Structure of the lateral mass of the ethmoid by curved stacking of endoturbinal elements. AB - CONTEXT: According to evo-devo theory, the embryonic development of the nasal organ mimics its phylontogenic formation: the lateral masses of the human ethmoid bone develop by curved "onion" stacking of the endoturbinals (the horizontal bone septa of the mammalian olfactory chamber) under the impact of facial and skull base remodeling, rather than by pneumatization of cavities communicating via ostia. OBJECTIVES: To assess the frequency of the onion structure on coronal CT. MATERIAL AND METHODS: Three independent examiners performed a retrospective descriptive study of coronal CT scans taken ahead of septorhinoplasty between June 2010 and December 2012 in adult patients without history of sinonasal surgery. RESULTS: Fifty patients were included. In the anterior right and left and posterior right ethmoid, an onion arrangement of the endoturbinals was systematically found on at least 1 view, and on 60% of views taking all ethmoid compartments together. Two endoturbinals were generally involved, but a rolling up of 3 endoturbinals was also observed, significantly more frequently in the posterior compartments (P=0.004 on the right side, P=0.012 on the left). CONCLUSION: The onion structure of the lateral masses of the ethmoid can be observed on coronal CT scans. This structure confirms evo-devo theory. The ethmoid thus appears fundamentally different from the paranasal sinuses, suggesting that the pathogenesis of nasal polyposis and ethmoidectomy techniques need to be reconsidered. PMID- 27502822 TI - Single-center retrospective series of fourteen patients with mucosal melanoma of the nasal cavity and paranasal sinuses. AB - OBJECTIVES: Mucosal melanoma of the nasal cavity and paranasal sinuses is a rare and highly aggressive tumor. We report our experience over 20 years in management of this tumor. PATIENTS AND METHODS: A retrospective study included 14 patients with primary sinonasal mucosal melanoma. RESULTS: The series comprised 8 male and 6 female patients, with a median age at diagnosis of 67 years. Staging on the American Joint Committee on Cancer classification of sinus cancer was 14% T2, 22% T3, 75% T4a and 7% T4b. All patients underwent primary surgical treatment; 71% received adjuvant external radiotherapy. Median recurrence-free interval was 28.7 months. Two- and 5-year overall survival was 43% and 32%, respectively. Median follow-up was 43 months. CONCLUSIONS: Mucosal melanomas of the nasal cavity and paranasal sinuses are very specific entities. Limited pathophysiological knowledge still precludes effective medium- and long-term management. Future treatment will probably be based on global adjuvant or neoadjuvant-targeted chemotherapy. PMID- 27502823 TI - Use of auditory steady-state responses in children and comparison with other electrophysiological and behavioral tests. AB - OBJECTIVE: In patients who cannot or will not cooperate in behavioral hearing assessment, electrophysiological examinations are used, but are time-consuming because the subject has to remain immobile. The aim of this study was to assess whether auditory steady-state responses (ASSR) are sufficiently reliable, compared to auditory brainstem responses (ABR) and free-field audiometry, for assessment to begin with ASSR instead of ABR. MATERIAL AND METHODS: A retrospective study was performed between January 2012 and April 2013, including children less than 6 years of age who could not be tested via headphones. ASSR and ABR were measured during natural sleep or under phenobarbital-alimemazine sedation. Subjective pure-tone audiometry was performed, using the visual reinforcement audiometry method, in 69 children who were able and willing to cooperate. RESULTS: A total of 175 children were included. ASSR and ABR thresholds showed good positive correlation (338 ears; Pearson's correlation coefficient, 0.87). Behavioral thresholds correlated significantly with ASSR thresholds (Student t-test for matched series; P<0.05). ASSR thresholds were usually better than behavioral thresholds, with a difference of 8-15dB HL. CONCLUSION: ASSR is reliable in children under 6 years of age, and should be performed before ABR when hearing threshold rather than latency is to be determined. PMID- 27502824 TI - Exoskeletal cuticle of cavernicolous and epigean terrestrial isopods: A review and perspectives. AB - Comparative ultrastructural studies of the integument in terrestrial isopod crustaceans show that specific environmental adaptations of different eco morphotypes are reflected in cuticle structure. The biphasic molting in isopods is a valuable experimental model for studies of cuticular matrix secretion and degradation in the same animal. The aim of this review is to show structural and functional adaptations of the tergal cuticle in terrestrial isopods inhabiting cave habitats. Exoskeletal cuticle thickness, the number of cuticular layers, epicuticle structure, mineralization, pigmentation and complexity of sensory structures are compared, with greater focus on the well-studied cave trichoniscid Titanethes albus. A large number of thinner cuticular layers in cave isopods compared to fewer thicker cuticular layers in related epigean species of similar body-sizes is explained as a specific adaptation to the cavernicolous life style. The epicuticle structure and composition are compared in relation to their potential waterproofing capacity in different environments. Cuticle mineralization is described from the functional point of view as well as from the aspect of different calcium storage sites and calcium dynamics during the molt cycle. We also discuss the nature and reduction of pigmentation in the cave environment and outline perspectives for future research. PMID- 27502825 TI - Angiotensin-converting enzyme inhibitor-associated angioedema treated with c1 esterase inhibitor: A case report and review of the literature. AB - CASE REPORT: A 59-year old man currently on >5 years of angiotensin-converting enzyme inhibitor (ACEI) therapy presented to the emergency department with angioedema of the tongue and difficulty swallowing. After receiving conventional therapy of antihistamine, steroids, and epinephrine, the patient's condition continued to deteriorate, with imminent intubation. The patient was treated with a C1-esterase inhibitor (C1-INH) and experienced rapid resolution of symptoms, which avoided airway complications. DISCUSSION: Although no therapy has been approved for the treatment of ACEI-associated angioedema (AAE), the conventional therapy (antihistamine, steroids, and epinephrine) often proves ineffective in this bradykinin-mediated angioedema. There are drugs approved and used for hereditary angioedema that may be effective in the acute phase of ACEI-AAE that may prevent the need for further interventions, such as intubation and tracheotomy. These drugs include icatibant, ecallantide, fresh frozen plasma, and C1-INH. CONCLUSION: The literature and clinical evidence indicate C1-INH can be effectively used in the treatment of ACEI-AAE to halt the progression of the condition, prevent airway compromise and the need for intervention, and lead to rapid resolution of symptoms. PMID- 27502826 TI - The Role of Trace Elements in Tinnitus. AB - In this study, we aimed to investigate the role of three trace elements, namely, zinc, copper, and lead, in tinnitus by analyzing the serum level of copper and lead and both the serum and tissue level of zinc. Eighty patients, who applied to outpatient otolaryngology clinic with the complaints of having tinnitus, and 28 healthy volunteers were included. High-frequency audiometry was performed, and participants who had hearing loss according to the pure tone average were excluded; tinnitus frequency and loudness were determined and tinnitus reaction questionnaire scores were obtained from the patients. Of all the participants, serum zinc, copper, and lead values were measured; moreover, zinc levels were examined in hair samples. The levels of trace elements were compared between tinnitus and control groups. The level of copper was found to be significantly lower in the tinnitus group (p = 0.02), but there was no significant difference between the groups in terms of the levels of zinc, neither in serum nor in hair, and lead in serum (p > 0.05). The lack of trace elements, especially that of "zinc," have been doubted for the etiopathogenesis of tinnitus in the literature; however, we only found copper levels to be low in patients having tinnitus. PMID- 27502828 TI - Attitudes to diagnosis and management in dementia care: views of future general practitioners. AB - Considerable international governmental support is focused on the timely diagnosis of dementia and post-diagnostic care of people with dementia. Identifying those at high risk of dementia is one approach to timely diagnosis. General practitioners (GPs) are well-placed clinicians in the community to provide both pre- and post-diagnostic dementia care. However, GPs have in the past consistently demonstrated low confidence in both diagnosing dementia and providing care for these complex patients particularly for patients in the post diagnostic phase. It is currently unclear how future GPs view dementia care. We aimed to evaluate the current attitudes and experiences of future GPs in dementia care and their views on targeting high risk groups. All (n = 513) GP trainees were approached by email to participate in a cross-sectional web and paper-based survey in the North of England. A further reminder was sent out two months after the initial invitation. We received 153 responses (29.8% response rate, 66.7% female, average age 31 (range 25-55 years old). The main difficulties encountered included coordinating supporting services for carers and the person with dementia and responding to co-existing behavioral and psychiatric symptoms. Further education in dementia management was considered to be important by respondents. GP trainees were generally very positive about their future role in caring for people with dementia, particularly in the area of earlier diagnosis via identification of high-risk individuals. Future GPs in one area of England are very positive about their key role in dementia care. In order to facilitate the delivery of high quality, community-based care, work is required to establish core post-diagnostic dementia support services. Further research is needed to identify effective systems to enable accurate assessment and to ensure earlier diagnosis in high-risk groups. PMID- 27502827 TI - Dietary pattern transitions, and the associations with BMI, waist circumference, weight and hypertension in a 7-year follow-up among the older Chinese population: a longitudinal study. AB - BACKGROUND: Few studies explored the effects of nutritional changes on body mass index (BMI), weight (Wt), waist circumference (WC) and hypertension, especially for the older Chinese population. METHODS: By using China Health and Nutrition Survey 2004-2011 waves, a total of 6348 observations aged >= 60 were involved in the study. The number of participants dropped from 2197 in 2004, to 1763 in 2006, 1303 in 2009, and 1085 in 2011. Dietary information was obtained from participants using 24 hour-recall over three consecutive days. Height, Wt, WC, systolic and diastolic blood pressure were also measured in each survey year. The dietary pattern was derived by exploratory factor analysis using principal component analysis methods. Linear Mixed Models were used to investigate associations of dietary patterns with BMI, Wt and WC. Generalized Estimating Equation models were used to assess the associations between dietary patterns and hypertension. RESULTS: Over time, older people's diets were shifting towards a modern dietary pattern (high intake of dairy, fruit, cakes and fast food). Traditional and modern dietary patterns had distinct associations with BMI, Wt and WC. Participants with a diet in the highest quartile for traditional composition had a beta (difference in mean) of -0.23 (95 % CI: -0.44; -0.02) for BMI decrease, beta of -0.90 (95 % CI: -1.42; -0.37) for Wt decrease; and beta of 1.57 (95 % CI: -2.32; -0.83) for WC decrease. However, participants with a diet in the highest quartile for modern diet had a beta of 0.29 (95 % CI: 0.12; 0.47) for BMI increase; beta of 1.02 (95 % CI: 0.58; 1.46) for Wt increase; and beta of 1.44 (95 % CI: 0.78; 2.10) for Wt increase. No significant associations were found between dietary patterns and hypertension. CONCLUSIONS: We elucidate the associations between dietary pattern and change in BMI, Wt, WC and hypertension in a 7-year follow-up study. The strong association between favourable body composition and traditional diet, compared with an increase in BMI, WC and Wt with modern diet suggests that there is an urgent need to develop age-specific dietary guideline for older Chinese people. PMID- 27502829 TI - Differentiating sibling species of Zeugodacus caudatus (Insecta: Tephritidae) by complete mitochondrial genome. AB - Zeugodacus caudatus is a pest of pumpkin flowers. It has a Palearctic and Oriental distribution. We report here the complete mitochondrial genome of the Malaysian and Indonesian samples of Z. caudatus determined by next-generation sequencing of genomic DNA and determine their taxonomic status as sibling species and phylogeny with other taxa of the genus Zeugodacus. The whole mitogenome of both samples possessed 37 genes (13 protein-coding genes-PCGs, 2 rRNA and 22 tRNA genes) and a control region. The mitogenome of the Indonesian sample (15,885 bp) was longer than that of the Malaysian sample (15,866 bp). In both samples, TPsiC loop was absent in trnF and DHU-loop was absent in trnS1. Molecular phylogeny based on 13 PCGs was concordant with 15 mitochondrial genes (13 PCGs and 2 rRNA genes), with the two samples of Z. caudatus forming a sister group and the genus Zeugodacus was monophyletic. The Malaysian and Indonesian samples of Z. caudatus have a genetic distance of p = 7.8 % based on 13 PCGs and p = 7.0 % based on 15 mitochondrial genes, indicating status of sibling species. They are proposed to be accorded specific status as members of a species complex. PMID- 27502830 TI - Introduction to Special Issue on Mitochondrial Redox Signaling in Health and Disease. PMID- 27502831 TI - Community Federally Qualified Health Centers as Homes for HIV Preexposure Prophylaxis: Perspectives from South Florida. AB - Preexposure prophylaxis (PrEP) for HIV has the potential to reduce HIV incidence in highly affected areas. The Southeastern United States is disproportionately impacted by HIV, and 3 counties in South Florida have the highest incidence of new HIV infections in the United States. This study explored the feasibility, acceptability, and uptake of PrEP in South Florida. Focus groups consisting of providers, administrators, and case managers at HIV-servicing community health centers and federally qualified health centers in South Florida reported broad support but low implementation of PrEP. Generally, participants indicated that the centers were appropriate locations for implementation. However, practical concerns and perceived limitations due to financial, insurance, and immigration status of those who would potentially benefit from the intervention were widely reported. Addressing provider concerns appears necessary for successful expansion of PrEP implementation in highly impacted areas such as South Florida. PMID- 27502832 TI - Association Between Monetary Deposits and Weight Loss in Online Commitment Contracts. AB - PURPOSE: To examine the characteristics of voluntary online commitment contracts that may be associated with greater weight loss. DESIGN: Retrospective analysis of weight loss commitment contracts derived from a company that provides web based support for personal commitment contracts. Using regression, we analyzed whether percentage weight loss differed between participants who incentivized their contract using monetary deposits and those who did not. SETTING: Online. PARTICIPANTS: Users (N = 3857) who voluntarily signed up online in 2013 for a weight loss contract. INTERVENTION: Participants specified their own weight loss goal, time period, and self-reported weekly weight. Deposits were available in the following 3 categories: charity, anticharity (a nonprofit one does not like), or donations made to a friend. MEASURES: Percentage weight loss per week. ANALYSIS: Multivariable linear regressions. RESULTS: Controlling for several participant and contract characteristics, contracts with anticharity, charity, and friend deposits had greater reported weight loss than nonincentivized contracts. Weight change per week relative to those without deposits was -0.33%, 0.28%, and -0.25% for anti-charity, charity, and friend, respectively ( P < 0.001). Contracts without a weight verification method claimed more weight loss than those with verification. CONCLUSION: Voluntary use of commitment contracts may be an effective tool to assist weight loss. Those who choose to use monetary incentives report more weight loss. It is not clear whether this is due to the incentives or higher motivation. PMID- 27502834 TI - Biomanufacture of nano-Pd(0) by Escherichia coli and electrochemical activity of bio-Pd(0) made at the expense of H2 and formate as electron donors. AB - OBJECTIVE: Palladised cells of Desulfovibrio desulfuricans and Shewanella oneidensis have been reported as fuel cell electrocatalysts but growth at scale may be unattractive/costly; we have evaluated the potential of using E. coli, using H2/formate for Pd-nanoparticle manufacture. RESULTS: Using 'bio-Pd' made under H2 (20 wt%) cyclic voltammograms suggested electrochemical activity of bio NPs in a native state, attributed to proton adsorption/desorption. Bio-Pd prepared using formate as the electron donor gave smaller, well separated NPs; this material showed no electrochemical properties, and hence little potential for fuel cell use using a simple preparation technique. Bio-Pd on S. oneidensis gave similar results to those obtained using E. coli. CONCLUSION: Bio-Pd is sufficiently conductive to make an E. coli-derived electrochemically active material on intact, unprocessed bacterial cells if prepared at the expense of H2, showing potential for fuel cell applications using a simple one-step preparation method. PMID- 27502833 TI - A/T Run Geometry of B-form DNA Is Independent of Bound Methyl-CpG Binding Domain, Cytosine Methylation and Flanking Sequence. AB - DNA methylation in a CpG context can be recognised by methyl-CpG binding protein 2 (MeCP2) via its methyl-CpG binding domain (MBD). An A/T run next to a methyl CpG maximises the binding of MeCP2 to the methylated DNA. The A/T run characteristics are reported here with an X-ray structure of MBD A140V in complex with methylated DNA. The A/T run geometry was found to be strongly stabilised by a string of conserved water molecules regardless of its flanking nucleotide sequences, DNA methylation and bound MBD. New water molecules were found to stabilise the Rett syndrome-related E137, whose carboxylate group is salt bridged to R133. A structural comparison showed no difference between the wild type and MBD A140V. However, differential scanning calorimetry showed that the melting temperature of A140V constructs in complex with methylated DNA was reduced by ~7 degrees C, although circular dichroism showed no changes in the secondary structure content for A140V. A band shift analysis demonstrated that the larger fragment of MeCP2 (A140V) containing the transcriptional repression domain (TRD) destabilises the DNA binding. These results suggest that the solution structure of MBD A140V may differ from the wild-type MBD although no changes in the biochemical properties of X-ray A140V were observed. PMID- 27502835 TI - Expression of a high sweetness and heat-resistant mutant of sweet-tasting protein, monellin, in Pichia pastoris with a constitutive GAPDH promoter and modified N-terminus. AB - OBJECTIVES: To improve the stability and sweetness of the sweet-tasting protein, monellin, by using site-directed mutagenesis and a Pichia pastoris expression system with a GAPDH constitutive promoter. RESULTS: Both wild-type and E2 N mutant of single-chain monellin gene were cloned into the PGAPZalphaA vector and expressed in Pichia pastoris. The majority of the secreted recombinant protein, at 0.15 g/l supernatant, was monellin. This was purified by Sephadex G50 chromatography. The sweetness threshold of wild-type and E2 N were 30 MUg/ml and 20 MUg/ml, respectively. Compared with the proteins expressed in Escherichia coli, the thermostability of both proteins was improved. The N-terminal sequence is determinative for the sweetness of the proteins expressed in yeast strains. CONCLUSIONS: Site-directed mutagenesis, modification of the N-terminus of monellin, and without the need of methanol induction in P. pastoris expression system, indicate the possibility for large-scale production of this sweet-tasting protein. PMID- 27502836 TI - Solving the "Personhood Jigsaw Puzzle" in Residential Care Homes for the Elderly in the Hong Kong Chinese Context. AB - End-of-life care studies on the nature of personhood are bourgeoning; however, the practices utilized for achieving personhood in end-of-life care, particularly in a cultural context in which interdependent being and collectivism prevail, remain underexplored. This study seeks to examine and conceptualize good practices for achieving the personhood of the dying elderly in residential care homes in a Chinese context. Twelve interviews were conducted with both medical and social care practitioners in four care homes to collect narratives of practitioners' practices. Those narratives were utilized to develop an "end-of life case graph." Constant comparative analysis led to an understanding of the practice processes, giving rise to a process model of "solving the personhood jigsaw puzzle" that includes "understanding the person-in-relationship and person in-time," "identifying the personhood-inhibiting experiences," and "enabling personalized care for enhanced psychosocial outcomes." Findings show how the "relational personhood" of the elderly can be maintained when physical deterioration and even death are inevitable. PMID- 27502838 TI - Sixth International AFM BioMed Conference on AFM in life sciences and medicine, December 13 to 17, 2014, San Diego, California. PMID- 27502837 TI - Classical Galactosaemia and CDG, the N-Glycosylation Interface. A Review. AB - Classical galactosaemia is a rare disorder of carbohydrate metabolism caused by galactose-1-phosphate uridyltransferase (GALT) deficiency (EC 2.7.7.12). The disease is life threatening if left untreated in neonates and the only available treatment option is a long-term galactose restricted diet. While this is lifesaving in the neonate, complications persist in treated individuals, and the cause of these, despite early initiation of treatment, and shared GALT genotypes remain poorly understood. Systemic abnormal glycosylation has been proposed to contribute substantially to the ongoing pathophysiology. The gross N glycosylation assembly defects observed in the untreated neonate correct over time with treatment. However, N-glycosylation processing defects persist in treated children and adults.Congenital disorders of glycosylation (CDG) are a large group of over 100 inherited disorders affecting largely N- and O glycosylation.In this review, we compare the clinical features observed in galactosaemia with a number of predominant CDG conditions.We also summarize the N glycosylation abnormalities, which we have described in galactosaemia adult and paediatric patients, using an automated high-throughput HILIC-UPLC analysis of galactose incorporation into serum IgG with analysis of the corresponding N glycan gene expression patterns and the affected pathways. PMID- 27502840 TI - Molybdenum carbide nanotubes: a novel multifunctional material for label-free electrochemical immunosensing. AB - Herein, a multifunctional nanoarchitecture has been developed by integrating well crystalline molybdenum carbide (Mo2C) nanotubes and an electrochemical indicator thionin (TH). The Mo2C nanotubes were synthesized through the self-degradable template method and high-temperature calcination, and their structure and morphology were characterized through scanning electron microscopy (SEM), X-ray diffraction (XRD) and transmission electron microscopy (TEM). Due to the high electrocatalytic properties, excellent conductivity and highly active surface area of Mo2C nanotubes, the Mo2C-based material was used as a nanocarrier to load TH molecules for the development of a label-free electrochemical immunosensor for alpha-fetoprotein (AFP) detection. The decorated TH probe on the Mo2C nanotubes not only acted as a bridging molecule to effectively capture and immobilize primary anti-AFP on the Mo2C nanotubes, but also acted as a signal indicator for the detection of AFP. The proposed immunosensor exhibited excellent selectivity (with a detection limit of 3 pg mL(-1)), high stability and good reproducibility by combining the unique structure and features of the Mo2C nanotubes. Furthermore, this sensing platform was finally used for the detection of AFP in human serum with satisfactory results. Therefore, the Mo2C nanotubes can be considered as a candidate carbon material for fabrication of simple, label-free and ultrasensitive electrochemical sensors, broadening the application of this material. PMID- 27502839 TI - The role of mTOR signalling in the regulation of skeletal muscle mass in a rodent model of resistance exercise. AB - Resistance exercise (RE) activates signalling by the mammalian target of rapamycin (mTOR), and it has been suggested that rapamycin-sensitive mTOR signalling controls RE-induced changes in protein synthesis, ribosome biogenesis, autophagy, and the expression of peroxisome proliferator gamma coactivator 1 alpha (PGC-1alpha). However, direct evidence to support the aforementioned relationships is lacking. Therefore, in this study, we investigated the role of rapamycin-sensitive mTOR in the RE-induced activation of muscle protein synthesis, ribosome biogenesis, PGC-1alpha expression and hypertrophy. The results indicated that the inhibition of rapamycin-sensitive mTOR could prevent the induction of ribosome biogenesis by RE, but it only partially inhibited the activation of muscle protein synthesis. Likewise, the inhibition of rapamycin sensitive mTOR only partially blocked the hypertrophic effects of chronic RE. Furthermore, both acute and chronic RE promoted an increase in PGC-1alpha expression and these alterations were not affected by the inhibition of rapamycin sensitive mTOR. Combined, the results from this study not only establish that rapamycin-sensitive mTOR plays an important role in the RE-induced activation of protein synthesis and the induction of hypertrophy, but they also demonstrate that additional (rapamycin-sensitive mTOR-independent) mechanisms contribute to these fundamentally important events. PMID- 27502841 TI - Conductive Carbon Network inside a Sulfur-Impregnated Carbon Sponge: A Bioinspired High-Performance Cathode for Li-S Battery. AB - A highly conductive sulfur cathode is crucial for improving the kinetic performance of a Li-S battery. The encapsulation of sulfur in porous nanocarbons is expected to benefit the Li(+) migration, yet the e(-) conduction is still to be improved due to a low graphitization degree of a conventional carbon substrate, especially that pyrolyzed from carbohydrates or polymers. Aiming at facilitating the e(-) conduction in the cathode, here we propose to use ketjen black, a highly graphitized nanocarbon building block to form a conductive network for electrons in a biomass-derived, hierarchically porous carbon sponge by a easily scaled-up approach at a low cost. The specifically designed carbon host ensures a high loading and good retention of active sulfur, while also provides a faster electron transmission to benefit the lithiation/delithiation kinetics of sulfur. The sulfur cathode prepared from the carbon network shows excellent cycling and rate performance in a Li-S battery, rendering its practicality for emerging energy storage opportunities such as grids or automobiles. PMID- 27502842 TI - Risks of undernutrition and malnutrition in hospitalized pediatric patients with spinal cord injury. AB - STUDY DESIGN: Prospective study. OBJECTIVES: To describe the nutritional risk/status of Chinese children with spinal cord injury (SCI) at admission and determine the relationship between nutritional risk/status and demography/SCI characteristics. SETTING: China Rehabilitation Research Center, Beijing, China. METHODS: Baseline clinical data, appetite level, anthropometric measurements and Screening Tool for the Assessment of Malnutrition in Pediatrics (STAMP) scores were obtained for pediatric SCI patients. The relationships among the demographic/SCI characteristics and STAMP score and z-scores of weight-for-age (WAZ), height-for-age (HAZ) and body mass index-for-age (BAZ) were assessed. The risk of undernutrition was compared with actual nutritional status. RESULTS: Forty-five children including 12 boys and 33 girls were included. The risks of undernutrition using the STAMP tool and malnutrition were 51.1% and 55.6%, respectively. Children with different demographic characteristics had similar nutritional status and risk of malnutrition. The risk of undernutrition was associated with nutritional status, including WAZ (P<0.001), HAZ (P=0.001), BAZ (P<0.001) and appetite level (P<0.001). Compared with nutritional status, STAMP had a sensitivity of 100%, a specificity of 73.3% and an overall agreement of 82.2%. As the duration of SCI increased, the risks of overweight and stunting increased. CONCLUSIONS: Nutritional screening in all pediatric SCI patients should be performed periodically. The decreasing trends in nutritional status and appetite level after SCI require special attention. The STAMP may be an alternative method for assessing nutritional status in Chinese children with SCI. PMID- 27502843 TI - Chronic abdominal pain in long-term spinal cord injury: a follow-up study. AB - STUDY DESIGN: A longitudinal postal survey. OBJECTIVES: To evaluate the prevalence and characteristics of abdominal pain in long-term spinal cord injury (SCI). SETTING: Members of the Danish SCI Association. METHODS: In 2006, a questionnaire on chronic abdominal pain and discomfort was sent to the 284 members of the Danish SCI association who had been members for at least 10 years; 203 of them responded. An almost identical questionnaire including questions on intensity and interference of pain within the past 7 days, as well as descriptors and treatment, was sent to the 178 surviving members in 2015. RESULTS: Of 130 (73%) responders, 125 answered the question on chronic abdominal pain. The mean time since injury was 30.5 (9.8) years. Chronic abdominal pain or discomfort was reported by 32.8% (41/125), and 23% (29/125) of responders had been at least moderately bothered by this in the past week. Abdominal pain or discomfort was more common in women and in those with self-reported constipation. The median intensity (numeric rating scale) was 6.0 (range 3-10) and it was often associated with autonomic symptoms. Nine (8%) of the 115 individuals who responded in both 2006 and 2015 had developed new abdominal pain or discomfort, 30 (26%) no longer reported it, and 28 (24%) reported it at both time points with a similar intensity. CONCLUSIONS: Chronic abdominal pain or discomfort is common and bothersome in long-term SCI. It has a late onset, but the prevalence and severity do not seem to further increase between 20 and 30 years following SCI. PMID- 27502844 TI - Mode jumping of split-ring resonator metamaterials controlled by high permittivity BST and incident electric fields. AB - We investigate the resonant modes of split-ring resonator (SRR) metamaterials that contain high-permittivity BST block numerically and experimentally. We observe interesting mode-jumping phenomena from the BST-included SRR absorber structure as the excitation wave is incident perpendicularly to the SRR plane. Specifically, when the electric field is parallel to the SRR gap, the BST block in the gap will induce a mode jumping from the LC resonance to plasmonic resonance (horizontal electric-dipole mode), because the displacement current excited by the Mie resonance in the dielectric block acts as a current channel in the gap. When the electric field is perpendicular to the gap side, the plasmonic resonance mode (vertical electric-dipole mode) in SRR changes to two joint modes contributed simultaneously by the back layer, SRR and BST block, as a result of connected back layer and SRR layer by the displacement current in the BST dielectric block. Based on the mode jumping effect as well as temperature and electric-field dependent dielectric constant, the BST-included SRR metamaterials may have great potentials for the applications in electromagnetic switches and widely tunable metamaterial devices. PMID- 27502845 TI - Permutation-based inference for the AUC: A unified approach for continuous and discontinuous data. AB - We investigate rank-based studentized permutation methods for the nonparametric Behrens-Fisher problem, that is, inference methods for the area under the ROC curve. We hereby prove that the studentized permutation distribution of the Brunner-Munzel rank statistic is asymptotically standard normal, even under the alternative. Thus, incidentally providing the hitherto missing theoretical foundation for the Neubert and Brunner studentized permutation test. In particular, we do not only show its consistency, but also that confidence intervals for the underlying treatment effects can be computed by inverting this permutation test. In addition, we derive permutation-based range-preserving confidence intervals. Extensive simulation studies show that the permutation based confidence intervals appear to maintain the preassigned coverage probability quite accurately (even for rather small sample sizes). For a convenient application of the proposed methods, a freely available software package for the statistical software R has been developed. A real data example illustrates the application. PMID- 27502846 TI - Albuminuria and cardiovascular events in patients with acute coronary syndromes: Results from the TRACER trial. AB - BACKGROUND: Albuminuria is associated with cardiovascular (CV) outcomes. We evaluated albuminuria, alone and in combination with estimated glomerular filtration rate (eGFR), as a predictor of mortality and CV morbidity in 12,944 patients with non-ST-segment elevation acute coronary syndromes. METHODS: Baseline serum creatinine and urinary dipsticks were obtained, with albuminuria stratified into no/trace albuminuria, microalbuminuria (>=30 but <300 mg/dL), or macroalbuminuria (>=300 mg/dL). Kaplan-Meier rates and proportional Cox hazards models of CV death, overall mortality, CV death or myocardial infarction (MI), and bleeding were calculated. Incidence of acute kidney injury, identified by adverse event reporting and creatinine increase (absolute >=0.3 mg/dL or relative >=50%), was descriptively reported. RESULTS: Both dipstick albuminuria and creatinine values were available in 9473 patients (73.2%). More patients with macroalbuminuria, versus no/trace albuminuria, had diabetes (66% vs 27%) or hypertension (86% vs 68%). Rates for CV death and overall mortality per strata were 3.1% and 4.8% (no/trace albuminuria); 5.8% and 9.0% (microalbuminuria); and 7.7% and 12.6% (macroalbuminuria) at 2 years of follow-up. Corresponding rates for CV death or MI were 12.2%, 16.9%, and 23.5%, respectively. Observed acute kidney injury rates were 0.6%, 1.2%, and 2.9% (n = 79), respectively. Adjusted HRs for macroalbuminuria on CV mortality were 1.65 (95% CI 1.15-2.37), and after adjustment with eGFR, 1.37 (95% CI 0.93-2.01). Corresponding HRs for overall mortality were 1.82 (95% CI 1.37-2.42) and 1.47 (95% CI 1.08-1.98). CONCLUSIONS: High-risk patients with non-ST-segment elevation acute coronary syndromes and albuminuria have increased morbidity and increased overall mortality independent of eGFR. PMID- 27502847 TI - Rationale and design of a randomized cluster trial to improve guideline-adherence of secondary preventive drugs prescription after coronary artery bypass grafting in China: Measurement and Improvement Studies of Surgical Coronary Revascularization: Secondary Prevention (MISSION-1) Study. AB - OBJECTIVES: The benefits of secondary preventive drugs after coronary artery bypass grafting have been thoroughly established. However, the prescription rates of these drugs are low at discharge in China. We sought to evaluate the effectiveness of continuous quality improvement with mobile-based interventions for clinicians on improving the guideline-adherence of secondary preventive drugs prescription. METHODS AND RESULTS: The quality MISSION-1 study is a cluster randomized controlled trial. We enrolled 60 hospitals with a bypass surgery volume of more than 30 a year and randomly assigned them into the intervention group or the control group in a 1:1 ratio using minimized random grouping. The intervention group undertakes a series of mobile-based interventions, while the control group maintains a routine practice pattern. All sites consecutively register patients who underwent isolated coronary artery bypass grafting and submit in-hospital data. We require supporting documents regarding prescription information at discharge to adjudicate the outcome measures. The estimated sample size of enrolled patients is 9,600. The primary outcome measure is the prescription rate of statins for eligible patients at discharge. The secondary outcome measures are beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and optimal medical therapy. MISSION-1 study is now recruiting patients. CONCLUSIONS: The MISSION-1 study has the potential to identify the effectiveness of interventions on improving secondary prevention adherence at discharge after bypass surgery in China and further disseminate findings to other settings to improve the quality of care. PMID- 27502848 TI - Impact of baseline mitral regurgitation on short- and long-term outcomes following transcatheter aortic valve replacement. AB - BACKGROUND: The prevalence of concomitant significant mitral regurgitation (MR) in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) ranges from 2% to 33%. The impact of significant MR on post-TAVR outcomes remains controversial. METHODS: The data from a cohort of patients with symptomatic severe AS undergoing TAVR at out institution were retrospectively analyzed. The last transthoracic echocardiogram (TTE) before the index TAVR procedure was selected as the baseline assessment of the degree of MR. The total study cohort (N = 589) was divided into 2 groups: significant >=moderate MR (n = 68) versus nonsignificant =moderate MR on mortality at short- and long-term follow-up periods. RESULTS: Patients with >=moderate MR had a higher mortality rate versus patients with =moderate group, 62.5% and 77.7% of patients had improved to 35% and <=45%, >45% and <55%, and >=55%) and as a continuous variable. Secondary outcomes of interest were 1-year all-cause, cardiovascular, and heart failure readmissions. RESULTS: The risk of 1-year mortality was 29.0% in patients with EF <= 35%, compared with 13.0% in patients in the reference group, EF >= 55% (adjusted hazard ratio [HR] 1.58, 95% CI 1.51-1.66). Relative to patients with EF >= 55%, patients with EF <= 35% had an increased risk of 1-year all-cause readmission (adjusted HR 1.20, 95% CI 1.17-1.24), cardiovascular readmission (adjusted HR 1.36, 95% CI 1.31-1.41), and heart failure readmission (adjusted HR 2.43, 95% CI 2.28-2.60). For patients with EF <= 40%, the hazard of mortality increased by 26% for every 5% decrease in EF, a finding that remained after risk adjustment (adjusted HR 1.11, 95% CI 1.09-1.12). CONCLUSIONS: Low EF after MI remains an important risk factor for postdischarge mortality and hospital readmission, even after adjustment for patient and hospital characteristics. PMID- 27502854 TI - Blood pressure control and stroke or bleeding risk in anticoagulated patients with atrial fibrillation: Results from the ROCKET AF Trial. AB - BACKGROUND: We conducted a retrospective analysis examining the association between systolic blood pressure (SBP) or hypertension bracket and stroke risk in patients with atrial fibrillation (AF). METHODS: The study included 14,256 anticoagulated patients in the ROCKET AF trial. Cox proportional hazards models were used to compare the risk of adverse outcomes by European Society of Cardiology hypertension bracket and screening SBP. RESULTS: In total, 90.5% of patients had hypertension (55.8% controlled, 34.6% uncontrolled). The adjusted risk of stroke or systemic embolism (SE) increased significantly for every 10-mm Hg increase in screening SBP (hazard ratio [HR] 1.07, 95% CI 1.02-1.13). There was a trend toward an increased adjusted risk of stroke or SE in patients with controlled (HR 1.22, 95% CI 0.89-1.66) and uncontrolled hypertension (HR 1.42, 95% CI 1.03-1.95) (P = .06). In contrast, the adjusted risk of major bleeding was similar between hypertensive brackets and did not vary significantly by screening SBP. The benefit of rivaroxaban versus warfarin in preventing stroke or SE was consistent among patients regardless of SBP (P interaction = .69). CONCLUSIONS: In a trial of anticoagulated patients with AF, increasing screening SBP was independently associated with stroke and SE, and one-third of patients had uncontrolled hypertension. The relative effectiveness and safety of rivaroxaban versus warfarin were consistent across all levels of screening SBP. A single SBP may be an important factor in reducing the overall risk of stroke and SE in anticoagulated patients with AF. PMID- 27502855 TI - Effects of interactive patient smartphone support app on drug adherence and lifestyle changes in myocardial infarction patients: A randomized study. AB - BACKGROUND: Patients with myocardial infarction (MI) seldom reach recommended targets for secondary prevention. This study evaluated a smartphone application ("app") aimed at improving treatment adherence and cardiovascular lifestyle in MI patients. DESIGN: Multicenter, randomized trial. METHODS: A total of 174 ticagrelor-treated MI patients were randomized to either an interactive patient support tool (active group) or a simplified tool (control group) in addition to usual post-MI care. Primary end point was a composite nonadherence score measuring patient-registered ticagrelor adherence, defined as a combination of adherence failure events (2 missed doses registered in 7-day cycles) and treatment gaps (4 consecutive missed doses). Secondary end points included change in cardiovascular risk factors, quality of life (European Quality of Life-5 Dimensions), and patient device satisfaction (System Usability Scale). RESULTS: Patient mean age was 58 years, 81% were men, and 21% were current smokers. At 6 months, greater patient-registered drug adherence was achieved in the active vs the control group (nonadherence score: 16.6 vs 22.8 [P = .025]). Numerically, the active group was associated with higher degree of smoking cessation, increased physical activity, and change in quality of life; however, this did not reach statistical significance. Patient satisfaction was significantly higher in the active vs the control group (system usability score: 87.3 vs 78.1 [P = .001]). CONCLUSIONS: In MI patients, use of an interactive patient support tool improved patient self-reported drug adherence and may be associated with a trend toward improved cardiovascular lifestyle changes and quality of life. Use of a disease specific interactive patient support tool may be an appreciated, simple, and promising complement to standard secondary prevention. PMID- 27502856 TI - Association of hospital myocardial infarction volume with adherence to American College of Cardiology/American Heart Association performance measures: Insights from the National Cardiovascular Data Registry. AB - BACKGROUND: Adherence to guideline-based therapy improves patient outcomes after acute myocardial infarction (AMI) and hospital AMI volume is associated with reperfusion care, but the extent hospital AMI volume is associated with overall guideline adherence is unclear. METHODS AND RESULTS: We studied 486 hospitals treating 249,877 AMI patients in ACTION Registry-GWTG from January 1, 2007, to March 31, 2011. Hospital adherence to each American College of Cardiology/American Heart Association performance measure was compared between tertiles defined by hospital AMI volume: low (<=108 cases/y), middle (>=109 and <=227 cases/y), and high (>=228 cases/y). Multivariable logistic regression, adjusting for patient and hospital characteristics, was used to examine the association between annual AMI volume and adherence to each measure. Similar modeling was used to evaluate the relationship between AMI volume and in-hospital mortality. Compared with high-volume hospitals, lower-volume hospitals were less likely to be academically affiliated, or to have cardiac surgery capabilities, electronic health records, or dedicated tobacco treatment services. Higher-volume hospitals had greater adherence to each performance measure, except aspirin use at arrival and reperfusion therapy. The greatest difference was in the rates of referral to cardiac rehabilitation (59%, 76%, and 83% in low-, middle-, and high volume hospitals, respectively). After multivariable adjustment, higher AMI volume (up to 400 AMI patients/y) remained associated with higher-performance measure adherence. There was no association between AMI volume and in-hospital mortality after adjusting for patient and hospital characteristics. CONCLUSIONS: Higher hospital AMI volume was correlated with better adherence to process of care measures, but not in-hospital mortality. PMID- 27502857 TI - Effect of ColchiciNe on the InciDence of Atrial Fibrillation in Open Heart Surgery Patients: END-AF Trial. AB - BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia in patients undergoing cardiac surgery and may result in significant morbidity and increased hospital stay. This study was conducted to determine if colchicine administered preoperatively to patients undergoing cardiac surgery and continued during hospitalization is effective in reducing the incidence of postoperative AF. METHODS: In this multicenter prospective randomized open-label study, consecutive patients with no history of AF and scheduled to undergo elective cardiac surgery (n = 360) were randomized to colchicine (n = 179) or no-colchicine (n = 181). Main exclusion criteria were history of AF or supraventricular arrhythmias or absence of sinus rhythm at enrolment, and contraindications to colchicine. Colchicine was orally administered 12 to 24 hours preoperatively and continued until hospital discharge. The primary efficacy end point was documented AF lasting more than 5 minutes. Safety end point was colchicine adverse effects. RESULTS: In-hospital mortality was 3.3%. The primary end point of AF occurred in 63 patients (17.5%): 26 (14.5%) in the colchicine group and 37 (20.5%) in the no colchicine group (relative risk reduction 29.3% [P = .14]). Diarrhea occurred in 54 patients, 44 (24.6%) on colchicine and 10 (5.5%) on no-colchicine (P < .001). Diarrhea led to discontinuation of colchicine in 23 (52%) of the 44 patients. CONCLUSION: Colchicine administered preoperatively to patients undergoing cardiac surgery and continued until hospital discharge failed to significantly reduce the incidence of early postoperative AF. Diarrhea was the most common adverse effect of colchicine leading to its discontinuation in more than half of the patients with this adverse effect. PMID- 27502858 TI - Reactive hyperemia is associated with adverse clinical outcomes in heart failure. AB - INTRODUCTION: Impaired endothelial function, as assessed by brachial artery flow mediated dilation (FMD), is an established risk factor for cardiovascular events. FMD is impaired in heart failure (HF) patients, but less is known about hyperemic brachial artery flow. We investigated the relationship between FMD and hyperemic flow with adverse clinical outcomes in HF patients. METHODS: Brachial artery FMD and hyperemic flow were assessed in 156 patients (70.5 % Male; 45.5% Caucasian; mean age (+/- SD) = 56.2 (+/-12.4) years) with HF and reduced left ventricular ejection fraction (LVEF). Cox proportional hazard models were used to assess the potential explanatory association of FMD and hyperemic flow with the composite outcome of death or cardiovascular hospitalization over a median 5-year follow-up period. RESULTS: Both FMD and hyperemic flow were negatively correlated with age, but unrelated to sex, race, body mass index, LVEF or N-terminal pro-B-Type natriuretic peptide (NT-ProBNP). Reduced hyperemic flow, but not FMD, was associated with an increased risk of death or cardiac hospitalization after controlling for traditional risk factors. CONCLUSION: The association of reduced hyperemic flow with increased risk of adverse clinical outcomes suggests that micro-vascular function may be an important prognostic marker in patients with HF. PMID- 27502859 TI - Time course, predictors, and prognostic implications of significant mitral regurgitation after ST-segment elevation myocardial infarction. AB - BACKGROUND: Ischemic mitral regurgitation (MR) is a known complication of ST segment elevation myocardial infarction (STEMI) with important prognostic implications. We evaluated changes over time in ischemic MR after STEMI and the prevalence and predictors of significant (grade >=2) MR at 12 months. Furthermore, the prognostic additional value of significant MR at 12-month follow up over acute MR was assessed. METHODS: STEMI patients (n = 1,599; 77% male; 60 +/- 12 years) treated with primary percutaneous coronary intervention underwent echocardiography <48 hours of admission (baseline) and at 12 months. Mortality data were collected during long-term follow-up. RESULTS: At baseline, significant MR was present in 103 (6%) patients. After 12 months, MR worsened >=1 grade in 321 (20%) patients, remained stable in 963 (60%), and improved >=1 grade in 315 (20%). Significant MR was present in 135 patients at 12 months (8%, P = .01 vs baseline). Age, left ventricular end-systolic volume, and significant MR at baseline were independently associated with significant MR at follow-up. During follow-up (median, 50 months), 121 (8%) patients died (40% of cardiovascular cause). Significant MR at follow-up was independently associated with all-cause (hazard ratio, 1.65, 95% CI, 1.02-2.99) and cardiovascular mortality (hazard ratio, 2.47; 95% CI, 1.24-4.92), also after adjusting for significant MR at baseline. CONCLUSIONS: The prevalence of significant MR after STEMI increases over time. Age, baseline left ventricular end-systolic volume, and baseline significant MR are independently associated with significant MR at follow-up. Significant MR at 12 months is associated with subsequent all-cause and cardiovascular mortality and shows additional prognostic value over acute MR. PMID- 27502860 TI - Left atrial thrombus resolution in atrial fibrillation or flutter: Results of a prospective study with rivaroxaban (X-TRA) and a retrospective observational registry providing baseline data (CLOT-AF). AB - BACKGROUND: Data on left atrial/left atrial appendage (LA/LAA) thrombus resolution after non-vitamin K antagonist (VKA) oral anticoagulant treatment are scarce. The primary objective of X-TRA was to explore the use of rivaroxaban for the resolution of LA/LAA thrombi in patients with nonvalvular atrial fibrillation (AF) or atrial flutter, with the CLOT-AF registry providing retrospective data after standard-of-care therapy in this setting. METHODS: X-TRA was a prospective, single-arm, open-label, multicenter study that investigated rivaroxaban treatment for 6 weeks for LA/LAA thrombus resolution in patients with nonvalvular AF or atrial flutter and LA/LAA thrombus confirmed at baseline on a transesophageal echocardiogram (TEE). CLOT-AF retrospectively collected thrombus-related patient outcome data after standard-of-care anticoagulant treatment for 3 to 12 weeks in patients with nonvalvular AF or atrial flutter who had LA/LAA thrombi on TEE recorded in their medical file. RESULTS: In X-TRA, patients were predominantly (95.0%) from Eastern European countries. The adjudicated thrombus resolution rate was 41.5% (22/53 modified intention-to-treat [mITT] patients, 95% CI 28.1%-55.9%) based on central TEE assessments. Resolved or reduced thrombus was evident in 60.4% (32/53 mITT patients, 95% CI 46.0%-73.6%) of patients. In CLOT-AF, the reported thrombus resolution rate was 62.5% (60/96 mITT patients, 95% CI 52.0% 72.2%) and appeared better in Western European countries (34/50; 68.0%) than in Eastern European countries (26/46; 56.5%). CONCLUSION: X-TRA is the first prospective, multicenter study examining LA/LAA thrombus resolution with a non VKA oral anticoagulant in VKA-naive patients or in patients with suboptimal VKA therapy. Rivaroxaban could be a potential option for the treatment of LA/LAA thrombi. PMID- 27502861 TI - Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and design of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Lipid Lowering and SPIRE Cardiovascular Outcomes Trials. AB - BACKGROUND: Although statins significantly reduce vascular event rates, residual cholesterol risk remains high in many patient groups, including those with known vascular disease as well as in the setting of high-risk primary prevention. Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), prolongs the half-life of hepatic low density lipoprotein (LDL) receptors, and reduces circulating atherogenic cholesterol levels. DESIGN: The SPIRE program comprises 6 lipid-lowering studies and 2 cardiovascular outcomes trials, each comparing bococizumab (150 mg subcutaneously every 2 weeks) to matching placebo. The 6 SPIRE lipid-lowering studies include 3 parallel 12-month assessments of bococizumab on atherogenic lipids among statin-treated individuals at high residual risk (SPIRE-HR, SPIRE LDL, SPIRE-LL), one 12-month study of bococizumab among individuals with familial hypercholesterolemia (SPIRE-FH), one 6-month study of bococizumab among those with statin intolerance (SPIRE-SI), and one 3-month study of bococizumab delivery using an auto-injector device (SPIRE-AI). The SPIRE-1 and SPIRE-2 event-driven cardiovascular outcome trials will assess the efficacy and safety of bococizumab in the prevention of incident vascular events in high-risk populations with and without clinically evident cardiovascular disease who have directly measured entry LDL cholesterol levels >=70 mg/dL (SPIRE-1, n = 17,000) or >=100 mg/dL (SPIRE-2, n = 11,000). SUMMARY: The SPIRE trials, inclusive of more than 30,000 participants worldwide, will ascertain the magnitude of reduction in atherogenic lipids that accrue with bococizumab and determine whether the addition of this PCSK9 inhibitor to standard treatment significantly reduces cardiovascular morbidity and mortality in high-risk patients, including those without a history of clinical cardiovascular events. PMID- 27502862 TI - Effect of apixaban on brain infarction and microbleeds: AVERROES-MRI assessment study. AB - BACKGROUND: Clinical and subclinical (covert) stroke is a cause of cognitive loss and functional impairment. In the AVERROES trial, we performed serial brain magnetic resonance imaging (MRI) scans in a subgroup to explore the effect of apixaban, compared with aspirin, on clinical and covert brain infarction and on microbleeds in patients with atrial fibrillation. METHODS: We performed brain MRI (T1, T2, fluid-attenuated inversion recovery, and T2* gradient echo sequences) in 1,180 at baseline and in 931 participants at follow-up. Mean interval from baseline to follow-up MRI scans was 1.0 year. The primary outcome was a composite of clinical ischemic stroke and covert embolic pattern infarction (defined as infarction >1.5 cm, cortical-based infarction, or new multiterritory infarction). Secondary outcomes included new MRI-detected brain infarcts and microbleeds and change in white matter hyperintensities. RESULTS: Baseline MRI scans revealed brain infarct(s) in 26.2% and microbleed(s) in 10.5%. The rate of the primary outcomes was 2.0% in the apixaban group and 3.3% in the aspirin group (hazard ratio [HR] 0.55; 0.27-1.14) from baseline to follow-up MRI scan (mean duration of follow-up: 1 year). In those who completed baseline and follow-up MRI scans, the rate of new infarction detected on MRI was 2.5% in the apixaban group and 2.2% in the aspirin group (HR 1.09; 0.47-2.52), but new infarcts were smaller in the apixaban group (P = .03). There was no difference in proportion with new microbleeds on follow-up MRI (HR 0.92; 0.53-1.60) between treatment groups. CONCLUSIONS: Apixaban treatment was associated with a nonsignificant trend toward reduction in the composite of clinical ischemic stroke and covert embolic-pattern infarction and did not increase the number of microbleeds in patients with atrial fibrillation compared with aspirin. PMID- 27502863 TI - Clinical and echocardiographic characteristics and outcomes in congestive heart failure at the Hospital of The State University of Haiti. AB - BACKGROUND: This study aimed to evaluate the clinical and epidemiologic profile of congestive heart failure at the principal free-care hospital in Haiti. Cardiovascular disease represents the most prevalent cause of admissions to the medical service of the University Hospital of the State of Haiti. No previous study has examined the demographics of congestive heart failure in urban Haiti. METHODS: Two hundred forty-seven patients presented to the inpatient service between May 2011 and May 2013. Evaluation included history and physical, CBC, renal/metabolic profile, serum glucose, anti-HIV antibody, ECG, chest radiograph and echocardiogram. Treatment included angiotensin converting enzyme inhibitors, furosemide and spironolactone, carvedilol, digoxin and anticoagulation. RESULTS: Women (62.4%) outnumbered men; patients were relatively young (mean age 50.1) and from the lowest socio-economic levels of the population. Nearly all (98.8%) presented with NYHA III-IV status, with correspondingly high mortality (23.3%). Echocardiography showed 73% dilated cardiomyopathy; 83% showed moderate to severe LV systolic dysfunction (mean EF 36.5 +/- 15%) and 17% preserved LV systolic function. The three principal etiologies were dilated cardiomyopathy (29%) hypertensive cardiomyopathy (27%) and peripartum cardiomyopathy (20%). Ischemic cardiomyopathy was rare (3.4%). At 27 months follow-up, 76.7% of the patients were alive and well. Among those who died, mean survival time was 113 days. Readmission carried a poor prognosis. CONCLUSIONS: This congestive heart failure study from Haiti shows an unusually high proportion of young women, primarily due to peripartum cardiomyopathy. Ischemic cardiomyopathy is rare, as in Africa. Further study is warranted to address the particular problem of the high frequency of peripartum cardiomyopathy in this population. PMID- 27502864 TI - Defining nonvalvular atrial fibrillation: A quest for clarification. AB - Non-vitamin K oral anticoagulants (NOACs) are currently recommended for patients with nonvalvular atrial fibrillation since the publication of the 4 major pivotal trials evaluating the efficacy and safety of factor IIa and factor Xa inhibitors. The definition of nonvalvular atrial fibrillation is unclear, varying from one trial to another and even between North American and European guidelines, which is a source of uncertainties in clinical practice. However, many patients with atrial fibrillation present signs of valvular involvement, and clarification of this term is needed to not deny NOACs to patients based on the wrong perception that they may have valvular atrial fibrillation. The currently unique contraindications to NOACs are patients with mechanical heart valves and those with moderate-to-severe mitral stenosis, as stated by the recent 2015 position paper of the European Heart Rhythm Association. Patients with native heart valve involvement, regardless of their severity, are suitable for NOAC therapy. Patients with bioprosthetic heart valves and mitral valve repair may be suitable for NOACs except for the first 3 and the first 3-6 months postoperatively, respectively. Patients with transaortic valve implantation or percutaneous transluminal aortic valvuloplasty are also considered as being eligible for NOACs, although the bleeding risk has to be carefully considered in this population often requiring a combination with antiplatelet therapy. Future studies are warranted to increase the level of evidence of use of NOACs, particularly in patients with transaortic valve implantation and valvular surgery, and to determine whether they could be used in the future in the only 2 remaining contraindications. PMID- 27502865 TI - Very early administration of glucose-insulin-potassium by emergency medical service for acute coronary syndromes: Biological mechanisms for benefit in the IMMEDIATE Trial. AB - AIMS: In the IMMEDIATE Trial, intravenous glucose-insulin-potassium (GIK) was started as early as possible for patients with suspected acute coronary syndrome by ambulance paramedics in communities. In the IMMEDIATE Biological Mechanism Cohort substudy, reported here, we investigated potential modes of GIK action on specific circulating metabolic components. Specific attention was given to suppression of circulating oxygen-wasting free fatty acids (FFAs) that had been posed as part of the early GIK action related to averting cardiac arrest. METHODS: We analyzed the changes in plasma levels of FFA, glucose, C-peptide, and the homeostasis model assessment (HOMA) index. RESULTS: With GIK, there was rapid suppression of FFA levels with estimated levels for GIK and placebo groups after 2 hours of treatment of 480 and 781 MUmol/L (P<.0001), even while patterns of FFA saturation remained unchanged. There were no significant changes in the HOMA index in the GIK or placebo groups (HOMA index: placebo 10.93, GIK 12.99; P = .07), suggesting that GIK infusions were not countered by insulin resistance. Also, neither placebo nor GIK altered endogenous insulin secretion as reflected by unchanging C-peptide levels. CONCLUSION: These mechanistic observations support the potential role of FFA suppression in very early cardioprotection by GIK. They also suggest that the IMMEDIATE Trial GIK formula is balanced with respect to its insulin and glucose composition, as it induced no endogenous insulin secretion. PMID- 27502866 TI - Effect of age on efficacy and safety of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial. AB - BACKGROUND: Antithrombotic therapy plays an important role in the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS) but is associated with bleeding risk. Advanced age may modify the relationship between efficacy and safety. METHODS: Efficacy and safety of vorapaxar (a protease-activated receptor 1 antagonist) was analyzed across ages as a continuous and a categorical variable in the 12,944 patients with NSTE ACS enrolled in the TRACER trial. To evaluate the effect of age, Cox regression models were developed to estimate hazard ratios (HRs) with the adjustment of other baseline characteristics and randomized treatment for the primary efficacy composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, and the primary safety composite of moderate or severe Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding. RESULTS: The median age of the population was 64years (25th, 75th percentiles = 58, 71). Also, 1,791 patients (13.8%) were <=54years of age, 4,968 (38.4%) were between 55 and 64 years, 3,979 (30.7%) were between 65 and 74 years, and 2,206 (17.1%) were 75years or older. Older patients had higher rates of hypertension, renal insufficiency, and previous stroke and worse Killip class. The oldest age group (>=75years) had substantially higher 2-year rates of the composite ischemic end point and moderate or severe GUSTO bleeding compared with the youngest age group (<=54years). The relationships between treatment assignment (vorapaxar vs placebo) and efficacy outcomes did not vary by age. For the primary efficacy end point, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were as follows: 1.12 (0.88-1.43), 0.88 (0.76-1.02), 0.89 (0.76-1.04), and 0.88 (0.74-1.06), respectively (P value for interaction = .435). Similar to what was observed for efficacy outcomes, we did not observe any interaction between vorapaxar and age on bleeding outcomes. For the composite of moderate or severe bleeding according to the GUSTO classification, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were 1.73 (0.89-3.34), 1.39 (1.04-1.86), 1.10 (0.85-1.42), and 1.73 (1.29-2.33), respectively (P value for interaction = .574). CONCLUSION: Older patients had a greater risk for ischemic and bleeding events; however, the efficacy and safety of vorapaxar in NSTE ACS were not significantly influenced by age. PMID- 27502867 TI - Risky business: Personalizing the approach to percutaneous coronary intervention. PMID- 27502868 TI - Predicting in-hospital worsening heart failure at time of admission, but do we really need another heart failure risk model? PMID- 27502870 TI - Development and validation of a risk model for in-hospital worsening heart failure from the Acute Decompensated Heart Failure National Registry (ADHERE). AB - BACKGROUND: A subset of patients hospitalized with acute heart failure experiences in-hospital worsening heart failure, defined as persistent or worsening signs or symptoms requiring an escalation of therapy. METHODS: We analyzed data from the Acute Decompensated Heart Failure National Registry (ADHERE) linked to Medicare claims to develop and validate a risk model for in hospital worsening heart failure. Our definition of in-hospital worsening heart failure included events such as escalation of medical therapy (eg, inotropic medications) >12hours after admission. We considered candidate risk prediction variables routinely assessed at admission, including age, medical history, biomarkers, and renal function. We used logistic regression with robust standard errors to generate a risk model in a 66% random derivation sample; we validated the model in the remaining 34%. We evaluated the calibration and discrimination of the model in both samples. RESULTS: We evaluated 23,696 patients hospitalized with acute heart failure. Baseline characteristics were well matched in the derivation and validation samples, and the occurrence of in-hospital worsening heart failure was similar in both samples (15.4% and 15.6%, respectively). In the multivariable model, the strongest predictors of in-hospital worsening heart failure were increased troponin and creatinine. The model was well calibrated and had good discrimination in the derivation sample (c statistic, 0.74) and validation sample (c statistic, 0.72). CONCLUSIONS: The ADHERE worsening heart failure risk model is a clinical tool with good discrimination for use in patients hospitalized with acute heart failure to identify those at increased risk for in-hospital worsening heart failure. This tool may be useful to target treatment strategies for patients at high risk for in-hospital worsening heart failure. PMID- 27502871 TI - Asymptomatic severe aortic stenosis: Cardiopulmonary exercise testing in "The World of AVATAR". PMID- 27502869 TI - Understanding physician-level barriers to the use of individualized risk estimates in percutaneous coronary intervention. AB - BACKGROUND: The foundation of precision medicine is the ability to tailor therapy based upon the expected risks and benefits of treatment for each individual patient. In a prior study, we implemented a software platform, ePRISM, to execute validated risk-stratification models for patients undergoing percutaneous coronary intervention and found substantial variability in the use of the personalized estimates to tailor care. A better understanding of physicians' perspectives about the use of individualized risk-estimates is needed to overcome barriers to their adoption. METHODS: In a qualitative research study, we conducted interviews, in-person or by telephone, with 27 physicians at 8 centers that used ePRISM until thematic saturation occurred. Data were coded using descriptive content analyses. RESULTS: Three major themes emerged among physicians who did not use ePRISM to support decision making: (1) "Experience versus Evidence," physicians' preference to rely upon personal experience and subjective assessments rather than objective risk estimates; (2) "Omission of Therapy," the perception that the use of risk models leads to unacceptable omission of potentially beneficial therapy; and (3) "Unnecessary Information," the opinion that information derived from risk models is not needed because physicians' decision making is already sound and they already know the information. CONCLUSIONS: Barriers to the use of risk models in clinical practice include physicians' perceptions that their experience is sufficient, that models may lead to omission of therapy in patients that may benefit from therapy, and that they already provide good care. Anticipating and overcoming these barriers may improve the adoption of precision medicine. PMID- 27502872 TI - Response: Asymptomatic severe aortic stenosis: Cardiopulmonary exercise testing in "the world of AVATAR". PMID- 27502873 TI - To the Editor. PMID- 27502874 TI - In response to Letter to the Editor. PMID- 27502875 TI - Greater Attention to Task-Relevant Threat Due to Orbitofrontal Lesion. AB - Injury to the orbitofrontal cortex (OFC) is a frequent consequence of head injury and may lead to dysfunctional regulation of emotional and social behavior. Dysfunctional emotional behavior may partly be related to the role of the OFC in emotion-attention interaction, as reported previously. In order to better understand its role in emotion-attention and emotion-cognitive control interactions, we investigated attention allocation to task-relevant and task irrelevant threat-related emotional stimuli during a task requiring cognitive control in patients with lesion to the OFC. We measured the behavioral performance and event-related potentials (ERP) of 13 patients with OFC lesion and 11 control subjects during a Go/NoGo visual discrimination task. In the task, line drawings of threatening (spider) and neutral (flower) figures served as either task-relevant Go or NoGo signals, or as task-irrelevant distractors. Overall performance did not differ between the groups. In contrast to the control group performance, the orbitofrontal group performance was improved by relevant threat signal in comparison with neutral signal. Further, task-relevant threat signals evoked larger frontocentral N2-P3 amplitude in the orbitofrontal group. Taken together, behavioral and electrophysiological results suggest that patients with OFC injury allocated more attentional and cognitive control resources in the context of task-relevant emotional stimuli. This study provides new evidence for the role of the OFC in emotion-attention and emotion-cognitive control interactions. Further, the OFC seems to contribute to the balance between voluntary and involuntary attention networks in context of emotional stimuli. Better understanding of alterations in emotion-attention interaction offers insight into affective dysfunction due to OFC lesion. PMID- 27502876 TI - Factors affecting orocutaneous fistula formation following head and neck reconstructive surgery. AB - This paper explores factors associated with the formation of orocutaneous fistula following head and neck reconstructive surgery, and considers ways this complication may be reduced. We retrospectively analysed the medical notes of 102 patients who had reconstructive surgery at the study centre over a 17-month period. Information included patient comorbidities, previous oncological treatment, duration of hospital stay, complications, incidence of fistulas, and the day on which oral intake started. Patients who had previously had chemoradiotherapy were significantly more likely to develop a fistula than those who had not (p=0.008). Associations between other variables were not significant. Our analysis identifies a considerable number of patients who require head and neck reconstructive surgery as a result of new primary or recurrent tumours within previously irradiated fields. It also demonstrates the impact of previous chemoradiotherapy on many elements of recovery and rehabilitation, including but not limited to fistula formation. Treatment for this group of patients requires careful consideration and planning, as their recovery trajectory may be different from those patients who undergo surgery as a primary intervention. We suggest ways to reduce the incidence of fistulas, which include the avoidance of oral intake before the eighth postoperative day. PMID- 27502877 TI - Physiological marker and surgical ligation of patent ductus arteriosus in neonates. AB - BACKGROUND: In preterm infants, immediate complications of surgical closure of a patent ductus arteriosus (PDA) are often serious and due to haemorrhage or ligation of incorrect structures. The aim of this study was to measure blood pressure (BP) changes during ligation and hence introduce a novel physiological marker to alert surgeons to the ligation of incorrect structures. MATERIALS AND METHODS: This study included 146 preterm babies (<=35 weeks of gestation) who underwent surgical PDA closure of a left-to-right unidirectional PDA between June 2006 and December 2015. The median weight was 920 g (range, from 520 to 2200 g). In all cases, the PDA was test cross-clamped, and the lower limb or umbilical artery BP was recorded before ligation. RESULTS: Based on preoperative echocardiography, the PDA diameter range was 2-4 mm in 135 cases and 5-6 mm in 11 cases. During test clamping of the PDA, a 20-60% rise in mean BP was recorded. The lower figure was observed with smaller PDAs. CONCLUSION: It is estimated that the mean BP should rise by 10% for every mm of PDA diameter during test clamping and ligation of the PDA, irrespective of weight or age. The absence of this expected rise in mean BP indicates that an incorrect structure might have been clamped. PMID- 27502878 TI - Management of oesophageal atresia in a developing country: Is primary repair forbidden? AB - BACKGROUND: The aim of the study was to evaluate the outcomes of initial surgical procedures for oesophageal atresia at our institution. Primary repair of oesophageal atresia at our centre was perceived to be associated with a high mortality rate. In view of this, almost all patients seen since January 2014 were offered initial surgery for staged repair. MATERIALS AND METHODS: A retrospective review of records of infants with oesophageal atresia seen at the centre from January 2007 to December 2014 was used in this study. RESULTS: Eighty-five cases of oesophageal atresia were seen over the study period. Of these, 74 (87.1) had surgery performed. Surgical outcome was, however, indicated in 67 of the 74, with overall survival rate of 40.3%. Among the 67 patients, early primary repair was performed in 24 (35.8%) with a survival rate of 45.8% (11 patients). Totally, 12 (17.9%) of the 67 had initial procedure for delayed primary repair, with a survival rate of 16.7% (2 patients). The remaining 31 (46.3%) patients had initial surgery for staged repair, with survival rate of 45.2% (14 patients). There was no association between the type of surgery and the surgical outcome (chi2 = 3.396, df = 2, P = 0.183). CONCLUSION: The overall surgical survival rate of 40.3% for oesophageal atresia at our institution is low. This study did not show any difference in the survival rate of 45.8% and 45.2% associated with primary repair and staged repair respectively. PMID- 27502879 TI - Clinical spectrum of neonates presenting with pneumoperitoneum: A retrospective study. AB - BACKGROUND: Neonatal pneumoperitoneum is attributed, in most of the reported cases, to necrotising enterocolitis (NEC). There are also other causes leading to free intraperitoneal air. The aim of this study is to describe the clinical spectrum, causes, management and outcome of neonates admitted with pneumoperitoneum in the paediatric surgery unit of a university hospital. SUBJECTS AND METHODS: This retrospective study included neonates having radiographic evidences of pneumoperitoneum from 2012 to the end of 2014. Patients' files were analysed regarding age at admission, birth weight, history, clinical picture, management, operative findings and subsequent outcome. RESULTS: Fifty-six out of 379 neonates (14.7%) were found to have pneumoperitoneum during the study period. There were 35 males (62.5%) and 21 females (37.5%). Cases diagnosed as NEC represented 27 neonates (48.2%). There were 29 cases (51.8%) with causes not related to NEC. Non-NEC causes were spontaneous intestinal perforation (8.9%), ano-rectal malformations (7.1%), Hirschsprung's disease (14.2%), ileal atresia (3.5%), incarcerated inguinal hernia (1.7%), gastric perforation (1.7%) and meconium ileus (1.7%). In seven patients (12.5%), those who were managed conservatively (8.9%) or whose laparotomy was negative (3.6%), no cause of pneumoperitoneum could be reached. Overall mortality was 25%, 78.5% of which was NEC-related. CONCLUSIONS: Neonatal pneumoperitoneum is an alerting finding for paediatric surgeons. Most cases imply serious causes with a significant morbidity and mortality, NEC being the most common cause. On the other hand, pneumoperitoneum is not an absolute indication for surgery. Careful assessment and tailored management can limit the morbidity of unnecessary laparotomies. PMID- 27502880 TI - Lower limbs deformities in patients with McCune-Albright syndrome: Tomography and treatment. AB - BACKGROUND: The skeletal changes in McCune-Albright disease are usually severe because of the polyostotic form of the disease. Trendelenberg gait and limited mobility are the most common presenting features. The constellation of Cafe-au lait spots and polyostotic bone involvement is commonly referred to as McCune Albright's syndrome (MAS). MATERIALS AND METHODS: One boy and 4 girls (7-16 years) were sought in our departments from 1998 to 2012. Limb length discrepancy was the main clinical presentation. Repetitive micro-fractures caused the development of 'Shepherd crook' deformity with pain were the main burden. RESULTS: Because of the repetitive micro-fractures and the significant deformity that distorted the integrity of the long bones which were associated with pain. We referred to re-alignment valgus osteotomy with internal fixation to preserve proper alignment. Moreover, guided growth technique with 8-plates was performed in 1 case. CONCLUSION: Tendency to progressive unilateral lower limb deformity in patients with MAS is usually associated with thinning and expansion of the cortex and distortion of the normal lower limb integrity secondary to repetitive micro fractures. The latter is a situation which warrants surgical treatment to re align the deformity and to preserve function. Prophylactic intramedullary nailing via the application of locking nails to ensure stabilisation of the femoral neck was found to be effective. However, nevertheless, the mosaic nature of MAS means any cell, tissue and organ in any site of the body could be affected to varying degrees. The clinical manifestations are a diversity of the disorder ranging from mild clinical signs to severe life-threatening disease. PMID- 27502881 TI - Digital camera image analysis of faeces in detection of cholestatic jaundice in infants. AB - BACKGROUND: Stool colour assessment is a screening method for biliary tract obstruction in infants. This study is aimed to be a proof of concept work of digital photograph image analysis of stool colour compared to colour grading by a colour card, and the stool bilirubin level test. MATERIALS AND METHODS: The total bilirubin (TB) level contents in stool samples from 17 infants aged less than 1 year, seven with confirmed cholestatic jaundice and ten healthy subjects was measured, and outcome correlated with the physical colour of the stool. RESULTS: The seven infants with cholestasis included 6 cases of biliary atresia and 1 case of pancreatic mass. All pre-operative stool samples in these cases were indicated as grade 1 on the stool card (stool colour in healthy infants ranges from 4 to 6). The average stool TB in the pale stool group was 43.07 MUg/g compared to 101.78 MUg/g in the non-pale stool group. Of the 3 colour channels assessed in the digital photographs, the blue and green light were best able to discriminate accurately between the pre-operative stool samples from infants with cholestasis and the samples from the healthy controls. With red, green, and blue (RGB) image analysis using wave level as the ANN input, the system predicts the stool TB with a relationship coefficient of 0.96, compared to 0.61 when stool colour card grading was used. CONCLUSION: Input from digital camera images of stool had a higher predictive capability compared to the standard stool colour card, indicating using digital photographs may be a useful tool for detection of cholestasis in infants. PMID- 27502882 TI - Association between plasma kisspeptin levels and adolescent gynecomastia. AB - BACKGROUND: Gynecomastia is defined as benign proliferation of male breast glandular tissue. To date, the pathophysiology of adolescent gynecomastia (AG) remains unclear. Kisspeptin is a polypeptide that plays an important role in the regulation of the hypothalamic-pituitary-gonadal hormonal axis. In this study, we investigated whether there is a relationship between kisspeptin and AG. MATERIALS AND METHODS: This study included 40 males between 9 and 18 years of age diagnosed with gynecomastia. The control group consisted of 30 young healthy males in the same age range. The participants were evaluated with respect to anthropometric measurements (age, height, body weight, body mass index, breast and pubic stages and testicular volume). The levels of kisspeptin, follicle-stimulating hormone, luteinizing hormone, estradiol (E2), testosterone (T), and ratio of E2 to T were measured in both groups. RESULTS: The mean age was 13.8 years. There were no differences between the groups in terms of anthropometric parameters, plasma gonadotropin levels, estrogen levels, and E2/T (P > 0.05). Plasma kisspeptin (0.77 and 0.54 ng/mL, P < 0.05) and T (253.9 ng/dL and 117.9 ng/dL) levels were significantly higher in the AG group than in the control group (P < 0.001). CONCLUSION: Kisspeptin levels are an important factor in AG. PMID- 27502883 TI - The value of using loupe magnification and methylene blue dye in intra-operative identification of thyroglossal duct tract. AB - BACKGROUND: This was a comparative randomised study to find out the value of using loupe magnification and methylene blue dye in identification of the thyroglossal duct and to compare between them. PATIENTS AND METHODS: Twenty-two patients who presented with infrahyoid thyroglossal duct cyst were subjected to excision of the cyst with two methods for identification of thyroglossal duct track during the operation. Data were anlysed for identification of multiple tracts, the tract relation to the hyoid bone, incidence of complications and operative time. RESULTS: We found that multiple tracts were present in 9.1% of the patients in Group I and 36.3% in Group II, with no statistically significant difference between the two groups. The incidence of complications was 27.2% in Group I and 9.1% in Group II, with no statistically significant difference between both groups. However, the incidence of identification of the tract, and its relation to the hyoid bone was higher in Group II (90.9%) than in Group I (45.5%) , with a statistically significant difference between both groups. Also the incidence of identification of the extension level of the tract above the hyoid bone and up to the tongue base was significantly higher in Group II (72.8%) as compared to Group I (9.1%). The operative time was significantly shorter in Group II (54.35 min) and was 76.55 min in Group I, (P = 0.0001). CONCLUSION: Intra-operative identification of the thyroglossal tract is an essential step in the removal of the thyroglossal duct cyst. Both loupe magnification and methylene blue dye help in the tract identification, however, the usage of surgical loupes enhances better and safe results. PMID- 27502884 TI - Mixed gonadal dysgenesis in Yaounde: A preliminary experience about three cases. AB - Mixed gonadal dysgenesis is characterised by unilateral chromosomal abnormality, which is probably the result of anaphase lag during mitosis. The 45, XO/46, XY karyotype is the most common form of mosaicism involving the Y chromosome. It is a rare clinical entity with a worldwide incidence of 1.5/10,000 live births. Its epidemiology in Sub-Saharan Africa is not known. This study reports experience in the management of 3 cases at the Yaounde Gynecologic-Obstetric and Paediatric Hospital. From November 2009 to November 2014, 3 cases were successfully managed at our institution. RESULTS: All patients presented with asymmetrical gonadal differentiation. On one side of the body, a poorly-developed testicular gonad and on the other side a gonadal streak. A persistent Momicronllerian remnant was equally found in the 3 cases. Management of mixed gonadal dysgenesis should be done in tertiary health care centres. A multidisciplinary team approach is recommended. PMID- 27502885 TI - Laparoscopic management of an axially torsed gangrenous Meckel's diverticulum in a child. AB - Meckel's diverticulum (MD) is the most common congenital anomaly of the gastrointestinal tract. Most often is asymptomatic but it may give a number of complications including gastrointestinal bleeding, obstruction and inflammation. Axial torsion and gangrene of MD are exceptional. The correct diagnosis of MD could only be made during surgery. Early surgery is important to reduce morbidity, especially perforation. Laparoscopy aided in the diagnosis and adequate treatment. We herein describe the case of a 4-year-old boy with axial torsion of MD. Clinical and radiographic finding suggest a segmental volvulus. Laparoscopy contributes to diagnosis and treatment of torted MD. PMID- 27502886 TI - A case report of Cowper's syringocele in an 18-months old infant at the Yaounde Gynaeco-Obstetric and Pediatric Hospital. AB - Syringocele or dilatation of the duct of the bulbo-urethral (Cowper's) gland is usually of congenital origin but can be acquired. It is a very rare deformity, <10 cases have been reported in literature. The main objective is to describe an additional case of syringocele of Cowper's glands and review the literature. An 18-month-old infant presented with a history of acute urinary retention 3 days after birth and a cystostomy was done. Voiding cystourethrogram was normal and cystourethroscopy showed a syringocele. Endoscopic incision was performed in our patient with satisfactory results. No complications were noted. Syringocele or cystic dilatation of Cowper's gland duct usually has a congenital aetiology. Diagnosis is confirmed by endoscopy. Treatment is by marsupialisation in the urethra by endoscopy. Syringocele is a rare pathology usually congenital. It should be suspected in all case of lower urinary tract obstruction in children. PMID- 27502887 TI - Penetrating chest wound of the foetus. AB - Traumas of the foetus caused by stabbings are rare but actually life-threatening for both the foetus and the mother. We report a case of penetrating chest wound on a baby taken from the obstetrics unit to the paediatric surgical department. His mother was assaulted by his father, a mentally sick person with no appropriate follow-up. The foetus did not show any sign of vital distress. Surgical exploration of the wound has revealed a section of the 10 th rib, a laceration of the pleura and a tearing of the diaphragm. A phrenorraphy and a pleural drainage were performed. The new-born and its mother were released from hospital after 5 days and the clinical control and X-ray checks 6 months later showed nothing abnormal. We insisted a medical, psychiatric follow-up be initiated for the father. As regards pregnant women with penetrating wounds, the mortality rate of the foetus is 80%. The odds are good for our newborn due to the mild injuries and good professional collaboration of the medical staff. Penetrating transuterine wounds of the foetus can be very serious. The health care needed should include many fields due to the mother and the foetus' lesions extreme polymorphism. In our case, it could have prevented by a good psychiatric followed up of the offender. PMID- 27502888 TI - Visceral basidiobolomycosis. PMID- 27502889 TI - Traumatic chest injury in children. PMID- 27502890 TI - Post-traumatic growth in breast cancer: how and when do distress and stress contribute? AB - OBJECTIVE: While several theoretical models provide explanation for the genesis and development of post-traumatic growth (PTG) in the aftermath of stressful events, empirical evidence regarding the predictors and consequences of PTG in breast cancer patients in active treatment and early survivorship is inconclusive. This study, therefore, examines the role of distress and stress as predictors and outcomes of PTG in women with breast cancer over an 18-month period. METHODS: These effects are tested in two structural equation models that track pathways of PTG in a sample of 253 recently diagnosed women. Questionnaires were completed at diagnosis and at 4 follow-up time points assessing cancer specific stress (Impact of Events Scale), global stress (Perceived Stress Scale), and depression and anxiety (Hospital Anxiety and Depression Scale). Post traumatic growth (Silver Lining Questionnaire) was assessed at follow-up time points. RESULTS: Cancer-specific stress was related to higher PTG concurrently and longitudinally. Anxiety was related concurrently to higher PTG, but overall general distress had minimal impact on PTG. Global stress was inversely related to PTG. Positive growth at 6 months was associated with subsequent reduction in stress. CONCLUSIONS: This study showing that early stage higher cancer-specific stress and anxiety were related to positive growth supports the idea that struggle with a challenging illness may be instrumental in facilitating PTG, and findings show positive implications of PTG for subsequent adjustment. PMID- 27502892 TI - Difference between SB4 and reference etanercept in the hepatobiliary disorders not considered to be caused by SB4: response to letter by Scheinberg and Azevedo. PMID- 27502891 TI - Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. AB - OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma compared with the general population. There are concerns that tumour necrosis factor inhibitors (TNFi) may exacerbate this risk. However, since the excess risk of lymphoma in RA is related to the cumulative burden of inflammation, TNFi may conversely reduce the risk of lymphoma by decreasing the burden of inflammation. The aim of this study was to compare the risk of lymphoma in subjects with RA treated with TNFi with those treated with non-biological therapy. METHODS: Subjects diagnosed by a rheumatologist with RA enrolled in the British Society for Rheumatology Rheumatoid Arthritis Register (BSRBR-RA), a prospective cohort study, were followed until first lymphoma, death or until 30 November 2013. Rates of lymphoma in the TNFi and non-biological-treated cohorts were compared using Cox regression. RESULTS: 11 931 TNFi-treated patients were compared with 3367 biological-naive patients. 84 lymphomas (88 (95% CI 70 to 109) per 100 000 person-years) were reported in the TNFi cohort and 30 lymphomas (154 (95% CI 104 to 220)) in the biological-naive cohort. After adjusting for differences in baseline characteristics, there was no difference in the risk of lymphoma for the TNFi versus the biological-naive group: HR 1.00 (95% CI 0.56 to 1.80). No risk differences were observed for individual TNFi. CONCLUSIONS: In medium-term follow-up, there is no evidence that tumour necrosis factor inhibition influences the risk of lymphoma over the background risk in subjects with RA. PMID- 27502893 TI - Caenorhabditis elegans chronically exposed to a Mn/Zn ethylene-bis dithiocarbamate fungicide show mitochondrial Complex I inhibition and increased reactive oxygen species. AB - Reports have linked human exposure to Mn/Zn ethylene-bis-dithiocarbamate (Mn/Zn EBDC) fungicides with multiple pathologies, from dermatitis to central nervous system dysfunction. Although members of this family of agrochemicals have been available for over 50 years, their mechanism of toxicity in humans is still unclear. Since mitochondrial inhibition and oxidative stress are implicated in a wide variety of diseases, we hypothesized that Caenorhabditis elegans (C. elegans) exposed to a commercially-available formulation of an Mn/Zn-EBDC containing fungicide (Manzate; MZ) would also show these endpoints. Thus, worms were treated chronically (24h) with various MZ concentrations and assayed for reduced mitochondrial function and increased levels of reactive oxygen species (ROS). Oxygen consumption studies suggested Complex I inhibition in all treatment groups compared to controls (**p<0.01). In order to verify these findings, assays specific for Complex II or Complex IV activity were also completed. Data analysis from these studies indicated that neither complex was adversely affected by MZ treatment. Additional data from ATP assays indicated a statistically significant decrease (***p<0.001) in ATP levels in all treatment groups when compared to control worms. Further studies were completed to determine if exposure of C. elegans to MZ also resulted in increased ROS concentrations. Studies demonstrated that hydrogen peroxide, but not superoxide or hydroxyl radical, levels were statistically significantly increased (*p<0.05). Since hydrogen peroxide is known to up-regulate glutathione-S-transferase (GST), we used a GST:green fluorescent protein transgenic worm strain to test this hypothesis. Results from these studies indicated a statistically significant increase (***p<0.001) in green pixel number following MZ exposure. Taken together, these data indicate that C. elegans treated with MZ concentrations to which humans are exposed show mitochondrial Complex I inhibition with concomitant hydrogen peroxide production. Since these mechanisms are associated with numerous human diseases, we suggest further studies to determine if MZ exposure induces similar toxic mechanisms in mammals. PMID- 27502894 TI - Primary syphilis: An uncommon manifestation in the oral cavity. PMID- 27502895 TI - Fracture resistance of dental nickel-titanium rotary instruments with novel surface treatment: Thin film metallic glass coating. AB - BACKGROUND/PURPOSE: Dental nickel-titanium (NiTi) rotary instruments are widely used in endodontic therapy because they are efficient with a higher success rate. However, an unpredictable fracture of instruments may happen due to the surface characteristics of imperfection (or irregularity). This study assessed whether a novel surface treatment could increase fatigue fracture resistance of dental NiTi rotary instruments. METHODS: A 200- or 500-nm thick Ti-zirconium-boron (Ti-Zr-B) thin film metallic glass was deposited on ProTaper Universal F2 files using a physical vapor deposition process. The characteristics of coating were analyzed by scanning electron microscopy, transmission electron microscopy, and X-ray diffractometry. In cyclic fatigue tests, the files were performed in a simulated root canal (radius=5 mm, angulation=60 degrees ) under a rotating speed of 300rpm. The fatigue fractured cross sections of the files were analyzed with their fractographic performances through scanning electron microscopy images. RESULTS: The amorphous structure of the Ti-Zr-B coating was confirmed by transmission electron microscopy and X-ray diffractometry. The surface of treated files presented smooth morphologies without grinding irregularity. For the 200- and 500-nm surface treatment groups, the coated files exhibited higher resistance of cyclic fatigue than untreated files. In fractographic analysis, treated files showed significantly larger crack-initiation zone; however, no significant differences in the areas of fatigue propagation and catastrophic fracture were found compared to untreated files. CONCLUSION: The novel surface treatment of Ti Zr-B thin film metallic glass on dental NiTi rotary files can effectively improve the fatigue fracture resistance by offering a smooth coated surface with amorphous microstructure. PMID- 27502896 TI - Novel approaches to characterize age-related remodelling of the dermal-epidermal junction in 2D, 3D and in vivo. AB - BACKGROUND/PURPOSE: The dermal-epidermal junction (DEJ) forms epidermal protrusions down into the dermis (rete ridges) and dermal projections up into the epidermis (dermal papillae). Usually visualized in two-dimensions (2D), our knowledge of how the DEJ changes with ageing is limited. We aimed to characterize how this structure exists in 3D and changes with age. METHODS: Photoprotected and photoexposed skin were imaged using reflectance confocal microscopy (RCM) in young and aged individuals. Biopsies of the imaged areas were processed for histological sectioning and for imaging using micro-computed X-ray tomography (microCT). RESULTS: Images obtained from RCM and microCT were used to 3D reconstruct the DEJ. DEJ heights obtained from microCT images showed strong correlation with histology-measured heights. We proposed a novel definition of rete ridges (RRm ) and dermal papillae (DPm ), which allowed easier automated measurement of reduced DPm and RRm volumes in aged skin from microCT reconstructions. An algorithm to map DPm connectivity showed reduced lengths of DPm branches with age. CONCLUSION: Three-dimensional images illustrated the complex topography of the DEJ and highlighted the distinct morphology of dermal papillae compared with rete ridges, which is not evident when evaluating 2D sections. Ex vivo imaging was more successful in differentiating DEJ architecture with respect to age. PMID- 27502897 TI - Inhibition of Autophagy Enhances Curcumin United light irradiation-induced Oxidative Stress and Tumor Growth Suppression in Human Melanoma Cells. AB - Malignant melanoma is the most aggressive form of skin carcinoma, which possesses fast propagating and highly invasive characteristics. Curcumin is a natural phenol compound that has various biological activities, such as anti proliferative and apoptosis-accelerating impacts on tumor cells. Unfortunately, the therapeutical activities of Cur are severely hindered due to its extremely low bioavailability. In this study, a cooperative therapy of low concentration Cur combined with red united blue light irradiation was performed to inspect the synergistic effects on the apoptosis, proliferation and autophagy in human melanoma A375 cell. The results showed that red united blue light irradiation efficaciously synergized with Cur to trigger oxidative stress-mediated cell death, induce apoptosis and inhibit cell proliferation. Meanwhile, Western blotting revealed that combined disposure induced the formation of autophagosomes. Conversely, inhibition of the autophagy enhanced apoptosis, obstructed cell cycle arrest and induced reversible proliferation arrest to senescence. These findings suggest that Cur combined with red united blue light irradiation could generate photochemo-preventive effects via enhancing apoptosis and triggering autophagy, and pharmacological inhibition of autophagy convert reversible arrested cells to senescence, therefore reducing the possibility that damaged cells might escape programmed death. PMID- 27502898 TI - Boron exposure through drinking water during pregnancy and birth size. AB - BACKGROUND: Boron is a metalloid found at highly varying concentrations in soil and water. Experimental data indicate that boron is a developmental toxicant, but the few human toxicity data available concern mostly male reproduction. OBJECTIVES: To evaluate potential effects of boron exposure through drinking water on pregnancy outcomes. METHODS: In a mother-child cohort in northern Argentina (n=194), 1-3 samples of serum, whole blood and urine were collected per woman during pregnancy and analyzed for boron and other elements to which exposure occurred, using inductively coupled plasma mass spectrometry. Infant weight, length and head circumference were measured at birth. RESULTS: Drinking water boron ranged 377-10,929MUg/L. The serum boron concentrations during pregnancy ranged 0.73-605MUg/L (median 133MUg/L) and correlated strongly with whole-blood and urinary boron, and, to a lesser extent, with water boron. In multivariable-adjusted linear spline regression analysis (non-linear association), we found that serum boron concentrations above 80MUg/L were inversely associated with birth length (B-0.69cm, 95% CI -1.4; -0.024, p=0.043, per 100MUg/L increase in serum boron). The impact of boron appeared stronger when we restricted the exposure to the third trimester, when the serum boron concentrations were the highest (0.73-447MUg/L). An increase in serum boron of 100MUg/L in the third trimester corresponded to 0.9cm shorter and 120g lighter newborns (p=0.001 and 0.021, respectively). CONCLUSIONS: Considering that elevated boron concentrations in drinking water are common in many areas of the world, although more screening is warranted, our novel findings warrant additional research on early-life exposure in other populations. PMID- 27502899 TI - Mechanisms of arsenic disruption on gonadal, adrenal and thyroid endocrine systems in humans: A review. AB - Due to its toxicity as a carcinogen and wide distribution in the environment, arsenic (As) exposure in humans is of public concern globally. Many studies have manifested that As exposure induces cancers besides pathological effects in humans. Animal studies showed that chronic As exposure induces serious neurological effects. Based on recent studies, researchers proposed that As, including arsenate (AsV) and arsenite (AsIII), is also an endocrine disruptor. This review discusses the mechanisms of As toxicity on three endocrine systems including gonadal, adrenal and thyroid endocrine systems. Arsenic methylation and oxidative stress are responsible for As-induced disorders of endocrine systems, however, strong binding of AsIII to thiols also play an important role. Some studies showed AsV toxicity on endocrine systems, but mechanistic investigation is lacking. Research is needed to look into their toxicity mechanisms to help cure the illnesses caused by As-induced endocrine system disorders. PMID- 27502901 TI - The Longest Wait: Examining the Impact of Utah's 72-Hour Waiting Period for Abortion. AB - PURPOSE: To assess the impact of Utah's 2012 law increasing the mandatory abortion waiting period from 24 to 72 hours. METHODS: This paper includes two assessments of this change: (1) Comparison of the proportion of women returning for an abortion after counseling before and after the introduction of the 72-hour law and (2) self-reported wait times between abortion and procedure, distance traveled, financial expenditures, and perceived impact of the law in a subset of women who were surveyed. MAIN FINDINGS: Aggregate counseling and procedural data were available at three Utah clinics; 2,793 of 3,618 women (77%) returned for abortion procedures under the 72-hour law, compared with 2,513 of 3,130 (80%) in the previous year (p < .05). Among 307 women surveyed, 63% reported more than 7 days between signing the consent form and their procedure, and women frequently had to travel further to get their procedure than they did for the counseling. Close to two-thirds (62%) reported the 72-hour wait affected them negatively in some way, including the lost wages of needing to take extra time off work (47%), increased transportation cost (30%), lost wages by family or friend(s) (27%), and having to disclose their abortion to someone they would not had told without the waiting period (33%). CONCLUSION: Utah's extended waiting period showed a small reduction in the proportion of counseled women who returned for their abortion procedure statewide. Women who had abortions after the law was enacted reported several burdensome aspects of the law. PMID- 27502900 TI - No evidence for spectral jamming avoidance in echolocation behavior of foraging pipistrelle bats. AB - Frequency shifts in signals of bats flying near conspecifics have been interpreted as a spectral jamming avoidance response (JAR). However, several prerequisites supporting a JAR hypothesis have not been controlled for in previous studies. We recorded flight and echolocation behavior of foraging Pipistrellus pipistrellus while flying alone and with a conspecific and tested whether frequency changes were due to a spectral JAR with an increased frequency difference, or whether changes could be explained by other reactions. P. pipistrellus reacted to conspecifics with a reduction of sound duration and often also pulse interval, accompanied by an increase in terminal frequency. This reaction is typical of behavioral situations where targets of interest have captured the bat's attention and initiated a more detailed exploration. All observed frequency changes were predicted by the attention reaction alone, and do not support the JAR hypothesis of increased frequency separation. Reaction distances of 1-11 m suggest that the attention response may be elicited either by detection of the conspecific by short range active echolocation or by long range passive acoustic detection of echolocation calls. PMID- 27502902 TI - Chromatographic method for clobetasol propionate determination in hair follicles and in different skin layers. AB - Clobetasol propionate (CLO) is a potent steroid used for the treatment of several dermatological diseases. Recent studies suggest its additional use in alopecia topical treatment, generating a demand for novel formulations with specific delivery into hair follicles. Hence, a selective analytical method for drug quantification in follicular structures and skin layers is required. For this, a simple HPLC-UV method was developed. Quantification was performed using a RP-C18 column (4.6 mm * 15 cm, 5 MUm), with a mixture of methanol-acetonitrile-water (50:15:35 v/v) as mobile phase, a flow rate of 1.2 mL/min, oven temperature of 30 degrees C, injection volume of 50 MUL and detection at 240 nm. The optimized conditions enabled a 12 min running with CLO elution at 10.1 min and resolution of 2.424 from skin matrix interferences. Validation was performed in accordance with International Conference on Harmonization guidelines and fulfilled the criteria of selectivity, linearity (0.5-15.0 MUg/mL), robustness, precision, accuracy and limits of detection and quantification (0.02 and 0.07 MUg/mL, respectively). The validated method was successfully applied for CLO quantification following in vitro skin permeation experiments and differential tape-stripping for hair follicle deposition determination, demonstrating its suitability. PMID- 27502903 TI - The hills and valleys of calcium signaling. PMID- 27502904 TI - Recent advances in the research for the homolog of breast cancer associated gene AtROW1 in higher plants. AB - BARD1 (BRCA1 associated RING domain protein 1), as an important animal tumor suppressor gene associated with many kinds of cancers, has been intensively studied for decades. Surprisingly, homolog of BARD1 was found in plants and it was renamed AtROW1 (repressor of Wuschel-1) according to its extremely important function with regard to plant stem cell homeostasis. Although great advances have been made in human BARD1, the function of this animal tumor-suppressor like gene in plant is not well studied and need to be further elucidated. Here, we review and summarize past and present work regarding this protein. Apart from its previously proposed role in DNA repair, recently it is found essential for shoot and root stem cell development and differentiation in plants. The study of AtROW1 in plant may provide an ideal model for further elucidating the functional mechanism of BARD1 in mammals. PMID- 27502905 TI - Prevalence and phylogenetic characterization of canine coronavirus from diseased pet dogs in Beijing, China. PMID- 27502906 TI - Heart Failure With Preserved Ejection Fraction: A Kidney Disorder? PMID- 27502907 TI - Parsing Atherosclerosis: The Unnatural History of Peripheral Artery Disease. PMID- 27502908 TI - Global Disparities of Hypertension Prevalence and Control: A Systematic Analysis of Population-Based Studies From 90 Countries. AB - BACKGROUND: Hypertension is the leading preventable cause of premature death worldwide. We examined global disparities of hypertension prevalence, awareness, treatment, and control in 2010 and compared secular changes from 2000 to 2010. METHODS: We searched MEDLINE from 1995 through 2014 and supplemented with manual searches of retrieved article references. We included 135 population-based studies of 968 419 adults from 90 countries. Sex- and age-specific hypertension prevalences from each country were applied to population data to calculate regional and global numbers of hypertensive adults. Proportions of awareness, treatment, and control from each country were applied to hypertensive populations to obtain regional and global estimates. RESULTS: In 2010, 31.1% (95% confidence interval, 30.0%-32.2%) of the world's adults had hypertension; 28.5% (27.3% 29.7%) in high-income countries and 31.5% (30.2%-32.9%) in low- and middle-income countries. An estimated 1.39 (1.34-1.44) billion people had hypertension in 2010: 349 (337-361) million in high-income countries and 1.04 (0.99-1.09) billion in low- and middle-income countries. From 2000 to 2010, the age-standardized prevalence of hypertension decreased by 2.6% in high-income countries, but increased by 7.7% in low- and middle-income countries. During the same period, the proportions of awareness (58.2% versus 67.0%), treatment (44.5% versus 55.6%), and control (17.9% versus 28.4%) increased substantially in high-income countries, whereas awareness (32.3% versus 37.9%) and treatment (24.9% versus 29.0%) increased less, and control (8.4% versus 7.7%) even slightly decreased in low- and middle-income countries. CONCLUSIONS: Global hypertension disparities are large and increasing. Collaborative efforts are urgently needed to combat the emerging hypertension burden in low- and middle-income countries. PMID- 27502909 TI - Still on the Road to Worldwide Hypertension Control. PMID- 27502911 TI - Letter by Aparci et al Regarding Article, "Characterization of Myocardial Repolarization Reserve in Adolescent Females With Anorexia Nervosa". PMID- 27502912 TI - Response by Padfield and Krahn to Letter Regarding Article, "Characterization of Myocardial Repolarization Reserve in Adolescent Females With Anorexia Nervosa". PMID- 27502913 TI - Letter by Papalia and Okonko Regarding Article, "Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure". PMID- 27502914 TI - Response by Shirakabe et al to Letter Regarding Article, "Drp1-Dependent Mitochondrial Autophagy Plays a Protective Role Against Pressure Overload-Induced Mitochondrial Dysfunction and Heart Failure". PMID- 27502915 TI - Letter by Carlstrom and Lundberg Regarding Article, "SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction". PMID- 27502916 TI - Response by Lai and Gladwin to Letter Regarding Article, "SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction". PMID- 27502917 TI - Assessment of a cytomegalovirus serology dual-testing strategy in hematopoietic stem cell transplant recipients. AB - BACKGROUND: Accurate determination of recipient cytomegalovirus (CMV) serostatus before allogeneic hematopoietic stem cell transplantation (HSCT) is critical, as it is the most important predictor of post-transplant CMV infection and remains associated with non-relapse mortality. The purpose of this study was to assess a recipient dual-testing strategy before HSCT. METHODS: CMV serologic testing was performed before allogeneic HSCT using 2 different assays: reference laboratory (RL) and American Red Cross (ARC). In all cases, blood samples were obtained for RL testing either before ARC testing (median 130 days before HSCT [range 12 2594]) or at the same time (median 25 days before HSCT [range 8-129]). The results of serologic testing were correlated with CMV viremia post HSCT. RESULTS: Of 287 recipients evaluated, 76 (26.5%) had discordant results, of which 74 (97.4%) tested RL-/ARC+. Ten had RL and ARC testing performed on simultaneously obtained samples, 3 of which (30%) were discordant (3 [100%] RL-/ARC+). Acute myeloid leukemia and receipt of blood product transfusion in the interval between testing were associated with RL-/ARC+ discordance. Correlation with viremia after HSCT suggested that RL-/ARC+ discordance was caused by detection of anti-CMV immunoglobulin transferred in transfused blood products and reduced specificity of the ARC assay. CONCLUSION: CMV-seronegative hematopoietic stem cell transplant recipients may be misclassified as seropositive if testing is performed after receipt of blood products or when using assays optimized for sensitivity at the expense of specificity. This misclassification may negatively affect post-HSCT outcomes for individual patients and studies that rely on accurate CMV serology reporting. PMID- 27502918 TI - Abstracts of the German STI-Congress and Leopoldina-Symposium 2016, 06. 09.07.2016, Berlin. PMID- 27502919 TI - The untold story of IFN-gamma in cancer biology. AB - Interferon (IFN)-gamma is the uppermost cytokine implicated in anti-tumor immunity. With its cytostatic, pro-apoptotic and immune-provoking effects, IFN gamma plays a central role in the recognition and elimination of transformed cells. Considering well-characterized anti-tumor effects of this cytokine, many clinical trials and immunotherapy approaches have been designed to reinforce IFN gamma-mediated immunity for different types of cancer. However, the outcomes were not satisfactory and leaded to questioning of alternative actions of IFN-gamma. Many regulatory pathways can be induced by IFN-gamma to protect the normal tissues from collateral damage and to facilitate the re-establishment of homeostasis. Nevertheless, malignant cells can take the advantage of IFN-gamma as an inducer of mediators inhibiting anti-tumor immune reactions. In addition, under the influence of tumor-derived factors, certain types of immune cells are also licensed by IFN-gamma to perform regulatory actions. This review focuses on the immune modulatory functions of IFN-gamma in cancer as an alternative story to be told. PMID- 27502920 TI - Infant and young child feeding practices differ by ethnicity of Vietnamese mothers. AB - BACKGROUND: Limited studies have examined ethnic variation in breastfeeding and complementary feeding practices in developing countries. This study investigated ethnic variation in feeding practices in mothers with children 0-23 months old in Vietnam. METHODS: We used data on 1875 women who came from the ethnic majority, Kinh (n = 989, randomly sampled from 9875 surveyed Kinh mothers, 10 % from each province) and three ethnic minorities: E De-Mnong (n = 309), Thai-Muong (n = 229) and Tay-Nung (n = 348). Ethnic minorities were compared with the Kinh group using logistic regression model. RESULTS: Prevalence of breastfeeding initiation within an hour of birth was 69 % in Thai-Muong, but ~50 % in other ethnicities. In logistic regression, the prevalence of breastfeeding within one hour was lower in Tay-Nung (OR: 0.54; 95 % CI: 0.38, 0.77) than the majority Kinh. Prevalence of exclusive breastfeeding under 6 months was 18, 10, 17, and 33 % in Kinh, Thai Muong, Tay-Nung, and E De-Mnong, respectively; compared to the majority Kinh, the prevalence was lower in Thai-Muong (OR: 0.42; 95 % CI: 0.25, 0.71) and higher in E De-Mnong (OR: 1.99; 95 % CI: 1.04, 3.82). Overall prevalence of bottle feeding in Thai-Muong and E De-Mnong (~20 %) was lower than in Kinh (~33 %): Thai-Muong (OR: 0.50; 95 % CI: 0.37, 0.68) and E De-Mnong (OR: 0.69; 95 % CI: 0.50, 0.95). Compared with Kinh (75 %), fewer ethnic minority children received minimum acceptable diets (33 % in Thai-Muong, 46 % in E De-Mnong, and 52 % in Tay-Nung; P < 0.05). Prevalence of minimum acceptable diet (met both dietary frequency and diversity) was lower in Thai-Muong (OR: 0.23; 95 % CI: 0.11, 0.46), Tay-Nung (OR: 0.52; 95 % CI: 0.39, 0.69), and E De-Mnong (OR: 0.55; 95 % CI: 0.33, 0.89) than the majority Kinh. CONCLUSIONS: Breastfeeding practices were suboptimal and differed by ethnicity, which suggests need for tailored interventions at multiple levels to address ethnic-specific challenges and norms. Complementary feeding practices were less optimal among ethnic minorities compared to Kinh, which suggests need for broad intervention including improved food availability, accessibility, and security. PMID- 27502921 TI - Postoperative chemoradiotherapy versus chemotherapy for R0 resected gastric cancer with D2 lymph node dissection: an up-to-date meta-analysis. AB - BACKGROUND: This meta-analysis aims to provide more evidence on the role of postoperative chemoradiotherapy (CRT) for gastric cancer (GC) patients in Asian countries where D2 lymphadenectomy is prevalent. METHODS: We conducted a systematic review of randomized controlled trials (RCTs), extracted data of survival and toxicities, and pooled data to evaluate the efficacy and toxicities of CRT compared with chemotherapy (CT) after D2 lymphadenectomy. RESULTS: A total of 960 patients from four RCTs were selected. The results showed that postoperative CRT significantly reduced loco-regional recurrence rate (LRRR: RR = 0.50, 95 % CI = 0.34-0.74, P = 0.0005) and improved disease-free survival (DFS: HR = 0.73, 95 % CI = 0.60-0.89, P = 0.002). However, CRT did not affect distant metastasis rate (DMR: RR = 0.81, 95 % CI = 0.60-1.08, P = 0.15) and overall survival (OS: HR = 0.91, 95 % CI = 0.74-1.11, P = 0.34). The main grade 3-4 toxicities manifested no significant differences between the two groups. CONCLUSIONS: Overall, CRT after D2 lymphadenectomy may reduce LRRR and prolong DFS. The role of postoperative CRT should be further investigated in the population with high risk of loco-regional recurrence. PMID- 27502922 TI - Disentangling psychopathology, substance use and dependence: a factor analysis. AB - BACKGROUND: The notion that substance use can induce symptoms of depression and anxiety is influential in clinical practice, however questions remain about the empirical support for this hypothesis. METHODS: We analysed mental health and substance dependence screening records for 280 outpatients in addictions treatment. Item-level data for depression (PHQ-9), anxiety (GAD-7), severity of dependence (SDS) and self-reported weekly substance use were studied using factor analysis and correlations. Symptom-level associations between substance use and psychological distress symptoms were examined after controlling for underlying levels of psychopathology. RESULTS: We obtained a two-factor solution accounting for approximately 48 % of total variance. Depression and anxiety symptoms loaded onto a single psychopathology factor. Severity of dependence (SDS) and substance use measures loaded onto a distinct but correlated factor. After controlling for latent levels of psychopathology, the only remaining symptom-level associations were impaired concentration linked to cannabis use and irritability linked to alcohol use. Dependence (SDS) was prominently associated with depressive rumination, and negatively correlated with residual anxiety symptoms related to substance use (e.g., craving). CONCLUSIONS: Overall, this analysis supports a psychological understanding of comorbidity; with dependence, craving, negative reinforcement and rumination as key variables. PMID- 27502923 TI - Role of plant MicroRNA in cross-species regulatory networks of humans. AB - BACKGROUND: It has been found that microRNAs (miRNAs) can function as a regulatory factor across species. For example, food-derived plant miRNAs may pass through the gastrointestinal (GI) tract, enter into the plasma and serum of mammals, and interact with endogenous RNAs to regulate their expression. Although this new type of regulatory mechanism is not well understood, it provides a fresh look at the relationship between food consumption and physiology. To investigate this new type of mechanism, we conducted a systematic computational study to analyze the potential functions of these dietary miRNAs in the human body. RESULTS: In this paper, we predicted human and plant target genes using RNAhybrid and set some criteria to further filter them. Then we built the cross-species regulatory network according to the filtered targets, extracted central nodes by PageRank algorithm and built core modules. We summarized the functions of these modules to three major categories: ion transport, metabolic process and stress response, and especially some target genes are highly related to ion transport, polysaccharides and the lipid metabolic process. Through functional analysis, we found that human and plants have similar functions such as ion transport and stress response, so our study also indicates the existence of a close link between exogenous plant miRNA targets and digestive/urinary organs. CONCLUSIONS: According to our analysis results, we suggest that the ingestion of these plant miRNAs may have a functional impact on consuming organisms in a cross-kingdom way, and the dietary habit may affect the physiological condition at a genetic level. Our findings may be useful for discovering cross-species regulatory mechanism in further study. PMID- 27502925 TI - Lumbar puncture simulation in pediatric residency training: improving procedural competence and decreasing anxiety. AB - BACKGROUND: Pediatric residents must become proficient with performing a lumbar puncture (LP) during training. Residents have traditionally acquired LP skills by observing the procedure performed by a more senior resident or staff physician and then attempting the procedure themselves. This process can result in variable procedural skill acquisition and trainee discomfort. This study assessed changes in resident procedural skill and self-reported anxiety when residents were provided with an opportunity to participate in an interactive training session and practice LPs using a simulator. METHODS: All pediatric residents at our institution were invited to participate. Residents were asked to report their post-graduate year (PGY), prior LP attempts and self-reported anxiety scores as measured by the standardized State-Trait Anxiety Inventory - State Anxiety Scale (STAI-S) prior to completing an observed pre-test using an infant-sized LP simulator. Staff physicians observed and scored each resident's procedural skill using a previously published 21-point scoring system. Residents then participated in an interactive lecture on LP technique and were given an opportunity for staff supervised, small group simulator-based practice within 1 month of the pre-test. Repeat post-test was performed within 4 months. RESULTS: Of the pediatric residents who completed the pre-test (N = 20), 16/20 (80 %) completed both the training session and post-test. Their PGY training level was: PGY1 (38 %), PGY2 (25 %), PGY3 (25 %) or PGY4 (12 %). Procedural skill improved in 15/16 residents (paired t-test; p < 0.001), driven by a significant improvement in skill for residents in PGY1 (P = 0.015) and PGY2 (p = 0.003) but not PGY3 or PGY4. Overall anxiety scores were higher at baseline than at post testing (mean +/- SD; 44.8 +/ 12.1 vs 39.7 +/- 9.4; NS) however only PGY1 residents experienced a significant reduction in anxiety (paired t-test, p = 0.04). CONCLUSION: LP simulation training combined with an interactive training session may be a useful tool for improving procedural competence and decreasing anxiety levels, particularly among those at an earlier stage of residency training. PMID- 27502924 TI - Role of different Culicoides vectors (Diptera: Ceratopogonidae) in bluetongue virus transmission and overwintering in Sardinia (Italy). AB - BACKGROUND: Bluetongue (BT) epidemics have affected the Mediterranean island of Sardinia since 2000. While Culicoides imicola represents the main bluetongue virus (BTV) vector, other European Culicoides biting midges, possibly implicated in virus transmission, have been detected here. Understanding their distribution, seasonal abundance, and infection rates is necessary to predict disease incidence and spread across coastal and inland areas, and to define their role in virus overwintering. METHODS: Biting midge abundance was determined by light traps on selected farms representing diverse climatic conditions of Sardinia. Livestock associated Culicoides species were morphologically and molecularly identified. Infection rates in prevailing midge species captured in 2013 during a BTV-1 outbreak were determined using RT-qPCR based virus detection in insect body pools, supplemented by specific body region analyses. The seasonal infection prevalence in Culicoides samples collected in 2001 in a BTV-2 affected farm was also determined. RESULTS: The Newsteadi complex (C. newsteadi species A and species B) prevailed among all biting midge species (47.7 %), followed by C. imicola (27.8 %) and the Obsoletus complex (C. obsoletus and C. scoticus) (17.6 %). Whilst Culicoides imicola was more abundant along the coast, the Newsteadi complex was frequently collected at higher altitude and the Obsoletus complex was notably associated to cattle farms. Culicoides pulicaris and C. punctatus abundance was found to be marginal in all farms. BTV was detected in parous female samples of all these species, and the full dissemination of the virus within the body of C. imicola, C. obsoletus, C. scoticus, and Newsteadi complex species was confirmed by analyses of thorax and head, containing salivary glands. Higher infection rates were associated with C. scoticus, C. newsteadi species A and species B, compared to C. imicola. The virus was detected in C. newsteadi species A and C. obsoletus in winter and spring, whereas it was mainly found in summer and autumn in C. imicola. CONCLUSIONS: In Sardinia, bluetongue virus is transmitted by multiple Culicoides vectors, including C. imicola and the Newsteadi complex being the most important. The Newsteadi complex and other midge species can play an important role in internal areas and are likely to be directly involved in virus overwintering. PMID- 27502926 TI - A volatolomic approach for studying plant variability: the case of selected Helichrysum species (Asteraceae). AB - The species of Helichrysum sect. Stoechadina (Asteraceae) are well-known for their secondary metabolite content and the characteristic aromatic bouquets. In the wild, populations exhibit a wide phenotypic plasticity which makes critical the circumscription of species and infraspecific ranks. Previous investigations on Helichrysum italicum complex focused on a possible phytochemical typification based on hydrodistilled essential oils. Aims of this paper are three-fold: (i) characterizing the volatile profiles of different populations, testing (ii) how these profiles vary across populations and (iii) how the phytochemical diversity may contribute in solving taxonomic problems. Nine selected Helichrysum populations, included within the H. italicum complex, Helichrysum litoreum and Helichrysum stoechas, were investigated. H. stoechas was chosen as outgroup for validating the method. After collection in the wild, plants were cultivated in standard growing conditions for over one year. Annual leafy shoots were screened in the post-blooming period for the emissions of volatile organic compounds (VOCs) by means of headspace solid phase microextraction coupled with gas chromatography and mass spectrometry (HS-SPME-GC/MS). The VOC composition analysis revealed the production of overall 386 different compounds, with terpenes being the most represented compound class. Statistical data processing allowed the identification of the indicator compounds that differentiate the single populations, revealing the influence of the geographical provenance area in determining the volatile profiles. These results suggested the potential use of VOCs as valuable diacritical characters in discriminating the Helichrysum populations. In addition, the cross-validation analysis hinted the potentiality of this volatolomic study in the discrimination of the Helichrysum species and subspecies, highlighting a general congruence with the current taxonomic treatment of the genus. The consistency between this phytochemical approach and the traditional morphometrical analysis in studying the Helichrysum populations supports the validity of the VOC profile in solving taxonomic problems. PMID- 27502927 TI - Reproducibility of dalbavancin MIC test results and an updated surrogate accuracy analysis of vancomycin MIC values to infer dalbavancin susceptibility (2014). PMID- 27502928 TI - Design of the FemCure study: prospective multicentre study on the transmission of genital and extra-genital Chlamydia trachomatis infections in women receiving routine care. AB - BACKGROUND: In women, anorectal infections with Chlamydia trachomatis (CT) are about as common as genital CT, yet the anorectal site remains largely untested in routine care. Anorectal CT frequently co-occurs with genital CT and may thus often be treated co-incidentally. Nevertheless, post-treatment detection of CT at both anatomic sites has been demonstrated. It is unknown whether anorectal CT may play a role in post-treatment transmission. This study, called FemCure, in women who receive routine treatment (either azithromycin or doxycycline) aims to understand the post-treatment transmission of anorectal CT infections, i.e., from their male sexual partner(s) and from and to the genital region of the same woman. The secondary objective is to evaluate other reasons for CT detection by nucleic acid amplification techniques (NAAT) such as treatment failure, in order to inform guidelines to optimize CT control. METHODS: A multicentre prospective cohort study (FemCure) is set up in which genital and/or anorectal CT positive women (n = 400) will be recruited at three large Dutch STI clinics located in South Limburg, Amsterdam and Rotterdam. The women self-collect anorectal and vaginal swabs before treatment, and at the end of weeks 1, 2, 4, 6, 8, 10, and 12. Samples are tested for presence of CT-DNA (by NAAT), load (by quantitative polymerase chain reaction -PCR), viability (by culture and viability PCR) and CT type (by multilocus sequence typing). Sexual exposure is assessed by online self administered questionnaires and by testing samples for Y chromosomal DNA. Using logistic regression models, the impact of two key factors (i.e., sexual exposure and alternate anatomic site of infection) on detection of anorectal and genital CT will be assessed. DISCUSSION: The FemCure study will provide insight in the role of anorectal chlamydia infection in maintaining the CT burden in the context of treatment, and it will provide practical recommendations to reduce avoidable transmission. Implications will improve care strategies that take account of anorectal CT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02694497 . PMID- 27502929 TI - The correlation between Toxoplasma gondii infection and prenatal depression in pregnant women. AB - Previous studies have demonstrated that latent toxoplasmosis is associated with neuropsychiatric disorders. We evaluated the correlation between Toxoplasma gondii infection and prenatal depression. In this case-control study, we enrolled 116 depressed pregnant women and 244 healthy controls. The Edinburgh Postpartum Depression Scale (EPDS) was used to evaluate the depression symptom severity in study participants. All participants were screened for the anti-Toxoplasma IgG by enzyme-linked immunosorbent assay. Seroprevalence of T. gondii did not significantly differ between the depressed pregnant women and healthy controls (OR = 1.4; 95 % CI = 0.9-2.19; P = 0.142). T. gondii IgG titer was significantly higher in depressed women (18.6 +/- 10.9 IUs) than those in the control group (13.6 +/- 8.1 IUs) (z = -5.36, P < 0.001). The T. gondii-positive depressed women showed a positive correlation of T. gondii IgG titer with the EPDS scores (r = 0.52; P < 0.01). The mean EPDS score was also significantly higher in the T. gondii-positive depressed women (20.7 +/- 2.7) compared with the controls (18.36 +/- 2.7) (P < 0.001). The results obtained from the current study revealed that T. gondii infection might affect susceptibility to depression and severity of depressive symptoms in pregnant women, particularly in those patients who have high antibody titers. Further study is required to fully elucidate the characteristics and mechanisms of this association. PMID- 27502930 TI - Etiology and clinical features of 229 cases of bloodstream infection among Chinese HIV/AIDS patients: a retrospective cross-sectional study. AB - Bloodstream infections (BSIs) are prevalent among people living with HIV/AIDS. The etiology varies in different regions and different periods. We aimed to survey the etiological and clinical features of BSIs in HIV patients in mainland China. We assessed all HIV patients with a positive blood culture in a Chinese teaching hospital from September 2009 through December 2014. We excluded those with specimens likely to have been contaminated. We used Pearson's chi-squared test to measure the differences in characteristics among subgroups of different pathogens. Among 2442 Chinese HIV-seropositive inpatients, 229 (9.38 %) experienced BSIs. The most common pathogens detected included Cryptococcus neoformans (22.7 %), Penicillium marneffei (18.8 %), Mycobacterium tuberculosis (15.3 %), and non-tuberculous mycobacterium (14.8 %). 30/229 (13.1 %) HIV patients with BSIs had a poor prognosis. BSIs are prevalent in hospitalized patients with HIV/AIDS in China. Fungi and mycobacteria are the predominant pathogens. PMID- 27502931 TI - Computed tomography findings associated with bacteremia in adult patients with a urinary tract infection. AB - The use of computed tomography (CT) in the diagnosis of urinary tract infection (UTI) has rapidly increased recently at acute stage, but the CT findings associated with bacteremia in UTI patients are unknown. 189 UTI patients were enrolled who underwent a CT scan within 24 h after hospital admission. We classified CT findings into eight types: a focal or multifocal wedge-shaped area of hypoperfusion, enlarged kidneys, perinephric fat stranding, ureteritis or pyelitis, complicated renal cyst, renal papillary necrosis, hydronephrosis, and renal and perirenal abscess. A retrospective analysis was conducted to evaluate the CT findings associated with bacteremia. The mean age of these patients was 60 +/- 17.2 years, and 93.1 % were women. Concurrent bacteremia was noted in 40.2 % of the patients. Abnormal CT findings were noted in 96.3 % of the patients and 62.4 % had two or more abnormal findings. The most frequent abnormal CT finding was a focal or multifocal wedge-shaped area of hypoperfusion (77.2 %), followed by perinephric fat stranding (29.1 %). Perinephric fat stranding, hydronephrosis, and the presence of two or more abnormal CT findings were significantly associated with bacteremia in patients with community-acquired UTI. In the multivariate logistic regression analysis, age [odds ratio (OR) 1.03; 95 % confidence interval (CI) 1.009-1.062], two or more abnormal CT findings (OR 3.163; 95 % CI 1.334-7.498), and hydronephrosis (OR 13.160; 95 % CI 1.048 165.282) were significantly associated with bacteremia. Physicians should be aware that appropriate early management is necessary to prevent fatality in patients with these CT findings. PMID- 27502933 TI - Dose-Adjusted EPOCH-R and Mid-Cycle High Dose Methotrexate for Patients with Systemic Lymphoma and secondary CNS Involvement. PMID- 27502932 TI - Comparison on cellular mechanisms of iron and cadmium accumulation in rice: prospects for cultivating Fe-rich but Cd-free rice. AB - Iron (Fe) is essential for rice growth and humans consuming as their staple food but is often deficient because of insoluble Fe(III) in soil for rice growth and limited assimilation for human bodies, while cadmium (Cd) is non-essential and toxic for rice growth and humans if accumulating at high levels. Over-accumulated Cd can cause damage to human bodies. Selecting and breeding Fe-rich but Cd-free rice cultivars are ambitious, challenging and meaningful tasks for researchers. Although evidences show that the mechanisms of Fe/Cd uptake and accumulation in rice are common to some extent as a result of similar entry routes within rice, an increasing number of researchers have discovered distinct mechanisms between Fe/Cd uptake and accumulation in rice. This comprehensive review systematically elaborates and compares cellular mechanisms of Fe/Cd uptake and accumulation in rice, respectively. Mechanisms for maintaining Fe homeostasis and Cd detoxicification are also elucidated. Then, effects of different fertilizer management on Fe/Cd accumulation in rice are discussed. Finally, this review enumerates various approaches for reducing grain Cd accumulation and enhancing Fe content in rice. In summary, understanding of discrepant cellular mechanisms of Fe/Cd accumulation in rice provides guidance for cultivating Fe-fortified rice and has paved the way to develop rice that are tolerant to Cd stress, aiming at breeding Fe-rich but Cd-free rice. PMID- 27502934 TI - Does lymph node dissection during nephroureterectomy affect oncological outcomes in upper tract urothelial carcinoma patients without suspicious lymph node metastasis on preoperative imaging studies? AB - PURPOSE: This study aimed to investigate the effects of lymph node dissection (LND) on upper tract urothelial carcinoma (UTUC) without suspicious lymph node (LN) metastasis on preoperative imaging studies. METHODS: From 1998 to 2012, 418 UTUC patients without suspicious LN metastasis on preoperative imaging studies were included. Patients were divided into two groups according to the performance of LND. The effects of LND on oncological outcomes were assessed after adjusting other variables. The mean follow-up duration was 69 months. RESULTS: Among the 132 patients who underwent LND, LN metastasis was pathologically identified in 16 patients (12.1 %). The median number of resected LNs for patients who underwent LND was 7. On multivariate analysis, the number of resected LNs and pathologic T stage was significant predictors of LN metastasis. The 5-year recurrence-free survival was 76.4 % for patients without LND and 65.4 % for patients with LND (p = 0.126). In addition, there was no difference in 5-year overall survival between the 2 groups (without LND; 71.7 % vs. with LND; 72.1 %, p = 0.756). Multivariate analysis showed that pathologic T stage, tumor grade, and lymphovascular invasion were risk factors for recurrence. Age at surgery, tumor size, pathologic T stage, tumor grade, and lymphovascular invasion were significantly associated with overall survival. However, performance of LND was not associated with recurrence and survival. CONCLUSIONS: LND could be selectively performed in patients with clinically LN-negative UTUC based on patient/tumor characteristics and operative findings although sufficient LNs should be removed if LND is to be performed. PMID- 27502936 TI - Modified method to enhanced recovery of Toxocara cati larvae for the purposes of diagnostic and therapeutic. AB - Human toxocariasis, extraintestinal-migration of Toxocara species, is a worldwide helminthic zoonosis in many places of the undeveloped countries. Toxocara cati is one of the common helminths in cats and it is a potentially preventable disease. Its diagnosis and treatment depend on the demonstration of specific excretory secretory Toxocara antibodies from Toxocara larvae by immunological assays. This study provides a simple manual technique which can be performed in any laboratory for recovering a large number of Toxocara cati larvae from the thick-shelled eggs. The devices that are required contain a manual homogenizer and a filter membrane of 40 MUm mesh; the rest of materials and solutions is standard laboratory ware. In the modified method the larval yields were 2.7 times higher (3000 larval/ml) and the time spent in performing the modified method was shorter (75 min). Further benefits over already techniques are the easy and repeatable, inexpensive and convenient materials, simplicity to perform and require less time for recovery of Toxocara cati larvae for subsequent cultivation and harvest of the larval excretory-secretory antigens for diagnostic or treatment purposes. PMID- 27502935 TI - Cytoreductive radical prostatectomy in metastatic prostate cancer: Does it really make sense? AB - PURPOSE: Surgical removal of the primary tumor in metastatic prostate cancer (mPCa) is becoming a hotly debated issue. The purpose of this review was to summarize the current knowledge on cytoreductive radical prostatectomy (cRP) in this setting. MATERIALS AND METHODS: We performed a non-systematic Medline/PubMed literature search of articles published in the field between January 2000 and April 2015. RESULTS: Cytoreductive surgery has demonstrated its benefit in various malignancies with a solid biological rationale to justify its assessment in mPCa. cRP appears as a safe and feasible procedure in expert hands and well selected patients. A growing body of evidence suggests a survival benefit for patients undergoing cRP as a part of a multimodal approach compared to those treated with systemic treatment alone. Nevertheless, little is known about the best clinical and tumor characteristics for the selection of patients most likely to benefit from cRP. The current literature is based on retrospective studies with small cohorts and limited follow-up or large uncontrolled population-based studies. CONCLUSIONS: Data from various other malignancies together with the biological rationale and preliminary results in PCa suggest that cytoreductive surgery may be an option in some mPCa patients. The lack of randomized controlled trials and the low level of evidence in the current literature preclude any firms conclusion on the benefit of cRP in mPCa. Ongoing phase II and future phase III studies are mandatory to define the exact role of cRP in mPCa and to identify the patients who are most likely to benefit from cRP. PMID- 27502937 TI - Winter is coming: The recurring risk of carbon monoxide poisoning. PMID- 27502938 TI - Abnormal Expression of FBXL20 in Refractory Epilepsy Patients and a Pilocarpine Induced Rat Model. AB - E3 ubiquitin ligases are important protein-modifying enzymes involved in the pathogenesis of a variety of neurodegenerative diseases. F-box and leucine-rich repeat protein 20 (FBXL20), an E3 ubiquitin ligase widely expressed in the central nervous system, plays an important role in the ubiquitin-dependent degradation of regulating synaptic membrane exocytosis 1 (RIM1), which is an important factor in the release of synaptic vesicles. FBXL20 has been associated with a variety of neurodegenerative diseases; thus, we hypothesized that FBXL20 is involved in the development of epilepsy. Herein, we used immunofluorescence staining, immunohistochemistry and western blotting to determine the expression pattern of FBXL20 in temporal lobe epilepsy patients and pilocarpine-induced epilepsy animal models. We also injected SD rats with lentivirus-vector mediated overexpression of FBXL20. The results showed that FBXL20 is expressed in the membrane and the cytoplasm of cortical neurons, and overexpression of FBXL20 decreased the onset level of spontaneous seizure, the frequency and duration of seizures. Additionally, FBXL20 protein level was decreased but RIM1 protein level was increased in the epileptic group compared with the LV-FBXL20 and LV-GFP group. These findings in humans were consistent with the results from a pilocarpine-induced animal model of chronic epilepsy. Thus, abnormal expression of FBXL20 might play an important role in the development of epilepsy. PMID- 27502939 TI - The Search for New Screening Models of Pharmacoresistant Epilepsy: Is Induction of Acute Seizures in Epileptic Rodents a Suitable Approach? AB - Epilepsy, a prevalent neurological disease characterized by spontaneous recurrent seizures (SRS), is often refractory to treatment with anti-seizure drugs (ASDs), so that more effective ASDs are urgently needed. For this purpose, it would be important to develop, validate, and implement new animal models of pharmacoresistant epilepsy into drug discovery. Several chronic animal models with difficult-to-treat SRS do exist; however, most of these models are not suited for drug screening, because drug testing on SRS necessitates laborious video-EEG seizure monitoring. More recently, it was proposed that, instead of monitoring SRS, chemical or electrical induction of acute seizures in epileptic rodents may be used as a surrogate for testing the efficacy of novel ASDs against refractory SRS. Indeed, several ASDs were shown to lose their efficacy on acute seizures, when such seizures were induced by pentylenetetrazole (PTZ) in epileptic rather than nonepileptic rats, whereas this was not observed when using the maximal electroshock seizure test. Subsequent studies confirmed the loss of anti-seizure efficacy of valproate against PTZ-induced seizures in epileptic mice, but several other ASDs were more potent against PTZ in epileptic than nonepileptic mice. This was also observed when using the 6-Hz model of partial seizures in epileptic mice, in which the potency of levetiracetam, in particular, was markedly increased compared to nonepileptic animals. Overall, these observations suggest that performing acute seizure tests in epileptic rodents provides valuable information on the pharmacological profile of ASDs, in particular those with mechanisms inherent to disease-induced brain alterations. However, it appears that further work is needed to define optimal approaches for acute seizure induction and generation of epileptic/drug refractory animals that would permit reliable screening of new ASDs with improved potential to provide seizure control in patients with pharmacoresistant epilepsy. PMID- 27502940 TI - Interactions between Glu-1 and Glu-3 loci and associations of selected molecular markers with quality traits in winter wheat (Triticum aestivum L.) DH lines. AB - The quality of wheat depends on a large complex of genes and environmental factors. The objective of this study was to identify quantitative trait loci controlling technological quality traits and their stability across environments, and to assess the impact of interaction between alleles at loci Glu-1 and Glu-3 on grain quality. DH lines were evaluated in field experiments over a period of 4 years, and genotyped using simple sequence repeat markers. Lines were analysed for grain yield (GY), thousand grain weight (TGW), protein content (PC), starch content (SC), wet gluten content (WG), Zeleny sedimentation value (ZS), alveograph parameter W (APW), hectolitre weight (HW), and grain hardness (GH). A number of QTLs for these traits were identified in all chromosome groups. The Glu D1 locus influenced TGW, PC, SC, WG, ZS, APW, GH, while locus Glu-B1 affected only PC, ZS, and WG. Most important marker-trait associations were found on chromosomes 1D and 5D. Significant effects of interaction between Glu-1 and Glu-3 loci on technological properties were recorded, and in all types of this interaction positive effects of Glu-D1 locus on grain quality were observed, whereas effects of Glu-B1 locus depended on alleles at Glu-3 loci. Effects of Glu A3 and Glu-D3 loci per se were not significant, while their interaction with alleles present at other loci encoding HMW and LMW were important. These results indicate that selection of wheat genotypes with predicted good bread-making properties should be based on the allelic composition both in Glu-1 and Glu-3 loci, and confirm the predominant effect of Glu-D1d allele on technological properties of wheat grains. PMID- 27502941 TI - The genome-scale DNA-binding profile of BarR, a beta-alanine responsive transcription factor in the archaeon Sulfolobus acidocaldarius. AB - BACKGROUND: The Leucine-responsive Regulatory Protein (Lrp) family is a widespread family of regulatory transcription factors in prokaryotes. BarR is an Lrp-like transcription factor in the model archaeon Sulfolobus acidocaldarius that activates the expression of a beta-alanine aminotransferase gene, which is involved in beta-alanine degradation. In contrast to classical Lrp-like transcription factors, BarR is not responsive to any of the alpha-amino acids but interacts specifically with beta-alanine. Besides the juxtaposed beta-alanine aminotransferase gene, other regulatory targets of BarR have not yet been identified although beta-alanine is the precursor of coenzyme A and thus an important central metabolite. The aim of this study is to extend the knowledge of the DNA-binding characteristics of BarR and of its corresponding regulon from a local to a genome-wide perspective. RESULTS: We characterized the genome-wide binding profile of BarR using chromatin immunoprecipation combined with high throughput sequencing (ChIP-seq). This revealed 21 genomic binding loci. High enrichment binding regions were validated to interact with purified BarR protein in vitro using electrophoretic mobility shift assays and almost all targets were also shown to harbour a conserved semi-palindromic binding motif. Only a small subset of enriched genomic sites are located in intergenic regions at a relative short distance to a promoter, and qRT-PCR analysis demonstrated that only one additional operon is under activation of BarR, namely the glutamine synthase operon. The latter is also a target of other Lrp-like transcription factors. Detailed inspection of the BarR ChIP-seq profile at the beta-alanine aminotransferase promoter region in combination with binding motif predictions indicate that the operator structure is more complicated than previously anticipated, consisting of multiple (major and auxiliary) operators. CONCLUSIONS: BarR has a limited regulon, and includes also glutamine synthase genes besides the previously characterized beta-alanine aminotransferase. Regulation of glutamine synthase is suggestive of a link between beta-alanine and alpha-amino acid metabolism in S. acidocaldarius. Furthermore, this work reveals that the BarR regulon overlaps with that of other Lrp-like regulators. PMID- 27502942 TI - Clinical comparison of the two-stranded single and four-stranded double Krackow techniques for acute Achilles tendon ruptures. AB - PURPOSE: Several different Krackow stitch configurations have been used for acute Achilles tendon rupture repair. Although several biomechanical studies compared different Krackow stitch configurations, to our knowledge, no previous studies compared the clinical outcome of these different suture methods. Therefore, in this study, we aimed to compare the clinical outcomes and complications of the two-stranded single and four-stranded double Krackow techniques. METHODS: Sixty eight consecutive patients who underwent open repair by using the four-stranded double Krackow (33 patients, group A) or the two-stranded single Krackow (35 patients, group B) techniques between September 2011 and August 2014 were reviewed retrospectively. The isokinetic strength of plantar flexion and dorsiflexion of both ankles was assessed on a Cybex dynamometer 3 and 6 months after surgery. Clinical outcomes were evaluated 3, 6, and 12 months post operatively. RESULTS: No significant differences were found between the groups regarding patient demographics or activity levels prior to treatment. Significant differences in the Achilles tendon Total Rupture Score, the American Orthopaedic Foot and Ankle Society Ankle-Hindfoot score, or the four-point Boyden scale were not found at any time during follow-up. Rerupture occurred only in one patient from group A. No significant differences were observed between the groups regarding the isokinetic plantar flexion and dorsiflexion strength at any time or any test speed. CONCLUSION: Equally favourable clinical outcomes and isokinetic muscle strength and a low complication rate were achieved with the two-stranded single Krackow technique as compared with the four-stranded double Krackow technique for acute Achilles tendon rupture repair. LEVEL OF EVIDENCE: III. PMID- 27502943 TI - Possible Impact of Incremental Cost-Effectiveness Ratio (ICER) on Decision Making for Cancer Screening in Hong Kong: A Systematic Review. AB - OBJECTIVES: The aim of this paper was to critically review the literature on the cost effectiveness of cancer screening interventions, and examine the incremental cost-effectiveness ratios (ICERs) that may influence government recommendations on cancer screening strategies and funding for mass implementation in the Hong Kong healthcare system. METHODS: We conducted a literature review of cost effectiveness studies in the Hong Kong population related to cancer screening published up to 2015, through a hand search and database search of PubMed, Web of Science, Embase, and OVID Medline. Binary data on the government's decisions were obtained from the Cancer Expert Working Group, Department of Health. Mixed-effect logistic regression analysis was used to examine the impact of ICERs on decision making. Using Youden's index, an optimal ICER threshold value for positive decisions was examined by area under receiver operating characteristic curve (AUC). RESULTS: Eight studies reporting 30 cost-effectiveness pairwise comparisons of population-based cancer screening were identified. Most studies reported an ICER for a cancer screening strategy versus a comparator with outcomes in terms of cost per life-years (55.6 %), or cost per quality-adjusted life-years (55.6 %). Among comparisons with a mean ICER of US$102,931 (range 800 715,137), the increase in ICER value by 1000 was associated with decreased odds (odds ratio 0.990, 0.981-0.999; p = 0.033) of a positive recommendation. An optimal ICER value of US$61,600 per effectiveness unit yielded a high sensitivity of 90 % and specificity of 85 % for a positive recommendation. A lower ICER threshold value of below US$8044 per effectiveness unit was detected for a positive funding decision. CONCLUSIONS: Linking published evidence to Government recommendations and practice on cancer screening, ICERs influence decisions on the adoption of health technologies in Hong Kong. The potential ICER threshold for recommendation in Hong Kong may be higher than those of developed countries. PMID- 27502948 TI - Neurally adjusted ventilatory assist (NAVA) in preterm newborn infants with respiratory distress syndrome-a randomized controlled trial. AB - Neurally adjusted ventilatory assist (NAVA) improves patient-ventilator synchrony during invasive ventilation and leads to lower peak inspiratory pressures (PIP) and oxygen requirements. The aim of this trial was to compare NAVA with current standard ventilation in preterm infants in terms of the duration of invasive ventilation. Sixty infants born between 28 + 0 and 36 + 6 weeks of gestation and requiring invasive ventilation due to neonatal respiratory distress syndrome (RDS) were randomized to conventional ventilation or NAVA. The median durations of invasive ventilation were 34.7 h (quartiles 22.8-67.9 h) and 25.8 h (15.6-52.1 h) in the NAVA and control groups, respectively (P = 0.21). Lower PIPs were achieved with NAVA (P = 0.02), and the rapid reduction in PIP after changing the ventilation mode to NAVA made following the predetermined extubation criteria challenging. The other ventilatory and vital parameters did not differ between the groups. Frequent apneas and persistent pulmonary hypertension were conditions that limited the use of NAVA in 17 % of the patients randomized to the NAVA group. Similar cumulative doses of opiates were used in both groups (P = 0.71). CONCLUSIONS: NAVA was a safe and feasible ventilation mode for the majority of preterm infants suffering from RDS, but the traditional extubation criteria were not clinically applicable during NAVA. WHAT IS KNOWN: * NAVA improves patient ventilator synchrony during invasive ventilation. * Lower airway pressures and oxygen requirements are achieved with NAVA during invasive ventilation in preterm infants by comparison with conventional ventilation. What is new: * Infants suffering from PPHN did not tolerate NAVA in the acute phase of their illness. * The traditional extubation criteria relying on inspiratory pressures and spontaneous breathing efforts were not clinically applicable during NAVA. PMID- 27502949 TI - Binding of transition metals to monosilicic acid in aqueous and xylem (Cucumis sativus L.) solutions: a low-T electron paramagnetic resonance study. AB - The supplementation of monosilicic acid [Si(OH)4] to the root growing medium is known to protect plants from toxic levels of iron (Fe), copper (Cu) and manganese (Mn), but also to mitigate deficiency of Fe and Mn. However, the physicochemical bases of these alleviating mechanisms are not fully understood. Here we applied low-T electron paramagnetic resonance (EPR) spectroscopy to examine the formation of complexes of Si(OH)4 with Mn(2+), Fe(3+), and Cu(2+) in water and in xylem sap of cucumber (Cucumis sativus L.) grown without or with supply of Si(OH)4. EPR, which is also useful in establishing the redox state of these metals, was combined with measurements of total concentrations of metals in xylem sap by inductive coupled plasma. Our results show that Si(OH)4 forms coordination bonds with all three metals. The strongest interactions of Si(OH)4 appear to be with Cu(2+) (1/1 stoichiometry) which might lead to Cu precipitation. In line with this in vitro findings, Si(OH)4 supply to cucumber resulted in dramatically lower concentration of this metal in the xylem sap. Further, it was demonstrated that Si(OH)4 supplementation causes pro-reductive changes that contribute to the maintenance of Fe and, in particular, Mn in the xylem sap in bioavailable 2+ form. Our results shed more light on the intertwined reactions between Si(OH)4 and transition metals in plant fluids (e.g. xylem sap). PMID- 27502950 TI - Patient characteristics in a return to work programme for common mental disorders: a cross-sectional study. AB - BACKGROUND: Mental health problems are a growing cause of sickness absence. There are programmes in many countries to facilitate return to work (RTW) after sickness absence. In Norway, there has been some controversy about patients on sick-leave being prioritized over other patient groups, such as those with more severe diagnoses. However, it is not clear whether patients in RTW programmes actually do differ from patients in regular services. METHODS: This study compared 270 patients treated in an RTW outpatient clinic and 86 patients treated in a regular outpatient clinic, both in specialized mental health care, on patient characteristics, history of treatment and mental health status. Analyses of differences between groups were done by ANOVA tests, chi-square test and logistic regression. RESULTS: Patients in the RTW clinic had lower scores on the Clinical Outcomes in Routine Evaluation Outcome Measure (CORE-OM). There was no difference in health-related quality of life. RTW patients were somewhat older and more likely to live in relationships and have children, and they had higher incomes. Work participation, previous psychiatric hospitalization and present diagnosis contributed uniquely to an explanation of which patients were included in the respective clinics. The RTW clinic seems to reach its intended target group. Almost all of the patients in this group participated in the work arena, and their psychopathologies were clearly dominated by common mental disorders. Most RTW patients' general practitioners had followed them fairly closely in the year before referral, suggesting previous attempts at treatment in primary care settings. CONCLUSIONS: Relative to outpatients in a specialized mental health care setting, RTW patients had lower symptoms, but still in the same moderate range of severity. They suffered the same reduction in quality of life. Almost all of the RTW patients were diagnosed with illnesses that can be treated effectively, about half of them had recurring mental health problems and many of them had been treated in primary care settings before referral. These findings indicate that this group has significant health problems that can benefit from treatment in specialized health care settings. PMID- 27502951 TI - The Correlation Between Arterial Lactate and Venous Lactate in Patients With Sepsis and Septic Shock. AB - BACKGROUND: Applying peripheral venous lactate instead of arterial lactate in clinical practice is questionable because of deviation between both values. We aimed to find the relationship between the arterial lactate and the peripheral venous lactate before reasoned that the venous lactate could be used in substitution to the arterial lactate in sepsis. METHODS: We conducted a prospective, cross-sectional study at a university hospital. The patients with sepsis in ICU who required lactate level monitoring were enrolled in this research. The correlation and agreement between arterial lactate (A-LACT) and peripheral venous lactate (V-LACT) were the primary outcomes. RESULTS: A total of 63 paired samples were collected. The A-LACT and V-LACT were strongly correlated ( r = .934, P < .0001, r2 = .873). The regression equation was A-LACT = (0.934 * V-LACT) - 0.236. The mean difference between V-LACT and A-LACT was 0.66 +/- 1.53 mmol/L. The 95% limits of agreement were between -3.66 and 2.33 mmol/L. The V LACT >= 4 mmol/L can predict A-LACT level >= 4 mmol/L with 87.5% sensitivity and 91.5% specificity, and the area under receiver operating characteristic curve was 0.948. CONCLUSION: The present study demonstrated a strong correlation between A LACT and V-LACT, but an agreement between both parameters was poor. We suggest not to use the V-LACT in substitution to the A-LACT in sepsis regarding the absolute value and clearance rate, but the V-LACT >= 4.5 mmol/L may be used for predicting the A-LACT >= 4 mmol/L. PMID- 27502952 TI - Sympatric reinforcement of reproductive barriers between Neotinea tridentata and N. ustulata (Orchidaceae). AB - Reinforcement is the process by which selection favors traits that decrease mating between two incipient species in response to costly mating or the production of maladapted hybrids, causing the evolution of greater reproductive isolation between emerging species. I have studied a pair of orchids, Neotinea tridentata and N. ustulata, to examine the level of postmating pre- and post zygotic isolating mechanisms that maintain these species, and the degree to which the boundary may still be permeable to gene flow. In this study, I performed pollen tube growth rate experiments and I investigated pre- and post-zygotic barriers by performing hand pollination experiments in order to evaluate fruit set, embryonate seed set and seed germination rates by intra- and interspecific crosses. Fruit set, the percentage of embryonate seeds and germinability of interspecific crosses were reduced compared to intraspecific pollinations, showing significant differences between sympatric and allopatric populations. While in allopatric populations the post-pollination isolation index ranged between 0.40 and 0.11, in sympatric populations orchid pairs showed total isolation due to post-pollination prezygotic barriers, guaranteed at the level of pollen-stigma interactions. Indeed, in sympatric populations, pollen tubes reached the ovary after 24 h in only 8 out of 45 plants; in the remaining cases, the pollen tubes did not enter the ovary, and thus no fruit set occurred. This pair of orchids is characterized by postmating pre-zygotic reproductive isolation in sympatric populations that prevents the formation of hybrids. This mechanism of speciation, starting in allopatry and triggering the reinforcement mechanisms of reproductive isolation in secondary sympatry, is the most likely explanation for the pattern of evolutionary transitions found in this pair of orchids. PMID- 27502953 TI - Lead Modulates Calcium Entry and Beta-Adrenoceptors Signaling to Produce Myometrial Relaxation in Rats. AB - Modulation of myometrial spontaneity by lead acetate trihydrate (Pb) and its regulatory pathways were studied in estrogenized rats. Isometric tension in myometrial strips under a resting tension of 1 g was measured using data acquisition system-based physiograph and Lab Chart Pro v7.3.7 software. Lead produced a dose-dependent inhibitory effect on rat myometrium with a major effect on phasic contractions compared to tonic contractions along with a reduction in both amplitude and frequency of contraction. Lead (3 MUM) significantly (p < 0.05) reduced CaCl2, and 80 mM KDS induced contractile response while potentiated the relaxant effect of phenylephrine. Based on our findings, it may be inferred that lead blocks calcium entry through VDCC and/or stimulates beta-adrenoceptors adenylyl cyclase-C-AMP pathway to produce inhibitory effect on rat myometrium. PMID- 27502954 TI - Serum Macroelement and Microelement Concentrations in Patients with Polycystic Ovary Syndrome: a Cross-Sectional Study. AB - Polycystic ovarian syndrome (PCOS) is one of the most common endocrine diseases. However, its pathogenesis is unclear. We aim to explore the potential relationships between serum macroelements/microelements and PCOS. A total of 1137 women were involved in the current study. PCOS was defined according to ESHRE/ASRM, and complete blood samples were collected. Serum macroelements (calcium and magnesium) and microelements (copper, zinc, and iron) were assayed through atomic absorption spectrophotometry. PCOS patients had significantly higher copper concentrations than patients without PCOS (P < 0.001). By contrast, PCOS patients had lower serum calcium levels than patients without PCOS (P < 0.001). No significant differences were observed in the levels of serum zinc, magnesium, and iron between PCOS and non-PCOS patients. PCOS patients with acne had higher magnesium levels than those without acne (P = 0.020), and PCOS patients with hirsutism had lower magnesium levels than those without hirsutism (P = 0.037). High serum copper and low calcium levels may be correlated with PCOS. Magnesium concentrations are correlated with acne and hirsutism in PCOS patients. These results provide clues to explore the mechanism of PCOS and guidance for element treatments in PCOS patients. PMID- 27502955 TI - Scheduling rules to achieve lead-time targets in outpatient appointment systems. AB - This paper considers how to schedule appointments for outpatients, for a clinic that is subject to appointment lead-time targets for both new and returning patients. We develop heuristic rules, which are the exact and relaxed appointment scheduling rules, to schedule each new patient appointment (only) in light of uncertainty about future arrivals. The scheduling rules entail two decisions. First, the rules need to determine whether or not a patient's request can be accepted; then, if the request is not rejected, the rules prescribe how to assign the patient to an available slot. The intent of the scheduling rules is to maximize the utilization of the planned resource (i.e., the physician staff), or equivalently to maximize the number of patients that are admitted, while maintaining the service targets on the median, the 95th percentile, and the maximum appointment lead-times. We test the proposed scheduling rules with numerical experiments using real data from the chosen clinic of Tan Tock Seng hospital in Singapore. The results show the efficiency and the efficacy of the scheduling rules, in terms of the service-target satisfaction and the resource utilization. From the sensitivity analysis, we find that the performance of the proposed scheduling rules is fairly robust to the specification of the established lead-time targets. PMID- 27502956 TI - The Quality and Accuracy of Mobile Apps to Prevent Driving After Drinking Alcohol. AB - BACKGROUND: Driving after the consumption of alcohol represents a significant problem globally. Individual prevention countermeasures such as personalized mobile app aimed at preventing such behavior are widespread, but there is little research on their accuracy and evidence base. There has been no known assessment investigating the quality of such apps. OBJECTIVE: This study aimed to determine the quality and accuracy of apps for drink driving prevention by conducting a review and evaluation of relevant mobile apps. METHODS: A systematic app search was conducted following PRISMA guidelines. App quality was assessed using the Mobile App Rating Scale (MARS). Apps providing blood alcohol calculators (hereafter "calculators") were reviewed against current alcohol advice for accuracy. RESULTS: A total of 58 apps (30 iOS and 28 Android) met inclusion criteria and were included in the final analysis. Drink driving prevention apps had significantly lower engagement and overall quality scores than alcohol management apps. Most calculators provided conservative blood alcohol content (BAC) time until sober calculations. None of the apps had been evaluated to determine their efficacy in changing either drinking or driving behaviors. CONCLUSIONS: This novel study demonstrates that most drink driving prevention apps are not engaging and lack accuracy. They could be improved by increasing engagement features, such as gamification. Further research should examine the context and motivations for using apps to prevent driving after drinking in at risk populations. Development of drink driving prevention apps should incorporate evidence-based information and guidance, lacking in current apps. PMID- 27502957 TI - Sensitivity of Image Features to Noise in Conventional and Respiratory-Gated PET/CT Images of Lung Cancer: Uncorrelated Noise Effects. AB - The effect of noise on image features has yet to be studied in depth. Our objective was to explore how significantly image features are affected by the addition of uncorrelated noise to an image. The signal-to-noise ratio and noise power spectrum were calculated for a positron emission tomography/computed tomography scanner using a Ge-68 phantom. The conventional and respiratory-gated positron emission tomography/computed tomography images of 31 patients with lung cancer were retrospectively examined. Multiple sets of noise images were created for each original image by adding Gaussian noise of varying standard deviation equal to 2.5%, 4.0%, and 6.0% of the maximum intensity for positron emission tomography images and 10, 20, 50, 80, and 120 Hounsfield units for computed tomography images. Image features were extracted from all images, and percentage differences between the original image and the noise image feature values were calculated. These features were then categorized according to the noise sensitivity. The contour-dependent shape descriptors averaged below 4% difference in positron emission tomography and below 13% difference in computed tomography between noise and original images. Gray level size zone matrix features were the most sensitive to uncorrelated noise exhibiting average differences >200% for conventional and respiratory-gated images in computed tomography and 90% in positron emission tomography. Image feature differences increased as the noise level increased for shape, intensity, and gray-level co-occurrence matrix features in positron emission tomography and for gray-level co-occurrence matrix and gray-level size zone matrix features in conventional computed tomography. Investigators should be aware of the noise effects on image features. PMID- 27502958 TI - Adaptive Radiotherapy for Head and Neck Cancer. AB - OBJECTIVE: To investigate the effects of adaptive radiotherapy on dosimetric, clinical, and toxicity outcomes for patients with head and neck cancer undergoing chemoradiotherapy with intensity-modulated radiotherapy. METHODS: Fifty-one patients with advanced head and neck cancer underwent definitive chemoradiotherapy with the original plan optimized to deliver 70.2 Gy. All patients were resimulated at a median dose of 37.8 Gy (range, 27.0-48.6 Gy) due to changes in tumor volume and/or patient weight loss (>15% from baseline). Thirty-four patients underwent adaptive replanning for their boost planning (21.6 Gy). The dosimetric effects of the adaptive plan were compared to the original plan and the original plan copied on rescan computed tomography. Acute and late toxicities and tumor local control were assessed. Gross tumor volume reduction rate was calculated. RESULTS: With adaptive replanning, the maximum dose to the spinal cord, brain stem, mean ipsilateral, and contralateral parotid had a median reduction of -4.5%, -3.0%, -6.2%, and -2.5%, respectively (median of 34 patients). Median gross tumor volume and boost planning target volume coverage improved by 0.8% and 0.5%, respectively. With a median follow-up time of 17.6 months, median disease-free survival and overall survival was 14.8 and 21.1 months, respectively. Median tumor volume reduction rate was 35.2%. For patients with tumor volume reduction rate <=35.2%, median disease-free survival was 8.7 months, whereas it was 16.9 months for tumor volume reduction rate >35.2%. Four patients had residual disease after chemoradiotherapy, whereas 64.7% (20 of 34) of patients achieved locoregional control. CONCLUSION: Implementation of adaptive radiotherapy in head and neck cancer offers benefits including improvement in tumor coverage and decrease in dose to organs at risk. The tumor volume reduction rate during treatment was significantly correlated with disease-free survival and overall survival. PMID- 27502959 TI - Licoricidin, an isoflavonoid isolated from Glycyrrhiza uralensis Fisher, prevents UVA-induced photoaging of human dermal fibroblasts. AB - OBJECTIVE: Licoricidin is an isoflavonoid isolated from Glycyrrhiza uralensis Fisher. In this study, we investigated the effects of licoricidin on photoaging of UVA-irradiated human dermal fibroblasts (HDFs). METHODS: In vitro reactive oxygen species (ROS) scavenging activity, cellular protective effect and inhibition of elastase activity was determined by Fe3+ -EDTA/H2 O2 systems, photohaemolysis and elastase activity assay, respectively. Anti-oxidative capacity of the compound was evaluated by fluorescent ELISA and 2', 7' dichlorofluorescin-diacetate (DCF-DA) assay. The expression of protein and phosphorylation was examined using Western blot. RESULTS: The ROS scavenging activity (OSC50 ) of licoricidin was 2.77 MUM. It was 3.1-fold higher than that of L-ascorbic acid. Its protective effects were confirmed in a study of 1 O2 induced cellular damage to human erythrocytes. The tau50 value of 10 MUM of licoricidin was 71.0 min; this was markedly higher than that obtained with alpha tocopherol (37.0 min). The elastase inhibitory activity of licoricidin (IC50 of 61.2 MUM) was 2.1-fold more potent than that of oleanolic acid. Licoricidin markedly reduced the UVA-induced intracellular ROS in a concentration-dependent manner. Western blot revealed that licoricidin attenuated the UVA-dependent induction of MMP-1 protein. Mechanistically, this appeared to be due to licoricidin-dependent inhibition of mitogen-activated protein kinases (MAPK) phosphorylation, which resulted in decreased c-Jun activation and reduced c-Jun and c-Fos expression. CONCLUSION: Licoricidin blocks UVA-induced photoaging via ROS scavenging. This activity converges to limit the activity of MMP-1. These data suggest that licoricidin may be considered as an active ingredient in new topically applied anti-ageing formulations. PMID- 27502961 TI - Picturing a neuroanatomical vision in a cave. PMID- 27502960 TI - Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency. AB - Mitochondrial complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [(13)C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction. PMID- 27502962 TI - Spinal cord, vertebral body, paraspinal muscle, and rib infarction: Tiny thrombus detected by CT. PMID- 27502963 TI - The magnetic apraxia of Denny-Brown. PMID- 27502964 TI - Critically re-evaluating a common technique: Accuracy, reliability, and confirmation bias of EMG. PMID- 27502966 TI - Journal Club: Effect of comorbidity on mortality in multiple sclerosis. PMID- 27502965 TI - Summary of comprehensive systematic review: Rehabilitation in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. PMID- 27502967 TI - Teaching NeuroImages: The syndrome of cutaneous photosensitivity, growth failure, and basal ganglia calcification. PMID- 27502968 TI - Teaching NeuroImages: Chronic sinus thrombosis with patency of occipital and falcine cerebral venous sinuses. PMID- 27502969 TI - Teaching Video NeuroImages: Thalamic infarct with pseudo-abducens and vertical gaze palsies and an unusual stroke mechanism. PMID- 27502970 TI - Methods for detecting, quantifying, and adjusting for dissemination bias in meta analysis are described. AB - OBJECTIVE: To systematically review methodological articles which focus on nonpublication of studies and to describe methods of detecting and/or quantifying and/or adjusting for dissemination in meta-analyses. To evaluate whether the methods have been applied to an empirical data set for which one can be reasonably confident that all studies conducted have been included. STUDY DESIGN AND SETTING: We systematically searched Medline, the Cochrane Library, and Web of Science, for methodological articles that describe at least one method of detecting and/or quantifying and/or adjusting for dissemination bias in meta analyses. RESULTS: The literature search retrieved 2,224 records, of which we finally included 150 full-text articles. A great variety of methods to detect, quantify, or adjust for dissemination bias were described. Methods included graphical methods mainly based on funnel plot approaches, statistical methods, such as regression tests, selection models, sensitivity analyses, and a great number of more recent statistical approaches. Only few methods have been validated in empirical evaluations using unpublished studies obtained from regulators (Food and Drug Administration, European Medicines Agency). CONCLUSION: We present an overview of existing methods to detect, quantify, or adjust for dissemination bias. It remains difficult to advise which method should be used as they are all limited and their validity has rarely been assessed. Therefore, a thorough literature search remains crucial in systematic reviews, and further steps to increase the availability of all research results need to be taken. PMID- 27502972 TI - Epidemiology of hepatitis C virus and genotype distribution in immigrants crossing to Europe from North and sub-Saharan Africa. AB - BACKGROUND: The association between the prevalence of hepatitis C virus (HCV) and immigration is rarely studied, particularly for the immigrants crossing to the resettlement countries. Most of the published data are confined to those immigrants who were resident in European countries and rarely immigrated before they reach the final destination. Libya is a large country in North Africa with the longest coast of the Mediterranean Sea facing the European Union. It has been considered as the main transient station for African immigrants to Europe. The objectives of this study were to determine: (1) the prevalence of HCV in African immigrants gathered in Libya from different African countries on their way to Europe and (2) HCV genotype distribution in these immigrants and its correlation with different demographic factors. METHODS: A total of 14 205 serum samples were collected in a 3-year period (2013-2015) from different immigrants from North and sub-Saharan Africa who resided in the African immigrant campus, Tripoli, Libya. The participants were interviewed, and relevant information was collected, including socio-demographic, ethnic, and geographic variables. Each serum sample was tested for anti-HCV antibody using ELISA. The genotypes were determined and assigned using a specific genotyping assay and correlated with demographic and potential risk factors of the recruited individuals. RESULTS: Of the immigrants studied, 1078 (7.6%) were positive for HCV. The prevalence of HCV infection ranged from 1.4% to 18.7%; it was higher among individuals arriving from Nile river (3.6-18.7%) of North Africa, followed by those who arrived from the West African region (2.1-14.1%), Horn of Africa (HOA, 6.8-9.9%), and Maghreb countries (1.4-2.7%). The relative risk factor attributable to gender variation was not significant (95% Cl: 0.8513-1.2381). Five genotypes were detected in 911 African immigrants. Genotypic analysis showed that the predominant HCV genotypes in this group were genotypes 4, 1, and 2 that accounted for 329 (36.1%), 326 (35.8%), and 131 (14.4%) strains, respectively, followed by genotype 3 that accounted for 87 (9.5%) strains. Genotype 5 was isolated mainly from 18 HOA (2%) and 20 West African (2.2%) individuals. CONCLUSIONS: The prevalence of HCV is considered high with a unique disparate distribution among African immigrants crossing to Europe. This indicated that the prevalence of HCV is high among these immigrants and thus may be reflected on the HCV prevalence in the guest countries. The broad genetic heterogeneity of HCV genotypes detected here may impact the efficacy of prevention and control efforts for HCV in both Europe and North and sub-Saharan Africa; hence, an integrated global policy of actions is needed. PMID- 27502971 TI - Conservation and divergence within the clathrin interactome of Trypanosoma cruzi. AB - Trypanosomatids are parasitic protozoa with a significant burden on human health. African and American trypanosomes are causative agents of Nagana and Chagas disease respectively, and speciated about 300 million years ago. These parasites have highly distinct life cycles, pathologies, transmission strategies and surface proteomes, being dominated by the variant surface glycoprotein (African) or mucins (American) respectively. In African trypanosomes clathrin-mediated trafficking is responsible for endocytosis and post-Golgi transport, with several mechanistic aspects distinct from higher organisms. Using clathrin light chain (TcCLC) and EpsinR (TcEpsinR) as affinity handles, we identified candidate clathrin-associated proteins (CAPs) in Trypanosoma cruzi; the cohort includes orthologs of many proteins known to mediate vesicle trafficking, but significantly not the AP-2 adaptor complex. Several trypanosome-specific proteins common with African trypanosomes, were also identified. Fluorescence microscopy revealed localisations for TcEpsinR, TcCLC and TcCHC at the posterior region of trypomastigote cells, coincident with the flagellar pocket and Golgi apparatus. These data provide the first systematic analysis of clathrin-mediated trafficking in T. cruzi, allowing comparison between protein cohorts and other trypanosomes and also suggest that clathrin trafficking in at least some life stages of T. cruzi may be AP-2-independent. PMID- 27502973 TI - Changes in choroidal thickness after intraocular pressure reduction following trabeculectomy. PMID- 27502975 TI - Severe Sarcoidosis Phenotypes: An Occupational Hazard? PMID- 27502974 TI - A dynamical framework to relate perceptual variability with multisensory information processing. AB - Multisensory processing involves participation of individual sensory streams, e.g., vision, audition to facilitate perception of environmental stimuli. An experimental realization of the underlying complexity is captured by the "McGurk effect"- incongruent auditory and visual vocalization stimuli eliciting perception of illusory speech sounds. Further studies have established that time delay between onset of auditory and visual signals (AV lag) and perturbations in the unisensory streams are key variables that modulate perception. However, as of now only few quantitative theoretical frameworks have been proposed to understand the interplay among these psychophysical variables or the neural systems level interactions that govern perceptual variability. Here, we propose a dynamic systems model consisting of the basic ingredients of any multisensory processing, two unisensory and one multisensory sub-system (nodes) as reported by several researchers. The nodes are connected such that biophysically inspired coupling parameters and time delays become key parameters of this network. We observed that zero AV lag results in maximum synchronization of constituent nodes and the degree of synchronization decreases when we have non-zero lags. The attractor states of this network can thus be interpreted as the facilitator for stabilizing specific perceptual experience. Thereby, the dynamic model presents a quantitative framework for understanding multisensory information processing. PMID- 27502976 TI - 16 Years and Counting? Time to Implement Noninvasive Screening for ARDS. PMID- 27502977 TI - Toward Personalized Prescription of Systemic Steroids for Patients Hospitalized With COPD Exacerbations. PMID- 27502978 TI - Could Cryo-Biopsies Lead Bronchoscopy Into the Ice Age? PMID- 27502981 TI - Considerations for the Interpretation of the Results Described in "Analysis of National Trends in Admissions for Pulmonary Embolism". PMID- 27502982 TI - Is FGF23 or FGF21 a Promising Biomarker to Indicate the Aging Process in COPD? PMID- 27502983 TI - Hospitals' Patterns of Noninvasive Ventilation in Asthma: Evidence or Deep Recommendations Needed? PMID- 27502984 TI - Response. PMID- 27502985 TI - Comparison of the Accuracy of Nurse-Performed and Physician-Performed Lung Ultrasound in the Diagnosis of Cardiogenic Dyspnea. PMID- 27502986 TI - Normoxic Recovery Reverses Intermittent Hypoxia-Induced Systemic and Vascular Inflammation. PMID- 27502987 TI - Serum Surfactant Protein D as a Marker of Asthma Severity. PMID- 27502988 TI - Response. PMID- 27502989 TI - Sirolimus Therapy for Patients With Lymphangioleiomyomatosis Leads to Loss of Chylous Ascites and Circulating LAM Cells. AB - A young woman received a diagnosis of abdominal, sporadic lymphangioleiomyomatosis (LAM) and multiple abdominal lymphangioleiomyomas and was referred for recurrent chylous ascites responding only to a fat-free diet. On admission, pulmonary function test (PFT) results showed a moderate reduction in the transfer factor for carbon monoxide with normal exercise performance. The serum vascular endothelial growth factor D (VEGF-D) level was 2,209 pg/mL. DNA sequences, amplified at loci kg8, D16S3395, D16S3024, D16S521, and D16S291 on chromosome 16p13.3, showed a loss of heterozygosity (LOH) only for kg8. Fat-free total parenteral nutrition in association with sirolimus (2 mg po daily) was initiated. Serum sirolimus levels were maintained at concentrations between 5 and 15 ng/mL. After 1 month, reintroduction of a low-fat oral feeding was achieved without recurrence of ascites. PFT results were stable. Interestingly, clinical improvement was associated with a reduction in the VEGF-D serum level (1,558 pg/mL). LOH at the kg8 biomarker in blood LAM cells was no longer detected. PMID- 27502990 TI - A 56-Year-Old Woman With a Recurrent Pleural Effusion After Chest Trauma. PMID- 27502991 TI - "Code Blue" in a 66-Year-Old Man in the Cardiology Department. PMID- 27502992 TI - A 57-Year-Old Man With Insidious Dyspnea and Nonpleuritic Chest and Back Pain. AB - A 57-year-old man with a history of DVT and pulmonary embolism, transient ischemic attacks, prior 60 pack-year smoking history, and oxygen-dependent COPD presented with insidiously worsening dyspnea associated with new pleuritic chest and back pain. PMID- 27502993 TI - A 44-Year-Old Man With Sore Throat and Fatigue After Using an Old Camper Van. AB - A 44-year-old man from Connecticut with no significant past medical history presented to the ED with a 2-week history of sore throat and fatigue, subsequently developing cough, dyspnea, fevers, and chills. The patient reported buying an old camper van and noticed a large infestation of rodent droppings, which he had cleaned thoroughly from the cabin. He used the camper van on several camping trips in Vermont, and symptoms started on his return. PMID- 27502994 TI - A 29-Year-Old Woman With Severe Sepsis and Hemoptysis. AB - A 29-year-old woman presented with a 1-week history of fever, weakness, anorexia, darkened urine, and mild cough. The patient described her cough as nonproductive and without hemoptysis. She had no chest pain. The patient's medical history was significant for x-linked hypophosphatemia, renal stones, migraine headaches, and chronic back pain managed on prescribed oral opiates for some time. She reported regular cigarette smoking, but denied illicit or IV drug use or any recent travel or sick contacts. The patient also had no known pertinent family history. PMID- 27502995 TI - A 51-Year-Old Woman With Hypoacusia and Increased Respiratory Effort in the Supine Position and OSA. AB - A 51-year-old woman with a personal history of vitiligo, normal thyroid hormone studies, a simple hysterectomy for multiple uterine myomas at age 35 years, and childhood adenotonsillectomy was seen for progressive hearing loss. She reported mild asthenia, cold intolerance, mild dysphagia with frequent choking while eating and drinking, and a progressive increase in inspiratory effort, especially in the supine position. Her partner described a progressively worsening history of snoring and witnessed apneic episodes, mostly in the supine position. Mild to moderate daytime sleepiness was also present. PMID- 27502996 TI - 2017 Clinical trials update in new treatments of beta-thalassemia. AB - The underlying basis of beta-thalassemia pathology is the diminished beta-globin synthesis leading to alpha-globin accumulation and premature apoptotic destruction of erythroblasts, causing oxidative stress-induced ineffective erythropoiesis, bone marrow hyperplasia, splenomegaly, and increased intestinal iron absorption with progressive iron overload. Better understanding of the molecular mechanisms underlying this disease led to the recognition of new targets with potential therapeutic utility. Agents such as JAK2 inhibitors and TGF-beta ligand traps that reduce the ineffective erythropoiesis process are already being tested in clinical trials with promising results. Other agents that aim to reduce oxidative stress (activators of Foxo3, HRI-eIF2aP, Prx2, Hsp70, and PK anti-oxidant systems and inhibitors of HO-1) and to decrease iron overload (hepcidin agonists, erythroferrone inhibitors and exogenous transferrin) are also under experimental investigation. Significant progress has also been made in the area of allogeneic hematopoietic stem cell transplantation with several ongoing clinical trials examining new condition regimens as well as different donor selection and stem cell source options. Gene therapy has reached a critical point and phase 1 clinical trials have recently been launched to examine the effectiveness and especially long term safety. Epigenetic manipulation and genomic editing of the gamma- or beta-globin gene are novel and promising experimental gene therapy approaches for beta-thalassemia giving hope for cure for this chronic disease. This review outlines the key points of the molecular mechanisms underlying beta-thalassemia in relation to the development of new therapies and an update is given both at the pre-clinical and clinical level. Am. J. Hematol. 91:1135-1145, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27502997 TI - Borophene as an extremely high capacity electrode material for Li-ion and Na-ion batteries. AB - "Two-dimensional (2D) materials as electrodes" is believed to be the trend for future Li-ion and Na-ion battery technologies. Here, by using first-principles methods, we predict that the recently reported borophene (2D boron sheets) can serve as an ideal electrode material with high electrochemical performance for both Li-ion and Na-ion batteries. The calculations are performed on two experimentally stable borophene structures, namely beta12 and chi3 structures. The optimized Li and Na adsorption sites are identified, and the host materials are found to maintain good electric conductivity before and after adsorption. Besides advantages including small diffusion barriers and low average open circuit voltages, most remarkably, the storage capacity can be as high as 1984 mA h g(-1) in beta12 borophene and 1240 mA h g(-1) in chi3 borophene for both Li and Na, which are several times higher than the commercial graphite electrode and are the highest among all the 2D materials discovered to date. Our results highly support that borophenes can be appealing anode materials for both Li-ion and Na ion batteries with extremely high power density. PMID- 27502998 TI - Electronic properties of highly-active Ag3AsO4 photocatalyst and its band gap modulation: an insight from hybrid-density functional calculations. AB - The electronic structures of highly active Ag-based oxide photocatalysts Ag3AsO4 and Ag3PO4 are studied by hybrid-density functional calculations. It is revealed that Ag3AsO4 and Ag3PO4 are indirect band gap semiconductors. The Hartree-Fock mixing parameters are fitted for experimental band gaps of Ag3AsO4 (1.88 eV) and Ag3PO4 (2.43 eV). The smaller electron effective mass and the lower valence band edge of Ag3AsO4 are likely to be responsible for the superior photocatalytic oxidation reaction to Ag3PO4. The comparable lattice constant and analogous crystal structure between the two materials allow the opportunities of fine tuning the band gap of Ag3AsxP1-xO4 using a solid-solution approach. The development of Ag3AsxP1-xO4 should be promising for the discovery of novel visible-light sensitized photocatalysts. PMID- 27502999 TI - Negative Capacitance in BaTiO3/BiFeO3 Bilayer Capacitors. AB - Negative capacitances provide an approach to reduce heat generations in field effect transistors during the switch processes, which contributes to further miniaturization of the conventional integrated circuits. Although there are many studies about negative capacitances using ferroelectric materials, the direct observation of stable ferroelectric negative capacitances has rarely been reported. Here, we put forward a dc bias assistant model in bilayer capacitors, where one ferroelectric layer with large dielectric constant and the other ferroelectric layer with small dielectric constant are needed. Negative capacitances can be obtained when external dc bias electric fields are larger than a critical value. Based on the model, BaTiO3/BiFeO3 bilayer capacitors are chosen as study objects, and negative capacitances are observed directly. Additionally, the upward self-polarization effect in the ferroelectric layer reduces the critical electric field, which may provide a method for realizing zero and/or small dc bias assistant negative capacitances. PMID- 27503000 TI - Comparison and combination of blood DNA methylation at smoking-associated genes and at lung cancer-related genes in prediction of lung cancer mortality. AB - Epigenome-wide association studies have established methylation patterns related to smoking, the major risk factor of lung cancer (LC), which are distinct from methylation profiles disclosed in LC patients. This study simultaneously investigated associations of smoking-associated and LC-related methylation markers with LC mortality. DNA methylation was determined by HM450K assay in baseline blood samples of 1,565 older adults in a population-based case-cohort study. The associations of 151 smoking-associated CpGs (smoCpGs) and 3,806 LC related CpGs (caCpGs) with LC mortality were assessed by weighted Cox regression models, controlling for potential confounders. Multi-loci methylation scores were separately constructed based on smoCpGs and caCpGs. During a median follow-up of 13.8 years, 60 participants who had a first diagnosis of LC died from LC. The average time between sample collection and LC diagnosis was 5.8 years. Hypomethylation at 77 smoCpGs and 121 caCpGs, and hypermethylation at 4 smoCpGs and 66 caCpGs were associated with LC mortality. The associations were much stronger for smoCpGs than for caCpGs. Hazard ratios (95% CI) were 7.82 (2.91 21.00) and 2.27 (0.75-6.85), respectively, for participants in highest quartile of Score I (based on 81 smoCpGs) and Score II (based on 187 caCpGs), compared with participants in the corresponding lower three quartiles. Score I outperformed Score II, with an optimism-corrected C-index of 0.87 vs. 0.77. In conclusion, although methylation changes of both smoking-associated and LC related genes are associated with LC mortality, only smoking-associated methylation markers predict LC mortality with high accuracy, and may thus serve as promising candidates to identify high risk populations for LC screening. PMID- 27503001 TI - Comparison of neuropsychological and functional outcomes in Alzheimer's disease patients with good or bad response to a cognitive stimulation treatment: a retrospective analysis. AB - BACKGROUND: The benefit of cognitive stimulation (CS) treatments in dementia is unequal. This study has sought to identify cognitive and functional measurements before and after the treatment which are indicative of a better response to a one year CS program. METHODS: A retrospective observational study was conducted between 2004 and 2012 in a sample of 60 users diagnosed with mild Alzheimer's disease (AD) who followed a one-year CS program and underwent a cognitive and functional assessment before and after the intervention. As a primary measure of treatment response, we used the annual change of the Mini-Mental State Examination (MMSE) scores, which distinguished good responders (R) from non responders (NR). RESULTS: 51.7% of patients classified as R at baseline had a higher cognitive performance in attention, immediate verbal memory, language, and working memory compared to NR. No initial statistically significant differences were found between R and NR in any sociodemographic variables, medical conditions, anxiety and/or depressive symptoms, treatment with cholinesterase inhibitors (ChEIs), level of insight, global cognitive function (MMSE), or functional capacity. After 12 months of treatment, R had significantly better results than NR on MMSE, temporal orientation, category evocation, and Philadelphia Geriatric Center-Instrumental Activities of Daily Living (PGC-IADL). CONCLUSION: The response to a CS treatment of some subjects over others is linked to cognitive and functional capacity. This research contributes to characterize the neuropsychological profile that differentiates subjects who respond better than others before and after the treatment. This should contribute to customize and optimize neuropsychological interventions in patients with AD. PMID- 27503002 TI - Electron acceptor redox potential globally regulates transcriptomic profiling in Shewanella decolorationis S12. AB - Electron acceptor redox potential (EARP) was presumed to be a determining factor for microbial metabolism in many natural and engineered processes. However, little is known about the potentially global effects of EARP on bacteria. In this study, we compared the physiological and transcriptomic properties of Shewanella decolorationis S12 respiring with different EARPs in microbial electrochemical systems to avoid the effects caused by the other physicochemical properties of real electron acceptor. Results showed that the metabolic activities of strain S12 were nonlinear responses to EARP. The tricarboxylic acid cycle for central carbon metabolism was down-regulated while glyoxylate shunt was up-regulated at 0.8 V compared to 0.2 and -0.2 V, which suggested that EARP is an important but not the only determinant for metabolic pathways of strain S12. Moreover, few cytochrome c genes were differentially expressed at different EARPs. The energy intensive flagella assembly and assimilatory sulfur metabolism pathways were significantly enriched at 0.8 V, which suggested strain S12 had stronger electrokinesis behavior and oxidative stress-response at high EARP. This study provides the first global information of EARP regulations on microbial metabolism, which will be helpful for understanding microorganism respiration. PMID- 27503003 TI - Cranberry-derived proanthocyanidins impair virulence and inhibit quorum sensing of Pseudomonas aeruginosa. AB - Bacteria have evolved multiple strategies for causing infections that include producing virulence factors, undertaking motility, developing biofilms, and invading host cells. N-acylhomoserine lactone (AHL)-mediated quorum sensing (QS) tightly regulates the expression of multiple virulence factors in the opportunistic pathogenic bacterium Pseudomonas aeruginosa. Thus, inhibiting QS could lead to health benefits. In this study, we demonstrate an anti-virulence activity of a cranberry extract rich in proanthocyanidins (cerPAC) against P. aeruginosa in the model host Drosophila melanogaster and show this is mediated by QS interference. cerPAC reduced the production of QS-regulated virulence determinants and protected D. melanogaster from fatal infection by P. aeruginosa PA14. Quantification of AHL production using liquid chromatography-mass spectrometry confirmed that cerPAC effectively reduced the level of AHLs produced by the bacteria. Furthermore, monitoring QS signaling gene expression revealed that AHL synthases LasI/RhlI and QS transcriptional regulators LasR/RhlR genes were inhibited and antagonized, respectively, by cerPAC. Molecular docking studies suggest that cranberry-derived proanthocyanidin binds to QS transcriptional regulators, mainly interacting with their ligand binding sites. These findings provide insights into the underlying mechanisms of action of a cerPAC to restrict the virulence of P. aeruginosa and can have implications in the development of alternative approaches to control infections. PMID- 27503004 TI - Women's birth place preferences in the United Kingdom: a systematic review and narrative synthesis of the quantitative literature. AB - BACKGROUND: Current clinical guidelines and national policy in England support offering 'low risk' women a choice of birth setting, but despite an increase in provison of midwifery units in England the vast majority of women still give birth in obstetric units and there is uncertainty around how best to configure services. There is therefore a need to better understand women's birth place preferences. The aim of this review was to summarise the recent quantitative evidence on UK women's birth place preferences with a focus on identifying the service attributes that 'low risk' women prefer and on identifying which attributes women prioritise when choosing their intended maternity unit or birth setting. METHODS: We searched Medline, Embase, PsycINFO, Science Citation Index, Social Science Index, CINAHL and ASSIA to identify quantitative studies published in scientific journals since 1992 and designed to describe and explore women's preferences in relation to place of birth. We included experimental stated preference studies, surveys and mixed-methods studies containing relevant quantitative data, where participants were 'low risk' or 'unselected' groups of women with experience of UK maternity services. RESULTS: We included five experimental stated preference studies and four observational surveys, including a total of 4201 respondents. Most studies were old with only three conducted since 2000. Methodological quality was generally poor. The attributes and preferences most commonly explored related to pain relief, continuity of midwife, involvement/availability of medical staff, 'homely' environment/atmosphere, decision-making style, distance/travel time and need for transfer. Service attributes that were almost universally valued by women included local services, being attended by a known midwife and a preference for a degree of control and involvement in decision-making. A substantial proportion of women had a strong preference for care in a hospital setting where medical staff are not necessarily involved in their care, but are readily available. CONCLUSIONS: The majority of women appear to value some service attributes while preferences differ for others. Policy makers, commissioners and service providers might usefully consider how to extend the availability of services that most women value while offering a choice of options that enable women to access services that best fit their needs and preferences. PMID- 27503005 TI - mTOR Inhibitors in Castration-Resistant Prostate Cancer: A Systematic Review. AB - BACKGROUND: The progression of prostate cancer to castration-resistant prostate cancer (CRPC) is often a result of somatic alterations in the PI3K/Akt/mTOR (mammalian target of rapamycin) pathway, suggesting that therapies targeting this pathway might lead to improved survival and efficacy. Here, we systematically evaluate the results of clinical trials investigating mTOR inhibition in CRPC and utilize preclinical data to predict clinical outcomes. METHODS: Trials included in the study were identified through PubMed and via review of conference abstracts cited by relevant review articles. The eligibility of trials was independent of sample size, clinical setting, or date. RESULTS: A total of 14 studies were eligible for qualitative analysis. The clinical setting was variable among studies, and all utilized an allosteric mTOR inhibitor as either a monotherapy or in combination. Molecular criteria were evaluated in three trials. Among most studies, the prostate-specific antigen level declined during treatment, but often increased shortly thereafter. Partial responses to treatment were minimal, and no complete responses were reported. Two studies exploring therapy with an mTOR inhibitor in combination with bicalutamide resulted in minimal efficacy. Overall, allosteric mTOR inhibition was deemed to be inadequate for the treatment of CRPC. CONCLUSION: Preclinical data suggest that a reciprocal feedback mechanism between PI3K and androgen receptor signaling is a potential mechanism behind the clinical inefficacy of mTOR inhibitors in CRPC, indicating combinatorial targeting of PI3K, mTORC1/2, and the androgen receptor might be more effective. Comprehensive analysis of preclinical data to assess clinical trial targets and efficacy may reduce the number of unproductive trials and identify potentially beneficial combinatorial therapies for resistant disease. PMID- 27503006 TI - Impact of Diabetes on Outcomes of Sorafenib Therapy for Hepatocellular Carcinoma. AB - BACKGROUND: Patients with diabetes are at increased risk of developing hepatocellular carcinoma (HCC) and have a poorer prognosis as compared to non diabetics when HCC occurs. Diabetics with non-HCC cancers are at higher risk of toxicity related to systemic therapy, but data on HCC are lacking. OBJECTIVE: The aim of this study was to evaluate safety and effectiveness of sorafenib in HCC patients according to the presence/absence of diabetes. PATIENTS AND METHODS: From October 2008 to June 2014, 313 patients with HCC treated with sorafenib were enrolled. The patients were staged according to the BCLC system. Treatment response was evaluated according to the mRECIST criteria. The main evaluated outcomes were the overall survival and the safety in the two groups. RESULTS: Patients were divided in two groups: 80 diabetics (DIAB) and 233 nondiabetics (nDIAB). The median treatment duration was 4 months in DIAB and 3 months in nDIAB. Main adverse events occurred with comparable frequency in both groups, with the exception of rash, that was more frequent among DIAB than in nDIAB: 27.5 % vs 17.6 % (P = .047). The median overall survival was 9 months in nDIAB and 10 months in DIAB group (P = .535). Median time-to-progression (TTP) was longer the in DIAB than the nDIAB group (P = .038). CONCLUSIONS: Sorafenib was as safe as effective in DIAB and in nDIAB patients. The longer TTP observed among DIAB than in nDIAB patients might suggest a better anticancer effect of sorafenib in patients with diabetes. PMID- 27503007 TI - Motor priming in virtual reality can augment motor-imagery training efficacy in restorative brain-computer interaction: a within-subject analysis. AB - BACKGROUND: The use of Brain-Computer Interface (BCI) technology in neurorehabilitation provides new strategies to overcome stroke-related motor limitations. Recent studies demonstrated the brain's capacity for functional and structural plasticity through BCI. However, it is not fully clear how we can take full advantage of the neurobiological mechanisms underlying recovery and how to maximize restoration through BCI. In this study we investigate the role of multimodal virtual reality (VR) simulations and motor priming (MP) in an upper limb motor-imagery BCI task in order to maximize the engagement of sensory-motor networks in a broad range of patients who can benefit from virtual rehabilitation training. METHODS: In order to investigate how different BCI paradigms impact brain activation, we designed 3 experimental conditions in a within-subject design, including an immersive Multimodal Virtual Reality with Motor Priming (VRMP) condition where users had to perform motor-execution before BCI training, an immersive Multimodal VR condition, and a control condition with standard 2D feedback. Further, these were also compared to overt motor-execution. Finally, a set of questionnaires were used to gather subjective data on Workload, Kinesthetic Imagery and Presence. RESULTS: Our findings show increased capacity to modulate and enhance brain activity patterns in all extracted EEG rhythms matching more closely those present during motor-execution and also a strong relationship between electrophysiological data and subjective experience. CONCLUSIONS: Our data suggest that both VR and particularly MP can enhance the activation of brain patterns present during overt motor-execution. Further, we show changes in the interhemispheric EEG balance, which might play an important role in the promotion of neural activation and neuroplastic changes in stroke patients in a motor-imagery neurofeedback paradigm. In addition, electrophysiological correlates of psychophysiological responses provide us with valuable information about the motor and affective state of the user that has the potential to be used to predict MI-BCI training outcome based on user's profile. Finally, we propose a BCI paradigm in VR, which gives the possibility of motor priming for patients with low level of motor control. PMID- 27503008 TI - Fragile X mental retardation protein knockdown in the developing Xenopus tadpole optic tectum results in enhanced feedforward inhibition and behavioral deficits. AB - BACKGROUND: Fragile X Syndrome is the leading monogenetic cause of autism and most common form of intellectual disability. Previous studies have implicated changes in dendritic spine architecture as the primary result of loss of Fragile X Mental Retardation Protein (FMRP), but recent work has shown that neural proliferation is decreased and cell death is increased with either loss of FMRP or overexpression of FMRP. The purpose of this study was to investigate the effects of loss of FMRP on behavior and cellular activity. METHODS: We knocked down FMRP expression using morpholino oligos in the optic tectum of Xenopus laevis tadpoles and performed a series of behavioral and electrophysiological assays. We investigated visually guided collision avoidance, schooling, and seizure propensity. Using single cell electrophysiology, we assessed intrinsic excitability and synaptic connectivity of tectal neurons. RESULTS: We found that FMRP knockdown results in decreased swimming speed, reduced schooling behavior and decreased seizure severity. In single cells, we found increased inhibition relative to excitation in response to sensory input. CONCLUSIONS: Our results indicate that the electrophysiological development of single cells in the absence of FMRP is largely unaffected despite the large neural proliferation defect. The changes in behavior are consistent with an increase in inhibition, which could be due to either changes in cell number or altered inhibitory drive, and indicate that FMRP can play a significant role in neural development much earlier than previously thought. PMID- 27503009 TI - Models of wound healing: an emphasis on clinical studies. AB - BACKGROUND: The healing of wounds has always provided challenges for the medical community whether chronic or acute. Understanding the processes which enable wounds to heal is primarily carried out by the use of models, in vitro, animal and human. It is generally accepted that the use of human models offers the best opportunity to understand the factors that influence wound healing as well as to evaluate efficacy of treatments applied to wounds. OBJECTIVES: The objective of this article is to provide an overview of the different methodologies that are currently used to experimentally induce wounds of various depths in human volunteers and examines the information that may be gained from them. METHODS: There is a number of human volunteer healing models available varying in their invasiveness to reflect the different possible depth levels of wounds. RESULTS: Currently available wound healing models include sequential tape stripping, suction blister, abrasion, laser, dermatome, and biopsy techniques. The various techniques can be utilized to induce wounds of variable depth, from removing solely the stratum corneum barrier, the epidermis to even split-thickness or full thickness wounds. CONCLUSION: Depending on the study objective, a number of models exist to study wound healing in humans. These models provide efficient and reliable results to evaluate treatment modalities. PMID- 27503010 TI - Reconstruct the proximal radius with iliac graft and elastic intramedullary nail fixation after tumor resection. AB - BACKGROUND: This study aims to introduce a novel technique in treating benign bone tumors of the proximal radius by elastic intramedullary nail fixation and iliac graft after tumor resection. METHOD: In this retrospective case series, the treatment outcomes of 17 patients with benign bone tumor involving the proximal radius were reported from January 2010 to August 2014. All the patients received reconstruction surgery with iliac graft and elastic intramedullary nail fixation after tumor resection. Pain scoring was assessed using the 0 to 10 numerical rating scale. The quality of life scoring was assessed using the SF-30 scoring system. In addition, functional outcome was assessed with the Musculoskeletal Tumor Society score and the Disabilities of the Arm, Shoulder, and Hand score. RESULTS: The mean follow-up was 16 months (range, 10-22). The average bone consolidate time was 19.2 weeks (range, 16-24 weeks). The pre- and postoperative pain scores were 5.47 +/- 1.58 and 1.18 +/- 0.39, respectively. The pain symptom was significantly ameliorated after the operation (t = 13.50, p < 0.01). The pre- and postoperative and the quality of life scores were 48.29 +/- 6.58 and 77.47 +/ 5.89, respectively; the quality of life score was dramatically improved (t = 20.11, p < 0.01). The mean Musculoskeletal Tumor Society score was 83.41 % (range, 63-93 %) and the mean Disabilities of the Arm, Shoulder, and Hand score was 14.1 (range, 5.8-38.3). CONCLUSION: Taken together, the application of iliac graft and elastic intramedullary nail fixation after excision of lesions might be associated to a significant reduction of the pain and improvement of QOL (quality of life) and limb function of patients with benign bone tumors of proximal radius. PMID- 27503011 TI - The New Era of Organ Transplantation in China. PMID- 27503013 TI - Prognostic Significance of Frontal QRS-T Angle in Patients with Idiopathic Dilated Cardiomyopathy. AB - BACKGROUND: Current risk stratification of idiopathic dilated cardiomyopathy (IDC) lacks sufficient sensitivity and specificity. The objective of this study was to investigate the predictive role of frontal QRS-T angles in IDC. METHODS: A prospective study with 509 IDC patients was performed from February 2008 to December 2013 in the Affiliated Drum Tower Hospital, Nanjing University School of Medicine. Baseline values and changes in QRS-T angles were recorded. Follow-up was conducted every 6 months. Analyses by Cox Proportional Hazards model were performed to evaluate the association between QRS-T angle and outcomes. The primary outcome of interest was all-cause mortality. RESULTS: During a median follow-up of 34 months, 90 of 316 patients with QRS-T angles >90 degrees died compared to 31 of 193 patients with QRS-T angles <=90 degrees (hazard ratio [HR] =2.4, P < 0.001). Cardiac death was more prevalent in patients with a wide QRS-T angle (HR = 2.4, P < 0.001), similar to heart failure rehospitalization (HR = 2.5, P < 0.001). After adjustment for potential prognostic factors, the QRS-T angle was independently associated with all-cause mortality (HR = 2.5, P < 0.05), cardiac mortality (HR = 1.9, P < 0. 05), and heart failure rehospitalization (HR = 2.3, P < 0.01). Optimized therapy significantly narrowed the frontal QRS-T angle (100.9 +/- 53.4 degrees vs. 107.2 +/- 54.4 degrees , P < 0.001). The frontal QRS-T angle correlated well with established risk factors, such as left ventricular ejection fraction, brain natriuretic peptide, and New York Heart Association functional class. CONCLUSIONS: The frontal QRS-T angle is a powerful predictor of all-cause mortality, cardiac mortality, and worsening heart failure in IDC patients, independent of well-established prognostic factors. Optimized therapy significantly narrows the QRS-T angle, which might be an indicator of medication compliance, but this requires further investigation. PMID- 27503014 TI - Is There a Reliable Method to Predict the Limb Length Discrepancy after Chemotherapy and Limb Salvage Surgery in Children with Osteosarcoma? AB - BACKGROUND: For a child with osteosarcoma, prediction of the limb length discrepancy at maturity is important when planning for limb salvage surgery. The purpose of this study was to provide a reliable prediction method. METHODS: A retrospective review of Chinese children receiving chemotherapy for osteosarcoma before skeletal maturity was conducted. Standing full-length radiographs of the lower extremity were used for length measurements. Length-for-age curves were constructed using the LMS method. The lower limb multiplier for a specific age and gender was calculated using the formula M = Lm/L, where M was the gender- and age-specific multiplier, Lmwas the bone length at maturity, and L was the age specific bone length. Prematurity and postmaturity radiographs were used to assess the accuracy of the prediction methods. RESULTS: A total of 513 radiographs of 131 boys and 314 radiographs of 86 girls were used to calculate the coefficients of the multiplier. The multipliers of 8-, 9-, 10-, 11-, 12-, 13 , 14-, 15-, 16-, 17-, and 18-year-old boys after chemotherapy for osteosarcoma were 1.394, 1.306, 1.231, 1.170, 1.119, 1.071, 1.032, 1.010, 1.004, 1.001, and 1.000, respectively; while for girls at the same ages, the multipliers were 1.311, 1.221, 1.146, 1.092, 1.049, 1.021, 1.006, 1.001, 1.000, 1.000, and 1.000, respectively. Prematurity and postmaturity femoral and tibial lengths of 21 patients were used to assess the prediction accuracy. The mean prediction error was 0 cm, 0.8 cm, and 1.6 cm for the multiplier method using our coefficients, Paley's coefficients, and Anderson's method, respectively. CONCLUSIONS: Our coefficients for the multiplier method are reliable in predicting lower limb length growth of Chinese children with osteosarcoma. PMID- 27503012 TI - Efficacy of Leflunomide, Telmisartan, and Clopidogrel for Immunoglobulin A Nephropathy: A Randomized Controlled Trial. AB - BACKGROUND: The efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for immunoglobulin A nephropathy (IgAN) are unclear. This study was designed to evaluate the efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for IgAN. METHODS: It is a multicenter, prospective, double-dummy randomized controlled trial. Primary IgAN patients were recruited in 13 renal units across Beijing, China, from July 2010 to June 2012. After a 4-week telmisartan (80 mg/d) wash-in, 400 patients continuing on 80 mg/d telmisartan were randomly assigned to additionally receive placebo (Group A), 50 mg/d clopidogrel (Group B), 20 mg/d leflunomide (Group C), or 50 mg/d clopidogrel and 20 mg/d leflunomide (Group D). The 24-week intervention was completed by 360 patients. The primary endpoint was change in 24 h proteinuria at 24 weeks. A linear mixed-effect model was used to analyze the changes at 4, 12, and 24 weeks. Generalized estimating equations were used to evaluate changes in hematuria grade. This trial was registered at the Chinese Clinical Trial Registry. RESULTS: The effects of telmisartan combined with leflunomide on changes in proteinuria (0.36 [95% confidence interval (CI) 0.18 0.55] g/d, P < 0.001), in serum uric acid (76.96 [95% CI 57.44-96.49] MUmol/L, P < 0.001), in serum creatinine (9.49 [95% CI 6.54-12.44] MUmol/L, P < 0.001), and in estimated glomerular filtration rate (-6.72 [95% CI-9.46 to -3.98] ml.min 1.1.73 m-2, P < 0.001) were statistically significant, whereas they were not statistically significant on changes in systolic and diastolic blood pressure and weight (P > 0.05). Telmisartan combined with clopidogrel had no statistical effect on any outcome, and there was no interaction between the interventions. No obvious adverse reactions were observed. CONCLUSIONS: Telmisartan combined with leflunomide, not clopidogrel, is safe and effective for decreasing proteinuria in certain IgAN patients. TRIAL REGISTRATION: chictr.org.cn, ChiCTR-TRC-10000776; http://www.chictr.org.cn/showproj.aspx?proj=8760. PMID- 27503015 TI - Inserting the Ulnar Prosthesis into Radius as a Novel Salvage Surgery for Revision Total Elbow Arthroplasty with Massive Bone Defect. AB - BACKGROUND: Infection and aseptic loosening are common complications of total elbow arthroplasty (TEA) and often require revision surgery. However, bone defects, along with other complications, bring an extra difficulty to the second surgery, especially for patients with a massive bone defect in the proximal ulna. Several methods including allograft or autograft have been introduced into practice, but none sufficiently solves these problems. METHODS: We conducted a new surgical method for patients with a massive ulnar bone defect needing revision TEA. During revision arthroplasty, the ulnar prosthesis was inserted into the radius as a salvage procedure. Four consecutive patients received revision arthroplasty with this method between 2013 and 2016. Patients' data were collected to evaluate the clinical outcome. RESULTS: All patients had a Grade III ulnar bone defect. At the last follow-up session, all patients reported a painless, functional elbow joint. Three patients suffered from a periprosthetic infection that was completely cured using the two-stage method. No major complications, including infection, aseptic loosening, or wound problems were found. One patient had a transient ulnar neuritis, and another had a transient radial neuritis. Both patients had full recovery at the last follow-up session. CONCLUSIONS: Inserting an ulnar prosthesis into the radius is a novel procedure for patients with a massive bone defect due to infection or aseptic loosening. It is a safe, quick, and effective treatment with a promising short-term outcome. This method should be provided as a salvage procedure for patients with a nonreconstructable ulnar bone defect. PMID- 27503016 TI - Cognitive Function of Children and Adolescents with Attention Deficit Hyperactivity Disorder and Learning Difficulties: A Developmental Perspective. AB - BACKGROUND: The cognitive function of children with either attention deficit hyperactivity disorder (ADHD) or learning disabilities (LDs) is known to be impaired. However, little is known about the cognitive function of children with comorbid ADHD and LD. The present study aimed to explore the cognitive function of children and adolescents with ADHD and learning difficulties in comparison with children with ADHD and healthy controls in different age groups in a large Chinese sample. METHODS: Totally, 1043 participants with ADHD and learning difficulties (the ADHD + learning difficulties group), 870 with pure ADHD (the pure ADHD group), and 496 healthy controls were recruited. To investigate the difference in cognitive impairment using a developmental approach, all participants were divided into three age groups (6-8, 9-11, and 12-14 years old). Measurements were the Chinese-Wechsler Intelligence Scale for Children, the Stroop Color-Word Test, the Trail-Making Test, and the Behavior Rating Inventory of Executive Function-Parents (BRIEF). Multivariate analysis of variance was used. RESULTS: The results showed that after controlling for the effect of ADHD symptoms, the ADHD + learning difficulties group was still significantly worse than the pure ADHD group, which was, in turn, worse than the control group on full intelligence quotient (98.66 +/- 13.87 vs. 105.17 +/- 14.36 vs. 112.93 +/- 13.87, P < 0.001). The same relationship was also evident for shift function (shifting time of the Trail-Making Test, 122.50 [62.00, 194.25] s vs. 122.00 [73.00, 201.50] s vs. 66.00 [45.00, 108.00] s, P< 0.001) and everyday life executive function (BRIEF total score, 145.71 +/- 19.35 vs. 138.96 +/- 18.00 vs. 122.71 +/- 20.45, P < 0.001) after controlling for the effect of the severity of ADHD symptoms, intelligence quotient, age, and gender. As for the age groups, the differences among groups became nonsignificant in the 12-14 years old group for inhibition (meaning interference of the Stroop Color-Word Test, 18.00 [13.00, 25.00] s vs. 17.00 [15.00, 26.00] s vs. 17.00 [10.50, 20.00] s , P = 0.704) and shift function (shifting time of the Trail-Making Test, 62.00 [43.00, 97.00] s vs. 53.00 [38.00, 81.00] s vs. 101.00 [88.00, 114.00] s, P = 0.778). CONCLUSIONS: Children and adolescents with ADHD and learning difficulties have more severe cognitive impairment than pure ADHD patients even after controlling for the effect of ADHD symptoms. However, the differences in impairment in inhibition and shift function are no longer significant when these individuals were 12-14 years old. PMID- 27503017 TI - Self-controlled Study of Onychomycosis Treated with Long-pulsed Nd:YAG 1064-nm Laser Combined with Itraconazole. AB - BACKGROUND: Onychomycosis is a fungal infection of the nail plate and subungual area. In this study, we examined the efficacy of laser treatment using self controlled study programs involving a long-pulsed Nd:YAG 1064-nm laser combined with oral medication. METHODS: Self-controlled strategies were followed in this study. The patients received treatment with oral itraconazole in conjunction with long-pulsed Nd:YAG 1064-nm laser treatment at the nails of the unilateral limb once a week for a total of four times. A total of 84 affected nails were divided into Group A (mild to moderate) and Group B (severe) according to disease severity. Affected nails with the same Scoring Clinical Index for Onychomycosis scores were selected to compare the therapeutic effects of the pure medication treatment group and the combination treatment group with a 24-week follow-up period. RESULTS: In Group A, at the 8th, 16th, and 24th weeks of follow-up, the efficacies in the pure medication treatment group were 81.0%, 81.0%, and 90.5%, respectively, while those in the combination treatment group were 100%, 95.2%, and 90.5%, respectively. The differences between groups were not significant (8th week: chi2 = 4.421, P> 0.05; 16th week: chi2 = 2.043, P> 0.05; 24th week: chi2 = 0.00, P > 0.05). In Group B, at the 8th, 16th, and 24th weeks of follow-up, the efficacies in the pure medication treatment group were 61.9%, 66.7%, and 52.4%, respectively, while those in the combination treatment group were 95.2%, 90.5%, and 100%, respectively. The differences between groups at the 8th and 24th weeks of follow-up were statistically significant (8th week: chi2 = 6.929, P< 0.05; 24th week: chi2 = 13.125, P < 0.05). CONCLUSIONS: For patients with mild or moderate onychomycosis, we recommended a pure medication treatment or combination treatment with medication and laser. For those patients with severe onychomycosis, we recommended a combination of medication and laser therapy. PMID- 27503018 TI - Usage of a Reward System for Dealing with Pediatric Dental Fear. AB - BACKGROUND: Pediatric dental fear, if left unchecked, can persist for a lifetime and adversely impact the physical and psychological health of a patient. In this study, a feasible nonmedical method for relieving pediatric dental fear was investigated. METHODS: A randomized, single-blind, controlled trial model was applied. The juvenile patients experiencing dental fear, whose parents or guardian had signed an informed consent form, were randomly divided into two groups. Group A (n = 50) was the control group, while Group B (n = 50) was the reward group. Participants in Group A accepted routine treatment. Participants in Group B were told that they would obtain a gift as a rewarda for their good behavior if they were compliant during their dental treatments. The Chinese version of the Children's Fear Survey Schedule-Dental Subscale (CFSS-DS) was used to evaluate the level of dental fear of each patient both before and after each treatment. A contrast analysis and a correlation analysis of the results were used to assess the efficacy of the reward mechanism. RESULTS: All participants in Group B, were obedient during the dental treatment, and they also successfully chose the present they wanted at the end of their dental treatment. Children at different ages showed different reward preferences. Significant difference in the fear scores of the participants in Group B before the treatment and after receiving the reward was found (independent samples t-test, t = 14.72, P < 0.001). In Group A, 86% children's fear score did not undergo a noticeable change. CONCLUSIONS: A reward system is proved feasible to relieve pediatric dental fear, and the form of reward should meet the demand of patients. PMID- 27503019 TI - Viral and Bacterial Etiology of Acute Diarrhea among Children under 5 Years of Age in Wuhan, China. AB - BACKGROUND: Acute diarrhea remains the serious problem in developing countries, especially among children under 5 years of age. Currently, only two or three common diarrhea pathogens were screened at most hospitals in China. The aim of this study was to provide a wide variety of diarrhea pathogens and their antimicrobial resistance patterns in children under 5 years of age. METHODS: Totally 381 stool samples collected from Tongji Hospital between July 1, 2014 and June 30, 2015 were tested by culture and/or polymerase chain reaction for eight kinds of bacteria and five kinds of viruses. An antimicrobial sensitivity test was performed using dilution method recommended by the Clinical and Laboratory Standards Institute. RESULTS: Viral infections were mainly identified in infants (0-11 months), whereas bacterial infections were more prevalent in the age of 24 59 months. About 69.8% of samples were positive for at least one pathogen, 51.7% of samples were virus positive, followed by bacteria positive cases (19.4%), and 12.6% of cases displayed co-infections with two viruses or a virus and a bacterium. Rotavirus was the most prevalent pathogen, followed closely by norovirus, while Salmonella was the most commonly isolated bacteria, followed by diarrheagenic Escherichia coli (DEC) and Campylobacter. More than 40% of Salmonella spp. and DEC isolates were resistant to first-line antibiotics (ampicillin, trimethoprim-sulfamethoxazole, and tetracycline). Around 10% of Salmonella spp. isolates were resistant to ceftriaxone and ciprofloxacin simultaneously. Campylobacter spp. displayed high resistance to ciprofloxacin but kept low resistance to azithromycin and doxycycline. CONCLUSIONS: The etiology of acute diarrhea varies in children of different age groups. The high frequency of infection with viruses suggests the urgent demand for new viral vaccine development. Proper use of antibiotics in the treatment of acute diarrhea is crucial due to the high level of antibiotic resistance. PMID- 27503020 TI - Clinical and Molecular Characteristics in 100 Chinese Pediatric Patients with m.3243A>G Mutation in Mitochondrial DNA. AB - BACKGROUND: Mitochondrial diseases are a group of energy metabolic disorders with multisystem involvements. Variable clinical features present a major challenge in pediatric diagnoses. We summarized the clinical spectrum of m.3243A>G mutation in Chinese pediatric patients, to define the common clinical manifestations and study the correlation between heteroplasmic degree of the mutation and clinical severity of the disease. METHODS: Clinical data of one-hundred pediatric patients with symptomatic mitochondrial disease harboring m.3243A>G mutation from 2007 to 2013 were retrospectively reviewed. Detection of m.3243A>G mutation ratio was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Correlation between m.3243A>G mutation ratio and age was evaluated. The differences in clinical symptom frequency of patients with low, middle, and high levels of mutation ratio were analyzed by Chi-square test. RESULTS: Sixty six patients (66%) had suffered a delayed diagnosis for an average of 2 years. The most frequent symptoms were seizures (76%), short stature (73%), elevated plasma lactate (70%), abnormal magnetic resonance imaging/computed tomography (MRI/CT) changes (68%), vomiting (55%), decreased vision (52%), headache (50%), and muscle weakness (48%). The mutation ratio was correlated negatively with onset age (r = -0.470, P < 0.001). Myopathy was more frequent in patients with a high level of mutation ratio. However, patients with a low or middle level of m.3243A>G mutation ratio were more likely to suffer hearing loss, decreased vision, and gastrointestinal disturbance than patients with a high level of mutation ratio. CONCLUSIONS: Our study showed that half of Chinese pediatric patients with m.3243A>G mutation presented seizures, short stature, abnormal MRI/CT changes, elevated plasma lactate, vomiting, and headache. Pediatric patients with these recurrent symptoms should be considered for screening m.3243A>G mutation. Clinical manifestations and laboratory abnormalities should be carefully monitored in patients with this point mutation. PMID- 27503021 TI - Vascular Endothelial Growth Factor and Cluster of Differentiation 34 for Assessment of Perioperative Bleeding Risk in Gastric Cancer Patients. AB - BACKGROUND: Angiogenesis is the formation of new blood vessels to supply nutrients to tumors. Vascular endothelial growth factor (VEGF) and cluster of differentiation 34 (CD34) are important signaling proteins involved in angiogenesis. Many studies have demonstrated that VEGF and CD34 are related to tumor progression. This study focused on the relationship between VEGF, CD34, and perioperative hemorrhage in patients with gastric cancer. METHODS: To observe the relationship between VEGF and CD34, we tracked 112 patients with advanced gastric cancer for 5 years to assess factors related to hemorrhage, using immunohistochemistry. The results were subjected to statistical analysis using a 2 * 2 contingency table, logistic regression, and receiver operating characteristic (ROC) test. RESULTS: The concentrations of VEGF and CD34 were critically correlated with perioperative hemorrhage and neural invasion in patients with gastric cancer (P < 0.05). Expression of VEGF and CD34 was related (P < 0.05, chi2 = 6.834). VEGF and CD34 co-expression strongly increased the risk of preoperative bleeding (area under the ROC curve >0.7, P < 0.05). CONCLUSIONS: Expression of VEGF and CD34 was critically correlated with perioperative hemorrhage in gastric cancer patients. Co-expression of VEGF and CD34 could be an effective indicator for evaluating the risk of perioperative bleeding in gastric cancer patients. PMID- 27503022 TI - Ginsenoside Rd Attenuates DNA Damage by Increasing Expression of DNA Glycosylase Endonuclease VIII-like Proteins after Focal Cerebral Ischemia. AB - BACKGROUND: Ginsenoside Rd (GSRd), one of the main active ingredients in traditional Chinese herbal Panax ginseng, has been found to have therapeutic effects on ischemic stroke. However, the molecular mechanisms of GSRd's neuroprotective function remain unclear. Ischemic stroke-induced oxidative stress results in DNA damage, which triggers cell death and contributes to poor prognosis. Oxidative DNA damage is primarily processed by the base excision repair (BER) pathway. Three of the five major DNA glycosylases that initiate the BER pathway in the event of DNA damage from oxidation are the endonuclease VIII like (NEIL) proteins. This study aimed to investigate the effect of GSRd on the expression of DNA glycosylases NEILs in a rat model of focal cerebral ischemia. METHODS: NEIL expression patterns were evaluated by quantitative real-time polymerase chain reaction in both normal and middle cerebral artery occlusion (MCAO) rat models. Survival rate and Zea-Longa neurological scores were used to assess the effect of GSRd administration on MCAO rats. Mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damages were evaluated by the way of real-time analysis of mutation frequency. NEIL expressions were measured in both messenger RNA (mRNA) and protein levels by quantitative polymerase chain reaction and Western blotting analysis. Apoptosis level was quantitated by the expression of cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling assay. RESULTS: We found that GSRd administration reduced mtDNA and nDNA damages, which contributed to an improvement in survival rate and neurological function; significantly up-regulated NEIL1 and NEIL3 expressions in both mRNA and protein levels of MCAO rats; and reduced cell apoptosis and the expression of cleaved caspase-3 in rats at 7 days after MCAO. CONCLUSIONS: Our results indicated that the neuroprotective function of GSRd for acute ischemic stroke might be partially explained by the up-regulation of NEIL1 and NEIL3 expressions. PMID- 27503023 TI - Cryobiological Characteristics of L-proline in Mammalian Oocyte Cryopreservation. AB - BACKGROUND: L-proline is a natural, nontoxic cryoprotectant that helps cells and tissues to tolerate freezing in a variety of plants and animals. The use of L proline in mammalian oocyte cryopreservation is rare. In this study, we explored the cryobiological characteristics of L-proline and evaluated its protective effect in mouse oocyte cryopreservation. METHODS: The freezing property of L proline was detected by Raman spectroscopy and osmometer. Mature oocytes obtained from 8-week-old B6D2F1 mice were vitrified in a solution consisting various concentration of L-proline with a reduced proportion of dimethyl sulfoxide (DMSO) and ethylene glycol (EG), comparing with the control group (15% DMSO and 15% EG without L-proline). The survival rate, 5-methylcytosine (5-mC) expression, fertilization rate, two-cell rate, and blastocyst rate in vitro were assessed by immunofluorescence and in vitro fertilization. Data were analyzed by Chi-square test. RESULTS: L-proline can penetrate the oocyte membrane within 1 min. The osmotic pressure of 2.00 mol/L L-proline mixture is similar to that of the control group. The survival rate of the postthawed oocyte in 2.00 mol/L L-proline combining 7.5% DMSO and 10% EG is significantly higher than that of the control group. There is no difference of 5-mC expression between the L-proline combination groups and control. The fertilization rate, two-cell rate, and blastocyst rate in vitro from oocyte vitrified in 2.00 mol/L L-proline combining 7.5% DMSO and 10% EG solution are similar to that of control. CONCLUSIONS: It indicated that an appropriate concentration of L-proline can improve the cryopreservation efficiency of mouse oocytes with low concentrations of DMSO and EG, which may be applicable to human oocyte vitrification. PMID- 27503024 TI - Comparison between Minimally Invasive Transforaminal Lumbar Interbody Fusion and Conventional Open Transforaminal Lumbar Interbody Fusion: An Updated Meta analysis. AB - BACKGROUND: The previous studies agree that minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) has better function outcomes, less blood loss, and shorter hospital stay, when compared to open-TLIF. However, there are no significance differences on operative time, complication, and reoperation rate between the two procedures. This could be from less relative literatures and lower grade evidence. The further meta-analysis is needed with more and higher grade evidences to compare the above two TLIF procedures. METHODS: Prospective and retrospective studies that compared open-TLIF and MIS-TLIF were identified by searching the Medline, Embase, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP database (the literature search comprised Medical Subject Heading terms and key words or Emtree term). The retrieval time ranged from the date when the database was founded to January 2015. Pooled risk ratios (RR s) and weighted mean differences (WMDs) with 95% confidence intervals were calculated for the clinical outcomes and perioperative data. RESULTS: Twenty four studies (n = 1967 patients) were included in this review (n = 951, open TLIF, n = 1016, MIS-TLIF). MIS-TLIF was associated with a significant decrease in the visual analog score (VAS)-back pain score (WMD = -0.44; P = 0.001), Oswestry Disabilities Index (WMD = -1.57; P = 0.005), early ambulation (WMD = -1.77; P = 0.0001), less blood loss (WMD = -265.59; P < 0.00001), and a shorter hospital stay (WMD = -1.89; P < 0.0001). However, there were no significant differences in the fusion rate (RR = 0.99; P = 0.34), VAS-leg pain (WMD = -0.10; P = 0.26), complication rate (RR = 0.84; P = 0.35), operation time (WMD = -5.23; P = 0.82), or reoperation rate (RR = 0.73; P = 0.32). CONCLUSIONS: MIS-TLIF resulted in a similar fusion rate with better functional outcome, less blood loss, shorter ambulation, and hospital stay; furthermore, it did not increase the complication or reoperation rate based on the existing evidence. PMID- 27503025 TI - Synovial Fluid C-reactive Protein as a Diagnostic Marker for Periprosthetic Joint Infection: A Systematic Review and Meta-analysis. AB - BACKGROUND: Periprosthetic joint infection (PJI) is the main cause of failure following total joint arthroplasty. Until now, the diagnosis of PJI is still confronted with technical limitations, and the question of whether synovial fluid biomarker, C-reactive protein (CRP), can provide high value in the diagnosis of PJI remains unanswered and, therefore, was the aim of the study. METHODS: First, we conducted a systematic review on CRP in the diagnosis of PJI by searching online databases using keywords such as "periprosthetic joint infection", "synovial fluid", and "C-reactive protein". Eligible studies providing sufficient data to construct 2 * 2 contingency tables were then selected based on the list of criteria and the quality of included studies was assessed subsequently. Finally, the reported sensitivity, specificity, diagnostic odds ratio (DOR), summary receiver operating characteristic (SROC) curve, and the area under the SROC (AUSROC) were pooled together and used to evaluate overall diagnostic performance. RESULTS: Seven studies were included in our review, six of which comprising a total of 456 participants were further investigated in our meta analysis. The pooled sensitivity, specificity, and DOR were 0.92 (95% confidence interval [CI]: 0.86-0.96), 0.90 (95% CI: 0.87-0.93), and 101.40 (95% CI: 48.07 213.93), respectively. The AUSROC was 0.9663 (standard error, 0.0113). CONCLUSIONS: Synovial fluid CRP is a good biomarker for the diagnosis of PJI with high sensitivity and specificity. PMID- 27503027 TI - Corrigendum: Preparation and Characterization of Paclitaxel-loaded Poly Lactic Acid-co-glycolic Acid Coating Tracheal Stent. PMID- 27503026 TI - Cerebrospinal Fluid Leakage after Thoracic Decompression. AB - OBJECTIVE: The objective of this study is to review cerebrospinal fluid leakage (CSFL) after thoracic decompression and describe its regular and special features. DATA SOURCES: Literature cited in this review was retrieved from PubMed and Medline and was primarily published during the last 10 years. "Cerebrospinal fluid", "leakage", "dural tears", and "thoracic decompression" were the indexed terms. Relevant citations in the retrieved articles were also screened to include more data. STUDY SELECTION: All retrieved literature was scrutinized, and four categories were recorded: incidence and risk factors, complications, treatment modalities, and prognosis. RESULTS: CSFL is much more frequent after thoracic decompression than after cervical and lumbar spinal surgeries. Its occurrence is related to many clinical factors, especially the presence of ossified ligaments and the adhesion of the dural sac. While its impact on the late neurological recovery is currently controversial, CSFL increases the risk of other perioperative complications, such as low intracranial pressure symptoms, infection, and vascular events. The combined use of primary repairs during the operation and conservative treatment postoperatively is generally effective for most CSFL cases, whereas lumbar drains and reoperations should be implemented as rescue options for refractory cases only. CONCLUSIONS: CSFL after thoracic decompression has not been specifically investigated, so the present study provides a systematic and comprehensive review of the issue. CSFL is a multi factor-related complication, and pathological factors play a decisive role. The importance of CSFL is in its impact on the increased risk of other complications during the postoperative period. Methods to prevent these complications are in need. In addition, though the required treatment resources are not special for CSFL after thoracic decompression, most CSFL cases are conservatively curable, and surgeons should be aware of it. PMID- 27503028 TI - Idebenone Maintains Survival of Mutant Myocilin Cells by Inhibiting Apoptosis. PMID- 27503029 TI - Surgical Repair and Detection of Cerebrospinal Fluid Rhinorrhea using Magnetic Resonance Cisternography and Skull Base Coronal Thin-section Computed Tomography Scan. PMID- 27503030 TI - Three Cases of Idiopathic Superior Laryngeal Neuralgia Treated by Superior Laryngeal Nerve Block under Ultrasound Guidance. PMID- 27503031 TI - Symptomatic Rathke's Cleft Cyst with Rapid Enlargement Masquerading as Rathke's Cleft Cyst Apoplexy. PMID- 27503032 TI - Adult Monosymptomatic Nocturnal Enuresis with Obstructive Sleep Apnea Syndrome. PMID- 27503033 TI - First Case of Laboratory-confirmed Zika Virus Infection Imported into China. PMID- 27503034 TI - Single-puncture Method of Laparoscopic Herniorrhaphy in Children. PMID- 27503035 TI - Treatment of In-Stent Restenosis in Patients with Renal Artery Stenosis. AB - PURPOSE: To determine clinical outcomes of patients treated for renal artery in stent restenosis (ISR) with atherosclerotic renal artery stenosis. MATERIALS AND METHODS: A retrospective review was performed of the clinical data of all patients who underwent renal artery stent placement for atherosclerotic renal artery stenosis from 1996 to 2009. Medical records of patients were reviewed for relevant clinical history, including blood pressure, antihypertensive medications, and renal function data before and after an intervention. In 1,052 patients, 1,090 renal artery stent placements were performed. Of these, 101 stents in 79 patients developed ISR, which was treated with either percutaneous transluminal angioplasty (PTA) or repeat stent placement. Procedural details, including modality of intervention, stent diameter, and time to restenosis, were recorded. Hypertensive agent and use of statins were recorded. Univariate analysis was performed to identify risk factors associated with restenosis after treatment of ISR. RESULTS: Patients treated with repeat stent placement were 6.89 times more likely to lose patency after treatment than patients treated with PTA (P < .01). No additional clinical or procedural factor, including smoking history; presence of cardiac, renal, or metabolic disease; use of statin at time of ISR treatment; or diameter of treatment (stent or PTA), had a significant association with duration of stent or angioplasty patency. CONCLUSIONS: Treatment of renal artery ISR with PTA among patients with atherosclerotic renal artery stenosis has a lower rate of subsequent ISR compared with repeat stent placement. PMID- 27503036 TI - An online psychological intervention can improve the sexual satisfaction of men following treatment for localized prostate cancer: outcomes of a Randomised Controlled Trial evaluating My Road Ahead. AB - BACKGROUND: Prostate cancer treatment often results in significant psycho-sexual challenges for men following treatment; however, many men report difficulty in accessing appropriate care. METHODS: A randomized controlled trial was undertaken to assess the efficacy of a 10-week self-guided online psychological intervention called My Road Ahead (MRA) for men with localized prostate cancer in improving sexual satisfaction. Participants were randomized to 1 of 3 conditions MRA alone or MRA plus online forum, or forum access alone. Pre, post, and follow-up assessments of overall sexual satisfaction were conducted. Mixed models and structural equation modeling were used to analyze the data. RESULTS: One hundred forty-two men (mean age 61 y; SD = 7) participated. The majority of participants had undergone radical prostatectomy (88%) and all men had received treatment for localized prostate cancer. Significant differences were obtained for the 3 groups (P = .026) and a significant improvement in total sexual satisfaction was observed only for participants who were allocated to MRA + forum with a large effect size (P = .004, partial eta2 = 0.256). Structural equation modeling indicated that increases in sexual function, masculine self-esteem, and sexual confidence contributed significantly to overall sexual satisfaction for the MRA + forum plus forum condition. CONCLUSIONS: This study is the first, to our knowledge, that has evaluated a self-guided online psychological intervention tailored to the specific needs of men with prostate cancer. The findings indicate the potential for MRA to deliver support that men may not otherwise receive and also highlight the importance of psychological intervention to facilitate improved sexual outcomes. PMID- 27503038 TI - Cognition Effects of Low-Grade Hypoxia. AB - INTRODUCTION: The effects of low-grade hypoxia on cognitive function are reported in this paper. The study compared cognitive function during short exposures at four different altitudes. METHODS: Ninety-one subjects were exposed to simulated altitudes of ground level, 1524, 2438, and 3658 m (5000, 8000, and 12,000 ft) in the Brooks City-Base altitude pressure chamber in a balanced design. Oxygen saturation, heart rate, and cognitive performance on seven different cognitive tasks were measured. In addition, subjects indicated their symptoms from a 33 item subjective symptom survey. RESULTS: As designed, oxygen saturation decreased and heart rate increased with higher altitudes. Very small degradations in performance were found at the two highest altitudes for only two of the cognitive tasks (continuous performance and grammatical reasoning). In the subjective symptom survey, 18 of the 33 possible symptoms were more common at 3658 m (12,000 ft) than at ground level. CONCLUSIONS: The findings indicated a minimal influence of low-grade hypoxia on cognitive performance in contrast to some existing classic symptoms of hypoxia. Pilmanis AA, Balldin UI, Fischer JR. Cognition effects of low-grade hypoxia. Aerosp Med Hum Perform. 2016; 87(7):596-603. PMID- 27503039 TI - Frequency, Not Amplitude, of Latency Affects Subjective Sickness in a Head Mounted Display. AB - BACKGROUND: Interactions between frequency and amplitude of latency in head mounted displays (HMDs) are thought to affect simulator sickness. Many studies have linked system latency to subjective sickness, but recent research has found that at least with the case of inertia-based head tracking technology, latency is not a constant; rather it varies systematically over time due to sensor errors and clock asynchronization. The purpose of this experiment was to further explore the relationship between frequency and amplitude of latency as they relate to subjective sickness experienced in an HMD. METHODS: In a 2 (frequency) * 2 (amplitude) design, 120 subjects were randomly assigned to 4 latency conditions. Frequency of latency was either 0.2 Hz or 1.0 Hz. Amplitude of latency was either 100 ms fixed or 20-100 ms varying. RESULTS: A main effect of frequency of latency was found. Subjects reported greater sickness in the 0.2-Hz frequency conditions (39.0 +/- 27.8) compared to the 1-Hz conditions (30.3 +/- 17.0). Additionally, 18 subjects withdrew their participation early in the 0.2-Hz conditions compared to 7 in the 1.0-Hz conditions. DISCUSSION: In conclusion, frequency of latency appears to play a role in the experience of sickness in HMDs in both subjective reporting of symptoms and subject performance. The current study confirms results of earlier studies, finding that real motion around a frequency of 0.2 Hz is more sickening than other frequencies. Future work should continue to parse the effects of frequency and amplitude of latency in head-tracked HMDs. Kinsella A, Mattfeld R, Muth E, Hoover A. Frequency, not amplitude, of latency affects subjective sickness in a head-mounted display. Aerosp Med Hum Perform. 2016; 87(7):604-609. PMID- 27503040 TI - Neuromuscular Adaptations Following 90 Days Bed Rest With or Without Resistance Exercise. AB - INTRODUCTION: This study examined the effects of long-term bed rest with or without a concurrent resistance exercise protocol on different muscle function indices of the knee extensors and their influence on previously shown atrophy, neural impairment, and slow-to-fast phenotype shift. METHODS: Nine men underwent 90 d of bed rest only (BR), while eight men in addition performed maximal supine squats every third day (BRE). Before and at day 1 and 5 following bed rest, surface quadriceps electromyographic (EMG) activity was measured during a sustained (60-s) submaximal isometric action and rate of force development (RFD) was assessed during a maximal isometric action, both in the supine squat position. Maximal torque was measured during isokinetic knee extensions at different angular velocities before and after (day 2 and 11) bed rest. RESULTS: EMG amplitude at a fixed submaximal load increased in BR, but not in BRE. The increase in amplitude during the sustained action was elevated in BR but not in BRE. RFD decreased in BR; this effect was attenuated day 1 and normalized day 5 in BRE. RFD expressed relative to maximal force was maintained in both groups. Angle-specific torque decreased equally for all velocities in BR. The decrease in isokinetic strength was attenuated day 2 in BRE. DISCUSSION: Phenotype changes were not reflected in muscle function measurements, probably because they were overridden by the effects of atrophy and neural adaptation. The protective effect of resistance exercise was more pronounced in tasks similar to the training action, inferring great impact of neural mechanisms. Alkner BA, Norrbrand L, Tesch PA. Neuromuscular adaptations following 90 days bed rest with or without resistance exercise. Aerosp Med Hum Perform. 2016; 87(7):610-617. PMID- 27503041 TI - Aeromedical Hazard Comparison of FAA Medically Certified Third-Class and Medically Uncertified Pilots. AB - BACKGROUND: Since 2004, in the United States, light sport aircraft (LSA) and some aircraft with standard airworthiness certificates can be operated for recreational purposes with a valid state driver's license rather than a Federal Aviation Administration (FAA)-issued aeromedical certificate. There have been recent efforts to allow operation of much larger, heavier, faster, and more complex aircraft without requiring a medical certificate. The primary objective of this research was to compare hazards to flight safety identified in fatally injured pilots required to possess a valid FAA third-class medical certificate to hazards in fatally injured pilots who were not required to possess a valid medical certificate. METHODS: A search of all fatal U.S. aircraft accidents in the FAA Medical ANalysis and TRAcking (MANTRA) registry between January 1, 2011, and April 30, 2014, identified 1084 individuals. A review of accident pilots' medical, autopsy, and toxicological data was conducted. After applying exclusion criteria, 467 pilots remained, including 403 medically certified and 64 medically uncertified pilots. RESULTS: A significant difference was found in a surrogate measure for risk between medically certified and uncertified pilots (25% vs. 59%). This difference remained significant after adjustment for age. No significant difference was found in the proportions of hazards identified on toxicological review. CONCLUSION: The results of this study suggest that the risk of an adverse medical event is reduced in pilots required to possess a valid medical certificate. Ricaurte EM, Mills WD, DeJohn CA, Laverde-Lopez MC, Porras Sanchez DF. Aeromedical hazard comparison of FAA medically certified third-class and medically uncertified pilots. Aerosp Med Hum Perform. 2016; 87(7):618-621. PMID- 27503042 TI - Cognitive Performance Effects of Bilastine 20 mg During 6 Hours at 8000 ft Cabin Altitude. AB - INTRODUCTION: Bilastine is a new oral, second generation antihistamine used in the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. It is considered a nonsedating antihistamine and might be recommended for use in pilots, pending research on the effects on flying-related performance under hypobaric conditions that prevail in an airliner. We assessed the effects of a single dose of bilastine 20 mg on alertness and complex task performance of healthy volunteers in a hypobaric chamber at 75.2 kPa (8000 ft/2438 m cabin altitude). METHODS: In a randomized, double-blind, crossover study, 24 volunteers received a single dose of bilastine 20 mg, hydroxyzine 50 mg (active control), and placebo. Using the Vigilance and Tracking Task, Multi-Attribute Task Battery, and Stanford Sleepiness Scale, assessments were made before and up to 6 h after intake of the study medication. RESULTS: Bilastine 20 mg had no impairing effects on sleepiness levels, vigilance, or complex task performance for up to 6 h post dose. Hydroxyzine 50 mg (active control) was associated with significant sleepiness and impaired performance across this time period, confirming the sensitivity of the tests. CONCLUSION: Bilastine 20 mg did not cause sleepiness or impaired performance on tasks related to flying. It is anticipated that a single dose of bilastine 20 mg will not affect flying performance. Bilastine may provide a safe therapeutic alternative for pilots suffering from allergic rhinitis or urticaria. Our findings might also have implications for the treatment of allergic disorders of personnel involved in other safety-sensitive jobs. Valk PJL, Simons R, Jetten AM, Valiente R, Labeaga L. Cognitive performance effects of bilastine 20 mg during 6 hours at 8000 ft cabin altitude. Aerosp Med Hum Perform. 2016; 87(7):622-627. PMID- 27503043 TI - Demographic, Lifestyle Factors, and Reasons for Use of Dietary Supplements by Air Force Personnel. AB - BACKGROUND: Dietary supplement (DS) use is common among U.S. Army personnel to purportedly improve health, provide energy, and increase strength. However, a comprehensive analysis of DS use among U.S. Air Force (USAF) personnel has not been conducted using the same survey instrument, which would permit direct comparisons to DS use by Army personnel. METHODS: A standardized questionnaire was used to assess DS use, demographic factors, and reasons for use of DS by USAF personnel (N = 1750). Logistic regression models adjusted for age, sex, and rank were used to determine relationships among categories of DS (multivitamin and multimineral, individual vitamins and minerals, protein/amino acid supplements, combination products, herbal supplements, purported steroid analogs, and other) and demographic factors. Findings were compared to reports from other military services and civilian populations. RESULTS: DS were used by 68% of USAF personnel: 35% used 1-2 DS >= 1 time/wk, 13% 3-4 DS >= 1 time/wk, and 20% >= 5 DS >= 1 time/wk. There were 45% of personnel who used a multivitamin and mineral, 33% protein supplements, 22% individual vitamins/minerals, 22% combination products, and 7% herbals. Logistic regression demonstrated aerobic exercise duration and strength training were associated with increased DS use. Individuals who previously deployed were more likely to use DS. CONCLUSIONS: Like Army personnel, college students and athletes, USAF personnel use more DS than the general population and are more likely to use purported performance enhancing DS, such as protein supplements, and concurrently consume multiple DS. Austin KG, Price LL, McGraw SM, Leahy G, Lieberman HR. Demographic, lifestyle factors, and reasons for use of dietary supplements by Air Force personnel. Aerosp Med Hum Perform. 2016; 87(7):628-637. PMID- 27503044 TI - Sleep Disturbance in Female Flight Attendants and Teachers. AB - BACKGROUND: Flight attendants (FAs) may experience circadian disruption due to travel during normal sleep hours and through multiple time zones. This study investigated whether FAs are at higher risk for sleep disturbance compared to teachers, as assessed by questionnaire, diary, and activity monitors. METHODS: Sleep/wake cycles of 45 FAs and 25 teachers were studied. For one menstrual cycle, participants wore an activity monitor and kept a daily diary. Sleep metrics included total sleep in the main sleep period (MSP), sleep efficiency (proportion of MSP spent sleeping), and nocturnal sleep fraction (proportion of sleep between 10 p.m. to 8 a.m. home time). Relationships between sleep metrics and occupation were analyzed with mixed and generalized linear models. RESULTS: Both actigraph and diary data suggest that FAs sleep longer than teachers. However, several actigraph indices of sleep disturbance indicated that FAs incurred significant impairment of sleep compared to teachers. FAs were more likely than teachers to have poor sleep efficiency [adjusted odds ratio (OR) for lowest quartile of sleep efficiency = 1.9, 95% Confidence Interval (CI) 1.2 - 3.0] and to have a smaller proportion of their sleep between 10 p.m. and 8 a.m. home time (adjusted OR for lowest quartile of nocturnal sleep fraction = 3.1, CI 1.1 -9.0). DISCUSSION: Study FAs experienced increased sleep disturbance compared to teachers, which may indicate circadian disruption. Grajewski B, Whelan EA, Nguyen MM, Kwan L, Cole RJ. Sleep disturbance in female flight attendants and teachers. Aerosp Med Hum Perform. 2016; 87(7)638-645. PMID- 27503045 TI - Gaze Behavior While Operating a Complex Instrument Control Task. AB - INTRODUCTION: The recent developments of technology in almost all areas of industrial processing, workplace, smart homes, mobility, media, and communication change humans' everyday life environment and behavioral responses in numerous ways. Our main objective in this study was to determine whether subjects' operator performance in a complex sensorimotor task is associated with their gaze behavior. METHODS: In two experiments subjects operated a complex control task. To this end they watched multiple displays, made strategic decisions, and used multiple actuators to maximize their virtual earnings from operating a virtual power plant. In Experiment 1 we compared gaze behavior during the tasks with respect to operator performance in two different age groups (young vs. old), and in Experiment 2 in two different gravity conditions (normal vs. microgravity). RESULTS: We found gaze pattern changed in older subjects as well as in microgravity. Older adults and subjects in microgravity looked longer at areas that are less relevant for task success. Most importantly, these changes in gaze pattern accounted for the effects of age and microgravity and on total earnings in the instrument-control task. DISCUSSION: In conclusion, age- and gravity related changes of gaze behavior show a similar pattern. Gaze behavior seems to play an important role in complex control tasks and might predict alterations of operational performance. Kalicinski M, Steinberg F, Dalecki M, Bock O. Gaze behavior while operating a complex instrument control task. Aerosp Med Hum Perform. 2016; 87(7):646-651. PMID- 27503046 TI - Personal Flying Accident Rates of Selected Light Sport Aircraft Compared with General Aviation Aircraft. AB - BACKGROUND: The issue of expanding flight privileges that do not require medical oversight is currently an important topic, especially in the United States. We compared personal flying accident rates in aircraft with special light sport aircraft (SLSA) and experimental light sport aircraft (ELSA) airworthiness certificates to accident rates for personal flying in other general aviation (GA) aircraft. METHODS: To calculate accident rates, personal flying hours were obtained from the annual FAA General Aviation and Part 135 Activity Surveys, and numbers of personal flying accidents were obtained from the NTSB accident database. Overall and fatal personal flying accident rates for the SLSA and ELSA groups and other GA aircraft were calculated and accident rates were compared. RESULTS: The overall personal flying accident rate for SLSA and ELSA was found to be 29.8 per 100,000 flight hours and the fatal accident rate was 5.2 per 100,000 flying hours. These are both significantly greater than the overall personal flying rate of 12.7 per 100,000 h and fatal rate of 2.6 per 100,000 h for other GA aircraft. DISCUSSION: Although this study has several limitations, the significantly higher accident rates in the sport pilot aircraft suggests caution when expanding sport pilot privileges to include larger, more complex aircraft. Mills WD, DeJohn CA. Personal flying accident rates of selected light sport aircraft compared with general aviation aircraft. Aerosp Med Hum Perform. 2016; 87(7):652-654. PMID- 27503047 TI - A Report of Transverse Process Fractures Secondary to the Centrifuge in a Healthy Aviator. AB - BACKGROUND: Centrifuge training, while an integral component in pilot training, is not without risks. To date there has never been a reported case of isolated transverse process fractures associated with centrifuge training. CASE REPORT: A 32-yr-old Flight Surgeon underwent centrifuge training as part of an educational course. She had increasing back pain after exposure to the centrifuge. Follow-up studies showed left L2 and bilateral L3 transverse process fractures. No other contributory causes could be identified except for mild vitamin D deficiency. DISCUSSION: The etiology, incidence, and treatment of transverse process fractures are examined to better prepare the clinician for the management of these cases. Puderbaugh MA. A report of transverse process fractures secondary to the centrifuge in a healthy aviator. Aerosp Med Hum Perform. 2016; 87(7):655-658. PMID- 27503048 TI - Use of Gene Expression Biomarkers to Predict Suicidality. AB - Since the tragic accident of Germanwings flight 4U9525, there has been discussion about methods to identify and prevent suicidality in pilots. Neurogenetic scientists claim that biomarker tests for suicidality as part of healthcare assessments may lead to early identification of suicidal behavior. In this commentary the value of these gene expression biomarkers for aeromedical purposes is evaluated based on relevant literature. It is concluded that the currently identified biomarkers for suicidality need thorough validation before they can be used. The aeromedical examiner's most important tool is still an anamnesis, in which warning signs of suicidal behavior can be picked up. Simons R. Use of gene expression biomarkers to predict suicidality. Aerosp Med Hum Perform. 2016; 87(7):659-660. PMID- 27503049 TI - You're the Flight Surgeon. AB - Rojas J. You're the flight surgeon: F-16 pilot with papular rash. Aerosp Med Hum Perform. 2016; 87(7):661-663. PMID- 27503050 TI - This Month in Aerospace Medicine History. PMID- 27503052 TI - In silico modeling for tumor growth visualization. AB - BACKGROUND: Cancer is a complex disease. Fundamental cellular based studies as well as modeling provides insight into cancer biology and strategies to treatment of the disease. In silico models complement in vivo models. Research on tumor growth involves a plethora of models each emphasizing isolated aspects of benign and malignant neoplasms. Biologists and clinical scientists are often overwhelmed by the mathematical background knowledge necessary to grasp and to apply a model to their own research. RESULTS: We aim to provide a comprehensive and expandable simulation tool to visualizing tumor growth. This novel Web-based application offers the advantage of a user-friendly graphical interface with several manipulable input variables to correlate different aspects of tumor growth. By refining model parameters we highlight the significance of heterogeneous intercellular interactions on tumor progression. Within this paper we present the implementation of the Cellular Potts Model graphically presented through Cytoscape.js within a Web application. The tool is available under the MIT license at https://github.com/davcem/cpm-cytoscape and http://styx.cgv.tugraz.at:8080/cpm-cytoscape/ . CONCLUSION: In-silico methods overcome the lack of wet experimental possibilities and as dry method succeed in terms of reduction, refinement and replacement of animal experimentation, also known as the 3R principles. Our visualization approach to simulation allows for more flexible usage and easy extension to facilitate understanding and gain novel insight. We believe that biomedical research in general and research on tumor growth in particular will benefit from the systems biology perspective. PMID- 27503053 TI - AC105 Increases Extracellular Magnesium Delivery and Reduces Excitotoxic Glutamate Exposure within Injured Spinal Cords in Rats. AB - Magnesium (Mg2+) homeostasis is impaired following spinal cord injury (SCI) and the loss of extracellular Mg2+ contributes to secondary injury by various mechanisms, including glutamate neurotoxicity. The neuroprotective effects of high dose Mg2+ supplementation have been reported in many animal models. Recent studies found that lower Mg2+ doses also improved neurologic outcomes when Mg2+ was formulated with polyethylene glycol (PEG), suggesting that a PEG/ Mg2+ formulation might increase Mg2+ delivery to the injured spinal cord, compared with that of MgSO4 alone. Here, we assessed spinal extracellular Mg2+ and glutamate levels following SCI in rats using microdialysis. Basal levels of extracellular Mg2+ (~0.5 mM) were significantly reduced to 0.15 mM in the core and 0.12 mM in the rostral peri-lesion area after SCI. A single intravenous infusion of saline or of MgSO4 at 192 MUmoL/kg did not significantly change extracellular Mg2+ concentrations. However, a single infusion of AC105 (a MgCl2 in PEG) at an equimolar Mg2+ dose significantly increased the Mg2+ concentration to 0.3 mM (core area) and 0.25 mM (rostral peri-lesion area). Moreover, multiple AC105 treatments completely restored the depleted extracellular Mg2+ concentrations after SCI to levels in the uninjured spinal cord. Repeated MgSO4 infusions slightly increased the Mg2+ concentrations while saline infusion had no effect. In addition, AC105 treatment significantly reduced extracellular glutamate levels in the lesion center after SCI. These results indicate that intravenous infusion of PEG-formulated Mg2+ normalized the Mg2+ homeostasis following SCI and reduced potentially neurotoxic glutamate levels, consistent with a neuroprotective mechanism of blocking excitotoxicity. PMID- 27503054 TI - Polychlorinated biphenyls and organochlorine pesticides in River Brahmaputra from the outer Himalayan Range and River Hooghly emptying into the Bay of Bengal: Occurrence, sources and ecotoxicological risk assessment. AB - River Brahmaputra (RB) from the outer Himalayan Range and River Hooghly (RH), a distributary of River Ganga, are the two largest transboundary perennial rivers supplying freshwater to the northeastern and eastern states of India. Given the history of extensive usage of organochlorine pesticides and increasing industrialization along the banks of these rivers we investigated selected organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in the surface water of River Brahmaputra and River Hooghly. Geomean of SigmaOCPs (53 ng L-1) and Sigma19PCBs (108 ng L-1) was higher in RH compared with geomean of SigmaOCPs (24 ng L-1) and Sigma19PCBs (77 ng L-1) in RB. Among OCPs, gamma-HCH showed maximum detection frequency in both the rivers reflecting ongoing lindane usage. DDT and endosulfan residues were observed at specific locations where past or ongoing sources exist. Elevated concentrations of heavier congeners (penta hepta) were observed in those sites along RH where port and industrial activities were prevalent including informal electronic waste scrap processing units. Furthermore along River Hooghly PCB-126 was high in the suburban industrial belt of Howrah district. PCBs were found to be ubiquitously distributed in RB. Atmospheric transport of tri- and tetra-PCB congeners from the primary source regions might be a major contributor for PCBs in RB. Heavier congeners (penta nona) in the urban centers of RB were likely due to industrial wastewater runoff from the oil refineries in the Brahmaputra valley. Sigma19PCBs concentrations in this study exceeded the USEPA recommended limit for freshwater. Ecotoxicological risk assessment showed the possibility of adverse impact on the organisms in the lower trophic level due to DDT and lindane contamination. Impact of endosulfan on fishes might be of considerable concern for aquatic environment. PMID- 27503055 TI - Changes of primary and secondary metabolites in barley plants exposed to CdO nanoparticles. AB - The environmental fate of airborne nanoparticles and their toxicity to plants is not yet fully understood. Pot-grown barley plants with second leaves developed were therefore exposed to CdO nanoparticles (CdONPs) of ecologically relevant size (7-60 nm) and concentration (2.03 +/- 0.45 * 105 particles cm-3) in air for 3 weeks. An experiment was designed to test the effects of different treatments when only leaves (T1); leaves and soil substrate (T2); and leaves, soil, and water supply were exposed to nanoparticles (T3). A fourth, control group of plants was left without treatment (T0). Although CdONPs were directly absorbed by leaves from the air, a part of leaf-allocated Cd was also transported from roots by transpiration flow. Chromatographic assays revealed that CdONPs had a significant effect on total content of primary metabolites (amino acids and saccharides) but no significant effect on total content of secondary metabolites (phenolic compounds, Krebs cycle acids, and fatty acids). In addition, the compositions of individual metabolite classes were affected by CdONP treatment. For example, tryptophan and phenylalanine were the most affected amino acids in both analysed organs, while ferulic acid and isovitexin constituted the polyphenols most affected in leaves. Even though CdONP treatment had no effect on total fatty acids content, there were significant changes in the composition of saturated and unsaturated fatty acids in both the roots and leaves of treated plants. Although the results indicate the most pronounced effect in T3 plants as compared to T1 and T2 plants, even just leaf exposure to CdONPs has the potential to induce changes in plant metabolism. PMID- 27503056 TI - Serum POP concentrations are highly predictive of inner blubber concentrations at two extremes of body condition in northern elephant seals. AB - Long-lived, upper trophic level marine mammals are vulnerable to bioaccumulation of persistent organic pollutants (POPs). Internal tissues may accumulate and mobilize POP compounds at different rates related to the body condition of the animal and the chemical characteristics of individual POP compounds; however, collection of samples from multiple tissues is a major challenge to ecotoxicology studies of free-ranging marine mammals and the ability to predict POP concentrations in one tissue from another tissue remains rare. Northern elephant seals (Mirounga angustirostris) forage on mesopelagic fish and squid for months at a time in the northeastern Pacific Ocean, interspersed with two periods of fasting on land, which results in dramatic seasonal fluctuations in body condition. Using northern elephant seals, we examined commonly studied tissues in mammalian toxicology to describe relationships and determine predictive equations among tissues for a suite of POP compounds, including SigmaDDTs, SigmaPCBs, Sigmachlordanes, and SigmaPBDEs. We collected paired blubber (inner and outer) and blood serum samples from adult female and male seals in 2012 and 2013 at Ano Nuevo State Reserve (California, USA). For females (N = 24), we sampled the same seals before (late in molting fast) and after (early in breeding fast) their approximately seven month foraging trip. For males, we sampled different seals before (N = 14) and after (N = 15) their approximately four month foraging trip. We observed strong relationships among tissues for many, but not all compounds. Serum POP concentrations were strong predictors of inner blubber POP concentrations for both females and males, while serum was a more consistent predictor of outer blubber for males than females. The ability to estimate POP blubber concentrations from serum, or vice versa, has the potential to enhance toxicological assessment and physiological modeling. Furthermore, predictive equations may illuminate commonalities or distinctions in bioaccumulation across marine mammal species. PMID- 27503058 TI - Increase in moped injuries requiring emergency care. AB - BACKGROUND: There has been a marked increased in moped use over the past few years. In addition, there has been an increase in moped-related injuries presenting to the emergency department (ED). The objective of this study is to characterize moped-related injuries presenting to US EDs and obtain national estimates of moped injury incidence over time. METHODS: Data regarding moped injuries were queried from the National Electronic Injury Surveillance System from calendar year 2007 to 2015. Data included diagnosis, body part injured, ED disposition, and patient demographics. RESULTS: There were an estimated 114 729 moped-related injuries treated in US EDs from 2007 to 2015 (95% confidence interval, 102 156-127 302). In addition, there was an increase in the number of moped injuries annually (B = 762.1, P < .01). The average number of moped injuries yearly was 12 748. The mean age was 34 years. Patients between ages 19 and 38 years represented 42% of the study population. Men (74%) and whites (55%) accounted for most of the injured population. Most injuries were stabilized in the ED and discharged home (85%). Approximately 9% of injuries were admitted to the hospital, and fractures constituted 59% of all diagnoses admitted to the hospital. Contusions (27%) and fractures (24%) accounted for most diagnoses. The most common body part injured was the head (16%). CONCLUSIONS: Moped injuries have increased since 2007 and mopeds are associated with severe injuries. Education and reexamination of current moped laws may decrease the number and severity of moped-related injuries. PMID- 27503057 TI - Neutron Scattering Studies of the Interplay of Amyloid beta Peptide(1-40) and An Anionic Lipid 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol. AB - The interaction between lipid bilayers and Amyloid beta peptide (Abeta) plays a critical role in proliferation of Alzheimer's disease (AD). AD is expected to affect one in every 85 humans by 2050, and therefore, deciphering the interplay of Abeta and lipid bilayers at the molecular level is of profound importance. In this work, we applied an array of neutron scattering methods to study the structure and dynamics of Abeta(1-40) interacting 1,2-dimyristoyl-sn-glycero-3 phosphoglycerol (DMPG) bilayers. In the structural investigations of lipid bilayer's response to Abeta binding, Small Angle Neutron Scattering and Neutron Membrane Diffraction revealed that the Abeta anchors firmly to the highly charged DMPG bilayers in the interfacial region between water and hydrocarbon chain, and it doesn't penetrate deeply into the bilayer. This association mode is substantiated by the dynamics studies with high resolution Quasi-Elastic Neutron Scattering experiments, showing that the addition of Abeta mainly affects the slower lateral motion of lipid molecules, especially in the fluid phase, but not the faster internal motion. The results revealed that Abeta associates with the highly charged membrane in surface with limited impact on the structure, but the altered membrane dynamics could have more influence on other membrane processes. PMID- 27503059 TI - Application of nitroglycerin patch to treat finger cyanosis due to unintentional injection of epinephrine. PMID- 27503060 TI - Pharmacist impact on time to antibiotic administration in patients with sepsis in an ED. AB - PURPOSE: The purpose was to determine if the physical presence of a clinical pharmacist in the emergency department (ED) would decrease antibiotic order to administration time in adult patients with sepsis, severe sepsis, or septic shock. METHODS: We conducted a retrospective review of adult patients presenting to the ED between January and December 2014 with a diagnosis of sepsis, severe sepsis, or septic shock who required intravenous antibiotics. RESULTS: A total of 186 patients (92 patients when an ED pharmacist was present and 94 when no ED pharmacist was present) were included in the analysis. Baseline characteristics were similar between groups. When a pharmacist was present, patients received antibiotics sooner (median 0.61 vs 0.88 hour, P=.001), Surviving Sepsis Campaign goals for antibiotic administration time were more likely to be met (88% vs 72%, P=.0097), and initial antibiotics were appropriate more often (97% vs 81%, P=.0008). No significant differences were noted in intensive care unit length of stay, hospital length of stay, ventilator days, or in-hospital mortality. CONCLUSIONS: Physical presence of a clinical pharmacist in the ED decreased time to administration and increased appropriateness of intravenous antibiotics for adult patients with sepsis, severe sepsis, or septic shock. PMID- 27503061 TI - The role of prehospital advanced airway management on outcomes for out-of hospital cardiac arrest patients: a meta-analysis. AB - OBJECTIVE: The objective of this meta-analysis was to compare the benefits of prehospital advanced airway management (AAM) and basic airway management (BAM) for out-of-hospital cardiac arrest (OHCA) patients. METHODS: Two investigators performed a systematic review of PubMed, EMBASE, and the Cochrane Database to identify all peer-reviewed articles relevant to this meta-analysis. We included all articles describing emergency medical system-treated nontraumatic OHCAs; specifically, all articles that described intervention of the prehospital AAM type were considered. The primary outcome was survival to discharge, whereas the secondary outcome was neurologic recovery after an OHCA event. For subgroup analysis, we compared the clinical outcome of endotracheal intubation (ETI), a specific type of AAM, vs BAM. RESULTS: We reviewed 1452 studies, 10 of which satisfied all the inclusion criteria and involved 17 380 patients subjected to AAM and 67 525 subjected to BAM. Based on the full random effects model, patients who received AAM had lower odds of survival (odds ratio [OR], 0.51; 95% confidence interval [CI], 0.29-0.90) compared with BAM. Subgroup analysis for ETI vs BAM showed no significant association with respect to survival (OR, 0.44; 95% CI, 0.16-1.23). There were no significant differences in the odds of neurologic recovery between AAM and BAM (OR, 0.64; 95% CI, 0.03-1.37). CONCLUSIONS: Our results reveal decreased survival odds for OHCA patients treated with AAM by emergency medical service personnel compared with BAM. However, the role of prehospital AAM, especially ETI, on achieving neurologic recovery remains unclear. PMID- 27503062 TI - A survival case of tension gastrothorax due to hiatal hernia, the key of life saving is thoracotomy. PMID- 27503063 TI - Severe diabetic ketoacidosis presenting with negative serum ketones. PMID- 27503064 TI - A dramatic case of malignant atrophic papulosis (Kohlmeier-Degos disease) with fatal outcome. PMID- 27503065 TI - Severe respiratory disease with rhinovirus detection: Role of bacteria in the most severe cases. PMID- 27503066 TI - An expedient reverse-phase high-performance chromatography (RP-HPLC) based method for high-throughput analysis of deferoxamine and ferrioxamine in urine. AB - The present study was planned to optimize and validate an expedient reverse-phase high chromatography (RP-HPLC) based protocol for the analysis of deferoxamine (DFO) and ferrioxamine (FO) in urinary execration of patients suffering beta thalassemia major. The optimized RP-HPLC method was found to be linear over the wide range of DFO and FO concentration (1-90 MUg/mL) with appreciable recovery rates (79.64-97.30%) of quality controls at improved detection and quantitation limits and acceptable inter and intraday variability. Real-time analysis of DFO and FO in the urine of thalassemic patients (male and female) at different intervals of Desferal(r)(Novartis Pharmaceuticals Corporation) injection revealed DFO and FO excretion at significantly (p < 0) different rates. The maximum concentrations of DFO (76.7 +/- 3.06 MUg/mL) and FO (74.2 +/- 3.25 MUg/mL) were found in urine samples, collected after 6 h of drug infusion while the minimum levels of DFO (1.10 +/- 0.12 MUg/mL) and FO (2.97 +/- 0.13 MUg/mL) were excreted by patients after 24 h. The present paper offers balanced conditions for an expedient, reliable and quick determination of DFO and FO in urine samples. PMID- 27503067 TI - Palliative Care and Cardiovascular Disease and Stroke: A Policy Statement From the American Heart Association/American Stroke Association. AB - The mission of the American Heart Association/American Stroke Association includes increasing access to high-quality, evidence-based care that improves patient outcomes such as health-related quality of life and is consistent with the patients' values, preferences, and goals. Awareness of and access to palliative care interventions align with the American Heart Association/American Stroke Association mission. The purposes of this policy statement are to provide background on the importance of palliative care as it pertains to patients with advanced cardiovascular disease and stroke and their families and to make recommendations for policy decisions. Palliative care, defined as patient- and family-centered care that optimizes health-related quality of life by anticipating, preventing, and treating suffering, should be integrated into the care of all patients with advanced cardiovascular disease and stroke early in the disease trajectory. Palliative care focuses on communication, shared decision making about treatment options, advance care planning, and attention to physical, emotional, spiritual, and psychological distress with inclusion of the patient's family and care system. Our policy recommendations address the following: reimbursement for comprehensive delivery of palliative care services for patients with advanced cardiovascular disease and stroke; strong payer-provider relationships that involve data sharing to identify patients in need of palliative care, identification of better care and payment models, and establishment of quality standards and outcome measurements; healthcare system policies for the provision of comprehensive palliative care services during hospitalization, including goals of care, treatment decisions, needs of family caregivers, and transition to other care settings; and health professional education in palliative care as part of licensure requirements. PMID- 27503068 TI - Prospective evaluation of SeptiFast Multiplex PCR in children with systemic inflammatory response syndrome under antibiotic treatment. AB - BACKGROUND: Antimicrobially pre-treated children with systemic inflammation often pose a diagnostic challenge to the physician. We aimed to evaluate the additional use of SeptiFast multiplex polymerase chain reaction (PCR) to identify causative pathogens in children with suspected systemic bacterial or fungal infection. METHODS: Prospective observational study in 39 children with systemic inflammatory response syndrome (SIRS) under empiric antibiotic treatment. Primary outcome was the rate of positive blood cultures (BC), compared to the rate of positive SeptiFast (SF) results. RESULTS: In total, 14 SF-samples yielded positive results, compared to 4 positive BC (p < 0.05). All blood cultures and 13 of 14 positive SF-tests were considered infection. Median time for positive BC was 2 days, and time to definite result was 6 days, compared to 12 h for SF. Antimicrobial therapy was adapted in 7 of the 14 patients with positive SeptiFast, and in 3 of the 4 patients with positive BC. Best predictive power for positive SF shown by receiver-operating characteristic was demonstrated for procalcitonin PCT (Area under the curve AUC: 0.79), compared to C-reactive protein CRP (AUC: 0.51) and leukocyte count (AUC: 0.46). A procalcitonin threshold of 0.89 ng/ml yielded a sensitivity of 0.82 and a specifity of 0.7. Children with a positive SeptiFast result on day 0 had a significantly higher risk to require treatment on the Pediatric Intensive Care Unit or to be deceased on day 30 (Odds-Ratio 8.62 (CI 1.44-51.72). CONCLUSIONS: The additional testing with SeptiFast in antimicrobially pre-treated children with systemic inflammation enhances the rate of pathogen detection. The influence of multiplex PCR on clinically relevant outcome parameters has to be further evaluated. ( TRIAL REGISTRATION: DRKS00004694). PMID- 27503069 TI - Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection. AB - Major histocompatibility complex class II (MHC II) expression is tightly regulated, being subjected to cell type-specific mechanisms that closely control its levels at the cell surface. Ubiquitination by the E3 ubiquitin ligase MARCH 1 regulates MHC II expression in dendritic cells and B cells. In this study, we demonstrate that the related ligase MARCH 8 is responsible for regulating surface MHC II in thymic epithelial cells (TECs). March8(-/-) mice have elevated MHC II at the surface of cortical TECs and autoimmune regulator (AIRE)(-) medullary TECs (mTECs), but not AIRE(+) mTECs. Despite this, thymic and splenic CD4(+) T cell numbers and repertoires remained unaltered in March8(-/-) mice. Notably, the ubiquitination of MHC II by MARCH 8 is controlled by CD83. Mice expressing a mutated form of CD83 (Cd83(anu/anu) mice) have impaired CD4(+) T cell selection, but deleting March8 in Cd83(anu/anu) mice restored CD4(+) T cell selection to normal levels. Therefore, orchestrated regulation of MHC II surface expression in TECs by MARCH 8 and CD83 plays a major role in CD4(+) T cell selection. Our results also highlight the specialized use of ubiquitinating machinery in distinct antigen-presenting cell types, with important functional consequences and implications for therapeutic manipulation. PMID- 27503070 TI - Multiple allogeneic progenitors in combination function as a unit to support early transient hematopoiesis in transplantation. AB - Cord blood (CB) is a valuable donor source in hematopoietic cell transplantation. However, the initial time to engraftment in CB transplantation (CBT) is often delayed because of low graft cell numbers. This limits the use of CB. To overcome this cell dose barrier, we modeled an insufficient dose CBT setting in lethally irradiated mice and then added hematopoietic stem/progenitor cells (HSCs/HPCs; HSPCs) derived from four mouse allogeneic strains. The mixture of HSPCs rescued recipients and significantly accelerated hematopoietic recovery. Including T cells from one strain favored single-donor chimerism through graft versus graft reactions, with early hematopoietic recovery unaffected. Furthermore, using clinically relevant procedures, we successfully isolated a mixture of CD34(+) cells from multiple frozen CB units at one time regardless of HLA-type disparities. These CD34(+) cells in combination proved transplantable into immunodeficient mice. This work provides proof of concept that when circumstances require support of hematopoiesis, combined multiple units of allogeneic HSPCs are capable of early hematopoietic reconstitution while allowing single-donor hematopoiesis by a principal graft. PMID- 27503071 TI - Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83. AB - Deficiency of CD83 in thymic epithelial cells (TECs) dramatically impairs thymic CD4 T cell selection. CD83 can exert cell-intrinsic and -extrinsic functions through discrete protein domains, but it remains unclear how CD83's capacity to operate through these alternative functional modules relates to its crucial role in TECs. In this study, using viral reconstitution of gene function in TECs, we found that CD83's transmembrane domain is necessary and sufficient for thymic CD4 T cell selection. Moreover, a ubiquitination-resistant MHCII variant restored CD4 T cell selection in Cd83(-/-) mice. Although during dendritic cell maturation CD83 is known to stabilize MHCII through opposing the ubiquitin ligase March1, regulation of March1 did not account for CD83's TEC-intrinsic role. Instead, we provide evidence that MHCII in cortical TECs (cTECs) is targeted by March8, an E3 ligase of as yet unknown physiological substrate specificity. Ablating March8 in Cd83(-/-) mice restored CD4 T cell development. Our results identify CD83 mediated MHCII stabilization through antagonism of March8 as a novel functional adaptation of cTECs for T cell selection. Furthermore, these findings suggest an intriguing division of labor between March1 and March8 in controlling inducible versus constitutive MHCII expression in hematopoietic antigen-presenting cells versus TECs. PMID- 27503072 TI - An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth. AB - The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover, this active ADAM10 form marks cancer stem-like cells with active Notch signaling, known to mediate chemoresistance. Importantly, specific targeting of active ADAM10 with 8C7 inhibits Notch activity and tumor growth in mouse models, particularly regrowth after chemotherapy. Our results indicate targeted inhibition of active ADAM10 as a potential therapy for ADAM10-dependent tumor development and drug resistance. PMID- 27503073 TI - Inflammatory monocytes and NK cells play a crucial role in DNAM-1-dependent control of cytomegalovirus infection. AB - The poliovirus receptor (PVR) is a ubiquitously expressed glycoprotein involved in cellular adhesion and immune response. It engages the activating receptor DNAX accessory molecule (DNAM)-1, the inhibitory receptor TIGIT, and the CD96 receptor with both activating and inhibitory functions. Human cytomegalovirus (HCMV) down regulates PVR expression, but the significance of this viral function in vivo remains unknown. Here, we demonstrate that mouse CMV (MCMV) also down-regulates the surface PVR. The m20.1 protein of MCMV retains PVR in the endoplasmic reticulum and promotes its degradation. A MCMV mutant lacking the PVR inhibitor was attenuated in normal mice but not in mice lacking DNAM-1. This attenuation was partially reversed by NK cell depletion, whereas the simultaneous depletion of mononuclear phagocytes abolished the virus control. This effect was associated with the increased expression of DNAM-1, whereas TIGIT and CD96 were absent on these cells. An increased level of proinflammatory cytokines in sera of mice infected with the virus lacking the m20.1 and an increased production of iNOS by inflammatory monocytes was observed. Blocking of CCL2 or the inhibition of iNOS significantly increased titer of the virus lacking m20.1. In this study, we have demonstrated that inflammatory monocytes, together with NK cells, are essential in the early control of CMV through the DNAM-1-PVR pathway. PMID- 27503074 TI - Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1 dependent gene regulation and IFN-gamma-mediated host defenses. AB - An early hallmark of Toxoplasma gondii infection is the rapid control of the parasite population by a potent multifaceted innate immune response that engages resident and homing immune cells along with pro- and counter-inflammatory cytokines. In this context, IFN-gamma activates a variety of T. gondii-targeting activities in immune and nonimmune cells but can also contribute to host immune pathology. T. gondii has evolved mechanisms to timely counteract the host IFN gamma defenses by interfering with the transcription of IFN-gamma-stimulated genes. We now have identified TgIST (T. gondii inhibitor of STAT1 transcriptional activity) as a critical molecular switch that is secreted by intracellular parasites and traffics to the host cell nucleus where it inhibits STAT1-dependent proinflammatory gene expression. We show that TgIST not only sequesters STAT1 on dedicated loci but also promotes shaping of a nonpermissive chromatin through its capacity to recruit the nucleosome remodeling deacetylase (NuRD) transcriptional repressor. We found that during mice acute infection, TgIST-deficient parasites are rapidly eliminated by the homing Gr1(+) inflammatory monocytes, thus highlighting the protective role of TgIST against IFN-gamma-mediated killing. By uncovering TgIST functions, this study brings novel evidence on how T. gondii has devised a molecular weapon of choice to take control over a ubiquitous immune gene expression mechanism in metazoans, as a way to promote long-term parasitism. PMID- 27503075 TI - Widespread transneuronal propagation of alpha-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson's disease. AB - Parkinson's disease (PD) is characterized by the progressive appearance of intraneuronal Lewy aggregates, which are primarily composed of misfolded alpha synuclein (alpha-syn). The aggregates are believed to propagate via neural pathways following a stereotypical pattern, starting in the olfactory bulb (OB) and gut. We hypothesized that injection of fibrillar alpha-syn into the OB of wild-type mice would recreate the sequential progression of Lewy-like pathology, while triggering olfactory deficits. We demonstrate that injected alpha-syn fibrils recruit endogenous alpha-syn into pathological aggregates that spread transneuronally over several months, initially in the olfactory network and later in distant brain regions. The seeded inclusions contain posttranslationally modified alpha-syn that is Thioflavin S positive, indicative of amyloid fibrils. The spreading alpha-syn pathology induces progressive and specific olfactory deficits. Thus, we demonstrate that propagating alpha-syn pathology triggered in the OB is functionally detrimental. Collectively, we have created a mouse model of prodromal PD. PMID- 27503076 TI - Empirical monotherapy with meropenem or combination therapy: the microbiological point of view. AB - The increase in the number of clinical isolates of multiresistant Enterobacteriaceae and Pseudomonas aeruginosa raises problems in decision-making on empirical treatments for severe Gram-negative bacilli-associated infections. The aim of our study is to determine the resistance of meropenem in our setting and the co-resistance of a combination of this compound with two antibiotics from different families: amikacin and ciprofloxacin. Between 2009 and 2013, a total of 81,310 clinical isolates belonging to the main species of Enterobacteriaceae and 39,191 clinical isolates of P. aeruginosa isolated in 28 hospitals in the Valencian Community on the South East Mediterranean Coast of Spain were analyzed using data provided by RedMiva (microbiological surveillance network of the Valencian Community). Meropenem resistance in Enterobacteriaceae increased from 0.16 % in 2009 to 1.25 % in 2013. Very few Enterobacteriaceae strains resistant to meropenem were sensitive to ciprofloxacin; in contrast, the combination of meropenem and amikacin led to a marked decrease in the risk of the microorganisms being resistant to both drugs (RR = 34 in 2013). In the case of P. aeruginosa, meropenem resistance also increased (from 14.32 % in 2009 to 24.52 % in 2013). Most meropenem-resistant P. aeruginosa isolates were also resistant to fluoroquinolones. However, the addition of amikacin led to a more than three-fold decrease in the risk of resistance. In our setting, empirical treatment with meropenem is adequate in enterobacterial infections, but poses difficulties when infection due to P. aeruginosa is suspected, in which case a combination of meropenem and amikacin has been shown to have a higher microbiological success rate. PMID- 27503077 TI - Large-Scale medical image analytics: Recent methodologies, applications and Future directions. AB - Despite the ever-increasing amount and complexity of annotated medical image data, the development of large-scale medical image analysis algorithms has not kept pace with the need for methods that bridge the semantic gap between images and diagnoses. The goal of this position paper is to discuss and explore innovative and large-scale data science techniques in medical image analytics, which will benefit clinical decision-making and facilitate efficient medical data management. Particularly, we advocate that the scale of image retrieval systems should be significantly increased at which interactive systems can be effective for knowledge discovery in potentially large databases of medical images. For clinical relevance, such systems should return results in real-time, incorporate expert feedback, and be able to cope with the size, quality, and variety of the medical images and their associated metadata for a particular domain. The design, development, and testing of the such framework can significantly impact interactive mining in medical image databases that are growing rapidly in size and complexity and enable novel methods of analysis at much larger scales in an efficient, integrated fashion. PMID- 27503078 TI - Reflections on ultrasound image analysis. AB - Ultrasound (US) image analysis has advanced considerably in twenty years. Progress in ultrasound image analysis has always been fundamental to the advancement of image-guided interventions research due to the real-time acquisition capability of ultrasound and this has remained true over the two decades. But in quantitative ultrasound image analysis - which takes US images and turns them into more meaningful clinical information - thinking has perhaps more fundamentally changed. From roots as a poor cousin to Computed Tomography (CT) and Magnetic Resonance (MR) image analysis, both of which have richer anatomical definition and thus were better suited to the earlier eras of medical image analysis which were dominated by model-based methods, ultrasound image analysis has now entered an exciting new era, assisted by advances in machine learning and the growing clinical and commercial interest in employing low-cost portable ultrasound devices outside traditional hospital-based clinical settings. This short article provides a perspective on this change, and highlights some challenges ahead and potential opportunities in ultrasound image analysis which may both have high impact on healthcare delivery worldwide in the future but may also, perhaps, take the subject further away from CT and MR image analysis research with time. PMID- 27503079 TI - 20th anniversary of the Medical Image Analysis journal (MedIA). PMID- 27503080 TI - Quantitative analysis of retinal OCT. AB - Clinical acceptance of 3-D OCT retinal imaging brought rapid development of quantitative 3-D analysis of retinal layers, vasculature, retinal lesions as well as facilitated new research in retinal diseases. One of the cornerstones of many such analyses is segmentation and thickness quantification of retinal layers and the choroid, with an inherently 3-D simultaneous multi-layer LOGISMOS (Layered Optimal Graph Image Segmentation for Multiple Objects and Surfaces) segmentation approach being extremely well suited for the task. Once retinal layers are segmented, regional thickness, brightness, or texture-based indices of individual layers can be easily determined and thus contribute to our understanding of retinal or optic nerve head (ONH) disease processes and can be employed for determination of disease status, treatment responses, visual function, etc. Out of many applications, examples provided in this paper focus on image-guided therapy and outcome prediction in age-related macular degeneration and on assessing visual function from retinal layer structure in glaucoma. PMID- 27503081 TI - Renal transplantation in human immunodeficiency virus-infected recipients: a case control study from the Brazilian experience. AB - BACKGROUND: Highly active antiretroviral therapy has turned human immunodeficiency virus (HIV)-infected patients with end-stage renal disease into suitable candidates for renal transplantation. We present the Brazilian experience with kidney transplantation in HIV-infected recipients observed in a multicenter study. METHODS: HIV-infected kidney transplant recipients and matched controls were evaluated for the incidence of delayed graft function (DGF), acute rejection (AR), infections, graft function, and survival of patients and renal grafts. RESULTS: Fifty-three HIV-infected recipients and 106 controls were enrolled. Baseline characteristics were similar, but a higher frequency of pre transplant positivity for hepatitis C virus and cytomegalovirus infections was found in the HIV group. Immunosuppressive regimens did not differ, but a trend was observed toward lower use of anti-thymocyte globulin in the group of HIV infected recipients (P = 0.079). The HIV-positive recipient group presented a higher incidence of treated AR (P = 0.036) and DGF (P = 0.044). Chronic Kidney Disease Epidemiology Collaboration estimated that glomerular filtration rate was similar at 6 months (P = 0.374) and at 12 months (P = 0.957). The median number of infections per patient was higher in the HIV-infected group (P = 0.018). The 1 year patient survival (P < 0.001) and graft survival (P = 0.004) were lower, but acceptable, in the group of HIV-infected patients. CONCLUSIONS: In the Brazilian experience, despite somewhat inferior outcomes, kidney transplantation is an adequate therapy for selected HIV-infected recipients. PMID- 27503082 TI - Patients' Perspective of Medication Adherence in Chronic Conditions: A Qualitative Study. AB - INTRODUCTION: About 50% of patients do not take their long-term therapy for chronic conditions as prescribed. Many studies have centered on patients' adherence to a specific treatment or single conditions, but few have taken all chronic conditions into consideration from a patient's perspective. This study aims to explore factors that impact on drug compliance and to identify strategies to improve this from the perspective of patients with at least one chronic condition. METHODS: Patients were recruited by healthcare professionals from a hospital pharmacy, four community pharmacies, patient associations, and a primary care center in Barcelona. Five focus groups were conducted (N = 36). Conversations were audiotaped and transcribed verbatim to allow qualitative analysis. RESULTS: Study subjects were aged 39-90 years (mean 65 years) and the mean number of comorbidities per patient was 2.3 (range 1-7). The main modifiers of therapeutic conduct were: patients' health beliefs, patient-prescriber relationships, and patients' motivation and perception of illness control. Study participants wanted greater participation in decision-making concerning their health and increased education about their illness and medication. They also wanted individualized healthcare that took their preferences and personal and emotional issues into account. CONCLUSION: Our results highlight how the patient prescriber's relationship and factors such as health beliefs, motivation and perception of illness control impact on medication adherence in chronic patients. Future interventions to optimize adherence to treatment should focus on shared decision-making and more extensive health education. FUNDING: Celgene Corporation. PMID- 27503083 TI - A systematic review of the effects of low-frequency repetitive transcranial magnetic stimulation on cognition. AB - rTMS is increasingly used for a variety of neuropsychiatric conditions. There are data to support 'fast' rTMS (>=10 Hz) having some positive effects on cognitive functioning, but a dearth of research looking at any such effects of 'slow' rTMS. This question is important as cognitive dysfunction accompanies many neuropsychiatric conditions and neuromodulation that potentially enhances or hinders such functioning has important clinical consequences. To determine cognitive effects of slow (<=1 Hz) rTMS, a systematic review of randomized control trials assayed cognition in neurological, psychiatric, and healthy volunteer <=1 Hz rTMS paradigms. Both active (fast rTMS) and placebo comparators were included. 497 Records were initially obtained; 20 met inclusion criteria for evaluation. Four major categories emerged: mood disorders; psychotic disorders; cerebrovascular accidents; and 'other' (PTSD, OCD, epilepsy, anxiety, and tinnitus). Cognitive effects were measured across several domains: attention, executive functioning, learning, and psychomotor speed. Variability of study paradigms and reporting precluded meta-analytical analysis. No statistically significant improvement or deterioration was consistently found in any cognitive domain or illness category. These data support the overall safety of rTMS in not adversely affecting cognitive functioning. There are some data indicating that rTMS might have cognitive enhancing potential, but these are too limited at this time to make any firm conclusions, and the literature is marked by considerable heterogeneity in study parameters that hinder interpretation. Greater consensus is required in future studies in cognitive markers, and particularly in reporting of protocols. Future work should evaluate the effects of rTMS on cognitive training. PMID- 27503084 TI - Prolyl oligopeptidase and dipeptidyl peptidase II/dipeptidyl peptidase IV ratio in the cerebrospinal fluid in Parkinson's disease: historical overview and future prospects. AB - Prolyl oligopeptidase (also named prolyl endopeptidase; PREP) hydrolyzes the Pro Xaa bonds of biologically active oligopeptides on their carboxyl side. In 1987, we detected PREP activity in human cerebrospinal fluid (CSF) using highly sensitive liquid chromatography-fluorometry with succinyl-Gly-Pro-4-methyl coumarin amide as a new synthetic substrate, and found a marked decrease in its activity in the cerebrospinal fluid (CSF) from patients with Parkinson's disease (PD) as compared with its level in control patients without neurological diseases. In 2013, Hannula et al. found co-localization of PREP with alpha synuclein in the postmortem PD brain. Several recent studies also suggest that the level of PREP in the brain of PD patients may be related to dopamine (DA) cell death via promotion of alpha-synuclein oligomerization and that inhibitors of PREP may play a neuroprotective role in PD. Although the relationship between another family of prolyl oligopeptidase enzymes, dipeptidyl peptidase II (DPP II) and dipeptidyl peptidase IV (DPP IV), and alpha-synuclein in the PD brain is not yet clear, we found that the DPP II activity/DPP IV activity ratio in the CSF was significantly increased in PD patients. This review discusses the possibility of PREP as well as the DPP II/DPP IV ratio in the CSF as potential biomarkers of PD. PMID- 27503085 TI - [Extensive yellowish fundus changes in a 6-year-old child]. AB - We describe a 6-year-old, symptom-free girl presenting with a best corrected visual acuity of 0.6 on both eyes. Clinically we found yellowish subretinal lesions in the macula and around the vessel arcade without signs of vasculitis or abnormal vessels in the angiography. Fundus autofluorescence was marked and SD OCT showed subretinal hyperreflective masses. With the help of molecular genetics we could make the diagnosis of an autosomal recessive bestrophinopathy (ARB). The natural history over 22 months revealed a slight recovery of the visual acuity as well as a slight reduction of the subretinal deposits. PMID- 27503087 TI - Urogynecology digest : Presented by Katie Propst. PMID- 27503088 TI - Vaginal hysterectomy, vaginal salpingoophorectomy and uterosacral ligament colpopexy: a view from above (in English and Spanish). AB - AIM OF THE VIDEO: The aim of this video is to make vaginal hysterectomy (TVH), vaginal salpingoophorectomy and uterosacral ligament (USL) colpopexy approachable by showing the key procedural steps from both the vaginal and abdominal perspectives. METHODS: This production shows TVH with salpingoophorectomy and USL colpopexy that was performed on a cadaver and filmed simultaneously from the vaginal and abdominal views. The video begins with an anatomy overview from the open abdomen and proceeds with the TVH. The anterior and posterior peritoneal entries, a technique to safely and easily access the adnexa, as well as the placement of USL suspension sutures are highlighted. The proximity of the ureter and its distance from the three locations most vulnerable to injury during this procedure (the uterine artery pedicle, the infundibulopelvic ligament and the USL) are illustrated. The location of the USL suspension sutures in relation to the ischial spine, the rectum and the sacrum are demonstrated. For all of these crucial steps, a series of picture-in-picture views simultaneously showing the abdominal and vaginal perspectives are presented so that the viewer may better understand the spatial anatomy. CONCLUSION: This video provides the viewer with a unique anatomic perspective and helps more confidently perform TVH, vaginal salpingooophorectomy and USL colpopexy. PMID- 27503086 TI - Bioinformatic prediction of transcription factor binding sites at promoter regions of genes for photoperiod and vernalization responses in model and temperate cereal plants. AB - BACKGROUND: Many genes involved in responses to photoperiod and vernalization have been characterized or predicted in Arabidopsis (Arabidopsis thaliana), Brachypodium (Brachypodium distachyon), wheat (Triticum aestivum) and barley (Hordeum vulgare). However, little is known about the transcription regulation of these genes, especially in the large, complex genomes of wheat and barley. RESULTS: We identified 68, 60, 195 and 61 genes that are known or postulated to control pathways of photoperiod (PH), vernalization (VE) and pathway integration (PI) in Arabidopsis, Brachypodium, wheat and barley for predicting transcription factor binding sites (TFBSs) in the promoters of these genes using the FIMO motif search tool of the MEME Suite. The initial predicted TFBSs were filtered to confirm the final numbers of predicted TFBSs to be 1066, 1379, 1528, and 789 in Arabidopsis, Brachypodium, wheat and barley, respectively. These TFBSs were mapped onto the PH, VE and PI pathways to infer about the regulation of gene expression in Arabidopsis and cereal species. The GC contents in promoters, untranslated regions (UTRs), coding sequences and introns were higher in the three cereal species than those in Arabidopsis. The predicted TFBSs were most abundant for two transcription factor (TF) families: MADS-box and CSD (cold shock domain). The analysis of publicly available gene expression data showed that genes with similar numbers of MADS-box and CSD TFBSs exhibited similar expression patterns across several different tissues and developmental stages. The intra specific Tajima D-statistics of TFBS motif diversity showed different binding specificity among different TF families. The inter-specific Tajima D-statistics suggested faster TFBS divergence in TFBSs than in coding sequences and introns. Mapping TFBSs onto the PH, VE and PI pathways showed the predominance of MADS-box and CSD TFBSs in most genes of the four species, and the difference in the pathway regulations between Arabidopsis and the three cereal species. CONCLUSION: Our approach to associating the key flowering genes with their potential TFs through prediction of putative TFBSs provides a framework to explore regulatory mechanisms of photoperiod and vernalization responses in flowering plants. The predicted TFBSs in the promoters of the flowering genes provide a basis for molecular characterization of transcription regulation in the large, complex genomes of important crop species, wheat and barley. PMID- 27503089 TI - Inhibitor treatment of peripheral mononuclear cells from Parkinson's disease patients further validates LRRK2 dephosphorylation as a pharmacodynamic biomarker. AB - Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with increased risk of Parkinson's disease (PD). Thus, LRRK2 kinase inhibitors are in development as potential Parkinson's disease therapeutics. A reduction in the constitutive levels of phosphorylation on leucine-rich repeat kinase 2 (LRRK2) is currently used to measure target engagement of LRRK2 kinase inhibitors in cell and animal models. We aimed to determine if reduced phosphorylation of LRRK2 following inhibitor treatment is also a valid measure of target engagement in peripheral mononuclear cells from Parkinson's disease patients. Peripheral mononuclear cells from idiopathic Parkinson's disease patients and controls were treated ex vivo with two structurally distinct inhibitors of LRRK2, at four different doses, and immunoblotting was used to assess the reduction in LRRK2 phosphorylation at Ser910, Ser935, Ser955 and Ser973. Both inhibitors showed no acute toxicity in primary cells and both inhibitors reduced the constitutive phosphorylation of LRRK2 at all measured residues equally in both control and Parkinson's disease groups. Measuring the reduction in LRRK2 phosphorylation resulting from LRRK2 kinase inhibition, is thus a valid measure of acute peripheral target engagement in Parkinson's disease patients. This is important if LRRK2 kinase inhibitors are to be used in a clinical setting. PMID- 27503091 TI - Safety Assessment of Liver Injury with Quetiapine Fumarate XR Management in Very Heavy Drinking Alcohol-Dependent Patients. AB - BACKGROUND: Studies have reported liver injury as a consequence of antipsychotic treatment. Very heavy alcohol drinking (ten or more drinks/day for men and eight for women) also causes liver injury. This study aims to evaluate liver injury with quetiapine extended release (XR) in very heavy drinking alcohol-dependent (AD) patients. METHODS: Two hundred and eighteen AD patients, 18-65 years of age, received 12 weeks of quetiapine XR or placebo treatment in a dose-escalated manner reaching the full dose of 400 mg/day during week 4. Blood chemistry and hematology were assessed at baseline (W0), post-titration at the end of week 3 (W4), week 8 (W8), and end of week 12 (W13). Patients were further grouped as GR.1 (no liver injury, ALT <=40) and GR.2 (pre-existing liver injury, ALT >40) within each treatment. Drinking history, fasting blood glucose concentration (FBG), and lipid panel were used as covariates in the analyses. RESULTS: Liver injury and total drinks and average drinking measures from the Timeline follow back questionnaire (TLFB) were highly associated. No significant exacerbation in liver injury was observed in patients treated with quetiapine XR in GR.2. Liver injury as determined by elevated alanine aminotransaminase (ALT) was reported in a few patients in GR.1 who received quetiapine XR; however, the occurrence was low, and the level of liver injury was not significant. FBG and lipid measures showed some elevation, but did not show any significant association with liver injury. CONCLUSION: Quetiapine XR did not show any significant exacerbation of liver injury in very heavy drinking alcohol-dependent patients with pre-existing liver injury. Frequency and severity of new liver injury cases in quetiapine XR treated patients without any pre-existing liver injury was also low. Study findings support medical management of AD patients with heavy drinking profile using quetiapine XR formulation. PMID- 27503092 TI - QTLs for earliness and yield-forming traits in the Lubuski * CamB barley RIL population under various water regimes. AB - Drought has become more frequent in Central Europe causing large losses in cereal yields, especially of spring crops. The development of new varieties with increased tolerance to drought is a key tool for improvement of agricultural productivity. Material for the study consisted of 100 barley recombinant inbred lines (RILs) (LCam) derived from the cross between Syrian and European parents. The RILs and parental genotypes were examined in greenhouse experiments under well-watered and water-deficit conditions. During vegetation the date of heading, yield and yield-related traits were measured. RIL population was genotyped with microsatellite and single nucleotide polymorphism markers. This population, together with two other populations, was the basis for the consensus map construction, which was used for identification of quantitative trait loci (QTLs) affecting the traits. The studied lines showed a large variability in heading date. It was noted that drought-treatment negatively affected the yield and its components, especially when applied at the flag leaf stage. In total, 60 QTLs were detected on all the barley chromosomes. The largest number of QTLs was found on chromosome 2H. The main QTL associated with heading, located on chromosome 2H (Q.HD.LC-2H), was identified at SNP marker 5880-2547, in the vicinity of Ppd-H1 gene. SNP 5880-2547 was also the closest marker to QTLs associated with plant architecture, spike morphology and grain yield. The present study showed that the earliness allele from the Syrian parent, as introduced into the genome of an European variety could result in an improvement of barley yield performance under drought conditions. PMID- 27503090 TI - Solute Carriers in the Blood-Brain Barier: Safety in Abundance. AB - Blood-brain barrier formed by brain capillary endothelial cells, being in contact with astrocytes endfeet and pericytes, separates extracellular fluid from plasma. Supply of necessary nutrients and removal of certain metabolites takes place due to the activity of transporting proteins from ABC (ATP binding cassette) and SLC (solute carrier) superfamilies. This review is focused on the SLC families involved in transport though the blood-brain barrier of energetic substrates (glucose, monocarboxylates, creatine), amino acids, neurotransmitters and their precursors, as well as organic ions. Members of SLC1, SLC2, SLC3/SLC7, SLC5, SLC6, SLC16, SLC22, SLC38, SLC44, SLC47 and SLCO (SLC21), whose presence in the blood-brain barriers has been demonstrated are characterized with a special emphasis put on polarity of transporters localization in a luminal (blood side) versus an abluminal (brain side) membrane. PMID- 27503094 TI - Visualization of CSF Flow with Time-resolved 3D MR Velocity Mapping in Aqueductal Stenosis Before and After Endoscopic Third Ventriculostomy : A Feasibility Study. AB - PURPOSE: The aim of this study was to evaluate timed-resolved three-dimensional (3D) magnetic resonance (MR) velocity mapping as a method for investigation of cerebrospinal fluid (CSF) flow changes in patients with aqueductal stenosis (AS) treated by endoscopic third ventriculostomy (ETV). METHODS: The MR velocity mapping was performed in 12 AS patients before and after ETV and in 10 healthy volunteers by using a 3-Tesla MR system. Time-resolved 3D MR velocity mapping data were acquired with a standard 3D phase contrast (PC) sequence with cardiac triggering. Values of mean (vmean) and maximum (vpeak) velocity were measured at several ventricular structures using dedicated software. RESULTS: Of the patients 11 showed a satisfactory clinical improvement after ETV, whereas one patient needed subsequent shunt implantation. All AS patients showed significant hypomotile CSF flow dynamics in the third ventricle when compared to healthy subjects before surgery (p < 0.05). In contrast, CSF flow velocity was increased within the Foramen of Monro in AS patients. After ETV, all AS patients showed a decrease of CSF flow dynamics within the third ventricle. Mean and peak CSF flow velocities through the ventriculostomy were 1.72 +/- 0.59 cm/s (vmean) and 3.53 +/- 0.79 cm/s (vpeak), respectively after ETV. The patient who needed shunt implantation after ETV had the lowest flow velocities through the ventriculostomy. CONCLUSION: This study demonstrates that timed-resolved 3D MR velocity mapping is a useful imaging investigation for diagnostics and follow-up in patients with AS. This new technique provides an insight into the physiological CSF flow changes related with AS and its treatment. PMID- 27503095 TI - Improving knowledge and behaviours related to the cause, transmission and prevention of Tuberculosis and early case detection: a descriptive study of community led Tuberculosis program in Flores, Indonesia. AB - BACKGROUND: The community's awareness of Tuberculosis (TB) and delays in health care seeking remain important issues in Indonesia despite the extensive efforts of community-based TB programs delivered by a non-government organisation (NGO). This study explored the knowledge and behaviours in relation to TB and early diagnosis before and after an asset-based intervention designed to improve these issues. METHODS: Six villages in Flores, Indonesia were purposively selected to participate in this study. Three villages served as intervention villages and the other three villages provided a comparison group. Data collection included interviews, group discussions, observations, field notes and audit of records. RESULTS: In total, 50 participants across six villages were interviewed and three group discussions were conducted in the intervention villages supplemented by 1 - 5 h of observation during monthly visits. Overall, participants in all villages had limited knowledge regarding the cause and transmission of TB before the intervention. The delay in health seeking behaviour was mainly influenced by ignorance of TB symptoms. Health care providers also contributed to delayed diagnosis by ignoring the symptoms of TB suspects at the first visit and failing to examine TB suspects with sputum tests. Stigmatisation of TB patients by the community was reported, although this did not seem to be common. Early case detection was less than 50 % in four of the six villages before the asset-based intervention. Knowledge of TB improved after the intervention in the intervention villages alongside improved education activities. Early case detection also increased in the intervention villages following this intervention. The behaviour changes related to prevention of TB were also obvious in the intervention villages but not the comparison group. CONCLUSION: This small project demonstrated that an asset-based intervention can result in positive changes in community's knowledge and behaviour in relation to TB and early case detection. A continuing education process is like to be required to maintain this outcome and to reach a wider community. Promoting community involvement and local initiatives and engaging health care providers were important elements in the community-based TB program implemented. PMID- 27503096 TI - Crossing technological frontiers in radioguided intervention. PMID- 27503097 TI - Prodromal symptoms of Parkinson's disease: Implications for epidemiological studies of disease etiology. AB - In recent years, there has been a major shift in our understanding of the course of Parkinson's disease (PD) from a disease of the brain to a disease of long latency, characterized by the progressive emergence of multiple non-motor symptoms, including hyposmia, constipation, depression, anxiety, rapid eye movement (REM) sleep behavior disorder and excessive daytime sleepiness, as well as subtle motor signs, before the typical motor signs appear. Epidemiological studies have made major contributions by allowing better characterization of subsequent PD risk in relation to non-motor symptoms. Such findings have profound implications for the conduct of epidemiological studies examining risk and protective factors in PD, and the interpretation of their findings. Given the length of the prodromal period, reverse causation in particular is a major concern with many reported associations. One striking feature of PD etiology, compared with other diseases, is the presence of numerous inverse associations. If these associations are truly causal, they would have major implications for disease prevention and for slowing disease progression. However, whether these associations are truly causal remains to be demonstrated in future studies. Experimental studies play an important role by offering a better understanding of the underlying mechanisms. Well-designed epidemiological studies using innovative approaches will also be key in elucidating whether these intriguing associations are causal or a consequence of reverse causation. PMID- 27503093 TI - Strategies of targeting the extracellular domain of RON tyrosine kinase receptor for cancer therapy and drug delivery. AB - PURPOSE: Cancer is one of the most important life-threatening diseases in the world. The current efforts to combat cancer are being focused on molecular targeted therapies. The main purpose of such approaches is based on targeting cancer cell-specific molecules to minimize toxicity for the normal cells. RON (Recepteur d'Origine Nantais) tyrosine kinase receptor is one of the promising targets in cancer-targeted therapy and drug delivery. METHODS: In this review, we will summarize the available agents against extracellular domain of RON with potential antitumor activities. RESULTS: The presented antibodies and antibody drug conjugates against RON in this review showed wide spectrum of in vitro and in vivo antitumor activities promising the hope for them entering the clinical trials. CONCLUSION: Due to critical role of extracellular domain of RON in receptor activation, the development of therapeutic agents against this region could lead to fruitful outcome in cancer therapy. PMID- 27503099 TI - Large soft-tissue masses in an adult patient with Gaucher disease. AB - Extra-osseous masses are rarely seen in Gaucher disease. Here we present a case of a 30-year-old patient with Gaucher disease type 3, receiving beta glucocerebrosidase enzyme replacement therapy, who presented with slowly enlarging masses along her back. There was no osseous extension seen on imaging. Biopsy of the mass ultimately showed extensive soft tissue infiltration by Gaucher cells. No other cases of soft-tissue masses of this extent have been described in the literature, and therefore management remains unclear. PMID- 27503098 TI - Hypnosis and movement disorders: State of the art and perspectives. AB - INTRODUCTION: Hypnosis might represent an interesting complementary therapeutic approach to movement disorders, as it takes into account not only symptoms, but also well-being, and empowers patients to take a more active role in their treatment. METHODS: Our review of the literature on the use of hypnosis to treat movement disorders was done by systematically searching the PubMed database for reports published between 1984 and November 2015. The following variables were extracted from each selected paper: study design; sample size; type of movement disorder; hypnotic procedure; treatment duration; and efficacy. RESULTS: Thirteen papers were selected for detailed analysis. Most concerned tremor in Parkinson's disease and tics in Gilles de la Tourette syndrome. Although promising, the data were insufficient to allow conclusions to be drawn on the efficacy of hypnosis in movement disorders or to recommend its use in this setting. CONCLUSION: Well designed studies taking into account some specific methodological challenges are needed to determine the possible therapeutic utility of hypnosis in movement disorders. In addition to the potential benefits for such patients, hypnosis might also be useful for studying the neuroanatomical and functional underpinnings of normal and abnormal movements. PMID- 27503101 TI - Correcting motion in multiplanar cardiac magnetic resonance images. AB - BACKGROUND: Misalignment in cardiac magnetic resonance (CMR) images can adversely affect three-dimensional left ventricle modelling and downstream quantitative analysis. Currently, there are two types of approaches for dealing with realignment and motion distortion problems, one image based and the other geometry based. Image-based approaches are limited by the inherent non homogeneity and anisotropy of CMR images. Geometry-based approaches rely on idealized models and over-simplified assumptions. This study was motivated by the need for a robust and effective approach for correcting motion related distortions due to misalignment in CMR images. METHODS: A cine cardiac magnetic resonance image sequence was acquired using our routine clinical imaging protocol. The left ventricular endocardium was delineated manually with software assistance on all long and short-axis images. Long and short-axis contours were projected onto a patient-based coordinate system and then realigned using iterative registration. The realigned contour points were used to reconstruct the shape of the left ventricle for quantitative validation. RESULTS: The method was tested on five myocardial infarction patients whose images showed substantial misalignment. Realignment time was about 16 seconds per case, using a 2.5 GHz CPU desktop with obvious elimination of the distortion in the reconstructed model. Using the long-axis contour as a reference in evaluating the reconstructed models, it was apparent that the models with realigned contours had better accuracy than the non-realigned ones. CONCLUSION: This study presents a novel, geometry-based method for correcting motion distortions in CMR images. The method incorporates (1) manual delineation, (2) registration based on a generalized, iterative closest point algorithm, and (3) reconstruction of the shape of the left ventricle for quantitative validation. The effectiveness of our approach is corroborated both visually and by quantitative assessment. We envision the use of our method in current clinical practice as a means of improving accuracy in the evaluation of cardiac function. PMID- 27503102 TI - Does chronic exposure to high levels of nitrogen dioxide exacerbate the short term effects of airborne particles? AB - BACKGROUND: Long-term exposure to air pollutants has been hypothesised as a factor in susceptibility to short-term exposure to particulate matter (PM), but results are not coherent. We studied the short-term effects of PM10 on mortality and assessed whether long-term exposure to nitrogen dioxide (NO2) modifies this association. METHODS: We used a case-crossover design to evaluate daily PM10 related mortality among 124 432 35+ year-old participants who died in Rome between 2001 and 2010 and maintained the same address for at least 5 years before death. Modification of PM10-related mortality by long-term NO2 exposure was determined by two-way interaction, while a three-way interaction was used to assess effect modification of high NO2 levels in population groups defined by sociodemographic position and pre-existing diseases. RESULTS: Mortality increased by 0.82% (0.23-1.41%) for each 10 ug/m3 increase in PM10. Mortality rose by 1.22% (0.17-2.38%) in participants exposed to NO2 levels >=50 ug/m3 and by 0.69% (0.03 1.34%) in those exposed to levels <50 ug/m3 with no effect modification (p interaction 0.378). A suggestion of effect modification was seen in 85+-year-olds (3.10%; p-interaction 0.043), as well as in those with a pre-existing arrhythmia (3.26%; p-interaction 0.014) and chronic obstructive pulmonary disease (3.52%; p interaction 0.042). CONCLUSIONS: Long-term exposure to NO2 is not likely to induce susceptibility to short-term PM10 exposure in the overall population. However, an effect modification of NO2 is probable in the elderly and in those suffering from arrhythmias and chronic obstructive pulmonary disease. PMID- 27503103 TI - An Integrative Review of the Quality and Outcomes of Diabetes Education Programs for Children and Adolescents. AB - PURPOSE: The purpose of this study was twofold: (1) to describe the content of recent diabetes education programs and their outcomes in terms of glycemic control, disease management, and psychosocial criteria for children and adolescents with type 1 diabetes and (2) to gauge the match between these programs and the recommendations of the International Society for Pediatric and Adolescent Diabetes (ISPAD). METHODS: The integrative review was carried out according to the Cochrane recommendations. Thirteen databases were searched for evaluations of education programs published from 2009 to 2014. Program characteristics and outcomes were described. Quality of studies was assessed, and program match with ISPAD recommendations was gauged. RESULTS: Of 2528 studies found, 43 covering 36 education programs intended for youth with type 1 diabetes were retained for review. Nine of these centered on self-care competencies, 18 on psychosocial competencies, and 9 on both types of competency (mixed program). Programs varied widely in terms of organization, procedure, and content. Glycemic control was an indicator assessed in the majority of programs, but only half of these (for the most part, self-care programs) reported positive findings in this regard. Few programs seemed to affect psychosocial indicators. An online mixed program, which was the program that best met the ISPAD recommendations, proved to have an influence on glycemic control and several psychosocial criteria. CONCLUSIONS: Various avenues can be considered to improve participant engagement in education programs and to align these programs more closely with international recommendations. Further research is required to enhance knowledge in this field. PMID- 27503104 TI - Polymorphism of the 3'-UTR of the dopamine transporter gene (DAT) in New World monkeys. AB - Genetic polymorphism in the 3'-untranslated region (3'-UTR) of the dopamine transporter (DAT) gene has been reported in both human and nonhuman primates, and the variable number of tandem repeats (VNTR) polymorphism has been related to several neurological and psychiatric disorders. As New World primates have been employed as models in biomedical research in these fields, in the present study we assessed genetic variation in the DAT gene in 25 robust capuchin monkeys (Sapajus spp.) and 39 common marmosets (Callithrix jacchus). Using enzymatic amplification followed by sequencing of amplified fragments, a VNTR polymorphism in the 3'-UTR region of the DAT gene was identified in both robust capuchins and common marmosets. The polymorphic tandem repeat of 40-bp basic units is similar to the human VNTR consensus sequence, with size variants composed of 9, 10, and 11 units in marmosets and 8, 9, 13, and 17 basic units in capuchins. We found behavioral evidence that carrying the 10-repeat DAT allele promotes flexible choice and maximization of foraging in marmosets tested in an operant choice paradigm. Moreover, in an intertemporal choice task, capuchins with longer repeat variants show less self-controlled choices than capuchins with at least one short repeat variant. Future research should focus on the relationship between these DAT polymorphisms, dopamine reuptake via the dopamine transporter, and behavioral and cognitive variation across New World monkey individuals. PMID- 27503105 TI - The Contribution of the C-Terminal Tails of Microtubules in Altering the Force Production Specifications of Multiple Kinesin-1. AB - The extent to which beta tubulin isotypes contribute to the function of microtubules and the microtubule-driven transport of molecular motors is poorly understood. The major differences in these isotypes are associated with the structure of their C-terminal tails. Recent studies have revealed a few aspects of the C-terminal tails' regulatory role on the activities of some of the motor proteins on a single-molecule level. However, little attention is given to the degree to which the function of a team of motor proteins can be altered by the microtubule's tail. In a set of parallel experiments, we investigated this open question by studying the force production of several kinesin-1 (kinesin) molecular motors along two groups of microtubules: regular ones and those microtubules whose C-terminals are cleaved by subtilisin digestion. The results indicate that the difference between the average of the force production of motors along two types of microtubules is statistically significant. The underlying mechanism of such production is substantially different as well. As compared to untreated microtubules, the magnitude of the binding time of several kinesin-1 is almost three times greater along subtilisin-treated microtubules. Also, the velocity of the group of kinesin molecules shows a higher sensitivity to external loads and reduces significantly under higher loads along subtilisin treated microtubules. Together, this work shows the capacity of the tails in fine tuning the force production characteristics of several kinesin molecules. PMID- 27503106 TI - Dual targeting of Hsp90 in childhood acute lymphoblastic leukaemia. PMID- 27503107 TI - Determining Survey Satisficing of Online Longitudinal Survey Data in the Multicenter AIDS Cohort Study: A Group-Based Trajectory Analysis. AB - BACKGROUND: Survey satisficing occurs when participants respond to survey questions rapidly without carefully reading or comprehending them. Studies have demonstrated the occurrence of survey satisficing, which can degrade survey quality, particularly in longitudinal studies. OBJECTIVE: The aim of this study is to use a group-based trajectory analysis method to identify satisficers when similar survey questions were asked periodically in a long-standing cohort, and to examine factors associated with satisficing in the surveys having sensitive human immunodeficiency virus (HIV)-related behavioral questions. METHODS: Behavioral data were collected semiannually online at all four sites of the Multicenter AIDS Cohort Study (MACS) from October 2008 through March 2013. Based on the start and end times, and the word counts per variable, response speed (word counts per second) for each participant visit was calculated. Two-step group-based trajectory analyses of the response speed across 9 study visits were performed to identify potential survey satisficing. Generalized linear models with repeated measures were used to investigate the factors associated with satisficing on HIV-related behavioral surveys. RESULTS: Among the total 2138 male participants, the median baseline age was 51 years (interquartile range, 45-58); most of the participants were non-Hispanic white (62.72%, 1341/2138) and college graduates (46.59%, 996/2138), and half were HIV seropositive (50.00%, 1069/2138). A total of 543 men (25.40%, 543/2138) were considered potential satisficers with respect to their increased trajectory tendency of response speed. In the multivariate analysis, being 10 years older at the baseline visit increased the odds of satisficing by 44% (OR 1.44, 95% CI 1.27-1.62, P<.001). Compared with the non-Hispanic white participants, non-Hispanic black participants were 122% more likely to satisfice the HIV-related behavioral survey (OR 2.22, 95% CI 1.69-2.91, P<.001), and 99% more likely to do so for the other race/ethnicity group (OR 1.99, 95% CI 1.39-2.83, P<.001). Participants with a high school degree or less were 67% more likely to satisfice the survey (OR 1.67, 95% CI 1.26-2.21, P<.001) compared with those with a college degree. Having more than one sex partner and using more than one recreational drug reduced the odds of satisficing by 24% (OR 0.76, 95% CI 0.61-0.94, P=.013) and 28% (OR 0.72, 95% CI 0.55-0.93, P=.013), respectively. No statistically significant association of HIV serostatus with satisficing was observed. CONCLUSIONS: Using a group-based trajectory analysis method, we could identify consistent satisficing on HIV-related behavioral surveys among participants in the MACS, which was associated with being older, being non-white, and having a lower education level; however, there was no significant difference by HIV serostatus. Methods to minimize satisficing using longitudinal survey data are warranted. PMID- 27503109 TI - No effect of juvenile hormone on task performance in a bumblebee (Bombus terrestris) supports an evolutionary link between endocrine signaling and social complexity. AB - A hallmark of insect societies is a division of labor among workers specializing in different tasks. In bumblebees the division of labor is related to body size; relatively small workers are more likely to stay inside the nest and tend ("nurse") brood, whereas their larger sisters are more likely to forage. Despite their ecological and economic importance, very little is known about the endocrine regulation of division of labor in bumblebees. We studied the influence of juvenile hormone (JH) on task performance in the bumblebee Bombus terrestris. We first used a radioimmunoassay to measure circulating JH titers in workers specializing in nursing and foraging activities. Next, we developed new protocols for manipulating JH titers by combining a size-adjusted topical treatment with the allatotoxin Precocene-I and replacement therapy with JH-III. Finally, we used this protocol to test the influence of JH on task performance. JH levels were either similar for nurses and foragers (three colonies), or higher in nurses (two colonies). Nurses had better developed ovaries and JH levels were typically positively correlated with ovarian state. Manipulation of JH titers influenced ovarian development and wax secretion, consistent with earlier allatectomy studies. These manipulations however, did not affect nursing or foraging activity, or the likelihood to specialize in nursing or foraging activity. These findings contrast with honeybees in which JH influences age-related division of labor but not adult female fertility. Thus, the evolution of complex societies in bees was associated with modifications in the way JH influences social behavior. PMID- 27503108 TI - Association of affective temperaments with blood pressure and arterial stiffness in hypertensive patients: a cross-sectional study. AB - BACKGROUND: Affective temperaments (anxious, depressive, cyclothymic, irritable and hyperthymic) measure subclinical manifestations of major mood disorders. Furthermore, cumulating evidence suggests their involvement in somatic disorders as well. We aimed to assess associations between affective temperament scores and blood pressure and arterial stiffness parameters in hypertensive patients. METHODS: In this cross-sectional study, 173 patients with well-controlled or grade 1 chronic hypertension, with no history of depression, completed the TEMPS A, Beck Depression Inventory (BDI) and Hamilton Anxiety Scale (HAM-A) questionnaires in three GP practices. Arterial stiffness was measured with tonometry (PulsePen). RESULTS: According to multiple linear regression analysis, cyclothymic temperament score was positively associated with brachial systolic blood pressure independently of age, sex, total cholesterol, brachial diastolic blood pressure, BDI, HAM-A and the use of alprazolam (beta = 0.529, p = 0.042), while hyperthymic temperament score was negatively related to augmentation index independent of age, sex, smoking, heart rate, BDI, HAM-A and the use of alprazolam (beta = -0.612, p = 0.013). A significant interaction was found between cyclothymic temperament score and sex in predicting brachial systolic blood pressure (p = 0.025), between irritable and anxious temperament scores and sex in predicting pulse wave velocity (p = 0.021, p = 0.023, respectively) and an interaction with borderline significance between hyperthymic temperament score and sex in predicting augmentation index (p = 0.052). CONCLUSIONS: The present findings highlight elevated blood pressure among subjects with high cyclothymic temperament as well as an increased level of arterial stiffening in subjects with low hyperthymic scores suggesting that affective temperaments may play a role in the development of hypertension and arterial stiffening and may thus represent markers of cardiovascular risk. Sex differences were also present in these associations. PMID- 27503111 TI - The analysis of scalp irritation by coacervates produced in hair shampoo via FTIR with focal plane array detector, X-ray photoelectron microscopy and HaCaT cells. AB - OBJECTIVE: Coacervates are inevitably formed on scalp on using hair washing products. Our goal was to analyse the coacervates in detail to identify the part responsible for scalp stimulation. METHODS: Shampoo that increases coacervate formation was applied to in vitro skin and was washed. The residue was then analysed using Fourier transform infrared spectroscopy-focal plane array (FTIR FPA) and X-ray photoelectron microscopy (XPS). And HaCaT cells were used for irritant test of coacervate. RESULTS: Through this research, it was confirmed that the coacervate was a macromolecule structurally similar to a cationic polymer and contains an anionic surfactant. Its anionic surfactant was structurally semi-stable so that it released onto scalp when it absorbs moisture. CONCLUSION: Coacervate releases sulphate bonding into the matrix when it is exposed to water. Thus, the scalp stimulation would be expected. PMID- 27503110 TI - Use of metabolomics for the identification and validation of clinical biomarkers for preterm birth: Preterm SAMBA. AB - BACKGROUND: Spontaneous preterm birth is a complex syndrome with multiple pathways interactions determining its occurrence, including genetic, immunological, physiologic, biochemical and environmental factors. Despite great worldwide efforts in preterm birth prevention, there are no recent effective therapeutic strategies able to decrease spontaneous preterm birth rates or their consequent neonatal morbidity/mortality. The Preterm SAMBA study will associate metabolomics technologies to identify clinical and metabolite predictors for preterm birth. These innovative and unbiased techniques might be a strategic key to advance spontaneous preterm birth prediction. METHODS/DESIGN: Preterm SAMBA study consists of a discovery phase to identify biophysical and untargeted metabolomics from blood and hair samples associated with preterm birth, plus a validation phase to evaluate the performance of the predictive modelling. The first phase, a case-control study, will randomly select 100 women who had a spontaneous preterm birth (before 37 weeks) and 100 women who had term birth in the Cork Ireland and Auckland New Zealand cohorts within the SCOPE study, an international consortium aimed to identify potential metabolomic predictors using biophysical data and blood samples collected at 20 weeks of gestation. The validation phase will recruit 1150 Brazilian pregnant women from five participant centres and will collect blood and hair samples at 20 weeks of gestation to evaluate the performance of the algorithm model (sensitivity, specificity, predictive values and likelihood ratios) in predicting spontaneous preterm birth (before 34 weeks, with a secondary analysis of delivery before 37 weeks). DISCUSSION: The Preterm SAMBA study intends to step forward on preterm birth prediction using metabolomics techniques, and accurate protocols for sample collection among multi-ethnic populations. The use of metabolomics in medical science research is innovative and promises to provide solutions for disorders with multiple complex underlying determinants such as spontaneous preterm birth. PMID- 27503112 TI - Feasibility of a walking virtual reality system for rehabilitation: objective and subjective parameters. AB - BACKGROUND: Even though virtual reality (VR) is increasingly used in rehabilitation, the implementation of walking navigation in VR still poses a technological challenge for current motion tracking systems. Different metaphors simulate locomotion without involving real gait kinematics, which can affect presence, orientation, spatial memory and cognition, and even performance. All these factors can dissuade their use in rehabilitation. We hypothesize that a marker-based head tracking solution would allow walking in VR with high sense of presence and without causing sickness. The objectives of this study were to determine the accuracy, the jitter, and the lag of the tracking system and its elicited sickness and presence in comparison of a CAVE system. METHODS: The accuracy and the jitter around the working area at three different heights and the lag of the head tracking system were analyzed. In addition, 47 healthy subjects completed a search task that involved navigation in the walking VR system and in the CAVE system. Navigation was enabled by natural locomotion in the walking VR system and through a specific device in the CAVE system. An HMD was used as display in the walking VR system. After interacting with each system, subjects rated their sickness in a seven-point scale and their presence in the Slater-Usoh-Steed Questionnaire and a modified version of the Presence Questionnaire. RESULTS: Better performance was registered at higher heights, where accuracy was less than 0.6 cm and the jitter was about 6 mm. The lag of the system was 120 ms. Participants reported that both systems caused similar low levels of sickness (about 2.4 over 7). However, ratings showed that the walking VR system elicited higher sense of presence than the CAVE system in both the Slater-Usoh-Steed Questionnaire (17.6 +/- 0.3 vs 14.6 +/- 0.6 over 21, respectively) and the modified Presence Questionnaire (107.4 +/- 2.0 vs 93.5 +/- 3.2 over 147, respectively). CONCLUSIONS: The marker-based solution provided accurate, robust, and fast head tracking to allow navigation in the VR system by walking without causing relevant sickness and promoting higher sense of presence than CAVE systems, thus enabling natural walking in full-scale environments, which can enhance the ecological validity of VR-based rehabilitation applications. PMID- 27503113 TI - Canthin-4-ones as Novel Antibacterial Agents. AB - Based on the chemotype of canthin-4-one alkaloids with moderate antimicrobial activity, a collection of variously substituted canthin-4-ones and desaza analogs were synthesized. Key steps in the syntheses were regioselective halogenations of (desaza) canthin-4-one, followed by Pd-catalyzed cross-coupling reactions. The in vitro screening for antimicrobial activity revealed that two 5-substituted canthin-4-ones (3-pyridyl, 2-bromophenyl) exhibit significant activity against Streptococcus entericus, coupled with high selectivity and the lack of cytotoxicity against mammalian cells. The intact canthin-4-one ring system was demonstrated to be essential for antibacterial activity. PMID- 27503114 TI - Simultaneous CT angiography and whole-body CT is an effective imaging approach before multiorgan retrieval. AB - PURPOSE: To assess the role of whole-body computed tomography (CT) for determining morphological suitability before multiorgan retrieval (MOR) in brain dead patients. MATERIALS AND METHODS: Fifty-one clinically brain dead patients (21 women, 30 men; mean age 61 year+/-15) were included in this prospective, single center study. All patients had CT angiography of the brain and whole-body CT examination. CT images were evaluated for the presence of morphological abnormalities of lungs, liver and other abdominal organs and presence of vascular anatomical variants. The results of CT examinations were compared to intraoperative findings observed during organ harvesting and/or the results of histopathological analysis of biopsy specimens. The impact of whole-body CT examination on the harvesting process was evaluated. RESULTS: Ninety-five percent of vascular anatomical variants that were found intraoperatively were depicted on CT. CT density measurements predicted surgical finding of steatosis in 80% of patients. Whole-body CT changed the MOR strategy in 21/51 patients (41%) including 3 MOR cancellations and 8 grafts refusals, whereas organ harvesting was continued in 10 patients after histopathological analysis was performed. CONCLUSION: Selection of potential graft donors using whole-body CT is reliable and improves graft selection during MOR. PMID- 27503115 TI - Unenhanced respiratory-navigated NATIVE(r) TrueFISP magnetic resonance angiography in the evaluation of renal arteries: Comparison with contrast enhanced magnetic resonance angiography. AB - PURPOSE: To compare unenhanced three-dimensional (3D) NATIVE(r) true fast imaging with steady-state precession (TrueFISP) magnetic resonance (MR) angiography with the more conventional MR angiography technique obtained after intravenous administration of a gadolinium chelate in the evaluation of renal arteries and their branches in patients with suspected renal artery stenosis. MATERIALS AND METHODS: A total of 39 patients (25 men, 14 women) with a mean age of 51.4+/ 17.5years (SD) (range: 10-82years) were included in the study. All patients with suspected renal artery stenosis underwent unenhanced 3D NATIVE(r) TrueFISP MR angiography and contrast-enhanced MR angiography. The two MR angiography methods were compared by two independent readers for image quality using a four-point scale, diagnostic performance and grading of renal artery stenosis on a total of 78 renal arteries. RESULTS: For both readers image quality of unenhanced 3D NATIVE(r) TrueFISP MR angiography (3.12 to 3.63) was greater than that of contrast-enhanced MR angiography (1.94 to 2.71) for renal artery ostium-trunk and the left renal artery segmental branches. The sensitivity of 3D NATIVE(r) TrueFISP MR angiography for the diagnosis of renal artery stenosis was 100% for both readers for the right renal artery and 66% and 80% for the left renal artery for reader 1 and reader 2, respectively. Agreement between 3D NATIVE(r) TrueFISP MR angiography and CE-MR angiography was 95% (74/78) for reader 1 and 92% (72/78) for reader 2. CONCLUSION: Unenhanced NATIVE(r) TrueFISP magnetic resonance angiography can play an additional role in the evaluation of renal arteries in patients with hypertension, especially in subjects at risk of nephrogenic systemic fibrosis. PMID- 27503116 TI - Image fusion-guided portal vein puncture during transjugular intrahepatic portosystemic shunt placement. AB - PURPOSE: The purpose of this study was to assess the feasibility and utility of image fusion (Easy-TIPS) obtained from pre-procedure CT angiography and per procedure real-time fluoroscopy for portal vein puncture during transjugular intrahepatic portosystemic shunt (TIPS) placement. MATERIALS AND METHODS: Eighteen patients (15 men, 3 women) with a mean age of 63 years (range: 48-81 years; median age, 65 years) were included in the study. All patients underwent TIPS placement by two groups of radiologists (one group with radiologists of an experience<3 years and one with an experience>=3 years) using fusion imaging obtained from three-dimensional computed tomography angiography of the portal vein and real-time fluoroscopic images of the portal vein. Image fusion was used to guide the portal vein puncture during TIPS placement. At the end of the procedure, the interventional radiologists evaluated the utility of fusion imaging for portal vein puncture during TIPS placement. Mismatch between three dimensional computed tomography angiography and real-time fluoroscopic images of the portal vein on image fusion was quantitatively analyzed. Posttreatment CT time, number of the puncture attempts, total radiation exposure and radiation from the retrograde portography were also recorded. RESULTS: Image fusion was considered useful for portal vein puncture in 13/18 TIPS procedures (72%). The mean posttreatment time to obtain fusion images was 16.4minutes. 3D volume rendered CT angiography images was strictly superimposed on direct portography in 10/18 procedures (56%). The mismatch mean value was 0.69cm in height and 0.28cm laterally. A mean number of 4.6 portal vein puncture attempts was made. Eight patients required less than three attempts. The mean radiation dose from retrograde portography was 421.2dGy.cm2, corresponding to a mean additional exposure of 19%. CONCLUSION: Fusion imaging resulting from image fusion from pre procedural CT angiography is feasible, safe and makes portal puncture easier during TIPS placement. PMID- 27503117 TI - Croceicoccus pelagius sp. nov. and Croceicoccus mobilis sp. nov., isolated from marine environments. AB - Strain Ery9T, isolated from surface seawater of the Atlantic Ocean, and strain Ery22T, isolated from deep-sea sediment of the Indian Ocean, were subjected to a taxonomic study using a polyphasic approach. Cells of the two strains were Gram stain-negative, aerobic and rod-shaped. They produced yellow pigments and lacked bacteriochlorophyll a. On the basis of 16S rRNA gene sequence analysis, strain Ery9T was closely related to Croceicoccus naphthovorans PQ-2T (with 16S rRNA gene sequence similarity of 97.7 %), and strain Ery22T was closely related to Croceicoccusmarinus E4A9T (98.3 %). The 16S rRNA gene sequence similarity between strain Ery9T and strain Ery22T was 96.6 %. Phylogenetic analyses revealed that strains Ery9T and Ery22T fell within the cluster of the genus Croceicoccus and represented two independent lineages. The average nucleotide identity (ANI) values and the genome-to-genome distances between strains Ery9T and Ery22T and the type strains of species of the genus Croceicoccus with validly published names were 73.7-78.4 % and 20.1-22.3 %, respectively. The major respiratory quinone of the two isolates was ubiquinone-10 (Q-10). The DNA G+C contents of strains Ery9T and Ery22T were 62.8 and 62.5 mol%, respectively. Differential phylogenetic distinctiveness and chemotaxonomic differences, together with phenotypic properties, revealed that strains Ery9T and Ery22T could be differentiated from their closely related species. Therefore, it is concluded that strains Ery9T and Ery22T represent two novel species of the genus Croceicoccus, for which the names Croceicoccus pelagius sp. nov. (type strain Ery9T=CGMCC 1.15358T=DSM 101479T) and Croceicoccus mobilis sp. nov. (type strain Ery22T=CGMCC 1.15360T=DSM 101481T), are proposed. PMID- 27503118 TI - ARN: analysis and prediction by adipogenic professional database. AB - Adipogenesis is the process of cell differentiation by which mesenchymal stem cells become adipocytes. Extensive research is ongoing to identify genes, their protein products, and microRNAs that correlate with fat cell development. The existing databases have focused on certain types of regulatory factors and interactions. However, there is no relationship between the results of the experimental studies on adipogenesis and these databases because of the lack of an information center. This information fragmentation hampers the identification of key regulatory genes and pathways. Thus, it is necessary to provide an information center that is quickly and easily accessible to researchers in this field. We selected and integrated data from eight external databases based on the results of text-mining, and constructed a publicly available database and web interface (URL: http://210.27.80.93/arn/ ), which contained 30873 records related to adipogenic differentiation. Then, we designed an online analysis tool to analyze the experimental data or form a scientific hypothesis about adipogenesis through Swanson's literature-based discovery process. Furthermore, we calculated the "Impact Factor" ("IF") value that reflects the importance of each node by counting the numbers of relation records, expression records, and prediction records for each node. This platform can support ongoing adipogenesis research and contribute to the discovery of key regulatory genes and pathways. PMID- 27503120 TI - Study and interest of cellular load in respiratory samples for the optimization of molecular virological diagnosis in clinical practice. AB - BACKGROUND: Respiratory viral diagnosis of upper respiratory tract infections has largely developed through multiplex molecular techniques. Although the sensitivity of different types of upper respiratory tract samples seems to be correlated to the number of sampled cells, this link remains largely unexplored. METHODS: Our study included 800 upper respiratory tract specimens of which 400 negative and 400 positive for viral detection in multiplex PCR. All samples were selected and matched for age in these 2 groups. For the positive group, samples were selected for the detected viral species. RESULTS: Among the factors influencing the cellularity were the type of sample (p < 0.0001); patient age (p < 0.001); viral positive or negative nature of the sample (p = 0.002); and, for the positive samples, the number of viral targets detected (0.004 < p < 0.049) and viral species. CONCLUSION: The cellular load of upper respiratory samples is multifactorial and occurs for many in the sensitivity of molecular detection. However it was not possible to determine a minimum cellularity threshold allowing molecular viral detection. The differences according to the type of virus remain to be studied on a larger scale. PMID- 27503119 TI - 2D versus 3D fluoroscopy-based navigation in posterior pelvic fixation: review of the literature on current technology. AB - PURPOSE: Percutaneous sacroiliac (SI) fixation of unstable posterior pelvic ring injuries is a widely accepted procedure. The complex sacral anatomy with narrow osseous corridors for SI screw placement makes this procedure technically challenging. Techniques are constantly evolving as a result of better understanding of the posterior pelvic anatomy. Recently developed tools include fluoroscopy-based computer-assisted navigation, which can be two-dimensional (2D) or three-dimensional (3D). Our goal is to determine the relevant technical considerations and clinical outcomes associated with these modalities by reviewing the published research. We hypothesize that 3D fluoroscopy-based navigation is safer and superior to its 2D predecessor with respect to lower radiation dose and more accurate SI screw placement. METHODS: We searched four medical databases to identify English-language studies of 2D and 3D fluoroscopy based navigation from January 1990 through August 2015. We included articles reporting imaging techniques and outcomes of closed posterior pelvic ring fixation with percutaneous SI screw fixation. Injuries included in the study were sacral fractures (52 patients), sacroiliac fractures (88 patients), lateral compression fractures (20 patients), and anteroposterior compression type pelvic fractures (8 patients). We excluded articles on open reduction of posterior pelvic ring injuries and solely anatomic studies. We then reviewed these studies for technical considerations and outcomes associated with these technologies. RESULTS: Six studies were included in our analysis. Results of these studies indicate that 3D fluoroscopy-based navigation is associated with a lower radiation dose and lower rate of screw malpositioning compared with 2D fluoroscopy-based systems. CONCLUSIONS: It may be advantageous to combine modern imaging modalities such as 3D fluoroscopy with computer-assisted navigation for percutaneous screw fixation in the posterior pelvis. PMID- 27503121 TI - Temporal and Spatial Evolution of Raised Intraspinal Pressure after Traumatic Spinal Cord Injury. AB - Traumatic spinal cord injury (SCI) often leads to permanent neurological impairment. Currently, the only clinically effective intervention for patients with acute SCI is surgical decompression by removal of impinging bone fragments within 24 h after injury. Recent clinical studies suggest that elevated intraparenchymal spinal pressure (ISP) limits functional recovery following SCI. Here, we report on the temporal and spatial patterns of elevated ISP following a moderate rodent contusion SCI. Compared with physiological ISP in the intact cord (2.7 +/- 0.5 mm Hg), pressures increase threefold 30 min following injury (8.9 +/ 1.1 mm Hg, p < 0.001) and remain elevated for up to 7 days (4.3 +/- 0.8 mm Hg). Measurements of rostrocaudal ISP distribution reveal peak pressures in the injury center and in segments rostral to the injury during the acute phase(<= 24 h). During the subacute phase(>= 72 h), peak ISP decreases while a 7.5 mm long segment of moderately elevated ISP remains, centered on the initial contusion site. Interestingly, the contribution of the dural and pial compartments toward increased ISP changes with time after injury: Dural and pial linings contribute almost equally to increased ISP during the acute phase, whereas the dural lining is primarily responsible for elevated ISP during the subacute phase (78.9%). Our findings suggest that a rat contusion SCI model in combination with novel micro catheters allows for direct measurement of ISP after SCI. Similarly to traumatic brain injury, raised tissue pressure is likely to have detrimental effects on spontaneous recovery following SCI. PMID- 27503122 TI - Environmental chemicals impact dog semen quality in vitro and may be associated with a temporal decline in sperm motility and increased cryptorchidism. AB - Adverse temporal trends in human semen quality and cryptorchidism in infants have been associated with exposure to environmental chemicals (ECs) during development. Here we report that a population of breeding dogs exhibit a 26 year (1988-2014) decline in sperm quality and a concurrent increased incidence of cryptorchidism in male offspring (1995-2014). A decline in the number of males born relative to the number of females was also observed. ECs, including diethylhexyl phthalate (DEHP) and polychlorinated biphenyl 153 (PCB153), were detected in adult dog testes and commercial dog foods at concentrations reported to perturb reproductive function in other species. Testicular concentrations of DEHP and PCB153 perturbed sperm viability, motility and DNA integrity in vitro but did not affect LH stimulated testosterone secretion from adult testis explants. The direct effects of chemicals on sperm may therefore contribute to the decline in canine semen quality that parallels that reported in the human. PMID- 27503123 TI - c-Cbl-mediated ubiquitination of IRF3 negatively regulates IFN-beta production and cellular antiviral response. AB - Induction of type I interferon is a fundamental cellular response to viral infection. Interferon regulatory factor 3 (IRF3) plays an essential role in Toll like receptor (TLR) and retinoic acid-inducible gene I (RIG-I) mediated induction of type I interferon and host antiviral responses. However, posttranslational regulation of IRF3 remains to be fully understood. In this study, we identified E3 ubiquitin ligase Casitas B-lineage lymphoma (c-Cbl) as a negative regulator for IRF3 protein stability and IFN-beta signal pathway. Knockdown of c-Cbl expression by small interfering RNA enhanced virus-induced IFN-beta production as well as cellular antiviral response, whereas overexpression of c-Cbl inhibited virus-induced IFN-beta signaling. Coimmunoprecipitation experiments demonstrated that c-Cbl interacted with IRF3 via TKB domain of c-Cbl and IRF association domain of IRF3, promoting K48-linked polyubiquitination and proteasomal degradation of IRF3. Therefore, our findings suggest that c-Cbl negatively regulates IFN-beta signaling and cellular antiviral response by promoting IRF3 ubiquitination and degradation, providing a new mechanism for control of type I interferon induction. PMID- 27503125 TI - Merocyanine 540 adsorbed on polyethylenimine-functionalized graphene oxide nanocomposites as a turn-on fluorescent sensor for bovine serum albumin. AB - Graphene oxide (GO)-based fluorescence sensors are attractive and versatile tools for various sensing applications. Herein, we report the photophysical properties of merocyanine 540 (MC540) in an aqueous dispersion including graphene oxide (GO) and GO chemically functionalized with branched polyethylenimine (PEI), and the application of a novel designed MC540/PEI-GO system for BSA (bovine serum albumin) detection. Initially, the negatively charged GO surface was modified using PEI to form high positively charged PEI-GO nanocomposites via the amine groups of PEI. Later, to form MC540/PEI-GO system, MC540 molecules were assembled on PEI-GO nanocomposites having an attractive surface for negatively charged functional materials. The interaction of MC540 molecules with PEI-GO nanocomposites in aqueous dispersion led to a change in the photophysical properties of the dye. The variations in the photophysical properties of MC540 were spectroscopically characterized and explained. It was determined that the interaction of MC540 with GO sheets and PEI-GO nanocomposites strongly quenched the fluorescence of the dye. However, the quenching effect of the PEI-GO nanocomposites on the fluorescence of MC540 was specifically prevented by the addition of BSA, in which the fluorescence of MC540 was nearly recovered. By using the PEI-GO nanocomposites-based fluorescence platform, BSA has been detected with a LOD (limit of detection) of 7.45 nM, which is one of the best applications among BSA sensors to date. The designed sensor system was easily applied for the detection of BSA in commonly used biological media and clinical injectable fluids. Consequently, we suggest a simple, fast, sensitive and selective BSA sensor designed by assembling MC540 molecules on PEI-GO nanocomposites. PMID- 27503124 TI - The combination of herbal medicine Weng-li-tong with Tolterodine may be better than Tolterodine alone in the treatment of overactive bladder in women: a randomized placebo-controlled prospective trial. AB - BACKGROUND: To assess the efficacy and safety of the herbal medicine, Weng-li tong (WLT) as monotherapy or combined with tolterodine in women with overactive bladder (OAB). METHODS: A prospective, randomized, single-blind multi-center trial was performed which included 182 OAB patients treated with either placebo (n = 26), WLT (n = 52), tolterodine (n = 52) or WLT plus tolterodine (n = 52). The overactive bladder symptom score (OABSS) and micturition behavior were measured to evaluate treatment efficacy. RESULTS: In total, 146 patients [placebo (n = 23), WLT (n = 39), tolterodine (n = 41) and WLT plus tolterodine (n = 43)] completed 8 weeks of treatment. Compared to those treated with placebo, patients in three intervention groups showed significant improvements in the OABSS, voiding frequency, average voided volume and urgency incontinence. WLT had a slower onset than tolterodine or combination therapy in reducing urgency incontinence. Compared with tolterodine, WLT had a weaker effect in improving OABSS (P = 0.022) and daily voiding frequency (P = 0.034). The combination therapy had better efficacy than WLT or tolterodine alone in improving the OABSS, voiding frequency and voided volume. No significant differences in the changes in quality of life scores were observed among the three intervention groups. Residual urine increased significantly in tolterodine group (P = 0.004), but not in combination group. WLT resulted in fewer adverse effects than tolterodine such as dry mouth (P = 0.002), weak stream (P = 0.002) and less residual urine (P < 0.001). CONCLUSIONS: WLT could improve OAB symptoms in women, while it had slower onset and weaker efficacy but fewer adverse effects than tolterodine. The combination of WLT and tolterodine was more efficacious than tolterodine alone in improving OAB symptoms. TRIAL REGISTRATION: Chinese Clinical Trial Registry [ ChiCTR-IPR-14005626 ]. Date of registration: 7 December 2014. PMID- 27503126 TI - Rehabilitation of atrophic anophthalmic cavity with orthostatic ocular prosthesis: A clinical report. AB - The absence of the eyeball can generate psychosocial and facial harmony changes, such as atrophy of the muscles around it. In these cases, the use of an orthostatic prosthesis with expanding function fosters distension of the tissues for subsequent rehabilitation. This technique consists of making individual ocular prostheses with gradual enlargement of size. The aim of this following clinical report was to describe the technique used in the standing prosthetic rehabilitation of a patient, 73 years old, who underwent enucleation of the right eye as a result of glaucoma. Clinical and laboratory procedures were performed such as impression, adjusting curvature of the sclera, centering the pupil area and processing in heat-cured acrylic resin three prostheses made according to the expansion of the anophthalmic cavity. At the end of treatment, there was a considerable increase of the cavity, allowing for volume replacement similar to that existing in the patient's contralateral orbit, thus generating a satisfactory facial harmony. PMID- 27503127 TI - Oral exposure to environmental pollutant benzo[a]pyrene impacts the intestinal epithelium and induces gut microbial shifts in murine model. AB - Gut microbiota dysbiosis are associated with a wide range of human diseases, including inflammatory bowel diseases. The physiopathology of these diseases has multifactorial aetiology in which environmental factors, particularly pollution could play a crucial role. Among the different pollutants listed, Polycyclic Aromatic Hydrocarbons (PAHs) are subject to increased monitoring due to their wide distribution and high toxicity on Humans. Here, we used 16S rRNA gene sequencing to investigate the impact of benzo[a]pyrene (BaP, most toxic PAH) oral exposure on the faecal and intestinal mucosa-associated bacteria in C57BL/6 mice. Intestinal inflammation was also evaluated by histological observations. BaP oral exposure significantly altered the composition and the abundance of the gut microbiota and led to moderate inflammation in ileal and colonic mucosa. More severe lesions were observed in ileal segment. Shifts in gut microbiota associated with moderate inflammatory signs in intestinal mucosa would suggest the establishment of a pro-inflammatory intestinal environment following BaP oral exposure. Therefore, under conditions of genetic susceptibility and in association with other environmental factors, exposure to this pollutant could trigger and/or accelerate the development of inflammatory pathologies. PMID- 27503128 TI - Familial occurrence of autoimmune liver disease with overlapping features of primary biliary cholangitis and autoimmune hepatitis in a mother and her daughter. AB - We encountered two patients with overlapping features of primary biliary cholangitis and autoimmune hepatitis within the same family. A 68-year-old woman presented at our hospital from a previous medical institution because of the diagnosis of primary biliary cholangitis. Her 49-year-old daughter was admitted with liver dysfunction 4 years later. When compared, these two related patients were found to have overlapping features of primary biliary cholangitis and autoimmune hepatitis. Their human leukocyte antigen haplotype was DRB1*04:05/DRB1*15:02. The clinical and biochemical findings of these two patients immediately improved following treatment with a combination of prednisolone and ursodeoxycholic acid, in accordance with the Japanese guidelines. It is extremely important to identify such pathological conditions as quickly as possible, particularly with the appearance of severe liver dysfunction due to liver cirrhosis, as observed in our case. The Japanese guidelines are considered to be a realistic and useful clinical policy for the swift and efficient treatment of patients with overlapping features of primary biliary cholangitis and autoimmune hepatitis. We suggest that our two patients presented with a genetic predisposition to autoimmune liver disease with overlapping features of primary biliary cholangitis and autoimmune hepatitis within the same family. PMID- 27503129 TI - Mesalazine allergy in a boy with ulcerative colitis: clinical usefulness of mucosal biopsy criteria. AB - 5-Aminosalicylic acid preparations have been used as first-line drugs for treatment of ulcerative colitis (UC). However, some patients with UC present with exacerbation of symptoms because of allergy to mesalazine. Diagnosis of mesalazine allergy in active UC may be challenging because its symptoms mimic those of UC. Here we describe a 13-year-old boy with mesalazine allergy who achieved remission when his medication was changed from mesalazine to salazosulfapyridine. During his clinical course mesalazine was prescribed twice, and on each occasion exacerbation of the symptoms occurred. We considered a diagnosis of mesalazine allergy, and this was confirmed by a drug lymphocyte stimulation test; the result for salazosulfapyridine was negative. On the basis of criteria involving simple mucosal biopsy combined with endoscopy for predicting patients with UC who would ultimately require surgery, we considered that the UC in this case might be susceptible to steroid treatment, and we therefore treated the patient with salazosulfapyridine and prednisolone. Shortly afterwards, remission was achieved and the patient has remained in good condition on salazosulfapyridine alone. When treating patients with mesalazine, the possibility of allergy should always be borne in mind, especially when the clinical course is inconsistent with the results of biopsy. PMID- 27503130 TI - Can interprofessional practice solve the vexing question of 'What is occupational therapy'? PMID- 27503131 TI - There is some evidence from non-randomised trials that team interventions improve processes and outcomes in rehabilitation and chronic care settings. PMID- 27503132 TI - A single virtual patient education activity led to improvements in some self reported interprofessional competencies in approximately 40% of students. PMID- 27503134 TI - The role of periodic serum CA19-9 test in surveillance after colorectal cancer surgery. AB - BACKGROUND: The serum carcinoembryonic antigen (CEA) test is mainly used for postoperative surveillance of colorectal cancer patients in Western and Japanese guidelines, but evidence to support the use of CA19-9 is scarce. METHODS: We analyzed the cohort data from 22 institutions of the Japanese Study Group for Postoperative Follow-up of Colorectal Cancer. Patients who had undergone curative surgery for primary colorectal cancer (pathological stage I-III) between 1997 and 2006 were eligible for analysis. Sensitivities of CEA and CA19-9 at the time of recurrence and the contribution of CA19-9 to detecting recurrences were assessed. RESULTS: A total of 17,833 patients were eligible, and the overall recurrence rate was 18 %. The sensitivity of CA19-9 in detecting recurrence was lower than that of CEA (29 vs. 57 %). Among patients with recurrence, recurrences were first suspected in 96 % using standard surveillance modalities (CEA elevation, CT scan, clinic visit, and colonoscopy), whereas recurrences were suspected because of CA19-9 elevation in an estimated 1.3 % of patients. With regard to prognosis after recurrences, the sensitivity of CA19-9 was lower than that of CEA in the detection of surgically treatable recurrences (22 vs. 49 %). In terms of overall survival after recurrences, CA19-9 and CEA had almost comparable hazard ratios (1.66 and 1.48, respectively). CONCLUSIONS: Our data suggested that the sensitivity of serum CA19-9 test is low, and that adding it to the current standard surveillance strategies is not beneficial. PMID- 27503135 TI - Erratum to: Why so many deep brain stimulation targets in Tourette's syndrome? Toward a broadening of the definition of the syndrome. PMID- 27503136 TI - A nickel iron diselenide-derived efficient oxygen-evolution catalyst. AB - Efficient oxygen-evolution reaction catalysts are required for the cost-effective generation of solar fuels. Metal selenides have been reported as promising oxygen evolution catalysts; however, their active forms are yet to be elucidated. Here we show that a representative selenide catalyst, nickel selenide, is entirely converted into nickel hydroxide under oxygen-evolution conditions. This result indicates that metal selenides are unstable during oxygen evolution, and the in situ generated metal oxides are responsible for their activity. This knowledge inspired us to synthesize nanostructured nickel iron diselenide, a hitherto unknown metal selenide, and to use it as a templating precursor to a highly active nickel iron oxide catalyst. This selenide-derived oxide catalyses oxygen evolution with an overpotential of only 195 mV for 10 mA cm(-2). Our work underscores the importance of identifying the active species of oxygen-evolution catalysts, and demonstrates how such knowledge can be applied to develop better catalysts. PMID- 27503137 TI - Association of nerve conduction impairment and insulin resistance in children with obesity. AB - AIM: The objective of our study was to investigate nerve conduction in normoglycemic obese children. METHODS: A total of 60 children with obesity (30 female and 30 male) and 30 healthy children (15 female and 15 male) were enrolled in the study. Insulin resistance (IR) and other metabolic disturbances were investigated and nerve conduction was measured in all participants. Obese children were divided into groups according to the presence of IR. All results were compared between these subgroups. RESULTS: The nerve conduction velocity (NCV) of motor median nerves in the IR+ group was significantly higher than that in the IR- group and lower than that in the control group. The NCV of the motor peroneal nerve in the IR+ group was significantly lower than that in the IR- group. The sensory nerve action potential (SNAP) of the sensory median nerve was significantly lower in the IR+ group compared to that in the IR- group. The sensory sural nerve's SNAP was significantly lower in the IR+ group than that in the control group. CONCLUSION: Nerve conduction tests may help to detect early pathologies in peripheral nerves and to decrease morbidities in obese children. PMID- 27503139 TI - Dynamic self-representation of interdependent Chinese: The effect of bicultural experience. AB - The process of globalisation has increased the opportunity for Chinese individuals to utilise influences from other cultures that differ from their own collectivistic culture. The explorations of the impact of acculturation on Chinese individuals' self-construals have become intriguing. Thus, we recruited German-Chinese (N = 192) people who live in Germany and had direct bicultural experiences, as well as Mainland-Chinese (N = 192) people who live in Mainland China and had internalised a second culture through more indirect means of exposure. We investigated their accessibility to both interdependent and independent cultural frameworks using temporal self-construal priming. The results showed that priming effects were observed in both cultural groups. However, the self-construals of the German-Chinese participants were more flexible than those of Mainland-Chinese under self-construal priming. Also, the results suggested that women were easier to be influenced by direct bicultural experiences, due to their private and collective self were different between the two cultures. These findings provide evidence regarding the opinion that individuals could use influences from more than one culture. More importantly, these results suggest that the acculturation induced by direct bicultural experiences facilitates cultural frame switching. PMID- 27503140 TI - Beard alopecia areata: a multicentre review of 55 patients. AB - BACKGROUND: Alopecia areata on the beard area (BAA) is a common clinical manifestation, but there are no studies about its characteristics. OBJECTIVE: To describe the epidemiology, comorbidities, clinical presentation, evolution, diagnostic findings and therapeutic choices in a series of patients with BAA. METHODS: This retrospective multicentre review included patients diagnosed with BAA as the first and unique clinical manifestation with at least 12 months of follow-up. Diagnosis was performed based on the typical clinical features. Extra beard involvement was monitored in all cases. RESULTS: Overall, 55 male patients with a mean age of 39.1 years (range 20-74) were included. Twenty-five patients (45.5%) developed alopecia of the scalp during follow-up and more than 80% of cases appeared in the first 12.4 months. Clinical presentation of AA on the scalp was patchy AA (less than 5 patches) (52%), multifocal AA (28%), AA totalis (12%) and AA universalis (8%). Multivariate analysis revealed a trend of association between scalp involvement and family history of AA without statistical significance. CONCLUSIONS: According to this study, BAA may progress to scalp AA in a significant number of patients (45.5% of the patients with a follow-up interval of at least 12 months). In the group of patients who developed scalp AA, 80% of them did it within the first 12 months, so follow-up of patients with BAA is highly encouraged. PMID- 27503138 TI - A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. AB - The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients' treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas. PMID- 27503143 TI - Nondestructive Encapsulation of CdSe/CdS Quantum Dots in an Inorganic Matrix by Pulsed Laser Deposition. AB - We report the successful encapsulation of colloidal quantum dots in an inorganic matrix by pulsed laser deposition. Our technique is nondestructive and thus permits the incorporation of CdSe/CdS core/shell colloidal quantum dots in an amorphous yttrium oxide matrix (Y2O3) under full preservation of the advantageous optical properties of the nanocrystals. We find that controlling the kinetic energy of the matrix precursors by means of the oxygen pressure in the deposition chamber facilitates the survival of the encapsulated species, whose well conserved optical properties such as emission intensity, luminescence spectrum, fluorescence lifetime, and efficiency as single-photon emitters we document in detail. Our method can be extended to different types of nanoemitters (e.g., nanorods, dots-in-rods, nanoplatelets) as well as to other matrices (oxides, semiconductors, metals), opening up new vistas for the realization of fully inorganic multilayered active devices based on colloidal nano-objects. PMID- 27503141 TI - Advances in the characterization of RNA-binding proteins. AB - From transcription, to transport, storage, and translation, RNA depends on association with different RNA-binding proteins (RBPs). Methods based on next generation sequencing and protein mass-spectrometry have started to unveil genome wide interactions of RBPs but many aspects still remain out of sight. How many of the binding sites identified in high-throughput screenings are functional? A number of computational methods have been developed to analyze experimental data and to obtain insights into the specificity of protein-RNA interactions. How can theoretical models be exploited to identify RBPs? In addition to oligomeric complexes, protein and RNA molecules can associate into granular assemblies whose physical properties are still poorly understood. What protein features promote granule formation and what effects do these assemblies have on cell function? Here, we describe the newest in silico, in vitro, and in vivo advances in the field of protein-RNA interactions. We also present the challenges that experimental and computational approaches will have to face in future studies. WIREs RNA 2016, 7:793-810. doi: 10.1002/wrna.1378 For further resources related to this article, please visit the WIREs website. PMID- 27503144 TI - Structural Stability and Deformation of Solvated Sm@C2(42)-C90 under High Pressure. AB - Solvated fullerenes recently have been shown to exhibit novel compression behaviors compared with the pristine fullerenes. However, less attention has been focused on the large cage endohedral metallofullerenes. Here, we have firstly synthesized solvated Sm@C90 microrods by a solution drop-drying method, and then studied the transformations under high pressure. The pressure-induced structural evolutions of Sm@C90 molecules both undergo deformation and collapse. The band gaps of both samples decrease with increasing pressure. The trapped Sm atom plays a role in restraining the compression of the adjacent bonds. The solvent plays a role in protecting Sm@C90 against collapse in the region of 12-20 GPa, decreasing and postponing the change of band gap. Above 30 GPa, the carbon cages collapse. Released from 45 GPa, the compressed solvated Sm@C90 forms a new ordered amorphous carbon cluster (OACC) structure with metal atoms trapped in the units of amorphous carbon clusters, which is different from the OACC structure formed by compressing solvated C60 and C70. This discovery opens the door for the creation of new carbon materials with desirable structural and physical properties when suitable starting materials are selected. PMID- 27503142 TI - The venom gland transcriptome of the parasitoid wasp Nasonia vitripennis highlights the importance of novel genes in venom function. AB - BACKGROUND: Prior to egg laying the parasitoid wasp Nasonia vitripennis envenomates its pupal host with a complex mixture of venom peptides. This venom induces several dramatic changes in the host, including developmental arrest, immunosuppression, and altered metabolism. The diverse and potent bioactivity of N. vitripennis venom provides opportunities for the development of novel acting pharmaceuticals based on these molecules. However, currently very little is known about the specific functions of individual venom peptides or what mechanisms underlie the hosts response to envenomation. Many of the venom peptides also lack bioinformatically derived annotations because no homologs can be identified in the sequences databases. The RNA interference system of N. vitripennis provides a method for functional characterisation of venom protein encoding genes, however working with the current list of 79 candidates represents a daunting task. For this reason we were interested in determining the expression levels of venom encoding genes in the venom gland, as this information could be used to rank candidates for further study. To do this we carried out deep transcriptome sequencing of the venom gland and ovary tissue and used RNA-seq to rank the venom protein encoding genes by expression level. The generation of a specific venom gland transcriptome dataset also provides further opportunities to investigate novel features of this specialised organ. RESULTS: RNA-seq revealed that the highest expressed venom encoding gene in the venom gland was 'Venom protein Y'. The highest expressed annotated gene in this tissue was serine protease Nasvi2EG007167, which has previously been implicated in the apoptotic activity of N. vitripennis venom. As expected the RNA-seq confirmed that venom encoding genes are almost exclusively expressed in the venom gland relative to the neighbouring ovary tissue. Novel genes appear to perform key roles in N. vitripennis venom function, with over half of the 15 highest expressed venom encoding loci lacking bioinformatic annotations. The high throughput sequencing data also provided evidence for the existence of an additional 472 previously undescribed transcribed regions in the N. vitripennis genome. Finally, metatranscriptomic analysis of the venom gland transcriptome finds little evidence for the role of Wolbachia in the venom system. CONCLUSIONS: The expression level information provided here for the N. vitripennis venom protein encoding genes represents a valuable dataset that can be used by the research community to rank candidates for further functional characterisation. These candidates represent bioactive peptides valuable in the development of new pharmaceuticals. PMID- 27503145 TI - Extensive herpes simplex infection of the skin in an immunocompetent, previously skin-healthy female patient. PMID- 27503147 TI - Reflections on my association with Henry G. Kunkel. PMID- 27503146 TI - The Kunkel legacy and hepatitis C virus infection. AB - In commemoration of Henry Kunkel's 100th birthday, the effect of his legacy on the investigation of hepatitis C virus is recounted. The delineation of a major cross-idiotype (WA) among patients with essential mixed cryoglobulinemia led to the discovery that HCV was the etiologic agent for this disease. Studies of the cryoglobulins led to the discovery that WA RF reacted specifically with HCV-VLDL like particles that on electronmicroscopy and binding studies appeared to be the virion within a lipid shell. This particle mediates cell entry via LDLr and may serve to avoid the immune response by masking the virion. In addition, the WA B cell may be a prognostic marker for cutaneous vasculitis and B cell malignancy in HCV-infected patients. In commemoration of Henry Kunkel's 100th birthday, this is an account of how his legacy had a role in the investigation of hepatitis C virus (HCV) infection. There is a bit of a historical basis for the legacy of this great immunologist having a role in virology. He began his research career studying hepatitis. Later he worked with HCV in his studies of mixed cryoglobulins although he didn't know it at the time. There may also have been a Kunkel historical basis for why he accepted me as fellow in his laboratory considering that my credentials paled in comparison with those of the fellows and PhD students in his laboratory. Like Henry I was drafted into the Navy following my internship, I had had minimal research experience in medical school and only one minor publication, and I had a passion for clinical investigation. It may have been fortuitous that while on active duty at the Bayonne NJ Naval Base I visited Henry Kunkel in my Navy uniform and told him I was interested in studying SLE. I did not know at the time the dramatic role the Navy had played in his career or that one of his major training goals was to teach MDs to use clinical observation as a focus for delineating disease mechanisms in the laboratory. When I started work in the laboratory on discharge from the Navy, the first thing he told me was that it took five years to make a clinical investigator so I might as well get a Rockefeller University PhD while working in his laboratory. I was sure I would leave the laboratory after two years so I declined his offer. I did not leave until six years later! PMID- 27503148 TI - 3D Printing Variable Stiffness Foams Using Viscous Thread Instability. AB - Additive manufacturing of cellular structures has numerous applications ranging from fabrication of biological scaffolds and medical implants, to mechanical weight reduction and control over mechanical properties. Various additive manufacturing processes have been used to produce open regular cellular structures limited only by the resolution of the printer. These efforts have focused on printing explicitly designed cells or explicitly planning offsets between strands. Here we describe a technique for producing cellular structures implicitly by inducing viscous thread instability when extruding material. This process allows us to produce complex cellular structures at a scale that is finer than the native resolution of the printer. We demonstrate tunable effective elastic modulus and density that span two orders of magnitude. Fine grained cellular structures allow for fabrication of foams for use in a wide range of fields ranging from bioengineering, to robotics to food printing. PMID- 27503150 TI - Phosphonium pillar[5]arenes as a new class of efficient biofilm inhibitors: importance of charge cooperativity and the pillar platform. AB - Biofilm formation, which frequently occurs in microbial infections and often reduces the efficacy of antibiotics, also perturbs many industrial and domestic processes. We found that a new class of water soluble pillar[5]arenes bearing phosphonium moieties (1, 2) and their respective ammonium analogues (3, 4) inhibit biofilm formation with IC50 values in the range of 0.67-1.66 MUM. These compounds have no antimicrobial activity, do not damage red blood cell membranes, and do not affect mammalian cell viability in culture. Comparison of the antibiofilm activities of the phosphonium-decorated pillar[5]arene derivatives 1 and 2 with their respective ammonium counterparts 3 and 4 and their monomers 5 and 6, demonstrate that while positive charges, charge cooperativity and the pillararene platform are essential for the observed antibiofilm activity the nature of the charges is not. PMID- 27503149 TI - A sex difference in oxidative stress and behavioral suppression induced by ethanol withdrawal in rats. AB - Ethanol withdrawal (EW) is referred to the abrupt termination of long-term heavy drinking, and provokes oxidative brain damage. Here, we investigated whether the cerebellum and hippocampus of female rats are less affected by prooxidant EW than male rats due to the antioxidant effect of 17beta-estradiol (E2). Female and male rats received a four-week ethanol diet and three-week withdrawal per cycle for two cycles. Some female rats were ovariectomized with E2 or antioxidant (Vitamin E+Co-Q10) treatment. Measurements were cerebellum (Rotarod) and hippocampus (water-maze)-related behaviors, oxidative markers (O2(-), malondialdehyde, protein carbonyls), mitochondrial membrane swelling, and a key mitochondrial enzyme, cytochrome c oxidase (CcO). Separately, HT22 (hippocampal) cells were subjected to ethanol-exposure and withdrawal for two cycles to assess the effect of a CcO inhibitor on E2's protection for mitochondrial respiration and cell viability. Ethanol-withdrawn female rats showed a smaller increase in oxidative markers in cerebellum and hippocampus than male rats, and E2 treatment decreased the oxidative markers. Compared to male counterparts, ethanol-withdrawn female rats showed better Rotarod but poorer water-maze performance, accompanied by more severe mitochondrial membrane swelling and CcO suppression in hippocampus. E2 or antioxidant treatment improved Rotarod but not water-maze performance. In the presence of a CcO inhibitor, E2 treatment failed to protect mitochondrial respiration and cell viability from EW. These data suggest that antioxidant E2 contributes to smaller oxidative stress in ethanol-withdrawn female than male rats. They also suggest that EW-induced severe mitochondrial damage in hippocampus may blunt E2's antioxidant protection for hippocampus-related behavior. PMID- 27503151 TI - What's in a name? Pancreatic pseudocysts, walled-off necrosis, and pancreatic fluid collections. PMID- 27503152 TI - Utility of endoscopic ultrasound in the diagnosis and management of esophagogastric varices. AB - Endoscopic ultrasound (EUS) has significantly improved our understanding of the complex vascular structural changes in patients with portal hypertension. At present, EUS is a useful diagnostic tool for the evaluation of esophagogastric varices (EGVs) and guidance of endoscopic therapy. Several studies have employed this new technique for the diagnosis and management of esophageal and gastric varices, respectively. In the present review, we have summarized the current status of EUS for the diagnosis and management of EGVs and clarified the clinical feasibility of this procedure. New indications for EUS can be developed in the future after adequate validation. PMID- 27503153 TI - Efforts to improve the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration for pancreatic tumors. AB - Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is widely used to obtain a definitive diagnosis of pancreatic tumors. Good results have been reported for its diagnostic accuracy, with high sensitivity and specificity of around 90%; however, technological developments and adaptations to improve it still further are currently underway. The endosonographic technique can be improved when several tips and tricks useful to overcome challenges of EUS-FNA are known. This review provides various techniques and equipment for improvement in the diagnostic accuracy in EUS-FNA. PMID- 27503155 TI - In vivo cytological observation of liver and spleen by using high-resolution microendoscopy system under endoscopic ultrasound guidance: A preliminary study using a swine model. AB - Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is useful to obtain specimens from lesions underlying deep parts of the liver and spleen. However, the development of novel ancillary techniques must be explored to reduce the number of needle passes and potential adverse effects during this procedure. We conducted an animal study using a swine to demonstrate technical feasibility of in vivo cytological observation of liver and spleen using the high-resolution microendoscopy (HRME) system under EUS guidance. We successfully performed the study. No significant acute adverse events occurred during the procedure. The HRME system could obtain clear images representing cytology-level morphology of spleen and liver. Hence, it is found out that in vivo cytological observation of liver and spleen using the HRME system under EUS guidance is technically feasible. PMID- 27503154 TI - Endobronchial ultrasound elastography. AB - Elastographic techniques have recently become available as advanced diagnostic tools for tissue characterization. Strain elastography is a real-time technique used with transcutaneous ultrasound (US) and endoscopic US. Convincing evidence is available demonstrating a significant value of strain elastography for the discrimination of benign and malignant lymph nodes (LNs). This paper reviews preliminary data demonstrating the feasibility of performing real-time elastography during endobronchial US (EBUS) and a potential application of this technique for selection of LNs for EBUS-guided transbronchial needle aspiration in patients with lung cancer and extrathoracic malignancies. PMID- 27503156 TI - Usefulness of lymphoid granulomatous inflammation culture obtained by endobronchial ultrasound-guided transbronchial needle aspiration in a fungal endemic area. AB - BACKGROUND AND OBJECTIVES: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the procedure of choice for the evaluation of mediastinal/hilar lymph node enlargements. Granulomatous inflammation of the mediastinal/hilar lymph nodes is often identified on routine histology. In addition, mediastinal lymphadenopathy may be present with undiagnosed infection. We sought to determine the usefulness of routine cultures and histology for infectious etiologies in a fungal endemic area when granulomatous inflammation is identified. MATERIALS AND METHODS: We identified 56 of 210 patients with granulomatous inflammation on EBUS-TBNA biopsies from October 2012 through October 2014. An onsite cytologist evaluated all biopsies and an additional TBNA pass for microbiologic stains and cultures were obtained in those with granulomatous inflammation. RESULTS: Of the 56 patients with granulomatous inflammation, 20 patients had caseating (necrotizing) granulomas while noncaseating (nonnecrotizing) granulomas were detected in 36 of the remainder patients. In patients with caseating granulomas, fungal elements were identified in 6 of 20 (30%) patients (histoplasma; N = 5, blastomyces; N = 1) on Grocott methenamine silver (GMS) stain. Lymph node cultures identified 3 of 20 (20%) patients as being positive for Mycobacterium tuberculosis (N = 1), Histoplasma capsulatum (N = 1), and Blastomyces dermatitidis (N = 1). Among patients with noncaseating granulomas, only 2 out of 36 (5%) were positive for fungal elements on GMS stain, identified as Histoplasma, although the lymph node cultures remained negative. CONCLUSION: The incidence of granulomatous inflammation of mediastinal lymph nodes was 26.6% in our series. Of these patients, noncaseating granulomas were more common (64% vs. 36%). Infectious organisms, fungal or acid fast bacilli (AFB), on either staining or lymph node culture were rarely identified in noncaseating granulomas, 5% and none, respectively. Caseating granulomas were more commonly associated with positive lymph node fungal stain and culture, 35% and 15%, respectively. In a fungal endemic area, lymph node staining and culture can be considered in cases with caseating granulomatous inflammation, if known at the time of biopsy. PMID- 27503157 TI - Endoscopic ultrasound characteristics of pancreatic lymphoepithelial cysts: A case series from a large referral center. AB - BACKGROUND AND OBJECTIVES: Lymphoepithelial cysts (LECs) of the pancreas are benign lesions that can mimic cystic neoplasms on imaging. Endoscopic ultrasound (EUS) features have not been well described. We aimed to describe the clinical and EUS characteristics of LECs and the present outcomes of management at a high volume referral center. MATERIALS AND METHODS: We identified patients who underwent EUS and were found to have LECs based on fine-needle aspiration (FNA) cytology or surgical pathology from existing databases. EUS features, imaging characteristics, and pathology results were described. RESULTS: Sixteen patients were found to have 17 LECs. The mean size was 33 mm +/- 15 mm. Locations within the pancreas included 10 lesions in the tail, 3 in the body, 1 in the uncinate process; the remaining 3 were exophytic. Six lesions were anechoic, 6 were hypoechoic, and 5 had mixed echogenicity. Nine lesions had mixed solid/cystic components, 7 were purely cystic, and 1 was solid. Cyst fluid was thick or viscous in six cases and thin in three. Eleven patients had diagnostic cytopathology. Six patients ultimately underwent surgery due to symptoms, nondiagnostic FNA, or other clinical concerns for malignancy. CONCLUSIONS: Pancreatic LECs have variable morphology and echogenicity on EUS, but the appearance of a cyst with variable solid and cystic components combined with the appearance of thick, turbid, and viscous aspirate should raise suspicion for an LEC. The majority of patients with LECs at our center avoided surgery for LECs on the basis of diagnostic EUS-FNA. PMID- 27503158 TI - Exploration under the dome: Esophageal ultrasound with the ultrasound bronchoscope is indispensible. AB - BACKGROUND: Effective use of the convex curvilinear ultrasound bronchoscope in the esophagus (EUS-B) for fine needle aspiration biopsy of mediastinal structures is now well described. In contrast, there is little to no reporting, depending on the site of EUS-B for access to sub-diaphragmatic structures. Our practice has been accessing sub-diaphragmatic sites for years. This review documents our experience with EUS-B to biopsy liver, left adrenal glands, and coeliac lymph nodes. METHODS: After Institutional Review Board's approval, all endosonographic procedures performed by interventional pulmonary between July 2013 and June 2015 were reviewed. Those including biopsy of sub-diaphragmatic sites were then selected for analysis. RESULTS: Over the study interval, 45 sub-diaphragmatic biopsy procedures (25 left adrenal glands, 7 liver, and 13 celiac node) were performed with EUS-B. In all cases, cellular adequacy was present, and samples were large enough for immunohistochemistry and any relevant ancillary studies. Metastatic malignancy was documented in 58% of cases, 16% of cases contained benign diagnostic findings, and in 27% of cases, normal organ tissue was documented. There were no complications. CONCLUSIONS: Operators comfortable with the endobronchial ultrasound scope in both the airway and the esophagus can actively seek and successfully perform biopsy of sub-diaphragmatic abnormalities when present and can thereby add to the diagnostic value of the procedure. PMID- 27503159 TI - Repeat endoscopic ultrasound fine needle aspiration after a first negative procedure is useful in pancreatic lesions. AB - BACKGROUND AND OBJECTIVES: There is no consensus about the ideal method for diagnosis in patients who have already undergone endoscopic ultrasound fine needle aspiration (EUS-FNA), and the inconclusive material is often obtained. The aim was to evaluate the diagnostic yield of the second EUS-FNA of pancreatic lesions. MATERIALS AND METHODS: A retrospective analysis of prospectively collected data of patients with EUS-FNA of pancreatic lesions is performed. All patients who underwent more than one EUS-FNA for the evaluation of suspected pancreatic cancer over a 7-year period were included in the analysis. RESULTS: A total of 296 EUS-FNAs of the pancreas were performed in 257 patients. The diagnostic yield with the first EUS-FNA was 78.6% (202/257). Thirty-nine (13.3%) FNAs were repeated in 34 patients; 17 (50%) patients were women. The mean +/- standard deviation (SD) age was 58.8 +/- 16.1 years. The location of the lesions in the pancreatic gland, from which the second biopsies were taken, was head of the pancreas, n = 28 (82.4%), body of the pancreas, n = 3 (8.8%), and tail, n = 3 (8.8%). The mean +/- SD of the size of the lesion was 36.3 +/- 14.6 mm. The second EUS-FNA was more likely to be positive for diagnosis in patients with an "atypical" histological result in the first EUS-FNA (odds ratio [OR]: 4.04; 95% confidence interval [CI]: 0.9-18.3), in contrast to patients with a first EUS-FNA reported as "normal" (OR: 0.21; 95% CI: 0.06-0.71). Overall, the diagnostic yield of the second EUS-FNA was 58.8% (20/34) with an increase to 86.3% overall (222/257). CONCLUSION: Repeat EUS-FNA in pancreatic lesions is necessary in patients with a negative first EUS-FNA because it improves the diagnostic yield. PMID- 27503160 TI - Endoscopic ultrasound-guided puncture suture device versus metal clip for gastric defect closure after endoscopic full-thickness resection: A randomized, comparative, porcine study. AB - OBJECTIVE: The secure closure of the wall defect is a critical stage of endoscopic full-thickness resection (EFTR). The aim of this study was to compare the closure of post-EFTR defects using an endoscopic ultrasound-guided puncture suture device (PSD) with the metal clip (MC) technique in a randomized, comparative, porcine study. METHODS: We performed a randomized comparative survival study that included 18 pigs. The circular EFTR defects with a diameter of approximately 20 mm were closed with either a PSD or MC. Serum levels of interleukin-6 (IL-6) were determined preoperatively and on a postoperative day (POD) 1, 3, and 7. Three animals from each group were sacrificed at the end of the 7 th , 14 th , and 30 th POD. Tissue samples retrieved from the closure sites were examined macroscopically and microscopically. RESULTS: Resection and closure were performed in 18 pigs (100%) without major perioperative complications. The mean closure time was significantly longer in the MC group than in the PSD group (25.00 +/- 3.16 min vs. 1.56 +/- 0.39 min; P < 0.05). Preoperative and POD 7 serum levels of IL-6 did not differ between the two groups. However, on POD 1, the IL-6 levels were observed to be significantly greater in the MC group than in the PSD group (P < 0.005). No significant differences between the PSD and MC groups were observed at necropsy. CONCLUSION: In this in vivo porcine model, PSD is a feasible device that achieves post-EFTR defect closure with a much shorter closure time and with less immunological responses than the MC technique. PMID- 27503161 TI - Opium-related sphincter of Oddi dysfunction causing double duct sign. AB - Double duct sign where there is a simultaneous dilatation of both the common bile duct (CBD) and pancreatic duct is usually associated with sinister causes like malignancies of pancreatic head or ampulla. Occasionally, benign causes like chronic pancreatitis or sphincter of Oddi dysfunction (SOD) may cause double duct sign. Chronic opium abuse is a rare cause of the double duct sign, and endoscopic ultrasound (EUS) findings of this rare entity have been occasionally reported. We report about a 54-year-old male with a history of chronic alcohol and opioid abuse evaluated for episodes of abdominal pain and found to have opioid-related SOD and improved with biliary sphincterotomy. EUS was done to rule out malignancy and revealed hypoechoic prominence around terminal CBD suggestive of hypertrophied muscle. PMID- 27503162 TI - Endobronchial ultrasound for the detection of chronic pulmonary artery thrombus. AB - Endobronchial ultrasound (EBUS) has been shown to be able to successfully identify acute/subacute pulmonary thromboembolism (PE). Most reported cases have required confirmation by computerized tomography (CT) angiography. This report demonstrates a case where CT angiography was not conclusive and the EBUS was useful in clarifying the chronic process inside the pulmonary artery compatible with clinical diagnosis of chronic pulmonary artery thrombosis. PMID- 27503163 TI - Biliary intraductal papillary-mucinous neoplasm in the left hepatic lobe diagnosed by endoscopic ultrasonography: Report of a case. PMID- 27503164 TI - Endoscopic ultrasound-guided internalization of a pancreaticocutaneous fistula without need for percutaneous manipulation. PMID- 27503165 TI - EUS-FNA diagnosis of a rare case of esophageal teratoma. PMID- 27503166 TI - The relationship between living alone and depressive symptoms among older gay men: the moderating role of sense of belonging with gay friends. AB - BACKGROUND: Living alone is a risk factor for depressive symptoms among older adults, although it is unclear if it is a risk factor for older gay men. A sense of belonging to the gay community is protective and might compensate for living alone. This research investigated whether a sense of belonging with gay friends weakened the relationship between living alone and depressive symptoms among older gay men. METHODS: A community sample of 160 Australian gay men aged 65-92 years completed the Center for Epidemiologic Studies Depression Scale and two visual analogue scales assessing a sense of belonging with gay friends. RESULTS: Results supported the moderation model, with increasing levels of belonging with gay friends weakening the relationship between living alone and depressive symptoms. CONCLUSION: Results imply that enhancing a sense of belonging with gay friends among older gay men who live alone is likely to be a protective factor in relation to depressive symptoms. PMID- 27503167 TI - Development of myotendinous-like junctions that anchor cardiac valves requires fibromodulin and lumican. AB - BACKGROUND: There are many patients that exhibit connective tissue related cardiac malformations but do not have mutations in collagen genes. The Small Leucine Rich Proteoglycans (SLRP) fibromodulin (FMOD) and lumican (LUM) bind collagen and regulate fibril assembly in other biological contexts. RESULTS: FMOD deficient mice and double deficient FMOD; LUM mice exhibited anomalies in regions where cardiac valve tissue interdigitates with adjacent muscle for support. Ectopic connective and/or myocardial tissue(s) was associated with the more severe cardiac valve anomalies in FMOD; LUM deficient mice. At postnatal day 0 (P0) there was an increase in the mesenchymal cell number in the regions where valve cusps anchor in FMOD; LUM deficient mice compared to WT. The cardiac valve anomalies correlated with the highest levels of FMOD expression in the heart and also where myotendinous junctions (MTJ) components biglycan, collagen type I alpha 1, and collagen type VI, are also localized. CONCLUSIONS: The postnatal assembly of the collagen-rich ECM in regions where cardiac valves anchor, that we have designated 'myotendinous-like junctions' (MTLJ) requires the SLRPs FMOD and LUM. Moreover, FMOD and LUM may facilitate mesenchymal cell differentiation in late stages of cardiac valve development. Developmental Dynamics 245:1029-1042, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27503168 TI - Screening anti-allergic components of Astragali Radix using LAD2 cell membrane chromatography coupled online with UHPLC-ESI-MS/MS method. AB - Huangqi (Astragali Radix), a traditional Chinese herb, is widely used in clinical therapy in China. In addition, an anti-allergic effect of constituents in Huangqi has been reported in the scientific literature. In the present study, cell membrane chromatography coupled online with UHPLC-ESI-MS/MS method was developed to screen, analyze and identify the anti-allergic components of Huangqi. The Laboratory of Allergic Disease 2 (LAD2) cell was used to establish cell membrane chromatography, which was combined with UHPLC-ESI-MS/MS. The coupled system was then used to screen anti-allergic components from Huangqi. Effects of active components were verified by histamine release assay. A component retained on the LAD2 cell membrane chromatography was identified as formononetin. Bioactivity of formononetin was investigated by histamine release assay in LAD2 cells, and it was found that formononetin could inhibit histamine release in a dose-dependent manner from 1 to 100 MUm. The LAD2 cell membrane chromatography online with UHPLC ESI-MS/MS method is an effective technique for screening the anti-allergic components of Huangqi. PMID- 27503169 TI - A 'suicide' CRISPR-Cas9 system to promote gene deletion and restoration by electroporation in Cryptococcus neoformans. AB - Loss-of-function mutagenesis is an important tool used to characterize gene functions, and the CRISPR-Cas9 system is a powerful method for performing targeted mutagenesis in organisms that present low recombination frequencies, such as the serotype D strains of Cryptococcus neoformans. However, when the CRISPR-Cas9 system persists in the host cells, off-target effects and Cas9 cytotoxicity may occur, which might block subsequent genetic manipulation. Here, we report a method of spontaneously eliminating the CRISPR-Cas9 system without impairing its robust editing function. We successfully expressed single guide RNA under the driver of an endogenous U6 promoter and the human codon-optimized Cas9 endonuclease with an ACT1 promoter. This system can effectively generate an indel mutation and efficiently perform targeted gene disruption via homology-directed repair by electroporation in yeast. We then demonstrated the spontaneous elimination of the system via a cis arrangement of the CRISPR-Cas9 expression cassettes to the recombination construct. After a system-mediated double crossover, the CRISPR-Cas9 cassettes were cleaved and degraded, which was validated by Southern blotting. This 'suicide' CRISPR-Cas9 system enables the validation of gene functions by subsequent complementation and has the potential to minimize off-target effects. Thus, this technique has the potential for use in functional genomics studies of C. neoformans. PMID- 27503171 TI - Considerations concerning the definition of sarcopenia: response to comments. PMID- 27503170 TI - Associations of dietary calcium intake with metabolic syndrome and bone mineral density among the Korean population: KNHANES 2008-2011. AB - : Excessive amount of calcium intake increased risk for metabolic syndrome in men. However, modest amount decreased the risk of metabolic syndrome and osteoporosis in postmenopausal women. Modest amount of calcium also increased bone mineral density (BMD) in both men and postmenopausal women. INTRODUCTION: The present study aimed to evaluate the associations of dietary calcium intake with metabolic syndrome and bone mineral density (BMD) in Korean men and women, especially postmenopausal women. METHODS: The study was performed using data from the Korean National Health and Nutrition Examination Survey (2008-2011) and included 14,705 participants (5953 men, 4258 premenopausal women, and 4494 postmenopausal women). Clinical and other objective characteristics, presence of metabolic syndrome, and the BMD of the femur neck and lumbar spine were evaluated according to dietary calcium intake. RESULTS: There was a higher tendency for metabolic syndrome in men with a dietary calcium intake of >1200 mg/day than with <=400 mg of calcium intake; >400 and <=800 mg of calcium intake was helpful for postmenopausal women to decrease risk for metabolic syndrome. Overall, the group with calcium intake >400 and <=800 mg daily had significantly increased BMD in both femoral neck and lumbar spine from both men and postmenopausal women. From both femoral neck and lumbar spine, the prevalence of osteoporosis in postmenopausal women significantly decreased in the group whose calcium intake was >400 and <=800 mg daily. CONCLUSION: Excessive dietary calcium may increase the prevalence of metabolic syndrome in men. For postmenopausal women, calcium intake does not increase the risk of metabolic syndrome, but modest amount decreases the risk. It may increase the BMD in men and postmenopausal women, and also reduce the prevalence of both osteoporosis and metabolic syndrome in postmenopausal women. PMID- 27503172 TI - Considerations concerning the definition of sarcopenia: comments. PMID- 27503173 TI - Health-related quality of life in older people with osteoporotic vertebral fractures: clinically important vs. statistically significant. PMID- 27503174 TI - Health-related quality of life in older people with osteoporotic vertebral fractures: response to comments by Sani et al. PMID- 27503175 TI - Thalassemia-associated osteoporosis: a systematic review on treatment and brief overview of the disease. AB - Thalassemia-associated osteoporosis constitutes a major complication in patients with thalassemia. This review presents the existing studies on the treatment of thalassemia-associated osteoporosis and discusses the management of this debilitating complication. A brief presentation of the disease characteristics and pathogenetic mechanisms is also provided. The life expectancy of patients with thalassemia has increased markedly in recent years resulting in the aging of the population and the emergence of new comorbidities. The majority of patients with thalassemia have low bone mineral density and experience lifelong fracture rates as high as 71 %. The pathogenesis of thalassemia-associated osteoporosis (TAO) is multifactorial with anemia and iron overload playing crucial role in its development. Data concerning the prevention and treatment of TAO are extremely limited. We performed a literature research in Pubmed and Scopus to identify interventional studies evaluating the effects of various agents on TAO. Seventeen studies were retrieved. We present the results of these studies as well as a brief overview of TAO including presentation, pathogenesis, and management. Most of the studies identified are of poor quality, are not randomized controlled, and include small number of participants. There are no data concerning effects on fracture rates. Bisphosphonates are the most widely studied agents and among them zoledronic acid is the most well studied. Hormone replacement treatment (HRT) shows beneficial but small effects. Denosumab and strontium ranelate have each been evaluated in only a single study, while there are no data about the effects of anabolic agents. Given the increased life expectancy and the increase in fracture rates with age, more data about the management of TAO are warranted. Moreover, due to the need for lifelong management starting at young age, careful treatment plans which may include sequential treatment may often be required. However, currently, there are no relevant data available. PMID- 27503176 TI - The Association of Vitamin D With Estimated Glomerular Filtration Rate and Albuminuria: 5th Korean National Health and Nutritional Examination Survey 2011 2012. AB - OBJECTIVES: The kidney plays a key role in the metabolism of vitamin D. However, the relationship between GFR and 25(OH)D is not well understood. Moreover, few studies have investigated the effect of albuminuria, a known mediator of kidney function, on vitamin D levels. Our aim was to investigate the associations among estimated GFR (eGFR), albumin-creatinine ratio (ACR), and 25(OH)D. METHODS: We investigated the relationship of 25-hydroxyvitamin D (25[OH]D) with eGFR and albuminuria in 11,336 adults who participated in the 5th Korea National Health and Nutrition Examination Survey (KNHANES) 2011-2012. The eGFR, ACR, and serum 25(OH)D were measured in participants who met the detailed inclusion criteria. RESULTS: We found that after adjusting for covariates and log-ACR values, the mean (95% CI) eGFR decreased significantly with increasing 25(OH)D levels (Q1: 93.4 [92.7-94.0]; Q2: 91.9 [91.2-92.5]; Q3: 90.9 [90.3-91.6]; and Q4: 90.2 [89.5 90.8] mL/min/1.73m2; P < .001). However, the mean 25(OH)D value was highest at eGFR 61-90 mL/min per 1.73 m2 and decreased significantly with decreasing eGFR levels (>90: 17.3 [17.1-17.5]; 61-90: 17.6 [17.4-17.8]; 46-60: 17.1 [16.2-18.0]; 31-45: 16.2 [14.2-18.2]; <=30: 13.8 [17.0-10.7] ng/mL; P = .008). After adjusting for covariates and log-eGFR, the mean ACR decreased significantly with increasing 25(OH)D quartiles (Q1: 22.0 [18.1-25.9]; Q2: 20.4 [16.6-24.2]; Q3: 16.3 [12.5 20.0]; Q4: 15.0 [11.2-18.8] MUg/mg; P = .043). CONCLUSIONS: The mean eGFR values were negatively associated with 25(OH)D levels independently of ACR. However, the mean 25(OH)D values were decreased significantly with decreasing eGFR levels in moderate and severe chronic kidney disease stages. Also, the mean ACR values were negatively associated with 25(OH)D levels independently of eGFR in an Korean adult population. PMID- 27503177 TI - Japanese secular trends in birthweight and the prevalence of low birthweight infants during the last three decades: A population-based study. AB - Since low birthweight has been correlated with both neonatal and long-term health, we performed this epidemiological study to evaluate the Japanese secular trends in mean birthweight and the prevalence of preterm/term low birthweight infants during the last three decades. We used population-based birth certificate data from January 1979 to December 2010. Time trends were analysed using a linear regression model. During the study period, we observed a significant decrease in the mean birthweight for singleton live births (3,152 +/- 436 g in 1979 and 3,018 +/- 421 g in 2010 p < 0.001) and an increase in the prevalence of preterm/term low birthweight infants. A 96.3% increase in the proportion of term low birthweight infants was observed during the study period (2.7% in 1979 and 5.3% in 2010). In addition, an increased proportion of preterm/low birthweight infants born to younger women was observed (<35 years vs. >=35 years). These trends may be related to changing patterns in Japanese women's nutritional status and the relatively strict recommended limit on weight gain during pregnancy. Understanding the long-term trends for singleton births may allow us to identify the associated risk factors and reduce the future socioeconomic burden that is associated with low birthweight infants. PMID- 27503178 TI - Effect of autoimmunity risk loci on the honeymoon phase in type 1 diabetes. AB - OBJECTIVE: To analyze the correlation between duration and depth of honeymoon phase in patients with type 1 diabetes (T1DM) and autoimmunity risk loci. METHODS: From a database of 567 individuals with clinical data, we selected 210 patients for whom we had dense genotyping results of single-nucleotide polymorphisms (SNPs) from our previous genome-wide association studies (GWAS) or targeted genotyping data. Using PLINK software, we analyzed the association between time spent in honeymoon phase as our quantitative trait, and 24 known autoimmunity predisposing SNPs. RESULTS: We found one allele on chromosome 5, rs4613763 mapping to a Prostaglandin Receptor EP4 (PTGER4) to reach statistical significance (P = .0067), in determining a larger proportion of T1DM patients with a detectable honeymoon phase. This polymorphism determines risk for inflammatory bowel disease (IBD) but not T1DM. CONCLUSION: By showing the role of PTGER4 in autoimmune diseases and its effect on inflammatory responses via its interaction with NF-kB, we hypothesize that PTGER4 modulates honeymoon phase in patients with T1DM without influencing the risk of developing T1DM. We hypothesize that this quantitative trait locus promotes inflammatory suppression of beta cells without directly promoting beta-cell destruction. Understanding SNPs that effect function can provide insight in to pathogenesis of T1DM and the mechanism of the honeymoon phase. Because this is a hypothesis-generating study, it needs to be replicated in an additional larger cohort. PMID- 27503179 TI - Nano-Bio Interactions: Guiding the Development of Nanoparticle Therapeutics, Diagnostics, and Imaging Agents. PMID- 27503180 TI - Newly Approved Agents for the Treatment and Prevention of Pediatric Migraine. AB - Treatment of pediatric migraine remains an unmet medical need. There continues to be a paucity of pediatric randomized controlled trials for the treatment of migraine, both in the acute and preventive settings. Pediatric studies are often complicated by high placebo-response rates and much of our current practice is based on adult trials. This lack of significant pediatric studies results in a wide variation in migraine management both amongst clinicians and between institutions, and evidence-based treatments are not always administered. In this article, we aim to briefly review newly approved abortive and preventive agents for migraine in the pediatric age group. Over-the-counter anti-inflammatory medications, including ibuprofen, naproxen sodium, aspirin, and acetaminophen are reasonable first-line options for abortive therapy. In addition, studies have shown triptans, or migraine-specific agents, to be safe and effective in children and adolescents and several formulations have been approved for the pediatric population, including rizatriptan, almotriptan, zolmitriptan nasal spray, and naproxen sodium/sumatriptan in combination. PMID- 27503182 TI - Electronic Consultations in Nephrology: Pilot Implementation and Evaluation. PMID- 27503181 TI - Brivaracetam: A Review in Partial-Onset (Focal) Seizures in Patients with Epilepsy. AB - Brivaracetam (Briviact((r)); BRIVLERATM) is a high affinity synaptic vesicle protein 2A (SV2A) ligand available orally (as a tablet or solution) or intravenously (as a bolus or infusion) in various countries worldwide, including the USA, Canada and those of the EU. It is approved as adjunctive therapy for the treatment of partial-onset seizures (POS) in adults (aged >=18 years) [USA, EU and Canada] and adolescents (aged 16 to <18 years) [USA and EU] with epilepsy. In multinational, phase III studies in adults and adolescents (aged >=16 years), oral brivaracetam as adjunctive therapy to other antiepileptic drugs (AEDs) was generally associated with significant median percent reductions over placebo in seizure frequency and significant improvements in the proportion of patients achieving a >=50 % reduction in seizure frequency compared with placebo. These benefits appeared to be sustained during up to 96 months' therapy in follow-up studies. Whether administered orally or intravenously, adjunctive brivaracetam was generally well tolerated in clinical studies, with the majority of treatment emergent adverse events (TEAEs) being mild or moderate in intensity. In the absence of head-to-head studies, definitive conclusions on the comparative efficacy and tolerability of brivaracetam versus newer AEDs are not yet possible. In the meantime, brivaracetam extends the options currently available for the treatment of POS in patients aged >=16 years with epilepsy. PMID- 27503183 TI - Febuxostat in Hyperuricemic Patients With Advanced CKD. PMID- 27503184 TI - The influence of tibial resection on the PCL in PCL-retaining total knee arthroplasty: A clinical and cadaveric study. AB - BACKGROUND: The influence of tibial resection on the joint gap and on stability against posterior laxity in posterior cruciate ligament-retaining total knee arthroplasty (CR-TKA) remains unclear. In addition, there are no detailed reports regarding how much of the tibial attachment of the posterior cruciate ligament (PCL) is preserved during tibial resection. Our goals were to evaluate the influence of tibial resection on the intraoperative joint gap and on postoperative anteroposterior stability in a clinical population, and to assess the preserved area of the tibial PCL attachment using cadaveric knees. METHODS: In 20 consecutive patients, the joint gaps before and after tibial resection at 90 degrees flexion and full extension were analyzed during CR-TKA, and anteroposterior stability was evaluated postoperatively. In 11 cadaveric knees, tibial resection with a thickness of 8, 10, 12, or 14 mm and a posterior slope of 3, 4, 5, 6, or 7 degrees was simulated using computed tomography images, and the percentage of the preserved area of the attachment was calculated. RESULTS: The flexion gaps before and after tibial resection were 18.1 +/- 1.9 mm and 18.4 +/- 2.2 mm, respectively, with no statistically significant difference (p = 0.08). Similarly, the extension gap did not increase significantly before and after tibial resection (20.8 +/- 2.5 mm and 21.0 +/- 2.6 mm; p = 0.45). All knees maintained anteroposterior stability at the follow-up period (32.0 +/- 1.9 months). The posterior slope of the tibial resection was 5.9 +/- 1.4 degrees , and the thickness of the lateral tibial resection was 10.4 +/- 1.1 mm. The cutoffs to preserve more than 50% of the attachment were 10-mm thickness and 5 degrees slope. CONCLUSIONS: Our results showed that tibial resection did not influence the intraoperative joint gap or postoperative anteroposterior stability. However, our analysis demonstrated that increased amounts of tibial resection led to considerable damage to the attachment. PMID- 27503185 TI - Leukocyte concentration and composition in platelet-rich plasma (PRP) influences the growth factor and protease concentrations. AB - BACKGROUND: Platelet-rich plasma (PRP) therapy has become an increasingly popular treatment for orthopaedics and sports-related injuries, and various clinically available PRP preparation methods exist. However, the differences in PRP quality among numerous preparation methods remain unclear. Specifically, the benefit of including leukocytes in the PRP product remains controversial, and few studies have been conducted to evaluate the effects of the interaction between platelets and leukocytes on the growth factor concentrations. The aim of the present study was to compare the biological characteristics of PRPs focusing on the leukocyte concentration and composition. METHODS: Leucocyte rich (LR)-PRP, leucocyte poor (LP)-PRP, and pure-PRP were prepared from the peripheral blood of 6 healthy male volunteers (mean age: 31.3 years). The concentrations of platelets, leukocytes, erythrocytes, growth factors (transforming growth factor-beta 1: TGF-beta1; fibroblast growth factor-basic: FGF-b; platelet-derived growth factor-BB: PDGF BB; vascular endothelial growth factor: VEGF) and matrix metalloproteinase-9 (MMP 9) from each of the PRP samples were measured. Considering the interaction between platelets and leukocytes, correlations between platelets/leukocytes and growth factors/MMP-9 were analyzed using partial correlation coefficients. RESULTS: The platelet concentration did not differ among the three PRP preparation methods. Conversely, the leukocyte concentration was dramatically different: 14.9 +/- 4.5 (10(3)/MUl) in LR-PRP, 2.4 +/- 1.3 (10(3)/MUl) in LP-PRP, 0.2 +/- 0.2 (10(3)/MUl) in pure-PRP. The platelet concentration positively correlated with all growth factors. On the other hand, the leukocyte concentration positively correlated with PDGF-BB and the VEGF concentration, while it negatively correlated with FGF-b. Regarding catabolic factors, the MMP-9 concentration strongly correlated with the leukocyte concentration, while there was no correlation between the platelet and MMP-9 concentrations. CONCLUSIONS: These findings demonstrate that leukocytes strongly influence the quality of PRPs. Therefore, modifying the PRP preparation method according to the pathology is essential to achieve better clinical results with PRP therapy. PMID- 27503186 TI - Paraarticular osteochondroma of a lumbar facet joint presenting with radiculopathy. PMID- 27503187 TI - Evaluation of three-dimensional scapular kinematics and shoulder function in patients with short malunion of clavicle fractures. AB - BACKGROUND: The presence of short malunion of clavicle fractures could result in alterations in static scapular position and dynamic scapular motion. Nevertheless, no report has ever addressed the kinematic changes of the scapula in patients with short malunion of clavicular fractures. The goal of this study was to compare the changes of shoulder function, and the consequent scapular kinematic changes between the fractured side and the sound side of the shoulder in non-surgically treated patients. METHODS: Fourteen patients with a short malunion (>10 mm) of midshaft clavicular fracture following conservative treatment were recruited. Outcome analysis included standard clinical follow-up, plain radiography, Shoulder Pain and Disability Index (SPADI) score, shoulder range of motion (ROM), shoulder muscle strength and scapular resting position. The 3-dimensional scapular motion during arm movement in the scapular plane was recorded using an electromagnetic tracking device. The kinematic changes between the fractured side and sound side were analyzed. RESULTS: The mean shortening length of the clavicle was 12.9 +/- 2.8 mm. The fractured sides showed a significantly higher SPADI score and limited ROM in both shoulder flexion and abduction. Significantly weaker shoulder external rotators (1.1 kg, p = 0.017) and lower trapezius (0.7 kg, p = 0.041) were found in the fractured sides when compared with the sound side. The fractured side exhibited significantly more forward shoulder (3.9 mm, p = 0.034) and slightly more anteriorly tilted scapula (5.8 degrees , p = 0.094) in static scapular position. Scapular kinematics showed that the fractured side trended toward greater scapular internal rotation and smaller posterior tilt during arm elevation and lowering phases, especially after the arm rising above horizontal level. CONCLUSIONS: This study showed that significant changes in scapular kinematics and shoulder function were found after short malunion of clavicle fractures. Recognition and evaluation of the changes could lead to a comprehensive framework regarding the treatment of shortened clavicle fractures. PMID- 27503188 TI - Chemically-doped graphene with improved surface plasmon characteristics: an optical near-field study. AB - One of the most fascinating and important merits of graphene plasmonics is their tunability over a wide range. While chemical doping has proven to be a facile and effective way to create graphene plasmons, most of the previous studies focused on the macroscopic behaviors of the plasmons in chemically-doped graphene and little was known about their nanoscale responses and related mechanisms. Here, to the best of our knowledge, we present the first experimental near-field optical study on chemically-doped graphene with improved surface plasmon characteristics. By using a scattering-type scanning near-field optical microscope (s-SNOM), we managed to show that the graphene plasmons can be tuned and improved using a facile chemical doping method. Specifically, the plasmon interference patterns near the edge of the monolayer graphene were substantially enhanced via nitric acid (HNO3) exposure. The plasmon-related characteristics can be deduced by analyzing such plasmonic fringes, which exhibited a longer plasmon wavelength and reduced plasmon damping rate. In addition, the local carrier density and therefore the Fermi energy level (EF) of graphene can be obtained from the plasmonic nano-imaging, which indicated that the enhanced plasmon oscillation originated from the injection of free holes into graphene by HNO3. These findings were further corroborated by theoretical calculations using density functional theory (DFT). We believe that our findings provide a clear nanoscale picture on improving graphene plasmonics by chemical doping, which will be helpful for optimizing graphene plasmonics and for elucidating the mechanisms of two dimensional light confinement by atomically thick materials. PMID- 27503189 TI - Richness of ectoparasitic flies (Diptera: Streblidae) of bats (Chiroptera)-a systematic review and meta-analysis of studies in Brazil. AB - The family Streblidae consists of obligate hematophagous ectoparasites of bats. The richness of Streblidae may be affected by environmental and host-related variables, collection methods, and sampling effort. The purposes of this study were to list the Streblidae species recorded in Brazil, verify their distribution in the Brazilian biomes and states, and pinpoint the parameters that favored the greatest richness. Through queries in online databases and libraries, 86 publications were found containing records of 83 species in 24 genera. The state with the largest number of publications was Sao Paulo and Federal District presented the highest richness of Streblidae. The largest number of records of Streblidae species was in Cerrado biome. The meta-analyses utilizing 26 Brazilian inventories showed that the richness of Streblidae was positively correlated with the number of flies and richness and abundance of Phyllostomidae. We hope that the results of this study will contribute to a better understanding of the distribution of research on Streblidae in Brazil and confirming the specificity between Streblidae and Phyllostomidae. PMID- 27503190 TI - A Survey of Graduates of Combined Emergency Medicine-Pediatrics Residency Programs: An Update. AB - BACKGROUND: In 1998, emergency medicine-pediatrics (EM-PEDS) graduates were no longer eligible for the pediatric emergency medicine (PEM) sub-board certification examination. There is a paucity of guidance regarding the various training options for medical students who are interested in PEM. OBJECTIVES: We sought to to determine attitudes and personal satisfaction of graduates from EM PEDS combined training programs. METHODS: We surveyed 71 graduates from three EM PEDS residences in the United States. RESULTS: All respondents consider their combined training to be an asset when seeking a job, 92% find it to be an asset to their career, and 88% think it provided added flexibility to job searches. The most commonly reported shortcoming was their ineligibility for the PEM sub-board certification. The lack of this designation was perceived to be a detriment to securing academic positions in dedicated children's hospitals. When surveyed regarding which training offers the better skill set for the practice of PEM, 90% (44/49) stated combined EM-PEDS training. When asked which training track gives them the better professional advancement in PEM, 52% (23/44) chose combined EM PEDS residency, 27% (12/44) chose a pediatrics residency followed by a PEM fellowship, and 25% (11/44) chose an EM residency then a PEM fellowship. No EM PEDS respondents considered PEM fellowship training after the completion of the dual training program. CONCLUSION: EM-PEDS graduates found combined training to be an asset in their career. They felt that it provided flexibility in job searches, and that it was ideal training for the skill set required for the practice of PEM. EM-PEDS graduates' practices varied, including mixed settings, free-standing children's hospitals, and community emergency departments. PMID- 27503192 TI - Design, syntheses, characterization, and cytotoxicity studies of novel heterobinuclear oxindolimine copper(II)-platinum(II) complexes. AB - Herein, the design and syntheses of two new mononuclear oxindolimine-copper(II) (1 and 2) and corresponding heterobinuclear oxindolimine Cu(II)Pt(II) complexes (3 and 4), are described. All the isolated complexes were characterized by spectroscopic techniques (UV/Vis, IR, EPR), in addition to elemental analysis and mass spectrometry. Cyclic voltammetry (CV) measurements showed that in all cases, one-electron quasi-reversible waves were observed, and ascribed to the formation of corresponding copper(I) complexes. Additionally, waves related to oxindolimine ligand reduction was verified, and confirmed using analogous oxindolimine-Zn(II) complexes. The Pt(IV/II) reduction, and corresponding oxidation, for complexes 3 and 4 occurred at very close values to those observed for cisplatin. By complementary fluorescence studies, it was shown that glutathione (GSH) cannot reduce any of these complexes, under the experimental conditions (room temperature, phosphate buffer 50mM, pH7.4), using an excess of 20-fold [GSH]. All these complexes showed characteristic EPR spectral profile, with parameters values g||>g? suggesting an axially distorted environment around the copper(II) center. Interactions with calf thymus-DNA, monitored by circular dichroism (CD), indicated different effects modulated by the ligands. Finally, the cytotoxicity of each complex was tested toward different tumor cells, in comparison to cisplatin, and low values of IC50 in the range 0.6 to 4.0MUM were obtained, after 24 or 48h incubation at 37 degrees C. The obtained results indicate that such complexes can be promising alternative antitumor agents. PMID- 27503191 TI - Identifying common barriers and facilitators to linkage and retention in chronic disease care in western Kenya. AB - BACKGROUND: Sub-Saharan Africa is increasingly being challenged in providing care and treatment for chronic diseases, both communicable and non-communicable. In order to address the challenges of linkage to and retention in chronic disease management, there is the need to understand the factors that can influence engagement in care. We conducted a qualitative study to identify barriers and facilitators to linkage and retention in chronic care for HIV, tuberculosis (TB) and Hypertension (HTN) as part of the Academic Model Providing Access to Healthcare (AMPATH) program in western Kenya. METHODS: In-depth interviews and focus group discussions were conducted July 2012-August 2013. Study participants were purposively sampled from three AMPATH clinics and included patients within the AMPATH program receiving HIV, TB, and HTN care, as well as caregivers of children with HIV, community leaders, and healthcare providers. A set of interview guides were developed to explore perceived barriers and facilitators to chronic disease management, particularly related to linkage to and retention in HIV, TB and HTN care. Data were coded and various themes were identified. We organized the concepts and themes generated using the Andersen-Newman Framework of Health Services Utilization. RESULTS: A total of 235 participants including 110 individuals living with HIV (n = 50), TB (n = 39), or HTN (n = 21); 24 caregivers; 10 community leaders; and 62 healthcare providers participated. Barriers and facilitators were categorized as predisposing characteristics, enabling resources and need factors. Many of the facilitators and barriers reported in this study were consistently reported across disease categories including personal drive, patient-provider relationships and the need for social and peer support. CONCLUSIONS: Our findings provide insight into the individual as well as broader structural factors that can deter or encourage linkage and retention that are relevant across communicable and non-communicable chronic diseases. The findings of the present study suggest that interventions should consider the logistical aspects of accessing care in addition to predisposing and need factors that may affect an individuals' decision to seek out and remain in appropriate care. PMID- 27503193 TI - Prognostic impact of tumour burden assessed by metabolic tumour volume on FDG PET/CT in anal canal cancer. AB - PURPOSE: The aim of this study was to confirm the prognostic value of metabolic tumour volume (MTV) at the primary site on initial work-up FDG PET/CT in patients with squamous cell carcinoma (SCC) of the anal canal. METHODS: Patients with a recent diagnosis of SCC of the anal canal without metastases undergoing PET/CT for initial work-up and treated with (chemo)radiotherapy were retrospectively reviewed. Computer-aided MTV and SUVmax were determined. Survival rates were estimated using the Kaplan-Meier method. Cox regression analysis was used to evaluate prognostic variables of progression-free survival and overall survival (OS). RESULTS: The study group comprised 75 patients who had an initial work-up PET/CT. Five patients (6.7 %) had stage I disease, 22 (29.3 %) stage II disease, 20 (26.7 %) stage IIIA disease, and 28 (37.3 %) stage IIIB disease. Median follow up was 51 months (range 10 - 117 months). Global 4-year OS was 82.7 %, ranging from 100 % in patients with stage I disease to 75 % in patients with stage IIIB disease. MTV at the primary site was significantly and independently correlated with OS (p < 0.05), as patients with MTV less than 7 cm3 had a better prognosis. SUVmax was not correlated with survival parameters. Metabolic involvement of the inguinal lymph nodes was also correlated with a poor outcome in the univariate analysis (p < 0.05). CONCLUSION: MTV at the primary site is a prognostic biomarker in anal canal cancer. Hypermetabolic inguinal lymph nodes also appear to be correlated with survival. PMID- 27503194 TI - Researchers' choice of the number and range of levels in experiments affects the resultant variance-accounted-for effect size. AB - In psychology, the reporting of variance-accounted-for effect size indices has been recommended and widely accepted through the movement away from null hypothesis significance testing. However, most researchers have paid insufficient attention to the fact that effect sizes depend on the choice of the number of levels and their ranges in experiments. Moreover, the functional form of how and how much this choice affects the resultant effect size has not thus far been studied. We show that the relationship between the population effect size and number and range of levels is given as an explicit function under reasonable assumptions. Counterintuitively, it is found that researchers may affect the resultant effect size to be either double or half simply by suitably choosing the number of levels and their ranges. Through a simulation study, we confirm that this relation also applies to sample effect size indices in much the same way. Therefore, the variance-accounted-for effect size would be substantially affected by the basic research design such as the number of levels. Simple cross-study comparisons and a meta-analysis of variance-accounted-for effect sizes would generally be irrational unless differences in research designs are explicitly considered. PMID- 27503195 TI - Abstract-concept learning in Black-billed magpies (Pica hudsonia). AB - relational concepts depend upon relationships between stimuli (e.g., same vs. different) and transcend features of the training stimuli. Recent evidence shows that learning abstract concepts is shared across a variety species including birds. Our recent work with a highly-skilled food-storing bird, Clark's nutcracker, revealed superior same/different abstract-concept learning compared to rhesus monkeys, capuchin monkeys, and pigeons. Here we test a more social, but less reliant on food-storing, corvid species, the Black-billed magpie (Pica hudsonia). We used the same procedures and training exemplars (eight pairs of the same rule, and 56 pairs of the different rule) as were used to test the other species. Magpies (n = 10) showed a level of abstract-concept learning that was equivalent to nutcrackers and greater than the primates and pigeons tested with these same exemplars. These findings suggest that superior initial abstract concept learning abilities may be shared across corvids generally, rather than confined to those strongly reliant on spatial memory. PMID- 27503196 TI - Removing Cardiac Artefacts in Magnetoencephalography with Resampled Moving Average Subtraction. AB - Magnetoencephalography (MEG) signals are commonly contaminated by cardiac artefacts (CAs). Principle component analysis and independent component analysis have been widely used for removing CAs, but they typically require a complex procedure for the identification of CA-related components. We propose a simple and efficient method, resampled moving average subtraction (RMAS), to remove CAs from MEG data. Based on an electrocardiogram (ECG) channel, a template for each cardiac cycle was estimated by a weighted average of epochs of MEG data over consecutive cardiac cycles, combined with a resampling technique for accurate alignment of the time waveforms. The template was subtracted from the corresponding epoch of the MEG data. The resampling reduced distortions due to asynchrony between the cardiac cycle and the MEG sampling times. The RMAS method successfully suppressed CAs while preserving both event-related responses and high-frequency (>45 Hz) components in the MEG data. PMID- 27503197 TI - [Health as a commodity : The deprofessionalization of physicians]. AB - The German health care delivery system is increasingly drawn into the framework and profit expectations of an industrial economic system. This development is one of the consequences of global political and economic restructuring, and can hardly be influenced by national health policy. Physicians are marginalized. Their professional work is reduced to certain core activities, often directed by commercial interests. PMID- 27503198 TI - Survival of Del17p CLL Depends on Genomic Complexity and Somatic Mutation. AB - PURPOSE: Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL. EXPERIMENTAL DESIGN: We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLLs as well as wild-type CLL and analyzed the genetic basis of their clinical heterogeneity. RESULTS: We found that increased somatic mutation number associates with poor overall survival independent of 17p deletion (P = 0.003). TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del(17p) exhibit shorter overall survival than subclonal mutations with del(17p) (P = 0.019). Del(17p) CLL has a unique driver mutation profile, including NOTCH1 (15%), RPS15 (12%), DDX3X (8%), and GPS2 (6%). We found that about half of del(17p) CLL cases have recurrent deletions at 3p, 4p, or 9p and that any of these deletions significantly predicts shorter overall survival. In addition, the number of CNAs, but not somatic mutations, predicts shorter time to treatment among patients untreated at sampling. Indolent del(17p) CLLs were characterized by absent or subclonal TP53 mutation and few CNAs, with no difference in somatic mutation number. CONCLUSIONS: We conclude that del(17p) has a unique genomic profile and that clonal TP53 mutations, 3p, 4p, or 9p deletions, and genomic complexity are associated with shorter overall survival. Clin Cancer Res; 23(3); 735-45. (c)2016 AACR. PMID- 27503199 TI - Genetic and Methylation-Induced Loss of miR-181a2/181b2 within chr9q33.3 Facilitates Tumor Growth of Cervical Cancer through the PIK3R3/Akt/FoxO Signaling Pathway. AB - PURPOSE: Loss of Chr9q31-33 is one of the most common chromosome imbalances of cervical cancer, but the underlying mechanism has not been well documented. EXPERIMENTAL DESIGN: The loss of heterozygosity (LOH) status of Chr9q31-33 was investigated utilizing 26 microsatellite markers. We detected the expression of miR-181a2/181b2 by qRT-PCR analysis of cervical cancer cell lines and 100 paired tumor samples and corresponding adjacent non-tumor tissues. Kaplan-Meier and Cox proportional hazard regression analyses were performed to identify the prognostic value of miR-181a2/181b2. Regulation of expression was analyzed by methylation specific PCR. The tumor-suppressing effects of miR-181a2/181b2 were determined in vitro and in vivo The target gene and signaling pathway that mediated the function of miR-181a2/181b2 were also identified. RESULTS: Chr9q33.3 was identified as one of the most deleted regions in cervical cancer. Underexpression of miR-181a2/181b2 was detected in 46% of cervical cancer and was induced by the LOH of chr9q33.3 and promoter hypermethylation. Attenuated miR-181a2/181b2 expression predicted a poor prognostic phenotype and advanced clinical stage of cervical cancer. miR-181a2/181b2 prominently dampened cell-cycle progression, suppressed cell growth, and promoted apoptosis of tumor cells in vitro They also effectively impeded tumor formation and growth in vivo miR-181a2/181b2 exert the tumor suppressor ability by depressing the direct target PIK3R3 (p55gamma) and consequently modulating the PIK3R3/Akt/FoxO signaling pathway. CONCLUSIONS: We demonstrated a cause-and-effect event beginning from loss of chr9q33.3, a frequent event in cervical cancer, to the underexpression of miR-181a2/181b2, leading to the elevated activation of the PI3K pathway. Clin Cancer Res; 23(2); 575-86. (c)2016 AACR. PMID- 27503201 TI - e-Corrigendum. PMID- 27503202 TI - Galagos as avian nest predators in South Africa. AB - Galagos are generally regarded as dietary specialists that feed predominantly on insects and gum. The diet of the thick-tailed greater galago is more varied and also includes fruit and small vertebrates, although the latter is rare and restricted to certain populations. The southern lesser galago is seemingly a more specialist forager, but frugivory was recently reported in two separate populations, suggesting at least some dietary plasticity in this species. The species is not known to consume vertebrates. Here I report on observations of avian nest predation by both thick-tailed greater and southern lesser galagos in Roodewal State Forest Reserve in South Africa. Galagos were responsible for 56 % of nest losses captured on trail cameras. Both species consumed eggs and nestlings of six species of passerines ranging in size from recently hatched to ~30 g nestlings almost ready to fledge. The consumption of vertebrates by the southern lesser galago represents an extension of its diet, as this has not been reported before. The results suggest that eggs and nestlings comprise part of the regular diet of thick-tailed greater galagos in the study area, albeit only seasonal. The consumption of vertebrate prey by southern lesser galagos may represent the expression of latent behavior which is only expressed under certain environmental conditions, e.g., a severe drought, when its regular food base may be diminished. PMID- 27503200 TI - A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia. AB - PURPOSE: In preclinical studies, the PARP inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies. EXPERIMENTAL DESIGN: Patients received veliparib [20-200 mg once a day on day 1 and twice daily on days 4-12 in cycle 1 (days 1-8 in cycle >=2)] and temozolomide [150-200 mg/m2 daily on days 3-9 in cycle 1 (days 1-5 in cycle >=2)] every 28 to 56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter, and integrity of the Fanconi anemia pathway were also examined. RESULTS: Forty eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting >7 days. The MTD was veliparib 150 mg twice daily with temozolomide 200 mg/m2 daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34+ cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR. CONCLUSIONS: Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted. Clin Cancer Res; 23(3); 697-706. (c)2016 AACR. PMID- 27503205 TI - Correlation between the serum levels of type IV collagen 7s domain and the risk of intractable ascites following liver resection for hepatocellular carcinoma: A propensity score-matched analysis. AB - BACKGROUND: The severity of liver fibrosis has been reported to be correlated with the risk of intractable ascites after hepatectomy for hepatocellular carcinoma. Since 2009, we have measured routinely the serum concentrations of type IV collagen 7s domain (7s collagen), a biochemical marker of liver fibrosis and applied limited resection to patients with elevation of the serum 7s collagen concentrations above the upper limit of normal (6.0 ng/mL). The aim of this study was to assess the potential benefits of our treatment strategy on the postoperative outcomes of patients with hepatocellular carcinoma. METHODS: A propensity score-matched analysis was performed to compare the outcomes between patients who underwent initial hepatectomy for hepatocellular carcinoma before or after 2009 (2009 to April 2015; period 2) and those who underwent the operation prior to 2009 (1990-2008; period 1; n = 129 in each period). RESULTS: The incidence of intractable ascites was significantly lower in period 2 than in period 1 (2.3 vs 14.7%; P < .001), although the other short-term and long-term outcomes were comparable between the 2 groups. A multivariate analysis identified elevation of the serum 7s collagen concentrations to >=7.4 ng/mL as an independent predictor of IA (odds ratio 14.1, 95% confidence interval 2.8 to 106.7; P = .001), with the area under the receiver-operating characteristic curve of 0.820 (0.648-0.919, P = .005). CONCLUSION: Modification of the surgical procedure according to the serum 7s collagen concentration is beneficial for reducing the risk of development of intractable ascites after hepatectomy for hepatocellular carcinoma. PMID- 27503203 TI - Zebrafish models of cardiovascular disease. AB - Cardiovascular disease (CVD) is one of the leading causes of death worldwide. The most significant risk factors associated with the development of heart diseases include genetic and environmental factors such as hypertension, high blood cholesterol levels, diabetes, smoking, and obesity. Coronary artery disease accounts for the highest percentage of CVD deaths and stroke, cardiomyopathies, congenital heart diseases, heart valve defects and arrhythmias follow. The causes, prevention, and treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies published on a weekly basis. Generating animal models of cardiovascular diseases is the main approach used to understand the mechanism of pathogenesis and also design and test novel therapies. Here, we will focus on recent advances to finding the genetic cause and the molecular mechanisms of CVDs as well as novel drugs to treat them, using a small tropical freshwater fish native to Southeast Asia: the zebrafish (Danio rerio). Zebrafish emerged as a high-throughput but low cost model organism that combines the advantages of forward and reverse genetics with phenotype-driven drug screenings. Noninvasive imaging allows in vivo analyses of cardiovascular phenotypes. Functional verification of candidate genes from genome-wide association studies has verified the role of several genes in the pathophysiology of CVDs. Also, zebrafish hearts maintain their ability to regenerate throughout their lifetime, providing novel insights to understand human cardiac regeneration. PMID- 27503204 TI - Therapeutic Potential of Secreted Molecules Derived from Human Amniotic Fluid Mesenchymal Stem/Stroma Cells in a Mice Model of Colitis. AB - Inflammatory bowel diseases (IBDs) are the result of pathological immune responses due to environmental factors or microbial antigens into a genetically predisposed individual. Mainly due to their trophic properties, a mounting interest is focused on the use of human mesenchymal stem/stromal cells (hMSCs) to treat IBD disease in animal models. The aim of the study is to test whether the secreted molecules, derived from a specific population of second trimester amniotic fluid mesenchymal stem/stromal cells, the spindle-shaped MSCs (SS-AF MSCs), could be utilized as a novel therapeutic, cell free approach for IBD therapy. Induction of colitis was achieved by oral administration of dextran sulphate sodium (DSS) (3 % w/v in tap water), for 5 days, to 8-week-old NOD/SCID mice. The progression of colitis was assessed on a daily basis through recording the body weight, stool consistency and bleeding. Conditioned media (CM) derived from SS-AF-MSCs were collected, concentrated and then delivered intraperitoneally into DSS treated mice. To evaluate and determine the inflammatory cytokine levels, histopathological approach was applied. Administration of CM derived from SS-AF-MSCs cells reduced the severity of colitis in mice. More importantly, TGFb1 protein levels were increased in the mice received CM, while TNFa and MMP2 protein levels were decreased, respectively. Accordingly, IL-10 was significantly increased in mice received CM, whereas TNFa and IL-1b were decreased at mRNA level. Our results demonstrated that CM derived from SS-AF-MSCs cells is able to ameliorate DSS-induced colitis in immunodeficient colitis mouse model, and thus, it has a potential for use in IBD therapy. PMID- 27503206 TI - An Online Learning Module to Increase Self-Efficacy and Involvement in Care for Patients With Advanced Lung Cancer: Research Protocol. AB - BACKGROUND: Improving patient care for individuals with lung cancer is a priority due to the increasing burden of the disease globally. One way this can be done is by improving patient self-management capabilities through increasing their self efficacy. This can improve positive outcomes for patients with chronic conditions and increase their ability to manage the challenges of such illnesses. Unfortunately, patients with chronic conditions often struggle to travel far from home to engage with patient education events, a common means of improving self efficacy. The development of more accessible tools for improving patient self efficacy is required to increase quality of life for patients with chronic conditions. OBJECTIVE: To evaluate the feasibility of delivering symptom identification and management information to patients with advanced lung cancer using an online program. METHODS: This article describes a pre-post test study to evaluate a Qstream online learning platform to improve patient self-efficacy for managing advanced lung cancer symptoms. Undertaking this program should increase participant knowledge about the side-effects they may experience as a result of their treatment and in turn increase help-seeking behavior and self-efficacy for the participant cohort. Quantitative data collected by the Qstream platform on the completion rates of participants will be used as a tool to evaluate the intervention. Additionally, validated scales will be used to collect data on patient self-efficacy. Qualitative data will also be collected via an exit survey and thematic content analysis of semi-structured interviews. RESULTS: The research is in the preliminary stages but thus far a protocol has been approved in support of the project. Additionally, advisory committee members have been identified and initial meetings have been undertaken. CONCLUSIONS: Development of new approaches for increasing patient understanding of their care is important to ensure high quality care continues to be delivered in the clinical setting. PMID- 27503207 TI - Single or dual experimental infections with Vibrio aestuarianus and OsHV-1 in diploid and triploid Crassostrea gigas at the spat, juvenile and adult stages. AB - French production of the Pacific cupped oyster, Crassostrea gigas, is currently threatened by two pathogens, OsHV-1 and V. aestuarianus. While oysters selected for their higher resistance to OsHV-1 are now available for the industry, the impact of V. aestuarianus on such oysters is unknown, especially for triploids. In addition, experimental infection has used the virus or the bacteria alone, but there have been no investigations of dual exposure to these pathogens. This study is the first report of single or dual exposure in spat (Spat1 and Spat2), juvenile and adult naive oysters. For each of the two stocks evaluated, unselected oysters and oysters selected for their higher resistance to OsHV-1 infection were tested, as well as their triploid siblings of the selected oysters produced using cytochalasin B. We confirmed that resistance to OsHV-1 infection and susceptibility to V. aestuarianus increased with age and size, although selected oysters were not significantly impacted by OsHV-1 whatever their ploidy, size or age. We found different mortality patterns depending on the pathogen tested. The mortality pattern was similar for oysters exposed to OsHV-1 or to both pathogens in the Spat1 trial (4months old and 1.9g). The mortality pattern was similar for oysters exposed to V. aestuarianus or to both pathogens in the Adult trial (25months old and 63.1g). Surprisingly, mortality was much higher (ranging from 75.9% to 100%), in particular for the selected oysters, for the Spat2 (8months old/3.9g) and Juvenile trials (16months old/18.4g) given a dual exposure, regardless of the level of selection for OsHV-1 and the ploidy state. Our findings highlight an important threat for oyster farmers: oysters exposed to both pathogens could experience dramatic mortality rates, even in oysters selected for their higher resistance to OsHV-1. Finally, our study demonstrated for the first time that triploid oysters were more susceptible to experimental challenges with V. aestuarianus at the spat stage than their diploid siblings. However, the difference in mortality between the triploids and diploids remained limited and ranged from 22.9% to 6.6% for spat and adults, respectively with a relatively regularly decrease in the difference with increased age. PMID- 27503208 TI - Immunotherapy Expands and Maintains the Function of High-Affinity Tumor Infiltrating CD8 T Cells In Situ. AB - Cancer cells harbor high-affinity tumor-associated Ags capable of eliciting potent antitumor T cell responses, yet detecting these polyclonal T cells is challenging. Therefore, surrogate markers of T cell activation such as CD69, CD44, and programmed death-1 (PD-1) have been used. We report in this study that in mice, expression of activation markers including PD-1 is insufficient in the tumor microenvironment to identify tumor Ag-specific T cells. Using the Nur77GFP T cell affinity reporter mouse, we highlight that PD-1 expression can be induced independent of TCR ligation within the tumor. Given this, we characterized the utility of the Nur77GFP model system in elucidating mechanisms of action of immunotherapies independent of PD-1 expression. Coexpression of Nur77GFP and OX40 identifies a polyclonal population of high-affinity tumor-associated Ag-specific CD8(+) T cells, which produce more IFN-gamma in situ than OX40 negative and doubles in quantity with anti-OX40 and anti-CTLA4 mAb therapy but not with anti PD-1 or programmed death ligand-1. Moreover, expansion of these high-affinity CD8 T cells prolongs survival of tumor-bearing animals. Upon chronic stimulation in tumors and after adoptive cell therapy, CD8 TCR signaling and Nur77GFP induction is impaired, and tumors progress. However, this can be reversed and overall survival significantly enhanced after adoptive cell therapy with agonist OX40 immunotherapy. Therefore, we propose that OX40 agonist immunotherapy can maintain functional TCR signaling of chronically stimulated tumor-resident CD8 T cells, thereby increasing the frequency of cytotoxic, high-affinity, tumor-associated Ag specific cells. PMID- 27503210 TI - lck-Driven Cre Expression Alters T Cell Development in the Thymus and the Frequencies and Functions of Peripheral T Cell Subsets. AB - Conditional gene targeting using the bacteriophage-derived Cre recombinase is widely applied for functional gene studies in mice. Mice transgenic for Cre under the control of the lck gene promoter are used to study the role of loxP-targeted genes in T cell development and function. In this article, we show a striking 65% reduction in cellularity, preferential development of gammadelta versus alphabeta T cells, and increased expression of IL-7R in the thymus of mice expressing Cre under the proximal lck promoter (lck-cre(+) mice). The transition from CD4/CD8 double-negative to double-positive cells was blocked, and lck-cre(+) double positive cells were more prone to apoptosis and showed higher levels of Cre expression. Importantly, numbers of naive T cells were reduced in spleens and lymph nodes of lck-cre(+) mice. In contrast, frequencies of gammadelta T cells, CD44(+)CD62L(-) effector T cells, and Foxp3(+) regulatory T cells were elevated, as was the frequency of IFN-gamma-secreting CD4(+) and CD8(+) T cells. A literature survey of 332 articles that used lck-cre(+) mice for deletion of floxed genes indicated that results are statistically influenced by the control used (lck-cre(+) or lck-cre(-)), more frequently resembling the lck-cre(+) phenotype described in this article if lck-cre(-) controls were used. Altogether, care should be taken when interpreting published results and to properly control targeted gene deletions using the lck-cre(+) strain. PMID- 27503209 TI - TLR2 Activation Limits Rhinovirus-Stimulated CXCL-10 by Attenuating IRAK-1 Dependent IL-33 Receptor Signaling in Human Bronchial Epithelial Cells. AB - Airway epithelial cells are the major target for rhinovirus (RV) infection and express proinflammatory chemokines and antiviral cytokines that play a role in innate immunity. Previously, we demonstrated that RV interaction with TLR2 causes ILR-associated kinase-1 (IRAK-1) depletion in both airway epithelial cells and macrophages. Further, IRAK-1 degradation caused by TLR2 activation was shown to inhibit ssRNA-induced IFN expression in dendritic cells. Therefore, in this study, we examined the role of TLR2 and IRAK-1 in RV-induced IFN-beta, IFN lambda1, and CXCL-10, which require signaling by viral RNA. In airway epithelial cells, blocking TLR2 enhanced RV-induced expression of IFNs and CXCL-10. By contrast, IRAK-1 inhibition abrogated RV-induced expression of CXCL-10, but not IFNs in these cells. Neutralization of IL-33 or its receptor, ST2, which requires IRAK-1 for signaling, inhibited RV-stimulated CXCL-10 expression. In addition, RV induced expression of both ST2 and IL-33 in airway epithelial cells. In macrophages, however, RV-stimulated CXCL-10 expression was primarily dependent on TLR2/IL-1R. Interestingly, in a mouse model of RV infection, blocking ST2 not only attenuated RV-induced CXCL-10, but also lung inflammation. Finally, influenza- and respiratory syncytial virus-induced CXCL-10 was also found to be partially dependent on IL-33/ST2/IRAK-1 signaling in airway epithelial cells. Together, our results indicate that RV stimulates CXCL-10 expression via the IL 33/ST2 signaling axis, and that TLR2 signaling limits RV-induced CXCL-10 via IRAK 1 depletion at least in airway epithelial cells. To our knowledge, this is the first report to demonstrate the role of respiratory virus-induced IL-33 in the induction of CXCL-10 in airway epithelial cells. PMID- 27503211 TI - TLR Tolerance as a Treatment for Central Nervous System Autoimmunity. AB - The role of TLR signaling in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is unclear. This role is especially controversial in models of adoptive transfer EAE in which no adjuvant and no TLR ligands are administered. We recently reported that a microbiome-derived TLR2 ligand, Lipid 654 (L654), is present in healthy human serum but significantly decreased in the serum of MS patients. This suggested that microbiome products that gain access to the systemic circulation, rather than being proinflammatory, may normally play an immune-regulatory role by maintaining a state of relative TLR tolerance. Therefore, a loss of microbiome-mediated TLR tolerance, as suggested by lower serum levels of L654, may play a role in the pathogenesis of MS. As proof of concept we asked whether administering low-level TLR2 ligands in adoptive transfer EAE induces TLR2 tolerance and attenuates disease. We administered low level Pam2CSK4 or L654 to mice receiving encephalitogenic cells and in doing so induced both TLR2 tolerance and attenuation of EAE. Disease attenuation was accompanied in the CNS by a decrease in macrophage activation, a decrease in a specific proinflammatory macrophage population, and a decrease in Th17 cells. In addition, disease attenuation was associated with an increase in splenic type 1 regulatory T cells. Kinetic tolerance induction studies revealed a critical period for TLR2 involvement in adoptive transfer EAE. Overall, these results suggest that inducing TLR tolerance may offer a new approach to treating CNS autoimmune diseases such as MS. PMID- 27503212 TI - The Effect of Bariatric Surgery on Mobility, Health-Related Quality of Life, Healthcare Resource Utilization, and Employment Status. AB - BACKGROUND: A sub-study of the Ontario Bariatric Registry was conducted to evaluate the impact of bariatric surgery on mobility, health-related quality of life (HRQoL), healthcare resource utilization (HRU), and employment status. METHODS: The 1-year change in mobility following bariatric surgery was evaluated using the mobility domain of the EuroQOL-5D-5L (EQ-5D-5L), which was self administered at baseline and 1 year after bariatric surgery along with questions on HRU. Another questionnaire was used to document employment status at time of surgery and 1 year later. RESULTS: The population included 304 individuals (mean age = 46 years; 85 % female). At baseline, 68 % of participants had some problems in walking compared to 14 % at 1 year following surgery (p < 0.001). The EQ-5D-5L health utility score increased from 0.73 to 0.90 (p < 0.001). The number of hospitalizations increased significantly before and after surgery (p = 0.021). Of the 304 study participants, 138 completed the questionnaire and responses indicated that more individuals reported a change in their employment status within 1 year following surgery (26 %) compared to 1 year prior to the surgery (9 %) (p < 0.001). CONCLUSIONS: Within the limitations of this study, there is a suggestion that bariatric surgery has a major impact on mobility and HRQoL. More research is warranted to understand the benefits, costs, and cost-effectiveness of bariatric surgery in Canada. PMID- 27503213 TI - Internal Cardioverter Defibrillator Indications and Therapies after Atrial Baffle Procedure for d-Transposition of the Great Arteries: A Multicenter Analysis. AB - BACKGROUND: Sudden cardiac death (SCD) is the most important cause of late mortality after atrial baffle procedure for d-transposition of the great arteries (d-TGA). Experience with internal cardioverter defibrillator (ICD) therapy in this population is limited. We conducted a multicenter cohort study to determine the current state of ICD therapy in individuals after atrial baffle procedure. METHODS: Demographic and clinical data as well as data on device implantation, programming, ICD discharges, and complications after atrial baffle procedure for d-TGA from four German centers were analyzed retrospectively. RESULTS: ICD implantation was undertaken in 33 subjects. ICD implantation was undertaken as primary prevention in 29 (88%) and secondary prevention in four (12%) individuals. There were 21 (64%) subjects with atrial reentrant tachycardia (IART). During a median follow-up of 4.8 years, seven appropriate ICD therapies were delivered in three (10%) individuals with primary prevention indication. No appropriate shocks were documented in subjects with secondary prevention indication. A total of 12 inappropriate ICD discharges occurred in eight (24%) individuals due to IART (n = 6) or lead failure (n = 2). ICD-related complications were noted in seven individuals (21%): lead dislodgement/failure in five (15%) and ICD infection in two subjects (6%). CONCLUSIONS: The majority of individuals received an ICD for primary prevention of SCD, thus representing a liberal attitude of physicians for ICD implantation. During a median follow-up of 4.8 years, the rate of appropriate ICD therapies was low and clearly exceeded by inappropriate ICD discharges. Lead failure and IART were present in >20% of the individuals and were frequent reasons for inappropriate ICD discharges. Facing these results, rigorous treatment of IART and careful ICD programming seems mandatory. PMID- 27503214 TI - Excessive bleeding is a normal cleansing process: a qualitative study of postpartum haemorrhage among rural Uganda women. AB - BACKGROUND: Postpartum haemorrhage (PPH) remains the leading cause of maternal morbidity and mortality worldwide. The main strategy for preventing PPH is the use of uterotonic drugs given prophylactically by skilled health workers. However, in settings where many women still deliver at home without skilled attendants, uterotonics are often inaccessible. In such cases, women and their caregivers need to recognize PPH promptly so, as to seek expert care. For this reason, it is important to understand how women and their caregivers recognize PPH, as well as the actions they undertake to prevent and treat PPH in home births. Such knowledge can also inform programs aiming to make uterotonics accessible at the community level. METHODS: Between April and June 2012, a phenomenological study was carried out in a rural Ugandan district involving 15 in-depth interviews. Respondents were purposively sampled and included six women who had delivered at home in the past year and nine traditional birth attendants (TBAs). The interviews explored how PPH was recognized, its perceived causes, and the practices that respondents used in order to prevent or treat it. Phenomenological descriptive methodology was used to analyse the data. RESULTS: Bleeding after childbirth was considered to be a normal cleansing process, which if stopped or inhibited would lead to negative health consequences to the mother. Respondents used a range of criteria to recognize PPH: rate of blood flow, amount of blood (equivalent to two clenched fists), fainting, feeling thirsty, collapsing or losing consciousness immediately after birth. As a group, respondents seemed to correctly identify women at risk of PPH (those with twin pregnancies, high parity or prolonged labour), but many individuals did not know all the reasons. Respondents used cold drink, uterine massage and traditional medicine to treat PPH. CONCLUSION: The community viewed bleeding after childbirth as a normal process and their methods of determining excessive bleeding are imprecise and varied. This opens the door for intervention for reducing delays in the home diagnosis of PPH. This includes increasing awareness among TBAs, women and their families about the risk of death due to excessive bleeding in the immediate postpartum period. PMID- 27503215 TI - The impact of positive, negative and neutral stimuli in a virtual reality cognitive-motor rehabilitation task: a pilot study with stroke patients. AB - BACKGROUND: Virtual Reality (VR) based methods for stroke rehabilitation have mainly focused on motor rehabilitation, but there is increasing interest in integrating motor and cognitive training to increase similarity to real-world settings. Unfortunately, more research is needed for the definition of which type of content should be used in the design of these tools. One possibility is the use of emotional stimuli, which are known to enhance attentional processes. According to the Socioemotional Selectivity Theory, as people age, the emotional salience arises for positive and neutral, but not for negative stimuli. METHODS: For this study we developed a cognitive-motor VR task involving attention and short-term memory, and we investigated the impact of using emotional images of varying valence. The task consisted of finding a target image, shown for only two seconds, among fourteen neutral distractors, and selecting it through arm movements. After performing the VR task, a recall task took place and the patients had to identify the target images among a valence-matched number of distractors. Ten stroke patients participated in a within-subjects experiment with three conditions based on the valence of the images: positive, negative and neutral. Eye movements were recorded during VR task performance with an eye tracking system. RESULTS: Our results show decreased attention for negative stimuli in the VR task performance when compared to neutral stimuli. The recall task shows significantly more wrongly identified images (false memories) for negative stimuli than for neutral. Regression and correlation analyses with the Montreal Cognitive Assessment and the Geriatric Depression Scale revealed differential effects of cognitive function and depressive symptomatology in the encoding and recall of positive, negative and neutral images. Further, eye movement data shows reduced search patterns for wrongly selected stimuli containing emotional content. CONCLUSIONS: The results of this study suggest that it is feasible to use emotional content in a VR based cognitive-motor task for attention and memory training after stroke. Stroke survivors showed less attention towards negative information, exhibiting reduced visual search patterns and more false memories. We have also shown that the use of emotional stimuli in a VR task can provide additional information regarding patient's mood and cognitive status. PMID- 27503216 TI - Auxin Influx Carrier AUX1 Confers Acid Resistance for Arabidopsis Root Elongation Through the Regulation of Plasma Membrane H+-ATPase. AB - The plant plasma membrane (PM) H+-ATPase regulates pH homeostasis and cell elongation in roots through the formation of an electrochemical H+ gradient across the PM and a decrease in apoplastic pH; however, the detailed signaling for the regulation of PM H+-ATPases remains unclear. Here, we show that an auxin influx carrier, AUXIN RESISTANT1 (AUX1), is required for the maintenance of PM H+ ATPase activity and proper root elongation. We isolated a low pH-hypersensitive 1 (loph1) mutant by a genetic screen of Arabidopsis thaliana on low pH agar plates. The loph1 mutant is a loss-of-function mutant of the AUX1 gene and exhibits a root growth retardation restricted to the low pH condition. The ATP hydrolysis and H+ extrusion activities of the PM H+-ATPase were reduced in loph1 roots. Furthermore, the phosphorylation of the penultimate threonine of the PM H+-ATPase was reduced in loph1 roots under both normal and low pH conditions without reduction of the amount of PM H+-ATPase. Expression of the DR5:GUS reporter gene and auxin-responsive genes suggested that endogenous auxin levels were lower in loph1 roots than in the wild type. The aux1-7 mutant roots also exhibited root growth retardation in the low pH condition like the loph1 roots. These results indicate that AUX1 positively regulates the PM H+-ATPase activity through maintenance of the auxin accumulation in root tips, and this process may serve to maintain root elongation especially under low pH conditions. PMID- 27503217 TI - The Pepper RING-Type E3 Ligase, CaAIP1, Functions as a Positive Regulator of Drought and High Salinity Stress Responses. AB - Plant adaptive responses to osmotic stress are co-ordinated by restriction of growth and developmental processes and by molecular and physiological activities. The phytohormone ABA is the primary regulator that induces and responds to osmotic stress, and its sensitivity markedly influences osmotic stress tolerance levels. Several E3 ubiquitin ligases act as positive or negative regulators of ABA, thereby mediating sensitivity to osmotic stress in higher plants. Here, we report that the C3H2C3-type RING finger E3 ligase, CaAIP1, regulates osmotic stress responses via ABA-mediated signaling. CaAIP1 contains a RING finger motif, which functions during attachment of ubiquitins to the target proteins. Expression of CaAIP1 was induced by ABA, drought and NaCl treatments, suggesting its role in the osmotic stress response. CaAIP1-silenced pepper plants displayed a drought-sensitive phenotype characterized by a high level of transpirational water loss in the drought-treated leaves. CaAIP1-overexpressing (OX) plants exhibited increased sensitivity to ABA, but an NaCl- and mannitol-tolerant phenotype during seed germination and seedling growth. CaAIP1-OX plants further displayed enhanced tolerance to drought stress, characterized by low levels of transpirational water loss via increased stomatal closure and leaf temperature. Our data indicate that CaAIP1 is a positive regulator of the osmotic stress tolerance mechanism. PMID- 27503218 TI - Sperm motility and morphology changes in rats exposed to cadmium and diazinon. AB - BACKGROUND: Humans are ubiquitously exposed to multiple environmental contaminants. Consequences of combined action on the reproductive system remain unknown. This study aimed to assess single and joint effects of cadmium and diazinon exposure on sperm quality parameters. METHODS: Male adult Wistar rats were randomized into 4 groups of ten animals each. Group A was used as a control, animals from group B were exposed to cadmium (30 mg/L), rats from group C were administered with diazinon (40 mg/L), and rats from group D were exposed simultaneously to cadmium (30 mg/L) and diazinon (40 mg/L) via drinking water for 90 days. Sperm morphology and motility were evaluated using a bright field microscope and a computer-assisted semen analysis. RESULTS: The percentage of motile spermatozoa and morphologically normal sperm was markedly reduced in rats from the group B. Rats from the C group showed an increase in velocity parameters, amplitude of lateral head displacement, decrease in beat-cross frequency, and an increase in abnormal sperm morphology. Simultaneous coexposure to cadmium and diazinon increased distance and velocity parameters, and amplitude of lateral head displacement. Reductions were observed in straightness, linearity, wobble, and beat-cross frequency. The decreased normal sperm morphology rates were related to defects of the sperm tail. CONCLUSIONS: Exposure to cadmium and diazinon at relatively low doses impairs sperm quality and can reduce male fertility. Cadmium and diazinon caused significant changes on sperm morphology with varying effects on motility patterns. These parameters were significantly higher in the group D as compared to the group C. The findings have important implications for reproductive risk assessment of combined exposures to multiple chemicals. PMID- 27503220 TI - Leena Peltonen-Palotie: 1952-2010. PMID- 27503219 TI - Chelatococcus reniformis sp. nov., isolated from a glacier. AB - A Gram-stain-negative, non-motile, reniform bacterial strain, B2974T, was isolated from an ice core of the Muztagh Glacier, on the Tibetan Plateau, China. Strain B2974T grew optimally at pH 7.0-7.5 and 25-30 degrees C in the presence of 0-2.0 % (w/v) NaCl. 16S rRNA gene sequence similarity analysis indicated that strain B2974T was closely related to Chelatococcus asaccharovorans LMG 25503T at a level of 97.1 %. The major quinone of strain B2974T was ubiquinone Q10. The predominant fatty acids were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C19 : 0 cyclo omega8c. sym-Homospermidine was the major polyamine. The genomic DNA G+C content of the strain was 64 mol%. In DNA-DNA hybridization tests, strain B2974T shared 49.32 % DNA-DNA relatedness with the type strain of Chelatococcus asaccharovorans LMG 25503T. Based on the results of phenotypic and chemotaxonomic characteristics, strain B2974T was considered as a novel species of the genus Chelatococcus, for which the name Chelatococcus reniformis sp. nov. is proposed. The type strain is B2974T (=JCM 30308T=CGMCC 1.12919T). PMID- 27503222 TI - BiDiFuse: a FIJI plugin for fusing bi-directionally recorded microscopic image volumes. AB - : Deep tissue imaging is increasingly used for non-destructive interrogation of intact organs and small model organisms. An intuitive approach to increase the imaging depth by almost a factor of 2 is to record a sample from two sides and fuse both image stacks. However, imperfect three-dimensional alignment of both stacks presents a computational challenge. We have developed a FIJI plugin, called BiDiFuse, which merges bi-directionally recorded image stacks via 3D rigid transformations. The method is broadly applicable, considering it is compatible with all optical sectioning microscopes and it does not rely on fiducial markers for image registration. AVAILABILITY AND IMPLEMENTATION: The method is freely available as a plugin for FIJI from https://github.com/JanDetrez/BiDiFuse/ CONTACT: winnok.devos@uantwerpen.be. PMID- 27503221 TI - A profile-based method for identifying functional divergence of orthologous genes in bacterial genomes. AB - MOTIVATION: Next generation sequencing technologies have provided us with a wealth of information on genetic variation, but predicting the functional significance of this variation is a difficult task. While many comparative genomics studies have focused on gene flux and large scale changes, relatively little attention has been paid to quantifying the effects of single nucleotide polymorphisms and indels on protein function, particularly in bacterial genomics. RESULTS: We present a hidden Markov model based approach we call delta-bitscore (DBS) for identifying orthologous proteins that have diverged at the amino acid sequence level in a way that is likely to impact biological function. We benchmark this approach with several widely used datasets and apply it to a proof of-concept study of orthologous proteomes in an investigation of host adaptation in Salmonella enterica We highlight the value of the method in identifying functional divergence of genes, and suggest that this tool may be a better approach than the commonly used dN/dS metric for identifying functionally significant genetic changes occurring in recently diverged organisms. AVAILABILITY AND IMPLEMENTATION: A program implementing DBS for pairwise genome comparisons is freely available at: https://github.com/UCanCompBio/deltaBS CONTACT: nicole.wheeler@pg.canterbury.ac.nz or lars.barquist@uni wuerzburg.deSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27503223 TI - Bayesian network feature finder (BANFF): an R package for gene network feature selection. AB - MOTIVATION: Network marker selection on genome-scale networks plays an important role in the understanding of biological mechanisms and disease pathologies. Recently, a Bayesian nonparametric mixture model has been developed and successfully applied for selecting genes and gene sub-networks. Hence, extending this method to a unified approach for network-based feature selection on general large-scale networks and creating an easy-to-use software package is on demand. RESULTS: We extended the method and developed an R package, the Bayesian network feature finder (BANFF), providing a package of posterior inference, model comparison and graphical illustration of model fitting. The model was extended to a more general form, and a parallel computing algorithm for the Markov chain Monte Carlo -based posterior inference and an expectation maximization-based algorithm for posterior approximation were added. Based on simulation studies, we demonstrate the use of BANFF on analyzing gene expression on a protein-protein interaction network. AVAILABILITY: https://cran.r project.org/web/packages/BANFF/index.html CONTACT: jiankang@umich.edu, tianwei.yu@emory.eduSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27503224 TI - PathScore: a web tool for identifying altered pathways in cancer data. AB - : PathScore quantifies the level of enrichment of somatic mutations within curated pathways, applying a novel approach that identifies pathways enriched across patients. The application provides several user-friendly, interactive graphic interfaces for data exploration, including tools for comparing pathway effect sizes, significance, gene-set overlap and enrichment differences between projects. AVAILABILITY AND IMPLEMENTATION: Web application available at pathscore.publichealth.yale.edu. Site implemented in Python and MySQL, with all major browsers supported. Source code available at: github.com/sggaffney/pathscore with a GPLv3 license. CONTACT: stephen.gaffney@yale.edu. PMID- 27503225 TI - RNAcommender: genome-wide recommendation of RNA-protein interactions. AB - MOTIVATION: Information about RNA-protein interactions is a vital pre-requisite to tackle the dissection of RNA regulatory processes. Despite the recent advances of the experimental techniques, the currently available RNA interactome involves a small portion of the known RNA binding proteins. The importance of determining RNA-protein interactions, coupled with the scarcity of the available information, calls for in silico prediction of such interactions. RESULTS: We present RNAcommender, a recommender system capable of suggesting RNA targets to unexplored RNA binding proteins, by propagating the available interaction information taking into account the protein domain composition and the RNA predicted secondary structure. Our results show that RNAcommender is able to successfully suggest RNA interactors for RNA binding proteins using little or no interaction evidence. RNAcommender was tested on a large dataset of human RBP-RNA interactions, showing a good ranking performance (average AUC ROC of 0.75) and significant enrichment of correct recommendations for 75% of the tested RBPs. RNAcommender can be a valid tool to assist researchers in identifying potential interacting candidates for the majority of RBPs with uncharacterized binding preferences. AVAILABILITY AND IMPLEMENTATION: The software is freely available at http://rnacommender.disi.unitn.it CONTACT: gianluca.corrado@unitn.it or andrea.passerini@unitn.itSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27503226 TI - shinyGEO: a web-based application for analyzing gene expression omnibus datasets. AB - : The Gene Expression Omnibus (GEO) is a public repository of gene expression data. Although GEO has its own tool, GEO2R, for data analysis, evaluation of single genes is not straightforward and survival analysis in specific GEO datasets is not possible without bioinformatics expertise. We describe a web application, shinyGEO, that allows a user to download gene expression data sets directly from GEO in order to perform differential expression and survival analysis for a gene of interest. In addition, shinyGEO supports customized graphics, sample selection, data export and R code generation so that all analyses are reproducible. The availability of shinyGEO makes GEO datasets more accessible to non-bioinformaticians, promising to lead to better understanding of biological processes and genetic diseases such as cancer. AVAILABILITY AND IMPLEMENTATION: Web application and source code are available from http://gdancik.github.io/shinyGEO/ CONTACT: dancikg@easternct.eduSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27503227 TI - SRinversion: a tool for detecting short inversions by splitting and re-aligning poorly mapped and unmapped sequencing reads. AB - MOTIVATION: Rapid development in sequencing technologies has dramatically improved our ability to detect genetic variants in human genome. However, current methods have variable sensitivities in detecting different types of genetic variants. One type of such genetic variants that is especially hard to detect is inversions. Analysis of public databases showed that few short inversions have been reported so far. Unlike reads that contain small insertions or deletions, which will be considered through gap alignment, reads carrying short inversions often have poor mapping quality or are unmapped, thus are often not further considered. As a result, the majority of short inversions might have been overlooked and require special algorithms for their detection. RESULTS: Here, we introduce SRinversion, a framework to analyze poorly mapped or unmapped reads by splitting and re-aligning them for the purpose of inversion detection. SRinversion is very sensitive to small inversions and can detect those less than 10 bp in size. We applied SRinversion to both simulated data and high-coverage sequencing data from the 1000 Genomes Project and compared the results with those from Pindel, BreakDancer, DELLY, Gustaf and MID. A better performance of SRinversion was achieved for both datasets for the detection of small inversions. AVAILABILITY AND IMPLEMENTATION: SRinversion is implemented in Perl and is publicly available at http://paed.hku.hk/genome/software/SRinversion/index.html CONTACT: yangwl@hku.hkSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27503228 TI - PRODIGY: a web server for predicting the binding affinity of protein-protein complexes. AB - : Gaining insights into the structural determinants of protein-protein interactions holds the key for a deeper understanding of biological functions, diseases and development of therapeutics. An important aspect of this is the ability to accurately predict the binding strength for a given protein-protein complex. Here we present PROtein binDIng enerGY prediction (PRODIGY), a web server to predict the binding affinity of protein-protein complexes from their 3D structure. The PRODIGY server implements our simple but highly effective predictive model based on intermolecular contacts and properties derived from non interface surface. AVAILABILITY AND IMPLEMENTATION: PRODIGY is freely available at: http://milou.science.uu.nl/services/PRODIGY CONTACT: a.m.j.j.bonvin@uu.nl, a.vangone@uu.nl. PMID- 27503229 TI - Kinematics of anterior cruciate ligament-deficient knees in a Chinese population during stair ascent. AB - BACKGROUND: The purpose of this study was to measure the tibiofemoral kinematics of anterior cruciate ligament (ACL) deficiency in a Chinese population and compare the kinematics with published data about a Caucasian population. METHODS: Unilateral knees of 18 Chinese ACL-deficient (ACL-D) subjects were studied while subjects ascended stairs. Kinematic alteration was compared between ACL-D knees and contralateral ACL-intact (ACL-I) knees. The kinematic alteration of ACL deficiency was also compared between the Chinese population and published data about a Caucasian population. RESULTS: A statistical difference was found in the three-dimensional rotations between ACL-D and ACL-I knees. In the sagittal plane, ACL-I knees had a larger flexion angle than ACL-D knees during 40 to 50 % of the activity during stair ascent (P < 0.027) and throughout the gait cycle. A significant difference in rotational motion between ACL-D and ACL-I knees was also observed in the frontal plane during 40 to 60 % (P < 0.017) of the activity and in the transverse plane during 70 to 80 % (P < 0.028) of the activity. A greater tibial varus was demonstrated in the Chinese population while the published data revealed external tibial rotation and a statistical difference in translation in the Caucasian population. CONCLUSIONS: ACL-D knees show different kinematics than ACL-I knees in the Chinese population. ACL-I knees had a larger flexion angle than ACL-D knees in the middle stage of the activity during stair ascent. A significant difference in rotational motion between ACL-D and ACL-I knees was also observed in the frontal plane during the middle phase and in the transverse plane during the terminal phase of the activity. A greater tibial varus was demonstrated in the Caucasian population while the published data revealed external tibial rotation and a statistical difference in translation in the Caucasian population. PMID- 27503231 TI - Community-acquired pneumonia in children: what to do when there is no response to standard empirical treatment? PMID- 27503230 TI - Traditional and HIV-specific risk factors for cardiovascular morbidity and mortality among HIV-infected adults in Brazil: a retrospective cohort study. AB - BACKGROUND: Antiretroviral therapy (ART) agents potentially associated with adverse metabolic profiles are commonly used in low- and middle-income countries. We assessed risk factors for cardiovascular disease (CVD)-related morbidity and mortality in a cohort of HIV-infected, ART-treated adults in Rio de Janeiro, Brazil. METHODS: Hospital records and mortality data between 2000-2010 were examined for incident CVD-related ICD-10 and Coding of Death in HIV diagnoses among adults >=18 years old on ART, enrolled in an observational cohort. Poisson regression models assessed associations between demographic and clinical characteristics and ART agent or class on CVD event risk. RESULTS: Of 2960 eligible persons, 109 had a CVD event (89 hospitalizations, 20 deaths). Participants were 65 % male, 54 % white, and had median age of 37 and 4.6 years on ART. The median nadir CD4(+) T lymphocyte count was 149 cells/mm(3). The virologic suppression rate at the end of study follow-up was 60 %. In multivariable models, detectable HIV-1 RNA prior to the event, prior CVD, less time on ART, age >=40 at study baseline, nadir CD4(+) T lymphocyte count <=50 cells/mm(3), non-white race, male gender, and a history of hypertension were significantly associated with CVD event incidence (p < 0.05), in order of decreasing strength. In multivariate models, cumulative use of tenofovir, zidovudine, efavirenz and ritonavir-boosted atazanavir, darunavir and/or lopinavir were associated with decreased CVD event risk. Recent tenofovir and boosted atazanavir use were associated with decreased risk, while recent stavudine, nevirapine and unboosted nelfinavir and/or indinavir use were associated with increased CVD event risk. CONCLUSIONS: Virologic suppression and preservation of CD4(+) T-lymphocyte counts were as important as traditional CVD risk factor burden in determining incident CVD event risk, emphasizing the overall benefit of ART on CVD risk and the need for metabolically-neutral first- and second-line ART in resource-limited settings. PMID- 27503232 TI - The obstructive sleep apnoea syndrome in adolescents. AB - BACKGROUND: The obstructive sleep apnoea syndrome (OSAS) results from a combination of structural and neuromotor factors; however, the relative contributions of these factors have not been studied during the important developmental phase of adolescence. We hypothesised that adenotonsillar volume (ATV), nasopharyngeal airway volume (NPAV), upper airway critical closing pressure (Pcrit) in the hypotonic and activated neuromotor states, upper airway electromyographic response to subatmospheric pressure and the ventilatory response to CO2 during sleep would be major predictors of OSAS risk. METHODS: 42 obese adolescents with OSAS and 37 weight-matched controls underwent upper airway MRI, measurements of Pcrit, genioglossal electromyography and ventilatory response to CO2 during wakefulness and sleep. RESULTS: ATV, NPAV, activated and hypotonic Pcrit, genioglossal electromyography and ventilatory response to CO2 during sleep were all associated with OSAS risk. Multivariate models adjusted for age, gender, body mass index and race indicated that ATV, NPAV and activated Pcrit each independently affected apnoea risk in adolescents; genioglossal electromyography was independently associated in a reduced sample. There was significant interaction between NPAV and activated Pcrit (p=0.021), with activated Pcrit more strongly associated with OSAS in adolescents with larger NPAVs and NPAV more strongly associated with OSAS in adolescents with more negative activated closing pressure. CONCLUSIONS: OSAS in adolescents is mediated by a combination of anatomic (ATV, NPAV) and neuromotor factors (activated Pcrit). This may have important implications for the management of OSAS in adolescents. PMID- 27503233 TI - FUT2 genotype influences lung function, exacerbation frequency and airway microbiota in non-CF bronchiectasis. AB - OBJECTIVE: To assess whether FUT2 (secretor) genotype affects disease severity and airway infection in patients with non-cystic fibrosis bronchiectasis. PARTICIPANTS: Induced sputum samples were obtained from 112 adult patients with high-resolution CT scan-proven bronchiectasis and at least two exacerbations in the previous year, as part of an unrelated randomised control trial. OUTCOME MEASURES: Presence of null FUT2 polymorphisms were determined by gene sequencing and verified by endobronchial biopsy histochemical staining. Outcome measures were FEV1% predicted, exacerbation frequency, and bacterial, fungal and viral components of the microbiota (measured by culture independent approaches). RESULTS: Patients were grouped by FUT2 loss-of-function genotype; categorised as non-secretors (n=27, sese), heterozygous secretors (n=54, Sese) or homozygous secretors (n=31, SeSe). FEV1% was significantly lower in SeSe patients compared with sese patients (mean 61.6 (SD 20.0) vs 74.5 (18.0); p=0.023). Exacerbation frequency was significantly higher in SeSe (mean count 5.77) compared with sese (4.07; p=0.004) and Sese (4.63; p=0.026) genotypes. The time until first exacerbation was significantly shorter in SeSe compared with Sese (HR=0.571 (95% CI 0.343 to 0.950); p=0.031), with a similar trend for sese patients (HR=0.577 (0.311 to 1.07); p=0.081). sese had a significantly reduced frequency of Pseudomonas aeruginosa-dominated airway infection (8.7%) compared with Sese (31%; p=0.042) and SeSe (36%; p=0.035). In contrast, fungal, viral and non-dominant bacterial components of the microbiome were not significantly different between FUT2 genotypes. CONCLUSIONS: FUT2 genotype in patients with non-cystic fibrosis bronchiectasis was significantly associated with disease outcomes, with homozygous secretors exhibiting lower lung function, higher exacerbation number and a higher frequency of P. aeruginosa-dominated infection. TRIAL REGISTRATION NUMBER: ACTRN12609000578202 (anzctr.org.au); Pre-results. PMID- 27503234 TI - Assessment of a rapid liquid-based cytology method for measuring sputum cell counts. AB - Differential sputum cell counting is not widely available despite proven clinical utility in the management of asthma. We compared eosinophil counts obtained using liquid-based cytology (LBC), a routine histopathological processing method, and the current standard method. Eosinophil counts obtained using LBC were a strong predictor of sputum eosinophilia (>=3%) determined by the standard method suggesting LBC could be used in the management of asthma. PMID- 27503235 TI - The iLappSurgery taTME app: a modern adjunct to the teaching of surgical techniques. AB - Application-based technology has emerged as a method of modern information communication, and this has been applied towards surgical training and education. It allows surgeons the ability to obtain portable and instant access to information that is otherwise difficult to deliver. The iLappSurgery Foundation has recently launched the transanal total mesorectal excision educational application (taTME app) which provides a useful adjunct, especially for surgeons interested in mastery of the taTME technique and its principles. The article provides a detailed review of the application, which has achieved a large user base since its debut in June, 2016. PMID- 27503236 TI - Prostaglandin D2 receptor antagonism: a novel therapeutic option for eosinophilic asthma? PMID- 27503237 TI - Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. AB - BACKGROUND: Eosinophilic airway inflammation is often present in asthma, and reduction of such inflammation results in improved clinical outcomes. We hypothesised that fevipiprant (QAW039), an antagonist of prostaglandin D2 receptor 2, might reduce eosinophilic airway inflammation in patients with moderate-to-severe eosinophilic asthma. METHODS: We performed a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial at Glenfield Hospital (Leicester, UK). We recruited patients with persistent, moderate-to severe asthma and an elevated sputum eosinophil count (>=2%). After a 2-week single-blind placebo run-in period, patients were randomly assigned (1:1) by the trial pharmacist, using previously generated treatment allocation cards, to receive fevipiprant (225 mg twice per day orally) or placebo, stratified by the use of oral corticosteroid treatment and bronchoscopy. The 12-week treatment period was followed by a 6-week single-blind placebo washout period. The primary outcome was the change in sputum eosinophil percentage from baseline to 12 weeks after treatment, analysed in the intention-to-treat population. All patients who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01545726, and with EudraCT, number 2011-004966-13. FINDINGS: Between Feb 10, 2012, and Jan 30, 2013, 61 patients were randomly assigned to receive fevipiprant (n=30) or placebo (n=31). Three patients in the fevipiprant group and four patients in the placebo group withdrew because of asthma exacerbations. Two patients in the fevipiprant group were incorrectly given placebo (one at the mid-treatment visit and one throughout the course of the study). They were both included in the fevipiprant group for the primary analysis, but the patient who was incorrectly given placebo throughout was included in the placebo group for the safety analyses. Between baseline and 12 weeks after treatment, sputum eosinophil percentage decreased from a geometric mean of 5.4% (95% CI 3.1-9.6) to 1.1% (0.7-1.9) in the fevipiprant group and from 4.6% (2.5-8.7) to 3.9% (CI 2.3-6.7) in the placebo group. Compared with baseline, mean sputum eosinophil percentage was reduced by 4.5 times in the fevipiprant group and by 1.3 times in the placebo group (difference between groups 3.5 times, 95% CI 1.7-7.0; p=0.0014). Fevipiprant had a favourable safety profile, with no deaths or serious adverse events reported. No patient withdrawals were judged by the investigator to be related to the study drug. INTERPRETATION: Fevipiprant reduces eosinophilic airway inflammation and is well tolerated in patients with persistent moderate-to-severe asthma and raised sputum eosinophil counts despite inhaled corticosteroid treatment. FUNDING: Novartis Pharmaceuticals, AirPROM project, and the UK National Institute for Health Research. PMID- 27503238 TI - Disseminated necrotizing leukoencephalopathy eight months after alemtuzumab treatment for multiple sclerosis. PMID- 27503240 TI - Genetic and phylogenetic analysis of a novel parvovirus isolated from chickens in Guangxi, China. AB - A previously unidentified chicken parvovirus (ChPV) strain, associated with runting-stunting syndrome (RSS), is now endemic among chickens in China. To explore the genetic diversity of ChPV strains, we determined the first complete genome sequence of a novel ChPV isolate (GX-CH-PV-7) identified in chickens in Guang Xi, China, and showed moderate genome sequence similarity to reference strains. Analysis showed that the viral genome sequence is 86.4 %-93.9 % identical to those of other ChPVs. Genetic and phylogenetic analyses showed that this newly emergent GX-CH-PV-7 is closely related to Gallus gallus enteric parvovirus isolate ChPV 798 from the USA, indicating that they may share a common ancestor. The complete DNA sequence is 4612 bp long with an A+T content of 56.66 %. We determined the first complete genome sequence of a previously unidentified ChPV strain to elucidate its origin and evolutionary status. PMID- 27503239 TI - MATSAP: An automated analysis of stretch-attend posture in rodent behavioral experiments. AB - Stretch-attend posture (SAP) occurs during risk assessment and is prevalent in common rodent behavioral tests. Measuring this behavior can enhance behavioral tests. For example, stretch-attend posture is a more sensitive measure of the effects of anxiolytics than traditional spatiotemporal indices. However, quantifying stretch-attend posture using human observers is time consuming, somewhat subjective, and prone to errors. We have developed MATLAB-based software, MATSAP, which is a quick, consistent, and open source program that provides objective automated analysis of stretch-attend posture in rodent behavioral experiments. Unlike human observers, MATSAP is not susceptible to fatigue or subjectivity. We assessed MATSAP performance with videos of male Swiss mice moving in an open field box and in an elevated plus maze. MATSAP reliably detected stretch-attend posture on par with human observers. This freely available program can be broadly used by biologists and psychologists to accelerate neurological, pharmacological, and behavioral studies. PMID- 27503242 TI - Exploring the link between organizational climate and the use of psychotropic medicines in nursing homes: A qualitative study. AB - BACKGROUND: Research concerning the overprescribing of psychotropic medicines in nursing homes suggests that organizational climate plays a significant role in the use of psychotropic medicines. Organizational climate refers to how members of the organization perceive their work environment as well as interactions with each other or outsiders. OBJECTIVES: This study aimed to explore the key dimensions of organizational climate and their subsequent influence on the use of psychotropic medicines. METHODS: Semi-structured interviews were conducted with 40 on-site and visiting staff from eight nursing homes in Sydney, Australia. Purposive sampling was used to recruit participants representing a broad range of health disciplines and roles. Transcripts were content coded for participants' perceptions related to the work environment and descriptions of psychotropic medicines use. Thematic analysis was used to derive key concepts. RESULTS: Three salient dimensions of organizational climate were linked to the use of psychotropic medicines in nursing homes: staffing, managerial expectations and teamwork among visiting and on-site staff. Inadequate staffing levels were perceived to influence on-site staff requests for initiation of psychotropic medicines to cope with high workload. Participants reported managers that prioritized the non-pharmacological management of behavioral disturbances led other on-site staff to have a reduced preference for psychotropic medicines. In addition, trust and open communication among on-site and visiting staff facilitated the cessation of psychotropic medicines. CONCLUSION: This study illustrates that organizational climate is an important factor influencing the use of psychotropic medicines. Furthermore, the study highlights what aspects of organizational climate need to be addressed to reduce the inappropriate prescribing of psychotropic medicines. PMID- 27503241 TI - A novel role for beta2-microglobulin: a precursor of antibacterial chemokine in respiratory epithelial cells. AB - We analyzed a panel of cationic molecules secreted in the culture medium of human respiratory epithelial cells (REC) upon activation by IL-1beta and different pathogen-associated molecular patterns. A 9 kDa fragment derived from beta2 microglobulin (B2M) was identified and named shed 9 kDa B2M (sB2M-9). The primary structure of sB2M-9 was revealed to increase its pI value that potentially could play an important role in innate defense. sB2M-9 exhibits antibacterial activity against Gram positive Staphylococcus aureus (SA) but not against Gram negative Klebsiella pneumonia (KP). Upon its binding to SA, sB2M-9 induces clumps, a phenomenon not observed with B2M. Migration of THP-1 monocytes exposed to SA clumps was significantly greater than that to SA without clumps. sB2M-9 binds to SA, more likely as a chemokine, to facilitate THP-1 migration. As a whole, we demonstrated that REC release a novel chemokine with antibacterial activity that is shed from B2M to facilitate THP-1 migration. PMID- 27503243 TI - There is still a case for a generic qualitative approach in some pharmacy practice research. PMID- 27503245 TI - An inflammatory fascination for thrombosis. PMID- 27503244 TI - The role of antagonists of the PD-1:PD-L1/PD-L2 axis in head and neck cancer treatment. AB - We review the current clinical knowledge surrounding one of the most promising immune checkpoint pathways currently investigated in head and neck squamous cell carcinoma patients, programmed cell death-1 (PD-1) and its ligands (PD-L1 and PD L2). We review ongoing clinical trials and associated clinical responses observed with targeting the receptor, PD-1, and its ligand, PD-L1. A recent phase III clinical trial (Checkmate 141) demonstrated an improved overall survival in head and neck cancer patients treated with anti-PD-1 monotherapy as compared to standard of care for recurrent and/or metastatic disease, which raises questions on how best to incorporate immunotherapy in the context of standard of care. We discuss biomarkers of response to this class of novel drugs, which is an area of active investigation. Lastly, we project future directions in the field wherein understanding how the Fc portions of the various monoclonal antibodies may impact their clinical efficacy as well as discuss areas where our next advances may take place, such as combination strategies. PMID- 27503246 TI - FleQ of Pseudomonas putida KT2440 is a multimeric cyclic diguanylate binding protein that differentially regulates expression of biofilm matrix components. AB - The intracellular signal molecule cyclic di-GMP (c-di-GMP) is an important element in regulation of biofilm formation by bacteria. In Pseudomonas aeruginosa, FleQ functions as a c-di-GMP-dependent transcriptional regulator of expression of flagellar genes and the exopolysaccharide (EPS) Pel, a component of the biofilm extracellular matrix. In the plant-beneficial bacterium Pseudomonas putida KT2440, a mutation in fleQ reduces biofilm formation and colonization of plant surfaces. Using isothermal titration calorimetry and electrophoretic mobility shift assays, we show in this work that FleQ of P. putida interacts with c-di-GMP and directly binds the promoter regions of flagellar and EPS genes. Data obtained by analytical gel filtration and ultracentrifugation indicate that FleQ is in multiple oligomeric states in solution (dimers, tetramers and hexamers), which do not show altered equilibrium in the presence of c-di-GMP. DNA binding is independent of c-diGMP, although it is favored by the second messenger in the case of the promoter of the operon responsible for synthesis of the species specific EPS Pea. Analysis of expression using transcriptional fusions showed an influence of FleQ upon two of the four EPS operons under regular growth conditions. Finally, a consensus sequence for promoter recognition by FleQ in P. putida is also proposed. PMID- 27503247 TI - Use of dermal regeneration template to close a giant myelomeningocele in a newborn. AB - Many techniques are available to close a myelomeningocele, but large lesions can be particularly difficult to close given the absence of surrounding tissue. The authors present the case of a 2-day-old girl with a large lumbosacral myelomeningocele who underwent a staged repair using dermal regeneration template (DRT; Integra) followed by split-thickness skin grafting. The results demonstrated that the combined use of myofascial turnover flaps and DRT with delayed skin grafting is a safe, effective option for this challenging reconstructive dilemma. PMID- 27503248 TI - Timing of cranial vault remodeling in nonsyndromic craniosynostosis: a single institution 30-year experience. AB - OBJECTIVE Due to the changing properties of the infant skull, there is still no clear consensus on the ideal time to surgically intervene in cases of nonsyndromic craniosynostosis (NSC). This study aims to shed light on how patient age at the time of surgery may affect surgical outcomes and the subsequent need for reoperation. METHODS A retrospective cohort review was conducted for patients with NSC who underwent primary cranial vault remodeling between 1990 and 2013. Patients' demographic and clinical characteristics and surgical interventions were recorded. Postoperative outcomes were assessed by assigning each procedure to a Whitaker category. Multivariate logistic regression analysis was performed to determine the relationship between age at surgery and need for minor (Whitaker I or II) versus major (Whitaker III or IV) reoperation. Odds ratios (ORs) for Whitaker category by age at surgery were assigned. RESULTS A total of 413 unique patients underwent cranial vault remodeling procedures for NSC during the study period. Multivariate logistic regression demonstrated increased odds of requiring major surgical revisions (Whitaker III or IV) in patients younger than 6 months of age (OR 2.49, 95% CI 1.05-5.93), and increased odds of requiring minimal surgical revisions (Whitaker I or II) in patients older than 6 months of age (OR 2.72, 95% CI 1.16-6.41). CONCLUSIONS Timing, as a proxy for the changing properties of the infant skull, is an important factor to consider when planning vault reconstruction in NSC. The data presented in this study demonstrate that patients operated on before 6 months of age had increased odds of requiring major surgical revisions. PMID- 27503250 TI - [Not Available]. PMID- 27503249 TI - Randomized Pharmacokinetic Crossover Study Comparing 2 Curcumin Preparations in Plasma and Rectal Tissue of Healthy Human Volunteers. AB - Curcumin is poorly absorbed, which is interest in new preparations. However, little is known about variations in its pharmacokinetics and tissue bioavailability between formulations. In this randomized, crossover study we evaluated the relationship between steady-state plasma and rectal tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts. There was no difference in the geometric mean plasma AUCs when adjusted for the 10-fold difference in curcumin dose between the 2 formulations. Phosphatidylcholine curcumin extract yielded only 20% to 30% plasma demethoxycurcumin and bisdemethoxycurcumin conjugates compared to standard extract, yet yielded 20-fold greater hexahydrocurcumin. When adjusting for curcumin dose, tissue curcumin concentrations were 5-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than to plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at steady state in both plasma and rectal tissues. PMID- 27503251 TI - [IgG4-related disease]. PMID- 27503252 TI - Effects of cranial integration on hominid endocranial shape. AB - Because brains do not fossilize, the internal surface of the braincase (endocast) serves as an important source of information about brain growth, development, and evolution. Recent studies of endocranial morphology and development in great apes, fossil hominins, and modern humans have revealed taxon-specific differences. However, it remains to be investigated to which extent differences in endocranial morphology reflect differences in actual brain morphology and development, and to which extent they reflect different interactions of the brain and its case with the cranial base and face. Here we address this question by analyzing the effects of cranial integration on endocranial morphology. We test the 'spatial packing' and 'facial orientation' hypotheses, which propose that size and orientation of the neurocranium relative to the viscerocranium influence endocranial shape. Results show that a substantial proportion of endocranial shape variation along and across ontogenetic trajectories is due to cranial integration. Specifically, the uniquely globular shape of the human endocast mainly results from the combination of an exceptionally large brain with a comparatively small face. Overall, thus, cranial integration has pervasive effects on endocranial morphology, and only a comparatively small proportion of inter- and intra-taxon variation can directly be associated with variation in brain morphology. PMID- 27503253 TI - Bibliometric analysis on global Behcet disease publications during 1980-2014: is there a Silk Road in the literature? AB - BACKGROUND: Behcet disease (BD) is a chronic and multisystemic vasculitis characterized with recurrent oral and genital ulcers, uveitis, arthritis and skin manifestations. The highest prevalence of the disease has been reported in regions historically involved in the Silk Road routes. OBJECTIVE: We aimed to analyse Behcet literature and evaluate whether there is a concordance between ancient Silk Road regions and the distribution of publication productivity. METHODS: The bibliometric analysis of the publications published during 1980-2014 using Thomson Reuters Web of Science database was performed. We generated infographics of productivity and also analysed the correlations among economical productivities, technological advancement levels and humanity index and productivity performances of 78 countries in Behcet literature. RESULTS: Turkey ranked first in Behcet literature with 1837 articles followed by Japan and the USA. Turkey, Tunisia and Israel occupied the first three places in productivity. Significant correlations were noted between 2014 gross economic and technological indices and publication numbers of the countries. We found that European countries had high productivity, although they had low prevalence of BD. We detected no concordance between the productivity density of the countries and the ancient Silk Road routes. CONCLUSION: Most publications were reported from developed countries although undeveloped or developing countries had higher prevalence of BD. Physicians in undeveloped and developing countries should be supported and encouraged to perform novel studies on BD. PMID- 27503254 TI - Stabilization of Charge Carriers in Picket-Fence Polythiophenes Using Dielectric Side Chains. AB - Insulated molecular wires (IMWs) are pi-conjugated polymers that are molecularly sheathed with an insulating layer and are structurally analogous to electric power cords at the nanoscale. Such unique architectures are expected in molecular electronics and organic devices. Herein, we propose a new molecular design concept of IMWs, in which the sheaths can be customized, thereby enabling the modulation of the electronic properties of the interior pi-conjugated systems. To this end, we focused our attention on the dielectric constant of the sheaths, as it governs the electrostatic interaction between charges. Upon doping, charge carriers, such as polaron and bipolaron, were generated regardless of the dielectric properties of the sheaths. Flash-photolysis time-resolved microwave conductivity measurements revealed that intrawire charge carrier mobility was independent of the sheaths. However, we found that the charge carriers could be stabilized by the sheaths with a high dielectric constant owing to the charge screening effect. We expect that IMWs designed in this way will be useful in a variety of applications, where the nature of charge carriers plays an important role, and particularly when redox switching is required (e.g., electrochromic, magnetic, and memory applications). PMID- 27503256 TI - Cu0.89Zn0.11O, A New Peroxidase-Mimicking Nanozyme with High Sensitivity for Glucose and Antioxidant Detection. AB - Nanomaterial-based enzyme mimetics (nanozymes) is an emerging field of research that promises to produce alternatives to natural enzymes for a variety of applications. The search for the most cost-effective and efficient inorganic nanomaterials, such as metal oxides, cannot be won by pristine CuO. However, unlike CuO, the Zn-doped CuO (Zn-CuO) nanoparticles reported in this paper reveal superior peroxidase-like enzyme activity. This places Zn-CuO in a good position to participate in a range of activities aimed at developing diverse enzyme applications. The peroxidase-like activity was tested and confirmed against various chromogenic substrates in the presence of H2O2 and obeyed the Michaelis Menten enzymatic pathway. The mechanism of enhanced enzymatic activity was proved by employing terephthalic acid as a fluorescence probe and by electron spin resonance. The nanozyme, when tested for the detection of glucose, showed a substantial enhancement in the detection selectivity. The limit of detection (LOD) was also decreased reaching a limit as low as 0.27 ppm. Such a low LOD has not been reported so far for the metal oxides without any surface modifications. Moreover, the nanozyme (Zn-CuO) was utilized to detect the three antioxidants tannic acid, tartaric acid, and ascorbic acid and the relative strength of their antioxidant capacity was compared. PMID- 27503257 TI - Chickpea Ferritin CaFer1 Participates in Oxidative Stress Response, and Promotes Growth and Development. AB - Ferritins store and sequester iron, and regulate iron homeostasis. The cDNA for a stress-responsive phytoferritin, previously identified in the extracellular matrix (ECM) of chickpea (Cicer arietinum), was cloned and designated CaFer1. The CaFer1 transcript was strongly induced in chickpea exposed to dehydration, hypersalinity and ABA treatment. Additionally, it has role in the defense against Fusarium oxysporum infection. Functional complementation of the yeast frataxin deficient mutant, Deltayfh1, indicates that CaFer1 functions in oxidative stress. The presence of CaFer1 in the extracellular space besides chloroplast establishes its inimitable nature from that of other phytoferritins. Furthermore, CaFer1 expression in response to iron suggests its differential mechanism of accumulation at two different iron conditions. CaFer1-overexpressing transgenic plants conferred improved growth and development, accompanied by altered expression of iron-responsive genes. Together, these results suggest that the phytoferritin, CaFer1, might play a key role in maintenance of iron buffering and adaptation to environmental challenges. PMID- 27503258 TI - Eosinophilic esophageal myositis diagnosed by endoscopic ultrasound-guided fine needle aspiration biopsy: a case report. AB - Eosinophilic esophagitis (EoE) is diagnosed by microscopic findings of eosinophilic infiltration into the squamous epithelium. In contrast, another disease concept termed "eosinophilic esophageal myositis (EoEM)" has been proposed, whereby there is eosinophilic infiltration into the muscularis propria instead. A 60-year-old man was referred to our hospital for chest pain, dysphagia, and several episodes of esophageal food impaction. Although EoE was suspected based on clinical features, biopsy specimens showed no mucosal eosinophilic infiltration. Endoscopic ultrasound (EUS) showed thickening of the muscularis propria layer and subsequent EUS-guided fine-needle aspiration biopsy (EUS-FNA) revealed eosinophilic infiltration into the muscularis propria. Although the patient's symptoms gradually improved after steroid administration, complete remission was not achieved after 1 year of treatment. This case may reflect a disorder distinct from typical EoE based on eosinophilic infiltration of the muscularis propria but not the squamous epithelium, and we, therefore, diagnosed it as EoEM using the EUS-FNA findings as reference. PMID- 27503260 TI - Mesocrystals: structural and morphogenetic aspects. AB - Mesocrystals are a fascinating class of crystalline nanostructured materials since they combine the properties of nanoparticles with order on the microscopic or even macroscopic length scale. This tutorial review deals with the structural aspects of mesocrystals as well as their formation mechanisms known so far. The goal is to reach an understanding about what is special about the structuration principles of mesocrystals and their complex structures and what are the possibilities to control their formation processes. PMID- 27503259 TI - Computational characterization of Iron metabolism in the Tsetse disease vector, Glossina morsitans: IRE stem-loops. AB - BACKGROUND: Iron metabolism and regulation is an indispensable part of species survival, most importantly for blood feeding insects. Iron regulatory proteins are central regulators of iron homeostasis, whose binding to iron response element (IRE) stem-loop structures within the UTRs of genes regulate expression at the post-transcriptional level. Despite the extensive literature on the mechanism of iron regulation in human, less attention has been given to insect and more specifically the blood feeding insects, where research has mainly focused on the characterization of ferritin and transferrin. We thus, examined the mechanism of iron homeostasis through a genome-wide computational identification of IREs and other enriched motifs in the UTRs of Glossina morsitans with the view to identify new IRE-regulated genes. RESULTS: We identified 150 genes, of which two are known to contain IREs, namely the ferritin heavy chain and the MRCK-alpha. The remainder of the identified genes is considered novel including 20 hypothetical proteins, for which an iron-regulatory mechanism of action was inferred. Forty-three genes were found with IRE signatures of regulation in two or more insects, while 46 were only found to be IRE-regulated in two species. Notably 39 % of the identified genes exclusively shared IRE-signatures in other Glossina species, which are potentially Glossina specific adaptive measures in addressing its unique reproductive biology and blood meal-induced iron overload. In line with previous findings, we found no evidence pertaining to an IRE regulation of Transferrin, which highlight the importance of ferritin heavy chain and the other proposed transporters in the tsetse fly. In the context of iron-sequestration, key players of tsetse immune defence against trypanosomes have been introduced namely 14 stress and immune response genes, while 28 cell-envelop, transport, and binding genes were assigned a putative role in iron trafficking. Additionally, we identified and annotated enriched motifs in the UTRs of the putative IRE-regulated genes to derive at a co regulatory network that maintains iron homeostasis in tsetse flies. Three putative microRNA-binding sites namely Gy-box, Brd-box and K-box motifs were identified among the regulatory motifs, enriched in the UTRs of the putative IRE regulated genes. CONCLUSION: Beyond our current view of iron metabolism in insects, with ferritin and transferrin as its key players, this study provides a comprehensive catalogue of genes with possible roles in the acquisition; transport and storage of iron hence iron homeostasis in the tsetse fly. PMID- 27503255 TI - A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. AB - Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 * 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain. PMID- 27503261 TI - WHO medical eligibility criteria update. PMID- 27503262 TI - Risk-benefit analysis of navigation techniques for vertebral transpedicular instrumentation: a prospective study. AB - BACKGROUND CONTEXT: Pedicle screws in spinal surgery have allowed greater biomechanical stability and higher fusion rates. However, malposition is very common and may cause neurologic, vascular, and visceral injuries and compromise mechanical stability. PURPOSE: The purpose of this study was to compare the malposition rate between intraoperative computed tomography (CT) scan assisted navigation and free-hand fluoroscopy-guided techniques for placement of pedicle screw instrumentation. STUDY DESIGN/SETTING: This is a prospective, randomized, observational study. PATIENT SAMPLE: A total of 114 patients were included: 58 in the assisted surgery group and 56 in the free-hand fluoroscopy-guided surgery group. OUTCOME MEASURES: Analysis of screw position was assessed using the Heary classification. Breach severity was defined according to the Gertzbein classification. Radiation doses were evaluated using thermoluminescent dosimeters, and estimates of effective and organ doses were made based on scan technical parameters. METHODS: Consecutive patients with degenerative disease, who underwent surgical procedures using the free-hand, or intraoperative navigation technique for placement of transpedicular instrumentation, were included in the study. RESULTS: Forty-four out of 625 implanted screws were malpositioned: 11 (3.6%) in the navigated surgery group and 33 (10.3%) in the free-hand group (p<.001). Screw position according to the Heary scale was Grade II (4 navigated surgery, 6 fluoroscopy guided), Grade III (3 navigated surgery, 11 fluoroscopy guided), Grade IV (4 navigated surgery, 16 fluoroscopy guided), and Grade V (1 fluoroscopy guided). There was only one symptomatic case in the conventional surgery group. Breach severity was seven Grade A and four Grade B in the navigated surgery group, and eight Grade A, 24 Grade B, and one Grade C in free-hand fluoroscopy-guided surgery group. Radiation received per patient was 5.8 mSv (4.8-7.3). The median dose received in the free-hand fluoroscopy group was 1 mGy (0.8-1.1). There was no detectable radiation level in the navigation assisted surgery group, whereas the effective dose was 10 uGy in the free-hand fluoroscopy-guided surgery group. CONCLUSIONS: Malposition rate, both symptomatic and asymptomatic, in spinal surgery is reduced when using CT-guided placement of transpedicular instrumentation compared with placement under fluoroscopic guidance, with radiation values within the safety limits for health. Larger studies are needed to determine risk-benefit in these patients. PMID- 27503263 TI - Transient physical and psychosocial activities increase the risk of nonpersistent and persistent low back pain: a case-crossover study with 12 months follow-up. AB - BACKGROUND CONTEXT: A previous study has shown that transient physical and psychosocial activities increased the risk of developing low back pain. However, the link between these factors in triggering nonpersistent or persistent episodes remains unclear. PURPOSE: We aimed to investigate the association of transient exposures to physical and psychosocial activities with the development of nonpersistent or persistent low back pain. STUDY DESIGN: This was a case crossover study with 12 months follow-up. PATIENT SAMPLE: We included 999 consecutive participants seeking care for a sudden onset of low back pain. OUTCOME MEASURES: Development of low back pain was the outcome measure. MATERIALS AND METHODS: At baseline, participants reported transient exposures to 12 predefined activities over the 4 days preceding pain onset. After 12 months, participants were asked whether they had recovered and the date of recovery. Exposures in the 2-hour period preceding pain onset (case window) were compared with the 2-hour period, 24 hours before pain onset (control window) in a case crossover design for all participants. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CI), and interaction analyses were used to compare estimates of nonpersistent (i.e., <6 weeks duration) and persistent cases. This study received funding from Australia's National Health and Medical Research Council (APP1003608). RESULTS: There were 832 participants (83%) who completed the 12 months follow-up successfully. Of these, 430 participants had nonpersistent low back pain (<6 weeks duration), whereas 352 reported persistent symptoms (>=6 weeks duration). Exposure to several transient activities, such as manual tasks involving heavy loads, awkward postures, live people or animals, moderate or vigorous physical activity, and being fatigued or tired during a task or activity, significantly increased the risk of both nonpersistent and persistent low back pain, with ORs ranging from 2.9 to 11.7. Overall, the risk of developing a persistent or a nonpersistent episode of low back pain associated with the included physical factors did not differ significantly. CONCLUSIONS: Our results revealed that previously identified triggers contribute equally to the development of both nonpersistent and persistent low back pain. Future prevention strategies should focus on controlling exposure to these triggers as they have the potential to decrease the burden associated with both acute and chronic low back pain. PMID- 27503264 TI - Preoperative and postoperative sagittal plane analysis in adult idiopathic scoliosis in patients older than 40 years of age. AB - BACKGROUND CONTEXT: Most of the papers correlate sagittal radiographic parameters with health-related quality of life (HRQOL) scores for patients with scoliosis. However, we do not know how changes in sagittal profile influence clinical outcomes after surgery in adult population operated for mainly frontal deformity. PURPOSE: This study aimed to analyze spinal sagittal profile in a population operated on adult idiopathic scoliosis (AS) and to describe variations in sagittal parameters after surgery and the association between those variations and clinical outcomes. DESIGN/SETTING: This is a historical cohort study. PATIENT SAMPLE: We included in this study 40 patients operated on AS, older than 40 at the time of surgery (mean age 54.9), and with more than 2-year follow-up (mean 7.4 years). OUTCOME MEASURES: Full-length free-standing radiographs, Scoliosis Research Society 22 (SRS22) and Short Form 36 (SF36) instruments, and satisfaction with outcomes were available at final follow-up. METHODS: Sagittal preoperative and final follow-up radiographic parameters, radiographic correlation with HRQOL scores at final follow-up, and association between satisfaction and changes in sagittal profile were analyzed. A multivariate analysis was performed. No funds were received for this article. RESULTS: Preoperatively, the spinal sagittal plane tended to exhibit kyphosis. Most sagittal parameters did not improve at final follow-up with respect to preoperative values. We saw, after univariate analysis, that worse sagittal profile leads to worse HRQOL, but after multivariate analysis, only spinal tilt (ST) persisted as possible predictor for worse SRS activity scores. Frontal Cobb significantly improved. Most patients (82%) were satisfied with final outcomes. Variations in sagittal profile parameters did not differ between satisfied and dissatisfied patients. CONCLUSIONS: Although most sagittal plane parameters did not improve after surgery, surgical treatment in AS achieves a high satisfaction rate. Good clinical results do not correlate with improving sagittal plane parameters. Sagittal profile measurements are not helpful to decide surgical treatment in patients with mainly frontal deformity. PMID- 27503265 TI - The impact of generalized joint laxity (GJL) on the posterior neck pain, cervical disc herniation, and cervical disc degeneration in the cervical spine. AB - BACKGROUND CONTEXT: Generalized joint laxity (GJL) can have a negative impact on lumbar spine pathology, including low back pain, disc degeneration, and disc herniation, but the relationship between GJL and cervical spine conditions remains unknown. PURPOSE: To investigate the relationship between GJL and cervical spine conditions, including the prevalence of posterior neck pain (PNP), cervical disc herniation (CDH), and cervical disc degeneration (CDD), in a young, active population. STUDY DESIGN: Retrospective 1:2 matched cohort (case-control) study from prospectively collected data PATIENT SAMPLE: Of a total of 1853 individuals reviewed, 73 individuals with GJL (study group, gruop A) and 146 without GJL (control group, Group B) were included in the study according to a 1:2 case-control matched design for age, sex, and body mass index. OUTCOME MEASURE: The primary outcome measure was the prevalence and intensity of PNP at enrollment based on a visual analogue scale score for pain. The secondary outcome measures were (1) clinical outcomes as measured with the neck disability index (NDI) and 12-item short form health survey (SF-12) at enrollment, and (2) radiological outcomes of CDH and CDD at enrollment. METHODS: We compared baseline data between groups. Descriptive statistical analyses were performed to compare the 2 groups in terms of the outcome measures. RESULTS: The prevalence and intensity of PNP were significantly greater in group A (patients with GJL) than in group B (patients without GJL) (prevalence: p=.02; intensity: p=.001). Clinical outcomes as measured with NDI and SF-12 did not differ significantly between groups. For radiologic outcomes, the prevalence of CDD was significantly greater in group A than in group B (p=.04), whereas the prevalence of CDH did not differ significantly between groups (p=.91). CONCLUSIONS: The current study revealed that GJL was closely related to the prevalence and intensity of PNP, suggesting that GJL may be a causative factor for PNP. In addition, GJL may contribute to the occurrence of CDD, but not CDH. Spine surgeons should screen for GJL in patientswith PNP and inform patients of its potential negative impact on disc degeneration of the cervical spine. PMID- 27503266 TI - The computed tomography angiography study of the spatial relationship between C1 transpedicular screw trajectory and V3 segment of vertebral artery. AB - BACKGROUND CONTEXT: To our knowledge, there is no study that has systematically analyzed the relationship between C1 transpedicular screw trajectory and V3 segment of vertebral artery (VA V3 segment). PURPOSE: To study the relationship between C1 transpedicular screw trajectory and VA V3 segment. STUDY DESIGN: A morphologic computed tomography angiography (CTA) analysis of the spatial relationship between C1 transpedicular screw trajectory and VA V3 segment. METHODS: Measurements were made on a workstation by using CTA data of 62 patients. Firstly, parameters related to the relationship between C1 vertebral artery groove (VAG) and vertebral artery (VA) were measured: (A) the shortest distance between the posterosuperior aspect of C1 posterior arch and VA; (B) distance between the outer aspect of VAG and VA; (C) distance between midpoint of VAG and VA; and (D) distance between the inner aspect of the VAG and VA. Then, the central axis of trajectory perpendicular to the coronal plane (axis P) and the central axis of trajectory with a medial inclination (axis M) were designed for the basis of measurements. Parameters related to the relationship between axis P/M and VA V3 segment were measured respectively: (E, E'), distance between insertion point and anterior aspect of VA along axis P/M; (F, F'), the shortest distance between axis P/M and the outer cortex of C1 transverse foramen; and (G, G'), the narrowest width of C1 internal medullary canal along axis P/M. RESULT: A, B, C, and D were 1.7+/-1.0 mm, 1.6+/-0.9 mm, 1.5+/-0.7 mm, 2.3+/-1.1 mm, respectively. E, E' were 5.5+/-1.7 mm and 4.1+/-2.3 mm. F, F' were 1.9+/-0.7 mm and 2.9+/-0.7 mm. G, G' were 3.7+/-1.4 mm and 4.8+/-1.2 mm. There was a little interspace between atlas VAG and VA, which was mainly filled with venous plexus. CONCLUSIONS: There is a close relationship between C1 transpedicular screw trajectory and VA V3 segment. Trajectory with medial inclination technique is suggested especially for female patients. PMID- 27503268 TI - Infant Strangulation from an Amber Teething Necklace. AB - Amber teething necklaces supposedly provide analgesia for teething infants. Their use is becoming more widespread, despite lack of peer-reviewed evidence and warnings from Health Canada that they pose a strangulation and aspiration risk. To date, there have been no published reports of strangulation secondary to amber teething necklaces. In this report we present a case of non-fatal infant strangulation from the first time use of an amber teething necklace. We will also discuss the role of physicians as advocates in reporting similar cases and educating families. Finally, we will comment on the responsibility of all professionals and professional organizations that work with infants and toddlers to advocate for children by raising concerns and counselling parents. PMID- 27503267 TI - Prostate-specific extracellular vesicles as a novel biomarker in human prostate cancer. AB - Extracellular vesicles (EVs) may play an important role in cancer development and progression. We aimed to investigate the prognostic potential of prostate specific EVs in prostate cancer (PCa) patients. Plasma and prostate tissue were collected from patients who underwent surgery for PCa (n = 82) or benign prostatic hyperplasia (BPH, n = 28). To analyze the quantity of EVs in prostate, we performed transmission electron microscopy (TEM), immuno-TEM with CD63 and prostate-specific membrane antigen (PSMA), and immunofluorescence staining. After EV isolation from plasma, CD63 and PSMA concentration was measured using ELISA kits. PSMA-positive areas in prostate differed in patients with BPH, and low-, intermediate-, and high-risk PCa (2.4, 8.2, 17.5, 26.5%, p < 0.001). Plasma PSMA positive EV concentration differed in patients with BPH, and low-, intermediate-, and high-risk PCa (21.9, 43.4, 49.2, 59.9 ng/mL, p < 0.001), and ROC curve analysis indicated that plasma PSMA-positive EV concentration differentiated PCa from BPH (AUC 0.943). Patients with lower plasma PSMA-positive EV concentration had greater prostate volume (50.2 vs. 33.4 cc, p < 0.001) and lower pathologic Gleason score (p = 0.025). During the median follow-up of 18 months, patients with lower plasma PSMA-positive EV concentration tended to have a lower risk of biochemical failure than those with higher levels of prostate-specific EVs (p = 0.085). PMID- 27503269 TI - Drosophila glob1 is required for the maintenance of cytoskeletal integrity during oogenesis. AB - BACKGROUND: Hemoglobins (Hbs) are evolutionarily conserved heme-containing metallo-proteins of the Globin protein family that harbour the characteristic "globin fold." Hemoglobins have been functionally diversified during evolution and their usual property of oxygen transport is rather a recent adaptation. Drosophila genome possesses three globin genes (glob1, glob2, and glob3), and we have reported earlier that adequate expression of glob1 is required for various aspects of development, as well as to regulate the cellular level of reactive oxygen species (ROS). The present study illustrates the explicit role of Drosophila globin1 in progression of oogenesis. RESULTS: We demonstrate a dynamic expression pattern of glob1 in somatic and germ cell derivatives of developing egg chambers during various stages of oogenesis, which largely confines around the F-actin-rich cellular components. Reduced expression of glob1 leads to various types of abnormalities during oogenesis, which were primarily mediated by the inappropriately formed F-actin-based cytoskeleton. Our subsequent analysis in the somatic and germ line clones shows cell autonomous role of glob1 in the maintenance of the integrity of F-actin-based cytoskeleton components in the somatic and germ cell derivatives. CONCLUSIONS: Our study establishes a novel role of glob1 in maintenance of F-actin-based cytoskeleton during progression of oogenesis in Drosophila. Developmental Dynamics 245:1048-1065, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27503271 TI - Increased Blood Viscosity in Ischemic Stroke Patients with Small Artery Occlusion Measured by an Electromagnetic Spinning Sphere Viscometer. AB - BACKGROUND AND PURPOSE: High blood viscosity causes blood stagnation and subsequent pathological thrombotic events, resulting in the development of ischemic stroke. We hypothesize that the contribution of blood viscosity may differ among ischemic stroke subtypes based on specific pathological conditions. We tried to verify this hypothesis by measuring blood viscosity in acute ischemic stroke patients using a newly developed electromagnetic spinning sphere (EMS) viscometer. METHODS: Measurements in acute ischemic stroke patients were performed 4 times during admission and data were compared with those obtained from 100 healthy outpatient volunteers. RESULTS: We enrolled 92 patients (cardioembolism: 25, large artery atherosclerosis: 42, and small artery occlusion [SAO]: 25) in this study. Comparisons of blood viscosity between the ischemic stroke subgroups and control group revealed that blood viscosity at the date of admission was significantly higher in the SAO group (5.37 +/- 1.11 mPa?s) than in the control group (4.66 +/- .72 mPa?s) (P < .01). Among all subtype groups showing a reduction in blood viscosity after 2 weeks, the SAO group showed the highest and most significant reduction, indicating that SAO patients had the most concentrated blood at the onset. CONCLUSIONS: Blood viscosity was significantly increased in the SAO group at the date of admission, which indicated the contribution of dehydration to the onset of ischemic stroke. The importance of dehydration needs to be emphasized more in the pathogenesis of SAO. The clinical application of the EMS viscometer is promising for understanding and differentiating the pathogenesis of ischemic stroke. PMID- 27503270 TI - Composite Membranes of Recombinant Silkworm Antimicrobial Peptide and Poly (L lactic Acid) (PLLA) for biomedical application. AB - Antimicrobial peptides, produced by innate immune system of hosts in response to invading pathogens, are capable of fighting against a spectrum of bacteria, viruses, fungi, parasites and cancer cells. Here, a recombinant silkworm AMP Bmattacin2 from heterologous expression is studied, indicating a broad spectrum of antibacterial activity and showing selective killing ability towards skin and colon cancer cells over their normal cell counterparts. For the purpose of biomedical application, the electrospinning fabrication technique is employed to load Bmattacin2 into PLLA nanofibrous membrane. In addition to a good compatibility with the normal cells, Bmattacin2 loaded nanofibrous membranes demonstrate instant antibacterial effects and sustained anticancer effects. The cancer cell and bacteria targeting dynamics of recombinant Bmattacin2 are investigated. With these characteristics, PLLA/Bmattacin2 composite membranes have a great potential for developing novel biomedical applications such as cancer therapies and wound healing treatments. PMID- 27503272 TI - Can Prediction of Functional Outcome after Stroke Be Improved by Adding Fibrinogen to Prognostic Model? AB - BACKGROUND: Several studies demonstrated that elevated plasma fibrinogen level is associated with poor functional outcome after ischemic stroke. It remains, however, unclear if prediction of functional outcome after stroke can be improved by adding fibrinogen to prognostic model. We aimed to determine the prognostic value of plasma fibrinogen for the prediction of functional outcome after ischemic stroke. METHODS: We retrospectively analyzed the data of 727 ischemic stroke patients (median age: 70; 48% men). The functional outcome was assessed 1 month after stroke onset using modified Rankin Scale. Unfavorable outcome was defined as modified Rankin Scale score higher than 2. Using C-statistic and reclassification measures (net reclassification improvement-NRI and integrated discrimination improvement-IDI), we compared the predictive abilities of 2 models. The first model contained stroke severity and age, and the second one included fibrinogen in addition. RESULTS: After adjusting for age and stroke severity, plasma fibrinogen level higher than 2.95 g/L was associated with unfavorable outcome (OR: 1.80, 95% CI: 1.20-2.72, P < .01). The addition of fibrinogen did not lead to an improvement in predictive ability of the model. C statistic did not differ between models (.90 versus .90, P = .34). The categorical NRI was .01 (P = .66) and the IDI was .006 (P = .08). CONCLUSIONS: The addition of fibrinogen to predictive model including age and stroke severity does not improve discrimination between favorable and unfavorable outcomes after ischemic stroke. PMID- 27503273 TI - Blood Pressure Is the Determinant for the Increased Risk for Intracranial Arterial Stenosis in Subjects with Elevated Glycated Hemoglobin Levels: The Kangbuk Samsung Health Study. AB - BACKGROUND AND PURPOSE: Ischemic stroke is known to be an important vascular complication of diabetes. Intracranial arterial stenosis (ICAS) is considered as an important cause of stroke in Asians. We aimed to analyze the risk for ICAS assessed by transcranial Doppler (TCD) ultrasonography in different groups of young Korean subjects divided by glycated hemoglobin (HbA1c) levels. METHODS: This study included 10,437 participants without history of cardiovascular diseases (81.3% men, mean age 43 years) from a health screening program, in whom TCD ultrasonography was used to detect greater than 50% ICAS based on criteria modified from the SONIA (Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis) trial. The subjects were divided into 3 groups according to HbA1c levels: HbA1c < 5.7%, 5.7 <= HbA1c < 6.5%, and HbA1c >= 6.5% or under medication for diabetes. RESULTS: Among the participants, 3.0% of the subjects had ICAS. The subjects with ICAS tended to have higher mean HbA1c level compared with those without ICAS (5.8 +/- .8 versus 5.7 +/- .6, P = .063). The proportion of subjects with ICAS significantly increased as the HbA1c increased from the first to the third group (2.8%, 3.0%, 4.6%, P for linear trend = .022). In logistic regression analysis with ICAS as the dependent variable, the group with HbA1c >= 6.5% showed significantly increased odds ratio for ICAS with subjects with HbA1c < 5.7% as the reference after adjustment for confounding variables (1.575, 95% confidence interval 1.056-2.347). However, this significance disappeared with inclusion of presence of hypertension in the model. CONCLUSIONS: The risk for ICAS assessed by TCD was increased in young Korean subjects with HbA1c >= 6.5%. However, this significance was attenuated after adjustment for presence of hypertension, suggesting the importance of hypertension in ICAS. PMID- 27503274 TI - A hole inversion layer at the BiVO4/Bi4V2O11 interface produces a high tunable photovoltage for water splitting. AB - The conversion of solar energy into hydrogen fuel by splitting water into photoelectrochemical cells (PEC) is an appealing strategy to store energy and minimize the extensive use of fossil fuels. The key requirement for efficient water splitting is producing a large band bending (photovoltage) at the semiconductor to improve the separation of the photogenerated charge carriers. Therefore, an attractive method consists in creating internal electrical fields inside the PEC to render more favorable band bending for water splitting. Coupling ferroelectric materials exhibiting spontaneous polarization with visible light photoactive semiconductors can be a likely approach to getting higher photovoltage outputs. The spontaneous electric polarization tends to promote the desirable separation of photogenerated electron- hole pairs and can produce photovoltages higher than that obtained from a conventional p-n heterojunction. Herein, we demonstrate that a hole inversion layer induced by a ferroelectric Bi4V2O11 perovskite at the n-type BiVO4 interface creates a virtual p-n junction with high photovoltage, which is suitable for water splitting. The photovoltage output can be boosted by changing the polarization by doping the ferroelectric material with tungsten in order to produce the relatively large photovoltage of 1.39 V, decreasing the surface recombination and enhancing the photocurrent as much as 180%. PMID- 27503275 TI - Effect of pre-miRNA-1658 gene polymorphism on chicken growth and carcass traits. AB - OBJECTIVE: Polymorphisms occurring in the precursor region of microRNAs (miRNAs) affect the target gene and alter the biogenesis of miRNAs, resulting in phenotypic variation. The purpose of the study was to investigate the genetic effects of rs16681031 (C>G) mutation in the precursor region of gga-miR-1658 on the economic traits of the Gushi-Anka chicken F2 resource population. METHODS: To explore the effect of miR-1658 polymorphisms on chicken economic traits, the SNP was genotyped by MassArray matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The association between the SNP and chicken body size, growth and carcass traits was determined by linear mixed models. RESULTS: The SNP was not only significantly associated with body weight at the age of 6, 8, 10, 12 weeks, respectively, but also with the breadth of the chicken chest, body slanting length and pelvic breadth at 4 weeks, chest depth at 8 weeks of age, and body slanting length at 12 weeks (p<0.05), respectively. CONCLUSION: Our data serve as a useful resource for further analysis of miRNA function, and represent a molecular genetic basis for poultry breeding. PMID- 27503276 TI - Allosteric HIV-1 integrase inhibitors promote aberrant protein multimerization by directly mediating inter-subunit interactions: Structural and thermodynamic modeling studies. AB - Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) bind at the dimer interface of the IN catalytic core domain (CCD), and potently inhibit HIV-1 by promoting aberrant, higher-order IN multimerization. Little is known about the structural organization of the inhibitor-induced IN multimers and important questions regarding how ALLINIs promote aberrant IN multimerization remain to be answered. On the basis of physical chemistry principles and from our analysis of experimental information, we propose that inhibitor-induced multimerization is mediated by ALLINIs directly promoting inter-subunit interactions between the CCD dimer and a C-terminal domain (CTD) of another IN dimer. Guided by this hypothesis, we have built atomic models of inter-subunit interfaces in IN multimers by incorporating information from hydrogen-deuterium exchange (HDX) measurements to drive protein-protein docking. We have also developed a novel free energy simulation method to estimate the effects of ALLINI binding on the association of the CCD and CTD. Using this structural and thermodynamic modeling approach, we show that multimer inter-subunit interface models can account for several experimental observations about ALLINI-induced multimerization, including large differences in the potencies of various ALLINIs, the mechanisms of resistance mutations, and the crucial role of solvent exposed R-groups in the high potency of certain ALLINIs. Our study predicts that CTD residues Tyr226, Trp235 and Lys266 are involved in the aberrant multimer interfaces. The key finding of the study is that it suggests the possibility of ALLINIs facilitating inter-subunit interactions between an external CTD and the CCD-CCD dimer interface. PMID- 27503277 TI - The role of glycemia in insulin resistance in youth with type 1 and type 2 diabetes. AB - BACKGROUND: Hyperglycemia has traditionally been considered a major contributor to insulin resistance (IR) in type 1 diabetes (T1D), yet studies examining the relationship between HbA1c and IR are conflicting. Glucose measures captured by continuous glucose monitoring (CGM) (eg, peak glucose, standard deviation, hypoglycemia) in youth have not been explored as predictors of insulin sensitivity (IS). OBJECTIVE: Assess the relationship between IS and glycemia in youth with T1D and type 2 diabetes (T2D). METHODS: Sedentary 12-19 year olds with diabetes had peripheral IS measured by hyperinsulinemic-euglycemic clamp. HbA1c and 3 days of CGM data were also collected. Spearman correlation coefficients were calculated to examine the association between variables. RESULTS: Participants included 100 youth with T1D [46% male, median body mass index (BMI) 74 percentile, HbA1c 8.5%] and 42 with T2D (26% male, BMI 99 percentile, HbA1c 6.9%). Nineteen with T1D and 13 with T2D also wore CGM. In T2D youth, higher HbA1c, average sensor glucose, area under the CGM curve, and metabolic syndrome characteristics correlated with lower IS. In T1D youth, higher BMI percentile, waist circumference, triglycerides, and LDL cholesterol, but not HbA1c, correlated with lower IS. Moreover, higher CGM overnight means glucose correlated with greater IS, and CGM hypoglycemia correlated with lower IS. CONCLUSIONS: Markers of metabolic syndrome and hyperglycemia predicted decreased IS in T2D youth. Paradoxically, hypoglycemia predicted decreased IS in T1D youth and hyperglycemia, particularly overnight, predicted improved IS. These preliminary results imply different mechanisms underlying IR in T1D vs T2D and suggest a role for non-insulin therapies in T1D to improve IR. PMID- 27503278 TI - [Aplasia cutis congenita: Update and management]. AB - Congenital skin aplasia, or aplasia cutis congenita (ACC) is a rare congenital disease. It is characterized by the absence of skin at birth, localized or widespread, of one or several areas. This condition commonly involve the scalp but can also involve more rarely the trunk or limbs. However it is most frequently an isolated disorder, it can be associated with other anomalies, such as the Adams-Oliver syndrome, the association with a fetus papyraceus or with an epidermolysis bullosa. Many hypothesis have been suggested: vascular, genetic, traumatic, pharmacological or an anomaly in the neural tube closure process, but the exact mechanism is still unknown. Morbidity and mortality of this malformation depends on the affected area and the size of the defect. The main risk is the infection, hemorrhage and thrombosis in the case of a scalp defect with an underlying bone defect, the exposure of the meninges and the superior sagittal sinus. The initial management of ACC will therefore involve several plastic surgery techniques, from more simple to more complex, using conservative wound care to flaps techniques. Other techniques can be performed later, in the management of ACC sequelae, such as skin expansion for scarring alopecia. PMID- 27503279 TI - The solely motif-doped Au36-xAgx(SPh-tBu)24 (x = 1-8) nanoclusters: X-ray crystal structure and optical properties. AB - We report the observation of new doping behavior in Au36-xAgx(SR)24 nanoclusters (NCs) with x = 1 to 8. The atomic arrangements of Au and Ag atoms are determined by X-ray crystallography. The new gold-silver bimetallic NCs share the same framework as that of the homogold counterpart, i.e. possessing an fcc-type Au28 kernel, four dimeric AuAg(SR)3 staple motifs and twelve simple bridging SR ligands. Interestingly, all the Ag dopants in the Au36-xAgx(SR)24 NCs are selectively incorporated into the surface motifs, which is in contrast to the previously reported Au-Ag alloy structures with the Ag dopants preferentially displacing the core gold atoms. This distinct doping behavior implies that the previous assignments of an fcc Au28 core with four dimers and 12 bridging thiolates for Au36(SR)24 are more justified than other assignments of core vs. surface motifs. The UV-Vis adsorption spectrum of Au36-xAgx(SR)24 is almost the same as that of Au36(SR)24, indicating that the Ag dopants in the motifs do not change the optical properties. The similar UV-Vis spectra are further confirmed by TD-DFT calculations. DFT also reveals that the energies of the HOMO and LUMO of the motif-doped AuAg alloy NC are comparable to those of the homogold Au36 NC, indicating that the electronic structure is not disturbed by the motif Ag dopants. Overall, this study reveals a new silver-doping mode in alloy NCs. PMID- 27503280 TI - Early recognition of coeliac disease through community pharmacies: a proof of concept study. AB - Setting Fifteen community pharmacies in the UK. Objective Proof of concept study to test the use of community pharmacies for active case finding of patients with coeliac disease. Methods Customers accessing over-the counter and prescription medicines indicated in the treatment of possible symptoms of coeliac disease over a 6 month period were offered a free point of care test. All patients were given advice regarding the test results and those who tested positive were advised to make an appointment with their general practitioner. Patients and pharmacists involved in service provision were asked to complete a satisfaction survey. Pharmacists were additionally invited to undertake interviews to better understand their views on the service. Main outcome measures Feasibility of service, acceptability to stakeholders and proportion testing positive for coeliac disease. Results Of the 551 individuals tested, 52 (9.4 %) tested positive. 277 (50.3 %) were tested for accessing irritable bowel syndrome treatment, 142 (25.8 %) due to presenting for diarrhoea. The proportion of patients testing positive with different symptoms or for different treatments were similar. Of 43 customers who returned the satisfaction survey, all would recommend the service to others, believing the community pharmacy to be a suitable location. Community pharmacists believed that it enabled them to improve relationships with their customers and that medical practices were receptive to the service. Conclusion This proof of concept study has shown that community pharmacies using a point of care test can effectively recognise and refer patients for confirmatory coeliac disease testing with high levels of customer and service provider satisfaction. PMID- 27503281 TI - Patients' knowledge and attitude towards therapeutic reference pricing system in Slovenia. AB - Background The therapeutic reference pricing (TRP) in Slovenia was implemented for proton pump inhibitors in 2013 and for angiotensin-converting enzyme inhibitors and lipid-lowering medicines in 2014. Objective The study aimed to assess patients' knowledge and attitude towards the TRP system. Moreover, the patients' willingness to pay was evaluated for patients who rejected the substitution of a current medicine within a therapeutic class by the reference medicine for which no co-payment is needed. Setting Invitation of patients to participate in a survey and filling in the first part of the questionnaire was run in the community pharmacies in Slovenia. The second part of the questionnaire was filled in at patients' home. Method A representative sample of 676 patients that had been prescribed at least one medicine from the three therapeutic classes was surveyed. The survey was carried out from 15th May to 15th June 2014 in 40 community pharmacies with the help of the pharmacists, who filled in the first part of the questionnaire in the presence of the patients. The second part of the questionnaire was filled in by 475 patients at home and returned by prepaid mail. Main outcome measure Patients' knowledge of and attitude to the TRP system implemented into Slovenian health care practice. Results Most of the statements describing patient' rights and duties within the TRP system were known by approximately 50 % of the patients. Patients were inhomogeneous in their view about the necessity and benefits of the TRP system, most of them regarded it as an unnecessary burden. Among 50.4 % of the patients who were required to copay for their medicine, 46.7 % accepted and 3.7 % rejected co-payment. The average co payment was ? 6.92, while the expressed average willingness to co-pay was ? 10.4 per 3 months of therapy. Conclusion Our results indicate that the implementation of the TRP system and potential upgrades represent a significant challenge for the patients. PMID- 27503282 TI - Potentially inappropriate prescribing in nursing home residents detected with the community pharmacist specific GheOP(3)S-tool. AB - Background The Ghent Older People's Prescriptions community Pharmacy Screening (GheOP3S-)tool was recently developed to screen for potentially inappropriate prescribing (PIP). Objective We aimed (1) to determine PIP prevalence in older nursing home (NH) residents with polypharmacy using the GheOP3S-tool and (2) to identify those PIPs that are most frequently detected. Method A cross-sectional study was carried out between February and June 2014 in 10 NHs in Belgium, supplied by a community pharmacy chain. For each NH, 40 residents (>=70 years, using >=5 chronic drugs) were included. PIP prevalence was determined using the GheOP3S-tool. Results 400 NH residents were included [mean age (+/-SD) 86.2 (+/ 6.3) years; median number of drugs (+/-IQR) 10 (7-12)]. A total of 1728 PIPs were detected in 387 (97 %) participants (Median 4; IQR 2-6). The most prevalent items can be assigned to three categories: long-term use of central nervous system drugs (i.e. benzodiazepines, antidepressants and antipsychotics), use of anticholinergic drugs (mutual combinations and with underlying constipation/dementia) and underuse of osteoporosis prophylaxis. Conclusion Screening for PIP by means of the GheOP3S-tool revealed a high prevalence of PIP among older NH residents with polypharmacy. This finding urges for initiatives on the patient-level, but also on a broader, institutional level. PMID- 27503283 TI - Sources and magnitude of error in preparing morphine infusions for nurse-patient controlled analgesia in a UK paediatric hospital. AB - Background Administering nurse/patient controlled analgesia (N/PCA) to children requires complex dose calculations and multiple manipulations to prepare morphine solutions in 50 mL syringes for administration by continuous infusion with additional boluses. Objective To investigate current practice and accuracy during preparation of morphine N/PCA infusions in hospital theatres and wards at a UK children's hospital. Methods Direct observation of infusion preparation methods and morphine concentration quantification using UV-Vis spectrophotometry. The British Pharmacopoeia specification for morphine sulphate injection drug content (+/-7.5 %) was used as a reference limit. Results Preparation of 153 morphine infusions for 128 paediatric patients was observed. Differences in preparation method were identified, with selection of inappropriate syringe size noted. Lack of appreciation of the existence of a volume overage (i.e. volume in excess of the nominal volume) in morphine ampoules was identified. Final volume of the infusion was greater than the target (50 mL) in 33.3 % of preparations. Of 78 infusions analysed, 61.5 % had a morphine concentration outside 92.5-107.5 % of label strength. Ten infusions deviated by more than 20 %, with one by 100 %. Conclusions Variation in morphine infusion preparation method was identified. Lack of appreciation of the volume overage in ampoules, volumetric accuracy of different syringe sizes and ability to perform large dilutions of small volumes were sources of inaccuracy in infusion concentration, resulting in patients receiving morphine doses higher or lower than prescribed. PMID- 27503284 TI - Comment on: "Safety and Tolerability of Pharmacological Treatment of Alcohol Dependence: Comprehensive Review of Evidence". PMID- 27503285 TI - Authors' Reply to Alain Braillon's Comment on "Safety and Tolerability of Pharmacological Treatment of Alcohol Dependence: Comprehensive Review of Evidence". PMID- 27503286 TI - Patient-centeredness and its impact on patient satisfaction and treatment outcomes in medical rehabilitation. AB - OBJECTIVE: To examine the impact of patient-centeredness for patient satisfaction and treatment outcomes. METHOD: A multicenter cross-sectional survey study with patients (n=1033) in nine medical rehabilitation centers in Germany was conducted. Data was analyzed with multiple linear regression. Predictors were patient-centeredness (CCRQ-15) and patients age, employment and therapeutic indication; outcomes were patient satisfaction and treatment outcomes (changes in living conditions and health status). RESULTS: The regression model could explain 54% of variance in patient satisfaction. The strongest predictor was decision making/communication (beta=0.34). In treatment outcome, 19% of variance of changes in living conditions and 21% of variance of changes in state of health could be explained. The strongest predictor in both variables was self management/empowerment (beta=0.40 and 0.32, respectively). CONCLUSION: The results emphasize the relevance of patient-centered treatments for patient satisfaction and treatment results. The evidence is provided for the first time in medical rehabilitation. PRACTICE IMPLICATIONS: Further studies should consider multilevel modeling and diverse survey methods. Continued implementation and evaluation of patient-centeredness in the medical rehabilitation treatment are recommended measures. Promoting shared decision-making, effective clinician patient communication, and increased patient empowerment are essential, e.g. by patient education programs or staff training in shared decision-making. PMID- 27503287 TI - "We'll call you when the results are in": Preferences for how medical test results are delivered. AB - OBJECTIVE: Whether healthy or sick, adults undergo frequent medical testing; however, no guidelines currently exist as to how patients are informed of their medical test results. This short report provides an initial look at how healthcare professionals deliver medical test results and patient preferences regarding these procedures. METHODS: We specifically focus on two options for delivery of results: (1) open-ended timing, in which patients are contacted without warning when test results become available; or (2) closed-ended timing, in which patients are provided with a specific day and time when they will learn their test results. Participants who underwent a recent medical test indicated which delivery method their healthcare professional provided and their preferred method. RESULTS: Findings demonstrate a large discrepancy between actual and preferred timing, stemming from a general trend towards providing open-ended timing, whereas patient preferences were evenly split between the two options. CONCLUSION: This study provides a first step in understanding the merits of two options for delivering medical test results to patients and suggests an opportunity to improve patient care. PRACTICE IMPLICATIONS: The findings from this study provide first steps toward the development of guidelines for delivering test results in ways that maximize the quality of patient care. PMID- 27503288 TI - Identification of susceptibility gene associated with female primary Sjogren's syndrome in Han Chinese by genome-wide association study. AB - Primary Sjogren's syndrome (PSS) is an autoimmune disease targeting exocrine glands. It ten times more dominantly affects women than men with an onset peak at menopause. The genetic factor predisposing women to PSS remains unclear. Therefore, we aimed to identify susceptibility loci for PSS in women. We performed genome-wide association study (GWAS) using 242 female PSS patients and 1444 female control in Han Chinese population residing in Taiwan. Replication was conducted in an independent cohort of 178 female PSS and 14,432 control subjects. We identified rs117026326 on GTF2I with GWAS significance (P = 1.10 * 10-15) and rs13079920 on RBMS3 with suggestive significance (P = 2.90 * 10-5) associating with PSS in women. The association of RBMS3 was further evidenced by imputation in which rs13072846 (P = 4.89 * 10-5) was identified and confirmed as female PSS associating SNP within the same LD with rs13079920. PSS pathogenesis involves both immune (effector) and exocrine (target) system. We suggested that while GTF2I is a previously reported associating gene which may function in immune system, RBMS3 is a novel susceptibility gene that predisposes women to PSS potentially through modulating acinar apoptosis and TGF-beta signaling in target exocrine system. PMID- 27503289 TI - Mutations in CIT, encoding citron rho-interacting serine/threonine kinase, cause severe primary microcephaly in humans. AB - Primary microcephaly is a clinical phenotype in which the head circumference is significantly reduced at birth due to abnormal brain development, primarily at the cortical level. Despite the marked genetic heterogeneity, most primary microcephaly-linked genes converge on mitosis regulation. Two consanguineous families segregating the phenotype of severe primary microcephaly, spasticity and failure to thrive had overlapping autozygomes in which exome sequencing identified homozygous splicing variants in CIT that segregate with the phenotype within each family. CIT encodes citron, an effector of the Rho signaling that is required for cytokinesis specifically in proliferating neuroprogenitors, as well as for postnatal brain development. In agreement with the critical role assigned to the kinase domain in effecting these biological roles, we show that both splicing variants predict variable disruption of this domain. The striking phenotypic overlap between CIT-mutated individuals and the knockout mice and rats that are specifically deficient in the kinase domain supports the proposed causal link between CIT mutation and primary microcephaly in humans. PMID- 27503290 TI - Mechanistically Distinct Pathways of Divergent Regulatory DNA Creation Contribute to Evolution of Human-Specific Genomic Regulatory Networks Driving Phenotypic Divergence of Homo sapiens. AB - Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the hypothesis that unique to human phenotypes result from human-specific alterations of genomic regulatory networks. Collectively, a compendium of multiple diverse families of HSRS that are functionally and structurally divergent from Great Apes could be defined as the backbone of human specific genomic regulatory networks. Here, the conservation patterns analysis of 18,364 candidate HSRS was carried out requiring that 100% of bases must remap during the alignments of human, chimpanzee, and bonobo sequences. A total of 5,535 candidate HSRS were identified that are: (i) highly conserved in Great Apes; (ii) evolved by the exaptation of highly conserved ancestral DNA; (iii) defined by either the acceleration of mutation rates on the human lineage or the functional divergence from non-human primates. The exaptation of highly conserved ancestral DNA pathway seems mechanistically distinct from the evolution of regulatory DNA segments driven by the species-specific expansion of transposable elements. Genome-wide proximity placement analysis of HSRS revealed that a small fraction of topologically associating domains (TADs) contain more than half of HSRS from four distinct families. TADs that are enriched for HSRS and termed rapidly evolving in humans TADs (revTADs) comprise 0.8-10.3% of 3,127 TADs in the hESC genome. RevTADs manifest distinct correlation patterns between placements of human accelerated regions, human-specific transcription factor-binding sites, and recombination rates. There is a significant enrichment within revTAD boundaries of hESC-enhancers, primate-specific CTCF-binding sites, human-specific RNAPII binding sites, hCONDELs, and H3K4me3 peaks with human-specific enrichment at TSS in prefrontal cortex neurons (P < 0.0001 in all instances). Present analysis supports the idea that phenotypic divergence of Homo sapiens is driven by the evolution of human-specific genomic regulatory networks via at least two mechanistically distinct pathways of creation of divergent sequences of regulatory DNA: (i) recombination-associated exaptation of the highly conserved ancestral regulatory DNA segments; (ii) human-specific insertions of transposable elements. PMID- 27503291 TI - Inevitability of Genetic Parasites. AB - Almost all cellular life forms are hosts to diverse genetic parasites with various levels of autonomy including plasmids, transposons and viruses. Theoretical modeling of the evolution of primordial replicators indicates that parasites (cheaters) necessarily evolve in such systems and can be kept at bay primarily via compartmentalization. Given the (near) ubiquity, abundance and diversity of genetic parasites, the question becomes pertinent: are such parasites intrinsic to life? At least in prokaryotes, the persistence of parasites is linked to the rate of horizontal gene transfer (HGT). We mathematically derive the threshold value of the minimal transfer rate required for selfish element persistence, depending on the element duplication and loss rates as well as the cost to the host. Estimation of the characteristic gene duplication, loss and transfer rates for transposons, plasmids and virus-related elements in multiple groups of diverse bacteria and archaea indicates that most of these rates are compatible with the long term persistence of parasites. Notably, a small but non-zero rate of HGT is also required for the persistence of non-parasitic genes. We hypothesize that cells cannot tune their horizontal transfer rates to be below the threshold required for parasite persistence without experiencing highly detrimental side-effects. As a lower boundary to the minimum DNA transfer rate that a cell can withstand, we consider the process of genome degradation and mutational meltdown of populations through Muller's ratchet. A numerical assessment of this hypothesis suggests that microbial populations cannot purge parasites while escaping Muller's ratchet. Thus, genetic parasites appear to be virtually inevitable in cellular organisms. PMID- 27503292 TI - Diurnal Transcriptional Regulation of Endosymbiotically Derived Genes in the Chlorarachniophyte Bigelowiella natans. AB - Chlorarachniophyte algae possess complex plastids acquired by the secondary endosymbiosis of a green alga, and the plastids harbor a relict nucleus of the endosymbiont, the so-called nucleomorph. Due to massive gene transfer from the endosymbiont to the host, many proteins involved in plastid and nucleomorph are encoded by the nuclear genome. Genome sequences have provided a blueprint for the fate of endosymbiotically derived genes; however, transcriptional regulation of these genes remains poorly understood. To gain insight into the evolution of endosymbiotic genes, we performed genome-wide transcript profiling along the cell cycle of the chlorarachniophyte Bigelowiella natans, synchronized by light and dark cycles. Our comparative analyses demonstrated that transcript levels of 7,751 nuclear genes (35.7% of 21,706 genes) significantly oscillated along the diurnal/cell cycles, and those included 780 and 147 genes for putative plastid and nucleomorph-targeted proteins, respectively. Clustering analysis of those genes revealed the existence of transcriptional networks related to specific biological processes such as photosynthesis, carbon metabolism, translation, and DNA replication. Interestingly, transcripts of many plastid-targeted proteins in B. natans were induced before dawn, unlike other photosynthetic organisms. In contrast to nuclear genes, 99% nucleomorph genes were found to be constitutively expressed during the cycles. We also found that the nucleomorph DNA replication would be controlled by a nucleus-encoded viral-like DNA polymerase. The results of this study suggest that nucleomorph genes have lost transcriptional regulation along the diurnal cycles, and nuclear genes exert control over the complex plastid including the nucleomorph. PMID- 27503293 TI - Multiple Lines of Evidence from Mitochondrial Genomes Resolve Phylogenetic Relationships of Parasitic Wasps in Braconidae. AB - The rapid increase in the number of mitochondrial genomes in public databases provides opportunities for insect phylogenetic studies; but it also provides challenges because of gene rearrangements and variable substitution rates among both lineages and sites. Typically, phylogenetic studies use mitochondrial sequence data but exclude other features of the mitochondrial genome from analyses. Here, we undertook large-scale sequencing of mitochondrial genomes from a worldwide collection of specimens belonging to Braconidae, one of the largest families of Metazoa. The strand-asymmetry of base composition in the mitochondrial genomes of braconids is reversed, providing evidence for monophyly of the Braconidae. We have reconstructed a backbone phylogeny of the major lineages of Braconidae from gene order of the mitochondrial genomes. Standard phylogenetic analyses of DNA sequences provided strong support for both Cyclostomes and Noncyclostomes. Four subfamily complexes, that is, helconoid, euphoroid, sigalphoid, and microgastroid, within the Noncyclostomes were reconstructed robustly, the first three of which formed a monophyletic group sister to the last one. Aphidiinae was recovered as a lineage sister to other groups of Cyclostomes, while the Ichneutinae was recovered as paraphyletic. Separate analyses of the subdivided groups showed congruent relationships, employing different matrices and methods, for the internal nodes of the Cyclostomes and the microgastroid complex of subfamilies. This research, using multiple lines of evidence from mitochondrial genomes, illustrates multiple uses of mitochondrial genomes for phylogenetic inference in Braconidae. PMID- 27503294 TI - Epigenetic Variability across Human Populations: A Focus on DNA Methylation Profiles of the KRTCAP3, MAD1L1 and BRSK2 Genes. AB - Natural epigenetic diversity has been suggested as a key mechanism in microevolutionary processes due to its capability to create phenotypic variability within individuals and populations. It constitutes an important reservoir of variation potentially useful for rapid adaptation in response to environmental stimuli. The analysis of population epigenetic structure represents a possible tool to study human adaptation and to identify external factors that are able to naturally shape human DNA methylation variability. The aim of this study is to investigate the dynamics that create epigenetic diversity between and within different human groups. To this end, we first used publicly available epigenome-wide data to explore population-specific DNA methylation changes that occur at macro-geographic scales. Results from this analysis suggest that nutrients, UVA exposure and pathogens load might represent the main environmental factors able to shape DNA methylation profiles. Then, we evaluated DNA methylation of candidate genes (KRTCAP3, MAD1L1, and BRSK2), emerged from the previous analysis, in individuals belonging to different populations from Morocco, Nigeria, Philippines, China, and Italy, but living in the same Italian city. DNA methylation of the BRSK2 gene is significantly different between Moroccans and Nigerians (pairwise t-test: CpG 6 P-value = 5.2*10 (-) (3); CpG 9 P value = 2.6*10 (-) (3); CpG 10 P-value = 3.1*10 (-) (3); CpG 11 P-value = 2.8*10 (-) (3)). Comprehensively, these results suggest that DNA methylation diversity is a source of variability in human groups at macro and microgeographical scales and that population demographic and adaptive histories, as well as the individual ancestry, actually influence DNA methylation profiles. PMID- 27503295 TI - The Role of Retrotransposons in Gene Family Expansions in the Human and Mouse Genomes. AB - Retrotransposons comprise a large portion of mammalian genomes. They contribute to structural changes and more importantly to gene regulation. The expansion and diversification of gene families have been implicated as sources of evolutionary novelties. Given the roles retrotransposons play in genomes, their contribution to the evolution of gene families warrants further exploration. In this study, we found a significant association between two major retrotransposon classes, LINEs and LTRs, and lineage-specific gene family expansions in both the human and mouse genomes. The distribution and diversity differ between LINEs and LTRs, suggesting that each has a distinct involvement in gene family expansion. LTRs are associated with open chromatin sites surrounding the gene families, supporting their involvement in gene regulation, whereas LINEs may play a structural role promoting gene duplication. Our findings also suggest that gene family expansions, especially in the mouse genome, undergo two phases. The first phase is characterized by elevated deposition of LTRs and their utilization in reshaping gene regulatory networks. The second phase is characterized by rapid gene family expansion due to continuous accumulation of LINEs and it appears that, in some instances at least, this could become a runaway process. We provide an example in which this has happened and we present a simulation supporting the possibility of the runaway process. Altogether we provide evidence of the contribution of retrotransposons to the expansion and evolution of gene families. Our findings emphasize the putative importance of these elements in diversification and adaptation in the human and mouse lineages. PMID- 27503296 TI - Comparative Large-Scale Mitogenomics Evidences Clade-Specific Evolutionary Trends in Mitochondrial DNAs of Bivalvia. AB - Despite the figure of complete bivalve mitochondrial genomes keeps growing, an assessment of the general features of these genomes in a phylogenetic framework is still lacking, despite the fact that bivalve mitochondrial genomes are unusual under different aspects. In this work, we constructed a dataset of one hundred mitochondrial genomes of bivalves to perform the first systematic comparative mitogenomic analysis, developing a phylogenetic background to scaffold the evolutionary history of the class' mitochondrial genomes. Highly conserved domains were identified in all protein coding genes; however, four genes (namely, atp6, nad2, nad4L, and nad6) were found to be very divergent for many respects, notwithstanding the overall purifying selection working on those genomes. Moreover, the atp8 gene was newly annotated in 20 mitochondrial genomes, where it was previously declared as lacking or only signaled. Supernumerary mitochondrial proteins were compared, but it was possible to find homologies only among strictly related species. The rearrangement rate on the molecule is too high to be used as a phylogenetic marker, but here we demonstrate for the first time in mollusks that there is correlation between rearrangement rates and evolutionary rates. We also developed a new index (HERMES) to estimate the amount of mitochondrial evolution. Many genomic features are phylogenetically congruent and this allowed us to highlight three main phases in bivalve history: the origin, the branching of palaeoheterodonts, and the second radiation leading to the present-day biodiversity. PMID- 27503297 TI - Weak Polygenic Selection Drives the Rapid Adaptation of the Chemosensory System: Lessons from the Upstream Regions of the Major Gene Families. AB - The animal chemosensory system is involved in essential biological processes, most of them mediated by proteins encoded in multigene families. These multigene families have been fundamental for the adaptation to new environments, significantly contributing to phenotypic variation. This adaptive potential contrasts, however, with the lack of studies at their upstream regions, especially taking into account the evidence linking their transcriptional changes to certain phenotypic effects. Here, we explicitly characterize the contribution of the upstream sequences of the major chemosensory gene families to rapid adaptive processes. For that, we analyze the genome sequences of 158 lines from a population of Drosophila melanogaster that recently colonized North America, and integrate functional and transcriptional data available for this species. We find that both, strong negative and strong positive selection, shape transcriptional evolution at the genome-wide level. The chemosensory upstream regions, however, exhibit a distinctive adaptive landscape, including multiple mutations of small beneficial effect and a reduced number of cis-regulatory elements. Together, our results suggest that the promiscuous and partially redundant transcription and function of the chemosensory genes provide evolutionarily opportunities for rapid adaptive episodes through weak polygenic selection. PMID- 27503298 TI - Mitochondrion-to-Chloroplast DNA Transfers and Intragenomic Proliferation of Chloroplast Group II Introns in Gloeotilopsis Green Algae (Ulotrichales, Ulvophyceae). AB - To probe organelle genome evolution in the Ulvales/Ulotrichales clade, the newly sequenced chloroplast and mitochondrial genomes of Gloeotilopsis planctonica and Gloeotilopsis sarcinoidea (Ulotrichales) were compared with those of Pseudendoclonium akinetum (Ulotrichales) and of the few other green algae previously sampled in the Ulvophyceae. At 105,236 bp, the G planctonica mitochondrial DNA (mtDNA) is the largest mitochondrial genome reported so far among chlorophytes, whereas the 221,431-bp G planctonica and 262,888-bp G sarcinoidea chloroplast DNAs (cpDNAs) are the largest chloroplast genomes analyzed among the Ulvophyceae. Gains of non-coding sequences largely account for the expansion of these genomes. Both Gloeotilopsis cpDNAs lack the inverted repeat (IR) typically found in green plants, indicating that two independent IR losses occurred in the Ulvales/Ulotrichales. Our comparison of the Pseudendoclonium and Gloeotilopsis cpDNAs offered clues regarding the mechanism of IR loss in the Ulotrichales, suggesting that internal sequences from the rDNA operon were differentially lost from the two original IR copies during this process. Our analyses also unveiled a number of genetic novelties. Short mtDNA fragments were discovered in two distinct regions of the G sarcinoidea cpDNA, providing the first evidence for intracellular inter-organelle gene migration in green algae. We identified for the first time in green algal organelles, group II introns with LAGLIDADG ORFs as well as group II introns inserted into untranslated gene regions. We discovered many group II introns occupying sites not previously documented for the chloroplast genome and demonstrated that a number of them arose by intragenomic proliferation, most likely through retrohoming. PMID- 27503300 TI - Feasibility of triphasic CT with a modified two-point Patlak plot to determine spit kidney glomerular filtration rate in clinical practice. AB - PURPOSE: To investigate whether triphasic CT with a simplified Patlak plot can be used in clinical practice for the estimate of split kidney glomerular filtration rate (SKGFR). MATERIALS AND METHODS: The animal experiment included 15 rabbits that underwent 40 dynamic contrast-enhanced CT scans of the kidneys with 1.5 s time interval. Patlak-derived SKGFR was obtained using standard forty-point, two point (unenhanced phase, arterial phase t alpha, and portovenous phase t beta), and a modified two-point (MTP) (unenhanced, t alpha, t beta, and a virtual t tau [t tau = (t alpha + t beta)/2]) image data, respectively. The MTP-Patlak plot approach was then validated in 13 patients who underwent a triphasic renal contrast-enhanced CT examination. SKGFR measured by 99mTc-DTPA clearance was as a standard reference. RESULTS: MTP-Patlak significantly reduced input function errors than two-point Patlak (21.1 +/- 16.2 % vs 30.8 +/- 15.2 %, p < 0.01) and showed good concordance with standard Patlak for measurement of SKGFR in animal experiment (1.20 +/- 0.38 mL/g/min vs 1.51 +/- 0.43 mL/g/min; linear correlation coefficient r = 0.87, p < 0.001). Human study showed that mean SKGFR was 45.7 mL/min (range, 26.5-86.2 mL/min) obtained from 99mTc-DTPA, and 38.2 mL/min (range, 18.6-79.3 mL/min) obtained from triphasic CT using MTP-Patlak plot. Linear correlation between the two methods was r = 0.75 (p < 0.01). The mean difference between SKGFRs as determined with the two methods was 7.4 +/- 9.0 mL/min. CONCLUSION: The MTP-Patlak approach, featured with simplicity, is feasible in a clinically indicated CT examination for the evaluation of split renal function. PMID- 27503299 TI - Comparative Metagenomic Analysis Reveals Mechanisms for Stress Response in Hypoliths from Extreme Hyperarid Deserts. AB - Understanding microbial adaptation to environmental stressors is crucial for interpreting broader ecological patterns. In the most extreme hot and cold deserts, cryptic niche communities are thought to play key roles in ecosystem processes and represent excellent model systems for investigating microbial responses to environmental stressors. However, relatively little is known about the genetic diversity underlying such functional processes in climatically extreme desert systems. This study presents the first comparative metagenome analysis of cyanobacteria-dominated hypolithic communities in hot (Namib Desert, Namibia) and cold (Miers Valley, Antarctica) hyperarid deserts. The most abundant phyla in both hypolith metagenomes were Actinobacteria, Proteobacteria, Cyanobacteria and Bacteroidetes with Cyanobacteria dominating in Antarctic hypoliths. However, no significant differences between the two metagenomes were identified. The Antarctic hypolithic metagenome displayed a high number of sequences assigned to sigma factors, replication, recombination and repair, translation, ribosomal structure, and biogenesis. In contrast, the Namib Desert metagenome showed a high abundance of sequences assigned to carbohydrate transport and metabolism. Metagenome data analysis also revealed significant divergence in the genetic determinants of amino acid and nucleotide metabolism between these two metagenomes and those of soil from other polar deserts, hot deserts, and non-desert soils. Our results suggest extensive niche differentiation in hypolithic microbial communities from these two extreme environments and a high genetic capacity for survival under environmental extremes. PMID- 27503301 TI - The Simple Video Coder: A free tool for efficiently coding social video data. AB - Videotaping of experimental sessions is a common practice across many disciplines of psychology, ranging from clinical therapy, to developmental science, to animal research. Audio-visual data are a rich source of information that can be easily recorded; however, analysis of the recordings presents a major obstacle to project completion. Coding behavior is time-consuming and often requires ad-hoc training of a student coder. In addition, existing software is either prohibitively expensive or cumbersome, which leaves researchers with inadequate tools to quickly process video data. We offer the Simple Video Coder-free, open source software for behavior coding that is flexible in accommodating different experimental designs, is intuitive for students to use, and produces outcome measures of event timing, frequency, and duration. Finally, the software also offers extraction tools to splice video into coded segments suitable for training future human coders or for use as input for pattern classification algorithms. PMID- 27503302 TI - Spanish semantic feature production norms for 400 concrete concepts. AB - Semantic feature production norms provide many quantitative measures of different feature and concept variables that are necessary to solve some debates surrounding the nature of the organization, both normal and pathological, of semantic memory. Despite the current existence of norms for different languages, there are still no published norms in Spanish. This article presents a new set of norms collected from 810 participants for 400 living and nonliving concepts among Spanish speakers. These norms consist of empirical collections of features that participants used to describe the concepts. Four files were elaborated: a concept feature file, a concept-concept matrix, a feature-feature matrix, and a significantly correlated features file. We expect that these norms will be useful for researchers in the fields of experimental psychology, neuropsychology, and psycholinguistics. PMID- 27503303 TI - Sgttoolbox: Utility for controlling SimpleGazeTracker from Psychtoolbox. AB - Eye movement analysis is effective for investigating visual perception and cognition. The cost of conducting eye movement studies has decreased as a result of the recent release of low-cost commercial and open-source eye trackers. However, synchronizing visual stimulus presentation with eye movement recording is still difficult, particularly if the eye tracker does not come with a practical application programming interface. This paper introduces a Matlab/Octave toolbox named Sgttoolbox, which works in conjunction with the widely used experiment control library Psychtoolbox to control a cross-platform open-source eye tracker named SimpleGazeTracker, which is an eye-tracking application of GazeParser software. Hardware and software requirements for Sgttoolbox and its main functions are described. A test of temporal accuracy showed that eye movement sampling frequency was stable when stimulus presentation and recording were performed on a single PC, although better performance was obtained when presentation and recording were performed on separate PCs. Transferring the latest eye position from SimpleGazeTracker to Psychtoolbox script takes 2 to 4 ms on average, which causes a delay in drawing multiple visual stimuli when recording and stimulus presentation were performed on a single PC. When such a transfer delay is not importnat, Sgttoolbox would be a good choice for Psychtoolbox users who wish to conduct eye-tracking studies. PMID- 27503304 TI - Statistical analyses of the resilience function. AB - The extent to which distracting information influences decisions can be informative about the nature of the underlying cognitive and perceptual processes. In a recent paper, a response time-based measure for quantifying the degree of interference (or facilitation) from distracting information termed resilience was introduced. Despite using a statistical measure, the analysis was limited to qualitative comparisons between different model predictions. In this paper, we demonstrate how statistical procedures from workload capacity analysis can be applied to the new resilience functions. In particular, we present an approach to null-hypothesis testing of resilience functions and a method based on functional principal components analysis for analyzing differences in the functional form of the resilience functions across participants and conditions. PMID- 27503305 TI - Clinical significance of noncalcified lung nodules in patients with breast cancer. AB - Patients with breast cancer are increasingly likely to have chest computed tomography (CT) performed. In many cases, small lung nodules will be detected, raising concern for metastases and causing considerable patient anxiety. The majority of these nodules, however, are benign, though the specific probability of malignancy is uncertain in any given case. Therefore, we analyzed the results of chest CT scans of a large number of patients with breast cancer, to determine characteristics and clinical significance of noncalcified lung nodules. 3313 patients were investigated, and 4889 CT scans from 1325 patients were retrospectively reviewed. Among the 1325 patients, 812 (59 %) had at least one noncalcified lung nodule, of which 330 (41 %) had malignant nodules, 197 (24 %) had large (>=10 mm) nodules, and 586 (72 %) had multiple nodules. Large nodules were more often malignant than benign (P < 0.001). In patients with multiple large nodules, the rate of malignancy rate was 83 %, and most of these were metastases. In the case of very small (2-4 mm) nodules, the malignancy rates for solitary and multiple nodules were 8 and 20 %, respectively. Lung metastases were more likely with breast cancer cell grade 3 (22 %) than grade 1-2 (10 %) (P < 0.001) and when patients were clinical stage 2-3 (14 %) than stage 0-1 (7.9 %) (P = 0.03). Lung metastases are highly likely in patients with multiple nodules greater than 10 mm. Higher cancer cell grades and clinical stage are also related to an increased likelihood of lung metastases. The great majority of small lung nodules in breast cancer patients are benign. PMID- 27503306 TI - [Preclinical fibrinolysis in patients with ST-segment elevation myocardial infarction in a rural region]. AB - BACKGROUND: In the current guidelines for the treatment of patients with ST segment elevation myocardial infarction (STEMI), the European Society of Cardiology (ESC) recommends preclinical fibrinolysis as a reperfusion therapy if, due to long transportation times, no cardiac catheterisation is available within 90-120 min. However, there is little remaining in-depth expertise in this method because fibrinolysis is presently only rarely indicated. METHODS: In a rural area in southwestern Germany, where an emergency primary percutaneous coronary intervention was not routinely available within 90-120 min, 156 STEMI patients underwent fibrinolysis with the plasminogen activator reteplase, performed by trained emergency physicians. The practicality of the treatment, as well as complications and the mortality of the patients in the preclinical phase until arrival at the hospital, were retrospectively studied. RESULTS: The mean time from onset of the symptoms to first medical contact was 114 +/- 116 min. The mean interval to the start of fibrinolysis of 13.5 +/- 6.4 min was within the 30 min mandated by the ESC. Patients with inferior STEMI represented the largest subgroup. Occurring in 39 cases (25 %), complications due to infarction were relatively common during the prehospital phase, including 15 cases (9.6 %) of cardiogenic shock, but in all cases the complications were manageable. No patient died before arrival at the hospital. As lysis-associated adverse effects, merely two uncomplicated mucosal haemorrhages and one case of mild allergic skin reactions were seen. CONCLUSION: In emergency situations with long transportation times to the nearest suitable cardiac catheterisation laboratory, preclinical fibrinolysis in STEMI still represents a workable method. Success of this strategy requires particularly strong training of the emergency physicians in ECG and lysis therapy, and co-operation with nearby cardiac centres. PMID- 27503307 TI - The association between ambient temperature and preterm birth in Shenzhen, China: a distributed lag non-linear time series analysis. AB - BACKGROUND: A few studies have examined the association between ambient temperature and preterm birth (PTB), and the results have been inconsistent. This study explored the association between ambient temperature and PTB in Shenzhen, China. METHODS: Data of daily singleton PTB, air pollution and meteorological variables from 2005 to 2011 were collected in Shenzhen. A distributed lag non linear model (DLNM) was used to investigate the association of the low and high temperatures (1st, 5th, 95th, and 99th percentiles) with PTB. RESULTS: The median temperature was 24.5 degrees C and the 1st, 5th, 95th, and 99th percentiles of daily mean temperatures were 9, 12.5, 29.9 and 30.7 degrees C, respectively. The prevalence of singleton PTB was 5.61 % in Shenzhen. The association between temperature and PTB was not linear. There was an immediate positive association of low temperature (1st and 5th percentiles) and a negative association of high temperature (95th and 99th percentiles) with PTB. The effect of low temperature 9 degrees C (1st) on PTB on the current day was stronger than that of 12.5 degrees C (5th), with a relative risk (RR) of 1.54 (95 % CI: 1.36-1.75) and 1.49 (95 % CI: 1.35-1.63), respectively. The cumulative RR (up to 30 days) of 9 and 12.5 degrees C was 1.72 (95 % CI: 1.28-2.33) and 1.96 (95 % CI: 1.60-2.39), respectively. The cumulative effects (up to 30 days) of high temperature (95th and 99th percentiles) on PTB were 0.69 (95 % CI: 0.60-0.80) and 0.62 (95 % CI: 0.52-0.74), respectively. The cumulative effect (up to 30 days) of low temperatures on vaginal delivery PTB was lower than that of the cesarean section PTB with an RR of 1.58 (95 % CI: 1.12-2.22) and 1.93 (95 % CI: 1.21-3.08), respectively. CONCLUSIONS: This study suggests that low temperature might be a risk factor, while high temperature might be a protective factor of PTB in Shenzhen. PMID- 27503308 TI - Diffusion-weighted echo planar MR imaging of the neck at 3 T using integrated shimming: comparison of MR sequence techniques for reducing artifacts caused by magnetic-field inhomogeneities. AB - OBJECTIVE: Our objective was to compare available techniques reducing artifacts in echo planar imaging (EPI)-based diffusion-weighed magnetic resonance imaging MRI (DWI) of the neck at 3 Tesla caused by B0-field inhomogeneities. MATERIALS AND METHODS: A cylindrical fat-water phantom was equipped with a Maxwell coil allowing for additional linear B0-field variations in z-direction. The effect of increasing strength of this superimposed gradient on image quality was observed using a standard single-shot EPI-based DWI sequence (sEPI), a zoomed single-shot EPI sequence (zEPI), a readout-segmented EPI sequence (rsEPI), and an sEPI sequence with integrated dynamic shimming (intEPI) on a 3-Tesla system. Additionally, ten volunteers were examined over the neck region using these techniques. Image quality was assessed by two radiologists. Scan durations were recorded. RESULTS: With increasing strength of the external gradient, marked distortions, signal loss, and failure of fat suppression were observed using sEPI, zEPI, and rsEPI. These artifacts were markedly reduced using intEPI. Significantly better in vivo image quality was also observed using intEPI compared with the other techniques. Scan time of intEPI was similar to sEPI and zEPI and shorter than rsEPI. CONCLUSION: The use of integrated 2D shim and frequency adjustment for EPI-based DWI results in a significant improvement in image quality of the head/neck region at 3 Tesla. Combining integrated shimming with rsEPI or zEPI can be expected to provide additional improvements. PMID- 27503309 TI - 3D single point imaging with compressed sensing provides high temporal resolution R 2* mapping for in vivo preclinical applications. AB - OBJECTIVE: Purely phase-encoded techniques such as single point imaging (SPI) are generally unsuitable for in vivo imaging due to lengthy acquisition times. Reconstruction of highly undersampled data using compressed sensing allows SPI data to be quickly obtained from animal models, enabling applications in preclinical cellular and molecular imaging. MATERIALS AND METHODS: TurboSPI is a multi-echo single point technique that acquires hundreds of images with microsecond spacing, enabling high temporal resolution relaxometry of large-R 2* systems such as iron-loaded cells. TurboSPI acquisitions can be pseudo-randomly undersampled in all three dimensions to increase artifact incoherence, and can provide prior information to improve reconstruction. We evaluated the performance of CS-TurboSPI in phantoms, a rat ex vivo, and a mouse in vivo. RESULTS: An algorithm for iterative reconstruction of TurboSPI relaxometry time courses does not affect image quality or R 2* mapping in vitro at acceleration factors up to 10. Imaging ex vivo is possible at similar acceleration factors, and in vivo imaging is demonstrated at an acceleration factor of 8, such that acquisition time is under 1 h. CONCLUSIONS: Accelerated TurboSPI enables preclinical R 2* mapping without loss of data quality, and may show increased specificity to iron oxide compared to other sequences. PMID- 27503310 TI - Polystyrene-Divinylbenzene-Based Adsorbents Reduce Endothelial Activation and Monocyte Adhesion Under Septic Conditions in a Pore Size-Dependent Manner. AB - Endothelial activation with excessive recruitment and adhesion of immune cells plays a central role in the progression of sepsis. We established a microfluidic system to study the activation of human umbilical vein endothelial cells by conditioned medium containing plasma from lipopolysaccharide-stimulated whole blood or from septic blood and to investigate the effect of adsorption of inflammatory mediators on endothelial activation. Treatment of stimulated whole blood with polystyrene-divinylbenzene-based cytokine adsorbents (average pore sizes 15 or 30 nm) prior to passage over the endothelial layer resulted in significantly reduced endothelial cytokine and chemokine release, plasminogen activator inhibitor-1 secretion, adhesion molecule expression, and in diminished monocyte adhesion. Plasma samples from sepsis patients differed substantially in their potential to induce endothelial activation and monocyte adhesion despite their almost identical interleukin-6 and tumor necrosis factor-alpha levels. Pre incubation of the plasma samples with a polystyrene-divinylbenzene-based adsorbent (30 nm average pore size) reduced endothelial intercellular adhesion molecule-1 expression to baseline levels, resulting in significantly diminished monocyte adhesion. Our data support the potential of porous polystyrene divinylbenzene-based adsorbents to reduce endothelial activation under septic conditions by depletion of a broad range of inflammatory mediators. PMID- 27503311 TI - Children's supernatural thinking as a signalling behaviour in early childhood. AB - In this study, we analysed the reaction times of 137 college students when making decisions on pairs of hypothetical children verbalizing different types of vignettes and/or exhibiting different physical appearance (photographs of faces). Vignettes depicted immature and mature versions of both supernatural (e.g., 'The sun's not out today because it's mad' vs. 'The sun's not out today because the clouds are blocking it') and natural ('I can remember all 20 cards!' vs. 'I can remember 6 or 7 cards') explanations to ordinary phenomena. Photographs of children's faces were morphed with a physical appearance of approximately 4-7 years old or approximately 8-10 years old. In earlier research, immature supernatural thinking produced positive-affect reactions from adults and older adolescents (14-18 years old) towards young children, with cognitive cues being more important than physical-appearance cues in influencing adults' judgements. Reaction times to make decisions varied for the Supernatural and Natural vignettes and for the immature and mature vignettes/faces, reflecting the differential cognitive effort adults used for making decisions about aspects of children's physical appearance and verbal expressions. The findings were interpreted in terms of the critical role that young children's immature supernatural thinking has on adults' perception, analogous to the evolved role of immature physical features on adults' perception of infants. PMID- 27503312 TI - ProBDNF inhibits collective migration and chemotaxis of rat Schwann cells. AB - Schwann cell migration, including collective migration and chemotaxis, is essential for the formation of coordinate interactions between Schwann cells and axons during peripheral nerve development and regeneration. Moreover, limited migration of Schwann cells imposed a serious obstacle on Schwann cell-astrocytes intermingling and spinal cord repair after Schwann cell transplantation into injured spinal cords. Recent studies have shown that mature brain-derived neurotrophic factor, a member of the neurotrophin family, inhibits Schwann cell migration. The precursor form of brain-derived neurotrophic factor, proBDNF, was expressed in the developing or degenerating peripheral nerves and the injured spinal cords. Since "the yin and yang of neurotrophin action" has been established as a common sense, proBDNF would be expected to promote Schwann cell migration. However, we found, in the present study, that exogenous proBDNF also inhibited in vitro collective migration and chemotaxis of RSC 96 cells, a spontaneously immortalized rat Schwann cell line. Moreover, proBDNF suppressed adhesion and spreading of those cells. At molecular level, proBDNF inhibits F actin polymerization and focal adhesion dynamics in cultured RSC 96 cells. Therefore, our results suggested a special case against the classical opinion of "the yin and yang of neurotrophin action" and implied that proBDNF might modulate peripheral nerve development or regeneration and spinal cord repair through perturbing native or transplanted Schwann cell migration. PMID- 27503313 TI - Volar locking plate vs epibloc system for distal radius fractures in the elderly. AB - PURPOSE: To compare clinical outcomes of ORIF with volar locking plates and the Epibloc system (ES) in the treatment of distal radius fractures (DRFs) in patients aged over 65 years. METHODS: We retrospectively examined a consecutive series of 100 patients with intra-articular or extra-articular DRF who were admitted to our Department of Orthopaedics and Traumatology between January 2007 and January 2013. Fifty patients were treated using the Epibloc System; and the other 50 patients using ORIF with volar locking plates. In all patients, functional evaluation (wrist range of motion [ROM], grip strength and Disability of the Arm, Shoulder and Hand [DASH] Score) and radiographic assessment (radial inclination, volar tilt, ulnar variance and articular congruity) were performed at 2 and 6 weeks, and 3, 6 and 12 months postoperatively; then every 12 months thereafter. RESULTS: ORIF with volar locking plates was associated with better outcome than ES in the intra-articular and extra-articular DRF groups, generating higher average ROM, DASH and visual analogue scale (VAS) scores. Grip strength mean values, however, were quantified over the minimum level for a functional wrist (>60%) in both groups. There were no differences between the two techniques in X-ray parameters, and no further correlation was found with functional outcome and ROM. CONCLUSIONS: In a low-functioning patient with multiple medical comorbidities, minimally-invasive surgery with the ES is a safe option, enables early mobilisation of the wrist and is likely to produce acceptable clinical outcomes. PMID- 27503314 TI - Complications in proximal humeral fractures. AB - Necrosis of the humeral head, infections and non-unions are among the most dangerous and difficult-to-treat complications of proximal humeral fractures. The aim of this work was to analyse in detail non-unions and post-traumatic bone defects and to suggest an algorithm of care. Treatment options are based not only on the radiological frame, but also according to a detailed analysis of the patient, who is classified using a risk factor analysis. This method enables the surgeon to choose the most suitable treatment for the patient, thereby facilitating return of function in the shortest possible time. The treatment of such serious complications requires the surgeon to be knowledgeable about the following possible solutions: increased mechanical stability; biological stimulation; and reconstructive techniques in two steps, with application of biotechnologies and prosthetic substitution. PMID- 27503315 TI - Retrievable inferior vena cava filters in geriatric trauma: Is there an age bias? AB - BACKGROUND: Trauma patients are at increased risk for developing venous thromboembolic (VTE) disease. The EAST (Eastern Association for the Surgery of Trauma) practice management guidelines identified risk factors for VTE, as well as indications for prophylactic inferior vena cava filters (IVCF). In a 2009 study, our institution found a 26% retrieval rate for IVCF. Lack of retrieval was most consistently due to lack of follow-up. Our study is a follow-up analysis for retrieval rate of IVCF, since the formation of a geriatric trauma service. We anticipated that geriatric trauma patients would have a lower rate of IVCF retrieval compared to the general trauma patient. METHODS: Our study population consisted of trauma patients admitted from January 2008 to August 2013, with documented VTE or high risk for VTE with contraindication to anticoagulation. INCLUSION CRITERIA: IVCF placed in trauma patients. EXCLUSION CRITERIA: permanent filters, retrievable filters placed permanently, non-trauma patients, superior vena cava filters and patients who died before discharge. RESULTS: During the study period, 160 trauma patients had an IVCF placed, of which 147 survived and were discharged. Of those patients, 66% (97/147) were planned for retrieval. Overall, the retrieval rate was 34% (33/97). Following age categorization, rates were 47% (30/64) and 9% (3/33) for those <65 and >/=65 years old, respectively. Applying Fisher's Exact Test to a crosstab of planned retrieval by age category yielded a statistically significant difference, p<0.0005 at alpha=0.05. In the geriatric population with IVCFs not retrieved, 23% (7/30) died and 67% (20/30) were lost to follow-up. CONCLUSION: IVCF plays a critical role in the management of trauma patients with VTE, particularly the geriatric population. Since our 2009 study, we have improved nearly ten percentage points (26% to 34%); however, we exposed an age bias with retrieval rate being lower in patients >/=65 compared to those <65 (9% vs. 47%). PMID- 27503316 TI - Allograft-prosthetic composite versus megaprosthesis in the proximal tibia-What works best? AB - Modular megaprosthesis (MP) and allograft-prosthetic composite (APC) are the most commonly used reconstructions for large bone defects of the proximal tibia. The primary objective of this study was to compare the two different techniques in terms of failures and functional results. A total of 42 consecutive patients with a mean age of 39.6 years (range 15-81 years) who underwent a reconstruction of the proximal tibia between 2001 and 2012 were included. Twenty-three patients were given an MP, and 19 patients received an APC. There were nine reconstruction failures after an average follow-up of 62 months: five in the MP group and four in the APC group (p=0.957). The 10-year implant survival rate was 78.8% for the MP and 93.7% for the APC (p=0.224). There were no relevant differences between the two groups in functional results. Both MP and APC are valid and satisfactory reconstructive options for massive bone defects in the proximal tibia. In high demanding patients with no further risk factors, an APC should be considered to provide the best possible functional result for the extensor mechanism. PMID- 27503317 TI - Lumbrokinase attenuates myocardial ischemia-reperfusion injury by inhibiting TLR4 signaling. AB - Lumbrokinase, a novel antithrombotic agent, purified from the earthworm Lumbricus rubellus, has been clinically used to treat stroke and cardiovascular diseases. However, inflammatory responses associated with the cardioprotective effect of lumbrokinase remain unknown. In this study, the signaling pathways involved in lumbrokinase-inhibited expressions of inflammation mediators were investigated in rats subjected to myocardial ischemia-reperfusion (I-R) injury. The left main coronary artery of anesthetized rats was subjected to 1h occlusion and 3h reperfusion. The animals were treated with/without lumbrokinase and the severities of I-R-induced arrhythmias and infarction were compared. Lumbrokinase inhibited I-R-induced arrhythmias and reduced mortality, as well as decreased the lactate dehydrogenase levels in carotid blood. Lumbrokinase also inhibited the enhancement of I-R induced expressions of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), and matrix metalloproteinase (MMP)-9 through toll like receptor 4 (TLR4) signaling pathway. Moreover, our results demonstrated that stimulation with lumbrokinase decreases the phosphorylation of JNK, IkappaB, and NF-kappaB. These findings suggested that lumbrokinase is a potent cardioprotective drug in rats with I-R injury. The cardioprotective effects of lumbrokinase may be correlated with its inhibitory effect on the I-R-induced expressions of COX-2, iNOS and MMP-9, mediated by TLR4 signaling through JNK and NF-kappaB pathways. PMID- 27503318 TI - HCG-mediated activation of mTORC1 signaling plays a crucial role in steroidogenesis in human granulosa lutein cells. AB - Luteinizing hormone/human chorionic gonadotropin stimulates progesterone biosynthesis in the corpus luteum by activating cyclic adenosine monophosphate/protein kinase A cascade. Recent studies have shown that cyclic adenosine monophosphate-mediated activation of protein kinase A interacts with the mammalian target of rapamycin signaling pathways. Furthermore, the use of mammalian target of rapamycin inhibitors for immunosuppression in transplant patients has shown adverse effects in reproductive functions. This study examined whether the mammalian target of rapamycin pathway plays any role in luteinizing hormone-mediated regulation of progesterone production. Human granulosa lutein cells were isolated from follicular aspirates of women undergoing in vitro fertilization. Cells were cultured for 72 h and treated with human chorionic gonadotropin (50 ng/ml) for different time periods with or without pretreatment with mammalian target of rapamycin complex 1 inhibitor, rapamycin, (20 nM) for 1 h. Expression of steroidogenic enzymes, including steroidogenic acute regulatory protein, cholesterol side chain cleavage enzyme, and 3beta-hydroxysteroid dehydrogenase type 1 messenger RNA, were examined by real-time polymerase chain reaction after 6 h of human chorionic gonadotropin treatment. Expressions of phospho-ribosomal protein S6 kinase and cholesterol side chain cleavage enzyme were analyzed after 15 min and 24 h of human chorionic gonadotropin treatment, respectively. Progesterone production was analyzed by an enzyme immunoassay kit after human chorionic gonadotropin (50 ng/ml) or forskolin (10 MUM) treatment for 24 h. Treatment with human chorionic gonadotropin increased the expression of downstream targets of mammalian target of rapamycin complex 1, as well as cholesterol side chain cleavage enzyme, 3beta-hydroxysteroid dehydrogenase type 1 and steroidogenic acute regulatory protein messenger RNAs. These increases were inhibited by rapamycin pretreatment. Increased progesterone production in response to treatment with human chorionic gonadotropin or forskolin was also blocked by rapamycin pretreatment. Our findings support a role for mammalian target of rapamycin complex 1 in regulating steroidogenesis in human granulosa lutein cells. PMID- 27503319 TI - Transient modulation of calcium and parathyroid hormone stimulates bone formation. AB - Intermittent administration of parathyroid hormone can stimulate bone formation. Parathyroid hormone is a natural hormone that responds to serum calcium levels. In this study, we examined whether a transient increase and/or decrease in the serum calcium can stimulate bone formation. Using a mathematical model previously developed, we first predicted the effects of administration of parathyroid hormone, neutralizing parathyroid hormone antibody, calcium, and EGTA (calcium chelator) on the serum concentration of parathyroid hormone and calcium. The model predicted that intermittent injection of parathyroid hormone and ethylene glycol tetraacetic acid transiently elevated the serum parathyroid hormone, while that of parathyroid hormone antibody and calcium transiently reduced parathyroid hormone in the serum. In vitro analysis revealed that parathyroid hormone's transient changes (both up and down) elevated activating transcription factor 4 mediated osteocalcin expression. In the mouse model of osteoporosis, both intermittent administration of calcium and ethylene glycol tetraacetic acid showed tendency to increase bone mineral density of the upper limb (ulna and humerus) and spine, but the effects varied in a region-specific manner. Collectively, the study herein supports a common bone response to administration of calcium and its chelator through their effects on parathyroid hormone. PMID- 27503320 TI - Serum anti-mullerian hormone and all-cause mortality in men. AB - Several studies have examined an association of anti-mullerian hormone to various risk factors for mortality, however, to the best of our knowledge, no study has reported a direct relationship between anti-mullerian hormone and all-cause mortality. Therefore, we examined the relationship between baseline anti mullerian hormone levels and subsequent all-cause mortality in men during median follow-up of 9.4 (range = 0-13) years. We used the continuous National Health and Nutrition Examination Surveys from 1999-2004 combined with National Death Index for vital status information through December 2011. Cox proportional hazard models were fit to estimate hazard ratios for all-cause mortality. Models were adjusted for age, ethnic background, body mass index, hypertension, diabetes, smoking status, c-reactive protein, total cholesterol, estimated glomerular filtration rate, serum estradiol, testosterone, sex hormone binding globulin, and androstenedione. Of the 989 men, 30 % were older than 65 years, 51 % were Caucasians, 33 % had hypertension, 27 % were active smokers, and 11 % had diabetes. Mean serum anti-mullerian hormone level of the population was 7.2 (6.3) ng/mL. During the 8943 person-years of follow-up, 164 (17 %) men died. In unadjusted analysis, each unit increase in serum anti-mullerian hormone level was associated with a 13 % lower risk of death (HR = 0.87; 95 %CI = 0.83-0.92). In multivariable models, the inverse association between serum anti-mullerian hormone levels and mortality remained significant (HR = 0.94; 95 %CI = 0.90-0.98) and was independent of confounding variables. Similarly, individuals in the highest quartile had significantly lower risk of death as compared to individuals in the lowest quartile (unadjusted HR = 0.13, 95 %CI = 0.07-0.25; adjusted HR = 0.36, 95 %CI = 0.16-0.81). We found an independent and inverse association between serum anti-mullerian hormone levels and all-cause mortality in men. The mechanism underlying this association is unknown. Further studies are needed to validate our findings in men and to examine this association in women. PMID- 27503322 TI - Structure elucidation of a new cycloartane triterpene glycoside from Souliea vaginata by NMR. PMID- 27503321 TI - Effect Of combining FK506 and neurotrophins on neurite branching and elongation. AB - INTRODUCTION: There is a clinical need to improve the outcomes of peripheral nerve regeneration and repair after injury. In addition to its immunosuppressive effects, FK506 (tacrolimus) has been shown to have neuroregenerative properties. To determine biologically relevant local FK506 and growth factor concentrations, we performed an in vitro bioassay using dorsal root ganglion (DRG) from chicken embryos. METHODS: Neurite elongation and neurite branching were analyzed microscopically after addition of FK506, glial cell line-derived neurotrophic factor (GDNF), and nerve growth factor (NGF), each alone and in combination. RESULTS: FK506 induced modest neurite elongation (~500-800 um) without improving neurite branching significantly. The combination of FK506 with NGF, GDNF, or both, exerted a potentiating or competitive effect on neurite elongation (~700 1100 um) based on dosage and competitive effect on neurite branching (~0.2-0.4). CONCLUSIONS: These results strongly suggest that the interaction of FK506 with GDNF and NGF mediates distinct enhancement of neurite growth. Muscle Nerve 55: 570-581, 2017. PMID- 27503323 TI - Takotsubo Syndrome as a Cause of False Acute Abdomen in the Early Postoperative Period After Bariatric Surgery-a Report of Two Cases. AB - Takotsubo syndrome, also known as broken-heart syndrome, stress-induced cardiomyopathy or transient apical ballooning syndrome, is a transient disorder characterized by segmental left ventricular failure in the absence of obstructive coronary artery disease. Most cases of Takotsubo syndrome are caused by acute stress that leads to a sudden, temporary weakening of the cardiac musculature. This stress triggers a rise in circulating catecholamine levels that results in acute ventricular dysfunction. In this report, we describe two cases of Takotsubo syndrome in the early postoperative period after bariatric surgery. PMID- 27503324 TI - Predictors of Intimate Partner Homicide in a Sample of Portuguese Male Domestic Offenders. AB - Intimate partner homicide (IPH) is a major social problem, and it is important to determine the predictors of this violent behavior. The purpose of this study was to examine the differences between intimate partner violence (IPV) and IPH and to identify the variables that predict IPH. The sample was composed of 35 perpetrators of IPH, who were compared with 137 perpetrators of IPV. The data were collected using the Spousal Abuse Risk Assessment. The data suggest that IPH presents different dynamics from IPV. Being older, exhibiting suicidal and/or homicidal ideation/intent, and the use of weapons and/or credible threats of death substantially increase a man's risk of committing IPH. Inversely, not being single, violating conditional release, and being victimized in childhood decrease the likelihood of committing IPH. These findings reinforce the assumption that IPV and IPH have both commonalities and differences and challenge the view that IPV and IPH are different phenomena and that intimate partner murder is an inexplicable event. Implications for preventing IPV and IPH are discussed. PMID- 27503325 TI - Wireless Participant Incentives Using Reloadable Bank Cards to Increase Clinical Trial Retention With Abused Women Drinkers: A Natural Experiment. AB - Retaining participants in longitudinal studies is a unique methodological challenge in many areas of investigation, and specifically for researchers aiming to identify effective interventions for women experiencing intimate partner violence (IPV). Individuals in abusive relationships are often transient and have logistical, confidentiality, and safety concerns that limit future contact. A natural experiment occurred during a large randomized clinical trial enrolling women in abusive relationships who were also heavy drinkers, which allowed for the comparison of two incentive methods to promote longitudinal retention: cash payment versus reloadable wireless bank cards. In all, 600 patients were enrolled in the overall trial, which aimed to incentivize participants using a reloadable bank card system to promote the completion of 11 weekly interactive voice response system (IVRS) phone surveys and 3-, 6-, and 12-month follow-up phone or in person interviews. The first 145 participants were paid with cash as a result of logistical delays in setting up the bank card system. At 12 weeks, participants receiving the bank card incentive completed significantly more IVRS phone surveys, odds ratio (OR) = 2.4, 95% confidence interval (CI) = [0.01, 1.69]. There were no significant differences between the two groups related to satisfaction or safety and/or privacy. The bank card system delivered lower administrative burden for tracking payments for study staff. Based on these and other results, our large medical research university is implementing reloadable bank card as the preferred method of participant incentive payments. PMID- 27503327 TI - Effect of Sampling Frequency for Real-Time Tablet Coating Monitoring Using Near Infrared Spectroscopy. AB - While the sampling of pharmaceutical products typically follows well-defined protocols, the parameterization of spectroscopic methods and their associated sampling frequency is not standard. Whereas, for blending, the sampling frequency is limited by the nature of the process, in other processes, such as tablet film coating, practitioners must determine the best approach to collecting spectral data. The present article studied how sampling practices affected the interpretation of the results provided by a near-infrared spectroscopy method for the monitoring of tablet moisture and coating weight gain during a pan-coating experiment. Several coating runs were monitored with different sampling frequencies (with or without co-adds (also known as sub-samples)) and with spectral averaging corresponding to processing cycles (1 to 15 pan rotations). Beyond integrating the sensor into the equipment, the present work demonstrated that it is necessary to have a good sense of the underlying phenomena that have the potential to affect the quality of the signal. The effects of co-adds and averaging was significant with respect to the quality of the spectral data. However, the type of output obtained from a sampling method dictated the type of information that one can gain on the dynamics of a process. Thus, different sampling frequencies may be needed at different stages of process development. PMID- 27503326 TI - Inhibition of ADAM10 promotes the clearance of Abeta across the BBB by reducing LRP1 ectodomain shedding. AB - BACKGROUND: Transport across the blood-brain barrier (BBB) is an important mediator of beta-amyloid (Abeta) accumulation in the brain and a contributing factor in the pathogenesis of Alzheimer's disease (AD). One of the receptors responsible for the transport of Abeta in the BBB is the low density lipoprotein receptor-related protein 1 (LRP1). LRP1 is susceptible to proteolytic shedding at the cell surface, which prevents endocytic transport of ligands. Previously, we reported a strong inverse correlation between LRP1 shedding in the brain and Abeta transit across the BBB. Several proteases contribute to the ectodomain shedding of LRP1 including the alpha-secretase, a desintegrin and metalloproteinase domain containing protein 10 (ADAM10). METHODS: The role of ADAM10 in the shedding of LRP1 and Abeta BBB clearance was assessed through pharmacological inhibition of ADAM10 in an in vitro model of the BBB and through the use of ADAM10 endothelial specific knock-out mice. In addition, an acute treatment paradigm with an ADAM10 inhibitor was also tested in an AD mouse model to assess the effect of ADAM10 inhibition on LRP1 shedding and Abetabrain accumulation. RESULTS: In the current studies, inhibition of ADAM10 reduced LRP1 shedding in brain endothelial cultures and increased Abeta42 transit across an in vitro model of the BBB. Similarly, transgenic ADAM10 endothelial knockout mice displayed lower LRP1 shedding in the brain and significantly enhanced Abeta clearance across the BBB compared to wild-type animals. Acute treatment with the ADAM10-selective inhibitor GI254023X in an AD mouse model substantially reduced brain LRP1 shedding and increased Abeta40 levels in the plasma, indicating enhanced Abeta transit from the brain to the periphery. Furthermore, both soluble and insoluble Abeta40 and Abeta42 brain levels were decreased following GI254023X treatment, but these effects lacked statistical significance. CONCLUSIONS: These studies demonstrate a role for ADAM10 in the ectodomain shedding of LRP1 in the brain and the clearance of Abeta across the BBB, which may provide a novel strategy for attenuating Abeta accumulation in the AD brain. PMID- 27503329 TI - Intrapancreatic Accessory Spleen Mimicking Pancreatic neoplasm. PMID- 27503328 TI - District health manager and mid-level provider perceptions of practice environments in acute obstetric settings in Tanzania: a mixed-method study. AB - BACKGROUND: In sub-Saharan Africa, the capacity of human resources for health (HRH) managers to create positive practice environments that enable motivated, productive, and high-performing HRH is weak. We implemented a unique approach to examining HRH management practices by comparing perspectives offered by mid-level providers (MLPs) of emergency obstetric care (EmOC) in Tanzania to those presented by local health authorities, known as council health management teams (CHMTs). METHODS: This study was guided by the basic strategic human resources management (SHRM) component model. A convergent mixed-method design was utilized to assess qualitative and quantitative data from the Health Systems Strengthening for Equity: The Power and Potential of Mid-Level Providers project. Survey data was obtained from 837 mid-level providers, 83 of whom participated in a critical incident interview whose aim was to elicit negative events in the practice environment that induced intention to leave their job. HRH management practices were assessed quantitatively in 48 districts with 37 members of CHMTs participating in semi-structured interviews. RESULTS: The eight human resources management practices enumerated in the basic SHRM component model were implemented unevenly. On the one hand, members of CHMTs and mid-level providers agreed that there were severe shortages of health workers, deficient salaries, and an overwhelming workload. On the other hand, members of CHMTs and mid-level providers differed in their perspectives on rewards and allocation of opportunities for in-service training. Although written standards of performance and supervision requirements were available in most districts, they did not reflect actual duties. Members of CHMTs reported high levels of autonomy in key HRH management practices, but mid-level providers disputed the degree to which the real situation on the ground was factored into job-related decision-making by CHMTs. CONCLUSIONS: The incongruence in perspectives offered by members of CHMTs and mid-level providers points to deficient HRH management practices, which contribute to poor practice environments in acute obstetric settings in Tanzania. Our findings indicate that members of CHMTs require additional support to adequately fulfill their HRH management role. Further research conducted in low income countries is necessary to determine the appropriate package of interventions required to strengthen the capacity of members of CHMTs. PMID- 27503331 TI - Migrated Biliary Stent Causing Entero-enteric Fistula. PMID- 27503330 TI - A Novel Nomogram to Predict the Prognosis of Patients Undergoing Liver Resection for Neuroendocrine Liver Metastasis: an Analysis of the Italian Neuroendocrine Liver Metastasis Database. AB - Even though surgery remains the only potentially curative option for patients with neuroendocrine liver metastases, the factors determining a patient's prognosis following hepatectomy are poorly understood. Using a multicentric database including patients who underwent hepatectomy for NELMs at seven tertiary referral hepato-biliary-pancreatic centers between January 1990 and December 2014, we sought to identify the predictors of survival and develop a clinical tool to predict patient's prognosis after liver resection for NELMs. The median age of the 238 patients included in the study was 61.9 years (interquartile range 51.5-70.1) and 55.9 % (n = 133) of patients were men. The number of NELMs (hazard ratio = 1.05), tumor size (HR = 1.01), and Ki-67 index (HR = 1.07) were the predictors of overall survival. These variables were used to develop a nomogram able to predict survival. According to the predicted 5-year OS, patients were divided into three different risk classes: 19.3, 55.5, and 25.2 % of patients were in low (>80 % predicted 5-year OS), medium (40-80 % predicted 5-year OS), and high (<40 % predicted 5-year OS) risk classes. The 10-year OS was 97.0, 55.9, and 20.0 % in the low, medium, and high-risk classes, respectively (p < 0.001). We developed a novel nomogram that accurately (c-index >70 %) staged and predicted the prognosis of patients undergoing liver resection for NELMs. PMID- 27503332 TI - Primary Castleman's Disease of the Liver. AB - Castleman's disease is a rare lymphoproliferative disorder that may affect the liver as part of mutlicentric disease or, rarely, as unicentric hepatic disease. Primary hepatic disease is difficult to diagnose but demonstrates diffusion restriction on magnetic resonance scan and can be treated curatively with hepatic resection. PMID- 27503333 TI - Williamsia herbipolensis sp. nov., isolated from the phyllosphere of Arabidopsis thaliana. AB - A Gram-stain-positive, non-endospore-forming actinobacterium (ARP1T) was isolated from the phyllosphere of Arabidopsis thaliana. On the basis of 16S rRNA gene sequence phylogeny strain ARP1T was placed into the genus Williamsia and the closest related species were Williamsia phyllosphaerae (98.5 % 16S rRNA gene sequence similarity), Williamsia deligens (98.5 %), Williamsia maris (98.3 %) and Williamsia serinedens (98.2 %). Genome-based comparison indicated a clear distinction to the type strains of those species with pairwise average nucleotide identities (ANI) between 76.4-78.4 %. The quinone system of strain ARP1T consisted predominantly of menaquinones MK-9(H2), MK-7(H2) and MK-8(H2), and the polar lipid profile contained the major compound diphosphatidylglycerol, and moderate amounts of phosphatidylethanolamine, phosphatidylglycerol and numerous unidentified lipids. Mycolic acids were present. These chemotaxonomic traits and the major fatty acids, which were C16 : 1omega7c, C16 : 0, C18 : 0, C18 : 1omega9c and tuberculostearic acid supported the affiliation of strain ARP1T to the genus Williamsia. Genotypic, physiological and biochemical testing revealed clear differences of strain ARP1T to the most closely related species of the genus Williamsia. Therefore strain ARP1T represents a novel species of this genus, for which the name Williamsia herbipolensis sp. nov. is proposed. The type strain is ARP1T (=DSM 46872T=LMG 28679T). PMID- 27503334 TI - Hyperandrogenism rule no longer in play at Rio Olympics. PMID- 27503335 TI - Improved hybrid de novo genome assembly of domesticated apple (Malus x domestica). AB - BACKGROUND: Domesticated apple (Malus * domestica Borkh) is a popular temperate fruit with high nutrient levels and diverse flavors. In 2012, global apple production accounted for at least one tenth of all harvested fruits. A high quality apple genome assembly is crucial for the selection and breeding of new cultivars. Currently, a single reference genome is available for apple, assembled from 16.9 * genome coverage short reads via Sanger and 454 sequencing technologies. Although a useful resource, this assembly covers only ~89 % of the non-repetitive portion of the genome, and has a relatively short (16.7 kb) contig N50 length. These downsides make it difficult to apply this reference in transcriptive or whole-genome re-sequencing analyses. FINDINGS: Here we present an improved hybrid de novo genomic assembly of apple (Golden Delicious), which was obtained from 76 Gb (~102 * genome coverage) Illumina HiSeq data and 21.7 Gb (~29 * genome coverage) PacBio data. The final draft genome is approximately 632.4 Mb, representing ~ 90 % of the estimated genome. The contig N50 size is 111,619 bp, representing a 7 fold improvement. Further annotation analyses predicted 53,922 protein-coding genes and 2,765 non-coding RNA genes. CONCLUSIONS: The new apple genome assembly will serve as a valuable resource for investigating complex apple traits at the genomic level. It is not only suitable for genome editing and gene cloning, but also for RNA-seq and whole-genome re sequencing studies. PMID- 27503336 TI - Deformable Self-Propelled Micro-Object Comprising Underwater Oil Droplets. AB - The self-propelled motion with deformation of micrometer-sized soft matter in water has potential application not only for underwater carriers or probes in very narrow spaces but also for understanding cell locomotion in terms of non equilibrium physics. As far as we know, there have been no reports about micrometer-sized self-propelled soft matter mimicking amoeboid motion underwater. Here, we report an artificial molecular system of underwater oil droplets exhibiting self-propelled motion with deformation as an initial experimental model. We describe the heterogeneity in a deformable self-propelled oil droplet system in aqueous and oil phases and at their interface based on the behavior and interaction of surfactant and oil molecules. The current results have great importance for scientific frontiers such as developing deformable micro-swimmers and exploring the emergence of self-locomotion of oil droplet-type protocells. PMID- 27503337 TI - Using willingness-to-pay to establish patient preferences for cancer testing in primary care. AB - BACKGROUND: Shared decision making is a stated aim of several healthcare systems. In the area of cancer, patients' views have informed policy on screening and treatment but there is little information about their views on diagnostic testing in relation to symptom severity. METHODS: We used the technique of willingness-to pay to determine public preferences around diagnostic testing for colorectal, lung, and pancreatic cancer in primary care in the UK. Participants were approached in general practice waiting rooms and asked to complete a two-stage electronic survey that described symptoms of cancer, the likelihood that the symptoms indicate cancer, and information about the appropriate diagnostic test. Part 1 asked for a binary response (yes/no) as to whether they would choose to have a test if it were offered. Part 2 elicited willingness-to-pay values of the tests using a payment scale followed by a bidding exercise, with the aim that these values would provide a strength of preference not detectable using the binary approach. RESULTS: A large majority of participants chose to be tested for all cancers, with only colonoscopy (colorectal cancer) demonstrating a risk gradient. In the willingness-to-pay exercise participants placed a lower value on an X-ray (lung cancer) than the tests for colorectal or pancreatic cancer and X ray was the only test where risk was clearly related to the willingness-to-pay value. CONCLUSION: Willingness-to-pay values did not enhance the binary responses in the way intended; participants appeared to be motivated differently when responding to the two parts of the questionnaire. More work is needed to understand how participants perceive risk in this context and how they respond to questions about willingness-to-pay. Qualitative methods could provide useful insights. PMID- 27503338 TI - Re-emergence of H3N2 strains carrying potential neutralizing mutations at the N linked glycosylation site at the hemagglutinin head, post the 2009 H1N1 pandemic. AB - BACKGROUND: Seasonally prevalent H1N1 and H3N2 influenza A viruses have evolved by antigenic drift; this evolution has resulted in the acquisition of asparagine (N)-linked glycosylation sites (NGSs) in the globular head of hemagglutinin (HA), thereby affecting the antigenic and receptor-binding properties, as well as virulence. An epidemiological survey indicated that although the traditional seasonal H1N1 strain had disappeared, H3N2 became predominant again in the seasons (2010-11 and 2011-12) immediately following the H1N1 pandemic of 2009. Interestingly, although the 2009 pandemic H1N1 strain (H1N1pdm09) lacks additional NGSs, clinically isolated H3N2 strains obtained during these seasons gained N (Asn) residues at positions 45 and 144 of HA that forms additional NGSs. METHODS: To investigate whether these NGSs are associated with re-emergence of H3N2 within the subtype, we tested the effect of amino acid substitutions on neutralizing activity by using the antisera raised against H3N2 strains with or without additional NGSs. Furthermore, because the N residue at position 144 of HA was identified as the site of mismatch between the vaccine and epidemic strains of 2011-2012, we generated mutant viruses by reverse genetics and tested the functional importance of this particular NGS for antibody-mediated neutralization by intranasal inoculation of mice. RESULTS: The results indicated that amino acid substitution at residue 144 significantly affected neutralization activity, acting as an escape mutation. CONCLUSIONS: Our data suggest that the newly acquired NGSs in the HA globular head may play an important role in the re emergence of endemic seasonal H3N2 strain by aiding the escape from humoral immunity. PMID- 27503339 TI - Transapical aortic valve implantation in patients with pre-existing mitral valve prostheses: a case report. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) has proven to be a valid option for patients with severe aortic stenosis who are at high perioperative risk, particularly in patients with previous cardiac surgery. Several patients with previous mitral valve surgery were reported to have been successfully treated with TAVI. CASE PRESENTATION: Two patients, one with mechanical and one with biological mitral valve prosthesis, presented with symptomatic severe aortic stenosis. After discussion among our multidisciplinary heart team transapical approach and a JenaValveTM prosthesis was used for TAVI. Main reasons were to decrease the perioperative risk, avoid a re-opening of the chest via median sternotomy, and discuss the possible superiority of the JenaValveTM device due to its design. The patients were successfully treated and discharged on the 11th and 14th post-operative day, respectively. Echocardiographic follow up before discharge and up to 2.8 years post-operatively showed excellent results. CONCLUSIONS: In conclusion, TAVI in patients with preexisting mitral prostheses-mechanical or biological-is feasible, safe, and effective and offers a valid alternative to conventional aortic valve replacement in this particular re-operation scenario. The JenaValveTM device does not interact with the mitral prosthesis and offers therefore due to its unique design a potential advantage. PMID- 27503340 TI - Precise Tuning of Facile One-Pot Gelatin Methacryloyl (GelMA) Synthesis. AB - Gelatin-methacryloyl (GelMA) is one of the most commonly used photopolymerizable biomaterials in bio-applications. However, GelMA synthesis remains suboptimal, as its reaction parameters have not been fully investigated. The goal of this study is to establish an optimal route for effective and controllable GelMA synthesis by systematically examining reaction parameters including carbonate-bicarbonate (CB) buffer molarity, initial pH adjustment, MAA concentration, gelatin concentration, reaction temperature, and reaction time. We employed several analytical techniques in order to determine the degree of substitution (DS) and conducted detailed structural analysis of the synthesized polymer. The results enabled us to optimize GelMA synthesis, showing the optimal conditions to balance the deprotonation of amino groups with minimizing MAA hydrolysis, which led to nearly complete substitution. The optimized conditions (low feed ratio of MAA to gelatin (0.1 mL/g), 0.25 M CB buffer at pH 9, and a gelatin concentration of 10 20%) enable a simplified reaction scheme that produces GelMA with high substitution with just one-step addition of MAA in one pot. Looking forward, these optimal conditions not only enable facile one-pot GelMA synthesis but can also guide researchers to explore the efficient, high methacrylation of other biomacromolecules. PMID- 27503341 TI - BMC Ecology Image Competition 2016: the winning images. AB - The 2016 BMC Ecology Image Competition marked another celebration of the astounding biodiversity, natural beauty, and biological interactions documented by talented ecologists worldwide. For our fourth annual competition, we welcomed guest judge Dr. Matthew Palmer of Columbia University, who chose the winning image from over 140 entries. In this editorial, we highlight the award winning images along with a selection of highly commended honorable mentions. PMID- 27503342 TI - Renal denervation and hypertension - The need to investigate unintended effects and neural control of the human kidney. AB - Increased renal sympathetic nerve activity (RSNA) is present in human and experimental forms of arterial hypertension. Experimental denervation studies showed that renal nerves contribute to the development of hypertension. Clinical trials provided equivocal results on the antihypertensive efficacy of renal denervation in patients spurring discussions on technical aspects of renal denervation and further research on the role of renal nerves for the regulation of kidney function as well as the pathophysiology of hypertension. This review summarizes recent findings on adrenoceptor expression and function in the human kidney, adrenoceptor-dependent regulation of sodium chloride transport in the distal nephron, experimental data on chronic RSNA and the development of high arterial pressure and consequences of renal denervation that may limit its antihypertensive efficacy. Future research needs to reduce the gap between our knowledge on neural control of renal function in animals vs. humans to facilitate translation of experimental animal data to humans. More experimental studies on the temporal relationship between RSNA and arterial pressure in the chronic setting are needed to better define the pathogenetic role of heightened RSNA in different forms of arterial hypertension in order to improve the rational basis for renal denervation in antihypertensive therapy. Finally, research on unintended consequences of renal denervation including but not limited to reinnervation and denervation supersensitivity needs to be intensified to further assess the potential of renal denervation to slow the progression of renal disease and hypertension. PMID- 27503344 TI - Evaluating the carotid bodies and renal nerves as therapeutic targets for hypertension. AB - Despite the plethora of current treatment options, hypertension remains a difficult condition to adequately control, and there is a pressing need for novel therapeutic strategies. The carotid body has recently become the focus of considerable interest as a potential novel treatment target in essential hypertension. Herein, we appraise the current literature suggesting that the carotid body plays an important causative role to generate sympathetic overactivity and drive increases in arterial pressure, in animal models of hypertension. We also review evidence from human studies showing cardiovascular benefits to the transient inactivation, or surgical removal of carotid bodies, and evaluate the potential benefits of pre-screening to identify patients likely to respond to carotid body-targeted therapy. Finally, given that a high proportion of patients who have undergone renal nerve ablation procedures remain hypertensive, we examine whether the renal nerves are necessary for the drop in blood pressure seen with carotid body removal. PMID- 27503343 TI - Predictors of autonomic neuropathy in rheumatoid arthritis. AB - OBJECTIVE: Autonomic dysfunction occurs in rheumatoid arthritis (RA). However, the association between the autonomic dysfunction and inflammation has not been investigated in RA. We investigated the relationship between inflammation and ANS function in RA. METHODS: In this cross-sectional study, 25 RA patients and 25 age and sex-matched healthy controls were recruited. Autonomic function assessed by five cardiovascular reflex tests according to Ewing. Parasympathetic dysfunction established by applying three tests: heart rate response to deep breath (HRD) and standing (HRS) and Valsalva tests. Sympathetic dysfunction examined by applying two tests: BP response to standing and handgrip test. Peripheral sympathetic autonomic function assessed by Sudoscan through measurement of electrochemical skin conductance of hands and feet. Sudoscan investigates the sweat gland activity and used as a surrogate to study the damage of sympathetic sudomotor nerves in neuropathy. It is an indirect assessment tool of sudomotor function. Disease-specific and inflammatory measures (DAS 28, ESR, CRP, TNF-alpha, IL-6 and IL-1) were determined. RESULTS: RA patients had significantly impaired HRD, HRS, BP response to hand grip and sudomotor function as compared to healthy controls. Pro-inflammatory cytokines were significantly higher in RA as compared to healthy controls (p<0.05). DAS 28 significantly correlated with HRD in RA. ESR significantly correlated with HRD and HRS. TNF-alpha significantly correlated with HRD, HRS, BP response to standing and sudomotor function. Significant correlation was found between IL-6 and HRS. Seropositive patients had more pronounced CAN and sudomotor dysfunction. CONCLUSION: Autonomic dysfunction in RA is related to disease activity, seropositivity and pro-inflammatory cytokines. PMID- 27503345 TI - Both low and high serum ferritin levels predict mortality risk in hemodialysis patients without inflammation. AB - BACKGROUND: Serum ferritin concentration >100 ng/mL was associated with a higher risk of death in hemodialysis patients in Japan, whereas such an association was less clear in hemodialysis patients in Western countries. Since Japanese dialysis patients are generally less inflamed than those in Western countries, inflammation may modify the association between serum ferritin and the adverse outcomes. METHODS: We performed an observational cohort study using data from 2606 Japanese hemodialysis patients who participated in the Dialysis Outcomes and Practice Patterns Study (DOPPS) III (2005-2008) or DOPPS IV (2009-2012). The predictor was serum ferritin category (<50, 50-99.9, 100-199.9, and >=200 ng/mL), and the primary and secondary outcomes were all-cause mortality and cardiovascular hospitalization, respectively. C-reactive protein (CRP, cut-off by 0.3 mg/dL) and serum albumin (cut-off by 3.8 g/dL) were stratification factors related to systemic inflammation. RESULTS: After adjustment for relevant confounding factors, a U-shaped association was observed between serum ferritin and all-cause mortality in the group with low CRP levels, whereas such relationship was not significant in the high CRP counterparts. In contrast, we found a linear association between serum ferritin and cardiovascular hospitalization in the low CRP and high CRP groups commonly. Similar results were obtained when the total cohort was stratified by serum albumin. CONCLUSIONS: Serum ferritin showed different patterns of association with all-cause mortality in hemodialysis patients with versus without inflammation, whereas its association with cardiovascular hospitalization was similar regardless of inflammatory conditions. PMID- 27503346 TI - Resting-state functional connectivity by independent component analysis-based markers corresponds to areas of initial seizure propagation established by prior modalities from the hypothalamus. AB - OBJECTIVE: The aims of this study were to evaluate a clinically practical functional connectivity protocol designed to blindly identify the corresponding areas of initial seizure propagation and also to differentiate these areas from remote secondary areas affected by seizure. The patients in this cohort had intractable epilepsy caused by intrahypothalamic hamartoma, which is the location of the ictal focus. The ictal propagation pathway is homogeneous and established, thus creating the optimum situation for the proposed method validation study. METHODS: Twelve patients with seizures from hypothalamic hamartoma and 6 normal control patients underwent resting state functional MRI, using independent component analysis to identify network differences in patients. This was followed by seed-based connectivity measures to determine the extent of functional connectivity derangement between hypothalamus and these areas. The areas with significant change in connectivity were compared with the results of prior studies' modalities used to evaluate seizure propagation. RESULTS: The left amygdala-parahippocampal gyrus area, cingulate gyrus, and occipito-temporal gyrus demonstrated the highest derangement in connectivity with the hypothalamus, p < 0.01, corresponding to the initial seizure propagation areas established by prior modalities. Areas of secondary ictal propagation were differentiated from these initial locations by first being identified as an abnormal neuronal signal source via independent component analysis, but did not show significant connectivity directly with the known ictal focus. CONCLUSION: Non-invasive connectivity measures correspond to areas of initial ictal propagation and differentiate such areas from secondary ictal propagation, which may aid in ictal focus surgical disconnection planning and support the use of this newer modality for adjunctive information in epilepsy surgery evaluation. PMID- 27503347 TI - Aquaporin 4-specific T cells and NMO-IgG cause primary retinal damage in experimental NMO/SD. AB - Neuromyelitis optica/spectrum disorder (NMO/SD) is a severe, inflammatory disease of the central nervous system (CNS). In the majority of patients, it is associated with the presence of pathogenic serum autoantibodies (the so-called NMO-IgGs) directed against the water channel aquaporin 4 (AQP4), and with the formation of large, astrocyte-destructive lesions in spinal cord and optic nerves. A large number of recent studies using optical coherence tomography (OCT) demonstrated that damage to optic nerves in NMO/SD is also associated with retinal injury, as evidenced by retinal nerve fiber layer (RNFL) thinning and microcystic inner nuclear layer abnormalities. These studies concluded that retinal injury in NMO/SD patients results from secondary neurodegeneration triggered by optic neuritis.However, the eye also contains cells expressing AQP4, i.e., Muller cells and astrocytes in the retina, epithelial cells of the ciliary body, and epithelial cells of the iris, which raised the question whether the eye can also be a primary target in NMO/SD. Here, we addressed this point in experimental NMO/SD (ENMO) induced in Lewis rat by transfer of AQP4268-285 specific T cells and NMO-IgG.We show that these animals show retinitis and subsequent dysfunction/damage of retinal axons and neurons, and that this pathology occurs independently of the action of NMO-IgG. We further show that in the retinae of ENMO animals Muller cell side branches lose AQP4 reactivity, while retinal astrocytes and Muller cell processes in the RNFL/ganglionic cell layers are spared. These changes only occur in the presence of both AQP4268-285-specific T cells and NMO-IgG.Cumulatively, our data show that damage to retinal cells can be a primary event in NMO/SD. PMID- 27503348 TI - Molecular epidemiology of J-subgroup avian leukosis virus isolated from meat-type chickens in southern China between 2013 and 2014. AB - Members of avian leukosis virus subgroup J (ALV-J) cause various diseases associated with tumor formation and decreased fertility, resulting in major economic losses in the poultry industry worldwide. To assess the status of ALV-J infection in meat-type chickens in southern China, the molecular epidemiology of ALV-J strains was investigated. A total of 265 clinical samples collected from southern China from 2013 to 2014 were investigated in this study for the presence of ALV-J, which resulted in 12 virus isolates. Phylogenetic analysis showed that 91.7 % (11/12) of the ALV-J isolates have possessed high homology to Chinese layer isolates and belong to one subgroup. One of the ALV isolates (designated GD1411-1) was relatively closely related to the ALV-J broiler isolates, indicating that the GD1411-1 isolate might be a transition strain. Several unique nucleotide substitutions in gp85 and the U3 region were detected in all 12 ALV-J isolates. This study provides some interesting information on the molecular characterization of ALV-J isolates. These findings will be beneficial for understanding of the pathogenic mechanism of ALV-J infection. PMID- 27503349 TI - Reasons for Trying E-cigarettes and Risk of Continued Use. AB - BACKGROUND: Longitudinal research is needed to identify predictors of continued electronic cigarette (e-cigarette) use among youth. We expected that certain reasons for first trying e-cigarettes would predict continued use over time (eg, good flavors, friends use), whereas other reasons would not predict continued use (eg, curiosity). METHODS: Longitudinal surveys from middle and high school students from fall 2013 (wave 1) and spring 2014 (wave 2) were used to examine reasons for trying e-cigarettes as predictors of continued e-cigarette use over time. Ever e-cigarette users (n = 340) at wave 1 were categorized into those using or not using e-cigarettes at wave 2. Among those who continued using e cigarettes, reasons for trying e-cigarettes were examined as predictors of use frequency, measured as the number of days using e-cigarettes in the past 30 days at wave 2. Covariates included age, sex, race, and smoking of traditional cigarettes. RESULTS: Several reasons for first trying e-cigarettes predicted continued use, including low cost, the ability to use e-cigarettes anywhere, and to quit smoking regular cigarettes. Trying e-cigarettes because of low cost also predicted more days of e-cigarette use at wave 2. Being younger or a current smoker of traditional cigarettes also predicted continued use and more frequent use over time. CONCLUSIONS: Regulatory strategies such as increasing cost or prohibiting e-cigarette use in certain places may be important for preventing continued use in youth. In addition, interventions targeting current cigarette smokers and younger students may also be needed. PMID- 27503350 TI - Pneumococcal Vaccines in Preterm Infants: Are More Doses Better? Implications for Other Vaccines. PMID- 27503351 TI - Schedules for Pneumococcal Vaccination of Preterm Infants: An RCT. AB - BACKGROUND AND OBJECTIVE: Premature infants have a higher risk of invasive pneumococcal disease and are more likely to have lower vaccine responses compared with term infants. Increasingly, immunization schedules are including a reduced, 2-dose, pneumococcal conjugate vaccine priming schedule. Our goal was to assess the immunogenicity of 3 commonly used 13-valent pneumococcal conjugate vaccine (PCV13) priming schedules in premature infants and their response to a 12-month booster dose. METHODS: Premature infants (<35 weeks' gestation) were randomized to receive PCV13 at 2 and 4 months (reduced schedule); 2, 3, and 4 months (accelerated schedule); or 2, 4, and 6 months (extended schedule). All infants received a 12-month PCV13 booster. Serotype-specific pneumococcal immunoglobulin G (IgG) for PCV13 serotypes was measured by using enzyme-linked immunosorbent assay 1 month after the primary and booster vaccinations. RESULTS: A total of 210 infants (median birth gestation, 29(+6) weeks; range, 23(+2)-34(+6) weeks) were included. After the primary vaccination, 75% (95% confidence interval [CI], 62 85), 88% (95% CI, 76-95), and 97% (95% CI, 87-99) of participants had protective antibody concentrations for at least one-half the PCV13 serotypes for the reduced, accelerated, and extended schedules, respectively. After the booster vaccination, participants receiving the extended schedule had significantly lower (P < .05) geometric mean concentrations compared with reduced (for 9 of 13 serotypes) and accelerated (for 4 of 13 serotypes) schedules, but nearly all participations, regardless of schedule or serotype, had seroprotective IgG concentrations. CONCLUSIONS: A reduced priming schedule of PCV13 resulted in higher post-booster IgG concentrations but lower post-primary concentrations. The optimum vaccine schedule for preterm infants will therefore depend on when they are most at risk for invasive pneumococcal disease. PMID- 27503352 TI - Studying the Evolution of the Vertebrate Circadian Clock: The Power of Fish as Comparative Models. AB - The utility of any model species cannot be judged solely in terms of the tools and approaches it provides for genetic analysis. A fundamental consideration is also how its biology has been shaped by the environment and the ecological niche which it occupies. By comparing different species occupying very different habitats we can learn how molecular and cellular mechanisms change during evolution in order to optimally adapt to their environment. Such knowledge is as important as understanding how these mechanisms work. This is illustrated by the use of fish models for studying the function and evolution of the circadian clock. In this review we outline our current understanding of how fish clocks sense and respond to light and explain how this differs fundamentally from the situation with mammalian clocks. In addition, we present results from comparative studies involving two species of blind cavefish, Astyanax mexicanus and Phreatichthys andruzzii. This work reveals the consequences of evolution in perpetual darkness for the circadian clock and its regulation by light as well as for other mechanisms such as DNA repair, sleep, and metabolism which directly or indirectly are affected by regular exposure to sunlight. Major differences in the cave habitats inhabited by these two cavefish species have a clear impact on shaping the molecular and cellular adaptations to life in complete darkness. PMID- 27503353 TI - Genomic and Transcriptomic Approaches to Study Cancer in Small Aquarium Fish Models. AB - Zebrafish and medaka that develop tumors have become valuable tools for experimental cancer research. With the advent of microarrays and new sequencing technologies it has become feasible to perform whole genome, exome, and transcriptome analyses in these fish models. Analyses that compare the two fish models with each other and with data from human tumors have revealed a plethora of important insights. An unexpected high degree of comparability of molecular features of fish and human tumors has been detected. Furthermore, analyses of the fish model data have uncovered molecules that have not received appropriate attention in studies on their human tumor counterparts and thus have provided valuable candidates for novel biomarkers and therapeutic targets. PMID- 27503354 TI - Gal4 Driver Transgenic Zebrafish: Powerful Tools to Study Developmental Biology, Organogenesis, and Neuroscience. AB - Targeted expression by the Gal4-UAS system is a powerful genetic method to analyze the functions of genes and cells in vivo. Although the Gal4-UAS system has been extensively used in genetic studies in Drosophila, it had not been applied to genetic studies in vertebrates until the mid-2000s. This was mainly due to the lack of an efficient transgenesis tool in model vertebrates, such as the P-transposable element of Drosophila, that can create hundreds or thousands of transgene insertions in different loci on the genome and thereby enables the generation of transgenic lines expressing Gal4 in various tissues and cells via enhancer trapping. This situation was revolutionized when a highly efficient transgenesis method using the Tol2 transposable element was developed in the model vertebrate zebrafish. By using the Tol2 transposon system, we and other labs successfully performed gene trap and enhancer trap screens in combination with the Gal4-UAS system. To date, numerous transgenic fish lines that express engineered versions of Gal4 in specific cells, organs, and tissues have been generated and used for various aspects of biological studies. By constructing transgenic fish lines harboring genes of interest downstream of UAS, the Gal4 expressing cells and tissues in those transgenic fish have been visualized and manipulated via the Gal4-UAS system. In this review, we describe how the Gal4-UAS system works in zebrafish and how transgenic zebrafish that express Gal4 in specific cells, tissues, and organs have been used for the study of developmental biology, organogenesis, and neuroscience. PMID- 27503355 TI - Whole-Organism Cellular Pathology: A Systems Approach to Phenomics. AB - Phenotype is defined as the state of an organism resulting from interactions between genes, environment, disease, molecular mechanisms, and chance. The purpose of the emerging field of phenomics is to systematically determine and measure phenotypes across biology for the sake of understanding. Phenotypes can affect more than one cell type and life stage, so ideal phenotyping would include the state of every cell type within the context of both tissue architecture and the whole organism at each life stage. In medicine, high-resolution anatomic assessment of phenotype is obtained from histology. Histology's interpretative power, codified by Virchow as cellular pathology, is derived from its ability to discern diagnostic and characteristic cellular changes in diseased tissues. Cellular pathology is observed in every major human disease and relies on the ability of histology to detect cellular change in any cell type due to unbiased pan-cellular staining, even in optically opaque tissues. Our laboratory has shown that histology is far more sensitive than stereomicroscopy for detecting phenotypes in zebrafish mutants. Those studies have also shown that more complete sampling, greater consistency in sample orientation, and the inclusion of phenotypes extending over longer length scales would provide greater coverage of common phenotypes. We are developing technical approaches to achieve an ideal detection of cellular pathology using an improved form of X-ray microtomography that retains the strengths and addresses the weaknesses of histology as a screening tool. We are using zebrafish as a vertebrate model based on the overlaps between zebrafish and mammalian tissue architecture, and a body size small enough to allow whole-organism, volumetric imaging at cellular resolution. Automation of whole-organism phenotyping would greatly increase the value of phenomics. Potential societal benefits would include reduction in the cost of drug development, a reduction in the incidence of unexpected severe drug and environmental toxicity, and more rapid elucidation of the contributions of genes and the environment to phenotypes, including the validation of candidate disease alleles identified in population and personal genetics. PMID- 27503356 TI - Evolutionary Genetics of the Cavefish Astyanax mexicanus. AB - Blind and depigmented fish belonging to the species Astyanax mexicanus are outstanding models for evolutionary genetics. During their evolution in the darkness of caves, they have undergone a number of changes at the morphological, physiological, and behavioral levels, but they can still breed with their river dwelling conspecifics. The fertile hybrids between these two morphotypes allow forward genetic approaches, from the search of quantitative trait loci to the identification of the mutations underlying the evolution of troglomorphism. We review here the past 30years of evolutionary genetics on Astyanax: from the first crosses and the discovery of convergent evolution of different Astyanax cavefish populations to the most recent evolutionary transcriptomics and genomics studies that have provided researchers with potential candidate genes to be tested using functional genetic approaches. Although significant progress has been made and some genes have been identified, cavefish have not yet fully revealed the secret of their adaptation to the absence of light. In particular, the genetic determinism of their loss of eyes seems complex and still puzzles researchers. We also discuss future research directions, including searches for the origin of cave alleles and searches for selection genome-wide, as well as the necessary but missing information on the timing of cave colonization by surface fish. PMID- 27503357 TI - Transcriptional Regulation During Zygotic Genome Activation in Zebrafish and Other Anamniote Embryos. AB - Embryo development commences with the fusion of two terminally differentiated haploid gametes into the totipotent fertilized egg, which through a series of major cellular and molecular transitions generate a pluripotent cell mass. The activation of the zygotic genome occurs during the so-called maternal to zygotic transition and prepares the embryo for zygotic takeover from maternal factors, in the control of the development of cellular lineages during differentiation. Recent advances in next generation sequencing technologies have allowed the dissection of the genomic and epigenomic processes mediating this transition. These processes include reorganization of the chromatin structure to a transcriptionally permissive state, changes in composition and function of structural and regulatory DNA-binding proteins, and changeover of the transcriptome as it is overhauled from that deposited by the mother in the oocyte to a zygotically transcribed complement. Zygotic genome activation in zebrafish occurs 10 cell cycles after fertilization and provides an ideal experimental platform for elucidating the temporal sequence and dynamics of establishment of a transcriptionally active chromatin state and helps in identifying the determinants of transcription activation at polymerase II transcribed gene promoters. The relatively large number of pluripotent cells generated by the fast cell divisions before zygotic transcription provides sufficient biomass for next generation sequencing technology approaches to establish the temporal dynamics of events and suggest causative relationship between them. However, genomic and genetic technologies need to be improved further to capture the earliest events in development, where cell number is a limiting factor. These technologies need to be complemented with precise, inducible genetic interference studies using the latest genome editing tools to reveal the function of candidate determinants and to confirm the predictions made by classic embryological tools and genome-wide assays. In this review we summarize recent advances in the characterization of epigenetic regulation, transcription control, and gene promoter function during zygotic genome activation and how they fit with old models for the mechanisms of the maternal to zygotic transition. This review will focus on the zebrafish embryo but draw comparisons with other vertebrate model systems and refer to invertebrate models where informative. PMID- 27503358 TI - The Zebrafish as Model for Deciphering the Regulatory Architecture of Vertebrate Genomes. AB - Despite enormous progress to map cis-regulatory modules (CRMs), like enhancers and promoters in genomes, elucidation of the regulatory landscape of the developing embryo remains a challenge. The zebrafish embryo with its experimental virtues has a great potential to contribute to this endeavor. However, so far progress remained behind expectation. We discuss here available methods and their limitations and how the zebrafish embryo could contribute in the future to unravel the wiring of the vertebrate genome. PMID- 27503359 TI - Transcriptomic Approaches in the Zebrafish Model for Tuberculosis-Insights Into Host- and Pathogen-specific Determinants of the Innate Immune Response. AB - Mycobacterium marinum infection in zebrafish has become a well-established model of tuberculosis. Both embryonic and adult zebrafish infection studies have contributed to our knowledge of the development and function of tuberculous granulomas, which are typical of mycobacterial pathogenesis. In this review we discuss how transcriptome profiling studies have helped to characterize this infection process. We illustrate this using new RNA sequencing (RNA-Seq) data that reveals three main phases in the host response to M. marinum during the early stages of granuloma development in zebrafish embryos and larvae. The early phase shows induction of complement and transcription factors, followed by a relatively minor induction of pro-inflammatory cytokines within hours following phagocytosis of M. marinum. A minimal response is observed in the mid-phase, between 6 hours and 1day post infection, when the tissue dissemination of M. marinum begins. During subsequent larval development the granulomas expand and a late-phase response is apparent, which is characterized by progressively increasing induction of complement, transcription factors, pro-inflammatory cytokines, matrix metalloproteinases, and other defense and inflammation-related gene groups. This late-phase response shares common components with the strong and acute host transcriptome response that has previously been reported for Salmonella typhimurium infection in zebrafish embryos. In contrast, the early/mid phase response to M. marinum infection, characterized by suppressed pro inflammatory signaling, is strikingly different from the acute response to S. typhimurium infection. Furthermore, M. marinum infection shows a collective and strongly fluctuating regulation of lipoproteins, while S. typhimurium infection has pronounced effects on amino acid metabolism and glycolysis. PMID- 27503360 TI - Peripheral biomarkers of stroke: Focus on circulatory microRNAs. AB - Stroke is the second leading cause of death in the world. Stroke occurs when blood flow stops, and that stoppage results in reduced oxygen supply to neurons in the brain. The occurrence of stroke increases with age, but anyone at any age can suffer from stroke. Recent research has implicated multiple cellular changes in stroke patients, including oxidative stress and mitochondrial dysfunction, inflammatory responses, and changes in mRNA and proteins. Recent research has also revealed that stroke is associated with modifiable and non-modifiable risk factors. Stroke can be controlled by modifiable risk factors, including diet, cardiovascular, hypertension, smoking, diabetes, obesity, metabolic syndrome, depression and traumatic brain injury. Stroke is the major risk factor for vascular dementia (VaD) and Alzheimer's disease (AD). The purpose of this article is to review the latest developments in research efforts directed at identifying 1) latest developments in identifying biomarkers in peripheral and central nervous system tissues, 2) changes in microRNAs (miRNAs) in patients with stroke, 3) miRNA profile and function in animal brain, and 4) protein biomarkers in ischemic stroke. This article also reviews research investigating circulatory miRNAs as peripheral biomarkers of stroke. PMID- 27503361 TI - Effects of Simple and Microencapsulated Lactobacillus acidophilus With or Without Inulin on the Broiler Meat Quality Infected by Avian Influenza Virus (H9N2). AB - The aims of the present study were to investigate the effects of simple and microencapsulated Lactobacillus acidophilus as probiotic with or without inulin as prebiotic on meat quality of broiler infected by avian influenza virus (H9N2). Two hundred-day-old chicks were randomly allocated into 14 groups based on simple, microencapsulated probiotic and prebiotic and based on vaccination and challenge with H9N2 virus. Groups 1-7 contained 20 chicks, and groups 8-12 and 14 contained 10 chicks. Group 13 was derived from group 1 with 10 chicks at challenge day with avian influenza virus (AIV). Half of the groups were vaccinated by H9N2 vaccine on day 5. All groups except the negative control and positive vaccine control were challenged with 106.5 EID50 of low-virulence H9N2 AIV at day 21. Each bird was received 109 CFU of simple or microencapsulated probiotic on days 0 and 17 by gavage. Prebiotic as dose as 0.1 % of feed weight was used daily. Increase in water-holding capacity, dry matter, ash and protein content, and decrease in dripping loss plus beneficial changes in lightness and redness of breast meat were detected in response to probiotic especially microencapsulated synbiotic. In conclusion, probiotic alone or with prebiotic was able to improve the physicochemical properties of chicken breast muscle in both healthy and AIV-infected chickens. PMID- 27503362 TI - Enrofloxacin and Probiotic Lactobacilli Influence PepT1 and LEAP-2 mRNA Expression in Poultry. AB - Expression of peptide transporter 1 (PepT1) and liver-expressed antimicrobial peptide 2 (LEAP-2) in chickens can be influenced by food deprivation, pathological conditions and drug administration. Effect of three putative probiotic Lactobacillus strains and enrofloxacin on the expression of PepT1 and LEAP-2 mRNA was investigated in Ross 308 chickens. One-day-old chicks (n = 24) were allocated to following groups: control (without treatment); group treated with probiotics via feed; group treated with a combination of probiotics and enrofloxacin; and a group given enrofloxacin only. The drug was administered at a dose of 10 mg kg-1, via drinking water for 5 days. Samples from liver, duodenum and jejunum were collected 126 h after the start of the treatment. Expression levels of PepT1 and LEAP-2 were determined by real-time polymerase chain reaction and were statistically evaluated by Mann-Whitney test. Enrofloxacin administered alone or in combination with probiotics provoked a statistically significant up regulation of PepT1 mRNA levels in the measured organ sites. These changes can be attributed to a tendency of improvement in utilization of dietary peptide and in body weight gain. LEAP-2 mRNA expression levels did not change significantly in enrofloxacin-treated chickens in comparison with control group. PMID- 27503363 TI - Genetic mapping of canine fear and aggression. AB - BACKGROUND: Fear/anxiety and anger/aggression greatly influence health, quality of life and social interactions. They are a huge burden to wellbeing, and personal and public economics. However, while much is known about the physiology and neuroanatomy of such emotions, little is known about their genetics - most importantly, why some individuals are more susceptible to pathology under stress. RESULTS: We conducted genomewide association (GWA) mapping of breed stereotypes for many fear and aggression traits across several hundred dogs from diverse breeds. We confirmed those findings using GWA in a second cohort of partially overlapping breeds. Lastly, we used the validated loci to create a model that effectively predicted fear and aggression stereotypes in a third group of dog breeds that were not involved in the mapping studies. We found that i) known IGF1 and HMGA2 loci variants for small body size are associated with separation anxiety, touch-sensitivity, owner directed aggression and dog rivalry; and ii) two loci, between GNAT3 and CD36 on chr18, and near IGSF1 on chrX, are associated with several traits, including touch-sensitivity, non-social fear, and fear and aggression that are directed toward unfamiliar dogs and humans. All four genome loci are among the most highly evolutionarily-selected in dogs, and each of those was previously shown to be associated with morphological traits. We propose that the IGF1 and HMGA2 loci are candidates for identical variation being associated with both behavior and morphology. In contrast, we show that the GNAT3-CD36 locus has distinct variants for behavior and morphology. The chrX region is a special case due to its extensive linkage disequilibrium (LD). Our evidence strongly suggests that sociability (which we propose is associated with HS6ST2) and fear/aggression are two distinct GWA loci within this LD block on chrX, but there is almost perfect LD between the peaks for fear/aggression and animal size. CONCLUSIONS: We have mapped many canine fear and aggression traits to single haplotypes at the GNAT3-CD36 and IGSF1 loci. CD36 is widely expressed, but areas of the amygdala and hypothalamus are among the brain regions with highest enrichment; and CD36-knockout mice are known to have significantly increased anxiety and aggression. Both of the other genes have very high tissue-specificity and are very abundantly expressed in brain regions that comprise the core anatomy of fear and aggression - the amygdala to hypothalamic-pituitary-adrenal (HPA) axis. We propose that reduced-fear variants at these loci may have been involved in the domestication process. PMID- 27503364 TI - Effect of Low-Furanocoumarin Hybrid Grapefruit Juice Consumption on Midazolam Pharmacokinetics. AB - The objectives of this study were to investigate the effect of grapefruit juice low in furanocoumarins on CYP3A activity and to summarize previous findings of enzyme inhibition measured by the metabolism of midazolam after intake of grapefruit juice. Twelve healthy volunteers participated in a prospective, randomized, double-blinded, 3-way crossover clinical study to determine the effect of regular grapefruit juice (RGJ) and a novel, low-furanocoumarin hybrid grapefruit juice (HGJ) on the metabolism of oral midazolam, used as a probe for in vivo CYP3A activity, compared with water as a control. The RGJ was 100% hand squeezed "Hudson" grapefruit juice, and the HGJ contained low amounts of furanocoumarin constituents. The point estimates (90% confidence intervals) for the RGJ/water midazolam AUC geometric mean ratio was 122% (107-140). The point estimate for the HGJ/water midazolam AUC ratio was within the 80% to 125% bioequivalence range, indicating an absence of interaction. This finding also prompted a systematic review of available evidence on the pharmacokinetic alteration of midazolam by grapefruit juice. Although most studies demonstrated alteration in midazolam pharmacokinetics supporting inhibition of CYP3A activity as a likely mechanism, the cohorts included in these studies and the extent of the pharmacokinetic interaction varied widely. The current study indicated grapefruit juice-drug interaction varies substantially based on patient characteristics and/or grapefruit juice product-related factors, including the amount of furanocoumarin constituents present in the juice. PMID- 27503365 TI - Comparison of the Aerosol Stability of 2 Strains of Zaire ebolavirus From the 1976 and 2013 Outbreaks. AB - The largest outbreak of Ebola virus disease began in Gueckedou, Guinea, West Africa, in December 2013 and rapidly spread to major population centers in 3 West African countries. Early reports in some scientific and public media speculated that the virus had evolved to more effectively transmit between humans. One route of transmission postulated was aerosol transmission, although there was little epidemiological evidence to support this claim. This study investigates the viability of 2 Zaire ebolavirus strains within aerosols at 22 degrees C and 80% relative humidity over time. The results presented here indicate that there is no difference in virus stability between the 2 strains and that viable virus can be recovered from an aerosol 180 minutes after it is generated. PMID- 27503366 TI - Reply to Lipsitch. PMID- 27503368 TI - Matsumiya et al (J Infect Dis 2015; 211:1499-509). PMID- 27503367 TI - Comment on "Gain-of-Function Research and the Relevance to Clinical Practice". PMID- 27503369 TI - Bhattacharya et al (J Infect Dis 2016; 214:196-204). PMID- 27503370 TI - Resistance to Increasing Chemical Classes of Fungicides by Virtue of "Selection by Association" in Botrytis cinerea. AB - Previous research has shown that Botrytis cinerea isolates with resistance to multiple chemical classes of fungicides exist in eastern strawberry fields. In this study, the fungicide resistance profiles of 2,130 isolates from flowers of commercial strawberry fields located in multiple states was determined over four consecutive strawberry production seasons. Producers were asked to alternate single-site fungicides that were considered low risk in their specific location based on resistance monitoring results in their fields. This recommendation led to an increase of chemical class diversity used in the spray programs. Results indicated that simultaneous resistance in individual isolates to two, three, four, five, six, and seven classes of fungicides increased over time. The increase in chemical class resistances within isolates was likely due to a process we termed "selection by association", where fungicide resistance traits were often linked to the trait being selected rather than the selectable trait itself. Data analysis also indicated that the odds were highest for isolates resistant to one chemical class (1CCR) to be resistant to thiophanate-methyl; for 2CCR isolates to be resistant to thiophanate-methyl and pyraclostrobin; and for 3CCR isolates to be resistant to thiophanate-methyl, pyraclostrobin, and either cyprodinil or fenhexamid. We hypothesize that the more chemical classes are used in a spray program, the faster isolates will be selected with increasing numbers of chemical class resistances by virtue of selection by association if such isolates preexist in the population. PMID- 27503371 TI - Effectors from Wheat Rust Fungi Suppress Multiple Plant Defense Responses. AB - Fungi that cause cereal rust diseases (genus Puccinia) are important pathogens of wheat globally. Upon infection, the fungus secretes a number of effector proteins. Although a large repository of putative effectors has been predicted using bioinformatic pipelines, the lack of available high-throughput effector screening systems has limited functional studies on these proteins. In this study, we mined the available transcriptomes of Puccinia graminis and P. striiformis to look for potential effectors that suppress host hypersensitive response (HR). Twenty small (<300 amino acids), secreted proteins, with no predicted functions were selected for the HR suppression assay using Nicotiana benthamiana, in which each of the proteins were transiently expressed and evaluated for their ability to suppress HR caused by four cytotoxic effector-R gene combinations (Cp/Rx, ATR13/RPP13, Rpt2/RPS-2, and GPA/RBP-1) and one mutated R gene-Pto(Y207D). Nine out of twenty proteins, designated Shr1 to Shr9 (suppressors of hypersensitive response), were found to suppress HR in N. benthamiana. These effectors varied in the effector-R gene defenses they suppressed, indicating these pathogens can interfere with a variety of host defense pathways. In addition to HR suppression, effector Shr7 also suppressed PAMP-triggered immune response triggered by flg22. Finally, delivery of Shr7 through Pseudomonas fluorescens EtHAn suppressed nonspecific HR induced by Pseudomonas syringae DC3000 in wheat, confirming its activity in a homologous system. Overall, this study provides the first evidence for the presence of effectors in Puccinia species suppressing multiple plant defense responses. PMID- 27503372 TI - Revisitation of autoimmune hypophysitis: knowledge and uncertainties on pathophysiological and clinical aspects. AB - PURPOSE: This publication reviews the accepted knowledges and the findings still discussed on several features of autoimmune hypophysitis, including the most recently described forms, such as IgG4 and cancer immunotherapy- related hypophysitis. METHODS: The most characteristic findings and the pending controversies were derived from a literature review and previous personal experiences. A single paragraph focused on some atypical examples of the disease presenting under confounding pretences. RESULTS: Headache, visual field alterations and impaired pituitary secretion are the most frequent clinical findings of the disease. Pituitary biopsy, still considered the gold diagnostic standard, does not always receive consent from the patients. The role of magnetic resonance imaging is limited, as this disease may generate images similar to those of other diseases. The role of antipituitary and antihypothalamus antibodies is still discussed owing to methodological difficulties and also because the findings on the true pituitary antigen(s) are still debated. However, the low sensitivity and specificity of immunofluorescence, one of the more widely employed methods to detect these antibodies, may be improved, considering a predetermined cut-off titre and a particular kind of immunostaining. CONCLUSION: Autoimmune hypophysitis is a multifaceted disease, which may certainly be diagnosed by pituitary biopsy. However, the possible different clinical, laboratory and imaging features must be considered by the physician to avoid a misdiagnosis when examining a possibly affected patient. Therapeutic choice has to be made taking into account the clinical conditions and the degree of hypothalamic-pituitary involvement, but also considering that spontaneous remissions can occur. PMID- 27503373 TI - An MRI study of white matter tract integrity in regular cannabis users: effects of cannabis use and age. AB - RATIONALE: Conflicting evidence exists on the effects of cannabis use on brain white matter integrity. The extant literature has exclusively focused on younger cannabis users, with no studies sampling older cannabis users. OBJECTIVES: We recruited a sample with a broad age range to examine the integrity of major white matter tracts in association with cannabis use parameters and neurodevelopmental stage. METHODS: Regular cannabis users (n = 56) and non-users (n = 20) with a mean age of 32 (range 18-55 years) underwent structural and diffusion MRI scans. White matter was examined using voxel-based statistics and via probabilistic tract reconstruction. The integrity of tracts was assessed using average fractional anisotropy, axial diffusivity and radial diffusivity. Diffusion measures were compared between users and non-users and as group-by-age interactions. Correlations between diffusion measures and age of onset, duration, frequency and dose of current cannabis use were examined. RESULTS: Cannabis users overall had lower fractional anisotropy than healthy non-users in the forceps minor tract only (p = .015, partial eta = 0.07), with no voxel-wise differences observed. Younger users showed predominantly reduced axial diffusivity, whereas older users had higher radial diffusivity in widespread tracts. Higher axial diffusivity was associated with duration of cannabis use in the cingulum angular bundle (beta = 5.00 * 10(-5), p = .003). Isolated higher AD in older cannabis users was also observed. CONCLUSIONS: The findings suggest that exogenous cannabinoids alter normal brain maturation, with differing effects at various neurodevelopmental stages of life. These age-related differences are posited to account for the disparate results described in the literature. PMID- 27503375 TI - Erratum to: Psychosis in Parkinson's Disease: Epidemiology, Pathophysiology, and Management. PMID- 27503374 TI - The early infant gut microbiome varies in association with a maternal high-fat diet. AB - BACKGROUND: Emerging evidence suggests that the in utero environment is not sterile as once presumed. Work in the mouse demonstrated transmission of commensal bacteria from mother to fetus during gestation, though it is unclear what modulates this process. We have previously shown in the nonhuman primate that, independent of obesity, a maternal high-fat diet during gestation and lactation persistently shapes the juvenile gut microbiome. We therefore sought to interrogate in a population-based human longitudinal cohort whether a maternal high-fat diet similarly alters the neonatal and infant gut microbiome in early life. METHODS: A representative cohort was prospectively enrolled either in the early third trimester or intrapartum (n = 163), with a subset consented to longitudinal sampling through the postpartum interval (n = 81). Multiple body site samples, including stool and meconium, were collected from neonates at delivery and by 6 weeks of age. A rapid dietary questionnaire was administered to estimate intake of fat, added sugars, and fiber over the past month (National Health and Examination Survey). DNA was extracted from each infant meconium/stool sample (MoBio) and subjected to 16S rRNA gene sequencing and analysis. RESULTS: On average, the maternal dietary intake of fat ranged from 14.0 to 55.2 %, with an average intake of 33.1 % (sigma = 6.1 %). Mothers whose diets significantly differed from the mean (+/-1 standard deviation) were separated into two distinct groups, a control group (n = 13, MU = 24.4 %) and a high-fat group (n = 13, MU = 43.1 %). Principal coordinate analysis revealed that the microbiome of the neonatal stool at birth (meconium) clustered differently by virtue of maternal gestational diet (PERMANOVA p = 0.001). LEfSe feature selection identified several taxa that discriminated the groups, with a notable relative depletion of Bacteroides in the neonates exposed to a maternal high-fat gestational diet (Student's t-test, p < 0.05) that persisted to 6 weeks of age. CONCLUSIONS: Similar to the primate, independent of maternal body mass index, a maternal high fat diet is associated with distinct changes in the neonatal gut microbiome at birth which persist through 4-6 weeks of age. Our findings underscore the importance of counseling pregnant mothers on macronutrient consumption during pregnancy and lactation. PMID- 27503376 TI - Osteokeratoprosthesis Using Tibial Bone: Surgical Technique and Outcomes. AB - PURPOSE: To analyze the anatomical and functional results of keratoprosthesis using tibial bone autograft. METHODS: We reviewed 113 charts of patients who underwent tibial bone osteokeratoprothesis implantation at the Centro de Oftalmologia Barraquer. Kaplan-Meier survival curves with 95% confidence interval were calculated for functional success, defined as best corrected visual acuity (BCVA) >=0.05 on the decimal scale, and for anatomical success, defined as retention of the keratoprosthesis lamina. Multivariate analysis was used to test the impact of clinical factors on anatomical and functional survival rates. RESULTS: Based on Kaplan-Meier analyses, tibial bone keratoprosthesis 5-year and 10-year anatomical survival rates were 69.5% and 53.5%, respectively. Functional survival rate at 5 years was 33% and at 10 years was 19.2%. Considering primary diagnosis, chemical burn had better anatomical and functional survival rates than autoimmune or infectious diseases. Patient age did not have a significant effect on keratoprosthesis survival rates. About 48.7% of the patients who underwent surgery had complications: keratoprosthesis extrusion, glaucoma, retinal detachment and buccal mucosa necrosis were the most frequent ones. CONCLUSION: Half of the patients with tibial bone KPro had retained the keratoprosthesis after 10 years post-surgery and one-fifth of them had visual acuity of 0.05 or better at the same period. Considering that these patients have no other way to recover their vision either because they have no canine tooth or their buccal or dental conditions are not adequate for OOKP, this modified surgery is their only hope. PMID- 27503377 TI - Altered expression of chemokines and their receptors at porcine maternal-fetal interface during early and mid-gestational fetal loss. AB - Chemokines play a significant role in pregnancy, especially during embryonic attachment and placental development. During early pregnancy, immune cells are recruited extensively to the endometrium in several species including pigs. However, this recruitment is solely mediated by the presence of the conceptus in pigs making it a unique feature compared with other species (humans, primates and mice). To understand the biological significance of chemokine expression and immune cell recruitment in the context of fetal loss, we investigate a well characterized porcine fetal loss model during the window of early pregnancy at gestational day (gd) 20 and mid-pregnancy (gd50). These periods coincide with 25 40 % of conceptus loss. Using targeted quantitative polymerase chain reaction and Western blot approaches, we screened a specific set of chemokines. Comparisons were made with endometrial lymphocytes (ENDO LY), endometrium and chorioallantoic membranes (CAM) associated with spontaneously arresting and healthy conceptus attachment sites (CAS). mRNA expression studies revealed an increased expression of CXCR3 and CCR5 in ENDO LY and of CXCL10, CXCR3, CCL5 and CCR5 in the endometrium associated with arresting CAS at gd20. DARC was decreased in the endometrium at gd50. CCL1 was increased in CAM associated with arresting CAS at gd50. Some of these differences were also noted at the protein level (CXCL10, CXCR3, CCL5 and CCR5) in the endometrium and CAM. CD45+ immunohistochemistry demonstrated a significantly higher localization in ENDO LY in the endometrium associated with healthy versus arresting counterparts. Most of these differences were observed in early pregnancy and might contribute towards a shift in immune cell functions. PMID- 27503379 TI - Erratum to: The ''abdominal whirlpool'' sign. PMID- 27503378 TI - MicroRNA-34b/c inhibits aldosterone-induced vascular smooth muscle cell calcification via a SATB2/Runx2 pathway. AB - Increasing evidence shows that aldosterone and specific microRNAs (miRs) contribute to vascular smooth muscle cell (VSMC) calcification. In this study, we aim to explore the mechanistic links between miR-34b/c and aldosterone in VSMC calcification. VSMC calcification models were established both in vitro and in vivo. First, the levels of aldosterone, miR-34b/c and special AT-rich sequence binding protein 2 (SATB2) were measured. Then, miR-34b/c mimics or inhibitors were transfected into VSMCs to evaluate the function of miR-34b/c. Luciferase reporter assays were used to demonstrate whether SATB2 was a direct target of miR 34b/c. Aldosterone and SATB2 were found to be markedly upregulated during VSMC calcification, whereas miR-34b/c expression was downregulated. Treatment with the mineralocorticoid receptor (MR) antagonist eplerenone inhibited VSMC calcification. In aldosterone-induced VSMC calcification, miR-34b/c levels were downregulated and SATB2 protein was upregulated. Furthermore, miR-34b/c overexpression alleviated aldosterone-induced VSMC calcification as well as inhibited the expression of SATB2 protein, whereas miR-34b/c inhibition markedly enhanced VSMC calcification and upregulated SATB2 protein. In addition, luciferase reporter assays showed that SATB2 is a direct target of miR-34b/c in VSMCs. Overexpression of SATB2 induced Runx2 overproduction and VSMC calcification. Therefore, miR-34b/c participates in aldosterone-induced VSMC calcification via a SATB2/Runx2 pathway. As miR-34b/c appears to be a negative regulator, it has potential as a therapeutic target of VSMC calcification. PMID- 27503380 TI - Contrast media for fluoroscopic examinations of the GI and GU tracts: current challenges and recommendations. AB - One of the significant challenges facing radiologists who perform and interpret studies of the gastrointestinal and genitourinary systems have been periodic interruptions in the availability of barium and iodinated contrast media specially formulated for gastrointestinal (GI) and genitourinary (GU) studies. These interruptions are due to the US Food and Drug Administration's recent requirement for more stringent documentation of the safety and efficacy of contrast media and the consolidation among contrast manufacturers. Therefore, radiologists may be required to recommend an alternative means of evaluation, such as computed tomography, magnetic resonance, or endoscopy, or they may need to substitute a different formulation of a contrast agent not specifically developed for GI or GU use, for example the utilization of an agent designed and marketed for vascular use. This article reviews the current status of fluoroscopic contrast media, and provides suggestions and recommendations for the optimal and alternative use of contrast media formulations. PMID- 27503381 TI - Iatrogenic, blunt, and penetrating trauma to the biliary tract. AB - Iatrogenic and traumatic bile leaks are uncommon. However, given the overall increase in number of hepatobiliary surgeries and the paradigm shift toward nonoperative management of patients with liver trauma, they have become more prevalent in recent years. Imaging is essential to establishing early diagnosis and guiding treatment as the clinical signs and symptoms of bile leaks are nonspecific, and a delay in recognition of bile leaks portends a high morbidity and mortality rate. Findings suspicious for a bile leak at computed tomography or ultrasonography include free or contained peri- or intrahepatic low density fluid in the setting of recent trauma or hepatobiliary surgery. Hepatobiliary scintigraphy and magnetic resonance cholangiopancreatography (MRCP) with hepatobiliary contrast agents can be used to detect active or contained bile leak. MRCP with hepatobiliary contrast agents has the unique ability to reveal the exact location of bile leak, which often governs whether endoscopic management or surgical management is warranted. Percutaneous transhepatic cholangiography and fluoroscopy via an indwelling catheter that is placed either percutaneously or surgically are useful modalities to guide percutaneous transhepatic biliary drain placement which can provide biliary drainage and/or diversion in the setting of traumatic biliary injury. Surgical treatment of a bile duct injury with Roux-en-Y hepaticojejunostomy is warranted if definitive treatment cannot be accomplished through percutaneous or endoscopic means. PMID- 27503382 TI - Abdominal radiograph pearls and pitfalls for the emergency department radiologist: a pictorial review. AB - Abdominal plain films are often the first imaging examination performed on a patient with abdominal pain in the emergency department. Radiograph findings can help guide clinical management and the need for advanced imaging. A pictorial review of a range of abdominal radiograph findings is presented, including bowel gas patterns, abdominal organ evaluation, pathologic gas, calcifications, implanted devices, and foreign bodies. PMID- 27503383 TI - The role of preoperative graded compression ultrasound in detecting acute appendicitis and influencing the negative appendectomy rate. AB - PURPOSE: The diagnosis of acute appendicitis is mainly clinical and is correct in about 80% of patients, but 20-33% present with atypical findings, which resulted in a negative appendectomy rate of 20-30%. The graded compression ultrasound method in the diagnosis of acute appendicitis was reported with a sensitivity of 89%, and specificity of 95%. In this study, we aim to evaluate the graded compression ultrasonography in the diagnosis of acute appendicitis, its influence on the clinical judgment to operate, and its role in lowering the negative appendectomy rate. METHODS: 1073 patients treated surgically for acute appendicitis between January 2005 and December 2014 were reviewed. Ultrasound findings, histopathological diagnosis, and positive or negative appendectomy rates were analyzed. RESULTS: 647 (60.3%) patients were males and 426 (39.7%) females. The mean age was 26.5 years. Positive ultrasound findings were recorded in 892 (83.13%), while negative findings were recorded in 181 (16.87%). Positive appendectomy was recorded in 983 (91.6%), while negative appendectomy was recorded in 90 (8.4%). The sensitivity was 83%, specificity was 100%, and the rate of negative appendectomy was 8.39%. CONCLUSION: Graded compression technique of ultrasound is a useful modality, in addition to the clinical judgment of the surgeon and clinical findings, in detecting true positive cases of acute appendicitis, and thus reducing the negative appendectomy rate. Values of 100% specificity, and 8.4% negative appendectomy rate, or better, could be achieved, when an experienced surgeon and a professional radiologist collaborate in the diagnosis of acute appendicitis. PMID- 27503384 TI - Editor's Highlight: Computational Modeling of Plasma Vitellogenin Alterations in Response to Aromatase Inhibition in Fathead Minnows. AB - In vertebrates, conversion of testosterone into 17beta-estradiol (E2) is catalyzed by cytochrome P450 (CYP) 19A aromatase. An important role of E2 in oviparous vertebrates such as fish is stimulation of hepatic synthesis of the glycolipoprotein vitellogenin (VTG), an egg yolk precursor essential to oocyte development and larval survival. In fathead minnows (FHMs) (Pimephales promelas) exposed to the aromatase inhibitor fadrozole, plasma VTG levels do not change in concert with plasma E2 levels. Specifically, while plasma VTG and E2 levels both drop quickly when aromatase is first inhibited, the recovery of plasma VTG upon cessation of aromatase inhibition is substantially delayed relative to the recovery of plasma E2. We modified an existing computational model of the FHM hypothalamic-pituitary-gonadal axis to evaluate alternative hypotheses that might explain this delay. In the first hypothesis, a feedback loop involving active transport of VTG from the blood into the ovary is used. The activity of the transporter is negatively regulated by ovarian VTG. In the second hypothesis, a type 1 coherent feed-forward loop is implemented in the liver. This loop has 2 arms, both requiring E2 activation. The first arm describes direct, canonical E2 driven transcriptional induction of VTG, and the second describes an E2-driven intermediate transcriptional regulator that is also required for VTG synthesis. Both hypotheses accurately described the observed VTG dynamics. This result could be used to guide design of laboratory experiments intended to determine if either of the motifs, or perhaps even both of them, actually do control VTG dynamics in FHMs exposed to aromatase inhibitors. PMID- 27503385 TI - Editor's Highlight: Development of an In vitro Assay Measuring Uterine-Specific Estrogenic Responses for Use in Chemical Safety Assessment. AB - A toxicity pathway approach was taken to develop an in vitro assay using human uterine epithelial adenocarcinoma (Ishikawa) cells as a replacement for measuring an in vivo uterotrophic response to estrogens. The Ishikawa cell was determined to be fit for the purpose of recapitulating in vivo uterine response by verifying fidelity of the biological pathway components and the dose-response predictions to women of child-bearing age. Expression of the suite of estrogen receptors that control uterine proliferation (ERalpha66, ERalpha46, ERalpha36, ERbeta, G-protein coupled estrogen receptor (GPER)) were confirmed across passages and treatment conditions. Phenotypic responses to ethinyl estradiol (EE) from transcriptional activation of ER-mediated genes, to ALP enzyme induction and cellular proliferation occurred at concentrations consistent with estrogenic activity in adult women (low picomolar). To confirm utility of this model to predict concentration-response for uterine proliferation with xenobiotics, we tested the concentration-response for compounds with known uterine estrogenic activity in humans and compared the results to assays from the ToxCast and Tox21 suite of estrogen assays. The Ishikawa proliferation assay was consistent with in vivo responses and was a more sensitive measure of uterine response. Because this assay was constructed by first mapping the key molecular events for cellular response, and then ensuring that the assay incorporated these events, the resulting cellular assay should be a reliable tool for identifying estrogenic compounds and may provide improved quantitation of chemical concentration response for in vitro-based safety assessments. PMID- 27503386 TI - Editor's Highlight: Interactive Genotoxicity Induced by Environmentally Relevant Concentrations of Benzo(a)Pyrene Metabolites and Arsenite in Mouse Thymus Cells. AB - Arsenic and polycyclic aromatic hydrocarbon (PAH) exposures affect many people worldwide leading to cancer and other diseases. Arsenite (As+3) and certain PAHs are known to cause genotoxicity. However, there is limited information on the interactions between As+3 and PAHs at environmentally relevant concentrations. The thymus is the primary immune organ for T cell development in mammals. Our previous studies showed that environmentally relevant concentrations of As+3 induce genotoxicity in mouse thymus cells through Poly(ADP-ribose) polymerase (PARP) inhibition. Certain PAHs, such as the metabolites of benzo(a)pyrene (BaP), are known to cause DNA damage by forming DNA adducts. In the present study, primary mouse thymus cells were examined for DNA damage following 18 hr in vitro treatments with 5 or 50 nM As+3 and 100 nM BaP, benzo[a]pyrene-7,8-dihydrodiol (BP-Diol), or benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). An interactive increase in genotoxicity and apoptosis were observed following treatments with 5 nM As + 3 + 100 nM BP-diol and 50 nM As + 3 + 100 nM BPDE. We attribute the increase in DNA damage to inhibition of PARP inhibition leading to decreased DNA repair. To further support this hypothesis, we found that a PARP inhibitor, 3,4 dihydro-5[4-(1-piperindinyl) butoxyl]-1(2H)-isoquinoline (DPQ), also interacted with BP-diol to produce an increase in DNA damage. Interestingly, we also found that As+3 and BP-diol increased CYP1A1 and CYP1B1 expression, suggesting that increased PAH metabolism may also contribute to genotoxicity. In summary, these results show that the suppression of PARP activity and induction of CYP1A1/CYP1B1 may act together to increase DNA damage produced by As+3 and PAHs. PMID- 27503387 TI - Identification of Drug-Drug Interactions In Vitro: A Case Study Evaluating the Effects of Sofosbuvir and Amiodarone on hiPSC-Derived Cardiomyocytes. AB - Drug-drug interactions pose a difficult drug safety problem, given the increasing number of individuals taking multiple medications and the relative complexity of assessing the potential for interactions. For example, sofosbuvir-based drug treatments have significantly advanced care for hepatitis C virus-infected patients, yet recent reports suggest interactions with amiodarone may cause severe symptomatic bradycardia and thus limit an otherwise extremely effective treatment. Here, we evaluated the ability of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to recapitulate the interaction between sofosbuvir and amiodarone in vitro, and more generally assessed the feasibility of hiPSC-CMs as a model system for drug-drug interactions. Sofosbuvir alone had negligible effects on cardiomyocyte electrophysiology, whereas the sofosbuvir amiodarone combination produced dose-dependent effects beyond that of amiodarone alone. By comparison, GS-331007, the primary circulating metabolite of sofosbuvir, had no effect alone or in combination with amiodarone. Further mechanistic studies revealed that the sofosbuvir-amiodarone combination disrupted intracellular calcium (Ca2+) handling and cellular electrophysiology at pharmacologically relevant concentrations, and mechanical activity at supra pharmacological (30x Cmax) concentrations. These effects were independent of the common mechanisms of direct ion channel block and P-glycoprotein activity. These results support hiPSC-CMs as a comprehensive, yet scalable model system for the identification and evaluation of cardioactive pharmacodynamic drug-drug interactions. PMID- 27503388 TI - From the Cover: Exposure to Oral Antibiotics Induces Gut Microbiota Dysbiosis Associated with Lipid Metabolism Dysfunction and Low-Grade Inflammation in Mice. AB - Due to a long history of improper and excessive use, Penicillin G (Pen G) and erythromycin (Ery) are regularly detected in environmental samples and pose a great threat to human health. Here, we set out to investigate effects of Pen G, Ery or their mixture on lipid metabolism and gut microbiota in order to better understand their toxicological mechanisms. Male C57BL/6J mice were exposed either to 60 MUg/ml Pen G, Ery or a half mixture of both for 6 weeks or to 10 MUg/ml Pen G, Ery or a half mixture of both for 14 weeks. In a recovery experiment, male mice were exposed to 60 MUg/ml Pen G or Ery for 2 weeks and then maintained without antibiotics for up to 8 weeks. It was observed that oral exposure to Pen G, Ery or their mixture induced lipid metabolism dysfunction, characterized by significantly increased lipid accumulations, triglycerides (TG) levels and expression of key genes involved in free fatty acid (FFA) synthesis, FFA transport and TG synthesis in the liver. In addition, Pen G and Ery exposure induced an inflammatory response as indicated by the increase of serum lipopolysaccharide levels and the up-regulation of key genes that regulate immune responses in the liver, fat, colon and ileum. Moreover, Pen G and Ery exposure rapidly and dramatically altered the composition of the microbiota in feces and cecum. Furthermore, high throughput sequencing of V3-V4 region of bacterial 16S rRNA gene revealed additional significant changes in the cecal microbiota of antibiotics-treated mice. Importantly, it took a very long time to reconstitute the normal composition of the gut microbiota after it was imbalanced by antibiotics exposure. Orally administered Pen G and Ery (especially to the latter) can induce gut microbiota dysbiosis, which may indirectly link antibiotic exposure to host metabolic disorders and inflammation. PMID- 27503389 TI - Geographic Variation in the Cumulative Risk of Imprisonment and Parental Imprisonment in the United States. AB - This article reports estimates of the cumulative risk of imprisonment and parental imprisonment for demographic groups in four regions and four states. Regional and state-level cumulative risks were markedly higher for African Americans and Latinos than for whites. African Americans faced the highest cumulative risks of imprisonment in the Midwest, Northeast, and two southern states. Latinos were most likely to serve time in state prison in the West, where their cumulative risk was comparable to that of African Americans. Latino children had a relatively high risk of having a parent imprisoned in the Northeast as well. Racial disparities in the cumulative risk of imprisonment and parental imprisonment did not increase linearly with increases in the cumulative risk for all groups. PMID- 27503390 TI - Age Differences in Cognitive and Affective Theory of Mind: Concurrent Contributions of Neurocognitive Performance, Sex, and Pulse Pressure. AB - OBJECTIVES: Theory of mind (ToM) allows us to detect and make inferences about cognitive and affective mental states. Mixed findings exist regarding (a) age differences in cognitive and affective ToM and (b) what mechanisms may underlie changes in the two components. We addressed these questions by examining the unique and joint contributions of neurocognitive performance, pulse pressure (PP), and biological sex to age differences in cognitive and affective ToM. METHOD: We tested 86 young and 85 older adults on standardized measures of neurocognitive performance and ToM. Predictors were derived from demographics (sex), in-office PP, and measures of executive functions, semantic memory, and episodic memory. We used path analysis to identify concurrent predictors of cognitive and affective ToM between groups and invariance analyses to assess age differences in the relative strength of identified predictors. RESULTS: We demonstrated robust age differences in cognitive and affective ToM. Certain neurocognitive predictors of ToM were more salient among older individuals; most predictors were shared across age groups and equivalent in magnitude. DISCUSSION: To our knowledge, this study represents the most comprehensive investigation to date of predictors of ToM in aging. Findings highlight the need for continued investigation of ToM within a multidimensional framework. PMID- 27503391 TI - Prevalence and quantification of geographic atrophy associated with newly diagnosed and treatment-naive exudative age-related macular degeneration. AB - OBJECTIVE: To identify and quantify geographic atrophy (GA) associated with neovascular age-related macular degeneration (AMD) at initial presentation using a fundus autofluorescence (FAF) semi-automated software and to correlate the results with demographic and clinical data. DESIGN: Retrospective, observational study. METHODS: The study population consisted of treatment-naive patients with newly diagnosed neovascular AMD. Best-corrected visual acuity, fundus photographs, infrared reflectance, FAF and spectral-domain optical coherence tomography were performed, associated with fluorescein and indocyanine green angiographies. Identification of GA was independently performed by three readers. Quantification of atrophy areas was done using RegionFinder Software (RFA), a semi-automated software embedded in Spectralis device (Heidelberg Engineering, Germany). RESULTS: We included 206 eyes of 173 consecutive patients (72% female, mean age: 79.7+/-9.1 years). Type I choroidal neovascularisation (CNV) was observed in 44.2% of eyes, type II CNV was observed in 20.9% and mixed CNV lesion was observed in 11.7%. Polypoidal choroidal vasculopathy was diagnosed in 7.7% and type III CNV was diagnosed in 15.5%. Analysis of FAF frames showed that GA was associated with nAMD in 46/206 eyes (22.3%). Taking into account data both from Region Finder and multimodal imaging, our results suggest that GA was present in 24.3% of eyes newly diagnosed with exudative AMD. Mean size of GA was 1.23+/-1.76 mm2 (range 0.03-7.39). CONCLUSION: GA is associated with nAMD in 1/4 of cases at initial presentation. Combined imaging, including RFA is an effective tool to identify and quantify GA at diagnosis. PMID- 27503392 TI - Non-traumatic corneal perforations: aetiology, treatment and outcomes. AB - PURPOSE: To report aetiology, characteristics, treatment and main outcomes of non traumatic corneal perforations in a single referral centre. METHODS: A retrospective review of clinical records of patients diagnosed with non-traumatic corneal perforation. The analysed data included demographic characteristics, medical history, initial and final corrected distance visual acuity (CDVA), perforation aetiology, size, location, initial therapy, surgical treatment, ocular integrity and complications. A comparison between non-infectious and infectious groups was performed. Different variables were analysed through a multiple logistic regression analysis for the probability to have at least one more procedure. RESULTS: We included 127 eyes of 116 patients with a mean age of 50 years and a mean follow-up of 11 months. The initial CDVA was 3.00 logarithm of the minimum angle of resolution (logMAR) and the final CDVA was 2.30 logMAR (p>0.5). Regarding treatment, of the 49 eyes with an initial cyanoacrylate patch, 35 eyes (71.4%) had at least one more procedure performed (p>0.001). In comparison, of the 49 eyes with an initial tectonic penetrating keratoplasty (PK), 33 (67.3%) eyes remained stable while 16 (32.7%) eyes needed one or more interventions (p=0.004). In a multiple logistic regression analysis, an initial cyanoacrylate patch represented a probability of 4.7 times to require a subsequent procedure in comparison with an initial PK. Overall, globe integrity was achieved in 96.1% of the cases. CONCLUSIONS: Corneal perforations represent an important cause of ocular morbidity. The use of a cyanoacrylate patch is useful as an initial therapy in corneal perforations; however, procedures such as PK are often necessary to achieve anatomical success, especially in non infectious aetiologies. PMID- 27503393 TI - Repeatability and interobserver reproducibility of a new optical biometer based on swept-source optical coherence tomography and comparison with IOLMaster. AB - OBJECTIVE: To evaluate the precision of the measurements in healthy subjects obtained with a new optical biometer (OA-2000, Tomey, Nagoya, Japan) using swept source optical coherence tomography (SS-OCT) and compare these measurements with those provided by the IOLMaster v5.4 (Carl Zeiss Meditec AG, Jena, Germany) using partial coherence interferometry (PCI). METHODS: Axial length (AL), keratometry (K) over 2.5 mm and 3.0 mm diameters, anterior chamber depth (ACD) (corneal epithelium to lens), lens thickness (LT), central corneal thickness and corneal diameter (CD) were measured with SS-OCT by two experienced operators. Intraobserver repeatability and interobserver reproducibility were assessed. AL, ACD, K and CD were also measured with PCI for agreement analysis using Bland Altman plots. RESULTS: Sixty-five eyes of 65 normal subjects were enrolled in the prospective study. The SS-OCT measurements revealed high repeatability and reproducibility with low test-retest repeatability, low within-subject coefficient of variation (CoV) and high intraclass correlation coefficients. Bland-Altman analysis showed narrow 95% limits of agreement for most parameters indicating excellent agreement for AL (-0.05 mm to 0.07 mm), K values both at 2.5 mm (-0.42 D to 0.20 D) and 3.0 mm (-0.42 D to 0.08 D) and ACD (-0.19 mm to 0.22 mm) except for the CD (-1.11 mm to -0.01 mm). CONCLUSIONS: The repeatability and reproducibility of SS-OCT were excellent for all parameters including AL, K, ACD, LT and CD values. High agreement was shown between SS-OCT and PCI for most biometrical parameters. PMID- 27503394 TI - Impact of initial visual acuity on anti-VEGF treatment outcomes in patients with macular oedema secondary to retinal vein occlusions in routine clinical practice. AB - AIM: To determine the impact of initial visual acuity (VA) on anti-vascular endothelial growth factor (VEGF) treatment outcomes in patients with macular oedema secondary to retinal vein occlusions in routine clinical practice. METHODS: A retrospective study was conducted at a single academic institution to identify 177 treatment naive patients with macular oedema secondary to branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO) and central retinal vein occlusion (CRVO) treated with intravitreal anti-VEGFs. Exclusion criteria included prior intravitreal injection or presence of active confounding ocular disease. Patients were stratified by initial VA; main outcomes measured were average change in VA and mean absolute change in central subfield thickness (CST) at 6 and 12 months. RESULTS: Patients with BRVO with initial VA of 20/40 or better had no significant changes in average letters gained and CST from baseline (+2.6 letters, p=0.42; -48.94 um, p=0.12) compared with patients with initial VA between 20/50 and 20/300 (+13.2 letters, p<0.001; -98.20 um, p<0.001) after 12 months. Patients with CRVO/HRVO with initial VA of 20/320 or worse had the most improvement in average letters gained and CST from baseline (+42.2 letters, p<0.001; -182.84 um, p=0.004) with anti-VEGF therapy compared with patients with initial VA between 20/50 and 20/300 (+9.4 letters, p=0.016; -160.87 um, p<0.001) and patients with initial VA of 20/40 or better (-9.6 letters, p=0.14; -47.92 um, p=0.38). CONCLUSIONS: For macular oedema secondary to retinal vein occlusion, anti-VEGF treatment can result in a greater improvement in average letters gained and in CST for those with poor initial VA compared with those with better initial VA. PMID- 27503395 TI - Visual object categorisation in people with glaucoma. AB - PURPOSE: There is evidence that people with glaucoma exhibit difficulties with some complex visual tasks such as face recognition, motion perception and scene exploration. The purpose of this study was to determine whether glaucoma affects the ability to categorise briefly presented visual objects in central vision. METHODS: Visual categorisation performance of 14 people with glaucoma (primary open angle glaucoma and preperimetric) and 15 age-matched controls was measured, assessing both accuracy and response times. Grey level photographs of objects (size) were presented for 28 ms foveally. Perimetric thresholds were normal for all participants within the central 3 degrees . Two levels of contrasts were included: one medium level at 50% and one with high contrast at 100%. RESULTS: On average, accuracy was significantly decreased by 7% (p=0.046) for the medium contrast stimuli in patients with glaucoma (87% of correct response, SD: 5%) compared with controls (94% of correct response, SD: 4.7%). Group average response times were significantly slower for the patients relative to the control group (712 ms, SD: 53 ms compared with 643 ms, SD: 34 ms for the control group; p<0.01). Performance was equivalent in the two groups when the picture contrast was 100%. CONCLUSIONS: The impairment observed in the categorisation task supports previous work that demonstrates that people with glaucoma can have greater difficulties with complex visual tasks than is predicted by their visual field loss. The performance was equivalent to age-matched controls when contrast was maximised. PMID- 27503396 TI - Optical coherence tomography angiography of type 3 neovascularisation in age related macular degeneration after antiangiogenic therapy. AB - BACKGROUND/AIMS: To assess the microvascular response of type 3 neovascularisation secondary to age-related macular degeneration (AMD) after antivascular endothelial growth factor (anti-VEGF) therapy using optical coherence tomography angiography (OCTA). METHODS: Consecutive patients diagnosed with AMD and type 3 neovascularisation based on clinical examination, structural optical coherence tomography and fluorescein angiography when available were retrospectively evaluated. En face OCTA imaging (3*3 mm scans) with quantitative microvascular analysis was performed at baseline and after a single anti-VEGF intravitreal injection. RESULTS: 17 eyes of 14 patients underwent OCTA before and after anti-VEGF treatment. OCTA demonstrated significant regression of small calibre type 3 neovascular tufts in all eyes. Median lesion area was 0.061 mm2 (range 0.003-0.198 mm2) at baseline and 0.009 mm2 (range 0-0.085 mm2, p=0.0003) at follow-up. Cystoid macular oedema and/or subretinal fluid resolved in all cases after treatment. The type 3 lesions became undetectable with OCTA post treatment in 5 of the 17 eyes. However, in 11 eyes, large feeder vessels were identified and remained unchanged after treatment. CONCLUSIONS: The microvascular morphology of type 3 neovascularisation secondary to AMD was assessed at baseline and follow-up and showed significant regression in response to anti-VEGF therapy by OCTA. Quantitative OCTA analysis was also performed and confirmed remarkable regression in response to a single intravitreal anti-VEGF injection. PMID- 27503397 TI - Metrics for monitoring cancer inequities: residential segregation, the Index of Concentration at the Extremes (ICE), and breast cancer estrogen receptor status (USA, 1992-2012). AB - PURPOSE: To address the paucity of evidence on residential segregation and cancer, we explored their relationship using a new metric: the Index of Concentration at the Extremes (ICE). We focused on breast cancer estrogen receptor (ER) status, a biomarker associated with survival and, etiologically, with social and economic privilege. METHODS: We obtained data from the 13 registry group of US Surveillance, Epidemiology, and End Results (SEER) program for 1992-2012 on all women aged 25-84 who were diagnosed with primary invasive breast cancer (n = 516,382). We appended to each case's record her annual county median household income quintile and the quintile for her annual county value for ICE measures for income (<=20th vs. >=80th household income quintile), race/ethnicity (black vs. white), and income plus race/ethnicity (low-income black vs. high-income white). The odds of being ER+ versus ER- were estimated in relation to the county-level income and ICE measures, adjusting for relevant covariates. RESULTS: Women in the most privileged versus deprived county quintile for household income and for all three ICE measures had a 1.1- to 1.3-fold increased odds (95 % confidence intervals excluding 1) of having an ER+ tumor. These results were robust to adjustment for age at diagnosis, cancer registry, tumor characteristics (tumor stage, size, histology, grade), and race/ethnicity. CONCLUSION: A focus on segregation offers news possibilities for understanding how inequitable group relations contribute to cancer inequities. The utility of employing the ICE for monitoring cancer inequities should be investigated in relation to other cancer outcomes. PMID- 27503398 TI - Multicolor Fluorescence Detection-Based Microfluidic Device for Single-Cell Metabolomics: Simultaneous Quantitation of Multiple Small Molecules in Primary Liver Cells. AB - Single-cell metabolomics can be used to study cell diversity and how cells respond to environment. There is an urgent need to develop effective detection methods for single-cell metabolomics. Microchip electrophoresis with laser induced fluorescence detection (MCE-LIFD) is a powerful tool to detect metabolites at the single-cell level. However, the existing one-laser excitation and one-color fluorescence collection in MCE-LIFD is not sufficient for the simultaneous detection of multiple small molecules with wide variations in their fluorescence excitation and emission spectra. In this manuscript, we describe a multicolor fluorescence detection-based microfluidic device (MFD-MD) for single cell metabolomics research. We selected primary liver cells from acute ethanol stimulated mice as the model cells and hydrogen peroxide (H2O2), glutathione (GSH), and cysteine (Cys) as representative small-molecule metabolites for single cell analysis. The microfluidic chip enabled accurate single-cell manipulation and effective electrophoresis separation. The new multicolor fluorescence detection permitted simultaneous analysis of H2O2, GSH, and Cys. Ethanol exposure induced an increase in H2O2 and a decrease in GSH and Cys. Obvious cell heterogeneity was observed. These results provide insights regarding the intracellular oxidative/antioxidative molecular mechanism in response to external stimuli. The MFD-MD provides a new opportunity for simultaneous single-cell analysis of multiple metabolites. PMID- 27503399 TI - Heat stroke admissions during heat waves in 1,916 US counties for the period from 1999 to 2010 and their effect modifiers. AB - BACKGROUND: Heat stroke is a serious heat-related illness, especially among older adults. However, little is known regarding the spatiotemporal variation of heat stroke admissions during heat waves and what factors modify the adverse effects. METHODS: We conducted a large-scale national study among 23.5 million Medicare fee-for-service beneficiaries per year residing in 1,916 US counties during 1999 2010. Heat wave days, defined as a period of at least two consecutive days with temperatures exceeding the 97th percentile of that county's temperatures, were matched to non-heat wave days by county and week. We fitted random-effects Poisson regression models to estimate the relative risk (RR) of heat stroke admissions on a heat wave day as compared to a matched non-heat wave day. A variety of effect modifiers were tested including individual-level covariates, community-level covariates, meteorological conditions, and the intensity and duration of the heat wave event. RESULTS: The RR declined substantially from 71.0 (21.3-236.2) in 1999 to 3.5 (1.9-6.5) in 2010, and was highest in the northeast and lowest in the west north central regions of the US. We found a lower RR among counties with higher central air conditioning (AC) prevalence. More severe and longer-lasting heat waves had higher RRs. CONCLUSIONS: Heat stroke hospitalizations associated with heat waves declined dramatically over time, indicating increased resilience to extreme heat among older adults. Considerable risks, however, still remain through 2010, which could be addressed through public health interventions at a regional scale to further increase central AC and monitoring heat waves. PMID- 27503400 TI - Changes of visual-field global indices after cataract surgery in primary open angle glaucoma patients. AB - PURPOSE: To determine changes of visual-field (VF) global indices after cataract surgery and the factors associated with the effect of cataracts on those indices in primary open-angle glaucoma (POAG) patients. METHODS: A retrospective chart review of 60 POAG patients who had undergone phacoemulsification and intraocular lens insertion was conducted. All of the patients were evaluated with standard automated perimetry (SAP; 30-2 Swedish interactive threshold algorithm; Carl Zeiss Meditec Inc.) before and after surgery. VF global indices before surgery were compared with those after surgery. The best-corrected visual acuity, intraocular pressure (IOP), number of glaucoma medications before surgery, mean total deviation (TD) values, mean pattern deviation (PD) value, and mean TD-PD value were also compared with the corresponding postoperative values. Additionally, postoperative peak IOP and mean IOP were evaluated. Univariate and multivariate logistic regression analyses were performed to identify the factors associated with the effect of cataract on global indices. RESULTS: Mean deviation (MD) after cataract surgery was significantly improved compared with the preoperative MD. Pattern standard deviation (PSD) and visual-field index (VFI) after surgery were similar to those before surgery. Also, mean TD and mean TD-PD were significantly improved after surgery. The posterior subcapsular cataract (PSC) type showed greater MD changes than did the non-PSC type in both the univariate and multivariate logistic regression analyses. In the univariate logistic regression analysis, the preoperative TD-PD value and type of cataract were associated with MD change. However, in the multivariate logistic regression analysis, type of cataract was the only associated factor. None of the other factors was associated with MD change. CONCLUSIONS: MD was significantly affected by cataracts, whereas PSD and VFI were not. Most notably, the PSC type showed better MD improvement compared with the non-PSC type after cataract surgery. Clinicians therefore should carefully analyze VF examination results for POAG patients with the PSC type. PMID- 27503401 TI - Changes in ocular higher-order aberrations following botulinum toxin treatment in patients with blepharospasm : BTX improves dry eye in patients with BEB. AB - BACKGROUND/AIMS: To evaluate the effects of botulinum toxin type A (BTX-A) treatment in patients with benign essential blepharospasm (BEB) by monitoring the ocular surface and ocular higher-order aberrations (HOAs) before and after treatment. METHODS: The present study reports a prospective case series of 38 patients (76 eyes, 11 men and 27 women; mean age 66.8 +/- 9.8 years) with BEB who underwent BTX-A treatment at Kokura Memorial Hospital between 2013 and 2014. Patients were evaluated for ophthalmoscopic findings, Schirmer I test, tear film break-up time (t-BUT), HOAs, fluctuation index (FI), stability index (SI) using a wavefront aberrometer, 15 subjective symptoms using the Dry Eye-Related Quality of Life Score (DEQS), and complications before and after the treatment. RESULTS: After BTX-A treatment, the Schirmer I test score improved significantly from 5.9 +/- 5.4 to 8.7 +/- 6.1 mm and t-BUT recovered from 5.2 +/- 1.7 to 7.3 +/- 1.7 s. HOAs were classified into four patterns: stable (60.5 %), small fluctuation (14.5 %), sawtooth (17.1 %), and reverse sawtooth (7.9 %), and they significantly reduced after the treatment. Only FI (not SI) showed a marked reduction, and the DEQS significantly improved from 44.7 +/- 21.6 to 37.6 +/- 21.0 after the treatment (p < 0.05). There were no complications during the observations. CONCLUSION: BTX-A is a treatment with a high potential to improve ocular surface disorders induced by BEB. PMID- 27503402 TI - Protein-like Nanoparticles Based on Orthogonal Self-Assembly of Chimeric Peptides. AB - A novel two-component self-assembling chimeric peptide is designed where two orthogonal protein folding motifs are linked side by side with precisely defined position relative to one another. The self-assembly is driven by a combination of symmetry controlled molecular packing, intermolecular interactions, and geometric constraint to limit the assembly into compact dodecameric protein nanoparticles. PMID- 27503403 TI - Impaired function of trophoblast cells derived from translocated hESCs may explain pregnancy loss in women with balanced translocation (11;22). AB - PURPOSE: The aim of the study was to study whether the trophoblasts carrying unbalanced translocation 11,22 [t(11;12)] display abnormal expression of trophoblastic genes and impaired functional properties that may explain implantation failure. METHODS: t(11;22) hESCs and control hESCs were differentiated in vitro into trophoblast cells in the presence of BMP4, and trophoblast vesicles (TBVs) were created in suspension. The expression pattern of extravillous trophoblast (EVT) genes was compared between translocated and control TBVs. The functional properties of the TBVs were evaluated by their attachment to endometrium cells (ECC1) and invasion through trans-well inserts. RESULTS: TBVs derived from control hESCs expressed EVT genes from functioning trophoblast cells. In contrast, TBVs differentiated from the translocated hESC line displayed impaired expression of EVT genes. Moreover, the number of TBVs that were attached to endometrium cells was significantly lower compared to the controls. Correspondingly, invasiveness of trophoblast-differentiated translocated cells was also significantly lower than that of the control cells. CONCLUSIONS: These results may explain the reason for implantation failure in couple carriers of t(11;22). They also demonstrate that translocated hESCs comprise a valuable in vitro human model for studying the mechanisms underlying implantation failure. PMID- 27503404 TI - Exenatide treatment increases serum irisin levels in patients with obesity and newly diagnosed type 2 diabetes. AB - OBJECTIVE: Irisin is a myokine secreted by skeletal muscle during exercise. Abnormal serum irisin levels are associated with obesity and type 2 diabetes (T2D). This study investigated the changes in serum irisin in the obese patients with newly diagnosed T2D following glucagon-like peptide-1 (GLP-1) receptor agonist (exenatide) treatment. METHODS: Fifty-four obese patients with T2D were treated with exenatide for 12weeks. The control group included 54 age-, sex-, and body mass index (BMI)-matched subjects with normal glucose tolerance. RESULTS: Patients with T2D had lower irisin than the control group (38.06 [29.29-53.79] vs. 58.01 [43.07-87.79] ng/mL, P<0.01]. Serum irisin was negatively associated with BMI (r=-0.178, P<0.05), fasting blood glucose (FBG; r=-0.170, P<0.05), and glycosylated hemoglobin (HbA1c; r=-0.189, P<0.01) in patients with T2D. Exenatide treatment markedly increased serum irisin by 19.28ng/mL (12.59-25.98) compared to baseline (P<0.01). Increased irisin was significantly correlated with decreased FBG and HbA1c after exenatide treatment (FBG: r=-0.35; HbA1c: r=-0.37; both P<0.05). CONCLUSIONS: Exenatide treatment significantly increased irisin in patients with T2D. Post-treatment changes in irisin were correlated with decreases in FBG and HbA1c. The upregulation of irisin might be a novel mechanism for the beneficial effects of exenatide in type 2 diabetic patients. PMID- 27503405 TI - Ten-year hemoglobin A1c trajectories and outcomes in type 2 diabetes mellitus: The Diabetes & Aging Study. AB - AIMS: To classify trajectories of long term HbA1c values in patients after diagnosis of type 2 diabetes and examine each trajectory's associations with subsequent microvascular and macrovascular events and mortality. METHODS: A longitudinal follow-up of 28,016 patients newly diagnosed with type 2 diabetes was conducted. Latent growth mixture modeling was used to identify ten-year HbA1c trajectories. Cox proportional hazards models were used to assess how HbA1c trajectories were associated with events (microvascular and macrovascular) and mortality. RESULTS: We identified 5 HbA1c trajectories: "low stable" (82.5%), "moderate increasing late" (5.1%), "high decreasing early" (4.9%), "moderate peaking late" (4.1%) and "moderate peaking early" (3.3%). After adjusting for average HbA1c, compared to the low stable trajectory, all non-stable trajectories were associated with higher incidences of microvascular events (hazard ratio (HR) range, 1.28 (95% CI, 1.08-1.53) (high decreasing early) to 1.45 (95% CI, 1.20 1.75) (moderate peaking early)). The high decreasing early trajectory was associated with an increased mortality risk (HR, 1.27 (95% CI, 1.03-1.58)). Trajectories were not associated with macrovascular events. CONCLUSIONS: Non stable HbA1c trajectories were associated with greater risk of microvascular events and mortality. These findings suggest a potential benefit of early diabetes detection, prioritizing good glycemic control, and maintaining control over time. PMID- 27503406 TI - Utility of existing diabetes risk prediction tools for young black and white adults: Evidence from the Bogalusa Heart Study. AB - AIMS: To evaluate several adult diabetes risk calculation tools for predicting the development of incident diabetes and pre-diabetes in a bi-racial, young adult population. METHODS: Surveys beginning in young adulthood (baseline age >=18) and continuing across multiple decades for 2122 participants of the Bogalusa Heart Study were used to test the associations of five well-known adult diabetes risk scores with incident diabetes and pre-diabetes using separate Cox models for each risk score. Racial differences were tested within each model. Predictive utility and discrimination were determined for each risk score using the Net Reclassification Index (NRI) and Harrell's c-statistic. RESULTS: All risk scores were strongly associated (p<.0001) with incident diabetes and pre-diabetes. The Wilson model indicated greater risk of diabetes for blacks versus whites with equivalent risk scores (HR=1.59; 95% CI 1.11-2.28; p=.01). C-statistics for the diabetes risk models ranged from 0.79 to 0.83. Non-event NRIs indicated high specificity (non-event NRIs: 76%-88%), but poor sensitivity (event NRIs: -23% to 3%). CONCLUSIONS: Five diabetes risk scores established in middle-aged, racially homogenous adult populations are generally applicable to younger adults with good specificity but poor sensitivity. The addition of race to these models did not result in greater predictive capabilities. A more sensitive risk score to predict diabetes in younger adults is needed. PMID- 27503407 TI - A new cyanoacrylate used as bronchial sealant in the endoscopic treatment of bronchopleural fistual. PMID- 27503408 TI - An SPR based sensor for allergens detection. AB - A simple, sensitive and label-free optical sensor method was developed for allergens analysis using alpha-casein as the biomarker for cow's milk detection, to be used directly in final rinse samples of cleaning in place systems (CIP) of food manufacturers. A Surface Plasmon Resonance (SPR) sensor chip consisting of four sensing arrays enabling the measurement of samples and control binding events simultaneously on the sensor surface was employed in this work. SPR offers several advantages in terms of label free detection, real time measurements and superior sensitivity when compared to ELISA based techniques. The gold sensor chip was used to immobilise alpha-casein-polyclonal antibody using EDC/NHS coupling procedure. The performance of the assay and the sensor was first optimised and characterised in pure buffer conditions giving a detection limit of 58ngmL-1 as a direct binding assay. The assay sensitivity can be further improved by using sandwich assay format and amplified with nanoparticles. However, at this stage this is not required as the detection limit achieved exceeded the required allergens detection levels of 2ugmL-1 for alpha-S1-casein. The sensor demonstrated good selectivity towards the alpha-casein as the target analyte and adequate recoveries from CIP final rinse wash samples. The sensor would be useful tool for monitoring allergen levels after cleaning procedures, providing additional data that may better inform upon wider food allergen risk management decision(s) that are made by food manufacturer. In particular, this sensor could potentially help validate or optimise cleaning practices for a given food manufacturing process. PMID- 27503409 TI - Selective isolation of magnetic nanoparticle-mediated heterogeneity subpopulation of circulating tumor cells using magnetic gradient based microfluidic system. AB - Relocation mechanisms of the circulating tumor cells (CTCs) from the primary site to the secondary site through the blood vessel network cause tumor metastasis. Despite of the importance to diagnose the cancer metastasis by CTCs, still it is formidable challenge to use in the clinical purpose because of the rarity and the heterogeneity of CTCs in the cancer patient's peripheral blood sample. In this study we have developed magnetic force gradient based microfluidic chip (Mag Gradient Chip) for isolating the total number of CTCs in the sample and characterizing the state of CTCs simultaneously with respect to the epithelial cell adhesion molecule (EpCAM) expression level. We have synthesized magnetic nanoparticles (MNPs) using hydrothermal method and functionalized anti-EpCAM on their surface for the specific binding with CTCs. The Mag-Gradient Chip designed to isolate and classify the CTCs by isolating at the different location in the chip using magnetic force differences depending on the EpCAM expression level. We observed 95.7% of EpCAM positive and 79.3% of EpCAM negative CTCs isolated in the Mag-Gradient Chip. At the same time, the 71.3% of isolated EpCAM positive CTCs were isolated at the first half area whereas the 76.9% of EpCAM negative CTCs were collected at the latter half area. The Mag-Gradient Chip can isolate the 3ml of heterogeneous CTCs sample in 1h with high isolating yield. The EpCAM expression level dose not means essential condition of the metastatic CTCs, but the Mag-Gradient Chip can shorten the date to diagnose the cancer metastasis in clinic. PMID- 27503410 TI - A review of recent progress in lens-free imaging and sensing. AB - Recently, lens-free imaging has evolved as an alternative imaging technology. The key advantages of this technology, including simplicity, compactness, low cost, and flexibility of integration with other components, have facilitated the realization of many innovative applications, especially, in the fields of the on chip lens-free imaging and sensing. In this review, we discuss the development of lens-free imaging, from theory to applications. This article includes the working principle of lens-free digital inline holography (DIH) with coherent and semi coherent light, on-chip lens-free fluorescence imaging and sensing, lens-free on chip tomography, lens-free on-chip gigapixel nanoscopy, detection of nanoparticles using on-chip microscopy, wide field microscopy, and lens-free shadow image based point-of-care systems. Additionally, this review also discusses the lens-free fluorescent imaging and its dependence on structure and optical design, the advantage of using the compact lens-free driven equilibrium Fourier transform (DEFT) resolved imaging technique for on-chip tomography, the pixel super-resolved algorithm for gigapixel imaging, and the lens-free technology for point-of-care applications. All these low-cost, compact, and fast processing lens-free imaging and sensing techniques may play a crucial role especially in the fields of environmental, pharmaceutical, biological, and clinical applications of the resource-limited settings. PMID- 27503411 TI - In vitro aging promotes endoplasmic reticulum (ER)-mitochondria Ca2+ cross talk and loss of store-operated Ca2+ entry (SOCE) in rat hippocampal neurons. AB - Aging is associated to cognitive decline and susceptibility to neuron death, two processes related recently to subcellular Ca2+ homeostasis. Memory storage relies on mushroom spines stability that depends on store-operated Ca2+ entry (SOCE). In addition, Ca2+ transfer from endoplasmic reticulum (ER) to mitochondria sustains energy production but mitochondrial Ca2+ overload promotes apoptosis. We have addressed whether SOCE and ER-mitochondria Ca2+ transfer are influenced by culture time in long-term cultures of rat hippocampal neurons, a model of neuronal aging. We found that short-term cultured neurons show large SOCE, low Ca2+ store content and no functional coupling between ER and mitochondria. In contrast, in long-term cultures reflecting aging neurons, SOCE is essentially lost, Stim1 and Orai1 are downregulated, Ca2+ stores become overloaded, Ca2+ release is enhanced, expression of the mitochondrial Ca2+ uniporter (MCU) increases and most Ca2+ released from the ER is transferred to mitochondria. These results suggest that neuronal aging is associated to increased ER mitochondrial cross talking and loss of SOCE. This subcellular Ca2+ remodeling might contribute to cognitive decline and susceptibility to neuron cell death in the elderly. PMID- 27503413 TI - KLICK syndrome: recognizable phenotype and hot-spot POMP mutation. PMID- 27503412 TI - Amorphous nickel boride membrane on a platinum-nickel alloy surface for enhanced oxygen reduction reaction. AB - The low activity of the oxygen reduction reaction in polymer electrolyte membrane fuel cells is a major barrier for electrocatalysis, and hence needs to be optimized. Tuning the surface electronic structure of platinum-based bimetallic alloys, a promising oxygen reduction reaction catalyst, plays a key role in controlling its interaction with reactants, and thus affects the efficiency. Here we report that a dealloying process can be utilized to experimentally fabricate the interface between dealloyed platinum-nickel alloy and amorphous nickel boride membrane. The coating membrane works as an electron acceptor to tune the surface electronic structure of the platinum-nickel catalyst, and this composite catalyst composed of crystalline platinum-nickel covered by amorphous nickel boride achieves a 27-times enhancement in mass activity relative to commercial platinum/carbon at 0.9 V for the oxygen reduction reaction performance. Moreover, this interactional effect between a crystalline surface and amorphous membrane can be readily generalized to facilitate the 3-times higher catalytic activity of commercial platinum/carbon. PMID- 27503414 TI - Interactions of two odorant-binding proteins influence insect chemoreception. AB - It is well known that the odorant-binding proteins (OBPs) play crucial roles in insect olfactory detection. To explore if interactions of OBPs affect olfactory coding in the rice leaffolder Cnaphalocrocis medinalis ligand-binding experiments, molecular docking, RNA interference and electrophysiological recording were performed. The binding activity of two C. medinalis OBPs (CmedOBPs) to rice plant volatiles showed wide flexibility depending on the structure of ligands and interactions of CmedOBPs involved. The binding sites of CmedOBP2 and CmedOBP3 to rice plant volatiles were well predicted by three dimensional structure modelling and molecular docking experiments. In addition, the interactions of these two CmedOBPs in the perception of rice volatiles were demonstrated by RNA interference experiments. When a single double-stranded RNA (dsRNA)-CmedOBP2 was injected, the expression of CmedOBP2 was significantly reduced and the expression of CmedOBP3 was significantly increased, and vice versa. When both dsRNA-CmedOBP2 and 3 were injected together, greater reduction of electroantennogram responses to rice plant volatiles was induced than that seen with individual injection of either dsRNA-CmedOBP2 or dsRNA-CmedOBP3. These results clearly indicate that the interactions of CmedOBP2 and CmedOBP3 have significant effects on C. medinalis during the detection of host plant volatiles. PMID- 27503415 TI - Quantitative trait gene Slit2 positively regulates murine hematopoietic stem cell numbers. AB - Hematopoietic stem cells (HSC) demonstrate natural variation in number and function. The genetic factors responsible for the variations (or quantitative traits) are largely unknown. We previously identified a gene whose differential expression underlies the natural variation of HSC numbers in C57BL/6 (B6) and DBA/2 (D2) mice. We now report the finding of another gene, Slit2, on chromosome 5 that also accounts for variation in HSC number. In reciprocal chromosome 5 congenic mice, introgressed D2 alleles increased HSC numbers, whereas B6 alleles had the opposite effect. Using gene array and quantitative polymerase chain reaction, we identified Slit2 as a quantitative trait gene whose expression was positively correlated with the number of HSCs. Ectopic expression of Slit2 not only increased the number of the long-term colony forming HSCs, but also enhanced their repopulation capacity upon transplantation. Therefore, Slit2 is a novel quantitative trait gene and a positive regulator of the number and function of murine HSCs. This finding suggests that Slit2 may be a potential therapeutic target for the effective in vitro and in vivo expansion of HSCs without compromising normal hematopoiesis. PMID- 27503417 TI - Revealing the role of catechol moieties in the interactions between peptides and inorganic surfaces. AB - Catechol (1,2-dihydroxy benzene) moieties are being widely used today in new adhesive technologies. Understanding their mechanism of action is therefore of high importance for developing their applications in materials science. This paper describes a single-molecule study of the interactions between catechol related amino acid residues and a well-defined titanium dioxide (TiO2) surface. It is the first quantified measurement of the adhesion of these residues with a well-defined TiO2 surface. Single-molecule force spectroscopy measurements with AFM determined the role of different substitutions of the catechol moiety on the aromatic ring in the adhesion to the surface. These results shed light on the nature of interactions between these residues and inorganic metal oxide surfaces. This information is important for the design and fabrication of catechol-based materials such as hydrogels, coatings, and composites. Specifically, the interaction with TiO2 is important for the development of solar cells. PMID- 27503416 TI - Effects of race and sex on cerebral hemodynamics, oxygen delivery and blood flow distribution in response to high altitude. AB - To assess racial, sexual, and regional differences in cerebral hemodynamic response to high altitude (HA, 3658 m). We performed cross-sectional comparisons on total cerebral blood flow (TCBF = sum of bilateral internal carotid and vertebral arterial blood flows = QICA + QVA), total cerebrovascular resistance (TCVR), total cerebral oxygen delivery (TCOD) and QVA/TCBF (%), among six groups of young healthy subjects: Tibetans (2-year staying) and Han (Han Chinese) at sea level, Han (2-day, 1-year and 5-year) and Tibetans at HA. Bilateral ICA and VA diameters and flow velocities were derived from duplex ultrasonography; and simultaneous measurements of arterial pressure, oxygen saturation, and hemoglobin concentration were conducted. Neither acute (2-day) nor chronic (>1 year) responses showed sex differences in Han, except that women showed lower TCOD compared with men. Tibetans and Han exhibited different chronic responses (percentage alteration relative to the sea-level counterpart value) in TCBF (-17% vs. 0%), TCVR (22% vs. 12%), TCOD (0% vs. 10%) and QVA/TCBF (0% vs. 2.4%, absolute increase), with lower resting TCOD found in SL- and HA-Tibetans. Our findings indicate racial but not sex differences in cerebral hemodynamic adaptations to HA, with Tibetans (but not Han) demonstrating an altitude-related change of CBF distribution. PMID- 27503418 TI - Evaluation of Life Events in Major Depression: Assessing Negative Emotional Bias. AB - BACKGROUND: Overly negative appraisals of negative life events characterize depression but patterns of emotion bias associated with life events in depression are not well understood. The goal of this paper is to determine under which situations emotional responses are stronger than expected given life events and which emotions are biased. METHODS: Depressed (n = 16) and non-depressed (n = 14) participants (mean age = 41.4 years) wrote about negative life events involving their own actions and inactions, and rated the current emotion elicited by those events. They also rated emotions elicited by someone else's actions and inactions. These ratings were compared with evaluations provided by a second, 'benchmark' group of non-depressed individuals (n = 20) in order to assess the magnitude and direction of possible biased emotional reactions in the two groups. RESULTS: Participants with depression reported greater anger and disgust than expected in response to both actions and inactions, whereas they reported greater guilt, shame, sadness, responsibility and fear than expected in response to inactions. Relative to non-depressed and benchmark participants, depressed participants were overly negative in the evaluation of their own life events, but not the life events of others. CONCLUSION: A standardized method for establishing emotional bias reveals a pattern of overly negative emotion only in depressed individuals' self-evaluations, and in particular with respect to anger and disgust, lending support to claims that major depressives' evaluations represent negative emotional bias and to clinical interventions that address this bias. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27503419 TI - Reducing low-value interventions in the emergency department: you may be part of the problem. PMID- 27503420 TI - Corrigendum: A Toxic RNA Catalyzes the In Cellulo Synthesis of Its Own Inhibitor. PMID- 27503422 TI - Distal Normograde Intramedullary Pin and Locking Plate Placement in the Canine Humerus: A Cadaveric Study. AB - OBJECTIVE: To identify a repeatable anatomic landmark for pin insertion and to describe the technique for placement of a distal normograde intramedullary (IM) pin of approximately 35% of the IM diameter using this approach combined with a locking compression plate (LCP) on the medial aspect of the canine humerus. STUDY DESIGN: Ex vivo anatomic study. SAMPLE POPULATION: Canine cadavers (n=10 Greyhounds). METHODS: An anatomic landmark for pin insertion was identified based on three-dimensional reconstructions of previous elbow computed tomography studies and cadaveric dissection of the medial aspect of the humeral condyle. Bilateral distal normograde IM pin and LCP placement were performed and confirmed radiographically and by disarticulation and sagittal sectioning. RESULTS: The anatomic landmark for pin insertion was consistently identified in each specimen using the technique described. Distal normograde insertion of a 3.5 mm IM pin was possible in Greyhound cadaveric humeri at the described location in conjunction with a 3.5 mm LCP with fixed angle, locked screws. A monocortical locking screw was required to avoid interference with the IM pin in 28 of 60 of the 3 proximal screw holes. No pin interference was encountered in any of the distal screw holes. CONCLUSION: The anatomic landmark and technique described in our study enabled repeatable successful placement of a distal normograde IM pin of approximately 35% of the IM diameter combined with an LCP on the medial aspect of the canine humerus. This technique may be useful for locking plate-rod fixation of distal humeral diaphyseal fractures. PMID- 27503423 TI - Characterization of fibrosis changes in chronic hepatitis C patients after virological cure: A systematic review with meta-analysis. AB - BACKGROUND AND AIM: Virological cure becomes available for most patients with chronic hepatitis C (CHC), but residual fibrosis can be an independent risk factor for liver-related complications. We aimed to characterize fibrosis change in CHC patients achieved virological cure. METHODS: We did a systematic literature search for studies that had pre and post-treatment evaluations of histologic fibrosis in CHC patients with sustained virological response (SVR). We identified the association of SVR with the incidence, extent, and velocity of fibrosis change. RESULTS: Overall, 3243 patients were included. Interferon-based regimens were used for all the patients, achieving a median SVR prevalence of 36.2%. Biopsy interval ranged from 1 to 10 years. Mean baseline fibrosis score (METAVIR) was 2.3 points. Compared with non-SVR patients, SVR patients could have higher incidence of fibrosis regression (35.1% vs 17.0%; OR: 3.3; P < 0.001), regardless of baseline fibrosis severity, way of biopsy evaluation, treatment regimen, or study design, and could have more extent of reduction (-0.31 points vs -0.00 points; P = 0.004). Baseline advanced fibrosis (F > 2) was associated with more rapid regression in both SVR and non-SVR patients (P < 0.05 for both). SVR patients could have lower incidence of fibrosis progression and maintenance than non-SVR patients by 4.8% versus 23.1% (OR: 0.20; P = 0.008) and 42.9% versus 55.2% (OR: 0.53; P < 0.001), respectively. CONCLUSIONS: There could be a favorable characteristic of fibrosis regression in SVR patients. However, residential fibrosis may remain an issue because of a non-ignorable prevalence of fibrosis maintenance among these patients. PMID- 27503424 TI - A Nanoscale Interface Promoting Molecular and Functional Differentiation of Neural Cells. AB - Potassium channels and aquaporins expressed by astrocytes are key players in the maintenance of cerebral homeostasis and in brain pathophysiologies. One major challenge in the study of astrocyte membrane channels in vitro, is that their expression pattern does not resemble the one observed in vivo. Nanostructured interfaces represent a significant resource to control the cellular behaviour and functionalities at micro and nanoscale as well as to generate novel and more reliable models to study astrocytes in vitro. However, the potential of nanotechnologies in the manipulation of astrocytes ion channels and aquaporins has never been previously reported. Hydrotalcite-like compounds (HTlc) are layered materials with increasing potential as biocompatible nanoscale interface. Here, we evaluate the effect of the interaction of HTlc nanoparticles films with primary rat neocortical astrocytes. We show that HTlc films are biocompatible and do not promote gliotic reaction, while favouring astrocytes differentiation by induction of F-actin fibre alignment and vinculin polarization. Western Blot, Immunofluorescence and patch-clamp revealed that differentiation was accompanied by molecular and functional up-regulation of both inward rectifying potassium channel Kir 4.1 and aquaporin 4, AQP4. The reported results pave the way to engineering novel in vitro models to study astrocytes in a in vivo like condition. PMID- 27503425 TI - The value of 11C-methionine PET in the early differentiation between tumour recurrence and radionecrosis in patients treated for a high-grade glioma and indeterminate MRI. AB - OBJECTIVE: To evaluate the contribution of 11C-Methionine PET in the early differentiation between tumour recurrence and radionecrosis in patients treated for a high grade glioma. METHOD: The study included 30 patients with glioma (III/IV grade) treated with surgery/radiotherapy/chemotherapy (5-8 months) and with an indeterminate MRI. All patients underwent a 11C-Methione PET (within 15 days of MRI) and studies were visually analysed (intensity and morphology of uptake), quantified (SUV max/SUV mean background), and coregistered to MRI (3D Flair). Patient management was decided by the neuro-oncology committee to clinical and imaging follow-up, second-line treatment, or surgery. RESULTS: There were 23 11C-Methionine PET studies visually positive. Morphology of uptake was focal in 15, diffuse in 4, and ring-shaped in 4. Three out of the focal uptake cases underwent resection (Histopathology +). Sixteen underwent second-line therapy (11 responded; 5 progressed). The 4 cases with ring-shaped uptake were followed-up, and progression was found in 2 (true-positive), and disease-free in 2 (follow-up of 6 and 7 months, respectively) (false-positive). Seven out of 11C Methionine studies PET were visually negative, and all of them were disease-free (follow-up of 3-12 months). SUV lesion/background was 2.79+/-1.35 in tumour recurrence, and 1.53+/-0.39 in radionecrosis (P<.05). Taking into account a SUV lesion/background threshold of 2.35, the sensitivity and specificity values were 90.5% and 100%, respectively. CONCLUSION: Visual analysis, quantitative and PET/MRI coregistration of 11C-Methionine PET showed their complementary role in patients with indeterminate MRI results, thus allowing early differentiation between tumour recurrence and radionecrosis, and helping in the individual therapy approach. PMID- 27503426 TI - The mRNA capping enzyme of Saccharomyces cerevisiae has dual specificity to interact with CTD of RNA Polymerase II. AB - RNA Polymerase II (RNAPII) uniquely possesses an extended carboxy terminal domain (CTD) on its largest subunit, Rpb1, comprising a repetitive Tyr1Ser2Pro3Thr4 Ser5Pro6Ser7 motif with potential phosphorylation sites. The phosphorylation of the CTD serves as a signal for the binding of various transcription regulators for mRNA biogenesis including the mRNA capping complex. In eukaryotes, the 5 prime capping of the nascent transcript is the first detectable mRNA processing event, and is crucial for the productive transcript elongation. The binding of capping enzyme, RNA guanylyltransferases to the transcribing RNAPII is known to be primarily facilitated by the CTD, phosphorylated at Ser5 (Ser5P). Here we report that the Saccharomyces cerevesiae RNA guanylyltransferase (Ceg1) has dual specificity and interacts not only with Ser5P but also with Ser7P of the CTD. The Ser7 of CTD is essential for the unconditional growth and efficient priming of the mRNA capping complex. The Arg159 and Arg185 of Ceg1 are the key residues that interact with the Ser5P, while the Lys175 with Ser7P of CTD. These interactions appear to be in a specific pattern of Ser5PSer7PSer5P in a tri-heptad CTD (YSPTSPPS YSPTSPSP YSPTSPPS) and provide molecular insights into the Ceg1-CTD interaction for mRNA transcription. PMID- 27503427 TI - Energy Bandgap and Edge States in an Epitaxially Grown Graphene/h-BN Heterostructure. AB - Securing a semiconducting bandgap is essential for applying graphene layers in switching devices. Theoretical studies have suggested a created bulk bandgap in a graphene layer by introducing an asymmetry between the A and B sub-lattice sites. A recent transport measurement demonstrated the presence of a bandgap in a graphene layer where the asymmetry was introduced by placing a graphene layer on a hexagonal boron nitride (h-BN) substrate. Similar bandgap has been observed in graphene layers on metal substrates by local probe measurements; however, this phenomenon has not been observed in graphene layers on a near-insulating substrate. Here, we present bulk bandgap-like features in a graphene layer epitaxially grown on an h-BN substrate using scanning tunneling spectroscopy. We observed edge states at zigzag edges, edge resonances at armchair edges, and bandgap-like features in the bulk. PMID- 27503428 TI - Paenibacillus hispanicus sp. nov. isolated from Triticum aestivum roots. AB - A bacterial strain designated AMTAE16T was isolated from a root of wheat in Spain. Phylogenetic analyses based on 16S rRNA gene sequences placed the isolate in the genus Paenibacilluswith its closest relative being Paenibacillus daejeonensis AP-20T with 99.0 % 16S rRNA gene sequence similarity. DNA-DNA hybridization studies showed a mean of 30 % DNADNA relatedness between strain AMTAE16T and the type strain of P. daejeonensis. The isolate was a Gram stainvariable, motile and sporulating rod. Catalase and oxidase activities were positive. Gelatin and starch were hydrolysed but not casein. Growth was supported by many carbohydrates and organic acids as carbon source. MK-7 was the only menaquinone detected and anteiso-C15 : 0, C16 : 0 and iso-C16 : 0 were the major fatty acids. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, two unidentified aminophospholipids, four unidentified phospholipids and two unidentified lipids. meso-Diaminopimelic acid was detected in the peptidoglycan. The DNA G+C content was 55.4 mol%. Phylogenetic, chemotaxonomic and phenotypic analyses showed that strain AMTAE16T represents a novel species of the genus Paenibacillus, for which the name Paenibacillus hispanicus sp. nov. is proposed. The type strain is AMTAE16T(=LMG 29501T=CECT 9124T). PMID- 27503429 TI - Post chemotherapy retroperitoneal lymph node dissection in germ cell tumor: robotic way. AB - Post chemotherapy residual masses are considered extremely challenging to remove even by the most experienced laparoscopic surgeons. Robotic technology has added a new dimension to the management of such cases and has lessened the fear and discomfort associated with such challenging surgery but is still evolving. We present our experience of management of post chemotherapy residual mass with robotic assistance along with tips and tricks required to perform such procedure. PMID- 27503431 TI - Enhancing photoluminescence properties of SiC/SiO2 coaxial nanocables by making oxygen vacancies. AB - Coaxial nanocables (CNs) with an SiC core and a SiO2 shell were fabricated at a large scale by a simple and low cost method. The thickness of the SiO2 shell could be controlled by etching in 1 M NaOH aqueous solution for different amounts of time. XRD, SEM, TEM, HRTEM, PL and UV-Vis spectra were adopted to investigate the morphology and optical properties of the obtained SiC/SiO2CNs. Blue photoluminescence was observed at room temperature from the coaxial structure. The intensity of the single emission band at 468 nm (2.65 eV) exhibited a strong dependence on the thickness of the SiO2 layer and was significantly enhanced when the outer SiO2 shell had a thickness of 2.8 nm. The enhancement effect was attributed to oxygen vacancies (OV) and this was verified by deliberately enriching the surface OV through hydrogen treatment. PMID- 27503430 TI - Tuberculosis infection control practices and associated factors among health care workers in health centers of West Gojjam zone, Northwest Ethiopia: a cross sectional study. AB - BACKGROUND: Tuberculosis (TB) remains a major global health problem. The emerging epidemic of multi- and extensively drug-resistant (M/XDR) TB further imperils health workers, patients and public health. Health facilities with inadequate infection control are risky environments for the emergence and transmission of TB. There was no study that presented data on infection control practices of health care workers. This study aimed to assess tuberculosis infection control practices and associated factors among health care workers in West Gojjam Zone, Northwest Ethiopia. METHODS: Institution based quantitative cross-sectional study triangulated with qualitative observation and key informant interview was conducted. Six hundred sixty two health care workers were selected by multistage random sampling method. Self-administered structured questionnaire was used to collect quantitative data. Observation checklists and key informant interview guides were used to collect qualitative data. Quantitative data were entered in to Epi Info version 3.5.3 and analyzed using SPSS version 20. Odds ratio with 95 % confidence interval was used to identify factors associated with TB infection control practice of health care workers. Qualitative data were translated, transcribed, analyzed and triangulated with the quantitative findings. RESULTS: The proportion of proper TB infection control (TBIC) practices was 38 %. Qualitative data showed that administrative, environmental and personal respiratory protection control measures were not practiced well. Knowledge on the presence of TBIC plan [AOR = 4.25, 95 % CI: 2.46 - 7.35], knowledge on the presence of national guideline [AOR = 8.95, 95 % CI: 4.35 - 18.40] and working department of the health care workers were independent predictors of TBIC practices. CONCLUSIONS: The proportion of proper TBIC practices of health care workers was low. TBIC practices were determined by knowing the presence of TBIC plan and national guideline and working department. Hence, supportive supervision and trainings should be given to health care workers who are working other than TB clinics to improve the knowledge of TBIC plan and guidelines. Health centers shall prepare TBIC plans and orient all health care workers. PMID- 27503432 TI - Could participant-produced photography augment therapeutic interventions for people with intellectual disabilities? A systematic review of the available evidence. AB - BACKGROUND: People with intellectual disabilities are entitled to equitable access to psychological support. Traditional therapeutic approaches often rely on a person's ability to verbally articulate a description of their life, which can be particularly difficult for emotionally salient information. METHODS: A systematic literature review was undertaken to determine the evidence base underpinning the use of participant-produced photography within therapeutic settings. Evidence across a range of specialisms was examined in order to extrapolate areas of best practice and make recommendations for its implementation alongside people with intellectual disabilities. RESULTS: A systematic search of peer-reviewed journals identified 13 relevant documents. Participant-produced photography showed promise, although evidence pertaining specifically to people with intellectual disabilities was sparse ( n = 2). CONCLUSION: Participant-produced photography within therapeutic settings shows promise for people with intellectual disabilities. Methodological limitations made it difficult to derive firm conclusions regarding the effectiveness of different approaches. Implications for clinical and research practice are discussed. PMID- 27503433 TI - Capsule Commentary on Axon et al., Differential Impact of Homelessness on Glycemic Control in Veterans with Type 2 Diabetes Mellitus. PMID- 27503434 TI - Capsule Commentary on Bailey et al., Effect of Gaining Insurance Coverage on Smoking Cessation in Community Health Centers: A Cohort Study. PMID- 27503435 TI - Erratum to: Improvement Happens -- Learning to Better Care for "Super-Utilizers" at Denver Health: An Interview with Holly Batal. PMID- 27503437 TI - Capsule Commentary of Shah et al., Targeted Reminder Phone Calls to Patients at High Risk to No-Show for Primary Care Appointment: A Randomized Trial. PMID- 27503436 TI - Targeted Reminder Phone Calls to Patients at High Risk of No-Show for Primary Care Appointment: A Randomized Trial. AB - BACKGROUND: No-shows, or missed appointments, are a problem for many medical practices. They result in fragmented care and reduce access for all patients. OBJECTIVE: To determine whether telephone reminder calls targeted to patients at high risk of no-show can reduce no-show rates. DESIGN: Single-center randomized controlled trial. PARTICIPANTS: A total of 2247 primary care patients in a hospital-based primary care clinic at high risk of no-show (>15 % risk) for their appointment in 7 days. INTERVENTION: Seven days prior to their appointment, intervention arm patients were placed in a calling queue to receive a reminder phone call from a patient service coordinator. Coordinators were trained to engage patients in concrete planning. All patients received an automated phone call (usual care). MAIN MEASURES: Primary outcome was no-show rate. Secondary outcomes included arrival rate, cancellation rate, reschedule rate, time to cancellation, and change in revenue. KEY RESULTS: The no-show rate in the intervention arm (22.8 %) was significantly lower (absolute risk difference -6.4 %, p < 0.01, 95 % CI [-9.8 to -3.0 %]) than that in the control arm (29.2 %). Arrival, cancellation, and reschedule rates did not differ significantly. In the intervention arm, rescheduling and cancellations occurred further in advance of the appointment (mean difference, 0.35 days; 95 % CI [0.07-0.64]; p = 0.01). Reimbursement did not differ significantly. CONCLUSIONS: A phone call 7 days prior to an appointment led to a significant reduction in no-shows and increased reimbursement among patients at high risk of no-show. The use of targeted interventions may be of interest to practices taking on increased accountability for population health. PMID- 27503438 TI - Vital Signs Are Still Vital: Instability on Discharge and the Risk of Post Discharge Adverse Outcomes. AB - BACKGROUND: Vital sign instability on discharge could be a clinically objective means of assessing readiness and safety for discharge; however, the association between vital sign instability on discharge and post-hospital outcomes is unclear. OBJECTIVE: To assess the association between vital sign instability at hospital discharge and post-discharge adverse outcomes. DESIGN: Multi-center observational cohort study using electronic health record data. Abnormalities in temperature, heart rate, blood pressure, respiratory rate, and oxygen saturation were assessed within 24 hours of discharge. We used logistic regression adjusted for predictors of 30-day death and readmission. PARTICIPANTS: Adults (>=18 years) with a hospitalization to any medicine service in 2009-2010 at six hospitals (safety-net, community, teaching, and non-teaching) in north Texas. MAIN MEASURES: Death or non-elective readmission within 30 days after discharge. KEY RESULTS: Of 32,835 individuals, 18.7 % were discharged with one or more vital sign instabilities. Overall, 12.8 % of individuals with no instabilities on discharge died or were readmitted, compared to 16.9 % with one instability, 21.2 % with two instabilities, and 26.0 % with three or more instabilities (p < 0.001). The presence of any (>=1) instability was associated with higher risk adjusted odds of either death or readmission (AOR 1.36, 95 % CI 1.26-1.48), and was more strongly associated with death (AOR 2.31, 95 % CI 1.91-2.79). Individuals with three or more instabilities had nearly fourfold increased odds of death (AOR 3.91, 95 % CI 1.69-9.06) and increased odds of 30-day readmission (AOR 1.36, 95 % 0.81-2.30) compared to individuals with no instabilities. Having two or more vital sign instabilities at discharge had a positive predictive value of 22 % and positive likelihood ratio of 1.8 for 30-day death or readmission. CONCLUSIONS: Vital sign instability on discharge is associated with increased risk-adjusted rates of 30-day mortality and readmission. These simple vital sign criteria could be used to assess safety for discharge, and to reduce 30-day mortality and readmissions. PMID- 27503439 TI - Patient Relationship Management: What the U.S. Healthcare System Can Learn from Other Industries. AB - As the U.S. healthcare system moves to value-based care, the importance of engaging patients and families continues to intensify. However, simply engaging patients and families to improve their subjective satisfaction will not be enough for providers who want to maximize value. True optimization entails developing deep and long-term relationships with patients. We suggest that healthcare organizations must build such a discipline of "patient relationship management" (PRM) just as companies in non-healthcare industries have done with the concept of customer relationship management (CRM). Some providers have already made strides in this area, but overall it has been underemphasized or ignored by most healthcare systems to date. As healthcare providers work to develop their dedicated PRM systems, tools, and processes, we suggest they may benefit from emulating companies in other industries who have been able to engage their customers in innovative ways while acknowledging the differences between healthcare and other industries. PMID- 27503440 TI - Patient-Centered Medical Home Implementation in the Veterans Health Administration and Primary Care Use: Differences by Patient Comorbidity Burden. AB - BACKGROUND: The patient-centered medical home (PCMH) model has several components to improve care for patients with high comorbidity, including greater access to face-to-face primary care. OBJECTIVE: We examined whether high-comorbidity patients had larger increases in primary care provider (PCP) visits attributable to PCMH implementation in a large integrated health system relative to other patients enrolled in primary care. DESIGN, SUBJECTS AND MAIN MEASURES: This longitudinal study examined a 1 % random sample of 9.3 million patients enrolled in the Veterans Health Administration (VHA) at any time between 2003 and 2013. Face-to-face visits with PCPs per quarter were identified through VHA administrative data. Comorbidity was measured using the Gagne index and patients with a weighted score of >= 2 were defined as high comorbidity. We applied interrupted time-series models to estimate marginal changes in PCP visits attributable to PCMH implementation. Differences in marginal changes were calculated across comorbidity groups (high vs. low). Analyses were stratified by age group to account for Medicare eligibility. KEY RESULTS: Among age 65+ patients, PCMH was associated with greater PCP visits starting four and ten quarters following implementation for high- and low-comorbidity patients, respectively. Changes were larger for high-comorbidity patients (eight to 11 greater visits per 1000 patients per quarter). Among patients age < 65, PCMH was associated with greater visits for high-comorbidity patients starting eight quarters following implementation, but fewer visits for low-comorbidity patients in all quarters. The difference in visit changes across groups ranged from 18 to 67 visits per 1000 patients per quarter. CONCLUSIONS: Increases in PCP visits attributable to PCMH were greater among patients with higher comorbidity. Health systems implementing PCMH should account for population-level comorbidity burden when planning for PCMH-related changes in PCP utilization. PMID- 27503441 TI - Comparison of immediate breast reconstruction after mastectomy and mastectomy alone for breast cancer: A meta-analysis. AB - BACKGROUND: The purpose of this study was to compare patient outcomes between immediate breast reconstruction (IBR) after mastectomy and mastectomy alone. METHODS: We conducted a comprehensive literature search of PUBMED, EMBASE, Web of Science, and Cochrane Library. The primary outcomes evaluated in this review were overall survival, disease-free survival and local recurrence. Secondary outcome was the incidence of surgical site infection. All data were analyzed using Review Manager 5.3. RESULTS: Thirty-one studies, involving of 139,894 participants were included in this paper. Pooled data demonstrated that women who had IBR after mastectomy were more likely to experience surgical site infection than those treated with mastectomy alone (risk ratios 1.51, 95% CI: 1.22-1.87; p = 0.0001). There were no significant differences in overall survival (hazard ratios 0.92, 95% CI: 0.80-1.06; p = 0.25) and disease-free survival (hazard ratios 0.96, 95% CI: 0.84-1.10; p = 0.54) between IBR after mastectomy and mastectomy alone. No significant difference was found in local recurrence between two groups (risk ratios 0.92, 95% CI: 0.75-1.13; p = 0.41). CONCLUSIONS: Our study demonstrates that IBR after mastectomy does not affect the overall survival and disease-free survival of breast cancer. Besides, no evidence shows that IBR after mastectomy increases the frequency of local recurrence. PMID- 27503442 TI - Re: Infection prevention in implant surgery - A review of the surgical evidence, guidelines and a checklist. PMID- 27503443 TI - Corrigendum to "Alkaline bioleaching of municipal solid waste incineration fly ash by autochthonous extremophiles" [Chemosphere vol. 160 (2016) 54-61]. PMID- 27503444 TI - Patterns of disease relapse in primary extremity soft-tissue sarcoma. AB - BACKGROUND: Extremity soft-tissue sarcomas comprise a range of distinct histological subtypes. This study aimed to characterize the patterns of disease relapse in patients undergoing resection of primary extremity soft-tissue sarcoma. METHODS: All patients who had resection of primary extremity soft-tissue sarcoma at the Royal Marsden Hospital between January 2004 and January 2014 were identified from an institutional database. RESULTS: In the period examined, 556 patients underwent resection. The most common histological subtypes were undifferentiated pleomorphic sarcoma (169 patients, 30.4 per cent), well differentiated liposarcoma (63, 11.3 per cent), myxoid liposarcoma (62, 11.2 per cent), myxofibrosarcoma (54, 9.7 per cent) and leiomyosarcoma (39, 7.0 per cent). Local recurrence-free survival (LRFS) did not differ significantly between histological subtypes (P = 0.222). Distant metastasis-free survival (DMFS) and disease-specific survival (DSS) were found to differ significantly between subtypes (P < 0.001 for both DMFS and DSS), with the worst outcomes in patients with undifferentiated pleomorphic sarcoma (5-year survival rate: 56.8 (95 per cent c.i. 52.5 to 61.1) per cent for DMFS; 60.1 (55.6 to 64.6) per cent for DSS). However, on multivariable analysis, histological subtype was not found to be independently prognostic for LRFS, DMFS or DSS. Metastatic disease developed in 149 patients, with the lungs being the most common site of first metastasis (120 patients, 80.5 per cent). The site of first metastasis differed between subtypes, with extrapulmonary metastases predominant in myxoid liposarcoma (11 of 13 patients; P < 0.001). CONCLUSION: Although histological subtype was not found to be an independent prognostic factor for oncological outcomes, the site of first metastasis differed significantly between subtypes. PMID- 27503445 TI - Seroprevalence of hepatitis B virus surface antigen (HBsAg) among clients visiting 'Tefera Hailu' memorial hospital, Sekota, Northern Ethiopia. AB - BACKGROUND: Hepatitis B virus is one of the most causative agents of human liver disease, including acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma. The disease is a great health problem worldwide, with estimated of 350 million chronically infected people. OBJECTIVE: The aim of this study was to determine the prevalence of hepatitis B virus in Tefera Hailu Memorial Hospital (THMH) for the last three years (2013, 2014, 2015) by using secondary data. METHOD: A three year retrospective record review was conducted from March 01/2015 July 30/2015. All registered data for hepatitis B virus serological screening of the specified period were included. The data were collected by predesigned data collection sheet. The sample size was calculated by simple statistical estimation to be 149 for each year. RESULT: Of 482 subjects, 215 (44.60 %) were females and 267 (55.40 %) were males. The overall prevalence of HBV was 102 (21.16 %). The positivity rate was 69 (14.31 %) in the age group between 15 and 45. There was a decrease in the prevalence of HBV from 2012 up to 2014. CONCLUSION: The seroprevalence of HBsAg was higher in males than in females and the yearly prevalence decreases from 2012-2014. But HBV infection is still a public health problem in Ethiopia. Therefore intensification of health education concerning modes of transmission and prevention of HBV, early case finding and treatment is recommended to reduce the spread of the disease. PMID- 27503446 TI - Imaging the Addicted Brain: Alcohol. AB - Alcohol use disorder (AUD) represents a major public health issue due to its prevalence and severe health consequences. It may affect several aspects of an individual's life including work and relationships, and it also increases risk for additional problems such as brain injury. The causes and outcomes of AUD are varied; thus, attempting to understand this complex phenomenon requires investigation from multiple perspectives. Magnetic resonance imaging (MRI) is a powerful means to investigate brain anatomical and functional alterations related to AUD. Recent advances in MRI methods allow better investigation of the alterations to structural and functional brain networks in AUD. Here, we focus on findings from studies using multiple MRI techniques, which converge to support the considerable vulnerability of frontal systems. Indeed, MRI studies provide evidence for a "disconnection syndrome" which could be involved in the poor behavioral control observed in AUD. PMID- 27503448 TI - Neurobiological Basis of Hypersexuality. AB - Until now, hypersexuality has not found entry into the common diagnostic classification systems. However it is a frequently discussed phenomenon consisting of excessive sexual appetite that is maladaptive for the individual. Initial studies investigated the neurobiological underpinnings of hypersexuality, but current literature is still insufficient to draw unequivocal conclusions. In the present review, we summarize and discuss findings from various perspectives: neuroimaging and lesion studies, studies on other neurological disorders that are sometimes accompanied by hypersexuality, neuropharmacological evidence, genetic as well as animal studies. Taken together, the evidence seems to imply that alterations in the frontal lobe, amygdala, hippocampus, hypothalamus, septum, and brain regions that process reward play a prominent role in the emergence of hypersexuality. Genetic studies and neuropharmacological treatment approaches point at an involvement of the dopaminergic system. PMID- 27503447 TI - Effects of Marijuana Use on Brain Structure and Function: Neuroimaging Findings from a Neurodevelopmental Perspective. AB - Marijuana, behind only tobacco and alcohol, is the most popular recreational drug in America with prevalence rates of use rising over the past decade. A wide range of research has highlighted neurocognitive deficits associated with marijuana use, particularly when initiated during childhood or adolescence. Neuroimaging, describing alterations to brain structure and function, has begun to provide a picture of possible mechanisms associated with the deleterious effects of marijuana use. This chapter provides a neurodevelopmental framework from which recent data on brain structural and functional abnormalities associated with marijuana use is reviewed. Based on the current data, we provide aims for future studies to more clearly delineate the effects of marijuana on the developing brain and to define underlying mechanisms of the potential long-term negative consequences of marijuana use. PMID- 27503450 TI - Imaging the Gambling Brain. AB - Neuroimaging studies examining the neurobiological basis of gambling disorder (GD) have increased over the past decade. Functional magnetic resonance imaging studies during appetitive cue and reward processing tasks demonstrate altered functioning in frontostriatal brain areas, including the ventral striatum and the ventromedial prefrontal cortex. Findings suggest differences in how the anticipation and outcome of rewards are processed in individuals with GD. Future research requires larger sample sizes and should include appropriate clinical reference groups. Overall, studies to date highlight a common pathophysiology between substance-based addictions and GD, the latter offering a unique condition in which to examine nonchemical factors in addiction. PMID- 27503449 TI - Psychological and Neurobiological Correlates of Food Addiction. AB - Food addiction (FA) is loosely defined as hedonic eating behavior involving the consumption of highly palatable foods (ie, foods high in salt, fat, and sugar) in quantities beyond homeostatic energy requirements. FA shares some common symptomology with other pathological eating disorders, such as binge eating. Current theories suggest that FA shares both behavioral similarities and overlapping neural correlates to other substance addictions. Although preliminary, neuroimaging studies in response to food cues and the consumption of highly palatable food in individuals with FA compared to healthy controls have shown differing activation patterns and connectivity in brain reward circuits including regions such as the striatum, amygdala, orbitofrontal cortex, insula, and nucleus accumbens. Additional effects have been noted in the hypothalamus, a brain area responsible for regulating eating behaviors and peripheral satiety networks. FA is highly impacted by impulsivity and mood. Chronic stress can negatively affect hypothalamic-pituitary-adrenal axis functioning, thus influencing eating behavior and increasing desirability of highly palatable foods. Future work will require clearly defining FA as a distinct diagnosis from other eating disorders. PMID- 27503452 TI - Treating Addiction: Perspectives from EEG and Imaging Studies on Psychedelics. AB - Despite reports of apparent benefits, social and political pressure beginning in the late 1960s effectively banned scientific inquiry into psychedelic substances. Covert examination of psychedelics persisted through the 1990s; the turn of the century and especially the past 10 years, however, has seen a resurgent interest in psychedelic substances (eg, LSD, ayahuasca, psilocybin). This chapter outlines relevant EEG and brain imaging studies evaluating the effects of psychedelics on the brain. This chapter also reviews evidence of the use of psychedelics as adjunct therapy for a number of psychiatric and addictive disorders. In particular, psychedelics appear to have efficacy in treating depression and alcohol-use disorders. PMID- 27503453 TI - Preface. PMID- 27503451 TI - Biomarkers for Success: Using Neuroimaging to Predict Relapse and Develop Brain Stimulation Treatments for Cocaine-Dependent Individuals. AB - Cocaine dependence is one of the most difficult substance use disorders to treat. While the powerful effects of cocaine use on behavior were documented in the 19th century, it was not until the late 20th century that we realized cocaine use was affecting brain tissue and function. Following a brief introduction (Section 1), this chapter will summarize our current knowledge regarding alterations in neural circuit function typically observed in chronic cocaine users (Section 2) and highlight an emerging body of literature which suggests that pretreatment limbic circuit activity may be a reliable predictor of clinical outcomes among individuals seeking treatment for cocaine (Section 3). Finally, as the field of addiction research strives to translate this neuroimaging data into something clinically meaningful, we will highlight several new brain stimulation approaches which utilize functional brain imaging data to design noninvasive brain stimulation interventions for individuals seeking treatment for substance dependence disorders (Section 4). PMID- 27503454 TI - The Sclerotinia sclerotiorum Slt2 mitogen-activated protein kinase ortholog, SMK3, is required for infection initiation but not lesion expansion. AB - Mitogen-activated protein kinases (MAPKs) play a central role in transferring signals and regulating gene expression in response to extracellular stimuli. An ortholog of the Saccharomyces cerevisiae cell wall integrity MAPK was identified in the phytopathogenic fungus Sclerotinia sclerotiorum. Disruption of the S. sclerotiorum Smk3 gene severely reduced virulence on intact host plant leaves but not on leaves stripped of cuticle wax. This was attributed to alterations in hyphal apical dominance leading to the inability to aggregate and form infection cushions. The mutation also caused loss of the ability to produce sclerotia, increased aerial hyphae formation, and altered hyphal hydrophobicity and cell wall integrity. Mutants had slower radial expansion rates on solid media but more tolerance to elevated temperatures. Loss of the SMK3 cell wall integrity MAPK appears to have impaired the ability of S. sclerotiorum to sense its surrounding environment, leading to misregulation of a variety of functions. Many of the phenotypes were similar to those observed in S. sclerotiorum adenylate cyclase and SMK1 MAPK mutants, suggesting that these signaling pathways co-regulate aspects of fungal growth, physiology, and pathogenicity. PMID- 27503455 TI - Corrigendum to "High diversity of beta-lactamases in the General Hospital Vienna verified by whole genome sequencing and statistical analysis" [Infect. Genet. Evol., Oct.;27 (2014) 408-417]. PMID- 27503456 TI - Discovery of potential prognostic long non-coding RNA biomarkers for predicting the risk of tumor recurrence of breast cancer patients. AB - Deregulation of long non-coding RNAs (lncRNAs) expression has been proven to be involved in the development and progression of cancer. However, expression pattern and prognostic value of lncRNAs in breast cancer recurrence remain unclear. Here, we analyzed lncRNA expression profiles of breast cancer patients who did or did not develop recurrence by repurposing existing microarray datasets from the Gene Expression Omnibus database, and identified 12 differentially expressed lncRNAs that were closely associated with tumor recurrence of breast cancer patients. We constructed a lncRNA-focus molecular signature by the risk scoring method based on the expression levels of 12 relapse-related lncRNAs from the discovery cohort, which classified patients into high-risk and low-risk groups with significantly different recurrence-free survival (HR = 2.72, 95% confidence interval 2.07-3.57; p = 4.8e-13). The 12-lncRNA signature also represented similar prognostic value in two out of three independent validation cohorts. Furthermore, the prognostic power of the 12-lncRNA signature was independent of known clinical prognostic factors in at least two cohorts. Functional analysis suggested that the predicted relapse-related lncRNAs may be involved in known breast cancer-related biological processes and pathways. Our results highlighted the potential of lncRNAs as novel candidate biomarkers to identify breast cancer patients at high risk of tumor recurrence. PMID- 27503457 TI - Preselection of A- and B- modified d-homo lactone and d-seco androstane derivatives as potent compounds with antiproliferative activity against breast and prostate cancer cells - QSAR approach and molecular docking analysis. AB - The problem with trial-and-error approach in organic synthesis of targeted anticancer compounds can be successfully avoided by computational modeling of molecules, docking studies and chemometric tools. It has been proven that A- and B- modified d-homo lactone and d-seco androstane derivatives are compounds with significant antiproliferative activity against estrogen-independent breast adenocarcinoma (ER-, MDA-MB-231) and androgen-independent prostate cancer cells (AR-, PC-3). This paper presents the quantitative structure-activity relationship (QSAR) models based on artificial neural networks (ANNs) which are able to predict whether d-homo lactone and/or d-seco androstane-based compounds will express antiproliferative activity against breast cancer cells (MDA-MB-231) or not. Also, the present paper describes the molecular docking study of 3beta acetoxy-5alpha,6alpha-epoxy- (3) and 6alpha,7alpha-epoxy-1,4-dien-3-one (24) d homo lactone androstane derivatives, as well as 4-en-3-one (15) d-seco androstane derivative, which are compounds with strong or moderate antiproliferative activity against prostate cancer cells (PC-3), and compares them with commercially available medicament for prostate cancer - abiraterone. The obtained promising results can be used as guidelines in further syntheses of novel d-homo lactone and d-seco androstane derivatives with antiproliferative activity against breast and prostate cancer cells. PMID- 27503458 TI - Nanovesicular liposome-encapsulated hemoglobin (LEH) prevents multi-organ injuries in a rat model of hemorrhagic shock. AB - The goals of resuscitation in hemorrhagic shock are to correct oxygen deficit and to maintain perfusion pressure to the vital organs. We created liposome encapsulated hemoglobin (LEH) as a nanoparticulate oxygen carrier (216+/-2nm) containing 7.2g/dl hemoglobin, and examined its ability to prevent the systemic manifestations of hemorrhagic shock (45% blood loss) in a rat model. We collected plasma after 6h of shock and LEH resuscitation, and determined the circulating biomarkers of systemic inflammation and functions of liver, gut, heart, and kidney. As is typical of the shock pathology, a significant increase in the plasma levels of cardiac troponin, liver function enzymes, soluble CD163 (macrophage activation), and creatinine, and the liver/gut myeloperoxidase activity was observed in the hemorrhaged rats. The plasma levels of TNF-alpha, IL 6, IL-1alpha, CINC-1, and IL-22 also increased after hemorrhagic shock. LEH administration prevented the hemorrhagic shock-induced accumulation of the markers of injury to the critical organs and pro-inflammatory cytokines. LEH also decreased the plasma levels of stress hormone corticosterone in hemorrhaged rats. Although saline also reduced the circulating corticosterone and a few other tissue injury markers, it was not as effective as LEH in restraining the plasma levels of creatinine, alanine transaminase, CD163, TNF-alpha, IL-6, and IL 1alpha. These results indicate that resuscitation with nanoparticulate LEH creates a pro-survival phenotype in hemorrhaged rats, and because of its oxygen carrying capacity, LEH performs significantly better than saline in hemorrhagic shock. PMID- 27503459 TI - Tailoring the mucoadhesive and sustained release characteristics of mesalamine loaded formulations for local treatment of distal forms of ulcerative colitis. AB - Direct delivery of sustained therapeutic levels of mesalamine (MS) via rectal systems to manage distal forms of ulcerative colitis was studied. The High molecular weight hydroxypropyl methylcellulose (HPMC K4M) polymer was combined with hydrophilic surfactants to control polymer hydration process allowing optimization of the mucoadhesive and controlled drug release properties for the rectal systems. Physical mixtures and granules of MS and HPMC K4M were prepared and in vitro characterized using scanning electron microscope, differential scanning calorimetry and X-ray diffraction techniques. Rectal formulations were prepared utilizing MS-HPMC K4M mixtures in different polyethylene glycol (PEG) combination bases. The developed rectal formulations were investigated for physical, mucoadhesion, in-vitro drug release and swelling characteristics. Results revealed acceptable physical characteristics of the prepared formulations with good content uniformity and minimum weight variation. Sustained release patterns of MS form HPMC K4M based formulations were observed. Formulations prepared using high proportions of the polymer or PEG 400 showed higher extent of mucoadhesion, swelling and greatly extended drug release time. Efficacy of an optimized formulation was assessed using the acetic acid induced colitis model in rats and compared to a reference polymer-free formulation of the drug. Clinical evaluation included bleeding from rectum, consistency of animal stool and colon/body weight ratio. Furthermore, histopathological analysis was carried out to evaluate the degree of inflammation and mucosal damage. Overall results showed a significant enhancement in the clinical pictures and colon histopathology of animals treated by the sustained release mucoadhesive formulation compared to the reference polymer free formulation and the non-treated colitis group. PMID- 27503460 TI - Novel antibodies to phosphorylated alpha-synuclein serine 129 and NFL serine 473 demonstrate the close molecular homology of these epitopes. AB - Pathological inclusions containing aggregated, highly phosphorylated (at serine129) alpha-synuclein (alphaS pSer129) are characteristic of a group of neurodegenerative diseases termed synucleinopathies. Antibodies to the pSer129 epitope can be highly sensitive in detecting alphaS inclusions in human tissue and experimental models of synucleinopathies. However, the generation of extensively specific pSer129 antibodies has been problematic, in some cases leading to the misinterpretation of alphaS inclusion pathology. One common issue is cross-reactivity to the low molecular mass neurofilament subunit (NFL) phosphorylated at Ser473. Here, we generated a series of monoclonal antibodies to the pSer129 alphaS and pSer473 NFL epitopes. We determined the relative abilities of the known alphaS kinases, polo-like kinases (PLK) 1, 2 and 3 and casein kinase (CK) II in phosphorylating NFL and alphaS, while using this information to characterize the specificity of the new antibodies. NFL can be phosphorylated by PLK1, 2 and 3 at Ser473; however CKII shows the highest phosphorylation efficiency and specificity for this site. Conversely, PLK3 is the most efficient kinase at phosphorylating alphaS at Ser129, but there is overlay in the ability of these kinases to phosphorylate both epitopes. Antibody 4F8, generated to the pSer473 NFL epitope, was relatively specific for phosphorylated NFL, however it could uniquely cross-react with pSer129 alphaS when highly phosphorylated, further showing the structural similarity between these phospho-epitopes. All of the new pSer129 antibodies detected pathological alphaS inclusions in human brains and mouse and cultured cell experimental models of induced synucleinopathies. Several of these pSer129 alphaS antibodies reacted with the pSer473 NFL epitope, but 2 clones (LS3-2C2 and LS4-2G12) did not. However, LS3 2C2 demonstrated cross-reactivity with other proteins. Our findings further demonstrate the difficulties in generating specific pSer129 alphaS antibodies, but highlights that the use of multiple antibodies, such as those generated here, can provide a sensitive and accurate assessment of alphaS pathology. PMID- 27503461 TI - Changes in rubisco, cysteine-rich proteins and antioxidant system of spinach (Spinacia oleracea L.) due to sulphur deficiency, cadmium stress and their combination. AB - Sulphur (S) deficiency, cadmium (Cd) toxicity and their combinations are of wide occurrence throughout agricultural lands. We assessed the impact of short-term (2 days) and long-term (4 days) applications of cadmium (40 MUg/g soil) on spinach plants grown on sulphur-sufficient (300 MUM SO42-) and sulphur-deficient (30 MUM SO42-) soils. Compared with the control (+S and -Cd), oxidative stress was increased by S deficiency (-S and -Cd), cadmium (+S and +Cd) and their combination stress (-S and +Cd) in the order of (S deficiency) < (Cd stress) < (S deficiency and +Cd stress). SDS-PAGE profile of leaf proteins showed a high vulnerability of rubisco large subunit (RbcL) to S deficiency. Rubisco small subunit (RbcS) was particularly sensitive to Cd as well as dual stress (+Cd and S) but increased with Cd in the presence of S. Cysteine content in low molecular weight proteins/peptide was also affected, showing a significant increase under cadmium treatment. Components of ascorbate-glutathione antioxidant system altered their levels, showing the maximum decline in ascorbate (ASA), dehydroascorbate (DHA), total ascorbate (ASA + DHA, hereafter TA), glutathione (GSH) and total glutathione (GSH + GSSG, hereafter TG) under S deficiency. However, total ascorbate and total glutathione increased, besides a marginal increase in their reduced and oxidized forms, when Cd was applied in the presence of sufficient S. Sulphur supply also helped in increasing the activity of superoxide dismutase (SOD), ascorbate peroxidase (APX), glutathione reductase (GR) and catalase (CAT) under Cd stress. However, their activity suffered by S deficiency and by Cd stress during S deficiency. Each stress declined the contents of soluble protein and photosynthetic pigments; the highest decline in contents of protein and pigments occurred under S deficiency and dual stress respectively. The fresh and dry weights, although affected adversely by every stress, declined most under dual stress. It may be concluded that an optimal level of S is required during Cd stress for better response of SOD, APX, GR and CAT activity, as well as synthesis of cysteine. RbcS is as highly sensitive to S deficiency as RbcL is to Cd stress. PMID- 27503462 TI - Prosurvival Factors Improve Functional Engraftment of Myogenically Converted Dermal Cells into Dystrophic Skeletal Muscle. AB - In Duchenne muscular dystrophy (DMD) and other muscle wasting disorders, cell therapies are a promising route for promoting muscle regeneration by supplying a functional copy of the missing dystrophin gene and contributing new muscle fibers. The clinical application of cell-based therapies is resource intensive, and it will therefore be necessary to address key limitations that reduce cell engraftment into muscle tissue. A pressing issue is poor donor cell survival following transplantation, which in preclinical studies limits the ability to effectively test the impact of cell-based therapy on whole muscle function. We, therefore, sought to improve engraftment and the functional impact of in vivo myogenically converted dermal fibroblasts (dFbs) using a prosurvival cocktail (PSC) that includes heat shock followed by treatment with insulin-like growth factor-1, a caspase inhibitor, a Bcl-XL peptide, a KATP channel opener, basic fibroblast growth factor, Matrigel, and cyclosporine A. Advantages of dFbs include compatibility with the autologous setting, ease of isolation, and greater proliferative potential than DMD satellite cells. dFbs expressed tamoxifen inducible MyoD and carried a mini-dystrophin gene driven by a muscle-specific promoter. After transplantation into muscles of mdx mice, a 70% reduction in donor cells was observed by day 5, and a 94% reduction by day 28. However, treatment with PSC gave a nearly three-fold increase in donor cells in early engraftment, and greatly increased the number of donor-contributed muscle fibers and total engrafted area in transplanted muscles. Furthermore, dystrophic muscles that received dFbs with PSC displayed reduced injury with eccentric contractions and an increase in maximum isometric force. Thus, enhancing survival of myogenic cells increases engraftment and improves structure and function of dystrophic muscle. PMID- 27503463 TI - [S2e guidelines "Gouty arthritis - specialist"]. PMID- 27503464 TI - A meta-analysis of the social communication questionnaire: Screening for autism spectrum disorder. AB - The current meta-analysis examines the previous research on the utility of the Social Communication Questionnaire as a screening instrument for autism spectrum disorder. Previously published reports have highlighted the inconsistencies between Social Communication Questionnaire-screening results and formal autism spectrum disorder diagnoses. The variations in accuracy resulted in some researchers questioning the validity of the Social Communication Questionnaire. This study systematically examined the accuracy of the Social Communication Questionnaire as a function of the methodological decisions made by researchers screening for autism spectrum disorder over the last 15 years. Findings from this study suggest that the Social Communication Questionnaire is an acceptable screening instrument for autism spectrum disorder (area under the curve = 0.885). Variations in methodological decisions, however, greatly influenced the accuracy of the Social Communication Questionnaire in screening for autism spectrum disorder. Of these methodological variations, using the Current instead of the Lifetime version of the Social Communication Questionnaire resulted in the largest detrimental effect ( d = -3.898), followed by using the Social Communication Questionnaire with individuals younger than 4 years of age ( d = 2.924) and relying upon convenience samples ( d = -4.828 for clinical samples, 2.734 for convenience samples, and -1.422 for community samples). Directions for future research and implications for using the Social Communication Questionnaire to screen for autism spectrum disorder are discussed. PMID- 27503465 TI - Equivalence of symptom dimensions in females and males with autism. AB - This study investigated equivalence of autism symptom domains in males and females with autism. Symptom data were obtained from 2643 children and adolescents with autism spectrum disorder (352 females, 2291 males; age range = 4 17 years) included in the Simons Simplex Collection. Items from the Social Responsiveness Scale and Autism Diagnostic Interview-Revised were mapped to nine a priori symptom dimensions. Multi-group confirmatory factor models, including measurement equivalence and item response theory analyses, examined whether males and females showed measurement or structural differences in autism symptom constructs. Results indicated mean differences in restricted interests that were not due to measurement bias. No other symptom dimension showed evidence of measurement bias and autism symptom structure was highly similar between males and females. Future studies are needed to carefully estimate any sex differences in the content, frequency, or intensity/severity of restricted interests in females and males. PMID- 27503466 TI - Monitoring recovery from neuromuscular block using acceleromyography at the trapezius muscle: problems that must be considered. PMID- 27503467 TI - Whole-genome regulation analysis of histone H3 lysin 27 trimethylation in subclinical mastitis cows infected by Staphylococcus aureus. AB - BACKGROUND: S. aureus is one of the major etiological agents causing bovine subclinical mastitis. The regulatory effects of H3K27me3 on gene expression in subclinical S. aureus mastitis cows are unknown. This study aimed to profile genome-wide transcriptional changes regulated by H3K27me3 in bovine lymphocytes applied in subclinical S. aureus mastitis cows and healthy controls. RESULTS: A total of 61 differentially expressed genes (DEGs) were detected in subclinical S. aureus mastitis cows compared to the healthy controls, of which 25 DEGs are up regulated and the rest are down-regulated genes in subclinical S.aureus mastitis cows. The up-regulated genes are mainly involved in the Jak-STAT signaling pathway, cytokine-cytokine receptor interaction, and T cell receptor-signaling pathway, while the down-regulated genes are related to metabolism pathways. Combination analysis of histone methylation and gene expression revealed that H3K27 trimethylation levels in silent genes were higher in subclinical S. aureus mastitis cattle than in healthy cows. The key regions of H3K27me3 target genes related to subclinical S. aureus mastitis were the upstream 2 kb regions of the DEGs relative to transcription start site (TSS). CONCLUSIONS: The current study provides a novel insight into the interaction between S. aureus and lymphocytes in lactating cows by histone H3 methylation regulation. The differentially expressed genes in bovine lymphocytes regulated by H3K27me3 on upstream 2 kb regions (IL10, PTX3 and etc.) may relate to S. aureus mastitis susceptibility and could be considered as key candidate genes for anti- S. aureus mastitis study and breeding. PMID- 27503469 TI - Decreased absorption of midazolam in the stomach due to low pH induced by co administration of Banha-sasim-tang. AB - OBJECTIVES: Banha-sasim-tang (BST), which consists of seven different herbs, is one of the most popular herbal formulae for treating gastrointestinal disorders in Eastern Asia. The commonly used herbal medicine is often co-administered with other therapeutic drugs, which raises the possibility of herb-drug interactions and may modify the clinical safety profile of therapeutic drugs. METHODS: We investigated the potential herb-drug interactions between BST extract and midazolam (MDZ) in mice. The area under the plasma concentration-time curve (AUC) of MDZ and 1'-hydroxymidazolam (1'-OH-MDZ) was evaluated for both oral and intraperitoneal administration of MDZ, following oral administration of BST (0.5 and 1 g/kg). RESULTS: It was found that the AUC of MDZ and 1'-OH-MDZ was lower in case of oral administration of MDZ. Administration of BST extract was not associated with hepatic cytochrome P450 activity. BST extract induced a strong reduction in pH and it has been reported that oral mucosal absorption of MDZ is lower at low pH. The decreased absorption rate of MDZ might be caused by the ingredients of BST and may not be related to other factors such as increased excretion of MDZ by P-glycoprotein. CONCLUSIONS: The altered pharmacokinetics of midazolam caused by co-administration with BST in vivo could be attributed to a decrease in pH and subsequent reduction of MDZ absorption rate. PMID- 27503468 TI - Growing Out of Stress: The Role of Cell- and Organ-Scale Growth Control in Plant Water-Stress Responses. AB - Water is the most limiting resource on land for plant growth, and its uptake by plants is affected by many abiotic stresses, such as salinity, cold, heat, and drought. While much research has focused on exploring the molecular mechanisms underlying the cellular signaling events governing water-stress responses, it is also important to consider the role organismal structure plays as a context for such responses. The regulation of growth in plants occurs at two spatial scales: the cell and the organ. In this review, we focus on how the regulation of growth at these different spatial scales enables plants to acclimate to water-deficit stress. The cell wall is discussed with respect to how the physical properties of this structure affect water loss and how regulatory mechanisms that affect wall extensibility maintain growth under water deficit. At a higher spatial scale, the architecture of the root system represents a highly dynamic physical network that facilitates access of the plant to a heterogeneous distribution of water in soil. We discuss the role differential growth plays in shaping the structure of this system and the physiological implications of such changes. PMID- 27503470 TI - Foraging Behavior Interactions Between Two non-Native Social Wasps, Vespula germanica and V. vulgaris (Hymenoptera: Vespidae): Implications for Invasion Success? AB - Vespula vulgaris is an invasive scavenging social wasp that has very recently arrived in Patagonia (Argentina), a territory previously invaded - 35 yrs earlier - by another wasp, Vespula germanica Although V. vulgaris wasps possess features that could be instrumental in overcoming obstacles through several invasion stages, the presence of preestablished populations of V. germanica could affect their success. We studied the potential role played by V. germanica on the subsequent invasion process of V. vulgaris wasps in Patagonia by focusing on the foraging interaction between both species. This is because food searching and exploitation are likely to overlap strongly among Vespula wasps. We carried out choice tests where two types of baits were presented in a pairwise manner. We found experimental evidence supporting the hypothesis that V. germanica and V. vulgaris have an asymmetrical response to baits with stimuli simulating the presence of each other. V. germanica avoided baits with either visual or olfactory cues indicating the V. vulgaris presence. However, V. vulgaris showed no preference between baits with or lacking V. germanica stimuli. These results suggest that the presence of an established population of V. germanica may not contribute to added biotic resistance to V. vulgaris invasion. PMID- 27503471 TI - Stability and localization of 14-3-3 proteins are involved in salt tolerance in Arabidopsis. AB - KEY MESSAGE: Salt stress induces the degradation of 14-3-3 proteins, and affects the localization of 14-3-3 lambda. Both the modulation of 14-3-3 protein stability and the subcellular localization of these proteins are involved in salt tolerance in plants. Salt tolerance in plants is regulated by multiple signaling pathways, including the salt overly sensitive (SOS) pathway, of which the SOS2 protein is a key component. SOS2 is activated under salt stress to enhance salt tolerance in plants. We previously identified 14-3-3 lambda and kappa as important regulators of salt tolerance. Both proteins interact with SOS2 to inhibit its kinase activity under normal growth conditions. In response to salt stress, 14-3-3 proteins dissociate from SOS2, releasing its activity and activating the SOS pathway to confer salt tolerance (Zhou et al. Plant Cell 26:1166-1182, 2014). Here we report that salt stress promotes the degradation of 14-3-3 lambda and kappa, at least in part via the actions of SOS3-like calcium binding protein 8/calcineurin-B-like10, and also decreases the plasma membrane (PM) localization of 14-3-3 lambda. Salt stress also partially represses the interaction of SOS2 and 14-3-3 lambda at the PM, but activates PM-localized SOS2. Together, these results suggest that, in plants, both the modulation of 14-3-3 stability and the subcellular localization of these proteins in response to salt stress are important for SOS2 activation and salt tolerance. These data provide new insights into the biological roles of 14-3-3 proteins in modulating salt tolerance. PMID- 27503472 TI - GH32 family activity: a topological approach through protein contact networks. AB - KEY MESSAGE: The application of Protein Contact Networks methodology allowed to highlight a novel response of border region between the two domains to substrate binding. Glycoside hydrolases (GH) are enzymes that mainly hydrolyze the glycosidic bond between two carbohydrates or a carbohydrate and a non carbohydrate moiety. These enzymes are involved in many fundamental and diverse biological processes in plants. We have focused on the GH32 family, including enzymes very similar in both sequence and structure, each having however clear specificities of substrate preferences and kinetic properties. Structural and topological differences among proteins of the GH32 family have been here identified by means of an emerging approach (Protein Contact network, PCN) based on the formalization of 3D structures as contact networks among amino-acid residues. The PCN approach proved successful in both reconstructing the already known functional domains and in identifying the structural counterpart of the properties of GH32 enzymes, which remain uncertain, like their allosteric character. The main outcome of the study was the discovery of the activation upon binding of the border (cleft) region between the two domains. This reveals the allosteric nature of the enzymatic activity for all the analyzed forms in the GH32 family, a character yet to be highlighted in biochemical studies. Furthermore, we have been able to recognize a topological signature (graph energy) of the different affinity of the enzymes towards small and large substrates. PMID- 27503473 TI - Assessing the reproducibility of exome copy number variations predictions. AB - BACKGROUND: Reproducibility is receiving increased attention across many domains of science and genomics is no exception. Efforts to identify copy number variations (CNVs) from exome sequence (ES) data have been increasing. Many algorithms have been published to discover CNVs from exomes and a major challenge is the reproducibility in other datasets. Here we test exome CNV calling reproducibility under three conditions: data generated by different sequencing centers; varying sample sizes; and varying capture methodology. METHODS: Four CNV tools were tested: eXome Hidden Markov Model (XHMM), Copy Number Inference From Exome Reads (CoNIFER), EXCAVATOR, and Copy Number Analysis for Targeted Resequencing (CONTRA). To examine the reproducibility, we ran the callers on four datasets, varying sample sizes of N = 10, 30, 75, 100, 300, and data with different capture methodology. We examined the false negative (FN) calls and false positive (FP) calls for potential limitations of the CNV callers. The positive predictive value (PPV) was measured by checking the CNV call concordance against single nucleotide polymorphism array. RESULTS: Using independently generated datasets, we examined the PPV for each dataset and observed wide range of PPVs. The PPV values were highly data dependent (p <0.001). For the sample sizes and capture method analyses, we tested the callers in triplicates. Both analyses resulted in wide ranges of PPVs, even for the same test. Interestingly, negative correlations between the PPV and the sample sizes were observed for CoNIFER (rho = -0.80). Further examination of FN calls showed that 44 % of these were missed by all callers and were attributed to the CNV size (46 % spanned <=3 exons). Overlap of the FP calls showed that FPs were unique to each caller, indicative of algorithm dependency. CONCLUSIONS: Our results demonstrate that further improvements in CNV callers are necessary to improve reproducibility and to include wider spectrum of CNVs (including the small CNVs). These CNV callers should be evaluated on multiple independent, heterogeneously generated datasets of varying size to increase robustness and utility. These approaches to the evaluation of exome CNV are essential to support wide utility and applicability of CNV discovery in exome studies. PMID- 27503474 TI - Effects of typhoid vaccine on inflammation and sleep in healthy participants: a double-blind, placebo-controlled, crossover study. AB - RATIONALE: An increasing body of evidence links the occurrence of sleep continuity disturbances with increased inflammation and both sleep disturbances and inflammation are associated with clinical depression. Typhoid vaccination results in a mild inflammatory response that significantly increases levels of the proinflammatory cytokine, interleukin (IL)-6. OBJECTIVES: The present exploratory study aimed to enhance our understanding of the link between inflammation, sleep and depression by examining the effects of typhoid vaccine on the sleep polysomnogram. METHODS: We studied the effects of a single injection of typhoid polysaccharide vaccine and placebo (saline solution) on sleep in 16 healthy male and female participants aged 20-38 years, sleeping at home in a randomized, double-blind, balanced order, crossover design. Subjective measures of mood, sleep and adverse effects were elicited and plasma samples analysed for IL-6 levels. RESULTS: IL-6 levels (in picogramme per millilitre) significantly increased 2 h post vaccine compared to placebo (0.90 vs 0.53, p = 0.026, r = 0.55). Relative to placebo, typhoid vaccination produced significant impairment in several measures of sleep continuity. Total sleep time (in minute) (426.1 vs 410.7, p = 0.005, r = 0.62) and sleep efficiency percent (94.3 vs 91.5, p = 0.007, r = 0.65) were decreased; with increases in wake after sleep onset (in minute) (25.5 vs 38.8, p = 0.007,r = 0.65), total wake (in minute) (34.9 vs 50.3, p = 0.005,r = 0.67), sleep stage transitions (155.9 vs 173.1, p = 0.026, r = 0.56), number of awakenings (27.2 vs 36.1, p = 0.007, r = 0.64) and awakening index (3.8 vs 5.3, p = 0.005, r = 0.67) (means, significance level and effect size). CONCLUSIONS: Inflammatory mechanisms may underlie the impairment in sleep efficiency which is a hallmark of major depression. Because impaired sleep is also a predictor of major depression, there may be a role for suitable anti inflammatory approaches in strategies designed to prevent the onset of depression. ClinicalTrials.gov ( http://www.clinicaltrials.gov ): NCT02628054. PMID- 27503475 TI - Cannabigerol is a novel, well-tolerated appetite stimulant in pre-satiated rats. AB - RATIONALE: The appetite-stimulating properties of cannabis are well documented and have been predominantly attributed to the hyperphagic activity of the psychoactive phytocannabinoid, ?(9)-tetrahydrocannabinol (?(9)-THC). However, we have previously shown that a cannabis extract devoid of ?(9)-THC still stimulates appetite, indicating that other phytocannabinoids also elicit hyperphagia. One possible candidate is the non-psychoactive phytocannabinoid cannabigerol (CBG), which has affinity for several molecular targets with known involvement in the regulation of feeding behaviour. OBJECTIVES: The objective of the study was to assess the effects of CBG on food intake and feeding pattern microstructure. METHODS: Male Lister hooded rats were administered CBG (30-120 mg/kg, per ora (p.o.)) or placebo and assessed in open field, static beam and grip strength tests to determine a neuromotor tolerability profile for this cannabinoid. Subsequently, CBG (at 30-240 mg/kg, p.o.) or placebo was administered to a further group of pre-satiated rats, and hourly intake and meal pattern data were recorded over 2 h. RESULTS: CBG produced no adverse effects on any parameter in the neuromotor tolerability test battery. In the feeding assay, 120-240 mg/kg CBG more than doubled total food intake and increased the number of meals consumed, and at 240 mg/kg reduced latency to feed. However, the sizes or durations of individual meals were not significantly increased. CONCLUSIONS: Here, we demonstrate for the first time that CBG elicits hyperphagia, by reducing latency to feed and increasing meal frequency, without producing negative neuromotor side effects. Investigation of the therapeutic potential of CBG for conditions such as cachexia and other disorders of eating and body weight regulation is thus warranted. PMID- 27503477 TI - The incredible shrinking problem of the device patient. PMID- 27503476 TI - Changes in symptoms of asthma and rhinitis by sensitization status over ten years in a cohort of young Chilean adults. AB - BACKGROUND: We investigated the net changes in prevalence of symptoms of asthma and rhinitis over 10 years in a cohort of young by baseline sensitization status. METHODS: One thousand one hundred ninety three Chilean adults subjects aged 22-28 living in a semi-rural area of central Chile answered a lifestyle and the European Community Respiratory Health Survey (ECRHS) questionnaires. Bronchial hyper-responsiveness (BHR) and skin prick test (SPT) to eight allergens were measured at baseline in 2001. Ten years later, 772 participants completed the questionnaires again. Estimates of adjusted net changes in prevalence of symptoms by sensitization status at baseline and association between sensitization status at baseline and respiratory symptoms ten years later were assessed. RESULTS: A quarter of the participants were sensitized to at least one allergen in 2001. Prevalence of wheeze had a net change per year of -0.37 % (95 % Confidence Interval -0.71 to 0.02 %; p = 0.067). Self-reported nasal allergies in the last 12 months increased by 0.83 % per year (95 % CI 0.49 to 1.17 %; p < 0.001). Those sensitized to either cat fur (OR 1.76; CI 1.01 to 3.05), cockroach, (OR 2.09; 1.13 to 3.86) blend of grass and pollens (1.78; 95 % CI 1.08 to 2.92), or weeds (OR 1.77; 95 % CI 1.01 to 3.12) in 2001 were more likely to have wheeze in the last 12 months 10 years later. CONCLUSION: Symptoms of asthma remained stable or slightly changed over 10 years in adults, whilst rhinitis and nasal allergies greatly increased. Being sensitized to at least one allergen is a risk factor for persistent symptoms of asthma and rhinitis, but not for determining net changes of symptoms over time. The underlying causes for the contrasting trends between asthma and nasal allergy are unknown. PMID- 27503478 TI - Reply to the Editor- Bipolar left ventricular pacing is associated with significant reduction in heart failure or death in CRT-D patients with LBBB. PMID- 27503479 TI - To the Editor- Bipolar left ventricular pacing is associated with significant reduction in heart failure or death in CRT-D patients with LBBB. PMID- 27503480 TI - Catheter ablation using the third-generation cryoballoon provides an enhanced ability to assess time to pulmonary vein isolation facilitating the ablation strategy: Short- and long-term results of a multicenter study. AB - BACKGROUND: Limited data exist on cryoablation of atrial fibrillation (Cryo-AF) using the newly available third-generation (Arctic Front Advance-Short Tip [AFA ST]) cryoballoon. OBJECTIVE: In this multicenter study, we evaluated the safety and efficacy of Cryo-AF using the AFA-ST vs the second-generation (Arctic Front Advance [AFA]) cryoballoon. METHODS: We examined the procedural safety and efficacy and the short- and long-term clinical outcomes associated with a first time Cryo-AF performed in 355 consecutive patients (254/355 [72%] with paroxysmal AF), using either the AFA-ST (n = 102) or the AFA (n = 253) cryoballoon catheters. RESULTS: Acute isolation was achieved in 99.6% of all pulmonary veins (PVs) (AFA-ST: 100% vs AFA: 99.4%; P = .920). Time to pulmonary vein isolation was recorded in 89.2% of PVs using AFA-ST vs 60.2% using AFA (P < .001). PVs targeted using AFA-ST required fewer applications (1.6 +/- 0.8 vs 1.7 +/- 0.8; P = .023), whereas there were no differences in the balloon nadir temperature (AFA ST: -47.0 degrees C +/- 7.3 degrees C vs AFA: -47.5 degrees C +/- 7.8 degrees C; P = .120) or thaw time (AFA-ST: 41 +/- 24 seconds vs AFA: 44 +/- 28 seconds; P = .056). However, AFA-ST was associated with shorter left atrial dwell time (43 +/- 5 minutes vs 53 +/- 16 minutes; P < .001) and procedure time (71 +/- 11 minutes vs 89 +/- 25 minutes; P < .001). Furthermore, Cryo-AF using AFA-ST was completed more frequently by "single-shot" PV ablation (27.4% vs 20.2%; P = .031). Persistent phrenic nerve palsy (AFA-ST: 0% vs AFA: 0.8%; P = .507) and procedure related adverse events (AFA-ST: 1.0% vs AFA: 1.6%; P = .554) were similar, as was the freedom from recurrent atrial arrhythmias at 10 months of follow-up (AFA-ST: 81.8% vs AFA: 79.9%; P = .658). CONCLUSION: Cryo-AF using the AFA-ST cryoballoon offers an enhanced ability to assess time to pulmonary vein isolation, allowing for fewer cryoapplications and shorter left atrial dwell time and procedure time. Consequently, this allowed for procedural completion more frequently using a "single-shot" PV ablation with equivalent safety and efficacy. PMID- 27503481 TI - Patellar height assessment in total knee arthroplasty: a new method. AB - INTRODUCTION: We described in 1981 a method to evaluate patellar height in normal and symptomatic knees on sagittal X-ray view. This index is a frequently used method, yet it is not suitable after a total knee arthroplasty (TKA). MATERIAL AND METHOD: The original method measures the distance between the distal margin of the articular surface of the patella (point A) and the anterosuperior angle of the tibial plateau (point T), then the length of the patellar articular surface (AP). The index is AT/AP ratio (normal values range from 0.8 to 1.2). After TKA, the T landmark is no longer available, so we must define a new T' landmark. This point is situated at the intersection between the line perpendicular to the tibial posterior cortex elevated at the tip of the fibular head and the tibial anterior cortex. This remarkable landmark can be identified before and after TKA, with a new relative index AT'/AP ratio. This modified method allows the comparison of patella height before and after TKA. RESULTS: We have used this modified index with the collaboration of several authors during the testing of different models of TKA, with an accurate reproducibility. Repeatability (usually called intra-observer reliability) was good, with intra-class correlation coefficients (ICCs) between 0.58 and 0.75 among the observers. Reproducibility (usually called inter-observer reliability) was also considered as good, with ICC ranging from 0.64 to 0.72. DISCUSSION: Patella height measurement has to be assessed with the original method (AT/AP) to detect patella infera that could influence the surgical approach. The correlation between original and modified indexes has to be assessed. The modification of patella height after TKA could be evaluated through the modified index and compared with functional results. PMID- 27503482 TI - Ingenol Disoxate: A Novel 4-Isoxazolecarboxylate Ester of Ingenol with Improved Properties for Treatment of Actinic Keratosis and Other Non-Melanoma Skin Cancers. AB - INTRODUCTION: Ingenol mebutate gel (Picato(r), LEO Pharma A/S) is approved for the field treatment of actinic keratosis and is characterized by high sustained clearance of actinic lesions. The inherent propensity of ingenol mebutate towards chemical rearrangement necessitates refrigeration of the final product. We sought to identify novel ingenol derivatives with enhanced chemical stability and similar or improved in vitro potency and in vivo efficacy. METHODS: A number of ingenol esters were synthesized with full regiocontrol from ingenol. Chemical stability was determined in aqueous buffer at physiological pH and hydroalcoholic gel at lower pH. Acute cytotoxicity was determined in HeLa or HSC-5 cells. Keratinocyte proliferation, viability and caspase 3/7 activation was measured in primary epidermal keratinocytes. Relative gene expression levels were determined by real-time quantitative PCR. Evaluation of in vivo tumor ablating potential was performed in the murine B16 melanoma mouse model and in the UV-induced skin carcinogenesis model in hairless SKH-1 mice following topical treatment for two consecutive days with test compounds formulated at 0.1% in a hydroalcoholic gel. RESULTS: This work resulted in the identification of ingenol disoxate (LEO 43204) displaying increased stability in a clinically relevant formulation and in aqueous buffer with minimal pH-dependent acyl migration degradation. Ingenol disoxate exhibited a significantly higher cytotoxic potency relative to ingenol mebutate. Likewise, cell growth arrest in normal human keratinocyte was more potently induced by ingenol disoxate, which was accompanied by protein kinase C dependent transcription of markers of keratinocyte differentiation. Most notably, ingenol disoxate possessed a superior antitumor effect in a B16 mouse melanoma model and significantly increased median survival time relative to ingenol mebutate. A significant effect on tumor ablation was also observed in a murine model of ultraviolet irradiation-induced skin carcinogenesis. CONCLUSION: These data illustrate that the favorable in vitro and in vivo pharmacological properties driving ingenol mebutate efficacy are either preserved or improved in ingenol disoxate. In combination with improved chemical stability to potentially facilitate storage of the final product at ambient temperatures, these features support further development of ingenol disoxate as a convenient and efficacious treatment modality of non-melanoma skin cancers. FUNDING: LEO Pharma A/S. PMID- 27503484 TI - Fermentation of de-oiled algal biomass by Lactobacillus casei for production of lactic acid. AB - De-oiled algal biomass (algal cake) generated as waste byproduct during algal biodiesel production is a promising fermentable substrate for co-production of value-added chemicals in biorefinery systems. We explored the ability of Lactobacillus casei 12A to ferment algal cake for co-production of lactic acid. Carbohydrate and amino acid availability were determined to be limiting nutritional requirements for growth and lactic acid production by L. casei. These nutritional requirements were effectively addressed through enzymatic hydrolysis of the algal cake material using alpha-amylase, cellulase (endo-1,4-beta-D glucanase), and pepsin. Results confirm fermentation of algal cake for production of value-added chemicals is a promising avenue for increasing the overall cost competiveness of the algal biodiesel production process. PMID- 27503483 TI - Comparability of automated human induced pluripotent stem cell culture: a pilot study. AB - Consistent and robust manufacturing is essential for the translation of cell therapies, and the utilisation automation throughout the manufacturing process may allow for improvements in quality control, scalability, reproducibility and economics of the process. The aim of this study was to measure and establish the comparability between alternative process steps for the culture of hiPSCs. Consequently, the effects of manual centrifugation and automated non centrifugation process steps, performed using TAP Biosystems' CompacT SelecT automated cell culture platform, upon the culture of a human induced pluripotent stem cell (hiPSC) line (VAX001024c07) were compared. This study, has demonstrated that comparable morphologies and cell diameters were observed in hiPSCs cultured using either manual or automated process steps. However, non-centrifugation hiPSC populations exhibited greater cell yields, greater aggregate rates, increased pluripotency marker expression, and decreased differentiation marker expression compared to centrifugation hiPSCs. A trend for decreased variability in cell yield was also observed after the utilisation of the automated process step. This study also highlights the detrimental effect of the cryopreservation and thawing processes upon the growth and characteristics of hiPSC cultures, and demonstrates that automated hiPSC manufacturing protocols can be successfully transferred between independent laboratories. PMID- 27503485 TI - Implementation and analysis of temperature control strategies for outdoor photobiological hydrogen production. AB - For outdoor photobiological hydrogen production, the effective control of temperature in photobioreactors is a challenge. In this work, an internal cooling system for outdoor tubular photobioreactors was designed, built, and tested. The temperatures in the reactors with bacteria were consistently higher than those without bacteria, and were also strongly influenced by solar irradiation and ambient air temperature. The cooling protocol applied successfully kept the reactor temperatures below the threshold limit (38 degrees C) required for the bioprocess and provided a uniform distribution of temperature along the reactor tube length. The biomass growth and hydrogen production were similar in the reactors cooled co-currently and counter-currently. The biomass growth rate was 0.1 l/h, the maximum hydrogen production rate was 1.28 mol/m3/h, and the overall hydrogen yield obtained was 20 %. The change in the biomass was fitted using the logistic model while cumulative hydrogen production was fitted using the modified Gompertz equation. PMID- 27503486 TI - Hydrophobic adsorption in ionic medium improves the catalytic properties of lipases applied in the triacylglycerol hydrolysis by synergism. AB - It is known that lipases may have their catalytic properties improved by the action of some salts or by the adsorption on hydrophobic supports. However, what we present in this work is more than that: we evaluate the combination of these two factors of hyperactivation of lipases from Acremonium-like ROG 2.1.9, a study that has not been done so far. This work proves that a synergistic effect occurs when the lipases are immobilized on hydrophobic supports at the presence of sodium chloride and are applied in triacylglycerol hydrolysis. This assay made it possible to achieve the highest hyperactivation of 500 % with the lipases immobilized on Phenyl-Sepharose and applied with 0.1 M of sodium chloride. Besides this positive effect on enzyme activity, the use of these two factors led to the thermal stability increasing of the immobilized lipases. For this derivative, the recovered activity was approximately 85 % after 6 h incubated at 55 degrees C and 1.0 M of the sodium chloride against 50 % of the same derivative without this salt. Furthermore, others assays were performed to prove the evidences about the synergistic effect, showing a promising method to improve the catalytic properties of the lipases from Acremonium-like ROG 2.1.9. PMID- 27503487 TI - Cobalt separation by Alphaproteobacterium MTB-KTN90: magnetotactic bacteria in bioremediation. AB - Bioremediation of toxic metals by magnetotactic bacteria and magnetic separation of metal-loaded magnetotactic bacteria are of great interest. This bioprocess technique is rapid, efficient, economical, and environmentally friendly. In this study, cobalt removal potential of a novel isolated magnetotactic bacterium (Alphaproteobacterium MTB-KTN90) as a new biosorbent was investigated. The effects of various environmental parameters in the cobalt removal and the technique of magnetic separation of cobalt-loaded bacterial cells were studied. Cobalt removal by MTB-KTN90 was very sensitive to pH solution; higher biosorption capacity was observed around pH 6.5-7.0. When biomass concentration increased from 0.009 to 0.09 g/l, the biosorption efficiency increased from 13.87 % to 19.22 %. The sorption of cobalt by MTB-KTN90 was rapid during the first 15 min (859.17 mg/g dry weight). With the increasing of cobalt concentrations from 1 to 225 mg/l, the specific cobalt uptake increased. Maximum cobalt removal (1160.51 +/- 15.42 mg/g dry weight) took place at optimum conditions; pH 7.0 with initial cobalt concentration of 115 mg/l at 60 min by 0.015 g/l of dry biomass. The results showed maximum values for constants of Langmuir and Freundlich models so far. The biosorption mechanisms were studied with FTIR, PIXE, and FESEM analysis. Cobalt-loaded MTB-KTN90 had ability to separate from solution by a simple magnetic separator. Magnetic response in MTB-KTN90 is due to the presence of unique intracellular magnetic nanoparticles (magnetosomes). The orientation magnetic separation results indicated that 88.55 % of cobalt was removed from solution. Consequently, Alphaproteobacterium MTB-KTN90 as a new biosorbent opens up good opportunities for the magnetic removal of cobalt from the polluted aquatic environments. PMID- 27503488 TI - Removal of pigments from molasses wastewater by combining micro-electrolysis with biological treatment method. AB - Pigments in molasses wastewater (MWW) effluent, such as melanoidins, were considered as kinds of the most recalcitrant and hazardous colorant contaminants to the environment. In this study, de-coloring the MWW by a synergistic combination of micro-electrolysis with bio-treatment was performed. Aiming to a high de-colorization yield, levels of nutrition source supplies, MWW dilution ratio, and micro-electrolysis reaction time were optimized accordingly. For a diluted (50 %, v/v) MWW, an maximum overall de-colorization yield (97.1 +/- 0.5 %, for absorbance at 475 nm) was achieved through the bio-electrolysis treatment. In electrolysis bio-treatment, the positive effect of micro-electrolysis was also revealed by a promoted growth of fungal biomass as well as activities of ligninolytic enzymes. Activities of lignin peroxidase, manganese peroxidase, and laccase were promoted by 111.2, 103.9, and 7.7 %, respectively. This study also implied that the bio-treatment and the micro-electrolysis had different efficiencies on removal of pigments with distinct polarities. PMID- 27503489 TI - Computation of a high-resolution MRI 3D stereotaxic atlas of the sheep brain. AB - The sheep model was first used in the fields of animal reproduction and veterinary sciences and then was utilized in fundamental and preclinical studies. For more than a decade, magnetic resonance (MR) studies performed on this model have been increasingly reported, especially in the field of neuroscience. To contribute to MR translational neuroscience research, a brain template and an atlas are necessary. We have recently generated the first complete T1-weighted (T1W) and T2W MR population average images (or templates) of in vivo sheep brains. In this study, we 1) defined a 3D stereotaxic coordinate system for previously established in vivo population average templates; 2) used deformation fields obtained during optimized nonlinear registrations to compute nonlinear tissues or prior probability maps (nlTPMs) of cerebrospinal fluid (CSF), gray matter (GM), and white matter (WM) tissues; 3) delineated 25 external and 28 internal sheep brain structures by segmenting both templates and nlTPMs; and 4) annotated and labeled these structures using an existing histological atlas. We built a quality high-resolution 3D atlas of average in vivo sheep brains linked to a reference stereotaxic space. The atlas and nlTPMs, associated with previously computed T1W and T2W in vivo sheep brain templates and nlTPMs, provide a complete set of imaging space that are able to be imported into other imaging software programs and could be used as standardized tools for neuroimaging studies or other neuroscience methods, such as image registration, image segmentation, identification of brain structures, implementation of recording devices, or neuronavigation. J. Comp. Neurol. 525:676-692, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27503490 TI - Low-dose aspirin or other nonsteroidal anti-inflammatory drug use and prostate cancer risk: a nationwide study. AB - PURPOSE: Increasing evidence suggests that aspirin use may protect against prostate cancer. In a nationwide case-control study, using Danish high-quality registry data, we evaluated the association between the use of low-dose aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk of prostate cancer. METHODS: We identified 35,600 patients (cases) with histologically verified prostate cancer during 2000-2012. Cases were matched to 177,992 population controls on age and residence by risk-set sampling. Aspirin and nonaspirin NSAID exposure was defined by type, estimated dose, duration, and consistency of use. We used conditional logistic regression to estimate odds ratios (ORs), with 95 % confidence intervals (CIs), for prostate cancer associated with low-dose aspirin (75-150 mg) or nonaspirin NSAID use, adjusted for potential confounders. RESULTS: Use of low-dose aspirin was associated with an OR for prostate cancer of 0.94 (95 % CI 0.91-0.97). Slightly lower ORs were seen with increasing cumulative amount, duration, and consistency of low-dose aspirin use (continuous use, >=5 years: OR 0.89; 95 % CI 0.82-0.97; >=10 years: OR 0.86; 95 % CI 0.70-1.06). Nonaspirin NSAID use was associated with a slightly increased OR for prostate cancer (1.13; 95 % CI 1.10-1.15); however, this association was confined to localized disease and did not vary materially with amount, duration, or consistency of nonaspirin NSAID use. CONCLUSIONS: Our study indicates that long-term, consistent low-dose aspirin use may provide modest protection against prostate cancer. The slightly increased risk of only localized prostate cancer with nonaspirin NSAID use suggests a noncausal explanation of the observed association. PMID- 27503491 TI - The Role of Laparoscopic Radical Hysterectomy in Early-Stage Adenocarcinoma of the Uterine Cervix. AB - OBJECTIVE: To compare long-term survival outcomes and patterns of recurrence of laparoscopic radical hysterectomy (LRH) and open radical hysterectomy (ORH) in early-stage cervical adenocarcinoma. METHODS: The medical records of 293 patients with stage IA2-IIA cervical adenocarcinomas who underwent radical hysterectomy were retrospectively reviewed. RESULTS: In total, 186 patients underwent LRH and 107 underwent ORH. There was no difference between the two surgery groups in clinicopathologic characteristics. There were no differences in disease-free survival (DFS) and overall survival (OS) between the LRH and ORH groups (88.7 vs. 84.1 %, P = 0.725; and 93.0 vs. 86.9 %, P = 0.735) for univariate analysis and multivariate analysis after adjusting for other significant prognostic factors. There was no difference in the patterns of recurrence between the two surgery groups (P = 0.220). The median time interval between surgery and the first recurrence were 25 months (range, 3-100 months) for LRH group and 14 months (range, 3-128 months) for ORH group (P = 0.230). The LRH group showed significantly fewer postoperative complications (P < 0.001), less estimated blood loss (P < 0.001), faster bowel movement recovery (P < 0.001), shorter postoperative hospital stay (P < 0.001), and a lower rate of wound dehiscence, ileus, lymphedema, infected lymphocele, and pelvic abscess (P = 0.004, 0.011, 0.017, and 0.040, respectively). CONCLUSIONS: LRH has comparable survival outcomes with ORH and did not affect the pattern of recurrence in early-stage adenocarcinoma of the uterine cervix. The surgical outcomes were more favorable than ORH. PMID- 27503492 TI - Time to Treatment: Measuring Quality Breast Cancer Care. AB - BACKGROUND: To optimize breast cancer care, several organizations have crafted guidelines to define best practices for treating breast cancer. In addition to recommended therapies, 'timeliness of treatment' has been proposed as a quality metric. Our study evaluates time to surgical treatment and its effect on overall survival (OS). METHODS: The National Cancer Data Base (NCDB) was used to identify women diagnosed with invasive breast cancer between 2004 and 2012. Time from diagnosis to surgical treatment was calculated and grouped according to predetermined time intervals. Univariate and multivariate Cox proportional hazard models were used to assess patient and treatment factors related to OS. RESULTS: Overall, 420,792 patients initially treated with surgery were identified. Increased time to surgical treatment >12 weeks was associated with decreased OS [hazard ratio (HR) 1.14, 95 % confidence interval (CI) 1.09-1.20]. When stratified by pathologic stage, stage I patients treated at 8 to <12 weeks (HR 1.07, 95 % CI 1.02-1.13) and >12 weeks (HR 1.19, 95 % CI 1.11-1.28), as well as stage II patients treated at >12 weeks (HR 1.16, 95 % CI 1.08-1.25), had decreased OS compared with patients treated at <4 weeks. Other variables associated with decreased survival were treatment at a community cancer program, Medicaid or Medicare insurance, Black race, increasing age, mastectomy, moderately and poorly differentiated tumor grade, increasing T and N stage, and higher Charlson Index Group. CONCLUSION: The survival benefit of expedited time to initial surgical treatment varies by stage and appears to have the greatest impact in early-stage disease. Prior to establishing standard metrics, further quantification of the impact on patient outcomes is needed. PMID- 27503493 TI - Exploiting Molecular and Immune Biology of Gastric and Gastroesophageal Adenocarcinomas to Discover Novel Therapeutic Targets. AB - Gastroesophageal carcinomas (GACs) are a significant problem worldwide, and despite many attempts to improve the outcomes of patients with these tumors, little progress has been made over the last several decades. In the past decade, only transtuzumab and ramucirumab, two drugs with marginal clinical benefit, have been approved for the treatment of patients with GACs. After second-line therapy, most treatment options are generally ineffective. Prior studies in this disease have been largely empiric, using unselected patient populations. More recently, detailed somatic genotyping, enrichment of patients based on biomarkers, and pharmacokinetic studies have opened new avenues for developing treatment options in patients with GAC. PMID- 27503494 TI - Racial Differences in Utilization of Breast Conservation Surgery: Results from the National Cancer Data Base (NCDB). AB - BACKGROUND: Whether rates of breast-conservation surgery (BCS) vary based on race and ethnicity has not been clearly elucidated on a national leve. METHODS: The National Cancer Data Base (NCDB) was used to identify women who underwent surgery for invasive breast cancer during 2010 and 2011. The effect of race and ethnicity on BCS rates was determined, independent of patient demographics, tumor-related variables, and geographic region. RESULTS: There were 299,827 patients with known race and ethnicity who underwent definitive breast surgery. BCS rates by race were as follows: 135,065/241,236 (56.0 %) for whites, 17,819/33,301 (53.5 %) for blacks, 4,722/9,508 (49.7 %) for Asian/Pacific Islanders, and 7,919/15,782 (50.2 %) for Hispanics (p < 0.001). Mean tumor size differed among the racial groups: 2.07 cm in whites, 2.54 cm in blacks, 2.23 cm in Asians, and 2.48 cm in Hispanics (p < 0.001). When stratified by tumor size, BCS was most common in blacks and least common in Asians for all tumors >2 cm (p < 0.001). On multivariable analysis adjusted for age, tumor size, nodal status, grade, molecular type, geographic area, urban/rural residence, insurance status, and census-derived median income and education for the patient's zip code, the odds ratio for BCS for blacks compared to whites was 1.23 (95 % confidence interval [CI] 1.20-1.27, p < 0.001), for Asians was 0.84 (95 % CI 0.80-0.88, p < 0.001), and for Hispanics was 1.00 (95 % CI 0.96-1.05, p = 0.885). CONCLUSIONS: When adjusted for patient demographics, tumor-related variables, and geographic area, BCS rates are higher in blacks and lower in Asians compared to whites. PMID- 27503495 TI - Blinded predictions of host-guest standard free energies of binding in the SAMPL5 challenge. AB - In the context of the SAMPL5 blinded challenge standard free energies of binding were predicted for a dataset of 22 small guest molecules and three different host molecules octa-acids (OAH and OAMe) and a cucurbituril (CBC). Three sets of predictions were submitted, each based on different variations of classical molecular dynamics alchemical free energy calculation protocols based on the double annihilation method. The first model (model A) yields a free energy of binding based on computed free energy changes in solvated and host-guest complex phases; the second (model B) adds long range dispersion corrections to the previous result; the third (model C) uses an additional standard state correction term to account for the use of distance restraints during the molecular dynamics simulations. Model C performs the best in terms of mean unsigned error for all guests (MUE [Formula: see text]-95 % confidence interval) for the whole data set and in particular for the octa-acid systems (MUE [Formula: see text]). The overall correlation with experimental data for all models is encouraging ([Formula: see text]). The correlation between experimental and computational free energy of binding ranks as one of the highest with respect to other entries in the challenge. Nonetheless the large MUE for the best performing model highlights systematic errors, and submissions from other groups fared better with respect to this metric. PMID- 27503496 TI - [Participatory research : Meaning, concept, objectives and methods]. AB - Shaping one's own life and feeling equal in society is an essential aspect of participation. Based on the UN Convention on the Rights of Persons with Disabilities, the Social Security Code IX and the International Classification of Functioning, Disability and Health (ICF), participation is relevant for the German health system. The cross-sectional discipline of participation research investigates conditions for self-determined and equal participation in society. Research results can reinforce and promote the participation of humans with disabilities. Participation research uses established quantitative and qualitative approaches. Moreover, participatory research is a relevant approach that demands involving persons with disabilities in decisions in the research process. In the future, it will be important to concentrate findings and to connect researchers. The participation research action alliance (Aktionsbundnis Teilhabeforschung), which was established in 2015, aims to make funding accessible as well as strengthen and profile participation research. PMID- 27503497 TI - [Environmental factors and the promotion of participation. The Perspective of medical rehabilitation]. AB - BACKGROUND: The International Classification of Functioning, Disability and Health (ICF), as well as the main goal of enabling participation, are of fundamental importance for medical rehabilitation. According to the logic of the ICF and its underlying multidimensional model of functioning and disability, the participation of a person can be influenced by modelling environmental factors. OBJECTIVES: This article presents environmental factors as defined by the ICF in the context of medical rehabilitation and aims to answer to what extent environmental factors are already involved in medical rehabilitation and if there are further environmental factors with the potential of being involved in interventions for improvement of participation. MATERIALS AND METHODS: An analysis of documents with relevance to medical rehabilitation was done. Text passages that referred to environmental factors were linked to the environmental factor codes of the ICF. RESULTS AND CONCLUSIONS: The ICF and its underlying model of functioning and disability provide a conceptual framework both for making the current usage of environmental factors apparent and for deriving and developing new intervention approaches with the involvement of environmental factors. The analysis of documents showed that environmental factor codes vary in how well they are represented in these documents. There are environmental factor codes that are barely or not at all represented, but do have potential to contribute to the improvement of participation. PMID- 27503498 TI - [Data on disability and participation in Germany : Requirements, analysis options and results]. AB - As a basis for political decisions and to meet the statistical requirements of the CRPD, reliable data and reporting on the situation of people with disabilities are essential. Based on results of the preliminary study for a German participation survey, this article firstly defines data requirements and areas of participation. Secondly, data sources regarding participation and disability in Germany that were identified in a literature search are described in detail. Only sources providing population-based data that are collected on a regular basis and that could contribute to participation reporting were taken into account. This includes data from official statistics, (panel) studies or surveys, administrative data and reporting systems. Finally, we exemplarily present the main statistical findings of the 2012 European health and social integration survey (EHSIS), a survey that was specifically designed to investigate participation of persons with disabilities. In addition to the surveys identified in the preliminary study for a German participation survey that could be used or expanded for participation reporting, and the data sources used in the participation report published by the federal government in 2013, the research yielded further publicly available data sources with a high potential for a participation reporting system. PMID- 27503499 TI - [Incapacitated persons - participation rights and the legal concept of the capacity to consent]. AB - Legal problems related to the capacity to consent and decision-making have recently become increasingly important. This concerns the prerequisites and limitations of legal participation as a basis of social participation. Among the relevant social spheres and fields of action, this particulary concerns medicine and health care as well as disability and care. At the normative level, with a view to those concerned, this leads to fundamental questions resulting from the tension between self-determination and care as basic legal and ethical standards. At the empirical level, there are debates between the law and the sciences with regard to the relevant knowledge base for the assessment of (in)capacity to consent. The traditional controversies about the relevant legal criteria determining the existence or absence of capacity to consent are intensified by some recent legal developments, two of which must be highlighted. One of these is the postulate, increasingly emphasized by courts and legislator, of an at least communicative involvement of persons incapable to give consent in the decision making process. The other is the fundamental discussion of medical ethics on concepts of assisted self-determination and supported decision-making, the consequences of which will also be of relevance at the legal level. Insofar, the development of guardianship law and the legal requirements of the UN Disability Rights Convention are of particular importance. PMID- 27503500 TI - [Antibiotic intake and resistance development - Knowledge, experience and behavior among the German general population]. AB - BACKGROUND: The network project RAI (Rational Use of Antibiotics via Information and Communication) is aimed at developing tailored information and communication tools on the subject of antibiotic (AB) resistance for various stakeholder groups. During the preparation phase, a survey was performed addressing the German general population. OBJECTIVES: To gain insights into the knowledge, attitudes, and behavior of nonprescribers concerning AB and multidrug-resistant organisms (MDRO). METHODS: Using computer-assisted, telephone-based interviews a random sample of 1,004 persons aged 14 years and older was surveyed. Descriptive reporting of data and multivariate analysis were performed, including sociodemographic variables. RESULTS: Only 24 % of participants knew that bacteria (but not viruses or humans) could develop AB resistance. However, this knowledge did not influence the outcome of other questions. Regardless of knowledge, 71 % thought that the subject was important, but 58 % did not believe in the influence of their own behavior on MDRO development. When visiting a physician, patients were given an antibiotic three times as often as information on AB resistance. 17 % did not take the AB as prescribed and 20 % of all participants stated that they personally knew at least one person with MDRO problems. This personal involvement had a significant effect on the rating of self-influence, on the importance of the subject, on the interaction between patient and physician (more information, less AB), and on AB intake compliance (less frequent). DISCUSSION: We found considerable knowledge gaps, but this had no impact on the assessment of the subject. A starting point for an intervention could be patient-physician communication. This seems more effective and safer than a public campaign. PMID- 27503501 TI - Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib. AB - Ibrutinib is not known to confer risk for Pneumocystis jirovecii pneumonia (PCP). We observed 5 cases of PCP in 96 patients receiving single-agent ibrutinib, including 4 previously untreated. Clinical presentations included asymptomatic pulmonary infiltrates, chronic cough, and shortness of breath. The diagnosis was often delayed. Median time from starting ibrutinib to occurrence of PCP was 6 months (range, 2-24). The estimated incidence of PCP was 2.05 cases per 100 patient-years (95% confidence interval, 0.67-4.79). At the time of PCP, all patients had CD4 T-cell count >500/MUL (median, 966/MUL) and immunoglobulin G (IgG) >500 mg/dL (median, 727 mg/dL). All patients underwent bronchoalveolar lavage. P jirovecii was identified by polymerase chain reaction in all 5 cases; direct fluorescence antibody staining was positive in 1. All events were grade <=2 and resolved with oral therapy. Secondary prophylaxis was not given to 3 patients; after 61 patient-months of follow up, no recurrence occurred. Lack of correlation with CD4 count and IgG level suggests that susceptibility to PCP may be linked to Bruton tyrosine kinase (BTK) inhibition. If confirmed, this association could result in significant changes in surveillance and/or prophylaxis, possibly extending to other BTK inhibitors. This trial was registered at www.clinicaltrials.gov as #NCT01500733 and #NCT02514083. PMID- 27503502 TI - Importance of environmental stiffness for megakaryocyte differentiation and proplatelet formation. AB - Megakaryocyte (MK) differentiation occurs within the bone marrow (BM), a complex 3-dimensional (3D) environment of low stiffness exerting local external constraints. To evaluate the influence of the 3D mechanical constraints that MKs may encounter in vivo, we differentiated mouse BM progenitors in methylcellulose (MC) hydrogels tuned to mimic BM stiffness. We found that MKs grown in a medium of 30- to 60-Pa stiffness more closely resembled those in the BM in terms of demarcation membrane system (DMS) morphological aspect and exhibited higher ploidy levels, as compared with MKs in liquid culture. Following resuspension in a liquid medium, MC-grown MKs displayed twice as much proplatelet formation as cells grown in liquid culture. Thus, the MC gel, by mimicking external constraints, appeared to positively influence MK differentiation. To determine whether MKs adapt to extracellular stiffness through mechanotransduction involving actomyosin-based modulation of the intracellular tension, myosin deficient (Myh9-/-) progenitors were grown in MC gels. Absence of myosin resulted in abnormal cell deformation and strongly decreased proplatelet formation, similarly to features observed for Myh9-/- MKs differentiated in situ but not in vitro. Moreover, megakaryoblastic leukemia 1 (MKL1), a well-known actor in mechanotransduction, was found to be preferentially relocated within the nucleus of MC-differentiated MKs, whereas its inhibition prevented MC-mediated increased proplatelet formation. Altogether, these data show that a 3D medium mimicking BM stiffness contributes, through the myosin IIA and MKL1 pathways, to a more favorable in vitro environment for MK differentiation, which ultimately translates into increased proplatelet production. PMID- 27503503 TI - Nocardiajiangsuensis sp. nov., an actinomycete isolated from coastal soil. AB - A novel actinomycete strain, designated strain KLBMP S0027T, was isolated from a coastal soil collected from the coastal region of Lianyungang, Jiangsu Province, in east China, and was studied in detail for its taxonomic position. Comparative 16S rRNA gene sequence analysis showed that this strain belonged to the genus Nocardia and was most closely related to Nocardia harenae WS-26T (98.5 %), Nocardiaasiatica NBRC 100129T (98.5 %), Nocardiaabscessus NBRC 100374T (98.2 %), Nocardia brasiliensis NBRC 14402T (98.2 %) and Nocardiacyriacigeorgica NBRC 100375T (98 %), respectively. The strain showed a combination of chemotaxonomic and morphological properties typical of the genus Nocardia. The cell wall contained meso-diaminopimelic acid (type IV), and whole-cell sugars were arabinose, galactose, glucose and ribose. Strain KLBMP S0027T contained MK 8(H4omega-cycl) as the predominant menaquinone; C16 : 0, C18 : 1omega9c, C18 : 0 10-methyl (TBSA) and summed feature 3 (C16 : 1omega7c/C16 : 1omega6c) were the major cellular fatty acids. The polar lipids detected were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, one unknown glycolipid and two unknown lipids. Mycolic acids were detected. The G+C content of the DNA was 70.5 %. However, a combination of DNA-DNA hybridization and phenotypic data demonstrated that strain KLBMP S0027T could be clearly distinguished from the type strain of the most closely related species, N. harenae WS-26T. On the basis of the data presented from a polyphasic study, it was evident that this strain should be assigned to a novel species of the genus Nocardia, for which the name Nocardia jiangsuensis sp. nov. is proposed. The type strain is KLBMP S0027T (=CGMCC 4.7330T=KCTC 39691T). PMID- 27503505 TI - Update on ultrasound in bowel obstruction. PMID- 27503504 TI - Combination of Paclitaxel and MG1 oncolytic virus as a successful strategy for breast cancer treatment. AB - BACKGROUND: Breast cancer is the most common malignant disease amongst Western women. The lack of treatment options for patients with chemotherapy-resistant or recurrent cancers is pushing the field toward the rapid development of novel therapies. The use of oncolytic viruses is a promising approach for the treatment of disseminated diseases like breast cancer, with the first candidate recently approved by the Food and Drug Administration for use in patients. In this report, we demonstrate the compatibility of oncolytic virotherapy and chemotherapy using various murine breast cancer models. This one-two punch has been explored in the past by several groups with different viruses and drugs and was shown to be a successful approach. Our strategy is to combine Paclitaxel, one of the most common drugs used to treat patients with breast cancer, and the oncolytic Rhabdovirus Maraba-MG1, a clinical trial candidate in a study currently recruiting patients with late-stage metastatic cancer. METHODS: We used the EMT6, 4 T1 and E0771 murine breast cancer models to evaluate in vitro and in vivo the effects of co-treatment with MG1 and Paclitaxel. Treatment-induced cytotoxicity was assessed and plaque assays, flow cytometry, microscopy and immunocytochemistry analysis were performed to quantify virus production and transgene expression. Orthotopically implanted tumors were measured during and after treatment to evaluate efficacy and Kaplan-Meier survival curves were generated. RESULTS: Our data demonstrate not only the compatibility of the treatments, but also their synergistic cytopathic activity. With Paclitaxel, EMT6 and 4 T1 tumors demonstrated increased virus production both in vitro and in vivo. Our results also show that Paclitaxel does not impair the safety profile of the virus treatment. Importantly, when combined, MG1 and the drug controlled tumor growth and prolonged survival. CONCLUSIONS: The combination of MG1 and Paclitaxel improved efficacy in all of the breast cancer models we tested and thus is a promising alternative approach for the treatment of patients with refractory breast cancer. Our strategy has potential for rapid translation to the clinic, given the current clinical status of both agents. PMID- 27503507 TI - Customary law, traditional punishment, and death in the Anangu Pitjantjatjara Yankunytjatjara (APY) lands of Central Australia. PMID- 27503506 TI - Natal habitat imprinting counteracts the diversifying effects of phenotype dependent dispersal in a spatially structured population. AB - BACKGROUND: Habitat selection may have profound evolutionary consequences, but they strongly depend on the underlying preference mechanism, including genetically-determined, natal habitat and phenotype-dependent preferences. It is known that different mechanisms may operate at the same time, yet their relative contribution to population differentiation remains largely unexplored empirically mainly because of the difficulty of finding suitable study systems. Here, we investigate the role of early experience and genetic background in determining the outcome of settlement by pied flycatchers (Ficedula hypoleuca) breeding in two habitat patches between which dispersal and subsequent reproductive performance is influenced by phenotype (body size). For this, we conducted a cross-fostering experiment in a two-patch system: an oakwood and a conifer plantation separated by only 1 km. RESULTS: Experimental birds mostly returned to breed in the forest patch where they were raised, whether it was that of their genetic or their foster parents, indicating that decisions on where to settle are determined by individuals' experience in their natal site, rather than by their genetic background. Nevertheless, nearly a third (27.6 %) moved away from the rearing habitat and, as previously observed in unmanipulated individuals, dispersal between habitats was phenotype-dependent. Pied flycatchers breeding in the oak and the pine forests are differentiated by body size, and analyses of genetic variation at microsatellite loci now provide evidence of subtle genetic differentiation between the two populations. This suggests that phenotype dependent dispersal may contribute to population structure despite the short distance and widespread exchange of birds between the study plots. CONCLUSIONS: Taken together, the current and previous findings that pied flycatchers do not always settle in the habitat to which they are best suited suggest that their strong tendency to return to the natal patch regardless of their body size might lead to maladaptive settlement decisions and thus constrain the potential of phenotype-dependent dispersal to promote microgeographic adaptation. PMID- 27503508 TI - Unintentional asphyxia, SIDS, and medically explained deaths: a descriptive study of outcomes of child death review (CDR) investigations following sudden unexpected death in infancy. AB - BACKGROUND: A comprehensive child death review (CDR) program was introduced in England and Wales in 2008, but as yet data have only been analyzed at a local level, limiting the learning from deaths. The aim of this study is to describe the profile of causes and risk factors for sudden unexpected death in infancy (SUDI) as determined by the new CDR program. METHODS: This was a descriptive outcome study using data from child death overview panel Form C for SUDI cases dying during 2010-2012 in the West Midlands region of England. The main outcome measures were: cause of death, risk factors and potential preventability of death, and determination of deaths probably due to unintentional asphyxia. RESULTS: Data were obtained for 65/70 (93 %) SUDI cases. 20/65 (31 %) deaths were initially categorized as due to medical causes; 21/65 (32 %) as SIDS; and 24/65 (37 %) as undetermined. Reanalysis suggested that 2/21 SIDS and 7/24 undetermined deaths were probably due to unintentional asphyxia, with 6 of these involving co sleeping and excessive parental alcohol consumption. Deaths classified as "undetermined" had significantly higher total family and environmental risk factor scores (mean 2.6, 95 % CI 2.0-3.3) compared to those classified as SIDS (mean 1.6, 95 % CI 1.2-1.9), or medical causes for death (mean 1.1, 95 % CI 0.8 1.3). 9/20 (47 %) of medical deaths, 19/21 (90 %) SIDS, and 23/24 (96 %) undetermined deaths were considered to be potentially preventable. There were inadequacies in medical provision identified in 5/20 (25 %) of medically explained deaths. CONCLUSIONS: The CDR program results in detailed information about risk factors for SUDI cases but failed to recognize deaths probably due to unintentional asphyxia. The misclassification of probable unintentional asphyxial deaths and SIDS as "undetermined deaths" is likely to limit learning from these deaths and inhibit prevention strategies. Many SUDI occurred in families with mental illness, substance misuse and chaotic lifestyles and most in unsafe sleep environments. This knowledge could be used to better target safe sleep advice for vulnerable families and prevent SUDI in the future. PMID- 27503509 TI - Stabbing energy and force required for pocket-knives to pierce ribs. AB - PURPOSE: In addition to reconstructing the course of events, the medical examiner will often have to answer questions regarding the force necessary to inflict a certain injury in stabbing incidents. Several groups have examined the force needed to penetrate soft-tissue and clothing; however, no studies addressing the energy needed for penetrating ribs exist. Therefore, we decided to investigate this force on an animal model. METHOD: Ribs from healthy, 8 to 10-month-old pigs were used as a substitute for human ribs. These ribs were then stabbed either transversely or longitudinally with two different pocket-knife blades, namely a Swiss Army pocket knife and a sturdier pocket knife (Classic Schnitzmesser, Herbertz Solingen) dropped from a drop-tower at defined heights and therefore defined energies. RESULTS: Longitudinally orientated stabs showed complete piercing of the ribs at approximately 11 Joules (J) or with a stabbing force in excess of 906 Newton (N) for both blade types. Transversely orientated stabs, however, displayed complete piercing between 11 and 16 J, or in excess of 1198 N, with the sturdy pocket knife tending to require a little more energy than the Swiss army pocket knife. CONCLUSIONS: Young adult porcine ribs are completely pierced by pocket knife blades at energies between 11 and 16 J. Assuming the porcine ribs are comparable to those ribs of young adult humans, our results indicate that a complete penetration of the chest wall through the ribs by stabbing with a pocket knife is rather easily achieved. PMID- 27503510 TI - Palliative care for patients with heart failure: facilitators and barriers - a cross sectional survey of German health care professionals. AB - BACKGROUND: Compared to patients with cancer, heart failure patients are seldom candidates for palliative care. Numerous studies have investigated reasons why heart failure patients do not receive palliative care; however, none of these studies have ever evaluated the situation in the German health care setting. This study aims to identify German healthcare providers' (HCP) perception of barriers and facilitators to palliative care of patients with chronic heart failure. METHODS: We conducted an online-survey with 315 nurses and physicians of different medical disciplines. RESULTS: Even though heart failure patients' need of palliative care and its advantages has been recognized, HCP see potential for development and improvement. A lack of knowledge about the content and measures of palliative care, poor communication and unclear responsibilities between medical disciplines, difficulties to determine the right time to initiate palliative care, and the feeling not to be prepared to discuss end-of-life issues with the patient has been identified as barriers. Further, HCP believe that patients and relatives do not possess adequate knowledge about the disease and its progression and are therefore unprepared in asking questions regarding palliative care. They rather tend to demand everything possible to be done in order prolong life, and are reluctant to accept that life is limited. Overall, HCP perceive that dying is a taboo subject within our society placing palliative care on the same level as assisted dying. In addition, results indicate that HCP have an inappropriate notion of ideal medicine fearing to lose patient and are worried about the appropriateness of PC remuneration. CONCLUSIONS: In order to overcome the described barriers, HCP, patients, and relatives need to be educated in palliative care. Information and education encompassing the aim, content and measures of palliative care needs to be provided for all parties in order to optimize patient care, to foster communication between healthcare professionals, patients, and relatives, and to overcome perceived barriers. TRIAL REGISTRATION: DRKS00007119. PMID- 27503511 TI - Supersuppression: Reservoir Competency and Timing of Mosquito Host Shifts Combine to Reduce Spillover of West Nile Virus. AB - In the eastern United States, human cases of West Nile virus (WNV) result from spillover from urban epizootic transmission between passerine birds and Culex mosquitoes. In Atlanta, GA, substantial WNV presence in hosts and vectors has not resulted in the human disease burden observed in cities with similar infection pressure. Our study goal was to investigate extrinsic ecological conditions that potentially contribute to these reduced transmission rates. We conducted WNV surveillance among hosts and vectors in urban Atlanta and recorded an overall avian seroprevalence of nearly 30%, which was significantly higher among northern cardinals, blue jays, and members of the mimid family, and notably low among American robins. Examination of temporal Culex feeding patterns showed a marked feeding shift from American robins in the early season to northern cardinals in the late season. We therefore rule out American robins as superspreaders in the Atlanta area and suggest instead that northern cardinals and mimids act as WNV "supersuppressor" species, which slow WNV transmission by drawing many infectious bites during the critical virus amplification period, yet failing to amplify transmission due to low host competencies. Of particular interest, urban forest patches provide spillover protection by increasing the WNV amplification fraction on supersuppressor species. PMID- 27503512 TI - Plasma Tryptophan and the Kynurenine-Tryptophan Ratio are Associated with the Acquisition of Statural Growth Deficits and Oral Vaccine Underperformance in Populations with Environmental Enteropathy. AB - Early childhood enteric infections have adverse impacts on child growth and can inhibit normal mucosal responses to oral vaccines, two critical components of environmental enteropathy. To evaluate the role of indoleamine 2,3-dioxygenase 1 (IDO1) activity and its relationship with these outcomes, we measured tryptophan and the kynurenine-tryptophan ratio (KTR) in two longitudinal birth cohorts with a high prevalence of stunting. Children in rural Peru and Tanzania (N = 494) contributed 1,251 plasma samples at 3, 7, 15, and 24 months of age and monthly anthropometrics from 0 to 36 months of age. Tryptophan concentrations were directly associated with linear growth from 1 to 8 months after biomarker assessment. A 1-SD increase in tryptophan concentration was associated with a gain in length-for-age Z-score (LAZ) of 0.17 over the next 6 months in Peru (95% confidence interval [CI] = 0.11-0.23, P < 0.001) and a gain in LAZ of 0.13 Z scores in Tanzania (95% CI = 0.03-0.22, P = 0.009). Vaccine responsiveness data were available for Peru only. An increase in kynurenine by 1 MUM was associated with a 1.63 (95% CI = 1.13-2.34) increase in the odds of failure to poliovirus type 1, but there was no association with tetanus vaccine response. A KTR of 52 was 76% sensitive and 50% specific in predicting failure of response to serotype 1 of the oral polio vaccine. KTR was associated with systemic markers of inflammation, but also interleukin-10, supporting the association between IDO1 activity and immunotolerance. These results strongly suggest that the activity of IDO1 is implicated in the pathophysiology of environmental enteropathy, and demonstrates the utility of tryptophan and kynurenine as biomarkers for this syndrome, particularly in identifying those at risk for hyporesponsivity to oral vaccines. PMID- 27503513 TI - Schistosoma mansoni in Gabon: Emerging or Ignored? AB - Schistosomiasis affects millions of people across Africa. We detected eggs of Schistosoma mansoni in western lowland gorilla and central chimpanzee fecal samples in Loango National Park, Gabon. We analyzed nuclear and mitochondrial DNA, namely internal transcribed spacer and cytochrome c oxidase subunit 1 fragments, and the resulting maximum likelihood phylogenetic analyses and haplotype network of the ITS and COI, respectively, showed that the samples from gorillas and chimpanzees clustered clearly within the S. mansoni clade. This is the first confirmed record of S. mansoni from Gabon, which urges surveillance in the area and prompts questions regarding the extent of zoonotic transmission and the clinical impact. PMID- 27503514 TI - Identification of a second HOXA2 nonsense mutation in a family with autosomal dominant non-syndromic microtia and distinctive ear morphology. AB - Microtia is a congenital defect affecting external ears, which appear smaller and sometimes malformed. Here we describe a five-generation family with isolated bilateral microtia segregating as an autosomal dominant trait. Similar features have been previously observed in an autosomal dominant family with non-syndromic microtia and hearing loss segregating with a HOXA2 nonsense variant. HOXA2 biallelic mutations were also described in an inbreed family with autosomal recessive microtia, hearing impairment and incomplete cleft palate. In our family, sequence analysis detected a heterozygous protein truncating nonsense variant [c.670G>T, p.(Glu224*)] segregating in all affected individuals and absent in public databases. This study confirms the role of HOXA2 gene in dominant isolated microtia and contribute to further define the dysmorphogenetic effect of this gene on ear development. PMID- 27503515 TI - Targeted delivery of vitamin D3-loaded nanoparticles to C6 glioma cell line increased resistance to doxorubicin, epirubicin, and docetaxel in vitro. AB - In recent years, targeted delivery systems have been used along with combinatorial therapy to decrease drug resistance and increase cancer therapy efficacy. The anti-proliferative effects of vitamin D3 (VD3) on cancerous cells, such as C6 glioma, with active hedgehog pathways raised the question as to whether pre-targeting C6 glioma cells with VD3-loaded nanoparticles (VD3NPs) can enhance the anti-tumor effects of doxorubicin, epirobicin, and docetaxel on this drug-resistant cell line. Here, studying at cellular, nuclear, protein, and gene levels we demonstrated that VD3NP-doxorubicin and VD3NP-epirobicin combinations increased the probability of chemotherapy/radiotherapy resistance and cancer stem cell (CSC) properties in C6 glioma significantly (P < 0.05), compared to doxorubicin and epirobicin alone. However, VD3NP-docetaxel combination may have the potential in sensitizing C6 cells to ionizing irradiation, but this combination also increased the CSC properties and the probability of drug resistance significantly (P < 0.05), compared to docetaxel alone. Although our previous study showed that targeted delivery of VD3 reduced the rate of proliferation significantly (P < 0.05) in C6 glioma cells (a drug-resistant cell line), here we concluded that combinatorial therapy of exogenous VD3 with doxorubicin, epirobicin, and docetaxel not only did not lead to the enhancement of cytotoxic effects of the aforementioned drugs but also increased the cancerous characteristics in C6 glioma, in vitro. PMID- 27503532 TI - Effusive-constrictive pericarditis, hepatitis, and pancreatitis in a patient with possible coxsackievirus B infection: a case report. AB - BACKGROUND: Coxsackie B is a viral pathogen that presents with various invasive diseases in adults. Historically, the majority of adult cases with pericarditis or myocarditis have been attributed to coxsackievirus B. The presentation of this viral infection causing effusive-constrictive pericarditis, hepatitis or pancreatitis is rare. This case report is the first to describe a patient with concomitant effusive-constrictive pericarditis, hepatitis and pancreatitis from possible coxsackievirus B infection. CASE PRESENTATION: A 26-year old female was admitted to our hospital with the diagnosis of effusive-constrictive pericarditis complicated by tamponade and cardiac arrest. An emergent pericardiocentesis was performed successfully. Hepatitis and pancreatitis were also identified in our patient. After an extensive workup, coxsackievirus B infection was suspected by positive serum complement fixation antibody titers. Our patient made a full recovery and was discharged from the hospital. CONCLUSION: Clinical suspicion of effusive-constrictive pericarditis with tamponade from coxsackievirus B should be considered in patients presenting with chest pain, dyspnea, jugular venous distention, hypotension, ST segment elevation on electrocardiogram, and ventricular interdependence with septal shift during diastole on transthoracic echocardiogram. Initial diagnoses of effusive-constrictive pericarditis resembling cardiac tamponade, hepatitis and pancreatitis can be challenging, and this case highlights the need for healthcare professionals to be cognizant of the association between these unusual clinical presentations and coxsackievirus B infection. PMID- 27503516 TI - Amniotic membrane mesenchymal stem cells can differentiate into germ cells in vitro. AB - This is the first report on differentiation of mouse amniotic membrane mesenchymal stem cells (AM-MSCs) into male germ cells (GCs). AM-MSCs have the multipotent differentiation capacity and can be differentiated into various cell types. In the present study, AM-MSCs were induced for differentiation into GCs. AM-MSCs were isolated from mouse embryonic membrane by enzymatic digestion. AM MSCs were characterized with osteogenic and adipogenic differentiation test and flow cytometric analysis of some CD-markers. AM-MSCs were induced to differentiate into GCs using a creative two-step method. Passage-3 AM-MSCs were firstly treated with 25 ng/ml bone morphogenetic protein 4 (BMP4) for 5 d and in continuing with 1 MUM retinoic acid (RA) for 12 d (total treatment time was 17 d). At the end of the treatment period, real-time reverse transcription (RT)-PCR was performed to evaluate the expression of GC-specific markers-Itgb1, Dazl, Stra8, Piwil2, Mvh, Oct4, and c-Kit- in the cells. Moreover, flow cytometry and immunofluorescence staining were performed to evaluate the expression of Mvh and Dazl at protein level. Real-time RT-PCR showed that most of the tested markers were upregulated in the treated AM-MSCs. Furthermore, flow cytometric and immunofluorescence analyses both revealed that a considerable part of the treated cells expressed GC-specific markers. The percentage of positive cells for Mvh and Dazl was about 23 and 46%, respectively. Our results indicated that a number of AM-MSCs successfully differentiated into the GCs. Finally, it seems that AM-MSCs would be a potential source of adult pluripotent stem cells for in vitro generation of GCs and cell-based therapies for treatment of infertility. PMID- 27503533 TI - Three-dimensional corrective osteotomies of complex malunited humeral fractures using patient-specific guides. AB - BACKGROUND: Corrective osteotomies of malunited fractures of the proximal and distal humerus are among the most demanding orthopedic procedures. Whereas the restoration of the normal humeral anatomy is the ultimate goal, the quantification of the deformity as well as the transfer of the preoperative plan is challenging. The purpose of this study was to provide a guideline for 3 dimensional (3D) corrective osteotomies of malunited intra-articular fractures of the humerus and a detailed overview of existing and novel instruments to enlarge the toolkit for 3D preoperative planning and intraoperative realization using patient-specific guides. METHODS: We describe the preoperative 3D deformity analysis, relevant considerations for the preoperative plan, design of the patient-specific guides, and surgical technique of corrective osteotomies of the humerus. RESULTS: The presented technique demonstrates the benefit of computer assisted surgery for complex osteotomies of the humerus from a preoperative deformity analysis to the creation of feasible surgical procedures and the generation of patient-specific guides. CONCLUSIONS: A 3D analysis of a post traumatic deformity of the humerus, 3D preoperative planning, and use of patient specific guides facilitate corrective osteotomies of complex malunited humeral fractures. PMID- 27503534 TI - In Situ and Timed Extraction of Cellular Peptides from Live HeLa Cells by Photo Switchable Mesoporous Silica Nanocarriers. AB - In situ and timed extraction of cellular peptides is a great challenge for dynamic and global proteomic investigation of live cells. In this work, a mesoporous silica nanocarrier with photoswitchable off/on coumarin gates (MSNcg) was developed for capturing peptides from the cytosol of living HeLa cells. The MSNcg was constructed from mesoporous silica nanoparticle (MSN) and its subsequent modifications with TAT peptides and coumarin, to endow the features of the size-exclusion effect of the mesoporous silica and the localization of nanocarrier at cytosol by TAT peptide and to control the closing and opening of the coumarin gates by reversible photodimerization and photocleavage. With the pre-endocytosing of MSNcg, 126 cytosol peptides were harvested and identified from living HeLa cells. Moreover, 3 peptides were captured containing dynamic and changeable information. The extraction strategy of using MSNcg exhibited promising potentials in the in situ and dynamic extraction of endogenous peptides and/or proteins from living systems. PMID- 27503535 TI - Identification of urinary tract pathogens after 3-hours urine culture by MALDI TOF mass spectrometry. AB - Complicated urinary tract infections, such as pyelonephritis, may lead to sepsis. Rapid diagnosis is needed to identify the causative urinary pathogen and to verify the appropriate empirical antimicrobial therapy. We describe here a rapid identification method for urinary pathogens: urine is incubated on chocolate agar for 3h at 35 degrees C with 5% CO2 and subjected to MALDI-TOF MS analysis by VITEK MS. Overall 207 screened clinical urine samples were tested in parallel with conventional urine culture. The method, called U-si-MALDI-TOF (urine short incubation MALDI-TOF), showed correct identification for 86% of Gram-negative urinary tract pathogens (Escherichia coli, Klebsiella pneumoniae, and other Enterobacteriaceae), when present at >10(5)cfu/ml in culture (n=107), compared with conventional culture method. However, Gram-positive bacteria (n=28) were not successfully identified by U-si-MALDI-TOF. This method is especially suitable for rapid identification of E. coli, the most common cause of urinary tract infections and urosepsis. Turnaround time for identification using U-si-MALDI-TOF compared with conventional urine culture was improved from 24h to 4-6h. PMID- 27503536 TI - Label-free analysis of mononuclear human blood cells in microfluidic flow by coherent imaging tools. AB - The investigation of the physical properties of peripheral blood mononuclear cells (PBMC) is of great relevance, as they play a key role in regulating human body health. Here we report the possibility to characterize human PBMC in their physiological conditions in a microfluidic-based measurement system. A viscoelastic polymer solution is adopted for 3D alignment of individual cells inflow. An optical signature (OS) acquisition of each flowing cell is performed using a wide angle light scattering apparatus. Besides, a quantitative phase imaging (QPI) holographic system is employed with the aim (i) to check the position in flow of individual cells using a holographic 3D cell tracking method; and (ii) to estimate their 3D morphometric features, such as their refractive index (RI). Results obtained by combining OS and QPI have been compared with literature values, showing good agreement. The results confirm the possibility to obtain sub-micrometric details of physical cell properties in microfluidic flow, avoiding chemical staining or fluorescent labelling. PMID- 27503537 TI - A genome-wide screening uncovers the role of CCAR2 as an antagonist of DNA end resection. AB - There are two major and alternative pathways to repair DNA double-strand breaks: non-homologous end-joining and homologous recombination. Here we identify and characterize novel factors involved in choosing between these pathways; in this study we took advantage of the SeeSaw Reporter, in which the repair of double strand breaks by homology-independent or -dependent mechanisms is distinguished by the accumulation of green or red fluorescence, respectively. Using a genome wide human esiRNA (endoribonuclease-prepared siRNA) library, we isolate genes that control the recombination/end-joining ratio. Here we report that two distinct sets of genes are involved in the control of the balance between NHEJ and HR: those that are required to facilitate recombination and those that favour NHEJ. This last category includes CCAR2/DBC1, which we show inhibits recombination by limiting the initiation and the extent of DNA end resection, thereby acting as an antagonist of CtIP. PMID- 27503538 TI - Fat removal using a new cryolipolysis device: a retrospective study of 418 procedures. PMID- 27503539 TI - Fine mapping and identification of candidate genes for a QTL affecting Meloidogyne incognita reproduction in Upland cotton. AB - BACKGROUND: The southern root-knot nematode (Meloidogyne incognita; RKN) is one of the most important economic pests of Upland cotton (Gossypium hirsutum L.). Host plant resistance, the ability of a plant to suppress nematode reproduction, is the most economical, practical, and environmentally sound method to provide protection against this subterranean pest. The resistant line Auburn 623RNR and a number of elite breeding lines derived from it remain the most important source of root-knot nematode (RKN) resistance. Prior genetic analysis has identified two epistatically interacting RKN resistance QTLs, qMi-C11 and qMi-C14, affecting gall formation and RKN reproduction, respectively. RESULTS: We developed a genetic population segregating only for the qMi-C14 locus and evaluated the genetic effects of this QTL on RKN resistance in the absence of the qMi-C11 locus. The qMi-C14 locus had a LOD score of 12 and accounted for 24.5 % of total phenotypic variation for egg production. In addition to not being significantly associated with gall formation, this locus had a lower main effect on RKN reproduction than found in our previous study, which lends further support to evidence of epistasis with qMi-C11 in imparting RKN resistance in the Auburn 623RNR source. The locus qMi-C14 was fine-mapped with the addition of 16 newly developed markers. By using the reference genome sequence of G. raimondii, we identified 20 candidate genes encoding disease resistance protein homologs in the newly defined 2.3 Mb region flanked by two SSR markers. Resequencing of an RKN resistant and susceptible G. hirsutum germplasm revealed non-synonymous mutations in only four of the coding regions of candidate genes, and these four genes are consequently of high interest. CONCLUSIONS: Our mapping results validated the effects of the qMi-C14 resistance locus, delimiting the QTL to a smaller region, and identified tightly linked SSR markers to improve the efficiency of marker assisted selection. The candidate genes identified warrant functional studies that will help in identifying and characterizing the actual qMi-C14 defense gene(s) against root-knot nematodes. PMID- 27503540 TI - Contemporary sex differences among patients with acute coronary syndrome treated by emergency percutaneous coronary intervention. AB - Acute coronary syndrome (ACS) is an important cause of mortality and morbidity in the general population. Recent advances in percutaneous coronary intervention (PCI) and optimal medical treatment have helped to improve the prognosis of patients with ACS. The previous reports indicated that women with ACS have a higher risk of adverse outcomes. However, sex differences in clinical outcomes with contemporary coronary revascularization and medical therapy for ACS have not been elucidated. We analyzed data from 676 consecutive patients with ACS (female, n = 166; male, n = 510) who were treated by emergency PCI between 2011 and 2014 at Juntendo Shizuoka Hospital. The patients were grouped according to sex. We defined major adverse cardiovascular events as a composite of all-cause death and ACS recurrence at 1 year and compared rates of major adverse cardiac events (MACE) between the groups. Women were older (75.4 +/- 11.0 vs. 66.2 +/- 12.2 years) and had a higher rate of multi-vessel disease, chronic kidney disease, and Killip IV at presentation. The cumulative rate of MACE at 1 year was significantly higher among women than men (17.5 vs. 10.2 %, p = 0.02, log-rank test). However, the association between women and a higher risk of MACE was attenuated after adjusting for age (HR 1.25, 95 % CI 0.77-2.00, p = 0.36) and other variables (HR 0.93, 95 % CI 0.36-2.44, p = 0.88). Adjustment for age and other risk factors attenuated sex differences in mid-term clinical outcomes among patients with ACS after emergency PCI. PMID- 27503541 TI - Erratum to: Characterization of iodinated disinfection by-products in chlorinated and chloraminated waters using Orbitrap based gas chromatography-mass spectrometry. PMID- 27503542 TI - An isotope dilution capillary electrophoresis/tandem mass spectrometry (CE-MS/MS) method for the simultaneous measurement of choline, betaine, and dimethylglycine concentrations in human plasma. AB - Plasma concentrations of choline, betaine, and dimethylglycine provide valuable information on the flow of methyl groups in key biological processes, particularly during folate deficiency states. We developed a new method to simultaneously measure these analytes in human plasma. Following sample deproteinization using acetonitrile, an aliquot was evaporated to dryness under vacuum to be then taken up by water. Finally, analytes were separated by capillary electrophoresis and detected by electrospray ionization triple quadrupole mass spectrometry, in multiple reaction monitoring mode, using two stable isotope-labeled internal standards. Linearity of the calibration curves of each analyte was good (R(2) > 0.99). Average limits of detection (LODs) and limits of quantification (LOQs) for choline, betaine, and dimethylglycine were, respectively, 0.43, 0.62, and 0.31 MUmol/L and 1.52, 2.11, and 0.97 MUmol/L. Mean recovery of three replicates of two spiked concentrations levels was close to 100 % for all of the analytes. Repeatability and intermediate precision, expressed as %RSD of measurements, were <9 %. The method, applied to measure analytes in samples from 30 patients with chronic kidney disease and 30 age- and sex-matched healthy controls, was able to detect differences between groups and the sexes. PMID- 27503543 TI - Development and application of ultrasound-assisted microextraction to analysis of fenitrothion in environmental samples. AB - A microextraction technique based on ultrasonic emulsification and demulsification was developed for detecting pesticides at trace levels in environmental water samples. In this ultrasound-assisted microextraction (UAME), chloroform was emulsified with an aqueous sample solution containing trace fenitrothion (MEP) by ultrasonic irradiation (48 kHz) for 5 min. The emulsion was then demulsified by ultrasonic irradiation (2.4 MHz) for 10 min. This resulted in phase separation of the water and chloroform without centrifugation. The demulsified chloroform was collected by a microsyringe and submitted to gas chromatography-mass spectrometry. In conventional extraction with mechanical stirring, the extraction recovery (ER) of MEP was strongly dependent on the sample/chloroform volume ratio. However, in UAME, the ER was independent of the volume ratio and the ER was >80 % when the enrichment factor was 40. In UAME, MEP was rapidly extracted into the chloroform because of the large specific surface areas of the small chloroform droplets in the oil-in-water (O/W) emulsion. This gave a high extraction efficiency for MEP. UAME is a simple method requiring only a change in the ultrasound frequency and with no pretreatment steps that could contaminate the sample. The suitability of UAME was demonstrated by application to the detection of trace levels of pesticides in a spiked water sample from a fish tank. Graphical abstract Schematic diagram of the ultrasound-assisted microextraction (UAME) method. PMID- 27503544 TI - Practical utilization of spICP-MS to study sucrose density gradient centrifugation for the separation of nanoparticles. AB - Single particle inductively coupled plasma mass spectrometry (spICP-MS) is shown to be a practical technique to study the efficacy of rate-zonal sucrose density gradient centrifugation (SDGC) separations of mixtures of gold nanoparticles (AuNPs) in liquid suspension. spICP-MS enabled measurements of AuNP size distributions and particle number concentrations along the gradient, allowing unambiguous evaluations of the effectiveness of the separation. Importantly, these studies were conducted using AuNP concentrations that are directly relevant to environmental studies (sub ng mL-1). At such low concentrations, other techniques [e.g., dynamic light scattering (DLS), transmission and scanning electron microscopies (TEM and SEM), UV-vis spectroscopy, atomic force microscopy (AFM)] do not have adequate sensitivity, highlighting the inherent value of spICP MS for this and similar applications. In terms of the SDGC separations, a mixture containing three populations of AuNPs, having mean diameters of 30, 80, and 150 nm, was fully separated, while separations of two other mixtures (30, 60, 100 nm; and 20, 50, 100 nm) were less successful. Finally, it is shown that the separation capacity of SDGC can be overwhelmed when particle number concentrations are excessive, an especially relevant finding in view of common methodologies taken in nanotechnology research. Graphical Abstract Characterization of the separation of a gold nanoparticle mixture by sucrose density gradient centrifugation by conventional and single particle ICP-MS analysis. PMID- 27503545 TI - Application of microwave-assisted extraction and ultra-high performance liquid chromatography-tandem mass spectrometry for the analysis of sex hormones and corticosteroids in sewage sludge samples. AB - Hormonal compounds are a concern to the international community because they can affect the aquatic biota and are therefore considered to be endocrine-disrupting compounds. These compounds have lipophilic properties, so they tend to accumulate in solid matrices, such as sewage sludge. This work presents the optimization of a microwave-assisted extraction process combined with ultra-high performance liquid chromatography-tandem mass spectrometry for the determination of 15 hormonal compounds in sludge samples. The proposed method has relative standard deviations below 23 %, good recoveries (over 71 %) for all compounds, detection limits that ranged from 1.1 to 7.9 ng g(-1) and quantification limits which ranged from 3.7 to 26.3 ng g(-1). The method was used to analyse sludge samples from four different wastewater treatment plants of Gran Canaria (Spain) with different wastewater treatments. 17beta-estradiol, 17alpha-ethynylestradiol, norgestrel and cortisone were detected in sludge samples at concentrations that ranged from 17.3 to 1.44 * 10(3) ng g(-1). The developed method permits the use of small quantities of sample and organic solvents, presents short extractions times and is the first one based on microwave-assisted extraction for the analysis of both sex hormones and corticosteroids. PMID- 27503546 TI - Silk-Fibroin and Graphene Oxide Composites Promote Human Periodontal Ligament Stem Cell Spontaneous Differentiation into Osteo/Cementoblast-Like Cells. AB - Graphene represents one of the most interesting additions to the tissue engineering toolbox. Novel graphene-based composites are required to improve the beneficial graphene properties in terms of tridimensional polymeric structure, conferring a higher mechanical strength and favoring the differentiation of human mesenchymal stem cells. Here, we have demonstrated in a wide range of composite combinations, the successful use of graphene and silk-fibroin constructs for future bioengineering applications in the field of clinical regenerative dentistry using human periodontal ligament stem cells. Our results provide exciting new data for the development of suitable scaffolds that allow good cell engrafting, preservation of cell viability and proliferation, promotion of spontaneous osteoblastic differentiation, and importantly, stimulation of a higher cementum physiological synthesis than using other different available biomaterials. PMID- 27503547 TI - Erratum: Graphic analysis of flow-volume curves: a pilot study. PMID- 27503548 TI - Contra-lateral hip fracture in the elderly: are decreased body mass index and skin thickness predictive factors? AB - PURPOSE: A correlation between soft tissue thickness and osteoporosis has been suggested. We aimed to estimate if a low body mass index (BMI) and/or a decrease of skin thickness could estimate the risk of contra-lateral hip fracture. METHODS: First, we performed a retrospective analysis of 1268 patients treated for a hip fracture. The 146 patients who had a contra-lateral hip fractures-study group-were compared with the 1078 patients who did not-control group. Four BMI categories were considered: obese, overweight, normal weight and low weight. Second, we enrolled prospectively 1000 consecutive patients in the emergency department. History of fractures, BMI, and skin aspect on the dorsum of both hands-classified as severe decrease thickness, moderate decrease thickness or normal-were recorded. RESULTS: pt?>In the first part, we found that patients with contra-lateral fractures had a significantly lower BMI than those in the control group (22.2 Vs 26.5 kg/m2, p = 0.01). In the second part, 48 on 1000 patients had a hip fracture. Among them, six had a contra-lateral fracture. BMI was 23.4 kg/m2 in bilateral hip fractures, 33.68 kg/m2 in the unilateral fracture group, and 28.04 kg/m2 in the non-fracture group (p = 0.04). Finally, patients with contra lateral hip fractures had a severe decrease thickness of the skin. CONCLUSION: A low BMI and a decreased skin thickness increase independently the risk of fractures by three times. When associated, they increase the risk of fracture risk by five times. This combination had a sensitivity at 71 % and a specificity at 90 % for predicting hip fracture. PMID- 27503549 TI - Rotavirus vaccines contribute towards universal health coverage in a mixed public private healthcare system. AB - OBJECTIVES: To evaluate rotavirus vaccination in Malaysia from the household's perspective. The extended cost-effectiveness analysis (ECEA) framework quantifies the broader value of universal vaccination starting with non-health benefits such as financial risk protection and equity. These dimensions better enable decision makers to evaluate policy on the public finance of health programmes. METHODS: The incidence, health service utilisation and household expenditure related to rotavirus gastroenteritis according to national income quintiles were obtained from local data sources. Multiple birth cohorts were distributed into income quintiles and followed from birth over the first five years of life in a multicohort, static model. RESULTS: We found that the rich pay more out of pocket (OOP) than the poor, as the rich use more expensive private care. OOP payments among the poorest although small are high as a proportion of household income. Rotavirus vaccination results in substantial reduction in rotavirus episodes and expenditure and provides financial risk protection to all income groups. Poverty reduction benefits are concentrated amongst the poorest two income quintiles. CONCLUSION: We propose that universal vaccination complements health financing reforms in strengthening Universal Health Coverage (UHC). ECEA provides an important tool to understand the implications of vaccination for UHC, beyond traditional considerations of economic efficiency. PMID- 27503550 TI - Coronary bifurcation stent morphology in dual-source CT: validation with micro CT. AB - The aim of this study is to analyze post-bifurcation coronary stent morphology in vitro using dual-source CT and validate those findings using micro-CT. Nine silicon coronary artery phantoms simulating main branch (MB) and side branch (SB) were prepared using a 3-D printer. After bifurcation stenting using Crush, Culotte, and T-stenting technique, in vitro CT imaging was conducted using both dual-source CT and micro-CT. Morphological change of the bifurcation stent including crushed segment and floating stent strut were evaluated. Dual-source CT was able to demonstrate morphologic changes of bifurcation stents and was comparable to micro-CT. In stents with Crush and T-stenting methods, crushed segment appeared denser and thicker than other stent parts and was located at MB side in all phantoms. Floating strut was observed in half of the phantoms with Crush technique and all phantoms with T-stenting. Parameters measured in both dual-source CT and micro-CT showed good correlation and high agreement (limits of agreement and correlation for length, perimeter and area, 0.3 +/- 3.5, 0.5 +/- 2.1 mm, and 0.0 +/- 1.5 mm2, r = 0.76, 0.92, and 0.91). The morphology of post bifurcation stent on dual-source CT correlates well with that of micro-CT in the coronary artery phantom. Coronary CT angiography may be a feasible method for the evaluation of stent morphology in patients who underwent bifurcation stenting. PMID- 27503552 TI - An atomic symmetry-controlled thermal switch. AB - We propose a simple diatomic system trapped inside an optical cavity to control the energy flow between two thermal baths. Through the action of the baths the system is driven to a non-equilibrium steady state. Using the Large Deviation theory we show that the number of photons flowing between the two baths is dramatically different depending on the symmetry of the atomic states. Here we present a deterministic scheme to prepare symmetric and antisymmetric atomic states with the use of external driving fields, thus implementing an atomic control switch for the energy flow. PMID- 27503551 TI - Early gadolinium enhancement in hypertrophic cardiomyopathy: a potential premature marker of myocardial damage. AB - Early gadolinium enhancement (EGE), one CMR diagnostic criteria in acute myocarditis, has been related with hyperemia and capillary leakage. The value of EGE in hypertrophic cardiomyopathy (HCM) remains unknown. Our aim was to determine the prevalence of EGE in patients with HCM, and its relation with late gadolinium enhancement (LGE). The association of EGE with morphological and clinical parameters was also evaluated. Sixty consecutive patients with HCM and CMR from our center were included. All the clinical and complementary test information was collected prospectively in our HCM clinic. Left ventricular (LV) measurements were calculated from cine sequences. EGE and LGE were quantified with a dedicated software. Clinical events were collected from medical records. A slow wash-out pattern on EGE was detected in up to 68 % of the patients, being an isolated finding without LGE in 10 (16 %). This cohort showed a greater maximal LV wall thickness (20.1 +/- 4 vs. 18.1 +/- 3.5 mm, p = 0.010) and asymmetry ratio (1.86 +/- 0.42 vs. 1.62 +/- 0.46; p = 0.039). The percentage of EGE/slice and the difference with the percentage LGE/slice demonstrated a significant positive correlation with the maximal LV wall thickness (Rho 0.450 and 0.386 respectively). EGE also correlated with number of segments with LVH (LV hypertrophy) and the asymmetry ratio. Neither EGE nor LGE were associated with classical risk factors, the risk score for sudden cardiac death, or with major clinical events. EGE was a frequent finding in HCM, even in absence of LGE. This phenomenon showed a positive correlation with morphological markers of disease burden. PMID- 27503553 TI - Heterologous production of an acidic thermostable lipase with broad-range pH activity from thermophilic fungus Neosartorya fischeri P1. AB - Thermophilic Neosartorya fischeri P1 is an excellent lipase producer and harbors seven lipase genes. All genes were found to be functional after heterologous expression in Escherichia coli. One of them, LIP09, showed high-level expression in Pichia pastoris with the yield of 2.0 g/L in a 3.7-L fermentor. Deduced amino acid sequence of LIP09 consists of a putative signal peptide (residues 1-19) and a mature polypeptide (residues 20-562). Compared with other fungal counterparts, purified recombinant LIP09 has some superior properties. It exhibited maximum activity at 60 degrees C and pH 5.0, had broad pH adaptability (>60% activity at pH 3.5-8.0) and stability (retaining >90% activity after incubation at pH 3.0-7.0 for 1 h at 40 degrees C), and was highly thermostable (retaining >96% activity after incubation at 50 degrees C for 30 min). The r-LIP09 had a preference for the medium-chain length p-nitrophenyl esters (C12) rather than short and long chain length substrates. The high-level expression and excellent properties make LIP09 a potential enzyme candidate in food and feed industries. PMID- 27503555 TI - Rapid and large-scale synthesis of bare Co3O4 porous nanostructures from an oleate precursor as superior Li-ion anodes with long-cycle lives. AB - In this study, we describe a rapid and environmentally friendly synthesis of bare Co3O4 nanocrystals derived from Co(ii) oleate complexes by calcination treatment. When directly used as anode materials for lithium-ion batteries (LIBs), the as prepared nanocrystals could deliver a high reversible capacity of 980 mA h g(-1) after 250 cycles at a current density of 100 mA g(-1) and excellent cycling performance, which may be beneficial to promote the further development of the next generation of lithium ion batteries. The synthetic route can offer great advantages for the flash preparation of other metal oxide nanocrystals for energy storage application. PMID- 27503554 TI - Estimating safe maximum levels of vitamins and minerals in fortified foods and food supplements. AB - PURPOSE: To show how safe maximum levels (SML) of vitamins and minerals in fortified foods and supplements may be estimated in population subgroups. METHODS: SML were estimated for adults and 7- to 10-year-old children for six nutrients (retinol, vitamins B6, D and E, folic acid, iron and calcium) using data on usual daily nutrient intakes from Irish national nutrition surveys. RESULTS: SML of nutrients in supplements were lower for children than for adults, except for calcium and iron. Daily energy intake from fortified foods in high consumers (95th percentile) varied by nutrient from 138 to 342 kcal in adults and 40-309 kcal in children. SML (/100 kcal) of nutrients in fortified food were lower for children than adults for vitamins B6 and D, higher for vitamin E, with little difference for other nutrients. Including 25 % 'overage' for nutrients in fortified foods and supplements had little effect on SML. Nutritionally significant amounts of these nutrients can be added safely to supplements and fortified foods for these population subgroups. The estimated SML of nutrients in fortified foods and supplements may be considered safe for these population subgroups over the long term given the food composition and dietary patterns prevailing in the respective dietary surveys. CONCLUSIONS: This risk assessment approach shows how nutrient intake data may be used to estimate, for population subgroups, the SML for vitamins and minerals in both fortified foods and supplements, separately, each taking into account the intake from other dietary sources. PMID- 27503557 TI - An Interview with Rick Neubig. PMID- 27503556 TI - Tristetraprolin as a Therapeutic Target in Inflammatory Disease. AB - Members of the tristetraprolin (TTP) family of RNA-binding proteins are found in all major eukaryotic groups. TTP family members, from plants through humans, can bind adenosine-uridine rich elements in target mRNAs with high affinity. In mammalian cells, these proteins then promote deadenylation and decay of target transcripts. Four such proteins are found in mice, of which the best studied is TTP. When the gene encoding TTP is disrupted in mice, the animals develop a severe syndrome of arthritis, autoimmunity, cachexia, dermatitis, and myeloid hyperplasia. Conversely, recent overexpression studies have demonstrated protection against several experimental models of immune inflammatory disease. This endogenous anti-inflammatory protein could serve as the basis for novel approaches to therapy of similar conditions in humans. PMID- 27503558 TI - N w-hydroxy-L-arginine as a novel ethnic specific indicator of estrogen-negative breast cancer. AB - As a heterogeneous disease, breast cancer can be divided into distinct subtypes. Among the two major subsets of estrogen receptor-negative (ER-) and ER-positive (ER+) tumors, the ER- is a more aggressive subtype, more difficult to treat, has greater ethnic disparity concerns, worse prognosis, and almost twice the risk of mortality. We provide here a fundamental delineation of N w-hydroxy-L-arginine as a sensitive and reliable ethnic specific indicator for ER- breast cancer early prognosis (United States provisional patent application number 62232816). PMID- 27503559 TI - Transglutaminase 2-specific coeliac disease autoantibodies induce morphological changes and signs of inflammation in the small-bowel mucosa of mice. AB - Coeliac disease is hallmarked by an abnormal immune reaction against ingested wheat-, rye- and barley-derived gluten and the presence of transglutaminase 2 (TG2)-targeted autoantibodies. The small-bowel mucosal damage characteristic of the disorder develops gradually from normal villus morphology to inflammation and finally to villus atrophy with crypt hyperplasia. Patients with early-stage coeliac disease have TG2-autoantibodies present in serum and small-intestinal mucosa and they may already suffer from abdominal symptoms before the development of villus atrophy. Previously, we have shown that intraperitoneal injections of coeliac patient-derived sera or purified immunoglobulin fraction into mice induce a condition mimicking early-stage coeliac disease. In the current study, we sought to establish whether recombinantly produced patient-derived TG2-targeted autoantibodies are by themselves sufficient for the development of such an experimentally induced condition in immune-compromised mice. Interestingly, mice injected with coeliac patient TG2-antibodies had altered small-intestinal mucosal morphology, increased lamina propria cellular infiltration and disease-specific autoantibodies deposited in the small bowel, but did not evince clinical features of the disease. Thus, coeliac patient-derived TG2-specific autoantibodies seem to be sufficient for the induction of subtle small-bowel mucosal alterations in mice, but the development of clinical features probably requires additional factors such as other antibody populations relevant in coeliac disease. PMID- 27503560 TI - 11,000 years of craniofacial and mandibular variation in Lower Nubia. AB - The transition to agriculture was a key event in human history. The extent to which this transition is associated with biological changes in different world regions remains debated. Cultural and osteological records in Lower Nubia throughout the Holocene have been interpreted as a result of in situ differentiation or alternatively as migratory events and possible admixture with surrounding populations. Here we investigated the patterns of craniofacial and mandibular variation from Mesolithic hunting-gathering to late farming, a period spanning 11,000 years. We analyzed 102 adult specimens spanning five cultural horizons: Mesolithic, A-group, C-group, Pharaonic and Meroitic, by means of 3D geometric morphometric methods, in order to assess shape variation and diachronic patterns at the transition to farming and in subsequent periods. Our results highlight a strong morphometric distinction between Mesolithic hunter-gatherers and farmers as well as differences between transitional and intensive farmers in mandibular variation which is consistent with differential impact of selective pressures on different regions of the skull. This study corroborates a major biological change during the transition from hunting to farming, supporting the masticatory-functional hypothesis for the mandible and suggesting population continuity among farming populations throughout the Holocene based on the overall shape of the cranium. PMID- 27503561 TI - Deciphering the role of the AT-rich interaction domain and the HMG-box domain of ARID-HMG proteins of Arabidopsis thaliana. AB - ARID-HMG DNA-binding proteins represent a novel group of HMG-box containing protein family where the AT-rich interaction domain (ARID) is fused with the HMG box domain in a single polypeptide chain. ARID-HMG proteins are highly plant specific with homologs found both in flowering plants as well as in moss such as Physcomitrella. The expression of these proteins is ubiquitous in plant tissues and primarily localises in the cell nucleus. HMGB proteins are involved in several nuclear processes, but the role of ARID-HMG proteins in plants remains poorly explored. Here, we performed DNA-protein interaction studies with Arabidopsis ARID-HMG protein HMGB11 (At1g55650) to understand the functionality of this protein and its individual domains. DNA binding assays revealed that AtHMGB11 can bind double-stranded DNA with a weaker affinity (Kd = 475 +/- 17.9 nM) compared to Arabidopsis HMGB1 protein (Kd = 39.8 +/- 2.68 nM). AtHMGB11 also prefers AT-rich DNA as a substrate and shows structural bias for supercoiled DNA. Molecular docking of the DNA-AtHMGB11 complex indicated that the protein interacts with the DNA major groove, mainly through its ARID domain and the junction region connecting the ARID and the HMG-box domain. Also, predicted by the docking model, mutation of Lys(85) from the ARID domain and Arg(199) & Lys(202) from the junction region affects the DNA binding affinity of AtHMGB11. In addition, AtHMGB11 and its truncated form containing the HMG-box domain can not only promote DNA mini-circle formation but are also capable of inducing negative supercoils into relaxed plasmid DNA suggesting the involvement of this protein in several nuclear events. Overall, the study signifies that both the ARID and the HMG-box domain contribute to the optimal functioning of ARID-HMG protein in vivo. PMID- 27503562 TI - Soliton driven angiogenesis. AB - Angiogenesis is a multiscale process by which blood vessels grow from existing ones and carry oxygen to distant organs. Angiogenesis is essential for normal organ growth and wounded tissue repair but it may also be induced by tumours to amplify their own growth. Mathematical and computational models contribute to understanding angiogenesis and developing anti-angiogenic drugs, but most work only involves numerical simulations and analysis has lagged. A recent stochastic model of tumour-induced angiogenesis including blood vessel branching, elongation, and anastomosis captures some of its intrinsic multiscale structures, yet allows one to extract a deterministic integropartial differential description of the vessel tip density. Here we find that the latter advances chemotactically towards the tumour driven by a soliton (similar to the famous Korteweg-de Vries soliton) whose shape and velocity change slowly. Analysing these collective coordinates paves the way for controlling angiogenesis through the soliton, the engine that drives this process. PMID- 25492891 TI - Transrectal ultrasonography of anorectal diseases: advantages and disadvantages. AB - Transrectal ultrasonography (TRUS) has been widely accepted as a popular imaging modality for evaluating the lower rectum, anal sphincters, and pelvic floor in patients with various anorectal diseases. It provides excellent visualization of the layers of the rectal wall and of the anatomy of the anal canal. TRUS is an accurate tool for the staging of primary rectal cancer, especially for early stages. Although magnetic resonance imaging is a modality complementary to TRUS with advantages for evaluating the mesorectum, external sphincter, and deep pelvic inflammation, three-dimensional ultrasonography improves the detection and characterization of perianal fistulas and therefore plays a crucial role in optimal treatment planning. The operator should be familiar with the anatomy of the rectum and pelvic structures relevant to the preoperative evaluation of rectal cancer and other anal canal diseases, and should have technical proficiency in the use of TRUS combined with an awareness of its limitations compared to magnetic resonance imaging. PMID- 27503564 TI - Publication of Cost-of-Illness Studies: Does Methodological Complexity Matter? PMID- 27503565 TI - The Six-Food Elimination Diet for Eosinophilic Esophagitis Increases Grocery Shopping Cost and Complexity. AB - The six-food elimination diet (SFED), where dairy, wheat, eggs, soy, nuts, and seafood are avoided, is an effective treatment for eosinophilic esophagitis (EoE). Patient-related costs of this approach, however, are unknown. We aimed to assess the cost of and ease of shopping for an SFED compared to an unrestricted diet. A dietitian with expertise in EoE generated menus meeting dietary requirements for a week's worth of meals for the SFED and an unrestricted diet. We compared prices and the number of missing items for both diets at standard and specialty grocery stores. The average weekly price of the SFED at a standard supermarket was $92.54 compared to $79.84 for an unrestricted diet (p = 0.0001). A patient shopping at a standard grocery store needed a higher proportion of items from a second store compared to an unrestricted diet (32 vs. 3 %, p = 0.0001). The prices of the SFED and unrestricted diet using a specialty supermarket were comparable ($106.47 vs. $105.96, p = 0.81), as was the percentage of items requiring a trip to a second store (6 vs. 2 % items, p = 0.03). Shopping at a specialty grocery store increased weekly grocery costs by $13.93 (p = 0.04) for the SFED and $26.12 (p = 0.03) for the unrestricted diet. In conclusion, for patients shopping at standard grocery stores, the cost of an SFED is higher, and an SFED requires more items from a second store. These differences disappear at specialty grocery stores, but costs were significantly higher. This cost and logistical burden can inform patients when selecting dietary therapy. PMID- 27503566 TI - A Comparative Study Between Two Sensory Stimulation Strategies After Two Weeks Treatment on Older Patients with Oropharyngeal Dysphagia. AB - Oropharyngeal dysphagia (OD) is a prevalent geriatric syndrome. Treatment is based on compensatory strategies to avoid complications. New treatments based on sensory stimulation to promote the recovery of the swallowing function have proved effective in acute studies but prolonged treatment needs further research. Our aim was to evaluate and compare the effect of two, longer-term sensory treatment strategies on older patients with OD. 38 older patients (>=70 years) were studied with videofluoroscopy (pre/posttreatment) and randomized into two 10 day treatment groups: Group A-transient receptor potential vanilloid 1 (TRPV1) agonist (capsaicin 1 * 10(-5) M) and Group B-transcutaneous sensory electrical stimulation (TSES) (Intelect VitalStim, biphasic pulses, 300 MUs, 80 Hz). Patients were analyzed for treatment response. Patients were old (80.47 +/- 5.2 years), with comorbidities (3.11 +/- 1.59 Charlson Index), polymedication (8.92 +/- 3.31 drugs/patient), and mild functional impairment (86.84 +/- 17.84 Barthel Index), and 28.9 % were at risk of malnutrition (MNA-sf). Overall, all patients had videofluoroscopic signs of impaired safety of swallow (ISS) with delayed oropharyngeal swallow response (OSR). After sensory stimulation, prevalence of ISS decreased to 68.42 % in both groups (P = 0.019). There were 68.42 % responders in Group A (TRPV1) and 42.11 % in Group B (TSES). Group A responders showed an improvement in the penetration-aspiration scale (PAS, 5.23 +/- 2.04 to 3 +/- 1.47; P = 0.002), and the same was true for those of Group B (4.63 +/- 1.41 to 2.13 +/- 0.64; P = 0.007). 10-day sensory stimulation with either therapy improved safety of swallow and OSR in older patients with OD, reducing the severity of OD in a significant subgroup of these patients. PMID- 27503567 TI - Carotid stiffness is associated with impairment of cognitive performance in individuals with and without type 2 diabetes. The Maastricht Study. AB - BACKGROUND AND AIMS: There is increasing evidence linking arterial (mainly aortic) stiffness and type 2 diabetes, a risk factor for arterial stiffness, to cognitive impairment and dementia. However, data on carotid stiffness, which may be especially relevant for cognitive performance, are scarce, and few studies have addressed the interplay between arterial stiffness, type 2 diabetes, and cognitive performance. METHODS: We studied individuals with (n = 197) and without (n = 528) type 2 diabetes, who completed a neuropsychological test battery and underwent applanation tonometry and vascular ultrasound to evaluate aortic (i.e. carotid-to-femoral pulse wave velocity) and carotid stiffness (i.e. distensibility, compliance and Young's elastic modulus). Linear regression analyses were performed and adjusted for demographics, vascular risk factors, and depression. RESULTS: Overall, our results showed that carotid, but not aortic, stiffness was associated with worse cognitive performance, primarily in the domains of processing speed (standardized regression coefficient for distensibility -0.083, p = 0.040; compliance -0.077, p = 0.032) and executive function and attention (distensibility -0.133, p = 0.001; compliance -0.090, p = 0.015; Young's elastic modulus -0.081, p = 0.027). These associations did not differ by diabetes status. The differences in cognitive performance between individuals with and without type 2 diabetes (mean difference in domain scores relative to those without diabetes for free recall memory -0.23, processing speed -0.19, executive function and attention -0.23; all p <= 0.009 and adjusted for demographics, traditional vascular risk factors, and depression) were not substantially altered after additional adjustment for carotid stiffness. CONCLUSIONS: Our findings suggest that carotid stiffness is associated with cognitive performance in both individuals with and without diabetes, but does not mediate the relationship between type 2 diabetes and cognitive dysfunction. PMID- 27503569 TI - Equal variations of the Fermi level and work function in graphene at the nanoscale. AB - If surface effects are neglected, any change of the Fermi level in a semiconductor is expected to result in an equal and opposite change of the work function. However, this is in general not observed in three-dimensional semiconductors, because of Fermi level pinning at the surface. By combining Kelvin probe force microscopy and scanning tunneling spectroscopy on single layer graphene, we measure both the local work function and the charge carrier density. The one-to-one equivalence of changes in the Fermi level and the work function is demonstrated to accurately hold in single layer graphene down to the nanometer scale. PMID- 27503568 TI - Vorinostat differentially alters 3D nuclear structure of cancer and non-cancerous esophageal cells. AB - The histone deacetylase (HDAC) inhibitor vorinostat has received significant attention in recent years as an 'epigenetic' drug used to treat solid tumors. However, its mechanisms of action are not entirely understood, particularly with regard to its interaction with the aberrations in 3D nuclear structure that accompany neoplastic progression. We investigated the impact of vorinostat on human esophageal epithelial cell lines derived from normal, metaplastic (pre cancerous), and malignant tissue. Using a combination of novel optical computed tomography (CT)-based quantitative 3D absorption microscopy and conventional confocal fluorescence microscopy, we show that subjecting malignant cells to vorinostat preferentially alters their 3D nuclear architecture relative to non cancerous cells. Optical CT (cell CT) imaging of fixed single cells showed that drug-treated cancer cells exhibit significant alterations in nuclear morphometry. Confocal microscopy revealed that vorinostat caused changes in the distribution of H3K9ac-marked euchromatin and H3K9me3-marked constitutive heterochromatin. Additionally, 3D immuno-FISH showed that drug-induced expression of the DNA repair gene MGMT was accompanied by spatial relocation toward the center of the nucleus in the nuclei of metaplastic but not in non-neoplastic cells. Our data suggest that vorinostat's differential modulation of 3D nuclear architecture in normal and abnormal cells could play a functional role in its anti-cancer action. PMID- 27503570 TI - Mechanism of action of pimavanserin in Parkinson's disease psychosis: targeting serotonin 5HT2A and 5HT2C receptors. AB - Pimavanserin, a novel agent approved for the treatment of Parkinson's disease psychosis, has potent actions as an antagonist/inverse agonist at serotonin 5HT2A receptors and less potent antagonist/inverse agonist actions at 5HT2C receptors. PMID- 27503571 TI - ICD and DSM: neuroplasticity and staging are still missing. AB - The two main diagnostic systems, the International Classification of Diseases (ICD) and the Diagnostic and Statistical Manual of Mental Disorders (DSM), have undergone a number of revisions since their first editions: whereas the fifth edition of the DSM has been published in 2013, the eleventh revision of the ICD is expected by 2018. Although the process of harmonization between the 2 systems is still a debated topic, the forthcoming revision of the ICD is seemingly converging toward the DSM approach in regard to the reclassification of a number of disorders. Nevertheless, the 2 systems still exhibit considerable differences, partly due to their different purposes, development and revision processes, and target audiences. Furthermore, while alternative and innovative classification approaches are emerging with the aim of integrating the latest findings from neuroscience and genomics, both the DSM and ICD still fail to incorporate core concepts such as the clinical staging of psychiatric disorders and "neuroprogression," as well as an adequate consideration of endophenotypes. PMID- 27503572 TI - The separation of adult separation anxiety disorder. AB - The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) categorization of mental disorders places "separation anxiety disorder" within the broad group of anxiety disorders, and its diagnosis no longer rests on establishing an onset during childhood or adolescence. In previous editions of DSM, it was included within the disorders usually first diagnosed in infancy, childhood, or adolescence, with the requirement for an onset of symptoms before the age of 18 years: symptomatic adults could only receive a retrospective diagnosis, based on establishing this early onset. The new position of separation anxiety disorder is based upon the findings of epidemiological studies that revealed the unexpectedly high prevalence of the condition in adults, often in individuals with an onset of symptoms after the teenage years; its prominent place within the DSM-5 group of anxiety disorders should encourage further research into its epidemiology, etiology, and treatment. This review examines the clinical features and boundaries of the condition, and offers guidance on how it can be distinguished from other anxiety disorders and other mental disorders in which "separation anxiety" may be apparent. PMID- 27503573 TI - Development of deep eutectic solvents applied in extraction and separation. AB - Deep eutectic solvents, as an alternative to ionic liquids, have greener credentials than ionic liquids, and have attracted considerable attention in related chemical research. Deep eutectic solvents have attracted increasing attention in chemistry for the extraction and separation of various target compounds from natural products. This review highlights the preparation of deep eutectic solvents, unique properties of deep eutectic solvents, and synthesis of deep-eutectic-solvent-based materials. On the other hand, application in the extraction and separation of deep eutectic solvents is also included in this report. In this paper, the available data and references in this field are reviewed to summarize the applications and developments of deep eutectic solvents. Based on the development of deep eutectic solvents, an exploitation of new deep eutectic solvents and deep eutectic solvents-based materials is expected to diversify into extraction and separation. PMID- 27503574 TI - Evolutionary theory of ageing and the problem of correlated Gompertz parameters. AB - The Gompertz mortality model is often used to evaluate evolutionary theories of ageing, such as the Medawar-Williams' hypothesis that high extrinsic mortality leads to faster ageing. However, fits of the Gompertz mortality model to data often find the opposite result that mortality is negatively correlated with the rate of ageing. This negative correlation has been independently discovered in several taxa and is known in actuarial studies of ageing as the Strehler-Mildvan correlation. We examine the role of mortality selection in determining late-life variation in susceptibility to death, which has been suggested to be the cause of this negative correlation. We demonstrate that fixed-frailty models that account for heterogeneity in frailty do not remove the correlation and that the correlation is an inherent statistical property of the Gompertz distribution. Linking actuarial and biological rates of ageing will continue to be a pressing challenge, but the Strehler-Mildvan correlation itself should not be used to diagnose any biological, physiological, or evolutionary process. These findings resolve some key tensions between theory and data that affect evolutionary and biological studies of ageing and mortality. Tests of evolutionary theories of ageing should include direct measures of physiological performance or condition. PMID- 27503575 TI - Perioperative Complications and Outcome of Laparoscopic Cholecystectomy in 20 Dogs. AB - OBJECTIVE: To report the complications and outcome of dogs undergoing laparoscopic cholecystectomy for uncomplicated gall bladder disease. STUDY DESIGN: Multi-institutional case series. ANIMALS: Client-owned dogs (n=20). METHODS: Medical records of dogs that underwent laparoscopic cholecystectomy were reviewed and signalment, history, clinical and ultrasound examination findings, surgical variables, and complications were collated. Laparoscopic cholecystectomy was performed using a multiport approach. Data were compared between dogs with successful laparoscopic cholecystectomy and dogs requiring conversion to open cholecystectomy. RESULTS: Six dogs (30%) required conversion from laparoscopic to open cholecystectomy due to inability to ligate the cystic duct (3), evidence of gall bladder rupture (1), leakage from the cystic duct during dissection (1), and cardiac arrest (1). Cystic duct dissection was performed in 19 dogs using an articulating dissector (10), right angle forceps (7), and unrecorded (2). The cystic duct was ligated in 15 dogs using surgical clips (5), suture (6), or a combination (4). All dogs were discharged from the hospital and had resolution of clinical signs, although 1 dog developed pancreatitis and 1 dog required revision surgery for bile peritonitis. There was no significant difference in preoperative blood analysis results, surgical technique, or duration of hospitalization between dogs undergoing laparoscopic cholecystectomy and cases converted to open cholecystectomy. CONCLUSION: Laparoscopic cholecystectomy can be performed successfully for uncomplicated gall bladder disease in dogs after careful case selection. The surgeon considering laparoscopic cholecystectomy should be familiar with a variety of methods for cystic duct dissection and ligation to avoid difficulties during the procedure. PMID- 27503576 TI - Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative. AB - BACKGROUND: The novel phenanthridinone derivative HA-719 has recently been identified as a highly potent and selective inhibitor of hepatitis C virus replication. To elucidate its mechanism of inhibition, we have isolated and analyzed a clone of hepatitis C virus replicon cells resistant to HA-719. METHODS: To isolate HA-719-resistant replicon cells, Huh-7 cells containing subgenomic hepatitis C virus replicons (genotype 1b) with a luciferase reporter (LucNeo#2) were cultured in the presence of G418 and escalating concentrations of HA-719. After several passages, total RNA was extracted from the growing cells, and Huh-7 cells were transfected with the extracted RNA. Limiting dilution of the transfected cells was performed to obtain an HA-719-resistant clone. RESULTS: The 50% effective concentration (EC50) of HA-719 for hepatitis C virus replication was 0.058 +/- 0.012 uM in LucNeo#2 cells. The replicon cells capable of growing in the presence of G418 and 3 uM HA-719 were obtained after 18 passages (72 days). The HA-719-resistant clone LucNeo719R showed 98.3-fold resistant to the compound (EC50 = 5.66 +/- 0.92 uM), but the clone had no cross-resistance to telaprevir (NS3 inhibitor), daclatasvir (NS5A inhibitor), and VX-222 (NS5B inhibitor). The sequence analysis for the wild-type and LucNeo719R identified 3, 2 and 7 mutations in NS3/4 A, NS4B, and NS5A, respectively, but no mutations in NS5B. CONCLUSION: None of the amino acid mutations in the resistant clone corresponds to those reported to confer drug-resistance to current anti-hepatitis C virus agents, suggesting that the target of HA-719 for hepatitis C virus inhibition differs from those of the existing agents. PMID- 27503577 TI - Melatonin decreases brain apoptosis, oxidative stress, and CD200 expression and increased survival rate in mice infected by Venezuelan equine encephalitis virus. AB - BACKGROUND: Pro-inflammatory and oxidative events during brain Venezuelan equine encephalitis virus infection could lead to apoptosis and induce anti-inflammatory responses (increased expression of CD200). The aim of this study was to determine the effect of melatonin on brain apoptosis, oxidative stress, and CD200 molecule in mice and neuroblastoma cultures infected by Venezuelan equine encephalitis virus. METHODS: Mice were infected with 10 median lethal doses (LD50) of Venezuelan equine encephalitis virus, treated with melatonin (500 ug/kg bw; three days before infection and during all experimental time) and sacrificed on days 1, 3, and 5 postinfection. Brain samples were obtained at those periods of time. In addition, infected neuroblastoma cell cultures (multiplicity of infection [MOI]: 1) were treated with 0, 0.1, 0.5, and 1 mM of melatonin and analyzed at 2, 4, and 6 h. CD200 and apoptosis expressions were analyzed by immunohistochemistry and TUNEL assay, respectively. Nitrites and malondialdehyde were determined by appropriate biochemical methods. RESULTS: Increased brain expression of apoptosis, nitrite, and malondialdehyde productions and CD200 of infected mice were found. Melatonin diminished those expressions. Similarly, high apoptosis expression and nitrite and malondialdehyde productions on infected neuroblastoma cultures were diminished by melatonin. Melatonin increased the survival rate (25%) in Venezuelan equine encephalitis virus-infected animals compared with untreated infected mice (0%). CONCLUSIONS: Neurological damage during brain Venezuelan equine encephalitis virus infection could be mediated by apoptosis and oxidative stress and CD200 molecule could be an important anti-inflammatory response. Melatonin could be beneficial reducing apoptosis and oxidative stress. PMID- 27503578 TI - Population differences in S-warfarin pharmacokinetics among African Americans, Asians and whites: their influence on pharmacogenetic dosing algorithms. AB - Using population pharmacokinetic analysis (PPK), we attempted to identify predictors of S-warfarin clearance (CL(S)) and to clarify population differences in S-warfarin pharmacokinetics among a cohort of 378 African American, Asian and white patients. Significant predictors of CL(S) included clinical (age, body weight and sex) and genotypic (CYP2C9*2,*3 and *8) factors, as well as African American ethnicity, the median CL(S) being 30% lower in the latter than in Asians and whites (170 versus 243 and 250 ml h-1, P<0.01). The plasma S-warfarin (Cp(S)) time courses following the genotype-based dosing algorithms simulated using the PPK estimates showed African Americans with CYP2C9*1/*1 and any of the VKORC1 genotypes would have an average Cp(S) at steady state 1.5-1.8 times higher than in Asians and whites. These results indicate warfarin dosing algorithms should be evaluated in each respective ethnic population. Further study of a large African American cohort will be necessary to confirm the present findings. PMID- 27503579 TI - Clinical relevance of EMT and stem-like gene expression in circulating tumor cells of metastatic colorectal cancer patients. AB - : Using approved methods, circulating tumor cells (CTCs) are only isolated from blood in 30%-50% of metastatic colorectal cancer (mCRC) patients. We previously validated a technique to isolate circulating tumor cells (CTCs) in a cohort of mCRC patients by combining immunomagnetic enrichment of EpCAM+/CD45- cells with qRT-PCR amplification of CK20 and survivin expression. Here, we examined the prognostic utility of CTC epithelial-mesenchymal transition (EMT) and stem cell gene expression. An 8 ml blood sample was collected from 78 consecutive mCRC patients before treatment with investigational and standard chemotherapeutics. The mRNA expression of EMT (PI3Kalpha, Akt-2, Twist1) and stem cell (ALDH1) markers was measured. Associations between CTC gene expression and progression free survival (PFS) and overall survival (OS) were determined using Cox regression models. Among patients without CK20 or survivin-expressing CTCs (n=17), 55% had expression of ALDH1, PI3Kalpha and/or Akt-2. Patients with positive CTC Akt-2 expression had a significantly shorter median PFS (3.0 versus 4.0 months) compared with those without CTC Akt-2 expression in univariable (hazard ratio (HR)=1.61; log-rank P=0.034) and multivariable analyses (HR=1.70; adjusted P=0.041). In univariable analysis, CTC ALDH1 expression was associated with shorter OS (10.0 versus 38.6 months; HR=2.04, P=0.021). Patients with CTCs expressing ALDH1, PI3Kalpha and/or Akt-2 had a significantly inferior PFS (3.0 versus 7.7 months; HR=1.88, P=0.015) and OS (10.0 versus 26.8+ months; HR=2.25, P=0.050) in univariable, but not multivariable, analysis. CONCLUSIONS: CTC Akt-2 expression may serve as a clinically useful prognostic marker in mCRC patients and warrants further evaluation in prospective trials. PMID- 27503580 TI - CXCR4 polymorphism predicts progression-free survival in metastatic colorectal cancer patients treated with first-line bevacizumab-based chemotherapy. AB - We analyzed associations between CXCR4/CXCL12 single-nucleotide polymorphisms and outcomes in metastatic colorectal cancer (mCRC) patients who underwent first-line bevacizumab-based chemotherapy. A total of 874 patients were included in this study: 144 treated with bevacizumab and FOLFOX or XELOX (training cohort), 653 treated with bevacizumab and FOLFIRI or FOLFOXIRI (validation cohort A or B) and 77 treated with cetuximab- and oxaliplatin-based regimens (control cohort). One CXCR4 polymorphism (rs2228014) and two CXCL12 polymorphisms (rs1801157 and rs3740085) were analyzed by PCR-based direct sequencing. Patients with a C/C genotype had a prolonged progression-free survival (PFS) compared with those with any T allele (P=0.030) in the training cohort. Similarly, patients with the C/C genotype had a superior PFS in the validation cohorts, but not in the control cohort. Our findings suggest that a common genetic variant, CXCR4 rs2228014, could predict PFS and may guide therapeutic decisions in mCRC patients receiving first-line bevacizumab-based chemotherapy. PMID- 27503581 TI - Irinotecan-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. AB - Irinotecan chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. This systematic review of systematic reviews synthesises all meta-analyses on biomarkers for irinotecan toxicity across all genetic models for Asians, Caucasians, low dose, medium/high dose and regimens with and without fluorouracil. False-positive findings are a problem in pharmacogenetics, increasing the importance of systematic reviews. Four systematic reviews that investigated the effect of the polymorphisms UGT1A1*6 and/or*28 on neutropenia or diarrhoea toxicity were included. Both UGT1A1*6 and *28 were reliably demonstrated to be risk factors for irinotecan induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. UGT1A1*6 and *28 were also related to diarrhoea toxicity; however, at low doses of irinotecan there was evidence that UGT1A1*28 was not. In synthesising the best available evidence, this umbrella systematic review provides a novel reference for clinicians applying personalised medicine and identifies important research gaps. PMID- 27503582 TI - Posterior Urethral Suspension During Robot-Assisted Radical Prostatectomy Improves Early Urinary Control: A Prospective Cohort Study. AB - PURPOSE: Early urinary control is a major goal for patients undergoing robot assisted radical prostatectomy (RARP). We report our technique of posterior urethral suspension (PUS) performed at the time of urethrovesical anastomosis. PATIENTS AND METHODS: We prospectively followed men with localized prostate cancer undergoing RARP by a single surgeon from August 2012 to October 2015. Patients before April 2014 underwent only bladder neck preservation (controls), while patients after April 2014 also underwent PUS. Patients were given a modified Expanded Prostate Cancer Index Composite questionnaire, along with questions depicting objective measures of urinary control (type of pad, number of pads, wetness of pad). Time points queried were preoperatively and postoperatively at weeks 1, 2, 4, and 12. Our primary outcome was pad-free survival. RESULTS: Questionnaire response rate was 52% (56/107) for controls and 43% (36/83) for PUS. There were no differences in baseline demographics, preoperative urinary control, intraoperative variables, or postoperative complications between groups. There were few subjective improvements in urinary control for PUS compared with controls. More notable, PUS patients had significantly improved objective measures of urinary control, including less protective incontinence products at 1 and 2 weeks after catheter removal (p < 0.03). They also wore fewer pads and had less leakage on each pad that lasted from week 1 to week 4 after catheter removal (p < 0.01). PUS patients had pad free rates of 37%, 47%, 54%, and 60% compared with controls 15%, 18%, 24%, and 36%, at weeks 1, 2, 4, and 12 after catheter removal (p = 0.07). CONCLUSION: PUS may improve objective measures of early urinary control compared with controls. With no increase in operative time and no change in complication rates, further work in a randomized setting would provide additional weight to our findings. PMID- 27503583 TI - J(Si,H) Coupling Constants in Nonclassical Transition-Metal Silane Complexes. AB - We will outline that the sign and magnitude of J(Si,H) coupling constants provide a highly sensitive tool to measure the extent of Si-H bond activation in nonclassical silane complexes. Up to now, this structure-property relationship was obscured by erroneous J(Si,H) sign determinations in the literature. These new findings also help to identify the salient control parameters of the Si-H bond activation process in nonclassical silane complexes. PMID- 27503585 TI - Conventional versus drug-eluting beads chemoembolization for hepatocellular carcinoma: Emphasis on the impact of tumor size. AB - BACKGROUND AND AIM: This study aims to evaluate clinical outcomes of patients with hepatocellular carcinoma who underwent transarterial chemoembolization (TACE) using drug-eluting beads (DEB). PATIENTS AND METHODS: This study retrospectively compared the clinical outcomes of 250 consecutive patients who underwent DEB-TACE (n = 106) or conventional TACE (cTACE) (n = 144) in a tertiary center between January 2010 and April 2014. The median age of the patients was 62 years and 81.6% were men. The primary endpoint was overall survival (OS). The time to progression (TTP), radiological response rate using modified response evaluation criteria in solid tumors criteria at 1 month after treatment, and complication rates within 1 month were also compared. RESULTS: The most common etiology was hepatitis B virus infection. The median index tumor size was 2.8 cm, and 150 (60.0%) patients had Barcelona Clinic Liver Cancer stage B. Median TTP in the cTACE group was longer than in the DEB-TACE group (13.3 vs10.8 months; P = 0.023). However, DEB-TACE and cTACE groups showed no significant differences for mean OS (46.6 vs 44.9 months; P = 0.660) and disease control rate at 1 month (78.3% vs 86.8%; P = 0.076). The OS, TTP, and disease control rate were also not different between two groups, even when subgrouped by index tumor size. The complication rates within 1 month were higher in the cTACE group (6.6% vs 14.6%; P = 0.048). CONCLUSIONS: Drug-eluting beads TACE appears to be a safe intra arterial therapy. However, it is not superior to cTACE in terms of efficacy. Tumor size might not be a criterion to select treatment modality between cTACE and DEB-TACE in terms of efficacy. PMID- 27503584 TI - Breast cancer cells alter the dynamics of stromal fibronectin-collagen interactions. AB - Breast cancer cells recruit surrounding stromal cells, such as cancer-associated fibroblasts (CAFs), to remodel their extracellular matrix (ECM) and promote invasive tumor growth. Two major ECM components, fibronectin (Fn) and collagen I (Col I), are known to interact with each other to regulate cellular behavior. In this study, we seek to understand how Fn and Col I interplay and promote a dysregulated signaling pathway to facilitate tumor progression. Specifically, we investigated the evolution of tumor-conditioned stromal ECM composition, structure, and relaxation. Furthermore, we assessed how evolving Fn-Col I interactions gradually affected pro-angiogenic signaling. Our data first indicate that CAFs initially assembled a strained, viscous, and unfolded Fn matrix. This early altered Fn matrix was later remodeled into a thick Col I-rich matrix that was characteristic of a dense tumor mass. Next, our results suggest that this ECM remodeling was primarily mediated by matrix metalloproteinases (MMPs). This MMP activity caused profound structural and mechanical changes in the developing ECM, which then modified vascular endothelial growth factor (VEGF) secretion by CAFs and matrix sequestration. Collectively, these findings enhance our understanding of the mechanisms by which Fn and Col I synergistically interplay in promoting a sustained altered signaling cascade to remodel the breast tumor stroma for invasive breast tumor growth. PMID- 27503586 TI - Brain enhancer activities at the gene-poor 5p14.1 autism-associated locus. AB - Due to the vast clinical and genetic heterogeneity, identification of causal genetic determinants for autism spectrum disorder (ASD) has proven to be complex. Whereas several dozen 'rare' genetic variants for ASD susceptibility have been identified, studies are still underpowered to analyse 'common' variants for their subtle effects. A recent application of genome-wide association studies (GWAS) to ASD indicated significant associations with the single nucleotide polymorphisms (SNPs) on chromosome 5p14.1, located in a non-coding region between cadherin10 (CDH10) and cadherin9 (CDH9). Here we apply an in vivo bacterial artificial chromosome (BAC) based enhancer-trapping strategy in mice to scan the gene desert for spatiotemporal cis-regulatory activities. Our results show that the ASD associated interval harbors the cortical area, striatum, and cerebellum specific enhancers for a long non-coding RNA, moesin pseudogene1 antisense (MSNP1AS) during the brain developing stages. Mouse moesin protein levels are not affected by exogenously expressed human antisense RNAs in our transgenic brains, demonstrating the difficulty in modeling rather smaller effects of common variants. Our first in vivo evidence for the spatiotemporal transcription of MSNP1AS however provides a further support to connect this intergenic variant with the ASD susceptibility. PMID- 27503588 TI - Vitamin K antagonists after all, or possibly not? PMID- 27503587 TI - Positive association between waist-to-height ratio and hypertension in adolescents. AB - INTRODUCTION: The obesity and overweight epidemic, together with increasing cardiovascular disease, represent a major public health problem worldwide, and their occurrence in childhood and adolescence has increased in recent decades. The objective of this study was to assess the association between waist-to-height ratio (WHR) and the incidence of hypertension in adolescents. METHODS: We performed a cross-sectional study of adolescents aged 10-17 years of both sexes attending municipal schools in inland Rio Grande do Sul, Brazil. Using a secondary database, weight and height measurements, blood pressure, and waist circumference (WC) were analyzed and body mass index (BMI) and WHR were calculated. Blood pressure was classified according to the Brazilian hypertension guidelines, BMI according to the curves of the World Health Organization, and WC according to Taylor et al. The cutoff used for WHR was 0.50 for both sexes. RESULTS: Of the 1030 adolescents studied, 29.6% (305) presented overweight/obesity and 30.4% (313) had hypertension; 24% (247) had high WC and 18.3% (189) presented high WHR. Participants with WHR >=0.50 were 2.4 times more likely to have hypertension than those with WHR <0.50 (OR 2.39; 95% CI 1.73-3.32; p<0.001). CONCLUSION: A positive association was found between WHR and the presence of hypertension in adolescents. PMID- 27503589 TI - Organization and implementation of a cardio-oncology program. AB - Considerable advances in cancer therapies in recent decades have reshaped the prognosis of cancer patients. There are now estimated to be over 20 million cancer survivors in the USA and Europe, numbers unimaginable a few years ago. However, this increase in survival, along with the aging of the patient population, has been accompanied by a rise in adverse cardiovascular effects, particularly when there is a previous history of heart disease. The incidence of cardiotoxicity continues to grow, which can compromise the effectiveness of cancer therapy. Cardiotoxicity associated with conventional therapies, especially anthracyclines and radiation, is well known, and usually leads to left ventricular dysfunction. However, heart failure represents only a fraction of the cardiotoxicity associated with newer therapies, which have diverse cardiovascular effects. There are few guidelines for early detection, prevention and treatment of cardiotoxicity of cancer treatments, and no well-established tools for screening these patients. Echocardiography is the method of choice for assessment of patients before, during and after cancer treatment. It therefore makes sense to adopt a multidisciplinary approach to these patients, involving cardiologists, oncologists and radiotherapists, collaborating in the development of new training modules, and performing clinical and translational research in a cardio-oncology program. Cardio-oncology is a new frontier in medicine and has emerged as a new medical subspecialty that concentrates knowledge, understanding, training and treatment of cardiovascular comorbidities, risks and complications in patients with cancer in a comprehensive approach to the patient rather than to the disease. PMID- 27503590 TI - The HIPOGAIA study: Monitoring of oral anticoagulation with vitamin K antagonists in the municipality of Gaia. AB - INTRODUCTION: Anticoagulant therapy is an effective measure in preventing thromboembolic adverse events. Of the diseases in which this treatment is indicated, atrial fibrillation (AF) has the highest incidence worldwide, with a prevalence of 1.5-2%. OBJECTIVES: To assess the quality of monitoring of patients with non-valvular AF under oral anticoagulation with vitamin K antagonists in Vila Nova de Gaia healthcare units. METHODS: This was a retrospective observational analytical study of the population registered at the 37 healthcare units of the Vila Nova de Gaia and Espinho health center area under oral anticoagulation with vitamin K antagonists during 2014. The data were collected using TAONet((r)) software. The variables studied were health units, age, gender, INR value, time in therapeutic range (TTR) and medication. TTR was calculated for each patient using the Rosendaal linear interpolation method. It was stipulated that each patient should have undergone at least six INR measurements. Data were analyzed using Microsoft Excel((r)) 2010 and SPSS((r)) version 21, using descriptive and inferential statistical techniques. RESULTS: A total of 479 patients with non-valvular AF were studied, corresponding to 5883 INR tests. Mean TTR was 67.4+/-6.5%, and 35.3% of patients exhibited poor control (TTR <60%). DISCUSSION: Our study showed moderate control of coagulation parameters, but better than in many international clinical trials and in another Portuguese observational study. Nevertheless, there is still room for improvement in anticoagulation monitoring in primary health care. PMID- 27503591 TI - Alcohol septal ablation in obstructive acromegalic hypertrophic cardiomyopathy - a first case report. AB - Acromegaly is a rare disease, mostly caused by a growth hormone (GH)-secreting benign pituitary tumor, with an increased production of GH and insulin-like growth factor 1 (IGF-1). Cardiovascular complications are common and are associated with cardiomyocyte apoptosis and concentric cardiac hypertrophy. Suppression of GH and IGF-1 appears to improve cardiac function only in the short term, with little or no decrease in left ventricular mass or improvement in cardiac function after prolonged treatment. Alcohol septal ablation (ASA) has emerged as a minimally invasive alternative to septal myectomy, with significant improvement in symptoms, gradients and left ventricular remodeling. In this report, we describe the case of a 73-year-old woman with acromegaly due to a pituitary adenoma diagnosed and treated surgically at the age of 38 but with recurrence and reoperation at the age of 50. She was referred to our cardiology department due to a three-month history of progressively worsening exercise induced dyspnea and orthopnea under optimal medical therapy. Echocardiography and magnetic resonance imaging revealed severe basal hypertrophy of the interventricular septum (19 mm), dynamic left ventricular outflow tract obstruction with a gradient of 70 mmHg at rest and 120 mmHg with Valsalva maneuver, and systolic anterior movement (SAM). Genetic testing excluded the most frequent forms of familial hypertrophic cardiomyopathy. ASA was performed with injection of 2 cc of alcohol in the first septal branch of the left coronary artery, without complications. At one-year reassessment, significant clinical and echocardiographic improvement was noted, with disappearance of SAM. To our knowledge, there have been no previously reported cases of ASA in hypertrophic cardiomyopathy due to acromegaly. We report a case of successful ASA in acromegalic cardiomyopathy. PMID- 27503592 TI - Intake of antioxidant nutrients and coefficients of variation in pregnant women with preeclampsia. AB - INTRODUCTION AND OBJECTIVE: Oxidative stress appears to play a critical role in the pathogenesis of preeclampsia. Evidence suggests that adequate intake of antioxidants can modulate this condition. The objective of this study was to assess the intake of antioxidant nutrients and coefficients of variation in pregnant women with preeclampsia. METHODS: In a cross-sectional study in the public health network of the city of Maceio, Brazil, a dietary survey was performed consisting of 24-hour food recalls, with subsequent adjustment of nutrients using the estimated average requirement as the cutoff point, and a questionnaire on frequency of consumption of antioxidants. RESULTS: We studied 90 pregnant women with preeclampsia (PWP) and 90 pregnant women without preeclampsia (PWoP) with mean ages of 25.8+/-6.7 years and 24.1+/-6.2 years (p=0.519), respectively. A low mean intake of antioxidants (vitamin A, selenium, zinc and copper) was observed in both PWP and PWoP, although intakes of vitamin A (p=0.045) and selenium (p=0.008) were higher in PWoP. In addition, we observed high coefficients of variation in nutrient intakes in both groups, which were higher for vitamin C (p<0.001), vitamin A (p=0.006) and copper (p=0.005) in PWP. CONCLUSIONS: Consumption of antioxidant nutrients by pregnant women with preeclampsia is inadequate, with considerable daily variations in intake, which points to a need for nutrition education strategies aimed at improving intakes, because diet is without doubt a key factor in the modulation of oxidative stress caused by preeclampsia. PMID- 27503593 TI - High prevalence of clade 8 Escherichia coli O157:H7 isolated from retail meat and butcher shop environment. AB - Escherichia coli O157:H7 is an enteric pathogen associated with food safety threats and with significant morbidity and mortality worldwide. In Argentina, post-enteric hemolytic uremic syndrome (HUS) is endemic, with >70% of cases associated with E. coli O157 infection. To date the biological basis behind the severity among E. coli O157 infections is unknown. However, single nucleotide polymorphism (SNP) typing has helped to define nine E. coli O157:H7 clades, of which clade 8 strains are associated with severe disease cases. The aim of this study was to characterize a collection of 20 STEC O157:H7 strains isolated between 2011 and 2013 from ground beef and different environmental samples from butcher shops of Argentina. All strains harbored the eae, ehxA, fliCH7, efa, iha, and toxB genes, with stx2a/stx2c as the predominant genotype (75%). The XbaI-PFGE analysis showed that the E. coli O157 strains had high genetic diversity. Nine strains were grouped in four XbaI-PFGE clusters, whereas 11 strains showed unique XbaI-PFGE patterns. In contrast, the SNP analysis allowed us to separate the strains in two distinct lineages representing clade 8 (70%) and clade 6 (30%). Our results show the molecular characterization of E. coli O157 strains isolated from ground beef and environmental samples from Argentinean butcher shops. PMID- 27503594 TI - Molecular characterisation and genetic variation of Elephant Endotheliotropic Herpesvirus infection in captive young Asian elephants in Thailand. AB - Elephant Endotheliotropic Herpesvirus (EEHV) is emerging as a new threat for elephant conservation, since being identified as the cause of severe, often fatal, haemorrhagic disease in young Asian elephants. To describe positive cases and the molecular relatedness of virus detected in elephants in Thailand, we re examined all available of EEHV samples occurring in young elephants in Thailand between 2006 and 2014 (n=24). Results indicated 75% (18/24) of suspected cases were positive for EEHV by semi-nested PCR. Further gene analysis identified these positive cases as EEHV1A (72%, 13/18 cases), EEHV1B (11%, 2/18) and EEHV4 (17%, 3/18). This study is the first to phylogenetically analyse and provide an overview of most of the known EEHV cases that have occurred in Thailand. Positive individuals ranged in age from one to nine years, with no sex association detected, and occurred across geographical locations throughout the country. All individuals, except one, were captive-born. No history of direct contact among the cases was recorded, and this together with the fact that various subtype clusters of virus were found, implied that none of the positive cases were epidemiologically related. These results concur with the hypothesis that EEHV1 is likely to be an ancient endogenous pathogen in Asian elephants. It is recommended that active surveillance and routine monitoring for EEHV should be undertaken in all elephant range countries, to gain a better understanding of the epidemiology, transmission and prevention of this disease. PMID- 27503595 TI - Identification of vaginal bacteria diversity and it's association with clinically diagnosed bacterial vaginosis by denaturing gradient gel electrophoresis and correspondence analysis. AB - Bacterial vaginosis (BV) is a common complex associated with numerous adverse health outcomes, affecting women of different ages throughout the world. The etiology of BV remains poorly understood due to the difficulty of establishing a molecular genetic criterion to recognize the vaginal microbiota of BV-positive women from that of the normal women. We used techniques of broad-range PCR-DGGE and gel imaging analysis system cooperated with 16S rRNA gene sequencing and statistical analysis to investigate the community structure of the healthy and BV affected vaginal microbial ecosystems. The community of vaginal bacteria detected in subjects with BV was far more luxuriant and diverse than in subjects without BV. The mean number of microbial species in 128 BV-positive women was nearly two times greater than in 68 subjects without BV(4.05+/-1.96 versus 2.59+/-1.14). Our sequencing efforts yielded many novel phylotypes (198 of our sequences represented 59 species), including several novel BV-associated bacteria (BVAB) and many belonging to opportunistic infections, which remain inexplicable for their roles in determining the health condition of vaginal microflora. This study identifies Algoriphagus aquatilis, Atopobium vaginae, Burkholderia fungorum, Megasphaera genomosp species as indicators to BV and subjects with BV harbor particularly taxon-rich and diverse bacterial communities. Maybe Bifidobacterium, Staphylococcus or even more alien species are commensal creatures in normal vaginal microbiota. PMID- 27503596 TI - Nutrition and health claims on healthy and less-healthy packaged food products in New Zealand. AB - Nutrition and health claims are displayed to influence consumers' food choices. This study assessed the extent and nature of nutrition and health claims on the front-of-pack of 'healthy' and 'less-healthy' packaged foods in New Zealand. Foods from eight categories, for which consumption may affect the risk of obesity and diet-related chronic diseases, were selected from the 2014 Nutritrack database. The internationally standardised International Network for Food and Obesity/Non-Communicable Diseases Research, Monitoring and Action Support (INFORMAS) taxonomy was used to classify claims on packages. The Nutrient Profiling Scoring Criterion (NPSC) was used to classify products as 'healthy' or 'less healthy'. In total, 7526 products were included, with 47 % (n 3557) classified as 'healthy'. More than one-third of products displayed at least one nutrition claim and 15 % featured at least one health claim on the front-of-pack. Claims were found on one-third of 'less-healthy' products; 26 % of those products displayed nutrition claims and 7 % featured health claims. About 45 % of 'healthy' products displayed nutrition claims and 23 % featured health claims. Out of 7058 individual claims, the majority (69 %) were found on 'healthy' products. Cereals displayed the greatest proportion of nutrition and health claims (1503 claims on 564 products), of which one-third were displayed on 'less healthy' cereals. Such claims could be misleading consumers' perceptions of nutritional quality of foods. It needs to be explored how current regulations on nutrition and health claims in New Zealand could be further strengthened (e.g. using the NPSC for nutrition claims, including general health claims as per the INFORMAS taxonomy) to ensure consumers are protected and not misled. PMID- 27503598 TI - Signatures of selection and host-adapted gene expression of the Phytophthora infestans RNA silencing suppressor PSR2. AB - Phytophthora infestans is a devastating pathogen in agricultural systems. Recently, an RNA silencing suppressor (PSR2, 'Phytophthora suppressor of RNA silencing 2') has been described in P. infestans. PSR2 has been shown to increase the virulence of Phytophthora pathogens on their hosts. This gene is one of the few effectors present in many economically important Phytophthora species. In this study, we investigated: (i) the evolutionary history of PSR2 within and between species of Phytophthora; and (ii) the interaction between sequence variation, gene expression and virulence. In P. infestans, the highest PiPSR2 expression was correlated with decreased symptom expression. The highest gene expression was observed in the biotrophic phase of the pathogen, suggesting that PSR2 is important during early infection. Protein sequence conservation was negatively correlated with host range, suggesting host range as a driver of PSR2 evolution. Within species, we detected elevated amino acid variation, as observed for other effectors; however, the frequency spectrum of the mutations was inconsistent with strong balancing selection. This evolutionary pattern may be related to the conservation of the host target(s) of PSR2 and the absence of known corresponding R genes. In summary, our study indicates that PSR2 is a conserved effector that acts as a master switch to modify plant gene regulation early during infection for the pathogen's benefit. The conservation of PSR2 and its important role in virulence make it a promising target for pathogen management. PMID- 27503597 TI - Variable proopiomelanocortin expression in tanycytes of the adult rat hypothalamus and pituitary stalk. AB - It is generally believed that proopiomelanocortin (POMC) is expressed exclusively by neurons in the adult rodent brain. Unbeknownst to most researchers, however, Pomc in situ hybridization studies in the rat show specific labeling in the ventral wall of the hypothalamic third ventricle, which is formed by specialized ependymal cells, called tanycytes. Here we characterized this non-neuronal POMC expression in detail using in situ hybridization and immunohistochemical techniques, and report two unique characteristics. First, POMC mRNA and precursor protein expression in non-neuronal cells varies to a great degree as to the extent and abundance of expression. In brains with low-level expression, POMC mRNA and protein was largely confined to a population of tanycytes within the infundibular stalk/caudal median eminence, termed here gamma tanycytes, and a subset of closely located beta and alpha2 tanycytes. In brains with high-level expression, POMC mRNA and protein was observed in the vast majority of alpha2, beta, and gamma tanycytes. This variability was observed in both adult males and females; of 41 rats between 8 and 15 weeks of age, 17 had low-, 9 intermediate-, and 15 high-level POMC expression in tanycytes. Second, unlike other known POMC expressing cells, tanycytes rarely contained detectable levels of adrenocorticotropin or alpha-melanocyte-stimulating hormone. The results indicate either a dynamic spatiotemporal pattern whereby low and high POMC syntheses in tanycytes occur periodically in each brain, or marked interindividual differences that may persist throughout adulthood. Future studies are required to examine these possibilities and elucidate the physiologic importance of POMC in tanycytes. J. Comp. Neurol. 525:411-441, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27503599 TI - BSHI Guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation. AB - A review of the British Society for Histocompatibility and Immunogenetics (BSHI) "Guideline for selection and HLA matching of related, adult unrelated donors and umbilical cord units for haematopoietic progenitor cell transplantation" was undertaken by a BSHI appointed writing committee. Literature searches were performed, and the data extracted were presented as recommendations according to the GRADE nomenclature. PMID- 27503601 TI - Sleep, rhythms and metabolism: too many links to be ignored. PMID- 27503600 TI - Performance evaluation of a rapid whole-blood immunoassay for the detection of IgG antibodies against Helicobacter pylori in daily clinical practice. AB - BACKGROUND: A growing number of rapid Helicobacter pylori antibody tests are commercially available now, however, some of these tests are often used without sufficient evaluation. The aim of this study was to evaluate the performance of a commercially available rapid whole-blood immunoassay (gabControl((r)) H. pylori; gabmed GmbH, Koln, Germany), for the qualitative detection of IgG antibodies against H. pylori with the (13)C-urea breath test ((13)C-UBT) serving as a reference method. METHODS: A total of 108 consecutive outpatients, who were referred for (13)C-UBT by general practitioners and specialists, were also tested for H. pylori infection by the gabControl((r)) H. pylori immunoassay. The clinical performance of this rapid whole-blood test was evaluated by determining the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) compared to the (13)C-UBT. The agreement between the two tests was calculated using Cohen's Kappa (kappa) with 95 % confidence intervals (CI). RESULTS: The agreement between the gabControl((r)) H. pylori assay and the (13)C-UBT was 0.62 [95 % confidence intervals (CIs) 0.47-0.76; P < 0.001]. With the (13)C-UBT serving as the non-invasive gold standard method of H. pylori diagnosis, the gabControl((r)) H. pylori assay demonstrated a sensitivity and specificity of 91.4 and 76.7 %, respectively, with a PPV of 65.3 % and a NPV of 94.9 %. Seventeen (15.7 %) individuals with a positive H. pylori anamnesis showed a negative (13)C-UBT and were typed positive by the gabControl((r)) H. pylori assay. Of these, 13 (76.5 %) and 3 individuals (17.6 %) had completed one and two eradication therapies, respectively. CONCLUSIONS: The gabControl((r)) H. pylori immunoassay is a rapid and easy to use first line screening tool for H. pylori IgG antibody detection in daily clinical practice. However, this assay should not be used for confirmation of the successful H. pylori eradication after antibiotic treatment. PMID- 27503602 TI - Vacuolar Chloride Fluxes Impact Ion Content and Distribution during Early Salinity Stress. AB - The ability to control the cytoplasmic environment is a prerequisite for plants to cope with changing environmental conditions. During salt stress, for instance, Na+ and Cl- are sequestered into the vacuole to help maintain cytosolic ion homeostasis and avoid cellular damage. It has been observed that vacuolar ion uptake is tied to fluxes across the plasma membrane. The coordination of both transport processes and relative contribution to plant adaptation, however, is still poorly understood. To investigate the link between vacuolar anion uptake and whole-plant ion distribution during salinity, we used mutants of the only vacuolar Cl- channel described to date: the Arabidopsis (Arabidopsis thaliana) ALMT9. After 24-h NaCl treatment, almt9 knock-out mutants had reduced shoot accumulation of both Cl- and Na+ In contrast, almt9 plants complemented with a mutant variant of ALMT9 that exhibits enhanced channel activity showed higher Cl- and Na+ accumulation. The altered shoot ion contents were not based on differences in transpiration, pointing to a vacuolar function in regulating xylem loading during salinity. In line with this finding, GUS staining demonstrated that ALMT9 is highly expressed in the vasculature of shoots and roots. RNA-seq analysis of almt9 mutants under salinity revealed specific expression profiles of transporters involved in long-distance ion translocation. Taken together, our study uncovers that the capacity of vacuolar Cl- loading in vascular cells plays a crucial role in controlling whole-plant ion movement rapidly after onset of salinity. PMID- 27503605 TI - 'Remind-to-move' treatment versus constraint-induced movement therapy for children with hemiplegic cerebral palsy: a randomized controlled trial. AB - AIM: To evaluate 'remind-to-move' (RTM) treatment by comparing it with constraint induced movement therapy (CIMT) and conventional rehabilitation of the upper extremity in children with hemiplegic cerebral palsy (CP). METHOD: Seventy-three children (44 males, 29 females; mean age 11y 8mo, standard deviation [SD] 3y 1mo) - with 20, 38, and 15 in Manual Ability Classification System levels I, II, and III respectively - were recruited from three special schools and randomly selected for an RTM (n=25) or CIMT (n=24) programme (for 75h over 3wks) or for conventional rehabilitation (n=24). The Jebsen-Taylor Hand Function Test, the Bruininks-Oseretsky Test of Motor Proficiency (Subtest 3), the Caregiver Functional Use Survey, and arm movement duration captured by accelerometers were used at the baseline, post-test, and 1-month and 3-month follow-ups. RESULTS: Both the RTM and CIMT treatments achieved significant gains in manual capacities and spontaneous hand use immediately after the intervention compared with conventional rehabilitation, but there were no significant differences between the two interventions. INTERPRETATION: The RTM treatment demonstrated similar therapeutic effects with CIMT in manual dexterity and functional hand use, but both interventions were superior to conventional rehabilitation. RTM is recommended as an alternative treatment for the hemiplegic upper extremity in children with CP. PMID- 27503603 TI - Glutaredoxin GRXS17 Associates with the Cytosolic Iron-Sulfur Cluster Assembly Pathway. AB - Cytosolic monothiol glutaredoxins (GRXs) are required in iron-sulfur (Fe-S) cluster delivery and iron sensing in yeast and mammals. In plants, it is unclear whether they have similar functions. Arabidopsis (Arabidopsis thaliana) has a sole class II cytosolic monothiol GRX encoded by GRXS17 Here, we used tandem affinity purification to establish that Arabidopsis GRXS17 associates with most known cytosolic Fe-S assembly (CIA) components. Similar to mutant plants with defective CIA components, grxs17 loss-of-function mutants showed some degree of hypersensitivity to DNA damage and elevated expression of DNA damage marker genes. We also found that several putative Fe-S client proteins directly bind to GRXS17, such as XANTHINE DEHYDROGENASE1 (XDH1), involved in the purine salvage pathway, and CYTOSOLIC THIOURIDYLASE SUBUNIT1 and CYTOSOLIC THIOURIDYLASE SUBUNIT2, both essential for the 2-thiolation step of 5-methoxycarbonylmethyl-2 thiouridine (mcm5s2U) modification of tRNAs. Correspondingly, profiling of the grxs17-1 mutant pointed to a perturbed flux through the purine degradation pathway and revealed that it phenocopied mutants in the elongator subunit ELO3, essential for the mcm5 tRNA modification step, although we did not find XDH1 activity or tRNA thiolation to be markedly reduced in the grxs17-1 mutant. Taken together, our data suggest that plant cytosolic monothiol GRXs associate with the CIA complex, as in other eukaryotes, and contribute to, but are not essential for, the correct functioning of client Fe-S proteins in unchallenged conditions. PMID- 27503604 TI - Chronic Iron Limitation Confers Transient Resistance to Oxidative Stress in Marine Diatoms. AB - Diatoms are single-celled, photosynthetic, bloom-forming algae that are responsible for at least 20% of global primary production. Nevertheless, more than 30% of the oceans are considered "ocean deserts" due to iron limitation. We used the diatom Phaeodactylum tricornutum as a model system to explore diatom's response to iron limitation and its interplay with susceptibility to oxidative stress. By analyzing physiological parameters and proteome profiling, we defined two distinct phases: short-term (<3 d, phase I) and chronic (>5 d, phase II) iron limitation. While at phase I no significant changes in physiological parameters were observed, molecular markers for iron starvation, such as Iron Starvation Induced Protein and flavodoxin, were highly up-regulated. At phase II, down regulation of numerous iron-containing proteins was detected in parallel to reduction in growth rate, chlorophyll content, photosynthetic activity, respiration rate, and antioxidant capacity. Intriguingly, while application of oxidative stress to phase I and II iron-limited cells similarly oxidized the reduced glutathione (GSH) pool, phase II iron limitation exhibited transient resistance to oxidative stress, despite the down regulation of many antioxidant proteins. By comparing proteomic profiles of P. tricornutum under iron limitation and metatranscriptomic data of an iron enrichment experiment conducted in the Pacific Ocean, we propose that iron-limited cells in the natural environment resemble the phase II metabolic state. These results provide insights into the trade-off between optimal growth rate and susceptibility to oxidative stress in the response of diatoms to iron quota in the marine environment. PMID- 27503606 TI - Alginate Sulfate-Nanocellulose Bioinks for Cartilage Bioprinting Applications. AB - One of the challenges of bioprinting is to identify bioinks which support cell growth, tissue maturation, and ultimately the formation of functional grafts for use in regenerative medicine. The influence of this new biofabrication technology on biology of living cells, however, is still being evaluated. Recently we have identified a mitogenic hydrogel system based on alginate sulfate which potently supports chondrocyte phenotype, but is not printable due to its rheological properties (no yield point). To convert alginate sulfate to a printable bioink, it was combined with nanocellulose, which has been shown to possess very good printability. The alginate sulfate/nanocellulose ink showed good printing properties and the non-printed bioink material promoted cell spreading, proliferation, and collagen II synthesis by the encapsulated cells. When the bioink was printed, the biological performance of the cells was highly dependent on the nozzle geometry. Cell spreading properties were maintained with the lowest extrusion pressure and shear stress. However, extruding the alginate sulfate/nanocellulose bioink and chondrocytes significantly compromised cell proliferation, particularly when using small diameter nozzles and valves. PMID- 27503608 TI - In vivo assessment of periodontal structures and measurement of gingival sulcus with Optical Coherence Tomography: a pilot study. AB - There has been increasing interest on the development of clinically acceptable, more sensitive and specific methods for non-invasive diagnosis in Periodontics. In this pilot study, the performance of an Optical Coherence Tomography (OCT) system in imaging periodontal structures in humans was evaluated. Gingival sulcus depth measurements were obtained and compared with traditional probes. In total, 445 sites of 23 periodontally healthy individuals were measured by 3 instruments: North Carolina manual probe, Florida automated probe and OCT at 1325 nm. To obtain quantitative measurements from OCT images, the gingival refractive index was also determined. Discomfort/pain perception and the duration of examinations were compared among the instruments. The analysis of OCT images allowed the identification of relevant anatomic dental and periodontal regions. The average sulcus depth measured by OCT, 0.85 +/- 0.27 mm and 0.87 +/- 0.28 mm, was lower than the values obtained by manual and automated probing. Discomfort/pain were prevalent for traditional probes, which are invasive methods, than for the non invasive OCT technique. OCT has the potential to be a reliable tool for in vivo periodontal tissues evaluation and for reproducible sulcus depth measurements in healthy sites. Further technological advances are required to reduce the procedure time and promote evaluation of posterior oral regions. Photonic assessment of periodontal tissue with OCT (top) in a clinical environment, showing tooth/gingiva features (bottom). PMID- 27503607 TI - Protease-Responsive Prodrug with Aggregation-Induced Emission Probe for Controlled Drug Delivery and Drug Release Tracking in Living Cells. AB - Controlled drug delivery and real-time tracking of drug release in cancer cells are essential for cancer therapy. Herein, we report a protease-responsive prodrug (DOX-FCPPs-PyTPE, DFP) with aggregation-induced emission (AIE) characteristics for controlled drug delivery and precise tracking of drug release in living cells. DFP consists of three components: AIE-active tetraphenylethene (TPE) derivative PyTPE, functionalized cell penetrating peptides (FCPPs) containing a cell penetrating peptide (CPP) and a short protease-responsive peptide (LGLAG) that can be selectively cleaved by a cancer-related enzyme matrix metalloproteinase-2 (MMP-2), and a therapeutic unit (doxorubicin, DOX). Without MMP-2, this prodrug cannot go inside the cells easily. In the presence of MMP-2, DFP can be cleaved into two parts. One is cell penetrating peptides (CPPs) linked DOX, which can easily interact with cell membrane and then go inside the cell with the help of CPPs. Another is the PyTPE modified peptide which will self aggregate because of the hydrophobic interaction and turn on the yellow fluorescence of PyTPE. The appearance of the yellow fluorescence indicates the release of the therapeutic unit to the cells. The selective delivery of the drug to the MMP-2 positive cells was also confirmed by using the intrinsic red fluorescence of DOX. Our result suggests a new and promising method for controlled drug delivery and real-time tracking of drug release in MMP-2 overexpression cells. PMID- 27503609 TI - Practice-induced and sequential modulations in the Simon task: evidence from pupil dilation. AB - Recent evidence showed that pupil dilation (PD) reflects modulations in the magnitude of the Simon interference effect due to correspondence sequence. In the present study we used this measure to assess whether these modulations, thought to result from cognitive control mechanisms, are influenced by prior practice with an incompatible stimulus-response (S-R) mapping. To this end, PD and reaction times (RTs) were recorded while participants performed a Simon task before and after executing a spatially incompatible practice. The sequential analysis revealed that PD mirrored the conflict-adaptation pattern observed in RTs. Crucially, sequential modulations were not affected by prior practice. These findings support the view that the modulations of the Simon effect due to prior practice and those due to correspondence sequence result from two different mechanisms, and suggest that PD can help to better understand the mechanisms underlying response selection and cognitive control in the Simon task. PMID- 27503610 TI - Ferromagnetic particles as magnetic resonance imaging temperature sensors. AB - Magnetic resonance imaging is an important technique for identifying different types of tissues in a body or spatial information about composite materials. Because temperature is a fundamental parameter reflecting the biological status of the body and individual tissues, it would be helpful to have temperature maps superimposed on spatial maps. Here we show that small ferromagnetic particles with a strong temperature-dependent magnetization, can be used to produce temperature-dependent images in magnetic resonance imaging with an accuracy of about 1 degrees C. This technique, when further developed, could be used to identify inflammation or tumours, or to obtain spatial maps of temperature in various medical interventional procedures such as hyperthermia and thermal ablation. This method could also be used to determine temperature profiles inside nonmetallic composite materials. PMID- 27503611 TI - Polygonibacillus indicireducens gen. nov., sp. nov., an indigo-reducing and obligate alkaliphile isolated from indigo fermentation liquor for dyeing. AB - Obligately alkaliphilic and halophilic strains, designated In2-9T and D2-7, were isolated from a fermented Polygonum indigo (Polygonum tinctorium Lour.) liquor sample obtained from a craft centre in Date City, Hokkaido, Japan. The 16S rRNA gene sequence phylogeny suggested that strain In2-9T is a member of the genus Bacillus with the closest relatives being the alkaliphilic species of the genus Bacillus, Bacillus hemicellulosilyticusJCM 9152T (96.4 % 16S rRNA gene sequence similarity) and Bacillus alcalophilus DSM 485T (96.5 %). Cells of the isolate stained Gram-positive and were facultatively anaerobic straight rods that were motile by peritrichous flagella. Strain In2-9T grew between 13 and 45 degrees C with optimum growth at approximately 35-37 degrees C. The isolates grew in the pH range of 8-12 with optimum growth at pH 10. The isoprenoid quinone detected was menaquinone-6 (MK-6) and the DNA G+C content was 39.4 mol%. The whole-cell fatty acid profile mainly (>10 %) consisted of iso-C15 : 0, anteiso-C15 : 0 and C16 : 0. Spore shape and location and chemotaxonomic characteristics revealed that the isolates were distinctly different from phylogenetic neighbouring alkaliphilic species of the genus Bacillus. On the basis of phenotypic and chemotaxonomic characteristics and phylogenetic data, the isolates represent a novel species of a new genus, for which the name Polygonibacillusindicireducens gen. nov., sp. nov. is proposed. The type strain of the type species is In2-9T (=JCM 30831T=NCIMB 14982T), and strain D2-7 is an additional strain of the species. PMID- 27503612 TI - Oestrogen-containing contraceptive pills increase vitamin D levels, study finds. PMID- 27503615 TI - [Long-term complications after appendectomy]. PMID- 27503613 TI - Cardiolipin deficiency causes a dissociation of the b 6 c:caa 3 megacomplex in B. subtilis membranes. AB - The associations among respiratory complexes in energy-transducing membranes have been established. In fact, it is known that the Gram-negative bacteria Paracoccus denitrificans and Escherichia coli have respiratory supercomplexes in their membranes. These supercomplexes are important for channeling substrates between enzymes in a metabolic pathway, and the assembly of these supercomplexes depends on the protein subunits and membrane lipids, mainly cardiolipin, which is present in both the mitochondrial inner membrane and bacterial membranes. The Gram positive bacterium Bacillus subtilis has a branched respiratory chain, in which some complexes generate proton motive force whereas others constitute an escape valve of excess reducing power. Some peculiarities of this respiratory chain are the following: a type II NADH dehydrogenase, a unique b 6 c complex that has a b 6 type cytochrome with a covalently bound heme, and a c-type heme attached to the third subunit, which is similar to subunit IV of the photosynthetic b 6 f complex. Cytochrome c oxygen reductase (caa 3 ) contains a c-type cytochrome on subunit I. We previously showed that the b 6 c and the caa 3 complexes form a supercomplex. Both the b 6 c and the caa 3 together with the quinol oxygen reductase aa 3 generate the proton motive force in B. subtilis. In order to seek proof that this supercomplex is important for bacterial growth in aerobic conditions we compared the b 6 c: caa 3 supercomplex from wild type membranes with membranes from two mutants lacking cardiolipin. Both mutant complexes were found to have similar activity and heme content as the wild type. Clear native electrophoresis showed that mutants lacking cardiolipin had b 6 c:caa 3 supercomplexes of lower mass or even individual complexes after membrane solubilization with digitonin. The use of dodecyl maltoside revealed a more evident difference between wild-type and mutant supercomplexes. Here we provide evidence showing that cardiolipin plays a role in the stability of the b 6 c:caa 3 supercomplex in B. subtilis. PMID- 27503614 TI - Fish Oil and Microalga Omega-3 as Dietary Supplements: A Comparative Study on Cardiovascular Risk Factors in High-Fat Fed Rats. AB - Dietary supplementation with marine omega-3 polyunsaturated fatty acids (n-3 PUFA) can have beneficial effects on a number of risk factors for cardiovascular disease (CVD). We compared the effects of two n-3 PUFA rich food supplements (freeze-dried Odontella aurita and fish oil) on risk factors for CVD. Male rats were randomly divided into four groups of six animals each and fed with the following diets: control group (C) received a standard diet containing 7 % lipids; second group (HF high fat) was fed with a high-fat diet containing 40 % lipids; third group (HFFO high fat+fish oil) was fed with the high-fat diet supplemented with 0.5 % fish oil; and fourth group (HFOA high fat+O. aurita) received the high-fat diet supplemented with 12 % of freeze-dried O. aurita. After 8 weeks rats fed with the high-fat diet supplemented with O. aurita displayed a significantly lower bodyweight than those in the other groups. Both the microalga and the fish oil significantly reduced insulinemia and serum lipid levels. O. aurita was more effective than the fish oil in reducing hepatic triacyglycerol levels and in preventing high-fat diet-induced steatosis. O. aurita and fish oil also reduced platelet aggregation and oxidative status induced by high fat intake. After an OA supplementation, the adipocytes in the HFOA group were smaller than those in the HF group. Freeze-dried O. aurita showed similar or even greater biological effects than the fish oil. This could be explained by a potential effect of the n-3 PUFA but also other bioactive compounds of the microalgae. PMID- 27503616 TI - [Intraoperative ERCP versus laparoscopic bile duct exploration for treatment of choledocholithiasis]. PMID- 27503617 TI - [Antibiotic treatment versus appendectomy for non-perforated appendicitis : Results of a meta-analysis]. PMID- 27503618 TI - [Extensive hepatopancreaticobiliary resections including arterial reconstruction for advanced cholangiocarcinoma]. PMID- 27503619 TI - Hyaluronic acid injection via a pneumatic microjet device to improve forehead wrinkles. PMID- 27503620 TI - In vivo uteroplacental release of placental growth factor and soluble Fms-like tyrosine kinase-1 in normal and preeclamptic pregnancies. AB - BACKGROUND: Preeclampsia is characterized by maternal endothelial dysfunction, which underlies a highly diverse clinical presentation. The pathophysiologic condition remains to be unraveled fully, but interplay between factors that are released from the placenta and maternal vascular vulnerability is likely. An imbalance in circulating angiogenic factors is a prominent feature of preeclampsia; placental growth factor and soluble Fms-like tyrosine kinase 1 have been implemented as biomarkers of placental function and preeclampsia. Their test accuracies are limited in a clinical setting, which urges better insight into their production and removal. Current data suggest that placental growth factor and soluble Fms-like tyrosine kinase 1 are released from the placenta. Both the circulating levels and the placental expression are altered in preeclamptic pregnancies. However, in vivo placental release has not been determined in human pregnancies. Moreover, there is evidence that extra-placental tissues might contribute to the circulating levels placental growth factor and soluble Fms-like tyrosine kinase 1 in normal and preeclamptic pregnancies. OBJECTIVES: We aimed to study the in vivo placental release of placental growth factor and soluble Fms like tyrosine kinase 1 by determining the uteroplacental arteriovenous differences in human pregnancies. Further, we investigated whether this release was altered in early-onset preeclampsia compared with control subjects and whether there was a release of placental growth factor and soluble Fms-like tyrosine kinase 1 from maternal systemic endothelium. STUDY DESIGN: We conducted a case-control study at Oslo University Hospital and included 23 women with preeclampsia (diagnosis <34 weeks) and 20 control subjects. During cesarean delivery, we sampled blood from 3 vessels simultaneously (uterine vein, radial artery, and antecubital vein). We determined concentrations of placental growth factor and soluble Fms-like tyrosine kinase 1 and calculated the arteriovenous differences. A possible net placental and extra-placental release was evaluated with the use of a Wilcoxon signed rank test. Differences between groups were compared by a Mann-Whitney U-test. RESULTS: The median gestational age at delivery was 33.4 weeks (Q1, 28.3; Q3, 34.4 weeks) in the preeclamptic group and 39.3 weeks (Q1, 39.0; Q3, 39.6 weeks) in the control subjects. Women with preeclampsia had lower plasma concentrations of placental growth factor and higher concentrations of soluble Fms-like tyrosine kinase 1 compared with control subjects (P<.001). There were significant uteroplacental arteriovenous differences of soluble Fms-like tyrosine kinase 1 in preeclampsia (P<.001), but not in the control subjects. The uteroplacental arteriovenous differences of placental growth factor were significant in both groups (P<.001). Despite lower concentrations of plasma placental growth factor in women with preeclampsia, the arteriovenous differences were not significantly different from normal pregnancies (P=.53), even when we corrected for placental weight (P=.79). We found no placental growth factor or soluble Fms-like tyrosine kinase 1 concentration differences between the radial artery and the antecubital vein. CONCLUSION: Our findings are consistent with a net release of soluble Fms-like tyrosine kinase 1 from the placenta in early-onset preeclampsia. This study demonstrated a placental release of placental growth factor to the maternal circulation but could not demonstrate that this release was impaired in the preeclamptic group. We could not find evidence of systemic endothelial release of placental growth factor and soluble Fms-like tyrosine kinase 1 by analyzing the arteriovenous differences in the forearm. This study contributes to the pathophysiologic understanding of preeclampsia by the use of the clinical setting to test current concepts in vivo and underscores that studies of in vivo degradation rates of placentally released compounds are needed. PMID- 27503621 TI - First evidence of a menstruating rodent: the spiny mouse (Acomys cahirinus). AB - BACKGROUND: Advances in research relating to menstruation and associated disorders (eg, endometriosis and premenstrual syndrome) have been hindered by the lack of an appropriate animal model. Menstruation, the cyclical shedding of the decidualized endometrium in the absence of pregnancy, is believed to be limited to 78 higher-order primates (human beings and Old World monkeys), 4 species of bat, and the elephant shrew. This represents only 1.5% of the known 5502 mammalian species and <0.09% of these are nonprimates. Thus, many aspects of menstruation remain poorly understood, limiting the development of effective treatments for women with menstrual disorders. Menstruation occurs as a consequence of progesterone priming of the endometrial stroma and a spontaneous decidual reaction. At the end of each infertile cycle as progesterone levels decline the uterus is unable to maintain this terminally differentiated stroma and the superficial endometrium is shed. True menstruation has never been reported in rodents. OBJECTIVE: Here we describe the first observation of menstruation in a rodent, the spiny mouse (Acomys cahirinus). STUDY DESIGN: Virgin female spiny mice (n = 14) aged 12-16 weeks were sampled through daily vaginal lavage for 2 complete reproductive cycles. Stage-specific collection of reproductive tissue and plasma was used for histology, prolactin immunohistochemistry, and enzyme-linked immunosorbent assay of progesterone (n = 4-5/stage of the menstrual cycle). Normally distributed data are reported as the mean +/- SE and significant differences calculated using a 1-way analysis of variance. Nonnormal data are displayed as the median values of replicates (with interquartile range) and significant differences calculated using Kruskal-Wallis test. RESULTS: Mean menstrual cycle length was 8.7 +/- 0.4 days with red blood cells observed in the lavages over 3.0 +/- 0.2 days. Cyclic endometrial shedding and blood in the vaginal canal concluding with each infertile cycle was confirmed in all virgin females. The endometrium was thickest during the luteal phase at 322.6 MUm (254.8, 512.2), when plasma progesterone peaked at 102.1 ng/mL (70.1, 198.6) and the optical density for prolactin immunoreactivity was strongest (0.071 +/- 0.01 arbitrary units). CONCLUSION: The spiny mouse undergoes spontaneous decidualization, demonstrating for the first time menstruation in a rodent. The spiny mouse provides a readily accessible nonprimate model to study the mechanisms of menstrual shedding and repair, and may therefore be useful in furthering studies of human menstrual and pregnancy-associated disorders. PMID- 27503622 TI - Low self-awareness of osteoporosis and fracture risk among postmenopausal women. AB - Postmenopausal women with a high risk of fractures may not perceive their risk. This study showed no concordance between the perceived and calculated risk of fracture. Almost 80 % of the women identified as a high risk of fracture by the FRAX algorithm tool perceived themselves to have little risk. PURPOSE: This study aimed to assess the concordance between self-perception of osteoporosis and fracture risk and the 10-year risk of fractures calculated by the FRAX algorithm. METHODS: A cross-sectional study was conducted in Santa Maria, RS, Brazil, between March 1 and August 31, 2013. Postmenopausal women over 55 years of age who have had at least one appointment at primary care in the 2 years prior to the enrolment were recruited. We excluded women with cognitive impairment. A standardized questionnaire regarding the perception of personal risk of osteoporosis and fractures was used. We also evaluated previous fractures, family history of fracture, smoking, alcohol consumption, use of glucocorticoids, and secondary causes of osteoporosis. Weight and height of the participants were measured. The risk of fractures of each participant was calculated using the FRAX algorithm (Fracture Risk Assessment Tool). RESULTS: Of the 1301 invited women, 1057 completed the survey. The average (mean [SD]) age and BMI were 67.2 (7.6) years and 29.3 (5.5) kg/m(2), respectively. Only 16.9 and 19.9 % participants believed themselves to be at a high risk of osteoporosis and fractures, respectively. There was no agreement between the perceived risk of fractures and the calculated FRAX risk of fractures. Moreover, almost 79.3 % of the women identified with a high risk of fractures by the FRAX algorithm perceived themselves as having little risk. CONCLUSION: These results show that postmenopausal women underestimate their risk of osteoporotic fractures when compared with their 10-year fracture risk according to FRAX algorithm. PMID- 27503623 TI - Elevated ferritin and circulating osteoprotegerin levels as independent predictors of hip fracture in postmenopausal women admitted for fragility fracture: time for new screening strategies? AB - Identification of risk factors may help us to understand the pathogenesis of osteoporotic hip fracture as well as to formulate development of better diagnostic, prevention and treatment strategies. The present study was designed to determine the impact of multiple metabolic risk factors such as markers of systemic inflammation (C-reactive protein), immune responses-acute phase reactants (ferritin), insulin resistance (HOMA-IR) and bone remodeling (osteoprotegerin), for the prediction of hip fractures in postmenopausal osteoporotic women. The study group consisted of 115 postmenopausal women divided into two groups: Group 1 consisted of 49 women hospitalized in the Orthopedic Department, Wolfson Medical Center for the diagnosis of non-traumatic hip fracture and Group 2 contained 66 postmenopausal osteoporotic women without a history of hip fracture. Metabolic parameters were determined. Circulating OPG was significantly higher in Group 1 than in Group 2 (205.2 +/- 177.1 vs 60.0 =/ 22.3, p < 0.0001). While levels of hemoglobin (Hbg) as well as MCV and MCH did not differ between groups, circulating ferritin was significantly increased in Group 1 compared to the control Group 2 (217.9 +/- 195.1 vs 49.7 +/- 31.3, p < 0.0001). In multiple linear regression analysis, which explains about 40 % of the variability in CRP, 42 % in OPG, and 28 % in ferritin, significant by-group differences in terms of these parameters persisted even after adjustment. Elevated serum ferritin concentrations and bone remodeling marker, osteoprotegerin, are independent predictors of hip fracture in postmenopausal women hospitalized for fragility fracture. PMID- 27503626 TI - Analysis of the improvement of selenite retention in smectite by adding alumina nanoparticles. AB - Smectite clay is used as barrier for hazardous waste retention and confinement. It is a powerful material to retain cations, but less effective for retaining anionic species like selenite. This study shows that the addition of a small percentage of gamma-Al2O3 nanoparticles to smectite significantly improves selenite sorption. gamma-Al2O3 nanoparticles provide high surface area and positively charged surface sites within a wide range of pH, since their point of zero charge is at pH8-9. An addition of 20wt% of gamma-Al2O3 to smectite is sufficient to approach the sorption capacity of pure alumina. To analyze the sorption behavior of the smectite/oxide mixtures, a nonelectrostatic surface complexation model was considered, accounting for the surface complexation of HSeO3- and SeO32-, the anion competition, and the formation of surface ternary complexes with major cations present in the solution. Selenite sorption in mixtures was satisfactorily described with the surface parameters and complexation constants defined for the pure systems, accounting only for the mixture weight fractions. Sorption in mixtures was additive despite the particle heteroaggregation observed in previous stability studies carried out on smectite/gamma-Al2O3 mixtures. PMID- 27503625 TI - Severe somatoform and dysautonomic syndromes after HPV vaccination: case series and review of literature. AB - Human papilloma virus (HPV) is recognized as a major cause for cervical cancer among women worldwide. Two HPV vaccines are currently available: Gardasil(r) and Cervarix(r). Both vaccines enclose viral antigenic proteins, but differ as to the biological systems of culture and the adjuvant components. Recently, a collection of symptoms, indicating nervous system dysfunction, has been described after HPV vaccination. We retrospectively described a case series including 18 girls (aged 12-24 years) referred to our "Second Opinion Medical Network" for the evaluation of "neuropathy with autonomic dysfunction" after HPV vaccination. All girls complained of long-lasting and invalidating somatoform symptoms (including asthenia, headache, cognitive dysfunctions, myalgia, sinus tachycardia and skin rashes) that have developed 1-5 days (n = 11), 5-15 days (n = 5) and 15-20 days (n = 2) after the vaccination. These cases can be included in the recently described immune dysfunction named autoimmune/inflammatory syndrome induced by adjuvants (ASIA). HPV vaccine, through its adjuvant component, is speculated to induce an abnormal activation of the immune system, involving glia cells in the nervous system too. Further researches should aim at defining the pathological and clinical aspects of these post-vaccination diseases and identifying a genetic background predisposing to these adverse reactions. PMID- 27503624 TI - cDNA phage display for the discovery of theranostic autoantibodies in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is the world's most common autoimmune disease mainly characterized by a chronic inflammation of multiple synovial joints. Rheumatologists now have a whole range of treatment options including glucocorticoids (GCs), classical synthetic and biological disease-modifying antirheumatic drugs (cs- and bDMARDS), resulting in a tremendous improvement in treatment outcomes for RA patients over the last two decades. Despite this progress, the choice of treatment regimen to achieve stable remission at the individual patient level still largely depends on trial and error. In this review, the need for novel theranostic markers that can predict a patient's response to methotrexate, the standard first-line csDMARD treatment, is discussed. Like in many autoimmune diseases, the majority of RA patients form a whole range of autoantibodies. We aim to find novel theranostic autoantibody markers using serological antigen selection, a high-throughput technique that uses cDNA phage display to identify novel antigen targets. We have constructed a barcoded cDNA phage display library from the synovial tissue of three RA patients by fusing cDNA products to the filamentous phage minor coat protein VI. This library contains a large proportion of full-length genes and gene fragments that are cloned in frame with the phage gene VI. By screening this library for antibody reactivity in serum samples of patients from the CareRA trial, which compared different intensive treatment strategies based on csDMARDs and a step down GC schedule, our cDNA phage display library has great potential for the discovery of novel theranostic autoantibody biomarkers. PMID- 27503627 TI - Drought and detritivores determine leaf litter decomposition in calcareous streams of the Ebro catchment (Spain). AB - Drought, an important environmental factor affecting the functioning of stream ecosystems, is likely to become more prevalent in the Mediterranean region as a consequence of climate change and enhanced water demand. Drought can have profound impacts on leaf litter decomposition, a key ecosystem process in headwater streams, but there is still limited information on its effects at the regional scale. We measured leaf litter decomposition across a gradient of aridity in the Ebro River basin. We deployed coarse- and fine-mesh bags with alder and oak leaves in 11 Mediterranean calcareous streams spanning a range of over 400km, and determined changes in discharge, water quality, leaf-associated macroinvertebrates, leaf quality and decomposition rates. The study streams were subject to different degrees of drought, specific discharge (Ls-1km-2) ranging from 0.62 to 9.99. One of the streams dried out during the experiment, another one reached residual flow, whereas the rest registered uninterrupted flow but with different degrees of flow variability. Decomposition rates differed among sites, being lowest in the 2 most water-stressed sites, but showed no general correlation with specific discharge. Microbial decomposition rates were not correlated with final nutrient content of litter nor to fungal biomass. Total decomposition rate of alder was positively correlated to the density and biomass of shredders; that of oak was not. Shredder density in alder bags showed a positive relationship with specific discharge during the decomposition experiment. Overall, the results point to a complex pattern of litter decomposition at the regional scale, as drought affects decomposition directly by emersion of bags and indirectly by affecting the functional composition and density of detritivores. PMID- 27503628 TI - The effect of periphyton on seed germination and seedling growth of rice (Oryza sativa) in paddy area. AB - Periphyton is widely distributed in paddy fields and its interactions with paddy soil and rice growth have been reported rarely. In this study, model paddy ecosystems with different additional soil substrates were simulated under controlled conditions to investigate the effects of periphyton on rice seed germination and seedling growth. Results show that the selected soil substrates had significant effects on the metabolic activities and growth of periphyton in paddy fields. The addition of straw to soil enhances but the addition of biochar leads to attenuation of periphyton growth. The presence of periphyton in the paddy system, especially with straw in soil greatly increased the germination index of rice seed (by maximally 21%). However, the biochar treatment in the presence of periphyton was detrimental for the seed vitality with a decrease of 30%. As a result, the periphyton cover on paddy soil surface significantly inhibited the growth of rice seedling, including rice height, leaf width and biomass. To summarize, this study indicates that the presence of periphyton during seed germination period was detrimental for rice growth, but could be used to control the weed growth. Thus, this study provided insight into understanding the periphyton-plant relationships with different soil-substrates and also new approaches to controlling weeds in paddy fields by regulating the growth of periphyton. PMID- 27503629 TI - Airborne bacterial contaminations in typical Chinese wet market with live poultry trade. AB - : Chinese wet markets with live poultry trade have been considered as major sources of pathogen dissemination, and sites for horizontal transfer of bacterial and viral pathogens. In this study, the pathogenic bacteria and antibiotic resistant genes (ARGs) in air samples collected at a typical Chinese wet market had been analysis and quantified. Corynebacterium minutissimum and other pathogenic bacteria accounted for 0.81-8.02% of the whole microbial community in different air samples. The four ARGs quantified in this study showed a comparable relative concentration (copies/ng_DNA) with municipal wastewater. Poultry manures were demonstrated to be important microbial contamination source in wet market, which was supported by both microbial composition based source tracking and the quantification of airborne microbial density. A series of Firmicutes and Bacteroidetes indicators of poultry area contamination were successfully screened, which will be useful for the more convenient monitoring of airborne poultry area contamination. Our results indicate bioaerosols acted as important route for the transmissions of pathogens and ARGs. Continued surveillance of airborne microbial contamination is required in poultry trade wet market. PRACTICAL IMPLICATIONS: Urban live poultry markets are important sources of pathogen dissemination, and sites for horizontal transfer of viral and bacterial pathogens. In the present field-study, pathogenic bacteria and antibiotic resistance genes were focused to provide quantitative information on the levels of microbial contaminations at the indoor air of wet markets. Results demonstrated that poultry manures were important microbial contamination source in wet market, and in the meanwhile bioaerosols were identified as important route for the transmissions of microbial contaminants. A series of Firmicutes and Bacteroidetes indicators of poultry area contamination were successfully screened, which will be useful for the more convenient monitoring of airborne poultry area contamination. PMID- 27503630 TI - Polychlorinated biphenyls in settled dust from informal electronic waste recycling workshops and nearby highways in urban centers and suburban industrial roadsides of Chennai city, India: Levels, congener profiles and exposure assessment. AB - Polychlorinated biphenyls (PCBs) were quantified in settled dust collected from informal electronic waste (e-waste) recycling workshops and nearby highways in the urban centers and roadside dust from the suburban industrial belt of Chennai city in India. Further dust samples were subjected to a high resolution field emission scanning electron microscope equipped with an energy dispersive X-ray spectrometer (FESEM/EDX) to characterize the shape, size and elemental composition of the dust particles. Geomean of total PCB concentration followed the following order: informal e-waste metal recovery workshops (53ngg-1)>e-waste dismantling sites (3.6ngg-1)>nearby highways (1.7ngg-1)>suburban industrial roadsides (1.6ngg-1). In e-waste workshops, tetra, penta and hexa-PCB homologs contributed two third of Sigma26PCB concentration. Informal e-waste recycling workshops contributed more than 80% concentration of all the PCB congeners loaded in the first principal component. Predominance of dioxin like PCBs, PCB-l14, -118 and -126 in the e-waste metal recovery sites were presumably due to combustion and pyrolytic processes performed during recycling of electrical components. According to the morphology and elemental composition, settled dust from e-waste workshops were irregular particles heavily embedded with toxic metals and industrial roadside dust were distinct angular particles. FESEM revealed that average particle size (in Ferret diameter) increased in the following order: e waste recycling workshops (0.5MUm)= 3 and n >= 3) quantum system. In particular, we give so far the smallest number of locally indistinguishable states of a completable orthogonal product basis in arbitrary quantum systems. Furthermore, we construct a series of small and locally indistinguishable orthogonal product bases in m ? n (m >= 3 and n >= 3). All the results lead to a better understanding of the structures of locally indistinguishable product bases in arbitrary bipartite quantum system. PMID- 27503635 TI - Detecting the Biopolymer Behavior of Graphene Nanoribbons in Aqueous Solution. AB - Graphene nanoribbons (GNR), can be prepared in bulk quantities for large-area applications by reducing the product from the lengthwise oxidative unzipping of multiwalled carbon nanotubes (MWNT). Recently, the biomaterials application of GNR has been explored, for example, in the pore to be used for DNA sequencing. Therefore, understanding the polymer behavior of GNR in solution is essential in predicting GNR interaction with biomaterials. Here, we report experimental studies of the solution-based mechanical properties of GNR and their parent products, graphene oxide nanoribbons (GONR). We used atomic force microscopy (AFM) to study their mechanical properties in solution and showed that GNR and GONR have similar force-extension behavior as in biopolymers such as proteins and DNA. The rigidity increases with reducing chemical functionalities. The similarities in rigidity and tunability between nanoribbons and biomolecules might enable the design and fabrication of GNR-biomimetic interfaces. PMID- 27503637 TI - Issues in Pain Prediction - More Gain than Pain. PMID- 27503636 TI - Maternal methylmercury exposure through rice ingestion and offspring neurodevelopment: A prospective cohort study. AB - BACKGROUND: Dietary methylmercury intake can occur not only through fish ingestion but also through rice ingestion; however, rice does not contain the same beneficial micronutrients as fish. OBJECTIVES: In rural China, where rice is a staple food, associations between prenatal methylmercury exposure (assessed using maternal hair mercury) and impacts on offspring neurodevelopment were investigated. METHODS: A total of 398 mothers were recruited at parturition at which time a sample of scalp hair was collected. Offspring (n=270, 68%) were assessed at 12 months using the Bayley Scales of Infant Development-II, yielding age-adjusted scores for the Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI). RESULTS: Among 270 mothers, 85% ingested rice daily, 41% never or rarely ingested fish/shellfish and 11% ingested fish/shellfish at least twice/weekly. Maternal hair mercury averaged 0.41MUg/g (median: 0.39MUg/g, range: 0.079-1.7MUg/g). In unadjusted models, offspring neurodevelopment (both MDI and PDI) was inversely correlated with hair mercury. Associations were strengthened after adjustment for fish/shellfish ingestion, rice ingestion, total energy intake (kcal), and maternal/offspring characteristics for both the MDI [Beta: -4.9, 95% Confidence Interval (CI): -9.7, -0.12] and the PDI (Beta: -2.7, 95% CI: -8.3, 2.9), although confidence intervals remained wide for the latter. CONCLUSIONS: For 12-month old offspring living in rural China, prenatal methylmercury exposure was associated with statistically significant decrements in offspring cognition, but not psychomotor development. Results expose potential new vulnerabilities for communities depending on rice as a staple food. PMID- 27503638 TI - High Prevalence of Carbapenemase-Producing Enterobacteriaceae among Hospitalized Children in Luanda, Angola. AB - This study aimed to evaluate the prevalence of carbapenemase-producing Enterobacteriaceae in Luanda, Angola. A total of 157 rectal samples were collected from children visiting a pediatric hospital in Luanda in March 2015. Fifty-seven imipenem-nonsusceptible enterobacterial isolates were recovered, most of which were non-clonally related. The blaOXA-181 (50/57) and blaNDM-1 (7/57) carbapenemase genes were identified. Notably, OXA-181-producing Escherichia coli isolates rarely coproduced extended-spectrum beta-lactamases and consequently remained susceptible to broad-spectrum cephalosporins. The blaOXA-181 gene was always located on an IncX3 plasmid, while the blaNDM-1 gene was located on either IncFIA or IncA/C plasmids. The study identified a high prevalence of OXA-181 among hospitalized children in Angola. PMID- 27503639 TI - The Synergistic Effect of Azoles and Fluoxetine against Resistant Candida albicans Strains Is Attributed to Attenuating Fungal Virulence. AB - This study evaluated the synergistic effects of the selective serotonin reuptake inhibitor, fluoxetine, in combination with azoles against Candida albicans both in vitro and in vivo and explored the underlying mechanism. MICs, sessile MICs, and time-kill curves were determined for resistant C. albicans Galleria mellonella was used as a nonvertebrate model for determining the efficacy of the drug combinations against C. albicans in vivo For the mechanism study, gene expression levels of the SAP gene family were determined by reverse transcription (RT)-PCR, and extracellular phospholipase activities were detected in vitro by the egg yolk agar method. The combinations resulted in synergistic activity against C. albicans strains, but the same effect was not found for the non albicans Candida strains. For the biofilms formed over 4, 8, and 12 h, synergism was seen for the combination of fluconazole and fluoxetine. In addition, the time kill curves confirmed the synergism dynamically. The results of the G. mellonella studies agreed with the in vitro analysis. In the mechanism study, we observed that fluconazole plus fluoxetine caused downregulation of the gene expression levels of SAP1 to SAP4 and weakened the extracellular phospholipase activities of resistant C. albicans The combinations of azoles and fluoxetine showed synergistic effects against resistant C. albicans may diminish the virulence properties of C. albicans. PMID- 27503641 TI - Development of an In Vitro Assay for Detection of Drug-Induced Resuscitation Promoting-Factor-Dependent Mycobacteria. AB - Tuberculosis is a major infectious disease that requires prolonged chemotherapy with a combination of four drugs. Here we present data suggesting that treatment of Mycobacterium tuberculosis, the causative agent of tuberculosis, and Mycobacterium smegmatis, a model organism widely used for the screening of antituberculosis agents, with first-line drugs resulted in the generation of substantial populations that could be recovered only by the addition of a culture supernatant from growing mycobacteria. These bacilli failed to grow in standard media, resulting in significant underestimation of the numbers of viable mycobacteria in treated samples. We generated M. smegmatis strains overexpressing M. tuberculosis resuscitation-promoting factors (Rpfs) and demonstrated their application for the detection of Rpf-dependent mycobacteria generated after drug exposure. Our data offer novel opportunities for validation of the sterilizing activity of antituberculosis agents. PMID- 27503640 TI - Preclinical Profile and Clinical Efficacy of a Novel Hepatitis C Virus NS5A Inhibitor, EDP-239. AB - EDP-239, a novel hepatitis C virus (HCV) inhibitor targeting nonstructural protein 5A (NS5A), has been investigated in vitro and in vivo EDP-239 is a potent, selective inhibitor with potency at picomolar to nanomolar concentrations against HCV genotypes 1 through 6. In the presence of human serum, the potency of EDP-239 was reduced by less than 4-fold. EDP-239 is additive to synergistic with other direct-acting antivirals (DAAs) or host-targeted antivirals (HTAs) in blocking HCV replication and suppresses the selection of resistance in vitro Furthermore, EDP-239 retains potency against known DAA- or HTA-resistant variants, with half-maximal effective concentrations (EC50s) equivalent to those for the wild type. In a phase I, single-ascending-dose, placebo-controlled clinical trial, EDP-239 demonstrated excellent pharmacokinetic properties that supported once daily dosing. A single 100-mg dose of EDP-239 resulted in reductions in HCV genotype 1a viral RNA of >3 log10 IU/ml within the first 48 h after dosing and reductions in genotype 1b viral RNA of >4-log10 IU/ml within 96 h. (This study has been registered at ClinicalTrials.gov under identifier NCT01856426.). PMID- 27503642 TI - Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients. AB - This study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, >=12 to <18 years; cohort 2, >=6 to <12 years; cohort 3, >=2 to <6 years; cohort 4, >=3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [>=40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (Cmax), and area under the concentration-time curve from time zero to infinity (AUC0-infinity) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.). PMID- 27503643 TI - Effects of Lipid-Lowering Drugs on Vancomycin Susceptibility of Mycobacteria. AB - Tuberculosis is still a cause of major concern, partly due to the emergence of multidrug-resistant strains. New drugs are therefore needed. Vancomycin can target mycobacteria with cell envelope deficiency. In this study, we used a vancomycin susceptibility assay to detect drugs hampering lipid synthesis in Mycobacterium bovis BCG and in Mycobacterium tuberculosis We tested three drugs already used to treat human obesity: tetrahydrolipstatin (THL), simvastatin, and fenofibrate. Only vancomycin and THL were able to synergize on M. bovis BCG and on M. tuberculosis, although mycobacteria could also be inhibited by simvastatin alone. Lipid analysis allowed us to identify several lipid modifications in M. tuberculosis H37Rv treated with those drugs. THL treatment mainly reduced the phthiocerol dimycocerosate (PDIM) content in the mycobacterial cell wall, providing an explanation for the synergy, since PDIM deficiency has been related to vancomycin susceptibility. Proteomic analysis suggested that bacteria treated with THL, in contrast to bacteria treated with simvastatin, tried to recover, inducing, among other reactions, lipid synthesis. The combination of THL and vancomycin should be considered a promising solution in developing new strategies to treat multidrug-resistant tuberculosis. PMID- 27503644 TI - Preclinical and Clinical Resistance Profile of EDP-239, a Novel Hepatitis C Virus NS5A Inhibitor. AB - EDP-239, a potent and selective hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor developed for the treatment of HCV infection, has been investigated in vitro and in vivo This study sought to characterize genotypic changes in the HCV NS5A sequence of genotype 1 (GT1) replicons and to compare those changes to GT1 viral RNA mutations isolated from clinical trial patients. Resistance selection experiments in vitro using a subgenomic replicon identified resistance-associated mutations (RAMs) at GT1a NS5A amino acid positions 24, 28, 30, 31, and 93 that confer various degrees of resistance to EDP-239. Key RAMs were similarly identified in GT1b NS5A at amino acid positions 31 and 93. Mutations F36L in GT1a and A92V in GT1b do not confer resistance to EDP-239 individually but were found to enhance the resistance of GT1a K24R and GT1b Y93H. RAMs were identified in GT1 patients at baseline or after dosing with EDP-239 that were similar to those detected in vitro Baseline RAMs identified at NS5A position 93 in GT1, or positions 28 or 30 in GT1a only, correlated with a reduced treatment response. RAMs at additional positions were also detected and may have contributed to reduced EDP-239 efficacy. The most common GT1a and GT1b RAMs found to persist up to weeks 12, 24, or 48 were those at NS5A positions 28, 30, 31, 58 (GT1a only), and 93. Those RAMs persisting at the highest frequencies up to weeks 24 or 48 were L31M and Q30H/R for GT1a and L31M and Y93H for GT1b. (This study has been registered at ClinicalTrials.gov under identifier NCT01856426.). PMID- 27503645 TI - Drug-Drug Interaction between the Direct-Acting Antiviral Regimen of Ombitasvir Paritaprevir-Ritonavir plus Dasabuvir and the HIV Antiretroviral Agent Dolutegravir or Abacavir plus Lamivudine. AB - The direct-acting antiviral regimen of 25 mg ombitasvir-150 mg paritaprevir-100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers (n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3 direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration (Cmax) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean Cmax and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean Cmax and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally well tolerated, with no evidence of increased rates of adverse events during combination administration. These data indicate that the 3-direct-acting-antiviral regimen can be administered with dolutegravir or abacavir plus lamivudine without dose adjustment. PMID- 27503646 TI - Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir. AB - Entecavir (ETV) is a first-line antiviral agent for the treatment of chronic hepatitis B virus infection. Renal excretion is the major elimination path of ETV, in which tubular secretion plays the key role. However, the secretion mechanism has not been clarified. We speculated that renal transporters mediated the secretion of ETV. Therefore, the aim of our study was to elucidate which transporters contribute to the renal disposition of ETV. Our results revealed that ETV (50 MUM) remarkably reduced the accumulation of probe substrates in MDCK cells stably expressing human multidrug and toxin efflux extrusion proteins (hMATE1/2-K), organic cation transporter 2 (hOCT2), and carnitine/organic cation transporters (hOCTNs) and increased the substrate accumulation in cells transfected with multidrug resistance-associated protein 2 (hMRP2) or multidrug resistance protein 1 (hMDR1). Moreover, ETV was proved to be a substrate of the above-described transporters. In transwell studies, the transport of ETV in MDCK hOCT2-hMATE1 showed a distinct directionality from BL (hOCT2) to AP (hMATE1), and the cellular accumulation of ETV in cells expressing hMATE1 was dramatically lower than that of the mock-treated cells. The accumulation of ETV in mouse primary renal tubular cells was obviously affected by inhibitors of organic anion transporter 1/3 (Oat1/3), Oct2, Octn1/2, and Mrp2. Therefore, the renal uptake of ETV is likely mediated by OAT1/3 and OCT2 while the efflux is mediated by MATEs, MDR1, and MRP2, and OCTN1/2 may participate in both renal secretion and reabsorption. PMID- 27503648 TI - IMP-27, a Unique Metallo-beta-Lactamase Identified in Geographically Distinct Isolates of Proteus mirabilis. AB - A novel metallo-beta-lactamase gene, blaIMP-27, was identified in unrelated Proteus mirabilis isolates from two geographically distinct locations in the United States. Both isolates harbor blaIMP-27 as part of the first gene cassette in a class 2 integron. Antimicrobial susceptibility testing indicated susceptibility to aztreonam, piperacillin-tazobactam, and ceftazidime but resistance to ertapenem. However, hydrolysis assays indicated that ceftazidime was a substrate for IMP-27. PMID- 27503649 TI - Emergence of ileS2-Carrying, Multidrug-Resistant Plasmids in Staphylococcus lugdunensis. AB - Of 137 Staphylococcus lugdunensis isolates collected from two nephrology centers in Hong Kong, 10 (7.3%) and 3 (2.2%) isolates had high-level and low-level mupirocin resistance, respectively. Isolates with high-level resistance contained the plasmid-mediated ileS2 gene, while isolates with low-level resistance contained the mutation V588F within the chromosomal ileS gene. All but one of the ileS2-positive isolates belong to the predominating clone HKU1. Plasmids carrying the ileS2 gene were mosaic and also cocarry multiple other resistance determinants. PMID- 27503647 TI - Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase. AB - The recent development and spread of extensively drug-resistant and totally drug resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid. PMID- 27503650 TI - First Report of the Globally Disseminated IncX4 Plasmid Carrying the mcr-1 Gene in a Colistin-Resistant Escherichia coli Sequence Type 101 Isolate from a Human Infection in Brazil. AB - A colistin-resistant Escherichia coli strain was recovered from a patient with a diabetic foot infection in Brazil. Whole-genome analysis revealed that the E. coli isolate belonged to the widespread sequence type (ST) 101 and harbored the mcr-1 gene on an IncX4 plasmid that was highly similar to mcr-1-bearing IncX4 plasmids that were recently identified in Enterobacteriaceae from food, animal, and human samples recovered on different continents. These results suggest that self-transmissible IncX4-type plasmids may represent promiscuous plasmids contributing to the intercontinental spread of the mcr-1 gene. PMID- 27503652 TI - mcr-1 in Multidrug-Resistant blaKPC-2-Producing Clinical Enterobacteriaceae Isolates in Singapore. PMID- 27503651 TI - Nicotiana alata Defensin Chimeras Reveal Differences in the Mechanism of Fungal and Tumor Cell Killing and an Enhanced Antifungal Variant. AB - The plant defensin NaD1 is a potent antifungal molecule that also targets tumor cells with a high efficiency. We examined the features of NaD1 that contribute to these two activities by producing a series of chimeras with NaD2, a defensin that has relatively poor activity against fungi and no activity against tumor cells. All plant defensins have a common tertiary structure known as a cysteine stabilized alpha-beta motif which consists of an alpha helix and a triple stranded beta-sheet stabilized by four disulfide bonds. The chimeras were produced by replacing loops 1 to 7, the sequences between each of the conserved cysteine residues on NaD1, with the corresponding loops from NaD2. The loop 5 swap replaced the sequence motif (SKILRR) that mediates tight binding with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and is essential for the potent cytotoxic effect of NaD1 on tumor cells. Consistent with previous reports, there was a strong correlation between PI(4,5)P2 binding and the tumor cell killing activity of all of the chimeras. However, this correlation did not extend to antifungal activity. Some of the loop swap chimeras were efficient antifungal molecules, even though they bound poorly to PI(4,5)P2, suggesting that additional mechanisms operate against fungal cells. Unexpectedly, the loop 1B swap chimera was 10 times more active than NaD1 against filamentous fungi. This led to the conclusion that defensin loops have evolved as modular components that combine to make antifungal molecules with variable mechanisms of action and that artificial combinations of loops can increase antifungal activity compared to that of the natural variants. PMID- 27503654 TI - Activity of Cysteamine against the Cystic Fibrosis Pathogen Burkholderia cepacia Complex. AB - There are no wholly successful chemotherapeutic strategies against Burkholderia cepacia complex (BCC) colonization in cystic fibrosis (CF). We assessed the impact of cysteamine (Lynovex) in combination with standard-of-care CF antibiotics in vitro against BCC CF isolates by the concentration at which 100% of bacteria were killed (MIC100) and checkerboard assays under CLSI standard conditions. Cysteamine facilitated the aminoglycoside-, fluoroquinolone- and folate pathway inhibitor-mediated killing of BCC organisms that were otherwise resistant or intermediately sensitive to these antibiotic classes. Slow-growing BCC strains are often recalcitrant to treatment and form biofilms. In assessing the impact of cysteamine on biofilms, we demonstrated inhibition of BCC biofilm formation at sub-MIC100s of cysteamine. PMID- 27503655 TI - Determining the Optimal Carbapenem MIC That Distinguishes Carbapenemase-Producing and Non-Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae. AB - Carbapenemase-producing (CP) Enterobacteriaceae are largely responsible for the rapid spread of carbapenem-resistant Enterobacteriaceae (CRE). Distinguishing CP CRE from non-CP-CRE has important infection control implications. In a cohort of 198 CRE isolates, for isolates that remained susceptible or intermediate to some carbapenem antibiotics, an ertapenem MIC of 0.5 MUg/ml and meropenem, imipenem, and doripenem MICs of 2 MUg/ml were best able to distinguish CP-CRE from non-CP CRE isolates. PMID- 27503653 TI - A Novel Spirooxindole Derivative Inhibits the Growth of Leishmania donovani Parasites both In Vitro and In Vivo by Targeting Type IB Topoisomerase. AB - Visceral leishmaniasis is a fatal parasitic disease, and there is an emergent need for development of effective drugs against this neglected tropical disease. We report here the development of a novel spirooxindole derivative, N-benzyl 2,2'alpha-3,3',5',6',7',7alpha,alpha'-octahydro-2methoxycarbonyl-spiro[indole 3,3'-pyrrolizidine]-2-one (compound 4c), which inhibits Leishmania donovani topoisomerase IB (LdTopIB) and kills the wild type as well as drug-resistant parasite strains. This compound inhibits catalytic activity of LdTopIB in a competitive manner. Unlike camptothecin (CPT), the compound does not stabilize the DNA-topoisomerase IB cleavage complex; rather, it hinders drug-DNA-enzyme covalent complex formation. Fluorescence studies show that the stoichiometry of this compound binding to LdTopIB is 2:1 (mole/mole), with a dissociation constant of 6.65 MUM. Molecular docking with LdTopIB using the stereoisomers of compound 4c produced two probable hits for the binding site, one in the small subunit and the other in the hinge region of the large subunit of LdTopIB. This spirooxindole is highly cytotoxic to promastigotes of L. donovani and also induces apoptosis like cell death in the parasite. Treatment with compound 4c causes depolarization of mitochondrial membrane potential, formation of reactive oxygen species inside parasites, and ultimately fragmentation of nuclear DNA. Compound 4c also effectively clears amastigote forms of wild-type and drug-resistant parasites from infected mouse peritoneal macrophages but has less of an effect on host macrophages. Moreover, compound 4c showed strong antileishmanial efficacies in the BALB/c mouse model of leishmaniasis. This compound potentially can be used as a lead for developing excellent antileishmanial agents against emerging drug resistant strains of the parasite. PMID- 27503656 TI - Gel-Entrapped Staphylococcus aureus Bacteria as Models of Biofilm Infection Exhibit Growth in Dense Aggregates, Oxygen Limitation, Antibiotic Tolerance, and Heterogeneous Gene Expression. AB - An experimental model that mimicked the structure and characteristics of in vivo biofilm infections, such as those occurring in the lung or in dermal wounds where no biomaterial surface is present, was developed. In these infections, microbial biofilm forms as cell aggregates interspersed in a layer of mucus or host matrix material. This structure was modeled by filling glass capillary tubes with an agarose gel that had been seeded with Staphylococcus aureus bacteria and then incubating the gel biofilm in medium for up to 30 h. Confocal microscopy showed that the bacteria formed in discrete pockets distributed throughout the gel matrix. These aggregates enlarged over time and also developed a size gradient, with the clusters being larger near the nutrient- and oxygen-supplied interface and smaller at greater depths. Bacteria entrapped in gels for 24 h grew slowly (specific growth rate, 0.06 h(-1)) and were much less susceptible to oxacillin, minocycline, or ciprofloxacin than planktonic cells. Microelectrode measurements showed that the oxygen concentration decreased with depth into the gel biofilm, falling to values less than 3% of air saturation at depths of 500 MUm. An anaerobiosis-responsive green fluorescent protein reporter gene for lactate dehydrogenase was induced in the region of the gel where the measured oxygen concentrations were low, confirming biologically relevant hypoxia. These results show that the gel biofilm model captures key features of biofilm infection in mucus or compromised tissue: formation of dense, distinct aggregates, reduced specific growth rates, local hypoxia, and antibiotic tolerance. PMID- 27503657 TI - In Vitro Activity of 3-Triazeneindoles against Mycobacterium tuberculosis and Mycobacterium avium. AB - Among 230 target-synthesized indole-based compounds, seven 3-triazenoindoles showed MICs of 0.2 to 0.5 MUg/ml against Mycobacterium tuberculosis strain H37Rv and isoniazid-resistant human isolate CN-40. The TU112 compound was active also against a dormant form of M. tuberculosis Some of these triazenoindoles were active against Mycobacterium avium, with MICs of 0.05 to 0.5 MUg/ml. The selectivity indices (SI) for M. tuberculosis and M. avium were significantly higher than 10, making these compounds acceptable for the next testing step. PMID- 27503658 TI - Increasing Trends in mcr-1 Prevalence among Extended-Spectrum-beta-Lactamase Producing Escherichia coli Isolates from French Calves despite Decreasing Exposure to Colistin. PMID- 27503659 TI - Phase 2, Dose-Ranging Study of Relebactam with Imipenem-Cilastatin in Subjects with Complicated Intra-abdominal Infection. AB - Relebactam (REL [MK-7655]) is a novel class A/C beta-lactamase inhibitor intended for use with imipenem for the treatment of Gram-negative bacterial infections. REL restores imipenem activity against some resistant strains of Klebsiella and Pseudomonas In this multicenter, double-blind, controlled trial (NCT01506271), subjects who were >=18 years of age with complicated intra-abdominal infection were randomly assigned (1:1:1) to receive 250 mg REL, 125 mg REL, or placebo, each given intravenously (i.v.) with 500 mg imipenem-cilastatin (IMI) every 6 h (q6h) for 4 to 14 days. The primary efficacy endpoint was the proportion of microbiologically evaluable (ME) subjects with a favorable clinical response at discontinuation of i.v. therapy (DCIV). A total of 351 subjects were randomized, 347 (99%) were treated, and 255 (73%) were ME at DCIV (55% male; mean age, 49 years). The most common diagnoses were complicated appendicitis (53%) and complicated cholecystitis (17%). Thirty-six subjects (13%) had imipenem-resistant Gram-negative infections at baseline. Both REL doses plus IMI were generally well tolerated and demonstrated safety profiles similar to that of IMI alone. Clinical response rates at DCIV were similar in subjects who received 250 mg REL plus IMI (96.3%) or 125 mg REL plus IMI (98.8%), and both were noninferior to IMI alone (95.2%; one-sided P < 0.001). The treatment groups were also similar with respect to clinical response at early and late follow-up and microbiological response at all visits. Pharmacokinetic/pharmacodynamic simulations show that imipenem exposure at the proposed dose of 500 mg IMI with 250 mg REL q6h provides coverage of >90% of carbapenem-resistant bacterial strains. PMID- 27503661 TI - Migraine-like headache caused by rheumatic heart disease: The second case of 'Mahler's migraine'? PMID- 27503660 TI - Genetic characterization of cysteine-rich type-b avenin-like protein coding genes in common wheat. AB - The wheat avenin-like proteins (ALP) are considered atypical gluten constituents and have shown positive effects on dough properties revealed using a transgenic approach. However, to date the genetic architecture of ALP genes is unclear, making it impossible to be utilized in wheat breeding. In the current study, three genes of type-b ALPs were identified and mapped to chromosomes 7AS, 4AL and 7DS. The coding gene sequence of both TaALP-7A and TaALP-7D was 855 bp long, encoding two identical homologous 284 amino acid long proteins. TaALP-4A was 858 bp long, encoding a 285 amino acid protein variant. Three alleles were identified for TaALP-7A and four for TaALP-4A. TaALP-7A alleles were of two types: type-1, which includes TaALP-7A1 andTaALP-7A2, encodes mature proteins, while type-2, represented byTaALP-7A3, contains a stop codon in the coding region and thus does not encode a mature protein. Dough quality testing of 102 wheat cultivars established a highly significant association of the type-1 TaALP-7A allele with better wheat processing quality. This allelic effects were confirmed among a range of commercial wheat cultivars. Our research makes the ALP be the first of such genetic variation source that can be readily utilized in wheat breeding. PMID- 27503663 TI - Corrigendum to "Generalization of treadmill perturbation to overground slip during gait: Effect of different perturbation distances on slip recovery" [J. Biomech. 49/2 (Jan. 2016) 149-154]. PMID- 27503662 TI - Pharmacokinetics of a Once-Daily Dose of Tacrolimus Early After Liver Transplantation: With Special Reference to CYP3A5 and ABCB1 Single Nucleotide Polymorphisms. AB - BACKGROUND The aim of the present study was to investigate the pharmacokinetics of the once-daily tacrolimus formulation (QD form) in relation to polymorphisms of the donor cytochrome P450 family 3 sub-family A polypeptide 5 (CYP3A5) gene and recipient adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1) gene. MATERIAL AND METHODS A total of 80 consecutive living-donor liver transplant (LDLT) recipients were started on the QD form of tacrolimus (day 1), and 60 patients were completely followed for 7 days early after liver transplantation in order to evaluate the pharmacokinetics. RESULTS The concentration/dose (C/D) ratio in recipients with the donor CYP3A5 *1 allele was significantly lower throughout the observation period compared with those with the CYP3A5 genotype *3/*3 (p<0.001), while no effect of single-nucleotide polymorphisms (SNPs) of ABCB1 was observed. The administered doses required to achieve the target trough level were significantly higher on day 7 than on day 1 among all groups, regardless of the differences in the SNPs, especially among those with donor CYP3A5 *1 allele. The tacrolimus concentration was kept within the targeted level all through the study regardless of SNPs. CONCLUSIONS The donor CYP3A5 *1 allele correlated with the lower C/D ratio after administration of the QD form, and higher doses of QD-form tacrolimus and careful monitoring for the trough level should be considered, especially in recipients with the donor CYP3A5 *1 allele. PMID- 27503665 TI - Dr Barnett Rosenberg - a Personal Perspective. PMID- 27503664 TI - Ballistocardiogram: Mechanism and Potential for Unobtrusive Cardiovascular Health Monitoring. AB - For more than a century, it has been known that the body recoils each time the heart ejects blood into the arteries. These subtle cardiogenic body movements have been measured with increasingly convenient ballistocardiography (BCG) instruments over the years. A typical BCG measurement shows several waves, most notably the "I", "J", and "K" waves. However, the mechanism for the genesis of these waves has remained elusive. We formulated a simple mathematical model of the BCG waveform. We showed that the model could predict the BCG waves as well as physiologic timings and amplitudes of the major waves. The validated model reveals that the principal mechanism for the genesis of the BCG waves is blood pressure gradients in the ascending and descending aorta. This new mechanistic insight may be exploited to allow BCG to realize its potential for unobtrusive monitoring and diagnosis of cardiovascular health and disease. PMID- 27503666 TI - Photosensitizer cross-linked nano-micelle platform for multimodal imaging guided synergistic photothermal/photodynamic therapy. AB - The multifunctional nano-micelle platform holds great promise to enhance the accuracy and efficiency of cancer diagnosis and therapy. In this work, an amphiphilic poly[(poly(ethylene glycol) methyl ether methacrylate)-co-(3 aminopropyl methacrylate)]-block-poly(methyl methacrylate) (P(PEGMA-co-APMA)-b PMMA) block copolymer was synthesized by successive RAFT polymerizations and subsequent chemical modification. Then the multifunctional micelles with high solubility in physiological environments were developed by a self-assembly and crosslinking processes. The photosensitizer segment, 5,10,15,20-tetrakis (4 carboxyphenyl) porphyrin (TCPP), serves as a tetra-functional cross-linker, photodynamic agent, fluorescence indicator, as well as magnetic resonance (MR) contrast agent after labelling with manganese ions (Mn(2+)), while IR825 simultaneously locating in the interior of the fabricated micelles contributed to the photoacoustic (PA) imaging ability and the photothermal effect. The prepared nanoparticles show great stability in a physiological environment with uniform morphology and diameters of around 80 nm as disclosed by stability investigation, TEM and DLS analysis. IR825@P(PEGMA-co-APMA)-b-PMMA@TCPP/Mn nanoparticles displayed high in vivo tumor uptake with a long blood circulation half-life (~3.64 h) by the EPR effect after intravenous (i.v.) injection, as revealed by fluorescence, MR and PA imaging models. In vivo anti-tumor effects were achieved via a combined photothermal and photodynamic therapy without noticeable dark toxicity, and this strategy was able to induce a remarkably improved synergistic therapeutic effect to both superficial and deep regions of tumors under mild conditions compared with either single photothermal or photodynamic mechanisms. PMID- 27503667 TI - Nano-Structured Materials as Separation Media. PMID- 27503669 TI - Errata. PMID- 27503670 TI - Elucidating the Stereochemistry of Enzymatic Benzylsuccinate Synthesis with Chirally Labeled Toluene. AB - Benzylsuccinate synthase is a glycyl radical enzyme that initiates anaerobic toluene metabolism by adding fumarate to the methyl group of toluene to yield (R) benzylsuccinate. To investigate whether the reaction occurs with retention or inversion of configuration at the methyl group of toluene, we synthesized both enantiomers of chiral toluene with all three H isotopes in their methyl groups. The chiral toluenes were converted into benzylsuccinates preferentially containing (2) H and (3) H at their benzylic C atoms, owing to a kinetic isotope effect favoring hydrogen abstraction from the methyl groups. The configuration of the products was analyzed by enzymatic CoA-thioester synthesis and stereospecific oxidation using enzymes involved in benzylsuccinate degradation. Assessment of the configurations of the benzylsuccinate isomers based on loss or retention of tritium showed that inversion of configuration at the methyl group occurs when the chiral toluenes react with fumarate. PMID- 27503671 TI - Differential effect of hypoxia on early endothelial-mesenchymal transition response to transforming growth beta isoforms 1 and 2. AB - Angiogenesis is essential for mammalian development and tissue homeostasis, and is involved in several pathological processes, including tumor growth and dissemination. Many factors within the tissue microenvironment are known to modulate angiogenesis, including cytokines, such as transforming growth factor beta (TGFbeta), and oxygen level. TGFbeta exists in three different isoforms (1, 2 and 3), all of which (albeit in different contexts) might mediate angiogenesis and are able to induce endothelial-mesenchymal transition (EndoMT), a process involved in heart development, pathologic fibrosis and, as recently reported, in angiogenesis. Low oxygen level, referred to as hypoxia, has been independently shown to induce angiogenesis, modulate TGFbeta signalling and promote EndoMT. However, how these phenomena might be interconnected to drive angiogenesis is rather unexplored. To begin addressing the potential contribution of TGFbeta induced EndoMT to angiogenesis, and to explore how microenvironmental hypoxia might influence these processes, we investigated the effect of TGFbeta isoforms 1 and 2 on early EndoMT response in cultured adult endothelium under standard (21 %) and hypoxic (1 %) culture conditions. Our data indicates that EndoMT-like changes, such as an increase in expression and nuclear translocation of Snail, Slug and Zeb1, and reduction of VE-cadherin expression, occur in response to TGFbeta1 and/or TGFbeta2 as early as 6h after stimulation and might be enhanced by hypoxia in an isoform-specific manner. Further, hypoxia enhances canonical TGFbeta signalling, and appears to be a key determinant of Snail's differential involvement in endothelial cell responses to TGFbeta1 versus TGFbeta2. PMID- 27503672 TI - Providing innovative solutions in a single pill: Servier's portfolio in hypertension. AB - Jean-Jacques Mourad & Jean-Christophe Guillerm speak to Henry Ireland, Drug Evaluation Editor: Jean-Jacques Mourad talks about his vision of the current landscape and unmet medical needs in the field of hypertension. Jean-Christophe Guillerm describes the family of antihypertensive treatments from Servier, which were designed to address the current challenges in the management of hypertension by providing an adapted solution to doctors and to the specific needs of each patient. Jean-Jacques Mourad currently works as Professor of Medicine and is the Head of the Hypertension Unit at the Hopital Avicenne in Bobigny, France. He completed his academic degrees at the Pierre and Marie Curie University, Paris VI in the field of internal and vascular medicine in 1996, and in the area of cardiovascular medicine and pharmacology in 2001. He is the past president of the French League Against Hypertension (since 2012), and the former General Secretary of the French Microcirculation Society. He is the actual Scientific Secretary of the French Society of Hypertension. He is also a member of the administrative council of the College Francais de Pathologie Vasculaire. His research focuses on the epidemiology of hypertension, arterial structure and function, determinants of adherence to chronic treatment and the effects of antihypertensive agents. He was involved in several studies and surveys. He is a co-author of more than 130 publications and of 900 communications presented at national and international meetings. Jean-Christophe Guillerm, joined the pharmaceutical industry 17 years ago. He is currently the Head of the Cardiovascular Division for Servier, in charge of both cardiology and hypertension's medical strategy at a global level. Prior to this, he was in charge of the diabetes and internal medicine franchise at a global level. He also has experience in French commercial operations. PMID- 27503673 TI - The Nutrition Society journals: vive la difference! PMID- 27503674 TI - Nutrition information and front-of-pack labelling: issues in effectiveness. PMID- 27503675 TI - How to talk about protein-level false discovery rates in shotgun proteomics. AB - A frequently sought output from a shotgun proteomics experiment is a list of proteins that we believe to have been present in the analyzed sample before proteolytic digestion. The standard technique to control for errors in such lists is to enforce a preset threshold for the false discovery rate (FDR). Many consider protein-level FDRs a difficult and vague concept, as the measurement entities, spectra, are manifestations of peptides and not proteins. Here, we argue that this confusion is unnecessary and provide a framework on how to think about protein-level FDRs, starting from its basic principle: the null hypothesis. Specifically, we point out that two competing null hypotheses are used concurrently in today's protein inference methods, which has gone unnoticed by many. Using simulations of a shotgun proteomics experiment, we show how confusing one null hypothesis for the other can lead to serious discrepancies in the FDR. Furthermore, we demonstrate how the same simulations can be used to verify FDR estimates of protein inference methods. In particular, we show that, for a simple protein inference method, decoy models can be used to accurately estimate protein level FDRs for both competing null hypotheses. PMID- 27503676 TI - Arginine (Di)methylated Human Leukocyte Antigen Class I Peptides Are Favorably Presented by HLA-B*07. AB - Alterations in protein post-translational modification (PTM) are recognized hallmarks of diseases. These modifications potentially provide a unique source of disease-related human leukocyte antigen (HLA) class I-presented peptides that can elicit specific immune responses. While phosphorylated HLA peptides have already received attention, arginine methylated HLA class I peptide presentation has not been characterized in detail. In a human B-cell line we detected 149 HLA class I peptides harboring mono- and/or dimethylated arginine residues by mass spectrometry. A striking preference was observed in the presentation of arginine (di)methylated peptides for HLA-B*07 molecules, likely because the binding motifs of this allele resemble consensus sequences recognized by arginine methyl transferases. Moreover, HLA-B*07-bound peptides preferentially harbored dimethylated groups at the P3 position, thus consecutively to the proline anchor residue. Such a proline-arginine sequence has been associated with the arginine methyl-transferases CARM1 and PRMT5. Making use of the specific neutral losses in fragmentation spectra, we found most of the peptides to be asymmetrically dimethylated, most likely by CARM1. These data expand our knowledge of the processing and presentation of arginine (di)methylated HLA class I peptides and demonstrate that these types of modified peptides can be presented for recognition by T-cells. HLA class I peptides with mono- and dimethylated arginine residues may therefore offer a novel target for immunotherapy. PMID- 27503677 TI - Synthesis and trypanocidal activity of novel benzimidazole derivatives. AB - The present work reports the synthesis and biological activity of a series of 14 benzimidazole derivatives designed to act on the enzyme triosephosphate isomerase of Trypanosoma cruzi (TcTIM). This enzyme is involved in the metabolism of glucose, the only source of energy for the parasite. In this study, we found four compounds that inhibit TcTIM moderately and lack inhibitory activity against human TIM (HsTIM). In vitro studies against T. cruzi epimastigotes showed two compounds that were more active than the reference drug nifurtimox, and these presented a low cytotoxic effect in mouse macrophages (J744 cell line). PMID- 27503678 TI - Ligand-based virtual screen for the discovery of novel M5 inhibitor chemotypes. AB - This Letter describes a ligand-based virtual screening campaign utilizing SAR data around the M5 NAMs, ML375 and VU6000181. Both QSAR and shape scores were employed to virtually screen a 98,000-member compound library. Neither approach alone proved productive, but a consensus score of the two models identified a novel scaffold which proved to be a modestly selective, but weak inhibitor (VU0549108) of the M5 mAChR (M5 IC50=6.2MUM, M1-4 IC50s>10MUM) based on an unusual 8-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)-1-oxa-4-thia-8 azaspiro[4,5]decane scaffold. [(3)H]-NMS binding studies showed that VU0549108 interacts with the orthosteric site (Ki of 2.7MUM), but it is not clear if this is negative cooperativity or orthosteric binding. Interestingly, analogs synthesized around VU0549108 proved weak, and SAR was very steep. However, this campaign validated the approach and warranted further expansion to identify additional novel chemotypes. PMID- 27503679 TI - Synthesis and bioactivities of novel pyrazole oxime derivatives containing a 1,2,3-thiadiazole moiety. AB - A series of new pyrazole oxime compounds bearing a 1,2,3-thiadiazole ring were designed, synthesized, and evaluated for their insecticidal, acaricidal and antitumor activities. Bioassays demonstrated that some title compounds displayed satisfactory insecticidal and acaricidal properties. Especially, compounds 8d and 8h exhibited 90% insecticidal activities against Aphis craccivora at the concentration of 100MUg/mL. Interestingly, some of the target compounds possessed significant antitumor activities against four human cancer cell lines in vitro. Among them, compounds 8e (IC50=7.19MUM), 8l (IC50=6.56MUM), 8m (IC50=8.12MUM), and 8r (IC50=7.06MUM) had better inhibitory activities against HCT-116 cells than the control 5-fluorouracil (IC50=29.50MUM). Additionally, compounds 8j, 8m, and 8r showed wonderful inhibitory activities against SGC-7901 cells with the IC50 values of 11.46, 9.41, and 8.64MUM, respectively, which were superior to that of the control 5-fluorouracil. PMID- 27503680 TI - Highly sensitive and selective detection of Al(III) ions in aqueous buffered solution with fluorescent peptide-based sensor. AB - A fluorescent sensor based on a tripeptide (SerGluGlu) with a dansyl fluorophore detected selectively Al(III) among 16 metal ions in aqueous buffered solutions without any organic cosolvent. The peptide-based sensor showed a highly sensitive turn on response to aluminium ion with high binding affinity (1.84*10(4)M(-1)) in aqueous buffered solutions. The detection limit (230nM, 5.98ppb) of the peptide based sensor was much lower than the maximum allowable level (7.41MUM) of aluminium ions in drinking water demanded by EPA. The binding mode of the peptide sensor with aluminium ions was characterized using ESI mass spectrometry, NMR titration, and pH titration experiments. PMID- 27503681 TI - Design, synthesis and evaluation of the multidrug resistance-reversing activity of pyridine acid esters of podophyllotoxin in human leukemia cells. AB - Multidrug resistance (MDR) is the main cause for chemotherapeutic failure in cancer treatment. To overcome MDR, a serious of pyridine acid esters of podophyllotoxin was synthesized and their antiproliferation activities were evaluated against two human chronic myeloid leukemia cell lines in vitro. Most of them exhibited potent growth inhibition with IC50 values in the nanomolar range as well as markedly reduced resistance factors. The most potent compound, Y8 exhibited an IC50 of 0.046+/-0.003MUM against resistance K562/ADR cells, showing more significant than that of adriamycin and etoposide, respectively. Furthermore, Y8 efficiently triggered cell cycle arrest at S phase and simultaneously induced apoptosis in K562/ADR cells. Meanwhile, Y8 also regulated the expression levels of cell cycle- and apoptosis-related proteins. Additionally, Y8 stimulated the ERK1/2 signalling and reduced the expression of Pgp protein. Finally, on the basis of results obtained using U0126, an ERK1/2 inhibitor, the ERK1/2 signalling pathway was proposed for the multidrug resistance-reversing effect of Y8 in K562/ADR cells. Together, Y8 could be a novel potential MDR reversal agent for the treatment of drug-resistant leukemia. PMID- 27503682 TI - Synthesis of novel flavone derivatives possessing substituted benzamides and their biological evaluation against human cancer cells. AB - Baicalein is a well-known flavone derivative that possesses diverse biological properties, such as anticancer, antioxidant and anti-inflammatory activities. Numerous baicalein derivatives, including 5,6,7-trimethoxyflavone, have been synthesized with the aim of enhancing its inherent biological activities. In the present work, new flavones, possessing an N-aroylamine-substituent on the B-ring, were synthesized to improve the cytotoxicity of baicalein and 5,6,7 trimethoxyflavone against human cancer cell lines. The majority of the flavones synthesized exhibited greater cytotoxicity than baicalein and 5,6,7 trimethoxyflavone against HepG2 and MCF-7 cells. Among them, compounds 5n, possessing a 3-methoxybenzoylamino group, exhibited great cytotoxic effects on HepG2 (GI50=7.06MUM) and MCF-7 (GI50=7.67MUM) cells. In contrast, N-aroylamine substituted 5-hydroxy-6,7-dimethoxyflavone derivatives showed greater cytotoxicity against MCF-7 than HepG2 cells, indicating that the replacement of a 5-methoxy group on the A-ring with a 5-hydroxy group has a marked influence on the cytotoxicity profile. PMID- 27503683 TI - Non-canonical modulators of nuclear receptors. AB - Like G protein-coupled receptors (GPCRs) and protein kinases, nuclear receptors (NRs) are a rich source of pharmaceutical targets. Over 80 NR-targeting drugs have been approved for 18 NRs. The focus of drug discovery in NRs has hitherto been on identifying ligands that bind to the canonical ligand binding pockets of the C-terminal ligand binding domains (LBDs). Due to the development of drug resistance and selectivity concerns, there has been considerable interest in exploring other, non-canonical ligand binding sites. Unfortunately, the potencies of compounds binding at other sites have generally not been sufficient for clinical development. However, the situation has changed dramatically over the last 3years, as compounds with sufficient potency have been reported for several NR targets. Here we review recent developments in this area from a medicinal chemistry point of view in the hope of stimulating further interest in this area of research. PMID- 27503684 TI - Systematic chemical modifications of single stranded siRNAs significantly improved CTNNB1 mRNA silencing. AB - Single-stranded silencing RNAs (ss siRNA), while not as potent as duplex RNAs, have the potential to become a novel platform technology in RNA interference based gene silencing by virtue of their simplicity and plausibly favorable characteristics in pharmacokinetics and biodistribution. Like other therapeutic pharmaceutical agents, ss siRNA can be optimized to achieve higher potency through a structure-activity based approach. Systematic chemical modification at each position of a 21-mer oligonucleotide identified 2',5'-linked 3' deoxythymidine (3dT) at position 1 and locked nucleic acids (LNAs) at the seed region as key components to afford significant enhancement in knockdown activity both in vitro and in vivo. Further optimization by additional chemical modifications should enable ss siRNA as an alternative gene silencing modality. PMID- 27503685 TI - Nature-inspired design of tetraindoles: Optimization of the core structure and evaluation of structure-activity relationship. AB - Building on the initial successful optimization of a novel series of tetraindoles, a second generation of the compounds with changes in the core phenyl ring was synthesized to improve anticancer properties. 17 new compounds with different rigidity, planarity, symmetry and degree of conjugation of their core structures to 5-hydroxyindole units were synthesized. All the compounds were fully characterized and tested against breast cancer cell line (MDA-MB-231). The results revealed that the core structure is required for activity and it should be aromatic, rigid, planar, symmetrical and conjugated for optimal activity. Compound 29, which has strong anticancer activity against various tumor-derived cell lines, including Mahlavu (hepatocellular), SK-HEP-1 (hepatic), HCT116 (colon), MIA PaCa-2 (pancreatic), H441 (lung papillary), A549 (lung), H460 (non small cell lung) and CL1-5 (lung carcinoma) with IC50 values ranging from 0.19 to 3.50MUM, was generated after series of successive optimizations. It was found to induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in the non-obese diabetic-severe combined immunodeficiency (NOD/SCID) mice bearing xenografted MIA PaCa-2 human pancreatic cancer. PMID- 27503686 TI - Amino acid amides of piperic acid (PA) and 4-ethylpiperic acid (EPA) as NorA efflux pump inhibitors of Staphylococcus aureus. AB - A total of eighteen piperic acid (PA) and 4-ethylpiperic acid (EPA) amides (C1 C18) with alpha-, beta- and gamma-amino acids were synthesized, characterized and evaluated for their efflux pump inhibitory activity against ciprofloxacin resistant Staphylococcus aureus. The amides were screened against NorA overexpressing S. aureus SA-1199B and wild type S. aureus SA-1199 using ethidium bromide as NorA efflux pump substrate. EPI C6 was found to be most potent and reduced the MIC of ciprofloxacin by 16 fold followed by C18 which showed 4 fold reduction of MIC. Ethidium bromide efflux inhibition and accumulation assay proved these compounds as NorA inhibitors. PMID- 27503687 TI - Metabolism of poplar salicinoids by the generalist herbivore Lymantria dispar (Lepidoptera). AB - The survival of insect herbivores on chemically defended plants may often depend on their ability to metabolize these defense compounds. However, only little knowledge is available on how insects actually process most plant defense compounds. We investigated the metabolism of salicinoids, a major group of phenolic glycosides in poplar and willow species, by a generalist herbivore, the gypsy moth (Lymantria dispar). Seven salicinoid metabolites identified in gypsy moth caterpillar feces were mostly conjugates with glucose, cysteine or glycine. Two of the glucosides were phosphorylated, a feature not previously reported for insect metabolites of plant defense compounds. The origins of these metabolites were traced to specific moieties of three major poplar salicinoids ingested, salicin, salicortin and tremulacin. Based on the observed metabolite patterns we were able to deduce the initial steps of salicinoid breakdown in L. dispar guts, which involves cleavage of ester bonds. The conjugated molecules were effectively eliminated within 24 h after ingestion. Some of the initial breakdown products (salicin and catechol) demonstrated negative effects on insect growth and survival in bioassays on artificial diets. Gypsy moth caterpillars with prior feeding experience on salicinoid-containing poplar foliage converted salicinoids to the identified metabolites more efficiently than caterpillars pre-fed an artificial diet. The majority of the metabolites we identified were also produced by other common poplar-feeding insects. The conversion of plant defenses like salicinoids to a variety of water-soluble sugar, phosphate and amino acid conjugates and their subsequent excretion fits the general detoxification strategy found in insect herbivores and other animals. PMID- 27503688 TI - u1 -Opioid receptors in the dorsomedial and ventrolateral columns of the periaqueductal grey matter are critical for the enhancement of post-ictal antinociception. AB - Generalised tonic and tonic-clonic seizures are followed by significant increase in nociceptive thresholds in both laboratory animals and humans. The endogenous opioid peptides play a role in antinociceptive signalling, and the periaqueductal grey matter (PAG) is recruited to induce analgesia. Thus, the aim of this investigation was to evaluate the role of u1 -opioid receptors in the dorsomedial (dm) and ventrolateral (vl) columns of PAG in post-ictal antinociception. Pentylenetetrazole (PTZ; 64 mg/kg), which is an ionotropic GABA-mediated Cl- influx antagonist, was intraperitoneally (IP) administered to induce tonic-clonic seizures in Wistar rats. The tail-flick test was used to measure the nociceptive threshold. Microinjections of naltrexone (5.0 ug/0.2 uL), which is a non selective opioid receptor antagonist, in both dmPAG and vlPAG decreased the tonic clonic seizure-induced antinociception in seizing animals from 10 to 120 min after seizures. Furthermore, microinjections of the u1 -opioid receptor-selective antagonist naloxonazine (5.0 ug/0.2 uL) into the dmPAG decreased post-ictal antinociception immediately after convulsive reactions and from 10 to 90 min after seizures. However, vlPAG-pretreatment with naloxonazine at the same concentration decreased the post-ictal antinociception 30 min after the onset of tonic-clonic seizures and the nociceptive threshold returned to basal values 120 min after seizures. These findings indicate that u1 -opioid receptor-signalling mechanisms in both dmPAG and vlPAG play a relevant role in the organisation of post-ictal antinociception. In addition, u1 -opioid receptors in the dmPAG rather than in vlPAG seem to be more critically recruited during the antinociception induced by generalised tonic-clonic seizures. PMID- 27503689 TI - Becoming business critical: Knowledge for Healthcare. AB - Significant progress has been made in implementing Knowledge for Healthcare. This editorial reports the central contribution of effective partnerships and the involvement of librarians and knowledge specialists in this work. There are compelling business priorities. Key elements of work-streams on demonstrating impact, workforce development and streamlining are indicated, along with areas of growing importance - knowledge management, embedded roles and health information for the public and patients. Knowledge, and the skills to help people to use it, are business critical. PMID- 27503690 TI - Demonstrating the financial impact of clinical libraries: a systematic review. AB - OBJECTIVE: The purpose of this review is to evaluate the tools used to measure the financial value of libraries in a clinical setting. METHODS: Searches were carried out on ten databases for the years 2003-2013, with a final search before completion to identify any recent papers. RESULTS: Eleven papers met the final inclusion criteria. There was no evidence of a single 'best practice', and many metrics used to measure financial impact of clinical libraries were developed on an ad hoc basis locally. The most common measures of financial impact were value of time saved, value of resource collection against cost of alternative sources, cost avoidance and revenue generated through assistance on grant submissions. Few papers provided an insight into the longer term impact on the library service resulting from submitting return on investment (ROI) or other financial impact statements. CONCLUSIONS: There are limited examples of metrics which clinical libraries can use to measure explicit financial impact. The methods highlighted in this literature review are generally implicit in the measures used and lack robustness. There is a need for future research to develop standardised, validated tools that clinical libraries can use to demonstrate their financial impact. PMID- 27503691 TI - Empowering international nursing students to become effective library users. AB - This article summarises the research conducted for a dissertation which addressed the needs of students and academic staff of the Bachelor of Nursing International programme at St. Angela's College, Ireland. Aoife Murray completed an MSc Econ Information and Library Studies in 2015 from Aberystwyth University via distance learning. She gained a distinction for her work and has co-written the article with Hugh Preston, her dissertation supervisor. Aoife highlights the recommendations she made as a result of her research and the programme put in place to deliver those recommendations. She also reports on some early evaluations of the new programme. AM. PMID- 27503692 TI - International collaborations in learning and teaching: perspectives from a visiting professorship. AB - This article provides a reflection on the outcomes of an international collaboration between health librarians and academics at York St John University and Pacific University Oregon. In particular, it describes how a month-long visiting professorship from an academic with a clinical librarian background at the Faculty of Health and Life Sciences helped to develop and inform teaching practice in the areas of information literacy and evidence-based health practice on health programmes at Pacific University. Perspectives are offered from both institutions on the rich exchange of knowledge and practice that took place during the visit and the ongoing impact it has had on teaching practices. H. S. PMID- 27503693 TI - Hormonal therapy for endometriosis: from molecular research to bedside. AB - Endometriotic lesions are associated with hormonal imbalance, including increased estrogen synthesis, metabolism and progesterone resistance. These hormonal changes cause increased proliferation, inflammation, pain and infertility. Hormonal imbalances are targets for treatment. Therapeutic strategies and innovations of hormonal drugs for endometriosis are increasing. Acting on estrogen receptors are hormonal drugs decreasing systemic and local estrogen synthesis (GnRH analogs, GnRH antagonists, Aromatase inhibitors) or estrogen activity (selective estrogen receptor modulators). The progesterone resistance is counteracted by progestins (Medroxyprogesterone acetate, Dienogest, Danazol, Levonorgestrel) or by Selective progesterone receptor modulators, a class of drugs under development. The future trend will be to define new drugs to use for prolonged period of time and with poor side effects considering endometriosis a chronic disease. PMID- 27503694 TI - Diagnosing Infection in Patients Undergoing Conversion of Prior Internal Fixation to Total Hip Arthroplasty. AB - BACKGROUND: Criteria for diagnosis of infected internal fixation implants at the time of conversion to total hip arthroplasty (THA) are not clear. The purpose of this study is to identify risk factors for infection in patients undergoing conversion to THA. METHODS: We retrospectively reviewed patients at a single institution who underwent conversion to THA from 2009 to 2014. Patients were diagnosed with infection preoperatively using Musculoskeletal Infection Society criteria or postoperatively if they were found to have positive cultures intraoperatively at the time of conversion surgery. Medical comorbidities and preoperative inflammatory markers were compared between infected and noninfected groups. Univariate and multivariate logistic regression analysis were performed to identify independent risk factors for infection. Receiver operating characteristic curves were generated to determine test performance of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). A post hoc power analysis was performed. RESULTS: Thirty-three patients were included in the study. Six patients (18%) were diagnosed with infection. We found no association between comorbidities and infection in this cohort. The mean ESR and CRP were higher in infected (ESR = 41.6 mm/h, CRP = 2.0 mg/dL) vs noninfected (ESR = 19.3 mm/h, CRP = 1.3 mg/dL) groups (both P < .01). ESR >30 mm/h (odds ratio 28.8, 95% confidence interval 2.6-315.4, P = .001) and CRP >1.0 mg/dL (odds ratio 11.5, 95% confidence interval 1.6-85.2, P = .01) were strongly associated with infection. Receiver operating characteristic curves for ESR (area under the curve [AUC] = 0.89) and CRP (AUC = 0.89) demonstrated good fit. CONCLUSION: We report a high incidence of infection in patients who underwent conversion to THA. Preoperative ESR and CRP are effective screening tools though occult infections may still be missed. Patients with borderline or elevated inflammatory markers should raise strong suspicion for infection. PMID- 27503695 TI - Preoperative Glycemic Control on Total Joint Arthroplasty Patient-Perceived Outcomes and Hospital Costs. AB - BACKGROUND: The purpose of this study was to determine the influence of preoperative glycemic control in diabetic patients undergoing a primary total hip or knee arthroplasty. We wanted to study patient-perceived outcomes in the medium term, the length of stay, hospital costs, and rate of short-term postoperative complications. METHODS: One hundred twenty consecutive primary total joint arthroplasties (TJAs) performed in type 2 diabetic patients were stratified into 2 groups representing optimal and suboptimal preoperative glycemic control, based on serum levels of glycated hemoglobin (HbA1c), and those groups compared. RESULTS: The mean follow-up time was 5.9 years (range, 2.1-10.7 years). Both groups demonstrated improvement in all patient-perceived outcome measures after TJA, with no significant difference detected in any change of a measure between the groups. No significant difference was detected in the length of stay, hospital costs, or rate of short-term postoperative complications between the groups. CONCLUSION: Preoperative glycemic control in type 2 diabetic patients undergoing TJA did not affect patient-perceived outcomes in the medium term. Optimal vs suboptimal glycemic control in these patients also had no effect on the length of stay, hospital costs, or rate of short-term postoperative complications. PMID- 27503696 TI - Infection Is Not a Risk Factor for Perioperative and Postoperative Blood Loss and Transfusion in Revision Total Hip Arthroplasty. AB - BACKGROUND: Septic hip revisions are associated with greater complications and higher costs than aseptic revisions. It is unclear whether blood loss and transfusion requirements are different in septic and aseptic revisions. We hypothesized that the blood loss and transfusion are dependent on the complexity of the revision surgery and patient's general health rather than the presence of infection. METHODS: We retrospectively reviewed 626 revision total hip arthroplasties in 547 patients between 2009 and 2013. All the procedures were classified as septic (n = 120) or aseptic (n = 506) based on the Musculoskeletal Infection Society criteria for periprosthetic joint infection. Independent risk factors for transfusion and blood loss were analyzed using a multiple regression analysis. RESULTS: The transfusion rate was higher in septic revisions (septic = 108/120 [90%], aseptic = 370/506 [73%]; P < .001), so was the average amount of blood loss (septic = 2533 +/- 161 mL, aseptic = 1974 +/- 68 mL; P < .001). After adjusting for potential confounders, infection was not an independent risk factor for transfusion (P = .176) or blood loss (P = .437). Increasing age (P = .004), higher American Society of Anesthesiologists score (P = .047), lower preoperative hemoglobin (P < .001), cell saver use (P < .001), and complex revision surgery (P < .001) were independently associated with greater risk of transfusion. CONCLUSIONS: Although blood loss and transfusion rates were higher in septic revisions, the presence of infection alone did not increase the risk of transfusion or blood loss. Blood management strategies in revision total hip arthroplasties should be guided by the type of surgery planned and patient's preoperative health rather than the presence of infection. PMID- 27503697 TI - Comparison of Midterm Outcomes of Minimally Invasive Computer-Assisted vs Minimally Invasive Jig-Based Total Knee Arthroplasty. AB - BACKGROUND: Minimally invasive surgery (MIS) has perceived advantages in the early postoperative stage for total knee arthroplasty (TKA). It is not clear whether the improved radiographic alignment achieved by computer-assisted navigation surgery (CAS) improves midterm clinical outcomes. The aim of this study was to compare patient outcomes of MIS TKA performed with and without CAS after a minimum follow-up of 7 years. METHODS: Between 2007 and 2009, 50 patients underwent CAS and MIS TKA, and 50 patients underwent jig-based MIS TKA in this prospective study. Ninety-six patients were evaluated after a mean follow-up of 7.7 years, and clinical and radiological evaluations were performed. RESULTS: Midterm results demonstrated that the Knee Society knee score, function score, and range of motion were comparable in the 2 groups. The percentage of patients with the mechanical axis within +/-3 degrees of neutral was significantly higher in the CAS group than in the jig-based group (94% vs 79%, respectively; P = .038). No knees had loosening after TKA. However, 1 patient in the CAS group demonstrated late infection 4 years postoperatively. CONCLUSION: CAS did not improve midterm outcomes after MIS TKA compared with jig-based surgery, although CAS reduced outliers in coronal alignment. PMID- 27503698 TI - Interactions between mitochondrial and nuclear DNA in mammalian cells are non random. AB - Chromosome Conformation Capture techniques regularly detect physical interactions between mitochondrial and nuclear DNA (i.e. mito-nDNA interactions) in mammalian cells. We have evaluated mito-nDNA interactions captured by HiC and Circular Chromosome Conformation Capture (4C). We show that these mito-nDNA interactions are statistically significant and shared between biological and technical replicates. The most frequent interactions occur with repetitive DNA sequences, including centromeres in human cell lines and the 18S rDNA in mouse cortical astrocytes. Our results demonstrate a degree of selective regulation in the identity of the interacting mitochondrial partners confirming that mito-nDNA interactions in mammalian cells are not random. PMID- 27503699 TI - Early changes of brain connectivity in primary open angle glaucoma. AB - Our aim was to assess in primary open angle glaucoma (POAG), a major cause of irreversible blindness worldwide, whether diffuse brain changes recently shown in advanced stage can be detected since the early stage. We used multimodal magnetic resonance imaging (MRI) in 57 patients with the three POAG stages and in 29 age matched normal controls (NC). Voxelwise statistics was performed with nonparametric permutation testing. Compared with NC, disrupted anatomical connectivity (AC) was found in the whole POAG group along the visual pathway and in nonvisual white matter tracts (P < 0.001). Moreover, POAG patients showed decreased functional connectivity (FC) in the visual (P = 0.004) and working memory (P < 0.001) networks whereas an increase occurred in the default mode (P = 0.002) and subcortical (P < 0.001) networks. Altered AC and FC were already present in early POAG (n = 14) in both visual and nonvisual systems (P <= 0.01). Only severe POAG (n = 30) showed gray matter atrophy and this mapped on visual cortex (P < 0.001) and hippocampus (P < 0.001). Increasing POAG stage was associated with worsening AC in both visual and nonvisual pathway (P < 0.001), progressive atrophy in the hippocampus and frontal cortex (P < 0.003). Most of the structural and functional alterations within and outside the visual system showed correlation (P < 0.001 to 0.02) with computerized visual field and retinal nerve fiber layer thickness. In conclusion, the complex pathogenesis of POAG includes widespread damage of AC and altered FC within and beyond the visual system since the early disease stage. The association of brain MRI changes with measures of visual severity emphasizes the clinical relevance of our findings. Hum Brain Mapp 37:4581-4596, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27503700 TI - Quantitative analyses of cellularity and proliferative activity reveals the dynamics of the central canal lining during postnatal development of the rat. AB - According to previous opinion, the derivation of neurons and glia from the central canal (CC) lining of the spinal cord in rodents should occur in the embryonic period. Reports of the mitotic activity observed in the lining during postnatal development have often been contradictory, and proliferation was ascribed to the generation of ependymocytes, which are necessary for the elongation of CC walls. Our study quantifies the intensity of proliferation and determines the cellularity of the CC lining in reference to lumbar spinal segment L4 during the postnatal development of rats. The presence of dividing cells peaks in the CC lining on postnatal day 8 (P8), with division occurring in 19.2% +/- 3.2% of cells. In adult rats, 3.6% +/- 0.9% of cells still proliferate, whereas, in mice, 10.3% +/- 2.3% of cells at P8 and only 0.6% +/- 0.2% of cells in the CC lining in adulthood are proliferating. In the rat, the length of the cell cycle increases from 100.3 +/- 35.7 hours at P1 to 401.4 +/- 80.6 hours at P43, with a sudden extension between P15 and P22. Despite the intensive proliferation, the total cellularity of the CC lining at the L4 spinal segment significantly descended in from P8 to P15. According to our calculations, the estimated cellularity was significantly higher compared with the measured cellularity of the CC lining at P15. Our results indicate that CC lining serves as a source of cells beyond ependymal cells during the first postnatal weeks of the rat. J. Comp. Neurol. 525:693-707, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27503701 TI - Effect of assisted hatching on pregnancy outcomes: a systematic review and meta analysis of randomized controlled trials. AB - Emerging evidence suggests that assisted hatching (AH) techniques may improve clinical pregnancy rates, particularly in poor prognosis patients; however, there still remains considerable uncertainty. We conducted a meta-analysis to verify the effect of AH on pregnancy outcomes. We searched for related studies published in PubMed, Web of Science, and Cochrane library databases from start dates to October 10, 2015. Totally, 36 randomized controlled trials with 6459 participants were included. Summary odds ratios (ORs) with 95% confidence intervals (CIs) for whether by AH or not were estimated. We found a significant increase in clinical pregnancy (OR = 1.16, 95% CI = 1.00-1.36, I(2) = 48.3%) and multiple pregnancy rates (OR = 1.50, 95% CI = 1.11-2.01, I(2) = 44.0%) with AH when compared to the control. Numerous subgroup analyses stratified by hatching method, conception mode, extent of AH, embryos transfer status, and previous failure history were also carried out. Interestingly, significant results of clinical pregnancy as well as multiple pregnancy rates were observed among women who received intracytoplasmic sperm injection, and who received AH which the zona were completely removed. In summary, this meta-analysis supports that AH was associated with an increased chance of achieving clinical pregnancy and multiple pregnancy. Whether AH significantly changes live birth and miscarriage rates needs further investigations. PMID- 27503702 TI - Learning from facial expressions in individuals with Williams syndrome. AB - BACKGROUND: Despite high levels of social engagement, the social competence of individuals with Williams syndrome (WS) is frequently compromised. This descriptive study explores the ability of young people with WS to learn from facial expressions when provided as a source of feedback for their actions. METHOD: Using a novel task, the ability to interpret facial expressions and adapt behaviour after receiving feedback in the form of happy or angry faces was assessed in 12 participants with WS aged between 10 and 28 years and with a mean nonverbal mental age of 6.5 years, and in typically developing (TD) children aged between 4 and 7 years. RESULTS: Individuals with WS were able to use facial expressions as feedback in a manner commensurate with their mental age, only when other cognitive demands were low. Their performance profile differed from that of the TD children matched for mental age and from the performance profile of 4 year olds. CONCLUSIONS: Possible explanations for the unique performance profile observed in the participants with WS are discussed. The results highlight the need to examine social competencies in the context of the cognitive demands characteristic of social environments. PMID- 27503703 TI - Prevalence of autism and attention-deficit-hyperactivity disorder in Down syndrome: a population-based study. AB - AIM: To investigate the prevalence of autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD) in a population-based group of children and adolescents with Down syndrome, and to relate the findings to level of intellectual disability and to medical conditions. METHOD: From a population based cohort of 60 children and adolescents with Down syndrome, 41 individuals (29 males, 12 females; mean age 11y, age range 5-17y) for whom parents gave consent for participation were clinically assessed with regard to ASD and ADHD. The main instruments used were the Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, Swanson, Nolan, and Pelham-IV Rating Scale, and the Adaptive Behavior Assessment System-II. RESULTS: High rates of ASD and ADHD were found: 17 (42%) and 14 (34%) of the 41 children met DSM criteria for ASD and ADHD respectively. INTERPRETATION: Children with Down syndrome and coexisting neurodevelopmental/neuropsychiatric disorders in addition to intellectual disability and medical disorders constitute a severely disabled group. Based on the results, we suggest that screening is implemented for both ASD and ADHD, at the age of 3 to 5 years and early school years respectively, to make adequate interventions possible. PMID- 27503704 TI - Molecular insights of organochlorine biocide-induced toxicity in zebrafish: Whole adult-organism toxicogenomics, targeted gene expression and histological analyses. PMID- 27503705 TI - ? AB - The identification of individual eukaryotic and prokaryotic cells is the backbone of clinical pathology and provides crucial information about the genesis and progression of a disease. While most commonly fluorescent-label based methods are applied, label-free methods, such as Raman spectroscopy, are elegant alternatives. A major disadvantage of Raman spectroscopy is the low signal yield resulting in long acquisition times, making it impractical for high-throughput clinical analysis. As a rule, Raman-based cell identification relies on high resolution Raman spectra. This comes at a cost of detected Raman photons. In this letter we show that while the proper biochemical characterization of cells requires high-resolution Raman spectra, the proper classification of cells does not. By varying the slit-width between 50 um and 500 um it is possible to show that detected Raman signal from eukaryotic cells increased up to seven-fold. Raman-based cell classification was performed on three cancer cell lines: Jurkat, MiaPaca2, and Capan1, at three different resolutions 8 cm-1 , 24 cm-1 , and 48 cm 1 . Moreover, we have simulated the resolution decrease due to low-diffraction gratings by binning neighboring pixels together. In both cases the cells were well classifiable using support vectors machine (SVM). For anyone working in the field of Raman spectroscopy this picture of Sir C.V. Raman is recognizable, even with reduced spatial resolution. Raman spectra of eukaryotic cells can also be recognized even with six fold reduced spectral resolution. PMID- 27503706 TI - NFL-lipid nanocapsules for brain neural stem cell targeting in vitro and in vivo. AB - The replacement of injured neurons by the selective stimulation of neural stem cells in situ represents a potential therapeutic strategy for the treatment of neurodegenerative diseases. The peptide NFL-TBS.40-63 showed specific interactions towards neural stem cells of the subventricular zone. The aim of our work was to produce a NFL-based drug delivery system able to target neural stem cells through the selective affinity between the peptide and these cells. NFL TBS.40-63 (NFL) was adsorbed on lipid nanocapsules (LNC) whom targeting efficiency was evaluated on neural stem cells from the subventricular zone (brain) and from the central canal (spinal cord). NFL-LNC were incubated with primary neural stem cells in vitro or injected in vivo in adult rat brain (right lateral ventricle) or spinal cord (T10). NFL-LNC interactions with neural stem cells were different depending on the origin of the cells. NFL-LNC showed a preferential uptake by neural stem cells from the brain, while they did not interact with neural stem cells from the spinal cord. The results obtained in vivo correlate with the results observed in vitro, demonstrating that NFL-LNC represent a promising therapeutic strategy to selectively deliver bioactive molecules to brain neural stem cells. PMID- 27503708 TI - Mode-locking via dissipative Faraday instability. AB - Emergence of coherent structures and patterns at the nonlinear stage of modulation instability of a uniform state is an inherent feature of many biological, physical and engineering systems. There are several well-studied classical modulation instabilities, such as Benjamin-Feir, Turing and Faraday instability, which play a critical role in the self-organization of energy and matter in non-equilibrium physical, chemical and biological systems. Here we experimentally demonstrate the dissipative Faraday instability induced by spatially periodic zig-zag modulation of a dissipative parameter of the system spectrally dependent losses-achieving generation of temporal patterns and high harmonic mode-locking in a fibre laser. We demonstrate features of this instability that distinguish it from both the Benjamin-Feir and the purely dispersive Faraday instability. Our results open the possibilities for new designs of mode-locked lasers and can be extended to other fields of physics and engineering. PMID- 27503707 TI - Ultrasound-guided therapeutic modulation of hepatocellular carcinoma using complementary microRNAs. AB - Treatment options for patients with hepatocellular carcinoma (HCC) are limited, in particular in advanced and drug resistant HCC. MicroRNAs (miRNA) are non coding small RNAs that are emerging as novel drugs for the treatment of cancer. The aim of this study was to assess treatment effects of two complementary miRNAs (sense miRNA-122, and antisense antimiR-21) encapsulated in biodegradable poly (lactic-co-glycolic acid) nanoparticles (PLGA-NP), administered by an ultrasound guided and microbubble-enhanced delivery approach in doxorubicin-resistant and non-resistant human HCC xenografts. Proliferation and invasiveness of human HCC cells after miRNA-122/antimiR-21 and doxorubicin treatment were assessed in vitro. Confocal microscopy and qRT-PCR were used to visualize and quantitate successful intracellular miRNA-loaded PLGA-NP delivery. Up and down-regulation of miRNA downstream targets and multidrug resistance proteins and extent of apoptosis were assessed in vivo in treated human HCC xenografts in mice. Compared to single miRNA therapy, combination therapy with the two complementary miRNAs resulted in significantly (P<0.05) stronger decrease in cell proliferation, invasion, and migration of HCC cells as well as higher resensitization to doxorubicin. Ultrasound-guided delivery significantly increased in vivo miRNA loaded PLGA-NP delivery in human HCC xenografts compared to control conditions by 5-9 fold (P<0.001). miRNA-loaded PLGA-NP were internalized in HCC cells and anti apoptotic proteins were down regulated with apoptosis in ~27% of the tumor volume of doxorubicin-resistant human HCC after a single treatment with complementary miRNAs and doxorubicin. Thus, ultrasound-guided delivery of complementary miRNAs is highly efficient in the treatment of doxorubicin- resistant and non-resistant HCC. Further development of this new treatment approach could aid in better treatment of patients with HCC. PMID- 27503709 TI - Pseudomonas turukhanskensis sp. nov., isolated from oil-contaminated soils. AB - A bacterial strain named IB1.1T was isolated in a screening of hydrocarbon degrading bacteria from oil-contaminated soils on the territory of the Turukhansk District of Krasnoyarsk Krai, East Siberia, Russia. The 16S rRNA gene sequence had 98.7 % identity with respect to the closest phylogenetic relative, Pseudomonas granadensis F-278,770T, and the next most closely related species with 98.6 % similarity was Pseudomonaspunonensis, suggesting that IB1.1T should be classified within the genus Pseudomonas. The analysis of housekeeping genes rpoB, rpoD and gyrB showed similarities lower than 90 % in all cases with respect to the closest relatives, confirming its phylogenetic affiliation. The strain showed a polar flagellum. The respiratory quinone was Q9. The major fatty acids were 16 : 1omega7c/16 : 1omega6c (summed feature 3), 18 : 1omega7c and 16 : 0. The strain was oxidase- and catalase-positive, but the arginine dihydrolase system was not present. Nitrate reduction, urease and beta-galactosidase production, and aesculin hydrolysis were negative. The temperature range for growth was 4-34 degrees C, and the strain could grow at pH 11. The DNA G+C content was 58.5 mol%. DNA-DNA hybridization results showed values of less than 30 % relatedness with respect to the type strains of the eight most closely related species. Therefore, the dataset of genotypic, phenotypic and chemotaxonomic data support the classification of strain IB1.1T into a novel species of the genus Pseudomonas, for which the name Pseudomonasturukhanskensis sp. nov. is proposed. The type strain is IB1.1T (=VKM B-2935T=CECT 9091T). PMID- 27503710 TI - Dietary alpha-ketoglutarate increases cold tolerance in Drosophila melanogaster and enhances protein pool and antioxidant defense in sex-specific manner. AB - Alpha-ketoglutarate (AKG) is an important intermediate in Krebs cycle which bridges the metabolism of amino acids and carbohydrates. Its effects as a dietary supplement on cold tolerance were studied in Drosophila melanogaster Canton S. Two-day-old adult flies fed at larval and adult stages with AKG at moderate concentrations (5-10mM) recovered faster from chill coma (0 degrees C for 15min or 3h) than control ones. The beneficial effect of AKG on chill coma recovery was not found at its higher concentrations, which suggests hormetic like action of this keto acid. Time of 50% observed mortality after 2h recovery from continuous cold exposure (-1 degrees C for 3-31h) (LTi50) was higher for flies reared on 10mM AKG compared with control ones, showing that the diet with AKG enhanced insect cold tolerance. In parallel with enhancement of cold tolerance, dietary AKG improved fly locomotor activity. Metabolic effects of AKG differed partly in males and females. In males fed on AKG, there were no differences in total protein and free amino acid levels, but the total antioxidant capacity, catalase activity and low molecular mass thiol content were higher than in control animals. In females, dietary AKG promoted higher total antioxidant capacity and higher levels of proteins, total amino acids, proline and low molecular mass thiols. The levels of lipid peroxides were lower in both fly sexes reared on AKG as compared with control ones. We conclude that both enhancement of antioxidant system capacity and synthesis of amino acids can be important for AKG-promoted cold tolerance in D. melanogaster. The involvement of AKG in metabolic pathways of Drosophila males and females is discussed. PMID- 27503711 TI - Local weather conditions have complex effects on the growth of blue tit nestlings. AB - Adverse weather conditions are expected to result in impaired nestling development in birds, but empirical studies have provided equivocal support for such a relationship. This may be because the negative effects of adverse weather conditions are masked by parental effects. Globally, ambient temperatures, rainfall levels and wind speeds are all expected to increase in a changing climate and so there is a need for a better understanding of the relationship between weather conditions and nestling growth. Here, we describe a correlative study that examined the relationships between local temperatures, rainfall levels and wind speeds and the growth of individual blue tit (Cyanistes caeruleus) nestlings in relation to their hatching order and sex. We found that changes in a range of morphological characters were negatively related to both temperature and wind speed, but positively related to rainfall. These patterns were further influenced by the hatching order of the nestlings but not by nestling sex. This suggests that the predicted changes in local weather conditions may have complex effects on nestling growth, but that parents may be able to mitigate the adverse effects via adaptive parental effects. We therefore conclude that local weather conditions have complex effects on avian growth and the implications for patterns of avian growth in a changing climate are discussed. PMID- 27503712 TI - The use of thermal imaging to assess the effectiveness of ice massage and cold water immersion as methods for supporting post-exercise recovery. AB - Cold water immersion (CWI) and ice massage (IM) are commonly used treatments to prevent the delay onset of muscle soreness (DOMS); however, little is known on their relative benefits and effectiveness to lower tissue temperature. This study was designed to evaluate the effectiveness of IM and CMI on tissue temperature and potential benefit to preventing DOMS. The research encompassed 36 subjects divided into three groups of twelve depending on the form of recovery: ice massage (IM), cold-water immersion (CWI), or passive recovery (PAS). All the participants were asked to jump as high as possible from a full squat for one minute. Thermal imaging was conducted at rest, immediately following the exercise, immediately after the trial, following the recovery treatment, and after 30min of rest. Their pain levels were assessed using the Visual Analogue Scale (VAS). After applying the selected method for supporting recovery, the LA level decreased by 4.25mmol/L in the IM group, and by 4.96mmol/L in the CWI group (IM vs. CWI p>0.05). The 2.75mmol/L decrease in lactate concentration in the PAS group was significantly lower than in the other groups (IM vs. PAS p<0.05/ CWI vs. PAS p<0.01). In both groups, Tsk after 30min was significantly lower (DeltaTsk~0.5 degrees C) than at rest (p<0.05). In turn, Tsk in the PAS group returned to the resting values (p>0.05). Seventy-two hours after the exercise, a clear decrease in discomfort was observed in the IM and CWI groups compared to the PAS group. The two applied treatments have proven to be effective both in utilizing lactate and preventing DOMS. Depending on training requirements, we recommend the use of IM when athletes experience localized muscle fatigue. One the other hand, CWI is recommended in situations of global or generalized muscle injury or fatigue. PMID- 27503713 TI - Mitigation of heat stress-related complications by a yeast fermentate product. AB - Heat stress results in a multitude of biological and physiological responses which can become lethal if not properly managed. It has been shown that heat stress causes significant adverse effects in both human and animals. Different approaches have been proposed to mitigate the adverse effects caused by heat stress, among which are special diet and probiotics. We characterized the effect of the yeast fermentate EpiCor (EH) on the prevention of heat stress-related complications in rats. We found that increasing the body temperature of animals from 37.1+/-0.2 to 40.6+/-0.2 degrees C by exposure to heat (45 degrees C for 25min) resulted in significant morphological changes in the intestine. Villi height and total mucosal thickness decreased in heat-stressed rats pre-treated with PBS in comparison with control animals not exposed to the heat. Oral treatment of rats with EH before heat stress prevented the traumatic effects of heat on the intestine. Changes in intestinal morphology of heat-stressed rats, pre-treated with PBS resulted in significant elevation of lipopolysaccharides (LPS) level in the serum of these animals. Pre-treatment with EH was effective in the prevention of LPS release into the bloodstream of heat-stressed rats. Our study revealed that elevation of body temperature also resulted in a significant increase of the concentration of vesicles released by erythrocytes in rats, pre treated with PBS. This is an indication of a pathological impact of heat on the erythrocyte structure. Treatment of rats with EH completely protected their erythrocytes from this heat-induced pathology. Finally, exposure to heat stress conditions resulted in a significant increase of white blood cells in rats. In the group of animals pre-treated with EH before heat stress, the white blood cell count remained the same as in non-heated controls. These results showed the protective effect of the EH product in the prevention of complications, caused by heat stress. PMID- 27503714 TI - Hypothermal effects on survival, energy homeostasis and expression of energy related genes of swimming crabs Portunus trituberculatus during air exposure. AB - Previously, dry or semi-dry approach under the hypothermal condition is proved to be an alternative method in transport of live swimming crabs Portunus trituberculatus. However, we wondered whether this method can improve crab survival when temperature is kept as cool as possible. In this study, we hypothesized that there is a thermal threshold below which dry or semi-dry approach (air exposure) could cause crab physiological disruption and therefore aggravate their mortality. To test the above hypothesis, crabs (23 degrees C) were exposed to air at temperatures ranging from 4 to 16 degrees C. Results showed that crabs had a worse survival and vigor at temperatures below 12 degrees C. Then we tested crab energy metabolism to explore the possible reason. It was shown that total adenine nucleotide and adenylate energy charge in gills were remarkably reduced by air exposure of below 12 degrees C. This increased the need for crabs to re-balance energy metabolism, which was indicated by the upregulation of AMPKalpha and HIF-1alpha. Meanwhile, there was a significant increase of the expression of Na(+)/K(+)-ATPase, V-type ATPase and HSP90 at temperatures below 12 degrees C, while all treatments shared a similar level of hemocyanin, urate and lactate in hemolymph and expression of cytochrome c oxidase and NADH-ubiquinone reductase in gills. These results implied that dry or semi dry approach below 12 degrees C could exert detrimental effects on P. trituberculatus, and perturbation of energy homeostasis, which is more related with changes of energy-demanding physiological pathways, is a possible reason of crab death and poor vigor. PMID- 27503715 TI - 'Optimal thermal range' in ectotherms: Defining criteria for tests of the temperature-size-rule. AB - Thermal performance curves for population growth rate r (a measure of fitness) were estimated over a wide range of temperature for three species: Coleps hirtus (Protista), Lecane inermis (Rotifera) and Aeolosoma hemprichi (Oligochaeta). We measured individual body size and examined if predictions for the temperature size rule (TSR) were valid for different temperatures. All three organisms investigated follow the TSR, but only over a specific range between minimal and optimal temperatures, while maintenance at temperatures beyond this range showed the opposite pattern in these taxa. We consider minimal and optimal temperatures to be species-specific, and moreover delineate a physiological range outside of which an ectotherm is constrained against displaying size plasticity in response to temperature. This thermal range concept has important implications for general size-temperature studies. Furthermore, the concept of 'operating thermal conditions' may provide a new approach to (i) defining criteria required for investigating and interpreting temperature effects, and (ii) providing a novel interpretation for many cases in which species do not conform to the TSR. PMID- 27503716 TI - Regional warming and the thermal regimes of American crocodile nests in the Tempisque Basin, Costa Rica. AB - Spatial variation in global climate change makes population-specific responses to this enigmatic threat pertinent on a regional scale. Organisms with temperature dependent sex determination (TSD) potentially possess a unique physiological susceptibility that threatens population viability if rapid environmental effects on sex ratios render populations non-viable. A heavily male-biased sex ratio for hatchling American crocodiles of the Tempisque Basin, Costa Rica requires assessment of how nest temperature affects sex determination at this site, how females might compensate for these effects when creating nests, and how current patterns of climate change might alter future sex ratios and survival in hatchling cohorts. We demonstrate high within-nest variation in temperature but predict a female bias at hatching based on nest temperatures quantified here. Further, our data suggest that egg size and metabolic heating associated with this factor outweighs microhabitat parameters and depth in influencing nest thermal regimes. Finally, we document regional warming in the Tempisque Basin over the last 15 years and project that further heating over the next 15 years will not yield hatchling sex ratios as male biased as those currently found at this site. Thus, we find no support for nest temperature or climate change as likely explanations for male-biased American crocodile (Crocodylus acutus) sex ratios in the Tempisque Basin. PMID- 27503717 TI - Acute effects of a dopamine/norepinephrine reuptake inhibitor on neuromuscular performance following self-paced exercise in cool and hot environments. AB - Dopamine/norepinephrine (DA/NE) reuptake inhibitors have been used to manipulate the central mechanisms affecting arousal and motivation during exercise. Eight healthy, physically active males performed 30min fixed-intensity cycling at 50% Wmax followed by 30min of self paced time trial (TT) with each section interspersed with a 30 s maximal sprint at 9, 19 and 29min. The DA/NE re-uptake inhibitor administered was bupropion (BUP) versus a placebo (PLA) in either warm (32 degrees C, BUP32 or PLA32) or moderate (20 degrees C; BUP20, PLA20) ambient conditions. Core and skin temperature, heart rate and perceptual responses, neuromuscular and hormonal measures were assessed at multiple times throughout the trials and post exercise. Time trial performance remained unchanged across conditions (12.7-13.1km) although core temperature was elevated in the fixed intensity section of the trials for BUP32 and BUP20 but continued to rise only in BUP32 during the time trial reaching 38.6 degrees C (P<0.05). NE increased in all conditions from pre-exercise with BUP32 values peaking at the end of TT to 1245.3+/-203.1pg/mL (P<0.05) compared to the other conditions. Neuromuscular responses were similar among conditions although peak force was significantly reduced from pre (262+/-31N) to post (202+/-31N, P<0.05) exercise along with contraction duration (22%, P<0.05) in BUP20. We conclude that DA/NE re-uptake inhibitors influenced thermoregulation in the heat but not exercise performance. DA/NE re-uptake inhibitors are likely to act centrally to override the inhibitory signals for the cessation of exercise with these drugs acting peripherally to reduce the twitch characteristics of skeletal muscle in cooler conditions. PMID- 27503718 TI - Thermal variation and factors influencing vertical migration behavior in Daphnia populations. AB - The antipredator behavior diel vertical migration (DVM), common in aquatic keystone species Daphnia, involves daily migration from warmer surface waters before dawn to cooler deeper waters after dusk. Plasticity in Daphnia DVM behavior optimizes fitness via trade-offs between growth, reproduction, and predator avoidance. Migration behavior is affected by co-varying biotic and abiotic factors, including light, predator cues, and anthropogenic stressors making it difficult to determine each factor's individual contribution to the variation in this behavior. This study aims to better understand this ecologically significant behavior in Daphnia by: (1) determining how Daphnia pulicaria thermal preferences vary within and among natural populations; (2) distinguishing the role of temperature verses depth in Daphnia vertical migration; and (3) defining how two anthropogenic stressors (copper and nickel) impact Daphnia migratory behavior. Simulated natural lake stratification were constructed in 8L (0.5m tall, 14.5cm wide) water columns to monitor under controlled laboratory conditions the individual effects of temperature gradients, depth, and metal stressors on Daphnia vertical migration. Three major findings are reported. First, while no difference in thermal preference was found among the four populations studied, within lake populations variability among isolates was high. Second, decoupling temperature and depth revealed that depth was a better predictor of Daphnia migratory patterns over temperature. Third, exposure to environmentally relevant concentrations of copper or nickel inhibited classic DVM behavior. These findings revealed the high variability in thermal preference found within Daphnia populations, elucidated the individual roles that depth and temperature have on migratory behavior, and showed how copper and nickel can interfere with the natural response of Daphnia to fish predator cues. Thus contributing to the body of knowledge necessary to predict how natural populations of Daphnia will be affected by climate related changes in lake temperatures and increased presence of anthropogenic stressors. PMID- 27503719 TI - Thermal equilibrium and temperature differences among body regions in European plethodontid salamanders. AB - Information on species thermal physiology is extremely important to understand species responses to environmental heterogeneity and changes. Thermography is an emerging technology that allows high resolution and accurate measurement of body temperature, but until now it has not been used to study thermal physiology of amphibians in the wild. Hydromantes terrestrial salamanders are strongly depending on ambient temperature for their activity and gas exchanges, but information on their body temperature is extremely limited. In this study we tested if Hydromantes salamanders are thermoconform, we assessed whether there are temperature differences among body regions, and evaluated the time required to reach the thermal equilibrium. During summers of 2014 and 2015 we analysed 56 salamanders (Hydromantes ambrosii and Hydromantes italicus) using infrared thermocamera. We photographed salamanders at the moment in which we found them and 1, 2, 3, 4, 5 and 15min after having kept them in the hands. Body temperature was equal to air temperature; salamanders attained the equilibrium with air temperature in about 8min, the time required to reach equilibrium was longer in individuals with large body size. We detected small temperature differences between body parts, the head being slightly warmer than the body and the tail (mean difference: 0.05 degrees C). These salamanders quickly reach the equilibrium with the environment, thus microhabitat measurement allows obtaining accurate information on their tolerance limits. PMID- 27503720 TI - Analysis of the energetic metabolism in cyclic Bedouin goats (Capra hircus): Nychthemeral and seasonal variations of some haematochemical parameters in relation with body and ambient temperatures. AB - Several studies have examined changes in some haematochemical parameters as a function of the different physiological status (cyclic, pregnant and lactating) of goats, but no relevant literature has exhaustively investigated these variations from anestrous to estrous stages in cyclic goats. In this paper, we report nychthemeral and seasonal variations in ambient and body temperatures, and in some haematochemical parameters (glycemia, cholesterolemia, triglyceridemia, creatininemia and uremia) measured during summer, winter and spring, in seven (7) experimental cyclic female Bedouin goats (Capra hircus) living in the Beni-Abbes region (Algerian Sahara desert). Cosinor rhythmometry procedure was used to determine the rhythmic parameters of ambient temperature and haematochemical parameters. To determine the effect of time of day on the rhythmicity of the studied parameters, as well as their seasonality, repeated measure analysis of variance (ANOVA) was applied. The results showed that in spite of the nychthemeral profile presented by the ambient temperature for each season, the body temperature remained in a narrow range, thus indicating a successful thermoregulation. The rhythmometry analysis showed a circadian rhythmicity of ambient temperature and haematochemical parameters with diurnal acrophases. A statistically significant effect of the time of day was shown on all studied haematochemical parameters, except on creatininemia. It was also found that only uremia, cholesterolemia and triglyceridemia followed the seasonal sexual activity of the studied ruminant. This study demonstrated the good physiological adaptation developed by this breed in response to the harsh climatic conditions of its natural environment. PMID- 27503721 TI - Effects of daily fluctuating temperatures on the Drosophila-Leptopilina boulardi parasitoid association. AB - Koinobiont parasitoid insects, which maintain intimate and long-term relationships with their arthropod hosts, constitute an association of ectothermic organisms that is particularly sensitive to temperature variations. Because temperature shows pronounced natural daily fluctuations, we examined if experiments based on a constant temperature range can mask the real effects of the thermal regime on host-parasitoid interactions. The effects of two fluctuating thermal regimes on several developmental parameters of the Drosophila larval parasitoid Leptopilina boulardi were analyzed in this study. Regime 1 included a range of 16-23-16 degrees C and regime 2 included a range of 16-21-26 21-16 degrees C (mean temperature 20.1 degrees C) compared to a 20.1 degrees C constant temperature. Under an average temperature of 20.1 degrees C, which corresponds to a cold condition of L. boulardi development, we showed that the success of parasitism is significantly higher under a fluctuating temperature regime than at constant temperature. A fluctuating regime also correlated with a reduced development time of the parasitoids. In contrast, the thermal regime did not affect the ability of Drosophila to resist parasitoid infestation. Finally, we demonstrated that daily temperature fluctuation prevented the entry into diapause for this species, which is normally observed at a constant temperature of 21 degrees C. Overall, the results reveal that constant temperature experiments can produce misleading results, highlighting the need to study the thermal biology of organisms under fluctuating regimes that reflect natural conditions as closely as possible. This is particularly a major issue in host parasitoid associations, which constitute a good model to understand the effect of climate warming on interacting species. PMID- 27503722 TI - Feeding rumen-protected gamma-aminobutyric acid enhances the immune response and antioxidant status of heat-stressed lactating dairy cows. AB - This experiment was conducted to investigate the effects of rumen-protected gamma aminobutyric acid (GABA) on immune function and antioxidant status in heat stressed dairy cows. Sixty Holstein dairy cows were randomly assigned to 1 of 4 treatments according to a completely randomized block design. The treatments consisted of 0 (control), 40, 80, or 120mg of GABA/kg DM from rumen-protected GABA. The trial lasted 10 weeks. The average temperature-humidity indices at 0700, 1400 and 2200h were 78.4, 80.2 and 78.7, respectively. Rectal temperatures decreased linearly at 0700, 1400, and 2200h with increasing GABA. As the GABA increased, the immunoglobulin (Ig) A and IgG contents and the proportions of CD4(+) and CD8(+) T lymphocytes increased linearly (P<0.05), whereas concentrations of interleukin (IL)-2, IL-4, IL-6 and tumor necrosis factor-alpha (TNF-alpha) decreased linearly (P<0.05). The activities of superoxide dismutase (SOD), glutathione-peroxidase (GSH-PX) and total antioxidant capacity (T-AOC) increased linearly (P<0.05), whereas malondialdehyde (MDA) content decreased linearly (P<0.05) with increasing GABA. These results indicate that rumen protected GABA supplementation to heat-stressed dairy cows can improve their immune function and antioxidant activity. PMID- 27503723 TI - The effect of skin reflectance on thermal traits in a small heliothermic ectotherm. AB - Variation in colour patterning is prevalent among and within species. A number of theories have been proposed in explaining its evolution. Because solar radiation interacts with the pigmentation of the integument causing light to either be reflected or absorbed into the body, thermoregulation has been considered to be a primary selective agent, particularly among ectotherms. Accordingly, the colour mediated thermoregulatory hypothesis states that darker individuals will heat faster and reach higher thermal equilibria while paler individuals will have the opposite traits. It was further predicted that dark colouration would promote slower cooling rates and higher thermal performance temperatures. To test these hypotheses we quantified the reflectance, selected body temperatures, performance optima, as well as heating and cooling rates of an ectothermic vertebrate, Lampropholis delicata. Our results indicated that colour had no influence on thermal physiology, as all thermal traits were uncorrelated with reflectance. We suggest that crypsis may instead be the stronger selective agent as it may have a more direct impact on fitness. Our study has improved our knowledge of the functional differences among individuals with different colour patterns, and the evolutionary significance of morphological variation within species. PMID- 27503724 TI - Bicephality, a seldom occurring developmental deformity in Tegenaria atrica caused by alternating temperatures. AB - The experiment was aimed at demonstrating the relationship between deformities of the front part of the prosoma accompanied by changes in the brain structure in bicephalous Tegenaria atrica and exposure of their embryos to temperature fluctuations. By exposing spider embryos to alternating temperatures of 14 and 32 degrees C for the first 10 days of embryonic development, we obtained eight two headed individuals, subsequently divided into three groups according to morphological differences. We described in detail morphological abnormalities of the prosoma identified in members of each group. Histological examination confirmed a close relationship between morphological deformities and the brain structure of teratogenically changed spiders. The fusion of appendages (pedipalps and chalicerae) was accompanied by the fusion of corresponding ganglia. The absence of appendages (pedipalps) was accompanied by the absence of corresponding ganglia. This correlation may have resulted from previously impaired neuromere development which led to changes in the morphological structure of the prosoma. Since no deformities were identified in control animals, it can be concluded that bicephaly was caused by exposing embryos to alternating temperatures. PMID- 27503725 TI - The role of nest surface temperatures and the brain in influencing ant metabolic rates. AB - Thermal limits of insects can be influenced by recent thermal history: here we used thermolimit respirometry to determine metabolic rate responses and thermal limits of the dominant meat ant, Iridomyrmex purpureus. Firstly, we tested the hypothesis that nest surface temperatures have a pervasive influence on thermal limits. Metabolic rates and activity of freshly field collected individuals were measured continuously while ramping temperatures from 44 degrees C to 62 degrees C at 0.25 degrees C/minute. At all the stages of thermolimit respirometry, metabolic rates were independent of nest surface temperatures, and CTmax did not differ between ants collected from nest with different surface temperatures. Secondly, we tested the effect of brain control on upper thermal limits of meat ants via ant decapitation experiments ('headedness'). Decapitated ants exhibited similar upper critical temperature (CTmax) results to living ants (Decapitated 50.3+/-1.2 degrees C: Living 50.1+/-1.8 degrees C). Throughout the temperature ramping process, 'headedness' had a significant effect on metabolic rate in total (Decapitated VCO2 140+/-30ulCO2mg(-1)min(-1): Living VCO2 250+/-50 CO2mg(-1)min( 1)), as well as at temperatures below and above CTmax. At high temperatures (>44 degrees C) pre- CTmax the relationships between I. purpureus CTmax values and mass specific metabolic rates for living ants exhibited a negative slope whilst decapitated ants exhibited a positive slope. The decapitated ants also had a significantly higher Q10:25-35 degrees C when compared to living ants (1.91+/ 0.43 vs. 1.29+/-0.35). Our findings suggest that physiological responses of ants may be able to cope with increasing surface temperatures, as shown by metabolic rates across the thermolimit continuum, making them physiologically resilient to a rapidly changing climate. We also demonstrate that the brain plays a role in respiration, but critical thermal limits are independent of respiration levels. PMID- 27503727 TI - Sitting in the sun: Nest microhabitat affects incubation temperatures in seabirds. AB - During incubation parent birds are committed to a nest site and endure a range of ambient conditions while regulating egg temperatures. Using artificial eggs containing temperature loggers alongside ambient temperature (Ta) controls, incubation profiles were determined for four tropical seabird species at different nest site locations. Camera traps were used for ad-hoc behavioural incubation observations. Eggs experienced a range of temperatures during incubation and varied significantly between species and in some cases between different microhabitats within a species. Such variation has important consequences in the phenotypic expression of both physical and physiological traits of chicks, and ultimately species fitness. Exposed nest sites were more strongly correlated to Tas. Camera traps highlighted different incubation strategies employed by these species that could be related to trade-offs in predator defence, feeding habits, and temperature regulation of eggs. This study provides evidence that species with similar breeding habits could be affected by environmental stressors in similar ways and that the differences shown in nest site selection could negate some of these effects. We propose that habitats providing suitable nest microclimates will become increasingly important for the successful breeding of seabird species, particularly under predicted climate change scenarios. PMID- 27503726 TI - Chronic oral administration of pine bark extract (flavangenol) attenuates brain and liver mRNA expressions of HSPs in heat-exposed chicks. AB - Exposure to a high ambient temperature (HT) can cause heat stress, which has a huge negative impact on physiological functions. Cellular heat-shock response is activated upon exposure to HT for cellular maintenance and adaptation. In addition, antioxidants are used to support physiological functions under HT in a variety of organisms. Flavangenol, an extract of pine bark, is one of the most potent antioxidants with its complex mixture of polyphenols. In the current study, chronic (a single daily oral administration for 14 days) or acute (a single oral administration) oral administration of flavangenol was performed on chicks. Then the chicks were exposed to an acute HT (40+/-1 degrees C for 3h) to examine the effect of flavangenol on the mRNA expression of heat-shock protein (HSP) in the brain and liver. Rectal temperature, plasma aspartate aminotransferase (AAT), a marker of liver damage, and plasma corticosterone as well as metabolites were also determined. HSP-70 and -90 mRNA expression, rectal temperature, plasma AAT and corticosterone were increased by HT. Interestingly, the chronic, but not the acute, administration of flavangenol caused a declining in the diencephalic mRNA expression of HSP-70 and -90 and plasma AAT in HT exposed chicks. Moreover, the hepatic mRNA expression of HSP-90 was also significantly decreased by chronic oral administration of flavangenol in HT chicks. These results indicate that chronic, but not acute, oral administration of flavangenol attenuates HSP mRNA expression in the central and peripheral tissues due to its possible role in improving cellular protective functions during heat stress. The flavangenol-dependent decline in plasma AAT further suggests that liver damage induced by heat stress was minimized by flavangenol. PMID- 27503729 TI - Black or white? Physiological implications of roost colour and choice in a microbat. AB - Although roost choice in bats has been studied previously, little is known about how opposing roost colours affect the expression of torpor quantitatively. We quantified roost selection and thermoregulation in a captive Australian insectivorous bat, Nyctophilus gouldi (n=12) in winter when roosting in black and white coloured boxes using temperature-telemetry. We quantified how roost choice influences torpor expression when food was provided ad libitum or restricted in bats housed together in an outdoor aviary exposed to natural fluctuations of ambient temperature. Black box temperatures averaged 5.1 degrees C (maximum 7.5 degrees C) warmer than white boxes at their maximum daytime temperature. Bats fed ad libitum chose black boxes on most nights (92.9%) and on 100% of nights when food-restricted. All bats used torpor on all study days. However, bats fed ad libitum and roosting in black boxes used shorter torpor and spent more time normothermic/active at night than food-restricted bats and bats roosting in white boxes. Bats roosting in black boxes also rewarmed passively more often and to a higher skin temperature than those in white boxes. Our study suggests that N. gouldi fed ad libitum select warmer roosts in order to passively rewarm to a higher skin temperature and thus save energy required for active midday rewarming as well as to maintain a normothermic body temperature for longer periods at night. This study shows that colour should be considered when deploying bat boxes; black boxes are preferable for those bats that use passive rewarming, even in winter when food availability is reduced. PMID- 27503728 TI - Impact of water temperature on the growth and fatty acid profiles of juvenile sea cucumber Apostichopus japonicus (Selenka). AB - The present study determined the changes in the fatty acid (FA) profiles of juvenile sea cucumber Apostichopus japonicus in response to the varied water temperature. Sea cucumbers with similar size (4.02+/-0.11g) were cultured for 8 weeks at 14 degrees C, 18 degrees C, 22 degrees C and 26 degrees C, respectively. At the end of the experiment, the specific growth rate (SGR) and the profiles of FAs in neutral lipids and phospholipids of the juvenile sea cucumbers cultured at different temperatures were determined. The SGRs of the sea cucumbers cultured at 26 degrees C significantly decreased 46.3% compared to thos cultured at 18 degrees C. Regression analysis showed that the SGR-temperature (T) relationship can be expressed as SGR=-0.0073T(2)+0.255T -1.0231 (R(2)=0.9936) and the highest SGR was predicted at 17.5 degrees C. For the neutral lipids, the sum of saturated FAs (SFAs), monounsaturated FAs (MUFAs) or polyunsaturated FAs (PUFAs) of the sea cucumbers that were cultured at the water temperature from 18 degrees C-26 degrees C did not change significantly, indicating the insensitivity of FA profiles for the neutral lipids of sea cucumbers in response to increasing water temperature. For phospholipids, the sum of PUFAs in the sea cucumbers dramatically decreased with the gradually increased water temperature. The sum of SFAs and MUFAs of sea cucumbers, however, increased with the gradually elevated water temperature. In particular, the contents of highly unsaturated fatty acids (HUFAs), including eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA), in the phospholipids of the sea cucumbers decreased 37.2% and 26.1%, respectively, when the water temperature increased from 14 degrees C to 26 degrees C. In summary, the sea cucumbers A. japonicus can regulate the FA compositions, especially the contents of EPA and DHA, in the phospholipids so as to adapt to varied water temperature. PMID- 27503730 TI - Nest thermoregulation of the paper wasp Polistes dominula. AB - Wasps of the genus Polistes build combs without any cover and hence are insufficiently protected against temperature fluctuations. Due to this fact, different types of thermoregulation of Polistes dominula nests were investigated using the modern method of thermography. The study of active mechanisms for nest thermoregulation revealed no brood incubation or clustering behaviour of P. dominula. Furthermore, we found out that wing fanning for cooling the nest was almost undetectable (4 documented cases). However, we could convincingly record that water evaporation is most effective for nest cooling. By the direct comparison of active (with brood and adults) and non-active (without brood and adults) nests, the start of cooling by water evaporation was detected above maximum outside temperatures of 25 degrees C or at nest temperatures above 35 degrees C. The powerful role of water in nest cooling was manifested by an average decrease of temperature of single cells of about 8 degrees C and a mean duration of 7min until the cells reached again their initial temperature. The investigation of passive thermoregulatory mechanisms revealed that the architecture of the nest plays an important role. Based on the presented results, it can be assumed that the vertical orientation of cells helps maintaining the warmth of nests during the night, whereas the pedicel assists in cooling the nest during the day. Therefore, our study of nest thermoregulation has revealed that P. dominula wasps regulate the temperature of their nest actively by evaporative cooling and passively by a careful site selection and the architecture of their nests. PMID- 27503731 TI - Seasonal metabolic acclimatization in the herbivorous desert lizard Uromastyx philbyi (Reptilia: Agamidea) from western Saudi Arabia. AB - Many ectotherms adjust their metabolic rate seasonally in association with variations in environmental temperatures. The range and direction of these seasonal changes in reptilian metabolic rates are thought to be linked to the seasonality of activity and energy requirements. The present study was conducted to measure the standard metabolic rate (SMR) of seasonally-acclimatized Uromastyx philbyi with different body masses at 20, 25, 30, 35 and 40 degrees C using open flow respirometry during the four seasons. SMR was mass-dependent. The mean exponent of mass, "b", in the metabolism-body mass relation was 0.76 (variance=0.0007). Likewise, SMR increased as temperature increased with low Q10 values at high temperatures and high Q10 values at low temperatures. The lowest and highest Q10 values were achieved for temperature ranges of 30-35 degrees C for summer-acclimatized dhabbs (Q10=1.6) and 20-25 degrees C for winter acclimatized dhabbs (Q10=3.9). Seasonal acclimatization effects were obvious at all temperatures (20-40 degrees C). Winter-acclimatized dhabbs had the lowest metabolic rates at all temperatures. The seasonal acclimatization patterns displayed by U. philbyi may represent a valuable adaptation for herbivorous desert lizards that inhabit subtropical deserts to facilitate activity during their active seasons and to conserve energy during inactivity at low temperatures. PMID- 27503732 TI - Effect of tidal regime on the thermal tolerance of the marine gastropod Lunella smaragda (Gmelin 1791). AB - The tidal cycle around New Zealand results in spring low tides consistently occurring during the hottest part of the day (mid-afternoon) in north-eastern New Zealand, and during the cooler dawn/dusk periods in the north-west of the country. We hypothesised that due to mid-afternoon spring low tides, intertidal populations residing at north-eastern sites would show greater thermotolerance than their north-west conspecifics. To test this we used the marine gastropod, Lunella smaragda, which were collected from sites on both the East and West coasts of the Auckland region and exposed to an acute heat shock. Thermotolerance was measured as survivorship (LT50), drop down time (time to heat coma) and thermal stability of the anaerobic energy producing enzyme Tauropine dehydrogenase. Furthermore, temperature loggers were deployed at each site so as to record and compare thermal regimes among sites. A strong temperature spike associated with spring low tide was found at all sites, and maximal temperatures of all East coast sites were higher than West coast sites (in some case by up to 10 degrees C). In terms of thermotolerance, mortality of L. smaragda occurred at 42 degrees C leading to 100% mortality at 45 degrees C. However, comparison of LT50 showed snails were equally thermotolerant regardless of site of collection. Similar results were found in TDH thermal stability with animals from all sites showing an approximately 80% decrease in enzyme activity after 10min exposure to 42 degrees C. Whilst drop down times were different among sites these were correlated with animal size as opposed to site of collection. Thus, East coast populations of L. smaragda appear no more thermotolerant than their West coast counterparts. Such a result is concerning as maximal temperatures at East coast sites already exceed the LT50 values of L. smaragda recorded in the lab suggesting these populations have less of a thermal safety margin. PMID- 27503733 TI - Brown adipose tissue thermogenesis does not explain the intra-administration hyperthermic sign-reversal induced by serial administrations of 60% nitrous oxide to rats. AB - Initial administration of >=60% nitrous oxide (N2O) to rats promotes hypothermia primarily by increasing whole-body heat loss. We hypothesized that the drug promotes heat loss via the tail and might initially inhibit thermogenesis via brown adipose tissue (BAT), major organs of thermoregulation in rodents. Following repeated administrations, N2O inhalation evokes hyperthermia underlain by increased whole-body heat production. We hypothesized that elevated BAT thermogenesis plays a role in this thermoregulatory sign reversal. Using dual probe telemetric temperature implants and infrared (IR) thermography, we assessed the effects of nine repeated 60% N2O administrations compared to control (con) administrations on core temperature, BAT temperature, lumbar back temperature and tail temperature. Telemetric core temperature, telemetric BAT temperature, and IR BAT temperature were reduced significantly during initial 60% N2O inhalation (p<=0.001 compared to con). IR thermography revealed that acute N2O administration unexpectedly reduced tail temperature (p=0.0001) and also inhibited IR lumbar temperature (p<0.0001). In the 9th session, N2O inhalation significantly increased telemetric core temperature (p=0.007) indicative of a hyperthermic sign reversal, yet compared to control administrations, telemetric BAT temperature (p=0.86), IR BAT temperature (p=0.85) and tail temperature (p=0.47) did not differ significantly. Thus, an initial administration of 60% N2O at 21 degrees C may promote hypothermia via reduced BAT thermogenesis accompanied by tail vasoconstriction as a compensatory mechanism to limit body heat loss. Following repeated N2O administrations rats exhibit a hyperthermic core temperature but a normalized BAT temperature, suggesting induction of a hyperthermia-promoting thermogenic adaptation of unknown origin. PMID- 27503734 TI - Non-linear dual-phase-lag model for analyzing heat transfer phenomena in living tissues during thermal ablation. AB - In this article, a non-linear dual-phase-lag (DPL) bio-heat transfer model based on temperature dependent metabolic heat generation rate is derived to analyze the heat transfer phenomena in living tissues during thermal ablation treatment. The numerical solution of the present non-linear problem has been done by finite element Runge-Kutta (4,5) method which combines the essence of Runge-Kutta (4,5) method together with finite difference scheme. Our study demonstrates that at the thermal ablation position temperature predicted by non-linear and linear DPL models show significant differences. A comparison has been made among non-linear DPL, thermal wave and Pennes model and it has been found that non-linear DPL and thermal wave bio-heat model show almost same nature whereas non-linear Pennes model shows significantly different temperature profile at the initial stage of thermal ablation treatment. The effect of Fourier number and Vernotte number (relaxation Fourier number) on temperature profile in presence and absence of externally applied heat source has been studied in detail and it has been observed that the presence of externally applied heat source term highly affects the efficiency of thermal treatment method. PMID- 27503735 TI - Thermal equilibrium responses in Guzerat cattle raised under tropical conditions. AB - The literature is very sparse regarding research on the thermal equilibrium in Guzerat cattle (Bos indicus) under field conditions. Some factors can modify the physiological response of Guzerat cattle, such as the reactivity of these animals to handling. Thus, the development of a methodology to condition and select Guzerat cattle to acclimate them to the routine collection of data without altering their physiological response was the objective of the preliminary experiment. Furthermore, the animals selected were used in the main experiment to determine their thermal equilibrium according to the thermal environment. For this proposal, the metabolic heat production and heat exchange between the animal and the environment were measured simultaneously in the field with an indirect calorimetry system coupled to a facial mask. The results of the preliminary experiment showed that the respiratory rate could demonstrate that conditioning efficiently reduced the reactivity of the animals to experimental handling. Furthermore, the respiratory rate can be used to select animals with less reactivity. The results of the main experiment demonstrate that the skin, hair coat surface and expired air temperature depend on the air temperature, whereas the rectal temperature depends on the time of day; consequently, the sensible heat flow was substantially reduced from 70 to 20Wm(-2) when the air temperature increased from 24 to 34 degrees C. However, the respiratory latent heat flow increased from 10 to 15Wm(-2) with the same temperature increase. Furthermore, the metabolic heat production remained stable, independent of the variation of the air temperature; however, it was higher in males than in females (by approximately 25%). This fact can be explained by the variation of the ventilation rate, which had a mean value of 1.6 and 2.2Ls(-1) for females and males, respectively. PMID- 27503736 TI - The impact of geographical origin of two strains of the herbivore, Eccritotarsus catarinensis, on several fitness traits in response to temperature. AB - Adaptation to temperature changes is vital to reduce adverse effects on individuals, and some may present phenotypic changes, which might be accompanied with physiological costs in fitness traits. The objective of this study was to determine whether the two strains of the herbivore Eccritotarsus catarinensis, a biological control agent against water hyacinth in South Africa, differ in their responses to temperature according to their geographical origin. We experimentally quantified the responses of the two strains, at three constant temperatures: 20 degrees C, 25 degrees C and 30 degrees C, using laboratory cultures that originated from Brazil and Peru, where climates differ. Reproductive output, egg hatching rate, sex ratio and longevity were recorded at each temperature. Fitness traits for both strains were significantly reduced at 30 degrees C compared with 25 degrees C and 20 degrees C in two successive generations. Nonetheless, Peruvian individuals continued their development at 30 degrees C, whereas Brazilian individuals that succeeded in emerging did not continue their development. In contrast, sex ratio was unaffected by temperature. The Peruvian strain of E. catarinensis presented different phenotypes depending on temperature and was more adapted to extreme high temperature than the Brazilian strain. The tropical origin of the population induces the insect to tolerate the extreme high temperature. We suggest that the Peruvian strain could be better suited for release to control water hyacinth in nature, particularly in regions where temperature is high. PMID- 27503737 TI - An efficient and inexpensive method for measuring long-term thermoregulatory behavior. AB - Thermoregulatory ability and behavior influence organismal responses to their environment. By measuring thermal preferences, researchers can better understand the effects that temperature tolerances have on ecological and physiological responses to both biotic and abiotic stressors. However, because of funding limitations and confounders, measuring thermoregulation can often be difficult. Here, we provide an effective, affordable (~$50 USD per unit), easy to construct, and validated apparatus for measuring the long-term thermal preferences of animals. In tests, the apparatus spanned temperatures from 9.29 to 33.94 degrees C, and we provide methods to further increase this range. Additionally, we provide simple methods to non-invasively measure animal and substrate temperatures and to prevent temperature preferences of the focal organisms from being confounded with temperature preferences of its prey and its humidity preferences. To validate the apparatus, we show that it was capable of detecting individual-level consistency and among individual-level variation in the preferred body temperatures of Southern toads (Anaxyrus terrestris) and Cuban tree frogs (Osteopilus septentrionalis) over three-weeks. Nearly every aspect of our design is adaptable to meet the needs of a multitude of study systems, including various terrestrial amphibious, and aquatic organisms. The apparatus and methods described here can be used to quantify behavioral thermal preferences, which can be critical for determining temperature tolerances across species and thus the resiliency of species to current and impending climate change. PMID- 27503738 TI - Thermal tolerance in the Andean toad Rhinella spinulosa (Anura: Bufonidae) at three sites located along a latitudinal gradient in Chile. AB - Rhinella spinulosa is one of the anuran species with the greatest presence in Chile. This species mainly inhabits mountain habitats and is distributed latitudinally along the western slope of the Andes Range. These habitats undergo great temperature fluctuations, exerting pressure on the amphibian. To identify the physiological strategies and thermal behavior of this species, we analyzed the temperature variables CTmin, CTmax, TTR, tauheat, and taucool in individuals of three sites from a latitudinal gradient (22 degrees S to 37 degrees S). The amphibians were acclimated to 10 degrees C and 20 degrees C and fed ad libitum. The results indicate that the species has a high thermal tolerance range, with a mean of 38.14+/-1.34 degrees C, a critical thermal maxima of 34.6-41.4 degrees C, and a critical thermal minima of 2.6-0.8 degrees C, classifying the species as eurythermic. Furthermore, there were significant differences in CTmax and TTR only in the northern site. The differences in thermal time constants between sites are due to the effects of size and body mass. For example, those from the central site had larger size and greater thermal inertia; therefore, they warmed and cooled in a slower manner. The wide thermal limits determined in R. spinulosa confirm that it is a thermo-generalist species, a characteristic that allows the species to survive in adverse microclimatic conditions. The level of plasticity in critical temperatures seems ecologically relevant and supports the acclimatization of thermal limits as an important factor for ectothermic animals to adapt to climate change. PMID- 27503739 TI - HIV charity criticises NHS England over "homophobic" PrEP statement. PMID- 27503740 TI - Identification of the earliest collagen- and plant-based coatings from Neolithic artefacts (Nahal Hemar cave, Israel). AB - Mortuary practices in human evolution record cognitive, social changes and technological innovations. The Neolithic Revolution in the Levant was a watershed in this domain that has long fascinated the archaeological community. Plaster modelled skulls are well known at Jericho and several other Neolithic sites, and in Nahal Hemar cave (Israel, ca. 8200 -7300 cal. BC) excavations yielded six unique human skulls covered with a black organic coating applied in a net pattern evoking a headdress. This small cave was used as storage for paraphernalia in the semi-arid area of the Judean desert and the dry conditions preserved other artefacts such as baskets coated with a similar dark substance. While previous analysis had revealed the presence of amino acids consistent with a collagen signature, in the present report, specific biomarkers were characterised using combined proteomic and lipid approaches. Basket samples yielded collagen and blood proteins of bovine origin (Bos genus) and a large sequence coverage of a plant protein charybdin (Charybdis genus). The skull residue samples were dominated by benzoate and cinnamate derivatives and triterpenes consistent with a styrax-type resin (Styrax officinalis), thus providing the earliest known evidence of an odoriferous plant resin used in combination with an animal product. PMID- 27503741 TI - New Insights into Dialysis Vascular Access: Introduction. PMID- 27503743 TI - Response to: a network meta-analysis of the relative efficacy of treatments for actinic keratosis of the face or scalp in Europe. PMID- 27503742 TI - Familial gain-of-function Nav1.9 mutation in a painful channelopathy. AB - OBJECTIVE: Gain-of-function mutations in Nav1.9 have been identified in three families with rare heritable pain disorders, and in patients with painful small fibre neuropathy. Identification and functional assessment of new Nav1.9 mutations will help to elucidate the phenotypic spectrum of Nav1.9 channelopathies. METHODS: Patients from a large family with early-onset pain symptoms were evaluated by clinical examination and genomic screening for mutations in SCN9A and SCN11A. Electrophysiological recordings and multistate modelling analysis were implemented for functional analyses. RESULTS: A novel Nav1.9 mutation, p.Arg222His, was identified in patients with early-onset pain in distal extremities including joints and gastrointestinal disturbances, but was absent from an asymptomatic blood relative. This mutation alters channel structure by substituting the highly conserved first arginine residue in transmembrane segment 4 (domain 1), the voltage sensor, with histidine. Voltage clamp recordings demonstrate a hyperpolarising shift and acceleration of activation of the p.Arg222His mutant channel, which make it easier to open the channel. When expressed in dorsal root ganglion neurons, mutant p.Arg222His channels increase excitability via a depolarisation of resting potential and increased evoked firing. CONCLUSIONS: This study expands the spectrum of heritable pain disorders linked to gain-of-function mutations in Nav1.9, strengthening human validation of this channel as a potential therapeutic target for pain. PMID- 27503744 TI - Proton Hopping as the Nerve Conduction Message. AB - BACKGROUND: The article proposes a new concept explaining nerve conduction information. The conduction is based upon proton hopping, the fastest known chemical reaction. A summary of the proton hopping at several parts of the nerve structure are described. METHODS: The details of each part of the nerve system are described in the article. RESULTS: A summary of the parts of the nerve structure involving the role of proton hopping, are expressed to give a complete picture of the nerve function and the role of proton hopping. CONCLUSION: An overall description of the function of the nerve is described in terms of the role of proton hopping as the mechanism of message passage. PMID- 27503745 TI - Association of HLA-DRB1 Gene Polymorphism with Risk of Asthma: A Meta-Analysis. AB - BACKGROUND The relationship between HLA-DRB1 alleles and asthma is controversial. The purpose of this study was to evaluate the relationship between HLA-DRB1 alleles and risk of asthma. MATERIAL AND METHODS We searched PubMed, Chinese National Knowledge Infrastructure (CNKI), Wan Fang (Chinese) database, and Chinese Biomedical Medical databases (CBM) to find studies on the relationship between HLA-DRB1 alleles and risk of asthma. We calculated the pooled odds ratio (OR) and 95% confidence interval (CI) using STATA 12.0. Finally, a total of 24 studies were included in this meta-analysis. RESULTS The results revealed that DRB1*03 was positively associated with risk of asthma (OR=1.51, 95%CI=1.27-1.80), and DRB1*15 was negatively associated with risk of asthma (OR=0.63, 95%CI=0.42 0.93), but no association was found in other HLA-DRB1 alleles. Subgroup analysis by age revealed that DRB1*03, DRB1*04, DRB1*09, and DRB1*15 were associated with asthma in children. Subgroup analysis by ethnicity showed that DRB1*03 and DRB1*15 were associated with asthma in whites, and DRB1*07 and DRB1*14 were associated with asthma in Asians. CONCLUSIONS This results of this meta-analysis suggest that HLA-DRB1 alleles are associated with asthma. PMID- 27503746 TI - What predicts a positive response to acupuncture? A secondary analysis of three randomised controlled trials of insomnia. AB - OBJECTIVE: Few studies have investigated the predictors of the specific and non specific effects of acupuncture. The aim of this secondary analysis was to determine patient characteristics that may predict a better treatment response to acupuncture for insomnia. METHODS: We pooled the data of three randomised, double blind, placebo-controlled trials of acupuncture for insomnia to examine sociodemographic variables, clinical characteristics, baseline sleep-wake variables, and treatment expectancy in relation to acupuncture response. Subjects with an improvement in insomnia severity index (ISI) scores of >=8 points from baseline to 1 week post-treatment were classified as responders. Factors were compared between responders and non-responders, and also by univariate and multivariate logistic regression analysis. RESULTS: A total of 116 subjects who received traditional needle acupuncture were included, of which 37 (31.9%) were classified as responders. Acupuncture responders had a higher educational level (p<0.01) and higher baseline ISI score (p<0.05), compared to non-responders. In the multivariate logistic regression analysis, only the number of years spent in full-time education remained significant as a predictor of treatment response (OR 1.21, 95% CI 1.06 to 1.38, p<0.01). CONCLUSIONS: Consistent with previous studies, our data suggest that the response to acupuncture is difficult to predict. Although the predictive power of educational level is weak overall, our findings provide potentially valuable information that could be built upon in further research (including a larger sample size), and may help to inform patient selection for the treatment of chronic insomnia with acupuncture in the future. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: #NCT00839592; Results, #NCT00838994; Results, and #NCT01707706; Results. PMID- 27503747 TI - Patient preference and evidence based decisions on anticoagulant therapy for atrial fibrillation. PMID- 27503748 TI - Shave to Save Face. AB - BACKGROUND: Basal cell carcinoma (BCC) is the most common cutaneous malignancy. Terminal hair is not routinely removed for assessment of BCCs on the scalp and yet may obscure the true size of scalp BCCs. This can compromise effective management. OBJECTIVE: To underscore the importance of removing terminal hair on the scalp for an accurate assessment of clinical margins of BCC on the scalp. METHODS: We report 2 cases of cutaneous BCC arising on the scalp. The size of the malignancies was underestimated because they were masked by hair growth. RESULTS: Removing terminal hair allowed for a full assessment of the extent of the tumours on hair-bearing scalp, which had been underestimated by 73% to 80% prior to shaving. CONCLUSION: Our cases highlight the importance of hair removal for complete assessment of cutaneous malignancy occurring on hair-bearing skin. PMID- 27503749 TI - A spectrophotometric assay for monoamine oxidase activity with 2, 4 dinitrophenylhydrazine as a derivatized reagent. AB - A simple, rapid and reliable spectrophotometry was developed to determine monoamine oxidase (MAO). In this study, 2,4-dinitrophenylhydrazine (DNPH), a classic derivatizing reagent, was used to detect MAO-dependent aldehyde production; and traditional DNPH spectrophotometry was simplified. Benzylamine and serotonin oxidation were catalyzed by MAO-B and MAO-A, respectively, to aldehydes. These were derivatized with DNPH, and the corresponding quinones were further formed by adding NaOH. These DNPH derivatives with large conjugated structures were directly measured spectrophotometrically at 465 nm and 425 nm, without the need for precipitating, washing and suspending procedures. The addition of NaOH caused a red shift of the maximum absorption wavelength of these derivatives, which reduced the interference of free DNPH. MAO-B protein was as low as 47.5 MUg in rat liver with correlation coefficients ranging within 0.995 0.999. This method is 2-3 times more sensitive than direct spectrophotometry. The detection of MAO inhibition through this method showed that IC50 values of rasagiline are 8.00 * 10(-9) M for MAO-B and 2.59 * 10(-7) M for MAO-A. These results are similar to the values obtained by direct spectrophotometry. Our study suggests that DNPH spectrophotometry is suitable to detect MAO activity, and has the potential for MAO inhibitor screening in the treatment of MAO-mediated diseases. PMID- 27503750 TI - Identification and comparative oridonin metabolism in different species liver microsomes by using UPLC-Triple-TOF-MS/MS and PCA. AB - Oridonin (ORI) is an active natural ent-kaurene diterpenoid ingredient with notable anti-cancer and anti-inflammation activities. Currently, a strategy was developed to identify metabolites and to assess the metabolic profiles of ORI in vitro using ultra-high-performance liquid chromatography-Triple/time-of-flight mass spectrometry (UPLC-Triple-TOF-MS/MS). Meanwhile, the metabolism differences of ORI in the liver microsomes of four different species were investigated using a principal component analysis (PCA) based on the metabolite absolute peak area values as the variables. Based on the proposed methods, 27 metabolites were structurally characterized. The results indicate that ORI is universally metabolized in vitro, and the metabolic pathway mainly includes dehydration, hydroxylation, di-hydroxylation, hydrogenation, decarboxylation, and ketone formation. Overall, there are obvious inter-species differences in types and amounts of ORI metabolites in the four species. These results will provide basic data for future pharmacological and toxicological studies of ORI and for other ent-kauranes diterpenoids. Meanwhile, studying the ORI metabolic differences helps to select the proper animal model for further pharmacology and toxicological assessment. PMID- 27503751 TI - Hepatic Vein Arrival Time for Diagnosis of Liver Cirrhosis: A 10-Year Single Center Experience With Contrast-Enhanced Sonography. AB - OBJECTIVES: To evaluate the performance of contrast-enhanced sonography with a second-generation contrast agent in assessing the severity of chronic diffuse liver disease and differentiating cirrhotic from noncirrhotic liver disease. METHODS: Contrast-enhanced sonography was performed after intravenous bolus injection of a second-generation contrast agent in 14 healthy control participants and 160 consecutive patients with cirrhotic and noncirrhotic liver disease (n = 78 and 82, respectively) enrolled between March 2004 and April 2014. The intensity of enhancement in a main hepatic vein was used to determine hepatic vein arrival time, time to peak intensity, and peak contrast enhancement. RESULTS: The hepatic vein arrival time was lower in cirrhotic patients compared with both noncirrhotic patients and controls (mean +/- SD, 15.0 +/- 2.8, 21.5 +/- 3.4, and 25.6 +/- 4.7 seconds, respectively; P < .05). The hepatic vein arrival time in noncirrhotic patients was also significantly lower than that in controls (P < .05). The time to peak intensity was significantly lower in cirrhotic patients compared with noncirrhotic patients and controls (40.7 +/- 13.7, 49.4 +/ 12.8, and 51.2 +/- 13.7 seconds; P < .05). A receiver operating characteristic curve analysis revealed that the hepatic vein arrival time more accurately excluded a diagnosis of liver cirrhosis than the time to peak intensity (area under the receiver operating characteristic curve, 0.953 versus 0.694). Specifically, a hepatic vein arrival time cutoff value of 17 seconds excluded liver cirrhosis with 91.1% sensitivity and 93.6% specificity. CONCLUSIONS: Contrast-enhanced sonography is a valid alternative method for noninvasive staging of liver diseases. The hepatic vein arrival time could be used to exclude liver cirrhosis in a clinical setting. PMID- 27503752 TI - Diagnostic Value of Contrast-Enhanced Sonography for Differentiation of Breast Lesions: A Meta-analysis. AB - OBJECTIVES: The purpose of this study was to systematically review and evaluate the diagnostic accuracy of contrast-enhanced sonography in the differential diagnosis of benign and malignant breast lesions. METHODS: The scientific literature databases PubMed and Embase were comprehensively searched for relevant studies before January 2015. Data were pooled to yield the summary sensitivity, specificity, and diagnostic odds ratio using meta-analysis software. RESULTS: A total of 29 studies with 2296 lesions were included in the analysis. The pooled sensitivity and specificity were 0.88 (95% confidence interval [CI], 0.86-0.90; inconsistency index [I(2)] = 77.9%) and 0.80 (95% CI, 0.78-0.83; I(2) = 84.0%), respectively. The pooled diagnostic odds ratio was 30.35 (95% CI, 15.75-58.48; I(2)= 82.1%), and the area under the summary receiver operating characteristic curve was 0.9115 (SE, 0.0243). CONCLUSIONS: The comprehensive results suggest that contrast-enhanced sonography could be a potentially effective method for differential diagnosis of benign and malignant breast lesions. PMID- 27503753 TI - Prenatal Diagnosis of an Aortopulmonary Window With an Interrupted Aortic Arch. AB - A prenatal aortopulmonary window with an interrupted aortic arch was detected in a 22-week-old fetus. The 3-vessel and trachea view showed a communication between the ascending aorta and the pulmonary artery. Early postnatal surgery was successful. A PubMed-based search identified all cases of prenatal aortopulmonary windows between 2002 and 2015. Nine articles were identified. The average gestational age at diagnosis was 28 weeks (range, 22-33 weeks). The most frequent aortopulmonary window was type I (40%). All cases were associated with congenital heart defects, mainly an interrupted aortic arch (50%). No chromosomal or extracardiac abnormalities were seen. Prenatal echocardiography is useful for early diagnosis of an aortopulmonary window. The prognosis depends on the time of surgery and the nature of the associated anomalies. PMID- 27503754 TI - Role of Strain Elastography in the Evaluation of Testicular Torsion: An Experimental Study. AB - OBJECTIVES: To evaluate the utility of real-time strain elastography in experimentally induced testicular torsion at different degrees and torsion hours. METHODS: Thirty-one Wistar albino rats were divided into 4 torsion groups by twisting left testes (group I, sham operated; group II, 360 degrees ; group III, 720 degrees ; and group IV, 1080 degrees ). Elastography was applied at the 8th and 24th hours of torsion. Elasticity patterns (pattern 1, soft testis; pattern 2, moderately soft testis; pattern 3, predominantly hard testis; and pattern 4, almost entirely hard testis) and strain ratios were recorded. Histopathologic evaluation was done at the 24th hour. Interobserver agreement was analyzed. RESULTS: Changes in elastographic patterns and strain ratios among groups II, III, and IV were statistically significant at both hours as determined by both radiologists (P < .01). Elastographic patterns changed from 2 to 3 in groups II and III to 4 in group III between the 8th and 24th hours (P < .05), but in group IV, patterns were reversed, and pattern 1 was observed at both hours. Pathologically severe necrosis (grade 4) was seen in left testes in group IV. In the other groups, pathologic grading in the left testes was as follows: mostly grade 1 in groups I and II and mostly grade 2 in group III. Elastography showed that right testes were affected in group IV, with significant differences in elastographic patterns and strain ratios (P < .01). Interobserver agreement for elastographic patterns in right testes was substantial at the 8th hour (kappa = 0.72) and otherwise excellent (kappa = 0.81-0.85). Concordance of strain ratios between observers was excellent for right and left testes at the 8th and 24th hours (intraclass correlation coefficients, 0.990 at the 8th hour and 0.987 at the 24th hour). CONCLUSIONS: Our results show that real-time strain elastography can be a complementary method in the evaluation of testicular tissue in testicular torsion and can guide surgeons in their surgical approach. PMID- 27503755 TI - On the Physical Basis of Pulmonary Sonographic Interstitial Syndrome. PMID- 27503756 TI - Contrast-Enhanced Sonographic Characteristics of Hepatic Inflammatory Pseudotumors. AB - A hepatic inflammatory pseudotumor, which can be misdiagnosed as a malignant tumor, is a relatively uncommon tumor with nonspecific imaging manifestations. As a new diagnostic technique, contrast-enhanced sonography has become increasingly important in the diagnosis of liver focal lesions. Here we present 3 cases of histologically confirmed hepatic inflammatory pseudotumors diagnosed with contrast-enhanced sonography. "Fast-in and centrifugal-out" may be a characteristic contrast-enhanced sonographic enhancement pattern in the diagnosis of hepatic inflammatory pseudotumors, which needs confirmation in further studies. PMID- 27503757 TI - Interobserver and Intraobserver Agreement on Qualitative Assessments of Right Ventricular Dysfunction With Echocardiography in Patients With Pulmonary Embolism. AB - OBJECTIVES: To evaluate observer agreement using qualitative goal-directed echocardiographic criteria for right ventricular (RV) dysfunction prognostication in submassive pulmonary embolism (PE). METHODS: Two emergency physicians and 2 cardiologists independently reviewed 31 packets of goal-directed echocardiographic video clips consisting of at least 3 windows obtained by emergency physicians from normotensive patients with PE. Nine packets were repeated to assess for intraobserver agreement. Right ventricular dysfunction criteria on goal-directed echocardiography were as follows: RV enlargement was present, with a right-to-left ventricular basal diameter ratio of 1.0 or higher and blunting of the apex of the RV in 2 or more different windows; RV systolic dysfunction was present if the tricuspid annulus moved toward the apex 10 mm or less and there was RV free wall hypokinesis; and septal deviation was present with any flattening or deviation of the ventricular septum toward the left ventricle. RESULTS: Among the 4 participants, there was 83.9% agreement on the presence or absence of RV enlargement (kappa = 0.84), 74.2% agreement on the presence or absence of RV systolic dysfunction (kappa = 0.69), and 71.0% agreement on the presence or absence of septal deviation (kappa = 0.59). Intraobserver agreement was 100% for each RV dysfunction variable for each observer (kappa = 1.0). CONCLUSIONS: Agreement was substantial for both severe RV enlargement and RV systolic dysfunction and moderate for septal deviation. Right ventricular dysfunction assessment with qualitative goal-directed echocardiographic criteria is reproducible for PE risk stratification. PMID- 27503758 TI - Prospective Study Comparing Two Second-Look Ultrasound Techniques: Handheld Ultrasound and an Automated Breast Volume Scanner. AB - OBJECTIVES: The aim of this study was to compare the diagnostic performance of handheld ultrasound (US) and an automated breast volume scanner (ABVS) as second look US techniques subsequent to preoperative breast magnetic resonance imaging (MRI). METHODS: We prospectively enrolled patients with breast cancer who underwent handheld US and ABVS examinations as second-look US modalities for additional suspicious lesions found via preoperative breast MRI. We reviewed each second-look US modality independently and evaluated the detection rate of each modality. We then analyzed the correlation between the detection rate and the MRI factors (size, distance, and enhancement type). RESULTS: From March to September 2014, both types of second-look US examinations were performed on 40 patients with breast cancer who had 76 additional suspicious lesions detected via preoperative breast MRI. The detection rate of the ABVS was higher than that of handheld US for the second-look examination (94.7% versus 86.8%; P< .05). Among the 76 total lesions, 7 were only identified by the ABVS, 1 was only found by handheld US, and 3 were not detected by either the ABVS or handheld US. When we analyzed the correlation between the detection rate and MRI factors, the only meaningful factor was the enhancement type. The ability to detect a nonmass lesion was lower than the ability to detect a mass-type lesion (P < 0.05) for both the ABVS and handheld US. CONCLUSIONS: For a second-look US examination subsequent to preoperative breast MRI in patients with breast cancer, the ABVS is a more efficient modality than handheld US for preoperative evaluations. However, both techniques have limitations in detecting nonmass lesions. PMID- 27503759 TI - Isolation of Live Premature Senescent Cells Using FUCCI Technology. AB - Cellular senescence plays an important role in diverse biological processes such as tumorigenesis and organismal aging. However, lack of methods to specifically identify and isolate live senescent cells hampers the precise understanding of the molecular mechanisms regulating cellular senescence. Here, we report that utilization of fluorescent ubiquitination-based cell cycle indicator (FUCCI) technology allows isolation of live premature senescent cells induced by doxorubicin treatment. Exposure of human foreskin fibroblasts (HFFs) to a low dose of doxorubicin led to cellular senescent phenotypes including formation of gamma-H2AX and 53BP1 foci indicative of DNA damage, decreased cell proliferation and increased senescence-associated beta-galactosidase (SA-beta-gal) activity. Importantly, doxorubicin-induced senescent cells were arrested at S/G2/M phases of cell cycle which can be reported by a construct encoding a fragment of hGeminin fused with monomeric Azami-Green (mAG-hGeminin). Flow cytometric sorting of GFP(+) cells from doxorubicin-treated HFFs carrying mAG-hGeminin reporter enabled isolation and enrichment of live senescent cells in the culture. Our study develops a novel method to identify and isolate live premature senescent cells, thereby providing a new tool to study cellular senescence. PMID- 27503760 TI - Huaier restrains proliferative and invasive potential of human hepatoma SKHEP-1 cells partially through decreased Lamin B1 and elevated NOV. AB - Hepatocellular carcinoma (HCC) is one of the most common cause of malignancy related mortality worldwide. It is urgently needed to develop potential drugs with good efficacy and low toxicity for HCC treatment. The anti-tumor effect of Traditional Chinese Medicine (TCM) has received increasing attention worldwide. Trametes robiniophila Murr. (Huaier) has been used in TCM for approximately 1,600 years. Clinically, Huaier has satisfactory therapeutic effects in cancer treatment, especially in HCC. However, the mechanisms underlying the anti-cancer effect of Huaier remain ill defined. Herein we have demonstrated that Huaier dramatically inhibited cell proliferation and induced apoptosis in human hepatoma cell line SKHEP-1. Importantly, Huaier restrained the metastatic capability of SKHEP-1 cells. Mechanistically, down-regulation of Lamin B1 and up-regulation of Nephroblastoma overexpressed (NOV) were at least partially responsible for the inhibitory effect of Huaier on the proliferative and invasive capacity of SKHEP-1 cells. Our finding provided new insights into mechanisms of anti-HCC effect of Huaier and suggested a new scientific basis for clinical medication. PMID- 27503761 TI - Fetal Bovine Serum RNA Interferes with the Cell Culture derived Extracellular RNA. AB - Fetal bovine serum (FBS) has been used in eukaryotic cell cultures for decades. However, little attention has been paid to the biological effects associated with RNA content of FBS on cell cultures. Here, using RNA sequencing, we demonstrate that FBS contains a diverse repertoire of protein-coding and regulatory RNA species, including mRNA, miRNA, rRNA, and snoRNA. The majority of them (>70%) are retained even after extended ultracentrifugation in the preparations of vesicle depleted FBS (vdFBS) commonly utilized in the studies of extracellular vesicles (EV) and intercellular communication. FBS-associated RNA is co-isolated with cell culture derived extracellular RNA (exRNA) and interferes with the downstream RNA analysis. Many evolutionally conserved FBS-derived RNA species can be falsely annotated as human or mouse transcripts. Notably, specific miRNAs abundant in FBS, such as miR-122, miR-451a and miR-1246, have been previously reported as enriched in cell-culture derived EVs, possibly due to the confounding effect of the FBS. Analysis of publically available exRNA datasets supports the notion of FBS contamination. Furthermore, FBS transcripts can be taken up by cultured cells and affect the results of highly sensitive gene expression profiling technologies. Therefore, precautions for experimental design are warranted to minimize the interference and misinterpretations caused by FBS-derived RNA. PMID- 27503762 TI - Pharmacological treatments of cardiovascular diseases: Evidence from real-life studies. AB - The management of chronic cardiovascular diseases has evolved greatly in the last decades. Over the last thirty years, the management of acute coronary syndrome has improved, leading to an important lowering of the mortality in the acute phase of the event. Consequently, the optimal management of the secondary prevention of acute coronary syndrome has greatly evolved. Moreover, the increased number of pharmacological alternatives for patients affected by chronic heart failure and by non-valvular atrial fibrillation reserves a number of challenges for their correct management. Moreover, these diseases are without any reasonable doubt the largest contributor to global mortality in the present and will continue to be it in the future. The aim of this study was to provide the most updated information of the real-life drug use and their effectiveness. This review was performed to assess the potential knowledge gaps in the treatments of these diseases and to indicate potential perspective of pharmaco-epidemiological research in this area. PMID- 27503763 TI - Biodegradable ECM-coated PCL microcarriers support scalable human early MSC expansion and in vivo bone formation. AB - BACKGROUND AIMS: Human mesenchymal stromal cells or marrow stromal cells (MSCs) are of great interest for bone healing due to their multi-potency and trophic effects. However, traditional MSC expansion methods using 2-dimensional monolayer (MNL) flasks or cell stacks are limited by labor-intensive handling, lack of scalability, the need for enzymatic cell harvesting and the need for attachment to a scaffold before in vivo delivery. Here, we present a biodegradable microcarrier and MSC bioprocessing system that may overcome the abovementioned challenges. METHODS: We cultured human early MSCs (heMSCs) on biodegradable polycaprolactone microcarriers (PCL MCs) coated with extracellular matrix (ECM) and evaluated the in vitro osteogenic differentiation and in vivo bone formation capacity of ECM-coated PCL MC-bound heMSCs compared with conventional MNL cultured cells. RESULTS: We found that heMSCs proliferate well on PCL MCs coated with a fibronectin, poly-l-lysine, and fibronectin (FN+PLL+FN) coating (cPCL MCs). During in vitro osteogenic induction, heMSCs cultured on cPCL MCs displayed a 68% increase in specific calcium deposition compared with cultures on MNL. In a mouse ectopic mineralization model, bone mass was equivalent for MNL-expanded and cPCL MC-bound heMSC implants but higher in both cases when compared with cell free cPCL MC implants at 16 weeks post-implantation. In summary, compared with MNL cultures, biodegradable MC MSC cultures provide the benefits of large-scale expansion of cells and can be delivered in vivo, thereby eliminating the need for cell harvesting and use of scaffolds for cell delivery. These results highlight the promise of delivering heMSCs cultured on cPCL MCs for bone applications. PMID- 27503764 TI - Bi(OTf)3-catalyzed addition of isocyanides to 2H-chromene acetals: an efficient pathway for accessing 2-carboxamide-2H-chromenes. AB - Bismuth triflate (Bi(OTf)3) is identified as an efficient catalyst for the direct addition of isocyanides to 2H-chromene acetals. The large scope of isocyanides and chromene acetals makes them suitable substrates in this catalytic system. By this synthetic strategy, a polyfunctional molecular scaffold, 2-carboxamide-2H chromenes could be prepared efficiently in one step up to 95% yield. In addition, this efficient and practical protocol proceeded smoothly in the gram scale even when the catalytic loading was reduced to 2 mol%. PMID- 27503765 TI - Scoping the effectiveness and evolutionary obstacles in using plasmid-dependent phages to fight antibiotic resistance. AB - AIM: To investigate the potential evolutionary obstacles in the sustainable therapeutic use of plasmid-dependent phages to control the clinically important conjugative plasmid-mediated dissemination of antibiotic resistance genes to pathogenic bacteria. MATERIALS & METHODS: The lytic plasmid-dependent phage PRD1 and the multiresistance conferring plasmid RP4 in an Escherichia coli host were utilized to assess the genetic and phenotypic changes induced by combined phage and antibiotic selection. RESULTS & CONCLUSIONS: Resistance to PRD1 was always coupled with either completely lost or greatly reduced conjugation ability. Reversion to full conjugation efficiency was found to be rare, and it also restored the susceptibility to plasmid-dependent phages. Consequently, plasmid dependent phages constitute an interesting candidate for development of sustainable anticonjugation/antiresistance therapeutic applications. PMID- 27503766 TI - Trinuclear nickel and cobalt complexes containing unsymmetrical tripodal tetradentate ligands: syntheses, structural, magnetic, and catalytic properties. AB - The coordination chemistries of the tetradentate N2O2-type ligands N-(2 pyridylmethyl)iminodiethanol (H2pmide) and N-(2-pyridylmethyl)iminodiisopropanol (H2pmidip) have been investigated with nickel(ii) and cobalt(ii/iii) ions. Three novel complexes prepared and characterized are [(Hpmide)2Ni3(CH3COO)4] (1), [(Hpmide)2Co3(CH3COO)4] (2), and [(pmidip)2Co3(CH3COO)4] (3). In 1 and 2, two terminal nickel(ii)/cobalt(ii) units are coordinated to one Hpmide(-) and two CH3CO2(-). The terminal units are each connected to a central nickel(ii)/cobalt(ii) cation through one oxygen atom of Hpmide(-) and two oxygen atoms of acetate ions, giving rise to nickel(ii) and cobalt(ii) trinuclear complexes, respectively. Trinuclear complexes 1 and 2 are isomorphous. In 3, two terminal cobalt(iii) units are coordinated to pmidip(2-) and two CH3CO2(-). The terminal units are each linked to a central cobalt(ii) cation through two oxygen atoms of pmidip(2-) and one oxygen atom of a bidentate acetate ion, resulting in a linear trinuclear mixed-valence cobalt complex. 1 shows a weak ferromagnetic interaction with the ethoxo and acetato groups between the nickel(ii) ions (g = 2.24, J = 2.35 cm(-1)). However, 2 indicates a weak antiferromagnetic coupling with the ethoxo and acetato groups between the cobalt(ii) ions (g = 2.37, J = 0.5 cm(-1)). Additionally, 3 behaves as a paramagnetic cobalt(ii) monomer, due to the diamagnetic cobalt(iii) ions in the terminal units (g = 2.53, |D| = 36.0 cm( 1)). No catalytic activity was observed in 1. However, 2 and 3 showed significant catalytic activities toward various olefins with modest to good yields. 3 was slightly less efficient toward olefin epoxidation reaction than 2. Also 2 was used for terminal olefin oxidation reaction and was oxidised to the corresponding epoxides in moderate yields (34-75%) with conversions ranging from 47-100%. The cobalt complexes 2 and 3 promoted the O-O bond cleavage to ~75% heterolysis and ~25% homolysis. PMID- 27503767 TI - Preparation and evaluation of immobilized 4-methylbenzoylcellulose stationary phases for enantioselective separations. AB - A photochemical method for immobilizing polysaccharide derivatives on silica gel has been developed and applied to 4-methylbenzoyl cellulose (PMBC). The photochemically immobilized materials have been used as chiral stationary phases (CSPs) for the chromatographic separation of the stereoisomers of chiral molecules. Through to the immobilization which makes the chromatographic material insoluble in almost all organic solvents, there no restriction regarding the kind of solvent used in the mobile phase. This feature permits to considerably extend the possibilities to improve the selectivity of the separations and or the solubility of the solute in the mobile phase. The influence of various parameters such as immobilization process, cross-linker type and amount on the chromatographic properties and chiral recognition ability of the resulting CSPs has been investigated using a set of chiral molecules. The impact of the amount of coated polysaccharide material on chiral recognition ability was also examined. PMID- 27503768 TI - Sex hormones modulate neurophysiological correlates of visual temporal attention. AB - The functional cerebral asymmetry (FCA) in processing targets within rapid serial visual presentation (RSVP) streams has been reported to fluctuate across the menstrual cycle, with identification of the second of two closely spaced targets being impaired when both targets occur in the left or the right hemifield stream during the luteal phase, while during the menstrual phase identification of the second target is only impaired for target pairs presented in the right hemifield stream. This fluctuation has been proposed to result from variations in estradiol levels. The current study used EEG to investigated whether the cycle-related fluctuation in RSVP target identification FCA relates to changes in early, stimulus-driven, bottom-up or in later, top down-driven aspects of FCA. While the former would be expected to become evident in the early visual evoked potentials (VEPs) P1 or N1, the latter would be evident in later event-related potentials (ERPs) such as N2pc or P3. Women performed a dual-stream RSVP task once during the menstrual phase and once during the follicular phase. Estradiol levels were determined from saliva samples. In contrast to previous findings, FCA in RSVP target identification was not affected by cycle phase. However, the impairment in second-target identification when targets where closely spaced was generally smaller during the menstrual phase than during the follicular phase. This effect was matched by shorter peak latencies of P1 VEPs for the menstrual phase, and by a reduction in the latency of the second-target P3 ERP for closely spaced relative to widely spaced target pairs, again for the menstrual phase. Results suggest that in a dual-stream RSVP setup, target identification, early stage stimulus processing, and target consolidation are affected by cycle phase, but that the asymmetry of these effects does not differ between menstrual and follicular phase. The observed cycle-related modulations in neurophysiology and behavior could relate to the effects of estradiol on the locus ceruleus norepinephrine (LC-NE) system, which is known to play a major role in arousal, attention and stress response. PMID- 27503769 TI - Musical experience facilitates lexical tone processing among Mandarin speakers: Behavioral and neural evidence. AB - Music and speech share many sound attributes. Pitch, as the percept of fundamental frequency, often occupies the center of researchers' attention in studies on the relationship between music and speech. One widely held assumption is that music experience may confer an advantage in speech tone processing. The cross-domain effects of musical training on non-tonal language speakers' linguistic pitch processing have been relatively well established. However, it remains unclear whether musical experience improves the processing of lexical tone for native tone language speakers who actually use lexical tones in their daily communication. Using a passive oddball paradigm, the present study revealed that among Mandarin speakers, musicians demonstrated enlarged electrical responses to lexical tone changes as reflected by the increased mismatch negativity (MMN) amplitudes, as well as faster behavioral discrimination performance compared with age- and IQ-matched nonmusicians. The current results suggest that in spite of the preexisting long-term experience with lexical tones in both musicians and nonmusicians, musical experience can still modulate the cortical plasticity of linguistic tone processing and is associated with enhanced neural processing of speech tones. Our current results thus provide the first electrophysiological evidence supporting the notion that pitch expertise in the music domain may indeed be transferable to the speech domain even for native tone language speakers. PMID- 27503770 TI - Reducible Polyethylenimine Nanoparticles for Efficient siRNA Delivery in Corneal Neovascularization Therapy. AB - The aim of this study is to establish the safe and effective ocular delivery system of therapeutic small interfering RNA (siRNA) in corneal neovascularization therapy. The major hurdle present in siRNA-based corneal neovascularization (CNV) therapy is severe cytotoxicity caused by repetitive drug treatment. A reducible branched polyethylenimine (rBPEI)-based nanoparticle (NP) system is utilized as a new siRNA carrier as a hope for CNV therapy. The thiolated BPEI is readily self crosslinked in mild conditions to make high molecular weight rBPEI thus allowing the creation of stable siRNA/rBPEI nanoparticles (siRNA-rBPEI-NPs). In the therapeutic region, the rBPEI polymeric matrix is effectively degraded into nontoxic LMW BPEI inside the reductive cytosol causing the rapid release of the encapsulated siRNA into the cytosol to carry out its function. The fluorescent labeled siRNA-rBPEI-NPs can release siRNA into the entire corneal region after subconjuctival injection into the eye of Sprague Dawley rats thus confirming the proof of concept of this system. PMID- 27503771 TI - Continuous care and patients' basic needs during weaning from mechanical ventilation: A qualitative study. AB - BACKGROUND: Mechanical ventilation is associated with a number of risks and complications. Thus, rapid and safe weaning from mechanical ventilation is of great importance. Weaning is a complex and challenging process, requiring continuous care and knowledge of the patient. AIMS: The aim of the present study was to describe the continuous care process during weaning as well as to analyse the facilitators and obstacles to the weaning process from start to finish from the perspective of intensive care unit (ICU) staff, particularly nurses. RESEARCH DESIGN: Twenty-two ICU staff members, including nurses and physicians, and three patients hospitalised in the ICU were enrolled in this qualitative study. Semi structured interviews were used for data collection and the transcripts were analysed using qualitative content analysis. FINDINGS: 'Continuous care' was found to be the patients' basic need during weaning from mechanical ventilation. Uninterrupted, stable, comprehensive and dynamic care and monitoring with immediate response to all physiological and psychological changes were features of continuous care. The three main themes identified by this study were time spent with the patient, comprehensive supervision and maintenance of the quality of care during shifts. CONCLUSION: Continuous and constant care should be provided during the weaning process. Such care will help to provide health care staff with a deeper understanding of the patient and his or her continuous changes, leading to a timely and favourable response during weaning. To achieve this goal, skill, communication and organisational changes are essential. PMID- 27503772 TI - Decreased between-hemisphere connectivity strength and network efficiency in geriatric depression. AB - White matter (WM) lesions have been recognized as a key etiological factor in geriatric depression. However, little is known about the topological pattern changes of WM in geriatric depression in the remitted state (RGD) and its relationship to depressive episodes. To address these questions, we acquired diffusion tensor images in 24 RGD and 24 healthy participants. Among them, 10 patients and 19 healthy controls completed a 1-year follow up. Between-hemisphere connectivity and graph theoretical methods were used to analyze the data. We found significantly reduced WM connectivity between the left and right hemisphere in the RGD group compared with the control group. Those with multiple depression episodes had greater reduction in between-hemisphere connectivity strength than those with fewer episodes. In addition, the RGD group had a reduced global clustering coefficient, global efficiency, and network strength, and an increased shortest path length compared with the controls. A lower clustering coefficient was correlated with poorer memory function. The reduction of nodal clustering coefficient, global efficiency, and network strength in several regions were associated with slower information processing speed. At 1-year follow up, the network properties in the RGD subjects were significantly changed suggesting instability of WM network properties of depressed patients. Together, our study provides direct evidence of reduced between-hemisphere WM connectivity with greater depressive episodes, and of alterations of network properties with cognitive dysfunction in geriatric depression. Hum Brain Mapp 38:53-67, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27503773 TI - Laparoscopic surgery on broken points for uterine sarcoma in the early stage decrease prognosis. AB - Uterine sarcoma, a rare solid tumor in uterus, is difficult to identify in the early stage from some benign uterine tumors, such as uterine fibroids. Hence, uterine sarcoma may be treated in the same way as uterine fibroids; and this may not be found until pathological diagnosis. Consequently, this can lead to tumor's abdominal spread, planting and local invasive growth, resulting in an early uterine sarcoma, an increased relapse rate after surgery and a decreased survival. Therefore, it's important to avoid these unintended and iatrogenic complications through an accurate diagnosis and an appropriate surgical approach. The surgical staging and a complete resection of the tumor are both important for patients' prognosis. In this review, we will discuss the laparoscopic surgery for uterine sarcoma in the early stage and patients' prognosis. PMID- 27503774 TI - 1H NMR-Linked Metabolomics Analysis of Liver from a Mouse Model of NP-C1 Disease. AB - Clinical manifestations of Niemann-Pick type C1 (NP-C1) disease include neonatal hepatosplenomegaly and in some patients progressive liver dysfunction and failure. This study involved a 1H NMR-linked metabolomics analysis of liver samples collected from a NP-C1 disease mutant mouse model in order to explore time-dependent imbalances in metabolic pathways associated with NP-C1 liver dysfunction, including fibrosis. NP-C1 mutant (Npc1-/-; NP-C1), control (Npc1+/+; WT), and NP-C1 heterozygous mice (Npc1+/-; HET) were generated from heterozygote matings. Aqueous extracts of these liver samples collected at time points of 3, 6, 9, and 11 weeks were subjected to high-resolution NMR analysis, and multivariate (MV) metabolomics analyses of data sets acquired were performed. A MV random forests (RFs) model effectively discriminated between NP-C1 and a combined WT/HET hepatic NMR profiles with very high predictive accuracy and reliability. Key distinguishing features included significant upregulations in the hepatic concentrations of phenylalanine, tyrosine, glutamate, lysine/ornithine, valine, threonine, and hypotaurine/methionine, and diminished levels of nicotinate/niacinamide, inosine, phosphoenolpyruvate, and 3 hydroxyphenylacetate. Quantitative pathway topological analysis confirmed that imbalances in tyrosine biosynthesis, and hepatic phenylalanine, tyrosine, glutamate/glutamine, and nicotinate/niacinamide metabolism were involved in the pathogenesis of NP-C1 disease-associated liver dysfunction/damage. 1H NMR-linked metabolomics analysis provides valuable biomarker information regarding hepatic dysfunction or damage in NP-C1 disease. PMID- 27503775 TI - The Holocene occurrence of Acipenser spp. in the southern North Sea: the archaeological record. AB - Archaeological sturgeon remains from the southern North Sea basin used to be automatically attributed to Acipenser sturio, since this was the only acipenserid species believed to occur there. These species identifications, however, were in need of revision after a growing number of indications were found for the historical presence of Acipenser oxyrinchus in western Europe. In this study, morphological and genetic data on sturgeon remains from archaeological sites along the southern North Sea are revised. A large number of Dutch, Belgian, British and some French archaeological sturgeon remains, dating from the Mesolithic up to Late Modern times, are morphologically examined and fish sizes are reconstructed. This study of >7000 acipenserid bones proves the sympatric occurrence of European sturgeon A. sturio and Atlantic sturgeon A. oxyrinchus in the southern North Sea at least since the Neolithic (fourth millennium BC onwards), with A. oxyrinchus remains always outnumbering those of A. sturio. Human influence is documented by the decrease in finds through time, but no clear evidence was found for a diachronic change in fish lengths that could possibly be related to fishing pressure. PMID- 27503776 TI - The case for investigating social context in laboratory studies of smoking. AB - BACKGROUND: With increasing frequency, addiction is conceived of as a brain disease, and such accounts seem especially pertinent with regard to the rapid delivery of nicotine to the brain via cigarette smoke. Moreover, drug administration trials (cigarette puffs) suggest that the behavior of smoking becomes automatized, with individuals developing prototypical approaches to smoking a cigarette. Compared with presumably more social activities, such as drinking alcohol, there may be little opportunity for social processes to influence smoking behavior. However, survey research examining smoking motivation often reveals a broadly defined 'social' factor and field research suggests that social context does influence smoking. ARGUMENT: We posit that laboratory smoking research has largely ignored social contextual factors that may help to understand better the precise mechanisms underlying smoking behavior and smoking motivation. METHOD: We reviewed laboratory studies examining the effect of social context (operationalized as modeling) on smoking behavior. Studies were identified by searching PsychInfo and Medline using the following keywords: smoking, nicotine, tobacco, cigarette, consumption, topography, puff, smoking behavior, cigarettes smoked, modeling, imitation, social context, social influence and peer pressure. The reference and citation lists of these studies were then searched to identify additional studies. CONCLUSIONS: Few laboratory smoking studies target social context. Those few studies indicate that smoking behavior can be influenced by the presence of others. There is also some evidence that social context influences the effects of smoking as well as processes related to self-perception and self-regulation that reinforce smoking and hamper smoking cessation efforts. PMID- 27503777 TI - Usefulness of Circulating B-cell-Activating Factor Serial Monitoring in Childhood Onset Ocular Myasthenia Gravis. PMID- 27503778 TI - An Atypical Case of Anti-N-Methyl-D-Aspartate Receptor Encephalitis. PMID- 27503779 TI - In Memoriam - Gordon Barry Pierce, 1925-2015. PMID- 27503780 TI - Comparison of photodynamic treatment produced cell damage between human breast cancer cell MCF-7 and its multidrug resistance cell. AB - BACKGROUND: Multidrug resistance (MDR) of breast cancer is a major obstacle in chemotherapy of cancer treatments. Recently the anti-tumor effects of Chlorin e6 (Ce6) mediated photodynamic therapy (Ce6-PDT) were reported in skin cancer and hepatoma in vitro. However, its therapeutic potential in killing human breast cancer especially those with MDR and the differences between MCF-7 and MCF-7/ADR after PDT treatment has not been fully investigated. METHODS: MTT assay was used to measure cell survival rate of MCF-7 cells and MCF-7/ADR cells. Intracellular reactive oxygen species (ROS) generation was measured by monitoring the fluorescence intensity of dichlorofluorescein (DCF) by flow cytometry. Nuclear morphology changes and DNA damage in both MCF-7 and MCF-7/ADR after Ce6-PDT were analyzed by hochest33342 staining and comet assay. Western blot and monodansylcadaverine (MDC) staining were used to monitor autophagic response in MCF-7/ADR. RESULTS: Ce6-PDT induced cell viability decrease, intracellular ROS generation, and DNA damage in concentration-dependent and cell-specific manner, and MCF-7 was more sensitive to Ce6-PDT than MCF-7/ADR cells at the same PDT condition. PDT treatment could trigger cell death via apoptosis in MCF-7 cells but autophagic cell death in MCF-7/ADR cells. CONCLUSION: These results suggested that MCF-7 was more sensitive to Ce6-PDT than MCF-7/ADR, and PDT treatment could trigger apoptotic response in MCF-7 cells, but stimulate autophagic response in MCF-7/ADR cells. PMID- 27503781 TI - Observation of clinical efficacy of photodynamic therapy in 3 patients with refractory plaque-stage mycosis fungoides. AB - Mycosis fungoides (MF) is one of the most common cutaneous T cell lymphomas (CTCLs). Currently there are a variety of treatment methods for early-stage MF, most of which are effective. However, some lesions in plaque-stage react poorly to conventional therapy. We chose 3 patients with plaque-stage MF who failed routine therapy, to perform 2-3 times Aminolaevulinic acid-based photodynamic therapy (ALA-PDT). And it turned out that these patients responded well to ALA PDT: the skin lesions of 2 patients subsided completely, and the last one had more than 75% of the lesions eliminated. In conclusion, compared with traditional therapy, ALA-PDT had tremendous therapeutic effect on refractory plaque-stage MF, with advantages of less side effects and quicker recovery. Therefore, ALA-PDT was an effective method for treating refractory plaque-stage MF. PMID- 27503782 TI - Effectiveness of amphibians as biodiversity surrogates in pond conservation. AB - Amphibian decline has led to worldwide conservation efforts, including the identification and designation of sites for their protection. These sites could also play an important role in the conservation of other freshwater taxa. In 89 ponds in Switzerland, we assessed the effectiveness of amphibians as a surrogate for 4 taxonomic groups that occur in the same freshwater ecosystems as amphibians: dragonflies, aquatic beetles, aquatic gastropods, and aquatic plants. The ponds were all of high value for amphibian conservation. Cross-taxon correlations were tested for species richness and conservation value, and Mantel tests were used to investigate community congruence. Species richness, conservation value, and community composition of amphibians were weakly congruent with these measures for the other taxonomic groups. Paired comparisons for the 5 groups considered showed that for each metric, amphibians had the lowest degree of congruence. Our results imply that site designation for amphibian conservation will not necessarily provide protection for freshwater biodiversity as a whole. To provide adequate protection for freshwater species, we recommend other taxonomic groups be considered in addition to amphibians in the prioritization and site designation process. PMID- 27503783 TI - Characterization of perioperative infection risk among patients undergoing radical cystectomy: Results from the national surgical quality improvement program. AB - OBJECTIVES: To evaluate the incidence, risk factors, and timing of infections following radical cystectomy (RC). METHODS: The American College of Surgeons National Surgical Quality Improvement Project database was queried to identify patients undergoing RC for bladder cancer from 2006 to 2013. Characteristics including year of surgery, age, sex body mass index, diabetes, smoking, renal function, steroid usage, preoperative albumin, preoperative hematocrit, perioperative blood transfusion (PBT), and operative time were assessed for association with the risk of infection within 30 days of RC using multivariable logistic regression. RESULTS: A total of 3,187 patients who had undergone RC were identified, of whom 766 (24.0%) were diagnosed with a postoperative infection, at a median of 13 days (interquartile ranges 8-19) after RC. Infections included surgical site infection (SSI) (404; 12.7%), sepsis/septic shock (405; 12.7%), and urinary tract infection (UTI) (309; 9.7%). On multivariable analysis, body mass index>=30kg/m2 (odds ratios [OR] = 1.52; P<0.01), receipt of a PBT (OR = 1.27; P<0.01), and operative time>=480 minutes (OR = 1.72; P<0.01) were significantly associated with the risk of infection. When the outcomes of UTI, SSI, and sepsis were analyzed separately, operative time>=480 minutes remained independently associated with increased infection risk in each model (OR = 2.11 for UTI, OR = 1.63 for SSI, and OR = 1.80 for sepsis/septic shock; all P<0.05), whereas PBT was associated with SSI and sepsis/septic shock (OR = 1.33 and OR = 1.29, respectively; both P< 0.05). CONCLUSIONS: Approximately 25% of patients undergoing RC experience an infection within 30 days of surgery. Several potentially modifiable risk factors for infection were identified, specifically PBT and prolonged operative time, which may represent opportunities for future care improvement. PMID- 27503785 TI - Interictal epileptiform discharges have an independent association with cognitive impairment in children with lesional epilepsy. AB - OBJECTIVES: The relative contribution of interictal epileptiform discharges (IEDs) to cognitive dysfunction in comparison with the underlying brain pathology is not yet understood in children with lesional focal epilepsy. METHODS: The current study investigated the association of IEDs with intellectual functioning in 103 children with medication-resistant focal epilepsy. Hierarchical multiple regression analyses were used to determine the independent contribution of IED features on intellectual functioning, after controlling for effects of lesional pathology, epilepsy duration, and medication. Exploratory analyses were conducted for language and memory scores as well as academic skills available in a subset of participants. RESULTS: The results reveal that IEDs have a negative association with IQ with independent, additive effects documented for frequent and bilaterally distributed IEDs as well as discharge enhancement in sleep. Left lateralized IEDs had a prominent effect on verbal intelligence, in excess of the influence of left-sided brain pathology. These effects extended to other cognitive functions, most prominently for sleep-enhanced IEDs to be associated with deficits in expressive and receptive language, reading, spelling and numerical skills. SIGNIFICANCE: Overall, IED effects on cognition were of a magnitude similar to lesional influences or drug effects (topiramate use). This study demonstrates an association between IEDs and cognitive dysfunction, independent of the underlying focal brain pathology. PMID- 27503786 TI - [Recommendations for the preparation and administration of antituberculosis drugs in children. Second phase of the Magistral Project of the Spanish Network for the Study of Paediatric Tuberculosis (pTBred)]. AB - The Spanish Network for the Study of Paediatric Tuberculosis has shown a lack of national consensus on the treatment of tuberculosis in children, partly due to the unavailability of paediatric presentations of antituberculosis drugs. The harmonisation of tuberculosis treatment in children is a priority in Spain. A joint action is proposed by a group of Spanish experts in childhood tuberculosis and in the area of Paediatric Pharmacology. To this end, a pTBred-led workgroup of members from five scientific bodies has been created. Drug pharmaceutical compounding in oral suspensions or oral solutions are recommended as follows: isoniazid 50mg/mL, pyrazinamide 100mg/mL, and ethambutol 50mg/mL. Raw materials, period of validity, and storage conditions are specified. Recommendations for the use of fixed-dose combination drugs are also established. If oral solutions/suspensions or fixed-dose combination drugs are not appropriate, the use of crushed tablets is recommended. Adherence to treatment and optimal dosing of antituberculosis drugs are critical in the control and eradication of TB. This multidisciplinary document provides an opportunity to promote the appropriate treatment of paediatric tuberculosis in Spain, and should become a useful tool for paediatricians and pharmacists. PMID- 27503787 TI - [Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome: A study and follow-up of 16 cases]. PMID- 27503784 TI - International consensus on the diagnosis and management of pediatric patients with hereditary angioedema with C1 inhibitor deficiency. AB - BACKGROUND: The consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) have focused on adult patients. Many of the previous recommendations have not been adapted to pediatric patients. We intended to produce consensus recommendations for the diagnosis and management of pediatric patients with C1-INH-HAE. METHODS: During an expert panel meeting that took place during the 9th C1 Inhibitor Deficiency Workshop in Budapest, 2015 (www.haenet.hu), pediatric data were presented and discussed and a consensus was developed by voting. RESULTS: The symptoms of C1-INH-HAE often present in childhood. Differential diagnosis can be difficult as abdominal pain is common in pediatric C1-INH-HAE, but also commonly occurs in the general pediatric population. The early onset of symptoms may predict a more severe subsequent course of the disease. Before the age of 1 year, C1-INH levels may be lower than in adults; therefore, it is advisable to confirm the diagnosis after the age of one year. All neonates/infants with an affected C1-INH-HAE family member should be screened for C1-INH deficiency. Pediatric patients should always carry a C1 INH-HAE information card and medicine for emergency use. The regulatory approval status of the drugs for prophylaxis and for acute treatment is different in each country. Plasma-derived C1-INH, recombinant C1-INH, and ecallantide are the only agents licensed for the acute treatment of pediatric patients. Clinical trials are underway with additional drugs. It is recommended to follow up patients in an HAE comprehensive care center. CONCLUSIONS: The pediatric-focused international consensus for the diagnosis and management of C1-INH-HAE patients was created. PMID- 27503788 TI - Killer-cell immunoglobulin-like receptors genotyping of 127 individuals from Terceira Island, Azores, Portugal. AB - One hundred and twenty-seven unrelated Azorean individuals were randomly selected to study the gene frequencies of Killer-cell immunoglobulin-like receptors (KIR) in the Azorean (Terceira) population. KIR genotyping was performed by polymerase chain reaction using commercial sequence-specific oligonucleotide probe kits. All loci were in HWE, showing no locus-level deviations. The genotype data is available in the Allele Frequencies Net Database under the population name "Azores Terceira Island KIR". PMID- 27503790 TI - Vaccinia virus K1 ankyrin repeat protein inhibits NF-kappaB activation by preventing RelA acetylation. AB - The vaccinia virus (VACV) K1 protein inhibits dsRNA-dependent protein kinase (PKR) activation. A consequence of this function is that K1 inhibits PKR-induced NF-kappaB activation during VACV infection. However, transient expression of K1 also inhibits Toll-like receptor (TLR)-induced NF-kappaB activation. This suggests that K1 has a second NF-kappaB inhibitory mechanism that is PKR independent. This possibility was explored by expressing K1 independently of infection and stimulating NF-kappaB under conditions that minimized or excluded PKR activation. K1 inhibited both TNF- and phorbol 12-myristate 13-acetate (PMA) induced NF-kappaB activation, as detected by transcription of synthetic (e.g. luciferase) and natural (e.g. CXCL8) genes controlled by NF-kappaB. K1 also inhibited NF-kappaB activity in PKRkd cells, cells that have greatly decreased amounts of PKR. K1 no longer prevented IkappaBalpha degradation or NF-kappaB nuclear translocation in the absence of PKR, suggesting that K1 acted on a nuclear event. Indeed, K1 was present in the nucleus and cytoplasm of stimulated and unstimulated cells. K1 inhibited acetylation of the RelA (p65) subunit of NF kappaB, a nuclear event known to be required for NF-kappaB activation. Moreover, p65-CBP (CREB-binding protein) interactions were blocked in the presence of K1. However, K1 did not preclude NF-kappaB binding to oligonucleotides containing kappaB-binding sites. The current interpretation of these data is that NF-kappaB promoter interactions still occur in the presence of K1, but NF-kappaB cannot properly trigger transcriptional activation because K1 antagonizes acetylation of RelA. Thus, in comparison to all known VACV NF-kappaB inhibitory proteins, K1 acts at one of the most downstream events of NF-kappaB activation. PMID- 27503791 TI - Leading pancreatic cancer researcher is struck off for fabricating data. PMID- 27503792 TI - Is State Care an Oxymoron? PMID- 27503793 TI - Adverse Childhood Experiences and Health in Adulthood in a Rural Population-Based Sample. AB - BACKGROUND: Adverse childhood experiences (ACEs), including emotional abuse, substance abuse in the household, separation or divorce, physical abuse, violence between adults, mental illness in the household, sexual abuse, or incarceration of a household member, have the potential to profoundly impact health and well being in adulthood. To assess whether previously reported relationships between ACEs and health outcomes withstand validation, we conducted a community-based ACE study with the unique capacity to link self-reported ACEs and other survey results to validated health data in an electronic medical record (EMR). METHODS: Information regarding ACEs and health outcomes was captured from 2013-2014 via a telephone survey of residents of the predominantly rural northern and central regions of Wisconsin and electronic abstraction of EMR data. ACE score was calculated by counting each exposure as one point. We examined the relationship between ACE score, type, and self-reported and validated health outcomes. RESULTS: A total of 800 participants completed the telephone survey. Overall, 62% reported at least one ACE and 15% reported experiencing four or more. All self reported measures of poor health were associated with increased ACE score. EMR data were positively correlated with ACE score for increased body mass index and diagnoses of depression, anxiety, and asthma. In contrast, diagnoses of hypertension, hypercholesterolemia, myocardial infarction, and skin and other cancers were inversely related to ACE score. Emotional abuse was the most common ACE reported followed by substance abuse in the household. ACEs tended to cluster so that people who reported at least one ACE were likely to have experienced multiple ACEs. There was no clear correlation between abuse type (e.g., direct abuse vs. household dysfunction) and health outcomes. CONCLUSIONS: In the first community-based study to link self-reported ACEs to comprehensive health measures documented in the medical record, we observed previously reported associations between childhood adversity and poor outcomes in adulthood, but also noted an inverse relationship between ACE score and certain medical diagnoses. Potential explanations for this finding warrant further investigation. PMID- 27503794 TI - Evaluation of delirium screening tools in geriatric medical inpatients: a diagnostic test accuracy study. AB - INTRODUCTION: screening all unscheduled older adults for delirium is recommended in national guidelines, but there is no consensus on how to perform initial assessment. AIM: to evaluate the test accuracy of five brief cognitive assessment tools for delirium diagnosis in routine clinical practice. METHODS: a consecutive cohort of non-elective, elderly care (older than 65 years) hospital inpatients admitted to a geriatric medical assessment unit of an urban teaching hospital. Reference assessments were clinical diagnosis of delirium performed by elderly care physicians. Routine screening tests were: Abbreviated Mental Test (AMT-10, AMT-4), 4 A's Test (4AT), brief Confusion Assessment Method (bCAM), months of the year backwards (MOTYB) and informant Single Question in Delirium (SQiD). RESULTS: we assessed 500 patients, mean age 83 years (range = 66-101). Clinical diagnoses were: 93 of 500 (18.6%) definite delirium, 104 of 500 (20.8%) possible delirium and 277 of 500 (55.4%) no delirium; 266 of 500 (53.2%) were identified as definite or possible dementia. For diagnosis of definite delirium, AMT-4 (cut point < 3/4) had a sensitivity of 92.7% (95% confidence interval (CI): 84.8 97.3), with a specificity of 53.7% (95% CI: 48.1-59.2); AMT-10 (<4/10), MOTYB (<4/12) and SQiD showed similar performance. bCAM had a sensitivity of 70.3% (95% CI: 58.5-80.3) with a specificity of 91.4% (95% CI: 87.7-94.3). 4AT (>4/12) had a sensitivity of 86.7% (95% CI: 77.5-93.2) and specificity of 69.5% (95% CI: 64.4 74.3). CONCLUSIONS: short screening tools such as AMT-4 or MOTYB have good sensitivity for definite delirium, but poor specificity; these tools may be reasonable as a first stage in assessment for delirium. The 4AT is feasible and appears to perform well with good sensitivity and reasonable specificity. PMID- 27503795 TI - A clock network for geodesy and fundamental science. AB - Leveraging the unrivalled performance of optical clocks as key tools for geo science, for astronomy and for fundamental physics beyond the standard model requires comparing the frequency of distant optical clocks faithfully. Here, we report on the comparison and agreement of two strontium optical clocks at an uncertainty of 5 * 10(-17) via a newly established phase-coherent frequency link connecting Paris and Braunschweig using 1,415 km of telecom fibre. The remote comparison is limited only by the instability and uncertainty of the strontium lattice clocks themselves, with negligible contributions from the optical frequency transfer. A fractional precision of 3 * 10(-17) is reached after only 1,000 s averaging time, which is already 10 times better and more than four orders of magnitude faster than any previous long-distance clock comparison. The capability of performing high resolution international clock comparisons paves the way for a redefinition of the unit of time and an all-optical dissemination of the SI-second. PMID- 27503796 TI - Proteome mapping of Plasmodium: identification of the P. yoelii remodellome. AB - Plasmodium associated virulence in the host is linked to extensive remodelling of the host erythrocyte by parasite proteins that form the "remodellome". However, without a common motif or structure available to identify these proteins, little is known about the proteins that are destined to reside in the parasite periphery, the host-cell cytoplasm and/or the erythrocyte membrane. Here, the subcellular fractionation of erythrocytic P. yoelii at trophozoite and schizont stage along with label-free quantitative LC-MS/MS analysis of the whole proteome, revealed a proteome of 1335 proteins. Differential analysis of the relative abundance of these proteins across the subcellular compartments allowed us to map their locations, independently of their predicted features. These results, along with literature data and in vivo validation of 61 proteins enabled the identification of a remodellome of 184 proteins. This approach identified a significant number of conserved remodelling proteins across plasmodium that likely represent key conserved functions in the parasite and provides new insights into parasite evolution and biology. PMID- 27503797 TI - Oral health of Hong Kong children: a historical and epidemiological perspective. AB - OBJECTIVE: To provide a historical and epidemiological overview of the oral health of Hong Kong children. METHODS: Literature published before 2014 related to the oral health of Hong Kong children, supplemented with information accessed from government-archived oral health reports, was sourced using electronic databases and hand searches. Dental caries experience, periodontal health, enamel defects, and malocclusion of Hong Kong children were reviewed. RESULTS: A decline in the prevalence and extent of dental caries was observed among Hong Kong schoolchildren and adolescents after the 1960s. Among preschool children, however, dental caries remains common and the extent appears to have increased. The periodontal health of Hong Kong children remains unsatisfactory. Recently, enamel defects/dental fluorosis have considerably reduced. Information about malocclusion in Hong Kong children is limited. CONCLUSIONS: Since the 1960s, following public health policies, health promotion activities, and the introduction of a School Dental Care Service, improvements in the oral health of schoolchildren are evident. Nonetheless, the oral health of preschool children remains a concern. Policies and practices to improve the oral health of preschool children in Hong Kong are required. PMID- 27503798 TI - Syntheses of pterocarpenes and coumestans via regioselective cyclodehydration. AB - A highly efficient synthetic route to pterocarpenes and coumestans is described. BCl3-mediated dehydrative cyclization of 1,3-diaryloxyacetones under mild conditions permitted regioselective ring closure to afford 3-((2 iodoaryloxy)methyl)benzofurans which were converted to the corresponding pterocarpenes by Pd-catalyzed intramolecular direct arylation. The subsequent benzylic oxidation led to coumestans. This sequence was applied to the formal syntheses of coumestrol and the proposed structure of plicadin as well as total syntheses of flemichapparins B and C. PMID- 27503799 TI - Development and pilot-testing of a new tool to screen psoriasis patients for the presence of psoriatic arthritis: the Simple Psoriatic Arthritis Screening (SiPAS) questionnaire. PMID- 27503800 TI - Glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding. AB - Adiponectin regulates glucose and lipid metabolism, acting against metabolic syndrome and atherosclerosis. Accumulating evidence suggest that adiponectin acts on the brain including hypothalamic arcuate nucleus (ARC), where proopiomelanocortin (POMC) neurons play key roles in feeding regulation. Several studies have examined intracerebroventricular (ICV) injection of adiponectin and reported opposite effects, increase or decrease of food intake. These reports used different nutritional states. The present study aimed to clarify whether adiponectin exerts distinct effects on food intake and ARC POMC neurons depending on the glucose concentration. Adiponectin was ICV injected with or without glucose for feeding experiments and administered to ARC slices with high or low glucose for patch clamp experiments. We found that adiponectin at high glucose inhibited POMC neurons and increased food intake while at low glucose it exerted opposite effects. The results demonstrate that glucose level determines excitatory or inhibitory effects of adiponectin on arcuate POMC neuron activity and feeding. PMID- 27503801 TI - Reciprocity in spatial evolutionary public goods game on double-layered network. AB - Spatial evolutionary games have mainly been studied on a single, isolated network. However, in real world systems, many interaction topologies are not isolated but many different types of networks are inter-connected to each other. In this study, we investigate the spatial evolutionary public goods game (SEPGG) on double-layered random networks (DRN). Based on the mean-field type arguments and numerical simulations, we find that SEPGG on DRN shows very rich interesting phenomena, especially, depending on the size of each layer, intra-connectivity, and inter-connected couplings, the network reciprocity of SEPGG on DRN can be drastically enhanced through the inter-connected coupling. Furthermore, SEPGG on DRN can provide a more general framework which includes the evolutionary dynamics on multiplex networks and inter-connected networks at the same time. PMID- 27503802 TI - Identification of structural determinants of NAD(P)H selectivity and lysine binding in lysine N(6)-monooxygenase. AB - l-lysine (l-Lys) N(6)-monooxygenase (NbtG), from Nocardia farcinica, is a flavin dependent enzyme that catalyzes the hydroxylation of l-Lys in the presence of oxygen and NAD(P)H in the biosynthetic pathway of the siderophore nocobactin. NbtG displays only a 3-fold preference for NADPH over NADH, different from well characterized related enzymes, which are highly selective for NADPH. The structure of NbtG with bound NAD(P)(+) or l-Lys is currently not available. Herein, we present a mutagenesis study targeting M239, R301, and E216. These amino acids are conserved and located in either the NAD(P)H binding domain or the l-Lys binding pocket. M239R resulted in high production of hydrogen peroxide and little hydroxylation with no change in coenzyme selectivity. R301A caused a 300 fold decrease on kcat/Km value with NADPH but no change with NADH. E216Q increased the Km value for l-Lys by 30-fold with very little change on the kcat value or in the binding of NAD(P)H. These results suggest that R301 plays a major role in NADPH selectivity by interacting with the 2'-phosphate of the adenine ribose moiety of NADPH, while E216 plays a role in l-Lys binding. PMID- 27503803 TI - Glycan structure of Gc Protein-derived Macrophage Activating Factor as revealed by mass spectrometry. AB - Disagreement exists regarding the O-glycan structure attached to human vitamin D binding protein (DBP). Previously reported evidence indicated that the O-glycan of the Gc1S allele product is the linear core 1 NeuNAc-Gal-GalNAc-Thr trisaccharide. Here, glycan structural evidence is provided from glycan linkage analysis and over 30 serial glycosidase-digestion experiments which were followed by analysis of the intact protein by electrospray ionization mass spectrometry (ESI-MS). Results demonstrate that the O-glycan from the Gc1F protein is the same linear trisaccharide found on the Gc1S protein and that the hexose residue is galactose. In addition, the putative anti-cancer derivative of DBP known as Gc Protein-derived Macrophage Activating Factor (GcMAF, which is formed by the combined action of beta-galactosidase and neuraminidase upon DBP) was analyzed intact by ESI-MS, revealing that the activating E. coli beta-galactosidase cleaves nothing from the protein-leaving the glycan structure of active GcMAF as a Gal-GalNAc-Thr disaccharide, regardless of the order in which beta galactosidase and neuraminidase are applied. Moreover, glycosidase digestion results show that alpha-N-Acetylgalactosamindase (nagalase) lacks endoglycosidic function and only cleaves the DBP O-glycan once it has been trimmed down to a GalNAc-Thr monosaccharide-precluding the possibility of this enzyme removing the O-glycan trisaccharide from cancer-patient DBP in vivo. PMID- 27503804 TI - Neuoroprotective efficacies by KUS121, a VCP modulator, on animal models of retinal degeneration. AB - Retinitis pigmentosa (RP) is one of the leading causes of adult blindness and has no established therapy. We have shown that valosin-containing protein (VCP) modulators, Kyoto University Substances (KUSs), ameliorated abnormally low ATP levels by inhibiting the ATPase of VCP, thereby protected several types of cells, including retinal neurons, from cell death-inducing insults. In this study, we found that KUS121, one of the VCP modulators, effectively protects photoreceptors both morphologically and functionally, in two animal models of retinal degeneration, rd12 mice and RP rabbits with a rhodopsin (Pro347Leu) mutation. In rd12 mice, KUS121 suppressed the loss of photoreceptors, not only rods but also cones, as well as the visual function deterioration. Significant protective effects existed even when the medication was started in later stages of the disease. In RP rabbits, KUS121 suppressed thinning of the outer nuclear layer and maintained visual function. In the retinas treated with KUS121, suppression of endoplasmic reticulum stress, activation of mammalian target of rapamycin and suppression of disease-associated apoptosis were evident. The ability of KUS121 to protect photoreceptors, especially cones, even in later stages of the disease may contribute to the preservation of central vision in RP patients, which is important for quality of vision. PMID- 27503805 TI - Defining myocardial tissue abnormalities in end-stage renal failure with cardiac magnetic resonance imaging using native T1 mapping. AB - Noninvasive quantification of myocardial fibrosis in end-stage renal disease is challenging. Gadolinium contrast agents previously used for cardiac magnetic resonance imaging (MRI) are contraindicated because of an association with nephrogenic systemic fibrosis. In other populations, increased myocardial native T1 times on cardiac MRI have been shown to be a surrogate marker of myocardial fibrosis. We applied this method to 33 incident hemodialysis patients and 28 age- and sex-matched healthy volunteers who underwent MRI at 3.0T. Native T1 relaxation times and feature tracking-derived global longitudinal strain as potential markers of fibrosis were compared and associated with cardiac biomarkers. Left ventricular mass indices were higher in the hemodialysis than the control group. Global, Septal and midseptal T1 times were all significantly higher in the hemodialysis group (global T1 hemodialysis 1171 +/- 27 ms vs. 1154 +/- 32 ms; septal T1 hemodialysis 1184 +/- 29 ms vs. 1163 +/- 30 ms; and midseptal T1 hemodialysis 1184 +/- 34 ms vs. 1161 +/- 29 ms). In the hemodialysis group, T1 times correlated with left ventricular mass indices. Septal T1 times correlated with troponin and electrocardiogram-corrected QT interval. The peak global longitudinal strain was significantly reduced in the hemodialysis group (hemodialysis -17.7+/-5.3% vs. -21.8+/-6.2%). For hemodialysis patients, the peak global longitudinal strain significantly correlated with left ventricular mass indices (R = 0.426), and a trend was seen for correlation with galectin-3, a biomarker of cardiac fibrosis. Thus, cardiac tissue properties of hemodialysis patients consistent with myocardial fibrosis can be determined noninvasively and associated with multiple structural and functional abnormalities. PMID- 27503806 TI - Hypoxia-inducible factor-1alpha promotes glomerulosclerosis and regulates COL1A2 expression through interactions with Smad3. AB - The function of hypoxia-inducible factor-1alpha (HIF-1alpha) in chronic kidney disease is disputed. Here we report that interactions of HIF-1alpha with transforming growth factor-beta (TGF-beta) signaling may promote its fibrotic effects. Knockout of HIF-1alpha is protective against glomerulosclerosis and glomerular type-I collagen accumulation in a mouse podocyte ablation model. Transcriptional analysis of cultured renal cells showed that alpha2(I) collagen expression is directly regulated by HIF-1alpha binding to a functional hypoxia responsive element in its promoter at -335 relative to the transcription start site. Activation of COL1A2 transcription by HIF-1alpha occurred in the absence of hypoxia and is strongly enhanced by TGF-beta signaling. TGF-beta, in addition to increasing HIF-1alpha levels, increased both HIF-1alpha binding to the COL1A2 promoter and HIF-1alpha N-terminal transactivation domain activity. These effects of TGF-beta on HIF-1alpha were inhibited in Smad3-null mouse embryonic fibroblasts, suggesting a requirement for Smad3. Phosphorylated Smad3 also associated with the -335 hypoxia-responsive element of the COL1A2 promoter independent of a Smad DNA binding sequence. Smad3 binding to the -335 hypoxia responsive element required HIF-1alpha both in vitro and in kidney lysate from the disease model, suggesting formation of an HIF-1alpha-Smad3 transcriptional complex. Thus, HIF-1alpha-Smad3 has a novel interaction in glomerulosclerosis. PMID- 27503807 TI - Polydopamine-Coated Porous Microspheres Conjugated with Immune Stimulators for Enhanced Cytokine Induction in Macrophages. AB - Polydopamine-coated porous microsphere (PPM) is investigated as a simple and versatile immobilization strategy for immune-stimulating biomolecules to enhance delivery efficiency and immune-stimulating effects such as cytokine induction in macrophages. The PPMs, with diameters of about 2 MUm, exhibit simultaneous and efficient incorporation of biomolecules (nucleotides and proteins), which is comparable to that achieved using microspheres carrying biomolecules internally by virtue of their porous structure. Ovalbumin-conjugated PPMs are internalized into macrophages efficiently and selectively via the phagocytic pathway, without any noticeable toxicity. Internalized CpG oligodeoxynucleotide (ODN)-conjugated PPMs (PPM-CpG) greatly enhance the induction of selected cytokines (TNF-alpha and IL-6) in RAW 264.7 cells compared to that by the soluble CpG ODN and ionic complexes. Therefore, PPMs generated in this study may serve as effective carriers of immune-stimulating biomolecules such as diverse toll-like receptor agonists. PMID- 27503808 TI - Band gap bowing in NixMg1-xO. AB - Epitaxial transparent oxide NixMg1-xO (0 <= x <= 1) thin films were grown on MgO(100) substrates by pulsed laser deposition. High-resolution synchrotron X-ray diffraction and high-resolution transmission electron microscopy analysis indicate that the thin films are compositionally and structurally homogeneous, forming a completely miscible solid solution. Nevertheless, the composition dependence of the NixMg1-xO optical band gap shows a strong non-parabolic bowing with a discontinuity at dilute NiO concentrations of x < 0.037. Density functional calculations of the NixMg1-xO band structure and the density of states demonstrate that deep Ni 3d levels are introduced into the MgO band gap, which significantly reduce the fundamental gap as confirmed by optical absorption spectra. These states broaden into a Ni 3d-derived conduction band for x > 0.074 and account for the anomalously large band gap narrowing in the NixMg1-xO solid solution system. PMID- 27503809 TI - Metastatic prostatic adenocarcinoma with neuroendocrine differentiation to meningioma. AB - The diagnosis of a tumor-to-tumor metastasis in the central nervous system most commonly involves metastasis to a meningioma. These combined lesions are often radiographically unsuspected and mimic a meningioma. Most commonly, the source of metastatic disease are carcinomas from the lung and breast. To our knowledge, fewer than a half dozen cases of metastatic prostatic adenocarcinoma to a meningioma have been documented in the literature. This report documents a 67 year-old man who presented with worsening confusion and altered mental status, accompanied by symptoms of increased urinary frequency, incontinence, and difficulty urinating. Imaging revealed a mass at the base of the bladder and an intracranial lesion, surrounded by edema, which was initially suspicious for intracranial metastasis of prostate cancer. Due to worsening neurological symptoms, the patient underwent craniotomy to remove the intracranial mass. The mass was comprised of a meningothelial meningioma, World Health Organization Grade I, accompanied by atypical epithelioid cells which demonstrated immunoreactivity to prostate specific antigen, chromogranin and neuron specific enolase antibodies, consistent with a metastatic prostatic adenocarcinoma with neuroendocrine differentiation. The patient suffered severe neurological complications post-operatively, developed multiple metastases and expired 12months later. The report reviews current theories as to why meningiomas are the most common host tumor for tumor-to-tumor metastases in the brain and reviews the literature on previously reported cases involving metastatic prostatic adenocarcinoma. PMID- 27503810 TI - NF-kappaB deregulation in splenic marginal zone lymphoma. AB - Splenic marginal zone lymphoma is a rare mature B-cell malignancy involving the spleen, bone marrow and blood. Over the past years, the rapid expansion of sequencing technologies allowing the genome-wide assessment of genomic, epigenetic and transcriptional changes has revolutionized our understanding of the biological basis of splenic marginal zone lymphoma by providing a comprehensive and unbiased view of the genes/pathways that are deregulated in this disease. NF-kappaB is a family of transcription factors that plays critical roles in development, survival, and activation of B lymphocytes. Consistent with the physiological involvement of NF-kappaB signalling in proliferation and commitment of mature B-cells to the marginal zone of the spleen, many oncogenic mutations involved in constitutive activation of the NF-kappaB pathway were recently identified in splenic marginal zone lymphoma. This review describes the progress in understanding the mechanism of NF-kappaB activation in splenic marginal zone lymphoma, including molecular, epigenetic and post-transcriptional modifications of NF-kappaB genes and of upstream pathways, and discusses how information gained from these efforts has provided new insights on potential targets of diagnostic, prognostic and therapeutic relevance for splenic marginal zone lymphoma. PMID- 27503816 TI - [The Neural Mechanism of Emotional Sweating]. AB - The autonomic nervous system mediates blood pressure, heart rate, and sweat secretion, which are strongly modulated by the limbic system. Moreover, the limbic system plays an important role in generating emotion. Therefore, monitoring autonomic activities, such as palmar sweating, could be useful to evaluate emotional responses. Palmar sweating is otherwise known as emotional sweating, and it's monitored for lie-detection or psychological therapy. The present review will be helpful for neurologists, psychiatrists, and psychologists seeking to understand the neural mechanism of emotional sweating. PMID- 27503811 TI - Effects of acute alcohol withdrawal on nest building in mice selectively bred for alcohol withdrawal severity. AB - Nest building has been used to assess thermoregulatory behavior and positive motivational states in mice. There are known genetic influences on ethanol withdrawal severity as well as individual/thermoregulatory nest building. Withdrawal Seizure-Prone (WSP-1, WSP-2) and Withdrawal Seizure-Resistant (WSR-1, WSR-2) mice were selectively bred for high vs low handling-induced convulsion (HIC) severity, respectively, during withdrawal from chronic ethanol vapor inhalation. They also differ in HIC severity during withdrawal from an acute, 4g/kg ethanol injection. In our initial study, withdrawal from an acute dose of ethanol dose-dependently impaired nest building over the initial 24h of withdrawal in genetically segregating Withdrawal Seizure Control (WSC) mice. In two further studies, acute ethanol withdrawal suppressed nest building for up to two days in WSP-1 females. Deficits in nest building from ethanol were limited to the initial 10h of withdrawal in WSR-1 females and to the initial 24h of withdrawal in WSP-1 and WSR-1 males. Effects of ethanol on nest building for up to two days were found in WSP-2 and WSR-2 mice of both sexes. Nest building deficits in female mice from the first replicate could not be explained by a general decrease in locomotor behavior. These results suggest that nest building is a novel behavioral phenotype for indexing the severity of acute ethanol withdrawal, and that genes contributing to this trait differ from those affecting acute withdrawal HIC severity. PMID- 27503817 TI - [Emotion Disorders and Abnormal Perspiration]. AB - This article reviewed the relationship between emotional disorders and abnormal perspiration. First, I focused on local brain areas related to emotional processing, and summarized the functions of the emotional network involving those local areas. Functional disorders followed by the damage in the amygdala, orbitofrontal cortex, and insular cortex were reviewed, including related abnormal perspiration. I then addressed the mechanisms of how autonomic disorders influence emotional processing. Finally, possible future directions for integrated understanding of the connection between neural activities and bodily reactions were discussed. PMID- 27503818 TI - [Functional Neuroimaging of Sweating]. AB - Central mechanisms of thermal and emotional sweating has been elucidated by using functional MRI in healthy human subjects. The hypothalamus (preoptic region) was specifically activated during thermal sweating, whereas prefrontal regions, insula, and anterior cingulate were activated during emotional sweating. Both thermal and emotional sweating were associated with activation in the dorsal midbrain and in the rostral lateral medulla. These results suggested that sweating in human represents not only sympathetic activation but also integrates emotional function, internal awareness, and attentional arousal in humans. PMID- 27503819 TI - [Decision Making and Electrodermal Activity]. AB - Decision making is aided by emotions. Bodily responses, such as sweating, heartbeat, and visceral sensation, are used to monitor the emotional state during decision making. Because decision making in dairy life is complicated and cognitively demanding, these bodily signals are thought to facilitate the decision making process by assigning positive or negative values for each of the behavioral options. The sweat response in a decision making task is measured by skin conductance response (SCR). SCR in decision making is divided into two categories: anticipatory SCR is observed before making decisions, and reward/punishment SCR is observed after the outcome of the decision is perceived. Brain lesion studies in human revealed that the amygdala and ventromedial prefrontal cortex are important in decision making. Patients with lesinon in the amygdala exhibit neither the anticipatory nor reward/punishment SCRs, while patients with the ventromedial prefrontal lesions have deficits only in the anticipatory SCRs. Decision making tasks and SCR analysis have contributed to reveal the implicit aspects of decision making. Further research is necessary for clarifying the role of explicit process of decision making and its relationship with the implicit process. PMID- 27503820 TI - [Biofeedback Therapy and Sweat]. AB - Biofeedback training is a technique through which one can learn to control usually uncontrollable inner body functions, such as brain waves, heart rate or electrodermal activity (EDA). These 'hidden' biological signals are measured from a participant and fed back during the training, e.g., through visual and auditory changes on a computer screen. With practice, the participant learns to control this feedback, and ultimately to control their bodily responses without needing the feedback. In this article, the application of EDA biofeedback will be introduced as a therapy for specific neurological conditions. PMID- 27503821 TI - [Role of Reelin during Layer Formation in the Cerebral Neocortex]. AB - Reelin controls the neuronal layer formation in the developing cerebral neocortex. The Reelin glycoprotein is mainly secreted from Cajal-Retzius cells in the marginal zone, and it guides the proper aggregation of the migrating neurons in a birth-dependent "inside-out" manner. Reelin also regulates the final process of neuronal migration (terminal translocation and somal translocation) by activating integrin and N-cadherin. It is also expressed around the subventricular zone and it controls the behavior of the migrating neurons. PMID- 27503822 TI - [The Social Costs of Dementia in Japan: Focusing on the Informal Care Cost]. AB - Due to the rapid increase of the number in people with dementia, social costs of dementia are also expected to rise. In 2014, the social cost of dementia in Japan was estimated to be 145,140 billion yen, 40 % of which was spent on informal care. To investigate whether each intervention is worth the investment, more research on aspects like cost-effective analysis is expected to be undertaken. PMID- 27503823 TI - [An Autopsy Case of Globular Glial Tauopathy Presenting with Amyotrophic Lateral Sclerosis with Dementia]. AB - We report an autopsy case of globular glial tauopathy (GGT) presenting clinically with amyotrophic lateral sclerosis (ALS) with dementia. A 79-year-old female developed weakness in the right upper limb, which progressed gradually. She developed apathy and speech disorder at 80 years of age. On neurological examination, she showed signs of upper and lower motor neuron disorder and dementia, but no extrapyramidal signs. The clinical diagnosis was ALS with dementia. The autopsy revealed left predominant marked atrophy of the frontal lobe due to severe neuronal loss and Gliosis. Immunohistochemistry using anti-4 repeat tau antibody revealed numerous globular glial inclusions. Severe neurodegeneration in the primary motor cortex and corticospinal tract was observed. There were distinctive tau-positive inclusions in both Betz and anterior horn cells. TDP-43-positive inclusions in motor neurons were not detected. Sequence analysis of the tau gene revealed no mutations in exons 1-5, 7, 9-13, or the adjacent intronic sequences. GGT can cause a clinical phenotype of ALS with dementia. (Received December 28, 2015; Accepted February 23, 2016; Published August 1, 2016). PMID- 27503824 TI - [Effective Microvascular Decompression of the Trigeminal Nerve in a Patient with SUNCT]. AB - A 43-year-old man presented with severe, saw-tooth pattern pain around the right eye that started with conjunctival injection, lacrimation and nasal discharge, lasting for about 1 hour, 4 months after the initial onset of lancinating pain in the same area. The patient was diagnosed with SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) according to the International Classification of Headache Disorders 3rd edition (beta version). The symptoms improved in 2 months but recurred 6 months later. He developed a toxic eruption after receiving a variety of antiepileptic agents including lamotrigine, which suggested refractory SUNCT. Head magnetic resonance imaging (MRI) showed neurovascular compression (NVC) involving the right trigeminal nerve. Microvascular decompression (MVD) was performed, and the pain was relieved postoperatively. MVD should be considered when treating refractory SUNCT because NVC may be involved in some cases. (Received February 29, 2016; Accepted April 4, 2016; Published August 1, 2016). PMID- 27503825 TI - [A Case of Spontaneous Putaminal Hemorrhage Responsible for the Rupture of Charcot Artery]. PMID- 27503826 TI - Inter- and Intra-Observer Agreement in Ultrasound BI-RADS Classification and Real Time Elastography Tsukuba Score Assessment of Breast Lesions. AB - Our aim was to prospectively evaluate inter- and intra-observer agreement between Breast Imaging Reporting and Data System (BI-RADS) classifications and Tsukuba elasticity scores (TSs) of breast lesions. The study included 164 breast lesions (63 malignant, 101 benign). The BI-RADS classification and TS of each breast lesion was assessed by the examiner and twice by three reviewers at an interval of 2 months. Weighted kappa values for inter-observer agreement ranged from moderate to substantial for BI-RADS classification (kappa = 0.585-0.738) and was substantial for TS (kappa = 0.608-0.779). Intra-observer agreement was almost perfect for ultrasound (US) BI-RADS (kappa = 0.847-0.872) and TS (kappa = 0.879 0.914). Overall, individual reviewers are highly self-consistent (almost perfect intra-observer agreement) with respect to BI-RADS classification and TS, whereas inter-observer agreement was moderate to substantial. Comprehensive training is essential for achieving high agreement and minimizing the impact of subjectivity. Our results indicate that breast US and real-time elastography can achieve high diagnostic performance. PMID- 27503827 TI - Nearly half of US pediatric trials are unfinished or unpublished, study finds. PMID- 27503828 TI - Significantly Accelerated Wound Healing of Full-Thickness Skin Using a Novel Composite Gel of Porcine Acellular Dermal Matrix and Human Peripheral Blood Cells. AB - Here we report the fabrication of a novel composite gel from decellularized gal gal-knockout porcine skin and human peripheral blood mononuclear cells (hPBMCs) for full-thickness skin wound healing. Decellularized skin extracellular matrix (ECM) powder was prepared via chemical treatment, freeze drying, and homogenization. The powder was mixed with culture medium containing hyaluronic acid to generate a pig skin gel (PSG). The effect of the gel in regeneration of full-thickness wounds was studied in nude mice. We found significantly accelerated wound closure already on day 15 in animals treated with PSG only or PSG + hPBMCs compared to untreated and hyaluronic acid-treated controls (p < 0.05). Addition of the hPBMCs to the gel resulted in marked increase of host blood vessels as well as the presence of human blood vessels. At day 25, histologically, the wounds in animals treated with PSG only or PSG + hPBMCs were completely closed compared to those of controls. Thus, the gel facilitated generation of new skin with well-arranged epidermal cells and restored bilayer structure of the epidermis and dermis. These results suggest that porcine skin ECM gel together with human cells may be a novel and promising biomaterial for medical applications especially for patients with acute and chronic skin wounds. PMID- 27503829 TI - Bayesian bent-cable growth mixture tobit models for longitudinal data with skewness and detection limit: application to AIDS studies. AB - This paper presents a new Bayesian methodology for identifying a transition period for the development of drug resistance to antiretroviral drug or therapy in HIV/AIDS studies or other related fields. Estimation of such a transition period requires an availability of longitudinal data where growth trajectories of a response variable tend to exhibit a gradual change from a declining trend to an increasing trend rather than an abrupt change. We assess this clinically important feature of the longitudinal HIV/AIDS data using the bent-cable framework within a growth mixture Tobit model. To account for heterogeneity of drug resistance among subjects, the parameters of the bent-cable growth mixture Tobit model are also allowed to differ by subgroups (subpopulations) of patients classified into latent classes on the basis of trajectories of observed viral load data with skewness and left-censoring. The proposed methods are illustrated using real data from an AIDS clinical study. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27503830 TI - Environmental and mucosal microbiota and their role in childhood asthma. AB - BACKGROUND: High microbial diversity in the environment has been associated with lower asthma risk, particularly in children exposed to farming. It remains unclear whether this effect operates through an altered microbiome of the mucosal surfaces of the airways. METHODS: DNA from mattress dust and nasal samples of 86 school age children was analyzed by 454 pyrosequencing of the 16S rRNA gene fragments. Based on operational taxonomic units (OTUs), bacterial diversity and composition were related to farm exposure and asthma status. RESULTS: Farm exposure was positively associated with bacterial diversity in mattress dust samples as determined by richness (P = 8.1 * 10-6 ) and Shannon index (P = 1.3 * 10-5 ). Despite considerable agreement of richness between mattress and nasal samples, the association of richness with farming in nasal samples was restricted to a high gradient of farm exposure, that is, exposure to cows and straw vs no exposure at all. In mattress dust, the genera Clostridium, Facklamia, an unclassified genus within the family of Ruminococcaceae, and six OTUs were positively associated with farming. Asthma was inversely associated with richness [aOR = 0.48 (0.22-1.02)] and Shannon index [aOR = 0.41 (0.21-0.83)] in mattress dust and to a lower extent in nasal samples [richness aOR 0.63 = (0.38-1.06), Shannon index aOR = 0.66 (0.39-1.12)]. CONCLUSION: The stronger inverse association of asthma with bacterial diversity in mattress dust as compared to nasal samples suggests microbial involvement beyond mere colonization of the upper airways. Whether inhalation of metabolites of environmental bacteria contributes to this phenomenon should be the focus of future research. PMID- 27503831 TI - The neurotrophin receptor signaling endosome: Where trafficking meets signaling. AB - Neurons are the largest cells in the body and form subcellular compartments such as axons and dendrites. During both development and adulthood building blocks must be continually trafficked long distances to maintain the different regions of the neuron. Beyond building blocks, signaling complexes are also transported, allowing for example, axons to communicate with the soma. The critical roles of signaling via ligand-receptor complexes is perhaps best illustrated in the context of development, where they are known to regulate polarization, survival, axon outgrowth, dendrite development, and synapse formation. However, knowing 'when' and 'how much' signaling is occurring does not provide the complete story. The location of signaling has a significant impact on the functional outcomes. There are therefore complex and functionally important trafficking mechanisms in place to control the precise spatial and temporal aspects of many signal transduction events. In turn, many of these signaling events affect trafficking mechanisms, setting up an intricate connection between trafficking and signaling. In this review we will use neurotrophin receptors, specifically TrkA and TrkB, to illustrate the cell biology underlying the links between trafficking and signaling. Briefly, we will discuss the concepts of how trafficking and signaling are intimately linked for functional and diverse signaling outputs, and how the same protein can play different roles for the same receptor depending on its localization. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 419-437, 2017. PMID- 27503832 TI - Vaccine Coverage for United States Infants at Milestone Ages: Missed Opportunities for Vaccination. AB - We used a claims database to assess coverage for rotavirus (RV), diphtheria tetanus-acellular pertussis, and pneumococcal conjugate vaccines among infants in the United States. Similar coverage was seen until 7 months of age, after which RV coverage lagged. Missed opportunities for vaccination at well-child visits were found to vary by age. PMID- 27503833 TI - Enhanced protective role in materials with gradient structural orientations: Lessons from Nature. AB - Living organisms are adept at resisting contact deformation and damage by assembling protective surfaces with spatially varied mechanical properties, i.e., by creating functionally graded materials. Such gradients, together with multiple length-scale hierarchical structures, represent the two prime characteristics of many biological materials to be translated into engineering design. Here, we examine one design motif from a variety of biological tissues and materials where site-specific mechanical properties are generated for enhanced protection by adopting gradients in structural orientation over multiple length-scales, without manipulation of composition or microstructural dimension. Quantitative correlations are established between the structural orientations and local mechanical properties, such as stiffness, strength and fracture resistance; based on such gradients, the underlying mechanisms for the enhanced protective role of these materials are clarified. Theoretical analysis is presented and corroborated through numerical simulations of the indentation behavior of composites with distinct orientations. The design strategy of such bioinspired gradients is outlined in terms of the geometry of constituents. This study may offer a feasible approach towards generating functionally graded mechanical properties in synthetic materials for improved contact damage resistance. STATEMENT OF SIGNIFICANCE: Living organisms are adept at resisting contact damage by assembling protective surfaces with spatially varied mechanical properties, i.e., by creating functionally-graded materials. Such gradients, together with multiple length-scale hierarchical structures, represent the prime characteristics of many biological materials. Here, we examine one design motif from a variety of biological tissues where site-specific mechanical properties are generated for enhanced protection by adopting gradients in structural orientation at multiple length-scales, without changes in composition or microstructural dimension. The design strategy of such bioinspired gradients is outlined in terms of the geometry of constituents. This study may offer a feasible approach towards generating functionally-graded mechanical properties in synthetic materials for improved damage resistance. PMID- 27503834 TI - Epigenetics and nutrition-related epidemics of metabolic diseases: Current perspectives and challenges. AB - We live in a world fascinated by the relationship between disease and nutritional disequilibrium. The subtle and slow effects of chronic nutrient toxicity are a major public health concern. Since food is potentially important for the development of "metabolic memory", there is a need for more information on the type of nutrients causing adverse or toxic effects. We now know that metabolic alterations produced by excessive intake of some nutrients, drugs and chemicals directly impact epigenetic regulation. We envision that understanding how metabolic pathways are coordinated by environmental and genetic factors will provide novel insights for the treatment of metabolic diseases. New methods will enable the assembly and analysis of large sets of complex molecular and clinical data for understanding how inflammation and mitochondria affect bioenergetics, epigenetics and health. Collectively, the observations we highlight indicate that energy utilization and disease are intimately connected by epigenetics. The challenge is to incorporate metabolo-epigenetic data in better interpretations of disease, to expedite therapeutic targeting of key pathways linking nutritional toxicity and metabolism. An additional concern is that changes in the parental phenotype are detectable in the methylome of subsequent offspring. The effect might create a menace to future generations and preconceptional considerations. PMID- 27503835 TI - Choice of non-medic to run radiology school was "ill conceived," says royal college. PMID- 27503836 TI - Drosophila wing imaginal discs respond to mechanical injury via slow InsP3R mediated intercellular calcium waves. AB - Calcium signalling is a highly versatile cellular communication system that modulates basic functions such as cell contractility, essential steps of animal development such as fertilization and higher-order processes such as memory. We probed the function of calcium signalling in Drosophila wing imaginal discs through a combination of ex vivo and in vivo imaging and genetic analysis. Here we discover that wing discs display slow, long-range intercellular calcium waves (ICWs) when mechanically stressed in vivo or cultured ex vivo. These slow imaginal disc intercellular calcium waves (SIDICs) are mediated by the inositol-3 phosphate receptor, the endoplasmic reticulum (ER) calcium pump SERCA and the key gap junction component Inx2. The knockdown of genes required for SIDIC formation and propagation negatively affects wing disc recovery after mechanical injury. Our results reveal a role for ICWs in wing disc homoeostasis and highlight the utility of the wing disc as a model for calcium signalling studies. PMID- 27503837 TI - A flexible parametric approach to examining spatial variation in relative survival. AB - Most of the few published models used to obtain small-area estimates of relative survival are based on a generalized linear model with piecewise constant hazards under a Bayesian formulation. Limitations of these models include the need to artificially split the time scale, restricted ability to include continuous covariates, and limited predictive capacity. Here, an alternative Bayesian approach is proposed: a spatial flexible parametric relative survival model. This overcomes previous limitations by combining the benefits of flexible parametric models: the smooth, well-fitting baseline hazard functions and predictive ability, with the Bayesian benefits of robust and reliable small-area estimates. Both spatially structured and unstructured frailty components are included. Spatial smoothing is conducted using the intrinsic conditional autoregressive prior. The model was applied to breast, colorectal, and lung cancer data from the Queensland Cancer Registry across 478 geographical areas. Advantages of this approach include the ease of including more realistic complexity, the feasibility of using individual-level input data, and the capacity to conduct overall, cause specific, and relative survival analysis within the same framework. Spatial flexible parametric survival models have great potential for exploring small-area survival inequalities, and we hope to stimulate further use of these models within wider contexts. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27503838 TI - Assessment of Early Tumour Shrinkage: Ready for Integration in the Treatment Strategy for Metastatic Renal Cell Carcinoma? PMID- 27503839 TI - Re: Prostate Cancer Detection with Magnetic Resonance-ultrasound Fusion Biopsy: The Role of Systematic and Targeted Biopsies. PMID- 27503840 TI - Improved Reporting of Randomized Controlled Trials in the Urologic Literature. AB - BACKGROUND: Well-designed randomized controlled trials (RCTs) have the potential to provide high-quality evidence to inform questions of therapy and prevention, but this potential is contingent on the use of appropriate methods and transparent reporting. OBJECTIVE: To systematically assess the quality of urology RCT reporting and identify trends over time. DESIGN, SETTING, AND PARTICIPANTS: All RCTs published in four leading urology journals in 2013 were identified and compared to a prior analysis of studies from 1996 and 2004. Two reviewers abstracted data based on the Consolidated Standards of Reporting Trials (CONSORT) checklist. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A summary reporting score (range: 0-22) for each study was determined. Mean overall scores for 1996, 2004, and 2013 were compared using analysis of variance. We used chi2 to compare the reporting frequency of individual criteria. RESULTS AND LIMITATIONS: Mean CONSORT scores for RCTs were 15.6+/-2.0 in 2013 (n=82), 12.0+/-0.3 in 2004 (n=87), and 10.2+/-0.3 in 1996 (n=65); p<0.01. Key deficiencies remain in reporting methods of allocation concealment and group assignment (selection bias), and blinding of participants, personnel, and outcome assessors (performance and detection bias). Study limitations are potential reviewer bias resulting from lack of journal deidentification and the relatively low number of studies reviewed. CONCLUSIONS: There has been a substantial improvement in reporting quality of RCTs in urology since CONSORT. Some methodological criteria remain underreported, and increased efforts are necessary to further this improvement. PATIENT SUMMARY: Treatment decisions are often based on data from randomized controlled trials. We looked at whether these trials in urology are transparent in reporting their design and conduct using a framework known as the CONSORT criteria and found significant improvements over time. Some areas of deficiency remain, and our paper aimed to highlight these drawbacks to promote continued high-quality research. PMID- 27503841 TI - Comparison of luminescence property of gamma-ray irradiated Tb3+ -doped and Ce3+ co-doped potassium halide single crystals. AB - Single crystals of KCl and KBr singly and doubly doped with Tb3+ and Ce3+ , respectively, were successfully grown using the Bridgeman technique. This work reports the comparative luminescence behavior and optical absorption characterization of non-irradiated and gamma-ray-irradiated single crystals of these materials. The existing defect and the defect created by gamma-ray irradiation were monitored by optical absorption spectra. The excitation and emission spectra of these materials were measured at room temperature with a spectrofluorometer and the pertaining results were compared. The F-band comparison was made when bleached with F-light for 2 mins. The trap-level changes in KCl and KBr when it is singly and doubly doped enabled us to draw conclusions on the nature of the defect and on the recombination processes involved. PMID- 27503842 TI - Seeing is Believing: Tracking Translation Dynamics In Vivo. AB - Translation is a crucial step in transmitting genetic information from mRNA to functional protein. Four recent papers provide novel imaging approaches to directly observe translation of single mRNAs in real time in live cells, and represent a powerful toolkit to dissect the molecular mechanisms of translation regulation. PMID- 27503843 TI - Neuroanatomical bases of effortful control: evidence from a large sample of young healthy adults using voxel-based morphometry. AB - Effortful control (EC) is a base of individuality in cognition and psychological adjustment. EC is defined as a capacity to control responses and behaviors. We investigated associations between individual differences of EC and regional gray and white matter volume (rGMV/rGMV) in 374 men and 306 women (age, 20.61 +/- 1.82 years) using Japanese version of Effortful control scale (J-ECS). J-ECS consists of three subscales such as inhibitory control (IC), activation control (ACTC), and attentional control (ATC). Results showed that (a) IC was associated with larger rGMV in the dorsal part of anterior cingulate cortex (dACC), the supplementary motor area (SMA) and the pre SMA and larger rWMV in the dACC, (b) ACTC was correlated with smaller rGMV in the insula and the putamen, and (c) ATC was associated with larger rWMV in the inferior frontal gyrus, orbital frontal gyrus, ACC, and insula. Our study revealed key neuroanatomical correlations between EC and rGMV and rWMV. PMID- 27503844 TI - The Risk of Hepatotoxicity, New Onset Diabetes and Rhabdomyolysis in the Era of High-Intensity Statin Therapy: Does Statin Type Matter? AB - The 2013 American College of Cardiology/American Heart Association guidelines on cholesterol management have placed greater emphasis on high-intensity statin dosing for those with known cardiovascular disease or diabetes mellitus. Differences in risk of hepatotoxicity, new onset diabetes and rhabdomyolysis specifically between the high-intensity statins and the most common moderate intensity statin, simvastatin, were not found to a significant degree in this review. Rather, baseline characteristics and drug-drug interactions (DDIs) appear to be more important regarding the risk of these adverse effects. Pharmacogenetic differences in statin metabolism may explain individual susceptibility, however genetic testing is not felt to be cost effective at this time. More importantly, statin choice should consider concomitant use of the many prevalent CYP3A4 inhibitors or inducers, and when present, rosuvastatin selection is recommended to reduce DDIs and risk of statin-induced adverse effects. PMID- 27503845 TI - DCLK1 phosphorylates the microtubule-associated protein MAP7D1 to promote axon elongation in cortical neurons. AB - Doublecortin-like kinase 1 (DCLK1) is a member of the neuronal microtubule associated doublecortin (DCX) family and functions in multiple stages of neural development including radial migration and axon growth of cortical neurons. DCLK1 is suggested to play the roles in part through its protein kinase activity, yet the kinase substrates of DCLK1 remain largely unknown. Here we have identified MAP7D1 (microtubule-associated protein 7 domain containing 1) as a novel substrate of DCLK1 by using proteomic analysis. MAP7D1 is expressed in developing cortical neurons, and knockdown of MAP7D1 in layer 2/3 cortical neurons results in a significant impairment of callosal axon elongation, but not of radial migration, in corticogenesis. We have further defined the serine 315 (Ser 315) of MAP7D1 as a DCLK1-induced phosphorylation site and shown that overexpression of a phosphomimetic MAP7D1 mutant in which Ser 315 is substituted with glutamic acid (MAP7D1 S315E), but not wild-type MAP7D1, fully rescues the axon elongation defects in Dclk1 knockdown neurons. These data demonstrate that DCLK1 phosphorylates MAP7D1 on Ser 315 to facilitate axon elongation of cortical neurons. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 419-437, 2017. PMID- 27503846 TI - StemCell KeepTM Is Effective for Cryopreservation of Human Embryonic Stem Cells by Vitrification. AB - Safe and stable cryopreservation is critical for research involving human embryonic stem cells (hESCs). Dimethyl sulfoxide (DMSO) is a popular cryoprotective agent; however, its cytotoxicity cannot be ignored. Thus, there is a need for an alternate cryoprotectant. We reported previously that a novel cryopreservation reagent, StemCell KeepTM (SCK), was effective for cryopreserving human induced pluripotent stem cells (hiPSCs) by vitrification. Because hESCs and hiPSCs are not identical, the current study examined the use of SCK on hESCs. hESCs cryopreserved with SCK were thawed and cultured on SNL 76/7 cells, which were derived from a mouse fibroblast STO cell line transformed with neomycin resistance and murine LIF genes. After cryopreservation, cultured hESCs were assessed for their attachment ability and characterized by alkaline phosphatase (AP) and immunocytochemical (ICC) staining, fluorescence-activated cell sorting (FACS), reverse transcription polymerase chain reaction (RT-PCR), and karyotyping. The proliferation of SCK-cryopreserved hESCs cultured on SNL cells, or in feeder-free conditions, was higher than that of cells preserved in a solution of 2 M DMSO, 1 M acetamide, and 3 M propylene glycol (DAP). The cell number with SCK-cryopreserved hESCs was about twice that of hESCs cryopreserved in DAP. The pluripotency of SCK-cryopreserved hESCs was similar to that of DAP cryopreserved hESCs based on AP staining. Data from ICC, FACS, and RT-PCR analyses showed that stem cell markers were continually expressed on SCK cryopreserved hESCs. The teratoma assay showed that SCK-cryopreserved hESCs differentiated into three germ layers. Furthermore, SCK-cryopreserved hESCs had normal karyotypes. These data indicate that SCK was effective for cryopreservation of hESCs by vitrification. PMID- 27503847 TI - Surgical Valvotomy Versus Balloon Valvuloplasty for Congenital Aortic Valve Stenosis: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Optimal initial treatment for congenital aortic valve stenosis in children remains unclear between balloon aortic valvuloplasty (BAV) and surgical aortic valvotomy (SAV). METHODS AND RESULTS: We performed a contemporary systematic review and meta-analysis to compare survival in children with congenital aortic valve stenosis. Secondary outcomes included frequency of at least moderate regurgitation at hospital discharge as well as rates of aortic valve replacement and reintervention. Single- and dual-arm studies were identified by a search of PubMed (Medline), Embase, and the Cochrane database. Overall 2368 patients from 20 studies were included in the analysis, including 1835 (77%) in the BAV group and 533 (23%) in the SAV group. There was no difference between SAV and BAV in hospital mortality (OR=0.98, 95% CI 0.5-2.0, P=0.27, I(2)=22%) or frequency of at least moderate aortic regurgitation at discharge (OR=0.58, 95% CI 0.3-1.3, P=0.09, I(2)=54%). Kaplan-Meier analysis showed no difference in long-term survival or freedom from aortic valve replacement but significantly more reintervention in the BAV group (10-year freedom from reintervention of 46% [95% CI 40-52] for BAV versus 73% [95% CI 68 77] for SAV, P<0.001). Results were unchanged in a sensitivity analysis restricted to infants (<1 year of age). CONCLUSIONS: Although higher rates of reintervention suggest improved outcomes with SAV, indications for reintervention may vary depending on initial intervention. When considering the benefits of a less-invasive approach, and clinical equipoise with respect to more clinically relevant outcomes, these findings support the need for a randomized controlled trial. PMID- 27503848 TI - Long-Term Prognosis of Brugada-Type ECG and ECG With Atypical ST-Segment Elevation in the Right Precordial Leads Over 20 Years: Results From the Circulatory Risk in Communities Study (CIRCS). AB - BACKGROUND: Brugada syndrome is recognized as being associated with sudden cardiac death; however, the prevalence of non-type 1 Brugada-type ECG (BrS) or atypical ST-segment elevation in the right precordial leads (STERP) and the long term prognosis for those patients remain unknown. METHODS AND RESULTS: We analyzed standard 12-lead ECGs of 7178 apparently healthy participants (age range 40-64 years) who underwent health checkups from 1982 to 1986 in the Circulatory Risk in Communities Study, a prospective, large, community-based cohort study in Japan. ECGs with J point amplitude >=0.2 mV in the right precordial leads were divided into 3 groups: (1) type 1 BrS, (2) type 2 or 3 BrS (non-type 1 BrS), and (3) STERP. The others served as the non-ST-segment elevation group. We identified 8 participants (0.1%) with type1 BrS, 84 (1.2%) with non-type 1 BrS, and 228 (3.2%) with STERP. During a median follow-up of 18.7 years (133 987.0 person years), sudden cardiac death was observed in no participants (0.0%) with type 1 BrS, in 1 (1.2%) with non-type 1 BrS, in 7 (3.1%) with STERP, and in 50 (0.7%) with non-ST-segment elevation. Participants with STERP had a markedly elevated risk of sudden cardiac death (multivariable hazard ratio 3.9, 95% CI 1.7-9.0). CONCLUSIONS: STERP was associated with an elevated risk of sudden cardiac death in a middle-aged population. PMID- 27503849 TI - Prognostic Value of the Change in Heart Rate From the Supine to the Upright Position in Patients With Chronic Heart Failure. AB - BACKGROUND: The prognostic value of the change in heart rate from the supine to upright position (?HR) in patients with chronic heart failure (HF) is unknown. METHODS AND RESULTS: ?HR was measured in patients enrolled in the Trial of Intensified Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-CHF) who were in sinus rhythm and had no pacemaker throughout the trial (n=321). The impact of ?HR on 18-month outcome (HF hospitalization-free survival) was assessed. In addition, the prognostic effect of changes in ?HR between baseline and month 6 on outcomes in the following 12 months was determined. A lower ?HR was associated with a higher risk of death or HF hospitalization (hazard ratio 1.79 [95% confidence interval {95% CI} 1.19-2.75] if ?HR <=3 beats/min [bpm], P=0.004). In the multivariate analysis, lower ?HR remained an independent predictor of death or HF hospitalization (hazard ratio 1.75 [95% CI, 1.18-2.61] if ?HR <=3 bpm, P=0.004) along with ischemic HF etiology, lower estimated glomerular filtration rate, presence and extent of rales, and no baseline beta-blocker use. In patients without event during the first 6 months, the change in ?HR from baseline to month 6 predicted death or HF hospitalization during the following 12 months (hazard ratio=2.13 [95% CI 1.12-5.00] if rise in ?HR <2 bpm; P=0.027). CONCLUSIONS: ?HR as a simple bedside test is an independent prognostic predictor in patients with chronic HF. ?HR is modifiable, and changes in ?HR also provide prognostic information, which raises the possibility that ?HR may help to guide treatment. CLINICAL TRIAL REGISTRATION INFORMATION: URL: www.isrctn.org. Unique identifier: ISRCTN43596477. PMID- 27503850 TI - Thrombin Generation and Atherothrombosis: What Does the Evidence Indicate? PMID- 27503851 TI - Hemodynamic and Autonomic Response to Different Salt Intakes in Normotensive Individuals. AB - BACKGROUND: Even if sodium sensitivity represents a risk factor at any blood pressure (BP) level, limited evidence is available that it may influence cardiovascular control in normotensives, particularly in white individuals. Therefore, the aim of the study was to investigate whether sodium sensitivity alters hemodynamic or autonomic responses to salt in normotensives. METHODS AND RESULTS: We evaluated the Sodium-Sensitivity Index (SS-Index) in 71 white normotensives after 5 days of high- and low-sodium diets. We measured BP continuously at the end of each period, estimating hemodynamic indices from BP waveform analysis, and autonomic indices from heart rate (HR) and BP variability. According to the SS-Index distribution, we defined 1 sodium-sensitive group (SS, with SS-Index >15 mm Hg/[mmol.day]), 1 sodium-resistant group, (unresponsive to sodium load with -15<= SS-Index <=+15), and 1 inverse sodium-sensitive group, responsive to sodium by decreasing BP, with SS-Index <-15). We compared the effects of the diets among groups, and correlated autonomic/hemodynamic indices with the SS-Index. After sodium loading, a significant decrease in systemic peripheral resistances, HR, spectral indices of BP modulation, and a significant increase of indices of HR vagal modulation were found in the inverse sodium sensitive group but not in SS normotensives. Moreover, the highest SS-Indices were associated with the lesser vagal HR decelerations. CONCLUSIONS: Our data suggest that salt sensitivity in white normotensive individuals is associated with impaired vasodilation and altered autonomic response to dietary salt. Such dysfunction may critically contribute to induce a BP response to dietary salt. PMID- 27503852 TI - Vaccination knowledge, attitude and practice among Chinese travelers who visit travel clinics in Preparation for international travel. AB - BACKGROUND: Although international travel has become increasingly more common in main land China, few data are available on vaccination knowledge, attitude and practice (KAP) among Chinese travelers. METHOD: In each of 14 International Travel Healthcare Centers (ITHCs) situated in mainland China 200 volunteers were recruited for a cross-sectional investigation by questionnaire on KAP related to travel vaccinations. For the evaluation the study subjects were grouped by demographic data, past travel experience, travel destination, duration of stay abroad, purpose of travel. RESULTS: Among the 2,800 Chinese travelers who participated in the study, 67.1% were aware of national and travel vaccination recommendations. The knowledge about vaccine preventable diseases was low. The most common sources (73.4%) of information were requirements by destination countries obtained in connection with the visa application, Chinese companies employing workers/laborers for assignments overseas, and foreign schools. The overall acceptance rate of recommended vaccines was 68.7%, but yellow fever was accepted by 99.8% of the participants when recommended. Among 81.1% respondents who recalled to have received vaccinations in the past, only 25.9% of them brought the old vaccination records with them to their ITHC consultations. CONCLUSION: The results indicate that increased awareness of the importance of pre-travel vaccination is needed among the travellers in order to improve their KAP. PMID- 27503853 TI - Older age, chronic medical conditions and polypharmacy in Himalayan trekkers in Nepal: an epidemiologic survey and case series. AB - BACKGROUND: The number of tourists in Nepal doubled between 2003 and 2013 is nearly 800 000. With the increased popularity of trekking, the number of those with pre-existing medical conditions requiring access to healthcare is likely to increase. We therefore sought to characterize the demographics and health status of trekkers on the Everest Base Camp route in the Solukhumbu Valley. In addition, we report cases that illustrate the potential complications of an ageing and medicated population of trekkers with underlying diseases. METHODS: Trekkers over 18 years were enrolled in a larger observational cohort study on blood pressure at high altitude at 2860 m. They answered a questionnaire regarding demographics, medical history and current medications. Acute medical problems relating to medication use that were brought to the attention of investigators were documented and are presented as case reports. RESULTS: We enrolled 670 trekkers, 394 (59%) male, with a mean age of 48 years (range 18-76). Pre-existing medical conditions were reported by 223 participants (33%). The most frequent conditions included hypertension, hypercholesterolemia, migraines and thyroid dysfunction. A total of 276 participants (41%) reported taking one or more medications. The most common medications were acetazolamide (79, 12%), antihypertensives (50, 8%) and NSAIDs (47, 7%), with 30 classes of drugs represented. Excluding acetazolamide, older trekkers (age >50 years) were more likely than younger ones to take medications (OR = 2.17; 95% CI 1.57-3.00; P <0.05). Acetazolamide use was not related to age. CONCLUSIONS: Our findings illustrate a wide variety of medical conditions present in trekkers in Nepal with wide-ranging potential complications that could pose difficulties in areas where medical care is scarce and evacuation difficult. Our cases illustrate the potential problems polypharmacy poses in trekkers, and the need for local and expedition healthcare workers to be aware of, and prepared for the common medical conditions present. PMID- 27503854 TI - Use of antimicrobial agents for treatment and prevention of travellers' diarrhoea in the face of enhanced risk of transient fecal carriage of multi-drug resistant enterobacteriaceae: setting the stage for consensus recommendations. AB - BACKGROUND: The recommendation that antibiotics should be used for routine therapy of travellers' diarrhoea is being reconsidered in view of growing evidence that the therapy may lead to intestinal carriage of multi-drug resistant (MDR) colonic microbiota. This review attempts to put the issues of therapy and MDR acquisition in perspective to help in the establishment of therapeutic recommendations for travellers' diarrhoea. METHODS: The existing literature showing the risk and consequences of acquisition of MDR microbiota in antibiotic treated travellers was reviewed. Issues important to the development of firm evidence-based recommendations for antibiotics use for treatment and prevention of travellers' diarrhoea were researched. RESULTS: Six areas of research needed to allow the development of evidence-based recommendations for antibiotic treatment and -prevention of travellers' diarrhoea were identified. CONCLUSIONS: Increasing worldwide occurrence of antibiotic resistance should alert public health officials of the importance of encouraging local antibiotic stewardship guidelines. Six areas to research are identified in this review to allow the development of evidence-based recommendations for use of antibiotics for treatment and selective prevention of travellers' diarrhoea. An interdisciplinary ISTM Consensus group will consider the data available and develop current recommendations for therapy and chemoprevention of travellers' diarrhoea considering groups who would benefit the most from antimicrobials while recognizing the hazards associated with broad use of these drugs. With interim recommendations and ultimately evidence-based recommendations, guidelines can be developed for management of travellers' diarrhoea considering populations and destinations. PMID- 27503855 TI - The Neutrophil Response Induced by an Agonist for Free Fatty Acid Receptor 2 (GPR43) Is Primed by Tumor Necrosis Factor Alpha and by Receptor Uncoupling from the Cytoskeleton but Attenuated by Tissue Recruitment. AB - Ligands with improved potency and selectivity for free fatty acid receptor 2 (FFA2R) have become available, and we here characterize the neutrophil responses induced by one such agonist (Cmp1) and one antagonist (CATPB). Cmp1 triggered an increase in the cytosolic concentration of Ca(2+), and the neutrophils were then desensitized to Cmp1 and to acetate, a naturally occurring FFA2R agonist. The antagonist CATPB selectively inhibited responses induced by Cmp1 or acetate. The activated FFA2R induced superoxide anion secretion at a low level in naive blood neutrophils. This response was largely increased by tumor necrosis factor alpha (TNF-alpha) in a process associated with a recruitment of easily mobilizable granules, but neutrophils recruited to an aseptic inflammation in vivo were nonresponding. Superoxide production induced by Cmp1 was increased in latrunculin A-treated neutrophils, but no reactivation of desensitized FFA2R was induced by this drug, suggesting that the cytoskeleton is not directly involved in terminating the response. The functional and regulatory differences between the receptors that recognize short-chain fatty acids and formylated peptides, respectively, imply different roles of these receptors in the orchestration of inflammation and confirm the usefulness of a selective FFA2R agonist and antagonist as tools for the exploration of the precise role of the FFA2R. PMID- 27503856 TI - Unravelling the Mechanism of TrkA-Induced Cell Death by Macropinocytosis in Medulloblastoma Daoy Cells. AB - Macropinocytosis is a normal cellular process by which cells internalize extracellular fluids and nutrients from their environment and is one strategy that Ras-transformed pancreatic cancer cells use to increase uptake of amino acids to meet the needs of rapid growth. Paradoxically, in non-Ras transformed medulloblastoma brain tumors, we have shown that expression and activation of the receptor tyrosine kinase TrkA overactivates macropinocytosis, resulting in the catastrophic disintegration of the cell membrane and in tumor cell death. The molecular basis of this uncontrolled form of macropinocytosis has not been previously understood. Here, we demonstrate that the overactivation of macropinocytosis is caused by the simultaneous activation of two TrkA-mediated pathways: (i) inhibition of RhoB via phosphorylation at Ser(185) by casein kinase 1, which relieves actin stress fibers, and (ii) FRS2-scaffolded Src and H-Ras activation of RhoA, which stimulate actin reorganization and the formation of lamellipodia. Since catastrophic macropinocytosis results in brain tumor cell death, improved understanding of the mechanisms involved will facilitate future efforts to reprogram tumors, even those resistant to apoptosis, to die. PMID- 27503857 TI - SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling. AB - The Ras/mitogen-activated protein kinase (MAPK) signaling pathway is tightly controlled by negative feedback regulators, such as the tumor suppressor SPRED1. The SPRED1 gene also carries loss-of-function mutations in the RASopathy Legius syndrome. Growth factor stimulation translocates SPRED1 to the plasma membrane, triggering its inhibitory activity. However, it remains unclear whether SPRED1 there acts at the level of Ras or Raf. We show that pharmacological or galectin-1 (Gal-1)-mediated induction of B- and C-Raf-containing dimers translocates SPRED1 to the plasma membrane. This is facilitated in particular by SPRED1 interaction with B-Raf and, via its N terminus, with Gal-1. The physiological significance of these novel interactions is supported by two Legius syndrome-associated mutations that show diminished binding to both Gal-1 and B-Raf. On the plasma membrane, SPRED1 becomes enriched in acidic membrane domains to specifically perturb membrane organization and extracellular signal-regulated kinase (ERK) signaling of active K-ras4B (here, K-ras) but not H-ras. However, SPRED1 also blocks on the nanoscale the positive effects of Gal-1 on H-ras. Therefore, a combinatorial expression of SPRED1 and Gal-1 potentially regulates specific patterns of K-ras- and H-ras-dependent signaling output. More broadly, our results open up the possibility that related SPRED and Sprouty proteins act in a similar Ras and Raf isoform-specific manner. PMID- 27503858 TI - Association between home birth and breast feeding outcomes: a cross-sectional study in 28 125 mother-infant pairs from Ireland and the UK. AB - OBJECTIVES: To examine the association between breast feeding outcomes and place of birth (home vs hospital birth). DESIGN: Population-based cross-sectional study. SETTING: Ireland and UK. PARTICIPANTS: 10 604 mother-infant pairs from the Growing Up in Ireland study (GUI, 2008-2009) and 17 521 pairs from the UK Millennium Cohort Study (UKMCS, 2001-2002) at low risk of delivery complications were included in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Breast feeding initiation, exclusivity and duration. RESULTS: Home birth was found to be significantly associated with breast feeding at all examined time points, including at birth, 8 weeks, 6 months and breast feeding exclusively at 6 months. In GUI, adjusted OR was 1.90 (95% CI 1.19 to 3.02), 1.78 (1.18 to 2.69), 1.85 (1.23 to 2.77) and 2.77 (1.78 to 4.33), respectively, and in UKMCS it was 2.49 (1.84 to 3.44), 2.49 (1.92 to 3.26), 2.90 (2.25 to 3.73) and 2.24 (1.14 to 4.03). CONCLUSIONS: Home birth was strongly associated with improved breast feeding outcomes in low-risk deliveries. While the association between home birth and breast feeding is unlikely to be directly causal, further research is needed to determine which factor(s) drive the observed differences, to facilitate development of perinatal care that supports breast feeding. PMID- 27503859 TI - Facilitating mental health research for patients, clinicians and researchers: a mixed-method study. AB - OBJECTIVES: Research registers using Consent for Contact (C4C) can facilitate recruitment into mental health research studies, allowing investigators to contact patients based on clinical records information. We investigated whether such a register was useful for mental health research, seeking the perspectives of patients and research investigators. SETTING AND DESIGN: In 2012, a C4C register was developed in a large secondary mental health provider within the UK; almost 9000 patients have joined. This mixed-method study audited the effectiveness of the register. PARTICIPANTS: A 'mystery shopper' exercise was conducted, and patients (n=21) were recruited to ask clinicians about the availability of research opportunities. Structured interviews were conducted with patients (n=52) about their experiences of being on the register. Similar interviews were conducted with 18 investigators from 19 studies, who had attempted to use the register to recruit participants. OUTCOME MEASURES: The impact of C4C on study recruitment, and whether it helped patients learn about research. RESULTS: So far, the register has provided 928 individuals with 1085 research opportunities (in 60% of cases, the individual agreed to participate in the study). Clinicians were willing to link patients to research opportunities, but often lacked information about studies. For patients, the register provided opportunities which they may not otherwise have; 27 of 52 had participated in studies since joining the register (18 participating for the first time). Most investigators used the register to supplement recruitment to their studies, but described problems in prescreening potential participants from a clinical record for complex studies. CONCLUSIONS: Although the register helped investigators recruit for studies, and provided patients with research opportunities, clinicians' input is still useful for identifying suitable participants. C4C registers should be adapted to provide clinicians with automatically updated information on local studies allowing them to match patients on their caseload with active studies. PMID- 27503860 TI - Prospective, observational study comparing automated and visual point-of-care urinalysis in general practice. AB - OBJECTIVE: Point-of-care testing (POCT) urinalysis might reduce errors in (subjective) reading, registration and communication of test results, and might also improve diagnostic outcome and optimise patient management. Evidence is lacking. In the present study, we have studied the analytical performance of automated urinalysis and visual urinalysis compared with a reference standard in routine general practice. SETTING: The study was performed in six general practitioner (GP) group practices in the Netherlands. Automated urinalysis was compared with visual urinalysis in these practices. Reference testing was performed in a primary care laboratory (Saltro, Utrecht, The Netherlands). PRIMARY AND SECONDARY OUTCOME MEASURES: Analytical performance of automated and visual urinalysis compared with the reference laboratory method was the primary outcome measure, analysed by calculating sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) and Cohen's kappa coefficient for agreement. Secondary outcome measure was the user-friendliness of the POCT analyser. RESULTS: Automated urinalysis by experienced and routinely trained practice assistants in general practice performs as good as visual urinalysis for nitrite, leucocytes and erythrocytes. Agreement for nitrite is high for automated and visual urinalysis. kappa's are 0.824 and 0.803 (ranked as very good and good, respectively). Agreement with the central laboratory reference standard for automated and visual urinalysis for leucocytes is rather poor (0.256 for POCT and 0.197 for visual, respectively, ranked as fair and poor). kappa's for erythrocytes are higher: 0.517 (automated) and 0.416 (visual), both ranked as moderate. The Urisys 1100 analyser was easy to use and considered to be not prone to flaws. CONCLUSIONS: Automated urinalysis performed as good as traditional visual urinalysis on reading of nitrite, leucocytes and erythrocytes in routine general practice. Implementation of automated urinalysis in general practice is justified as automation is expected to reduce human errors in patient identification and transcribing of results. PMID- 27503861 TI - Association of volunteering with mental well-being: a lifecourse analysis of a national population-based longitudinal study in the UK. AB - OBJECTIVES: The association of volunteering with well-being has been found in previous research, but mostly among older people. The aim of this study was to examine the association of volunteering with mental well-being among the British population across the life course. DESIGN: British Household Panel Survey, a population-based longitudinal study. SETTING: UK. PARTICIPANTS: 66 343 observations (person-years). MAIN OUTCOME MEASURES: Mental well-being was measured by using the General Health Questionnaire (GHQ-12 or GHQ); high values denote high mental disorder. Four groups of volunteering participation were created: frequent (once a week), infrequent (once a month/several times a year), rare (once or less a year) and never. Multilevel linear models were used to analyse variations in mental well-being over the life course by levels of volunteering. RESULTS: When not considering age, those who engaged in volunteering regularly appeared to experience higher levels of mental well-being than those who never volunteered. To explore the association of volunteering with the GHQ across the life course, interaction terms were fitted between age and volunteering. The interactions were significant, demonstrating that these associations vary by age. The association between volunteering and well-being did not emerge during early adulthood to mid-adulthood, instead becoming apparent above the age of 40 years and continuing up to old age. Moreover, in early adulthood, the absence of engagement in voluntary activity was not related to mental well-being, but GHQ scores for this group increased sharply with age, levelling off after the age of 40 and then increasing again above the age of 70 years. The study also indicates variation in GHQ scores (65%) within individuals across time, suggesting evidence of lifecourse effects. CONCLUSIONS: We conclude that volunteering may be more meaningful for mental well-being at some points of time in the life course. PMID- 27503862 TI - Determinants of out-of-hours service users' potentially inappropriate referral or non-referral to an emergency department: a retrospective cohort study in a local health authority, Veneto Region, Italy. AB - BACKGROUND: A growing presence of inappropriate patients has been recognised as one of the main factors influencing emergency department (ED) overcrowding, which is a very widespread problem all over the world. On the other hand, out-of-hours (OOH) physicians must avoid delaying the diagnostic and therapeutic course of patients with urgent medical conditions. The aim of this study was to analyse the appropriateness of patient management by OOH services, in terms of their potentially inappropriate referral or non-referral of non-emergency cases to the ED. METHODS: This was an observational retrospective cohort study based on data collected in 2011 by the local health authority No. 4 in the Veneto Region (Italy). After distinguishing between patients contacting the OOH service who were or were not referred to the ED, and checking for patients actually presenting to the ED within 24 hours thereafter, these patients' medical management was judged as potentially appropriate or inappropriate. RESULTS: The analysis considered 22 662 OOH service contacts recorded in 2011. The cases of potentially inappropriate non-referral to the ED were 392 (1.7% of all contacts), as opposed to 1207 potentially inappropriate referrals (5.3% of all contacts). Age, nationality, type of disease and type of intervention by the OOH service were the main variables associated with the appropriateness of patient management. CONCLUSIONS: These findings may be useful for pinpointing the factors associated with a potentially inappropriate patient management by OOH services and thus contribute to improving the deployment of healthcare and the quality of care delivered by OOH services. PMID- 27503863 TI - Scurvy and the enhancement of the senses. PMID- 27503864 TI - Impact of pharmacist administration of influenza vaccines on uptake in Canada. AB - BACKGROUND: Uptake of influenza vaccination in Canada remains suboptimal despite widespread public funding. To increase access, several provinces have implemented policies permitting pharmacists to administer influenza vaccines in community pharmacies. We examined the impact of such policies on the uptake of seasonal influenza vaccination in Canada. METHODS: We pooled data from the 2007-2014 cycles of the Canadian Community Health Survey (n = 481 526). To determine the impact of influenza vaccine administration by pharmacists, we estimated the prevalence ratio for the association between the presence of a pharmacist policy and individual-level vaccine uptake using a modified Poisson regression model (dependent variable: vaccine uptake) with normalized weights while controlling for numerous health and sociodemographic factors. RESULTS: Across all survey cycles combined, 28.8% of respondents reported receiving a seasonal influenza vaccine during the 12 months before survey participation. Introduction of a policy for pharmacist administration of influenza vaccine was associated with a modest increase in coverage (2.2%) and an individual's likelihood of uptake (adjusted prevalence ratio 1.05, 95% confidence interval 1.02-1.08). INTERPRETATION: Uptake of influenza immunization was modestly increased in Canadian jurisdictions that allowed pharmacists to administer influenza vaccines. PMID- 27503865 TI - A 12-year-old girl with eczema not responding to treatment. AB - A 12-year-old girl, who has had a history of intermittent skin rashes since infancy, presents for the sixth time in four months for exacerbation of eczema that is not responding to recommended treatment (daily baths, frequent moisturization and twice-daily application of medium-potency topical corticosteroids). Her parents express concern about the effect of her skin disease on the child's life. They are worried about her sleeping difficulties and decreased involvement in her regular activities; for example, she has stopped playing sports and attending school. During the interview, the patient makes minimal eye contact and appears agitated. Her medical history includes allergic rhinitis. She looks systemically well, with normal temperature and vital signs. Skin examination shows generalized xerotic skin and erythematous patches, with predominantly flexural and facial excoriations affecting about half of the body. There is no evidence of burrows, track marks, vesicular or pustular lesions, or honey-coloured crusts. The rest of the exam is unremarkable. PMID- 27503866 TI - Forming trust with vaccine fence-sitters. PMID- 27503867 TI - Suicide rate higher for indigenous people in Labrador. PMID- 27503868 TI - Why CMAJ writes editorials. PMID- 27503869 TI - Thyroid nodules. PMID- 27503870 TI - Taking action on the social determinants of health in clinical practice: a framework for health professionals. PMID- 27503871 TI - Acute coral contact dermatitis. PMID- 27503872 TI - Psychotic disorders induced by antiepileptic drugs in people with epilepsy. AB - Antiepileptic drug treatment can induce psychosis in some patients. However, there are no agreed definitions or diagnostic criteria for antiepileptic drug induced psychotic disorder in the classification systems of either epileptology or psychiatry. In this study we investigated the clinical spectrum of antiepileptic drug-induced psychotic disorder in patients with epilepsy. The medical records of all patients with epilepsy who were diagnosed by a neuropsychiatrist as having a psychotic disorder at the Royal Melbourne Hospital from January 1993 to June 2015 were reviewed. Data were extracted regarding epilepsy and its treatment, psychotic symptoms profile and outcome. The diagnosis of epilepsy was established in accordance to the classification system of the International League Against Epilepsy while that of psychotic disorder was made according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition and the proposal on neuropsychiatric disorders in epilepsy. Patients with antiepileptic drug-induced psychotic disorder were compared to those with psychotic disorders unrelated to antiepileptic drugs assessed over the same period (non-antiepileptic drug induced psychotic disorder group). Univariate comparisons were performed and variables with a value of P < 0.1 were selected for the multivariate logistic regression analysis. The records of 2630 in patients and outpatients with epilepsy were screened, from which 98 (3.7%) with psychotic disorders were identified. Among these, 14 (14.3%) were diagnosed to have antiepileptic drug-induced psychotic disorder. Excluding one patient who developed psychosis after valproate withdrawal, 76.9% in the antiepileptic drug induced psychotic disorder group were female and the percentage of temporal lobe involvement was higher in the antiepileptic drug induced psychotic disorder group (69.2% versus 38.1%, P < 0.05). Current use of levetiracetam was higher in antiepileptic drug-induced psychotic disorder group (84.6% versus 20.2%, P < 0.01) while use of carbamazepine was higher in the comparator group (15.4% versus 44.0%, P < 0.05). Multivariate logistic regression confirmed four factors associated with antiepileptic drug-induced psychotic disorder: female gender, temporal lobe involvement and use of levetiracetam, and a negative association with carbamazepine. Disorganized behaviours and thinking were more common in the antiepileptic drug-induced psychotic disorder group (100% versus 72.6% and 76.9% versus 38.1%, respectively; P < 0.05). The percentage of continuous treatment with antipsychotic drugs was lower in the antiepileptic drug-induced psychotic disorder group (15.4% versus 66.7%, P < 0.01). No patients experienced a chronic course in antiepileptic drug-induced psychotic disorder group whereas 40.5% did in non-antiepileptic drug induced psychotic disorder (P < 0.05). Our findings indicated that one in seven patients with epilepsy who developed psychosis had antiepileptic drug-induced psychotic disorder. In these patients, female gender, temporal lobe involvement and current use of levetiracetam were significantly associated with antiepileptic drug induced psychotic disorder compared to other types of psychosis, while carbamazepine had a negative association. Disorganized behaviours and thinking were predominant in antiepileptic drug-induced psychotic disorder. Patients with antiepileptic drug-induced psychotic disorder differed from non-antiepileptic drug-induced psychotic disorders in having better outcome. PMID- 27503873 TI - Sickle cell anemia mice develop a unique cardiomyopathy with restrictive physiology. AB - Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA. PMID- 27503874 TI - Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson's disease. AB - Circuitry models of Parkinson's disease (PD) are based on striatal dopamine loss and aberrant striatal inputs into the basal ganglia network. However, extrastriatal mechanisms have increasingly been the focus of attention, whereas the status of striatal discharges in the parkinsonian human brain remains conjectural. We now report the activity pattern of striatal projection neurons (SPNs) in patients with PD undergoing deep brain stimulation surgery, compared with patients with essential tremor (ET) and isolated dystonia (ID). The SPN activity in ET was very low (2.1 +/- 0.1 Hz) and reminiscent of that found in normal animals. In contrast, SPNs in PD fired at much higher frequency (30.2 +/- 1.2 Hz) and with abundant spike bursts. The difference between PD and ET was reproduced between 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated and normal nonhuman primates. The SPN activity was also increased in ID, but to a lower level compared with the hyperactivity observed in PD. These results provide direct evidence that the striatum contributes significantly altered signals to the network in patients with PD. PMID- 27503875 TI - FtsEX acts on FtsA to regulate divisome assembly and activity. AB - Bacterial cell division is driven by the divisome, a ring-shaped protein complex organized by the bacterial tubulin homolog FtsZ. Although most of the division proteins in Escherichia coli have been identified, how they assemble into the divisome and synthesize the septum remains poorly understood. Recent studies suggest that the bacterial actin homolog FtsA plays a critical role in divisome assembly and acts synergistically with the FtsQLB complex to regulate the activity of the divisome. FtsEX, an ATP-binding cassette transporter-like complex, is also necessary for divisome assembly and inhibits division when its ATPase activity is inactivated. However, its role in division is not clear. Here, we find that FtsEX acts on FtsA to regulate both divisome assembly and activity. FtsX interacts with FtsA and this interaction is required for divisome assembly and inhibition of divisome function by ATPase mutants of FtsEX. Our results suggest that FtsEX antagonizes FtsA polymerization to promote divisome assembly and the ATPase mutants of FtsEX block divisome activity by locking FtsA in the inactive form or preventing FtsA from communicating with other divisome proteins. Because FtsEX is known to govern cell wall hydrolysis at the septum, our findings indicate that FtsEX acts on FtsA to promote divisome assembly and to coordinate cell wall synthesis and hydrolysis at the septum. Furthermore, our study provides evidence that FtsA mutants impaired for self-interaction are favored for division, and FtsW plays a critical role in divisome activation in addition to the FtsQLB complex. PMID- 27503876 TI - Regulatory evolution of Tbx5 and the origin of paired appendages. AB - The diversification of paired appendages has been a major factor in the evolutionary radiation of vertebrates. Despite its importance, an understanding of the origin of paired appendages has remained elusive. To address this problem, we focused on T-box transcription factor 5 (Tbx5), a gene indispensable for pectoral appendage initiation and development. Comparison of gene expression in jawless and jawed vertebrates reveals that the Tbx5 expression in jawed vertebrates is derived in having an expression domain that extends caudal to the heart and gills. Chromatin profiling, phylogenetic footprinting, and functional assays enabled the identification of a Tbx5 fin enhancer associated with this apomorphic pattern of expression. Comparative functional analysis of reporter constructs reveals that this enhancer activity is evolutionarily conserved among jawed vertebrates and is able to rescue the finless phenotype of tbx5a mutant zebrafish. Taking paleontological evidence of early vertebrates into account, our results suggest that the gain of apomorphic patterns of Tbx5 expression and regulation likely contributed to the morphological transition from a finless to finned condition at the base of the vertebrate lineage. PMID- 27503877 TI - Climate warming reduces fish production and benthic habitat in Lake Tanganyika, one of the most biodiverse freshwater ecosystems. AB - Warming climates are rapidly transforming lake ecosystems worldwide, but the breadth of changes in tropical lakes is poorly documented. Sustainable management of freshwater fisheries and biodiversity requires accounting for historical and ongoing stressors such as climate change and harvest intensity. This is problematic in tropical Africa, where records of ecosystem change are limited and local populations rely heavily on lakes for nutrition. Here, using a ~1,500-y paleoecological record, we show that declines in fishery species and endemic molluscs began well before commercial fishing in Lake Tanganyika, Africa's deepest and oldest lake. Paleoclimate and instrumental records demonstrate sustained warming in this lake during the last ~150 y, which affects biota by strengthening and shallowing stratification of the water column. Reductions in lake mixing have depressed algal production and shrunk the oxygenated benthic habitat by 38% in our study areas, yielding fish and mollusc declines. Late-20th century fish fossil abundances at two of three sites were lower than at any other time in the last millennium and fell in concert with reduced diatom abundance and warming water. A negative correlation between lake temperature and fish and mollusc fossils over the last ~500 y indicates that climate warming and intensifying stratification have almost certainly reduced potential fishery production, helping to explain ongoing declines in fish catches. Long-term declines of both benthic and pelagic species underscore the urgency of strategic efforts to sustain Lake Tanganyika's extraordinary biodiversity and ecosystem services. PMID- 27503878 TI - Early emerging system for reasoning about the social nature of food. AB - Selecting appropriate foods is a complex and evolutionarily ancient problem, yet past studies have revealed little evidence of adaptations present in infancy that support sophisticated reasoning about perceptual properties of food. We propose that humans have an early-emerging system for reasoning about the social nature of food selection. Specifically, infants' reasoning about food choice is tied to their thinking about agents' intentions and social relationships. Whereas infants do not expect people to like the same objects, infants view food preferences as meaningfully shared across individuals. Infants' reasoning about food preferences is fundamentally social: They generalize food preferences across individuals who affiliate, or who speak a common language, but not across individuals who socially disengage or who speak different languages. Importantly, infants' reasoning about food preferences is flexibly calibrated to their own experiences: Tests of bilingual babies reveal that an infant's sociolinguistic background influences whether she will constrain her generalization of food preferences to people who speak the same language. Additionally, infants' systems for reasoning about food is differentially responsive to positive and negative information. Infants generalize information about food disgust across all people, regardless of those people's social identities. Thus, whereas food preferences are seen as embedded within social groups, disgust is interpreted as socially universal, which could help infants avoid potentially dangerous foods. These studies reveal an early-emerging system for thinking about food that incorporates social reasoning about agents and their relationships, and allows infants to make abstract, flexible, adaptive inferences to interpret others' food choices. PMID- 27503879 TI - Correction for Eklund et al., Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates. PMID- 27503880 TI - Increased water deficit decreases Douglas fir growth throughout western US forests. AB - Changes in tree growth rates can affect tree mortality and forest feedbacks to the global carbon cycle. As air temperature increases, evaporative demand also increases, increasing effective drought in forest ecosystems. Using a spatially comprehensive network of Douglas fir (Pseudotsuga menziesii) chronologies from 122 locations that represent distinct climate environments in the western United States, we show that increased temperature decreases growth via vapor pressure deficit (VPD) across all latitudes. Using an ensemble of global circulation models, we project an increase in both the mean VPD associated with the lowest growth extremes and the probability of exceeding these VPD values. As temperature continues to increase in future decades, we can expect deficit-related stress to increase and consequently Douglas fir growth to decrease throughout its US range. PMID- 27503881 TI - No relative expansion of the number of prefrontal neurons in primate and human evolution. AB - Human evolution is widely thought to have involved a particular expansion of prefrontal cortex. This popular notion has recently been challenged, although controversies remain. Here we show that the prefrontal region of both human and nonhuman primates holds about 8% of cortical neurons, with no clear difference across humans and other primates in the distribution of cortical neurons or white matter cells along the anteroposterior axis. Further, we find that the volumes of human prefrontal gray and white matter match the expected volumes for the number of neurons in the gray matter and for the number of other cells in the white matter compared with other primate species. These results indicate that prefrontal cortical expansion in human evolution happened along the same allometric trajectory as for other primate species, without modification of the distribution of neurons across its surface or of the volume of the underlying white matter. We thus propose that the most distinctive feature of the human prefrontal cortex is its absolute number of neurons, not its relative volume. PMID- 27503882 TI - Climate influence on Vibrio and associated human diseases during the past half century in the coastal North Atlantic. AB - Climate change is having a dramatic impact on marine animal and plant communities but little is known of its influence on marine prokaryotes, which represent the largest living biomass in the world oceans and play a fundamental role in maintaining life on our planet. In this study, for the first time to our knowledge, experimental evidence is provided on the link between multidecadal climatic variability in the temperate North Atlantic and the presence and spread of an important group of marine prokaryotes, the vibrios, which are responsible for several infections in both humans and animals. Using archived formalin preserved plankton samples collected by the Continuous Plankton Recorder survey over the past half-century (1958-2011), we assessed retrospectively the relative abundance of vibrios, including human pathogens, in nine areas of the North Atlantic and North Sea and showed correlation with climate and plankton changes. Generalized additive models revealed that long-term increase in Vibrio abundance is promoted by increasing sea surface temperatures (up to ~1.5 degrees C over the past 54 y) and is positively correlated with the Northern Hemisphere Temperature (NHT) and Atlantic Multidecadal Oscillation (AMO) climatic indices (P < 0.001). Such increases are associated with an unprecedented occurrence of environmentally acquired Vibrio infections in the human population of Northern Europe and the Atlantic coast of the United States in recent years. PMID- 27503883 TI - Belowground rhizomes in paleosols: The hidden half of an Early Devonian vascular plant. AB - The colonization of terrestrial environments by rooted vascular plants had far reaching impacts on the Earth system. However, the belowground structures of early vascular plants are rarely documented, and thus the plant-soil interactions in early terrestrial ecosystems are poorly understood. Here we report the earliest rooted paleosols (fossil soils) in Asia from Early Devonian deposits of Yunnan, China. Plant traces are extensive within the soil and occur as complex network-like structures, which are interpreted as representing long-lived, belowground rhizomes of the basal lycopsid Drepanophycus The rhizomes produced large clones and helped the plant survive frequent sediment burial in well drained soils within a seasonal wet-dry climate zone. Rhizome networks contributed to the accumulation and pedogenesis of floodplain sediments and increased the soil stabilizing effects of early plants. Predating the appearance of trees with deep roots in the Middle Devonian, plant rhizomes have long functioned in the belowground soil ecosystem. This study presents strong, direct evidence for plant-soil interactions at an early stage of vascular plant radiation. Soil stabilization by complex rhizome systems was apparently widespread, and contributed to landscape modification at an earlier time than had been appreciated. PMID- 27503884 TI - DNA damage checkpoint kinase ATM regulates germination and maintains genome stability in seeds. AB - Genome integrity is crucial for cellular survival and the faithful transmission of genetic information. The eukaryotic cellular response to DNA damage is orchestrated by the DNA damage checkpoint kinases ATAXIA TELANGIECTASIA MUTATED (ATM) and ATM AND RAD3-RELATED (ATR). Here we identify important physiological roles for these sensor kinases in control of seed germination. We demonstrate that double-strand breaks (DSBs) are rate-limiting for germination. We identify that desiccation tolerant seeds exhibit a striking transcriptional DSB damage response during germination, indicative of high levels of genotoxic stress, which is induced following maturation drying and quiescence. Mutant atr and atm seeds are highly resistant to aging, establishing ATM and ATR as determinants of seed viability. In response to aging, ATM delays germination, whereas atm mutant seeds germinate with extensive chromosomal abnormalities. This identifies ATM as a major factor that controls germination in aged seeds, integrating progression through germination with surveillance of genome integrity. Mechanistically, ATM functions through control of DNA replication in imbibing seeds. ATM signaling is mediated by transcriptional control of the cell cycle inhibitor SIAMESE-RELATED 5, an essential factor required for the aging-induced delay to germination. In the soil seed bank, seeds exhibit increased transcript levels of ATM and ATR, with changes in dormancy and germination potential modulated by environmental signals, including temperature and soil moisture. Collectively, our findings reveal physiological functions for these sensor kinases in linking genome integrity to germination, thereby influencing seed quality, crucial for plant survival in the natural environment and sustainable crop production. PMID- 27503885 TI - Secondary expansion of the transient subplate zone in the developing cerebrum of human and nonhuman primates. AB - The subplate (SP) was the last cellular compartment added to the Boulder Committee's list of transient embryonic zones [Bystron I, Blakemore C, Rakic P (2008) Nature Rev Neurosci 9(2):110-122]. It is highly developed in human and nonhuman primates, but its origin, mode, and dynamics of development, resolution, and eventual extinction are not well understood because human postmortem tissue offers only static descriptive data, and mice cannot serve as an adequate experimental model for the distinct regional differences in primates. Here, we take advantage of the large and slowly developing SP in macaque monkey to examine the origin, settling pattern, and subsequent dispersion of the SP neurons in primates. Monkey embryos exposed to the radioactive DNA replication marker tritiated thymidine ([(3)H]dT, or TdR) at early embryonic ages were killed at different intervals postinjection to follow postmitotic cells' positional changes. As expected in primates, most SP neurons generated in the ventricular zone initially migrate radially, together with prospective layer 6 neurons. Surprisingly, mostly during midgestation, SP cells become secondarily displaced and widespread into the expanding SP zone, which becomes particularly wide subjacent to the association cortical areas and underneath the summit of its folia. We found that invasion of monoamine, basal forebrain, thalamocortical, and corticocortical axons is mainly responsible for this region-dependent passive dispersion of the SP cells. Histologic and immunohistochemical comparison with the human SP at corresponding fetal ages indicates that the same developmental events occur in both primate species. PMID- 27503886 TI - Adiabatic quenches and characterization of amplitude excitations in a continuous quantum phase transition. AB - Spontaneous symmetry breaking occurs in a physical system whenever the ground state does not share the symmetry of the underlying theory, e.g., the Hamiltonian. This mechanism gives rise to massless Nambu-Goldstone modes and massive Anderson-Higgs modes. These modes provide a fundamental understanding of matter in the Universe and appear as collective phase or amplitude excitations of an order parameter in a many-body system. The amplitude excitation plays a crucial role in determining the critical exponents governing universal nonequilibrium dynamics in the Kibble-Zurek mechanism (KZM). Here, we characterize the amplitude excitations in a spin-1 condensate and measure the energy gap for different phases of the quantum phase transition. At the quantum critical point of the transition, finite-size effects lead to a nonzero gap. Our measurements are consistent with this prediction, and furthermore, we demonstrate an adiabatic quench through the phase transition, which is forbidden at the mean field level. This work paves the way toward generating entanglement through an adiabatic phase transition. PMID- 27503887 TI - Atom-scale depth localization of biologically important chemical elements in molecular layers. AB - In nature, biomolecules are often organized as functional thin layers in interfacial architectures, the most prominent examples being biological membranes. Biomolecular layers play also important roles in context with biotechnological surfaces, for instance, when they are the result of adsorption processes. For the understanding of many biological or biotechnologically relevant phenomena, detailed structural insight into the involved biomolecular layers is required. Here, we use standing-wave X-ray fluorescence (SWXF) to localize chemical elements in solid-supported lipid and protein layers with near Angstrom precision. The technique complements traditional specular reflectometry experiments that merely yield the layers' global density profiles. While earlier work mostly focused on relatively heavy elements, typically metal ions, we show that it is also possible to determine the position of the comparatively light elements S and P, which are found in the most abundant classes of biomolecules and are therefore particularly important. With that, we overcome the need of artificial heavy atom labels, the main obstacle to a broader application of high resolution SWXF in the fields of biology and soft matter. This work may thus constitute the basis for the label-free, element-specific structural investigation of complex biomolecular layers and biological surfaces. PMID- 27503888 TI - Time-resolved 2-million-year-old supernova activity discovered in Earth's microfossil record. AB - Massive stars ([Formula: see text]), which terminate their evolution as core collapse supernovae, are theoretically predicted to eject [Formula: see text] of the radioisotope (60)Fe (half-life 2.61 Ma). If such an event occurs sufficiently close to our solar system, traces of the supernova debris could be deposited on Earth. Herein, we report a time-resolved (60)Fe signal residing, at least partially, in a biogenic reservoir. Using accelerator mass spectrometry, this signal was found through the direct detection of live (60)Fe atoms contained within secondary iron oxides, among which are magnetofossils, the fossilized chains of magnetite crystals produced by magnetotactic bacteria. The magnetofossils were chemically extracted from two Pacific Ocean sediment drill cores. Our results show that the (60)Fe signal onset occurs around 2.6 Ma to 2.8 Ma, near the lower Pleistocene boundary, terminates around 1.7 Ma, and peaks at about 2.2 Ma. PMID- 27503889 TI - Ab initio molecular dynamics of solvation effects on reactivity at electrified interfaces. AB - Using ab initio molecular dynamics as implemented in periodic, self-consistent (generalized gradient approximation Perdew-Burke-Ernzerhof) density functional theory, we investigated the mechanism of methanol electrooxidation on Pt(111). We investigated the role of water solvation and electrode potential on the energetics of the first proton transfer step, methanol electrooxidation to methoxy (CH3O) or hydroxymethyl (CH2OH). The results show that solvation weakens the adsorption of methoxy to uncharged Pt(111), whereas the binding energies of methanol and hydroxymethyl are not significantly affected. The free energies of activation for breaking the C-H and O-H bonds in methanol were calculated through a Blue Moon Ensemble using constrained ab initio molecular dynamics. Calculated barriers for these elementary steps on unsolvated, uncharged Pt(111) are similar to results for climbing-image nudged elastic band calculations from the literature. Water solvation reduces the barriers for both C-H and O-H bond activation steps with respect to their vapor-phase values, although the effect is more pronounced for C-H bond activation, due to less disruption of the hydrogen bond network. The calculated activation energy barriers show that breaking the C H bond of methanol is more facile than the O-H bond on solvated negatively biased or uncharged Pt(111). However, with positive bias, O-H bond activation is enhanced, becoming slightly more facile than C-H bond activation. PMID- 27503890 TI - Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence. AB - Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition of MAP kinase signaling, suppressing c-Myc expression, or inhibiting telomerase activity, caused telomere dysfunction and proliferative defects in cells that had escaped senescence, whereas ectopic expression of hTERT facilitated OIS escape. In human early neoplastic skin and breast tissue, hTERT expression was detected in cells that displayed features of senescence, suggesting that reactivation of telomerase expression in senescent cells is an early event during cancer progression in humans. Together, our data demonstrate that cells arrested in OIS retain the potential to escape senescence by mechanisms that involve derepression of hTERT expression. PMID- 27503891 TI - Differential lipid binding of vinculin isoforms promotes quasi-equivalent dimerization. AB - The main cause of death globally remains debilitating heart conditions, such as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), which are often due to mutations of specific components of adhesion complexes. Vinculin regulates these complexes and plays essential roles in intercalated discs that are necessary for muscle cell function and coordinated movement and in the development and function of the heart. Humans bearing familial or sporadic mutations in vinculin suffer from chronic, progressively debilitating DCM that ultimately leads to cardiac failure and death, whereas autosomal dominant mutations in vinculin can also provoke HCM, causing acute cardiac failure. The DCM/HCM-associated mutants of vinculin occur in the 68-residue insert unique to the muscle-specific, alternatively spliced isoform of vinculin, termed metavinculin (MV). Contrary to studies that suggested that phosphoinositol-4,5 bisphosphate (PIP2) only induces vinculin homodimers, which are asymmetric, we show that phospholipid binding results in a domain-swapped symmetric MV dimer via a quasi-equivalent interface compared with vinculin involving R975. Although one of the two PIP2 binding sites is preserved, the symmetric MV dimer that bridges two PIP2 molecules differs from the asymmetric vinculin dimer that bridges only one PIP2 Unlike vinculin, wild-type MV and the DCM/HCM-associated R975W mutant bind PIP2 in their inactive conformations, and R975W MV fails to dimerize. Mutating selective vinculin residues to their corresponding MV residues, or vice versa, switches the isoform's dimeric constellation and lipid binding site. Collectively, our data suggest that MV homodimerization modulates microfilament attachment at muscular adhesion sites and furthers our understanding of MV mediated cardiac remodeling. PMID- 27503892 TI - Functional neuroanatomy of intuitive physical inference. AB - To engage with the world-to understand the scene in front of us, plan actions, and predict what will happen next-we must have an intuitive grasp of the world's physical structure and dynamics. How do the objects in front of us rest on and support each other, how much force would be required to move them, and how will they behave when they fall, roll, or collide? Despite the centrality of physical inferences in daily life, little is known about the brain mechanisms recruited to interpret the physical structure of a scene and predict how physical events will unfold. Here, in a series of fMRI experiments, we identified a set of cortical regions that are selectively engaged when people watch and predict the unfolding of physical events-a "physics engine" in the brain. These brain regions are selective to physical inferences relative to nonphysical but otherwise highly similar scenes and tasks. However, these regions are not exclusively engaged in physical inferences per se or, indeed, even in scene understanding; they overlap with the domain-general "multiple demand" system, especially the parts of that system involved in action planning and tool use, pointing to a close relationship between the cognitive and neural mechanisms involved in parsing the physical content of a scene and preparing an appropriate action. PMID- 27503893 TI - Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure. AB - Xk-related protein (Xkr) 8, a protein carrying 10 transmembrane regions, is essential for scrambling phospholipids during apoptosis. Here, we found Xkr8 as a complex with basigin (BSG) or neuroplastin (NPTN), type I membrane proteins in the Ig superfamily. In BSG(-/-)NPTN(-/-) cells, Xkr8 localized intracellularly, and the apoptosis stimuli failed to expose phosphatidylserine, indicating that BSG and NPTN chaperone Xkr8 to the plasma membrane to execute its scrambling activity. Mutational analyses of BSG showed that the atypical glutamic acid in the transmembrane region is required for BSG's association with Xkr8. In cells exposed to apoptotic signals, Xkr8 was cleaved at the C terminus and the Xkr8/BSG complex formed a higher-order complex, likely to be a heterotetramer consisting of two molecules of Xkr8 and two molecules of BSG or NPTN, suggesting that this cleavage causes the formation of a larger complex of Xkr8-BSG/NPTN for phospholipid scrambling. PMID- 27503894 TI - Salmonella Typhimurium utilizes a T6SS-mediated antibacterial weapon to establish in the host gut. AB - The mammalian gastrointestinal tract is colonized by a high-density polymicrobial community where bacteria compete for niches and resources. One key competition strategy includes cell contact-dependent mechanisms of interbacterial antagonism, such as the type VI secretion system (T6SS), a multiprotein needle-like apparatus that injects effector proteins into prokaryotic and/or eukaryotic target cells. However, the contribution of T6SS antibacterial activity during pathogen invasion of the gut has not been demonstrated. We report that successful establishment in the gut by the enteropathogenic bacterium Salmonella enterica serovar Typhimurium requires a T6SS encoded within Salmonella pathogenicity island-6 (SPI-6). In an in vitro setting, we demonstrate that bile salts increase SPI-6 antibacterial activity and that S Typhimurium kills commensal bacteria in a T6SS-dependent manner. Furthermore, we provide evidence that one of the two T6SS nanotube subunits, Hcp1, is required for killing Klebsiella oxytoca in vitro and that this activity is mediated by the specific interaction of Hcp1 with the antibacterial amidase Tae4. Finally, we show that K. oxytoca is killed in the host gut in an Hcp1-dependent manner and that the T6SS antibacterial activity is essential for Salmonella to establish infection within the host gut. Our findings provide an example of pathogen T6SS-dependent killing of commensal bacteria as a mechanism to successfully colonize the host gut. PMID- 27503895 TI - miR-579-3p controls melanoma progression and resistance to target therapy. AB - Therapy of melanoma patients harboring activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) oncogene with a combination of BRAF and MEK inhibitors is plagued by the development of drug resistance. Mutational events, as well as adaptive mechanisms, contribute to the development of drug resistance. In this context we uncover here the role of a miRNA, miR-579-3p. We first show that low expression of miR-579-3p is a negative prognostic factor correlating with poor survival. Expression levels of miR-579-3p decrease from nevi to stage III/IV melanoma samples and even further in cell lines resistant to BRAF/MEK inhibitors. Mechanistically, we demonstrate that miR-579-3p acts as an oncosuppressor by targeting the 3'UTR of two oncoproteins: BRAF and an E3 ubiquitin protein ligase, MDM2. Moreover miR-579-3p ectopic expression impairs the establishment of drug resistance in human melanoma cells. Finally, miR-579-3p is strongly down-regulated in matched tumor samples from patients before and after the development of resistance to targeted therapies. PMID- 27503896 TI - Specificity of Protein Covalent Modification by the Electrophilic Proteasome Inhibitor Carfilzomib in Human Cells. AB - Carfilzomib (CFZ) is a second-generation proteasome inhibitor that is Food and Drug Administration and European Commission approved for the treatment of relapsed or refractory multiple myeloma. CFZ is an epoxomicin derivative with an epoxyketone electrophilic warhead that irreversibly adducts the catalytic threonine residue of the beta5 subunit of the proteasome. Although CFZ produces a highly potent, sustained inactivation of the proteasome, the electrophilic nature of the drug could potentially produce off-target protein adduction. To address this possibility, we synthesized an alkynyl analog of CFZ and investigated protein adduction by this analog in HepG2 cells. Using click chemistry coupled with streptavidin based IP and shotgun tandem mass spectrometry (MS/MS), we identified two off-target proteins, cytochrome P450 27A1 (CYP27A1) and glutathione S-transferase omega 1 (GSTO1), as targets of the alkynyl CFZ probe. We confirmed the adduction of CYP27A1 and GSTO1 by streptavidin capture and immunoblotting methodology and then site-specifically mapped the adducts with targeted MS/MS methods. Although CFZ adduction of CYP27A1 and GSTO1 in vitro decreased the activities of these enzymes, the small fraction of these proteins modified by CFZ in intact cells should limit the impact of these off-target modifications. The data support the high selectivity of CFZ for covalent modification of its therapeutic targets, despite the presence of a reactive electrophile. The approach we describe offers a generalizable method to evaluate the safety profile of covalent protein-modifying therapeutics. PMID- 27503898 TI - Changing undergraduate human anatomy and physiology laboratories: perspectives from a large-enrollment course. AB - In the present article, a veteran lecturer of human anatomy and physiology taught several sections of the laboratory component for the first time and shares his observations and analysis from this unique perspective. The article discusses a large-enrollment, content-heavy anatomy and physiology course in relationship to published studies on learning and student self-efficacy. Changes in the laboratory component that could increase student learning are proposed. The author also points out the need for research to assess whether selective curricular changes could increase the depth of understanding and retention of learned material. PMID- 27503897 TI - Human Sirtuin 2 Localization, Transient Interactions, and Impact on the Proteome Point to Its Role in Intracellular Trafficking. AB - Human sirtuin 2 (SIRT2) is an NAD+-dependent deacetylase that primarily functions in the cytoplasm, where it can regulate alpha-tubulin acetylation levels. SIRT2 is linked to cancer progression, neurodegeneration, and infection with bacteria or viruses. However, the current knowledge about its interactions and the means through which it exerts its functions has remained limited. Here, we aimed to gain a better understanding of its cellular functions by characterizing SIRT2 subcellular localization, the identity and relative stability of its protein interactions, and its impact on the proteome of primary human fibroblasts. To assess the relative stability of SIRT2 interactions, we used immunoaffinity purification in conjunction with both label-free and metabolic labeling quantitative mass spectrometry. In addition to the expected associations with cytoskeleton proteins, including its known substrate TUBA1A, our results reveal that SIRT2 specifically interacts with proteins functioning in membrane trafficking, secretory processes, and transcriptional regulation. By quantifying their relative stability, we found most interactions to be transient, indicating a dynamic SIRT2 environment. We discover that SIRT2 localizes to the ER-Golgi intermediate compartment (ERGIC), and that this recruitment requires an intact ER Golgi trafficking pathway. Further expanding these findings, we used microscopy and interaction assays to establish the interaction and coregulation of SIRT2 with liprin-beta1 scaffolding protein (PPFiBP1), a protein with roles in focal adhesions disassembly. As SIRT2 functions may be accomplished via interactions, enzymatic activity, and transcriptional regulation, we next assessed the impact of SIRT2 levels on the cellular proteome. SIRT2 knockdown led to changes in the levels of proteins functioning in membrane trafficking, including some of its interaction partners. Altogether, our study expands the knowledge of SIRT2 cytoplasmic functions to define a previously unrecognized involvement in intracellular trafficking pathways, which may contribute to its roles in cellular homeostasis and human diseases. PMID- 27503899 TI - A method of providing engaging formative feedback to large cohort first-year physiology and anatomy students. AB - A growing body of evidence demonstrates a critical role for effective, meaningful feedback to enhance student learning. Effective feedback can become part of the learning cycle that is not only a learning opportunity for the student but can also be used to inform the teacher and ongoing curriculum development. Feedback is considered particularly important during the first year of university and can even be viewed as a retention strategy that can help attenuate student performance anxieties and solidify perceptions of academic support. Unfortunately, the provision of individualized, timely feedback can be particularly challenging in first-year courses as they tend to be large and diverse cohort classes that pose challenges of time and logistics. Various forms of generic feedback can provide rapid and cost-effect feedback to large cohorts but may be of limited benefit to students other than signaling weaknesses in knowledge. The present study describes a method that was used to provide formative task-related feedback to a large cohort of first-year physiology and anatomy students. Based on student evaluations presented in this study, this method provided feedback in a manner that engaged students, uncovered underlying misconceptions, facilitated peer discussion, and provided opportunity for new instruction while allowing the lecturer to recognize common gaps in knowledge and inform ongoing curriculum development. PMID- 27503900 TI - Engaging medical undergraduates in question making: a novel way to reinforcing learning in physiology. AB - The monotony of conventional didactic lectures makes students less attentive toward learning, and they tend to memorize isolated facts without understanding, just for the sake of passing exams. Therefore, to promote a habit of gaining indepth knowledge of basic sciences in medical undergraduates along with honing of their communication and analytical skills, we introduced this more interactive way of learning. The present study was performed on 99 first-semester medical students. After conventional didactic lectures, students were asked to prepare small conceptual questions on the topic. They were divided into two teams, which were made to ask questions to each other. If a team failed to answer, the student who questioned was supposed to answer to the satisfaction of the other team's student. Data were then obtained by getting feedback from the students on a 10 item questionnaire, and statistical evaluation was done using MS Excel and SPSS. To draft questions, students went through the whole system comprehensively and made questions from every possible aspect of the topic. Some of the questions (30%) were of recall type, but most judged higher cognitive domains. Student feedback revealed that they were satisfied, motivated to read more, and were confident of applying this learning and communication skills in future clinical practice. Students also expressed their desire to implement this activity as a regular feature of the curriculum. The activity resulted in an increase in student perceptions of their knowledge on the topic as well as communicative and analytical skills. This may eventually lead to better learning. PMID- 27503901 TI - Electrophysiology for biomedical engineering students: a practical and theoretical course in animal electrocorticography. AB - The major challenge in laboratory teaching is the application of abstract concepts in simple and direct practical lessons. However, students rarely have the opportunity to participate in a laboratory that combines practical learning with a realistic research experience. In the Biomedical Engineering career, we offer short and optional courses to complement studies for students as they initiate their Graduation Project. The objective of these theoretical and practical courses is to introduce students to the topics of their projects. The present work describes an experience in electrophysiology to teach undergraduate students how to extract cortical information using electrocorticographic techniques. Students actively participate in some parts of the experience and then process and analyze the data obtained with different signal processing tools. In postlaboratory evaluations, students described the course as an exceptional opportunity for students interested in following a postgraduate science program and fully appreciated their contents. PMID- 27503902 TI - Cold pressor test using strain-gauge plethysmography. AB - This laboratory activity is designed to teach students how to measure forearm muscle blood flow (FBF) to describe the mechanisms of peripheral blood flow thermal regulation in healthy subjects. The cold pressor test (CPT) is the clinical procedure used in the experiment to induce arterial vasoconstriction. Strain-gauge plethysmography is applied on the patient's forearm to noninvasive monitor vasoconstriction effects on local blood perfusion and physiological parameters such as blood pressure (BP) and heart rate (HR). Patients with an altered peripheral vascular resistance (e.g., in hypertension) have different responses to the CPT from healthy subjects. To date, experimental evidence remains unexplained, as we do not know if the BP and HR increase is caused by a decrease in flow rate or an increase in peripheral vascular resistance during the test. To clarify this situation, we have to quantify the parameter we assume is being conditioned by the regulatory physiological intervention, i.e., peripheral vascular resistance. Peripheral vascular resistance quantification can be calculated as the ratio between muscle flow and mean arterial pressure. Students will learn how to apply the instrumental procedure to collect and analyze data before, during, and after the CPT and to describe the physiological responses of the peripheral vascular system to external stressors. They will also learn how to distinguish healthy from pathological responses on the basis of how sympathetic nervous system reactions influence the biomechanics of peripheral vessels. PMID- 27503903 TI - The brain robot "Herr Tie": discovering basic principles of brain function at primary school. PMID- 27503904 TI - Perceptions of undergraduate students on the use of animals in practical classes. PMID- 27503905 TI - Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing-remitting multiple sclerosis patients: 3-year results of the Glatiramer Acetate Low-Frequency Administration open-label extension study. AB - BACKGROUND: The 1-year placebo-controlled (PC) phase of the Glatiramer Acetate Low-Frequency Administration (GALA) study showed that glatiramer acetate 40 mg/mL three times weekly (GA40) significantly reduced annualized relapse rate (ARR) and magnetic resonance imaging (MRI) activity in patients with relapsing-remitting multiple sclerosis. Patients completing the PC phase were invited to an open label (OL) extension. OBJECTIVE: To evaluate the effects of early start (ES) and delayed start (DS) of GA40 over 3 years. METHODS: A total of 97.2% of patients completing the PC phase received GA40 in the OL extension. ES ( n = 943) patients received GA40 throughout; DS ( n = 461) patients received placebo during the PC phase and GA40 during the OL phase. Relapse, MRI, disease progression, and safety were evaluated. RESULTS: A total of 1041 patients completed 3 years of follow-up. During the OL phase, ES and DS patients showed comparable ARRs (0.20-0.22) and similar numbers of gadolinium-enhancing T1 ( p = 0.49) and new or enlarging T2 lesions ( p = 0.51) at Year 3. ES patients showed significantly smaller changes in gray matter volume than DS patients from Months 12 to 36 (mean difference, 0.371%; p = 0.015), with similar trend in whole-brain volume ( p = 0.080). Adverse events were mild, consistent with the well-established glatiramer acetate (GA) safety profile. CONCLUSION: GA40 conferred treatment benefit over 3 years: sustained low ARR and lesion activity and favorable safety. PMID- 27503906 TI - The impact of drugs for multiple sclerosis on sleep. AB - Although there is a growing literature on the presence of sleep disorders in multiple sclerosis (MS), few studies have specifically addressed the impact of drugs on sleep of these patients. Moreover, even when sleep is considered, quantitative assessment by standardized questionnaires or polysomnography is lacking. The studies that have been done highlight that interferon-beta and some symptomatic medications may affect sleep, thus contributing to fatigue, depression, and poor quality of life; conversely, natalizumab and cannabinoids may improve sleep. Common limitations of the literature reviewed here are small sample size, selection bias, and often a lack of objective outcome measures. Clinicians need to remember to ask about sleep in all MS patients and intervene when appropriate. A systematic approach that takes sleep into account is recommended to enhance recognition and appropriate management of sleep disruption, including disorders related to medication. Consideration of the impact on sleep should also be part of the design of trials of new therapies. PMID- 27503907 TI - Increased ex vivo antigen presentation profile of B cells in multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is thought to be T cell mediated but the mechanisms eliciting such a dysregulated adaptative immune response remain enigmatic. OBJECTIVE: To examine the activation profile of antigen-presenting cells (APCs) in MS. METHODS: A total of 98 study subjects were enrolled including patients suffering from relapsing-remitting, secondary- and primary-progressive (PP) MS, other inflammatory neurological diseases, and healthy controls. Blood monocytes and B cells were stimulated using specific ligands of toll-like receptors (TLRs) or inflammasomes or Epstein-Barr virus (EBV) particles. Their activation profile was determined before or after stimulation by flow cytometry (CD40, CD80, CD83, CD86, and human leukocyte antigen-antigen D related (HLA-DR)) and Luminex assay, measuring the concentration of eight cytokines in culture supernatants. Differences among groups were assessed in a linear model framework. RESULTS: We demonstrate that relapsing MS patients exhibit an increased expression of HLA-DR and CD40 ex vivo, mostly at the surface of B cells. Specific stimulations of TLR or inflammasomes enhance the expression of components of the immunological synapse and the cytokine secretion but without differences between categories of study subjects. CONCLUSION: These data suggest that the activation profile of B cells is increased in MS. However, the perception of the danger signal by B lymphocytes and monocytes does not seem to be different in MS patients as compared to control subjects. PMID- 27503908 TI - Can Neurological Biomarkers of Brain Impairment Be Used to Predict Poststroke Motor Recovery? A Systematic Review. AB - Background There is growing interest to establish recovery biomarkers, especially neurological biomarkers, in order to develop new therapies and prediction models for the promotion of stroke rehabilitation and recovery. However, there is no consensus among the neurorehabilitation community about which biomarker(s) have the highest predictive value for motor recovery. Objective To review the evidence and determine which neurological biomarker(s) meet the high evidence quality criteria for use in predicting motor recovery. Methods We searched databases for prognostic neuroimaging/neurophysiological studies. Methodological quality of each study was assessed using a previously employed comprehensive 15-item rating system. Furthermore, we used the GRADE approach and ranked the overall evidence quality for each category of neurologic biomarker. Results Seventy-one articles met our inclusion criteria; 5 categories of neurologic biomarkers were identified: diffusion tensor imaging (DTI), transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), conventional structural MRI (sMRI), and a combination of these biomarkers. Most studies were conducted with individuals after ischemic stroke in the acute and/or subacute stage (~70%). Less than one-third of the studies (21/71) were assessed with satisfactory methodological quality (80% or more of total quality score). Conventional structural MRI and the combination biomarker categories ranked "high" in overall evidence quality. Conclusions There were 3 prevalent methodological limitations: (a) lack of cross-validation, (b) lack of minimal clinically important difference (MCID) for motor outcomes, and (c) small sample size. More high-quality studies are needed to establish which neurological biomarkers are the best predictors of motor recovery after stroke. Finally, the quarter-century old methodological quality tool used here should be updated by inclusion of more contemporary methods and statistical approaches. PMID- 27503910 TI - Hsp90-binding immunophilin FKBP52 modulates telomerase activity by promoting the cytoplasmic retrotransport of hTERT. AB - Telomerase is a unique ribonucleoprotein enzyme that is required for continued cell proliferation. To generate catalytically active telomerase, human telomerase reverse transcriptase (hTERT) must translocate to the nucleus and assemble with the RNA component of telomerase. The molecular chaperones heat shock protein 90 (Hsp90) and p23 maintain hTERT in a conformation that enables nuclear translocation. However, the regulatory role of chaperones in nuclear transport of hTERT remains unclear. In this work, we demonstrate that immunophilin FK506 binding protein (FKBP)52 linked the hTERT-Hsp90 complex to the dynein-dynactin motor, thereby promoting the transport of hTERT to the nucleus along microtubules. FKBP52 interacted with the hTERT-Hsp90 complex through binding of the tetratricopeptide repeat domain to Hsp90 and binding of the dynamitin (Dyt) component of the dynein-associated dynactin complex to the peptidyl prolyl isomerase domain. The depletion of FKBP52 inhibited nuclear transport of hTERT, resulting in cytoplasmic accumulation. Cytoplasmic hTERT was rapidly degraded through ubiquitin (Ub)-dependent proteolysis, thereby abrogating telomerase activity. In addition, overexpression of dynamitin, which is known to dissociate the dynein-dynactin motor from its cargoes, reduced telomerase activity. Collectively, these results provide a molecular mechanism by which FKBP52 modulates telomerase activity by promoting dynein-dynactin-dependent nuclear import of hTERT. PMID- 27503909 TI - Gsk3beta and Tomm20 are substrates of the SCFFbxo7/PARK15 ubiquitin ligase associated with Parkinson's disease. AB - Fbxo7 is a clinically relevant F-box protein, associated with both cancer and Parkinson's disease (PD). Additionally, SNPs within FBXO7 are correlated with alterations in red blood cell parameters. Point mutations within FBXO7 map within specific functional domains, including near its F-box domain and its substrate recruiting domains, suggesting that deficiencies in SCFFbxo7/PARK15 ubiquitin ligase activity are mechanistically linked to early-onset PD. To date, relatively few substrates of the ligase have been identified. These include HURP (hepatoma up-regulated protein), whose ubiquitination results in proteasome-mediated degradation, and c-IAP1 (inhibitor of apoptosis protein 1), TNF receptor associated factor 2 (TRAF2), and NRAGE, which are not destabilized as a result of ubiquitination. None of these substrates have been linked directly to PD, nor has it been determined whether they would directly engage neuronal cell death pathways. To discover ubiquitinated substrates of SCFFbxo7 implicated more directly in PD aetiology, we conducted a high-throughput screen using protein arrays to identify new candidates. A total of 338 new targets were identified and from these we validated glycogen synthase kinase 3beta (Gsk3beta), which can phosphorylate alpha-synuclein, and translocase of outer mitochondrial membrane 20 (Tomm20), a mitochondrial translocase that, when ubiquitinated, promotes mitophagy, as SCFFbxo7 substrates both in vitro and in vivo Ubiquitin chain restriction analyses revealed that Fbxo7 modified Gsk3beta using K63 linkages. Our results indicate that Fbxo7 negatively regulates Gsk3beta activity, rather than its levels or localization. In addition, Fbxo7 ubiquitinated Tomm20, and its levels correlated with Fbxo7 expression, indicating a stabilizing effect. None of the PD-associated mutations in Fbxo7 impaired Tomm20 ubiquitination. Our findings demonstrate that SCFFbxo7 has an impact directly on two proteins implicated in pathological processes leading to PD. PMID- 27503911 TI - Using the Intervention Mapping Protocol to develop an online video intervention for parents to prevent childhood obesity: Movie Models. AB - BACKGROUND: The increasing prevalence of childhood overweight/obesity caused by an unhealthy diet, insufficient physical activity (PA) and high levels of sedentary behaviour (SB) is a prominent public health concern. Parenting practices may contribute to healthy behaviour change in children, but well researched examples are limited. The aim of this study is to describe the systematic development of an intervention for parents to prevent childhood overweight/obesity through the improvement of parenting practices. METHODS: The six steps of the Intervention Mapping Protocol (IMP), a theory- and evidence based tool to develop health-related interventions, were used as a framework to develop the 'Movie Models' programme. RESULTS: In Step 1, a needs assessment was performed to better understand the health problem of overweight/obesity in children and its association with diet, PA and SB. In Step 2, the programme goal (increasing the adoption of effective parenting practices) was sub-divided into performance objectives. Change objectives, which specify explicit actions required to accomplish the performance objectives, were also identified. Step 3 included the selection of theoretical methods (e.g. 'modelling' and 'images'), which were then translated into the practical strategy of online parenting videos. Step 4 comprised the development of a final intervention framework, and Step 5 included the planning of programme adoption and implementation. The final phase, Step 6, included the development of an effect- and process-evaluation plan. DISCUSSION: The IMP was used to structure the development of 'Movie Models', an intervention targeting specific parenting practices related to children's healthy diet, PA, SB, and parental self-efficacy. A clear framework for process analyses is offered, which aims to increase the potential effectiveness of an intervention and can be useful for those developing health promotion programmes. PMID- 27503912 TI - Somatic Complaints Are Significantly Associated with Chronic Uninvestigated Dyspepsia and Its Symptoms: A Large Cross-sectional Population Based Study. AB - Background/Aims: Somatization may influence persistence and severity of symptoms in gastrointestinal diseases. Some studies suggest that somatization is associated with chronic uninvestigated dyspepsia (CUD); however, the association is unclear. We aimed to determine the association between the profiles of somatic complaints with CUD and its symptoms. Methods: In a cross-sectional study conducted on 4763 Iranian adults, somatic complaints were assessed using a comprehensive 31-items questionnaire. Patients with CUD were identified by the Rome III diagnostic criteria. Profiles of somatic complaints were derived from factor analysis. Logistic regression analysis was used to assess the relationship between extracted profiles with CUD and its symptoms. Results: CUD, bothersome postprandial fullness, early satiation, and epigastric pain or burning was identified in 723 (15.2%), 384 (8.1%), 302 (6.3%), and 371 (7.8%) of the study population. The frequency of all 31 somatic complaints was significantly higher in patients with CUD compared with controls (P < 0.001), and the most frequent was severe fatigue (45.1%). The profiles of somatic complaints were extracted in 4 domains, including "psychological", "gastrointestinal", "neuro-skeletal", and "pharyngeal-respiratory". The psychological (OR, 1.49; 95% CI, 1.44-1.54), gastrointestinal (OR, 2.22; 95% CI, 2.09-2.37), neuro-skeletal (OR, 1.52; 95% CI, 1.44-1.59), and pharyngeal-respiratory (OR, 2.09; 95% CI, 1.94-2.25) profiles were significantly associated with greater odds of CUD. Conclusions: CUD and its symptoms are strongly associated with higher levels of somatic complaints and their related extracted profiles. This perhaps explains that why it can be difficult to treat, however further prospective investigations are required to confirm these associations. PMID- 27503913 TI - Vertebral column anomalies in Indo-Pacific and Atlantic humpback dolphins Sousa spp. AB - Conspicuous vertebral column abnormalities in humpback dolphins (genus Sousa) were documented for the first time during 3 photo-identification field studies of small populations in Taiwan, Senegal and Angola. Seven Taiwanese humpback dolphins S. chinensis taiwanensis with vertebral column anomalies (lordosis, kyphosis or scoliosis) were identified, along with 2 possible cases of vertebral osteomyelitis. There was evidence from several individuals photographed over consecutive years that the anomalies became more pronounced with age. Three Atlantic humpback dolphins S. teuszii were observed with axial deviations of the vertebral column (lordosis and kyphosis). Another possible case was identified in a calf, and 2 further animals were photographed with dorsal indents potentially indicative of anomalies. Vertebral column anomalies of humpback dolphins were predominantly evident in the lumbo-caudal region, but one Atlantic humpback dolphin had an anomaly in the cervico-thoracic region. Lordosis and kyphosis occurred simultaneously in several individuals. Apart from the described anomalies, all dolphins appeared in good health and were not obviously underweight or noticeably compromised in swim speed. This study presents the first descriptions of vertebral column anomalies in the genus Sousa. The causative factors for the anomalies were unknown in every case and are potentially diverse. Whether these anomalies result in reduced fitness of individuals or populations merits attention, as both the Taiwanese and Atlantic humpback dolphin are species of high conservation concern. PMID- 27503914 TI - Acute necrotizing colitis with pneumatosis intestinalis in an Amazonian manatee calf. AB - On 25 January 2014, a 1 mo old female Amazonian manatee Trichechus inunguis calf weighing 12 kg was rescued by air transport in Guajara, Brazil, and transferred to Mamiraua Institute's Community-based Amazonian Manatee Rehabilitation Center. The calf presented piercing/cutting lesions on the back, neck, and head, in addition to dehydration and intermittent involuntary buoyancy. X-ray analysis revealed a large amount of gases in the gastrointestinal tract. Daily procedures included wound cleaning and dressing, clinical and laboratory monitoring, treatment for intestinal tympanism, and artificial feeding. Adaptation to the nursing formula included 2 kinds of whole milk. Up to 20 d post-rescue the calf presented appetite, was active, and gained weight progressively. Past this period the calf started losing weight and presented constant involuntary buoyancy and died after 41 d in rehabilitation. The major findings at necropsy were pneumatosis intestinalis in cecum and colon, pulmonary edema, and hepatomegaly. The microscopic examination revealed pyogranulomatous and necrohemohrragic colitis with multinucleated giant cells, acute multifocal lymphadenitis with lymphoid depletion in cortical and paramedullary regions of mesenteric lymph nodes, and diffuse severe acinar atrophy of the pancreas. Anaerobic cultures of fragments of cecum and colon revealed colonies genotyped as Clostridium perfringens type A. We speculate that compromised immunity, thermoregulatory failure, and intolerance to artificial diet may have been contributing factors to the infection, leading to enterotoxemia and death. PMID- 27503915 TI - Molecular and pathological characterization of Fusarium solani species complex infection in the head and lateral line system of Sphyrna lewini. AB - A severe fungal infection affecting the head and lateral line system was diagnosed in 7 captive scalloped hammerhead sharks Sphyrna lewini in an aquarium in Thailand. Extensive and severe necrotizing cellulitis was consistently observed microscopically along the cephalic and lateral line canals in conjunction with positive fungal cultures for Fusarium sp. Molecular phylogenetic analysis was performed from 3 isolates based on the nucleotide sequences containing internally transcribed spacer (ITS) and a portion of 5.8S and 28S rDNA. The fungus was highly homologous (100%) and closely related to F. solani species complex 2 (FSSC 2), which belongs to Clade 3 of the FSSC. Our results illustrate the histopathological findings and expand upon our knowledge of the prevalence of invasive fusariosis in the head and lateral line system of hammerhead sharks. PMID- 27503916 TI - First identification of Francisella noatunensis subsp. orientalis causing mortality in Mexican tilapia Oreochromis spp. AB - Francisellosis, an emerging disease in tilapia Oreochromis spp., is caused by the facultative, intracellular bacterium Francisella noatunensis subsp. orientalis, which is present in various countries where tilapia farming is commercially important. We confirmed the presence of francisellosis in Mexican tilapia cultures in association with an outbreak during the second semester of 2012. Broodstock fish presented a mortality rate of approximately 40%, and disease was characterized by histologically classified granulomas, or whitish nodules, in different organs, mainly the spleen and kidney. Through DNA obtained from infected tissue and pure cultures in a cysteine heart medium supplemented with hemoglobin, F. noatunensis subsp. orientalis was initially confirmed through the amplification and analysis of the 16S rRNA gene and the internal transcribed spacer region. Phylogenetic analysis of these genes demonstrated close similarity with previously reported F. noatunensis subsp. orientalis sequences obtained from infected tilapia from various countries. The identification of this subspecies as the causative agent of the outbreak was confirmed using the iglC gene as a target sequence, which showed 99.5% identity to 2 F. noatunensis subsp. orientalis strains (Ethime-1 and Toba04). These findings represent the first documented occurrence of francisellosis in Mexican tilapia cultures, which highlights the importance of establishing preventative measures to minimize the spread of this disease within the Mexican aquaculture industry. PMID- 27503917 TI - Virulence of Flavobacterium columnare genomovars in rainbow trout Oncorhynchus mykiss. AB - Flavobacterium columnare is the causative agent of columnaris disease and is responsible for significant economic losses in aquaculture. F. columnare is a Gram-negative bacterium, and 5 genetic types or genomovars have been described based on restriction fragment length polymorphism of the 16S rRNA gene. Previous research has suggested that genomovar II isolates are more virulent than genomovar I isolates to multiple species of fish, including rainbow trout Oncorhynchus mykiss. In addition, improved genotyping methods have shown that some isolates previously classified as genomovar I, and used in challenge experiments, were in fact genomovar III. Our objective was to confirm previous results with respect to genomovar II virulence, and to determine the susceptibility of rainbow trout to other genomovars. The virulence of 8 genomovar I, 4 genomovar II, 3 genomovar II-B, and 5 genomovar III isolates originating from various sources was determined through 3 independent challenges in rainbow trout using an immersion challenge model. Mean cumulative percent mortality (CPM) of ~49% for genomovar I isolates, ~1% for genomovar II, ~5% for the II-B isolates, and ~7% for the III isolates was observed. The inability of genomovar II isolates to produce mortalities in rainbow trout was unanticipated based on previous studies, but may be due to a number of factors including rainbow trout source and water chemistry. The source of fish and/or the presence of sub-optimal environment may influence the susceptibility of rainbow trout to different F. columnare genomovars. PMID- 27503918 TI - High prevalence of Enterocytozoon hepatopenaei in shrimps Penaeus monodon and Litopenaeus vannamei sampled from slow growth ponds in India. AB - Hepatopancreatic microsporidiosis in cultivated Litopenaeus vannamei and Penaeus monodon is caused by the newly emerged pathogen Enterocytozoon hepatopenaei (EHP). It has been detected in shrimp cultured in China, Vietnam and Thailand and is suspected to have occurred in Malaysia and Indonesia and to be associated with severely retarded growth. Due to retarded shrimp growth being reported at farms in the major grow-out states of Tamilnadu, Andhra Pradesh and Odisha in India, shrimp were sampled from a total of 235 affected ponds between March 2014 and April 2015 to identify the presence of EHP. PCR and histology detected a high prevalence of EHP in both P. monodon and L. vannamei, and infection was confirmed by in situ hybridization using an EHP-specific DNA probe. Histology revealed basophilic inclusions in hepatopancreas tubule epithelial cells in which EHP was observed at various developmental stages ranging from plasmodia to mature spores. The sequence of a region of the small subunit rDNA gene amplified by PCR was found to be identical to EHP sequences deposited in GenBank. Bioassays confirmed that EHP infection could be transmitted orally to healthy shrimp. Histology also identified bacterial co-infections in EHP-infected shrimp sampled from slow growth ponds with low-level mortality. The data confirm that hepatopancreatic microsporidiosis caused by EHP is prevalent in shrimp being cultivated in India. EHP infection control measures thus need to be implemented urgently to limit impacts of slowed shrimp growth. PMID- 27503919 TI - Ostreid herpesvirus in wild oysters from the Huelva coast (SW Spain). AB - This is the first report of ostreid herpesvirus 1 microvariant (OsHV-1 uVar) infecting natural oyster beds located in Huelva (SW Spain). The virus was detected in 3 oyster species present in the intertidal zone: Crassostrea gigas (Thunberg, 1793), C. angulata (Lamarck, 1819) and, for the first time, in Ostrea stentina Payraudeau, 1826. Oysters were identified by a specific polymerase chain reaction (PCR) and posterior restriction fragment length polymorphism (RFLP) analysis based on cytochrome oxidase I (COI) mitochondrial DNA. Results confirmed that C. angulata still remains the dominant oyster population in SW Spain despite the introduction of C. gigas for cultivation in the late 1970s, and its subsequent naturalization. C. angulata shows a higher haplotype diversity than C. gigas. OsHV-1 virus was detected by PCR with C2/C6 pair primers. Posterior RFLP analyses with the restriction enzyme MfeI were done in order to reveal the OsHV-1 uVar. Detections were confirmed by DNA sequencing, and infections were evidenced by in situ hybridization in C. gigas, C. angulata and O. stentina samples. The prevalence was similar among the 3 oyster species but varied between sampling locations, being higher in areas with greater harvesting activities. OsHV-1 uVar accounted for 93% of all OsHV-1 detected. PMID- 27503920 TI - Detection of Brucella spp. in bottlenose dolphins Tursiops truncatus by a real time PCR using blowhole swabs. AB - Blowhole swabs are a simple and non-invasive method for collecting samples from cetaceans and can be used for screening large numbers of animals in the field. This study reports a real-time PCR assay for the detection of Brucella spp. using blowhole swab samples from bottlenose dolphins Tursiops truncatus stranded in the coastal region of Virginia, South Carolina and northern Florida, USA, between 2013 and 2015. We used real-time PCR results on lung samples from the same dolphins in order to estimate the relative sensitivity and specificity of real time PCR of blowhole swabs. Brucella DNA was detected in lung tissue of 22% (18/81) and in blowhole swabs of 21% (17/81) of the sampled dolphins. The relative sensitivity and specificity of real-time PCR on blowhole swabs as compared to the real-time PCR on lung samples was 94% (17/18) and 100% (63/63), respectively. These results indicate that real-time PCR on blowhole swabs may be used as a non-invasive test for rapid detection of Brucella spp. in the respiratory tract of dolphins. To our knowledge, this is the first report on the use of blowhole swabs for detection of bacterial pathogens by real-time PCR in bottlenose dolphins. PMID- 27503921 TI - Cutaneous malignant melanoma in a Haller's round ray Urobatis halleri. AB - Multiple black raised nodular masses were noted on the dorsal surface of an adult male Haller's round ray Urobatis halleri. Biopsy of 2 masses was performed, and histopathology revealed proliferative sheets of melanocytes exhibiting mild anisocytosis and anisokaryosis, supporting a diagnosis of malignant melanoma. Approximately 2 mo following the biopsy procedure, the round ray became acutely anorexic and was found dead in its enclosure. A full necropsy was performed, and tissues were submitted for histopathology. The black raised nodular masses again exhibited histologic features of a melanoma. In addition to the nodular masses present, multiple flat areas of increased pigmentation were also present throughout the course of the case and were not suggestive of neoplasia histologically. The transformation of benign to malignant neoplasia has been well described in other species and may have played a role in the development of multiple tumors in this case. PMID- 27503922 TI - Larvae of Contracaecum sp. (Nematoda: Anisakidae) in the threatened freshwater fish Sandelia capensis (Anabantidae) in South Africa. AB - Third-stage larvae of the nematode genus Contracaecum Railliet et Henry, 1912 (Contracaecum sp.) were, for the first time, recorded from the abdominal cavity of the threatened endemic freshwater fish Sandelia capensis (Cuvier) in South Africa. The larval morphology indicated that they belong to a species of which the adults are parasitic in fish-eating birds. Although the nematode seems to be a common parasite of S. capensis in the locality under study (prevalence 23%), the low intensity of infection recorded (1 to 4) and the generally known low pathogenicity of Contracaecum larvae in fish indicate that this parasite probably does not represent a danger to the local population of this threatened fish species. PMID- 27503923 TI - Draining and liming of ponds as an effective measure for containment of CyHV-3 in carp farms. AB - Infections of common carp Cyprinus carpio and koi, its coloured morphotypes, with the cyprinid herpesvirus 3 (CyHV-3) can induce severe clinical signs and increased mortality in affected stocks. This may significantly challenge the economic basis of carp farming in Central Europe. To limit virus spread in carp farms, effective disinfection measures for ponds stocked with infected populations are required. In the traditional European pond aquaculture of carp, draining and liming of ponds with quicklime (CaO) up to pH 12 is a well established disinfection measure against various pathogens. The present field study investigated whether these measures are sufficient for the inactivation of CyHV-3 infectivity in carp ponds. After draining and liming, the ponds were stocked with carp fry from a CyHV-3-negative stock, and 2 ponds were examined for the presence of CyHV-3-specific DNA sequences during the growth period of the carp and in the harvested stock. Wild fish (from the ponds, and feeder and drainage canals) and water samples (from the ponds) were also examined for CyHV-3 specific DNA sequences; and naive carp were cohabited with wild fish, or exposed to the pondwater samples, to test for the presence of infectious virus. All examined samples remained negative for CyHV-3 throughout the study. This indicates that draining and liming with quicklime can be a suitable disinfection measure for ponds after a CyHV-3 outbreak in carp aquaculture. PMID- 27503924 TI - RNA Sequencing Identifies Transcriptionally Viable Gene Fusions in Esophageal Adenocarcinomas. AB - Esophageal adenocarcinoma is a deadly cancer with increasing incidence in the United States, but mechanisms underlying pathogenesis are still mostly elusive. In addressing this question, we assessed gene fusion landscapes by comprehensive RNA sequencing (RNAseq) of 55 pretreatment esophageal adenocarcinoma and 49 nonmalignant biopsy tissues from patients undergoing endoscopy for Barrett's esophagus. In this cohort, we identified 21 novel candidate esophageal adenocarcinoma-associated fusions occurring in 3.33% to 11.67% of esophageal adenocarcinomas. Two candidate fusions were selected for validation by PCR and Sanger sequencing in an independent set of pretreatment esophageal adenocarcinoma (N = 115) and nonmalignant (N = 183) biopsy tissues. In particular, we observed RPS6KB1-VMP1 gene fusion as a recurrent event occurring in approximately 10% of esophageal adenocarcinoma cases. Notably, esophageal adenocarcinoma cases harboring RPS6KB1-VMP1 fusions exhibited significantly poorer overall survival as compared with fusion-negative cases. Mechanistic investigations established that the RPS6KB1-VMP1 transcript coded for a fusion protein, which significantly enhanced the growth rate of nondysplastic Barrett's esophagus cells. Compared with the wild-type VMP1 protein, which mediates normal cellular autophagy, RPS6KB1-VMP1 fusion exhibited aberrant subcellular localization and was relatively ineffective in triggering autophagy. Overall, our findings identified RPS6KB1-VMP1 as a genetic fusion that promotes esophageal adenocarcinoma by modulating autophagy-related processes, offering new insights into the molecular pathogenesis of esophageal adenocarcinomas. Cancer Res; 76(19); 5628-33. (c)2016 AACR. PMID- 27503925 TI - Assessing Immune-Related Adverse Events of Efficacious Combination Immunotherapies in Preclinical Models of Cancer. AB - New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAE) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor-bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab-treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies had a high therapeutic window compared with DT plus anti-CD137. In contrast, DT plus anti-CD137-treated mice developed severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared because of an infiltration of activated proliferating effector T cells in the tissues producing IFNgamma and TNF; however, TNF blockade decreased irAEs severity without impacting on tumor growth. Cancer Res; 76(18); 5288-301. (c)2016 AACR. PMID- 27503926 TI - SIRT2 Deacetylates and Inhibits the Peroxidase Activity of Peroxiredoxin-1 to Sensitize Breast Cancer Cells to Oxidant Stress-Inducing Agents. AB - SIRT2 is a protein deacetylase with tumor suppressor activity in breast and liver tumors where it is mutated; however, the critical substrates mediating its antitumor activity are not fully defined. Here we demonstrate that SIRT2 binds, deacetylates, and inhibits the peroxidase activity of the antioxidant protein peroxiredoxin (Prdx-1) in breast cancer cells. Ectopic overexpression of SIRT2, but not its catalytically dead mutant, increased intracellular levels of reactive oxygen species (ROS) induced by hydrogen peroxide, which led to increased levels of an overoxidized and multimeric form of Prdx-1 with activity as a molecular chaperone. Elevated levels of SIRT2 sensitized breast cancer cells to intracellular DNA damage and cell death induced by oxidative stress, as associated with increased levels of nuclear FOXO3A and the proapoptotic BIM protein. In addition, elevated levels of SIRT2 sensitized breast cancer cells to arsenic trioxide, an approved therapeutic agent, along with other intracellular ROS-inducing agents. Conversely, antisense RNA-mediated attenuation of SIRT2 reversed ROS-induced toxicity as demonstrated in a zebrafish embryo model system. Collectively, our findings suggest that the tumor suppressor activity of SIRT2 requires its ability to restrict the antioxidant activity of Prdx-1, thereby sensitizing breast cancer cells to ROS-induced DNA damage and cell cytotoxicity. Cancer Res; 76(18); 5467-78. (c)2016 AACR. PMID- 27503927 TI - Anticancer Effects of Targeting Hsp70 in Tumor Stromal Cells. AB - The stress-induced chaperone protein Hsp70 enables the initiation and progression of many cancers, making it an appealing therapeutic target for development. Here, we show that cancer cells resistant to Hsp70 inhibitors in vitro remain sensitive to them in vivo, revealing the pathogenic significance of Hsp70 in tumor stromal cells rather than tumor cells as widely presumed. Using transgenic mouse models of cancer, we found that expression of Hsp70 in host stromal cells was essential to support tumor growth. Furthermore, genetic ablation or pharmacologic inhibition of Hsp70 suppressed tumor infiltration by macrophages needed to enable tumor growth. Overall, our results illustrate how Hsp70 inhibitors mediate the anticancer effects by targeting both tumor cells and tumor stromal cells, with implications for the broad use of these inhibitors as tools to ablate tumor associated macrophages that enable malignant progression. Cancer Res; 76(20); 5926-32. (c)2016 AACR. PMID- 27503928 TI - Snail1-Dependent Activation of Cancer-Associated Fibroblast Controls Epithelial Tumor Cell Invasion and Metastasis. AB - Snail1 transcriptional factor is essential for triggering epithelial-to mesenchymal transition (EMT) and inducing tumor cell invasion. We report here an EMT-independent action of Snail1 on tumor invasion, as it is required for the activation of cancer-associated fibroblasts (CAF). Snail1 expression in fibroblasts requires signals derived from tumor cells, such as TGFbeta; reciprocally, in fibroblasts, Snail1 organizes a complex program that stimulates invasion of epithelial cells independent of the expression of Snail1 in these cells. Epithelial cell invasion is stimulated by the secretion by fibroblast of diffusible signaling molecules, such as prostaglandin E2 The capability of human or murine CAFs to promote tumor invasion is dependent on Snail1 expression. Inducible Snail1 depletion in mice decreases the invasion of breast tumors; moreover, epithelial tumor cells coxenografted with Snail1-depleted fibroblasts originated tumors with lower invasion than those transplanted with control fibroblasts. Therefore, these results demonstrate that the role of Snail1 in tumor invasion is not limited to EMT, but it is also dependent on its activity in stromal fibroblasts, where it orchestrates the cross-talk with epithelial tumor cells. Cancer Res; 76(21); 6205-17. (c)2016 AACR. PMID- 27503929 TI - Chromatin-Remodeling Complex SWI/SNF Controls Multidrug Resistance by Transcriptionally Regulating the Drug Efflux Pump ABCB1. AB - Anthracyclines are among the most effective yet most toxic drugs used in the oncology clinic. The nucleosome-remodeling SWI/SNF complex, a potent tumor suppressor, is thought to promote sensitivity to anthracyclines by recruiting topoisomerase IIa (TOP2A) to DNA and increasing double-strand breaks. In this study, we discovered a novel mechanism through which SWI/SNF influences resistance to the widely used anthracycline doxorubicin based on the use of a forward genetic screen in haploid human cells, followed by a rigorous single and double-mutant epistasis analysis using CRISPR/Cas9-mediated engineering. Doxorubicin resistance conferred by loss of the SMARCB1 subunit of the SWI/SNF complex was caused by transcriptional upregulation of a single gene, encoding the multidrug resistance pump ABCB1. Remarkably, both ABCB1 upregulation and doxorubicin resistance caused by SMARCB1 loss were dependent on the function of SMARCA4, a catalytic subunit of the SWI/SNF complex. We propose that residual SWI/SNF complexes lacking SMARCB1 are vital determinants of drug sensitivity, not just to TOP2A-targeted agents, but to the much broader range of cancer drugs effluxed by ABCB1. Cancer Res; 76(19); 5810-21. (c)2016 AACR. PMID- 27503930 TI - TPL2 Is an Oncogenic Driver in Keratocanthoma and Squamous Cell Carcinoma. AB - Squamous cell carcinoma (SCC) and keratoacanthoma (KA; SCC/KA) research has been hampered mainly by our lack of understanding the underlying genetic and epigenetic alterations associated with SCC/KA development, as well as the lack of animal models that faithfully recapitulate histopathologic features of human SCC/KA. Here, we show that TPL2 overexpression induced both cell transformation in immortalized human keratinocytes and SCC and KA-like cutaneous SCC (cSCC) development in mice. Mechanistically, activation of TPL2 downstream signaling pathways such as MEK/ERK MAPK, mTOR, NF-kappaB, and p38 MAPK leads to TPL2 mediated cell transformation in immortalized human keratinocytes and tumorigenesis in mice. Most importantly, TPL2 overexpression is required for iTPL2 TG-driven SCC and KA-like cSCC tumor maintenance, validating TPL2 as a possible drug target for the treatment of SCC/KA. Finally, we verified that TPL2 is overexpressed in human cutaneous metastatic SCC and KA clinical specimens compared with normal skin. Taken together, our results establish TPL2 as an oncogenic driver in SCC/KA development. Cancer Res; 76(22); 6712-22. (c)2016 AACR. PMID- 27503931 TI - Inhibiting Mitochondrial DNA Ligase IIIalpha Activates Caspase 1-Dependent Apoptosis in Cancer Cells. AB - Elevated levels of DNA ligase IIIalpha (LigIIIalpha) have been identified as a biomarker of an alteration in DNA repair in cancer cells that confers hypersensitivity to a LigIIIalpha inhibitor, L67, in combination with a poly (ADP ribose) polymerase inhibitor. Because LigIIIalpha functions in the nucleus and mitochondria, we examined the effect of L67 on these organelles. Here, we show that, although the DNA ligase inhibitor selectively targets mitochondria, cancer and nonmalignant cells respond differently to disruption of mitochondrial DNA metabolism. Inhibition of mitochondrial LigIIIalpha in cancer cells resulted in abnormal mitochondrial morphology, reduced levels of mitochondrial DNA, and increased levels of mitochondrially generated reactive oxygen species that caused nuclear DNA damage. In contrast, these effects did not occur in nonmalignant cells. Furthermore, inhibition of mitochondrial LigIIIalpha activated a caspase 1 dependent apoptotic pathway, which is known to be part of inflammatory responses induced by pathogenic microorganisms in cancer, but not nonmalignant cells. These results demonstrate that the disruption of mitochondrial DNA metabolism elicits different responses in nonmalignant and cancer cells and suggests that the abnormal response in cancer cells may be exploited in the development of novel therapeutic strategies that selectively target cancer cells. Cancer Res; 76(18); 5431-41. (c)2016 AACR. PMID- 27503932 TI - Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid Derived Suppressor Cells. AB - Human cytomegalovirus (CMV)-induced adaptive natural killer (NK) cells display distinct phenotypic and functional characteristics, including properties of immune memory. We hypothesized that these cells may be more resistant to suppression mediated by immunoregulatory cell subsets, making them attractive for use in cancer therapy. Here we report that relative to conventional NK cells, adaptive NK cells express lower levels of the inhibitory receptor T-cell Ig and ITIM domain (TIGIT), which results in resistance to immune suppression mediated by myeloid-derived suppressor cells (MDSC), as derived from cytokine induction in normal blood or patients with myelodysplastic syndrome. In contrast, conventional NK cells were potently suppressed by MDSCs, an effect abrogated completely by TIGIT blockade. Mechanistically, TIGIT signaling in NK cells after MDSC coculture led to a decrease in the phosphorylation of ZAP70/Syk and ERK1/2. These effects were reversed by blocking TIGIT on NK cells or by inhibiting production of reactive oxygen species (ROS) by MDSCs, the latter of which upregulated the TIGIT ligand CD155 on MDSCs. Accordingly, the blunted cytotoxicity of NK cells cocultured with MDSCs against tumor cells could be reversed by blocking TIGIT or ROS production. Overall, our results show how adaptive NK cells arising in response to CMV infection can escape MDSC-mediated suppression, and defined TIGIT antagonists as a novel type of checkpoint inhibitor to enhance NK-cell-mediated responses against cancer and infection. Cancer Res; 76(19); 5696-706. (c)2016 AACR. PMID- 27503933 TI - Tissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells. AB - Breast tumors are stiffer and more hypoxic than nonmalignant breast tissue. Here we report that stiff and hypoxic microenvironments promote the development of breast cancer stem-like cells (CSC) through modulation of the integrin-linked kinase ILK. Depleting ILK blocked stiffness and hypoxia-dependent acquisition of CSC marker expression and behavior, whereas ectopic expression of ILK stimulated CSC development under softer or normoxic conditions. Stiff microenvironments also promoted tumor formation and metastasis in ovo, where depleting ILK significantly abrogated the tumorigenic and metastatic potential of invasive breast cancer cells. We further found that the ILK-mediated phenotypes induced by stiff and hypoxic microenvironments are regulated by PI3K/Akt. Analysis of human breast cancer specimens revealed an association between substratum stiffness, ILK, and CSC markers, insofar as ILK and CD44 were expressed in cancer cells located in tumor regions predicted to be stiff. Our results define ILK as a key mechanotransducer in modulating breast CSC development in response to tissue mechanics and oxygen tension. Cancer Res; 76(18); 5277-87. (c)2016 AACR. PMID- 27503934 TI - Magnetic Resonance-Guided Nasogastric Feeding Tube Placement for Neonates: A Preclinical Study. AB - BACKGROUND: Establishing postnatal nutrition delivery is challenging in neonates with immature sucking and swallowing ability. Enteral feeding is the gold standard for such patients, but their small size and fragility present challenges in nasogastric (NG) feeding tube placement. Feeding tubes are typically placed with x-ray guidance, which provides minimal soft tissue contrast and exposes the baby to ionizing radiation. This research investigates magnetic resonance (MR) guidance of NG feeding tube placement in neonates to provide improved soft tissue visualization without ionizing radiation. MATERIALS AND METHODS: A novel feeding tube incorporating 3 solenoid coils for real-time tracking and guidance in the MR environment was developed. The feeding tube was placed 5 times in a rabbit with conventional x-ray guidance to assess mechanical stability and function. After x ray procedures, the rabbit was transferred to a neonatal MR system, and the tube was placed 5 more times. RESULTS: In procedures guided by x-ray and MR, the feeding tube provided sufficient mechanical strength and functionality to access the esophagus and stomach of the rabbit. MR imaging provided significantly improved soft tissue contrast versus x-ray, which aided in proper tube guidance. Moreover, MR guidance allowed for real-time placement of the tube without the use of ionizing radiation. CONCLUSIONS: The feasibility and benefits offered by an MR guided approach to NG feeding tube placement were demonstrated. The ability to acquire high-quality MR images of soft tissue without ionizing radiation and a contrast agent, coupled with accurate 3-dimensional device tracking, promises to have a powerful impact on future neonatal feeding tube placements. PMID- 27503936 TI - Immunonutrition Is Associated With a Decreased Incidence of Graft-Versus-Host Disease in Bone Marrow Transplant Recipients: A Meta-Analysis. AB - INTRODUCTION: Graft-versus-host disease (GVHD) is a serious complication of bone marrow transplantation (BMT), requiring higher doses of glucocorticoids or immunosuppressive therapies and further straining transplant recipients. Immunonutrition, such as vitamins and amino acid supplements, increase immunity and decrease inflammation and oxidative stress. This meta-analysis examines the impact of immunonutrition on the incidence of GVHD and postoperative infections among BMT recipients. METHODS: A comprehensive literature search for all published randomized controlled trials was conducted with PubMed, Cochrane Central Registry of Controlled Trials, and Google Scholar (1966-2016). Keywords in the search included variations of terms related to immunonutrition, such as "vitamin," "glutamine," and "transplant." Outcomes included incidence of GVHD and infection. RESULTS: Ten randomized controlled trials involving 681 BMT recipients were analyzed: 332 receiving immunonutrition and 349 receiving standard nutrition. Immunonutrition is correlated with a decreased incidence of GVHD by 19% (relative risk [RR] = 0.810, 95% CI: 0.695-0.945, P = .007). There was no significant difference in the incidence of infections with immunonutrition (RR = 1.016, 95% CI: 0.819-1.261, P = .885). Subgroup analysis of glutamine compared with N-acetylcysteine, selenium, and eicosapentaenoic acid showed no significant difference in the incidence of GVHD or infections (RR = 0.913, 95% CI: 0.732 1.139, P = .419; RR = 0.951, 95% CI: 0.732-1.235; P = .708, respectively). CONCLUSION: The use of immunonutrition is associated with a reduced risk of GVHD in BMT recipients, potentially as a result of improved immune support and free radical scavenging. Providing immunonutrient supplements is a valuable adjunct in the routine care of BMT recipients, helping to alleviate a common and deadly complication. PMID- 27503935 TI - Preserved Gut Microbial Diversity Accompanies Upregulation of TGR5 and Hepatobiliary Transporters in Bile Acid-Treated Animals Receiving Parenteral Nutrition. AB - BACKGROUND: Parenteral nutrition (PN) is a lifesaving therapy but is associated with gut atrophy and cholestasis. While bile acids (BAs) can modulate intestinal growth via gut receptors, the gut microbiome likely influences gut proliferation and inflammation. BAs also regulate the bile salt export pump (BSEP) involved in cholestasis. We hypothesized that the BA receptor agonist oleanolic acid (OA) regulates gut TGR5 receptor and modulates gut microbiota to prevent PN-associated injury. MATERIALS AND METHODS: Neonatal piglets were randomized to approximately 2 weeks of isocaloric enteral nutrition (EN), PN, or PN + enteral OA. Serum alanine aminotransferase, bilirubin, BAs, hepatic BSEP, gut TGR5, gut, liver morphology, and fecal microbiome utilizing 16S rRNA sequencing were evaluated. Kruskal-Wallis test, pairwise Mann-Whitney U test, and multilevel logistic regression analysis were performed. RESULTS: PN support resulted in gut atrophy substantially prevented by OA. The median (interquartile range) for villous/crypt ratio was as follows: EN, 3.37 (2.82-3.80); PN, 1.73 (1.54-2.27); and OA, 2.89 (2.17-3.34; P = .006). Pairwise comparisons yielded P = .002 (EN vs PN), P = .180 (EN vs OA), P = .026 (PN vs OA). OA upregulated TGR5 and BSEP without significant improvement in serum bilirubin ( P = .095). A decreased microbial diversity and shift toward proinflammatory phylum Bacteroidetes were seen with PN, which was prevented by OA. CONCLUSIONS: OA prevented PN-associated gut mucosal injury, Bacterioides expansion, and the decreased microbial diversity noted with PN. This study demonstrates a novel relationship among PN-associated gut dysfunction, BA treatment, and gut microbial changes. PMID- 27503937 TI - Glucagon-Like Peptide 2 Stimulates Postresection Intestinal Adaptation in Preterm Pigs by Affecting Proteins Related to Protein, Carbohydrate, and Sulphur Metabolism. AB - BACKGROUND: Exogenous glucagon-like peptide 2 (GLP-2) stimulates intestinal adaptation after resection in animal models of pediatric short bowel syndrome (SBS). It is unknown whether the molecular mechanisms of such GLP-2 effects are similar to those of postresection spontaneous adaptation. Using preterm pigs as a model, we hypothesized that GLP-2 treatment would change the intestinal proteome within the first week after resection, relative to individuals not resected or resected without GLP-2 treatment. MATERIALS AND METHODS: Two-day-old preterm pigs were subjected to resection of 50% distal small intestine and fed total parenteral nutrition without (SBS) or with GLP-2 infusion (3.5 ug/kg/h, SBS+GLP 2) for 5 days. The proteome of the remnant proximal intestine was compared among the SBS, SBS+GLP-2, and unresected pigs, through gel-based proteomics. RESULTS: Thirty-two proteins with differential expression were identified. Ten of these proteins were affected by the resection alone (ie, SBS vs unresected pigs). Five of these resection-responsive proteins and another 22 proteins were affected by GLP-2 infusion (ie, SBS+GLP-2 vs SBS or unresected pigs). Resection alone mainly affected cellular structural proteins, while the added GLP-2 treatment affected proteins involved in protein processing and the metabolism of protein, carbohydrate, and sulphur. CONCLUSION: In the first days following resection, proteins affected by resection plus GLP-2 treatment differed markedly from those affected by the spontaneous intestinal adaptation following resection alone. Whether more long-term GLP-2 treatment may affect the intestinal proteome following intestinal resection remains unknown. PMID- 27503938 TI - Decision Aid for Nutrition Support in Pediatric Oncology: A Pilot Study. AB - BACKGROUND: Despite the importance of nutrition support in preventing malnutrition in pediatric oncology, the decision to initiate and choose which nutrition support method is most appropriate can be difficult for parents and healthcare professionals. Decision aids are decision-focused patient information materials. They can improve knowledge, reduce decisional conflict, improve patients' risk perception, and increase patient participation in the decision making process. They have never been evaluated for pediatric oncology nutrition decisions. We aimed to develop and pilot test a decision aid to assist parents making these decisions in collaboration with their healthcare team. MATERIALS AND METHODS: The decision aid was developed in accordance with the International Patient Decision Aid Standards guidelines and evaluated in a single-center pilot study. The parents and healthcare professionals of pediatric oncology patients were eligible. Participants read the decision aid and completed a questionnaire assessing acceptability, usability, and improvement in understanding. RESULTS: Thirty-one parents and 15 healthcare professionals participated. Parents found the decision aid balanced, relevant, and satisfactory overall. Some parents reported the decision aid was too long (26%). Healthcare professionals positively rated the development process, usefulness to parents, and content and format of the decision aid. Forty-three percent reported that using the decision aid would save them time. There were no significant associations between health literacy, decisional satisfaction, decisional regret, acceptability, and improvement in understanding. CONCLUSION: The decision aid appears acceptable and usable for our target population. Decision aid feedback provided critical data to make modifications before evaluating the decision aid in a randomized controlled trial. PMID- 27503939 TI - Evaluation of Mitochondrial Respiratory Chain on the Generation of Reactive Oxygen Species and Cytotoxicity in HaCaT Cells Induced by Nanosized Titanium Dioxide Under UVA Irradiation. AB - Nanosized titanium dioxide (nano-TiO2) is widely used in the chemical, electrical, and electronic industries. Nanosized TiO2 has been reported to be an efficient photocatalyst, which is able to produce reactive oxygen species (ROS) under UVA irradiation. In the present work, we evaluate the effect of mitochondrial respiratory chain on the generation of ROS and cytotoxicity in keratinocyte (HaCaT) cells induced by nano-TiO2 under UVA irradiation. HaCaT cells were pretreated with different inhibitors of mitochondrial respiratory chain and followed by treatment with 200 ug/mL nano-TiO2, then exposed to UVA (365 nm) for 1 hour and cultured for 24 hours. Our results demonstrated that the complexes I and III of the mitochondrial respiratory chain are the major site in the ROS generation induced by nano-TiO2 Our results also demonstrated that the uncouplers of mitochondrial oxidative phosphorylation resulted in obvious changes in the production of intracellular ROS induced by nano-TiO2 The ROS sources of lipoxygenase, cyclooxygenase, and nicotinamide adenine dinucleotide phosphate oxidase had no significant effect on the ROS production. To some extent, nitric oxide synthase had effect on the ROS production. These results indicated that mitochondrial respiratory chain may be the main source of intracellular ROS production induced by nano-TiO2. PMID- 27503940 TI - Successful treatment of recurrent pleural and pericardial effusions with tocilizumab in a patient with systemic lupus erythematous. AB - A 22-year-old Caucasian man presented to hospital with pleuritic chest pain. He had had a history of a sun-sensitive rash a year prior. Workup revealed normal cardiac enzymes and chest X-ray. However, electrocardiogram revealed ST elevation and PR depression, and echocardiogram revealed a slight pericardial effusion without other findings. A diagnosis of pericarditis was made. Subsequently, he was found to be positive for antinuclear antibodies (ANAs), as well as antibodies to SSA, SSB and double-stranded DNA; C3 was low, and C4 was undetectable. A diagnosis of systemic lupus erythematosus was made. The patient initially responded to high-dose ibuprofen. One month later, he developed a new pericardial effusion, this time with concomitant massive left-sided pleural effusion, requiring three separate thoracenteses draining a total of 6 L of pleural fluid. The recurrent effusion failed to respond to high-dose corticosteroid treatment. Owing to the severity and rapidity of the recurrence of pleural and pericardial effusion, intravenous tocilizumab was administered. The patient had excellent clinical and radiographic improvement. This case shows that tocilizumab may have a role in the treatment of intractable pleuropericardial effusion and other forms of lupus-associated serositis. PMID- 27503941 TI - Rare case of gallbladder agenesis presenting with pancreatitis. AB - Gallbladder agenesis (GA) is a rare congenital abnormality with an incidence of 0.01-0.09%. Majority of GA exist alone although it can be associated with other systemic malformations involving the gastrointestinal, genitourinary, cardiovascular and skeletal systems. It is thought that biliary and pancreatic pathologies coexist and this is the second case reported in the literature of GA presenting with pancreatitis. PMID- 27503942 TI - Cerebral venous thrombosis associated with thyrotoxicosis, the use of desmopressin and elevated factor VIII/von Willebrand factor. AB - Cerebral venous thrombosis (CVT) is an uncommon disorder associated with diverse processes. We report a patient who, while receiving desmopressin and contraceptive pills (OCP), developed straight sinus thrombosis. Clinical assessment and laboratory investigations revealed untreated hyperthyroidism and a hypercoagulable state, characterised by high levels of von Willebrand factor, factor VIII coagulant activity and IgM cardiolipin antibody. The clinical picture improved with anticoagulation, treatment of hyperthyroidism and discontinuation of OCP and desmopressin. To the best of our knowledge, the association between the use of oral desmopressin and CVT has not been described. The multiple risk factors present in our case were probably additive in increasing the risk of CVT. Although this case represents a rare occurrence, practitioners should be alerted to the possible associations of desmopressin, oral contraceptives and Graves' disease with venous thrombosis. PMID- 27503943 TI - The importance of gene-environment interactions in human obesity. AB - The worldwide obesity epidemic has been mainly attributed to lifestyle changes. However, who becomes obese in an obesity-prone environment is largely determined by genetic factors. In the last 20 years, important progress has been made in the elucidation of the genetic architecture of obesity. In parallel with successful gene identifications, the number of gene-environment interaction (GEI) studies has grown rapidly. This paper reviews the growing body of evidence supporting gene-environment interactions in the field of obesity. Heritability, monogenic and polygenic obesity studies provide converging evidence that obesity predisposing genes interact with a variety of environmental, lifestyle and treatment exposures. However, some skepticism remains regarding the validity of these studies based on several issues, which include statistical modelling, confounding, low replication rate, underpowered analyses, biological assumptions and measurement precision. What follows in this review includes (1) an introduction to the study of GEI, (2) the evidence of GEI in the field of obesity, (3) an outline of the biological mechanisms that may explain these interaction effects, (4) methodological challenges associated with GEI studies and potential solutions, and (5) future directions of GEI research. Thus far, this growing body of evidence has provided a deeper understanding of GEI influencing obesity and may have tremendous applications in the emerging field of personalized medicine and individualized lifestyle recommendations. PMID- 27503944 TI - Long non-coding RNAs-towards precision medicine in diabetic kidney disease? AB - Diabetic kidney disease (DKD) is escalating and is the major cause of end stage kidney failure. There is increasing evidence to support the role of epigenetic factors and metabolic memory in linking the environmental and genetic causes of this disease. Although our understanding of this disease has improved, there has been no significant efficacious therapeutic translation in the last decade. Current sequencing technology has allowed interrogation of the human transcriptome. It is evident that although approximately 80% of the genome is transcribed, only 1-2% is read and coded into protein. The remaining non-coding RNA, historically assumed to be 'junk', is now known to have key roles in regulating gene function and orchestrate how and when coding genes are expressed. This largest subset of non-coding RNAs called long non-coding RNAs (LNCRNAs) drives epigenetic changes and has functional relevance best characterized in cancers and cardiovascular disease. This understanding, coupled with the availability and affordability of RNA sequencing, has shifted our therapeutic strategies towards genomic therapy in DKD. The role of LNCRNAs with respect to DKD is only just emerging. In this review we summarize the role of LNCRNAs in DKD and the existing antisense oligonucleotide therapy that may provide precise and targeted medicine to treat DKD in this postgenomic era. PMID- 27503945 TI - Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance? AB - The worldwide obesity epidemic has become a major health concern, because it contributes to higher mortality due to an increased risk for noncommunicable diseases including cardiovascular diseases, type 2 diabetes, musculoskeletal disorders and some cancers. Insulin resistance may link accumulation of adipose tissue in obesity to metabolic diseases, although the underlying mechanisms are not completely understood. In the past decades, data from human studies and transgenic animal models strongly suggested correlative, but also causative associations between activation of proinflammatory pathways and insulin resistance. Particularly chronic inflammation in adipose tissue seems to play an important role in the development of obesity-related insulin resistance. On the other hand, adipose tissue inflammation has been shown to be essential for healthy adipose tissue expansion and remodelling. However, whether adipose tissue inflammation represents a consequence or a cause of impaired insulin sensitivity remains an open question. A better understanding of the molecular pathways linking excess adipose tissue storage to chronic inflammation and insulin resistance may provide the basis for the future development of anti-inflammatory treatment strategies to improve adverse metabolic consequences of obesity. In this review, potential mechanisms of adipose tissue inflammation and how adipose tissue inflammation may cause insulin resistance are discussed. PMID- 27503946 TI - Energy balance, body composition, sedentariness and appetite regulation: pathways to obesity. AB - Energy balance is not a simple algebraic sum of energy expenditure and energy intake as often depicted in communications. Energy balance is a dynamic process and there exist reciprocal effects between food intake and energy expenditure. An important distinction is that of metabolic and behavioural components of energy expenditure. These components not only contribute to the energy budget directly, but also by influencing the energy intake side of the equation. It has recently been demonstrated that resting metabolic rate (RMR) is a potential driver of energy intake, and evidence is accumulating on the influence of physical activity (behavioural energy expenditure) on mechanisms of satiety and appetite control. These effects are associated with changes in leptin and insulin sensitivity, and in the plasma levels of gastrointestinal (GI) peptides such as glucagon-like peptide-1 (GLP-1), ghrelin and cholecystokinin (CCK). The influence of fat-free mass on energy expenditure and as a driver of energy intake directs attention to molecules emanating from skeletal tissue as potential appetite signals. Sedentariness (physical inactivity) is positively associated with adiposity and is proposed to be a source of overconsumption and appetite dysregulation. The molecular signals underlying these effects are not known but represent a target for research. PMID- 27503947 TI - Pro-atherogenic mediators and subclinical atherogenesis are related to epicardial adipose tissue thickness in patients with cardiovascular risk. AB - Objective To evaluate the relationship between pro-atherogenic biomarkers and epicardial adipose tissue (EAT) thickness in patients with cardiovascular risk factors. Methods Plasma nitric oxide (NO), soluble intercellular adhesion molecule-1 and malondialdehyde (MDA) levels, EAT thickness, flow-mediated dilation (FMD) and carotid intima media thickness (CIMT) were determined in patients aged >18 years who were referred for echocardiography for heart ischemia or non-ischemic diseases. Cardiovascular risk factors (Framingham score [FS] >= 20) were weighted. Results Hypertension, dyslipidaemia and type 2 diabetes mellitus were prevalent (>=55% of 40 patients). Patients with FS >= 20 ( n = 21) showed significantly higher EAT and CIMT values. Globally, MDA, CIMT, age, waist circumference, high-density lipoprotein cholesterol (HDL-C) and FS were associated with EAT thickness. EAT was significantly associated with NO in patients with FS >= 20. Significant differences in EAT thickness were found between patients stratified by NO value, FMD, age, smoking status, dyslipidaemia, type 2 diabetes mellitus and FS. An EAT-associated atherogenic risk (CIMT >= 1 mm) model was statistically significant when MDA and type 2 diabetes mellitus were included. Conclusion EAT thickness was associated with MDA, CIMT, age, waist circumference, HDL-C and FS globally, but with NO only in patients with FS>=20. EAT may be used to identify vascular damage stage, possibly influenced by MDA and type 2 diabetes mellitus. PMID- 27503948 TI - Integrity of Amygdala Subregion-Based Functional Networks and Emotional Lability in Drug-Naive Boys With ADHD. AB - OBJECTIVE: This study evaluated the functional networks of amygdala subregions (basolateral [BLA], centromedial [CMA], and superficial amygdala [SFA]) in ADHD and their association with emotional lability (EL) symptoms. METHOD: Resting state functional connectivity (RSFC) of amygdala subregions and their correlations with EL scores were evaluated in 35 drug-naive boys with ADHD and 30 age-matched healthy controls (HC). RESULTS: Compared with HC, altered RSFC were detected differently for each amygdala subregion in ADHD: altered RSFC of BLA with the thalamus and vermis; aberrant RSFC of CMA with the superior temporal gyrus/pole and insula, precuneus and cerebellum; reduced RSFC of SFA with dorsal frontoparietal cortices. Within ADHD, higher EL scores were associated with reduced negative RSFC of SFA with the dorsolateral prefrontal cortex and inferior parietal lobe. CONCLUSION: Diffuse alterations of amygdala subregion-based networks are associated with ADHD, and the weaker SFA-frontoparietal networks might be involved in the hypothesized top-down effortful regulation of emotion. PMID- 27503950 TI - Epigenetic control of exercise training-induced cardiac hypertrophy by miR-208. AB - Aerobic exercise-induced cardiac hypertrophy (CH) is a physiological response involving accurate orchestration of gene and protein expression of contractile and metabolic components. The microRNAs: miR-208a, miR-208b and miR-499 are each encoded by a myosin gene and thus are also known as 'MyomiRs', regulating several mRNA targets that in turn regulate CH and metabolic pathways. To understand the role of myomiRs in the fine-tuning of cardiac myosin heavy chain (MHC) isoform expression by exercise training-induced physiological hypertrophy, Wistar rats were subjected to two different swim training protocols. We observed that high volume swim training (T2), improved cardiac diastolic function, induced CH and decreased the expression of miR-208a and miR-208b Consequently, the increased expression of their targets, sex determining region y-related transcription factor 6 (Sox6), Med13, Purbeta, specificity proteins (Sp)/Kruppel-like transcription factor 3 (SP3) and HP1beta (heterochromatin protein 1beta) was more prominent in T2, thus converging to modulate cardiac metabolic and contractile adaptation by exercise training, with an improvement in the alpha-MHC/beta-MHC ratio, bypassing the increase in PPARbeta and histone deacetylase (HDAC) class I and II regulation. Altogether, we conclude that high-volume swim training finely assures physiological cardiac remodelling by epigenetic regulation of myomiRs, because inhibition of miR-208a and miR-208b increases the expression of their target proteins and stimulates the interaction among metabolic, contractile and epigenetic genes. PMID- 27503949 TI - Administration of tauroursodeoxycholic acid prevents endothelial dysfunction caused by an oral glucose load. AB - Postprandial hyperglycaemia leads to a transient impairment in endothelial function; however, the mechanisms remain largely unknown. Previous work in cell culture models demonstrate that high glucose results in endoplasmic reticulum (ER) stress and, in animal studies, ER stress has been implicated as a cause of endothelial dysfunction. In the present study, we tested the hypothesis that acute oral administration of tauroursodeoxycholic acid (TUDCA, 1500 mg), a chemical chaperone known to alleviate ER stress, would prevent hyperglycaemia induced endothelial dysfunction. In 12 young healthy subjects (seven men, five women), brachial artery flow-mediated dilation (FMD) was assessed at baseline, and at 60 and 120 min after an oral glucose challenge. Subjects were tested on two separate visits in a single-blind randomized cross-over design: after oral ingestion of TUDCA or placebo capsules. FMD was reduced from baseline during hyperglycaemia under the placebo condition (-32% at 60 min and -28% at 120 min post oral glucose load; P<0.05 from baseline) but not under the TUDCA condition ( 4% at 60 min and +0.3% at 120 min post oral glucose load; P>0.05 from baseline). Postprandial plasma glucose and insulin were not altered by TUDCA ingestion. Plasma oxidative stress markers 3-nitrotyrosine and thiobarbituric acid reactive substance (TBARS) remained unaltered throughout the oral glucose challenge in both conditions. These results suggest that hyperglycaemia-induced endothelial dysfunction can be mitigated by oral administration of TUDCA, thus supporting the hypothesis that ER stress may contribute to endothelial dysfunction during postprandial hyperglycaemia. PMID- 27503951 TI - Basal ganglia necrosis: a 'best-fit' approach. AB - A previously well 16-year-old boy developed a rapid-onset hypokinetic syndrome, coupled with a radiological appearance of extensive and highly symmetrical basal ganglia and white matter change. The diagnostic process was challenging and we systematically considered potential causes. After excluding common causes of this clinico-radiological picture, we considered common disorders with this unusual radiological picture and vice versa, before finally concluding that this was a rare presentation of a rare disease. We considered the broad categories of: metabolic; toxic; infective; inflammatory, postinfective and immune-mediated; neoplastic; paraneoplastic and heredodegenerative. Long-term follow-up gave insight into the nature of the insult, confirming the monophasic course. During recovery, and following presumed secondary aberrant reinnervation, his disorder evolved from predominantly hypokinetic to hyperkinetic. Here, we explore the process of finding a 'best-fit' diagnosis: in this case, acute necrotising encephalopathy. PMID- 27503952 TI - An in silico algorithm for identifying stabilizing pockets in proteins: test case, the Y220C mutant of the p53 tumor suppressor protein. AB - The p53 tumor suppressor protein performs a critical role in stimulating apoptosis and cell cycle arrest in response to oncogenic stress. The function of p53 can be compromised by mutation, leading to increased risk of cancer; approximately 50% of cancers are associated with mutations in the p53 gene, the majority of which are in the core DNA-binding domain. The Y220C mutation of p53, for example, destabilizes the core domain by 4 kcal/mol, leading to rapid denaturation and aggregation. The associated loss of tumor suppressor functionality is associated with approximately 75 000 new cancer cases every year. Destabilized p53 mutants can be 'rescued' and their function restored; binding of a small molecule into a pocket on the surface of mutant p53 can stabilize its wild-type structure and restore its function. Here, we describe an in silico algorithm for identifying potential rescue pockets, including the algorithm's integration with the Dynameomics molecular dynamics data warehouse and the DIVE visual analytics engine. We discuss the results of the application of the method to the Y220C p53 mutant, entailing finding a putative rescue pocket through MD simulations followed by an in silico search for stabilizing ligands that dock into the putative rescue pocket. The top three compounds from this search were tested experimentally and one of them bound in the pocket, as shown by nuclear magnetic resonance, and weakly stabilized the mutant. PMID- 27503953 TI - GADIS: Algorithm for designing sequences to achieve target secondary structure profiles of intrinsically disordered proteins. AB - Many intrinsically disordered proteins (IDPs) participate in coupled folding and binding reactions and form alpha helical structures in their bound complexes. Alanine, glycine, or proline scanning mutagenesis approaches are often used to dissect the contributions of intrinsic helicities to coupled folding and binding. These experiments can yield confounding results because the mutagenesis strategy changes the amino acid compositions of IDPs. Therefore, an important next step in mutagenesis-based approaches to mechanistic studies of coupled folding and binding is the design of sequences that satisfy three major constraints. These are (i) achieving a target intrinsic alpha helicity profile; (ii) fixing the positions of residues corresponding to the binding interface; and (iii) maintaining the native amino acid composition. Here, we report the development of a G: enetic A: lgorithm for D: esign of I: ntrinsic secondary S: tructure (GADIS) for designing sequences that satisfy the specified constraints. We describe the algorithm and present results to demonstrate the applicability of GADIS by designing sequence variants of the intrinsically disordered PUMA system that undergoes coupled folding and binding to Mcl-1. Our sequence designs span a range of intrinsic helicity profiles. The predicted variations in sequence-encoded mean helicities are tested against experimental measurements. PMID- 27503954 TI - Conformational dynamics of cancer-associated MyD88-TIR domain mutant L252P (L265P) allosterically tilts the landscape toward homo-dimerization. AB - MyD88 is an essential adaptor protein, which mediates the signaling of the toll like and interleukin-1 receptors' superfamily. The MyD88 L252P (L265P) mutation has been identified in diffuse large B-cell lymphoma. The identification of this mutation has been a major advance in the diagnosis of patients with aldenstrom macroglobulinemia and related lymphoid neoplasms. Here we used computational methods to characterize the conformational effects of the mutation. Our molecular dynamics simulations revealed that the mutation allosterically quenched the global conformational dynamics of the toll/IL-1R (TIR) domain, and readjusted its salt bridges and dynamic community network. Specifically, the mutation changed the orientation and reduced the fluctuation of alpha-helix 3, possibly through eliminating/weakening ~8 salt bridges and enhancing the salt bridge D225-K258. Using the energy landscape of the TIR domains of MyD88, we identified two dynamic conformational basins, which correspond to the binding sites used in homo- and hetero-oligomerization, respectively. Our results indicate that the mutation stabilizes the core of the homo-dimer interface of the MyD88-TIR domain, and increases the population of homo-dimer-compatible conformational states in MyD88 family proteins. However, the dampened motion restricts its ability to heterodimerize with other TIR domains, thereby curtailing physiological signaling. In conclusion, the L252P both shifts the landscape toward homo dimerization and restrains the dynamics of the MyD88-TIR domain, which disfavors its hetero-dimerization with other TIR domains. We further put these observations within the framework of MyD88-mediated cell signaling. PMID- 27503955 TI - Disparities, Hospital Financing, And More. PMID- 27503956 TI - Tackling Disparities With Lessons From Abroad. AB - Countries endeavoring to reduce health disparities are looking for guidance from other nations, but challenges abound. PMID- 27503957 TI - Active Life Expectancy In The Older US Population, 1982-2011: Differences Between Blacks And Whites Persisted. AB - Understanding long-range trends in longevity and disability is useful for projecting the likely impact of the baby-boom generation on long-term care utilization and spending. We examine changes in active life expectancy in the United States from 1982 to 2011 for white and black adults ages sixty-five and older. For whites, longevity increased, disability was postponed to older ages, the locus of care shifted from nursing facilities to community settings, and the proportion of life at older ages spent without disability increased. In contrast, for blacks, longevity increases were accompanied by smaller postponements in disability, and the percentage of remaining life spent active remained stable and well below that of whites. Older black women were especially disadvantaged in 2011 in terms of the proportion of years expected to be lived without disability. Public health measures directed at older black adults-particularly women-are needed to offset impending pressures on the long-term care delivery system as the result of population aging. PMID- 27503958 TI - Sight-Threatening Ocular Diseases Remain Underdiagnosed Among Children Of Less Affluent Families. AB - Sight-threatening eye diseases such as strabismus (misaligned eyes) and amblyopia (lazy eye) develop during childhood. The earlier in life these diseases are diagnosed and effectively treated, the greater the chance of preventing irreversible long-term sight loss. Using 2001-14 claims data for nearly 900,000 US children with health insurance, we followed a cohort for up to fourteen years from birth, to assess whether household net worth affected rates of visits to ophthalmologists and optometrists or rates of diagnoses of strabismus and amblyopia. We found considerably lower use of eye care services among children in less affluent families than among those in more affluent ones, resulting in estimates of nearly 13,000 missed strabismus diagnoses and over 5,000 missed amblyopia diagnoses in a ten-year period. Despite ongoing efforts to improve screening rates for serious childhood ocular disorders, more attention should be directed to overcoming economic barriers that keep children from obtaining necessary eye care services. PMID- 27503959 TI - Using Genetic Technologies To Reduce, Rather Than Widen, Health Disparities. AB - Evidence shows that both biological and nonbiological factors contribute to health disparities. Genetics, in particular, plays a part in how common diseases manifest themselves. Today, unprecedented advances in genetically based diagnoses and treatments provide opportunities for personalized medicine. However, disadvantaged groups may lack access to these advances, and treatments based on research on non-Hispanic whites might not be generalizable to members of minority groups. Unless genetic technologies become universally accessible, existing disparities could be widened. Addressing this issue will require integrated strategies, including expanding genetic research, improving genetic literacy, and enhancing access to genetic technologies among minority populations in a way that avoids harms such as stigmatization. PMID- 27503960 TI - Racial Disparities In Geographic Access To Primary Care In Philadelphia. AB - Primary care is often thought of as the gateway to improved health outcomes and can lead to more efficient use of health care resources. Because of primary care's cardinal importance, adequate access is an important health policy priority. In densely populated urban areas, spatial access to primary care providers across neighborhoods is poorly understood. We examined spatial variation in primary care access in Philadelphia, Pennsylvania. We calculated ratios of adults per primary care provider for each census tract and included buffer zones based on prespecified drive times around each tract. We found that the average ratio was 1,073; the supply of primary care providers varied widely across census tracts, ranging from 105 to 10,321. We identified six areas of Philadelphia that have much lower spatial accessibility to primary care relative to the rest of the city. After adjustment for sociodemographic and insurance characteristics, the odds of being in a low-access area were twenty-eight times greater for census tracts with a high proportion of African Americans than in tracts with a low proportion of African Americans. PMID- 27503961 TI - Physicians' Participation In ACOs Is Lower In Places With Vulnerable Populations Than In More Affluent Communities. AB - Early evidence suggested that accountable care organizations (ACOs) could improve health care quality while constraining costs, and ACOs are expanding throughout the United States. However, if disadvantaged patients have unequal access to physicians who participate in ACOs, that expansion may exacerbate health care disparities. We examined the relationship between physicians' participation in both Medicare and commercial ACOs across the country and the sociodemographic characteristics of their likely patient populations. Physicians' participation in ACOs varied widely across hospital referral regions, from nearly 0 percent to over 85 percent. After we adjusted for individual physician and practice characteristics, we found that physicians who practiced in ZIP Code Tabulation Areas where a higher percentage of the population was black, living in poverty, uninsured, or disabled or had less than a high school education-compared to other areas-had significantly lower rates of ACO participation than other physicians. Our findings suggest that vulnerable populations' access to physicians participating in ACOs may not be as great as access for other groups, which could exacerbate existing disparities in health care quality. PMID- 27503962 TI - Across US Hospitals, Black Patients Report Comparable Or Better Experiences Than White Patients. AB - Patient-reported experience is a critical part of measuring health care quality. There are limited data on racial differences in patient experience. Using patient level data for 2009-10 from the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS), we compared blacks' and whites' responses on measures of overall hospital rating, communication, clinical processes, and hospital environment. In unadjusted results, there were no substantive differences between blacks' and whites' ratings of hospitals. Blacks were less likely to recommend hospitals but reported more positive experiences, compared to whites. Higher educational attainment and self-reported worse health status were associated with more negative evaluations in both races. Additionally, blacks rated minority-serving hospitals worse than other hospitals on all HCAHPS measures. Taken together, there were surprisingly few meaningful differences in patient experience between blacks and whites across US hospitals. Although blacks tend to receive care at worse-performing hospitals, compared to whites, within any given hospital black patients tend to report better experience than whites do. PMID- 27503963 TI - Language Services In Hospitals Vary By Ownership And Location. AB - Twenty-four million people in the United States have limited English proficiency. They experience barriers to health care because of their inability to communicate effectively with providers. Hospitals are required to provide language services that reflect the needs of people in their communities, but these services are not available systematically. PMID- 27503964 TI - Geographic Concentration Of Home-Based Medical Care Providers. AB - The United States faces a shortage of providers who care for homebound patients. About 5,000 primary care providers made 1.7 million home visits to Medicare fee for-service beneficiaries in 2013, accounting for 70 percent of all home-based medical visits. Nine percent of these providers performed 44 percent of visits. However, most homebound people live more than thirty miles from a high-volume provider. PMID- 27503965 TI - Achieving Health Equity: Closing The Gaps In Health Care Disparities, Interventions, And Research. AB - In the United States, racial/ethnic minority, rural, and low-income populations continue to experience suboptimal access to and quality of health care despite decades of recognition of health disparities and policy mandates to eliminate them. Many health care interventions that were designed to achieve health equity fall short because of gaps in knowledge and translation. We discuss these gaps and highlight innovative interventions that help address them, focusing on cardiovascular disease and cancer. We also provide recommendations for advancing the field of health equity and informing the implementation and evaluation of policies that target health disparities through improved access to care and quality of care. PMID- 27503967 TI - Strategies To Empower Communities To Reduce Health Disparities. AB - Community-based participatory research is a promising approach to reducing health disparities. It empowers individuals and communities to become the major players in solving their own health problems. We discuss the use of community-based participatory research and other strategies to enhance empowerment. We also discuss projects from the Centers for Population Health and Health Disparities that have empowered communities to achieve positive health outcomes aimed at reducing disparities. We offer recommendations to policy makers for involving residents in efforts to achieve health equity. PMID- 27503966 TI - Evaluating Strategies For Reducing Health Disparities By Addressing The Social Determinants Of Health. AB - The opportunities for healthy choices in homes, neighborhoods, schools, and workplaces can have decisive impacts on health. We review scientific evidence from promising interventions focused on the social determinants of health and discuss how such interventions can improve population health and reduce health disparities. We found sufficient evidence of successful outcomes to support disparity-reducing policy interventions targeted at education and early childhood; urban planning and community development; housing; income enhancements and supplements; and employment. Cost-effectiveness evaluations show that these interventions lead to long-term societal savings, but the interventions require more routine attention to cost considerations. We discuss challenges to implementation, including the need for long-term financing to scale up effective interventions for implementation at the local, state, and national levels. PMID- 27503968 TI - Multilevel Interventions To Address Health Disparities Show Promise In Improving Population Health. AB - Multilevel interventions are those that affect at least two levels of influence for example, the patient and the health care provider. They can be experimental designs or natural experiments caused by changes in policy, such as the implementation of the Affordable Care Act or local policies. Measuring the effects of multilevel interventions is challenging, because they allow for interaction among levels, and the impact of each intervention must be assessed and translated into practice. We discuss how two projects from the National Institutes of Health's Centers for Population Health and Health Disparities used multilevel interventions to reduce health disparities. The interventions, which focused on the uptake of the human papillomavirus vaccine and community-level dietary change, had mixed results. The design and implementation of multilevel interventions are facilitated by input from the community, and more advanced methods and measures are needed to evaluate the impact of the various levels and components of such interventions. PMID- 27503969 TI - Combined Regional Investments Could Substantially Enhance Health System Performance And Be Financially Affordable. AB - Leaders across the United States face a difficult challenge choosing among possible approaches to transform health system performance in their regions. The ReThink Health Dynamics Model simulates how alternative scenarios could unfold through 2040. This article compares the likely consequences if four interventions were enacted in layered combinations in a prototypical midsize US city. We estimated the effects of efforts to deliver higher-value care; reinvest savings and expand global payment; enable healthier behaviors; and expand socioeconomic opportunities. Results suggest that there may be an effective and affordable way to unlock much greater health and economic potential, ultimately reducing severe illness by 20 percent, lowering health care costs by 14 percent, and improving economic productivity by 9 percent. This would require combined investments in clinical and population-level initiatives, coupled with financial agreements that reduce incentives for costly care and reinvest a share of the savings to ensure adequate long-term financing. PMID- 27503970 TI - Medicare Advantage Plans Pay Hospitals Less Than Traditional Medicare Pays. AB - There is ongoing debate about how prices paid to providers by Medicare Advantage plans compare to prices paid by fee-for-service Medicare. We used data from Medicare and the Health Care Cost Institute to identify the prices paid for hospital services by fee-for-service (FFS) Medicare, Medicare Advantage plans, and commercial insurers in 2009 and 2012. We calculated the average price per admission, and its trend over time, in each of the three types of insurance for fixed baskets of hospital admissions across metropolitan areas. After accounting for differences in hospital networks, geographic areas, and case-mix between Medicare Advantage and FFS Medicare, we found that Medicare Advantage plans paid 5.6 percent less for hospital services than FFS Medicare did. Without taking into account the narrower networks of Medicare Advantage, the program paid 8.0 percent less than FFS Medicare. We also found that the rates paid by commercial plans were much higher than those of either Medicare Advantage or FFS Medicare, and growing. At least some of this difference comes from the much higher prices that commercial plans pay for profitable service lines. PMID- 27503971 TI - The Affordable Care Act's Effects On The Formation, Expansion, And Operation Of Physician-Owned Hospitals. AB - The Affordable Care Act (ACA) imposed new restrictions on the formation and expansion of physician-owned hospitals. These restrictions provided incentives for the hospitals and their owners to take preemptive actions before the effective dates of ACA provisions and modify their operations thereafter. We studied 106 physician-owned hospitals in Texas to determine how they responded to ACA restrictions. We found that there were significant pre-ACA increases in the formation, physician ownership, and physical capacity of physician-owned hospitals, which suggests that they reacted quickly to the policy changes. After the ACA's provisions took effect, the hospitals improved the use of their assets to generate increased amounts of services, revenue, and profits. We found no evidence that existing physician-owned hospitals stopped accepting Medicare to avoid the ACA restrictions, although some investors adopted a seemingly unsuccessful strategy of not accepting Medicare at physician-owned hospitals formed after implementation of the ACA. We conclude that the ACA restrictions effectively eliminated the formation of new physician-owned hospitals, thus accomplishing what previous legislative efforts had failed to do. PMID- 27503972 TI - Accounting For Patients' Socioeconomic Status Does Not Change Hospital Readmission Rates. AB - There is an active public debate about whether patients' socioeconomic status should be included in the readmission measures used to determine penalties in Medicare's Hospital Readmissions Reduction Program (HRRP). Using the current Centers for Medicare and Medicaid Services methodology, we compared risk standardized readmission rates for hospitals caring for high and low proportions of patients of low socioeconomic status (as defined by their Medicaid status or neighborhood income). We then calculated risk-standardized readmission rates after additionally adjusting for patients' socioeconomic status. Our results demonstrate that hospitals caring for large proportions of patients of low socioeconomic status have readmission rates similar to those of other hospitals. Moreover, readmission rates calculated with and without adjustment for patients' socioeconomic status are highly correlated. Readmission rates of hospitals caring for patients of low socioeconomic status changed by approximately 0.1 percent with adjustment for patients' socioeconomic status, and only 3-4 percent fewer such hospitals reached the threshold for payment penalty in Medicare's HRRP. Overall, adjustment for socioeconomic status does not change hospital results in meaningful ways. PMID- 27503973 TI - Uncompensated Care Decreased At Hospitals In Medicaid Expansion States But Not At Hospitals In Nonexpansion States. AB - One pillar of the Affordable Care Act (ACA) was its expected impact on the growing burden of uncompensated care costs for the uninsured at hospitals. However, little is known about how this burden changed as a result of the ACA's enactment. We examine how the Affordable Care Act (ACA)'s coverage expansions affected uncompensated care costs at a large, diverse sample of hospitals. We estimate that in states that expanded Medicaid under the ACA, uncompensated care costs decreased from 4.1 percentage points to 3.1 percentage points of operating costs. The reductions in Medicaid expansion states were larger at hospitals that had higher pre-ACA uncompensated care burdens and in markets where we predicted larger gains in coverage through expanded eligibility for Medicaid. Our estimates suggest that uncompensated care costs would have decreased from 5.7 percentage points to 4.0 percentage points of operating costs in nonexpansion states if they had expanded Medicaid. Thus, while the ACA decreased the variation in uncompensated care costs across hospitals within Medicaid expansion states, the difference between expansion and nonexpansion states increased substantially. Policy makers and researchers should consider how the shifting uncompensated care burden affects other hospital decisions as well as the distribution of supplemental public funding to hospitals. PMID- 27503974 TI - Medicaid Expansion In 2014 Did Not Increase Emergency Department Use But Did Change Insurance Payer Mix. AB - In 2014 twenty-eight states and the District of Columbia had expanded Medicaid eligibility while federal and state-based Marketplaces in every state made subsidized private health insurance available to qualified individuals. As a result, about seventeen million previously uninsured Americans gained health insurance in 2014. Many policy makers had predicted that Medicaid expansion would lead to greatly increased use of hospital emergency departments (EDs). We examined the effect of insurance expansion on ED use in 478 hospitals in 36 states during the first year of expansion (2014). In difference-in-differences analyses, Medicaid expansion increased Medicaid-paid ED visits in those states by 27.1 percent, decreased uninsured visits by 31.4 percent, and decreased privately insured visits by 6.7 percent during the first year of expansion compared to nonexpansion states. Overall, however, total ED visits grew by less than 3 percent in 2014 compared to 2012-13, with no significant difference between expansion and nonexpansion states. Thus, the expansion of Medicaid coverage strongly affected payer mix but did not significantly affect overall ED use, even though more people gained insurance coverage in expansion states than in nonexpansion states. This suggests that expanding Medicaid did not significantly increase or decrease overall ED visit volume. PMID- 27503975 TI - Delivering On Accountable Care: Lessons From A Behavioral Health Program To Improve Access And Outcomes. AB - Patients with behavioral health disorders often have worse health outcomes and have higher health care utilization than patients with medical diseases alone. As such, people with behavioral health conditions are important populations for accountable care organizations (ACOs) seeking to improve the efficiency of their delivery systems. However, ACOs have historically faced numerous barriers in implementing behavioral health population-based programs, including acquiring reimbursement, recruiting providers, and integrating new services. We developed an evidence-based, all-payer collaborative care program called Behavioral Health Associates (BHA), operated as part of UCLA Health, an integrated academic medical center. Building BHA required several innovations, which included using our enterprise electronic medical record for behavioral health referrals and documentation; registering BHA providers with insurance plans' mental health carve-out products; and embedding BHA providers in primary care practices throughout the UCLA Health system. Since 2012 BHA has more than tripled the number of patients receiving behavioral health services through UCLA Health. After receiving BHA treatment, patients had a 13 percent reduction in emergency department use. Our efforts can serve as a model for other ACOs seeking to integrate behavioral health care into routine practice. PMID- 27503976 TI - Medical Underwriting In Long-Term Care Insurance: Market Conditions Limit Options For Higher-Risk Consumers. AB - A key feature of private long-term care insurance is that medical underwriters screen out would-be buyers who have health conditions that portend near-term physical or cognitive disability. We applied common underwriting criteria based on data from two long-term care insurers to a nationally representative sample of individuals in the target age range (50-71 years) for long-term care insurance. The screening criteria put upper bounds on the current proportion of Americans who could gain coverage in the individual market without changes to medical underwriting practice. Specifically, our simulations show that in the target age range, approximately 30 percent of those whose wealth meets minimum industry standards for suitability for long-term care insurance would have their application for such insurance rejected at the underwriting stage. Among the general population-without considering financial suitability-we estimated that 40 percent would have their applications rejected. The predicted rejection rates are substantially higher than the rejection rates of about 20-25 percent of applicants in the actual market. In evaluating reforms for long-term care financing and their potential to increase private insurance rates, as well as to reduce financial pressure on public safety-net programs, policy makers need to consider the role of underwriting in the market for long-term care insurance. PMID- 27503977 TI - A Synchronized Prescription Refill Program Improved Medication Adherence. AB - Synchronizing medication refills-renewing all medications at the same time from the same pharmacy-is an increasingly popular strategy to improve adherence to medication regimens, but there has been little research regarding its effectiveness. In light of increasing policy interest, we evaluated the impact of a pilot refill synchronization program implemented by a large national insurer. A random sample of Medicare Advantage patients receiving mail-order refills for common maintenance medications (antihypertensive, lipid-lowering, or antidiabetic agents) were invited to join the program and followed for twelve months. On average, the absolute increase in the proportion of patients deemed adherent during follow-up was 3-10 percentage points for the intervention group, compared to 1-5 percentage points for the control group. Patients with poorer baseline adherence showed larger increases in the absolute proportion deemed adherent in intervention (23-26 percentage points) compared to a control group (13-15 percentage points). Synchronizing refills might be a promising intervention to improve adherence to maintenance medications, especially among Medicare patients with low baseline adherence. PMID- 27503978 TI - Gaps In Primary Care And Health System Performance In Six Latin American And Caribbean Countries. AB - The rapid demographic and epidemiological transitions occurring in Latin America and the Caribbean have led to high levels of noncommunicable diseases in the region. In addition to reduced risk factors for chronic conditions, a strong health system for managing chronic conditions is vital. This study assessed the extent to which populations in six Latin American and Caribbean countries receive high-quality primary care, and it examined the relationship between experiences with care and perceptions of health system performance. We applied a validated survey on access, use, and satisfaction with health care services to nationally representative samples of the populations of Brazil, Colombia, El Salvador, Jamaica, Mexico, and Panama. Respondents reported considerable gaps in the ways in which primary care is organized, financed, and delivered. Nearly half reported using the emergency department for a condition they considered treatable in a primary care setting. Reports of more primary care problems were associated with worse perceptions of health system performance and quality and less receipt of preventive care. Urgent attention to primary care performance is required as the region's population continues to age at an unprecedented rate. PMID- 27503979 TI - Grasping At The Moon: Enhancing Access To Careers In The Health Professions. AB - A former HHS secretary reflects on what's needed to enable more minorities to become doctors and other health professionals. PMID- 27503980 TI - New Directions For Foundations In Health Equity. AB - Rising income inequality and pessimism about the current and future status of race relations in the United States make this both a challenging time for the pursuit of health equity and also an important opportunity for action. We glean lessons from past and ongoing philanthropic investments in health equity and recommend approaches that can guide future work by foundations. Improving health equity is a complex process that must take into account a variety of factors that affect health, of which access to high-quality health care is just one element. Accordingly, improving health equity will require the combined forces of philanthropy, the public sector, and sectors that have not traditionally been identified with health. PMID- 27503982 TI - The Most Profitable US Hospitals. PMID- 27503983 TI - Profitable Hospitals: The Authors Reply. PMID- 27503984 TI - The Social Costs Of Lead Poisonings. PMID- 27503985 TI - Lead Poisonings: The Author Replies. PMID- 27503986 TI - The Therapeutic Relationship Is Key To Patient Engagement. PMID- 27503987 TI - Limited Resources For Health: Malaysia And Oman. PMID- 27503988 TI - Malaysian Health Care System Still Needs Work. PMID- 27503989 TI - Health Care in Malaysia: The Author Replies. PMID- 27503991 TI - Medical marijuana research. PMID- 27503992 TI - Why conscientious objection merits respect. PMID- 27503993 TI - Are we consistent? PMID- 27503994 TI - CIHR hikes grants. PMID- 27503995 TI - Synthetic Biology of Natural Products. AB - The diversity and natural modularity of their biosynthetic pathways has turned natural products into attractive, but challenging, targets for synthetic biology approaches. Here, we discuss the current state of the field, highlighting recent advances and remaining bottlenecks. Global genomic assessments of natural product biosynthetic capacities across large parts of microbial diversity provide a first survey of the available natural parts libraries and identify evolutionary design rules for further engineering. Methods for compound and pathway detection and characterization are developed increasingly on the basis of synthetic biology tools, contributing to an accelerated translation of genomic information into usable building blocks for pathway assembly. A wide range of methods is also becoming available for accessing ever larger parts of chemical space by rational diversification of natural products, guided by rapid progress in our understanding of the underlying biochemistry and enzymatic mechanisms. Enhanced genome assembly and editing tools, adapted to the needs of natural products research, facilitate the realization of ambitious engineering strategies, ranging from combinatorial library generation to high-throughput optimization of product titers. Together, these tools and concepts contribute to the emergence of a new generation of revitalized natural product research. PMID- 27503996 TI - Polymyxin: Alternative Mechanisms of Action and Resistance. AB - Antibiotic resistance among pathogenic bacteria is an ever-increasing issue worldwide. Unfortunately, very little has been achieved in the pharmaceutical industry to combat this problem. This has led researchers and the medical field to revisit past drugs that were deemed too toxic for clinical use. In particular, the cyclic cationic peptides polymyxin B and colistin, which are specific for Gram-negative bacteria, have been used as "last resort" antimicrobials. Before the 1980s, these drugs were known for their renal and neural toxicities; however, new clinical practices and possibly improved manufacturing have made them safer to use. Previously suggested to primarily attack the membranes of Gram-negative bacteria and to not easily select for resistant mutants, recent research exploring resistance and mechanisms of action has provided new perspectives. This review focuses primarily on the proposed alternative mechanisms of action, known resistance mechanisms, and how these support the alternative mechanisms of action. PMID- 27503997 TI - Somatic TP53 Mutations in the Era of Genome Sequencing. AB - Amid the complexity of genetic alterations in human cancer, TP53 mutation appears as an almost invariant component, representing by far the most frequent genetic alteration overall. Compared with previous targeted sequencing studies, recent integrated genomics studies offer a less biased view of TP53 mutation patterns, revealing that >20% of mutations occur outside the DNA-binding domain. Among the 12 mutations representing each at least 1% of all mutations, five occur at residues directly involved in specific DNA binding, four affect the tertiary fold of the DNA-binding domain, and three are nonsense mutations, two of them in the carboxyl terminus. Significant mutations also occur in introns, affecting alternative splicing events or generating rearrangements (e.g., in intron 1 in sporadic osteosarcoma). In aggressive cancers, mutation is so common that it may not have prognostic value (all these cancers have impaired p53 function caused by mutation or by other mechanisms). In several other cancers, however, mutation makes a clear difference for prognostication, as, for example, in HER2-enriched breast cancers and in lung adenocarcinoma with EGFR mutations. Thus, the clinical significance of TP53 mutation is dependent on tumor subtype and context. Understanding the clinical impact of mutation will require integrating mutation specific information (type, frequency, and predicted impact) with data on haplotypes and on loss of heterozygosity. PMID- 27503999 TI - Percutaneous mechanical circulatory support: current concepts and future directions. PMID- 27503998 TI - Mechanisms of Nucleosome Dynamics In Vivo. AB - Nucleosomes function to tightly package DNA into chromosomes, but the nucleosomal landscape becomes disrupted during active processes such as replication, transcription, and repair. The realization that many proteins responsible for chromatin regulation are frequently mutated in cancer has drawn attention to chromatin dynamics; however, the basic mechanisms whereby nucleosomes are disrupted and reassembled is incompletely understood. Here, I present an overview of chromatin dynamics as has been elucidated in model organisms, in which our understanding is most advanced. A basic understanding of chromatin dynamics during normal developmental processes can provide the context for understanding how this machinery can go awry during oncogenesis. PMID- 27504000 TI - The electronic health record as a catalyst for quality improvement in patient care. AB - Electronic health records (EHRs) are now broadly used, following decades of development and incentive programmes for their use. EHRs have been shown through use of reminders, electronic order sets and other means to improve reliability of performance of many basic tasks in acute, preventive and chronic care. They assist with collecting, summarising and displaying the large volumes of information in patient records and support the implementation of guidelines and care pathways. Broad use of EHRs has brought into focus weaknesses of the current generation of EHRs: their user interface, implementation difficulties, time required to use them and others. Addressing these weaknesses and adopting new technologies, including use of voice, natural language processing and data analytic techniques, is necessary for EHRs to achieve their full potential: to gather information from routine care, to learn from it and to be an integral component of efforts to continuously improve and to transform care. PMID- 27504001 TI - Effect of age and aortic valve anatomy on calcification and haemodynamic severity of aortic stenosis. AB - OBJECTIVE: To evaluate the effect of age and aortic valve anatomy (tricuspid (TAV) vs bicuspid (BAV) aortic valve) on the relationship between the aortic valve calcification (AVC) and the haemodynamic parameters of aortic stenosis (AS) severity. METHODS: Two hundred patients with AS and preserved left ventricular ejection fraction were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study and underwent a comprehensive Doppler echocardiography and multidetector CT (MDCT). Mean transvalvular gradient (MG) measured by Doppler echocardiography was used to assess AS haemodynamic severity and AVC was evaluated by MDCT using the Agatston method and indexed to the left ventricular outflow tract area to obtain AVC density (AVCd). All analyses were adjusted for sex. RESULTS: Thirty-nine patients had a BAV and 161 a TAV. Median age was 51 and 72 years for BAV and TAV patients, respectively. There was a modest correlation between MG and AVCd (rho=0.51, p<0.0001) in the whole cohort. After dichotomisation for valve anatomy, there was a good correlation between AVCd and MG in the TAV group (rho=0.61, p<0.0001) but weak correlation in the BAV group (rho=0.32, p=0.046). In the TAV group, the strength of the AVCd-MG correlation was similar in younger (<72 years old; rho=0.59, p<0.0001) versus older (>=72 years old; rho=0.61, p<0.0001) patients. In the BAV group, there was no correlation between AVCd and MG in younger patients (<51 years old; rho=0.12, p=0.65), whereas there was a good correlation in older patients (>=51 years old; rho=0.55, p=0.009). AVCd (p=0.005) and age (p=0.02) were both independent determinants of MG in BAV patients while AVCd (p<0.0001) was the only independent determinant of MG in TAV patients. CONCLUSIONS: In patients with TAV as well as in older patients with BAV, AVCd appears to be the main factor significantly associated with the haemodynamic severity of AS and so it may be used to corroborate AS severity in case of uncertain or discordant findings at echocardiography. However, among younger patients with BAV, some may have a haemodynamically significant stenosis with minimal AVCd. The results of MDCT AVCd should thus be interpreted cautiously in this subset of patients. TRIAL REGISTRATION NUMBER: NCT01679431; Pre-results. PMID- 27504002 TI - International patterns of dual antiplatelet therapy duration after acute coronary syndromes. AB - OBJECTIVE: To describe international patterns of dual antiplatelet therapy (DAPT) duration after acute coronary syndrome (ACS), and explore its determinants and correlation with clinical events. METHODS: EPICOR (long-tErm follow-uP of anti thrombotic management patterns In acute CORonary syndrome patients) is a prospective, international, observational study of 10 568 ACS hospital survivors enrolled in 555 centres from 20 countries across Europe and Latin America between 2010 and 2011, with telephone follow-up at quarterly intervals up to 24 months to assess treatment continuation and clinical events. RESULTS: Of 8593 patients discharged on DAPT, 4859 (57%) remained on uninterrupted DAPT at end of follow up. There were minor differences in rates of DAPT discontinuation according to age, gender, risk factors, therapeutic strategy or region, but major differences between countries. By study end, 555 of evaluable patients (5.7%) died, 727 (10.0%) experienced new cardiovascular (CV) events, 496 new coronary events (6.82%) and 154 (2.11%) clinically relevant bleeding (14 (6.7%) fatal). Most CV events and deaths (85%) occurred while on DAPT. DAPT interruption was associated with increased risk of CV events in the following week (HR 2.29; 95% CI 1.08 to 4.84) but not specifically with time to first coronary event or mortality. CONCLUSIONS: Despite guideline recommendations, most patients with ACS in Europe and Latin America remained on DAPT beyond 12 months, country being the most important determinant of DAPT duration. Increase in short-term CV risk was seen after switching from DAPT to less medication, as compared with continued DAPT, with no long-term effect on coronary or mortality risk. TRIAL REGISTRATION NUMBER: NCT01171404; Results. PMID- 27504004 TI - Antithrombotic drug use: scientific breakthroughs, biological limits and physician behaviour. PMID- 27504003 TI - Infarct size and left ventricular remodelling after preventive percutaneous coronary intervention. AB - OBJECTIVE: We hypothesised that, compared with culprit-only primary percutaneous coronary intervention (PCI), additional preventive PCI in selected patients with ST-elevation myocardial infarction with multivessel disease would not be associated with iatrogenic myocardial infarction, and would be associated with reductions in left ventricular (LV) volumes in the longer term. METHODS: In the preventive angioplasty in myocardial infarction trial (PRAMI; ISRCTN73028481), cardiac magnetic resonance (CMR) was prespecified in two centres and performed (median, IQR) 3 (1, 5) and 209 (189, 957) days after primary PCI. RESULTS: From 219 enrolled patients in two sites, 84% underwent CMR. 42 (50%) were randomised to culprit-artery-only PCI and 42 (50%) were randomised to preventive PCI. Follow up CMR scans were available in 72 (86%) patients. There were two (4.8%) cases of procedure-related myocardial infarction in the preventive PCI group. The culprit artery-only group had a higher proportion of anterior myocardial infarctions (MIs) (55% vs 24%). Infarct sizes (% LV mass) at baseline and follow-up were similar. At follow-up, there was no difference in LV ejection fraction (%, median (IQR), (culprit-artery-only PCI vs preventive PCI) 51.7 (42.9, 60.2) vs 54.4 (49.3, 62.8), p=0.23), LV end-diastolic volume (mL/m2, 69.3 (59.4, 79.9) vs 66.1 (54.7, 73.7), p=0.48) and LV end-systolic volume (mL/m2, 31.8 (24.4, 43.0) vs 30.7 (23.0, 36.3), p=0.20). Non-culprit angiographic lesions had low-risk Syntax scores and 47% had non-complex characteristics. CONCLUSIONS: Compared with culprit-only PCI, non-infarct-artery MI in the preventive PCI strategy was uncommon and LV volumes and ejection fraction were similar. PMID- 27504005 TI - Orthostatic Hypotension in Diabetics in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Blood Pressure Trial. PMID- 27504006 TI - Orthostatic Hypotension in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) Blood Pressure Trial: Prevalence, Incidence, and Prognostic Significance. AB - Orthostatic hypotension (OH) is associated with hypertension and diabetes mellitus. However, in populations with both hypertension and diabetes mellitus, its prevalence, the effect of intensive versus standard systolic blood pressure (BP) targets on incident OH, and its prognostic significance are unclear. In 4266 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) BP trial, seated BP was measured 3*, followed by readings every minute for 3 minutes after standing. Orthostatic BP change, calculated as the minimum standing minus the mean seated systolic BP and diastolic BP, was assessed at baseline, 12 months, and 48 months. The relationship between OH and clinical outcomes (total and cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, heart failure hospitalization or death and the primary composite outcome of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death) was assessed using proportional hazards analysis. Consensus OH, defined by orthostatic decline in systolic BP >=20 mm Hg or diastolic BP >=10 mm Hg, occurred at >=1 time point in 20% of participants. Neither age nor systolic BP treatment target (intensive, <120 mm Hg versus standard, <140 mm Hg) was related to OH incidence. Over a median follow-up of 46.9 months, OH was associated with increased risk of total death (hazard ratio, 1.61; 95% confidence interval, 1.11-2.36) and heart failure death/hospitalization (hazard ratio, 1.85, 95% confidence interval, 1.17-2.93), but not with the primary outcome or other prespecified outcomes. In patients with type 2 diabetes mellitus and hypertension, OH was common, not associated with intensive versus standard BP treatment goals, and predicted increased mortality and heart failure events. PMID- 27504007 TI - Revisiting Fibromuscular Dysplasia: Rationale of the European Fibromuscular Dysplasia Initiative. PMID- 27504008 TI - How much does curation cost? AB - NIH administrators have recently expressed concerns about the cost of curation for biological databases. However, they did not articulate the exact costs of curation. Here we calculate the cost of biocuration of articles for the EcoCyc database as $219 per article over a 5-year period. That cost is 6-15% of the cost of open-access publication fees for publishing biomedical articles, and we estimate that cost is 0.088% of the cost of the overall research project that generated the experimental results. Thus, curation costs are small in an absolute sense, and represent a miniscule fraction of the cost of the research. PMID- 27504009 TI - Improving the dictionary lookup approach for disease normalization using enhanced dictionary and query expansion. AB - The rapidly increasing biomedical literature calls for the need of an automatic approach in the recognition and normalization of disease mentions in order to increase the precision and effectivity of disease based information retrieval. A variety of methods have been proposed to deal with the problem of disease named entity recognition and normalization. Among all the proposed methods, conditional random fields (CRFs) and dictionary lookup method are widely used for named entity recognition and normalization respectively. We herein developed a CRF based model to allow automated recognition of disease mentions, and studied the effect of various techniques in improving the normalization results based on the dictionary lookup approach. The dataset from the BioCreative V CDR track was used to report the performance of the developed normalization methods and compare with other existing dictionary lookup based normalization methods. The best configuration achieved an F-measure of 0.77 for the disease normalization, which outperformed the best dictionary lookup based baseline method studied in this work by an F-measure of 0.13.Database URL: https://github.com/TCRNBioinformatics/DiseaseExtract. PMID- 27504010 TI - Crowdsourcing and curation: perspectives from biology and natural language processing. AB - Crowdsourcing is increasingly utilized for performing tasks in both natural language processing and biocuration. Although there have been many applications of crowdsourcing in these fields, there have been fewer high-level discussions of the methodology and its applicability to biocuration. This paper explores crowdsourcing for biocuration through several case studies that highlight different ways of leveraging 'the crowd'; these raise issues about the kind(s) of expertise needed, the motivations of participants, and questions related to feasibility, cost and quality. The paper is an outgrowth of a panel session held at BioCreative V (Seville, September 9-11, 2015). The session consisted of four short talks, followed by a discussion. In their talks, the panelists explored the role of expertise and the potential to improve crowd performance by training; the challenge of decomposing tasks to make them amenable to crowdsourcing; and the capture of biological data and metadata through community editing.Database URL: http://www.mitre.org/publications/technical-papers/crowdsourcing-and-curation perspectives. PMID- 27504011 TI - MODEM: multi-omics data envelopment and mining in maize. AB - MODEM is a comprehensive database of maize multidimensional omics data, including genomic, transcriptomic, metabolic and phenotypic information from the cellular to individual plant level. This initial release contains approximately 1.06 M high quality SNPs for 508 diverse inbred lines obtained by combining variations from RNA sequencing on whole kernels (15 days after pollination) of 368 lines and a 50 K array for all 508 individuals. As all of these data were derived from the same diverse panel of lines, the database also allows various types of genetic mapping (including characterization of phenotypic QTLs, pQTLs; expression QTLs, eQTLs and metabolic QTLs, mQTLs). MODEM is thus designed to promote a better understanding of maize genetic architecture and deep functional annotation of the complex maize genome (and potentially those of other crop plants) and to explore the genotype-phenotype relationships and regulation of maize kernel development at multiple scales, which is also comprehensive for developing novel methods. MODEM is additionally designed to link with other databases to make full use of current resources, and it provides visualization tools for easy browsing. All of the original data and the related mapping results are freely available for easy query and download. This platform also provides helpful tools for general analyses and will be continually updated with additional materials, features and public data related to maize genetics or regulation as they become available.Database URL: (http://modem.hzau.edu.cn). PMID- 27504012 TI - FNDC5 Alleviates Hepatosteatosis by Restoring AMPK/mTOR-Mediated Autophagy, Fatty Acid Oxidation, and Lipogenesis in Mice. AB - Fibronectin type III domain-containing 5 (FNDC5) protein induces browning of subcutaneous fat and mediates the beneficial effects of exercise on metabolism. However, whether FNDC5 is associated with hepatic steatosis, autophagy, fatty acid oxidation (FAO), and lipogenesis remains unknown. Herein, we show the roles and mechanisms of FNDC5 in hepatic steatosis, autophagy, and lipid metabolism. Fasted FNDC5-/- mice exhibited severe steatosis, reduced autophagy, and FAO, and enhanced lipogenesis in the liver compared with wild-type mice. Energy deprivation-induced autophagy, FAO, and AMPK activity were attenuated in FNDC5-/- hepatocytes, which were restored by activating AMPK with 5-aminoimidazole-4 carboxamide ribonucleotide (AICAR). Inhibition of mammalian target of rapamycin (mTOR) complex 1 with rapamycin enhanced autophagy and FAO and attenuated lipogenesis and steatosis in FNDC5-/- livers. FNDC5 deficiency exacerbated hyperlipemia, hepatic FAO and autophagy impairment, hepatic lipogenesis, and lipid accumulation in obese mice. Exogenous FNDC5 stimulated autophagy and FAO gene expression in hepatocytes and repaired the attenuated autophagy and palmitate-induced steatosis in FNDC5-/- hepatocytes. FNDC5 overexpression prevented hyperlipemia, hepatic FAO and autophagy impairment, hepatic lipogenesis, and lipid accumulation in obese mice. These results indicate that FNDC5 deficiency impairs autophagy and FAO and enhances lipogenesis via the AMPK/mTOR pathway. FNDC5 deficiency aggravates whereas FNDC5 overexpression prevents the HFD-induced hyperlipemia, hepatic lipid accumulation, and impaired FAO and autophagy in the liver. PMID- 27504013 TI - Insulin Resistance Is Accompanied by Increased Fasting Glucagon and Delayed Glucagon Suppression in Individuals With Normal and Impaired Glucose Regulation. AB - Hyperinsulinemia is an adaptive mechanism that enables the maintenance of normoglycemia in the presence of insulin resistance. We assessed whether glucagon is also involved in the adaptation to insulin resistance. A total of 1,437 individuals underwent an oral glucose tolerance test with measurements of circulating glucose, insulin, and glucagon concentrations at 0, 30 and 120 min. Early glucagon suppression was defined as suppression in the period from 0 to 30 min, and late glucagon suppression as 30 to 120 min after glucose intake. Insulin sensitivity was estimated by the validated insulin sensitivity index. Individuals with screen-detected diabetes had 30% higher fasting glucagon levels and diminished early glucagon suppression, but greater late glucagon suppression when compared with individuals with normal glucose tolerance (P <= 0.014). Higher insulin resistance was associated with higher fasting glucagon levels, less early glucagon suppression, and greater late glucagon suppression (P < 0.001). The relationship between insulin sensitivity and fasting glucagon concentrations was nonlinear (P < 0.001). In conclusion, increased fasting glucagon levels and delayed glucagon suppression, together with increased circulating insulin levels, develop in parallel with insulin resistance. Therefore, glucose maintenance during insulin resistance may depend not only on hyperinsulinemia but also on the ability to suppress glucagon early after glucose intake. PMID- 27504014 TI - The Stepwise Approach to Diabetes Prevention: Results From the D-CLIP Randomized Controlled Trial. AB - OBJECTIVE: This study tests the effectiveness of expert guidelines for diabetes prevention: lifestyle intervention with addition of metformin, when required, among people with prediabetes. RESEARCH DESIGN AND METHODS: The Diabetes Community Lifestyle Improvement Program (D-CLIP) is a randomized, controlled, translation trial of 578 overweight/obese Asian Indian adults with isolated impaired glucose tolerance (iIGT), isolated impaired fasting glucose (iIFG), or IFG+IGT in Chennai, India. Eligible individuals were identified through community based recruitment and randomized to standard lifestyle advice (control) or a 6 month, culturally tailored, U.S. Diabetes Prevention Program-based lifestyle curriculum plus stepwise addition of metformin (500 mg, twice daily) for participants at highest risk of conversion to diabetes at >=4 months of follow up. The primary outcome, diabetes incidence, was assessed biannually and compared across study arms using an intention-to-treat analysis. RESULTS: During 3 years of follow-up, 34.9% of control and 25.7% of intervention participants developed diabetes (P = 0.014); the relative risk reduction (RRR) was 32% (95% CI 7-50), and the number needed to treat to prevent one case of diabetes was 9.8. The RRR varied by prediabetes type (IFG+IGT, 36%; iIGT, 31%; iIFG, 12%; P = 0.77) and was stronger in participants 50 years or older, male, or obese. Most participants (72.0%) required metformin in addition to lifestyle, although there was variability by prediabetes type (iIFG, 76.5%; IFG+IGT, 83.0%; iIGT, 51.3%). CONCLUSIONS: Stepwise diabetes prevention in people with prediabetes can effectively reduce diabetes incidence by a third in community settings; however, people with iIFG may require different interventions. PMID- 27504015 TI - Expression of Organic Anion Transporting Polypeptide 1A2 in Red Blood Cells and Its Potential Impact on Antimalarial Therapy. AB - Important antimalarial drugs, including quinolines, act against blood schizonts by interfering with hemoglobin metabolism. To reach their site of action, these compounds have to cross the plasma membrane of red blood cells (RBCs). Organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs) are important uptake transporters and interesting candidates for local drug transport. We therefore studied their interaction with antimalarial compounds (quinine, chloroquine, mefloquine, pyrimethamine, artemisinin, and artesunate) and characterized the expression of OATP1A2 and OATP2B1 in RBCs. Competition assays using transporter-overexpressing Madin-Darby canine kidney (MDCKII) cells and the model substrate estrone-3-sulfate identified quinine and chloroquine as potent inhibitors of OATP1A2 function (IC50 quinine: 0.7 +/- 1.2 uM; chloroquine: 1.0 +/- 1.5 uM), but no or only moderate effects were observed for OATP2B1. Subsequently, quinine was identified as a substrate of OATP1A2 (Km 23.4 uM). The OATP1A2-mediated uptake was sensitive to the OATP1A2-specific inhibitor naringin. Both OATPs were expressed in human RBCs, and ex vivo transport studies demonstrated naringin-sensitive accumulation of quinine in these cells (60 pmol versus 38 pmol/5 * 10(5) RBCs). Additional transport studies using OCT1-3 and organic cation transporter novel type 1 (OCTN1) indicated only significant quinine uptake by OCT1, which was not detected in RBCs. In conclusion, our data demonstrate expression of OATP2B1 and OATP1A2 in RBCs as well as OATP1A2-mediated uptake of quinine. Therefore, modulation of OATP1A2 function may affect quinine uptake into erythrocytes. PMID- 27504016 TI - In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity. AB - Abiraterone acetate, the prodrug of the cytochrome P450 C17 inhibitor abiraterone, plus prednisone is approved for treatment of metastatic castration resistant prostate cancer. We explored whether abiraterone interacts with drugs metabolized by CYP2C8, an enzyme responsible for the metabolism of many drugs. Abiraterone acetate and abiraterone and its major metabolites, abiraterone sulfate and abiraterone sulfate N-oxide, inhibited CYP2C8 in human liver microsomes, with IC50 values near or below the peak total concentrations observed in patients with metastatic castration-resistant prostate cancer (IC50 values: 1.3-3.0 uM, 1.6-2.9 uM, 0.044-0.15 uM, and 5.4-5.9 uM, respectively). CYP2C8 inhibition was reversible and time-independent. To explore the clinical relevance of the in vitro data, an open-label, single-center study was conducted comprising 16 healthy male subjects who received a single 15-mg dose of the CYP2C8 substrate pioglitazone on day 1 and again 1 hour after the administration of abiraterone acetate 1000 mg on day 8. Plasma concentrations of pioglitazone, its active M-III (keto derivative) and M-IV (hydroxyl derivative) metabolites, and abiraterone were determined for up to 72 hours after each dose. Abiraterone acetate increased exposure to pioglitazone; the geometric mean ratio (day 8/day 1) was 125 [90% confidence interval (CI), 99.9-156] for Cmax and 146 (90% CI, 126-171) for AUClast Exposure to M-III and M-IV was reduced by 10% to 13%. Plasma abiraterone concentrations were consistent with previous studies. These results show that abiraterone only weakly inhibits CYP2C8 in vivo. PMID- 27504017 TI - The role of cell-free circulating microRNA in diagnostics in patients with rheumatoid arthritis. PMID- 27504018 TI - Antibody profile to Borrelia burgdorferi in veterinarians from Nuevo Leon, Mexico, a non-endemic area of this zoonosis. AB - OBJECTIVES: Lyme disease is a tick-borne disease caused by infections with Borrelia. Persons infected with Borrelia can be asymptomatic or can develop disseminated disease. Diagnosis and recognition of groups at risk of infection with Borrelia burgdorferi is of great interest to contemporary rheumatology. There are a few reports about Borrelia infection in Mexico, including lymphocytoma cases positive to B. burgdorferi sensu stricto by PCR and a patient with acrodermatitis chronica atrophicans. Veterinarians have an occupational risk due to high rates of tick contact. The aim of this work was to investigate antibodies to Borrelia in students at the Faculty of Veterinary Medicine and Zootechnics, at Nuevo Leon, Mexico, and determine the antibody profile to B. burgdorferi antigens. MATERIAL AND METHODS: Sera were screened using a C6 ELISA, IgG and IgM ELISA using recombinant proteins from B. burgdorferi, B. garinii and B. afzelii. Sera with positive or grey-zone values were tested by IgG Western blot to B. burgdorferi sensu stricto. RESULTS: All volunteers reported tick exposures and 72.5% remembered tick bites. Only nine persons described mild Lyme disease related symptoms, including headaches, paresthesias, myalgias and arthralgias. None of the volunteers reported erythema migrans. Nine samples were confirmed by IgG Western blot. The profile showed 89% reactivity to OspA, 67% to p83, and 45% to BmpA. CONCLUSIONS: Positive sera samples shared antibody reactivity to the markers of late immune response p83 and BmpA, even if individuals did not present symptoms of Lyme arthritis or post-Lyme disease. The best criterion to diagnose Lyme disease in our country remains to be established, because it is probable that different strains coexist in Mexico. This is the first report of antibodies to B. burgdorferi in Latin American veterinarians. Veterinarians and high-risk people should be alert to take precautionary measures to prevent tick-borne diseases. PMID- 27504019 TI - Influence of exogenous leptin on redox homeostasis in neutrophils and lymphocytes cultured in synovial fluid isolated from patients with rheumatoid arthritis. AB - OBJECTIVES: Leptin is an adipose cells derived hormone that regulates energy homeostasis within the body. Energy metabolism of immune cells influences their activity within numerous pathological states, but the effect of leptin on these cells in unclear. On the one hand, it was observed that leptin induces neutrophils chemotaxis and modulates phagocytosis. On the other hand, neutrophils exposed to leptin did not display detectable Ca(2+) ions mobilization or beta2 integrin upregulation. In this study, we investigated the effect of leptin on the redox homeostasis in lymphocytes and neutrophils. MATERIAL AND METHODS: Neutrophils and lymphocytes were isolated by density-gradient centrifugation of blood from healthy volunteers. Cells were cultured with or without leptin (100 ng/ml for lymphocytes and 500 ng/ml for neutrophils) or with or without synovial fluid (85%) for 0-72 h. Culture media were not changed during incubation. Cells were homogenized and homogenate was frozen until laboratory measurements. Redox homeostasis was assessed by the reduced glutathione (GSH) vs. oxidized glutathione (GSSG) ratio and membrane lipid peroxidation evaluation. RESULTS: Lymphocytes cultured with leptin and synovial fluid showed a significant increase of the GSSG level. The GSSG/GSH ratio increased by 184 +/-37%. In neutrophils incubated in a similar environment, the GSSG/GSH ratio increased by just 21 +/ 7%, and the effect was observed irrespectively of whether they were exposed to leptin or synovial fluid or both together. Neither leptin nor synovial fluid influenced lipid peroxidation in neutrophils, but in lymphocytes leptin intensified lipid peroxidation. CONCLUSIONS: Leptin altered the lymphocytes, but not neutrophils redox state. Because firstly neutrophils are anaerobic cells and have just a few mitochondria and secondly lymphocytes have typical aerobic metabolism, the divergence of our data supports the hypothesis that leptin induces oxidative stress by modulation of mitochondria. PMID- 27504020 TI - Radionuclide synovectomy - essentials for rheumatologists. AB - Radionuclide synovectomy is a minimally invasive method of treating persistent joint inflammation. It involves intra-articular injection of radioactive colloids which induce necrosis and fibrosis of hypertrophic synovial membrane. The most common indication for radiosynovectomy is rheumatoid arthritis, although patients with seronegative spondyloarthropathies, unclassified arthritis, haemophilic arthropathy and other less common arthropathies can also benefit from this method. Radiosynovectomy is safe, well tolerated and efficacious. About 70-80% of patients respond well to the therapy. However, the therapeutic effects are considerably worse in patients with co-existent osteoarthritis and advanced joint degeneration. Despite its advantages, radionuclide synovectomy is not performed as often as it could be, so greater knowledge and understanding of this method are needed. The authors present the most important facts about radiosynovectomy that may help rheumatologists in their daily clinical practice. PMID- 27504021 TI - Physical activity in the elderly who underwent joint replacement surgery in the course of rheumatic diseases. AB - According to the forecasts of the Central Statistical Office of Poland, in 2030 people at the age of 65 and older will account for 23.8%, i.e. their number will amount to approx. 8.5 m people. Geriatric rheumatic patients more often decide to undergo surgical joint replacement. According to the National Health Fund, the number of joint replacement services provided in 2014 increased by 93%, as compared to 2005. Improving the physical performance of this constantly expanding group of patients requires taking into account many factors to raise their functional status, reduce the risk of falling, teach rules of proper functioning with an artificial joint and encourage unassisted physical activity. Restoring fitness and independence is a difficult but necessary task due to an increasing number of seniors with replaced joint. PMID- 27504022 TI - Rheumatic diseases induced by drugs and environmental factors: the state-of-the art - part one. AB - The majority of rheumatic diseases belong to the group of autoimmune diseases and are associated with autoantibody production. Their etiology is not fully understood. Certain medications and environmental factors may have an influence on the occurrence of rheumatic diseases. Establishing a cause-effect relationship between a certain factor and disease induction is not always simple. It is important to administer the drug continuously or monitor exposure to a given factor in the period preceding the onset of symptoms. The lack of previously diagnosed autoimmune disease, or finally the lack of symptoms within a few weeks/months after discontinuation of the drug/cessation of exposure, is also important. The most frequently mentioned rheumatic diseases caused by drugs and environmental factors include systemic lupus erythematosus, scleroderma, systemic vasculitis, polymyositis, dermatomyositis, and Sjogren's syndrome. The objective of this study is to summarize current knowledge on rheumatic diseases induced by drugs and environmental factors. PMID- 27504023 TI - Cardiovascular risk assessment in rheumatoid arthritis - controversies and the new approach. AB - The current methods of cardiovascular (CV) risk assessment in the course of inflammatory connective tissue diseases are a subject of considerable controversy. Comparing different methods of CV risk assessment in current rheumatoid arthritis (RA) guidelines, only a few of them recommend the use of formal risk calculators. These are the EULAR guidelines suggesting the use of SCORE and the British Society for Rheumatology guidelines performed in collaboration with NICE preferring the use of QRISK-2. Analyzing the latest American and British reports, two main concepts could be identified. The first one is to focus on risk calculators developed for the general population taking into account RA, and the calculator that might fulfill this role is the new QRISK 2 presented by NICE in 2014. The second concept is to create RA-specific risk calculators, such as the Expanded Cardiovascular Risk Prediction Score for RA. In this review we also discuss the efficiency of a new Pooled Cohort Equation and other calculators in the general and RA population. PMID- 27504024 TI - Pachydermodactyly - a report of two cases. AB - Pachydermodactyly (PDD) is a rare and benign form of digital soft tissues fibromatosis, which affects the skin of the fingers. The disorder is characterized by asymptomatic, symmetric, progressive soft tissue swelling of the proximal interphalangeal (PIP) joints of the fingers. The etiology of disease remains unknown. It is usually acquired, even though there are some publications that document family cases. It affects mainly adolescent men. We report two boys with the bilateral swelling of the of the PIP joints of the fingers and skin and subcutaneous tissue thickening. Based on clinical manifestations, radiological study and histopathological examination, pachydermodactyly was diagnosed. PDD is a rare and benign disorder, although it is important to consider other diseases, especially rheumatic conditions, in the differential diagnosis in order to avoid unnecessary additional tests and treatments. PMID- 27504025 TI - The paediatric rheumatologist and orphan disease - a story without happy ending. AB - Orphan diseases are not a common challenge in the everyday practice of the rheumatologist. Despite their extremely rare occurrence one of the patients under our care developed one of them - neuronal ceroid lipofuscinosis, the most frequent neurodegenerative disease observed in the paediatric population. We report a case of 2-year-old girl diagnosed with oligoarticular form of juvenile idiopathic arthritis treated in our Department with steroids and methotrexate and staying in the stage of disease remission. During routine checkups at Outpatient Clinic we observed progressive deterioration of girls neurological condition resulting in ataxia, gait disturbances with no rheumatological cause behind and speech impairment. The appearance of the symptoms was accompanied by frequent episodes of epileptic seizures, with little clinical improvement on combined antiepileptic treatment. Magnetic resonance imaging that we performed showed a picture highly suggestive of neuronal ceroid lipofuscinosis - atrophy of the patients cerebrum and cerebellum. Genetic testing conducted resulted in the diagnosis of late infantile neuronal ceroid lipofuscinosis (LINCL). PMID- 27504026 TI - Rivaroxaban - a safe therapeutic option in patients with antiphospholipid syndrome? Our experience in 23 cases. AB - In the therapeutic approach to patients with antiphospholipid syndrome (APS) with thrombotic manifestations, oral vitamin K antagonists (VKA) remain the standard of care. However, the use of VKA is very often associated with inability to achieve a therapeutic dose even in patients maintaining nutritional and therapeutic restrictions. The non-vitamin-K oral anticoagulants (NOAC) have a lot of advantages, but their efficacy and safety in APS have not been proven. We present 23 patients with APS treated with rivaroxaban in our department. Recurrence of thrombosis was observed only in 1 patient. No major or minor bleeding occurred. It proves the efficacy of treatment with rivaroxaban, but our observations require further prospective, randomized studies. PMID- 27504027 TI - The role of melanin pathways in extremotolerance and virulence of Fonsecaea revealed by de novo assembly transcriptomics using illumina paired-end sequencing. AB - Melanisation has been considered to be an important virulence factor of Fonsecaea monophora. However, the biosynthetic mechanisms of melanisation remain unknown. We therefore used next generation sequencing technology to investigate the transcriptome and digital gene expression data, which are valuable resources to better understand the molecular and biological mechanisms regulating melanisation in F. monophora. We performed de novo transcriptome assembly and digital gene expression (DGE) profiling analyses of parent (CBS 122845) and albino (CBS 125194) strains using the Illumina RNA-seq system. A total of 17 352 annotated unigenes were found by BLAST search of NR, Swiss-Prot, Gene Ontology, Clusters of Orthologous Groups and Kyoto Encyclopedia of Genes and Genomes (KEGG) (E-value <1e-5). A total of 2 283 unigenes were judged to be the differentially expressed between the two genotypes. We identified most of the genes coding for key enzymes involved in melanin biosynthesis pathways, including polyketide synthase (pks), multicopper oxidase (mco), laccase, tyrosinase and homogentisate 1,2-dioxygenase (hmgA). DEG analysis showed extensive down-regulation of key genes in the DHN pathway, while up-regulation was noted in the DOPA pathway of the albino mutant. The transcript levels of partial genes were confirmed by real time RT-PCR, while the crucial role of key enzymes was confirmed by either inhibitor or substrate tests in vitro. Meanwhile, numbers of genes involved in light sensing, cell wall synthesis, morphology and environmental stress were identified in the transcriptome of F. monophora. In addition, 3 353 SSRs (Simple Sequence Repeats) markers were identified from 21 600 consensus sequences. Blocking of the DNH pathway is the most likely reason of melanin deficiency in the albino strain, while the production of pheomelanin and pyomelanin were probably regulated by unknown transcription factors on upstream of both pathways. Most of genes involved in environmental tolerance to oxidants, irradiation and extreme temperatures were also assembled and annotated in transcriptomes of F. monophora. In addition, thousands of identified cSSR (combined SSR) markers will favour further genetic linkage studies. In conclusion, these data will contribute to understanding the regulation of melanin biosynthesis and help to improve the studies of pathogenicity of F. monophora. PMID- 27504028 TI - Take-all or nothing. AB - Take-all disease of Poaceae is caused by Gaeumannomyces graminis (Magnaporthaceae). Four varieties are recognised in G. graminis based on ascospore size, hyphopodial morphology and host preference. The aim of the present study was to clarify boundaries among species and varieties in Gaeumannomyces by combining morphology and multi-locus phylogenetic analyses based on partial gene sequences of ITS, LSU, tef1 and rpb1. Two new genera, Falciphoriella and Gaeumannomycella were subsequently introduced in Magnaporthaceae. The resulting phylogeny revealed several cryptic species previously overlooked within Gaeumannomyces. Isolates of Gaeumannomyces were distributed in four main clades, from which 19 species could be delimited, 12 of which were new to science. Our results show that the former varieties Gaeumannomyces graminis var. avenae and Gaeumannomyces graminis var. tritici represent species phylogenetically distinct from G. graminis, for which the new combinations G. avenae and G. tritici are introduced. Based on molecular data, morphology and host preferences, Gaeumannomyces graminis var. maydis is proposed as a synonym of G. radicicola. Furthermore, an epitype for Gaeumannomyces graminis var. avenae was designated to help stabilise the application of that name. PMID- 27504029 TI - Active Patient Engagement: Long Overdue in Rehabilitation Research. PMID- 27504030 TI - Association between Neuropathic Pain and Reported Disability after Total Knee Arthroplasty. AB - PURPOSE: To determine whether reporting neuropathic pain (NP) at an average of 5 years after total knee arthroplasty (TKA) was related to patient age, sex, preoperative comorbidity, arthritis self-efficacy, or disability before surgery and at 1 year after surgery. The estimate of NP prevalence and cross-sectional group differences were explored at 5 years after surgery. METHODS: A subsample of participants in a formal research study was contacted via mail approximately 5 years after undergoing surgery and were sent four questionnaires: the Western Ontario and McMaster Universities Osteoarthritis Index, the Patient Health Questionnaire, the Self-Administered Leeds Assessment of Neuropathic Signs and Symptoms (S-LANSS), and a satisfaction questionnaire. NP was defined as an S LANSS score of 12 or more. RESULTS: Of 89 patients who met the inclusion criteria, data for 63 (71%) patients (47 women; mean age 67 [SD 8] y) were used for analysis. Of these 63, 9 (14%) were identified as having NP. None had a report of failure of prosthesis or other surgical complications according to most recent medical records. There was no relationship between preoperative patient characteristics and development of NP. However, the NP group on average had a higher report of stiffness (p=0.020), physical dysfunction (p=0.019), and pain (p=0.050) at 1 year after surgery. Cross-sectional comparisons showed higher levels of pain (p=0.001), stiffness (p=0.008), physical dysfunction (p=0.003), and depression (p=0.005) and lower satisfaction (p=0.018) at the time of the survey than the patients without NP. CONCLUSION: The estimated prevalence of NP was 14%. Patients with NP reported higher levels of disability as early as 1 year after surgery. They remained more disabled, with a higher level of depression and less satisfaction, at an average of 5 years after surgery. PMID- 27504031 TI - Effects of Autogenic Drainage on Sputum Recovery and Pulmonary Function in People with Cystic Fibrosis: A Systematic Review. AB - PURPOSE: To determine the effects of short- and long-term use of autogenic drainage (AD) on pulmonary function and sputum recovery in people with cystic fibrosis (CF). METHODS: The authors conducted a systematic review of randomized and quasi-randomized clinical trials in which participants were people with CF who use AD as their sole airway clearance technique. RESULTS: Searches in 4 databases and secondary sources using 5 key terms yielded 735 articles, of which 58 contained the terms autogenic drainage and cystic fibrosis. Ultimately, 4 studies, 2 of which were long term, were included. All measured forced expiratory volume in 1 second (FEV1) and found no change. The long-term studies were underpowered to detect change in FEV1; however, the short-term studies found a clinically significant sputum yield (>=4 g). CONCLUSION: AD has been shown to produce clinically significant sputum yields in a limited number of investigations. The effect of AD on the function of the pulmonary system remains uncertain, and questions have emerged regarding the appropriateness of FEV1 as a valid measure of airway clearance from peripheral lung regions. Further consideration should be given to the use of FEV1 as a primary measure of the effect of AD. PMID- 27504032 TI - Factors Affecting Length of Stay in Adult Outpatient Physical Rehabilitation: A Scoping Review of the Literature. AB - PURPOSE: To identify factors affecting length of stay (LOS) for adults participating in outpatient physical or occupational therapy programmes. METHOD: A scoping review of the literature was conducted using the Ovid MEDLINE, EMBASE, CINAHL, AMED, and Cochrane Library databases. RESULTS: A total of 19 articles were retained from the search, and 2 additional articles were retrieved from grey literature (i.e., non-published sources). Personal factors affecting LOS are age and sex, both of which had inconsistent effects on LOS, and communication, language, physical, and cognitive difficulties, for which higher levels of function were generally associated with shorter LOS. Institutional factors affecting LOS were location, interdisciplinary communication, number of disciplines involved, and type of rehabilitation setting. Finally, two clinician related factors-fewer treatment goals and a selection of evidence-informed treatment techniques-were associated with shorter LOS. CONCLUSIONS: Research on factors affecting adult outpatient rehabilitation LOS is limited and inconsistent. A preliminary list of LOS factors was produced, but this topic should be further explored with the collaboration of researchers and clinical institutions. PMID- 27504033 TI - What Makes a Leader: Identifying the Strengths of Canadian Physical Therapists. AB - PURPOSE: To identify the personal strengths of Canadian physical therapists who hold leadership positions and compare them with the strengths of Canadian physical therapists who do not occupy positions of leadership. METHODS: A quantitative, cross-sectional online survey was distributed to registered Canadian physical therapists. We used the Clifton StrengthsFinder to evaluate 34 characteristics and determine which characteristics described a participant's strengths. Population demographics and leadership strengths were described via frequency distributions and percentages; chi-square analyses and Fisher's exact tests were used to compare differences between groups. RESULTS: Of 173 physical therapists who completed the survey, 108 occupied a position of leadership, and 65 did not. Those in the leader group had significantly more experience and achieved a higher level of education. Leaders most frequently exhibited the strengths of learner, achiever, responsibility, input, and strategic, whereas non leaders most frequently displayed strengths of learner, achiever, input, relator, and harmony. Leaders were significantly more likely than non-leaders to possess the achiever strength. Gender, level of education, and years of experience did not significantly influence which strengths were present in the leadership profile. CONCLUSIONS: There is substantial overlap between leaders and non leaders in terms of leadership profiles. Future research should investigate whether leadership strengths vary depending on the leadership position occupied and whether leadership development initiatives promote leadership strengths. PMID- 27504034 TI - The Group Experience: Remodelling Outpatient Physiotherapy after Knee Replacement Surgery. AB - Purpose : To estimate responses to short-duration (4-6 weeks) group-based physiotherapy after knee replacement in terms of pain, function, and satisfaction. METHOD: The study used a prospective, observational design. A total of 169 participants (111 women, 58 men) were consecutively recruited to attend a twice-weekly post-operative knee replacement class focused on mobility, strength, balance, and functional retraining. Changes in pain, function, and satisfaction were measured using the P4 pain intensity measure, the Lower Extremity Functional Scale (LEFS), a timed stair test (TST), knee range of motion (ROM), the Patient Specific Functional Scale (PSFS), and the Client Satisfaction Questionnaire (CSQ 8). Using Stata version 12.1, the data were summarized descriptively, and change scores were calculated with 95% CIs. Results : On average, participants were discharged within 11 classes, having achieved their treatment goals. More than 77% exceeded the minimal detectable change at the 90% confidence level (MDC90) on the LEFS, TST, PSFS, and ROM assessments. The mean CSQ-8 score at discharge was 31.8 (SD 1.46); 66.7% recorded a perfect score of 32. Conclusions : Patients attending a short group-based outpatient knee replacement class demonstrated significant improvements in pain and lower extremity function and were highly satisfied with their physiotherapy treatment. PMID- 27504035 TI - Using Outcome Measures in Daily Practice: Development and Evaluation of an Implementation Strategy for Physiotherapists in the Netherlands. AB - PURPOSE: To describe the development of an educational programme for physiotherapists in the Netherlands, two toolkits of measurement instruments, and the evaluation of an implementation strategy. METHOD: The study used a controlled pre- and post-measurement design. A tailored educational programme for the use of outcome measures was developed that consisted of four training sessions and two toolkits of measurement instruments. Of 366 invited physiotherapists, 265 followed the educational programme (response rate 72.4%), and 235 randomly chosen control physiotherapists did not (28% response rate). The outcomes measured were participants' general attitude toward measurement instruments, their ability to choose measurement instruments, their use of measurement instruments, the applicability of the educational programme, and the changes in physiotherapy practice achieved as a result of the programme. RESULTS: Consistent (not occasional) use of measurement instruments increased from 26% to 41% in the intervention group; in the control group, use remained almost the same (45% vs 48%). Difficulty in choosing an appropriate measurement instrument decreased from 3.5 to 2.7 on a 5-point Likert-type scale. Finally, 91% of respondents found the educational programme useful, and 82% reported that it changed their physiotherapy practice. CONCLUSIONS: The educational programme and toolkits were useful and had a positive effect on physiotherapists' ability to choose among many possible outcome measures. PMID- 27504036 TI - An Evidence-Based Case Study of Unilateral Shin Splints: Do Red Flags Function in Paediatric Osteosarcoma? AB - Physiotherapists use red flags to screen for serious pathology. Paediatric osteosarcoma is a rare disease, occurring predominantly in the area of the knee and shoulder, and it is not always included by physiotherapists on a differential diagnosis list. Traditional red flags do not always correspond to the initial signs and symptoms of osteosarcoma. Physiotherapists should routinely palpate along the length of the bone to detect a potential mass. The detection of a mass or symptoms that do not follow the expected course indicates the need for reassessment and possibly referral for further investigation. PMID- 27504037 TI - Characteristics of People with Hip or Knee Osteoarthritis Deemed Not Yet Ready for Total Joint Arthroplasty at Triage. AB - PURPOSE: To identify the characteristics of people with hip or knee osteoarthritis (OA) attending a regional triage centre for an initial consult who are deemed not yet ready for total joint arthroplasty (TJA). METHODS: Initial consultation notes (n=482) were reviewed retrospectively. Predictive variables were derived from the literature a priori, and 14 of these variables were suitable for inclusion in stepwise multiple logistic regression analyses. RESULTS: Of the 222 eligible people, 131 (59%) were deemed not yet ready for TJA. Five variables entered into the model ([Formula: see text]=133.19, p<0.001) for an overall success rate of 81.1%. Those deemed not yet ready for TJA were more likely to have knee OA (vs. hip OA; odds ratio [OR]=0.352, p=0.018), to have less severe OA (OR=0.246 for each category increase in severity, p<0.001), to use no gait aid (vs. cane; OR=0.390, p=0.033), and to have a higher Lower Extremity Functional Scale score (OR=1.050 for each 1-point increase, p=0.003) and better joint status as measured by the Knee Society Scale or Hip Harris Scale (OR=3.946 for each category increase, p=0.007). CONCLUSION: Considering these characteristics will help clinicians to identify individuals likely to require interventions other than TJA. PMID- 27504038 TI - Standardized Patients versus Volunteer Patients for Physical Therapy Students' Interviewing Practice: A Pilot Study. AB - PURPOSE: To compare the use of standardized patients (SPs) and volunteer patients (VPs) for physical therapy students' interviewing practice in terms of students' perception and overall costs. METHODS: Students in the Master of Physical Therapy programme (n=80) at a Canadian university were divided into 20 groups of 4 and were randomly assigned to interview either an SP (10 groups) or a VP (10 groups). Students completed a survey about their perception of the usefulness of the activity and the ease and depth of information extraction. Survey responses as well as costs of the interview exercise were compared between SP and VP groups. RESULTS: No statistically significant between-groups difference was found for the majority of survey items. The cost of using an SP was $148, versus $50 for a VP. CONCLUSIONS: Students' perceptions of the usefulness of the activity in helping them to develop their interview skills and of the ease and depth of extracting information were similar for both SPs and VPs. Because the cost of using an SP is about three times that of using a VP, using VPs seem to be a more cost-effective option. PMID- 27504039 TI - Enhanced Patient-Centred Care: Physiotherapists' Perspectives on the Impact of International Clinical Internships on Canadian Practice. AB - PURPOSE: To explore the perspectives of physiotherapists who participated in an international clinical internship (ICI) in low- or middle-income countries (LMICs) during their physiotherapy (PT) training in a Canadian PT programme regarding the ICI's impact on their PT practice in Canada. METHODS: This qualitative descriptive study used in-depth semi-structured interviews. Data were organized using NVivo; inductive and deductive coding were used to analyze data and develop broader themes. RESULTS: The 13 practising Canadian physiotherapists interviewed described three enhanced capacities: (1) critical reflection on culture, values and practice; (2) communication skills; and (3) creativity and resourcefulness. These capacities were perceived to transfer to Canadian practice by enhancing participants' ability to deliver patient-centred care, specifically through an enhanced understanding of patients' values and social determinants of health, regardless of the Canadian setting or patient population. CONCLUSIONS: For PT students considering an ICI, the study findings provide insight into the perceived impact of ICIs on Canadian practice. For PT academic programmes, the findings can guide decisions on the extent of investment in ICIs as learning opportunities that will enhance practice in Canada. PMID- 27504040 TI - What Does the Cochrane Collaboration Say about the Effectiveness of Chest Physiotherapy in Respiratory Conditions? PMID- 27504041 TI - Cultural Humility: A Way of Thinking to Inform Practice Globally. PMID- 27504042 TI - Current Uses (and Potential Misuses) of Facebook: An Online Survey in Physiotherapy. AB - PURPOSE: In recent years, the use of social media such as Facebook has become extremely popular and widespread in our society. Among users are health care professionals, who must develop ways to extend their professionalism online. Before issuing formal guidelines, policies, or recommendations to guide online behaviours, there is a need to know to what extent Facebook influences the professional life of physiotherapy professionals. Our goal was to explore knowledge and behaviour that physiotherapists and physical rehabilitation therapists practicing in Quebec have of Facebook. METHOD: We used an empirical cross-sectional online survey design (n=322, response rate 4.5%). RESULTS: The results showed that 84.3% of physiotherapy professionals had a Facebook account. Almost all had colleagues or former colleagues as Facebook friends, 21% had patients as friends, and 27% had employers as friends. More than a third of workplaces had clinic pages with information intended for the public. Regarding workplace Facebook policies, 37.3% said that there was no policy and another 41.6% were not aware whether there was one or not. CONCLUSION: There appears to be a need to establish guidelines regarding the use of social media for physiotherapy professionals to ensure maintenance of professionalism and ethical conduct. PMID- 27504043 TI - Validity of the Handheld Dynamometer Compared with an Isokinetic Dynamometer in Measuring Peak Hip Extension Strength. AB - PURPOSE: To determine whether the handheld dynamometer (HHD) is an appropriate tool to assess and quantify peak hip extension strength in prone standing position by (1) evaluating the concurrent validity of the HHD versus an isokinetic dynamometer (IKD), (2) establishing the minimal detectable change (MDC), and (3) determining the validity of single-trial versus multi-trial measures. METHOD: A convenience sample of 20 healthy adults was recruited for this cross-sectional study. Measures of peak hip extension strength were collected in prone standing position with both the HHD and the IKD and in supine position with the IKD. RESULTS: Values of r were 0.37 for HHD versus IKD prone standing and 0.51 for HHD versus IKD supine. MDC was 14.8 Nm for the HHD, 25.6 Nm for IKD prone standing, and 41.5 Nm for IKD supine. High correlations (r values of 0.92-0.94) were observed between trial 1 and the mean of three trials. CONCLUSIONS: The HHD has moderate concurrent validity in measuring peak hip extension strength in the prone standing position in healthy adults. MDC for hip extension strength was lowest using the HHD. Single-trial values showed a high correlation with three-trial mean values. PMID- 27504044 TI - Shoulder Retractor Strengthening Exercise to Minimize Rhomboid Muscle Activity and Subacromial Impingement. AB - PURPOSE: We investigated the best position for shoulder retractor strengthening exercise to maximize middle trapezius activity and minimize rhomboid major activity. Although both trapezius and rhomboids are scapular retractors, rhomboids also act as downward rotators of the scapula, which can worsen subacromial impingement. METHODS: Twelve healthy participants (age 30 [SD 6] y) with no history of shoulder pain were recruited for this study, which used fine wire electromyography to examine maximal muscle activation of the middle trapezius and rhomboid major muscle fibres in four different positions: with the shoulder in 90 degrees abduction with elbow completely extended and (1) shoulder internal rotation, (2) shoulder neutral rotation, (3) shoulder external rotation, and (4) rowing (shoulder neutral rotation and elbow flexed 90 degrees ). The ratio of trapezius to rhomboid muscles was compared with Wilcoxon signed-rank tests. RESULTS: Muscle activation ratio during shoulder retraction exercise was significantly lower by 22% (i.e., rhomboid was more active than middle trapezius) when performed with the shoulder in rowing position (elbow flexed) than with the shoulder in external rotation (elbow extended) position (p=0.031). All four positions produced coactivation of trapezius and rhomboids. DISCUSSION: Rowing position may not be the best position for shoulder retractor strengthening in patients with impingement syndrome. The preferable position for maximizing middle trapezius activity and minimizing rhomboid activity may be shoulder external rotation with elbow extended. PMID- 27504045 TI - A Roland Morris Disability Questionnaire Target Value to Distinguish between Functional and Dysfunctional States in People with Low Back Pain. AB - PURPOSE: To estimate a threshold Roland Morris Disability Questionnaire (RMQ) value that could be used to classify patients with low back pain (LBP) as functional or dysfunctional. METHODS: In this secondary analysis of data from a study that estimated clinically important RMQ change scores, participants were adults with LBP attending one of three physical therapy clinics. Diagnostic test methodology and a reference standard of goals met were applied to estimate a threshold RMQ value that best distinguished between participants with a functional status and those whose status was dysfunctional. RESULTS: Of 143 participants, 104 (73%) met their goals. An RMQ threshold value of 4/24 best distinguished between those who met their goals and those who did not. Sensitivity and specificity for a threshold score of 4 were 94% (95% CI, 88-98) and 69% (95% CI, 52-83), respectively. CONCLUSIONS: A threshold value of 4 RMQ points provided a reasonably accurate classification of patients. Further research is necessary to cross-validate this estimate and to examine the stability of the estimated value in people with diverse functional demands. PMID- 27504046 TI - Promoting Physical Activity and Exercise in Daily Practice: Current Practices, Barriers, and Training Needs of Physiotherapists in Eastern Nigeria. AB - PURPOSE: To investigate current practices, barriers, and training needs for the promotion of physical activity (PA) in physiotherapy practices in eastern Nigeria. METHODS: A total of 141 fully licensed physiotherapists in southeast Nigeria were invited to participate in a cross-sectional survey consisting of 23 questions in five key sections, focusing mainly on risk-factor management practices of physiotherapists. RESULTS: A total of 103 questionnaires were returned. Respondents ranged in age from 25 to 54 years and reported a mean of 11 (SD 10) years of clinical experience. Respondents reported that they regularly assess and advise their clients on PA but rarely give written prescriptions. Although they are confident in assessing and advising their clients on PA and consider including PA intervention as a priority in daily practice, lack of time and lack of access to materials were reported as barriers to effective PA intervention. CONCLUSION: Findings showed the potential for physiotherapists to address physical inactivity and highlighted several barriers. Strategies are needed to improve contact time with clients and make material promoting PA available to practising physiotherapists. PMID- 27504047 TI - Correlation between Limb Muscle Endurance, Strength, and Functional Capacity in People with Chronic Obstructive Pulmonary Disease. AB - PURPOSE: To examine the correlation between limb muscle function (endurance and strength) and functional capacity in upper limbs (ULs) and lower limbs (LLs) of people with chronic obstructive pulmonary disease (COPD). METHOD: This article describes a secondary analysis of data from a randomized controlled trial. A stationary dynamometer was used to measure isokinetic muscle strength and endurance; the 6-minute walk test, the 6-minute pegboard and ring test, and the unsupported UL exercise test were used to measure functional capacity. RESULTS: Participants were 44 adults with COPD. Muscle strength and endurance in ULs and LLs demonstrated a moderate to strong correlation with functional capacity. When controlling for muscle strength, muscle endurance was moderately correlated with functional capacity in ULs and LLs, but when controlling for muscle endurance, there was no positive and significant correlation between muscle strength and functional capacity for the ULs or LLs. CONCLUSIONS: Functional capacity seems to be more closely related to limb muscle endurance than to limb muscle strength in people with COPD. PMID- 27504048 TI - Leadership in Physical Therapy: Characteristics of Academics and Managers: A Brief Report. AB - PURPOSE: To explore the characteristics of physical therapy leaders in academic and managerial roles. METHODS: This quantitative, cross-sectional study used an online questionnaire administered via email to Canadian physical therapists recruited through the Canadian Physiotherapy Association and via additional emails targeted to academic and health care institutions. Individuals who met the inclusion criteria after completion of the questionnaire were asked to complete the Clifton StrengthsFinder, which was used to objectively assess the extent to which participants exhibited personality characteristics. We calculated frequencies for demographic characteristics and the 10 most prominent characteristics for participants in academic and managerial roles. RESULTS: A total of 88 participants completed the questionnaire (52 managers, 36 academics). The most prevalent strengths among both academics and managers were the learner and achiever characteristics. CONCLUSIONS: Academics and managers in physical therapy share similar core characteristics, with slight variations in secondary characteristics. PMID- 27504049 TI - Mechanical Low Back Pain: Secular Trend and Intervention Topics of Randomized Controlled Trials. AB - PURPOSE: To evaluate the number of published randomized controlled trials (RCTs) focusing on mechanical low back pain (MLBP) rehabilitation, the secular (i.e., long-term) trend, and the distribution of interventions studied. METHODS: All included RCTs were extracted from all Cochrane systematic reviews focusing on rehabilitation therapies for MLBP, and two independent reviewers screened and analyzed the information on interventions. RESULTS: After removal of duplicates, the data set consisted of 196 RCTs published between 1961 and 2010. The number of RCTs published increased consistently over time: 2 trials (1% of the total) were published in 1961-1970, 10 (5%) in 1971-1980, 41 (21%) in 1981-1990, 68 (35%) in 1991-2000, and 75 (38%) in 2001-2010. The intervention of interest in the majority of RCTs was exercise therapy (115/399; 29%), followed by spinal manipulation therapies (60/399; 15%). CONCLUSION: The number of RCTs focusing on MLBP has risen over time; of all interventions studied, exercise therapy has attracted the most research interest. PMID- 27504050 TI - Canadian Physiotherapy Assessment of Clinical Performance: Face and Content Validity. AB - PURPOSE: To investigate face and content validity of a draft measure to be used across Canada to assess physiotherapy students' performance in clinical education, through broad consultation with physiotherapy clinical instructors (CIs) across Canada. METHODS: An online survey was used to collect input on the draft measure. In addition to demographics, the questionnaire included questions on the preferred rating scale, the items within the measure that should have their own rating scale, and general impressions. RESULTS: Among the 259 CIs who completed the survey, a discrete rating scale with six anchors and 10 boxes or a continuous-line rating scale with six anchors was preferred. Respondents favoured using one rating scale for each key competency in the Expert role but considered a single rating scale sufficient for assessing the Scholarly Practitioner role. CIs agreed that the proposed measure would allow them to assess a student who was performing poorly or very well. The name Canadian Physiotherapy Assessment of Clinical Performance (ACP) received the most votes in the questionnaire. CONCLUSIONS: CIs' collective preferences on the design, organization, and naming of the measure they will use in evaluating students are reflected in the second draft of the ACP. PMID- 27504051 TI - Diminishing Effect Sizes with Repeated Exposure to Evidence-Based Practice Training in Entry-Level Health Professional Students: A Longitudinal Study. AB - PURPOSE: To investigate the magnitude of change in outcomes after repeated exposure to evidence-based practice (EBP) training in entry-level health professional students. METHOD: Using an observational cross-sectional analytic design, the study tracked 78 students in physiotherapy, podiatry, health science, medical radiations, and human movement before and after two sequential EBP courses. The first EBP course was aimed at developing foundational knowledge of and skills in the five steps of EBP; the second was designed to teach students to apply these steps. Two EBP instruments were used to collect objective (actual knowledge) and self-reported (terminology, confidence, practice, relevance, sympathy) data. Participants completed both instruments before and after each course. RESULTS: Effect sizes were larger after the first course than after the second for relevance (0.72 and 0.26, respectively), practice (1.23 and 0.43), terminology (2.73 and 0.84), and actual knowledge (1.92 and 1.45); effect sizes were larger after the second course for sympathy (0.03 and 0.14) and confidence (0.81 and 1.12). CONCLUSIONS: Knowledge and relevance changed most meaningfully (i.e., showed the largest effect size) for participants with minimal prior exposure to training. Changes in participants' confidence and attitudes may require a longer time frame and repeated training exposure. PMID- 27504052 TI - Boys, Transitions, and Physical (In)activity: Exploring the Socio-Behavioural Mediators of Participation. AB - PURPOSE: To explore the socio-behavioural mechanisms that motivate or dissuade boys' participation in physical activity (PA) as they transition into adolescence and their implications for physical therapy. METHODS: This critical qualitative study involved in-depth interviews using active interviewing techniques with 15 adolescent boys. Data generation and analysis were driven by techniques of grounded theory and Bourdieu's sociology of practice. RESULTS: The analysis identified intersectional relationships among emotions, the inherent pleasures of movement, and a sense of connectedness to PA, each of which acted as a mediating mechanism in motivating participation in PA. Analogously, body dissatisfaction, negative self-perceptions, and repeated instances of explicit and symbolic bullying intersected to dissuade boys from participating and created apathy toward PA. CONCLUSION: Identifying socio-behavioural mechanisms that motivate or dissuade physically active behaviour contributes new knowledge toward understanding PA attrition among boys transitioning to adolescence. As health advocates and movement experts, physiotherapists have an important role in helping adolescents of all abilities to participate in activities that provide them with meaning, inclusivity, and a sense of connectedness to PA. PMID- 27504053 TI - What Does the Cochrane Collaboration Say about Interventions to Promote Physical Activity? PMID- 27504054 TI - The Efficacy and Safety of Antipsychotic Medications in the Treatment of Psychosis in Patients with Parkinson's Disease. AB - Psychotic symptoms are present in up to 50% of patients with Parkinson's disease. These symptoms have detrimental effects on patients' and caregivers' quality of life and may predict mortality. The pathogenesis of psychotic symptoms in Parkinson's disease is complex, but the use of dopaminergic medications is one of the risk factors. The treatment of psychotic symptoms in Parkinson's disease is complicated due to the ability of antipsychotic medications to worsen motor symptoms. The efficacy of clozapine in the treatment of psychosis in patients with Parkinson's disease has been confirmed in several clinical trials; however, the adverse effects and the necessity of blood count monitoring are the reasons why the use of this drug is challenging. The studies on safety and efficacy of other antipsychotics conflicting results. The use of antipsychotics in these patients is also associated with increased mortality. Psychotic symptoms in Parkinson's disease per se are also proven predictors of mortality. Thus it is necessary to treat psychotic symptoms but the choice of an antipsychotic should be based on careful risk/benefit assessment. Pimavanserin as a novel therapeutic option with more favorable adverse effects profile is now available for this indication, but careful postmarketing monitoring is necessary to establish the true picture of this drug's long-term safety and efficacy. PMID- 27504055 TI - 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-glucoside Isolated from Polygoni Multiflori Ameliorates the Development of Periodontitis. AB - Periodontitis, a chronic infection by periodontopathic bacteria, induces uncontrolled inflammation, which leads to periodontal tissue destruction. 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-glucoside (THSG), a polyphenol extracted from Polygoni Multiflori, reportedly has anti-inflammatory properties. In this study, we investigated the mechanisms of THSG on the Porphyromonas gingivalis induced inflammatory responses in human gingival fibroblasts and animal modeling of ligature-induced periodontitis. Human gingival fibroblast cells were treated with lipopolysaccharide (LPS) extracted from P. gingivalis in the presence of resveratrol or THSG to analyze the expression of TNF-alpha, IL-1beta, and IL-6 genes. Increased AMP-activated protein kinase (AMPK) activation and SirT1 expression were induced by THSG. Treatment of THSG decreased the expression of LPS-induced inflammatory cytokines, enhanced AMPK activation, and increased the expression of SirT1. In addition, it suppressed the activation of NF-kappaB when cells were stimulated with P. gingivalis LPS. The anti-inflammatory effect of THSG and P. Multiflori crude extracts was reproduced in ligature-induced periodontitis animal modeling. In conclusion, THSG inhibited the inflammatory responses of P. gingivalis-stimulated human gingival fibroblasts and ameliorated ligature-induced periodontitis in animal model. PMID- 27504056 TI - A radiographic simulation study of fixed superior pubic ramus fractures with retrograde screw insertion. AB - OBJECTIVES: The study's aim is to calculate the parameters for retrograde insertion points for fixed superior pubic ramus fractures. METHODS: From the pubic symphysis, diameter and length of the screw were measured, as well as the angle between the screw axis and the 3 planes. RESULTS: When the diameter was fixed at 4.5 mm, the maximum lengths were 125 mm and 119 mm. CONCLUSIONS: When the fracture occurs in Zone I, the penetration point could be selected in the pubic symphysis pubis angle to ensure that medial fracture fragments have sufficient screw channel length. PMID- 27504057 TI - Radiographic and functional evaluation of low profile dorsal versus volar plating for distal radius fractures. AB - INTRODUCTION: Fracture of the distal radius is a common clinical problem. Complex fracture requires open reduction and stabilization with plating to restore anatomy. Dorsal plating has advantages of buttressing the fracture better but often complicated with tendon problems as per literature. The rate of complications however, was not compared between the low-profile dorsal and the volar plates. METHODOLOGY: This was a retrospective study on seventy one patients with dorsally angulated or displaced distal radius fractures, who underwent fixation of fractures with either dorsal or volar locking plate from Jan - Nov 2012. Preoperative radiographs were classified based on Universal and Fernandez classification. Postoperative radiographs were assessed for anatomical restoration of Radial length, radial inclination and volar tilt. Tendon and nerve related complications were assessed and functional evaluation was performed on the basis of PRWE (Patient related wrist evaluation) score. RESULTS: Both groups were matched for their demographic profile and fracture types (p 0.033). Dorsal plating group had 89% excellent/good restoration and fair in 11%. Volar group had 96% excellent/good restoration and fair in 4%. Statistical analysis was performed with unpaired t test for radiographic parameters. Three patients had tendon related complications in dorsal plating group; two patients in volar group had nerve related complications. Functional outcome with PRWE was comparable between two groups. CONCLUSION: Results with low profile dorsal plating were comparable to volar plating. Therefore dorsal plating can be used as an alternative method when dorsal buttressing of comminuted fracture is required, especially with concomitant osteoporosis. PMID- 27504058 TI - The epidemiology of thoracolumbar trauma: A meta-analysis. AB - PURPOSE: To describe the epidemiology of thoracolumbar fractures and associated injuries in blunt trauma patients. METHODS: A systematic review and metaanalysis was performed based on a MEDLINE database search using MeSH terms for studies matching our inclusion criteria. The search yielded 21 full-length articles, each sub-grouped according to content. Data extraction and multiple analyses were performed on descriptive data. RESULTS: The rate of thoracolumbar fracture in blunt trauma patients was 6.90% (+/-3.77, 95% CI). The rate of spinal cord injury was 26.56% (+/-10.70), and non-contiguous cervical spine fracture occurred in 10.49% (+/-4.17). Associated injury was as follows: abdominal trauma 7.63% (+/ 9.74), thoracic trauma 22.64% (+/-13.94), pelvic trauma 9.39% (+/-6.45), extremity trauma 18.26% (+/-5.95), and head trauma 12.96% (+/-2.01). Studies that included cervical spine fracture with thoracolumbar fracture had the following rates of associated trauma: 3.78% (+/-5.94) abdominal trauma, 21.65% (+/-16.79) thoracic trauma, 3.62% (+/-1.07) pelvic trauma, 18.36% (+/-4.94) extremity trauma, and 15.45% (+/-11.70) head trauma. A subgroup of flexion distraction injuries showed an associated intra-abdominal injury rate of 38.70% (+/-13.30). The most common vertebra injured was L1 at a rate of 34.40% (+/-15.90). T7 was the most common non-junctional vertebra injured at 3.90% (+/-1.09). Burst/AO type A3 fractures were the most common morphology 39.50% (+/-16.30) followed by 33.60% (+/-15.10) compression/AO type A1, 14.20% (+/-8.08) fracture dislocation/AO type C, and 6.96% (+/-3.50) flexion distraction/AO type B. The most common etiology for a thoracolumbar fracture was motor vehicle collision 36.70% (+/-5.35), followed by high-energy fall 31.70% (+/-6.70). CONCLUSIONS: Here we report the incidence of thoracolumbar fracture in blunt trauma and the spectrum of associated injuries. To our knowledge, this paper provides the first epidemiological road map for blunt trauma thoracolumbar injuries. PMID- 27504059 TI - Total hip arthroplasty in patients with haemophilia - What are the risks of bleeding in the immediate peri-operative period? AB - BACKGROUND: Undergoing a major surgical intervention such as total hip arthroplasty (THA) with an underlying clotting disorder like haemophilia poses its own unique challenges. Despite the advances in factor replacement and medical management, the potential for excessive and uncontrolled haemorrhage still exists. The aim of this study was to quantify blood loss, peri-operative transfusion requirements and risk of haematoma formation in a cohort of patients with haemophilia undergoing THA. METHODS: All patients with haemophilia types A or B who had undergone THA in the previous 10 years were identified from the Hospital In-Patient Enquiry system and theatre logs. A comprehensive review of operative records, laboratory parameters and peri-operative haematological management was conducted. RESULTS: Eleven male patients (12 THA) were identified. The mean age was 56 years (range 28-76). The mean intra-operative blood loss was 502 ml (100-1250 ml) compared to an established normal blood loss of 400 ml. The mean drop in haemoglobin was 3.25 g/dl in 48 h. Only one patient required a post operative transfusion of two units of red cell concentrate. There were no complications of haematoma formation. CONCLUSION: The results in our institution compare favourably with the established blood loss reported in the literature and by assessment with International Guidelines. Average blood loss in patients with haemophilia was higher than the established normal, but there was no increased transfusion requirement. PMID- 27504060 TI - Death and Neurological Devastation From Intrathecal Vinca Alkaloids. AB - Inadvertent intrathecal vincristine administration causes fatalities. PMID- 27504062 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 27504061 TI - Compounding Pharmacists Unhappy With New FDA Guidance Documents : Rules Severely Limit Distribution. AB - Recent FDA compounding guidances raise hackles. PMID- 27504063 TI - Pharmaceutical Approval Update. AB - Venetoclax (Venclexta) for chronic lymphocytic leukemia; riboflavin 5'-phosphate solutions (Photrexa Viscous and Photrexa) for progressive keratoconus; and pimavanserin (Nuplazid) for Parkinson's disease psychosis. PMID- 27504064 TI - Ceftazidime-Avibactam (Avycaz): For the Treatment of Complicated Intra-Abdominal and Urinary Tract Infections. AB - Ceftazidime-avibactam (Avycaz) for the treatment of complicated infections. PMID- 27504065 TI - Congress and Federal Agencies Address Opioid Abuse Epidemic, But Will New Initiatives Be Successful? AB - In response to the alarming rate of opioid overdose deaths in the U.S., the President, Congress, and federal agencies are making efforts to reduce the number of fatalities. PMID- 27504066 TI - Immunization in the United States: Recommendations, Barriers, and Measures to Improve Compliance: Part 2: Adult Vaccinations. AB - Despite annual recommendations, American adults remain inadequately vaccinated. The author outlines how compliance may be improved through health care professional interventions, as well as government and community-based programs. PMID- 27504067 TI - An Annual Formulary Review Strategy Implemented by a Saudi Health System. AB - As in the U.S., there is no unified national formulary in Saudi Arabia, so individual institutions must develop their own medication lists. A Saudi health system's strategy for maintaining formulary safety, efficacy, and cost effectiveness is described. PMID- 27504068 TI - European League Against Rheumatism And American Diabetes Association. AB - We present EULAR sessions on the latest treatments for rheumatic disease with an infliximab biosimilar, certolizumab pegol, secukinumab, and bimekizumab. We also report on significant developments in diabetes presented at ADA's Scientific Sessions. PMID- 27504069 TI - Launch of Breakthrough Therapies Will Reshape Renal Cell Carcinoma Market. AB - Tyrosine kinase inhibitors (TKIs) are leading systemic therapies for the treatment of renal cell carcinoma. However, programmed death-1 inhibitors, promising new agents in development, may surpass TKIs as the standard of care in the future. PMID- 27504070 TI - Research Briefs. PMID- 27504072 TI - Microstructure and Mechanical Properties of Microwave Sintered ZrO2 Bioceramics with TiO2 Addition. AB - The microwave sintered zirconia ceramics with 0, 1, 3, and 5 wt% TiO2 addition at a low sintering temperature of 1300 degrees C and a short holding time of 1 hour were investigated. Effect of contents of TiO2 addition on microstructure and mechanical properties of microwave sintered zirconia bioceramics was reported. In the sintered samples, the main phase is monoclinic zirconia (m-ZrO2) phase and minor phase is tetragonal zirconia (t-ZrO2) phase. The grain sizes increased with increasing the TiO2 contents under the sintering temperature of 1300 degrees C. Although the TiO2 phase was not detected in the XRD pattern, Ti and O elements were detected in the EDS analysis. The presence of TiO2 effectively improved grain growth of the ZrO2 ceramics. The Vickers hardness was in the range of 125 to 300 Hv and increased with the increase of TiO2 contents. Sintering temperature dependence on the Vickers hardness was also investigated from 1150 degrees C to 1300 degrees C, showing the increase of Vickers hardness with the increase of the sintering temperature as well as TiO2 addition. PMID- 27504071 TI - Management of HIV Infection during Pregnancy in the United States: Updated Evidence-Based Recommendations and Future Potential Practices. AB - All HIV-infected women contemplating pregnancy should initiate combination antiretroviral therapy (cART), with a goal to achieve a maternal serum HIV RNA viral load beneath the laboratory level of detection prior to conceiving, as well as throughout their pregnancy. Successfully identifying HIV infection during pregnancy through screening tests is essential in order to prevent in utero and intrapartum transmission of HIV. Perinatal HIV transmission can be less than 1% when effective cART, associated with virologic suppression of HIV, is given during the ante-, intra-, and postpartum periods. Perinatal HIV guidelines, developed by organizations such as the World Health Organization, American College of Obstetricians and Gynecologists, and the US Department of Health and Human Services, are constantly evolving, and hence the aim of our review is to provide a useful concise review for medical providers caring for HIV-infected pregnant women, summarizing the latest and current recommendations in the United States. PMID- 27504073 TI - When Does Feature Search Fail to Protect Against Attentional Capture? AB - When participants search for a shape (e.g., a circle) among a set of homogenous shapes (e.g., triangles) they are subject to distraction by color singletons that are more salient than the target. However, when participants search for a shape among heterogeneous shapes, the presence of a non-target color singleton does not slow responses to the target. Attempts have been made to explain these results from both bottom-up and top-down perspectives. What both accounts have in common is that they do not predict the occurrence of attentional capture on typical feature search displays. Here, we present a case where manipulating selection history, rather than the displays themselves, leads to attentional capture on feature search trials. The ability to map specific colors to the target and distractor appears to be what enables resistance to capture during feature search. PMID- 27504074 TI - Measurement and modeling of polarized specular neutron reflectivity in large magnetic fields. AB - The presence of a large applied magnetic field removes the degeneracy of the vacuum energy states for spin-up and spin-down neutrons. For polarized neutron reflectometry, this must be included in the reference potential energy of the Schrodinger equation that is used to calculate the expected scattering from a magnetic layered structure. For samples with magnetization that is purely parallel or antiparallel to the applied field which defines the quantization axis, there is no mixing of the spin states (no spin-flip scattering) and so this additional potential is constant throughout the scattering region. When there is non-collinear magnetization in the sample, however, there will be significant scattering from one spin state into the other, and the reference potentials will differ between the incoming and outgoing wavefunctions, changing the angle and intensities of the scattering. The theory of the scattering and recommended experimental practices for this type of measurement are presented, as well as an example measurement. PMID- 27504075 TI - Investigation of dissimilar metal welds by energy-resolved neutron imaging. AB - A nondestructive study of the internal structure and compositional gradient of dissimilar metal-alloy welds through energy-resolved neutron imaging is described in this paper. The ability of neutrons to penetrate thick metal objects (up to several cm) provides a unique possibility to examine samples which are opaque to other conventional techniques. The presence of Bragg edges in the measured neutron transmission spectra can be used to characterize the internal residual strain within the samples and some microstructural features, e.g. texture within the grains, while neutron resonance absorption provides the possibility to map the degree of uniformity in mixing of the participating alloys and intermetallic formation within the welds. In addition, voids and other defects can be revealed by the variation of neutron attenuation across the samples. This paper demonstrates the potential of neutron energy-resolved imaging to measure all these characteristics simultaneously in a single experiment with sub-mm spatial resolution. Two dissimilar alloy welds are used in this study: Al autogenously laser welded to steel, and Ti gas metal arc welded (GMAW) to stainless steel using Cu as a filler alloy. The cold metal transfer variant of the GMAW process was used in joining the Ti to the stainless steel in order to minimize the heat input. The distributions of the lattice parameter and texture variation in these welds as well as the presence of voids and defects in the melt region are mapped across the welds. The depth of the thermal front in the Al-steel weld is clearly resolved and could be used to optimize the welding process. A highly textured structure is revealed in the Ti to stainless steel joint where copper was used as a filler wire. The limited diffusion of Ti into the weld region is also verified by the resonance absorption. PMID- 27504076 TI - Rotation of X-ray polarization in the glitches of a silicon crystal monochromator. AB - EXAFS studies on dilute samples are usually carried out by collecting the fluorescence yield using a large-area multi-element detector. This method is susceptible to the 'glitches' produced by all single-crystal monochromators. Glitches are sharp dips or spikes in the diffracted intensity at specific crystal orientations. If incorrectly compensated, they degrade the spectroscopic data. Normalization of the fluorescence signal by the incident flux alone is sometimes insufficient to compensate for the glitches. Measurements performed at the state of-the-art wiggler beamline I20-scanning at Diamond Light Source have shown that the glitches alter the spatial distribution of the sample's quasi-elastic X-ray scattering. Because glitches result from additional Bragg reflections, multiple beam dynamical diffraction theory is necessary to understand their effects. Here, the glitches of the Si(111) four-bounce monochromator of I20-scanning just above the Ni K edge are associated with their Bragg reflections. A fitting procedure that treats coherent and Compton scattering is developed and applied to a sample of an extremely dilute (100 micromolal) aqueous solution of Ni(NO3)2. The depolarization of the wiggler X-ray beam out of the electron orbit is modeled. The fits achieve good agreement with the sample's quasi-elastic scattering with just a few parameters. The X-ray polarization is rotated up to +/-4.3 degrees within the glitches, as predicted by dynamical diffraction. These results will help users normalize EXAFS data at glitches. PMID- 27504077 TI - Interfibrillar packing of bovine cornea by table-top and synchrotron scanning SAXS microscopy. AB - Bovine cornea was studied with scanning small-angle X-ray scattering (SAXS) microscopy, by using both synchrotron radiation and a microfocus laboratory source. A combination of statistical (adaptive binning and canonical correlation analysis) and crystallographic (pair distribution function analysis) approaches allowed inspection of the collagen lateral packing of the supramolecular structure. Results reveal (i) a decrease of the interfibrillar distance and of the shell thickness around the fibrils from the periphery to the center of the cornea, (ii) a uniform fibril diameter across the explored area, and (iii) a distorted quasi-hexagonal arrangement of the collagen fibrils. The results are in agreement with existing literature. The overlap between laboratory and synchrotron-radiation data opens new perspectives for further studies on collagen based/engineered tissues by the SAXS microscopy technique at laboratory-scale facilities. PMID- 27504078 TI - Dragonfly: an implementation of the expand-maximize-compress algorithm for single particle imaging. AB - Single-particle imaging (SPI) with X-ray free-electron lasers has the potential to change fundamentally how biomacromolecules are imaged. The structure would be derived from millions of diffraction patterns, each from a different copy of the macromolecule before it is torn apart by radiation damage. The challenges posed by the resultant data stream are staggering: millions of incomplete, noisy and un oriented patterns have to be computationally assembled into a three-dimensional intensity map and then phase reconstructed. In this paper, the Dragonfly software package is described, based on a parallel implementation of the expand-maximize compress reconstruction algorithm that is well suited for this task. Auxiliary modules to simulate SPI data streams are also included to assess the feasibility of proposed SPI experiments at the Linac Coherent Light Source, Stanford, California, USA. PMID- 27504079 TI - CFEL-ASG Software Suite (CASS): usage for free-electron laser experiments with biological focus. AB - CASS [Foucar et al. (2012). Comput. Phys. Commun.183, 2207-2213] is a well established software suite for experiments performed at any sort of light source. It is based on a modular design and can easily be adapted for use at free electron laser (FEL) experiments that have a biological focus. This article will list all the additional functionality and enhancements of CASS for use with FEL experiments that have been introduced since the first publication. The article will also highlight some advanced experiments with biological aspects that have been performed. PMID- 27504080 TI - WavePropaGator: interactive framework for X-ray free-electron laser optics design and simulations. AB - This article describes the WavePropaGator (WPG) package, a new interactive software framework for coherent and partially coherent X-ray wavefront propagation simulations. The package has been developed at European XFEL for users at the existing and emerging free-electron laser (FEL) facilities, as well as at the third-generation synchrotron sources and future diffraction-limited storage rings. The WPG addresses the needs of beamline scientists and user groups to facilitate the design, optimization and improvement of X-ray optics to meet their experimental requirements. The package uses the Synchrotron Radiation Workshop (SRW) C/C++ library and its Python binding for numerical wavefront propagation simulations. The framework runs reliably under Linux, Microsoft Windows 7 and Apple Mac OS X and is distributed under an open-source license. The available tools allow for varying source parameters and optics layouts and visualizing the results interactively. The wavefront history structure can be used for tracking changes in every particular wavefront during propagation. The batch propagation mode enables processing of multiple wavefronts in workflow mode. The paper presents a general description of the package and gives some recent application examples, including modeling of full X-ray FEL beamlines and start-to-end simulation of experiments. PMID- 27504081 TI - Condor: a simulation tool for flash X-ray imaging. AB - Flash X-ray imaging has the potential to determine structures down to molecular resolution without the need for crystallization. The ability to accurately predict the diffraction signal and to identify the optimal experimental configuration within the limits of the instrument is important for successful data collection. This article introduces Condor, an open-source simulation tool to predict X-ray far-field scattering amplitudes of isolated particles for customized experimental designs and samples, which the user defines by an atomic or a refractive index model. The software enables researchers to test whether their envisaged imaging experiment is feasible, and to optimize critical parameters for reaching the best possible result. It also aims to support researchers who intend to create or advance reconstruction algorithms by simulating realistic test data. Condor is designed to be easy to use and can be either installed as a Python package or used from its web interface (http://lmb.icm.uu.se/condor). X-ray free-electron lasers have high running costs and beam time at these facilities is precious. Data quality can be substantially improved by using simulations to guide the experimental design and simplify data analysis. PMID- 27504082 TI - Hyperbilirubinemia without Transaminitis during Combined Therapy with Daclatasvir and Asunaprevir. AB - Daclatasvir (DCV) and asunaprevir (ASV) are direct-acting antivirals (DAAs) used in the treatment of chronic hepatitis C virus (HCV) infection. Combined therapy with DCV and ASV shows high efficacy and safety even in patients with cirrhosis. We encountered a patient exhibiting severe hyperbilirubinemia during combined therapy, which is an unreported side effect of DCV and ASV. A 78-year-old woman with cirrhosis developed hyperbilirubinemia >10 mg/dl without transaminitis 3 weeks after starting combined therapy. We suspected DAAs-induced liver disorder and discontinued treatment, which resulted in the improvement of hyperbilirubinemia. Caution is required in the use of DAAs for patients with advanced cirrhosis. PMID- 27504083 TI - Very Early Presentation of Extrahepatic Portal Vein Obstruction Causing Portal Hypertension in an Infant: Uncertainties in the Management and Therapeutic Limitations. AB - Extrahepatic portal vein obstruction, although rare in children, is a significant cause of portal hypertension (PHT) leading to life-threatening gastrointestinal bleeding in the pediatric age group. PHT may also lead to other complications such as hyperesplenism, cholangyopathy, ascites, and even hepatopulmonary syndrome and portopulmonary hypertension that may require organ transplantation. Herein we report the case of an asymptomatic 11-month-old infant wherein a hepatomegaly and cavernous transformation of the portal vein was detected by liver ultrasound. Neither signs of thrombosis in arteriovenous system, nor affectation of biliary tract were identified in the magnetic resonance imaging study. A significant enlargement of the caudate lobe of the liver was reported. No risk factors were detected. The differential diagnosis performed was extensive. Inherited thrombophilia and storage disorders were especially considered. Liver biopsy was normal. Upper gastrointestinal esophagogastroduodenoscopy detected two small varicose cords on the distal third of the esophagus. Finding a cavernous transformation of the portal vein with evidence of collateral circulation in such an early age is a challenging condition for professionals, since PHT may lead to severe complications during childhood and can compromise growth and development. Evidence-based guidelines for the management of PHT in adults have been published. However, follow-up and treatment of pediatric patients have not yet been standardized. Moreover, management of PHT in infants faces particular difficulties such as technical restrictions that could hinder their treatment. PMID- 27504084 TI - Increased Expression of Osteopontin in Retinal Degeneration Induced by Blue Light Emitting Diode Exposure in Mice. AB - Osteopontin (OPN) is a multifunctional adhesive glycoprotein that is implicated in a variety of pro-inflammatory as well as neuroprotective and repair-promoting effects in the brain. As a first step towards understanding the role of OPN in retinal degeneration (RD), we examined changes in OPN expression in a mouse model of RD induced by exposure to a blue light-emitting diode (LED). RD was induced in BALB/c mice by exposure to a blue LED (460 nm) for 2 h. Apoptotic cell death was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. In order to investigate changes in OPN in RD, western blotting and immunohistochemistry were performed. Anti-OPN labeling was compared to that of anti-glial fibrillary acidic protein (GFAP), which is a commonly used marker for retinal injury or stress including inflammation. OPN expression in RD retinas markedly increased at 24 h after exposure, was sustained through 72 h, and subsided at 120 h. Increased OPN expression was observed co-localized with microglial cells in the outer nuclear layer (ONL), outer plexiform layer (OPL), and subretinal space. Expression was restricted to the central retina in which photoreceptor cell death occurred. Interestingly, OPN expression in the ONL/OPL was closely associated with microglia, whereas most of the OPN plaques observed in the subretinal space were not. Immunogold electron microscopy demonstrated that OPN was distributed throughout the cytoplasm of microglia and in nearby fragments of degenerating photoreceptors. In addition, we found that OPN was induced more acutely and with greater region specificity than GFAP. These results indicate that OPN may be a more useful marker for retinal injury or stress, and furthermore act as a microglial pro-inflammatory mediator and a phagocytosis inducing opsonin in the subretinal space. Taken together, our data suggest that OPN plays an important role in the pathogenesis of RD. PMID- 27504086 TI - Emergent Spatial Patterns of Excitatory and Inhibitory Synaptic Strengths Drive Somatotopic Representational Discontinuities and their Plasticity in a Computational Model of Primary Sensory Cortical Area 3b. AB - Mechanisms underlying the emergence and plasticity of representational discontinuities in the mammalian primary somatosensory cortical representation of the hand are investigated in a computational model. The model consists of an input lattice organized as a three-digit hand forward-connected to a lattice of cortical columns each of which contains a paired excitatory and inhibitory cell. Excitatory and inhibitory synaptic plasticity of feedforward and lateral connection weights is implemented as a simple covariance rule and competitive normalization. Receptive field properties are computed independently for excitatory and inhibitory cells and compared within and across columns. Within digit representational zones intracolumnar excitatory and inhibitory receptive field extents are concentric, single-digit, small, and unimodal. Exclusively in representational boundary-adjacent zones, intracolumnar excitatory and inhibitory receptive field properties diverge: excitatory cell receptive fields are single digit, small, and unimodal; and the paired inhibitory cell receptive fields are bimodal, double-digit, and large. In simulated syndactyly (webbed fingers), boundary-adjacent intracolumnar receptive field properties reorganize to within representation type; divergent properties are reacquired following syndactyly release. This study generates testable hypotheses for assessment of cortical laminar-dependent receptive field properties and plasticity within and between cortical representational zones. For computational studies, present results suggest that concurrent excitatory and inhibitory plasticity may underlie novel emergent properties. PMID- 27504087 TI - Apremilast Use for Moderate-to-Severe Atopic Dermatitis in Pediatric Patients. AB - Atopic dermatitis (AD) is a chronic, pruritic skin disease often complicated by bacterial superinfection affecting 10.7% of American children. The pathogenesis involves a skin barrier breakdown in addition to dysfunctional innate and adaptive immune response, including an unbalanced increase in T-helper 2 cells and hyperimmunoglobulinemia E. The increased numbers of T-helper 2 cells are involved in stimulating the production of immunoglobulin E and eosinophilia by releasing interleukin-4, -5, and -13 as well as in decreasing protection against bacterial superinfection by releasing interleukin-10. The current Food and Drug Administration-approved symptomatic treatment for AD includes topical ointments, topical and systemic corticosteroids, topical immunomodulant therapy, antibiotics, and phototherapy, but there are not approved targeted therapies or cures. By presenting a case of an 8-year-old African-American boy, this case report supports novel therapy of moderate-to-severe AD with apremilast, a phosphodiesterase type 4 inhibitor. Apremilast has recently completed the phase 2 clinical trial (NCT02087943) for treatment of AD in adults. This case report illustrates the potential for apremilast as a treatment for AD in children, where there is a great need for safe and effective medications. PMID- 27504085 TI - The Presynaptic Microtubule Cytoskeleton in Physiological and Pathological Conditions: Lessons from Drosophila Fragile X Syndrome and Hereditary Spastic Paraplegias. AB - The capacity of the nervous system to generate neuronal networks relies on the establishment and maintenance of synaptic contacts. Synapses are composed of functionally different presynaptic and postsynaptic compartments. An appropriate synaptic architecture is required to provide the structural basis that supports synaptic transmission, a process involving changes in cytoskeletal dynamics. Actin microfilaments are the main cytoskeletal components present at both presynaptic and postsynaptic terminals in glutamatergic synapses. However, in the last few years it has been demonstrated that microtubules (MTs) transiently invade dendritic spines, promoting their maturation. Nevertheless, the presence and functions of MTs at the presynaptic site are still a matter of debate. Early electron microscopy (EM) studies revealed that MTs are present in the presynaptic terminals of the central nervous system (CNS) where they interact with synaptic vesicles (SVs) and reach the active zone. These observations have been reproduced by several EM protocols; however, there is empirical heterogeneity in detecting presynaptic MTs, since they appear to be both labile and unstable. Moreover, increasing evidence derived from studies in the fruit fly neuromuscular junction proposes different roles for MTs in regulating presynaptic function in physiological and pathological conditions. In this review, we summarize the main findings that support the presence and roles of MTs at presynaptic terminals, integrating descriptive and biochemical analyses, and studies performed in invertebrate genetic models. PMID- 27504088 TI - A Case Of Bilateral Acquired Localized Lipoatrophy. AB - Lipoatrophy is characterized by inflammation and tissue loss in fatty tissue. This disease may be congenital or acquired, primary or secondary. Secondary lipoatrophy develops with infections, collagen tissue diseases, tumors and drug injections. In this report, we present the case of a 14-year-old female patient who developed lipoatrophy following intramuscular steroid injection to both buttocks. PMID- 27504089 TI - Inframammary Dermatitis: A Case of Localized Late-Onset Darier's Disease. AB - Darier's disease (DD) is an autosomal dominant inherited genodermatosis which is often under- or misdiagnosed. In the majority of cases, the disease manifests in adolescents or young adults with small brownish-yellow, warty, hyperkeratotic papules in multiple seborrheic areas of the body. Localized DD (LDD) is a clinical variant, first described by Kreibich in 1906; only a few cases are reported in the literature. We described the case of an aged woman presenting with LDD, and we review the literature on this subject. PMID- 27504090 TI - Nodular Cutaneous Amyloidosis at the Temple. AB - A 52-year-old woman presented with a large partially yellow and erythematous tumor on her right temple. She reported that it had grown over the last 4 years. Regional lymph nodes were impalpable. A punch biopsy showed eosinophilic material in the dermis and subcutis. Immunohistochemistry showed positive staining for kappa and lambda light chains. Electron microscopy showed the typical amyloid fibrils (7-10 nm in diameter). There was no evidence of systemic amyloidosis, paraproteinemia or underlying plasmacytoma. The tumor was completely removed via curettage. At follow-up, the patient presented in good health with no signs of relapse. PMID- 27504091 TI - A Young Woman with Ischemic Stroke: Should We Pay More Attention to Varicella Zoster Infection? AB - Ischemic and hemorrhagic stroke are recognized complications of Varicella zoster virus (VZV) infections, although uncommon and poorly documented. The authors report the case of a 31-year-old woman admitted with acute ischemic stroke of the right posterior cerebral artery and a history of a thoracic rash 1 month before. Aspirin and simvastatin were prescribed, but the patient suffered a stepwise deterioration the following days, with new areas of infarction on brain imaging. Despite no evidence of cardiac or large vessel embolic sources, anticoagulation was started empirically 6 days after stroke onset. One week later, symptomatic hemorrhagic transformation occurred. The diagnosis of VZV vasculopathy was then considered, and treatment with acyclovir and prednisolone was started with no further vascular events. Cerebrospinal fluid analysis and digital subtraction angiography findings corroborated the diagnosis. The patient was discharged to the rehabilitation center with a modified Rankin scale (mRS) score of 4. On the 6 month follow-up, she presented only a slight disability (mRS score 2). In conclusion, VZV vasculopathy needs to be considered in young adults with stroke. A high index of suspicion and early treatment seem to be important to minimize morbidity and mortality. Anticoagulation should probably be avoided in stroke associated with VZV vasculopathy. PMID- 27504092 TI - Brown Heroin-Associated Candida albicans Ventriculitis and Endophthalmitis Treated with Voriconazole. AB - Chronic meningitis and ventriculitis are defined as inflammatory pleocytoses in the cerebrospinal fluid (CSF) and ependyma that persists for at least 1 month without spontaneous resolution. Because the CSF communicates directly with the posterior compartments of the eye, fungal infections in the brain often cause secondary ophthalmologic complications. We report a 23-year-old male who presented to the emergency room with progressive severe headaches associated with insidious monocular vision loss. After extensive workup and a multidisciplinary team effort, the patient was diagnosed with ventriculitis and endogenous endopthalmitis. The etiology is suspected to be due to brown heroin use with secondary disseminated Candida albicans. PMID- 27504093 TI - Demyelinizing Neurological Disease after Treatment with Tumor Necrosis Factor alpha Antagonists. AB - PURPOSE: Demyelinizing neurological disease is a rare complication after treatment with tumor necrosis factor (TNF)alpha antagonists. We report on a case of multiple sclerosis after TNFalpha antagonist treatment and discuss its differential diagnosis. METHODS: This is an observational case study. RESULTS: A 48-year-old male was referred to Ophthalmology in January 2015 for an absolute scotoma in the superior quadrant of the visual field in his right eye. Visual acuity was 20/50 in the right eye and 20/20 in the left. Fundus examination was unremarkable bilaterally. Spectral domain optical coherence tomography revealed a normal macular retina structure. Visual field examination revealed a superior hemianopsia in the right eye. Head magnetic resonance imaging showed findings compatible with optic neuritis. The visual evoked potentials confirmed the presence of optic neuritis. The patient had been under therapy with adalimumab since January 2014, for Crohn's disease. Suspension of adalimumab was recommended, and it was substituted with tapered deltacortene, from 1 mg/kg/day. After 1 month, the scotoma was resolved completely. CONCLUSIONS: TNFalpha antagonists can provide benefit to patients with inflammatory autoimmune diseases. However, they can also be associated with severe adverse effects. Therefore, adequate attention should be paid to neurological abnormalities in patients treated with TNFalpha antagonists. PMID- 27504094 TI - A Ribonuclease Isolated from Wild Ganoderma Lucidum Suppressed Autophagy and Triggered Apoptosis in Colorectal Cancer Cells. AB - The mushroom Ganoderma lucidum (G. lucidum) has been consumed in China as a medicine for promoting health and longevity for thousands of years. Due to its paramount and multiple pharmaceutical effects, G. lucidum has received considerable attention from researchers and its chemical constituents as well as their respective functions were gradually unveiled by using modern research methods. Herein, we reported the isolation of a protein (Ganoderma lucidum ribonuclease, GLR) with anti-colorectal cancer activities from G. lucidum. This protein is a 17.4-kDa RNA degrading enzyme (ribonuclease) and was purified by using liquid chromatography procedures. GLR manifested potent anti-proliferative and anti-colony formation activities on HT29 and HCT116 colorectal cancer cells by inducing cell cycle arrest in G1 phase through the regulation of cyclin D1 and P53 expression. GLR was demonstrated to induce cell apoptosis in HCT116 cells by activating unfolded protein response and caspase-9 regulated pathways. Besides, the ability to undergo autophagy which is a stress adaption mechanism to cope with metabolic crisis was significantly suppressed by GLR treatment in HCT116 cells. The activation of apoptosis in GLR-treated HT29 cells was, however, independent of caspase-9 and the suppression of autophagy was also relatively minor. Thus the apoptosis of HT29 cells triggered by GLR was much milder than that in HCT116 cells. Our findings show that the RNase from G. lucidum may be one of the bioactive components that contribute to the anti-colorectal cancer activity of G. lucidum. PMID- 27504095 TI - A Standardized Chemically Modified Curcuma longa Extract Modulates IRAK-MAPK Signaling in Inflammation and Potentiates Cytotoxicity. AB - The TLR/IL-1R pathway is a critical signaling module that is misregulated in pathologies like inflammation and cancer. Extracts from turmeric (Curcuma longa L.) enriched in curcumin and carbonyls like turmerones have been shown to exert potent anti-inflammatory effects. The present study evaluated the anti inflammatory activity, cytotoxic effect and the underlying mechanism of a novel chemically modified, non-carbonyl compound enriched Curcuma longa L. (C. longa) extract (CMCE). CMCE (1 or 10 MUg/mL; 14 h) significantly decreased LPS (50-100 ng/mL) induced TNF-alpha and IL-1beta production in THP-1 cells, human, and mouse whole blood as measured by ELISA. LPS-induced IRAK1, MAPK activation, TLR4 expression, TLR4-MyD88 interaction, and IkappaBalpha degradation were significantly reduced in CMCE pre-treated THP-1 cells as assessed by Western blotting. CMCE (30, 100, and 300 mg/kg; 10 days p.o.) pre-treated and LPS (10 mg/kg) challenged Swiss mice exhibited attenuated plasma TNF-alpha, IL-1beta, nitrite, aortic iNOS expression, and vascular dysfunction. In a PI permeability assay, cell lines derived from acute myeloid leukemia were most sensitive to the cytotoxic effects of CMCE. Analysis of Sub-G1 phase, Annexin V-PI positivity, loss of mitochondrial membrane potential, increased caspase-3, and PARP-1 activation confirmed CMCE induced apoptosis in HL-60 cells. IRAK inhibition also sensitized HL-60 cells to CMCE induced cytotoxicity. The present study defines the mechanism underlying the action of CMCE and suggests a therapeutic potential for its use in sepsis and leukemia. PMID- 27504096 TI - Protective Effects of Otophylloside N on Pentylenetetrazol-Induced Neuronal Injury In vitro and In vivo. AB - Approximately 30% of epileptic patients worldwide are medically unable to control their seizures. In addition, repeated epileptic seizures generally lead to neural damage. Pentylenetetrazol (PTZ) is a clinical circulatory and respiratory stimulant that is experimentally used to mimic epileptic convulsion in epilepsy research. Here, we systematically explore the neuroprotective effects of a pure compound isolated from Cynanchum otophyllum Schneid (Qingyangshen), Otophylloside N (OtoN), against PTZ-induced neuronal injury. We used three models: in vitro primary cortical neurons, in vivo mice, and in vivo zebrafish. Our results revealed that OtoN treatment may attenuate PTZ-induced morphology changes, cell death, LDH efflux in embryonic neuronal cells of C57BL/6J mice, and convulsive behavior in zebrafish. Additionally, our Western blot and RT-PCR results demonstrated that OtoN may attenuate PTZ-induced apoptosis and neuronal activation in neuronal cells, mice, and zebrafish. OtoN may reduce PTZ-induced cleavage of poly ADP-ribose polymerase and upregulation of the Bax/Bcl-2 ratio and decrease the expression level of c-Fos. This study is the first investigation of the neuroprotective effects of OtoN, which might be developed as a novel antiepileptic drug. PMID- 27504097 TI - Voluntary Running Aids to Maintain High Body Temperature in Rats Bred for High Aerobic Capacity. AB - The production of heat, i.e., thermogenesis, is a significant component of the metabolic rate, which in turn affects weight gain and health. Thermogenesis is linked to physical activity (PA) level. However, it is not known whether intrinsic exercise capacity, aging, and long-term voluntary running affect core body temperature. Here we use rat models selectively bred to differ in maximal treadmill endurance running capacity (Low capacity runners, LCR and High capacity Runners, HCR), that as adults are divergent for aerobic exercise capacity, aging, and metabolic disease risk to study the connection between PA and body temperature. Ten high capacity runner (HCR) and ten low capacity runner (LCR) female rats were studied between 9 and 21 months of age. Rectal body temperature of HCR and LCR rats was measured before and after 1-year voluntary running/control intervention to explore the effects of aging and PA. Also, we determined whether injected glucose and spontaneous activity affect the body temperature differently between LCR and HCR rats at 9 vs. 21 months of age. HCRs had on average 1.3 degrees C higher body temperature than LCRs (p < 0.001). Aging decreased the body temperature level of HCRs to similar levels with LCRs. The opportunity to run voluntarily had a significant impact on the body temperature of HCRs (p < 0.001) allowing them to maintain body temperature at a similar level as when at younger age. Compared to LCRs, HCRs were spontaneously more active, had higher relative gastrocnemius muscle mass and higher UCP2, PGC-1alpha, cyt c, and OXPHOS levels in the skeletal muscle (p < 0.050). These results suggest that higher PA level together with greater relative muscle mass and higher mitochondrial content/function contribute to the accumulation of heat in the HCRs. Interestingly, neither aging nor voluntary training had a significant impact on core body temperature of LCRs. However, glucose injection resulted in a lowering of the body temperature of LCRs (p < 0.050), but not that of HCRs. In conclusion, rats born with high intrinsic capacity for aerobic exercise and better health have higher body temperature compared to rats born with low exercise capacity and disease risk. Voluntary running allowed HCRs to maintain high body temperature during aging, which suggests that high PA level was crucial in maintaining the high body temperature of HCRs. PMID- 27504099 TI - Quality of Life in Caregivers of ADHD Children and Diabetes Patients. AB - INTRODUCTION: Studies have shown that the presence of attention-deficit hyperactivity disorder (ADHD) causes great impairment in academic, social, and professional activities as well as in the quality of life (QoL) of its patients. Similarly, the impact caused by other chronic disorders, such as diabetes, in the patient's QoL has been emphasized in many studies. Despite its relevance, no study has yet investigated whether ADHD caregivers and diabetic patients would have similar QoL impairment. OBJECTIVES: This study was conducted in order to compare the QoL scores among ADHD caregivers and diabetic patients. METHODS: We evaluated 63 caregivers of ADHD children treated at the Child and Adolescent Psychiatric Unit at the Federal University of Sao Paulo (UPIA-UNIFESP) and 52 adult diabetic patients. Subjects were assessed with the World Health Organization quality of Life-Bref Version (WHOQOL-BREF), the Beck and Hamilton depression scales, and the Adult Self-Report Scale. RESULTS: When compared to the Brazilian normative data, ADHD caregivers had significantly lower scores in the social relations and environment WHOQOL domains. ADHD caregivers and diabetic patients had similar impairment in all WHOQOL domains except for the physical domain. CONCLUSION: ADHD affects the QoL of the patient's caregiver, with similar impairment, when compared to the QoL of diabetic patients. These results emphasize the need for assessing QoL of the caregivers as part of the treatment strategies. They also emphasize the need for future studies with larger sample sizes comparing how the QOL is impacted in different chronic disorders. PMID- 27504098 TI - Can Interoception Improve the Pragmatic Search for Biomarkers in Psychiatry? AB - Disrupted interoception is a prominent feature of the diagnostic classification of several psychiatric disorders. However, progress in understanding the interoceptive basis of these disorders has been incremental, and the application of interoception in clinical treatment is currently limited to panic disorder. To examine the degree to which the scientific community has recognized interoception as a construct of interest, we identified and individually screened all articles published in the English language on interoception and associated root terms in Pubmed, Psychinfo, and ISI Web of Knowledge. This search revealed that interoception is a multifaceted process that is being increasingly studied within the fields of psychiatry, psychology, neuroscience, and biomedical science. To illustrate the multifaceted nature of interoception, we provide a focused review of one of the most commonly studied interoceptive channels, the cardiovascular system, and give a detailed comparison of the most popular methods used to study cardiac interoception. We subsequently review evidence of interoceptive dysfunction in panic disorder, depression, somatic symptom disorders, anorexia nervosa, and bulimia nervosa. For each disorder, we suggest how interoceptive predictions constructed by the brain may erroneously bias individuals to express key symptoms and behaviors, and outline questions that are suitable for the development of neuroscience-based mental health interventions. We conclude that interoception represents a viable avenue for clinical and translational research in psychiatry, with a well-established conceptual framework, a neural basis, measurable biomarkers, interdisciplinary appeal, and transdiagnostic targets for understanding and improving mental health outcomes. PMID- 27504101 TI - Comparing Emotion Recognition Skills among Children with and without Jailed Parents. AB - Approximately five million children in the United States have experienced a co resident parent's incarceration in jail or prison. Parental incarceration is associated with multiple risk factors for maladjustment, which may contribute to the increased likelihood of behavioral problems in this population. Few studies have examined early predictors of maladjustment among children with incarcerated parents, limiting scholars' understanding about potential points for prevention and intervention. Emotion recognition skills may play a role in the development of maladjustment and may be amenable to intervention. The current study examined whether emotion recognition skills differed between 3- to 8-year-old children with and without jailed parents. We hypothesized that children with jailed parents would have a negative bias in processing emotions and less accuracy compared to children without incarcerated parents. Data were drawn from 128 families, including 75 children (53.3% male, M = 5.37 years) with jailed parents and 53 children (39.6% male, M = 5.02 years) without jailed parents. Caregivers in both samples provided demographic information. Children performed an emotion recognition task in which they were asked to produce a label for photos expressing six different emotions (i.e., happy, surprised, neutral, sad, angry, and fearful). For scoring, the number of positive and negative labels were totaled; the number of negative labels provided for neutral and positive stimuli were totaled (measuring negative bias/overextension of negative labels); and valence accuracy (i.e., positive, negative, and neutral) and label accuracy were calculated. Results indicated a main effect of parental incarceration on the number of positive labels provided; children with jailed parents presented significantly fewer positive emotions than the comparison group. There was also a main effect of parental incarceration on negative bias (the overextension of negative labels); children with jailed parents had a negative bias compared to children without jailed parents. However, these findings did not hold when controlling for child age, race/ethnicity, receipt of special education services, and caregiver education. The results provide some evidence for the effect of the context of parental incarceration in the development of negative emotion recognition biases. Limitations and implications for future research and interventions are discussed. PMID- 27504100 TI - Multivariate Imaging Genetics Study of MRI Gray Matter Volume and SNPs Reveals Biological Pathways Correlated with Brain Structural Differences in Attention Deficit Hyperactivity Disorder. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder affecting children, adolescents, and adults. Its etiology is not well understood, but it is increasingly believed to result from diverse pathophysiologies that affect the structure and function of specific brain circuits. Although one of the best-studied neurobiological abnormalities in ADHD is reduced fronto-striatal-cerebellar gray matter (GM) volume, its specific genetic correlates are largely unknown. METHODS: In this study, T1-weighted MR images of brain structure were collected from 198 adolescents (63 ADHD diagnosed). A multivariate parallel independent component analysis (Para-ICA) technique-identified imaging genetic relationships between regional GM volume and single nucleotide polymorphism data. RESULTS: Para-ICA analyses extracted 14 components from genetic data and 9 from MR data. An iterative cross-validation using randomly chosen subsamples indicated acceptable stability of these ICA solutions. A series of partial correlation analyses controlling for age, sex, and ethnicity revealed two genotype-phenotype component pairs significantly differed between ADHD and non-ADHD groups, after a Bonferroni correction for multiple comparisons. The brain phenotype component not only included structures frequently found to have abnormally low volume in previous ADHD studies but was also significantly associated with ADHD differences in symptom severity and performance on cognitive tests frequently found to be impaired in patients diagnosed with the disorder. Pathway analysis of the genotype component identified several different biological pathways linked to these structural abnormalities in ADHD. CONCLUSION: Some of these pathways implicate well-known dopaminergic neurotransmission and neurodevelopment hypothesized to be abnormal in ADHD. Other more recently implicated pathways included glutamatergic and GABA eric physiological systems; others might reflect sources of shared liability to disturbances commonly found in ADHD, such as sleep abnormalities. PMID- 27504102 TI - Reducing the Meta-Emotional Problem Decreases Physiological Fear Response during Exposure in Phobics. AB - Anxiety disorders may not only be characterized by specific symptomatology (e.g., tachycardia) in response to the fearful stimulus (primary problem or first-level emotion) but also by the tendency to negatively evaluate oneself for having those symptoms (secondary problem or negative meta-emotion). An exploratory study was conducted driven by the hypothesis that reducing the secondary or meta-emotional problem would also diminish the fear response to the phobic stimulus. Thirty three phobic participants were exposed to the phobic target before and after undergoing a psychotherapeutic intervention addressed to reduce the meta emotional problem or a control condition. The electrocardiogram was continuously recorded to derive heart rate (HR) and heart rate variability (HRV) and affect ratings were obtained. Addressing the meta-emotional problem had the effect of reducing the physiological but not the subjective symptoms of anxiety after phobic exposure. Preliminary findings support the role of the meta-emotional problem in the maintenance of response to the fearful stimulus (primary problem). PMID- 27504103 TI - Contribution of Pro-inflammatory Cytokine Signaling within Midbrain Periaqueductal Gray to Pain Sensitivity in Parkinson's Disease via GABAergic Pathway. AB - BACKGROUND/AIMS: Hypersensitive pain response is often observed in patients with Parkinson's disease (PD); however, the mechanisms responsible for hyperalgesia are not well understood. Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role for pro-inflammatory cytokines (PICs) system of PAG in regulating exaggerated pain evoked by PD. METHODS: We used a rat model of PD to perform the experimental protocols. PD was induced by microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle. Pain responses to mechanical and thermal stimulation were first examined in control rats and PD rats. Then, ELISA and Western Blot analysis were used to determine PIC levels and their receptors expression. RESULTS: Protein expression of IL-1beta, IL-6, and TNF-alpha receptors (namely, IL-1R, IL-6R, and TNFR subtype TNFR1) in the plasma membrane PAG of PD rats was upregulated, whereas the total expression of PIC receptors was not significantly altered. The ratio of membrane protein and total protein (IL-1R, IL-6R, and TNFR1) was 1.48 +/- 0.15, 1.59 +/- 0.18, and 1.67 +/- 0.16 in PAG of PD rats (P < 0.05 vs. their respective controls). This was accompanied with increases of PICs of PAG and decreases of GABA (623 +/- 21 ng/mg in control rats and 418 +/- 18 ng/mg in PD rats; P < 0.05 vs. control rats) and withdrawal thresholds to mechanical and thermal stimuli. Our data further showed that the concentrations of GABA and withdrawal thresholds were largely restored by blocking those PIC receptors in PAG of PD rats. Stimulation of GABA receptors in PAG of PD rats also blunted a decrease in withdrawal thresholds. CONCLUSION: Our data suggest that upregulation of the membrane PIC receptor in the PAG of PD rats is likely to impair the descending inhibitory pathways in regulating pain transmission and thereby plays a role in the development of hypersensitive pain response in PD. PMID- 27504104 TI - Functional Connectivity Is Altered in Concussed Adolescent Athletes Despite Medical Clearance to Return to Play: A Preliminary Report. AB - Recovery following sports-related concussion (SRC) is slower and often more complicated in young adolescent athletes than in collegiate players. Further, the clinical decision to return to play is currently based on symptoms and cognitive performance without direct knowledge of brain function. We tested the hypothesis that brain functional connectivity (FC) would be aberrant in recently concussed, asymptomatic athletes who had been cleared to return to play. A seed-based FC analysis measured the FC of the default mode network (DMN) (seeds = anterior cingulate cortex, posterior cingulate cortex (PCC), right lateral parietal cortex, and left lateral parietal cortex) 30 days after SRC in asymptomatic high school athletes cleared to return to play (n = 13) and was compared to the FC of high school athletes with orthopedic injury (OI) (n = 13). The SRC group demonstrated greater FC than the OI group between the PCC and the ventral lateral prefrontal cortex, as well as between the right lateral parietal cortex and lateral temporal cortex (with regions both outside of and within the DMN). Additionally, the OI group demonstrated greater FC than the SRC group between right lateral parietal cortex and supramarginal gyrus. When relating the FC results to verbal memory performance approximately 1 week and 1 month after injury, significantly different between-group relations were found for the posterior cingulate and right lateral parietal cortex seeds. However, the groups did not differ in verbal memory at 1 month. We suggest that changes in FC are apparent 1-month post-SRC despite resolution of post-concussion symptoms and recovery of cognitive performance in adolescent athletes cleared to return to play. PMID- 27504105 TI - Non-Motor Symptoms in Patients Suffering from Motor Neuron Diseases. AB - BACKGROUND: The recently postulated "disease spreading hypothesis" has gained much attention, especially for Parkinson's disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND. METHODS: We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls. RESULTS: In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression. CONCLUSION: NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated "disease spreading hypothesis." The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND. PMID- 27504106 TI - Prognostic Factors for Adrenocortical Carcinoma Outcomes. AB - PURPOSE: Adrenocortical carcinoma (ACC) is an aggressive tumor characterized by a high recurrence rate and poor response to treatment. This study analyzes a consecutive series of ACC patients to evaluate the prognostic value of various clinical and pathological characteristics. METHODS: We retrospectively evaluated 32 ACC patients followed at our Medical Center from 1997 to 2015 and evaluated the prognostic value of age at diagnosis, gender, tumor functional status, stage, and type of treatment with respect to overall survival (OS) and disease-free survival (DFS), as determined by Kaplan-Meier curves. RESULTS: ACC was associated with hormonal overproduction in 50% of cases, and patients with isolated hyperandrogenism had a better prognosis. Recurrence was observed in 12/26 (46.2%) patients with no evidence of disease after surgery. Tumor size [hazard ratio (HR) 1.32, 95% confidential intervals (CI) 1.12-1.64; p = 0.007], ki-67 (HR 1.06, 95% CI 1.02-1.11; p = 0.009) and advanced stage at diagnosis (III-IV) (HR 6.51, 95% CI 1.65-24.68; p = 0.006) were associated with recurrence in the 26 R0 patients in the univariate analysis. Advanced stage was an independent risk factor for recurrence in the multivariate analysis (HR 8.10, 95% CI 1.55-41.35; p = 0.01). Five-year survival was 40.0%. Positive resection margins (HR 10.61, 95% CI 3.02 38.31; p = < 0.001), ki-67 (HR 1.04, 95% CI 1.01-1.07; p = 0.01) and advanced stage (HR 11.31, 95% CI 1.45-87.76; p = 0.02) were associated with poor survival in all 32 patients, but only positive resection margins were an independent predictor of mortality in the multivariate analysis (HR 6.22, 95% CI 1.44-26.05; p = 0.01). CONCLUSION: ACC has a poor prognosis with a high recurrence rate. Tumor stage at diagnosis and the completeness of surgical excision are the most relevant prognostic factors. PMID- 27504107 TI - Bioassays for TSH Receptor Autoantibodies, from FRTL-5 Cells to TSH Receptor LH/CG Receptor Chimeras: The Contribution of Leonard D. Kohn. AB - Since the discovery 60 years ago of the "long-acting thyroid stimulator" by Adams and Purves, great progress has been made in the detection of thyroid-stimulating hormone (TSH) receptor (TSHR) autoantibodies (TRAbs) in Graves' disease. Today, commercial assays are available that can detect TRAbs with high accuracy and provide diagnostic and prognostic evaluation of patients with Graves' disease. The present review focuses on the development of TRAbs bioassays, and particularly on the role that Leonard D. Kohn had in this. Indeed, 30 years ago, the Kohn group developed a bioassay based on the use of FRTL-5 cells that was characterized by high reproducibility, feasibility, and diagnostic accuracy. Using this FRTL-5 bioassay, Kohn and his colleagues were the first to develop monoclonal antibodies (moAbs) against the TSHR. Furthermore, they demonstrated the multifaceted functional nature of TRAbs in patients with Graves' disease, with the identification of stimulating and blocking TRAbs, and even antibodies that activated pathways other than cAMP. After the cloning of the TSHR, the Kohn laboratory constructed human TSHR-rat luteinizing hormone/chorionic gonadotropin receptor chimeras. This paved the way to a new bioassay based on the use of non thyroid cells transfected with the Mc4 chimera. The new Mc4 bioassay is characterized by high diagnostic and prognostic accuracy, greater than for other assays. The availability of a commercial kit based on the Mc4 chimera is spreading the use of this assay worldwide, indicating its benefits for these patients with Graves' disease. This review also describes the main contributions made by other researchers in TSHR molecular biology and TRAbs assay, especially with the development of highly potent moAbs. A comparison of the diagnostic accuracies of the main TRAbs assays, as both immunoassays and bioassays, is also provided. PMID- 27504108 TI - Silver Nanoparticles, Ions, and Shape Governing Soil Microbial Functional Diversity: Nano Shapes Micro. AB - Silver nanoparticles (AgNPs) affect microbial metabolic processes at single cell level or lab-culture strains. However, the impact of different AgNPs properties such as the particle, ion release, and shape on functional responses of natural soil microbial communities remain poorly understood. Therefore, we assessed the relative importance of particles and ions of AgNPs in bacterial toxicity and how the functional diversity of soil microbial communities were impacted by AgNPs shapes (i.e., plates, spheres, and rods) in laboratory incubations. Our results showed that the relative contribution of AgNPs(particle) increased with increasing exposure concentrations (accounted for about 60-68% of the total toxicity at the highest exposure level). In addition, the functional composition of the microbial community differed significantly according to different AgNPs shapes. The various properties of AgNPs thus can significantly and differentially affect the functional composition of microbial communities and associated ecosystem processes depending on the level of environmental exposure. PMID- 27504109 TI - Fermented Foods: Are They Tasty Medicines for Helicobacter pylori Associated Peptic Ulcer and Gastric Cancer? AB - More than a million people die every year due to gastric cancer and peptic ulcer. Helicobacter pylori infection in stomach is the most important reason for these diseases. Interestingly, only 10-20% of the H. pylori infected individuals suffer from these gastric diseases and rest of the infected individuals remain asymptomatic. The genotypes of H. pylori, host genetic background, lifestyle including smoking and diet may determine clinical outcomes. People from different geographical regions have different food habits, which also include several unique fermented products of plant and animal origins. When consumed raw, the fermented foods bring in fresh inocula of microbes to gastrointestinal tract and several strains of these microbes, like Lactobacillus and Saccharomyces are known probiotics. In vitro and in vivo experiments as well as clinical trials suggest that several probiotics have anti-H. pylori effects. Here we discuss the possibility of using natural probiotics present in traditional fermented food and beverages to obtain protection against H. pylori induced gastric diseases. PMID- 27504110 TI - Leukocyte Ig-Like Receptors - A Model for MHC Class I Disease Associations. AB - MHC class I (MHC-I) polymorphisms are associated with the outcome of some viral infections and autoimmune diseases. MHC-I proteins present antigenic peptides and are recognized by receptors on natural killer cells and cytotoxic T lymphocytes, thus enabling the immune system to detect self-antigens and eliminate targets lacking self or expressing foreign antigens. Recognition of MHC-I, however, extends beyond receptors on cytotoxic leukocytes. Members of the leukocyte Ig like receptor (LILR) family are expressed on monocytic cells and can recognize both classical and non-classical MHC-I alleles. Despite their relatively broad specificity when compared to the T cell receptor or killer Ig-like receptors, variations in the strength of LILR binding between different MHC-I alleles have recently been shown to correlate with control of HIV infection. We suggest that LILR recognition may mediate MHC-I disease association in a manner that does not depend on a binary discrimination of self/non-self by cytotoxic cells. Instead, the effects of LILR activity following engagement by MHC-I may represent a "degrees of self" model, whereby strength of binding to different alleles determines the degree of influence exerted by these receptors on immune cell functions. LILRs are expressed by myelomonocytic cells and lymphocytes, extending their influence across antigen-presenting cell subsets including dendritic cells, macrophages, and B cells. They have been identified as important players in the response to infection, inflammatory diseases, and cancer, with recent literature to indicate that MHC-I recognition by these receptors and consequent allelic effects could extend an influence beyond the immune system. PMID- 27504111 TI - Habitat Temperature and Precipitation of Arabidopsis thaliana Ecotypes Determine the Response of Foliar Vasculature, Photosynthesis, and Transpiration to Growth Temperature. AB - Acclimatory adjustments of foliar vascular architecture, photosynthetic capacity, and transpiration rate in Arabidopsis thaliana ecotypes (Italian, Polish [Col-0], Swedish) were characterized in the context of habitat of origin. Temperatures of the habitat of origin decreased linearly with increasing habitat latitude, but habitat precipitation was greatest in Italy, lowest in Poland, and intermediate in Sweden. Plants of the three ecotypes raised under three different growth temperature regimes (low, moderate, and high) exhibited highest photosynthetic capacities, greatest leaf thickness, highest chlorophyll a/b ratio and levels of beta-carotene, and greatest levels of wall ingrowths in phloem transfer cells, and, in the Col-0 and Swedish ecotypes, of phloem per minor vein in plants grown at the low temperature. In contrast, vein density and minor vein tracheary to sieve element ratio increased with increasing growth temperature - most strongly in Col-0 and least strongly in the Italian ecotype - and transpirational water loss correlated with vein density and number of tracheary elements per minor vein. Plotting of these vascular features as functions of climatic conditions in the habitat of origin suggested that temperatures during the evolutionary history of the ecotypes determined acclimatory responses of the foliar phloem and photosynthesis to temperature in this winter annual that upregulates photosynthesis in response to lower temperature, whereas the precipitation experienced during the evolutionary history of the ecotypes determined adjustment of foliar vein density, xylem, and transpiration to temperature. In particular, whereas photosynthetic capacity, leaf thickness, and foliar minor vein phloem features increased linearly with increasing latitude and decreasing temperature of the habitats of origin in response to experimental growth at low temperature, transpiration rate, foliar vein density, and minor vein tracheary element numbers and cross-sectional areas increased linearly with decreasing precipitation level in the habitats of origin in response to experimental growth at high temperature. This represents a situation where temperature acclimation of the apparent capacity for water flux through the xylem and transpiration rate in a winter annual responded differently from that of photosynthetic capacity, in contrast to previous reports of strong relationships between hydraulic conductance and photosynthesis in other studies. PMID- 27504112 TI - Multi-Scale Characean Experimental System: From Electrophysiology of Membrane Transporters to Cell-to-Cell Connectivity, Cytoplasmic Streaming and Auxin Metabolism. AB - The morphology of characean algae could be mistaken for a higher plant: stem-like axes with leaf-like branchlets anchored in the soil by root-like rhizoids. However, all of these structures are made up of giant multinucleate cells separated by multicellular nodal complexes. The excised internodal cells survive long enough for the nodes to give rise to new thallus. The size of the internodes and their thick cytoplasmic layer minimize impalement injury and allow specific micro-electrode placement. The cell structure can be manipulated by centrifugation, perfusion of cell contents or creation of cytoplasmic droplets, allowing access to both vacuolar and cytoplasmic compartments and both sides of the cell membranes. Thousands of electrical measurements on intact or altered cells and cytoplasmic droplets laid down basis to modern plant electrophysiology. Furthermore, the giant internodal cells and whole thalli facilitate research into many other plant properties. As nutrients have to be transported from rhizoids to growing parts of the thallus and hormonal signals need to pass from cell to cell, Characeae possess very fast cytoplasmic streaming. The mechanism was resolved in the characean model. Plasmodesmata between the internodal cells and nodal complexes facilitate transport of ions, nutrients and photosynthates across the nodes. The internal structure was found to be similar to those of higher plants. Recent experiments suggest a strong circadian influence on metabolic pathways producing indole-3-acetic acid (IAA) and serotonin/melatonin. The review will discuss the impact of the characean models arising from fragments of cells, single cells, cell-to-cell transport or whole thalli on understanding of plant evolution and physiology. PMID- 27504113 TI - Water Deficit Affects Primary Metabolism Differently in Two Lolium multiflorum/Festuca arundinacea Introgression Forms with a Distinct Capacity for Photosynthesis and Membrane Regeneration. AB - Understanding how plants respond to drought at different levels of cell metabolism is an important aspect of research on the mechanisms involved in stress tolerance. Furthermore, a dissection of drought tolerance into its crucial components by the use of plant introgression forms facilitates to analyze this trait more deeply. The important components of plant drought tolerance are the capacity for photosynthesis under drought conditions, and the ability of cellular membrane regeneration after stress cessation. Two closely related introgression forms of Lolium multiflorum/Festuca arundinacea, differing in the level of photosynthetic capacity during stress, and in the ability to regenerate their cellular membranes after stress cessation, were used as forage grass models in a primary metabolome profiling and in an evaluation of chloroplast 1,6-bisphosphate aldolase accumulation level and activity, during 11 days of water deficit, followed by 10 days of rehydration. It was revealed here that the introgression form, characterized by the ability to regenerate membranes after rehydration, contained higher amounts of proline, melibiose, galactaric acid, myo-inositol and myo-inositol-1-phosphate involved in osmoprotection and stress signaling under drought. Moreover, during the rehydration period, this form also maintained elevated accumulation levels of most the primary metabolites, analyzed here. The other introgression form, characterized by the higher capacity for photosynthesis, revealed a higher accumulation level and activity of chloroplast aldolase under drought conditions, and higher accumulation levels of most photosynthetic products during control and drought periods. The potential impact of the observed metabolic alterations on cellular membrane recovery after stress cessation, and on a photosynthetic capacity under drought conditions in grasses, are discussed. PMID- 27504114 TI - GmCLC1 Confers Enhanced Salt Tolerance through Regulating Chloride Accumulation in Soybean. AB - The family of chloride channel proteins that mediate Cl(-) transportation play vital roles in plant nutrient supply, cellular action potential and turgor pressure adjustment, stomatal movement, hormone signal recognition and transduction, Cl(-) homeostasis, and abiotic and biotic stress tolerance. The anionic toxicity, mainly caused by chloride ions (Cl(-)), on plants under salt stress remains poorly understood. In this work, we investigated the function of soybean Cl(-)/H(+) antiporter GmCLC1 under salt stress in transgenic Arabidopsis thaliana, soybean, and yeast. We found that GmCLC1 enhanced salt tolerance in transgenic A. thaliana by reducing the Cl(-) accumulation in shoots and hence released the negative impact of salt stress on plant growth. Overexpression of GmCLC1 in the hairy roots of soybean sequestered more Cl(-) in their roots and transferred less Cl(-) to their shoots, leading to lower relative electrolyte leakage values in the roots and leaves. When either the soybean GmCLC1 or the yeast chloride transporter gene, GEF1, was transformed into the yeast gef1 mutant, and then treated with different chloride salts (MnCl2, KCl, NaCl), enhanced survival rate was observed. The result indicates that GmCLC1 and GEF1 exerted similar effects on alleviating the stress of diverse chloride salts on the yeast gef1 mutant. Together, this work suggests a protective function of GmCLC1 under Cl(-) stress. PMID- 27504115 TI - Comprehensive Analysis of the Triterpenoid Saponins Biosynthetic Pathway in Anemone flaccida by Transcriptome and Proteome Profiling. AB - BACKGROUND: Anemone flaccida Fr. Shmidt (Ranunculaceae), commonly known as 'Di Wu' in China, is a perennial herb with limited distribution. The rhizome of A. flaccida has long been used to treat arthritis as a tradition in China. Studies disclosed that the plant contains a rich source of triterpenoid saponins. However, little is known about triterpenoid saponins biosynthesis in A. flaccida. RESULTS: In this study, we conducted the tandem transcriptome and proteome profiling of a non-model medicinal plant, A. flaccida. Using Illumina HiSeq 2000 sequencing and iTRAQ technique, a total of 46,962 high-quality unigenes were obtained with an average sequence length of 1,310 bp, along with 1473 unique proteins from A. flaccida. Among the A. flaccida transcripts, 36,617 (77.97%) showed significant similarity (E-value < 1e (-5)) to the known proteins in the public database. Of the total 46,962 unigenes, 36,617 open reading frame (ORFs) were predicted. By the fragments per kilobases per million reads (FPKM) statistics, 14,004 isoforms/unigenes were found to be upregulated, and 14,090 isoforms/unigenes were down-regulated in the rhizomes as compared to those in the leaves. Based on the bioinformatics analysis, all possible enzymes involved in the triterpenoid saponins biosynthetic pathway of A. flaccida were identified, including cytosolic mevalonate pathway (MVA) and the plastidial methylerythritol pathway (MEP). Additionally, a total of 126 putative cytochrome P450 (CYP450) and 32 putative UDP glycosyltransferases were selected as the candidates of triterpenoid saponins modifiers. Among them, four of them were annotated as the gene of CYP716A subfamily, the key enzyme in the oleanane-type triterpenoid saponins biosynthetic pathway. Furthermore, based on RNA-Seq and proteome analysis, as well as quantitative RT-PCR verification, the expression level of gene and protein committed to triterpenoids biosynthesis in the leaf versus the rhizome was compared. CONCLUSION: A combination of the de novo transcriptome and proteome profiling based on the Illumina HiSeq 2000 sequencing platform and iTRAQ technique was shown to be a powerful method for the discovery of candidate genes, which encoded enzymes that were responsible for the biosynthesis of novel secondary metabolites in a non-model plant. The transcriptome data of our study provides a very important resource for the understanding of the triterpenoid saponins biosynthesis of A. flaccida. PMID- 27504116 TI - The Diagnostic Utility of the NINDS-CSN Neuropsychological Battery in Memory Clinics. AB - AIMS: To examine the diagnostic utility of the National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network (NINDS-CSN) neuropsychological battery in memory clinics comparing controls with patients with no cognitive impairment (NCI), patients with cognitive impairment-no dementia (CIND) at varying severity levels (mild/moderate), and patients with dementia. METHODS: A total of 405 participants with NCI, CIND or dementia were assessed with the NINDS-CSN battery. The discriminatory properties of all three protocols (5, 30 and 60 min) before and after education stratification (none/primary vs. secondary/above) were examined by receiver operating characteristic curves. RESULTS: Overall, the shorter protocols are equivalent to the longer protocol in diagnosing dementia, regardless of education. To discriminate between nondementia groups, before education stratification, the 5 min protocol showed varied discriminatory properties between different diagnostic/severity groups. After stratification, the 5-min protocol was broadly equivalent to the longer protocols in lower-education groups [area under the curve (AUC) range: 0.77-0.87] but was less accurate in the higher-education groups (AUC range: 0.68-0.78). The 30- and 60-min protocol constantly showed moderate-to-excellent differentiating capacities regardless of education (AUC range: 0.80-0.90). CONCLUSION: The NINDS-CSN neuropsychological battery can be applied in memory clinics and effectively discriminate between cognitively intact individuals and those with cognitive impairments of varying severity. Furthermore, level of education should be taken into consideration when choosing protocols with different lengths for cognitive assessment. PMID- 27504117 TI - Increased Cerebrospinal Fluid Levels of Ubiquitin Carboxyl-Terminal Hydrolase L1 in Patients with Alzheimer's Disease. AB - BACKGROUND: Dysfunctions of the ubiquitin proteasome system (UPS), including the highly abundant neuronal enzyme ubiquitin carboxyl-terminal hydrolase L1 (UCH L1), and autophagy-related changes (lysosomal degradation) are implicated in several neurodegenerative disorders including Alzheimer's disease (AD). METHOD: This study evaluated cerebrospinal fluid (CSF) levels of UCH-L1, protein deglycase (DJ-1), neuron-specific enolase (NSE), and tau phosphorylated at threonine 231 (P-tau231) in two independent patient and control cohorts. Cohort 1 included CSF samples from subjects having an AD biomarker profile (n = 10) or a control biomarker profile (n = 31), while cohort 2 was a monocenter clinical study including patients with AD (n = 32), mild cognitive impairment (n = 13), other dementias (n = 15), as well as cognitively healthy controls (n = 20). RESULTS: UCH-L1 and P-tau231 were elevated in AD patients compared to controls in both cohorts. CSF levels of DJ-1 and NSE were unchanged in the AD group, whereas they were decreased in the group of other dementia compared to controls in the clinical study. CONCLUSION: Our main findings support that the UPS pathway may be impaired in AD, and UCH-L1 may serve as an additional CSF biomarker for AD. PMID- 27504118 TI - Low Leptin Availability as a Risk Factor for Dementia in Chilean Older People. AB - OBJECTIVE: The aim was to study the role of leptin in the development of dementia. METHODS: Follow-up of the ALEXANDROS cohorts, with baseline measurements in 2000. From 1,136 available subjects free of dementia at baseline, 667 subjects had frozen baseline blood samples for measuring leptin and soluble leptin receptor (sOB-R). The free leptin index (FLI) was calculated as the ratio of leptin to sOB-R. Dementia was defined as an MMSE score <22 and a score >5 in the Pfeffer Activities Questionnaire. RESULTS: After 15 years of follow-up, 42 incident cases of dementia were identified. No difference in serum leptin was observed between people with and without dementia, but sOB-R was higher in demented than in nondemented subjects (sOB-R: 44.94 +/- 23.97 vs. 33.73 +/- 21.13 ng/ml). The adjusted risk for dementia increased, the higher the log sOB (hazard ratio = 3.58; 95% CI 1.72-7.45, p = 0.001). CONCLUSION: Lower availability of free leptin was found in demented than in nondemented people, suggesting a role of leptin in cognition. PMID- 27504119 TI - Low Cerebrospinal Fluid Amyloid-Beta Concentration Is Associated with Poorer Delayed Memory Recall in Women. AB - BACKGROUND: Data on the association of memory performance with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are inconsistent. The Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery (CERAD-NB) is a commonly used validated cognitive tool; however, only few studies have examined its relationship with CSF biomarkers for AD. We studied the correlation of pathological changes in CSF biomarkers with various CERAD-NB subtests and total scores. METHODS: Out of 79 subjects (36 men, mean age 70.5 years), 63 had undergone an assessment of cognitive status with CERAD-NB and a CSF biomarker analysis due to a suspected memory disorder, and 16 were controls with no memory complaint. RESULTS: In women we found a significant correlation between CSF amyloid-beta (Abeta1-42) and several subtests measuring delayed recall. Word List Recall correlated with all markers: Abeta1-42 (r = 0.323, p = 0.035), tau (r = -0.304, p = 0.050) and hyperphosphorylated tau (r = -0.331, p = 0.046). No such correlations were found in men. CONCLUSIONS: CSF biomarkers correlate with delayed memory scores in CERAD-NB in women, and women may have more actual AD pathology at the time of the investigations than men. PMID- 27504120 TI - Profile of the Spleen Transcriptome in Beef Steers with Variation in Gain and Feed Intake. AB - We have previously identified components of the immune system contributing to feed intake and gain in both the rumen and small intestine of beef steers. In this study, we examined the spleen, a major lymphatic organ near the digestive tract, to determine whether it was also influencing individual feed efficiency status through immune responses. Animals (n = 16) that were divergent for gain and intake were selected for tissue sampling. The spleen transcriptomes were evaluated by microarray. A total of 1216 genes were identified as differentially expressed. Genes were over-represented in Kyoto encyclopedia of genes and genomes (KEGG) pathways including biological regulation, protein folding, cell communication, immune systems process, response to stress, and RNA metabolic process. Several stress response or heat shock genes including HSPH1, HSPA1A, HSPA4, DNAJB4, DNAJA4, etc., were identified as a stress response functional gene cluster in the low gain-low intake animals. These genes were up-regulated amongst the low gain-low intake animals compared to all other groups. Canonical pathways associated with the differentially expressed genes included the coagulation system, extrinsic prothrombin activation, protein ubiquitination, unfolded protein response, and aldosterone signaling in epithelial cells. An analysis of expressed copy number variable (CNV) genes in the spleen produced some of the same genes and gene families that were differentially expressed. Our data suggests the splenic contribution to some of the underlying variation among gain and intake within this group of animals may be a result of immune function and stress response. In addition, some of the differences in immune response functions may be related to gene copy number. PMID- 27504121 TI - Ulcerative Colitis Activity Presenting as Fever of Unknown Origin, in a Patient with Longstanding Disease under Continuous Treatment with Mesalazine. AB - Background. The presence of ulcerative colitis (UC) with no bowel symptoms, as fever of unknown origin (FUO), is uncommon. Objective. To describe the case of an 80-year-old woman who presented with fever, with a history of UC under treatment with mesalazine. Case Presentation. She was admitted due to fever lasting for 12 days with no associated symptoms. Seven years earlier, she was diagnosed with UC. After an extended workup for FUO that failed to reach the diagnosis, she underwent a gallium-67 scintigraphy. This revealed a persistent diffuse concentration of gallium-67 in the ascending colon at 24-hour imaging that remained stable at 48- and 72-hour imaging without any topographic change after the use of laxatives. Considering the results and in the absence of another diagnosis, the patient was treated with 30 mg prednisone daily and mesalazine, as treatment of active UC. Subsequently, the patient's condition improved markedly and the fever retreated. One month later, she was reevaluated with a gallium-67 scintigraphy with total absence of gallium-67 concentration in the ascending colon. Conclusion. UC activity must be included in the differential diagnosis of FUO in patients with longstanding disease, since fever may present alone, with no other manifestations. PMID- 27504122 TI - Diversification of Antitumour Immunity in a Patient with Metastatic Melanoma Treated with Ipilimumab and an IDO-Silenced Dendritic Cell Vaccine. AB - Indoleamine 2,3-dioxygenase (IDO) expression in dendritic cells (DCs) inhibits T cell activation and promotes T-cell differentiation into regulatory T-cells. Moreover, IDO expression promotes resistance to immunotherapies targeting immune checkpoints such as the cytotoxic T lymphocyte antigen-4 (CTLA-4). Here, a patient with metastatic melanoma pretreated with ipilimumab, an anti-CTLA-4 blocking antibody, was vaccinated with IDO-silenced DCs cotransfected with mRNA for survivin or hTERT tumour antigens. During vaccination, T-cell responses to survivin and hTERT tumour antigens were generated, and a certain degree of clinical benefit was achieved, with a significant reduction in lung, liver, and skin metastases, along with a better performance status. T-cell responses against MART-1 and NY-ESO-1 tumour antigens were also detected in the peripheral blood. The patient also mounted an antibody response to several melanoma proteins, indicating diversification of the antitumour immunity in this patient. The identification of such serum antibody-reacting proteins could facilitate the discovery of tumour neoantigens. PMID- 27504123 TI - Mystixin-7 Peptide Protects Ionotropic Glutamatergic Mechanisms against Glutamate Induced Excitotoxicity In Vitro. AB - Hyperactivation of the N-methyl-D-aspartic acid type glutamate receptors (NMDARs) causes glutamate excitotoxicity, a process potentially important for many neurological diseases. This study aims to investigate protective effects of the synthetic corticotrophin-releasing factor-like peptide, mystixin-7 (MTX), on model glutamate-induced excitotoxicity in vitro. The technique online monitoring of electrophysiological parameters (excitatory glutamatergic alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic (AMPAR) and NMDAR-dependent postsynaptic mechanisms) in the olfactory cortex slices was used. Application of L-glutamate in toxic concentration (20 mM) on slices evoked hyperactivation of NMDARs and weaker activation of the AMPARs. Upon further action agonist, the excessive activation of glutamate receptors was replaced by their irreversible blockade. Pretreatment of the slices using MTX in different concentrations (50 and 100 mg/mL) protected both NMDARs and AMPARs from glutamate-induced damage. An enzymatic treatment of MTX reduced hyperactivation of both NMDARs and AMPARs. The present study demonstrated that MTX minipeptide protected the functioning of both NMDARs and AMPARs against glutamate-induced damage. The MTX peptide is a prospective candidate for elaborated medication in treatment of neurological diseases. PMID- 27504124 TI - Focal partial salvage low-dose-rate brachytherapy for local recurrent prostate cancer after permanent prostate brachytherapy with a review of the literature. AB - PURPOSE: To investigate the treatment results for focal partial salvage re implantation against local recurrence after permanent prostate brachytherapy. MATERIAL AND METHODS: Between January 2010 and September 2015, 12 patients were treated with focal partial salvage re-implantation for local recurrence after low dose-rate brachytherapy using (125)I seeds. The focal clinical target volume (F CTV) was delineated on positive biopsy areas in a mapping biopsy, combining the cold spots on the post-implant dosimetry for initial brachytherapy. The F-CTV was expanded by 3 mm to create the planning target volume (PTV) as a margin to compensate for uncertainties in image registration and treatment delivery. The prescribed dose to the PTV was 145 Gy. The characteristics and biochemical disease-free survival (BdFS) rates were analyzed. Genitourinary (GU) and gastrointestinal (GI) toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4. RESULTS: The median prostate-specific antigen (PSA) level at re-implantation was 4.09 ng/ml (range: 2.91-8.24 ng/ml). The median follow-up time was 56 months (range: 6-74 months). The median RD2cc and UD10 were 63 Gy and 159 Gy, respectively. The 4-year BdFS rate was 78%, which included non-responders. Biochemical recurrence occurred in two patients after 7 and 31 months, respectively. The former was treated with hormonal therapy after biochemical failure, and the latter underwent watchful waiting (PSA at the last follow-up of 53 months: 7.3 ng/ml) at the patient's request. No patients had grade 3 GU/GI toxicities or died after salvage re-implantation. CONCLUSIONS: The partial salvage low-dose-rate brachytherapy used to treat local recurrence after permanent prostate brachytherapy is well-tolerated, with high biochemical response rates. This treatment can be not only a method to delay chemical castration but also a curative treatment option in cases of local recurrence of prostate carcinoma after seed implantation. PMID- 27504125 TI - Institutional experience using interstitial brachytherapy for the treatment of primary and recurrent pelvic malignancies. AB - PURPOSE: The study assessed the outcomes of patients at a single institution with locally advanced primary and recurrent pelvic malignancies treated with interstitial high-dose-rate (HDR) or low-dose-rate (LDR) brachytherapy (BT), using a modified Syed-Neblett template. MATERIAL AND METHODS: Between 1996 and 2010, 60 patients with primary or recurrent pelvic malignancies were treated with interstitial BT. Thirty three patients had primary malignancies with 6.1% being stage I, 33.3% stage II, 45.5% stage III, and 15.2% stage IV; the remaining 27 patients were recurrent malignancies. Fifty four patients received external beam radiotherapy (EBRT) as part of their treatment course. The median EBRT, BT, and EBRT + BT doses were 45 Gy, 20 Gy, and 65 Gy, respectively. Thirty eight patients received concurrent chemotherapy with EBRT. Complete response (CR) was defined by absence of clinical and radiographic disease on first follow-up. Toxicity was graded as per Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: The median follow-up was 37 months (4-234 months) and initial CR was achieved in 91%. For primary cancers at diagnosis, 5-year local control (LC), 5 year progression-free survival (PFS), 5-year overall survival (OS) were 65%, 64%, and 42% respectively. For recurrent cancers at diagnosis, 5-year LC, 5-year PFS, and 5-year OS were 80%, 51%, and 37%, respectively. There was a significant difference in both OS and PFS among different tumor sites (p < 0.05), with vaginal cancers having the best 5-year OS (55%) and PFS (84%). There was a total of 1 acute toxicity >= grade 3, 6 late grade 3 toxicities, and late grade 4 toxicity. CONCLUSIONS: Our series suggests that interstitial BT using a modified Syed-Neblett template is a safe and effective treatment for primary or recurrent pelvic malignancies. This technique allowed effective LC and 97% of patients had preservation of both bladder and rectal function. PMID- 27504126 TI - Predictive criteria for MRI-based evaluation of response both during and after radiotherapy for cervical cancer. AB - PURPOSE: For cervical carcinoma, the presence of persistent disease after radiotherapy (RT) is a significant predictor for survival. To date, no standard protocol is available to evaluate a response. This study was performed to assess magnetic resonance imaging (MRI) to evaluate presence of local residual disease during and after RT for Federation of Gynecology and Obstetrics (FIGO) stage Ib1 IVa cervical cancer. MATERIAL AND METHODS: Forty-two patients were included. Patients underwent MRI before external beam RT, at final intracavitary brachytherapy (BCT) and 2-3 months after completion of RT. Two blinded radiologists (observer 1: experienced, observer 2: less experienced) scored the likelihood of residual tumor. Magnetic resonance imaging was evaluated by means of (a) 'subjective' visual evaluation of T2 weighted MRI images, and (b) 'objective' visual evaluation of T2 weighted MRI images according to predefined imaging criteria. RESULTS: Seven patients had residual disease. Area under the receiver operating characteristics curve (AUC) for 'subjective' visual assessment was 0.79/0.75 (observer 1/observer 2) after RT and 0.75/0.43 at final BCT. The combined 'objective' MRI criteria (isointense, nodular, and irregular) resulted in improved prediction of residual tumor (AUCs of 0.91/0.85 after RT). For the less experienced observer, the MRI criteria set significantly improved prediction of residual tumor compared to 'subjective' visual assessment. Observer dependency decreased, kappa of 0.41 compared to 0.84 for the MRI criteria set after RT. CONCLUSION: Compared to 'subjective' visual assessment, predefined 'objective' MRI criteria increase diagnostic performance and decrease observer dependency for assessing residual tumor after RT in cervical cancer. PMID- 27504127 TI - Clinical comparison of brachytherapy versus hypofractionated external beam radiation versus standard fractionation external beam radiation for non melanomatous skin cancers. AB - PURPOSE: Non-melanomatous skin cancer (NMSC) is the single most common cancer in the US. Radiation therapy is an excellent treatment alternative to surgery. High dose-rate (HDR) brachytherapy and external beam radiotherapy (EBRT) are commonly used radiation treatment modalities but little data is published comparing these modalities. We present our institution's experience and outcomes with these therapeutic options. MATERIAL AND METHODS: From June 2005 to March 2013, 61 patients were treated with HDR brachytherapy (n = 9), hypofractionated EBRT (n = 30), or standard fractionation EBRT (n = 22) for NMSC. The primary outcome measure was local control at most remote follow-up and secondary outcome measures were overall survival, cosmetic outcome, and toxicity. Univariate analysis was performed to compare outcomes between treatment modalities. Kaplan-Meier analysis and log-rank test were used to compare overall survival. RESULTS: Median follow up was 30 months. The most common histologies were BCC (47%) and SCC (44%); mean patient age was 83.3 years. Local control was 81% and 2-year actuarial overall survival was 89%. There was no statistical difference in local control or overall survival between treatment modalities. There was no statistical difference in cosmetic outcome or toxicity between treatment modalities, although five of six "poor" cosmetic outcomes and the only grade 3 toxic events were found in the standard fractionation EBRT group. CONCLUSIONS: All modalities investigated represent effective treatments for NMSC and have good cosmetic outcomes and acceptable toxicity profiles. The finding of higher grade toxicity and a greater portion of patients experiencing toxicity among standard fractionation therapy is counter to expectations. There was no statistical significance to the finding and it is not likely to be meaningful. PMID- 27504128 TI - Highly conformal CT based surface mould brachytherapy for non-melanoma skin cancers of earlobe and nose. AB - PURPOSE: Brachytherapy (BT), due to rapid dose fall off and minor set-up errors, should be superior to external beam radiotherapy (EBRT) for treatment of lesions in difficult locations like nose and earlobe. Evidences in this field are scarce. We describe computed tomography (CT) based surface mould BT for non-melanoma skin cancers (NMSC), and compare its conformity, dose coverage, and tissue sparing ability to EBRT. MATERIAL AND METHODS: We describe procedure of preparation of surface mould applicator and dosimetry parameters of BT plans, which were implemented in 10 individuals with NMSC of nose and earlobe. We evaluated dose coverage by minimal dose to 90% of planning target volume (PTV) (D90), volumes of PTV receiving 90-150% of prescribed dose (PD) (VPTV90-150), conformal index for 90 and 100% of PD (COIN90, COIN100), dose homogeneity index (DHI), dose nonuniformity ratio (DNR), exposure of organs. Prospectively, we created CT-based photons and electrons plans. We compared conformity (COIN90, COIN100), dose coverage of PTV (D90, VPTV90, VPTV100), volumes of body receiving 10-90% of PD (V10-V90) of EBRT and BT plans. RESULTS: We obtained mean BT-DHI = 0.76, BT-DNR = 0.23, EBRT-DHI = 1.26. We observed no significant differences in VPTV90 and D90 between BT and EBRT. Mean BT-VPTV100 (89.4%) was higher than EBRT-VPTV100 (71.2%). Both COIN90 (BT-COIN90 = 0.46 vs. EBRT-COIN90 = 0.21) and COIN100 (BT COIN100 = 0.52 vs. EBRT-COIN100 = 0.26) were superior for BT plans. We observed more exposure of normal tissues for small doses in BT plans (V10, V20), for high doses in EBRT plans (V70, V90). CONCLUSIONS: Computed tmography-based surface mould brachytherapy for superficial lesions on irregular surfaces is a highly conformal method with good homogeneity. Brachytherapy is superior to EBRT in those locations in terms of conformity and normal tissue sparing ability in high doses. PMID- 27504129 TI - Robustness of IPSA optimized high-dose-rate prostate brachytherapy treatment plans to catheter displacements. AB - PURPOSE: Inverse planning simulated annealing (IPSA) optimized brachytherapy treatment plans are characterized with large isolated dwell times at the first or last dwell position of each catheter. The potential of catheter shifts relative to the target and organs at risk in these plans may lead to a more significant change in delivered dose to the volumes of interest relative to plans with more uniform dwell times. MATERIAL AND METHODS: This study aims to determine if the Nucletron Oncentra dwell time deviation constraint (DTDC) parameter can be optimized to improve the robustness of high-dose-rate (HDR) prostate brachytherapy plans to catheter displacements. A set of 10 clinically acceptable prostate plans were re-optimized with a DTDC parameter of 0 and 0.4. For each plan, catheter displacements of 3, 7, and 14 mm were retrospectively applied and the change in dose volume histogram (DVH) indices and conformity indices analyzed. RESULTS: The robustness of clinically acceptable prostate plans to catheter displacements in the caudal direction was found to be dependent on the DTDC parameter. A DTDC value of 0 improves the robustness of planning target volume (PTV) coverage to catheter displacements, whereas a DTDC value of 0.4 improves the robustness of the plans to changes in hotspots. CONCLUSIONS: The results indicate that if used in conjunction with a pre-treatment catheter displacement correction protocol and a tolerance of 3 mm, a DTDC value of 0.4 may produce clinically superior plans. However, the effect of the DTDC parameter in plan robustness was not observed to be as strong as initially suspected. PMID- 27504130 TI - Clinical applications of custom-made vaginal cylinders constructed using three dimensional printing technology. AB - PURPOSE: Three-dimensional (3D) printing technology allows physicians to rapidly create customized devices for patients. We report our initial clinical experience using this technology to create custom applicators for vaginal brachytherapy. MATERIAL AND METHODS: Three brachytherapy patients with unique clinical needs were identified as likely to benefit from a customized vaginal applicator. Patient 1 underwent intracavitary vaginal cuff brachytherapy after hysterectomy and chemotherapy for stage IA papillary serous endometrial cancer using a custom printed 2.75 cm diameter segmented vaginal cylinder with a central channel. Patient 2 underwent interstitial brachytherapy for a vaginal cuff recurrence of endometrial cancer after prior hysterectomy, whole pelvis radiotherapy, and brachytherapy boost. We printed a 2 cm diameter vaginal cylinder with one central and six peripheral catheter channels to fit a narrow vaginal canal. Patient 3 underwent interstitial brachytherapy boost for stage IIIA vulvar cancer with vaginal extension. For more secure applicator fit within a wide vaginal canal, we printed a 3.5 cm diameter solid cylinder with one central tandem channel and ten peripheral catheter channels. The applicators were printed in a biocompatible, sterilizable thermoplastic. RESULTS: Patient 1 received 31.5 Gy to the surface in three fractions over two weeks. Patient 2 received 36 Gy to the CTV in six fractions over two implants one week apart, with interstitial hyperthermia once per implant. Patient 3 received 18 Gy in three fractions over one implant after 45 Gy external beam radiotherapy. Brachytherapy was tolerated well with no grade 3 or higher toxicity and no local recurrences. CONCLUSIONS: We established a workflow to rapidly manufacture and implement customized vaginal applicators that can be sterilized and are made of biocompatible material, resulting in high quality brachytherapy for patients whose anatomy is not ideally suited for standard, commercially available applicators. PMID- 27504131 TI - Potential role of TRAns Cervical Endosonography (TRACE) in brachytherapy of cervical cancer: proof of concept. AB - PURPOSE: Magnetic resonance imaging (MRI) is the gold standard for image guided adaptive brachytherapy (BT) of cervical cancer. Ultrasound is an attractive alternative with reasonable costs and high soft tissue depiction quality. This technical note aims to demonstrate the proof of principle for use of TRAns Cervical Endosonography with rotating transducer in the context of brachytherapy (TRACE BT). MATERIAL AND METHODS: TRACE BT presentation is based on a single stage IIB cervical cancer patient. Prior to second BT implant, rotating US transducer (6.9 mm diameter) was inserted in cervical canal and axial images obtained at 10 MHz, focal range of 30 mm, and axial resolution of 0.4 mm. Size and topography of hypo-echoic areas were assessed and optimal positions of interstitial needles were determined. Finally, intracavitary applicator was placed and needles inserted through vaginal ring-template according to TRACE pre plan. MRI-based high risk clinical target volume (CTVHR) dimensions were compared with hypoechoic areas on TRACE. Topography of parametrial needles on post insertion MRI was compared with TRACE pre-plan. RESULTS: Insertion of rotating mechanism into cervico-uterine cavity was safe, feasible and fast. The 360 degrees imaging in axial plane enabled real-time assessment of cervix, uterus, and adjacent parametria. Qualitative comparison of TRACE with post-insertion MRI revealed favorable agreement of findings. In-plane size of CTVHR on MRI was comparable to hypoechoic areas on TRACE. Needle positions on post-insertion MRI corresponded to TRACE-based pre-plan. Main limitation of TRACE was gradual deterioration of image quality due to coupling gel removal. CONCLUSIONS: Present proof of concept demonstrates potential role of TRACE-BT for cervical cancer as an attractive high-tech approach with reasonable costs. Prior to investigation of its clinical role, further development of TRACE methodology is needed. This includes reliable transducer-tissue coupling, applicator reconstruction, imaging range, limitations in extensive tumors, US-based contouring concepts, registration with other imaging methods, organ dose-assessment, real-time dosimetry, etc. PMID- 27504132 TI - Dosimetric study for cervix carcinoma treatment using intensity modulated radiation therapy (IMRT) compensation based on 3D intracavitary brachytherapy technique. AB - PURPOSE: Intensity modulated radiation therapy (IMRT) compensation based on 3D high-dose-rate (HDR) intracavitary brachytherapy (ICBT) boost technique (ICBT + IMRT) has been used in our hospital for advanced cervix carcinoma patients. The purpose of this study was to compare the dosimetric results of the four different boost techniques (the conventional 2D HDR intracavitary brachytherapy [CICBT], 3D optimized HDR intracavitary brachytherapy [OICBT], and IMRT-alone with the applicator in situ). MATERIAL AND METHODS: For 30 patients with locally advanced cervical carcinoma, after the completion of external beam radiotherapy (EBRT) for whole pelvic irradiation 45 Gy/25 fractions, five fractions of ICBT + IMRT boost with 6 Gy/fractions for high risk clinical target volume (HRCTV), and 5 Gy/fractions for intermediate risk clinical target volume (IRCTV) were applied. Computed tomography (CT) and magnetic resonance imaging (MRI) scans were acquired using an in situ CT/MRI-compatible applicator. The gross tumor volume (GTV), the high/intermediate-risk clinical target volume (HRCTV/IRCTV), bladder, rectum, and sigmoid were contoured by CT scans. RESULTS: For ICBT + IMRT plan, values of D90, D100 of HRCTV, D90, D100, and V100 of IRCTV significantly increased (p < 0.05) in comparison to OICBT and CICBT. The D2cc values for bladder, rectum, and sigmoid were significantly lower than that of CICBT and IMRT alone. In all patients, the mean rectum V60 Gy values generated from ICBT + IMRT and OICBT techniques were very similar but for bladder and sigmoid, the V60 Gy values generated from ICBT + IMRT were higher than that of OICBT. For the ICBT + IMRT plan, the standard deviations (SD) of D90 and D2cc were found to be lower than other three treatment plans. CONCLUSIONS: The ICBT + IMRT technique not only provides good target coverage but also maintains low doses (D2cc) to the OAR. ICBT + IMRT is an optional technique to boost parametrial region or tumor of large size and irregular shape when intracavitary/interstitial brachytherapy cannot be used. PMID- 27504133 TI - Development of a magnetic resonance imaging protocol to visualize encapsulated contrast agent markers in prostate brachytherapy recipients: initial patient experience. AB - PURPOSE: Computed tomography (CT)-based prostate post-implant dosimetry allows for definitive seed localization but is associated with high interobserver variation in prostate contouring. Currently, magnetic resonance imaging (MRI) based post-implant dosimetry allows for accurate anatomical delineation but is limited due to inconsistent seed localization. Encapsulated contrast agent markers were previously proposed to overcome the seed localization limitation on MRI images by placing hyperintense markers adjacent to hypointense seeds. The aim of this study was to assess the appearance of these markers in prostatic tissue, and develop an MRI protocol to enable marker visualization. MATERIAL AND METHODS: We acquired MRI scans in prostate implant patients (n = 10) on day 0 (day of implant) and day 30 (month after implant). Before implantation of the markers, the routine post-implant MRI protocol included a 3D T2-weighted fast-spin-echo (FSE) sequence with which markers and seeds could not be clearly visualized. To visualize the MRI markers, a 3D fast radiofrequency-spoiled gradient-recalled echo (FSPGR) sequence was evaluated for marker and seed visibility, as well as prostate boundary definitions. RESULTS: The 3D FSPGR sequence allowed for the visualization of markers in the prostate, enabling the distinction of signal voids as seeds versus needle tracks. The updated post-implant MRI protocol consists of this 3D FSPGR scan and an optional 3D T2-weighted FSE scan. The optional 3D T2-weighted FSE sequence may be employed to better visualize intraprostatic detail. We also described the observed image artifacts, including seed susceptibility, marker chemical shift, partial volume averaging, motion, and wraparound artifacts. CONCLUSIONS: We have demonstrated an MRI protocol for use with hyperintense encapsulated contrast agent markers to assist in the identification of hypointense seeds. PMID- 27504134 TI - Single fraction multimodal image guided focal salvage high-dose-rate brachytherapy for recurrent prostate cancer. AB - PURPOSE: We present a novel method for treatment of locally recurrent prostate cancer (PCa) following radiation therapy: focal, multimodal image guided high dose-rate (HDR) brachytherapy. MATERIAL AND METHODS: We treated two patients with recurrent PCa after primary (#1) or adjuvant (#2) external beam radiation therapy. Multiparametric magnetic resonance imaging (mpMRI), choline, positron emission tomography combined with computed tomography (PET/CT), or prostate specific membrane antigen (PSMA)-PET combined with CT identified a single intraprostatic lesion. Positron emission tomography or magnetic resonance imaging - transrectal ultrasound (MRI-TRUS) fusion guided transperineal biopsy confirmed PCa within each target lesion. We defined a PET and mpMRI based gross tumor volume (GTV). A 5 mm isotropic margin was applied additionally to each lesion to generate a planning target volume (PTV), which accounts for technical fusion inaccuracies. A D90 of 18 Gy was intended in one fraction to each PTV using ultrasound guided HDR brachytherapy. RESULTS: Six month follow-up showed adequate prostate specific antygen (PSA) decline in both patients (DeltaPSA 83% in patient 1 and DeltaPSA 59.3% in patient 2). Follow-up 3-tesla MRI revealed regressive disease in both patients and PSMA-PET/CT showed no evidence of active disease in patient #1. No acute or late toxicities occurred. CONCLUSIONS: Single fraction, focal, multimodal image guided salvage HDR brachytherapy for recurrent prostate cancer is a feasible therapy for selected patients with single lesions. This approach has to be evaluated in larger clinical trials. PMID- 27504135 TI - Image-guided high-dose-rate brachytherapy of malignancies in various inner organs - technique, indications, and perspectives. AB - In the last few years, minimally invasive tumor ablation performed by interventional radiologists has gained increasing relevance in oncologic patient care. Limitations of thermal ablation techniques such as radiofrequency ablation (RFA), microwave ablation (MWA), and laser-induced thermotherapy (LITT), including large tumor size, cooling effects of adjacent vessels, and tumor location near thermosensitive structures, have led to the development of image guided high-dose-rate (HDR) brachytherapy, especially for the treatment of liver malignancies. This article reviews technical properties of image-guided brachytherapy, indications and its current clinical role in multimodal cancer treatment. Furthermore, perspectives of this novel therapy option will be discussed. PMID- 27504136 TI - PGC-1alpha Mediated Peripheral Nerve Protection of Tongxinluo in STZ-Induced Diabetic Rats. AB - Aim. To investigate the effect of Tongxinluo (Txl), a Chinese herbal compound, on diabetic peripheral neuropathy (DPN). Methods and Results. Diabetic rat model was established by peritoneal injection of streptozotocin (STZ). Txl ultrafine powder treatment for 16 weeks from the baseline significantly reversed the impairment of motor nerve conductive velocity (MNCV), mechanical hyperalgesia, and nerve structure. We further proved that Tongxinluo upregulates PGC-1alpha and its downstream factors including COX IV and SOD, which were involved in mitochondrial biogenesis. Conclusion. Our study indicates that the protective effect of Txl in diabetic neuropathy may be attributed to the induction of PGC-1alpha and its downstream targets. This finding may further illustrate the pleiotropic effect of the medicine. PMID- 27504137 TI - Inhibitory Effect of Yongdamsagan-Tang Water Extract, a Traditional Herbal Formula, on Testosterone-Induced Benign Prostatic Hyperplasia in Rats. AB - Yongdamsagan-tang, a traditional herbal formula, is used widely for the treatment of inflammation and viral diseases. In this study, we investigated whether Yongdamsagan-tang water extract (YSTE) affects testosterone propionate- (TP-) induced benign prostatic hyperplasia (BPH) in a rat model. To induce BPH, rats were injected subcutaneously with 10 mg/kg of TP every day. YSTE was administrated daily by oral gavage at doses of 200 and 500 mg/kg along with the TP injection. After 4 weeks, prostates were collected, weighed, and analyzed. The relative prostrate weight was significantly lower in both YSTE groups (200 and 500 mg/kg/day) compared with the TP-induced BPH group. YSTE administration reduced the expression of proliferation markers PCNA, cyclin D1, and Ki-67 and the histological abnormalities observed in the prostate in TP-induced BPH rats. YSTE attenuated the increase in the TP-induced androgen concentration in the prostate. The YSTE groups also showed decreased lipid peroxidation and increased glutathione reductase activity in the prostate. These findings suggest that YSTE effectively prevented the development of TP-induced BPH in rats through antiproliferative and antioxidative activities and might be useful in the clinical treatment of BPH. PMID- 27504138 TI - Pain and Inflammation: Update on Emerging Phytotherapy, Zootherapy, and Nutritional Therapies. PMID- 27504139 TI - Extracorporeal Shock Wave Stimulation as Alternative Treatment Modality for Wrist and Fingers Spasticity in Poststroke Patients: A Prospective, Open-Label, Preliminary Clinical Trial. AB - Objective. To evaluate the effectiveness of radial shock waves (rESW) for wrist and fingers flexors spasticity in stroke patients. Methods. Twenty patients with upper limb muscle spasticity were enrolled in the study and treated with a single session of rESW. The spasticity level of the radio carpal (RC) and finger (FF) joints was assessed using Modified Ashworth Scale (MAS). The resting bioelectrical activity of the flexor carpi radialis (FCR) and flexor carpi ulnaris (FCU) was examined using surface electromyography (sEMG). Trophic conditions were measured using infrared thermal (IRT) imaging. All measurements were conducted at baseline (t 0), immediately after rESW (t 1), and 1 (t 2) and 24 (t 3) hours following rESW. Results. Significant reduction in MAS was observed for the RC joint in t 1, as well as for the FF joints in t 1, t 2, and t 3. A significant decrease in sEMG was shown for the FCR muscle in t 1 and t 2, as well as for the FCU muscle in t 1 and t 3. Also, a significant increase in IRT value was observed in t 3 only. Conclusions. A single session of rESW could be an effective alternative treatment for reduction of limb spasticity and could lead to improvement of trophic conditions of the spastic muscles. PMID- 27504140 TI - MAPK Pathways Are Involved in Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion. AB - The aim of the present study was to investigate whether the MAPK pathways were involved in the mechanism of neuropathic pain in rats with chronic compression of the dorsal root ganglion. We determined the paw withdrawal mechanical threshold (PWMT) of rats before and after CCD surgery and then after p38, JNK, or ERK inhibitors administration. Western blotting, RT-PCR, and immunofluorescence of dorsal root ganglia were performed to investigate the protein and mRNA level of MAPKs and also the alternation in distributions of positive neurons in dorsal root ganglia. Intrathecal administration of MAPKs inhibitors, SB203580 (p38 inhibitor), SP600125 (JNK inhibitor), and U0126 (ERK inhibitor), resulted in a partial reduction in CCD-induced mechanical allodynia. The reduction of allodynia was associated with significant depression in the level of both MAPKs mRNA and protein expression in CCD rats and also associated with the decreased ratios of large size MAPKs positive neurons in dorsal root ganglia. In conclusion, the specific inhibitors of MAPKs contributed to the attenuation of mechanical allodynia in CCD rats and the large size MAPKs positive neurons in dorsal root ganglia were crucial. PMID- 27504141 TI - System effectiveness of detection, brief intervention and refer to treatment for the people with post-traumatic emotional distress by MERS: a case report of community-based proactive intervention in South Korea. AB - BACKGROUND: Korea has experienced diverse kind of disasters these days. Among them the 2015 middle eastern respiratory syndrome (MERS) outbreak imposed great psychological stress on almost all Korean citizens. Following the MERS outbreak, government is reviewing overall infectious disease management system and prioritizing the establishment of mental health service systems for infectious disease. This study makes suggestions for implementing disaster-related mental health service systems by analyzing the example of Gyeonggi Province, which proactively intervened with residents' psychological problems caused by the large scale outbreak of an infectious disease. CASE DESCRIPTION: Mental health service system for MERS victims had the following two parts: a mental health service for people who had been placed in quarantine and a service provided to families of patients who had died or recovered patients. The government of Gyeonggi province, public health centers, regional and local Community Mental Health Centers and the National Center for Crisis Mental Health Management participated in this service system. Among 1221 Gyeonggi people placed in quarantine and who experienced psychological and emotional difficulties, 350 required continuing services; 124 of this group received continuing services. That is, 35 % of people who required psychological intervention received contact from service providers and received the required services. CONCLUSIONS: This study reflects a proactive monitoring system for thousands of people placed under quarantine for the first time in Korea. It is significant that the service utilization rate by a proactive manner, that is the professionals administering it actively approached and contacted people with problems rather than passively providing information was much higher than other general mental health situation in Korea. The core value of public mental health services is adequate public accessibility; it is therefore essential for governments to strengthen their professional competence and establish effective systems. These criteria should also be applied to psychological problems caused by disastrous infectious disease outbreaks. PMID- 27504142 TI - Thoughts about SLC16A2, TSIX and XIST gene like sites in the human genome and a potential role in cellular chromosome counting. AB - BACKGROUND: Chromosome counting is a process in which cells determine somehow their intrinsic chromosome number(s). The best-studied cellular mechanism that involves chromosome counting is 'chromosome-kissing' and X-chromosome inactivation (XCI) mechanism. It is necessary for the well-known dosage compensation between the genders in mammals to balance the number of active X chromosomes (Xa) with regard to diploid set of autosomes. At the onset of XCI, two X-chromosomes are coming in close proximity and pair physically by a specific segment denominated X-pairing region (Xpr) that involves the SLC16A2 gene. RESULTS: An Ensembl BLAST search for human and mouse SLC16A2/Slc16a2 homologues revealed, that highly similar sequences can be found at almost each chromosome in the corresponding genomes. Additionally, a BLAST search for SLC16A2/TSIX/XIST (genes responsible for XCI) reveled that "SLC16A2/TSIX/XIST like sequences" cover equally all chromosomes, too. With respect to this we provide following hypotheses. HYPOTHESES: If a single genomic region containing the SLC16A2 gene on X-chromosome is responsible for maintaining "balanced" active copy numbers, it is possible that similar sequences or gene/s have the same function on other chromosomes (autosomes). SLC16A2 like sequences on autosomes could encompass evolutionary older, but functionally active key regions for chromosome counting in early embryogenesis. Also SLC16A2 like sequence on autosomes could be involved in inappropriate chromosomes pairing and, thereby be involved in aneuploidy formation during embryogenesis and cancer development. Also, "SLC16A2/TSIX/XIST gene like sequence combinations" covering the whole genome, could be important for the determination of X:autosome ratio in cells and chromosome counting. CONCLUSIONS: SLC16A2 and/or SLC16A2/TSIX/XIST like sequence dispersed across autosomes and X-chromosome(s) could serve as bases for a counting mechanism to determine X:autosome ratio and could potentially be a mechanism by which a cell also counts its autosomes. It could also be that such specific genomic regions have the same function for each specific autosome. As errors during the obviously existing process of chromosome counting are one if not the major origin of germline/somatic aneuploidy the here presented hypotheses should further elaborated and experimentally tested. PMID- 27504143 TI - Neurophysiological hyperresponsivity to sensory input in autism spectrum disorders. AB - BACKGROUND: Atypical sensory processing is a common clinical observation in autism spectrum disorder (ASD). Neural hyperexcitability has been suggested as the cause for sensory hypersensitivity, a frequently reported clinical observation in ASD. We examined visual evoked responses to parametric increases in stimulus contrast in order to model neural responsivity of sensory systems in ASD. METHODS: Thirteen high-functioning individuals with ASD and 12 typically developing (TD) individuals completed a steady-state visual evoked potential study. Stimuli were vertical circular gratings oscillating at 3.76 Hz at varying contrasts (5, 10, 20,..., 90 % contrast, 10 levels). The average spectral power at the stimulus oscillation frequency was calculated for each contrast level. RESULTS: The magnitude of evoked sensory responses increased at a significantly greater rate and resulted in disproportionately elevated activation with higher contrasts in the ASD group. Approximately 45 % of ASD participants had rates of response increases greater than any TD participant. This alteration was highly associated with parental reports of these participants' sensory difficulties. CONCLUSIONS: Greater increases in visual responses over contrast manipulation suggest heightened excitability in the sensory cortex in ASD participants. Heightened neural excitability was observed in a substantial portion but not all of the ASD participants. This pattern suggests that individuals with higher excitability may constitute a neurobiologically distinct subgroup requiring individualized treatment interventions. PMID- 27504144 TI - Imaging of Retrosternal Space Lesions - A Pictorial Review. AB - The retrosternal region (RSS) can be involved by diverse lesions. The RSS is the region behind the sternum and anterior to the ascending aorta. It normally is less than 3 cm deep. Chest X-ray is usually the first imaging modality to raise a suspicion of RSS pathology; however computed tomography is the mainstay to delineate and characterize lesions in this location. Lesions in this location include thyroid, thymic and lymph node lesions; germ cell tumors and vascular lesions. Lesions arising from the sternum, lungs as well as the pleura can also involve this space. The pictorial review depicts the diverse spectrum of lesions in this location. PMID- 27504145 TI - Evaluation of the Course of the Inferior Alveolar Canal: The First CBCT Study in an Iranian Population. AB - BACKROUND: The frequent anatomical variations of the inferior alveolar nerve (IAN) course should be considered prior to any treatment in this area. The aim of this study was to evaluate the course of the inferior alveolar canal (IAC) as it appears in the archived CBCT images of the mandible. MATERIAL/METHOD: This cross- sectional study evaluated a sample of 156 CBCT examinations. The pattern of the IAC was evaluated and the prevalence of different patterns according to age and gender were recorded. In order to find the frequency of mandibular canal type among different ages, the patients were put into the three age groups (20-29, 30 44 and 45-59).The data were analyzed using Chi-square test and the significance level was set as p<=.05. RESULTS: Out of 156 patients, 52 canals was straight type, 52 had Catenary type and 52 of them were presented with Progressive descending type. There was not statistically significant difference between two genders (Pv=0.092). According to the type of the IAC course, there was a not statistically significant difference between the three age groups (Pv=0.32). CONCLUSIONS: Cone beam computed tomography is a useful method for precise assessment of the IAC course. PMID- 27504146 TI - Intranodal Palisaded Myofibroblastoma: Radiological and Cytological Overview. AB - BACKGROUND: Intranodal palisaded myofibroblastoma is a benign and very rare mesenchymal neoplasm of the lymph nodes originating from differentiated smooth muscle cells and myofibroblasts. CASE REPORT: We report a case of intranodal palisaded myofibroblastoma in an 84-year-old woman with Parkinson's disease that presented as a left inguinal mass. The diagnosis was made using ultrasound-guided fine needle aspiration biopsy and consequent cytopathological examination that included immunohistochemical analysis. Herein, we discuss the presentation of a rare intranodal palisaded myofibroblastoma with emphasis on its ultrasonographic and cytopathologic features. CONCLUSIONS: Intranodal palisaded myofibroblastoma should be considered in the differential diagnosis of inguinal lymphadenopathy and the diagnosis is possible with cytopathologic exam and immunohistochemical analysis using ultrasound-guided FNA biopsy, guiding the clinician to nodal excision rather than aggressive measures. PMID- 27504147 TI - Assessing worldwide research activity on probiotics in pediatrics using Scopus database: 1994-2014. AB - BACKGROUND: A wide variety of probiotic products has been introduced into the market in the past decade. Research trends and activity on probiotics help understand how these products were evolved and their potential future role in medicine. The objective of this study was to assess the research activity on probiotics in pediatrics using bibliometric indicators and network visualization. METHODS: Original and review articles on probiotics in pediatrics published worldwide were retrieved from SciVerse, Scopus (1994-2014) and analyzed. VOSviewer was used for network visualization. RESULTS: The total number of documents published on probiotics in pediatrics was 2817. Research activity on probiotics in pediatrics showed approximately 90- fold increase during the study period. Approximately 22 % of published articles originated from USA and has the greatest share, however, Finland ranked first when data were stratified by population or income. The most productive institution in this field was Turku University in Finland with 82 (2.91 %) articles. Half of the prolific authors were also from Finland. Most of the published research activity appeared in Journal of Pediatric Gastroenterology and Nutrition. Most frequently encountered title terms include nutrition, infant formula, necrotizing enetrocolitis, allergy, and diarrhea. The total number of citations for the retreived documents documents was 70991, and the average citation per article was 25.20. CONCLUSIONS: Interest in probiotic research and its potential benefits in pediatric ailments is relatively recent but significantly increasing. Bibliometric analysis can be used as an indicator of the importance and growth of probiotic use in pediatrics. PMID- 27504148 TI - Oxidative Stress Assessment in Response to Ultraendurance Exercise: Thiols Redox Status and ROS Production according to Duration of a Competitive Race. AB - Purpose. Response to an ultraendurance competitive race on thiols redox status, reactive oxygen species (ROS) production, and oxidative stress (OxS) was investigated according to duration. Methods. Twenty-four elite runners were examined: six completed 50 km and eighteen 100 km. Blood and urine samples were collected before and immediately after the race. Erythrocytes and plasma aminothiols by high-performance liquid chromatography, total antioxidant capacity (TAC), and OxS biomarkers (protein carbonyl (PC), thiobarbituric acid-reactive substances (TBARS), 8-isoprostane (8-iso-PGF2alpha), and 8-OH-2-deoxyguanosine (8 OH-dG)) by immunoenzymatic assays and ROS production by Electron Paramagnetic Resonance were assessed. Results. Significant increases (P between <0.05 and <0.0001) were recorded in plasma total and oxidized aminothiols concentration and TAC (P < 0.0001) only after 100 km: plasmatic (ROS production (+12 versus +29%), PC (+54 versus +115%), and TBARS (+28 versus +55%)) and urinary (8-OH dG.creatinine(-1) (+71 versus +158%) and 8-iso-PGF2alpha.creatinine(-1) (+43 versus +135%)) concentrations for 50 and 100 km (duration 4 h 3' versus 8 h 42'), respectively. Conclusion. Very prolonged ultraendurance exercise causes an increase in ROS production and OxS depending on specific biomarker examined but always linearly and directly related to exercise duration. Redox status of erythrocytes was preserved. A relationship between running performance and both prerace ROS production and antioxidant-redox status was found in 100 km race. PMID- 27504149 TI - "Cumulative Stress": The Effects of Maternal and Neonatal Oxidative Stress and Oxidative Stress-Inducible Genes on Programming of Atopy. AB - Although extensive epidemiological and laboratory studies have been performed to identify the environmental and immunological causes of atopy, genetic predisposition seems to be the biggest risk factor for allergic diseases. The onset of atopic diseases may be the result of heritable changes of gene expression, without any alteration in DNA sequences occurring in response to early environmental stimuli. Findings suggest that the establishment of a peculiar epigenetic pattern may also be generated by oxidative stress (OS) and perpetuated by the activation of OS-related genes. Analyzing the role of maternal and neonatal oxidative stress and oxidative stress-inducible genes, the purpose of this review was to summarize what is known about the relationship between maternal and neonatal OS-related genes and the development of atopic diseases. PMID- 27504150 TI - Hepatoprotective Effect of Quercetin on Endoplasmic Reticulum Stress and Inflammation after Intense Exercise in Mice through Phosphoinositide 3-Kinase and Nuclear Factor-Kappa B. AB - The mechanisms underlying intense exercise-induced liver damage and its potential treatments remain unclear. We explored the hepatoprotection and mechanisms of quercetin, a naturally occurring flavonoid, in strenuous exercise-derived endoplasmic reticulum stress (ERS) and inflammation. Intense exercise (28 m/min at a 5 degrees slope for 90 min) resulted in the leakage of aminotransferases in the BALB/C mice. The hepatic ultrastructural malformations and oxidative stress levels were attenuated by quercetin (100 mg/kg.bw). Intense exercise and thapsigargin- (Tg-) induced ERS (glucose-regulated protein 78, GRP78) and inflammatory cytokines levels (IL-6 and TNF-alpha) were decreased with quercetin. Furthermore, quercetin resulted in phosphoinositide 3-kinase (PI3K) induction, Ca(2+) restoration, and blockade of the activities of Jun N-terminal kinase (JNK), activating transcription factor 6 (ATF6) and especially NF-kappaB (p65 and p50 nuclear translocation). A PI3K inhibitor abrogated the protection of quercetin on ERS and inflammation of mouse hepatocytes. SP600125 (JNK inhibitor), AEBSF (ATF6 inhibitor), and especially PDTC (NF-kappaB inhibitor) enhanced the quercetin-induced protection against Tg stimulation. Collectively, intense exercise-induced ERS and inflammation were attenuated by quercetin. PI3K/Akt activation and JNK, ATF6, and especially NF-kappaB suppression were involved in the protection. Our results highlight a novel preventive strategy for treating ERS and inflammation-mediated liver damage induced by intense exercise using natural phytochemicals. PMID- 27504151 TI - Effect of Gestational Diabetes on Purkinje and Granule Cells Distribution of the Rat Cerebellum in 21 and 28 days of Postnatal Life. AB - INTRODUCTION: Diabetes mellitus is associated with nervous system alterations in both human and animal models. This study was done to determine the effect of gestational diabetes on the Purkinje and granular cells in the cerebellum of rat offspring. METHODS: 10 Wistar rats Dams were randomly allocated in control and diabetic group. The experimental group received 40 mg/kg/body weight of streptozotocin (STZ) at the first day of gestation and control groups received saline injection intraperitoneally (IP). Six male offsprings of gestational diabetic mothers and control dams, at the 21, 28 postnatal days were randomly scarified and coronal sections of cerebellum (6 micrometer) serially collected. The neurons were stained with cresyl violet. RESULTS: The Purkinje cells density in the apex and depth of cerebellum in P21, in the experimental group was reduced 23% and 15% in comparison with the control group (P<0.001). The granular cells density in the experimental group was reduced 19.58% and 18.3% in comparison with the controls (P<0.001). The Purkinje cells density of cerebellum in P28, in the diabetic group reduced to 22.12% and 12.62% in comparison with the control group (P<0.001). The granular cells density in the diabetic group reduced 17.14% and 16.12% in comparison with the control group (P<0.001). DISCUSSION: The Purkinje and granular cells significantly reduced in gestational diabetes rat offspring. PMID- 27504152 TI - Effects of Increase in Amplitude of Occipital Alpha & Theta Brain Waves on Global Functioning Level of Patients with GAD. AB - INTRODUCTION: The basic objective of this study is to investigate the effects of alpha and theta brain waves amplitude increase in occipital area on reducing the severity of symptoms of generalized anxiety disorder and to increase the global functioning level in patients with GAD. METHODS: This study is a quasi experimental study with pre-test and post-test with two groups. For this purpose, 28 patients who had been referred to Sohrawardi psychiatric and clinical psychology center in Zanjan were studied based on the interview with the psychiatrist, clinical psychologist and using clinical diagnostic criteria for the Diagnostic and Statistical Manual of Mental Disorders text revision - the DSM IV-TR Fourth Edition diagnosis of GAD, 14 subjects were studied in neurofeedback treatment group and 14 subjects in the waiting list group. Patients in both groups were evaluated at pre-test and post-test with General Anxiety Disorder Scale (GAD-7) and Global Assessment Functioning Scale (GAFs). The treatment group received fifteen 30-minute alpha training sessions and fifteen 30-minute theta brain training sessions in occipital area by neurofeedback training (treatment group). This evaluation was performed according to the treatment protocol to increase the alpha and theta waves. And no intervention was done in the waiting list group. But due to ethical issues after the completion of the study all the subjects in the waiting list group were treated. RESULTS: The results showed that increase of alpha and theta brain waves amplitude in occipital area in people with GAD can increase the global functioning level and can reduce symptoms of generalized anxiety disorder in a treatment group, but no such change was observed in the waiting list group. DISCUSSION: Increase of alpha and theta brain waves amplitude in occipital area can be useful in the treatment of people with GAD. PMID- 27504153 TI - Effects of Venlafaxine & Methadone Alone and in Combination with Spontaneous Morphine withdrawal Syndrome & Pain Sensation in Rats. AB - INTRODUCTION: Methadone has been used as a drug to detoxify opioid tolerance. Naloxane precipitated morphine withdrawal behaviours were attenuated by venlafaxine as an antidepressant. On the contrary, after detoxifying the opioids, spontaneous withdrawal syndrome may occur with pain sensitivity. Therefore the present study aimed to examine the effects of chronic methadone (70 mg/kg, in drinking water, 7 days), venlafaxine (80 mg/kg/day, intraperitoneally, 7 days) and their combinations with the spontaneous morphine withdrawal syndrome and pain sensitivity. METHODS: Twenty eight young male Sprague-Dawley rats were randomly divided into 4 groups: control, venlafaxine treated, methadone treated and venlafaxine + methadone treated. Morphine sulfate (10 mg/kg/day, subcutaneously, 4 days) was injected to all animals. Then primary withdrawal behaviours and tail flick test were performed. The test was then followed by methadone or its vehicle administration. Second intervention was venlafaxine or its vehicle injection. Then final withdrawal behaviours and tail flick test were performed. RESULTS: Combination of chronic methadone substitution and venlafaxine administration, significantly reduced freezing behaviour of spontaneous morphine withdrawal syndrome (P<0.01, 379+/-144%). Chronic methadone administration (P<0.05, 35+/-8% difference with venlafaxine treated group) induced hyperalgesia. A positive correlation (P=0.001, +63%) was observed between the animals final freezing scores and their response latencies to the painful stimulus. DISCUSSION: Combination of chronic methadone and venlafaxine administrations reduces freezing withdrawal behaviour. Further investigations on analgesic interventions are needed to overcome this hyperalgesia. PMID- 27504154 TI - Effect of Cinnamomum Verum Extract on the Amyloid Formation of Hen Egg-white Lysozyme and Study of its Possible Role in Alzheimer's Disease. AB - INTRODUCTION: Diagnosing and treating diseases associated with amyloid fibers remain a great challenge despite of intensive research carried out. One important approach in the development of therapeutics is the use of herbal extracts which are rich in aromatic small molecules. Cinnamomum verum extract (CE) contains proanthocyanidin and cinnamaldehyde, which have been suggested to be capable of directly inhibiting amyloid fibril formation in vitro. This study is aimed at characterizing the inhibitory activity of CE against the fibrillation of hen egg white lysozyme (HEWL). METHODS: Acidic pH and high temperatures were used to drive the protein towards amyloid formation. Lysozyme was dissolved at 2 mg/mL in 50mM glycine buffer (pH 2.5), and then incubated at 57 degrees C for the specified durations while stirred gently by Teflon magnetic bars. Various techniques including thioflavin T, fluorescence, Congo red absorbance assay and AFM micrography were used to characterize the HEWL fibrillation processes. RESULTS: In the absence of CE typical amyloid fibrils (like amyloids formed in Alzheimer disease) became evident after 48 h of incubation. Upon incubation with various extract concentrations in the range of 0.1-1 mg/ml, formation of fibrillar assemblies were significantly inhibited (P<0.05). AFM analysis and MTT assay also confirmed the role of the extract in amyloid inhibition. Our studies showed that the presence of CE did not have any effect on protein stabilization and thus directly interact with amyloid structure and inhibit formation of these structures. Furthermore, a docking experiment showed that a pi-pi interaction may occur between the aromatic component of cinnamaldehyde and W62. Interestingly, W62 is one of the principal aromatic residues that interact with glycine amide, which is an aggregation suppressor of HEWL. DISCUSSION: These observations suggest that aromatic small molecules of CE may directly insert into amyloidogenic core of early aggregates and inhibit amyloid fibril formation by disrupting the pi-pi interactions. PMID- 27504155 TI - Group A beta-hemolytic Streptococcal Infection in Children and the Resultant Neuro-psychiatric Disorder; a Cross Sectional Study; Tehran, Iran. AB - INTRODUCTION: Group A Beta-Hemolytic Streptococcus (GABHS) can induce PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection). GABHS is the most important and common bacterial cause of acute pharyngitis in Iranian children. We studied the role of GABHS (anti-streptococcal antibodies) in suspected cases of PANDAS in a cross sectional studies. METHODS: Across sectional study was done in 2 pediatric psychiatric/and neurologic clinics in Tehran (Rasul Akram and Aliasghar Hospital) during 2008-2010. We studied serum anti-streptococcal antibodies (anti streptolysin O, anti Deoxyribonuclease B, and anti-streptokinase (ABcam-ELISA, USA) in 76 cases with psychiatric manifestation (OCD, ADHD) in compare with 39 healthy controls. These antibodies were studied in 53 cases with movement disorders (Tic/Tourette syndrome) in compare with 76 healthy controls. Sensitivity, specificity and positive predictive value of tests were calculated. RESULTS: In movement disorders ASOT, Anti-DNase and Anti streptokinase was significantly higher than controls (P<0.0001, P=0.000, P<0.00001) ASOT (cut off level> 200 IU/ml) had 75% sensitivity; 84% specificity and 80% PPV; Anti-streptokinase (cut off level > 332 IU/ml) had 34% sensitivity; 85% specificity, and 72% PPV; Anti-DNase (cut off level > 140 IU/ml) had 70% sensitivity; 99% specificity and PPV 90% for differentiating the group. ASOT, Anti-DNase and Anti streptokinase titer was significantly higher than controls (P<0.0001, P=0.000, P<0.0001). ASOT had 90% sensitivity; 82% specificity, PPV 92%; Anti streptokinase: 82% sensitivity; 82% specificity, PPV 95%; Anti DNase: 92% sensitivity; 82% specificity, PPV 92% for differentiation the cases from normal controls. DISCUSSION: These findings support that a post infectious immune mechanism to GABHS may play a role in the pathogenesis of PANDAS in our children. A combination of throat culture, rapid antigen detection test, and serologic testing for GABHS is required to achieve maximum sensitivity and specificity for diagnosis. We prefer to use antibiotic prophylaxis in PANDAS cases for preventing recurrent streptococcal infections. Ongoing research is needed for identifying optimum diagnostic, prevention and therapeutic approach especially, aggressive treatment (intravenous immunoglobulin, plasmaphresis). PMID- 27504156 TI - Inter-pulse Interval Affects the Size of Single-pulse TMS-induced Motor Evoked Potentials: A Reliability Study. AB - INTRODUCTION: Measuring the size of motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS) is an investigational technique to show the level of corticospinal excitability; however, some of the fundamental methodological aspects of TMS (such as the effects of inter-pulse intervals (IPI) on MEP size) are not fully understood, this issue raises concerns about the reliability of MEPs, especially in pre-test post-test studies. METHODS: MEP size at short and long IPIs was assessed during two separate sessions. Inter- and intra-session reliability of MEP size also was assessed at both short and long IPIs. RESULTS: The results indicated that long IPIs induced larger MEPs (P< 0.05) across all time points. The intra-class correlation coefficient (ICC) indicated high intra- and inter-session reliability for short (0.87 to 0.96) and long (0.80 to 0.97) IPIs respectively. The amplitude of MEPs also had high intersession reliability for short (ICC=0.87) and long (ICC = 0.80) IPIs. DISCUSSION: This study provides evidence that the length of IPIs determines the size of MEPs. As a result, it is recommended to add the length of IPI to the international checklist of considerations for TMS application. PMID- 27504157 TI - cAMP-Epac Pathway Stimulation Modulate Connexin-43 and MicroRNA-21 Expression in Glioma Cells. AB - INTRODUCTION: Malignant astrocytic gliomas are the most common and lethal brain malignancies due to their refractory to the current therapies. Nowadays, molecular targeted therapy has attracted great attention in treatment of glioma. Connexin 43 (Cx43) and micro ribonucleic acid-21(miR-21) are among molecules that are involved in glioma development and progression. These molecules showed potential to be as target molecules with regard to glioma. Some studies have reported that cyclic adenosine monophosphate (cAMP) signaling could be effective on Cx43 and miR-21 in tissues other than in brain. We investigate possible relationship between beta-adrenergic receptor and its newly described downstream, exchange protein directly activated by cAMP (Epac) signaling pathway and expression of Cx43 and miR-21 in low (1321N1) and high grade (U87MG) glioma cell lines. METHODS: We treated cells with beta-adrenergic agonist and Epac activator with and without adenyl cyclase inhibitor. Cx43 and miR-21 expression were measured with real-time PCR. RESULTS: Our data showed that in 1321N1 cells, beta adrenergic-Epac pathway stimulation up and down-regulated Cx43 and miR-21 expression respectively. Whereas, in U87MG cells these interventions had no effect on Cx43 and miR-21 expression. DISCUSSION: These findings demonstrate that low grade astrocytoma cells have better response to our pharmacological interventions. PMID- 27504158 TI - Evaluation of Hemodynamic Response Function in Vision and Motor Brain Regions for the Young and Elderly Adults. AB - INTRODUCTION: Prior studies comparing Hemodynamic Response Function (HRF) in the young and elderly adults based on fMRI data have reported inconsistent findings for brain vision and motor regions in healthy aging. It is shown that the averaging method employed in all previous works has caused this inconsistency. The averaging is so sensitive to outliers and noise. However, fMRI data are obscured with a major contribution of noise particularly in the elderly case. METHODS: Deconvolution algorithm is here proposed for HRF extraction to achieve more robustness against noise. In spite of earlier works, proposed deconvolution algorithm yields compatible HRF results using either original or denoised fMRI data, though a large percentage of selected active voxels change in the latter case. In the current study, event-related fMRI data have been used for 18 subjects (8 young and 10 elderly adults) with a simple visual and motor task of pressing a key with index in response to the visual presentation of the word tap. Considering anatomically-defined vision and motor regions and preprocessing steps in FSL and SPM, the activated voxels have been selected according to t-test for which HRF is estimated using deconvolution method. RESULTS: Experimental results demonstrate that HRF peak amplitudes do not differ significantly (P=0.8) in the vision region for the young and the elderly. In motor region, the HRF peak significantly increases for the young compared to the elderly (P<0.03). Repeating the procedure on the denoised fMRI data using MDL algorithm, the same results have been obtained. DISCUSSION: In this study, a comparative study has been realized on the hemodynamic response properties associated with the young and the elderly adults on a simple visual and motor task. PMID- 27504159 TI - A Qualitative Study to Identify Skills and Competency Required for Hospital Managers. AB - INTRODUCTION: Hospital managers aim to improve the efficiency and effectiveness of their institutions through leadership and guidance of medical personnel. Fulfilling these objectives requires a holistic approach to both the management of people and institutional prioritization. The aim of this study was to identify the skills and competencies that hospital managers must demonstrate in order to achieve their objectives. METHODS: In 2015, a regional, multi-center qualitative study was undertaken in Shiraz, Iran. Interviews and focus group discussions were conducted with university hospital managers, senior managers, faculty members, and post-graduate students, and the results were analyzed using the content analysis method by MAXQDA software. RESULTS: Eight key skill themes (communication, experience, appreciation of institution logistics/infrastructure, management skills, motivation, systematic problem solving, ethics, and financial/legal awareness) were identified among the hospital managers. The common challenges that face hospital institutions include problems with hierarchical and organizational structure, excessive rules and regulations, lack of resources, poor post-graduate education, and overall management. Recurring themes with respect to how these could be addressed included changing the culture and belief structure of the hospital, restructuring the organizational hierarchy, and empowering the people. CONCLUSION: In our cohort, practical skills, such as communication and experience, were considered more important than theoretical skills for the effective management and administration of hospitals. Therefore, we suggest that practical, skill-based training should be emphasized for students of these disciplines so they will be better suited to deal with real world challenges. Further organizational improvements also can be attained by the active and constructive involvement of senior university managers. PMID- 27504160 TI - Mutational analysis of reverse transcriptase and surface proteins of patients with partial virological response during mono and combination antiviral therapies in genotype D chronic hepatitis B. AB - INTRODUCTION: The mutational pattern of chronic Hepatitis B virus (HBV) is unclear in patients who show incomplete response to antiviral therapy. The aims of this study were 1) to determine the benefit of combination therapy with adefovir dipivoxil (ADV) and Lamivudine (LAM) versus ADV or LAM alone in maintaining virological, biochemical and histological responses and 2) to investigate the patterns of mutations in the reverse transcriptase and surface proteins of HBV with LAM and/or ADF-resistant in partially-responded chronic hepatitis B (CHB) patients. METHODS: The study group consisted of 186 chronic HBV carriers who were admitted to the Tehran Hepatitis Network from 2010 to 2013. We retrospectively selected 86 patients who partially responded to different nucleoside analogue regimens. After 48 weeks of therapy, five groups of patients were defined including eight Lamivudine (LAM) Group (I), 30 Adefovir (ADV) Group (II), 16 ADV add on LAM Group (III), 32 ADV+LAM Group (IV), and 100 controls (no therapy). Reverse transcriptase (RT) and surface genes were amplified and sequenced for mutational analysis. RESULTS: All groups showed differences between mean values for age, gender, alanine transaminase (ALT), aspartate transaminase (AST), and HBV DNA levels groups showed significant differences than other groups (p < 0.05). The mutation frequencies for groups were I (1.7%), II (1.39%), III (2.28%), IV (2.0%), and V (0.38%). T54N, L80I/V, I91L/V, L180M, M204I/V, Q215P/S, and F221Y/S showed the highest number of mutations in all groups with different frequencies. Four new, unreported mutations were found. CONCLUSION: Those patients who failed to respond in the first 48 weeks, whether they were receiving mono or combination therapy, should be tested genotypically, for the early modification of treatment. PMID- 27504161 TI - Effect of Processed Honey and Royal Jelly on Cancer-Related Fatigue: A Double Blind Randomized Clinical Trial. AB - BACKGROUND: Cancer-related fatigue (CRF) is experienced by 50% to 90% of cancer patients and can severely affect their quality of life and functional capacity. Several randomized trials have recommended various ways to alleviate the symptoms of CRF with or without recourse to medications. OBJECTIVE: The aim of this study is to evaluate the effectiveness of processed honey and royal jelly on the symptoms of CRF in cancer patients who are undergoing hormone therapy, chemotherapy, chemo-radiation, or radiotherapy. METHODS: Fifty-two participants from the patients who visited the oncology clinic of Shohada-e-Tajrish hospital in Tehran (Iran) between May 2013 and August 2014 were selected and divided into two groups. The study group (26 patients) received processed honey and royal jelly, while the control group received pure honey. Both groups were instructed to consume their 5mL supplement twice daily for 4 weeks. Both groups were assessed at the beginning of the study, after 2 weeks, and then at the end of 4 weeks of treatment. Fatigue was measured using a visual analogue fatigue scale (VAFS) and fatigue severity scale (FSS). The results were compared between the two arms of study, and equality of probability distributions was assessed using a Kolmogorov-Smirnov test. RESULTS: The mean age of the 52 patients was 54.84. After two and four weeks of treatment with processed honey and royal jelly, VAFS and FSS due to treatment was better in the study group than in the control group, and the differences were statistically significant (p<0.001, p<0.001, respectively). CONCLUSION: To the best of our knowledge, our study provided support for the use of processed honey and royal jelly to ameliorate CRF. The positive results of this study warrant further studies in this field. CLINICAL TRIAL REGISTRATION: The study was registered in the Iranian Clinical Trial Registry Center (http://www.irct.ir) with the registration code: IRCT2015081423426N1. FUNDING: The authors received no financial support for the research, authorship, and/or publication of this article. PMID- 27504162 TI - The link between bone disease and cardiovascular complications in hemodialysis patients. AB - INTRODUCTION: The burden on the cardiovascular system is the main cause of mortality in chronic renal patients, and bone disease, which also may cause disability, is one of the most important complications in those patients. The aim of this study was to determine the link between cardiovascular and bone disease, which frequently occur together. METHODS: In this matched case-control study, 70 subjects were subjected for full laboratory assessment as well as estimation of parathyroid hormone (PTH) level, vitamin D level, complete echocardiography, and dual energy absorptiometry. Of the 70 patients, 50 were on regular hemodialysis, and there were 20 normal controls matched with the patients with respect to age and gender. RESULTS: There was a significant decrease in the mean value of serum vitamin D in the hemodialysis patients, i.e., their mean value was 20.47 +/- 9.60 whereas the controls had a mean value of 37.15 +/- 7.67. Thus, there was a highly significant, negative correlation between vitamin D and left ventricular mass (LVM) in the patients. We found that there was a highly-significant increase in the mean PTH levels of the patients (820.22 +/- 393.51), whereas it was 57.60 +/- 13.72 for the controls. The statistical significance was less than 0.001, a highly-significant increase in the mean of the T score levels in the patients ( 2.15 +/- 2.56), whereas it was -0.47 +/- 0.71 for the controls with a statistical significance of less than 0.001. There also was a highly-significant correlation between the T score and LVM. CONCLUSION: A significant correlation was found between bone disease and the occurrence of a left ventricular mass. We recommend early strict correction of the serum levels of vitamin D, PTH, calcium, and phosphorus. PMID- 27504163 TI - Public sexual health promotion interventions and strategies: A qualitative study. AB - INTRODUCTION: Sexual health promotion is the process of enabling people to increase control over their sexual health that should be based on people's needs and abilities. The aim of this study was to explore public sexual health promotion interventions and strategies. METHODS: This study was a qualitative content analysis approach. This qualitative study was a qualitative part of an exploratory sequential qualitative-quantitative study that took place between November 2014 and May 2015 and was conducted in Rasht, Iran. Data were collected using semi-structured interviews with 38 engaged and married men and women as well as nine key informants. The data were analyzed by the content analysis method and by using qualitative data analysis software MAXqda 2011. RESULTS: Analyzing participants' perspectives and experiences revealed two main categories, i.e., 1) General actions to promote sexual health (with three sub categories: public policies promoting sexual health, development of sexual health supporting environments, and removal of barriers to receiving services) and 2) Specific actions in the current health system (with three sub-categories: economic policy, empowering individuals and the society, and reviewing the current health system). CONCLUSIONS: General actions (public policies, supporting environments developed, and removal of barriers to receiving services) and integration of specific actions in the health system, such as empowering individuals' needs for promoting sexual health. Achieving these goals necessitates the review of the current health system in Iran. PMID- 27504164 TI - Estimation of the residential radon levels and the annual effective dose in dwellings of Shiraz, Iran, in 2015. AB - INTRODUCTION: Radon is the second most important cause of lung cancer after smoking. Thus, the determination of indoor radon concentrations in dwellings and workplaces is an important public health concern. The purpose of this research was to measure the concentration of radon gas in residential homes and public places in the city of Shiraz and its relationship with the type and age of the buildings as well as the type of materials used to construct the building (brick, block). We also determined the radon dosages that occupants of the building would receive. METHODS: The present study is a descriptive-analytical and cross sectional research that was conducted on the building's indoor air in the city of Shiraz in 2015. Using geographic information system (GIS) software and a spatial sampling cell with an area of 25 square kilometers, 200 points were selected. In this study, we used passive diffusive samplers as Solid State Nuclear Track Detector (SSNTD) CR-39 polycarbonate films for three months in the winter. Sampling was conducted in accordance with the U.S. Environmental Protection Agency's protocol. We determined the concentrations of radon gas at the time of sampling, and calibration factors were determined. The data were analyzed by IBM SPSS, version 20, descriptive statistics, Kruskal-Wallis, and Mann-Whitney tests. RESULTS: This study showed that the average radon concentration was 57.6 +/- 33.06 Bq/m(3) in residential dwellings. The average effective dose was 1.45 mSv/y. The concentration of radon in 5.4% of the houses was found to be greater than 100 Bq/m(3), which is above the level allowed by the World Health Organization (WHO). CONCLUSION: Since radon is the second leading cause of lung cancer, it seems necessary to increase the public's awareness of this issue and to take action to reduce radon in homes when the concentrations are above the WHO's guideline. PMID- 27504165 TI - Developing a conceptual model for the application of patient and public involvement in the healthcare system in Iran. AB - INTRODUCTION: Patient and public involvement is engaging patients, providers, community representatives, and the public in healthcare planning and decision making. The purpose of this study was to develop a model for the application of patient and public involvement in decision making in the Iranian healthcare system. METHODS: A mixed qualitative-quantitative approach was used to develop a conceptual model. Thirty three key informants were purposely recruited in the qualitative stage, and 420 people (patients and their companions) were included in a protocol study that was implemented in five steps: 1) Identifying antecedents, consequences, and variables associated with the patient and the publics' involvement in healthcare decision making through a comprehensive literature review; 2) Determining the main variables in the context of Iran's health system using conceptual framework analysis; 3) Prioritizing and weighting variables by Shannon entropy; 4) designing and validating a tool for patient and public involvement in healthcare decision making; and 5) Providing a conceptual model of patient and the public involvement in planning and developing healthcare using structural equation modeling. We used various software programs, including SPSS (17), Max QDA (10), EXCEL, and LISREL. Content analysis, Shannon entropy, and descriptive and analytic statistics were used to analyze the data. RESULTS: In this study, seven antecedents variable, five dimensions of involvement, and six consequences were identified. These variables were used to design a valid tool. A logical model was derived that explained the logical relationships between antecedent and consequent variables and the dimensions of patient and public involvement as well. CONCLUSION: Given the specific context of the political, social, and innovative environments in Iran, it was necessary to design a model that would be compatible with these features. It can improve the quality of care and promote the patient and the public satisfaction with healthcare and legitimate the representative of people they served for. This model can provide a practical guide for managers and policy makers to involve people in making the decisions that influence their lives. PMID- 27504166 TI - Features of a Health-Oriented Education Program during Daily Commutes: A Qualitative Study. AB - INTRODUCTION: Today, despite scientific advances, many people spend more time and distance between home and their workplaces because of various economic and population reasons. The aim of this study was to identify features of an appropriate health education program during commutes for factory staff at Ardakan county (Yazd province, Iran). METHODS: This qualitative study was conducted via the phenomenological method in 2014. The population of this study was members of the staff of Ardakan Steel Company. Nineteen specialists and 11 members of the factory's staff were invited to participate in the study, and data were collected using semi-structured interviews. The interviews took 20 to 40 minutes, and their content was analyzed using content analysis. RESULTS: Extraction of codes and themes and their placement in this study showed that an educational program during commutes should have nine features to have the desired effectiveness, i.e., the program must be audience-oriented, repeatable, participatory, technology-based, combinational, supportive, and motivational and interesting. Also, the program should have environmental and organizational support, and it must be evaluated for its effectiveness. CONCLUSION: Considering appropriate features of a health education program in educational situations, especially interventions related to daily commutes, is very important because the effectiveness of such health-oriented educational programs must be ensured. PMID- 27504167 TI - Expectation of fairness: a turning point in the professional satisfaction of Iranian nurses. AB - INTRODUCTION: The professional satisfaction of staff is one of the most challenging organizational concepts that can enhance the efficiency level of organizations. In a similar vein, the professional satisfaction of nurses is of considerable importance, in that, professional dissatisfaction among nurses could result in emotional detachment, depression, anger, evasion from work, and inefficacy and would negatively impact the organization's work rate. The aim of this study was to understand Iranian nurses' experiences of the concept of professional satisfaction. METHODS: This was a qualitative study conducted with a targeted sampling of 10 nurses (4 men and 6 women) in 2015. The data were collected through conducting in-depth interviews, and textual data were analyzed subsequently using the Qualitative Content Analysis (QCA) method. RESULTS: The findings of this study pointed to "fair conduct," which was comprised of three sub-categories, i.e., expectation of fairness in social-professional settings, expectation of fairness in receiving professional benefits, and expectation of fairness in the area of professional interactions. CONCLUSIONS: There are various ups and downs in nursing due to the challenging nature of the profession, from the initial education at the university until retirement. According to the findings of this study, a lack of fairness in social-professional settings, a lack of fairness in receiving professional benefits, and a lack of fairness in the area of professional interactions were among the factors that have great impacts on the degree of professional dissatisfaction among nurses. PMID- 27504168 TI - Nanocomposites in food packaging applications and their risk assessment for health. AB - Nanotechnology has shown many advantages in different fields. As the uses of nanotechnology have progressed, it has been found to be a promising technology for the food packaging industry in the global market. It has proven capabilities that are valuable in packaging foods, including improved barriers; mechanical, thermal, and biodegradable properties; and applications in active and intelligent food packaging. Examples of the latter are anti-microbial agents and nanosensors, respectively. However, the use of nanocomposites in food packaging might be challenging due to the reduced particle size of nanomaterials and the fact that the chemical and physical characteristics of such tiny materials may be quite different from those of their macro-scale counterparts. In order to discuss the potential risks of nanoparticles for consumers, in addition to the quantification of data, a thorough investigation of their characteristics is required. Migration studies must be conducted to determine the amounts of nanomaterials released into the food matrices. In this article, different applications of nanocomposites in food packaging, migration issues, analyzing techniques, and the main concerns about their usage are discussed briefly. PMID- 27504169 TI - The Results of Autologous Skin Test in Patients with Chronic Urticaria in Hamadan, Iran. AB - INTRODUCTION: The etiology of chronic urticaria is unknown in many cases. In this study, we demonstrated the presence of autoimmune antibodies in patients with chronic urticaria by using of the Autologous Serum Skin Test (ASST). METHODS: We performed a cross-sectional study to detect the presence of autologous antibodies in the serum of 38 patients (25 females and 13 males) with idiopathic chronic urticaria who were referred to the Hamedan Allergy Clinic in 2014. All of the necessary tests for demonstrating chronic urticaria were performed, including complete blood count (CBC), thyroid and liver functionality tests, and the prick test but they did not confirm the cause of chronic urticaria. We conducted the Autologous Serum Skin Test on the patients and analyzed the results. RESULTS: In 15 patients (39%), the ASST was positive. Of the 15 patients with positive autoimmune chronic urticaria, five patients (33%) were males, and 10 patients (67%) were females. CONCLUSION: We concluded that many patients with chronic urticaria have autoimmune urticaria. It is the reason for the lack of the response to treatment with common medications for urticaria. New ways of treatment must be considered for them. PMID- 27504170 TI - Laparoscopic Repair of Perforated Peptic Ulcer: Outcome and Associated Morbidity and Mortality. AB - INTRODUCTION: The mainstay of treatment for perforated peptic ulcer is Omental patch closure. With the advent of laparoscopic surgery, this approach is being used for the treatment of perforated peptic ulcer. The aim of this study was to evaluate the outcome of laparoscopy in Firoozgar general hospital over a period of 18 months. The outcome of the laparoscopic approach and the associated morbidity and mortality, operation time, conversion rate and hospital stay were assessed. METHODS: A prospective analysis of 29 consecutive patients (mean age 37.5 years; 23 men) with perforated peptic ulcers and who had undergone laparoscopic surgery was carried over a period of 18 months from March 2014 until September 2015. Pre-operative, intra-operative, and post-operative clinical data were collectively analyzed by SPSS 19 for Windows. RESULTS: Seventeen patients had a history of cigarette smoking, 11 patients had a history of opium consumption, 19 were chronic NSAID users, 26 had Helicobacter pylori infections, and six had a co-morbid condition. Previous surgical history included laparotomy for pancreatic cancer in two patients, for sigmoid colon cancer in one patient, and for acute appendicitis in four patients. The average operating time for all cases was 47.5 + 20 min. The mean lag time between onset of symptoms and surgery was 20.4 hours. All patients underwent laparoscopic closure of the perforation with Omental patch closure. No morbidity was observed, and none of the patients needed conversion to open surgery. One patient died after 11 months of follow-up due to the progression of underlying pancreatic cancer. The mean postoperative hospital stay was 4.2 days. CONCLUSIONS: The results of the laparoscopic approach for perforated peptic ulcer were promising, with no conversion to open surgery, no morbidity, and mortality. PMID- 27504171 TI - Investigating the Relationship between Insulin-like Growth Factor-1 (IGF-1) in diabetic mother's breast milk and the blood serum of their babies. AB - INTRODUCTION: Since research investigating IGF-1 levels in breast milk are few, the goal of this study was to analyze the IGF-1 levels in the breast milk of diabetic mothers as well as in the serum of their newborn babies and to identify what relationship exists between blood serum and IGF-1 milk levels through patient measurement of mothers and their babies. METHODS: This case control study was undertaken under the auspices of the Clinic of Neonatology at Al Minia University Pediatric Hospital over May 2012 through May 2013. With a total of 30 diabetic mothers and their babies forming the experimental group and the control group consisting of 15 non-diabetic mothers and their babies. A detailed medical history, anthropometric assessments, as well as the measurement of the baby's serum IGF-1 and their mother's breast milk IGF-1 levels were taken from all participants using ELSIA. The resulting data were analyzed via Statistical Package for the Social Sciences (SPSS) version 16 and measurements of descriptive statistics, t-test, Chi-square test, as well as the Pearson Correlation Coefficient. RESULTS: The Infants born to Diabetic Mothers (IDMs) demonstrated significantly greater anthropometric measurement. Both the serum levels and the milk IGF-1 levels as well as all of the physical measurements taken were found to have a positive correlation between the level of IGF-1 in mother's milk and all of the anthropometric measurements studied with the exception of delivered baby's length. CONCLUSION: Higher levels of IGF-1 are present in the milk of diabetic mothers and the blood serum of their babies and this characteristic could be used as a prenatal biomarker for macrosomia. PMID- 27504172 TI - Socio-Economic Factors Influencing on Total Fertility Rate in Iran: A Panel Data Analysis for the Period of 2002-2012. AB - INTRODUCTION: Over the last few decades, total fertility rate (TFR) has followed a downward trend in Iran. The consequences of this trend from the perspectives of some are negative. Considering the macro-population policies in recent years, this study aimed to examine the effect of some macro socio-economic variables, including divorce, marriage, urbanization, and unemployment rate on TFR in Iran from 2002 to 2012. METHODS: This time series research was conducted in 2015 using the databases of the National Organization for Civil Registration (NOCR) and the Statistical Center of Iran. The study population was the related data of provinces in the selected variables. The main methods used in the research were the common unit root test, Pedroni Cointegration test, redundant fixed effects tests, correlated random effects-Hausman test, and panel least squares of fixed effects. In order to determine the suitable model for estimating panel data, likelihood ratio and Huasman tests were done using Eviews software, and the fixed effects regression model was chosen as the dominant model. RESULTS: The results indicated that the divorce rate had a negative and significant effect on TFR (p < 0.05). A positive and significant relationship between marriage rate and TFR variables also was observed (p < 0.05). Urbanization rate (p = 0.24) and unemployment rate (p = 0.36) had no significant relationship with TFR. According to F statistic, significance of the overall model also was confirmed (p < 0.001). CONCLUSION: Due to the lower effect of the studied factors on the reduction of TFR, it seems that variables other than the ones studied, as well as cultural factors and values, might be fundamental factors for this change in the country. PMID- 27504173 TI - Isolation, Identification, and In Vitro Antifungal Susceptibility Testing of Dermatophytes from Clinical Samples at Sohag University Hospital in Egypt. AB - AIM: The objective of this study was to isolate, identify, and explore the in vitro antifungal susceptibility pattern of dermatophytes isolated from clinically suspected cases of dermatophytosis (tinea infections) attending the Dermatology Outpatient Clinic. METHODS: This study was conducted at Sohag University Hospital from December 2014 to December 2015. Clinical samples (e.g., skin scrapings and hair stumps) were collected under aseptic precautions. The identification of dermatophytes was performed through microscopic examination using 10% potassium hydroxide (KOH) with 40% dimethyl sulphoxide (DMSO) mounts and culture on Sabouraud dextrose agar (SDA) and on Dermasel agar base media, both supplemented with chloramphenicol and cycloheximide. All dermatophytes isolates were subjected to antifungal susceptibility testing using the agar-based disk diffusion (ABDD) method against Clotrimazole, Miconazole, Fluconazole, and Griseofulvin. Data were analyzed via SPSS 16, using Chi square and a screening test (cross-tabulation method). RESULTS: A total of 110 patients of dermatophytosis were studied. The patients were clinically diagnosed and mycologically confirmed as having tinea capitis (49), tinea corporis (30), tinea pedis (16), tinea cruris (9), or tinea barbae (6). The dermatophytes isolates belonged to 4 species: Microsporum canis 58 (52.7%), Microsporum gypseum 23 (20.9%), Trichophyton mentagrophytes 18 (16.4%), and Microsporum audouinii 11 (10%). The most effective antifungal drugs tested were Clotrimazole, followed by Miconazole (95.5% and 84.5% of isolates were susceptible, respectively). CONCLUSION: Every patient with a tinea infection should be properly studied for a mycological examination and should be treated accordingly. Dermasel agar is more useful as an identification medium in the isolation of dermatophytes. The ABDD method appears to be a simple, cost effective, and promising method for the evaluation of antifungal susceptibility of dermatophytes. PMID- 27504174 TI - The Abortificient Effects of Hydroalcoholic Extract of Lawsonia Inermis on BALB/c Mice. AB - INTRODUCTION: According to the traditional beliefs of certain cultures, Lawsonia inermis has been reported to cause the abortion or termination of an undesirable pregnancy. The present study was undertaken with the goal of studying the effect of Lawsonia inermis extract on abortion in pregnant BALB/c mice in 2013 in Shahrekord, Iran. METHODS: This research study used an experimental methodology and was conducted in 2013 in Shahrekord, Iran. Forty female BALB/c mice (30-40 gm, 8-12 weeks old) were randomly assigned to 4 groups. One male mouse was included for each two female mice (1:2) and they were maintained in a protective cage habitat. Pregnancy of the mice was confirmed by means of a vaginal smear. The doses of 1 mg/kg and 10 mg/kg of the hydroalcoholic extract of Lawsonia inermis were injected intraperitoneally into pregnant mice beginning on the first day and continuing through the seventh day of pregnancy. The control group did not receive any treatment, but was left completely unadministered. On the eighteenth day of pregnancy, the uterine tubes of mice were removed. The subsequent embryonic absorption is considered to be an abortion. The data were analyzed using SPSS software version 22 using Fisher's exact test and the Kruskal Wallis H tests. RESULTS: Abortions were observed more often in the experimental groups (p< 0.01). The mean of the serum estrogen level was significantly higher in the case control groups (p< 0.01) and the mean of progesterone level was also significantly lower in the experimental groups (p< 0.01). CONCLUSION: The use of Lawsonia inermis during pregnancy may cause abortion and therefore it should be considered as contraindication or use with caution. PMID- 27504176 TI - Anthropometric Profiling of New Zealand Junior Elite Triathletes. AB - INTRODUCTION: The triathlon involves a combination of three separate disciplines swimming, cycling and running. To date, very few studies have been conducted on the anthropometric characteristics of the New Zealand junior elite triathletes. The aim of this study was to determine the correlation between physical traits of calf girth or sum of eight skinfolds (anthropometry) and running or cycling performances in the triathlon event. METHODS: Eleven junior elite triathletes (6 females, 5 males; (Av. age: 17) who were selected for the New Zealand national squad, were examined in this cross-sectional study. All athletes were measured for the complete anthropometric profile, as per the International Society for Advancement of Kinanthropometry (ISAK) guidelines. It was then correlated with the cycling and running performances using interclass correlation (ICC) with 90% confidence interval (CI) limits. RESULTS: A non-significant positive correlation observed between eight skinfolds tests on running performance (ICC: 0.10; 90% CI: -0.68-0.77; p>0.05) and biking performance (ICC: 0.15; 90% CI: -0.65-0.79; p>0.05), suggested athletes with greater body fat may render a better athletic performance. Conversely, a significant negative correlation was observed between calf girth and running performance (ICC:-0.66; 90% CI: -0.94 - -0.12; p<0.05) and a non-significant negative correlation was observed between calf girth and cycling performance (ICC:-0.94; 90% CI: -0.97- 0.68; p>0.05). CONCLUSION: Anthropometric data can help in predicting an ideal body profile. This research indicates the similarities and differences of the New Zealand junior profile and the world junior profile. PMID- 27504175 TI - Visual Detection of Enterohemorrhagic Escherichia coli O157:H7 Using Loop Mediated Isothermal Amplification. AB - INTRODUCTION: Escherichia coli O157:H7, an important foodborne pathogen, can cause serious renal damage, which can also lead to mortality. Since a rapid and sensitive method is needed to identify this pathogenic agent, we evaluated Loop Mediated Isothermal Amplification Assay (LAMP) to detect Escherichia coli O157:H7. METHODS: We used six primers that specifically identified the rfbE gene. To examine the sensitivity of the method, different dilutions were subjected to the LAMP reaction. Other bacterial strains also were investigated to determine the specificity of the test. The turbidity of the amplified products was assayed by visual detection. The amplified products were detected by addition of SYBR Green II to the reaction tubes. RESULTS: Amplification products were observed as a ladder-like pattern on the agarose gel. A white turbidity emerged in the positive tubes. Under UV light, the positive samples were green, whereas the negative samples were orange. The detection limit of the LAMP was 78 pg/tube, and this indicated that it was 100 times more sensitive than PCR for the detection of EHEC. No LAMP products were detected when template DNA of non-EHEC strains were used, suggesting high specificity of the LAMP assay. CONCLUSION: The results indicated that the LAMP assay is a valuable diagnostic assay to identify EHEC O157:H7. In addition, the simplicity, sensitivity, specificity, and rapidity of this assay make it a useful method to diagnose pathogens in primary labs without any need for expensive equipment or specialized techniques. PMID- 27504177 TI - Severe angina pectoris in asthma attack: a case report. AB - Asthma is a chronic inflammatory disorder of the airways related to the obstruction of reversible airflow. Asthma presents as recurrent attacks of cough and dyspnea. Poor control causes recurrent admissions to the ICU, and mortality is related to poor drug compliance and follow-up. Angina pectoris is a syndrome of recurrent chest discomfort related to myocardial ischemia. The presence of these two disorders rarely has been reported. We reported a 12-year-old boy who was referred with exacerbation of asthma and developed angina pectoris during hospitalization. He had labored breathing and diffuse wheezing. During treatment of the asthma, the patient developed severe chest pain due to shunt formation and coronary hypoxia, caused by the sole administration of ventolin, since oxygen had been disconnected. After receiving appropriate therapy, both his asthma and angina recovered, and, to date, he has not experienced angina pectoris again. PMID- 27504178 TI - Embracing change: striated-for-smooth muscle replacement in esophagus development. AB - The esophagus functions to transport food from the oropharyngeal region to the stomach via waves of peristalsis and transient relaxation of the lower esophageal sphincter. The gastrointestinal tract, including the esophagus, is ensheathed by the muscularis externa (ME). However, while the ME of the gastrointestinal tract distal to the esophagus is exclusively smooth muscle, the esophageal ME of many vertebrate species comprises a variable amount of striated muscle. The esophageal ME is initially composed only of smooth muscle, but its developmental maturation involves proximal-to-distal replacement of smooth muscle with striated muscle. This fascinating phenomenon raises two important questions: what is the developmental origin of the striated muscle precursor cells, and what are the cellular and morphogenetic mechanisms underlying the process? Studies addressing these questions have provided controversial answers. In this review, we discuss the development of ideas in this area and recent work that has shed light on these issues. A working model has emerged that should permit deeper understanding of the role of ME development and maturation in esophageal disorders and in the functional and evolutionary underpinnings of the variable degree of esophageal striated myogenesis in vertebrate species. PMID- 27408685 TI - "The molecule's the thing:" the promise of molecular modeling and dynamic simulations in aiding the prioritization and interpretation of genomic testing results. AB - Clinical genomics is now a reality and lies at the heart of individualized medicine efforts. The success of these approaches is evidenced by the increasing volume of publications that report causal links between genomic variants and disease. In spite of early success, clinical genomics currently faces significant challenges in establishing the relevance of the majority of variants identified by next generation sequencing tests. Indeed, the majority of mutations identified are harbored by proteins whose functions remain elusive. Herein we describe the current scenario in genomic testing and in particular the burden of variants of uncertain significance (VUSs). We highlight a role for molecular modeling and molecular dynamic simulations as tools that can significantly increase the yield of information to aid in the evaluation of pathogenicity. Though the application of these methodologies to the interpretation of variants identified by genomic testing is not yet widespread, we predict that an increase in their use will significantly benefit the mission of clinical genomics for individualized medicine. PMID- 27429748 TI - High quality, small molecule-activity datasets for kinase research. AB - Kinases regulate cell growth, movement, and death. Deregulated kinase activity is a frequent cause of disease. The therapeutic potential of kinase inhibitors has led to large amounts of published structure activity relationship (SAR) data. Bioactivity databases such as the Kinase Knowledgebase (KKB), WOMBAT, GOSTAR, and ChEMBL provide researchers with quantitative data characterizing the activity of compounds across many biological assays. The KKB, for example, contains over 1.8M kinase structure-activity data points reported in peer-reviewed journals and patents. In the spirit of fostering methods development and validation worldwide, we have extracted and have made available from the KKB 258K structure activity data points and 76K associated unique chemical structures across eight kinase targets. These data are freely available for download within this data note. PMID- 27504181 TI - Assessing the sensitivity and representativeness of the Belgian Sentinel Network of Laboratories using test reimbursement data. AB - BACKGROUND: The Belgian Sentinel Network of Laboratories (SNL) was created in 1983 in order to monitor trends in infectious diseases. Given the evolution of the surveillance system, such as the waivers, fusions and adhesions of laboratories over time, it is important to evaluate whether the SNL is still fit for purpose. This study aims to evaluate aspects of the sensitivity and representativeness of the SNL by means of a test coverage analysis. METHODS: We estimated test coverage of the SNL using the ratio of reimbursed tests performed by participating laboratories to the total number of tests performed between 2007 and 2012, for 12 (groups of) pathogens. We further evaluated the geographical difference coverage of the SNL at regional and provincial levels. RESULTS: We found that test coverage of the SNL was stable over time and close to, or greater than, 50 % for the 12 (groups of) pathogens studied. These results hold for the three regions of Belgium but not for all provinces. We showed that some provinces had a low test coverage for some pathogens and that test coverage was more variable over time at provincial level. CONCLUSIONS: This sensitivity and representativeness study based on test coverage suggests that the SNL is capable to describe trend and to monitor changes in the 12 (groups of) pathogens studied both at national and regional levels. Therefore, the SNL is useful to contribute to estimate the burden of disease and to inform preventive measures. It should however be reinforced to allow to be used as an alert system at provincial level. PMID- 27504182 TI - The association between varicella (chickenpox) and group A streptococcus infections in historical perspective. AB - OBJECTIVES: The aim of the research is to investigate the historical relationship between varicella and Streptococcus pyogenes infections. In the past few decades, varicella has been identified as a risk factor for invasive group A streptococcus infections. The question is whether this relationship also existed between varicella and scarlet fever in the historical era. METHODS: The analysis begins with a search of historical medical reports on the relationship between varicella and scarlet fever epidemics in the late 19th and early 20th century, as well as in more recent empirical studies. Correlations and cross-correlations between varicella and scarlet fever are analyzed using weekly public health case reports from 1924 to 1932 for Boston, Chicago, New York City, and Philadelphia. Regression models are used to estimate the relationship between varicella and scarlet fever after controlling for seasonal forcing. RESULTS: Historical records give limited support for a causal relationship between varicella and scarlet fever but indicate that these diseases often occurred close in time to each other. Likewise, statistical analysis shows that varicella and scarlet fever epidemics are closely aligned with each other, and varicella has a strong relationship with scarlet fever. The relationship is stronger than reported in any previous research on the two diseases. CONCLUSION: The close correspondence of the two diseases likely depends on multiple factors, including seasonal forcing, a causal relationship, and co-infections. The results raise questions about whether this close relationship might have had a synergistic effect or a role in the evolution of S. pyogenes from the virulent, high incidence epidemics of the 19th century to the relatively benign scarlet fever of the 1950s. PMID- 27504183 TI - Is medical perspective on clinical governance practices associated with clinical units' performance and mortality? A cross-sectional study through a record linkage procedure. AB - OBJECTIVE: Assessment of the knowledge and application as well as perceived utility by doctors of clinical governance tools in order to explore their impact on clinical units' performance measured through mortality rates and efficiency indicators. METHODS: This research is a cross-sectional study with a deterministic record-linkage procedure. The sample includes n = 1250 doctors (n = 249 chiefs of clinical units; n = 1001 physicians) working in six public hospitals located in the Emilia-Romagna Region in Italy. Survey instruments include a checklist and a research-made questionnaire which were used for data collection about doctors' knowledge and application as well as perceived utility of clinical governance tools. The analysis was based on clinical units' performance indicators which include patients' mortality, extra-region active mobility rate, average hospital stay, bed occupancy, rotation and turnover rates, and the comparative performance index as efficiency indicators. RESULTS: The clinical governance tools are known and applied differently in all the considered clinical units. Significant differences emerged between roles and organizational levels at which the medical leadership is carried out. The levels of knowledge and application of clinical governance practices are correlated with the clinical units' efficiency indicators (bed occupancy rate, bed turnover interval, and extra-region mobility). These multiple linear regression analyses highlighted that the clinical governance knowledge and application is correlated with clinical units' mortality rates (odds ratio, -8.677; 95% confidence interval, 16.654, -0.700). CONCLUSION: The knowledge and application, as well as perceived utility by medical professionals of clinical governance tools, are associated with the mortality rates of their units and with some efficiency indicators. However, the medical frontline staff seems to not consider homogeneously useful the clinical governance tools application on its own clinical practice. PMID- 27504184 TI - Clinical impact and risk stratification of balloon angioplasty for femoropopliteal disease in nitinol stenting era: Retrospective multicenter study using propensity score matching analysis. AB - OBJECTIVE: Nitinol stenting could bring the better outcome in endovascular therapy for femoropopliteal disease. However, it might be expected that recent marked advances in both device technology and operator technique had led to improved efficacy of balloon angioplasty even in this segment. The aims of this study were to evaluate the clinical impact of balloon angioplasty for femoropopliteal disease and make risk stratification clear by propensity score matching analysis. METHODS: Based on the multicenter retrospective data, 2758 patients (balloon angioplasty: 729 patients and nitinol stenting: 2029 patients), those who underwent endovascular therapy for femoropopliteal disease, were analyzed. RESULTS: The propensity score matching procedure extracted a total of 572 cases per group, and the primary patency rate of balloon angioplasty and nitinol stenting groups after matching was significantly the same (77.2% vs 82.7% at 1 year; 62.2% vs 64.3% at 3 years; 47.8% vs 54.3% at 5 years). In multivariate Cox hazard regression analysis, significant predictors for primary patency were diabetes mellitus, regular dialysis, cilostazol use, chronic total occlusion, and intra-vascular ultra-sonography use. The strategy of balloon angioplasty was not evaluated as a significant predictor for the primary patency. After risk stratification using five items (diabetes mellitus, regular dialysis, no use of intra-vascular ultra-sonography, chronic total occlusion, and no use of cilostazol: the DDICC score), the estimated primary patency rates of each group (low, DDICC score 0-2; moderate, DDICC score 3; high risk, DDICC score 4-5) were 88.6%, 78.3%, and 63.5% at 1 year; 75.2%, 60.7%, and 39.8% at 3 years; and 66.0%, 47.1%, and 26.3% at 5 years (p < 0.0001). The primary patency rate of balloon angioplasty and nitinol stenting groups was significantly the same in each risk stratification. CONCLUSION: This study suggests that balloon angioplasty does not have inferiority to nitinol stenting but does have favorable efficacy in femoropopliteal segment by careful risk stratification with the recent advance of technique. PMID- 27504185 TI - Effects of electrical stimulation therapy on the blood flow in chronic critical limb ischemia patients following regenerative therapy. AB - OBJECTIVES: We investigated the effects of electrical stimulation therapy on cutaneous and muscle blood flow in critical limb ischemia patients following regenerative therapy. METHODS: Three groups were studied: 10 healthy young subjects, 10 elderly subjects, and 7 critical limb ischemia patients after regenerative therapy. After 5 min rest, electrical stimulation was applied at 5 Hz on the tibialis anterior muscle for 10 min. We estimated the relative changes in oxyhemoglobin and total hemoglobin compared to the basal values at rest (Delta[HbO2], Delta[Hbtot]), which reflected the blood flow in the skin and muscle layer, and we simultaneously measured the tissue O2 saturation (StO2) throughout the electrical stimulation and recovery phase by near-infrared spectroscopy. RESULTS: The Delta[HbO2] and Delta[Hbtot] values of the muscle layer in critical limb ischemia patients increased gradually and remained significantly higher at the 5-min and 10-min recovery periods after the electrical stimulation without reducing the StO2, but there is no significant change in the other two groups. Skin blood flow was not influenced by electrical stimulation in three groups. CONCLUSION: This improvement of the peripheral circulation by electrical stimulation would be beneficial as the adjunctive therapy after regenerative cell therapy. PMID- 27504186 TI - Cell-based laboratory evaluation of coagulation activation by antineoplastic drugs for the treatment of lymphoid tumors. AB - OBJECTIVES: Combining vorinostat, L-asparaginase, and doxorubicin (Dox) led to improved response rates in the treatment of lymphoid tumors. However, deep-vein thrombosis has been noted as one of the most serious side effects with these drugs, and how these regimens cause deep-vein thrombosis is unclear. METHODS: We investigated the procoagulant effects of vorinostat, L-asparaginase, and doxorubicin in lymphoid tumors, focusing on tissue factor, phosphatidylserine, and antithrombin. The human vascular endothelial cell line EAhy926 as well as the lymphoid neoplastic cell lines HUT78 (cutaneous T-cell lymphoma), Molt4 (acute T lymphoblastic leukemia), and Ramos (Burkitt lymphoma) were employed to investigate these procoagulant effects. RESULTS: Vorinostat, L-asparaginase, and doxorubicin induced exposure of phosphatidylserine and procoagulant activity on the surface of lymphoid tumor cells. Vorinostat and doxorubicin also induced phosphatidylserine exposure and increased procoagulant activity on EAhy926 cells. Expression of tissue factor antigen was induced by doxorubicin on the surface of each type of cells, whereas expression of tissue factor mRNA was unchanged. Secretion of antithrombin from HepG2 cells was reduced only by L-asparaginase. CONCLUSION: These data suggest that vorinostat and doxorubicin may induce procoagulant activity in vessels through apoptosis of tumor cells and through phosphatidylserine exposure and/or tissue factor expression on vascular endothelial cells. L-asparaginase may induce a thrombophilic state by reducing the secretion of anticoagulant proteins such as antithrombin. The laboratory methods described here could be useful to evaluate the procoagulant effects of antineoplastic drugs. PMID- 27504187 TI - "Varibaculum massiliense" sp. nov., a new bacterial species isolated from human urine. AB - We report the main characteristics of "Varibaculum massiliense" strain Marseille P2802(T) (=CSUR P2802), which was isolated from urine sample of a 59-year-old man with end-stage renal disease. PMID- 27504188 TI - A case of laryngeal cancer induced by exposure to asbestos in a construction site supervisor. AB - BACKGROUND: Construction site supervisors are exposed to many chemicals, dusts, and metals including asbestos. Asbestos is a hazardous chemical that is carcinogenic. Laryngeal cancer is not a rare disease in Korea. The most common causes of this disease are tobacco and alcohol, and representative occupational cause is asbestos. However, up to now, no case of laryngeal cancer induced by asbestos has been reported in Korea. In this study, we report such a case in a construction site supervisor. CASE PRESENTATION: A 60-year-old man who had been experiencing hoarseness for 2 months was diagnosed with laryngeal cancer. The pathologic diagnosis was squamous cell carcinoma in situ, based on examination of a biopsy specimen obtained by resection of the lesion. The patient had been exposed to asbestos for 38 years at construction sites where he worked until diagnosed with laryngeal cancer. He had been exposed to asbestos when demolishing buildings and inspecting materials. CONCLUSION: The patient in this case worked with construction materials including asbestos and supervised construction for 38 years, and was thus exposed to asbestos at construction sites. Much of the asbestos was highly concentrated especially during demolition processes. We therefore consider the laryngeal cancer of this patient to be a work-related disease. PMID- 27504189 TI - IgA nephropathy in a laboratory worker that progressed to end-stage renal disease: a case report. AB - BACKGROUND: IgA nephropathy (IgAN) is the most common form of glomerulonephritis, a principal cause of end-stage renal disease (ESRD) worldwide. The mechanisms of onset and progression of IgAN have not been fully revealed, and epidemiologic studies have yielded diverging opinions as to the role of occupational exposure to organic solvents in the initiation or worsening of IgAN. As the authors encountered a laboratory worker with IgAN that progressed to ESRD, we present a case report of IgAN progression due to dichloromethane exposure along with a review of literature. CASE PRESENTATION: A 41-year-old male laboratory worker began to experience gross painless hematuria after two years of occupational exposure to toluene. Although clinical follow-up was initiated under the impression of IgAN based on clinical findings, the patient continued to work for four more years in the same laboratory, during which he was in charge of laboratory analysis with direct exposure to a high concentration of dichloromethane without proper protective equipment. During that time, his renal function rapidly worsened and finally progressed to ESRD 10 years after the first clinical symptoms. The result of exposure assessment through reenactment of his work exceeded the occupational exposure limit for dichloromethane to a considerable degree. CONCLUSIONS: The causal association between occupational solvent exposure and IgAN is still unclear; therefore, this case report could be used as a basis to support the relevance of occupational solvent exposure to IgAN and/or its progression. Early intervention as well as close monitoring of laboratory workers exposed to various organic solvents is important to prevent or delay the progression of glomerulonephritis to ESRD in the occupational setting. PMID- 27504190 TI - Pharmacokinetics and dose adjustment of etoposide administered in a medium-dose etoposide, cyclophosphamide and total body irradiation regimen before allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: We investigated the pharmacokinetics of etoposide (ETP) to reduce the inter-individual variations of ETP concentrations in patients with acute leukemia who underwent allogeneic hematopoietic stem cell transplantation. We also carried out an in vivo study using rats to verify the dose adjustment. METHODS: This study included 20 adult patients. ETP was administered intravenously at a dose of 15 mg/kg once daily for 2 days (total dose: 30 mg/kg) combined with standard conditioning of cyclophosphamide and total body irradiation. In an in vivo study using rats, ETP was administered intravenously at a dose of 15 mg/kg or an adjusted dose. The ETP plasma concentration was determined by using HPLC. The pharmacokinetic parameters were estimated by using a 1-compartment model. RESULTS: The peak concentration (Cmax) of ETP and the area under the plasma concentration-time curve (AUC) of ETP differed greatly among patients (range of Cmax, 51.8 - 116.5 MUg/mL; range of AUC, 870 - 2015 MUg . h/mL). A significant relationship was found between Cmax and AUC (R = 0.85, P < 0.05). Distribution volume (Vd) was suggested to be one of the factors of inter-individual variation in plasma concentration of ETP in patients (range of Vd, 0.13 - 0.27 L/kg), and correlated with Alb and body weight (R = 0.56, P < 0.05; R = 0.40, P < 0.05 respectively). We predicted Vd of rats by body weight of rats (with normal albumin levels and renal function), and the dose of ETP was adjusted using predicted Vd. In the dose adjustment group, the target plasma ETP concentration was achieved and the variation of plasma ETP concentration was decreased. CONCLUSION: The results suggested that inter-individual variation of plasma concentration of ETP could be reduced by predicting Vd. Prediction of Vd is effective for reducing individual variation of ETP concentration and might enable a good therapeutic effect to be achieved. PMID- 27504191 TI - Effect of choline chloride supplementation on milk production and milk composition of Etawah grade goats. AB - BACKGROUND: The effect of choline chloride supplementation through forced drinking combined with concentrate diets containing Ca-fish oil on milk production and milk composition of Etawah Grade goats was evaluated. Choline chloride is an essential component in ruminant diets as it is required for fat metabolism. METHOD: The experiment was conducted in a completely randomized block design with three types of treatments and eight replications. The trial had two successive experimental periods; the first, during the eight weeks of late pregnancy, and the second, during the first 12 weeks of lactation. Twenty-four Etawah Grade does in the second gestation period were divided into three treatment groups. Commercial choline chloride 60 % in corncobs-based powder was used as a source of choline chloride. The treatments were no supplementation (control) and supplemented with either 4 g or 8 g/2days of choline chloride. Choline chloride was given to the animals through a forced drinking technique, after dissolving it in 60 ml drinking water. The initial body weight of does was 38.81 +/- 3.66 kg. The does were penned individually, and were given fresh chopped King Grass ad libitum and 700 g/day of concentrate diets containing Ca fish oil, starting eight weeks prior to expecting kidding and continuing for 12 weeks of parturition. RESULTS: All nutrient intakes were not significantly different (p > 0.05) among the treatments during the late pregnancy and the lactation periods. Supplementation did not affect (p > 0.05) the average daily gains and feed conversion ratio during pregnancy but gave effects (p < 0.05) on the average daily gains, feed conversion ratio and income over feed cost during lactation. The highest average daily milk yields and 4 % fat corrected milk yields were found in goats supplemented with 4 g/2days of choline chloride and increased by 17.00 % and 24.67 %, respectively, compared to the control. Moreover, milk composition percentage and milk constituent yields improved significantly (p < 0.05) in those supplemented with 4 g/2days of choline chloride. CONCLUSION: The supplementation of 4 g/2days of choline chloride through forced drinking increased milk yields, the 4 % fat corrected milk yields, milk composition, milk constituent yields, and improved feed conversion ratio and income over feed cost of Etawah Grade goats. PMID- 27504192 TI - CT findings associated with blastic plasmacytoid dendritic cell neoplasm: a case report. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that is frequently misdiagnosed. We present a case of a 53-year-old man diagnosed with blastic plasmacytoid dendritic cell neoplasm with extensive computed tomography (CT) findings and provide an imaging focused review of this uncommon malignancy. PMID- 27504193 TI - Testicular microlithiasis and preliminary experience of acoustic radiation force impulse imaging. AB - BACKGROUND: Elastography of the testis can be used as a part of multiparametric examination of the scrotum. PURPOSE: To determine the testicular stiffness using acoustic radiation force impulse imaging (ARFI) technique in men with testicular microlithiasis (TML). MATERIAL AND METHODS: In 2013, 12 patients with diagnosed testicular microlithiasis in 2008 (mean age, 51 years; age range, 25-76 years) underwent a 5-year follow-up B-mode ultrasonography with three ARFI elastography measurements of each testis. We used a Siemens Acuson S3000 machine. RESULTS: No malignancy was found at the 5-year follow-up B-mode and elastography in 2013. However, we found an increase in TML; in the previous ultrasonography in 2008, eight men had bilateral TML, whereas in 2013, 10 men were diagnosed with bilateral TML. The mean elasticity of testicles with TML was 0.82 m/s (interquartile range [IQR], 0.72-0.88 m/s; range, 65-1.08 m/s). CONCLUSION: Elastography velocity of testis with TML seems to be in the same velocity range as in men with normal testis tissue. PMID- 27504194 TI - Duplication of the superficial femoral artery: comprehensive review of imaging literature and insight into embryology. AB - An extremely rare case of duplicated superficial femoral artery (SFA) was incidentally observed on computed tomography angiogram (CTA) of the lower limbs for presurgical planning for an osteomyocutaneous fibula flap in a patient with T4a oropharyngeal squamous cell carcinoma (SCC). To our knowledge, this is the sixth reported case in the imaging literature. We performed a comprehensive review of the English literature and discuss the underlying embryological origin underpinning this rare anatomical variant. PMID- 27504195 TI - The Effects of Scleral Collagen Cross-Linking Using Glyceraldehyde on the Progression of Form-Deprived Myopia in Guinea Pigs. AB - To investigate the effects of collagen cross-linking using glyceraldehyde on the biomechanical properties of the sclera and the axial elongation of form-deprived myopia in the guinea pig. Thirty-six guinea pigs were randomly assigned to four groups: FDM (form-deprived myopia); FDMG (form-deprived myopia treated with glyceraldehyde); FDMS (form-deprived myopia treated with 0.9% isotonic sodium chloride); and normal control (free of form-deprivation). FDM was achieved in the right eye using a latex facemask. The right eye in FDMG was treated with a posterior subtenon injection of 0.5 M glyceraldehyde; 0.9% isotonic sodium chloride was administered to the right eye in FDMS group using the same method. Axial length, refraction, and stress-strain of the sclera were measured at scheduled time points. The treated eyes were also examined histologically by light microscopy. It was found that glyceraldehyde treatment significantly increased the stiffness of the sclera in the FDM eyes and abnormalities have not been observed in the retina and optic nerve of the treated eyes. But the development of myopia was not affected. PMID- 27504196 TI - Expression of TSLP and Downstream Molecules IL-4, IL-5, and IL-13 on the Eye Surface of Patients with Various Types of Allergic Conjunctivitis. AB - Background. The pathogenesis of allergic conjunctivitis has not been clearly established. Moreover, previous studies fail to consider human models of allergic conjunctivitis. This study investigated the expression of thymic stromal lymphopoiet in TSLP and its downstream molecules in conjunctival scrappings and tear. Methods. This cross-sectional study compares patients with vernal keratoconjunctivitis (VKC), seasonal allergic conjunctivitis (SAC), and perennial allergic conjunctivitis (PAC) with normal controls. There are 80 people recorded in Shanxi Eye Hospital. Increasingly, 20 are with VKC, 20 are with SAC, 20 are with PAC, and the remaining 20 are normal controls. Conjunctiva were harvested for total RNA extraction and gene expression by real-time polymerase chain reaction. Epithelial cells were collected to make pathological sections for immunohistochemical staining. Human tears were evaluated by Luminex microbead assay. A P value less than 0.05 from Dunnett's post hoc test in SPSS means a statistical significant distinction. Results. Positive expression in conjunctival cells of patients with allergic conjunctivitis. The expression of TSLP and IL-4, IL-5, and IL-13 mRNA shows a statistically significant difference (P < 0.05). TSLP and IL-4, IL-5, and IL-13 concentrations show a statistically significant difference (P < 0.01). Conclusions. This study suggests that TSLP and downstream molecules are expressed in patients with various types of allergic conjunctivitis. PMID- 27504197 TI - Effect of exercise on serum vitamin D and tissue vitamin D receptors in experimentally induced type 2 Diabetes Mellitus. AB - This work aimed to study the effect of swimming exercise on serum vitamin D level and tissue vitamin D receptors in experimentally induced type 2 Diabetes Mellitus. Sixty adult male rats were divided into control and diabetic groups. Each was further subdivided into sedentary and exercised subgroups. Diabetes Mellitus was induced by a single intraperitoneal dose of streptozotocin (50 mg/kg) dissolved in cold 0.01 M citrate buffer (pH 4.5). The exercised subgroups underwent swimming for 60 min, 5 times a week for 4 weeks. Serum glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), lipids, vitamin D and tissue Vitamin D receptors (VDR) were evaluated. Significant increase in serum glucose, insulin, HOMA-IR, cholesterol, triglycerides, and low density lipoprotein (LDL) levels in sedentary diabetic rats was detected. On the other hand, high density lipoprotein (HDL), free fatty acids, serum vitamin D and pancreatic, adipose, and muscular VDR showed a significant decrease in the same group. It is evident that all these parameters were reversed by swimming exercise indicating its beneficial role in type 2 Diabetes. In diabetic groups; serum vitamin D was found to be correlated negatively with serum glucose, insulin, HOMA, cholesterol, triglycerides, and LDL and positively correlated with HDL and tissue VDR. In conclusion, Disturbed vitamin D is associated with metabolic impairments in sedentary diabetic rats. Moderate swimming exercise is beneficial in improving these consequences through modulation of vitamin D status. Future studies could be designed to investigate the effect of the combination of vitamin D intake with exercise in diabetic patients. PMID- 27504198 TI - Metabolomics driven analysis of Erythrina lysistemon cell suspension culture in response to methyl jasmonate elicitation. AB - An MS-based metabolomic approach was used to profile the secondary metabolite of the ornamental plant Erythrina lysistemon via ultra-performance liquid chromatography coupled to photodiode array detection and high resolution q-TOF mass spectrometry (UPLC-PDA-MS). Cultures maintained the capacity to produce E. lysistemon flavonoid subclasses with pterocarpans amounting for the most abundant ones suggesting that it could provide a resource of such flavonoid subclass. In contrast, alkaloids, major constituents of Erythrina genus, were detected at trace levels in suspension cultures. Methyl jasmonate (MeJA), phytohormone, was further supplied to culture with the aim of increasing secondary metabolites production and with metabolite profiles subjected to multivariate data analysis to evaluate its effect. Results revealed that triterpene i.e. oleanolic acid and fatty acid i.e. hydroxy-octadecadienoic acid were elicited in response to methyl jasmonate, whereas pterocarpans i.e., isoneorautenol showed a decline in response to elicitation suggesting for the induction of terpenoid biosynthetic pathway and concurrent with a down regulation of pterocarpans. In conclusion, a total of 53 secondary metabolites including 3 flavones, 12 isoflavones, 4 isoflavanones, 4 alkaloids, 11 pterocarpans, and 5 phenolic acids were identified. PMID- 27504199 TI - Using Multidisciplinary Focus Groups to Inform the Development of mI SMART: A Nurse-Led Technology Intervention for Multiple Chronic Conditions. AB - Used as integrated tools, technology may improve the ability of healthcare providers to improve access and outcomes of care. Little is known about healthcare teams' preferences in using such technology. This paper reports the findings from focus groups aimed at evaluating a newly developed primary care technology platform. Focus groups were completed in academic, outpatient, and community settings. Focus groups were attended by 37 individuals. The participants included professionals from multiple disciplines. Both prescribing (N = 8) and nonprescribing healthcare team members (n = 21) completed the focus groups and survey. The majority were practicing for more than 20 years (44.8%) in an outpatient clinic (62%) for 20-40 hours per week (37.9%). Providers identified perceived obstacles of patient use as ability, willingness, and time. System obstacles were identified as lack of integration, lack of reimbursement, and cost. The positive attributes of the developed system were capability for virtual visits, readability, connectivity, user-friendliness, ability to capture biophysical measures, enhanced patient access, and incorporation of multiple technologies. Providers suggested increasing capability for biophysical and symptom monitoring for more common chronic conditions. Technology interventions have the potential to improve access and outcomes but will not be successful without the input of users. PMID- 27504200 TI - Bilateral Breast Reconstruction with Abdominal Free Flaps: A Single Centre, Single Surgeon Retrospective Review of 55 Consecutive Patients. AB - Breast reconstruction using free tissue transfer is an increasingly utilised oncoplastic procedure. The aim was to review all bilateral breast reconstructions using abdominal free flaps by a single surgeon over an 11-year period (2003 2014). A retrospective review was performed on all patients who underwent bilateral breast reconstruction using abdominal free flaps between 2003 and 2014 by the senior author (DAM). Data analysed included patient demographics, indication for reconstruction, surgical details, and complications. Fifty-five female patients (mean 48.6 years [24-71 years]) had bilateral breast reconstruction. The majority (41, 74.5%) underwent immediate reconstruction and DIEP flaps were utilised on 41 (74.5%) occasions. Major surgical complications occurred in 6 (10.9%) patients, all of which were postoperative vascular compromise of the flap. Failure to salvage the reconstruction occurred on 3 (5.5%) occasions resulting in a total flap failure rate of 2.7%. Obesity (>30 kg/m(2)) and age > 60 years were shown to have a statistically increased risk of developing postoperative complications (P < 0.05). Our experience demonstrates that abdominal free flaps for bilateral breast reconstruction fares well, with a flap failure rate of 2.7%. Increased body mass index and patient age (>60 years) were associated with higher complication rates. PMID- 27504201 TI - Healthy Aging from the Perspectives of 683 Older People with Multiple Sclerosis. AB - Purpose. The aim of this study was to determine what factors most greatly contributed to healthy aging with multiple sclerosis (MS) from the perspective of a large sample of older people with MS. Design and Methods. Participants (n = 683; >55 years of age with symptoms >20 years) provided answers to an open-ended question regarding healthy aging and were categorized into three groups, 55-64 (young), 65-74 (middle), and 75 and over (oldest old). Sociodemographic actors were compared using ANOVA. Two independent raters used the framework method of analyzing qualitative data. Results. Participants averaged 64 years of age (+/ 6.2) with MS symptoms for 32.9 years (+/-9.4). 531 participants were female (78%). The majority of participants lived in their own home (n = 657) with a spouse or partner (n = 483). Participants described seven themes: social connections, attitude and outlook on life, lifestyle choices and habits, health care system, spirituality and religion, independence, and finances. These themes had two shared characteristics, multidimensionality and interdependence. Implications. Learning from the experiences of older adults with MS can help young and middle aged people with MS plan to age in their own homes and communities. Our data suggests that older people with MS prioritize factors that are modifiable through targeted self-management strategies. PMID- 27504202 TI - Pregnant Women in Louisiana Are Not Meeting Dietary Seafood Recommendations. AB - Background. The 2015-2020 Dietary Guidelines for Americans recommend that pregnant women and women of childbearing ages consume 8-12 oz. of seafood per week. Fish are the major dietary source of omega-3 long chain polyunsaturated fatty acids, which have benefits for the mother and fetus. Methods. In this observational study, we investigated dietary habits of pregnant women in Baton Rouge, Louisiana, USA, to determine if they achieve recommended seafood intake. A print survey, which included commonly consumed foods from protein sources (beef, chicken, pork, and fish), was completed by pregnant women at a single-day hospital convention for expecting families in October 2015. Women (n = 221) chose from six predefined responses to answer how frequently they were consuming each food. Results. Chicken was consumed most frequently (75% of women), followed by beef (71%), pork (65%), and fish (22%), respectively. Consumption frequency for the most consumed fish (catfish, once per month) was similar to or lower than that of the least consumed beef, chicken, and pork foods. Consumption frequency for the most consumed chicken and beef foods was at least once per week. Conclusion. Our data indicate that pregnant women in Louisiana often consume protein sources other than fish and likely fail to meet dietary seafood recommendations. PMID- 27504203 TI - Cross-Cultural Adaptation and Validation of the Jebsen-Taylor Hand Function Test in an Italian Population. AB - Objective. This paper describes the Italian translation and adaptation to the Italian culture of the original version of the Jebsen-Taylor hand function test and conveys the procedure for testing its validity and reliability. Design. The cultural adaptation process and validation were based on data from a group of people with no clinical evidence of disease or impairment of the upper limbs. The process required a forward and reverse translation in its original language. The scale obtained was reviewed by 8 experts in the field of psychometrics dealing with statistical methods that are useful for the behavioral and social sciences. The Italian adapted version of the JTHFT was then produced and validated. Participants. The test was submitted to 320 people with no clinical evidence of disease in order to test its acceptability and consistency. Results. The total time required to perform each subtest was 80.16 +/- 43.13 seconds for the nondominant hand (NDH) and 49.97 +/- 27.28 seconds for the dominant hand (DH). The internal consistency (assessed with Pearson's r) and the reliability or the construct validity (assessed with Cronbach's alpha) are significative. Conclusions. This is the first study reporting the result of the translation, cultural adaptation, and validation protocols of the JTHFT in Italian. It provides a new tool for Italian professionals to measure the functionality of the hand in participants with various upper limb pathologies. PMID- 27504204 TI - Altered Cerebellar Circuitry following Thoracic Spinal Cord Injury in Adult Rats. AB - Cerebellar function is critical for coordinating movement and motor learning. However, events occurring in the cerebellum following spinal cord injury (SCI) have not been investigated in detail. We provide evidence of SCI-induced cerebellar synaptic changes involving a loss of granule cell parallel fiber input to distal regions of the Purkinje cell dendritic tree. This is accompanied by an apparent increase in synaptic contacts to Purkinje cell proximal dendrites, presumably from climbing fibers originating in the inferior olive. We also observed an early stage injury-induced decrease in the levels of cerebellin-1, a synaptic organizing molecule that is critical for establishing and maintaining parallel fiber-Purkinje cell synaptic integrity. Interestingly, this transsynaptic reorganizational pattern is consistent with that reported during development and in certain transgenic mouse models. To our knowledge, such a reorganizational event has not been described in response to SCI in adult rats. Regardless, the novel results of this study are important for understanding SCI induced synaptic changes in the cerebellum, which may prove critical for strategies focusing on promoting functional recovery. PMID- 27504205 TI - Dexamethasone Associated ST Elevation Myocardial Infarction Four Days after an Unremarkable Coronary Angiogram-Another Reason for Cautious Use of Steroids: A Case Report and Review of the Literature. AB - Drug induced myocardial infarction is a known entity with different forms of steroids linked to coronary artery disease (CAD) either through promoting its traditional risk factors, inducing coronary spasm, or by other unidentified mechanisms. Dexamethasone is known to promote an atherogenic and hypercoagulable state. We report a case of a 75-year-old woman who had ST elevation myocardial infarction (STEMI) associated with dexamethasone use just 4 days following an angiogram showing minor luminal irregularities. PMID- 27504206 TI - Testicular Signet-Ring Cell Metastasis from a Carcinoma of Unknown Primary Site: A Case Report and Literature Review. AB - Signet-ring cell carcinoma is a highly malignant adenocarcinoma consisting of cells characterized as cytoplasmic vacuoles filled with mucin. The most common primary location of this type of cancer is the stomach, but it may also be found in other organs such as prostate, testis, bladder, ovaries, or colon. To date, metastatic signet-ring cell carcinoma of unknown primary (CUP) site to the testis is an extremely rare entity in daily practice. Reviewing the literature, we have been able to detect only three cases of testicular metastases from CUP, two with histological diagnosis of a signet-ring cell carcinoma and one with an adenocarcinoma. In this short paper, we report a case of a 56-year-old man who presented to our Department with testicular mass and ascites. Following a standard diagnostic approach no primary tumor could be identified. CUP was the final clinical diagnosis, histologically characterized as poorly differentiated adenocarcinoma with signet-ring cells involving the peritoneum and the testicular structures. PMID- 27504207 TI - Spontaneous Minced Cartilage Procedure for Unexpectedly Large Femoral Condyle Surface Defect. AB - Articular cartilage defects at the knee joint are being identified and treated with increasing frequency. Chondrocytes may have strongest potential to generate high-quality repair tissue within the defective region, in particular when large diameter defects are present. Autologous chondrocyte implantation is not available in every country. We present a case where we spontaneously covered an acute cartilage defect, which was significantly larger than expected and loose during initial arthroscopic inspection after reading preoperative MRI, by mincing the separated fragment and directly implanting the autologous cartilage chips into the defective region. PMID- 27504208 TI - Pauci-Immune Crescentic Glomerulonephritis in Connective Tissue Disease. AB - Pauci-immune crescentic glomerulonephritis is commonly seen in ANCA-associated vasculitis but it is rarely seen during the course of other connective tissue diseases like lupus or Sjogren's syndrome or MCTD. We report 3 cases of pauci immune crescentic glomerulonephritis in patients with connective tissue disease other than vasculitis. We reviewed literature and made summary of previously reported cases of this rare entity. Clinical and laboratory features of these patients varied widely, but most of patients have met criteria for lupus. In this small population of patients there is no correlation with ANCAs. Most of the patients were treated with aggressive immunosuppression and did well if they were treated early in the course of their disease. One of our patients required renal transplant, but she presented late in the course of her disease, as evidenced by chronicity on her renal biopsy. Whether these patients are overlap of vasculitis and other connective tissue diseases or to be considered as a separate entity is yet to be described. Clinicians must be aware of these presentations because initial presentation can be severe. PMID- 27504209 TI - Synthesis of Polymerizable Cyclodextrin Derivatives for Use in Adhesion-Promoting Monomer Formulations. AB - The synthesis of the cyclodextrin derivatives reported herein was assisted by extensive literature research together with structure-property relationships derived from three-dimensional molecular modeling. These studies led to the hypothesis that many of the 21 hydroxyl groups on beta-cyclodextrin molecules could be derivatized to form a closely related family of analogous chemical compounds containing both polymerizable groups and hydrophilic ionizable ligand (substrate-binding) groups, each attached via hydrolytically-stable ether linkages. The vinylbenzylether polymerizable groups should readily homopolymerize and also copolymerize with methacrylates. This could be highly useful for dental applications because substantially all contemporary dental resins and composites are based on methacrylate monomers. Due to hydrophilic ligands and residual hydroxyl groups, these cyclodextrin derivatives should penetrate hydrated layers of dentin and enamel to interact with collagen and tooth mineral. Analyses indicated that the diverse reaction products resulting from the method of synthesis reported herein should comprise a family of copolymerizable molecules that collectively contain about 30 different combinations of vinylbenzyl and hexanoate groups on the various molecules, with up to approximately seven of such groups combined on some of the molecules. Although the hypothesis was supported, and adhesive bonding to dentin is expected to be significantly improved by the use of these polymerizable cyclodextrin derivatives, other efforts are planned for improved synthetic methods to ensure that each of the reaction-product molecules will contain at least one copolymerizable moiety. The long-term objective is to enable stronger and more durable attachments of densely cross linked polymers to hydrated hydrophilic substrates. Capabilities for bonding of hydrolytically stable polymers to dental and perhaps other hydrous biological tissues could provide widespread benefits. PMID- 27504210 TI - Adhesive Bonding to Dentin Improved by Polymerizable Cyclodextrin Derivatives. AB - The objective of this work was to determine bonding characteristics of a hydrophilic monomer formulation containing polymerizable cyclodextrin derivatives. The hypothesis was that a formulation containing hydrophilic cross linking diluent comonomers and cyclodextrins with functional groups attached by hydrolytically stable ether linkages could form strong adhesive bonds to dentin. The previously synthesized polymerizable cyclodextrin derivatives were formulated with sorbitol dimethacrylate, methacrylic acid and phenylbis(2,4,6 trimethylbenzoyl) phosphine oxide photoinitiator. The same formulation without the polymerizable cyclodextrin derivatives isolated the effects of the polymerizable cyclodextrin derivatives. A commercial self-etching bonding system was tested as a comparative control. Ground mid-coronal dentin was etched with 37 % phosphoric acid (H3PO4) for 15 s and rinsed with distilled water for 10 s. Formulations were applied to the moist dentin and light-cured 10 s. A packable composite was then applied through irises and light-cured 60 s. Teeth were stored in water for 24 h before bonds were tested in a shearing orientation. One-way ANOVA was performed on the data. The average values of shear bond strengths were defined as loads at fracture divided by the 4 mm diameter iris areas. The average value of shear bond strength for the formulation containing the polymerizable cyclodextrin derivatives was higher (p < 0.05), where p is a fraction of the probability distribution) than that of the same monomeric formulation except that the polymerizable cyclodextrin derivatives were not included. This was supporting evidence that the polymerizable cyclodextrin derivatives contributed to improved bonding. The average value of shear bond strength for the formulation containing the polymerizable cyclodextrin derivatives was also higher (p < 0.05) than that of the commercial self-etching bonding system. These preliminary results are in accordance with the hypothesis that formulations containing polymerizable cyclodextrin derivatives can form strong adhesive bonds to hydrated dentin surfaces. Further improvements in bonding to hydrated biological tissues by use of advanced formulations are anticipated. PMID- 27504211 TI - ASME B89.4.19 Performance Evaluation Tests and Geometric Misalignments in Laser Trackers. AB - Small and unintended offsets, tilts, and eccentricity of the mechanical and optical components in laser trackers introduce systematic errors in the measured spherical coordinates (angles and range readings) and possibly in the calculated lengths of reference artifacts. It is desirable that the tests described in the ASME B89.4.19 Standard [1] be sensitive to these geometric misalignments so that any resulting systematic errors are identified during performance evaluation. In this paper, we present some analysis, using error models and numerical simulation, of the sensitivity of the length measurement system tests and two face system tests in the B89.4.19 Standard to misalignments in laser trackers. We highlight key attributes of the testing strategy adopted in the Standard and propose new length measurement system tests that demonstrate improved sensitivity to some misalignments. Experimental results with a tracker that is not properly error corrected for the effects of the misalignments validate claims regarding the proposed new length tests. PMID- 27504213 TI - Implementation of Two-Dimensional Polycrystalline Grains in Object Oriented Micromagnetic Framework. AB - In response to the growing need for a more accurate micromagnetic model to understand switching phenomenon in nanoscale magnets, we developed the capability to simulate two-dimensional polycrystalline grains using the Object Oriented Micromagnetic Framework (OOMMF). This addition allows users full flexibility in determining the magnetocrystalline anisotropy and axe in each grain as well as the inter- and intragranular exchange coupling strength. PMID- 27504212 TI - Statistical Analysis of a Round-Robin Measurement Survey of Two Candidate Materials for a Seebeck Coefficient Standard Reference Material. AB - In an effort to develop a Standard Reference Material (SRMTM) for Seebeck coefficient, we have conducted a round-robin measurement survey of two candidate materials-undoped Bi2Te3 and Constantan (55 % Cu and 45 % Ni alloy). Measurements were performed in two rounds by twelve laboratories involved in active thermoelectric research using a number of different commercial and custom-built measurement systems and techniques. In this paper we report the detailed statistical analyses on the interlaboratory measurement results and the statistical methodology for analysis of irregularly sampled measurement curves in the interlaboratory study setting. Based on these results, we have selected Bi2Te3 as the prototype standard material. Once available, this SRM will be useful for future interlaboratory data comparison and instrument calibrations. PMID- 27504214 TI - Measurement of Absorption and Scattering With an Integrating Sphere Detector: Application to Microalgae. AB - A spectrometer with an integrating sphere (IS) detector was used to measure the absorbance due to scattering and absorption. Analysis of the measurement process showed that two measurements of the absorbance, one with the cuvette placed in the normal spectrometer position, and the second with the cuvette placed next to the entrance aperture of the IS detector, provide enough information to separate the contributions from scattering and molecular absorption. Measurements were carried out with mixtures of microsphere and chromophore solutions. Two cases were examined: microspheres suspended in an aqueous fluorescein solution, and microspheres suspended in an aqueous holmium oxide solution. In both cases, the proposed measurement model gave results which were in good agreement with the expected response. Measurements on microalgae suspensions yielded a molecular absorption contribution and a scattering contribution. The scattering contribution had significant spectral structure which was inversely related to the molecular absorption contribution. The absorption and scattering contributions may provide independent information on the status of chlorophyll molecules and the structure of chloroplasts in microalgae. PMID- 27504215 TI - Issues in Optical Diffraction Theory. AB - This paper focuses on unresolved or poorly documented issues pertaining to Fresnel's scalar diffraction theory and its modifications. In Sec. 2 it is pointed out that all thermal sources used in practice are finite in size and errors can result from insufficient coherence of the optical field. A quarter wave criterion is applied to show how such errors can be avoided by placing the source at a large distance from the aperture plane, and it is found that in many cases it may be necessary to use collimated light as on the source side of a Fraunhofer experiment. If these precautions are not taken the theory of partial coherence may have to be used for the computations. In Sec. 3 it is recalled that for near-zone computations the Kirchhoff or Rayleigh-Sommerfeld integrals are applicable, but fail to correctly describe the energy flux across the aperture plane because they are not continuously differentiable with respect to the assumed geometrical field on the source side. This is remedied by formulating an improved theory in which the field on either side of a semi-reflecting screen is expressed as the superposition of mutually incoherent components which propagate in the opposite directions of the incident and reflected light. These components are defined as linear combinations of the Rayleigh-Sommerfeld integrals, so that they are rigorous solutions of the wave equation as well as continuously differentiable in the aperture plane. Algorithms for using the new theory for computing the diffraction patterns of circular apertures and slits at arbitrary distances z from either side of the aperture (down to z = +/- 0.0003 lambda) are presented, and numerical examples of the results are given. These results show that the incident geometrical field is modulated by diffraction before it reaches the aperture plane while the reflected field is spilled into the dark space. At distances from the aperture which are large compared to the wavelength lambda these field expressions are reduced to the usual ones specified by Fresnel's theory. In the specific case of a diffracting half plane the numerical results obtained were practically the same as those given by Sommerfeld's rigorous theory. The modified theory developed in this paper is based on the explicit assumption that the scalar theory of light cannot explain plolarization effects. This premise is justified in Sec. 4, where it is shown that previous attempts to do so have produced dubious results. PMID- 27504216 TI - Priorities for Standards and Measurements to Accelerate Innovations in Nano Electrotechnologies: Analysis of the NIST-Energetics-IEC TC 113 Survey. AB - In 2008, the National Institute of Standards and Technology and Energetics Incorporated collaborated with the International Electrotechnical Commission Technical Committee 113 (IEC TC 113) on nano-electrotechnologies to survey members of the international nanotechnologies community about priorities for standards and measurements to accelerate innovations in nano-electrotechnologies. In this paper, we analyze the 459 survey responses from 45 countries as one means to begin building a consensus on a framework leading to nano-electrotechnologies standards development by standards organizations and national measurement institutes. The distributions of priority rankings from all 459 respondents are such that there are perceived distinctions with statistical confidence between the relative international priorities for the several items ranked in each of the following five Survey category types: 1) Nano-electrotechnology Properties, 2) Nano-electrotechnology Taxonomy: Products, 3) Nano-electrotechnology Taxonomy: Cross-Cutting Technologies, 4) IEC General Discipline Areas, and 5) Stages of the Linear Economic Model. The global consensus prioritizations for ranked items in the above five category types suggest that the IEC TC 113 should focus initially on standards and measurements for electronic and electrical properties of sensors and fabrication tools that support performance assessments of nano-technology enabled sub-assemblies used in energy, medical, and computer products. PMID- 27504217 TI - Calibration of Speed Enforcement Down-The-Road Radars. AB - We examine the measurement uncertainty associated with different methods of calibrating the ubiquitous down-the-road (DTR) radar used in speed enforcement. These calibration methods include the use of audio frequency sources, tuning forks, a fifth wheel attached to the rear of the vehicle with the radar unit, and the speedometer of the vehicle. We also provide an analysis showing the effect of calibration uncertainty on DTR-radar speed measurement uncertainty. PMID- 27504218 TI - High Speed Quantum Key Distribution Over Optical Fiber Network System. AB - The National Institute of Standards and Technology (NIST) has developed a number of complete fiber-based high-speed quantum key distribution (QKD) systems that includes an 850 nm QKD system for a local area network (LAN), a 1310 nm QKD system for a metropolitan area network (MAN), and a 3-node quantum network controlled by a network manager. This paper discusses the key techniques used to implement these systems, which include polarization recovery, noise reduction, frequency up-conversion detection based on a periodically polled lithium nitrate (PPLN) waveguide, custom high-speed data handling boards and quantum network management. Using our quantum network, a QKD secured video surveillance application has been demonstrated. Our intention is to show the feasibility and sophistication of QKD systems based on current technology. PMID- 27504219 TI - Method for the Characterization of Extreme-Ultraviolet Photoresist Outgassing. AB - Outgassing from photoresists illuminated by extreme ultraviolet radiation can lead to degradation of the very expensive multilayer-coated optics in an extreme ultraviolet stepper. Reliable quantification of the various organic molecules outgassed by photoresists has been a challenging goal. We have designed a compact system for this measurement. In the first step, the total number of molecules emitted by the photoresist is measured using a pressure-rise method in a closed vacuum chamber, with the pressure measured by mechanical means using a capacitance displacement gauge. To provide identification and relative abundances, the outgassed molecules are then collected in an evacuated trap cooled by liquid nitrogen for subsequent analysis by gas chromatography with mass spectrometry. We will discuss the design and performance of the system. PMID- 27504220 TI - The Detection of Lyman Alpha Radiation Formed by the Slowing Down of Protons and Tritons Produced by the (3)He (n, tp) Reaction-A Model Study. AB - The observation of Lyman alpha (Lalpha) radiation produced by the end products of the (3)He (n,tp) reaction has suggested the possibility of a new method of cold thermal neutron detection. In order for this goal to be achieved, a basic understanding of how the Lalpha radiation is formed and how it may be detected, is needed. The model study described here is an attempt to provide this basic understanding and to provide quantitative results that can be used in designing future experiments. PMID- 27504221 TI - Pass-Fail Testing: Statistical Requirements and Interpretations. AB - Performance standards for detector systems often include requirements for probability of detection and probability of false alarm at a specified level of statistical confidence. This paper reviews the accepted definitions of confidence level and of critical value. It describes the testing requirements for establishing either of these probabilities at a desired confidence level. These requirements are computable in terms of functions that are readily available in statistical software packages and general spreadsheet applications. The statistical interpretations of the critical values are discussed. A table is included for illustration, and a plot is presented showing the minimum required numbers of pass-fail tests. The results given here are applicable to one-sided testing of any system with performance characteristics conforming to a binomial distribution. PMID- 27504222 TI - Characterization of Probe Dynamic Behaviors in Critical Dimension Atomic Force Microscopy. AB - This paper describes a detailed computational model of the interaction between an atomic force microscope probe tip and a sample surface. The model provides analyses of dynamic behaviors of the tip to estimate the probe deflections due to surface intermittent contact and the resulting dimensional biases and uncertainties. Probe tip and cantilever beam responses to intermittent contact between the probe tip and sample surface are computed using the finite element method. Intermittent contacts with a wall and a horizontal surface are computed and modeled, respectively. Using a 75 nm Critical Dimension (CD) tip as an example, the responses of the probe to interaction forces between the sample surface and the probe tip are shown in both time and frequency domains. In particular, interaction forces between the tip and both a vertical wall and a horizontal surface of a silicon sample are modeled using Lennard-Jones theory. The Snap-in and Snap-out of the probe tip in surface scanning are calculated and shown in the time domain. Based on the given tip-sample interaction force model, the calculation includes the compliance of the probe and dynamic forces generated by an excitation. Cantilever and probe tip deflections versus interaction forces in the time domain can be derived for both vertical contact with a plateau and horizontal contact with a side wall. Dynamic analysis using the finite element method and Lennard-Jones model provide a unique means to analyze the interaction of the probe and sample, including calculation of the deflection and the gap between the probe tip and the measured sample surface. PMID- 27504223 TI - Procedures for Wavelength Calibration and Spectral Response Correction of CCD Array Spectrometers. AB - This work describes a procedure for acquiring a spectrum of an analyte over an extended range of wavelengths and validating the wavelength and intensity assignments. To acquire a spectrum over an extended range of wavelengths with a spectrometer with a charge coupled device (CCD) array detector, it is necessary to acquire many partial spectra, each at a different angular position of the grating, and splice the partial spectra into a single extended spectrum. The splicing procedure exposes instrument dependent artifacts. It is demonstrated that by taking a spectrum of a reference irradiance source and making spectral correction, the artifacts exposed by the splicing are removed from the analyte spectrum. This is because the irradiance reference spectrum contains the same artifacts as the analyte spectrum. The artifacts exposed by the splicing depend on the wavelength of the splice; therefore it is important to measure the irradiance reference spectrum for the same range of wavelengths used to measure the spectrum of the analyte solution. In other words, there is no general spectral correction factor which is applicable to spectra taken for different range of wavelengths. The wavelength calibration is also carried out by splicing many partial spectra from a source like a krypton lamp. However the wavelength assignments are not sensitive to the splicing procedure and the same wavelength calibration can be used for spectra acquired over different extended wavelength ranges. The wavelength calibration checks the validity of the setting of the grating angular position, and the assignment of wavelengths to individual pixels on the CCD array detector. The procedure is illustrated by measuring the spectrum of an orange glass and the spectrum of a suspension of microalgae. PMID- 27504224 TI - Design of the DEMO Fusion Reactor Following ITER. AB - Runs of the NSTAB nonlinear stability code show there are many three-dimensional (3D) solutions of the advanced tokamak problem subject to axially symmetric boundary conditions. These numerical simulations based on mathematical equations in conservation form predict that the ITER international tokamak project will encounter persistent disruptions and edge localized mode (ELMS) crashes. Test particle runs of the TRAN transport code suggest that for quasineutrality to prevail in tokamaks a certain minimum level of 3D asymmetry of the magnetic spectrum is required which is comparable to that found in quasiaxially symmetric (QAS) stellarators. The computational theory suggests that a QAS stellarator with two field periods and proportions like those of ITER is a good candidate for a fusion reactor. For a demonstration reactor (DEMO) we seek an experiment that combines the best features of ITER, with a system of QAS coils providing external rotational transform, which is a measure of the poloidal field. We have discovered a configuration with unusually good quasisymmetry that is ideal for this task. PMID- 27504225 TI - A Method for Assigning Priorities to United States Measurement System (USMS) Needs: Nano-Electrotechnologies. AB - In 2006, the National Institute of Standards and Technology conducted an assessment of the U.S. measurement system (USMS), which encompasses all private and public organizations that develop, supply, use, or ensure the validity of measurement results. As part of that assessment, NIST collaborated with Energetics Incorporated to identify and authenticate 723 measurement needs that are barriers to technological innovations. A number of these measurement needs (64) are relevant to accelerating innovation and commercialization of nano electrotechnologies. In this paper, we apply the taxonomy from a 2008 international survey that established a global consensus of priorities for standards and measurements in nano-electrotechnologies to rank in priority order the relevant 64 USMS-identified measurement needs. This paper presents a method for assigning priorities that is statistically based and represents a global consensus of stakeholders. Such a method is needed because limited resources exist to address the large number of measurement needs in nano electrotechnologies, and the most critical measurement needs should be addressed first. PMID- 27504226 TI - First-Principles Calculation of the Third Virial Coefficient of Helium. AB - Knowledge of the pair and three-body potential-energy surfaces of helium is now sufficient to allow calculation of the third density virial coefficient, C(T), with significantly smaller uncertainty than that of existing experimental data. In this work, we employ the best available pair and three-body potentials for helium and calculate C(T) with path-integral Monte Carlo (PIMC) calculations supplemented by semiclassical calculations. The values of C(T) presented extend from 24.5561 K to 10 000 K. In the important metrological range of temperatures near 273.16 K, our uncertainties are smaller than the best experimental results by approximately an order of magnitude, and the reduction in uncertainty at other temperatures is at least as great. For convenience in calculation of C(T) and its derivatives, a simple correlating equation is presented. PMID- 27504227 TI - Perturbations From Ducts on the Modes of Acoustic Thermometers. AB - We examine the perturbations of the modes of an acoustic thermometer caused by circular ducts used either for gas flow or as acoustic waveguides coupled to remote transducers. We calculate the acoustic admittance of circular ducts using a model based on transmission line theory. The admittance is used to calculate the perturbations to the resonance frequencies and half-widths of the modes of spherical and cylindrical acoustic resonators as functions of the duct's radius, length, and the locations of the transducers along the duct's length. To verify the model, we measured the complex acoustic admittances of a series of circular tubes as a function of length between 200 Hz and 10 kHz using a three-port acoustic coupler. The absolute magnitude of the specific acoustic admittance is approximately one. For a 1.4 mm inside-diameter, 1.4 m long tube, the root mean square difference between the measured and modeled specific admittances (both real and imaginary parts) over this frequency range was 0.018. We conclude by presenting design considerations for ducts connected to acoustic thermometers. PMID- 27504228 TI - Uncertainty Calculation for Spectral-Responsivity Measurements. AB - This paper discusses a procedure for measuring the absolute spectral responsivity of optical-fiber power meters and computation of the calibration uncertainty. The procedure reconciles measurement results associated with a monochromator-based measurement system with those obtained with laser sources coupled with optical fiber. Relative expanded uncertainties based on the methods from the Guide to the Expression of Uncertainty in Measurement and from Supplement 1 to the "Guide to the Expression of Uncertainty in Measurement"-Propagation of Distributions using a Monte Carlo Method are derived and compared. An example is used to illustrate the procedures and calculation of uncertainties. PMID- 27504229 TI - Calcium Fluoride Precipitation and Deposition From 12 mmol/L Fluoride Solutions With Different Calcium Addition Rates. AB - The effects of different Ca-addition rates on calcium fluoride (CaF2) precipitation and deposition were investigated in 12 mmol/L sodium fluoride solutions to which 0.1 mol/L calcium chloride solution was continuously added at average rates of (5, 7.5, 10, 12.5, 15 or 20) mmol L(-1) min(-1). The changes in ionic fluoride and calcium concentrations, as well as turbidity, were continuously recorded by F and Ca electrodes, and a fiber optic based spectrophotometer, respectively. The F(-) concentration decreased and turbidity increased with time indicating precipitation of CaF2. For the systems with Ca addition rates of (5, 7.5, 10, 12.5, 15, and 20) mmol L(-1) min(-1), the 1 min CaF2 depositions in the model substrate (cellulose filter paper, pores 0.2 um) expressed as mean +/- SD of deposited F per substrate surface area were (3.78 +/- 0.31, 11.45 +/- 0.89, 9.31 +/- 0.68, 8.20 +/- 0.56, 6.63 +/- 0.43, and 2.09 +/- 0.28) ug/cm(2), respectively (n = 10 for each group). The 1-min F depositions did not show positive correlation to Ca-addition rates. The lowest 1-min F deposition was obtained in the systems with the highest Ca-addition rate of 20 mmol L(-1) min(-1) for which CaF2 precipitation rate reached the maximum value of 0.31 mmol L(-1) s(-1) almost immediately after beginning of reaction (6 s). The largest 1 min F depositions were obtained from the systems with Ca addition rates of (7.5 to 12.5) mmol L(-1) min(-1) in which CaF2 precipitation rates continuously increased reaching the maximum values of (0.13 to 0.20) mmol L(-1) s(-1) after (18 to 29) s, respectively. The 1-min F depositions were greatly enhanced in comparison with the control F solutions that did not have continuous Ca-addition. This indicates that continuous Ca addition that controls the rate of CaF2 formation could be a critical factor for larger F depositions from F solutions. The efficacy of conventional F mouthrinses could be improved with addition of a substance that continuously releases Ca. PMID- 27504230 TI - New Spherical Gamma-Ray and Neutron Emitting Sources for Testing of Radiation Detection Instruments. AB - The National Institute of Standards and Technology (NIST) has developed new gamma ray and neutron emitting sources for testing radiation detection systems. These radioactive sources were developed for testing of detection systems in maritime applications. This required special source characteristics. PMID- 27504231 TI - Comparison of the NIST and PTB Air-Kerma Standards for Low-Energy X-Rays. AB - A comparison has been made of the air-kerma standards for low-energy x rays at the National Institute of Standards and Technology (NIST) and the Physikalisch Technische Bundesanstalt (PTB). The comparison involved a series of measurements at the PTB and the NIST using the air-kerma standards and two NIST reference class transfer ionization chamber standards. Results are presented for the reference radiation beam qualities in the range from 25 kV to 50 kV for low energy x rays, including the techniques used for mammography dose traceability. The tungsten generated reference radiation qualities, between 25 kV and 50 kV used for this comparison, are new to NIST; therefore this comparison will serve as the preliminary comparison for NIST and a verification of the primary standard correction factors. The mammography comparison will repeat two previously unpublished comparisons between PTB and NIST. The results show the standards to be in reasonable agreement within the standard uncertainty of the comparison of about 0.4 %. PMID- 27504232 TI - Elastic-Stiffness Coefficients of Titanium Diboride. AB - Using resonance ultrasound spectroscopy, we measured the monocrystal elastic stiffness coefficients, the Voigt C ij, of TiB2. With hexagonal symmetry, TiB2 exhibits five independent C ij: C 11, C 33, C 44, C 12, C 13. Using Voigt-Reuss Hill averaging, we converted these monocrystal values to quasiisotropic (polycrystal) elastic stiffnesses. Briefly, we comment on effects of voids. From the C ij, we calculated the Debye characteristic temperature, the Gruneisen parameter, and various sound velocities. Our study resolves the enormous differences between two previous reports of TiB2's C ij. PMID- 27504233 TI - DAVE: A Comprehensive Software Suite for the Reduction, Visualization, and Analysis of Low Energy Neutron Spectroscopic Data. AB - National user facilities such as the NIST Center for Neutron Research (NCNR) require a significant base of software to treat the data produced by their specialized measurement instruments. There is no universally accepted and used data treatment package for the reduction, visualization, and analysis of inelastic neutron scattering data. However, we believe that the software development approach adopted at the NCNR has some key characteristics that have resulted in a successful software package called DAVE (the Data Analysis and Visualization Environment). It is developed using a high level scientific programming language, and it has been widely adopted in the United States and abroad. In this paper we describe the development approach, elements of the DAVE software suite, its usage and impact, and future directions and opportunities for development. PMID- 27504236 TI - An iterative expanding and shrinking process for processor allocation in mixed parallel workflow scheduling. AB - Parallel computation has been widely applied in a variety of large-scale scientific and engineering applications. Many studies indicate that exploiting both task and data parallelisms, i.e. mixed-parallel workflows, to solve large computational problems can get better efficacy compared with either pure task parallelism or pure data parallelism. Scheduling traditional workflows of pure task parallelism on parallel systems has long been known to be an NP-complete problem. Mixed-parallel workflow scheduling has to deal with an additional challenging issue of processor allocation. In this paper, we explore the processor allocation issue in scheduling mixed-parallel workflows of moldable tasks, called M-task, and propose an Iterative Allocation Expanding and Shrinking (IAES) approach. Compared to previous approaches, our IAES has two distinguishing features. The first is allocating more processors to the tasks on allocated critical paths for effectively reducing the makespan of workflow execution. The second is allowing the processor allocation of an M-task to shrink during the iterative procedure, resulting in a more flexible and effective process for finding better allocation. The proposed IAES approach has been evaluated with a series of simulation experiments and compared to several well-known previous methods, including CPR, CPA, MCPA, and MCPA2. The experimental results indicate that our IAES approach outperforms those previous methods significantly in most situations, especially when nodes of the same layer in a workflow might have unequal workloads. PMID- 27504235 TI - Health related quality of life for young people receiving dialectical behaviour therapy (DBT): a routine outcome-monitoring pilot. AB - PURPOSE: Adults presenting with borderline personality disorder (BPD) score poorly on measures of health related quality of life (HRQoL). Little is known about HRQoL in adolescents with BPD type presentations and how treatment impacts quality of life. Our primary aim was to use routinely collected quality-of-life outcome measures pre and post-treatment in dialectical behaviour therapy (DBT) for adolescents to address this gap. Secondary aims were to benchmark these data against EuroQol 5 dimensions (EQ-5DTM) outcomes for clients treated in clinical trials and to assess the potential of the EQ-5DTM as a benchmarking tool. METHOD: Four adolescent DBT teams, routinely collecting outcome data using a pseudonymised secure web-based system, supplied data from consecutive discharges. RESULTS: Young people in the DBT programmes (n = 43) had severely impaired HRQoL scores that were lower at programme admission than those reported in published studies using the EQ-5DTM in adults with a BPD diagnosis and in one study of adolescents treated for depression. 40 % of adolescents treated achieved Reliable Clinical Change. HRQoL improved between admission and discharge with a large effect size. These results were not statistically significant when clustering in programme outcomes was accounted for. CONCLUSION: Young people treated in NHS DBT programmes for BPD type presentations had poorer HRQoL than adults with a BPD diagnosis and adolescents with depression treated in published clinical trials. The EQ-5DTM detected reliable change in this group of adolescents. Programme outcome clustering suggests that both the measure and the web-based monitoring system provide a mechanism for benchmarking clinical programmes. PMID- 27504234 TI - Helping patients to reduce tobacco consumption in oncology: a narrative review. AB - The present overview focuses on evidence of smoking cessation approaches in oncology settings with the aim to provide health personnel a critical perspective on how to help their patients. This narrative review is structured in two main sections: the first one describes the psycho-cognitive variables involved in the decision to continue smoking after a cancer diagnosis and during the treatment; the second section relates methods and tools may be recommended, being evidence based, to support smoking cessation in oncology settings. Active smoking increases not only susceptibility to common cancers in the general population, but also increases disease severity and comorbidities in cancer patients. Nowadays, scientific evidence has identified many strategies to give up smoking, but a lack of knowledge exists for treatment of nicotine dependence in the cancer population. Health personnel is often ambiguous when approaching the problem, while their contribution is essential in guiding patients towards healthier choices. We argue that smoking treatments for cancer patients deserve more attention and that clinical features, individual characteristics and needs of the patient should be assessed in order to increase the attempts success rate. Health personnel that daily work and interact with cancer patients and their caregivers have a fundamental role in the promotion of the health changing. For this reason, it is important that they have adequate knowledge and resources in order to support cancer patients to stop tobacco cigarette smoking and promoting and healthier lifestyle. PMID- 27504237 TI - SentiHealth: creating health-related sentiment lexicon using hybrid approach. AB - The exponential increase in the health-related online reviews has played a pivotal role in the development of sentiment analysis systems for extracting and analyzing user-generated health reviews about a drug or medication. The existing general purpose opinion lexicons, such as SentiWordNet has a limited coverage of health-related terms, creating problems for the development of health-based sentiment analysis applications. In this work, we present a hybrid approach to create health-related domain specific lexicon for the efficient classification and scoring of health-related users' sentiments. The proposed approach is based on the bootstrapping modal, a dataset of health reviews, and corpus-based sentiment detection and scoring. In each of the iteration, vocabulary of the lexicon is updated automatically from an initial seed cache, irrelevant words are filtered, words are declared as medical or non-medical entries, and finally sentiment class and score is assigned to each of the word. The results obtained demonstrate the efficacy of the proposed technique. PMID- 27504238 TI - Joint large deviation result for empirical measures of the coloured random geometric graphs. AB - We prove joint large deviation principle for the empirical pair measure and empirical locality measure of the near intermediate coloured random geometric graph models on n points picked uniformly in a d-dimensional torus of a unit circumference. From this result we obtain large deviation principles for the number of edges per vertex, the degree distribution and the proportion of isolated vertices for the near intermediate random geometric graph models. PMID- 27504239 TI - Contextual determinants on the meaning of the N word. AB - Use of the word nigger is very often castigated as slurring the referent, but this ignores the context of use. For many people the word itself is a slur no matter what the context, and such people argue for its eradication from the English language. Eradicationists confuse the form of the word with its frequent use as a slur that discredits, slights, smears, stains, besmirches people of black African descent. In this paper I discuss several occurrences of the N word in Quentin Tarantino's film 'Pulp Fiction'. At least one is a slur. As with many slurs, in-group usage by people who might themselves have been slurred with the term by out-groupers, nigger is used among African Americans to express camaraderie. Three instances of this are examined. Another instance is where black gangster millionaire Marcellus Wallace, after handing white boxer Butch Coolidge money to go down in the fifth round, tells him 'You're my nigger' to which Butch replies 'Certainly appears so'. Lastly I consider the tricky situation where a white uses the term nigger to a black friend, not as a term of address and not as a slur either, I argue. I discuss the composition of context and the semantics and connotations of nigger. I examine the place and function of the uses of nigger within the context of the film, 'Pulp Fiction', to demonstrate that the affective quality of a linguistic expression should never be judged without taking account of its intended perlocutionary effect within the context in which it is uttered. We see that the basic semantic content invariably contributes to the functional (compositional) meaning, but that pragmatic input from connotations is essential in determining the truth value of the utterance in which nigger appears. PMID- 27504240 TI - Improved control configuration of PWM rectifiers based on neuro-fuzzy controller. AB - It is well-known that rectifiers are used widely in many applications required AC/DC transformation. With technological advances, many studies are performed for AC/DC converters and many control methods are proposed in order to improve the performance of these rectifiers in recent years. Pulse width modulation (PWM) based rectifiers are one of the most popular rectifier types. PWM rectifiers have lower input current harmonics and higher power factor compared to classical diode and thyristor rectifiers. In this study, neuro-fuzzy controller (NFC) which has robust, nonlinear structure and do not require the mathematical model of the system to be controlled has been proposed for PWM rectifiers. Three NFCs are used in control scheme of proposed PWM rectifier in order to control the dq-axis currents and DC voltage of PWM rectifier. Moreover, simulation studies are carried out to demonstrate the performance of the proposed control scheme at MATLAB/Simulink environment in terms of rise time, settling time, overshoot, power factor, total harmonic distortion and power quality. PMID- 27504241 TI - A methodology to determine the maximum value of weighted Gini-Simpson index. AB - Weighted Gini-Simpson index is an analytical tool that promises to be widely used concerning biological and economics applications, relative to the assessment of diversity measured by compositional proportions of a system defined with a finite number of elementary states characterized by positive weights. In this paper, a current literature review on the theme is presented and the mathematical properties of the index are outlined, focusing on the location of the maximizer (maximum point) and evaluation of the maximum value, with emphasis in the role of the Lagrange multiplier critical value-closely related with the harmonic mean of the weights-which is shown to be a barrier concerning the feasibility of the solution. Sequential procedures are presented, either backward or forward, which are used to obtain the correct values of the maximum point coordinates, thus allowing for the computation of the right maximum value of the index. Also, new theoretical results are provided, such as the calculus of limits and partial derivatives related to the critical solution, used to assess of the effectiveness of the algorithms herein proposed and discussed. PMID- 27504242 TI - Effects of tongue-hold swallows on suprahyoid muscle activation according to the relative tongue protrusion length: a preliminary study. AB - Tongue-hold swallow (THS) is a therapeutic maneuver used to increase the posterior pharyngeal wall motion during swallowing. This maneuver has also been reported to result in increased activation of the suprahyoid muscles. The hypothesis of this study was that the degree of suprahyoid muscle activation would depend on the tongue protrusion-length. The aim of this study was to investigate the activation levels of the suprahyoid muscles by surface electromyography (sEMG) while performing the THS maneuver at three tongue protrusion lengths. Suprahyoid muscle activity during THSs was recorded in 25 adult volunteers (17 women and 8 men; age range 20-38 years). To record the activity of the suprahyoid muscles while the participants performed the maneuver, surface wireless EMG electrodes separated by a distance of 1 cm were placed on the skin on both sides of the midline under the chin. Each activity was recorded three times. Data analysis was performed by repeated-measures analysis of variance. Our results revealed that participants exhibited greater electrical activity during THS with 2/3rd or maximal tongue protrusion as compared to THS with 1/3rd tongue protrusion (p <= 0.001). To maximize the therapeutic effect of the THS maneuver, it is advised to protrude the tongue maximally as long as swallowing is possible. PMID- 27504243 TI - The valuation of currency options by fractional Brownian motion. AB - This research aims to investigate a model for pricing of currency options in which value governed by the fractional Brownian motion model (FBM). The fractional partial differential equation and some Greeks are also obtained. In addition, some properties of our pricing formula and simulation studies are presented, which demonstrate that the FBM model is easy to use. PMID- 27504244 TI - Low neutrophil alkaline phosphatase score is a new aspect of calreticulin-mutated myeloproliferative neoplasms. AB - Calreticulin (CALR) and JAK2-V617F gene mutations, which are major genetic mutations in patients with primary myelofibrosis (PMF) and essential thrombocythemia (ET), exert different effects on the clinical features and outcomes of these diseases. We analyzed 88 and 9 patients with ET and PMF, respectively, and determined the differences in the clinical characteristics of ET patients with JAK2-V617F compared with CALR mutations. The frequency of the JAK2-V617F and CALR mutations were 64 and 22 %, respectively. Patients with CALR mutations were younger, had a lower white blood cell count, and had a lower rate of thrombotic events than patients with the JAK2 mutation. The neutrophil alkaline phosphatase (NAP) score of 16 patients with CALR mutations was significantly lower than the normal controls, which was mainly due to the high proportion of NAP-negative neutrophils. This is the first report to show an association between CALR mutations in patients with myeloproliferative neoplasms (MPN) and the NAP score. Although the mechanism is unclear, the NAP score could be a useful and reliable biochemical marker to discriminate the mutational status of MPN patients. Further investigation is warranted to determine whether these characteristics contribute to the pathogenesis of MPN and the NAP score. PMID- 27504245 TI - Fabrication and vibration characterization of curcumin extracted from turmeric (Curcuma longa) rhizomes of the northern Vietnam. AB - In this report, we present the research results on using the conventional method and microwave technology to extract curcuminoid from turmeric roots originated in different regions of Northern Vietnam. This method is simple, yet economical, non toxic and still able to achieve high extraction performance to get curcuminoid from turmeric roots. The detailed results on the Raman vibration spectra combined with X-ray powder diffraction and high-performance liquid chromatography/mass spectrometry allowed the evaluation of each batch of curcumin crystalline powder sample received, under the conditions of applied fabrication technology. Also, the absorption and fluorescence spectroscopies of the samples are presented in the paper. The information to be presented in this paper: absorption and fluorescence spectroscopies of the samples; new experimental study results on applied technology to mass-produce curcumin from turmeric rhizomes; comparative study results between fabricated samples and marketing curcumin products-to state the complexity of co-existing crystalline phase in curcumin powder samples. We noticed that, it is possible to use the vibration line at ~959 cm(-1) characteristic of the nu C=O vibration, and the ~1625 cm(-1) line-characteristic of the nu C=O and nu C=C vibration in curcumin molecules, for preliminary quality assessment of naturally originated curcumin crystalline powder samples. Data on these new optical spectra will contribute to the bringing of detailed information on natural curcumin in Vietnam, serving research purposes and applications of natural curcumin powder and nanocurcumin in Vietnam, as well as being initial materials for the pharmaceutical, cosmetics or functional food industries. PMID- 27504246 TI - Efficacy and safety of mini percutaneous nephrolithotomy in obese patients. AB - PURPOSE: We aimed to evaluate the effect of obesity on surgical outcomes of mini percutaneous nephrolithotomy (Mini-PNL). METHODS: Hundred and eighty two Mini-PNL procedures were performed between May 2013 and January 2015 and their results were evaluated retrospectively. Patients were classified as non-obese (BMI, 18.5 30 kg/m(2)) and obese (>=30 kg/m(2)) groups. Obese and non-obese patients were compared according to pre-operative demographic values, intra-operative surgery techniques and post-operative results. RESULTS: BMI values of 133 patients were lower than 30 kg/m(2) while 49 patient's BMI values were higher than 30 kg/m(2). There were no significant difference between operation time, fluoroscopy time, number of access and access sites when two groups were compared. No significant difference was found in total length of hospital stay, hemoglobin drop, and complication rates. Stone-free rates were 70.7 % in the non-obese and 71.4 % in the obese group (p = 0.9). CONCLUSIONS: Mini-PNL procedure is a safe and effective treatment modality, which should be strongly considered for obese patients with appropriate sized stones. PMID- 27504247 TI - Numerical solution of the one-dimensional fractional convection diffusion equations based on Chebyshev operational matrix. AB - In this paper, we are concerned with nonlinear one-dimensional fractional convection diffusion equations. An effective approach based on Chebyshev operational matrix is constructed to obtain the numerical solution of fractional convection diffusion equations with variable coefficients. The principal characteristic of the approach is the new orthogonal functions based on Chebyshev polynomials to the fractional calculus. The corresponding fractional differential operational matrix is derived. Then the matrix with the Tau method is utilized to transform the solution of this problem into the solution of a system of linear algebraic equations. By solving the linear algebraic equations, the numerical solution is obtained. The approach is tested via examples. It is shown that the proposed algorithm yields better results. Finally, error analysis shows that the algorithm is convergent. PMID- 27504248 TI - Lane changing trajectory planning and tracking control for intelligent vehicle on curved road. AB - This paper explores lane changing trajectory planning and tracking control for intelligent vehicle on curved road. A novel arcs trajectory is planned for the desired lane changing trajectory. A kinematic controller and a dynamics controller are designed to implement the trajectory tracking control. Firstly, the kinematic model and dynamics model of intelligent vehicle with non-holonomic constraint are established. Secondly, two constraints of lane changing on curved road in practice (LCCP) are proposed. Thirdly, two arcs with same curvature are constructed for the desired lane changing trajectory. According to the geometrical characteristics of arcs trajectory, equations of desired state can be calculated. Finally, the backstepping method is employed to design a kinematic trajectory tracking controller. Then the sliding-mode dynamics controller is designed to ensure that the motion of the intelligent vehicle can follow the desired velocity generated by kinematic controller. The stability of control system is proved by Lyapunov theory. Computer simulation demonstrates that the desired arcs trajectory and state curves with B-spline optimization can meet the requirements of LCCP constraints and the proposed control schemes can make tracking errors to converge uniformly. PMID- 27504249 TI - The efficacy, safety, and tolerability of ivermectin compared with current topical treatments for the inflammatory lesions of rosacea: a network meta analysis. AB - BACKGROUND: Rosacea is a common chronic skin condition that manifests as recurrent inflammatory lesions. Long-term treatment is required to control symptoms and disease progression, with topical treatments being the first-line choice. Ivermectin 1 % cream is a new once-daily (QD) topical treatment for the inflammatory lesions of rosacea, and it is important to compare the efficacy, safety, and tolerability of ivermectin with other currently available topical treatments. METHODS: A systematic literature review was performed from January 2011 to June 2015, with articles published prior to 2011 retrieved from a Cochrane review on rosacea. Randomized controlled trials of the topical treatment of adult patients with moderate-to-severe papulopustular rosacea were identified from electronic databases and trial registers, and supplemented with data from clinical study reports. Mixed treatment comparisons (MTCs) were conducted to compare different treatments according to Bayesian methodology. RESULTS: 57 studies were identified, with 19 providing data suitable for MTC. Ivermectin 1 % cream QD led to a significantly greater likelihood of success compared with azelaic acid 15 % gel twice-daily (BID) [relative risk (95 % credible interval): 1.25 (1.14-1.37)], and metronidazole 0.75 % cream BID [1.17 (1.08-1.29)] at 12 weeks. Ivermectin 1 % cream QD also demonstrated a significant reduction in inflammatory lesion count compared with azelaic acid 15 % gel BID [-8.04 (-12.69 to -3.43)] and metronidazole 0.75 % cream BID [-9.92 (-13.58 to -6.35)] at 12 weeks. Ivermectin 1 % cream QD led to a significantly lower risk of developing any AE or TRAE compared with azelaic acid 15 % gel BID [0.83 (0.71-0.97) and 0.47 (0.32-0.67), respectively]. CONCLUSIONS: Ivermectin 1 % cream QD appears to be a more effective topical treatment than other current options for the inflammatory lesions of rosacea, with at least an equivalent safety and tolerability profile, and could provide physicians and dermatologists with an alternative first-line treatment option. PMID- 27504250 TI - An efficient identification strategy of clonal tea cultivars using long-core motif SSR markers. AB - Microsatellites, or simple sequence repeats (SSRs), especially those with long core motifs (tri-, tetra-, penta-, and hexa-nucleotide) represent an excellent tool for DNA fingerprinting. SSRs with long-core motifs are preferred since neighbor alleles are more easily separated and identified from each other, which render the interpretation of electropherograms and the true alleles more reliable. In the present work, with the purpose of characterizing a set of core SSR markers with long-core motifs for well fingerprinting clonal cultivars of tea (Camellia sinensis), we analyzed 66 elite clonal tea cultivars in China with 33 initially-chosen long-core motif SSR markers covering all the 15 linkage groups of tea plant genome. A set of 6 SSR markers were conclusively selected as core SSR markers after further selection. The polymorphic information content (PIC) of the core SSR markers was >0.5, with <=5 alleles in each marker containing 10 or fewer genotypes. Phylogenetic analysis revealed that the core SSR markers were not strongly correlated with the trait 'cultivar processing-property'. The combined probability of identity (PID) between two random cultivars for the whole set of 6 SSR markers was estimated to be 2.22 * 10(-5), which was quite low, confirmed the usefulness of the proposed SSR markers for fingerprinting analyses in Camellia sinensis. Moreover, for the sake of quickly discriminating the clonal tea cultivars, a cultivar identification diagram (CID) was subsequently established using these core markers, which fully reflected the identification process and provided the immediate information about which SSR markers were needed to identify a cultivar chosen among the tested ones. The results suggested that long-core motif SSR markers used in the investigation contributed to the accurate and efficient identification of the clonal tea cultivars and enabled the protection of intellectual property. PMID- 27504251 TI - Measuring serum matrix metalloproteinase-9 levels in peripheral blood after subarachnoid hemorrhage to predict cerebral vasospasm. AB - PURPOSE: We aimed to investigate serum levels of matrix metalloproteinase-9 in both subarachnoid hemorrhage and control groups for prediction of cerebral vasospasm in this study. METHODS: Venous serum matrix metalloproteinase-9 levels were prospectively measured four times (days 1, 3, 7, and 14) for 34 consecutive patients with subarachnoidal hemorrhage (n = 27) and for elective aneurysm clipping (control, n = 7). RESULTS: Vasospasm developed in 11/34 (32.4 %) patients between 3 and 10 days after subarachnoid hemorrhage (median 5.58 days), mean peak serum matrix metalloproteinase-9 compared with the non-vasospasm cohort. Matrix metalloproteinase-9 levels were higher in subarachnoid hemorrhage patients than in the controls. CONCLUSION: Increased serum matrix metalloproteinase-9 could be an accurate biomarker to predict the onset of cerebral vasospasm after subarachnoid hemorrhage. PMID- 27504252 TI - Disruptive behavior among elementary students in physical education. AB - The aim of this study was to determine which disruptive behaviors occur most often in physical education (PE) classes, and to identify the existence of a pattern of behavior that leads to this disruptive behavior. With this in mind, we analyzed five PE sessions taken by pupils at different elementary school in the region of Murcia. The total sample size was 96 students aged between 10 and 13. Data was recorded using an observation instrument (a combination of a field format and a categorical system) and was then analyzed using the "HOISAN" software tool, with a sequential analysis and polar coordinates being conducted. The results of the study revealed that disruptive behaviors (52 %) occur more frequently than non-relevant behaviors (48 %), the most common of them being disinterested behavior (29 %), followed by indiscipline (15 %), with no statistically significant differences being detected in violent behavior. As regards patterns of behavior, disinterested behavior is stimulated by "no eye contact", "middle distance", "inside the task", "no use of material", "giving orders" and "registering of activities", while indiscipline is stimulated by "no eye contact", "far distance", "outside the task", "use of material", "grouping in pairs" and "preparation of material". In conclusion, it can be stated that disruptiveness is far more common in physical education sessions, affects the development of sessions and has a negative impact on student learning. A solution to this problem should therefore be sought immediately in order to ensure quality education. PMID- 27504253 TI - Development of a new testing equipment that combines the working principles of both the split Hopkinson bar and the drop weight testers. AB - In the current work, a new high strain rate tensile testing equipment is proposed. The equipment uses a pendulum device to generate an impact load and a three-bar mechanism to bring that load to act upon a specially designed specimen. As the standard impact testing apparatus uses pendulum device and the well-known SHB high strain rate tester adopts the above-mentioned mechanism, the introduced equipment can be dealt with as an impact apparatus in which the base that supports the V-shape specimen is replaced with the three-bar configuration that the traditional SHB uses. In order to demonstrate the applicability of the new tester, virtual design tools were used to determine the most appropriate configuration for it. Then, a detailed design was created, and a full-scale prototype was produced, calibrated, instrumented and tested. The obtained results demonstrate that the new tester is capable of axially straining steel specimens up to failure at a maximum rate of about 250 s(-1), which is reasonable when compared with a more established high strain rate testers. PMID- 27504254 TI - Impact of pipelines on land use in rural areas in Turkey. AB - This paper examines whether the parcelization of land through easement as a result of the construction of pipelines in rural areas in Turkey has any negative effects on productive land use. The current legislation in Turkey does not allow the division of land in most rural areas into parcels smaller than 5000 m(2). Therefore, the smallest parcel that can be productively used was considered as 5000 m(2). On the basis of the analysis of the data pertaining to the easement rights having two different widths and collected from three different regions having different parcel sizes, the research aims to find out the number of parcels with an area less than 5000 m(2) (excluding the easement) that were created by the construction of pipelines and to investigate whether a significant number of areas less than 5000 m(2) remain. This study also demonstrates a method that can be used in studies on this subject according to the various parcel sizes that were created by the allotment of parcels due to the easement of the construction of pipelines. PMID- 27504255 TI - The qualitative and quantitative analysis of the coupled C, N, P and Si retention in complex of water reservoirs. AB - The Solina-Myczkowce complex of reservoirs (SMCR) accounts about 15 % of the water storage in Poland. On the base of historical (2004-2006 years) data, the mass balance of nitrogen, phosphorus, total organic carbon and dissolved silicon were calculated. Large, natural affluents were the main source of the biogenic compounds in the studied ecosystem, delivering 90 % of TOC, 87 % of TN and 81 % of TP and DSi load. Moreover, results show that SMCR is an important sink for all the analysed biogenic elements. About 15-30 % of external loads were retained in the reservoir mainly in upper Solina. Due to the intensive processes of primary production, inorganic forms of nitrogen and phosphorus were mainly retained. Internal production of organic matter lead to an amount of the organic matter deposited in the sediments greater than was anticipated on the basis of the mass balance calculations. A constant load of dissolved silicon originating only from natural sources did not contribute to supplement deficits of Si present in the body of water in the reservoirs, promoting disturbances in N:C:P:Si ratios and another growth condition for other types of algae. PMID- 27504256 TI - Effect of vertically aligned carbon nanotube density on the water flux and salt rejection in desalination membranes. AB - In this paper, vertically aligned carbon nanotube (VACNT) membranes of different densities are developed and their performances are investigated. VACNT arrays of densities 5 * 10(9), 10(10), 5 * 10(10) and 10(11) tubes cm(-2), are initially grown on 1 cm * 1 cm silicon substrates using chemical vapour deposition. A VACNT membrane is realised by attaching a 300 MUm-thick 1 cm * 1 cm VACNT array on silicon to a 4" glass substrate, applying polydimethylsiloxane (PDMS) through spin coating to fill the gaps between the VACNTs, and using a microtome to slice the VACNT-PDMS composite into 25-MUm-thick membranes. Experimental results show that the permeability of the developed VACNT membranes increases with the density of the VACNTs, while the salt rejection is almost independent of the VACNT density. The best measured permeance is attained with a VACNT membrane having a CNT density of 10(11) tubes cm(-2) is 1203 LMH at 1 bar. PMID- 27504257 TI - Exploring the nature of science through courage and purpose: a case study of Nikolai Vavilov and plant biodiversity. AB - INTRODUCTION: Historical biographies facilitate teaching the 'nature of science'. This case study focuses on how Nikolai Vavilov's unrelenting sense of purpose, courage, and charismatic personality was maintained during violent revolutionary change in Russia. CASE DESCRIPTION: The rediscovery of Gregor Mendel's laws of inheritance provided Vavilov with a scientific foundation for crop improvement, this foundation was later bolstered by Vavilov's personal drive to conserve plant biodiversity. As he advanced theories and pragmatic approaches for genetic improvement and conservation of plants, political leaders in Russian came to reject Mendel's principles and eventually Vavilov's work. DISCUSSION AND EVALUATION: This rejection occurred because Joseph Stalin was desperate for a quick remedy to the famine and suffering from forced collective agriculture. Vavilov's work continued, modernizing Russian crop research while inspiring other scientists to save seeds stored in the world's first gene bank. Three themes illustrating the nature of science help examine Vavilov's life: explaining natural phenomena, uncompromising human endeavor, and revising scientific knowledge. CONCLUSIONS: The case study concludes with four questions to stimulate student inquiry and self-guided research. They also deepen student understanding of Vavilov's personal sacrifices to ensure use and conservation of plant biodiversity. PMID- 27504258 TI - Kinetics, equilibrium, and thermodynamics investigation on the adsorption of lead(II) by coal-based activated carbon. AB - The goal of this research is to investigate the feasibility of using activated coal-based activated carbon (CBAC) to adsorb Pb(II) from aqueous solutions through batch tests. Effects of contact time, pH, temperature and initial Pb(II) concentration on the Pb(II) adsorption were examined. The Pb(II) adsorption is strongly dependent on pH, but insensitive to temperature. The best pH for Pb(II) removal is in the range of 5.0-5.5 with more than 90 % of Pb(II) removed. The equilibrium time was found to be 60 min and the adsorption data followed the pseudo-second-order kinetics. Isotherm data followed Langmuir isotherm model with a maximum adsorption capacity of 162.33 mg/g. The adsorption was exothermic and spontaneous in nature. The Fourier transform infrared spectroscopy and scanning electron microscopy analysis suggested that CBAC possessed a porous structure and was rich in carboxyl and hydroxyl groups on its surface, which might play a major role in Pb(II) adsorption. These findings indicated that CBAC has great potential as an alternative adsorbent for Pb(II) removal. PMID- 27504259 TI - Constitutive expression of genes encoding notch receptors and ligands in developing lymphocytes, nTreg cells and dendritic cells in the human thymus. AB - The thymus is the site of T cell maturation. Notch receptors (Notch1-4) and ligands (DLL1-3 and Jagged1-2) constitute one of several pathways involved in this process. Our data revealed differential constitutive expression of Notch genes and ligands in T lymphocytes and thymic dendritic cells (tDCs), suggesting their participation in human thymocyte maturation. nTreg analyses indicated that the Notch components function in parallel to promote maturation in the thymus. PMID- 27504260 TI - De novo assembly of the blunt snout bream (Megalobrama amblycephala) gill transcriptome to identify ammonia exposure associated microRNAs and their targets. AB - De novo transcriptome sequencing is a robust method for microRNA (miRNA) target gene prediction, especially for organisms without reference genomes. Following exposure of Megalobrama amblycephala to ammonia (0.1 or 20 mg L(-1) ), two cDNA libraries were constructed from the fish gills and sequenced using Illumina HiSeq 2000. Over 90 million reads were generated and de novo assembled into 46, 615 unigenes, which were then extensively annotated by comparing to different protein databases, followed by biochemical pathway prediction. The expression of 2666 unigenes significantly differed; 1961 were up-regulated, while 975 were down regulated. Among these, 250 unigenes were identified as the targets for 10 conserved and 4 putative novel miRNA families by miRNA target computational prediction. We examined expression of ssa-miRNA-21 and its target genes by real time quantitative PCR and found agreement with the sequencing data. This study demonstrates the feasibility of identifying miRNA targets by transcriptome analysis. The transcriptome assembly data represent a substantial increase in the genomic resources available for Megalobrama amblycephala and will be useful for gene expression profile analysis and miRNA functional annotation. PMID- 27504261 TI - Disrupted functional connectivity in adolescent obesity. AB - BACKGROUND/OBJECTIVE: Obesity has been associated with brain alterations characterised by poorer interaction between a hypersensitive reward system and a comparatively weaker prefrontal-cognitive control system. These alterations may occur as early as in adolescence, but this notion remains unclear, as no studies so far have examined global functional connectivity in adolescents with excess weight. SUBJECTS/METHODS: We investigated functional connectivity in a sample of 60 adolescents with excess weight and 55 normal weight controls. We first identified parts of the brain displaying between-group global connectivity differences and then characterised the extent of the differences in functional network integrity and their association with reward sensitivity. RESULTS: Adolescent obesity was linked to neuroadaptations in functional connectivity within brain hubs linked to interoception (insula), emotional memory (middle temporal gyrus) and cognitive control (dorsolateral prefrontal cortex) (pFWE < 0.05). The connectivity between the insula and the anterior cingulate cortex was reduced in comparison to controls, as was the connectivity between the middle temporal gyrus and the posterior cingulate cortex and cuneus/precuneus (pFWE < 0.05). Conversely, the middle temporal gyrus displayed increased connectivity with the orbitofrontal cortex (pFWE < 0.05). Critically, these networks were correlated with sensitivity to reward (p < 0.05). CONCLUSIONS: These findings suggest that adolescent obesity is linked to disrupted functional connectivity in brain networks relevant to maintaining balance between reward, emotional memories and cognitive control. Our findings may contribute to reconceptualization of obesity as a multi-layered brain disorder leading to compromised motivation and control, and provide a biological account to target prevention strategies for adolescent obesity. PMID- 27504263 TI - Wolf-Hirschhorn (4p-) syndrome with West syndrome. AB - Wolf-Hirschhorn syndrome (WHS) is a chromosome disorder (4p-syndrome) which is characterized by craniofacial features and epileptic seizures. Here, we report a case of WHS with West syndrome, in whom the seizures were refractory to several antiepileptic drugs but were responsive to the addition of lamotrigine. The patient had epileptic spasms at age seven months. The interictal electroencephalogram was hypsarrhythmic. After adding lamotrigine, seizures decreased remarkably, and spasms disappeared. We have identified and described the very rare case of a girl with WHS who also developed West syndrome. In this case, adding lamotrigine to her medications effectively treated the spasms. PMID- 27504262 TI - Associations of limbic-affective brain activity and severity of ongoing chronic arthritis pain are explained by trait anxiety. AB - Functional magnetic resonance imaging studies (fMRI) have transformed our understanding of central processing of evoked pain but the typically used block and event-related designs are not best suited to the study of ongoing pain. Here we used arterial spin labelling (ASL) for cerebral blood flow mapping to characterise the neural correlates of perceived intensity of osteoarthritis (OA) pain and its interrelation with negative affect. Twenty-six patients with painful knee OA and twenty-seven healthy controls underwent pain phenotyping and ASL MRI at 3T. Intensity of OA pain correlated positively with blood flow in the anterior mid-cingulate cortex (aMCC), subgenual cingulate cortex (sgACC), bilateral hippocampi, bilateral amygdala, left central operculum, mid-insula, putamen and the brainstem. Additional control for trait anxiety scores reduced the pain-CBF association to the aMCC, whilst pain catastrophizing scores only explained some of the limbic correlations. In conclusion, we found that neural correlates of reported intensity of ongoing chronic pain intensity mapped to limbic-affective circuits, and that the association pattern apart from aMCC was explained by trait anxiety thus highlighting the importance of aversiveness in the experience of clinical pain. PMID- 27504264 TI - Atypical benign partial epilepsy of childhood with acquired neurocognitive, lexical semantic, and autistic spectrum disorder. AB - Atypical benign partial epilepsy (ABPE) of childhood or pseudo-Lennox syndrome is a form of idiopathic focal epilepsy characterized by multiple seizure types, focal and/or generalized epileptiform discharges, continuous spike-wave during sleep (CSWS), and sometimes reversible neurocognitive deficits. There are few reported cases of ABPE describing detailed correlative longitudinal follow-up of the various associated neurocognitive, language, social communicative, or motor deficits, in parallel with the epilepsy. Furthermore, the molecular inheritance pattern for ABPE and the wider spectrum of epilepsy aphasia disorders have yet to be fully elucidated. We describe the phenotype-genotype study of a boy with ABPE with follow-up from ages 5 to 13 years showing acquired oromotor and, later, a specific lexical semantic and pervasive developmental disorder. Exome sequencing identified variants in SCN9A, CPA6, and SCNM1. A direct role of the epilepsy in the pathogenesis of the oromotor and neurocognitive deficits is apparent. PMID- 27504265 TI - Towards the development of an enzyme replacement therapy for the metabolic disorder propionic acidemia. AB - Propionic acidemia (PA) is a life-threatening disease caused by the deficiency of a mitochondrial biotin-dependent enzyme known as propionyl coenzyme-A carboxylase (PCC). This enzyme is responsible for degrading the metabolic intermediate, propionyl coenzyme-A (PP-CoA), derived from multiple metabolic pathways. Currently, except for drastic surgical and dietary intervention that can only provide partial symptomatic relief, no other form of therapeutic option is available for this genetic disorder. Here, we examine a novel approach in protein delivery by specifically targeting and localizing our protein candidate of interest into the mitochondrial matrix of the cells. In order to test this concept of delivery, we have utilized cell penetrating peptides (CPPs) and mitochondria targeting sequences (MTS) to form specific fusion PCC protein, capable of translocating and localizing across cell membranes. In vitro delivery of our candidate fusion proteins, evaluated by confocal images and enzymatic activity assay, indicated effectiveness of this strategy. Therefore, it holds immense potential in creating a new paradigm in site-specific protein delivery and enzyme replacement therapeutic for PA. PMID- 27504266 TI - Diagnosis of adenylosuccinate lyase deficiency by metabolomic profiling in plasma reveals a phenotypic spectrum. AB - Adenylosuccinate lyase (ADSL) deficiency is a rare autosomal recessive neurometabolic disorder that presents with a broad-spectrum of neurological and physiological symptoms. The ADSL gene produces an enzyme with binary molecular roles in de novo purine synthesis and purine nucleotide recycling. The biochemical phenotype of ADSL deficiency, accumulation of SAICAr and succinyladenosine (S-Ado) in biofluids of affected individuals, serves as the traditional target for diagnosis with targeted quantitative urine purine analysis employed as the predominate method of detection. In this study, we report the diagnosis of ADSL deficiency using an alternative method, untargeted metabolomic profiling, an analytical scheme capable of generating semi-quantitative z-score values for over 1000 unique compounds in a single analysis of a specimen. Using this method to analyze plasma, we diagnosed ADSL deficiency in four patients and confirmed these findings with targeted quantitative biochemical analysis and molecular genetic testing. ADSL deficiency is part of a large a group of neurometabolic disorders, with a wide range of severity and sharing a broad differential diagnosis. This phenotypic similarity among these many inborn errors of metabolism (IEMs) has classically stood as a hurdle in their initial diagnosis and subsequent treatment. The findings presented here demonstrate the clinical utility of metabolomic profiling in the diagnosis of ADSL deficiency and highlights the potential of this technology in the diagnostic evaluation of individuals with neurologic phenotypes. PMID- 27504267 TI - A simple, low cost GC/MS method for the sub-nanogram per litre measurement of organotins in coastal water. AB - Tributyltin (TBT) is a legacy pollutant in the aquatic environment, predominantly from its use in anti-foulant paints and is listed as a priority hazardous substance in the European Union's Water Framework Directive (WFD). Measuring low concentrations of TBT and other organotins (e.g. monobutyltin (MBT), dibutyltin (DBT), diphenyltin (DPhT) and triphenyltin (TPhT)) at sub ng/L concentrations in coastal waters using standard laboratory instrumentation is very challenging. Conventional, low injection volume gas chromatography/mass spectrometry (GC/MS) combined with liquid-liquid extraction typically achieves limits of detection for TBT ~10 ng L(-1). We describe a simple, programmed temperature vaporisation-large injection volume (50 MUL), GC/MS selected ion monitoring method for measuring DBT, TBT, DPhT and TPhT in coastal waters at lower concentrations. Quantification of MBT was not possible using these injection volumes but was achieved using a 10 MUL injection volume together with a reduced injection speed. This new approach offers: *When using a 50 MUL injection, limits of detection = 0.70 ng L(-1) and limits of quantification = 2.1 ng L(-1) for TBT were achieved in derivatised standards.*Recoveries of TBT and TPhT from coastal water >97%.*Time consuming, off-line sample pre-concentration methods are unnecessary. PMID- 27504268 TI - Hedgehog Signalling in the Embryonic Mouse Thymus. AB - T cells develop in the thymus, which provides an essential environment for T cell fate specification, and for the differentiation of multipotent progenitor cells into major histocompatibility complex (MHC)-restricted, non-autoreactive T cells. Here we review the role of the Hedgehog signalling pathway in T cell development, thymic epithelial cell (TEC) development, and thymocyte-TEC cross-talk in the embryonic mouse thymus during the last week of gestation. PMID- 27504269 TI - Incidence of Foramen of Huschke in South Andhra Population of India. AB - INTRODUCTION: Foramen of Huschke (FH) is an opening present in anteroinferior wall of External Acoustic Meatus (EAM) on the tympanic plate of temporal bone. The developing tympanic ring normally gets closed by the age of 5 years, if not, leads to the persistence of FH, shows a communication between the EAM and mandibular fossa of temporal bone. AIM: The aim of the present study was to report on the incidence of FH in adult skulls and individual temporal bones, belonging to South Coastal Andhra population. MATERIALS AND METHODS: Ninety three skulls and 34 temporal bones (18 right and 16 left) obtained from the Department of Anatomy and ENT respectively, irrespective of their sex were utilized. This Tympanic Plates (TP) was observed for the occurrence of FH. RESULTS: Incidence of FH was found in 18 (16.22%) on right and 24 (22.02%) on left side. Bilateral FH was seen in 13 (13.98%) and multiple FH was 13 (5.91%). Mostly it was situated on left than the right side. CONCLUSION: This study revealed that about 38% of South Coastal Andhra crania have FH. The presence of FH may render external and middle ear structures vulnerable to injury during arthroscopy of the Temporomandibular Joint (TMJ). Since FH can result in TMJ herniation and salivary gland fistulisation through the anterior wall of the bony EAM, surgeons working in this area must be cautious during surgical procedures. Also, data obtained from different populations, as observed from our study can be useful in racial and anthropological studies. PMID- 27504270 TI - Cadaveric Study on Morphology of Dorsal Interossei of Hand and its Anatomical Variation. AB - INTRODUCTION: The dorsal interossei are the abductors of the fingers and the knowledge of its variation help the surgeon in treatment of fractures, claw hand and compartment syndromes. AIM: To note the origin, insertion, pattern of muscle fibres and tendon length of all the dorsal interossei of hand. MATERIALS AND METHODS: Routinely dissected 30 formalin fixed hand in the Department of Anatomy, KMC, Manipal, were observed for origin, insertion and tendon length and muscle pattern of dorsal interossei. RESULTS: Out of 30 hands, presence of supernumerary muscle was observed in three hands. Presence of three heads of dorsal interossei was noted in one hand. CONCLUSION: The finding of present study is of importance to surgeons and orthopaedicians during conservative and surgical management of hand deformity. Adequate knowledge of these muscular variations is also important in treatment of fractures, stiff hand, claw hand or tendon transfer. PMID- 27504271 TI - Cadaveric Study of Berretini Communications in North Indian Population. AB - INTRODUCTION: Intercommunication between peripheral nerves deserves special attention in view of their clinical significance. Superficial palmar communication between the median nerve and ulnar nerve is referred to as Berrettini Anastomosis. The presence or absence of this communicating branch varies between individuals. Earlier, incidence of Berretini communication reported varied significantly (4-94%). AIM: The aim of this study was to find out the frequency with which Berretini communication is found in North Indians. MATERIALS AND METHODS: The present study was conducted on 60 upper limbs of 30 cadavers at the Government Medical College, Amritsar. The whole course of the median nerve and the ulnar nerve was exposed. Communicating rami in the hand were identified, cleaned and photographed. RESULTS: In all the six (10%) variant limbs, the communicating branch originated from lateral common palmar digital branch of ulnar nerve and joined medial common palmar digital branch of median nerve. Single communication with oblique course was seen in all the variants. Further, its ontogeny and clinical implications have been discussed in detail. CONCLUSION: The Berretini anastomosis was seen in 10% upper limbs of the present study. Damage to the communicating branch or the severing of the branch might result in sensory loss which may be difficult to diagnose owing to the large number of variations in the origin of the communicating branch. The patterns of sensory impairment may vary depending upon the branch of median and ulnar nerve it is seen connecting. PMID- 27504272 TI - Unusual Origin of a Double Upper Subscapular Nerve from the Suprascapular Nerve and the Posterior Division of the Upper Trunk of the Brachial Plexus: A Case Report. AB - A double upper subscapular nerve on the right side was detected in a male cadaver, with the proximal one arising from the suprascapular nerve and the distal one from the posterior division of the upper trunk of the brachial plexus. Both of them penetrated and supplied the uppermost portion of the right subscapularis muscle. That anatomic variation was associated with a median nerve formed by two lateral roots. The origin and pattern of the upper subscapular nerve displays high variability, however the presented combination of the variable origin of a double upper subscapular nerve has rarely been described in the literature. The knowledge of such an anatomic variation is essential for the surgeon operating in the region especially in instances of brachial plexus' repair after any traumatic injury. Moreover, the awareness of the precise origin and topography of these nerves is important for the physician attempting to block these nerves or utilizing these nerves as grafts for neurotization of adjacent damaged nerves of the brachial plexus. PMID- 27504273 TI - Looped and Tortuous Ulnar Artery - An Erratic Unilateral Vascular Presentation in the Proximal Forearm. AB - Precise and detailed knowledge of possible anatomical variations of the arterial pattern in the upper extremity is vital during reparative surgery in this region. Scientific literatures witnessed several reports on variant origin and branching pattern of ulnar artery. But report on looped and tortuous ulnar artery is lacking in the literature. We report here a unique case of ulnar artery having double loop at its commencement giving it an appearance of sigmoid shape and its undue tortuous course in the forearm. Such an unusual and unpredictable variation of ulnar artery is vulnerable for life threatening hemorrhage during clinical approaches. It could also lead to misinterpretation of CT scans as presence of tumours. Awareness on such exceptional anatomical discrepancy of ulnar artery is important to clinicians, neuroradiologists and radiologists in general. PMID- 27504274 TI - Unusual Variation in the Branching Pattern of the Celiac Trunk and Its Embryological and Clinical Perspective. AB - Knowledge of variations in the branching pattern of Celiac Trunk (CT) is important for surgeries of stomach, duodenum, pancreas and hepatobiliary region, for abdominal aortic aneurysm, for liver transplant and chaemoembolization of hepatic tumours. An unusual variation in the branching pattern of CT was observed in 50-year-old male cadaver of Indian origin. CT divided into six branches out of which right & left inferior phrenic arteries originated as first two branches and left gastric artery as the third branch. CT ended into three terminal branches as common hepatic artery, splenic artery & dorsal pancreatic artery. Right gastric artery originated from left hepatic artery instead of common hepatic artery. A variant hepatic artery to the left lobe of liver was also observed which originated from right gastric artery. Anatomical variations in the branching pattern of CT are due to developmental changes in ventral splanchnic artery. PMID- 27504275 TI - Comparison of Oxidative Stress Markers and Serum Cortisol between Normal Labor and Selective Cesarean Section Born Neonates. AB - INTRODUCTION: An imbalance between antioxidant and oxidant-generating systems in newborns can cause oxidative damage. The effect of modes of delivery on oxidative stress in neonates is not fully investigated. AIM: This study was aimed to examine the effects of modes of delivery on oxidative stress markers and cortisol in newborns. MATERIALS AND METHODS: In this study 60 term neonates {30 born via Normal Delivery (ND) and 30 born via elective Caesarean Delivery (CS)} at birth were enrolled. Glutathione Peroxidase (GPx), Catalase (CAT) and Superoxide Dismutase (SOD) activities were determined in umbilical cord blood in all neonates. Moreover serum cortisol, uric acid and Total Antioxidant Capacity (TAC) were measured. RESULTS: GPx and SOD activities in cesarean born neonates were significantly higher than those of control subjects (p<0.05). TAC and CAT were not significantly different between the two groups. Serum cortisol was lower in caesarean born subjects as compared to normal born neonates. On the other hand uric acid concentration was higher in caesarean born neonates. CONCLUSION: The obtained data indicated that babies born via caesarean section might be predisposed to pathological conditions due to altered antioxidant levels. PMID- 27504276 TI - A Study of the Extended Lipid Profile including Oxidized LDL, Small Dense LDL, Lipoprotein (a) and Apolipoproteins in the Assessment of Cardiovascular Risk in Hypothyroid Patients. AB - INTRODUCTION: Hypothyroidism is one of the most common metabolic disorders associated with dyslipidemia which poses a higher risk of Coronary Artery Disease (CAD) in such patients. Biochemical markers which can pick up the risk promptly are becoming imperative now-a-days and thus the assessment beyond the conventional lipid profile is the need of the hour. AIMS: To assess the association of non-conventional lipid parameters like small dense Low Density Lipoprotein (sd LDL), oxidized Low Density Lipoprotein (ox LDL), Apolipoprotein A (Apo A1), Apolipoprotein B (Apo B) and Lipoprotein (a) {Lp(a)} in hypothyroid patients and compare their values with the conventional lipid parameters such as Total Cholesterol (TC), Triglyceride (TG), Low-Density Lipoprotein Cholesterol (LDL-C) and High-Density Lipoprotein Cholesterol (HDL-C). MATERIALS AND METHODS: One hundred and thirty clinically proven patients of hypothyroidism aged 20-60 years and equal number of age and gender matched healthy individuals were included in this case control study. Serum sd LDL, ox LDL, Apo A1, Apo B, Lp (a), lipid profile, Thyroid Stimulating Hormone (TSH), Free Triiodothyronine (FT3) and Free Tetraiodothyronine (FT4) levels were measured in both the groups. The data was recorded and analysed on SPSS system. The results of cases and controls were compared by student t-test and one-way ANOVA. All the parameters were correlated with TSH by Pearson's correlation. RESULTS: We found significantly high levels of sd LDL, ox LDL, Apo B, Lp (a), TC, TG, LDL-C in cases as compared to the controls. Ox LDL has shown maximum correlation with serum TSH (p<0.0001, r=0.801) followed by sd LDL (p<0.0001, r=0.792), Apo B (p<0.001, r=0.783) and LDL-C (p<0.001, r=0.741). Moreover, ox LDL and sd LDL were found to be increased in normolipidemic hypothyroid patients thereby giving a strong supportive evidence that estimation of these parameters can become fundamental in prompt identification of the high risk patients of CAD in hypothyroid population. CONCLUSION: Non-conventional lipid parameters appear to be better markers for the assessment of cardiovascular risk in hypothyroidism and might help in the designing of the effective treatment protocols and areas of intervention by the clinicians as well as researchers. PMID- 27504277 TI - Aptamers in Therapeutics. AB - Aptamers are single strand DNA or RNA molecules, selected by an iterative process known as Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Due to various advantages of aptamers such as high temperature stability, animal free, cost effective production and its high affinity and selectivity for its target make them attractive alternatives to monoclonal antibody for use in diagnostic and therapeutic purposes. Aptamer has been generated against vesicular endothelial growth factor 165 involved in age related macular degeneracy. Macugen was the first FDA approved aptamer based drug that was commercialized. Later other aptamers were also developed against blood clotting proteins, cancer proteins, antibody E, agents involved in diabetes nephropathy, autoantibodies involved in autoimmune disorders, etc. Aptamers have also been developed against viruses and could work with other antiviral agents in treating infections. PMID- 27504278 TI - The Long Term Kinetic of Plasma Lipids and Lipoproteins in Tyloxapol Injected Rats. AB - INTRODUCTION: The level of plasma triglyceride is balanced by the rate of secretion into and clearance from the plasma. Tyloxapol (Triton WR1339) is a nonionic detergent that inhibits lipoprotein lipase and hence clearance of triglyceride from the plasma. AIM: To determine the kinetic of plasma lipids and lipoproteins following injection of tyloxapol over a period of two weeks. MATERIALS AND METHODS: Fifteen male rats were starved over-night and injected intravenously with tyloxapol (400mg/kg). Blood samples were taken in three steps as, the early (1-6 hours), the middle (1-2 days) and the third (3-9 days) phase. Plasma total cholesterol and triglyceride were measured by enzymatic methods and total phospholipids were analysed as molybdenum blue. Serum lipoproteins were fractionated by electrophoresis on agarose gel (Sebia Inc). RESULTS: The changes of plasma lipids following tyloxapol injection showed three distinctive phases. The early phase lasts at least 6 hours, and the concentrations of triglyceride, total cholesterol and phospholipids increased linearly. The rate of triglyceride secretion was 259.7 +/- 8.1 mg/h.dl in this phase, which was comparable to the mean rate of 250.6 +/- 37.0 mg/h.dl or 102.8 +/- 15.2 mg/h.kg body in starved male rat. During the next 48 hour the lipids continued to accumulate but at a lower rate, and the levels of triglyceride, cholesterol and total phospholipids rose up to about 3200, 586 and 715 mg/dl respectively. In the last phase, the levels of plasma lipids decreased toward the basal levels after 5 days. In serum lipoprotein electrophoresis, the VLDL and LDL increased and HDL fraction disappeared simultaneously during the initial 2 hours of tyloxapol injection. The VLDL fell down toward the normal range, preceded to the reappearance of HDL during 5 days. CONCLUSION: A single intravenous injection of tyloxapol shows three distinctive phases. In the early phase, triglyceride accumulates linearly and the rate of its increment in plasma is a good estimate of the rate of VLDL secretion from the liver. PMID- 27504279 TI - Effects of Diaceto-Dipropyl-Disulphide on Plasma Sialic Acid and Renal Tissue Thiol Levels in Alloxan Diabetic Rats. AB - INTRODUCTION: Plasma sialic acid levels are elevated in Diabetes Mellitus (DM) patients with proteinuria. Renal damage is mainly caused by free radicals that are excessively generated in DM. Thiols play an important role in the cellular antioxidative defence mechanisms mainly through thiol-disulphide exchange reaction. Diallyl disulphide, a garlic oil principle component, is known for its anti-diabetic properties. Its structural analogue, Diaceto-Dipropyl Disulphide (DADPDS), is a less toxic and more palatable disulphide and possesses similar anti-diabetic actions. AIM: This study was undertaken to assess the usefulness of DADPDS in prevention of de-sialation of Glomerular Basement Membrane (GBM) in alloxan diabetic rats and to assess effect of DADPDS on renal tissue thiol levels. MATERIALS AND METHODS: Rats were divided into Normal, Diabetic and DADPDS treated diabetic groups. Diabetes was induced by intraperitoneal injection (IP) of alloxan. DADPDS was fed by gastric intubation. Plasma Sialic acid was determined by Ehrlich's method and renal tissue thiol levels by Nitroprusside reaction method. RESULTS: This study showed a significant decrease (p<0.001) in plasma sialic acid, plasma glucose and renal tissue TBARS levels along with significant increase (p<0.001) in renal tissue thiol levels in DADPDS treated alloxan diabetic rats when compared to diabetic control rats. CONCLUSION: Hence it may be concluded that DADPDS helps in preventing de-sialation of GBM in alloxan diabetic rats and improves renal tissue antioxidant defence mechanisms, may be through thiol-disulphide exchange reaction and thereby exhibits a possible clinical use in prevention of renal complications like diabetic nephropathy. PMID- 27504280 TI - Anthropometric Predictors of Bio-Impedance Analysis (BIA) Phase Angle in Healthy Adults. AB - INTRODUCTION: Phase Angle (PhA) is a ratio of whole body reactance and resistance obtained from Bioelectrical Impedance Analysis (BIA). It indicates cellular health and integrity and is considered as prognostic tool in medical disorders. In spite of prognostic potentials of PhA, it has limited usefulness in clinical practice and in population studies because of non-availability of normal population reference limits for comparison. Moreover, it is influenced by various factors like age, sex, race and body composition (i.e. body fat, muscle mass, visceral fat, body cell mass, total body water, etc). AIM: The aim of this study was to evaluate predictors of phase angle which will be useful in formulation of reference values for Indian population. MATERIALS AND METHODS: BIA was performed by Tanita Body Composition Analyser on healthy adults aged 17-24 years. The inbuilt software measured the phase angle by the formula: Phase angle (PhA) = Reactance (xc)/Resistance (R)* (180/pi). Phase angle values were compared across categories of age, sex, weight, height, Body Mass Index (BMI), total fat, visceral fat and muscle mass. RESULTS: Mean value of phase angle was found to be 5.65. Phase angle was significantly (p< 0.001) higher in male than in female. Phase angle was significantly predicted from height (p< 0.001), weight (p< 0.002), muscle mass (p< 0.002) and visceral fat (p< 0.02) in multiple regression models. CONCLUSION: Phase angle differs across anthropometric and body composition categories. Thus height, weight and muscle mass should also be taken into consideration while deriving population specific reference limits of phase angle. PMID- 27504281 TI - Serum Proteins Alteration in Association with Body Mass Index in Human Volunteers. AB - INTRODUCTION: Serum proteins are an important indicator of the nutritional status in an individual. There is a worldwide prevalence of both undernourishment and obesity. It has been suggested that low Body Mass Index (BMI) is associated with a decrease in serum protein levels predisposing them to other illnesses. Overweight and obese individuals carry risk for various other non-communicable diseases. AIM: To compare the serum protein levels in underweight, overweight and obese individuals with that of normal body mass index individuals. MATERIALS AND METHODS: This prospective study was conducted in subjects who attended the master health checkup clinic of PSG hospitals. Subjects in the age group of 20-50 years were selected. Their serum proteins and BMI was measured. Twenty subjects each of underweight, normal, overweight and obese individuals were selected, categorized and compared. RESULTS: The serum protein level of normal individuals (Group I) was compared with underweight (Group II), overweight (Group III) and obese subjects (Group IV) by one-way ANOVA analysis. The mean serum total proteins in gm/dl in group I controls was 7.555+/-0.37 compared to Group II (underweight) which was 7.295+/-0.419. Low BMI was found to be associated with a decrease in serum protein level which was not statistically significant. Elevated BMI as in overweight and obese subjects showed no significant alterations in serum protein levels with p >0.05 and the changes were found to be independent of the body mass index. CONCLUSION: Underweight individuals showed a decrease in serum protein levels whereas there were no significant changes in the serum protein levels in overweight and obese individuals. PMID- 27504282 TI - A Study on the Impact of Hyperhidrosis on the Quality of Life among College Students. AB - INTRODUCTION: Hyperhidrosis (HH) is a condition characterized by excessive sweating or perspiration. General population, especially in developing countries like India are seldom aware of this condition and sparsely seek medical attention. The tropical climate and the environment also influence this condition to a greater extent. This can be a hindrance in their professional and social life. Though, it is a widely explored topic, studies on hyperhidrosis from India are rare. AIM: The current study was aimed at estimating the prevalence of hyperhidrosis among college students subjectively and to assess the quality of life using Dermatology Life Quality Index (DLQI). MATERIALS AND METHODS: Five hundred students with age ranging from 17 to 21 years of both genders were included in this study using convenient sampling method. After explaining the study and getting written consent, the students were requested to respond to two questionnaires, one for the subjective diagnosis of hyperhidrosis using a standardized questionnaire developed by North Jersey Thoracic Surgical Associates and the other to assess the quality of life using DLQI. Based on the subjective prevalence scores, the students were divided into 3 groups as "Not bothersome" group, "Somewhat bothersome group" and "Extremely bothersome" group. The DLQI scores of these three groups were compared by ANOVA using SPSS 21.0. RESULTS: The study revealed that overall, 38% of the students were suffering from somewhat bothersome to extremely bothersome hyperhidrosis. Gender analysis showed that male students were affected more (58%), especially with palmar hyperhidrosis and were significantly requiring treatment when compared to female students. Analysis of DLQI scores using ANOVA revealed the fact that overall quality of life was significantly affected in almost 35% of students to the extent that they require appropriate treatment and care. CONCLUSION: This study brings into light the higher prevalence of hyperhidrosis and also its impact on the quality of life among college students in this tropical region. PMID- 27504283 TI - Dengue: Lessons of an Outbreak. AB - INTRODUCTION: Since 1967 there have been many outbreaks of dengue in Delhi. In the year 2015 Delhi has suffered it's one of the worst dengue outbreaks, with more than 15000 dengue confirmed cases and the highest number of deaths (60) in recent years. AIM: To determine the status of Dengue cases as compared to previous six years, the ratio of primary and secondary dengue cases and to review the effectiveness of the one test strategy (either NS1 antigen or IgM antibody) for the confirmation of Dengue. MATERIALS AND METHODS: A cross-sectional study was performed in the year 2015. A total of 7177 serum samples were tested for the confirmation of suspected cases of dengue at our institute. We performed dengue NS1 antigen and dengue IgM antibody ELISA tests for the confirmation of dengue cases in acute and convalescent fever cases respectively. Hundred random samples negative for NS1 antigen were tested for IgM antibody and 100 random samples negative for IgM antibody were tested for NS1 antigen. For determination of ratio of primary and secondary dengue cases, IgG Avidity ELISA was performed on random 76 dengue positive samples. RESULTS: Out of 7177 samples tested, 2358 were positive either by NS1 antigen or for IgM antibody from January to December. Percentage positivity rates for IgM antibody detection and NS1 antigen detection tests were 24.8% (626) and 37.1% (1732) respectively. Out of 100 NS1 negative samples 8 were positive for IgM antibody and out of 100 IgM negative samples 6 were positive for NS1 antigen. Among the 76 samples tested for dengue IgG Avidity ELISA 52 (68.4%) were found to be of secondary dengue. CONCLUSION: Number of dengue cases is constantly rising in Delhi since 2011 and 2014. IgM antibody detection and NS1 antigen detection both the tests should be performed for each patient. Due to the increased prevalence of past infection of dengue, percentage of secondary dengue cases is also increasing in Delhi. PMID- 27504284 TI - Molecular Characterisation of nfsA Gene in Nitrofurantoin Resistant Uropathogens. AB - INTRODUCTION: Majority of Urinary Tract Infections (UTI's) are lower UTI's which constitute the real burden in the primary care setting and are usually treated empirically. Nitrofurantoin is an underused antimicrobial for empiric therapy for community-acquired and nosocomial lower UTIs. Nitrofurantoin has a wide spectrum of action against Escherichia coli, Klebsiella pneumonia and Enterococci, which are the frequent causes of nosocomial lower UTIs and also against multidrug resistant gram-negative organisms including extended spectrum beta lactamase (ESBL) producers, Amp-C producers and Carbapenamase producers. AIM: The study was conducted to describe the resistance pattern of nitrofurantoin and to identify the genes responsible for nitrofurantoin resistance (i.e.) nfsA and the type of mutations involved. SETTINGS AND DESIGN: This study was conducted in a tertiary care hospital for a period of six months which caters to a total of 1200 beds. MATERIALS AND METHODS: A total of 115 clinical strains of Escherichia coli and Klebsiella pneumoniae including ESBL and Carbapenemase producing isolates were analysed for susceptibility to commonly used antimicrobials. RESULTS: ESBL producers 65% and 51% of carbapenems resistant strains were susceptible to nitrofurantoin by minimal inhibitory concentration. MIC to nitrofurantoin was determined by E-strip method. Nitroreductase nfsA gene was detected by PCR in 64 of 70 E.coli isolates with reduced susceptibility to nitrofurantoin. Gene sequencing was done using BLAST algorithm and substitution (N=12) and insertion mutation (N=1) were observed in the resistant strains. CONCLUSION: Nitrofurantoin being an oral antibiotic, its usage in ESBL producers and carbapenamase producers is still warranted. Surprisingly, resistance to nitrofurantoin remains minimal even after extensive use and may be related to the fact that it has multiple mechanisms of action hence may require organisms to develop more than a single mutation to concur resistance. PMID- 27504285 TI - Detection of Respiratory Syncytial Virus using Direct Fluorescent Antibody Assay in Paediatric Patients with Acute Respiratory Tract Infection. AB - INTRODUCTION: Severe Respiratory Syncytial Virus (RSV) pulmonary disease manifesting as bronchiolitis and pneumonia continues to play a major role in the childhood mortality and morbidity. Hence the present study was undertaken to evaluate the prevalence of RSV among hospitalized children presenting with Acute Respiratory Tract Infection (ARTI) and its correlation with risk factors. AIM: To determine the occurrence of RSV related respiratory tract infection in paediatric patients and to access the risk factors and clinical features associated. MATERIALS AND METHODS: RSV antigen detection was performed by Direct Fluorescent Antibody (DFA) staining on 100 nasopharyngeal aspirate collected from hospitalized children below 5 years of age with a diagnosis of ARTI. RESULTS: Out of the 100 samples tested for RSV with DFA, 22 (22%) were found RSV positive with a mean age of 12 months and a male to female ratio of (1.75:1). Clinical features significantly associated with RSV were wheezing and breathlessness. Congenital heart disease (CHD) and prematurity were the risk factors significantly associated with RSV infection. CONCLUSION: RSV infection is a significant cause of morbidity among children presenting with ARTI. In resource limited countries DFA can be used as an important tool for rapid detection of RSV and can potentially eliminate prolonged hospitalization and unnecessary use of antibiotics. PMID- 27504286 TI - Pyogenic Liver Abscess Caused by Acinetobacter lwoffii: A Case Report. AB - Acinetobacter lwoffii is a gram negative aerobic non-fermenter bacilli. It is considered as an important emerging pathogen after Acinetobacter baumannii in patients with impaired immune system and in nosocomial infections. Here, we present a case of community acquired pyogenic liver Abscess caused by Acinetobacter lwoffii in a diabetic patient. PMID- 27504287 TI - Acute Pancreatitis, Hepatitis and Bone Erosion in Acute Yellow Phosphorous Compound Poisoning - A Rare Complication. AB - We report a case of acute pancreatitis and hepatitis following ingestion of yellow phosphorous. The condition of the patient progressed to encephalopathy and bony erosion of the nasal septum. Fungal mass was observed in both the nasal cavities by endoscopy. Microbiological investigation revealed the identity of the fungus as Aspergillus flavus and Candida tropicalis. Patient improved with fluconazole treatment. PMID- 27504288 TI - Biofilm in Osteomyelitis caused by a Rare Pathogen, Morganella morganii : A Case Report. AB - Morganella morganii is a member of Enterobacteriaceae family, whose natural habitat is the human gastrointestinal tract. It rarely causes infection alone and is generally encountered in immunosuppressed patients. Osteoarticular pathologies are not commonly observed with Morganella morganii and infections by it have high mortality rate. Biofilm colonization is a causative factor behind the chronicity and/or refractoriness of certain infections. Biofilms colonize on inert medical devices, prosthesis, fibrosed tissues, sinus tracts as well as dead bones as in case of chronic osteomyelitis. Morganella morganii is not a common pathogen to produce biofilm. In this case report, we present a 56-year-old male patient with chronic osteomyelitis of right proximal tibia caused by biofilm producing strain of Morganella morganii, following trauma. PMID- 27504289 TI - Detection of Salivary IgA Antibodies Against the HlyE Antigen as a Diagnosis of Typhoid Fever. AB - INTRODUCTION: The Salmonella typhi (S. typhi) haemolysin E protein (HlyE) has been shown to be a sensitive and specific antigen for the detection of typhoid fever through the detection of anti-HlyE antibodies in sera. Saliva can also be a useful diagnostic fluid as it also contains antibodies against bacterial pathogens. AIM: This study aims to evaluate the potential detection of salivary anti-HlyE antibodies as a diagnosis of typhoid fever. MATERIALS AND METHODS: Saliva was collected from acute typhoid patients (n=16) who presented at Hospital Universiti Sains Malaysia with prolonged fever of more than five days and were positive for S. Typhi blood culture. Saliva was also collected from convalescent typhoid patients (n=11), patients with other febrile fevers (n=15), and from healthy individuals (n=25). An ELISA was developed to detect the presence of IgA antibodies against HlyE in the saliva of typhoid patients. RESULTS: The acute typhoid group had a higher mean absorbance value of 1.496 compared to the convalescent typhoid (0.538), other febrile fevers (0.678), and healthy individuals (0.457) group. CONCLUSION: This study demonstrated the utility of salivary anti-HlyE IgA antibody as a biomarker for the diagnosis of typhoid fever. Follow-up studies with a larger sample size will allow the optimization of the sensitivity and specificity of the assay. This non-invasive method can be useful for mass screening programs. PMID- 27504290 TI - Expression of Cytokeratin-19 and Thyroperoxidase in Relation to Morphological Features in Non-Neoplastic and Neoplastic Lesions of Thyroid. AB - INTRODUCTION: Thyroperoxidase (TPO) is a protein involved in thyroid hormone synthesis. TPO gene suppression and mutation were involved in thyroid tumours. CK 19 plays important role in the structural integrity of epithelial cells. Reduced TPO expression with increased CK-19 immunoreactivity has been implicated as a marker for differentiating non neoplastic and neoplastic thyroid lesions. AIM: To study the histopathological features of thyroid lesions and to evaluate the diagnostic role of thyroperoxidase and CK-19 in non-neoplastic and neoplastic thyroid lesions. MATERIALS AND METHODS: Prospective observational study of 65 thyroid specimens was studied for detailed histopathological examination and Expression of Immunohistochemical Markers Cytokeratin-19 (CK-19) and Thyroperoxidase. RESULTS: TPO IHC marker was expressed by non-neoplastic and benign lesions of thyroid but not in malignancy. CK-19 was expressed 100% in papillary carcinoma of thyroid and its variants, focal and weak staining noted in goitre and hyperplastic areas. CONCLUSION: Most of the non-neoplastic and neoplastic lesions were diagnosed based on histopathological features. When the histopathological diagnosis are equivocal, immunohistochemical markers aids in diagnosing malignancy. Diffuse and strong TPO expression indicates non-neoplastic thyroid lesions whereas diffused and strong CK-19 expression indicates thyroid malignancy. PMID- 27504291 TI - Morphological Spectrum of Basal Cell Carcinoma in Southern Karnataka. AB - INTRODUCTION: Basal Cell Carcinoma (BCC) is the most common skin cancer worldwide, which appears over sun-exposed skin as slow-growing, locally invasive lesion that rarely metastasizes. Many phenotypic presentations are possible. BCCs are more common in males and tend to occur in older people. Majority is found on the head and neck. Many histopathological subtypes have been defined including nodular, micronodular, cystic, superficial, pigmented, adenoid, infiltrating, sclerosing, keratotic, infundibulocystic, metatypical, basosquamous and fibroepitheliomatous. Mixed patterns are common. AIM: The aim was to study morphological spectrum of BCC in a tertiary care hospital in southern Karnataka. MATERIALS AND METHODS: This was a retrospective analysis of 100 cases of BCCs reported in the Department of Pathology over a 9-year period from 2006 to 2014. RESULTS: The mean age of presentation was 62 years. There was slight female preponderance (56%). The most common location was face (65%) and the most common presentation was ulceration (45%). Of the 100 BCCs, 50% were nodular, 13% infiltrating, 6% basosquamous, 4% superficial, 3% keratotic, 3% multinodular and 1% mixed. CONCLUSION: BCC, besides being the commonest cutaneous cancer, is also known for its numerous histological patterns which are shown to have prognostic implications. This study reveals the frequency of the various histological patterns of BCC in southern Karnataka, where it has been rarely studied before. PMID- 27504292 TI - Anaemia in Systemic Lupus Erythematosus Based on Iron Studies and Soluble Transferrin Receptor Levels. AB - INTRODUCTION: Haematological alterations such as anaemia, neutropenia and thrombocytopenia are frequent in Systemic Lupus Erythematosus (SLE). Ferritin being an acute phase reactant can be falsely elevated in lupus cases. AIM: To evaluate the haematological alterations and to re-categorise the types of anemia by soluble transferrin receptor levels in diagnosed cases of SLE. MATERIALS AND METHODS: A sample of 30 newly diagnosed ANA positive SLE patients was taken. Complete blood counts, ESR, reticulocyte count, coagulation studies, diluted Russel Viper Venom Test (dRVVT), mixing studies, serological tests, high sensitivity CRP along with iron profile, transferrin saturation, soluble transferrin receptor (sol TFR) levels, anti-beta2 glycoprotein1, direct and indirect Coomb's test were estimated in cases diagnosed as SLE. Clinical symptoms were co-related with and Systemic Lupus Erythaematosus Disease Activity Index (SLEDAI) was estimated. RESULTS: Anaemia was the most prevalent haematological alteration followed by thrombocytopenia. Further sub typing of anaemia was done by serum ferritin levels and using sol TFR assays. Ferritin is an acute phase reactant; it underestimated iron deficiency in patients of SLE. When sol TFR was used; patients with pure Anaemia of Chronic Disease (ACD) reduced from 68% to 26%, those with pure IDA reduced from 32% to 16% and a group with co-existing IDA & ACD (58%) was defined {Agreement=53%, p=0.09} by sol TFR which co-related with clinical response to Iron therapy in these patients. CRP was significantly raised in association with disease activity. Fever (p<0.0001), arthritis (p<0.03) were significantly related and CRP was elevated (p<0.04) in cases with high SLEDAI (severe flare). CONCLUSION: Thus, in SLE, anaemia is the most frequent hematological alteration; iron deficiencies supercede in contrast to ACD and further autoimmune haemolytic anaemia. Sol TFR emerged as a better parameter to detect iron deficiency in patients of non- haemolytic anaemia in contrast to iron profile and ferritin levels. PMID- 27504293 TI - Enigmatic Weak D antigen: An Experience in a Tertiary Care Hospital of East Delhi. AB - INTRODUCTION: The Rh blood group system is one of the most polymorphic and immunogenic blood group systems in humans. The expression of Rh blood group antigen is complex, among that Rh-D antigen is the most important antigen because of its immunogenicity. It is easy to detect D antigen in most of the cases. Sometimes, variable expression of Rh-D antigen leads to presence of weak forms. Weak D reacts variably with anti D sera and poses a problem in blood banking. Molecular genetics of Rh-D revealed that weak D antigen is a Rh-D phenotype that possesses less numbers of complete D antigens on the surface of red blood cells. AIM: Present study was carried out to study weak D positivity in a tertiary neuropsychiatry hospital of East Delhi for compatibility testing in blood transfusion, to assess the implications and need of weak D testing and for population genetics study. This study tried to observe pattern of weak D antigen in four broadly classified religious communities also (Hindus, Muslims, Sikhs and Christians). MATERIALS AND METHODS: This was a two years prospective hospital based study including patients as well as donors. All patients were tested for Rh D factor by commercially available monoclonal anti-D sera. The individuals who were found negative with anti-D were further investigated for weak D antigen by using indirect antiglobulin test (IAT) by tube as well as gel card technique. RESULTS: The results were compiled by using SPSS software version 21.0 and Microsoft excel. Among 3619 cases, 3502 (96.7%) were Rh-D factor positive while 117(3.2%) were Rh D factor negative. Among these 117 Rh-D negative cases, 9 (7.6% out of total Rh-D negatives and 0.25% out of total samples) were weak D positive and 108(2.98%) were actually D negative individuals after IAT. Weak D positivity showed a slight predominance in females (55.5%). As per broad religious communities, weak D antigen was found in Hindus only and not observed in Muslims, Sikhs and Christians. In weak D positive individuals, B phenotype (0.43%) was found to be most common followed by A (0.26%) and O (0.2%). CONCLUSION: Considerably high frequency of weak D antigen was noticed in study samples of this hospital. With this data based information, it is felt worthwhile to perform weak D testing routinely of those individuals who are negative with saline anti-D to prevent possibility of haemolysis and for efficient blood transfusion practices by making compatible blood available. PMID- 27504294 TI - Histopathological Trends of Testicular Neoplasm: An Experience over a Decade in a Tertiary Care Centre in the Malwa Belt of Central India. AB - INTRODUCTION: Testicular and para-testicular neoplasm are rare type of tumours affecting adolescents and young adults, reflected by the paucity of published data in India. AIM: This study was undertaken to estimate the epidemiological characteristics and histological types and subtypes of testicular neoplasm according to the WHO classification in our patient group. Identification of histopathological pattern of testicular tumour is immensely important for improved management protocols. MATERIALS AND METHODS: This was a retrospective study done over a period of ten years from 2004 to 2014 in a tertiary care centre. All relevant clinical data including patient's age, laterality, history of risk factors and serum tumour markers were collected from records. Histopathological slides were retrieved and reviewed for tumour and its subtype and classified according to WHO classification (2004). RESULTS: A total of 37 cases of testicular and paratesticular neoplasm were encountered in our study with a mean age of 38.1 years. Right testis was affected in 70.3% of cases. The most common clinical presentation was scrotal swelling with heaviness. Germ cell tumour was the most common type accounting for 77.1% followed by lymphomas (17.1%). Germ cell tumours were categorized into seminomatous (48.2%) and non seminomatous tumours (51.8%). The most common subtype of non-seminomatous tumours was mixed germ cell tumour accounting for 85.8%. CONCLUSION: The incidence of testicular neoplasm among general population in Asian countries is low, as reflected in the very few studies that have been performed and published in literature. Epidemiological and histomorphological spectrum of our study was comparable to most of the countries except for some African and Western countries. PMID- 27504295 TI - Clinicopathological Study of Non-Infectious Erythaematous Papulosquamous Skin Diseases. AB - INTRODUCTION: Papulosquamous diseases are characterized by scaly papules and plaques with similar clinical picture which amounts to confusion and hence, a definitive histopathological diagnosis goes a long way in treatment of such diseases. AIM: The aim of the study was to study the histomorphology of non infectious, erythaematous, papulosquamous lesions of skin with clinicopathological correlation. MATERIALS AND METHODS: Skin biopsies from 150 clinically diagnosed/suspected non-infectious erythaematous, papulosquamous skin diseases were received in the Department of Pathology. The specimens obtained were subjected to formalin fixation and paraffin embedding, stained with haematoxylin and eosin and studied. The lesions were classified as psoriasis, lichen planus, lichen nitidus, lichen striatus, pityriasis rosea and pityriasis rubra pilaris and clinicopathological correlation was done. RESULTS: Papulosquamous lesions were common in the elderly. Males were commonly affected except in pityriasis rosea. Among the 150 cases studied, 72 cases (48%) were histopathologically confirmed to be papulosquamous lesions. Psoriasis was the most common lesion. CONCLUSION: Key histopathological features and clinicopathological correlation gives a conclusive diagnosis. The importance of specific histomorphological diagnosis lies in distinguishing these lesions as the treatment and prognosis varies widely. PMID- 27504297 TI - Papillary Cystadenocarcinoma of the Parotid Gland: A Rare Case Report. AB - Papillary cystadenocarcinoma is a rare malignant neoplasm of the salivary gland, characterized by noticeable cystic and solid areas with papillary endophytic projections. These tumours lack features that characterize cystic variants of several more common salivary gland carcinomas. It was first described in 1991 by World Health Organization as a separate entity and cystadenocarcinoma with or without papillary component in the AFIP classification. Most of these tumours occurred in the major salivary glands followed by minor salivary glands. Cystadenocarcinoma is the malignant counterpart of cystadenoma. We report a case of papillary cystadenocarcinoma of parotid. A 40-year-old lady presented with gradually progressive swelling below the right ear associated with occasional pain. Clinical and radiological features suggested benign neoplasm. Right lobe superficial parotidectomy was performed. The histopathologic diagnosis showed papillary cystadenocarinoma of the parotid gland. Histologic confirmation of stromal invasion is required to differentiate it from the benign lesion. Conservative wide local surgical excision is the treatment of choice. PMID- 27504296 TI - Diagnostic and Prognostic Significance of Various Histopathological Features in Extrahepatic Biliary Atresia. AB - INTRODUCTION: Extrahepatic biliary atresia is a progressive disorder characterised by fibroinflammatory obliteration or stenosis of the extrahepatic biliary tree leading to obstruction of bile flow and cholestatic jaundice. It is the most common cause for cholestasis in newborn. Histopathological criteria for diagnosing biliary atresia from liver biopsy have not been clearly defined. AIM: This study was undertaken to analyse the significance of the various histopathological features in diagnosis and prognosis of extrahepatic biliary atresia from liver biopsy specimens. MATERIALS AND METHODS: This was a retrospective study of 43 cases of extra-hepatic biliary atresia diagnosed and treated at a tertiary care hospital between January 2010 to December 2014. Formalin fixed paraffin embedded liver biopsy tissues were processed by standard technique and the slides were stained with haematoxylin and eosin. All the slides were reviewed and graded by a semi-quantitative scoring system. Features such as increased age at kasai's portoenterostomy, portal fibrosis, bile duct proliferation, cholestasis, portal inflammation and duct plate malformation were studied. Statistical analysis was worked out using SPSS 17.0 (statistical package for the social science software). Chi-square test was used to find association between various parameters with respect to mortality and Kaplan-Meier estimator was used for survival analysis of the population under study. RESULTS: In this study comprising of 43 cases, only 6 cases (13.95%) were alive at the end of 6 months follow-up. Twenty patients who died and the 17 cases with poor survival had greater degrees of fibrosis, bile duct proliferation and cholestasis. Majority of the cases with duct plate malformation expired inspite of earlier surgical intervention. Thus proving the association of fibrosis, bile duct proliferation, cholestasis and duct plate malformation with the survival and prognosis of biliary atresia cases. Age at surgery did not show any correlation with prognosis as cases operated even at <60 days had poor survival. CONCLUSION: From this study it can be concluded that in extrahepatic biliary atresia patients, presence of duct plate malformation, greater degrees of fibrosis, bile duct proliferation and cholestasis were strongly associated with poor prognosis. PMID- 27504298 TI - Non-Secretory Myeloma, Diagnosed on Renal Biopsy as Cast Nephropathy. AB - Multiple myeloma is a disorder of plasma cells which can involve kidneys in the form of cast nephropathy. Neoplastic plasma cells produce either complete immunoglobulins or fragments of immunoglobulins leading to a monoclonal spike in the serum and/or Bence Jones proteinuria. Very few patients present as non secretory myeloma when no immunoglobulins (M spike) are produced or only light chains are secreted which can only be detected in urine. Acute renal failure due to cast nephropathy can rarely be the first presentation of multiple myeloma. We here in report a case in which primary diagnosis of multiple myeloma was made on renal biopsy due to its characteristic histomorphology. The diagnosis was later on supported by presence of neoplastic plasma cells in the aspirate and biopsy of bone marrow. PMID- 27504299 TI - A Solid Pseudopapillary Tumour of the Head of Pancreas: A Rare Case Report Diagnosed by Fine Needle Aspiration Cytology. AB - Solid Pseudopapillary Tumour (SPPT) is a distinctive tumour of low malignant potential with a striking and unexplained predilection for adolescent girls and young women. Hence it is important to distinguish this rare tumour from other pancreatic tumours with similar cytomorphologic features because an accurate preoperative diagnosis is highly desirable since these patients can have long survival with adequate surgery. We report a case of the rare SPPT of the pancreas in a young girl who presented with nonspecific pain in the abdomen. Radiological investigations revealed a solid cystic mass in relation to the uncinate process of pancreas and third part of duodenum. The mass was diagnosed to be a solid pseudopapillary neoplasm of pancreas on ultrasound guided FNAC. Surgical removal of the pancreatic tumour and detailed histologic study confirmed the cytologic diagnosis. We present this case because, to date, there are few case reports on the cytological diagnosis of this tumour, about 60 cases, diagnosed by Fine Needle Aspiration Cytology (FNAC) are reported in the literature. With widespread availability of high-quality imaging systems and a better understanding of its pathology, the number of cases reported in the literature has been steadily increasing in recent years. In our case, the cytological diagnosis was done even before the detailed imaging findings were available, the cytological features of this tumour are highly characteristic and it is possible to differentiate it from other pancreatic tumours with relative ease. PMID- 27504300 TI - Idiopathic Fatal Pancytopenia: A Case Report. AB - Pancytopenia is defined as decrease in red blood cells, white blood cells and platelets. Many disease processes involve the bone marrow primarily or secondarily resulting in pancytopenia. A 55-year-old male presented with generalized body weakness and few episodes of malena for last one year. Physical and systemic examination was unremarkable. CBC report revealed pancytopenia. Other haematological parameters were within normal limit. Stool for occult blood was positive. USG and CECT abdomen showed no abnormality. The patient was evaluated for any evidence of malignancy but no clue was found. Bone marrow examination was done as patient was having pancytopenia. Bone marrow smears, clot sections and bone marrow biopsy was normal. Immunohistochemistry and cytogenetics study was unremarkable. Patient was admitted in hospital for 1 month and his condition rapidly deteriorated. The cause of pancytopenia remained unexplained and therefore it was named as Idiopathic fatal pancytopenia. "Idiopathic Fatal Pancytopenia (IFP)" is an emerging new entity with a grave prognosis. We wish to sensitize the medical community and the scientists to this rapidly fatal condition. PMID- 27504301 TI - Tufted Angioma of Eyelid in an Adult - A Case Report. AB - Tufted Angiomas also known as angioblastomas /Angioblastoma of Nagakawa are rare vascular neoplasms localised to the skin and subcutaneous tissues with the upper trunk and neck being most common sites. They are mainly seen in children but a few cases in juveniles and adults have been reported. We hereby report this case, a 40-year-old male who presented with a right lower lid, painless, slowly progressive, firm swelling diagnosed as Tufted Angioma on histopathology and immunohistochemistry. PMID- 27504302 TI - Aneurysmal Bone Cyst: An Uncommon Secondary Event in Calcaneal Chondroblastoma. AB - Chondroblastoma is an uncommon benign bone tumour, involvement of epiphysis of long bones is typical. Chondroblastoma of the calcaneum is uncommon and its association with secondary aneurysmal bone cyst is even rarer. Only two cases of calcaneal chondroblastoma associated with secondary aneurysmal bone cyst have been reported till date. A 22-year-old male presented to the department of orthopaedics with complains of pain and swelling in the left heel since the last 10 months. On clinico-radiological grounds differentials considered were giant cell tumour of bone and aneurysmal bone cyst. In view of the histopathological findings of bone curettage and results of special stain and immunohistochemical marker, final diagnosis of chondroblastoma with secondary aneurysmal bone cyst, left calcaneum was rendered. Although rare, chondroblastoma should always be considered in osteolytic lesions of calcaneum. The identification of secondary aneurysmal bone cyst component is important as it has higher chances of recurrence than usual chondroblastoma. PMID- 27504303 TI - Extramedullary Haematopoiesis in a Case of Pilomatricoma. AB - Pilomatricoma is a benign follicular skin appendage tumour. It usually occurs as solitary lesion and is most commonly seen in the face and upper extremeties. Here we report a rare case of extramedullary haematopoiesis (EMH) in pilomatricoma in a 38-year-old lady. PMID- 27504304 TI - A Rare Mimicker in the Placenta. PMID- 27504305 TI - Evaluation of Hand Written and Computerized Out-Patient Prescriptions in Urban Part of Central Gujarat. AB - INTRODUCTION: Prescription order is an important therapeutic transaction between physician and patient. A good quality prescription is an extremely important factor for minimizing errors in dispensing medication and it should be adherent to guidelines for prescription writing for benefit of the patient. AIM: To evaluate frequency and type of prescription errors in outpatient prescriptions and find whether prescription writing abides with WHO standards of prescription writing. MATERIALS AND METHODS: A cross-sectional observational study was conducted at Anand city. Allopathic private practitioners practising at Anand city of different specialities were included in study. Collection of prescriptions was started a month after the consent to minimize bias in prescription writing. The prescriptions were collected from local pharmacy stores of Anand city over a period of six months. Prescriptions were analysed for errors in standard information, according to WHO guide to good prescribing. STATISTICAL ANALYSIS: Descriptive analysis was performed to estimate frequency of errors, data were expressed as numbers and percentage. RESULTS: Total 749 (549 handwritten and 200 computerised) prescriptions were collected. Abundant omission errors were identified in handwritten prescriptions e.g., OPD number was mentioned in 6.19%, patient's age was mentioned in 25.50%, gender in 17.30%, address in 9.29% and weight of patient mentioned in 11.29%, while in drug items only 2.97% drugs were prescribed by generic name. Route and Dosage form was mentioned in 77.35%-78.15%, dose mentioned in 47.25%, unit in 13.91%, regimens were mentioned in 72.93% while signa (direction for drug use) in 62.35%. Total 4384 errors out of 549 handwritten prescriptions and 501 errors out of 200 computerized prescriptions were found in clinicians and patient details. While in drug item details, total number of errors identified were 5015 and 621 in handwritten and computerized prescriptions respectively. CONCLUSION: As compared to handwritten prescriptions, computerized prescriptions appeared to be associated with relatively lower rates of error. Since out-patient prescription errors are abundant and often occur in handwritten prescriptions, prescribers need to adapt themselves to computerized prescription order entry in their daily practice. PMID- 27504306 TI - A Retrospective Study of the Treatment Outcome of Drug Therapies used in Heart Failure Patients with Associated Co-morbidities in a Tertiary Care Hospital. AB - INTRODUCTION: Heart failure is one of the most common heart problems seen in the Indian population. There are various drugs used to prevent further progression of the disease. In India, there are few studies in relation to treatment outcome in a tertiary care hospital. AIM: To study the treatment outcome of drug therapies used in heart failure patients with associated co-morbidities in a tertiary care hospital. MATERIALS AND METHODS: This was an observational study conducted on 250 patients with heart failure. Details collected using the proforma were demography (age, gender); medical history; medication history for heart failure patients on admission and discharge; ejection fraction; median length of stay in hospital; number of readmissions & in-hospital mortality. RESULTS: One hundred and twenty eight patients categorized into LVSD group (ejection fraction <40%) and 122 patients in PSF group (ejection fraction > 40%). Medical history of coronary artery disease (54%) was significantly higher in LVSD group (p<0.05) and anaemia (19%) was significantly higher in PSF group (p<0.05). On admission, inotropes (30%), digoxin (59%) and statins (54%) were prescribed more in LVSD patients (p<0.05) while calcium channel blockers (20%) were prescribed more in PSF group (p<0.05). At discharge, patients with LVSD were receiving ACE inhibitors (51%), beta blockers (30%), digoxin (67%) and statins (59%) (p<0.05) while calcium channel blockers (20%) was prescribed more in PSF group. The median length of stay was slightly higher in patients with PSF (7 days) as compared to LVSD (6 days). In-hospital mortality was lower in patients with PSF (6%) than patients with LVSD (20%). The percentage of readmissions within one month was slightly higher in patients with PSF (15%) compared to LVSD (14%). CONCLUSION: Length of stay in hospital was 6-7 days in heart failure patients. In hospital mortality in LVSD patients (20%) was higher compared to PSF patients (6%). A 15% heart failure patient were readmitted within 1month of discharge. PMID- 27504307 TI - The Zest for Patient Empowerment. AB - Patient Empowerment (PE) can be considered as an active and self-determining role of patient than a passive recipient of health related services. It encourages the provider-patient relationship to blossom and helps in clearing patients' doubts, confusion and fears to bring in clarity, relief and assurance. For the active involvement of the patient's in own health management they need to be awakened, motivated, educated and enlightened to enable them to exercise their rights. Active patient involvement in the decision-making achieves favourable health outcome. In an empowerment based approach, the focus is not on defining a particular type of behaviour, but on how the behaviour is defined as a goal to be achieved by a particular individual. As a result of their empowerment process, the patients can better self-manage their illness and their lives. Thus empowerment of the patients will positively help medical uprising of the community by creating an educated, health aware, informed and health conscious mass. PMID- 27504308 TI - Preventive and Protective Effect of Nishamalaki in STZ Induced Diabetic Complications in Wistar Rats. AB - INTRODUCTION: Diabetes is a metabolic disease of vital health importance because of the complications associated with it. Clinical trials and animal studies have demonstrated the anti-hyperglycaemic effect of Nishamalaki. Present study was planned to evaluate the protective potential of Nishamalaki on diabetic complication in rats. AIM: To study the Nephro-protective effect and to assess the protective potential on retinal changes of Nishamalaki in diabetic wistar rats. MATERIALS AND METHODS: Diabetes induced with 60 mg/kg of Streptozotocin and 110 mg/kg Nicotinamide IP. Nishamalaki, a combination of Curcuma longa and Emblica officinalis administered orally with honey. Rats divided into six groups, control and diabetic rats with blood glucose above 250 mg/dl were divided into 5 groups. After 8 weeks test animals were treated with Nishamalaki, Enalapril and control with saline for 30 days. Biochemical parameters measured like Serum BSL, BUN and Creatinine and rats were observed for development of cataract. Rats sacrificed and kidney samples were taken to examine histopathological changes. RESULTS: Blood Urea Nitrogen and Creatinine values were significantly (p<0.01) reduced in Nishamalaki group than control group. Nishamalaki showed the protective effect on kidney pathology as seen on histopathology by near normal glomerular and tubular structures. Control group showed shrunken glomerulus and tubular vacuolations. In Nishamalaki group immature sub capsular cataract with mild lenticular opacity were seen compared to the mature cataract with significant lenticular opacity and corneal vascularisation in control group. CONCLUSION: Nishamalaki showed protective effect on development of Nephrotoxicity and it has also delayed the progression of cataract in rats. PMID- 27504309 TI - Red Lentil Extract: Neuroprotective Effects on Perphenazine Induced Catatonia in Rats. AB - INTRODUCTION: Parkinsonism is a neurodegenerative disease that is defined by certain symptoms such as muscle rigidity, impaired movement, catatonia, tremor and disorientation of body. AIM: The aim was to investigate the effect of red lentil extract on perphenazine-induced Catatonia in model of rat. MATERIALS AND METHODS: This experimental study was done on 48 male albino rats (weight 180 200g) of the Sprague-Dawley strain. Animals were randomly divided into six groups and were pre-treated with a single dose of red lentil extract (200, 400, 800 and 1000 mg/kg), most effective dose of bromocriptine (30mg/kg) and normal saline (5ml/kg) via intraperitoneal (IP) route. perphenazine (5 mg/kg) was after 30 minutes, administered (IP) to induce catatonia. The scoring method of Morpurgo was used to determine the muscular rigidity of animals. RESULTS: The results showed that the 200mg/kg red lentil extract treated group had no significant reduction in catatonic responses after perphenazine administration in comparison with control group while the groups that received 800 and 1000mg/kg of red lentil extract showed significant difference (p<0.05) at all the time points. CONCLUSION: The results revealed that hydroalcoholic extract of red lentil has protective effect on Catatonia induced by perphenazine in rats. So this extract may be probably beneficial for catatonia in Parkinsonism. PMID- 27504310 TI - The Portal Hypertensive Gastropathy: A Case and Review of Literature. AB - Upper gastrointestinal bleeding is a cause of high risk for morbidity and mortality. It has been debated in alcoholic cirrhosis, if alcohol exerts an exclusive and causal role upon gastropathy or whether it is linked to cirrhotic portal hypertension. The authors describe an autopsy report regarding mortality caused by gastric bleeding in a 53-year-old patient who suffered from cirrhosis. Literature has evidence of direct, marked damage of alcohol upon the gastric mucosa and there is noteworthy statistical data implying the revaluation of the pathogenesis of the bleeding. PMID- 27504311 TI - Quality of Life in Infertile Menopausal Women; Development and Psychometric of an Instrument. AB - INTRODUCTION: So far few studies have been designed to evaluate the quality of life instrument in infertile women. AIM: The present study was decided to design a valid and reliable instrument to assess quality of life in Iranian infertile women in postmenopausal period. MATERIALS AND METHODS: Both quantitative and qualitative research methods were applied. The process was divided into three main stages including: instrument development, instrument validity and instrument reliability. Instrument development used three main steps, including determining content domain, item generation and instrument construction. Instrument was validated using face validity, content validity and factor analysis. Both internal consistency and test-retest reliability methods were used to confirm the reliability of the questionnaire. RESULTS: During content development, domain step obtained 83 items in all demission of life in infertile women. In the qualitative and quantitative face validity, 25 items had item impact less than 1.5 and were excluded from the questionnaire. In the content validity section, 17 items failure to obtain necessary score based on Lawshe formula, so were excluded from the questionnaire. Overall, 8 factors were extracted by factor analysis test. However, 67.38% of the total variance was explained by 4 factors, other 4 next factors explained the remaining 32.62% of the total variance. Totally, 34.01% of rotation variance was explained by first factor and 24.37% by second factor. In questionnaire internal consistency, 8 items had Cronbach's alpha 0.942. CONCLUSION: Therefore, we recommend the use of present questionnaire as a valid tool to evaluate the quality of life in infertile women during postmenopausal period. PMID- 27504312 TI - Standardized Patient's Views About their Role in the Teaching-Learning Process of Undergraduate Basic Science Medical Students. AB - INTRODUCTION: Standardized Patients (SPs) are widely used in medical education. SPs have a number of advantages but also have certain limitations. At the institution, SPs have been used since January 2013 for both teaching-learning and assessment during the basic science years of the undergraduate medical program. AIM: The present study was conducted to investigate the perception of SPs about various aspects of the program and obtain suggestions for further improvement. MATERIALS AND METHODS: A Focus Group Discussion (FGD) was conducted with a group of five SPs during the second week of November 2015. Respondents were explained the aims and objectives of the study and invited to participate. Written informed consent was obtained. The FGD was conducted using a discussion guide and was audio recorded. Various aspects of the SP program at the institution were discussed. Motivation/s for joining the program and suggestions for further improvement were obtained. Transcripts were created after listening to the recordings and were read through multiple times. Similar responses were coded. Items with similar codes were grouped together into themes. RESULTS: Three respondents were female while two were male. The major advantage of SPs was their flexibility and ability to present a standardized response to the student. Students become familiar and comfortable with SPs. However, as a SP is simulating an illness s/he may not always be able to do complete justice to the role. The process used by SPs to prepare themselves to portray various diseases was highlighted. The use of SPs both during teaching-learning and assessment was also discussed. Some SPs are trained to provide feedback to students. Most SPs joined the program based on invitations from their friends who were already SPs. Challenges in recruiting SPs in a small island were discussed. Suggestions for further improvement were obtained. CONCLUSION: The present study obtained the perception of SPs regarding various aspects of the SP program at the institution. The overall opinion of SPs was positive. PMID- 27504313 TI - Surveillance of Anaemia: Mapping and Grading the High Risk Territories and Populations. AB - INTRODUCTION: Surveillance of anaemia is an ongoing process for assessing iron status and anaemia prevalence among individuals and the communities they live in. Measuring blood haemoglobin levels is the commonest method espoused worldwide for screening individuals and populations for anaemia and iron deficiency. World Health Organization (WHO) proposed a classification of public health significance of anaemia in populations on the basis of prevalence estimated from blood levels of haemoglobin. India falls under "Severe public health problem" category. An attempt has been made to categorise "Severe public health problem" into grades of severity that will help in prioritising the states and districts for targeted action. AIM: To adapt the "WHO Classification of anaemia as a problem of public health significance" and to use the same to identify and map high risk population groups in the southern states of India. MATERIALS AND METHODS: The category of 'Severe Public Health Problem' has been graded based on prevalence of anaemia. Secondary data published in the District Level Household and Facility Survey - 4 is analysed for five states and 1 UT (Union Territory) of southern part of India. Choropleth Mapping was done to visually depict the intensity of anaemia problem across the geographic territories. RESULTS: Children from 6 months to 59 months were having highest prevalence of both, anaemia (68%) and severe anaemia (10%). This was followed by pregnant women aged 15 to 49 years and Girl Child 6 to 9 years. Four of the Southern states of India including Andhra Pradesh, Karnataka, Telangana and Tamil Nadu fall in the Grade 2 SPHP (Severe Public Health Problem). CONCLUSION: The sixteen districts fall under Grade 3 Severe Public Health Problem in the states of Andhra Pradesh, Karnataka and Telangana, require special focus for identifying and addressing the determinants of such high prevalence of Anaemia. These populations and territories require priority in the Government of India's Rashtriya Bal Swasthya Karyakram (RBSK) in the National Health Mission to address iron deficiency anaemia. The problem needs to be addressed through dietary diversification and improved access to foods that have high levels of bioavailable iron, including animal products apart from iron supplementation. PMID- 27504314 TI - Perspectives and Challenges of HMIS Officials in the Implementation of Health Management Information System (HMIS) with Reference to Maternal Health Services in Assam. AB - INTRODUCTION: Health Management Information System (HMIS) is one of the important components of National Rural Health Mission (NRHM). The web portal of HMIS was launched by the Ministry of Health and Family Welfare (MOHFW), Govt. of India (GOI) in 21(st) Oct. 2008 to enable capturing of public health data from both public and private institutions in rural and urban areas across the country. AIM: The aim of the study was to assess the quality perspectives and challenges among HMIS officials in implementing HMIS at their respective levels, i.e. district and block level. MATERIALS AND METHODS: We conducted a pilot qualitative study in two districts of Assam. HMIS officials working at district and block level were interviewed in-depth with the help of a semi-structured interview schedule which lasted from May to July 2014. RESULTS: Both HMIS and MCTS (Mother and Child Tracking System) formats were considered useful, by the HMIS officials, for data collection, planning at various levels, tracking maternal and neonatal deaths, institutional deliveries. HMIS officials reported that MCTS is useful for monitoring individual health status especially the status of the mother and child and HMIS being helpful as a health facility monitoring tool. CONCLUSION: The study used a small sample size, hence similar type of studies are required with large sample size to understand the perspectives and challenges of HMIS officials in the implementation of HMIS. PMID- 27504315 TI - Health System Delay among the Pulmonary Tuberculosis Patients Presenting in the DOTS Centers of Nepal. AB - INTRODUCTION: Health system delay is the time for complete diagnosis of the disease after patient approaches a health care provider. AIM: The study aims to identify the characteristics and the determinants of unacceptable health system delay (>= 7 days delay from health system) in diagnosis of new pulmonary tuberculosis patients attending in Direct Observation Treatment Short course (DOTS) centers of Nepal. MATERIALS AND METHODS: An analytical cross-sectional study was conducted by administrating a structured questionnaire interview and reviewing the medical record of the new sputum smear positive pulmonary tuberculosis cases during January-May 2015. The generalized linear model (GLM) was applied to control the clustering effects. Multiple logistic regressions were performed to identify the association between variables with >= 7 days of unacceptable health system delay. RESULTS: Of the 374 new sputum smear positive pulmonary tuberculosis cases, the factors that were associated with unacceptable health system delay (time >= 7 days) were doing business (adj.OR= 1.61, 95% CI: 1.22-2.11; p-value <0.001) and unemployed (adj.OR= 3.04, 95% CI: 1.53-6.04; p value <0.001) had chances of health system delay. However, getting support from parents (adj.OR= 0.55, 95% CI: 0.44-0.68; p-value <0.001), consultation with the private practitioners/ pharmacists (adj.OR= 0.24, 95% CI: 0.07-0.81; p-value 0.021), visiting government health facilities (adj.OR= 0.31, 95% CI: 0.13-0.73; p value 0.008), using X-ray (adj.OR= 0.69, 95% CI: 0.49-0.97; p-value 0.032) and advance technologies for diagnosis of TB (adj.OR= 0.60, 95% CI: 0.39-0.94; p value 0.024) were found contributing to reduce health system delay while controlling socio-economic, knowledge, presence of symptoms and attitude factors. CONCLUSION: About a quarter of new TB patients faced health system delay problems. Socioeconomic factors, unemployment, influences the health system delay when controlled for other covariates. PMID- 27504316 TI - Assessment of Economic Impact Among In-Patients with Non-Communicable Diseases in a Private Tertiary Care Hospital in Southern India. AB - INTRODUCTION: Non-communicable diseases (NCDs) are currently responsible for tremendous economic impact on households. AIM: This study was done to estimate the direct, indirect and total costs incurred by households of in-patients with non-communicable diseases admitted in a Private tertiary care hospital. MATERIALS AND METHODS: It was a cross-sectional study conducted in a private tertiary care hospital of Mangalore city in June 2012 by interviewing 30 patients and their attenders using a validated interview schedule. RESULTS: Direct cost constituted 58.6% of the total expenses during the course of stay in the hospital. Mean direct cost was more among patients with cancers (p=0.049). Indirect cost was associated with educational status (p=0.04), occupational status (p<0.001) and socio economic status (ses) (p<0.001) of patients. Total cost was more among patients from upper middle ses households (p=0.012). Direct and indirect cost constituted 5-10% each and total cost > 20% of the annual income of majority of households. Medical insurance scheme was not availed by 26 (86.7%) patients due to ignorance. CONCLUSION: Economic burden imposed by a single admission among inpatients with NCDs was tremendous on their households. Hence, information on various medical insurance schemes needs to be popularized among people to improve its utilization. Health care providers need to introduce more financial schemes to minimize health care costs among poor households. PMID- 27504317 TI - Life Course Socioeconomic Transition and its Association with Early Onset Type 2 Diabetes: Protocol for a Sequential Exploratory Mixed Method Study. AB - INTRODUCTION: The prevalence of early onset type 2 diabetes (Diabetes below the age of 45 years) is increasing worldwide. Transition in socio-economic position i.e. Life Course Socio-Economic Transition (LSET) - may contribute to the development of early onset T2D through complex processes involving economic and occupational opportunities as well as individual life style choices. AIM: To develop and validate the life course socioeconomic transition questionnaire and to know the association between life courses socioeconomic transition and early onset type 2 diabetes. MATERIALS AND METHODS: This study follows sequential exploratory mixed method study design. It consists of one qualitative strand followed by two quantitative strands. Qualitative strand consist of in- depth interview among the community dwellers to develop a tool for measuring LSET. Two quantitative strands consist of the validation of the questionnaire by conducting cross-sectional survey among 200 randomly selected community dwellers and a hospital based case control study using the same questionnaire. RESULTS: Those who have a history of lower SEP during his childhood period and enjoying higher SEP during his adulthood period have an increased risk for developing type 2 diabetes at their younger age (18-45 years). CONCLUSION: This study will help to develop a validated life course socioeconomic transition questionnaire and application of that tool in an epidemiological study. PMID- 27504318 TI - Parathyroid Adenoma Completely Impacted within the Thyroid Gland: A Case Report. AB - Ectopic parathyroid adenoma can be seen in various locations. Sometimes ultrasound and even fine needle aspiration studies cannot distinguish this lesion from thyroid lesions. A 29-year-old woman with a prominent nodule of left thyroid lobe was referred to surgical department. Thyroid function test were normal. She had no family history of parathyroid disease, other endocrine disease, and any other malignancies and had received no radiation. Ultrasonography revealed a solid and hypoechoic mass, 25x20 mm in size, with a regular shape and contour without calcification in the inferior of left lobe of the thyroid gland. For definite diagnosis, immunohistochemistry study of the lesion with three markers was done. Finally, PTH marker was positive in cytoplasms of cells so parathyroid adenoma was confirmed. Fine needle aspiration of the nodule was suspicious for follicular neoplasm; however, postoperative histopathology and immunohistochemistry revealed a parathyroid adenoma. Ultrasonography may be helpful to identify localized thyroid lesions especially in parathyroid adenoma. PMID- 27504319 TI - Indications and Visual Outcome of Penetrating Keratoplasty in Tertiary Eye Care Institute in Uttarakhand. AB - INTRODUCTION: Corneal blindness forms significant proportion of visual blindness in developing countries and penetrating keratoplasty (PK) can restore vision for this. The prognosis of PK is dependent on the corneal diseases responsible for corneal blindness. AIM: To evaluate the indications and visual outcome of PK in tertiary eye care institute in Uttarakhand. MATERIALS AND METHODS: Data was reviewed from the medical records of 145 PK done in Department of Ophthalmology, Himalayan Institute of Medical Sciences from January 2012 to October 2014. Analysis of data was done for evaluation of the indications and visual outcome by Paired student's t-test for hypothesis testing of grouped values of preoperative and last follow-up best corrected visual acuity in cases of optical and therapeutic grafts. A p-value < 0.05 was considered statistically significant. RESULTS: In this study data of 145 eyes of 138 patients was reviewed. The most common indication for keratoplasty was corneal scarring including adherent leucoma 48 (33.10%). Therapeutic keratoplasty was done for 33 cases with maximum 30(20.68%) cases of infectious keratitis. One case of tectonic graft was included in therapeutic keratoplasty group for analysis. There was statistically significant difference (p=.0001) in best corrected visual acuity improvement from 1.39 logMAR+ 0.022(SD) preoperatively to 0.367 logMAR+0.44(SD) postoperatively and 1.4 logMAR+.000(SD) preoperatively to 0.16 logMAR+0.57(SD) postoperatively for optical and therapeutic grafts respectively. CONCLUSION: Infective keratitis either active or healed was the major indication for keratoplasty. Poor prognosis indications were most common in this part of the country. The visual outcome following corneal transplantation was encouraging particularly in cases of optical keratoplasty. PMID- 27504320 TI - Therapeutic effect of 0.1% Tacrolimus Eye Ointment in Allergic Ocular Diseases. AB - INTRODUCTION: Allergic Ocular Diseases (AODs) like Atopic Keratoconjunctivitis (AKC) and Vernal Keratoconjunctivitis (VKC) are chronic forms of ocular allergy that can cause severe visual complications. Pathogenesis of AODs is uncertain and treatment has been a challenge for ophthalmologists. Tacrolimus, a 23-member cyclic macrolide lactone derived from [streptomyces tsukubaensis] now in ointment form has been successfully used in AODs. AIM: To study the therapeutic effect of 0.1% Tacrolimus eye ointment in patients with Allergic Ocular Diseases (AODs). MATERIALS AND METHODS: This prospective observational study was conducted on 36 patients with severe AOD and moderate cases not responding to conventional treatment. They were treated with 0.1% tacrolimus eye ointment twice daily for minimum three months in addition to conventional treatment and observed for a period of 6 months. Symptoms and signs after treatment were evaluated. Grades of clinical signs were assessed based on slit lamp clinical photographs; development of possible complications was assessed and analysed by Wilcoxon signed rank test. RESULTS: Mean age of patients was 9.3+/-4.3 years and mean duration of AODs was 3.1+/-1.8 years. The scores on both the four point scales for signs and symptoms decreased significantly (p<0.0001) after 1 month of 0.1% Tacrolimus eye ointment treatment. Itching was the first symptom to show dramatic relief and conjunctival hyperaemia was the first sign to show improvement. 88.88% of patients were successfully weaned off topical steroids in 6 months into Tacrolimus treatment. Even in patients unresponsive to 0.1% topical Cyclosporine, symptoms and signs scores decreased significantly (p<0.0001). The most common adverse reaction was a transient burning sensation (36.11%). CONCLUSION: Topical 0.1% Tacrolimus eye ointment was found to be a safe and effective treatment in cases of AODs and also worked as steroid sparing and replacing agent. It was also found effective in patient's refractory to topical Cyclosporine. PMID- 27504321 TI - Mechanical Ptosis in Neurofibromatosis Type 1 Heralding the Diagnosis of Right Sided Cervical Vagus Nerve Neurofibroma: A Rare Case Report. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant, multisystem disorder. In NF1, involvement of vagus nerve can occur in the form of neurofibroma. A few cases of neurofibroma of thoracic vagus nerve have been reported while neurofibroma of cervical vagus nerve with NF1 is quite rare. A 19-year-old male came with complaints of decreased vision of both eyes and right sided drooping of eyelid since childhood. He was diagnosed as having NF1 with neurofibroma of right cervical vagus nerve. PMID- 27504322 TI - A Rare Case of Orbital Apex Syndrome in Herpes Zoster Ophthalmicus. AB - Orbital Apex Syndrome (OAS) is a rare complication of Herpes Zoster Ophthalmicus (HZO). We are reporting a case of 65-year-old male who developed OAS following HZO. Patient presented with vesicular rash in the typical dermatomal distribution, severe periocular congestion and limited ocular motility in all gazes along with loss of vision. Soft tissue inflammation improved within 4 weeks of initiation of treatment while ocular motility slowly improved over 3 months. Patient did not gain vision despite receiving systemic steroids and systemic anti viral medication. Variable improvement in ocular motility and visual function in our patient points towards multiple mechanisms involved in pathogenesis of this disease, some of which are yet to be understood. PMID- 27504323 TI - Simple Limbal Epithelial Transplantation in Acid Injury and Severe Dry Eye. AB - The epithelial cells of cornea constantly undergo renewal and regeneration and the stem cells responsible for renewal resides within basal epithelium at the limbus in palisades of Vogt. Simple limbal epithelial transplantation (SLET) is a simplified technique for limbal stem cell deficiency and it combines the benefits of both conjunctival limbal autografting and cultivated limbal epithelial transplantation by being single-stage and utilizing minimal donor tissue. We will be discussing two cases of ocular surface disorder which were managed successfully by new technique simple limbal epithelial transplantation. Two patients one with unilateral Limbal Stem Cell Deficiency (LSCD) following acid injury and other with bilateral LSCD due to severe dry eye underwent limbal epithelial transplantation using the SLET method after taking prior consent for the procedure. Success was termed complete when a completely epithelialized, avascular and stable corneal surface was seen. The follow up examinations were done on first day, at 1 week, 2 weeks, 4 weeks and at 3 months after the surgery. A completely epithelialised, avascular and stable corneal surface was achieved by 4 weeks in both patients. Simple limbal epithelial transplantation is a new technique which is simple, cheap and easily affordable and it has decreased the dependence on stem cell laboratory. PMID- 27504324 TI - A Comparative Study to Assess the Determinants and Outcomes of Sepsis Treated in Medical Wards and ICU in an Indian Teaching Hospital. AB - INTRODUCTION: Sepsis is the primary cause of death from infection worldwide. In resource-limited countries, increasing number of sepsis is managed in non-ICU settings, in Medical Wards (MW). AIM: To compare the burden, aetiology and short term outcome of sepsis treated in MW with ICU. MATERIALS AND METHODS: Prospective, observational, analytical study in sepsis patients in general MW and medical ICU in a tertiary care hospital. Two hundred forty five sepsis patients (MW=150, ICU=95), >=18 years, selected randomly, were studied to compare aetiology, co-morbidities, clinical & microbiological profile and short-term outcome between MW and ICU sepsis. Sepsis following surgery, trauma, those transferred to/from ICU, those with other life threatening diseases were excluded. Chi-square test/Fisher's-exact test was used for comparing ratios. A 'p value' <0.05 was considered statistically significant. RESULTS: Sepsis was more common in elderly males, both in MW and ICU (median age: 56.7, 59.2 years; male: female ratios = 1.34:1, 1.63:1 respectively). Frequency of presenting symptoms, co-morbidities and sources of sepsis were similar in both groups (p>0.05). Frequency of positive microbiological culture, pattern of microbial flora and antimicrobial resistance patterns were similar in both groups (p>0.05). Number of antibiotics used was significantly higher in ICU compared to MW (p<0.01); multi organ dysfunction and mortality were significantly higher in ICU settings (55.8% vs. 38.7%, p=0.04; 48.4% vs. 32.6%, p=0.041 respectively). While sepsis and severe sepsis were significantly higher in MW (34.6% vs. 22.1 %, p=0.03; 47.3% vs. 26.3%, p<0.01 respectively), septic shock was significantly higher in ICU (51.6% vs. 18.0%, p<0.01). Mortality in both settings was highest in septic shock (55.5% and 61.2%, p>0.05) and multi-organ dysfunction (55.1% and 64.2%, p>0.05). Duration of hospital stay was significantly shorter in MW than ICU (7.3 vs. 11.0 days, p<0.01). CONCLUSION: Our study aimed to identify determinants and outcome of sepsis in MW and compare with ICU settings. Antibiotic usage in the two settings differed: concurrent use of >=3 antibiotics, and carbapenems & linezolid usage were significantly higher in ICU compared to MW. Sepsis in MW had significantly lower incidence of multi-organ failure, lower mortality and shorter hospital stay compared to ICU. PMID- 27504325 TI - A Prospective Study of the Clinical Profile, Outcome and Evaluation of D-dimer in Cerebral Venous Thrombosis. AB - INTRODUCTION: Cerebral Venous Thrombosis (CVT) is a well known disease with diverse clinical presentation and causes. With advances in neuroimaging and changing lifestyles, the clinical profile and causes of CVT are changing. D-dimer has been studied in early diagnosis of CVT with variable results. This prospective study was carried out to assess the clinical profile of CVT and role of D-dimer in diagnosis of CVT. AIM: To study various aspects of CVT and role of D-dimer. MATERIALS AND METHODS: The study period was September 2012 to July 2014 and included 80 imaging proven patients of CVT. We also included 39 controls for assessing D-dimer. Data was collected according to a preformed format. D-dimer was assessed by a rapid semi-quantitative latex agglutination assay. Discharged patients were followed up to six months. RESULTS: Of the total 44 were women and 36 were men (F: M=1.2:1). The mean age of the patients was 29.5+/-9.68 years. Most common clinical features were headache 77 (96.25%), papilloedema (67.5%) and seizures 51 (63.75%). Pregnancy was the most common cause of CVT. Superior sagittal and transverse sinuses were the most common sinuses to be affected. The sensitivity and specificity of D-dimer for diagnosing CVT was 84.62% and 80% respectively. The risk factors for poor prognosis were altered sensorium, presence of sepsis, increased sinus involvement and deep sinus thrombosis. CONCLUSION: CVT affects both sexes equally. Puerperium still contributes to majority of the cases. Iron deficiency anaemia needs to be evaluated as a contributing factor for incidence of CVT. D-dimer is not useful in puerperal female with CVT. Positive D-dimer will strengthen the suspicion of CVT in patients with acute headache followed by a neurological deficit. PMID- 27504326 TI - En-Plaque Central Nervous System Tuberculoma - An Uncommon Entity: Clinico Radiological Profile in a Cohort from a Tertiary Referral Centre. AB - INTRODUCTION: Case reports pertaining to Magnetic Resonance Imaging (MRI) diagnosis of en-plaque tuberculoma are limited. To the best of our knowledge, descriptions about en-plaque tuberculoma are limited to few isolated case reports. This paper comprehensively depicts the clinical and radiological features in such patients and may serve not to miss this uncommon manifestation of a common central nervous system infection. MATERIALS AND METHODS: A descriptive documentation of the patient cohort with a detailed history and neurological examination were carried out in all the patients. All underwent MRI Brain which revealed en-plaque tuberculoma. Relevant investigations including Cerebrospinal Fluid (CSF) were done in all patients. CSF Polymerase Chain Reaction (PCR) was done in all. RESULTS: Eight adult patients (two women and six men) with MRI showing en-plaque CNS tuberculoma were seen during a period of five years. None had suffered from TB in the past nor had history of contact with tuberculosis. All patients demonstrated extra axial dural based lesions and none had cerebral ooedema, parenchymal lesions, mass effect or midline shift. The lesions were located in bilateral corresponding regions in two patients and the rest six had unilateral lesions. Seven patients had lesions located in the supratentorial compartment; one had lesion extending to the infratentorium along the tentorium cerebelli. Various patterns of enhancement were noted in our patients: thin peripheral (n=3), homogenous (n=3), varied enhancement (n=1) and open ring enhancement (n=1). CSF Polymerase Chain Reaction (PCR) was tested positive for tuberculosis in all of our patients. CONCLUSION: While MRI provides an understanding of the topography of the lesion, PCR helped in establishing the diagnosis of tuberculosis in our patients. Awareness about en-plaque tuberculomas can heighten the index of suspicion and can thus prevent aggressive surgical resections and thereby reduce mortality and morbidity. PMID- 27504327 TI - Study of Aplastic Anaemia with Cyclosporine in Resource Poor Setting. AB - INTRODUCTION: Aplastic Anaemia (AA) is a syndrome characterized by peripheral pancytopenia with hypo-cellular marrow. Acquired idiopathic AA is the most common variety, probably of an autoimmune aetiology. Bone Marrow Transplantation (BMT) is the treatment of choice but cost is the limiting factor. Antithymocyte Globulin and Cyclosporine-A is an alternative to BMT. Cyclosporine alone has been tried as a single agent in resource poor setting. AIM: The study was conducted with the aim to observe the treatment response in aplastic anaemia to Cycloserine A. MATERIALS AND METHODS: Patients who were diagnosed as AA and opted for Cyclosporine with informed consent were included in the study. All the subjects were started on 5mg/kg of Cyclosporine and were followed up for three months to see the treatment response. This study had the approval from IEC. RESULTS: Twenty patients were enrolled in the study. Age of the patients ranged from 10 to 65 years. Maximum number (10/20) of patients was in the 2(nd) decade. Most of the patients presented with mucosal bleeds and breathlessness on exertion; the predominant sign was pallor. Eleven patients had severe AA, eight had non severe and one had very severe anaemia. Out of 20, three patients were lost to follow-up and one patient discontinued therapy due to renal dysfunction; finally sixteen patients' data was analysed. Out of 16 patients, 9 responded was and 7 did not respond. Complete response was observed in three patients, partial response in six patients. Seven patients had drug toxicity in the form of acute renal failure and gum hypertrophy. CONCLUSION: Cyclosporine seems to be a reasonable therapeutic option with good response rate and minimal side effects. PMID- 27504328 TI - Fertility Desires and Intentions among People Living with HIV/AIDS (PLWHA) in Southern India. AB - INTRODUCTION: The desire of people living with HIV/AIDS (PLWHA) to have children can have significant public health implications. Combination Antiretroviral Therapy (cART) has increased the life expectancy of PLWHA as a result of which they may consider child bearing. There are hardly any studies from India addressing the fertility desires among PLWHA. AIM: This study was done to assess the fertility desires of PLWHA in Southern India. MATERIALS AND METHODS: It was a cross-sectional study conducted among 230 HIV-positive men and women who presented to Kasturba Medical College (KMC), Mangalore, India. Study was conducted between October 2012 and October 2014. Statistical analysis was performed using SPSS software version 11.5. Chi-square test, Fisher's exact test and student t-test was used to find out the association of various factors affecting fertility desire. A p-value of less than 0.05 was considered statistically significant. RESULTS: The mean age of our study population was 36.3+/-5.5 years. The mean age of males was 37.3+/-6 years and for female 34.9+/ 5 years. In our study 132 (57.4%) were males. Majority were literate 229 (99%). Majority of patients were employed 166 (72%). In our study 195 (84.7%) were on cART. Out of 230 PLWHA 39 (16.95%) were unmarried and 151(65.5%) married PLHIV were living with partners at the time of study. In our study 77 (33.5%) patients had fertility desire. Age, gender, marital status, number of children, partner's fertility desire and HIV status of partner had an association with fertility desire. CONCLUSION: Providing universal access to cART is the main aim of national programs. It is high time that these programs focus on fertility issues of PLWHA. Reproductive rights of PLWHA need to be respected. Physicians and HIV counselors should proactively discuss and address reproductive issues of PLWHA. PMID- 27504329 TI - The Ultrasonographic Determination of the Position of the Mental Foramen and its Relation to the Mandibular Premolar Teeth. AB - INTRODUCTION: The position of the mental foramen has been well researched in cadaver specimens, radiographically as well as intraoperatively. To our knowledge, this landmark study is the first to make use of ultrasonography in a study population to determine the position of the mental foramen in relation to the mandibular premolar teeth. Ultrasonography has great potential to further revolutionize the practice of medicine and dento-maxillofacial surgery. AIM: To make use of ultrasound to determine the position of the mental foramen and its relation to the mandibular premolar teeth. MATERIALS AND METHODS: One hundred Black and Caucasian subjects were enrolled. A high frequency (8MHz) transducer (PLF.805ST) of a diagnostic ultrasound system (model SSA-510A) was applied above the inferior border of the mandible, just lateral to the mentum. With the marker of the transducer pointing cranially, the position of the mental foramen in relation to the closest mandibular premolar tooth was determined. The position was compared across race, sex and age groups. RESULTS: All mental foramina (100%) were visualised. Overall the most frequent position of the mental foramen was in line with the long axis of the second premolar on the right (44%) and between the first and second premolars on the left (44%). There were no statistical differences (p >0.05) between race groups, sex and age groups with regard to the position of the mental foramen in relation to the mandibular premolars. However, in Blacks, the most frequent position of the mental foramen was in line with the long axis of the second premolar and in Caucasians the most common position was between the first and second premolars. The most frequent position of the mental foramen in females was in line with the long axis of the second premolar on the right and between the first and second premolars on the left. In males, the most frequent position of the mental foramen was in line with the long axis of the second premolar bilaterally. The most common position of the mental foramen in the age group category 18-30 years was between the first and second premolars. In patients aged 31-60 years the most frequent position was in line with the long axis of the second premolar. CONCLUSION: Ultrasound is a sensitive modality to locate the mental foramen. There are differences in the most common position of the mental foramen with regard to the long axis of the premolar teeth. Ultrasonography has the potential to revolutionize the practice of dento maxillofacial surgery. PMID- 27504330 TI - A Therapeutic Effects of Atorvastatin on Genetic Damage in Coronary Artery Disease. AB - INTRODUCTION: Coronary Artery Disease (CAD) a multifactorial chronic heart disease and the most frequent cause of death and disabling symptoms worldwide, occurs due to the formation of atheromatous lipid rich plaques in the arteries. Statins, which inhibit cholesterol biosynthesis, have both pleiotropic and Low Density Lipoprotein (LDL)-lowering properties. Atorvastatin is one of the choices for the primary and secondary prevention of cardiovascular disease and management of hypercholesterolaemia. However, there is a paucity of data regarding the changes in the DNA damage in patients with coronary atherosclerosis after statin use. AIM: The aim of the present study was to evaluate atorvastatin treatment efficacy on lipid profiles and DNA damage in CAD patients. MATERIALS AND METHODS: The current observational study was conducted on 180 CAD patients between November 2011 to December 2013 at Durgabai Deshmukh Hospital and Research Centre, Vidya Nagar, Hyderabad, India. Atorvastatin administered and blood samples were collected at index hospitalization and after 6 months statin therapy and lipid profiles and DNA damage was compared with 200 healthy control. RESULTS: Lipid profiles and DNA damage were found to be significantly high (p < 0.01) in CAD patients before atorvastatin therapy compared to after 6 months statin therapy and healthy controls. CONCLUSION: The study suggests that atorvastatin might help in regression of lipid profile as well as DNA damage of CAD patients. PMID- 27504331 TI - Factors Contributing Towards Poor Asthma Control in Patients on Regular Medication. AB - INTRODUCTION: In-spite of the availability of effective medications, it is observed that patients with bronchial asthma on treatment are poorly controlled. An objective evaluation of asthma control especially with respect to inflammation and the factors contributing towards poor control is crucial in obtaining relief of symptoms. AIM: 1) To measure the asthma control using modified Mini Asthma Quality Of Life Questionnaire (MAQOL) and sputum eosinophil count; 2) To identify the role of factors viz. age, duration of asthma, severity, compliance, technique of inhalation and knowledge of asthma action plan on asthma control. MATERIALS AND METHODS: Total 50 asthmatic patients on regular medication were included in the study after obtaining written informed consent. The asthma-control was evaluated based on history, clinical symptoms, need for short-acting bronchodilators, FEVs1 and sputum eosinophil count with the help of modified MAQOL. A global score of <80% was considered as poor control. The proportion of patients under each factor, in poorly-controlled group (PC) was compared with the well-controlled group (WC). The results were analysed using descriptive statistics and unpaired student's t-test. RESULTS: Of the total, 33 (66%) patients were in PC category with a mean global asthma score of 58.46 +/- 2.881 vs 85.2 +/- 1.19 in the WC group (34%) (p<0.05). The mean age in PC was 41.41 +/- 2.413 vs 29.00 +/- 2.157(p<0.05) in the WC. The mean duration of asthma was 16.76 +/- 2.761 in PC vs 7.882 +/- 2.065 years in WC (p<0.05). The severity score was 7.265 +/- 0.4434 in PC vs 6.706 +/- 0.64 in WC. Eight patients in PC and six in WC were unaware of the treatment plan. One in PC group and three in WC were unaware of technique of inhalation. One in PC group and three in WC were non compliant. Mean sputum eosinophil count was 7.441 +/- 1.081 in PC vs 5.176 +/- 1.201 in WC. CONCLUSION: MAQOL is useful in evaluating asthma-control. Sputum eosinophil count correlates with asthma-control. Duration of asthma, age and severity contributed significantly to the poor control of asthma. There is a need for an objective monitoring in asthma and the treatment strategies need to be modified accordingly. PMID- 27504332 TI - Benign Recurrent Intrahepatic Cholestasis in a Young Adult. AB - Benign Recurrent Intrahepatic Cholestasis (BRIC) is a rare genetic disorder characterized by recurrent episodes of cholestatic jaundice. The initial episode of jaundice generally occurs before second decade of life and can persist for several weeks to months before resolving spontaneously. It is a benign disease and even after repeated episodes of jaundice, fibrosis of liver cell does not occur. We had a young adult patient who was having recurrent episodes of cholestatic jaundice with intervening symptom free period for last 20 years. He had first episode of jaundice at the age of eight and since then had several similar episodes. Diagnosis was made by classical clinical presentation and histopathological findings. We intend to report this case due to rarity of this disease in India. PMID- 27504333 TI - Association of Systemic Lupus Erythematosus and Beta Thalassaemia Trait- A Case Report. AB - Systemic Lupus Erythematosus (SLE) is a multisystem chronic inflammatory disease of autoimmune aetiology. It has a predilection for female gender and presence of photosensitive rash over the sun exposed area gives a clue to the diagnosis. Diagnosis in a male patient with atypical manifestations is unusual and difficult. A 25-year-old male presented with fever, fatigue, vomiting, abdominal pain and loss of weight. He had sustained injury on his right arm following which he developed abscess at the trauma site and severe anaemia. Further evaluation revealed pancytopenia and peritonitis. Though peritonitis is rare in SLE, it was considered in the differential diagnosis after ruling out bacterial and tubercular peritonitis. Positive anti-dsDNA and antiSm antibodies confirmed the diagnosis. While evaluating for microcytic anaemia it was found that iron studies were normal and A2 fraction was raised in haemoglobin electrophoresis. The symptoms and laboratory parameters improved remarkably with steroid therapy. Beta thalassaemia trait is rare in patients with SLE, but when they co-exist the manifestations can be severe. High degree of suspicion is required to diagnose SLE in male patients in absence of typical photosensitive rash. Beta thalassaemia trait often does not require any treatment except genetic counseling. However empirical treatment with iron should be avoided. PMID- 27504334 TI - Herpes Zoster Infection Involving Mandibular Division of Trigeminal Nerve and Ramsay Hunt Syndrome with Meningitis in an Immunocompetent Patient: A Rare Association. AB - Herpes zoster is a unilateral painful vesicular cutaneous eruption caused by the reactivation of the Varicella zoster virus. It commonly affects the older people and immunocompromised individuals. The dermatomes from T3 to L3 are most frequently involved. Its three stages include prodromal stage, active stage and chronic stage. The common complications of the infection include post-herpetic neuralgia, Ramsay Hunt syndrome, Guillain-Barre syndrome, transverse myelitis and encephalomyelitis. This case report summarizes a very rare association of herpes zoster meningitis with the involvement of mandibular division of the trigeminal nerve and facial nerve. The patient improved with intravenous acyclovir and prednisolone treatment. PMID- 27504335 TI - Resistant Hypertension due to Fibromuscular Dysplasia in a Young Male: A Rare Case Report. AB - Fibromuscular Dysplasia (FMD) is a sporadic non-atherosclerotic disease. FMD has been established in nearly every arterial bed. However, the most frequent arteries affected are the renal and carotid arteries. Disease presentation may vary broadly, depending upon the arterial bed complication and the severity of illness. Hypertension, particularly resistant type, headache and dizziness are the most common presentations. String of beads appearance in angiographic views due to post-stenotic aneurysms is the characteristic view. It is most commonly described in young aged females; but in rare male cases has also been reported. Moreover, balloon angioplasty is standard and effective therapy for FMD. We present a young 28-year-old man who was referred for evaluation of resistant hypertension for nearly 3 years without comprehensive workup. The patient underwent renal artery angiography which confirmed beading narrowing of the right renal artery with significant stenosis at mid portion compatible with FMD; and balloon angioplasty was done. This case highlights that FMD should be kept in mind as a rare cause of resistant hypertension in young males; although it is most common in young females. PMID- 27504336 TI - ECMO Rescue Therapy in Diffuse Alveolar Haemorrhage: A Case Report with Review of Literature. AB - Extracorporeal Membrane Oxygenation (ECMO) has evolved as a treatment option for patients having potentially reversible severe respiratory failure who are deteriorating on conventional ventilation. During ECMO, systemic anticoagulation is needed to maintain patency of the circuit. Therefore, ongoing haemorrhage remains a relative contra-indication to ECMO as it can further increase the bleeding. There is only limited evidence available for the use of ECMO in patients with alveolar haemorrhage. Most of these patients did not receive any anticoagulation during ECMO. We describe our experience with a patient who received intravenous anticoagulation during ECMO for refractory hypoxemic respiratory failure due to Diffuse Alveolar Haemorrhage (DAH) associated with Granulomatosis polyangitis (Wegner's GPA). ECMO sustained life by maintaining gas exchange support and provided the time for the immunotherapy to be effective. We report the successful use of anticoagulation during ECMO in a patient with DAH. PMID- 27504337 TI - Sero-Negative Systemic Sclerosis: A Rare Presentation. AB - Systemic Sclerosis is a multisystem disease associated with progressive fibrosis of skin and internal organs. It is diagnosed by presence of characteristic clinical findings and is supported by specific serologic abnormalities. ANA is positive in case of systemic sclerosis in 90 percent of cases. We report a rare case of this rare disease where patient was ANA, Antitopoisomerase I (anti-Scl 70), Anticenteromere antibody negative. PMID- 27504338 TI - Acute Myocardial Infarction Following Blunt Chest Trauma and Coronary Artery Dissection. AB - Blunt chest traumatic coronary artery dissection is an uncommon cause of atherosclerotic and non-atherosclerotic Acute Myocardial Infarction (AMI). Injuries of the coronary artery after blunt chest trauma are caused by different mechanisms such as vascular spasm, dissection and intimal tear or rupture of an existing thrombus formation. Chest pain might be masked by other injuries in patients with multiple traumas in car accident. Present case report is on a 37 year-old male without any specific past medical history who reported to the emergency department of a hospital with chest discomfort and was discharged with the impression of chest wall pain. After three days he experienced severe chest pain and he was admitted with the impression of acute coronary syndrome and underwent coronary angiography which showed Left Anterior Descending (LAD) artery dissection. The possibility of injury of the coronary artery should be kept in mind after blunt trauma to the chest. This condition is sometimes underdiagnosed. Its diagnosis may be difficult because chest pain can be interpreted as being secondary to chest wall contusion or it may be overshadowed by other injuries. Coronary dissection diagnosis after chest trauma requires clinical suspicion and systematic evaluation. Electrocardiography (ECG) should be done for every patient with thoracic trauma as the clinical findings may be misleading. PMID- 27504339 TI - Systemic Sclerosis with Multiple Pulmonary Manifestations. AB - Systemic sclerosis (SSc) is a chronic autoimmune multisystem disorder characterized by endothelial dysfunction and fibroblast dysfunction, which results in progressive fibrosis of the skin and internal organs more frequently the lungs and gastro intestinal tract. Pulmonary involvement is common in the course of SSc, with Interstitial Lung Disease (ILD) and Pulmonary Arterial Hypertension (PAH) being the leading causes of death. Here we report, case of an elderly female patient presenting with Diffuse SSc with multiple uncommon pulmonary manifestations like ILD with Usual Interstitial Pneumonia (UIP) pattern (usually less common), PAH and right sided pleural effusion. PMID- 27504340 TI - Clinical and Neuroradiological Spectrum of Metronidazole Induced Encephalopathy: Our Experience and the Review of Literature. AB - Metronidazole is an antimicrobial agent mainly used in the treatment of several protozoal and anaerobic infections, additionally, is often used in hepatic encephalopathy and Crohn disease. Apart from peripheral neuropathy, metronidazole can also cause symptoms of central nervous system dysfunction like ataxic gait, dysarthria, seizures, and encephalopathy which may result from both short term and chronic use of this drug and is collectively termed as "metronidazole induced encephalopathy"(MIE). Neuroimaging forms the backbone in clinching the diagnosis of this uncommon entity, especially in cases where there is high index of suspicion of intoxication. Although typical sites of involvement include cerebellum, brain stem and corpus callosum, however, lesions of other sites have also been reported. Once diagnosed, resolution of findings on Magnetic Resonance Imaging (MRI) of the Brain along with clinical improvement remains the mainstay of monitoring. Here we review the key clinical features and MRI findings of MIE as reported in medical literature. We also analyze implication of use of this drug in special situations like hepatic encephalopathy and brain abscess and discuss our experience regarding this entity. PMID- 27504341 TI - Differences in Bacterial Colonization and Biofilm Formation Property of Uropathogens between the Two most Commonly used Indwelling Urinary Catheters. AB - INTRODUCTION: Catheter Associated Urinary Tract Infections (CAUTI) are one of the most common cause of nosocomial infections. Many bacterial species show biofilm production, which provides survival benefit to them by providing protection from environmental stresses and causing decreased susceptibility to antimicrobial agents. Two most common types of catheters used in our setup are pure silicone catheter and silicone coated latex catheter. The advantage of pure silicone catheter for long term catheterization is well established. But there is still a controversy about any advantage of the silicone catheter regarding bacterial colonization rates and their biofilm production property. AIMS: The aim of our study was to compare the bacterial colonization and the biofilm formation property of the colonizing bacteria in patients with indwelling pure silicone and silicone coated latex catheters. MATERIALS AND METHODS: This prospective observational study was conducted in the Urology Department of our institute. Patients who needed catheterization for more than 5 days during the period July 2015 to January 2016 and had sterile precatheterisation urine were included in the study. Patients were grouped into 2 groups of 50 patients each, Group A with the pure silicone catheter and Group B with the silicone coated latex catheter. Urine culture was done on the 6(th) day of indwelling urinary catheter drainage. If growth was detected, then that bacterium was tested for biofilm production property by tissue culture plate method. STATISTICAL ANALYSIS: Statistical analyses were performed using the Statistical Package for the Social Science Version 22 (SPSS-22). RESULTS: After 5 days of indwelling catheterization, the pure silicone catheter had significantly less bacterial colonization than the silicone coated latex catheter (p-value=0.03) and the biofilm forming property of colonizing bacteria was also significantly less in the pure silicone catheter as compared to the silicone coated latex catheter (p-value=0.02). There were no significant differences in the colonizing bacteria in the 2 groups. In both the groups the most common bacteria were Escherichia coli. CONCLUSION: The pure silicone catheter is advantageous over the silicone coated latex catheter in terms of incidence of bacterial colonization as well as the biofilm formation and hence in the management of CAUTI. PMID- 27504342 TI - Total Thyroidectomy for Benign Thyroid Diseases: What is the Price to be Paid? AB - INTRODUCTION: Total thyroidectomy has been used to treat patients with malignant thyroid disease. But for patients with benign thyroid disease, the safety and efficacy of total thyroidectomy is a matter of debate. Subtotal thyroidectomy that was previously the treatment of choice for benign thyroid disease has been associated with high recurrence rates. The risk of permanent complications is greatly increased in patients who undergo surgery for recurrence of benign thyroid disease. Total thyroidectomy is an operation that can be safely performed, with low incidence of permanent complications, which allows one to broaden its indications in various benign thyroid diseases, thus avoiding future recurrences and reoperations. AIM: To assess the benefits of total thyroidectomy for benign thyroid diseases. MATERIALS AND METHODS: This randomized prospective study was conducted between Feb 2013 and Nov 2014 in the Department of General Surgery at Bangalore Medical College and Research Institute. It included 116 patients undergoing total thyroidectomy procedure for benign thyroid disease. All cases were followed-up for a period of 6 months for incidence of RLN palsy, hypoparathyroidism, disease recurrence and number of incidental malignancies detected on postoperative histological analyses of the thyroid specimens. RESULTS: Most of the patients were in the third decade of their lives. The female to male ratio was 6.7:1. Total thyroidectomy was done for 116 benign thyroid diseases with multinodular goiter as the most common diagnosis. The incidence of postoperative hypocalcaemia was 16.37% (however, only 1 patient developed permanent hypocalcaemia) and that of wound infection was 2.58% and seroma formation was 2.58%. None of the patients included in this study had haematoma formation or RLN paralysis. An incidental malignancy was identified in 11.20% patients. CONCLUSION: Total thyroidectomy shows benefits in eradicating multinodular goiter, alleviating Grave's opthalmopathy, treating Hashimoto's thyroiditis and preventing recurrence. It decreases the likelihood of future operations for recurrent disease or completion thyroidectomy for incidental thyroid cancer thus decreasing the associated risks of increased morbidity associated with second operation. Therefore, for benign thyroid diseases requiring surgical management total thyroidectomy can be considered the treatment of choice. PMID- 27504343 TI - Effect of Lump Size and Nodal Status on Prognosis in Invasive Breast Cancer: Experience from Rural India. AB - INTRODUCTION: Breast cancer is now the leading cause of cancer among Indian women. Usually large tumour size and axillary lymph node involvement are linked with adverse outcome and this notion forms the basis of screening programs i.e. early detection. AIM: The present study was carried out to analyse relationship between tumour size, lymph node status and there relation with outcome after treatment. MATERIALS AND METHODS: Fifty patients with cytology-proven invasive breast tumours were evaluated for size, clinical and pathologic characteristics of tumour, axillary lymph node status and outcome data recorded on sequential follow-up. RESULTS: Mean age of all participated patients was 52.24+/-10 years. Most common tumour location was in the upper outer quadrant with mean size of primary tumour being 3.31+/-1.80cm. On pathology number of lymph nodes examined ranged from 10 to 24 and 72% of patients recorded presence of disease in axilla. Significant positive correlation (p<0.013; r(2)=0.026) between tumour size and axillary lymph node involvement on linear regression. Also an indicative correlation between size and grade of tumour and axillary lymph node status was found with survival from the disease. CONCLUSION: The present study highlights that the size of the primary tumour and the number of positive lymph nodes have an inverse linear relationship with prognosis. Despite advances in diagnostic modalities, evolution of newer markers and genetic typing both size of tumour as T and axillary lymphadenopathy as N form an integral part of TNM staging and are of paramount importance for their role in treatment decisions and illustrate prognosis in patients with invasive breast cancer. PMID- 27504344 TI - Changing Trends of Skin Cancer: A Tertiary Care Hospital Study in Malwa Region of Punjab. AB - INTRODUCTION: Skin cancer constitutes a small but significant proportion of patients with cancer. Although the presence of eumelanin in dark skin is protective against the development of skin cancer, it is increasingly being diagnosed in the Indian population. AIM: To study the profile of skin cancer patients presenting to a tertiary hospital in Malwa area of Punjab, India. MATERIALS AND METHODS: Retrospective study was done to analyse the profile of skin cancer patients who attended the institution over one year from 1(st) December 2013 to 30(th) November 2014. A comprehensive review of aetiology and related risk factors was done to correlate the environmental factors with high skin cancer prevalence in this region. RESULTS: Skin cancer constituted (3.18%) 84 out of 2638 patients registered with cancer of all types. The age of the patients was 62+/-14.2 years and ranged from 27 to 92 yrs. Basal cell carcinoma (BCC) was the most common histological type(46/84, 54.76%) followed by squamous cell carcinoma (SCC) (31/84, 36.91%) and malignant melanoma (MM) (7/84, 8.33%). Male: female ratio was found to be 0.79:1. BCC showed higher female preponderance (p<0.05). Head and Neck was the commonest site involved (p<0.05). Majority (88%) of patients were from rural area. 92% of patients were directly into the profession of agriculture with history of prolonged exposure to sunlight. CONCLUSION: Skin cancer constitutes a small but significant proportion of patients with cancers. This study highlights a paradoxically increasing trend of BCC and female preponderance. Head and neck is the most common site involved. Exposure to Ultra Violet B (UVB) radiation and higher levels of arsenic in drinking water has been reported to be associated with skin cancers. Limited studies show that levels of arsenic and pesticides were higher in the samples of drinking water in Malwa area of Punjab. Therefore a multipronged strategy to provide safe drinking water supply and discouraging the indiscriminate use of pesticides is recommended. PMID- 27504345 TI - 'Ubiquitous' Tumour Elsewhere, But Uncommon in the Colon! Can We Ignore this Lesion? AB - Lipoma, a benign tumour of mature fat cells, can occur anywhere in the body and hence termed 'ubiquitous tumour'. But it rarely occurs in the colon and can present with complications and mimic malignancy. We present a case of descending colonic lipoma which led to a diagnostic dilemma. PMID- 27504346 TI - Case Report: Collision Tumour of Colon Leiomyosarcoma and Adenocarcinoma. AB - The colon is an exceedingly rare site of primary leiomyosarcoma and only a few cases have been published to date. Of the reported cases of collision tumours, collision tumours that specifically occurred in the colon have consisted of combinations of adenoma or adenocarcinoma with lymphomas or neuroendocrine tumours. Here, not only do we report a case of colon leiomyosarcoma, but we report, what is to our knowledge, the first case of collision tumour consisting of colon leiomyosarcoma and adenocarcinoma. Cause, prognosis, and treatment of colon collision tumours vary and are yet to be understood. PMID- 27504347 TI - Scalp Haematoma in Cerebral Palsy Case due to Unknown Cause - A Rare Case Report. AB - Incidences of cerebral palsy (CP) in children are not quite common even though it is the most common motor disorder in children. Further quality of life in CP cases is not so good in young adult stages and has to face certain problems. However scalp haematoma formation in CP patient without injury to head is rarely been reported. The case is being reported for the first time from Malaysia. We report on a unique case of scalp haematoma in an 18-year-old girl of known CP patient with unknown cause. No history of trauma or fall with any of the focal neurological signs or symptoms was found. Clinical examination showed soft boggy swelling of 8 x 10 cm size, involving most of scalp and upper face. CT - scan showed scalp haematoma with right orbital extraconal lesion. She underwent incision and drainage of scalp lesion; consequently around 100 ml of clotted blood came out. At follow-up she was doing well. PMID- 27504348 TI - Dilatation of the Proximal Cystic Duct: Is It a Variant to "Type VI" Choledochal Cyst? AB - Choledochal cysts are rare congenital malformations, comprising of dilatation of the biliary tree of different localization. Classically, classification of choledochal cysts describes five variants of the disease. Type VI choledochal cyst is considered by many authors as the sixth variant of this classification and is described either as a dilatation of the cystic duct or as a cystic duct cyst. We present a rare case of cystic duct dilatation that presented with acute cholangiopancreatitis and a clinical picture consistent of a choledochal cyst in a 10-year-old female patient. Cholecystectomy with excision of the cystic duct was performed. Histopathologic examination did not reveal any findings consistent with choledochal cyst. Based on these findings we speculate that in our case the dilatation of the cystic duct is a variant to type VI choledochal cyst, based on the fact that no cystic-like malformation has been identified in histology. We provide details of the pre-operative work-up and compare them with intraoperative findings in order to increase awareness of the condition. PMID- 27504349 TI - Diagnostic Dilemma in a Thyroid Incidentaloma: Second Primary versus Metastatic Nodule? AB - With the increasing use of 18F-Fluro-Deoxyglucose (FDG) Positron Emission Tomography (PET) the number of thyroid incidentalomas is on the rise. Focal thyroid incidentalomas identified by FDG-PET have been reported to have a high incidence of malignancy. Neuroendocrine tumours of the thyroid are rare entities. The most common neuroendocrine tumour of the thyroid is medullary carcinoma. A thyroid nodule in a patient with a known neuroendocrine tumour must be differentiated from a primary medullary carcinoma which can present as a diagnostic challenge to the clinician. A 65-year-old female patient was referred for thyroidectomy for a FNAC diagnosed follicular neoplasm of the left lobe of the thyroid, detected on FDG PET follow up. She was a known case of neuroendocrine tumour of the pancreas with no features suggestive of familial Multiple Endocrine Neoplasia (MEN) syndrome. The patient had undergone Whipple's procedure elsewhere, 5 years back. Following total thyroidectomy, the final histopathology report was suggestive of a primary neuroendocrine tumour. We present this case to highlight the clinical dilemma in diagnosing a thyroid incidentaloma as a second primary neuroendocrine tumour versus a solitary metastatic nodule in the background of metastatic gastroentero pancreatic neuroendocrine tumour. Although clinically, a metastatic nodule should have been the obvious diagnosis, the histopathological and immunohistochemical features were in favour of a primary non-medullary Neuroendocrine Tumor (NET) of the thyroid. PMID- 27504350 TI - Giant Intramuscular Nodular Fasciitis Masquerading as Soft Tissue Sarcoma with Neural Involvement - A Case Report. AB - Nodular Fasciitis (NF) is described as a benign reactive proliferation of myofibroblasts that occurs predominantly in the subcutaneous location. Most commonly presents as rapidly growing swelling in the young adults, with usual size of less than 4cm and located commonly in the extremities. We hereby report a case of giant nodular fasciitis of 10cm diameter which presented in an unusual location (gluteal region) and rare plane of origin (intramuscular) with unusual symptom of sciatic nerve involvement. Because of the size, location and neural involvement a clinical diagnosis of soft tissue sarcoma was made. After investigating with trucut biopsy and magnetic resonance imaging, benign nature of the lesion confirmed and treated with complete excision, carefully preserving the sciatic nerve. This case is presented for its rarity in size, location, plane of origin and neural compression. To the best of our knowledge this is the first case of nodular fasciitis of 10cm size and in the gluteal muscles. PMID- 27504351 TI - Sebaceous Gland Carcinoma of the Lower Eyelid Reconstructed with a Composite Flap: A Case Report. AB - Sebaceous gland carcinomas are skin adnexal tumours occurring in the periocular region of elderly females. It is an uncommon malignancy usually involving the upper eyelid and has an indolent course. Mainstay of treatment is surgical excision. Here we present a case of a sebaceous gland carcinoma of the lower eyelid for which wide local excision was done and the lower eyelid reconstructed using a composite flap of nasal chondromucosal graft with a nasolabial flap. PMID- 27504352 TI - First Branchial Arch Fistula: A Rarity and a Surgical Challenge. AB - Although 2(nd) Branchial arch fistulae (from incomplete closure of Cervical sinus of His) are well known, 1(st) arch fistulae are much rarer (<10%) and are usually not tackled comprehensively. We present a case of a rare first branchial arch fistula of the type II Arnot classification, which presented with two external openings of more than 20 years duration. Patient had a successful resection of all the concerned fistulous tract. Review of literature and the surgical challenges of the procedure are presented herewith. PMID- 27504353 TI - Video Assisted Thoracoscopic Surgery (VATS) for Excision of an Ectopic Anterior Mediastinal Intra-Thymic Parathyroid Adenoma. AB - Ectopic anterior mediastinal parathyroid adenoma is a rare cause of Primary Hyperparathyroidism (PHPT). Imaging studies such as Technetium-99m ((99m)Tc) sestamibi parathyroid scan along with a Single Photon Emission Computerized Tomogram (SPECT), and contrast enhanced Computerized Tomogram (CT) of the neck and thorax can precisely localize the ectopic mediastinal parathyroid adenoma. We report a 40-year-old gentleman who presented with persistent pain in the right shoulder following trivial trauma. His biochemical investigations showed an elevated serum calcium of 11.6mg% (Normal: 8.3-10.4 mg%) along with an elevated iPTH of 1443 pg/ml (normal: 8-70 pg/ml) which were suggestive of primary hyperparathyroidism. The localization studies revealed an ectopic cystic parathyroid adenoma in the anterior mediastinum that was not accessible from the neck. He underwent a Video Assisted Thoracoscopic (VAT) excision procedure with normalization of serum calcium and an uncomplicated recovery. The VAT approach is a successful minimally invasive technique for mediastinal parathyroidectomy. PMID- 27504354 TI - Successful Resuscitation of a Cardiac Arrest following Slit Neck and Carotid Artery Injury: A Case Report. AB - Carotid artery injuries constitute a specific and relatively small group of vascular trauma among the traumatic injuries to neck. They have the potential of killing the patients within minutes to hours due to haemodynamic instability if not managed by the specialist team within time. Central Neurologic deficit from cerebral hypoxia either resulting primarily from trauma or secondarily from surgery is a major concern. We hereby present a case of a 22-year-old man who presented to emergency department with alleged assault and vascular trauma to neck in a state of cardiac arrest. On exploration patient had injuries to external and internal carotid arteries and external jugular vein. Combined effort of trauma team lead to successful resuscitation and saved the life of the patient. PMID- 27504355 TI - A Rare Case Report of Inguinal Hernia with Persistent Mullerian Duct and Klinefelter Syndrome. AB - Inguinal hernia in male is a common problem but having female reproductive organs in hernial sac is rare. It occur because of failure of mullerian duct to regress in a male fetus during embryonic development, result in a syndrome known as Persistent Mullerian Duct Syndrome (PMDS), which is a rare entity of male pseudohermaphroditism. We hereby present a case of 21-year-old male patient reported with complains of cryptorchidism and inguinal hernia. Generally diagnosis of PMDS was established during investigation like ultrasonography, MRI for localization of undescended testis and during surgical exploration for inguinal hernia or cryptorchidism. Our patient was operated by bilateral inguinal incision; hernial sac contained adult size uterus fallopian tube and upper 2/3(rd) of vagina. On karyotyping it was found that he was a case of klinefelter syndrome also. Association of PMDS with klinefelter syndrome is very rare. PMID- 27504356 TI - Rare Undifferentiated Tumour of Thyroid: Primary Thyroid Fibrosarcoma. AB - Primary thyroid fibrosarcoma cases are very rare. Although it is a known fact that soft tissue sarcomas show slow growth, there have been some cases in literature similar to our case in which there was a fast-growing tumour tissue causing breathing and swallowing difficulties due to painless pressure. For diagnosis, there is no specific clinical or radiological finding. We report a 67 year-old male with a mobile fast-growing mass covering almost all over the neck that appeared 2 months prior to the admission. Laboratory findings showed that the patient was euthyroid. Fine needle aspiration biopsy results are consistent with suspicion of a mesenchymal, histiocytic, epithelial or lymphoid tissue origined malignancy. Patient was taken into surgical operation. The thyroid tissue invaded the main vascular structure, trachea and esophagus. Due to this situation R1 resection was applied. Immunohistopathological examination showed a conventional type of fibrosarcoma. After the surgery, radiotherapy and chemotherapy had been planned and applied. Patients died before the radiotherapy sessions ended. It should be kept in mind that a rapid growth in thyroid tissue can be thyroid fibrosarcoma, there could be a rapid clinical course and poor prognosis after operation. PMID- 27504357 TI - Clinical Study of Endometrial Polyp and Role of Diagnostic Hysteroscopy and Blind Avulsion of Polyp. AB - INTRODUCTION: Endometrial polyp is one of the common causes of Abnormal Uterine Bleeding (AUB) in the reproductive age group as well as postmenopausal age group. AIM: To study the clinical features of endometrial polyp and the safety and feasibility of blind polypectomy following diagnostic hysteroscopy. MATERIALS AND METHODS: Total of 256 women who were diagnosed to have endometrial polyp by transvaginal ultrasound and underwent diagnostic hysteroscopy and blind polypectomy by simple avulsion in the period of January 2008 to December 2014 were included in our study. Polyp was confirmed by the histopathology. RESULTS: The prevalence of polyp among women who underwent diagnostic hysteroscopy and blind polypectomy was more common in the age group of 40-49years. Polyps manifested as AUB in 45.6% of our study population. The mean size of the polyp was not significantly different between premenopausal and postmenopausal women and single and multiple polyps. Histopathological study of the polyp showed two malignant polyps in our study population. Premalignant lesions i.e., endometrial hyperplasia without atypia and with atypia was found in 33 women. There was one uterine perforation, one cervical tear; one false passage and one patient had mild bleeding after the procedure. In our study, in the mean follow-up period of 37.57+/-28.12 months, 3.9% (7 women) had recurrence. In the follow-up period of 16.56+/-18.96 months, 78.9% women didn't have recurrence. CONCLUSION: Diagnostic hysteroscopy and blind polypectomy has low complication rate and recurrence rate and technically feasible for the practicing gynaecologists which don't need much training and is cost-effective also. PMID- 27504358 TI - Association of Intrauterine Device (IUD) and Cervical Neoplasia - A Study in a Poor Nigerian Population. AB - INTRODUCTION: Intrauterine Device (IUD) is a contraceptive method used by women of reproductive age group. However, there are conflicting reports on the association between IUD and cervical neoplasia. These controversies may further hamper the poor uptake of modern contraception in Nigeria. AIM: This study was therefore aimed at evaluating the association between IUD and cervical neoplasia. MATERIALS AND METHODS: This was a case control study in which Pap smear results of 156 participants on IUD were compared with those of 156 non-users of modern contraception. The participants who were found to have abnormal cervical smear cytology results were further subjected to colposcopy. Biopsy specimens for histology were collected from the participants with obvious cervical lesions or those with suspicious lesions on colposcopy. The results were analysed with descriptive and inferential statistics at 95% level of confidence. RESULTS: Seven (4.5%) and 2(1.3%) of participants using IUD had Cervical Intraepithelial Neoplasia (CIN) 1 and CIN 2 respectively. Also, 5(3.2%) and 1(0.6%) of non-users of modern contraception had CIN 1 and CIN 2 respectively. The prevalence of cervical neoplasia among all the participants was 4.8%. Although, the proportion of women who had CIN was more among participants using IUD than non-users of modern contraception, the difference was not statistically significant. CONCLUSION: There was no significant association between IUD and cervical neoplasia in this study. PMID- 27504359 TI - Intracranial Tuberculoma Presenting as Atypical Eclampsia: A Case Report. AB - Occurrence of eclampsia before 20 weeks of pregnancy and after 48 hours of delivery in the absence of typical signs of hypertension and or proteinuria is termed as atypical eclampsia. Atypical or non-classic eclampsia will have some symptoms of eclampsia but without the usual proteinuria or hypertension. All patients with atypical onset should undergo neurological evaluation to rule out neurologic causes of seizures. Cerebral tuberculosis is a rare and serious form of disease secondary to haematogenous spread of Mycobacterium tuberculosis. Here we present a case of cerebral tuberculoma with seizures in late pregnancy mimicking eclampsia. PMID- 27504360 TI - Prospective Randomized Study of Oral Diazepam and Baclofen on Spasticity in Cerebral Palsy. AB - INTRODUCTION: Spastic cerebral palsy (CP) is the most common form of CP. Diazepam and Baclofen are the most commonly used oral drugs to manage spasticity. Study was designed to evaluate and compare their effects and safety in CP children. AIM: Study was aimed to assess and compare outcome of oral Diazepam and Baclofen in spastic cerebral palsy children in terms of extent of reduction of spasticity and side effects profile. MATERIALS AND METHODS: Randomized prospective follow-up study was done for one year after giving Diazepam and Baclofen in weekly incremental doses upto recommended maximum dose to 60 children for three months. Two primary outcome measures were spasticity reduction and adverse effect profile. Spasticity reduction was measured by Modified Ashworth's Scale (MAS) and Range of Motion improvement (ROM). RESULTS: After random allocation, there was no baseline difference between groups. Mean MAS score improved from 1.96+/-0.4 at baseline to 1.63+/-0.40 and 1.41+/- 0.36 at 1 month and 3 months for Diazepam and from 1.84+/-0.64 to 1.57+/-0.59 and 1.31+/- 0.48 respectively for Baclofen. Within the group reduction was significant with p-value = 0.0001. Intergroup comparison showed no statistically significant difference with p-value of 0.48 and 0.22 at 1 and 3 months. Baseline ROM showed significant improvement at 1 and 3 months with p value of 0.004 and 0.001 for Diazepam and 0.01 and 0.000 for Baclofen respectively with no statistically significant difference among two groups. Drowsiness was most common observed side effect in both the groups. CONCLUSION: Patients showed significant improvement in spasticity as measured by Mean MAS score and range of motion in Diazepam as well as Baclofen group. Both drugs were found safe for use in children. Study couldn't establish any difference between the two drugs. However studies with bigger sample size and longer follow- up assessing functional improvement in patients will be required in near future. PMID- 27504361 TI - The Effect of Some Polymorphisms in Vitamin D Receptor Gene in Menopausal Women with Osteoporosis. AB - INTRODUCTION: Vitamin D receptor gene is one of candidate genes related to osteoporosis expansion. The association of ApaI, TaqI, BsmI polymorphisms in vitamin D receptor gene with bone metabolism and density has been area of interest in many studies. AIM: This study was conducted to further investigate the association between the ApaI, TaqI, BsmI polymorphisms and bone density. This study was analytical study. Centers for bone density measurement in southwestern Iran. MATERIALS AND METHODS: In this analytical study, 200 participants aged 45- and above 45-year-old women referring the centers of bone density measurement participated. The bone density of femoral neck and lumbar vertebrae was measured using dual-energy X-ray absorptiometry method. Based on t-score, the participants were assigned into patients (n=130) and healthy individuals (n=70). Different genotypes of ApaI (AA/Aa/aa), TaqI (TT/Tt/tt), and BsmI (BB/Bb/bb) were determined by PCR-RFLP. The data on bone density and PCR-RFLP were analysed by chi-square and ANOVA. Also, triad combination of the genotypes was statistically analysed. For each genotype combination, chi-square was run between the patients and control group and p-value was calculated. RESULTS: No significant association was seen between ApaI polymorphism and bone density (p>0.05). TaqI and BsmI polymorphisms had a significant association with femoral neck's bone density (p<0.05), but these polymorphisms were not significantly associated with lumbar vertebrae's (p>0.05). Patients with homozygous dominant TT genotype had the least bone density in femoral neck compared to other genotypes. Lumbar vertebrae's bone density was similar in three TaqI genotypes. The patients with homozygous recessive bb genotype had the least bone density in femoral neck and lumbar vertebrae compared to other genotypes. CONCLUSION: TaqI and BsmI polymorphisms could be desirable markers in diagnosis of women at risk of osteoporosis in the studied region in Iran. Therefore, these women will receive suitable medical treatment at proper time. PMID- 27504362 TI - An Innovative Method of Assessing the Mechanical Axis Deviation in the Lower Limb in Standing Position. AB - INTRODUCTION: Various methods of measuring mechanical axis deviation of lower limb have been described including radiographic and CT scanogram, intraoperative fluoroscopy with the use of an electrocautery cord. These methods determine the mechanical axis in a supine, non-weight bearing position. Although long cassette standing radiographic view is used for the purpose but is not available at most centres. A dynamic method of determining the mechanical axis in a weight bearing position was devised in this study. AIM: The aim of the study was to describe a simpler and newer method in quantifying the mechanical axis deviation in places where full length cassettes for standing X rays are not available. MATERIALS AND METHODS: A pilot study was conducted on 15 patients. The deviation from the mechanical axis was measured using a manually operated, hydraulic mechanism based, elevating scissor lift table. Patient was asked to stand erect over the elevating lift table with both patellae facing forward and C-arm image intensifier was positioned horizontally. Radiological markers were tied to a radio-opaque thread and placed at the centre of head of the femur and another at the centre of the tibio-talar joint. C-arm views of the hip, ankle and knee joint were taken to confirm the correct position of the marker by varying the height of the lift table. RESULTS: The mechanical axis deviation values were recorded by measuring distance between the centre of the knee and radio-opaque thread in cm. This was measured in each case both clinically and from the image on the monitor. The two values were found to be statistically same. Pain was measured on VAS. Mechanical axis deviation values and VAS score were found to be positively significantly correlated. CONCLUSION: This technique is dynamic, unique and accurate as compared to other methods for assessing mechanical axis deviation in a weight bearing position. PMID- 27504363 TI - Solitary Fibrous Tumour of the Clavicle: A Rare Case Report. AB - A Solitary Fibrous Tumour (SFT) is the preferred term by most of the pathologists than "haemangiopericytoma". SFT is a heterogeneous group of benign and malignant neoplasms along a morphologic continuum. Here we report a case of SFT of the clavicle in a 26-year-old male patient, who presented to us with complaints of pain and swelling over the dominant shoulder. No signs of metastasis were noted clinically and radiologically. He underwent surgical resection of swelling. At 6 months after resection and after 22 cycles of radiotherapy, he was noted to have excellent prognosis with satisfactory shoulder function. PMID- 27504364 TI - Deep Soft Tissue Leiomyoma of Forearm: A Case Report and Review of Literature. AB - Leiomyomas are benign tumours of smooth-muscle origin representing 4.4% of all benign soft-tissue neoplasms. They are classified as cutaneous, vascular and leiomyomas of deep soft tissues. Leiomyomas rarely occur in extremities and are more common in the lower limb than in the upper extremity. Deep soft tissue leiomyomas are even rare with a very few reported cases so far in the literature. A 25-year-old female presented to us with an atraumatic slowly enlarging mass in the right forearm from 6 months with mild erosion of cortex of radius. She was otherwise healthy, MRI revealed a soft tissue lesion involving the interosseous space, isointense on T1, slightly hyperintense on T2 and hyperintense on STIR images. The tumour was excised intoto. The case is presented due to its rarity and the risk of tumor misdiagnosis. It should be considered in the differential diagnosis of any solitary painful slow growing mass of the extremities. If adequate margins are obtained recurrence of this tumour is very rare. PMID- 27504365 TI - Bilateral Clavicle Fractures: A Report of Three Cases. AB - Bilateral clavicle fractures are uncommonly reported in the literature with the incidence being less than 0.5% of all the clavicle fractures. Bilateral clavicle fractures are caused either by high-energy transfer of compression forces across both shoulder girdles or by a direct trauma to one clavicle followed by that to the other clavicle. These fractures could be missed due to their association with more severe chest injuries or a more symptomatically displaced fracture on one side or due to inadequate chest radiographs. We report three cases of traumatic bilateral clavicle fractures with three modes of injuries in different age groups. All the fractures were treated conservatively with good functional outcomes without any sequelae. Bilateral clavicle fractures should be actively sought by every trauma team with proper clinical examination and chest radiographs including both shoulder joints in high-energy trauma cases or with bilateral shoulder compression injuries. PMID- 27504366 TI - Skeletal Maturation and Mineralisation of Children with Moderate to Severe Spastic Quadriplegia. AB - INTRODUCTION: Diminished bone mineral density and delayed skeletal maturation are common in children with spastic quadriplegia. AIM: The purpose of our study was to evaluate the Bone Mineral Density (BMD) of children with moderate to severe spastic quadriplegia and its relationship with other variables like nutrition and growth. MATERIALS AND METHODS: This was a hospital based, cross- sectional, case control study. Forty-two (28 males, 14 females) children with spastic quadriplegia and 42 (24 males, 18 females) healthy children were included in the study. BMD of cases and control were measured by Dual Energy X-ray Absorptiometry (DEXA). Radiographs of left hand and wrist of cases and controls were taken and bone age was determined. RESULTS: BMD values of upper extremity, lower extremity, thoraco-lumbar spine and pelvis in cases were lower than those of controls (p <0.0001). In children with non severe malnutrition, 75% of the cases had lower bone age than chronological age, whereas all cases with severe malnutrition had lower bone age than chronological age. Step wise regression analysis showed that nutritional status independently contributed to lower BMD values but the BMD values did not correlate significantly with the use of anticonvulsant drugs and presence of physical therapy. CONCLUSION: Decreased BMD and delayed bone age is prevalent in children with spastic quadriplegia and nutritional status is an important contributing factor. PMID- 27504367 TI - Ventilator-Associated Pneumonia: Incidence, Risk Factors and Outcome in Paediatric Intensive Care Units at Cairo University Hospital. AB - INTRODUCTION: Ventilator-Associated Pneumonia (VAP) is a major cause of hospital morbidity, mortality and increased health care costs. Although the epidemiology, pathogenesis and outcome of VAP are well described in adults; few data exist regarding VAP in paediatric patients, especially in developing countries. AIM: To determine the incidence, risk factors and outcome of VAP in two Paediatric Intensive Care Units (PICUs) at Cairo University Hospital. MATERIALS AND METHODS: A total of 427 patients who received Mechanical Ventilation (MV) were included in this prospective study during the period from September 2014 till September 2015. Patients were observed daily till VAP occurrence, discharge from the unit or death, whichever came first. Demographic, clinical characteristics, laboratory results, radiographic and microbiological reports were recorded for all patients. RESULTS: Nearly 31% patients developed VAP among the entire cohort. The incidence density was 21.3 per 1000 ventilator days. The most frequently isolated organisms from VAP patients were Pseudomonas aeruginosa (47.7%), Acinetobacter (18.2%) and Methicillin-resistant Staphylococcus aureus (MRSA) (14.4%). VAP patients were significantly younger than non-VAP ones. The incidence of VAP in comatose patients and those with MOSF was significantly higher. Prior antibiotic use for > 48 h before MV, supine body positioning and reintubation were significantly associated with VAP. On multiple logistic regression analysis, MOSF; prior antibiotic use > 48h; reintubation; coma; and age remained independent predictors of VAP. Mortality rate among the VAP group was significantly higher compared to the non-VAP one (68.2% vs. 48.5%, p<0.001). Survival curve analysis showed a shorter median survival time in VAP patients. CONCLUSION: Identification of risk factors and outcome of VAP in PICUs may help in reducing the incidence and improving patients' outcomes. The incidence of VAP in this study was relatively high. The most prominent risk factors for occurrence of VAP were MOSF, prior antibiotic use for > 48 h before MV, reintubation, coma and age. Proper use of antibiotics before MV in PICUs is essential. Also, adequate training of nurses and strict supervision of infection control protocols are crucial. Lack of a gold standard for the diagnosis of VAP and difficulty in sampling procedures were among the study limitations. PMID- 27504369 TI - A Case Report of Childhood Recurrent Autoimmune Pancreatitis: A Rare Emerging Entity. AB - Autoimmune pancreatitis (AIP) is a rare entity in the paediatric population and its aetiology is unknown. Here, we report a 10-year-old girl with recurrent abdominal pain. A diagnosis of AIP was made based on elevated pancreatic enzymes, elevated IgG 4 and image findings. She responded to corticosteroid treatment. AIP should be considered in the differential diagnosis of recurrent pancreatitis. Correct diagnosis can help avert the consequences of progressive disease and unnecessary surgery. PMID- 27504368 TI - Predictors of Mortality in Paediatric Myocarditis. AB - INTRODUCTION: Paediatric myocarditis can present as mild flu like symptoms to fulminent form. Early identification of the severity of illness and prioritization of intensive care is helpful especially in developing countries with limited resources. AIM: To know the factors at admission that can predict mortality in paediatric myocarditis. MATERIALS AND METHODS: This was an observational study which enrolled children who presented with fever of acute onset (less than 15 days in duration), and were diagnosed as suspected myocarditis on the basis of clinical features, Troponin I and echocardiography, according to Expanded criteria for myocarditis in Paediatric ward at our institute over a period from August 2014 to December 2015. Their clinical features, cardiac biomarkers and echocardiography findings were compared between survivors and non-survivors. STATISTICAL ANALYSIS: All statistical analysis was done using graphpad Prism 5 and SPSS statistical software. A Fisher exact p-value <0.05 was regarded as significant. Multivariate Logistic Regression was carried out to quantify the relationship between cardiac death and other predictor variables. The logistic coefficients for the predictor variables and their exponents, that is, log odds were calculated. Statistical significance of these predictor variables was interpreted by p-values. RESULTS: A 17.7% (n=11/62) patients of paediatric myocarditis died in this study. New York Heart Association (NYHA) class IV dyspnea (p=0.0115) and hypotension (p=0.0174) were more in patients who did not survive. The mean value of Troponin I was more in the non survivor group (0.958 +/- 1.13ng/ml); (p=0.0074). More number of patients who died had Brain Natriuretic Peptide (BNP) levels increased in their plasma (p=0.0087) with higher mean value (p=0.0175). LV ejection fraction was decreased markedly in non survivor group with mean value of 37+/-8.09 % as compared to survivor group with mean value of 46.6+/-10.5%, (p=0.0115). On multivariate analysis, NYHA class IV dyspnea (p=0.0113), BNP (p=0.015) and ejection fraction (p = 0.0284) independently are the predictors of mortality in our study group. CONCLUSION: Children with myocarditis having hypotension, raised Troponin I, BNP and decreased ejection fraction are more prone to die. NYHA IV dyspnea, higher levels of BNP and decreased EF are independently related to worst outcome. PMID- 27504370 TI - Eosinophilia in an Acutely Limping Child: An Easy Guess of Rare Systemic Aetiology! AB - Painful limping child is often considered due to septic arthritis. Iliopsoas abscess (IPA) is rare in adults and children. The aetiology is often related to tuberculosis of spine. Hereby we report a case of staphylococcal IPA where incidental evaluations led to obvious diagnosis of a rare primary immunodeficiency syndrome called Job syndrome or hyperimmunoglobulin E and Eosinophilia Syndrome (HIES). This was the first case of IPA in a case of immunodeficiency syndrome including HIES. PMID- 27504371 TI - Asplenia Syndrome in a Neonate: A Case Report. AB - Asplenia syndrome is a syndrome of right isomerism or attempted bilateral right sidedness. It includes congenital asplenia in association with complex congenital cyanotic heart disease and situs anomalies of the other thoracoabdominal organs. Herein we report a case of asplenia syndrome so as to highlight and refocus attention on the possibility of this rare syndrome that must be considered in a neonate presenting with congenital cyanotic heart disease. PMID- 27504372 TI - Congenital Ichthyosis - Collodion Baby Case Report. PMID- 27504373 TI - Prevalence of Nosocominal Toxigenic Clostridium difficile in Children Under 5 Years in Hajar Hospital, Shahrekord, Iran. PMID- 27504374 TI - Spectrum of Renal and Urinary Tract Diseases in Kashmiri Children. AB - INTRODUCTION: Definite paucity of data pertaining to spectrum of renal and urinary tract diseases in our state and in various parts of India forms the basis of this study. Available data has emphasized more on specific clinical syndromes and chronic renal diseases rather than over all spectrums of renal and urinary tract diseases, that too in adult population. AIM: The present study a retrospective analysis, forms one of the basic data of paediatric nephrology and urology related disorders in our state. MATERIALS AND METHODS: Retrospective analysis of the case records of all the hospitalized patients with renal and urinary tract diseases between 2012 and 2013 were performed. Case records were analysed and categorized into various groups like; Urinary Tract Infections (UTI), Acute Kidney Injury (AKI), Acute Glomerulonephritis (AGN), Nephrotic Syndrome (NS), haematuria, Polycystic Kidney Disease (PCKD), Posterior Urethral Valve (PUV), Vesicoureteric Reflux (VUR), Chronic Kidney Disease (CKD), Congenital Anomalies of Kidney and Urinary Iract (CAKUT) and others. These groups were divided into subgroups to get more insight about the pattern of these diseases. RESULTS: Out of 28114 patients hospitalized between 2012 and 2013 years, 447 (232 males and 215 females) patients were diagnosed of renal and urinary tract diseases which forms 1.58% the total admitted patients. Among these patients 32.9% (147/447) were diagnosed Acute Kidney Injury (AKI); 24.1% (108/447): Urinary Tract Infection (UTI); 9.6% (43/447): Acute Glomerulonephritis (AGN); 5.6% (25/447): bilateral hydronephrosis with UTI; 4.47% (20/447): nephrotic syndrome (NS); 3.5% (16/447): haematuria; and 4% (18/447) were having CAKUT (Congenital Anomalies Of Kidney And Urinary Tract). In addition to this there were 17 cases of Renal Tubular Acidosis (RTA), 3 cases of Barter syndrome and one case of Liddle syndrome. CONCLUSION: A substantial number of children are hospitalized with renal and urinary tract diseases with delayed ages of presentation, which at times have suffered irreversible renal damage that could have been prevented or treated if diagnosed earlier. Our study indicates that majority of these renal and urinary tract diseases are preventable and treatable. Henceforth, there is a need to develop a comprehensive service for the children with renal and urinary tract diseases in Jammu & Kashmir (J&K) India. PMID- 27504375 TI - Accuracy of MRI in Prediction of Tumour Thickness and Nodal Stage in Oral Tongue and Gingivobuccal Cancer With Clinical Correlation and Staging. AB - INTRODUCTION: Squamous cell carcinoma of lower gingivo-buccal complex and tongue are the most common cancer in the Indian sub-continent. The value of imaging in the staging of Oral Squamous Cell Carcinoma (OSCC) is in judging operability, assessment of the prognostic characteristics and dimensions of the primary tumour, depth of tumour invasion, the presence of cervical metastasis and detection of bone infiltration. AIM: This study evaluated squamous cell carcinomas of the oral cavity (tongue and gingivo-buccal complex) on the basis of their appearance, soft tissue extent, depth of tumour invasion and staging. Further, this study assessed the accuracy of MRI in the detection of cervical lymph nodal metastasis on the basis of ADC values on diffusion weighted MR sequence. MATERIALS AND METHODS: T1- and T2-weighted MR, diffusion-weighted sequences and post contrast T1W sequences were performed in various planes on biopsy proven squamous cell carcinomas (61 cases) involving tongue and/or gingivo buccal region. Depth of tumour invasion was calculated on axial images of post contrast T1W images. The Apparent Diffusion Coefficient (ADC) was measured by using two b factors (500 and 1000 s/mm(2)). MRI findings were compared clinically and histopathologically. RESULTS: Average depth of invasion calculated on MRI was 8.47mm and by histopathology was 6.85mm. Pearson's correlation coefficient was 0.988. Shrinkage factor was 0.8. A 71% of patients with depth of invasion greater than 9mm showed evidence of cervical lymph nodal metastasis at one or another levels. Cut-off value to discriminate between malignant and benign lymph nodes was 1.038 x10-3 mm(2)/s in the present study. CONCLUSION: Depth of tumour invasion in oral malignancies can be measured reliably on MRI which helps in predicting cervical lymph node metastasis. Benign or malignant cervical lymph nodes can be differentiated on diffusion-weighted imaging of MRI on the basis of their ADC values. PMID- 27504376 TI - CT Evaluation of Acute Pancreatitis and its Prognostic Correlation with CT Severity Index. AB - INTRODUCTION: Pancreatitis is one of most complex and clinically challenging of all abdominal disorders. USG and abdominal CT are the most commonly used diagnostic imaging modalities for the evaluation of pancreas. Computed Tomography (CT) is highly accurate and sensitive than USG in both diagnosing as well as demonstrating the extent. Early assessment of the cause and severity of acute pancreatitis is of utmost importance for prompt treatment and close monitoring of patient with severe disease. CT is the imaging method of choice for assessing the extent of acute pancreatitis and for evaluating complications. AIM: To assess prognostic correlation and clinical outcome of acute pancreatitis on the basis of CT severity index. MATERIALS AND METHODS: A prospective study of 50 cases was carried out in the Department of Radio Diagnosis, with complaint suggestive of acute pancreatitis on the basis of clinical/laboratory/ultrasonography findings were evaluated in Siemens somatom 40 slice CT. The severity of pancreatitis was scored using CT severity index, modified severity index and revised Atlanta classification and classified into mild, moderate, severe categories. Clinical follow-up of the patients was done in terms of the following parameters: Length of hospital stay, Need for surgery or percutaneous intervention, Evidence of infection in any organ system, Occurrence of organ failure- respiratory, cardiovascular, renal, hepatic and haematological system, death. The clinical outcome was compared with the currently accepted Balthazar's CTSI and Modified Mortele's CTSI and revised Atlanta classification in all the cases. RESULTS: Gall stone disease was most common aetiological factor seen in 40% cases, it was more common in females than males. Alcohol was second most common aetiological factor seen in 38% cases and was noted only in males. Pleural effusion was the most common extra-pancreatic complication seen in 46% cases. Balthazar grade C was the most common (40%) followed by grade D and E (25% each). Acute peri-pancreatic collection was the most common findings seen in 72% cases. Majority of the cases (42%) were categorized as mild pancreatitis according Balthazar CTSI score. Majority of the cases (44%) were categorized as severe pancreatitis according modified CTSI. Majority of the cases were categorized as mild pancreatitis according revised Atlanta classification. Organ system failure, death were more seen in severe grade in modified CTSI and revised Atlanta classification. CONCLUSION: Modified CT severity index makes the score easier to calculate and reduces the inter-observer variation. Scores obtained with the modified Mortele index, show a stronger statistical correlation for all clinical outcome parameters in all the patients better than the Balthazar index. PMID- 27504377 TI - Wine Glass Sign and Empty Delta Sign: A Rare Imaging Presentation of Postpartum Encephalopathy in Dehydration. AB - Rapid correction of hyponatremia is a well-known cause of central pontine and extrapontine myelinolysis. But uncommonly seen and rarely reported in Hypernatraemia. We report a rare case presenting as postpartum psychosis, wherein imaging revealed myelinolysis of corticospinal tracts in wine glass distribution and empty delta sign due to cortical venous thrombosis. At follow-up 3 months later, revealed significant neurological improvement. Concurrance occurrence of this dual pathology is not been described, which in our case was due to high serum sodium levels at presentation and dehydration. PMID- 27504378 TI - Superior Mesentric Artery Syndrome in a Patient with Subacute Intestinal Obstruction: A Case Report. AB - Superior Mesenteric Artery (SMA) syndrome is one of the rare cause of proximal small bowel obstruction wherein, the third part of the duodenum is compressed between the SMA at its origin and abdominal aorta due to decreased angulations in these two vessels. This decreased angulation exerts a compression effect on third part of the duodenum, resulting in duodenal obstruction which may be complete or partial. There are number of causes which can lead to this entity and will be discussed briefly. Here we report imaging findings of such a rare cause of proximal small bowel obstruction in a young male patient who presented to the emergency surgical department with non specific symptoms of pain abdomen and abdominal fullness. Patient was evaluated under the standard protocol in management of abdominal pain. General physical examination, erect and supine radiograph were taken. On barium meal follow-through examination, there was paucity of contrast agent distal to the second part of duodenum with proximal dilation of stomach, first and second part of duodenum which raised us the possibility of SMA syndrome. Reconstructed CECT abdomen confirmed the decreased angulation between SMA and abdominal aorta and diagnosed it as SMA syndrome. Findings were correlated on duodenojejunostomy anastomotic surgical procedure. Diagnosing and reporting such a case of SMA syndrome is of utmost importance because the clinical presentation being non-specific pertaining to small bowel obstruction which may pose a diagnostic difficulty to the surgeon and with the further delay in diagnosis, patients may end up with chronic symptoms and complications of the disease, repeated hospital visits and electrolyte abnormalities. PMID- 27504379 TI - Cardiac Pseudoaneurysm- A Death Defying Entity. AB - A pseudoaneurysm refers to a contained rupture of the myocardium with a tenuous pericardium walling off the leak. It needs to be differentiated from a true aneurysm by the fact that there is lack of myocardial tissue in the wall of a pseudoaneurysm. The differentiation between the two is pertinent as true aneurysms can be treated medically while pseudoaneurysms require urgent surgical treatment. Untreated pseudoaneurysms carry a high risk of rupture and mortality. We report a case of cardiac pseudoaneurysm developing in a 46-year-old male who had suffered myocardial infarction four months back. The patient now presented with chest pain and dyspnoea. CECT chest revealed a partially thrombosed large pseudoaneurysm arising from the posterior wall of left ventricle. While the clinical diagnosis of this entity is difficult, CECT plays a pivotal role in the non-invasive detection of pseudoaneurysms. PMID- 27504380 TI - Fetal MR Imaging Analysis of Sirenomelia with Clinico Radiographic Correlation: A Case Report. AB - Sirenomelia is a social curiosity, a medical and diagnostic challenge prenatally compounded by varied diagnostic difficulties. Prenatal diagnosis of sirenomelia was and continues to be a challenge although von klippel et al., described a case at 10 weeks of gestational age. However, they needed a second imaging at 12(th) week for confirmation. First trimester or early second trimester anatomic survey on ultrasound and MRI is accurate for the diagnosis thereby avoiding unnecessary complex pregnancy. We report a case of second trimester diagnosed sirenomelia, with detailed analysis of image findings on ultrasound and fetal MRI. PMID- 27504381 TI - Illustrated Imaging Essay on Congenital Heart Diseases: Multimodality Approach Part II: Acyanotic Congenital Heart Disease and Extracardiac Abnormalities. AB - Acyanotic heart disease constitutes a significant majority of patient who may present with non-cardiac symptoms. Either they are detected incidentally or present with respiratory complaints. Equipped with knowledge of anatomy by echocardiography and radiographic methods described in previous part of this presentation, diagnosis may be confidently attempted. On plain radiography acyanotic congenital heart diseases have variable appearance depending upon severity of disease. Cardiac size, chamber enlargement and pulmonary vascular pattern are key elements. Typically left to right shunts with large volume flow are associated with pulmonary plethora. Plain radiography has an important role in detecting manifestation of pulmonary arterial hypertension. Severe stenosis of pulmonary valve is associated with pulmonary oligemia. Small intra-cardiac shunts and anomalies of coronary arteries generally present with normal cardiac size and pulmonary arterial pattern. Disease spectrum presented in this illustration demands thorough scrutiny of pulmonary, osseous and abdominal abnormalities. This section illustrates some commonly encountered spectrum of acyanotic cardiac disease. PMID- 27504382 TI - Comparison of Albumin, Hydroxyethyl Starch and Ringer Lactate Solution as Priming Fluid for Cardiopulmonary Bypass in Paediatric Cardiac Surgery. AB - INTRODUCTION: In paediatric cardiac surgery, there is still not any information with regard to the best choice of priming fluids for Cardiopulmonary Bypass (CPB). Albumin, Hydroxyethyl Starch (HES) & ringer lactate are equally used, but each has its advantages & disadvantages. Albumin & HES had better fluid balance which affect outcome in paediatric cardiac surgery significantly. AIM: To compare priming solution containing albumin, hydroxyethyl starch and ringer lactate during elective open-heart surgery in paediatrics aged up to 3 years. MATERIALS AND METHODS: All patients were managed by standardized institution protocol and were randomly distributed into three groups based on the priming solution which is used in the CPB Circuit and having 35 patients in each group. Group A: Receive albumin 10 ml/kg in priming solution, Group B: Receive Hydroxyethyl starch (HES130/0.4) 6% 20ml/kg in priming solution, Group C: Receive ringer lactate priming solution. Primary outcome variable included perioperative haemoglobin, total protein, colloid osmotic pressure, platelets, fluid balance, urine output, post-operative blood loss, blood products usage, renal & liver function, extubation time, ICU stay & outcome. RESULTS: Patients receiving albumin had higher perioperative platelet count, total protein level & colloid osmotic pressure, lesser post-operative blood loss & blood products requirement. Patients receiving HES had lower level of platelets postoperatively than ringer lactate group but not associated with increase blood loss. HES did not affect renal function & haemostasis in this dose. Patients receiving ringer lactate had positive fluid balance intraoperatively. All three groups have similar effect on renal & liver function, urine output, time to extubation, ICU stay & outcome. CONCLUSION: We conclude that albumin is expensive but better prime as maintain haemostasis, colloid oncotic pressure & reduced blood product requirement. HES will not hamper haemostasis & renal function in lower dose & better than crystalloid as maintain negative fluid balance. Patient outcome & ICU stay was similarly affected by priming solutions. PMID- 27504383 TI - Transdermal Buprenorphine Patches for Postoperative Pain Control in Abdominal Surgery. AB - INTRODUCTION: Buprenorphine is a semi-synthetic derivative of thebaine; its low concentration is sufficient to provide effective pain relief. AIM: To evaluate the efficacy of transdermal buprenorphine patch in postoperative pain management. MATERIALS AND METHODS: After ethical approval and taking informed consent from the patients, they were randomized into three groups (n=30 in each group) using a computer generated random number table. Group A: placebo patch; Group B: buprenorphine (10mg) patch and Group C: buprenorphine (20mg) patch. Haemodynamic and analgesic effects were compared by using analysis of variance (ANOVA) followed by Turkey's post hoc test. The proportion of side effects was compared using the Chi-square test. RESULTS: Haemodynamic changes were not statistically different in all the three groups A, B and C, whereas at the end of surgery VAS score of Group A subjects was significantly higher (4.93+/-0.98) as compared to Group B (1.73+/-0.64) and Group C (1.40+/-0.50). On 2(nd) postoperative day, no pain was reported by the Group C patients and on 4(th) day after surgery, no pain was reported by Group B patients. CONCLUSION: The transdermal buprenorphine patch (20mg) was effective in attenuating postoperative pain, maintaining haemodynamic stability requiring no rescue analgesia, with fewer postoperative rescue analgesic requirements in low dose of buprenorphine patch (10mg) group. PMID- 27504384 TI - Supraclavicular Brachial Plexus Block With or Without Dexamethasone as an Adjuvant to 0.5% Levobupivacaine: A Comparative Study. AB - INTRODUCTION: Brachial plexus block is an excellent method for attaining optimal operating conditions by producing complete muscular relaxation, maintaining stable intraoperative haemodynamics and the associated sympathetic block. In addition, they provide extended postoperative analgesia with minimal side effects. Different adjuvants have been described in literature to hasten the onset and prolong the duration of block. The present study was conducted to study the effect of adding dexamethasone to levobupivacaine in supraclavicular brachial plexus block. AIM: To observe the effect of dexamethasone on onset and duration of anaesthesia, when used as an adjuvant to levobupivacaine in supraclavicular brachial plexus block. MATERIALS AND METHODS: A total of 60 patients in the age group of 18-65 years belonging to ASA physical status I or II were included in the study. They are randomly allocated in two groups and each group included 30 patients. In group 1, patients received 30ml of 0.5% isobaric levobupivacaine with 2ml of isotonic sodium chloride. In group 2 patients received 8mg (2ml) dexamethasone in addition to 30ml of 0.5% isobaric levobupivacaine. RESULTS: The results showed that the onset of sensory and motor block were faster in group 2(p<0.05). The duration of sensory and motor block were significantly longer in group 2 (p<0.05). VAS score at 12 hours were significantly lower in group 2 (p<0.05). None of the patients had bradycardia, hypotension or any other side effects. CONCLUSION: Dexamethasone added to levobupivacaine for supraclavicular brachial plexus block reduces the time to onset of sensory and motor blockage and prolongs the duration of analgesia. PMID- 27504385 TI - LBBB with History of Complete Atrioventricular Dissociation Underwent Bipolar Hemiarthroplasty. AB - A 70-year-old female patient, known case of hypertension and incomplete Left bundle branch block (LBBB), posted for bipolar hemiarthroplasty. A geriatric patient with LBBB and systemic hypertension is a fatal combination; it may precipitate into complete AV dissociation during anaesthesia and surgical stress. We are reporting this interesting case as our patient had developed complete Atrioventricular (AV) dissociation when scheduled earlier for surgery and got postponed. We had given combined spinal epidural anaesthesia and managed successfully without any complication. PMID- 27504386 TI - Anaesthetic Management of Caesarean Section in a Term Pregnancy with Ventricular Septal Defect and Pulmonary Hypertension with Severe Pulmonary Stenosis. AB - Pregnancy with pulmonary hypertension - WHO risk class IV cardiac disease is associated with significant haemodynamic burden due to cardiocirculatory changes which is a significant indirect cause of maternal mortality. We report a very rare case - primigravida term pregnancy with pulmonary hypertension, large ventricular septal defect (2.4 cm(2)), bidirectional shunt mainly left to right with severe pulmonary stenosis with peak gradient of 144mmHg. Caesarean section was done under general anaesthesia with successful maternal and neonatal outcome. PMID- 27504387 TI - Effects of Yoga on Physiological Indices, Anxiety and Social Functioning in Multiple Sclerosis Patients: A Randomized Trial. AB - INTRODUCTION: Multiple sclerosis (MS) as a chronic disease could affect patients' various domains of life. AIM: This study was conducted to study the effect of yoga on the physiological indices, anxiety and social functioning of patients with MS in southwest, Iran. MATERIALS AND METHODS: In this clinical trial study, 60 MS patients were enrolled according to inclusion criteria and randomly assigned to two groups of 30 each. Prior to and after intervention, the patients' vital signs were measured. For case group yoga exercises were performed three sessions a week for 12 weeks while control group performed no exercise. The data were gathered by questionnaire and analysed by descriptive and analytical statistics in SPSS. RESULTS: Prior to intervention, there was no significant difference in fatigue severity and pain between the two groups but the mean fatigue severity and pain in case group decreased compared to the control group after the intervention. Prior to intervention, there was no significant difference in mean physiological indices between the two groups but the mean physiological indices in case group decreased significantly after the intervention (p<0.05). CONCLUSION: Yoga is likely to increase self-efficacy of MS patients through enhancing physical activity, increasing the strength of lower limbs and balance, and decreasing fatigue and pain, and finally to promote social functioning and to relieve stress and anxiety in these patients. PMID- 27504388 TI - Rising Trend of Use of Antidepressants Induced Non- Puerperal Lactation: A Case Report. AB - Non puerperal lactation or galactorrhea is a well known side effect of antipsychotic drugs but has been infrequently described with the use of antidepressants. In past few decades, there have been emerging trend of isolated case reports of selective serotonin reuptake inhibitors induced non puerperal lactation. We report a case of non puerperal lactation following usage of second generation tricyclic antidepressant, nortriptyline and resolution on withdrawing the drug. Literature review has been done for antidepressant induced galactorrhea to understand the current trends, putative mechanism as different from one implicated for antipsychotics and its clinical utility. PMID- 27504389 TI - Digital Acrometastasis as Initial Presentation in Carcinoma of Lung A Case Report and Review of Literature. AB - Bony metastases develop in 30% of all the cancers, but out of which only 1% to 3% occurs in the hand. Lung is the most common site for acrometastasis, followed by breast and renal cell cancer. Metastases to the digits are with non-specific presentation. We reported a case of 79-year-old male patient with initial presentation of swelling over left index finger, which was found to be squamous cell carcinoma of finger on histopathological examination. He was subsequently diagnosed as a case of squamous cell carcinoma of lung with acrometastasis. PMID- 27504390 TI - Adenolipoma of the Breast: A Clinicoradiological Entity and Pathologist's Dilemma! AB - Breast hamartomas are benign lesions composed of variety of normal breast components arranged in disorganized manner. These are rare and classified as adenolipoma, fibrolipoma, adenofibrolipoma, etc. Clinically these present as painless well-circumscribed, mobile lumps of breast. Incidence and etiology remain obscure due to its rarity. These have been described in women in their 40's or 50's. Mammographically they appear non homogenous mass with circumscribed fatty masses. Histologically they appear as circumscribed masses with variable amount of fat, fibrous and glandular tissue. Here we are presenting adenolipoma in 29-year-old woman with review of literature. PMID- 27504391 TI - Exploring the Management of Radiation Proctitis in Current Clinical Practice. AB - INTRODUCTION: Radiation proctitis is radiation induced rectal mucositis, occurring as a consequence to radiation therapy of the pelvic organs for various pelvic region malignancies. The management of radiation proctitis is extremely challenging as no recommended guidelines are available and limited number of studies are there in the literature involving the various treatment options. AIM: The aim of the study is the in-depth review of published literature to see the role of various treatment modalities in the management of radiation proctitis. MATERIALS AND METHODS: An integrative review was undertaken within PubMed, MEDLINE, PMC, GOOGLE SEARCH databases and articles published upto February 2015 were reviewed and analysed. A total of 54 studies were included. RESULTS: Literature suggests that non surgical therapies are the first line of treatment and surgery is reserved for advanced or refractory cases. Endoscopic therapies form the mainstay of treatment in managing the patients of radiation proctitis. Argon plasma coagulation and laser therapies are preferred. Radiofrequency ablation, cryoablation and mesenchymal stem cell therapy are the upcoming modalities. Medical therapy can be tried alone or in conjunction to endoscopic therapies. In the resistant or refractory cases, surgery can be looked for in the form of diversion or resection with or without anastamosis. CONCLUSION: Though, a number of options are available, still a lot can be explored in this field to improve the morbidity in the patients and to confirm the superiority of one treatment over other. PMID- 27504392 TI - Primary Hodgkin's Lymphoma of the Sternum: Report of a Case and Review of the Literature. AB - Sternal masses present a unique diagnostic challenge in clinical practice. A wide array of differential diagnosis of a sternal mass includes osteomyelitis, tuberculosis, eosinophilic granuloma, sarcoma and lymphoma (usually Non Hodgkin's) amongst others. Sternum is a rare site of Hodgkin's lymphoma and is usually misdiagnosed as tuberculosis or eosinophilic granuloma on routine histopathology. This delayed diagnosis culminates in death of patients. We report a 30-year-old lady who presented with swelling in upper part of chest wall since 1 month. Past history was significant for a similar swelling 2 years back, which was diagnosed as hodgkin's lymphoma and treated with 4 cycles of chemotherapy at another centre (which led to resolution of the swelling). Examination revealed a 6x6.5cm firm swelling originating from the upper part of sternum. There was no lymphadenopathy or organomegaly. Histopathological examination (with immunohistochemistry) of the trucut biopsy from the swelling confirmed the diagnosis of Hodgkin's lymphoma (nodular sclerosis). Patient was diagnosed as a late relapse of primary sternal Hodgkin's lymphoma (stage IBE) and was administered 4 cycles of ABVD followed by local radiotherapy to the involved site which led to complete resolution of the disease as assessed by PET scan. We present this unusual case of primary sternal Hodgkin's lymphoma. Rarity of this entity, with diagnostic challenges encountered and treatment options available are highlighted in the current report. A pubmed search revealed 18 cases of sternal involvement in Hodgkin's lymphoma which have been tabulated. PMID- 27504393 TI - Multiple Myeloma: An Unusual Cause of Extensive Bone Marrow Necrosis. PMID- 27504394 TI - Evaluation of Autonomic Dysfunction in Obese and Non-Obese Hypertensive Subjects. AB - INTRODUCTION: Obesity and more specifically, visceral obesity, has been consistently associated with hypertension and increased cardiovascular risk. Epidemiological studies indicate that at least two-third of the prevalence of hypertension can be directly attributed to obesity. Studies also suggest that hypertensive patients have impaired cardiac autonomic function. AIM: The objective of the study was to examine any added effects of obesity on cardiac autonomic dysfunction in hypertensive patients. MATERIALS AND METHODS: Hypertensive subjects (n=45) between 35-60 years of age were divided into two groups; Group A (n=30) consisted of non-obese hypertensive subjects and Group B (n=15) consisted of obese (BMI>=30kg/m(2)) hypertensive subjects. Cardiac autonomic function was assessed using four tests - Heart rate response to immediate standing (30:15 ratio), standing to lying ratio (S/L ratio), Blood pressure response to immediate standing and Cold Pressor Test (CPT). RESULTS: There were no significant differences for autonomic function tests between obese and non-obese hypertensive subjects (p >0.05). CONCLUSION: The results showed that there are no significant differences in the cardiac autonomic function responses between obese and non-obese hypertensive subjects. PMID- 27504395 TI - An Accelerated Multi-Modality Rehabilitation Protocol Combined with Botulinum Toxin-A Injection in Adult Idiopathic Toe Walking: Case Report. AB - Diagnosis of Adult Idiopathic Toe Walking (AITW) is very rare in clinical practice. High quality studies regarding AITW and its treatment options have not been conducted previously. A 28-year-old male patient complaining of lower leg pain was referred to outpatient rehabilitation clinic. Physical examination revealed a gait abnormality of insufficient heel strike at initial contact. The aetiology was investigated and the patient's walking parameters were assessed using a computerized gait analysis system. The AITW was diagnosed. Botulinum toxin-A (Dysport((r))) was injected to the bilateral gastrocnemius muscles. A combined 10-days rehabilitation program was designed, including a daily one-hour physiotherapist supervised exercise program, ankle dorsiflexion exercises using an EMG-biofeedback unit assisted virtual rehabilitation system (Biometrics) and virtual gait training (Rehawalk) every other day. After treatment, the patient was able to heel strike at the initiation of the stance phase of the gait. Ankle dorsiflexion range of motions increased. The most prominent improvement was seen in maximum pressure and heel force. In addition center of pressure evaluations were also improved. To the best of our knowledge this is the first case, of AITW treated with combined botulinum toxin, exercise and virtual rehabilitation systems. This short report demonstrates the rapid effect of this 10-days combined therapy. PMID- 27504396 TI - An Insight into Health Care Setup in National Capital Region of India using Dimensions of Learning Organizations Questionnaire (DLOQ)- A Cross-Sectional Study. AB - INTRODUCTION: Over the past decades India, though being a developing country has progressed in multiple sectors but has not shown a substantial qualitative progress in healthcare. To be able to evaluate learning organization in a healthcare setup would thrust millennium development goals and infuse continuous learning model into health sector. AIM: To assess health care context using the Dimensions of the Learning Organization Questionnaire (DLOQ) in a health care setting in National Capital Region of India. MATERIALS AND METHODS: DLOQ proforma were distributed among 315 employees at all levels of the hospital. Data was analysed using SPSS software version 19.0 and was subjected to quantitative analysis and non-parametric tests. RESULTS: The Kruskal-Wallis test indicated a significant difference between the means of the different professions where as Mann-Whitney tests compared the relation between each of the profession and a significant difference (p < 0.05) was noted, except dimension "systems connection". CONCLUSION: The results provided sufficient inputs about the multidimensional learning organization capacity of a health care setting in a rapidly developing country. PMID- 27504397 TI - Efficacy of Different Methods for Removing Root Canal Filling Material in Retreatment - An In-vitro Study. AB - INTRODUCTION: Although success of endodontic therapy has significantly improved in the last few decades due to the introduction of novel materials and techniques, failures of endodontic therapy requiring re-treatment still comprise a significant percentage of patients requiring root canal treatment. AIM: To evaluate and compare the effective removal of gutta percha and sealer, amount of apical debris extrusion and time required for gutta percha removal using various endodontic files. MATERIALS AND METHODS: Total 48 extracted mandibular premolars were mounted on acrylic blocks and endodontic procedure was carried out using size 40 K file and obturated using guttapercha and zinc oxide eugenol sealer. After one month storage, samples were decoronated, mounted on screw capped vials and subjected to removal of obturated material by four instruments: H files, safe sided H files, protaper universal retreatment rotary system and ultrasonic retreatment tip, grouped as 1, 2, 3, and 4 respectively. Only 2mm of obturated material from the coronal part was removed using no. 3 Gates Glidden drill, guttapercha was softened with a drop of xylene for 2 mins for each canal and retreatment was performed. The retreatment procedure was said to be complete when no visible debris were observed on the instrument flutes. The samples split into two halves and examined under stereomicroscope, photographed, assessed using AUTOCAD software and percentage of remaining filling material in coronal, middle, apical thirds of the canal was calculated in mm(2). Retreatment time was recorded in seconds and apically extruded debris was assessed by microbalance in grams for each tooth. The data was analyzed by using descriptive statistics, ANOVA and Scheffe's post hoc test through SPSS for windows (v 16.0). RESULTS: The ultrasonic retreatment tip had less percentage of residual guttapercha/sealer, shorter mean operating time and little apical extrusion with a significant difference (p<0.05) between the other groups. CONCLUSION: All techniques retained guttapercha/sealer remnants within the root canal. The ultrasonic retreatment tip proved to be an efficient method of removing obturated material. It was fastest with least apical debris extrusion. PMID- 27504398 TI - Comparative Evaluation of Preemptive Analgesic Effect of Injected Intramuscular Diclofenac and Ketorolac after Third Molar Surgery- A Randomized Controlled Trial. AB - INTRODUCTION: Analgesia pre-emptively administered effect-ively aid in management of pain. Pre-emptive analgesia is anti-nociceptive treatment which prevents altered central sensitization of afferent inputs. AIM: To compare and evaluate the pre-emptive analgesic efficacy of preoperatively administered ketorolac and diclofenac for controlling postoperative pain after third molar surgery. MATERIALS AND METHODS: A total of 50 patients with symmetrically impacted third molars were divided into two groups, 30mg intramuscular injection of ketorolac and 75 mg diclofenac sodium were used in the respective groups. The visual analogue scale was used to assess post operative pain for three days and the patients were also evaluated for the number of rescue analgesia. RESULTS: The data was statistically evaluated with paired t- test. The maximum time taken for pain perception for Group A Ketoralac was 5.48 hrs and Group B Diclofenac sodium was 4.9 hrs and p=0.235 which was not significant. The mean number of tablets taken by the patients in the first three post operative days was 3.24 in Group A i.e., Ketorolac and 4.04 in Group B i.e., Diclofenac sodium. The values were compared using the paired t test. The p value = 0.004, which was significant. CONCLUSION: Ketoralac showed better pre-emptive analgesic effect for post operative pain management after third molar extraction. The immediate post operative pain free period provided by both ketorolac and diclofenac by intramuscular route was same. PMID- 27504399 TI - Evaluation of a New Self-Reported Tool for Periodontitis Screening. AB - INTRODUCTION: Periodontitis is still highly prevalent in industrial population whereas at the same time appropriate screening programs are missing. AIM: To evaluate, a self-reported questionnaire about periodontal risk factors in combination with the Periodontal Screening Index (PSI) to identify an existing need for periodontal treatment combined with the early recognition of high-risk patients. MATERIALS AND METHODS: Total 200 patients took part in the questionnaire based study and were examined using the PSI. Thereafter the participants were divided into two groups, subjects with periodontitis (Group 1; PSI 0-2) and subjects without periodontitis (Group 2; PSI 3-4). The answers were evaluated using a point system ranging from 0 to 8, based on known periodontal risk factors and their assumed degree of influence. Receiver-Operating Characteristic (ROC) curve analysis were applied to examine the overall discriminatory power, sensitivity, specificity and corresponding cut-off points of the self-reported periodontal disease scale. RESULTS: There was a significant difference between Group 1 and 2 concerning the majority of the inquired items (12 of 16, p<0.05). The distribution of the individual total score exhibited a high statistical significance (p<0.001) of robustness in terms of differing definitions of periodontitis. The Area Under the Curve (AUC) was 0.912 with a sensitivity of 86% and a specificity of 76%. CONCLUSION: The questionnaire produced a reliable assessment of the individual risk (total score) and the need for periodontal treatment as well as the differentiation between gingivitis and periodontitis. CLINICAL RELEVANCE: Patient-based data (clinical variables and periodontal risk factors of periodontitis) were adequate to make a preliminary assessment of a possible need for periodontal treatment. PMID- 27504400 TI - Evaluation of Antibacterial Efficacy of MTA with and without Additives Like Silver Zeolite and Chlorhexidine. AB - INTRODUCTION: Microorganisms, predominantly Enterococcus faecalis are found responsible in the progression of pulpal, periradicular diseases and in endodontic failures. Unsuccessful conventional treatment might necessitate the need for a surgical approach; where in retrograde restorative materials are used to seal the apex. Among the root end filling materials, Mineral Trioxide Aggregate (MTA) is considered biocompatible and is most commonly used in clinical applications but it has limited antibacterial activity. Metallic silver and chlorhexidine have been added into various dental materials to enhance the antibacterial activity. AIM: This study aimed to compare the antibacterial effect of MTA, MTA mixed with silver zeolite and MTA mixed with chlorhexidine against Enterococcus faecalis. MATERIALS AND METHODS: Test materials used in the study were divided into three groups namely Group 1- MTA, Group 2-MTA + Silver Zeolite, Group 3-MTA + Chlorhexidine. Direct contact test was done by placing a standardized suspension of Enterococcus faecalis on the test materials in a 96 well microtiter plate. The bacterial growth was measured spectrophotometrically using ELISA reader at intervals of one, three and seven days. STATISTICAL ANALYSIS: Data was collected by recording the optical density and analyzed using two-way ANOVA and Tukey's multiple post hoc test followed by paired-t test. RESULTS AND CONCLUSION: All test groups showed antibacterial activity against Enterococcus faecalis at day one, three and seven. MTA with silver zeolite showed the maximum antibacterial activity followed by MTA with 2% chlorhexidine. The least antibacterial effect was shown by MTA mixed with sterile water. PMID- 27504401 TI - Clinical Evaluation of Proclination of Lower Anterior Teeth during Alignment using a Single Width Bracket-A Pilot Study. AB - INTRODUCTION: The pre-adjusted brackets are available in various prescriptions and sizes; nevertheless there are still many controversies as to which pre adjusted edgewise bracket offers the maximum clinical efficiency. AIM: This study was conducted to determine and compare the amount of lower incisor proclination during de-crowding if any of the Mini-Uni Twin Brackets with that of the standard double width brackets. MATERIALS AND METHODS: A total of 20 patients i.e., 10 patients in each group both males and females were randomly selected for the study from subjects seeking treatment, the selected samples were grouped as follows. Group I - Double Width Brackets (3M Unitek Gemini Series) 0.018" slot with Roth prescription. Group II - Mini Uni-Twin Bracket (3M Unitek) 0.018" slot with Roth prescription. RESULTS: The Mini-Uni Twin Brackets had statistically significant (p = 0.01) amount of proclination of the lower anteriors (0.8(o)+/- 0.3(o)) after de-crowding as compared to the standard Double Width Brackets and since the mean change in the Incisor Mandibular Plane Angle (IMPA) was lesser than 1(o), its clinical significance could be questionable. CONCLUSION: The Mini Uni Twin brackets are comparatively efficient in the lower anterior decrowding but further comparative clinical studies need to be performed on these Mini Uni Twin brackets, with an increase in the sample size and also the number of parameters to prove its total clinical efficiency. PMID- 27504402 TI - Minocycline Ointment as a Local Drug Delivery in the Treatment of Generalized Chronic Periodontitis - A Clinical Study. AB - INTRODUCTION: The primary goal in periodontal therapy includes removal of the etiological factors by mechanical periodontal treatment, which sometimes fail to eliminate the anaerobic infection at the base of the pocket and requires adjuvant chemical therapy. AIM: The aim of the study was to evaluate the effectiveness of 2% minocycline ointment when used as an adjunct to periodontal flap surgery and post-operative maintenance period for the treatment of generalized chronic periodontitis. MATERIALS AND METHODS: The study included 30 subjects comprising of 60 posterior sextants in a split mouth design in which 30 sextants were treated as experimental and 30 sextants as control with a probing pocket depth>=6mm. In Group A (experimental group) 30 sextants were treated with open flap debridement followed by the application of minocycline ointment as a local drug delivery. In Group B (control group) 30 sextants were treated with open flap debridement alone. Minocycline hydrochloride ointment was applied on the 0 day and 3(rd) month. The clinical parameters such as plaque index, probing pocket depth, clinical attachment level and gingival bleeding index were recorded at 0 day, 3(rd) month and 6(th) month in both the groups. Paired and unpaired t-test were used to compare the means of the two groups. RESULTS: When Group A and Group B were compared, Group A showed significantly greater reduction in gingival bleeding index, probing pocket depth and gain in clinical attachment level than Group B, from 0 day to 3 months and from 0 day to 6 months. Group A showed significant reduction in plaque index than Group B when they were compared at 6 months. CONCLUSION: The results demonstrate that there was significant reduction in the clinical parameters with improvement in the periodontal status on application of minocycline ointment as an adjunct to periodontal flap surgery in generalized chronic periodontitis. PMID- 27504403 TI - Comparison of K-loop Molar Distalization with that of Pendulum Appliance - A Prospective Comparative Study. AB - INTRODUCTION: Molar distalization is the non extraction method of managing Class II malocclusions. AIM: The purpose of this study was to evaluate the skeletal and dentoalveolar effects of maxillary molar distalization with K-loop appliance, and to compare these effects with that of pendulum group. MATERIALS AND METHODS: Class I and dental Class II malocclusions were divided into two groups of 15 each: In Group 1 (nine females and six males; mean age, 16.0+/-2.6 years) patients were treated with K-Loop molar distalization supported palatally by Nance button, while in Group 2 (seven females and eight males; mean age, 15.4+/ 4.7 years), the patients were treated with conventional pendulum appliance. Standardized lateral cephalograms were taken at the beginning of treatment (T0) and at the end of molar distalization (T1) and the changes were statistically analyzed with paired t-test. RESULTS: The results showed no statistically significant difference in the amount of molar distalization in either of the appliance groups: the mean amount of molar distal movement of 5.1+/-0.8 mm and 4.93+/-1.68 mm was observed in the Group 1 and 2 respectively. The incisors moved mesially by 1.3+/-0.63 mm in Group 1 and 1.57+/-0.58 mm in Group 2. CONCLUSION: K Loop molar distalizing appliance has similar skeletal and dentoalveolar effects as that of pendulum appliance, with the advantages of simple yet efficient to control the moment-force ratio to produce all types of tooth movements and also requires minimal patient co-operation. PMID- 27504404 TI - Assessment of Factors Affecting Adolescent Patients' Compliance with Hawley and Vacuum Formed Retainers. AB - INTRODUCTION: Success of orthodontic retention with removable retainers almost entirely depends on patients' compliance. AIM: This study was carried out to investigate the relationship between adolescent orthodontic patients' compliance and various clinical and social factors. MATERIALS AND METHODS: The data were collected from 77 orthodontic patients aged 7-11 years old who had finished the full fixed appliance therapy. Hawley's retainers were used in 34 patients and 43 patients used Vacuum Formed Retainers (VFRs). The subjects completed a questionnaire including several identifiers allowing the respondents to be classified into subgroups. They were also asked to indicate how long they wore their retainers during the day, by writing the number of hours in the report-card for the next three months. Comparison of the results was performed by one-way ANOVA and independent sample-t tests. RESULTS: No significant differences were found between males and females. Type of the retainer, patients' grade of study, mothers' occupation, clinicians' and parents' attitudes and filling the report cards had significant effect on mean wear hours per day. When compliance of the patients was assessed according to treatment location, Living place, parents' educational degrees and ethnicity, no significant differences could be found. CONCLUSION: The adolescent patients' compliance was greater with VFRs than with Hawley's retainers. Parental attitude and doctor-patient relationship had a great impact on adolescent patients' compliance. PMID- 27504405 TI - Expression of CD1a by Langerhan's Cells in Oral Lichen Planus - A Retrospective Analysis. AB - INTRODUCTION: Langerhan's Cells (LCs) are dendritic cells of the oral epithelium which play a role in a series of oral lesions from gingivitis to oral cancer. Oral Lichen Planus (OLP) is an oral mucosal T-lymphocyte mediated immunologic reaction to an unidentified putative antigen or allergen. AIM: The aim of this study was to quantify the presence of immature LCs in OLP comparing them with normal epithelium. MATERIALS AND METHODS: A retrospective study using 30 of OLP cases were conducted. Immunohistochemistry was performed using polyclonal anti CD1a antibodies to identify LCs in 10 cases of normal tissue and 30 samples of OLP. The distribution of LCs among lesional tissue and normal mucosa was analysed using Mann-Whitney U test. RESULTS: LC population in OLP was significantly higher when compared to the normal epithelium (p<0.001). CONCLUSION: The increase in LCs indicates the active role played during the antigen detection in OLP and subsequent presentation to T-lymphocytes. PMID- 27504406 TI - Detection of Porphyromonas gingivalis fimA Type I Genotype in Gingivitis by Real Time PCR-A Pilot Study. AB - INTRODUCTION: Published literature till date reveals a high prevalence of Porphyromonas gingivalis fimA type I genotype among healthy subjects. Quite a few studies have reported its prevalence also in periodontitis patients. Nevertheless incidence of this genotype in gingivitis is lacking in adult population. AIM: The present study was chosen to detect P. gingivalis fimA type I genotype among chronic gingivitis patients. MATERIALS AND METHODS: A total of 46 subgingival plaque samples collected from chronic marginal gingivitis (n=23) and chronic periodontitis subjects (control group) (n=23) were subjected to Real-Time Polymerase Chain Reaction to detect the P. gingivalis fimA type I gene. Statistical analysis was performed using chi-square test. RESULTS: Prevalence of P. gingivalis fimA type I gene among chronic periodontitis and chronic gingivitis patients were 8.7% and 30.4% respectively. P. gingivalis fimA type I genotype prevalence was found to be statistically insignificant between the two study groups (p=0.135). CONCLUSION: The avirulent P. gingivalis fimA type I genotype, occurred in high prevalence among chronic gingivitis patients, while its presence was low in chronic periodontitis patients. Presence of this avirulent genotype in chronic marginal gingivitis signifies its reversible condition. PMID- 27504407 TI - Effects of Preheated Composite on Micro leakage-An in-vitro Study. AB - INTRODUCTION: Resin composites have been the pinnacle of direct esthetic restorations ever since its discovery. However, it comes with its own disadvantages. Post-operative sensitivity and marginal discoloration frequently occur due to polymerization shrinkage and micro leakage, which is the major cause of failure in resin composite restorations. AIM: To evaluate the effects of preheated composite at different temperatures on microleakage. MATERIALS AND METHODS: A total of 60 extracted non-carious human premolars were collected and class 1 cavity (1.5x4x 3mm) was prepared in each and were randomly divided into three groups. Group 1 (n=20) was filled with microhybrid resin composite (Heraeus Charisma Smile) at room temperature. Group 2 (n=20) was filled with the same resin composite which was preheated to 50 degrees C and Group 3 (n=20) was filled with resin composite preheated to 60 degrees C. Teeth were subjected to a thermocycling regime (500X, 5 - 55 degrees C), followed by a dye infiltration by immersing in basic fuschin for 24 hours. The tooth was sectioned longitudinally and the extent or absence of micro-leakage was determined by the amount of dye penetration along the resin composite-tooth interface using a confocal microscope. RESULTS: There was minor micro-leakage detected at the occlusal margin of the control tooth specimen. The sample with preheated composite restoration at 50 degrees C showed an intact tooth-restoration interface with no micro leakage. However, the preheated composite at 60 degrees C showed large amount of microleakage. CONCLUSION: Under the current limitation of the study, preheated composite at 50 degrees C showed the least micro-leakage. PMID- 27504409 TI - Effect of Calcium Hydroxide, Chlorhexidine Digluconate and Camphorated Monochlorophenol on the Sealing Ability of Biodentine Apical Plug. AB - INTRODUCTION: Teeth with immature apex are managed by establishing an apical plug using various materials and techniques. However, the use of previously placed intracanal medicament may affect the sealing ability of permanent filling material used as an apical plug. AIM: To evaluate the effect of removal of previously placed Calcium Hydroxide, Chlorhexidine Digluconate and Camphorated Monochlorophenol as an intracanal medicament on the sealing ability of the Biodentine as an apical plug. MATERIALS AND METHODS: A total of 72 recently extracted human permanent teeth with single root were selected and stored in saline at room temperature. The crown portion of each tooth was removed at the level of cemento enamel junction; 14mm root length was taken as standard length. All the roots were submerged in 20% sulphuric acid up to 3 mm from the apex, for four days for root resorption. One sample was cut longitudinally to look for root resorption under stereo microscope. The canal preparation was done; the roots were kept in moist gauze after instrumentation. A total of 71 roots were randomly divided into three groups. GROUP 1:Calcium hydroxide paste, GROUP 2: Chlorhexidine digluconate, GROUP 3: Camphorated Monochlorophenol (CMCP). The medicaments were removed with stainless steel hand files and 0.5% sodium hypochlorite irrigation. After removal of medicament Biodentine was placed in apical third of resorbed roots and the remaining portion of the canals was filled with gutta-percha. All the 71 roots were analysed with fluid filtration method for evaluating microleakage. RESULTS: Comparing all the three groups statistically there was no significant difference. The mean values were found more for group 1 followed by group 2 & 3. CONCLUSION: All the groups showed microleakage. Calcium hydroxide showed the maximum microleakage followed by Chlorhexidine digluconate and least with CMCP. PMID- 27504408 TI - An in vitro Comparative Evaluation of Three Remineralizing Agents using Confocal Microscopy. AB - INTRODUCTION: The caries process has been thought to be irreversible, resulting in the permanent loss of tooth substance and eventually the development of a cavity. Recent approaches focused on application of remineralizing agents to incipient carious lesions, aim at controlling demineralization and promoting remineralization. Remineralizing agents create a supersaturated environment around the lesion; thus, preventing mineral loss and forces calcium and phosphate ions in the vacant areas. AIM: To compare and evaluate the remineralization potential of Fluoride Varnish, CPP-ACP Paste (Casein Phosphopeptide-Amorphous Calcium Phosphate) and fTCP Paste (functionalized Tricalcium Phosphate) using confocal microscope. MATERIALS AND METHODS: Two windows of 3X3mm were created on the labial cervical and incisal thirds in 60 permanent maxillary central incisors. The teeth were demineralized to create artificial caries and divided into three groups of 20 each. Group I specimens were coated with Fluoride Varnish once whereas those in CPP-ACP paste group and fTCP group were brushed for 2 minutes, twice daily for 20 and 40 days. The specimens were stored in artificial saliva during the study period and were later sectioned and observed under confocal microscope. Data obtained was statistically analyzed using Fischer's exact test, ANOVA and post-hoc Bonferroni's test. RESULTS: Fluoride Varnish, CPP ACP Paste and fTCP Paste showed remineralization of artificial carious lesions at both the time intervals. Fluoride varnish showed the highest remineralization followed by CPP-ACP Paste and fTCP Paste. A statistically significant increase in remineralization potential of CPP-ACP Paste and fTCP Paste was observed at the end of 40 days as compared to 20 days. CONCLUSION: Fluoride varnish showed the greatest remineralization potential of artificial carious lesions followed by CPP ACP Paste and fTCP Paste respectively. PMID- 27504410 TI - Comparative Evaluation of Ciprofloxacin Levels in GCF and Plasma of Chronic Periodontitis Patients: Quasi Experimental Study. AB - INTRODUCTION: For any antimicrobial approach to be successful in periodontal therapy, it is important that the antimicrobial agent targets the sub-gingival biofilm by attaining sufficient concentration at the sub-gingival site. AIM: The purpose of the present study was to determine and compare the concentrations of ciprofloxacin present in Gingival Crevicular Fluid (GCF) and plasma after its systemic administration. MATERIALS AND METHODS: A total of 20 subjects, in the age group of 30-60 years satisfying the inclusion and exclusion criteria, were chosen from the outpatient Department of Periodontology, Government Dental College and Hospital, Hyderabad and consent was obtained. Subjects were put on oral ciprofloxacin therapy (Baycip, Bayer Corporation) of 500mg twice daily doses for five days to establish steady state tissue levels of the agent. GCF and serum samples were collected at the 72(nd) hour after the first dose of ciprofloxacin and were compared using unpaired t test. RESULTS: The mean gingival index value of the subjects was 1.8 +/- 0.59 and the mean probing depth of the subjects taken in the study was 5.724 +/- 0.47mm. The results of this study showed that ciprofloxacin concentrations were significantly higher (p<0.001) in GCF than in plasma. CONCLUSION: Results from the present study and those from the earlier studies clearly indicate the ciprofloxacin's ability to reach and concentrate in infected periodontal sites via GCF. This property of ciprofloxacin may be useful for eradication of periodontal pathogens, thus improving the outcome of periodontal therapy. PMID- 27504411 TI - Assessment of Skeletal Maturation in Concordance to Statural Height and Body Weight in 12-Year-Old Children - A Cross-Sectional Study. AB - INTRODUCTION: To analyse the importance of bodily characteristics of growing children and its correlation towards skeletal maturity. This further aids orthodontists in proper treatment planning. AIM: The purpose of this study was to assess the correlation between cervical vertebrae maturation, statural height and body weight as measured in 12 -year-old children. MATERIALS AND METHODS: Lateral cephalograms were taken as a part of treatment records in 94 children along with their statural height and body weight. The Cervical Vertebrae Maturation Index (CVMI) was used to trace the C2, C3 and C4 vertebrae respectively and the data were then correlated to the chart provided by the Indian Council for Medical Research (ICMR). RESULTS: The overall sample showed a statistically significant correlation between CVMI and height (p=0.047). Girls showed significant correlation in their mean heights to the CVMI staging (p=0.012) while the boys exhibited a maximal mean height value in Cervical Stage (CS) 5 followed by CS3. There was no significant correlation between weight and CVMI. The mean CVMI stage seen in boys and girls were CS2 and CS3 respectively. CONCLUSION: There exists a definitive correlation between height and CVMI stages in growing children. Girls showed an advanced level of skeletal maturity in comparison to boys. CVMI staging should be used along with statural height and body weight when considering growth modification procedures. PMID- 27504412 TI - Estimation of Salivary and Serum Biomarkers in Diabetic and Non Diabetic Patients - A Comparative Study. AB - INTRODUCTION: Blood is the gold standard body fluid for diagnosis of Diabetes Mellitus (DM) but saliva offers an alternative to serum as a biological fluid for diagnostic purposes because it contains serum constituents. AIM: The study was conducted to estimate and compare serum and salivary glucose, amylase, proteins, calcium and phosphorus levels in DM and healthy subjects and to evaluate whether saliva can be used as a diagnostic fluid in DM patients. MATERIALS AND METHODS: Study consisted of 120 subjects from OPD of Surendera Dental College, Sriganganagar, Rajasthan, India. The study groups were divided into Group I-60 DM patients (Type I & II) and Group II-60 healthy subjects. The saliva and serum samples were collected from each subject and levels of different biochemical parameters were estimated. RESULTS: Mean serum level of glucose (211.50 +/- 43.82), amylase (79.86 +/- 16.23), total proteins (6.65 +/- 0.84), calcium (7.17 +/- 0.91) and phosphorus (3.68+/-0.65) as observed in Group I while in Group II, glucose (88.81+/-11.29), amylase (77.67+/-14.88), total proteins (6.35+/-0.76), calcium (7.52+/-0.97) and phosphorus (3.96 +/- 0.91) were noted. Mean salivary level of glucose (14.10+/-6.99), amylase (1671.42+/-569.86), total proteins (1.33+/-1.11), calcium (10.06+/-2.76) and phosphorus (13.75+/-4.45) as observed in Group I while in Group II, glucose (5.87+/- 2.42), amylase (1397.59 +/ 415.97), total proteins (1.36+/-0.81), calcium (7.73+/-2.78) and phosphorus (8.39 +/- 1.95) were noted. On comparing values in saliva and serum, among two groups, an insignificant difference (p>0.005) was found between few of them. CONCLUSION: Values regarding blood and salivary biochemical parameters were distinctly different between two groups suggesting salivary parameters can be used as a diagnostic alternative to blood parameters for diabetes mellitus. PMID- 27504413 TI - Buccal Micronucleus Cytome Assay in Sickle Cell Disease. AB - INTRODUCTION: Sickle Cell Anaemia (SCA) is a commonly inherited blood disorder preceded by episodes of pain, chronic haemolytic anaemia and severe infections. The underlying phenomenon which causes this disease is the point mutation in the haemoglobin beta gene (Hbbeta) found on chromosome 11 p. Increased oxidative stress leads to DNA damage. DNA damage occurring in such conditions can be studied by the buccal micronucleus cytome assay, which is a minimally invasive method for studying chromosomal instability, cell death and regenerative potential of human buccal tissue. AIM: To evaluate genomic instability in patients with sickle cell disease by buccal micronucleus cytome assay. MATERIALS AND METHODS: The study included 40 sickle cell anemia patients (Group A) and 40 age and sex matched controls (Group B). Buccal swabs were collected and stained with Papanicolaou (PAP). Number of cells with micronucleus, binuclei, nuclear bud, pyknosis and karyolysis were counted in two groups as parameters for the evaluation of genome stability. RESULTS: All the analysis was done using t-test. A p-value of <0.001 was considered statistically significant. There was a statistically significant increase in micronuclei number in SCA patients when compared with controls. Karyolytic (un-nucleated) cell number in Group A was more than to those of the controls. CONCLUSION: The results might suggest that patients with sickle cell anaemia have genome instability which is represented by the presence of micronuclei in the somatic cells. Presence of apoptotic cells might only indicate the bodily damage to the tissue as a result of the disease. PMID- 27504414 TI - Assessment of Oral Health Knowledge, Attitude and Self-Care Practice Among Adolescents - A State Wide Cross- Sectional Study in Manipur, North Eastern India. AB - INTRODUCTION: The World Health Organization global strategy of promoting oral health have shown vast improvements in developed countries but the scenario is glum among underprivileged communities due to lacunae in implementation of these promotional programs. Manipur, a North Eastern state in India, is one such marginalized area. AIM: The study aimed to evaluate Knowledge, Attitude and Practice (KAP) towards oral health in 15-18 year adolescents residing in Manipur together with the association of these variables to sociodemographic factors. MATERIALS AND METHODS: This cross-sectional study included 810 healthy adolescents drawn from various primary health care centers spanning in all the nine districts of Manipur. A closed ended questionnaire for the purpose of collecting data was used in the survey. RESULTS: Of the total participants 90.9% had high knowledge, 79.8% had favorable attitude and 70.4% had adequate practice towards oral health. Education of the parents and respondents was the only factor significantly associated with all three variables, knowledge, attitude and practice. Significant and positive linear correlation between knowledge-attitude (r=0.369, p<0.01) knowledge-practice (r=0.405, p<0.01) and attitude-practice (r =0.353, p<0.01), were observed. CONCLUSION: An overwhelming majority of the respondents had high knowledge, favorable attitude and sound practice with respect to oral health. A positive linear correlation exists between the knowledge, attitude and practice. Evidence based reinforcement programs should be introduced to further reduce the gap between knowledge, attitude and practice. The study will also serve as a reference value for use in future evaluation to help measure the effectiveness of the planned activities. Future research needs to focus on establishing the dental caries prevalence and oral hygiene status of Manipuri youth. PMID- 27504415 TI - Comparison of the Antimicrobial Efficacy of Octenidine Dihydrochloride and Chlorhexidine with and Without Passive Ultrasonic Irrigation - An Invitro Study. AB - INTRODUCTION: Elimination of microorganisms from infected root canals is a complicated task. Numerous measures have been described to reduce the microbial load in the root canal system, including the use of various instrumentation techniques, irrigation regimens and intracanal medicaments. The drawbacks of few commonly used irrigants include toxic and harmful side effects, microbial resistance to antimicrobial agents and staining. Hence there is a need for alternative agents which are nontoxic, effective and safe. AIM: To compare and evaluate antimicrobial effects of 2% Chlorhexidine (CHX) versus 0.1% Octenidine Dihydrochloride (OCT) as root canal irrigant with and without passive ultrasonic irrigation against Enterococcus faecalis (E. faecalis) in vitro and to evaluate the depth of penetration of irrigant solution into the dentinal tubules at the junction of middle and apical third. MATERIALS AND METHODS: Forty eight freshly extracted, single rooted human mandibular premolars were decoronated and root specimen standardized to 14mm. Biofilm of E. faecalis (strain ATCC 29212) was grown for seven days and the specimens were divided into four groups (n=12) based on irrigation protocol : Group I- Conventional Syringe Irrigation (CSI) with 2% CHX, Group II- CSI + 0.1% OCT, Group III-Passive Ultrasonic Irrigation (PUI) + 2% CHX and Group IV- PUI+ 0.1% OCT. Dentin shavings were collected at two depths (200MUm and 400MUm) and total number of colony forming units were determined. The data were statistically analyzed using ANOVA, Scheffes multiple comparison of means and paired t-test (p<0.05). RESULTS: Group III and IV (PUI) showed significant difference compared to Group I and II (CSI) both at 200MUm and 400MUm (p=0.000). For Group III and Group IV no significant differences were found at 200MUm and 400MUm (p=1.000 and 0.363 respectively), however significant difference was found between data at 200MUm and 400MUm for all the four groups (p=0.000). CONCLUSION: Octenidine (0.1%) was more effective than 2% Chlorhexidine against E. faecalis both at 200MUm and 400MUm. Passive ultrasonic irrigation proved to enhance the antimicrobial action of the irrigants. PMID- 27504417 TI - Evaluation of Effect of Brushite-Calcite and Two Indigenous Herbs in Removal of Fluoride from Water. AB - INTRODUCTION: The acceptable concentration of fluoride in drinking water is 1.5mg/l. Excess fluoride in drinking water causes fluorosis. Fluorosis is an important public health problem in India. Several treatment technologies suggested in the past for removing excess fluoride generated and causes various chemical byproductswhich are hazardous to public. In recent years, there has been a resurgence of interest to use natural materials due to cost and associated health and environmental concerns of synthetic organic polymers and inorganic chemicals. AIM: The aim of this study was to evaluate and compare the defluoridating capability of the brushite-calcite with that of two indigenous herbs, tulsi and wheat grass. MATERIALS AND METHODS: One gram of brushite-calcite combination, tulsi and wheat grass were separately added to 10 containers, each containing 1.0 l of prepared distilled water with a fluoride concentration of 5ppm and naturally fluoridated water at 2ppm. Half of the samples were boiled for one minute in a domestic electric kettle for one minute and allowed to cool. The remaining half of the samples was left un-boiled. Fluoride concentration in all the samples was assessed at the end of 30 minutes and 24 hours using fluoride ion selective electrode method. Data was analyzed using unpaired t-test and one-way ANOVA. RESULTS: For water with 2ppm and 5ppm fluoride, brushite-calcite had shown highest de-fluoridation capacity (p=0.001) at the end of both 30 minutes and 24 hours in boiled samples whereas tulsi (p=0.001) was most effective in un-boiled samples. CONCLUSION: The results of the study suggest that tulsi can be used for domestic water defluoridation as it is economic, safe and effective. PMID- 27504416 TI - Comparison of Dental Caries Experience in Children Suffering From Epilepsy with and without Administration of Long Term Liquid Oral Medication. AB - INTRODUCTION: Sucrose is added as sweetening agent in liquid oral medication (LOM) to mask the acrid taste of medicines which may be potentially cariogenic. Many children under long term LOM therapy for treatment of epilepsy may be susceptible to dental caries. AIM: To assess and compare dental caries experience in children under long term liquid oral medication with those not under such medication among 2-12 years old children suffering from epilepsy. MATERIALS AND METHODS: A cross-sectional study was undertaken on a total of 84 children aged 2 12 years, who were suffering from epilepsy receiving liquid oral medication for more than 3 months were selected (study group) and for comparison 106 children of similar age group and disease but on other forms of medication were included as control group. Dental caries was assessed using DMFT/DMFS (Decayed, Missing, Fillled Teeth / Surfaces), dmft/dft and dmfs/dfs indices. One-way ANOVA and t test were used with p-value fixed at 0.05. Univariate logistic regression was applied. RESULTS: Children on LOM were at increased risk of dental caries than those with other forms of medications (OR: 2.55, 95% CI (2.37-4.15) p=0.000, HS). Caries prevalence was high in the study group (76.1%) when compared to control group (55.6%). CONCLUSION: Long term use of liquid medicines containing sucrose is a risk factor for dental caries among children with epilepsy. PMID- 27504418 TI - Evaluation of TLR2 and 4 in Chronic Periodontitis. AB - INTRODUCTION: Periodontal disease is the major cause of adult tooth loss and is commonly characterized by a chronic inflammation caused by infection due to oral bacteria. Members of Toll-Like Receptor (TLR) family recognize conserved microbial structures, such as bacterial lipopolysaccharides and activate signalling pathways that result in immune responses against microbial infections. AIM: The aim of the present study was to assess the mRNA expression of Toll-Like Receptor 2 and 4 in tissues with or without chronic periodontitis. MATERIALS AND METHODS: Gingival tissue samples were collected from controls (30 subjects with healthy periodontal tissues) and experimental group (30 subjects with chronic periodontitis). Total RNA was extracted and RT-PCR was done for evaluation of TLR 2 and TLR-4. Mann Whitney U-test, Pearson Chi-square Test was used for statistics. RESULTS: The results showed that there is a significant (p-value= 0.004) association between TLR-4 and the experimental group comprising of chronic periodontitis patients in comparison to the insignificant (p-value= 0.085) TLR-2 expression. CONCLUSION: This study concludes that TLR-2 and TLR-4 expressed in the gingival tissues recognize different bacterial cell wall components thus helping us to associate its potential in diagnosing periodontal disease. Hence, in the future, these scientific findings can pave the way in using TLR as a diagnostic biomarker for periodontal disease. PMID- 27504419 TI - Evaluation of Antifungal Efficacy of Ethanolic Crude Lawsone and Listerine Mouthwash in Uncontrolled Diabetics and Denture Wearers - A Randomized Clinical Trial. AB - INTRODUCTION: Lawsonia Inermis (LI) is a shrub cultivated throughout India. Many in vitro studies have been done on antifungal activity of LI, although none of the studies have been conducted invivo. AIM: To evaluate the antifungal efficacy of ethanolic extract of crude lawsone in comparison with listerine mouth wash in known diabetics and wearing dentures. MATERIALS AND METHODS: A total of 60 subjects were taken and randomly divided into two groups of 30 each. Group 1 received crude lawsone mouthwash and Group 2 received listerine mouth wash. Oral rinse technique was performed. Each subject was given distilled water at baseline and Colony Forming Units (CFU) of candidal species was determined. Post therapeutic samples were then collected 1hr and 1week following drug usage and they were further advised to use given mouth washes twice daily with volume of 5ml/rinse for 30 seconds and CFU was evaluated. RESULTS: Crude lawsone mouthwash showed superior antifungal activity when compared to listerine mouthwash. On individual comparison of both mouth washes at baseline, 1hr and 1week highly significant results were obtained using inferential statistics. The inter group comparison was done using independent t-test where lawsone was considered to be more effective in reducing CFU, at 1hr and 1week of using the mouth wash (p<0.01). Subjective symptoms like taste and smell were determined by chi square test where good taste was felt for lawsone and olfactory satisfaction was good with listerine (p<0.01). Burning sensation was found to be more with listerine mouth wash. CONCLUSION: The present study revealed superior antifungal activity with ethanolic extract of crude lawsone mouth wash compared with listerine mouthwash. PMID- 27504420 TI - An Evaluation of the Stress Distribution in Screw Retained Implants of Different Crown Implant Ratios in Different Bone Densities Under Various Loads-A FEM Study. AB - INTRODUCTION: Studies on stress distribution around screw retained implants in different bone densities are limited. In clinical situations crowns of different heights are placed on the implants and the effect of varying crown implant ratio on the bone is not understood properly. AIM: To evaluate and compare the stress distribution in different screw retained implants for different crown-implant ratios in different bone densities under various occlusal loads using three dimensional finite element analyses. MATERIALS AND METHODS: In this invitro study the stress distribution was evaluated and compared between two different crown heights (7.5mm, 10mm) retained on implants by using different screw materials (commercially pure titanium, titanium alloy) in two different densities of bone D2, D3 under various load (100N, 200N) applications by using finite element analysis. RESULTS: For crown height of 7.5mm, in D2 bone density when vertical load of 200N was applied, the maximum stress concentration was 1780N/cm(2), for oblique load of 100N it was 2936N/cm(2) respectively and in D3 bone density when vertical load of 200N was applied, the maximum stress concentration was 1820N/cm(2), for oblique load of 100N it was 3477N/cm(2) respectively. When the crown height is increased to 10mm, the maximum stress concentration in D2 bone was 1875N/cm(2) for vertical load, 4015N/cm(2) for oblique load and in D3 bone the maximum stress concentration was 2123N/cm(2) for vertical load and 4236N/ cm(2) for oblique load. In case of titanium screws for crown height of 7.5 mm, when vertical load was applied, stress concentration was 1603 N/cm(2) where as for titanium alloy screw it was 1820N/cm(2). In case of 10mm crown height stress concentration was 1904N/cm(2) for titanium screw and 2123N/cm(2) for titanium alloy screw. In case of oblique loading for 7.5mm crown height stress concentration was 3155N/cm(2) for titanium screw 3477N/cm(2) for titanium alloy screw. For 10mm crown height stress concentration was 4236N/cm(2) for titanium screw, 4663N/cm(2) for titanium alloy screw. CONCLUSION: Stress concentration was less and stress distribution was better in D2 bone density than in D3 bone density. Stress concentration was less and stress distribution was better in commercially pure titanium screw than in titanium alloy screw. With the increase in the height of crown (i.e., from 7.5mm to 10mm) stress concentration and stress distribution also increased. PMID- 27504421 TI - Surgical Re-entry of an Intentionally Replanted Periodontally Compromised Tooth Treated with Platelet Rich Fibrin (PRF): Hopeless to Hopeful. AB - Intentional replantation is generally contraindicated in periodontally compromised teeth however, there are reports suggesting that it can be a successful treatment alternative for periodontally involved hopeless teeth. Currently there is dearth of evidence regarding the success of this therapy, especially evidence for the effectiveness of autologous platelet rich fibrin is lacking. We present a case report of a 23-year-old male patient with periodontally hopeless left maxillary central incisor having bone loss extending beyond root apex. The tooth was gently extracted and replanted utilizing root conditioning and combined regenerative therapy (Xenograft, PRF and Type I Collagen Membrane). Surgical re-entry at nine months revealed bone formation in the apical third of the tooth. At one year, 87% radiographic bone gain was accomplished. The improvement in the clinical and radiographic parameters reinforced by the re-entry surgery findings strongly suggest that intentional replantation may be a cost-effective substitute to implants and tooth supported prosthesis in situations where conventional periodontal therapy would yield compromised outcomes. PMID- 27504422 TI - Clinicopathological and Immunohistochemical Characteristics of Verruciform Xanthoma of the Lower Gingiva: A Case Report. AB - Verruciform xanthoma (VX) is a rare benign lesion and mainly effects the oral mucosa. This slow-growing asymptomatic lesion typically develops along the gingival margin of the masticatory mucosa, followed by the hard palate, tongue, buccal mucosa, floor of the mouth, alveolar mucosa, soft palate and junction between the hard and soft palate. Moreover, this lesion can also affect the skin and genital organs. Clinically, VX generally presents a sessile or pedunculated appearance, forming a papule or single plaque with verrucous or papillomatous mucosal growth. The colour (white, pink, grey, or yellow) depends on the thickness of the overlying epidermis. In fact, the clinical findings of VX are similar to those of verrucous carcinoma and other benign tumours, such as squamous papilloma, verruca vulgaris and mucosal fibroma. For this reason, clinical and histopathological examinations are essential for accurate differential diagnosis. Histologically, VX is characterized by parakeratosis, rete ridges of uniform depth and the accumulation of foam cells, which are also called "xanthoma cells". Here, we describe the clinicopathological and immunohistochemical findings of a VX located on the lower gingiva of a 64-year old male patient. PMID- 27504423 TI - Zinsser-Cole-Engman Syndrome: A Rare Case Report. AB - Zinsser-Cole-Engmann syndrome also called Dyskeratosis Congenita (DKC) is a rare genodermatosis first described by Zinsser in 1906. Mutations in DKC1 gene is responsible for DKC. It is usually inherited as an X-linked recessive trait, resulting in a striking male predilection. It is characterized by a triad of reticular skin pigmentation, nail dystrophy and mucosal leukoplakia. Complications include predisposition to malignancy and bone marrow failure. Here, we report a case of DKC in a 9-year-old boy with classic triad of signs. Special investigations like endoscopy, barium swallow and bone-marrow aspiration study confirmed the diagnosis. There is no effective treatment for DKC. Some preventive measures can be adopted and the only long term cure for the haematological abnormalities is allogenic haemopoietic stem cell transplantation. PMID- 27504424 TI - A Rare Case of Tamarind Seed Induced Oral Submucous Fibrosis in a 12-Year-Old Indian Boy. AB - Oral Submucous Fibrosis (OSMF) is a chronic debilitating, potentially malignant disorder of the oral cavity. It is characterized by restricted mouth opening which results due to abnormal accumulation of collagen in the sub-epithelial layers leading to dense fibrous bands in the mouth. The pathogenesis of the disease is believed to be multifactorial. However, literature reports suggest a strong association of OSMF and arecanut chewing habit. The present paper presents a case of OSMF in a 12-year-old boy without arecanut chewing habit, but with a heavy practice of chewing tamarind seeds. PMID- 27504425 TI - Malignant Peripheral Nerve Sheath Tumor -A Rare Malignancy in Mandible. AB - Malignant Peripheral Nerve Sheath Tumor (MPNST) is biologically an aggressive tumor that is usually found in the extremities, trunk and infrequently found in the head and neck area particularly in the jaws, arising from the cells allied with nerve sheath. Mandibular MPNST may either arise from a preexisting neurofibroma or develop de novo. Because of the greater variability from case to case in overall appearance both clinically and histologically, a case of MPNST of the mandible in a 25-year-old female patient is reported. The lesion was excised and immunohistological studies (S-100 & Neuron specific enolase) were conducted to confirm the neural origin. PMID- 27504426 TI - Mystery behind Non-Healing Wound at Chin Region - Myiasis due to Neglected Trauma - A Case Report with Review of Literature. AB - Myiasis is the infestation of human beings with fly larvae which feed on host's living or dead tissue. Diagnosis of this condition is made by the presence of larvae in affected body parts. The standard treatment is the mechanical removal of the maggots from the lesion and management of the general systemic condition. This paper report a case of myiasis at the chin region in a 45-year-old male managed by manual removal of larvae after topical application of turpentine oil, surgical debridement of necrotic tissues and antimicrobial therapy. PMID- 27504427 TI - An Approach with Hybrid Segmental Mechanics. AB - Present case report provides an insight into the hybrid segmental mechanics with treatment of 13-year-old male, considering the side effects of sole continuous arch wire sliding mechanics. Patient was diagnosed as a case of skeletal class I jaw relationship, low mandibular plane angle, class II molar relation on right and class I molar relation on left side, anterior cross bite, crowding of 12mm in upper, 5mm in lower arch. He also had proclined upper and lower anteriors by 2mm, convex profile and incompetent lips. Total treatment duration was 20 months, during which segmental canine retraction was performed with TMA (Titanium, Molybdenum, Aluminum) 'T' loop retraction spring followed by consolidation of spaces with continuous arch mechanics. Most of the treatment objectives were met with good intraoral and facial results within reasonable framework of time. This approach used traditional twin brackets, which offered the versatility to use continuous arch-wire mechanics, segmental mechanics and hybrid sectional mechanics. PMID- 27504428 TI - Classical Cases of Lymphangioma - As Multiple Vesicular Eruptions. AB - Lymphangiomas are uncommon congenital hamartomas of the lymphatic system, usually diagnosed in infancy and early childhood. They are rarely situated in oral cavity and most commonly identified on the anterior two-thirds of the tongue. Though rarely seen in the oral cavity, lymphangiomas are the entities which should be taken into consideration by the clinician while examining vesicular lesions of the oral cavity. Early recognition is of utmost importance for the initiation of proper treatment and to avoid serious complications. We hereby report two classical cases of lymphangioma of the buccal mucosa with multiple vesicular eruptions, a rare site. PMID- 27504429 TI - Benign Fibrous Histiocytoma of Mandible: A Case Report and Updated Review. AB - Benign Fibrous Histiocytoma (BFH) is a well recognised tumour of the soft tissue, developing entirely within the subcutaneous tissue, the deep soft tissues or in the parenchymal organs. However, BFH of bones is poorly defined. It has been rarely reported in the bones with femur, tibia and pelvic bone being the most commonly affected bones. Involvement of the jawbones is rare. Their clinical and radiographic features often simulate the common odontogenic and non-odontogenic lesions of the jaws. Hence, it is imperative for a dentist to have proper knowledge of various conditions affecting the jaws. Here we report a case of BFH which presented as an indolent swelling of the right mandibular posterior region for 15 years. The case emphasizes the need for considering BFH in the differential diagnosis of swellings of the jaws. PMID- 27504430 TI - Test Tube Tooth: The Next Big Thing. AB - Unlike some vertebrates and fishes, humans do not have the capacity for tooth regeneration after the loss of permanent teeth. Although artificial replacement with removable dentures, fixed prosthesis and implants is possible through advances in the field of prosthetic dentistry, it would be ideal to recreate a third set of natural teeth to replace lost dentition. For many years now, researchers in the field of tissue engineering have been trying to bioengineer dental tissues as well as whole teeth. In order to attain a whole tooth through dental engineering, that has the same or nearly same biological, mechanical and physical properties of a natural tooth, it's necessary to deal with all the cells and tissues which are concerned with the formation, maintenance and repair of the tooth. In this article we review the steps involved in odontogenesis or organogenesis of a tooth and progress in the bioengineering of a whole tooth. PMID- 27504431 TI - Prevalence of Periodontal Disease in the General Population of India-A Systematic Review. AB - INTRODUCTION: Periodontal disease is a chronic inflammatory disease resulting in destruction of tissues and structures surrounding the teeth thus, if left untreated causes loss of teeth and ultimately results in edentulism, posing a great negative impact on individuals' quality of life. Hence the global epidemiological data suggests periodontal disease to be one of a major burden on oral diseases. To reduce this burden it is necessary to know the true prevalence of the disease according to which proper initiatives can be formulated. India being home to nearly 1.2 billion people and one amongst the rapidly developing country, its population requires being systemically as well as orally healthy to lead a good quality of life. However due to large heterogenecity amongst its residing population in terms of geographical area, culture, education, socioeconomic status, a variety of oral diseases like periodontal diseases are prevalent here. Even though the early studies suggested that the population is highly susceptible to the disease, the true prevalence of periodontal disease has not been found yet due to paucity in literature available. AIM: To systematically review the available literature taken from various parts of India and find the prevalence rate of periodontal disease amongst the general population of India. MATERIALS AND METHODS: A literature search was performed using PUB MED, COCHRANE and EMBASE databases on August 6, 2015. Following full text assessment a thorough references search was made and potential studies were included. A Quality assessment of retrieved articles from 2(nd) round was done using a self designed questionnaire and only field survey studies were included in the systematic review. RESULTS: The literature search yielded six studies which had performed field surveys to find the prevalence of periodontal disease in their respective areas. These studies have observed different sets of age groups and the same has been accomplished by using Community Periodontal Index (CPI) or Community Periodontal Index of Treatment Needs (CPITN). It was also found that no prevalence studies have been carried out in few North and North Eastern states and Union Territories of India. CONCLUSION: Due to non-availability of same age groups in selected studies an overall prevalence rate could not be obtained. However, it was observed that few areas of states like West Bengal, Uttar Pradesh and Assam have reported a prevalence rate of periodontal disease of more than 85% in their general population. The data from the present systematic review calls for a combined initiative from the Government of India and Dental council of India to have a nationwide multicentric prevalence studies to obtain the true prevalence rate of periodontal disease in India and interventions should be provided for the same to maintain the oral health and quality of life of the affected population. PMID- 27504432 TI - Certainty of S100 from Physiology to Pathology. AB - S100 exists in wide variety of tissues and cell types, originally isolated from brain tissue and they are of low molecular weight proteins. S100 is evenly distributed in cytoplasm and also in nucleoplasm and is involved in both intercellular and extracellular functions. S100 protein is generally expressed in normal and also in pathological conditions. In current review, we discuss: a) update nomenclature of the various S100 proteins, b) expression of S100 in oral diseases (different soft tissue tumors, odontogenic cyst and tumor) for diagnostic value and also to know their histogenesis, c) role of S100 and RAGE receptor in oral squamous cell carcinoma. PMID- 27504433 TI - Transposition with Fusion of Maxillary Incisors in Primary Dentition: A Report of a Rare Case. PMID- 27504434 TI - Giant Sialolith of Wharton's Duct Treated Economically in a Poor Patient. PMID- 27504435 TI - Endodontic Management of a Three Rooted Maxillary Premolar: A Report of 3 Cases. PMID- 27504436 TI - Melanotic Neuroectodermal Tumor of Infancy. PMID- 27504437 TI - Atypical Response of Gingival Tissue to Extruded Metapex. PMID- 27504438 TI - Revisited:Association of Serum Cholesterol, Triglyceride, High and Low Density Lipoprotein (HDL and LDL) Levels in Chronic Periodontitis Subjects with Risk for Cardiovascular Disease (CVD): A Cross Sectional Study. PMID- 27504439 TI - Correction. AB - [This corrects the article DOI: 10.7860/JCDR/2016/18458.7824.]. PMID- 27504440 TI - Abdominal Symptoms and Incident Gallstones in a Population Unaware of Gallstone Status. AB - Introduction. Symptoms associated with newly formed gallstones have never been studied in a population unaware of their gallstones. The objective of this population-based cohort study was to determine which debut of abdominal symptoms was associated with newly formed gallstones. Materials and Methods. A cohort study was performed of a random sample from general population of Copenhagen. Participants had ultrasound examinations and answered questionnaires about abdominal symptoms at baseline and two reexaminations over 12 years. Participants were not informed of gallstone status. Inclusion criteria were no gallstones or cholecystectomy at baseline and attending a reexamination. Results. Of 3,785 participants, 2,845 fulfilled inclusion criteria. Changes in overall abdominal pain were not significantly different between incident gallstones or gallstone free participants. Multiple adjusted logistic regression analyses showed that incident gallstones were significantly associated with debut of abdominal pain with projection, localized in the whole upper abdomen, and of longer duration. No significant associations for functional symptoms were identified. Conclusions. A new onset of abdominal pain with projection, localized in the whole upper abdomen, and of longer duration is associated with newly formed gallstones in participants unaware of gallstone status. Functional symptoms should not be the indication for surgical treatment. PMID- 27504442 TI - Slowly Growing Nodule on the Trunk: Cutaneous Granular Cell Tumor. AB - Granular cell tumor (GCT) is a rare benign neoplasm of the skin that accounts for 0.5% of all soft-tissue tumors. The tumor mostly presents with a symptomatic slowly growing solitary nodule and overlying normal skin; therefore, it is not always considered in the differential diagnosis. Here, we report a 58-year-old female patient who presented with a 4-year history of a slowly growing mass, with a dimension of 5 * 4 cm on her left waist, diagnosed as a GCT at the histopathological examination. The neoplastic cells had centrally located nuclei and granular eosinophilic cytoplasm and stained positively for S100, neuron specific enolase, and CD68 antibodies. Fifteen months after surgery, the patient still showed no signs of local recurrence or metastases. Although a large diameter is a feature of malignant GCT, our case with cutaneous GCT was localized on the trunk and did not present malignant features clinically and histopathologically. PMID- 27504441 TI - Season of Birth Predicts Emotional and Behavioral Regulation in 18-Month-Old Infants: Hamamatsu Birth Cohort for Mothers and Children (HBC Study). AB - BACKGROUND: Previous research has demonstrated that the season of birth may predict development of emotional and behavioral regulation during childhood or adolescence. This study examined whether the season of birth predicts effortful control (i.e., the ability to voluntarily choose course of actions during conflict and to plan for the future) and aggression (i.e., the use of physical force and expression of anger toward others) in 18-month-old infants. METHODS: Participants included 885 infants who were enrolled in the Hamamatsu Birth Cohort for Mothers and Children in Hamamatsu, Japan. Seasons of birth were categorized into winter (December, January, and February), spring (March, April, and May), summer (June, July, and August), and autumn (September, October, and November). At 18 months of age, effortful control was assessed using the Early Childhood Behavior Questionnaire, and aggression was measured using the Cardiff Infant Contentiousness Scale. Structural equation modeling analysis with measurement and structural equations was conducted to test our prediction. RESULTS: Effortful control was higher in infants born in spring [B = 0.095, 95% CI (0.014 to 0.175), p = 0.021, beta = 0.146] and summer [B = 0.078, 95% CI (0.001 to 0.156), p = 0.049, beta = 0.118] than in those born in winter. In addition, aggression was lower in those born in spring [B = -0.286, 95% CI (-0.551 to -0.021), p = 0.035, beta = -0.135] than those born in winter, even after controlling for seven covariates. CONCLUSION: The findings suggest that season of birth may determine development of emotional and behavioral regulation skills during early infancy. Future research should pay more attention to the underlying mechanisms of the effects of birth season on development of emotional and behavioral regulation during infancy. PMID- 27504443 TI - Bednar Tumor: An Uncommon Entity. AB - Bednar tumor is an uncommon variant of dermatofibrosarcoma protuberans. Also known as pigmented dermatofibrosarcoma protuberans, this tumor is of intermediate grade. It is seen in adults and has a predisposition to affect the shoulder region. We report a rare case of Bednar tumor in a 40-year-old female patient. The diagnosis of Bednar tumor must be considered while reporting pigmented subcutaneous spindle cell lesions. PMID- 27504444 TI - Paraneoplastic Dermatosis in a Patient with Anaplastic Large-Cell Lymphoma: Case Report and Literature Review. AB - BACKGROUND/AIMS: Paraneoplastic dermatoses are skin disorders that are associated with malignancy. Anaplastic large T-cell lymphoma (ALTCL) has rarely been associated with paraneoplastic skin manifestations such as gangrenous foot ulcers and erythroderma. METHODS: We describe a case of ALTCL presenting as a large annular skin rash. The clinical picture, course, and treatment will be discussed along with current hypotheses on the mechanism of paraneoplastic syndromes. RESULTS: Skin manifestations in ALTCL most commonly arise in two distinct ways; either as primary cutaneous lymphoma manifestation or as systemic disease with secondary metastasis. Less commonly, systemic disease causes skin manifestations secondary to a paraneoplastic process without infiltration of malignant cells. This is thought to be mediated by an immunologic reaction to tumor antigen or the result of cytokines and other inflammatory markers produced by the tumor itself. CONCLUSION: Paraneoplastic dermatoses could be the initial presentations of systemic lymphoma. Knowledge about their association with anaplastic large-cell lymphoma may help with timely diagnosis. In a patient with unexplained dermatosis associated with B symptoms who is unresponsive to topic treatment, an investigation for systemic lymphoma workup is warranted. PMID- 27504445 TI - Lrig1 Expression in Human Sebaceous Gland Tumors. AB - BACKGROUND: Sebaceous glands contribute significantly to the barrier functions of the skin. However, little is known about their homeostasis and tumorigenesis. Recently, increased expression of stem cell marker Lrig1 has been reported in sebaceous carcinoma-like tumors of K14DeltaNLef1 transgenic mice. In this study, we analyzed the Lrig1 expression in human sebaceous tumors. METHODS: Twenty-eight formalin-fixed paraffin-embedded sebaceous tumor specimens (7 sebaceous hyperplasias, 7 sebaceous adenomas, 10 sebaceomas and 4 sebaceous carcinomas) were stained with anti-Lrig1, anti-CD44v3 and anti-Ki67 antibody. RESULTS: Four (100%) sebaceous carcinomas, 8 (80%) sebaceomas, 3 (43%) sebaceous adenomas and no sebaceous hyperplasia showed Lrig1 overexpression. DISCUSSION AND CONCLUSION: Lrig1 is a known tumor suppressor gene and is usually considered to be an indicator of poorly aggressive tumors. In human sebaceous tumors, the stronger Lrig1 staining in sebaceous carcinoma compared to other sebaceous tumors might be a feature of an advanced stage in tumorigenesis and a bad prognosis. In our study, 100% of sebaceous carcinomas revealed Lrig1 overexpression. We propose that Lrig1 may be used as a possible new marker of poorly differentiated sebaceous carcinoma. PMID- 27504446 TI - A 65-Year-Old Female from Connecticut with Orf Infection. AB - The virus, which causes orf and induces acute pustular skin lesions in sheep and goats, is transmissible to humans yet is rarely observed in North America. We present a case of a 65-year-old female farmer from Connecticut who contracted orf from her sheep. The clinical and histopathologic features, important to arrive at the correct diagnosis of this uncommon yet important infection, are described. We also discuss the benign nature of this condition and emphasize that treatment is not required. PMID- 27504447 TI - Injected Hyaluronidase Reduces the Volume of Exogenous Hyaluronate Fillers in Mice and Results in Clinical Improvement in a Patient with Pretibial Myxedema. AB - BACKGROUND: Hyaluronidases are essential for the breakdown of hyaluronate (HA) in tissues and may be used to prevent the adverse effects of HA fillers. OBJECTIVES: We explored the effect of hyaluronidase on exogenous and endogenous HA in vitro and in vivo. MATERIALS AND METHODS: HA fillers were incubated with different concentrations of hyaluronidase and visualized by electrophoresis. HA fillers were injected in the skin of hairless mice, and 4 h later hyaluronidase was injected in the papules of exogenous HA. Hyaluronidase was injected in the nodule of pretibial myxedema of a male patient with Graves' disease. Skin sections of mice and of the patient were performed, and a skin ultrasound system was used to monitor the evolution of skin lesions. RESULTS: Hyaluronidase showed a degrading effect on HA with increasing concentrations. Hyaluronidase injection significantly decreased the content of exogenous HA within 3 days. Intralesional injection of hyaluronidase resulted in dissolution of the nodule of pretibial myxedema with no recurrence during 3 months. CONCLUSION: These results show that the injection of hyaluronidase is capable of degrading exogenous HA in mouse skin and endogenous HA in human skin in vivo and may be a therapeutic option for skin diseases characterized by abnormal accumulation of HA. PMID- 27504448 TI - Carbon Dioxide Laser Microsurgical Median Glossotomy for Resection of Lingual Dermoid Cysts. AB - Dermoid cysts are epithelial-lined cavities with skin adnexae in the capsule. Only 7% is present in the head and neck. Between 2004 and 2013, four patients with a lingual dermoid cyst underwent a microsurgical carbon dioxide laser resection via a median sagittal glossotomy approach. This approach is an elegant technique combining superior visualization, hemostasis, and little postoperative edema with good wound healing, allowing for perfect function preservation of the tongue. PMID- 27504449 TI - Biology of Saccular Cerebral Aneurysms: A Review of Current Understanding and Future Directions. AB - Understanding the biology of intracranial aneurysms is a clinical quandary. How these aneurysms form, progress, and rupture is poorly understood. Evidence indicates that well-established risk factors play a critical role, along with immunologic factors, in their development and clinical outcomes. Much of the expanding knowledge of the inception, progression, and rupture of intracranial aneurysms implicates inflammation as a critical mediator of aneurysm pathogenesis. Thus, therapeutic targets exploiting this arm of aneurysm pathogenesis have been implemented, often with promising outcomes. PMID- 27504451 TI - The Current Landscape of Genetic Testing in Cardiovascular Malformations: Opportunities and Challenges. AB - Human cardiovascular malformations (CVMs) frequently have a genetic contribution. Through the application of novel technologies, such as next-generation sequencing, DNA sequence variants associated with CVMs are being identified at a rapid pace. While clinicians are now able to offer testing with NGS gene panels or whole exome sequencing to any patient with a CVM, the interpretation of genetic variation remains problematic. Variable phenotypic expression, reduced penetrance, inconsistent phenotyping methods, and the lack of high-throughput functional testing of variants contribute to these challenges. This article elaborates critical issues that impact the decision to broadly implement clinical molecular genetic testing in CVMs. Major benefits of testing include establishing a genetic diagnosis, facilitating cost-effective screening of family members who may have subclinical disease, predicting recurrence risk in offsprings, enabling early diagnosis and anticipatory management of CV and non-CV disease phenotypes, predicting long-term outcomes, and facilitating the development of novel therapies aimed at disease improvement or prevention. Limitations include financial cost, psychosocial cost, and ambiguity of interpretation of results. Multiplex families and patients with syndromic features are two groups where disease causation could potentially be firmly established. However, these account for the minority of the overall CVM population, and there is increasing recognition that genotypes previously associated with syndromes also exist in patients who lack non-CV findings. In all circumstances, ongoing dialog between cardiologists and clinical geneticists will be needed to accurately interpret genetic testing and improve these patients' health. This may be most effectively implemented by the creation and support of CV genetics services at centers committed to pursuing testing for patients. PMID- 27504450 TI - Coexistence of Acute Crescent Glomerulonephritis and IgG4-Related Kidney Disease. AB - INTRODUCTION: IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder that may involve almost each organ or system. IgG4-related kidney disease (IgG4-RKD) refers to renal lesions associated with IgG4-RD. The most frequent morphological type of renal lesions is IgG4-related tubulointerstitial nephritis (IgG4-TIN) which is associated with increased IgG4-positive plasma cell infiltration and interstitial fibrosis. CASE REPORT: Herein, we present a rare case with coexisting IgG4-RKD and acute crescent glomerulonephritis with concomitant severe tubulointerstitial lesions instead of classic IgG4-TIN. CONCLUSION: IgG4-RKD and acute crescent glomerulonephritis can occur in the same patient. This case may give us a clearer viewpoint of the disease. PMID- 27504452 TI - Mitochondrial Cardiomyopathies. AB - Mitochondria are found in all nucleated human cells and perform various essential functions, including the generation of cellular energy. Mitochondria are under dual genome control. Only a small fraction of their proteins are encoded by mitochondrial DNA (mtDNA), whereas more than 99% of them are encoded by nuclear DNA (nDNA). Mutations in mtDNA or mitochondria-related nDNA genes result in mitochondrial dysfunction leading to insufficient energy production required to meet the needs for various organs, particularly those with high energy requirements, including the central nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine system. Because cardiac muscles are one of the high energy demanding tissues, cardiac involvement occurs in mitochondrial diseases with cardiomyopathies being one of the most frequent cardiac manifestations found in these disorders. Cardiomyopathy is estimated to occur in 20-40% of children with mitochondrial diseases. Mitochondrial cardiomyopathies can vary in severity from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. Hypertrophic cardiomyopathy is the most common type; however, mitochondrial cardiomyopathies might also present as dilated, restrictive, left ventricular non-compaction, and histiocytoid cardiomyopathies. Cardiomyopathies are frequent manifestations of mitochondrial diseases associated with defects in electron transport chain complexes subunits and their assembly factors, mitochondrial transfer RNAs, ribosomal RNAs, ribosomal proteins, translation factors, mtDNA maintenance, and coenzyme Q10 synthesis. Other mitochondrial diseases with cardiomyopathies include Barth syndrome, Sengers syndrome, TMEM70-related mitochondrial complex V deficiency, and Friedreich ataxia. PMID- 27504453 TI - Importance of Quality of Life for Adherence to Sublingual Immunotherapy. AB - Background. Nonperception of efficacy ranks among the most commonly cited causes for nonadherence to sublingual immunotherapy (SLIT). Quality of life (QoL) in patients is a determining factor influencing adherence. We investigated QoL and adherence separately in SLIT patients at one pediatric practice in Germany. Methods. We conducted a noninterventional, cross-sectional, retrospective, quality-of-life survey among pediatric patients treated with SLIT. QoL was assessed using the generic SF-12 health survey in German. The items contained in the SF-12 health survey are weighted, added up, and converted to obtain a physical component score (PCS) and a mental component score (MCS). Each component score ranges from 0 to 100; the higher the score, the better the QoL perceived. Results. 201 surveyed patients who had undergone SLIT showed PCS-12 of 49.3 (+/- 7.0) and MCS-12 of 52.6 (+/- 7.2). These figures correlate strongly with those reported for the German general population (n = 2453): PCS-12 of 49.6 (+/- 8.7) and MCS-12 of 52.3 (+/- 8.0). 70.2% (73) of 104 patients were adherent at this practice. Conclusions. QoL in the SLIT patients surveyed here appears as good as that of the general population. Adherence to SLIT at this practice was remarkably better than that reported elsewhere. PMID- 27504454 TI - Heterologous, Expression, and Characterization of Thermostable Glucoamylase Derived from Aspergillus flavus NSH9 in Pichia pastoris. AB - A novel thermostable glucoamylase cDNA without starch binding domain (SBD) of Aspergillus flavus NSH9 was successfully identified, isolated, and overexpressed in Pichia pastoris GS115. The complete open reading frame of glucoamylase from Aspergillus flavus NSH9 was identified by employing PCR that encodes 493 amino acids lacking in the SBD. The first 17 amino acids were presumed to be a signal peptide. The cDNA was cloned into Pichia pastoris and the highest expression of recombinant glucoamylase (rGA) was observed after 8 days of incubation period with 1% methanol. The molecular weight of the purified rGA was about 78 kDa and exhibited optimum catalytic activity at pH 5.0 and temperature of 70 degrees C. The enzyme was stable at higher temperature with 50% of residual activity observed after 20 min at 90 degrees C and 100 degrees C. Low concentration of metal (Mg(++), Fe(++), Zn(++), Cu(++), and Pb(++)) had positive effect on rGA activity. This rGA has the potential for use and application in the saccharification steps, due to its thermostability, in the starch processing industries. PMID- 27504455 TI - Effects of Erythropoietin Administration on Adrenal Glands of Landrace/Large White Pigs after Ventricular Fibrillation. AB - Aim. To evaluate the effects of erythropoietin administration on the adrenal glands in a swine model of ventricular fibrillation and resuscitation. Methods. Ventricular fibrillation was induced via pacing wire forwarded into the right ventricle in 20 female Landrace/Large White pigs, allocated into 2 groups: experimental group treated with bolus dose of erythropoietin (EPO) and control group which received normal saline. Cardiopulmonary resuscitation (CPR) was performed immediately after drug administration as per the 2010 European Resuscitation Council (ERC) guidelines for Advanced Life Support (ALS) until return of spontaneous circulation (ROSC) or death. Animals who achieved ROSC were monitored, mechanically ventilated, extubated, observed, and euthanized. At necroscopy, adrenal glands samples were formalin-fixed, paraffin-embedded, and routinely processed. Sections were stained with hematoxylin-eosin. Results. Oedema and apoptosis were the most frequent histological changes and were detected in all animals in the adrenal cortex and in the medulla. Mild and focal endothelial lesions were also detected. A marked interindividual variability in the degree of the intensity of apoptosis and oedema at cortical and medullary level was observed within groups. Comparing the two groups, higher levels of pathological changes were detected in the control group. No significant difference between the two groups was observed regarding the endothelial changes. Conclusions. In animals exposed to ventricular fibrillation, EPO treatment has protective effects on the adrenal gland. PMID- 27504456 TI - "Slalom": Microsurgical Cross-Over Decompression for Multilevel Degenerative Lumbar Stenosis. AB - Objective. Selective, bilateral multisegmental microsurgical decompression of lumbar spinal canal stenosis through separate, alternating cross-over approaches. Indications. Two-segmental and multisegmental degenerative central and lateral lumbar spinal stenosis. Contraindications. None. Surgical Technique. Minimally invasive, muscle, and facet joint-sparing bilateral decompression of the lumbar spinal canal through 2 or more alternating microsurgical cross-over approaches from one side. Results. From December 2010 until December 2015 we operated on 202 patients with 2 or multisegmental stenosis (115 f; 87 m; average age 69.3 yrs, range 51-91 yrs). All patients were suffering from symptoms typical of a degenerative lumbar spinal stenosis. All patients complained about back pain; however the leg symptoms were dominant in all cases. Per decompressed segment, the average OR time was 36 min and the blood loss 45.7 cc. Patients were mobilized 6 hrs postop and hospitalization averaged 5.9 days. A total of 116/202 patients did not need submuscular drainage. 27/202 patients suffered from a complication (13.4%). Dural tears occurred in 3.5%, an epidural hematoma in 5.5%, a deep wound infection in 1.98%, and a temporary radiculopathy postop in 1.5%. Postop follow-up ranged from 12 to 24 months. There was a significant improvement of EQ 5 D, Oswestry Disability Index (ODI), VAS for Back and Leg Pain, and preoperative standing times and walking distances. PMID- 27504457 TI - Systematic Analysis of the Cytokine and Anhedonia Response to Peripheral Lipopolysaccharide Administration in Rats. AB - Inflammatory processes may cause depression in subsets of vulnerable individuals. Inflammation-associated behavioral changes are commonly modelled in rodents by administration of bacterial lipopolysaccharide (LPS). However, the time frame in which immune activation and depressive-like behavior occur is not very clear. In this study, we showed that systemic administration of LPS robustly increased circulating levels of corticosterone, leptin, pro- and anti-inflammatory cytokines, and chemokines. Serum concentrations of most analytes peaked within the first 6 h after LPS injection and returned to baseline values by 24 h. Chemokine levels, however, remained elevated for up to 96 h. Using an optimized sucrose preference test (SPT) we showed that sickness behavior was present from 2 to 24 h. LPS-induced anhedonia, as measured by decreased sucrose preference, lasted up to 96 h. To mimic the human situation, where depression develops after chronic inflammation, rats were preexposed to repeated LPS administration or subchronic restraint stress and subsequently challenged with LPS. While these procedures did not increase the duration of anhedonia, our results do indicate that inflammation may cause depressive symptoms such as anhedonia. Using our SPT protocol, more elaborate rodent models can be developed to study the mechanisms underlying inflammation-associated depression in humans. PMID- 27504458 TI - Association between Serum Albumin Concentration and Ketosis Risk in Hospitalized Individuals with Type 2 Diabetes Mellitus. AB - Objective. This study examined the association between serum albumin concentration and ketosis risk in hospitalized individuals with type 2 diabetes mellitus (T2DM). Methods. A retrospective cross-sectional study was conducted at a medical center in Taiwan. Inclusion criteria were endocrinology ward inpatients exceeding 21 years of age, with preexisting diagnosis of T2DM, and blood glucose above 13.9 millimoles per liter (mmol/L) at admission. Individuals without measurement of serum albumin, urine ketone, or hemoglobin A1C, or harboring active infection, myocardial infarction, cerebrovascular event, cirrhosis, malignancy, or overt proteinuria were excluded. Using serum albumin concentration below 3.0 grams per deciliter to define hypoalbuminemia, 151 hypoalbuminemic cases and 104 normoalbuminemic controls were enrolled. The presence of ketones in urine established ketosis. Results. The prevalence of ketonuria was 48% in hypoalbuminemic subjects compared to 30% in normoalbuminemic controls (odds ratio (OR): 2.15; 95% confidence interval (CI): 1.26-3.57; P = 0.004). Moreover, among the 156 subjects with serum beta-hydroxybutyrate measurement in addition to urine ketone, 33% of the hypoalbuminemic individuals had ketonemia exceeding 3 mmol/L compared to 19% of those with normoalbuminemia (OR: 2.12, 95% CI: 0.99-4.48, P = 0.051). Conclusions. Serum albumin concentration is inversely associated with ketosis risk in hospitalized individuals with T2DM. PMID- 27504459 TI - Small Mouse Islets Are Deficient in Glucagon-Producing Alpha Cells but Rich in Somatostatin-Secreting Delta Cells. AB - Small and big mouse islets were compared with special reference to their content of glucagon-producing alpha-cells and somatostatin-producing delta-cells. Areas stained for glucagon and somatostatin were measured in the largest cross section of small (diameter < 60 MUm) and big (diameter > 100 MUm) islets. Comparison of the areas indicated proportionally more delta- than alpha-cells in the small islets. After isolation with collagenase these islets were practically devoid of alpha-cells. We evaluated the functional importance of the islet size by measuring the Ca(2+) signal for insulin release. A majority of the small islets responded to the hyperpolarization action of somatostatin with periodic decrease of cytoplasmic Ca(2+) when glucose was elevated after tolbutamide blockade of the KATP channels. PMID- 27504462 TI - An Uncommon Association of Familial Partial Lipodystrophy, Dilated Cardiomyopathy, and Conduction System Disease. AB - A 46-year-old African American woman presented with severe respiratory distress requiring intubation and was diagnosed with nonischemic cardiomyopathy. She had the typical phenotype of familial partial lipodystrophy 2 (FPLD2). Sequence analysis of LMNA gene showed a heterozygous missense mutation at exon 8 (c.1444C>T) causing amino acid change, p.R482W. She later developed severe coronary artery disease requiring multiple percutaneous coronary interventions and coronary artery bypass surgery. She was later diagnosed with diabetes, primary hyperparathyroidism, and euthyroid multinodular goiter. She had sinus nodal and atrioventricular nodal disease and had an implantable cardioverter defibrillator implantation due to persistent left ventricular dysfunction. The device eroded through the skin few months after implantation and needed a re implant on the contralateral side. She had atrial flutter requiring ablation. This patient with FPLD2 had most of the reported cardiac complications of FPLD2. This case is presented to improve the awareness of the presentation of this disease among cardiologists and internists. PMID- 27504460 TI - Impact of the Type of Continuous Insulin Administration on Metabolism in a Diabetic Rat Model. AB - Exogenous insulin is the only treatment available for type 1 diabetic patients and is mostly administered by subcutaneous (SC) injection in a basal and bolus scheme using insulin pens (injection) or pumps (preimplanted SC catheter). Some divergence exists between these two modes of administration, since pumps provide better glycaemic control compared to injections in humans. The aim of this study was to compare the impacts of two modes of insulin administration (single injections of long-acting insulin or pump delivery of rapid-acting insulin) at the same dosage (4 IU/200 g/day) on rat metabolism and tissues. The rat weight and blood glucose levels were measured periodically after treatment. Immunostaining for signs of oxidative stress and for macrophages was performed on the liver and omental tissues. The continuous insulin delivery by pumps restored normoglycaemia, which induced the reduction of both reactive oxygen species and macrophage infiltration into the liver and omentum. Injections controlled the glucose levels for only a short period of time and therefore tissue stress and inflammation were elevated. In conclusion, the insulin administration mode has a crucial impact on rat metabolic parameters, which has to be taken into account when studies are designed. PMID- 27504461 TI - Soluble Urokinase Receptors in Focal Segmental Glomerulosclerosis: A Review on the Scientific Point of View. AB - Focal segmental glomerulosclerosis (FSGS) is one of the primary glomerular disorders in both children and adults which can progress to end-stage renal failure. Although there are genetic and secondary causes, circulating factors have also been regarded as an important factor in the pathogenesis of FSGS, because about 40% of the patients with FSGS have recurrence after renal transplantation. Soluble urokinase-type plasminogen activator receptor (suPAR) is a soluble form of uPAR, which is a membrane-bound protein linked to GPI in various immunologically active cells, including podocytes. It has recently been suggested as a potential circulating factor in FSGS by in vitro podocyte experiments, in vivo mice models, and human studies. However, there have also been controversies on this issue, because subsequent studies showed conflicting results. suPAR levels were also increased in patients with other glomerular diseases and were inversely correlated with estimated glomerular filtration rate. Nevertheless, there has been no balanced review on this issue. In this review, we compare the conflicting data on the involvement of suPAR in the pathogenesis of FSGS and shed light on interpretation by taking into account many points and the potential variables and confounders influencing serum suPAR levels. PMID- 27504464 TI - Epidemiology of Operative Procedures in an NCAA Division I Football Team Over 10 Seasons. AB - BACKGROUND: Injury rates are high for collegiate football players. Few studies have evaluated the epidemiology of surgical procedures in National Collegiate Athletic Association (NCAA) Division I collegiate football players. PURPOSE: To determine the most common surgical procedures performed in collegiate football players over a 10-year period. STUDY DESIGN: Descriptive epidemiological study. METHODS: From the 2004-2005 season through the 2013-2014 season, all surgical procedures performed on athletes from a single NCAA Division I college football team during athletic participation were reviewed. Surgeries were categorized by anatomic location, and operative reports were used to obtain further surgical details. Data collected over this 10-season span included type of injury, primary procedures, reoperations, and cause of reoperation, all categorized by specific anatomic locations and position played. RESULTS: From the 2004-2005 through the 2013-2014 seasons, 254 operations were performed on 207 players, averaging 25.4 surgical procedures per year. The majority of surgeries performed were orthopaedic procedures (92.1%, n = 234). However, there were multiple nonorthopaedic procedures (7.9%, n = 20). The most common procedure performed was arthroscopic shoulder labral repair (12.2%, n = 31). Partial meniscectomy (11.8%, n = 30), arthroscopic anterior cruciate ligament (ACL) reconstruction (9.4% n = 24), and arthroscopic hip labral repair (5.9% n = 15) were the other commonly performed procedures. There were a total of 29 reoperations performed; thus, 12.9% of primary procedures had a reoperation. The most common revision procedure was a revision open reduction internal fixation of stress fractures in the foot as a result of a symptomatic nonunion (33.33%, n = 4) and revision ACL reconstruction (12.5%, n = 3). By position, relative to the number of athletes at each position, linebackers (30.5%) and defensive linemen (29.1%) were the most likely to undergo surgery while kickers (6%) were the least likely. CONCLUSION: In NCAA Division I college football players, the most commonly performed surgeries conducted for injuries were orthopaedic in nature. Of these, arthroscopic shoulder labral repair was the most common, followed closely by partial meniscectomy. Nonorthopaedic procedures nonetheless accounted for a sizable portion of surgical volume. Familiarity with this injury and surgical spectrum is of utmost importance for the team physician treating these high-level contact athletes. PMID- 27504463 TI - Fibular Strut Graft Augmentation for Open Reduction and Internal Fixation of Proximal Humerus Fractures: A Systematic Review and the Authors' Preferred Surgical Technique. AB - BACKGROUND: Proximal humerus fractures are common problems plaguing the elderly population. PURPOSE: The purposes of this study were to determine the outcomes of fibular strut allografts in treatment of proximal humerus fractures with open reduction internal fixation (ORIF) and to present the authors' preferred surgical technique. The hypothesis was that the use of fibular strut allografts in treating proximal humerus fractures with ORIF will provide low reoperation rates with acceptable outcomes. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic review was registered with PROSPERO and performed with PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines using 3 publicly available free databases. Therapeutic clinical outcome investigations reporting arthroscopic elbow outcomes with levels of evidence 1 through 4 were eligible for inclusion. All study, subject, and surgical technique demographics were analyzed and compared between continents and countries. Statistics were calculated using Student t tests, 1-way analysis of variance, chi-square tests, and 2-proportion Z tests. RESULTS: Four studies met the inclusion criteria. While there is great heterogeneity existing in the literature surrounding use of a fibular strut allograft as an adjunct to ORIF of proximal humerus fractures, current evidence shows a humeral head screw penetration rate of 3.7% with acceptable functional outcome scores, with a reoperation rate of 4.4% at a weighted mean 80.78 weeks (1.55 years) of postoperative follow-up. CONCLUSION: There is great heterogeneity that exists in the literature surrounding the use of a fibular strut allograft as an adjunct to ORIF of proximal humerus fractures. Current evidence shows a screw penetration rate of 3.7% with acceptable functional outcome scores, demonstrating fibular strut allograft is a viable option for treating proximal humerus fractures. PMID- 27504465 TI - Kinematics of Shooting in High School and Collegiate Lacrosse Players With and Without Low Back Pain. AB - BACKGROUND: Low back pain (LBP) and motion alterations can occur in athletes who engage in high-speed throwing motions. The relationship between LBP and shooting motion in lacrosse players is not yet known. PURPOSE: To quantify the effects of LBP on key kinematic parameters of the lacrosse shot and determine the contribution of the severity of LBP on specific kinematic parameters of the shooting motion. STUDY DESIGN: Controlled laboratory study. METHODS: High school and collegiate players (N = 24) were stratified into 2 groups based on back pain symptoms (LBP or no pain). Three-dimensional motion capture of overhead throws was used to collect data on knee, pelvis, trunk, and shoulder kinematics as well as crosse stick (the stick capped with a strung net) and ball speed. RESULTS: Mean low back numeric pain rating scale (NRSpain) score was 2.9. Knee flexion at ball release was greater in the LBP than no pain group, indicating a more bent knee (P = .04). The LBP group demonstrated less angular velocity transfer from pelvis to trunk than the no pain group (P = .05). Total range of motion of the pelvis and shoulders during the shot and follow-through were less in the LBP group than the no pain group (83.6 degrees +/- 24.5 degrees vs 75.9 degrees +/ 24.5 degrees , P = .05). Age- and sex-adjusted regression analyses revealed that the low back NRSpain rating contributed 6.3% to 25.0% of the variance to the models of shoulder transverse rotation range of motion, trunk and shoulder rotation angular velocities, and knee flexion angle (P < .05). CONCLUSION: LBP severity significantly contributes to trunk and shoulder motion restriction during lacrosse shooting. Inclusion of lumbopelvic and core training and prehabilitation programs for high school and collegiate players may reduce pain in affected players as well as help them to attain appropriate motion parameters and avoid secondary musculoskeletal injuries. CLINICAL RELEVANCE: This research identified a prehabilitation need in the understudied lacrosse population. Therapeutic strategies can be developed to strengthen the throwing motion, which could control mechanical loading patterns on the low back and minimize pain symptoms in players with chronic LBP. PMID- 27504466 TI - Closed-Loop Double Endobutton Technique for Repair of Unstable Distal Clavicle Fractures. AB - BACKGROUND: Displaced fractures of the distal clavicle are inherently unstable and lead to nonunion in a high percentage of cases. The optimal surgical management remains controversial. HYPOTHESIS: Indirect osteosynthesis with a closed-loop double endobutton construct would result in reliable fracture union and obviate the need for additional surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Eight patients with an acute unstable Neer type IIB distal clavicle fracture were treated with a closed-loop double endobutton implant. Mean follow-up averaged 3.4 years (range, 1-9 years). Two patients were lost to follow up. The remaining 6 patients underwent a detailed functional and radiologic evaluation. RESULTS: Definitive fracture healing was achieved in all patients. There were no complications, and no patients required additional surgery related to the index procedure. The mean Constant score was 97 at final follow-up. CONCLUSION: The closed-loop double endobutton technique was reliable and effective in achieving fracture union in all patients with unstable Neer type IIB fractures of the distal clavicle. This technique obviates the need for late hardware removal that is often necessary when direct osteosynthesis is used and avoids potential complications associated with coracoclavicular cerclage constructs that require knot fixation. PMID- 27504467 TI - Meniscal Ramp Lesions: Anatomy, Incidence, Diagnosis, and Treatment. AB - Meniscal ramp lesions are more frequently associated with anterior cruciate ligament (ACL) injuries than previously recognized. Some authors suggest that this entity results from disruption of the meniscotibial ligaments of the posterior horn of the medial meniscus, whereas others support the idea that it is created by a tear of the peripheral attachment of the posterior horn of the medial meniscus. Magnetic resonance imaging (MRI) scans have been reported to have a low sensitivity, and consequently, ramp lesions often go undiagnosed. Therefore, to rule out a ramp lesion, an arthroscopic evaluation with probing of the posterior horn of the medial meniscus should be performed. Several treatment options have been reported, including nonsurgical management, inside-out meniscal repair, or all-inside meniscal repair. In cases of isolated ramp lesions, a standard meniscal repair rehabilitation protocol should be followed. However, when a concomitant ACL reconstruction (ACLR) is performed, the rehabilitation should follow the designated ACLR postoperative protocol. The purpose of this article was to review the current literature regarding meniscal ramp lesions and summarize the pertinent anatomy, biomechanics, diagnostic strategies, recommended treatment options, and postoperative protocol. PMID- 27504468 TI - Comparison of Short-term Complications Between 2 Methods of Coracoclavicular Ligament Reconstruction: A Multicenter Study. AB - BACKGROUND: Numerous techniques have been used to treat acromioclavicular (AC) joint dislocation, with anatomic reconstruction of the coracoclavicular (CC) ligaments becoming a popular method of fixation. Anatomic CC ligament reconstruction is commonly performed with cortical fixation buttons (CFBs) or tendon grafts (TGs). PURPOSE: To report and compare short-term complications associated with AC joint stabilization procedures using CFBs or TGs. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: We conducted a retrospective review of the operative treatment of AC joint injuries between April 2007 and January 2013 at 2 institutions. Thirty-eight patients who had undergone a procedure for AC joint instability were evaluated. In these 38 patients with a mean age of 36.2 years, 18 shoulders underwent fixation using the CFB technique and 20 shoulders underwent reconstruction using the TG technique. RESULTS: The overall complication rate was 42.1% (16/38). There were 11 complications in the 18 patients in the CFB group (61.1%), including 7 construct failures resulting in a loss of reduction. The most common mode of failure was suture breakage (n = 3), followed by button migration (n = 2) and coracoid fracture (n = 2). There were 5 complications in the TG group (25%), including 3 cases of asymptomatic subluxation, 1 symptomatic suture granuloma, and 1 superficial infection. There were no instances of construct failure seen in TG fixations. CFB fixation was found to have a statistically significant increase in complications (P = .0243) and construct failure (P = .002) compared with TG fixation. CONCLUSION: CFB fixation was associated with a higher rate of failure and higher rate of early complications when compared with TG fixation. PMID- 27504469 TI - Regulation of proliferation and histone acetylation in embryonic neural precursors by CREB/CREM signaling. AB - The transcription factor CREB (cAMP-response element binding protein) regulates differentiation, migration, survival and activity-dependent gene expression in the developing and mature nervous system. However, its specific role in the proliferation of embryonic neural progenitors is still not completely understood. Here we investigated how CREB regulates proliferation of mouse embryonic neural progenitors by a conditional mutant lacking Creb gene in neural progenitors. In parallel, we explored possible compensatory effects by the genetic ablation of another member of the same gene family, the cAMP-responsive element modulator (Crem). We show that CREB loss differentially impaired the proliferation, clonogenic potential and self-renewal of precursors derived from the ganglionic eminence (GE), in comparison to those derived from the cortex. This phenotype was associated with a specific reduction of histone acetylation in the GE of CREB mutant mice, and this reduction was rescued in vivo by inhibition of histone deacetylation. These observations indicate that the impaired proliferation could be caused by a reduced acetyltransferase activity in Creb conditional knock-out mice. These findings support a crucial role of CREB in controlling embryonic neurogenesis and propose a novel mechanism by which CREB regulates embryonic neural development. PMID- 27504470 TI - Radial glia in the proliferative ventricular zone of the embryonic and adult turtle, Trachemys scripta elegans. AB - To better understand the role of radial glial (RG) cells in the evolution of the mammalian cerebral cortex, we investigated the role of RG cells in the dorsal cortex and dorsal ventricular ridge of the turtle, Trachemys scripta elegans. Unlike mammals, the glial architecture of adult reptile consists mainly of ependymoradial glia, which share features with mammalian RG cells, and which may contribute to neurogenesis that continues throughout the lifespan of the turtle. To evaluate the morphology and proliferative capacity of ependymoradial glia (here referred to as RG cells) in the dorsal cortex of embryonic and adult turtle, we adapted the cortical electroporation technique, commonly used in rodents, to the turtle telencephalon. Here, we demonstrate the morphological and functional characteristics of RG cells in the developing turtle dorsal cortex. We show that cell division occurs both at the ventricle and away from the ventricle, that RG cells undergo division at the ventricle during neurogenic stages of development, and that mitotic Tbr2+ precursor cells, a hallmark of the mammalian SVZ, are present in the turtle cortex. In the adult turtle, we show that RG cells encompass a morphologically heterogeneous population, particularly in the subpallium where proliferation is most prevalent. One RG subtype is similar to RG cells in the developing mammalian cortex, while 2 other RG subtypes appear to be distinct from those seen in mammal. We propose that the different subtypes of RG cells in the adult turtle perform distinct functions. PMID- 27504471 TI - Characterization of Np95 expression in mouse brain from embryo to adult: A novel marker for proliferating neural stem/precursor cells. AB - Nuclear protein 95 KDa (Np95, also known as UHRF1 or ICBP90) plays an important role in maintaining DNA methylation of newly synthesized DNA strands by recruiting DNA methyltransferase 1 (DNMT1) during cell division. In addition, Np95 participates in chromatin remodeling by interacting with histone modification enzymes such as histone deacetylases. However, its expression pattern and function in the brain have not been analyzed extensively. We here investigated the expression pattern of Np95 in the mouse brain, from developmental to adult stages. In the fetal brain, Np95 is abundantly expressed at the midgestational stage, when a large number of neural stem/precursor cells (NS/PCs) exist. Interestingly, Np95 is expressed specifically in NS/PCs but not in differentiated cells such as neurons or glial cells. Furthermore, we demonstrate that Np95 is preferentially expressed in type 2a cells, which are highly proliferative NS/PCs in the dentate gyrus of the adult hippocampus. Moreover, the number of Np95-expressing cells increases in response to kainic acid administration or to voluntary running, which are known to enhance the proliferation of adult NS/PCs. These results suggest that Np95 participates in the process of proliferation and differentiation of NS/PCs, and that it should be a useful novel marker for proliferating NS/PCs, facilitating the analysis of the complex behavior of NS/PCs in the brain. PMID- 27504472 TI - MicroRNAs of the miR379-410 cluster: New players in embryonic neurogenesis and regulators of neuronal function. AB - The imprinted miR379-410 cluster contains 38 microRNAs (miRNAs) that are involved in diverse neurodevelopmental processes and are important regulators of neuronal function. The implications of these miRNAs in neurological diseases have been recently recognized.In the present minireview, the current findings regarding the brain-specific functions of miR379-410 cluster miRNAs are summarized and discussed. PMID- 27504473 TI - Identification and expression patterns of novel long non-coding RNAs in neural progenitors of the developing mammalian cortex. AB - Long non-coding (lnc)RNAs play key roles in many biological processes. Elucidating the function of lncRNAs in cell type specification during organ development requires knowledge about their expression in individual progenitor types rather than in whole tissues. To achieve this during cortical development, we used a dual-reporter mouse line to isolate coexisting proliferating neural stem cells, differentiating neurogenic progenitors and newborn neurons and assessed the expression of lncRNAs by paired-end, high-throughput sequencing. We identified 379 genomic loci encoding novel lncRNAs and performed a comprehensive assessment of cell-specific expression patterns for all, annotated and novel, lncRNAs described to date. Our study provides a powerful new resource for studying these elusive transcripts during stem cell commitment and neurogenesis. PMID- 27504474 TI - Role of dual energy spectral computed tomography in characterization of hepatocellular carcinoma: Initial experience from a tertiary liver care institute. AB - OBJECTIVE: To investigate dual-energy spectral CT in characterization of hepatocellular Carcinoma (HCC) in patients with chronic liver disease. METHODS: Dynamic computed tomography (CT) was performed in 3600 patients (2879 males; 721 females, mean age 50.9 +/- 11.9 years) with working clinical diagnosis of liver cirrhosis for hepatocellular carcinoma screening and other clinical indications. The study was conducted over a period of 3 years. During dynamic CT scanning, spectral (monochromatic) and routine (polychromatic) CT acquisitions were obtained on a single tube, dual energy, 64 slice multi-detector CT scanner. Imaging findings were studied on routine CT. On the basis of routine CT findings, indeterminate lesions (lesions not showing characteristic hypervascularity followed by washout on dynamic routine CT scan) that were referred for biopsy or surgery were segregated. A retrospective blinded review of the lesions, acquired by the spectral CT acquisitions was done with the help of gem stone imaging (GSI) software to characterize these lesions. All the above lesions were analyzed qualitatively in the arterial phase for lesion conspicuity as well as quantitatively using the monochromatic data sets and nodule Iodine concentration on material density maps, respectively. This data was studied with respect to predictability of HCC using the spectral CT technique. Iodine density of the lesion, surrounding liver parenchyma, and lesion to liver parenchyma ratio (LLR) were derived and statistically analyzed. Histopathology of the lesion in question was treated as gold standard for analysis. RESULTS: It was observed via statistical analysis that the value of iodine density of the lesion on material density sets of >=29.5 mg/dl, enabled a discriminatory power of 86.5%, sensitivity of 90.5% with 95% confidence Interval (CI) (69.2-98.8%) and specificity of 81.2% with 95% Confidence Interval (54.4-95.9%) in predicting HCC. Qualitative assessment also showed higher lesion conspicuity with spectral CT image sets as compared to routine CT data. CONCLUSION: This study reveals that spectral imaging is an excellent qualitative as well as a quantitative tool for assessing and predicting hepatocellular carcinoma in cirrhotic patients. PMID- 27504475 TI - From first to latest imaging technology: Revisiting the first mummy investigated with X-ray in 1896 by using dual-source computed tomography. AB - PURPOSE: The aim of this study was to systematically reinvestigate the first human mummy that was ever analyzed with X-ray imaging in 1896, using dual-source computed tomography (DSCT) in order to compare the earliest and latest imaging technologies, to estimate preservation, age at death, sex, anatomical variants, paleopathological findings, mummification, embalming and wrapping of the child mummy from ancient Egypt. Radiocarbon dating was used to determine the mummy's age and to specify the child's living period in the Egyptian chronology. MATERIAL AND METHODS: The ancient Egyptian child mummy is kept in the Senckenberg Museum of Natural History in Frankfurt am Main, Germany. An accelerator mass spectrometer (MICADAS) was used for radiocarbon dating. DSCT was performed using a 2 * 64 slice dual-source CT system (Siemens Healthineers, Forchheim, Germany). A thorough visual examination of the mummy, a systematic radiological evaluation of the DICOM datasets, and established methods in physical anthropology were applied to assess the bio-anthropological data and the post mortem treatment of the body. RESULTS: Radiocarbon dating yielded a calibrated age between 378 and 235 cal BC (95.4% confidence interval), corresponding with the beginning of the Ptolemaic period. The mummy was a male who was four to five years old at the time of death. Remnants of the brain and inner organs were preserved by the embalmers, which is regularly observed in ancient Egyptian child mummies. Skin tissue, inner organs, tendons and/or musculature, cartilage, nerves and vasculature could be identified on the DSCT dataset. The dental health of the child was excellent. Anatomical variants and pathological defects included a congenital Pectus excavatum deformity, hepatomegaly, Harris lines, and longitudinal clefts in the ventral cortices of both femora. CONCLUSION: Our results highlight the enormous progress achieved form earliest to latest imaging technology for advanced mummy research using the first human mummy investigated with X-ray. With the application of DSCT, detailed knowledge regarding age at death, sex, diseases, death, and mummification of a child from Ptolemaic Egypt are revealed while considering the temporary rites of body treatment and burial for children. PMID- 27504476 TI - Intra-individual diagnostic image quality and organ-specific-radiation dose comparison between spiral cCT with iterative image reconstruction and z-axis automated tube current modulation and sequential cCT. AB - OBJECTIVES: To prospectively evaluate image quality and organ-specific-radiation dose of spiral cranial CT (cCT) combined with automated tube current modulation (ATCM) and iterative image reconstruction (IR) in comparison to sequential tilted cCT reconstructed with filtered back projection (FBP) without ATCM. METHODS: 31 patients with a previous performed tilted non-contrast enhanced sequential cCT aquisition on a 4-slice CT system with only FBP reconstruction and no ATCM were prospectively enrolled in this study for a clinical indicated cCT scan. All spiral cCT examinations were performed on a 3rd generation dual-source CT system using ATCM in z-axis direction. Images were reconstructed using both, FBP and IR (level 1-5). A Monte-Carlo-simulation-based analysis was used to compare organ specific-radiation dose. Subjective image quality for various anatomic structures was evaluated using a 4-point Likert-scale and objective image quality was evaluated by comparing signal-to-noise ratios (SNR). RESULTS: Spiral cCT led to a significantly lower (p < 0.05) organ-specific-radiation dose in all targets including eye lense. Subjective image quality of spiral cCT datasets with an IR reconstruction level 5 was rated significantly higher compared to the sequential cCT acquisitions (p < 0.0001). Consecutive mean SNR was significantly higher in all spiral datasets (FBP, IR 1-5) when compared to sequential cCT with a mean SNR improvement of 44.77% (p < 0.0001). CONCLUSIONS: Spiral cCT combined with ATCM and IR allows for significant-radiation dose reduction including a reduce eye lens organ-dose when compared to a tilted sequential cCT while improving subjective and objective image quality. PMID- 27504477 TI - Data on the impact of SSRIs and depression symptoms on the neural activities in obsessive-compulsive disorder at rest. AB - The data provided here related to our research article (Chen et al., 2016) [1]. We provide whole-brain intrinsic functional connectivity patterns in obsessive compulsive disorder at resting-state [1]. This article also provides supplementary information to our research article, i.e., between - group comparisons of the effect of selective serotonin reuptake inhibitors (SSRIs) and combined depression symptoms on resting-state neural activities in obsessive compulsive disorder. The data presented here provide novel insights into the effect of SSRIs and combined depression symptoms on the neural activities at rest. PMID- 27504478 TI - Extraction of phenolic compounds from extra virgin olive oil by a natural deep eutectic solvent: Data on UV absorption of the extracts. AB - This data article refers to the paper "Towards green analysis of virgin olive oil phenolic compounds: extraction by a natural deep eutectic solvent and direct spectrophotometric detection" [1]. A deep eutectic solvent (DES) based on lactic acid and glucose was used as green solvent for phenolic compounds. Eight standard phenolic compounds were solubilized in the DES. Then, a set of extra virgin olive oil (EVOO) samples (n=65) were submitted to liquid-liquid extraction by the DES. The standard solutions and the extracts were analyzed by UV spectrophotometry. This article reports the spectral data of both the standard solutions and the 65 extracts, as well as the total phenolic content of the corresponding oils, assessed by the Folin-Ciocalteu assay. PMID- 27504480 TI - Sclerosing sweat duct carcinoma of the lower extremity treated with Mohs micrographic surgery. PMID- 27504479 TI - Perianal streptococcal infection precipitating pustular psoriasis in an adult. PMID- 27504481 TI - Bullous leukemia cutis in a patient with T-cell prolymphocytic leukemia. PMID- 27504482 TI - Pembrolizumab-associated sarcoidosis. PMID- 27504483 TI - Case series: The use of a dehydrated human amnion/chorion membrane allograft to enhance healing in the repair of lower eyelid defects after Mohs micrographic surgery. PMID- 27504484 TI - Muscle Activation Differs between Three Different Knee Joint-Angle Positions during a Maximal Isometric Back Squat Exercise. AB - The purpose of this study was to compare muscle activation of the lower limb muscles when performing a maximal isometric back squat exercise over three different positions. Fifteen young, healthy, resistance-trained men performed an isometric back squat at three knee joint angles (20 degrees , 90 degrees , and 140 degrees ) in a randomized, counterbalanced fashion. Surface electromyography was used to measure muscle activation of the vastus lateralis (VL), vastus medialis (VM), rectus femoris (RF), biceps femoris (BF), semitendinosus (ST), and gluteus maximus (GM). In general, muscle activity was the highest at 90 degrees for the three quadriceps muscles, yet differences in muscle activation between knee angles were muscle specific. Activity of the GM was significantly greater at 20 degrees and 90 degrees compared to 140 degrees . The BF and ST displayed similar activation at all joint angles. In conclusion, knee position alters muscles activation of the quadriceps and gluteus maximus muscles. An isometric back squat at 90 degrees generates the highest overall muscle activation, yet an isometric back squat at 140 degrees generates the lowest overall muscle activation of the VL and GM only. PMID- 27504485 TI - A Scoping Review of the Associations of Golf with Eye Injuries in Adults and Children. AB - Introduction. Sport presents a risk of ocular trauma and accounts for a significant number of eye injuries that require hospital admission. The sport of golf presents a risk to eyesight from fast moving objects such as golf clubs and balls. This study aims to investigate the associations of golf with eye injuries and the reasons that these injuries occur. Material/Methods. A literature search was conducted using the databases MEDLINE, Web of Science, SPORTDiscus, and PsycINFO. Grey literature was searched using the WHO international clinical trials registry platform, Google Scholar, and ProQuest. Data was extracted using a standardised form and summarised into a report. Results and Discussion. Twenty three studies were found relating to eye injuries in golf. Injuries appear to be rare, but more frequent in men and children. Injuries resulted in high rates of enucleation and visual impairment. Children sustained more injury from golf clubs whereas adults sustained more injuries from golf balls. Conclusion. Efforts are needed to encourage golf participants to understand the risks of ocular and indeed other head injuries. Initiatives to provide appropriate supervision and education on this topic are merited. Further research is needed to investigate the circumstances of eye injury in golf and assess the effects of interventions aimed at reducing risk of injury. PMID- 27504486 TI - Future Perspectives of ERAS: A Narrative Review on the New Applications of an Established Approach. AB - ERAS approach (Enhanced Recovery After Surgery) is a multimodal, perioperative pathway designed to achieve early recovery after surgery. ERAS has shown documented efficacy in elective surgery, and the concept of "multimodal" and "multidisciplinary" approach seems still to be of higher importance than each single item within ERAS protocols. New perspectives include the use of ERAS in emergency surgery, where efficacy and safety on outcome have been documented, and flexibility of traditional items may add benefits for traditionally high-risk patients. Obstetric surgery, as well, may open wide horizons for future research, since extremely poor data are currently available, and ERAS benefits may translate even on the baby. Finally, the concept of "outcome" may be extended when considering the specific setting of cancer surgery, in which variables like cancer recurrence, early access to adjuvant therapies, and, finally, long-term survival are as important as the reduced perioperative complications. In this perspective, different items within ERAS protocols should be reinterpreted and eventually integrated towards "protective" techniques, to develop cancer-specific ERAS approaches keeping pace with the specific aims of oncologic surgery. PMID- 27504487 TI - Exercise Your Brain. PMID- 27504488 TI - A Conversation with Amy Clippinger. PMID- 27504489 TI - Does Nanomedicine Have a Delivery Problem? PMID- 27504490 TI - Protein Calligraphy: A New Concept Begins To Take Shape. AB - The ability to assemble molecules into supramolecular architectures of controllable size and symmetry is a long sought after goal of nanotechnology and material engineering. Proteins are particularly attractive for molecular assembly due to their inherent molecular recognition and self-assembly capabilities. Advances in the computational prediction of protein folding and quaternary assembly have enabled the design of proteins that self-assemble into complex yet predictable shapes. These protein nanostructures are opening new possibilities in biomaterials, metabolic engineering, molecular delivery, tissue engineering, and a plethora of nanomaterials. Images of protein constructs assembled from simpler structures draw comparison to characters of calligraphy. In both cases, elaborate designs emerge from basic subunits, resulting in the translation of form into function with a high degree of artistry. PMID- 27504491 TI - Deciphering the Interplay among Multisite Phosphorylation, Interaction Dynamics, and Conformational Transitions in a Tripartite Protein System. AB - Multisite phosphorylation is a common pathway to regulate protein function, activity, and interaction pattern in vivo, but routine biochemical analysis is often insufficient to identify the number and order of individual phosphorylation reactions and their mechanistic impact on the protein behavior. Here, we integrate complementary mass spectrometry (MS)-based approaches to characterize a multisite phosphorylation-regulated protein system comprising Polo-like kinase 1 (Plk1) and its coactivators Aurora kinase A (Aur-A) and Bora, the interplay of which is essential for mitotic entry after DNA damage-induced cell cycle arrest. Native MS and cross-linking-MS revealed that Aur-A/Bora-mediated Plk1 activation is accompanied by the formation of Aur-A/Bora and Plk1/Bora heterodimers. We found that the Aur-A/Bora interaction is independent of the Bora phosphorylation state, whereas the Plk1/Bora interaction is dependent on extensive Bora multisite phosphorylation. Bottom-up and top-down proteomics analyses showed that Bora multisite phosphorylation proceeds via a well-ordered sequence of site-specific phosphorylation reactions, whereby we could reveal the involvement of up to 16 phosphorylated Bora residues. Ion mobility spectrometry-MS demonstrated that this multisite phosphorylation primes a substantial structural rearrangement of Bora, explaining the interdependence between extensive Bora multisite phosphorylation and Plk1/Bora complex formation. These results represent a first benchmark of our multipronged MS strategy, highlighting its potential to elucidate the mechanistic and structural implications of multisite protein phosphorylation. PMID- 27504492 TI - Reconstitution and Functional Analysis of a Full-Length Hepatitis C Virus NS5B Polymerase on a Supported Lipid Bilayer. AB - Therapeutic targeting of membrane-associated viral proteins is complicated by the challenge of investigating their enzymatic activities in the native membrane bound state. To permit functional characterization of these proteins, we hypothesized that the supported lipid bilayer (SLB) can support in situ reconstitution of membrane-associated viral protein complexes. As proof-of principle, we selected the hepatitis C virus (HCV) NS5B polymerase which is essential for HCV genome replication, and determined that the SLB platform enables functional reconstitution of membrane protein activity. Quartz crystal microbalance with dissipation (QCM-D) monitoring enabled label-free detection of full-length NS5B membrane association, its interaction with replicase subunits NS3, NS5A, and template RNA, and most importantly its RNA synthesis activity. This latter activity could be inhibited by the addition of candidate small molecule drugs. Collectively, our results demonstrate that the SLB platform can support functional studies of membrane-associated viral proteins engaged in critical biological activities. PMID- 27504493 TI - Morphologies Observed in Ultraflexible Microemulsions with and without the Presence of a Strong Acid. AB - We show that three different morphologies exist near the two-phase boundary of ternary systems containing a hydrotropic cosolvent. Based on synchrotron small- and wide-angle X-ray scattering combined with molecular dynamics, we rationalize the specific scattering signature of direct, bicontinuous, and reverse mesoscale solubilization. Surprisingly, these mesostructures are resilient toward strong acids, which are required in industrial applications. However, on a macroscopic scale, the phase boundary shifts in salting-in and salting-out in the direct and respectively reverse regime, leading to a crossing of the binodals. PMID- 27504494 TI - In Vivo Bioorthogonal Chemistry Enables Local Hydrogel and Systemic Pro-Drug To Treat Soft Tissue Sarcoma. AB - The ability to activate drugs only at desired locations avoiding systemic immunosuppression and other dose limiting toxicities is highly desirable. Here we present a new approach, named local drug activation, that uses bioorthogonal chemistry to concentrate and activate systemic small molecules at a location of choice. This method is independent of endogenous cellular or environmental markers and only depends on the presence of a preimplanted biomaterial near a desired site (e.g., tumor). We demonstrate the clear therapeutic benefit with minimal side effects of this approach in mice over systemic therapy using a doxorubicin pro-drug against xenograft tumors of a type of soft tissue sarcoma (HT1080). PMID- 27504495 TI - Complex relation of HLA-DRB1*1501, age at menarche, and age at multiple sclerosis onset. AB - OBJECTIVE: To examine the relationship between 2 markers of early multiple sclerosis (MS) onset, 1 genetic (HLA-DRB1*1501) and 1 experiential (early menarche), in 2 cohorts. METHODS: We included 540 white women with MS or clinically isolated syndrome (N = 156 with genetic data available) and 1,390 white women without MS but with a first-degree relative with MS (Genes and Environment in Multiple Sclerosis [GEMS]). Age at menarche, HLA-DRB1*1501 status, and age at MS onset were analyzed. RESULTS: In both cohorts, participants with at least 1 HLA-DRB1*1501 allele had a later age at menarche than did participants with no risk alleles (MS: mean difference = 0.49, 95% confidence interval [CI] = [0.03-0.95], p = 0.036; GEMS: mean difference = 0.159, 95% CI = [0.012-0.305], p = 0.034). This association remained after we adjusted for body mass index at age 18 (available in GEMS) and for other MS risk alleles, as well as a single nucleotide polymorphism near the HLA-A region previously associated with age of menarche (available in MS cohort). Confirming previously reported associations, in our MS cohort, every year decrease in age at menarche was associated with a 0.65-year earlier MS onset (95% CI = [0.07-1.22], p = 0.027, N = 540). Earlier MS onset was also found in individuals with at least 1 HLA-DRB1*1501 risk allele (mean difference = -3.40 years, 95% CI = [-6.42 to -0.37], p = 0.028, N = 156). CONCLUSIONS: In 2 cohorts, a genetic marker for earlier MS onset (HLA-DRB1*1501) was inversely related to earlier menarche, an experiential marker for earlier symptom onset. This finding warrants broader investigations into the association between the HLA region and hormonal regulation in determining the onset of autoimmune disease. PMID- 27504496 TI - Trans-pQTL study identifies immune crosstalk between Parkinson and Alzheimer loci. AB - OBJECTIVE: Given evidence from genetic studies, we hypothesized that there may be a shared component to the role of myeloid function in Parkinson and Alzheimer disease (PD and AD) and assessed whether PD susceptibility variants influenced protein expression of well-established AD-associated myeloid genes in human monocytes. METHODS: We repurposed data in which AD-related myeloid proteins CD33, TREM1, TREM2, TREML2, TYROBP, and PTK2B were measured by flow cytometry in monocytes from 176 participants of the PhenoGenetic Project (PGP) and Harvard Aging Brain Study. Linear regression was used to identify associations between 24 PD risk variants and protein expression. The 2 cohorts were meta-analyzed in a discovery analysis, and the 4 most strongly suggestive results were validated in an independent cohort of 50 PGP participants. RESULTS: We discovered and validated an association between the PD risk allele rs12456492(G) in the RIT2 locus and increased CD33 expression (p joint = 3.50 * 10(-5)) and found strongly suggestive evidence that rs11060180(A) in the CCDC62/HIP1R locus decreased PTK2B expression (p joint = 1.12 * 10(-4)). Furthermore, in older individuals, increased CD33 expression on peripheral monocytes was associated with a greater burden of parkinsonism (p = 0.047), particularly bradykinesia (p = 6.64 * 10( 3)). CONCLUSIONS: We find that the rs12456492 PD risk variant affects expression of AD-associated protein CD33 in peripheral monocytes, which suggests that genetic factors for these 2 diseases may converge to influence overlapping innate immune-mediated mechanisms that contribute to neurodegeneration. Furthermore, the effect of the rs12456492(G) PD risk allele on increased CD33 suggests that the inhibition of certain myeloid functions may contribute to PD susceptibility, as is the case for AD. PMID- 27504497 TI - Env7p Associates with the Golgin Protein Imh1 at the trans-Golgi Network in Candida albicans. AB - Vesicular dynamics is one of the very important aspects of cellular physiology, an imbalance of which leads to the disorders or diseases in higher eukaryotes. We report the functional characterization of a palmitoylated protein kinase from Candida albicans whose homologue in Saccharomyces cerevisiae has been reported to be involved in negative regulation of membrane fusion and was named Env7. However, the downstream target of this protein remains to be identified. Env7 in C. albicans (CaEnv7) could be isolated from the membrane fraction and localized to vesicular structures associated with the Golgi apparatus. Our work reports Env7 in C. albicans as a new player involved in maintaining the functional dynamics at the trans-Golgi network (TGN) by interacting with two other TGN resident proteins, namely, Imh1p and Arl1p. Direct interaction could be detected between Env7p and the golgin protein Imh1p. Env7 is itself phosphorylated (Env7p) and phosphorylates Imh1 in vivo. An interaction between Env7 and Imh1 is required for the targeted localization of Imh1. CaEnv7 has a putative palmitoylation site toward both N and C termini. An N-terminal palmitoylation-defective strain retains its ability to phosphorylate Imh1 in vitro. An ENV7 homozygous mutant showed compromised filamentation in solid media and attenuated virulence, whereas an overexpressed strain affected cell wall integrity. Thus, Env7 plays a subtle but important role at the level of multitier regulation that exists at the TGN. IMPORTANCE A multitier regulation exists at the trans-Golgi network in all higher organisms. We report a palmitoylated protein kinase, Env7, that functions at the TGN interface by interacting with two more TGN-resident proteins, namely, Imh1 and Arl1. Palmitoylation seems to be important for the specific localization. This study focuses on the involvement of a ubiquitous protein kinase, whose substrates had not yet been reported from any organism, as an upstream signaling component that modulates the activity of the Imh1-Arl1 complex crucial for maintaining membrane asymmetry. Virulence is significantly diminished in an Env7 mutant. The functioning of this protein in C. albicans seems to be quite different from its nearest homologue in S. cerervisiae, which reflects the evolutionary divergence between these two organisms. PMID- 27504498 TI - Replacement of Glycoprotein B in Alcelaphine Herpesvirus 1 by Its Ovine Herpesvirus 2 Homolog : Implications in Vaccine Development for Sheep-Associated Malignant Catarrhal Fever. AB - Vaccine development is a top priority in malignant catarrhal fever (MCF) research. In the case of sheep-associated MCF (SA-MCF) caused by ovine herpesvirus 2 (OvHV-2), progress toward this objective has been hindered by the absence of methods to attenuate or modify the virus, since it cannot be propagated in vitro. As an alternative for vaccine development, in this study, we tested the hypothesis that one of the SA-MCF vaccine candidate targets, OvHV-2 glycoprotein B (gB), could be expressed by a nonpathogenic alcelaphine herpesvirus 1 (AlHV-1) and then evaluated the potential of the AlHV-1/OvHV-2 chimera to be used as a vaccine and a diagnostic tool. The construction and characterization of an AlHV-1/OvHV-2 chimeric virus that is nonpathogenic and expresses an OvHV-2 vaccine target are significant steps toward the development of an SA-MCF vaccine and also provide a valuable means to study OvHV-2 biology. PMID- 27504499 TI - First Detection of Bat White-Nose Syndrome in Western North America. AB - White-nose syndrome (WNS) is an emerging fungal disease of bats caused by Pseudogymnoascus destructans. Since it was first detected near Albany, NY, in 2006, the fungus has spread across eastern North America, killing unprecedented numbers of hibernating bats. The devastating impacts of WNS on Nearctic bat species are attributed to the likely introduction of P. destructans from Eurasia to naive host populations in eastern North America. Since 2006, the disease has spread in a gradual wavelike pattern consistent with introduction of the pathogen at a single location. Here, we describe the first detection of P. destructans in western North America in a little brown bat (Myotis lucifugus) from near Seattle, WA, far from the previously recognized geographic distribution of the fungus. Whole-genome sequencing and phylogenetic analyses indicated that the isolate of P. destructans from Washington grouped with other isolates of a presumed clonal lineage from the eastern United States. Thus, the occurrence of P. destructans in Washington does not likely represent a novel introduction of the fungus from Eurasia, and the lack of intensive surveillance in the western United States makes it difficult to interpret whether the occurrence of P. destructans in the Pacific Northwest is disjunct from that in eastern North America. Although there is uncertainty surrounding the impacts of WNS in the Pacific Northwest, the presence of the pathogen in western North America could have major consequences for bat conservation. IMPORTANCE White-nose syndrome (WNS) represents one of the most consequential wildlife diseases of modern times. Since it was first documented in New York in 2006, the disease has killed millions of bats and threatens several formerly abundant species with extirpation or extinction. The spread of WNS in eastern North America has been relatively gradual, inducing optimism that disease mitigation strategies could be established in time to conserve bats susceptible to WNS in western North America. The recent detection of the fungus that causes WNS in the Pacific Northwest, far from its previous known distribution, increases the urgency for understanding the long-term impacts of this disease and for developing strategies to conserve imperiled bat species. PMID- 27504500 TI - Impact of Education on School-aged Children's Knowledge of and Participation in "The Choking Game". AB - OBJECTIVES: To better understand school-aged children's awareness of and attitudes about the Choking Game (TCG). To determine if education can increase awareness of the risk of injury when playing TCG and to determine if education can decrease interest in TCG participation. DESIGN: Anonymous pre- and post education surveys. SETTING: Two middle/high schools; one in Utah and one in California. SUBJECTS: 291 participants (163 in Utah, 128 in California) aged 9 18, 68% under age 15, 32% 15 and older; 65% white, 35% non-white; 52% female, 48% male. RESULTS: 76% of participants knew about TCG, of those 62% heard about it at school. 32% knew someone who had played, and twelve (4%) had played, usually with others. Most frequently cited as reasons for participation were curiosity, peer pressure, and competition. School was the most common location for playing. In California education significantly increased risk awareness, and significant positive attitude changes were observed regarding interest in playing TCG. Utah participants also exhibited attitude changes in the desired direction (less interest in playing TCG, would warn friends, and realized it was not safe to stop breathing), although results were not statistically significant, possibly due to previous education and four recent and highly publicized TCG deaths in the community. CONCLUSION: Results indicate that interactive, standardized, and skills-based education can increase student awareness of TCG risks and decrease interest in participation. Students reported that the schools were often where they first heard about TCG and where TCG was commonly played. Educators and associated health care professionals should therefore be encouraged to provide preventative education as part of school curricula. PMID- 27504506 TI - A molecularly imprinted electrochemiluminescence sensor based on the mimetic enzyme catalytic effect for ultra-trace Ni2+ determination. AB - A novel molecularly imprinted polymer (MIP) electrochemiluminescence (MIP-ECL) sensor was developed for the highly sensitive and selective determination of ultra-trace levels of Ni2+. The complex Ni2+-dimethylglyoxime (Ni-DMG) was chosen as the template molecule to construct the MIP and then acted as a mimetic enzyme to catalyse the oxidisation of luminol to enhance the ECL signal. When the imprinted cavities were occupied by Ni-DMG in the rebinding process, the ECL intensities produced by the luminol-H2O2 ECL system on the MIP-modified electrode surface increased with increased concentration of the Ni-DMG complex. The highly sensitive determination of Ni2+ was achieved through a catalytic reaction. This technique could be used for the quantitative analysis of Ni2+ with concentrations from 3.0 * 10-12 mol L-1 to 6.0 * 10-9 mol L-1. The detection limit was 1.01 * 10 12 mol L-1, which is much lower than that reported previously. In addition, the allowable amounts of interference ions in the MIP-ECL sensor were higher than that in other common molecularly imprinted sensors because of its excellent recognition of 3D cavity-to-complex molecules and ligand-to-metal ions. This method was successfully used to determine Ni2+ in real samples, such as apples, carrots and grapes, and has been proven feasible for practical applications. PMID- 27504507 TI - To the Editor. PMID- 27504508 TI - Fate of Australia's wildlife in the balance. PMID- 27504509 TI - Q & A: Hugh Dickinson. PMID- 27504510 TI - In memoriam Peter Mazur--cryobiologist. PMID- 27504511 TI - Letter to the Editor. Re: "Acute pancreatitis as the first manifestation of duodenal MALT lymphoma" by Ivona Simkova et al. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2015;159(4):688-94. doi: 10.5507/bp.2015.047. PMID- 27504512 TI - Comment on the letter from the author Vitorino Modesto dos Santos. PMID- 27504513 TI - Introduction to the Special Issue on Celebrating the 50th Anniversary of the Allan Variance. PMID- 27504514 TI - Mechanisms of Corneal Pain and Implications for Postoperative Pain After Laser Correction of Refractive Errors. AB - OBJECTIVE: The cornea is the target of most surgeries for refractive disorders, as myopia. It is estimated that almost 1 million patients undergo corneal refractive surgery each year in the United States. Refractive surgery includes photorefractive keratectomy (PRK) that produces intense postoperative pain. This review presents the main pain mechanisms behind PRK-related pain and the available therapeutic options for its management. METHODS: Data sources included literature of cornea anatomy, treatment of PRK postoperative pain, mechanisms of corneal pain, in 3 electronic databases: Pubmed, Scopus, and Web of Science. Only double-blinded controlled trials on pain control after PRK were selected to show the endpoints, treatment, and control strategies. RESULTS: A total of 18 double blind, controlled trials were identified. These studies have shown the use of topical nonsteroidal anti-inflammatory drugs, topical steroidal anti-inflammatory drugs, systemic analgesics, cold balanced saline solution, topical anesthetic, gabapentin, and morphine to treat postoperative pain in PRK. DISCUSSION: The percentage of responders has seldom been reported, and few studies allow for the formal calculation of the number necessary to treat. Postoperative intense pain after PRK laser surgery remains the main challenge to its widespread use for the correction of refractive errors. PMID- 27504516 TI - Biological roles of milk osteopontin. AB - PURPOSE OF REVIEW: Osteopontin (OPN) is an extensively phosphorylated acidic glycoprotein that is present at high concentration in human milk. Bovine milk OPN has recently become commercially available, and can thus be added to infant formula as well as other food products. Studies in experimental animals as well as a clinical trial in human infants reveal important biological roles for milk OPN. RECENT FINDINGS: Newborn wild-type mice nursing knock-out dams lacking milk OPN showed impaired cognitive development, reduced brain OPN and myelin-related proteins as compared with pups nursing wild-type dams. Transcriptomic analysis of intestinal biopsies from infant rhesus monkeys fed formula with added bovine milk OPN showed that OPN positively regulated intestinal proliferation, cell migration, and cellular chemotaxis via binding to integrin receptors. A clinical trial on human infants fed formula with added bovine milk OPN showed significantly reduced levels of serum tumor necrosis factor a and fewer days of fever as compared with infants fed regular formula. Further, their immune cell profile was more similar to that of breast-fed infants. SUMMARY: Milk OPN affects immune functions, and intestinal development in the newborn as well as brain development in a mouse model. Addition of bovine milk OPN to infant formula may improve the performance of formula-fed infants and make them more similar to breast-fed infants. Due to its multiple functions, milk OPN is also used for various adult applications. PMID- 27504517 TI - Nutrition in the preterm infant: what's new? AB - PURPOSE OF REVIEW: The increasing recognition of the role of nutritional care for preterm infants continues to result in a proliferation of review articles, systematic reviews, observational studies and trials. In this article, we review a selection of important studies published in the last 12-18 months. RECENT FINDINGS: The selected studies demonstrate the potential importance of light protecting parenteral nutrition solutions, the benefits of standardized concentrated parenteral nutrition solutions and the importance of insulin-like growth factor I in early life. Trials of immunonutrients (such as bile salt stimulated lipase) and other bioactive peptides such as lactoferrin are in progress, and emerging data highlight the importance of vitamin D for immune regulation, and therefore its role in sepsis and gut function. Early oro pharyngeal administration of colostrum appears to safely improve early immune development, and supports the increasingly common practice of immediate commencement of mothers' own breast milk. Despite this, studies continue to show that breastfeeding continuation rates could be improved. Data also highlight the potential role of macronutrient supply on other functional outcomes, such as retinopathy of prematurity. Finally, the importance of the unique nutritional needs of late and moderately preterm infants is starting to be recognized - a much larger group than the extremely preterm infants in whom many studies are focused. SUMMARY: Earlier, more aggressive nutrient supply and feeding regimes, including optimal support of breastfeeding mothers to ensure adequate provision of own mother's milk, appear to improve growth and neurodevelopmental outcomes. The addition of bioactive proteins shows promise. Special focus needs to be reestablished for late and moderately preterm infants, who have particular nutritional and feeding support requirements. This review has highlighted the need for further research particularly in the areas of early parenteral nutrition, the optimal regime to improve early growth and neuronal effects, the optimal rate of growth and/or catch-up, and the role of immune nutrients. PMID- 27504518 TI - [Germany joins the Nagoya Protocol: campaign against biopiracy]. PMID- 27504519 TI - [Prevention of pedophilia: therapy for more than 500 men]. PMID- 27504520 TI - [Announcement: palliative care specialty congress]. PMID- 27504521 TI - [Staffing in nursing homes now being negotiated: a new "nursing care need" concept leads to increased personnel costs]. PMID- 27504522 TI - [Nurses must make a greater effort to adapt to migrants: study shows deficits in culturally sensitive nursing]. PMID- 27504523 TI - [Ethics board: patient welfare in the hospital falls by the wayside: due to economization no time is left for communication]. PMID- 27504524 TI - [Addiction in the elderly: new information for nurses]. PMID- 27504525 TI - Single-Molecule Rotational Switch on a Dangling Bond Dimer Bearing. AB - One of the key challenges in the construction of atomic-scale circuits and molecular machines is to design molecular rotors and switches by controlling the linear or rotational movement of a molecule while preserving its intrinsic electronic properties. Here, we demonstrate both the continuous rotational switching and the controlled step-by-step single switching of a trinaphthylene molecule adsorbed on a dangling bond dimer created on a hydrogen-passivated Ge(001):H surface. The molecular switch is on-surface assembled when the covalent bonds between the molecule and the dangling bond dimer are controllably broken, and the molecule is attached to the dimer by long-range van der Waals interactions. In this configuration, the molecule retains its intrinsic electronic properties, as confirmed by combined scanning tunneling microscopy/spectroscopy (STM/STS) measurements, density functional theory calculations, and advanced STM image calculations. Continuous switching of the molecule is initiated by vibronic excitations when the electrons are tunneling through the lowest unoccupied molecular orbital state of the molecule. The switching path is a combination of a sliding and rotation motion over the dangling bond dimer pivot. By carefully selecting the STM conditions, control over discrete single switching events is also achieved. Combined with the ability to create dangling bond dimers with atomic precision, the controlled rotational molecular switch is expected to be a crucial building block for more complex surface atomic-scale devices. PMID- 27504526 TI - A multi-rater framework for studying personality: The trait-reputation-identity model. AB - Personality and social psychology have historically been divided between personality researchers who study the impact of traits and social-cognitive researchers who study errors in trait judgments. However, a broader view of personality incorporates not only individual differences in underlying traits but also individual differences in the distinct ways a person's personality is construed by oneself and by others. Such unique insights are likely to appear in the idiosyncratic personality judgments that raters make and are likely to have etiologies and causal force independent of trait perceptions shared across raters. Drawing on the logic of the Johari window (Luft & Ingham, 1955), the Self Other Knowledge Asymmetry Model (Vazire, 2010), and Socioanalytic Theory (Hogan, 1996; Hogan & Blickle, 2013), we present a new model that separates personality variance into consensus about underlying traits (Trait), unique self-perceptions (Identity), and impressions conveyed to others that are distinct from self perceptions (Reputation). We provide three demonstrations of how this Trait Reputation-Identity (TRI) Model can be used to understand (a) consensus and discrepancies across rating sources, (b) personality's links with self-evaluation and self-presentation, and (c) gender differences in traits. We conclude by discussing how researchers can use the TRI Model to achieve a more sophisticated view of personality's impact on life outcomes, developmental trajectories, genetic origins, person-situation interactions, and stereotyped judgments. (PsycINFO Database Record PMID- 27504527 TI - Synthesis of the Acyclic Carbon Skeleton of Filipin III. AB - The synthesis of the carbon skeleton of filipin III, a polyenic macrolactone possessing 11 stereogenic centers, was achieved using a convergent strategy with the longest linear sequence of 19 steps starting from hexanal. Construction of the polyene was realized using two successive Heck couplings as the key steps. Control of the stereogenic centers of the polyol fragment was performed by utilizing an Evans aldolization, a 1,3-syn aldolization, enantio- and diastereoselective allylations, a hemiacetalization/oxa-Michael sequence, and a 1,3-syn reduction. The polyol and polyenic fragments were coupled using a 1,5 anti diastereoselective aldolization followed by a 1,3-anti reduction. PMID- 27504528 TI - Multimodality Imaging of Neurodegenerative Processes: Part 2, Atypical Dementias. AB - OBJECTIVE: The purpose of this article is to describe the role of multimodality imaging in the evaluation of atypical neurodegenerative conditions. An imaging approach to the more common dementia disease processes was described in part 1. This article, part 2, briefly discusses current Centers for Medicare & Medicaid Services coverage for imaging patients with dementia and illustrates the basic concepts of combining anatomic, metabolic, and amyloid imaging in the evaluation of patients with atypical neurodegenerative dementia. Although these disease processes are rare, the growing repertoire of clinically available imaging techniques necessitates an understanding of their imaging patterns. CONCLUSION: Despite the rarity of these conditions, imaging of patients with neurodegenerative disorders is on the rise, and familiarity with the imaging appearances of these atypical causes is increasingly important. PMID- 27504529 TI - Solution to the pi-Distortivity Problem. AB - Traditionally, the delocalized pi system of benzene is believed to be responsible for its perfectly symmetric D6h geometry. However, it has also been suggested that the pi system prefers a distorted D3h geometry. Arguments for this have been based on clever use of VB methods as well as through shifts in the frequency of the distortive b2u mode. Evidence has been provided through different ways of partitioning the total electronic energy between the sigma and the pi systems. These methods are plagued by the fact that there is no unique way to partition the energy, leading to questions regarding the validity of the conclusions. Here we note that even though energy cannot be partitioned exactly, force acting on a nucleus depends only on the single particle density and can hence be partitioned exactly. Using good-quality wave functions that are numerically found to obey the Hellmann-Feynman theorem to good accuracy, we calculate the sigma and pi components of the force and provide conclusive evidence of pi-distortivity at the HF level. Our approach provides an unambiguous way to approach the problem with wave functions that account for electron correlation. Our calculations suggest that the conclusion is valid at the MP2 level, too. PMID- 27504530 TI - Lichenoid drug eruption caused by clonazepam. PMID- 27504531 TI - Tissue Reaction to a Novel Bone Substitute Material Fabricated With Biodegradable Polymer-Calcium Phosphate Nanoparticle Composite. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of a novel bone substitute material fabricated using a biodegradable polymer-calcium phosphate nanoparticle composite. METHODS: Porous structured poly-L-lactic acid (PLLA) and hydroxyapatite (HA) nanoparticle composite, which was fabricated using solid liquid phase separation and freeze-drying methods, was grafted into bone defects created in rat calvarium or tibia. Rats were killed 4 weeks after surgery, and histological analyses were performed to evaluate new bone formation. RESULTS: Scanning electron microscopic observation showed the interconnecting pores within the material and the pore diameter was approximately 100 to 300 MUm. HA nanoparticles were observed to be embedded into the PLLA beams. In the calvarial implantation model, abundant blood vessels and fibroblastic cells were observed penetrating into pores, and in the tibia model, newly formed bone was present around and within the composite. CONCLUSIONS: The PLLA-HA nanoparticle composite bone substitute developed in this study showed biocompatibility, elasticity, and operability and thus has potential as a novel bone substitute. PMID- 27504532 TI - Growth Factors in Bone Marrow Blood of the Mandible With Application of Extracorporeal Shock Wave Therapy. AB - INTRODUCTION: Enhancement of bone regeneration is crucial to dental implantology. Growth factors play a significant role during osteogenesis and angiogenesis. Extracorporeal shock wave therapy (ESWT) enhances bone healing; however, no studies have yet been performed in oral implantology. MATERIALS AND METHODS: Twenty patients who underwent bilateral mandibular wisdom tooth removal were included. ESWT was applied to 1 side of the jaw. Blood samples were collected from the peripheral vein (PB), mandibular bone marrow without and with ESWT (BM /+SW). Quantity and quality of the growth factors bone morphogenetic protein (BMP)-2, BMP-4, insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), and transforming growth factor-beta (TGF-beta) were investigated via ELISA and cell proliferation assay. RESULTS: ELISA revealed superior amounts of IGF-1 and VEGF in BM-/+SW compared to PB (P < 0.05). TGF-beta demonstrated no variance. Levels of BMP-2 and BMP-4 were too low for adequate detection in the ELISA. No difference was noticed upon ESWT. The cell proliferation assay did not identify any changes comparing PB versus BM-SW versus BM + SW. CONCLUSION: IGF-1 and VEGF are present at higher levels in mandibular bone marrow than in peripheral blood (PB). This study did not identify any benefits of extracorporeal shock wave therapy to increase the investigated growth factors. PMID- 27504533 TI - Periimplantitis Treatment: Long-Term Comparison of Laser Decontamination and Implantoplasty Surgery. AB - PURPOSE: Periimplantitis is the most frequent cause of late implant failure; however, little is known about the long-term success of periimplantitis treatment and the effectiveness of various therapeutic interventions. MATERIALS AND METHODS: A total of 142 patients were referred to the Academy for Oral Implantology in Vienna for the treatment of recurrent periimplantitis around single-tooth implants. Of them, 72 patients (51%) were treated by laser decontamination, 47 patients (33%) by implantoplasty surgery, and 23 patients (16%) by a combination of both approaches. RESULTS: Overall success of periimplantitis therapy was 89% after 9 years of follow-up, and it did not differ significantly between female and male patients (P = 0.426). The number of implant failures that could not be prevented by periimplantitis treatment was 6 after laser decontamination (8%), 6 after implantoplasty surgery (13%), and 4 after a combination of both therapies (17%). Implant loss occurred after 4.9 +/- 1.9 years of therapy, on average. No significant difference between the 3 treatment groups could be observed (P = 0.393). CONCLUSION: The present results suggest that success rates of periimplantitis therapy with either laser decontamination or surgical implantoplasty are high. These success rates do not appear to be associated with patient gender or treatment strategy. PMID- 27504534 TI - The Effect of Platform Switching on Periimplant Crevicular Fluid Content During Early Wound Healing. AB - PURPOSE: The objective of this study was to investigate the soft tissue response and periimplant crevicular fluid (PICF) content around platform-switched (PS) and platform-matched (PM) implants during early healing. MATERIALS AND METHODS: Nonsmokers treatment planned to receive a single implant in 2 quadrants were recruited. Two-stage implant placement protocol with 1 PM and 1 PS implant was implemented. Periimplant probing depths (PDs), modified sulcus bleeding index, and plaque indices were recorded, and PICF was collected at 1, 2, 4, and 6 weeks after abutment connection. RESULTS: PD readings were higher at week 1 than at week 6 for both groups (P = 0.0005). PD was statistically deeper in PM than in PS at week 1 (P = 0.03). There was a time-dependent decrease in total PICF volume for both groups. This decrease was statistically significant for PS (P = 0.0005), with no differences between the 2 groups at any time (P > 0.05). The decrease observed in both PM and PS for PICF interleukin 6 and macrophage inflammatory protein-1beta, and in PS for tumor necrosis factor-alpha (TNF-alpha) was statistically significant (P <= 0.03). TNF-alpha was statistically higher in PS than in PM at week 1 (P = 0.005). CONCLUSION: Within the limits of this study, it seems that periimplant soft tissue response around PM and PS implants is mostly similar during the early healing period. PMID- 27504535 TI - Clinical and Microcomputed Topography Evaluation of the Concentrated Growth Factors as a Sole Material in a Cystic Bony Defect in Alveolar Bone Followed by Dental Implantation: A Case Report. AB - Concentrated growth factors (CGFs) can be used to enhance wound healing. This case report describes a short-term effect of CGF grafting followed by implant placement in a cystic bony defect within the mandible. Healing conditions were monitored by 2 implant-related surgeries, radiographs, and a microcomputed topography examination. Continuous increase of radiopacity in radiographs was noticed till 6 months after grafting. Bone core specimen was taken at 3.5 months after grafting, and percent bone volume reached 32.7% analyzed by microcomputed topography. In conclusion, the present case showed bone regeneration in the cystic bony defect grafted by CGFs alone. PMID- 27504536 TI - Alignment of Biological Apatite c-Axis Under Functional Loading: A Preliminary Report. AB - PURPOSE: To understand the bone modeling/remodeling process of functionally loaded implants by observing the alignment of the biological apatite (BAp) c axis. MATERIALS AND METHODS: Commercially available titanium implants with TiO2 grit-blasted surfaces were placed in the fourth premolar and the first molar of the beagle dog and were functionally loaded with casted crowns and were compared to the non-loaded controls. After being killed, the samples were subjected to histological observation and to a microbeam x-ray diffraction (MUXRD) analysis with a transmission optical system to evaluate the preferential BAp c-axis alignment. RESULTS: The non-loaded group presented mostly nonoriented BAp c-axis around the implant, whereas for the loaded group, preferential alignment of BAp c axis was observed along the loading direction of the implant suggesting that the Bap aligned itself based on the direction of the functional mechanical loading. CONCLUSION: The MUXRD revealed that the c-axis orientation was perpendicular to the implant thread working against the functional loaded direction, which may contribute in designing an optimal implant macrogeometry. PMID- 27504537 TI - Dihydrobenzofuran Neolignanamides: Laccase-Mediated Biomimetic Synthesis and Antiproliferative Activity. AB - The biomimetic synthesis of a small library of dihydrobenzofuran neolignanamides (the natural trans-grossamide (4) and the related compounds 21-28) has been carried out through an eco-friendly oxidative coupling reaction mediated by Trametes versicolor laccase. These products, after complete spectroscopic characterization, were evaluated for their antiproliferative activity against Caco-2 (colon carcinoma), MCF-7 (mammary adenocarcinoma), and PC-3 (prostate cancer) human cells, using an MTT bioassay. The racemic neolignamides (+/-)-21 and (+/-)-27, in being the most lipophilic in the series, were potently active, with GI50 values comparable to or even lower than that of the positive control 5 FU. The racemates were resolved through chiral HPLC, and the pure enantiomers were subjected to ECD measurements to establish their absolute configurations at C-2 and C-3. All enantiomers showed potent antiproliferative activity, with, in particular, a GI50 value of 1.1 MUM obtained for (2R,3R)-21. The effect of (+/-) 21 on the Caco-2 cell cycle was evaluated by flow cytometry, and it was demonstrated that (+/-)-21 exerts its antiproliferative activity by inducing cell cycle arrest and apoptosis. PMID- 27504538 TI - Decomposition and Cell Failure Mechanisms in Lead Halide Perovskite Solar Cells. AB - Perovskite solar cells have experienced a remarkably rapid rise in power conversion efficiencies, with state-of-the-art devices now competing with multicrystalline silicon and thin-film cadmium telluride in terms of efficiency. Unfortunately, the lead halide perovskite absorbers suffer from a lack of chemical stability and decompose in response to a variety of environmental stimuli. In this Forum Article, we provide a brief overview of the decomposition mechanisms in lead halide perovskite thin films, as well as the processes contributing to cell failure in finished devices. We finish by briefly surveying recent efforts to extend the device lifetime. Ultimately, if perovskite solar cells can be made stable, they will be an exciting, highly complementary addition to existing photovoltaic technologies. PMID- 27504539 TI - Building the bacterial cell wall at the pole. AB - Polar growth is the predominant mode of cell wall extension in the Actinobacteria and the alphaproteobacterial clade Rhizobiales. The observation of polar elongation in taxonomically diverse bacteria suggests that polar growth may have evolved independently. Indeed, the regulatory mechanisms governing the assembly of cell wall biosynthesis machinery at the pole are distinct in the Actinobacteria and Rhizobiales. Here we highlight recent advances in our understanding of polar growth mechanisms in bacteria, with an emphasis on Streptomyces and Agrobacterium. This review illustrates that common themes are emerging in the regulation of polar growth in diverse bacteria. Emerging themes include the use of landmark proteins to direct growth to the pole and coordination of polar growth with cell-cycle progression. PMID- 27504540 TI - Cell biology of corn smut disease-Ustilago maydis as a model for biotrophic interactions. AB - Ustilago maydis is a well-established model system for biotrophic fungal plant pathogens. The fungus has a dimorphic life cycle with a yeast-like saprophytic phase switching to filamentous, pathogenic growth upon hyphal fusion. Due to its highly differentiated development and the amenability for reverse-genetics U. maydis provides a model system for both fungal cell biology as well as the study of biotrophic plant interaction. The present article highlights key findings in different aspects of cell biology on the corn smut disease and provides an outlook on the most intriguing open questions. PMID- 27504541 TI - New Oral Anticoagulants: Need and Challenges in a Developing Country. PMID- 27504542 TI - Determination of Prevalence of Dental Erosion in 12 - 14 Years School Children and Its Relationship with Dietary Habits. AB - OBJECTIVE: To determine the frequency of dental erosion in 12-14 years school children and its association with dietary habits. STUDY DESIGN: Observational cross-sectional analytical study. PLACE AND DURATION OF STUDY: Fatima Jinnah Dental College, Karachi, from January to June 2010. METHODOLOGY: School children aged between 12 - 14 years were included in this study. Dental erosion was detected by visual examination. Aself-developed questionnaire was used to assess the dietary habits of children. Acidic diet was considered a diet that has an acidic pH. The amount of consumption of acidic drinks and food per week was categorized into low consumption (1 - 7 times / week) and medium consumption (8 - 21 times / week). Chi-square test was applied to see any statistical difference between diet and tooth erosion at 95% CI. RESULTS: The results showed a high frequency of (46%) dental erosion in children, which was significantly higher (p < 0.001) in children with more acidic diet. CONCLUSION: This study highlights the impact of dietary habits on the prevalence of dental erosion in children. Acidic diets need to be controlled in frequency to prevent dental erosion. PMID- 27504543 TI - Efficacy of Trichloro-Acetic Acid Peel Alone Versus Combined Topical Magnesium Ascorbyl Phosphate for Epidermal Melasma. AB - OBJECTIVE: To compare the efficacy in terms of reduction in melasma area and severity index (MASI) score by more than 10 of a combination of 20% trichloro acetic acid peel plus 5% topical magnesium ascorbyl phosphate versus 20% trichloroacetic acid peel alone in the treatment of epidermal melasma. STUDY DESIGN: Randomized controlled trial. PLACE AND DURATION OF STUDY: Department of Dermatology, Lady Reading Hospital (LRH), Peshawar, from May 2012 to May 2013. METHODOLOGY: Patients aged 18 - 65 years, with Fitzpatrick skin type III-V were divided into two equal groups having 74 patients each. Detailed history was taken and Wood's lamp examination done to rule out mixed and dermal melasma. Melasma area and severity index (MASI) score was calculated for every patient. Priming was done for all patients with tretinoin cream applied once daily at night for 2 weeks, and to use a broad spectrum sun block cream before sun exposure. Patients in group Awere subjected to combined treatment, i.e. trichloro-acetic acid peel 20% (weekly) plus magnesium ascorbyl phosphate cream (applied once daily), while patients in group B were subjected to trichloro-acetic acid peel 20% (weekly) alone. Treatment was continued for 6 weeks. After completion of treatment, MASI score was recalculated. Proportion of patients with significant MASI score reduction was compared using chi-square test with significance at p < 0.05. RESULTS: Male and female patients were 11 (14.9%) and 63 (85.1%), respectively in group A, whereas 13 (17.6%) and 61 (82.4%) in group B. The mean age in group Awas 30.28 +/-8.08 years, and 29.36 +/-6.84 years in group B. Significant MASI score reduction in group Awas seen in 60 (81.1%) patients and in group B 49 (66.2%, p= 0.040). CONCLUSION: Combination of trichloro-acetic acid peel and topical magnesium ascorbyl phosphate cream was significantly more effective than trichloro-acetic acid peel alone in treatment of melasma. PMID- 27504544 TI - Diagnostic Accuracy of Perfusion Computed Tomography in Cerebral Glioma Grading. AB - OBJECTIVE: To determine the diagnostic accuracy of perfusion computed tomography (PCT) in the grading of cerebral glioma. STUDY DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: Department of Radiology, Allied Hospital, Faisalabad, from January to June 2014. METHODOLOGY: All the patients with untreated glioma had an initial non-contrast head CT and then PCT using 128 multidetector CTscanner. Perfusion maps of permeability surface (PS) and cerebral blood volume (CBV) were generated and measured. As control, a second volume of interest was placed in the contralateral healthy cortex. PCT parameters were compared with World Health Organization (WHO) glioma grades. RESULTS: Fifty patients of 30 - 70 years of age of both genders (mean 45.13 +/-5.54), 31 (62%) males and 19 (38%) females were studied. These patients were classified as low grade glioma group (22 patients) and high-grade glioma group (28 patients). PS showed the sensitivity of 95.45%, specificity of 92.86% and diagnostic accuracy of 94% in differentiating the low-grade and high-grade glioma by using a cut-off value of 3.6 ml/100 g/minute. By using a cut-off value of CBV of 2.08 (ml/100 g) among low-grade and high-grade glioma group, CBV showed the sensitivity of 77.3%, specificity of 89.3%, and diagnostic accuracy of 84%. CONCLUSION: The derived parameters (PS and CBV) correlate well with tumor histopathology, differentiating low-grade from high-grade gliomas. PS showed better accuracy for glioma grading. PMID- 27504545 TI - Frequency of Hepatic Hydrothorax and its Association with Child Pugh Class in Liver Cirrhosis Patients. AB - OBJECTIVE: To determine the frequency of hepatic hydrothorax and its association with Child Pugh Class in patients with liver cirrhosis. STUDY DESIGN: Descriptive, analytical study. PLACE AND DURATION OF STUDY: Jinnah Postgraduate Medical Centre, Karachi, Medical Unit-III, (Ward- 7), from June 2012 to May 2013. METHODOLOGY: All patients with established diagnosis of decompensated chronic liver disease were included. Detailed history, thorough physical examination, routine laboratory investigations, chest X-ray and abdominal ultrasound were carried out in all patients to find out the presence of pleural effusion and ascites, respectively. Fifty milliliters of pleural fluid was aspirated in all patients with pleural effusion using the transthoracic approach, taking ultrasound guidance, wherever required. Fluid was sent for microscopic, biochemical, and microbial analysis. SBEM defined if pleural fluid with polymorphonuclear (PMN) cell count > 500 cells/mm3 or positive culture with PMN cell count > 250 cells/mm3 with exclusion of a parapneumonic effusion. RESULTS: Two hundred and six patients met the inclusion criteria, with mean age of 41.25 +/-13.59 years. Among them, 149 (72.3%) were males and 57 (27.7%) females. Twenty three (11.2%) had hydrothorax; right sided involvement was in 18 (78.3%) subjects, 3 (13%) had left sided while bilateral pleural effusion was found in 2 (8.7%) cases. SBEM was found in 07 (30.43%) cases. Mean serum albumin 3.125 +/ 0.71 gram/dl. There was association between serum albumin levels and hydrothorax. Asignificant association of hydrothorax with Child Pugh scoring system (p=0.018), but not with serum albumin (p=0.15). CONCLUSION: The frequency of hepatic hydrothorax has a significant association with hepatic function as assessed by Child Pugh scoring system, but not with serum albumin. PMID- 27504546 TI - Immunohistochemical Expression of Epidermal Growth Factor Receptor and c-Kit in Triple Negative Breast Cancer. AB - OBJECTIVE: To determine the frequency of immunohistochemical expression of epidermal growth factor receptor (EGFR) and c-KITin triple negative breast cancer (TNBC). STUDY DESIGN: Descriptive, cross-sectional study. PLACE AND DURATION OF STUDY: Armed Forces Institute of Pathology (AFIP), Rawalpindi, from January to December 2014. METHODOLOGY: Fifty cases of triple negative breast cancer diagnosed on immunohistochemistry were included in the study. Patients'gender and age were noted. Immunohistochemistry for EGFR and c-KITwere applied and the results were recorded. The data were analyzed by using computer software programme SPSS version 19. Descriptive statistics, frequencies and percentages were calculated. RESULTS: Out of 50 patients of TNBC, all patients were females. The ages of the patients ranged between 30 and 80 years with an average age of 48.9 years and standard deviation of +/-10.0. Out of 50 cases, 29 cases (58%) were positive for EGFR while 15 cases (30%) were positive for c-KIT. Thirteen cases (26%) were positive for both EGFR and c-KIT. Nineteen cases (38%) were negative for both EGFR and c-KIT. CONCLUSION: EGFR expression was observed in 58% and c-KITexpression was seen in 30% of the cases. The results of EGFR expression are almost similar while those of c-KIT are different from international studies which suggest immunohistochemical differences between the studied populations. PMID- 27504547 TI - Peer-Assisted Learning: Who Should Be the Tutor, Fellow Student or Senior Resident? AB - OBJECTIVE: To compare student-tutor guided peer-assisted learning (STPAL) and resident-tutor guided peer-assisted learning (RTPAL) for its impact on performance of students in summative assessment. STUDY DESIGN: Quasi-experimental study. PLACE AND DURATION OF STUDY: Gujranwala Medical College, from February to September 2015. METHODOLOGY: Four batches each of final year MBBS students were first trained for clinical skills by resident-tutors for 2 weeks and had a pre test. Two students with highest marks were selected as student-tutors. Half of the batch had a further 2 weeks skill training by the student-tutors while other half by resident-tutor, post-test was carried out after 2 weeks. Improvement in scores was compared between STPAL and RTPAL groups, using unpaired student t test. The batch underwent same intervention for the next month with cross-over of STPAL and RTPAL groups. RESULTS: Study population was 152 out of expected 188 as batch D underwent the study only once and 13 students were either absent or had decline in scores, so were excluded. Among 74 (48.68%) STPALand 78 (51.23%) RTPAL students, median improvement in scores was 8 for STPAL group as compared to 7 for RTPALgroup; the difference was not statistically significant (p= 0.61). CONCLUSION: Student-tutor guided peer-assisted learning is as effective as resident-tutor peer assisted learning in improving performance of the students. PMID- 27504548 TI - ICU Pathogens: A Continuous Challenge. AB - OBJECTIVE: To determine the frequency and antibiogram of pathogens in an intensive care unit (ICU). STUDY DESIGN: Cross-sectional, observational study. PLACE AND DURATION OF STUDY: Department of Microbiology, Army Medical College, National University of Science and Technology, Islamabad, from January 2013 to January 2014. METHODOLOGY: Clinical samples, received from patients admitted in ICU, were inoculated on various medias like blood agar, chocolate agar, MacConkey agar and urine samples on CLED. These were then incubated at 37 degrees C for 24 hours. Isolates were identified by colony morphology, Gram reaction, catalase test, oxidase test. Species identification in case of Gram Negative Rods was done by using API 20E (BioMerieux). Antibiotic susceptibility was done by using modified KirbyBauer disc diffusion technique. Bacterial isolates were prepared and inoculated on Mueller-Hinton agar plates followed by application of various antibiotic disc (Oxoid, UK) as per manufacturer's instructions. The plates were then incubated at 37 degrees C aerobically for 18 - 24 hours. Zone diameters were measured and interpreted as sensitive and resistant, according to Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS: Out of the 367 positive cultures, 116 (31.08%) were Acinetobacter baumanniisusceptible to minocycline and tigecycline followed by Klebsiella pneumoniae (n=71, 16%) susceptible to tigecycline and meropenem. Others were Pseudomonas aeruginosa, Escherichia coli,Coagulase Negative Staphylococcus, Staphylococcus aureus, Enterococcus spp., Streptococcus spp., Klebsiella oxytoca, Stenotrophomonas maltophilia,and Candida spp. CONCLUSION: Acinetobacter baumanniiwas the most frequently isolated pathogen. Most of the cultures yielding pathogens were from respiratory tract samples. Gram negative isolates were multidrug resistant but most were tigecycline and susceptible to meropenem. PMID- 27504549 TI - Species Identification and Antibiotic Susceptibilities of Coagulase- Negative Staphylococci Isolated from Urinary Tract Infection Specimens. AB - OBJECTIVE: To determine the incidence of Coagulase- negative S. aureusin urinary tract infections and sensitivities of these isolates to antimicrobial agents. STUDY DESIGN: Cohort study. PLACE AND DURATION OF STUDY: Dr. Essa Laboratory and Immunology and Infectious Disease Research Laboratory (IIDRL), Microbiology Department, University of Karachi, from January 2009 to January 2010. METHODOLOGY: Urine specimens, suggestive of urinary tract infection (UTI), were identified. Speciation of isolates was done using API-20 Staph.system. Screening of extracellular products was done using SDS-PAGE electrophoresis and Hemolysin on blood-agar plates. Minimum inhibitory concentration (MICs) of antibiotics was estimated by microtiter well plate method. Frequency and percentages were determined and chi-square test was used for comparing proportions with significance at p < 0.05. RESULTS: Coagulase - negative S. aureus(CONS) were the cause of urinary tract infection in 56 out of 1866 outpatient (3%) and 164 of 1261 inpatient (13%), urinary tract infections (p < 0.001). Two hundred and twenty CONS isolates were identified. The most common CONS identified was S. saprophyticus (31%, 68 strains). The relative frequency of Coagulase - negative S. aureuswas 6% (13 strains). All isolates were sensitive to Vancomycin and Linezolid. Resistance was 69% to Ampicillin, 53% to Methicillin, and 37.5% to Ciprofloxacin. CONCLUSION: CONS are a potential uropathogens, with capability of slime production and resistance to common empirical prescriptions. This also warrants formulation of an appropriate antibiotic policy that covers CONS. PMID- 27504550 TI - Pattern of Polymicrobial Isolates and Antimicrobial Susceptibility from Blood. AB - OBJECTIVE: To determine the pattern of polymicrobial isolates in blood cultures and antimicrobial susceptibility in a tertiary care hospital of Karachi. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan, from September to November 2014. METHODOLOGY: Blood culture samples were received from patients, which were processed by BACTEC 9240 system (Becton Dickinson). All positive blood samples were further analyzed. Susceptibility to antimicrobial agents was determined according to the Clinical and Laboratory Standards Institute (CLSI) criteria of the year. Identification of growth was based on Gram staining, colony morphology and appropriate biochemical tests. Antibiotic susceptibility was done as per Clinical and Laboratory Standards Institute (CLSI) recommendations. RESULTS: Out of the 7251 samples submitted, 2931 (40.42%) were positive for growth, 2389 (81.5%) samples were monomicrobial, whereas 542 (18.5%) samples were polymicrobial. Among the polymicrobial isolates, 468 (86.34%) blood culture samples yielded two, 66 (12.17%) yielded three, and 8 (1.47%) yielded four organisms. Gram positive isolates were 281 (51.84%) and Gram negative were 261 (48.15%). The most frequent isolates in polymicrobial blood stream infection were Acinetobacterspp. (51/542, 9.4%) and Coagulase negative Staphylococcus(84/542, 15.5%), respectively. Staphylococcus aureus isolates, which were resistant to Methicillin, accounted for 24.65%. Third generation Cephalosporins resistance in Klebsiella spp. and Eschericia (E.) coli was found to be 63.6% and 58%, respectively. Carbapenem resistance was seen in 5.9% of Pseudomonas aeruginosaand 17.6% Acinetobacter spp. CONCLUSION: Gram positive bacteria were more commonly involved in polymicrobial blood stream infections with Coagulase negative Staphylococcusbeing the most common Gram positive isolate. Methicillin-resistant Staphylococcus aureusaccounted for one-fourth of isolates. Higher resistance to third generation Cephalosporins was seen in Klebsiella spp. and E.coli isolates. Resistance of Pseudomonas aeruginosaand Acinetobacter species to Carbapenems was found out to be on the lower side. PMID- 27504551 TI - Comparison of Efficacy of Tacrolimus Versus Cyclosporine in Childhood Steroid Resistant Nephrotic Syndrome. AB - OBJECTIVE: To compare the efficacy of tacrolimus versus cyclosporine (Calcineurin Inhibitors) in the management of childhood steroid-resistant nephritic syndrome (SRNS). STUDY DESIGN: Quasi-experimental study. PLACE AND DURATION OF STUDY: Department of Paediatric Nephrology at The Children's Hospital and Institute of Child Health, Lahore, from August 2014 to September 2015. METHODOLOGY: Patients of either gender aged 1 - 12 years, with the diagnosis of mesangioproliferative glomerulonephritis (MesangioPGN), focal segmental glomerulosclerosis (FSGS) or minimal-change disease (MCD) were included. Patients were assigned into two groups, one given tacrolimus in dose of 0.1 - 0.2 mg/kg/day in two divided doses, and other given cyclosporine in dose of 150 - 200 mg/m2/day in two divided doses along with oral steroids 30 mg/m2/day in divided doses, followed by alternate day with tapering dosage. Trough drug levels were done with dose adjustment accordingly. Patients were monitored and followed for the response to treatment and adverse effects of these two calcineurin inhibitors. RESULTS: Atotal of 84 patients, 58% males and 42% females, were included in the study. The age ranged from 1.25 to 12 years. The most common histopathological diagnosis was MesangioPGN (69.04%), FSGS (21.4%), and MCD (9.52%). Complete response was seen in 80.95% and 97.6% patients treated with cyclosporine and tacrolimus, respectively. Partial response was in 19.05% patients treated with cyclosporine and 2.4% in patients with tacrolimus. The most common adverse effect with cyclosporine and tacrolimus was hypertrichosis in 80.95% and 2.38%, hypertension 16.66% and 11.9% respectively while gum hypertrophy with cyclosporine was seen in 26.19% patients. CONCLUSION: Tacrolimus was more efficacious than cyclosporine in achieving remission in childhood SRNS with insignificant adverse effects. PMID- 27504552 TI - Effects of Cobalt Nitrate on Histopathological and Morphometric Changes in Rat Femoral Artery Vasospasm Model. AB - OBJECTIVE: To determine the effects of cobalt nitrate on the arterial wall in a rat femoral artery vasospasm model. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Faculty of Medicine, Istanbul University, between November 2009 and September 2010. METHODOLOGY: Twenty-four rats were separated into three groups named group 1 (n=8, sham-control); group 2 (n=8, vasospasm), and group 3 (n=8, vasospasm + cobalt nitrate treated). Group 3 rats were subjected to intraperitoneal administration of 0.1 mg/kg/day cobalt nitrate for 7 days, followed by histological and morphometric analyses. ANOVAand post hoc analyses were carried out. RESULTS: The mean vascular wall thickness of the group 1, 2 and 3 rats was found to be 133 +/-13, 210 +/-15 and 160 +/-11 micron, respectively. The mean vascular lumen diameter of the group 1, 2 and 3 rats was 698 +/-20, 240 +/-15 and 540 +/-22 micron, respectively. Arteries in the group 3 had thin smooth endothelium, thin mildly folded internal elastic lamina, and concentric smooth muscle cells. The mean vascular lumen diameter of the group 3 rats showed a significant decrease compared to the group 2 rats. CONCLUSION: Cobalt nitrate may potentially serve as an agent in preventing cerebral vasospasm after a hemorrhagic episode. PMID- 27504553 TI - Retinal Thickness and Visual Acuity in Diabetic Macular Edema: An Optical Coherence Tomography-Based Study. AB - OBJECTIVE: To determine the relationship between foveal (retinal) thickness and visual acuity in diabetic macular edema through optical coherence tomography (OCT) mapping software. STUDY DESIGN: Cross-sectional descriptive study. PLACE AND DURATION OF STUDY: The Retina Clinic of Al-Shifa Trust Eye Hospital, Rawalpindi, from August 2011 to August 2012. METHODOLOGY: Eighty eyes of 68 patients with clinical diagnosis of diabetic macular edema, based on complete ophthalmic examination, were enrolled. The best-corrected visual acuity was recorded on logMar scale. OCTimaging was performed through dilated pupil by experienced operator. Foveal thickness was determined. OCTparameters of macular thickness were analysed with baseline variables including age, duration since diagnosed with diabetes, and visual acuity. RESULTS: The mean visual acuity was 0.81 (0.2 - 1.8) logMar units. The average foveal thickness was 395.09 +/-142.26 (183 - 825 um). There was moderate correlation between foveal thickness and visual acuity (rs= 0.574, p < 0.001), absent in those who had visual acuity worse than 1 logMar. There was a weak positive association between foveal thickness and the duration of diabetes (rs=0.249, p < 0.05). There was, however, no correlation between foveal thickness and age (rs= 0.012, p=0.919). CONCLUSION: There is a moderate correlation between visual acuity and degree of foveal thickening in diabetic macular edema, hence two cannot be used interchangeably in clinical practice. PMID- 27504554 TI - Arterial and Ventricular Elastance and Ventriculo-arterial Coupling in Asthmatic Children. AB - OBJECTIVE: To compare arterial and ventricular end-systolic elastance and ventriculo-arterial coupling between asthma and healthy children and correlate these all three parameters with pulmonary function tests in subjects with asthma. STUDY DESIGN: Across-sectional analytical study. PLACE AND DURATION OF STUDY: Department of Pediatrics, Bozok University Medical Faculty,Yozgat, Turkey, from January 2012 to November 2014. METHODOLOGY: Transthoracic and Doppler echocardiography and pulmonary function tests in patients with asthma aged 7 - 12 years and control subjects. Forty stable asthma patients on prophylactic inhaled corticosteroids and 97 healthy subjects were investigated. Both groups were matched for age, gender, blood pressure, heart rate, body surface area, echocardiographic parameters and pulmonary function tests. RESULTS: There was no difference regarding left ventricular elastance at end-systole derived by single beat/body surface area (Ees(sb)/BSA) between asthmatic patients and healthy children (2.59 +/-1.29 mmHg/ml/m2, 2.43 +/-1.28 mmHg/ml/m2 respectively, p=0.504), arterial elastance/BSA(Ea/BSA) (2.10 +/-0.97, 1.75 +/-0.89 respectively, p=0.041), and ventriculoarterial coupling (VAC) (0.83 +/-0.13, 0.74 +/-0.13, respectively, p < 0.001) were higher in asthmatic group than controls. There was no correlation between Ea, Ees (sb), VAC and pulmonary function tests. CONCLUSION: Arterial elastance increase and stiffness decrease in asthmatic patients. This may be due to using prophylactic inhaled corticosteroids. Using inhaled corticosteroids have protective effects against atherosclerosis. As a result of this higher arterial elastance, asthmatic children had higher VAC resulting in less efficient cardiovascular function. PMID- 27504555 TI - Childhood Trauma and Alexithymia in Patients with Conversion Disorder. AB - OBJECTIVE: To determine the relationship between childhood trauma (physical, sexual, emotional abuse and neglect) and alexithymia in patients with conversion disorder, and to identify it as a predictor of alexithymia in conversion disorder. STUDY DESIGN: An analytical study. PLACE AND DURATION OF STUDY: Multiple public sector hospitals in Lahore, from September 2012 to July 2013. METHODOLOGY: Eighty women with conversion disorder were recruited on the basis of DSM IV-TR diagnostic criteria checklist to screen conversion disorder. Childhood abuse interview to measure childhood trauma and Bermond Vorst Alexithymia Questionnaire, DSM-IV TR Dianostic Criteria Checklist, and Childhood Abuse Interview to assess alexithymia were used, respectively. RESULTS: The mean age of the sample was 18 +/-2.2 years. Thirty-six cases had a history of childhood trauma, physical abuse was the most reported trauma (f = 19, 23.8%) in their childhood. Patients with conversion disorder has a significant association with alexithymia (p < 0.05). Multiple regression analysis showed that childhood sexual abuse could predict alexithymia (F= 7.05, p < 0.05). Among the alexithymia domain, childhood physical abuse significantly predicted the difficulty in verbalizing emotions among the abused patients (F= 6.40, p < 0.05). CONCLUSION: The study highlighted childhood abuse and emotional pent up as an etiological factor of conversion disorder. Strategies should be devised to reduce this disorder among women in Pakistani society. PMID- 27504556 TI - AParadigm Shift: The New Novel Oral Anticoagulation Agents. AB - Atrial fibrillation (AF) is the most common arrhythmia and represents one-third of the arrhythmia-related hospital admissions in the developed countries. Embolic strokes associated with AF are more severe and disabling. Thromboembolic stroke prevention is a major goal in treatment of AF and Warfarin has successfully served this purpose for many years. Drug-drug interaction and regular monitoring with Warfarin pose a significant challenge where health care system has limited resources; and lack of a well-structured health system, hinders regular International Normalized Ratio (INR) monitoring. Novel oral anticoagulants (NOACs) have opened up a new exciting chapter in the field of anticoagulation in non-valvular atrial fibrillation (NVAF). This review discussed the landmark trials that led to the development of NOACs and explored the potentials of these new agents with simultaneous comparison of Warfarin. PMID- 27504557 TI - Major Lower Limb Amputations: Experience of a Tertiary Care Hospital in Sri Lanka. AB - OBJECTIVE: To determine the epidemiology and conditions frequently seen in major lower extremity amputation. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Teaching Hospital Karapitiya, Sri Lanka, from October 2013 to September 2014. METHODOLOGY: Major lower limb amputations were identified according to ICD 10 criteria. Data was retrospectively collected. Type of the amputation, indication for the amputation, gender and age of the patients, and mortality were noted. RESULTS: Eighty-five cases of major lower limb amputations were analyzed, including 43 above-knee amputations, 40 below-knee amputations, and 2 through knee amputations. Most of the patients were in their 7th (38.8%, n=33) and the 8th (21%, n=18) decade of life. Female to male ratio was 1:1.7. Indications of lower extremity amputation were diabetic foot ulcer (37.6%, n=32), peripheral vascular disease (31.7%, n=27), followed by trauma (n=6), acute limb ischemia and infections (n=5 each), chronic osteomyelitis (n=4), tumors (n=3), elephantiasis, pressure sore and chronic wound (n=1 each). Overall diabetes frequency was 52.9% (n=45). In-hospital mortality rate was 9.4%. Main cause of deaths was septicemia. CONCLUSION: In the study population, major lower limb amputations were more common in males compared to females, with highest incidence in the 7th and 8th decades. Diabetes mellitus contributed to more than 50% of amputations directly or indirectly, and septicemia was responsible for the most mortality. PMID- 27504558 TI - Spindle Cell Sarcoma Presenting as Pancoast Syndrome. AB - This report describes a patient who presented with pancoast syndrome, secondary to spindle cell sarcoma of the lung. A 56-year man presented with dyspnea, engorged neck veins and bilateral upper limb pitting edema. The patient also had ptosis and miosis in the right eye. Right ulnar nerve palsy with atrophy of hand muscles was seen. His chest X-ray showed bilateral pleural effusion with an opacity involving the apex of the right lung along with mediastinal widening. Echocardiography revealed a pericardial effusion which was drained. The patient's CTscan of chest strongly suspected a malignant mass in right upper lobe with extensive mediastinal lymphadenopathy, pleural metastases and pericardial involvement. He was started on oxygen inhalation, dexamethasone, and clopidogrel. Bronchoscopic biopsy confirmed the diagnosis of spindle cell sarcoma. Meanwhile, he was advised radiotherapy. The tumour was not amenable to surgery. Spindle cell sarcoma is a rare connective tissue tumor that replicates rapidly. To the best of the authors' knowledge, it is hereby reported the first case of spindle cell sarcoma of the lung presenting as Pancoast syndrome. PMID- 27504559 TI - Pneumocephalus in Child Following Bilateral Otomastoiditis and Nasal Septum Infection. AB - Pneumocephalus is collection of gas or air within the cranial cavity, commonly associated with trauma, cranial surgery, air embolism, open meningomyelocele; and rarely as a result of central nervous system infections. Asymptomatic pneumocephalus usually recovers spontaneously within few days. Untreated pneumocephalus can progress to tension pneumocephalus, manifesting as severe headache, dizziness, cranial nerve palsy, mental changes, seizure and disorientation. Herein, we report a rare case of pneumocephalus in a 9-month infant with subdural effusion following infection of nasal septum and otomastoiditis. There was no sign of meningitis but CThead showed communication of intracranial dura mater across widened foramen caecum with pre-nasal space, and bilateral otomastoiditis with erosion of anterior and lateral wall of right mastoid bone. The patient was treated successfully and discharged without sequelae. PMID- 27504560 TI - Nd YAG Laser Embolysis in a Young Woman with Hemiretinal Artery Occlusion. AB - Retinal artery occlusion is an uncommon condition but can lead to grave consequences if not managed in time. Elderly population with other comorbid conditions like hypertension, ischemic heart disease, hyperlipidemia and stroke are commonly affected. However, this condition may affect younger population with entirely different systemic associations. Thromboembolism, which usually takes place secondary to cardiac emboli or hypercoagulable states cause retinal artery occlusion in young population. A24-year lady presented with a short history of unilateral altitudinal visual loss. On examination, she was found to have hemiretinal artery occlusion. Ocular massage, anterior chamber paracentesis was performed initially, followed by Nd YAG laser embolysis, which led to successful restoration of retinal circulation and significant improvement in visual field loss. Detailed evaluation and systemic investigations were carried out to identify the underlying cause, but no systemic association could be found. PMID- 27504561 TI - Angioleiomyoma of Gingiva Masquerading as Pyogenic Granuloma. AB - Leiomyomas are benign soft tissue neoplasms that arise from smooth muscles. Three distinctive patterns of leiomyoma have been described as piloleiomyomas, angioleiomyomas and genital leiomyomas. Here in, we report the case of 39-year male with chief complain of growth on his lower left front region of the jaw. On the basis of clinical examination, it was provisionally diagnosed as pyogenic granuloma; however, histopathological examination made to the final diagnosis of angioleiomyoma. Excision led to uneventful recovery. PMID- 27504562 TI - Efficacy of Ganglioside GM1 in the Treatment of Postherpetic Neuralgia. AB - Postherpetic neuralgia (PHN) is a commonest and difficult-to-manage complication of Herpes zoster. This comparative study included 140 cases of PHN admitted in the department of dermatology in Renmin Hospital of Wuhan University, Wuhan, China, from March 2014 to February 2015, divided into a control and a study group. In addition to the combination of antiviral, analgesic, and neurotrophic agents given to the control group, additional ganglioside GM1 was given to patients in the study group. Pain assessment was performed at the time of admission, and then on the third, seventh and tenth day of treatment, on both groups, using a 10 cm visual analogue scale (VAS). There was a significant statistical difference between the pain VAS score of the two groups, on the seventh day (3.73 +/-1.66 vs. 3.03 +/-1.86, p=0.024) and on the tenth day (3.25 +/-1.78 vs. 2.20 +/-1.59, p=0.006) of treatment. The number of patients who have good /and complete response (37.5%) were largely higher in the study group than those in the control group (15%, p < 0.05). This finding demonstrates that the administration of ganglioside GM1 may potentially serve as a neoadjuvant therapy to reduce the severity and duration of pain in PHN patients. PMID- 27504563 TI - Awareness Regarding Application of Endotracheal Tube (ETT) Cuff Pressure Measuring Gauge in Anesthesia Practice; ACritical Step to Avoid Postintubation Tracheal Stenosis in Critically ill Patients on Prolonged Mechanical Ventilator. PMID- 27504564 TI - A Proposed Classification to Identify the Oral Manifestations of Genodermatoses. PMID- 27504565 TI - Intraosseous Vascular Tumor of Mandible. PMID- 27504566 TI - Percutaneous Endoscopic Lumbar Discectomy for Cauda Equina Syndrome. PMID- 27504567 TI - Testicular Preserving Surgery: AJudicious Approach for Benign Testicular Lesion. PMID- 27504568 TI - Gold Medal Award for Life Achievement in the Application of Psychology: David W. Johnson. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and enduring records of accomplishment in four areas of psychology. The 2016 recipient of Gold Medal Award for Life Achievement in the Application of Psychology is David W. Johnson. Dorothy W. Cantor, president of the APF, will present the APF Gold Medal Awards at the 124th Annual Convention of the American Psychological Association on August 5, 2016, at 4:00 p.m. Members of the 2016 APF Board of Trustees are Dorothy W. Cantor, president; David H. Barlow, vice president; Melba J. T. Vasquez, secretary; Richard C. McCarty, treasurer; Elisabeth R. Straus, executive vice president/executive director; Cynthia Belar; Camilla Benbow; Rosie Phillips Bingham; Connie S. Chan; Anthony Jackson; Terence M. Keane; Archie L. Turner; W. Bruce Walsh; and Bonnie Markham and Rick McGraw, APA Board of Directors liaisons. (PsycINFO Database Record PMID- 27504569 TI - Gold Medal Award for Life Achievement in the Practice of Psychology: Sandra L. Shullman. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and enduring records of accomplishment in four areas of psychology. The 2016 recipient of Gold Medal Award for Life Achievement in the Practice of Psychology is Sandra L. Shullman. Dorothy W. Cantor, president of the APF, will present the APF Gold Medal Awards at the 124th Annual Convention of the American Psychological Association on August 5, 2016, at 4:00 p.m. Members of the 2016 APF Board of Trustees are Dorothy W. Cantor, president; David H. Barlow, vice president; Melba J. T. Vasquez, secretary; Richard C. McCarty, treasurer; Elisabeth R. Straus, executive vice president/executive director; Cynthia Belar; Camilla Benbow; Rosie Phillips Bingham; Connie S. Chan; Anthony Jackson; Terence M. Keane; Archie L. Turner; W. Bruce Walsh; and Bonnie Markham and Rick McGraw, APA Board of Directors liaisons. (PsycINFO Database Record PMID- 27504570 TI - Gold Medal Award for Life Achievement in Psychology in the Public Interest: Beatrice A. Wright. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and enduring records of accomplishment in 4 areas of psychology. The 2016 recipient of Gold Medal Award for Life Achievement in Psychology in the Public Interest is Beatrice A. Wright. Dorothy W. Cantor, president of the APF, will present the APF Gold Medal Awards at the 124th Annual Convention of the American Psychological Association on August 5, 2016, at 4:00 p.m. Members of the 2016 APF Board of Trustees are: Dorothy W. Cantor, president; David H. Barlow, vice president; Melba J. T. Vasquez, secretary; Richard C. McCarty, treasurer; Elisabeth R. Straus, executive vice president/executive director; Cynthia Belar; Camilla Benbow; Rosie Phillips Bingham; Connie S. Chan; Anthony Jackson; Terence M. Keane; Archie L. Turner; W. Bruce Walsh; and Bonnie Markham and Rick McGraw, APA Board of Directors liaisons. (PsycINFO Database Record PMID- 27504571 TI - Gold Medal Award for Life Achievement in the Science of Psychology: Richard E. Nisbett. AB - The American Psychological Foundation (APF) Gold Medal Awards recognize distinguished and enduring records of accomplishment in four areas of psychology. The 2016 recipient of Gold Medal Award for Life Achievement in the Science of Psychology is Richard E. Nisbett. Dorothy W. Cantor, president of the APF, will present the APF Gold Medal Awards at the 124th Annual Convention of the American Psychological Association on August 5, 2016, at 4:00 p.m. Members of the 2016 APF Board of Trustees are Dorothy W. Cantor, president; David H. Barlow, vice president; Melba J. T. Vasquez, secretary; Richard C. McCarty, treasurer; Elisabeth R. Straus, executive vice president/executive director; Cynthia Belar; Camilla Benbow; Rosie Phillips Bingham; Connie S. Chan; Anthony Jackson; Terence M. Keane; Archie L. Turner; W. Bruce Walsh; and Bonnie Markham and Rick McGraw, APA Board of Directors liaisons. (PsycINFO Database Record PMID- 27504572 TI - Charles L. Brewer Award for Distinguished Teaching of Psychology: Sue Frantz. AB - The American Psychological Foundation (APF) Charles L. Brewer Distinguished Teaching of Psychology Award recognizes an outstanding career contribution to the teaching of psychology. The 2016 recipient of the Distinguished Teaching Award is Sue Frantz. Dorothy W. Cantor, president of the APF, will present the Distinguished Teaching Award at the 124th Annual Convention of the American Psychological Association on August 5, 2016, at 4:00 p.m. Members of the 2016 APF Board of Trustees are Dorothy W. Cantor, president; David H. Barlow, vice president; Melba J. T. Vasquez, secretary; Richard C. McCarty, treasurer; Elisabeth R. Straus, executive vice president/executive director; Cynthia Belar; Camilla Benbow; Rosie Phillips Bingham; Connie S. Chan; Anthony Jackson; Terence M. Keane; Archie L. Turner; W. Bruce Walsh; and Bonnie Markham and Rick McGraw, APA Board of Directors liaisons. (PsycINFO Database Record PMID- 27504573 TI - Proceedings of the American Psychological Association, Incorporated, for the legislative year 2015: Minutes of the Annual Meeting of the Council of Representatives February 20-22, 2015, Washington, DC, and August 5 and August 7, 2015, Washington, DC, and minutes of the February, June, August, and December 2015 meetings of the Board of Directors. AB - This article provides the minutes of the Annual Meeting of the Council of Representatives February 20-22, 2015, Washington, DC, and August 5 and August 7, 2015, Washington, DC, and minutes of the February, June, August, and December 2015 meetings of the Board of Directors. These minutes are the official record of the actions of the Association taken during the year by both the Board of Directors (the Board) and the Council of Representatives (Council). They are arranged in topical rather than chronological order, and subheadings are used when appropriate. (PsycINFO Database Record PMID- 27504574 TI - Responding to change in a challenging climate: 2015 five-year report of the Policy and Planning Board. AB - The American Psychological Association (APA) Bylaws Article XI.7 (http://www.apa.org/about/governance/bylaws/article-11.aspx) requires that the Policy and Planning Board report annually by publication to the membership and review the structure and function of the association as a whole every fifth year. This report details the board's 5-year review, including APA's challenges and achievements from 2011 through 2015 within the context of broader social and environmental changes. Recommended priorities for future change are offered. (PsycINFO Database Record PMID- 27504575 TI - Report of the Ethics Committee, 2015. AB - The Report of the Ethics Committee, 2015, provides information on activities of the Ethics Committee and Ethics Office during that year. In 2015, the Ethics Office and Committee continued their work of adjudication, ethics education, and ethics consultations. The Ethics Committee adopted minor changes to its "Rules and Procedures" to increase the efficiency of the adjudication process. These changes were approved by the APA Board of Directors to become effective on March 1, 2016. The Independent Review Report by David H. Hoffman was released in July. The ethics office director also departed in July, and an interim ethics director was appointed. The process for establishing a Commission on Ethics Processes was also begun. The Commission has the charge of evaluating and recommending changes to the American Psychological Association's current ethics program. Data for adjudication processing in 2015 as well as comparisons to the previous 4 years are provided. (PsycINFO Database Record PMID- 27504576 TI - Summary Report of Journal Operations, 2015. AB - Provides a summary report of Journal Operations. This summary is compiled from the 2015 annual reports of the Council of Editors and from Central Office records. (PsycINFO Database Record PMID- 27504578 TI - Supplement to listing of accredited doctoral, internship, and postdoctoral training programs in professional psychology. AB - The Commission on Accreditation has provided a list announcing the following status changes for Accredited doctoral (clinical, counseling, school, or a combination thereof and developed practice area), doctoral internship, and postdoctoral residency programs in professional psychology as of April 1, 2016. (PsycINFO Database Record PMID- 27504579 TI - Richard I. Evans (1922-2015). AB - Presents an obituary for Richard I. Evans, who passed away on April 20, 2015, in Houston, Texas, at the age of 92. Evans was a noted social and health psychologist. He was one of the founding members of APA's division of Health Psychology and served a term as president of the division. He had a major impact on the history of psychology and media psychology, and was a central figure in the development of the fields of health psychology and behavioral medicine. (PsycINFO Database Record PMID- 27504580 TI - Richard Michael Suzman (1942-2015). AB - Presents an obituary for Richard Michael Suzman, who died on April 16, 2015. Suzman was trained as a sociologist and anthropologist, but he was attracted to the approaches of demography and economics. He came to know a great deal about diverse fields of science, including health, physiology, psychology, genetics, and economics. He was a scientific leader who was on a quest to develop new transdisciplinary fields and to mobilize the best scientists to work in them. Suzman's passion for transdisciplinary science was fully expressed in his greatest achievement: the famous Health and Retirement Survey (HRS), which he initiated in 1988 and continued to guide and inspire. (PsycINFO Database Record PMID- 27504581 TI - Julian Meltzoff (1921-2015). AB - Presents an obituary for Julian Meltzoff, who died on December 22, 2015, in his La Jolla, California home. Meltzoff was a major architect of modern clinical psychology. His innovative contributions in the arena of human service delivery, his empirical evaluations of the efficacy of psychotherapy, and his creative strategy for training clinical psychologists were truly ground breaking. (PsycINFO Database Record PMID- 27504582 TI - Judy Estes Hall (1940-2015). AB - Presents an obituary for Judy Estes Hall, who passed away on November 24, 2015. Hall served as the Executive Officer of the National Register of Health Service Psychologists until her retirement in 2013. She is a recognized expert in the development of education and training standards for the profession of psychology, she also made significant contributions in the field of international psychology, where she was a renowned expert in cross-national credentialing and an advocate for commonality in licensing standards. She was the coauthor of one edited volume and author of more than 60 journal articles, book chapters, and professional publications. A passionate advocate for the advancement of women in psychology, a devoted mother and grandmother, a connoisseur of wine and international traveler extraordinaire, she touched the personal and professional lives of many. (PsycINFO Database Record PMID- 27504583 TI - 2015 Annual Report of the American Psychological Association. AB - Presents the 2015 Annual Report of the American Psychological Association. In his introduction, President Barry Anton describes how 2015 was among APA's most challenging. Although 2015 ushered in an era of greater transparency within the association and enhanced communications to members and the public, it also required painful self-reflection stemming from the revelations of an independent review by an outside law firm. The review examined the question of whether APA played any role related to the Bush administration's use of abusive interrogation techniques during the war on terror. Anton's introduction also discusses (1) the APA convention, (2) representing APA at a White House meeting with health care providers and insurance companies, (3) APA's effort to increase the number of APA accredited internships, (4) international activities, and (5) the global summit on psychology and integrated care. (PsycINFO Database Record PMID- 27504584 TI - High-Resolution Tracking Asymmetric Lithium Insertion and Extraction and Local Structure Ordering in SnS2. AB - In the rechargeable lithium ion batteries, the rate capability and energy efficiency are largely governed by the lithium ion transport dynamics and phase transition pathways in electrodes. Real-time and atomic-scale tracking of fully reversible lithium insertion and extraction processes in electrodes, which would ultimately lead to mechanistic understanding of how the electrodes function and why they fail, is highly desirable but very challenging. Here, we track lithium insertion and extraction in the van der Waals interactions dominated SnS2 by in situ high-resolution TEM method. We find that the lithium insertion occurs via a fast two-phase reaction to form expanded and defective LiSnS2, while the lithium extraction initially involves heterogeneous nucleation of intermediate superstructure Li0.5SnS2 domains with a 1-4 nm size. Density functional theory calculations indicate that the Li0.5SnS2 is kinetically favored and structurally stable. The asymmetric reaction pathways may supply enlightening insights into the mechanistic understanding of the underlying electrochemistry in the layered electrode materials and also suggest possible alternatives to the accepted explanation of the origins of voltage hysteresis in the intercalation electrode materials. PMID- 27504585 TI - The Science of Herbal Galactogogues. PMID- 27504586 TI - The prevalence of hepatitis B infection in central China: An adult population based serological survey of a large sample size. AB - The objective of this study was to determine the prevalence of serum HBsAg among adults in Henan province, China. A provincial serosurvey of people aged 18-74 years was conducted and individuals for analysis were selected using a multistage stratified random cluster sampling method. A 5-ml serum sample from each person was collected and the serum was tested for the presence of HBsAg, HBcAb, HBsAb, HBeAg, and HBeAb by ELISA. Multivariate analysis was used to identify factors associated with the prevalence of HBsAg. A total of 16,685 residents, aged 18-74 years who resided in 60 communities or villages in Henan, China were surveyed. Among the eligible study population, 642 HBsAg positive cases (3.7%) were found. The prevalence increased steadily from 3.1% among population aged 18-35 years old, to 5.1% among population aged 55-74 years. Accordingly, HBsAb declined steadily from 53.4% to 24.7%. Six hundred and forty-two positive HBsAg blood samples were screened for the HBeAg and HBeAb. HBeAg prevalence declined steadily from 27.7% among population age 18-35 years old to 6.8% among population age 55 74 years old. The single factor analysis was used for 16 possible risk factors and multivariate analysis showed that five risk factors were significantly related to HBV infection. HBV infection is a serious public health problem among adult population in Henan. Strengthening administrative regulations of medical practices, especially in rural areas, and providing health education propaganda to the public of HBV infection should be given more attention on public health policy. J. Med. Virol. 89:450-457, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27504587 TI - DNA-reactive B cells in lupus. AB - IgG anti-DNA antibodies are both diagnostic and pathogenic for systemic lupus erythematosus (SLE). They contribute to tissue inflammation through direct tissue binding and to systemic inflammation through activation of Toll-like receptors by nucleic acid-containing immune complexes. IgG DNA-reactive antibodies originate when B cell tolerance mechanisms are impaired. The heterogeneous immune perturbations in SLE lead to the survival and activation of DNA-reactive B cells in various B cell subsets at distinct stages of B cell maturation and differentiation. We propose that the spectrum of B cell alterations and failed tolerance mechanisms for DNA-reactive B cells in lupus patients is best understood by studying genetic risk alleles. This implies that the B cells producing IgG anti-DNA antibodies and the failed tolerance mechanisms(s) will differ across patients. A better understanding of these differences should lead to better patient stratification, improved outcomes of clinical trials, and the identification of novel therapeutic targets. PMID- 27504588 TI - AIRE-mutations and autoimmune disease. AB - The gene causing the severe organ-specific autoimmune disease autoimmune polyendocrine syndrome type-1 (APS-1) was identified in 1997 and named autoimmune regulator (AIRE). AIRE plays a key role in shaping central immunological tolerance by facilitating negative selection of T cells in the thymus, building the thymic microarchitecture, and inducing a specific subset of regulatory T cells. So far, about 100 mutations have been identified. Recent advances suggest that certain mutations located in the SAND and PHD1 domains exert a dominant negative effect on wild type AIRE resulting in milder seemingly common forms of autoimmune diseases, including pernicious anemia, vitiligo and autoimmune thyroid disease. These findings indicate that AIRE also contribute to autoimmunity in more common organ-specific autoimmune disorders. PMID- 27504589 TI - Potential preadaptation to anthropogenic pollution: evidence from a common quantitative trait locus for zinc and cadmium tolerance in metallicolous and nonmetallicolous accessions of Arabidopsis halleri. AB - As a drastic environmental change, metal pollution may promote the rapid evolution of genetic adaptations contributing to metal tolerance. In Arabidopsis halleri, genetic bases of zinc (Zn) and cadmium (Cd) tolerance have been uncovered only in a metallicolous accession, although tolerance is species-wide. The genetic determinants of Zn and Cd tolerance in a nonmetallicolous accession were thus investigated for the first time. The genetic architecture of tolerance was investigated in a nonmetallicolous population (SK2) by using first backcross progeny obtained from crosses between SK2 and Arabidopsis lyrata petraea, a nonmetallophyte species. Only one significant and common quantitative trait locus (QTL) region was identified explaining 22.6% and 31.2% of the phenotypic variation for Zn and Cd tolerance, respectively. This QTL co-localized with HEAVY METAL ATPASE 4 (AhHMA4), which was previously validated as a determinant of Zn and Cd tolerance in a metallicolous accession. Triplication and high expression of HMA4 were confirmed in SK2. In contrast, gene duplication and high expression of METAL TOLERANT PROTEIN 1A (MTP1A), which was previously associated with Zn tolerance in a metallicolous accession, were not observed in SK2. Overall, the results support the role of HMA4 in tolerance capacities of A. halleri that may have pre-existed in nonmetallicolous populations before colonization of metal polluted habitats. Preadaptation to metal-contaminated sites is thus discussed. PMID- 27504590 TI - Clinician's Commentary on Desveaux et al.(1). PMID- 27504591 TI - Left and right ventricular kinetic energy using time-resolved versus time-average ventricular volumes. AB - PURPOSE: To measure the effects of using time-resolved (TR) versus time-averaged (TA) ventricular segmentation on four-dimensional flow-sensitive (4D flow) magnetic resonance imaging (MRI) kinetic energy (KE) calculations. MATERIALS AND METHODS: Right (RV) and left (LV) ventricular KE was calculated from 4D flow MRI data acquired at 3.0T in 10 healthy volunteers and five subjects with cardiac disease using TR and TA segmentation. KE was calculated from the mass of blood within the ventricles multiplied by the velocities squared. Differences in TR and TA KE and interobserver variability were quantified with Bland-Altman analysis. RESULTS: In healthy volunteers, peak systolic RV KE (KERV ) were 4.89 +/- 1.49 mJ using TR and 5.53 +/- 1.62 mJ using TA segmentation (P = 0.016); peak systolic LV KE (KELV ) were 3.29 +/- 0.96 mJ and 4.16 +/- 1.26 mJ (P = 0.005). Peak diastolic KERV were 3.33 +/- 0.90 mJ (TR) and 3.61 +/- 1.12 mJ (TA) (P = 0.082), while peak diastolic KELV were 4.90 +/- 1.49 mJ and 5.31 +/- 1.59 mJ (P = 0.044). In patient volunteers, peak systolic KERV were 4.34 +/- 3.78 mJ using TR and 4.88 +/- 3.98 mJ using TA segmentation (P = 0.26); peak systolic KELV were 4.39 +/- 4.21 mJ and 4.36 +/- 3.84 mJ (P = 0.91). Peak diastolic KERV were 3.34 +/- 2.08 mJ (TR) and 4.05 +/- 1.12 mJ (TA) (P = 0.08), while peak diastolic KELV were 4.34 +/- 5.11 mJ and 4.06 +/- 3.47 mJ (P = 0.75). Interobserver differences in KELV were greater for TR than TA calculations; bias ranged from 3 +/- 30% for TA peak systolic KELV to 36 +/- 30% for TR peak diastolic KELV . CONCLUSION: Although qualitatively similar, KE values calculated through TA segmentation were consistently greater than TR KE, with differences more pronounced during systole and in the LV. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:821-828. PMID- 27504592 TI - Nonpigmented hair removal using photodynamic therapy in animal model. AB - BACKGROUND AND OBJECTIVE: Lasers have been successfully used for decades to remove dark hair. However, laser removal of nonpigmented hair is challenging due to the lack of chromophores. The aim of this study was to use photodynamic therapy (PDT) to remove nonpigmented hair. STUDY DESIGN/MATERIAL AND METHODS: We compared the efficacy of permanent hair reduction in white BALB/c and black C57BL/6 mice treated with PDT or an 800-nm diode laser. We collected skin biopsy specimens and investigated post-PDT histologic changes and molecular changes. RESULTS: We observed keratin 15 staining in the bulge area and alkaline phosphatase staining in the dermal papilla following PDT. We observed a temporary, catagen-like transformation in nonpigmented hair follicles after PDT. We observed apoptotic cells in the hair matrix after PDT. Irradiation with an 800 nm diode laser did not achieve nonpigmented hair removal. Multiple PDT sessions achieved permanent reduction of nonpigmented hair. Interestingly, removal of black hair using PDT was less efficient. CONCLUSION: Our results suggest that PDT can damage the nonpigmented hair matrix, but not stem cells or dermal papillae. Repeated PDT may impair the hair-regeneration capacity via a bystander effect on bulge stem cells or dermal papillae. In this study, we found it was possible to remove nonpigmented hair using PDT. Lasers Surg. Med. 48:748-762, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27504593 TI - Neurological, Metabolic, and Psychiatric Adverse Events in Children and Adolescents Treated With Aripiprazole. AB - Aripiprazole is a partial dopamine agonist with only minor neurological and psychiatric adverse effects, making it a potential first-line drug for the treatment of psychiatric disorders. However, the evidence of its use in children and adolescents is rather sparse. The aim of this case study is to discuss adverse drug reaction (ADR) reports concerning aripiprazole-associated neurological and psychiatric events in children and adolescents. The ADR report database at Danish Medicines Agency was searched for all ADRs involving children and adolescents (<18 years) reported by the search term [aripiprazole] AND all spontaneous reports since the introduction of aripiprazole in 2003 until December 31, 2015. Nineteen case reports were included in the study and included both patients with psychotic disorders (PS group) and nonpsychotic disorders (non-PS group). The PS group consisted of 5 patients with schizophrenia and psychoses, not otherwise specified; and the non-PS group consisted of fourteen cases including autism spectrum disorders, attention deficit and hyperactivity disorder, obsessive-compulsive disorder, and Tourette syndrome. The main reported adverse effects in the non-PS group were chronic insomnia, Parkinsonism, behavioral changes psychoses, and weight gain, whereas the adverse effects in the PS group was predominantly anxiety, convulsions, and neuroleptic malignant syndrome. Although aripiprazole is considered safe and well tolerated in children and adolescents, severe adverse events as neuroleptic malignant syndrome, extreme insomnia, and suicidal behavior has been reported to health authorities. Clinicians should pay attention to these possible hazards when prescribing aripiprazole to this vulnerable group of patients. PMID- 27504594 TI - The culture of pretence: a hidden barrier to recognising, disclosing and ending domestic violence. AB - AIMS AND OBJECTIVES: To explore in detail how women perceived their experience of domestic violence and leaving or ending the abuse. This research also examined how service providers identified their professional role in assisting women to end such relationships. BACKGROUND: Domestic violence against women continues to occur internationally. Reliable statistics are difficult to capture because of inconsistent definitions, contradictory methods of acquiring data and unreported incidents. DESIGN: A qualitative study, undertaken in two phases, was conducted in Australia. METHODS: Twelve women who had experienced domestic violence and ended those relationships participated in one semistructured interview (Phase 1). Twenty-five professionals from health, social sciences and law, whose work included assisting women experiencing domestic violence, participated in three focus groups (Phase 2). Thematic analysis guided by a narrative inquiry approach forms the framework for information collection and interpretation of data in this project. FINDINGS: The barriers that impede women from disclosing abuse and taking action to end domestic violence are complex and varied between participants. Women did not always acknowledge or realise their relationship was precarious and often denied or minimised the abuse to cope with the domestic violence. Professionals identified that women did not always identify or acknowledge abuse inherent in their relationship although this delayed the provision of appropriate services. CONCLUSION: Whether women disclose abuse or deny violence in their relationship, acceptance by service providers and the offer of support is crucial to assisting women in violent relationships. RELEVANCE TO CLINICAL PRACTICE: It is hoped that the findings may assist health practitioners, including nurses, to provide nonjudgemental support to women experiencing domestic violence whether women acknowledge the abusive relationship or not. PMID- 27504595 TI - Colorimetric determination of Timolol concentration based on localized surface plasmon resonance of silver nanoparticles. AB - In this work, a rapid and simple colorimetric method based on the surface plasmon resonance of silver nanoparticles (AgNPs) was developed for the detection of the drug Timolol. The method used is based on the interaction of Timolol with the surface of the as-synthesized AgNPs, which promotes aggregation of the nanoparticles. This aggregation exploits the surface plasmon resonance through the electric dipole-dipole interaction and coupling among the agglomerated particles, hence bringing forth distinctive changes in the spectra as well as the color of colloidal silver. UV-vis spectrophotometery was used to monitor the changes of the localized surface plasmon resonance of AgNPs at wavelengths of 400 and 550 nm. The developed colorimetric sensor has a wide dynamic range of 1.0 * 10(-7) M-1.0 * 10(-3) M for detection of Timolol with a low detection limit of 1.2 * 10(-6) M. The proposed method was successfully applied for the determination of Timolol concentration in ophthalmic eye-drop solution with a response time lower than 40 s. PMID- 27504596 TI - Separating neural activity associated with emotion and implied motion: An fMRI study. AB - Previous research provides evidence for an emo-motoric neural network allowing emotion to modulate activity in regions of the nervous system related to movement. However, recent research suggests that these results may be due to the movement depicted in the stimuli. The purpose of the current study was to differentiate the unique neural activity of emotion and implied motion using functional MRI. Thirteen healthy participants viewed 4 sets of images: (a) negative stimuli implying movement, (b) negative stimuli not implying movement, (c) neutral stimuli implying movement, and (d) neutral stimuli not implying movement. A main effect for implied motion was found, primarily in regions associated with multimodal integration (bilateral insula and cingulate), and visual areas that process motion (bilateral middle temporal gyrus). A main effect for emotion was found primarily in occipital and parietal regions, indicating that emotion enhances visual perception. Surprisingly, emotion also activated the left precentral gyrus, a motor region. These results demonstrate that emotion elicits activity above and beyond that evoked by the perception of implied movement, but that the neural representations of these characteristics overlap. (PsycINFO Database Record PMID- 27504597 TI - Emotional memory: No source memory without old-new recognition. AB - Findings reported in the memory literature suggest that the emotional components of an encoding episode can be dissociated from nonemotional memory. In particular, it has been found that the previous association with threatening events can be retrieved in aversive conditioning even in the absence of item identification. In the present study, we test whether emotional source memory can be independent of item recognition. Participants saw pictures of snakes paired with threatening and nonthreatening context information (poisonousness or nonpoisonousness). In the source memory test, participants were required to remember whether a snake was associated with poisonousness or nonpoisonousness. A simple extension of a well-established multinomial source monitoring model was used to measure source memory for unrecognized items. By using this model, it was possible to assess directly whether participants were able to associate a previously seen snake with poisonousness or nonpoisonousness even if the snake itself was not recognized as having been presented during the experiment. In 3 experiments, emotional source memory was only found for recognized items. While source memory for recognized items differed between emotional and nonemotional information, source memory for unrecognized items was equally absent for emotional and nonemotional information. We conclude that emotional context information is bound to item representations and cannot be retrieved in the absence of item recognition. (PsycINFO Database Record PMID- 27504598 TI - Docosahexaenoic Acid Conjugation Enhances Distribution and Safety of siRNA upon Local Administration in Mouse Brain. AB - The use of siRNA-based therapies for the treatment of neurodegenerative disease requires efficient, nontoxic distribution to the affected brain parenchyma, notably the striatum and cortex. Here, we describe the synthesis and activity of a fully chemically modified siRNA that is directly conjugated to docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the mammalian brain. DHA conjugation enables enhanced siRNA retention throughout both the ipsilateral striatum and cortex following a single, intrastriatal injection (ranging from 6 60 MUg). Within these tissues, DHA conjugation promotes internalization by both neurons and astrocytes. We demonstrate efficient and specific silencing of Huntingtin mRNA expression in both the ipsilateral striatum (up to 73%) and cortex (up to 51%) after 1 week. Moreover, following a bilateral intrastriatal injection (60 MUg), we achieve up to 80% silencing of a secondary target, Cyclophilin B, at both the mRNA and protein level. Importantly, DHA-hsiRNAs do not induce neural cell death or measurable innate immune activation following administration of concentrations over 20 times above the efficacious dose. Thus, DHA conjugation is a novel strategy for improving siRNA activity in mouse brain, with potential to act as a new therapeutic platform for the treatment of neurodegenerative disorders. PMID- 27504599 TI - Are Physicians Influenced by Their Own Specialty Society's Guidelines Regarding Mammography Screening? An Analysis of Nationally Representative Data. AB - OBJECTIVE: The purpose of this study is to determine whether primary care physicians were influenced by their own specialty society's mammography screening recommendations after the 2009 U.S. Preventive Services Task Force's (USPSTF) revised recommendations were released. MATERIALS AND METHODS: We performed an analysis of cross-sectional nationally representative data for 2007-2012 from the National Ambulatory Medical Care Survey (NAMCS). All office-based preventive services visits for women 40 years old or older were included. Multivariate regression analyses were used to identify changes over time in the mammography referral rate per 1000 visits by physician specialty, adjusting for patient- and office-level covariates. All analyses were weighted to account for the multistage probability sampling design of NAMCS. RESULTS: Our analysis represented an average of 35,947,290 office visits per year. Overall, between 2007-2008 and 2011 2012, mammography referral rates (per 1000 visits) decreased from 285 to 215 referrals (-25.0% adjusted change; p = 0.006). The largest decrease was among family physicians (from 230 to 128; -49.0% adjusted change; p < 0.001), followed by internal medicine physicians (from 135 to 79; -45.8% adjusted change; p = 0.038). No statistically significant change was noted among obstetricians and gynecologists over time (from 476 to 419; -14.4% adjusted change; p = 0.23). DISCUSSION: Family and internal medicine physicians, whose societies adhered to 2009 USPSTF recommendations for biennial screening starting at age 50 years, showed statistically significant decreases in mammography referral rates over time. Obstetricians and gynecologists, whose society continued to recommend annual screening starting at age 40 years, showed no statistically significant change in mammography referral rates over time. Physicians may be influenced by their own society's recommendations, which may influence their shared decision making discussions with patients. PMID- 27504600 TI - Structural Impact of Single Ribonucleotide Residues in DNA. AB - Single ribonucleotide intrusions represent the most common nonstandard nucleotide type found incorporated in genomic DNA, yet little is known of their structural impact. This lesion incurs genomic instability in addition to affecting the physical properties of the DNA. To probe for structural and dynamic effects of single ribonucleotides in various sequence contexts-AxC, CxG, and GxC, where x=rG or dG-we report the structures of three single-ribonucleotide-containing DNA duplexes and the corresponding DNA controls. The lesion subtly and locally perturbs the structure asymmetrically on the 3' side of the lesion in both the riboguanosine-containing and the complementary strand of the duplex. The perturbations are mainly restricted to the sugar and phosphodiester backbone. The ribose and 3'-downstream deoxyribose units are predominately in N-type conformation; backbone torsion angles epsilon and/or zeta of the ribonucleotide or upstream deoxyribonucleotide are affected. Depending on the flanking sequences, the C2'-OH group forms hydrogen bonds with the backbone, 3' neighboring base, and/or sugar. Interestingly, even in similar purine-rG pyrimidine environments (A-rG-C and G-rG-C), a riboguanosine unit affects DNA in a distinct manner and manifests different hydrogen bonds, which makes generalizations difficult. PMID- 27504601 TI - Spatial integration of E-cadherin adhesion, signalling and the epithelial cytoskeleton. AB - The characteristic tall and elongated shape of epithelial cells requires specialized adhesive structures and a distinct organization of cytoskeletal filaments. Cytoskeletal networks coordinate a precise organization of adhesive and signalling complexes along cell-cell contacts and enable exquisite strong cohesion among epithelial cells. E-cadherin, a calcium-dependent adhesion receptor, is an essential adhesive system in epithelia and its dynamic regulation and pathways that stabilize cell-cell adhesion have been extensively studied. This review highlights the less understood mechanisms underlying how cadherin receptor signalling drives cytoskeletal rearrangements which ultimately define the epithelial cell shape. In the past two years, new insights identify specific actin-binding proteins and regulators of the epithelial cytoskeleton as a framework to support junction dynamics, plasticity and maintenance. PMID- 27504602 TI - Synthesis, Electrochemistry, and Photophysical Studies of Ruthenium(II) Polypyridine Complexes with D-pi-A-pi-D Type Ligands and Their Application Studies as Organic Memories. AB - A new class of ruthenium(II) polypyridine complexes with a series of D-pi-A-pi-D type (D=donor, A=acceptor) ligands was synthesized and characterized by 1 H NMR spectroscopy, mass spectrometry, and elemental analysis. The photophysical and electrochemical properties of the complexes were also investigated. The newly synthesized ruthenium(II) polypyridine complexes were found to exhibit two intense absorption bands at both high-energy (lambda=333-369 nm) and low-energy (lambda=520-535 nm) regions. They are assigned as intraligand (IL) pi->pi* transitions of the bipyridine (bpy) and pi-conjugated bpy ligands, and IL charge transfer (CT) transitions from the donor to the acceptor moiety with mixing of dpi(RuII )->pi*(bpy) and dpi(RuII )->pi*(L) MLCT characters, respectively. In addition, all complexes were demonstrated to exhibit intense red emissions at approximately lambda=727-744 nm in degassed dichloromethane at 298 K or in n butyronitrile glass at 77 K. Nanosecond transient absorption (TA) spectroscopy has also been carried out, establishing the presence of the charge-separated state. In order to understand the electrochemical properties of the complexes, cyclic voltammetry has also been performed. Two quasi-reversible oxidation couples and three quasi-reversible reduction couples were observed. One of the ruthenium(II) complexes has been utilized in the fabrication of memory devices, in which an ON/OFF current ratio of over 104 was obtained. PMID- 27504603 TI - Trauma in Veterans With Substance Use Disorder: Similar Treatment Need Among Urban and Rural Residents. AB - PURPOSE: The objective of this study is to determine whether rural residence is associated with trauma exposure or posttraumatic stress disorder symptoms among military veterans seeking treatment for substance use disorder (SUD) through the Department of Veterans Affairs (VA), Delivering mental health services to veterans in rural areas is a challenge, so identifying differences in the causes and outcomes of trauma exposure would assist in effectively targeting service delivery. METHODS: Veterans (N = 196) entering SUD treatment at 3 Midwestern VA treatment centers were designated as either urban or rural, based on rural-urban commuting area (RUCA) codes. The veterans completed the Life Events Checklist, the Posttraumatic Stress Disorder Checklist, and the Addiction Severity Index's psychiatric status subscale. Hypothesized relationships between rural-urban residence and both trauma exposure and symptomology were tested using independent samples t tests, chi-square tests, and ordinary least squares regression. FINDINGS: The range of traumatic experiences was similar between rural and urban veterans, and rural-urban residence was not significantly associated with the overall array of traumas experienced or the symptom measures' overall scores or subscores. Of 17 possible traumatic lifetime experiences, rural veterans differed from urban veterans on only 2, reporting significantly lower rates of transportation accidents and unwanted sexual experiences. CONCLUSIONS: In both the causes of trauma and the need for treatment, veterans residing in rural areas differ little from their urban counterparts. PMID- 27504604 TI - Fe-Catalyzed Cross-Coupling Reaction of Vinylic Ethers with Aryl Grignard Reagents. AB - Iron-catalyzed cross-coupling reaction of vinylic ethers with aryl Grignard reagents is described. The reaction proceeded at room temperature with catalytic amounts of an iron salt without the aid of costly ligands and additives. In this catalytic system, vinylic C-O bonds were preferentially cleaved over aromatic C-O bonds of aryl ethers or aryl sulfonates. PMID- 27504606 TI - Time trends in the incidence of oesophageal cancer in Asia: Variations across populations and histological types. AB - OBJECTIVE: We aimed to assess temporal trends in incidence rates of oesophageal cancer in Asian countries. MATERIALS AND METHODS: Using data from the Cancer Incidence in Five Continents series, we examined the temporal trends in incidence rates of oesophageal cancer by population and histological type in seven Asian countries in 1988-2007. Age-period-cohort analyses estimated the overall annual percentage changes (net drifts) and their 95% confidence intervals (CIs) in incidence rates. RESULTS: The age-standardised incidence rate of oesophageal cancer declined in most Asian populations, but remained relatively unchanged in Japan and Israel. The rate of oesophageal squamous cell carcinoma decreased in Hong Kong, Singapore and Israel, but was stable in Japan. The net drifts were statistically significant in men in Hong Kong (-3.4%, 95% CI: -6.1%, -0.7%) and in women in Singapore (-10.1%, 95% CI: -14.4%, -5.5%). The age-standardised incidence rates of oesophageal adenocarcinoma were below 2 and 0.5 per 100 000 in men and women, respectively, across all periods in the all registers containing valid data on histological type. The age-standardised incidence rate of oesophageal adenocarcinoma slightly increased in Japan, Singapore, and Israel, although the net drift was statistically significant only in Israeli men (4.9%, 95% CI: 0.8%, 9.1%). CONCLUSION: The overall incidence rates of oesophageal cancer declined in most Asian countries, which is due to a decrease in oesophageal squamous cell carcinoma incidence. However, attention needs to be paid to a probable beginning of an increasing incidence of oesophageal adenocarcinoma in Asia. PMID- 27504605 TI - Inflammatory biomarkers, aspirin, and risk of colorectal cancer: Findings from the physicians' health study. AB - BACKGROUND: Chronic inflammation has been implicated in colorectal carcinogenesis. However, the associations between plasma inflammatory markers and risk of colorectal cancer have been inconsistent. METHODS: In a nested case control study in the Physicians' Health Study, we prospectively investigated the associations of plasma C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor receptor 2 (TNFR-2) with risk of colorectal cancer, and whether aspirin modified these associations among 268 colorectal cancer patients and 446 age- and smoking-matched controls. RESULTS: In multivariate-adjusted models, plasma levels of CRP, IL-6 and TNFR-2 were not significantly associated with risk of colorectal cancer, although a positive trend was observed for TNFR-2 (RRhighestvs.lowestquartile=1.55; 95% CI=0.95-2.54; Ptrend=0.05). We observed a statistically significant association between elevated TNFR-2 levels and colorectal cancer risk in the placebo arm (RRhighestvs.lowesttertile=1.77; 95% CI=1.02-3.06; Ptrend=0.02), but not in the aspirin arm (Ptrend=0.72). However, the interaction between TNFR-2 and aspirin was not statistically significant (Pinteraction=0.34). CONCLUSION: Plasma inflammatory markers were not significantly associated with colorectal cancer risk among men, though there was a statistically non-significant positive trend between TNFR-2 and colorectal cancer risk. More studies are required to understand the relationship between the role of TNFalpha pathway, aspirin, and colorectal cancer risk. PMID- 27504607 TI - C-N Bond Formation from a Masked High-Valent Copper Complex Stabilized by Redox Non-Innocent Ligands. AB - The reactivity of a stable copper(II) complex bearing fully oxidized iminobenzoquinone redox ligands towards nucleophiles is described. In sharp contrast with its genuine low-valent counterpart bearing reduced ligands, this complex performs high-yielding C-N bond formations. Mechanistic studies suggest that this behavior could stem from a mechanism akin to reductive elimination occurring at the metal center but facilitated by the ligand: it is proposed that a masked high oxidation state of the metal can be stabilized as a lower copper(II) oxidation state by the redox ligands without forfeiting its ability to behave as a high-valent copper(III) center. These observations are substantiated by a combination of advanced EPR spectroscopy techniques with DFT studies. This work sheds light on the potential of redox ligands as promoters of unusual reactivities at metal centers and illustrates the concept of masked high-valent metallic species. PMID- 27504608 TI - Dedicator of Cytokinesis 2 in Cell Signaling Regulation and Disease Development. AB - Dedicator of cytokinesis 2 (DOCK2) is a CDM family protein containing DOCK homology region (DHR)-1 and DHR-2, Src-homology 3 (SH3) domain, and C-terminal polybasic amino acid cluster. The CDM family consists of 11 mammalian members and is classified into four subfamilies, the DOCK-A, -B, -C, and -D. DOCK2 is a member of DOCK-A subfamily and an atypical guanine exchange factor regulating the loading of GTP to activate Rac. It is primarily found in peripheral blood, spleen, and thymus and mainly expressed in lymphocytes and macrophages of various organs. DOCK2 is also expressed in microglial in brain and is induced in neointima smooth muscle following vascular injury. Functionally, DOCK2 is involved in cell motility, polarity, adhesion, proliferation, and apoptosis. It is essential for lymphocyte migration and activation as well as neutrophil chemotaxis. DOCK2 also regulates the differentiation of natural killer T cells, type 2 T helper cells, and plasmacytoid dendritic cells. In addition, it is important for the growth of B cell lymphoma and prostate cancer cells. Deletion of DOCK2 enables long-term cardiac allograft survival. Moreover, DOCK2 is associated with the Alzheimer Disease, HIV development, and the early-onset of invasive infections. Recently, we found that DOCK2 plays a critical role in SMC phenotypic modulation and vascular remodeling. In this review, we will briefly summarize recent advancement of DOCK2 function. J. Cell. Physiol. 232: 1931-1940, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27504609 TI - Differential modulation of visual object processing in dorsal and ventral stream by stimulus visibility. AB - As a functional organization principle in cortical visual information processing, the influential 'two visual systems' hypothesis proposes a division of labor between a dorsal "vision-for-action" and a ventral "vision-for-perception" stream. A core assumption of this model is that the two visual streams are differentially involved in visual awareness: ventral stream processing is closely linked to awareness while dorsal stream processing is not. In this functional magnetic resonance imaging (fMRI) study with human observers, we directly probed the stimulus-related information encoded in fMRI response patterns in both visual streams as a function of stimulus visibility. We parametrically modulated the visibility of face and tool stimuli by varying the contrasts of the masks in a continuous flash suppression (CFS) paradigm. We found that visibility - operationalized by objective and subjective measures - decreased proportionally with increasing log CFS mask contrast. Neuronally, this relationship was closely matched by ventral visual areas, showing a linear decrease of stimulus-related information with increasing mask contrast. Stimulus-related information in dorsal areas also showed a dependency on mask contrast, but the decrease rather followed a step function instead of a linear function. Together, our results suggest that both the ventral and the dorsal visual stream are linked to visual awareness, but neural activity in ventral areas more closely reflects graded differences in awareness compared to dorsal areas. PMID- 27504610 TI - "Cognitive, emotion control, and motor performance of adolescents in the NCANDA study: Contributions from alcohol consumption, age, sex, ethnicity, and family history of addiction": Correction to Sullivan et al. (2016). AB - Reports an error in "Cognitive, emotion control, and motor performance of adolescents in the NCANDA study: Contributions from alcohol consumption, age, sex, ethnicity, and family history of addiction" by Edith V. Sullivan, Ty Brumback, Susan F. Tapert, Rosemary Fama, Devin Prouty, Sandra A. Brown, Kevin Cummins, Wesley K. Thompson, Ian M. Colrain, Fiona C. Baker, Michael D. De Bellis, Stephen R. Hooper, Duncan B. Clark, Tammy Chung, Bonnie J. Nagel, B. Nolan Nichols, Torsten Rohlfing, Weiwei Chu, Kilian M. Pohl and Adolf Pfefferbaum (Neuropsychology, 2016[May], Vol 30[4], 449-473). A problem with a computation to invert speed scores is noted and explained in this correction. All statements indicating group differences in speed scores, as well as Table 5 and Figure 8A, have been corrected in the online version of this article. (The following abstract of the original article appeared in record 2016-00613-001.) OBJECTIVE: To investigate development of cognitive and motor functions in healthy adolescents and to explore whether hazardous drinking affects the normal developmental course of those functions. METHOD: Participants were 831 adolescents recruited across 5 United States sites of the National Consortium on Alcohol and NeuroDevelopment in Adolescence 692 met criteria for no/low alcohol exposure, and 139 exceeded drinking thresholds. Cross-sectional, baseline data were collected with computerized and traditional neuropsychological tests assessing 8 functional domains expressed as composite scores. General additive modeling evaluated factors potentially modulating performance (age, sex, ethnicity, socioeconomic status, and pubertal developmental stage). RESULTS: Older no/low-drinking participants achieved better scores than younger ones on 5 accuracy composites (general ability, abstraction, attention, emotion, and balance). Speeded responses for attention, motor speed, and general ability were sensitive to age and pubertal development. The exceeds-threshold group (accounting for age, sex, and other demographic factors) performed significantly below the no/low-drinking group on balance accuracy and on general ability, attention, episodic memory, emotion, and motor speed scores and showed evidence for faster speed at the expense of accuracy. Delay Discounting performance was consistent with poor impulse control in the younger no/low drinkers and in exceeds-threshold drinkers regardless of age. CONCLUSIONS: Higher achievement with older age and pubertal stage in general ability, abstraction, attention, emotion, and balance suggests continued functional development through adolescence, possibly supported by concurrently maturing frontal, limbic, and cerebellar brain systems. Determination of whether low scores by the exceeds threshold group resulted from drinking or from other preexisting factors requires longitudinal study. PMID- 27504611 TI - [Medical Studies + Internship + Vocational Training = A Complete Ophthalmic Surgeon? A Theoretical Analysis of the Ophthalmic Surgery Training from the Perspective of Medical and Educational Sciences]. AB - "Let's have the courage to train young doctors to conduct ophthalmic surgery!" - This is the final plea of this theoretical article, which appeals for greater collaboration between medical and educational sciences in the training of ophthalmic surgeons. It will be discussed whether surgery-based training is adequate, from the point of view of both medical knowledge and learning theory. Standard requirements for the specialist qualification in ophthalmic surgery are presented for Bavaria, Austria and Switzerland; these are then compared and contrasted with the experience-based practice of vocational training. Assuming that vocational training can be understood as providing the context for action oriented learning, the relevance of procedural knowledge will be discussed for the development of practical surgical skills. A model for expertise in ophthalmic surgery will be outlined. Instructors' didactic skills and expertise will be discussed in relation to the requirements and guidelines for receiving the license to train assistants. In general, the article highlights the relevance of performance in learning surgery, and calls for the provision of sufficient possibilities to learn surgery in the course of assistant doctors' vocational training. This article addresses those who are involved in ophthalmologists' and ophthalmic surgeons' vocational training (e.g. medical instructors, medical associations, assistant doctors) and who welcome thought-provoking impulses from unfamiliar academic disciplines on key questions and concerns in practical vocational training. PMID- 27504612 TI - [Are Visual Field Defects Reversible? - Visual Rehabilitation with Brains]. AB - Visual field defects are considered irreversible because the retina and optic nerve do not regenerate. Nevertheless, there is some potential for recovery of the visual fields. This can be accomplished by the brain, which analyses and interprets visual information and is able to amplify residual signals through neuroplasticity. Neuroplasticity refers to the ability of the brain to change its own functional architecture by modulating synaptic efficacy. This is actually the neurobiological basis of normal learning. Plasticity is maintained throughout life and can be induced by repetitively stimulating (training) brain circuits. The question now arises as to how plasticity can be utilised to activate residual vision for the treatment of visual field loss. Just as in neurorehabilitation, visual field defects can be modulated by post-lesion plasticity to improve vision in glaucoma, diabetic retinopathy or optic neuropathy. Because almost all patients have some residual vision, the goal is to strengthen residual capacities by enhancing synaptic efficacy. New treatment paradigms have been tested in clinical studies, including vision restoration training and non-invasive alternating current stimulation. While vision training is a behavioural task to selectively stimulate "relative defects" with daily vision exercises for the duration of 6 months, treatment with alternating current stimulation (30 min. daily for 10 days) activates and synchronises the entire retina and brain. Though full restoration of vision is not possible, such treatments improve vision, both subjectively and objectively. This includes visual field enlargements, improved acuity and reaction time, improved orientation and vision related quality of life. About 70 % of the patients respond to the therapies and there are no serious adverse events. Physiological studies of the effect of alternating current stimulation using EEG and fMRI reveal massive local and global changes in the brain. These include local activation of the visual cortex and global reorganisation of neuronal brain networks. Because modulation of neuroplasticity can strengthen residual vision, the brain deserves a better reputation in ophthalmology for its role in visual rehabilitation. For patients, there is now more light at the end of the tunnel, because vision loss in some areas of the visual field defect is indeed reversible. PMID- 27504613 TI - The fabrication of well-interconnected polycaprolactone/hydroxyapatite composite scaffolds, enhancing the exposure of hydroxyapatite using the wire-network molding technique. AB - In this study, the fabrication method was proposed for the well-interconnected polycaprolactone/hydroxyapatite composite scaffold with exposed hydroxyapatite using modified WNM technique. To characterize well-interconnected scaffolds in terms of hydroxyapatite exposure, several assessments were performed as follows: morphology, mechanical property, wettability, calcium ion release, and cell response assessments. The results of these assessments were compared with those of control scaffolds which were fabricated by precision extruding deposition (PED) apparatus. The control PED scaffolds have interconnected pores with nonexposed hydroxyapatite. Consequently, cell attachment of proposed WNM scaffold was improved by increased hydrophilicity and surface roughness of scaffold surface resulting from the exposure of hydroxyapatite particles and fabrication process using powders. Moreover, cell proliferation and differentiation of WNM scaffold were increased, because the exposure of hydroxyapatite particles may enhance cell adhesion and calcium ion release. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2315-2325, 2017. PMID- 27504614 TI - Application of Concept Mapping as a Visual Thinking Strategy in an Asynchronous Online Graduate Informatics Course. PMID- 27504615 TI - Member Highlights at New England Nursing Informatics Consortium's 2016 Annual Symposium. PMID- 27504616 TI - Integrating an Academic Electronic Health Record: Challenges and Success Strategies. PMID- 27504617 TI - Eco-friendly larvicides from Indian plants: Effectiveness of lavandulyl acetate and bicyclogermacrene on malaria, dengue and Japanese encephalitis mosquito vectors. AB - Mosquitoes (Diptera: Culicidae) are a key threat for millions of people and animals worldwide, since they act as vectors for devastating pathogens and parasites, including malaria, dengue, Japanese encephalitis, filiariasis and Zika virus. Mosquito young instars are usually targeted using organophosphates, insect growth regulators and microbial agents. Indoor residual spraying and insecticide treated bed nets are also employed. However, these chemicals have negative effects on human health and the environment and induce resistance in a number of vectors. In this scenario, newer and safer tools have been recently implemented to enhance mosquito control. The concrete potential of screening plant species as sources of metabolites for entomological and parasitological purposes is worthy of attention, as recently elucidated by the Y. Tu's example. Here we investigated the toxicity of Heracleum sprengelianum (Apiaceae) leaf essential oil and its major compounds toward third instar larvae of the malaria vector Anopheles subpictus, the arbovirus vector Aedes albopictus and the Japanese encephalitis vector Culex tritaeniorhynchus. GC-MS analysis showed that EO major components were lavandulyl acetate (17.8%) and bicyclogermacrene (12.9%). The EO was toxic to A. subpictus, A. albopictus, and C. tritaeniorhynchus, with LC50 of 33.4, 37.5 and 40.9ug/ml, respectively. Lavandulyl acetate was more toxic to mosquito larvae if compared to bicyclogermacrene. Their LC50 were 4.17 and 10.3ug/ml for A. subpictus, 4.60 and 11.1ug/ml for A. albopictus, 5.11 and 12.5ug/ml for C. tritaeniorhynchus. Notably, the EO and its major compounds were safer to three non-target mosquito predators, Anisops bouvieri, Diplonychus indicus and Gambusia affinis, with LC50 ranging from 206 to 4219ug/ml. Overall, this study highlights that H. sprengelianum EO is a promising source of eco-friendly larvicides against three important mosquito vectors with moderate toxicity against non-target aquatic organisms. PMID- 27504618 TI - Gestational diabetes: paradigm lost? PMID- 27504621 TI - Ninety-First Annual Business Meeting. PMID- 27504619 TI - Normal multiplanar movement of the spinal cord during unilateral and bilateral straight leg raise: Quantification, mechanisms, and overview. AB - The purpose of this investigation was to provide a full set of normal data describing neural biomechanics within the vertebral canal in all three planes with unilateral and bilateral SLR tests to allow for clinical comparison with clinical cases. This is done following the notion that, due to neural continuum, tensile forces are transmitted through the lumbosacral nerve roots and dura to the conus medullaris (linear dependency principle). In this controlled radiologic study 10 asymptomatic volunteers were scanned with 1.5T magnetic resonance scanner (Siemens Magnetom Aera, Erlangen, Germany) using different scanning sequences for planning and for measurement purposes. Conus displacement in both antero-posterior direction (sagittal slices) and lateral direction (axial slices) was quantified during unilateral passive left, right SLR, and bilateral SLR and compared with the position of the conus in the neutral (anatomic) position. It is shown that the conus medullaris displaced laterally and anteroposteriorly in response to unilateral and bilateral SLRs. Pearson's correlations were higher than 0.95 for both intra- and inter-observer reliability. The observed power was higher than 0.99 for all the variables tested. Following this, the authors conclude that lateral and antero-posterior displacement of conus medullaris into the vertebral canal occurs consistently with unilateral and bilateral SLRs following directions predicted by tension vectors. Summative information collected in this line of research in neuroradiology is here presented. We believe we have presented the first conclusive and complete full set of normal data on non-invasive, in vivo, normative measurement of spinal cord displacement with the SLR ever presented. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1335-1342, 2017. PMID- 27504622 TI - One Hundred and Sixth Annual Council Meeting. PMID- 27504623 TI - Chromosomal Spreading of Microsatellites and (TTAGGG)n Sequences in the Characidium zebra and C. gomesi Genomes (Characiformes: Crenuchidae). AB - Sex chromosome evolution involves the accumulation of repeat sequences such as multigenic families, noncoding repetitive DNA (satellite, minisatellite, and microsatellite), and mobile elements such as transposons and retrotransposons. Most species of Characidium exhibit heteromorphic ZZ/ZW sex chromosomes; the W is characterized by an intense accumulation of repetitive DNA including dispersed satellite DNA sequences and transposable elements. The aim of this study was to analyze the distribution pattern of 18 different tandem repeats, including (GATA)n and (TTAGGG)n, in the genomes of C. zebra and C. gomesi, especially in the C. gomesi W chromosome. In the C. gomesi W chromosome, weak signals were seen for (CAA)10, (CAC)10, (CAT)10, (CGG)10, (GAC)10, and (CA)15 probes. (GA)15 and (TA)15 hybridized to the autosomes but not to the W chromosome. The (GATA)n probe hybridized to the short arms of the W chromosome as well as the (CG)15 probe. The (GATA)n repeat is known to be a protein-binding motif. GATA-binding proteins are necessary for the decondensation of heterochromatic regions that hold coding genes, especially in some heteromorphic sex chromosomes that may keep genes related to oocyte development. The (TAA)10 repeat is accumulated in the entire W chromosome, and this microsatellite accumulation is probably involved in the sex chromosome differentiation process and crossover suppression in C. gomesi. These additional data on the W chromosome DNA composition help to explain the evolution of sex chromosomes in Characidium. PMID- 27504624 TI - Using Carbohydrate Interaction Assays to Reveal Novel Binding Sites in Carbohydrate Active Enzymes. AB - Carbohydrate active enzymes often contain auxiliary binding sites located either on independent domains termed carbohydrate binding modules (CBMs) or as so-called surface binding sites (SBSs) on the catalytic module at a certain distance from the active site. The SBSs are usually critical for the activity of their cognate enzyme, though they are not readily detected in the sequence of a protein, but normally require a crystal structure of a complex for their identification. A variety of methods, including affinity electrophoresis (AE), insoluble polysaccharide pulldown (IPP) and surface plasmon resonance (SPR) have been used to study auxiliary binding sites. These techniques are complementary as AE allows monitoring of binding to soluble polysaccharides, IPP to insoluble polysaccharides and SPR to oligosaccharides. Here we show that these methods are useful not only for analyzing known binding sites, but also for identifying new ones, even without structural data available. We further verify the chosen assays discriminate between known SBS/CBM containing enzymes and negative controls. Altogether 35 enzymes are screened for the presence of SBSs or CBMs and several novel binding sites are identified, including the first SBS ever reported in a cellulase. This work demonstrates that combinations of these methods can be used as a part of routine enzyme characterization to identify new binding sites and advance the study of SBSs and CBMs, allowing them to be detected in the absence of structural data. PMID- 27504625 TI - Clinical Q & A: Translating Therapeutic Temperature Management from Theory to Practice. PMID- 27504626 TI - Site-Specific Ligand Interactions Favor the Tetragonal Distortion of PbS Nanocrystal Superlattices. AB - We analyze the structure and morphology of mesocrystalline, body-centered tetragonal (bct) superlattices of PbS nanocrystals functionalized with oleic acid. On the basis of combined scattering and real space imaging, we derive a three-dimensional (3D) model of the superlattice and show that the bct structure benefits from a balanced combination of {100}PbS-{100}PbS and {111}PbS-{111}PbS interactions between neighboring layers of nanocrystals, which uniquely stabilizes this structure. These interactions are enabled by the coaxial alignment of the atomic lattices of PbS with the superlattice. In addition, we find that this preferential orientation is already weakly present within isolated monolayers. By adding excess oleic acid to the nanocrystal solution, tetragonal distortion is suppressed, and we observe assembly into a bilayered hexagonal lattice reminiscent of a honeycomb with grain sizes of several micrometers. PMID- 27504627 TI - Diallel Analysis and Growth Parameters as Selection Tools for Drought Tolerance in Young Theobroma cacao Plants. AB - This study aimed to estimate the combining ability, of T. cacao genotypes preselected for drought tolerance through diallel crosses. The experiment was conducted under greenhouse conditions at the Cacao Research Center (CEPEC), Ilheus, Bahia, Brazil, in a completely randomized block design, in an experimental arrangement 21 x 2 [21 complete diallel crosses and two water regimes (control and stressed)]. In the control, soil moisture was kept close to field capacity, with predawn leaf water potential (PsiWL) ranging from -0.1 to 0.5 MPa. In the drought regime, the soil moisture was reduced gradually by decreasing the amount of water application until PsiWL reached -2.0 to -2.5 MPa. Significant differences (p < 0.05) were observed for most morphological attributes analyzed regarding progenies, water regime and their interactions. The results of the joint diallel analysis revealed significant effects between general combining ability (GCA) x water regimes and between specific combining ability (SCA) x water regimes. The SCA 6 genetic material showed high general combining ability for growth variables regardless of the water regime. In general, the water deficit influenced the production of biomass in most of the evaluated T. cacao crosses, except for SCA-6 x IMC-67, Catongo x SCA, MOC-01 x Catongo, Catongo x IMC-67 and RB-40 x Catongo. Multivariate analysis showed that stem diameter (CD), total leaf area (TLA), leaf dry biomass (LDB), stem dry biomass (SDB), root dry biomass (RDB), total dry biomass (TDB), root length (RL), root volume (RV), root diameter (RD) <1 mm and 1 <(RD) <2 mm were the most important growth parameters in the separation of T. cacao genotypes in to tolerant and intolerant to soil water deficit. PMID- 27504628 TI - Soluble CD14 Enhances the Response of Periodontal Ligament Stem Cells to P. gingivalis Lipopolysaccharide. AB - Periodontal ligament stem cells (PDLSCs) are lacking membrane CD14, which is an important component of lipopolysaccharide (LPS) signaling through toll-like receptor (TLR) 4. In the present study we investigated the effect of soluble CD14 on the response of human PDLSCs to LPS of Porphyromonas (P.) gingivalis. Human PDLSCs (hPDLSCs) were stimulated with P. gingivalis LPS in the presence or in the absence of soluble CD14 (sCD14) and the production of interleukin (IL)-6, chemokine C-X-C motif ligand 8 (CXCL8), and chemokine C-C motif ligand 2 (CCL2) was measured. The response to P. gingivalis LPS was compared with that to TLR4 agonist Escherichia coli LPS and TLR2-agonist Pam3CSK4. The response of hPDLSCs to both P. gingivalis LPS and E. coli LPS was significantly enhanced by sCD14. In the absence of sCD14, no significant difference in the hPDLSCs response to two kinds of LPS was observed. These responses were significantly lower compared to that to Pam3CSK4. In the presence of sCD14, the response of hPdLSCs to P. gingivalis LPS was markedly higher than that to E. coli LPS and comparable with that to Pam3CSK4. The response of hPdLSCs to bacterial LPS is strongly augmented by sCD14. Local levels of sCD14 could be an important factor for modulation of the host response against periodontal pathogens. PMID- 27504629 TI - Modeling of Large-Scale Functional Brain Networks Based on Structural Connectivity from DTI: Comparison with EEG Derived Phase Coupling Networks and Evaluation of Alternative Methods along the Modeling Path. AB - In this study, we investigate if phase-locking of fast oscillatory activity relies on the anatomical skeleton and if simple computational models informed by structural connectivity can help further to explain missing links in the structure-function relationship. We use diffusion tensor imaging data and alpha band-limited EEG signal recorded in a group of healthy individuals. Our results show that about 23.4% of the variance in empirical networks of resting-state functional connectivity is explained by the underlying white matter architecture. Simulating functional connectivity using a simple computational model based on the structural connectivity can increase the match to 45.4%. In a second step, we use our modeling framework to explore several technical alternatives along the modeling path. First, we find that an augmentation of homotopic connections in the structural connectivity matrix improves the link to functional connectivity while a correction for fiber distance slightly decreases the performance of the model. Second, a more complex computational model based on Kuramoto oscillators leads to a slight improvement of the model fit. Third, we show that the comparison of modeled and empirical functional connectivity at source level is much more specific for the underlying structural connectivity. However, different source reconstruction algorithms gave comparable results. Of note, as the fourth finding, the model fit was much better if zero-phase lag components were preserved in the empirical functional connectome, indicating a considerable amount of functionally relevant synchrony taking place with near zero or zero phase lag. The combination of the best performing alternatives at each stage in the pipeline results in a model that explains 54.4% of the variance in the empirical EEG functional connectivity. Our study shows that large-scale brain circuits of fast neural network synchrony strongly rely upon the structural connectome and simple computational models of neural activity can explain missing links in the structure-function relationship. PMID- 27504630 TI - IgM-Enriched Immunoglobulin Attenuates Systemic Endotoxin Activity in Early Severe Sepsis: A Before-After Cohort Study. AB - INTRODUCTION: Sepsis remains associated with a high mortality rate. Endotoxin has been shown to influence viscoelastic coagulation parameters, thus suggesting a link between endotoxin levels and the altered coagulation phenotype in septic patients. This study evaluated the effects of systemic polyspecific IgM-enriched immunoglobulin (IgM-IVIg) (Pentaglobin(r) [Biotest, Dreieich, Germany]) on endotoxin activity (EA), inflammatory markers, viscoelastic and conventional coagulation parameters. METHODS: Patients with severe sepsis were identified by daily screening in a tertiary, academic, surgical ICU. After the inclusion of 15 patients, the application of IgM-IVIg (5 mg/kg/d over three days) was integrated into the unit's standard operation procedure (SOP) to treat patients with severe sepsis, thereby generating "control" and "IgM-IVIg" groups. EA assays, thrombelastometry (ROTEM(r)) and impedance aggregometry (Multiplate(r)) were performed on whole blood. Furthermore, routine laboratory parameters were determined according to unit's standards. RESULTS: Data from 26 patients were included. On day 1, EA was significantly decreased in the IgM-IVIg group following 6 and 12 hours of treatment (0.51 +/-0.06 vs. 0.26 +/-0.07, p<0.05 and 0.51 +/-0.06 vs. 0.25 +/-0.04, p<0.05) and differed significantly compared with the control group following 6 hours of treatment (0.26 +/-0.07 vs. 0.43 +/-0.07, p<0.05). The platelet count was significantly higher in the IgM-IVIg group following four days of IgM-IVIg treatment (200/nl +/-43 vs. 87/nl +/-20, p<0.05). The fibrinogen concentration was significantly lower in the control group on day 2 (311 mg/dl +/-37 vs. 475 mg/dl +/-47 (p = 0.015)) and day 4 (307 mg/dl +/-35 vs. 420 mg/dl +/-16 (p = 0.017)). No differences in thrombelastometric or aggregometric measurements, or inflammatory markers (interleukin-6 (IL-6), leukocyte, lipopolysaccharide binding protein (LBP)) were observed. CONCLUSION: Treatment with IgM-enriched immunoglobulin attenuates the EA levels in patients with severe sepsis and might have an effect on septic thrombocytopenia and fibrinogen depletion. Viscoelastic, aggregometric or inflammatory parameters were not influenced. TRIAL REGISTRATION: clinicaltrials.gov NCT02444871. PMID- 27504631 TI - Deep Brain Stimulation of Medial Dorsal and Ventral Anterior Nucleus of the Thalamus in OCD: A Retrospective Case Series. AB - BACKGROUND: The current notion that cortico-striato-thalamo-cortical circuits are involved in the pathophysiology of obsessive-compulsive disorder (OCD) has instigated the search for the most suitable target for deep brain stimulation (DBS). However, despite extensive research, uncertainty about the ideal target remains with many structures being underexplored. The aim of this report is to address a new target for DBS, the medial dorsal (MD) and the ventral anterior (VA) nucleus of the thalamus, which has thus far received little attention in the treatment of OCD. METHODS: In this retrospective trial, four patients (three female, one male) aged 31-48 years, suffering from therapy-refractory OCD underwent high-frequency DBS of the MD and VA. In two patients (de novo group) the thalamus was chosen as a primary target for DBS, whereas in two patients (rescue DBS group) lead implantation was performed in a rescue DBS attempt following unsuccessful primary stimulation. RESULTS: Continuous thalamic stimulation yielded no significant improvement in OCD symptom severity. Over the course of thalamic DBS symptoms improved in only one patient who showed "partial response" on the Yale-Brown Obsessive Compulsive (Y-BOCS) Scale. Beck Depression Inventory scores dropped by around 46% in the de novo group; anxiety symptoms improved by up to 34%. In the de novo DBS group no effect of DBS on anxiety and mood was observable. CONCLUSION: MD/VA-DBS yielded no adequate alleviation of therapy-refractory OCD, the overall strategy in targeting MD/VA as described in this paper can thus not be recommended in DBS for OCD. The magnocellular portion of MD (MDMC), however, might prove a promising target in the treatment of mood related and anxiety disorders. PMID- 27504632 TI - Modelling Vulnerability and Range Shifts in Ant Communities Responding to Future Global Warming in Temperate Forests. AB - Global warming is likely leading to species' distributional shifts, resulting in changes in local community compositions and diversity patterns. In this study, we applied species distribution models to evaluate the potential impacts of temperature increase on ant communities in Korean temperate forests, by testing hypotheses that 1) the risk of extinction of forest ant species would increase over time, and 2) the changes in species distribution ranges could drive upward movements of ant communities and further alter patterns of species richness. We sampled ant communities at 335 evenly distributed sites across South Korea and modelled the future distribution range for each species using generalized additive models. To account for spatial autocorrelation, autocovariate regressions were conducted prior to generalized additive models. Among 29 common ant species, 12 species were estimated to shrink their suitable geographic areas, whereas five species would benefit from future global warming. Species richness was highest at low altitudes in the current period, and it was projected to be highest at the mid-altitudes in the 2080s, resulting in an upward movement of 4.9 m yr-1. This altered the altitudinal pattern of species richness from a monotonic decrease curve (common in temperate regions) to a bell-shaped curve (common in tropical regions). Overall, ant communities in temperate forests are vulnerable to the on-going global warming and their altitudinal movements are similar to other faunal communities. PMID- 27504633 TI - The Promise of Mineralocorticoid Antagonism in Acute Kidney Injury. AB - Acute kidney injury (AKI) is a major cause of morbidity and mortality in hospitalized patients. Despite substantial progress being made in understanding the mechanisms contributing to the pathophysiology of AKI, we have so far been unsuccessful in devising adequate therapeutic strategies against the disease. A growing body of evidence suggests that the activation of mineralocorticoid receptors (MRs) may contribute to the exacerbation of AKI. Indeed, several studies have demonstrated the potential of MR antagonists in preventing and treating certain forms of experimental AKI. However, the main drawback of these medications is their side-effect profile. This has been addressed with the development of newer nonsteroidal MR antagonists, which have a comparable therapeutic profile without the side effects. This mini review aims at providing a brief overview of the rationale, potential benefits and challenges associated with the use of MR antagonists, particularly the novel nonsteroidal MR blockers, as therapy against AKI. (c) 2016 S. Karger AG, Basel. PMID- 27504634 TI - Recovery from Borderline Personality Disorder: A Systematic Review of the Perspectives of Consumers, Clinicians, Family and Carers. AB - PURPOSE: Longitudinal studies support that symptomatic remission from Borderline Personality Disorder (BPD) is common, but recovery from the disorder probably involves a broader set of changes in psychosocial function over and above symptom relief. A systematic review of literature on both symptomatic and personal recovery from BPD was conducted including the views of consumers, clinicians, family and carers. MATERIALS AND METHODS: A PRISMA guided systematic search identified research examining the process of recovery from BPD. Longitudinal studies with a follow-up period of five or more years were included to avoid treatment effects. RESULTS: There were 19 studies, representing 11 unique cohorts (1,122 consumers) meeting the review criteria. There was a limited focus on personal recovery and the views of family and carers were absent from the literature. Rates of remission and recovery differ depending upon individual and methodological differences between studies. Data on symptomatic remission, recurrence and diagnosis retainment suggests that BPD is a stable condition, where symptomatic remission is possible and the likelihood of recurrence following a period of remission is low. CONCLUSION: Symptomatic remission from BPD is common. However, recovery including capacities such as engaging in meaningful work was seldom described. Future research needs broader measures of recovery as a sub-syndromal experience, monitoring consumer engagement in meaningful vocation and relationships, with or without the limitations of BPD. PMID- 27504635 TI - Protective Effect of ALA in Crushed Optic Nerve Cat Retinal Ganglion Cells Using a New Marker RBPMS. AB - In this study we first sought to determine whether RNA-binding protein with multiple splicing (RBPMS) can serve as a specific marker for cat retina ganglion cells (RGCs) using retrograde labeling and immunohistochemistry staining. RBPM was then used as an RGC marker to study RGC survival after optic nerve crush (ONC) and alpha-lipoic acid (ALA) treatment in cats. ALA treatment yielded a peak density of RBPMS-alpha cells within the peak isodensity zone (>60/mm2) which did not differ from ONC retinas. The area within the zone was significantly enlarged (control: 2.3%, ONC: 0.06%, ONC+ALA: 0.1%). As for the 10-21/mm2 zone, ALA treatment resulted in a significant increase in area (control: 34.5%, ONC: 12.1%, ONC+ALA: 35.9%). ALA can alleviate crush-induced RGC injury. PMID- 27504636 TI - Analysis of Two Putative Candida albicans Phosphopantothenoylcysteine Decarboxylase / Protein Phosphatase Z Regulatory Subunits Reveals an Unexpected Distribution of Functional Roles. AB - Protein phosphatase Z (Ppz) is a fungus specific enzyme that regulates cell wall integrity, cation homeostasis and oxidative stress response. Work on Saccharomyces cerevisiae has shown that the enzyme is inhibited by Hal3/Vhs3 moonlighting proteins that together with Cab3 constitute the essential phosphopantothenoylcysteine decarboxylase (PPCDC) enzyme. In Candida albicans CaPpz1 is also involved in the morphological changes and infectiveness of this opportunistic human pathogen. To reveal the CaPpz1 regulatory context we searched the C. albicans database and identified two genes that, based on the structure of their S. cerevisiae counterparts, were termed CaHal3 and CaCab3. By pull down analysis and phosphatase assays we demonstrated that both of the bacterially expressed recombinant proteins were able to bind and inhibit CaPpz1 as well as its C-terminal catalytic domain (CaPpz1-Cter) with comparable efficiency. The binding and inhibition were always more pronounced with CaPpz1-Cter, indicating a protective effect against inhibition by the N-terminal domain in the full length protein. The functions of the C. albicans proteins were tested by their overexpression in S. cerevisiae. Contrary to expectations we found that only CaCab3 and not CaHal3 rescued the phenotypic traits that are related to phosphatase inhibition by ScHal3, such as tolerance to LiCl or hygromycin B, requirement for external K+ concentrations, or growth in a MAP kinase deficient slt2 background. On the other hand, both of the Candida proteins turned out to be essential PPCDC components and behaved as their S. cerevisiae counterparts: expression of CaCab3 and CaHal3 rescued the cab3 and hal3 vhs3 S. cerevisiae mutations, respectively. Thus, both CaHal3 and CaCab3 retained the PPCDC related functions and have the potential for CaPpz1 inhibition in vitro. The fact that only CaCab3 exhibits its phosphatase regulatory potential in vivo suggests that in C. albicans CaCab3, but not CaHal3, acts as a moonlighting protein. PMID- 27504637 TI - Uptake of Home-Based HIV Testing, Linkage to Care, and Community Attitudes about ART in Rural KwaZulu-Natal, South Africa: Descriptive Results from the First Phase of the ANRS 12249 TasP Cluster-Randomised Trial. AB - BACKGROUND: The 2015 WHO recommendation of antiretroviral therapy (ART) for all immediately following HIV diagnosis is partially based on the anticipated impact on HIV incidence in the surrounding population. We investigated this approach in a cluster-randomised trial in a high HIV prevalence setting in rural KwaZulu Natal. We present findings from the first phase of the trial and report on uptake of home-based HIV testing, linkage to care, uptake of ART, and community attitudes about ART. METHODS AND FINDINGS: Between 9 March 2012 and 22 May 2014, five clusters in the intervention arm (immediate ART offered to all HIV-positive adults) and five clusters in the control arm (ART offered according to national guidelines, i.e., CD4 count <= 350 cells/MUl) contributed to the first phase of the trial. Households were visited every 6 mo. Following informed consent and administration of a study questionnaire, each resident adult (>=16 y) was asked for a finger-prick blood sample, which was used to estimate HIV prevalence, and offered a rapid HIV test using a serial HIV testing algorithm. All HIV-positive adults were referred to the trial clinic in their cluster. Those not linked to care 3 mo after identification were contacted by a linkage-to-care team. Study procedures were not blinded. In all, 12,894 adults were registered as eligible for participation (5,790 in intervention arm; 7,104 in control arm), of whom 9,927 (77.0%) were contacted at least once during household visits. HIV status was ever ascertained for a total of 8,233/9,927 (82.9%), including 2,569 ascertained as HIV-positive (942 tested HIV-positive and 1,627 reported a known HIV-positive status). Of the 1,177 HIV-positive individuals not previously in care and followed for at least 6 mo in the trial, 559 (47.5%) visited their cluster trial clinic within 6 mo. In the intervention arm, 89% (194/218) initiated ART within 3 mo of their first clinic visit. In the control arm, 42.3% (83/196) had a CD4 count <= 350 cells/MUl at first visit, of whom 92.8% initiated ART within 3 mo. Regarding attitudes about ART, 93% (8,802/9,460) of participants agreed with the statement that they would want to start ART as soon as possible if HIV-positive. Estimated baseline HIV prevalence was 30.5% (2,028/6,656) (95% CI 25.0%, 37.0%). HIV prevalence, uptake of home-based HIV testing, linkage to care within 6 mo, and initiation of ART within 3 mo in those with CD4 count <= 350 cells/MUl did not differ significantly between the intervention and control clusters. Selection bias related to noncontact could not be entirely excluded. CONCLUSIONS: Home-based HIV testing was well received in this rural population, although men were less easily contactable at home; immediate ART was acceptable, with good viral suppression and retention. However, only about half of HIV positive people accessed care within 6 mo of being identified, with nearly two thirds accessing care by 12 mo. The observed delay in linkage to care would limit the individual and public health ART benefits of universal testing and treatment in this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT01509508. PMID- 27504638 TI - Comparisons of the Tono-Pen(r) and Goldmann Applanation Tonometer in the Measurement of Intraocular Pressure of Primary Open Angle Glaucoma Patients in a Hospital Population in Southwest Nigeria. AB - OBJECTIVE: The aim of this study was to compare intraocular pressure (IOP) measured with the Tono-Pen(r) to that measured using the Goldmann applanation tonometer (GAT) in patients with primary open angle glaucoma attending a glaucoma clinic. SUBJECTS AND METHODS: A comparative clinic-based observational study was conducted involving 75 patients (39 men and 36 women) attending a glaucoma clinic in Southwest Nigeria. A pretested structured questionnaire was used to collect sociodemographic data. The Tono-Pen and the GAT were used to measure the IOP in each patient. Central corneal thickness (CCT) was measured with an ultrasonic pachymeter, and the corrected GAT value was calculated for each patient. The Tono Pen readings were compared with the uncorrected and corrected GAT readings. Descriptive and comparative analyses were performed. Values for p < 0.05 were considered statistically significant. RESULTS: The mean age of the participants was 60.39 +/- 16.71 years. The mean IOP using the Tono-Pen was 21.1 +/- 6.8 mm Hg versus the mean uncorrected GAT value of 17.1 +/- 6.9 mm Hg and the corrected GAT value of 18.9 +/- 7.5 mm Hg. The mean CCT was 510.5 +/- 29.6 um. The mean differences between the Tono-Pen reading and uncorrected and corrected GAT readings were 3.9 +/- 2.6 and 2.1 +/- 3.5 mm Hg, respectively. Gender (Tono-Pen vs. GAT; p = 0.981 vs. 0.437) and corneal thickness (p = 0.057) did not significantly affect the IOP value. Of the 75 patients, 68 (90.7%) preferred the Tono-Pen to the GAT. CONCLUSION: In this study, the Tono-Pen gave a higher value for IOP than the uncorrected and corrected GAT values. Gender and corneal thickness did not significantly affect the measurements. Most patients found the Tono-Pen more acceptable than the GAT. PMID- 27504639 TI - Real-Time Diffusion of Information on Twitter and the Financial Markets. AB - Do spikes in Twitter chatter about a firm precede unusual stock market trading activity for that firm? If so, Twitter activity may provide useful information about impending financial market activity in real-time. We study the real-time relationship between chatter on Twitter and the stock trading volume of 96 firms listed on the Nasdaq 100, during 193 days of trading in the period from May 21, 2012 to September 18, 2013. We identify observations featuring firm-specific spikes in Twitter activity, and randomly assign each observation to a ten-minute increment matching on the firm and a number of repeating time indicators. We examine the extent that unusual levels of chatter on Twitter about a firm portend an oncoming surge of trading of its stock within the hour, over and above what would normally be expected for the stock for that time of day and day of week. We also compare the findings from our explanatory model to the predictive power of Tweets. Although we find a compelling and potentially informative real-time relationship between Twitter activity and trading volume, our forecasting exercise highlights how difficult it can be to make use of this information for monetary gain. PMID- 27504640 TI - Do organizational expectations influence workers' implementation perceptions? AB - The purpose of this article is to report on the use of empirically supported treatments (ESTs) among clinical addiction workers, in order to relate the use of ESTs to both perceived agency expectations and worker-level attitudes. We recruited a convenience sample of 120 frontline workers within 4 agencies providing addiction services in St. Louis. The results found that agency expectations were related to clinician's reported use of ESTs, but were unrelated to clinician attitudes. The regression results revealed that reported use of ESTs was associated with openness to ESTs, but was not associated with favoring clinical experience. Organizational leaders interested in using ESTs should send clear, strong messages that they expect workers to use ESTs during clinical practice. (PsycINFO Database Record PMID- 27504641 TI - Violence risk assessment and psychological treatment in correctional and forensic settings: Advances in research and practice. AB - This article is an introduction to the special section "Correctional and Criminal Justice Psychology." The eight articles in this issue advance the goals of delivering and assessing psychological services within the legal and correctional systems and achieving lasting change in individuals, groups, and systems. (PsycINFO Database Record PMID- 27504642 TI - The increasing influence of risk assessment on forensic patient review board decisions. AB - Previous studies of decisions about forensic patients' placement in secure hospitals indicate some changes over time in the use of empirically supported risk factors. Our aim was to investigate whether, in more recent cases, risk assessment instruments were cited by a forensic patient review board or by the clinicians who made recommendations to the board and whether there was evidence of an association between risk assessment results and either dispositions or recommendations. Among review board hearings held in 2009-2012 pertaining to 63 different maximum security patients found not criminally responsible on account of mental disorder in Ontario, Canada, dispositions were most strongly associated with psychiatrists' testimony, consistent with previous studies. However, dispositions were associated with the scores on the Violence Risk Appraisal Guide (VRAG), such that transferred patients had a lower risk of violent recidivism than detained patients. An association between clinical opinions and risk assessment results was also evident and significantly larger than in previous research. There was no evidence that risk assessment was cited selectively in higher risk cases or when scores were concordant with the review board decision. This research may provide a baseline for studies of the effect of 2014 legislation introducing a high-risk designation for forensic patients in Canada. We recommend further efforts to measure the effect of nonpharmacological treatment participation and in-hospital security decisions on forensic decision making. (PsycINFO Database Record PMID- 27504643 TI - The predictive validity of the Two-Tiered Violence Risk Estimates Scale (TTV) in a long-term follow-up of violent offenders. AB - Over the past few decades many structured risk appraisal measures have been created to respond to this need. The Two-Tiered Violence Risk Estimates Scale (TTV) is a measure designed to integrate both an actuarial estimate of violence risk with critical risk management indicators. The current study examined interrater reliability and the predictive validity of the TTV in a sample of violent offenders (n = 120) over an average follow-up period of 17.75 years. The TTV was retrospectively scored and compared with the Violence Risk Appraisal Guide (VRAG), the Statistical Information of Recidivism Scale-Revised (SIR-R1), and the Psychopathy Checklist-Revised (PCL-R). Approximately 53% of the sample reoffended violently, with an overall recidivism rate of 74%. Although the VRAG was the strongest predictor of violent recidivism in the sample, the Actuarial Risk Estimates (ARE) scale of the TTV produced a small, significant effect. The Risk Management Indicators (RMI) produced nonsignificant area under the curve (AUC) values for all recidivism outcomes. Comparisons between measures using AUC values and Cox regression showed that there were no statistical differences in predictive validity. The results of this research will be used to inform the validation and reliability literature on the TTV, and will contribute to the overall risk assessment literature. (PsycINFO Database Record PMID- 27504644 TI - Specialty courts: Who's in and are they working? AB - The effectiveness of specialty courts has been well established in the literature; however, previous studies have not taken into account referral biases that may exist based on offenders' race, socioeconomic status (SES), attorney status, and so forth. The current study hypothesized that (a) Participants who are racially diverse, of lower SES, and represented by privately retained attorneys would be referred less frequently to specialty courts, and (b) Participants in specialty courts would evidence reductions in missed court appointments and failed urinary analyses (UAs) compared with peers not enrolled in specialty courts. Participants (N = 274) were probationers who were involved in 1 of 3 specialty court programs (i.e., drug, driving while intoxicated [DWI], or reentry courts) or a matched sample of probationers not in specialty court services. Results indicated that, in general and with few exceptions, specialty courts did not have differential referral rates based on offender demographics including race, ethnicity, SES, or attorney status (court appointed vs. privately retained). Results examining the effectiveness of the specialty courts were mixed. Participants in the in-prison treatment program reentry court missed a greater proportion of scheduled court meetings than did their matched sample counterparts; however, the other specialty court programs did not significantly differ from their matched-sample counterparts. Participants in the DWI court had a significantly smaller proportion of UA failures to total UAs than did their matched sample peers; however, the drug court and reentry court programs did not significantly differ from their matched sample counterparts. Implications, future directions, and limitations are discussed. (PsycINFO Database Record PMID- 27504645 TI - Recidivism risk factors are correlated with a history of psychiatric hospitalization among sex offenders. AB - Sexual offenders are more likely to have a history of psychiatric hospitalization compared with the general population. This finding suggests that a history of psychiatric hospitalization is a plausible risk factor for the initiation of sexual crimes. It is less clear, however, whether psychiatric hospitalization is associated with risk factors for criminal recidivism. Consequently, the current study examined the correlates of psychiatric hospitalization and its relevance for risk assessment in a sample of sexual offenders on community supervision (N = 947). In this sample, a history of psychiatric hospitalization significantly increased the rate of sexual recidivism (hazard ratio = 1.95). After controlling for well-established risk factors, however, the association was no longer statistically significant. Consequently, this study supported an indirect effect of a history of psychiatric hospitalization, such that the association between psychiatric symptoms and recidivism was mediated by criminogenic needs (e.g., poor general self-regulation, loneliness, and social rejection). Replication studies are needed to confirm this association, and to further understand the link between mental illness and recidivism for sexual offenders. (PsycINFO Database Record PMID- 27504646 TI - Connecting the disconnected: Preliminary results and lessons learned from a telepsychology initiative with special management inmates. AB - The use of telepsychology, such as videoconferencing (VC) systems, has been rapidly increasing as a tool for the provision of mental health services to underserved clients in difficult to access settings. Inmates detained in restrictive housing appear to be at an increased risk of experiencing emotional and behavioral disturbances compared to their general population counterparts, yet they are less likely to receive appropriate treatment due to security constraints. The primary purpose of this article is to describe the process of implementing a novel telepsychology intervention specifically designed to offer group therapy to high-security, administratively segregated inmates. In addition, preliminary results on treatment and therapeutic process outcomes in a sample of 49 participants are reported. Although some evidence indicated that telepsychology was less preferred than in-person sessions, group differences on measures of psychological functioning and criminal thinking were not found across 3 conditions (telepsychology, in-person, and a no-treatment control). Furthermore, a number of limitations associated with program implementation and study design suggest that results be interpreted with caution and should not be used to discount the use of telepsychology as a viable treatment delivery option. Recommendations for future development and evaluation of telepsychological programs are discussed within the context of correctional settings and beyond. (PsycINFO Database Record PMID- 27504647 TI - Potential risks to offspring of intrauterine exposure to maternal age-related obstetric complications. AB - Several hypotheses have been proposed to explain the negative effects of delayed motherhood on an offspring's morbidity later in life. However, these hypotheses are not supported by clinical and epidemiological evidence. Because advanced maternal age is associated with increased risk of obstetric complications, the aim of the present study was to ascertain whether the negative effects on offspring of intrauterine exposure to maternal age-related obstetric complications may explain the reported negative effects of delayed motherhood on offspring. To this end, a literature search was performed to identify relevant publications up to March 2016 on PubMed; references cited in relevant articles were also searched. There was a direct correlation between the risks to offspring conferred by intrauterine exposure to at least one of the obstetric complications present at the time of delivery in women aged >=35 years and the risks to offspring of delayed motherhood. This correlation was not observed when comparing the risks to offspring of delayed motherhood and the risks associated with maternal transmission of defective mitochondria, chromosomal anomalies or DNA double-strand breaks. Most of the effects on offspring of intrauterine exposure to maternal age-related obstetric complications may be induced by epigenetic DNA reprogramming during critical periods of embryo or fetal development. Women wanting to enrol in a fertility preservation program to offset age-related declines in fertility should be informed not only about their chances of pregnancy and the percentage of live births, but also about the risks to themselves and their prospective offspring of delaying motherhood. PMID- 27504648 TI - Prophylactic Cerclage With Braided Polyblend Suture During Femoral Broaching. AB - Femur fractures occur during broaching and impaction of the implant during hip arthroplasty. Prophylactic cerclage of the proximal femur with braided cable and steel wire has been shown to decrease hoop stresses and has been posited as a way to decrease the incidence of intraoperative fracture. In this biomechanical study, the authors investigated the strain across the proximal femur during broaching after the application of stainless steel wire, comparing it with that for braided polyblend suture. Nine femur models were prepared, and strain gauges were applied to each of 3 groups. The control group received no cerclage, the second group received a double loop of suture, and the third group received a single loop of steel wire. A broach was firmly seated in each femur and sequentially increasing axial loads were applied at 1000 N, 2000 N, 3000 N, 4000 N, 5000 N, and 6000 N and to failure. Strain at all loads was lower in both cerclage groups than in the control group. Strain was 28.6%+/-12.4% lower in the suture group than in the control group (P=.0003). Strain was 30.8%+/-10.7% lower in the steel wire group than in the control group (P=.0011). There was no statistically significant difference between suture cerclage and steel wire cerclage (P=.7367). When used for prophylactic cerclage of the proximal femur, braided polyblend suture increases hoop stress resistance, decreases strain, and may play a clinically useful role in decreasing intraoperative proximal femur fractures during hip arthroplasty. [Orthopedics. 2016; 39(6):e1183-e1187.]. PMID- 27504649 TI - Bone Reduction Clamp to Gain Length in Repairing Chronic Achilles Tendon Ruptures. AB - Chronic Achilles tendon ruptures occur after an unrecognized, untreated, or misdiagnosed acute Achilles tendon rupture and present a potentially debilitating injury for the patient. Various techniques have been described to reconstruct the Achilles tendon after chronic ruptures. The technique chosen depends on the length of tendon defect that is present after debridement. If the tendon gap is greater than 3 cm, additional techniques are generally used, as direct repair is often not possible. The authors present a novel intraoperative technique using pointed reduction clamps to gain and maintain length of the Achilles tendon to decrease the gap between ends of the Achilles tendon and allow for end-to-end repair when it may have otherwise not been possible. [Orthopedics. 2016; 39(6):e1223-e1225.]. PMID- 27504650 TI - The Mini C-arm Adds Quality and Efficiency to the Pediatric Orthopedic Outpatient Clinic. AB - The mini C-arm has become increasingly popular in the practice of orthopedics. To the authors' knowledge, its use in the pediatric orthopedic outpatient clinic has not been reported. The purpose of this study was to evaluate the practice efficiency and radiation exposure to the patient when the mini C-arm was used in the pediatric orthopedic outpatient clinic. One hundred consecutive midshaft and distal forearm fractures were evaluated by one orthopedic surgeon in follow-up using a mini C-arm. For each case, the radiation physicist calculated the amount of skin exposure in milligray (mGy). The average skin exposure to the patient from the mini C-arm was 0.58 mGy, compared with 0.2 mGy for anteroposterior view and lateral view radiographs. Use of the mini C-arm, in place of plain radiographs obtained in the radiology department, decreased time waiting during clinic visits by 23 minutes. This study reports 2 important findings. First, surprisingly, the mini C-arm used a slightly higher radiation dose than standard imaging with plain radiographs. Second, use of the mini C-arm saved time and improved the efficiency of the clinic visit. Overall, the mini C-arm improves quality and efficiency in the pediatric orthopedic outpatient clinic. [Orthopedics. 2016; 39(6):e1097-e1099.]. PMID- 27504651 TI - Wear Analysis of Second-generation Highly Cross-Linked Polyethylene in Primary Total Hip Arthroplasty. AB - A major limiting factor in the longevity of total hip replacement is the wear rate of the hip bearing. As manufacturing technology has improved during the past several decades, much attention has been focused on developing newer generations of polyethylene that have lower rates of wear while minimizing free radical formation and subsequent osteolysis. The turning point for the manufacture of polyethylene was moving from gamma irradiation in air to irradiation in a low oxygen environment, which reduced free radical formation while increasing the wear resistance. New polyethylene manufacturing methods, including multiple cycles of irradiation and annealing, have resulted in greater wear resistance. Wear analysis studies are essential to determine if these new liners actually show a benefit from prior generations of polyethylene and, more importantly, if they are safe to use. This study involved a single center retrospective review of 60 patients with a mean follow-up of 5.5 years who underwent primary total hip arthroplasty with a second-generation highly cross-linked polyethylene manufactured by 3 cycles of sequential irradiation and annealing. Linear and volumetric wear rates were determined from digitized radiographs using contemporary wear analysis software. The mean linear wear rate for the entire group was 0.025 millimeters per year (mm/y). This value represents a linear wear rate 2.7 times less than that of a first-generation highly cross-linked polyethylene and 4.2 times less than that of a conventional polyethylene. At an average of 5 years, compared with a first-generation highly cross-linked polyethylene, a second-generation highly cross-linked polyethylene appears to show significant improvement regarding wear. [Orthopedics. 2016; 39(6):e1178 e1182.]. PMID- 27504652 TI - The effects of proximal withdrawal states on job attitudes, job searching, intent to leave, and employee turnover. AB - We present the first major test of proximal withdrawal states theory (PWST; Hom, Mitchell, Lee, & Griffeth, 2012). In addition, we develop and test new ideas to demonstrate how PWST improves our understanding and prediction of employee turnover. Across 2 studies, we corroborate that reluctant stayers (those who want to leave but have to stay) are similar to enthusiastic leavers (those who want to leave and can leave) in affective commitment, job satisfaction, and job embeddedness, and that reluctant leavers (those who want to stay but have to leave) are similar to enthusiastic stayers (those who want to stay and can stay) on these dimensions. We find that job satisfaction and job embeddedness more strongly influence the intent to leave and job search behavior for enthusiastic stayers and leavers than for reluctant stayers and leavers. More important, we show that for those experiencing low control over their preference for leaving or staying (i.e., reluctant stayers and leavers), traditional variables such as job satisfaction, job embeddedness, and intent to leave are poor predictors of their turnover behavior. We further demonstrate that focusing on enthusiastic stayers and leavers can significantly enhance the accuracy of job satisfaction, job embeddedness, and intent to leave for predicting actual employee turnover. (PsycINFO Database Record PMID- 27504653 TI - Do it well and do it right: The impact of service climate and ethical climate on business performance and the boundary conditions. AB - Prior research has demonstrated that service climate can enhance unit performance by guiding employees' service behavior to satisfy customers. Extending this literature, we identified ethical climate toward customers as another indispensable organizational climate in service contexts and examined how and when service climate operates in conjunction with ethical climate to enhance business performance of service units. Based on data collected in 2 phases over 6 months from multiple sources of 196 movie theaters, we found that service climate and ethical climate had disparate impacts on business performance, operationalized as an index of customer attendance rate and operating income per labor hour, by enhancing service behavior and reducing unethical behavior, respectively. Furthermore, we found that service behavior and unethical behavior interacted to affect business performance, in such a way that service behavior was more positively related to business performance when unethical behavior was low than when it was high. This interactive effect between service and unethical behaviors was further strengthened by high market turbulence and competitive intensity. These findings provide new insight into theoretical development of service management and offer practical implications about how to maximize business performance of service units by managing organizational climates and employee behaviors synergistically. (PsycINFO Database Record PMID- 27504654 TI - The problem of effect size heterogeneity in meta-analytic structural equation modeling. AB - Scholars increasingly recognize the potential of meta-analytic structural equation modeling (MASEM) as a way to build and test theory (Bergh et al., 2016). Yet, 1 of the greatest challenges facing MASEM researchers is how to incorporate and model meaningful effect size heterogeneity identified in the bivariate meta analysis into MASEM. Unfortunately, common MASEM approaches in applied psychology (i.e., Viswesvaran & Ones, 1995) fail to account for effect size heterogeneity. This means that MASEM effect sizes, path estimates, and overall fit values may only generalize to a small segment of the population. In this research, we quantify this problem and introduce a set of techniques that retain both the true score relationships and the variability surrounding those relationships in estimating model parameters and fit indices. We report our findings from simulated data as well as from a reanalysis of published MASEM studies. Results demonstrate that both path estimates and overall model fit indices are less representative of the population than existing MASEM research would suggest. We suggest 2 extension MASEM techniques that can be conducted using online software or in R, to quantify the stability of model estimates across the population and allow researchers to better build and test theory. (PsycINFO Database Record PMID- 27504655 TI - Are organizational justice rules gendered? Reactions to men's and women's justice violations. AB - Research has shown that gender role prescriptions can bias reactions to men's and women's work behaviors. The current work draws upon this idea and extends it to consider violations of procedural and interactional justice rules. The results of four experimental studies demonstrate that men and women receive differential performance evaluation ratings and reward recommendations when they violate those organizational justice rules that coincide with the content of prescriptive gender stereotypes. Specifically, women were rated less favorably than men when they exhibited interactional injustice (Study 1 and Study 4), but not when they engaged in procedural injustice (Study 2). Findings also indicate that interactional justice violations (e.g., being impolite, not caring about the well being of subordinates), but not procedural justice violations, are deemed less acceptable for female managers than male managers (Study 3). Overall, the findings suggest that reactions to injustice can be influenced by expectations of how men and women should behave. (PsycINFO Database Record PMID- 27504656 TI - Impressed by impression management: Newcomer reactions to ingratiated supervisors. AB - Organizational newcomers are unfamiliar with many aspects of their workplace and look for information to help them reduce uncertainty and better understand their new environment. One aspect critical to newcomers is the disposition of their supervisor-the person who arguably can impact the newcomer's career the most. To form an impression of their new supervisor, newcomers look to social cues from coworkers who have interpersonal contact with the supervisor. In the present research, we investigate the ways newcomers use observed ingratiation-a common impression management strategy whereby coworkers try to appear likable (Schlenker, 1980)-to form impressions of a supervisor's warmth. Research on social influence cannot easily account for how third parties will interpret ingratiation, as the behaviors linked to ingratiation suggest something positive about the target, yet the unsavory aspects of the behavior imply it may not have the same effects as other positive behaviors. Our findings suggest that newcomers are unique in that they are motivated to learn about their new supervisor, and are prone to ignore those unsavory aspects and infer something positive about a supervisor targeted with ingratiation. Our findings also suggest that this effect can be weakened based on the supervisor's response. In other words, newcomers rely less on evidence from a coworker's ingratiation in the presence of direct behaviors from the supervisor. (PsycINFO Database Record PMID- 27504657 TI - Multisource feedback, human capital, and the financial performance of organizations. AB - We investigated the relationship between organizations' use of multisource feedback (MSF) programs and their financial performance. We proposed a moderated mediation framework in which the employees' ability and knowledge sharing mediate the relationship between MSF and organizational performance and the purpose for which MSF is used moderates the relationship of MSF with employees' ability and knowledge sharing. With a sample of 253 organizations representing 8,879 employees from 2005 to 2007 in South Korea, we found that MSF had a positive effect on organizational financial performance via employees' ability and knowledge sharing. We also found that when MSF was used for dual purpose (both administrative and developmental purposes), the relationship between MSF and knowledge sharing was stronger, and this interaction carried through to organizational financial performance. However, the purpose of MSF did not moderate the relationship between MSF and employees' ability. The theoretical relevance and practical implications of the findings are discussed. (PsycINFO Database Record PMID- 27504658 TI - Who strikes back? A daily investigation of when and why incivility begets incivility. AB - Incivility at work-low intensity deviant behaviors with an ambiguous intent to harm-has been on the rise, yielding negative consequences for employees' well being and companies' bottom-lines. Although examinations of incivility have gained momentum in organizational research, theory and empirical tests involving dynamic, within-person processes associated with this negative interpersonal behavior are limited. Drawing from ego depletion theory, we test how experiencing incivility precipitates instigating incivility toward others at work via reduced self-control. Using an experience sampling design across 2 work weeks, we found that experiencing incivility earlier in the day reduced one's levels of self control (captured via a performance-based measure of self-control), which in turn resulted in increased instigated incivility later in the day. Moreover, organizational politics-a stable, environmental factor-strengthened the relation between experienced incivility and reduced self-control, whereas construal level a stable, personal factor-weakened the relation between reduced self-control and instigated incivility. Combined, our results yield multiple theoretical, empirical, and practical implications for the study of incivility at work. (PsycINFO Database Record PMID- 27504659 TI - Facilitating women's success in business: Interrupting the process of stereotype threat through affirmation of personal values. AB - Two field experiments examined if and how values affirmations can ameliorate stereotype threat-induced gender performance gaps in an international competitive business environment. Based on self-affirmation theory (Steele, 1988), we predicted that writing about personal values unrelated to the perceived threat would attenuate the gender performance gap. Study 1 found that an online assignment to write about one's personal values (but not a similar writing assignment including organizational values) closed the gender gap in course grades by 89.0% among 423 Masters of Business Administration students (MBAs) at an international business school. Study 2 replicated this effect among 396 MBAs in a different cohort with random assignment and tested 3 related mediators (self efficacy, self-doubt, and self-criticism). Personal values reflection (but not reflecting on values including those of the organization or writing about others' values) reduced the gender gap by 66.5%, and there was a significant indirect effect through reduced self-doubt. These findings show that a brief personal values writing exercise can dramatically improve women's performance in competitive environments where they are negatively stereotyped. The results also demonstrate that stereotype threat (Steele & Aronson, 1995) can occur within a largely non-American population with work experience and that affirming one's core personal values (without organizational values) can ameliorate the threat. (PsycINFO Database Record PMID- 27504660 TI - The dynamics of team cognition: A process-oriented theory of knowledge emergence in teams. AB - Team cognition has been identified as a critical component of team performance and decision-making. However, theory and research in this domain continues to remain largely static; articulation and examination of the dynamic processes through which collectively held knowledge emerges from the individual- to the team-level is lacking. To address this gap, we advance and systematically evaluate a process-oriented theory of team knowledge emergence. First, we summarize the core concepts and dynamic mechanisms that underlie team knowledge building and represent our theory of team knowledge emergence (Step 1). We then translate this narrative theory into a formal computational model that provides an explicit specification of how these core concepts and mechanisms interact to produce emergent team knowledge (Step 2). The computational model is next instantiated into an agent-based simulation to explore how the key generative process mechanisms described in our theory contribute to improved knowledge emergence in teams (Step 3). Results from the simulations demonstrate that agent teams generate collectively shared knowledge more effectively when members are capable of processing information more efficiently and when teams follow communication strategies that promote equal rates of information sharing across members. Lastly, we conduct an empirical experiment with real teams participating in a collective knowledge-building task to verify that promoting these processes in human teams also leads to improved team knowledge emergence (Step 4). Discussion focuses on implications of the theory for examining team cognition processes and dynamics as well as directions for future research. (PsycINFO Database Record PMID- 27504661 TI - Are genetic and environmental influences on job satisfaction stable over time? A three-wave longitudinal twin study. AB - Job satisfaction research has unfolded as an exemplary manifestation of the "person versus environment" debate in applied psychology. With the increasing recognition of the importance of time, it is informative to examine a question critical to the dispositional view of job satisfaction: Are genetic influences on job satisfaction stable across different time points? Drawing upon dispositional and situational perspectives on job satisfaction and recent research in developmental behavioral genetics, we examined whether the relative potency of genetic (i.e., the person) and environmental influences on job satisfaction changed over time in a 3-wave longitudinal twin study. Biometric behavioral genetics analyses showed that genetic influences accounted for 31.2% of the variance in job satisfaction measured at approximately Age 21, which was markedly greater than the 18.7% and 19.8% of variance explained by genetic factors at Age 25 and Age 30. Such genetic influences were mediated via positive affectivity and negative affectivity, but not via general mental ability. After partialing out genetic influences, environmental influences on job satisfaction were related to interpersonal conflict at work and occupational status, and these influences were relatively stable across the 3 time points. These results offer important implications for organizations and employees to better understand and implement practices to enhance job satisfaction. (PsycINFO Database Record PMID- 27504662 TI - Fit and frustration as drivers of targeted counterproductive work behaviors: A multifoci perspective. AB - In this article, the authors integrate the theory of work adjustment (Dawis, England, & Lofquist, 1964) and the stressor emotion model of counterproductive work behaviors (CWBs; Spector & Fox, 2005) to examine workplace frustration as an intervening mechanism that mediates relations between person-environment (P-E) fit and CWBs. Moreover, we adopt a multifoci perspective to estimate effects for multiple fit, frustration, and CWB foci. We examine the nature of relations between fit, frustration, and CWB for like foci (target similar effects), as well as cross-foci effects. Study 1 examines proposed effects in a sample of 447 employee-coworker dyads. Study 2 uses a 3-wave survey design and tests effects in a sample of 669 employees. Results from both studies suggest that (a) frustration mediates the effects of P-E fit on CWBs and (b) the most consistent effects were observed among the variables with matching foci. Implications for research and practice are discussed. (PsycINFO Database Record PMID- 27504663 TI - When do high-context communicators speak up? Exploring contextual communication orientation and employee voice. AB - Past research suggests that individuals oriented toward high-context communication are less likely than are others to voice (i.e., speak up) at work. In the current article, we rely on high-/low-context theory to explore potential boundary conditions of this relationship. We conducted 2 studies exploring the relationship between contextual communication orientation and 2 distinct types of voice (prohibitive and promotive). As hypothesized, both studies showed that the negative relationship between contextual communication orientation and voice was weaker for prohibitive (compared with promotive) voice. Results of Study 1 showed that, as hypothesized, leader-member exchange (LMX) moderated the relationship between contextual communication orientation and promotive voice, such that the relationship was negative when LMX was low but not significant when high. The interaction was not significant in predicting prohibitive voice in Study 1 or in predicting either voice type in Study 2. (PsycINFO Database Record PMID- 27504664 TI - "Demographic faultlines: A meta-analysis of the literature": Retraction of Thatcher and Patel (2011). AB - Reports the retraction of "Demographic faultlines: A meta-analysis of the literature" by Sherry M. B. Thatcher and Pankaj C. Patel (Journal of Applied Psychology, 2011[Nov], Vol 96[6], 1119-1139). At the request of the editor and in consultation with the American Psychological Association, the article is being retracted. This action is a result of a review by the editor and two additional experts that determined that there are significant errors in Tables 1, 2, and 3 which may affect the overall conclusions of the article. Co-author Pankaj C. Patel led the analysis, and both authors acknowledge that inaccuracies were made. The retraction of this article does not preclude resubmission of a new article that addresses the issues noted in the retraction. (The following abstract of the original article appeared in record 2011-12686-001.) We propose and test a theoretical model focusing on antecedents and consequences of demographic faultlines. We also posit contingencies that affect overall team dynamics in the context of demographic faultlines, such as the study setting and performance measurement. Using meta-analysis structural equation modeling with a final data set consisting of 311 data points (i.e., k [predictor-criterion relationships]), from 39 studies that were obtained from 36 papers with a total sample size of 24,388 individuals in 4,366 teams, we found that sex and racial diversity increased demographic faultline strength more than did diversity on the attributes of functional background, educational background, age, and tenure. Demographic faultline strength was found to increase task and relationship conflict as well as decrease team cohesion. Furthermore, although demographic faultline strength decreased both team satisfaction and team performance, there was a stronger decrease in team performance than in team satisfaction. The strength of these relationships increased when the study was conducted in the lab rather than in the field. We describe the theoretical and practical implications of these findings for advancing the study of faultlines. PMID- 27504665 TI - In Vitro Evaluation of CRISPR/Cas9 Function by an Electrochemiluminescent Assay. AB - The CRISPR/Cas9 system is a revolutionary genome-editing tool that enables targeted and efficient gene knockouts. However, the off-target effects and loci dependent enzyme activity limit its uses on the field of research and treatment. In this study, we designed a convenient and sensitive in vitro test method, which was based on electrochemiluminescence (ECL) technology for evaluating cleavage activity of the CRISPR/Cas9 system. It was find that Cas9 can tolerate some common genetic modifications to its target DNA. It was also find that target DNA/sgRNA with single-base mismatch and UV damages of target DNA resulted in significantly reduction of Cas9 cleavage efficiency. Comparing with traditional method, the proposed method reduced the evaluation time from weeks to 2 h. Therefore, our study provides a versatile in vitro method for a priori analysis of CRISPR/Cas9 system and highlights the potential to guide in vivo genome editing. PMID- 27504666 TI - Dimensionless Equation of State to Predict Microemulsion Phase Behavior. AB - Prediction of microemulsion phase behavior for changing state variables is critical to formulation design of surfactant-oil-brine (SOB) systems. SOB systems find applications in various chemical and petroleum processes, including enhanced oil recovery. A dimensional equation-of-state (EoS) was recently presented by Ghosh and Johns1 that relied on estimation of the surfactant tail length and surface area. We give an algorithm for flash calculations for estimation of three phase Winsor regions that is more robust, simpler, and noniterative by making the equations dimensionless so that estimates of tail length and surface area are no longer needed. We predict phase behavior as a function temperature, pressure, volume, salinity, oil type, oil-water ratio, and surfactant/alcohol concentration. The dimensionless EoS is based on coupling the HLD-NAC (Hydrophilic Lipophilic Difference-Net Average Curvature) equations with new relationships between optimum salinity and solubility. An updated HLD expression that includes pressure is also used to complete the state description. A significant advantage of the dimensionless form of the EoS over the dimensional version is that salinity scans are tuned based only on one parameter, the interfacial volume ratio. Further, stability conditions are developed in a simplified way to predict whether an overall compositions lies within the single, two-, or three-phase regions. Important new microemulsion relationships are also found, the most important of which is that optimum solubilization ratio is equal to the harmonic mean of the oil and water solubilization ratios in the type III region. Thus, only one experimental measurement is needed in the three-phase zone to estimate the optimum solubilization ratio, a result which can aid experimental design and improve estimates of optimum from noisy data. Predictions with changing state variables are illustrated by comparison to experimental data using standard diagrams including a new type of dimensionless fish plot. The results show that the optimum solubilization ratio and salinity using the tuned dimensionless EoS are within average errors of 2.44% and 1.17% of experimental values for the fluids examined. We then use the dimensionless equations and thermodynamic first-principles to derive the constant in Huh's equation for interfacial tension prediction. PMID- 27504667 TI - Application of Coiled Coil Peptides in Liposomal Anticancer Drug Delivery Using a Zebrafish Xenograft Model. AB - The complementary coiled coil forming peptides E4 [(EIAALEK)4] and K4 [(KIAALKE)4] are known to trigger liposomal membrane fusion when tethered to lipid vesicles in the form of lipopeptides. In this study, we examined whether these coiled coil forming peptides can be used for drug delivery applications. First, we prepared E4 peptide modified liposomes containing the far-red fluorescent dye TO-PRO-3 iodide (E4-Lipo-TP3) and confirmed that E4-liposomes could deliver TP3 into HeLa cells expressing K4 peptide on the membrane (HeLa-K) under cell culture conditions in a selective manner. Next, we prepared doxorubicin-containing E4-liposomes (E4-Lipo-DOX) and confirmed that E4-liposomes could also deliver DOX into HeLa-K cells. Moreover, E4-Lipo-DOX showed enhanced cytotoxicity toward HeLa-K cells compared to free doxorubicin. To prove the suitability of E4/K4 coiled coil formation for in vivo drug delivery, we injected E4-Lipo-TP3 or E4-Lipo-DOX into zebrafish xenografts of HeLa-K. As a result, E4 liposomes delivered TP3 to the implanted HeLa-K cells, and E4-Lipo-DOX could suppress cancer proliferation in the xenograft when compared to nontargeted conditions (i.e., zebrafish xenograft with free DOX injection). These data demonstrate that coiled coil formation enables drug selectivity and efficacy in vivo. It is envisaged that these findings are a step forward toward biorthogonal targeting systems as a tool for clinical drug delivery. PMID- 27504668 TI - Identification of Mitosis-Specific Phosphorylation in Mitotic Chromosome Associated Proteins. AB - During mitosis, phosphorylation of chromosome-associated proteins is a key regulatory mechanism. Mass spectrometry has been successfully applied to determine the complete protein composition of mitotic chromosomes, but not to identify post-translational modifications. Here, we quantitatively compared the phosphoproteome of isolated mitotic chromosomes with that of chromosomes in nonsynchronized cells. We identified 4274 total phosphorylation sites and 350 mitosis-specific phosphorylation sites in mitotic chromosome-associated proteins. Significant mitosis-specific phosphorylation in centromere/kinetochore proteins was detected, although the chromosomal association of these proteins did not change throughout the cell cycle. This mitosis-specific phosphorylation might play a key role in regulation of mitosis. Further analysis revealed strong dependency of phosphorylation dynamics on kinase consensus patterns, thus linking the identified phosphorylation sites to known key mitotic kinases. Remarkably, chromosomal axial proteins such as non-SMC subunits of condensin, TopoIIalpha, and Kif4A, together with the chromosomal periphery protein Ki67 involved in the establishment of the mitotic chromosomal structure, demonstrated high phosphorylation during mitosis. These findings suggest a novel mechanism for regulation of chromosome restructuring in mitosis via protein phosphorylation. Our study generated a large quantitative database on protein phosphorylation in mitotic and nonmitotic chromosomes, thus providing insights into the dynamics of chromatin protein phosphorylation at mitosis onset. PMID- 27504669 TI - Hernandezine, a Bisbenzylisoquinoline Alkaloid with Selective Inhibitory Activity against Multidrug-Resistance-Linked ATP-Binding Cassette Drug Transporter ABCB1. AB - The overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 (P glycoprotein, MDR1) is the most studied mechanism of multidrug resistance (MDR), which remains a major obstacle in clinical cancer chemotherapy. Consequently, resensitizing MDR cancer cells by inhibiting the efflux function of ABCB1 has been considered as a potential strategy to overcome ABCB1-mediated MDR in cancer patients. However, the task of developing a suitable modulator of ABCB1 has been hindered mostly by the lack of selectivity and high intrinsic toxicity of candidate compounds. Considering the wide range of diversity and relatively nontoxic nature of natural products, developing a potential modulator of ABCB1 from natural sources is particularly valuable. Through screening of a large collection of purified bioactive natural products, hernandezine was identified as a potent and selective reversing agent for ABCB1-mediated MDR in cancer cells. Experimental data demonstrated that the bisbenzylisoquinoline alkaloid hernandezine is selective for ABCB1, effectively inhibits the transport function of ABCB1, and enhances drug-induced apoptosis in cancer cells. More importantly, hernandezine significantly resensitizes ABCB1-overexpressing cancer cells to multiple chemotherapeutic drugs at nontoxic, nanomolar concentrations. Collectively, these findings reveal that hernandezine has great potential to be further developed into a novel reversal agent for combination therapy in MDR cancer patients. PMID- 27504670 TI - Microglia-Based Phenotypic Screening Identifies a Novel Inhibitor of Neuroinflammation Effective in Alzheimer's Disease Models. AB - Currently, anti-AD drug discovery using target-based approaches is extremely challenging due to unclear etiology of AD and absence of validated therapeutic protein targets. Neuronal death, regardless of causes, plays a key role in AD progression, and it is directly linked to neuroinflammation. Meanwhile, phenotypic screening is making a resurgence in drug discovery process as an alternative to target-focused approaches. Herein, we employed microglia-based phenotypic screenings to search for small molecules that modulate the release of detrimental proinflammatory cytokines. The identified novel pharmacological inhibitor of neuroinflammation (named GIBH-130) was validated to alter phenotypes of neuroinflammation in AD brains. Notably, this molecule exhibited comparable in vivo efficacy of cognitive impairment relief to donepezil and memantine respectively in both beta amyloid-induced and APP/PS1 double transgenic Alzheimer's murine models at a substantially lower dose (0.25 mg/kg). Therefore, GIBH-130 constitutes a unique chemical probe for pathogenesis research and drug development of AD, and it also suggests microglia-based phenotypic screenings that target neuroinflammation as an effective and feasible strategy to identify novel anti-AD agents. PMID- 27504671 TI - Copper-Catalyzed Intramolecular Benzylic C-H Amination for the Synthesis of Isoindolinones. AB - A copper-catalyzed intramolecular amination occurs at the benzylic C-H of 2 methylbenzamides to deliver the corresponding isoindolinones of great interest in medicinal chemistry. The mild and abundant MnO2 works well as a terminal oxidant, and the reaction proceeds smoothly under potentially explosive organic peroxide free conditions. Additionally, the directing-group-dependent divergent mechanisms are proposed: 8-aminoquinoline-containing benzamides include a Cu-mediated organometallic pathway whereas an aminyl radical-promoted Hofmann-Loffler-Freytag (HLF)-type mechanism can be operative in the case of N-naphthyl-substituted substrates. PMID- 27504672 TI - How Do Distance and Solvent Affect Halogen Bonding Involving Negatively Charged Donors? AB - It was reported that negatively charged donors can form halogen bonding, which is stable, especially, in a polar environment. On the basis of a survey of the Protein Data Bank, we noticed that the distance between the negative charge center and the halogen atom of an organohalogen may vary greatly. Therefore, a series of model systems, composed of 4-halophenyl-conjugated polyene acids and ammonia, were designed to explore the potential effect of distance on halogen bonding in different solvents. Quantum mechanics (QM) calculations demonstrated that the longer the distance, the stronger the bonding. The energy decomposition analysis on all of the model systems demonstrated that electrostatic interaction contributes the most (44-56%) to the overall binding, followed by orbital interaction (42-36%). Natural bond orbital calculations showed that electron transfer takes place from the acceptor to the donor, whereas the halogen atom becomes more positive during the bonding, which is in agreement with the result of neutral halogen bonding. QM/molecular mechanics calculations demonstrated that the polarity of binding pockets makes all of the interactions attractive in a protein system. Hence, the strength of halogen bonding involving negatively charged donors could be adjusted by changing the distance between the negative charge center and halogen atom and the environment in which the bonding exists, which may be applied in material and drug design for tuning their function and activity. PMID- 27504673 TI - Dispersed Fluorescence Spectroscopy of Jet-Cooled Isobutoxy and 2-Methyl-1-butoxy Radicals. AB - We report dispersed fluorescence (DF) spectra of the isobutoxy and 2-methyl-1 butoxy radicals produced by photolysis of corresponding nitrites in supersonic jet expansion. Different vibrational structures have been observed in the DF spectra when different vibronic bands in the laser-induced fluorescence (LIF) spectra of each radical were pumped, which suggests that those vibronic bands be assigned to different conformers. Spectra simulated using calculated vibrational frequencies and Franck-Condon factors well reproduce the experimentally observed ones and support the assignment of the vibronic bands in the LIF spectra to the two lowest-energy conformers of each radical. DF spectra obtained by pumping the B <- X origin bands of the LIF spectra are dominated by CO stretch progressions because of the large difference in CO bond length between the ground (X) and the second excited (B) electronic states. Furthermore, with non-CO stretch bands pumped, the DF spectra are dominated by progressions of combination bands of the CO stretch and the pumped modes as a result of Duschinsky mixing. A-X separation of both conformers of the isobutoxy radical has also been determined in the experiment. PMID- 27504674 TI - K3B3O4(OH)4.2H2O: A UV Nonlinear Optical Crystal with Isolated [B3O4(OH)4](3-) Anion Groups. AB - A potential ultraviolet (UV) nonlinear optical (NLO) material, K3B3O4(OH)4.2H2O, was successfully synthesized by hydrothermal methods. The compound crystallizes into the Cmc21 space group and exhibits isolated [B3O4(OH)4](3-) anion groups connected by O-H...O hydrogen bonds. The UV-vis diffuse reflectance spectrum shows that K3B3O4(OH)4.2H2O has a wide transparency range with an absorption edge below 190 nm. Powder second harmonic generation (SHG) measurements using 1064 nm radiation revealed a moderate efficiency, 0.8 * KDP. Additional particle size vs SHG efficiency measurements indicate that K3B3O4(OH)4.2H2O is type I phase matchable. Our calculated results show that the borate groups as well as the waters of hydration determine the NLO properties of K3B3O4(OH)4.2H2O. PMID- 27504675 TI - Toward Lower Overpotential through Improved Electron Transport Property: Hierarchically Porous CoN Nanorods Prepared by Nitridation for Lithium-Oxygen Batteries. AB - To lower the overpotential of a lithium-oxygen battery, electron transport at the solid-to-solid interface between the discharge product Li2O2 and the cathode catalyst is of great significance. Here we propose a strategy to enhance electron transport property of the cathode catalyst by the replace of oxygen atoms in the generally used metal oxide-based catalysts with nitrogen atoms to improve electron density at Fermi energy after nitridation. Hierarchically porous CoN nanorods were obtained by thermal treatment of Co3O4 nanorods under ammonia atmosphere at 350 degrees C. Compared with that of the pristine Co3O4 precursor before nitridation, the overpotential of the obtained CoN cathode was significantly decreased. Moreover, specific capacity and cycling stability of the CoN nanorods were enhanced. It is assumed that the discharged products with different morphologies for Co3O4 and CoN cathodes might be closely associated with the variation in the electronic density induced by occupancy of nitrogen atoms into interstitial sites of metal lattice after nitridation. The nitridation strategy for improved electron density proposed in this work is proved to be a simple but efficient way to improve the electrochemical performance of metal oxide based cathodes for lithium-oxygen batteries. PMID- 27504676 TI - Clinician's Commentary on Chan et al.(1). PMID- 27504677 TI - An eye-tracking investigation of written sarcasm comprehension: The roles of familiarity and context. AB - This article addresses a current theoretical debate between the standard pragmatic model, the graded salience hypothesis, and the implicit display theory, by investigating the roles of the context and of the properties of the sarcastic utterance itself in the comprehension of a sarcastic remark. Two eye-tracking experiments were conducted where we manipulated the speaker's expectation in the context and the familiarity of the sarcastic remark. The results of the first eye tracking study showed that literal comments were read faster than unfamiliar sarcastic comments, regardless of whether an explicit expectation was present in the context. The results of the second eye-tracking study indicated an early processing difficulty for unfamiliar sarcastic comments, but not for familiar sarcastic comments. Later reading time measures indicated a general difficulty for sarcastic comments. Overall, results seem to suggest that the familiarity of the utterance does indeed affect the time course of sarcasm processing (supporting the graded salience hypothesis), although there is no evidence that making the speaker's expectation explicit in the context affects it as well (thus failing to support the implicit display theory). (PsycINFO Database Record PMID- 27504678 TI - Benchmark eye movement effects during natural reading in autism spectrum disorder. AB - In 2 experiments, eye tracking methodology was used to assess on-line lexical, syntactic and semantic processing in autism spectrum disorder (ASD). In Experiment 1, lexical identification was examined by manipulating the frequency of target words. Both typically developed (TD) and ASD readers showed normal frequency effects, suggesting that the processes TD and ASD readers engage in to identify words are comparable. In Experiment 2, syntactic parsing and semantic interpretation requiring the on-line use of world knowledge were examined, by having participants read garden path sentences containing an ambiguous prepositional phrase. Both groups showed normal garden path effects when reading low-attached sentences and the time course of reading disruption was comparable between groups. This suggests that not only do ASD readers hold similar syntactic preferences to TD readers, but also that they use world knowledge on-line during reading. Together, these experiments demonstrate that the initial construction of sentence interpretation appears to be intact in ASD. However, the finding that ASD readers skip target words less often in Experiment 2, and take longer to read sentences during second pass for both experiments, suggests that they adopt a more cautious reading strategy and take longer to evaluate their sentence interpretation prior to making a manual response. (PsycINFO Database Record PMID- 27504679 TI - Prospective memory in context: Moving through a familiar space. AB - Successful completion of delayed intentions is a common but important aspect of daily behavior. Such behavior requires not only memory for the intended action but also recognition of the opportunity to perform that action, known collectively as prospective memory. The fact that prospective memory tasks occur in the midst of other activities is captured in laboratory tasks by embedding the prospective memory task in an ongoing activity. In many cases the requirement to perform the prospective memory task results in a reduction in ongoing performance relative to when the ongoing task is performed alone. This is referred to as the cost to the ongoing task and reflects the allocation of attentional resources to the prospective memory task. The current study examined the pattern of cost across the ongoing task when the ongoing task provided contextual information that in turn allowed participants to anticipate when target events would occur within the ongoing task. The availability of contextual information reduced ongoing task response times overall, with an increase in response times closer to the target locations (Experiments 1-3). The fourth study, drawing on the Event Segmentation Theory, provided support for the proposal made by the Preparatory Attentional and Memory Processes theory of prospective memory that decisions about the allocation of attention to the prospective memory task are more likely to be made at points of transition. (PsycINFO Database Record PMID- 27504680 TI - Is it all task-specific? The role of binary responses, verbal mediation, and saliency for eliciting language-space associations. AB - Associations between language and space are of central interest for grounded models of language comprehension. Various studies show that reading words such as bird or shoe results in faster responses toward the typical location of the corresponding entity (e.g., after bird, upward responses are faster than downward responses). Critically, as of yet, the mechanisms underlying these effects and their boundary conditions are widely unknown. In fact, it cannot be ruled out that these effects are by-products of processing that only occur in very specific task settings. Here we investigated the role of 3 major processes (response set, labeling, and saliency) that might underlie these compatibility effects in Stroop like paradigms. In Experiment 1, we aimed at overcoming the binary nature of the response set by including responses both in the vertical and the horizontal dimension. In Experiment 2 no memorizing of the color-to-response mapping was required, making internal response labeling unnecessary. In Experiment 3 this was replicated in a mouse-tracking setup. In all experiments a clear language-space association was observed. Critically, in a final experiment not only the saliency of verticality in the response set but also in the stimulus set was reduced. Here no language-space association was observed. Together these results suggest that language-space associations extend beyond bipolar response settings and that internal response labeling is not a precondition for finding these compatibility effects. However, the vertical dimension needs to be salient either in the stimulus or response set. Implications for models of language comprehension are discussed. (PsycINFO Database Record PMID- 27504681 TI - Out of place, out of mind: Schema-driven false memory effects for object-location bindings. AB - Events consist of diverse elements, each processed in specialized neocortical networks, with temporal lobe memory systems binding these elements to form coherent event memories. We provide a novel theoretical analysis of an unexplored consequence of the independence of memory systems for elements and their bindings, 1 that raises the paradoxical prediction that schema-driven false memories can act solely on the binding of event elements despite the superior retrieval of individual elements. This is because if 2, or more, schema-relevant elements are bound together in unexpected conjunctions, the unexpected conjunction will increase attention during encoding to both the elements and their bindings, but only the bindings will receive competition with evoked schema expected bindings. We test our model by examining memory for object-location bindings in recognition (Study 1) and recall (Studies 2 and 3) tasks. After studying schema-relevant objects in unexpected locations (e.g., pan on a stool in a kitchen scene), participants who then viewed these objects in expected locations (e.g., pan on stove) at test were more likely to falsely remember this object-location pairing as correct, compared with participants that viewed a different unexpected object-location pairing (e.g., pan on floor). In recall, participants were more likely to correctly remember individual schema-relevant objects originally viewed in unexpected, as opposed to expected locations, but were then more likely to misplace these items in the original room scene to expected places, relative to control schema-irrelevant objects. Our theoretical analysis and novel paradigm provide a tool for investigating memory distortions acting on binding processes. (PsycINFO Database Record PMID- 27504682 TI - Chinese readers can perceive a word even when it's composed of noncontiguous characters. AB - This study explored whether readers could recognize a word composed of noncontiguous characters (a cross-character word) in Chinese reading. All 3 experiments employed Chinese 4-character strings ABCD, where both AB and CD were 2-character words. In the cross-character word condition, AC was a word but in the control condition, AC was not a word. A character identification task was employed in Experiment 1 and sentence reading tasks were employed in Experiments 2 and 3. In all 3 experiments, an AC word produced inhibition effects. In Experiment 1, an AC word decreased the accuracy of character B identification, but increased the accuracy of character C identification. In Experiments 2 and 3, an AC word slowed reading on CD, indicating that the cross-character words were activated. These results imply that Chinese character encoding leading to word recognition does not proceed in a strictly serial way from left to right, or is strictly constrained by invisible word boundaries. (PsycINFO Database Record PMID- 27504683 TI - Morphine-Modified Hepatobiliary Scanning Protocol for the Diagnosis of Acute Cholecystitis. AB - OBJECTIVE: We report a morphine-modified hepatoiminodiacetic acid (HIDA) scanning protocol that uses 2 mg of morphine IV push at the bedside as a pretreatment. We compared this protocol with the original HIDA scanning protocol, which included delayed imaging for up to 4 hours without the use of morphine. Moreover, we contrast our results with the results of studies in the literature. MATERIALS AND METHODS: We retrospectively reviewed the charts of inpatients who underwent HIDA scanning for the diagnosis of acute cholecystitis between 2003 and 2013. The study group consisted of 374 HIDA studies of 365 patients who received 2 mg of morphine IV push at bedside and then underwent dynamic imaging for 1 hour using 222 MBq of 99mTc-mebrofenin. No delayed images were obtained. The control group consisted of 232 studies of 227 patients who underwent conventional HIDA scanning using our standard protocol with delayed imaging and without morphine. Either strict pathologic criteria or the results of a percutaneous gallbladder drainage procedure were used for the confirmation of acute cholecystitis. RESULTS: The true-negative rate in the study group was 77% and in the control group, 72%. The positive predictive value in the study group was 81% and in the control group, 45%. The negative predictive value in the study group was 98% and in the control group, 99%. The accuracy in the study group was 95% and in the control group, 84%. The sensitivity in the study group was 93% and in the control group, 93%. The specificity in the study group was 95% and in the control group, 83%. The differences in the true-negative rate, accuracy, specificity, and positive predictive value of the morphine-modified protocol used for the study group and the original protocol used for the control group were statistically significant (p < 0.0005). CONCLUSION: Pretreatment using 2 mg of IV morphine at bedside before radionuclide imaging is superior to routine HIDA scanning with only delayed images for the diagnosis of acute cholecystitis. The results of our pretreatment morphine-modified protocol are comparable to those reported in the literature for posttreatment morphine-augmented protocols. PMID- 27504684 TI - Feasibility of free-breathing dynamic contrast-enhanced MRI of the abdomen: a comparison between CAIPIRINHA-VIBE, Radial-VIBE with KWIC reconstruction and conventional VIBE. AB - OBJECTIVE: To evaluate the feasibilities of controlled aliasing in parallel imaging results in higher acceleration with volumetric interpolated breath-hold examination (CAIPIRINHA-VIBE), radial acquisition of VIBE (Radial-VIBE) with k space-weighted image contrast (KWIC) reconstruction (KWIC-Radial-VIBE) and conventional-VIBE (c-VIBE) for free-breathing dynamic contrast-enhanced (DCE)-MRI of the abdomen. METHODS: 23 prospectively enrolled patients underwent DCE-MRI of the abdomen with CAIPIRINHA-VIBE (n = 10), KWIC-Radial-VIBE (n = 6) or c-VIBE (n = 7). Qualitative image quality of the DCE-MR images and perfusion maps was independently scored by two abdominal radiologists using a 5-point scale (from 1, uninterpretable, to 5, very good). For quantitative analysis, the signal-to-noise ratio (SNR) of the liver and goodness-of-fit (GOF) of the time-intensity curve were measured. RESULTS: In the three tested sequences, DCE-MRI had good temporal (5 s) and spatial resolution (1.48 * 1.48 * 4 mm/voxel). Interobserver agreement in the qualitative analysis was good (K = 0.753; 95% confidence interval, 0.610 0.895). Therefore, the mean scores were used in the data analysis. Overall image quality was comparable between CAIPIRINHA-VIBE (3.52 +/- 0.55) and KWIC-Radial VIBE (3.72 +/- 0.37; p = 1.000), and both were significantly better than c-VIBE (2.71 +/- 0.34; p < 0.001). Perfusion map quality score was highest with KWIC Radial-VIBE (4.33 +/- 0.65), followed by CAIPIRINHA-VIBE (3.70 +/- 0.73) and c VIBE (3.14 +/- 0.66), but without statistical significance between CAIPIRINHA VIBE and KWIC-Radial-VIBE (p = 0.167). The SNR of the liver and GOF of the time intensity curve did not significantly differ between the three sequences (p = 0.116 and 0.224, respectively). CONCLUSION: CAIPIRINHA-VIBE and KWIC-Radial-VIBE provide comparably better performance than c-VIBE. Both can be feasible sequences with acceptable good image quality for free-breathing DCE-MRI. ADVANCES IN KNOWLEDGE: CAIPIRINHA-VIBE and KWIC-Radial-VIBE provide comparably better quality of free-breathing DCE-MRIs than c-VIBE. PMID- 27504685 TI - Introduction of President Mark E. Siddall. PMID- 27504686 TI - Electrochemical sensing of bisphenol using a multilayer graphene nanobelt modified photolithography patterned platinum electrode. AB - An electrochemical sensor has been developed for the detection of Bisphenol-A (BPA) using photolithographically patterned platinum electrodes modified with multilayer graphene nanobelts (GNB). Compared to bare electrodes, the GNB modified electrode exhibited enhanced BPA oxidation current, due to the high effective surface area and high adsorption capacity of the GNB. The sensor showed a linear response over the concentration range from 0.5 MUM-9 MUM with a very low limit of detection = 37.33 nM. In addition, the sensor showed very good stability and reproducibility with good specificity, demonstrating that GNB is potentially a new material for the development of a practical BPA electrochemical sensor with application in both industrial and plastic industries. PMID- 27504687 TI - Editorial: Indicators of OTJR's Growth and Success. PMID- 27504688 TI - Caregivers' Impressions Predicting Fitness to Drive in Persons With Parkinson's. AB - Parkinson's disease (PD) is a common neurodegenerative disease, increasing in incidence, with a known impact on fitness to drive. Although great progress has been made on evidence-based guidelines for assessing fitness to drive of persons with PD, a need remains for early identification of at-risk drivers in need of comprehensive assessment. This study investigated whether caregivers of drivers with PD could predict the driver's on-road outcome. We also investigated whether the predictive value of their impressions differed from that of drivers themselves, their neurologist, or from information provided by standardized measures of visual and divided attention. Caregivers' risk impressions (odds ratio [OR] = 13.76, p = .03) and Trail Making Test Part B (Trails B; OR = 0.41, p = .02) emerged as significant predictors of passing an on-road assessment. Our findings suggest that caregiver impressions, with a measure of set shifting, may be used as an efficient screen to identify drivers with PD who are potentially at risk for failing an on-road assessment. PMID- 27504689 TI - Quality and Reporting of Cluster Randomized Controlled Trials Evaluating Occupational Therapy Interventions: A Systematic Review. AB - Growing use of cluster randomized control trials (RCTs) in health care research requires careful attention to study designs, with implications for the development of an evidence base for practice. The objective of this study is to investigate the characteristics, quality, and reporting of cluster RCTs evaluating occupational therapy interventions to inform future research design. An extensive search of cluster RCTs evaluating occupational therapy was conducted in several databases. Fourteen studies met our inclusion criteria; four were protocols. Eleven (79%) justified the use of a cluster RCT and accounted for clustering in the sample size and analysis. All full studies reported the number of clusters randomized, and five reported intercluster correlation coefficients (50%): Protocols had higher compliance. Risk of bias was most evident in unblinding of participants. Statistician involvement was associated with improved trial quality and reporting. Quality of cluster RCTs of occupational therapy interventions is comparable with those from other areas of health research and needs improvement. PMID- 27504690 TI - Understanding Family Interaction Patterns in Families With Alzheimer's Disease. AB - This qualitative study explores the dynamic changes that occur in family interaction patterns when Alzheimer's disease is present. Semi-structured interviews were conducted with 15 participants who have a family member with the disease. Using modified analytic induction, guided by the dimensions of the Family Fundamental Interpersonal Relations Orientation (FIRO) Model, participants shared how Alzheimer's disease affected family structure, control dynamics, and intimacy among family members. Findings demonstrate that (a) families reorganize and restructure based on geographic proximity and shifting roles, act out of filial responsibility, and strive to preserve shared meanings and rituals; (b) decision making increases around care of the person with Alzheimer's disease and shifts to the primary caregiver or other family members based on their abilities; and (c) expressions of intimacy intensify while personality is preserved in the person with the disease. The Family FIRO model can inform practitioners using family-centered care with families with Alzheimer's disease. PMID- 27504691 TI - Non-Pharmacological Approaches to Reducing Negative Behavioral Symptoms: A Scoping Review. AB - The management of negative behavioral symptoms among residents with dementia is a challenge that nursing homes face in delivering quality care. This study examines evidence documenting non-pharmacological interventions that reduce negative behavioral symptoms among nursing home residents with dementia and the role occupational therapy practitioners have in this area. A scoping review was completed for intervention studies published from 1987 to 2014, targeting negative behavioral symptoms among nursing home residents above 60 years of age with dementia. Interventions were categorized based on the American Occupational Therapy Association (AOTA) Occupational Therapy Practice Framework. Twenty-two studies met the inclusion criteria. Four types of interventions were identified: occupation-based interventions, context and environment interventions, exercise interventions, and daily routine-based interventions. The non-pharmacological interventions were found to align with the scope of occupational therapy. This suggests that occupational therapy practitioners can contribute to the development and evaluation of non-pharmacological interventions aimed to reduce negative behavioral symptoms. PMID- 27504693 TI - Acid-Catalyzed Multicomponent Tandem Double Cyclization: A One-pot, Metal-free Route to Synthesize Polyfunctional 4,9-Dihydropyrrolo[2,1-b]quinazolines. AB - An acid-catalyzed multicomponent tandem double cyclization protocol has been developed for the synthesis of polyfunctional 4,9-dihydropyrrolo[2,1 b]quinazolines from simple and readily available arylglyoxal monohydrates, 2 aminobenzylamine, and trans-beta-nitrostyrenes. This practical and metal-free reaction proceeds through an imine formation/cyclization/Michael addition/Henry cyclization protocol, resulting in the construction of four new bonds and two ring moieties directly in one pot. PMID- 27504694 TI - The role of encoding strategy in younger and older adult associative recognition: A think-aloud analysis. AB - Older adults have especially poor recognition memory for word pairs, and research suggests this associative deficit manifests primarily in older adults' higher rates of false alarms. This could result from older adults either failing to generate meaningful (deep) mediators at study, or failing to benefit from having generated deep mediators at test. Younger and older adults performed a recognition memory task for words and word pairs. A think-aloud analysis of their spontaneous encoding strategies (repetition, shallow mediators, deep mediators) revealed that generation of deep mediators did not differ between younger and older adults, and was associated with high hit rates for items and associates in both age groups. However, generation of deep mediators was inversely related to false alarm rates in younger adults but not older adults. A trial-level analysis of encoding strategies and recognition responses revealed that younger adults benefited from having generated deep mediators when presented with corresponding recombined pairs at test as shown in their lower false alarm rates. In contrast, older adults who generated deep mediators during study (e.g., to blanket-figure) did not benefit from having done so when they encountered the corresponding recombined pairs at test (blanket-summer and district-figure). Their false alarm rates to pairs at test were unrelated to generation of deep mediators at study. These results suggest that many older adults have difficulty retrieving their mediators when presented with recombined pairs at test, or their mediators are not distinct enough to distinguish intact pairs from recombined pairs at test, or some combination of both. (PsycINFO Database Record PMID- 27504695 TI - "Are vocabulary tests measurement invariant between age groups? An item response analysis of three popular tests": Correction to Fox, Berry, and Freeman (2014). AB - Reports an error in "Are vocabulary tests measurement invariant between age groups? An item response analysis of three popular tests" by Mark C. Fox, Jane M. Berry and Sara P. Freeman (Psychology and Aging, 2014[Dec], Vol 29[4], 925-938). In the article, unneeded zeros were inadvertently included at the beginnings of some numbers in Tables 1-4. In addition, the right column in Table 4 includes three unnecessary zeros after asterisks. (The following abstract of the original article appeared in record 2014-49140-001.) Relatively high vocabulary scores of older adults are generally interpreted as evidence that older adults possess more of a common ability than younger adults. Yet, this interpretation rests on empirical assumptions about the uniformity of item-response functions between groups. In this article, we test item response models of differential responding against datasets containing younger-, middle-aged-, and older-adult responses to three popular vocabulary tests (the Shipley, Ekstrom, and WAIS-R) to determine whether members of different age groups who achieve the same scores have the same probability of responding in the same categories (e.g., correct vs. incorrect) under the same conditions. Contrary to the null hypothesis of measurement invariance, datasets for all three tests exhibit substantial differential responding. Members of different age groups who achieve the same overall scores exhibit differing response probabilities in relation to the same items (differential item functioning) and appear to approach the tests in qualitatively different ways that generalize across items. Specifically, younger adults are more likely than older adults to leave items unanswered for partial credit on the Ekstrom, and to produce 2-point definitions on the WAIS-R. Yet, older adults score higher than younger adults, consistent with most reports of vocabulary outcomes in the cognitive aging literature. In light of these findings, the most generalizable conclusion to be drawn from the cognitive aging literature on vocabulary tests is simply that older adults tend to score higher than younger adults, and not that older adults possess more of a common ability. PMID- 27504696 TI - 25G PARS PLANA VITRECTOMY AND IRIDO-ZONULO-HYALOIDO-VITRECTOMY IN THE MANAGEMENT OF MALIGNANT GLAUCOMA IN PHAKIC EYES FOLLOWING TRABECULECTOMY. AB - PURPOSE: To describe a new surgical technique in the management of malignant glaucoma in phakic eyes. METHODS: We performed 25-gauge pars plana vitrectomy with anterior irido-zonulo-hyaloido-vitrectomy in 2 young phakic patients with malignant glaucoma after trabeculectomy. This technique allowed posteroanterior aqueous communication, relieved aqueous misdirection, helped restoring anterior chamber depth, normalized the intraocular pressure and most importantly helped to preserve the crystalline lens. RESULTS: At 8 months follow-up, both patients have stable visual acuity, normal intraocular pressure, well-functioning blebs, and clear crystalline lens. CONCLUSION: One can consider 25-gauge pars plana vitrectomy with anterior irido-zonulo-hyaloido-vitrectomy as a safe and effective treatment option for the management of malignant glaucoma in phakic eyes. PMID- 27504697 TI - FULL-THICKNESS MACULAR HOLE COMBINED WITH PIGMENT EPITHELIAL DETACHMENT USING MULTIMODAL IMAGING. AB - PURPOSE: To describe two patients who showed full-thickness macular holes (FTMH) combined with pigment epithelial detachments (PED) and had contrasting outcomes to treatment. METHODS: A retrospective report of two cases. RESULTS: Case 1 was treated with intravitreal antivascular endothelial growth factor and photodynamic therapy, and the PED flattened. Subsequently, a vitrectomy was performed and the FTMH closed. Her visual acuity improved from 20/200 to 20/25. In Case 2, the same medical therapy, with less frequency compared with Case 1, did not affect the PED, and the FTMH failed to close with surgery. Later, a spontaneous collapse of the PED occurred but the FTMH was persistent with an associated poor visual acuity of 20/200. CONCLUSION: Full-thickness macular hole is rare, but can occur in association with large PEDs. Although the pathologic mechanism was uncertain, visual outcomes were dependent on response to treatments of the PED, as well as anatomical closure of the FTMH. PMID- 27504698 TI - Charge Density and Electrostatic Potential Study of 16alpha,17beta-Estriol and the Binding of Estrogen Molecules to the Estrogen Receptors ERalpha and ERbeta. AB - An accurate X-ray diffraction study at 20 K combined with DFT theoretical calculations has been performed for the estriol crystal with two conformationally different molecules in the asymmetric unit. The electron density has been modeled via a multipole expansion, using both experimental and theoretical structure factors, and a topological analysis has been performed. The experimental molecular geometry, hydrogen bonding, atomic charges, dipole moments, and other topological characteristics are compared with those calculated theoretically. In particular, the molecular electrostatic potential has been extracted and compared with those reported for other estrogen molecules exhibiting different binding affinities to the estrogen receptors (ERalpha and ERbeta). PMID- 27504699 TI - Fall Prevention in a Primary Care Setting. AB - BACKGROUND: Falls and fall-related injuries are common in community-dwelling elderly people. Effective multifactorial fall prevention programs in the primary care setting may be a promising approach to reduce the incidence rate of falls. METHODS: In a cluster randomized trial in 33 general practices 378 people living independently and at high risk of falling (65 to 94 years old; 285 women) were allocated to either a 16 week exercise-based fall prevention program including muscle strengthening and challenging balance training exercises, combined with a 12 week home-based exercise program (222 participants), or to usual care (156 participants). The main outcome was number of falls over a period of 12 months. Secondary outcomes were the number of fall-related injuries, physical function (Timed-Up-and-Go-Test, TUG, Chair-Stand-Test, CST, modified Romberg Test), and fear of falling. RESULTS: In the intervention group (n=222 patients in 17 general practices) 291 falls occurred, compared to 367 falls in the usual care group (n=156 patients in 16 general practices). We observed a lower incidence rate for falls in the intervention group (incidence rate ratio/IRR: 0.54; 95% confidence interval (CI): [0.35; 0.84], p=0.007) and for fall-related injuries (IRR: 0.66; [0.42; 0.94], p=0.033). Additionally, patients in the intervention group showed significant improvements in secondary endpoints (TUG: -2.39 s, [-3.91; -0.87], p=0.014; mRomberg: 1.70 s, [0.35; 3.04], p=0.037; fear of falling: -2.28 points, [-3.87; -0.69], p=0.022) compared to usual care. CONCLUSION: A complex falls prevention program in a primary care setting was effective in reducing falls and fall-related injuries in community dwelling older adults at risk. PMID- 27504700 TI - Prospective Studies from Germany Are Lacking. PMID- 27504701 TI - In Reply. PMID- 27504702 TI - Relevant Errors Relating to the Measuring Method. PMID- 27504703 TI - In Reply. PMID- 27504704 TI - Intra-arterial Treatment. PMID- 27504705 TI - Hemodilution. PMID- 27504706 TI - In Reply. PMID- 27504707 TI - The Diagnosis and Treatment of Hair and Scalp Diseases. AB - BACKGROUND: Hair loss is caused by a variety of hair growth disorders, each with its own pathogenetic mechanism. METHODS: This review is based on pertinent articles retrieved by a selective search in PubMed, on the current German and European guidelines, and on the authors' clinical and scientific experience. RESULTS: Excessive daily hair loss (effluvium) may be physiological, as in the postpartum state, or pathological, due for example to thyroid disturbances, drug effects, iron deficiency, or syphilis. Androgenetic alopecia generally manifests itself in women as diffuse thinning of the hair over the top of the scalp, and in men as receding temporal hairlines and loss of hair in the region of the whorl on the back of the head. Alopecia areata is patchy hair loss arising over a short time and involving the scalp, eyebrows, beard, or entire body. The hair loss of alopecia areata is reversible in principle but hard to treat. Folliculitis decalvans is a form of alopecia with scarring, characterized by inflamed papules, pustules, and crusts at the edges of the lesions. Lichen planopilaris generally presents with small patches of baldness, peripilar erythema, and round areas of skin scaling. Kossard's frontal fibrosing alopecia is characterized by a receding hairline and loss of eyebrows. CONCLUSION: Hair loss is a symptom, not a diagnosis. The pathogenesis of the alopecias involves a range of genetic, endocrine, immune, and inflammatory processes, each of which calls for its own form of treatment. PMID- 27504708 TI - Decoration of silicon nanowires with silver nanoparticles for ultrasensitive surface enhanced Raman scattering. AB - Silicon nanowires (Si NWs), produced by the chemical etching technique, were decorated with silver nanoparticles (NPs) produced at room temperature by the pulsed laser deposition (PLD) technique. Silver NPs were obtained by means of nanosecond pulsed laser ablation of a target in the presence of a controlled Ar atmosphere. Two different laser pulse numbers and Si NWs having different lengths were used to change the NP number density on the Si NW surface. The resulting Ag NP morphologies were studied by scanning electron microscopy imaging. The results show that this industrially compatible technological approach allows the coverage of the Si NW walls with Ag NPs with a strong control of the NP size distribution and spatial arrangement. The obtained Ag NP decorated Si NWs are free from chemicals contamination and there is no need of post deposition high temperature processes. The optical properties of Si NW arrays were investigated by reflectance spectroscopy that showed the presence of a plasmon related absorption peak, whose position and width is dependent on the Ag NP surface morphology. Coupling the huge surface-to-volume ratio of Si NW arrays with the plasmonic properties of silver nanoparticles resulted in a 3D structure suitable for very sensitive surface enhanced Raman scattering (SERS) applications, as demonstrated by the detection of Rhodamine 6G in aqueous solution at a concentration level of 10(-8) M. PMID- 27504709 TI - Association of Xerostomia and Ultrasonographic Features of the Major Salivary Glands After Radioactive Iodine Ablation for Papillary Thyroid Carcinoma. AB - OBJECTIVE: The objective of this study is to evaluate the association between xerostomia and sonographic features of the major salivary glands after patients undergo radioactive iodine ablation (RIA) for papillary thyroid carcinoma (PTC). MATERIALS AND METHODS: The study included 256 consecutive patients who underwent total thyroidectomy, RIA, and neck ultrasound examinations. Changes in the ultrasound features of the parotid and submandibular glands after RIA were evaluated retrospectively by a single radiologist, on the basis of direct comparison of sonograms obtained before and after RIA. Clinical data, including the presence of xerostomia, were investigated retrospectively by the same radiologist via a review of the electronic medical records. RESULTS: For 111 of the 256 patients (43.4%), ultrasound examination revealed changes in the major salivary glands after RIA. The presence of xerostomia was undetermined in 85 of the 256 patients. Among the remaining 171 patients, the frequency of xerostomia was 36.8% (63/171). When patients with xerostomia were compared with those without xerostomia, no statistically significant differences in patient sex and age, the dose of RIA received, or the number of RIA sessions were noted (p > 0.05). Considering the changes in the ultrasound features of the major salivary glands after RIA, no statistically significant association was found between xerostomia and the number of involved major salivary glands or the presence of an involved submandibular gland (p > 0.05). CONCLUSION: In this study, ultrasound was unhelpful for evaluating xerostomia after RIA in patients with PTC. PMID- 27504710 TI - Using two tools to identify Potentially Inappropriate Medications (PIM) in elderly patients in Southern Chile. AB - OBJECTIVES: To assess and compare the prevalence of prescribing of potentially inappropriate medications (PIMs) identified using the Beers and STOPP criteria; and to determine the clinical variables related with the prescription of PIMs in older adults. METHODS: An observational study of 250 patients aged 65 years or older was conducted in a large teaching hospital. Beers (2012) and STOPP (2008) criteria were utilized to identify PIMs. Data on age, sex, admission and discharge dates, diagnoses, and medications prescribed were obtained from medical records. Multivariate logistic regression was used to determine patient variables related with the prescription of PIMs. KEY FINDINGS: Using Beers criteria, 375 PIMs were identified in 198 patients. 32% of these patients were prescribed one PIM, 20% were prescribed two PIMs, and 48% were prescribed more than two PIMs. Using STOPP criteria, 148 PIMs were identified in 120 patients. 41% of these patients were prescribed one PIM, 51% were prescribed two PIMs, and 8% were prescribed more than two PIMs. An association between PIM prescribing and polypharmacy was detected with both criteria. After adjusting for confounding variables, the prescription of Beers-identified PIMs was significantly associated with patients older than 80 (OR: 2.99; 95% CI: 1.13-7.89) and with length of hospital stay of more than 15days (OR: 2.78; 95% CI: 1.20-6.44). CONCLUSION: These two criteria showed that the prescription of PIMs is prevalent in hospitalized elderly patients. It may be beneficial to educate healthcare teams about these criteria to reduce the prescription of PIMs. PMID- 27504711 TI - Use of NMR-Based Metabolomics To Chemically Characterize the Roasting Process of Chicory Root. AB - Roasted chicory root (Cichorium intybus) has been widely accepted as the most important coffee substitute. In this study, a nuclear magnetic resonance (NMR) based comprehensive analysis was performed to monitor the substantial changes in the composition of chicory root during the roasting process. A detailed signal assignment of dried raw and roasted chicory roots was carried out using 1H, 13C, 1H-1H DQF-COSY, 1H-13C edited-HSQC, 1H-13C CT-HMBC, and 1H-13C HSQC-TOCSY NMR spectra. On the basis of the signal assignments, 36 NMR-visible components were monitored simultaneously during roasting. Inulins, sucrose, and most of the amino acids were largely degraded during the roasting process, whereas monosaccharides decreased at the beginning and then increased until the dark roasting stage. Acetamide, 5-hydroxymethylfurfural, di-d-fructose dianhydride, and norfuraneol were newly formed during roasting. Furthermore, a principal component analysis score plot indicated that similar chemical composition profiles could be achieved by roasting the chicory root either at a higher firepower for a shorter time or at a lower firepower for a longer time. PMID- 27504712 TI - MAP4K4 deficiency in CD4(+) T cells aggravates lung damage induced by ozone oxidized black carbon particles. AB - As the main composition of combustion, black carbon (BC) is becoming more and more noticeable at home and abroad. Ozone-oxidized black carbon (oBC) was produced through aging of ozone, one of the near-surface pollutants, to black carbon. And oBC was found to be more oxidation and cell toxicity when compared with BC. Besides, as a key cell of immunity, whether CD4(+) T cell would involve in lung inflammation induced by particular matter is still unclear. This study aims to observe the effect of oBC on lung damage in mice and discuss how the functional MAP4K4 defect CD4(+) T cells (conditional knockout of MAP4K4) presents its role in this process. In our study, MAP4K4 deletion in CD4(+) T cells (MAP4K4 cKO) could increase cell number of macrophages, lymphocytes and neutrophils in bronchoalveolar lavage fluid (BALF) exposed to oBC. MAP4K4 deletion in CD4(+) T cell also affected CD4(+) T cell differentiation in mediastinal lymph nodes after oBC stimulation. The number of CD4(+) IL17(+) T cell increased obviously. The levels of IL-6 mRNA of lung in MAP4K4 cKO mice was higher than that in wild type mice after exposed to oBC, while the level of IL-6 in BALF had the same trend. Histological examination showed that MAP4K4 deletion in CD4(+) T cells affected lung inflammation induced by oBC. Results indicated that MAP4K4 cKO in CD4(+) T cells upgraded the level of inflammation in lung when exposed to oBC, which may be connected to the CD4(+) T cell differentiation and JNK, ERK and P38 pathways. PMID- 27504713 TI - Comparison of ferumoxytol-enhanced MRA with conventional angiography for assessment of severity of transplant renal artery stenosis. AB - PURPOSE: To determine the accuracy of ferumoxytol-enhanced magnetic resonance angiography (MRA) in assessing the severity of transplant renal artery stenosis (TRAS), using digital subtraction angiography (DSA) as the reference standard. MATERIALS AND METHODS: Our Institutional Review Board approved this retrospective, Health Insurance Portability and Accountability Act-compliant study. Thirty-three patients with documented clinical suspicion for TRAS (elevated serum creatinine, refractory hypertension, edema, and/or audible bruit) and/or concerning sonographic findings (elevated renal artery velocity and/or intraparenchymal parvus tardus waveforms) underwent a 1.5T MRA with ferumoxytol prior to DSA. All DSAs were independently reviewed by an interventional radiologist and served as the reference standard. The MRAs were reviewed by three readers who were blinded to the ultrasound and DSA findings for the presence and severity of TRAS. Sensitivity, specificity, and accuracy for identifying substantial stenoses (>50%) were determined. Intraclass correlation coefficients (ICCs) were calculated among readers. Mean differences between the percent stenosis from each MRA reader and DSA were calculated. RESULTS: On DSA, a total of 42 stenoses were identified in the 33 patients. The sensitivity, specificity, and accuracy of MRA in detecting substantial stenoses were 100%, 75-87.5%, and 95.2-97.6%, respectively, among the readers. There was excellent agreement among readers as to the percent stenosis (ICC = 0.82). MRA overestimated the degree of stenosis by 3.9-9.6% compared to DSA. CONCLUSION: Ferumoxytol-enhanced MRA provides high sensitivity, specificity, and accuracy for determining the severity of TRAS. Our results suggest that it can potentially be used as a noninvasive examination following ultrasound to reduce the number of unnecessary conventional angiograms. LEVEL OF EVIDENCE: 3 J. Magn. Reson. Imaging 2017;45:779-785. PMID- 27504714 TI - Could MRI Become the First-Line Investigation in Suspected Appendicitis? PMID- 27504715 TI - Shuttling of (deoxy-) purine nucleotides between compartments of the diatom Phaeodactylum tricornutum. AB - Diatom plastids show several peculiarities when compared with primary plastids of higher plants or algae. They are surrounded by four membranes and depend on nucleotide uptake because, unlike in plants, nucleotide de novo synthesis exclusively occurs in the cytosol. Previous analyses suggest that two specifically adapted nucleotide transporters (NTTs) facilitate the required passage of nucleotides across the innermost plastid membrane. However, nucleotide transport across the additional plastid membranes remains to be clarified. Phylogenetic studies, transport assays with the recombinant protein as well as GFP-based targeting analyses allowed detailed characterization of a novel isoform (PtNTT5) of the six NTTs of Phaeodactylum tricornutum. PtNTT5 exhibits low amino acid similarities and is only distantly related to all previously characterized NTTs. However, in a heterologous expression system, it acts as a nucleotide antiporter and prefers various (deoxy-) purine nucleotides as substrates. Interestingly, PtNTT5 is probably located in the endoplasmic reticulum, which in diatoms also represents the outermost plastid membrane. PtNTT5, with its unusual transport properties, phylogeny and localization, can be taken as further evidence for the establishment of a sophisticated and specifically adapted nucleotide transport system in diatom plastids. PMID- 27504716 TI - Genes Interacting with Occupational Exposures to Low Molecular Weight Agents and Irritants on Adult-Onset Asthma in Three European Studies. AB - BACKGROUND: The biological mechanisms by which cleaning products and disinfectants-an emerging risk factor-affect respiratory health remain incompletely evaluated. Studying genes by environment interactions (G * E) may help identify new genes related to adult-onset asthma. OBJECTIVES: We identified interactions between genetic polymorphisms of a large set of genes involved in the response to oxidative stress and occupational exposures to low molecular weight (LMW) agents or irritants on adult-onset asthma. METHODS: Our data came from three large European cohorts: Epidemiological Family-based Study of the Genetics and Environment of Asthma (EGEA), Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA), and European Community Respiratory Health Survey in Adults (ECRHS). A candidate pathway-based strategy identified 163 genes involved in the response to oxidative stress and potentially related to exposures to LMW agents/irritants. Occupational exposures were evaluated using an asthma job-exposure matrix and job-specific questionnaires for cleaners and healthcare workers. Logistic regression models were used to detect G * E interactions, adjusted for age, sex, and population ancestry, in 2,599 adults (mean age, 47 years; 60% women, 36% exposed, 18% asthmatics). p-Values were corrected for multiple comparisons. RESULTS: Ever exposure to LMW agents/irritants was associated with current adult-onset asthma [OR = 1.28 (95% CI: 1.04, 1.58)]. Eight single nucleotide polymorphism (SNP) by exposure interactions at five loci were found at p < 0.005: PLA2G4A (rs932476, chromosome 1), near PLA2R1 (rs2667026, chromosome 2), near RELA (rs931127, rs7949980, chromosome 11), PRKD1 (rs1958980, rs11847351, rs1958987, chromosome 14), and PRKCA (rs6504453, chromosome 17). Results were consistent across the three studies and after accounting for smoking. CONCLUSIONS: Using a pathway-based selection process, we identified novel genes potentially involved in adult asthma by interaction with occupational exposure. These genes play a role in the NF kappaB pathway, which is involved in inflammation. Citation: Rava M, Ahmed I, Kogevinas M, Le Moual N, Bouzigon E, Curjuric I, Dizier MH, Dumas O, Gonzalez JR, Imboden M, Mehta AJ, Tubert-Bitter P, Zock JP, Jarvis D, Probst-Hensch NM, Demenais F, Nadif R. 2017. Genes interacting with occupational exposures to low molecular weight agents and irritants on adult-onset asthma in three European studies. Environ Health Perspect 125:207-214; http://dx.doi.org/10.1289/EHP376. PMID- 27504717 TI - Positional plagiocephaly reduces parental adherence to SIDS Guidelines and inundates the health system. AB - BACKGROUND: This study sought to better understand parent, grandparent and clinician views of prevention, treatment and costs of plagiocephaly. METHODS: A qualitative study was conducted using focus groups and semi-structured interviews. A grounded theory approach was taken to build theories from the qualitative data collected. A subjectivist epistemological orientation was taken under the paradigm of positivism. RESULTS: Ninety-one parents, 6 grandparents and 24 clinicians were recruited from the community as well as primary and tertiary care clinics. Plagiocephaly worried most parents because it could permanently affect their child's 'looks' and some thought it would affect a child's development. Parents were 'willing to do anything' to prevent plagiocephaly including using products or sleeping positions that are contraindicated under sudden infant death syndrome guidelines. Parents found the care pathway convoluted and inconsistent messages were given from different health providers. For clinicians, the high prevalence of flat head is 'clogging up their patient pool', taking up time they used to spend with children with more severe conditions. CONCLUSION: There is a need to re-emphasize sudden infant death syndrome guidelines for families when they present with an infant with plagiocephaly. Stronger messaging regarding the lack of safety of current pillows marketed to prevent flat head may be useful to decrease their use. Increasing education for all health professionals including general practitioners, allied health and complementary health providers and standardizing assessment and referral criteria may allow the majority of diagnosis and treatment of positional plagiocephaly to occur at points of first contact (e.g. general practitioners, community nurse) and may prevent further burden on the health care system. PMID- 27504718 TI - Chemoselective Preparation of Clickable Aryl Sulfonyl Fluoride Monomers: A Toolbox of Highly Functionalized Intermediates for Chemical Biology Probe Synthesis. AB - Sulfonyl fluoride (SF)-based activity probes have become important tools in chemical biology. Herein, exploiting the relative chemical stability of SF to carry out a number of unprecedented SF-sparing functional group manipulations, we report the chemoselective synthesis of a toolbox of highly functionalized aryl SF monomers that we used to quickly prepare SF chemical biology probes. In addition to SF, the monomers bear an embedded click handle (a terminal alkyne that can perform copper(I)-mediated azide-alkyne cycloaddition). The monomers can be used either as fragments to prepare clickable SF analogues of drugs (biologically active compounds) bearing an aryl ring or, alternatively, attached to drugs as minimalist clickable aryl SF substituents. PMID- 27504719 TI - Encapsulation of Perovskite Solar Cells for High Humidity Conditions. AB - We examined different encapsulation strategies for perovskite solar cells by testing the device stability under continuous illumination, elevated temperature (85 degrees C) and ambient humidity of 65 %. The effects of the use of different epoxies, protective layers and the presence of desiccant were investigated. The best stability (retention of ~80 % of initial efficiency on average after 48 h) was obtained for devices protected by a SiO2 film and encapsulated with a UV curable epoxy including a desiccant sheet. However, the stability of ZnO-based cells encapsulated by the same method was found to be inferior to that of TiO2 based cells. Finally, outdoor performance tests were performed for TiO2 -based cells (30-90 % ambient humidity). All the stability tests were performed following the established international summit on organic photovoltaic stability (ISOS) protocols for organic solar cell testing (ISOS-L2 and ISOS-O1). PMID- 27504720 TI - Characterization of Medication Velocity and Size Distribution from Pressurized Metered-Dose Inhalers by Phase Doppler Anemometry. AB - BACKGROUND: Particle size and velocity are two of the most significant factors that impact the deposition of pressurized metered-dose inhaler (pMDI) sprays in the mouth cavity. pMDIs are prominently used around the world in the treatment of patients suffering from a variety of lung diseases such as asthma and chronic obstructive pulmonary disease. Since their introduction in the field, and as a result of their effectiveness and simplicity of usage, pMDIs are considered to be the most widely prescribed medical aerosol delivery system. METHODS: In the current study, particle velocity and size distribution were measured at three different locations along the centerline of a pMDI spray using Phase Doppler Anemometry. pMDIs from four different pharmaceutical companies were tested, each using salbutamol sulfate as the medication. RESULTS AND CONCLUSIONS: Measurements along at the pMDI centerline (at 0, 75, and 100 mm downstream of the inhaler mouthpiece) showed that the spray velocities were bimodal in time for all four pMDI brands. The first peak occurred as the spray was leaving the mouthpiece, while the second peak (at the same location, 0 mm) occurred at around 60, 95, 95, and 115 milliseconds later, respectively, for the four tested inhalers, with a drop in the velocity between the two peaks. Three probability density functions (PDFs) were tested, and the Rosin-Rammler PDF best fit the empirical data, as determined using a chi-squared test. These results suggest that there is a difference in the mean particle velocities at the centerline for the tested pMDIs and the diameter of released particles varied statistically for each brand. PMID- 27504721 TI - Dithiocarbamate Self-Assembled Monolayers as Efficient Surface Modifiers for Low Work Function Noble Metals. AB - Tuning the work function of the electrode is one of the crucial steps to improve charge extraction in organic electronic devices. Here, we show that N,N-dialkyl dithiocarbamates (DTC) can be effectively employed to produce low work function noble metal electrodes. Work functions between 3.1 and 3.5 eV are observed for all metals investigated (Cu, Ag, and Au). Ultraviolet photoemission spectroscopy (UPS) reveals a maximum decrease in work function by 2.1 eV as compared to the bare metal surface. Electronic structure calculations elucidate how the complex interplay between intrinsic dipoles and dipoles induced by bond formation generates such large work function shifts. Subsequently, we quantify the improvement in contact resistance of organic thin film transistor devices with DTC coated source and drain electrodes. These findings demonstrate that DTC molecules can be employed as universal surface modifiers to produce stable electrodes for electron injection in high performance hybrid organic optoelectronics. PMID- 27504722 TI - Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N-Oxide Lewis Base Catalysts. AB - Atropisomeric biaryl pyridine and isoquinoline N-oxides were synthesized enantioselectively by dynamic kinetic resolution (DKR) of rapidly racemizing precursors exhibiting free bond rotation. The DKR was achieved by ketoreductase (KRED) catalyzed reduction of an aldehyde to form a configurationally stable atropisomeric alcohol, with the substantial increase in rotational barrier arising from the loss of a bonding interaction between the N-oxide and the aldehyde. Use of different KREDs allowed either the M or P enantiomer to be synthesized in excellent enantiopurity. The enantioenriched biaryl N-oxide compounds catalyze the asymmetric allylation of benzaldehyde derivatives with allyltrichlorosilane. PMID- 27504723 TI - [Editor's Comment]. PMID- 27504724 TI - [Needle electromyography of facial muscles]. PMID- 27504725 TI - [Not Available]. PMID- 27504726 TI - [Lipoid Pneumonia Associated with Lipid-Containing Nasal Sprays and Nose Drops]. AB - BACKGROUND: Regularly updating the German pharmacopoeia on contemporary preparations DAC/NRF, chapter "Nasal Applications" and the recommendations on "Nasal Oils" as well as "Nasal Ointments and Emulsions", the issue of the risk of lipoid pneumonia associated with the use of plant oils and when compared to mineral oils arose. MATERIAL AND METHODS: We searched different databases: the "Grosse Deutsche Arzneimittelspezialitaten-Taxe" containing all products available in German pharmacies, the Cochrane Library, the pharmacovigilance database of the BfArM, and Medline to evaluate the benefit/risk-ratio of plant oils in nasal drops and sprays. RESULTS: In German pharmacies, a number of both, mineral oil-containing drugs for nasal application and plant oil-containing medical devices are available. The risk of lipoid pneumonia described for mineral oil-containing nasal products can not entirely be transferred to plant oil containing products. However, evidence from the literature suggests a risk for lipoid pneumonia, which needs to be considered given the non-proven efficacy of such medical devices in the majority of proposed indications. To minimize risks, recommendations are made for patient groups that should not use lipid-containing nasal products. CONCLUSIONS: Acknowledging the potential lethal outcome of lipoid pneumonia, a demanding diagnosis, and absence of a specific therapy, lipid containing nasal products should be used only with great caution. Based on the current knowledge, the statements regarding the risk of lipoid pneumonia for lipid-containing nasal products in the DAC/NRF should not be modified. PMID- 27504727 TI - [Eustachian Tube Dilatation? What are the Pros?]. PMID- 27504728 TI - [Eustachian Tube Dilatation? What are the Cons?]. PMID- 27504729 TI - [Not Available]. PMID- 27504730 TI - [Headache and Degraded Speech Recognition in a Patient with Unilateral Cochlear Implant]. PMID- 27504731 TI - [Cave on Early Discharge Against Medical Advises: More Liability Less Money]. PMID- 27504732 TI - [Not Available]. PMID- 27504734 TI - [Not Available]. PMID- 27504733 TI - [Not Available]. PMID- 27504736 TI - Microencapsulation of advanced solvents for carbon capture. AB - Purpose-designed, water-lean solvents have been developed to improve the energy efficiency of CO2 capture from power plants, including CO2-binding organic liquids (CO2BOLs) and ionic liquids (ILs). Many of these solvents are highly viscous or change phases, posing challenges for conventional process equipment. Such problems can be overcome by encapsulation. Micro-Encapsulated CO2 Sorbents (MECS) consist of a CO2-absorbing solvent or slurry encased in spherical, CO2 permeable polymer shells. The resulting capsules have diameters in the range of 100-600 MUm, greatly increasing the surface area and CO2 absorption rate of the encapsulated solvent. Encapsulating these new solvents requires careful selection of shell materials and fabrication techniques. We find several common classes of polymers are not compatible with MECS production, but we develop two custom formulations, a silicone and an acrylate, that show promise for encapsulating water-lean solvents. We make the first demonstration of an encapsulated IL for CO2 capture. The rate of CO2 absorption is enhanced by a factor of 3.5 compared to a liquid film, a value that can be improved by further development of shell materials and fabrication techniques. PMID- 27504737 TI - The induction of CXCR4 expression in human osteoblast-like cells (MG63) by CoCr particles is regulated by the PLC-DAG-PKC pathway. AB - BACKGROUND: Osteolysis which leads to aseptic loosening of implants is a fundamental problem in joint replacement surgery (arthroplasty) and the leading cause for implant failure and revision surgery. Metal (CoCr) particles separated from implants by wear cause osteolysis and the failure of orthopedic implants, but the molecular mechanism is not clear. The chemokine receptor CXCR4 has been shown to play a pivotal role in periprosthetic osteolysis. The aim of this study was to determine which signal transduction pathway (PLC-DAG-PKC or MAPK/ERK) induces CXCR4 expression in osteoblast-like cells (MG63) cells. METHODS: MG63 and Jurkat cells were stimulated with different amounts of particles (107 , 106 , and 105 ) for different time periods (30 min to 24 h), in the presence and absence of specific inhibitors (chelerythrine for the PLC-DAG-PKC pathway and PD98059 for the MAPK/ERK pathway). The expression of CXCR4-specific mRNA was determined by real-time polymerase chain reaction (PCR), and the PKC activity was measured by Western Blot using an antibody specific for PKC-related phosphorylation. RESULTS: Real-time PCR data showed that CXCR4 mRNA expression in MG63 cells induced by CoCr particles was significantly diminished by the PKC-specific inhibitor chelerythrine. This effect was not observed with the MAPK/ERK inhibitor PD98059. The involvement of PKC was also confirmed by an intensified phosphorylation pattern after stimulation with CoCr particles. In Jurkat cells, none of the inhibitors exhibited any effect. CONCLUSION: The induction of CXCR4-specific mRNA expression in MG63 cells after stimulation with CoCr particles is regulated by the PLC-DAG-PKC pathway and not by the MAPK/ERK pathway. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2326-2332, 2017. PMID- 27504738 TI - Near-Infrared Polymeric Nanoparticles with High Content of Cyanine for Bimodal Imaging and Photothermal Therapy. AB - The discovery and synthesis of theranostic nanomedicines with high loading of imaging and therapeutic agents is challenging. In this work, a polymer assembling strategy was used to make nanoparticles with exceptionally high loading of theranostic agent. As an example, poly(heptamethine) was synthesized via multicomponent Passerini reaction, and then assembled into nanoparticles in the presence of poly(ethylene glycol)2k-block-poly(d,l-lactide)2k (PEG-PLA) with high heptamethine loading (>50%). The formed nanoparticles could be used for bimodal bioimaging and photothermal therapy. The bimodal bioimaging provided complementary message about biodistribution, and photothermal treatment inhibited the growth of cervical carcinoma upon laser irradiation. This assembly of polymers formed by imaging and therapeutic agents opens new possibilities for the construction of multifunctional nanomedicines. PMID- 27504739 TI - Methylglyoxal is associated with changes in kidney function among individuals with screen-detected Type 2 diabetes mellitus. AB - AIMS: The glycolysis-derived metabolite methylglyoxal has been linked to clinical microvascular complications, including diabetic nephropathy. We aimed to further investigate the hypothesis that methylglyoxal is involved in decline in renal function by assessing the associations between measures of renal function during a 6-year follow-up in 1481 people with screen-detected Type 2 diabetes, as part of the Danish arm of the ADDITION-Europe trial (ADDITION-DK). METHODS: Biobank serum samples collected at ADDITION-DK baseline (2001-2006) and follow-up (2009 2010) were used in the current analysis of methylglyoxal. We assessed cross sectional baseline and longitudinal associations between methylglyoxal and urinary albumin-to-creatinine ratio (ACR) or estimated GFR (eGFR), and between methylglyoxal and categories of albuminuria or reduced eGFR. RESULTS: Baseline methylglyoxal was positively associated with ACR at baseline (12% higher ACR per doubling in methylglyoxal levels), and change in methylglyoxal during 6 years of follow-up was inversely associated with change in eGFR (-1.6 ml/min/1.73 m2 per doubling in methylglyoxal change), in models adjusted for age, sex, HbA1c , systolic blood pressure, anti-hypertensive treatment, LDL-cholesterol, lipid lowering treatment, C-reactive protein and smoking. CONCLUSIONS: In a population of people with screen-detected Type 2 diabetes, we observed associations between methylglyoxal and markers of renal function: 6-year change in methylglyoxal was inversely associated with 6-year change in eGFR. Also, methylglyoxal at baseline was positively associated with ACR at baseline. Our study lends further support to a role for methylglyoxal in the pathogenesis of diabetic nephropathy. PMID- 27504740 TI - Influence of the anti-inflammatory cytokine interleukin-4 on human joint capsule myofibroblasts. AB - Post-traumatic joint contracture was reported to be associated with elevated numbers of contractile myofibroblasts (MFs) in the healing capsule. During the physiological healing process, the number of MFs declines; however, in fibroconnective disorders, MFs persist. The manifold interaction of the cytokines regulating the appearance and persistence of MFs in the pathogenesis of joint contracture remains to be elucidated. The objective of our current study was to analyze the impact of the anti-inflammatory cytokine interleukin (IL)-4 on functional behavior of MFs. Cells were isolated from human joint capsule specimens and challenged with three different concentrations of IL-4 with or without its neutralizing antibody. MF viability, contractile properties, and the gene expression of both alpha-smooth muscle actin (alpha-SMA) and collagen type I were examined. Immunofluorescence staining revealed the presence of IL-4 receptor (R)-alpha (alpha) on the membrane of cultured MFs. The cytokine IL-4 promoted MF viability and enhanced MF modulated contraction of collagen gels. Moreover, IL-4 intervened in gene expression by up-regulation of alpha-SMA and collagen type I mRNA. These effects could be specifically lowered by the neutralizing IL-4 antibody. On the basis of our findings we conclude that the anti-inflammatory cytokine IL-4 specifically regulates viability and the contractile properties of MFs via up-regulating the gene expression of alpha-SMA and collagen type I. IL-4 may be a helpful target in developing anti-fibrotic therapeutics for post traumatic joint contracture in human. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1290-1298, 2017. PMID- 27504741 TI - Importance of spike timing in touch: an analogy with hearing? AB - Touch is often conceived as a spatial sense akin to vision. However, touch also involves the transduction and processing of signals that vary rapidly over time, inviting comparisons with hearing. In both sensory systems, first order afferents produce spiking responses that are temporally precise and the timing of their responses carries stimulus information. The precision and informativeness of spike timing in the two systems invites the possibility that both implement similar mechanisms to extract behaviorally relevant information from these precisely timed responses. Here, we explore the putative roles of spike timing in touch and hearing and discuss common mechanisms that may be involved in processing temporal spiking patterns. PMID- 27504742 TI - Topical cetirizine and oral vitamin D: a valid treatment for hypotrichosis caused by ectodermal dysplasia. AB - BACKGROUND: Ectodermal dysplasia is a clinically and genetically heterogeneous group of inherited disorders characterized by abnormal development of two or more of the following ectodermal-derived structures: hair, teeth, nails and sweat glands. The hair is the most frequently affected structure. Hair shaft abnormalities are of great concern to these patients, but no effective treatments are available. METHODS: We describe three girls with congenital hypotrichosis (9, 5 and 6 years old) caused by ectodermal dysplasia treated with topical cetirizine solution (2 mL. once daily) and oral vitamin D supplementation (1000 IU daily). RESULTS: After 6 months of treatment, the density of hair on the scalp increased in all patients. The vellus hair was replaced by terminal hair. Hair regrowth was evaluated both from the clinical and trichoscopic point of view. CONCLUSION: We propose a combination of topical cetirizine and oral vitamin D as a rational treatment of choice in congenital hypotrichosis caused by ectodermal dysplasia. PMID- 27504743 TI - Unusual Mn(III/IV)4 Cubane and Mn(III)16M4 (M = Ca, Sr) Looplike Clusters from the Use of Dimethylarsinic Acid. AB - Three complexes are reported from the initial use of dimethylarsinic acid (Me2AsO2H) in Mn(III/IV) cluster chemistry, [Mn4O4(O2AsMe2)6] (3; 2Mn(III), 2Mn(IV)), and [Mn16X4O8(O2CPh)16(Me2AsO2)24] (X = Ca(2+) (4) or Sr(2+) (5); 16Mn(III)). They were obtained from reactions with [Mn12O12(O2CR)16(H2O)4] (R = Me, Ph) either without (3) or with (4 and 5) the addition of X(2+) salts. Complex 3 contains a [Mn4O4](6+) cubane, whereas isostructural 4 and 5 contain a planar loop structure comprising four Mn4 asymmetric "butterfly" units linked by alternating anti,anti MU-O2AsMe2 and {X2(O2AsMe2)(O2CPh)2} units. Variable temperature magnetic susceptibility (chiM) data were collected on dried microcrystalline samples of 3-5 in the 5.0-300 K range in a 0.1 T (1000 G) direct current (dc) magnetic field. Data for 3 were fit to the appropriate Van Vleck equation (using the [Formula: see text] = -2JSi.Sj convention) for a cubane of virtual C2v symmetry, giving J33 = 0.0(1) cm(-1), J34 = -3.4(4) cm(-1), J44 = 9.8(2) cm(-1), and g = 1.99(1), where the Jij subscripts refer to the oxidation states of the interacting Mn atoms. The ground state thus consists of two coupled Mn(IV) and two essentially noninteracting Mn(III). For 4 and 5, low-lying excited states from the high nuclearity and weak couplings prevent fits of dc magnetization data, but in-phase alternating current susceptibility chi'MT data down to 1.8 K indicate them to possess S = 4 ground states, if considered single Mn16 units. If instead they are treated as tetramers of weakly coupled Mn4 units, then each of the latter has an S = 2 ground state. Complexes 4 and 5 also exhibit very weak out-of-phase chi"M signals characteristic of slow relaxation, and magnetization versus dc field scans on a single crystal of 4.15MeCN at T >= 0.04 K showed hysteresis loops but with unusual features suggesting the magnetization relaxation barrier consists of more than one contribution. PMID- 27504744 TI - Face morphology: Can it tell us something about body weight and fat? AB - This paper proposes a method for an automatic extraction of geometric features, related to weight parameters, from 3D facial data acquired with low-cost depth scanners. The novelty of the method relies both on the processing of the 3D facial data and on the definition of the geometric features which are conceptually simple, robust against noise and pose estimation errors, computationally efficient, invariant with respect to rotation, translation, and scale changes. Experimental results show that these measurements are highly correlated with weight, BMI, and neck circumference, and well correlated with waist and hip circumference, which are markers of central obesity. Therefore the proposed method strongly supports the development of interactive, non obtrusive systems able to provide a support for the detection of weight-related problems. PMID- 27504745 TI - Using action research to build mentor capacity to improve orientation and quality of nursing students' aged care placements: what to do when the phone rings. AB - AIMS AND OBJECTIVES: To describe whether an action research approach can be used to build capacity of residential aged care facility staff to support undergraduate nursing students' clinical placements in residential aged care facilities, using development of an orientation programme as an exemplar. BACKGROUND: Aged care facilities are unpopular sites for nursing students' clinical placements. A contributing factor is the limited capacity of staff to provide students with a positive placement experience. Strategies to build mentor capability to shape student placements and support learning and teaching are critical if nursing students are to have positive placements that attract them to aged care after graduation, an imperative given the increasing care needs of the ageing population worldwide. DESIGN: Action research approach employing mixed methods data collection (primarily qualitative with a quantitative component). METHODS: Aged care facility staff (n = 32) formed a mentor group at each of two Tasmanian facilities and met regularly to support undergraduate nursing students (n = 40) during placements. Group members planned, enacted, reviewed and reflected on orientation procedures to welcome students, familiarise them with the facility and prepare them for their placement. Data comprised transcripts from these and parallel student meetings, and orientation data from student questionnaires from two successive placement periods (2011/2012). RESULTS: Problems were identified in the orientation processes for the initial student placements. Mentors implemented a revised orientation programme. Evaluation demonstrated improved programme outcomes for students regarding knowledge of facility operations, their responsibilities and emergency procedures. CONCLUSION: Action research provides an effective approach to engage aged care facility staff to build their capacity to support clinical placements. RELEVANCE TO CLINICAL PRACTICE: Building capacity in the aged care workforce is vital to provide appropriate care for residents with increasing care needs. PMID- 27504746 TI - Covalent Conjugation of Small-Molecule Adjuvants to Nanoparticles Induces Robust Cytotoxic T Cell Responses via DC Activation. AB - Specific recognitions of pathogen associated molecular patterns by Toll-like receptors (TLRs) initiate dendritic cell (DC) activation, which is critical for coordinating innate and adaptive immune responses. Imidazoquinolines as small molecule TLR7 agonists often suffer from prompt dissemination and short half-life in the bloodstream, preventing their localization to the corresponding receptors and effective DC activation. We postulated that covalent incorporation of imidazoquinoline moieties onto the surface of biocompatible nanoparticles (~30 nm size) would enhance their chemical stability, cellular uptake efficiency, and adjuvanticity. The fully synthetic adjuvant-nanocomplexes led to successful DC activation at lower nanomolar doses compared with free small-molecule agonists. Once a model antigen such as ovalbumin was used for immunization, we found that the nanocomplexes promoted an unusually strong cytotoxic T lymphocyte response, revealing their unique immunostimulatory capacity benefiting from multivalency and efficient transport to endosomal TLR7. PMID- 27504747 TI - Clinician's Commentary on Morgan et al.(1). PMID- 27504748 TI - Analysis of a Nitroreductase-Based Hypoxia Sensor in Primary Neuronal Cultures. AB - The ability to assess oxygenation within living cells is much sought after to more deeply understand normal and pathological cell biology. Hypoxia Red manufactured by Enzo Life Sciences is advertised as a novel hypoxia detector dependent on nitroreducatase activity. We sought to use Hypoxia Red in primary neuronal cultures to test cell-to-cell metabolic variability in response to hypoxic stress. Neurons treated with 90 min of hypoxia were labeled with Hypoxia Red. We observed that, even under normoxic conditions neurons expressed fluorescence robustly. Analysis of the chemical reactions and biological underpinnings of this method revealed that the high uptake and reduction of the dye is due to active nitroreductases in normoxic cells that are independent of oxygen availability. PMID- 27504749 TI - Radiation protection training for cardiologists in the era of multiple imaging techniques and complex interventions. AB - Cardiologists are among the heaviest medical users of ionising radiation. This usage is growing in proportion to the expanding range of cardiac diagnostic tests and interventional treatments. The primary focus of cardiologists is achieving clear diagnoses as well as technically and clinically successful treatments. That has to be set alongside strong awareness of the properties of ionising radiation and associated safety issues. This article illustrates some of the interplay between contemporary cardiology, radiological techniques, cardiology training and ionising radiation regulations and aims to set context for training and accreditation of cardiologists who use ionising radiation. PMID- 27504750 TI - Families in the context of macroeconomic crises: A systematic review. AB - The present study is a systematic review of empirical literature from the last 35 years on families' responses to economic distress in the context of macroeconomic crises. Thirty-nine studies published between 1983 and 2015 in 12 countries were identified, resulting in 3 main findings. First, economic distress was associated with negative changes in family dynamics, specifically couple relationships and parenting. Second, protective factors were found to buffer the adverse effects of economic distress on family and individual outcomes. Third, the results suggest that individual responses to macroeconomic crises may be moderated by sex. Implications for future research encompass using validated assessment instruments, including participants beyond 2-parent families with adolescent children and conducting both longitudinal and qualitative studies that focus on the processes and meanings of adaptation within this risk context. Conclusions highlighted the need to assist families dealing with macroeconomic crises' demands, encouraging the development and validation of macrosystemic intervention programs. (PsycINFO Database Record PMID- 27504751 TI - Randomized trial of parent training to prevent adolescent problem behaviors during the high school transition. AB - This randomized controlled trial tested a widely used general parent training program, Common Sense Parenting (CSP), with low-income 8th graders and their families to support a positive transition to high school. The program was tested in its original 6-session format and in a modified format (CSP-Plus), which added 2 sessions that included adolescents. Over 2 annual cohorts, 321 families were enrolled and randomly assigned to either the CSP, CSP-Plus, or minimal-contact control condition. Pretest, posttest, 1-year follow-up, and 2-year follow-up survey data on parenting as well as youth school bonding, social skills, and problem behaviors were collected from parents and youth (94% retention). Extending prior examinations of posttest outcomes, intent-to-treat regression analyses tested for intervention effects at the 2 follow-up assessments, and growth curve analyses examined experimental condition differences in yearly change across time. Separate exploratory tests of moderation by youth gender, youth conduct problems, and family economic hardship also were conducted. Out of 52 regression models predicting 1- and 2-year follow-up outcomes, only 2 out of 104 possible intervention effects were statistically significant. No statistically significant intervention effects were found in the growth curve analyses. Tests of moderation also showed few statistically significant effects. Because CSP already is in widespread use, findings have direct implications for practice. Specifically, findings suggest that the program may not be efficacious with parents of adolescents in a selective prevention context and may reveal the limits of brief, general parent training for achieving outcomes with parents of adolescents. (PsycINFO Database Record PMID- 27504752 TI - Mexican-origin parents' differential treatment and siblings' adjustment from adolescence to young adulthood. AB - Parents' differential treatment is a common family dynamic that has been linked to youth's well-being in childhood and adolescence in European American families. Much less is known, however, about this family process in other ethnic groups. The authors examined the longitudinal associations between parents' differential treatment (PDT) and both depressive symptoms and risky behaviors of Mexican origin sibling pairs from early adolescence through young adulthood. They also tested the moderating roles of cultural orientations as well as youth age, gender and sibling dyad gender constellation in these associations. Participants were mothers, fathers, and 2 siblings from 246 Mexican-origin families who participated in individual home interviews on 3 occasions over 8 years. Multilevel models revealed that, controlling for dyadic parent-child relationship qualities (i.e., absolute levels of warmth and conflict), adolescents who had less favorable treatment by mothers relative to their sibling reported more depressive symptoms and risky behavior, on average. Findings for fathers' PDT emerged at the within-person level indicating that, on occasions when adolescents experienced less favorable treatment by fathers than usual, they reported more depressive symptoms and risky behavior. However, some of these effects were moderated by youth age and cultural socialization. For example, adolescents who experienced relatively less paternal warmth than their siblings also reported poorer adjustment, but this effect did not emerge for young adults; such an effect also was significant for unfavored youth with stronger but not weaker cultural orientations. (PsycINFO Database Record PMID- 27504753 TI - Parents behaving badly: Gender biases in the perception of parental alienating behaviors. AB - According to gender role theory, individuals who confirm expectations associated with their gender roles are rewarded and judged against these expectations when they deviate. Parental roles are strongly tied to gender, and there are very different expectations for behaviors of mothers and fathers. This study examined how mothers' and fathers' behaviors that support or discourage a positive relationship with the other parent are perceived in terms of their acceptability. Two-hundred twenty-eight parents completed an online survey assessing perceptions of acceptability of negative (parental alienating) and positive coparenting behaviors. Results provided support for our hypothesis: Although parental alienating behaviors were rated unacceptable, they were more acceptable for mothers than fathers. Expectancy violation theory can explain why parental alienating behaviors are not viewed as negatively when mothers exhibit them than fathers. (PsycINFO Database Record PMID- 27504754 TI - Daily patterns of stress and conflict in couples: Associations with marital aggression and family-of-origin aggression. AB - For many married individuals, the ups and downs of daily life are connected such that stressors impacting one person also impact the other person. For example, stress experienced by one individual may "spill over" to negatively impact marital functioning. This study used both partners' daily diary data to examine same-day and cross-day links between stress and marital conflict and tested several factors that make couples vulnerable to spillover. Assessment of 25 wide ranging sources of daily stress included both paid and unpaid work, health issues, financial concerns, and having to make difficult decisions. Results showed that both husbands' and wives' experiences of total daily stress were associated with greater same-day marital conflict and that conflict was greater on days both spouses experienced high levels of stress. Evidence of cross-day spillover was found only in those couples with high concurrent marital aggression and in couples where wives reported high family-of-origin aggression. These results highlight both the common, anticipated nature of same-day spillover and the potentially problematic aspects of more prolonged patterns representing failure to recover from stressors that occurred the previous day. The discussion focuses on how reactivity in one life domain puts that individual at risk for generating stress in another life domain and how current marital aggression and family-of-origin aggression are associated with difficulty recovering from stressful events. (PsycINFO Database Record PMID- 27504756 TI - What Brexit means for biotech. PMID- 27504757 TI - 'Brexit' stuns UK biotech into waiting game, but not all signals are red. PMID- 27504755 TI - Large-Conductance Transmembrane Porin Made from DNA Origami. AB - DNA nanotechnology allows for the creation of three-dimensional structures at nanometer scale. Here, we use DNA to build the largest synthetic pore in a lipid membrane to date, approaching the dimensions of the nuclear pore complex and increasing the pore-area and the conductance 10-fold compared to previous man made channels. In our design, 19 cholesterol tags anchor a megadalton funnel shaped DNA origami porin in a lipid bilayer membrane. Confocal imaging and ionic current recordings reveal spontaneous insertion of the DNA porin into the lipid membrane, creating a transmembrane pore of tens of nanosiemens conductance. All atom molecular dynamics simulations characterize the conductance mechanism at the atomic level and independently confirm the DNA porins' large ionic conductance. PMID- 27504758 TI - Genentech's PD-L1 agent approved for bladder cancer. PMID- 27504759 TI - Biogen and UPenn join forces to commercialize gene therapies. PMID- 27504760 TI - Juno's wild ride. PMID- 27504761 TI - Cancer anabolic metabolism inhibitors move into clinic. PMID- 27504762 TI - First-in-human CRISPR trial. PMID- 27504763 TI - Synthetic human genome set to spur applications. PMID- 27504764 TI - Gilead's first pan-genotypic HCV cure. PMID- 27504765 TI - Around the world in a month. PMID- 27504766 TI - Drug pipeline: 2Q16. PMID- 27504767 TI - 2Q16-biotech claws back. PMID- 27504768 TI - Research biotech patenting 2015. PMID- 27504769 TI - First Rounders Podcast: David Baltimore. PMID- 27504770 TI - Nanopore development at Oxford Nanopore. PMID- 27504771 TI - Rapid, semi-automated protein terminal characterization using ISDetect. PMID- 27504773 TI - Recent patents in synthetic biology. PMID- 27504772 TI - The rise and fall of innovation in biofuels. PMID- 27504774 TI - Deep phenotyping predicts Huntington's genotype. PMID- 27504775 TI - An edible switch for gene therapy. PMID- 27504776 TI - Automated design of DNA origami. PMID- 27504779 TI - Erratum: No longer going to waste. PMID- 27504780 TI - Erratum: Near-optimal probabilistic RNA-seq quantification. PMID- 27504781 TI - Erratum: Genome-wide analysis reveals specificities of Cpf1 endonucleases in human cells. PMID- 27504782 TI - Erratum: Nature Biotechnology's academic spinouts of 2015. PMID- 27504778 TI - Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. AB - The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry (MS) techniques are well-suited to high-throughput characterization of NP, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social Molecular Networking (GNPS; http://gnps.ucsd.edu), an open-access knowledge base for community-wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS, crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of 'living data' through continuous reanalysis of deposited data. PMID- 27504783 TI - Second-quarter biotech job picture. PMID- 27504785 TI - Branching Ratios and Vibrational Distributions in Water-Forming Reactions of OH and OD Radicals with Methylamines. AB - Reactions of OH and OD radicals with (CH3)3N, (CH3)2NH, and CH3NH2 were studied by Fourier transform infrared emission spectroscopy (FTIR) of the water product molecules from a fast-flow reactor at 298 K. The rate constants (4.4 +/- 0.5) * 10(-11), (5.2 +/- 0.8) * 10(-11), and (2.0 +/- 0.4) * 10(-11) cm(3) molecule(-1) s(-1) were determined for OD + (CH3)3N, (CH3)2NH, and CH3NH2, respectively, by comparing the HOD emission intensities to the HOD intensity from the OD reaction with H2S. Abstraction from the nitrogen site competes with abstraction from the methyl group, as obtained from an analysis of the HOD and D2O emission intensities from the OD reactions with the deuterated reactants, (CD3)2NH and CD3NH2. After adjustment for the hydrogen-deuterium kinetic isotope effect, the product branching fractions of the hydrogen abstraction from the nitrogen for di- and monomethylamine were found to be 0.34 +/- 0.04 and 0.26 +/- 0.05, respectively. Vibrational distributions of the H2O, HOD, and D2O molecules are typical for direct hydrogen atom abstraction from polar molecules, even though activation energies are negative because of the formation of pre-transition-state complexes. Comparison is made to the reactions of hydroxyl radicals with ammonia and with other compounds with primary C-H bonds to discuss specific features of disposal of energy to water product. PMID- 27504787 TI - Store-Operated Ca2+ Entry in Oocytes Modulate the Dynamics of IP3 -Dependent Ca2+ Release From Oscillatory to Tonic. AB - Ca2+ signaling is ubiquitous and mediates various cellular functions encoded in its spatial, temporal, and amplitude features. Here, we investigate the role of store-operated Ca2+ entry (SOCE) in regulating the temporal dynamics of Ca2+ signals in Xenopus oocytes, which can be either oscillatory or tonic. Oscillatory Ca2+ release from intracellular stores is typically observed at physiological agonist concentration. When Ca2+ release leads to Ca2+ store depletion, this triggers the activation of SOCE that translates into a low-amplitude tonic Ca2+ signal. SOCE has also been implicated in fueling Ca2+ oscillations when activated at low levels. Here, we show that sustained SOCE activation in the presence of IP3 to gate IP3 receptors (IP3 R) results in a pump-leak steady state across the endoplasmic reticulum (ER) membrane that inhibits Ca2+ oscillations and produces a tonic Ca2+ signal. Tonic signaling downstream of SOCE activation relies on focal Ca2+ entry through SOCE ER-plasma membrane (PM) junctions, Ca2+ uptake into the ER, followed by release through open IP3 Rs at distant sites, a process we refer to as "Ca2+ teleporting." Therefore, sustained SOCE activation in the presence of an IP3 -dependent "leak" pathway at the ER membrane results in a switch from oscillatory to tonic Ca2+ signaling. J. Cell. Physiol. 232: 1095 1103, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27504786 TI - Structural Characterization of Serum N-Glycans by Methylamidation, Fluorescent Labeling, and Analysis by Microchip Electrophoresis. AB - To characterize the structures of N-glycans derived from human serum, we report a strategy that combines microchip electrophoresis, standard addition, enzymatic digestion, and matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS). We compared (i) electrophoretic mobilities of known N-glycans from well-characterized (standard) glycoproteins through standard addition, (ii) the electrophoretic mobilities of N-glycans with their molecular weights determined by MALDI-MS, and (iii) electrophoretic profiles of N-glycans enzymatically treated with fucosidase. The key step to identify the sialylated N-glycans was to quantitatively neutralize the negative charge on both alpha2,3- and alpha2,6 linked sialic acids by covalent derivatization with methylamine. Both neutralized and nonsialylated N-glycans from these samples were then reacted with 8 aminopyrene-1,3,6-trisulfonic acid (APTS) to provide a fluorescent label and a triple-negative charge, separated by microchip electrophoresis, and detected by laser-induced fluorescence. The methylamidation step leads to a 24% increase in the peak capacity of the separation and direct correlation of electrophoretic and MALDI-MS results. In total, 37 unique N-glycan structures were assigned to 52 different peaks recorded in the electropherograms of the serum samples. This strategy ensures the needed separation efficiency and detectability, easily resolves linkage and positional glycan isomers, and is highly reproducible. PMID- 27504788 TI - Transition-Metal-Free Diastereoselective Epoxidation of Trifluoromethylketones with N-Tosylhydrazones: Access to Tetrasubstituted Trifluoromethylated Oxiranes. AB - The first example of the epoxidation reaction of trifluoromethylketones with N tosylhydrazones under transition-metal free conditions is reported. This epoxidation reaction provided tetrasubstituted trifluoromethylated oxiranes with excellent yields and diastereoselectivities. The salient features of this reaction include readily available starting materials, mild conditions, broad substrate scope, high efficiency, and valuable further applications. Remarkably, this reaction proceeded through an unprecedented nucleophilic addition process, and the ammonium O-anion intermediate was detected and characterized by NMR and HRMS analysis. PMID- 27504790 TI - Synthesis of l-Pyranosides by Hydroboration of Hex-5-enopyranosides Revisited. AB - Extensive study of the diastereoselective synthesis of l-pyranosides utilizing hydroboration of substituted exo-glucals (5-enopyranosides) obtained from d sugars is presented. On the basis of this study we present the empirical rules describing the reaction stereoselectivity and the correlation between the yield of the l-ido product and the size of protecting groups used. Application of these guidelines revealed that the hydroboration of methyl 2,3-O-methyl-6-deoxy-alpha-d xylo-hex-5-enopyranoside resulted in exclusive formation of l-ido product with high yield. This method can be successfully applied to the synthesis of l iduronic acid being an essential component of anticoagulant drugs with diastereoselectivity superior to previously published protocols. PMID- 27504789 TI - An old culprit but a new story: bisphenol A and "NextGen" bisphenols. AB - The concept that developmental events shape adult health and disease was sparked by the recognition of a link between maternal undernutrition and coronary disease in adults. From that beginning, a new field-the developmental origins of health and disease-emerged, and attention has focused on the effects of a wide array of developmental perturbations. Exposure to endocrine-disrupting chemicals has been of particular interest, and a ubiquitous environmental contaminant bisphenol A (BPA) has become the endocrine-disrupting chemical poster child. Bisphenol A has been the subject of intense investigation for nearly two decades, and exposure effects have been described in hundreds of experimental, epidemiological, and clinical studies. From the standpoint of reproductive health, the findings are particularly important, as they suggest that the ovary, testis, and reproductive tract in both sexes are targets of BPA action. The findings and the media and regulatory attention garnered by them have generated increasing public concern and resulted in legislative bans on BPA in some countries. The subsequent introduction of BPA-free products, although a masterful marketing strategy, is in reality only the beginning of a new and complex chapter of the BPA story. In this review we attempt to summarize what we have learned about the reproductive effects of BPA, present the reasons why studying the effects of this chemical in humans is no longer sufficient, and outline the challenges that the growing array of next generation bisphenols represents to clinicians, researchers, federal agencies, and the general public. PMID- 27504791 TI - Analysis of melamine in milk powder by using a magnetic molecularly imprinted polymer based on carbon nanotubes with ultra high performance liquid chromatography and tandem mass spectrometry. AB - A new magnetic molecularly imprinted polymer was coupled with ultra high performance liquid chromatography and tandem mass spectrometry for the selective determination of melamine in milk powder. The magnetic molecularly imprinted polymer has been prepared by using carbon nanotubes as the matrix, Fe3 O4 particles as the magnetic ingredient, melamine as the template molecule, methacrylic acid as the functional monomer, ethylene glycol dimethacrylate as the cross-linker and polyvinylpyrrolidone as the dispersant. The polymer was characterized with scanning electron microscopy, Fourier transform infrared spectroscopy and a physical property measurement system. The isothermal adsorption, kinetics adsorption, and selectivity were studied to evaluate the rebinding properties of the magnetic molecularly imprinted polymer. Various parameters affecting the extraction efficiency such as the amount of polymer, extraction time, and eluting solution were evaluated. The limit of detection was 0.00075 mg/kg. The relative standard deviations of the intraday and interday precision are 0.4-2.7 and 2.3-5.1%, respectively. The proposed method was successfully applied to determine melamine in different milk powder samples from different provenances, and satisfactory recoveries of 89.0-95.6% were obtained. This method has great significance for quality control and is simple and suitable for the rapid determination of melamine in milk powder. PMID- 27504792 TI - Printed organo-functionalized graphene for biosensing applications. AB - Graphene is a highly promising material for biosensors due to its excellent physical and chemical properties which facilitate electron transfer between the active locales of enzymes or other biomaterials and a transducer surface. Printing technology has recently emerged as a low-cost and practical method for fabrication of flexible and disposable electronics devices. The combination of these technologies is promising for the production and commercialization of low cost sensors. In this review, recent developments in organo-functionalized graphene and printed biosensor technologies are comprehensively covered. Firstly, various methods for printing graphene-based fluids on different substrates are discussed. Secondly, different graphene-based ink materials and preparation methods are described. Lastly, biosensing performances of printed or printable graphene-based electrochemical and field effect transistor sensors for some important analytes are elaborated. The reported printed graphene based sensors exhibit promising properties with good reliability suitable for commercial applications. Among most reports, only a few printed graphene-based biosensors including screen-printed oxidase-functionalized graphene biosensor have been demonstrated. The technology is still at early stage but rapidly growing and will earn great attention in the near future due to increasing demand of low-cost and disposable biosensors. PMID- 27504793 TI - CdTe/CdSe quantum dot-based fluorescent aptasensor with hemin/G-quadruplex DNzyme for sensitive detection of lysozyme using rolling circle amplification and strand hybridization. AB - Lysozyme with a small monomeric globular enzymatic protein is part of the innate immune system, and its deficiency can cause the increased incidence of disease. Herein, we devise a new signal-enhanced fluorescence aptasensing platform for quantitative screening of lysozyme by coupling with rolling circle amplification (RCA) and strand hybridization reaction, accompanying the assembly of CdTe/CdSe quantum dots (QDs) and hemin/G-quadruplex DNzyme. Initially, target-triggered release of the primer was carried out from DNA duplex via the reaction of the aptamer with the analyte, and the released primer could be then utilized as the template to produce numerous repeated oligonucleotide sequences by the RCA reaction. Following that, the formed long-stranded DNA simultaneously hybridized with the CdTe/CdSe QD-labeled probe and hemin/G-quadruplex DNzyme strand in the system, thereby resulting in the quenching of QD fluorescent signal through the proximity hemin/G-quadruplex DNzyme on the basis of transferring photoexcited conduction band electrons of quantum dots to Fe(III)/Fe(II)-protoporphyrin IX (hemin) complex. Under optimal conditions, the fluorescent signal decreased with the increasing target lysozyme within the dynamic range from 5.0 to 500nM with a detection limit (LOD) of 2.6nM at the 3sblank criterion. Intra-assay and interassay coefficients of variation (CVs) were below 8.5% and 11.5%, respectively. Finally, the system was applied to analyze spiked human serum samples, and the recoveries in all cases were 85-111.9%. PMID- 27504794 TI - Adverse Reactions to Gadoterate Meglumine: Review of Over 25 Years of Clinical Use and More Than 50 Million Doses. AB - OBJECTIVE: The aim of this study was to evaluate the safety profile of gadoterate meglumine from clinical trials, postmarketing observational studies, and pharmacovigilance reports of adverse drug reactions (ADRs) encompassing 25 years of clinical use and over 50 million administered doses. MATERIALS AND METHODS: Assessment of the safety of gadoterate meglumine through processing and review of all safety data was collected after magnetic resonance imaging procedures. All ADRs originated from 3 major sources: (1) a clinical study database including 50 phase I to IV studies involving 2822 patients, (2) a safety database including 8 postmarketing safety studies (PMSs) involving 151,050 patients, and (3) a pharmacovigilance database compiling safety experience following over 50 million doses administered between March 1989 and September 2015. RESULTS: Among the 2822 patients receiving gadoterate meglumine in the clinical trials, 241 (8.5%) experienced 405 postinjection adverse events (AEs), considered related to the contrast agent for 113 patients (4.0%). Serious AEs were reported for 27 patients (1.0%) and assessed as related to gadoterate meglumine for 2 patients (0.07%). None of the PMS studies showed evidence of unexpected safety issues, with a very low rate of AEs (<1%). Postmarketing safety experience with over 50 million doses of gadoterate meglumine prescribed for 25 years of approved use worldwide compiled spontaneous reports for 3797 patients who experienced 8397 ADRs, yielding a very low reported incidence of ADRs of 0.007% of patients. There was no single-agent case of confirmed nephrogenic systemic fibrosis with gadoterate meglumine either from clinical development programs or from postmarketing experience. CONCLUSIONS: Based on clinical trials, postmarketing observational studies and pharmacovigilance data, a very low incidence of ADRs was reported with gadoterate meglumine, which has no impact on its favourable benefit-risk ratio. PMID- 27504795 TI - Temporal Changes of Texture Features Extracted From Pulmonary Nodules on Dynamic Contrast-Enhanced Chest Computed Tomography: How Influential Is the Scan Delay? AB - OBJECTIVES: The aim of this study was to describe the temporal changes of various texture features extracted from pulmonary nodules on dynamic contrast-enhanced computed tomography (DCE-CT) and to compare the feature values among multiple scanning time points. We also aimed to analyze the variability of texture features across multiple scan delay times. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board of Seoul National University Hospital with waiver of patients' informed consent. Twenty patients (M:F, 6:14; mean age, 60.25 +/- 11.97 years) with 20 lung nodules (mean size, 24.1 +/- 12.3 mm) underwent DCE-CT with multiple scan delays (30, 60, 90, 120, 150, 180, 210, 240, 300, and 480 seconds) after precontrast scans. Lung nodule segmentation and texture feature extraction were performed at each time point using in-house software. Texture feature values were compared among the multiple time points using the Friedman test with post hoc pairwise Wilcoxon signed rank test. In addition, the dynamic range (DR) reflecting the variability between 2 time points to the interpatient range was calculated. Thereafter, we determined the stable time range that met both "DR greater than 0.90" and "no statistically significant difference" between all time point pairs for each feature. The degree of variability across all scan delay times was obtained using coefficients of variation. RESULTS: Standard deviation, variance, entropy, sphericity, discrete compactness, gray-level cooccurrence matrix (GLCM) inverse difference moment (IDM), GLCM contrast, and GLCM entropy did not show significant differences between scan delays of 30 and 180 seconds with DR greater than 0.90 between all time point pairs. When the range was narrowed down to 60 to 150 seconds, an additional 2 values (mean and homogeneity) showed stability. Among the 13 texture features, entropy, sphericity, discrete compactness, and GLCM entropy exhibited the lowest variability (coefficient of variation <=5%). CONCLUSIONS: Most texture features exhibited stability with low variation between 60 and 150 seconds on DCE-CT. Thus, texture features extracted from contrast enhanced CT with a scan delay range of 60 to 150 seconds can be used for tumor characterization despite the heterogeneity in delay time. PMID- 27504796 TI - Multifrequency Magnetic Resonance Elastography for the Assessment of Renal Allograft Function. AB - OBJECTIVE: The aim of this study was to apply multifrequency magnetic resonance elastography (MMRE) for assessment of kidney function based on renal stiffness of allografts in transplant recipients and native kidneys in controls. METHODS: In this prospective study, MMRE was used to measure stiffness in transplant kidneys in 22 recipients (age range, 23-73 years; 7 females) and in native kidneys in 11 controls (age range, 26-55 years; 4 females) after internal review board approval. The MMRE was performed on a 1.5 T magnetic resonance imaging scanner using 4 vibration frequencies from 40 to 70 Hz. Stiffness maps were computed by multifrequency reconstruction of the magnitude shear modulus (|G*|). Clinical markers such as glomerular filtration rate (GFR) and resistive index (RI) were acquired. Differences in renal stiffness among groups were compared by Mann Whitney U test. Correlations were tested using Pearson correlation. RESULTS: Functioning transplants had higher stiffness (|G*| = 9.00 +/- 1.71 kPa) than nonfunctioning transplants (|G*| = 5.88 +/- 1.71 kPa, P < 0.001) and native kidneys (|G*| = 6.63 +/- 1.63 kPa, P < 0.01). A cutoff value of 7.04 kPa provided sensitivity (83.33%) and specificity (86.67%) for detecting renal allograft dysfunction with an area under the receiver operating characteristic curve value of 0.9278 (95% confidence interval, 0.83-1.00). |G*| correlated positively with GFR (r = 0.52, P = 0.015) and negatively with RI (r = -0.52, P = 0.016). CONCLUSIONS: Multifrequency magnetic resonance elastography has good diagnostic accuracy in detecting renal allograft dysfunction. Renal stiffness is significantly lower in recipients with nonfunctioning transplant kidneys and correlates with clinical markers such as GFR and RI. PMID- 27504797 TI - Exploring the association of ego defense mechanisms with problematic internet use in a Pakistani medical school. AB - The present study was designed to analyze association between problematic internet use and use of ego defense mechanisms in medical students. This cross sectional study was undertaken at CMH Lahore Medical College (CMH LMC) in Lahore, Pakistan from 1st March, 2015 to 30th May, 2015. 522 medical and dental students were included in the study. The questionnaire consisted of three sections: a) demographic characteristics of respondent b) the Defense Style Questionnaire-40 (DSQ-40) and c) the Internet Addiction Test (IAT). All data were analyzed in SPSS v20. Chi square, Independent sample t test and One Way ANOVA were run to analyze association of different variables with scores on IAT. Multiple regression analysis was used to delineate ego defenses as predictors of problematic internet use. A total of 32 (6.1%) students reported severe problems with internet usage. Males had higher scores on IAT i.e had more problematic use of internet. Scores on internet addiction test (IAT) were negatively associated with sublimation and positively associated with projection, denial, autistic fantasy, passive aggression and displacement. There was a high prevalence of problematic use of internet among medical and dental students. It had significant associations with several defense mechanisms. PMID- 27504798 TI - Regional Intestinal Permeability of Three Model Drugs in Human. AB - Currently there are only a limited number of determinations of human Peff in the distal small intestine and none in the large intestine. This has hindered the validation of preclinical models with regard to absorption in the distal parts of the intestinal tract, which can be substantial for BCS class II-IV drugs, and drugs formulated into modified-release (MR) dosage forms. To meet this demand, three model drugs (atenolol, metoprolol, and ketoprofen) were dosed in solution intravenously, and into the jejunum, ileum, and colon of 14 healthy volunteers. The Peff of each model drug was then calculated using a validated deconvolution method. The median Peff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 * 10(-4) cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 * 10(-4) cm/s, and for ketoprofen 8.85, 6.53, and 3.37 * 10(-4) cm/s, respectively. This is the first study where the human Peff of model drugs has been determined in all parts of the human intestinal tract in the same subjects. The jejunal values were similar to directly determined values using intestinal single-pass perfusion, indicating that the deconvolution method is a valid approach for determining regional Peff. The values from this study will be highly useful in the validation of preclinical regional absorption models and in silico tools. PMID- 27504800 TI - Osteopontin Blockade Attenuates Renal Injury After Ischemia Reperfusion by Inhibiting NK Cell Infiltration. AB - Renal ischemia-reperfusion (RIR) injury is a common occurrence after major surgery and shock, leading to acute kidney injury (AKI). Osteopontin (OPN) is a secreted glycoprotein that acts as a proinflammatory cytokine and activator of T lymphocytes. We hypothesized that blockade of OPN reduces the severity of inflammation and injury in RIR. Renal ischemia was induced in adult C57BL/6 mice via bilateral clamping of renal pedicles for 35 min, followed by reperfusion for 24 h. Anti-OPN antibody (Ab), nonimmunized isotype immunoglobulin G, or normal saline was injected intravenously at the time of reperfusion. Blood and kidneys were collected for analysis. At 24 h after RIR, OPN mRNA and protein levels were significantly increased in renal tissue compared with sham mice. In serum, elevated levels of blood urea nitrogen and creatinine were reduced in anti-OPN Ab treated mice compared with vehicle. Anti-OPN Ab-treated mice also had decreased mRNA levels of injury markers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 compared with the vehicle. The histologic architecture and apoptosis of renal tissue were improved in the anti-OPN Ab-treated mice. In renal tissue, inflammatory cytokines interleukin 6 and tumor necrosis factor alpha protein levels were reduced in the Ab-treated mice. Natural killer (NK) cell infiltration was decreased after anti-OPN Ab treatment, as was neutrophil infiltration, shown by reduced chemokine expression and Gr1 renal immunohistochemical staining. These findings demonstrate a beneficial role of OPN blockade in RIR associated with NK cell-mediated downregulation of inflammatory cytokines and chemokines. Administration of anti-OPN Ab may therefore serve as an immunomodulatory adjunct in the treatment of RIR-induced AKI. PMID- 27504801 TI - Mean Platelet Volume to Platelet Count Ratio as a Promising Predictor of Early Mortality in Severe Sepsis. AB - PURPOSE: We evaluated the mean platelet volume (MPV) to platelet ratio to determine its significance as a prognostic marker for early mortality in critically ill patients with suspected sepsis receiving early goal-directed therapy (EGDT). METHODS: We retrospectively reviewed the records from a prospective EGDT registry and screened eligible adult patients who were admitted to the emergency department (ED) with severe sepsis and/or septic shock. The MPV/platelet ratio was estimated as the MPV value divided by the platelet count on each day of hospitalization. The clinical outcome was 28-day mortality. RESULTS: We included 120 patients receiving EGDT. In the multivariate Cox proportional hazard models, higher MPV/platelet ratios on admission (HR: 1.04; 95% CI: 1.015-1.066; P = 0.002) and at 24 h (HR: 1.032; 95% CI: 1.012-1.054; P = 0.002) were significant risk factors for mortality at 28 days. An increased trend for 28-day mortality was associated with a MPV/platelet ratio >3.71 on admission (HR: 4.274; 95% CI: 1.228-14.874; P = 0.023) and a higher MPV/platelet ratio (>6.49) at 24 h (HR: 2.719; 95% CI: 1.048-7.051; P = 0.04) in patients with severe sepsis receiving EGDT. CONCLUSION: In our study, MPV or platelet count alone did not predict shock and 28-day mortality in patients with severe sepsis receiving EGDT. However, the MPV/platelet ratio at ED admission and on day 1 is a promising prognostic marker for 28-day mortality in patients with severe sepsis. PMID- 27504802 TI - alpha-Lactose Improves the Survival of Septic Mice by Blockade of TIM-3 Signaling to Prevent NKT Cell Apoptosis and Attenuate Cytokine Storm. AB - Sepsis is the leading cause of death among critically ill patients and natural killer T (NKT) cell activation is essential to induce inflammatory cytokine cascade in sepsis. However, little is known about what regulates the NKT cell function during sepsis. Herein, we showed that T-cell immunoglobulin and mucin domain 3 (Tim-3) expression in NKT cells is elevated in experimental mice during sepsis. Tim-3 expression was positively correlated with NKT cell activation and apoptosis. In sepsis, interleukin (IL)-12 secreted by dendritic cell exposure to lipopolysaccharide increased the expression of Tim-3 in NKT cells. Administration of alpha-lactose to block Tim-3 signaling pathway significantly improved the survival of septic mice, concomitant with reduced IL-12 production by dendritic cells, reduced Tim-3 expression, prevented NKT cell apoptosis, and attenuated production of inflammatory cytokines. Collectively, Tim-3 signaling in NKT cells plays a critical role in the immunopathogenesis of sepsis. Thus, alpha-lactose could be a promising immunomodulatory agent in the treatment of sepsis. PMID- 27504803 TI - Coarse-Grained Molecular Dynamics Study of the Curing and Properties of Highly Cross-Linked Epoxy Polymers. AB - In this work, a coarse-grained model is developed for highly cross-linked bisphenol A diglycidyl ether epoxy resin with diaminobutane hardener. In this model, all conformationally relevant coarse-grained degrees of freedom are accounted for by sampling over the free-energy surfaces of the atomic structures using quantum mechanical simulations. The interaction potentials between nonbonded coarse-grained particles are optimized to accurately predict the experimentally measured density and glass-transition temperature of the system. In addition, a new curing algorithm is also developed to model the creation of highly cross-linked epoxy networks. In this algorithm, to create a highly cross linked network, the reactants are redistributed from regions with an excessive number of reactive molecules to regions with a lower number of reactants to increase the chances of cross-linking. This new algorithm also dynamically controls the rate of cross-linking at each local region to ensure uniformity of the resulting network. The curing simulation conducted using this algorithm is able to develop polymeric networks having a higher average degree of cross linking, which is more uniform throughout the simulation cell as compared to that in the networks cured using other curing algorithms. The predicted gel point from the current curing algorithm is in the acceptable theoretical and experimental range of measured values. Also, the resulting cross-linked microstructure shows a volume shrinkage of 5%, which is close to the experimentally measured volume shrinkage of the cured epoxy. Finally, the thermal expansion coefficients of materials in the glassy and rubbery states show good agreement with the experimental values. PMID- 27504804 TI - Metal and Metalloid Size-Fractionation Strategies in Spatial High-Resolution Sediment Pore Water Profiles. AB - Sediment water interfaces (SWIs) are often characterized by steep biogeochemical gradients determining the fate of inorganic and organic substances. Important transport processes at the SWI are sedimentation and resuspension of particulate matter and fluxes of dissolved materials. A microprofiling and micro sampling system (missy), enabling high resolution measurements of sediment parameters in parallel to a direct sampling of sediment pore waters (SPWs), was combined with two fractionation approaches (ultrafiltration (UF) and cloud point extraction (CPE)) to differentiate between colloidal and dissolved fractions at a millimeter scale. An inductively coupled plasma-quadrupole mass spectrometry method established for volumes of 300 MUL enabled the combination of the high resolution fractionation with multi-element analyzes. UF and CPE comparably indicated that manganese is predominantly present in dissolved fractions of SPW profiles. Differences found for cobalt and iron showed that the results obtained by size dependent UF and micelle-mediated CPE do not necessarily coincide, probably due to different fractionation mechanisms. Both methods were identified as suitable for investigating fraction-related element concentrations in SPW along sediment depth profiles at a millimeter scale. The two approaches are discussed with regard to their advantages, limitations, potential sources of errors, further improvements, and potential future applications. PMID- 27504805 TI - The hominoid-specific gene TBC1D3 promotes generation of basal neural progenitors and induces cortical folding in mice. AB - Cortical expansion and folding are often linked to the evolution of higher intelligence, but molecular and cellular mechanisms underlying cortical folding remain poorly understood. The hominoid-specific gene TBC1D3 undergoes segmental duplications during hominoid evolution, but its role in brain development has not been explored. Here, we found that expression of TBC1D3 in ventricular cortical progenitors of mice via in utero electroporation caused delamination of ventricular radial glia cells (vRGs) and promoted generation of self-renewing basal progenitors with typical morphology of outer radial glia (oRG), which are most abundant in primates. Furthermore, down-regulation of TBC1D3 in cultured human brain slices decreased generation of oRGs. Interestingly, localized oRG proliferation resulting from either in utero electroporation or transgenic expression of TBC1D3, was often found to underlie cortical regions exhibiting folding. Thus, we have identified a hominoid gene that is required for oRG generation in regulating the cortical expansion and folding. PMID- 27504806 TI - Adaptive learning and decision-making under uncertainty by metaplastic synapses guided by a surprise detection system. AB - Recent experiments have shown that animals and humans have a remarkable ability to adapt their learning rate according to the volatility of the environment. Yet the neural mechanism responsible for such adaptive learning has remained unclear. To fill this gap, we investigated a biophysically inspired, metaplastic synaptic model within the context of a well-studied decision-making network, in which synapses can change their rate of plasticity in addition to their efficacy according to a reward-based learning rule. We found that our model, which assumes that synaptic plasticity is guided by a novel surprise detection system, captures a wide range of key experimental findings and performs as well as a Bayes optimal model, with remarkably little parameter tuning. Our results further demonstrate the computational power of synaptic plasticity, and provide insights into the circuit-level computation which underlies adaptive decision-making. PMID- 27504808 TI - Primary Neuroendocrine Carcinoma of the Kidney on FDG PET/CT. AB - A 28-year-old woman presented gradually worsening intermittent right groin pain for 10 months. FDG PET/CT was performed to evaluate the suspected renal malignancy. The images demonstrated a large hypermetabolic tumor occupying the entire right kidney. Pathological examination demonstrated a primary neuroendocrine carcinoma of the kidney. PMID- 27504807 TI - Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development. AB - Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. We report that disruption of the mixed-lineage protein kinase (MLK) - cJun NH2-terminal kinase (JNK) signaling pathway in endothelial cells causes severe blockade of blood flow and failure to recover in the murine femoral artery ligation model of hindlimb ischemia. We show that the MLK-JNK pathway is required for the formation of native collateral arteries that can restore circulation following arterial occlusion. Disruption of the MLK-JNK pathway causes decreased Dll4/Notch signaling, excessive sprouting angiogenesis, and defects in developmental vascular morphogenesis. Our analysis demonstrates that the MLK-JNK signaling pathway is a key regulatory mechanism that protects against ischemia in arterial occlusive disease. PMID- 27504809 TI - Significant 99mTc-MDP but Unimpressive 18F-NaF Gastric Activity in a Patient With Multiple Myeloma. AB - A 69-year-old man with a history of low back pain for more than 4 months underwent Tc-MDP bone scan to determine the cause of the symptoms. In addition to the osseous lesions, significant activity in the stomach wall was noted. However, a subsequent F-NaF PET/CT only revealed bone lesion without increased activity in the stomach wall. The cause of the back pain was eventually confirmed due to multiple myeloma. PMID- 27504810 TI - Chiral-index resolved length mapping of carbon nanotubes in solution using electric-field induced differential absorption spectroscopy. AB - The length of single-walled carbon nanotubes (SWCNTs) is an important metric for the integration of SWCNTs into devices and for the performance of SWCNT-based electronic or optoelectronic applications. In this work we propose a rather simple method based on electric-field induced differential absorption spectroscopy to measure the chiral-index-resolved average length of SWCNTs in dispersions. The method takes advantage of the electric-field induced length dependent dipole moment of nanotubes and has been verified and calibrated by atomic force microscopy. This method not only provides a low cost, in situ approach for length measurements of SWCNTs in dispersion, but due to the sensitivity of the method to the SWCNT chiral index, the chiral index dependent average length of fractions obtained by chromatographic sorting can also be derived. Also, the determination of the chiral-index resolved length distribution seems to be possible using this method. PMID- 27504811 TI - The Zombie Plot: A Simple Graphic Method for Visualizing the Efficacy of a Diagnostic Test. AB - OBJECTIVE: One of the most important jobs of a radiologist is to pick the most appropriate imaging test for a particular clinical situation. Making a proper selection sometimes requires statistical analysis. The objective of this article is to introduce a simple graphic technique, an ROC plot that has been divided into zones of mostly bad imaging efficacy (ZOMBIE, hereafter referred to as the "zombie plot"), that transforms information about imaging efficacy from the numeric domain into the visual domain. CONCLUSION: The numeric rationale for the use of zombie plots is given, as are several examples of the clinical use of these plots. Two online calculators are described that simplify the process of producing a zombie plot. PMID- 27504812 TI - The Natural History of Primary Sclerosing Cholangitis in Children: A Large Single Center Longitudinal Cohort Study. AB - OBJECTIVES: Data regarding pediatric primary sclerosing cholangitis (PSC) natural history are limited. We describe a large pediatric PSC cohort with longitudinal follow-up. METHODS: The present study records review of pediatric patients with PSC diagnosed between 1984 and 2014. RESULTS: N = 120 (63% M) ages 1 to 21 years (median 14 years) at diagnosis. 27% (31/113) had autoimmune sclerosing cholangitis (ASC), 24% had exclusive small duct PSC, METAVIR stage was F3-F4 in 41%. Eighty-one percent of patients with PSC had inflammatory bowel disease (IBD); most had ulcerative/indeterminate colitis (72/97), typically pancolitis (40/72). PSC-IBD was more common than ASC-IBD (85% vs 68%, P = 0.03). Median follow-up was 3.7 years (interquartile range [IQR] 1.5, 6.9). Median gamma glutamyl transferase decreased from baseline of 221 U/L (IQR 110, 425) to 104 U/L by 1 year postdiagnosis ([IQR 18,229], P < 0.0001), and then changed little. Mean fibrosis stage at diagnosis was 2.3 +/- 1.4 (N = 91), and at 1 to 5 years was 2.6 +/- 1.3 (N = 20). Transplant-free survival at 10 year was 89%; there were 6 liver transplants, 2 in patients with small duct PSC and 4 with diffuse large duct PSC. Although the cirrhosis rate was not significantly different in PSC with IBD versus without (22% vs 41%, P = 0.06), the former had a lower rate of liver transplantation (2% vs 18%, P = 0.01). The rate of cirrhosis was lower in patients diagnosed with IBD before PSC (15% vs 31%, P = 0.05). CONCLUSIONS: In this largest reported pediatric PSC cohort, liver transplantation rate at 10 years was lower than that reported in adults. ASC and PSC had similar biochemical abnormalities and degree of fibrosis at diagnosis. PSC that developed after IBD diagnosis had a milder course, possibly reflecting earlier disease detection or milder phenotype. PMID- 27504813 TI - "Twin" Biliary Trees in a Patient With Heterotaxy Syndrome. PMID- 27504814 TI - Predictive Value of Fecal Calprotectin in Pediatric Graft-Versus-Host Disease. PMID- 27504815 TI - Adenomyomatosis of the Gallbladder with Pancreaticobiliary Maljunction in a Child. PMID- 27504817 TI - Technical adequacy of growth estimates from a computer adaptive test: Implications for progress monitoring. AB - Computer adaptive tests (CATs) hold promise to monitor student progress within multitiered systems of support. However, the relationship between how long and how often data are collected and the technical adequacy of growth estimates from CATs has not been explored. Given CAT administration times, it is important to identify optimal data collection schedules to minimize missed instructional time. We used simulation methodology to investigate how the duration and frequency of data collection influenced the reliability, validity, and precision of growth estimates from a math CAT. A progress monitoring dataset of 746 Grade 4, 664 Grade 5, and 400 Grade 6 students from 40 schools in the upper Midwest was used to generate model parameters. Across grades, 53% of students were female and 53% were White. Grade level was not as influential as the duration and frequency of data collection on the technical adequacy of growth estimates. Low-stakes decisions were possible after 14-18 weeks when data were collected weekly (420 540 min of assessment), 20-24 weeks when collected every other week (300-360 min of assessment), and 20-28 weeks (150-210 min of assessment) when data were collected once a month, depending on student grade level. The validity and precision of growth estimates improved when the duration and frequency of progress monitoring increased. Given the amount of time required to obtain technically adequate growth estimates in the present study, results highlight the importance of weighing the potential costs of missed instructional time relative to other types of assessments, such as curriculum-based measures. Implications for practice, research, as well as future directions are also discussed. (PsycINFO Database Record PMID- 27504818 TI - Optical analysis of samarium doped sodium bismuth silicate glass. AB - Samarium doped sodium bismuth silicate glass was synthesized using the melt quenching method. Detailed optical spectroscopic studies of the glassy material were carried out in the UV-Vis-NIR spectral range. Using the optical absorption spectra Judd-Ofelt (JO) parameters are derived. The calculated values of the JO parameters are utilized in evaluating the various radiative parameters such as electric dipole line strengths (Sed), radiative transition probabilities (Arad), radiative lifetimes (taurad), fluorescence branching ratios (beta) and the integrated absorption cross- sections (sigmaa) for stimulated emission from various excited states of Sm3+? ion. The principal fluorescence transitions are identified by recording the fluorescence spectrum. Our analysis revealed that the novel glassy system has the optimum values for the key parameters viz. spectroscopic quality factor, optical gain, stimulated emission cross section and quantum efficiency, which are required for a high performance optical amplifier. Calculated chromaticity co-ordinates (0.61, 0.38) also confirm its application potential in display devices. PMID- 27504819 TI - Synthesis and improved photochromic properties of pyrazolones in the solid state by incorporation of halogen. AB - Four novel photochromic pyrazolones have been prepared by introducing halogen atoms as substituents on the benzene ring. All as-synthesized compounds exhibited excellent reversible photochromic performances in the solid state. Upon UV light irradiation, the as-synthesized compounds can change their structures from E-form to K-form with yellow coloration. Further processed by heating, they rapidly reverted to their initial states at 120 degrees S. Their photo-response and thermal bleaching kinetics were detailed investigated by UV absorption spectra. The results showed that the time constants were higher than that of our previously reported compounds at least one order of magnitude and the rate constants of the as-synthesized compounds were significantly influenced by the size and electronegativity of different halogen atoms. The fluorescence emission were modulated in a high degree via photoisomerization of pyrazolones, which might be due to the efficient energy transfer from E-form to K-form isomers for their partly overlaps between their E-form absorption spectra and K-form fluorescence spectra. PMID- 27504820 TI - Effectiveness of the transpalatal arch in controlling orthodontic anchorage in maxillary premolar extraction cases: A systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the effectiveness of the transpalatal arch (TPA) as an anchorage device in preventing maxillary molar mesialization during retraction of the anterior teeth after premolar extraction. MATERIALS AND METHODS: This systematic review intended to include patients indicated for upper premolar bilateral extraction and subsequent retraction of anterior teeth, considering the use of TPA as an anchorage tool in one of the treatment groups. The search was systematically performed, up to April 2015, in the following electronic databases: Medline, Embase, and all evidence-based medicine reviews via OVID, Cochrane Library, Scopus, PubMed, and Web of Science. Risk of bias assessment was performed using Cochrane's Risk of Bias Tool for randomized clinical trials (RCTs) and Methodological Index for Nonrandomized Studies (MINORS) for non-RCTs. RESULTS: Fourteen articles were finally included. Nine RCTs and five non-RCTs presented moderate to high risk of bias. Only one study investigated the use of TPA in comparison with no anchorage, failing to show significant differences regarding molar anchorage loss. A meta-analysis showed a significant increase in anchorage control when temporary anchorage devices were compared with TPA (mean difference [MD] 2.09 [95% confidence interval {CI} 1.80 to 2.38], seven trials), TPA + headgear (MD 1.71 [95% CI 0.81 to 2.6], four trials), and TPA + utility arch (MD 0.63 [95% CI 0.12 to 1.15], 3 trials). CONCLUSION: Based on mostly moderate risk of bias and with some certainty level, TPA alone should not be recommended to provide maximum anchorage during retraction of anterior teeth in extraction cases. PMID- 27504821 TI - Orthodontically induced external apical root resorption in patients treated with fixed appliances vs removable aligners. AB - OBJECTIVE: To determine whether orthodontic treatment with removable aligners vs fixed orthodontic appliances is associated with a different frequency of orthodontically induced external apical root resorption (OIEARR) when genetic, radiographic, and clinical factors are accounted for. MATERIALS AND METHODS: Three hundred seventy-two orthodontic patients treated with removable aligners (Invisalign) or fixed appliances were genetically screened for interleukin 1B gene (IL1B) (rs1143634), interleukin 1 receptor antagonist gene (IL1RN) (rs419598), and osteopontin gene (SPP1) (rs9138/rs11730582). Twelve clinical variables, potentially associated with OIEARR, were also considered. Subjects were divided according to the presence of radiographically determined OIEARR (>2 mm). The association between OIEARR and appliance type, and radiographic, clinical and genetic factors, was assessed using backward stepwise conditional logistic regression. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported. RESULTS: Reliability of the methods was adequate. Clinical case complexity (American Board of Orthodontics [ABO] Discrepancy Index) (OR: 1.032; 95% CI: 1.005-1.061; P = .021) and extent of incisor apical displacement in the sagittal plane (OR: 1.478; 95% CI: 1.285-1.699; P = .001) were associated with an increased OIEARR risk. After adjusting for associations between clinical/radiographic/genetic factors, there were no statistically significant differences with respect to OIEARR or type of orthodontic appliance used, whether removable aligners or fixed appliances (OR: 1.662; 95% CI: 0.945-2.924; P = .078). Only subjects homozygous for the T allele of IL1RN (rs419598) were more prone to OIEARR during orthodontic treatment (OR: 3.121; CI: 1.93-5.03; P < .001). CONCLUSIONS: A similar OIEARR predisposition was identified using either removable aligners (Invisalign) or fixed appliances. PMID- 27504822 TI - The Role of p-STAT3 as a Prognostic and Clinicopathological Marker in Colorectal Cancer: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: High expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) has been detected in a variety of human tumors. However, the association of positive p-STAT3 expression with clinicopathological parameters and the prognosis of colorectal cancer patients remain controversial. To identify the relationship between p-STAT3 expression and clinicopathological parameters and prognosis in patients with colorectal cancer, a systematic review and meta-analysis were performed. METHODS: We performed a comprehensive literature search from PubMed, EMBASE, and SinoMed through 27 March, 2016. Hazard ratios (HRs) with 95% confidence intervals (CI) were combined to evaluate the association between p-STAT3 expression and overall survival of colorectal cancer patients. Odds ratios (ORs) with 95% CI were combined to evaluate the association between p-STAT3 expression and clinicopathological parameters in patients with colorectal cancer. RESULTS: Seventeen studies including a total of 2,346 colorectal cancer patients were included in this meta-analysis. The combined HR was 1.43 (95% CI: 1.23-1.67, P < 0.001), which suggested a positive relationship between p-STAT3 overexpression and poorer overall survival of colorectal cancer patients. In addition, the results indicated that positive p-STAT3 expression was significantly associated with the presence of lymph node metastasis (OR: 2.43, 95% CI: 1.18-5.01, P = 0.02) but was not associated with TNM stage, tumor differentiation or gender. CONCLUSION: The meta-analysis results suggest that p STAT3 overexpression is unfavorable for the prognosis of colorectal cancer patients, and p-STAT3 overexpression is associated with the presence of lymph node metastasis among colorectal cancer patients. PMID- 27504823 TI - Cluster Sampling Bias in Government-Sponsored Evaluations: A Correlational Study of Employment and Welfare Pilots in England. AB - For pilot or experimental employment programme results to apply beyond their test bed, researchers must select 'clusters' (i.e. the job centres delivering the new intervention) that are reasonably representative of the whole territory. More specifically, this requirement must account for conditions that could artificially inflate the effect of a programme, such as the fluidity of the local labour market or the performance of the local job centre. Failure to achieve representativeness results in Cluster Sampling Bias (CSB). This paper makes three contributions to the literature. Theoretically, it approaches the notion of CSB as a human behaviour. It offers a comprehensive theory, whereby researchers with limited resources and conflicting priorities tend to oversample 'effect enhancing' clusters when piloting a new intervention. Methodologically, it advocates for a 'narrow and deep' scope, as opposed to the 'wide and shallow' scope, which has prevailed so far. The PILOT-2 dataset was developed to test this idea. Empirically, it provides evidence on the prevalence of CSB. In conditions similar to the PILOT-2 case study, investigators (1) do not sample clusters with a view to maximise generalisability; (2) do not oversample 'effect-enhancing' clusters; (3) consistently oversample some clusters, including those with higher than-average client caseloads; and (4) report their sampling decisions in an inconsistent and generally poor manner. In conclusion, although CSB is prevalent, it is still unclear whether it is intentional and meant to mislead stakeholders about the expected effect of the intervention or due to higher-level constraints or other considerations. PMID- 27504824 TI - Spontaneous Alpha Power Lateralization Predicts Detection Performance in an Un Cued Signal Detection Task. AB - Focusing one's attention by external guiding stimuli towards a specific area of the visual field produces systematical neural signatures. One of the most robust is the change in topological distribution of oscillatory alpha band activity across parieto-occipital cortices. In particular, decreases in alpha activity over contralateral and/or increases over ipsilateral scalp sites, respect to the side of the visual field where attention was focused. This evidence comes mainly from experiments where an explicit cue informs subjects where to focus their attention, thus facilitating detection of an upcoming target stimulus. However, recent theoretical models of attention have highlighted a stochastic or non deterministic component related to visuospatial attentional allocation. In an attempt to evidence this component, here we analyzed alpha activity in a signal detection paradigm in the lack of informative cues; in the absence of preceding information about the location (and time) of appearance of target stimuli. We believe that the unpredictability of this situation could be beneficial for unveiling this component. Interestingly, although total alpha power did not differ between Seen and Unseen conditions, we found a significant lateralization of alpha activity over parieto-occipital electrodes, which predicted behavioral performance. This effect had a smaller magnitude compared to paradigms in which attention is externally guided (cued). However we believe that further characterization of this spontaneous component of attention is of great importance in the study of visuospatial attentional dynamics. These results support the presence of a spontaneous component of visuospatial attentional allocation and they advance pre-stimulus alpha-band lateralization as one of its neural signatures. PMID- 27504825 TI - Global Electricity Trade Network: Structures and Implications. AB - Nations increasingly trade electricity, and understanding the structure of the global power grid can help identify nations that are critical for its reliability. This study examines the global grid as a network with nations as nodes and international electricity trade as links. We analyze the structure of the global electricity trade network and find that the network consists of four sub-networks, and provide a detailed analysis of the largest network, Eurasia. Russia, China, Ukraine, and Azerbaijan have high betweenness measures in the Eurasian sub-network, indicating the degrees of centrality of the positions they hold. The analysis reveals that the Eurasian sub-network consists of seven communities based on the network structure. We find that the communities do not fully align with geographical proximity, and that the present international electricity trade in the Eurasian sub-network causes an approximately 11 million additional tons of CO2 emissions. PMID- 27504826 TI - Towards a Collaborative Research: A Case Study on Linking Science to Farmers' Perceptions and Knowledge on Arabica Coffee Pests and Diseases and Its Management. AB - The scientific community has recognized the importance of integrating farmer's perceptions and knowledge (FPK) for the development of sustainable pest and disease management strategies. However, the knowledge gap between indigenous and scientific knowledge still contributes to misidentification of plant health constraints and poor adoption of management solutions. This is particularly the case in the context of smallholder farming in developing countries. In this paper, we present a case study on coffee production in Uganda, a sector depending mostly on smallholder farming facing a simultaneous and increasing number of socio-ecological pressures. The objectives of this study were (i) to examine and relate FPK on Arabica Coffee Pests and Diseases (CPaD) to altitude and the vegetation structure of the production systems; (ii) to contrast results with perceptions from experts and (iii) to compare results with field observations, in order to identify constraints for improving the information flow between scientists and farmers. Data were acquired by means of interviews and workshops. One hundred and fifty farmer households managing coffee either at sun exposure, under shade trees or inter-cropped with bananas and spread across an altitudinal gradient were selected. Field sampling of the two most important CPaD was conducted on a subset of 34 plots. The study revealed the following findings: (i) Perceptions on CPaD with respect to their distribution across altitudes and perceived impact are partially concordant among farmers, experts and field observations (ii) There are discrepancies among farmers and experts regarding management practices and the development of CPaD issues of the previous years. (iii) Field observations comparing CPaD in different altitudes and production systems indicate ambiguity of the role of shade trees. According to the locality specific variability in CPaD pressure as well as in FPK, the importance of developing spatially variable and relevant CPaD control practices is proposed. PMID- 27504827 TI - Health-Related Quality of Life (HRQoL) in Idiopathic Inflammatory Myopathy: A Systematic Review. AB - Health-related quality of life (HRQoL) is a research priority in chronic diseases. We undertook a systematic review (registration #CRD42015024939) to identify, appraise and synthesize the evidence relating to HRQoL in idiopathic inflammatory myopathies (IIM). A comprehensive search was conducted in August 2015 using CINAHL, EMBase and Pubmed to identify studies reporting original data on HRQoL in IIM using generic HRQoL instruments. Characteristics of samples and results from selected studies were extracted and appraised using a standardized approach. Qualitative synthesis of the results was performed. Ten studies including a total of 654 IIM subjects were included in this systematic review. HRQoL was significantly impaired in all subsets of IIM compared with the general population. Disease activity, disease damage and chronic disease course were associated with poorer HRQoL. Insufficient or conflicting results were found in associations between clinical features, treatment, disease duration and mood or illness perception, and HRQoL in IIM. This study suggests that HRQoL is impaired in IIM. However, due to the paucity and heterogeneity of the evidence to date, robust estimates are lacking and significant knowledge gaps persist. There is a need for studies that systematically investigate the correlates and trajectory of HRQoL in IIM. PMID- 27504828 TI - Asymptomatic Vivax and Falciparum Parasitaemia with Helminth Co-Infection: Major Risk Factors for Anaemia in Early Life. AB - BACKGROUND: Anaemia in children under five years old is associated with poor health, growth and developmental outcomes. In Papua, Indonesia, where the burden of anaemia in infants is high, we conducted a community survey to assess the association between Plasmodium infection, helminth carriage and the risk of anaemia. METHODS: A cross sectional household survey was carried out between April and July 2013 in 16 villages in the District of Mimika using a multistage sampling procedure. A total of 629 children aged 1-59 months from 800 households were included in the study. Demographic, symptom and anthropometry data were recorded using a standardized questionnaire. Blood and stool samples were collected for examination. RESULTS: Of the 533 children with blood film examination, 8.8% (47) had P. vivax parasitaemia and 3.9% (21) had P. falciparum; the majority of children with malaria were asymptomatic (94.4%, 68/72). Soil transmitted helminth (STH) infection was present in 43% (105/269) of children assessed; those with STH were at significantly greater risk of P. vivax parasitaemia compared to those without STH (OR = 3.7 [95%CI 1.5-9.2], p = 0.004). Anaemia (Hb<10 g/dl) was present in 24.5% (122/497) of children and associated with P. vivax parasitaemia (OR = 2.9 [95%CI, 1.7-4.9], p = 0.001), P. falciparum parasitaemia (OR = 4.3 [95%CI, 2.0-9.4], p<0.001), hookworm carriage (OR = 2.6 [95%CI, 1.2-5.8], p = 0.026), Plasmodium-helminth coinfection (OR 4.0 [95%CI, 1.4 11.3], p = 0.008) and severe stunting (OR = 1.9 ([95%CI, 1.1-3.3], p = 0.012). CONCLUSIONS: Asymptomatic P. vivax and P. falciparum infections and hookworm all contribute to risk of paediatric anaemia in coendemic areas and should be targeted with prevention and treatment programs. The relationship between helminth infections and the increased risk of P. vivax parasitaemia should be explored prospectively. PMID- 27504829 TI - Linking Core Promoter Classes to Circadian Transcription. AB - Circadian rhythms in transcription are generated by rhythmic abundances and DNA binding activities of transcription factors. Propagation of rhythms to transcriptional initiation involves the core promoter, its chromatin state, and the basal transcription machinery. Here, I characterize core promoters and chromatin states of genes transcribed in a circadian manner in mouse liver and in Drosophila. It is shown that the core promoter is a critical determinant of circadian mRNA expression in both species. A distinct core promoter class, strong circadian promoters (SCPs), is identified in mouse liver but not Drosophila. SCPs are defined by specific core promoter features, and are shown to drive circadian transcriptional activities with both high averages and high amplitudes. Data analysis and mathematical modeling further provided evidence for rhythmic regulation of both polymerase II recruitment and pause release at SCPs. The analysis provides a comprehensive and systematic view of core promoters and their link to circadian mRNA expression in mouse and Drosophila, and thus reveals a crucial role for the core promoter in regulated, dynamic transcription. PMID- 27504830 TI - A Family History of Stroke Is Associated with Increased Intima-Media Thickness in Young Ischemic Stroke - The Norwegian Stroke in the Young Study (NOR-SYS). AB - BACKGROUND AND PURPOSE: Positive family history (FH+) of cardiovascular disease (CVD) is a risk factor for own CVD. We aimed to analyze the effect of different types of FH (stroke, coronary heart disease (CHD), peripheral artery disease (PAD) on carotid intima-media thickness (cIMT) in young and middle-aged ischemic stroke patients. METHODS: First-degree FH of CVD was assessed in ischemic stroke patients <= 60y using a standardized interview. Carotid ultrasound was performed and far wall cIMT in three carotid artery segments was registered, representing the common carotid (CCA-IMT), carotid bifurcation (BIF-IMT) and the internal carotid artery (ICA-IMT). Measurements were compared between FH+ and FH negative groups and stepwise backward regression analyses were performed to identify factors associated with increased cIMT. RESULTS: During the study period 382 patients were enrolled, of which 262 (68%) were males and 233 (61%) reported FH of CVD. Regression analyses adjusting for risk factors revealed age as the most important predictor of cIMT in all segments. The association between FH+ and cIMT was modified by age (p = 0.014) and was significant only regarding ICA-IMT. FH+ was associated with increased ICA-IMT in patients aged < 45y (p = 0.001), but not in patients >= 45y (p = 0.083). The association with ICA-IMT was present for a FH of stroke (p = 0.034), but not a FH+ of CHD or PAD. CONCLUSIONS: FH of stroke is associated with higher ICA-IMT in young ischemic stroke patients. Subtyping of cardiovascular FH is important to investigate heredity in young ischemic stroke patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01597453. PMID- 27504831 TI - Correction: Guidelines for Accurate and Transparent Health Estimates Reporting: the GATHER statement. AB - [This corrects the article DOI: 10.1371/journal.pmed.1002056.]. PMID- 27504832 TI - Biological Maturity Status Strongly Intensifies the Relative Age Effect in Alpine Ski Racing. AB - The relative age effect (RAE) is a well-documented phenomenon in youth sports. This effect exists when the relative age quarter distribution of selected athletes shows a biased distribution with an over-representation of relatively older athletes. In alpine ski racing, it exists in all age categories (national youth levels up to World Cup). Studies so far could demonstrate that selected ski racers are relatively older, taller and heavier. It could be hypothesized that relatively younger athletes nearly only have a chance for selection if they are early maturing. However, surprisingly this influence of the biological maturity status on the RAE could not be proven, yet. Therefore, the aim of the present study was to investigate the influence of the biological maturity status on the RAE in dependence of the level of competition. The study investigated 372 elite youth ski racers: 234 provincial ski racers (P-SR; high level of competition) and 137 national ski racers (N-SR; very high level of competition). Anthropometric characteristics were measured to calculate the age at peak height velocity (APHV) as an indicator of the biological maturity status. A significant RAE was present among both P-SR and N-SR, with a larger effect size among the latter group. The N SR significantly differed in APHV from the P-SR. The distribution of normal, early and late maturing athletes significantly differed from the expected normal distribution among the N-SR, not among the P-SR. Hardly any late maturing N-SR were present; 41.7% of the male and 34% of the female N-SR of the last relative age quarter were early maturing. These findings clearly demonstrate the significant influence of the biological maturity status on the selection process of youth alpine ski racing in dependence of the level of competition. Relatively younger athletes seem to have a chance of selection only if they are early maturing. PMID- 27504833 TI - Elements of Effective Interventions for Addressing Intimate Partner Violence in Latina Women: A Systematic Review. AB - BACKGROUND: Intimate partner violence remains a global problem and is of particular concern in Latina diasporas. AIM: To identify effective elements of interventions to address intimate partner violence in Latina women. METHOD: The systematic review was undertaken according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We focused the search on intervention studies assessing intimate partner violence as an outcome measure and on publications in English and Spanish from the last 11 years (2004-2015). RESULTS: Despite the scope of the problem, from the 1,274 studies screened only four met the search criteria and only a single study included an exclusive Latino population. Of the four interventions, one was only as effective as the control treatment. Heterogeneity of study populations and designs prohibited meta analytic methods. CONCLUSIONS: Theoretically derived interventions that are gender specific, culturally appropriate, target mutual aid through group dynamics, and that are developed collaboratively with the target population are likely to be most effective. PMID- 27504834 TI - [Calf health and antimicrobial use in Swiss dairy herds: Management, prevalence and treatment of calf diseases]. AB - INTRODUCTION: Fifty-two dairy herds in the canton Fribourg were included during one winter in a study on calf management, prevalence and treatments of calf diseases. Colostrum management was optimal in 46.2% of the herds only, and 51.3% of the calves had been sick at least once during the observation period. The most commonly observed diseases included respiratory disease (57.5%), diarrhea (32.8%) and umbilical disease (5.7%). Cases of pneumonia were treated with antimicrobials first by the farmers in 65.4% of the herds. Calf diarrhea was treated with antimicrobial drugs by 57.7% of the farmers. Fluorochinolones were used in 47% of all parenteral treatments and oral antimicrobial drugs included macrolides in 11% of the cases. These results provide information on calf management, calf health and treatment strategies in an area where dairying is the most important sector of the farming industry. They show clearly that the farmers are not sufficiently informed about the use of critically important antimicrobial drugs and about the etiology of calf diarrhea. Improvements in colostrum management and treatment strategies are urgently needed. PMID- 27504835 TI - [Bacterial resistance in bacteria isolated from the nasal cavity of Swiss dairy calves]. AB - INTRODUCTION: Fifty-six E. coli, 37 P. multocida und 8 M. haemolytica were isolated from 157 nasal swabs taken from calves in 52 dairy herds. The antibiotic susceptibility of the organisms was determined by measurement of the minimal inhibitory concentrations. Of the 56 E. coli isolates, 55.3% exhibited resistance to tetracyclines, 55.3% to sulfonamides, 39.3% to beta-lactams, 30.3% to aminoglycosides, 8.9% to fluorochinolones and 3.5% to 3rd generation cephalosporins. The 3rd generation cephalosporin- resistant isolates contained the extended spectrum-beta-lactamase gene blaCTX-M-14 and came from 2 farms where the milk of cows under antimicrobial treatment was fed to the calves and mastitis was treated with cefquinome as first line therapy. Of the 37 P. multocida isolates, 48.6% exhibited resistance to tetracyclines, 16.2% to beta-lactams, and 5.4% each to macrolides, aminoglycosides and sulfonamides. The 8 M. haemolytica isolates showed no resistances against the tested antibiotics. PMID- 27504836 TI - Antimicrobial susceptibility of Brachyspira hyodysenteriae in Switzerland. AB - INTRODUCTION: Brachyspira (B.) hyodysenteriae is the causative agent of swine dysentery (SD), a severe mucohaemorrhagic diarrheal disease in pigs worldwide. So far, the antimicrobial susceptibility patterns of B. hyodysenteriae in Switzerland have not been investigated. Therefore, a panel of 30 porcine B. hyodysenteriae isolates were tested against 6 antimicrobial agents by using the VetMIC Brachy panel, a broth microdilution test. Tiamulin and valnemulin showed high antimicrobial activity inhibiting all isolates at low concentrations. The susceptibility testing of doxycycline revealed values from <=0.25 MUg/ ml (47%) to 2 MUg/ml (10%). The MIC values of lincomycin ranged between <=0.5 MUg/ml (30%) and 32 MUg/ml (43%). For tylosin, 57% of the isolates could not be inhibited at the highest concentration of >=128 MUg/ml. The MIC values for tylvalosin were between <=0.25 MUg/ml (10%) and 8 MUg/ml (20%). These findings reveal Switzerland's favourable situation compared to other European countries. Above all, tiamulin and valnemulin are still effective antimicrobial agents and can be further used for the treatment of SD. PMID- 27504837 TI - The effect of the administration of three different antimicrobial premix formulations via the liquid feeding system on the occurrence of Enterobacteriaceae resistant to tetracycline in the liquid feed for pigs. AB - INTRODUCTION: The oral group treatment is still a common procedure in swine production. This project studied the effect of the application of 3 different formulations of antimicrobial premixes (1. chlortetracycline, 2. chlortetracycline + sulfadimidine + tylosin, 3. sulfadimidine + sulfathiazole + trimethoprim) via the liquid feeding system on the occurrence of tetracycline resistant Enterobacteriaceae (Ent-Tetr) in the liquid feed. 156 and 112 feed samples were collected between April and December 2015 in 13 case and 14 control farms, respectively. The 27 farms were randomly selected pig fattening farms located in different parts of Switzerland. The number of feed samples that contained Ent-Tetr as well as the number of Enterobacteriaceae resistant to tetracycline per sample was significantly higher in the case group than in the control group. The use of any of the 3 antimicrobial combinations turned out to be the main risk factor for the occurrence of Ent-Tetr in the liquid feed. Our results suggest that liquid feed containing antimicrobials is a reservoir of antimicrobial resistant bacteria in swine production. PMID- 27504838 TI - A retrospective analysis of antimicrobial resistance in bacterial pathogens in an equine hospital (2012-2015). AB - INTRODUCTION: Antimicrobial resistance has become an important concern in veterinary medicine. The aim of this study was to describe the rate of antimicrobial resistance in common equine pathogens and to determine the occurrence of multidrug-resistant isolates. A retrospective analysis of all susceptibility testing results from bacterial pathogens cultured from horses at the University of Zurich Equine Hospital (2012-2015) was performed. Strains exhibiting resistance to 3 or more antimicrobial categories were defined as multidrug-resistant. Susceptibility results from 303 bacterial pathogens were analyzed, most commonly Escherichia coli (60/303, 20%) and Staphylococcus aureus (40/303, 13%). High rates of acquired resistance against commonly used antimicrobials were found in most of the frequently isolated equine pathogens. The highest rate of multidrug resistance was found in isolates of Acinetobacter baumannii (23/24, 96%), followed by Enterobacter cloacae complex (24/28, 86%) and Escherichia coli (48/60, 80%). Overall, 60% of Escherichia coli isolates were phenotypically ESBL-producing and 68% of Staphylococcus spp. were phenotypically methicillin-resistant. High rates of acquired antimicrobial resistance towards commonly used antibiotics are concerning and underline the importance of individual bacteriological and antimicrobial susceptibility testing to guide antimicrobial therapy. Minimizing and optimizing antimicrobial therapy in horses is needed. PMID- 27504839 TI - Methicillin-resistant Staphylococcus aureus isolated from dogs and cats in Switzerland. AB - INTRODUCTION: Twenty-two methicillin-resistant Staphylococcus aureus (MRSA) strains isolated from various infected locations in domestic cats and dogs between June 2008 and September 2014 were analyzed for their genotype, genetic fingerprint, virulence and antibiotic resistance profile. Eighteen strains belonged to the clonal complex (CC) 22 [ST22(MLST)-A(PFGE)-t032(spa)-IV(SCCmec) and ST22-A-t1214-IV], 2 strains to the livestock associated MRSA ST398-t011-IV and two were individual strains of ST5-t002-II and ST1-t001-IV. They contained virulence factors such as gamma-hemolysins, beta-hemolysin converting phage genes, leukocidins and enterotoxins. Most widespread resistances were observed against beta-lactams, trimethoprim and fluoroquinolones, but single strains also exhibited resistance to macrolides, lincosamides, aminoglycosides, tetracycline, chloramphenicol and/or mupirocin. The predominant presence of CC22 MRSA strongly indicates clonal spread of a human associated lineage in Swiss companion animals. It is therefore of public health importance to maintain a low level of MRSA infections in animals to avoid uncontrolled dissemination of MRSA clones in humans and animals. PMID- 27504840 TI - Characteristics of ESBL-producing Enterobacteriaceae and Methicillinresistant Staphylococcus aureus (MRSA) isolated from Swiss and imported raw poultry meat collected at retail level. AB - INTRODUCTION: This study was conducted to investigate the occurrence and genetic characteristics of extended spectrum beta-lactamase (ESBL) and methicillin resistant Staphylococcus aureus (MRSA) in 80 samples of Swiss (n=36) and imported (n=44) raw chicken meat collected at retail level. In addition, ESBL-producers were screened for the presence of the plasmid-mediated colistin resistance gene mcr-1. Countries of import included Argentina (n=2), Austria (n=1), Brazil (n=3), Denmark (n=5), France (n=1), Germany (n=13), Hungary (n=5), Italy (n=8), and Slovenia (n=6). Forty ESBL-producing E. coli strains were isolated from 33 (41.3%) of the 80 samples, comprising seven (19.4%) of the Swiss and 26 (59%) of the imported samples. The most common blaESBL among the isolates were blaCTX-M-1 (n=14) and blaSHV-12 (n=16). Other genes comprised blaTEM-52 (n=4), blaCTX-M-2 (n=3), blaCTX-M-8 (n=1), blaCTX-M-14 (n=1) and a novel blaCTX-M-14-like variant (n=1). Two ESBL-producers isolated from samples from Germany (n=1) and Italy (n=1) tested additionally positive for the plasmid-mediated colistin resistance gene mcr-1. Six (7.5%) samples, all imported from Germany, were found to contain MRSA. Three isolates belonged to the livestock-associated CC398-MRSA-V-t034, and 3 to CC9-MRSA-IV-t13177, described here for the first time in chicken meat. PMID- 27504841 TI - Occurrence and features of chromosomally encoded carbapenemases in Gram-negative bacteria in farm animals sampled at slaughterhouse level. PMID- 27504842 TI - Review of the Tuberous Sclerosis Renal Guidelines from the 2012 Consensus Conference: Current Data and Future Study. AB - Renal-related disease is the most common cause of tuberous sclerosis complex (TSC)-related death in adults, and renal angiomyolipomas can lead to complications that include chronic kidney disease (CKD) and hemorrhage. International TSC guidelines recommend mammalian target of rapamycin (mTOR) inhibitors as first-line therapy for management of asymptomatic, growing angiomyolipomas >3 cm in diameter. This review discusses data regarding patient outcomes that were used to develop current guidelines for embolization of renal angiomyolipomas and presents recent data on 2 available mTOR inhibitors - sirolimus and everolimus - in the treatment of angiomyolipoma. TSC-associated renal angiomyolipomas can recur after embolization. Both sirolimus and everolimus have shown effectiveness in reduction of angiomyolipoma volume, with an acceptable safety profile that includes preservation of renal function with long term therapy. The authors propose a hypothesis for mTORC1 haploinsufficiency as an additional mechanism for CKD and propose that preventive therapy with mTOR inhibitors might have a role in reducing the number of angiomyolipoma-related deaths. Because mTOR inhibitors target the underlying pathophysiology of TSC, patients might benefit from treatment of multiple manifestations with one systemic therapy. Based on recent evidence, new guidelines should be considered that support the earlier initiation of mTOR inhibitor therapy for the management of renal angiomyolipomas to prevent future serious complications, rather than try to rescue patients after the complications have occurred. PMID- 27504843 TI - Aortic Stiffness and Inflammation: Dyslipidemia or Matrix Metalloproteinases? PMID- 27504844 TI - Rethinking happiness: using your power for purposea. PMID- 27504845 TI - Comparison of Oral Health Education and Fluoride Varnish to Prevent Early Childhood Caries: A Randomized Clinical Trial. AB - Early childhood caries, a serious health problem among young children, can be prevented with effective intervention. The aim of this study was to evaluate the efficacy of oral health education and a fluoride varnish in the prevention of caries in children under the age of 3 years. For this single-blind randomized parallel group 1-year clinical trial in Shiraz, 300 children aged 12-24 months with sound primary teeth were selected and randomly divided into three groups (n = 100): (1) control: no preventive intervention; (2) oral health counseling, and (3) oral health counseling and fluoride varnish at baseline and 6 months later. At baseline and 4, 8 and 12 months after the intervention, caries risk reduction was recorded as the primary outcome. The mothers' knowledge and performance regarding oral health in children was used as a secondary outcome. A total of 260 children (mean age: 20.49 +/- 7.33 months) completed the study. Compared to group 1, caries risk reduction in group 2 was 28% (95% CI: -39.05 to -17.45) and 31% in group 3 (95% CI: -41.88 to -21.73). However, there was no significant difference between groups 2 and 3 (95% CI: -8.58 to 1.47). In all groups, mothers' knowledge and performance at baseline were low; however, they increased significantly in follow-up appointments in groups 2 and 3 (p < 0.001). Oral health education increased mothers' knowledge and performance regarding oral health in children. Oral health counseling alone or associated with the use of fluoride varnish reduced the caries incidence in young children. PMID- 27504846 TI - A Catalytic Nanoreactor Based on in Vivo Encapsulation of Multiple Enzymes in an Engineered Protein Nanocompartment. AB - Bacterial protein compartments concentrate and sequester enzymes, thereby regulating biochemical reactions. Here, we generated a new functional nanocompartment in Escherichia coli by engineering the MS2 phage capsid protein to encapsulate multiple cargo proteins. Sequestration of multiple proteins in MS2 based capsids was achieved by SpyTag/SpyCatcher protein fusions that covalently crosslinked with the interior surface of the capsid. Further, the functional two enzyme indigo biosynthetic pathway could be targeted to the engineered capsids, leading to a 60 % increase in indigo production in vivo. The enzyme-loaded particles could be purified in their active form and showed enhanced long-term stability in vitro (about 95 % activity after seven days) compared with free enzymes (about 5 % activity after seven days). In summary, this engineered in vivo encapsulation system provides a simple and versatile way for generating highly stable multi-enzyme nanoreactors for in vivo and in vitro applications. PMID- 27504847 TI - Response to: Surgical trainee research collaboratives in the UK: An observational study of research activity and publication productivity. PMID- 27504848 TI - Laparoscopic versus open repair for perforated peptic ulcer: A meta analysis of randomized controlled trials. AB - INTRODUCTION: The role of laparoscopic surgery in the repair for peptic ulcer disease is unclear. The present study aimed to compare the safety and efficacy of laparoscopic versus open repair for peptic ulcer disease. METHODS: Randomized controlled trials (RCTs) comparing laparoscopic versus open repair for peptic ulcer disease were identified from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and references of identified articles and relevant reviews. Primary outcomes were postoperative complications, mortality, and reoperation. Secondary outcomes were operative time, postoperative pain, postoperative hospital stay, nasogastric tube duration, and time to resume diet. Statistical analysis was carried out by Review Manage software. RESULTS: Five RCTs investigating a total of 549 patients, of whom, 279 received laparoscopic repair and 270 received open repair, were included in the final analysis. There were no significant differences between these two procedures in some primary outcomes including overal postoperative complication rate, mortality, and reoperation rate. Subcategory analysis of postoperative complications showed that laparoscopic repair had also similar rates of repair site leakage, intra abdominal abscess, postoperative ileus, pneumonia, and urinary tract infection as open surgery, except of the lower surgical site infection rate (P < 0.05). In addition, there were also no significant differences between these two procedures in some second outcomes including operative time, postoperative hospital stay, and time to resume diet, but laparoscopic repair had shorter nasogastric tube duration (P < 0.05) and less postoperative pain (P < 0.05) than open surgery. CONCLUSIONS: Laparoscopic surgery is comparable with open surgery in the setting of repair for perforated peptic ulcer. The obvious advantages of laparoscopic surgery are the lower surgical site infection rate, shorter nasogastric tube duration and less postoperative pain. However, more higher quality studies should be undertaken to further assess the safety and efficacy of laparoscopic repair for peptic ulcer disease. PMID- 27504849 TI - Limited effectiveness of patent blue dye in addition to isotope scanning for identification of sentinel lymph nodes: Cross-sectional real-life study in 1024 breast cancer patients. AB - BACKGROUND: Although morbidity is reduced when sentinel lymph node (SLN) biopsy is performed with dual isotopic and blue dye identification, the effectiveness of adding blue dye to radioisotope remains debated because side effects including anaphylactic reactions. PATIENTS AND METHODS: Using data from a prospectively maintained database, 1884 lymph node-negative breast cancer patients who underwent partial mastectomy with SLN mapping by a dual-tracer using patent blue dye (PBD) and radioisotope were retrospectively studied between January 2000 and July 2013. Patients with tumors <3 cm and with >1 node detected by one of the two techniques (N = 1024) were included in this real-life cross-sectional study. RESULTS: Among the 1024 patients, 274 had positive SLN detected by isotopic and/or PBD staining. Only 4 patients having no detectable radioactivity in the axilla had SLN identified only by PBD staining (blue-only) while 26 patients had SLN only identified by isotopic detection (hot-only) illustrating failure rates of 9.5% (26/274) and 1.5% (4/274), respectively. Among these four patients, two had negative lymphoscintigraphy. Therefore, the contribution of PBD to metastatic nodes identification was relevant for only 2/274 patients (0.8%). Three patients (0.3%) had an allergic reaction with PBD, and anaphylactic shock occurred in two cases (0.2%). CONCLUSIONS: The added-value of PBD to reduce the false-negative rate of SLN mapping is only limited to the rare cases in which no radioactivity is detectable in the axilla (<1%). When a radioisotope mapping agent is available, the use of PBD should be avoided, because it can induce anaphylaxis. PMID- 27504850 TI - Retinol-Binding Protein 4 Induces Hepatic Mitochondrial Dysfunction and Promotes Hepatic Steatosis. AB - CONTEXT AND OBJECTIVE: Elevated serum retinol-binding protein 4 (RBP4) has been implicated in insulin resistant and nonalcoholic fatty liver disease (NAFLD) subjects; however, the molecular mechanism of RBP4 in NAFLD remains obscure. DESIGN AND PARTICIPANTS: Hepatic RBP4 mRNA level and its association with lipid accumulation were examined in NAFLD patients and mouse model. Furthermore, human RBP4 overexpressing (RBP4-Tg) mice were metabolically phenotyped after either a regular chow or high-fat diet. RESULTS: RBP4 mRNA was aberrantly elevated in NAFLD models and positively associated with increased hepatic triglyceride accumulation. Compared with their wild-type littermates, RBP4-Tg mice fed regular chow had increased hepatic lipid accumulation associated with cellular ballooning and inflammatory changes, which was exacerbated when challenged with high-fat diet. The acceleration of NAFLD in RBP4-Tg mice was mainly attributed to reduced mitochondrial content and impaired mitochondrial fatty acid beta-oxidation. RBP4 overexpression promoted the acetylation of long-chain acyl-coenzyme A dehydrogenase through inhibiting the expression and activity of NAD-dependent deacetylase sirtuin-3 and significantly hampered the binding of long-chain acyl coenzyme A dehydrogenase and NAD-dependent deacetylase sirtuin-3. Moreover, RBP4 induced mitochondrial dysfunction preceded the deterioration of lipid metabolism. CONCLUSIONS: These results have unraveled a novel role of RBP4 in hepatic mitochondrial dysfunction and steatosis and suggest that RBP4 might be a potential target for the early prevention of NAFLD. PMID- 27504851 TI - Steroid Metabolomic Disease Signature of Nonsyndromic Childhood Obesity. AB - CONTEXT: The profile of urinary steroids as measured by gas chromatography-mass spectrometry defines a subject's "steroidal fingerprint." OBJECTIVE: Here, we clustered steroidal fingerprints to characterize patients with nonsyndromic childhood obesity by "steroid metabolomic signatures." HYPOTHESIS: Nonsyndromic obesity is a symptom of different diseases and conditions, some of them will have their own signature. DESIGN: A total of 31 steroid metabolites were quantified by gas chromatography-mass spectrometry, and their excretion rates were z transformed. Using MetaboAnalyst 3.0, we divided the subjects into 5 distinctive groups by k-means clustering. Steroidal fingerprints and clinical/biochemical data of patients in each cluster were analyzed. PATIENTS: A total of 87 obese children (44 females), aged 8.5-17.9 years, were clinically characterized, and their 24-hour urine was collected. RESULTS: Cluster 1 (n = 39, 21 females) had normal steroid profile. Cluster 2 (n = 20, 11 females) showed mild, nonspecific elevation of C19 and C21 steroids, females' resistance to polycystic ovary morphology, and hirsutism. Cluster 3 (n = 7 female), with relative 21-hydroxylase insufficiency, was characterized by partial or full polycystic ovary syndrome. Cluster 4 (n = 4 males), showed markedly elevated C21 steroids and imbalance in the 11beta-hydroxysteroid dehydrogenase system, higher insulin, increased frequency of glucose/insulin index more than 0.3, gamma-glutamyl transpeptidase activity, systolic blood pressure, and tendency to liver steatosis. Cluster 5 (n = 17, 5 females) had elevated dehydroepiandrosterone and 17-OH-pregnenolone metabolites, suggesting 3beta-hydroxysteroid dehydrogenase insufficiency but no clinically unique phenotype. Z-score body mass index values were not significantly different between the clusters. CONCLUSIONS: We defined a novel concept of disease-specific steroid metabolomic signature based on urinary steroidal gas chromatography-mass spectrometry. Clustering by software designed for metabolic data analysis reclassified childhood obesity into 5 groups with distinctive signatures; groups require further definition and may require cluster specific therapeutic strategies. PMID- 27504852 TI - Insulinoma Due to Multiple Pancreatic Microadenoma Localized by Multimodal Imaging. AB - CONTEXT: Insulinomas are usually due to a solitary tumor, but they can be challenging to localize. CASE DESCRIPTION: A 66-year-old woman presented with a 1 year history of episodic neuroglycopenic hypoglycemia and was suspected of having an insulinoma. On a supervised fast, she was found to be hypoglycemic at 39 mg/dL, with an insulin of 40 MUU/mL 26 hours into the fast and a proinsulin of 35 pmol/L. Contrast-enhanced computed tomography and magnetic resonance imaging did not localize a pancreatic lesion. Intra-arterial calcium stimulation testing showed a step-up of venous insulin levels at injection of the superior mesenteric artery and proximal and mid-splenic artery, and a 68Ga-DOTATATE positron emission tomography/computed tomography showed focal uptake in the neck of the pancreas with a standardized uptake value of 12. Despite negative intraoperative pancreatic palpation and ultrasound, the patient underwent an extended distal pancreatectomy with normalization of biochemical levels and resolution of her symptoms. Pathology showed four subcentimeter neuroendocrine tumors that were positive for insulin, consistent with a diagnosis of multiple microadenomas. CONCLUSIONS: Multiple microadenomas are a rare cause of hyperinsulinemic hypoglycemia and localization, and resection of these tumors may be facilitated by multimodal imaging. PMID- 27504853 TI - Quantitative model for the blood pressure-lowering interaction of valsartan and amlodipine. AB - AIMS: The objective of this study was to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model to quantitatively describe the antihypertensive effect of combined therapy with amlodipine and valsartan. METHODS: PK modelling was used with data collected from 48 healthy volunteers receiving a single dose of combined formulation of 10 mg amlodipine and 160 mg valsartan. Systolic (SBP) and diastolic blood pressure (DBP) were recorded during combined administration. SBP and DBP data for each drug alone were gathered from the literature. PKPD models of each drug and for combined administration were built with NONMEM 7.3. RESULTS: A two-compartment model with zero order absorption best described the PK data of both drugs. Amlodipine and valsartan monotherapy effects on SBP and DBP were best described by an Imax model with an effect compartment delay. Combined therapy was described using a proportional interaction term as follows: (D1 + D2 ) +ALPHA*(D1 * D2 ). D1 and D2 are the predicted drug effects of amlodipine and valsartan monotherapy respectively. ALPHA is the interaction term for combined therapy. Quantitative estimates of ALPHA were -0.171 (95% CI: -0.218, -0.143) for SBP and -0.0312 (95% CI: -0.07739, -0.00283) for DBP. These infra-additive interaction terms for both SBP and DBP were consistent with literature results for combined administration of drugs in these classes. CONCLUSION: PKPD models for SBP and DBP successfully described the time course of the antihypertensive effects of amlodipine and valsartan. An infra additive interaction between amlodipine and valsartan when used in combined administration was confirmed and quantified. PMID- 27504854 TI - Sex and pairing status explain variations in the activation of nonapeptide receptors in song and motivation regions. AB - The nonapeptides oxytocin and vasopressin have been implicated in a variety of social behaviors. In zebra finches, oxytocin antagonists decrease pairing in both sexes, and pairing, in turn, increases expression of both mesotocin (the avian homologue of oxytocin) and vasotocin (the avian homologue of vasopressin). Increases in mesotocin and vasotocin mRNA are correlated with the amount of directed singing by males. Thus, in the present study, we examined the hypothesis that activation of cells containing nonapeptide receptors in song-related regions (ventral tegmental area, lateral septum, and medial preoptic nucleus) would also be correlated with directed singing in males. To rule out the possibility that these regions are involved in general pairing motivation, we also included females as subjects. In the ventral tegmental area, males had higher ZENK and V1aR than females and paired animals (regardless of sex) had higher ZENK and V1aR than did unpaired animals. In the medial preoptic nucleus, paired animals had higher ZENK than did unpaired animals, and there were no sex or pairing effects in the lateral septum. Only ZENK + V1aR in the medial preoptic nucleus was correlated with singing in males. These findings suggest that pairing is associated activation of nonapeptide receptors in the ventral tegmental area and the medial preoptic nucleus, but there is only partial evidence that courtship singing accounts for these findings. (PsycINFO Database Record PMID- 27504855 TI - Lipoprotein lipase in chronic lymphocytic leukemia: function and prognostic implications. AB - Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation of a clonal population of B cells in peripheral blood, bone marrow, and lymphoid organs. More than 10 years ago, lipoprotein lipase (LPL) mRNA was identified as being strongly expressed in patients experiencing a more aggressive phenotype, while CLL patients with an indolent disease course lack expression of this marker. Since then, several reports confirmed the capability of LPL to predict CLL disease evolution at the moment of diagnosis. In contrast, data on the functional implications of LPL in CLL are scarce. LPL exerts a central role in overall lipid metabolism and transport, but plays additional, non-catalytic roles as well. Which of those is more important in the pathogenesis of CLL remains largely unclear. Here, we review the current knowledge on the prognostic and biological relevance of LPL in CLL. PMID- 27504856 TI - Further Evolution of Multifunctional Niosomes Based on Pluronic Surfactant: Dual Active Targeting and Drug Combination Properties. AB - The loading of chemotherapics into smart nanocarriers that simultaneously possess more than one useful property for specifically targeting a tumor site improves their therapeutic effectiveness, reducing their side effects. Hence, we proposed a combined approach for the treatment of human breast cancer (BC) consisting of the co-encapsulation of doxorubicin and curcumin or doxorubicin and quercetin into multifunctional niosomes, which results in prolonged blood circulation and an ability to spontaneously accumulate at the tumor site (passive target) and to recognize and bind the tumor cells through dual ligand-receptor interactions (active target). The drug-loaded vesicles showed high stability and good capability of loading doxorubicin and antioxidants alone or in combination. Their diameter was around 400 nm. The drugs released from the vesicles were found to be controlled and sustained for over 24 h, with a strong dependence on the co presence of the loaded molecules. Transferrin and/or folic acid were conjugated on the external surface of the niosomes as ligands, considerably improving the cellular uptake into MCF-7 and MDA-MB-231 malignant cells when compared with the uptake of nonconjugated samples. In vitro evaluation of anticancer activity demonstrated the strong potential of niosomes loaded with a doxorubicin/curcumin combination as useful devices in breast tumor treatment. These features hold great promise for the development of multifunctional devices that combine several advantages such as biocompatibility, stealth properties, loading capability, and active targeting, moving toward the development of more specific and efficient carriers for personalized tumoral therapy. PMID- 27504857 TI - Physics behind Water Transport through Nanoporous Boron Nitride and Graphene. AB - In this work, molecular dynamics simulations were used to determine the surface tension profile of water on graphene and boron nitride (BN) multilayers and to predict water permeation through nanoporous graphene and BN membranes. For both graphene and BN multilayers, a decrease in surface tension (gamma) was evidenced as the number of layers increased. This lessening in gamma was shown to result from a negative surface tension contribution due to long-range wetting of water, which also contributes to lower water permeation through a two-layer membrane with respect to permeation through a monolayer. We also showed that a decrease in water surface tension on a BN monolayer with regards to graphene was at the origin of an increase in water permeation through BN. Our findings suggest that nanoporous BN membranes could be attractive candidates for desalination applications. PMID- 27504858 TI - Novel H2S Releasing Nanofibrous Coating for In Vivo Dermal Wound Regeneration. AB - Hydrogen sulfide (H2S), together with nitric oxide and carbon monoxide, has been recognized as an important gasotransmitter. It plays an essential physiological role in regulating cyto-protective signal process, and H2S-based therapy is considered as the next generation of promising therapeutic strategies for many biomedical applications, such as the treatment of cardiovascular disease. Through electrospinning of polycaprolactone (PCL) containing JK1, a novel pH-controllable H2S donor, nanofibers with H2S releasing function, PCL-JK1, are fabricated. This fibrous scaffold showed a pH-dependent H2S releasing behavior, i.e., lower pH induced greater and faster H2S release. In addition, the H2S release of JK1 was prolonged by the fibrous matrix as shown by decreased releasing rates compared to JK1 in solutions. In addition, in vitro studies indicated that PCL-JK1 exhibited excellent cyto-compatibility, similar to PCL fibers. Finally, we investigated PCL JK1 as a wound dressing toward a cutaneous wound model in vivo and found that PCL JK1 could significantly enhance the wound repair and regeneration compared with the control PCL scaffold, likely due to the release of H2S, which results in a broad range of physiologically protective functions toward the wound. PMID- 27504859 TI - Comparative approaches to cortical microcircuits. AB - Recent trends in neuroscience have narrowed the scope of this field, notably through the progressive elimination of 'model systems' that were key to the development of modern molecular, developmental and functional neuroscience. Although the fantastic opportunities offered by modern molecular biology entirely justify the use of selected organisms (e.g., for their genetic advantages), we argue that a diversity of model systems is essential if we wish to identify the brain's computational principles. It is through comparisons that we can hope to separate mechanistic details (results of each organism's specific history) from functional principles, those that will hopefully one day lead to a theory of the brain. PMID- 27504861 TI - Copper(II)-Graphitic Carbon Nitride Triggered Synergy: Improved ROS Generation and Reduced Glutathione Levels for Enhanced Photodynamic Therapy. AB - Graphitic carbon nitride (g-C3 N4 ) has been used as photosensitizer to generate reactive oxygen species (ROS) for photodynamic therapy (PDT). However, its therapeutic efficiency was far from satisfactory. One of the major obstacles was the overexpression of glutathione (GSH) in cancer cells, which could diminish the amount of generated ROS before their arrival at the target site. Herein, we report that the integration of Cu(2+) and g-C3 N4 nanosheets (Cu(2+) -g-C3 N4 ) led to enhanced light-triggered ROS generation as well as the depletion of intracellular GSH levels. Consequently, the ROS generated under light irradiation could be consumed less by reduced GSH, and efficiency was improved. Importantly, redox-active species Cu(+) -g-C3 N4 could catalyze the reduction of molecular oxygen to the superoxide anion or hydrogen peroxide to the hydroxyl radical, both of which facilitated the generation of ROS. This synergy of improved ROS generation and GSH depletion could enhance the efficiency of PDT for cancer therapy. PMID- 27504862 TI - Cutaneous presentation of Chagas' disease reactivation in a heart-transplant patient. PMID- 27504860 TI - A comparative approach to cerebellar function: insights from electrosensory systems. AB - Despite its simple and highly-ordered circuitry the function of the cerebellum remains a topic of vigorous debate. This review explores connections between the cerebellum and sensory processing structures that closely resemble the cerebellum in terms of their evolution, development, patterns of gene expression, and circuitry. Recent studies of cerebellum-like structures involved in electrosensory processing in fish have provided insights into the functions of granule cells and unipolar brush cells-cell types shared with the cerebellum. We also discuss the possibility, supported by recent studies, that generating and subtracting predictions of the sensory consequences of motor commands may be core functions shared by both cerebellum-like structures and the cerebellum. PMID- 27504864 TI - Risk factors for recurrent admissions with diabetic ketoacidosis: importance of mental health. PMID- 27504865 TI - The Effect of Muscarinic Receptor Modulators on the Antinociception Induced by CB2 Receptor Agonist, JWH133 in Mice. AB - There is no published study regarding the interaction between muscarinic receptor modulators and antinociception induced by cannabinoid receptor (CB2) agonist. The effect of pilocarpine (a muscarinic agonist) and atropine (a muscarinic antagonist) on JWH-133 (a CB2 agonist) induced analgesia in mice was studied. First the analgesic effect of JWH-133 (0.001-1 mg/Kg) or pilocarpine (2.5-20 mg/kg) or atropine (0.2-5 mg/kg) was evaluated. Subsequently, the effect of co administration of pilocarpine (2.5 mg/kg) or atropine (5 mg/kg) and JWH-133 (0.001-1 mg/Kg) were studied too. JWH-133 and pilocarpine provoked antinociception in mice but atropine did not. Pilocarpine potentiated the analgesic effect of JWH-133 but atropine antagonized that. It can be concluded that JWH-133 induced antinociception is affected by muscarinic receptor modulators in mice. PMID- 27504863 TI - Comparison of tibiofemoral joint space width measurements from standing CT and fixed flexion radiography. AB - The objective of this project was to determine the relationship between medial tibiofemoral joint space width measured on fixed-flexion radiographs and the three-dimensional joint space width distribution on low-dose, standing CT (SCT) imaging. At the 84-month visit of the Multicenter Osteoarthritis Study, 20 participants were recruited. A commercial SCT scanner for the foot and ankle was modified to image knees while standing. Medial tibiofemoral joint space width was assessed on radiographs at fixed locations from 15% to 30% of compartment width using validated software and on SCT by mapping the distances between three dimensional subchondral bone surfaces. Individual joint space width values from radiographs were compared with three-dimensional joint space width values from corresponding sagittal plane locations using paired t-tests and correlation coefficients. For the four medial-most tibiofemoral locations, radiographic joint space width values exceeded the minimal joint space width on SCT by a mean of 2.0 mm and were approximately equal to the 61st percentile value of the joint space width distribution at each respective sagittal-plane location. Correlation coefficients at these locations were 0.91-0.97 and the offsets between joint space width values from radiographs and SCT measurements were consistent. There were greater offsets and variability in the offsets between modalities closer to the tibial spine. Joint space width measurements on fixed-flexion radiographs are highly correlated with three-dimensional joint space width from SCT. In addition to avoiding bony overlap obscuring the joint, a limitation of radiographs, the current study supports a role for SCT in the evaluation of tibiofemoral OA. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1388-1395, 2017. PMID- 27504866 TI - Potential Contribution of Antioxidant Mechanism in the Defensive Effect of Lycopene Against Partial Sciatic Nerve Ligation Induced Behavioral, Biochemical and Histopathological Modification in Wistar Rats. AB - Neuropathic pain is a severe and unbearable condition which arises due to activation of peripheral nociceptors after tissue damage, neuropathic pain is caused from anomalous physiology of central or peripheral nervous system and it may not be related to the ongoing tissue damage or inflammation. Involvement of oxidative damage has been reported in the pathophysiology of neuropathic pain. The purpose of this study was to examine the effect of lycopene to quench the free radicals produced as a result of the increased oxidative stress in neuropathic pain. Neuropathic pain was induced in wistar rats by partial sciatic nerve ligation. The effect was evaluated by assessing various behavioral parameters (thermal hyperalgesia, cold hyperalgesia), biochemical parameters (lipid peroxidation, reduced glutathione, superoxide dismutase and catalase) as well as histopathological parameters in sciatic nerve. During the experiment group of 8 rats each was administered drugs once daily intraperitonealy (I.P.) and naive groups, sham group and sciatic nerve ligated group were treated with vehicle for the duration of 14 days. Partial sciatic nerve ligation (PSNL) significantly caused thermal hyperalgesia, cold hyperalgesia and oxidative damage compared to normal and sham groups. Daily administration of lycopene (25 mg/kg, 50 mg/kg) and gabapentin (100 mg/kg) considerably reversed hyperalgesia, cold hyperalgesia and attenuated oxidative stress when compared to control group. There was significant histological improvement in the in the architecture of myelinated and unmyelinated fibers. The results indicated that free radical generation mechanism might be involved in PSNL induced behavior, biochemical and histopathological changes in wistar rats. PMID- 27504867 TI - Efficacy of Full u-Opioid Receptor Agonists is not Impaired by Concomitant Buprenorphine or Mixed Opioid Agonists/Antagonists - Preclinical and Clinical Evidence. AB - Buprenorphine and the mixed agonists/antagonists nalbuphine and pentazocine, formerly classified as u-opioid (MOP) receptor antagonists, have more recently been shown to be partial to full agonists of the human MOP receptor. These receptors do not necessarily have to be maximally activated for a full physiological response. Partial agonists can also sufficiently stimulate signaling processes leading to a full analgesic response, as shown by the effectiveness of buprenorphine, nalbuphine and pentazocine in animal pain models and in clinical settings where these drugs induce analgesia with full efficacy without a ceiling effect. Submaximal doses of MOP receptor analgesics combined with submaximal doses of buprenorphine, pentazocine, or nalbuphine result in additive to over-additive antinociceptive effects in animal experiments. Only when doses are given that exceed the therapeutic dose range may the antinociceptive effect be reduced to the effect of either opioid alone. The analgesic effects of pentazocine and nalbuphine combined with morphine are reported to be additive or over-additive in various clinical pain conditions. Buprenorphine, which clinically behaves as a full MOP receptor agonist for pain relief, can be combined with full opioid agonists without precipitating withdrawal. Thus, the overall evidence on the analgesic effects of buprenorphine, pentazocine or nalbuphine combined with opioid analgesics under various clinical pain conditions contradicts the consensus that these compounds diminish MOP receptor analgesia when co-administered with a full MOP receptor agonist. PMID- 27504868 TI - Agomelatine and Transient Elevation of Creatine Phosphokinase. AB - Agomelatine is an antidepressant drug with moderate agonistic action at the melatonine receptor MT1 and weak effect at MT2. According to clinical studies, agomelatine ameliorates depressive symptoms and improves sleep quality. Side effects such as elevated liver enzymes are well-known. Therefore, routine laboratory monitoring of liver function is recommended periodically throughout treatment because of a rare risk of more serious liver reactions. 2 patients with creatine phosphokinase elevation during treatment with agomelatine are presented. We recommend a check of the creatine phosphokinase level during the initial treatment phase in patients receiving agomelatine for the first time. PMID- 27504869 TI - Construction of Chiral [4 + 4] and [2 + 2] Schiff-Base Macrocyclic Zinc(II) Complexes Influenced by Counterions and Pendant Arms. AB - Chiral and racemic 68-membered [4 + 4] tetranuclear and 34-membered [2 + 2] dinuclear Schiff-base macrocyclic zinc(II) complexes 1-10 can be selectively synthesized based on the secondary template effects of counterions and pendant arms, when [(S,S), (R,R), (+/-)]-1,2-diaminocyclohexane precursors are first used to react with a pair of extended dialdehydes with different pendant arms via zinc(II) ion template-assisted imine condensation. PMID- 27504870 TI - Phase I metabolism of the highly potent synthetic cannabinoid MDMB-CHMICA and detection in human urine samples. AB - Among the recently emerged synthetic cannabinoids, MDMB-CHMICA (methyl N-{[1 (cyclohexylmethyl)-1H-indol-3-yl]carbonyl}-3-methylvalinate) shows an extraordinarily high prevalence in intoxication cases, necessitating analytical methods capable of detecting drug uptake. In this study, the in vivo phase I metabolism of MDMB-CHMICA was investigated using liquid chromatography electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry (LC-ESI-Q ToF-MS) techniques. The main metabolites are formed by hydrolysis of the methyl ester and oxidation of the cyclohexyl methyl side chain. One monohydroxylated metabolite, the ester hydrolysis product and two further hydroxylated metabolites of the ester hydrolysis product are suggested as suitable targets for a selective and sensitive detection in urine. All detected in vivo metabolites could be verified in vitro using a human liver microsome assay. Two of the postulated main metabolites were successfully included in a comprehensive LC-ESI-MS/MS screening method for synthetic cannabinoid metabolites. The screening of 5717 authentic urine samples resulted in 818 cases of confirmed MDMB-CHMICA consumption (14%). Since the most common route of administration is smoking, smoke condensates were analyzed to identify relevant thermal degradation products. Pyrolytic cleavage of the methyl ester and amide bond led to degradation products which were also formed metabolically. This is particularly important in hair analysis, where detection of metabolites is commonly considered a proof of consumption. In addition, intrinsic activity of MDMB-CHMICA at the CB1 receptor was determined applying a cAMP accumulation assay and showed that the compound is a potent full agonist. Based on the collected data, an enhanced interpretation of analytical findings in urine and hair is facilitated. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27504871 TI - Transport phenomena of nanoparticles in plants and animals/humans. AB - The interaction of a plethora nanoparticles with major biota such as plants and animals/humans has been the subject of various multidisciplinary studies with special emphasis on toxicity aspects. However, reports are meager on the transport phenomena of nanoparticles in the plant-animal/human system. Since plants and animals/humans are closely linked via food chain, discussion is imperative on the main processes and mechanisms underlying the transport phenomena of nanoparticles in the plant-animal/human system, which is the main objective of this paper. Based on the literature appraised herein, it is recommended to perform an exhaustive exploration of so far least explored aspects such as reproducibility, predictability, and compliance risks of nanoparticles, and insights into underlying mechanisms in context with their transport phenomenon in the plant-animal/human system. The outcomes of the suggested studies can provide important clues for fetching significant benefits of rapidly expanding nanotechnology to the plant-animal/human health-improvements and protection as well. PMID- 27504872 TI - Immunomodulatory effects of exposure to polychlorinated biphenyls and perfluoroalkyl acids in East Greenland ringed seals (Pusa hispida). AB - To better elucidate the potential immune-related health effects of exposure to environmentally persistent organic pollutants (POP), such as polychlorinated biphenyls (PCBs) and perfluoroalkyl substances (PFASs), in ringed seals (Pusa hispida), a sentinel Arctic species, we assessed 1) associations between mitogen induced lymphocyte proliferation and in vivo tissue contaminant burdens, and 2) the concentration-response effects of in vitro exposure to PFASs and PCB congeners on mitogen-induced lymphocyte proliferation. Upon in vitro contaminant exposure, the non-coplanar PCB congeners CB 138, 153, and 180, but not the coplanar CB 169, significantly reduced lymphocyte proliferation between 10 and 20ugg-1 ww. The respective in vitro EC50 values for these congeners were 13.3, 20.7, 20.8, and 54.6ugg-1 ww. No modulation of lymphocyte proliferation was observed upon in vitro exposure to two individual PFASs, perfluorooctane sulphonic acid (PFOS) and perfluorooctanoic acid (PFOA), at concentrations up to 1000ngg-1. In addition, no significant correlations were found between lymphocyte proliferation and any blood or blubber contaminant measured. Taken together, these data suggest this population of ringed seals is not currently at high risk of altered lymphocyte proliferation from exposure to the POPs or PFASs in this study. PMID- 27504873 TI - Human exposure to endocrine disrupting compounds: Their role in reproductive systems, metabolic syndrome and breast cancer. A review. AB - Endocrine disrupting chemicals (EDCs) are released into the environment from different sources. They are mainly used in packaging industries, pesticides and food constituents. Clinical evidence, experimental models, and epidemiological studies suggest that EDCs have major risks for humans by targeting different organs and systems in the body (e.g. reproductive system, breast tissue, adipose tissue, pancreas, etc.). Due to the ubiquity of human exposure to these compounds the aim of this review is to describe the most recent data on the effects induced by phthalates, bisphenol A and parabens in a critical window of exposure: in utero, during pregnancy, infants, and children. The interactions and mechanisms of toxicity of EDCs in relation to human general health problems, especially those broadening the term of endocrine disruption to 'metabolic disruption', should be deeply investigated. These include endocrine disturbances, with particular reference to reproductive problems and breast, testicular and ovarian cancers, and metabolic diseases such as obesity or diabetes. PMID- 27504875 TI - Understanding the bereavement care roles of nurses within acute care: a systematic review. AB - AIMS AND OBJECTIVES: To investigate nurses' roles and responsibilities in providing bereavement care during the care of dying patients within acute care hospitals. BACKGROUND: Bereavement within acute care hospitals is often sudden, unexpected and managed by nurses who may have limited access to experts. Nurses' roles and experience in the provision of bereavement care can have a significant influence on the subsequent bereavement process for families. Identifying the roles and responsibilities, nurses have in bereavement care will enhance bereavement supports within acute care environments. DESIGN: Mixed-methods systematic review. METHODS: The review was conducted using the databases Cumulative Index Nursing and Allied Health Literature Plus, Embase, Ovid MEDLINE, PsychINFO, CareSearch and Google Scholar. Included studies published between 2006 2015, identified nurse participants, and the studies were conducted in acute care hospitals. Seven studies met the inclusion criteria, and the research results were extracted and subjected to thematic synthesis. RESULTS: Nurses' role in bereavement care included patient-centred care, family-centred care, advocacy and professional development. Concerns about bereavement roles included competing clinical workload demands, limitations of physical environments in acute care hospitals and the need for further education in bereavement care. CONCLUSIONS: Further research is needed to enable more detailed clarification of the roles nurse undertake in bereavement care in acute care hospitals. There is also a need to evaluate the effectiveness of these nursing roles and how these provisions impact on the bereavement process of patients and families. RELEVANCE TO CLINICAL PRACTICE: The care provided by acute care nurses to patients and families during end-of-life care is crucial to bereavement. The bereavement roles nurses undertake are not well understood with limited evidence of how these roles are measured. Further education in bereavement care is needed for acute care nurses. PMID- 27504874 TI - Risk and impact of pulmonary complications in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. AB - BACKGROUND: Pulmonary complications after cancer therapy are varied. This study describes pulmonary outcomes among childhood cancer survivors and evaluates their impact on daily activities. METHODS: The incidence of pulmonary outcomes (asthma, chronic cough, emphysema, lung fibrosis, oxygen need, and recurrent pneumonia) reported among 5-year cancer survivors (n = 14,316) and the incidence of death due to pulmonary causes among all eligible survivors (n = 20,690) in the Childhood Cancer Survivor Study were compared with those for sibling controls (n = 4027) with cumulative incidence, standardized mortality ratio (SMR), and piecewise exponential models. Logistic regression with random effects was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for activity limitations with pulmonary complications. RESULTS: By the age of 45 years, the cumulative incidence of any pulmonary condition was 29.6% (95% CI, 29.1%-30.0%) for cancer survivors and 26.5% (95% CI, 24.9%-28.0%) for siblings. Fewer survivors reported ever smoking (23.6% vs 36.4%, P < .001), but survivors were more likely to report chronic cough (rate ratio [RR], 1.6; 95% CI, 1.4-1.9), oxygen need (RR, 1.8; 95% CI, 1.5-2.2), lung fibrosis (RR, 3.5; 95% CI, 2.3-5.4), and recurrent pneumonia (RR, 2.0; 95% CI, 1.4-3.0). The SMR for death due to pulmonary causes was 5.9 (95% CI, 4.2-8.1), and it was associated with platinum exposure and lung radiation (P < .01). The impact of chronic cough on daily activities for survivors (OR vs survivors without chronic cough, 2.7) was greater than that for siblings (OR, 2.0; P = .04). CONCLUSIONS: Pulmonary complications are substantial among adult survivors of childhood cancer and can affect daily activities. Cancer 2016;122:3687-96. (c) 2016 American Cancer Society. PMID- 27504876 TI - Relevance of New Definitions to Incidence and Prognosis of Acute Kidney Injury in Hospitalized Patients with Cirrhosis: A Retrospective Population-Based Cohort Study. AB - BACKGROUND: The implementation of new serum creatinine (SCr)-based criteria for acute kidney injury (AKI) has brought to light several areas of uncertainty in patients with cirrhosis. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: Adults with cirrhosis hospitalized between 2002-2012. PREDICTOR: We aimed to address the prognostic implications of the new AKI criteria in cirrhosis. OUTCOMES: Baseline kidney function was defined from all outpatient SCr within 3 months before hospitalization. Cox proportional hazards models were fit to examine associations between AKI, renal recovery and all-cause mortality. RESULTS: 4,733 patients were studied. The 30-day mortality was higher for participants with AKI (43.9% vs 8.5%; p-value<0.001), and increased with AKI severity. The highest incidence of AKI occurred when the lowest SCr within the three months prior to admission was used to define baseline. The hazard ratio for mortality using the lowest SCr within 3 months and the closest pre-admission SCr (definition suggested by the recent consensus guideline) were similar, validating the use of the latter measure. As compared to patients without AKI, stage 1 AKI with maximum SCr <=132 mmol/L remained associated with a 3.5-fold increased hazard of death at 30 days (95% CI 2.6 to 4.7). LIMITATIONS: As an observational study, the results were vulnerable to residual confounding and ascertainment bias in the use of laboratory data to identify AKI. We did not have access to liver function or disease etiology variables and were unable to adjust for these in our analyses. CONCLUSIONS: These results confirm the graded relationship between AKI severity, renal recovery, and mortality and further clarify previously discordant reports about the prognostic relevance of new AKI criteria in patients with cirrhosis. PMID- 27504878 TI - Longitudinal Predictors of Outcomes for Adults With Autism Spectrum Disorder: Systematic Review. AB - To generate an evidence-based understanding of longitudinal predictors of social outcomes (i.e., employment, social relationships/participation, independent living) of adults with autism spectrum disorder (ASD), we conducted a systematic literature review of publications since 2000. Twelve publications deriving from eight study samples fit inclusion/exclusion criteria for the review. In these publications, statistically significant predictors of social outcomes fell into five categories: (a) personal characteristics, (b) individual functioning, (c) family context, (d) services, and (e) other factors (i.e., peer influence, health status). However, only two studies demonstrated high methodological quality, and only one category of predictors-individual functioning-was identified across multiple study samples. To inform practices for youth with ASD, there remains a need for high-quality outcome research related to adults with ASD to better understand predictors, especially related to environmental factors such as related to the family and services received. PMID- 27504877 TI - Identification and Functional Testing of ERCC2 Mutations in a Multi-national Cohort of Patients with Familial Breast- and Ovarian Cancer. AB - The increasing application of gene panels for familial cancer susceptibility disorders will probably lead to an increased proposal of susceptibility gene candidates. Using ERCC2 DNA repair gene as an example, we show that proof of a possible role in cancer susceptibility requires a detailed dissection and characterization of the underlying mutations for genes with diverse cellular functions (in this case mainly DNA repair and basic cellular transcription). In case of ERCC2, panel sequencing of 1345 index cases from 587 German, 405 Lithuanian and 353 Czech families with breast and ovarian cancer (BC/OC) predisposition revealed 25 mutations (3 frameshift, 2 splice-affecting, 20 missense), all absent or very rare in the ExAC database. While 16 mutations were unique, 9 mutations showed up repeatedly with population-specific appearance. Ten out of eleven mutations that were tested exemplarily in cell-based functional assays exert diminished excision repair efficiency and/or decreased transcriptional activation capability. In order to provide evidence for BC/OC predisposition, we performed familial segregation analyses and screened ethnically matching controls. However, unlike the recently published RECQL example, none of our recurrent ERCC2 mutations showed convincing co-segregation with BC/OC or significant overrepresentation in the BC/OC cohort. Interestingly, we detected that some deleterious founder mutations had an unexpectedly high frequency of > 1% in the corresponding populations, suggesting that either homozygous carriers are not clinically recognized or homozygosity for these mutations is embryonically lethal. In conclusion, we provide a useful resource on the mutational landscape of ERCC2 mutations in hereditary BC/OC patients and, as our key finding, we demonstrate the complexity of correct interpretation for the discovery of "bonafide" breast cancer susceptibility genes. PMID- 27504879 TI - Item-Level Psychometrics of the Glasgow Outcome Scale: Extended Structured Interviews. AB - The Glasgow Outcome Scale-Extended (GOSE) structured interview captures critical components of activities and participation, including home, shopping, work, leisure, and family/friend relationships. Eighty-nine community dwelling adults with mild-moderate traumatic brain injury (TBI) were recruited (average = 2.7 year post injury). Nine items of the 19 items were used for the psychometrics analysis purpose. Factor analysis and item-level psychometrics were investigated using the Rasch partial-credit model. Although the principal components analysis of residuals suggests that a single measurement factor dominates the measure, the instrument did not meet the factor analysis criteria. Five items met the rating scale criteria. Eight items fit the Rasch model. The instrument demonstrated low person reliability (0.63), low person strata (2.07), and a slight ceiling effect. The GOSE demonstrated limitations in precisely measuring activities/participation for individuals after TBI. Future studies should examine the impact of the low precision of the GOSE on effect size. PMID- 27504880 TI - Life Balance and Stress in Adults With Medical Conditions or Obesity. AB - This cross-sectional research examined differences in life balance and perceived stress by body mass index (BMI) levels and self-reported medical conditions that limited physical activity. The sample consisted of 2,338 participants between the ages of 18 and 49 years who took the Life Balance Inventory, the Perceived Stress Scale, and provided demographic information including height and weight. Findings showed that individuals who were obese (BMI > 30.0) reported significantly lower life balance scores and higher stress scores than participants without obesity (p < .001). Also, individuals who had medical conditions that resulted in activity limitations reported significantly less life balance and more stress than individuals without medical conditions (p < .001). These findings highlight the importance of addressing activity participation as a means to promote health and wellness. PMID- 27504881 TI - Developing a Canadian-Specific Version of the Fitness-to-Drive Screening Measure(c). AB - The Fitness-to-Drive Screening Measure((c)) (FTDS) is a valid and reliable screening tool that identifies at-risk older drivers. Although 12,300 Canadians have used the FTDS in the last 2 years, the resources/recommendations targeted the U.S. CONTEXT: The objective of this article is to identify the FTDS resources/recommendations appropriate for Canadian users and the barriers that Canadian stakeholders experience when promoting older driver fitness. Twenty stakeholders from three provinces (eight occupational therapists, three certified driver rehabilitation specialists, four physicians, and five members of advocacy organizations) participated in semi-structured interviews. We conducted summative and thematic content analysis. A comprehensive set of resources/recommendations was identified. Barriers to older driver fitness decisions included fear of losing the license, compromising the physician-client relationship, insufficient training/resources for health care professionals, and inadequate alternative transportation. Canadian context-specific resources/recommendations were integrated into a Canadian version of the FTDS. This version may better serve Canadian older drivers, caregivers, and health care professionals. PMID- 27504882 TI - Integrating the Science of Habit: Opportunities for Occupational Therapy. AB - Chronic diseases are the leading causes of early morbidity and mortality in the United States. Because personal behaviors are the primary risk factors for developing chronic diseases, developing effective strategies to modify personal behaviors remains a national imperative. Occupational therapy can help address this problematic situation through interventions based on an understanding of habit and principles of habit modification. The objective of this paper is to provide an evidence-based argument for occupational therapy research and practice targeting health-promoting lifestyle behaviors as habits. We discuss empirical research conducted over the previous decade with a focus on the role of habit in daily behavior, key evidence-based strategies for changing existing habits and developing new habits, and recent advances in habit measurement in relation to issues of intervention design. Understanding habit development, function, and change offers a novel orientation for occupational therapy toward practice and research on many complex health problems. PMID- 27504884 TI - [Impact of entry age and veterinary care on health and performance of veal calves. I. Mortality and antimicrobial use]. AB - INTRODUCTION: The objective of this field study was to describe the impact of the entry age and intensive veterinary care on mortality and antimicrobial use of veal calves in Switzerland. From July until October 2012, a total of 316 young calves (aged o 10.8 days) and from November 2012 until May 2013 a total of 425 market calves (aged o 39.5 days) were housed on a welcome-farm, where they obtained daily veterinary care during the first 6 weeks of the production cycle. As a 3rd category 2 groups of 34 and 31 old calves (aged o 61.5 days), respectively, were housed on a commercial farm. From entry to slaughter the daily doses of antibiotics on group level averaged 35.6 in young calves, 26.2 in commercial calves, and 21.0 in old calves. On the welcome-farm 45.9% and 48.5% of the young and market calves, respectively, were individually treated, and in the finishing period of the production cycle 10.4% and 3.3% of the young and market calves, respectively. Of the old calves 16.9% were individually treated. Mortality was 6.7% in young calves, 8.2% in commercial calves, and 4.6% in old calves. Intensive veterinary care guaranteed early recognition of disease and euthanasia of terminally morbid calves. The different entry ages did not lead to any reduction in mortality or in antimicrobial use compared to previous studies. PMID- 27504885 TI - [Impact of the entry age and veterinary care on the health and performance of veal calves. II. Blood values, performance and carcass quality]. AB - INTRODUCTION: The objective of this field study was to investigate the impact of the entry age and of veterinary care on blood values, performance and carcass quality of veal calves in Switzerland. From July 2012 until May 2013 a total of 316 young calves (aged o 10.8 days), 425 market calves (aged o 39.5 days), and 65 old calves (aged o 61.5 days) were observed during the production cycle. As control calves 9'019 veal calves fattened at the same time as the market calves were available. At time of entry the average hemoglobin value of 88.2 g/l in market calves was significantly (p < 0.001) lower than in young (96.2 g/l), old (95.0 g/l) and control calves (95.0 g/l). At time of slaughter the hemoglobin of control calves was 101.2 g/l and significantly (p < 0.001) lower than in young (129.6 g/l) and market calves (131.6 g/l). The average daily weight gain reached 1.21 kg in young calves, 1.28 kg in market calves, 1.29 kg in old calves and 1.30 kg in control calves. The premature slaughter rate was 3.4% in control calves, 8.1% young (p < 0.001), 3.4% in commercial and 0% in old calves (p = 0.17). The percentage of the favorite carcass quality was 53.8% in control calves and differed significantly (p < 0.001) from young (43.5%) and market calves (42.8%), but not from old calves (50.8%, p = 0.9). The carcass color with the average photometric L-value of 41.5 in young and 41.6 in market calves differed significantly (p < 0.001) from old (44.4) and control calves (45.4). The intensive veterinary care and the different entry ages had no positive effect on performance and carcass quality. The iron supply resulted in increased hemoglobin values and in reddish carcass color in more than 50% of the investigated calves. PMID- 27504886 TI - Evaluation of antimicrobial activity of Italian honey for wound healing application in veterinary medicine. AB - INTRODUCTION: Honey as a topical treatment for infected wounds dates back to ancient times. However, few studies have been reported concerning the medical properties of Italian honey. In this study, the microbial contamination, the antimicrobial activity and the antibiotic residues of 6 different varieties of Piedmont honeys were evaluated. The antimicrobial activity of honeys was tested by agar well diffusion method and 1 honey for each variety has been selected and tested by broth micro-dilution test to determine Minimum Inhibitory Concentrations (MICs) and evaluated by Minimum Bactericidal Concentrations (MBCs). The honeys with a high level of antibacterial activity were analyzed for the presence of tetracyclines, sulfonamides and macrolide residues. The agar well diffusion method showed the greatest antimicrobial activity for honeydew, chestnut and lime tree honeys. The MICs and MBCs identified the close similarity to the medical manuka honey of honeydew, polyfloral and chestnut honey. The levels of antibiotic residues on these honeys were below the limit of quantification. Based on our results the Italian variety of honeydew showed the best antimicrobial activity and can be considered for the treatment of infected wounds in animals. PMID- 27504887 TI - Outbreak of sheeppox in farmed sheep in Kyrgystan: Histological, eletron microscopical and molecular characterization. AB - INTRODUCTION: On a farm in the Kyrgyz Republic, several dead sheep were found without any history of illness. The sheep showed several ulcerations on lips and bare-skinned areas. At necropsy the lungs showed multiple firm nodules, which were defined as pox nodules histologically. In the rumen hyperkeratotic plaques were visible. With electron microscopy pox viral particles were detected and confirmed with q PCR as Capripoxviruses. Although all members of the Capripoxvirus genus are eradicated in western countries, this study should remind us of the classical lesions observed in poxvirus infections. PMID- 27504888 TI - Epidemiology of Parkinson's Disease: A Population-Based Study in Primary Care in Italy. AB - BACKGROUND: There are no studies on prevalence, incidence and comorbidities of Parkinson's disease (PD) in the Italian population. METHODS: The database of 700 Italian general practitioners (population, 923,356) was investigated. All patients with International Classification of Diseases Ninth Revision - Clinical Modification (ICD-9-CM) diagnosis of PD during the period 2002-2012 were included. Parkinsonisms were excluded. Clinical conditions preceding PD were identified through ICD-9-CM codes. The Charlson Comorbidity Index was used. PD crude and standardized prevalence and annual incidence were calculated. Crude and adjusted hazard ratios were calculated for comorbidities. RESULTS: A total of 2,204 patients (1,140 men, 1,064 women, age 22-95 years) were included. The crude prevalence of PD was 239/100,000. Prevalence increased exponentially with age. Standardized prevalence was 233 (95% CI 232-235). One hundred ninety-four patients were newly diagnosed, giving a crude incidence of 22/100,000 and a standardized incidence of 23.1/100,000 (95% CI 22.9-23.2). Incidence increased steadily until age 75-84 years and then decreased. Older age, cardiovascular and gastrointestinal disorders, diabetes, and restless-legs syndrome were associated with increased PD risk and smoking and hypersomnia with decreased PD risk. The Charlson Comorbidity Index was associated with PD risk with a documented gradient. CONCLUSIONS: Prevalence and incidence of PD in Italy are in line with studies with the highest case ascertainment. PD risk varies with the number and type of comorbidities. PMID- 27504889 TI - Examining the Feasibility and Predictive Validity of the SAGAT Tool to Assess Situation Awareness Among Medical Trainees. AB - INTRODUCTION: Situational awareness (SA) describes a team's ability to perceive environmental elements, comprehend their meaning, and anticipate future events. Although SA is consistently described as a critical competency among surgical teams, there is a dearth of research identifying efficacious methods to assess and develop SA in such settings. The aim of this study was to investigate the feasibility of implementing an objective tool that has been used to measure SA in other intense and dynamic environments -the Situation Awareness Global Assessment Technique (SAGAT)-and to examine its ability to predict surgical trainee team performance. METHODS: Ten team-training sessions were conducted involving 2 standardized high-fidelity trauma simulation scenarios. Teams consisted of 4 or 5 participants, and roles were randomly assigned. Team situational awareness was assessed using the SAGAT method, which involves intermittent freezes to probe trainee awareness of the situation. Team performance was assessed using the Mayo High-Performance Teamwork Scale. Hierarchical regression was used to examine SA performance relationships for each scenario. RESULTS: Forty-three third-year medical students participated in the training sessions. Team SA ranged from 45% to 79% and 46% to 97% for the first and second scenarios, respectively. Additionally, team SA significantly predicted team performance for both the first scenario (F(1, 42)=19.57; P<0.001; R=0.30) and second scenario (F(1,42)=26.18, P<0.001; R=0.38). CONCLUSIONS: The SAGAT is a valid, reliable tool for assessing surgical trainee SA. Information provided by the SAGAT can help diagnose team performance problems, inform debriefing discussion points, and inform curriculum development endeavors. PMID- 27504890 TI - Improving Nurses' Peripheral Intravenous Catheter Insertion Knowledge, Confidence, and Skills Using a Simulation-Based Blended Learning Program: A Randomized Trial. AB - INTRODUCTION: Peripheral intravenous catheter (PIVC) insertion is one of the most common invasive procedures performed in a hospital, but most nurses receive little formal training in this area. Blended PIVC insertion training programs that incorporate deliberate simulated practice have the potential to improve clinical practice and patient care. METHODS: The study was a randomized, wait list control group with crossover using nurses on three medical/surgical units. Baseline PIVC knowledge, confidence, and skills assessments were completed for both groups. The intervention group then received a 2-hour PIVC online course, followed by an 8-hour live training course using a synergistic mix of three simulation tools. Both groups were then reassessed. After crossover, the wait list group received the same intervention and both groups were reassessed. RESULTS: At baseline, both groups were similar for knowledge, confidence, and skills. Compared with the wait-list group, the intervention group had significantly higher scores for knowledge, confidence, and skills upon completing the training program. After crossover, the wait-list group had similarly higher scores for knowledge, confidence, and skills than the intervention group. Between the immediate preintervention and postintervention periods, the intervention group improved scores for knowledge by 31%, skills by 24%, and decreased confidence by 0.5%, whereas the wait-list group improved scores for knowledge by 28%, confidence by 16%, and skills by 15%. CONCLUSIONS: Results demonstrate significant improvements in nurses' knowledge, confidence, and skills with the use of a simulation-based blended learning program for PIVC insertion. Transferability of these findings from a simulated environment into clinical practice should be further explored. PMID- 27504891 TI - Multifunctional Magnetoliposomes for Sequential Controlled Release. AB - The simultaneous or sequential delivery of multiple therapeutic active principles to a specific target is one of the main challenges of nanomedicine. This goal requires the construction of complex devices often extremely time and cost consuming. Supramolecular self-assemblies, with building blocks of different nature, each providing a specific function to the final construct, can combine a facile synthetic route with a high tunability and structural control. In this study we provide the proof-of-principle of a drug delivery system, DDS, constituted of (i) liposomes, providing a fully biocompatible lipid scaffold suitable to host both hydrophobic and hydrophilic drugs; (ii) a double-stranded DNA conjugated with a cholesteryl unit that spontaneously inserts into the lipid membrane; and (iii) hydrophobic and hydrophilic superparamagnetic iron oxide nanoparticles (SPIONs) embedded inside the lipid membrane of liposomes or connected to the DNA, respectively. Upon application of an alternating magnetic field, the SPIONs can trigger, through thermal activation, the release of a DNA strand or of the liposomal payload, depending on the frequency and the application time of the field, as proved by both steady-state and time-resolved fluorescence studies. This feature is due to the different localization of the two kinds of SPIONS within the construct and demonstrates the feasibility of a multifunctional DDS, built up from self-assembly of biocompatible building blocks. PMID- 27504892 TI - Genetic Differentiation, Isolation-by-Distance, and Metapopulation Dynamics of the Arizona Treefrog (Hyla wrightorum) in an Isolated Portion of Its Range. AB - Population attributes such as diversity, connectivity, and structure are important components of understanding species persistence and vulnerability to extinction. Hyla wrightorum, the Arizona treefrog, is native to the southwestern United States and Mexico, and an isolated group of populations exists in the Huachuca Mountains and Canelo Hills (HMCH) of southeastern Arizona, USA. Due to concerns about declining observations of the species within the isolated HMCH portion of its range, the HMCH group is currently a candidate for federal protection under the U.S. Endangered Species Act. We present results of a genetic study examining population diversity, structure, and connectivity within the HMCH region. We sampled DNA from H. wrightorum larvae and adults from ten distinct locations, 8 of which were breeding sites and 4 of which were previously undescribed localities for the species. We developed and genotyped 17 polymorphic microsatellite loci and quantified genetic diversity, population differentiation, and landscape influences on population genetic structure. We found evidence of larger than expected effective population sizes, significant genetic differentiation between populations, and evidence of distance being the primary driver of genetic structure of populations with some influence of slope and canopy cover. We found little evidence of recent genetic bottlenecks, and individual-based analyses indicate admixture between populations despite significant genetic differentiation. These patterns may indicate that the breeding sites within the Huachuca Mountains constitute a metapopulation. We suggest that the HMCH region may contain larger and more connected breeding populations than previously understood, but the dynamics of this system and the limited geographic extent of the HMCH group justify current concern for the persistence of the species in this region. Efforts to ensure availability of high quality breeding habitats and control for local threats such as effects of invasive predators may be critical to the persistence of these unique populations of H. wrightorum. PMID- 27504893 TI - Differential microRNA Expression and Regulation in the Rat Model of Post Infarction Heart Failure. AB - BACKGROUND: Heart failure is a complex end stage of various cardiovascular diseases with a poor prognosis, and the mechanisms for development and progression of heart failure have always been a hot point. However, the molecular mechanisms underlying the post transcriptional regulation of heart failure have not been fully elucidated. Current data suggest that microRNAs (miRNAs) are involved in the pathogenesis of heart failure and could serve as a new biomarker, but the precise regulatory mechanisms are still unclear. METHODS: The differential miRNA profile in a rat model of post-infarction heart failure was determined using high throughout sequencing and analyzed through bioinformatics approaches. The results were validated using qRT-PCR for 8 selected miRNAs. Then the expression patterns of 4 miRNAs were analyzed in different periods after myocardial infarction. Finally, gain- and loss-of-function experiments of rno-miR 122-5p and rno-miR-184 were analyzed in H2O2 treated H9c2 cells. RESULTS: In the heart failure sample, 78 miRNAs were significantly upregulated and 28 were downregulated compared to the controls. GO and KEGG pathway analysis further indicated the likely roles of these miRNAs in heart failure. Time-course analysis revealed different expression patterns of 4 miRNAs: rno-miR-122-5p, rno-miR-199a 5p, rno-miR-184 and rno-miR-208a-3p. Additionally, rno-miR-122-5p and rno-miR-184 were proved to promote apoptosis in vitro. CONCLUSIONS: Differential profile and expression patterns of miRNAs in the rats model of post-infarction heart failure were found, and the pro-apoptotic roles of rno-miR-122-5p and rno-miR-184 were revealed. These findings may provide a novel way that may assist in heart failure diagnosis and treatment. PMID- 27504894 TI - Developmental Toxicity of Zinc Oxide Nanoparticles to Zebrafish (Danio rerio): A Transcriptomic Analysis. AB - Zinc oxide nanoparticles (ZnO NPs) are being utilized in an increasing number of fields and commercial applications. While their general toxicity and associated oxidative stress have been extensively studied, the toxicological pathways that they induce in developmental stages are still largely unknown. In this study, the developmental toxicity of ZnO NPs to embryonic/larval zebrafish was investigated. The transcriptional expression profiles induced by ZnO NPs were also investigated to ascertain novel genomic responses related to their specific toxicity pathway. Zebrafish embryos were exposed to 0.01, 0.1, 1, and 10 mg/L ZnO NPs for 96 h post fertilization. The toxicity of ZnO NPs, based on their Zn concentration, was quite similar to that in embryonic/larval zebrafish exposed to corresponding ZnSO4 concentrations. Pericardial edema and yolk-sac edema were the principal malformations induced by ZnO NPs. Gene-expression profiling using microarrays demonstrated 689 genes that were differentially regulated (fold change >1.5) following exposure to ZnO NPs (498 upregulated, 191 downregulated). Several genes that were differentially regulated following ZnO NP exposure shared similar biological pathways with those observed with ZnSO4 exposure, but six genes (aicda, cyb5d1, edar, intl2, ogfrl2 and tnfsf13b) associated with inflammation and the immune system responded specifically to ZnO NPs (either in the opposite direction or were unchanged in ZnSO4 exposure). Real-time reverse-transcription quantitative polymerase chain reaction confirmed that the responses of these genes to ZnO NPs were significantly different from their response to ZnSO4 exposure. ZnO NPs may affect genes related to inflammation and the immune system, resulting in yolk-sac edema and pericardia edema in embryonic/larval developmental stages. These results will assist in elucidating the mechanisms of toxicity of ZnO NPs during development of zebrafish. PMID- 27504895 TI - Electronic and Photophysical Properties of [Re (L)(CO)3(phen)](+) and [Ru(L)2(bpy)2](2+) (L = imidazole), Building Units for Long-Range Electron Transfer in Modified Blue Copper Proteins. AB - The electronic, optical, and photophysical properties of [Re(im)(CO)3(phen)](+) and [Ru(bpy)2(im)2](2+) (im = imidazole; phen = 1,10-phenanthroline; bpy = 2,2' bipyridine) in water, including spin-orbit coupling (SOC) effects, were studied by means of density functional theory (DFT) and time-dependent DFT. The main features of the visible experimental absorption spectra of both molecules are well-reproduced. Whereas the theoretical spectrum of the Re(I) complex is characterized by one metal-to-ligand charge transfer (MLCTphen) state of low intensity at 394 nm and a strongly absorbing MLCTphen state calculated at 370 nm, the spectrum of the Ru(II) complex presents a high density of singlet MLCTbpy excited states with significant oscillator strengths that contribute to the two broad bands centered at 490 and 340 nm. The absorption spectrum of [Re(im) (CO)3(phen)](+) is perturbed by SOC with non-negligible mixing between the low lying triplet and singlet absorbing states, while SOC has no effect on the absorption spectrum of [Ru(bpy)2(im)2](2+). A detailed structural investigation of the two lowest singlet and four lowest triplet excited states of the Re(I) complex point to MLCTphen (S1, S2, T1, T2) and intra-ligand ILphen (T3) localized spin-densities characterized by small contractions from both Re-N and phen CC central bonds in the MLCT states and nearly no deformation in the IL state. A mechanism of luminescent decay of [Re(im) (CO)3(phen)](+) is proposed on the basis of the calculated energy minima and wavelengths of emission for the interpretation of the three frequency/time-scale signals put in evidence by ultrafast experiments. The long-lived emissive properties of [Ru(bpy)2(im)2](2+) are analyzed on the basis of the relative energies of the two lowest (3)MLCTbpy and metal-centered (3)MC excited states. The minimum corresponding to the (3)MC spin density shows a significant structural rearrangement with an increase of the Ru-N bond distance of 0.33 A and a closure of the N-Ru-N bond angle of 20 degrees inducing a large distortion of the octahedral motif. The spin-density associated with the lowest (3)MLCTbpy localized on one bpy ligand suggests the presence of a second degenerate (3)MLCTbpy minimum. The luminescence of the Ru(II) complex calculated at 669 nm is partially quenched by the presence of the low (3)MC nonradiative state at 1064 nm. When interacting with modified metal-based proteins the two complexes will behave differently because of these distinctive photophysical properties. PMID- 27504896 TI - Deep Brain Stimulation for Status Dystonicus: A Case Series and Review of the Literature. AB - BACKGROUND: Status dystonicus (SD) is a rare and potentially life-threatening complication of primary or secondary dystonia, characterized by acute worsening of dystonic movements. There is no consensus regarding optimal treatment, which may be medical and/or surgical. METHODS: We present our experience with pallidal deep brain stimulation (DBS) in 5 DYT1-positive patients with SD and provide a review of the literature to examine optimal management. RESULTS: Of the 5 patients treated with pallidal DBS, all experienced postoperative resolution of their dystonic crisis within a range of 1-21 days. Long-term follow-up resulted in 1 patient returning to preoperative baseline, 3 patients improving from baseline, and 1 patient making a complete recovery. Of the 28 SD patients (including our 5 patients) reported in the literature who were treated with DBS or ablative surgery, 26 experienced cessation of their dystonic crisis with a return to baseline function and, in most cases, clinical improvement. CONCLUSION: DBS is an effective therapeutic modality for the treatment of SD. In addition to the long-term benefits of stimulation, early and aggressive treatment may improve the overall outcome. PMID- 27504897 TI - Association of Intestinal Microbiota with Metabolic Markers and Dietary Habits in Patients with Type 2 Diabetes. AB - BACKGROUND/AIMS: Evidence suggests that intestinal microbiota, along with factors such as diet and host genetics, contributes to obesity, metabolic dysfunction and diabetes. Therefore, we examined the relationship between gut microbiota, blood metabolic markers, dietary habits and fecal short-chain fatty acids (SCFAs) in patients with type 2 diabetes mellitus (T2DM). METHODS: Dietary habits, blood and fecal samples from 59 T2DM patients were recruited, and the association of intestinal microbiota with metabolic markers and dietary habits was analyzed. RESULTS: Total energy intake was 1,692 +/- 380 kcal/day. Carbohydrate, fat and protein intakes were 57.5 +/- 5.2, 23.2 +/- 5.3 and 13.2 +/- 2.2%, respectively. Dietary habits - high carbohydrate, fat, and protein intake - were associated with increased counts of Clostridium clusters IV and XI and decreased counts of Bifidobacterium spp., order Lactobacillales and Clostridium cluster IV. Protein intake was negatively correlated with fecal acetate and total SCFAs. Total SCFAs, propionate and acetate were negatively correlated with blood insulin levels and the homeostasis model of insulin resistance. CONCLUSION: Diets low in protein and carbohydrates favor a healthy gut microbiome and improve glucose tolerance in T2DM patients, although further elucidation of the role of the gut microbiome could lead to better therapies and prophylaxes. PMID- 27504899 TI - The development of peer reflective supervision amongst nurse educator colleagues: An action research project. AB - This action research study developed the use of peer reflective supervision (PRS) amongst eight nurse educators contributing to an undergraduate Adult Nursing programme at a UK University. During the academic year (2013-14), nurse educator co-researchers met for an introductory workshop and then met regularly in pairs to facilitate each other's reflection. This provided an opportunity for nurse educators to reflect on identified issues linked to their role with a facilitative peer. Educators met three additional times in a Reflexive Learning Group (RLG), to gather data on their use of PRS. Audio-recordings from the RLGs were transcribed and analysed using Norton's (2009) thematic analysis framework. Co-researchers iteratively validated the data and an external validation group critically viewed the evidence. Overall, seven themes were generated from the three research cycles. These were: PRS as a Valuable Affirming Experience; Time Issues; Facilitation- Support, Trust and Challenge; Developing a Flexible 'Toolbox'; To Write or Not to Write; Drawing on Literature; and Requirement for Action. Findings add new evidence regarding use of a flexible toolbox of resources to develop reflection and offer practical guidance on the development of PRS. Nurse educators often experienced similar concerns, and a facilitative supervision structure allowed co-researchers to positively explore these. Recognition of work pressures and requirement for time and space for reflection was highlighted, particularly regarding writing, and exploring the literature, to develop critical analysis of experiences. The importance of action as part of the reflective process was emphasised. Co-researchers reported positive personal change as well as the opportunity to highlight issues through their reflection for further action within the organisation. The study adds constructive evidence for the use of reflection to explore professional work, make sense of experiences and develop positive action. It has transferability to a wider international audience interested in the development of reflection amongst colleagues and the use of insider research techniques to challenge and develop practice. PMID- 27504898 TI - Social image concerns promote cooperation more than altruistic punishment. AB - Human cooperation is enigmatic, as organisms are expected, by evolutionary and economic theory, to act principally in their own interests. However, cooperation requires individuals to sacrifice resources for each other's benefit. We conducted a series of novel experiments in a foraging society where social institutions make the study of social image and punishment particularly salient. Participants played simple cooperation games where they could punish non cooperators, promote a positive social image or do so in combination with one another. We show that although all these mechanisms raise cooperation above baseline levels, only when social image alone is at stake do average economic gains rise significantly above baseline. Punishment, either alone or combined with social image building, yields lower gains. Individuals' desire to establish a positive social image thus emerges as a more decisive factor than punishment in promoting human cooperation. PMID- 27504900 TI - On the validity of self-report assessment of cognitive abilities: Attentional control scale associations with cognitive performance, emotional adjustment, and personality. AB - Individual differences in attentional control involve the ability to voluntarily direct, shift, and sustain attention. In studies of the role of attentional control in emotional adjustment, social relationships, and vulnerability to the effects of stress, self-report questionnaires are commonly used to measure this construct. Yet, convincing evidence of the association between self-report scales and actual cognitive performance has not been demonstrated. Across 2 independent samples, we examined associations between self-reported attentional control (Attentional Control Scale; ACS), self-reported emotional adjustment, Five-Factor Model personality traits (NEO Personality Inventory-Revised) and performance measures of attentional control. Study 1 examined behavioral performance on the Attention Network Test (ANT; Fan, McCandliss, Sommer, Raz, & Posner, 2002) and the Modified Switching Task (MST; Suchy & Kosson, 2006) in a large sample (n = 315) of healthy young adults. Study 2 (n = 78) examined behavioral performance on standardized neuropsychological tests of attention, including Conner's Continuous Performance Test-II and subtests from the Wechsler Adult Intelligence Scales, Third Edition (WAIS-III; Psychological Corporation, 1997) and Delis-Kaplan Executive Function System (D-KEFS; Delis, Kaplan, & Kramer, 2001). Results indicated that the ACS was largely unrelated to behavioral performance measures of attentional control but was significantly associated with emotional adjustment, neuroticism, and conscientiousness. These findings suggest that although self-reported attentional control may be a useful construct, researchers using the ACS should exercise caution in interpreting it as a proxy for actual cognitive ability or performance. (PsycINFO Database Record PMID- 27504901 TI - The development and validation of attention constructs from the First Year Inventory. AB - Individual differences in early attention are associated with later social, cognitive, and emotional development, and attentional deficits in the first year are associated with risk for developmental disorders such as Autism Spectrum Disorder (ASD). The First Year Inventory (FYI; Baranek, Watson, Crais, & Reznick, 2003) was developed to identify 12-month-olds at risk for an ASD diagnosis. The current study identifies FYI items that reflect aspects of early attention that might predict future typical and atypical social, cognitive, and emotional development. Using a series of theoretical and statistical methods, we developed 3 attention-based constructs from the FYI: Responding to Social Attention (RSA), Initiating Social Attention (ISA), and Nonsocial Sensory Attention (NSA). A database with completed FYIs was analyzed using these constructs to determine the strength of relations among items. Cronbach's alpha analyses indicated good internal consistency, and item distribution was further supported using a confirmatory factor analysis. Data analyses showed statistically significant relations between the scores on these domains at 12 months and subsequent social responsiveness scores at 3 years. Analyses demonstrating the statistical and predictive validity of these 3 FYI attention constructs support their use for innovative explorations of infant behavioral patterns that can be used to predict typical and atypical individual trajectories in the development of later social, cognitive, and emotional skills. (PsycINFO Database Record PMID- 27504902 TI - Cognitive discrepancy models for specific learning disabilities identification: Simulations of psychometric limitations. AB - Few studies have investigated specific learning disabilities (SLD) identification methods based on the identification of patterns of processing strengths and weaknesses (PSW). We investigated the reliability of SLD identification decisions emanating from different achievement test batteries for 1 method to operationalize the PSW approach: the concordance/discordance model (C/DM; Hale & Fiorello, 2004). Two studies examined the level of agreement for SLD identification decisions between 2 different simulated, highly correlated achievement test batteries. Study 1 simulated achievement and cognitive data across a wide range of potential latent correlations between an achievement deficit, a cognitive strength and a cognitive weakness. Latent correlations permitted simulation of case-level data at specified reliabilities for cognitive abilities and 2 achievement observations. C/DM criteria were applied and resulting SLD classifications from the 2 achievement test batteries were compared for agreement. Overall agreement and negative agreement were high, but positive agreement was low (0.33-0.59) across all conditions. Study 2 isolated the effects of reduced test reliability on agreement for SLD identification decisions resulting from different test batteries. Reductions in reliability of the 2 achievement tests resulted in average decreases in positive agreement of 0.13. Conversely, reductions in reliability of cognitive measures resulted in small average increases in positive agreement (0.0-0.06). Findings from both studies are consistent with prior research demonstrating the inherent instability of classifications based on C/DM criteria. Within complex ipsative SLD identification models like the C/DM, small variations in test selection can have deleterious effects on classification reliability. (PsycINFO Database Record PMID- 27504903 TI - Can the Frost Multidimensional Perfectionism Scale assess perfeccionismo? AB - Although culture-based measurement bias threatens the validity of intergroup comparison research, measurement invariance is often assumed rather than demonstrated by researchers who draw conclusions about cross-cultural similarities or differences. The current article investigates the cross-cultural invariance of a popular measure of perfectionism, the Frost Multidimensional Perfectionism Scale (F-MPS; Frost, Marten, Lahart, & Rosenblate, 1990) for a Hispanic/Latina sample. Perfectionism, which encompasses high goal setting and sensitivity to critical evaluation, is a transdiagnostic risk factor for internalizing psychopathology that especially warrants focus among groups burdened by mental health disparities. Multiple samples were used in a series of analyses to construct a baseline first-order measurement model and test for cross group equivalence. For model development, confirmatory factor analyses (CFAs) were used with 320 female participants (Mage = 19.61 years) who identified primarily (n = 301) as European/European American. Measurement invariance testing was conducted with multigroup CFAs using another sample of female adults (n = 574; Mage = 21.21 years), identifying either as European/European American (n = 217) or Hispanic/Latina/Latin American (n = 357). Evidence was found for invariance across the revised F-MPS factor structure, pattern of factor loadings, and factor variances/covariances. Results indicate that predictive relationships may be compared across these groups, but caution is suggested when interpreting raw mean score differences due to intercept nonequivalence. Further, second-order model testing demonstrated support for the bidimensional model of perfectionism cross-culturally. Future research on perfectionism within the Latino/a population is encouraged using this equivalent item set. (PsycINFO Database Record PMID- 27504904 TI - Resilience in the United States Air Force: Psychometric properties of the Connor Davidson Resilience Scale (CD-RISC). AB - Results are presented for the largest study (N = 53,692) ever conducted on the 25 item Connor-Davidson Resilience Scale (CD-RISC), a popular measure of resilience. We examined the internal consistency of the CD-RISC items and associated mean resilience levels within a sample of enlisted basic trainees in the United States Air Force. In addition, the predictive validity of the CD-RISC Total Score was examined for real-life military outcomes, including attrition from service and mental health diagnosis. The CD-RISC items demonstrated strong internal consistency. Item-level examinations of scores revealed that most trainees reported relatively high resilience. Results indicated that resilience measured at the beginning of military service is a significant predictor of (a) attrition from service and (b) obtaining a mental health diagnosis within 6 months of entry. Implications and future directions are discussed. (PsycINFO Database Record PMID- 27504905 TI - Evaluation of the Response Bias Scale and Improbable Failure Scale in assessing feigned cognitive impairment. AB - The present study evaluated the Response Bias scale (RBS), a symptom validity test embedded within the Minnesota Multiphasic Personality Inventory (MMPI)-2 Restructured Form (MMPI-2-RF) that assesses for feigned neurocognitive complaints, in a sample of pretrial incompetent to stand trial (IST) criminal defendants. Additionally, we examined the Improbable Failure (IF) scale, a performance validity test embedded within the Structured Interview of Reported Symptoms, Second Edition (SIRS-2), which similarly assesses for feigned cognitive impairment (FCI). Results indicated that both the RBS (area under the curve [AUC] = .76) and IF scale (AUC = .72) achieved moderate classification accuracy using the Test of Memory Malingering (TOMM) as the criterion. Further, the RBS and IF scale appeared to be most useful for screening out those defendants who presented as genuine (specificity = 99% and 88%, respectively), and less effective at classifying those defendants suspected of feigning according to the TOMM (sensitivity = 29% and 46%, respectively). In order to identify a significant proportion of IST defendants who may be feigning impairment, considerably lower cutoff scores than those recommended in each measure's manual were evaluated. An RBS T score of 63 (sensitivity = 86%; specificity = 37%), and IF scale raw score of 2 (sensitivity = 80%; specificity = 43%), was required to achieve >=80% sensitivity; these alternate cutoff scores may therefore be useful when screening inpatient forensic psychiatric IST defendants. Further, the 2 scales effectively predicted TOMM classification in combination, although only the RBS significantly contributed to the model. Implications for the assessment of FCI in forensic psychiatric settings are discussed. (PsycINFO Database Record PMID- 27504906 TI - Use of universal screening scores to predict distal academic and behavioral outcomes: A multilevel approach. AB - Initial research suggests screening for behavioral and emotional risk has been found to predict important behavioral and academic outcomes. The current study seeks to investigate the predictive validity of a novel screening measure, the Social, Academic, and Emotional Behavior Risk Screener-Teacher Rating Scale (SAEBRS-TRS). Although the SAEBRS-TRS has demonstrated initial evidence of strong psychometric properties (including reliability and validity), less is known about the SAEBRS-TRS's prediction of important student academic and behavioral outcomes. Hierarchical linear modeling (HLM) was employed due to the nested nature of the data of screening school-age children within classrooms. Results revealed that fall behavior screening data significantly and positively predicted spring reading scores, office disciplinary referrals, and student absences. Very little variance in the current model was due to differences between classrooms. Results suggest screening may be an important tool for school personnel seeking to use preventative methods for addressing student barriers to learning. (PsycINFO Database Record PMID- 27504907 TI - Evaluating juvenile detainees' Miranda misconceptions: The discriminant validity of the Juvenile Miranda Quiz. AB - Most juvenile arrestees in custodial settings waive their Miranda rights almost immediately, and many then provide incriminating statements, if not outright confessions. Forensic practitioners are then asked to provide retrospective determinations regarding whether these waivers were effectuated knowingly, voluntarily, and intelligently. At present, the forensic assessment instrument for juvenile Miranda issues consists of the Miranda Rights Comprehension Instruments (MRCI)-which as its name implies-focuses mostly on Miranda comprehension with a de-emphasis of Miranda reasoning. In partially addressing this gap, the current study investigated the clinical utility of the Juvenile Miranda Quiz (JMQ) for evaluating key Miranda misconceptions, a critically important component of Miranda reasoning. Using data from 201 juvenile detainees, we evaluated the JMQ's discriminability with regards to cognitive variables and MRCI scales. Many moderate effect sizes in the predicted direction were found for the JMQ Primary Total and Juvenile Total scores. Finally, these detainees were tested using a mock crime scenario with a representative Miranda warning plus a brief interrogation to evaluate whether they would waive their rights, and if so, whether they would confess. Using Miranda measures to predict problematic outcomes (i.e., impaired waivers followed by confessions), the JMQ Juvenile Total proved the most successful. These findings are discussed within the context of the "intelligent" prong of Miranda waivers. (PsycINFO Database Record PMID- 27504908 TI - Mechanism and Kinetics of Heterogeneous Reactions of Unsaturated Organic Acids on alpha-Al2 O3 and CaCO3. AB - Heterogeneous reactions have a vital role in the atmosphere due to their significant effects on the evolution of atmospheric aerosols, which in turn contribute to air pollution. However, the mechanism and kinetics of these processes involving unsaturated organic acids, important types of volatile organic compounds, are still unclear. In this work, the heterogeneous uptake of two representative atmospheric unsaturated organic acids (acrylic acid and methacrylic acid) on mineral aerosols including alpha-Al2 O3 and CaCO3 are investigated using a Knudsen cell reactor and an in situ diffuse reflectance infrared Fourier transform spectrometry (DRIFTS) reactor. The corresponding reaction pathways are proposed from the DRIFTS analysis. In addition, the initial uptake coefficients of unsaturated organic acids and their heterogeneous fate are obtained for the first time. Our results suggest that heterogeneous reactions on alpha-Al2 O3 and CaCO3 can be important sinks for acrylic acid and methacrylic acid, as well as possible contributors to the organic coating found on atmospheric aerosols, especially in high-pollution events. PMID- 27504909 TI - Enhancer decommissioning by Snail1-induced competitive displacement of TCF7L2 and down-regulation of transcriptional activators results in EPHB2 silencing. AB - Transcriptional silencing is a major cause for the inactivation of tumor suppressor genes, however, the underlying mechanisms are only poorly understood. The EPHB2 gene encodes a receptor tyrosine kinase that controls epithelial cell migration and allocation in intestinal crypts. Through its ability to restrict cell spreading, EPHB2 functions as a tumor suppressor in colorectal cancer whose expression is frequently lost as tumors progress to the carcinoma stage. Previously we reported that EPHB2 expression depends on a transcriptional enhancer whose activity is diminished in EPHB2 non-expressing cells. Here we investigated the mechanisms that lead to EPHB2 enhancer inactivation. We show that expression of EPHB2 and SNAIL1 - an inducer of epithelial-mesenchymal transition (EMT) - is anti-correlated in colorectal cancer cell lines and tumors. In a cellular model of Snail1-induced EMT, we observe that features of active chromatin at the EPHB2 enhancer are diminished upon expression of murine Snail1. We identify the transcription factors FOXA1, MYB, CDX2 and TCF7L2 as EPHB2 enhancer factors and demonstrate that Snail1 indirectly inactivates the EPHB2 enhancer by downregulation of FOXA1 and MYB. In addition, Snail1 induces the expression of Lymphoid enhancer factor 1 (LEF1) which competitively displaces TCF7L2 from the EPHB2 enhancer. In contrast to TCF7L2, however, LEF1 appears to repress the EPHB2 enhancer. Our findings underscore the importance of transcriptional enhancers for gene regulation under physiological and pathological conditions and show that SNAIL1 employs a combinatorial mechanism to inactivate the EPHB2 enhancer based on activator deprivation and competitive displacement of transcription factors. PMID- 27504910 TI - Fizzy Extraction of Volatile and Semivolatile Compounds into the Gas Phase. AB - Extraction of volatile and semivolatile compounds from liquid matrixes with high yields, and transferring the extracts to detectors in real time, is challenging. Common extraction procedures involve heating the samples to release the analytes to the gas phase and, in some cases, trapping the gas-phase analytes into sorbents or containers. Here, we propose a new method for fast extraction of volatile and semivolatile compounds from liquid matrixes. This method involves dissolution of a carrier gas in the liquid sample by applying a moderate overpressure (~150 kPa) and stirring the sample. An abrupt decompression of the extraction chamber leads to effervescence. In this step, many bubbles are instantly formed in the sample matrix. The dissolved carrier gas as well as dissolved volatiles are liberated into the headspace of the extraction chamber within a short period of time (few seconds). The gaseous effluent of the extraction chamber is immediately transferred to the online detector; in this case, an atmospheric pressure chemical ionization interface of a triple quadrupole mass spectrometer. The fast release of the gas-phase extract gives rise to a high signal recorded by the detector; several times higher than the signal recorded during direct infusion of headspace vapors without fizzy extraction. This feature provides the means to detect and quantify analytes present in solutions in a short period of time. Here we show that fizzy extraction is suitable for analysis of volatile/semivolatile compounds present in various samples, including those containing complex matrixes. PMID- 27504911 TI - Metformin use and risk of lactic acidosis in people with diabetes with and without renal impairment: a cohort study in Denmark and the UK. AB - AIMS: To assess risk of lactic acidosis among metformin users compared with other glucose-lowering agent users, according to renal function. METHODS: Using routine registries and databases, we conducted a cohort study. Of 43 580 metformin and 37 788 other glucose-lowering agent users in northern Denmark and 102 688 metformin and 28 788 other glucose-lowering agent users in the UK during 2001-2011, we identified lactic acidosis using diagnostic codes. We calculated the incidence rates of lactic acidosis in metformin and other glucose-lowering agent users overall and according to baseline estimated GFR (eGFR) levels. RESULTS: In Denmark, the incidence rates of lactic acidosis were 11.6 (95% CI 7.0-18.1) and 1.8 (95% CI 0.4-5.4) per 100 000 person-years of metformin use and of other glucose-lowering agent use, respectively. In the UK, the corresponding lactic acidosis incidence rates were 6.8 (95% CI 4.6-9.6) and 1.0 (95% CI 0.01-5.7) per 100 000 person-years of metformin use and of other glucose-lowering agent use. The incidence rates increased with decreasing baseline eGFR in both countries. Of the metformin-exposed people with lactic acidosis, 37% in Denmark and 34% in the UK experienced a decline in renal function in the year before the diagnosis. CONCLUSIONS: Risk of lactic acidosis was higher in metformin users than in other glucose-lowering agent users, and increased with decreasing eGFR, although this could be attributable to surveillance bias; however, diagnosed lactic acidosis was rare and can occur regardless of renal function. PMID- 27504912 TI - Determinants of Salivary Cotinine among Smokeless Tobacco Users: A Cross Sectional Survey in Bangladesh. AB - INTRODUCTION: More than 80% of all smokeless tobacco (ST) products in the world are consumed in South Asia; yet little is known about their consumption behaviour, addictiveness, and toxic properties. This paper, for the first time, describes associations between salivary cotinine concentrations among ST users in Bangladesh and their socio-demographic characteristics and tobacco use behaviours. METHODS: In a survey of ST users in Dhaka, Bangladesh, we purposively recruited 200 adults who were non-smokers but consumed ST on a regular basis. In person interviews were conducted to obtain information about socio-demographic and ST use behaviours, and saliva samples were collected to measure cotinine concentration. Simple and multiple linear regression analyses were conducted to test associations between the log transformed salivary cotinine concentration and other study variables. RESULTS: The geometric mean of cotinine concentration among ST users was 380ng/ml (GSD:2). Total duration of daily ST use in months had a statistically significant association with cotinine concentration. Other ST use characteristics including type and quantity of ST use, swallowing of tobacco juice, urges and strength of urges and attempts to cut down on tobacco use were not found to be associated with cotinine concentration in a multivariable model. CONCLUSION: This is the first report from Bangladesh studying cotinine concentration among ST users and it points towards high levels of addiction. This warrants effective tobacco control policies to help ST cessation and prevention. PMID- 27504913 TI - Effectiveness of abdominal shields in chest radiography: a Monte Carlo evaluation. AB - OBJECTIVE: The aims of this study were to assess the effectiveness of abdominal shields in reducing the dose to shielded organs during posteroanterior (PA) chest radiographic examinations, to evaluate the various factors contributing to the dose under the shield and to address the concern that internal scatter from the shield may lead to a dose increase to shielded organs. METHODS: Monte Carlo simulations of radiographic exposures to a soft-tissue "patient" phantom of 80 * 34 * 24 cm were performed at the peak X-ray tube voltage of 100 kV. The abdominal shield was simulated as 0.5-mm lead with/without a 0.2-mm-thick plastic film cover. The shield-to-phantom spacing varied from 0 to 40 cm. RESULTS: The dose to the phantom at different phantom depths and distances from the X-ray field edge was recorded. At the level of the uterus and ovaries (approximately 8-cm deep and 15 cm from the field of view), the dose reduction was approximately 0.035 uGy or 4%. A small dose increase (maximum: 0.4 uGy) to the phantom surface layer was also observed. CONCLUSION: In general, there was a small dose reduction in regions protected by the shield. However, the overall risk benefit to a patient would be negligible. ADVANCES IN KNOWLEDGE: Abdominal shields used during PA chest radiography provide a small dose reduction to organs at depth by removing the primary X-ray beam photons that are scattered in air, while giving a small increase in skin dose due to X-rays scattered from the abdominal shield internal surface. PMID- 27504914 TI - Efficacy and safety of adalimumab in Chinese patients with moderate-to-severe plaque psoriasis: results from a phase 3, randomized, placebo-controlled, double blind study. AB - BACKGROUND: This phase 3 trial is the first to evaluate the efficacy and safety of treatment with the systemic TNF-alpha inhibitor, adalimumab, for Chinese patients with moderate-to-severe plaque psoriasis. METHODS: In the 12-week, double-blind, placebo-controlled Period A, patients were randomized 4 : 1 to receive adalimumab 40 mg every-other-week (following a single 80 mg dose), or placebo every-other-week. In the subsequent 12-week, open-label, Period B, all patients received adalimumab 40 mg every-other-week starting at week 13, following a single, blinded dose at week 12 of adalimumab 80 mg or matching placebo (for patients receiving placebo or adalimumab in Period A respectively). In Period A, efficacy was analysed for all randomized patients and safety for all patients receiving >=1 dose of the study drug. RESULTS: For the 425 patients in this study (87 placebo; 338 adalimumab), a higher percentage randomized to adalimumab achieved the primary endpoint of >=75% improvement from baseline in PASI score (PASI 75) at week 12: placebo 11.5% (10/87); adalimumab 77.8% (263/338; P < 0.001). Physician's Global Assessment of clear to minimal was achieved at week 12 by 14.9% placebo (13/87) and 80.5% adalimumab (272/338; P < 0.001). For patients who received adalimumab at any time during the study (All adalimumab Population), treatment-emergent adverse events (AEs) were reported by 63.4%; the most common was upper respiratory infection (16.1%). Serious AEs were reported by 3.5% of the All-adalimumab Population, and serious infectious AEs by 1.2%, which include lung infection, pneumonia and tuberculosis [2 (0.5%) patients each]. There was one death (chronic heart failure). CONCLUSION: In these Chinese patients with moderate-to-severe psoriasis, a significantly greater percentage treated with adalimumab compared with placebo achieved efficacy endpoints at week 12 and efficacy was sustained to week 24. Safety results were consistent with the known adalimumab safety profile; no new safety signals were identified in the 24 weeks of treatment. PMID- 27504915 TI - Psychometric Properties of the Problematic Internet Use Questionnaire Short-Form (PIUQ-SF-6) in a Nationally Representative Sample of Adolescents. AB - Despite the large number of measurement tools developed to assess problematic Internet use, numerous studies use measures with only modest investigation into their psychometric properties. The goal of the present study was to validate the short (6-item) version of the Problematic Internet Use Questionnaire (PIUQ) on a nationally representative adolescent sample (n = 5,005; mean age 16.4 years, SD = 0.87) and to determine a statistically established cut-off value. Data were collected within the framework of the European School Survey Project on Alcohol and Other Drugs project. Results showed an acceptable fit of the original three factor structure to the data. In addition, a MIMIC model was carried out to justify the need for three distinct factors. The sample was divided into users at risk of problematic Internet use and those with no-risk using a latent profile analysis. Two latent classes were obtained with 14.4% of adolescents belonging to the at-risk group. Concurrent and convergent validity were tested by comparing the two groups across a number of variables (i.e., time spent online, academic achievement, self-esteem, depressive symptoms, and preferred online activities). Using the at-risk latent profile analysis class as the gold standard, a cut-off value of 15 (out of 30) was suggested based on sensitivity and specificity analyses. In conclusion, the brief version of the (6-item) PIUQ also appears to be an appropriate measure to differentiate between Internet users at risk of developing problematic Internet use and those not at risk. Furthermore, due to its brevity, the shortened PIUQ is advantageous to utilize within large-scale surveys assessing many different behaviors and/or constructs by reducing the overall number of survey questions, and as a consequence, likely increasing completion rates. PMID- 27504916 TI - Cultivating the social-emotional imagination in gifted education: insights from educational neuroscience. AB - Evidence from education, psychology, and neuroscience suggests that investing in the development of the social-emotional imagination is essential to cultivating giftedness in adolescents. Nurturing these capacities may be especially effective for promoting giftedness in students who are likely to lose interest and ambition over time. Giftedness is frequently equated with high general intelligence as measured by IQ tests, but this narrow conceptualization does not adequately capture students' abilities to utilize their talents strategically to fully realize their future possible selves. The brain's default mode network is thought to play an important role in supporting imaginative thinking about the self and others across time. Because this network's functioning is temporarily attenuated when individuals engage in task- and action-oriented focus (mindsets thought to engage the brain's executive attention network), we suggest that consistently focusing students on tasks requiring immediate action could undermine long-term cultivation of giftedness. We argue that giftedness-especially in science, technology, engineering, and mathematics (STEM)-can be cultivated by encouraging adolescents' intellectual curiosity and supporting their ability to connect schoolwork to a larger purpose. Improving STEM and gifted education may depend upon a shift from knowledge transmission and regimented evaluation to creative exploration, intentional reflectiveness, and mindful switching between task focus and imagining. PMID- 27504917 TI - Intra-Arterial Chemotherapy as Primary Therapy for Retinoblastoma in Infants Less than 3 Months of Age: A Series of 10 Case-Studies. AB - PURPOSE: Retinoblastoma is the most common primary malignant intra-ocular tumor in children. Although intra-arterial chemotherapy (IAC) by selectively infusing chemotherapy through the ophthalmic artery has become an essential technique in the treatment of advanced intra-ocular retinoblastoma in children, the outcome of IAC as primary therapy for infants less than 3 months of age remains unknown. In this retrospective study, we reviewed the outcome of IAC as primary therapy for retinoblastoma in infants less than 3 months of age. METHODS: We retrospectively reviewed ten retinoblastoma patients attending our center from January 2009 to September 2015 and beginning primary IAC before the age of 3 months. The patient characteristics, overall outcomes and therapy-related complications were assessed. RESULTS: The mean patient age at the first IAC treatment was 10.4 weeks (range 4.9-12.9 weeks). These eyes were classified according to the International Classification of Retinoblastoma (ICRB) as group A (n = 0), B (n = 2), C (n = 0), D (n = 9), or E (n = 2). A total of 28 catheterizations were performed, and the procedure was stopped in one patient because of internal carotid artery spasm. Each eye received a mean of 2.6 cycles of IAC (range 2-4 cycles). After IAC with a mean follow-up of 28.3 months (range 9-65 months), tumor regression was observed in 12 of 13 eyes. One eye was enucleated due to tumor progression. All patients are alive and no patient has developed metastatic disease or other malignancies. CONCLUSIONS: Our experience suggests IAC as primary therapy is a feasible and promising treatment for retinoblastoma in infants less than 3 months of age. PMID- 27504918 TI - Effectiveness and cost-effectiveness of pessary treatment compared with pelvic floor muscle training in older women with pelvic organ prolapse: 2-year follow-up of a randomized controlled trial in primary care. AB - OBJECTIVE: We investigated the effectiveness and cost-effectiveness of pessary treatment compared with pelvic floor muscle training (PFMT) in women with pelvic organ prolapse over a 2-year period. METHODS: Randomized controlled trial with women (>=55 y) with symptomatic pelvic organ prolapse, identified by screening. Participants were recruited from 20 primary care practices (October 2009-December 2012). Primary outcome was the difference in change of pelvic floor symptoms (PFDI-20 score) between groups over 24 months. Secondary outcomes included prolapse, urinary, and anorectal symptoms; quality of life; costs; sexual functioning; prolapse stage; pelvic floor muscle function; and participants' perceived symptom improvement. RESULTS: There was a nonsignificant difference in the primary outcome between pessary treatment (n = 82) and PFMT (n = 80) with a mean difference of -3.7 points (95% CI, -12.8 to 5.3; P = 0.42) in favor of pessary treatment. A significantly greater improvement in the prolapse symptom score was, however, seen with pessary treatment (mean difference -3.2 points [95% CI, -6.3 to -0.0; P = 0.05]). Direct medical costs over the 2-year study were $309 and $437 per person for pessary treatment and PFMT, respectively. CONCLUSIONS: In older women with symptomatic prolapse, there was no significant difference between pessary treatment and PFMT in reducing pelvic floor symptoms, but specific prolapse-related symptoms did improve more with pessary treatment. Pessary treatment was preferable in the cost-effectiveness analysis. When counseling women for prolapse treatment it should, however, be taken into account that pessary fitting fails in a considerable portion of women and that pessary treatment was associated with more side effects compared with PFMT. PMID- 27504919 TI - Use of systemic hormone therapy in BRCA mutation carriers. AB - As more women are being counseled and tested, clinicians increasingly encounter women with identified BRCA1 and BRCA2 gene mutations. Existing, albeit limited, data indicate that risks of breast cancer are not increased with use of systemic hormone therapy by menopausal BRCA mutation carriers with intact breasts. Young mutation carriers with or without intact breasts should not defer or avoid risk reducing (and lifesaving) bilateral salpingo-oophorectomy because of concerns that subsequent use of systemic hormone therapy will elevate breast cancer risk. PMID- 27504920 TI - Ultraviolet Light Catalyzed Gelation of 3-Methacryloxypropyltrimethoxysilane via Altered Silicate Spatial Structure. AB - The gelation of 3-methacryloxypropyltrimethoxysilane (MAPTMS) is much more difficult to achieve in conventional conditions. This article describes a novel and concise approach to acquire transparent and firm hybrid gel material by one step promptly without photoinitiator or other tetraalkoxysilane. MAPTMS was hydrolyzed in acidified aqueous solution, which became homogeneous sol in 3 min, and then the sol was irradiated with UV light for a few minutes to form gel. The experimental results indicated that MAPTMS sol gelled in the presence of UV irradiation was mainly attributed to altering Si-O-Si skeleton structure through hydroxyl radicals, and the gelation originated from the hydrolytic polycondensation of MAPTMS rather than the polymerization of methacryloxy substituent groups. The hydroxyl radicals could break the Si-O-Si ring structure to form cross-linker like species, and these cross-linkers chemically joined linear chains together to form the gel network. This investigation offers not only the photoinduced gelation strategy for MAPTMS sol but also the new insight into the effect of UV-irradiation on the sol-gel process of organotrialkoxysilanes. PMID- 27504921 TI - The influence of gender on suicidal ideation following military sexual trauma among Veterans in the Veterans Health Administration. AB - No studies have examined whether military sexual trauma, as measured and defined within the Veterans Health Administration (VHA), is associated with suicidal ideation among Veterans in VHA care, when taking prior suicide attempts into account. Research regarding the role of gender in this association is also limited. The present study examined: (1) whether military sexual trauma was associated with the presence of past-week suicidal ideation among 354 Veterans in VHA (310 men, 44 women); (2) whether gender moderated the association between military sexual trauma and suicidal ideation. Information regarding military sexual trauma, suicidal ideation, suicide attempt, and psychiatric diagnoses was obtained from self-report instruments and medical records. Adjusting for age, gender, combat, posttraumatic stress disorder, depressive disorders, negative affect, and lifetime suicide attempt, Veterans with military sexual trauma were significantly more likely to report suicidal ideation, compared to Veterans without military sexual trauma. Furthermore, the association between military sexual trauma and suicidal ideation was stronger for men compared to women. These results contribute to a growing literature identifying military sexual trauma as a risk factor for suicidal thoughts and behaviors among Veterans in VHA care and emphasize the importance of screening for suicidal ideation among survivors of military sexual trauma. PMID- 27504922 TI - Accurate Cytotoxicity and Proliferation Determination: Advantages of a High Throughput Phenotypic Approach Over ATP Luminescence Assays. AB - Cell viability and proliferation assays are a fundamental tool in the drug discovery process and are used to evaluate both the antiproliferative potency and toxicity of compounds. Some lead discovery groups generate cell viability data for up to two million compounds per screen, so any method used to assess these parameters needs to deliver not only on data quality but also on throughput and assay cost per well. Most methods used to determine cell viability cannot deliver on all three of these requirements, so compromises have to be made. Here we show the development and implementation of a cost-effective, no-wash phenotypic assay to simultaneously report the number of cells, percentage of live cells, and cell cycle phase distribution as markers of proliferation and viability. We demonstrate that this assay can be applied to high-density plate formats and be imaged and analyzed in 8 min per plate on a laser scanning imaging cytometer. By comparing the drug-responses of several well-characterized anticancer drugs on HeLa cells, we highlight the key differences between the phenotypic assay and a commercial ATP luminescence detection system. PMID- 27504923 TI - Brief Opioid Overdose Knowledge (BOOK): A Questionnaire to Assess Overdose Knowledge in Individuals Who Use Illicit or Prescribed Opioids. AB - BACKGROUND: Opioid overdose is a public health crisis. This study describes efforts to develop and validate the Brief Opioid Overdose Knowledge (BOOK) questionnaire to assess patient knowledge gaps related to opioid overdose risks. METHODS: Two samples of illicit opioid users and a third sample of patients receiving an opioid for the treatment of chronic pain (total N = 848) completed self-report items pertaining to opioid overdose risks. RESULTS: A 3-factor scale was established, representing Opioid Knowledge (4 items), Opioid Overdose Knowledge (4 items), and Opioid Overdose Response Knowledge (4 items). The scale had strong internal and face validity. Patients with chronic pain performed worse than illicit drug users in almost all items assessed, highlighting the need to increase knowledge of opioid overdose risk to this population. CONCLUSIONS: This study sought to develop a brief, internally valid method for quickly assessing deficits in opioid overdose risk areas within users of illicit and prescribed opioids, to provide an efficient metric for assessing and comparing educational interventions, facilitate conversations between physicians and patients about overdose risks, and help formally identify knowledge deficits in other patient populations. PMID- 27504924 TI - Substance Use as a Risk Factor for Sleep Problems Among Adolescents Presenting to the Emergency Department. AB - OBJECTIVES: To determine correlates of sleep problems among adolescents. Specifically, to assess the relative strength of associations between sleep problems and dating victimization, reasons for emergency department (ED) visit, depression, unhealthy alcohol use, and other drug use (marijuana, nonmedical use of prescription opioids, stimulants, and tranquilizers). METHODS: A total of 1852 adolescents aged 14 to 20 years presenting for care to the University of Michigan Emergency Department, Ann Arbor, Michigan, during 2011-2012, self-administered a computerized health survey. Sleep problems were identified if any of the 4 items on the Sleep Problems Questionnaire were rated by a patient as greater than 3 on a 0 to 5 scale. Adolescents who were too sick to be screened in the ED were eligible to participate in the study during their inpatient stay. Exclusion criteria for baseline included insufficient cognitive orientation precluding informed consent, not having parent/guardian present if younger than 18 years, medical severity precluding participation, active suicidal/homicidal ideation, non-English-speaking, deaf/visually impaired, or already participated in this study on a prior visit. RESULTS: 23.5% of adolescents reported clinically significant sleep problems. Female gender, depression, dating victimization, tobacco use, nonmedical use of prescription medication, and an ED visit for medical reasons were each associated with sleep problems among adolescents, even while controlling for age, other types of drug use, receiving public assistance, and dropping out of school. CONCLUSIONS: These exploratory findings indicate that ED-based screening and brief intervention approaches addressing substance use and/or dating victimization may need to account for previously undiagnosed sleep problems. PMID- 27504925 TI - Immediate Versus Delayed Computerized Brief Intervention for Illicit Drug Misuse. AB - OBJECTIVE: Computerized brief interventions are a promising approach for integrating substance use interventions into primary care settings. We sought to examine the effectiveness of a computerized brief intervention for illicit drug misuse, which prior research showed performed no worse than a traditional in person brief intervention. METHODS: Community health center patients were screened for eligibility using the World Health Organization Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). Participants were adult patients (aged 18-62 years; 53% female) with moderate-risk illicit drug use (N = 80), randomized to receive the computerized brief intervention either immediately or at their 3-month follow-up. Assessments were conducted at baseline, 3, and 6 month follow-up, and included the ASSIST and drug hair testing. RESULTS: Most participants in the sample (90%) reported moderate-risk marijuana use. Although the sample as a whole reported significant decreases in ASSIST Global Drug Risk scores and ASSIST marijuana-specific scores, no significant differences were detected between "immediate" and "delayed" conditions on either of these measures. Likewise, no significant differences were detected between conditions in drug-positive hair test results at either follow-up. CONCLUSIONS: This study did not find differences between immediate versus delayed computerized brief intervention in reducing drug use or associated risks, suggesting potential regression to the mean or reactivity to the consent, screening, or assessment process. The findings are discussed in light of the study's limitations and directions for future research. PMID- 27504926 TI - The Availability of Ancillary Counseling in the Practices of Physicians Prescribing Buprenorphine. AB - OBJECTIVE: We set out to examine physicians' perceptions of the provision of ancillary services for opioid dependent patients receiving buprenorphine. METHODS: An e-mail invitation describing the study was sent out by the American Society of Addiction Medicine to its membership (approximately 3700 physicians) and other entities (for a total of approximately 7000 e-mail addresses). E-mail recipients were invited to participate in a research study funded by the National Institutes on Drug Abuse involving completion of an online survey; 346 physicians completed the survey. RESULTS: The majority of the 346 respondents were internal or family medicine (37%), or addiction medicine providers (30%), who were practicing in urban (57%) or suburban settings (27%). Most respondents reported either offering (66%) or referring patients for ancillary counseling (31%). Interventions that were most frequently offered or referrals provided were individual counseling (51%) and self-help groups (63%), respectively. Counseling availability differed significantly by provider specialization for any, individual, group, family or couples, and self-help groups. CONCLUSIONS: Generally, respondents reported compliance with ancillary counseling requirements for buprenorphine treatment of opioid use disorder. In addition to examining the efficacy of a variety of ancillary counseling services for patients receiving opioid agonist treatment, further research should examine physicians' attitudes toward the role of such counseling in buprenorphine treatment. Although the study sample was relatively large, the generalizability of the findings is unclear, suggesting that further investigation of the availability of ancillary counseling in buprenorphine treatment among a larger nationally representative sample of providers may be warranted. PMID- 27504927 TI - Bupropion "Abuse" Reported to US Poison Centers. AB - OBJECTIVES: Bupropion use to obtain nonmedical psychoactive effects has been reported. The objective was to determine the prevalence, characteristics, clinical effects, and outcomes of bupropion "abuse." METHODS: A 14-year retrospective review was conducted of single substance bupropion cases with "intentional abuse" as the coded reason for exposure in individuals 13 and older reported to the National Poison Data System. Data were evaluated for prevalence, demographics, clinical effect, route, final management site, and coded outcome. RESULTS: There were 975 bupropion abuse cases, which accounted for 3.3% of single substance bupropion cases reported to US poison centers. The prevalence of abuse increased by 75%, from 2000 to 2012, declining slightly in 2013. The majority of cases were 13 to 29 years old (67.4%). The most frequent clinical effects were tachycardia (57.0%), seizures (33.5%), agitation/irritable (20.2%), hallucinations/delusions (14.0%), and tremor (13.1%). Most exposures were ingestions (745) followed by insufflation (166), parenteral (17), and other/unknown (17); 30 cases involved 2 routes. Seizure frequency was not significantly different between routes (P = 0.783) or exposure chronicity (P = 0.264). Final management sites were predominantly emergency department (36.9%) and admission to critical care unit (27.3%) or noncritical care unit (20.1%). Outcomes were major (11.4%), moderate (48.2%), minor (24.5%), and no effect (15.5%). There were 4 deaths. CONCLUSIONS: Most bupropion abuse occurs in adolescents and young adults. Tachycardia and seizures are common indicating the potential for serious effects. Seizures occur regardless of route. Providers should be aware of risk of bupropion abuse. PMID- 27504928 TI - Sex Differences in the Association Between Internalizing Symptoms and Craving in Methamphetamine Users. AB - OBJECTIVES: Methamphetamine (MA) users often have substantial psychiatric comorbidities, with nearly a third reporting lifetime mood disorders and over a quarter reporting lifetime anxiety disorders. Female MA users are more likely to endorse depression and anxiety symptoms compared with men. Craving has been related to mood/anxiety symptoms in MA users. To extend the literature on sex differences in MA use disorder, the present study examines the role of sex as a moderator of the relationship between mood/anxiety symptoms and MA craving. METHODS: Participants (N = 203) were nontreatment-seeking, current MA users, recruited from the Los Angeles community for enrollment in a larger pharmacotherapy trial. At the assessment visit, participants completed multiple measures including the Methamphetamine Urge Questionnaire, the Beck Depression Inventory, and the Beck Anxiety Inventory. RESULTS: The relationship between depression symptomatology and MA craving was moderated by sex (F = 6.18, P = 0.01), such that the relationship was positive and significant for men (P < 0.001), but was not significant for women. Similarly, sex significantly moderated the relationship between anxiety and MA craving (F = 5.99, P = 0.02), such that the relationship was also positive and significant in men, but not in women (P < 0.001). CONCLUSIONS: These results suggest that men may be more sensitive to the effects of internalizing symptoms on MA craving than women. Given craving's propensity to predict relapse, these initial findings indicate the necessity of treating comorbid psychiatric problems in male MA users, which may in turn assist in the attenuation of craving. PMID- 27504929 TI - Poly(colloid)s: "Polymerization" of Poly(l-tyrosine)-silica Composite Particles through the Photoinduced Cross-Linking of Unmodified Proteins Method. AB - Photoinduced cross-linking of unmodified proteins, PICUP, was extended to core shell silica-polypeptide composite particles to produce poly(colloid)s. Silica particles coated with poly(l-tyrosine), PTYR-SiO2, served as the monomer units. The PICUP reaction accomplished the formation of dityrosil linkages between the tyrosine units by illumination of photo-oxidizing ruthenium(II) bipyridyl catalyst under physiological conditions. The PICUP method was compared with an enzymatic route intermediated by horseradish peroxidase as catalyst. The PTYR SiO2 particles feature high PTYR content in the shell, which facilitated the formation of heavily cross-linked but unstructured aggregates. After magnetic alignment of superparamagnetic PTYR-SiO2-cobalt composite particles, only the PICUP approach enabled the preparation of isolated chain-like poly(colloid)s. The cross-linking products were confirmed by FTIR. The native secondary structure of poly(l-tyrosine) is preserved in these poly(colloid)s. Because the PICUP reaction does not require the modification of the polypeptide structure, the cross-linked PTYR will retain its characteristic functions as a poly(amino acid). The PICUP method opens the door to a variety of PTYR-based poly(colloid) architectures. PMID- 27504930 TI - Enzymatic assays for detecting lactose and sucrose in urine to reveal intravenous drug abuse with emphasis on buprenorphine. AB - Buprenorphine and methadone are commonly used medications for opioid maintenance treatment (OMT), using sublingual and oral administration, respectively. Although beneficial for OMT, these drugs can also be abused by intravenous administration. In intravenous abuse cases, the adjuvants lactose and sucrose are excreted in urine without hydrolysis to monosaccharides, since there are no disaccharidases in the blood. We validated enzymatic methods for the analysis of lactose and sucrose in urine. The analytical performance of both assays was considered appropriate for detecting intravenous drug abuse. The principle was proven by analyzing 93 postmortem (PM) urine samples for lactose, following comprehensive toxicological drug screening. In addition, 32 clinical urine samples from potential drug abusers were analyzed to assess the effect of PM changes on the assay. The mean level of lactose was low in clinical samples and relatively low in PM samples in which no drugs were found. Markedly elevated levels were seen in many of the buprenorphine positive samples, suggesting intravenous administration. Enzymatic methods could provide a simple and cost effective way to assess the intravenous administration of OMT drugs or drugs of abuse. Very high levels of glucose in urine may interfere with the assays. Furthermore, other causes for elevated urine disaccharides, such as hypolactasia and increased intestinal permeability, need to be considered in the interpretation of the results. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27504931 TI - Top-down, in-plane GaAs nanowire MOSFETs on an Al2O3 buffer with a trigate oxide from focused ion-beam milling and chemical oxidation. AB - The top-down fabrication of an in-plane nanowire (NW) GaAs metal-oxide semiconductor field-effect transistor (MOSFET) with a trigate oxide implemented by liquid-phase chemical-enhanced oxidation (LPCEO) is reported. A 2 MUm long channel having an effective cross section ~70 * 220 nm(2) is directly fabricated into an epitaxial n (+)-GaAs layer. This in-plane NW structure is achieved by focused ion beam (FIB) milling and hydrolyzation oxidation resulting in electronic isolation from the substrate through a semiconductor-on-insulator structure with an n (+)-GaAs/Al2O3 layer stack. The channel is epitaxially connected to the MUm-scale source and drain within a single layer for a planar MOSFET to avoid any issues of ohmic contact and LPCEO to the NW. To fabricate a MOSFET, the top and the two sidewalls of the in-plane NW are oxidized by LPCEO to relieve the surface damage from FIB as well as to transform these surfaces to a ~15 nm thick gate oxide. This trigate device has threshold voltage ~0.14 V and peak transconductance ~35 MUS MUm(-1) with a subthreshold swing ~150 mV/decade and on/off ratio of drain current ~10(3), comparable to the performance of bottom up NW devices. PMID- 27504932 TI - Chemoresistance of Lung and Breast Cancer Cells Growing Under Prolonged Periods of Serum Starvation. AB - The efficacy of chemotherapy is hindered by both tumor heterogeneity and acquired or intrinsic multi-drug resistance caused by the contribution of multidrug resistance proteins and stemness-associated prosurvival markers. Therefore, targeting multi-drug resistant cells would be much more effective against cancer. In this study, we characterized the chemoresistance properties of adherent (anchorage-dependent) lung H460 and breast MCF-7 cancer cells growing under prolonged periods of serum starvation (PPSS). We found that under PPSS, both cell lines were highly resistant to Paclitaxel, Colchicine, Hydroxyurea, Obatoclax, Wortmannin, and LY294002. Levels of several proteins associated with increased stemness such as Sox2, MDR1, ABCG2, and Bcl-2 were found to be elevated in H460 cells but not in MCF-7 cells. While pharmacological inhibition of either MDR1, ABCG2, Bcl-2 with Verapamil, Sorafenib, or Obatoclax, respectively decreased the levels of their target proteins under routine culture conditions as expected, such inhibition did not reverse PX resistance in PPSS conditions. Paradoxically, treatment with inhibitors in serum-starved conditions produced an elevation of their respective target proteins. In addition, we found that Digitoxin, an FDA approved drug that decrease the viability of cancer cells growing under PPSS, downregulates the expression of Sox2, MDR1, phospho- AKT, Wnt5a/b, and beta catenin. Our data suggest that PPSS-induced chemoresistance is the result of extensive rewiring of intracellular signaling networks and that multi-resistance can be effectively overcome by simultaneously targeting multiple targets of the rewired network. Furthermore, our PPSS model provides a simple and useful tool to screen drugs for their ability to target multiple pathways of cancer resistance. J. Cell. Physiol. 232: 2033-2043, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27504933 TI - Attention and associative learning in humans: An integrative review. AB - This article presents a comprehensive survey of research concerning interactions between associative learning and attention in humans. Four main findings are described. First, attention is biased toward stimuli that predict their consequences reliably (learned predictiveness). This finding is consistent with the approach taken by Mackintosh (1975) in his attentional model of associative learning in nonhuman animals. Second, the strength of this attentional bias is modulated by the value of the outcome (learned value). That is, predictors of high-value outcomes receive especially high levels of attention. Third, the related but opposing idea that uncertainty may result in increased attention to stimuli (Pearce & Hall, 1980), receives less support. This suggests that hybrid models of associative learning, incorporating the mechanisms of both the Mackintosh and Pearce-Hall theories, may not be required to explain data from human participants. Rather, a simpler model, in which attention to stimuli is determined by how strongly they are associated with significant outcomes, goes a long way to account for the data on human attentional learning. The last main finding, and an exciting area for future research and theorizing, is that learned predictiveness and learned value modulate both deliberate attentional focus, and more automatic attentional capture. The automatic influence of learning on attention does not appear to fit the traditional view of attention as being either goal-directed or stimulus-driven. Rather, it suggests a new kind of "derived" attention. PMID- 27504934 TI - A meta-analytic review of the association between perceived social support and depression in childhood and adolescence. AB - This meta-analysis evaluated the relation between social support and depression in youth and compared the cumulative evidence for 2 theories that have been proposed to explain this association: the general benefits (GB; also known as main effects) and stress-buffering (SB) models. The study included 341 articles (19% unpublished) gathered through a search in PsycINFO, PsycARTICLES, ERIC, and ProQuest, and a hand search of 11 relevant journals. Using a random effects model, the overall effect size based on k = 341 studies and N = 273,149 participants was r = .26 (95% CI [.24, .28]), with robust support for the GB model and support for the SB model among medically ill youth. Stress-buffering analyses suggest that different stressful contexts may not allow youth to fully draw on the benefits of social support, and we propose value in seeking to better understand both stress-buffering (effects of social support are enhanced) and reverse stress-buffering (effects of social support are dampened) processes. Key findings regarding other moderators include a different pattern of effect sizes across various sources of support. In addition, gender differences were largely absent from this study, suggesting that social support may be a more critical resource for boys than is typically acknowledged. Results also demonstrated the importance of using instruments with adequate psychometric support, with careful consideration of methodological and conceptual issues. Building upon these collective findings, we provide recommendations for theory and practice, as well as recommendations for addressing limitations in the extant literature to guide future investigations. (PsycINFO Database Record PMID- 27504935 TI - Trait entitlement: A cognitive-personality source of vulnerability to psychological distress. AB - Psychological entitlement is a personality trait characterized by pervasive feelings of deservingness, specialness, and exaggerated expectations. The present review expands upon this understanding by conceptualizing entitlement as a cognitive-personality vulnerability to psychological distress. A review of research is conducted, and a novel, multipart model is described by which entitlement may be seen as such a vulnerability. First, exaggerated expectations, notions of the self as special, and inflated deservingness associated with trait entitlement present the individual with a continual vulnerability to unmet expectations. Second, entitled individuals are likely to interpret these unmet expectations in ways that foster disappointment, ego threat, and a sense of perceived injustice, all of which may lead to psychological distress indicators such as dissatisfaction across multiple life domains, anger, and generally volatile emotional responses. Furthermore, in the wake of disappointment, ego threat, or perceived injustice, entitled individuals are likely to attempt to bolster their entitled self-concept, leading to a reinforcement of entitled beliefs, thereby initiating the cycle again. At each stage of this process, entitlement presents the individual with the possibility of experiencing distress, predisposes further risk factors for distress (e.g., the subsequent steps in the model), and increases the risk of interpersonal conflict, again leading to distress. A review of relevant empirical data suggests preliminary support for this conceptual model of entitlement. (PsycINFO Database Record PMID- 27504936 TI - Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs. AB - : Spleen tyrosine kinase (SYK) is a cytosolic nonreceptor protein tyrosine kinase that mediates key signal transduction pathways following the activation of immune cell receptors. SYK regulates cellular events induced by the B-cell receptor and Fc receptors with high intrinsic activity. Furthermore, SYK has been regarded as an attractive target for the treatment of autoimmune diseases and cancers. Here, we report the crystal structures of SYK in complex with seven newly developed inhibitors (G206, G207, O178, O194, O259, O272, and O282) to provide structural insights into which substituents of the inhibitors and binding regions of SYK are essential for lead compound optimization. Our kinase inhibitors exhibited high inhibitory activities against SYK, with half-maximal inhibitory concentrations (IC50 ) of approximately 0.7-33 nm, but they showed dissimilar inhibitory activities against KDR, RET, JAK2, JAK3, and FLT3. Among the seven SYK inhibitors, O272 and O282 exhibited highly specific inhibitions against SYK, whereas O194 exhibited strong inhibition of both SYK and FLT3. Three inhibitors (G206, G207, and O178) more efficiently inhibited FLT3 while still substantially inhibiting SYK activity. The binding mode analysis suggested that a highly selective SYK inhibitor can be developed by optimizing the functional groups that facilitate direct interactions with Asn499. DATABASE: The atomic coordinates and structure factors for human SYK are in the Protein Data Bank under accession codes 4XG2 (inhibitor-free form), 4XG3 (G206), 4XG4 (G207), 5GHV (O178), 4XG6 (O194), 4XG7 (O259), 4XG8 (O272), and 4XG9 (O282). PMID- 27504937 TI - Novel pyrazolylphosphite- and pyrazolylphosphinite-ruthenium(ii) complexes as catalysts for hydrogenation of acetophenone. AB - The new compounds and potential ligands 2-(3,5-di-tert-butyl-1H-pyrazol-1 yl)ethyldiphenlyphosphinite (L1), 2-(3,5-di-tert-butyl-1H-pyrazol-1 yl)ethyldiethylphosphite (L2), 2-(3,5-di-tert-butyl-1H-pyrazol-1-yl)ethyl diethylphosphite (L3) and 2-(3,5-diphenyl-1H-pyrazol-1-yl)ethyldiethylphosphite (L4) were prepared from the reaction of (3,5-(disubstituted)pyrazol-1H-yl)ethanol and the appropriate phosphine chloride. The phosphinite (L1) and phosphites (L2 L4) and 2-(3,5-diphenyl-1H-pyrazol-1-yl)ethyldiphenylphosphinite (L5) were reacted with [Ru(p-cymene)Cl2]2 to afford the ruthenium(ii) complexes [Ru(p cymene)Cl2(L1)] (1), [Ru(p-cymene)Cl2(L2)] (2), [Ru(p-cymene)Cl2(L3)] (3), [Ru(p cymene)Cl2(L4)] (4), and [Ru(p-cymene)Cl2(L5)] (5). All ruthenium complexes were characterized by a combination of NMR spectroscopy, elemental analysis and, in selected cases, by single crystal X-ray crystallography. Complexes 1-5 and [Ru(p cymene)Cl2(L6)] (6) (prepared from 2-(3,5-dimethyl-1H-pyrazol-1 yl)ethyldiphenylphosphinite (L6)) were investigated as catalysts for both transfer and molecular hydrogenation of acetophenone to 1-phenylethanol. At 80 degrees C the percent conversion of acetophenone in transfer hydrogenation was moderate to high over 10 h (42-87%); for molecular hydrogenation acetophenone, conversions were as high as 98% in 6 h. PMID- 27504938 TI - Validation of the Polish version of P-QoL questionnaire. AB - OBJECTIVE: Pelvic organ prolapse (POP) is a common morbidity that affects many women and significantly decreases quality of life. The severity and the impact of the prolapse on the quality of life are important parameters in the management and follow-up of affected patients. The aim of this validation study was to validate the Polish version of the Prolapse Quality of Life questionnaire (P QoL). MATERIAL AND METHODS: The P-QOL questionnaire was translated into Polish and administered to women recruited from two gynecological outpatient clinics (n = 231). Both symptomatic and asymptomatic women were included in the study and examined in supine position using the Pelvic Organ Prolapse Quantification System (POP-Q). The validity was assessed by comparing symptom scores and quality-of life scores between symptomatic and asymptomatic women. RESULTS: A total number of 154 symptomatic and 77 asymptomatic women were included. There was a strong correlation between severity of the disease based on physical findings (POP-Q scale) and the P-QoL scores in main prolapse quality-of-life domains. The overall scores for each life domain were significantly different between symptomatic and asymptomatic women (p < 0.001). All the questions regarding symptoms showed significant differences (p < 0.001) between both groups. CONCLUSIONS: The Polish version of P-QoL is a valid, reliable, and easily comprehensible instrument to assess quality of life and symptoms in Polish-speaking women suffering from urogenital prolapse. PMID- 27504939 TI - The role of early determination of beta-human chorionic gonadotropin levels in predicting the success of single-dose methotrexate treatment in ectopic pregnancy. AB - OBJECTIVE: The aim of the study was to determine the importance of beta-hCG level on day 4 following methotrexate (MTX) administration, and the difference between beta-hCG levels assessed on day 0 and day 4 in predicting treatment success. MATERIAL AND METHODS: A total of 68 women with tubal pregnancy, treated with a single dose of MTX, were selected for this retrospective study. RESULTS: The success rate of single-dose MTX treatment in our clinic was 75% (51/68). Among 51 patients in whom MTX treatment was successful, 25 (36.8%) showed a decrease in beta-hCG level of > 15% on days 0 and 4, and 44 (64.7%) showed a beta-hCG level decrease of > 15% on days 4 and 7. For subjects with beta-hCG decrease of > 15% on days 4 and 7, the standard error was 6.5%, and the area under the ROC curve was 81.7%, while the corresponding values for days 0 and 4 were 7.2% and 64%, respectively. CONCLUSIONS: A decrease of > 15 % in beta-hCG levels between days 0 and 4 does not seem to be a better predictor for success of single-dose MTX treatment for ectopic pregnancy than between days 4 and 7. A statistically significant difference was observed only in beta-hCG levels on day 7 in both, successful and unsuccessful single-dose MTX groups. PMID- 27504940 TI - Comparison of endometrial biopsy and postoperative hysterectomy specimen findings in patients with atypical endometrial hyperplasia and endometrial cancer. AB - OBJECTIVES: The aim of the study was to assess the concordance between the preoperative endometrial sampling and microscopic examination of the hysterectomy specimens in patients surgically treated for atypical endometrial hyperplasia and endometrial carcinoma. MATERIAL AND METHODS: We analysed a group of 204 patients, of whom 160 (78.43%) underwent surgical treatment for cancer of the corpus uteri and 44 (21.57%) for atypical endometrial hyperplasia. The preoperative diagnosis was based on the histological examination of endocervical and endometrial samples obtained by fractional curettage and it was compared to the histological findings at hysterectomy. The comparison was made for the basic diagnosis, the histological type of the cancer and the grade of tumour differentiation. RESULTS: When the histological types of cancer diagnosed in endometrial curettage and hysterectomy specimens were com-pared, the concordance was observed in 134/160 patients (83.75%). The highest concordance was found for endometrioid carcinoma (127/148 patients, 85.81%). The grade of tumour differentiation was accurate in 69.31% of patients. The highest concordance was for moderately differentiated carcinomas. Of 44 patients who underwent surgical treatment for atypical endometrial hyperplasia, the preoperative diagnosis was confirmed by the postoperative histopathological examination in 21 patients (47.73%). In 15 patients (34.09%) endometrial cancer was diagnosed at hysterectomy. CONCLUSIONS: In endometrial cancer our findings demonstrate a high level of concordance between the histological diagnosis on endometrial curettage and at hysterectomy. Own observations have confirmed that over 30% of patients undergoing surgical treatment for atypical endometrial hyperplasia have concurrent endometrial cancer which is determined by surgery. PMID- 27504941 TI - Prognostic value of 18F-FDG PET/CT for identifying high- and low-risk endometrial cancer patients. AB - OBJECTIVES: To assess the usefulness of adding PET/CT as a preoperative test for determining the extent of endometrial cancer and discriminating low- and high risk patients to identify candidates for surgical staging. MATERIAL AND METHODS: We retrospectively reviewed 86 patients with pathologically proven endometrial cancer who had undergone preoperative 18F-FDG PET/CT. The prognostic relationships between PET/CT parameters and pathology reports were assessed. RESULTS: The SUVmax was significantly higher in patients with FIGO stage IB or higher compared with those with stage IA; for stage III-IV compared with stage I II; and for patients with lymph node metastasis compared with those without lymph node metastasis. Using 6.70 as a cut-off for SUVmax, low-risk patients can be identified with a sensitivity of 92.9%. CONCLUSIONS: PET/CT imaging can be used not only for determining malignancy and lymph node involvement but also for determining candidates for surgical staging with high sensitivity. PMID- 27504942 TI - Antenatal corticosteroids and respiratory distress syndrome - the first Polish national survey. AB - OBJECTIVES: Our retrospective study aimed to evaluate the rate and the appropriate use of antenatal corticosteroid therapy, and their effect on the incidence and treatment of respiratory distress syndrome (RDS) and its complications. MATERIAL AND METHODS: A retrospective analysis of clinical practice in Poland was performed using standard investigating tools: a questionnaire on the frequency of using antennal corticosteroids in the selected centers, as well as neonatal data. A total of 987 newborns at <= 32 weeks of gestation, treated in 54 centers (including 42 tertiary and 12 secondary referral centers) over a period of 6 months in 2013, were deemed eligible. The study group consisted of 749 newborns whose mothers received antenatal steroids. The non steroid group included 238 newborns. RESULTS: Antenatal corticosteroids were administered to 75.89% of the neonates from the study group, with 79% and 21% receiving one and two courses, respectively. Children whose mothers received prenatal steroids presented with less extensive radiographic changes typical of RDS, and less often required surfactant therapy (70% vs. 78%; p = 0.0143). In the group of children undergoing antenatal steroid therapy, the percentage of BPD was lower (13.27% vs. 18.63%) (p = 0.0881). The mortality rates were 20.91% and 10.81% in controls and the study group, respectively (p = 0.0001). CONCLUSIONS: The percentage of antenatal steroid use in secondary and tertiary referral centers in Poland is unsatisfactorily low (76%). Antenatal corticosteroids demonstrated high efficacy in decreasing severe forms of RDS, less need for surfactant therapy, and reduced BPD and mortality rates. PMID- 27504943 TI - Correlation between factor VII and PAI-1 genetic variants and recurrent miscarriage. AB - BACKGROUND: Polymorphisms which are presented below may be the cause of inherited thrombophilia and may result in pregnancy loss. The hypothesis is based on a number of cardiology studies which have confirmed the involvement of these polymorphisms in thrombotic incidents. OBJECTIVES: To evaluate the role of polymorphisms of factor VII gene (Arg353Gln, -122T > C) and PAI-1 gene (-675 4G/5G) in the etiology of recurrent miscarriage. MATERIAL AND METHODS: The study group included 152 women with a positive history of >= 2 consecutive pregnancy losses (114 and 38 women with 2 and >= 3 miscarriages, respectively), while 180 healthy women were recruited as controls. Genetic analysis was performed with the use of PCR/RFLP. RESULTS: Lower frequency of Arg353/Gln353 was observed in women with 2 and >= 3 miscarriages as compared to controls (21.1% vs. 23.9% and 13.2% vs. 23.9%, respectively). The frequency of Gln353 was lower in women with >= 3 miscarriages as compared to controls (6.6% vs. 11.9%, p = ns). The frequency of 122TT was higher in women with >= 3 miscarriages as compared to controls (86.84% vs. 76.67%, p = ns), whereas -122TC was more frequent in controls (13.16% vs. 22.78% in controls, p = ns). The frequency of -122T was higher in patients with >= 3 abortions as compared to controls (93.42% vs. 88.06%, p = ns), and -122C was observed more frequently in controls (6.58% vs. 11.94% in controls, p = ns). There were no significant differences as far as the -675 4G/5G polymorphism was concerned. CONCLUSIONS: The obtained results suggest a possible protective role of Gln353 and -122C alleles in recurrent miscarriage. PMID- 27504944 TI - Assessment of ultrasound and Doppler parameters in the third trimester of pregnancy as predictors of adverse perinatal outcome in unselected pregnancies. AB - OBJECTIVES: The aim of the study was to investigate ultrasound and Doppler parameters in the third trimester of pregnancy as possible predictors of adverse perinatal outcome in unselected pregnancies. MATERIAL AND METHODS: We performed a retrospective cross-sectional study including unselected pregnant women be-tween 27 and 36 + 6 weeks of gestation. The following ultrasound and Doppler parameters were assessed: estimated fetal weight (EFW) [g], EFW percentile, placental maturity grade (Grannum classification), single vertical deepest pocket (SVDP) of amniotic fluid [cm], amniotic fluid index (AFI) [cm], mean uterine artery (UtA) pulsatility index (PI), umbilical artery (UA) PI, middle cerebral artery (MCA) PI, MCA peak systolic velocity (PSV) [cm/s], and cerebroplacental ratio (CPR). Adverse perinatal outcome was defined as Apgar score of < 7 at 1 min, birth weight of < 2500 g at delivery, and gestational age of < 37 weeks at delivery. The unpaired t test was used to compare the groups. RESULTS: AFI (p = 0.01), mean UtA PI (p = 0.04) and mean UA PI (p = 0.03) were significantly different with regard to the Apgar score at 1 min. EFW, EFW percentile, SVDP of amniotic fluid, AFI, mean UtA PI, UA PI, and MCA PI were significantly different (p < 0.001) in terms of birth weight. Placental maturity grade (p = 0.02), SVDP of the amniotic fluid (p < 0.001), AFI (p < 0.001), mean UtA PI (p < 0.001), UA PI (p = 0.001), and MCA PI (p < 0.001) were significantly different as far as gestational age at delivery is concerned. CONCLUSION: Ultrasound and Doppler parameters may predict adverse perinatal outcomes in unselected pregnancies in the third trimester of pregnancy. PMID- 27504945 TI - Chemotherapy-induced peripheral neuropathy - diagnosis, evolution and treatment. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent neurologic complications experienced by patients receiving antineoplastic drugs. Involvement of the peripheral nerves may have an important impact on daily activi ties and lead to severe impairment of the patient's quality of life (QoL). It seems to be of crucial importance to make a correct and early diagnosis of polyneuropathy and, if possible, spare the patient unnecessary suffering or loss of function. In the preceding article we have presented epidemiology, grading and pathogenesis of the toxic CIPN. The purpose of this article is to review current knowledge of diagnostic techniques, prevention and management strategies in the context of CIPN. PMID- 27504946 TI - Current methods for preimplantation genetic diagnosis. AB - Preimplantation Genetic Diagnosis (PGD) used in assisted reproduction techniques is designed to provide help for couples trying to conceive a child, as it helps deliver healthy offspring. After in vitro fertilization, material is collected from the oocyte (polar body), 3-day-old embryo, or increasingly often, from the trophectoderm of a blastocyst. Selection of the diagnostic method depends on the testing center, but methods such as aCGH (Comparative Genomic Hybridization Array) and NGS (Next-Generation Sequencing) are supposed to have the highest reliability and precision. This paper presents a review of the most important methods used in PGD, their advantages and disadvantages as well as efficacy in the procedures in which they are used. PMID- 27504947 TI - Psychosocial aspects of infertility and its treatment. AB - Nowadays, more and more couples face impediments associated with conception. Infertility is related with experiencing psychological problems by both partners. One of the infertility treatment procedures is in vitro fertilization. Using this method has significant influence on patients and their family's psychology. This essay reviews literature about IVF treatment and discusses the significance of infertility to a couple, children development and psychosocial functioning, their relation with parents and public opinion about in vitro fertilization. PMID- 27504948 TI - Anti-Mullerian hormone: a critical factor for female fertility and reproductive health. AB - Anti-Mullerian hormone (AMH) is a glycoprotein produced by the granulosa cells of preantral and small antral follicles. AMH concentrations reflect ovarian physiology with high precision, thus serving as a more sensitive marker of the ovarian re-serve than chronological age. This hormone plays a role in the pathogenesis of menstrual disorders and fertility in both obesity and polycystic ovary syndrome. The evaluation of AMH may also be useful in diagnosing or monitoring therapy of granulosa cell ovarian tumors. PMID- 27504949 TI - Zika virus intrauterine infections from the obstetrician's perspective. AB - Zika virus (ZIKAV) infections could potentially occur in Poland due to international travel made by its nationals to regions where the Aedes mosquito is active. A causal relationship between prenatal ZIKAV infection and microcephaly and other serious brain anomalies has been found due to the time association between the infection in pregnancy and a presence of congenital nervous system malformations, together with the detectable pathogen in amniotic fluid and fetus's tissues. Two ZIKAV infection cases of pregnant women who were diagnosed with fetal microcephaly in the state of Paraiba, Brazil, later described in Ultrasound Obstetrics and Gynecology by Oliveira Mello et al. are discussed, in the context of the possible introduction of ZIKAV into Poland and the role the obstetrician should play in the detection and rapid reaction to potential threats. According to recommendations of international agencies for disease control and prevention, Polish obstetricians who take care of pregnant women and of those planning to become pregnant in the nearest future, and declaring travels to areas of the Aedes mosquito activity, should advise their patients to consider postponing travel or if they must travel, to take necessary precautionary measures to avoid mosquito bites. Pregnant women who have travelled to areas with ZIKAV transmission, or whose male partners had travelled to such areas and returned in the period of their female part-ner's pregnancy, should be monitored appropriately in the context of congenital abnormalities, including microcephaly. PMID- 27504951 TI - Dense, Regular GaAs Nanowire Arrays by Catalyst-Free Vapor Phase Epitaxy for Light Harvesting. AB - Density dependent growth and optical properties of periodic arrays of GaAs nanowires (NWs) by fast selective area growth MOVPE are investigated. As the period of the arrays is decreased from 500 nm down to 100 nm, a volume growth enhancement by a factor of up to four compared with the growth of a planar layer is observed. This increase is explained as resulting from increased collection of precursors on the side walls of the nanowires due to the gas flow redistribution in the space between the NWs. Normal spectral reflectance of the arrays is strongly reduced compared with a flat substrate surface in all fabricated arrays. Electromagnetic modeling reveals that this reduction is caused by antireflective action of the nanowire arrays and nanowire-diameter dependent light absorption. Irrespective of the periodicity and diameter, Raman scattering and grazing angle X-ray diffraction show signal from zinc blende and wurtzite phases, the latter originating from stacking faults as observed by high resolution transmission electron microscopy. Raman spectra contain intense surface phonons peaks, whose intensity depends strongly on the nanowire diameters as a result of potential structural changes and as well as variations of optical field distribution in the nanowires. PMID- 27504953 TI - The 4(th) MS Food Day Conference: mass spectrometry applications in food analysis. PMID- 27504950 TI - Use of a Cholesterol Recognition Amino Acid Consensus Peptide To Inhibit Binding of a Bacterial Toxin to Cholesterol. AB - Recognition of and binding to cholesterol on the host cell membrane is an initial step in the mechanism of numerous pathogens, including viruses, bacteria, and bacterial toxins; however, a viable method of inhibiting this interaction has not yet been uncovered. Here, we describe the mechanism by which a cholesterol recognition amino acid consensus peptide interacts with cholesterol and inhibits the activity of a cholesterol-binding bacterial leukotoxin (LtxA). Using a series of biophysical techniques, we have shown that the peptide recognizes the hydroxyl group of cholesterol with nanomolar affinity and does not disrupt membrane packing, suggesting that it sits primarily near the membrane surface. As a result, LtxA is unable to bind to cholesterol or subsequently become internalized in host cells. Additionally, because cholesterol is not being removed from the cell membrane, the peptide-treated target cells remain viable over extended periods of time. We have demonstrated the use of this peptide in the inhibition of toxin activity for an antivirulence approach to the treatment of bacterial disease, and we anticipate that this approach might have broad utility in the inhibition of viral and bacterial pathogenesis. PMID- 27504952 TI - Genetic Barrier to Direct Acting Antivirals in HCV Sequences Deposited in the European Databank. AB - BACKGROUND & AIMS: Development of resistance results from mutations in the viral genome, and the presence of selective drug pressure leads to the emergence of a resistant virus population. The aim of this study was to analyze the impact of genetic variability on the genetic barrier to drug resistance to DAAs. METHODS: The genetic barrier was quantified based on the number and type of nucleotide mutations required to impart resistance, considering full-length HCV NS3, NS5A and NS5B regions segregated by genotype into subtypes 1a, 1b, 2a, 2b and 3a. This study analyzeds 789 NS3 sequences, 708 sequences and 536 NS5B sequences deposited in the European Hepatitis C Virus Database, in the following resistance associated positions: NS3: F43/I/L/S/V, Q80K/R, R155K/G, A156G/S/T and D168A/C/E/G/H/N/T/V/Y; NS5A: L/M28A/T/V, Q30E/H/R, L31F/I/M/V, H58D or P58S and Y93C/F/H/N/S; NS5B: S282P/R/T, C316H/N/Y, S368T, Y448C/H, S556G/R, D559R. RESULTS: Variants that require only one transversion in NS3 were found in 4 positions and include F43S, R80K, R155K/G and A156T. The genetic barrier to resistance shows subtypic differences at position 155 of the NS3 gene where a single transition is necessary in subtype 1a. In the NS5A gene, 5 positions where only one nucleotide change can confer resistance were found, such as L31M which requires one transversion in all subtypes, except in 0.28% of 1b sequences; and R30H, generated by a single transition, which was found in 10.25% of the sequences of genotype 1b. Other subtypic differences were observed at position 58, where resistance is less likely in genotype 1a because a transversion is required to create the variant 58S. For the NS5B inhibitors, the genetic barrier at positions conferring resistance was nearly identical in subtypes 1a and 1b, and single transitions or transversions were necessary in 5 positions to generate a drug-resistant variant of HCV. The positions C316Y and S556D required only one transition in all genotypes, Y448H and S556 G/N/R positions required only one transition for up to 98.8% of the sequences analyzed. A single variant in position 448 in genotype 1a is less likely to become the resistance variant 448H because it requires two transversions. Also, in the position 559D a transversion and a transition were necessary to generate the resistance mutant D559H. CONCLUSION: Results revealed that in 14 out of 16 positions, conversion to a drug resistant variant of HCV required only one single nucleotide substitutions threatening direct acting antivirals from all three classes. PMID- 27504954 TI - Evaluation of a Urine Pooling Strategy for the Rapid and Cost-Efficient Prevalence Classification of Schistosomiasis. AB - BACKGROUND: A key epidemiologic feature of schistosomiasis is its focal distribution, which has important implications for the spatial targeting of preventive chemotherapy programs. We evaluated the diagnostic accuracy of a urine pooling strategy using a point-of-care circulating cathodic antigen (POC-CCA) cassette test for detection of Schistosoma mansoni, and employed simulation modeling to test the classification accuracy and efficiency of this strategy in determining where preventive chemotherapy is needed in low-endemicity settings. METHODOLOGY: We performed a cross-sectional study involving 114 children aged 6 15 years in six neighborhoods in Azaguie Ahoua, south Cote d'Ivoire to characterize the sensitivity and specificity of the POC-CCA cassette test with urine samples that were tested individually and in pools of 4, 8, and 12. We used a Bayesian latent class model to estimate test characteristics for individual POC CCA and quadruplicate Kato-Katz thick smears on stool samples. We then developed a microsimulation model and used lot quality assurance sampling to test the performance, number of tests, and total cost per school for each pooled testing strategy to predict the binary need for school-based preventive chemotherapy using a 10% prevalence threshold for treatment. PRINCIPAL FINDINGS: The sensitivity of the urine pooling strategy for S. mansoni diagnosis using pool sizes of 4, 8, and 12 was 85.9%, 79.5%, and 65.4%, respectively, when POC-CCA trace results were considered positive, and 61.5%, 47.4%, and 30.8% when POC-CCA trace results were considered negative. The modeled specificity ranged from 94.0 97.7% for the urine pooling strategies (when POC-CCA trace results were considered negative). The urine pooling strategy, regardless of the pool size, gave comparable and often superior classification performance to stool microscopy for the same number of tests. The urine pooling strategy with a pool size of 4 reduced the number of tests and total cost compared to classical stool microscopy. CONCLUSIONS/SIGNIFICANCE: This study introduces a method for rapid and efficient S. mansoni prevalence estimation through examining pooled urine samples with POC-CCA as an alternative to widely used stool microscopy. PMID- 27504955 TI - Use of systemic therapy with definitive radiotherapy for elderly patients with head and neck cancer: A National Cancer Data Base analysis. AB - BACKGROUND: The purpose of this study was to investigate the use of systemic therapy along with definitive radiotherapy for elderly patients with head and neck cancer. METHODS: Patients who were 71 years old or older with stage III to IVB squamous cell carcinoma of the nasopharynx, oropharynx, larynx, or hypopharynx treated with definitive radiotherapy with or without systemic therapy were identified from the National Cancer Data Base. Patterns of systemic therapy use before or during definitive radiotherapy were investigated. The association between systemic therapy use and overall survival was investigated with a multivariate, inverse probability-weighted propensity score-adjusted Cox proportional hazards model. RESULTS: Elderly patients treated between 2004 and 2012 (n = 4165) were identified, and 80.4% received systemic therapy. The median follow-up was 26 months (range, 1.8-125 months), and the 3-year overall survival rate was 51.6% (95% confidence interval, 50.0%-53.2%). During the study period, there was an increase in the frequency of systemic therapy use from 64% in 2004 to 86% in 2012. The use of systemic therapy was associated with improved overall survival in the multivariate model (hazard ratio, 1.456; 95% confidence interval, 1.308-1.620; P < .0001). A threshold age above which the use of systemic therapy was not associated with improved overall survival in select patients was not identified. CONCLUSIONS: In contrast to the available prospective evidence, the majority of elderly patients with locoregionally advanced head and neck cancer treated with definitive radiotherapy also receive systemic therapy. The use of systemic therapy is associated with improved overall survival and should be a patient-specific decision in all age groups. Cancer 2016;122:3472-3483. (c) 2016 American Cancer Society. PMID- 27504956 TI - The Grapevine Uncharacterized Intrinsic Protein 1 (VvXIP1) Is Regulated by Drought Stress and Transports Glycerol, Hydrogen Peroxide, Heavy Metals but Not Water. AB - A MIP (Major Intrinsic Protein) subfamily called Uncharacterized Intrinsic Proteins (XIP) was recently described in several fungi and eudicot plants. In this work, we cloned a XIP from grapevine, VvXIP1, and agrobacterium-mediated transformation studies in Nicotiana benthamiana revealed that the encoded aquaporin shows a preferential localization at the endoplasmic reticulum membrane. Stopped-flow spectrometry in vesicles from the aqy-null yeast strain YSH1172 overexpressing VvXIP1 showed that VvXIP1 is unable to transport water but is permeable to glycerol. Functional studies with the ROS sensitive probe CM H2DCFDA in intact transformed yeasts showed that VvXIP1 is also able to permeate hydrogen peroxide (H2O2). Drop test growth assays showed that besides glycerol and H2O2, VvXIP1 also transports boric acid, copper, arsenic and nickel. Furthermore, we found that VvXIP1 transcripts were abundant in grapevine leaves from field grown plants and strongly repressed after the imposition of severe water-deficit conditions in potted vines. The observed downregulation of VvXIP1 expression in cultured grape cells in response to ABA and salt, together with the increased sensitivity to osmotic stress displayed by the aqy-null yeast overexpressing VvXIP1, corroborates the role of VvXIP1 in osmotic regulation besides its involvement in H2O2 transport and metal homeostasis. PMID- 27504957 TI - Effect of Edible and Active Coating (with Rosemary and Oregano Essential Oils) on Beef Characteristics and Consumer Acceptability. AB - The effects of an alginate-based edible coating containing natural antioxidants (rosemary and oregano essential oils) on lipid oxidation, color preservation, water losses, texture and pH of beef steaks during 14 days of display were studied. The essential oil, edible coating and beef antioxidant activities, and beef consumer acceptability were also investigated. The edible coatings decreased lipid oxidation of the meat compared to the control. The coating with oregano was most effective (46.81% decrease in lipid oxidation) and also showed the highest antioxidant activity. The coatings significantly decreased color losses, water losses and shear force compared to the control. The coatings had a significant effect on consumer perception of odor, flavor and overall acceptance of the beef. In particular, the oregano coating showed significantly high values (approximately 7 in a 9-point scale). Active edible coatings containing natural antioxidants could improve meat product stability and therefore have potential use in the food industry. PMID- 27504958 TI - Therapeutic potential of recombinant thrombomodulin for lung injury after pneumonectomy via inhibition of high-mobility group box 1 in mice. AB - BACKGROUND: Surgical acute respiratory distress syndrome (ARDS) is an extremely critical condition which may occur after major lung resection. Despite advances in minimally invasive surgical procedures and progress in the therapeutic management of this disease, prognosis remains poor. In this study, we investigated the contribution of high-mobility group box 1 (HMGB1) in a surgical ARDS model and evaluated the possible therapeutic effect of recombinant thrombomodulin (rTM) for the treatment of surgical ARDS. METHODS: C57BL/6J mice underwent left pneumonectomy. rTM was injected at 12 hours before surgery, followed by 12 hours for 3 days after surgery. Lipopolysaccharide (LPS) was administered at 2 hours after surgery. We conducted a histologic analysis and measured HMGB1, IL-6, IL-1beta, and TNF-alpha in bronchoalveolar lavage fluid on day 3 after pneumonectomy. Data were compared between the treatment groups. RESULTS: On histologic analysis, left pneumonectomy followed by LPS administration induced both severe inflammatory cellular infiltration and alveolar wall congestion with hemorrhage. rTM administration rescued these histologic changes. The level of HMGB1, IL-6, IL-1beta, and TNF-alpha in bronchoalveolar lavage fluid was significantly increased by LPS administration after pneumonectomy and significantly decreased by rTM administration with LPS and pneumonectomy (p < 0.001). Also, LPS alone showed no statistical differences in HMGB1 or proinflammatory cytokine level compared with pneumonectomy (PNX) group. In addition, the survival outcome was also improved by rTM administration. CONCLUSIONS: LPS administration after left pneumonectomy could induce the severe lung injury. PNX and LPS have similar contribution to this model and may play a synergistic role in this process. rTM may have the potential therapeutic effect for surgical ARDS via suppression of HMGB1 and the secretion of proinflammatory cytokines induced by the administration of LPS after left pneumonectomy. PMID- 27504959 TI - Environmental Life Cycle Assessment of Diets with Improved Omega-3 Fatty Acid Profiles. AB - A high incidence of cardiovascular disease is observed worldwide, and dietary habits are one of the risk factors for these diseases. Omega-3 polyunsaturated fatty acids in the diet help to prevent cardiovascular disease. We used life cycle assessment to analyse the potential of two strategies to improve the nutritional and environmental characteristics of French diets: 1) modifying diets by changing the quantities and proportions of foods and 2) increasing the omega-3 contents in diets by replacing mainly animal foods with equivalent animal foods having higher omega-3 contents. We also investigated other possibilities for reducing environmental impacts. Our results showed that a diet compliant with nutritional recommendations for macronutrients had fewer environmental impacts than the current average French diet. Moving from an omnivorous to a vegetarian diet further reduced environmental impacts. Increasing the omega-3 contents in animal rations increased Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) in animal food products. Providing these enriched animal foods in human diets increased their EPA and DHA contents without affecting their environmental impacts. However, in diets that did not contain fish, EPA and DHA contents were well below the levels recommended by health authorities, despite the inclusion of animal products enriched in EPA and DHA. Reducing meat consumption and avoidable waste at home are two main avenues for reducing environmental impacts of diets. PMID- 27504960 TI - Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis. AB - BACKGROUND: The anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost effectiveness by heterogeneity in age and estrogen receptor (ER) and progesterone receptor (PR) status, which has previously been unexplored, to assist prioritisation. METHODS AND FINDINGS: A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014) effectiveness measures from landmark randomised trials. A New Zealand (NZ) health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50-54 y; 95% CI 2.29 2.37) for the worst prognosis (ER-/PR-) subtype compared to the best prognosis (ER+/PR+) subtype, causing incremental cost-effectiveness ratios (ICERs) for the former to be less than half those of the latter for the age groups from 25-29 to 90-94 y (0.44 times for the age group 50-54 y; 95% CI 0.43-0.45). If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]-adjusted: US$30,300; ?23,700; L21,200), our study suggests that trastuzumab (2011 PPP adjusted US$45,400/?35,900/L21,900 for 1 y at formulary prices) may not be cost effective for ER+ (which are 61% of all) node-positive HER2+ early breast cancer patients but cost-effective for ER-/PR- subtypes (37% of all cases) to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR- cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had the same result. A key limitation was a lack of treatment-effect data by hormone receptor subtype. Heterogeneity was restricted to age and hormone receptor status; tumour size/grade heterogeneity could be explored in future work. CONCLUSIONS: This study highlights how cost-effectiveness can vary greatly by heterogeneity in age and hormone receptor subtype. Resource allocation and licensing of subsidised therapies such as trastuzumab should consider demographic and clinical heterogeneity; there is currently a profound disconnect between how funding decisions are made (largely agnostic to heterogeneity) and the principles of personalised medicine. PMID- 27504961 TI - Trauma and psychological distress in Latino citizen children following parental detention and deportation. AB - : The mental health impact of parental detention and deportation on citizen children is a topic of increasing concern. Forced parent-child separation and parental loss are potentially traumatic events (PTEs) with adverse effects on children's mental health. OBJECTIVE: This study examines posttraumatic stress disorder (PTSD) symptoms and psychological distress among 91 Latino U.S.-born children (ages 6 to 12), living in mixed-status families with a least 1 undocumented parent at risk for detention or deportation. METHOD: Multiagent (child, parent, teacher, clinician) and standardized assessments were conducted at baseline to assess for child trauma and psychological distress. RESULTS: Analyses indicate that PTSD symptoms as reported by parent were significantly higher for children of detained and deported parents compared to citizen children whose parents were either legal permanent residents or undocumented without prior contact with immigration enforcement. Similarly, findings revealed differences in child internalizing problems associated with parental detention and deportation as reported by parent as well as differences in overall child functioning as reported by clinician. In addition, teachers reported higher externalizing for children with more exposure to PTEs. CONCLUSIONS: These findings lend support to a reconsideration and revision of immigration enforcement practices to take into consideration the best interest of Latino citizen children. Trauma-informed assessments and interventions are recommended for this special population. (PsycINFO Database Record PMID- 27504962 TI - Role of Islamic appraisals, trauma-related appraisals, and religious coping in the posttraumatic adjustment of Muslim trauma survivors. AB - OBJECTIVE: This research investigated the role of Islamic appraisals, trauma related appraisals, and religious coping in Muslim trauma survivors. METHOD: We report 2 studies of Muslim trauma survivors with and without posttraumatic stress disorder (PTSD) living in the United Kingdom (Study 1) and a sample of Muslim trauma survivors living in Northern Iraq (Study 2). In both studies participants completed the Posttraumatic Stress Diagnostic Scale, Brief Religious Coping Scale, Islamic Appraisal Questionnaire, and Posttraumatic Cognitions Inventory in Arabic. RESULTS: First, it was found that negative religious coping differentiated between trauma survivors with and without PTSD (Study 1) and was significantly correlated with PTSD symptoms (Study 2). Second, negative Islamic appraisals were significantly associated with greater PTSD symptoms whereas positive Islamic appraisals were significantly associated with fewer PTSD symptoms (Study 2). Third, negative trauma-related appraisals correlated significantly with, and uniquely predicted, PTSD symptoms (Study 2). Finally, trauma-related appraisals were found to mediate the relationship between negative Islamic appraisals and negative religious coping and PTSD symptoms. CONCLUSIONS: These findings suggest that the theoretical emphasis on trauma-related cognitions may also be applicable to our understanding of PTSD in Muslim trauma survivors. However, for this population, trauma-related appraisals and subsequent coping strategies may be influenced by Islamic beliefs and values. Clinically, our findings suggest that addressing PTSD symptoms in Muslim trauma survivors may require clinicians to consider the impact of trauma on the survivor's religious appraisals and relationship with God. (PsycINFO Database Record PMID- 27504963 TI - Aromatic Cluster Sensor of Protein Folding: Near-UV Electronic Circular Dichroism Bands Assigned to Fold Compactness. AB - Both far- and near-UV electronic circular dichroism (ECD) spectra have bands sensitive to thermal unfolding of Trp and Tyr residues containing proteins. Beside spectral changes at 222 nm reporting secondary structural variations (far UV range), Lb bands (near-UV range) are applicable as 3D-fold sensors of protein's core structure. In this study we show that both Lb (Tyr) and Lb (Trp) ECD bands could be used as sensors of fold compactness. ECD is a relative method and thus requires NMR referencing and cross-validation, also provided here. The ensemble of 204 ECD spectra of Trp-cage miniproteins is analysed as a training set for "calibrating" Trp<->Tyr folded systems of known NMR structure. While in the far-UV ECD spectra changes are linear as a function of the temperature, near UV ECD data indicate a non-linear and thus, cooperative unfolding mechanism of these proteins. Ensemble of ECD spectra deconvoluted gives both conformational weights and insight to a protein folding<->unfolding mechanism. We found that the Lb293 band is reporting on the 3D-structure compactness. In addition, the pure near-UV ECD spectrum of the unfolded state is described here for the first time. Thus, ECD folding information now validated can be applied with confidence in a large thermal window (5<=T<=85 degrees C) compared to NMR for studying the unfolding of Trp<->Tyr residue pairs. In conclusion, folding propensities of important proteins (RNA polymerase II, ubiquitin protein ligase, tryptase inhibitor etc.) can now be analysed with higher confidence. PMID- 27504964 TI - Dermoscopy of trichofolliculoma: a rare hair follicle hamartoma. PMID- 27504965 TI - Accuracy of an International Classification of Diseases Code Surveillance System in the Identification of Traumatic Brain Injury. AB - BACKGROUND: Use of International Classification of Disease (ICD) codes for traumatic brain injury (TBI) in healthcare administrative databases may underestimate the epidemiology of TBI. The present study examined the use of ICD 10 codes in a population-based New Zealand sample. METHODS: TBI related ICD-codes within the New Zealand health database were examined for all incident cases from a population-based TBI sample (n = 1,369). Impact of age, gender, ethnicity, presence/absence of skull fracture, where the case was located (i.e., hospital) on receipt of an ICD code was examined. RESULTS: Individuals who received a TBI related ICD-code accounted for 18.6% of the studied population. The most frequent codes were brief loss of consciousness, head injury not otherwise specified, and concussion. Receipt of a code was not impacted by gender. Those with skull fracture (chi2 (1) = 69.983, p < 0.001), and/or attending hospital (chi2 (2) = 81.507, p < 0.001), and of older age (chi2 (1) = 56.473, p < 0.001) were more likely to receive a code. CONCLUSIONS: Reported incidence of TBI, when based upon health registration data, is likely to be a significant underestimate. Specific research needs to be conducted to identify the barriers to medical personnel implementing the ICD head injury codes and to identify ways in which the use of the codes can be improved. PMID- 27504966 TI - Ruthenium-Catalyzed Hydroalkynylative Cyclization of 1,6-Enynes Induced by Substituent Effects. AB - The ruthenium-catalyzed 1,6-enyne cyclization in the presence of bulky substituted terminal alkyne proceeds smoothly at room temperature to afford highly substituted five-membered cyclic compounds featuring a 1,5-enyne motif. Deuterium-labeling experiments showed that the key ruthenacyclopentene intermediate undergoes cleavage of metal-carbon bonds through the metal-assisted sigma-bond metathesis reaction, thus leading to the formation of C(sp(2))-H and C(sp(3))-C(sp) bonds. PMID- 27504967 TI - Hearing lessons from flies. AB - Studying the auditory system of the fruit fly can reveal how hearing works in mammals. PMID- 27504968 TI - Septin/anillin filaments scaffold central nervous system myelin to accelerate nerve conduction. AB - Myelination of axons facilitates rapid impulse propagation in the nervous system. The axon/myelin-unit becomes impaired in myelin-related disorders and upon normal aging. However, the molecular cause of many pathological features, including the frequently observed myelin outfoldings, remained unknown. Using label-free quantitative proteomics, we find that the presence of myelin outfoldings correlates with a loss of cytoskeletal septins in myelin. Regulated by phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2)-levels, myelin septins (SEPT2/SEPT4/SEPT7/SEPT8) and the PI(4,5)P2-adaptor anillin form previously unrecognized filaments that extend longitudinally along myelinated axons. By confocal microscopy and immunogold-electron microscopy, these filaments are localized to the non-compacted adaxonal myelin compartment. Genetic disruption of these filaments in Sept8-mutant mice causes myelin outfoldings as a very specific neuropathology. Septin filaments thus serve an important function in scaffolding the axon/myelin-unit, evidently a late stage of myelin maturation. We propose that pathological or aging-associated diminishment of the septin/anillin-scaffold causes myelin outfoldings that impair the normal nerve conduction velocity. PMID- 27504970 TI - Effects of Nitrogen Availability and Form on Phytoplankton Growth in a Eutrophied Estuary (Neuse River Estuary, NC, USA). AB - Nitrogen availability and form are important controls on estuarine phytoplankton growth. This study experimentally determined the influence of urea and nitrate additions on phytoplankton growth throughout the growing season (March 2012, June 2011, August 2011) in a temperate, eutrophied estuary (Neuse River Estuary, North Carolina, USA). Photopigments (chlorophyll a and diagnostic photopigments: peridinin, fucoxanthin, alloxanthin, zeaxanthin, chlorophyll b) and microscopy based cell counts were used as indicators of phytoplankton growth. In March, the phytoplankton community was dominated by Gyrodinium instriatum and only fucoxanthin-based growth rates were stimulated by nitrogen addition. The limited response to nitrogen suggests other factors may control phytoplankton growth and community composition in early spring. In June, inorganic nitrogen concentrations were low and stimulatory effects of both nitrogen forms were observed for chlorophyll a- and diagnostic photopigment-based growth rates. In contrast, cell counts showed that only cryptophyte and dinoflagellate (Heterocapsa rotundata) growth were stimulated. Responses of other photopigments may have been due to an increase in pigment per cell or growth of plankton too small to be counted with the microscopic methods used. Despite high nitrate concentrations in August, growth rates were elevated in response to urea and/or nitrate addition for all photopigments except peridinin. However, this response was not observed in cell counts, again suggesting that pigment-based growth responses may not always be indicative of a true community and/or taxa-specific growth response. This highlights the need to employ targeted microscopy-based cell enumeration concurrent with pigment-based technology to facilitate a more complete understanding of phytoplankton dynamics in estuarine systems. These results are consistent with previous studies showing the seasonal importance of nitrogen availability in estuaries, and also reflect taxa-specific responses nitrogen availability. Finally, this study demonstrates that under nitrogen-limiting conditions, the phytoplankton community and its various taxa are capable of using both urea and nitrate to support growth. PMID- 27504969 TI - A shared numerical representation for action and perception. AB - Humans and other species have perceptual mechanisms dedicated to estimating approximate quantity: a sense of number. Here we show a clear interaction between self-produced actions and the perceived numerosity of subsequent visual stimuli. A short period of rapid finger-tapping (without sensory feedback) caused subjects to underestimate the number of visual stimuli presented near the tapping region; and a period of slow tapping caused overestimation. The distortions occurred both for stimuli presented sequentially (series of flashes) and simultaneously (clouds of dots); both for magnitude estimation and forced-choice comparison. The adaptation was spatially selective, primarily in external, real-world coordinates. Our results sit well with studies reporting links between perception and action, showing that vision and action share mechanisms that encode numbers: a generalized number sense, which estimates the number of self-generated as well as external events. PMID- 27504971 TI - miR-4443 Participates in the Malignancy of Breast Cancer. AB - PURPOSE: Chemo-resistance is the leading cause of failure in cancer therapy, however, much remains to be understood about the intrinsic mechanisms. In the present study, we discovered the novel miR-4443 that regulated malignancy of breast cancer both in vitro and in vivo. METHODS: We examined the expression of miR-4443 in MDA-MB-231/S and MDA-MB-231 Epirubicin-resistant cell lines with 76 breast cancer formalin-fixed paraffin-embedded tissues by real-time PCR. Also, we investigated the loss- and gain-functions of miR-4443 by MTT assay and flow cytometry. Furthermore, we detected miR-4443 mediated tissue inhibitor of metalloproteinase 2 expression in cells by TargetScan, RT-qPCR and western blot. RESULTS: We identified the up-regulated expression of miR-4443 in Epi-resistant cell lines versus MDA-MB-231/S cell(Epi versus S) and in post-chemotherapy FFPE tissues, along with statistically differential expressions in PR(partial response) versus SD(stable disease)/PD(progressive disease) patients. Overexpression of miR-4443 increased the IC50 value of Epi for the target cells transfected, while inhibition of miR-4443 could restored sensitivity of the target cells to Epi. Besides, down-regulation of endogenous miR-4443 by miRNA inhibitors significantly enhanced Epi-induced apoptosis while up-regulation of miR-4443 by miRNA-mimics lead to less Epi-induced apoptotic cells. Consequently, changes in TIMP2 mRNA and protein expression revealed that miR-4443 mimics suppressed expression of TIMP2 and induced migration in breast cancer cells. Furthermore, TIMP2 expression associated with better prognosis(HR = 0.721, 95%CI: 0.529-0.983). CONCLUSIONS: We revealed that miR-4443 induced malignancy of breast cancer mainly in chemo-resistance aspect for the very first time, providing a novel biomarker in breast cancer diagnosis and therapy. PMID- 27504972 TI - Iron accumulates in the primate choroid of the eye with aging as revealed with synchrotron X-ray fluorescence microscopy. AB - Aging leads to an increase in iron-loaded cellular structures in the choroid of the eye. This study was carried out to determine the distribution and content of iron, zinc and copper in the macular retina, choroid and retrobulbar optic nerve of young (4-5 years, n = 3) and aged (15-16 years, n = 5) male non-human primates, Macaca fascicularis, whose ocular anatomy is similar to humans. Thirty MUm-thick tissue sections were analysed with synchrotron X-ray fluorescence and stained histologically for iron deposition. Quantitative measurements showed high levels of iron, zinc and copper in the choroid and retinal pigment epithelium in the macular area and arachnoid layer in the retrobulbar optic nerve. In aged animals compared to young ones, there was an increase in iron in the choroid with larger deposits and iron-loaded cellular structures. Iron-accumulation within these cellular structures may contribute to choroidal function impairment in aging and age-related macular degeneration. PMID- 27504974 TI - Standardized Grading of Shock Wave Lithotripsy Complications with Modified Clavien System. AB - INTRODUCTION: Definitive consensus on grading of complications of shock wave lithotripsy (SWL) does not exist. The objective of this study was to grade complications of SWL in relation to different stone and shock wave parameters, according to the modified Clavien system. MATERIALS AND METHODS: Complications observed in 2,648 patients who underwent SWL between January 2003 and May 2014 were evaluated statistically and stratified into 5 grades by the modified Clavien system focusing on stone and shock wave parameters. RESULTS: Statistically significant association (p <= 0.05) was found between SWL outcome, Clavien grade of complications and stone and shock wave parameters. According to the modified Clavien system, grades I, II, IIIa, IIIb, IV and V complications were observed in 1,811 (68.39%), 619 (23.37%), 183 (6.91%), 34 (1.28%), nil (0.00%) and 1 (0.03%) patients, respectively. The overall success rate at 3 months was 87.72%. CONCLUSIONS: The modified Clavien system provides a standardized grading of SWL complications and can be used to standardize procedural errors and maintain quality, thereby preventing associated complications and improving the overall management and hence outcome of SWL. PMID- 27504973 TI - Salmonella Bacterial Monotherapy Reduces Autochthonous Prostate Tumor Burden in the TRAMP Mouse Model. AB - Attenuated Salmonella typhimurium injected in the circulatory system of mammals selectively targets tumors. Using weekly intraperitoneal injections of attenuated Salmonella strain CRC2631, we tested for regression and/or inhibition of tumor development in the TRAMP prostate tumor mouse model, which utilizes SV40 early region expression for autochthonous formation of prostate tumors that progress into metastatic, poorly differentiated prostatic carcinomas in an immunocompetent murine model. Thirteen weekly intraperitoneal administrations of 105-107 CFU CRC2631 into 10 week old mice were well tolerated by the TRAMP model. Sacrifice and histological analysis of TRAMP prostates at 22 weeks indicated that Salmonella monotherapy at administrated levels decrease visible tumor size (>29%) but did not significantly inhibit previously described SV40 expression-driven TRAMP tumor progression to undifferentiated carcinomas when histologically examined. In conclusion, this work demonstrates baseline results for CRC2631 Salmonella monotherapy using the immunocompetent TRAMP prostate tumor model in preparation for study of combination therapies that resolve autochthonously generated TRAMP prostate tumors, further reduce tumor size, or inhibit prostate tumor progression. PMID- 27504975 TI - Evaluation of the Western blotting method for the diagnosis of congenital toxoplasmosis. AB - OBJECTIVE: To evaluate the Western blotting method for the detection of IgG anti Toxoplasma gondii (T. gondii) (IgG-WB) in the serum of children with suspected congenital toxoplasmosis. METHODS: We accompanied 47 mothers with acquired toxoplasmosis in pregnancy and their children, between June of 2011 and June of 2014. The IgG-WB was done in house and the test was considered positive if the child had antibodies that recognized at least one band on IgG blots different from the mother's or with greater intensity than the corresponding maternal band, during the first three months of life. RESULTS: 15 children (15.1%) met the criteria for congenital toxoplasmosis and 32 (32.3%) had the diagnosis excluded. The symptoms were observed in 12 (80.0%) children and the most frequent were cerebral calcification in 9 (60.0%), chorioretinitis in 8 (53.3%), and hydrocephalus in 4 (26.6%). IgM antibodies anti-T. gondii detected by chemiluminescence (CL) were found in 6 (40.0%) children and the polymerase chain reaction (PCR) for detection of T. gondii DNA was positive in 5 of 7 performed (71.4%). The sensitivity of IgG-WB was of 60.0% [95% confidence interval (CI) 32.3-83.7%] and specificity 43.7% (95% CI 26.7-62.3%). The sensitivity of IgG-WB increased to 76.0 and 89.1% when associated to the research of IgM anti-T. gondii or PCR, respectively. CONCLUSIONS: The IgG-WB showed greater sensitivity than the detection of IgM anti-T. gondii; therefore, it can be used for the diagnosis of congenital toxoplasmosis in association with other congenital infection markers. PMID- 27504976 TI - Early changes in adipokines from overweight to obesity in children and adolescents. AB - OBJECTIVE: Childhood obesity has been associated with metabolic syndrome and cardiovascular diseases. This study aimed to compare plasma levels of traditional metabolic markers, adipokines and soluble tumor necrosis factor receptor type 1 (sTNFR1) in overweight, obese and lean children. We also assessed the relationships of these molecules with classical metabolic risk factors. METHODS: This study included 104 children and adolescents, which were grouped as: lean (n=24), overweight (n=30), and obese subjects (n=50). They were subjected to anthropometrical, clinical and laboratorial measurements. All measurements were compared between groups. Correlation analyses were also performed to evaluate the association between clinical data, traditional metabolic markers, adipokines and sTNFR1. RESULTS: Fasting glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), LDL-cholesterol and triglycerides were comparable in lean, overweight and obese subjects. Plasma levels of sTNFR1 were similar in lean and overweight subjects, but significantly increased in obese group. Leptin, adiponectin and resistin levels did not differ when overweight were compared to obese subjects. However, all adipokines differed significantly when lean subjects were compared to overweight and obese individuals. Plasma levels of adiponectin were negatively correlated with body mass index (BMI), whereas leptin, resistin and sTNFR1 concentrations positively correlated with BMI. CONCLUSION: Our results showed significant differences in circulating levels of the evaluated markers when lean, overweight and obese individuals were compared, suggesting that these biomarkers may change from lean to overweight and from overweight to obesity. PMID- 27504977 TI - Misuse of Substitution Drugs in the Substitution-Based Therapy. AB - BACKGROUND: The reasons for, and the extent of, misuse of prescribed substitution medication as well as parallel consumption of other drugs during substitution based therapy have still not been adequately researched in Germany. METHODS: This study examines the use of substitution medication in German substitution clinics utilizing a nationwide survey with anonymised questionnaires. RESULTS: The analysis of the 605 questionnaires showed a 30-day consumption prevalence of 8.8% with regard to misuse of substitution substances. The lack of available heroin (38%) and the lack of open spots in treatment programs (21%) were quoted as being the main reasons for the misuse of substitution medication. CONCLUSION: Although the misuse of substitution medications is considered an important problem, our study showed that the current misuse was prevalent only among a minority of the patients. German regulations focused on the avoidance of misuse might be partially contributing to the problem. PMID- 27504978 TI - Do organisational constraints explain the use of restraint? A comparative ethnographic study from three nursing homes in Norway. AB - AIMS AND OBJECTIVES: To investigate (1) what kind of restraint is used in three nursing homes in Norway and (2) how staff use restraint under what organisational conditions. BACKGROUND: Restraint use in residents living with dementia in nursing homes is controversial, and at odds with fundamental human rights. Restraint is a matter of hindering residents' free movement and will by applying either interactional, physical, medical, surveillance or environmental restraint. Previous research has identified use of restraint related to individual resident characteristics such as agitation, aggressiveness and wandering. DESIGN: This model is embedded in an overall mixed-method education intervention design study called Modelling and evaluating evidence-based continuing education program in dementia care (MEDCED), applying ethnography postintervention to examine the use of restraint in 24 nursing homes in Norway. METHOD: Based on restraint diversity measured in the trial, ethnographic investigation was carried out in three different nursing homes in Norway over a 10-month period to examine restraint use in relation to organisational constraints. RESULTS: Several forms of restraint were observed; among them, interactional restraint was used most frequently. We identified that use of restraint relates to the characteristics of individual residents, such as agitation, aggressiveness and wandering. However, restraint use should also be explained in relation to organisational conditions such as resident mix, staff culture and available human resources. CONCLUSION: A fluctuating and dynamic interplay between different individual and contextual factors determines whether restraint is used - or not in particular situations with residents living with dementia. RELEVANCE TO CLINICAL PRACTICE: Educational initiatives targeting staff to reduce restraint must be sensitive towards fluctuating organisational constraints. PMID- 27504979 TI - Glucagon Like Peptide-1 Promotes Adipocyte Differentiation via the Wnt4 Mediated Sequestering of Beta-Catenin. AB - Glucagon-like peptide-1 (GLP-1) plays a role in the regulation of adipogenesis; however, the precise underlying molecular mechanism has not been fully defined. Wnt was recently identified as an important regulator of adipogenesis. This study aimed to investigate the involvement of the Wnt signaling pathway in the effects of GLP-1 on adipocyte differentiation. 3T3-L1 cells were induced to differentiate. The changes in the expression levels of adipogenic transcription factors and Wnts and the phosphorylation level and subcellular localization of beta-catenin were quantified after GLP-1 treatment. GLP-1 stimulated adipocyte differentiation and lipid accumulation, which were accompanied by the expression of adipocyte marker genes. The expression of Wnt4 was upregulated in the process of adipocyte differentiation, which was further enhanced by treatment with GLP-1. beta-catenin, an important mediator of the Wnt pathway, was immediately dephosphorylated and translocated from cytoplasm to nucleus when differentiation was induced. In the presence of GLP-1, however, beta-catenin was redirected to the cell plasma membrane leading to its decreased accumulation in the nucleus. Knockdown of Wnt4 blocked the effect of GLP-1 on the cellular localization of beta-catenin and expression level of adipogenic transcription factors. Our findings showed that GLP-1 promoted adipogenesis through the modulation of the Wnt4/beta-catenin signaling pathway, suggesting that the GLP-1-Wntbeta-catenin system might be a new target for the treatment of metabolic disease. PMID- 27504981 TI - Understanding How Isotopes Affect Charge Transfer in P3HT/PCBM: A Quantum Trajectory-Electronic Structure Study with Nonlinear Quantum Corrections. AB - The experimentally observed effect of selective deuterium substitution on the open circuit voltage for a blend of poly(3-hexylthiophene) (P3HT) and [6,6] phenyl-C61-butyric acid methyl ester (PCBM; Nat. Commun. 2014, 5, 3180) is explored using a 221-atom model of a polymer-wrapped PCBM molecule. The protonic and deuteronic wave functions for the H/D isotopologues of the hexyl side chains are described within a quantum trajectory/electronic structure approach where the dynamics is performed with newly developed nonlinear corrections to the quantum forces, necessary to describe the nuclear wave functions; the classical forces are generated with a density functional tight binding method. The resulting protonic and deuteronic time-dependent wave functions are used to assess the effects of isotopic substitution (deuteration) on the energy gaps relevant to the charge transfer for the donor and acceptor electronic states. While the isotope effect on the electronic energy levels is found negligible, the quantum-induced fluctuations of the energy gap between the charge transfer and charge separated states due to nuclear wave functions may account for experimental trends by promoting charge transfer in P3HT:PCBM and increasing charge recombination on the donor in the deuterium substituted P3HT:PCBM. PMID- 27504980 TI - A Novel Approach to Helicobacter pylori Pan-Genome Analysis for Identification of Genomic Islands. AB - Genomes of a given bacterial species can show great variation in gene content and thus systematic analysis of the entire gene repertoire, termed the pan-genome, is important for understanding bacterial intra-species diversity, population genetics, and evolution. Here, we analyzed the pan-genome from 30 completely sequenced strains of the human gastric pathogen Helicobacter pylori belonging to various phylogeographic groups, focusing on 991 accessory (not fully conserved) orthologous groups (OGs). We developed a method to evaluate the mobility of genes within a genome, using the gene order in the syntenically conserved regions as a reference, and classified the 991 accessory OGs into five classes: Core, Stable, Intermediate, Mobile, and Unique. Phylogenetic networks based on the gene content of Core and Stable classes are highly congruent with that created from the concatenated alignment of fully conserved core genes, in contrast to those of Intermediate and Mobile classes, which show quite different topologies. By clustering the accessory OGs on the basis of phylogenetic pattern similarity and chromosomal proximity, we identified 60 co-occurring gene clusters (CGCs). In addition to known genomic islands, including cag pathogenicity island, bacteriophages, and integrating conjugative elements, we identified some novel ones. One island encodes TerY-phosphorylation triad, which includes the eukaryote type protein kinase/phosphatase gene pair, and components of type VII secretion system. Another one contains a reverse-transcriptase homolog, which may be involved in the defense against phage infection through altruistic suicide. Many of the CGCs contained restriction-modification (RM) genes. Different RM systems sometimes occupied the same (orthologous) locus in the strains. We anticipate that our method will facilitate pan-genome studies in general and help identify novel genomic islands in various bacterial species. PMID- 27504982 TI - Accessory Anterolateral Talar Facet in Populations With and Without Symptoms: Prevalence and Relevant Associated Ankle MRI Findings. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of and relevant findings associated with the accessory anterolateral talar facet, which may have a role in talocalcaneal impingement and sinus tarsi syndrome, on ankle MR images of persons with and those without symptoms. SUBJECTS AND METHODS: In this case-control study, three observers independently reviewed 1.5-T or 3-T MR images of 110 ankles with symptoms in 100 consecutively registered patients (age range, 16-79 years; mean, 41.5 years) and limited 1.5-T MR images of 104 age-, sex-, and side-matched ankles in 104 volunteers without symptoms for the presence of an accessory anterolateral talar facet, calcaneal cortical thickness, subjacent talar or calcaneal cystic and bone marrow edema-like changes at the angle of Gissane, and sinus tarsi fat obliteration. RESULTS: An accessory anterolateral talar facet was present in 36 (32.7%) ankles with symptoms versus 27 (26.0%) symptom-free ankles (p = 0.297). Interobserver agreement was almost perfect (kappa = 0.851; 95% CI, 0.772-0.929) for the detection of accessory anterolateral talar facet and substantial for the detection of sinus tarsi fat obliteration (kappa = 0.671; 95% CI, 0.427-0.915). The angle of Gissane was significantly smaller in persons with an accessory anterolateral talar facet, either with or without symptoms (p < 0.0001). Subjacent talar (p = 0.003) and calcaneal (p = 0.033) bone marrow edema-like change and sinus tarsi fat obliteration (p = 0.034) were significantly more frequent in persons with accessory anterolateral talar facet, but chronic reactive osseous changes at the angle of Gissane were not (p > 0.05). CONCLUSION: The higher prevalence of the MRI finding of an accessory anterolateral talar facet in ankles with and without symptoms is not statistically significant. This facet may be associated with subjacent talar bone marrow edema-like change on MR images of individuals with and those without symptoms and with sinus tarsi fat obliteration in individuals with symptoms. PMID- 27504983 TI - A test to identify persistent picky eaters. AB - BACKGROUND: Picky eating is common and usually relatively brief as new foods are accepted. Persistent picky eating, however, is often associated with comorbid psychopathology. OBJECTIVE: The aim of this study was to use parent-reported child feeding behaviors to identify which picky eaters persist. DESIGN: Participants were a subsample from the Stanford Infant Growth Study a prospective study of child development. Out of the 216 infants, 86 were identified as picky eaters. Picky eaters were separated into two groups using a median split: short term (n=40) and persistent picky eaters (n=46). RESULTS: Recursive Partitioning detected three significant parent-reported feeding questions that may identify persistent picky eaters at an early age: Is your child a picky eater? (yes), does s/he have strong likes with regard to food (yes), does your child accept new foods readily? (no). DISCUSSION: These results provide a first step allowing providers to identify persistent picky eaters and possibly enable intervention at an early age. Further studies are needed to replicate and extend these findings in another sample of picky eaters. PMID- 27504984 TI - Poly(I:C) Induces Human Lung Endothelial Barrier Dysfunction by Disrupting Tight Junction Expression of Claudin-5. AB - Viral infections are often accompanied by pulmonary microvascular leakage and vascular endothelial dysfunction via mechanisms that are not completely defined. Here, we investigated the effect of the Toll-like receptor 3 (TLR3) ligand polyinosinic-polycytidylic acid [Poly(I:C)], a synthetic analog of viral double stranded RNA (dsRNA) commonly used to simulate viral infections, on the barrier function and tight junction integrity of primary human lung microvascular endothelial cells. Poly(I:C) stimulated IL-6, IL-8, TNFalpha, and IFNbeta production in conjunction with the activation of NF-kappaB and IRF3 confirming the Poly(I:C)-responsiveness of these cells. Poly(I:C) increased endothelial monolayer permeability with a corresponding dose- and time-dependent decrease in the expression of claudin-5, a transmembrane tight junction protein and reduction of CLDN5 mRNA levels. Immunofluorescence experiments revealed disappearance of membrane-associated claudin-5 and co-localization of cytoplasmic claudin-5 with lysosomal-associated membrane protein 1. Chloroquine and Bay11-7082, inhibitors of TLR3 and NF-kappaB signaling, respectively, protected against the loss of claudin-5. Together, these findings provide new insight on how dsRNA-activated signaling pathways may disrupt vascular endothelial function and contribute to vascular leakage pathologies. PMID- 27504985 TI - Olanzapine-depot administration induces time-dependent changes in adipose tissue endocrine function in rats. AB - OBJECTIVE: Metabolic adverse effects of atypical antipsychotics (AAP) contribute significantly to increased risk of cardiovascular morbidity and mortality in patients suffering from schizophrenia. Extensive preclinical research has addressed this issue over the past years, though mechanisms underlying these adverse effects of AAP are still not understood completely. Recently, attention is drawn towards the role of adipose tissue metabolism and neurohormonal regulations. METHODS: The aim of this study was to evaluate the time-dependent effects of olanzapine depot administration at clinically relevant dosing on the regulation of energy homeostasis, glucose and lipid metabolism, gastrointestinal and adipose tissue-derived hormones involved in energy balance regulations in female Sprague-Dawley rats. The study lasted 8 weeks and the markers were assayed at day 8, 15, 29, 43 and 57. RESULTS: The results indicate that in the absence of hyperphagia, olanzapine chronic exposure induced weight gain from the beginning of the study. In the later time-point, increased adiposity was also observed. In the initial phase of the study, lipid profile was altered by an early increase in triglyceride level and highly elevated leptin level was observed. Clear bi-phasic time-dependent effect of olanzapine on leptin serum concentration was demonstrated. Olanzapine treatment did not lead to changes in serum levels of ghrelin, FGF-21 and pro-inflammatory markers IL-1a, IL-6 and TNF-alpha at any time-point of the study. CONCLUSION: This study provides data suggesting early alteration in adipose tissue endocrine function as a factor involved in mechanisms underlying metabolic adverse effects of antipsychotics. PMID- 27504986 TI - Concentration-Dependent Proton Transfer Mechanisms in Aqueous NaOH Solutions: From Acceptor-Driven to Donor-Driven and Back. AB - Proton transfer processes play an important role in many fields of chemistry. In dilute basic aqueous solutions, proton transfer from water molecules to hydroxide ions is aided by "presolvation", i.e., thermal fluctuations that modify the hydrogen-bonding environment around the proton-receiving OH(-) ion to become more similar to that of a neutral H2O molecule. In particular at high concentrations, however, the underlying mechanisms and especially the role of the counterions are little understood. As a prototypical case, we investigate aqueous NaOH solutions using molecular dynamics simulations employing a reactive high-dimensional neural network potential constructed from density functional theory reference data. We find that with increasing concentration the predominant proton transfer mechanism changes from being "acceptor-driven", i.e., governed by the presolvation of OH( ), to "donor-driven", i.e., governed by the presolvation of H2O, and back to acceptor-driven near the room-temperature solubility limit of 19 mol/L, which corresponds to an extremely solvent-deficient system containing only about one H2O molecule per ion. Specifically, we identify concentration ranges where the proton transfer rate is mostly affected by OH(-) losing an accepted hydrogen bond, OH(-) forming a donated hydrogen bond, H2O forming an accepted hydrogen bond, or H2O losing a coordinated Na(+). Presolvation also manifests itself in the shortening of the Na(+)-OH2 distances, in that the Na(+) "pushes" one of the H2O protons away. PMID- 27504987 TI - Phase-contrast MRI with hybrid one and two-sided flow-encoding and velocity spectrum separation. AB - PURPOSE: To develop and evaluate a phase-contrast MRI (PC-MRI) technique with hybrid one and two-sided flow-encoding and velocity spectrum separation (HOTSPA) for accelerated blood flow and velocity measurement. METHODS: In the HOTSPA technique, the two-sided flow encoding (FE) is used for two FE directions and one sided is used for the remaining FE direction. Such a temporal modulation of the FE strategy allows for separations of the Fourier velocity spectrum into components for the flow-compensated and the three-directional velocity waveforms, accelerating PC-MRI by encoding three-directional velocities using only two repetition times (TRs) instead of four TRs as in standard PC-MRI. The HOTSPA was evaluated and compared with standard PC-MRI in the common carotid arteries of six healthy volunteers. RESULTS: Total volumetric flow and peak velocity measurements based on HOTSPA and the conventional PC-MRI were in good agreement with a bias of -0.005 mL (-0.1% relative bias error) for total volumetric flow and 1.21 cm/s (1.1% relative bias error) for peak velocity, although the total acquisition time was 50% of the conventional PC-MRI. CONCLUSION: The proposed HOTSPA technique achieved nearly two-fold acceleration of PC-MRI while maintaining accuracy for total volumetric flow and peak velocity quantification by separating the paired acquisitions in the Fourier velocity spectrum domain. Magn Reson Med 78:182-192, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27504988 TI - Metal-Free Activation of a C(sp)-H Bond of Aryl Acetylenes. AB - C(sp)-H Bond activation of acetylene molecule still remains a challenge for synthetic organic chemists. In practice, acetylenes are activated by strong bases and metals. The first example for activating acetylenic protons under base and metal-free conditions is reported here. It involves a general method for synthesizing propargylic derivatives of cotarnine. An array of tetrahydroisoquinolines alkaloids was synthesized by C(sp)-H bond activation of aromatic acetylenes with cotarnine at room temperature. A DFT-based mechanism is proposed for the reaction. PMID- 27504989 TI - The State-of-the-Science on Somatosensory Function and Its Impact on Daily Life in Adults and Older Adults, and Following Stroke: A Scoping Review. AB - The aim was to identify and synthesize research evidence about how adults and older adults process somatosensory information in daily activities, and the interventions available to regain somatosensory function following stroke. We developed two interacting concept maps to address the research questions. The scoping review was conducted from 2005 to 2015 across Web of Science, AMED, CINAHL, Embase, Medline, and PsychInfo databases. Search terms included somatosensory, perception, performance, participation, older adult, stroke, intervention, discrimination, learning, and neuroplasticity. Contributions from 103 articles for Concept 1 and 14 articles for Concept 2 are reported. Measures of somatosensory processing, performance, and participation used are identified. Interventions available to treat somatosensory loss are summarized in relation to approach, outcome measures, and theory/mechanisms underlying. A gap exists in the current understanding of how somatosensory function affects the daily lives of adults. A multidisciplinary approach that includes performance and participation outcomes is recommended to advance the field. PMID- 27504990 TI - The State of the Science on Sensory Factors and Their Impact on Daily Life for Children: A Scoping Review. AB - The objective of this study was to identify and synthesize research about how sensory factors affect daily life of children. We designed a conceptual model to guide a scoping review of research published from 2005 to October 2014 (10 years). We searched MEDLINE, CINAHL, and PsycINFO and included studies about sensory perception/processing; children, adolescents/young adults; and participation. We excluded studies about animals, adults, and review articles. Our process resulted in 261 articles meeting criteria. Research shows that children with conditions process sensory input differently than peers. Neuroscience evidence supports the relationship between sensory-related behaviors and brain activity. Studies suggest that sensory processing is linked to social participation, cognition, temperament, and participation. Intervention research illustrates the importance of contextually relevant practices. Future work can examine the developmental course of sensory processing aspects of behavior across the general population and focus on interventions that support children's sensory processing as they participate in their daily lives. PMID- 27504991 TI - (13)C or Not (13)C: Selective Synthesis of Asymmetric Carbon-13-Labeled Platinum(II) cis-Acetylides. AB - Asymmetric isotopic labeling of parallel and identical electron- or energy transfer pathways in symmetrical molecular assemblies is an extremely challenging task owing to the inherent lack of isotopic selectivity in conventional synthetic methods. Yet, it would be a highly valuable tool in the study and control of complex light-matter interactions in molecular systems by exclusively and nonintrusively labeling one of otherwise identical reaction pathways, potentially directing charge and energy transport along a chosen path. Here we describe the first selective synthetic route to asymmetrically labeled organometallic compounds, on the example of charge-transfer platinum(II) cis-acetylide complexes. We demonstrate the selective (13)C labeling of one of two acetylide groups. We further show that such isotopic labeling successfully decouples the two nu(C=C) in the mid-IR region, permitting independent spectroscopic monitoring of two otherwise identical electron-transfer pathways, along the (12)C=(12)C and (13)C=(13)C coordinates. Quantum-mechanical mixing leads to intriguing complex features in the vibrational spectra of such species, which we successfully model by full-dimensional anharmonically corrected DFT calculations, despite the large size of these systems. The synthetic route developed and demonstrated herein should lead to a great diversity of asymmetric organometallic complexes inaccessible otherwise, opening up a plethora of opportunities to advance the fundamental understanding and control of light-matter interactions in molecular systems. PMID- 27504992 TI - Team Reading (Peer Review) of Suspicious/Positive Slides for Continuous Quality Improvement in Cervical-Vaginal Cytology: A Comparison between Methods and Indicators. AB - AIM: In 2013, the Local Health Unit Roma 2 ex C screening laboratory introduced a new set of indicators for quality assurance. We compare 2 sets of indicators based on routine multiple readings (peer review) for their ability to identify problems in single-reader accuracy. METHODS: All suspect slides were blindly reviewed by all the cytologists of the laboratory. The standard set of indicators includes interreader Cohen's kappa, positivity rate and atypical squamous cell of undetermined significance/squamous intraepithelial lesion (ASC-US/SIL) ratio. The new set included sensitivity for cervical intraepithelial neoplasia of grade 2 or worse (CIN2+), positive predictive value (PPV) and percentage of positive high risk (HR)-HPV cases among ASC-US. In order to estimate sensitivity and PPV, we considered all women for whom there was a consensus of negative cytology, negative HR-HPV test, negative colposcopy or negative histology true negative. RESULTS: Kappa values ranged from 0.521 to 0.753, with narrow 95% confidence intervals (CIs). Positivity rate ranged from 73.9 to 85.7 and the ASC-US/SIL ratio from 0.61 to 0.81. Sensitivity for CIN2+ at the low-grade SIL threshold ranged from 85.8 to 94.2, PPV ranged from 14.8 to 19.4, and both had a broad 95% CI. Readers with low sensitivity did not show low kappa values. The percentage proportion of HR-HPV-positives (HR-HPV+) among ASC-US ranged from 39.9 to 43.8% with a narrow 95% CI. CONCLUSION: The proportion of HR-HPV+ among ASC-US cases is a powerful indicator to address in training. PMID- 27504993 TI - Laser, radiofrequency, and ethanol ablation for the management of thyroid nodules. AB - PURPOSE OF REVIEW: The majority of benign thyroid nodules are nearly asymptomatic, remain stable in size, and do not require treatment. However, a minority of patients with growing nodules may complain of local symptoms or have cosmetic concerns, and thus seek surgical consultation. RECENT FINDINGS: The timely use of ultrasound-guided minimally invasive procedures can change the natural history of benign enlarging thyroid nodules. The procedures produce persistent shrinkage of thyroid nodules and are associated with improvement of local symptoms. Among the various procedures, percutaneous ethanol injection represents the first-line treatment for relapsing thyroid cysts. In solid nonfunctioning nodules, laser and radiofrequency ablation produces a more than 50% reduction in nodular volume that remains persistent over several years. For hyperfunctioning nodules, thermal ablation techniques are not appropriate unless radioactive iodine is contraindicated or not accessible. SUMMARY: MITs are best suited for the management of medium or large-sized nodules that are sonographically well visualized. Conversely, large nodules or nodular goiters that extend into the chest are difficult to treat. MITs are performed in outpatient clinics, are less expensive, and have a lower risk of complications, compared to surgery, and usually do not induce thyroid dysfunction. However, malignancy should be ruled out with a dedicated ultrasound neck assessment and repeat fine needle aspiration of the lesion before treatment. PMID- 27504994 TI - Dispersion and Hydrogen Bonding Rule: Why the Vaporization Enthalpies of Aprotic Ionic Liquids Are Significantly Larger than those of Protic Ionic liquids. AB - It is well known that gas-phase experiments and computational methods point to the dominance of dispersion forces in the molecular association of hydrocarbons. Estimates or even quantification of these weak forces are complicated due to solvent effects in solution. The dissection of interaction energies and quantification of dispersion interactions is particularly challenging for polar systems such as ionic liquids (ILs) which are characterized by a subtle balance between Coulomb interactions, hydrogen bonding, and dispersion forces. Here, we have used vaporization enthalpies, far-infrared spectroscopy, and dispersion corrected calculations to dissect the interaction energies between cations and anions in aprotic (AILs), and protic (PILs) ionic liquids. It was found that the higher total interaction energy in PILs results from the strong and directional hydrogen bonds between cation and anion, whereas the larger vaporization enthalpies of AILs clearly arise from increasing dispersion forces between ion pairs. PMID- 27504995 TI - Light/dark cycle of microalgae cells in raceway ponds: Effects of paddlewheel rotational speeds and baffles installation. AB - The aim of this work was to study the light/dark (L/D) cycle in raceway ponds (RWPs) by the computational fluid dynamics (CFD) method via determining the hydrodynamics of culture media and cell trajectories. The effects of paddlewheel rotational speed and flow-deflector baffles installation on the L/D cycle were analyzed. The results indicated that, the L/D cycles of microalgae cells decreased with the increase of the paddlewheel rotational speeds, when the paddlewheel rotational speeds ranged from 5 to 12rpm. In addition, the installation of the flow-deflector baffles in RWPs can greatly increase the light time and the ratio of light time to L/D cycle for microalgae cells. The study provided an effective method to characterize the L/D cycles in RWPs, and may have important implications for designing the effective large-scale microalgae culture system. PMID- 27504996 TI - Recently characterized molecular events in uncommon gynaecological neoplasms and their clinical importance. AB - The introduction of new sequencing technologies has resulted in the discovery of commonly mutated genes in uncommon cancers, including non-epithelial ovarian neoplasms and other rare gynaecological tumours, such as cervical embryonal rhabdomyosarcoma. In some of these neoplasms, mutations in certain genes are both frequent and specific enough for the genomic mutations and sometimes their associated protein loss or overexpression to be used as an aid to diagnosis. In this review, we contrast previous gene identification methods with newer ones, and discuss how the new sequencing technologies (collectively referred to as 'next-generation sequencing') have permitted the identification of specific molecular events that characterize several rare gynaecological neoplasms. We highlight the value of using sequencing to complement traditional pathological methods when diagnosing certain tumours, and provide practical advice to pathologists dealing with these neoplasms. We focus on adult granulosa cell tumours (somatic monoallelic mutations in FOXL2), Sertoli-Leydig cell tumours, gynaecological embryonal rhabdomyosarcomas (germline and somatic mutations in DICER1), and small-cell carcinoma of the ovary, hypercalcaemic type (biallelic mutations in SMARCA4). The new genetic findings provided by next-generation sequencing in these uncommon neoplasms have brought these disorders back into focus, and point the way towards new diagnostic, preventive and therapeutic avenues. PMID- 27504997 TI - 3 Tesla-Diffusion Tensor Imaging in Autosomal Dominant Polycystic Kidney Disease: The Nephrologist's Point of View. AB - BACKGROUND/AIMS: CT, MRI and ultrasound are currently used for screening and follow-up of individuals affected by autosomal dominant polycystic kidney disease (ADPKD). Dynamic contrast-enhanced MRI studies renal perfusion after gadolinium administration, with possible side effects, such as nephrogenic systemic fibrosis. The aim of our study was to evaluate the clinical application of 3 Tesla (3T)-diffusion tensor image (DTI) in ADPKD patients, correlating its parameters, such as fractional anisotropy (FA), and apparent diffusion coefficient (ADC) with kidney function tests. METHODS: Eight ADPKD patients and 6 healthy volunteers (HS) were enrolled. FA and ADC mean values were calculated. And correlations between DTI-parameters, creatinine and estimated glomerular filtration rate (eGFR) were evaluated. RESULTS: Parenchymal FA was significantly lower in ADPKD than HS (FA: 0.17 +/- 0.03 vs. 0.22 +/- 0.01; p = 0.02), whereas parenchymal ADC was higher in patients than controls (2.48 (*10-3) +/- 0.16 vs. 2.28 (*10-3) +/- 0.09), but a statistically significant difference was not achieved (p = 0.27). Direct correlations were revealed between eGFR and FA (r = 0.82; p = 0.0003), whereas an inverse correlation was found with creatinine (r = 0.77; p = 0.001). Similarly, ADC closely correlated with creatinine (r = 0.79; p = 0.0006) and eGFR (r = -0.620; p = 0.01). CONCLUSION: 3T-DTI is a promising radiological tool that could be used by nephrologists to evaluate ADPKD patients, highlighting early micro-structure alterations, without side effects and contrast agent administration. PMID- 27504998 TI - The Urinary Phosphate to Serum Fibroblast Growth Factor 23 Ratio Is a Useful Marker of Atherosclerosis in Early-Stage Chronic Kidney Disease. AB - BACKGROUND: Fibroblast growth factor 23 (FGF23) regulates mineral homeostasis. In developed renal dysfunction, FGF23 levels increase to maintain the phosphate excretion capacity. However, in diabetic patients with early-stage renal impairment, the FGF23 elevation is not very sensitive. We hypothesized that urinary phosphate (U-P)/serum FGF23 ratio would theoretically be an index that reflects the number of nephrons (nephron index). In this study, we determined whether the nephron index would be associated with renal function and vascular diseases in diabetic patients. METHODS: In total, 142 patients with diabetes mellitus were enrolled. The nephron index was calculated using the following formula: U-P (mg/day)/ serum FGF23 (pg/ml). RESULTS: The mean age was 63 +/- 11 years and eGFR levels were 79.5 +/- 25.4 ml/min/1.73 m2, respectively. Thirty patients had a medical history of macroangiopathy. The Nephron index was significantly decreased in subjects with macroangiopathy compared with those without macroangiopathy. A multivariate analysis of risk factors for macroangiopathy revealed that duration of diabetes, eGFR, and nephron index were significantly associated with a higher frequency of arteriosclerotic disease. CONCLUSION: These findings suggest that a decrease in nephron index reflects early-stage renal impairment and is an independent risk factor of macroangiopathy in diabetic patients. PMID- 27505000 TI - An Inverse Method to Estimate the Root Water Uptake Source-Sink Term in Soil Water Transport Equation under the Effect of Superabsorbent Polymer. AB - The widespread use of superabsorbent polymers (SAPs) in arid regions improves the efficiency of local land and water use. However, SAPs' repeated absorption and release of water has periodic and unstable effects on both soil's physical and chemical properties and on the growth of plant roots, which complicates modeling of water movement in SAP-treated soils. In this paper, we proposea model of soil water movement for SAP-treated soils. The residence time of SAP in the soil and the duration of the experiment were considered as the same parameter t. This simplifies previously proposed models in which the residence time of SAP in the soil and the experiment's duration were considered as two independent parameters. Numerical testing was carried out on the inverse method of estimating the source/sink term of root water uptake in the model of soil water movement under the effect of SAP. The test results show that time interval, hydraulic parameters, test error, and instrument precision had a significant influence on the stability of the inverse method, while time step, layering of soil, and boundary conditions had relatively smaller effects. A comprehensive analysis of the method's stability, calculation, and accuracy suggests that the proposed inverse method applies if the following conditions are satisfied: the time interval is between 5 d and 17 d; the time step is between 1000 and 10000; the test error is >= 0.9; the instrument precision is <= 0.03; and the rate of soil surface evaporation is <= 0.6 mm/d. PMID- 27504999 TI - Hepatocarcinogenesis associated with hepatitis B, delta and C viruses. AB - Globally, over half a billion people are persistently infected with hepatitis B (HBV) and/or hepatitis C viruses. Chronic HBV and HCV infection frequently lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Co-infections with hepatitis delta virus (HDV), a subviral satellite requiring HBV for its propagation, accelerates the progression of liver disease toward HCC. The mechanisms by which these viruses cause malignant transformation, culminating in HCC, remain incompletely understood, partially due to the lack of adequate experimental models for dissecting these complex disease processes in vivo. PMID- 27505001 TI - Comparative Genomics Analysis of Streptococcus tigurinus Strains Identifies Genetic Elements Specifically and Uniquely Present in Highly Virulent Strains. AB - Streptococcus tigurinus is responsible for severe invasive infections such as infective endocarditis, spondylodiscitis and meningitis. As described, S. tigurinus isolates AZ_3aT and AZ_14 were highly virulent (HV phenotype) in an experimental model of infective endocarditis and showed enhanced adherence and invasion of human endothelial cells when compared to low virulent S. tigurinus isolate AZ_8 (LV phenotype). Here, we sought whether genetic determinants could explain the higher virulence of AZ_3aT and AZ_14 isolates. Several genetic determinants specific to the HV strains were identified through extensive comparative genomics amongst which some were thought to be highly relevant for the observed HV phenotype. These included i) an iron uptake and metabolism operon, ii) an ascorbate assimilation operon, iii) a newly acquired PI-2-like pilus islets described for the first time in S. tigurinus, iv) a hyaluronate metabolism operon, v) an Entner-Doudoroff pathway of carbohydrates metabolism, and vi) an alternate pathways for indole biosynthesis. We believe that the identified genomic features could largely explain the phenotype of high infectivity of the two HV S. tigurinus strains. Indeed, these features include determinants that could be involved at different stages of the disease such as survival of S. tigurinus in blood (iron uptake and ascorbate metabolism operons), initial attachment of bacterial pathogen to the damaged cardiac tissue and/or vegetation that formed on site (PI-2-like pilus islets), tissue invasion (hyaluronate operon and Entner-Doudoroff pathway) and regulation of pathogenicity (indole biosynthesis pathway). PMID- 27505002 TI - Zika Virus, a New Threat for Europe? AB - BACKGROUND: Since its emergence in 2007 in Micronesia and Polynesia, the arthropod-borne flavivirus Zika virus (ZIKV) has spread in the Americas and the Caribbean, following first detection in Brazil in May 2015. The risk of ZIKV emergence in Europe increases as imported cases are repeatedly reported. Together with chikungunya virus (CHIKV) and dengue virus (DENV), ZIKV is transmitted by Aedes mosquitoes. Any countries where these mosquitoes are present could be potential sites for future ZIKV outbreak. We assessed the vector competence of European Aedes mosquitoes (Aedes aegypti and Aedes albopictus) for the currently circulating Asian genotype of ZIKV. METHODOLOGY/PRINCIPAL FINDINGS: Two populations of Ae. aegypti from the island of Madeira (Funchal and Paul do Mar) and two populations of Ae. albopictus from France (Nice and Bar-sur-Loup) were challenged with an Asian genotype of ZIKV isolated from a patient in April 2014 in New Caledonia. Fully engorged mosquitoes were then maintained in insectary conditions (28 degrees +/-1 degrees C, 16h:8h light:dark cycle and 80% humidity). 16-24 mosquitoes from each population were examined at 3, 6, 9 and 14 days post infection to estimate the infection rate, disseminated infection rate and transmission efficiency. Based on these experimental infections, we demonstrated that Ae. albopictus from France were not very susceptible to ZIKV. CONCLUSIONS/SIGNIFICANCE: In combination with the restricted distribution of European Ae. albopictus, our results on vector competence corroborate the low risk for ZIKV to expand into most parts of Europe with the possible exception of the warmest regions bordering the Mediterranean coastline. PMID- 27505003 TI - Correction: Advance Care Planning in Dementia: Do Family Carers Know the Treatment Preferences of People with Early Dementia? AB - [This corrects the article DOI: 10.1371/journal.pone.0159056.]. PMID- 27505004 TI - Cyclin-Dependent Kinase 14 Promotes Cell Proliferation, Migration and Invasion in Ovarian Cancer by Inhibiting Wnt Signaling Pathway. AB - OBJECTIVE: The study aimed to investigate cyclin-dependent kinase 14 (CDK14) and its co-function with Wnt signaling pathway on cell proliferation, migration and invasion in ovarian cancer. METHODS: CDK14 expressions were detected by quantitative real-time polymerase chain reaction. The expressions c-Myc, cyclinD1, PFTK1, ki67 and OGT were examined by Western blot. MTT assay was applied to observe cell proliferation after transfection of pEGFP-N1/CDK14-siRNA and pEGFP-N1 into SKOV3 cells, and scratch test and Transwell assay to observe invasion and migration ability. Transfected tumor model in nude mice was established. RESULTS: CDK14 was upregulated in the ovarian cancer tissues and cell lines (both p < 0.05). Expressions of downstream molecules in Wnt signaling pathway as well as the proliferation, invasion and migration ability of the SKOV3 cells were reduced when CDK14 was inhibited (all p < 0.05). The expression of beta-catenin in the nucleus was also decreased when CDK14 was inhibited (p < 0.05). In the transfected tumor model of nude mice, the results showed, compared with the pEGFP-N1 group and blank control group, that the expressions of c-Myc, cyclinD1, PFTK1, ki67 and OGT in the pEGFP-N1/CDK14-siRNA group in the transplantation tumor tissues decreased significantly (all p < 0.05). CONCLUSION: CDK14 suppression-mediated Wnt signaling pathway can inhibit cell proliferation, invasion and migration in ovarian cancer. PMID- 27505005 TI - Vaccine Potential and Diversity of the Putative Cell Binding Factor (CBF, NMB0345/NEIS1825) Protein of Neisseria meningitidis. AB - The cbf gene from Neisseria meningitidis strain MC58 encoding the putative Cell Binding Factor (CBF, NMB0345/NEIS1825) protein was cloned into the pRSETA system and a ~36-kDa recombinant (r)CBF protein expressed in Escherichia coli and purified by metal affinity chromatography. High titres of rCBF antibodies were induced in mice following immunization with rCBF-saline, rCBF-Al(OH)3, rCBF Liposomes or rCBF-Zwittergent (Zw) 3-14 micelles, both with and without incorporated monophosphoryl lipid A (MPLA) adjuvant. Anti-rCBF sera reacted in western blots of meningococcal lysates with a single protein band of molecular mass ~29.5 kDa, indicative of mature CBF protein, but did not react with a lysate of a Deltanmb0345 mutant (CBF-), demonstrating specificity of the murine immune responses. CBF protein was produced by all strains of meningococci studied thus far and the protein was present on the surface of MC58 (CBF+) bacteria, but absent on Deltanmb0345 mutant (CBF-) bacteria, as judged by FACS reactivity of anti-rCBF sera. Analysis of the NEIS1825 amino acid sequences from 6644 N. meningitidis isolates with defined Alleles in the pubmlst.org/Neisseria database showed that there were 141 ST types represented and there were 136 different allelic loci encoding 49 non-redundant protein sequences. Only 6/6644 (<0.1%) of N. meningitidis isolates lacked the nmb0345 gene. Amongst serogroup B isolates worldwide, ~68% and ~20% expressed CBF encoded by Allele 1 and 18 respectively, with the proteins sharing >99% amino acid identity. Murine antisera to rCBF in Zw 3-14 micelles + MPLA induced significant serum bactericidal activity (SBA) against homologous Allele 1 and heterologous Allele 18 strains, using both baby rabbit serum complement and human serum complement (h)SBA assays, but did not kill strains expressing heterologous protein encoded by Alelle 2 or 3. Furthermore, variable bactericidal activity was induced by murine antisera against different meningococcal strains in the hSBA assay, which may correlate with variable surface exposure of CBF. Regardless, the attributes of amino acid sequence conservation and protein expression amongst different strains and the ability to induce cross-strain bactericidal antibodies indicates that rCBF could be a potential meningococcal vaccine antigen and merits further testing. PMID- 27505006 TI - Diagnosis and outcome of Clostridium difficile infection by toxin enzyme immunoassay and polymerase chain reaction in an island population. AB - BACKGROUND AND AIM: Clostridium difficile infection (CDI) is a potentially life threatening cause of diarrhea. Correct laboratory diagnosis is essential to differentiate CDI from other causes of diarrhea. A positive fecal C. difficile toxin (CDT) is the best indicator of CDI, but the significance of a positive fecal nucleic acid amplification test (NAAT) remains unclear. Our aim was to elucidate the significance of CDI diagnostics in patients in Jersey. METHODS: A retrospective, 5-year study was conducted at an island district general hospital of patients who developed CDI. Patients were grouped according to CDT and NAAT status and their association with outcome (indicators of severity and 30-day case fatality rate) compared. RESULTS: A total of 207 specimens were toxin positive, 92 NAAT positive and toxin negative, and 39 had a stool sample negative by both toxin and NAAT testing. A positive toxin stool sample was associated with both significantly higher white cell count (14.5 * 109 /L vs 11.3 * 109 /L, P = 0.003) and C-reactive protein (114.7 mg/dL vs 82.9 mg/dL, P = 0.001), but NAAT positivity was not (P = 0.269, 0.728). A positive CDT assay was a significant independent predictor of death (odds ratio [OR]: 1.89 [95% CI: 1.04-3.43], P = 0.046), but a positive NAAT in CDT negative samples was not (OR: 1.02 [95% CI: 0.34-3.12], P = 1.0). CONCLUSIONS: The findings of this study, derived from evolving clinical practice, provide greater clarity in the interpretation of CDI diagnostics. In CDT-negative disease, a positive NAAT neither predicts disease severity nor mortality. NAAT-positive and toxin-negative patients require instigation of infection control measures, but the need for specific treatment remains unclear. PMID- 27505007 TI - Effect of Chemical Charging/Discharging on Plasmonic Behavior of Silver Metal Nanoparticles Prepared using Citrate-Stabilized Cadmium Selenide Quantum Dots. AB - The thermodynamics and kinetics of the chemical and electrochemical charging of a catalyst surface are very important to understand its applicability as a catalyst material, particularly in redox catalysis. Through the present study, we hereby communicate the results obtained from our detailed investigations related to the effect of chemical charging on the plasmonic behavior of silver metal nanoparticles (Ag MNPs) as redox catalysts. Two different batches of Ag MNPs were prepared through thermally assisted chemical reduction of silver ions. The difference in these batches was the use or not of citrate-capped cadmium selenide quantum dots (Q-CdSe) for the reduction of solution-phase silver ions to their colloidal plasmonic phase. The charge on the surfaces of the Ag MNPs was varied by the chemical electron injection method by using BH4- ions from a NaBH4 solution. The processes of charging and discharging were monitored by using UV/Vis absorption spectroscopy. The impact of the concentration of the reductant on the charging and discharging processes was also investigated. The Ag MNPs were also tested for their voltammetric response, wherein it was observed that it was more difficult to oxidize the Ag MNPs prepared with Q-CdSe seeds than to oxidize Ag MNPs prepared without Q-CdSe particles. Our results demonstrate that Q-CdSe seeds not only enhance the redox catalytic activity of Ag MNPs but also provide stability towards polarization of their plasmonic behavior. PMID- 27505008 TI - Molecular Paleoclimate Reconstructions over the Last 9 ka from a Peat Sequence in South China. AB - To achieve a better understanding of Holocene climate change in the monsoon regions of China, we investigated the molecular distributions and carbon and hydrogen isotope compositions (delta13C and deltaD values) of long-chain n alkanes in a peat core from the Shiwangutian (SWGT) peatland, south China over the last 9 ka. By comparisons with other climate records, we found that the delta13C values of the long-chain n-alkanes can be a proxy for humidity, while the deltaD values of the long-chain n-alkanes primarily recorded the moisture source deltaD signal during 9-1.8 ka BP and responded to the dry climate during 1.8-0.3 ka BP. Together with the average chain length (ACL) and the carbon preference index (CPI) data, the climate evolution over last 9 ka in the SWGT peatland can be divided into three stages. During the first stage (9-5 ka BP), the delta13C values were depleted and CPI and Paq values were low, while ACL values were high. They reveal a period of warm and wet climate, which is regarded as the Holocene optimum. The second stage (5-1.8 ka BP) witnessed a shift to relatively cool and dry climate, as indicated by the more positive delta13C values and lower ACL values. During the third stage (1.8-0.3 ka BP), the delta13C, deltaD, CPI and Paq values showed marked increase and ACL values varied greatly, implying an abrupt change to cold and dry conditions. This climate pattern corresponds to the broad decline in Asian monsoon intensity through the latter part of the Holocene. Our results do not support a later Holocene optimum in south China as suggested by previous studies. PMID- 27505009 TI - Genetic Structure in a Small Pelagic Fish Coincides with a Marine Protected Area: Seascape Genetics in Patagonian Fjords. AB - Marine environmental variables can play an important role in promoting population genetic differentiation in marine organisms. Although fjord ecosystems have attracted much attention due to the great oscillation of environmental variables that produce heterogeneous habitats, species inhabiting this kind of ecosystem have received less attention. In this study, we used Sprattus fuegensis, a small pelagic species that populates the inner waters of the continental shelf, channels and fjords of Chilean Patagonia and Argentina, as a model species to test whether environmental variables of fjords relate to population genetic structure. A total of 282 individuals were analyzed from Chilean Patagonia with eight microsatellite loci. Bayesian and non-Bayesian analyses were conducted to describe the genetic variability of S. fuegensis and whether it shows spatial genetic structure. Results showed two well-differentiated genetic clusters along the Chilean Patagonia distribution (i.e. inside the embayment area called TicToc, and the rest of the fjords), but no spatial isolation by distance (IBD) pattern was found with a Mantel test analysis. Temperature and nitrate were correlated to the expected heterozygosities and explained the allelic frequency variation of data in the redundancy analyses. These results suggest that the singular genetic differences found in S. fuegensis from inside TicToc Bay (East of the Corcovado Gulf) are the result of larvae retention bya combination of oceanographic mesoscale processes (i.e. the west wind drift current reaches the continental shelf exactly in this zone), and the local geographical configuration (i.e. embayment area, islands, archipelagos). We propose that these features generated an isolated area in the Patagonian fjords that promoted genetic differentiation by drift and a singular biodiversity, adding support to the existence of the largest marine protected area (MPA) of continental Chile, which is the Tic-Toc MPA. PMID- 27505010 TI - Renal Autotransplantation at Three Academic Institutions in Turkey. AB - OBJECTIVE: The objective of this study is to present the experience of 3 institutions performing renal autotransplantation (RAT) and to discuss surgical techniques employed and the results in the light of the medical literature. MATERIALS AND METHODS: A total of 14 patients (11 male and 3 female) with a mean age of 47 +/- 8 years (35-61 years), who underwent RAT procedure at 3 different institutions between October 2006 and November 2014, in Turkey, were evaluated retrospectively. Indications for RAT procedure are ureteral avulsion, renal artery aneurysm and intimal dissection caused by percutaneous transluminal renal artery angioplasty (PTRA). Twelve patients with ureteral avulsion, 1 patient with renal artery aneurysm and 1 patient with intimal dissection caused by PTRA were followed-up for 103 months. Seven (50%) open and 7 (50%) laparoscopic nephrectomies were performed. Nine patients (64.3%) were right-sided and 5 patients (35.7%) were left-sided. Complications of grade III and above as per Clavien-Dindo classification were assessed. RESULTS: Mean time from injury to RAT was 21.2 +/- 40.1 days. However, 5 (35.7%) patients were treated on the same day of the injury. As per Clavien-Dindo classification, 2 (14.2%) grade IVa and 1 (7.1%) grade IIIa complications were reported. However, no significant correlation was observed between the complications and graft loss regarding type and side of the nephrectomy performed (p = 0.462 and p = 0.505, respectively) and timing of the intervention (p = 0.692). CONCLUSION: RAT is a safe procedure in combination with minimally invasive laparoscopic technique in carefully selected patients; however, it requires expertise and proficiency in laparoscopy, reconstructive urology and transplantation. Nevertheless RAT should be considered as the last resort, when other modalities fail. PMID- 27505011 TI - Effects of walking in deep venous thrombosis: a new integrated solid and fluid mechanics model. AB - Deep venous thrombosis (DVT) is a common disease. Large thrombi in venous vessels cause bad blood circulation and pain; and when a blood clot detaches from a vein wall, it causes an embolism whose consequences range from mild to fatal. Walking is recommended to DVT patients as a therapeutical complement. In this study the mechanical effects of walking on a specific patient of DVT were simulated by means of an unprecedented integration of 3 elements: a real geometry, a biomechanical model of body tissues, and a computational fluid dynamics study. A set of computed tomography images of a patient's leg with a thrombus in the popliteal vein was employed to reconstruct a geometry model. Then a biomechanical model was used to compute the new deformed geometry of the vein as a function of the fiber stretch level of the semimembranosus muscle. Finally, a computational fluid dynamics study was performed to compute the blood flow and the wall shear stress (WSS) at the vein and thrombus walls. Calculations showed that either a lengthening or shortening of the semimembranosus muscle led to a decrease of WSS levels up to 10%. Notwithstanding, changes in blood viscosity properties or blood flow rate may easily have a greater impact in WSS. PMID- 27505012 TI - Understanding Alzheimer's disease and the aging brain: An Interview with Dr. Christopher van Dyck. PMID- 27505013 TI - Amyloid-beta Alzheimer targets - protein processing, lipid rafts, and amyloid beta pores. AB - Amyloid beta (Abeta), the hallmark of Alzheimer's Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Abeta fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Abeta aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Abeta aggregates, and current therapeutics are summarized in this review. PMID- 27505014 TI - Neural stem/progenitor cells in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and a worldwide health challenge. Different therapeutic approaches are being developed to reverse or slow the loss of affected neurons. Another plausible therapeutic way that may complement the studies is to increase the survival of existing neurons by mobilizing the existing neural stem/progenitor cells (NSPCs) - i.e. "induce their plasticity" - to regenerate lost neurons despite the existing pathology and unfavorable environment. However, there is controversy about how NSPCs are affected by the unfavorable toxic environment during AD. In this review, we will discuss the use of stem cells in neurodegenerative diseases and in particular how NSPCs affect the AD pathology and how neurodegeneration affects NSPCs. In the end of this review, we will discuss how zebrafish as a useful model organism with extensive regenerative ability in the brain might help to address the molecular programs needed for NSPCs to respond to neurodegeneration by enhanced neurogenesis. PMID- 27505015 TI - Side effects of a dopamine agonist therapy for Parkinson's disease: a mini-review of clinical pharmacology. AB - Dopamine agonists (DA) are therapeutic agents that are commonly used in the treatment of Parkinson's disease (PD). They can reduce undesired motor fluctuations and delay the administration of levodopa therapy. However, this drug family is associated with specific side effects that can significantly diminish the quality of life among PD patients. Some of them impose significant risks for individuals who have a history of cardiovascular diseases, psychosis, and depression, or those older patients who suffer from renal or hepatic insufficiency. Various pharmacokinetic and pharmacodynamic considerations need to be taken into account when administering DA therapy. The goal of this review is to provide a comprehensive, up-to-date overview of DA therapeutic modalities for PD. PMID- 27505016 TI - The Significance of the Default Mode Network (DMN) in Neurological and Neuropsychiatric Disorders: A Review. AB - The relationship of cortical structure and specific neuronal circuitry to global brain function, particularly its perturbations related to the development and progression of neuropathology, is an area of great interest in neurobehavioral science. Disruption of these neural networks can be associated with a wide range of neurological and neuropsychiatric disorders. Herein we review activity of the Default Mode Network (DMN) in neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, Epilepsy (Temporal Lobe Epilepsy - TLE), attention deficit hyperactivity disorder (ADHD), and mood disorders. We discuss the implications of DMN disruptions and their relationship to the neurocognitive model of each disease entity, the utility of DMN assessment in clinical evaluation, and the changes of the DMN following treatment. PMID- 27505018 TI - Neurodegeneration and Neuroprotection in Glaucoma. AB - Glaucoma is the principal cause of irreversible blindness in the world. The disease leads to progressive optic nerve degeneration with a gradual loss of retinal ganglion cells. Neurodegeneration in glaucoma extends beyond the eye into the lateral geniculate nucleus and visual cortex, and the disease even shares some characteristics with other central nervous system degenerative disorders. Glaucoma destroys neurons through oxidative stress, impairment in axonal transport, neuroinflammation, and excitotoxicity. Autophagy may promote or inhibit disease progression. Currently, lowering intraocular pressure is the only way proven to delay glaucoma advancement. However, many new therapies are being developed, including antioxidants, adenosine receptor antagonists, Rho-pathway inhibitors, stem cell therapy, and neurotrophic factors. These therapies focus on neuroprotection, and they may eventually halt glaucoma progression or reverse the process of the disease itself. PMID- 27505017 TI - Neurocardiovascular Instability and Cognition. AB - Neurocardiovascular instability (NCVI) refers to abnormal neural control of the cardiovascular system affecting blood pressure and heart rate behavior. Autonomic dysfunction and impaired cerebral autoregulation in aging contribute to this phenomenon characterized by hypotension and bradyarrhythmia. Ultimately, this increases the risk of falls and syncope in older people. NCVI is common in patients with neurodegenerative disorders including dementia. This review discusses the various syndromes that characterize NCVI icluding hypotension, carotid sinus hypersensitivity, postprandial hypotension and vasovagal syncope and how they may contribute to the aetiology of cognitive decline. Conversely, they may also be a consequence of a common neurodegenerative process. Regardless, recognition of their association is paramount in optimizing management of these patients. PMID- 27505019 TI - Cross-education of strength and skill: an old idea with applications in the aging nervous system. AB - Edward Wheeler Scripture's 1894 work out of the Yale Psychological Laboratory has been influential in identifying the nervous system's contribution to the bilateral improvements that are seen with unilateral strength and skill training. Scripture coined the term "cross-education" to describe this improvement in the untrained contralateral limb. While physiological changes accompany aging that may negatively affect the performance of physical tasks, far too much credit has been given to the natural aging process rather than the effects of inactivity. Emerging evidence indicates strength or skill training interventions induce significant neuroplasticity in an aging population. The model of unilateral training provides a unique approach in which to elicit such plasticity. This brief review highlights the innate ability of the nervous system to adapt to unilateral strength and skill training interventions, regardless of age, and provides a novel perspective on the robust plastic ability of the aging nervous system. PMID- 27505020 TI - Social capital, health, and elderly driver status. AB - Driving a car enables many people to engage in meaningful activities that, in turn, help develop and maintain personal social capital. Social capital, a combination of community participation and social cohesion, is important in maintaining well-being. This paper argues that social capital can provide a framework for investigating the general role of transportation and driving a car specifically to access activities that contribute to connectedness and well-being among older people. This paper proposes theoretically plausible and empirically testable hypotheses about the relationship between driver status, social capital, and well-being. A longitudinal study may provide a new way of understanding, and thus of addressing, the well-being challenges that occur when older people experience restrictions to, or loss of, their driver's license. PMID- 27505021 TI - The Knowledge of Memory Aging Questionnaire: Factor Structure and Correlates in a Lifespan Sample. AB - The authors examined the factor structure of the Knowledge of Memory Aging Questionnaire (KMAQ) [1] using confirmatory factor analysis in a lifespan sample of 933 individuals who ranged in age from 18 to 101. Participants were college students at Louisiana State University and adults from the community enrolled in the Louisiana Healthy Aging Study (LHAS). A two-factor solution was expected, consistent with the normal and pathological memory aging dimensions that comprise the KMAQ. A bi-factor solution with items loading on a general response bias factor and either a normal or pathological knowledge-specific factor showed good model fit. Knowledge scores were correlated with demographic and cognitive performance variables. Implications of these data for clinical settings and research are considered. PMID- 27505022 TI - Substance Misuse Education for Physicians: Why Older People are Important. AB - This perspective article focuses on the need for training and education for undergraduate medical students on substance-related disorders, and describes initiatives undertaken in the United Kingdom (UK), Netherlands, United States (US), and Norway to develop the skills, knowledge, and attitudes needed by future doctors to treat patients adequately. In addition, we stress that in postgraduate training, further steps should be taken to develop Addiction Medicine as a specialized and transverse medical domain. Alcohol use disorder is a growing public health problem in the geriatric population, and one that is likely to continue to increase as the baby boomer generation ages. Prescription drug misuse is a major concern, and nicotine misuse remains problematic in a substantial minority. Thus, Addiction Medicine training should address the problems for this specific population. In recent years, several countries have started an Addiction Medicine specialty. Although addiction psychiatry has been a subspecialty in the UK and US for more than 20 years, in most countries it has been a more recent development. Additional courses on addiction should be integrated into the curriculum at both undergraduate and postgraduate levels, as well as form part of the continuous training of other medical specialists. It is recommended that further research and mapping of what is currently taught in medical programs be undertaken, so as to enhance medical education in addiction and improve treatment services. PMID- 27505023 TI - Palliative Care and the Humanities: Centralizing the Patient at the End of Life. AB - Palliative care is a quickly growing facet of modern medicine. While scientific advancements have broken new ground for the possibilities of end-of-life care, sensitive treatment of the patient as an individual has lagged behind and has frequently led to an unsatisfactory experience for patients, families, and the medical community at large. This essay argues that centralizing patients during the terminal phases of treatment by using humanistic perspectives has the potential to bring new meaning and improved effectiveness to patients and physicians alike. PMID- 27505024 TI - Inhibiting the Self-Sorting Behavior in the Blends of a Homologous Set of Polyurethane Model Compounds. AB - Self-sorting is the phenomenon in which there is high fidelity recognition and preference only for self and avoidance of nonself (narcissistic self-sorting). It has been observed in a number of biological systems and chiral synthetic molecules. We found that blends of biscarbamates, which are model compounds for polyurethanes, self-sort during crystallization [ J. Phys. Chem. B 2008 , 112 , 4223 - 4232 ], although these are not chiral molecules. Even if the two components in the blend differ only by a couple of CH2 groups in the side chain length, no intercomponent hydrogen bond forms, and the molecules self-sort. They do not show any cocrystallization despite being part of a homologous series. We believe that it is the first reported example such behavior among synthetic nonchiral molecules. This is similar to the behavior of blends of hydrogen bonding polymers including polyurethanes. We show that the difference in the growth rates of the individual species is responsible for the self-sorting behavior in these nonchiral synthetic compounds. While self-sorting might be advantageous for separation of blends, it poses a challenge for modifying properties such as the melting temperatures, spherulite size, etc., for various applications. We will discuss methods that were attempted to bridge the self and nonself that would lead to a more homogeneous system. We evaluated the miscibility using differential scanning calorimetry (DSC), since the occurrence of a single or multiple endotherms would indicate molecular level miscibility. This is similar to the behavior of glass transition temperatures in the case of polymer blends. Optical microscopy (OM) and X-ray diffraction (XRD) were also used. It is concluded that irrespective of the protocol followed for preparing the mixtures, mutual plasticization occurred in most cases (i.e., mixing of domains of the two species) and not molecular mixing. PMID- 27505025 TI - Topical anticholinergic drugs in the treatment of multiple hidrocystomas: a cross over, randomized, double-blind, placebo-controlled study. PMID- 27505026 TI - Multiparametric evaluation of low grade gliomas at follow-up: comparison between diffusion and perfusion MR with (18)F-FDOPA PET. AB - OBJECTIVE: To compare MRI using perfusion and diffusion techniques with 6-[(18)F] fluoro-L-3,4-dihydroxyphenylalanine ((18)F-FDOPA) positron emission tomography (PET) in the follow-up of low-grade gliomas (LGGs) and to identify the best imaging parameter to differentiate patients with different prognosis. METHODS: Between 2010 and 2015, 12 patients with a pathology-proven diagnosis of LGG and MR (with perfusion and diffusion sequences) and a PET study during their follow up were retrospectively included in our study. Cerebral blood volume (CBV) and apparent diffusion coefficient (ADC) maps on MR studies and PET images were evaluated using a region of interest-based method. All patients were categorized as stable or as having progressive disease at 1-year follow-up. Statistical analysis was performed using Pearson's correlation test and multivariate analysis of variance (p < 0.05). RESULTS: No significant correlations were found between PET parameters [maximum tumour-to-controlateral normal brain ratio (T/Nmax) and tumour-to-striatum ratio] and ADC or relative CBV values measured in both PET hotspot regions and areas of maximum signal alterations. T/Nmax demonstrated a good sensitivity (83%) and specificity (100%) for differentiating two subgroups of patients with different outcomes at 1-year-follow-up (p < 0.05). CONCLUSION: Perfusion and diffusion MR images provide different information compared with (18)F-FDOPA PET in LGGs during follow-up and therefore, they should be considered as complementary tools in the evaluation of these tumours. (18)F-FDOPA PET showed a significant prognostic role in the follow-up of LGGs and appeared to be a better tool than MR advanced techniques for outcome prediction. These results need to be confirmed with longitudinal studies on a larger population. ADVANCES IN KNOWLEDGE: This is the first study that compared (18)F-FDOPA PET with perfusion and diffusion MR in LGGs during follow-up. These preliminary results highlight the importance of a multimodality approach in this field and evidence a potential role for (18)F-FDOPA PET to predict patients at risk for tumour progression. PMID- 27505027 TI - Short and Long Term Behavioral and Pathological Changes in a Novel Rodent Model of Repetitive Mild Traumatic Brain Injury. AB - A history of concussion, particularly repeated injury, has been linked to an increased risk for the development of neurodegenerative diseases, particularly chronic traumatic encephalopathy (CTE). CTE is characterized by abnormal accumulation of hyperphosphorylated tau and deficits in learning and memory. As yet the mechanisms associated with the development of CTE are unknown. Accordingly, the aim of the current study was to develop and characterize a novel model of repetitive mTBI that accurately reproduces the key short and long-term functional and histopathological features seen clinically. Forty male Sprague Dawley rats were randomly assigned to receive 0, 1 or 3x mTBI spaced five days apart using a modified version of the Marmarou impact-acceleration diffuse-TBI model to deliver 110G of linear force. Functional outcomes were assessed six and twelve weeks post-injury, with histopathology assessed twenty-four hours and twelve weeks post-injury. Repetitive mTBI resulted in mild spatial and recognition memory deficits as reflected by increased escape latency on the Barnes maze and decreased time spent in the novel arm of the Y maze. There was a trend towards increased anxiety-like behavior, with decreased time spent in the inner portion of the open field. At 24 hours and 12 weeks post injury, repetitive mTBI animals showed increased tau phosphorylation and microglial activation within the cortex. Increases in APP immunoreactivity were observed in repetitive mTBI animals at 12 weeks indicating long-term changes in axonal integrity. This novel model of repetitive mTBI with its persistent cognitive deficits, neuroinflammation, axonal injury and tau hyperphosphorylation, thus represents a clinically relevant experimental approach to further explore the underlying pathogenesis of CTE. PMID- 27505028 TI - Pathophysiology of the Desmo-Adhesome. AB - Advances in our understanding of desmosomal diseases have provided a clear demonstration of the key role played by desmosomes in tissue and organ physiology, highlighting the importance of their dynamic and finely regulated structure. In this context, non-desmosomal regulatory molecules have acquired increasing relevance in the study of this organelle resulting in extending the desmosomal interactome, named the "desmo-adhesome." Spatiotemporal changes in the expression and regulation of the desmo-adhesome underlie a number of genetic, infectious, autoimmune, and malignant conditions. The aim of the present article was to examine the structural and functional relationship of the desmosome, by providing a comprehensive, yet focused overview of the constituents targeted in human disease. The inclusion of the novel regulatory network in the desmo adhesome pathophysiology opens new avenues to a deeper understanding of desmosomal diseases, potentially unveiling pathogenic mechanisms waiting to be explored. J. Cell. Physiol. 232: 496-505, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27505029 TI - Effects of Exposure to the Sound from Seismic Airguns on Pallid Sturgeon and Paddlefish. AB - This study examined the effects of exposure to a single acoustic pulse from a seismic airgun array on caged endangered pallid sturgeon (Scaphirhynchus albus) and on paddlefish (Polyodon spathula) in Lake Sakakawea (North Dakota, USA). The experiment was designed to detect the onset of physiological responses including minor to mortal injuries. Experimental fish were held in cages as close as 1 to 3 m from the guns where peak negative sound pressure levels (Peak- SPL) reached 231 dB re 1 MUPa (205 dB re 1 MUPa2.s sound exposure level [SEL]). Additional cages were placed at greater distances in an attempt to develop a dose-response relationship. Treatment and control fish were then monitored for seven days, euthanized, and necropsied to determine injuries. Necropsy results indicated that the probability of delayed mortality associated with pulse pressure following the seven day monitoring period was the same for exposed and control fish of both species. Exposure to a single pulse from a small air gun array (10,160 cm3) was not lethal for pallid sturgeon and paddlefish. However, the risks from exposure to multiple sounds and to sound exposure levels that exceed those reported here remain to be examined. PMID- 27505030 TI - Letter: The Impact of Guidelines on Clinical Practice: Survey of the Use of Methylprednisolone for Acute Spinal Cord Injury. PMID- 27505031 TI - Solution- and Solid-Phase Macrocyclization of Peptides by the Ugi-Smiles Multicomponent Reaction: Synthesis of N-Aryl-Bridged Cyclic Lipopeptides. AB - A new multicomponent methodology for the solution- and solid-phase macrocyclization of peptides is described. The approach comprises the utilization of the Ugi-Smiles reaction for the cyclization of 3-nitrotyrosine-containing peptides either by the N-terminus or the lysine side-chain amino groups. Both the on-resin and solution cyclizations took place with good to excellent efficiency in the presence of an aldehyde and a lipidic isocyanide, while the use of paraformaldehyde required an aminocatalysis-mediated imine formation prior to the on-resin Ugi-Smiles ring closure. The introduction of a turn motif in the peptide sequence facilitated the cyclization step, shortened the reaction time, and delivered crude products with >90% purity. This powerful method provided a variety of structurally novel N-aryl-bridged cyclic lipopeptides occurring as single atropisomers. PMID- 27505033 TI - Heterogeneity of osteoclast activity and bone turnover in different skeletal sites. AB - OBJECTIVE: To compare osteoclasts and bone turnover in the cranial and appendicular skeletons of mice and determine whether estrogen depletion has an impact on these differences. DESIGN: In vitro osteoclastogenesis (OCG) was performed on osteoclasts precursors derived from calvarial, mandibular and femoral bone marrow. In vitro, mature osteoclasts were stained with TRAP in plastic petri dishes and with DAPI and Phalloidin on glass coverslips to identify mature osteoclasts and compare osteoclast surface area and nuclei number in the different bone sites, respectively. Quantification of osteoclast resorption pit (Rpit) volume and surface area from different bone sites was achieved using dentin slices stained with Picrosirius red and confocal microscopy. In vivo TRAP, static and dynamic histomorphometric analyses were performed on 5-month-old mouse calvarial, long bone and mandibular trabecular bone to compare bone resorption and formation rates, respectively. Mice were ovariectomized (OVX) at 5 months of age and sacrificed at 6 months of age to establish an osteoporosis model for differences in osteoclasts activity and to monitor the changes in bone turnover rates in the three bone sites upon estrogen depletion. RESULT: s Phalloidin stained calvarial osteoclasts were larger compared to long bone and mandibular osteoclasts. Rpits from osteoclasts derived from mandibular bone were smaller and had lower volume values compared to long bone and calvarial bone Rpits. In vivo analysis showed significant increases in bone formation rates in calvarial trabecular bone compared to long bone and mandibular trabecular bone. Turnover was enhanced upon estrogen depletion in calvarial trabecular bone. Resorption was increased without a corresponding increase in bone formation in the trabecular metaphysis of long bone. Mandibular trabecular bones do not appear to be affected by OVX. CONCLUSION: The cranial and appendicular skeletons differ from one another in that osteoclasts from calvarial bone have the highest resorptive capacity which is coupled to bone formation both pre and post-OVX. Mandibular bones show the lowest turnover rates and are not affected by OVX. PMID- 27505032 TI - Chaperonin-Based Biolayer Interferometry To Assess the Kinetic Stability of Metastable, Aggregation-Prone Proteins. AB - Stabilizing the folded state of metastable and/or aggregation-prone proteins through exogenous ligand binding is an appealing strategy for decreasing disease pathologies caused by protein folding defects or deleterious kinetic transitions. Current methods of examining binding of a ligand to these marginally stable native states are limited because protein aggregation typically interferes with analysis. Here, we describe a rapid method for assessing the kinetic stability of folded proteins and monitoring the effects of ligand stabilization for both intrinsically stable proteins (monomers, oligomers, and multidomain proteins) and metastable proteins (e.g., low Tm) that uses a new GroEL chaperonin-based biolayer interferometry (BLI) denaturant pulse platform. A kinetically controlled denaturation isotherm is generated by exposing a target protein, immobilized on a BLI biosensor, to increasing denaturant concentrations (urea or GuHCl) in a pulsatile manner to induce partial or complete unfolding of the attached protein population. Following the rapid removal of the denaturant, the extent of hydrophobic unfolded/partially folded species that remains is detected by an increased level of GroEL binding. Because this kinetic denaturant pulse is brief, the amplitude of binding of GroEL to the immobilized protein depends on the duration of the exposure to the denaturant, the concentration of the denaturant, wash times, and the underlying protein unfolding-refolding kinetics; fixing all other parameters and plotting the GroEL binding amplitude versus denaturant pulse concentration result in a kinetically controlled denaturation isotherm. When folding osmolytes or stabilizing ligands are added to the immobilized target proteins before and during the denaturant pulse, the diminished population of unfolded/partially folded protein manifests as a decreased level of GroEL binding and/or a marked shift in these kinetically controlled denaturation profiles to higher denaturant concentrations. This particular platform approach can be used to identify small molecules and/or solution conditions that can stabilize or destabilize thermally stable proteins, multidomain proteins, oligomeric proteins, and, most importantly, aggregation-prone metastable proteins. PMID- 27505034 TI - The downregulation of ANGPTL4 inhibits the migration and proliferation of tongue squamous cell carcinoma. AB - OBJECTIVE: Tongue squamous cell carcinoma (TSCC) is the most common malignant cancer in the oral cavity, with a high rate of metastasis to the neck lymphoid node. Angiopoietin-like protein 4 (ANGPTL4) and microvessel density (MVD) may be novel indicators for tumor metastasis. The aim of the present study was to investigate the expression and function of ANGPTL4 in TSCC and the relationship between ANGPTL4 and MVD. METHODS: The expression levels of ANGPTL4 and MVD (CD34) were analyzed in 65 TSCC specimens and the adjacent non-cancerous tissues using immunohistochemistry (IHC). siRNA was delivered into TSCCA cells to downregulate ANGPTL4 expression. Subsequently, validation with real-time RT-PCR and western blot analyses was performed to analyze ANGPTL4 expression levels. In addition, a proliferation assay, migration and invasion assays were carried out. RESULTS: ANGPTL4 expression was associated with tumor stage, lymph node metastasis and MVD expression. Cox regression analysis showed that high levels of ANGPTL4 expression were closely associated with poor survival time. In vitro analyses using qRT-PCR and western blot confirmed that ANGPTL4 was successfully inhibited in TSCCA cells. Suppressing ANGPTL4 resulted in the inhibition of cell proliferation and migration, but neither invasion nor cisplatin resistance was significantly affected. CONCLUSION: High expression levels of ANGPTL4 are associated with the T stage, lymphatic metastasis, angiogenesis and poor overall survival in TSCC patients. The downregulation of ANGPTL4 inhibits the migration and proliferation of cells in TSCC. Taken together, ANGPTL4 may serve as a novel biomarker and therapeutic target for TSCC. PMID- 27505035 TI - 2,3,7,8-Tetrachlorodibenzo-p-dioxin Mediated Cleft palate by Mouse Embryonic Palate Mesenchymal Cells. AB - OBJECTIVE: To evaluate the effects of mouse embryonic palatal mesenchymal (MEPM) cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced. STUDY DESIGN: An experimental study at Xinxiang Medical University. METHODS: Primary MEPM cells were derived from palatal tissue on 30 pregnant C57BL/6 female mice (embryonic day13, GD13). The MEPM cells were placed in a humidified incubator at 37 degrees C with 5% CO2 atmosphere with media replaced every other day. The third passage cells were seeded, and one part of cells were treated with 10nM TCDD (TCDD group). And others were treated with DMSO (<=0.05%, as control group). After 72h, MTT assay was analysed cell viability. Scratch wound-healing was analysed cell motility. Flow cytometry was analysed cell apoptosis and cycle. Western blot was analysed the expression of cyclinE, CDK2, P16 and P21. RESULTS: TCDD inhibited the growth and migration of MEPM cells, while increased cell apoptosis. TCDD exposure inhibited the progression of cells from G1 to S phase and tended to reduce the number of cells entering the G2/M phase. TCDD inhibited expression of cyclinE and CDK2 at the protein level, instead increased the expression of P16 and p21 proteins. CONCLUSIONS: TCDD might induce cleft palate by altering MEPM cells. PMID- 27505036 TI - Race does not predict the development of metastases in men with nonmetastatic castration-resistant prostate cancer. AB - BACKGROUND: Although race is associated with prostate cancer progression in early stage disease, once men have advanced disease, it is unclear whether race continues to predict a poor outcome. The authors hypothesized that, in an equal access setting among patients with castration-resistant prostate cancer (CRPC) and no known metastases (M0/Mx), black men would receive imaging tests at similar rates as nonblack men (ie, there would be an equal opportunity to detect metastases) but would have a higher risk of metastatic disease. METHODS: In total, 837 men who were diagnosed with M0/Mx CRPC during 2000 through 2014 from 5 Veterans Affairs hospitals in the SEARCH (Shared Equal Access Regional Cancer Hospital) database were analyzed. Data on all imaging tests after CRPC diagnosis were collected, including date, type, and outcome. Multivariable Cox models were used to test associations between race and the time to first metastasis, first bone metastasis, first bone scan, second bone scan among men who had a negative first bone scan, and overall survival. RESULTS: Black men (n = 306) were equally as likely as nonblack men (n = 531) to receive a first and second bone scan after a diagnosis of CRPC. There were no significant differences in the risk of developing any metastases, bone metastases, time to bone scans, or overall survival between black men and nonblack men (all P > .2). CONCLUSIONS: The lack of racial differences in the development of metastases and scanning practices observed in this study suggests that, once men have a diagnosis of M0/Mx CRPC, race may not be a prognostic factor. Efforts to understand prostate cancer racial disparities may derive greater benefit by focusing on the risk of developing prostate cancer and on the outcomes of men who have early stage disease. Cancer 2016;122:3848-3855. (c) 2016 American Cancer Society. PMID- 27505037 TI - Real Time Monitoring of Containerless Microreactions in Acoustically Levitated Droplets via Ambient Ionization Mass Spectrometry. AB - Direct in-droplet (in stillo) microreaction monitoring using acoustically levitated micro droplets has been achieved by combining acoustic (ultrasonic) levitation for the first time with real time ambient tandem mass spectrometry (MS/MS). The acoustic levitation and inherent mixing of microliter volumes of reactants (3 MUL droplets), yielding total reaction volumes of 6 MUL, supported monitoring the acid-catalyzed degradation reaction of erythromycin A. This reaction was chosen to demonstrate the proof-of-principle of directly monitoring in stillo microreactions via hyphenated acoustic levitation and ambient ionization mass spectrometry. The microreactions took place completely in stillo over 30, 60, and 120 s within the containerless stable central pressure node of an acoustic levitator, thus readily promoting reaction miniaturization. For the evaluation of the miniaturized in stillo reactions, the degradation reactions were also carried out in vials (in vitro) with a total reaction volume of 400 MUL. The reacted in vitro mixtures (6 MUL total) were similarly introduced into the acoustic levitator prior to ambient ionization MS/MS analysis. The in stillo miniaturized reactions provided immediate real-time snap-shots of the degradation process for more accurate reaction monitoring and used a fraction of the reactants, while the larger scale in vitro reactions only yielded general reaction information. PMID- 27505038 TI - BAIT DEVELOPMENT FOR ORAL DELIVERY OF PHARMACEUTICALS TO RACCOONS (PROCYON LOTOR) AND STRIPED SKUNKS (MEPHITIS MEPHITIS). AB - Oral vaccination is one tool used to control wildlife diseases. A challenge to oral vaccination is identifying baits specific to target species. The US has been conducting oral vaccination against rabies since the 1990s. Improvements in bait development will hasten disease elimination. In Colorado, we examined a novel bait for oral vaccination and offered two different flavors, sweet and fish, to captive raccoons ( Procyon lotor ) and striped skunks ( Mephitis mephitis ) to assess consumption and flavor preference and observed bait removal by target and nontarget species in the field. During captive trials, raccoons and skunks consumed 98% and 87% of offered baits, respectively. Baits contained a sachet to simulate a vaccine package. Raccoons and skunks consumed 98% and 94% of the sachets, respectively. All unconsumed sachets were punctured, suggesting that animals had oral exposure to the contents. Raccoons preferred fish-flavored bait, but skunks did not have a preference. In the field, raccoons consumed the most baits, followed by fox squirrels ( Sciurus niger ). Other rabies host species (striped skunks, red foxes [ Vulpes vulpes ], coyotes [ Canis latrans ]) had very low visitation and were never observed consuming baits. High consumption rates by raccoons and skunks in captivity and observance of raccoons consuming baits in the field suggest that these baits may be useful for oral delivery of pharmaceuticals. Further field research is warranted to determine how to best optimize bait delivery. PMID- 27505039 TI - FORCED MOLT IN FOUR JUVENILE YELLOW-EYED PENGUINS (MEGADYPTES ANTIPODES). AB - Penguins are dependent on waterproof plumage for survival. The molt in sub Antarctic penguin species is a seasonal and catastrophic process during which the animals go through periods of fasting and high levels of stress. Their entire plumage is usually replaced in 3 wk. Attempts at consistent hormonal induction of molt in penguins have been unsuccessful. Four Yellow-eyed Penguins ( Megadyptes antipodes ) were referred for treatment at Wildbase, Massey University, Palmerston North, New Zealand, in late April 2014, following loss of waterproofing, feather breakage, increased body weight, pododermatitis, and damage to caudal feathers from hock sitting. Feather plucking of damaged areas to stimulate feather regrowth was attempted with poor results. Waiting 10-12 mo for a natural molt was not tenable. Catastrophic molt was induced by treatment with 10 g/kg of fresh beef thyroid gland orally once a day. The molt was complete in 18-26 d during which the animals regained full plumage and waterproofing after feather regrowth. The forced molt feathers had abnormal pigmentation but were of sufficient quality to allow release of the birds back to the wild. PMID- 27505040 TI - Dermatophilus congolensis Infection in Platypus ( Ornithorhynchus anatinus ), Tasmania, Australia, 2015. AB - We report disease due to Dermatophilus congolensis infection in three of 13 (23%) platypuses ( Ornithorhynchus anatinus ) from a catchment in Tasmania, Australia. This pathogen has not previously been reported in platypuses. Two of the three infected platypuses had extensive scab formations, but no substantial hair loss was apparent. PMID- 27505041 TI - Formation of Ultrathin Liesegang Patterns. AB - For many years, it has been believed that self-organized periodic ring structures known by the name of Liesegang patterns (LPs) are formed only in quite thick media, typically thicker than at least several micrometers. Actually growing LPs in ultrathin films is extremely difficult because of the drying of film and susceptibility to rapid capillary wetting. The present work reports how we obtain successful LPs in ultrathin films of 65 nm thick. The key parameters are temperature control and the introduction of equilibrium water vapor in the sample environment. Atomic force microscope images clearly showed that the LPs are composed of 300-600 nm laterally coagulated particles. We have also evaluated the densities and thicknesses of the ultrathin films by X-ray reflectivity. During the present research, new patterns, which are different from ordinary LPs, have been discovered for the first time in the outermost part of the whole pattern. Studying LPs in ultrathin films may help to forge a better understanding of the mechanism underlying the intriguing phenomenon. Because of nanoscale scale thicknesses, self-organized periodic structures including so-called LPs will open up new opportunities in nanotechnologies. PMID- 27505042 TI - Oxazolinyl derivatives of [17(20)E]-21-norpregnene differing in the structure of A and B rings. Facile synthesis and inhibition of CYP17A1 catalytic activity. AB - Five 4,5-dihydro-1,3-oxazole derivatives of [17(20)E]-21-norpregnene, comprising 3beta-hydroxy-5-ene (1), 3,6-dioxo-4-ene (2), 3-oxo-4-ene (3), 3alpha,5alpha cyclo-6-oxo (4), 3beta-hydroxy-6-oxo (5) fragments were synthesized. Synthesis was conducted with improved procedure, based on reaction of suitably protected [17(20)E]-pregnen-21-oic acids with ethanolamine in presence of triphenyl phosphine, carbon tetrachloride, and triethyl amine. Potency of the compounds 1-5 to inhibit 17alpha-hydroxylase/17,20-lyase (CYP17A1) activity was studied by highly sensitive electrochemical method, using the enzyme immobilization technique. Compounds 1 and 3 were found to be potent CYP17A1 inhibitors, compounds 2 and 5 were not active, compound 4 strongly and irreversibly suppressed the enzyme activity. Molecular docking of compounds 1-5 in the active site of CYP17A1 showed that positions of all compounds in the enzyme active site were similar. PMID- 27505043 TI - Selective Cooperation in Early Childhood - How to Choose Models and Partners. AB - Cooperation is essential for human society, and children engage in cooperation from early on. It is unclear, however, how children select their partners for cooperation. We know that children choose selectively whom to learn from (e.g. preferring reliable over unreliable models) on a rational basis. The present study investigated whether children (and adults) also choose their cooperative partners selectively and what model characteristics they regard as important for cooperative partners and for informants about novel words. Three- and four-year old children (N = 64) and adults (N = 14) saw contrasting pairs of models differing either in physical strength or in accuracy (in labeling known objects). Participants then performed different tasks (cooperative problem solving and word learning) requiring the choice of a partner or informant. Both children and adults chose their cooperative partners selectively. Moreover they showed the same pattern of selective model choice, regarding a wide range of model characteristics as important for cooperation (preferring both the strong and the accurate model for a strength-requiring cooperation tasks), but only prior knowledge as important for word learning (preferring the knowledgeable but not the strong model for word learning tasks). Young children's selective model choice thus reveals an early rational competence: They infer characteristics from past behavior and flexibly consider what characteristics are relevant for certain tasks. PMID- 27505045 TI - Comparison of the Results of Early Flap Coverage with Late Flap Coverage in High Voltage Electrical Injury. AB - Patients with high-voltage electrical injuries had very high rates of infection, morbidity, and limb amputation. The results of early and late flap coverage in these patients were prospectively compared. The patients were divided into two groups, early flap group (<=3 weeks) and late flap group (>3 weeks), according to the length of time from injury to wound coverage with flap. Age, sex, demographic data, time taken for flap coverage, time taken for pedicle division, time taken to discharge, wound infection, range of motion in joints, amputation, mortality, and outcome were gathered in a special questionnaire. This study included 55 patients, 31 within the early flap group and 24 within the late flap group. Of the 55 patients, 94.6% were male; mean (SD) of age was 29.04 (10.11) and of TBSA was 13.8 (10.07). Length of stay was significantly longer in the late flap group. The rates of infection and amputation were lower in the early flap group. There was no correlation between the type and the number of flaps and amputations. Early flap repair reduces the length of stay by 56%, rate of amputation by 54%, and also 86.1% in the rate of infection in the burn site. PMID- 27505044 TI - OxaD: A Versatile Indolic Nitrone Synthase from the Marine-Derived Fungus Penicillium oxalicum F30. AB - Indole alkaloids are a diverse class of natural products known for their wide range of biological activities and complex chemical structures. Rarely observed in this class are indolic nitrones, such as avrainvillamide and waikialoid, which possess potent bioactivities. Herein the oxa gene cluster from the marine-derived fungus Penicillium oxalicum F30 is described along with the characterization of OxaD, a flavin-dependent oxidase that generates roquefortine L, a nitrone-bearing intermediate in the biosynthesis of oxaline. Nitrone functionality in roquefortine L was confirmed by spectroscopic methods and 1,3-dipolar cycloaddition with methyl acrylate. OxaD is a versatile biocatalyst that converts an array of semisynthetic roquefortine C derivatives bearing indoline systems to their respective nitrones. This work describes the first implementation of a nitrone synthase as a biocatalyst and establishes a novel platform for late-stage diversification of a range of complex natural products. PMID- 27505046 TI - Profile of Patients Without Burn Scar Contracture Development. AB - Burn scar contractures (BSCs) are a frequently recognized problem for survivors of burn injury. In the burn literature, many reports focus on the frequency and factors associated with the BSC development. To the contrary, few burn rehabilitation publications report on patients who are able to successfully avoid developing BSC. From a prospective, multicenter study, data were extracted and reviewed on a group of 56 adult burn survivors who were discharged from their acute hospitalization without any measured BSCs. Forty-three variables with a recognized or presumed association with the development of BSCs were analyzed and are reported. Highlighted features of the noncontracted group included being an adult male with an educated background and few associated physical, medical, or social problems. The group had relatively small burn sizes that nonetheless required hospitalization. Despite the overall TBSA, the majority of the burn areas required skin grafting, although this area also represented a small area. The patient group had a longer than expected hospital stay. Rehabilitation was provided to patients on 80% of their hospital days. In addition, patients received sufficient rehabilitation treatment based on the number of cutaneous functional units involved in the burn injury. Patients were judged to have a high pain tolerance and compliant with rehabilitation. The results of this study document the clinical circumstances that patients with burn injury can be discharged from their acute hospitalization with the development of BSC. This study challenges the rehabilitation personnel to expand the upper limit of burn severity that can result in similar positive outcomes. PMID- 27505047 TI - MicroRNA-148b Acts as a Tumor Suppressor in Cervical Cancer by Inducing G1/S Phase Cell Cycle Arrest and Apoptosis in a Caspase-3-Dependent Manner. AB - BACKGROUND The purpose of our study was to investigate the role of microRNA (miR) 148b in cervical cancer. MATERIAL AND METHODS The expression of miR-148b was determined in HPV-16-immortalized cervical epithelial cell line CRL-2614 cells and in cervical cancer cell line HeLa cells. The miR-148b mimics or scrambled RNA were then transfected into Hela cells. Forty-eight hours after transfection, the mRNA expression of miR-148b and DNA methyltransferase 1 (DNMT1) were confirmed. Cell proliferation ability (cell viability and colony formation ability), invasion ability, and apoptosis were assessed after transfection with miR-148b mimics or scrambled RNA, as well as the protein expression of cyclin D1 and caspase-3. RESULTS The expression of miR-148b was significantly downregulated in HeLa cells compared with CRL2614 cells (P<0.05), but was statistically upregulated by transfection with miR-148b mimics compared with the cells transfected with scrambled RNA (P<0.05). Also, we found that the expression of DNMT1 was significantly decreased by transfection with miR-148b mimics (P<0.05). Additionally, miR-148b mimics significantly decreased the cell proliferation ability and invasion ability, and statistically induced apoptosis. Furthermore, the expression of cyclin D1 protein was significantly decreased and the expression of caspase-3 protein was significantly increased by miR-148b mimics compared with that in the cells transfected with scrambled RNA (P<0.05). CONCLUSIONS Our results suggest that overexpression of miR-148b protects against cervical cancer by inducing G1/S-phase cell cycle arrest and apoptosis through caspase-3-dependent manner, and overexpression of miR-148b might develop a therapeutic intervention for cervical cancer. PMID- 27505048 TI - Almost human: Anthropomorphism increases trust resilience in cognitive agents. AB - We interact daily with computers that appear and behave like humans. Some researchers propose that people apply the same social norms to computers as they do to humans, suggesting that social psychological knowledge can be applied to our interactions with computers. In contrast, theories of human-automation interaction postulate that humans respond to machines in unique and specific ways. We believe that anthropomorphism-the degree to which an agent exhibits human characteristics-is the critical variable that may resolve this apparent contradiction across the formation, violation, and repair stages of trust. Three experiments were designed to examine these opposing viewpoints by varying the appearance and behavior of automated agents. Participants received advice that deteriorated gradually in reliability from a computer, avatar, or human agent. Our results showed (a) that anthropomorphic agents were associated with greater trust resilience, a higher resistance to breakdowns in trust; (b) that these effects were magnified by greater uncertainty; and c) that incorporating human like trust repair behavior largely erased differences between the agents. Automation anthropomorphism is therefore a critical variable that should be carefully incorporated into any general theory of human-agent trust as well as novel automation design. PMID- 27505049 TI - Effects of cues in a binary categorization task on dual-task performance, mental workload, and effort. AB - Binary cues help operators perform binary categorization tasks, such as monitoring for system failures. They may also allow them to attend to other tasks they concurrently perform. If the time saved by using cues is allocated to other concurrent tasks, users' overall effort may remain unchanged. In 2 experiments, participants performed a simulated quality control task, together with a tracking task. In half the experimental blocks cues were available, and participants could use them in their decisions about the quality of products (intact or faulty). In Experiment 1, the difficulty of tracking was constant, while in Experiment 2, tracking difficulty differed in the 2 halves of the experiment. In both experiments, participants reported on the NASA Task Load Index that cues improved their performance and reduced their frustration. Consequently, their overall score on mental workload (MWL) was lower with cues. They also reported, however, that cues did not reduce their effort. We conclude that cues and other forms of automation may support task performance and reduce overall MWL, but this will not necessarily mean that users will work less hard. Thus, effort and overall MWL should be evaluated separately, if one wants to obtain a full picture of the effects of automation. (PsycINFO Database Record PMID- 27505050 TI - Increased prevalence of human herpesvirus type 8 (HHV-8) genome among blood donors from North-Western Argentina. AB - The prevalence of HHV-8 infection varies widely in South American populations, displaying geographical variations in its distribution. The heterogeneous genetic contributions provided by the transatlantic parental populations that modified the Native American genomes may explain this epidemiological observation. Aiming to determine the prevalence of HHV-8 genome among healthy South American blood donors and its potential association with genetic ancestry, 772 individuals were screened by a highly sensitive PCR protocol and ancestry was assessed in 414 samples. HHV-8 DNA was significantly more prevalent among North-western Argentines than among those from the metropolitan region (P = 0.001) and Bolivians (P = 0.0008), but no differences were found when compared with Peruvians and Paraguayans. Although significant differences were observed in the ancestry components of the studied populations, no association was found in the genetic admixture between HHV-8 [+] and HHV-8 [-] samples from the same place. These results support the hypothesis of the existence of geographical factors related to HHV-8 prevalence which could be explained by the presence of specific risk factors, cultural characteristics or behaviors, probably related to contaminated saliva and/or sexual transmission. The presence of HHV-8 in South American blood units available for transfusion and an increased risk of infection in some provinces of North-western Argentina represent a hazard for immunosuppressed recipients. J. Med. Virol. 89:518-527, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27505052 TI - Reflectometry-Ellipsometry Reveals Thickness, Growth Rate, and Phase Composition in Oxidation of Copper. AB - The oxidation of copper is a complicated process. Copper oxide develops two stable phases at room temperature and standard pressure (RTSP): cuprous oxide (Cu2O) and cupric oxide (CuO). Both phases have different optical and electrical characteristics that make them interesting for applications such as solar cells or resistive switching devices. For a given application, it is necessary to selectively control oxide thickness and cupric/cuprous oxide phase volume fraction. The thickness and composition of a copper oxide film growing on the surface of copper widely depend on the characteristics of as-deposited copper. In this Research Article, two samples, copper films prepared by two different deposition techniques, electron-beam evaporation and sputtering, were studied. As the core part of the study, the formation of the oxidized copper was analyzed routinely over a period of 253 days using spectroscopic polarized reflectometry spectroscopic ellipsometry (RE). An effective medium approximation (EMA) model was used to fit the RE data. The RE measurements were complemented and validated by using X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM) and X-ray diffraction (XRD). Our results show that the two samples oxidized under identical laboratory ambient conditions (RTSP, 87% average relative humidity) developed unique oxide films following an inverse-logarithmic growth rate with thickness and composition different from each other over time. Discussion is focused on the ability of RE to simultaneously extract thickness (i.e., growth rate) and composition of copper oxide films and on plausible physical mechanisms responsible for unique oxidation habits observed in the two copper samples. It appears that extended surface characteristics (i.e., surface roughness and grain boundaries) and preferential crystalline orientation of as-deposited polycrystalline copper films control the growth kinetics of the copper oxide film. Analysis based on a noncontact and nondestructive measurement, such as RE, to extract key material parameters is beneficial for conveniently understanding the oxidation process that would ultimately enable copper oxide-based devices at manufacturing scales. PMID- 27505051 TI - Core Outcomes for Colorectal Cancer Surgery: A Consensus Study. AB - BACKGROUND: Colorectal cancer (CRC) is a major cause of worldwide morbidity and mortality. Surgical treatment is common, and there is a great need to improve the delivery of such care. The gold standard for evaluating surgery is within well designed randomized controlled trials (RCTs); however, the impact of RCTs is diminished by a lack of coordinated outcome measurement and reporting. A solution to these issues is to develop an agreed standard "core" set of outcomes to be measured in all trials to facilitate cross-study comparisons, meta-analysis, and minimize outcome reporting bias. This study defines a core outcome set for CRC surgery. METHODS AND FINDINGS: The scope of this COS includes clinical effectiveness trials of surgical interventions for colorectal cancer. Excluded were nonsurgical oncological interventions. Potential outcomes of importance to patients and professionals were identified through systematic literature reviews and patient interviews. All outcomes were transcribed verbatim and categorized into domains by two independent researchers. This informed a questionnaire survey that asked stakeholders (patients and professionals) from United Kingdom CRC centers to rate the importance of each domain. Respondents were resurveyed following group feedback (Delphi methods). Outcomes rated as less important were discarded after each survey round according to predefined criteria, and remaining outcomes were considered at three consensus meetings; two involving international professionals and a separate one with patients. A modified nominal group technique was used to gain the final consensus. Data sources identified 1,216 outcomes of CRC surgery that informed a 91 domain questionnaire. First round questionnaires were returned from 63 out of 81 (78%) centers, including 90 professionals, and 97 out of 267 (35%) patients. Second round response rates were high for all stakeholders (>80%). Analysis of responses lead to 45 and 23 outcome domains being retained after the first and second surveys, respectively. Consensus meetings generated agreement on a 12 domain COS. This constituted five perioperative outcome domains (including anastomotic leak), four quality of life outcome domains (including fecal urgency and incontinence), and three oncological outcome domains (including long-term survival). CONCLUSION: This study used robust consensus methodology to develop a core outcome set for use in colorectal cancer surgical trials. It is now necessary to validate the use of this set in research practice. PMID- 27505053 TI - Behavioral interventions for improving contraceptive use among women living with HIV. AB - BACKGROUND: Contraception services can help meet the family planning goals of women living with HIV as well as prevent mother-to-child transmission. Due to antiretroviral therapy, survival has improved for people living with HIV, and more HIV-positive women may desire to have a child or another child. Behavioral interventions, involving counseling or education, can help women choose and use an appropriate contraceptive method. OBJECTIVES: We systematically reviewed studies of behavioral interventions for HIV-positive women intended to inform contraceptive choice, encourage contraceptive use, or promote adherence to a contraceptive regimen. SEARCH METHODS: Until 2 August 2016, we searched MEDLINE, CENTRAL, Web of Science, POPLINE, ClinicalTrials.gov and ICTRP. For the initial review, we examined reference lists and unpublished project reports, and we contacted investigators in the field. SELECTION CRITERIA: Studies evaluated a behavioral intervention for improving contraceptive use for family planning (FP). The comparison could have been another behavioral intervention, usual care, or no intervention. We also considered studies that compared HIV-positive versus HIV negative women. We included non-randomized studies as well as randomized controlled trials (RCTs).Primary outcomes were pregnancy and contraception use, e.g. uptake of a new method or improved use or continuation of current method. Secondary outcomes were knowledge of contraceptive effectiveness and attitude about contraception or a specific contraceptive method. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data. One entered the data into RevMan and a second verified accuracy. We evaluated RCTs according to recommended principles. For non-randomized studies, we examined the quality of evidence using the Newcastle-Ottawa Quality Assessment Scale. Given the need to control for confounding factors in non-randomized studies, we used adjusted estimates from the models when available. Where we did not have adjusted analyses, we calculated the odds ratio (OR) with 95% confidence interval (CI). Due to varied study designs and interventions, we did not conduct meta-analysis. MAIN RESULTS: With three new reports, 10 studies from seven African countries met our eligibility criteria. Eight non-randomized studies included 8980 participants. Two cluster RCTs had 7136 participants across 36 sites. Three studies compared a special FP intervention versus usual care, three examined FP services integrated with HIV services, and four compared outcomes for HIV-positive and HIV-negative women.In four studies with high or moderate quality evidence, the special intervention was associated with contraceptive use or pregnancy. A study from Nigeria compared enhanced versus basic FP services. All sites had integrated FP and HIV services. Women with enhanced services were more likely to use a modern contraceptive method versus women with basic services (OR 2.48, 95% CI 1.31 to 4.72). A cluster RCT conducted in Kenya compared integrated FP and HIV services versus standard referral to a separate FP clinic. Women with integrated services were more likely to use more effective contraception (adjusted OR 1.81, 95% CI 1.24 to 2.63). Another cluster RCT compared an HIV prevention and FP intervention versus usual care in Kenya, Namibia, and Tanzania. Women at the special intervention sites in Tanzania were more likely to use highly effective contraception (adjusted OR 2.25, 95% CI 1.24 to 4.10). They were less likely to report unprotected sex (no condom use) at last intercourse (adjusted OR 0.23, 95% CI 0.14 to 0.40). Across the three countries, women at the special intervention sites were less likely to report any unprotected sex in the past two weeks (adjusted OR 0.56, 95% CI 0.32 to 0.99). A study in Cote d'Ivoire integrated HIV and FP services. HIV-positive women had a lower incidence of undesired pregnancy, but not overall pregnancy, compared with HIV-negative women (1.07 versus 2.38; reported P = 0.023). AUTHORS' CONCLUSIONS: The studies since 2009 focused on using modern or more effective methods of contraception. In those later reports, training on FP methods and counseling was more common, which may strengthen the intervention and improve the ability to meet clients' needs. The quality of evidence was moderate from the more recent studies and low for those from the 1990s.Comparative research involving contraceptive counseling for HIV-positive women is limited. The FP field needs better ways to help women choose an appropriate contraceptive and continue using that method. Improved counseling methods are especially needed for limited resource settings, such as clinics focusing on people living with HIV. PMID- 27505054 TI - Two Simple and Efficient Algorithms to Compute the SP-Score Objective Function of a Multiple Sequence Alignment. AB - BACKGROUND: Multiple sequence alignment (MSA) is a crucial step in many molecular analyses and many MSA tools have been developed. Most of them use a greedy approach to construct a first alignment that is then refined by optimizing the sum of pair score (SP-score). The SP-score estimation is thus a bottleneck for most MSA tools since it is repeatedly required and is time consuming. RESULTS: Given an alignment of n sequences and L sites, I introduce here optimized solutions reaching O(nL) time complexity for affine gap cost, instead of O(n2L), which are easy to implement. PMID- 27505055 TI - To Assess the Association between Glucose Metabolism and Ectopic Lipid Content in Different Clinical Classifications of PCOS. AB - AIMS: There are emerging data indicating an association between PCOS (polycystic ovary syndrome) and metabolic derangements with potential impact on its clinical presentation. This study aims to evaluate the pathophysiological processes beyond PCOS with particular focus on carbohydrate metabolism, ectopic lipids and their possible interaction. Differences between the two established classifications of the disease should be additionally evaluated. METHODS: A metabolic characterization was performed in 53 untreated PCOS patients as well as 20 controls including an extended oral glucose tolerance test (OGTT, to assess insulin sensitivity, secretion and beta-cell function) in addition to a detailed examination of ectopic lipid content in muscle and liver by nuclear magnetic resonance spectroscopy. RESULTS: Women with PCOS classified by the original NIH 1990 definition showed a more adverse metabolic risk profile compared to women characterized by the additional Rotterdam 2003 phenotypes. Subtle metabolic derangements were observed in both subgroups, including altered shapes of OGTT curves, impaired insulin action and hyperinsulinemia due to increased secretion and attenuated hepatic extraction. No differences were observed for ectopic lipids between the groups. However, particularly hepatocellular lipid content was significantly related to clinical parameters of PCOS like whole body insulin sensitivity, dyslipidemia and free androgen index. CONCLUSIONS: Subtle alterations in carbohydrate metabolism are present in both PCOS classifications, but more profound in subjects meeting the NIH 1990 criteria. Females with PCOS and controls did not differ in ectopic lipids, however, liver fat was tightly related to hyperandrogenism and an adverse metabolic risk profile. PMID- 27505056 TI - Alternatively Activated Mononuclear Phagocytes from the Skin Site of Infection and the Impact of IL-4Ralpha Signalling on CD4+T Cell Survival in Draining Lymph Nodes after Repeated Exposure to Schistosoma mansoni Cercariae. AB - In a murine model of repeated exposure of the skin to infective Schistosoma mansoni cercariae, events leading to the priming of CD4 cells in the skin draining lymph nodes were examined. The dermal exudate cell (DEC) population recovered from repeatedly (4x) exposed skin contained an influx of mononuclear phagocytes comprising three distinct populations according to their differential expression of F4/80 and MHC-II. As determined by gene expression analysis, all three DEC populations (F4/80-MHC-IIhigh, F4/80+MHC-IIhigh, F4/80+MHC-IIint) exhibited major up-regulation of genes associated with alternative activation. The gene encoding RELMalpha (hallmark of alternatively activated cells) was highly up-regulated in all three DEC populations. However, in 4x infected mice deficient in RELMalpha, there was no change in the extent of inflammation at the skin infection site compared to 4x infected wild-type cohorts, nor was there a difference in the abundance of different mononuclear phagocyte DEC populations. The absence of RELMalpha resulted in greater numbers of CD4+ cells in the skin draining lymph nodes (sdLN) of 4x infected mice, although they remained hypo responsive. Using mice deficient for IL-4Ralpha, in which alternative activation is compromised, we show that after repeated schistosome infection, levels of regulatory IL-10 in the skin were reduced, accompanied by increased numbers of MHC-IIhigh cells and CD4+ T cells in the skin. There were also increased numbers of CD4+ T cells in the sdLN in the absence of IL-4Ralpha compared to cells from singly infected mice. Although their ability to proliferate was still compromised, increased cellularity of sdLN from 4x IL-4RalphaKO mice correlated with reduced expression of Fas/FasL, resulting in decreased apoptosis and cell death but increased numbers of viable CD4+ T cells. This study highlights a mechanism through which IL-4Ralpha may regulate the immune system through the induction of IL-10 and regulation of Fas/FasL mediated cell death. PMID- 27505058 TI - Depression correlates with quality of life in people with epilepsy independent of the measures used. AB - PURPOSE: A number of studies have suggested that depressed mood is one of the most important predictors of quality of life (QoL) in patients with epilepsy. However, the QoL measure used in previous studies was limited to the Quality of Life in Epilepsy (QOLIE) scales. It could be questioned whether correlation of QOLIE with measures of depression is influenced by the properties of the instruments used rather than being a valid effect. By using visual analogue scales, the current study aimed to clarify whether depression and QoL are truly correlated in patients with epilepsy. METHODS: Data from a sample of 261 outpatients with epilepsy attending the Epilepsy Clinics of the Atkinson Morley Outpatient Department, St George's Hospital in London, were analyzed. Patients were screened using the European Quality-of-Life scale (EQ-5D-3L) which includes an overall visual analogue score (EQ-VAS), the Emotional Thermometer (ET7), the Beck Depression inventory-II (BDI-II), the Hospital Anxiety and Depression scale (HADS), and the Major Depression inventory (MDI). RESULTS: Depression was found to significantly correlate with EQ-VAS score with r coefficient ranging from 0.42 to 0.51 and r(2) coefficients ranging between 0.18 and 0.26. In addition, we identified patients who were depressed according to DSM-IV criteria (MD) and those with atypical forms of depression (AD). The EQ-5D-3L scores in these subjects compared with those without depression (ND) showed a different impact of AD and MD on QoL. CONCLUSIONS: The relationship between depression and QoL in people with epilepsy has been demonstrated to be a robust and valid effect, not a result of potential bias of the specific measures used. However, the strength of the association is influenced by the individual instrument. Atypical or subsyndromic forms of depression are as relevant as DSM-based depression in terms of impact on QoL. PMID- 27505057 TI - An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens. AB - The healthy lung maintains a steady state of immune readiness to rapidly respond to injury from invaders. Integrins are important for setting the parameters of this resting state, particularly the epithelial-restricted alphaVbeta6 integrin, which is upregulated during injury. Once expressed, alphaVbeta6 moderates acute lung injury (ALI) through as yet undefined molecular mechanisms. We show that the upregulation of beta6 during influenza infection is involved in disease pathogenesis. beta6-deficient mice (beta6 KO) have increased survival during influenza infection likely due to the limited viral spread into the alveolar spaces leading to reduced ALI. Although the beta6 KO have morphologically normal lungs, they harbor constitutively activated lung CD11b+ alveolar macrophages (AM) and elevated type I IFN signaling activity, which we traced to the loss of beta6 activated transforming growth factor-beta (TGF-beta). Administration of exogenous TGF-beta to beta6 KO mice leads to reduced numbers of CD11b+ AMs, decreased type I IFN signaling activity and loss of the protective phenotype during influenza infection. Protection extended to other respiratory pathogens such as Sendai virus and bacterial pneumonia. Our studies demonstrate that the loss of one epithelial protein, alphaVbeta6 integrin, can alter the lung microenvironment during both homeostasis and respiratory infection leading to reduced lung injury and improved survival. PMID- 27505059 TI - Primary Hydromorphone-Related Intrathecal Catheter Tip Granulomas: Is There a Role for Dose and Concentration? AB - BACKGROUND: Intrathecal drug delivery therapy has been used effectively in treating patients with intractable chronic pain. The development of an intrathecal catheter tip granuloma (ICTG) related to delivery of intrathecal opiates is a relatively infrequent, but potentially devastating complication. While there are many morphine-related ICTG cases described, reports of hydromorphone-related ICTG are limited. In addition, studies suggest a strong correlation between the use of higher doses and concentrations of intrathecal opiates and ICTG formation. OBJECTIVE: The objective of this study is to determine the incidence and the association of intrathecal hydromorphone dose, concentration, duration of treatment and concomitant agents with ICTG formation. STUDY DESIGN: This is a retrospective analysis of 101 consecutive patients implanted with intrathecal infusion delivery devices. Data were collected from chart review, and records of pump refills from the division of Pain Medicine of University Hospitals or outsourced to a home pump refill service. RESULTS: From a cohort of 101 consecutively implanted patients, 69 were treated with intrathecal hydromorphone and followed up postimplant for an average of 33.5 +/- 24 months (range 0-93 months; 95% CI of 27-39 months). The incidence of ICTG in our patient population was 8.7% during this period of time postimplant with mean time to granuloma detection 35.1 +/- 7.9 months. Patients developing granuloma (n = 6) were treated with a combination of intrathecal hydromorphone and bupivacaine infusion. Exposure time to intrathecal agents was not different between the granuloma and nongranuloma group. Monthly dose increase of hydromorphone was higher in granuloma group vs. non-granuloma group (58 +/- 34 mcg/month n = 6 vs. 25 +/- 8 mcg/month n = 63). Four out of six granuloma cases occurred with low dose and concentration of IT hydromorphone (160-370 mcg/day; 0.75-1.0 mg/mL concentration). Intrathecal bupivacaine dose was not different between groups. A subset of patients was treated with intrathecal fentanyl and bupivacaine. No intrathecal granulomas occurred in this patient cohort. CONCLUSION: This is the first clinical report demonstrating an association of hydromorphone with intrathecal granulomas, particularly at low doses and concentrations of hydromorphone. This study supports the notion that using low dose of IT opioids might not protect against ICTG development but that the level of exposure and type of opioid used in IT space might be highly correlated with ICTG development. Further research and recommendations related to chronic intrathecal opioid infusions are necessary to raise awareness of significant incidence of ICTG and development of tests to isolate patient populations at high risk. PMID- 27505060 TI - Nucleus Ruber of Actinopterygians. AB - Nucleus ruber is known as an important supraspinal center that controls forelimb movements in tetrapods, and the rubral homologue may serve similar functions in fishes (motor control of pectoral fin). However, two apparently different structures have been identified as 'nucleus ruber' in actinopterygians. One is nucleus ruber of Goldstein (1905) (NRg), and the other nucleus ruber of Nieuwenhuys and Pouwels (1983) (NRnp). It remains unclear whether one of these nuclei (or perhaps both) is homologous to tetrapod nucleus ruber. To resolve this issue from a phylogenetic point of view, we have investigated the distribution of tegmental neurons retrogradely labeled from the spinal cord in eight actinopterygian species. We also investigated the presence/absence of the two nuclei with Nissl- or Bodian-stained brain section series of an additional 28 actinopterygian species by comparing the morphological features of candidate rubral neurons with those of neurons revealed by the tracer studies. Based on these analyses, the NRg was identified in all actinopterygians investigated in the present study, while the NRnp appears to be absent in basal actinopterygians. The phylogenetic distribution pattern indicates that the NRg is the more likely homologue of nucleus ruber, and the NRnp may be a derived nucleus that emerged during the course of actinopterygian evolution. PMID- 27505061 TI - The impact of viscoplastic drops on a heated surface in the Leidenfrost regime. AB - The impact morphology of viscoplastic drops on a heated surface in the Leidenfrost regime is investigated experimentally by high-speed imaging. In particular several important parameters which characterize the impact morphology (such as maximum spreading diameter, minimum retracting diameter and maximum bouncing height etc.) are measured by analysing the impact process, recorded using a high-speed camera. It is shown that as the yield stress grows, surface forces are no longer able to minimize the free surface of the drop, and the inertial deformation upon impact becomes permanent. For small values of the yield stress, the impact morphology of viscoplastic Leidenfrost drops is similar to that of Newtonian drops. These effects can be interpreted in terms of the Bingham Capillary number, which compares the yield stress magnitude and the capillary (Laplace) pressure. These results suggest that the main contribution to drop rebound is due to surface forces, and not to the intrinsic elasticity of the vapour cushion between the drop and the surface, which is a major assumption in one of the existing models. PMID- 27505062 TI - Commensal Bacteria-Induced Inflammasome Activation in Mouse and Human Macrophages Is Dependent on Potassium Efflux but Does Not Require Phagocytosis or Bacterial Viability. AB - Gut commensal bacteria contribute to the pathogenesis of inflammatory bowel disease, in part by activating the inflammasome and inducing secretion of interleukin-1beta (IL-1beta). Although much has been learned about inflammasome activation by bacterial pathogens, little is known about how commensals carry out this process. Accordingly, we investigated the mechanism of inflammasome activation by representative commensal bacteria, the Gram-positive Bifidobacterium longum subspecies infantis and the Gram-negative Bacteroides fragilis. B. infantis and B. fragilis induced IL-1beta secretion by primary mouse bone marrow-derived macrophages after overnight incubation. IL-1beta secretion also occurred in response to heat-killed bacteria and was only partly reduced when phagocytosis was inhibited with cytochalasin D. Similar results were obtained with a wild-type immortalized mouse macrophage cell line but neither B. infantis nor B. fragilis induced IL-1beta secretion in a mouse macrophage line lacking the nucleotide-binding/leucine-rich repeat pyrin domain containing 3 (NLRP3) inflammasome. IL-1beta secretion in response to B. infantis and B. fragilis was significantly reduced when the wild-type macrophage line was treated with inhibitors of potassium efflux, either increased extracellular potassium concentrations or the channel blocker ruthenium red. Both live and heat-killed B. infantis and B. fragilis also induced IL-1beta secretion by human macrophages (differentiated THP-1 cells or primary monocyte-derived macrophages) after 4 hours of infection, and the secretion was inhibited by raised extracellular potassium and ruthenium red but not by cytochalasin D. Taken together, our findings indicate that the commensal bacteria B. infantis and B. fragilis activate the NLRP3 inflammasome in both mouse and human macrophages by a mechanism that involves potassium efflux and that does not require bacterial viability or phagocytosis. PMID- 27505063 TI - Optimization of Non-Thermal Plasma Treatment in an In Vivo Model Organism. AB - Non-thermal plasma is increasingly being recognized for a wide range of medical and biological applications. However, the effect of non-thermal plasma on physiological functions is not well characterized in in vivo model systems. Here we use a genetically amenable, widely used model system, Drosophila melanogaster, to develop an in vivo system, and investigate the role of non-thermal plasma in blood cell differentiation. Although the blood system in Drosophila is primitive, it is an efficient system with three types of hemocytes, functioning during different developmental stages and environmental stimuli. Blood cell differentiation in Drosophila plays an essential role in tissue modeling during embryogenesis, morphogenesis and also in innate immunity. In this study, we optimized distance and frequency for a direct non-thermal plasma application, and standardized doses to treat larvae and adult flies so that there is no effect on the viability, fertility or locomotion of the organism. We discovered that at optimal distance, time and frequency, application of plasma induced blood cell differentiation in the Drosophila larval lymph gland. We articulate that the augmented differentiation could be due to an increase in the levels of reactive oxygen species (ROS) upon non-thermal plasma application. Our studies open avenues to use Drosophila as a model system in plasma medicine to study various genetic disorders and biological processes where non-thermal plasma has a possible therapeutic application. PMID- 27505064 TI - Computer-Based Vertebral Tumor Cryoablation Planning and Procedure Simulation Involving Two Cases Using MRI-Visible 3D Printing and Advanced Visualization. AB - OBJECTIVE: We report the development and use of MRI-compatible and MRI-visible 3D printed models in conjunction with advanced visualization software models to plan and simulate safe access routes to achieve a theoretic zone of cryoablation for percutaneous image-guided treatment of a C7 pedicle osteoid osteoma and an L1 lamina osteoblastoma. Both models altered procedural planning and patient care. CONCLUSION: Patient-specific MRI-visible models can be helpful in planning complex percutaneous image-guided cryoablation procedures. PMID- 27505065 TI - Surface Enhanced Raman Scattering and Gated Materials for Sensing Applications: The Ultrasensitive Detection of Mycoplasma and Cocaine. AB - We present herein a novel combination of gated mesoporous silica nanoparticles (MSNs) and surface-enhanced Raman scattering (SERS) for sensing applications. As a proof-of-concept, we show the design of a system comprising MSNs loaded with crystal violet (CV), a molecule with high Raman cross section acting as SERS reporter, and capped with either a suitable DNA sequence for the detection of Mycoplasma genomic DNA or with an aptamer that selectively coordinates cocaine. In both cases the presence of the corresponding target analyte in solution (i.e., genomic DNA or cocaine) resulted in the release of CV. CV delivery was detected by SERS upon adsorption on gold nanotriangles (AuNTs), which display an efficient electromagnetic field enhancement and a high colloidal stability. By using this novel procedure a limit of detection of at least 30 copies DNA per MUL was determined for the detection of Mycoplasma genomic DNA, whereas cocaine was detected at concentrations as low as 10 nm. PMID- 27505066 TI - Why Are Nigeria-Cameroon Chimpanzees (Pan troglodytes ellioti) Free of SIVcpz Infection? AB - Simian immunodeficiency virus (SIV) naturally infects two subspecies of chimpanzee: Pan troglodytes troglodytes from Central Africa (SIVcpzPtt) and P. t. schweinfurtii from East Africa (SIVcpzPts), but is absent in P. t. verus from West Africa and appears to be absent in P. t. ellioti inhabiting Nigeria and western Cameroon. One explanation for this pattern is that P. t. troglodytes and P. t schweinfurthii may have acquired SIVcpz after their divergence from P. t. verus and P. t. ellioti. However, all of the subspecies, except P. t. verus, still occasionally exchange migrants making the absence of SIVcpz in P. t. ellioti puzzling. Sampling of P. t. ellioti has been minimal to date, particularly along the banks of the Sanaga River, where its range abuts that of P. t. troglodytes. This study had three objectives. First, we extended the sampling of SIVcpz across the range of chimpanzees north of the Sanaga River to address whether under-sampling might account for the absence of evidence for SIVcpz infection in P. t. ellioti. Second, we investigated how environmental variation is associated with the spread and prevalence of SIVcpz in the two chimpanzee subspecies inhabiting Cameroon since environmental variation has been shown to contribute to their divergence from one another. Finally, we compared the prevalence and distribution of SIVcpz with that of Simian Foamy Virus (SFV) to examine the role of ecology and behavior in shaping the distribution of diseases in wild host populations. The dataset includes previously published results on SIVcpz infection and SFVcpz as well as newly collected data, and represents over 1000 chimpanzee fecal samples from 41 locations across Cameroon. Results revealed that none of the 181 P. t. ellioti fecal samples collected across the range of P. t. ellioti tested positive for SIVcpz. In addition, species distribution models suggest that environmental variation contributes to differences in the distribution and prevalence of SIVcpz and SFVcpz. The ecological niches of these two viruses are largely non-overlapping, although stronger statistical support for this conclusion will require more sampling. Overall this study demonstrates that SIVcpz infection is absent or very rare in P. t. ellioti, despite multiple opportunities for transmission. The reasons for its absence remain unclear, but might be explained by one or more factors, including environmental variation, viral competition, and/or local adaptation-all of which should be explored in greater detail through continued surveillance of this region. PMID- 27505067 TI - Neutrophil Gelatinase-Associated Lipocalin as a Diagnostic Marker for Acute Kidney Injury in Oliguric Critically Ill Patients: A Post-Hoc Analysis. AB - BACKGROUND: Oliguria occurs frequently in critically ill patients, challenging clinicians to distinguish functional adaptation from serum-creatinine-defined acute kidney injury (AKIsCr). We investigated neutrophil gelatinase-associated lipocalin (NGAL)'s ability to differentiate between these 2 conditions. METHODS: This is a post-hoc analysis of a prospective cohort of adult critically ill patients. Patients without oliguria within the first 6 h of admission were excluded. Plasma and urinary NGAL were measured at 4 h after admission. AKIsCr was defined using the AKI network criteria with pre-admission serum creatinine or lowest serum creatinine value during the admission as the baseline value. Hazard ratios for AKIsCr occurrence within 72 h were calculated using Cox regression and adjusted for risk factors such as sepsis, pre-admission serum creatinine, and urinary output. Positive predictive values (PPV) and negative predictive values (NPV) were calculated for the optimal cutoffs for NGAL. RESULTS: Oliguria occurred in 176 patients, and 61 (35%) patients developed AKIsCr. NGAL was a predictor for AKIsCr in univariate and multivariate analysis. When NGAL was added to a multivariate model including sepsis, pre-admission serum creatinine and lowest hourly urine output, it outperformed the latter model (plasma p = 0.001; urinary p = 0.048). Cutoff values for AKIsCr were 280 ng/ml for plasma (PPV 80%; NPV 79%), and 250 ng/ml for urinary NGAL (PPV 58%; NPV 78%). CONCLUSIONS: NGAL can be used to distinguish oliguria due to the functional adaptation from AKIsCr, directing resources to patients more likely to develop AKIsCr. PMID- 27505068 TI - A comparison of the response of two Burkholderia fungorum strains grown as planktonic cells versus biofilm to dibenzothiophene and select polycyclic aromatic hydrocarbons. AB - In natural environments, bacteria often exist in close association with surfaces and interfaces by establishing biofilms. Here, we report on the ability of Burkholderia fungorum strains DBT1 and 95 to survive in high concentrations of hydrocarbons, and we compare their growth as a biofilm vs. planktonic cells. The 2 compounds tested were dibenzothiophene (DBT) and a mixture of naphthalene, phenanthrene, and pyrene (5:2:1) as representative compounds of thiophenes and polycyclic aromatic hydrocarbons (PAHs), respectively. The results showed that both strains were able to degrade DBT and to survive in the presence of up to a 2000 mg.L-1 concentration of this compound both as a biofilm and as free-living cells. Moreover, B. fungorum DBT1 showed reduced tolerance towards the mixed PAHs (2000 mg.L-1 naphthalene, 800 mg.L-1 phenanthrene, and 400 mg.L-1 pyrene) both as a biofilm and as free-living cells. Conversely, biofilms of B. fungorum 95 enhanced resistance against these toxic compounds compared with planktonic cells (P < 0.05). Visual observation through confocal laser scanning microscopy showed that exposure of biofilms to DBT and PAHs altered their structure: high concentrations of DBT triggered an aggregation of biofilm cells. These findings provide new perspectives on the effectiveness of using DBT-degrading bacterial strains in bioremediation of hydrocarbon-contaminated sites. PMID- 27505069 TI - Grandparent involvement and children's health outcomes: The current state of the literature. AB - INTRODUCTION: Grandparents are often highly involved as secondary caregivers for their grandchildren and may influence children's psychological and physical health outcomes. The purpose of the current review was to gather and synthesize research findings on the effects of grandparent involvement on children's physical health outcomes. METHOD: PubMed, PsycInfo, and MedLine were searched by 3 independent reviewers for articles that reported on grandparent involvement and children's health. Twenty-six articles were included for final review based on selection criteria. RESULTS: Relatively few studies have examined the effects of grandparent involvement on children's health outcomes; therefore, the degree of their influence remains unclear. Four categories of children's health outcomes (disease/illness, weight, eating behaviors, and injury/safety) emerged during this review. Results indicated that the majority of studies available reported a negative effect of grandparent involvement on child's weight status. However, it is important to note that in most of these studies, the effects of grandparent involvement were not a primary outcome, and the amount of time grandparents spent with their grandchildren was not accounted for. Many studies in this review were qualitative studies, limiting the types of analyses that could be conducted. In addition, few longitudinal studies have been conducted in this area. DISCUSSION: Based on this review, it is clear that grandparents are involved in caretaking for children across many cultures but to understand their role in children's health outcomes, more systematic and longitudinal research needs to be conducted. (PsycINFO Database Record PMID- 27505070 TI - Patient navigation to facilitate early intervention referral completion among poor urban children. AB - INTRODUCTION: Few eligible children participate in early intervention (EI) programs. The objective of this study was to determine feasibility and outcomes of a novel patient navigation program on EI referrals among a diverse group of at risk children. METHODS: During a 6-month period, a patient navigator was assigned to an urban pediatric clinic to engage families, provide education on early child development and EI, and assist families with completing multidisciplinary evaluations. Families were eligible to participate if they spoke English, had a child <34 months old with a suspected developmental delay, and were referred to EI for evaluation. Families completed measures of demographics, language preference, and the Newest Vital Sign, a validated literacy measure. Outcomes on completion of EI referrals were obtained from the county EI provider. RESULTS: Of 88 EI referrals during the study period, 53 patients were eligible and enrolled. Patients were predominantly male, racially diverse, on public health insurance, with a mean age of 18.4 months. Most caregivers of patients had less than a high school education, spoke a non-English language at home, and had limited literacy. Forty-two families (79.2%) completed a referral, and 34 (81.0%) of those were eligible for EI services. There were no significant differences in demographic, language, or literacy measures between those who completed and did not complete EI referrals. DISCUSSION: A patient navigation program to facilitate EI referrals was feasible in a diverse urban patient population. Preliminary results of the patient navigation program on EI referral completion were promising and warrant further study. (PsycINFO Database Record PMID- 27505071 TI - Weight conversations in romantic relationships: What do they sound like and how do partners respond? AB - INTRODUCTION: The limited research examining weight conversations (i.e., conversations about weight, body shape, or size) in adult romantic relationships has shown associations between engaging in these conversations and disordered eating behaviors, overweight/obesity, and psychosocial problems in adults. Given the potential harmful consequences of these conversations, it is important to gather more rich qualitative data to understand how weight talk is experienced in romantic relationships and how romantic partners respond to these conversations. METHODS: Adults (n = 118; mean age 35 years) from a cross-sectional study were interviewed in their homes. The majority of adults (90% female; mean age = 35 years) were from minority (64% African American) and low-income (<$25,000/year) households. Qualitative data were analyzed using inductive content analysis. RESULTS: Sixty-five percent of participants reported that weight conversations were occurring in their romantic relationships. Qualitative themes included the following: (a) Weight conversations were direct and focused on physical characteristics; (b) weight conversations included joking or sarcastic remarks; (c) weight conversations focused on "we" and being healthy; (d) weight conversations occurred after watching TV or movies, as a result of insecurities in oneself, as length of the relationship increased, or as partners aged; and (e) partners responded to weight conversations by feeling insecure or by engaging in reciprocal weight conversations with their romantic partner. DISCUSSION: Weight conversations were prevalent in romantic relationships, with some conversations experienced as negative and some positive. Qualitative themes from the current study should be confirmed in quantitative studies to inform future intervention research targeting weight conversations in romantic relationships. (PsycINFO Database Record PMID- 27505072 TI - Interview with Kaylene Simpson, PhD. PMID- 27505073 TI - Electrophysiology-Based Assays to Detect Subtype-Selective Modulation of Human Nicotinic Acetylcholine Receptors. AB - The Family Smoking Prevention and Tobacco Control Act of 2009 (Public Law 111-31) gave the US Food and Drug Administration (FDA) the responsibility for regulating tobacco products. Nicotine is the primary addictive component of tobacco and its effects can be modulated by additional ingredients in manufactured products. Nicotine acts by mimicking the neurotransmitter acetylcholine on neuronal nicotinic acetylcholine receptors (nAChRs), which function as ion channels in cholinergic modulation of neurotransmission. Subtypes within the family of neuronal nAChRs are defined by their alpha- and beta-subunit composition. The subtype-selective profiles of tobacco constituents are largely unknown, but could be essential for understanding the physiological effects of tobacco products. In this report, we report the development and validation of electrophysiology-based high-throughput screens (e-HTS) for human nicotinic subtypes, alpha3beta4, alpha3beta4alpha5, alpha4beta2, and alpha7 stably expressed in Chinese Hamster Ovary cells. Assessment of agonist sensitivity and acute desensitization gave results comparable to those obtained by conventional manual patch clamp electrophysiology assays. The potency of reference antagonists for inhibition of the receptor channels and selectivity of positive allosteric modulators also were very similar between e-HTS and conventional manual patch voltage clamp data. Further validation was obtained in pilot screening of a library of FDA-approved drugs that identified alpha7 subtype-selective positive allosteric modulation by novel compounds. These assays provide new tools for profiling of nicotinic receptor selectivity. PMID- 27505074 TI - Analytical Characteristics of a Noninvasive Gene Expression Assay for Pigmented Skin Lesions. AB - We previously reported clinical performance of a novel noninvasive and quantitative PCR (qPCR)-based molecular diagnostic assay (the pigmented lesion assay; PLA) that differentiates primary cutaneous melanoma from benign pigmented skin lesions through two target gene signatures, LINC00518 (LINC) and preferentially expressed antigen in melanoma (PRAME). This study focuses on analytical characterization of this PLA, including qPCR specificity and sensitivity, optimization of RNA input in qPCR to achieve a desired diagnostic sensitivity and specificity, and analytical performance (repeatability and reproducibility) of this two-gene PLA. All target qPCRs demonstrated a good specificity (100%) and sensitivity (with a limit of detection of 1-2 copies), which allows reliable detection of gene expression changes of LINC and PRAME between melanomas and nonmelanomas. Through normalizing RNA input in qPCR, we converted the traditional gene expression analyses to a binomial detection of gene transcripts (i.e., detected or not detected). By combining the binomial qPCR results of the two genes, an improved diagnostic sensitivity (raised from 52%- 65% to 71% at 1 pg of total RNA input, and to 91% at 3 pg of total RNA input) was achieved. This two-gene PLA demonstrates a high repeatability and reproducibility (coefficient of variation <3%) and all required analytical performance characteristics for the commercial processing of clinical samples. PMID- 27505075 TI - Adaptive Benefits of Storage Strategy and Dual AMPK/TOR Signaling in Metabolic Stress Response. AB - Cellular metabolism must ensure that supply of nutrient meets the biosynthetic and bioenergetic needs. Cells have therefore developed sophisticated signaling and regulatory pathways in order to cope with dynamic fluctuations of both resource and demand and to regulate accordingly diverse anabolic and catabolic processes. Intriguingly, these pathways are organized around a relatively small number of regulatory hubs, such as the highly conserved AMPK and TOR kinase families in eukaryotic cells. Here, the global metabolic adaptations upon dynamic environment are investigated using a prototypical model of regulated metabolism. In this model, the optimal enzyme profiles as well as the underlying regulatory architecture are identified by combining perturbation and evolutionary methods. The results reveal the existence of distinct classes of adaptive strategies, which differ in the management of storage reserve depending on the intensity of the stress and in the regulation of ATP-producing reaction depending on the nature of the stress. The regulatory architecture that optimally implements these adaptive features is characterized by a crosstalk between two specialized signaling pathways, which bears close similarities with the sensing and regulatory properties of AMPK and TOR pathways. PMID- 27505076 TI - Modes of Large-Scale Brain Network Organization during Threat Processing and Posttraumatic Stress Disorder Symptom Reduction during TF-CBT among Adolescent Girls. AB - Posttraumatic stress disorder (PTSD) is often chronic and disabling across the lifespan. The gold standard treatment for adolescent PTSD is Trauma-Focused Cognitive-Behavioral Therapy (TF-CBT), though treatment response is variable and mediating neural mechanisms are not well understood. Here, we test whether PTSD symptom reduction during TF-CBT is associated with individual differences in large-scale brain network organization during emotion processing. Twenty adolescent girls, aged 11-16, with PTSD related to assaultive violence completed a 12-session protocol of TF-CBT. Participants completed an emotion processing task, in which neutral and fearful facial expressions were presented either overtly or covertly during 3T fMRI, before and after treatment. Analyses focused on characterizing network properties of modularity, assortativity, and global efficiency within an 824 region-of-interest brain parcellation separately during each of the task blocks using weighted functional connectivity matrices. We similarly analyzed an existing dataset of healthy adolescent girls undergoing an identical emotion processing task to characterize normative network organization. Pre-treatment individual differences in modularity, assortativity, and global efficiency during covert fear vs neutral blocks predicted PTSD symptom reduction. Patients who responded better to treatment had greater network modularity and assortativity but lesser efficiency, a pattern that closely resembled the control participants. At a group level, greater symptom reduction was associated with greater pre-to-post-treatment increases in network assortativity and modularity, but this was more pronounced among participants with less symptom improvement. The results support the hypothesis that modularized and resilient brain organization during emotion processing operate as mechanisms enabling symptom reduction during TF-CBT. PMID- 27505077 TI - PCNA SUMOylation protects against PCNA polyubiquitination-mediated, Rad59 dependent, spontaneous, intrachromosomal gene conversion. AB - Homologous recombination is crucial in both the maintenance of genome stability and the generation of genetic diversity. Recently, multiple aspects of the recombination machinery functioning at arrested DNA replication forks have been established, yet the roles of diverse modifications of PCNA, the key platform organizing the replication complex, in intrachromosomal recombination have not been comprehensively elucidated. Here, we report how PCNA SUMOylation and/or polyubiquitination affects recombination between direct repeats in S. cerevisiae. Our results show that these PCNA modifications primarily affect gene conversion, whereas their effect on the recombination-mediated deletion of intervening sequence is much less obvious. Siz1-dependent PCNA SUMOylation strongly limits Rad52/Rad51/Rad59-dependent gene conversion. A 5- to 10-fold increase in the frequency of such recombination events is observed in Siz1-defective strains, but this increase is fully suppressed when PCNA polyubiquitination is also compromised. PCNA polyubiquitination can stimulate gene conversion in both PCNA SUMOylation-proficient and SUMOylation-deficient strains. On the other hand, in PCNA polyubiquitination-deficient strains, the lack of PCNA SUMOylation does not affect GC levels. Therefore, we postulate that the antirecombinogenic activity of Siz1 mainly concerns recombination induced by PCNA polyubiquitination. In the absence of PCNA SUMOylation, the frequency of PCNA polyubiquitination-mediated gene conversion is not only increased, but it is also channeled into the Rad59 dependent pathway. Additionally, we show a weak inhibitory effect of Rad5 on Rad52/Rad59-directed single-strand annealing. PMID- 27505078 TI - Multi-inhibitor prodrug constructs for simultaneous delivery of anti-inflammatory agents to mustard-induced skin injury. AB - The molecular pathology of sulfur mustard injury is complex, with at least nine inflammation-related enzymes and receptors upregulated in the zone of the insult. A new approach wherein inhibitors of these targets have been linked by hydrolyzable bonds, either one to one or via separate preattachment to a carrier molecule, has been shown to significantly enhance the therapeutic response compared with the individual agents. This article reviews the published work of the authors in this drug development domain over the last 8 years. PMID- 27505079 TI - Delayed diagnosis of single compartment muscle contusion after radical hysterectomy in the lithotomy position: A case report. AB - INTRODUCTION: Muscle contusions usually occur as a result of blunt trauma, which damages the muscle fibers and connective tissue without breaking the skin. Rapid bleeding can cause an increase in pressure that requires surgical intervention, commonly referred to as compartment syndrome. Here, we report a case with delayed diagnosis of single compartment muscle contusion in which compartment syndrome did not develop. PRESENTATION OF CASE: A 50-year-old woman underwent radical hysterectomy. She complained of edema and tenderness in the lower left leg on postoperative day 6. The serum creatine phosphokinase level was slightly elevated at 177 IU/L (normal range: 6-142 IU/L). T2-weighted magnetic resonance imaging revealed swelling of the muscle in the deep posterior compartment of the lower left leg, edematous fascia, and subcutaneous adipose tissue. She recovered naturally without other complications. DISCUSSION: In the lithotomy position during surgery, muscle contusion might occur, without general symptoms. CONCLUSION: Magnetic resonance imaging is useful for diagnosis. For patients who complain of edema and tenderness in the lower leg after surgery in the lithotomy position, muscle contusions should be considered. PMID- 27505080 TI - Hyperfunctioning papillary thyroid carcinoma: A case report with literature review. AB - INTRODUCTION: Thyroid malignant tumors are rarely associated with hyperfunctioning thyroid. The incidence of this co-incidence is highly variable. Here we report a rare case of papillary thyroid cancer associated with hyperthyroidism with brief literature review. CASE REPORT: A 40-year-old male, presented with palpitation, excess sweating and weight loss for one month duration. There was asymmetrical swelling of the neck, more on right side, mobile. Free T3: 11.09pmol/L, free T4: 34.41pmol/L, TFT: less than 0.005mIU/ml, Neck ultrasound showed features of background thyroiditis. Left lobe contained 9*7*5mm nodule with irregular outline and multiple dots of calcification, other nodules are of the same features. Under ultrasound guide, fine needle aspiration cytology showed features of papillary carcinoma. After preparation, total thyrodectomy done and the result of histopathological examination confirmed papillary thyroid carcinoma. The patient was put on 0.2mg thyroxine daily. DISCUSSION: Literature review has showed an increasing number of papers reporting the association of high level of thyroid function tests and thyroid malignancy. The cause of high level of TH in thyroid malignancy is thought to be due to an active mutation of the gene of TH receptor. Niepomniszcze and colleagues found that a combination of TSH receptor mutations and Ki-RAS was the main etiological factor for hyperfunction of the thyroid malignancy. CONCLUSION: Although the coexistence of them is rare, thyroid malignancy should be put in the differential diagnosis of hyperthyroid goiter. PMID- 27505081 TI - High-frequency operation of a pulsatile VAD - a simulation study. AB - Ventricular assist devices (VADs) are mechanical blood pumps that are clinically used to treat severe heart failure. Pulsatile VADs (pVADs) were initially used, but are today in most cases replaced by turbodynamic VADs (tVADs). The major concern with the pVADs is their size, which prohibits full pump body implantation for a majority of patients. A reduction of the necessary stroke volume can be achieved by increasing the stroke frequency, while maintaining the same level of support capability. This reduction in stroke volume in turn offers the possibility to reduce the pump's overall dimensions. We simulated a human cardiovascular system (CVS) supported by a pVAD with three different stroke rates that were equal, two- or threefold the heart rate (HR). The pVAD was additionally synchronized to the HR for better control over the hemodynamics and the ventricular unloading. The simulation results with a HR of 90 bpm showed that a pVAD stroke volume can be reduced by 71%, while maintaining an aortic pulse pressure (PP) of 30 mm Hg, avoiding suction events, reducing the ventricular stroke work (SW) and allowing the aortic valve to open. A reduction by 67% offers the additional possibility to tune the interaction between the pVAD and the CVS. These findings allow a major reduction of the pVAD's body size, while allowing the physician to tune the pVAD according to the patient's needs. PMID- 27505082 TI - Shear stress and von Mises stress distributions in the periphery of an embedded acetabular cup implant during impingement. AB - As literature implies, daily activities of total hip arthroplasty (THA) patients may include movements prone to implant-implant impingement. Thus, high shear stresses may be induced at the acetabular implant-bone interface, increasing the risk of implant loosening. The aim of the current study is to determine whether or not impingement events may pose an actual risk to acetabular periprosthetic bone. An existing experimental workflow was augmented to cover complete three dimensional strain gage measurement. von Mises and shear stresses were calculated from 1620 measured strain values, collected around a hemispherical cup implant at 2.5 mm interface distance during worst-case impingement loading. A shear stress criterion for acetabular periprosthetic bone was derived from the literature. At the impingement site, magnitudes of von Mises stress amount to 0.57 MPa and tilting shear stress amount to -0.3 MPa at 2.5 mm interface distance. Conclusion can be drawn that worst-case impingement events are unlikely to pose a risk of bone material failure in the periphery around fully integrated cementless acetabular hip implants in otherwise healthy THA patients. As numerical predictions in the literature suggested, it can now be confirmed that impingement moments are unlikely to cause acetabular implant-bone interface fixation failures. PMID- 27505083 TI - Hematological changes in severe early onset growth-restricted fetuses with absent and reversed end-diastolic flow in the umbilical artery. AB - BACKGROUND: Erythropoietin seems to play an important role in the regulation of fetal hypoxemia. The present prospective study was designed to determine if changes in erythropoietin levels can be found in fetuses with severe early-onset growth restriction and hemodynamic compromise. METHODS AND RESULTS: Erythropoietin, hemoglobin, hematocrit, platelet counts, normoblasts, lacate, arterial and venous blood gasses in the umbilical cord were determined in 42 fetuses with fetal growth restriction (IUGR) with absent (zero-flow) and 26 IUGR fetuses with retrograde end-diastolic flow (reverse-flow) in the umbilical artery. Color Doppler measurements were performed on the middle cerebral artery (PI) and ductus venosus [(S-a)/D and (S-a)/Vmean]. Erythropoietin concentrations were significantly lower in the zero-flow group (median: 128.0 mU/mL; range: 60.3 213 mU/mL) compared with the reverse-flow group (median: 202.5 mU/mL; range: 166 1182 mU/mL). Significant differences in median lactate concentrations were observed between the zero-flow group: 3.28 mmol/L (range; 2.3-4.7 mmol/L), and reverse-flow group: 5.6 mmol/L (range: 3.8-7.5 mmol/L). Fetuses with reverse-flow had significantly lower median platelet counts than fetuses with zero-flow (74 vs. 155/MUL) and significantly lower normoblast counts (63 vs. 342/100 WBC). CONCLUSIONS: Fetuses with severe IUGR due to chronic placental insufficiency and absent or reversed flow in the umbilical artery show increased erythropoietin levels. PMID- 27505084 TI - Is vaping a gateway to smoking: a review of the longitudinal studies. AB - BACKGROUND: The use of e-cigarettes (ECs) is rising globally. There is concern that e-cigarette may actually lead to smoking, especially amongst adolescents. OBJECTIVE: To perform a comprehensive review of literature reporting the longitudinal effects of e-cigarette use on onset of smoking among adolescents and young adults. METHODS: A search was conducted using PubMed, Google Scholar, Scopus, and Web of Science in February 2016 to identify the studies containing data on EC use among adolescents and young adults (age<30 years). We then narrowed our search to only include longitudinal studies with data on EC and conventional cigarette smoking among this population. RESULTS: Four longitudinal studies were identified that analyzed the use of ECs and smoking at both baseline and follow-ups in the target population. These studies demonstrated that EC use is associated with an increase in combustible cigarette smoking, even amongst the adolescents who were not susceptible to smoking. CONCLUSION: This review highlights the strong evidence that not only are ECs are not an effective tool for smoking cessation among adolescents, they actually are associated with higher incidence of combustible cigarette smoking. Policy makers need to recognize of the insidious nature of this campaign by the tobacco industry and design policies to regulate it. PMID- 27505085 TI - Integrated oral, mental and sexual health management for adolescents: a call for professional collaboration. AB - BACKGROUND: Globally, young people account for 15.5% of the total global disability-adjusted life-years burden for all age groups. They face mental health, nutritional problems, accidental and intentional injuries, sexual and reproductive health problems, and substance abuse. These health challenges have effects on their oral health. This paper discusses the oral health problems adolescents face and suggests approaches for providing integrated oral and general health care for adolescents. DISCUSSION: Oral health issues linked with adolescent health concerns include: malocclusion and esthetic concerns linked with mental health status; oral and maxillofacial injuries linked with accidental and intentional injuries; oral manifestations of sexually transmitted infections; oral leukoplakia and oral cancers linked with alcohol, tobacco and psychoactive substance abuse; and oral manifestations of anemia resulting from nutritional problems. Training oral health care providers on adolescent health and care could promote prompt diagnosis, management and prevention of complications associated with major health challenges affecting adolescents. CONCLUSION: Adolescent oral health care needs focused attention: as a possible route for early diagnosis and management of general health problems and for promoting adolescent oral health care. Oral health care should be integrated into adolescent friendly services and oral health care providers should learn how to handle adolescents' health needs. PMID- 27505086 TI - A novel insulin receptor mutation in an adolescent with acanthosis nigricans and hyperandrogenism. AB - Insulin receptor mutations cause extreme insulin resistance resulting in acanthosis nigricans and hyperandrogenism. We report a pre-menarchal adolescent female with normal weight, with severe acanthosis nigricans, acne, and hirsutism. Initial investigation revealed elevated fasting and post-prandial insulin and high testosterone and androstenedione levels. Her father had frequent complaints of hypoglycemia. Coding sequence and splice junction analysis of the INSR gene, in our patient and her father, revealed a heterozygous missense mutation in the beta subunit of the insulin receptor (Arg1131Trp), resulting in receptor loss of function. Metformin therapy and carbohydrate control improved acanthosis and menarche ensued within 3 months. Our case highlights the importance of distinguishing insulin resistance commonly associated with obesity from monogenic defects. Although, there is no consensus on treatment of children with monogenic forms of insulin resistance due to its rarity, dietary and lifestyle modifications and insulin-sensitizing agents play a key role in management. PMID- 27505087 TI - Biological evaluation and docking studies of some benzoxazole derivatives as inhibitors of acetylcholinesterase and butyrylcholinesterase. AB - A series of 2,5-disubstituted-benzoxazole derivatives (1-13) were evaluated as possible inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results demonstrated that the compounds exhibited a broad spectrum of AChE and BChE inhibitory activity ranging between 6.80% and 90.21% except one compound which showed no activity against AChE at the specified molar concentration. Another derivative displayed a similar activity to that of reference drug (galanthamine) for inhibition of AChE and BChE. In addition, molecular docking of the compounds into active site of AChE was performed using recombinant human AChE (PDB ID: 4ey6) in order to understand ligand-protein interactions. PMID- 27505088 TI - Highlight: annexins in health and disease. PMID- 27505089 TI - Development of a rapid and quantitative lateral flow assay for the simultaneous measurement of serum kappa and lambda immunoglobulin free light chains (FLC): inception of a new near-patient FLC screening tool. AB - BACKGROUND: Serum free light chains (FLC) are sensitive biomarkers used for the diagnosis and management of plasma cell dyscrasias, such as multiple myeloma (MM), and are central to clinical screening algorithms and therapy response criteria. We have developed a portable, near-patient, lateral-flow test (Seralite(r)) that quantitates serum FLC in 10 min, and is designed to eliminate sample processing delays and accelerate decision-making in the clinic. METHODS: Assay interference, imprecision, lot-to-lot variability, linearity, and the utility of a competitive-inhibition design for the elimination of antigen-excess ('hook effect') were assessed. Reference ranges were calculated from 91 healthy donor sera. Preliminary clinical validation was conducted by retrospective analysis of sera from 329 patients. Quantitative and diagnostic results were compared to Freelite(r). RESULTS: Seralite(r) gave a broad competitive-inhibition calibration curve from below 2.5 mg/L to above 200 mg/L, provided good assay linearity (between 1.6 and 208.7 mg/L for kappa FLC and between 3.5 and 249.7 mg/L for lambda FLC) and sensitivity (1.4 mg/L for kappa FLC and 1.7 mg/L for lambda FLC), and eliminated anomalous results from antigen-excess. Seralite(r) gave good diagnostic concordance with Freelite(r) (Roche Hitachi Cobas C501) identifying an abnormal FLC ratio and FLC difference in 209 patients with newly diagnosed MM and differentiating these patients from normal healthy donors with polyclonal FLC. CONCLUSIONS: Seralite(r) sensitively quantitates FLC and rapidly identifies clinical conditions where FLC are abnormal, including MM. PMID- 27505091 TI - How can we evaluate differences between serial measurements on the same sample? A new approach based on within-subject biological variation. PMID- 27505090 TI - Pediatric reference intervals for alkaline phosphatase. AB - BACKGROUND: Interpretation of alkaline phosphatase activity in children is challenging due to extensive changes with growth and puberty leading to distinct sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics and seem reasonable for an analyte as closely linked to growth as alkaline phosphatase. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, resulting in limitations when clinical decisions are based on alkaline phosphatase activity. METHODS: We applied an indirect method to generate percentile charts for alkaline phosphatase activity using clinical laboratory data collected during the clinical care of patients. A total of 361,405 samples from 124,440 patients from six German tertiary care centers and one German laboratory service provider measured between January 2004 and June 2015 were analyzed. Measurement of alkaline phosphatase activity was performed on Roche Cobas analyzers using the IFCC's photometric method. RESULTS: We created percentile charts for alkaline phosphatase activity in girls and boys from birth to 18 years which can be used as reference intervals. Additionally, data tables of age- and sex-specific percentile values allow the incorporation of these results into laboratory information systems. CONCLUSIONS: The percentile charts provided enable the appropriate differential diagnosis of changes in alkaline phosphatase activity due to disease and changes due to physiological development. After local validation, integration of the provided percentile charts into result reporting facilitates precise assessment of alkaline phosphatase dynamics in pediatrics. PMID- 27505092 TI - Therapeutic decision-making process in the intensive care unit: role of biological point-of-care testing. PMID- 27505093 TI - Thiol/disulfide parameters as a novel oxidative marker in medical labor induction with oxytocin. AB - BACKGROUND: The aim of this study was to analyze the alterations in thiol levels among mothers and neonates who were prone to medical oxytocin induction. MATERIALS AND METHODS: A total of 40 pregnant women who underwent medical labor induction with oxytocin (Group A) were compared with 53 women whose labor progressed spontaneously without any kind of induction (Group B). We measured the thiol/disulfide homeostasis parameters (native thiol, total thiol, disulfide, disulfide/total thiol, disulfide/native thiol) of maternal and cord blood. RESULTS: There were no statistically significant differences with respect to the maternal and cord blood thiol/disulfide homeostasis between the two groups. CONCLUSION: Being an artificial intervention during labor, oxytocin induction has been found to be safe in terms of oxidative stress (OS) according to the results of this study. Both the maternal and the fetal sides were safe in this molecular manner against oxytocin infusion. PMID- 27505095 TI - Bcl-2 family proteins: master regulators of cell survival. AB - The most prominent function of proteins of the Bcl-2 family is regulation of the initiation of intrinsic (mitochondrial) pathways of apoptosis. However, recent research has revealed that in addition to regulation of mitochondrial apoptosis, proteins of the Bcl-2 family play important roles in regulating other cellular pathways with a strong impact on cell survival like autophagy, endoplasmic reticulum (ER) stress response, intracellular calcium dynamics, cell cycle progression, mitochondrial dynamics and energy metabolism. This review summarizes the recent knowledge about functions of Bcl-2 family proteins that are related to cell survival. PMID- 27505094 TI - Alzheimer's disease: presence and role of microRNAs. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for the most cases of dementia. AD affects more than 25 million people globally and is predicted to affect nearly one in 85 people worldwide by 2050. AD is characterized by the accumulation of dense plaques of beta-amyloid peptide (Abeta) and neurofibrillary tangles of hyperphosphorylated tau that cause impairment in memory, cognition, and daily activities. Although early-onset AD has been linked to several mutations, reliable genetic markers for late-onset AD are lacking. Further, the diagnosis of AD biomarkers has its limitations and cannot detect early-stage AD. The identification of accurate, early, and non invasive biomarkers for AD is, therefore, an unmet challenge. Recently, microRNAs (miRNAs) have emerged as a novel class of gene regulatory elements with conserved roles in development and disease. Recent discoveries have uncovered roles of miRNAs in several model organisms during aging and have identified potential miRNAs biomarkers of AD. Here we will discuss this emerging field of miRNAs associated with AD and prospects for the future. PMID- 27505096 TI - An observational study of secondary task engagement while driving on urban streets in Iranian Safe Communities. AB - In Iran the prevalence of traffic injuries and death from vehicle collisions are high. Driver engagement in non-driving-related tasks has been previously identified as an important contributing factor to crashes. Therefore, the objective of the present study was to investigate the prevalence of drivers' engagement in potentially distracting activities in Kashmar, Khalilabad and Bardaskan, which are three Iranian International Safe Communities. Observations took place at 12 randomly selected roadside locations in each city, which were comprised of six main streets and six side streets. In total 7979 drivers were observed. The prevalence rates of potentially distracting activities in Kashmar, Khalilabad and Bardaskan were 24.3%, 26% and 24.9%, respectively. In both Kashmar and Khalilabad the most frequently observed secondary tasks were drivers talking to passengers (10.6% and 11.5%, respectively) followed by mobile phone use (3.4% and 4.0%, respectively). Although in Bardaskan the most commonly observed secondary task was also talking to passengers (12.7%), the second most common was reaching for an object (3.2%). In all three cities younger drivers were significantly more likely to be observed engaged in a secondary task while driving. Furthermore, involvement in secondary tasks while driving was significantly higher amongst females and those driving on a working day. The percentage of drivers identified as potentially distracted in these three Safe Communities was worryingly high. Thus, interventions should be integrated into the WHO Safe Community network in these cities, including: education regarding the risks associated with engaging in secondary activities while driving, law enforcement, tougher legislation, periodic assessment, raising public awareness, as well as attracting political and social support. PMID- 27505097 TI - Role of sensory and cognitive conspicuity in the prevention of collisions between motorcycles and trucks at T-intersections. AB - Motorcyclists are particularly vulnerable to injury in crashes with heavy vehicles due to substantial differences in vehicle mass, the degree of protection and speed. There is a considerable difference in height between motorcycles and trucks; motorcycles are viewed by truck drivers from downward angles, and shorter distances between them mean steeper downward angles. Hence, we anticipated that the effects of motorcycle conspicuity treatments would be different for truck drivers. Therefore, this study aims to evaluate the effects of motorcycle conspicuity treatments on the identification and detection of motorcycles by truck drivers. Two complementary experiments were performed; the first experiment assessed the impact of motorcycle sensory conspicuity on the ability of un alerted truck drivers to detect motorcycles, and the second experiment assessed the motorcycle cognitive conspicuity to alerted truck drivers. The sensory conspicuity was measured in terms of motorcycle detection rates by un-alerted truck drivers when they were not anticipating a motorcycle within a realistic driving scene, while the cognitive conspicuity was determined by the time taken by alerted truck drivers to actively search for a motorcycle. In the first experiment, the participants were presented with 10 pictures and were instructed to report the kinds of vehicles that were presented in the pictures. Each picture was shown to the participants for 600ms. In the second experiment, the participants were presented with the same set of pictures and were instructed to respond by clicking the right button on a mouse as soon as they detected a motorcycle in the picture. The results indicate that the motorcycle detection rate increases, and the response time to search for a motorcycle decreases, as the distance between the targeted motorcycle and the viewer decreases. This is true regardless of the type of conspicuity treatment used. The use of daytime running headlights (DRH) was found to increase the detection rate and the identification of a motorcycle by a truck driver at a farther distance, but effect deteriorates as the distance decreases. The results show that the detection rate and the identification of a motorcyclist wearing a black helmet with a reflective sticker increases as the distance between the motorcycle and the truck decreases. We also found that a motorcyclist wearing a white helmet and a white outfit is more identifiable and detectable at both shorter and longer distances. In conclusion, although this study provides evidence that the use of appropriate conspicuity treatments enhances motorcycle conspicuity to truck drivers, we suggest that more attention should be paid to the effect of background environment on motorcycle conspicuity. PMID- 27505098 TI - Exploring factors affecting pedestrians' red-light running behaviors at intersections in China. AB - Pedestrians' Red-light running behavior is one of the most critical factors for pedestrian involved traffic crashes at intersections in China. The primary objective of this study is to explore how various factors affect pedestrians' red light running behaviors at intersection areas, using the data collected from Hefei, China. A questionnaire was well designed aiming at collecting pedestrians' socio-economic characteristics, trip related features, and attribute variables in different crossing facilities. Based on 631 valid samples, a binomial logistic model was established to evaluate the impacts of contributing factors on pedestrians' red-light running behavior. The modeling results show that four variables significantly affect the probability of pedestrians' red-light running behavior, which are the trip purpose, time period in one day, pedestrian's attitude towards whether to run a red light when in hurry, and pedestrian's attitude towards whether quality of road facility affects crossing behavior. With those variables, the probability of pedestrians' red-light running behavior at intersections could be predicted. Findings of this study can help understand why pedestrians in China run red-lights and identify which pedestrian groups and intersections are more likely to have such behaviors. This study can also help propose countermeasures more efficiently to reduce pedestrian-related crashes at intersections in China. PMID- 27505099 TI - Examining driver injury severity outcomes in rural non-interstate roadway crashes using a hierarchical ordered logit model. AB - Rural non-interstate crashes induce a significant amount of severe injuries and fatalities. Examination of such injury patterns and the associated contributing factors is of practical importance. Taking into account the ordinal nature of injury severity levels and the hierarchical feature of crash data, this study employs a hierarchical ordered logit model to examine the significant factors in predicting driver injury severities in rural non-interstate crashes based on two year New Mexico crash records. Bayesian inference is utilized in model estimation procedure and 95% Bayesian Credible Interval (BCI) is applied to testing variable significance. An ordinary ordered logit model omitting the between-crash variance effect is evaluated as well for model performance comparison. Results indicate that the model employed in this study outperforms ordinary ordered logit model in model fit and parameter estimation. Variables regarding crash features, environment conditions, and driver and vehicle characteristics are found to have significant influence on the predictions of driver injury severities in rural non interstate crashes. Factors such as road segments far from intersection, wet road surface condition, collision with animals, heavy vehicle drivers, male drivers and driver seatbelt used tend to induce less severe driver injury outcomes than the factors such as multiple-vehicle crashes, severe vehicle damage in a crash, motorcyclists, females, senior drivers, driver with alcohol or drug impairment, and other major collision types. Research limitations regarding crash data and model assumptions are also discussed. Overall, this research provides reasonable results and insight in developing effective road safety measures for crash injury severity reduction and prevention. PMID- 27505100 TI - How rare are large, multiple-fatality work-related incidents? AB - Despite their salience, the prevalence of incidents that result in many work related deaths is not well-documented. This study estimated probabilities of observing large scale work-related fatal incidents using 1995-2010 records from the Census of Fatal Occupational Injuries. A range of model estimates suggest approximately a one-in-four annual chance of observing an incident resulting in 20 or more work-related fatalities. The most likely contributors are aircraft incidents, and fires and explosions. The probability that a large scale incident occurs has declined in recent years due to a general decline in the number of fatal incidents, and due to a compositional shift away from those types of incidents more likely to result in large scale outcomes. PMID- 27505101 TI - Light-Triggered Release from Pickering Emulsions Stabilized by TiO2 Nanoparticles with Tailored Wettability. AB - In this work, a new strategy for developing light-triggered Pickering emulsions as smart soft vehicles for on-demand release is proposed. Initially, UV-induced tailored wettability allows anchoring of TiO2 nanoparticles at the interface to prepare stable water in oil emulsions. Such emulsions show the efficacy of microencapsulation and controlled release by demulsification due to the hydrophilic conversion of the TiO2 nanoparticles using a noninvasive light irradiation trigger. A molecule of interest is selected as a model cargo to quantitatively evaluate the as-prepared Pickering emulsions for their encapsulation and release behaviors. Moreover, light-responsive emulsion destabilization mechanism is studied as a function of particle concentration, light wavelength, and light intensity, respectively, determined by drop diameter evolution and droplet coalescence kinetics plots. For consideration of application in life sciences, Pickering emulsions sensitive to visible light are also established based on nitrogen doping of TiO2 nanoparticle emulsifiers. PMID- 27505105 TI - Long-Term Outcome of Nephron-Sparing Surgery Compared to Radical Nephrectomy for Renal Cell Carcinoma >=4 cm - A Matched-Pair Single Institution Analysis. AB - PURPOSE: We investigated the long-term oncological and functional outcome of nephron-sparing surgery/partial nephrectomy (PN) versus radical nephrectomy (RN) for any renal cell carcinoma (RCC) >=4 cm. PATIENTS AND METHODS: Between 1997 and 2013, we identified 128 patients undergoing PN for RCC >=4 cm and matched this collective to 128 patients undergoing RN. We then compared overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS) and functional parameters in both groups. The median follow-up time was 58 months (3-210 months). RESULTS: Compared to RN, patients with a PN showed a significantly higher 10-year OS (77.0 vs. 63.0%, p = 0.04), CSS (90.6 vs. 71.7%, p = 0.002) and PFS (82.9 vs. 57.4%, p <= 0.001). Renal function preservation was better in the PN group (24 months estimated glomerular filtration rate: 68.2 ml/min for PN vs. 40.6 ml/min for RN, p <= 0.01) with significantly less new onset chronic kidney diseases. Total complication rate was comparable, whereas PN procedures showed more Clavien-Dindo grade I + II complications, portraying the technical challenge of PN in larger RCCs. CONCLUSIONS: Whenever feasible, PN should be considered for renal masses >=4 cm, as this technique shows better long-term results regarding disease-specific survival and renal function preservation in our study group. PMID- 27505107 TI - Computational Design of Non-natural Sugar Alcohols to Increase Thermal Storage Density: Beyond Existing Organic Phase Change Materials. AB - Thermal storage, a technology that enables us to control thermal energy, makes it possible to reuse a huge amount of waste heat, and materials with the ability to treat larger thermal energy are in high demand for energy-saving societies. Sugar alcohols are now one promising candidate for phase change materials (PCMs) because of their large thermal storage density. In this study, we computationally design experimentally unknown non-natural sugar alcohols and predict their thermal storage density as a basic step toward the development of new high performance PCMs. The non-natural sugar alcohol molecules are constructed in silico in accordance with the previously suggested molecular design guidelines: linear elongation of a carbon backbone, separated distribution of OH groups, and even numbers of carbon atoms. Their crystal structures are then predicted using the random search method and first-principles calculations. Our molecular simulation results clearly demonstrate that the non-natural sugar alcohols have potential ability to have thermal storage density up to ~450-500 kJ/kg, which is significantly larger than the maximum thermal storage density of the present known organic PCMs (~350 kJ/kg). This computational study suggests that, even in the case of H-bonded molecular crystals where the electrostatic energy contributes mainly to thermal storage density, the molecular distortion and van der Waals energies are also important factors to increase thermal storage density. In addition, the comparison between the three eight-carbon non-natural sugar alcohol isomers indicates that the selection of preferable isomers is also essential for large thermal storage density. PMID- 27505106 TI - Association Between Acute Infectious Mononucleosis and Vitamin D Deficiency. AB - Epstein-Barr virus and vitamin D both have been implicated in the pathogenesis of autoimmune diseases, especially multiple sclerosis (MS). Vitamin D influences both innate and adaptive immune responses and has been linked to increased susceptibility to other viral infections such as influenza. Here we aimed to examine the association between vitamin D and acute infectious mononucleosis (IM).This study is a case-control study that was conducted on IM patients and a control group of healthy individuals at infectious disease clinics of Isfahan University of Medical Sciences. Patients were recruited from January to December 2014. The viral capsid antigen (VCA) IgM titer and vitamin D levels were measured at the time of acute infection in IM patients. We also measured vitamin D levels in healthy controls recruited during the same period of time. A total number of 60 IM patients with the mean age of 23.26 +/- 7.59 and a healthy control group with the mean age of 25.13 +/- 6.72 were enrolled. In the IM patients, there was no significant association between 25(OH) D3 levels and VCA IgM titers (r = 0.190, p = 0.146). Mean 25(OH) D3 levels in IM patients were significantly lower than in the control group (15.61 +/- 9.72 vs. 21.41 +/- 12.64, p = 0.006). Our findings showed significantly lower vitamin D levels in IM patients at the time of infection than in the control group, providing some evidence that the two major risk factors for autoimmune diseases (e.g., MS) might not be independent risk factors. PMID- 27505108 TI - Semiquantitative Volumetry by Sequential PET/CT May Improve Prediction of Complete Response to Neoadjuvant Chemoradiation in Patients With Distal Rectal Cancer. AB - BACKGROUND: Previous studies using PET/CT imaging have failed to accurately identify complete responders to neoadjuvant chemoradiation among patients with rectal cancer. The use of metabolic parameters alone or imprecise delineation of baseline and residual tumor volumes may have contributed for these disappointing findings. OBJECTIVE: The purpose of this study was to determine the accuracy of complete response identification in rectal cancer after neoadjuvant chemoradiation by sequential PET/CT imaging with a decrease in tumor metabolism and volume using optimal tumor volume delineation. DESIGN: This was a retrospective comparison of prospectively collected data from a clinical trial (National Clinical Trial 00254683). SETTINGS: The study was conducted at a single research center. PATIENTS: Ninety patients with cT2-4N0-2M0 distal rectal cancer underwent sequential PET/CT at baseline and 12 weeks after neoadjuvant chemoradiation. Quantitative metabolic analysis (median and maximal standard uptake values), volumetric estimates (metabolic tumor volume), and composite estimates incorporating volume and quantitative data (total lesion glycolysis) were compared for the assessment of response to neoadjuvant chemoradiation using receiver operating characteristic curves. Individual standard uptake value thresholds were used according to response to neoadjuvant chemoradiation to match metabolic activity and optimize volume delineation. MAIN OUTCOME MEASURES: The accuracy of complete response identification by multiple volumetric and metabolic parameters using sequential PET/CT imaging was measured. RESULTS: Variation in total lesion glycolysis between baseline and 12-week PET/CT scans was associated with the best area under the curve (area under the curve = 0.81 (95% CI, 0.69 0.92)) when compared with standard uptake value or metabolic tumor volume for the identification of a complete responder. Patients with a >=92% decrease in total lesion glycolysis between baseline and 12-week PET/CT scan had a 90% chance to harbor complete response. LIMITATIONS: This study was limited by its lack of interobserver agreement analysis. CONCLUSIONS: PET/CT scan using volume and metabolic estimates with individual standard uptake value thresholds for volume determination may provide a useful tool to predict response to neoadjuvant chemoradiation in distal rectal cancer. PMID- 27505109 TI - Wound Complications and Perineal Pain After Extralevator Versus Standard Abdominoperineal Excision: A Nationwide Study. AB - BACKGROUND: Extralevator abdominoperineal excision was introduced as an alternative to conventional abdominoperineal excision for low rectal cancers. The perineal dissection is more extensive with extralevator abdominoperineal excision and leaves a greater defect. OBJECTIVE: The aim of this study was to evaluate, on a national basis, the risk of perineal wound complications, pain, and hernia after conventional and extralevator abdominoperineal excision performed for low rectal cancer. DESIGN: This was a retrospective study collecting data from the Danish Colorectal Cancer Group database and from electronic medical files of patients. SETTINGS: The study was conducted at Danish surgical departments. PATIENTS: A total of 445 patients operated between 2009 and 2012 with extralevator or conventional abdominoperineal excision were included. MAIN OUTCOME MEASURES: The main end points of this study were perineal wound complications and pain lasting for >30 days after the operation. RESULTS: The 2 groups were demographically similar except for a higher ASA score in the conventional group. In the extralevator group, neoadjuvant chemoradiation was more frequent (71% vs 41%; p < 0.001), T stage was higher (more T3 tumors; 52% vs 38%; p = 0.006), and more tumors were fixed (21% vs 12%; p = 0.02). Perineal wound complications and pain were more frequent after extralevator versus conventional excision (44% vs 25%; p < 0.001 and 38% vs 22%; p < 0.001). After multivariate analyses, neoadjuvant chemoradiation, extralevator excision, and operation early in the study period were found to have a significant influence on the risk of long-term wound complications. Neoadjuvant chemoradiation and wound complications were significant risk factors for long-term perineal pain. Results were similar after subgroup analyses on low tumors only. LIMITATIONS: This was a retrospective study. The 2 groups were not completely comparable at baseline. CONCLUSIONS: Neoadjuvant chemoradiation, extralevator compared with conventional excision, and operation early in the study period were significant factors for predicting perineal wound complications. Neoadjuvant chemoradiation and wound complications were predictors of long-term perineal pain. PMID- 27505110 TI - Prospective and Longitudinal Study of Urogenital Dysfunction After Proctectomy for Rectal Cancer. AB - BACKGROUND: Urogenital dysfunctions after rectal cancer treatment are well recognized, although incidence and evolution over time are less well known. OBJECTIVE: We aimed to assess the evolution of urogenital functions over time after the treatment for rectal cancer. DESIGN: This is a prospective, longitudinal cohort study. SETTINGS: This study was conducted at a quaternary referral center for colorectal surgery. PATIENTS: A total of 250 consecutive patients treated for rectal cancer were prospectively enrolled for urogenital assessment. MAIN OUTCOME MEASURES: End points were the International Prostatic Symptom Score, the International Index of Erectile Function, and the Female Sexual Index obtained by questionnaires before (baseline status) and after preoperative radiotherapy and 3, 6, and 12 months after surgery. RESULTS: Overall, 169 patients (68%) responded to the questionnaires. The urinary function decreased temporary after irradiation in men (International Prostatic Symptom Score: 7.8 vs 4.9; p < 0.001). Sexual activity decreased significantly in women after radiotherapy (p = 0.02), and in all patients after surgery (p < 0.001). At 12 months, sexual activity in women declined from 59% before treatment to 36% (p = 0.02). In men, sexual activity (82% vs 57%), erectile function (71% vs 24%), and ejaculatory function (78% vs 32%) decreased from baseline (p < 0.001). Stage T3T4 tumors (OR = 5.72 (95% CI, 1.24-26.36)) and low rectal tumors (OR = 17.86 (95% CI, 1.58-20.00)) were independent factors of worse sexual function. LIMITATIONS: This study was limited by the proportion of uncompleted questionnaires, especially in women, and by its monocentric feature. CONCLUSIONS: Most patients experienced sexual dysfunction at 12 months after surgery for rectal cancer, and predictive factors for this dysfunction were related to characteristics of the tumor. PMID- 27505111 TI - Outcomes of Pelvic Exenteration with en Bloc Partial or Complete Pubic Bone Excision for Locally Advanced Primary or Recurrent Pelvic Cancer. AB - INTRODUCTION: Neoplasms infiltrating the pubic bone have until recently been considered a contraindication to surgery. Paucity of existing published data in regard to surgical techniques and outcomes exist. OBJECTIVE: This study aims to address outcomes of our recently published technique for en bloc composite pubic bone excision during pelvic exenteration. DESIGN: A prospective database was reviewed to identify patients who underwent a partial or complete pubic bone composite excision over a 12-year period. SETTINGS: This study was conducted at a tertiary level exenteration unit. MAIN OUTCOME MEASURES: Primary outcomes measured were resection margin and survival. Secondary outcomes included patient and operative demographics, type of cancer, extent of pubic bone excision, morbidity, and 30-day mortality. RESULTS: Twenty-nine of over 500 patients undergoing exenterations (mean age, 57.9; 20 males) underwent en bloc complete (11 patients) or partial (18 patients) composite pubic bone excision. Twenty-two patients (76%) underwent resection for recurrent as opposed to advanced primary malignant disease of which rectal adenocarcinoma was the most common followed by squamous-cell carcinoma. The median operating time was 10.5 (range, 6-15) hours, and median blood loss was 2971 (range, 300-8600) mL. Seventeen (59%) patients had a concurrent sacrectomy performed mainly S3 and below. A total cystectomy was performed in 26 patients (90%). Fifteen of 20 male patients (75%) had a perineal urethrectomy. A clear (R0) resection margin was achieved in 22 patients (76%) with a 5-year overall survival of 53% after a median follow-up of 3.2 years (r = 1.4-12.3 years). There was no 30-day mortality. Seventy percent of patients experienced morbidity with a pelvic collection the most common. LIMITATIONS: This study was limited because it was a retrospective review, it occurred at a single site, and it used a small heterogeneous sample. CONCLUSION: Within the realm of evolving exenteration surgery, en bloc composite pubic bone excision offers results comparable to central, lateral, and posterior compartment excisions, and, as such, is a reasonable strategy in the management of neoplasms infiltrating the pubic bone. PMID- 27505112 TI - Progression From Perianal High-Grade Anal Intraepithelial Neoplasia to Anal Cancer in HIV-Positive Men Who Have Sex With Men. AB - BACKGROUND: High-grade intraepithelial neoplasia is known to progress to invasive squamous-cell carcinoma of the anus. There are limited reports on the rate of progression from high-grade intraepithelial neoplasia to anal cancer in HIV positive men who have sex with men. OBJECTIVES: The purpose of this study was to describe in HIV-positive men who have sex with men with perianal high-grade intraepithelial neoplasia the rate of progression to anal cancer and the factors associated with that progression. DESIGN: This was a prospective cohort study. SETTINGS: The study was conducted at an outpatient clinic at a tertiary care center in Toronto. PATIENTS: Thirty-eight patients with perianal high-grade anal intraepithelial neoplasia were identified among 550 HIV-positive men who have sex with men. INTERVENTION: All of the patients had high-resolution anoscopy for symptoms, screening, or surveillance with follow-up monitoring/treatment. MAIN OUTCOME MEASURES: We measured the incidence of anal cancer per 100 person-years of follow-up. RESULTS: Seven (of 38) patients (18.4%) with perianal high-grade intraepithelial neoplasia developed anal cancer. The rate of progression was 6.9 (95% CI, 2.8-14.2) cases of anal cancer per 100 person-years of follow-up. A diagnosis of AIDS, previously treated anal cancer, and loss of integrity of the lesion were associated with progression. Anal bleeding was more than twice as common in patients who progressed to anal cancer. LIMITATIONS: There was the potential for selection bias and patients were offered treatment, which may have affected incidence estimates. CONCLUSIONS: HIV-positive men who have sex with men should be monitored for perianal high-grade intraepithelial neoplasia. Those with high-risk features for the development of anal cancer may need more aggressive therapy. PMID- 27505113 TI - A National Database Analysis Comparing the Nationwide Inpatient Sample and American College of Surgeons National Surgical Quality Improvement Program in Laparoscopic vs Open Colectomies: Inherent Variance May Impact Outcomes. AB - BACKGROUND: Clinical and administrative databases each have fundamental distinctions and inherent limitations that may impact results. OBJECTIVE: This study aimed to compare the American College of Surgeons National Surgical Quality Improvement Program and the Nationwide Inpatient Sample, focusing on the similarities, differences, and limitations of both data sets. DESIGN: All elective open and laparoscopic segmental colectomies from American College of Surgeons National Surgical Quality Improvement Program (2006-2013) and Nationwide Inpatient Sample (2006-2012) were reviewed. International Classification of Diseases, Ninth Revision, Clinical Modification coding identified Nationwide Inpatient Sample cases, and Current Procedural Terminology coding for American College of Surgeons National Surgical Quality Improvement Program. Common demographics and comorbidities were identified, and in-hospital outcomes were evaluated. SETTINGS: A national sample was extracted from population databases. PATIENTS: Data were derived from the Nationwide Inpatient Sample database: 188,326 cases (laparoscopic = 67,245; open = 121,081); and American College of Surgeons National Surgical Quality Improvement Program: 110,666 cases (laparoscopic = 54,191; open = 56,475). MAIN OUTCOME MEASURES: Colectomy data were used as an avenue to compare differences in patient characteristics and outcomes between these 2 data sets. RESULTS: Laparoscopic colectomy demonstrated superior outcomes compared with open; therefore, results focused on comparing a minimally invasive approach among the data sets. Because of sample size, many variables were statistically different without clinical relevance. Coding discrepancies were demonstrated in the rate of conversion from laparoscopic to open identified in the National Surgical Quality Improvement Program (3%) and Nationwide Inpatient Sample (15%) data sets. The prevalence of nonmorbid obesity and anemia from National Surgical Quality Improvement Program was more than twice that of Nationwide Inpatient Sample. Sepsis was statistically greater in National Surgical Quality Improvement Program, with urinary tract infections and acute kidney injury having a greater frequency in the Nationwide Inpatient Sample cohort. Surgical site infections were higher in National Surgical Quality Improvement Program (30-day) vs Nationwide Inpatient Sample (8.4% vs 2.6%; p < 0.01), albeit less when restricted to infections that occurred before discharge (3.3% vs 2.6%; p < 0.01). LIMITATIONS: This is a retrospective study using population-based data. CONCLUSION: This analysis of 2 large national databases regarding colectomy outcomes highlights the incidence of previously unrecognized data variability. These discrepancies can impact study results and subsequent conclusions/recommendations. These findings underscore the importance of carefully choosing and understanding the different population-based data sets before designing and when interpreting outcomes research. PMID- 27505114 TI - Clostridium difficile Infection Is Associated With Lower Inpatient Mortality When Managed by GI Surgeons. AB - BACKGROUND: Patients admitted with Clostridium difficile infection are managed in a variety of settings. If their care is inadequate, these patients can rapidly deteriorate. OBJECTIVE: The purpose of this study was to evaluate whether mortality for patients admitted with C difficile differed between medical and general/colorectal surgery services. DESIGN: This was a retrospective cohort study with multivariable logistic regression used to evaluate the effect of admitting service on in-hospital mortality rates, with propensity score matching used to validate this relationship. SETTINGS: The study was conducted at a single, tertiary care center. PATIENTS: Inpatients with a positive C difficile stool test within 24 hours of admission to medical or surgical services were identified (2005-2015) using institutional electronic data sources. MAIN OUTCOME MEASURE: We measured inpatient mortality rate. RESULTS: Of 1175 patients, 985 (83%) were admitted to medical services, whereas 190 (17%) were admitted by surgeons. Medical patients were older (63.9 vs 58.9 years; p = 0.001) and had a mean of 0.6 additional comorbidities (p < 0.001); cohorts were similar regarding vasopressors, peak white blood cell counts, and rate of intensive care unit admissions. Mortality was lower among surgery patients (2.6% vs 6.8%; p = 0.028), and logistic regression demonstrated lower odds of mortality for this group OR = 0.18 (95% CI, 0.05-0.58)). After propensity score matching for age, comorbidities, and severity of disease, this difference was confirmed (2.6% vs. 9.5%). A higher incidence of total colectomy for surgery patients (14.2% vs 0.4%) was a causal factor in their longer lengths of stay and higher total hospital costs. The time between orders for stool testing and metronidazole therapy was shorter in the surgery group (1.8 vs 3.8 hours; p = 0.002), although this trend was not observed with vancomycin therapy. LIMITATIONS: This was a retrospective study from a single institution, thereby limiting generalizability, with a lack of information regarding premorbid creatinine levels, ileus, or megacolon. CONCLUSIONS: In-hospital mortality rates for patients admitted with C difficile were lower on surgery services, perhaps in part related to higher colectomy rates. PMID- 27505115 TI - Effectiveness of Liposomal Bupivacaine in Colorectal Surgery: A Pragmatic Nonsponsored Prospective Randomized Double Blinded Trial in a Community Hospital. AB - BACKGROUND: Prior industry conducted studies have shown that long acting liposomal bupivacaine injection improves pain control postoperatively. OBJECTIVE: To evaluate whether liposomal bupivacaine reduced the use of postoperative opioid (http://links.lww.com/DCR/A253) pain medication as compared to standard bupivacaine following colorectal surgery. DESIGN: A double blinded, prospective, randomized controlled trial comparing liposomal bupivacaine versus standard bupivacaine in patients undergoing elective colon resection. SETTINGS: Community hospital with general surgery residency program with all cases performed by colorectal surgeons. PATIENTS: Fifty-seven patients were randomized and reported as intention-to-treat analysis with 6 protocol violations. Sensitivity analysis excluding these 6 patients demonstrated no change in study results or conclusion. Mean age was 67 +/- 2 years and 56% were male. There were 36 patients who underwent minimally invasive surgery, and 21 patients had an open colon resection. INTERVENTIONS: Experimental arm received liposomal bupivacaine while control arm received standard bupivacaine. MAIN OUTCOME MEASURES: Primary outcome measure was intravenous hydromorphone equivalent used via PCA during first 48 hours after operation. RESULTS: There was no significant difference between the two groups in the amount of opioid used orally or intravenously in the postoperative period. The primary outcome measure was PCA hydromorphone consumption during first two postoperative days after operation (hydromorphone equivalent use in standard bupivacaine group 11.3 +/- 8.9 mg versus 13.3 +/- 11.9 mg in liposomal bupivacaine group, p = 0.58 Mann-Whitney test). LIMITATIONS: Small pragmatic trials typically remain underpowered for secondary analyses. A larger study could help to further delineate other outcomes that are impacted by postoperative pain. CONCLUSIONS: Liposomal bupivacaine did not change the amount of opioid used postoperatively. Based on our study, liposomal bupivacaine does not provide any added benefit over conventional bupivacaine after colon resection. (ClinicalTrials.gov: NCT02052557). PMID- 27505116 TI - Seasonal Variation in Diverticulitis: Evidence From Both Hemispheres. AB - BACKGROUND: Diverticulitis is a common and morbid disease with incompletely understood risk factors and pathophysiology. Geographic and, recently, seasonal trends in diverticulitis have been described in the United States. OBJECTIVE: The purpose of this study was to investigate and compare seasonal trends in urgent hospital admission for diverticulitis in geographically distinct populations in the northern and southern hemispheres. DESIGN: Inpatient, urgent admissions for diverticulitis were identified within the Dr Foster Intelligence Global Comparators Dataset, a global benchmarking collaborative. SETTINGS: Admissions to participating hospitals in the United Kingdom, Australia, and the United States were identified between 2008 and 2013. PATIENTS: A total of 18,672 urgent admissions for diverticulitis were identified among 5.5-million admissions. MAIN OUTCOME MEASURES: Four separate hypothesis testing methods were used to identify seasonal trends in diverticulitis admissions among international patient populations. RESULTS: Seasonal trends were present in all 3 countries. A summer peak was observed in both hemispheres using multiple statistical testing methods. Logistic regression analyses identified summer months as significantly associated with diverticulitis admission in all 3 countries. LIMITATIONS: This study is limited by restriction to inpatient admissions, reliance on administrative data, and participation of select hospitals within the database. CONCLUSIONS: These data suggest a shared seasonal risk factor among geographically distinct populations for diverticulitis. PMID- 27505117 TI - Sacral Nerve Stimulation Fails to Offer Long-term Benefit in Patients With Slow Transit Constipation. AB - BACKGROUND: Sacral nerve stimulation is proposed as a treatment for slow-transit constipation. However, in our randomized controlled trial we found no therapeutic benefit over sham stimulation. These patients have now been followed-up over a long-term period. OBJECTIVE: The purpose of this study was to assess the long term efficacy of sacral nerve stimulation in patients with scintigraphically confirmed slow-transit constipation. DESIGN: This study was designed for long term follow-up of patients after completion of a randomized controlled trial. SETTINGS: It was conducted at an academic tertiary public hospital in Sydney. PATIENTS: Adults with slow-transit constipation were included. MAIN OUTCOME MEASURES: At the 1- and 2-year postrandomized controlled trial, the primary treatment outcome measure was the proportion of patients who reported a feeling of complete evacuation on >2 days per week for >=2 of 3 weeks during stool diary assessment. Secondary outcome was demonstration of improved colonic transit at 1 year. RESULTS: Fifty-three patients entered long-term follow-up, and 1 patient died. Patient dissatisfaction or serious adverse events resulted in 44 patients withdrawing from the study because of treatment failure by the end of the second year. At 1 and 2 years, 10 (OR = 18.8% (95% CI, 8.3% to 29.3%)) and 3 patients (OR = 5.7% (95% CI, -0.5% to 11.9%)) met the primary outcome measure. Colonic isotope retention at 72 hours did not differ between baseline (OR = 75.6% (95% CI, 65.7%-85.6%)) and 1-year follow-up (OR = 61.7% (95% CI, 47.8%-75.6%)). LIMITATIONS: This study only assessed patients with slow-transit constipation. CONCLUSIONS: In these patients with slow-transit constipation, sacral nerve stimulation was not an effective treatment. PMID- 27505118 TI - Optimal Dosing of Botulinum Toxin for Treatment of Chronic Anal Fissure: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Chronic anal fissures are associated with significant morbidity and reduced quality of life. Studies have investigated the efficacy of botulinum toxin with variable results; thus, there is currently no consensus on botulinum toxin dose or injection sites. OBJECTIVE: This study aimed to systematically analyze trials studying the efficacy of botulinum toxin for treatment of chronic anal fissure to identify an optimum dosage and injection regimen. DATA SOURCES: A comprehensive review of the literature was conducted according to PRISMA guidelines. PubMed/Medline, Embase, Scopus, and the Cochrane Library were searched from inception to June 2015. STUDY SELECTION: All clinical trials that investigated the efficacy of botulinum toxin for chronic anal fissure were selected according to specific criteria. INTERVENSIONS: The interventions used were various doses of botulinum toxin. OUTCOME MEASURES: Clinical outcomes, dosage, and injection site data were evaluated with weighted pooled results for each dosage and 95% confidence intervals. RESULTS: There were 1158 patients, with 661 in botulinum toxin treatment arms, from 18 clinical trials included in this review. The outcomes of interest were 3-month healing, incontinence, and recurrence rates. Meta-regression analysis demonstrated a small decrease in healing rate (0.34%; 95% CI, 0-0.68; p = 0.048) with each increase in dosage, a small increase in incontinence rate (1.02 times; 95% CI, 1.0002-1.049; p = 0.048) with each increase in dosage and a small increase in recurrence rate (1.037 times; 95% CI, 1.018-1.057; p = 0.0002) with each increase in dosage. The optimum injection site could not be determined. LIMITATIONS: This study was limited by weaknesses in the underlying evidence, such as variable quality, short follow-up, and a limited range of doses represented. CONCLUSIONS: Fissure healing with lower doses of botulinum toxin is as effective as with high doses. Lower doses also reduce the risk of incontinence and recurrence in the long term. PMID- 27505119 TI - Should We Give Up The Search for a Clinically Useful Gene Signature for the Prediction of Response of Rectal Cancer to Neoadjuvant Chemoradiation? PMID- 27505120 TI - Lessons Learned From the Quest for Gene Signatures That Predict Treatment Response in Rectal Cancer. PMID- 27505121 TI - How to Size the Anal Canal Circumference When Implanting a Magnetic Anal Sphincter for Fecal Incontinence. Evolution and Update of a New Surgical Technique. AB - INTRODUCTION: Magnetic anal sphincter augmentation improves function and quality of life of patients with severe fecal incontinence substantially. Measuring the anal circumference exactly with a sizing tool represents a crucial step of the procedure because it determines the correct size and success of the definite implant. OBJECTIVE: This study aims to illustrate the consequent development of 3 different sizing models and the use of the recent sizing tool. TECHNIQUE: After dissection of a tunnel around the anal canal through a ventral perineal incision, the sizing tool is inserted by using a specially designed introducer to measure the circumference for the appropriate size of implant. First- and second generation sizing tools could only approximate the final implant size and impeded standardization. The latest sizing model resembles the actual implant with magnetic beads, it is nonstretchable, and it is closable end-to-end. RESULTS: The development of 3 measuring tools has progressively improved the accuracy of estimating the correct size of the definitive implant, and the application of the latest sizer seems easy, comfortable in use, and accurate as experienced in our first cases. CONCLUSION: The latest device contributes to standardization of the procedure and therefore facilitates the learning curve for newcomers of the method and could avoid the need for radiological on-table control in the near future. PMID- 27505124 TI - Helping the Helpers: Assisting Staff and Volunteer Workers Before, During, and After Disaster Relief Operations. AB - Self-care strategies and system supports employed in preparation for, during, and after disaster relief operations (DROs) are crucial to relief worker well-being and the overall effectiveness of relief efforts. Relief organizations and management must structure DROs in a manner that promotes self-care and workers must implement proper self-care strategies. Proper self-care before, during, and after a DRO can reduce negative reactions to stressful emergency work and promote growth, mastery, and self-efficacy after the experience. Therefore, the purpose of this article is to discuss the importance of organizational supports and self care strategies in disaster relief settings. This article emphasizes the role of both individual and management participation and commitment to relief worker support and positive experience in DROs and provides suggestions for doing so. These suggestions are derived from the empirical and experiential literature and extensions from the theoretical background, and from our experience as managers in DROs. PMID- 27505126 TI - Isolation and Structure of Germylene-Germyliumylidenes Stabilized by N Heterocyclic Imines. AB - The ditopic germanium complex FGe(NIPr)2 Ge[BF4 ] (3[BF4 ]; IPr=1,3-bis(2,6 diisopropylphenyl)imidazolin-2-ylidene) is prepared by the reaction of the amino(imino)germylene (Me3 Si)2 NGeNIPr (1) with BF3 ?OEt2 . This monocation is converted into the germylene-germyliumylidene 3[BAr(F) 4 ] [Ar(F) =3,5-(CF3 )2 C6 H3 ] by treatment with Na[BAr(F) 4 ]. The tetrafluoroborate salt 3[BF4 ] reacts with 2 equivalents of Me3 SiOTf to give the novel complex (OTf)(GeNIPr)2 [OTf] (4[OTf]), which affords 4[BAr(F) 4 ] and 4[Al(OR(F) )4 ] [R(F) =C(CF3 )3 ] after anion exchange with Na[BAr(F) 4 ] or Ag[Al(OR(F) )4 ], respectively. The computational, as well as crystallographic study, reveals that 4(+) has significant bis(germyliumylidene) dication character. PMID- 27505125 TI - Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice. AB - AIMS: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. RESULTS: Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC alpha1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGCalpha1 allele [sGCalpha1-/-CM]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGCalpha1-/-CM than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGCalpha1 mutant (DNsGCalpha1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGCalpha1tg/+, but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGCalpha1tg/+ and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGCalpha1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGCalpha1 deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin-associated cardiotoxicity. Antioxid. Redox Signal. 26, 153-164. PMID- 27505127 TI - Development and validation of UHPLC-MS/MS methods for the quantification of colistin in plasma and dried plasma spots. AB - Quantification of colistin in plasma samples may be very useful in optimizing therapy especially in special patients' population. Nevertheless, therapeutic drug monitoring of colistin is still limited probably for the low number of laboratories which perform this analysis and for high shipment costs. We developed and validated new UHPLC-MS/MS methods to quantify colistin in plasma and in dried plasma spots (DPS) collected on dried sample spots devices (DSSD). Colistin A, Colistin B and polimixin B, used as internal standard, were detected using multiple reaction monitoring (MRM) of the following specific transitions: 585.5->534.9; 576, 578.5->527.9; 568.9 and 602.5->100.9, 551.9, 592.8, respectively. Colistin A and B were extracted from plasma using protein precipitation and from DSSD using an extraction basic solution. Both methods were validated, and the mean intra and inter-day accuracies and precisions were in accordance with FDA and EMA guidelines. Colistin in DPS was found to be stable for at least one week at room temperature (20-25 degrees C). A statistically significant linear correlation was found between colistin extracted from plasma and from DPS [r(2) 0.9864 (P<0.0001, 95% CI 0.9699-0.9939) for colistin A and 0.9695 (P<0.0001, 95% CI 0.9310-0.9866) for colistin B, respectively]. DPS on DSSD represents a safe and cheap strategy to store and ship at room temperature plasma samples. Thus, it is suited for pharmacokinetic studies and therapeutic drug monitoring of colistin. PMID- 27505129 TI - "In Times Like These". PMID- 27505128 TI - Development of a simple, rapid, and robust liquid chromatographic method for the simultaneous determination of sulfalene, sulfadoxine, and pyrimethamine in tablets. AB - A simple, cost effective, accurate, and precise RP-HPLC method was developed for the simultaneous determination of sulfalene and sulfadoxine in fixed dose dual combinations with pyrimethamine together with their related substances. Proprietary products containing these combinations are often being prescribed in malaria endemic countries. Quantification of the active compounds and impurity profiling was achieved using two standard C18 columns with a mobile phase being composed of 60% (v/v) of a 0.05M KH2PO4 buffer solution (pH=2.6) and 40% (v/v) of methanol, applying an isocratic elution mode and a detection wavelength of 215nm. The method allows a quick quantitative determination of sulfadoxine and sulfalene and the separation of the respective impurities within a total runtime of approximately 15min and was validated with respect to specificity, linearity, precision, accuracy, limits of detection and quantification, robustness, and stability of the standard and sample solutions. The method is simpler than the corresponding method described in the International Pharmacopoeia and the United States Pharmacopoeia in terms of being easy to apply, being less time consuming, and utilizing reagents and chemicals which are cost efficient. PMID- 27505130 TI - Use of Surface Photovoltage Spectroscopy to Measure Built-in Voltage, Space Charge Layer Width, and Effective Band Gap in CdSe Quantum Dot Films. AB - Surface photovoltage spectroscopy (SPS) was used to study the photochemistry of mercaptoethanol-ligated CdSe quantum dot (2.0-4.2 nm diameter) films on indium doped tin oxide (ITO) in the absence of an external bias or electrolyte. The n type films generate negative voltages under super band gap illumination (0.1-0.5 mW cm(-2)) by majority carrier injection into the ITO substrate. The photovoltage onset energies track the optical band gaps of the samples and are assigned as effective band gaps of the films. The photovoltage values (-125 to -750 mV) vary with quantum dot sizes and are modulated by the built-in potential of the CdSe ITO Schottky type contacts. Deviations from the ideal Schottky model are attributed to Fermi level pinning in states approximately 1.1 V negative of the ITO conduction band edge. Positive photovoltage signals of +80 to +125 mV in films of >4.0 nm nanocrystals and in thin (70 nm) nanocrystal films are attributed to electron-hole (polaron) pairs that are polarized by a space charge layer at the CdSe-ITO boundary. The space charge layer is 70-150 nm wide, based on thickness-dependent photovoltage measurements. The ability of SPS to directly measure built-in voltages, space charge layer thickness, sub-band gap states, and effective band gaps in drop-cast quantum dot films aids the understanding of photochemical charge transport in quantum dot solar cells. PMID- 27505131 TI - Palladium-Catalyzed Enantioselective Three-Component Synthesis of alpha Arylglycines. AB - A general Pd-catalyzed, enantioselective three-component synthesis of alpha arylglycines starting from sulfonamides, glyoxylic acid derivatives, and boronic acids was developed. This operationally straightforward procedure enables the preparation of a wide variety of alpha-arylglycines in high yields and excellent levels of enantioselectivity from a simple set of readily available starting materials. Incorporation of Pbf-amides gives a racemization-free access to N unprotected alpha-arylglycines. PMID- 27505132 TI - Successful surgery in lesional epilepsy secondary to posterior quandrant ulegyria coexisting with benign childhood focal epilepsy: A case report. AB - The present study reports, for the first time, a rare case of benign childhood focal epilepsy(BCFE) coexisting with lesional epilepsy secondary to parietooccipital ulegyria. The patient underwent right parietooccipital lobe disconnection plus tailored resection of temporooccipitoparietal junction cortex under electrocorticography (ECoG) monitoring. Post-operatively, there was no impairment of neurological function and the patient only experiences a few breakthrough benign partial seizures during sleep. PMID- 27505133 TI - Prognosis of meningiomas in the early 1970s and today. AB - OBJECTIVE: The benefit of the current strategy of diagnosis and treatment of meningiomas in contrast to the standard treatment in use before computer tomographic and magnetic resonance imaging and before the microsurgical era has not yet been determined. METHODS: Two groups of patients were compared, those on which surgery was performed before the year of 1985, when computer tomographic (CT) imaging was not yet available in our clinic and those who were treated after at the Neurosurgical Department of Saarland University. Average follow-up time was 17.9+/-9.3years for group 1 and 9.2+/-4.3years for group 2. RESULTS: The number of patients with advanced age who had surgical treatment was significantly increased in the second group, whereas the number of perioperative complications found was nearly equal in both groups (17.8% vs. 18.8%). Nevertheless, perioperative morbidity was reduced from 2.2% to 1.2%. The postoperative recurrence free time period could be revealed to be longer in the first collective (p<0.0001). Furthermore, this study shows a notable increase of the incidence of WHO grade II meningiomas in patients treated after 1985. CONCLUSIONS: Based on the presented results, the overall prognosis for patients with meningiomas has changed from the 1960s until today, since over the last two decades there has been a prolonged progression free survival time in addition to a reduced perioperative mortality rate. In the postoperative management of these patients genetic aberrations and microbiological markers should be considered as prognostic factors for meningiomas in addition to histopathological grading. PMID- 27505134 TI - L1CAM expression in endometrial carcinomas: an ENITEC collaboration study. AB - BACKGROUND: Identification of aggressive endometrioid endometrial carcinomas (EECs) and non-endometrioid carcinomas (NEECs) is essential to improve outcome. L1 cell adhesion molecule (L1CAM) expression is a strong prognostic marker in stage I EECs, but less is known about L1CAM expression in advanced-stage EECs and NEECs. This study analyses L1CAM expression in a clinically representative cohort of endometrial carcinomas. METHODS: The expression of L1CAM was immunohistochemically determined in 1199 endometrial carcinomas, treated at one of the European Network for Individualized Treatment of Endometrial Cancer (ENITEC) centres. Staining was considered positive when >10% of the tumour cells expressed L1CAM. The association between L1CAM expression and several clincopathological characteristics and disease outcome was calculated. RESULTS: In all, L1CAM was expressed in 10% of the 935 stage I EECs, 18% of the 160 advanced stage EECs, and 75% of the 104 NEECs. The expression of L1CAM was associated with advanced stage, nodal involvement, high tumour grade, non endometrioid histology, lymphovascular space invasion, and distant recurrences in all cases, and with reduced survival in the EECs, but not in the NEECs. CONCLUSIONS: The expression of L1CAM is a strong predictor of poor outcome in EECs, but not NEECs. It is strongly associated with non-endometrioid histology and distant spread, and could improve the postoperative selection of high-risk endometrial carcinomas. The value of L1CAM expression in the preoperative selection of high-risk endometrial carcinomas should be studied. PMID- 27505135 TI - Excessive blood pressure increase with exercise and risk of all-cause mortality and cardiac events. AB - BACKGROUND: The association of an excessive blood pressure increase with exercise (EBPIE) on cardiovascular outcomes remains controversial. We sought to assess its impact on the risk of all-cause mortality and major cardiac events in patients with known or suspected coronary artery disease (CAD) referred for stress testing. MATERIALS AND METHODS: Exercise echocardiography was performed in 10 047 patients with known or suspected CAD. An EBPIE was defined as an increase in systolic blood pressure with exercise >= 80 mmHg. The endpoints were all-cause mortality and major cardiac events (MACE), including cardiac death or nonfatal myocardial infarction (MI). RESULTS: Overall, 573 patients exhibited an EBPIE during the tests. Over a mean follow-up of 4.8 years, there were 1950 deaths (including 725 cardiac deaths), 1477 MI and 1900 MACE. The cumulative 10-year rates of all-cause mortality, cardiac death, nonfatal MI and MACE were 32.9%, 13.1%, 26.9% and 33% in patients who did not develop an EBPIE vs. 18.9%, 4.7%, 17.5% and 20.7% in those experiencing an EBPIE, respectively (P < 0.001 for all comparisons). In Cox regression analyses, an EBPIE remained predictive of all cause mortality (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.59-0.91, P = 0.004), cardiac death (HR 0.67, 95% CI 0.46-0.98, P = 0.04), MI (HR 0.67, 95% CI 0.52-0.86, P = 0.002) and MACE (HR 0.69, 95% CI 0.56-0.86, P = 0.001). CONCLUSIONS: An EBPIE was associated with a significantly lower risk of mortality and MACE in patients with known or suspected CAD referred for stress testing. PMID- 27505136 TI - Chemoenzymatic Total Synthesis of (+)-Galanthamine and (+)-Narwedine from Phenethyl Acetate. AB - The stereoselective total synthesis of unnatural (+)-galanthamine starting from phenethyl acetate is described. Chirality was introduced via microbial dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) to the corresponding cis-cyclohexadi-enediol, configuration of which provided the absolute stereochemistry of the ring C of (+)-galanthamine. Intramolecular Heck cyclization was used to form the quaternary carbon and dibenzofuran functionality. The synthesis of (+)-galanthamine was completed in a total of ten steps and an overall yield of 5.5 %. Experimental and spectral data are provided for all new compounds. PMID- 27505137 TI - A novel system for embryo-larval toxicity testing of pelagic fish: Applications for impact assessment of Deepwater Horizon crude oil. AB - Key differences in the developmental process of pelagic fish embryos, in comparison to embryos of standard test fish species, present challenges to obtaining sufficient control survival needed to successfully perform traditional toxicity testing bioassays. Many of these challenges relate to the change in buoyancy, from positive to negative, of pelagic fish embryos that occurs just prior to hatch. A novel exposure system, the pelagic embryo-larval exposure chamber (PELEC), has been developed to conduct successful bioassays on the early life stages (ELSs; embryos/larvae) of pelagic fish. Using this unique recirculating upwelling system, it was possible to significantly improve control survival in pelagic fish ELS bioassays compared to commonly used static exposure methods. Results demonstrate that control performance of mahi-mahi (Coryphaena hippurus) embryos in the PELEC system, measured as percent survival after 96-hrs, significantly outperformed agitated static exposure and static exposure systems. Similar significant improvements in 72-hr control survival were obtained with yellowfin tuna (Thunnus albacares). The PELEC system was subsequently used to test the effects of photo-induced toxicity of crude oil to mahi-mahi ELSs over the course of 96-hrs. Results indicate a greater than 9-fold increase in toxicity of Deepwater Horizon (DWH) crude oil during co-exposure to ambient sunlight compared to filtered ambient sunlight, revealing the importance of including natural sunlight in 96-hr DWH crude oil bioassays as well as the PELEC system's potential application in ecotoxicological assessments. PMID- 27505138 TI - Nanocomposite of exfoliated bentonite/g-C3N4/Ag3PO4 for enhanced visible-light photocatalytic decomposition of Rhodamine B. AB - Novel visible-light-driven heterojunction photocatalyst comprising exfoliated bentonite, g-C3N4 and Ag3PO4 (EB/g-C3N4/Ag3PO4) was synthesized by a facile and green method. The composites EB/g-C3N4/Ag3PO4 were characterized by X-ray diffraction, Transmission electron microscopy, Fourier transform infrared spectroscopy, UV-Vis diffuse reflectance spectroscopy and the Brunauer, Emmett, and Teller (BET) surface area method. Under visible light irradiation, EB/g C3N4/Ag3PO4 composites displayed much higher photocatalytic activity than that of either pure g-C3N4 or pure Ag3PO4 in the degradation of Rhodamine B (RhB). Among the hybrid photocatalysts, EB/g-C3N4/Ag3PO4 composite containing 20 wt% Ag3PO4 exhibited the highest photocatalytic activity for the decolorization of RhB. Under the visible-light irradiation, the RhB dye was completely decolorized in less than 60 min. The enhanced photocatalytic performance is attributed to the stable structure, enlarged surface area, strong adsorbability, strong light absorption ability, and high-efficiency separation rate of photoinduced electron hole pairs. Our finding paves a way to design highly efficient and stable visible light-induced photocatalysts for practical applications in wastewater treatment. PMID- 27505140 TI - A case of pulmonary artery sling where onset Was induced by therapeutic hypothermia. AB - A neonate with severe neonatal asphyxia was treated with therapeutic hypothermia. He developed hypothermia-induced respiratory deterioration, after which congenital tracheal stenosis and pulmonary artery sling were diagnosed. Even low grade hypothermia is likely to induce bronchial narrowing in neonates, especially in neonates with congenital respiratory tract anomalies. Congenital tracheal stenosis represents a potential pitfall in differential diagnosis and should be carefully ruled out in cases of bronchial narrowing episode induced by therapeutic hypothermia. Pediatr Pulmonol. 2017;52:E7-E10. (c) 2016 Wiley Periodicals, Inc. PMID- 27505139 TI - miR-17-3p Exacerbates Oxidative Damage in Human Retinal Pigment Epithelial Cells. AB - Oxidative stress has been shown to contribute to the development of age-related macular degeneration (AMD). MicroRNAs (miRNA) are small non-coding RNA molecules that function in RNA silencing and post-transcriptional regulation of gene expression. We showed miR-17-3p to be elevated in macular RPE cells from AMD patients and in ARPE-19 cells under oxidative stress. Transfection of miR-17-3p mimic in ARPE-19 induced cell death and exacerbated oxidative lethality that was alleviated by miR-17-3p inhibitor. The expression of antioxidant enzymes manganese superoxide dismutase (MnSOD) and thioredoxin reductase-2 (TrxR2) were suppressed by miR-17-3p mimic and reversed by miR-17-3p inhibitor. These results suggest miR-17-3p aggravates oxidative damage-induced cell death in human RPE cells, while miR-17-3p inhibitor acts as a potential protector against oxidative stress by regulating the expression of antioxidant enzymes. PMID- 27505141 TI - Quercetin Influence on Thermal Denaturation of Bovine Serum Albumin. AB - The effect of quercetin (QUER) binding on bovine serum albumin (BSA) thermal denaturation was systematically investigated by means of differential scanning calorimetry (DSC). Additional information concerning thermodynamic and structural binding parameters was provided by isothermal titration calorimetry (ITC) and molecular docking. The most relevant effect of QUER is manifested in the modification of the two-step thermal fingerprint of protein denaturation. Higher QUER concentrations result in a single-step denaturation thermogram, ascribed to the interplay between specific and nonspecific binding and enhancement of the solvent unfolding action. Analysis of ITC data indicate sequential binding of two molecules of QUER occurring spontaneously at different binding sites of BSA involving hydrophobic, electrostatic and hydrogen binding forces. Identification of QUER binding sites was possible through corroboration of DSC runs in the presence of site markers and molecular docking. Modeling of ligand-protein interaction confirmed the experimental data. On one hand, a neutral form of QUER binds in a nonplanar conformation to Sudlow's site I, a large hydrophobic cavity of subdomain IIA of BSA and decreases its thermal stability. On the other hand, a second molecule of QUER, the anionic form, is bound in planar conformation to Sudlow's site II, situated in the subdomain IIIA of the folded protein, and increases the thermal stability of the corresponding structural domain of the protein. PMID- 27505142 TI - Utilization and efficacy of computational gait analysis for hamstring lengthening surgery. AB - A retrospective analysis of computational gait studies performed in a single lab over a 12 year period was undertaken to characterize how recommendations to perform or not to perform hamstring lengthenings were utilized by physicians and the effect on outcomes. 131 Subjects were identified as either having hamstring lengthening considered by the referring surgeon, recommended by gait analysis data, or performed. A subset of this data meeting inclusion criteria for pre- and post-surgical timeframes, and bilateral diagnosis was further analyzed to assess the efficacy of the recommendations. There was initial agreement between planned procedures and recommended procedures in just 41% of the cases. Including the cases where there was agreement, gait analysis altered the initial procedure in 54%. In the cases where the initial plan was not supported by gait data, surgeons followed gait recommendations in 77%. In subjects who underwent hamstring lengthening, when surgeons followed or agreed with gait recommendations, patients were 3.6 times more likely to experience a positive outcome. PMID- 27505143 TI - Reference data for performances on the standardized walking obstacle course in children developing typically. AB - PURPOSE: To establish reference performance groups on the Standardized Walking Obstacle Course (SWOC) a pathway to screen ambulation for children developing typically. METHODS: SWOC tests ambulation under three conditions: walk (W), walk with tray (WT) and walk wearing sunglasses (WG). One trial consisted of standing up, walking the course in one direction and sitting down. Children (n=355) completed two trials per condition. Trial measures included time to complete (seconds) and numbers of steps, stumbles, and steps off path. RESULTS: Trial 1 and trial 2 for time and number of steps are significantly different (p=0.0005), but highly correlated (r=0.93 and r=0.96) therefore their average was used to establish reference data. Gender was not a significant factor. Age and height predict performances in all conditions, but measures between age groups were not always significantly different. Significant different measures by height groups could be established across all conditions, therefore reference data was established using three height groups. CONCLUSION: Reference values will assist clinicians to compare a child's performance on the SWOC based on an individual height because this can vary within and between ages thus screening for possible ambulation limitations. PMID- 27505144 TI - Postural sway in children: A literature review. AB - BACKGROUND AND AIM: Static posturography can serve as an easy and fast way to determine whether a child possesses sufficient balance control in different sensory conditions. Therefore, the aim of this review is to map age-related differences in postural sway during childhood in typically developing children, using static posturography and to provide an overview of the available (age specific) reference values in scientific literature. METHODS: The search strategy was performed in five databases (Pubmed, Web of Science, ScienceDirect, Cochrane Clinical Trials, Medline (Ovid)) November 2nd 2014 and updated twice: March 16th 2015 and July 20th 2015. The following keywords were used: (children OR child) AND ("postural control" OR "postural stability" OR equilibrium OR posture OR "postural balance"[mesh]) AND ("quiet stance" OR standing OR stance OR "quiet stance" OR static) AND ("postural sway" OR posturography OR "body sway" OR stabilography OR "trunk sway" OR "medio-lateral sway" OR "antero-posterior sway"). Relevant studies were identified using predefined selection criteria, applied on title and abstract (phase 1) and on full text (phase 2), supplemented with reference screening after the second phase. RESULTS: A total of 14 studies met the criteria. This review showed three main findings: 1) during natural bipedal stance with the eyes open, all studies reported a decrease in postural sway with increasing age, with conflicting results on the (non-)linearity of its development, 2) with eyes closed, all children show more sway than with eyes open and 3) only four studies reported numeric sway values that could serve as reference values, mainly focusing on children aged five and older. CONCLUSION: Considerable disagreement exists on the (non-)linearity of the development of postural sway in children. By choosing arbitrary age categories, it remains unclear between which age groups differences are situated. Future research is necessary to determine for which age groups age-specific reference values are relevant. PMID- 27505145 TI - Serum HBV core-related antigen is a good predictor for spontaneous HBeAg seroconversion in chronic hepatitis B patients. AB - Early prediction of spontaneous hepatitis B virus e antigen (HBeAg) seroconversion is pivotal in the prevention of unnecessary drug prescription, corresponding financial burden, and adverse reactions. One hundred and thirteen chronic hepatitis B patients with HBeAg-positive in the immune active phase were followed up for about 1.5 years. Patients were classified into two groups: spontaneous HBeAg seroconversion group (group A, n = 18) and non-spontaneous HBeAg seroconversion group. Among the non-spontaneous HBeAg seroconversion group, 35 patients were selected as controls (group B, n = 35). At week 12, there was a significant difference in hepatitis B core-related antigen (HBcrAg) levels between the two groups (group A 4.32 +/- 1.05 log10 kU/ml, and group B 5.16 +/- 0.53 log10 kU/ml, P = 0.004), and this significance magnified at week 28. Only two variables, HBcrAg level and the reduction in the HBcrAg levels (DeltaHBcrAg) at week 28 were enrolled, with the odds ratio of 4.19 and 0.21, respectively. The optimal cutoffs of HBcrAg levels and the DeltaHBcrAg at week 28 were 4.90 and 2.00 log10 kU/ml, respectively. The positive predictive value and negative predictive value of HBcrAg levels at week 28 were 73.9% and 96.7%, respectively. The positive predictive value and negative predictive value of the DeltaHBcrAg at week 28 were 76.2% and 93.8%, respectively. The measurement of HBcrAg is useful for monitoring the natural course of chronic hepatitis B virus infection. The dynamics of HBcrAg levels could accurately predict the spontaneous HBeAg seroconversion. J. Med. Virol. 89:463-468, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27505146 TI - La2SrCr2O7: Controlling the Tilting Distortions of n = 2 Ruddlesden-Popper Phases through A-Site Cation Order. AB - Structural characterization by neutron diffraction, supported by magnetic, SHG, and MU(+)SR data, reveals that the n = 2 Ruddlesden-Popper phase La2SrCr2O7 adopts a highly unusual structural configuration in which the cooperative rotations of the CrO6 octahedra are out of phase in all three Cartesian directions (PhiPhiPhiz/PhiPhiPhiz; a(-)a(-)c(-)/a(-)a(-)c(-)) as described in space group A2/a. First-principles DFT calculations indicate that this unusual structural arrangement can be attributed to coupling between the La/Sr A-site distribution and the rotations of the CrO6 units, which combine to relieve the local deformations of the chromium-oxygen octahedra. This coupling suggests new chemical "handles" by which the rotational distortions or A-site cation order of Ruddlesden-Popper phases can be directed to optimize physical behavior. Low temperature neutron diffraction data and MU(+)SR data indicate La2SrCr2O7 adopts a G-type antiferromagnetically ordered state below TN ~ 260 K. PMID- 27505147 TI - Tumor Necrosis Factor Alpha Promotes Osteoclast Formation Via PI3K/Akt Pathway Mediated Blimp1 Expression Upregulation. AB - Tumor necrosis factor alpha (TNF-alpha)-induced osteoclastogenesis have profound effects in states of inflammatory osteolysis such as rheumatoid arthritis, periprosthetic implant loosening, and periodontitis. However, the exact mechanisms by which TNF-alpha promotes RANKL-induced osteoclast formation remains poorly understood. B lymphocyte-induced maturation protein-1 (Blimp1) is a transcriptional repressor that plays crucial roles in the differentiation and/or function of various kinds of cells including osteoclasts. A novel mechanism was identified where TNF-alpha-mediated Blimp1 expression, which contributed to RANKL induced osteoclastogenesis. It is shown that TNF-alpha could promote the level of Blimp1 expression during osteoclast differentiation. Silencing of Blimp1 in osteoclast precursor cells obviously attenuated the stimulatory effect of TNF alpha on osteoclastogenesis. Mechanistically, TNF-alpha-induced Blimp1 expression was markedly rescued by blocking the PI3K/Akt signaling pathway, which suggested that PI3K/Akt signaling was involved in the regulation of TNF-alpha-stimulated Blimp1 expression. Taken together, the results established a molecular mechanism of TNF-alpha-induced osteoclasts differentiation, and provided insights into the potential contribution of Blimp1 in the regulation of osteoclastogenesis by TNF alpha. J. Cell. Biochem. 118: 1308-1315, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27505148 TI - Program Directors' Perceptions of Resident Education in Women's Health: A National Survey. AB - BACKGROUND: Despite professional societies' emphasis on women's health in internal medicine (IM) resident curricula, national implementation has varied. This study describes IM program directors' perceptions of women's health topics that residents should master and the current state of women's health education in IM residency programs. MATERIALS AND METHODS: We recruited 408 program directors of IM residency programs to complete an electronic cross-sectional survey. Participants were surveyed about expected resident mastery of twelve women's health topics in the context of their program's current characteristics, core curricula, and training opportunities. RESULTS: One hundred twelve IM program directors completed the survey (response rate 27%). The percentage of program directors who perceived that residents should master each of the twelve women's health topics ranged from 48% to 98%, with the most program directors expecting mastery of osteoporosis (N = 110, 98%), sexually transmitted infection (N = 110, 98%), and gender-specific cancer (N = 109, 97%). These topics, however, were not currently included in the core curricula of 6%-12% of programs. Programs offered varied opportunities in women's health, including dedicated women's health electives (N = 76, 68%), concentrations or tracks (N = 8, 7%), and continuity clinics (N = 15, 13%). Most program directors were interested (N = 90, 80%) in expanding women's health opportunities in their programs. CONCLUSION: While women's health topics were perceived by program directors as a priority for IM resident mastery, certain priority topics and training opportunities were limited. Additional studies are needed to explore barriers to expansion of resident education in women's health and potential solutions. PMID- 27505149 TI - Anxiety, depression and suicide in patients with prurigo nodularis. PMID- 27505150 TI - Glycemic Control and the Risk of Tuberculosis: A Cohort Study. AB - BACKGROUND: Diabetes is a well-known risk factor for tuberculosis (TB) and is increasingly prevalent in low- and middle-income countries, where the burden of TB is high. Glycemic control has the potential to modify the risk of TB. However, there are few studies on the association between glycemic control and TB risk, and the results are inconsistent. METHODS AND FINDINGS: We assembled a cohort using 123,546 individuals who participated in a community-based health screening service in northern Taiwan from 5 March 2005 to 27 July 2008. Glycemic control was measured using fasting plasma glucose (FPG) at the time of screening. The cohort was followed up to 31 December 2012 for the occurrence of TB by cross matching the screening database to the national health insurance database. Multiple imputation was used to handle missing information. During a median follow-up of 4.6 y, 327 cases of TB occurred. In the multivariable Cox regression model, diabetic patients with poor glycemic control (FPG > 130 mg/dl) had a significantly higher hazard of TB (adjusted hazard ratio [aHR] 2.21, 95% CI 1.63 2.99, p < 0.001) compared to those without diabetes. The hazard of TB in diabetic patients with good glycemic control (FPG <= 130 mg/dl) did not differ significantly from that in nondiabetic individuals (aHR 0.69, 95% CI 0.35-1.36, p = 0.281). In the linear dose-response analysis, the hazard of TB increased with FPG (aHR 1.06 per 10-mg/dl increase in FPG, 95% CI 1.03-1.08, p < 0.001). Assuming the observed association between glycemic control and TB was causal, an estimated 7.5% (95% CI 4.1%-11.5%) of incident TB in the study population could be attributed to poor glycemic control. Limitations of the study include one-time measurement of fasting glucose at baseline and voluntary participation in the health screening service. CONCLUSIONS: Good glycemic control could potentially modify the risk of TB among diabetic patients and may contribute to the control of TB in settings where diabetes and TB are prevalent. PMID- 27505151 TI - Music, Spatial Task Performance, and Brain Plasticity in Elderly Adults. PMID- 27505152 TI - Improved Interfacial Affinity and CO2 Separation Performance of Asymmetric Mixed Matrix Membranes by Incorporating Postmodified MIL-53(Al). AB - Asymmetric mixed matrix membranes(MMMs) with MOFs hold great application potential for energy-efficient gas separations. However, the particle aggregation and nonselective interfacial microvoids restrict the gas separation performance of asymmetric MMMs. Herein, nanoporous metal-organic framework (MOF) of MIL 53(Al) was modified with aminosilane after solvothermal synthesis. The postfunctionalization by grafting alkyl chains can form hydrogen bonds with polymer chains to enhance the affinity with polymer matrix and facilitate the preferential adsorption of CO2 by dipole-quadrupole interaction with the functional group. Then the postmodified MIL-53(Al) was incorporated as filler into poly(ether imide) Ultem1000 to fabricate high-quality asymmetric MMMs with well dispersed particles in polymer matrix and good adhesion at the MOFs-polymer interface. The Ultem/S-MIL-53(Al) asymmetric MMMs exhibited remarkable combinations of gas permeance and ideal selectivity for CO2/N2 separation at 10 wt % filler loading. The CO2 permeance achieved 24.1 GPU, an increase of 165% compared with pure Ultem membrane. Meanwhile, the ideal CO2/N2 selectivity also increased from 31.0 up to 41.1. The strategy of post covalent modification for MOFs provides an effective way to improve the interfacial affinity and gas separation performance. PMID- 27505153 TI - Evaluation of transient elastography in assessing liver fibrosis in patients with autoimmune hepatitis. AB - BACKGROUND AND AIM: Transient elastography (TE) can reliably stage liver fibrosis via liver stiffness measurement (LSM) in chronic liver disease. However, the accuracy of TE for assessment of liver fibrosis in patients with autoimmune hepatitis (AIH) is still limited. We evaluate TE in staging liver fibrosis in AIH patients and compare with other noninvasive diagnostic tools. METHODS: A total of 100 patients with biopsy-proven AIH were included. The correlation between LSM and fibrosis stage was analyzed using Spearman correlation test. The optimal cut off values of LSM were calculated for predicting individual fibrosis stages using receiver-operating characteristic curve. The diagnostic accuracy of LSM for severe fibrosis was compared with those of serum biochemical scores. RESULTS: Median LSM in AIH patients was higher than that of healthy controls (11.2 +/- 8.2 kPa vs 4.3 +/- 1.4 kPa, P < 0.01). LSM had significant correlation with fibrosis (r = 0.752, P < 0.01) and increased progressively with increasing fibrosis stages in AIH patients. AUROC values of LSM for stages F >= 2, F >= 3, and F4 were 0.878 (95%CI: 0.789-0.967), 0.883 (0.820-0.946), and 0.914 (0.852-0.976), respectively. The optimal cut-off values of LSM for fibrosis stages F >= 2, F >= 3, and F4 were 6.45, 8.75, and 12.50 kPa, respectively. LSM was superior to APRI score and FIB-4 score in detecting severe fibrosis (F >= 3). Serum ALT levels had minor effect on LSM values. CONCLUSIONS: Transient elastography is an accurate and reliable noninvasive tool in assessing liver fibrosis in AIH. Hepatic inflammatory activity had no significant effect on LSM determination. PMID- 27505154 TI - When does making detailed predictions make predictions worse? AB - [Correction Notice: An Erratum for this article was reported in Vol 145(10) of Journal of Experimental Psychology: General (see record 2016-42695-001). In the article, the symbols in Figure 2 were inadvertently altered in production. All versions of this article have been corrected.] In this article, we investigate whether making detailed predictions about an event worsens other predictions of the event. Across 19 experiments, 10,896 participants, and 407,045 predictions about 724 professional sports games, we find that people who made detailed predictions about sporting events (e.g., how many hits each baseball team would get) made worse predictions about more general outcomes (e.g., which team would win). We rule out that this effect is caused by inattention or fatigue, thinking too hard, or a differential reliance on holistic information about the teams. Instead, we find that thinking about game-relevant details before predicting winning teams causes people to give less weight to predictive information, presumably because predicting details makes useless or redundant information more accessible and thus more likely to be incorporated into forecasts. Furthermore, we show that this differential use of information can be used to predict what kinds of events will and will not be susceptible to the negative effect of making detailed predictions. PMID- 27505155 TI - A Power-Law Growth and Decay Model with Autocorrelation for Posting Data to Social Networking Services. AB - We propose a power-law growth and decay model for posting data to social networking services before and after social events. We model the time series structure of deviations from the power-law growth and decay with a conditional Poisson autoregressive (AR) model. Online postings related to social events are described by five parameters in the power-law growth and decay model, each of which characterizes different aspects of interest in the event. We assess the validity of parameter estimates in terms of confidence intervals, and compare various submodels based on likelihoods and information criteria. PMID- 27505156 TI - Parainfluenza virus 5 upregulates CD55 expression to produce virions with enhanced resistance to complement-mediated neutralization. AB - Many enveloped RNA viruses recruit host cell proteins during assembly as a mechanism to limit antiviral effects of complement. Using viruses which incorporated CD46 alone, CD55 alone or both CD46 and CD55, we addressed the role of these two host cell regulators in limiting complement-mediated neutralization of Parainfluenza virus 5 (PIV5). PIV5 incorporated functional forms of both CD55 and CD46 into virions. PIV5 containing CD55 was highly resistant to complement mediated neutralization, whereas CD46-containing PIV5 was as sensitive to neutralization as virus lacking both regulators. PIV5 infected cells had increased levels of cell surface CD55, which was further upregulated by exogenous treatment with tumor necrosis factor alpha. PIV5 derived from cells with higher CD55 levels was more resistant to complement-mediated neutralization in vitro than virus from control cells. We propose a role for virus induction of host cell complement inhibitors in defining virus growth and tissue tropism. PMID- 27505157 TI - Pharmacist-Physician Communications in a Highly Computerised Hospital: Sign-Off and Action of Electronic Review Messages. AB - BACKGROUND: Some hospital Computerized Physician Order Entry (CPOE) systems support interprofessional communication. The aim of this study was to investigate the effectiveness of pharmacist-physician messages sent via a CPOE system. METHOD: Data from the year 2012 were captured from a large university teaching hospital CPOE database on: 1) review messages assigned by pharmacists; 2) details of the prescription on which the messages were assigned; and 3) details of any changes made to the prescription following a review message being assigned. Data were coded for temporal, message and prescription factors. Messages were analysed to investigate: 1) whether they were signed-off; and 2) the time taken. Messages that requested a measurable action were further analysed to investigate: 1) whether they were actioned as requested; and 2) the time taken. We conducted a multivariable analysis using Generalised Estimating Equations (GEE) to account for the effects of multiple factors simultaneously, and to adjust for any potential correlation between outcomes for repeated review messages on the same prescription. All analyses were performed using SPSS 22 (IBM SPSS Inc., Chicago, IL, USA), with p<0.05 considered significant. RESULTS: Pharmacists assigned 36,245 review messages to prescriptions over the 12 months, 34,506 of which were coded for analysis after exclusions. Nearly half of messages (46.6%) were signed off and 65.5% of these were signed-off in <= 48 hours. Of the 9,991 further analysed for action, 35.8% led to an action as requested by the pharmacist and just over half of these (57.0%) were actioned in <= 24 hours. Factors predictive of an action were the time since the prescription was generated (p<0.001), pharmacist grade (p<0.001), presence of a high-risk medicine (p<0.001), messages relating to reconciliation (p = 0.004), theme of communication (p<0.001), speciality, (p<0.001), category of medicine (p<0.001), and regularity of the prescription (p<0.001). CONCLUSION: In this study we observed a lower rate of sign-off and action than we might have expected, suggesting uni-directional communication via the CPOE system may not be optimal. An established pharmacist physician collaborative working relationship is likely to influence the prioritisation and response to messages, since a more desirable outcome was observed in settings and with grades of pharmacists where this was more likely. Designing systems that can facilitate collaborative communication may be more effective in practice. PMID- 27505158 TI - Nonpathogenic SIV and Pathogenic HIV Infections Associate with Disparate Innate Cytokine Signatures in Response to Mycobacterium bovis BCG. AB - Infections with mycobacteria, including Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis (M. bovis) BCG, are a leading cause of morbidity and mortality for HIV-infected persons. In contrast to HIV, nonpathogenic SIV infections of sooty mangabeys are characterized by a lack of clinical disease including an absence of opportunistic infections. The goal of this study was to identify innate immune responses to M. bovis BCG maintained during nonpathogenic lentiviral infections through a comparison of functional responses during pathogenic HIV or nonpathogenic SIV infections. Monocytes were evaluated for their ability to express key anti-mycobacterial cytokines TNF-alpha and IL-12 following a six-hour ex vivo BCG exposure. While HIV-infection was associated with a decreased percentage of IL-12-producing monocytes, nonpathogenic SIV infection was associated with an increased percentage of monocytes producing both cytokines. Gene expression analysis of PBMC following ex vivo BCG exposure identified differential expression of NK cell-related genes and several cytokines, including IFN-gamma and IL-23, between HIV-infected and control subjects. In contrast, SIV-infected and uninfected-control mangabeys exhibited no significant differences in gene expression after BCG exposure. Finally, differential gene expression patterns were identified between species, with mangabeys exhibiting lower IL-6 and higher IL-17 in response to BCG when compared to humans. Overall, this comparison of immune responses to M. bovis BCG identified unique immune signatures (involving cytokines IL-12, TNF-alpha, IL-23, IL-17, and IL-6) that are altered during HIV, but maintained or increased during nonpathogenic SIV infections. These unique cytokine and transcriptome signatures provide insight into the differential immune responses to Mycobacteria during pathogenic HIV-infection that may be associated with an increased incidence of mycobacterial co-infections. PMID- 27505159 TI - Risk Factors for Stroke in People with End-Stage Kidney Disease: A Cohort Study. AB - BACKGROUND: It is unclear how traditional cardiovascular risk factors and different treatment modalities for end-stage kidney disease (ESKD) affect stroke risk in people with ESKD. We aimed to identify the risk factors for stroke (ischemic and hemorrhagic) in people with ESKD. METHODS: We conducted a retrospective cohort study using data linkage between the Australian and New Zealand Dialysis and Transplant Registry, clinical and administrative datasets. Using Cox proportional hazards models, we estimated the magnitudes of risk of hospitalization with different subtypes of strokes associated with traditional cardiovascular risk factors and ESKD treatment modalities (hemodialysis (HD), peritoneal dialysis (PD) and kidney transplantation). Results were expressed as hazard ratios (HRs) with 95% CIs. RESULTS: A total of 10,745 people received treatment for ESKD in New South Wales, Australia, between 2000 and 2010. We observed 640 hospitalizations for stroke in 49,497 person-years of follow-up (129.4 per 10,000 person years). Some risk factors were consistent with those found in the general population, including smoking and a history of previous stroke. Other risk factors were novel for people with ESKD. Women were 85% more likely to have an intracerebral hemorrhage (HR 1.85, 95% CI 1.22-2.79) and 30% more likely to have an ischemic stroke (HR 1.30, 95% CI 1.01-1.66) than men. Compared to people on HD, people with kidney transplants had a 65% lower risk of intracerebral hemorrhage (HR 0.35, 95% CI 0.18-0.69) but a similar risk of ischemic stroke (HR 0.97, 95% CI 0.64-1.49). People on PD had a 36% higher risk of ischemic stroke (HR 1.36, 95% CI 1.05-1.76) but a similar risk of intracerebral hemorrhage compared to people on HD (HR 0.69, 95% CI 0.43-1.11). CONCLUSIONS: These findings could be used to establish reliable estimates of the risk of stroke in people with ESKD and identify those who are most likely to benefit from preventive treatments. PMID- 27505160 TI - Polarized Cell Division of Chlamydia trachomatis. AB - Bacterial cell division predominantly occurs by a highly conserved process, termed binary fission, that requires the bacterial homologue of tubulin, FtsZ. Other mechanisms of bacterial cell division that are independent of FtsZ are rare. Although the obligate intracellular human pathogen Chlamydia trachomatis, the leading bacterial cause of sexually transmitted infections and trachoma, lacks FtsZ, it has been assumed to divide by binary fission. We show here that Chlamydia divides by a polarized cell division process similar to the budding process of a subset of the Planctomycetes that also lack FtsZ. Prior to cell division, the major outer-membrane protein of Chlamydia is restricted to one pole of the cell, and the nascent daughter cell emerges from this pole by an asymmetric expansion of the membrane. Components of the chlamydial cell division machinery accumulate at the site of polar growth prior to the initiation of asymmetric membrane expansion and inhibitors that disrupt the polarity of C. trachomatis prevent cell division. The polarized cell division of C. trachomatis is the result of the unipolar growth and FtsZ-independent fission of this coccoid organism. This mechanism of cell division has not been documented in other human bacterial pathogens suggesting the potential for developing Chlamydia-specific therapeutic treatments. PMID- 27505161 TI - Activation of the cAMP Pathway Induces RACK1-Dependent Binding of beta-Actin to BDNF Promoter. AB - RACK1 is a scaffolding protein that contributes to the specificity and propagation of several signaling cascades including the cAMP pathway. As such, RACK1 participates in numerous cellular functions ranging from cell migration and morphology to gene transcription. To obtain further insights on the mechanisms whereby RACK1 regulates cAMP-dependent processes, we set out to identify new binding partners of RACK1 during activation of the cAMP signaling using a proteomics strategy. We identified beta-actin as a direct RACK1 binding partner and found that the association between beta-actin and RACK1 is increased in response to the activation of the cAMP pathway. Furthermore, we show that cAMP dependent increase in BDNF expression requires filamentous actin. We further report that beta-actin associates with the BDNF promoter IV upon the activation of the cAMP pathway and present data to suggest that the association of beta actin with BDNF promoter IV is RACK1-dependent. Taken together, our data suggest that beta-actin is a new RACK1 binding partner and that the RACK1 and beta-actin association participate in the cAMP-dependent regulation of BDNF transcription. PMID- 27505162 TI - Cognitive Offloading Does Not Prevent but Rather Promotes Cognitive Development. AB - We investigate the relation between the development of reactive and cognitive capabilities. In particular we investigate whether the development of reactive capabilities prevents or promotes the development of cognitive capabilities in a population of evolving robots that have to solve a time-delay navigation task in a double T-Maze environment. Analysis of the experiments reveals that the evolving robots always select reactive strategies that rely on cognitive offloading, i.e., the possibility of acting so as to encode onto the relation between the agent and the environment the states that can be used later to regulate the agent's behavior. The discovery of these strategies does not prevent, but rather facilitates, the development of cognitive strategies that also rely on the extraction and use of internal states. Detailed analysis of the results obtained in the different experimental conditions provides evidence that helps clarify why, contrary to expectations, reactive and cognitive strategies tend to have synergetic relationships. PMID- 27505163 TI - Do Bioimpedance Measurements of Over-Hydration Accurately Reflect Post Haemodialysis Weight Changes? AB - INTRODUCTION: Bioelectrical impedance spectroscopy (BIS) devices are being used to determine ultrafiltration requirements to achieve target weight for haemodialysis (HD) patients. Pre-dialysis measurements are more convenient for both patients and staff. We wished to compare the changes in pre- and post dialysis hydration measured by BIS with actual weight loss. METHODS: We compared paired BIS measurements made pre and post HD using a BIS device based on a 3 compartmental model, designed to provide information on extracellular water (ECW) excess. RESULTS: BIS was measured in 49 HD patients, 35 male (71.4%) with mean age 67.6 +/- 14.2. Weight fell significantly from 69.2 +/- 17.8 to 67.6 +/- 17.4 kg, and BIS over hydration (OH) from 4.5 +/- 3.3.4 to 3.4 +/- 2.9 litres, and ECW from 16.8 +/- 4.8 to 15.5 +/- 4.4 litres, but there was no change in the amount of intracellular water. Weight loss correlated positively with the change in ECW, but exceeded the fall in OH; mean bias -0.58 (95% confidence limits -3.6 to 4.8 kg). SUMMARY: We measured OH pre and post HD, but did not find that the change in OH correlated with changes in body weight. Although there was a correlation between changes in OH and ECW, there was none for weight. Our findings do not support total reliance on pre-dialysis BIS alone for assessing volume status in HD patients, but rather BIS should be considered an aid to clinical assessment of volume status. PMID- 27505164 TI - Simultaneously saccharification and fermentation approach as a tool for enhanced fossil fuels biodesulfurization. AB - Biodesulfurization can be a complementary technology to the hydrodesulfurization, the commonly physical-chemical process used for sulfur removal from crude oil. The desulfurizing bacterium Gordonia alkanivorans strain 1B as a fructophilic microorganism requires fructose as C-source. In this context, the main goal of this work was the optimization of a simultaneous saccharification and fermentation (SSF) approach using the Zygosaccharomyces bailii strain Talf1 crude enzymes with invertase activity and sucrose as a cheaper fructose-rich commercial C-source (50% fructose) towards dibenzothiophene (DBT) desulfurization by strain 1B. The determination of optimal conditions, for both sucrose hydrolysis and DBT desulfurization was carried out through two sequential experimental uniform designs according to the Doehlert distribution for two factors: pH (5.5-7.5) and temperature (28-38 degrees C), with the enzyme load of 1.16 U/g/L; and enzyme load (0-4 U/g/L) and temperature (28-38 degrees C), with pH at 7.5. Based on 2 hydroxybiphenyl production, the analysis of the response surfaces obtained pointed out for pH 7.5, 32 degrees C and 1.8 U/g/L as optimal conditions. Further optimized SSF of sucrose during the DBT desulfurization process permitted to attain a 4-fold enhanced biodesulfurization. This study opens a new focus of research through the exploitation of sustainable low cost sucrose-rich feedstocks towards a more economical viable bioprocess scale-up. PMID- 27505165 TI - Sludge reduction by uncoupling metabolism: SBR tests with para-nitrophenol and a commercial uncoupler. AB - Nowadays cost reduction is a very important issue in wastewater treatment plants. One way, is to minimize the sludge production. Microorganisms break down the organic matter into inorganic compounds through catabolism. Uncoupling metabolism is a method which promote catabolism reactions instead of anabolism ones, where adenosine triphosphate synthesis is inhibited. In this work, the influence of the addition of para-nitrophenol and a commercial reagent to a sequencing batch reactor (SBR) on sludge production and process performance has been analyzed. Three laboratory SBRs were operated in parallel to compare the effect of the addition of both reagents with a control reactor. SBRs were fed with synthetic wastewater and were operated with the same conditions. Results showed that sludge production was slightly reduced for the tested para-nitrophenol concentrations (20 and 25 mg/L) and for a LODOred dose of 1 mL/day. Biological process performance was not influenced and high COD removals were achieved. PMID- 27505166 TI - The use of novel packing material for improving methane oxidation in biofilters. AB - The use of biofilters (working bed volume of 7.85 L) for the oxidation of CH4 at low concentrations (from 0.17%v/v to 3.63%v/v, typically in waste gas from anaerobic sewage treatment) was investigated and four empty bed residence times were tested (in min): 42.8, 29.5, 19.6, and 7.4. Mixtures of organic (composted leaves) and three non-organic materials (sponge-based material - SBM, blast furnace slag - BFS, and expanded vermiculite - ExpV) were used as packing media. Along 188 operational days after the steady state was reached (95 days for start up), the CH4 mineralization decreased while the inlet loads gradually increased from 3.0 +/- 0.8 gCH4 m(-3) h(-1) to 148.8 +/- 4.4 gCH4 m(-3) h(-1). The biofilter packed with ExpV showed the best results, since the CH4 conversions decreased from 95.0 +/- 5.0% to 12.7 +/- 3.7% as a function of inlet concentration, compared to the other two biofilters (SBM and BFS) which showed CH4 conversions decreasing from 56.0 +/- 5.4% to 3.5 +/- 1.2% as a function of inlet concentration. The methanotrophic activity of biomass taken from ExpV biofilter was three times higher than the activity of biomass from the other two biofilters. Taken together, these results suggested that ExpV provides an attractive environment for microbial growth, besides the mechanical resistance provided to the whole packing media, showing the potential to its use in biofiltration of diffuse CH4 emissions. PMID- 27505167 TI - Characterization of wood mulch and leachate/runoff from three wood recycling facilities. AB - Large-scale open storage of wood mulch is common practice at wood recycling facilities. During rain and snow melt, leachate with soluble compounds and suspended particles is released from mulch stockpiles. The objective of this study was to determine the quality of leachate/runoff from wood recycling facilities to evaluate its potential to contaminate receiving waterbodies. Wood mulch (n = 30) and leachate/runoff (n = 26) samples were collected over 1.5 years from three wood recycling facilities in New Jersey, USA. Differences by site were found (p < 0.05) for most of the 21 constituents tested in the solid wood mulch samples. Biochemical oxygen demand (range <20-3000 mg/L), chemical oxygen demand (134-6000 mg/L) and total suspended solids (69-401 mg/L) median concentrations of the leachate/runoff samples were comparable to those of untreated domestic wastewater. Total Kjeldahl N, total P and fecal coliform median values were slightly lower than typical wastewater values. Dose-response studies with leachate/runoff samples using zebrafish (Danio rerio) embryos showed that mortality and developmental defects typically did not occur even at the highest concentration tested, indicating low toxicity, although delayed development did occur. Based on this study, leachate/runoff from wood recycling facilities should not be released to surface waters as it is a potential source of organic contamination and low levels of nutrients. A study in which runoff from a controlled drainage area containing wood mulch of known properties is monitored would allow for better assessment of the potential impact of stormwater runoff from wood recycling facilities. PMID- 27505168 TI - Natural Cubic Spline Regression Modeling Followed by Dynamic Network Reconstruction for the Identification of Radiation-Sensitivity Gene Association Networks from Time-Course Transcriptome Data. AB - Gene expression time-course experiments allow to study the dynamics of transcriptomic changes in cells exposed to different stimuli. However, most approaches for the reconstruction of gene association networks (GANs) do not propose prior-selection approaches tailored to time-course transcriptome data. Here, we present a workflow for the identification of GANs from time-course data using prior selection of genes differentially expressed over time identified by natural cubic spline regression modeling (NCSRM). The workflow comprises three major steps: 1) the identification of differentially expressed genes from time course expression data by employing NCSRM, 2) the use of regularized dynamic partial correlation as implemented in GeneNet to infer GANs from differentially expressed genes and 3) the identification and functional characterization of the key nodes in the reconstructed networks. The approach was applied on a time resolved transcriptome data set of radiation-perturbed cell culture models of non tumor cells with normal and increased radiation sensitivity. NCSRM detected significantly more genes than another commonly used method for time-course transcriptome analysis (BETR). While most genes detected with BETR were also detected with NCSRM the false-detection rate of NCSRM was low (3%). The GANs reconstructed from genes detected with NCSRM showed a better overlap with the interactome network Reactome compared to GANs derived from BETR detected genes. After exposure to 1 Gy the normal sensitive cells showed only sparse response compared to cells with increased sensitivity, which exhibited a strong response mainly of genes related to the senescence pathway. After exposure to 10 Gy the response of the normal sensitive cells was mainly associated with senescence and that of cells with increased sensitivity with apoptosis. We discuss these results in a clinical context and underline the impact of senescence-associated pathways in acute radiation response of normal cells. The workflow of this novel approach is implemented in the open-source Bioconductor R-package splineTimeR. PMID- 27505170 TI - High-Efficiency Microiterative Optimization in QM/MM Simulations of Large Flexible Systems. AB - We present here a double-optimizations-of-buffer-region (DOBR) microiterative scheme for high-efficiency energy minimizations of large, flexible systems in combined quantum-mechanical/molecular-mechanical (QM/MM) calculations. In the DOBR scheme, an entire system is divided into three regions: the core, buffer, and outer regions. The core region includes QM atoms and the MM atoms within a cutoff distance R1 to the QM atoms (denoted by MM1 atoms), and the buffer region consists of MM atoms within another cutoff distance R2 to MM1 atoms. Each DOBR microcycle involves two steps: First, QM atoms are assigned electrostatic potential (ESP) charges, and the buffer and outer regions are optimized at the MM level with the core region kept frozen. Second, the core and buffer regions are optimized at the QM/MM level using the electrostatic embedding with the outer region kept frozen. The two steps are repeated until two optimizations converge at one structure. The DOBR scheme was tested in the optimizations of nucleobases solvated in water spheres of 30 A radius, where the initial geometries were extracted from the trajectories of classical molecular dynamics simulations, and the cutoff distances R1 and R2 were set to 5.0 and 4.0 A, respectively. For comparisons, the optimizations were also carried out by a "standard" scheme without microiteration and by the two-region microiterative (TRM) method. We found that the averaged number of QM calculations for the DOBR scheme is only ~1% of that of the standard scheme and ~6% of the TRM approach. The promising results indicate that the DOBR scheme could significantly increase the efficiency of geometry optimizations for large, flexible systems in QM/MM calculations. PMID- 27505169 TI - Dendritic Cells from HIV Controllers Have Low Susceptibility to HIV-1 Infection In Vitro but High Capacity to Capture HIV-1 Particles. AB - HIV controllers (HICs), rare HIV-1 infected individuals able to control viral replication without antiretroviral therapy, are characterized by an efficient polyfunctional and cytolytic HIV-specific CD8+ T cell response. The mechanisms underlying the induction and maintenance of such response in many HICs despite controlled viremia are not clear. Dendritic cells play a crucial role in the generation and reactivation of T cell responses but scarce information is available on those cells in HICs. We found that monocyte derived dendritic cells (MDDCs) from HICs are less permissive to HIV-1 infection than cells from healthy donors. In contrast MDDCs from HICs are particularly efficient at capturing HIV-1 particles when compared to cells from healthy donors or HIV-1 patients with suppressed viral load on antiretroviral treatment. MDDCs from HICs expressed on their surface high levels of syndecan-3, DC-SIGN and MMR, which could cooperate to facilitate HIV-1 capture. The combination of low susceptibility to HIV-1 infection but enhanced capacity to capture particles might allow MDDCs from HICs to preserve their function from the deleterious effect of infection while facilitating induction of HIV-specific CD8+ T cells by cross-presentation in a context of low viremia. PMID- 27505171 TI - Accumulation of Advanced Glycation End Products Involved in Inflammation and Contributing to Severe Preeclampsia, in Maternal Blood, Umbilical Blood and Placental Tissues. AB - OBJECTIVE: To investigate the expression of advanced glycation end products (AGEs) and the receptor for AGE (RAGEs) in maternal blood, umbilical blood and placental tissues in women with severe preeclampsia (sPE) as well as any association with inflammatory processes. METHODS: The expressions of AGEs, RAGE, tumor necrosis factor-alpha (TNF)-alpha and vascular cell adhesion molecule-1 (VCAM)-1 in placental tissues were measured using immunohistochemistry. The levels of AGEs, RAGE, TNF-alpha and VCAM-1 in maternal blood, umbilical blood and placental extracts were assessed using enzyme-linked immunosorbent assays. Placental RAGE, TNF-alpha and VCAM-1 mRNA expression levels were determined by PCR. Placental AGEs, RAGE, TNF-alpha and VCAM-1 protein levels were determined by western blotting. RESULTS: The levels of AGEs, TNF-alpha and VCAM-1 in the maternal tissues and umbilical blood were significantly higher in the sPE group than in the normal pregnancy (NP) controls (p < 0.05). The serum level of sRAGE in the umbilical blood was lower in the sPE group than in the NP controls (p < 0.05), while sRAGE was higher in the maternal blood of sPE than in the NP (p < 0.05). The maternal serum levels of AGEs were positively correlated with that of TNF-alpha and VCAM-1 in the maternal blood. There were no correlations between the levels of RAGE, TNF-alpha or VCAM-1 in maternal blood or umbilical serum. There were no correlations between the levels of sRAGE and TNF-alpha or VCAM-1 in maternal blood or umbilical serum. The levels of AGEs were positively correlated with those of TNF-alpha and VCAM-1 in placental lysates. CONCLUSION: AGEs and RAGE appear to act as important mediators in regulating the inflammatory pathways of preeclampsia. PMID- 27505172 TI - On the Apportionment of Population Structure. AB - Measures of population differentiation, such as FST, are traditionally derived from the partition of diversity within and between populations. However, the emergence of population clusters from multilocus analysis is a function of genetic structure (departures from panmixia) rather than of diversity. If the populations are close to panmixia, slight differences between the mean pairwise distance within and between populations (low FST) can manifest as strong separation between the populations, thus population clusters are often evident even when the vast majority of diversity is partitioned within populations rather than between them. For any given FST value, clusters can be tighter (more panmictic) or looser (more stratified), and in this respect higher FST does not always imply stronger differentiation. In this study we propose a measure for the partition of structure, denoted EST, which is more consistent with results from clustering schemes. Crucially, our measure is based on a statistic of the data that is a good measure of internal structure, mimicking the information extracted by unsupervised clustering or dimensionality reduction schemes. To assess the utility of our metric, we ranked various human (HGDP) population pairs based on FST and EST and found substantial differences in ranking order. EST ranking seems more consistent with population clustering and classification and possibly with geographic distance between populations. Thus, EST may at times outperform FST in identifying evolutionary significant differentiation. PMID- 27505174 TI - Design, Characterization, and Use of a Novel Amyloid beta-Protein Control for Assembly, Neurotoxicity, and Gene Expression Studies. AB - A key pathogenic agent in Alzheimer's disease (AD) is the amyloid beta-protein (Abeta), which self-assembles into a variety of neurotoxic structures. Establishing structure-activity relationships for these assemblies, which is critical for proper therapeutic target identification and design, requires aggregation and neurotoxicity experiments that are properly controlled with respect to the Abeta peptide itself. "Reverse" Abeta or non-Abeta peptides suffer from the fact that their biophysical properties are too similar or dissimilar, respectively, to those of native Abeta for them to be appropriate controls. For this reason, we used simple protein design principles to create scrambled Abeta peptides predicted to behave distinctly from native Abeta. We showed that our prediction was true by monitoring secondary structure dynamics with thioflavin T fluorescence and circular dichroism spectroscopy, determining oligomer size distributions, and assaying neurotoxic activity. We then demonstrated the utility of the scrambled Abeta peptides by using them to control experiments examining the effects of Abeta monomers, dimers, higher-order oligomers, and fibrils on gene expression in primary rat hippocampal neurons. Significant changes in gene expression were observed for all peptide assemblies, but fibrils induced the largest changes. Weighted gene co-expression network analysis revealed two predominant gene modules related to Abeta treatment. Many genes within these modules were associated with inflammatory signaling pathways. PMID- 27505175 TI - Depth-Profiling Electronic and Structural Properties of Cu(In,Ga)(S,Se)2 Thin Film Solar Cell. AB - Utilizing a scanning photoelectron microscope (SPEM) and grazing-incidence X-ray powder diffraction (GIXRD), we studied the electronic band structure and the crystalline properties of the pentanary Cu(In,Ga)(S,Se)2 (CIGSSe) thin-film solar cell as a function of sample depth on measuring the thickness-gradient sample. A novel approach is proposed for studying the depth-dependent information on thin films, which can provide a gradient thickness and a wide cross-section of the sample by polishing process. The results exhibit that the CIGSSe absorber layer possesses four distinct stoichiometries. The growth mechanism of this distinctive compositional distribution formed by a two-stage process is described according to the thermodynamic reaction and the manufacturing process. On the basis of the depth-profiling results, the gradient profiles of the conduction and valence bands were constructed to elucidate the performance of the electrical properties (in this case, Voc = 620 mV, Jsc = 34.6 mA/cm(2), and eta = 14.04%); the valence band maxima (VBM) measured with a SPEM in the spectroscopic mode coincide with this band-structure model, except for a lowering of the VBM observed in the surface region of the absorber layer due to the ordered defect compound (ODC). In addition, the depth-dependent texturing X-ray diffraction pattern presents the crystalline quality and the residual stress for each depth of a thin-film device. We find that the randomly oriented grains in the bottom region of the absorber layer and the different residual stress between the underlying Mo and the absorber interface, which can deteriorate the electrical performance due to peeling-off effect. An anion interstitial defect can be observed on comparing the anion concentration of the elemental distribution with crystalline composition; a few excess sulfur atoms insert in interstitial sites at the front side of the absorber layer, whereas the interstitial selenium atoms insert at the back side. PMID- 27505176 TI - Comparison of Holmium: YAG Laser and Pneumatic Lithotripsy in the Treatment of Ureteral Stones: An Update Meta-Analysis. AB - PURPOSE: Holmium YAG laser lithotripsy (LL) and pneumatic lithotripsy (PL) are the most commonly used procedures in the treatment of ureteral calculi. In a previous meta-analysis examining the treatment effect of the 2 modalities, the authors highlighted the need for large sample size and high quality trials to provide more uncovered outcome. Recently, several randomized controlled trials (RCTs) evaluating the same issue with larger patient number and more complicated data have been published. Therefore, we conducted this meta-analysis to update and synthesize evidence on the efficacy and safety of the 2 procedures in the treatment of ureteral calculi. METHODS: The relevant studies were identified by searching Medline, EMBASE and Cochrane Library Database from January 1990 to November 2015. RCTs assessing the efficacy and safety of Holmium YAG laser and PL for ureteral stones were included. Two reviewers independently screened studies and extracted data. RESULTS: A total of 8 studies were identified including 1,555 patients. Compared with PL, Holmium YAG LL significantly reduced the mean operative time (weighted mean difference = -11.52, 95% CI -17.06 to -5.99, p < 0.0001) and increased the early stone-free rate (OR 2.69, 95% CI 1.91-3.78, p < 0.00001) and the delayed stone-free rate (OR 2.12, 95% CI 1.40-3.21, p = 0.0004). However, a higher postoperative ureteral stricture rate (OR 3.38, 95% CI 1.56 7.31, p = 0.002) was observed in LL group over PL group. There was no statistical significance in the ureteral perforation rate (OR 1.19, 95% CI 0.65-2.16, p = 0.58), the stone migration rate (OR 0.64, 95% CI 0.41-1.00, p = 0.05), the postoperative gross hematuria rate (OR 0.71, 95% CI 0.40-1.25, p = 0.23) and the postoperative fever rate (OR 0.73, 95% CI 0.50-1.09, p = 0.12). CONCLUSIONS: Our data reconfirmed that Holmium LL for ureteral stones can achieve shorter mean operative time, better early and delayed stone-free rate with larger sample size and more high quality studies. And further trials are unlikely to considerably alter this conclusion. In terms of higher risk of postoperative ureteral stricture in LL group over PL group observed in our review, more high quality, multicenter RCTs with long-term follow-up outcome are warranted to better assess this issue. PMID- 27505177 TI - Spotlights on our sister journals: Chem. Eur. J. 34/2016. PMID- 27505173 TI - Transcriptional Profiling of Cultured, Embryonic Epicardial Cells Identifies Novel Genes and Signaling Pathways Regulated by TGFbetaR3 In Vitro. AB - The epicardium plays an important role in coronary vessel formation and Tgfbr3-/- mice exhibit failed coronary vessel development associated with decreased epicardial cell invasion. Immortalized Tgfbr3-/- epicardial cells display the same defects. Tgfbr3+/+ and Tgfbr3-/- cells incubated for 72 hours with VEH or ligands known to promote invasion via TGFbetaR3 (TGFbeta1, TGFbeta2, BMP2), for 72 hours were harvested for RNA-seq analysis. We selected for genes >2-fold differentially expressed between Tgfbr3+/+ and Tgfbr3-/- cells when incubated with VEH (604), TGFbeta1 (515), TGFbeta2 (553), or BMP2 (632). Gene Ontology (GO) analysis of these genes identified dysregulated biological processes consistent with the defects observed in Tgfbr3-/- cells, including those associated with extracellular matrix interaction. GO and Gene Regulatory Network (GRN) analysis identified distinct expression profiles between TGFbeta1-TGFbeta2 and VEH-BMP2 incubated cells, consistent with the differential response of epicardial cells to these ligands in vitro. Despite the differences observed between Tgfbr3+/+ and Tgfbr3-/- cells after TGFbeta and BMP ligand addition, GRNs constructed from these gene lists identified NF-KB as a key nodal point for all ligands examined. Tgfbr3-/- cells exhibited decreased expression of genes known to be activated by NF-KB signaling. NF-KB activity was stimulated in Tgfbr3+/+ epicardial cells after TGFbeta2 or BMP2 incubation, while Tgfbr3-/- cells failed to activate NF-KB in response to these ligands. Tgfbr3+/+ epicardial cells incubated with an inhibitor of NF-KB signaling no longer invaded into a collagen gel in response to TGFbeta2 or BMP2. These data suggest that NF-KB signaling is dysregulated in Tgfbr3-/- epicardial cells and that NF-KB signaling is required for epicardial cell invasion in vitro. Our approach successfully identified a signaling pathway important in epicardial cell behavior downstream of TGFbetaR3. Overall, the genes and signaling pathways identified through our analysis yield the first comprehensive list of candidate genes whose expression is dependent on TGFbetaR3 signaling. PMID- 27505178 TI - Initiation time of renal replacement therapy on patients with acute kidney injury: A systematic review and meta-analysis of 8179 participants. AB - The early initiation of renal replacement therapy has been recommended for patients with acute renal failure by some studies, but its effects on mortality and renal recovery are unknown. We conducted an updated meta-analysis to provide quantitative evaluations of the association between the early initiation of renal replacement therapy and mortality for patients with acute kidney injury. After applying inclusion/exclusion criteria, 51 studies, including 10 randomized controlled trials, with a total of 8179 patients were analyzed. Analysis of the included trials showed that patients receiving early renal replacement therapy had a 25% reduction in all-cause mortality compared to those receiving late renal replacement therapy (risk ratio [RR] 0.75, 95% CI [0.69, 0.82]). We also noted a 30% increase in renal recovery (RR 1.30, 95% CI [1.07, 1.56]), a reduction in hospitalization of 5.84 days (mean difference [MD], 95% CI [-10.27, -1.41]) and a reduction in the duration of mechanical ventilation of 2.33 days (MD, 95% CI [ 3.40, -1.26]) in patients assigned to early renal replacement therapy. The early initiation of renal replacement therapy was associated with a decreased risk of all-cause mortality compared with the late initiation of RRT in patients with acute kidney injury. These findings should be interpreted with caution given the heterogeneity between studies. Further studies are needed to identify the causes of mortality and to assess whether mortality differs by dialysis dose. PMID- 27505179 TI - [Access to medicines for Alzheimer's disease provided by the Brazilian Unified National Health System in Minas Gerais State, Brazil]. AB - This study evaluated barriers to access to treatment for Alzheimer's disease based on administrative cases involving cholinesterase inhibitors (ChEIs) and submitted to the Minas Gerais State Health Secretariat in Brazil in 2012 and 2013. Drawing on data from 165 randomly selected cases, the study addressed the following dimensions of access: geographic accessibility, accommodation, acceptability, availability, and affordability. The administrative processing to supply ChEIs took an average of 39 days and was influenced by characteristics of the path taken by the user. The majority of the prescribers met less than 80% of the required criteria in the Clinical Protocol and Therapeutic Guidelines (CPTG) for Alzheimer's disease. As a result, 38% of requests for medication were denied. Private treatment with ChEIs cost the equivalent of 21 days of the monthly minimum wage. In conclusion, bureaucratic administrative procedures and prescribers' difficulty in following the CPTG hindered access to treatment of Alzheimer's disease and imposed a heavy burden on patients' pockets. PMID- 27505180 TI - Microchemical Pen: An Open Microreactor for Region-Selective Surface Modification. AB - Various micro surface-modification approaches including photolithography, dip-pen lithography and ink-jet systems have been developed and used to extend the functionalities of solid surfaces. While those approaches work in the "open space", push-pull systems which work in solutions have recently drawn considerable attention. However, the confining flows performed by push-pull systems have realized only the dispense process, while microscale, region selective chemical reactions have remained unattainable. This study reports a microchemical pen that enables region-selective chemical reactions for the micro surface modification/patterning. The chemical pen is based on the principle of microfluidic laminar flows and the resulting mixing of reagents by the mutual diffusion. The tiny diffusion layer performs as the working region. This report represents the first demonstration of an open microreactor in which two different reagents react on a real solid sample. The multifunctional characteristics of the microchemical pen are confirmed by different types of reactions in many research areas, including inorganic chemistry, polymer science, electrochemistry and biological sample treatment. PMID- 27505182 TI - Rescue of Premature Coronal Suture Fusion with TGF-beta2 Neutralizing Antibody in Rabbits with Delayed-Onset Synostosis. AB - OBJECTIVES: An overexpression of Tgf-beta2 leads to calvarial hyperostosis and suture fusion in individuals with craniosynostosis. Inhibition of Tgf-beta2 may help rescue fusing sutures and restore normal growth. The present study was designed to test this hypothesis. DESIGN: Twenty-eight New Zealand White rabbits with delayed-onset coronal synostosis had radiopaque markers placed on either side of the coronal sutures at 10 days of age. The rabbits were randomly assigned to: (1) sham control rabbits (n = 10), (2) rabbits with control IgG (100 MUg/suture) delivered in a collagen vehicle (n = 9), and (3) rabbits with Tgf beta2 neutralizing antibody (100 MUg/suture) delivered in a collagen vehicle (n = 9). Longitudinal growth data were collected at 10, 25, 42, and 84 days of age. Sutures were harvested at 84 days of age for histomorphometry. RESULTS: Radiographic analysis showed significantly greater ( P < .05) coronal suture marker separation, craniofacial length, cranial vault length, height, shape indices, cranial base length, and more lordotic cranial base angles in rabbits treated with anti-Tgf-beta2 antibody than in controls at 42 and 84 days of age. Histologically, rabbits treated with anti-Tgf-beta2 antibody at 84 days of age had patent and significantly ( P < .05) wider coronal sutures and greater sutural area compared to controls. CONCLUSIONS: These data support our hypothesis that antagonism of Tgf-beta2 may rescue fusing coronal sutures and facilitate craniofacial growth in this rabbit model. These findings also suggest that cytokine therapy may have clinical significance in infants with progressive postgestational craniosynostosis. PMID- 27505181 TI - Hypertelorism and Orofacial Clefting Revisited: An Anthropometric Investigation. AB - OBJECTIVE: Since the 1960s, multiple studies have reported a tendency toward hypertelorism in individuals with nonsyndromic orofacial clefts (OFCs). However, the association between specific cleft types and increased interorbital distance has been inconsistent. Using three-dimensional (3D) surface imaging, we tested whether different forms of clefting showed evidence of increased interorbital distance. METHODS: Intercanthal and outercanthal distances and intercanthal indices were calculated from 3D facial surface images of 287 individuals with repaired OFCs. Raw measurements were converted to sex and age-normalized Z scores. Mean Z-scores for individuals with cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) were compared with reference normative values (controls) and one another directly using t tests and analysis of variance. RESULTS: The CLP group showed a significant increase in intercanthal width (P = .001) and intercanthal index (P < .001) compared with reference norms. The CP group showed a significant decrease (P < .001) in outercanthal width. The CL group showed no difference from reference norms. The proportion of clinically hyperteloric individuals was generally low but highest in the CLP group (7.4%). Cleft severity had little effect on interorbital spacing. CONCLUSIONS: Individuals with CLP exhibited on average a tendency toward mild hypertelorism, driven primarily by an increase in intercanthal distance. This tendency was not seen in CL or CP. PMID- 27505183 TI - A virtually 1H-free birdcage coil for zero echo time MRI without background signal. AB - PURPOSE: MRI of tissues with rapid transverse relaxation can be performed efficiently using the zero echo time (ZTE) technique. At high bandwidths leading to large relative initial radiofrequency (RF) dead times, the method becomes increasingly sensitive to artifacts related to signal stemming from outside the field of view, particularly from the RF coils. Therefore, in this work, a birdcage coil was designed that is virtually free of 1H signal. METHODS: A transmit-receive birdcage RF coil for MRI of joints at 7T was designed by rigorously avoiding materials containing 1H nuclei, by using purely mechanical connections without glue, and by spoiling of unwanted signal by application of ferromagnetic materials. The coil was tested for residual 1H signal using ZTE phantom and in vivo joint imaging. RESULTS: In standard ZTE imaging, no 1H signal was detected above noise level. Only at extreme averaging, residual signal was observed close to conductors associated with 1H-containing molecules at adjacent glass surfaces. Phantom images with dead times up to 3.8 Nyquist dwells were obtained with only negligible background artifacts. Furthermore, high-quality ZTE images of human joints were acquired. CONCLUSION: A virtually 1H-free birdcage coil is presented, thus enabling in vivo ZTE MRI practically free of background signal, even at high bandwidths. Magn Reson Med 78:399-407, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27505184 TI - Indeterminate but Likely Unimportant Extracolonic Findings at Screening CT Colonography (C-RADS Category E3): Incidence and Outcomes Data From a Clinical Screening Program. AB - OBJECTIVE: The purpose of this study was to analyze the incidence and outcomes of unsuspected indeterminate but likely unimportant extracolonic findings (CT Colonography Reporting and Data System [C-RADS] category E3) at screening CT colonography (CTC). MATERIALS AND METHODS: Over 99 months (April 2004 through June 2012), 7952 consecutive adults without symptoms of colorectal cancer (4277 women, 3675 men; mean age +/- SD, 56.7 +/- 7.3 years) underwent first-time screening CTC. Findings prospectively placed into C-RADS category E3 were retrospectively reviewed, including follow-up (range, 2-10 years) and ultimate clinical outcome. RESULTS: Unsuspected C-RADS category E3 extracolonic findings were detected in 9.1% (725/7952) of our patient population. A total of 751 category E3 findings were detected among these 725 patients; 25 patients had multiple findings. Commonly involved organ systems included gynecologic (24.4%, 183/751), genitourinary (20.9%, 157/751), lung (20.6%, 155/751), and gastrointestinal (16.1%, 121/751). Consideration for further imaging, if clinically warranted, was suggested in 83.8% (608/725). Sixty-five patients were lost to follow-up. Conditions requiring treatment or surveillance were ultimately diagnosed in 8.3% (55/660), including eight malignant neoplasms. In the remaining 605 patients, 25 (4.1%) underwent invasive biopsy or surgery to prove benignity (including 18 complex adnexal masses), and 278 (46.0%) received additional imaging follow-up. CONCLUSION: Indeterminate but likely unimportant extracolonic findings (C-RADS category E3) occurred in less than 10% of adults without symptoms of colorectal cancer who underwent screening CTC. Over 90% of these findings ultimately proved to be clinically insignificant, with fewer than 5% requiring an invasive procedure to prove benign disease, the majority of which (> 70%) were complex adnexal lesions in women. PMID- 27505185 TI - Endothelial Nitric Oxide Synthase Prevents Heparanase Induction and the Development of Proteinuria. AB - Endothelial nitric oxide synthase (eNOS) deficiency exacerbates proteinuria and renal injury in several glomerular diseases, but the underlying mechanism is not fully understood. We recently showed that heparanase is essential for the development of experimental diabetic nephropathy and glomerulonephritis, and hypothesize that heparanase expression is regulated by eNOS. Here, we demonstrate that induction of adriamycin nephropathy (AN) in C57BL/6 eNOS-deficient mice leads to an increased glomerular heparanase expression accompanied with overt proteinuria, which was not observed in the AN-resistant wild type counterpart. In vitro, the eNOS inhibitor asymmetric dimethylarginine (ADMA) induced heparanase expression in cultured mouse glomerular endothelial cells. Moreover, ADMA enhanced transendothelial albumin passage in a heparanase-dependent manner. We conclude that eNOS prevents heparanase induction and the development of proteinuria. PMID- 27505186 TI - Associations between Mental Health and Ebola-Related Health Behaviors: A Regionally Representative Cross-sectional Survey in Post-conflict Sierra Leone. AB - BACKGROUND: Little attention has been paid to potential relationships between mental health, trauma, and personal exposures to Ebola virus disease (EVD) and health behaviors in post-conflict West Africa. We tested a conceptual model linking mental health and trauma to EVD risk behaviors and EVD prevention behaviors. METHODS AND FINDINGS: Using survey data from a representative sample in the Western Urban and Western Rural districts of Sierra Leone, this study examines associations between war exposures, post-traumatic stress disorder (PTSD) symptoms, depression, anxiety, and personal EVD exposure (e.g., having family members or friends diagnosed with EVD) and EVD-related health behaviors among 1,008 adults (98% response rate) from 63 census enumeration areas of the Western Rural and Western Urban districts randomly sampled at the height of the EVD epidemic (January-April 2015). Primary outcomes were EVD risk behaviors (14 items, Cronbach's alpha = 0.84) and EVD prevention behaviors (16 items, Cronbach's alpha = 0.88). Main predictors comprised war exposures (8 items, Cronbach's alpha = 0.85), anxiety (10 items, Cronbach's alpha = 0.93), depression (15 items, Cronbach's alpha = 0.91), and PTSD symptoms (16 items, Cronbach's alpha = 0.93). Data were analyzed using two-level, population-weighted hierarchical linear models with 20 multiply imputed datasets. EVD risk behaviors were associated with intensity of depression symptoms (b = 0.05; 95% CI 0.00, 0.10; p = 0.037), PTSD symptoms (b = 0.10; 95% CI 0.03, 0.17; p = 0.008), having a friend diagnosed with EVD (b = -0.04; 95% CI -0.08, -0.00; p = 0.036), and war exposures (b = -0.09; 95% CI -0.17, -0.02; p = 0.013). EVD prevention behaviors were associated with higher anxiety (b = 0.23; 95% CI 0.06, 0.40; p = 0.008), having a friend diagnosed with EVD (b = 0.15; 95% CI 0.04, 0.27; p = 0.011), and higher levels of war exposure (b = 0.45; 95% CI 0.16, 0.74; p = 0.003), independent of mental health. PTSD symptoms were associated with lower levels of EVD prevention behavior (b = -0.24; 95% CI -0.43, -0.06; p = 0.009). CONCLUSIONS: In post-conflict settings, past war trauma and mental health problems are associated with health behaviors related to combatting EVD. The associations between war trauma and both EVD risk behaviors and EVD prevention behaviors may be mediated through two key mental health variables: depression and PTSD symptoms. Considering the role of mental health in the prevention of disease transmission may help fight continuing and future Ebola outbreaks in post conflict Sierra Leone. This sample is specific to Freetown and the Western Area and may not be representative of all of Sierra Leone. In addition, our main outcomes as well as personal EVD exposure, war exposures, and mental health predictors rely on self-report, and therefore raise the possibility of common methods bias. However, the findings of this study may be relevant for understanding dynamics related to EVD and mental health in other major capital cities in the EVD-affected countries of West Africa. PMID- 27505187 TI - Affective instability as a clinical feature of avoidant personality disorder. AB - The current study's main goal was to examine whether affective instability is elevated among individuals suffering from avoidant personality disorder (APD) by comparing it to the affective instability found among individuals suffering from borderline personality disorder (BPD) as well that found among healthy controls. Adults (N = 152, aged 18-65 years) with BPD, APD, or no psychopathology participated in a 3-week computerized diary study. We examined temporal instability in negative affect using experience-sampling methods. Both within and between days, individuals with APD showed greater affective instability compared to the healthy control individuals, although less affective instability compared to individuals with BPD. The findings are in line with affective instability (or emotional lability) as a key dimension relevant across personality disorders. Additionally, they emphasize the need for research and clinical attention to affective characteristics (alongside the more readily recognized interpersonal characteristics) of APD. (PsycINFO Database Record PMID- 27505188 TI - Ecological momentary assessment of nonsuicidal self-injury in youth with borderline personality disorder. AB - Nonsuicidal self-injury (NSSI) is highly prevalent among individuals with borderline personality disorder (BPD). The aim of this study was to investigate the cognitive, emotional, and contextual experience of NSSI in 107 youth (aged 15 25 years) with BPD who had minimal prior exposure to treatment. Using ecological momentary assessment, participants completed a randomly prompted questionnaire about their affect, self-injurious thoughts, and behaviors six times per day for 6 days. Twenty-four youth with BPD engaged in 52 counts of NSSI, with 56 motives identified. Open-ended questions revealed that on occasions of NSSI, a large minority of participants could identify neither their motives (27%, n = 15) nor the environmental precipitants (46%, n = 24) for NSSI. Changes in affect revealed a pattern of increasing negative and decreasing positive affect prior to NSSI, with a reduction in negative and an increase in positive affect following NSSI. These changes were absent for those who did not engage in NSSI. Initial self injurious thoughts and changes in negative and positive affect occurred a median of 35, 15, and 10 hr prior to NSSI, respectively. These findings suggest that youth with BPD have limited capacity to reflect on their motives and environment preceding NSSI. The patterns of affect change indicate that NSSI is maintained by reward incentives as well as negative reinforcement. The time between initial self-injurious thoughts and engagement in NSSI reveals a window of opportunity for intervention. (PsycINFO Database Record PMID- 27505189 TI - Loneliness, social networks, and social functioning in borderline personality disorder. AB - Persistent loneliness is often reported by patients with borderline personality disorder (BPD). However, empirical studies investigating this aspect of BPD psychopathology are sparse. Studies from social psychology revealed that social isolation and low social functioning contribute to loneliness, that is, the subjective feeling of being alone. The aim of the present study was to contribute to the understanding of loneliness in BPD by investigating its relation to social isolation and functioning in different domains of life. Subjective experience of loneliness was measured in 80 women (40 BPD patients, 40 healthy controls) with the UCLA Loneliness Scale. Social isolation and social functioning were assessed with the Social Network Inventory and the Social Functioning Scale. In addition, we assessed global functioning with the Global Assessment of Functioning. BPD patients reported stronger feelings of loneliness compared to healthy participants. In general, the level of loneliness was linked to network size, social engagement, and prosocial behavior. Diversity of social networks and functioning in the domain of interpersonal communication were associated with the level of loneliness only in BPD. A reduced variety of roles in social life together with impairments in interpersonal communication were particularly relevant for the experience of loneliness in BPD, suggesting an indirect path to target this psychopathological feature in therapeutic interventions. However, both social isolation and social functioning were not sufficient to explain the severely increased loneliness experienced by these patients, stressing the need for further investigation of determinants of loneliness in this clinical population. (PsycINFO Database Record PMID- 27505190 TI - Insight and the Dark Triad: Comparing self- and meta-perceptions in relation to psychopathy, narcissism, and Machiavellianism. AB - The "Dark Triad" consists of 3 partially overlapping trait configurations that manifest in problematic interpersonal outcomes: narcissism, psychopathy, and Machiavellianism. Comparing meta-perception-based reports of personality, or how people believe others see them, to self-reports in relation to informant-reports allows for a direct test of the extent to which people are accurate in understanding how they are perceived by others. The present study (n = 993 target participants) investigated how Dark Triad personality styles are viewed from multiple perspectives, including self-report, meta-perception, informant-report (n = 213), and informant perceived meta-perception (n = 178) in an undergraduate sample. Absolute level differences were investigated; self-report ratings were associated with significantly more Machiavellianism and less narcissism than both informant-reports and meta-perceptions. The relative convergence between meta perceptions and informant-reports was moderate, and similar to the convergence between self-reports and informant-reports. Multiple regression analyses in which self-reports and meta-perceptions predicted informant-reports identified several significant differences, with meta-perceptions more frequently emerging as a stronger predictor of informant-reports. These findings suggest that while self reports and meta-perceptions are closely related, the latter perspective provides some incremental validity with regard to the constructs that comprise the Dark Triad. (PsycINFO Database Record PMID- 27505191 TI - Changing perceptions and efficacy of generic medicines: An intervention study. AB - OBJECTIVE: Generic medicines provide a safe and economical medical treatment and are used routinely throughout the world. However, a significant proportion of individuals view generic medicines as less safe, less effective and of lower quality compared with their equivalent branded medicines. This study aimed to investigate the effect of an educational intervention on improving perceptions and perceived efficacy of generic medicines. METHOD: Seventy participants who experienced frequent tension headaches were randomized to receive an educational video about generic medicines or a control video. Participants then alternatively took branded and generic ibuprofen to treat their next two consecutive headaches. Changes in perceptions of generic medicines, pain relief and side effects were measured. RESULTS: The intervention was effective in modifying and improving perceptions of generic medicines in the areas of understanding (p < .05), preference for a generic medicine to treat a serious illness (p < .05), and overall preference for generic medicines (p < .01). However, contrary to predictions, participants in the intervention group reported significantly less pain relief (p = .03) and more symptoms (p = .04) after taking generic ibuprofen compared with branded ibuprofen. CONCLUSION: This study identified that an educational intervention is effective in modifying and improving perceptions of generic medicines but produced paradoxical effects on drug efficacy and side effects. These findings suggest that complex mechanisms are involved in the relationship between perceptions and drug efficacy and contradict the assumption that improving attitudes toward generic medicines will have a flow-on effect to improving health outcomes. (PsycINFO Database Record PMID- 27505192 TI - Environmental and psychosocial correlates of objectively measured physical activity among older adults. AB - OBJECTIVE: Neighborhood environments can support or hinder physical activity especially as health declines with age. This study puts psychological theories of health behavior change in context with built environment research to better understand the interplay of environmental and psychosocial characteristics impacting older adults' sedentary behavior and physical activity. METHOD: The Active Streets, Active People study recruited 193 older adults living in a highly walkable neighborhood in Vancouver, British Columbia, Canada. Participants completed questionnaires on attitudes toward walking, behavioral control for walking, and perceived built environment variables. To assess behavior, participants wore an ActiGraph GT3X + accelerometer for 7 consecutive days. Regression-based path analysis was conducted to examine whether the link between the perceived environment and behavior is mediated by psychosocial variables. RESULTS: In total, 174 participants had valid accelerometry data (Mage = 70.3, SD = 7.2) and demonstrated a daily average of 525.7 min of sedentary behavior (SD = 65.1) as well as high levels of total physical activity (M = 254.3, SD = 65.1 min/day). Mediation analysis revealed that perceived street connectivity and diversity of land use were negatively related to sedentary behavior, but only indirectly through behavioral control. Similarly, effects of street connectivity and diversity of land use on physical activity were mediated by behavioral control. CONCLUSIONS: Results highlighted that the perceived built environment is important for physical activity and sedentary behavior, largely because these environmental perceptions are positively linked to older adults' confidence in walking. By integrating environmental and psychosocial correlates of preventive health behaviors within a theoretical structure, the psychosocial mechanisms through which the environment affects activity can be better understood. (PsycINFO Database Record PMID- 27505193 TI - Viral challenge reveals further evidence of skin-deep resilience in African Americans from disadvantaged backgrounds. AB - OBJECTIVE: Studies have revealed a phenomenon called skin-deep resilience, which develops in upwardly mobile African American youth. They perform well in school, maintain good mental health, and avoid legal problems. Despite outward indications of success, they also show evidence of worse health in biomarker studies. Here we extend this research, asking whether it manifests in differential susceptibility to upper respiratory infection, and if it emerges in European Americans as well. METHODS: The sample included 514 adults in good health, as judged by physician examination and laboratory testing. Participants completed questionnaires about lifecourse socioeconomic conditions, conscientiousness, psychosocial adjustment, and lifestyle factors. They were subsequently inoculated with a rhinovirus that causes upper respiratory infection, and monitored in quarantine for 5 days the development of illness. RESULTS: Consistent with past work, African Americans from disadvantaged backgrounds displayed indications of skin-deep resilience. To the extent these participants were high in conscientiousness, they fared better across multiple domains of psychosocial functioning, as reflected in educational attainment, symptoms of depression, and close relationship quality (p values = .01-.04). But analyses of these participants' susceptibility to infection revealed the opposite pattern; higher conscientiousness was associated with a greater likelihood of becoming ill following inoculation (p value = .03). In European Americans, there was no evidence of skin-deep resilience; conscientiousness was associated with better psychosocial outcomes, but not infection risk. CONCLUSIONS: These observations suggest that resilience may be a double-edged sword for African Americans from disadvantaged backgrounds. The same characteristics associated with academic success and psychological adjustment forecast increased vulnerability to health problems. (PsycINFO Database Record PMID- 27505195 TI - Implicit processes in health psychology: Diversity and promise. AB - Implicit processes refer to cognitive, affective, and motivational processes that influence health decisions and behavior without the person intending that influence. This special issue aims to increase appreciation of the diverse and promising research on implicit processes in health psychology, and to promote discussion about how this research improves understanding of health behavior change and can be harnessed to meet public health mandates. The articles included in the special issue showcase this diversity and promise, and present not only new findings, but also new theories, new measures, and state-of-the- art summaries of progress. The research demonstrates the added value of considering implicit processes for understanding health behaviors, their interactions with explicit processes and neural mechanisms, as well as the benefits of targeting implicit processes in health behavior interventions. At the same time, however, the papers in this special issue also point to potential boundary conditions, the importance of good measures and appropriate tests of implicit processes, and the challenges involved in assessing implicit processes' causal role in determining health behaviors. (PsycINFO Database Record PMID- 27505194 TI - Emotion dysregulation and loss-of-control eating in children and adolescents. AB - OBJECTIVE: To examine the associations among self-reported loss-of-control (LOC) eating, emotion dysregulation, body mass, and objective energy intake among youth. Emotion dysregulation may be 1 individual factor that promotes excess energy intake and increases in body mass among youth with LOC eating. METHOD: Children and adolescents (N = 230; 8 to 17 years) enrolled in a nonintervention study completed a structured interview to determine the presence or absence of self-reported LOC eating. Children's emotion dysregulation was assessed via parent-report with the Child Behavior Checklist. Youth also completed 2 test meals to capture "binge" and "normal" eating. Body composition was examined using air displacement plethysmography. RESULTS: After controlling for relevant covariates, youth with self-reported LOC eating had higher parent-reported emotion dysregulation than those without LOC. Parent-reported emotion dysregulation was also associated with greater observed energy intake (after accounting for body mass), as well as higher fat mass. Emotion dysregulation also moderated associations between LOC status/gender and body mass variables; among youth with self-reported LOC eating and girls, those with high parent-described emotion dysregulation (vs. low) had significantly higher fat mass and BMIz. CONCLUSIONS: Data from the current study suggest that emotion dysregulation may play a role in energy intake and obesity, particularly among youth with self reported LOC eating and girls. Additional studies are needed to identify the prospective mechanisms linking poor emotion regulation and LOC eating. These mechanisms, in turn, may inform future interventions targeting excess energy intake and obesity in pediatric samples. (PsycINFO Database Record PMID- 27505196 TI - The role of attentional bias in obesity and addiction. AB - OBJECTIVES: The purpose of this article is to critically evaluate the following claims derived from contemporary theoretical models of attentional bias (AB) for food- and drug-related stimuli: (a) AB is a characteristic feature of obesity and addiction, (b) AB predicts future behavior, (c) AB exerts a causal influence on consummatory behavior, and (d) AB reflects appetitive motivational processes. METHOD: A focused discussion of the relevant literature is presented. RESULTS: The available evidence reveals inconsistencies with the aforementioned claims. Specifically, AB is not consistently associated with individual differences in body weight or drug use, AB does not consistently predict or influence distal consummatory behavior, and AB may be influenced by both appetitive and aversive motivational processes. These insights are synthesized into a theoretical account that claims that AB for food- and drug-related stimuli arises from momentary changes in evaluations of those stimuli that can be either positive (when the incentive value of the food or drug is high), negative (when individuals have a goal to change their behavior, and those stimuli are perceived as aversive), or both (when individuals experience motivational conflict, or ambivalence). CONCLUSIONS: The proposed theoretical synthesis may account for the contributions of appetitive and aversive motivational processes involved in self-regulatory conflicts to AB, and it yields testable predictions about the conditions under which AB should predict and have a causal influence on future consummatory behavior. This has implications for the prediction and modification of unhealthy behaviors and associated disorders. (PsycINFO Database Record PMID- 27505197 TI - Using fuzzy-trace theory to understand and improve health judgments, decisions, and behaviors: A literature review. AB - OBJECTIVE: Fuzzy-trace theory is a dual-process model of memory, reasoning, judgment, and decision making that contrasts with traditional expectancy-value approaches. We review the literature applying fuzzy-trace theory to health with 3 aims: evaluating whether the theory's basic distinctions have been validated empirically in the domain of health; determining whether these distinctions are useful in assessing, explaining, and predicting health-related psychological processes; and determining whether the theory can be used to improve health judgments, decisions, or behaviors, especially compared to other approaches. METHOD: We conducted a literature review using PubMed, PsycINFO, and Web of Science to identify empirical peer-reviewed papers that applied fuzzy-trace theory, or central constructs of the theory, to investigate health judgments, decisions, or behaviors. RESULTS: Seventy nine studies (updated total is 94 studies; see Supplemental materials) were identified, over half published since 2012, spanning a wide variety of conditions and populations. Study findings supported the prediction that verbatim and gist representations are distinct constructs that can be retrieved independently using different cues. Although gist-based reasoning was usually associated with improved judgment and decision making, 4 sources of bias that can impair gist reasoning were identified. Finally, promising findings were reported from intervention studies that used fuzzy-trace theory to improve decision making and decrease unhealthy risk taking. CONCLUSIONS: Despite large gaps in the literature, most studies supported all 3 aims. By focusing on basic psychological processes that underlie judgment and decision making, fuzzy-trace theory provides insights into how individuals make decisions involving health risks and suggests innovative intervention approaches to improve health outcomes. (PsycINFO Database Record PMID- 27505198 TI - Techniques for modifying impulsive processes associated with unhealthy eating: A systematic review. AB - OBJECTIVE: This systematic review aimed to (a) identify and categorize techniques used to modify or manage impulsive processes associated with unhealthy eating behavior, (b) describe the mechanisms targeted by such techniques, and (c) summarize available evidence on the effectiveness of these techniques. METHOD: Searches of 5 bibliographic databases identified studies, published in English since 1993, that evaluated at least 1 technique to modify impulsive processes affecting eating in adults. Data were systematically extracted on study characteristics, population, study quality, intervention techniques, proposed mechanisms of action, and outcomes. Effectiveness evidence was systematically collated and described without meta-analysis. RESULTS: Ninety-two studies evaluated 17 distinct impulse management techniques. They were categorized according to whether they aimed to (a) modify the strength of impulses or (b) engage the reflective system or other resources in identifying, suppressing, or otherwise managing impulses. Although higher quality evidence is needed to draw definitive conclusions, promising changes in unhealthy food consumption and food cravings were observed for visuospatial loading, physical activity, and if-then planning, typically for up to 1-day follow-up. CONCLUSIONS: A wide range of techniques have been evaluated and some show promise for use in weight management interventions. However, larger-scale, more methodologically robust, community based studies with longer follow-up times are needed to establish whether such techniques can have a long-term impact on eating patterns. (PsycINFO Database Record PMID- 27505199 TI - Macro-level implicit HIV prejudice and the health of community residents with HIV. AB - OBJECTIVES: This study examined how community levels of implicit HIV prejudice are associated with the psychological and physical well-being of people with HIV living in those same communities. It also examined whether community motivation to control prejudice and/or explicit HIV prejudice moderates the relationship of implicit prejudice and well-being. METHOD: Participants were 206 people with HIV living in 42 different communities in New England who completed measures that assessed psychological distress, thriving, and physical well-being. Telephone surveys of 347 residents of these same communities (selected via random digit dialing) were used to assess community explicit HIV prejudice and motivation to control HIV prejudice. These community residents then completed an online measure of implicit prejudice toward people with HIV, the Implicit Association Test (IAT; Greenwald, McGhee, & Schwartz, 1998). RESULTS: Multilevel analyses showed that higher community implicit HIV prejudice was associated with greater psychological distress among residents with HIV living in that community. The physical well being of participants with HIV was negatively related to community implicit HIV prejudice in communities in which residents were unmotivated to control HIV prejudice or had high levels of explicit HIV prejudice. CONCLUSIONS: These findings indicate that implicit prejudice of residents of real-world communities may create an environment that may impair the well-being of stigmatized people. Implicit prejudice can therefore be considered an element of macro-level or structural stigma. The discussion considered the possible role of implicit HIV prejudice on a community's social capital as a pathway by which it compromises the well-being of residents with HIV. (PsycINFO Database Record PMID- 27505200 TI - Automatic attitudes and health information avoidance. AB - OBJECTIVE: Early detection of disease is often crucially important for positive health outcomes, yet people sometimes decline opportunities for early detection (e.g., opting not to screen). Although some health-information avoidance reflects a deliberative decision, we propose that information avoidance can also reflect an automatic, nondeliberative reaction. In the present research, we investigated whether people's automatic attitude toward learning health information predicted their avoidance of risk feedback. METHOD: In 3 studies, we gave adults the opportunity to learn their risk for a fictitious disease (Study 1), melanoma skin cancer (Study 2), or heart disease (Study 3), and examined whether they opted to learn their risk. The primary predictors were participants' attitudes about learning health information measured using a traditional (controlled) self-report instrument and using speeded (automatic) self-report measure. In addition, we prompted participants in Study 3 to contemplate their motives for seeking or avoiding information prior to making their decision. RESULTS: Across the 3 studies, self-reported (controlled) and implicitly measured (automatic) attitudes about learning health information independently predicted avoidance of the risk feedback, suggesting that automatic attitudes explain unique variance in the decision to avoid health information. In Study 3, prompting participants to contemplate their reasons for seeking versus avoiding health information reduced information avoidance. Surprisingly, it did so by inducing reliance on automatic, rather than controlled, attitudes. CONCLUSION: The data suggests that automatic processes play an important role in predicting health information avoidance and suggest that interventionists aiming to increase information seeking might fruitfully target automatic processes. (PsycINFO Database Record PMID- 27505201 TI - "Are we overestimating the prevalence of depression in chronic illness using questionnaires? Meta-analytic evidence in obstructive sleep apnoea": Correction to Nanthakumar et al. (2016). AB - Reports an error in "Are we overestimating the prevalence of depression in chronic illness using questionnaires? Meta-analytic evidence in obstructive sleep apnoea" by Shenooka Nanthakumar, Romola S. Bucks and Timothy C. Skinner (Health Psychology, 2016[May], Vol 35[5], 423-432). In the article, "Cognitive items" should read "Cognition items" in column 1, line 7 of Table 2. (The following abstract of the original article appeared in record 2015-49649-001.) INTRODUCTION: Depression is common in chronic illness, albeit prevalence can be highly variable. This variability may be a function of symptom overlap between depression and chronic illness. Using Obstructive Sleep Apnoea (OSA) as an exemplar, this meta-analysis explored whether the proportion of overlapping symptoms between OSA and depression, within different depression questionnaires, moderates prevalence estimates. METHODS: A systematic search identified 13 studies meeting eligibility criteria. RESULTS: Based on depression questionnaires, the prevalence of depression in OSA ranged from 8% to 68%, reflecting marked heterogeneity. Prevalence estimates based on questionnaires with greater symptom overlap between OSA and depression were higher, whereas questionnaires with a higher proportion of anhedonia symptoms were associated with lower prevalence estimates. DISCUSSION: Overall, these data suggest that when using depression questionnaires to assess the prevalence of depression in OSA, questionnaires that have a lower proportion of symptom overlap between OSA and depression, as well as a higher proportion of anhedonia symptoms, reduce the likelihood of overestimating the prevalence of depression in OSA. This study has implications for other chronic illnesses with symptom overlap with depression, for example diabetes, chronic kidney disease, or heart disease, as well as suggesting that depression questionnaires are not equally appropriate for assessing depression symptomatology in chronic illness populations. PMID- 27505202 TI - Self-reported and automatic cognitions are associated with exercise behavior in cancer survivors. AB - OBJECTIVE: Physical activity is beneficial for cancer survivors, but exercise participation is low in this population. It is therefore important to understand the psychological factors underlying exercise uptake so that more effective interventions can be developed. Social-cognitive theory constructs such as outcome expectancies predict exercise behavior, but self-report measures have several limitations. We examined the associations between implicit (automatic) cognitions and exercise behavior and self-efficacy in endometrial cancer survivors. METHOD: This was a longitudinal study to examine predictors of exercise behavior in female endometrial cancer survivors who all received an exercise intervention. Participants (N = 100, mean age of 57.0) completed questionnaires to assess self-report exercise-related measures (outcome expectancy and attitudes about and identification with exercise) and reaction time (RT) tasks to assess implicit exercise cognitions (expectancy accessibility, implicit attitudes about exercise, and implicit self-identification with exercise) at baseline and at 2, 4, and 6 months at follow-up. Exercise behavior was measured using accelerometers and self-report. Data were analyzed using linear mixed models. RESULTS: Expectancy accessibility was associated with exercise duration independent of the corresponding self-report measure. Exercise implicit attitudes and self-identification were prospectively associated with exercise self-efficacy only after adjustment for the corresponding self-report measures and baseline self-efficacy. Self-report measures were also associated with study outcomes. CONCLUSIONS: Both self-reported cognitions and implicit cognitions may be useful to identify individuals at risk of failing to exercise. Individuals so identified might be provided with a different or more intensive intervention. The data also suggest cognitive targets for intervention. (PsycINFO Database Record PMID- 27505203 TI - Implicit attitudes predict drinking onset in adolescents: Shaping by social norms. AB - OBJECTIVE: Implicit attitudes toward alcohol predict drinking among adults and adolescents. If implicit attitudes reflected associations learned through direct experience with drinking, then they would likely only predict drinking among individuals who have previously consumed alcohol. In contrast, if implicit attitudes reflected indirect experience through social messages, they might also then predict future drinking, even among individuals with no drinking experience. In this study, we tested whether implicit attitudes would predict initiation of drinking for the first time, and whether parents' and friends' norms toward alcohol would influence the development of implicit attitudes. METHOD: For this study, we followed 868 adolescents between the ages of 12 and 15 years for 3 years. Implicit attitudes were measured using the affect misattribution procedure (Payne, Cheng, Govorun, & Stewart, 2005; Payne, Govorun, & Arbuckle, 2008). Explicit intentions to drink and the frequency of drinking and binge drinking were measured at each of 3 annual waves. RESULTS: Implicit attitudes toward alcohol predicted future drinking behavior 1 year later, and effects were similar for adolescents who had previously tried alcohol and for those who had not. To understand what factors might shape implicit attitudes among participants without drinking experience, we examined the role of parental norms and friends' norms toward drinking. Parental approval of drinking predicted the development of more positive implicit attitudes, which in turn predicted later drinking. CONCLUSION: Implicit attitudes toward alcohol can develop in advance of direct experience drinking alcohol. Results have implications for the implicit processes underpinning adolescent drinking, and the processes by which implicit associations are learned. (PsycINFO Database Record PMID- 27505204 TI - Perceived controllability of condom use shifts reliance on implicit versus explicit affect. AB - OBJECTIVES: This study integrated the framework of the behavioral affective associations model with dual process theories to investigate whether feelings about condoms operate at both implicit and explicit levels to influence condom use. We then tested whether 2 factors related to the perceived controllability of condom use (perceived behavioral control and past experience losing control in the heat of the moment) moderated the reliance on implicit versus explicit affect. METHOD: Sexually active young adults (N = 54) completed measures of implicit and explicit affect surrounding condoms, perceived behavioral control, and whether they attributed their prior unprotected sex to getting lost in the heat of the moment. They then completed 30 daily reports of their sexual activity and condom use. Multiple moderation analysis using generalized estimating equation (GEE) models tested the relative influence of implicit and explicit affect on condom use at varying levels of perceived controllability. RESULTS: Both perceived behavioral control and past unprotected sex because of getting lost in the heat of the moment moderated the effects of both implicit and explicit affect on behavior, ps < .05. Only implicit affect predicted condom use among participants who had gotten lost in the heat of the moment and who had low perceived behavioral control. Only explicit affect predicted condom use among participants without a history of getting lost in the heat of the moment and who had high perceived behavioral control. CONCLUSION: Feelings about condoms predicted condom use at either an implicit or explicit level, depending on perceived controllability, suggesting this is an important moderator of whether implicit processes drive condom use. (PsycINFO Database Record PMID- 27505205 TI - Pairing images of unhealthy and healthy foods with images of negative and positive health consequences: Impact on attitudes and food choice. AB - OBJECTIVE: To examine the impact of presenting images of foods paired with images of positive and negative health consequences of their consumption on food choice and attitudes. METHOD: Participants (N = 711) were randomly allocated in a 2 * 3 factorial design (Food Type * Affective Valence) to 1 of 6 conditioning procedures that paired images of either energy-dense snack foods or fruit, with (a) images of negative health outcomes, (b) images of positive health outcomes, or (c) a no image control. The primary outcome was food choice assessed postintervention with a behavioral choice task. Secondary outcomes were implicit attitudes (assessed pre- and postintervention) and explicit attitudes (assessed postintervention). RESULTS: Presenting images of negative health outcomes led to more healthy food choices relative to control and positive image conditions, irrespective of whether they were paired with images of energy-dense snack foods or fruit. This relationship was partially mediated by changes in implicit and explicit attitudes. Images of positive health outcomes did not alter food choices. CONCLUSIONS: This study replicates and extends previous research showing that presenting images of negative health consequences increases healthy food choices. Because effects were elicited by manipulating affective valence irrespective of paired food type, these results appear more consistent with an explanation based on priming than on evaluative conditioning. (PsycINFO Database Record PMID- 27505206 TI - Generalization of evaluative conditioning toward foods: Increasing sensitivity to health in eating intentions. AB - OBJECTIVE: Evaluative conditioning (EC), the pairing of objects (conditioned stimuli; CS) with positive and negative unconditioned stimuli (US) in order to induce attitude change, has proven to be a viable method of changing attitudes toward foods and corresponding eating behaviors. Positively conditioning healthy foods and negatively conditioning unhealthy foods should result in healthier food choices. Of interest in the current research is the extent to which EC can generalize beyond the conditioned foods to entire dimensions underlying food judgment, such as health and taste. METHOD: The current research included 2 EC experiments configured in accord with the Implicit Misattribution Model (IMM; Jones, Fazio, & Olson, 2009). Four healthy CS foods were paired with positive US and 4 unhealthy CS foods were paired with negative US. Participants then reported eating intentions for a variety of foods, including non-CS foods. RESULTS: Experiment 1 demonstrated that conditioning a few exemplar food items increased sensitivity to health and decreased sensitivity to taste when judging a variety of additional foods. Experiment 2 replicated the generalization effect with regard to health sensitivity, but only when a task that preceded the EC procedure promoted, rather than interfered with, categorization of the CS foods by health. CONCLUSIONS: This research shows that EC can generalize to an entire dimension underlying food judgment and that this effect is facilitated by accessibility of the health dimension at the time of exposure to the EC pairings. (PsycINFO Database Record PMID- 27505207 TI - To accurately estimate implicit influences on health behavior, accurately estimate explicit influences. AB - OBJECTIVE: This project considered how inattention to left-out variable error and measurement correspondence in the assessment of explicit measures can result in upwardly biased estimates of the predictive utility of implicit measures designed to predict health behaviors. METHOD: A pilot study (n = 96) used a cross sectional design to predict beer consumption and a main study (n = 132) used a longitudinal design to predict binge drinking. In each study, a battery of 4 implicit inventories (implicit association test, personalized implicit association test, evaluative priming, and attribution misattribution paradigm) and a battery of correspondent explicit measures (based on the Reasoned Action Model and the Prototype Willingness Model) were administered to college youth. RESULTS: The Implicit Association Test and evaluative priming measures were not predictive of alcohol consumption in either study, but the personalized implicit association test (PIAT) and affective misattribution paradigm (AMP) accounted for between 5% and 12% in behavioral criteria, when analyzed in isolation or after explicit measures were statistically controlled following measurement conventions in this research domain. When implicit measures were folded into a structural equation model derived from the Reasoned Action and Prototype Willingness Models, The PIAT was no longer a significant predictor of behavior and the AMP resulted in a 1%-2% incremental increase in accounted for variance. CONCLUSION: Left-out variable error and measurement correspondence are core principles that need to be considered when modeling the relative contributions of implicit and explicit constructs in the prediction of health behaviors. (PsycINFO Database Record PMID- 27505208 TI - Implicit stigmatization-related biases in individuals with skin conditions and their significant others. AB - OBJECTIVE: Stigmatization is common in people with chronic skin conditions and may also affect their significant others (SOs). The fast and implicit processing of stigmatization-related stimuli has received little attention in these populations; however, such knowledge may offer indications for new treatment methods. This study aimed to investigate implicit processing of stigmatization related stimuli in people with skin conditions and their SOs. METHOD: A modified Stroop task and 2 approach-avoidance tasks were administered to participants with chronic skin conditions (alopecia: n = 50 and psoriasis: n = 50); their significant others (alopecia SOs: n = 47 and psoriasis SOs: n = 50); and controls (n = 50). The aim was to examine attentional and behavioral biases toward disease related and social threat-related stigmatization stimuli. RESULTS: An attentional bias to disease-related stimuli was found in participants with alopecia and their SOs, compared with controls (p < .001). This effect was not found for participants with psoriasis and their SOs. Increased behavioral avoidance of disgusted faces was found in participants with psoriasis and their SOs, compared with controls (p = .047). This effect was not found in participants with alopecia and their SOs. CONCLUSIONS: These results provide support for the idea that individuals with skin conditions and their SOs are characterized by a stigmatization-related stimulus bias regarding implicit cognitive and behavioral reactions, in comparison to healthy individuals. Furthermore, preliminary results suggest that these processes may differ across skin conditions, with people with psoriasis being more affected by social reactions (i.e., disgusted faces) and people with alopecia by disease-related cues possibly related to internalized self-stigma. (PsycINFO Database Record PMID- 27505209 TI - Smokers exhibit biased neural processing of smoking and affective images. AB - OBJECTIVE: There has been growing interest in the role that implicit processing of drug cues can play in motivating drug use behavior. However, the extent to which drug cue processing biases relate to the processing biases exhibited to other types of evocative stimuli is largely unknown. The goal of the present study was to determine how the implicit cognitive processing of smoking cues relates to the processing of affective cues using a novel paradigm. METHOD: Smokers (n = 50) and nonsmokers (n = 38) completed a picture-viewing task, in which participants were presented with a series of smoking, pleasant, unpleasant, and neutral images while engaging in a distractor task designed to direct controlled resources away from conscious processing of image content. Electroencephalogram recordings were obtained throughout the task for extraction of event-related potentials (ERPs). RESULTS: Smokers exhibited differential processing of smoking cues across 3 different ERP indices compared with nonsmokers. Comparable effects were found for pleasant cues on 2 of these indices. Late cognitive processing of smoking and pleasant cues was associated with nicotine dependence and cigarette use. CONCLUSIONS: Results suggest that cognitive biases may extend across classes of stimuli among smokers. This raises important questions about the fundamental meaning of cognitive biases, and suggests the need to consider generalized cognitive biases in theories of drug use behavior and interventions based on cognitive bias modification. (PsycINFO Database Record PMID- 27505210 TI - A randomized controlled trial of Web-based Attentional Bias Modification to help smokers quit. AB - OBJECTIVE: To assess the efficacy of a multiple-sessions Web-based Attentional Bias Modification (ABM) self-help intervention in 434 smokers who made a quit attempt. METHOD: Respondents were randomized to receive 6 sessions of ABM- or placebo-training in a period of 2 weeks. Smoking-related cognitions (e.g., self efficacy and intention to quit) and cognitive biases (i.e., attentional and approach bias) for smoking-cues were assessed before training (pretest). Primary outcome-variable was continued abstinence, 6 months after baseline. Bias reduction at the posttraining assessment was the secondary outcome. A 2 * 2 mixed analysis of variance (ANOVA) and logistic regression analyses were conducted using the whole sample (N = 434) as well as subsamples of light to moderate smokers (<15 cigarettes, N = 115) and heavy smokers (15 or more cigarettes, N = 319). Conservative analyses (coding drop-outs as smokers) as well as complete case analyses were conducted. RESULTS: The ABM training had no significant effect regarding bias reduction and no behavioral effects in the whole sample of smokers. Subsample analyses revealed a significant positive effect on continued abstinence in heavy smokers only (complete case analyses: odds ratio [OR] = 3.15; p = .02; confidence interval [CI] = 1.24-7.99; conservative analyses: OR = 2.49; p = .02; CI = 1.13-5.48). CONCLUSION: Web-based ABM training is ineffective in fostering cognitive bias reduction and continued smoking abstinence. However, the positive effects in heavy smokers-as indicated by exploratory subsample analyses warrant further research into the potential of multiple sessions ABM training to foster continued smoking abstinence in heavy smokers who make a quit-attempt. (PsycINFO Database Record PMID- 27505212 TI - Attentional effects of self-affirmation in response to graphic antismoking images. AB - OBJECTIVE: Self-affirmation has been shown to reduce defensive responding to threatening information. However, little is known about the cognitive and attentional processes underlying these effects. In the current eye-movement study, the authors explored whether self-affirmation affects attention allocation (i.e., number of fixations) among those for whom a threatening health message is self-relevant. METHODS: After a self-affirmation manipulation, 47 smokers and 52 nonsmokers viewed a series of cigarette packs displaying high or low threat smoking-related images accompanied by a brief smoking message containing risk, coping or neutral textual information. RESULTS: Self-affirmed smokers made more fixations to the cigarette packs than did nonaffirmed smokers (across both high and low threat images), whereas self-affirmed nonsmokers made fewer fixations to the cigarette packs than did nonaffirmed nonsmokers (again across both image types). The textual information did not moderate responses. CONCLUSIONS: Findings indicate attention-increasing effects of self-affirmation among those for whom the information is self-relevant (smokers) and attention-decreasing effects of self-affirmation among those for whom the information is not self-relevant (nonsmokers). Such findings are consistent with the calibration model of self affirmation (Griffin & Harris, 2011) in which self-affirmation increases sensitivity to the self-relevance of health-risk information. The use of an implicit measure of visual orienting informs our understanding of the working mechanisms of self-affirmation when encoding health information, and may also hold practical implications for the design and delivery of graphic warning labels. (PsycINFO Database Record PMID- 27505211 TI - Attentional bias to negative affect moderates negative affect's relationship with smoking abstinence. AB - OBJECTIVE: To examine whether initial orienting (IO) and inability to disengage (ITD) attention from negative affective stimuli moderate the association of negative affect with smoking abstinence during a quit attempt. METHOD: Data were from a longitudinal cohort study of smoking cessation (N = 424). A negative affect modified Stroop task was administered 1 week before and on quit day to measure IO and ITD. Ecological Momentary Assessments were used to create negative affect intercepts and linear slopes for the week before quitting and on quit day. Quit day and long-term abstinence measures were collected. RESULTS: Continuation ratio logit model analyses found significant interactions for prequit negative affect slope with prequit ITD, odds ratio (OR) = 0.738 (0.57, 0.96), p = .02, and for quit day negative affect intercept with quit day ITD, OR = 0.62 (0.41, 950), p = .03, predicting abstinence. The Prequit Negative Affect Intercept * Prequit IO interaction predicting quit day abstinence was significant, OR = 1.42 (1.06, 1.90), p = .02, as was the Quit Day Negative Affect Slope * Quit Day IO interaction predicting long-term abstinence, OR = 1.45 (1.02, 2.08), p = .04. CONCLUSION: The hypothesis that the association of negative affect with smoking abstinence would be moderated by ITD was generally supported. Among individuals with high ITD, negative affect was inversely related to abstinence, but unrelated to abstinence among individuals with lower levels of ITD. Unexpectedly, among individuals with low IO, negative affect was inversely related to abstinence, but unrelated to abstinence among individuals with higher levels of ITD. (PsycINFO Database Record PMID- 27505213 TI - When is an image a health claim? A false-recollection method to detect implicit inferences about products' health benefits. AB - OBJECTIVE: Images on food and dietary supplement packaging might lead people to infer (appropriately or inappropriately) certain health benefits of those products. Research on this issue largely involves direct questions, which could (a) elicit inferences that would not be made unprompted, and (b) fail to capture inferences made implicitly. Using a novel memory-based method, in the present research, we explored whether packaging imagery elicits health inferences without prompting, and the extent to which these inferences are made implicitly. METHOD: In 3 experiments, participants saw fictional product packages accompanied by written claims. Some packages contained an image that implied a health-related function (e.g., a brain), and some contained no image. Participants studied these packages and claims, and subsequently their memory for seen and unseen claims were tested. RESULTS: When a health image was featured on a package, participants often subsequently recognized health claims that-despite being implied by the image-were not truly presented. In Experiment 2, these recognition errors persisted despite an explicit warning against treating the images as informative. In Experiment 3, these findings were replicated in a large consumer sample from 5 European countries, and with a cued-recall test. CONCLUSION: These findings confirm that images can act as health claims, by leading people to infer health benefits without prompting. These inferences appear often to be implicit, and could therefore be highly pervasive. The data underscore the importance of regulating imagery on product packaging; memory-based methods represent innovative ways to measure how leading (or misleading) specific images can be. (PsycINFO Database Record PMID- 27505214 TI - "Relational effects on physical activity: A dyadic approach to the theory of planned behavior": Correction to Howland et al. (2016). AB - Reports an error in "Relational effects on physical activity: A dyadic approach to the theory of planned behavior" by Maryhope Howland, Allison K. Farrell, Jeffry A. Simpson, Alexander J. Rothman, Rachel J. Burns, Jennifer Fillo and Jhon Wlaschin (Health Psychology, 2016[Jul], Vol 35[7], 733-741). In the article, NIAAA Grant 5T32-AA07290 provided funding support for manuscript preparation but was omitted from the author note. (The following abstract of the original article appeared in record 2016-10019-001.) OBJECTIVE: Despite growing appreciation of how close relationships affect health outcomes, there remains a need to explicate the influence romantic partners have on health behavior. In this paper, we demonstrate how an established model of behavior change-the theory of planned behavior (TPB)- can be extended from an individual level to a dyadic (couple) model to test the influence that relationship partners have on a key determinant of health behavior-behavioral intentions. METHODS: Two hundred romantic couples (400 individuals) completed TPB measures regarding physical activity for themselves and their romantic partner as well as a measure of relationship quality. RESULTS: Above and beyond the individual-level TPB predictors of behavioral intentions (i.e., attitudes, subjective norms, and perceived behavioral control), the romantic partner's perceived behavioral control (PBC) regarding physical activity predicted each individual's behavioral intentions and moderated the influence of each individual's PBC on his or her own behavioral intentions. Additionally, the romantic partner's perceptions of each individual's TPB measures predicted each individual's behavioral intentions to be physically active. Quality of the relationship also moderated some partner influences on individuals' intentions. CONCLUSIONS: This paper provides a roadmap for integrating a dyadic framework into individual-level models of behavior change. The findings suggest that data from both partners and relationship quality are important to consider when trying to understand and change health-related behavior such as physical activity. The results broaden the potential applications of the TPB as well as our understanding of how romantic partners might influence important health-related practices. PMID- 27505216 TI - Targeting implicit approach reactions to snack food in children: Effects on intake. AB - OBJECTIVE: Implicit approach reactions to energy-dense snack food can facilitate unhealthy eating in children. Therefore, an experiment was conducted to test whether modifying implicit reactions to snack food by means of a go/no-go task can reduce consumption of this food. The effectiveness of this intervention on actual snack intake after exposure to a food or a control advertisement was tested. METHOD: Children (133; age range = 7-10 years) played an advergame promoting either energy-dense food or nonfood products. Subsequently, children conducted either a go/no-go food task in which the advertised food was consistently associated with no-go cues, or a go/no-go control task in which colored circles were consistently associated with no-go cues. Afterward, they could eat the advertised food and a new food. Candy intake was weighed and caloric intake was determined. RESULTS: Results show that children who performed the go/no-go food task consumed significantly and considerably fewer calories (34%) than the children who carried out the control task. No main effect of type of advertisement was found. Furthermore, the effect of the go/no-go food task was similar after each type of advertisement, similar for advertised and new foods, and was significant for both girls and boys. CONCLUSION: Targeting implicit reactions to high-energy snacks proved effective in decreasing intake of snacks in children. Furthermore, the previously reported stimulating effect of food promoting advergames on intake may disappear when a short cognitive task is presented directly after the game. Future work should evaluate the clinical implications of these findings. (PsycINFO Database Record PMID- 27505215 TI - Implicit alcohol associations, especially drinking identity, predict drinking over time. AB - OBJECTIVE: There is considerable excitement about implicit alcohol associations (IAAs) as predictors of college-student hazardous drinking; however, few studies have investigated IAAs prospectively, included multiple assessments, or controlled for previous drinking. Doing so is essential for showing the utility of these associations as predictors, and ultimately, targets for screening or intervention. Therefore, 3 IAAs (i.e., drinking identity, alcohol approach, and alcohol excitement) were evaluated as prospective predictors of drinking in 1st- and 2nd-year undergraduates in the United States. METHOD: A sample of 506 undergraduates completed 8 online assessments of IAAs, explicit measures of the IAA constructs, and hazardous drinking (i.e., consumption, problems, and risk of alcohol-use disorders) every 3 months over a 21-month period. Retention rates, ordered by follow-up time points, were 90%, 76%, 76%, 77%, 72%, 67%, and 66%, respectively. Half of the participants were nondrinkers at baseline; 21% were above clinical cutoffs for hazardous drinking. RESULTS: Drinking-identity and alcohol-excitement associations predicted future alcohol consumption and problems after controlling for previous drinking and explicit measures; drinking identity also predicted future risk of alcohol-use disorder. Relative to the other IAAs, drinking identity predicted alcohol consumption for the longest duration (i.e., 21 months). Alcohol-approach associations rarely predicted variance in drinking. CONCLUSION: IAAs vary in their utility as prospective predictors of college student hazardous drinking. Drinking identity and, to a lesser extent, alcohol excitement, emerged as robust prospective predictors of hazardous drinking. Intervention and screening efforts could likely benefit from targeting those associations. (PsycINFO Database Record PMID- 27505217 TI - Snack intake is reduced using an implicit, high-level construal cue. AB - OBJECTIVES: Priming a high level construal has been shown to enhance self-control and reduce preference for indulgent food. Subtle visual cues have been shown to enhance the effects of a priming procedure. The current study therefore examined the combined impact of construal level and a visual cue reminder on the consumption of energy-dense snacks. METHOD: A student and community-based adult sample with a wide age and body mass index (BMI) range (N = 176) were randomly assigned to a high or low construal condition in which a novel symbol was embedded. Afterward participants completed a taste test of ad libitum snack foods in the presence or absence of the symbol. RESULTS: The high (vs. the low) construal level prime successfully generated more abstract responses (p < .0001) and reduced intake when the cue-reminder was present (p = .02) but not when it was absent (p = .40). CONCLUSIONS: Priming high construal level thinking reduces consumption of high energy dense snacks in the presence of a visual cue-reminder. This may be a practical technique for reducing overeating and has the potential to be extended to other unhealthy behaviors. (PsycINFO Database Record PMID- 27505218 TI - The Impact of Integrated Psychological Services in a Safety Net Primary Care Clinic on Medical Utilization. AB - OBJECTIVE: The integration of psychological and behavioral health services into safety net primary care clinics has been viewed as a step toward reducing disparities in mental health treatment and addressing behavioral factors in chronic diseases. Though it is posited that integrated behavioral health (IBH) reduces preventable medical costs, this premise has yet to be tested in a safety net primary care clinic. METHOD: Retrospective pre- and posttreatment analysis with quasi-experimental control group was constructed using propensity score matching. Participants included 1,440 adult patients at a safety net primary care clinic, 720 of whom received IBH services, and 720 of whom received medical treatment only. RESULTS: Analysis showed that rates of preventable inpatient utilization decreased significantly among IBH-treated patients compared to no change among control patients. CONCLUSION: IBH was associated with decreased rates of preventable inpatient visits. IBH may present opportunities to deliver improved holistic patient care while reducing unnecessary inpatient medical utilization. PMID- 27505219 TI - Supramolecular Photochirogenesis with a Higher-Order Complex: Highly Accelerated Exclusively Head-to-Head Photocyclodimerization of 2-Anthracenecarboxylic Acid via 2:2 Complexation with Prolinol. AB - An unprecedented 2:2 complex was shown to intervene in the enantiodifferentiating photocyclodimerization of 2-anthracenecarboxylic acid (A) mediated by a hydrogen bonding template l-prolinol (P) to accelerate the formation of chiral anti-head to-head and achiral syn-head-to-head cyclodimers in >99% combined yield with enhanced enantioselectivities of up to 72% ee for the former. The supramolecular complexation and photochirogenic behaviors, as well as the plausible structures, of intervening Am.Pn complexes (m, n = 1 or 2) were elucidated by combined theoretical and experimental spectroscopic, photophysical, and photochemical studies. Furthermore, the photochemical chiral amplification was achieved for the first time by utilizing the preferential 2:2 complexation of A with homochiral P to give normalized product enantioselectivities higher than those of the template used. The present strategy based on the higher-order hydrogen-bonding motif, which is potentially applicable to a variety of carboxylic acids and beta aminoalcohols, is not only conceptually new and expandable to other (photo)chirogenic and sensing systems but also may serve as a versatile tool for achieving photochemical asymmetric amplification and constructing chiral functional supramolecular architectures. PMID- 27505220 TI - Comparison of the Motor Performance and Vestibular Function in Infants with a Congenital Cytomegalovirus Infection or a Connexin 26 Mutation: A Preliminary Study. AB - OBJECTIVES: Hearing-impaired children are at risk for vestibular damage and delayed motor development. Two major causes of congenital hearing loss are cytomegalovirus (CMV) infection and connexin (Cx) 26 mutations. Comparison of the motor performance and vestibular function between these specific groups is still underexplored. The objective of this study was to investigate the impact of congenital (c)CMV and Cx26 on the motor performance and vestibular function in 6 months old infants. DESIGN: Forty children (mean age 6.7 months; range 4.8 to 8.9 months) participated in this cross-sectional design and were recruited from the Flemish CMV registry. They were divided into five age-matched groups: normal hearing control, asymptomatic cCMV, normal-hearing symptomatic cCMV, hearing impaired symptomatic cCMV, and hearing-impaired Cx26. Children were examined with the Peabody Developmental Motor Scales-2 and cervical vestibular-evoked myogenic potential (cVEMP) test. RESULTS: Symptomatic hearing-impaired cCMV children demonstrated a significantly lower gross motor performance compared with the control group (p = 0.005), the asymptomatic cCMV group (p = 0.034), and the Cx26 group (0.016). In this symptomatic hearing-impaired cCMV group, 4 out of 8 children had absent cVEMP responses that were related to the weakest gross motor performance. The Cx26 children showed no significant delay in motor development compared with the control children and none of these children had absent cVEMP responses. CONCLUSIONS: The weakest gross motor performance was found in symptomatic hearing-impaired cCMV-infected children with absent cVEMP responses. These results suggest that abnormal saccular responses are a major factor for this delayed motor development, although more work is needed including comprehensive vestibular function testing to verify this. PMID- 27505221 TI - Infant Cortical Auditory Evoked Potentials to Lateralized Noise Shifts Produced by Changes in Interaural Time Difference. AB - OBJECTIVES: Newborns reliably orient to sound location soon after birth; by age 1 month this orienting disappears until after age 4 months. It has been suggested that orienting by the newborn reflects subcortical-mediated reflexes, which are suppressed by age 1 month; reappearance of orienting then occurs after age 4 months with maturation of cortical mechanisms of sound localization. In the present study, we assess auditory lateralization in young infants (and adults) by recording slow cortical auditory evoked potentials to lateralization shifts in dichotic noise produced by changes in interaural time difference (ITD). DESIGN: Fifteen normal infants aged under 4 months (mean = 10.7 weeks) had cortical auditory evoked potentials assessed in response to (1) diotic "onset" noise bursts (0 msec ITD) and (2) shifts in continuous lateralized noise (75 dB SPL) produced by ITD shifts of 0.5, 0.8, 1, 2, 4, and 8 msec. Shifts alternated between ears occurred every 2 sec. Stimuli were presented using insert earphones; infants slept during recordings. For comparison, similar recordings were obtained in 11 normal-hearing, awake, adults. Additionally, "control" recordings to the ITD-shift stimuli presented to only one ear were obtained in the adults. RESULTS: Similar to previous research, adults showed clear N1-P2 responses to the lateralization shifts (ITD 0.5 to 2.0 msec). Responses decreased for longer ITD shifts, with no adult responses to the 8-msec ITD shift. N1 latencies to ITD shift stimuli were 28 to 34 msec longer than to the onset stimuli. No responses were seen in the control conditions when ITD-shift stimuli were presented to only one ear (confirming the binaural nature of the ITD-shift responses). All infants showed P2 responses to one or more of the ITD-shift stimuli up to +/-1 msec; compared with adults, infants showed larger amplitude decreases and fewer responses to longer ITD-shift stimuli. As was seen with the adult responses, infant response (P2) latencies to ITD shifts were longer compared with their responses to the onset stimuli; however, these increases, 32 to 78 msec, were significantly longer than those seen in the adults. CONCLUSIONS: Young infants (even as young as 5 weeks) show clear evidence of auditory cortical responsivity to lateralization shifts produced by changes in the ITD of continuous noise, indicating that they have the capacity to process binaural ITD timing cues well before the age of 4 months. Further research is required to determine whether the larger latency increase in infants for ITD-shift stimuli (relative to the onset stimuli) and the greater effect of longer ITD shifts on response presence and amplitude in infants reflects immaturity of lateralization processing and/or reduced responses recorded during sleep. Slow cortical auditory evoked potentials elicited to lateralization shifts in dichotic noise provide a method to investigate binaural hearing processes in young children with normal or impaired hearing. PMID- 27505222 TI - The role of dimension relevance in features' access to response-selection mechanisms. AB - It is widely agreed that attending to a stimulus entails that all its features are processed. However, whether all these features are granted access to response selection mechanisms remains a debated issue. Some authors suggest that all the features of the attended object affect response selection, irrespective of their relevance to the task at hand, whereas others claim that only its currently relevant features do. Yet others suggest that irrelevant features of an attended object affect response selection only if this object is the target, that is, only if it is selected for action. The results from 3 experiments show that responses associated with an attended object's irrelevant dimension interfered with response selection even when this object was not selected for action, but to a lesser extent than the responses associated with its relevant dimension. Our findings also show that interference from the irrelevant dimension can be masked when the response codes associated with the relevant and irrelevant dimensions compete. We suggest a parsimonious account of the findings from the extant literature that obviates the need to postulate a qualitative distinction between attention and selection for action. (PsycINFO Database Record PMID- 27505223 TI - Parallel streams versus integrated timing in multilimb pattern generation: A test of Korte's Third Law. AB - Skilled drummers performed a 4:3:2 polyrhythm with 2 hands and 1 foot. For each pair of limbs patterns of temporal covariation were used to infer relatively independent parallel streams versus integrated timing relationships. Parallel timing was more prevalent between hand and foot than between the 2 hands, and parallel timing generally increased with tapping rate. Different combinations of integrated and parallel timing were found among the 3 limbs. A second experiment used a wider range of tapping rates and explored 3:2 tapping with 2 hands, 2 feet, or hand and foot. The latter 2 limb pairs resulted in greater prevalence of parallel timing. These results can be interpreted in terms of a Gestalt principle of grouping known as Korte's Third Law, which can be extended from the perceptual domain to the perceptual-motor domain. This principle indicates that perceived velocity is a key factor in determining whether a sequence of events is represented as a single integrated pattern or as multiple parallel patterns. The present results put disparate previous findings on bimanual polyrhythmic tapping and rhythmic aspects of the golf swing under a common theoretical perspective. (PsycINFO Database Record PMID- 27505224 TI - Auditory stimuli automatically grab attention: Evidence from eye tracking and attentional manipulations. AB - Simultaneously presenting auditory and visual stimuli can hinder performance for one modality while the other dominates. For approximately 40 years, research with adults has primarily indicated visual dominance, while recent research with infants and young children has revealed auditory dominance. The current study further investigates modality dominance with adults, finding evidence for both auditory and visual dominance across 3 experiments. Using a simple discrimination task, Experiment 1 revealed that cross-modal presentation attenuated discrimination of auditory input, while at the same time, also slowed down visual processing. Even when participants were instructed to only pay attention to the visual stimuli, both spoken nonsense words and nonlinguistic sounds slowed down visual processing (Experiment 2). Experiment 3 used a similar discrimination task while utilizing an eye tracker to examine how auditory input affects visual fixations. Cross-modal presentation attenuated auditory discrimination; however, it also slowed down visual response times. In addition, adults also made longer fixations and were slower to make their first fixation when images were paired with sounds. The latter finding is novel and consistent with a proposed mechanism of auditory dominance: auditory stimuli automatically engage attention and attenuate or delay visual processing. (PsycINFO Database Record PMID- 27505225 TI - Assessing the functional role of motor response during the integration process. AB - The aim of this study was to provide evidence that actions performed by an individual influence the sensorimotor memory processing and, in particular, the integration process. We conducted 3 experiments that highlighted the multimodal aspect of memory traces. The 1st experiment consisted of a short-term priming paradigm based on 2 phases: a learning phase, consisting of the association between a shape and a sound, and a test phase, examining the priming effect of the shape seen in the learning phase on the processing of target tones. The participants' motor response became a factor in Experiments 2 and 3, allowing us to observe its influence on the integration between the shape and the sound. In Experiment 1, we showed that (a) the prime associated with the sound in the learning phase had an effect on target processing and (b) the component reactivated by the prime was perceptual in nature (i.e., auditory). Experiment 2 showed that the participants' responses were faster when the association of a shape and a sound had been learned with a motor response rather than without. Experiment 3 showed that the integration process required the individual to act while learning the association between the shape and the sound; otherwise no integration effect was observed. Our results highlight the role of motor responses as a necessary criterion for the integration process to take place. (PsycINFO Database Record PMID- 27505226 TI - Where to start? Bottom-up attention improves working memory by determining encoding order. AB - The present study aimed to characterize the mechanism by which working memory is enhanced for items that capture attention because of their novelty or saliency that is, via bottom-up attention. The first experiment replicated previous research by corroborating that bottom-up attention directed to an item is sufficient for enhancing working memory and, moreover, generalized the effect to the domain of verbal working memory. The subsequent 3 experiments sought to determine how bottom-up attention affects working memory. We considered 2 hypotheses: (1) Bottom-up attention enhances the encoded representation of the stimulus, similar to how voluntary attention functions, or (2) It affects the order of encoding by shifting priority onto the attended stimulus. By manipulating how stimuli were presented (simultaneous/sequential display) and whether the cue predicted the tested items, we found evidence that bottom-up attention improves working memory performance via the order of encoding hypothesis. This finding was observed across change detection and free recall paradigms. In contrast, voluntary attention improved working memory regardless of encoding order and showed greater effects on working memory. We conclude that when multiple information sources compete, bottom-up attention prioritizes the location at which encoding should begin. When encoding order is set, bottom-up attention has little or no benefit to working memory. (PsycINFO Database Record PMID- 27505227 TI - Differentiating global and local contour completion using a dot localization paradigm. AB - Competing theories of partially occluded object perception (amodal completion) emphasize either relatively local contour relationships or global factors such as symmetry. These disparate theories may reflect 2 separate processes: a low-level contour interpolation process and a higher-order global recognition process. The 2 could be distinguished experimentally if only the former produces precise representations of occluded object boundaries. Using a dot localization paradigm, we measured the precision and accuracy of perceived object boundaries for participants instructed to complete occluded objects with divergent local and global interpretations. On each trial, a small red dot was flashed on top of an occluder. Participants reported whether the dot fell inside or outside the occluded object's boundaries. Interleaved, 2-up, 1-down staircases estimated points on the psychometric function where the probability was .707 that the dot would be seen as either outside or inside the occluded object's boundaries. The results reveal that local contour interpolation produces precise and accurate representations of occluded contours, and consistency across observers, but completion according to global symmetry does not. These results support a distinction between local, automatic contour interpolation processes and global processes based on recognition from partial information. (PsycINFO Database Record PMID- 27505228 TI - Is There a Need for Viral Load Testing to Assess Treatment Failure in HIV Infected Patients Who Are about to Change to Tenofovir-Based First-Line Antiretroviral Therapy? Programmatic Findings from Myanmar. AB - BACKGROUND: WHO recommends that stavudine is phased out of antiretroviral therapy (ART) programmes and replaced with tenofovir (TDF) for first-line treatment. In this context, the Integrated HIV Care Program, Myanmar, evaluated patients for ART failure using HIV RNA viral load (VL) before making the change. We aimed to determine prevalence and determinants of ART failure in those on first-line treatment. METHODS: Patients retained on stavudine-based or zidovudine-based ART for >12 months with no clinical/immunological evidence of failure were offered VL testing from August 2012. Plasma samples were tested using real time PCR. Those with detectable VL>250 copies/ml on the first test were provided with adherence counseling and three months later a second test was performed with >1000 copies/ml indicating ART failure. We calculated the prevalence of ART failure and adjusted relative risks (aRR) to identify associated factors using log binomial regression. RESULTS: Of 4934 patients tested, 4324 (87%) had an undetectable VL at the first test while 610 patients had a VL>250 copies/ml. Of these, 502 had a second VL test, of whom 321 had undetectable VL and 181 had >1000 copies/ml signifying ART failure. There were 108 who failed to have the second test. Altogether, there were 94% with an undetectable VL, 4% with ART failure and 2% who did not follow the VL testing algorithm. Risk factors for ART failure were age 15-24 years (aRR 2.4, 95% CI: 1.5-3.8) compared to 25-44 years and previous ART in the private sector (aRR 1.6, 95% CI: 1.2-2.2) compared to the public sector. CONCLUSIONS: This strategy of evaluating patients on first-line ART before changing to TDF was feasible and identified a small proportion with ART failure, and could be considered by HIV/AIDS programs in Myanmar and other countries. PMID- 27505229 TI - Association between reduced white matter integrity in the corpus callosum and serotonin transporter gene DNA methylation in medication-naive patients with major depressive disorder. AB - Previous evidence suggests that the serotonin transporter gene (SLC6A4) is associated with the structure of brain regions that are critically involved in dysfunctional limbic-cortical network activity associated with major depressive disorder (MDD). Diffusion tensor imaging (DTI) and tract-based spatial statistics were used to investigate changes in white matter integrity in patients with MDD compared with healthy controls. A possible association between structural alterations in white matter tracts and DNA methylation of the SLC6A4 promoter region was also assessed. Thirty-five medication-naive patients with MDD (mean age: 40.34, male/female: 10/25) and age, gender and education level matched 49 healthy controls (mean age: 41.12, male/female: 15/34) underwent DTI. SLC6A4 DNA methylation was also measured at five CpG sites of the promoter region, and the cell type used was whole-blood DNA. Patients with MDD had significantly lower fractional anisotropy (FA) values for the genu of the corpus callosum and body of the corpus callosum than that in healthy controls (family-wise error corrected, P<0.01). Significant inverse correlations were observed between SLC6A4 DNA methylation and FA (CpG3, Pearson's correlation: r=-0.493, P=0.003) and axial diffusivity (CpG3, Pearson's correlation: r=-0.478, P=0.004) values of the body of the corpus callosum in patients with MDD. These results contribute to evidence indicating an association between epigenetic gene regulation and structural brain alterations in depression. Moreover, we believe this is the first report of a correlation between DNA methylation of the SLC6A4 promoter region and white matter integrity in patients with MDD. PMID- 27505230 TI - Increased DNA and RNA damage by oxidation in patients with bipolar I disorder. AB - The mechanisms underlying bipolar disorder (BD) and the associated medical burden are unclear. Damage generated by oxidation of nucleosides may be implicated in BD pathophysiology; however, evidence from in vivo studies is limited and the extent of state-related alterations is unclear. This prospective study investigated for we believe the first time the damage generated by oxidation of DNA and RNA strictly in patients with type I BD in a manic or mixed state and subsequent episodes and remission compared with healthy control subjects. Urinary excretion of 8-oxo-deoxyguanosine (8-oxodG) and 8-oxo-guanosine (8-oxoGuo), valid markers of whole-body DNA and RNA damage by oxidation, respectively, was measured in 54 patients with BD I and in 35 healthy control subjects using a modified ultraperformance liquid chromatography and mass spectrometry assay. Repeated measurements were evaluated in various affective phases during a 6- to 12-month period and compared with repeated measurements in healthy control subjects. Independent of lifestyle and demographic variables, a 34% (P<0.0001) increase in RNA damage by oxidation across all affective states, including euthymia, was found in patients with BD I compared with healthy control subjects. Increases in DNA and RNA oxidation of 18% (P<0.0001) and 8% (P=0.02), respectively, were found in manic/hypomanic states compared with euthymia, and levels of 8-oxodG decreased 15% (P<0.0001) from a manic or mixed episode to remission. The results indicate a role for DNA and RNA damage by oxidation in BD pathophysiology and a potential for urinary 8-oxodG and 8-oxoGuo to function as biological markers of diagnosis, state and treatment response in BD. PMID- 27505232 TI - WGO La Paz Training Center and Gastro 2016: EGHS-WGO International Congress in Abu Dhabi. PMID- 27505231 TI - Impact of polygenic schizophrenia-related risk and hippocampal volumes on the onset of psychosis. AB - Alterations in hippocampal volume are a known marker for first-episode psychosis (FEP) as well as for the clinical high-risk state. The Polygenic Schizophrenia related Risk Score (PSRS), derived from a large case-control study, indicates the polygenic predisposition for schizophrenia in our clinical sample. A total of 65 at-risk mental state (ARMS) and FEP patients underwent structural magnetic resonance imaging. We used automatic segmentation of hippocampal volumes using the FSL-FIRST software and an odds-ratio-weighted PSRS based on the publicly available top single-nucleotide polymorphisms from the Psychiatric Genomics Consortium genome-wide association study (GWAS). We observed a negative association between the PSRS and hippocampal volumes (beta=-0.42, P=0.01, 95% confidence interval (CI)=(-0.72 to -0.12)) across FEP and ARMS patients. Moreover, a higher PSRS was significantly associated with a higher probability of an individual being assigned to the FEP group relative to the ARMS group (beta=0.64, P=0.03, 95% CI=(0.08-1.29)). These findings provide evidence that a subset of schizophrenia risk variants is negatively associated with hippocampal volumes, and higher values of this PSRS are significantly associated with FEP compared with the ARMS. This implies that FEP patients have a higher genetic risk for schizophrenia than the total cohort of ARMS patients. The identification of associations between genetic risk variants and structural brain alterations will increase our understanding of the neurobiology underlying the transition to psychosis. PMID- 27505233 TI - Manganese-Catalyzed Carboacylations of Alkenes with Alkyl Iodides. AB - A manganese-catalyzed carboacylation of alkenes with alkyl iodides and carbon monoxide is described. This carbonylative difunctionalization uses both primary and secondary alkyl iodides in reactions with a diverse array of cyclic and acyclic substrates. Examples of successful applications to the synthesis of five , six-, and seven-membered rings are provided. The inexpensive, first-row catalytic system and mild reaction conditions are expected to facilitate applications in complex synthesis. PMID- 27505234 TI - Phenotypic Variations in the Foliar Chemical Profile of Persea americana Mill. cv. Hass. AB - The Hass avocado tree Persea americana cv. Hass was derived from a single hybrid tree of P. americana var. drymifolia and P. americana var. guatemalensis, and it is propagated clonally by grafting. This cultivar is the most widely planted in the world but its profile of secondary metabolites has been studied rarely despite of its importance in plant protection. We illustrate the variability of the volatilome of mature leaves by describing the average chemical composition and the phenotypic variability found in 70 trees. Contrary to the uniformity expected in the Hass cultivar, high variability coefficients were found for most of the 36 detected foliar volatile compounds; furthermore we found six chemotypes grouping the foliar phenotypes of the sampled trees using hierarchical cluster analysis. About 48% of trees were grouped in one chemotype; five chemotypes grouped the remaining trees. The compounds that determined these chemotypes were: estragole, alpha-farnesene, beta-caryophyllene, germacrene D, alpha-cubebene and eugenol. This striking variation in a cultivar propagated clonally is discussed in terms of somatic mutation. PMID- 27505235 TI - Salamandra. AB - Beukema et al. Introduce the genus salamandra comprising the well-known fire salamanders. PMID- 27505236 TI - The origin of ambling horses. AB - Horseback riding is the most fundamental use of domestic horses and has had a huge influence on the development of human societies for millennia. Over time, riding techniques and the style of riding improved. Therefore, horses with the ability to perform comfortable gaits (e.g. ambling or pacing), so-called 'gaited' horses, have been highly valued by humans, especially for long distance travel. Recently, the causative mutation for gaitedness in horses has been linked to a substitution causing a premature stop codon in the DMRT3 gene (DMRT3_Ser301STOP) [1]. In mice, Dmrt3 is expressed in spinal cord interneurons and plays an important role in the development of limb movement coordination [1]. Genotyping the position in 4396 modern horses from 141 breeds revealed that nowadays the mutated allele is distributed worldwide with an especially high frequency in gaited horses and breeds used for harness racing [2]. Here, we examine historic horse remains for the DMRT3 SNP, tracking the origin of gaitedness to Medieval England between 850 and 900 AD. The presence of the corresponding allele in Icelandic horses (9(th)-11(th) century) strongly suggests that ambling horses were brought from the British Isles to Iceland by Norse people. Considering the high frequency of the ambling allele in early Icelandic horses, we believe that Norse settlers selected for this comfortable mode of horse riding soon after arrival. The absence of the allele in samples from continental Europe (including Scandinavia) at this time implies that ambling horses may have spread from Iceland and maybe also the British Isles across the continent at a later date. PMID- 27505237 TI - What is the association between religious affiliation and children's altruism? AB - Decety et al.[1] examined the relationships between household religiosity and sociality in children sampled from six countries. We were keenly interested in Decety et al.[1]'s conclusions about a negative relationship between religiosity and generosity - measured with the Dictator Game - as our team has investigated related questions, often with potentially contrasting findings [2-5]. We argue here that, after addressing peculiarities in their analyses, Decety et al.[1]'s data are consistent with a different interpretation. PMID- 27505238 TI - Neuroscience: Hunger Pangs in the Fly Brain. AB - Which neurons in the brain become engaged when the body is deprived of food? A new study addresses this question using the vinegar fly Drosophila melanogaster, examining a group of neurons in the brain that show alterations in neural activity when flies are satiated or starved. PMID- 27505239 TI - Autophagy: Press and Push for Destruction. AB - Recent publications illustrate an extensive crosstalk between the actin cytoskeleton and autophagy, a program for self-digestion. Actin polymerization provides a pushing force for organelle shaping and trafficking during autophagy, but the cytoskeleton is also targeted by autophagy under mechanical strain. PMID- 27505240 TI - Retinal Physiology: Non-Bipolar-Cell Excitatory Drive in the Inner Retina. AB - The long-held view that bipolar cells provide the exclusive excitatory drive to the mammalian inner retina has been challenged: new studies indicate that, instead, at least two cells that lack the dendrites characteristic for bipolar cells, and therefore resemble amacrine cells, excite inner retinal circuits using glutamate. PMID- 27505241 TI - Ecology: The Upside-Down World of Coral Reef Predators. AB - Examination of a large aggregation of sharks demonstrates that trophic pyramids with greater amounts of high-level predators than prey can occur on coral reefs. This is possible because the high-level predators obtain food from sources outside their home location. PMID- 27505242 TI - Chromatin: Polycomb Group SAMs Unite. AB - Polycomb Group (PcG) proteins assemble a chromatin state that maintains developmental gene repression. A new study combining structure and in vivo analysis details a molecular network from DNA recognition to PcG recruitment, highlighting the essential role of Sterile Alpha Motifs. PMID- 27505243 TI - Neuroscience: Peeking Under the Sombrero. AB - A recent study has introduced a new analytical approach to understanding neural circuits which has revealed previously hidden neural interactions in a large population of cells in the primate retina. The neural circuit described likely contributes to encoding visual motion. PMID- 27505244 TI - Wound Signaling: Monkeywrenching Macrophage Migration with Microscopes, Movies, and Math. AB - Drosophila hemocytes (blood cells) have emerged as a powerful system to image wound-induced inflammatory responses in vivo. New work reveals that layering mathematical modeling on top of imaging may be the most powerful tool yet for determining the properties of wound-induced signals. PMID- 27505245 TI - Behavior: Knowing When to Walk Away, Knowing When to Run. AB - A new model has been proposed indicating that humans and other animals weigh the metabolic cost of pursuit in deciding how fast to move toward a given reward, providing a powerful framework for understanding behavior. PMID- 27505246 TI - Actomyosin Ring Formation and Tension Generation in Eukaryotic Cytokinesis. AB - Cell division facilitated by a contractile ring is an almost universal feature across all branches of cellular life, with the notable exception of higher plants. In all organisms that use a contractile ring for cell division, the process of cytokinesis can be divided into four distinct stages. Firstly, the cell needs to specify a location at which to place the cell division ring to ensure proper separation of the cell contents into two daughter cells. Secondly, the cell needs to be able to transport all the necessary components to this region, and construct the cell division ring reliably and efficiently. Thirdly, the cell division ring needs to generate contractile stress in a regulated manner, to physically cleave the mother cell into two daughter cells. Finally, the ring must be disassembled to allow for the final abscission and separation of the daughter cells. In this review, we will discuss some of the proposed mechanisms by which eukaryotic cells are able to complete the first three of these stages. While there is a good understanding of the mechanisms of division site specification in most organisms, and the mechanisms of actomyosin ring formation are well studied in fission and budding yeast, there is relatively poor understanding of how actomyosin interactions are able to generate contractile stresses during ring constriction, although a number of models have been proposed. We also discuss a number of myosin motor-independent mechanisms that have been proposed to generate contractile stress in various organisms. PMID- 27505248 TI - Nonfocal Symptoms in Patients with Transient Ischemic Attack or Ischemic Stroke: Occurrence, Clinical Determinants, and Association with Cardiac History. AB - BACKGROUND: Transient ischemic attacks (TIAs) accompanied by nonfocal symptoms are associated with a higher risk of cardiovascular events, in particular cardiac events. Reported frequencies of TIAs accompanied by nonfocal symptoms range from 18 to 53%. We assessed the occurrence of nonfocal symptoms in patients with TIA or minor ischemic stroke in a neurological outpatient clinic in terms of clinical determinants, cardiac history, and atrial fibrillation (AF). METHODS: We included 1,265 consecutive patients with TIA or minor stroke who visited the outpatient clinic. During these visits, we systematically asked for nonfocal symptoms. Nonfocal symptoms included decreased consciousness, amnesia, positive visual phenomena, non-rotatory dizziness, and paresthesias. Relative risks for the presence of nonfocal symptoms in relation to clinical determinants, AF, and cardiac history were calculated. RESULTS: In 243 (19%) of 1,265 patients, TIA or minor ischemic stroke was accompanied by one or more nonfocal symptoms. Non rotatory dizziness, paresthesia, and amnesia were the most common nonfocal symptoms. In patients with an event of the posterior circulation or obesity, the qualifying TIA or minor stroke was more frequently accompanied by nonfocal symptoms, and in patients with significant carotid stenosis, nonfocal symptoms occurred less frequently. AF was related only with amnesia. CONCLUSION: Nonfocal symptoms are present in one out of 5 patients with TIA or ischemic stroke, in particular when located in the posterior circulation. A cardiac history or AF was not directly related to nonfocal symptoms. A heterogeneous etiology is suggested. PMID- 27505247 TI - CCL21/CCR7 Axis Contributed to CD133+ Pancreatic Cancer Stem-Like Cell Metastasis via EMT and Erk/NF-kappaB Pathway. AB - BACKGROUND: Tumor metastasis is driven by malignant cells and stromal cell components of the tumor microenvironment. Cancer stem cells (CSCs) are thought to be responsible for metastasis by altering the tumor microenvironment. Epithelial mesenchymal transition (EMT) processes contribute to specific stages of the metastatic cascade, promoted by cytokines and chemokines secreted by stromal cell components in the tumor microenvironment. C-C chemokine receptor 7 (CCR7) interacts with its ligand, chemokine ligand 21(CCL21), to mediate metastasis in some cancer cells lines. This study investigated the role of CCL21/CCR7 in promoting EMT and metastasis of cluster of differentiation 133+ (CD133+) pancreatic cancer stem-like cells. METHODS: Panc-1, AsPC-1, and MIA PaCa-2 pancreatic cancer cells were selected because of their aggressive invasive potentials. CCR7 expression levels were examined in total, CD133+ and CD133- cell fractions by Immunofluorescence analysis and real time-quantitative polymerase chain reaction (RT-qPCR). The role of CCL21/CCR7 in mediating metastasis and survival of CD133+ pancreatic cancer stem-like cells was detected by Transwell assays and flow cytometry, respectively. EMT and lymph node metastasis related markers (E-cadherin, N- cadherin, LYVE-1) were analyzed by western blot. CCR7 expression levels were analyzed by immunohistochemical staining and RT-qPCR in resected tumor tissues, metastatic lymph nodes, normal lymph nodes and adjacent normal tissues from patients with pancreatic carcinoma. RESULTS: CCR7 expression was significantly increased in CD133+ pancreatic cancer stem-like cells, resected pancreatic cancer tissues, and metastatic lymph nodes, compared with CD133- cancer cells, adjacent normal tissues and normal lymph nodes, respectively. CCL21/CCR7 promoted metastasis and survival of CD133+ pancreatic cancer stem-like cells and regulated CD133+ pancreatic cancer stem-like cells metastasis by modulating EMT and Erk/NF-kappaB pathway. CONCLUSIONS: These results indicate a specific role for CCL21/CCR7 in promoting EMT and metastasis in CD133+ pancreatic cancer stem-like cells. Furthermore the data also indicated the potential importance of developing therapeutic strategies targeting cancer stem-like cells and CCL21/CCR7 for reducing metastasis. PMID- 27505249 TI - Determinants of acquired activated protein C resistance and D-dimer in breast cancer. AB - BACKGROUND: We have previously reported acquired activated protein C (APC) resistance and elevated plasma D-dimer levels in breast cancer patients. Here, we aimed to identify phenotypic and genetic determinants that contribute to the acquired APC resistance and increased D-dimer levels in breast cancer. Healthy controls served as reference. We also addressed whether higher APC resistance or D-dimer levels could be potential markers of clinicopathological breast cancer characteristics. MATERIALS AND METHODS: 358 breast cancer patients and 273 healthy controls were enrolled and hemostatic plasma parameters were determined; factor (F) V, FVIII, FIX, FX, fibrinogen, von Willebrand factor (VWF), normalized APC sensitivity ratio (n-APC-sr), protein C, protein S, antithrombin, tissue factor pathway inhibitor (TFPI), and D-dimer. Common single nucleotide polymorphisms were genotyped in coagulation-related genes in the breast cancer patients. RESULTS: The phenotypic hemostatic factors explained 25% and 31% of the variability in acquired APC resistance and D-dimer levels, respectively, in the breast cancer patients. Fibrinogen (beta=-0.35, P<0.001), protein C (beta=0.28, P<0.001), and FIX (beta=0.22, P=0.026) were identified as determinants of n-APC sr (in FV Leiden non-carriers), whereas TFPI (beta=0.28, P<0.001), antithrombin (beta=-0.25, P<0.001), and FX (beta=0.15, P=0.040) were the major determinants of D-dimer. Moreover, borderline higher APC resistance (>75th percentile) was found in patients with triple negative tumors (odds ratio (OR) 1.97, 95% CI 0.99-3.90). CONCLUSIONS: This study reports phenotypic hemostatic parameters that determine acquired APC resistance and D-dimer levels in breast cancer patients. The explanatory power was modest, however, our findings are hypothesis generating and may contribute to further understand the background for cancer associated coagulopathy and thrombosis. PMID- 27505250 TI - Isolation of All CD44 Transcripts in Human Epidermis and Regulation of Their Expression by Various Agents. AB - CD44, a cell surface proteoglycan, is involved in many biological events. CD44 transcripts undergo complex alternative splicing, resulting in many functionally distinct isoforms. To date, however, the nature of these isoforms in human epidermis has not been adequately determined. In this study, we isolated all CD44 transcripts from normal human epidermis, and studied how their expressions are regulated. By RT-PCR, we found that a number of different CD44 transcripts were expressed in human epidermis, and we obtained all these transcripts from DNA bands in agarose and acrylamide gels by cloning. Detailed sequence analysis revealed 18 CD44 transcripts, 3 of which were novel. Next, we examined effects of 10 different agents on the expression of CD44 transcripts in cultured human keratinocytes, and found that several agents, particularly epidermal growth factor, hydrogen peroxide, phorbol 12-myristate 13-acetate, retinoic acid, calcium and fetal calf serum differently regulated their expressions in various patterns. Furthermore, normal and malignant keratinocytes were found to produce different CD44 transcripts upon serum stimulation and subsequent starvation, suggesting that specific CD44 isoforms are involved in tumorigenesis via different CD44-mediated biological pathways. PMID- 27505252 TI - Oliguria and Biomarkers of Acute Kidney Injury: Star Struck Lovers or Strangers in the Night? AB - Oliguria is a common phenomenon that is found in hospitalized patients . Although a rapid reduction in urine excretion rate may reflect a precipitous fall in the glomerular filtration rate, in many cases it may not. Given the common physiological finding of oliguria, we explore the relationship between the functional biomarker of renal injury (oliguria) with the increasing number of markers of renal injury to see if this combination may aid in risk stratification. (c) 2016 S. Karger AG, Basel. PMID- 27505251 TI - Del1 Knockout Mice Developed More Severe Osteoarthritis Associated with Increased Susceptibility of Chondrocytes to Apoptosis. AB - OBJECTIVE: We identified significant expression of the matricellular protein, DEL1, in hypertrophic and mature cartilage during development. We hypothesized that this tissue-specific expression indicated a biological role for DEL1 in cartilage biology. METHODS: Del1 KO and WT mice had cartilage thickness evaluated by histomorphometry. Additional mice underwent medial meniscectomy to induce osteoarthritis, and were assayed at 1 week for apoptosis by TUNEL staining and at 8 weeks for histology and OA scoring. In vitro proliferation and apoptosis assays were performed on primary chondrocytes. RESULTS: Deletion of the Del1 gene led to decreased amounts of cartilage in the ears and knee joints in mice with otherwise normal skeletal morphology. Destabilization of the knee led to more severe OA compared to controls. In vitro, DEL1 blocked apoptosis in chondrocytes. CONCLUSION: Osteoarthritis is among the most prevalent diseases worldwide and increasing in incidence as our population ages. Initiation begins with an injury resulting in the release of inflammatory mediators. Excessive production of inflammatory mediators results in apoptosis of chondrocytes. Because of the limited ability of chondrocytes to regenerate, articular cartilage deteriorates leading to the clinical symptoms including severe pain and decreased mobility. No treatments effectively block the progression of OA. We propose that direct modulation of chondrocyte apoptosis is a key variable in the etiology of OA, and therapies aimed at preventing this important step represent a new class of regenerative medicine targets. PMID- 27505253 TI - Building Global Capacity for Conducting Operational Research Using the SORT IT Model: Where and Who? AB - SETTING: Research capacity is weakest in low and middle-income countries (LMICs) where operational research is highly relevant and needed. Structured Operational Research and Training Initiative (SORT IT) courses have been developed to train participants to conduct and publish operational research and influence policy and practice. Twenty courses were completed in Asia, Africa, Europe and the South Pacific between 2009 and 2014. OBJECTIVES: In the 20 completed SORT IT courses, to assess where the research was conducted, who was trained, who became facilitators in subsequent courses and course outcomes. DESIGN: A cohort study of completed SORT IT courses. RESULTS: There were 236 participants (41% female) including 64 nationalities who conducted research in 59 countries, mostly from Asia and Africa (mean course duration = 9.7 months). Most participants (68%) were from government health programs and non-governmental agencies. A total of 213(90%) participants completed all milestones successfully with 41(19%) becoming subsequent course facilitators, 88% of whom were from LMICs. Of 228 manuscripts submitted to scientific journals, 197(86%) were either published or in press; in 86%, the principal investigator (first author) was a LMIC national. Papers were published in 23 scientific journals (impact factor 0.5-4.4) and covered 21 disease categories (median publication time = 5.7 months). Published papers (186) had 94,794 cumulative article views/downloads. Article views/downloads for immediate open access articles were double those from closed access journals. CONCLUSION: The SORT IT model has been effective in training personnel to produce relevant operational research in LMICs. It merits continued commitment and support for further scale-up and development. PMID- 27505254 TI - Pollinator Foraging Adaptation and Coexistence of Competing Plants. AB - We use the optimal foraging theory to study coexistence between two plant species and a generalist pollinator. We compare conditions for plant coexistence for non adaptive vs. adaptive pollinators that adjust their foraging strategy to maximize fitness. When pollinators have fixed preferences, we show that plant coexistence typically requires both weak competition between plants for resources (e.g., space or nutrients) and pollinator preferences that are not too biased in favour of either plant. We also show how plant coexistence is promoted by indirect facilitation via the pollinator. When pollinators are adaptive foragers, pollinator's diet maximizes pollinator's fitness measured as the per capita population growth rate. Simulations show that this has two conflicting consequences for plant coexistence. On the one hand, when competition between pollinators is weak, adaptation favours pollinator specialization on the more profitable plant which increases asymmetries in plant competition and makes their coexistence less likely. On the other hand, when competition between pollinators is strong, adaptation promotes generalism, which facilitates plant coexistence. In addition, adaptive foraging allows pollinators to survive sudden loss of the preferred plant host, thus preventing further collapse of the entire community. PMID- 27505255 TI - Oxidation Ability of Plasmon-Induced Charge Separation Evaluated on the Basis of Surface Hydroxylation of Gold Nanoparticles. AB - The oxidation ability of plasmonic photocatalysts, which has its origins in plasmon-induced charge separation and has not yet been studied quantitatively and systematically, is important for designing practical photocatalytic systems. Oxidation ability was investigated on the basis of surface hydroxylation of Au nanoparticles on TiO2 at various irradiation wavelengths and electrolyte pH values. The reaction proceeds only when the sum of the flat band potential of TiO2 and the irradiated photon energy is close to, or more positive than, the theoretical potential for the reaction. PMID- 27505256 TI - The role of progranulin in arthritis. AB - Progranulin (PGRN) is a growth factor with a unique beads-on-a-string structure that is involved in multiple pathophysiological processes, including anti inflammation, tissue repair, wound healing, neurodegenerative diseases, and tumorigenesis. This review presents up-to-date information concerning recent studies on the role of PGRN in inflammatory arthritis and osteoarthritis, with a special focus on the involvement of the interactions and interplay between PGRN and tumor necrosis factor receptor (TNFR) family members in regulating such musculoskeletal diseases. In addition, this paper highlights the applications of atsttrin, an engineered protein comprising three TNFR-binding fragments of PGRN, as a promising intervention in treating arthritis. PMID- 27505257 TI - Clinician's Commentary on Laliberte et al.(1). PMID- 27505258 TI - Diabetes Prevention Through Antiviral Treatment in Biobreeding Rats. AB - A picornavirus (Ljungan virus) has been associated with diabetes in its wild rodent reservoir and in diabetes-prone biobreeding (DP-BB) rats. We attempted to alter the development of diabetes in DP-BB rats using two anti-picornavirus compounds (pleconaril and APO-N039), singly or in combination. Antiviral therapy was initiated 2 weeks before expected onset of diabetes. Pleconaril or APO-N039 alone did not affect the debut of diabetes. However, animals receiving a combination of both compounds were protected for at least the entire period of treatment (4 weeks after expected time of diabetes onset). Immunohistochemistry demonstrated that the presence and distribution of virus antigen in the pancreatic islets coincided with the clinical status of the animal. Data indicate that a treatable picornavirus can be involved in the cellular assault resulting in diabetes and in these cases the disease mechanism appears to involve a virus present in the pancreatic beta cell mass itself. PMID- 27505259 TI - Formation of Interfacial Janus Nanomicelles by Reactive Blending and Their Compatibilization Effects on Immiscible Polymer Blends. AB - Micellization of in situ formed graft copolymers during reactive blending is commonly observed. Numerous studies have been carried out to minimize the formation of micelles and enhance emulsification efficiency. Herein, we investigated the formation of interfacial Janus nanomicelles (JNMs) and their compatibilization effects on immiscible polymer blends when reactive graft copolymers (RGCs) are used as compatibilizers. Poly(styrene-co-glycidyl methacrylate)-graft-poly(methyl methacrylate) RGCs were synthesized and used as compatibilizers for immiscible poly(l-lactide) (PLLA)/poly(vinylidene fluoride) (PVDF) blends. Numerous nanomicelles were formed in situ during melt blending by grafting of PLLA onto the RGCs. The formation and location of JNMs depended not only on the molecular architecture of the RGCs but also on the melt processing sequence and molecular weight of the components. Interfacial JNMs can effectively improve the miscibility of polymer blends, thereby enhancing the performance of immiscible polymer blends. PMID- 27505260 TI - Supramolecular Spangling, Crocheting, and Knitting of Functionalized Pyrene Molecules on a Silver Surface. AB - Pyrenes, as photoactive polycyclic aromatic hydrocarbons (PAHs), represent promising modules for the bottom-up assembly of functional nanostructures. Here, we introduce the synthesis of a family of pyrene derivatives peripherally functionalized with pyridin-4-ylethynyl termini and comprehensively characterize their self-assembly abilities on a smooth Ag(111) support by scanning tunneling microscopy. By deliberate selection of number and geometric positioning of the pyridyl-terminated substituents, two-dimensional arrays, one-dimensional coordination chains, and chiral, porous kagome-type networks can be tailored. A comparison to phenyl-functionalized reference pyrenes, not supporting the self assembly of ordered structures at low coverage, highlights the role of the pyridyl moieties for supramolecular crocheting and knitting. Furthermore, we demonstrate the selective spangling of pores in the two-dimensional pyrene assemblies by a distinct number of iodine atoms as guests by atomically resolved imaging and complementary X-ray photoelectron spectroscopy. PMID- 27505261 TI - Manganese-Promoted Ring-Opening Hydrazination of Cyclobutanols: Synthesis of Alkyl Hydrazines. AB - We herein disclose an efficient manganese-promoted hydrazination of cyclobutanols through cyclic C-C bond cleavage. The ring opening occurs under mild reaction conditions, readily affording a variety of alkyl hydrazines in synthetically useful yields and exclusive regioselectivities. The chain reaction mechanism involving the addition of alkyl carbon radical to azodicarboxylate is proposed. PMID- 27505262 TI - Investigating the evolution of summertime secondary atmospheric pollutants in urban Beijing. AB - Understanding the formation of tropospheric ozone (O3) and secondary particulates is essential for controlling secondary pollution in megacities. Intensive observations were conducted to investigate the evolution of O3, nitrate (NO3-), sulfate (SO42-) and oxygenated organic aerosols ((OOAs), a proxy for secondary organic aerosols) and the interactions between O3, NOx oxidation products (NOz) and OOA in urban Beijing in August 2012. The O3 concentrations exhibited similar variations at both the urban and urban background sites in Beijing. Regarding the O3 profile, the O3 concentrations increased with increasing altitude. The peaks in O3 on the days exceeding the 1h or 8h O3 standards (polluted days) were substantially wider than those on normal days. Significant increases in the NOz mixing ratio (i.e., NOy - NOx) were observed between the morning and early afternoon, which were consistent with the increasing oxidant level. A discernable NO3- peak was also observed in the morning on the polluted days, and this peak was attributed to vertical mixing and strong photochemical production. In addition, a SO42- peak at 18:00 was likely caused by a combination of local generation and regional transport. The OOA concentration cycle exhibited two peaks at approximately 10:00 and 19:00. The OOA concentrations were correlated well with SO42- ([OOA]=0.55*[SO42-]+2.1, r2=0.69) because they both originated from secondary transformations that were dependent on the ambient oxidization level and relative humidity. However, the slope between OOA and SO42- was only 0.35, which was smaller than the slope observed for all of the OOA and SO42- data, when the RH ranged from 40 to 50%. In addition, a photochemical episode was selected for analysis. The results showed that regional transport played an important role in the evolution of the investigated secondary pollutants. The measured OOA and Ox concentrations were well correlated at the daily scale, whereas the hourly OOA and Ox concentrations were insignificantly correlated in urban Beijing. The synoptic situation and the differences in the VOC oxidation contributing to O3 and SOAs may have resulted in the differences among the correlations between OOA and Ox at different time scale. We calculated OOA production rates using the photochemical age (defined as -log10(NOx/NOy)) in urban plumes. The CO-normalized OOA concentration increased with increasing photochemical age, with production rates ranging from 1.1 to 8.5MUgm-3ppm-1h-1 for the plume from the NCP. PMID- 27505263 TI - Persistence of glyphosate and aminomethylphosphonic acid in loess soil under different combinations of temperature, soil moisture and light/darkness. AB - The dissipation kinetics of glyphosate and its metabolite aminomethylphosphonic acid (AMPA) were studied in loess soil, under biotic and abiotic conditions, as affected by temperature, soil moisture (SM) and light/darkness. Nonsterile and sterile soil samples were spiked with 16mgkg-1 of glyphosate, subjected to three SM contents (20% WHC, 60% WHC, saturation), and incubated for 30days at 5 degrees C and 30 degrees C, under dark and light regimes. Glyphosate and AMPA dissipation kinetics were fit to single-first-order (SFO) or first-order-multicompartment (FOMC) models, per treatment combination. AMPA kinetic model included both the formation and decline phases. Glyphosate dissipation kinetics followed SFO at 5 degrees C, but FOMC at 30 degrees C. AMPA followed SFO dissipation kinetics for all treatments. Glyphosate and AMPA dissipation occurred mostly by microbial activity. Abiotic processes played a negligible role for both compounds. Under biotic conditions, glyphosate dissipation and AMPA formation/dissipation were primarily affected by temperature, but also by SM. Light regimes didn't play a significant role. Glyphosate DT50 varied between 1.5 and 53.5days, while its DT90 varied between 8.0 and 280days, depending on the treatment. AMPA persisted longer in soil than glyphosate, with its DT50 at 30 degrees C ranging between 26.4 and 44.5days, and its DT90 between 87.8 and 148days. The shortest DT50/DT90 values for both compounds occurred at 30 degrees C and under optimal/saturated moisture conditions, while the largest occurred at 5 degrees C and reaching drought stress conditions. Based on these results, we conclude that glyphosate and AMPA dissipate rapidly under warm and rainy climate conditions. However, repeated glyphosate applications in fallows or winter crops in countries where cold and dry winters normally occur could lead to on-site soil pollution, with consequent potential risks to the environment and human health. To our knowledge, this study is the first evaluating the combined effect of temperature, soil moisture and light/dark conditions on AMPA formation/dissipation kinetics and behaviour. PMID- 27505265 TI - Ecotoxicological water assessment of an estuarine river from the Brazilian Northeast, potentially affected by industrial wastewater discharge. AB - Water pollution generated by industrial effluents discharge is a threat to the maintenance of aquatic ecosystems and human development. The Jundiai River estuarine, located in Northeast Brazil, receives an industrial pretreated effluent load from the city of Macaiba/RN/Brazil. The present study aimed to assess the water quality of this water reservoir through i) physicochemical characterization, ii) quantification of metal concentration and iii) by an ecotoxicological assessment carried out using Mysidopsis juniae and Pomacea lineata. The study was performed throughout the period comprising May to September 2014. Physicochemical variables such as chloride, total solids and electrical conductivity presented values in the waste discharge point, significantly different with those located out of the waste releasing point. Apart from that, metal concentration showed variable behavior throughout the monitored period. Levels of Al, Fe, Cu, Cd, Cr, Ni, Pb and Ag were over the considered guidelines. Both natural and anthropogenic sources seem to be involved in the resulting environmental scenario. A reduction in the fecundity rate (using Mysidopsis juniae) along with an increase in mortality rate (in both species) was observed ratifying the presence of toxic substances in this water reservoir. Moreover, a correlation analysis stated an association of the aforementioned toxicological effects with the delivery of industrial waste products. The ecotoxicological assessment performed highlighted the presence of toxic substance/s in water from the Jundiai River. Especially as a consequence of industrial activity, a fact that might threaten the bioma and, therefore, the human health of the population settled in the studied region. PMID- 27505264 TI - Entomopathogenic nematode food webs in an ancient, mining pollution gradient in Spain. AB - Mining activities pollute the environment with by-products that cause unpredictable impacts in surrounding areas. Cartagena-La Union mine (Southeastern Spain) was active for >2500years. Despite its closure in 1991, high concentrations of metals and waste residues remain in this area. A previous study using nematodes suggested that high lead content diminished soil biodiversity. However, the effects of mine pollution on specific ecosystem services remain unknown. Entomopathogenic nematodes (EPN) play a major role in the biocontrol of insect pests. Because EPNs are widespread throughout the world, we speculated that EPNs would be present in the mined areas, but at increased incidence with distance from the pollution focus. We predicted that the natural enemies of nematodes would follow a similar spatial pattern. We used qPCR techniques to measure abundance of five EPN species, five nematophagous fungi species, two bacterial ectoparasites of EPNs and one group of free-living nematodes that compete for the insect-cadaver. The study comprised 193 soil samples taken from mining sites, natural areas and agricultural fields. The highest concentrations of iron and zinc were detected in the mined area as was previously described for lead, cadmium and nickel. Molecular tools detected very low numbers of EPNs in samples found to be negative by insect-baiting, demonstrating the importance of the approach. EPNs were detected at low numbers in 13% of the localities, without relationship to heavy-metal concentrations. Only Acrobeloides-group nematodes were inversely related to the pollution gradient. Factors associated with agricultural areas explained 98.35% of the biotic variability, including EPN association with agricultural areas. Our study suggests that EPNs have adapted to polluted habitats that might support arthropod hosts. By contrast, the relationship between abundance of Acrobeloides-group and heavy-metal levels, revealed these taxa as especially well suited bio-indicators of soil mining pollution. PMID- 27505266 TI - Measurement of volatile organic compounds (VOCs) in libraries and archives in Florence (Italy). AB - Indoor air samples from libraries and archives in Florence, Italy, were collected and analysed for a variety of volatile organic compounds. The aim was to perform a characterisation of the indoor air quality, and try to elucidate if there are VOCs that may cause or result from the determination of the cultural heritage institutions. All compounds of interest were regularly detected, with BTEXs (Benzene, Toluene, Ethylbenzene, Xylenes) being the most abundant and followed by cyclic volatile methylsiloxanes, aldehydes, terpenes and organic acids. The prevalence and qualitative characteristics, such as concentrations, profiles and indoor/outdoor ratios of BTEXs underline the important influence of the outdoor air infiltrations on the indoor air concentrations. Acetic acid that is a substance that can oxidise books and other exposed objects was detected at concentrations ranging between 1.04 and 18.9MUgm-3, while furfural, that is a known marker of paper degradation, was constantly present at concentrations that ranged between 5.26 and 32.6MUgm-3. This work shows the importance that indoor air quality monitoring campaigns can have in order to give early warning to cultural heritage institution managers about the impact that indoor air quality can have on exposed and/or preserved objects. PMID- 27505267 TI - Impact of Behavioral Symptoms in Dementia Patients on Depression in Daughter and Daughter-in-Law Caregivers. AB - BACKGROUND: One caregiver relationship that has been neglected in caregiver depression research is the daughter-in-law. Compared with Western countries, in which those who are closer in familial relationships such as the spouse or child usually take care of the patient, in many Asian countries, the daughter-in-law often assumes the caretaker role. However, not much research has been done on how this relationship may result in different caregiver outcomes. We sought to identify whether the association between patient characteristics and caregiver depressive symptoms differs according to the familial relationship between caregiver and patient. MATERIALS AND METHODS: Ninety-five daughter (n = 47) and daughter-in-law (n = 48) caregivers of dementia patients were asked to report their own depressive symptoms and patient behavioral symptoms. Patients' cognitive abilities, daily activities, and global dementia ratings were obtained. Hierarchical linear regression was employed to determine predictors of depressive symptoms. RESULTS: Daughters-in-law had marginally higher depressive scores. After adjusting for caregiver and patient characteristics, in both groups, greater dependency in activities of daily living and more severe and frequent behavioral symptoms predicted higher caregiver depressive scores. However, greater severity and frequency of behavioral symptoms predicted depression to a greater degree in daughters compared with daughters-in-law. CONCLUSIONS: Although behavioral symptoms predicted depression in both caregiver groups, the association was much stronger for daughters. This suggests that the emotional relationship between the daughter and patient exacerbates the negative effect of behavioral symptoms on caregiver depression. The familial relationship between the caregiver and dementia patient should be considered in managing caregiver stress. PMID- 27505269 TI - Developmental and molecular biology of annelid regeneration: a comparative review of recent studies. AB - Studies of annelid regeneration have greatly increased in frequency in recent years, providing new insights into the developmental basis and evolution of regeneration. In this review, we summarize recent findings related to regeneration in annelids, focusing on molecular and developmental studies of epimorphic (blastema-based) regeneration, morphallactic (tissue-remodeling based) regeneration, and development and regeneration of putative stem cells of the posterior growth zone and germline. Regeneration is being investigated in a broad range of annelids spanning the phylum, and comparing findings among species reveals both widely conserved features that may be ancestral for the phylum as well as features that are variable across the group. PMID- 27505271 TI - Exertional Heat Illness in American Football Players: When Is the Risk Greatest? AB - CONTEXT: Knowledge about the specific environmental and practice risks to participants in American intercollegiate football during preseason practices is limited. Identifying risks may mitigate occurrences of exertional heat illness (EHI). OBJECTIVE: To evaluate the associations among preseason practice day, session number, and wet bulb globe temperature (WBGT) and the incidence of EHI. DESIGN: Descriptive epidemiology study. SETTING: Sixty colleges and universities representing 5 geographic regions of the United States. PATIENTS OR OTHER PARTICIPANTS: National Collegiate Athletic Association football players. MAIN OUTCOME MEASURE(S): Data related to preseason practice day, session number, and WBGT. We measured WBGT every 15 minutes during the practice sessions and used the mean WBGT from each session in the analysis. We recorded the incidence of EHIs and calculated the athlete-exposures (AEs). RESULTS: A total of 553 EHI cases and 365 810 AEs were reported for an overall EHI rate of 1.52/1000 AEs (95% confidence interval [CI] = 1.42, 1.68). Approximately 74% (n = 407) of the reported EHI cases were exertional heat cramps (incidence rate = 1.14/1000 AEs; 95% CI = 1.03, 1.25), and about 26% (n = 146) were a combination of exertional heat syncope and heat exhaustion (incidence rate = 0.40/1000 AEs; 95% CI = 0.35, 0.48). The highest rate of EHI occurred during the first 14 days of the preseason period, and the greatest risk was during the first 7 days. The risk of EHI increased substantially when the WBGT was 82.0 degrees F (27.8 degrees C) or greater. CONCLUSIONS: We found an increased rate of EHI during the first 14 days of practice, especially during the first 7 days. When the WBGT was greater than 82.0 degrees F (27.8 degrees C), the rate of EHI increased. Sports medicine personnel should take all necessary preventive measures to reduce the EHI risk during the first 14 days of practice and when the environmental conditions are greater than 82.0 degrees F (27.8 degrees C) WBGT. PMID- 27505270 TI - Clinical and Molecular Characteristics of Neonatal Extended-Spectrum beta Lactamase-Producing Gram-Negative Bacteremia: A 12-Year Case-Control-Control Study of a Referral Center in Taiwan. AB - Extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteremia (GNB) in the neonatal intensive care unit was characterized by comparison with two control groups: a susceptible control group and a general base population group over 2001 to 2012. The influence of ESBL production on mortality was studied in all study subjects and ESBL-GNB isolates were microbiologically characterized. We identified 77 episodes of ESBL-GNB (14.2% of all neonatal late-onset GNB), which were caused by Klebsiella spp. (62.3%), E. coli (20.8%) and Enterobacter spp. (16.9%). Most ESBL-GNB strains were genetically unrelated and the SHV-type ESBLs were the most prevalent (67% of isolates). Comparison with both control groups disclosed previous usage of 3rd generation cephalosporin (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.03-10.97; P < 0.001), and underlying renal disease (OR, 4.07; 95% CI, 1.10-15.08; P = 0.035) as independent risk factors for ESBL-GNB. Inadequate empiric antibiotics, a higher illness severity, higher rates of infectious complications and sepsis-attributable mortality were more frequently seen in neonates with ESBL-GNB than those with non-ESBL GNB (20.8% and 15.6% vs. 9.2% and 7.9%, respectively; P = 0.008 and 0.049, respectively). Neonates with underlying secondary hypertension (OR, 7.22; 95% CI, 2.17-24.06) and infectious complications after bacteremia (OR, 6.66; 95% CI, 1.81-19.31) were identified as independent risk factor for in-hospital mortality. ESBL-GNB accounted for one-seventh of all neonatal gram-negative bacteremia, especially in neonates exposed to broad-spectrum cephalosporins. Neonates with ESBL-GNB bacteremia more frequently received inadequate empirical antibiotic therapy, which were associated with a higher rate of infectious complications and an adverse outcome. PMID- 27505272 TI - Primary Nonendoscopic Endonasal Versus Delayed External Dacryocystorhinostomy in Acute Dacryocystitis. AB - PURPOSE: Conventional treatment for acute dacryocystitis consists of medical management followed by elective delayed external dacryocystorhinostomy (EXT-DCR). The purpose of this study was to compare the outcome after primary nonendoscopic endonasal dacryocystorhinostomy (NEN-DCR) versus conventional treatment in acute dacryocystitis. METHODS: Retrospective chart analysis of all consecutive patients of acute dacryocystitis presenting between 2011 and 2015 was performed. Group A had patients who underwent primary NEN-DCR within 2 weeks of presentation. Group B comprised age- and gender-matched patients who received conventional treatment. RESULTS: Forty-six patients were included with 23 patients in each group. Mean age (45.2 +/- 14.7 vs. 47.5 +/- 14 years) and gender distribution (women 17/23 in group A vs. 15/23 in group B) in both groups were comparable. Mean duration from presentation to surgery was 7.82 +/- 4.65 days for group A versus 27.3 +/- 12 days for group B (p = 0.00001, independent T test). Mean time for complete resolution of symptoms was 21.4 +/- 6 days for group A versus 38.69 +/- 15.8 for group B (p = 0.000014, independent T test). Mitomycin-C usage (0.04%; 17 vs. 14) and mean follow up of both groups (6.4 vs. 5.7 months) were comparable. While functional success was similar (20/23) in both, anatomical success was seen in 22/23 and 21/23 in groups A and B, respectively. Complications included disfiguring scar in 4, recurrent acute dacryocystitis in 3, and punctal ectropion in one patient in the EXT-DCR group. CONCLUSIONS: Primary NEN-DCR leads to faster resolution facilitating earlier rehabilitation with comparable anatomical and functional outcomes compared with conventional delayed EXT-DCR in acute dacryocystitis. PMID- 27505273 TI - Cyanide oxidation by singlet oxygen generated via reaction between H2O2 from cathodic reduction and OCl(-) from anodic oxidation. AB - Cyanide is widely present in electroplating wastewater or metallurgical effluents. In the present study, the electrochemical destruction of cyanide with various anode and cathode compositions under alkaline conditions was investigated. The results indicated that the electrochemical system using RuO2/Ti as anode and activated carbon fiber (ACF) as cathode in the presence of sodium chloride was efficient for the cyanide removal. In this system, in situ generation of HClO by anodic oxidation of Cl(-) at RuO2/Ti anode occurred with the H2O2 generation by O2 reduction at ACF cathode. As confirmed by the electron spin resonance technique, the reaction between HClO and H2O2 led to the generation of singlet oxygen, which was responsible for the cyanide removal. Further experiment indicated that the cyanide removal efficiency increased with the increase of the current density or the sodium chloride concentration. Cyanate was identified as main product in the system. Besides, the system exhibited good stability for the cyanide removal, which was beneficial to its practical application. PMID- 27505274 TI - Investigation of metal ion interaction with a lipid cubic phase using electrochemical impedance spectroscopy. AB - HYPOTHESIS: Electrochemical impedance spectroscopy, EIS, can be used as a complementary technique to investigate ion interaction with the headgroup region in the aqueous channels of a lipid cubic phase, LCP. EXPERIMENTS: A freestanding membrane made of monoolein LCP was formed by filling a small aperture that separates two cell compartments. The cell compartments were filled with electrolyte solutions at two different ionic strengths: i.e.: 10 and 100mM, of KCl, CsBr and CaCl2. Electrochemical impedance spectroscopy was recorded between two platinum electrodes that were present at each side of the membrane. FINDINGS: The membrane resistance and capacitance were estimated from equivalent circuit fitting of the impedance data. It was confirmed that calcium ions interacts strongly with the headgroup region in the aqueous channels giving significantly higher membrane resistances compared to monovalent alkali metal ions. The membrane capacitance with Ca(2+)(aq) in solution was concentration dependent, which for the first time indicates formation of two different cubic phases at these conditions. PMID- 27505275 TI - CdS-graphene Nanocomposite for Efficient Visible-light-driven Photocatalytic and Photoelectrochemical Applications. AB - This paper reports cadmium sulphide nanoparticles-(CdS NPs)-graphene nanocomposite (CdS-Graphene), prepared by a simple method, in which CdS NPs were anchored/decorated successfully onto graphene sheets. The as-synthesized nanocomposite was characterized using standard characterization techniques. A combination of CdS NPs with the optimal amount of two-dimensional graphene sheets had a profound influence on the properties of the resulting hybrid nanocomposite, such as enhanced optical, photocatalytic, and photo-electronic properties. The photocatalytic degradation ability of the CdS-Graphene nanocomposite was evaluated by degrading different types of dyes in the dark and under visible light irradiation. Furthermore, the photoelectrode performance of the nanocomposite was evaluated by different electrochemical techniques. The results showed that the CdS-Graphene nanocomposite can serve as an efficient visible light-driven photocatalyst as well as photoelectrochemical performance for optoelectronic applications. The significantly enhanced photocatalytic and photoelectrochemical performance of the CdS-Graphene nanocomposite was attributed to the synergistic effects of the enhanced light absorption behaviour and high electron conductivity of the CdS NPs and graphene sheets, which facilitates charge separation and lengthens the lifetime of photogenerated electron-hole pairs by reducing the recombination rate. The as-synthesized narrow band gap CdS Graphene nanocomposite can be used for wide range of visible light-induced photocatalytic and photoelectrochemical based applications. PMID- 27505276 TI - Ionosilicas as efficient sorbents for anionic contaminants: Radiolytic stability and ion capacity. AB - Ammonium based hybrid ionosilicas were prepared from tetrasilylated ammonium precursors. The formed material exhibited high specific surface area together with mesoporosity. Our results indicate that ionosilicas display high exchange capacity for iodide. They were submitted to 10MeV electron irradiation at a total dose of 1.7MGy. Irradiation was shown not to alter the properties of ionosilica: the morphological, textural and surface properties of the material are hardly modified. The sorption properties (sorption capacity and cumulative displacement enthalpy) are similar before and after electron irradiation. This high radiolytical stability confirms that these innovative materials have therefore high potential as anion traps for future applications in decontamination processes or long term storage of radioactive waste. PMID- 27505277 TI - Bioinspired polydopamine particles-assisted construction of superhydrophobic surfaces for oil/water separation. AB - Frequent oil spillages and industrial discharge of oils/organic solvents have induced severe environmental pollution and ecological damage, and a great cost in energy and finance has been consumed to solve the problems raised. Therefore, it is urgent to develop a surface hydrophobic modification that can be applied to materials with desired properties of high separation efficiency, excellent selectivity and stable performance in extreme conditions during the oil/water separation. Herein, with combined bioinspirations from mussel adhesive protein (polydopamine) and superhydrophobic lotus leaf (hierarchical structures), we develop a general way to superhydrophobically modify various commercial materials, aiming for the selective removal of oils/organic solvents from water. In this procedure, immersing commercial materials (e.g. melamine sponge, stainless steel mesh, nylon netting and cotton cloth) into water/ethanol/ammonia mixtures at a low concentration of dopamine (DA, 2mg/mL) allows a polydopamine (PDA) coating with a tunable roughness appearing on the substrate in one step. This is because DA can self-polymerize and form PDA particles with a catalyst of ammonia, attaching to any surfaces due to abundant catechol and amine groups in PDA, and ultimately, resulting in hierarchical structures. The subsequent decoration with 1H, 1H, 2H, 2H-perfluorodecanethiol features the surface superhydrophobic and superoleophilic. This approach is straightforward and economic, and carried out under a mild, environmental-benign circumstance, with nonspecific substrate demands. In addition, the as-prepared superhydrophobic materials exhibit excellent separation performances including high absorption/separation capacity, excellent selectivity, and extraordinary recyclability for collecting various oils/organic solvents from water. These superhydrophobic materials have also verified to be highly chemical resistant, environment stable and mechanically durable. Therefore, this simplicity and versatility of the direct mussel-inspired approach may facilitate the fast development of oil/water separation materials for applications in the field of water remediation, clean-up of oil spills and oil recovery. PMID- 27505278 TI - Au nanorods modulated NIR fluorescence and singlet oxygen generation of water soluble dendritic zinc phthalocyanine. AB - A novel cyano-terminated zinc phthalocyanine (ZnPc-CN) exhibiting visible near infrared (vis-NIR) emitting around 690nm in N,N-dimethylformamide (DMF) solvent has been synthesized. Furthermore, the peripheral cyano groups of newly synthesized zinc phthalocyanine were hydrolyzed in strong basic solution, leading to water soluble carboxylated zinc phthalocyanine (ZnPc-COOH) with completely quenched fluorescence in aqueous solution. Interestingly, we found that the NIR fluorescence of aqueous ZnPc-COOH was dramatically recovered in the presence of gold nanorods (Au NR), which was due to the alternation of ZnPc-COOH molecules self-assembling via electrostatic interaction between cetyltrimethylammonium bromide (CTAB) on the surface of Au NR and peripheral carboxyl of ZnPc-COOH. In addition, ZnPc-COOH/Au NR conjugates demonstrated an improved singlet oxygen generation, which could be served as potential bioimaging probe and photosensitizer for photodynamic therapy. PMID- 27505280 TI - High-throughput microsatellite genotyping in ecology: improved accuracy, efficiency, standardization and success with low-quantity and degraded DNA. AB - Microsatellite markers have played a major role in ecological, evolutionary and conservation research during the past 20 years. However, technical constrains related to the use of capillary electrophoresis and a recent technological revolution that has impacted other marker types have brought to question the continued use of microsatellites for certain applications. We present a study for improving microsatellite genotyping in ecology using high-throughput sequencing (HTS). This approach entails selection of short markers suitable for HTS, sequencing PCR-amplified microsatellites on an Illumina platform and bioinformatic treatment of the sequence data to obtain multilocus genotypes. It takes advantage of the fact that HTS gives direct access to microsatellite sequences, allowing unambiguous allele identification and enabling automation of the genotyping process through bioinformatics. In addition, the massive parallel sequencing abilities expand the information content of single experimental runs far beyond capillary electrophoresis. We illustrated the method by genotyping brown bear samples amplified with a multiplex PCR of 13 new microsatellite markers and a sex marker. HTS of microsatellites provided accurate individual identification and parentage assignment and resulted in a significant improvement of genotyping success (84%) of faecal degraded DNA and costs reduction compared to capillary electrophoresis. The HTS approach holds vast potential for improving success, accuracy, efficiency and standardization of microsatellite genotyping in ecological and conservation applications, especially those that rely on profiling of low-quantity/quality DNA and on the construction of genetic databases. We discuss and give perspectives for the implementation of the method in the light of the challenges encountered in wildlife studies. PMID- 27505279 TI - Monitoring of freshwater toxins in European environmental waters by using novel multi-detection methods. AB - Monitoring the quality of freshwater is an important issue for public health. In the context of the European project MUAqua, 150 samples were collected from several waters in France, Germany, Ireland, Italy, and Turkey for 2 yr. These samples were analyzed using 2 multitoxin detection methods previously developed: a microsphere-based method coupled to flow-cytometry, and an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. The presence of microcystins, nodularin, domoic acid, cylindrospermopsin, and several analogues of anatoxin-a (ATX-a) was monitored. No traces of cylindrospermopsin or domoic acid were found in any of the environmental samples. Microcystin-LR and microcystin-RR were detected in 2 samples from Turkey and Germany. In the case of ATX-a derivatives, 75% of samples contained mainly H2 -ATX-a and small amounts of H2 -homoanatoxin-a, whereas ATX-a and homoanatoxin-a were found in only 1 sample. These results confirm the presence and wide distribution of dihydro derivatives of ATX-a toxins in European freshwaters. Environ Toxicol Chem 2017;36:645-654. (c) 2016 SETAC. PMID- 27505281 TI - Molecular epidemiology of enterovirus and parechovirus infections according to patient age over a 4-year period in Spain. AB - The epidemiology and clinical association of enterovirus (EV) and parechovirus (HPeV) infections, as well as the type-distribution-according-to-age, were determined during a 4-year study period in Spain. During 2010-2013, a total of 21,832 clinical samples were screened for EV and the detection frequency was 6.5% (1,430). Of the total EV-negative samples, only 1,873 samples from 2011 to 2013 were available for HPeV testing. HPeV was detected in 42 (2%) of them. Positive samples were genotyped using PCR and sequencing. EV infections occurred in all age groups of patients: neonates (17%), children 28 days to 2 years (29%), children 2-14 years (40%), and adults (14%). Thirty-four different EV types were identified. HPeV infections were detected exclusively in infants <8 m (70% neonates, P < 0.05). All but one HPeV were HPeV-3. Differences in type frequency detection were found according to age and clinical manifestation. Coxsackievirus (CV)-B4 (61%), CV-B5 (83%), and HPeV-3 (64%) were more frequent in neonates than in older patients (P < 0.05). Echovirus (E)-3 (60%), E-18 (47%), E-25 (62%), CV A6 (61%), CV-A16 (72%), and EV-71 (75%) were mainly detected in children 28 days to 2 years (P < 0.05), whereas, E-6 (79%), E-20 (88%), and E-30 (85%) were predominant in children >2 years and adults (P < 0.05). Clinically, meningitis was associated with EV (P < 0.01) whereas, encephalitis was more frequent in HPeV infected patients. CV-B types were associated with myocarditis (90%; P < 0.05) and EV species A with hand-foot-mouth-disease/atypical exanthema (88%; P < 0.05). J. Med. Virol. 89:435-442, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27505282 TI - How do depressive symptoms in husbands and wives relate to the interpersonal dynamics of marital interactions? AB - We investigated how depressive symptoms in husbands and wives may affect patterns of interpersonal behavior during marital conflict discussions. Using the Continuous Assessment of Interpersonal Dynamics (CAID) approach, observers rated moment-to-moment levels of dominance and affiliation for each partner, from which dynamic indices were derived, including the slopes for each partner and the degree of rhythmic entrainment between partners. Results supported predictions that the wife's depressive symptoms would be related to alterations in the dynamics of dominance, whereas the husband's depressive symptoms would be related to alterations in the dynamics of affiliation. For example, the higher the husband's depressive symptoms, the less affiliative both the wife and husband became over the interaction and the less entrained the partners were on affiliation. The results shed new light on gender differences in the impact of depressive symptoms on the management of marital disagreements. (PsycINFO Database Record PMID- 27505283 TI - Vocational interests in the United States: Sex, age, ethnicity, and year effects. AB - Vocational interests predict educational and career choices, job performance, and career success (Rounds & Su, 2014). Although sex differences in vocational interests have long been observed (Thorndike, 1911), an appropriate overall measure has been lacking from the literature. Using a cross-sectional sample of United States residents aged 14 to 63 who completed the Strong Interest Inventory assessment between 2005 and 2014 (N = 1,283,110), I examined sex, age, ethnicity, and year effects on work related interest levels using both multivariate and univariate effect size estimates of individual dimensions (Holland's Realistic, Investigative, Artistic, Social, Enterprising, and Conventional). Men scored higher on Realistic (d = -1.14), Investigative (d = -.32), Enterprising (d = .22), and Conventional (d = -.23), while women scored higher on Artistic (d = .19) and Social (d = .38), mostly replicating previous univariate findings. Multivariate, overall sex differences were very large (disattenuated Mahalanobis' D = 1.61; 27% overlap). Interest levels were slightly lower and overall sex differences larger in younger samples. Overall sex differences have narrowed slightly for 18-22 year-olds in more recent samples. Generally very small ethnicity effects included relatively higher Investigative and Enterprising scores for Asians, Indians, and Middle Easterners, lower Realistic scores for Blacks and Native Americans, higher Realistic, Artistic, and Social scores for Pacific Islanders, and lower Conventional scores for Whites. Using Prediger's (1982) model, women were more interested in people (d = 1.01) and ideas (d = .18), while men were more interested in things and data. These results, consistent with previous reviews showing large sex differences and small year effects, suggest that large sex differences in work related interests will continue to be observed for decades. (PsycINFO Database Record PMID- 27505284 TI - The influence of multiple oppressions on women of color's experiences with insidious trauma. AB - In this study, we examined the relations between multiple forms of oppressive experiences (i.e., racism, sexism, and sexual objectification) and trauma symptoms among Women of Color (WOC). In addition, self-esteem was explored as a partial mediating variable in these links, and ethnic identity strength was proposed to buffer the negative relationship between multiple forms of oppression and self-esteem, and the positive relationship between oppressive experiences and trauma symptoms. Results suggested that self-esteem partially mediated the positive relationship between racist experiences and trauma symptoms, such that racism was related to lower self-esteem, which was then related to more trauma symptoms. Sexism and sexual objectification were directly linked with trauma symptoms. Moreover, average and high levels of ethnic identity strength buffered the positive link between racism and trauma symptoms. Consistent with an additive intersectionality framework, results demonstrate the importance of attending to multiple forms of oppression as they relate to trauma symptoms among WOC. (PsycINFO Database Record PMID- 27505285 TI - Confirmatory factor analytic investigation of variance composition, gender invariance, and validity of the Male Role Norms Inventory-Adolescent-revised (MRNI-A-r). AB - Confirmatory factor analysis of responses to the Male Role Norms Inventory Adolescent-revised (MRNI-A-r) from 384 middle school students (163 boys, 221 girls) indicated that the best fit to the data was a bifactor model incorporating the hypothesized 3-factor structure while explicitly modeling an additional, general factor. Specifically, each item-level indicator loaded simultaneously on 2 factors: a general traditional masculinity ideology factor and a specific factor corresponding to 1 of the 3 hypothesized masculine norms for adolescents: Emotionally Detached Dominance, Toughness, and Avoidance of Femininity. Invariance testing across gender supported metric invariance for the general factor only. Although item loadings on the general factor were similar across boys and girls, the specific factor loadings varied substantially, with many becoming nonsignificant in the presence of the general factor for girls. A structural regression analysis predicting latent variables of the Meanings of Adolescent Masculinity Scale (MAMS), the Rosenberg Self-esteem Scale, and the Discipline, School Difficulties, and Positive Behavior Scale (DSDPBS) indicated that the general factor was a strong predictor of MAMS for both genders and DSDPBS for girls. Findings indicate that the MRNI-A-r general factor is a valid and reliable indicator of overall internalization of traditional masculinity ideology in adolescents; however, the specific factors may have different meanings for boys as compared with girls and lack validity in the presence of the general factor. These findings are consistent with a developmental perspective of gender ideology that views adolescence as a time when a differentiated cognitive schema of masculine norms is beginning to develop. (PsycINFO Database Record PMID- 27505286 TI - Mode-Specific SN2 Reaction Dynamics. AB - Despite its importance in chemistry, the microscopic dynamics of bimolecular nucleophilic substitution (SN2) reactions is still not completely elucidated. In this publication, the dynamics of a prototypical SN2 reaction (F(-) + CH3Cl -> CH3F + Cl(-)) is investigated using a high-dimensional quantum mechanical model on an accurate potential energy surface (PES) and further analyzed by quasi classical trajectories on the same PES. While the indirect mechanism dominates at low collision energies, the direct mechanism makes a significant contribution. The reactivity is found to depend on the specific reactant vibrational mode excitation. The mode specificity, which is more prevalent in the direct reaction, is rationalized by a transition-state-based model. PMID- 27505287 TI - Registered Nurses' Perceptions about the Situation of Family Caregivers to Patients with Heart Failure - A Focus Group Interview Study. AB - INTRODUCTION: Heart failure is a growing public health problem associated with poor quality of life and significant morbidity and mortality. The majority of heart failure care is provided by family caregivers, and is associated with caregiver burden and reduced quality of life. Research emphasizes that future nursing interventions should recognize the importance of involving family caregivers to achieve optimal outcomes. AIMS: The aims of this study are to explore registered nurses' perceptions about the situation of family caregivers to patients with heart failure, and registered nurses' interventions, in order to improve family caregivers' situation. METHODS: The study has a qualitative design with an inductive approach. Six focus group interviews were held with 23 registered nurses in three hospitals and three primary health care centres. Data were analysed using qualitative content analysis. RESULTS: Two content areas were identified by the a priori study aims. Four categories and nine sub-categories emerged in the analysis process. The content area "Family caregivers' situation" includes two categories: "To be unburdened" and "To comprehend the heart failure condition and its consequences". The content area "Interventions to improve family caregivers' situation" includes two categories: "Individualized support and information" and "Bridging contact". CONCLUSIONS: Registered nurses perceive family caregivers' situation as burdensome, characterized by worry and uncertainty. In the PHCCs, the continuity and security of an RN as a permanent health care contact was considered an important and sustainable intervention to better care for family caregivers' worry and uncertainty. In the nurse-led heart failure clinics in hospitals, registered nurses can provide family caregivers with the opportunity of involvement in their relative's health care and address congruence and relationship quality within the family through the use of "Shared care" and or Family-centred care. Registered nurses consider it necessary to have a coordinated individual care plan as a basis for collaboration between the county council and the municipality. PMID- 27505288 TI - Joint toxicity prediction of nanoparticles and ionic counterparts: Simulating toxicity under a fate scenario. AB - The joint effects of NPs with other chemicals is not fully yet understood along with the joint effects of the particulate and dissolved forms/fractions. The predictability of joint effects is of great importance for environmental risk assessment. Therefore this study aimed at inferring on the predictability of NPs binary mixture toxicity based on their ionic counterparts' mixtures, and evaluating if the joint toxicity of two forms of the same element (NP and ion) acts as dilution of each other. Effects of individual and mixtures of ZnO and Ag NPs and their respective salts (AgNO3 and ZnCl2) were studied in immobilization and feeding tests using Daphnia magna. NPs mixture toxicity patterns did not mirror their ionic counterparts' mixture toxicity responses and therefore their prediction should not rely on the available knowledge for regular chemicals. Regarding mixtures from the same element with different forms (NP and ions), both Zn and Ag mixtures showed a deviation from additivity, relying on the interaction between NP and ions. A synergistic effect was depicted when the concentrations of Ag ions increased, while antagonism was observed with AgNP increase in suspension. This is an expected pattern in long term studies due to dissolution, relating fate and toxicity. PMID- 27505289 TI - Prevalence and dissemination of antibiotic resistance genes and coselection of heavy metals in Chinese dairy farms. AB - This study aims to explore prevalence and dissemination of antibiotic resistance genes (ARGs) in dairy farms. A variety of ARGs conferring resistance to most classes of antibiotics were detected in feces and soil samples obtained from dairy farms, using a high-throughput metagenomic sequencing approach. The ARGs observed in the feces and the soil samples were significantly correlated (p<0.01). The abundance of mobile genetics elements, such as transposase, was also examined to evaluate the potential risk of horizontal ARGs transfer. The positive correlation (p<0.001) between the total abundance of transposase genes and ARGs in the soil samples suggested strong dissemination capacity of ARGs in soil. In addition, the ARGs and metal resistance genes (MRGs) were significantly correlated with heavy metals in the feces (p<0.01), suggesting that the heavy metals promoted the emergence of metal resistance, and participated in the coselection processes for ARGs. The prevalence of ARGs with high levels of genetic mobile elements in the dairy farms suggests that cattle excrement is a major reservoir of ARGs with a high risk of dissemination, which increases the potential risk of environmental pollution and threatens public health. PMID- 27505290 TI - Experimental investigation of spontaneous ignition and flame propagation at pressurized hydrogen release through tubes with varying cross-section. AB - An experimental investigation of spontaneous ignition and flame propagation at high-pressure hydrogen release via cylindrical tubes with varying cross-section is presented. Tubes with different transverse cross-sections are considered in the experiments: (1) local contraction, (2) local enlargement, (3) abrupt contraction, and (4) abrupt enlargement. The results show that the presence of the varying cross-section geometries can significantly promote the occurrence of spontaneous ignition. Compared to the tube with constant cross-section, the minimum pressure release needed for spontaneous ignition for the varying cross sections tubes is considerably lower. Moreover, the initial ignition location is closer to the disk in the presence of varying cross-section geometries in comparison with straight channel. As the flame emerges from the outlet of the tube, the velocity of the flame front in the vicinity of the nozzle increases sharply. Then, a deflagration develops across the mixing zone of hydrogen/air mixture. The maximum deflagration overpressure increases linearly with the release pressure. Subsequently, a hydrogen jet flame is produced and evolves different shapes at different release stages. A fireball is formed after the jet flame spouts in the open air. Later, the fireball develops into a jet flame which shifts upward and continues to burn in the vertical direction. PMID- 27505291 TI - Iron phthalocyanine supported on amidoximated PAN fiber as effective catalyst for controllable hydrogen peroxide activation in oxidizing organic dyes. AB - Iron(II) phthalocyanine was immobilized onto amidoximated polyacrylonitrile fiber to construct a bioinspired catalytic system for oxidizing organic dyes by H2O2 activation. The amidoxime groups greatly helped to anchor Iron(II) phthalocyanine molecules onto the fiber through coordination interaction, which has been confirmed by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and UV-vis diffuse reflectance spectroscopy analyses. Electron spin resonance studies indicate that the catalytic process of physically anchored Iron(II) phthalocyanine performed via a hydroxyl radical pathway, while the catalyst bonded Iron(II) phthalocyanine through coordination effect could selectively catalyze the H2O2 decomposition to generate high-valent iron-oxo species. This may result from the amidoxime groups functioning as the axial fifth ligands to favor the heterolytic cleavage of the peroxide OO bond. This feature also enables the catalyst to only degrade the dyes adjacent to the catalytic active centers and enhances the efficient utilization of H2O2. In addition, this catalyst could effectively catalyze the mineralization of organic dyes and can be easily recycled without any loss of activity. PMID- 27505292 TI - Symptomatic Primary Selective Immunoglobulin M Deficiency with Nonprotective Pneumococcal Titers Responsive to Subcutaneous Immunoglobulin Treatment. AB - Selective immunoglobulin M deficiency (SIgMD) is a rare disorder with varying clinical features. The prevalence of SIgMD is 0.03-3%. Patients may be asymptomatic or else present with recurrent infection, autoimmunity, atopic disease and/or malignancy. About 50% of patients with symptomatic SIgMD also have impaired antibody responses to the pneumococcal polysaccharide vaccine. We report on an adult who presented with symptomatic SIgMD with impaired pneumococcal polysaccharide antibody responses and lymphopenia, who experienced a significant clinical improvement in the frequency of infections after subcutaneous immunoglobulin replacement therapy. PMID- 27505293 TI - Anti-Viral Therapy and Decreased Sexual Desire in Patients with Chronic Hepatitis C. AB - PURPOSE: Peg-interferon (PegIFN)alpha2a or PegIFNalpha2b plus ribavirin (RBV) is the standard therapy for chronic hepatitis C virus (HCV) infection in Taiwan and Asia. It is commonly associated with adverse effects, but the issue of sexual and mental health is not well reported. This study aimed to evaluate the impact of anti-viral therapy with PegIFNalpha plus RBV on sexual desire and depression. METHODS: This prospective cohort study from 2009 to 2014 enrolled 181 patients with HCV who received PegIFNalpha2a (180 mcg/week) or PegIFNalpha2b (1.5 mcg/Kg/week) plus RBV (800-1200 mg/day) according to response-guide therapy for 24 to 48 weeks in a tertiary medical center. Patients with decreased sexual desire (DSD) before PegIFNalpha plus RBV were excluded. Patients were evaluated at baseline (week 0) and after 2, 4, 8, 12, 16, 20, and 24 weeks of PegIFNalpha plus RBV treatment using the structured Mini-International Neuropsychiatric Interview, for the diagnosis of a major depressive episode, and the 21-item Beck Depression Inventory (BDI), for monitoring depressive symptoms. The 21st item of the BDI was used to evaluate DSD. RESULTS: During therapy, 124 (68.5%) patients had DSD. The BDI score peaked at 14.8 weeks. The severity of DSD was greatest at 16 weeks of treatment. The average score of the 21st item of the BDI correlated with DSD. Depression history and the prevalence of subsequent major depressive disorder after anti-viral therapy was correlated to DSD (p = 0.05 and 0.001). Male patients complained of DSD more significantly than females (p = 0.031). CONCLUSIONS: Decreased sexual desire is common but is usually neglected in patients with chronic hepatitis C undergoing anti-viral therapy, especially among male patients. Physicians must be monitoring the side effects of sexual health and depression. PMID- 27505294 TI - Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies. AB - Animal seizure and epilepsy models continue to play an important role in the early discovery of new therapies for the symptomatic treatment of epilepsy. Since 1937, with the discovery of phenytoin, almost all anti-seizure drugs (ASDs) have been identified by their effects in animal models, and millions of patients world wide have benefited from the successful translation of animal data into the clinic. However, several unmet clinical needs remain, including resistance to ASDs in about 30% of patients with epilepsy, adverse effects of ASDs that can reduce quality of life, and the lack of treatments that can prevent development of epilepsy in patients at risk following brain injury. The aim of this review is to critically discuss the translational value of currently used animal models of seizures and epilepsy, particularly what animal models can tell us about epilepsy therapies in patients and which limitations exist. Principles of translational medicine will be used for this discussion. An essential requirement for translational medicine to improve success in drug development is the availability of animal models with high predictive validity for a therapeutic drug response. For this requirement, the model, by definition, does not need to be a perfect replication of the clinical condition, but it is important that the validation provided for a given model is fit for purpose. The present review should guide researchers in both academia and industry what can and cannot be expected from animal models in preclinical development of epilepsy therapies, which models are best suited for which purpose, and for which aspects suitable models are as yet not available. Overall further development is needed to improve and validate animal models for the diverse areas in epilepsy research where suitable fit for purpose models are urgently needed in the search for more effective treatments. PMID- 27505295 TI - Nature and incidence of severe limbal stem cell deficiency in Australia and New Zealand. AB - BACKGROUND: This study aimed to determine the nature and incidence of severe limbal stem cell deficiency (LSCD) in Australia and New Zealand. DESIGN: A 1-year pilot surveillance study with a 1-year follow-up period was conducted in association with the Australian and New Zealand Ophthalmic Surveillance Unit. PARTICIPANTS: The study included patients reported by practising ophthalmologists on the Surveillance Unit's database. METHODS: Ophthalmologists were provided with a definition of severe limbal stem cell deficiency, contacted on a monthly basis by the Unit and asked to report newly diagnosed cases. MAIN OUTCOME MEASURES: Severe LSCD was defined as at least 6 clock hours of whorl-like epitheliopathy, an opaque epithelium arising from the limbus, late fluorescein staining of the involved epithelium and superficial corneal neovascularization or conjunctivalization. RESULTS: On average, 286 report cards were sent by the Surveillance Unit to practising ophthalmologists each month (total 3429 over 12 months) and the Unit received an average of 176 responses per month (total 2111; 62% response rate). During the 1-year study period from April 2013 to March 2014, 14 positive cases were reported to the Unit. A range of underlying aetiologies were implicated, with contact lens over-wear and cicatrizing conjunctivitis being the most common (n = 3). CONCLUSIONS: This surveillance study is the first worldwide to document the incidence of limbal stem cell deficiency; however, because of study design limitations, it is likely to have been under-reported. It provides novel data on the demographics, clinical conditions and management of patients with limbal stem cell deficiency as reported by treating ophthalmologists. PMID- 27505296 TI - 2016 European guideline on Mycoplasma genitalium infections. AB - Mycoplasma genitalium infection contributes to 10-35% of non-chlamydial non gonococcal urethritis in men. In women, M. genitalium is associated with cervicitis and pelvic inflammatory disease (PID). Transmission of M. genitalium occurs through direct mucosal contact. Asymptomatic infections are frequent. In women, symptoms include vaginal discharge, dysuria or symptoms of PID - abdominal pain and dyspareunia. In men, urethritis, dysuria and discharge predominates. Besides symptoms, indication for laboratory test is a high-risk sexual behaviour. Diagnosis is achievable only through nucleic acid amplification testing (NAAT). If available, NAAT diagnosis should be followed with an assay for macrolide resistance. Therapy for M. genitalium is indicated if M. genitalium is detected or on an epidemiological basis. Doxycycline has a low cure rate of 30-40%, but does not increase resistance. Azithromycin has a cure rate of 85-95% in macrolide susceptible infections. An extended course appears to have a higher cure rate. An increasing prevalence of macrolide resistance, most likely due to widespread use of azithromycin 1 g single dose without test of cure, is drastically decreasing the cure rate. Moxifloxacin can be used as second-line therapy, but resistance is increasing. Uncomplicated M. genitalium infection should be treated with azithromycin 500 mg on day one, then 250 mg on days 2-5 (oral), or josamycin 500 mg three times daily for 10 days (oral). Second line treatment and treatment for uncomplicated macrolide resistant M. genitalium infection is moxifloxacin 400 mg od for 7-10 days (oral). For third line treatment of persistent M. genitalium infection after azithromycin and moxifloxacin doxycycline 100 mg two times daily for 14 days can be tried and may cure 30%. Pristinamycin 1 g four times daily for 10 days (oral) has a cure rate of app. 90%. Complicated M. genitalium infection (PID, epididymitis) is treated with moxifloxacin 400 mg od for 14 days. PMID- 27505297 TI - Misdiagnosis of asthma in schoolchildren. AB - BACKGROUND: A correct diagnosis of asthma is the cornerstone of asthma management. Few pediatric studies have examined the accuracy of physician diagnosed asthma. OBJECTIVES: We determined the accuracy of parent reported physician-diagnosed asthma in children sampled from a community cohort. METHODS: Nested case-control study that recruited 203 children, aged 9-12, from a community-based sample. Three groups were recruited: asthma cases had a parental report of physician-diagnosed asthma, symptomatic controls had respiratory symptoms without a diagnosis of asthma, and asymptomatic controls had no respiratory symptoms. All participants were assessed and assigned a clinical diagnosis by one of three study physicians, and then completed spirometry, methacholine challenge, and allergy skin testing. The reference standard of asthma required a study physician's clinical diagnosis of asthma and either reversible bronchoconstriction or a positive methacholine challenge. Diagnostic accuracy, sensitivity and specificity were calculated for parent-reported asthma diagnosis compared to the reference standard. RESULTS: One hundred two asthma cases, 52 controls with respiratory symptoms but no asthma diagnosis, and 49 asymptomatic controls were assessed. Physician agreement for the diagnosis of asthma was moderate (kappa 0.46-0.81). Compared to the reference standard, 45% of asthma cases were overdiagnosed and 10% of symptomatic controls were underdiagnosed. Parental report of physician-diagnosed asthma had 75% sensitivity and 92% specificity for correctly identifying asthma. CONCLUSIONS: There is significant misclassification of childhood asthma when the diagnosis relies solely on a clinical history. This study highlights the importance of objective testing to confirm the diagnosis of asthma. Pediatr Pulmonol. 2017;52:293-302. (c) 2016 Wiley Periodicals, Inc. PMID- 27505298 TI - Solution Binding and Structural Analyses Reveal Potential Multidrug Resistance Functions for SAV2435 and CTR107 and Other GyrI-like Proteins. AB - Multidrug resistance (MDR) refers to the acquired ability of cells to tolerate a broad range of toxic compounds. One mechanism cells employ is to increase the level of expression of efflux pumps for the expulsion of xenobiotics. A key feature uniting efflux-related mechanisms is multidrug (MD) recognition, either by efflux pumps themselves or by their transcriptional regulators. However, models describing MD binding by MDR effectors are incomplete, underscoring the importance of studies focused on the recognition elements and key motifs that dictate polyspecific binding. One such motif is the GyrI-like domain, which is found in several MDR proteins and is postulated to have been adapted for small molecule binding and signaling. Here we report the solution binding properties and crystal structures of two proteins containing GyrI-like domains, SAV2435 and CTR107, bound to various ligands. Furthermore, we provide a comparison with deposited crystal structures of GyrI-like proteins, revealing key features of GyrI-like domains that not only support polyspecific binding but also are conserved among GyrI-like domains. Together, our studies suggest that GyrI-like domains perform evolutionarily conserved functions connected to multidrug binding and highlight the utility of these types of studies for elucidating mechanisms of MDR. PMID- 27505299 TI - Synthetic Utilization of alpha-Aminoalkyl Radicals and Related Species in Visible Light Photoredox Catalysis. AB - Single electron oxidation of amines provides an efficient way to access synthetically useful alpha-aminoalkyl radicals as reactive intermediates. After the single electron oxidation of amines, fragmentation of the resulting radical cations proceeds to give the alpha-aminoalkyl radicals along with generation of a proton. In the synthetic utilization of the alpha-aminoalkyl radicals, precise control of single electron transfer is essential, because further oxidation of the alpha-aminoalkyl radicals occurs more easily than the starting amines and the alpha-aminoalkyl radicals are converted into the corresponding iminium ions. As a result, photoinduced single electron transfer is quite attractive in the synthetic utilization of the alpha-aminoalkyl radicals. Recently, visible light photoredox catalysis using transition metal-polypyridyl complexes and other dyes as catalysts has attracted considerable attention, where useful molecular transformations can be achieved through the single electron transfer process between the excited catalysts and substrates. In this context, MacMillan et al. ( Science 2011, 334 , 1114 , DOI: 10.1126/science.1213920 ) reported an aromatic substitution reaction of cyanoarenes with amines, where alpha-aminoalkyl radicals work as key reactive intermediates. Pandey and Reiser et al. ( Org. Lett. 2012 , 14 , 672 , DOI: 10.1021/ol202857t ) and our group ( Nishibayashi et al. J. Am. Chem. Soc. 2012 , 134 , 3338 , DOI: 10.1021/ja211770y ) independently reported reactions of amines with alpha,beta-unsaturated carbonyl compounds, where addition of alpha-aminoalkyl radicals to alkenes is a key step. After these earliest examples, nowadays, a variety of transformations using the alpha aminoalkyl radicals as reactive intermediates have been reported by many groups. The alpha-aminoalkyl radicals are usually produced from amines by single electron oxidation and the subsequent deprotonation of the C-H bond adjacent to the nitrogen atom. In addition, the alpha-aminoalkyl radicals are also produced from alpha-silylamines and alpha-amino acids in high efficiency through desilylation or decarboxylation after the single electron oxidation. The generated alpha aminoalkyl radicals are utilized in a variety of reaction systems. In fact, reactions based on the addition of alpha-aminoalkyl radicals to alkenes and other unsaturated bonds have been extensively studied. Aromatic and other types of substitution reactions have also been investigated. Some of these transformations are achieved by combination of photoredox catalysts and other catalysts such as Bronsted and Lewis acids, organocatalysts, and transition metal catalysts. It is also noteworthy that the enantioselective reactions have been accomplished by combination of photoredox catalysts and chiral catalysts. The strategy for the generation of alpha-aminoalkyl radicals can be applied to utilize other types of alkyl radicals. In the generation of alpha-aminoalkyl radicals, the bond dissociation of the radical cations occurs at the alpha-position of amines. In relation to this process, synthetic utilization of other types of alkyl radicals generated by the bond dissociation of the radical cations at a remote position has been also investigated. These alkyl radicals have been applied to molecular transformations in a manner similar to the alpha-aminoalkyl radicals. Recently, organic synthesis using the alpha-aminoalkyl radicals and related alkyl radicals has been studied extensively. In this Account, we describe recent advances in photoredox-catalyzed synthetic utilization of these alkyl radicals. PMID- 27505300 TI - Radio-protective effect of some new curcumin analogues. AB - In the present study, novel symmetrical curcumin analogues (2-7) have been synthesized by substituting the phenolic OH of curcumin with different linkers providing additional keto-enol tautomerism, very essential for radioprotective activity. The structures of the synthesized compounds (2-7) were elucidated by elemental analysis, IR, (1)H-NMR, (13)C-NMR and mass spectral data and were found consistent with the assigned structures. The curative effect of these new compounds, against the oxidative stress due to exposure of rats to the whole body gamma-irradiation (7Gy) was investigated. Gamma-irradiated rats exhibited elevations of ALT, AST activities, urea, creatinine, triglycerides, total cholesterol, malondialdehyde (MDA), nitric oxide (NO), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-alpha) and Nuclear Factor-kappa B (NF-kappaB) levels. Contrariwise, the total protein, albumin, total calcium level, SOD, CAT, GSH-Px, GST activities and GSH content were decreased. Treatment of gamma irradiated rats with the new curcumin analogues (2-7) showed significant amelioration in the in-vivo antioxidant status, liver and kidney functions, as well as the anti-inflammatory markers (IL-6, TNF-alpha and NF-kappaB). Inhibition of NF-kappaB could be responsible for the improvement of the antioxidant and anti inflammatory status in gamma-irradiated animals, by down-regulation of IL-1beta and TNF-alpha level. In conclusion, the new curcumin analogues (2-7) exhibited post-protective effect on gamma-irradiation, by NF-kappaB inhibition. PMID- 27505301 TI - Randomized clinical trial comparing 10- or 14-day sequential therapy and 10- or 14-day concomitant therapy for the first line empirical treatment of Helicobacter pylori infection. AB - BACKGROUND AND AIM: Whether concomitant therapy is superior to sequential therapy (ST) as first-line therapy of Helicobacter pylori in areas with high clarithromycin resistance remains controversial. The aim of this study was to compare the efficacy and tolerability of 10- or 14-day ST with 10- or 14-day concomitant therapy (CT). METHODS: This was a prospective randomized study comparing 10- or 14-day ST with 10- or 14-day CT. The ST-10 and ST-14 groups received pantoprazole 40 mg and amoxicillin 1 g twice a day for the first 5 and 7 days followed by pantoprazole 40 mg, clarithromycin 500 mg, and metronidazole 500 mg twice a day for the remaining 5 and 7 days, respectively. The CT-10 and CT-14 groups received pantoprazole 40 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg twice daily for 10 and 14 days, respectively. RESULTS: Three hundred forty-one patients were randomly allocated to the four groups. The modified intention-to-treat eradication rates of ST-10, ST-14, CT-10, and CT-14 were 91.7%, 91.2%, 94.2%, and 98.5%, respectively. The corresponding per protocol eradication rates were 91.4%, 91.0%, 95.6%, and 98.5%. There was no difference in compliance and adverse events in the four groups. Eradication rates increased sequentially with statistical significance in the following order: ST-10, ST-14, CT-10, and CT-14 (P = 0.044). CONCLUSIONS: All four regimens achieved eradication rates >90% in per protocol analyses in a country with high clarithromycin resistance. There was no difference in tolerability among the four regimens. PMID- 27505303 TI - Synthetic Tuning of Redox, Spectroscopic, and Photophysical Properties of {Mo6I8}(4+) Core Cluster Complexes by Terminal Carboxylate Ligands. AB - The reactions between the tetra-n-butylammonium salt of [{Mo6I8}I6](2-) and silver carboxylates RCOOAg (R = CH3 (1), C(CH3)3 (2), alpha-C4H3O (3), C6H5 (4), alpha-C10H7 (5), or C2F5 (6)) in CH2Cl2 afforded new carboxylate complexes [{Mo6I8}(RCOO)6](2-). The complexes were characterized by X-ray single-crystal diffraction and elemental analysis, cyclic/differential pulse voltammetry, and IR, NMR, and UV-visible spectroscopies. The emission properties of the complexes 1-6, and those of the earlier reported complexes with R = CF3 (7) and n-C3F7 (8), were studied both in acetonitrile solution and in the solid state. In deaerated CH3CN at 298 K, all of the complexes 1-8 exhibit intense and long-lived emission with the quantum yield and lifetime being 0.48-0.73 and 283-359 MUs, respectively. The oxidation (Eox)/reduction (Ered) potentials of the complexes correlate linearly with the pKa value of the terminal carboxylate ligands L = RCOO (pKa(L)). Reflecting the pKa(L) dependences of Eox/Ered, the emission energy (nuem) of the complexes was also shown to correlate with pKa(L). The present study successfully demonstrates synthetic tuning of the redox, spectroscopic, and photophysical characteristics of a {Mo6I8}(4+)-based cluster complex with pKa(L). PMID- 27505302 TI - Importance of the Anchor Group Position (Para versus Meta) in Tetraphenylmethane Tripods: Synthesis and Self-Assembly Features. AB - The efficient synthesis of tripodal platforms based on tetraphenylmethane with three acetyl-protected thiol groups in either meta or para positions relative to the central sp(3) carbon for deposition on Au (111) surfaces is reported. These platforms are intended to provide a vertical arrangement of the substituent in position 4 of the perpendicular phenyl ring and an electronic coupling to the gold substrate. The self-assembly features of both derivatives are analyzed on Au (111) surfaces by low-temperature ultra-high-vacuum STM, high-resolution X-ray photoelectron spectroscopy, near-edge X-ray absorption fine structure spectroscopy, and reductive voltammetric desorption studies. These experiments indicated that the meta derivative forms a well-ordered monolayer, with most of the anchoring groups bound to the surface, whereas the para derivative forms a multilayer film with physically adsorbed adlayers on the chemisorbed para monolayer. Single-molecule conductance values for both tripodal platforms are obtained through an STM break junction experiment. PMID- 27505304 TI - Paper Thermoelectrics: Merging Nanotechnology with Naturally Abundant Fibrous Material. AB - The development of paper-based sensors, antennas, and energy-harvesting devices can transform the way electronic devices are manufactured and used. Herein we describe an approach to fabricate paper thermoelectric generators for the first time by directly impregnating naturally abundant cellulose materials with p- or n type colloidal semiconductor quantum dots. We investigate Seebeck coefficients and electrical conductivities as a function of temperature between 300 and 400 K as well as in-plane thermal conductivities using Angstrom's method. We further demonstrate equipment-free fabrication of flexible thermoelectric modules using p and n-type paper strips. Leveraged by paper's inherently low thermal conductivity and high flexibility, these paper modules have the potential to efficiently utilize heat available in natural and man-made environments by maximizing the thermal contact to heat sources of arbitrary geometry. PMID- 27505305 TI - Effectiveness of a Predictive Algorithm in the Prevention of Exercise-Induced Hypoglycemia in Type 1 Diabetes. AB - BACKGROUND: Sensor-augmented pump therapy (SAPT) with a predictive algorithm to suspend insulin delivery has the potential to reduce hypoglycemia, a known obstacle in improving physical activity in patients with type 1 diabetes. The predictive low glucose management (PLGM) system employs a predictive algorithm that suspends basal insulin when hypoglycemia is predicted. The aim of this study was to determine the efficacy of this algorithm in the prevention of exercise induced hypoglycemia under in-clinic conditions. METHODS: This was a randomized, controlled cross-over study in which 25 participants performed 2 consecutive sessions of 30 min of moderate-intensity exercise while on basal continuous subcutaneous insulin infusion on 2 study days: a control day with SAPT alone and an intervention day with SAPT and PLGM. The predictive algorithm suspended basal insulin when sensor glucose was predicted to be below the preset hypoglycemic threshold in 30 min. We tested preset hypoglycemic thresholds of 70 and 80 mg/dL. The primary outcome was the requirement for hypoglycemia treatment (symptomatic hypoglycemia with plasma glucose <63 mg/dL or plasma glucose <50 mg/dL) and was compared in both control and intervention arms. RESULTS: Results were analyzed in 19 participants. In the intervention arm with both thresholds, only 6 participants (32%) required treatment for hypoglycemia compared with 17 participants (89%) in the control arm (P = 0.003). In participants with a 2-h pump suspension on intervention days, the plasma glucose was 84 +/- 12 and 99 +/- 24 mg/dL at thresholds of 70 and 80 mg/dL, respectively. CONCLUSIONS: SAPT with PLGM reduced the need for hypoglycemia treatment after moderate-intensity exercise in an in-clinic setting. PMID- 27505306 TI - Barriers to and enablers of insulin self-titration in adults with Type 2 diabetes: a qualitative study. AB - AIMS: To identify the barriers to and enablers of effective insulin self titration in people with Type 2 diabetes. METHODS: A qualitative semi-structured interview approach was used. Questions were structured according to the Theoretical Domains Framework, which outlines 14 domains that can act as barriers to and enablers of changing behaviour. Interviews were audio-recorded and transcribed verbatim. The data were coded according to the 14 domains, belief statements were created within each domain, and a frequency count of the most reported barriers and enablers was then carried out. Analyses were conducted by two researchers, and discrepancies agreed with a third researcher. RESULTS: A total of 18 adults with Type 2 diabetes took part in an interview. The majority were of South-Asian ethnicity (n = 8) and were men (n = 12). Their mean age was 61 years old. The mean duration of diabetes was 16 years and time on insulin 9 years. Inter-rater reliability for each of the domains varied (29-100%). The most frequently reported domains were Social Influence and Beliefs about Consequences; the least frequently reported were Optimism and Reinforcement. Interviewees reported receiving support to self-titrate from a range of sources. Self titrating was perceived to have a range of both positive and negative consequences, as was not titrating. CONCLUSIONS: The findings highlight that those interviewed experienced a range of barriers and enablers when attempting to self-titrate. Improved education and training when initiating insulin treatment among adults with Type 2 diabetes, and throughout their journey on insulin therapy could help identify and address these barriers in order to optimize self titration. PMID- 27505307 TI - Oxytocin and arginine vasopressin receptor evolution: implications for adaptive novelties in placental mammals. AB - Oxytocin receptor (OXTR) and arginine vasopressin receptors (AVPR1a, AVPR1b, and AVPR2) are paralogous genes that emerged through duplication events; along the evolutionary timeline, owing to speciation, numerous orthologues emerged as well. In order to elucidate the evolutionary forces that shaped these four genes in placental mammals and to reveal specific aspects of their protein structures, 35 species were selected. Specifically, we investigated their molecular evolutionary history and intrinsic protein disorder content, and identified the presence of short linear interaction motifs. OXTR seems to be under evolutionary constraint in placental mammals, whereas AVPR1a, AVPR1b, and AVPR2 exhibit higher evolutionary rates, suggesting that they have been under relaxed or experienced positive selection. In addition, we describe here, for the first time, that the OXTR, AVPR1a, AVPR1b, and AVPR2 mammalian orthologues preserve their disorder content, while this condition varies among the paralogues. Finally, our results reveal the presence of short linear interaction motifs, indicating possible functional adaptations related to physiological and/or behavioral taxa-specific traits. PMID- 27505309 TI - Comparison of Early Submucosal Enhancement and Tumor Stalk in Staging Bladder Urothelial Carcinoma. AB - OBJECTIVE: The purpose of this study was to compare the efficacy of submucosal enhancement on dynamic contrast-enhanced MRI (DCE-MRI) and detection of a stalk on DWI for differentiating stage T1 from stage T2 bladder urothelial carcinoma. SUBJECTS AND METHODS: Our prospective study was approved by the institutional medical ethics committee and informed consent was obtained from all patients. Fifty-nine patients (92 tumors in total) with urothelial bladder cancer underwent MRI within 2 weeks before surgery. Two image sets of T2-weighted MRI with DWI and T2-weighted with DCE-MRI were interpreted independently at 2-week intervals by two uroradiologists without any knowledge of the surgical or histologic findings. The tumor was categorized as stage T1 or lower when a stalk was evident at the tumor base on DWI or when continuous linear submucosal enhancement was detected in the early phase of DCE-MRI. Tumors without stalks or with discontinuous linear submucosal enhancement were categorized as stage T2. RESULTS: Of the 42 tumors with stalks on DWI, 41 showed continuous and one had discontinuous submucosal enhancement on DCE-MRI. In 50 carcinomas without stalks on DWI, submucosal enhancement was absent in 34, continuous in 12, and discontinuous in four. The staging accuracy of DWI (91.3%, 84/92) and DCE-MRI (91.3%, 84/92) was improved to 94.6% (87/92) by combining the interpretations of both DWI and DCE-MRI. CONCLUSION: Submucosal linear enhancement under the tumor base on DCE-MRI complements tumor stalk detection on DWI for differentiating stage T1 from stage T2 bladder urothelial carcinoma. PMID- 27505308 TI - Plant senescence and proteolysis: two processes with one destiny. AB - Senescence-associated proteolysis in plants is a complex and controlled process, essential for mobilization of nutrients from old or stressed tissues, mainly leaves, to growing or sink organs. Protein breakdown in senescing leaves involves many plastidial and nuclear proteases, regulators, different subcellular locations and dynamic protein traffic to ensure the complete transformation of proteins of high molecular weight into transportable and useful hydrolysed products. Protease activities are strictly regulated by specific inhibitors and through the activation of zymogens to develop their proteolytic activity at the right place and at the proper time. All these events associated with senescence have deep effects on the relocation of nutrients and as a consequence, on grain quality and crop yield. Thus, it can be considered that nutrient recycling is the common destiny of two processes, plant senescence and, proteolysis. This review article covers the most recent findings about leaf senescence features mediated by abiotic and biotic stresses as well as the participants and steps required in this physiological process, paying special attention to C1A cysteine proteases, their specific inhibitors, known as cystatins, and their potential targets, particularly the chloroplastic proteins as source for nitrogen recycling. PMID- 27505310 TI - Comparison of the extent and pattern of cognitive impairment among predialysis, dialysis and transplant patients: A cross-sectional study from Australia. AB - AIM: The aim of this study was to compare the extent of cogntive impairment and the types of cognitive deficits in an Australian cohort of four patient groups with end stage kidney disease. Characteristics predicting the presence of cognitive impairment were also evaluated. METHODS: Observational cross-sectional study of 155 patients with end stage kidney disease are recruited from a regional Australian renal unit. Eligible participants included those whose estimated Glomerular Filtration Rate was < 30 ml/min per 1.73 m2 , were undertaking peritoneal or haemodialysis, or had received a kidney transplant. The Montreal Cognitive Assessment tool was used to screen the study participants for cognitive impairment and evaluate cognitive deficits. Cognitive impairment was defined as a total Montreal Cognitive Assessment tool score <=24/30. RESULTS: The extent of cognitive impairment varied between the four groups with end stage kidney disease. Factors predicting the presence of cognitive impairment included undertaking dialysis, age >=65, male gender and the presence of diabetes or cerebrovascular disease. Deficits in executive function, attention, language, visuospatial skills, memory and orientation were common among the study participants, and the extent of these deficits varied between groups. Limitations to the study included the cross-sectional design, and that the presence of confounders like depression were not recorded. CONCLUSION: The impact of disparities in the cognitive capabilities identified in this study are likely to be far reaching. Tailoring of education and self-management programmes to the cognitive deficits of individuals is required. PMID- 27505311 TI - Combining Placido and Corneal Wavefront Data for the Detection of Forme Fruste Keratoconus. AB - PURPOSE: To evaluate the accuracy of a new objective method based on Placido disk derived data for the detection of eyes at risk of ectasia. METHODS: One hundred nineteen eyes of 176 patients were included and separated into two groups, normal and forme fruste keratoconus (FFKC), using automated corneal classification software. Normal eyes (n = 114) were classified as negative for keratoconus and keratoconus suspect and had undergone LASIK with unremarkable follow-up for 4 years. The FFKC group was composed of 62 topographically normal eyes of patients with keratoconus in the fellow eye. Anterior topographic parameters, obtained from specular topography using Placido-based indices and corneal wavefront Zernike coefficients, were compared between groups. Receiver operating characteristic (ROC) curves were used to identify cut-off points in discriminating between keratoconic and normal eyes. Validation was performed on an external group of eyes. RESULTS: A discriminant function was built combining four corneal wavefront variables and four Placido variables. The area under the receiver operating characteristic was 0.970 with this eight-variable model. The validation of this function had 63% sensitivity for detecting FFKC and 100% sensitivity for detecting keratoconus, with a specificity of 82%. CONCLUSIONS: Indices generated from corneal wavefront and Placido measurements can assist in identifying early or mild forms of keratoconus undetected by a Placido-based neural network program. [J Refract Surg. 2016;32(8):510-516.]. PMID- 27505313 TI - Clinical Evaluation of Reading Performance Using the Salzburg Reading Desk With a Refractive Rotational Asymmetric Multifocal Intraocular Lens. AB - PURPOSE: To evaluate functional results and reading performance using the Salzburg Reading Desk after implantation of a sector-shaped near-embedded, rotational asymmetrical multifocal intraocular lens (IOL) and a multifocal toric IOL with a +3.00 diopter (D) near addition. METHODS: In a prospective study, the LentisMplus and Mplus toric IOLs (Oculentis GmbH, Berlin, Germany) were implanted in 34 eyes of 18 patients at the University Eye Hospital of Heidelberg. Uncorrected and corrected distance visual acuity (UDVA, CDVA) and uncorrected and corrected near visual acuity (UNVA, CNVA) were evaluated using standardized visual acuity charts (ETDRS). The Salzburg Reading Desk was used to analyze unilateral and bilateral uncorrected and corrected reading acuity, reading distance, reading speed, and the smallest log-scaled print size that could be read effectively at a set (40 cm/80 cm) and subjective chosen near and intermediate distance. RESULTS: Postoperatively, the median UDVA was 0.08 logMAR (20/25 Snellen) and the median CDVA was 0.01 logMAR (20/20 Snellen). The median UNVA was 0.12 logMAR (20/25 Snellen) and the median CNVA was 0.03 logMAR (20/20 Snellen). The median uncorrected reading acuity measured with the Salzburg Reading Desk for near distance at 40 cm was 0.18 logMAR (20/32 Snellen). The subjectively preferred near distance was 39 cm and revealed similar visual acuity results. The best reading acuity for intermediate distance with a median of 0.22 logMAR (20/32 Snellen) was achieved at a median distance of 62 cm. CONCLUSIONS: Reading performance of the multifocal IOL corresponded for near standardized and individual distance, whereas reading function was better at the patient's preferred intermediate distance. [J Refract Surg. 2016;32(8):526-532.]. PMID- 27505312 TI - Long-term Effects of LASIK on Corneal Innervation and Tear Neuropeptides and the Associations With Dry Eye. AB - PURPOSE: To investigate the associations between dry eye, corneal nerves, and tear neuroptides in dry eye after LASIK. METHODS: A single visit cross-sectional study was performed. Twenty participants who had LASIK more than 12 months prior and 20 healthy participants were recruited. Ocular comfort, tear functions, ocular surface sensitivity, basal tear collection, and corneal nerve morphology assessments were conducted. Tear substance P and calcitonin gene-related peptide (CGRP) concentrations were determined using ELISAs. Differences in variables between groups were examined using an independent t test or Mann-Whitney U test, as appropriate. Associations between variables in the post-LASIK group were examined using a Spearman's correlation test. A P value of less than .05 was considered significant. RESULTS: Central corneal nerve morphology parameters were all altered in the post-LASIK group (P < .05). Higher ocular discomfort (P = .01), tear CGRP concentration (P = .001), and conjunctival sensitivity (P < .009) were found in the post-LASIK group. There was a positive association between dry eye symptoms and superior corneal sensitivity (P = .51, P = .02) and tear substance P concentration (P = .52, P < .03). CONCLUSIONS: This study provides evidence of the association between tear neuropeptides, conjunctival sensitivity, and symptoms in symptomatic patients after LASIK. The differences in nerve morphology, neuropeptide, and ocular surface sensitivity between symptomatic and asymptomatic patients after LASIK are required to better understand the mechanism of dry eye after LASIK. [J Refract Surg. 2016;32(8):518-524.]. PMID- 27505314 TI - Pediatric Keratoconus in a Tertiary Referral Center: Incidence, Presentation, Risk Factors, and Treatment. AB - PURPOSE: To report the incidence, clinical presentation, risk factors, and treatment outcome of pediatric keratoconus in a tertiary referral eye hospital in Beirut, Lebanon. METHODS: In this retrospective study, the authors evaluated all patients with keratoconus 14 years or younger newly diagnosed at the Beirut Eye Specialist Hospital, Beirut, Lebanon, between January 2010 and December 2014. The incidence of pediatric keratoconus among all pediatric patients and among patients with keratoconus of all ages was assessed. Patients with pediatric keratoconus were evaluated for keratoconus stage, initial presentation, uncorrected distance visual acuity, corrected distance visual acuity (CDVA), corneal topography, and pachymetry. Patients were classified according to different treatment regimen groups and different follow-up visits were evaluated. RESULTS: During 5 years, 16,808 patients were examined, of whom 2,972 were 14 years or younger. A total of 541 patients were diagnosed as having keratoconus; of those, 16 were 14 years or younger at the time of diagnosis. Hence, the incidence of keratoconus was 0.53% among pediatric patients and 3.78% among adult patients (> 14 years). Initial presentation was during routine checkup (1 of 16) for allergic conjunctivitis (3 of 16), reduced vision (10 of 16), and corneal hydrops (mimicking keratitis) (2 of 16). Except for 2 patients lost to follow-up, all eyes received corneal cross-linking treatment and 16 eyes received additional intracorneal ring segment implantation. CONCLUSIONS: The incidence of pediatric keratoconus indicates that increased awareness for keratoconus among children is needed, mainly in cases of family history of keratoconus, ocular allergy/pruritus, poor CDVA, corneal hydrops, and/or high astigmatism. [J Refract Surg. 2016;32(8):534-541.]. PMID- 27505315 TI - Comparison of Simulated Keratometric Changes Following Wavefront-Guided and Wavefront-Optimized Myopic Photorefractive Keratectomy. AB - PURPOSE: To determine the relationship between change in simulated keratometry and corrected refractive error in both wavefront-guided and wavefront-optimized myopic photorefractive keratectomy (PRK), and to determine whether there is a difference in this relationship between these two ablation profiles. METHODS: Sixty-eight patients received wavefront-guided PRK in one eye and wavefront optimized PRK in the contralateral eye. The changes in simulated keratometry and corresponding refractive changes for both were determined at 1 year postoperatively. Linear regression was employed to calculate the slope of change in simulated keratometry (DeltaK) for change in refractive error (DeltaSE) for both wavefront-guided and wavefront-optimized PRK and compared. The mean ratio DeltaK/DeltaSE was also calculated for both wavefront-guided and wavefront optimized PRK and compared. RESULTS: There was no significant difference in the ratio of DeltaK to DeltaSE between wavefront-optimized and wavefront-guided PRK by both linear regression modeling and comparison of the mean ratio DeltaK/DeltaSE. Linear regression modeling revealed that the ratio of DeltaK/DeltaSE was greater for small amounts of change in refractive error and smaller for large amounts of change in refractive error. This trend was only statistically significant for the wavefront-optimized group when comparing the means of the ratio DeltaK/DeltaSE (P = .0287). CONCLUSIONS: The change in corneal curvature induced for a given degree of refractive correction was similar for both wavefront-optimized and wavefront-guided PRK. For both, a proportionally smaller amount of corneal flattening was required for larger degrees of refractive correction compared to smaller degrees. [J Refract Surg. 2016;32(8):542-548.]. PMID- 27505316 TI - Influence of Pachymetry and Intraocular Pressure on Dynamic Corneal Response Parameters in Healthy Patients. AB - PURPOSE: To evaluate the influence of pachymetry, age, and intraocular pressure in normal patients and to provide normative values for all dynamic corneal response parameters (DCRs) provided by dynamic Scheimpflug analysis. METHODS: Seven hundred five healthy patients were included in this multicenter retrospective study. The biomechanical response data were analyzed to obtain normative values with their dependence on corrected and clinically validated intraocular pressure estimates developed using the finite element method (bIOP), central corneal thickness (CCT), and age, and to evaluate the influence of bIOP, CCT, and age. RESULTS: The results showed that all DCRs were correlated with bIOP except deflection amplitude (DefA) ratio, highest concavity (HC) radius, and inverse concave radius. The analysis of the relationship of DCRs with CCT indicated that HC radius, inverse concave radius, deformation amplitude (DA) ratio, and DefA ratio were correlated with CCT (rho values of 0.343, -0.407, 0.444, and -0.406, respectively). The age group subanalysis revealed that primarily whole eye movement followed by DA ratio and inverse concave radius were the parameters that were most influenced by age. Finally, custom software was created to compare normative values to imported examinations. CONCLUSIONS: HC radius, inverse concave radius, DA ratio, and DefA ratio were shown to be suitable parameters to evaluate in vivo corneal biomechanics due to their independence from IOP and their correlation with pachymetry and age. The creation of normative values allows the interpretation of an abnormal examination without the need to match every case with another normal patient matched for CCT and IOP. [J Refract Surg. 2016;32(8):550-561.]. PMID- 27505318 TI - Reversible Femtosecond Laser-Assisted Endokeratophakia Using Cryopreserved Allogeneic Corneal Lenticule. AB - PURPOSE: To evaluate outcomes, reversibility, and wound healing response after the femtosecond laser-assisted endokeratophakia procedure in a rabbit model. METHODS: Allogeneic rabbit corneal lenticules were cryopreserved in liquid nitrogen for 3 months. Twenty rabbits underwent the monocular endokeratophakia procedure and were divided into four groups according to the follow-up periods. The first three groups were killed at 3 days, 2 weeks, and 6 months after endokeratophakia, respectively. The rabbits in the fourth group received re extraction of implanted lenticules at 6 months after endokeratophakia and were killed at 1 month after re-extraction. The rabbits were monitored by slit-lamp microscopy, ultrasonic pachymetry, in vivo confocal microscopy, optical coherence tomography (OCT), Corvis ST tonometry (Oculus Optikgerate, Wetzlar, Germany), and Ocular Response Analyzer (Reichert Ophthalmic Instruments, Depew, NY). The tissue responses were analyzed by immunohistochemistry and transmission electron microscopy. RESULTS: After endokeratophakia, corneal clarity improved continually with time. The changes in the refraction and corneal thickness were stable after implantation and could be reversed after re-extracting the lenticules. The interfaces were clearly visible on confocal microscopy and transmission electron microscopy images over the entire follow-up period. There were significant numbers of TUNEL-positive keratocytes in lenticules after endokeratophakia. CD11b positive cells and deposition of fibronectin and tenascin were observed at earlier follow-up times. No alpha-smooth muscle actin-positive fibroblasts could be detected. In addition, the corneal biomechanics parameters were not significantly increased after endokeratophakia. CONCLUSIONS: The endokeratophakia procedure using allogeneic cryopreserved lenticules was clinically stable and could be reversed. The wound healing response was mild, limited, and produced no scars. [J Refract Surg. 2016;32(8):569-576.]. PMID- 27505317 TI - Investigating Elastic Anisotropy of the Porcine Cornea as a Function of Intraocular Pressure With Optical Coherence Elastography. AB - PURPOSE: To evaluate the elastic anisotropy of porcine corneas at different intraocular pressures (IOPs) using a noncontact optical coherence elastography (OCE) technique. METHODS: A focused air-pulse induced low amplitude (<= 10 um) elastic waves in fresh porcine corneas (n = 7) in situ in the whole eye globe configuration. A home-built phase-stabilized swept source optical coherence elastography (PhS-SSOCE) system imaged the elastic wave propagation at different stepped radial directions. A closed-loop feedback system was used to artificially control the IOP and the OCE measurements were repeated as the IOP was incrementally increased from 15 to 30 mm Hg in 5-mm Hg increments. RESULTS: The OCE measurements demonstrated that the stiffness of the cornea increased as a function of IOP and elastic anisotropy of the cornea became more pronounced at higher IOPs. The standard deviation of the modified planar anisotropy coefficient increased from 0.72 +/- 0.42 at an IOP of 15 mm Hg to 1.58 +/- 0.40 at 30 mm Hg. CONCLUSIONS: The presented noncontact OCE method was capable of detecting and assessing the corneal elastic anisotropy as a function of IOP. Due to the noninvasive nature and small amplitude of the elastic wave, this method may be able to provide further information about corneal health and integrity in vivo. [J Refract Surg. 2016;32(8):562-567.]. PMID- 27505319 TI - Circulating miR-148b-3p and miR-409-3p as biomarkers for heart failure in patients with mitral regurgitation. AB - BACKGROUND: MicroRNAs (miRs) regulate gene expression in heart failure. Circulating miRs as biomarkers for heart failure in mitral regurgitation patients (MR) remain unexplored. METHODS: This case-control study enrolled 32 MR patients with heart failure, 16 asymptomatic MR patients, and 12 control subjects without heart failure. We used next generation sequencing to study the gene expression profiles in the sera, and quantitative RT-PCR to study serum and tissue miRs in the left atria. RESULTS: Next generation sequencing analysis and enrichment analysis showed that 25 miRs were differentially expressed in the sera of MR patients with heart failure compared to control subjects. The circulating miR 148b-3p (p=0.002) and miR-409-3p (p=0.010) were significantly down-regulated in the MR patients with heart failure compared to control subjects. However, only circulation miR-148b-3p was significantly down-regulated in the MR patients without heart failure compared to control subjects (p=0.009). The tissue miR-409 3p was significantly down-regulated in the MR patients with heart failure compared to 3 purchased normal controls (p=0.041). Notably, the tissue RASGRP3 mRNA, target gene of miR-409-3p, was significantly up-regulated in the MR patients with heart failure compared to normal controls (p=0.010). The tissue FRY (p=0.010) and GADD45A (p=0.010) mRNAs, target genes of miR-148b-3p, were significantly up-regulated in the MR patients with heart failure compared to normal controls. CONCLUSIONS: Circulating miR-148b-3p might serve as biomarker for future development of heart failure and miR-409-3p might serve as biomarker for incident heart failure in MR patients. PMID- 27505320 TI - The role of implantable cardioverter-defibrillators in patients with continuous flow left ventricular assist devices - A meta-analysis. AB - BACKGROUND: Left ventricular assist devices (LVADs) and implantable cardioverter defibrillators (ICD) are each known to improve mortality in patients with advanced congestive heart failure (CHF). If ICDs contribute to improved survival specifically in recipients of LVADs is currently unknown. AIM: To evaluate the impact of presence of ICD on mortality in continuous flow LVAD recipients. METHODS: A meta- analysis of available literature was performed. PubMed, Embase and Google Scholar databases were searched for studies that compared mortality in continuous flow LVAD patients with ICDs (new implantation or no de-activation) and without ICDs (including de-activation of existing implant). Pooled analysis using a fixed effects model was used for outcomes of interest. RESULTS: We included 3 observational studies for a total of 292 patients (203 (69.5%) with ICD versus 89 (30.5%) without ICD). The presence of an active ICD was not associated with improved survival [OR 0.63, 95% CI 0.33-1.18; p=0.15]. In bridge to transplantation [BT] patients (224 patients, 149 with ICD versus 75 without ICD), an active ICD was not associated with a higher probability of survivzal [OR 1.47, 95% CI 0.78-2.76; p=0.23]. There was no difference in the occurrence of severe right ventricular dysfunction or failure between two groups [OR 0.78, 95% CI 0.42-1.47; p=0.45]. The risk of LVAD related complications were similar [OR 0.68, 95% CI 0.35-1.31; P=0.25]. CONCLUSION: This meta-analysis demonstrates that there is no survival benefit with ICD in heart failure patients supported with continuous flow LVAD. There is an urgent need of large-scale randomized trials to specifically address this issue. PMID- 27505321 TI - Determinants of temporal changes in galectin-3 level in the general population: Data of PREVEND. AB - BACKGROUND: High baseline galectin-3 levels are associated with increased risk for adverse cardiovascular outcomes in the general population, but determinants of changes in galectin-3 levels over time have not been established. Therefore, we aimed to identify determinants of (temporal) change in galectin-3 levels. METHODS: Galectin-3 plasma levels were measured in a large community based cohort (PREVEND study) at 3 different time points: at baseline, after ~4 and ~9years. The association of baseline clinical and biochemical factors and (temporal) changes in galectin-3 level was assessed using multivariable mixed-effects regression modeling. RESULTS: In 4355 subjects, galectin-3 plasma levels were available at all time points (mean age: 48+/-12years; 50% female). Median galectin-3 level at baseline was 10.7 [8.9-12.7] ng/mL which gradually increased to 11.5 [9.4-14.3] ng/mL after ~9years. Using mixed-effects regression modeling, we first validated as independent determinants of baseline circulating galectin 3: eGFR (chi square (chi(2)):210.27, p<0.0001), gender (chi(2):43.85; p<0.0001), BMI (chi(2):19.68, p=0.0001), NT-proBNP (chi(2):18.76, p=0.0001) and serum (total) cholesterol (chi(2):8.63, p=0.01). Furthermore, we identified urinary albumin excretion (chi(2):34.03, p-value: <0.0001) and systolic blood pressure (chi(2):16.81, p=0.002) as independent determinants of temporal changes of galectin-3. CONCLUSIONS: In the general population, urinary albumin excretion >30mg/24h and systolic blood pressure >170mmHg were identified as significant determinants of dynamic increases in galectin-3 levels over time. These results implicate that treatment of high blood pressure might be effective to prevent increasing galectin-3 levels and its associated conditions. PMID- 27505322 TI - Effect of remote ischemic preconditioning on myocardial injury and inflammatory response induced by ablation for atrial fibrillation: A randomized controlled trial. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) has been suggested to reduce postoperative release of cardiac and inflammatory markers in patients undergoing cardiac surgery. This study aimed to evaluate the effect of RIPC on nonischemic myocardial damage and inflammatory response in patients undergoing radiofrequency catheter ablation for paroxysmal atrial fibrillation (AF). METHODS: Seventy-two patients with drug-refractory paroxysmal AF undergoing radiofrequency catheter ablation were randomized into RIPC or control groups. RIPC (intermittent arm ischemia through four cycles of 5-min inflation and 5-min deflation of a blood pressure cuff) was performed once daily on 2 consecutive days before the ablation and immediately before ablation. Cardiac troponin-I (cTnI), high-sensitive C reactive protein (hs-CRP), and interleukin (IL)-6 levels were measured before RIPC/sham RIPC, after the ablation, and 24 and 72h later. The early recurrence of atrial fibrillation (ERAF) in the two groups was observed over the subsequent 3months. RESULTS: Radiofrequency ablation resulted in a significant rise in cTnI, hs-CRP, and IL-6 in both groups, which persisted for 72h. The RIPC group showed a lower increase in cTnI (P<0.001), hs-CRP (P=0.003), and IL-6 (P=0.008) than the control and tended to have a lower risk of ERAF (hazard ratio [HR]=0.77, 95% confidence interval [CI]: 0.32-1.88). CONCLUSIONS: These results show that RIPC before ablation for paroxysmal AF significantly reduces the increase in cTnI, hs CRP, and IL-6 associated with the procedure and results in a lower risk of ERAF. These findings suggest that RIPC could provide cardioprotection against nonischemic myocardial damage. PMID- 27505323 TI - An unusual case of cardiogenic shock in which thiamine administration led to reversal of lactic acidosis and heart function recovery: Shoshin beriberi in an adolescent. PMID- 27505324 TI - Ulnar pseudoaneurysm after transulnar coronary angiogram treated with percutaneous ultrasound-guided thrombin injection. PMID- 27505325 TI - GT-repeat length polymorphism in heme oxygenase-1 promoter determines the effect of cilostazol on vascular smooth muscle cells. AB - BACKGROUND: Cilostazol, a potent type 3 phosphodiesterase inhibitor, is found to reduce neointimal formation by inhibiting vascular smooth muscle cell (VSMC) proliferation. The aim of this study is to investigate whether the inhibitory effect of cilostazol on VSMC proliferation is operated via heme oxygenase-1 (HO 1). METHODS AND RESULTS: In rat carotid arteries, cilostazol up-regulated HO-1 in the neointima of balloon-injured arteries. Treatment of human VSMCs with cilostazol enhanced the expression of HO-1, which was mainly regulated at the transcriptional level. Small interfering RNA knock-down of HO-1 attenuated the inhibitory effect of cilostazol on VSMC proliferation, suggesting the critical role of HO-1 in cilostazol effect. The transcriptional responsiveness of HO-1 to cilostazol was inversely correlated with the length of GT-repeat in human HO-1 promoter. Deletion and mutational analysis of HO-1 promoter along with chromatin immunoprecipitation showed that cyclic AMP response element (CRE)-binding protein (CREB) participated in cilostazol-induced HO-1 transcription. Furthermore, cilostazol triggered a linkage between the CRE and GT-repeat regions in the HO-1 promoter. The promoting effect of cilostazol on HO-1 expression, proliferation inhibition, and chromatin conformation in the HO-1 promoter was greater in VSMCs from subjects with shorter GT-repeat alleles than those with longer alleles. CONCLUSIONS: Cilostazol inhibits VSMC proliferation involving an association between CREB and HO-1. The length polymorphism of GT-repeat in human HO-1 promoter determines the effect of cilostazol. PMID- 27505326 TI - Association between levels of anti-angiogenic isoform of vascular endothelial growth factor A and pulmonary hypertension. AB - BACKGROUNDS: Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure due to vasoconstriction and remodeling of the pulmonary microvasculature. Vascular endothelial growth factor (VEGF) is a key contributor for angiogenesis and vasculogenesis. VEGF165b is recently identified as an anti angiogenic splicing variant of VEGF. The aim of this study was to examine the association between circulating levels of VEGF165b in PH patients under consideration with classifications of PH. METHODS AND RESULTS: We measured plasma levels of VEGF165b in the PH group (pulmonary artery hypertension [PAH], n=26; chronic thromboembolic pulmonary hypertension [CTEPH], n=13) and control group (n=30). Circulating levels of VEGF165b were higher in PH group than controls (97.1 vs. 53.3pg/ml, P<0.01). The multiple regression analysis demonstrated that the independent factor to determine the plasma levels of VEGF165b was the presence of PH (P=0.04). Next, we focused on differences in VEGF165b levels and classifications of PH. Plasma VEGF165b level was higher only in idiopathic PAH (n=9) than in control (137.1 vs. 53.3pg/ml, P<0.01), but not in PH related to collagen disease (n=7), congenital heart disease (n=10) and CTEPH (n=13). CONCLUSIONS: We demonstrated associations between circulating levels of VEGF165b and classifications of PH. VEGF165b, anti-angiogenic isoform, might contribute to the pathophysiology in PH, especially in idiopathic PAH. The level of plasma VEGF165b might be a novel marker that reflects the pathological conditions in patients with PH. PMID- 27505327 TI - Subsequent thrombus formation in a patient with apical ballooning. PMID- 27505328 TI - Role of right ventricular three-dimensional electroanatomic voltage mapping for arrhythmic risk stratification of patients with corrected tetralogy of Fallot or other congenital heart disease involving the right ventricular outflow tract. AB - BACKGROUND: The post-surgical history of repaired congenital heart disease (rCHD), in particular tetralogy of Fallot (TOF), is often complicated by sudden death. Electrical myocardial abnormalities could be a substrate for malignant ventricular arrhythmias. METHODS AND RESULTS: 146 patients with TOF or other rCHD involving a subpulmonary right ventricle, considered to be at high arrhythmic risk, underwent right ventricular (RV) electroanatomic voltage mapping (EVM). Maps showed endocardial scars (<0.5mV) in all cases, mainly involving the RV outflow tract (n=141, 96.6%). In 28 cases (19.2%), other areas were involved. Total scar extension, expressed as % of total endocardial area, was significantly higher in patients with QRS >=180ms [4.5% (+/-2.5) vs 2.8% (+/-2.4), p=0.014], left and right ventricular systolic dysfunction [4.5% (+/-3.2) vs 2.8% (+/-2.3), p=0.016 and 3.5% (+/-3.0) vs 2.6% (+/-1.9), p=0.03, respectively], premature ventricular contractions (PVCs) [3.2% (+/-2.6) vs 2.2% (+/-1.8), p<0.05], exercise-induced PVCs [3.8% (+/-2.4) vs 2.6% (+/-2.2), p=0.01], previous shunt [4.0% (+/-2.7) vs 2.6% (+/-2.2), p=0.01] and reintervention [4.2% (+/-3.2) vs 2.6% (+/-2.0), p=0.008]. Scar size also showed a positive correlation with duration of post-surgical follow-up (rho=0.01), age at correction (rho=0.01) and absolute QRS duration (rho=0.05). CONCLUSIONS: Patients with rCHD involving the right ventricle show electrical scars with variable distribution, not necessarily matching with sites of surgical lesions. Scar extension correlates with some of the risk factors for life-threatening arrhythmias in CHD, such as prolonged QRS. Thus EVM could be considered an additional tool in the assessment of risk stratification in this particular population. PMID- 27505329 TI - Geographic and socio-demographic differences in uptake of population-based screening for atrial fibrillation: The STROKESTOP I study. AB - BACKGROUND: The rationale behind screening for atrial fibrillation (AF) is to prevent ischemic stroke. Socio-demographic differences are expected to affect screening uptake. Geographic differences may provide further insights leading to targeted interventions for improved uptake. The objective of this study was to evaluate geographic and socio-demographic differences in uptake of AF screening in the population-based study STROKESTOP I. METHODS: STROKESTOP was carried out in two Swedish counties with a total population of 2.3 million inhabitants. Half of the residents aged 75-76years were randomized to the screening arm: invitation to clinical examination followed by ambulant ECG recording. Information on each invited person's residential parish (n=157) was used. On parish-level, aggregated data for the participants and non-participants, respectively, were obtained with respect to socioeconomic variables: educational level, disposable income, immigrant and marital status. Geo-maps displaying participation ratios were estimated by hierarchical Bayes methods. RESULTS: The overall participation rate was similar in men and women but lower in Stockholm, 47.6% (5665/11,903) than in Halland, 61.2% (1495/2443). Participation was clearly associated with the socioeconomic variables. Participation not taking into account socioeconomy varied more markedly across the parishes in the Stockholm county (range: 0.65 1.26) than in the Halland county (0.94-1.27). After adjustment for socioeconomic variables, a geographic variation remained in Stockholm, but not in Halland. CONCLUSION: Participation in AF screening varied according to socioeconomic conditions. Geographic variation in participation was marked in the Stockholm county, with only one screening clinic. Geo-mapping of participation yielded useful information needed to intervene for improved screening uptake. PMID- 27505330 TI - A novel polymer-free drug-eluting stent coated with everolimus using nitrogen doped titanium dioxide film deposition in a porcine coronary restenosis model. AB - BACKGROUND: Titanium dioxide (TiO2) films have superior biocompatibility and may be effective as drug-binding matrices for drug-eluting stents (DESs). We sought to evaluate efficacy of a polymer-free DES coated with everolimus using nitrogen doped TiO2 film deposition in a porcine coronary restenosis model. METHODS: Forty coronary arteries in 20 pigs were randomly allocated to group 1 (bare-metal stents (BMSs), 3.0*18mm, n=10), group 2 (BMSs with nitrogen-doped TiO2 film deposition, 3.0*18mm, n=10), group 3 [commercial everolimus-eluting stent, 3.0*18mm, n=10], and group 4 (polymer-free everolimus-eluting stent using nitrogen-doped TiO2 film deposition, 3.0*18mm, n=10). Stents were randomly implanted in the left anterior descending coronary artery and left circumflex artery with stent:artery ratio of 1.3. Four weeks later, pigs underwent follow-up coronary angiography and were sacrificed for histopathologic analysis. RESULTS: Percent area stenosis was greater in group 1 compared to groups 3 and 4 (46.4+/ 13.8% vs. 30.2+/-11.7% vs. 29.2+/-8.9%, respectively, p=0.005). Fibrin score was lower in groups 1 and 2, compared to groups 3 and 4: 0.87+/-0.67 vs. 0.76+/-0.61 vs. 2.27+/-0.24 vs. 1.75+/-0.31, respectively, p<0.001). Injury score and inflammation score were not different. Comparison between DES showed a higher fibrin score in group 3 than group 4 (2.27+/-0.24 vs. 1.75+/-0.31, p=0.023). CONCLUSIONS: In a porcine model of coronary restenosis, a novel polymer-free DES using nitrogen-doped TiO2 film deposition shows higher biocompatibility and compares favorably with a commercial DES. PMID- 27505331 TI - Evolution of acute ischemic stroke therapy from lysis to thrombectomy: Similar or different to acute myocardial infarction? AB - Acute ischemic stroke remains a major global cause of death, permanent disability, and dementia. For nearly two decades, intravenous tissue plasminogen activator (tPA) has been the only recommended therapy, albeit administered within the recommended time window (i.e., <4.5h). However, intravenous tPA is associated with modest recanalization rates, with a majority of patients having poor functional outcomes despite timely administration. Endovascular therapy has recently been introduced as adjunctive management of acute ischemic stroke. First generation endovascular thrombectomy devices have failed to improve outcomes compared with intravenous tPA. However, recent randomized trials utilizing stent retrievers demonstrated that these devices improve functional outcomes in patients with acute ischemic stroke secondary to large-artery occlusion. Introduction of stent retrieves has begun a new era for acute ischemic stroke therapy. This comprehensive review discusses the evolution of acute ischemic stroke therapy over the last two decades, with emphasis on recent randomized trials evaluating stent retrievers. Additionally, similarities and differences between the evolution of therapy in ST elevation myocardial infarction and acute ischemic stroke will be highlighted. PMID- 27505332 TI - Neonatal epicardial-derived progenitors aquire myogenic traits in skeletal muscle, but not cardiac muscle. AB - BACKGROUND/OBJECTIVES: Epicardium-derived progenitor cells (EPDCs) differentiate into all heart cell types in the embryonic heart, yet their differentiation into cardiomyocytes in the adult heart is limited and poorly described. This may be due to EPDCs lacking myogenic potential or the inert adult heart missing regenerative signals essential for directed differentiation of EPDCs. Herein, we aimed to evaluate the myogenic potential of neonatal EPDCs in adult and neonatal mouse myocardium, as well as in skeletal muscle. The two latter tissues have an intrinsic capability to develop and regenerate, in contrast to the adult heart. METHODS: Highly purified mouse EPDCs were transplanted into damaged neonatal and adult myocardium as well as regenerating skeletal muscle. Co-cultures with skeletal myoblasts were used to distinguish fusion independent myogenic conversion. RESULTS: No donor EPDC-derived cardiomyocytes were observed in hearts. In contrast, a remarkable contribution of EPDCs to skeletal muscle myofiber formation was evident in vivo. Furthermore, co-cultures of EPDCs with myoblasts showed that EPDCs became part of multinucleated fibers and appeared to acquire myogenic traits independent of a fusion event. Fluorescence activated cell sorting of EPDCs co-cultured with and without myoblasts and subsequent qRT PCR of 64 transcripts established that the myogenic phenotype conversion was accomplished through induction of a transcriptional myogenic program. CONCLUSION: These results suggest that EPDCs may be more myogenic than previously anticipated. But, the heart may lack factors for induction of myogenesis of EPDCs, a scenario that should be taken into consideration when aiming for repair of damaged myocardium by stem cell transplantation. PMID- 27505333 TI - Sarcopenia and physical activity in older male cardiac patients. AB - BACKGROUND: There is little information on the association of sarcopenia with physical activity in elderly cardiac patients. This study determined differences in physical activity and cutoff values for physical activity according to the presence or absence of sarcopenia in elderly male cardiac patients. METHODS AND RESULTS: Sixty-seven consecutive men aged >=65 years with cardiac disease were enrolled. We defined sarcopenia using the European Working Group on Sarcopenia in Older People algorithm. Patients were divided into the sarcopenia group (n=25) and the non-sarcopenia group (n=42). In the patients with and without sarcopenia of physical activities were evaluated to determine cutoff values of physical activity. RESULTS: After adjusting for patient characteristics, both the average daily number of steps (3361.43+/-793.23 vs. 5991.55+/-583.57 steps, P=0.021) and the average daily energy expenditure of physical activity (71.84+/-22.19 vs. 154.57+/-16.18kcal, P=0.009) were significantly lower in the sarcopenia versus non-sarcopenia group. Receiver-operating characteristic analysis identified a cutoff value for steps of physical activity of 3551.80steps/day for 1 week, with a sensitivity of 0.73 and 1-specificity of 0.44 and a cutoff value for energy expenditure of physical activity of 85.17kcal/day for 1 week, with a sensitivity of 0.73 and 1-specificity of 0.27. CONCLUSIONS: Physical activity in the male cardiac patients with sarcopenia was significantly lower than that in those without sarcopenia. The cutoff values reported here may be useful values to aid in the identification of elderly male cardiac patients with sarcopenia. PMID- 27505334 TI - Association between preoperative depression and long-term survival following coronary artery bypass surgery - A systematic review and meta-analysis. AB - BACKGROUND: Depression is common in patients with cardiovascular disease. The importance of preoperative depression for long-term survival following coronary artery bypass grafting (CABG) is not well known. The aim was to provide a summary estimate of the association between preoperative depression and long-term survival in adults who underwent CABG. METHODS: We did a systematic search of MEDLINE, EMBASE, Cochrane Library, PsycINFO, Web of Science, and PubMed from inception to November, 2015, including cohort studies with at least one month of follow-up that reported hazard ratios (HR) and 95% confidence intervals (CI) for long-term all-cause mortality following CABG in patients with preoperative depression compared to non-depressed patients. Two reviewers independently extracted data on populations, exposure, outcome, risk of bias, and quality of evidence. We calculated HR and 95% CIs for all-cause mortality using random effects meta-analyses and performed subgroup and sensitivity analyses. RESULTS: Seven studies were included with a combined study population of 89,490 patients (4002 depressed/85,488 non-depressed). All studies observed a positive association between preoperative depression and all-cause mortality, and in 4 studies the association was statistically significant. Patients with depression had a pooled hazard ratio of 1.46 (95% CI: 1.23-1.73, p<0.0001) for all-cause mortality with moderate heterogeneity (I(2)=50.1%, p=0.061). CONCLUSIONS: This systematic review and meta-analysis indicates that patients with preoperative depression are at increased risk for long-term, all-cause mortality following CABG compared with those without depression. Systematic screening for depression prior to cardiac surgery could identify those at higher risk. PMID- 27505335 TI - Intensive atorvastatin improves endothelial function and decreases ADP-induced platelet aggregation in patients with STEMI undergoing primary PCI: A single center randomized controlled trial. AB - BACKGROUND: Intensive atorvastatin may be beneficial for patients with ST segment elevated myocardial infarction (STEMI). However, its effects on endothelial and residual platelet function remain uninvestigated in these patients. METHODS: This single-center single-blinded prospective randomized controlled trial included STEMI patients undergoing PCI, aiming to investigate the acute effects of intensive atorvastatin (40mg) vs. standard atorvastatin (20mg) on serum endothelin-1 (ET-1) and ADP-induced platelet clot strength (MA-ADP), which were measured before and after 7days of atorvastatin treatment respectively. MA-ADP was measured by thromboelastography. The tolerance and safety of intensive atorvastatin therapy in these patients were also observed. RESULTS: A total of 120 patients (60 patients in the intensive group and 60 patients in the standard group) with STEMI, who are undergoing primary PCI, were included into this study (mean age, 63.5years). Patients from these two groups were matched for baseline characteristics. Atorvastatin did not significantly affect the serum level of LDL C or CRP in either the standard or intensive group. Furthermore, ET-1 did not significantly change following treatment with atorvastatin in the standard group. However, intensive treatment with atorvastatin significantly reduced ET-1 serum level (0.65+/-0.38pmol/L vs. 0.49+/-0.21pmol/L, P<0.05) and achieved a greater reduction of MA-ADP (49.2+/-12.1 vs. 38.4+/-17.4mm, P<0.05). In addition, although not statistically significant, patients assigned to the intensive group appeared to suffer from less major adverse cardiovascular events. CONCLUSIONS: Periprocedural intensive atorvastatin is associated with improved endothelial function and platelet inhibition, and is well-tolerated in STEMI patients undergoing PCI. PMID- 27505336 TI - Anti-inflammatory diet and 10-year (2002-2012) cardiovascular disease incidence: The ATTICA study. AB - BACKGROUND/OBJECTIVES: The aim of the present work was to evaluate the association between the inflammatory potential of the diet and the 10-year cardiovascular disease (CVD) incidence in the ATTICA Study, and whether this is modified by the baseline presence or absence of metabolic syndrome (MetS). METHODS: During 2001-2002, 3042 healthy adults (1514 men and 1528 women) living in the greater area of Athens were voluntarily recruited to the ATTICA study. In 2011-2012, the 10-year follow-up was performed in 2583 participants (15% of the participants were lost to follow-up). Incidence of fatal or non-fatal CVD event was recorded using WHO-ICD-10 criteria and MetS was defined by the National Cholesterol Education Program Adult Treatment panel III (revised) definition. A proxy dietary anti-inflammatory index (D-AII) score computed using participants' diet records. RESULTS: The 10-year fatal or non-fatal CVD event rate was 157 cases/1000 participants. After adjusting for several confounding factors, an anti inflammatory diet, as expressed by higher DII scores, was borderline associated with 10-year CVD incidence (OR3rd tertile vs. 1st tertile=0.98, 95%CI: 0.96 1.01). This inverse association was also verified among participants without MetS at baseline (OR3rd tertile vs. 1st tertile=0.97, 95%CI: 0.94-0.99), but not among participants with the MetS. CONCLUSIONS: Results of the present work verified the protective effect of an anti-inflammatory diet towards the 10-year CVD incidence among participants without MetS. In contrast, the presence of MetS already at baseline seemed to impede this anti-inflammatory diet protective effect, which underlines the independent importance of MetS on CVD risk. PMID- 27505337 TI - Phaeochromocytoma and transient left ventricular apical ballooning syndrome. PMID- 27505338 TI - Long-term major adverse cardiovascular events and quality of life after coronary angiography in elderly patients with acute coronary syndrome. AB - BACKGROUND: Although the elderly comprise the majority of acute coronary syndrome (ACS) patients, limited data exist on major adverse cardiovascular events (MACEs) and quality of life (QoL). OBJECTIVES: To study MACEs and QoL prospectively in ACS patients >70years referred for coronary angiography. METHODS: A prospective observational study that included ACS patients >70years undergoing coronary angiography. The outcomes were MACEs and QoL 3years after inclusion. MACEs were defined as death, recurrent ACS, new-onset of heart failure and repeated revascularization by coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). A QoL questionnaire was completed by the patients along with a physical examination and a personal interview at the 3-year follow up. Multivariate analysis was performed to identify the predictors for MACEs. RESULTS: In total, 138 patients (mean age 78.8+/-3.8years) with ACS were included in the study. Mean follow-up was 1196+/-296days. In all, 42% of the patients had MACEs and 25% had post-ACS heart failure. The mortality rate was 11%. After adjusting for significant cardiovascular risk factors, the following factors were significantly associated with MACEs: Age, high-sensitive troponin T (hsTNT), use of diuretics and reduced left ventricular ejection fraction (LVEF). Furthermore, the QoL evaluated with SF-36 in survivors from ACS at the end of study was similar to the QoL in an age-matched healthy Swedish population. CONCLUSIONS: In this prospective study on elderly ACS patients MACEs still occurred in 42% of the cases (despite low mortality and good QoL), with post-ACS heart failure as the most important event. PMID- 27505339 TI - Efficacy and safety of biodegradable polymer sirolimus-eluting stents versus durable polymer drug-eluting stents: A meta-analysis of randomized trials. AB - BACKGROUND: A meta-analysis was performed to investigate the safety and efficacy of biodegradable polymer sirolimus-eluting stents (BP-SESs) compared with durable polymer drug-eluting stents (DP-DESs). METHODS: Online databases, including PubMed, EMBASE and the Cochrane Library, were searched for randomized controlled trials that compared BP-SESs and DP-DESs and reported rates of overall and cardiac mortality, myocardial infarction (MI), stent thrombosis (ST), target lesion revascularization (TLR), target vessel revascularization (TVR) and late lumen loss (LLL). RESULTS: A total of 15 studies investigating 14,187 patients were included in the meta-analysis. The BP-SESs significantly reduced the risk of late ST (OR: 0.57; 95% CI: 0.33-0.98; p=0.04), very late ST (OR: 0.53; 95% CI: 0.29-0.97; p=0.04) and in-stent LLL (MD: -0.06, 95% CI: -0.11 to -0.01; p=0.01) compared with the DP-DESs but did not improve mortality (OR: 0.95; 95% CI: 0.81 1.11; p=0.52), cardiac mortality (OR: 0.89; 95% CI: 0.72-1.10; p=0.27), MI (OR: 0.90; 95% CI: 0.76-1.08; p=0.27), TLR (OR: 0.95; 95% CI: 0.81-1.11; p=0.51), TVR (OR: 0.96; 95% CI: 0.81-1.13; p=0.62) or in-segment LLL (MD: -0.03, 95% CI: -0.06 0.01; p=0.10). CONCLUSIONS: In this meta-analysis of randomized controlled trials, the BP-SESs were superior to the DP-DESs in terms of late ST, very late ST and in-stent LLL. Further large randomized controlled trials with long-term follow-up are required to validate the benefits of BP-SESs. PMID- 27505340 TI - Optical coherence tomography for hypertensive pulmonary vasculature. AB - BACKGROUND: Optical coherence tomography (OCT) is an intravascular imaging modality capable of providing in situ images of tissues at near histologic resolution. In this study we examine the utility of OCT in identifying vascular changes related to pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS AND RESULTS: OCT of four different distal pulmonary arteries was performed during right heart catheterization in 87 patients, 64 patients with PAH and 23 patients with CTEPH. The mean luminal diameter measured by OCT for all patients was 2.26mm. Intimal thickening was significantly increased in all PAH patients (0.26+/-0.05mm in idiopathic PAH, 0.24+/-0.03mm in connective tissue disease related PAH, 0.26+/ 0.06mm in congenital heart disease related PAH and 0.22+/-0.04mm in CTEPH, respectively) compared with controls (0.13+/-0.03mm) (all p<0.05). An intimal thickness of >=0.176mm had a 91% positive predictive value for pulmonary hypertension. The anatomic abnormalities revealed by OCT tended to be severe in the idiopathic PAH group and mild in the CTEPH group. Signs of intravascular webs were found in 60.9% of CTEPH patients, but no other patients. Intimal thickness was moderately correlated with pulmonary arterial pressure and pulmonary vascular resistance (r=0.423 and 0.439, respectively, p<0.001). CONCLUSIONS: OCT provides important information for assessment of pulmonary arterial remodeling in patients with PAH and improves diagnostic capability of angiographically undetected distal thrombotic lesions in patients with CTEPH. PMID- 27505341 TI - Electrophysiocardiogram: For the first time EPCG has been recorded on human body surface. AB - Since ECG was invented in 1903, this is the first time in history that a full information multi-band and multi-linear electrophysiological cardiogram has been used to successfully scan and record on the human body surface. Since it is able to record various multi-band, multi-track linear electric signals of cardiac electrophysiological activities that correspond to different regions of the entire heart, it has thus been denominated as "electrophysiocardiogram" (EPCG). A traditional ECG is always represented by a characteristic wave form, which resembles a string. For a long period of time, ECG has had a lot of mysteries surrounding it, it maybe because ECG has a lot of mixed signals buried in such convolutionary forms, which limits the amount of the signals that are discernable and determinable. For the first time, the EPCG technology has allowed cardiac signals to be convoluted into the linear wave form, which is then processed through various new approaches featuring multiple frequency bands, multiple dimensions and multiple patterns, and consequentially recorded as the following types of signals within the ranges of P wave and T wave: multiple frequency band signals, signals of different regions and different locations, forward waves and negative waves. Therefore, EPCG may help to solve many puzzling scientific questions regarding heart, such as exactly how many electric signals are involved in heart excitation, pacing, conduction and action, as well as many other intriguing questions about heart, and thus would become a very helpful tool in clinical practice. PMID- 27505342 TI - Atrial fibrillation classification and association between the natural frequency and the autonomic nervous system. AB - BACKGROUND: The feasibility study of the natural frequency (omega) obtained from a second-order dynamic system applied to an ECG signal was discovered recently. The heart rate for different ECG signals generates different omega values. The heart rate variability (HRV) and autonomic nervous system (ANS) have an association to represent cardiovascular variations for each individual. This study further analyzed the omega for different ECG signals with HRV for atrial fibrillation classification. METHODS: This study used the MIT-BIH Normal Sinus Rhythm (nsrdb) and MIT-BIH Atrial Fibrillation (afdb) databases for healthy human (NSR) and atrial fibrillation patient (N and AF) ECG signals, respectively. The extraction of features was based on the dynamic system concept to determine the omega of the ECG signals. There were 35,031 samples used for classification. RESULTS: There were significant differences between the N & NSR, N & AF, and NSR & AF groups as determined by the statistical t-test (p<0.0001). There was a linear separation at 0.4s(-1) for omega of both databases upon using the thresholding method. The feature omega for afdb and nsrdb falls within the high frequency (HF) and above the HF band, respectively. The feature classification between the nsrdb and afdb ECG signals was 96.53% accurate. CONCLUSIONS: This study found that features of the omega of atrial fibrillation patients and healthy humans were associated with the frequency analysis of the ANS during parasympathetic activity. The feature omega is significant for different databases, and the classification between afdb and nsrdb was determined. PMID- 27505343 TI - A joint allergist/cardiologist classification for thienopyridines hypersensitivity reactions based on their symptomatic patterns and its impact on the management strategies. AB - The role and importance of thienopyridines such as ticlopidine, clopidogrel, and prasugrel is well-established for several indications, ranging from prevention of acute coronary syndromes to percutaneous coronary interventions, where the dual antiplatelet therapy represents the gold standard to avoid denovo coronary stenosis. However, there is a significant cohort of patients with coronary artery disease who may manifest hypersensitivity reactions to thienopyridines. The examination of the various case reports from medical literature leads to identify mainly four clinical patterns of hypersensitivity to thienopyridines which involves more frequently cutaneous, hematologic, and articular tissues, therefore the kind and predominance of clinical symptoms may determine a different clinical approach to overcome or neutralize thienopyridines hypersensitivity. PMID- 27505344 TI - Vitamin D deficiency is independently associated with greater prevalence of erectile dysfunction: The National Health and Nutrition Examination Survey (NHANES) 2001-2004. AB - BACKGROUND AND AIMS: Erectile dysfunction (ED) and atherosclerotic cardiovascular disease (ASCVD) share many common risk factors, and vascular ED is a marker for increased ASCVD risk. Low 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with increased ASCVD risk, but less is known regarding the relationship of low 25(OH)D with ED. We determined whether 25(OH)D deficiency is associated with ED independent of ASCVD risk factors. METHODS: We performed cross sectional analyses of 3390 men aged >=20 years free of ASCVD who participated in NHANES 2001-2004. Serum 25(OH)D was measured by the DiaSorin radioimmunoassay; deficiency was defined as levels <20 ng/ml (<50 nmol/L). Self-reported ED, assessed by a single validated question, was defined as men who reported being "never" or "sometimes able" to maintain an erection. We assessed the relationship between 25(OH)D deficiency and ED prevalence using adjusted Poisson regression methods. RESULTS: After accounting for NHANES sampling, the weighted prevalence of 25(OH)D deficiency and of ED were 30% and 15.2%, respectively. 25(OH)D levels were lower in men with vs. those without ED (mean 22.8 vs 24.3 ng/mL, respectively; p = 0.0005). After adjusting for lifestyle variables, comorbidities, and medication use, men with 25(OH)D deficiency had a higher prevalence of ED compared to those with levels >=30 ng/ml (Prevalence Ratio 1.30, 95% CI 1.08-1.57). CONCLUSION: In this cross-sectional analysis of a representative sample of U.S. men, vitamin D deficiency was associated with an increased prevalence of ED independent of ASCVD risk factors. Additional research is needed to evaluate whether treating vitamin D deficiency improves erectile function. PMID- 27505345 TI - Genomics of variation in nitrogen fixation activity in a population of the thermophilic cyanobacterium Mastigocladus laminosus. AB - Variation in phenotypic traits that contribute to fitness influences a population's evolutionary response and its impact on ecosystem function following environmental change, yet its amount and nature are rarely known. Here, we investigated variation in nitrogen (N) fixation activity and its genetic basis for a random sample of laboratory strains of the cyanobacterium Mastigocladus laminosus from a N-limited, geothermally influenced stream in Yellowstone National Park. In a linear mixed-effects model, temperature and genetic differences among strains were the most important factors explaining variation in activity. Genome-wide analyses of genetic divergence between groups of strains that varied in N fixation activity revealed that few loci were strongly associated with these phenotypic differences. Notably, a single nonsynonymous polymorphism in the sulfate assimilation gene apsK explained >25% of the variation in activity at high temperature. We further identified a role for allelic variation of multiple terminal cytochrome oxidases for different aspects of N fixation. In addition, genomes of strains that fixed the most N overall contained a nonsense mutation in a histidine kinase gene that is expected to disrupt normal protein function and may result in transcriptional rewiring. This study illustrates how taking complementary approaches to link phenotype and genotype can inform our understanding of microbial population diversity. PMID- 27505346 TI - Distinct gene expression profile of Xanthomonas retroflexus engaged in synergistic multispecies biofilm formation. AB - It is well known that bacteria often exist in naturally formed multispecies biofilms. Within these biofilms, interspecies interactions seem to have an important role in ecological processes. Little is known about the effects of interspecies interactions on gene expression in these multispecies biofilms. This study presents a comparative gene expression analysis of the Xanthomonas retroflexus transcriptome when grown in a single-species biofilm and in dual- and four-species consortia with Stenotrophomonas rhizophila, Microbacterium oxydans and Paenibacillus amylolyticus. The results revealed complex interdependent interaction patterns in the multispecies biofilms. Many of the regulated functions are related to interactions with the external environment and suggest a high phenotypic plasticity in response to coexistence with other species. Furthermore, the changed expression of genes involved in aromatic and branched chain amino acid biosynthesis suggests nutrient cross feeding as a contributing factor for the observed synergistic biofilm production when these four species coexists in a biofilm. PMID- 27505347 TI - The methanogenic redox cofactor F420 is widely synthesized by aerobic soil bacteria. AB - F420 is a low-potential redox cofactor that mediates the transformations of a wide range of complex organic compounds. Considered one of the rarest cofactors in biology, F420 is best known for its role in methanogenesis and has only been chemically identified in two phyla to date, the Euryarchaeota and Actinobacteria. In this work, we show that this cofactor is more widely distributed than previously reported. We detected the genes encoding all five known F420 biosynthesis enzymes (cofC, cofD, cofE, cofG and cofH) in at least 653 bacterial and 173 archaeal species, including members of the dominant soil phyla Proteobacteria, Chloroflexi and Firmicutes. Metagenome datamining validated that these genes were disproportionately abundant in aerated soils compared with other ecosystems. We confirmed through high-performance liquid chromatography analysis that aerobically grown stationary-phase cultures of three bacterial species, Paracoccus denitrificans, Oligotropha carboxidovorans and Thermomicrobium roseum, synthesized F420, with oligoglutamate sidechains of different lengths. To understand the evolution of F420 biosynthesis, we also analyzed the distribution, phylogeny and genetic organization of the cof genes. Our data suggest that although the Fo precursor to F420 originated in methanogens, F420 itself was first synthesized in an ancestral actinobacterium. F420 biosynthesis genes were then disseminated horizontally to archaea and other bacteria. Together, our findings suggest that the cofactor is more significant in aerobic bacterial metabolism and soil ecosystem composition than previously thought. The cofactor may confer several competitive advantages for aerobic soil bacteria by mediating their central metabolic processes and broadening the range of organic compounds they can synthesize, detoxify and mineralize. PMID- 27505348 TI - Metagenomic recovery of phage genomes of uncultured freshwater actinobacteria. AB - Low-GC Actinobacteria are among the most abundant and widespread microbes in freshwaters and have largely resisted all cultivation efforts. Consequently, their phages have remained totally unknown. In this work, we have used deep metagenomic sequencing to assemble eight complete genomes of the first tailed phages that infect freshwater Actinobacteria. Their genomes encode the actinobacterial-specific transcription factor whiB, frequently found in mycobacteriophages and also in phages infecting marine pelagic Actinobacteria. Its presence suggests a common and widespread strategy of modulation of host transcriptional machinery upon infection via this transcriptional switch. We present evidence that some whiB-carrying phages infect the acI lineage of Actinobacteria. At least one of them encodes the ADP-ribosylating component of the widespread bacterial AB toxins family (for example, clostridial toxin). We posit that the presence of this toxin reflects a 'trojan horse' strategy, providing protection at the population level to the abundant host microbes against eukaryotic predators. PMID- 27505349 TI - Illness management and recovery in community practice. AB - OBJECTIVE: To examine provider competence in providing Illness Management and Recovery (IMR), an evidence-based self-management program for people with severe mental illness, and the association between implementation supports and IMR competence. METHOD: IMR session recordings, provided by 43 providers/provider pairs, were analyzed for IMR competence using the IMR Treatment Integrity Scale. Providers also reported on receipt of commonly available implementation supports (e.g., training, consultation). RESULTS: Average IMR competence scores were in the "needs improvement" range. Clinicians demonstrated low competence in several IMR elements: significant other involvement, weekly action planning, action plan follow-up, cognitive-behavioral techniques, and behavioral tailoring for medication management. These elements were commonly absent from IMR sessions. Competence in motivational enhancement strategies and cognitive-behavioral techniques differed based on the module topic covered in a session. Generally, receipt of implementation supports was not associated with increased competence; however, motivational interviewing training was associated with increased competence in action planning and review. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: IMR, as implemented in the community, may lack adequate competence and commonly available implementation supports do not appear to be adequate. Additional implementation supports that target clinician growth areas are needed. (PsycINFO Database Record PMID- 27505350 TI - Activation of Platinum(IV) Prodrugs by Cytochrome c and Characterization of the Protein Binding Sites. AB - Platinum(IV) complexes generally require reduction to reactive Pt(II) species to exert their chemotherapeutic activity. The process of reductive activation of (15)N-labeled (OC-6-43)-bis(acetato)diamminedichloridoplatinum(IV), in the presence of nicotinamide adenine dinucleotide (NADH) and horse heart cytochrome c (cyt c), was monitored by (1)H,(15)N-HSQC NMR spectroscopy and protein digestion experiments. It has been shown that cyt c plays a catalytic role in the transfer of two reducing equivalents from NADH to Pt(IV) species. Noncovalent interactions between reduced monoaqua cisplatin (cis-[PtCl((15)NH3)2(H2O)](+)) and the protein, in the proximity of the heme cofactor, and also covalent binding of platinum to the protein region around Met65 and Met80 take place. PMID- 27505352 TI - Engineered Nanoparticles as Potential Food Contaminants and Their Toxicity to Caco-2 Cells. AB - Engineered nanoparticles (ENPs), such as metallic or metallic oxide nanoparticles (NPs), have gained much attention in recent years. Increasing use of ENPs in various areas may lead to the release of ENPs into the environment and cause the contamination of agricultural and food products by ENPs. In this study, we selected two important ENPs (zinc oxide [ZnO] and silver [Ag] NPs) as potential food contaminants and investigated their toxicity via an in vitro model using Caco-2 cells. The physical properties of ENPs and their effects on Caco-2 cells were characterized by electron microscopy and energy dispersive X-ray spectroscopic (EDS) techniques. Results demonstrate that a significant inhibition of cell viability was observed after a 24-h of exposure of Caco-2 cells to 3-, 6 , and 12-mM ZnO NPs or 0.5-, 1.5-, and 3-mM Ag NPs. The noticeable changes of cells include the alteration in cell shape, abnormal nuclear structure, membrane blebbing, and cytoplasmic deterioration. The toxicity of ZnO NPs, but not that of Ag NPs after exposure to simulated gastric fluid, significantly decreased. Scanning transmission electron microscopy shows that ZnO and Ag NPs penetrated the membrane of Caco-2 cells. EDS results also confirm the presence of NPs in the cytoplasm of the cells. This study demonstrates that ZnO and Ag NPs have cytotoxic effects and can inhibit the growth of Caco-2 cells. PMID- 27505353 TI - The Hippo/MST Pathway Member SAV1 Plays a Suppressive Role in Development of the Prehierarchical Follicles in Hen Ovary. AB - The Hippo/MST signaling pathway is a critical player in controlling cell proliferation, self-renewal, differentiation, and apoptosis of most tissues and organs in diverse species. Previous studies have shown that Salvador homolog 1 (SAV1), a scaffolding protein which functions in the signaling system is expressed in mammalian ovaries and play a vital role in governing the follicle development. But the exact biological effects of chicken SAV1 in prehierarchical follicle development remain poorly understood. In the present study, we demonstrated that the SAV1 protein is predominantly expressed in the oocytes and undifferentiated granulosa cells in the various sized prehierarchical follicles of hen ovary, and the endogenous expression level of SAV1 mRNA appears down regulated from the primordial follicles to the largest preovulatory follicles (F2 F1) by immunohistochemistry and real-time RT-PCR, respectively. Moreover, we found the intracellular SAV1 physically interacts with each of the pathway members, including STK4/MST1, STK3/MST2, LATS1 and MOB2 using western blotting. And SAV1 significantly promotes the phosphorylation of LATS1 induced by the kinase of STK4 or STK3 in vitro. Furthermore, SAV1 knockdown by small interfering RNA (siRNA) significantly increased proliferation of granulosa cells from the prehierarchical follicles (6-8 mm in diameter) by BrdU-incorporation assay, in which the expression levels of GDF9, StAR and FSHR mRNA was notably enhanced. Meanwhile, these findings were consolidated by the data of SAV1 overexpression. Taken together, the present results revealed that SAV1 can inhibit proliferation of the granulosa cells whereby the expression levels of GDF9, StAR and FSHR mRNA were negatively regulated. Accordingly, SAV1, as a member of the hippo/MST signaling pathway plays a suppressive role in ovarian follicle development by promoting phosphorylation and activity of the downstream LATS1, may consequently lead to prevention of the follicle selection during ovary development. PMID- 27505354 TI - The Hydrated Electron at the Surface of Neat Liquid Water Appears To Be Indistinguishable from the Bulk Species. AB - Experiments have suggested that the aqueous electron, e(-)(aq), may play a significant role in the radiation chemistry of DNA. A recent measurement of the energy (below vacuum level) of the putative "interfacial" hydrated electron at the water/vacuum interface, performed using liquid microjet photoelectron spectroscopy, has been interpreted to suggest that aqueous electrons at the water/biomolecule interface may possess the appropriate energetics to induce DNA strand breaks, whereas e(-)(aq) in bulk water lies too far below the vacuum level to induce such reactions. Other such experiments, however, find no evidence of a long-lived feature at low binding energy. We employ a variety of computational strategies to demonstrate that the energetics of the hydrated electron at the surface of neat liquid water are not significantly different from those of e( )(aq) in bulk water and as such are incompatible with dissociative electron attachment reactions in DNA. We furthermore suggest that no stable interfacial species may exist at all, consistent with the interpretation of certain surface sensitive spectroscopy measurements, and that even if a short-lived, metastable species does exist at the vacuum/water interface, it would be extremely difficult to distinguish, experimentally, from e(-)(aq) in bulk water, using either optical absorption or photoelectron spectroscopy. PMID- 27505355 TI - Transitioning to Country Ownership of HIV Programs in Rwanda. AB - Agnes Binagwaho and colleagues describe how Rwanda achieved country ownership of its HIV programs. PMID- 27505357 TI - Inversion method based on stochastic optimization for particle sizing. AB - A stochastic inverse method is presented based on a hybrid evolutionary optimization algorithm (HEOA) to retrieve a monomodal particle-size distribution (PSD) from the angular distribution of scattered light. By solving an optimization problem, the HEOA (with the Fraunhofer approximation) retrieves the PSD from an intensity pattern generated by Mie theory. The analyzed light scattering pattern can be attributed to unimodal normal, gamma, or lognormal distribution of spherical particles covering the interval of modal size parameters 46<=alpha<=150. The HEOA ensures convergence to the near-optimal solution during the optimization of a real-valued objective function by combining the advantages of a multimember evolution strategy and locally weighted linear regression. The numerical results show that our HEOA can be satisfactorily applied to solve the inverse light-scattering problem. PMID- 27505356 TI - Simultaneous cytosolic delivery of a chemotherapeutic and siRNA using nanoparticle-stabilized nanocapsules. AB - We report on nanoparticle-stabilized capsules (NPSCs) as a platform for the co delivery of survivin-targeted siRNA and tamoxifen. These capsules feature an inner oil core that provides a carrier for tamoxifen, and is coated on the surface with positively charged nanoparticles self-assembled with siRNA. The multifaceted chemical nature of the NPSC system enables the simultaneous delivery of both payloads directly into the cytosol in vitro. The NPSC co-delivery of tamoxifen and survivin-targeted siRNA into breast cancer cells disables the pathways that inhibit apoptosis, resulting in enhanced breast cell death. PMID- 27505358 TI - Rapid fabrication of a silicon modification layer on silicon carbide substrate. AB - We develop a kind of magnetorheological (MR) polishing fluid for the fabrication of a silicon modification layer on a silicon carbide substrate based on chemical theory and actual polishing requirements. The effect of abrasive concentration in MR polishing fluid on material removal rate and removal function shape is investigated. We conclude that material removal rate will increase and tends to peak value as the abrasive concentration increases to 0.3 vol. %, and the removal function profile will become steep, which is a disadvantage to surface frequency error removal at the same time. The removal function stability is also studied and the results show that the prepared MR polishing fluid can satisfy actual fabrication requirements. An aspheric reflective mirror of silicon carbide modified by silicon is well polished by combining magnetorheological finishing (MRF) using two types of MR polishing fluid and computer controlled optical surfacing (CCOS) processes. The surface accuracy root mean square (RMS) is improved from 0.087lambda(lambda=632.8 nm) initially to 0.020lambda(lambda=632.8 nm) in 5.5 h total and the tool marks resulting from MRF are negligible. The PSD analysis results also shows that the final surface is uniformly polished. PMID- 27505359 TI - Variability of particle size distribution with respect to inherent optical properties in Poyang Lake, China. AB - Suspended particulate matter plays a significant role in the studies of sediment fluxes, phytoplankton dynamics, and water optical properties. This study focuses on the relationships between particle size distribution (PSD), water's inherent optical properties (IOPs), and water constituents. We investigated the complex waters of Poyang Lake, the largest freshwater lake in China, in wet and dry seasons during 2008-2011. Because of the distinct temporal-spatial variation of Poyang Lake, these parameters and relationships also demonstrate seasonal and regional variability. The variation range of the concentration of suspended particulate matter is 0.32-69.08 mg/l, with a mean value of 22.21 mg/l. The median particle size in the dry season is much larger than that of the wet season. The Junge distribution fits the PSD of Poyang Lake very well in the scope of 6.21-331 MUm. Furthermore, the slopes of the PSD range from 3.54 to 4.69, with a mean value of 4.11, with the steepest slopes (>4.5) occurring in the waters around Songmen Mountain Island and the northern waterway. A negative correlation was found between median particle size (Dv50) and the mass-specific absorption coefficient at 443 nm [apm(443)] for both wet and dry seasons. Identical to analogous waters, the spectral slopes of the PSD correlate well with the spectral slopes of the attenuation coefficient, but with different fitted formulas. In the dry season, the particle size can better explain the variability of the scattering coefficient, while the mass-specific scattering coefficient is better explained by the apparent density. However, no similar results were found for the wet season. In addition, the spectral slopes of the backscattering coefficient correlated well with the PSD slope, and the bulk refractive index calculated from the backscattering ratio and PSD slope can indicate the particle composition of Poyang Lake. Overall, the knowledge on the PSD and IOPs gained in this study broadens our understanding of water optics in highly turbid water columns. PMID- 27505360 TI - Photonic generation of high frequency millimeter-wave and transmission over optical fiber. AB - A novel technique of photonic generation of millimeter-waves beyond the presently reported 120 GHz and with a wider tunability (~240 GHz) is proposed and demonstrated through a simulation experiment. The scheme consists of generating 24 times the frequency of a conventional low frequency microwave source using a combination of a LiNbO3 Mach-Zehnder modulator and four-wave mixing in a semiconductor optical amplifier. The filtering of a high frequency sideband and the suppression of a carrier are achieved by incorporating an optical band pass and fiber Bragg grating filters, respectively. Next, the spectral purity of the generated millimeter-wave parameters is evaluated after propagation through a conventional fiber of different lengths by digitally modulating it at 2.5 Gbps and generating an eye diagram. The constraints on the selection of the frequency of the millimeter-wave and length of fiber are discussed. The present method of millimeter-wave generation and distribution will find applications in photonic up/down conversion, phase-array antennas, photonic sensors, radars, and terahertz applications. PMID- 27505361 TI - Experimental demonstration of highway I2V using visible light communications. AB - A visible light communication (VLC)-based intelligent transportation system (ITS) has drawn much interest from telematics and automobile industries due to its enhanced safety and cost effectiveness. Within the framework of ITS, vehicle-to vehicle and infrastructure-to-vehicle (I2V) communications have largely been considered. I2V can be viewed as an important ITS technology that broadcasts traffic information from fixed traffic infrastructure. In this paper, an experimental demonstration of a highway VLC-based I2V system is presented. For robust and reliable detection in the VLC-based I2V, the receiver structure of the proposed system is comprised of an optical filter, a color filter, and a Fresnel lens. We consider two primary atmospheric conditions in the highway I2V, i.e., sunlight and cloud effects. To alleviate these adverse effects, we propose an efficient and robust zone detection (ZD) and adaptive decision threshold (ADT) method. The sunlight effect is reduced predominantly by the ZD, while the cloud effect is lessened significantly by the ADT. The experimental results demonstrate that the proposed method performs well to counter the sunlight and cloud effects. It is found that the proposed ZD and ADT method provides an approximate SNR improvement ranging from 16 to 26 dB, depending upon measurement times of the day. PMID- 27505362 TI - Extending lock-in methods: term isolation detection of nonlinear signals. AB - We show that components of a nonlinear signal can be measured using phase sensitive detection at unconventional demodulation frequencies, allowing us to isolate individual terms from the signal. To demonstrate this technique, autocorrelation measurements of an ultrafast pulsed laser were performed using two-photon absorption. In this example, the isolation of individual autocorrelation terms may provide internal consistency checks to improve the precision and accuracy of pulse characterization. More generally, this scheme can be extended to a range of nonlinear measurements. As a demonstration, we analyze a three-photon autocorrelation model, showing that many nonlinear signals can be studied with this method. We anticipate that term isolation detection will find application in a broad range of experiments, such as multidimensional Fourier transform spectroscopy or coherent anti-Stokes Raman spectroscopy. PMID- 27505363 TI - Diffraction by random Ronchi gratings. AB - In this work, we obtain analytical expressions for the near-and far-field diffraction of random Ronchi diffraction gratings where the slits of the grating are randomly displaced around their periodical positions. We theoretically show that the effect of randomness in the position of the slits of the grating produces a decrease of the contrast and even disappearance of the self-images for high randomness level at the near field. On the other hand, it cancels high-order harmonics in far field, resulting in only a few central diffraction orders. Numerical simulations by means of the Rayleigh-Sommerfeld diffraction formula are performed in order to corroborate the analytical results. These results are of interest for industrial and technological applications where manufacture errors need to be considered. PMID- 27505364 TI - Effect of direction of incident light on the basic performance of a TeO2 acousto-optic tunable filter. AB - The selection of the ultrasonic polar angle is vitally important to the performance of an acousto-optic tunable filter (AOTF). The effects of ultrasonic angle on various properties of AOTFs were studied. Then, according to the selected ultrasonic angle, the changes of internal and external separation angles were analyzed in detail when the light was incident upon the crystal surface in two different ways. Additionally, the drift of diffracted light caused by chromatic aberration was analyzed, and an appropriate compensation wedge angle was calculated by the improved derivation formula. The external separation angle increased obviously after placing a wedge angle on the output end. Finally, the effect of incident beam with a cone angle on spectral bandwidth and diffraction efficiency is discussed. PMID- 27505365 TI - Simultaneous displacement and slope measurement in electronic speckle pattern interferometry using adjustable aperture multiplexing. AB - This paper suggests the use of adjustable aperture multiplexing (AAM), a method which is able to introduce multiple tunable carrier frequencies into a three-beam electronic speckle pattern interferometer to measure the out-of-plane displacement and its first-order derivative simultaneously. In the optical arrangement, two single apertures are located in the object and reference light paths, respectively. In cooperation with two adjustable mirrors, virtual images of the single apertures construct three pairs of virtual double apertures with variable aperture opening sizes and aperture distances. By setting the aperture parameter properly, three tunable spatial carrier frequencies are produced within the speckle pattern and completely separate the information of three interferograms in the frequency domain. By applying the inverse Fourier transform to a selected spectrum, its corresponding phase difference distribution can thus be evaluated. Therefore, we can obtain the phase map due to the deformation as well as its slope of the test surface from two speckle patterns which are recorded at different loading events. By this means, simultaneous and dynamic measurements are realized. AAM has greatly simplified the measurement system, which contributes to improving the system stability and increasing the system flexibility and adaptability to various measurement requirements. This paper presents the AAM working principle, the phase retrieval using spatial carrier frequency, and preliminary experimental results. PMID- 27505366 TI - Quantitative vibration analysis using a single fringe pattern in time-average speckle interferometry. AB - In this paper, a novel technique for quantitative vibration analysis using time average electronic speckle pattern interferometry is proposed. An amplitude varied time-average refreshing reference frame method is used to capture a fringe pattern with a better fringe contrast than the conventional reference frame technique. The recorded fringe patterns with improved contrast provide better mode shape visibility and are easier to process. A derivative-based regularized phase tracker model is used to retrieve vibration amplitudes from a single fringe pattern. The method does not require a phase shifter to obtain the mode shape or amplitude. The method provides unwrapped amplitude and amplitude derivatives maps directly, so a separate phase unwrapping process is not required. Experimental work is carried out using a circular aluminum plate test specimen and the results are compared with a finite element method modal analysis. Both experimental and numerical results show that the proposed method is robust and accurate. PMID- 27505367 TI - Zernike polynomials as a basis for modal fitting in lateral shearing interferometry: a discrete domain matrix transformation method. AB - A Zernike-polynomials-based wavefront reconstruction method for lateral shearing interferometry is proposed. Shear matrices are calculated using matrix transformation instead of mathematical derivation. Simulation results show that the shear matrices calculated using the proposed method are the same as those obtained from mathematical derivation. The advantage of the proposed method is that high order shear matrices can be obtained easily; thus, wavefront reconstruction can be extended to higher order Zernike terms, and reconstruction accuracy can be improved. PMID- 27505368 TI - Colossal Kerr nonlinearity based on electromagnetically induced transparency in a five-level double-ladder atomic system. AB - The paper is aimed at modeling the enhanced Kerr nonlinearity in a five-level double-ladder-type atomic system based on electromagnetically induced transparency (EIT) by using the semi-classical density matrix method. We present an analytical model to explain the origin of Kerr nonlinearity enhancement. The scheme also results in a several orders of magnitude increase in the Kerr nonlinearity in comparison with the well-known four- and three-level atomic systems. In addition to the steady-state case, the time-dependent Kerr nonlinearity and the switching feature of EIT-based colossal Kerr nonlinearity is investigated for the proposed system. PMID- 27505369 TI - RCWA-EIS method for interlayer grating coupling. AB - The grating coupling efficiencies for interlayer connection (overlaid chips) were previously calculated using the new rigorous coupled-wave analysis equivalent index-slab (RCWA-EIS) method. The chip-to-chip coupling efficiencies were determined for rectangular-groove (binary) gratings. In the present work, the search algorithms used in the RCWA-EIS method are optimized giving rise to improved definition of equivalent indices. Further, the versatility of the RCWA EIS method is demonstrated by extending it to (nonbinary) parallelogramic gratings, sawtooth gratings, and volume gratings. The finite-difference time domain method is used to verify the results. This demonstrates the flexibility of the RCWA-EIS method in analyzing arbitrary 1D gratings. PMID- 27505370 TI - Analysis of junction temperature and modification of luminous flux degradation for white LEDs in a thermal accelerated reliability test. AB - An accelerated aging test is the main method in evaluation of the reliability of light-emitting diodes (LEDs), and the first goal of this study is to investigate how the junction temperature (Tj) of the LED varies during accelerated aging. The Tj measured by the forward voltage method shows an upward trend over the aging time, which gives a variation about 6 degrees C-8 degrees C after 3,000 h of aging under an ambient temperature of 80 degrees C. The second goal is to investigate how the variation of Tj affects the lifetime estimation. It is verified that at a certain aging stage, as Tj increases, the normalized luminous flux linearly decreases with variation rate of microns (MU) (1/ degrees C). Then, we propose a method to modify the luminous flux degradation with the Tj and MU to meet the requirements of a constant degradation rate in the data fitting. The experimental results show that with the proposed method, the accelerated lifetimes of samples are bigger than that of the current method with increment values from 8.8% to 21.4% in this research. PMID- 27505371 TI - Hybrid algorithm for three-dimensional flame chemiluminescence tomography based on imaging overexposure compensation. AB - Flame tomography of chemiluminescence is a necessary combustion diagnostic technique that provides instantaneous 3D information on flame structure and excited species concentrations. During combustion diagnostics, imaging overexposure always causes missing information, which obviously decreases the accuracy in further reconstructions. In order to compensate imaging overexposure, a hybrid algorithm combining weight correction and Tikhonov's regularization is proposed in this paper. The intensity of the overexposure region can be estimated via the accumulation of weight coefficients. Meanwhile, Tikhonov's regularization is utilized to ameliorate the quality of reconstruction. The numerical simulation quantitatively evaluates the performance of the hybrid algorithm. Additionally, an experiment system consisting of 12 cameras was established to reconstruct the 3D combustion structure of axisymmetric flame with different exposure time settings. This work further investigates dynamic nonaxisymmetric propane diffusion flame. The obtained results show that the hybrid algorithm can effectively reveal the flame structure less influenced by imaging overexposure and achieve better results. PMID- 27505372 TI - Field of view of limitations in see-through HMD using geometric waveguides. AB - Geometric waveguides are being integrated into head-mounted display (HMD) systems, where having see-through capability in a compact, lightweight form factor is required. We developed methods for determining the field of view (FOV) of such waveguide HMD systems and have analytically derived the FOV for waveguides using planar and curved geometries. By using real ray-tracing methods, we are able to show how the geometry and index of refraction of the waveguide, as well as the properties of the coupling optics, impact the FOV. Use of this analysis allows one to determine the maximum theoretical FOV of a planar or curved waveguide-based system. PMID- 27505373 TI - Dependence of depth of focus on spherical aberration of optical systems. AB - This paper presents a theoretical analysis and computation of aberration coefficients of the third and fifth order of transverse spherical aberration of an optical system, which generates a ray bundle with a diameter of a geometric optical circle of confusion smaller than a predetermined limit value. Equations were derived for the calculation of aberration coefficients of an optical system, which satisfy given conditions, and for the determination of the maximum possible depth of focus for given conditions. PMID- 27505374 TI - Analysis of three-dimensional interference patterns of an inclined capillary. AB - We study the interference patterns from an inclined capillary tube filled with liquid by using the ray tracing method and interference theory. A beautiful elliptical pattern is found on the screen, with refined fringes embedded in it. Particularly, the fringes on top of the pattern are continuously swallowed to the center with the angle of incidence increasing. In addition, a method is demonstrated to determine the refractive index of the liquid and the wavelength of the incident light by measuring the capillary tilt of every 10-fringe being swallowed, which looks like fringe crossover, with respect to the change of the inclined angle of the capillary. PMID- 27505375 TI - Intensity and angle-of-arrival spectra of laser light propagating through axially homogeneous buoyancy-driven turbulence. AB - Frequency spectra obtained from the measurements of light intensity and angle of arrival (AOA) of parallel laser light propagating through the axially homogeneous, axisymmetric buoyancy-driven turbulent flow at high Rayleigh numbers in a long (length-to-diameter ratio of about 10) vertical tube are reported. The flow is driven by an unstable density difference created across the tube ends using brine and fresh water. The highest Rayleigh number is about 8*109. The aim of the present work is to find whether the conventional Obukhov-Corrsin scaling or Bolgiano-Obukhov (BO) scaling is obtained for the intensity and AOA spectra in the case of light propagation in a buoyancy-driven turbulent medium. Theoretical relations for the frequency spectra of log amplitude and AOA fluctuations developed for homogeneous isotropic turbulent media are modified for the buoyancy-driven flow in the present case to obtain the asymptotic scalings for the high and low frequency ranges. For low frequencies, the spectra of intensity and vertical AOA fluctuations obtained from measurements follow BO scaling, while scaling for the spectra of horizontal AOA fluctuations shows a small departure from BO scaling. PMID- 27505376 TI - Adaptive multidirectional frequency domain filter for noise removal in wrapped phase patterns. AB - In order to avoid the detrimental effects of excessive noise in the phase fringe patterns of a laser digital interferometer over the accuracy of phase unwrapping and the successful detection of mechanical fatigue defects, an effective method of adaptive multidirectional frequency domain filtering is introduced based on the characteristics of the energy spectrum of localized wrapped phase patterns. Not only can this method automatically set the cutoff frequency, but it can also effectively filter out noise while preserving the image edge information. Compared with the sine and cosine transform filtering and the multidirectional frequency domain filtering, the experimental results demonstrate that the image filtered by our method has the fewest number of residues and is the closest to the noise-free image, compared to the two aforementioned methods, demonstrating the effectiveness of this adaptive multidirectional frequency domain filter. PMID- 27505377 TI - High-resolution and wide-bandwidth light intensity fiber optic displacement sensor for MEMS metrology. AB - We report on the design, properties, and applications of a high-resolution and wide-bandwidth light intensity fiber optic displacement sensor for microelectromechanical system (MEMS) metrology. There are two types of structures that the system is dedicated to: vibrating with both high and low frequencies. In order to ensure high-frequency and high-resolution measurements, frequency down mixing and selective signal processing were applied. The obtained effective measuring bandwidth ranges from single hertz to 1 megahertz. The achieved resolution presented here is 116 pm/Hz1/2 and 138 pm/Hz1/2 for low-frequency and high-frequency operation modes, respectively, whereas the measurement of static displacement is 100 MUm. PMID- 27505378 TI - Automated alignment of a reconfigurable optical system using focal-plane sensing and Kalman filtering. AB - Automation of alignment tasks can provide improved efficiency and greatly increase the flexibility of an optical system. Current optical systems with automated alignment capabilities are typically designed to include a dedicated wavefront sensor. Here, we demonstrate a self-aligning method for a reconfigurable system using only focal plane images. We define a two lens optical system with 8 degrees of freedom. Images are simulated given misalignment parameters using ZEMAX software. We perform a principal component analysis on the simulated data set to obtain Karhunen-Loeve modes, which form the basis set whose weights are the system measurements. A model function, which maps the state to the measurement, is learned using nonlinear least-squares fitting and serves as the measurement function for the nonlinear estimator (extended and unscented Kalman filters) used to calculate control inputs to align the system. We present and discuss simulated and experimental results of the full system in operation. PMID- 27505379 TI - Design of apochromatic lens with large field and high definition for machine vision. AB - Precise machine vision detection for a large object at a finite working distance (WD) requires that the lens has a high resolution for a large field of view (FOV). In this case, the effect of a secondary spectrum on image quality is not negligible. According to the detection requirements, a high resolution apochromatic objective is designed and analyzed. The initial optical structure (IOS) is combined with three segments. Next, the secondary spectrum of the IOS is corrected by replacing glasses using the dispersion vector analysis method based on the Buchdahl dispersion equation. Other aberrations are optimized by the commercial optical design software ZEMAX by properly choosing the optimization function operands. The optimized optical structure (OOS) has an f-number (F/#) of 3.08, a FOV of phi60 mm, a WD of 240 mm, and a modulated transfer function (MTF) of all fields of more than 0.1 at 320 cycles/mm. The design requirements for a nonfluorite material apochromatic objective lens with a large field and high definition for machine vision detection have been achieved. PMID- 27505380 TI - Nonparaxial geometrical Ronchi test for spherical mirrors: an inverse ray-tracing approach. AB - A geometrical model based on an inverse ray-tracing approach to describe the Ronchi test for a concave spherical mirror is presented. In contrast to the conventional ray-tracing method, which refers to information unavailable in ronchigrams, the proposed model provides an explicit relation between the available information in the ronchigram and the parameters of the setup (radius of the sphere, position of the source, position and orientation of the observation, and grating planes). This allows for extracting the parameters of interest by a simple fitting procedure, as demonstrated by an application. The derived model exhibits new unexplored potential applications of the Ronchi test, establishing it as a very useful, simple, and universal tool for optical evaluation. PMID- 27505381 TI - Surface-enhanced coherent anti-Stokes Raman imaging of lipids. AB - This work describes in detail a wide-field surface-enhanced coherent anti-Stokes Raman scattering (CARS) microscope, which enables enhanced detection of sample structures in close proximity (~100 nm) of the substrate interface. Unlike conventional CARS microscopy, where the sample is illuminated with freely propagating light, the current implementation uses evanescent fields to drive Raman coherences across the entire object plane. By coupling the pump and Stokes excitation beams to the surface plasmon-polariton mode at the interface of a 30 nm thick gold film, we obtained strong CARS signals from cholesteryl oleate droplets adhered to the surface. The surface-enhanced CARS imaging system visualizes lipid structures with vibrational selectivity using illumination doses per unit area that are more than four orders of magnitude lower than in point scanning CARS microscopy. PMID- 27505382 TI - Degradation nonuniformity in the solar diffuser bidirectional reflectance distribution function. AB - The assumption of angular dependence stability of the solar diffuser (SD) throughout degradation is critical to the on-orbit calibration of the reflective solar bands (RSBs) in many satellite sensors. Recent evidence has pointed to the contrary, and in this work, we present a thorough investigative effort into the angular dependence of the SD degradation for the Visible Infrared Imaging Radiometer Suite (VIIRS) onboard the Suomi National Polar-orbiting Partnership (SNPP) satellite and for the twin Moderate-resolution Imaging Spectroradiometer (MODIS) onboard Terra and Aqua spacecrafts. One common key step in the RSB calibration is the use of the SD degradation performance measured by an accompanying solar diffuser stability monitor (SDSM) as a valid substitute for the SD degradation factor in the direction of the RSB view. If SD degradations between these two respective directions do not maintain the same relative relationship over time, then the unmitigated use of the SDSM-measured SD degradation factor in the RSB calibration calculation will generate bias, and consequently, long-term drift in derived science products. We exploit the available history of the on-orbit calibration events to examine the response of the SDSM and the RSB detectors to the incident illumination reflecting off SD versus solar declination angle and show that the angular dependency, particularly at short wavelengths, evolves with respect to time. The generalized and the decisive conclusion is that the bidirectional reflectance distribution function (BRDF) of the SD degrades nonuniformly with respect to both incident and outgoing directions. Thus, the SDSM-based measurements provide SD degradation factors that are biased relative to the RSB view direction with respect to the SD. The analysis also reveals additional interesting phenomena, for example, the sharp behavioral change in the evolving angular dependence observed in Terra MODIS and SNPP VIIRS. For SNPP VIIRS the mitigation for this "SD degradation nonuniformity effect" with respect to angles relies on a "hybrid methodology" using lunar-based calibration to set the reliable long-term baseline. For MODIS, the use of earth targets in the major release Collection 6 to improve calibration coefficients and time-dependent response-versus-scan-angle characterization inherently averts the use of SD and its associated issues. The work further supports that having an open-close operational capability for the space view door can minimize SD degradation and its associated effects due to solar exposure, and thus provide long-term benefits for maintaining calibration and science data accuracy. PMID- 27505383 TI - Compensation of fringe distortion for phase-shifting three-dimensional shape measurement by inverse map estimation. AB - For three-dimensional shape measurement, phase-shifting techniques are widely used to recover the objective phase containing height information from images of projected fringes. Although such techniques can provide an accurate result in theory, there might be considerable error in practice. One main cause of such an error is distortion of fringes due to nonlinear responses of a measurement system. In this paper, a postprocessing method for compensating distortion is proposed. Compared to other compensation methods, the proposed method is flexible in two senses: (1) no specific model of nonlinearity (such as the gamma model) is needed, and (2) no special calibration data are needed (only the observed image of the fringe is required). Experiments using simulated and real data confirmed that the proposed method can compensate multiple types of nonlinearity without being concerned about the model. PMID- 27505384 TI - Characterization of optical polarization properties for liquid crystal-based retarders. AB - We present the analysis and implementation of a set of experimental procedures to characterize optical polarization properties as a function of the applied voltage for liquid-crystal variable retarders (LCVRs) in the transmission mode. The studied properties are those involved in the operation of the LCVRs and, generally, are the most significant for optical applications: retardance, diattenuation, optical axes position, and output depolarization effects. The correct characterization of these polarization properties can be useful to improve results or estimate errors in applications using these devices. The results obtained show good accuracy and good agreement with the expected results. PMID- 27505385 TI - Smart electro-optical iris diaphragm based on liquid crystal film coating with photoconductive polymer of poly(N-vinylcarbazole). AB - This study develops a light shutter whose transmittance can be tuned electro optically. The liquid crystal (LC) film applies the photoconductive material of poly(N-vinylcarbazole) (PVK) based on twisted nematic (TN) liquid crystals (LCs). The hole-transport layer of PVK could reduce the built-in electric field of the LC film under the exposure of UV light. The driving voltage is considerably decreased with the aid of UV light exposure. The repeating optical switching is performed under sunlight illumination with an external bias of electric field ~5 V. Further, it could be operated under a parallel/cross-polarizer to change the light beam/ring as an iris and used to automatically block the UV light to protect an optical integrated system. PMID- 27505386 TI - Ground-based detection of nighttime clouds above Manila Observatory (14.64 degrees N, 121.07 degrees E) using a digital camera. AB - Ground-based cloud detection at nighttime is achieved by using cameras, lidars, and ceilometers. Despite these numerous instruments gathering cloud data, there is still an acknowledged scarcity of information on quantified local cloud cover, especially at nighttime. In this study, a digital camera is used to continuously collect images near the sky zenith at nighttime in an urban environment. An algorithm is developed to analyze pixel values of images of nighttime clouds. A minimum threshold pixel value of 17 is assigned to determine cloud occurrence. The algorithm uses temporal averaging to estimate the cloud fraction based on the results within the limited field of view. The analysis of the data from the months of January, February, and March 2015 shows that cloud occurrence is low during the months with relatively lower minimum temperature (January and February), while cloud occurrence during the warmer month (March) increases. PMID- 27505387 TI - Volume holographic printing using unconventional angular multiplexing for three dimensional display. AB - We propose and demonstrate a volume holographic printing method for dynamic three dimensional (3D) display with an expanded space-bandwidth product (SBP) using unconventional angular multiplexing techniques. By wavefront encoding of the 3D scene, with the help of computer-generated holography, the object beam is loaded onto a 2D phase spatial light modulator (SLM) with a limited SBP. The printing method then writes a single hologram through the interference of the object beam with a reference beam as a holographic element (hogel) in the volume holographic polymer. In addition, multiple 3D scenes can be recorded and dynamically reconstructed by angular multiplexing in the same hogel location. The SBP can be increased by two orders of magnitude compared to the conventional holographic printing method, showing the potential to realize a dynamic and high-resolution 3D display. PMID- 27505388 TI - Least-squares method for data reconstruction from gradient data in deflectometry. AB - Least-squares integration (LSI) and radial basis function integration (RBFI) methods are widely used to reconstruct specular surface shapes from gradient data in a deflectometry measurement. The traditional LSI method requires gradient data having a rectangular grid, and the RBFI method is effective at handling small size measurement data sets. Practically, the amount of gradient data is rather large, and data grids are in quadrilateral shapes. With this in mind, a new LSI method is proposed to integrate gradient data, which is based on an approximation that the normal vector of one point is perpendicular to the vectors connecting points at either side. A small measurement data set integrated by the RBFI method is employed as a supplementary constraint of the proposed method. Simulation and experimental results show that this proposed method is effective and accurate at handling deflectometry measurement. PMID- 27505389 TI - Improved quantitative visualization of hypervelocity flow through wavefront estimation based on shadow casting of sinusoidal gratings. AB - A simple noninterferometric optical probe is developed to estimate wavefront distortion suffered by a plane wave in its passage through density variations in a hypersonic flow obstructed by a test model in a typical shock tunnel. The probe has a plane light wave trans-illuminating the flow and casting a shadow of a continuous-tone sinusoidal grating. Through a geometrical optics, eikonal approximation to the distorted wavefront, a bilinear approximation to it is related to the location-dependent shift (distortion) suffered by the grating, which can be read out space-continuously from the projected grating image. The processing of the grating shadow is done through an efficient Fourier fringe analysis scheme, either with a windowed or global Fourier transform (WFT and FT). For comparison, wavefront slopes are also estimated from shadows of random-dot patterns, processed through cross correlation. The measured slopes are suitably unwrapped by using a discrete cosine transform (DCT)-based phase unwrapping procedure, and also through iterative procedures. The unwrapped phase information is used in an iterative scheme, for a full quantitative recovery of density distribution in the shock around the model, through refraction tomographic inversion. Hypersonic flow field parameters around a missile-shaped body at a free-stream Mach number of ~8 measured using this technique are compared with the numerically estimated values. It is shown that, while processing a wavefront with small space-bandwidth product (SBP) the FT inversion gave accurate results with computational efficiency; computation-intensive WFT was needed for similar results when dealing with larger SBP wavefronts. PMID- 27505390 TI - Single-shot dual-wavelength phase reconstruction in off-axis digital holography with polarization-multiplexing transmission. AB - A new system for single-shot dual-wavelength digital holographic microscopy with polarization-multiplexing path-shared transmission is presented. The key feature of the optical configuration is that the interference waves of two wavelengths having orthogonal polarization can transmit in the same interferometer paths at the same time, and two polarizers orthogonal to each other are placed in front of the CCD to realize single-shot recording of two holograms. The correlative filtering algorithm of the spatial-frequency spectrum for dual-wavelength digital holograms is reliable and efficient in the dual-wavelength path-shared configuration. The phase reconstruction in dual-wavelength digital holographic imaging is achieved by using this filtering algorithm. The experiment results of phase reconstruction of a groove grating demonstrate the reliability and validity of this optical configuration and the correlative filtering algorithm. This polarization-multiplexing configuration for dual-wavelength digital holography is compact and has more flexibility for the replacement of different-wavelength lasers. PMID- 27505391 TI - Effects of femtosecond laser pulse width on the formation of microstructured silicon. AB - We experimentally investigated the properties of surface microstructured silicon fabricated by 15 and 130 fs laser pulses. By changing parameters of femtosecond laser pulses, including laser flux, actual pulse acting time, and laser peak intensity, we found that the average height of spikes on the surface of microstructured silicon are only determined by the laser peak intensity. These results are important for the preparation and structure control of microstructured silicon. PMID- 27505392 TI - Diffraction-based sensitivity analysis for an external occulter laboratory demonstration. AB - An external flower-shaped occulter flying in formation with a space telescope can theoretically provide sufficient starlight suppression to enable direct imaging of an Earth-like planet. Occulter shapes are scaled to enable experimental validation of their performance at laboratory dimensions. Previous experimental results have shown promising performance but have not realized the full theoretical potential of occulter designs. Here, we develop a two-dimensional diffraction model for optical propagations for occulters incorporating experimental errors. We perform a sensitivity analysis, and comparison with experimental results from a scaled-occulter testbed validates the optical model to the 10-10 contrast level. The manufacturing accuracy along the edge of the occulter shape is identified as the limiting factor to achieving the theoretical potential of the occulter design. This hypothesis is experimentally validated using a second occulter mask manufactured with increased edge feature accuracy and resulting in a measured contrast level approaching the 10 12 level-a better than one order of magnitude improvement in performance. PMID- 27505393 TI - Creating Airy beams employing a transmissive spatial light modulator. AB - We present a detailed study of two novel methods for shaping the light optical wavefront by employing a transmissive spatial light modulator (SLM). Conventionally, optical Airy beams are created by employing SLMs in the so-called all-phase mode. In the first method, a numerically simulated lens phase distribution is loaded directly onto the SLM, together with the cubic phase distribution. An Airy beam is generated at the focal plane of the numerical lens. We provide for the first time, to the best of our knowledge, quantitative properties of the formed Airy beam. We derive the formula for deflection of the intensity maximum of the so-formed Airy beam, which is different from the quadratic deflection typical of Airy beams. We cross-validate the derived formula by both simulations and experiment. The second method is based on the fact that a system consisting of a transmissive SLM sandwiched between two polarizers can create a transmission function with negative values. This observation alone has the potential for various other wavefront modulations where the transmission function requires negative values. As an example for this method, we demonstrate that a wavefront can be modulated by passing the SLM system with transmission function with negative values by loading an Airy function distribution directly onto the SLM. Since the Airy function is a real-valued function but also with negative values, an Airy beam can be generated by direct transfer of the Airy function distribution onto such an SLM system. In this way, an Airy beam is generated immediately behind the SLM. As both new methods do not employ a physical lens, the two setups are more compact than conventional setups for creating Airy beams. We compare the performance of the two novel methods and the properties of the created Airy beams. PMID- 27505394 TI - Development of an optical microscopy system for automated bubble cloud analysis. AB - Recently, the number of uses of bubbles has begun to increase dramatically, with medicine, biofuel production, and wastewater treatment just some of the industries taking advantage of bubble properties, such as high mass transfer. As a result, more and more focus is being placed on the understanding and control of bubble formation processes and there are currently numerous techniques utilized to facilitate this understanding. Acoustic bubble sizing (ABS) and laser scattering techniques are able to provide information regarding bubble size and size distribution with minimal data processing, a major advantage over current optical-based direct imaging approaches. This paper demonstrates how direct bubble-imaging methods can be improved upon to yield high levels of automation and thus data comparable to ABS and laser scattering. We also discuss the added benefits of the direct imaging approaches and how it is possible to obtain considerable additional information above and beyond that which ABS and laser scattering can supply. This work could easily be exploited by both industrial scale operations and small-scale laboratory studies, as this straightforward and cost-effective approach is highly transferrable and intuitive to use. PMID- 27505395 TI - Annealing effects on microstructure and laser-induced damage threshold of HfO2/SiO2 multilayer mirrors. AB - HfO2/SiO2 periodic multilayer high reflection mirrors have been prepared by a reactive electron-beam evaporation technique. The deposited mirrors were annealed in the temperature range from 300 degrees C to 500 degrees C. The effects of annealing on optical, microstructural, and laser-induced damage characteristics of the mirrors have been investigated. The high reflection band of the mirror shifts toward a shorter wavelength with increasing annealing temperature. As-deposited and annealed mirrors show polycrystalline structure with a monoclinic phase of HfO2. Crystalinity and grain size increase upon annealing. The laser-induced damage threshold (LIDT) has been assessed using a 532 nm pulsed laser at a pulse width of 7 ns. The LIDT value of the multilayer mirror increases from 44.1 J/cm2 to 77.6 J/cm2 with annealing up to 400 degrees C. The improvement of LIDT with annealing is explained through oxygen vacancy defects as well as grain-size-dependent thermal conductivity. Finally, the observed laser damage morphology, such as circular scalds and ablated multilayer stacks with terrace structure, are analyzed. PMID- 27505396 TI - Linearity enhancement of scale factor in an optical interrogated micromechanical accelerometer. AB - A method to reduce the residual stress of support arms in an optical interrogated micromechanical accelerometer is proposed in order to enhance the linearity of the scale factor of the accelerometer. First, the behavior of residual stress in support arms is analyzed in detail, and the simulation of shape curvature caused by residual stress in aluminum-made support arms is completed using finite element analysis. Then, by comparing two different materials of support arms (aluminum-made and silicon-made support arms), a modified fabrication is introduced in order to reduce the unexpected residual stress in support arms. Finally, based on contrast experiments, the linearity of the scale factor of accelerometers with aluminum-made and silicon-made support arms is measured using the force feedback test system, respectively. Results show that the linearity of the scale factor of the accelerometer with silicon-made support arms is 0.85%, which is reduced about an order of magnitude compared to that of the accelerometer with aluminum-made support arms with the linearity of scale factor of 7.48%; linearity enhancement of the scale factor is validated. This allows accuracy improvement of the optical interrogated micromechanical accelerometer in the application of inertial navigation and positioning. PMID- 27505397 TI - All-fiber, narrow linewidth and linearly polarized fiber laser in a single-mode multimode-single-mode cavity. AB - We report the design of an all-fiber, linearly polarized Yb-doped fiber laser at 1064 nm with a narrow linewidth and high output power required by the master oscillator of the amplifier for high-power spectral beam combining. The laser has achieved linearly polarized output with a polarization extinction ratio of 23 dB, a narrow linewidth of <=52 pm, and an output power of 32.7 W. Such performance was obtained by the cavity design that incorporated a wavelength-shifted PM fiber Bragg grating pair and single-mode-multimode-single-mode structure. PMID- 27505398 TI - High Raman-to-fluorescence ratio of Rhodamine 6G excited with 532 nm laser wavelength using a closely packed, self-assembled monolayer of silver nanoparticles. AB - A highly efficient Raman-to-fluorescence ratio of Rhodamine 6G is obtained by means of 532 nm laser wavelength, which is in close proximity of the dye's absorption maximum. Closely packed, gap-filled self-assembled monolayers of silver nanoparticles were produced to observe the Raman signals of Rhodamine 6G. Two mechanisms contribute to detect the Raman signals of the fluorescent sample: surface-enhanced Raman scattering (SERS) and nanomaterial surface energy transfer (NSET). Self-assembled monolayers of silver nanoparticles with different coverage densities and also those filled with probe molecules were prepared through variations of the substrate's immersion time in a nanoparticle solution and drying the substrate, respectively. Examination of the effects of these two factors on the plasmonic response and SERS efficiency of the substrate revealed that in a gap-filled dense coverage, near-field interactions dominate, which remarkably increase the Raman-to-fluorescence ratio (RFR). To have a perfect dense coverage, the efficient immersion time was obtained at about 48 h. Drying the substrates also caused further enhancement in RFR through filling interparticle spaces with dye molecules and, accordingly, an increase in NSET efficiency. PMID- 27505399 TI - Scintillation analysis of multiple-input single-output underwater optical links. AB - Multiple-input single-output (MISO) techniques are employed in underwater wireless optical communication (UWOC) links to mitigate the degrading effects of oceanic turbulence. In this paper, we consider a MISO UWOC system which consists of a laser beam array as transmitter and a point detector as receiver. Our aim is to find the scintillation index at the detector in order to quantify the system performance. For this purpose, the average intensity and the average of the square of the intensity are derived in underwater turbulence by using the extended Huygens-Fresnel principle. The scintillation index and the average bit error-rate (?BER?) formulas presented in this paper depend on the oceanic turbulence parameters, such as the rate of dissipation of the mean-squared temperature, rate of dissipation of kinetic energy per unit mass of fluid, Kolmogorov microscale, and the ratio of temperature to salinity contributions to the refractive index spectrum, the link length, and the wavelength. Recently, we have derived an equivalent structure constant of atmospheric turbulence and expressed it in terms of the oceanic turbulence parameters [Appl. Opt.55, 1228 (2016)APOPAI0003-693510.1364/AO.55.001228]. In the formulation in this paper, this equivalent structure constant is utilized, which enables us to employ the existing similar formulation valid in atmospheric turbulence. PMID- 27505400 TI - Real-time two-dimensional beam steering with gate-tunable materials: a theoretical investigation. AB - A leaky-wave antenna is proposed that furnishes two-dimensional (2-D) beam scanning in both elevation and azimuth planes via electrical control in real time, and at a single frequency. The structure consists of a graphene sheet on a metal-backed substrate. The 2-D beam-scanning performance is achieved through the proper biasing configuration of graphene. Traditional pixel-by-pixel electrical control makes the biasing network a huge challenge for chip-scale designs in the terahertz regime and beyond. The method presented here enables dynamic control by applying two groups of one-dimensional biasing on the sides of the sheet. They are orthogonal and decoupled, with one group offering monotonic impedance variation along one direction, and the other sinusoidal impedance modulation along the other direction. The conductivity profile of the graphene sheet for a certain radiation angle, realized by applying proper voltage to each pad underneath the sheet, is determined by a holographic technique and can be reconfigured electronically and desirably. Such innovative biasing design makes real-time control of the beam direction and beamwidth simple and highly integrated. The concept is not limited to graphene-based structures, and can be generalized to any available gate-tunable material system. PMID- 27505401 TI - PEG Insertion in Patients With Dementia Does Not Improve Nutritional Status and Has Worse Outcomes as Compared With PEG Insertion for Other Indications. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) tubes are commonly utilized as a method of enteral feeding in patients unable to obtain adequate oral nutrition. Although some studies have shown improved mortality in select populations, the safety and effectiveness of PEG insertion in patients with dementia compared with those with other neurological diseases or head and neck malignancy remains less well defined. OBJECTIVE: To evaluate the nutritional effectiveness, rate of rehospitalization, and risk of mortality among patients with dementia compared with patients with other neurological diseases or head and neck cancers who undergo PEG placement. MATERIALS AND METHODS: We conducted a retrospective analysis from a prospective database of patients who underwent PEG placement at an academic tertiary center between 2008 and 2013. The following data were collected: indication for PEG, patient demographics, biochemical markers of nutritional status rehospitalization, and survival rates. RESULTS: During the study period, 392 patients underwent PEG tube placement. Indications for PEG were dementia (N=165, group A), cerebrovascular accident (N=124, group B), and other indications such as oropharyngeal cancers and motor neuron disease (N=103, group C). The mean follow-up time after PEG was 18 months (range, 3 to 36 mo). No differences in baseline demographics were noted. PEG insertion in the dementia (group A) neither reduced the rehospitalization rate 6 months' postprocedure compared with groups B and C (2.45 vs. 1.86 and 1.65, respectively; P=0.05), nor reduced the mortality rate within the first year post-PEG placement (75% vs. 58% and 38% for groups A, B, and C, respectively, P=0.001), as well, it did not improve survival at 1 month after the procedure (15% vs. 3.26% and 7.76%, for groups A, B, C, respectively, P<0.01). The presence of dementia was also associated with shorter mean time to death (7.2 vs. 8.85 and 8 mo for groups A, B, C, respectively, P<0.05). The rate of improvement of the nutritional biomarker albumin was lower in the dementia group [3.1. to 2.9 vs. 3.2 to 3.3 and 3 to 3.3 g/dL for groups A, B, and C, respectively (P<0.02)]. Multivariate regression analysis showed that the presence of dementia was an independent predictor for mortality rate within the first year and 1-month mortality rate in patients undergoing PEG insertion with odds ratio 3.22 (95% confidence interval, 1.52 4.32) and odds ratio 2.52 (95% confidence interval, 1.22-3.67). CONCLUSIONS: PEG insertion in patients with dementia neither improve both short-term and long-term mortality nor rehospitalization rate as compared with patients who underwent PEG placement for alternate indications such as other neurological diseases or head and neck malignancy and even was associated with shorter time to death. Furthermore, PEG insertion in patients with dementia did not improve albumin. Therefore, careful selection of patients with dementia is warranted before PEG placement weighing the risks and benefits on a personalized basis. PMID- 27505402 TI - Value of Oral Proton Pump Inhibitors in Acute, Nonvariceal Upper Gastrointestinal Bleeding: A Network Meta-Analysis. AB - BACKGROUND: Intravenous (IV) proton pump inhibitors (PPI) are the standard medical treatment in acute nonvariceal upper gastrointestinal bleeding (ANVGIB). Optimal route of PPI delivery has been questioned. AIM: The aim was to perform a systematic review and network meta-analysis for the endpoints of risk of rebleeding, length of stay (LOS), surgery (ROS), mortality, and total units of blood transfused (UBT) among trials evaluating acid suppressive medications in ANVGIB. METHODS: A total of 39 studies using IV PPI drip, IV scheduled PPI, oral PPI, H2-receptor antagonists, and placebo were identified. Network meta-analysis was used for indirect comparisons and Bayesian Markov Chain Monte Carlo methods for calculation of probability superiority. RESULTS: No difference was observed between IV PPI drip and scheduled IV PPI for mortality (relative risk=1.11; 95% credibility interval, 0.56-2.21), LOS (0.04, -0.49 to 0.44), ROS (1.27, 0.64 2.35) and risk of rebleeding within 72 hours, 1 week, and 1 month [(0.98, 0.48 1.95), (0.59, 0.13-2.03), (0.82, 0.28-2.16)]. Oral PPIs were as effective as IV scheduled PPIs and IV PPI drip for LOS (0.22, -0.61 to 0.79 and 0.16, -0.56 to 0.80) and UBT (-0.25, -1.23 to 0.65 and -0.06, -0.71 to 0.65) and superior to IV PPI drip for ROS (0.30, 0.10 to 0.78). CONCLUSION: Scheduled IV PPIs were as effective as IV PPI drip for most outcomes. Oral PPIs were comparable to scheduled IV for LOS and UBT and superior to IV PPI drip for ROS. Conclusions should be tempered by low frequency endpoints such as ROS, but question the need for IV PPI drip in ANVGIB. PMID- 27505403 TI - Current Status of Immunotherapy Treatments for Pancreatic Cancer. AB - Pancreatic cancer (PC) is a lethal disease representing the seventh most frequent cause of death from cancer worldwide. Resistance of pancreatic tumors to current treatments leads to disappointing survival rates, and more specific and effective therapies are urgently needed. In recent years, immunotherapy has been proposed as a promising approach to the treatment of PC, and encouraging results have been published by various preclinical and clinical studies. This review provides an overview of the latest developments in the immunotherapeutic treatment of PC and summarizes the most recent and important clinical trials. PMID- 27505404 TI - Factors Associated With Metachronous Gastric Cancer Development After Endoscopic Submucosal Dissection for Early Gastric Cancer. AB - GOALS: To clarify the factors associated with metachronous gastric cancer development after endoscopic submucosal dissection (ESD) for early gastric cancer. BACKGROUND: Patients who undergo ESD for early gastric cancer have an appreciable risk of developing metachronous gastric cancer. However, there have been few reports on the association between life style and the development of such cancer. STUDY: Patients with early gastric cancer who underwent ESD at our institution between 2003 and 2012 were enrolled. Metachronous gastric cancer was defined as secondary gastric cancer detected >1 year after initial ESD. Factors, including age, gender, body mass index, eradication of Helicobacter pylori, cigarette smoking, drinking, and continuous use of a proton pump inhibitor, associated with metachronous gastric cancer development were evaluated by Cox proportional hazard regression analysis. RESULTS: A total of 539 patients with a mean 53.6-month follow-up period were analyzed. The 5-year cumulative incidence of secondary gastric cancer was 13.0%. Multivariate analysis exhibited that age of 60 years and above [hazard ratio (95% confidence interval)=4.05 (1.23-13.4)] and cigarette smoking [2.12 (1.19-3.78)] were independent risk factors for metachronous gastric cancer development. Furthermore, >=20 pack-years of smoking [1.51 (1.03-2.24)] was a significant risk factor with a dose-response relationship (P for trend=0.042). There was no significant association between Helicobacter pylori eradication and metachronous gastric cancer development. CONCLUSIONS: This is the first study to demonstrate the detailed association between cigarette smoking and metachronous gastric cancer development. PMID- 27505405 TI - Alcohol-related genes show an enrichment of associations with a persistent externalizing factor. AB - Research using twins has found that much of the variability in externalizing phenotypes-including alcohol and drug use, impulsive personality traits, risky sex, and property crime-is explained by genetic factors. Nevertheless, identification of specific genes and variants associated with these traits has proven to be difficult, likely because individual differences in externalizing are explained by many genes of small individual effect. Moreover, twin research indicates that heritable variance in externalizing behaviors is mostly shared across the externalizing spectrum rather than specific to any behavior. We use a longitudinal, "deep phenotyping" approach to model a general externalizing factor reflecting persistent engagement in a variety of socially problematic behaviors measured at 11 assessment occasions spanning early adulthood (ages 18 to 28). In an ancestrally homogenous sample of non-Hispanic Whites (N = 337), we then tested for enrichment of associations between the persistent externalizing factor and a set of 3,281 polymorphisms within 104 genes that were previously identified as associated with alcohol-use behaviors. Next, we tested for enrichment among domain-specific factors (e.g., property crime) composed of residual variance not accounted for by the common factor. Significance was determined relative to bootstrapped empirical thresholds derived from permutations of phenotypic data. Results indicated significant enrichment of genetic associations for persistent externalizing, but not for domain-specific factors. Consistent with twin research findings, these results suggest that genetic variants are broadly associated with externalizing behaviors rather than unique to specific behaviors. (PsycINFO Database Record PMID- 27505406 TI - Clinical and personality traits in emotional disorders: Evidence of a common framework. AB - Certain clinical traits (e.g., ruminative response style, self-criticism, perfectionism, anxiety sensitivity, fear of negative evaluation, and thought suppression) increase the risk for and chronicity of emotional disorders. Similar to traditional personality traits, they are considered dispositional and typically show high temporal stability. Because the personality and clinical traits literatures evolved largely independently, connections between them are not fully understood. We sought to map the interface between a widely studied set of clinical and personality traits. Two samples (N = 385 undergraduates; N = 188 psychiatric outpatients) completed measures of personality traits, clinical traits, and an interview-based assessment of emotional-disorder symptoms. First, the joint factor structure of these traits was examined in each sample. Second, structural equation modeling was used to clarify the effects of clinical traits in the prediction of clinical symptoms beyond negative temperament. Third, the incremental validity of clinical traits beyond a more comprehensive set of higher order and lower-order personality traits was examined using hierarchical regression. Clinical and personality traits were highly correlated and jointly defined a 3-factor structure-Negative Temperament, Positive Temperament, and Disinhibition-in both samples, with all clinical traits loading on the Negative Temperament factor. Clinical traits showed modest but significant incremental validity in explaining symptoms after accounting for personality traits. These data indicate that clinical traits relevant to emotional disorders fit well within the traditional personality framework and offer some unique contributions to the prediction of psychopathology, but it is important to distinguish their effects from negative temperament/neuroticism. (PsycINFO Database Record PMID- 27505407 TI - Attentional bias temporal dynamics in remitted depression. AB - Theory implicates attentional bias (AB) or dysregulated attentional processing of emotional information in the recurrence of major depressive episodes. However, empirical study of AB among remitted depressed patients is limited in scope and has yielded mixed findings. Mixed findings may be accounted for by how the field has conceptualized and thereby studied AB. We propose that a novel temporal dynamic process perspective on AB may help disambiguate extant findings and elucidate the nature of AB in remitted depression. Thus, we reexamined Dot Probe data among remitted depressed patients (RMD; n = 328) and nondepressed controls (NDC; n = 82) that previously yielded null effects when AB was quantified by means of the traditional aggregated mean bias score (Vrijsen et al., 2014). We reanalyzed data using a novel computational approach that extracts a series of bias estimations from trial to trial (Zvielli, Bernstein, & Koster, 2015). Key features of these dynamic process signals revealed moderate to excellent reliability relative to the traditional aggregated mean bias scores. These features of AB dynamics-specifically temporal variability in AB including AB toward and away from emotional stimuli-were significantly elevated among RMDs relative to NDCs. Moreover, among RMDs, a greater number of past depressive episodes were associated with elevation in these features of AB dynamics. Effects were not accounted for by residual depressive symptoms or social anxiety symptoms. Findings indicate that dysregulation in attentional processing of emotional information reflected in AB dynamics may be key to depression vulnerability. (PsycINFO Database Record PMID- 27505408 TI - The reciprocal predictive relationship between high-risk personality and drinking: An 8-wave longitudinal study in early adolescents. AB - In youth, maladaptive personality traits such as urgency (the tendency to act rashly when highly emotional) predict early onset alcohol consumption. In adults, maladaptive behaviors, including substance use, predict negative personality change. This article reports on a test of hypothesized maladaptive, reciprocal prediction between youth drinking and the trait of urgency. In a sample of 1,906 youth assessed every 6 months from the spring of 5th grade through the spring of 8th grade, and again in the spring of 9th grade, the authors found such reciprocal prediction. Over each 6 month and then 12 month time lag, urgency predicted increased subsequent drinking. In addition, over 6 of the 7 time lags, drinking behavior predicted subsequent increases in urgency. During early adolescence, maladaptive personality and dysfunctional behavior each led to increases in the other. The results of this process include cyclically increasing risk for youth drinking and may include increasing risk for the multiple maladaptive behaviors predicted by the trait of urgency. (PsycINFO Database Record PMID- 27505409 TI - Theory of mind is not theory of emotion: A cautionary note on the Reading the Mind in the Eyes Test. AB - The ability to represent mental states (theory of mind [ToM]) is crucial in understanding individual differences in social ability and social impairments evident in conditions such as autism spectrum disorder (ASD). The Reading the Mind in the Eyes Test (RMET) is a popular measure of ToM ability, validated in part by the poor performance of those with ASD. However, the RMET requires recognition of facial emotion, which is impaired in those with alexithymia, which frequently co-occurs with ASD. Thus, it is unclear whether the RMET indexes emotion recognition, associated with alexithymia, or ToM, associated with ASD. We therefore investigated the independent contributions of ASD and alexithymia to performance on the RMET. ASD and alexithymia-matched control participants did not differ on RMET performance, whereas ASD participants demonstrated impaired performance on an alternative test of ToM, the Movie for Assessment of Social Cognition (MASC). Furthermore, alexithymia, but not ASD diagnosis, significantly influenced RMET performance but did not affect MASC performance. These results suggest that the RMET measures emotion recognition rather than ToM ability and support the alexithymia hypothesis of emotion-related deficits in ASD. (PsycINFO Database Record PMID- 27505410 TI - Chemical Constituents Isolated from Bletilla striata and Their Inhibitory Effects on Nitric Oxide Production in RAW 264.7 Cells. AB - Bioassay-guided fractionation of the MeOH extract of the tubers of Bletilla striata led to the isolation of two new C-methylated flavan-3-ols, bletillanols A (1) and B (2), along with ten known compounds (3 - 12). Their structures were determined by using extensive spectroscopic analysis including 1D-, 2D-NMR, and circular dichroism data. All of the isolated compounds were tested for their inhibitory potential on the nitric oxide generation in LPS-stimulated RAW 264.7 cells. PMID- 27505411 TI - Second-Order Systematicity of Associative Learning: A Paradox for Classical Compositionality and a Coalgebraic Resolution. AB - Systematicity is a property of cognitive architecture whereby having certain cognitive capacities implies having certain other "structurally related" cognitive capacities. The predominant classical explanation for systematicity appeals to a notion of common syntactic/symbolic structure among the systematically related capacities. Although learning is a (second-order) cognitive capacity of central interest to cognitive science, a systematic ability to learn certain cognitive capacities, i.e., second-order systematicity, has been given almost no attention in the literature. In this paper, we introduce learned associations as an instance of second-order systematicity that poses a paradox for classical theory, because this form of systematicity involves the kinds of associative constructions that were explicitly rejected by the classical explanation. Our category theoretic explanation of systematicity resolves this problem, because both first and second-order forms of systematicity are derived from the same categorical construction: universal morphisms, which generalize the notion of compositionality of constituent representations to (categorical) compositionality of constituent processes. We derive a model of systematic associative learning based on (co)recursion, which is an instance of a universal construction. These results provide further support for a category theory foundation for cognitive architecture. PMID- 27505412 TI - Role for Torsin in Lipid Metabolism. AB - DYT1 dystonia is a neurological disease that causes involuntary twisting movements, often caused by dysfunction of the TorsinA gene. In this issue of Developmental Cell, Grillet et al. (2016) use Drosophila to discover that TorsinA regulates lipid metabolism, opening up future directions of research into the causes of this disease. PMID- 27505413 TI - Of Mice and Snakes: A Tail of Oct4. AB - The vertebrate axial skeleton comprises regions of specialized vertebrae, which vary in length between lineages. Aires et al. (2016) uncover a key role for Oct4 in determining trunk length in mice. Additionally, a heterochronic shift in Oct4 expression may underlie the extreme elongation of the trunk in snakes. PMID- 27505414 TI - Keratins Are Going Nuclear. AB - Previously thought to reside exclusively in the cytoplasm, the cytoskeletal protein keratin 17 (K17) has been recently identified inside the nucleus of tumor epithelial cells with a direct impact on cell proliferation and gene expression. We comment on fundamental questions raised by this new finding and the associated significance. PMID- 27505415 TI - Nonrandom Germline Transmission of Mouse Spermatogonial Stem Cells. AB - Genes are thought to be transmitted to offspring by random fertilization of a small number of oocytes with numerous spermatozoa. Here we analyzed the dynamics of male germline transmission by genetic marking and transplantation of spermatogonial stem cells (SSCs). We found that offspring deriving from a small number of specific SSCs appear within a limited time. Interestingly, the same SSC clones reappear later with an average functional lifespan of ~124.4 days. Cyclic offspring production from SSCs was not caused by changes in SSC self-renewal activity because lineage-tracing analyses suggested that all SSCs actively proliferated. Selection appears to occur during the differentiating spermatogonia stage, when extensive apoptosis was observed. The pattern of germline transmission could be predicted using a mathematical model in which SSCs repeat cycles of transient spermatogenic burst and refractory periods. Thus, spermatogenesis is a regulated process whereby specific SSC clones are repeatedly recruited for fertilization with long-term cycles. PMID- 27505416 TI - Adhesion and Fusion of Muscle Cells Are Promoted by Filopodia. AB - Indirect flight muscles (IFMs) in Drosophila are generated during pupariation by fusion of hundreds of myoblasts with larval muscle templates (myotubes). Live observation of these muscles during the fusion process revealed multiple long actin-based protrusions that emanate from the myotube surface and require Enabled and IRSp53 for their generation and maintenance. Fusion is blocked when formation of these filopodia is compromised. While filopodia are not required for the signaling process underlying critical myoblast cell-fate changes prior to fusion, myotube-myoblast adhesion appears to be filopodia dependent. Without filopodia, close apposition between the cell membranes is not achieved, the cell-adhesion molecule Duf is not recruited to the myotube surface, and adhesion-dependent actin foci do not form. We therefore propose that the filopodia are necessary to prime the heterotypic adhesion process between the two cell types, possibly by recruiting the cell-adhesion molecule Sns to discrete patches on the myoblast cell surface. PMID- 27505417 TI - Protocadherin-17 Mediates Collective Axon Extension by Recruiting Actin Regulator Complexes to Interaxonal Contacts. PMID- 27505418 TI - Involving High School Students in Computational Physics University Research: Theory Calculations of Toluene Adsorbed on Graphene. AB - To increase public awareness of theoretical materials physics, a small group of high school students is invited to participate actively in a current research projects at Chalmers University of Technology. The Chalmers research group explores methods for filtrating hazardous and otherwise unwanted molecules from drinking water, for example by adsorption in active carbon filters. In this project, the students use graphene as an idealized model for active carbon, and estimate the energy of adsorption of the methylbenzene toluene on graphene with the help of the atomic-scale calculational method density functional theory. In this process the students develop an insight into applied quantum physics, a topic usually not taught at this educational level, and gain some experience with a couple of state-of-the-art calculational tools in materials research. PMID- 27505419 TI - A Cost-Effective Approach to Sequence Hundreds of Complete Mitochondrial Genomes. AB - We present a cost-effective approach to sequence whole mitochondrial genomes for hundreds of individuals. Our approach uses small reaction volumes and unmodified (non-phosphorylated) barcoded adaptors to minimize reagent costs. We demonstrate our approach by sequencing 383 Fundulus sp. mitochondrial genomes (192 F. heteroclitus and 191 F. majalis). Prior to sequencing, we amplified the mitochondrial genomes using 4-5 custom-made, overlapping primer pairs, and sequencing was performed on an Illumina HiSeq 2500 platform. After removing low quality and short sequences, 2.9 million and 2.8 million reads were generated for F. heteroclitus and F. majalis respectively. Individual genomes were assembled for each species by mapping barcoded reads to a reference genome. For F. majalis, the reference genome was built de novo. On average, individual consensus sequences had high coverage: 61-fold for F. heteroclitus and 57-fold for F. majalis. The approach discussed in this paper is optimized for sequencing mitochondrial genomes on an Illumina platform. However, with the proper modifications, this approach could be easily applied to other small genomes and sequencing platforms. PMID- 27505420 TI - Automated Texture Analysis and Determination of Fibre Orientation of Heart Tissue: A Morphometric Study. AB - The human heart has a heterogeneous structure, which is characterized by different cell types and their spatial configurations. The physical structure, especially the fibre orientation and the interstitial fibrosis, determines the electrical excitation and in further consequence the contractility in macroscopic as well as in microscopic areas. Modern image processing methods and parameters could be used to describe the image content and image texture. In most cases the description of the texture is not satisfying because the fibre orientation, detected with common algorithms, is biased by elements such as fibrocytes or endothelial nuclei. The goal of this work is to figure out if cardiac tissue can be analysed and classified on a microscopic level by automated image processing methods with a focus on an accurate detection of the fibre orientation. Quantitative parameters for identification of textures of different complexity or pathological attributes inside the heart were determined. The focus was set on the detection of the fibre orientation, which was calculated on the basis of the cardiomyocytes' nuclei. It turned out that the orientation of these nuclei corresponded with a high precision to the fibre orientation in the image plane. Additionally, these nuclei also indicated very well the inclination of the fibre. PMID- 27505421 TI - Highly Conductive Anion-Exchange Membranes from Microporous Troger's Base Polymers. AB - The development of polymeric anion-exchange membranes (AEMs) combining high ion conductivity and long-term stability is a major challenge for materials chemistry. AEMs with regularly distributed fixed cationic groups, based on the formation of microporous polymers containing the V-shape rigid Troger's base units, are reported for the first time. Despite their simple preparation, which involves only two synthetic steps using commercially available precursors, the polymers provide AEMs with exceptional hydroxide conductivity at relatively low ion-exchange capacity, as well as a high swelling resistance and chemical stability. An unprecedented hydroxide conductivity of 164.4 mS cm(-1) is obtained at a relatively a low ion-exchange capacity of 0.82 mmol g(-1) under optimal operating conditions. The exceptional anion conductivity appears related to the intrinsic microporosity of the charged polymer matrix, which facilitates rapid anion transport. PMID- 27505422 TI - Vitamin D3 Partly Antagonizes Advanced-Glycation Endproducts-Induced NFkappaB Activation in Mouse Podocytes. AB - BACKGROUND/AIMS: We have previously shown that advanced glycation-endproducts (AGEs) induced NFkappaB activation in differentiated mouse podocytes. This NFkappaB activation may contribute to the progression of renal disease and mediation of fibrosis by various mechanisms. This study was undertaken to test whether this detrimental response may be reversed by vitamin D3 or its analogue paricalcitol. METHODS: Differentiated mouse podocytes were challenged with glycated bovine serum albumin (AGE-BSA), or non-glycated control BSA (in the presence or absence of various concentrations of vitamin D3 (decostriol, 1alpha,25-dihydroxyvitamin D3)) or its active analog paricalcitol. Quantitative mRNA expressions were measured by real-time PCR, whereas protein expressions were determined by Western blotting followed by densitometry. Cytoplasmic and nuclear protein expression of the NFkappaB subunit p65 (Rel A) were determined by Western blotting. Furthermore, the ratio of phosphorylated to non-phosphorylated IkappaB alpha was measured using specific antibodies. Electrophoretic mobility shift assays and a capture ELISA assay were used to assess NFkappaB transactivation in vitro. In addition, NFkappaB transactivation was also monitored in HEK-NFkappaBIA reporter cells using live cell luminometry. RESULTS: Podocytes expressed the receptor for vitamin D. The vitamins did not suppress receptor for AGEs (RAGE) expression; instead, they rather upregulated RAGE. Although vitamin D3 and paricalcitol partly and differentially modified some of the studied parameters, both hormones inhibited AGE-BSA-induced NFkappaB transactivation, presumably by various mechanisms including the upregulation of IkappaB-alpha protein, keeping NFkappaB sequestered in an inactive state in the cytoplasm. CONCLUSION: Vitamin D3 or its analog paricalcitol partly prevented AGE-mediated NFkappaB activation, an important feature of diabetic nephropathy (DN). Whether this in vitro finding is of clinical relevance to prevent/treat DN requires further studies. PMID- 27505423 TI - Intestinal Microbial Metabolites Are Linked to Severity of Myocardial Infarction in Rats. AB - Intestinal microbiota determine severity of myocardial infarction in rats. We determined whether low molecular weight metabolites derived from intestinal microbiota and transported to the systemic circulation are linked to severity of myocardial infarction. Plasma from rats treated for seven days with the non absorbed antibiotic vancomycin or a mixture of streptomycin, neomycin, polymyxin B and bacitracin was analyzed using mass spectrometry-based metabolite profiling platforms. Antibiotic-induced changes in the abundance of individual groups of intestinal microbiota dramatically altered the host's metabolism. Hierarchical clustering of dissimilarities separated the levels of 284 identified metabolites from treated vs. untreated rats; 193 were altered by the antibiotic treatments with a tendency towards decreased metabolite levels. Catabolism of the aromatic amino acids phenylalanine, tryptophan and tyrosine was the most affected pathway comprising 33 affected metabolites. Both antibiotic treatments decreased the severity of an induced myocardial infarction in vivo by 27% and 29%, respectively. We then determined whether microbial metabolites of the amino acids phenylalanine, tryptophan and tyrosine were linked to decreased severity of myocardial infarction. Vancomycin-treated rats were administered amino acid metabolites prior to ischemia/reperfusion studies. Oral or intravenous pretreatment of rats with these amino acid metabolites abolished the decrease in infarct size conferred by vancomycin. Inhibition of JAK-2 (AG-490, 10 MUM), Src kinase (PP1, 20 MUM), Akt/PI3 kinase (Wortmannin, 100 nM), p44/42 MAPK (PD98059, 10 MUM), p38 MAPK (SB203580, 10 MUM), or KATP channels (glibenclamide, 3 MUM) abolished cardioprotection by vancomycin, indicating microbial metabolites are interacting with cell surface receptors to transduce their signals through Src kinase, cell survival pathways and KATP channels. These inhibitors have no effect on myocardial infarct size in untreated rats. This study links gut microbiota metabolites to severity of myocardial infarction and may provide future opportunities for novel diagnostic tests and interventions for the prevention of cardiovascular disease. PMID- 27505424 TI - Switching Away from Utilitarianism: The Limited Role of Utility Calculations in Moral Judgment. AB - Our moral motivations might include a drive towards maximizing overall welfare, consistent with an ethical theory called "utilitarianism." However, people show non-utilitarian judgments in domains as diverse as healthcare decisions, income distributions, and penal laws. Rather than these being deviations from a fundamentally utilitarian psychology, we suggest that our moral judgments are generally non-utilitarian, even for cases that are typically seen as prototypically utilitarian. We show two separate deviations from utilitarianism in such cases: people do not think maximizing welfare is required (they think it is merely acceptable, in some circumstances), and people do not think that equal welfare tradeoffs are even acceptable. We end by discussing how utilitarian reasoning might play a restricted role within a non-utilitarian moral psychology. PMID- 27505426 TI - The cytotoxic T lymphocyte immune synapse at a glance. AB - The immune synapse provides an important structure for communication with immune cells. Studies on immune synapses formed by cytotoxic T lymphocytes (CTLs) highlight the dynamic changes and specialised mechanisms required to facilitate focal signalling and polarised secretion in immune cells. In this Cell Science at a Glance article and the accompanying poster, we illustrate the different steps that reveal the specialised mechanisms used to focus secretion at the CTL immune synapse and allow CTLs to be such efficient and precise serial killers. PMID- 27505427 TI - Regulation of myogenesis by environmental hypoxia. AB - In aerobic organisms, oxygen is a critical factor for tissue and organ morphogenesis from embryonic development throughout the adult life. It regulates various intracellular pathways involved in cellular metabolism, proliferation, cell survival and fate. Organisms or tissues rapidly respond to changes in oxygen availability by activating complex signalling networks, which culminate in the control of mRNA translation and/or gene expression. This Commentary presents the effects of hypoxia during embryonic development, myoblasts and satellite cell proliferation and differentiation in vertebrates. We also outline the relationship between Notch, Wnt and growth factor signalling pathways, as well as the post-transcriptional regulation of myogenesis under conditions of hypoxia. PMID- 27505429 TI - The role of palmitoylation and transmembrane domain in sorting of transmembrane adaptor proteins. PMID- 27505428 TI - Molecular organization of the desmosome as revealed by direct stochastic optical reconstruction microscopy. AB - Desmosomes are macromolecular junctions responsible for providing strong cell cell adhesion. Because of their size and molecular complexity, the precise ultrastructural organization of desmosomes is challenging to study. Here, we used direct stochastic optical reconstruction microscopy (dSTORM) to resolve individual plaque pairs for inner and outer dense plaque proteins. Analysis methods based on desmosomal mirror symmetry were developed to measure plaque-to plaque distances and create an integrated map. We quantified the organization of desmoglein 3, plakoglobin and desmoplakin (N-terminal, rod and C-terminal domains) in primary human keratinocytes. Longer desmosome lengths correlated with increasing plaque-to-plaque distance, suggesting that desmoplakin is arranged with its long axis at an angle within the plaque. We next examined whether plaque organization changed in different adhesive states. Plaque-to-plaque distance for the desmoplakin rod and C-terminal domains decreased in PKP-1-mediated hyperadhesive desmosomes, suggesting that protein reorganization correlates with function. Finally, in human epidermis we found a difference in plaque-to-plaque distance for the desmoplakin C-terminal domain, but not the desmoplakin rod domain or plakoglobin, between basal and suprabasal cells. Our data reveal the molecular organization of desmosomes in cultured keratinocytes and skin as defined by dSTORM. PMID- 27505430 TI - Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak. PMID- 27505432 TI - Real-Life Study for the Diagnosis of House Dust Mite Allergy - The Value of Recombinant Allergen-Based IgE Serology. AB - BACKGROUND: Dermatophagoides pteronyssinus is one of the most important perennial allergen sources worldwide. Molecular diagnostics using the commercially available major allergens (Der p 1 and Der p 2) in combination with Der p 10 do not detect house dust mite (HDM) sensitization in a number of cases when used alone. The objective was to evaluate the IgE reactivity profiles of these patients using an experimental immunoassay biochip. METHODS: Sera of HDM-allergic patients (positive skin prick test, CAP class >=1 for allergen extract, and positive intranasal provocation) were tested for IgE antibodies against Der p 1, Der p 2, and Der p 10 by ImmunoCAP fluorescence enzyme immunoassay. Negatively tested sera were examined by an experimental chip containing 13 microarrayed HDM allergens. RESULTS: Of 97 patients tested, 16 showed negative results to Der p 1, Der p 2, and Der p 10. MeDALL chip evaluation revealed 5 patients monosensitized to Der p 23, and 11 patients were negative for all HDM MeDALL chip components. Seven sera were available for further testing, and 3 of them showed IgE reactivity to dot-blotted nDer p 1, and 2 reacted with high-molecular weight components (>100 kDa) in nitrocellulose-blotted HDM extract when tested with 125I labeled anti-IgE in a RAST-based assay. The HDM extract-specific IgE levels of the 11 patients were <3.9 kU/l. CONCLUSIONS: Recombinant allergen-based IgE serology is of great value when conventional IgE diagnostics fails. Der p 23 is an important HDM allergen, especially when major allergens are negative. Therefore, it would be desirable to have Der p 23 commercially available. Further research concerning the prevalence and clinical significance of different HDM allergens is needed. PMID- 27505431 TI - Epigenetics of Epileptogenesis-Evoked Upregulation of Matrix Metalloproteinase-9 in Hippocampus. AB - Enhanced levels of Matrix Metalloproteinase-9 (MMP-9) have been implicated in the pathogenesis of epilepsy in humans and rodents. Lack of Mmp-9 impoverishes, whereas excess of Mmp-9 facilitates epileptogenesis. Epigenetic mechanisms driving the epileptogenesis-related upregulation of MMP-9 expression are virtually unknown. The aim of this study was to reveal these mechanisms. We analyzed hippocampi extracted from adult and pediatric patients with temporal lobe epilepsy as well as from partially and fully pentylenetetrazole kindled rats. We used a unique approach to the analysis of the kindling model results (inclusion in the analysis of rats being during kindling, and not only a group of fully kindled animals), which allowed us to separate the molecular effects exerted by the epileptogenesis from those related to epilepsy and epileptic activity. Consequently, it allowed for a disclosure of molecular mechanisms underlying causes, and not consequences, of epilepsy. Our data show that the epileptogenesis-evoked upregulation of Mmp-9 expression is regulated by removal from Mmp-9 gene proximal promoter of the two, interweaved potent silencing mechanisms-DNA methylation and Polycomb Repressive Complex 2 (PRC2)-related repression. Demethylation depends on a gradual dissociation of the DNA methyltransferases, Dnmt3a and Dnmt3b, and on progressive association of the DNA demethylation promoting protein Gadd45beta to Mmp-9 proximal gene promoter in vivo. The PRC2-related mechanism relies on dissociation of the repressive transcription factor YY1 and the dissipation of the PRC2-evoked trimethylation on Lys27 of the histone H3 from the proximal Mmp-9 promoter chromatin in vivo. Moreover, we show that the DNA hydroxymethylation, a new epigenetic DNA modification, which is localized predominantly in the gene promoters and is particularly abundant in the brain, is not involved in a regulation of MMP-9 expression during the epileptogenesis in the rat hippocampus as well as in the hippocampi of pediatric and adult epileptic patients. Additionally, we have also found that despite of its transient nature, the histone modification H3S10ph is strongly and gradually accumulated during epileptogenesis in the cell nuclei and in the proximal Mmp-9 gene promoter in the hippocampus, which suggests that H3S10ph can be involved in DNA demethylation in mammals, and not only in Neurospora. The study identifies MMP-9 as the first protein coding gene which expression is regulated by DNA methylation in human epilepsy. We present a detailed epigenetic model of the epileptogenesis-evoked upregulation of MMP-9 expression in the hippocampus. To our knowledge, it is the most complex and most detailed mechanism of epigenetic regulation of gene expression ever revealed for a particular gene in epileptogenesis. Our results also suggest for the first time that dysregulation of DNA methylation found in epilepsy is a cause rather than a consequence of this condition. PMID- 27505433 TI - Rapid, in Situ Synthesis of High Capacity Battery Anodes through High Temperature Radiation-Based Thermal Shock. AB - High capacity battery electrodes require nanosized components to avoid pulverization associated with volume changes during the charge-discharge process. Additionally, these nanosized electrodes need an electronically conductive matrix to facilitate electron transport. Here, for the first time, we report a rapid thermal shock process using high-temperature radiative heating to fabricate a conductive reduced graphene oxide (RGO) composite with silicon nanoparticles. Silicon (Si) particles on the order of a few micrometers are initially embedded in the RGO host and in situ transformed into 10-15 nm nanoparticles in less than a minute through radiative heating. The as-prepared composites of ultrafine Si nanoparticles embedded in a RGO matrix show great performance as a Li-ion battery (LIB) anode. The in situ nanoparticle synthesis method can also be adopted for other high capacity battery anode materials including tin (Sn) and aluminum (Al). This method for synthesizing high capacity anodes in a RGO matrix can be envisioned for roll-to-roll nanomanufacturing due to the ease and scalability of this high-temperature radiative heating process. PMID- 27505434 TI - Chromosome Territory Modeller and Viewer. AB - This paper presents ChroTeMo, a tool for chromosome territory modelling, accompanied by ChroTeVi-a chromosome territory visualisation software that uses the data obtained by ChroTeMo. These tools have been developed in order to complement the molecular cytogenetic research of interphase nucleus structure in a model grass Brachypodium distachyon. Although the modelling tool has been initially created for one particular species, it has universal application. The proposed version of ChroTeMo allows for generating a model of chromosome territory distribution in any given plant or animal species after setting the initial, species-specific parameters. ChroTeMo has been developed as a fully probabilistic modeller. Due to this feature, the comparison between the experimental data on the structure of a nucleus and the results obtained from ChroTeMo can indicate whether the distribution of chromosomes inside a nucleus is also fully probabilistic or is subjected to certain non-random patterns. The presented tools have been written in Python, so they are multiplatform, portable and easy to read. Moreover, if necessary they can be further developed by users writing their portions of code. The source code, documentation, and wiki, as well as the issue tracker and the list of related articles that use ChroTeMo and ChroTeVi, are accessible in a public repository at Github under GPL 3.0 license. PMID- 27505435 TI - The Prognostic Value of a Four-Dimensional CT Angiography-Based Collateral Grading Scale for Reperfusion Therapy in Acute Ischemic Stroke Patients. AB - OBJECTIVE: Leptomeningeal collaterals, which affects tissue fate, are still challenging to assess. Four-dimensional CT angiography (4D CTA) originated from CT perfusion (CTP) provides the possibility of non-invasive and time-resolved assessment of leptomeningeal collateral flow. We sought to develop a comprehensive rating system to integrate the speed and extent of collateral flow on 4D CTA, and investigate its prognostic value for reperfusion therapy in acute ischemic stroke (AIS) patients. METHODS: We retrospectively studied 80 patients with M1 +/- internal carotid artery (ICA) occlusion who had baseline CTP before intravenous thrombolysis. The velocity and extent of collaterals were evaluated by regional leptomeningeal collateral score on peak phase (rLMC-P) and temporally fused intensity projections (tMIP) (rLMC-M) on 4D CTA, respectively. The cutoffs of rLMC-P and rLMC-M score for predicting good outcome (mRS score <= 2) were integrated to develop the collateral grading scale (CGS) (rating from 0-2). RESULTS: The CGS score was correlated with 3-months mRS score (non-recanalizers: rho = -0.495, p = 0.01; recanalizers: rho = -0.671, p < 0.001). Patients with intermediate or good collaterals (CGS score of 1 and 2) who recanalized were more likely to have good outcome than those without recanalization (p = 0.038, p = 0.018), while there was no significant difference in outcome in patients with poor collaterals (CGS score of 0) stratified by recanalization (p = 0.227). CONCLUSIONS: Identification of collaterals based on CGS may help to select good responders to reperfusion therapy in patients with large artery occlusion. PMID- 27505436 TI - Total Synthesis of the Resorcyclic Acid Lactone Spiroketal Citreoviranol. AB - The first total synthesis of resorcyclic acid lactone spiroketal citreoviranol (1) is described. The synthesis was completed in nine steps and via Sonogashira cross-coupling, gold-catalyzed cyclization, and an unusual base-induced ketalization. The relative and absolute stereochemistry of citreoviranol was unambiguously confirmed using 2D NMR spectroscopy and X-ray crystallography. PMID- 27505437 TI - Saguaro (Carnegiea gigantea) Mortality and Population Regeneration in the Cactus Forest of Saguaro National Park: Seventy-Five Years and Counting. AB - Annual census data spanning seventy-five years document mortality and regeneration in a population of saguaro cactus (Carnegiea gigantea) in the Cactus Forest of the Rincon Mountain District of Saguaro National Park near Tucson, AZ. On 6 four-hectare plots, each saguaro was censused and a methodical search for new saguaros was conducted annually each year from 1942 through 2016, with the exception of 1955. Regeneration has been episodic with 828 plants established from 1959 through 1993 compared with 34 plants established between 1942 and 1958 and only three plants established after 1993. The years preceding 1959 and following 1993, include some of the driest decades in centuries in southern Arizona. While woodcutting and cattle grazing are believed to be among the causes of decades of failed regeneration prior to 1958, neither of these factors contributed to the failed regeneration following 1993. The height structure of the population from 1942 to 2016 shifted dramatically from a population dominated by large saguaros (> 5.4 m tall) in the first three decades of the study to a population dominated by small saguaros (< 1.8 m tall) in the most recent two decades. Mortality is shown to be strongly age dependent. In the year following the 2011 catastrophic freeze, 21 of 59 plants older than 80 years died compared with zero deaths in 270 plants between the ages of 29 and 80 years. Saguaros under 40 years old, growing under small shrubs or in the open, have a lower probability of survival than better protected saguaros. Long-term population monitoring is essential to understanding the complex impacts of human and environmental factors on the population dynamics of long-lived species. PMID- 27505438 TI - Re: Carrier Screening is a Deficient Strategy for Determining Sperm Donor Eligibility and Reducing Risk of Disease in Recipient Children (From: Silver AJ, Larson JL, Silver MJ, et al. Genet Test Mol Biomarkers 2016;20:276-284). PMID- 27505439 TI - Authors' Response to Wong et al. PMID- 27505440 TI - A large single ethnicity study of prepulse inhibition in schizophrenia: Separate analysis by sex focusing on effect of symptoms. AB - Deficits in sensorimotor gating, as measured with prepulse inhibition (PPI), have been considered an endophenotype of schizophrenia. However, the question remains whether these deficits are related to current symptoms. This single site study aimed to explore clinical features related to the modulation of startle reflex in a large sample of Japanese patients with schizophrenia (DSM-IV). The subjects comprised 181 patients and 250 healthy controls matched for age and sex. Schizophrenia symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Startle reflex to acoustic stimuli was recorded using a startle stimulus of 115 dB and a prepulse of four different conditions (intensity: 86 dB or 90 dB; lead interval: 60 ms or 120 ms). Patients exhibited significantly reduced startle magnitude (p < 0.001), habituation (p = 0.001), and PPI (90 dB, 60 ms, p = 0.016; 90 dB, 120 ms, p = 0.001) compared with controls. Patients of both sexes exhibited significantly lower habituation and PPI (90 dB, 120 ms) compared with the same sex controls. We could not detect a significant correlation with any clinical variable in the entire patients, however, when men and women were examined separately, there was a negative correlation with the PANSS cognitive domain (rho = -0.33, p = 0.008) in men, but not in women. Moreover, when patients were subdivided into four clusters, two clusters with high positive symptoms showed significant PPI deficits in men. Our results suggest that sensorimotor gating is impaired in schizophrenia of both sexes, and PPI deficits may be related to thought disturbance and disorganization in male patients with schizophrenia. PMID- 27505441 TI - Discovery, Synthesis, and Evaluation of 2,4-Diaminoquinazolines as a Novel Class of Pancreatic beta-Cell-Protective Agents against Endoplasmic Reticulum (ER) Stress. AB - Pancreatic insulin-producing beta-cell dysfunction and death plays central roles in the onset and progression of both type 1 and type 2 diabetes. Current antidiabetic drugs cannot halt the ongoing progression of beta-cell dysfunction and death. In diabetes, a major cause for the decline in beta-cell function and survival is endoplasmic reticulum (ER) stress. Here, we identified quinazoline derivatives as a novel class of beta-cell protective agents against ER stress induced dysfunction and death. A series of quinazoline derivatives were synthesized from dichloroquiazoline utilizing a sequence of nucleophilic reactions. Through SAR optimization, 2,4-diaminoquinazoline compound 9c markedly protects beta-cells against ER stress-induced dysfunction and death with 80% maximum rescue activity and an EC50 value of 0.56 MUM. Importantly, 9c restores the ER stress-impaired glucose-stimulated insulin secretion response and survival in primary human islet beta-cells. We showed that 9c protects beta-cells by alleviating ER stress through the suppression of the induction of key genes of the unfolded protein response and apoptosis. PMID- 27505442 TI - Bacterial Light-Harvesting Complexes Showing Giant Second-Order Nonlinear Optical Response as Revealed by Hyper-Rayleigh Light Scattering. AB - The second-order nonlinear optical (NLO) properties of light-harvesting complexes (LHs) from the purple photosynthetic bacteria Thermochromatium (Tch.) tepidum were investigated for the first time by means of hyper-Rayleigh scattering (HRS). The carotenoid (Car) molecules bound to the isolated LH1 and LH2 proteins gave rise to second-harmonic scattering; however, they showed an opposite effect of the collective contribution from Car, that is, the first hyperpolarizability (beta) reduced substantially from (10 510 +/- 370) * 10(-30) esu for LH1 to (360 +/- 120) * 10(-30) esu for LH2. Chromatophores of Tch. tepidum also showed a giant hyperpolarizability of (11 640 +/- 630) * 10(-30) esu. On the basis of the structural information on bacterial LHs, it is found that the effective beta of an LH is governed by the microenvironment and orientational correlation among the Car chromophores, which is concluded to be coherently enhanced for LH1. For LH2, however, additional destructive effects between different Car molecules may account for the small beta value. This work demonstrates that LH1 and native membranes of purple bacteria can be potent NLO materials and that HRS is a promising spectroscopic means for investigating structural information of pigment protein supramolecules. PMID- 27505443 TI - Prevalence and Factors Associated With Statin Use Among a Nationally Representative Sample of US Adults: National Health and Nutrition Examination Survey, 2011-2012. AB - The 2013 American College of Cardiology/American Heart Association guidelines recommend statins for adults age <=75 years who have clinical atherosclerotic cardiovascular disease (IA) and adults age 40 to 75 years with diabetes mellitus and LDL-C 70-189 mg/dl (IA). Our aim was to estimate the prevalence and likelihood of statin use among selected statin benefit groups. Using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2012, we examined 5319 adults age >=20 years. We estimated weighted frequencies and prevalence of statin use for adults with diabetes mellitus and dyslipidemia (or low-density lipoprotein cholesterol >=70 mg/dL), defined as statin benefit group 1 (SBG1); and for adults with atherosclerotic cardiovascular disease, defined as statin benefit group 2 (SBG2). We constructed a logistic regression model to estimate odds of statin use in SBG1. Overall, an estimated 38.6 million Americans are on a statin. In adjusted models, uninsured and Hispanic adults were less likely to be on a statin compared with white adults; 59.5% (95% confidence interval [CI]: 53.0-66.1) of all adults in SBG1, 58.8% (95% CI: 51.5-66.1) of adults age 40 to 75 in SBG1, and 63.5% (95% CI: 55.6-71.4) of all adults in SBG2 were on a statin. Although the prevalence of statin use has increased over time, Hispanic ethnicity and lack of insurance remain barriers to statin use. Black white racial disparities were not significant. Our study provides a baseline estimate of statin use in the noninstitutionalized population just prior to introduction of the new guidelines and provides a reference for evaluating the impact of the new guidelines on statin utilization. PMID- 27505444 TI - Accelerating the Uptake and Timing of Antiretroviral Therapy Initiation in Sub Saharan Africa: An Operations Research Agenda. AB - Sydney Rosen and colleagues describe an operations research agenda to accelerating uptake of HIV treatment initiation. PMID- 27505445 TI - Plasmachemical Double Click Thiol-ene Reactions for Wet Electrical Barrier. AB - Click thiol-ene chemistry is demonstrated for the reaction of thiol containing molecules with surface alkene bonds during electrical discharge activation. This plasmachemical reaction mechanism is shown to be 2-fold for allyl mercaptan (an alkene and thiol group containing precursor), comprising self-cross-linked nanolayer deposition in tandem with interfacial cross-linking to the surface alkene bonds of a polyisoprene base layer. A synergistic multilayer structure is attained which displays high wet electrical barrier performance during immersion in water. PMID- 27505446 TI - Novel mouse model for primary uveal melanoma: a pilot study. AB - BACKGROUND: To establish a mouse model with the aim of studying the tumour biology and metastasis formation of uveal melanoma. METHODS: Two human primary uveal melanoma cell lines (UMT2 and UMT42) were injected into the choroid of BALB/c nude mouse eyes. Intraocular tumour growth and metastasis formation in the liver and lungs were assessed after 13 to 22 weeks. Formalin-fixed, paraffin embedded material was processed via haematoxylin and eosin staining for histological examination and periodic acid Schiff staining to search for extravascular matrix patterns. Immunohistochemistry for Melan A, CD34 and Ki67 was performed to assess the expression of a melanocytic lineage marker, angiogenesis and proliferative activity. RESULTS: All eyes injected with UMT2 cells, but only 25% of eyes treated with UMT42, developed intraocular tumour growth. The morphology of intraocular melanomas resembled that of primary tumours and showed signs of malignancy, including retinal invasion, optic nerve invasion and scleral penetration with extraocular tumour growth. UMT2 tumours formed extravascular matrix patterns exclusively. Most of the tumour cells expressed Melan A. Intratumoural angiogenesis was detected in both tumour entities. Proliferative activity was verified in all but one tumour. However, no metastases appeared in the liver or lungs. CONCLUSIONS: The mouse model presented with the UMT2 cell line allows for investigations of tumour biology of the primary UM because of the high degree of similarity between the tumours generated in the mouse eyes and the corresponding primary human UM. Unfortunately, the model is not suitable for investigations of metastasis formation. PMID- 27505447 TI - Fat Grafting for Neuropathic Pain After Severe Burns: Reply. PMID- 27505448 TI - Myxofibrosarcoma in the Thenar Eminence. AB - Myxofibrosarcoma is a rare cause of swelling in the upper extremities. The rarer form arising in the deep tissues can present a diagnostic difficulty. The treatment of high-grade myxofibrosarcoma in the extremity requires tissue diagnosis, accurate staging, careful multidisciplinary agreement on treatment, accurate execution of that treatment, and finally regular specialist surveillance. The treatment must be planned on an individual basis, weighing the risk of distant metastasis against the potential for severe functional impairment should radical excision or amputation be performed. The grade of tumor, clinical stage as well as the site, local extent, and the comorbidity of the patient influence the decision.We present the case of an elderly woman with an expanding high-grade myxofibrosarcoma within the thenar musculature of the nondominant hand. She presented with early signs of complex regional pain syndrome, leading to a treatment dilemma. We feel this case has important learning points on assessing objectives, risks, and outcomes in the management of these types of cases, and it highlights the role of multidisciplinary involvement in sarcoma management. PMID- 27505449 TI - The Impact of Diabetes Mellitus on Wound Healing in Breast Reconstruction. AB - BACKGROUND: Although diabetes mellitus (DM) is a known risk factor for surgical complications in general, there is little published evidence to establish such an effect among patients undergoing breast reconstruction (BR). The purpose of this study was to assess the impact of DM on complications in patients undergoing postmastectomy BR. METHODS: Patients who underwent BR at our institution from November 2002 to November 2012 were identified. Clinical and demographic data of patients with type 1 or type 2 DM were reviewed. Complications occurring within 60 days of surgery were compared between diabetic and nondiabetic patients for both autologous and nonautologous reconstruction types. RESULTS: A total of 1371 BR were performed in 1035 patients. There were 877 (64.0%) autologous reconstructions and 494 (36.0%) implant-based reconstructions. Patients with DM (n = 64) had significantly higher preoperative blood glucose levels (137.5 vs 100.1, P < 0.05). Postoperatively, DM patients reconstructed with implants had a significantly higher incidence of delayed wound healing (22.2% vs 9.7%; P = 0.04). This was not observed in patients with DM reconstructed with autologous tissue (7.4% vs 6.6%; P = 0.70). Diabetic patients had a significantly higher incidence of hypertension and were older than nondiabetic patients. To control for these variables and other potential confounders, multiple logistic regression analysis was performed. Again, diabetic patients had a significantly higher incidence of delayed wound healing following implant-based reconstruction (odds ratio, 2.52, 95% confidence interval = 1.2-6.2) but not autologous reconstruction (odds ratio, 0.97; 95% confidence interval = 0.2-4.6). CONCLUSIONS: Diabetes heightens the risk of wound healing complications among patients undergoing implant-based reconstruction. PMID- 27505450 TI - Management of the Nipple-Areola Complex in Selected Patients Undergoing Primary Breast Reconstruction: A Comparison of Immediate Replantation and Delayed Reconstruction. AB - BACKGROUND: Management of the nipple-areola complex is an important issue in primary breast reconstruction. When nipple-sparing mastectomy is not suitable, alternatives are immediate nipple-areola complex replantation and delayed reconstruction. The aim of this study was to examine whether patients benefit more from nipple-areola complex preservation by immediate replantation or delayed nipple-areola complex reconstruction. METHODS: Postoperative results and patient satisfaction after 54 primary breast reconstructions with immediate nipple-areola complex replantation or delayed nipple-areola complex reconstruction were retrospectively evaluated. RESULTS: The nipple-areola complex was replanted immediately in 37 cases and reconstructed later with nipple sharing and full thickness skin grafting in 17 cases. Compared with immediate replantation, delayed reconstruction resulted in significantly better postoperative nipple projection (P = 0.01*, Mann-Whitney U test), greater similarity of color and projection with the contralateral side and greater patient satisfaction (Breast Q). Complete loss of projection occurred in 4 of the 37 replanted nipple-areola complexes. No complete nipple-areola complex necrosis or tumor recurrence was observed in any patient. CONCLUSIONS: Immediate nipple-areola complex replantation is a safe and reliable procedure for selected patients with contraindications for nipple-sparing mastectomy who have a strong desire to maintain their own nipple-areola complexes, or in bilateral cases. However, drawbacks of this procedure include loss of projection and depigmentation. Delayed reconstruction with nipple sharing and full-thickness skin grafting is a good alternative, especially in unilateral cases; it leads to better postoperative results and greater patient satisfaction, but it involves a nipple areola complex-free period. PMID- 27505451 TI - The new generation synthetic reconstituted surfactant CHF5633 suppresses LPS induced cytokine responses in human neonatal monocytes. AB - BACKGROUND: New generation synthetic surfactants represent a promising alternative in the treatment of respiratory distress syndrome in preterm infants. CHF5633, a new generation reconstituted agent, has demonstrated biophysical effectiveness in vitro and in vivo. In accordance to several well-known surfactant preparations, we recently demonstrated anti-inflammatory effects on LPS-induced cytokine responses in human adult monocytes. The present study addressed pro- and anti-inflammatory effects of CHF5633 in human cord blood monocytes. METHODS: Purified neonatal CD14(+) cells, either native or simultaneously stimulated with E. coli LPS, were exposed to CHF5633. TNF-alpha, IL-1beta, IL-8 and IL-10 as well as TLR2 and TLR4 expression were analyzed by means of real-time quantitative PCR and flow cytometry. RESULTS: CHF5633 did not induce pro-inflammation in native human neonatal monocytes and did not aggravate LPS-induced cytokine responses. Exposure to CHF5633 led to a significant decrease in LPS-induced intracellular TNF-alpha protein expression, and significantly suppressed LPS-induced mRNA and intracellular protein expression of IL-1beta. CHF5633 incubation did not affect cell viability, indicating that the suppressive activity was not due to toxic effects on neonatal monocytes. LPS-induced IL-8, IL 10, TLR2 and TLR4 expression were unaffected. CONCLUSION: Our data confirm that CHF5633 does not exert unintended pro-apoptotic and pro-inflammatory effects in human neonatal monocytes. CHF5633 rather suppressed LPS-induced TNF-alpha and IL 1beta cytokine responses. Our data add to previous work and may indicate anti inflammatory features of CHF5633 on LPS-induced monocyte cytokine responses. PMID- 27505452 TI - Frontal fibrosing alopecia in male patients: a report of 12 cases. PMID- 27505453 TI - Clinician's Commentary on Keep et al.(1). PMID- 27505454 TI - Beauty from the beast: Avoiding errors in responding to client questions. AB - Those rare moments when clients ask direct questions of their therapists likely represent a point when they are particularly open to new considerations, thereby representing an opportunity for substantial therapeutic gains. However, clinical errors abound in this area because clients' questions often engender apprehension in therapists, causing therapists to respond with too little or too much information or shutting down the discussion prematurely. These response types can damage the therapeutic relationship, the psychotherapy process, or both. We explore the nature of these clinical errors in response to client questions by providing examples from our own clinical work, suggesting potential reasons why clinicians may not make optimal use of client questions, and discussing how the mixed psychological literature further complicates the issue. We also present four guidelines designed to help therapists, trainers, and supervisors respond constructively to clinical questions in order to create constructive interactions. (PsycINFO Database Record PMID- 27505455 TI - Clinical errors in cognitive-behavior therapy. AB - Although cognitive-behavioral therapy (CBT) has been shown to be highly effective for a wide range of disorders, many patients do not benefit. The failure to fully benefit from CBT may be due to a wide range of factors, one of which includes "clinical errors" that often occur during the therapeutic process. We briefly note 4 such clinical errors including neglecting to conduct a detailed functional analysis of the presenting problem(s), not adequately engaging the patient in developing a case formulation for the purposes of treatment planning, getting wrapped up in simply examining beliefs without behavioral tests, and not holding patients accountable for fear of rupturing the therapeutic alliance. We then discuss the context in which these clinical errors may occur during CBT and highlight alternative approaches. Being mindful of these and other potential clinical errors during CBT may facilitate better treatment outcomes. (PsycINFO Database Record PMID- 27505456 TI - Can we collaborate? Mistakes made when group and individual therapists ignore multiple realities. AB - Often, group therapists collaborate with individual therapists in conjoint treatment. Many of these patients start in individual therapy and are referred to the group to help facilitate the treatment and address interpersonal and relational issues that either cannot or will not be addressed in the individual work. Although this has the potential to foster incredible growth for patients, it may also cause problems in treatment when collaboration between therapists falls apart. The current paper will examine mistakes made when multiple realities about a patient are ignored during the pregroup screening and preparation, and feedback from group treatment is not integrated into individual therapy. Clinical examples will be used with specific recommendations for combined treatment planning and interventions. (PsycINFO Database Record PMID- 27505457 TI - Clinical errors that can occur in the treatment decision-making process in psychotherapy. AB - Clinical errors occur in the psychotherapy decision-making process whenever a less-than-optimal treatment or approach is chosen when working with clients. A less-than-optimal approach may be one that a client is unwilling to try or fully invest in based on his/her expectations and preferences, or one that may have little chance of success based on contraindications and/or limited research support. The doctor knows best and the independent choice models are two decision making models that are frequently used within psychology, but both are associated with an increased likelihood of errors in the treatment decision-making process. In particular, these models fail to integrate all three components of the definition of evidence-based practice in psychology (American Psychological Association, 2006). In this article we describe both models and provide examples of clinical errors that can occur in each. We then introduce the shared decision making model as an alternative that is less prone to clinical errors. PMID- 27505458 TI - Characterization of the Bread Made with Durum Wheat Semolina Rendered Gluten Free by Sourdough Biotechnology in Comparison with Commercial Gluten-Free Products. AB - Durum wheat semolina was fermented with sourdough lactic acid bacteria and fungal proteases aiming at a complete gluten hydrolysis. The gluten-free (GF) semolina, added with naturally GF ingredients and structuring agents, was used to produce bread (rendered GF bread; rGFB) at industrial level. An integrated approach including the characterization of the main chemical, nutritional, structural, and sensory features was used to compare rGFB to a gluten-containing bread and to 5 commercial naturally GF breads. High-performance liquid chromatography was used for free amino acids (FAAs), organic acids, and ethanol analysis. A methanolic extract was used for determining total phenols and antioxidant activity. The bread characterization also included the analysis of dietary fibers, mycotoxins, vitamins, and heavy metals. Beyond chemical analysis, nutritional profile was evaluated considering the in vitro protein digestibility and the predicted glycemic index, while the instrumental texture profile analysis was performed to investigate the structure and the physical/mechanical properties of the baked goods. Beyond the huge potential of market expansion, the main advantages of durum wheat semolina rendered GF can be resumed in the high availability of FAAs, the high protein digestibility, the low starch hydrolysis index, and the better technological properties of bread compared to the commercial GF products currently present on the market. Vitamins, minerals, and dietary fiber profiles are comparable to those of gluten-containing wheat bread. Also the sensory profile, determined by a panel test, can be considered the most similar to those of conventional baked goods, showing all the sourdough bread classic attributes. PMID- 27505459 TI - cis-2,5-Diaminobicyclo[2.2.2]octane, a New Chiral Scaffold for Asymmetric Catalysis. AB - Catalysis of widely used chemical transformations in which the goal is to obtain the product as a pure enantiomer has become a major preoccupation of synthetic organic chemistry over the past three decades. A large number of chiral entities has been deployed to this end, many with considerable success, but one of the simplest and most effective catalytic systems to have emerged from this effort is that based on a chiral diamine, specifically trans-1,2-diaminocyclohexane. While there have been attempts to improve upon this scaffold in asymmetric synthesis, few have gained the recognition needed to take their place alongside this classic diamine. The challenge is to design a scaffold that retains the assets of trans 1,2-diaminocyclohexane while enhancing its intrinsic chirality and maximizing the scope of its applications. It occurred to us that cis-2,5 diaminobicyclo[2.2.2]octane could be such a scaffold. Synthesis of this diamine in enantiopure form was completed from benzoic acid, and the (1R,2R,4R,5R) enantiomer was used in all subsequent experiments in this laboratory. Condensation of the diamine with various salicyl aldehydes generated imine derivatives which proved to be excellent "salen" ligands for encapsulation of transition and other metals. In total, 12 salen-metal complexes were prepared from this ligand, many of which were crystalline and three of which, along with the ligand itself, yielded to X-ray crystallography. An advantage of this ligand is that it can be tuned sterically or electronically to confer specific catalytic properties on the salen-metal complex, and this feature was used in several applications of our salen-metal complexes in asymmetric synthesis. Thus, replacement of one of the tert-butyl groups in each benzenoid ring of the salen ligand by a methoxy substituent enhanced the catalytic efficiency of a cobalt(II) salen complex used in asymmetric cyclopropanation of 1,1-disubstituted alkenes; the catalyst was employed in an improved synthesis of the cyclopropane-containing drug candidate Synosutine. Reduction of the pair of imine functions of the ligand to secondary amines permitted formation of a copper(I)-salen complex that catalyzed asymmetric Henry ("nitroaldol") condensation with excellent efficiency; this catalyst was applied in an economical synthesis of three drugs of the "beta blocker" family including (S)-Propanolol. Chromium(II) and chromium(III) complexes were prepared from our bicyclooctane-salen ligand bearing a pair of tert-butyl groups in each benzenoid ring. These complexes were found to catalyze, respectively, enantioselective formation of homoallylic alcohols from Nozaki Hiyama-Kishi allylation of aromatic aldehydes and dihydropyranones from hetero Diels-Alder cycloaddition. Plausible reaction models emerging from knowledge of the absolute configuration of products from each of these reactions place the metal-coordinated substrate in a quadrant beneath the bicyclooctane scaffold so that one face of the substrate is blocked by an aryl ring of the salen ligand while the opposite face is left open to attack. The consistent and predictable stereochemical outcome from reactions catalyzed by salen-metal complexes derived from our diaminobicyclo[2.2.2]octane scaffold adds a valuable new dimension to asymmetric synthesis. PMID- 27505460 TI - Erratum. PMID- 27505463 TI - Instructions for Contributors. PMID- 27505461 TI - Erratum. PMID- 27505464 TI - Lipodystrophy, Diabetes and Normal Serum Insulin in PPARgamma-Deficient Neonatal Mice. AB - Peroxisome proliferator activated receptor gamma (PPARgamma) is a pleiotropic ligand activated transcription factor that acts in several tissues to regulate adipocyte differentiation, lipid metabolism, insulin sensitivity and glucose homeostasis. PPARgamma also regulates cardiomyocyte homeostasis and by virtue of its obligate role in placental development is required for embryonic survival. To determine the postnatal functions of PPARgamma in vivo we studied globally deficient neonatal mice produced by epiblast-restricted elimination of PPARgamma. PPARgamma-rescued placentas support development of PPARgamma-deficient embryos that are viable and born in near normal numbers. However, PPARgamma-deficient neonatal mice show severe lipodystrophy, lipemia, hepatic steatosis with focal hepatitis, relative insulin deficiency and diabetes beginning soon after birth and culminating in failure to thrive and neonatal lethality between 4 and 10 days of age. These abnormalities are not observed with selective PPARgamma2 deficiency or with deficiency restricted to hepatocytes, skeletal muscle, adipocytes, cardiomyocytes, endothelium or pancreatic beta cells. These observations suggest important but previously unappreciated functions for PPARgamma1 in the neonatal period either alone or in combination with PPARgamma2 in lipid metabolism, glucose homeostasis and insulin sensitivity. PMID- 27505465 TI - Homoleptic Poly(nitrato) Complexes of Group 14 Stable at Ambient Conditions. AB - Using a novel approach in homoleptic nitrate chemistry, Sn(NO3)6(2-) (3c) as well as the previously unknown hexanitrato complexes Si(NO3)6(2-) (1c), Ge(NO3)6(2-) (2c) were synthesized from the element tetranitrates as salt-like compounds which were isolated and characterized using (1)H, (14)N, and (29)Si NMR and IR spectroscopies, elemental and thermal analyses, and single-crystal XRD. All hexanitrates are moderately air-sensitive at 298 K and possess greater thermal stability toward NO2 elimination than their charge-neutral tetranitrato congeners as solids and in solution. The complexes possess distorted octahedral coordination skeletons and adopt geometries that are highly symmetric (3c) or deformed (1c, 2c) depending on the degree of steric congestion of the ligand sphere. As opposed to the kappa(2)O,O' coordination mode reported for Sn(NO3)4 previously,1 all nitrato ligands of 3c coordinate in kappa(1)O mode. Six geometric isomers of E(NO3)6(2-) were identified as minima on the PES using DFT calculations at the B3LYP/6-311+G(d,p) level of which two were observed experimentally. PMID- 27505466 TI - Moral typecasting underlies punitive responses to crime. AB - We examine the role of moral typecasting in lay individuals' punitive responses to crime. Individuals perceive criminal offenders and victims in ways that are biased by their perceptions of the actors' moral roles in prior simulated criminal incidents. We find that this psychological process of moral typecasting has important implications for punitive responses to criminal offenders, and these findings make 2 major contributions to the literature. First, we show that moral agency is distinct from moral deservingness, which is 1 of the dominant explanations for punitive behavior in social psychology. Second, the role of moral typecasting in punitive responses means that these responses can occur regardless of the valence of moral character. We argue that theories of lay punitive responding that do not take moral typecasting processes into account are incomplete. (PsycINFO Database Record PMID- 27505467 TI - Health Care Use Outcomes of an Integrated Hospital-to-Home Mother-Preterm Infant Intervention. AB - OBJECTIVE: To compare health care use from initial hospital discharge through 6 weeks corrected age in two groups of mother-preterm infant dyads: those who received an intervention, Hospital to Home: Optimizing Premature Infant's Environment (H-HOPE), and an attention control group. DESIGN: Prospective randomized controlled trial. SETTING: Two community hospital NICUs. PARTICIPANTS: Mothers (n = 147) with social-environmental risk factors and their stable preterm infants. METHODS: Mother-infant dyads were randomly assigned to the H-HOPE or control group. When infants reached 6 weeks corrected age, information about health care visits since their hospital discharges was collected through an interview. RESULTS: Only half of all infants received all recommended well-child visits. Infants in H-HOPE were half as likely to have acute care episodes (illness visit to the clinic or emergency department or hospital readmission) as control infants (odds ratio [OR] = 0.46, 95% confidence interval [CI] [0.22, 0.95]). Infants of mothers with high trait anxiety were nearly 3 times more likely to have an acute care episode (OR = 2.78, 95% CI [1.05, 7.26]), and mothers who had low education levels (OR = .22, 95% CI [0.08, 0.60]) were less likely to have acute care episodes. There was a trend toward fewer acute care visits for infants whose mothers preferred an English interview (OR = .47, 95% CI [0.21, 1.06]). CONCLUSION: Findings emphasize the importance of reinforcing well child visits for vulnerable preterm infants. H-HOPE, an integrated mother-infant intervention, reduces acute care episodes (visits to the clinic or emergency department or hospital readmissions) for preterm infants. PMID- 27505606 TI - Liberating the kidney from continuous renal replacement therapy. PMID- 27505605 TI - The rocking method of artificial respiration. PMID- 27505607 TI - Procedural pain in intensive care: translating awareness into practice. PMID- 27505608 TI - Images of Australians and Anaesthesia from World War 1. PMID- 27505611 TI - The Effect of Ginger on Breast Milk Volume in the Early Postpartum Period: A Randomized, Double-Blind Controlled Trial. AB - BACKGROUND: In Thailand, ginger is a popular natural galactagogue among breastfeeding women. However, there has never been evidence to support the effectiveness of ginger in increasing the breast milk volume. OBJECTIVES: To compare breast milk volume on the third and seventh day postpartum between lactating mothers who receive 500 mg dried ginger capsules twice daily with those receiving placebo. MATERIALS AND METHODS: A randomized, double-blind controlled trial was conducted. Women who deliver a term baby were randomly assigned to receive dried ginger or placebo for 7 days postpartum. Breast milk volume was measured on third day postpartum using test weight method for a period of 24 hours and on seventh day postpartum using 1 hour milk production. We also compared the third day serum prolactin level between the two groups. RESULTS: Data from 63 women were available for analysis, 30 from the ginger group and 33 from the placebo group. The two groups were similar regarding baseline characteristics. Women in the ginger group have higher milk volume than the placebo group (191.0 +/- 71.2 mL/day versus 135.0 +/- 61.5 mL/day, p < 0.01). However, the seventh day milk volume in the ginger group does not differ from the placebo group (80.0 +/- 58.5 mL versus 112.1 +/- 91.6 mL, p = 0.24). The mean serum prolactin levels were similar in both groups (321.5 +/- 131.8 ng/L in the ginger group, and 331.4 +/- 100.7 ng/L in the placebo group, p = 0.74). No side effect was reported in this study. CONCLUSION: Ginger is a promising natural galactagogue to improve breast milk volume in the immediate postpartum period without any notable side effect. PMID- 27505612 TI - Ultrasound-Guided Placement of Gold Fiducial Markers for Stereotactic Partial Breast Irradiation. AB - OBJECTIVE: A novel technique of placing gold fiducial markers in the breast using ultrasound guidance was developed and performed in 51 of 55 consecutive postlumpectomy patients enrolled in a phase I dose escalation trial of accelerated partial-breast irradiation (APBI) using robotic-based stereotactic body radiation therapy (SBRT). CONCLUSION: All 51 postoperative patients underwent successful fiducial placement without complications. Our technique of placing gold fiducial markers in proximity to the seroma cavity is considered safe and effective for breast cancer patients being treated with APBI using robotic-based SBRT. PMID- 27505613 TI - Imaging nanoscale lattice variations by machine learning of x-ray diffraction microscopy data. AB - We present a novel methodology based on machine learning to extract lattice variations in crystalline materials, at the nanoscale, from an x-ray Bragg diffraction-based imaging technique. By employing a full-field microscopy setup, we capture real space images of materials, with imaging contrast determined solely by the x-ray diffracted signal. The data sets that emanate from this imaging technique are a hybrid of real space information (image spatial support) and reciprocal lattice space information (image contrast), and are intrinsically multidimensional (5D). By a judicious application of established unsupervised machine learning techniques and multivariate analysis to this multidimensional data cube, we show how to extract features that can be ascribed physical interpretations in terms of common structural distortions, such as lattice tilts and dislocation arrays. We demonstrate this 'big data' approach to x-ray diffraction microscopy by identifying structural defects present in an epitaxial ferroelectric thin-film of lead zirconate titanate. PMID- 27505614 TI - Heterocyclic Bismuth(III) Dithiocarbamato Complexes as Single-Source Precursors for the Synthesis of Anisotropic Bi2 S3 Nanoparticles. AB - New complexes catena-(MU2 -nitrato O,O')bis(piperidinedithiocarbamato)bismuth(III) (1) and tetrakis(MU nitrato)tetrakis[bis(tetrahydroquinolinedithiocarbamato)bismuth(III)] (2) were synthesised and characterised by elemental analysis, FTIR spectroscopy and thermogravimetric analysis. The single-crystal X-ray structures of 1 and 2 were determined. The coordination numbers of the Bi(III) ion are 8 for 1 and >=6 for 2 when the experimental electron density for the nominal 6s(2) lone pair of electrons is included. Both complexes were used as single-source precursors for the synthesis of dodecylamine-, hexadecylamine-, oleylamine and tri-n octylphosphine oxide-capped Bi2 S3 nanoparticles at different temperatures. UV/Vis spectra showed a blueshift in the absorbance band edge characteristic of a quantum size effect. High-quality, crystalline, long and short Bi2 S3 nanorods were obtained depending on the thermolysis temperature, which was varied from 190 to 270 degrees C. A general trend of increasing particle breadth with increasing reaction temperature and increasing length of the carbon chain of the amine (capping agent) was observed. Powder XRD patterns revealed the orthorhombic crystal structure of Bi2 S3 . PMID- 27505615 TI - Application of Chemical Force Microscopy for Finding Selective Functional Groups for Discriminating Different Electronic Type Single-Walled Carbon Nanotubes. PMID- 27505616 TI - MSL1 is a mechanosensitive ion channel that dissipates mitochondrial membrane potential and maintains redox homeostasis in mitochondria during abiotic stress. AB - Mitochondria must maintain tight control over the electrochemical gradient across their inner membrane to allow ATP synthesis while maintaining a redox-balanced electron transport chain and avoiding excessive reactive oxygen species production. However, there is a scarcity of knowledge about the ion transporters in the inner mitochondrial membrane that contribute to control of membrane potential. We show that loss of MSL1, a member of a family of mechanosensitive ion channels related to the bacterial channel MscS, leads to increased membrane potential of Arabidopsis mitochondria under specific bioenergetic states. We demonstrate that MSL1 localises to the inner mitochondrial membrane. When expressed in Escherichia coli, MSL1 forms a stretch-activated ion channel with a slight preference for anions and provides protection against hypo-osmotic shock. In contrast, loss of MSL1 in Arabidopsis did not prevent swelling of isolated mitochondria in hypo-osmotic conditions. Instead, our data suggest that ion transport by MSL1 leads to dissipation of mitochondrial membrane potential when it becomes too high. The importance of MSL1 function was demonstrated by the observation of a higher oxidation state of the mitochondrial glutathione pool in msl1-1 mutants under moderate heat- and heavy-metal-stress. Furthermore, we show that MSL1 function is not directly implicated in mitochondrial membrane potential pulsing, but is complementary and appears to be important under similar conditions. PMID- 27505617 TI - Super Aryl-Extended Calix[4]pyrroles: Synthesis, Binding Studies, and Attempts To Gain Water Solubility. AB - We describe the synthesis of unprecedented calix[4]pyrrole receptors featuring "super aryl extended" (SAE) cavities. We elaborated the aromatic cavity provided by the alphaalphaalphaalpha-isomer of para-tetraiodo-meso-phenyl calix[4]pyrrole by installing ethynyl-aryl substituents at its upper rim. We report the binding properties of the prepared SAE-calix[4]pyrrole tetraester towards pyridyl-N oxides. The binding data revealed the formation of thermodynamically and kinetically highly stable 1:1 complexes. The complexation-induced chemical shifts indicated the formation of hydrogen bonds and aromatic interactions with the calix-core adopting the cone conformation. We quantified the additional interactions established between the four terminal aryl groups and the para phenyl substituent of 4-phenyl pyridine N-oxide to be in the order of 1 kcal mol( 1) . The complex formation rate was found to be close to the diffusion control suggesting that the free host adopted a 1,3-alternate conformation. Finally, we attempted to gain water solubility of SAE-calix[4]pyrroles using derivatives that display four ionizable or charged groups at their upper rims. PMID- 27505619 TI - Imaging review of hepatocellular carcinoma after thermal ablation: The good, the bad, and the ugly. AB - Image-guided thermal ablation is a well-established locoregional technique for the treatment of hepatocellular carcinoma (HCC). HCC surveillance programs have led to an increase in the number of patients diagnosed at an early stage of the disease who are eligible for thermal ablation. Tumor response is assessed on imaging and requires extensive follow-up; thus, radiologists play a key role in defining the technical success and efficacy of treatment as well as identifying progressive disease. Although they are rare, complications, such as secondary infections, must also be identified. Several contrast-enhanced imaging techniques can be used at different postprocedural timepoints but magnetic resonance imaging (MRI) and computed tomography (CT), which allow both liver-centered and whole body imaging are the cornerstones of follow-up. This review describes the imaging features of HCC following thermal ablation. After describing the basic technical elements of follow-up imaging, imaging findings are divided into three groups: normal and expected features (the good), abnormal features, uncontrolled disease, and complications (the bad), and atypical or rare presentations (the ugly). J. Magn. Reson. Imaging 2016;44:1070-1090. PMID- 27505620 TI - Using Guest-Host Interactions To Optimize the Efficiency of TADF OLEDs. AB - We show that the emitter and host combination must be optimized to minimize the reverse intersystem crossing (rISC) barrier and maximize thermally activated delayed fluorescence (TADF). The blue TADF emitter, 2,7-bis(9,9-dimethyl-acridin 10-yl)-9,9-dimethylthioxanthene-S,S-dioxide (DDMA-TXO2), has strong TADF character due to efficient charge transfer (CT) state formation. By combining DDMA-TXO2 with a host of correct polarity (DPEPO) that relaxes the CT manifolds' energy to become resonant with the lowest-energy local triplet state of DDMA TXO2, the emitter and host combination produce a minimum rISC barrier (DeltaEST), which maximizes TADF efficiency. We show that the sensitivity of these splittings is highly dependent on emitter environment and must be carefully tuned to optimize device performance. Devices utilizing DDMA-TXO2 in the DPEPO host show blue electroluminescence (EL), with commission internationale de l'eclairage (CIE) chromaticity coordinates of CIE (0.16, 0.24), with a maximum external quantum efficiency of 22.4%. This high device performance is a direct consequence of optimizing the TADF efficiency by this "host tuning". PMID- 27505621 TI - Combination of a peptide-modified gellan gum hydrogel with cell therapy in a lumbar spinal cord injury animal model. AB - Spinal Cord Injury (SCI) is a highly incapacitating condition for which there is still no cure. Current clinical approaches are mainly based on palliative care, so there is a need to find possible treatments to SCI. Cellular transplantation is regarded with great expectation due to the therapeutic potential of cells such as Adipose tissue-derived Stromal/Stem Cells (ASCs) or Olfactory Ensheathing Cells (OECs). Both are accessible sources and present positive paracrine and cell to-cell interactions, previously reported by our group. Additionally, biomaterials such as hydrogels have been applied in SCI repair with promising results. We propose to combine a GRGDS-modified gellan gum hydrogel with ASCs and OECs in order to promote SCI regeneration. In vitro, ASCs and OECs could be co cultured within GG-GRGDS hydrogels inducing a more robust neurite outgrowth when compared to controls. In vivo experiments in a hemisection SCI rat model revealed that the administration of ASCs and OECs encapsulated in a GG-GRGDS hydrogel led to significant motor improvements when compared to both control (SCI) and hydrogel alone (GG-GRGDS) groups. This was accompanied by a decreased infiltration of inflammatory cells and astrocytes, and by an increased intensity of neurofilament. These results suggest evident gains induced by the encapsulation of ASCs and OECs in GG-GRGDS based hydrogels. PMID- 27505622 TI - Identifying highly influential nodes in the complicated grief network. AB - The network approach to psychopathology conceptualizes mental disorders as networks of mutually reinforcing nodes (i.e., symptoms). Researchers adopting this approach have suggested that network topology can be used to identify influential nodes, with nodes central to the network having the greatest influence on the development and maintenance of the disorder. However, because commonly used centrality indices do not distinguish between positive and negative edges, they may not adequately assess the nature and strength of a node's influence within the network. To address this limitation, we developed 2 indices of a node's expected influence (EI) that account for the presence of negative edges. To evaluate centrality and EI indices, we simulated single-node interventions on randomly generated networks. In networks with exclusively positive edges, centrality and EI were both strongly associated with observed node influence. In networks with negative edges, EI was more strongly associated with observed influence than was centrality. We then used data from a longitudinal study of bereavement to examine the association between (a) a node's centrality and EI in the complicated grief (CG) network and (b) the strength of association between change in that node and change in the remainder of the CG network from 6- to 18-months postloss. Centrality and EI were both correlated with the strength of the association between node change and network change. Together, these findings suggest high-EI nodes, such as emotional pain and feelings of emptiness, may be especially important to the etiology and treatment of CG. (PsycINFO Database Record PMID- 27505623 TI - Trends in diabetes and obesity in Samoa over 35 years, 1978-2013. AB - AIMS: Population surveys of Type 2 diabetes mellitus and obesity conducted in Samoa over three decades have used varying methodologies and definitions. This study standardizes measures, and trends of Type 2 diabetes mellitus and obesity for 1978-2013 are projected to 2020 for adults aged 25-64 years. METHODS: Unit records from eight surveys (n = 12 516) were adjusted to the previous census for Division of residence, sex and age to improve national representativeness. Type 2 diabetes mellitus is defined as a fasting plasma glucose >= 7.0 mmol/l and/or on medication. Obesity is defined as BMI >= 30 kg/m2 . Random effects meta regression was employed to assess time trends following logit transformation. Poisson regression from strata was used to assess the effects of mean BMI changes on Type 2 diabetes mellitus period trends. RESULTS: Over 1978-2013, Type 2 diabetes mellitus prevalence increased from 1.2% to 19.6% in men (2.3% per 5 years), and from 2.2% to 19.5% in women (2.2% per 5 years). Obesity prevalence increased from 27.7% to 53.1% in men (3.6% per 5 years) and from 44.4% to 76.7% (4.5% per 5 years) in women. Type 2 diabetes mellitus and obesity prevalences increased in all age groups. From period trends, Type 2 diabetes mellitus prevalence in 2020 is projected to be 26% in men and women. Projected obesity prevalence is projected to be 59% in men and 81% in women. Type 2 diabetes mellitus period trends attributable to BMI increase are estimated as 31% (men) and 16% (women), after adjusting for age. CONCLUSION: This is the first study to produce trends of Type 2 diabetes mellitus and obesity in Samoa based on standardized data from population surveys. Type 2 diabetes mellitus is equally prevalent in both sexes, and obesity is widespread. Type 2 diabetes mellitus prevalence in Samoa is likely to continue to increase in the near future. PMID- 27505624 TI - Vision Therapy for Post-Concussion Vision Disorders. AB - PURPOSE: To determine the frequency and types of vision disorders associated with concussion, and to determine the success rate of vision therapy for these conditions in two private practice settings. METHODS: All records over an 18 month period of patients referred for post-concussion vision problems were reviewed from two private practices. Diagnoses of vergence, accommodative, or eye movement disorders were based on pre-established, clinical criteria. Vision therapy was recommended based on clinical findings and symptoms. RESULTS: Two hundred eighteen patient records were found with a diagnosis of concussion. Fifty six percent of the concussions were related to sports, 20% to automobile accidents, and 24% to school, work, or home-related incidents. The mean age was 20.5 years and 58% were female. Eighty-two percent of the patients had a diagnosis of an oculomotor problem [binocular problems (62%), accommodative problems (54%), eye movement problems (21%)]. The most prevalent diagnoses were convergence insufficiency (CI, 47%) and accommodative insufficiency (AI, 42%). Vision therapy was recommended for 80% of the patients. Forty-six per cent (80/175) either did not pursue treatment or did not complete treatment. Of the 54% (95/175) who completed therapy, 85% of patients with CI were successful and 15% were improved, and with AI, 33% were successful and 67% improved. Clinically and statistically significant changes were measured in symptoms, near point of convergence, positive fusional vergence, and accommodative amplitude. CONCLUSIONS: In this case series, post-concussion vision problems were prevalent and CI and AI were the most common diagnoses. Vision therapy had a successful or improved outcome in the vast majority of cases that completed treatment. Evaluation of patients with a history of concussion should include testing of vergence, accommodative, and eye movement function. Prospective clinical trials are necessary to assess the natural history of concussion-related vision disorders and treatment effectiveness. PMID- 27505625 TI - Association of monocyte chemoattractant protein-1 gene 2518A/G polymorphism with diabetic retinopathy in type 2 diabetes mellitus: A meta-analysis. AB - AIMS: The relationship between monocyte chemoattractant protein-1 (MCP-1) 2518 A/G polymorphism and diabetic retinopathy (DR) attracted intense interest recently, but the reported results are controversial. A meta-analysis was performed to assess the MCP-1 polymorphism associated with DR susceptibility in type 2 diabetes mellitus. METHODS: Eligible studies were identified from PubMed, Embase, Web of science, Chinese Biomedical database, and references of retrieved articles. Pooled odds ratios (ORs) with their 95% confidence intervals (95%CI) were calculated by fixed or random-effects models. RESULTS: Six studies involving 3415 patients without DR and 3468 with any DR were included in the final meta analysis. Each 5 studies evaluated the associations of MCP-1 polymorphism and any DR and proliferative DR (PDR), respectively. Meta-analysis in fixed model demonstrated a significant association between MCP-1 polymorphism and any DR under the homozygous model (OR=1.36; 95%CI: 1.15-1.62, P<0.001), heterozygous model (OR=1.20; 95%CI: 1.02-1.42, P=0.031), dominant model (OR=1.28; 95%CI: 1.10 1.50, P=0.002), recessive model (OR=1.17; 95%CI: 1.05-1.31, P=0.004), and allelic model (OR=1.16; 95%CI: 1.07-1.25, P<0.001). Furthermore, a significant association of MCP-1 polymorphism and DR progression from non-proliferative DR to proliferative DR was identified under heterozygous model (OR=1.45; 95%CI: 1.04 2.02, P=0.030). Sensitivity analyses did not draw different findings. CONCLUSIONS: Meta-analysis of existing data suggested that MCP-1 2518 A/G polymorphism affected the risk of presence and progression of DR in type 2 diabetes mellitus. PMID- 27505626 TI - Comparative Transcriptome Profiling of Human Foreskin Fibroblasts Infected with the Sylvio and Y Strains of Trypanosoma cruzi. AB - Trypanosoma cruzi, the causative agent of Chagas Disease, is phylogeneticaly distributed into nearly identical genetic strains which show divergent clinical presentations including differences in rates of cardiomyopathy in humans, different vector species and transmission cycles, differential congenital transmission in a mouse model, and differing immune and heart inflammation response in dogs. The population structure of these strains divides into two groups, which are geographically and clinically distinct. The aim of this study was to compare the transcriptome of two strains of T. cruzi, Sylvio vs. Y, to identify differences in expression that could account for clinical and biochemical differences. We collected and sequenced RNA from T. cruzi-infected and control Human Foreskin Fibroblasts at three timepoints. Differential expression analysis identified gene expression different timepoints in Sylvio infections, and between Sylvio and Y infections in both parasite and host. The Sylvio strain parasite and the host response to Sylvio infection largely mirrored the host-pathogen interaction seen in our previous Y strain work. IL-8 was more highly expressed in Sylvio-infected HFFs than in Y-infected HFFs. PMID- 27505628 TI - Evaluation of smokers with and without asthma in terms of smoking cessation outcome, nicotine withdrawal symptoms, and craving: Findings from a self-guided quit attempt. AB - INTRODUCTION: The aim of the current study was to evaluate smoking cessation outcome, nicotine withdrawal symptoms, and craving between smokers with (n=47; 46.8% male, Mage=40.0years, SD=11.7) and without (n=45; 51.1% male, Mage=37.5years, SD=11.1) asthma during a self-guided quit attempt. METHODS: After completing a baseline assessment visit, participants attended study sessions on their scheduled quit day as well as follow-up visits (3days, 7days, 14days, and 28days) after their quit day. RESULTS: Smokers with and without asthma did not differ in abstinence rates, smoking lapse, and rate of change in urge to smoke to reduce negative affect. However, smokers with asthma demonstrated a slower rate of decline in nicotine withdrawal symptoms and craving over time. CONCLUSIONS: These findings suggest that smokers with asthma may benefit from specialized smoking cessation treatments to address prolonged withdrawal symptoms and craving. PMID- 27505629 TI - Long-term oncological safety of minimally invasive surgery in high-risk endometrial cancer. AB - BACKGROUND: Several studies showed that women with low-risk endometrial cancers staged by minimally invasive surgery (MIS) experience fewer postoperative complications compared to those staged by laparotomy with similar disease-free survival (DFS) and overall survival (OS). However, high-risk patients were poorly represented. In this study, we compared DFS and OS in high-risk endometrial cancer patients who underwent surgical staging via MIS versus laparotomy. METHODS: Using a multicentric database, we compared DFS and OS between 114 patients with high-risk histology who underwent surgical staging via MIS and 114 patients who underwent laparotomy. Patients were matched for age, tumour type, FIGO stage and management criteria. RESULTS: Among the 114 patients who underwent MIS, 93 underwent laparoscopy and 21 robotic surgery. Groups were comparable for stage, body mass index, histology and adjuvant therapies. However, patients in the MIS group underwent paraaortic lymphadenectomy less frequently (13% versus 29%; p = 0.01), had less lymph nodes removed (19.0 versus 28.6; p < 0.01) and had lower mean tumour size (30 versus 40 mm; p < 0.01). With a median follow-up time of 49 months, DFS and OS were not significantly different between the surgical cohorts. In multivariable analysis, both higher stage (hazard ratio [HR] = 2.2) and histology (HR = 4.9) were associated with DFS in contrast to surgical procedure (HR = 0.9). CONCLUSIONS: Beyond the benefit of MIS on immediate surgical outcome, our results show that fear for a poor long-term outcome should not be the reason to refrain from MIS in patients with high-risk endometrial cancer. PMID- 27505630 TI - New Look, New Features: An Update From the Journal of Clinical Neurophysiology. PMID- 27505631 TI - Pierre J. Meunier. PMID- 27505632 TI - Aerobic photoreactivity of synthetic eumelanins and pheomelanins: generation of singlet oxygen and superoxide anion. AB - In this work, we examined photoreactivity of synthetic eumelanins, formed by autooxidation of DOPA, or enzymatic oxidation of 5,6-dihydroxyindole-2-carboxylic acid and synthetic pheomelanins obtained by enzymatic oxidation of 5-S cysteinyldopa or 1:1 mixture of DOPA and cysteine. Electron paramagnetic resonance oximetry and spin trapping were used to measure oxygen consumption and formation of superoxide anion induced by irradiation of melanin with blue light, and time-resolved near-infrared luminescence was employed to determine the photoformation of singlet oxygen between 300 and 600 nm. Both superoxide anion and singlet oxygen were photogenerated by the synthetic melanins albeit with different efficiency. At 450-nm, quantum yield of singlet oxygen was very low (~10-4 ) but it strongly increased in the UV region. The melanins quenched singlet oxygen efficiently, indicating that photogeneration and quenching of singlet oxygen may play an important role in aerobic photochemistry of melanin pigments and could contribute to their photodegradation and photoaging. PMID- 27505633 TI - Clinical Features and Treatment Outcomes of Patients with Drug-Resistant and Drug Sensitive Tuberculosis: A Historical Cohort Study in Porto Alegre, Brazil. AB - PURPOSE: To evaluate the clinical features and treatment outcomes of patients with pulmonary tuberculosis, stratified by level of drug resistance. METHODS: This was a historical cohort study based on data from the II National Anti Tuberculosis Drug Resistance Survey (2006-2007) collected at eight participating health care facilities in Porto Alegre, southern Brazil. The cohort was followed for 3 years after the start of treatment. RESULTS: Of 299 cases of smear-positive pulmonary tuberculosis included in the study, 216 (72.2%) were diagnosed at five public primary health care units and 83 (27.8%) at three public hospitals. Among these cases, the prevalence of drug-resistant tuberculosis was 14.4%, and that of multidrug-resistant tuberculosis was 4.7%. Overall, 32.0% of drug-resistant and 2.0% of multidrug-resistant cases occurred in previously treated patients. The most common comorbidity in the sample was HIV infection (26.2%). There was no association between drug-resistant or multidrug-resistant tuberculosis and sociodemographic variables. Cure was achieved in 66.7% of patients, and the default rate was 21.2%. The 2-month sputum conversion rate was 34.2%, and the relapse rate was 16.9%. Patients with drug-resistant tuberculosis had lower rates of cure (45.2%) and 2-month sputum conversion (25%), as well as a higher relapse rate (30.7%). CONCLUSION: These results highlight the urgent need for a more effective TB control program in this geographical setting, with a major emphasis on treatment of drug-resistant and multidrug-resistant tuberculosis. PMID- 27505634 TI - Sensitivity Analysis and Optimal Control of Anthroponotic Cutaneous Leishmania. AB - This paper is focused on the transmission dynamics and optimal control of Anthroponotic Cutaneous Leishmania. The threshold condition R0 for initial transmission of infection is obtained by next generation method. Biological sense of the threshold condition is investigated and discussed in detail. The sensitivity analysis of the reproduction number is presented and the most sensitive parameters are high lighted. On the basis of sensitivity analysis, some control strategies are introduced in the model. These strategies positively reduce the effect of the parameters with high sensitivity indices, on the initial transmission. Finally, an optimal control strategy is presented by taking into account the cost associated with control strategies. It is also shown that an optimal control exists for the proposed control problem. The goal of optimal control problem is to minimize, the cost associated with control strategies and the chances of infectious humans, exposed humans and vector population to become infected. Numerical simulations are carried out with the help of Runge-Kutta fourth order procedure. PMID- 27505635 TI - DWI in Pediatric Small-Bowel Crohn Disease: Are Apparent Diffusion Coefficients Surrogates for Disease Activity in Patients Receiving Infliximab Therapy? AB - OBJECTIVE: The purpose of this study was to determine prospectively whether bowel wall apparent diffusion coefficient (ADC) measurements can be used to monitor treatment response to infliximab therapy in the setting of pediatric small-bowel Crohn disease. SUBJECTS AND METHODS: Twenty-eight pediatric subjects with newly diagnosed biopsy-proven Crohn disease of the distal or terminal ileum treated with infliximab were enrolled. Subjects underwent MR enterography at baseline, 1 month after therapy, and 6 months after therapy. Imaging features were documented, including bowel wall ADC and arterial or enteric phase contrast enhanced signal intensity normalized to that of unenhanced imaging. A linear mixed model assessed the relationship between ADC and time; patient age and sex and azathioprine combination therapy were covariates. The diagnostic performance (with 95% CIs) of an increase in bowel wall ADC of 20% or more for identifying response to infliximab was calculated using a decrease in normalized contrast enhanced bowel wall signal intensity of 20% or more as the reference standard. RESULTS: Bowel wall ADC increased over time (mean [+/- SD], 1180 +/- 200 * 10-6 mm2/s at baseline, 1420 +/- 420 * 10-6 mm2/s at 1 month, and 1450 +/- 450 * 10-6 mm2/s at 6 months; p = 0.0003); azathioprine therapy modulated this rate of change (p = 0.003). There was a statistically significant negative correlation between change in ADC and change in normalized contrast-enhanced signal intensity over time (rho = -0.36; p < 0.001). The diagnostic performance of change in ADC for identifying response to infliximab therapy was sensitivity of 0.58 (95% CI, 0.34-0.80), specificity of 0.52 (95% CI, 0.31-0.72), positive predictive value of 0.48 (95% CI, 0.27-0.69), and negative predictive value of 0.62 (95% CI, 0.38 0.82). CONCLUSION: Bowel wall ADC increases over time in pediatric subjects receiving infliximab, but the diagnostic performance of ADC is likely insufficient for reliable treatment monitoring. PMID- 27505636 TI - Resolving and Tuning Mechanical Anisotropy in Black Phosphorus via Nanomechanical Multimode Resonance Spectromicroscopy. AB - Black phosphorus (P) has emerged as a layered semiconductor with a unique crystal structure featuring corrugated atomic layers and strong in-plane anisotropy in its physical properties. Here, we demonstrate that the crystal orientation and mechanical anisotropy in free-standing black P thin layers can be precisely determined by spatially resolved multimode nanomechanical resonances. This offers a new means for resolving important crystal orientation and anisotropy in black P device platforms in situ beyond conventional optical and electrical calibration techniques. Furthermore, we show that electrostatic-gating-induced straining can continuously tune the mechanical anisotropic effects on multimode resonances in black P electromechanical devices. Combined with finite element modeling (FEM), we also determine the Young's moduli of multilayer black P to be 116.1 and 46.5 GPa in the zigzag and armchair directions, respectively. PMID- 27505637 TI - Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients. AB - Ponatinib is approved for adults with refractory chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia, including those with the T315I BCR-ABL1 mutation. We pooled data from 3 clinical trials (N=671) to determine the impact of ponatinib dose intensity on the following adverse events: arterial occlusive events (cardiovascular, cerebrovascular, and peripheral vascular events), venous thromboembolic events, cardiac failure, thrombocytopenia, neutropenia, hypertension, pancreatitis, increased lipase, increased alanine aminotransferase, increased aspartate aminotransferase, rash, arthralgia, and hypertriglyceridemia. Multivariate analyses allowed adjustment for covariates potentially related to changes in dosing or an event. Logistic regression analysis identified significant associations between dose intensity and most events after adjusting for covariates. Pancreatitis, rash, and cardiac failure had the strongest associations with dose intensity (odds ratios >2). Time to-event analyses showed significant associations between dose intensity and risk of arterial occlusive events and each subcategory. Further, these analyses suggested that a lag exists between a change in dose and the resulting change in event risk. No significant association between dose intensity and risk of venous thromboembolic events was evident. Collectively, these findings suggest a potential causal relationship between ponatinib dose and certain adverse events and support prospective investigations of approaches to lower average ponatinib dose intensity. PMID- 27505638 TI - A Novel Plasmid, pSx1, Harboring a New Tn1696 Derivative from Extensively Drug Resistant Shewanella xiamenensis Encoding OXA-416. AB - The whole genome sequencing of extensively drug-resistant Shewanella xiamenensis T17 isolated from hospital effluents in Algeria revealed the presence of a novel 268.4 kb plasmid designated pSx1, which carries several antibiotic-resistance genes in the novel Tn1696 derivative (Tn6297), in addition to the chromosomal blaOXA-48-like gene (blaOXA-416). The presence of the plasmid was confirmed by nuclease S1-PFGE analysis and transformation by electroporation into Escherichia coli DH10B. Tn6297 contains an In27 class 1 integron harboring the dfrA12-orfF aadA2 array, msr(E) and mph(E) associated with IS26; a new efflux pump multidrug resistance composite transposon delimited by two ISEc29s; Tn-tet harboring tetR and tetA(C); a class 1 integron with the qacG gene cassette; qnrVC6 and dfrA23 associated with ISCR1; and a complex class 1 integron In4-like containing aacC1, aadA1, blaVEB-16, catA2, sul1Delta, cmlA9, tetR, tetA(G), aac(6')-II, and blaPSE 1. Its mer operon carries merB, but lacks merC, in contrast to Tn1696 and Tn21. This study represents the first characterization of a multidrug-resistant transposon and multidrug resistance plasmid in Shewanella and is the first report of blaOXA-416 in Algeria, providing evidence that Shewanella spp. could be an important reservoir and vehicle for drug resistance genes. PMID- 27505639 TI - Spectrum of classes of point emitters: new tool for nonparaxial optical field modeling. AB - Numerical modeling of optical fields provides valuable support to both theoretical research and technological development in many optics fields. Fourier methods have been the most widely used tools of numerical modeling. However, important limitations have restricted their application in contemporary research that involve high numerical apertures, short propagation distances, and spatially partially coherent states of light, for instance. The spectrum of classes of point emitters is introduced as a numerical tool that overcomes such limitations for the design, analysis, and synthesis of nonparaxial optical fields in arbitrary states of spatial coherence. In this context, optical processing is realized as the filtering on the spectrum of classes of point emitters performed by the complex degree of spatial coherence that could be implemented dynamically by using programmable devices. PMID- 27505640 TI - Salient object detection fusing global and local information based on nonsubsampled contourlet transform. AB - The nonsubsampled contourlet transform (NSCT) has properties of multiresolution, localization, directionality, and anisotropy. The directionality property permits it to resolve intrinsic directional features that characterize the analyzed image. In this paper, we present a bottom-up salient object detection approach fusing global and local information based on NSCT. Images are first decomposed by applying NSCT. The coefficients of bandpass subbands are categorized and optimized accordingly to get better representation. Then feature maps are obtained by performing the inverse NSCT on these optimized coefficients. The global and local saliency maps are generated from these feature maps. Global saliency is obtained by utilizing the likelihood of features, and local saliency is measured by calculating the local self-information. In the end, the final saliency map is computed by fusing the global and local saliency maps together. Experimental results on MSRA 10K demonstrate the effectiveness and promising performance of our proposed method. PMID- 27505641 TI - Propagation properties of an optical vortex carried by a Bessel-Gaussian beam in anisotropic turbulence. AB - Rytov theory was employed to establish the transmission model for the optical vortices carried by Bessel-Gaussian (BG) beams in weak anisotropic turbulence based on the generalized anisotropic von Karman spectrum. The influences of asymmetry anisotropic turbulence eddies and source parameters on the signal orbital angular momentum (OAM) mode detection probability of partially coherent BG beams in anisotropic turbulence were discussed. Anisotropic characteristics of the turbulence could enhance the OAM mode transmission performance. The spatial partially coherence of the beam source would increase turbulent aberration's effect on the optical vortices. BG beams could dampen the influences of the turbulence because of their nondiffraction and self-healing characteristics. PMID- 27505642 TI - Average intensity and directionality of partially coherent model beams propagating in turbulent ocean. AB - We studied Gaussian beams with three different partially coherent models, including the Gaussian-Schell model (GSM), Laguerre-Gaussian Schell model (LGSM), and Bessel-Gaussian Schell model (BGSM), propagating through oceanic turbulence. The expressions of average intensity, beam spreading, and beam wander for GSM, LGSM, and BGSM beams in the paraxial channel are derived. We make a contrast for the three models in numerical simulations and find that the GSM beam has smaller spreading than the others, and the LGSM beam needs longer propagation distance to transform into a well-like profile of average intensity than the BGSM beam in the same conditions. The salinity fluctuation has a greater contribution to the wander of LGSM and BGSM beams than that of the temperature fluctuation. Our results can be helpful in the design of an optical wireless communication link operating in oceanic environment. PMID- 27505643 TI - Variational principle in optics II: Dissipative wave equations. AB - The problem of phase retrieval from intensity measurements is examined for the case of dissipative wave equations. Unlike the conservative case, it is not clear if and when the problem is solvable at all. We provide two solutions. First, it is shown that, for a certain class of dissipating potentials, the problem can be fully solved by converting it through a simple transformation to the framework of the weighted least action principle. Second, for all other dissipating potentials, a deep result from the theory of elliptic partial differential equations is used to show that the problem is always solvable up to a scaling of one of the measured intensities. Moreover, the solution in this general case can be obtained by solving a Monge-Ampere type differential equation. Two numerical examples are given to illustrate some of the theoretical considerations. PMID- 27505644 TI - Characteristic functionals in imaging and image-quality assessment: tutorial. AB - Characteristic functionals are one of the main analytical tools used to quantify the statistical properties of random fields and generalized random fields. The viewpoint taken here is that a random field is the correct model for the ensemble of objects being imaged by a given imaging system. In modern digital imaging systems, random fields are not used to model the reconstructed images themselves since these are necessarily finite dimensional. After a brief introduction to the general theory of characteristic functionals, many examples relevant to imaging applications are presented. The propagation of characteristic functionals through both a binned and list-mode imaging system is also discussed. Methods for using characteristic functionals and image data to estimate population parameters and classify populations of objects are given. These methods are based on maximum likelihood and maximum a posteriori techniques in spaces generated by sampling the relevant characteristic functionals through the imaging operator. It is also shown how to calculate a Fisher information matrix in this space. These estimators and classifiers, and the Fisher information matrix, can then be used for image quality assessment of imaging systems. PMID- 27505645 TI - Spectral image analysis of mutual illumination between florescent objects. AB - This paper proposes a method for modeling and component estimation of the spectral images of the mutual illumination phenomenon between two fluorescent objects. First, we briefly describe the bispectral characteristics of a single fluorescent object, which are summarized as a Donaldson matrix. We suppose that two fluorescent objects with different bispectral characteristics are located close together under a uniform illumination. Second, we model the mutual illumination between two objects. It is shown that the spectral composition of the mutual illumination is summarized with four components: (1) diffuse reflection, (2) diffuse-diffuse interreflection, (3) fluorescent self luminescence, and (4) interreflection by mutual fluorescent illumination. Third, we develop algorithms for estimating the spectral image components from the observed images influenced by the mutual illumination. When the exact Donaldson matrices caused by the mutual illumination influence are unknown, we have to solve a non-linear estimation problem to estimate both the spectral functions and the location weights. An iterative algorithm is then proposed to solve the problem based on the alternate estimation of the spectral functions and the location weights. In our experiments, the feasibility of the proposed method is shown in three cases: the known Donaldson matrices, weak interreflection, and strong interreflection. PMID- 27505646 TI - Correction technology of a polarization lidar with a complex optical system. AB - A complex optical system used in polarization lidars often modifies the input polarization of the return signal so that it may significantly impact depolarization estimates and introduce errors to polarization lidar measurements. In most cases, retardation, depolarization, and misalignment of the system exist at the same time and interact with each other. Polarization effects of the system cannot be represented by a simple correction coefficient, so they cannot be removed using a traditional calibration method. Detailed analysis and correction technologies were provided to remove systematic biases in estimating depolarization values from a polarization lidar owing to multiple optical components. The Mueller matrices from an emitter to a receiver were calculated, and the expression for an aerosol depolarization parameter including system polarization effects was derived and obtained. In addition, the correction algorithm based on the Mueller matrix was introduced and provided. A polarization lidar was established, and the polarization characteristics of its optical components were measured with a laboratory ellipsometer; then, the Mueller matrix of the receiver was calculated and obtained. Lidar observations were performed, and our correction algorithm was applied to lidar field data. The results show that the correction method can significantly remove systematic polarization effects. PMID- 27505647 TI - Can spherical eukaryotic microalgae cells be treated as optically homogeneous? AB - This study aims to answer the question of whether spherical unicellular photoautotrophic eukaryotic microalgae cells, consisting of various intracellular compartments with their respective optical properties, can be modeled as homogeneous spheres with some effective complex index of refraction. The spectral radiation characteristics in the photosynthetically active region of a spherical heterogeneous microalgae cell, representative of Chlamydomonas reinhardtii and consisting of spherical compartments corresponding to the cell wall, cytoplasm, chloroplast, nucleus, and mitochondria, were estimated using the superposition T matrix method. The effects of the presence of intracellular lipids and/or starch accumulation caused by stresses, such as nitrogen limitation, were explored. Predictions by the T-matrix method were qualitatively and quantitatively consistent with experimental measurements for various microalgae species. The volume-equivalent homogeneous sphere approximation with volume-averaged effective complex index of refraction gave accurate estimates of the spectral (i) absorption and (ii) scattering cross sections of the heterogeneous cells under both nitrogen-replete and nitrogen-limited conditions. In addition, the effect of a strongly refracting cell wall, representative of Chlorella vulgaris, was investigated. In this case, for the purpose of predicting their integral radiation characteristics, the microalgae should be represented as a coated sphere with a coating corresponding to the cell wall and a homogeneous core with volume-averaged complex index of refraction for the rest of the cell. However, both homogeneous sphere and coated sphere approximations predicted strong resonances in the scattering phase function and spectral backscattering cross section that were not observed in that of the heterogeneous cells. PMID- 27505648 TI - Reconstruction of an optical surface from a given source-target map. AB - We propose a new method for the reconstruction of a reflecting (refracting) surface from a given source-target map defining the relationships between the directions of incident and reflected (refracted) rays. In the proposed method, the optical surface is represented as an envelope of a set of paraboloids (reflecting surface) or ellipsoids (refracting surface). This representation allows the problem of design of an optical surface to be reduced to the reconstruction of a function from its total differential. We illustrate the proposed approach by designing mirrors generating a far-field uniform illuminance in a square target. The calculation results show that the proposed method enables the generation of high-quality illuminance distributions even when the integrability condition is not satisfied. PMID- 27505649 TI - Refined treatment of single-edge diffraction effects in radiometry. AB - This work treats diffraction corrections in radiometry for cases of point and extended sources in cylindrically symmetrical three-element systems. It considers diffraction effects for spectral power and total power in cases of Planck sources. It improves upon an earlier work by the author by giving a simpler rendering of leading terms in asymptotic expansions for diffraction effects and reliable estimates for the remainders. This work also demonstrates a framework for accelerating the treatment of extended sources and simplifying the calculation of diffraction effects over a range of wavelengths. This is especially important in the short-wavelength region, where dense sampling of wavelength values is in principle necessitated by the rapidly oscillatory behavior of diffraction effects as a function of wavelength. We demonstrate the methodology's efficacy in two radiometric applications. PMID- 27505650 TI - Symmetric form-invariant dual Pearcey beams. AB - We introduce another type of Pearcey beam, namely, dual Pearcey (DP) beams, based on the Pearcey function of catastrophe theory. DP beams are experimentally generated by applying Fresnel diffraction of bright elliptic rings. Form invariant Bessel distribution beams can be regarded as a special case of DP beams. Subsequently, the basic propagation characteristics of DP beams are identified. DP beams are the result of the interference of two half DP beams instead of two classical Pearcey beams. Moreover, we also verified that half DP beams (including special-case parabolic-like beams) generated by half elliptical rings (circular rings) are a new member of the family of form-invariant beams. PMID- 27505651 TI - Spherical aberration in electrically thin flat lenses. AB - We analyze the spherical aberration of a new generation of lenses made of flat electrically thin inhomogeneous media. For such lenses, spherical aberration is analyzed quantitatively and qualitatively, and comparison is made to the classical gradient index rod. Both flat thin and thick lenses are made of gradient index materials, but the physical mechanisms and design equations are different. Using full-wave three-dimensional numerical simulation, we evaluate the spherical aberrations using the Marechal criterion and show that the thin lens gives significantly better performance than the thick lens (rod). Additionally, based on ray tracing formulation, third-order analysis for longitudinal aberration and optical path difference are presented, showing strong overall performance of thin lenses in comparison to classical rod lenses. PMID- 27505652 TI - First-order method of zoom lens design by means of generalized parameters. AB - A method of paraxial zoom lens design is proposed that makes it possible to determine the optical powers and component movements of a zoom lens with the required zoom ratio. The method is based on the theory of generalized parameters, which can be used to analyze a zoom system by varying only one parameter. All possible zoom lenses with two movable components are considered for an object at infinity. PMID- 27505653 TI - Pupil dynamics with periodic flashes: effect of age on mesopic adaptation. AB - The purpose of this study is to determine the pupillary dynamics with periodical flashes from a peripheral glare source, in similar conditions to night driving, while focusing on dependence with age. We measured two groups of people: youth and adults. Maximum pupil size decreases due to periodic flashes. Latency does not present significant differences. The reduction of pupil size is greater for older adults. The presence of a peripheral and periodic glare source modifies the pupil size. This leads to a reduction of retinal illuminance, which is greater for older adults. PMID- 27505654 TI - Optical Hall effect-model description: tutorial. AB - The optical Hall effect is a physical phenomenon that describes the occurrence of magnetic-field-induced dielectric displacement at optical wavelengths, transverse and longitudinal to the incident electric field, and analogous to the static electrical Hall effect. The electrical Hall effect and certain cases of the optical Hall effect observations can be explained by extensions of the classic Drude model for the transport of electrons in metals. The optical Hall effect is most useful for characterization of electrical properties in semiconductors. Among many advantages, while the optical Hall effect dispenses with the need of electrical contacts, electrical material properties such as effective mass and mobility parameters, including their anisotropy as well as carrier type and density, can be determined from the optical Hall effect. Measurement of the optical Hall effect can be performed within the concept of generalized ellipsometry at an oblique angle of incidence. In this paper, we review and discuss physical model equations, which can be used to calculate the optical Hall effect in single- and multiple-layered structures of semiconductor materials. We define the optical Hall effect dielectric function tensor, demonstrate diagonalization approaches, and show requirements for the optical Hall effect tensor from energy conservation. We discuss both continuum and quantum approaches, and we provide a brief description of the generalized ellipsometry concept, the Mueller matrix calculus, and a 4*4 matrix algebra to calculate data accessible by experiment. In a follow-up paper, we will discuss strategies and approaches for experimental data acquisition and analysis. PMID- 27505655 TI - Analytical expression for pixel-averaged point sources as observed by a focal plane array. AB - A closed-form expression is derived for pixel-averaged point source signals as observed by an imaging array. Obtaining this solution requires the probability distribution of squared Euclidean distances in two dimensions when the end points are confined to a uniformly spaced square domain. The derivation and associated expression are provided. PMID- 27505656 TI - Estimating individual cone fundamentals from their color-matching functions. AB - Estimation of individual spectral cone fundamentals from color-matching functions is a classical and longstanding problem in color science. In this paper we propose a novel method to carry out this estimation based on a linear optimization technique, employing an assumption of a priori knowledge of the retinal absorptance functions. The result is an estimation of the combined lenticular and macular filtration for an individual, along with the nine coefficients in the linear combination that relates their color-matching functions to their estimated spectral-cone fundamentals. We test the method on the individual Stiles and Burch color-matching functions and derive cone fundamental estimations for different viewing fields and matching experiment repetition. We obtain cone-fundamental estimations that are remarkably similar to those available in the literature. This suggests that the method yields results that are close to the true fundamentals. PMID- 27505657 TI - Toward omnidirectional and automated imaging system for measuring oceanic whitecap coverage. AB - Accurate measurements of oceanic whitecap coverage from whitecap images are required for better understanding air-gas transfer and aerosol production processes. However, this is a challenging task because whitecap patches are formed immediately after a wave breaks and are spread over a wide area. The main challenges in designing whitecaps imaging instrument are the small field of view of the camera lens, processing huge numbers of images, recording data over long time periods, and deployment difficulties in stormy conditions. This paper describes the hardware design of a novel high-resolution optical instrument for imaging oceanic whitecaps and the automated algorithm processing the collected images. The instrument was successfully deployed in 2013 as part of the HiWINGS campaign in the North Atlantic Ocean. The instrument uses a fish-eye camera lens to image the whitecaps in a wide angle of view (180 degrees ). PMID- 27505658 TI - Eye movements and information geometry. AB - The human visual system uses eye movements to gather visual information. They act as visual scanning processes and can roughly be divided into two different types: small movements around fixation points and larger movements between fixation points. The processes are often modeled as random walks, and recent models based on heavy tail distributions, also known as Levy flights, have been used in these investigations. In contrast to these approaches we do not model the stochastic processes, but we will show that the step lengths of the movements between fixation points follow generalized Pareto distributions (GPDs). We will use general arguments from the theory of extreme value statistics to motivate the usage of the GPD and show empirically that the GPDs provide good fits for measured eye tracking data. In the framework of information geometry the GPDs with a common threshold form a two-dimensional Riemann manifold with the Fisher information matrix as a metric. We compute the Fisher information matrix for the GPDs and introduce a feature vector describing a GPD by its parameters and different geometrical properties of its Fisher information matrix. In our statistical analysis we use eye tracker measurements in a database with 15 observers viewing 1003 images under free-viewing conditions. We use Matlab functions with their standard parameter settings and show that a naive Bayes classifier using the eigenvalues of the Fisher information matrix provides a high classification rate identifying the 15 observers in the database. PMID- 27505659 TI - Foucault test: a quantitative evaluation method. AB - Reliable and accurate testing methods are essential to guiding the polishing process during the figuring of optical telescope mirrors. With the natural advancement of technology, the procedures and instruments used to carry out this delicate task have consistently increased in sensitivity, but also in complexity and cost. Fortunately, throughout history, the Foucault knife-edge test has shown the potential to measure transverse aberrations in the order of the wavelength, mainly when described in terms of physical theory, which allows a quantitative interpretation of its characteristic shadowmaps. Our previous publication on this topic derived a closed mathematical formulation that directly relates the knife edge position with the observed irradiance pattern. The present work addresses the quite unexplored problem of the wavefront's gradient estimation from experimental captures of the test, which is achieved by means of an optimization algorithm featuring a proposed ad hoc cost function. The partial derivatives thereby calculated are then integrated by means of a Fourier-based algorithm to retrieve the mirror's actual surface profile. To date and to the best of our knowledge, this is the very first time that a complete mathematical-grounded treatment of this optical phenomenon is presented, complemented by an image processing algorithm which allows a quantitative calculation of the corresponding slope at any given point of the mirror's surface, so that it becomes possible to accurately estimate the aberrations present in the analyzed concave device just through its associated foucaultgrams. PMID- 27505660 TI - Unwrapped wavefront evaluation in phase-shifting interferometry based on 3D dynamic fringe processing in state space. AB - Recovery of an unwrapped wavefront in phase-shifting interferometry is considered when the wavefront phase increments are determined between previous and subsequent fringe patterns as well as between adjacent pixels of the current fringe pattern. A parametric model of a three-dimensional interferometric signal and the recurrence processing algorithm in state space are utilized, providing an evaluation of an unwrapped wavefront phase at each phase shift step in dynamic mode. Estimates of the achievable accuracy and experimental results of the wavefront recovery are presented. Comparison with the conventional seven-frame phase-shifting algorithm, which is one of the most accurate, confirmed the high accuracy and noise immunity of the proposed method. PMID- 27505661 TI - Relating wavefront error, apodization, and the optical transfer function: on-axis case: comment. AB - In a recent paper [J. Opt. Soc. Am. A31, 2476 (2014)JOAOD60740 323210.1364/JOSAA.31.002476], a linear expansion of the optical transfer function (OTF) of an imaging system in which the expansion coefficients are related to its wavefront errors has been developed. It is claimed that the OTF can be calculated quickly by using this approach. We provide instead closed-form basis functions that are not determined recursively. Numerical examples demonstrate that the OTF calculation by a digital autocorrelation of the pupil function is much faster regardless of the wavefront complexity. PMID- 27505662 TI - Relating wavefront error, apodization, and the optical transfer function: on-axis case: reply. AB - Efficient coding enables rapid calculation of basis functions for a linear expansion of the optical transfer function. PMID- 27505663 TI - Performance evaluation of modulation and multiple access schemes in ultraviolet optical wireless connections for two atmosphere thickness cases. AB - The exploitation of optical wireless communication channels in a non-line-of sight regime is studied for point-to-point and networking configurations considering the use of light-emitting diodes. Two environments with different scattering center densities are considered, assuming operation at 265 nm. The bit error rate performance of both pulsed and multicarrier modulation schemes is examined, using numerical approaches. In the networking scenario, a central node only receives data, one node transmits useful data, and the rest of them act as interferers. The performance of the desirable node's transmissions is evaluated. The access to the medium is controlled by a code division multiple access scheme. PMID- 27505664 TI - Single-order transmission diffraction gratings based on dispersion engineered all dielectric metasurfaces. AB - A single-order transmission diffraction grating based on dispersion engineered all-dielectric metasurfaces is proposed, and its wavelength discriminating properties have been theoretically described and confirmed using numerical simulations. The metasurface is designed using a 2D array of all-dielectric resonators, which emulates a Huygens' source configuration to achieve a perfect match to free space in broad bandwidth. Using a holey dielectric nanodisk structure as the unit cell, the resonant wavelength is tapered across the metasurface to engineer the wavelength-dependent spatial phase gradient, to emulate a dispersive prism. Consequently, different wavelengths are steered toward different directions and thus are discriminated on the output image plane. Due to the subwavelength periodicities involved, wavelength discrimination is achieved directly in the zeroth diffraction order of the device, unlike conventional diffraction gratings, thereby providing a high-efficiency wavelength discriminating device. PMID- 27505665 TI - Combinatorial Tethering: A Novel Mode to Recruit Non-canonical PRC1 for Normal and Malignant GC B Cell Development. AB - Polycomb repressive complexes (PRCs) are key to normal development and are frequently deregulated in human cancer. In this issue of Cancer Cell, Beguelin et al. report a mechanism of non-canonical PRC1 recruitment by BCL6 in collaboration with EZH2-mediated H3K27me3 for establishment of stable repressive complexes in germinal center B cells. PMID- 27505666 TI - Functionally Assessing Candidate Drivers Advances Precision Cancer Medicine. AB - The complexity of genomic alterations in cancer has made it difficult to identify oncogenic drivers for the development of targeted therapies. The study by Berger et al. in this issue of Cancer Cell demonstrates that high-throughput functional profiling can uncover impactful mutations and oncogenic driver alleles. PMID- 27505667 TI - Pre-Metastatic Niche Formation Has Taken Its TOLL. AB - Pre-Metastatic Niches (PMNs) result from communications between primary tumors and the microenvironment of future distant metastasis via tumor-derived factors. In this issue of Cancer Cell, Liu et al. show that TLR3 activation in lung epithelial cells by tumor exosomal RNAs triggers neutrophil recruitment, which contributes to PMN formation and metastasis. PMID- 27505668 TI - IDH1, Histone Methylation, and So Forth. AB - IDH mutants cause aberrant DNA and histone methylation and contribute to hematological and neuronal malignancies. In this issue of Cancer Cell, Inoue et al. describe a potential specific effect of IDH1 mutations that reduces Atm expression via inhibition of H3K9 demethylases, which may represent a first step toward cellular transformation. PMID- 27505669 TI - Sticking It to Cancer with Molecular Glue for SHP2. AB - Much effort has been expended to develop inhibitors against protein-tyrosine phosphatases (PTPs), nearly all of it unsuccessful. A recent report, describing a highly specific, orally bioavailable inhibitor of the PTP oncoprotein SHP2 with in vivo activity, suggests that allostery might provide a way forward for PTP inhibitor development. PMID- 27505670 TI - EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis. AB - The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site specific binding by the BCL6 transcriptional repressor and the presence of a non canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs. PMID- 27505671 TI - Tumor Exosomal RNAs Promote Lung Pre-metastatic Niche Formation by Activating Alveolar Epithelial TLR3 to Recruit Neutrophils. AB - The pre-metastatic niche educated by primary tumor-derived elements contributes to cancer metastasis. However, the role of host stromal cells in metastatic niche formation and organ-specific metastatic tropism is not clearly defined. Here, we demonstrate that lung epithelial cells are critical for initiating neutrophil recruitment and lung metastatic niche formation by sensing tumor exosomal RNAs via Toll-like receptor 3 (TLR3). TLR3-deficient mice show reduced lung metastasis in the spontaneous metastatic models. Mechanistically, primary tumor-derived exosomal RNAs, which are enriched in small nuclear RNAs, activate TLR3 in lung epithelial cells, consequently inducing chemokine secretion in the lung and promoting neutrophil recruitment. Identification of metastatic axis of tumor exosomal RNAs and host lung epithelial cell TLR3 activation provides potential targets to control cancer metastasis to the lung. PMID- 27505672 TI - Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming. AB - Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an "actionable" therapeutic target in cancer. PMID- 27505673 TI - Regulation of OGT by URI in Response to Glucose Confers c-MYC-Dependent Survival Mechanisms. AB - Cancer cells can adapt and survive under low nutrient conditions, but underlying mechanisms remain poorly explored. We demonstrate here that glucose maintains a functional complex between the co-chaperone URI, PP1gamma, and OGT, the enzyme catalyzing O-GlcNAcylation. Glucose deprivation induces the activation of PKA, which phosphorylates URI at Ser-371, resulting in PP1gamma release and URI mediated OGT inhibition. Low OGT activity reduces O-GlcNAcylation and promotes c MYC degradation to maintain cell survival. In the presence of glucose, PP1gamma bound URI increases OGT and c-MYC levels. Accordingly, mice expressing non phosphorylatable URI (S371A) in hepatocytes exhibit high OGT activity and c-MYC stabilization, accelerating liver tumorigenesis in agreement with c-MYC oncogenic functions. Our work uncovers that URI-regulated OGT confers c-MYC-dependent survival functions in response to glucose fluctuations. PMID- 27505674 TI - Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53/MDM2 Autoregulatory Loop in Multiple Myeloma Development. PMID- 27505675 TI - Loss of the Par3 Polarity Protein Promotes Breast Tumorigenesis and Metastasis. PMID- 27505676 TI - A Critical Role for Notch Signaling in the Formation of Cholangiocellular Carcinomas. PMID- 27505677 TI - Small Molecule Inhibitors of Aurora-A Induce Proteasomal Degradation of N-Myc in Childhood Neuroblastoma. PMID- 27505678 TI - A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis. PMID- 27505679 TI - Wip1 Controls Global Heterochromatin Silencing via ATM/BRCA1-Dependent DNA Methylation. PMID- 27505680 TI - DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias. PMID- 27505682 TI - The Multifaceted Role of Perivascular Macrophages in Tumors. PMID- 27505683 TI - Gaining insights from social media language: Methodologies and challenges. AB - Language data available through social media provide opportunities to study people at an unprecedented scale. However, little guidance is available to psychologists who want to enter this area of research. Drawing on tools and techniques developed in natural language processing, we first introduce psychologists to social media language research, identifying descriptive and predictive analyses that language data allow. Second, we describe how raw language data can be accessed and quantified for inclusion in subsequent analyses, exploring personality as expressed on Facebook to illustrate. Third, we highlight challenges and issues to be considered, including accessing and processing the data, interpreting effects, and ethical issues. Social media has become a valuable part of social life, and there is much we can learn by bringing together the tools of computer science with the theories and insights of psychology. (PsycINFO Database Record PMID- 27505684 TI - Split face evaluation of long-pulsed non-ablative 1,064 nm Nd:YAG laser for treatment of direct browplasty scars. AB - PURPOSE: To investigate 1,064 nm long-pulse Nd:YAG laser for postoperative treatment of direct browplasty scars. METHODS: Nine patients who underwent direct browplasty were enrolled in this prospective study. Subjects were randomized to unilateral laser treatment at 2-week intervals for six total treatments, with the contralateral scar used as a control. Prior to each treatment, subjects rated treated and control scars on overall cosmesis. Post-treatment, subjects rated each for erythema, swelling, discomfort, and perceived hair loss. Finally, examiners masked to treatment side were asked to judge side-by-side photographs of first and final visits for improvement and side effects. RESULTS: Subjects rated the overall appearance of the treated scar significantly higher at the time of treatment number 5 (mean score 5.13 +/- 2.03, P = 0.008) and treatment number 6 (6.25 +/- 1.98, P = 0.005) compared to treatment 1 (3.75 +/- 2.12); by contrast, they failed to rate the control scar more highly. On masked examination of photographs, the treated scar was selected as most improved 50.0 +/- 12.5% of the time. Both subjects and graders reported side effects as transient and mild to moderate (mean score 1-4), with no reports of hair loss from either subjects or observers. CONCLUSIONS: The 1,064 nm Nd:YAG laser provided significant improvement in scar cosmesis after direct browplasty, as rated by subject self report, but not by masked observers, and appears to be a useful tool for increasing satisfaction among those dissatisfied with direct browplasty scars. Side effects-including erythema, edema, and discomfort-were transient and universally rated as mild to moderate. Lasers Surg. Med. 48:742-747, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27505681 TI - Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma. PMID- 27505685 TI - Canine and feline lymphoma: challenges and opportunities for creating a paradigm shift. PMID- 27505686 TI - Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides. AB - Phenotypic whole-cell screening in erythrocytic cocultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure-activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure-property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as 10b. Analogues 13h and 13i, with structural modifications at each site, were shown to possess excellent antimalarial activity in vivo. The (+)-(3S,4S) enantiomer of 13i and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-13i for further study as a preclinical candidate. PMID- 27505687 TI - Water Diffusion from a Bacterial Cell in Low-Moisture Foods. AB - We used a Fick's unsteady state diffusion equation to estimate the time required for a single spherical shaped bacterium (assuming Enterococcus faecium as the target microorganism) in low-moisture foods to equilibrate with the environment. We generated water sorption isotherms of freeze-dried E. faecium. The water activity of bacterial cells at given water content increased considerably as temperature increased from 20 to 80 degrees C, as observed in the sorption isotherms of bacterial cells. When the water vapor diffusion coefficient was assumed as between 10(-12) and 10(-10) m(2) /s for bacterial cells, the predicted equilibration times (teq ) ranged from 8.24*10(-4) to 8.24*10(-2) s. Considering a cell membrane barrier with a lower water diffusion coefficient (10(-15) m(2) /s) around the bacterial cell with a water diffusion coefficient of 10(-12) m(2) /s, the teq predicted using COMSOL Multiphysics program was 3.8*10(-1) s. This result suggests that a single bacterium equilibrates rapidly (within seconds) with change in environmental humidity and temperature. PMID- 27505688 TI - High level of serum human interleukin-18 in a patient with pyogenic arthritis, pyoderma gangrenosum and acne syndrome. PMID- 27505689 TI - Biogeography as critical nursing pedagogy: Breathing life into nurse education. AB - Insights from the social sciences, including geography, sociology, and anthropology, have long been incorporated into pre-registration nursing programmes. However, scholars have suggested that their inclusion has been sporadic and lacks clear theoretical rationale. In this paper we argue anew that the social sciences - and particularly, human geography - could be central to nurse education. Specifically, we recast the concept of 'biogeography' drawn from human geography that emphasises the interplay between life (bio) and place (geo) to propose pedagogy that theoretically justifies and practically enables the inclusion of the social sciences in nurse education. Biogeography can breathe new life into nursing curricula by animating our students through the cultivation of three 'spirits of nursing'. First, a 'spirit of empathy' that can shatter patient professional dualisms by facilitating person-centred and place-sensitive care. Second, a 'spirit of engagement' that situates practice in social structures awakening a desire to effect change by fomenting an acute sense of social justice. Third, a 'spirit of enquiry' that holds in critical tension the theory practice gap by fostering continual questioning and pursuit of evidence. In so doing, biogeographical pedagogy releases the latent potential of the social sciences to revitalise nurse education, reinvigorate our students, and renew ourselves as nurse educators. PMID- 27505690 TI - Clinician's Commentary on Stratford and Riddle(1). PMID- 27505691 TI - Photochemical Stereocontrol Using Tandem Photoredox-Chiral Lewis Acid Catalysis. AB - The physical, biological, and materials properties of organic compounds are determined by their three-dimensional molecular shape. The development of methods to dictate the stereochemistry of organic reactions has consequently emerged as one of the central themes of contemporary synthetic chemistry. Over the past several decades, chiral catalysts have been developed to control the enantioselectivity of almost every class of synthetically useful transformation. Photochemical reactions, however, are a conspicuous exception. Relatively few examples of highly enantioselective catalytic photoreactions have been reported to date, despite almost a century of research in this field. The development of robust strategies for photochemical enantiocontrol has thus proven to be a long standing and surprisingly difficult challenge. For the past decade, our laboratory has been studying the application of transition metal photocatalysts to a variety of problems in synthetic organic chemistry. These efforts have recently culminated in the discovery of an effective system in which the activity of a visible light absorbing transition metal photoredox catalyst is combined with a second stereocontrolling chiral Lewis acid catalyst. This dual catalyst strategy has been applied to a diverse range of photochemical reactions; these have included highly enantioselective photocatalytic [2 + 2] cycloadditions, [3 + 2] cycloadditions, and radical conjugate addition reactions. This Account describes the development of the tandem Lewis acid photoredox catalysis strategy utilized in our laboratory. It provides an analysis of the factors that we believe to be particularly important to the success of this seemingly robust approach to photocatalytic stereocontrol. (1) The photocatalysts utilized in our systems are activated by wavelengths of visible light where the organic substrates are transparent, which minimizes the possibility of competitive racemic background photoreactions. (2) The high degree of tolerance that Ru(bpy)32+ and similar octahedral metal polypyridine complexes exhibit toward Lewis acids affords great flexibility in tuning the structure of the stereocontrolling chiral catalyst without perturbing the photoredox properties of the photocatalyst. (3) Synthetic chemists have amassed a substantial understanding of the features that are common in highly successful chiral Lewis acid catalyzed reactions, and these deep, well-validated insights are readily applied to the reactions of a variety of photogenerated intermediates. We hope that the recent success of this and similar dual catalytic systems will provide a useful foundation for the further development of powerful, stereocontrolled photochemical reactions. PMID- 27505693 TI - Maternal behavior predicts infant neurophysiological and behavioral attention processes in the first year. AB - We apply a biopsychosocial conceptualization to attention development in the 1st year and examine the role of neurophysiological and social processes on the development of early attention processes. We tested whether maternal behavior measured during 2 mother-child interaction tasks when infants (N = 388) were 5 months predicted infant medial frontal (F3/F4) EEG power and observed attention behavior during an attention task at 10 months. After controlling for infant attention behavior and EEG power in the same task measured at an earlier 5-month time point, results indicated a significant direct and positive association from 5-month maternal positive affect to infant attention behavior at 10 months. However, maternal positive affect was not related to medial frontal EEG power. In contrast, 5-month maternal intrusive behavior was associated with infants' task related EEG power change at the left frontal location, F3, at 10 months of age. The test of indirect effects from 5-month maternal intrusiveness to 10-month infant attention behavior via infants' EEG power change at F3 was significant. These findings suggest that the development of neural networks serving attention processes may be 1 mechanism through which early maternal behavior is related to infant attention development in the 1st year and that intrusive maternal behavior may have a particularly disruptive effect on this process. (PsycINFO Database Record PMID- 27505694 TI - The role of age, working memory, and response inhibition in deviance distraction: A cross-sectional study. AB - Sounds deviating from an otherwise repeated or structured sequence capture attention and affect performance in an ongoing visual task negatively, testament to the balance between selective attention and change detection. Although deviance distraction has been the object of much research, its modulation across the life span has been more scarcely addressed. Recent findings suggest possible connections with working memory and response inhibition. In this study we measured the performance of children and young and older adults in a cross-modal oddball task (deviance distraction), a working memory task (working memory capacity), and a response inhibition task (ability to voluntarily inhibit an already planned action) with the aim to establish the contribution of the latter 2 to the first. Older adults exhibited significantly more deviance distraction than children and young adults (who did not differ from each other). Working memory capacity mediated deviance distraction in children and older adults (though in opposite directions) but not in young adults. Response inhibition capacities did not mediate deviance distraction in any of the age groups. Altogether the results suggest that although the increase in deviance distraction observed in old age may partly reflect the relative impairment of working memory mechanisms, there is no straightforward and stable relation between working memory capacity and deviance distraction across the life span. Furthermore, our results indicate that deviance distraction is unlikely to reflect the temporary inhibition of responses. (PsycINFO Database Record PMID- 27505695 TI - Emotional interactions in European American mother-infant firstborn and secondborn dyads: A within-family study. AB - The developmental science literature is riven with respect to (a) parental similar versus different treatment of siblings and (b) sibling similarities and differences. Most methodologies in the field are flawed or confounded. To address these issues, this study employed a within-family longitudinal design to examine developmental processes of continuity and stability in emotional interactions in mothers with their firstborn and secondborn 5-month-old infants (ns = 61 mothers and 122 infants). As independently rated by the Emotional Availability Scales, mothers' observed and coded behavioral expressions of sensitivity, structuring, nonintrusiveness, and nonhostility were consistent in group mean levels between firstborns and secondborns and (largely) between daughters and sons. Neither firstborns and secondborns, nor girls and boys, differed in their responsiveness or involvement of mother. However, mothers' emotional interactions with their firstborn and secondborn children were uncorrelated, as were firstborn and secondborn infants' interactions with their mother. These group-mean consistencies and individual-differences inconsistencies in emotional interactions are discussed in relation to the shared and nonshared lives of siblings in the same family. (PsycINFO Database Record PMID- 27505692 TI - The Enzymology of Organic Transformations: A Survey of Name Reactions in Biological Systems. AB - Chemical reactions that are named in honor of their true, or at least perceived, discoverers are known as "name reactions". This Review is a collection of biological representatives of named chemical reactions. Emphasis is placed on reaction types and catalytic mechanisms that showcase both the chemical diversity in natural product biosynthesis as well as the parallels with synthetic organic chemistry. An attempt has been made, whenever possible, to describe the enzymatic mechanisms of catalysis within the context of their synthetic counterparts and to discuss the mechanistic hypotheses for those reactions that are currently active areas of investigation. This Review has been categorized by reaction type, for example condensation, nucleophilic addition, reduction and oxidation, substitution, carboxylation, radical-mediated, and rearrangements, which are subdivided by name reactions. PMID- 27505696 TI - The development of adaptive decision making: Recognition-based inference in children and adolescents. AB - Judgments about objects in the world are often based on probabilistic information (or cues). A frugal judgment strategy that utilizes memory (i.e., the ability to discriminate between known and unknown objects) as a cue for inference is the recognition heuristic (RH). The usefulness of the RH depends on the structure of the environment, particularly the predictive power (validity) of recognition. Little is known about developmental differences in use of the RH. In this study, the authors examined (a) to what extent children and adolescents recruit the RH when making judgments, and (b) around what age adaptive use of the RH emerges. Primary schoolchildren (M = 9 years), younger adolescents (M = 12 years), and older adolescents (M = 17 years) made comparative judgments in task environments with either high or low recognition validity. Reliance on the RH was measured with a hierarchical multinomial model. Results indicated that primary schoolchildren already made systematic use of the RH. However, only older adolescents adaptively adjusted their strategy use between environments and were better able to discriminate between situations in which the RH led to correct versus incorrect inferences. These findings suggest that the use of simple heuristics does not progress unidirectionally across development but strongly depends on the task environment, in line with the perspective of ecological rationality. Moreover, adaptive heuristic inference seems to require experience and a developed base of domain knowledge. (PsycINFO Database Record PMID- 27505698 TI - Why do some adolescents encounter everyday events that increase their civic interest whereas others do not? AB - Using a longitudinal design, we asked 2 age cohorts of adolescents (15- and 18 year-olds) whether they, during the last year, had experienced events that had increased their civic interest and about details of their experiences. Based on self-determination theory, we predicted that the adolescents who reported having experienced events of this kind had already been more interested and had had more positive feelings about politics much earlier in time, and that this original interest would have increased more over time, than that of other adolescents. Second, we proposed that the adolescents who had encountered events that triggered their civic interest would have been engaged in behaviors that reflected their needs for autonomy, relatedness, and competence, much earlier in time, and that, over time, they would have increased these behaviors more than other adolescents. These 2 predictions were largely confirmed. As for the content of the events the adolescents reported, many of them concerned national and international issues experienced as threatening, and that challenged the adolescents' beliefs and morality. Overall, a previous interest in politics and engagement in exploratory behaviors that reflect the adolescents' psychological needs seem to play crucial roles in understanding why adolescents in their everyday life encounter events that trigger their civic interest. Further, the findings show that having had everyday experiences that trigger the adolescents' civic interests are associated with a later increase in political interest more broadly. (PsycINFO Database Record PMID- 27505697 TI - Little relation of adult age with cognition after controlling general influences. AB - Both general (i.e., shared across different cognitive measures) and specific (i.e., unique to particular cognitive measures) influences can be postulated to contribute to the relations between adult age and measures of cognitive functioning. Estimates of general and specific influences on measures of memory, speed, reasoning, and spatial visualization were derived in cross-sectional (N = 5,014) and 3-occasion longitudinal (N = 1,353) data in adults between 18 and 99 years of age. Increased age was negatively associated with estimates of general influences on cognitive functioning in both the cross-sectional differences and the longitudinal changes. Furthermore, after statistically controlling general influences, the relations of age on the cognitive measures were much smaller than were those in the original measures. Results from these and other analytical procedures converge on the conclusion that adult age appears to have weak relations with specific measures of cognitive functioning, defined as independent of influences shared across different types of cognitive measures, and that this is true in both cross-sectional and longitudinal comparisons. An implication of these findings is that general, as well as domain-specific, influences should be considered when attempting to explain the relations of age on cognitive functioning. (PsycINFO Database Record PMID- 27505699 TI - Generics license 30-month-olds' inferences about the atypical properties of novel kinds. AB - We examined whether the distinction between generic and nongeneric language provides toddlers with a rapid and efficient means to learn about kinds. In Experiment 1, we examined 30-month-olds' willingness to extend atypical properties to members of an unfamiliar category when the properties were introduced in 1 of 3 ways: (a) using a generic noun phrase ("Blicks drink ketchup"); (b) using a nongeneric noun phrase ("These blicks drink ketchup"); and (c) using an attentional phrase ("Look at this"). Hearing a generic noun phrase boosted toddlers' extension of properties to both the model exemplars and to novel members of the same category, relative to when a property had been introduced with a nongeneric noun phrase or an attentional phrase. In Experiment 2, properties were introduced with a generic noun phrase, and toddlers extended novel properties to members of the same-category, but not to an out-of-category object. Taken together, these findings demonstrate that generics highlight the stability of a feature and foster generalization of the property to novel within category exemplars. (PsycINFO Database Record PMID- 27505700 TI - Fadeout in an early mathematics intervention: Constraining content or preexisting differences? AB - A robust finding across research on early childhood educational interventions is that the treatment effect diminishes over time, with children not receiving the intervention eventually catching up to children who did. One popular explanation for fadeout of early mathematics interventions is that elementary school teachers may not teach the kind of advanced content that children are prepared for after receiving the intervention, so lower-achieving children in the control groups of early mathematics interventions catch up to the higher-achieving children in the treatment groups. An alternative explanation is that persistent individual differences in children's long-term mathematical development result more from relatively stable preexisting differences in their skills and environments than from the direct effects of previous knowledge on later knowledge. We tested these 2 hypotheses using data from an effective preschool mathematics intervention previously known to show a diminishing treatment effect over time. We compared the intervention group to a matched subset of the control group with a similar mean and variance of scores at the end of treatment. We then tested the relative contributions of factors that similarly constrain learning in children from treatment and control groups with the same level of posttreatment achievement and preexisting differences between these 2 groups to the fadeout of the treatment effect over time. We found approximately 72% of the fadeout effect to be attributable to preexisting differences between children in treatment and control groups with the same level of achievement at posttest. These differences were fully statistically attenuated by children's prior academic achievement. (PsycINFO Database Record PMID- 27505701 TI - Social engagement and adaptive functioning during early childhood: Identifying and distinguishing among subgroups differing with regard to social engagement. AB - This study tested the hypothesis that social engagement (SE) with peers is a fundamental aspect of social competence during early childhood. Relations between SE and a set of previously validated social competence indicators, as well as additional variables derived from observation and sociometric interviews were assessed using both variable-centered and person-centered approaches (N = 1453, 696 girls) in 4 samples (3 U.S.A., 1 Portuguese). Directly observed SE was positively associated with broad-band measures of socially competent behavior, peer acceptance, being a target of peers' attention, and also with broad-band personality dimensions. Using individual Q-items significantly associated with SE in 3 of our 4 samples, a hierarchical cluster analysis yielded a 5-cluster solution that grouped cases efficiently. Tests on relations between cluster membership and the set of social competence and other variables revealed significant main effects of cluster membership in the full sample and within each individual sample, separately. With the exception of tests for peer negative preference, children in the lowest SE cluster also had significantly lower overall social competence, personality functioning scores than did children in higher SE clusters. (PsycINFO Database Record PMID- 27505702 TI - Maternal scaffolding and home stimulation: Key mediators of early intervention effects on children's cognitive development. AB - This study contributes to the understanding of how early parenting interventions implemented in low- and middle-income countries during the first 2 years of children's lives are sustained longitudinally to promote cognitive skills in preschoolers. We employed path analytic procedures to examine 2 family processes the quality of home stimulation and maternal scaffolding behaviors-as underlying mechanisms through which a responsive stimulation intervention uniquely predicted children's verbal intelligence, performance intelligence, and executive functioning. The sample included 1,302 highly disadvantaged children and their mothers living in rural Pakistan, who from birth participated in a 2-year, community-based, cluster-randomized, controlled trial designed to promote sensitive and responsive caregiving. Family processes were assessed at 2 developmental time points using parent reports, ratings of home environments, and observed parent-child interactions. Cognitive skills at age 4 were assessed using standardized tests. Controlling for socioeconomic risk (e.g., wealth, maternal education, food insecurity) and individual factors (e.g., gender, growth status), the quality of current home stimulation as well as both earlier and concurrent measures of maternal scaffolding independently mediated the intervention effects on cognitive skills at age 4. In addition, the intervention had a significant direct effect on executive functioning and performance intelligence over and above significant family processes and other covariates. We highlight implications for future program design and evaluation studies. (PsycINFO Database Record PMID- 27505703 TI - The Academy of Breastfeeding Medicine's Communications Committee. PMID- 27505704 TI - Multimodality Imaging of Neurodegenerative Processes: Part 1, The Basics and Common Dementias. AB - OBJECTIVE: Multimodality imaging plays an important role in the structural and functional characterization of neurodegenerative conditions. This article illustrates the basic concepts of anatomic, metabolic, and amyloid imaging and describes the application of a multimodality approach in the evaluation of patients with the more common neurodegenerative dementia processes. Proper utilization of clinically available imaging techniques allows greater insight into these common disease processes. CONCLUSION: Recognizing the strength of combined anatomic, metabolic, and amyloid imaging can allow a more complete and confident assessment of patients with common degenerative dementias. This added knowledge can improve clinical care, allow initiation of appropriate therapies and counseling, and improve prognostication. PMID- 27505705 TI - Phase I study of azacitidine following donor lymphocyte infusion for relapsed acute myeloid leukemia post allogeneic stem cell transplantation. AB - Donor lymphocyte infusion (DLI) without prophylactic immunosuppression has been used for relapsed AML after allogeneic stem cell transplant (allo-SCT). However DLI is associated with an increased incidence of acute Graft vs. Host Disease (aGVHD). In mice, administration of azacitidine (AzaC) on days 4, 6, 8, and 10 post DLI increases regulatory T cell (Treg) numbers and prevents GVHD without hindering Graft vs. Leukemia (GVL). Based on these findings, we conducted a phase 1 study of AzaC post DLI for AML relapse post allo-SCT. AzaC was administered on days 4, 6, 8 and 10 post-DLI. Dose escalation was done using a 3+3 design with three AzaC dose levels: 30mg/m(2) (level -1), 45mg/m(2) (level 1) and 75mg/m(2) (level 2). Three patients were treated in the 45mg/m(2) dose level and 5 patients were treated in the 75mg/m(2) dose level; no DLTs or grade 3-5 treatment related toxicities were observed. After a median follow-up of 5.2 months, no patients developed grade III-IV aGVHD and no patients died of aGVHD. Six out of 8 patients in the treatment group responded to treatment including two cytogenetic complete remissions, one hematologic complete remission, and three complete remissions with incomplete count recovery. In conclusion, administration of AzaC early post DLI is well tolerated and can potentially prevent GVHD after DLI. Further studies are required to evaluate the effect of azacitidine early post DLI on GVHD and GVL. PMID- 27505706 TI - The etemic model of Gypsy Roma Traveller community vulnerability: is it time to rethink our understanding of vulnerability? AB - AIMS AND OBJECTIVES: To present a new etemic model of vulnerability. BACKGROUND: Despite vulnerability being identified as a core consequence of health and health experiences, there has been little research exploring the meaning of vulnerability as a concept. Yet, being vulnerable is known to have dire physical/mental health consequences. It is therefore a fundamental issue for nurses to address. To date, the meaning of the term vulnerability has been influenced by the work of Spiers (Journal of Advanced Nursing, 31, 2000, 715, The Essential Concepts of Nursing: Building Blocks for Practice, 2005, Elsevier, London). Spiers identified two aspects of vulnerability: the etic (external judgment of another persons' vulnerability) and the emic (internal lived experience of vulnerability). This approach has led to a plethora of research which has explored the etic (external judgment) of vulnerability and rendered the internal lived (or emic) experience invisible. Consequences of this, for marginalised communities such as Gypsy Roma Travellers include a lack of culturally sensitive services compounding health inequalities. DESIGN: Position paper. METHOD: Drawing upon a qualitative phenomenological research study exploring the lived experience of vulnerability from a Gypsy Roma Travelling community (published previously), this paper presents a new model of vulnerability. This etemic model of vulnerability values both external and internal dimensions of vulnerability and argues for a fusion of these two opposing perspectives. CONCLUSIONS: If nurses and other health- and social care professionals wish to develop practice that is successful in engaging with Gypsy Roma Travellers, then there is a need to both understand and respect their community. This can be achieved through an etemic approach to understanding their vulnerability achieved by eliciting lived experience alongside the appreciation of epidemiological studies. RELEVANCE TO CLINICAL PRACTICE: If nurses and health practitioners used this etemic approach to practice then it would enable both the development and delivery of culturally sensitive services facilitating health access to this community. Only then, will their poor health status be successfully addressed. PMID- 27505707 TI - Structure Determination of an Ag(I) -Mediated Cytosine-Cytosine Base Pair within DNA Duplex in Solution with (1) H/(15) N/(109) Ag NMR Spectroscopy. AB - The structure of an Ag(I) -mediated cytosine-cytosine base pair, C-Ag(I) -C, was determined with NMR spectroscopy in solution. The observation of 1-bond (15) N (109) Ag J-coupling ((1) J((15) N,(109) Ag): 83 and 84 Hz) recorded within the C Ag(I) -C base pair evidenced the N3-Ag(I) -N3 linkage in C-Ag(I) -C. The triplet resonances of the N4 atoms in C-Ag(I) -C demonstrated that each exocyclic N4 atom exists as an amino group (-NH2 ), and any isomerization and/or N4-Ag(I) bonding can be excluded. The 3D structure of Ag(I) -DNA complex determined with NOEs was classified as a B-form conformation with a notable propeller twist of C-Ag(I) -C (-18.3+/-3.0 degrees ). The (109) Ag NMR chemical shift of C-Ag(I) -C was recorded for cytidine/Ag(I) complex (delta((109) Ag): 442 ppm) to completed full NMR characterization of the metal linkage. The structural interpretation of NMR data with quantum mechanical calculations corroborated the structure of the C Ag(I) -C base pair. PMID- 27505708 TI - Core 2 beta1,6-N-acetylglucosaminyltransferase-I, crucial for P-selectin ligand expression is controlled by a distal enhancer regulated by STAT4 and T-bet in CD4+ T helper cells 1. AB - P-selectin ligands (P-ligs) support the recruitment of lymphocytes into inflamed tissues. Binding to P-selectin is mediated by oligosaccharide groups synthesized by means of several glycosyltransferases including core 2 beta1,6-N acetylglucosaminyltransferase-I (C2GlcNAcT-I), encoded by the gene Gcnt1. Using Gcnt1(-/-) Th1 cells, we show that C2GlcNAcT-I is crucial for inflammatory T cell homing in vivo. To understand the molecular regulation of Gcnt1 in CD4(+) T helper cells, we performed ChIP-on-chip experiments across the Gcnt1 locus assessing the chromatin structure in P-lig-expressing versus non-expressing CD4(+) T cells. This identified a distal region about 20kb upstream of the promoter where the presence of a H3K27me3 mark correlated with Gcnt1 repression. This region possessed IL-12-dependent enhancer activity in reporter assays, in accordance with preferential IL-12-dependent induction of Gcnt1 in vitro. STAT4 and T-bet cooperated in control of the enhancer activity. Deficiency in either one resulted in drastically reduced Gcnt1 mRNA expression in differentiated Th1 cells. While both STAT4 and T-bet were bound to the enhancer early after activation only T-bet binding persisted throughout the expansion phase after TCR signal cessation. This suggests sequential action of STAT4 and T-bet at the enhancer. In summary, we show that Gcnt1 transcription and subsequent P-lig induction in Th1 cells is governed by binding of STAT4 and T-bet to a distal enhancer and further regulated by epigenetic marks such as H3K27me3. PMID- 27505709 TI - Generation and characterization of human B lymphocyte stimulator blocking monoclonal antibody. AB - The cytokine, B lymphocyte stimulator (Blys) is essential for activation and proliferation of B cells and is involved in the pathogenesis of B-cell mediated autoimmune diseases. Based on its essential activity, Blys may be a potential therapeutic target for human autoimmune diseases. In this article, we have described the development of a novel humanized anti-Blys antibody, NMB04, that binds with high affinity and specificity to both soluble and membrane bound Blys. This monoclonal antibody has the potential to block Blys binding to all its three receptors, TACI, BCMA and BR-3. Further in vivo studies revealed that NMB04 possessed more potent inhibitory activity against human Blys as compared to an existing antibody, Belimumab. Therefore, NMB04 may have potential as a therapeutic candidate targeting autoimmune diseases. PMID- 27505710 TI - SIRT1 inhibits inflammatory response partly through regulation of NLRP3 inflammasome in vascular endothelial cells. AB - Emerging evidence has indicated that vascular endothelial cells (ECs) not only form the barrier between blood and the vessel wall but also serve as conditional innate immune cells. Our previous study found that SIRT1, a class III histone deacetylase, inhibits the inflammatory response in ECs. Recent studies revealed that SIRT1 also participates in the modulation of immune responses. Although the NLRP3 inflammasome is known to be a crucial component of the innate immune system, there is no direct evidence demonstrating the anti-inflammatory effect of SIRT1 on ECs through the NLRP3 inflammasome. In this study, we observed that lipopolysaccharide (LPS) and adenosine triphosphate (ATP) triggered the activation of NLRP3 inflammasome in human umbilical vein ECs (HUVECs). Moreover, SIRT1 expression was reduced in HUVECs stimulated with LPS and ATP. SIRT1 activator inhibited the expression of monocyte chemotactic protein-1 (MCP-1) and C-reactive protein (CRP), whereas SIRT1 knockdown resulted in significant increases in MCP-1 and CRP levels in HUVECs stimulated with LPS and ATP. Importantly, the lack of SIRT1 enhanced NLRP3 inflammasome activation and subsequent caspase-1 cleavage. On the other hand, NLRP3 siRNA blocked the activation of the NLRP3 inflammasome in HUVECs stimulated with LPS plus ATP. Further study revealed that NLRP3 inflammasome blockade significantly reduced MCP 1 and CRP production in HUVECs. In vivo studies indicated that implantation of the periarterial carotid collar inhibited arterial SIRT1 expression in rabbits. Meanwhile, treatment with a SIRT1 activator decreased the expression levels of MCP-1 and CRP in collared arteries and the interleukin (IL)-1beta level in serum. Taken together, these findings indicate that NLRP3 inflammasome activation promoted endothelial inflammation and that SIRT1 inhibits the inflammatory response partly through regulation of the NLRP3 inflammasome in ECs. PMID- 27505711 TI - Aire knockdown in medullary thymic epithelial cells affects Aire protein, deregulates cell adhesion genes and decreases thymocyte interaction. AB - We demonstrate that even a partial reduction of Aire mRNA levels by siRNA-induced Aire knockdown (Aire KD) has important consequences to medullary thymic epithelial cells (mTECs). Aire knockdown is sufficient to reduce Aire protein levels, impair its nuclear location, and cause an imbalance in large-scale gene expression, including genes that encode cell adhesion molecules. These genes drew our attention because adhesion molecules are implicated in the process of mTEC thymocyte adhesion, which is critical for T cell development and the establishment of central self-tolerance. Accordingly, we consider the following: 1) mTECs contribute to the elimination of self-reactive thymocytes through adhesion; 2) Adhesion molecules play a crucial role during physical contact between these cells; and 3) Aire is an important transcriptional regulator in mTECs. However, its role in controlling mTEC-thymocyte adhesion remains unclear. Because Aire controls adhesion molecule genes, we hypothesized that the disruption of its expression could influence mTEC-thymocyte interaction. To test this hypothesis, we used a murine Aire(+) mTEC cell line as a model system to reproduce mTEC-thymocyte adhesion in vitro. Transcriptome analysis of the mTEC cell line revealed that Aire KD led to the down-modulation of more than 800 genes, including those encoding for proteins involved in cell adhesion, i.e., the extracellular matrix constituent Lama1, the CAM family adhesion molecules Vcam1 and Icam4, and those that encode peripheral tissue antigens. Thymocytes co cultured with Aire KD mTECs had a significantly reduced capacity to adhere to these cells. This finding is the first direct evidence that Aire also plays a role in controlling mTEC-thymocyte adhesion. PMID- 27505712 TI - A Lamellar Coordination Polymer with Remarkable Catalytic Activity. AB - A positively charged lamellar coordination polymer based on a flexible triphosphonic acid linker is reported. [Gd(H4 nmp)(H2 O)2 ]Cl?2 H2 O (1) [H6 nmp=nitrilotris(methylenephosphonic acid)] was obtained by a one-pot approach by using water as a green solvent and by forcing the inclusion of additional acid sites by employing HCl in the synthesis. Compound 1 acts as a versatile heterogeneous acid catalyst with outstanding activity in organic reactions such as alcoholysis of styrene oxide, acetalization of benzaldehyde and cyclohexanaldehyde and ketalization of cyclohexanone. For all reaction systems, very high conversions were reached (92-97 %) in only 15-30 min under mild conditions (35 degrees C, atmospheric pressure). The coordination polymer exhibits a protonic conductivity of 1.23*10(-5) S cm(-1) at 98 % relative humidity and 40 degrees C. PMID- 27505713 TI - Flat metallic surface gratings with sub-10 nm gaps controlled by atomic-layer deposition. AB - Atomic layer lithography is a recently reported new technology to fabricate deep subwavelength features down to 1-2 nm, based on combinations of electron beam lithography (EBL) and atomic layer deposition (ALD). However, the patterning area is relatively small as limited by EBL, and the fabrication yield is not very high due to technical challenges. Here we report an improved procedure to fabricate flat metallic surfaces with sub-10 nm features based on ALD processes. To demonstrate the scalability of the new manufacturing method, we combine the ALD process with large area optical interference patterning, which is particularly promising for the development of practical applications for nanoelectronics and nanophotonics with extremely strong confinement of electromagnetic fields. PMID- 27505714 TI - Catalytic Fehling's Reaction: An Efficient Aerobic Oxidation of Aldehyde Catalyzed by Copper in Water. AB - The first example of homogeneous copper-catalyzed aerobic oxidation of aldehydes is reported. This method utilizes atmospheric oxygen as the sole oxidant, proceeds under extremely mild aqueous conditions, and covers a wide range of various functionalized aldehydes. Chromatography is generally not necessary for product purification. PMID- 27505715 TI - Enterovirus D68 in Critically Ill Children: A Comparison With Pandemic H1N1 Influenza. AB - OBJECTIVE: In 2014, the Unites States experienced an outbreak of enterovirus D68 associated with severe respiratory illness. The clinical characteristics associated with severe illness from enterovirus D68 during this outbreak compared with those associated with the 2009 H1N1 influenza virus outbreak are unknown. DESIGN AND SETTING: In this retrospective cohort study, we characterized the clinical features of children with enterovirus D68 admitted to the PICU between August 1, 2014, and November 1, 2014, and compared them with critically ill children infected with H1N1 influenza during the pandemic admitted between May 1, 2009, and January 31, 2010. PATIENTS: PICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ninety-seven severely ill children with enterovirus D68 infections were compared with 68 children infected with H1N1 influenza during the 2009 pandemic. Children with enterovirus D68 were more likely to have asthma (62% vs 23%; p < 0.001) and present with reactive airway disease exacerbations, with greater receipt of albuterol (94% vs 49%) and steroids (89% vs 40%; p < 0.0001 for both). Although more children with enterovirus D68 were admitted to the ICU compared with those with H1N1 influenza, they had a shorter hospital length of stay (4 vs 7 d; p < 0.0001), with lower intubation rates (7% vs 44%), vasopressor use (3% vs 32%), acute respiratory distress syndrome (3% vs 24%), shock (0% vs 16%), and death (0% vs 12%; p < 0.05 for all). Compared with children with other enteroviruses and rhinoviruses, children with enterovirus D68 were more likely to have a history of asthma (64% vs 45%) or multiple prior wheezing episodes (54% vs 34%; p < 0.01 for both). CONCLUSIONS: Critically ill children with enterovirus D68 were more likely to present with reactive airway disease exacerbations, whereas children with H1N1 influenza were more likely to present with pneumonia. Compared with the pandemic H1N1 influenza outbreak, the enterovirus D68 outbreak resulted in more children requiring admission to the ICU, but was associated with less severe outcomes. PMID- 27505716 TI - Procedural Sedation Outside of the Operating Room Using Ketamine in 22,645 Children: A Report From the Pediatric Sedation Research Consortium. AB - OBJECTIVE: Most studies of ketamine administered to children for procedural sedation are limited to emergency department use. The objective of this study was to describe the practice of ketamine procedural sedation outside of the operating room and identify risk factors for adverse events. DESIGN: Observational cohort review of data prospectively collected from 2007 to 2015 from the multicenter Pediatric Sedation Research Consortium. SETTING: Sedation services from academic, community, free-standing children's hospitals and pediatric wards within general hospitals. PATIENTS: Children from birth to 21 years old or younger. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Describe patient characteristics, procedure type, and location of administration of ketamine procedural sedation. Analyze sedation-related adverse events and severe adverse events. Identify risk factors for adverse events using multivariable logistic regression. A total of 22,645 sedations performed using ketamine were analyzed. Median age was 60 months (range, < 1 mo to < 22 yr); 72.0% were American Society of Anesthesiologists-Physical Status less than III. The majority of sedations were performed in dedicated sedation or radiology units (64.6%). Anticholinergics, benzodiazepines, or propofol were coadministered in 19.8%, 57.9%, and 35.4%, respectively. The overall adverse event occurrence rate was 7.26% (95% CI, 6.92-7.60%), and the frequency of severe adverse events was 1.77% (95% CI, 1.60-1.94%). Procedures were not completed in 39 of 19,747 patients (0.2%). Three patients experienced cardiac arrest without death, all associated with laryngospasm. CONCLUSIONS: This is a description of a large prospectively collected dataset of pediatric ketamine administration predominantly outside of the operating room. The overall incidence of severe adverse events was low. Risk factors associated with increased odds of adverse events were as follows: cardiac and gastrointestinal disease, lower respiratory tract infection, and the coadministration of propofol and anticholinergics. PMID- 27505717 TI - Frequency, Composition, and Predictors of In-Transit Critical Events During Pediatric Critical Care Transport. AB - OBJECTIVES: Transport of pediatric patients is common due to healthcare regionalization. We set out to determine the frequency of in-transit critical events during pediatric critical care transport and identify factors associated with these events. DESIGN: Retrospective cohort study using administrative and clinical data. SETTING: Single pediatric critical care transport provider in Ontario, Canada. PATIENTS: All pediatric care transports between January 1, 2005, and December 31, 2010. MEASUREMENTS AND MAIN RESULTS: The primary outcome was in transit critical events, defined by an adaptation of a recent consensus definition. In-transit critical events occurred in 1,094 (12.3%) of 8,889 transports. Hypotension (3.6%), tachycardia (3.7%), and bradycardia (3.3%) were the most common critical events. Crews performed medical interventions in 194 transports (2.2%). The frequency and makeup of critical events varied across patient age groups. Age, pretransport mechanical ventilation, pretransport cardiovascular instability, transport duration, scene calls, and paramedic crew level were independently associated with increased risk of in-transit critical events in multivariate analysis. A Transport Pediatric Early Warning Score of 7 or greater predicted in-transit critical events with high specificity but low sensitivity (92.0% and 20.0%, respectively), but was not superior of the combination of pretransport mechanical ventilation and pretransport cardiovascular instability (sensitivity and specificity of 12.6% and 97.4%, respectively). Removal of early warning signs from the definition resulted in critical event rates comparable to those published in adults and improved predictive performance. CONCLUSIONS: Using new consensus definitions of transport related critical events, we found critical events occurred in almost one in eight transports, and were strongly associated with pretransport cardiovascular instability. Transport Pediatric Early Warning Score was poorly predictive of in transit critical events, and was not superior to the presence of pretransport mechanical ventilation and cardiovascular instability. Future prospective studies are required to elucidate the optimal matching of transport resources to patients, in particular those with both pretransport cardiovascular instability and mechanical ventilation. PMID- 27505718 TI - Concurrent decrease of brain white matter tracts' thicknesses and fractional anisotropy after antenatal hypoxia-ischemia detected with tract-based spatial statistics analysis. AB - PURPOSE: To examine the extent of gray and white matter (WM) injury following global antenatal hypoxia-ischemia (H-I) and resulting in muscle hypertonia in newborns in a rabbit cerebral palsy model. MATERIALS AND METHODS: Rabbit dams (n = 15) underwent uterine ischemia procedure resulting in a global fetal H-I at embryonic day 22 (embryonic 22 days gestation). Newborn's brains underwent high resolution diffusion tensor imaging on a 14 Tesla magnet ex vivo. Fractional anisotropy (FA) in brains of hypertonic (n = 9), nonhypertonic (n = 6), and sham control (n = 5) kits were compared voxel-wise using Tract-Based Spatial Statistics (TBSS) approach. Herein, we used a novel method to assess local WM tracts' thicknesses in TBSS analysis and compare between the groups. RESULTS: Significant (corrected P < 0.05) reduction of WM FA was found in corpus callosum splenium (91.2%), periventricular WM (83.5%), fimbria hippocampi (78.8%), cingulum (81.4%), anterior commissure (95%), internal capsule (83.2%), and optic tract (82.9%) in the hypertonic group. Significant (corrected P < 0.05) reduction in WM tracts' thicknesses was found in corpus callosum (73.3%), periventricular WM (82.5%), cingulum (73.4%), bilaterally in the hypertonic group. CONCLUSION: WM injury in newborn hypertonic kits 10 days after global fetal H-I is widespread and involves not only motor but also limbic and commissural fibers in multiple regions. WM injury in newborn hypertonic kits is manifested by changes in microstructural properties and decreased FA, as well as reduction of WM volumes, relative to nonhypertonic kits. J. Magn. Reson. Imaging 2017;45:700-709. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:829-838. PMID- 27505719 TI - Postpartum hypoglycaemia is common in the immediate postpartum period in Type 1 diabetes. PMID- 27505720 TI - Andrographolide recovers cognitive impairment in a natural model of Alzheimer's disease (Octodon degus). AB - The social species Octodon degus (degu) is the only wild-type South American rodent that develops Alzheimer's-like pathology with age. Here, we evaluated the ability of a natural product (Andrographolide, ANDRO), a diterpene of the labdane family obtained from the Asian plant Andrographis paniculata, to recover the cognitive decline in this long-lived animal model. We administered ANDRO to aged degus (56-month old) for 3 months. In addition, in 2 control groups (young degus: 12-month old and aged degus: 56-month old), we administrated saline solution as a vehicle. We evaluated cognitive performance through several behavioral tests. We also performed a series of physiological and biochemical analyses (e.g., electrophysiological and immunoblotting assessment) to identify possible mechanisms underlying cognitive performance associated with age. Our results suggest that there is an effect of aging on the loss of cognitive function, and this decrease in cognitive function was also related to a decrease in the synaptic functions and an increase in the main hallmarks of Alzheimer's disease (AD). More importantly, ANDRO treatments showed the following beneficial effects: (1) recovery of spatial memory and learning performance; (2) recovery of synaptic basal transmission; (3) partial or complete protection of certain synaptic proteins; and (4) a specific neuroprotective effect, including the reduction of phosphorylated tau protein and amyloid beta aggregate maturation in aged degus. Taken together, our results suggest that ANDRO could be used as a potential therapy for AD and support the use of O. degus as a natural model in which to study both neural damage associated with aging processes and the behavioral and neuropathological hallmarks of aging-related diseases such as AD. PMID- 27505721 TI - FGF21 Is Not a Major Mediator for Bone Homeostasis or Metabolic Actions of PPARalpha and PPARgamma Agonists. AB - Results of prior studies suggest that fibroblast growth factor 21 (FGF21) may be involved in bone turnover and in the actions of peroxisome proliferator-activated receptor (PPAR) alpha and gamma in mice. We have conducted independent studies to examine the effects of FGF21 on bone homeostasis and the role of FGF21 in PPARalpha and gamma actions. High-fat-diet-induced obesity (DIO) mice were administered vehicle or recombinant human FGF21 (rhFGF21) intraperitoneally at 0 (vehicle), 0.1, 1, and 3 mg/kg daily for 2 weeks. Additional groups of DIO mice received water or 10 mg/kg rosiglitazone daily. Mice treated with rhFGF21 or rosiglitazone showed expected metabolic improvements in glucose, insulin, and lipid levels. However, bone loss was not detected in rhFGF21-treated mice by dual energy X-ray absorptiometry (DXA), micro-CT, and histomorphometric analyses. Mineral apposition rate, a key bone formation parameter, was unchanged by rhFGF21, while significantly decreased by rosiglitazone in DIO mice. Bone resorption markers, OPG/RANKL mRNA expression, and histological bone resorption indices were unchanged by rhFGF21 or rosiglitazone. Bone marrow fat was unchanged by rhFGF21, while increased by rosiglitazone. Furthermore, FGF21 knockout mice did not show high bone mass phenotype. Treatment with PPARalpha or PPARgamma agonists caused similar metabolic effects in FGF21 knockout and wild-type mice. These results contrast with previous findings and suggest that FGF21 is not critical for bone homeostasis or actions of PPARalpha and PPARgamma. (c) 2016 American Society for Bone and Mineral Research. PMID- 27505723 TI - Evaluating the Biological and Ecological Factors Influencing Transmission of Larval Digenetic Trematodes: A Test of Second Intermediate Host Specificity of Two North American Halipegus Species. AB - Host specificity of parasites is a basic principle in parasitology; however, it is not easily measured. Previously, host specificity was calculated as the number of species that a parasite infected, but this is not an accurate description of host usage because some species are capable of being infected but do not contribute to the completion of the life cycle. Instead, measures of host specificity should take into consideration interactions between a parasite and a potential host species as well as interactions between current and subsequent hosts in the life cycle. The objectives of this study were to track the development of 2 trematode species, Halipegus eccentricus and Halipegus occidualis , in 3 phylogenetically and ecologically distinct microcrustacean second intermediate hosts, and then evaluate the extent to which each of these hosts contributed to transmission of each Halipegus species to the next odonate host in the life cycle. All 3 microcrustacean species exposed became infected with both species of Halipegus. The patterns of growth of H. eccentricus and H. occidualis were similar, but there were consistent differences in the rates of growth among the microcrustacean species in both Halipegus species. Regardless of host species infected, all individuals of both species were considered to be developmentally infective to the next host in the life cycle by 19 days postexposure (DPE) when they lost their excretory bladder. Worms of varying sizes were capable of surviving without this structure, suggesting that there is not a strong relationship between the rate of growth of the metacercariae and the development of their osmoregulatory system. Although Halipegus species were capable of living without an excretory bladder at 19 DPE, there were differences in their size and rates at which the 3 microcrustaceans contributed to transmission of the parasites to subsequent odonate hosts. Collectively, under controlled laboratory conditions, there was an approximate 2-fold difference in the average percentage of worms that established in odonates from the ostracod, Cypridopsis sp., than from the harpacticoid copepod, Phyllognathopus sp., and the difference was nearly 3-fold between Cypridopsis sp. and the cyclopoid copepod, Thermocyclops sp. Therefore, despite all 3 microcrustacean species becoming infected, not all species were equally suited for transmission and completion of the life cycle. Differences among the 3 microcrustacean species in cercaria ingestion, metacercarial growth and development, and odonate predation rates on infected microcrustacean species were important factors in determining transmission of the 2 Halipegus species to odonate hosts. PMID- 27505724 TI - Diagnostic accuracy of Japanese posttraumatic stress measures after a complex disaster: The Fukushima Health Management Survey. AB - BACKGROUND: The Posttraumatic Stress Disorder (PTSD) Checklist (PCL) has been widely used among traumatized populations to screen people with PTSD; however, the Japanese version of the PCL has yet to be validated. We examined the diagnostic accuracy of the Japanese version PCL-Specific (PCL-S) and the abbreviated versions of the PCL-S among the evacuees of the Fukushima Daiichi Nuclear Power Plant accident. METHODS: Fifty-one participants were recruited from an evacuee and clinical sample. The PCL-S, Impact of Event Scale-Revised (IES-R), and World Health Organization Composite International Diagnostic Interview were administered. Screening properties of the PCL-S, IES-R, and abbreviated PCL-S against PTSD diagnosis, including sensitivity, specificity, and diagnostic efficiency, were calculated. Receiver operating characteristic curves were drawn, and optimal cutoff points were examined. RESULTS: The sensitivity, specificity, and diagnostic efficiency of the PCL-S were 66.7%, 84.9%, and 79.2%, respectively (at 52, the area under the curve was 0.83). The cutoff point method for the PCL-S performed better than did the symptom cluster method. The screening properties of the abbreviated versions were comparable with those of the full version. CONCLUSIONS: The Japanese version of the PCL-S showed moderate diagnostic accuracy and improved performance over the IES-R for PTSD diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. The Japanese version of the PCL-S was a reliable and valid measure, and its diagnostic accuracy was reasonable for both full and abbreviated versions. PMID- 27505725 TI - Boosted photocatalytic efficiency through plasmonic field confinement with bowtie and diabolo nanostructures under LED irradiation. AB - Photoresist and electron beam lithography techniques were used to fabricate embedded Ag bowtie and diabolo nanostructures with various apex angles on the surface of a TiO2 film. The reinforced localized surface plasmon resonance (LSPR) and electric field generated at both the Ag/TiO2 and air/TiO2 interfaces enabled high light absorbance in the TiO2 nanostructure. Results for both the bowtie and diabolo nanostructures showed that a reduction in the apex angle enhances both LSPR and Raman intensity. The maximum electric current density observed at the apex indicates that the strongest SPR confines at the tip gap of the bowtie and corners of the diabolo. In a long-wavelength region, as the apex angle increases, the resonant peak wavelength of the standing wave matches the increased length of the prism edges of the bowtie and diabolo to create a redshift. In a short wavelength region, as the apex angle increases, the blueshift of the resonant peak wavelength is presumably attributable to the increase in the effective index of the local surface plasmon polariton standing wave mainly residing along both the bowtie and diabolo axes. The redshift and blueshift trend in the simulation results for the resonant peak wavelength agrees well with the experimental results. The fastest photocatalytic rate was obtained by placing the Ag/TiO2 bowtie at an apex angle of 30 degrees in the methylene blue solution, revealing that the plasmonic photocatalysis causes the highest degradation efficiency. This is because the Schottky junction and LSPR can stimulate many valid radicals for the environmental improvement. PMID- 27505726 TI - Manganese-doped near-infrared emitting nanocrystals for in vivo biomedical imaging. AB - Nanoprobes with multiple imaging modality have attracted a great deal of attention due to the capability of offering complementary information from each individual component. This work presents a hybrid approach to synthesize manganese doped near infrared (NIR) emitting quantum dots. The Mn-doping process was accomplished in aqueous phase followed by a phase transfer to organic phase for ZnS coating. This bimodal nanoprobe displayed high NIR luminescence quantum yield (~14%) and capability of magnetic resonance imaging (MRI) (1.44 mM 1 s-1). The RGD-targeted nanoprobes have been exploited for in vitro cell labelling, in vivo tumor targeting and lymph node mapping. In addition, no adverse toxic effects were observed, demonstrating the high biocompatibility of this nanoprobe. PMID- 27505727 TI - Tensile-strained Ge/SiGe quantum-well photodetectors on silicon substrates with extended infrared response. AB - We report on tensile-strained Ge/Si0.11Ge0.89 quantum-well (QW) metal-semiconductor-metal (MSM) photodetectors on Si substrates. A tensile strain of 0.21% is introduced into the Ge wells by growing the QW stack on in situ annealed Ge-on-Si virtual substrates (VS). The optical characterization of Ge/Si0.11Ge0.89 QW MSM photodetectors indicates that the optical response increases to a wavelength of 1.5 MUm or higher owing to the strain-induced direct bandgap shrinkage. Analysis of the band structure by using a k . p model suggests that by optimizing the tensile strain and Ge well width, tensile-strained Ge/SiGe QW photodetectors can be designed to cover the telecommunication C-band and beyond for optical telecommunications and on-chip interconnection. PMID- 27505728 TI - Ultrafast pump-probe ellipsometry setup for the measurement of transient optical properties during laser ablation. AB - Ultrashort pulsed lasers offer a high potential in precise and efficient material processing and deep understanding of the fundamental laser-material interaction aspects is of great importance. The transient pulse reflectivity in conjunction with the transient absorption influences decisively the laser-material interaction. Direct measurements of the absorption properties by ultrafast time resolved ellipsometry are missing to date. In this work, a unique pump-probe ellipsometry microscope is presented allowing the determination of the transient complex refractive index with a sub-ps temporal resolution. Measurements on molybdenum show ultrafast optical penetration depth changes of -6% to + 77% already within the first 10 ps after the laser pulse impact. This indicates a significant absorption variation of the pump pulse or subsequent pulses irradiating the sample on this timescale and paves the road towards a better understanding of pulse duration dependent laser ablation efficiency, double or burst mode laser ablation and lattice modifications in the first ps after the laser pulse impact. PMID- 27505729 TI - Electrically controllable plasmonic enhanced coherent random lasing from dye doped nematic liquid crystals containing Au nanoparticles. AB - An electrically controllable plasmonic enhanced coherent random lasing from the dye-doped nematic liquid crystal containing Au nanoparticles is demonstrated. To achieve the optimal control of the RL properties, the polarization of the pump light should be parallel to the rubbing direction of the cells. The lasing output intensity is direction-dependent and the substantial output distributes in an angle range of 0 degrees ~30 degrees deviating from the direction of the pump stripe. The coherent feedback associated with the coherent random lasing mainly originates from the cooperative effect of the enhanced localized electric field in the vicinity of Au nanoparticles and the multiple scattering caused by the fluctuations of the liquid crystal director and local dielectric tensor. PMID- 27505730 TI - Acentric langanite La3Ga5.5Nb0.5O14 crystal: a new nonlinear crystal for the generation of mid-infrared parametric light. AB - The mid-infrared spectral range extending from 2 to 6 MUm is significant for scientific and technological applications. A promising nonlinear oxide crystal La3Ga5.5Nb0.5O14 (LGN) is proposed and fully characterized for the first time to our knowledge. The transparency range extends between 0.28 and 7.4 MUm. The two principal refractive indices were measured and we found that the nonlinear coefficient d11 = 3.0 +/- 0.1 pm/V at 0.532 MUm. The simultaneous fit of data allowed us to refine the Sellmeier equations of LGN and to calculate the tuning curves for optical parametric generation (OPG) pumped at 1.064 MUm. Calculations are consistent with recorded data and also show the generation of a supercontinuum between 1.5 and 3.5 MUm when pumped at 0.98 MUm by a Ti:Sapphire laser. PMID- 27505731 TI - Laser damage mechanisms in conductive widegap semiconductor films. AB - Laser damage mechanisms of two conductive wide-bandgap semiconductor films - indium tin oxide (ITO) and silicon doped GaN (Si:GaN) were studied via microscopy, spectroscopy, photoluminescence (PL), and elemental analysis. Nanosecond laser pulse exposures with a laser photon energy (1.03 eV, 1064 nm) smaller than the conductive films bandgaps were applied and radically different film damage morphologies were produced. The laser damaged ITO film exhibited deterministic features of thermal degradation. In contrast, laser damage in the Si:GaN film resulted in highly localized eruptions originating at interfaces. For ITO, thermally driven damage was related to free carrier absorption and, for GaN, carbon complexes were proposed as potential damage precursors or markers. PMID- 27505732 TI - Magneto-optical Q-switching using magnetic garnet film with micromagnetic domains. AB - High-power giant pulses can be used applied in various applications with Q switched micro-lasers. This method can shorten the pulse duration; however, active control is currently impossible in micro-lasers. To achieve precise pulse control while maintaining compactness and simplicity, we exploit the magneto optical effect in magnetic garnet films with micromagnetic domains that can be actively controlled by a pulsed magnetic field. Our Q-switching technique enhances the output power by a factor of 4 * 103. Moreover, the device itself is smaller than other Q-switching devices. This novel type of active Q switch can be combined with a micro-laser to obtain megawatt-order pulses. PMID- 27505733 TI - Large area compatible broadband superabsorber surfaces in the VIS-NIR spectrum utilizing metal-insulator-metal stack and plasmonic nanoparticles. AB - Plasmonically enhanced absorbing structures have been emerging as strong candidates for photovoltaic (PV) devices. We investigate metal-insulator-metal (MIM) structures that are suitable for tuning spectral absorption properties by modifying layer thicknesses. We have utilized gold and silver nanoparticles to form the top metal (M) region, obtained by dewetting process compatible with large area processes. For the middle (I) and bottom (M) layers, different dielectric materials and metals are investigated. Optimum MIM designs are discussed. We experimentally demonstrate less than 10 percent reflection for most of the visible (VIS) and near infrared (NIR) spectrum. In such stacks, computational analysis shows that the bottom metal is responsible for large portion of absorption with a peak of 80 percent at 1000 nm wavelength for chromium case. PMID- 27505734 TI - Remote beating of parallel or orthogonally polarized dual-wavelength optical carriers for 5G millimeter-wave radio-over-fiber link. AB - A novel millimeter-wave radio over fiber (MMW-RoF) link at carrier frequency of 35-GHz is proposed with the use of remotely beating MMW generation from reference master and injected slave colorless laser diode (LD) carriers at orthogonally polarized dual-wavelength injection-locking. The slave colorless LD supports lasing one of the dual-wavelength master modes with orthogonal polarizations, which facilitates the single-mode direct modulation of the quadrature amplitude modulation (QAM) orthogonal frequency division multiplexing (OFDM) data. Such an injected single-carrier encoding and coupled dual-carrier transmission with orthogonal polarization effectively suppresses the cross-heterodyne mode-beating intensity noise, the nonlinear modulation (NLM) and four-wave mixing (FWM) sidemodes during injection locking and fiber transmission. In 25-km single-mode fiber (SMF) based wireline system, the dual-carrier under single-mode encoding provides baseband 24-Gbit/s 64-QAM OFDM transmission with an error vector magnitude (EVM) of 8.8%, a bit error rate (BER) of 3.7 * 10-3, a power penalty of <1.5 dB. After remotely self-beating for wireless transmission, the beat MMW carrier at 35 GHz can deliver the passband 16-QAM OFDM at 4 Gbit/s to show corresponding EVM and BER of 15.5% and 1.4 * 10-3, respectively, after 25-km SMF and 1.6-m free-space transmission. PMID- 27505735 TI - Ultra-compact strain- and temperature-insensitive torsion sensor based on a line by-line inscribed phase-shifted FBG. AB - A novel temperature- and strain-independent optical fiber torsion sensor based on a phase-shifted fiber Bragg grating (PSFBG) inscribed by the line-by-line (LbL) technique in a standard single-mode fiber with a femtosecond laser has been proposed and experimentally demonstrated. The strong birefringence created by the LbL inscription technique leads to the significant polarization splitting of the transmission peak of the PSFBG. By simply monitoring the variation of the amplitude difference between the two polarization-peaks, the fiber torsion angle and the fiber torsion direction can be simultaneously deduced without temperature and strain confusion. The torsion sensor exhibits a high torsion sensitivity of up to -1032.71 dB/(rad/mm), with the distinct advantages of low manufacture cost, small dimension (just ~1.72mm), and extremely robust and simple structure, which make it very attractive for practical applications. To the best of our knowledge, this is the smallest torsion sensor ever reported. PMID- 27505736 TI - Sensitivity optimization with cladding-etched long period fiber gratings at the dispersion turning point. AB - This work presents a refractive index sensor based on a long period fiber grating (LPFG) made in a reduced cladding fiber whose low order cladding modes have the turning point at large wavelengths. The combination of these parameters results in an improved sensitivity of 8734 nm/refractive index unit (RIU) for the LP0,3 mode in the 1400-1650 wavelength range. This value is similar to that obtained with thin-film coated LPFGs, which permits to avoid the coating deposition step. The numerical simulations are in agreement with the experimental results. PMID- 27505737 TI - Novel 3D measurement system based on speckle and fringe pattern projection. AB - An efficient three-dimensional shape measurement system is proposed, which is based on the combining projection of single digital speckle pattern and phase shifting fringe patterns. At the beginning, the initial corresponding point for each pixel is obtained by a novel speckle-phase combination method. The initial information can be calculated by the single speckle pattern in a short time, while the phase information is used to ensure the results. Unlike the conventional methods, it is not necessary to obtain the unwrapped phase, therefore the number of projected patterns is reduced greatly. Then accurate corresponding coordinates are obtained according to the wrapped phase. Three cases are analyzed while adjusting the initial corresponding coordinates locally. Thus accuracy coordinates are obtained without missing or incorrect points. Experiments demonstrate that we can achieve accurate reconstruction results with reduced measurement time by the proposed method. PMID- 27505738 TI - Depth position recognition-related laser-induced damage test method based on initial transient damage features. AB - Even absorptive defects or inner cracks hiding several micrometers to a few dozen micrometers beneath the top surface can induce damage to transmission elements in the ultraviolet band. The extremely small size and disordered state of such defects or cracks hinder their detection using conventional methods. Therefore, the diagnosis of factors that limit damage resistance performance is a key technique for improving the fabrication technology of optical elements. With a focus on laser damage to third-harmonic transmission elements, this study establishes a micron space-resolved and nanosecond time-resolved imaging system on the basis of the pump-probe detection technique. The changes in the properties of defect-induced laser damage in the time domain are clarified. A diagnostic method for original damage depth in micron precision is proposed according to damage behaviors. This method can retrieve initial information on damage inducement and depth position. The recognition and diagnostic capabilities of such a technique are calibrated with artificial samples and then used to analyze real samples. PMID- 27505739 TI - Performance of GaN-on-Si-based vertical light-emitting diodes using silicon nitride electrodes with conducting filaments: correlation between filament density and device reliability. AB - Transparent conductive electrodes with good conductivity and optical transmittance are an essential element for highly efficient light-emitting diodes. However, conventional indium tin oxide and its alternative transparent conductive electrodes have some trouble with a trade-off between electrical conductivity and optical transmittance, thus limiting their practical applications. Here, we present silicon nitride transparent conductive electrodes with conducting filaments embedded using the electrical breakdown process and investigate the dependence of the conducting filament density formed in the transparent conductive electrode on the device performance of gallium nitride based vertical light-emitting diodes. Three gallium nitride-on-silicon-based vertical light-emitting diodes using silicon nitride transparent conductive electrodes with high, medium, and low conducting filament densities were prepared with a reference vertical light-emitting diode using metal electrodes. This was carried to determine the optimal density of the conducting filaments in the proposed silicon nitride transparent conductive electrodes. In comparison, the vertical light-emitting diodes with a medium conducting filament density exhibited the lowest optical loss, direct ohmic behavior, and the best current injection and distribution over the entire n-type gallium nitride surface, leading to highly reliable light-emitting diode performance. PMID- 27505740 TI - Bidirectional current triggering in planar devices based on serially connected VO2 thin films using 965 nm laser diode. AB - By incorporating a 965 nm laser diode, the bidirectional current triggering of up to 30 mA was demonstrated in a two-terminal planar device based on serially connected vanadium dioxide (VO2) thin films grown by pulsed laser deposition. The bidirectional current triggering was realized by using the focused beams of laser pulses through the photo-thermally induced phase transition of VO2. The transient responses of laser-triggered currents were also investigated when laser pulses excited the device at a variety of pulse widths and repetition rates of up to 4.0 Hz. A switching contrast between off- and on-state currents was obtained as ~8333, and rising and falling times were measured as ~39 and ~29 ms, respectively, for 50 ms laser pulses. PMID- 27505741 TI - Surface plasmon optical antennae in the infrared region with high resonant efficiency and frequency selectivity. AB - Infrared light has received attention for sensor applications, including fingerprint spectroscopy, in the bioengineering and security fields. Surface plasmon physics enables the operation of a light harvesting optical antenna. Gold nanochains exhibit localized surface plasmon resonance (LSPR) in the infrared region with high frequency selectivity. However, a feasible design for optical antennae with a higher resonant efficiency and frequency selectivity as a function of structural design and periodicity is still unknown. In the present study, we investigated the relationship between the resonant efficiency and frequency selectivity as a function of the structural design of gold nanochains and explored structural periodicity for obtaining highly frequency-selective optical antennae. An optical antenna design with higher resonant efficiency is proposed on the basis of its efficient interaction with non-polarized light. PMID- 27505742 TI - All-dielectric circular polarizer with nearly unit transmission efficiency based on cascaded tensor Huygens surface. AB - In this paper, we demonstrate a high-efficiency and broadband circular polarizer based on cascaded tensor Huygens surface capable of operating in the near infrared region. The high efficiency originates from the simultaneous excitation of the Mie-type electric and magnetic dipole resonances within an all-dielectric rotationally twisted strips array. Due to the symmetry breaking of the structure in the light propagation, one state of the circularly polarized light can pass through freely, while the other state is largely blocked. The maximum polarization transmission reaches 0.97 with a polarization suppression ratio of 911:1, which represents a major advance in the performance compared with previously reported circular polarizers. The proposed metamaterial possessing the merits of high efficiency and simple inclusions has potentials for applications in biological detector, optical communication and sensor. PMID- 27505743 TI - Polarization volume grating with high efficiency and large diffraction angle. AB - We propose a polarization volume grating (PVG), which exhibits nearly 100% diffraction efficiency and large diffraction angle. Both reflective and transmissive PVGs can be configured depending on application preference. Such a PVG is polarization-sensitive so that it can split an incident unpolarized beam into two well-separated yet polarized beams. These outstanding features make PVG a strong candidate for photonic and display applications. To investigate and optimize the diffraction properties, we build a rigorous simulation model based on finite element method. To illustrate its potential applications, we propose a simple 2D/3D wearable display using a planar waveguide comprising of two reflective PVGs. PMID- 27505744 TI - Broadband gold nanoantennas arrays with transverse dimension effects. AB - Broadband resonance in gold paired-rods nanoantennas and paired-strips gratings is investigated when the nanostructure's transverse (non-polarization) dimension is changed from paired-rods to paired-strips. Increasing the transverse dimension blue shifts the resonance wavelength and widens its bandwidth due to cancellation of the magnetic field between nanoantennas. A derived resistor-inductor-capacitor (RLC) equivalent circuit model verifies the nanostructures' resonance when elongating the transverse dimensions. Paired-strips gratings have a bandwidth 2.04 times that of paired-rods nanoantennas. PMID- 27505745 TI - Effects of losses in the atom-light hybrid SU(1,1) interferometer. AB - Collective atomic excitation can be realized by the Raman scattering. Such a photon-atom interface can form an SU(1,1)-typed atom-light hybrid interferometer, where the atomic Raman amplification processes take the place of the beam splitting elements in a traditional Mach-Zehnder interferometer. We numerically calculate the phase sensitivities and the signal-to-noise ratios (SNRs) of this interferometer with the method of homodyne detection and intensity detection, and give their differences of the optimal phase points to realize the best phase sensitivities and the maximal SNRs from these two detection methods. The difference of the effects of loss of light field and atomic decoherence on measure precision is analyzed. PMID- 27505746 TI - Random sources for cusped beams. AB - We introduce two novel classes of partially coherent sources whose degrees of coherence are described by the rectangular Lorentz-correlated Schell-model (LSM) and rectangular fractional multi-Gaussian-correlated Schell-model (FMGSM) functions. Based on the generalized Collins formula, analytical expressions are derived for the spectral density distributions of these beams propagating through a stigmatic ABCD optical system. It is shown that beams belonging to both classes form the spectral density apex that is much higher and sharper than that generated by the Gaussian Schell-model (GSM) beam with a comparable coherence state. We experimentally generate these beams by using a nematic, transmissive spatial light modulator (SLM) that serves as a random phase screen controlled by a computer. The experimental data is consistent with theoretical predictions. Moreover, it is illustrated that the FMGSM beam generated in our experiments has a better focusing capacity than the GSM beam with the same coherence state. The applications that can potentially benefit from the use of novel beams range from material surface processing, to communications and sensing through random media. PMID- 27505747 TI - Excitation powder dependent optical temperature behavior of Er3+ doped transparent Sr0.69La0.31F2.31 glass ceramics. AB - The knowledge of the pump power for which the population of thermally coupled energy levels (TCL) changes with power increase is of valuable importance for optical temperature sensors. In this paper, novel Er3+ doped transparent Sr0.69La0.31F2.31 glass ceramics was fabricated successfully, and its structure is studied by XRD, TEM and HRTEM analyses. The 2H11/2/4S3/2, 4F9/2(1)/4F9/2(2), and 4I9/2(1)/4I9/2(2) levels of Er3+ are proved as TCL by analyzing the temperature dependent fluorescence intensity ratios. The spectrum split, thermal quenching ratio, population stability, and temperature sensitivity from three TCL are observed to be dependent on the pump power. A new fitting method has been developed to establish the relation between fluorescence intensity ratios and temperature. It is found that the combined use of 2H11/2/4S3/2 and 4F9/2(1)/4F9/2(2) as thermally coupled energy levels will get a more precise temperature reading from 62.7 K to 800 K with the help of low excitation power at 66.8 mW/mm2. PMID- 27505748 TI - Analytical surrogate model for the aberrations of an arbitrary GRIN lens. AB - Current analytical expressions between Gradient-Index (GRIN) lens parameters and optical aberrations are limited to paraxial approximations, which are not suitable for realizing GRIN lenses with wide fields of view or small f-numbers. Here, an analytical surrogate model of an arbitrary GRIN lens ray-trace evaluation is formulated using multivariate polynomial regressions to correlate input GRIN lens parameters with output Zernike coefficients, without the need for approximations. The time needed to compute the resulting surrogate model is over one order-of-magnitude faster than traditional ray trace simulations with very little losses in accuracy, which can enable previously infeasible design studies to be completed. PMID- 27505749 TI - High-voltage integrated active quenching circuit for single photon count rate up to 80 Mcounts/s. AB - Single photon avalanche diodes (SPADs) have been subject to a fast improvement in recent years. In particular, custom technologies specifically developed to fabricate SPAD devices give the designer the freedom to pursue the best detector performance required by applications. A significant breakthrough in this field is represented by the recent introduction of a red enhanced SPAD (RE-SPAD) technology, capable of attaining a good photon detection efficiency in the near infrared range (e.g. 40% at a wavelength of 800 nm) while maintaining a remarkable timing resolution of about 100ps full width at half maximum. Being planar, the RE-SPAD custom technology opened the way to the development of SPAD arrays particularly suited for demanding applications in the field of life sciences. However, to achieve such excellent performance custom SPAD detectors must be operated with an external active quenching circuit (AQC) designed on purpose. Next steps toward the development of compact and practical multichannel systems will require a new generation of monolithically integrated AQC arrays. In this paper we present a new, fully integrated AQC fabricated in a high-voltage 0.18 um CMOS technology able to provide quenching pulses up to 50 Volts with fast leading and trailing edges. Although specifically designed for optimal operation of RE-SPAD devices, the new AQC is quite versatile: it can be used with any SPAD detector, regardless its fabrication technology, reaching remarkable count rates up to 80 Mcounts/s and generating a photon detection pulse with a timing jitter as low as 119 ps full width at half maximum. The compact design of our circuit has been specifically laid out to make this IC a suitable building block for monolithically integrated AQC arrays. PMID- 27505750 TI - Spectroscopic and laser characterization of Yb0.15:(LuxY1 x)3Al5O12 ceramics with different Lu/Y balance. AB - We report a broad comparative analysis of the spectroscopic and laser properties of solid solution Lutetium-Yttrium Aluminum Garnet (LuYAG, (LuxY1 x)3Al5O12) ceramics doped with Yb. The investigation was mainly aimed to assess the impact of the Lu/Y ratio on the Yb optical and laser properties. Therefore we analyzed a set of samples with different Y/Lu balance, namely 25/75, 50/50 and 75/25, with 15% Yb doping. We found that the Yb absorption and emission spectra changed from YAG to LuAG when gradually increasing in Lu content. Regarding the laser emission, remarkable results were achieved with all samples. Maximum output power was 8.2 W, 7.3 W and 8.7 W for Y/Lu balance 25/75, 50/50 and 75/25 respectively, at 1030 nm; the slope efficiency and the optical-to-optical efficiencies approached or exceeded 60% and 50% respectively. The tuning range was investigated using an intracavity ZnSe prism. The broadest tuning range (998 nm to 1063 nm) was obtained with Y/Lu balance 75/25, whereas the emission of the other two samples extended from 1000 nm to 1058 nm. To the best of our knowledge, this is the first comparative analysis of Yb:LuYAG ceramics or crystals as laser host across such a broad range of Y/Lu ratios. PMID- 27505751 TI - Broadband OPCPA system with 11 mJ output at 1 kHz, compressible to 12 fs. AB - We report on a broadband OPCPA system, pumped at 515 nm by frequency doubled Yb:YAG thin disk lasers. The system delivers 11.3 mJ pulses at a central wavelength of 800 nm with a spatial beam quality of M2 = 1.25 and > 25% pump-to-signal conversion efficiency. The broadband pulses were demonstrated to be compressible to 12 fs using a chirped mirror compressor. PMID- 27505752 TI - Near perfect mode overlap between independently seeded, gain-switched lasers. AB - We drastically improve the mode overlap between independently seeded, gain switched laser diodes operating at gigahertz repetition rates by implementing a pulsed light seeding technique. Injecting pulsed light reduces the emission time jitter and enables frequency chirp synchronization while maintaining random optical phases of the emitted laser pulses. We measure interference of these pulsed sources both in the macroscopic regime, where we demonstrate near perfect mode overlap, and in the single photon regime, where we achieve a Hong-Ou-Mandel dip visibility of 0.499 +/- 0.004, thus saturating the theoretical limit of 0.5. The measurement results are reproduced by Monte-Carlo simulations with no free parameters. Our light source is an ideal solution for generation of high rate, indistinguishable coherent pulses for quantum information applications. PMID- 27505753 TI - Third harmonic generation in exposed-core microstructured optical fibers. AB - Inter-modal phase-matched third harmonic generation has been demonstrated in an exposed-core microstructured optical fiber. Our fiber, with a partially open core having a diameter of just 1.85 um, shows efficient multi-peak third-harmonic generation between 500 nm and 530 nm, with a maximum visible-wavelength output of 0.96 MUW. Mode images and simulations show strong agreement, confirming the phase matching process and polarization dependence. We anticipate this work will lead to tailorable and tunable visible light sources by exploiting the open access to the optical fiber core, such as depositing thin-film coatings in order to shift the phase matching conditions. PMID- 27505754 TI - High luminous efficacy green light-emitting diodes with AlGaN cap layer. AB - We demonstrate very high luminous efficacy green light-emitting diodes employing Al0.30Ga0.70N cap layer grown on patterned sapphire substrates by metal organic chemical vapor deposition. The peak external quantum efficiency and luminous efficacies were 44.3% and 239 lm/w, respectively. At 20 mA (20 A/cm2) the light output power was 14.3 mW, the forward voltage was 3.5 V, the emission wavelength was 526.6 nm, and the external quantum efficiency was 30.2%. These results are among the highest reported luminous efficacy values for InGaN based green light-emitting diodes. PMID- 27505755 TI - Optical antennas with sinusoidal modulation in width. AB - Small metal structures sustaining plasmon resonances in the optical regime are of great interest due to their large scattering cross sections and ability to concentrate light to subwavelength volumes. In this paper, we study the dipolar plasmon resonances of optical antennas with a constant volume and a sinusoidal modulation in width. We experimentally show that by changing the phase of the width-modulation, with a small 10 nm modulation amplitude, the resonance shifts over 160 nm. Using simulations we show how this simple design can create resonance shifts greater than 600 nm. The versatility of this design is further shown by creating asymmetric structures with two different modulation amplitudes, which we experimentally and numerically show to give rise to two resonances. Our results on both the symmetric and asymmetric antennas show the capability to control the localization of the fields outside the antenna, while still maintaining the freedom to change the antenna resonance wavelength. The antenna design we tested combines a large spectral tunability with a small footprint: all the antenna dimensions are factor 7 to 13 smaller than the wavelength, and hold potential as a design element in meta-surfaces for beam shaping. PMID- 27505756 TI - Dynamically tunable plasmonically induced transparency in sinusoidally curved and planar graphene layers. AB - To achieve plasmonically induced transparency (PIT), general near-field plasmonic systems based on couplings between localized plasmon resonances of nanostructures rely heavily on the well-designed interantenna separations. However, the implementation of such devices and techniques encounters great difficulties mainly to due to very small sized dimensions of the nanostructures and gaps between them. Here, we propose and numerically demonstrate that PIT can be achieved by using two graphene layers that are composed of a upper sinusoidally curved layer and a lower planar layer, avoiding any pattern of the graphene sheets. Both the analytical fitting and the Akaike Information Criterion (AIC) method are employed efficiently to distinguish the induced window, which is found to be more likely caused by Autler-Townes splitting (ATS) instead of electromagnetically induced transparency (EIT). Besides, our results show that the resonant modes cannot only be tuned dramatically by geometrically changing the grating amplitude and the interlayer spacing, but also by dynamically varying the Fermi energy of the graphene sheets. Potential applications of the proposed system could be expected on various photonic functional devices, including optical switches, plasmonic sensors. PMID- 27505757 TI - Electrical and optical performance of plasmonic silicon solar cells based on light scattering of silver and indium nanoparticles in matrix-combination. AB - This study demonstrates the efficacy of combining a matrix of silver nanoparticles (Ag-NPs) with indium nanoparticles (In-NPs) to improve the electric and optical performance of plasmonic silicon solar cells. We examined the excitation of localized surface plasmons of Ag-NPs and In-NPs using surface enhanced Raman scattering measurements. Optical reflectance and external quantum efficiency (EQE) measurements demonstrate that the light scattering of Ag-NPs at short wavelengths can be improved by surrounding them with In-NPs. This also leads to high EQE band matching in the high energy band of the AM1.5G solar energy spectrum. Impressive improvements in optical reflectance and EQE response were also observed at short wavelengths. Cells with a matrix of Ag-NPs (20% surface coverage) surrounded by In-NPs (80% surface coverage) increased the overall efficiency of the cell by 31.83%, as confirmed by photovoltaic current density-voltage characterization under AM 1.5 G illumination. PMID- 27505758 TI - Enhance the light-harvesting capability of the ITO-free inverted small molecule solar cell by ZnO nanorods. AB - The ITO-free inverted SMPV1:PC71BM solar cells with an Al doped ZnO (AZO) transparent electrodes are fabricated. The AZO thin film prepared by pulsed laser deposition (PLD) technique exhibits high transmission (>85%) and low sheet resistance (~30 Omega/sq) and the power conversion efficiency (PCE) of devices based on AZO electrode can reach around 4%. To further enhance the light harvesting of the absorption layer of solar cells, ZnO nanorods interlayer is grown on the AZO layer before the deposition the active layer. The absorption spectrums of devices under various conditions are also simulated by RCWA method to identify the optical saturation length of the ZnO nanorods. The PCE of ITO free inverted small molecule solar cell improved with ZnO nanorods can reach 6.6%. PMID- 27505759 TI - Large spontaneous-emission enhancements in metallic nanostructures: towards LEDs faster than lasers. AB - Recent progress in the design and realization of optical antennas enclosing fluorescent materials has demonstrated large spontaneous-emission enhancements and, simultaneously, high radiation efficiencies. We discuss here that an important objective of such work is to increase spontaneous-emission rates to such a degree that light-emitting diodes (LEDs) can possess modulation speeds exceeding those of typical semiconductor lasers, which are usually in the range ~20-50 GHz. We outline the underlying physics that enable large spontaneous emission enhancements in metallic nanostructures, and we then discuss recent theoretical and experimentally promising results, where enhancements larger than a factor of ~300 have been reported, with radiation efficiencies exceeding 50%. We provide key comparative advantages of these structures in comparison to conventional dielectric microcavity designs, namely the fact that the enhancement of spontaneous emission can be relatively nonresonant (i.e., broadband) and that the antenna nanostructures can be spectrally and structurally compatible for integration with a wide class of emitters, including organic dyes, diamond nanocrystals and colloidal quantum dots. Finally, we point out that physical insight into the underlying effects can be gained by analyzing these metallic nanostructures in their equivalent-circuit (or nano-antenna) model, showing that all main effects (including the Purcell factor) can adequately be described in that approach. PMID- 27505760 TI - Estimating index of refraction from polarimetric hyperspectral imaging measurements. AB - Current material identification techniques rely on estimating reflectivity or emissivity which vary with viewing angle. As off-nadir remote sensing platforms become increasingly prevalent, techniques robust to changing viewing geometries are desired. A technique leveraging polarimetric hyperspectral imaging (P-HSI), to estimate complex index of refraction, N(nu), an inherent material property, is presented. The imaginary component of N(nu) is modeled using a small number of "knot" points and interpolation at in-between frequencies nu. The real component is derived via the Kramers-Kronig relationship. P-HSI measurements of blackbody radiation scattered off of a smooth quartz window show that N(nu) can be retrieved to within 0.08 RMS error between 875 cm-1 <= nu <= 1250 cm-1. P-HSI emission measurements of a heated smooth Pyrex beaker also enable successful N(nu) estimates, which are also invariant to object temperature. PMID- 27505761 TI - Consequences of femtosecond laser filament generation conditions in standoff laser induced breakdown spectroscopy. AB - The combination of femtosecond laser filament ablation and emission spectroscopy is a potential analytical tool for standoff characterization of samples of interest. We compare the emission features and physical conditions of plasmas generated from metal targets using either by loosely focused femtosecond filaments or by lens-free filaments. Our results show that the filament generation conditions influence the plasma properties appreciably which include the atomic and molecular emission features, persistence and plasma fundamentals (temperature and density). The loosely focused fs pulse filaments are found to generate ablation plumes with higher temperature and density along with increased persistence compared to plumes generated by lens-free filaments. PMID- 27505762 TI - Enhanced light extraction efficiency of OLEDs with quasiperiodic diffraction grating layer. AB - We presented enhanced light extraction efficiency of organic light emitting diodes (OLEDs) cells with a nano-sized diffraction grating layer. Various diffraction gratings of different morphologies including linear, cubic, hexagonal and quasiperiodic patterns were fabricated by multiplexing light interference exposure on an azobenzene thin film. The effect of diffraction grating layer on device performances including luminous properties and quantum efficiency was investigated. In contrast to periodic grating patterns, the quasiperiodic structures leading broadband light extraction resulted in improved external quantum efficiency and power efficiency by 73% and 63%, respectively, compared to conventional OLED with flat surface of glass substrate. PMID- 27505763 TI - High-resolution fiber Bragg grating based transverse load sensor using microwave photonics filtering technique. AB - In this paper, a new fiber Bragg grating (FBG) sensor exploiting microwave photonics filter technique for transverse load sensing is firstly proposed and experimentally demonstrated. A two-tap incoherent notch microwave photonics filter (MPF) based on a transverse loaded FBG, a polarization beam splitter (PBS), a tunable delay line (TDL) and a length of dispersion compensating fiber (DCF) is demonstrated. The frequency response of the filter with respect to the transverse load is studied. By detecting the resonance frequency shifts of the notch MPF, the transverse load can be determined. The theoretical and experimental results show that the proposed FBG sensor has a higher resolution than traditional methods based on optical spectrum analysis. The sensitivity of the sensor is measured to be as high as 2.5 MHz/N for a sensing fiber with a length of 18mm. Moreover, the sensitivity can be easily adjusted. PMID- 27505764 TI - Banded all-optical OFDM super-channels with low-bandwidth receivers. AB - We propose a banded all-optical orthogonal frequency division multiplexing (AO OFDM) transmission system based on synthesising a number of truncated sinc-shaped subcarriers for each sub-band. This approach enables sub-band by sub-band reception and therefore each receiver's electrical bandwidth can be significantly reduced compared with a conventional AO-OFDM system. As a proof-of-concept experiment, we synthesise 6 * 10-Gbaud subcarriers in both conventional and banded AO-OFDM systems. With a limited receiver electrical bandwidth, the experimental banded AO-OFDM system shows 2-dB optical signal to noise ratio (OSNR) benefit over conventional AO-OFDM at the 7%-overhead forward error correction (FEC) threshold. After transmission over 800-km of single-mode fiber, ~3-dB improvement in Q-factor can be achieved at the optimal launch power at a cost of increasing the spectral width by 14%. PMID- 27505765 TI - Highly sensitive and reconfigurable fiber optic current sensor by optical recirculating in a fiber loop. AB - An advanced fiber optic current sensor (FOCS) is proposed based on recirculating fiber loop architecture for significantly enhancing the current sensitivity. The recirculating loop is constructed by a 2X2 optical switch and the standard single mode fiber (SSMF) is used as the sensing head. The proposed FOCS is coupler-free with low insertion loss which results in a significantly improved current sensitivity. We experimentally obtained a sensitivity of 11.5 degrees/A for 1-Km SSMF FOCS and a sensitivity of 21.2 degrees/A for 500-m SSMF FOCS, both of which have been enhanced by more than ten times. The flexible switch control of recirculating can support the FOCS to work for different current scenarios with the same system and thus reconfigurable operation of the FOCS has been achieved. The significantly enhanced high sensitivity with reconfigurable operation capability makes the proposed FOCS a promising method for practical applications. PMID- 27505766 TI - Removing image artefacts in wire array metamaterials. AB - Hyperlenses and hyperbolic media endoscopes can overcome the diffraction limit by supporting propagating high spatial frequency extraordinary waves. While hyperlenses can resolve subwavelength details far below the diffraction limit, images obtained from them are not perfect: resonant high spatial frequency slab modes as well as diffracting ordinary waves cause image distortion and artefacts. In order to use hyperlenses as broad-band subwavelength imaging devices, it is thus necessary to avoid or correct such unwanted artefacts. Here we introduce three methods, namely convolution, field averaging, and power averaging, to remove imaging artefacts over wide frequency bands, and numerically demonstrate their effectiveness based on simulations of a wire medium endoscope. We also define a projection in spatial Fourier space to effectively filter out all ordinary waves, leading to considerable reduction in image distortion. These methods are outlined and demonstrated for simple and complex apertures. PMID- 27505767 TI - Broadly tunable mode-locked Ho:YAG ceramic laser around 2.1 um. AB - A passively mode-locked Ho:YAG ceramic laser around 2.1 um is demonstrated using GaSb-based near-surface SESAM as saturable absorber. Stable and self-starting mode-locked operation is realized in the entire tuning range from 2059 to 2121 nm. The oscillator operated at 82 MHz with a maximum output power of 230 mW at 2121 nm. The shortest pulses with duration of 2.1 ps were achieved at 2064 nm. We also present spectroscopic properties of Ho:YAG ceramics at room temperature. PMID- 27505768 TI - Remote and in situ sensing products in chemical reaction using a flexible terahertz pipe waveguide. AB - The feasibility of remote chemical detection is experimentally demonstrated by using a Teflon pipe as a scanning arm in a continuous-terahertz wave sensing and imaging system. Different tablets with distinct mixed ratios of aluminum and polyethylene powders are well distinguished by measuring the power reflectivities of 0.4 THz wave associated with their distinct terahertz refractive indices. Given its refractive index sensitivity and fast response, the reflective terahertz sensing system can be used to real-time trace and quantitatively analyze the ammonium-chloride aerosols produced by the chemical reaction between hydrochloric acid and ammonia vapors. With a tightly focusing terahertz beam spot, the spatial and concentration distributions of the generated chemical product are successfully mapped out by the 1D scan of the flexible pipe probe. In consideration of the responsitivity, power stability, and focused spot size of the system, its detection limit for the ammonium-chloride aerosol is estimated to be approximately 165 nmol/mm2. The reliable and compact terahertz pipe scan system is potentially suitable for practical applications, such as biomedical or industrial fiber endoscopy. PMID- 27505769 TI - High efficiency near diffraction-limited mid-infrared flat lenses based on metasurface reflectarrays. AB - We report the first demonstration of a mid-IR reflection-based flat lens with high efficiency and near diffraction-limited focusing. Focusing efficiency as high as 80%, in good agreement with simulations (83%), has been achieved at 45 degrees incidence angle at lambda = 4.6 MUm. The off-axis geometry considerably simplifies the optical arrangement compared to the common geometry of normal incidence in reflection mode which requires beam splitters. Simulations show that the effects of incidence angle are small compared to parabolic mirrors with the same NA. The use of single-step photolithography allows large scale fabrication. Such a device is important in the development of compact telescopes, microscopes, and spectroscopic designs. PMID- 27505770 TI - Multiocular image sensor with on-chip beam-splitter and inner meta-micro-lens for single-main-lens stereo camera. AB - We developed multiocular 1/3-inch 2.75-MUm-pixel-size 2.1M- pixel image sensors by co-design of both on-chip beam-splitter and 100-nm-width 800-nm-depth patterned inner meta-micro-lens for single-main-lens stereo camera systems. A camera with the multiocular image sensor can capture horizontally one-dimensional light filed by both the on-chip beam-splitter horizontally dividing ray according to incident angle, and the inner meta-micro-lens collecting the divided ray into pixel with small optical loss. Cross-talks between adjacent light field images of a fabricated binocular image sensor and of a quad-ocular image sensor are as low as 6% and 7% respectively. With the selection of two images from one-dimensional light filed images, a selective baseline for stereo vision is realized to view close objects with single-main-lens. In addition, by adding multiple light field images with different ratios, baseline distance can be tuned within an aperture of a main lens. We suggest the electrically selective or tunable baseline stereo vision to reduce 3D fatigue of viewers. PMID- 27505771 TI - Achromatic and athermal lens design by redistributing the element powers on an athermal glass map. AB - We propose a new graphical method for selecting a pair of optical and housing materials to simultaneously achromatize and athermalize a multilens system. To obtain the material combination using an athermal glass map, the material suitable for housing is graphically selected, and then the powers of elements constituting an equivalent single lens are redistributed. Although a material combination does not exist, we can continuously change the power of each element. Thus, we can reasonably identify a pair of optical and housing materials that simultaneously satisfies achromatic and athermal conditions. By applying this method to design a Tessar lens, the chromatic and thermal defocuses are reduced to less than the depth of focus, over the specified waveband and temperature ranges. PMID- 27505772 TI - Accidental degeneracy in photonic bands and topological phase transitions in two dimensional core-shell dielectric photonic crystals. AB - A simple core-shell two-dimensional photonic crystal is studied where the triangular lattice symmetry and the C6 point group symmetry give rich physics in accidental touching points of photonic bands. We systematically evaluate different types of accidental nodal points at the Brillouin zone center for transverse-magnetic harmonic modes when the geometry and permittivity of the core-shell material are continuously tuned. The accidental nodal points can have different dispersions and topological properties (i.e., Berry phases). These accidental nodal points can be the critical states lying between a topological phase and a normal phase of the photonic crystal. They are thus very important for the study of topological photonic states. We show that, without breaking time reversal symmetry, by tuning the geometry of the core-shell material, a phase transition into the photonic quantum spin Hall insulator can be achieved. Here the "spin" is defined as the orbital angular momentum of a photon. We study the topological phase transition as well as the properties of the edge and bulk states and their application potentials in optics. PMID- 27505773 TI - Trapping two types of particles by modified circular Airy beams. AB - The radiation force of modified circular Airy beams (MCAB) exerted on both a high refractive-index particle and a low-refractive-index particle are analyzed in this paper. Our results show that the two kinds of particles can be simultaneously stably trapped by MCAB at different positions. Compared with the common circular Airy beams (CAB) with the same parameters, trapping forces on the two kinds of particles are greatly increased because of the enhanced abruptly autofocusing property and the appearance of hollow region in MCAB. The trapping forces can be modulated by varying parameters of MCAB, and it is important to choose appropriate parameters to trap particles in practice. PMID- 27505774 TI - Propagation of the power-exponent-phase vortex beam in paraxial ABCD system. AB - The general analytical formula for the propagation of the power-exponent-phase vortex (PEPV) beam through a paraxial ABCD optical system is derived. On that basis the evolution of the intensity distribution of such a beam in free space and the focusing system is investigated. In addition, some experiments are carried out, which verify the theoretical predictions. Both of the theoretical and experimental results show that the beam's profile can be modulated by the topological charge and the power order of the PEPV beam. PMID- 27505775 TI - Capacity achieving nonbinary LDPC coded non-uniform shaping modulation for adaptive optical communications. AB - A mutual information inspired nonbinary coded modulation design with non-uniform shaping is proposed. Instead of traditional power of two signal constellation sizes, we design 5-QAM, 7-QAM and 9-QAM constellations, which can be used in adaptive optical networks. The non-uniform shaping and LDPC code rate are jointly considered in the design, which results in a better performance scheme for the same SNR values. The matched nonbinary (NB) LDPC code is used for this scheme, which further improves the coding gain and the overall performance. We analyze both coding performance and system SNR performance. We show that the proposed NB LDPC-coded 9-QAM has more than 2dB gain in symbol SNR compared to traditional LDPC-coded star-8-QAM. On the other hand, the proposed NB LDPC-coded 5-QAM and 7 QAM have even better performance than LDPC-coded QPSK. PMID- 27505776 TI - On the resilience of scalar and vector vortex modes in turbulence. AB - Free-space optical communication with spatial modes of light has become topical due to the possibility of dramatically increasing communication bandwidth via Mode Division Multiplexing (MDM). While both scalar and vector vortex modes have been used as transmission bases, it has been suggested that the latter is more robust in turbulence. Using orbital angular momentum as an example, we demonstrate theoretically and experimentally that the crosstalk due to turbulence is the same in the scalar and vector basis sets of such modes. This work brings new insights about the behaviour of vector and scalar modes in turbulence, but more importantly it demonstrates that when considering optimal modes for MDM, the choice should not necessarily be based on their vectorial nature. PMID- 27505777 TI - Improved halftoning method for autostereoscopic display based on float grid division multiplexing. AB - Autostereoscopic printing is one of the most common ways for three-dimensional display, because it can present finer results by printing higher dots per inches (DPI). However, there are some problems for current methods. First, errors caused by dislocation between integer grids and non-customized lenticular lens result in severe vision quality. Second, the view-number and gray-level cannot be set arbitrarily. In this paper, an improved halftoning method for autostereoscopic printing based on float grid-division multiplexing (fGDM) is proposed. FGDM effectively addresses above two problems. GPU based program of fGDM is enabled to achieve the result very fast. Films with lenticular lens array are implemented in experiments to verify the effectiveness of proposed method which provides an improved three-dimensional performance, compared with the AM screening and random screening. PMID- 27505778 TI - Rapid and economical data acquisition in ultrafast frequency-resolved spectroscopy using choppers and a microcontroller. AB - Spectrometers and cameras are used in ultrafast spectroscopy to achieve high resolution in both time and frequency domains. Frequency-resolved signals from the camera pixels cannot be processed by common lock-in amplifiers, which have only a limited number of input channels. Here we demonstrate a rapid and economical method that achieves the function of a lock-in amplifier using mechanical choppers and a programmable microcontroller. We demonstrate the method's effectiveness by performing a frequency-resolved pump-probe measurement on the dye Nile Blue in solution. PMID- 27505779 TI - High-repetition-rate and high-photon-flux 70 eV high-harmonic source for coincidence ion imaging of gas-phase molecules. AB - Unraveling and controlling chemical dynamics requires techniques to image structural changes of molecules with femtosecond temporal and picometer spatial resolution. Ultrashort-pulse x-ray free-electron lasers have significantly advanced the field by enabling advanced pump-probe schemes. There is an increasing interest in using table-top photon sources enabled by high-harmonic generation of ultrashort-pulse lasers for such studies. We present a novel high harmonic source driven by a 100 kHz fiber laser system, which delivers 1011 photons/s in a single 1.3 eV bandwidth harmonic at 68.6 eV. The combination of record-high photon flux and high repetition rate paves the way for time-resolved studies of the dissociation dynamics of inner-shell ionized molecules in a coincidence detection scheme. First coincidence measurements on CH3I are shown and it is outlined how the anticipated advancement of fiber laser technology and improved sample delivery will, in the next step, allow pump-probe studies of ultrafast molecular dynamics with table-top XUV-photon sources. These table-top sources can provide significantly higher repetition rates than the currently operating free-electron lasers and they offer very high temporal resolution due to the intrinsically small timing jitter between pump and probe pulses. PMID- 27505780 TI - Interaction potential between discrete solitons in waveguide arrays. AB - Using a variational approach, we obtained the interaction potential between two discrete solitons in optical waveguide arrays. The resulting potential bears the two features of soliton-soliton and soliton-waveguide interaction potentials where the former is similar to that of the continuum case and the latter is similar to the effective Pierls-Nabarro potential. The interplay between the two interaction potentials is investigated by studying its effect on the soliton molecule formation. It is found that the two solitons bind if their initial separation equals an odd number of waveguides, while they do not bind if their separation is an even number, which is a consequence of the two solitons being both either at the intersites (unstable) or being onsite (stable). We derived the equations of motion for the solitons' centre of mass and relative separation and provided analytic solutions for some specific cases. Favourable agreement between the analytical and numerical interaction potentials is obtained. Possible applications of our results to all-optical logic gates are pointed out. PMID- 27505781 TI - Micromanipulation of InP lasers with optoelectronic tweezers for integration on a photonic platform. AB - The integration of light sources on a photonic platform is a key aspect of the fabrication of self-contained photonic circuits with a small footprint that does not have a definitive solution yet. Several approaches are being actively researched for this purpose. In this work we propose optoelectronic tweezers for the manipulation and integration of light sources on a photonic platform and report the positional and angular accuracy of the micromanipulation of standard Fabry-Perot InP semiconductor laser die. These lasers are over three orders of magnitude bigger in volume than any previously assembled with optofluidic techniques and the fact that they are industry standard lasers makes them significantly more useful than previously assembled microdisk lasers. We measure the accuracy to be 2.5 +/- 1.4 um and 1.4 +/- 0.4 degrees and conclude that optoelectronic tweezers are a promising technique for the micromanipulation and integration of optoelectronic components in general and semiconductor lasers in particular. PMID- 27505782 TI - Enhancement of optical polarization degree of AlGaN quantum wells by using staggered structure. AB - Staggered AlGaN quantum wells (QWs) are designed to enhance the transverse electric (TE) polarized optical emission in deep ultraviolet (DUV) light- emitting diodes (LED). The optical polarization properties of the conventional and staggered AlGaN QWs are investigated by a theoretical model based on the k.p method as well as polarized photoluminescence (PL) measurements. Based on an analysis of the valence subbands and momentum matrix elements, it is found that AlGaN QWs with step-function-like Al content in QWs offers much stronger TE polarized emission in comparison to that from conventional AlGaN QWs. Experimental results show that the degree of the PL polarization at room temperature can be enhanced from 20.8% of conventional AlGaN QWs to 40.2% of staggered AlGaN QWs grown by MOCVD, which is in good agreement with the theoretical simulation. It suggests that polarization band engineering via staggered AlGaN QWs can be well applied in high efficiency AlGaN-based DUV LEDs. PMID- 27505783 TI - Optimization of multilayered nanotubes for maximal scattering cancellation. AB - An optimization for multilayered nanotubes that minimizes the scattering efficiency for a given polarization is derived. The cylindrical nanocavities have a radially periodic distribution, and the marginal layers that play a crucial role particularly in the presence of nonlocalities are disposed to reduce the scattering efficiency up to two orders of magnitude in comparison with previous proposals. The predominant causes leading to such invisibility effect are critically discussed. PMID- 27505784 TI - Performance and noise analysis of optical microresonator-based biochemical sensors using intensity detection. AB - Optical microcavity sensors using intensity detection open up the possibility to realize fully integrated high-performance sensing devices, which are significant for both fundamental study of molecular interaction and rapid disease diagnosis. Although the performance of microresonator-based sensors has been studied focusing on the resonance-tracking method, the situation can be much different for intensity-detection sensors. Here we conducted a systematically investigation on the noises sources in intensity detection scheme and their influences on key performance parameters, e.g., signal-to-noise ratio (SNR), limit-of-detection (LOD), and detection range, for various sensors configurations. Especially, the trade-off between SNR and LOD is identified and theoretically analyzed. With experiment noises taken into consideration, our work aims to provide design guidelines for integrated microresonator sensors with optimized performance. PMID- 27505785 TI - VUV and XUV reflectance of optically coated mirrors for selection of high harmonics. AB - We report the reflectance, ~1 degrees from normal incidence, of six different mirrors as a function of photon energy, using monochromatic vacuum ultraviolet (VUV) and extreme ultraviolet (XUV) radiation with energies between 7.5 eV and 24.5 eV. The mirrors examined included both single and multilayer optical coatings, as well as an uncoated substrate. We discuss the performance of each mirror, paying particular attention to the potential application of suppression and selection of high-order harmonics of a Ti:sapphire laser. PMID- 27505786 TI - Integrated nonlinear interferometer with wavelength multicasting functionality. AB - Nonlinear interference based on four wave mixing (FWM) is extremely attractive due to its phase sensitivity. On the other hand, wavelength multicasting, which supports data point-to-multipoint connections, is a key functionality to increase the network efficiency and simplify the transmitter and receiver in the wavelength-division multiplexing systems. We propose and experimentally demonstrate a nonlinear interferometer with wavelength multicasting functionality based on single-stage FWM in an integrated silicon waveguide. With a three-pump and dual-signal input, four phase sensitive idlers are obtained at the interferometer output. For a proof-of-concept application, we further theoretically demonstrate the multicasting logic exclusive-OR (XOR) gate for both intensity and phase modulated signals. The proposed scheme would be potentially applied in various on-chip applications for future optical communication system. PMID- 27505787 TI - Design of plasmonic photodetector with high absorptance and nano-scale active regions. AB - We propose a novel plasmonic photodetector with high responsivity, utilizing nano scale active regions. This design can be applied to diverse materials (group III V or IV materials) and different operation wavelengths covering the O-U bands. The periodic structure utilizing Surface Plasmon Polariton Bloch Waves (SPP-BWs) has low optical power loss. FDTD simulation shows an absorptance of 74.4% which means a responsivity of about 0.74 A/W at 1550 nm. The low capacitance brings low noise, reduced power consumption, and a high electrical bandwidth which is estimated to be 140 GHz. Among the plasmonic PDs with inherent high speeds but low responsivities, our design makes the obvious progress on improving the absorptance. PMID- 27505788 TI - Reconfigurable hybrid metamaterial waveguide system at terahertz regime. AB - We propose an optically controlled reconfigurable hybrid metamaterial waveguide system at terahertz frequencies, which consists of a two dimensional gold cut wire array deposited on top of a dielectric slab waveguide. Numerical findings reveal that this device is able to realize dynamic transformation from double electromagnetically induced transparency like material to ultra-narrow band guided mode resonance (GMR) filter by controlling the optically excited free carriers in gallium arsenide pads inserted between the gold cut wires. During this reconfiguration process of resonance modes, high quality factors up to ~104 and ~118 for the two EIT-like peaks and up to ~578 for the GMR filter are obtained. PMID- 27505789 TI - High-purity 60GHz band millimeter-wave generation based on optically injected semiconductor laser under subharmonic microwave modulation. AB - Based on an optically injected semiconductor laser (OISL) operating at period-one (P1) nonlinear dynamical state, high-purity millimeter-wave generation at 60 GHz band is experimentally demonstrated via 1/4 and 1/9 subharmonic microwave modulation (the order of subharmonic is with respect to the frequency fc of the acquired 60 GHz band millimeter-wave but not the fundamental frequency f0 of P1 oscillation). Optical injection is firstly used to drive a semiconductor laser into P1 state. For the OISL operates at P1 state with a fundamental frequency f0 = 49.43 GHz, by introducing 1/4 subharmonic modulation with a modulation frequency of fm = 15.32 GHz, a 60 GHz band millimeter-wave with central frequency fc = 61.28 GHz ( = 4fm) is experimentally generated, whose linewidth is below 1.6 kHz and SSB phase noise at offset frequency 10 kHz is about -96 dBc/Hz. For fm is varied between 13.58 GHz and 16.49 GHz, fc can be tuned from 54.32 GHz to 65.96 GHz under matched modulation power Pm. Moreover, for the OISL operates at P1 state with f0 = 45.02 GHz, a higher order subharmonic modulation (1/9) is introduced into the OISL for obtaining high-purity 60 GHz band microwave signal. With (fm, Pm) = (7.23 GHz, 13.00 dBm), a microwave signal at 65.07 GHz ( = 9fm) with a linewidth below 1.6 kHz and a SSB phase noise less than -98 dBc/Hz is experimentally generated. Also, the central frequency fc can be tuned in a certain range through adjusting fm and selecting matched Pm. PMID- 27505790 TI - Manipulation of wavefront using helical metamaterials. AB - Helical metamaterials, a kind of 3-dimensional structure, has relatively strong coupling effect among the helical nano-wires. Therefore, it is expected to be a good candidate for generating phase shift and controlling wavefront with high efficiency. In this paper, using the finite-difference time-domain (FDTD) method, we studied the phase shift properties in the helical metamaterials. It is found that the phase shift occurs for both transmitted and reflected light waves. And the maximum of reflection coefficients can reach over 60%. In addition, the phase shift (phi) is dispersionless in the range of 600 nm to 860 nm, that is, it is only dominated by the initial angle (theta) of the helix. The relationship between them is phi = +/- 2theta. Using Jones calculus we give a further explanation for these properties. Finally, by arranging the helixes in an array with a constant phase gradient, the phenomenon of anomalous refraction was also observed in a broad wavelength range. PMID- 27505791 TI - Snapshot fan beam coded aperture coherent scatter tomography. AB - We use coherently scattered X-rays to measure the molecular composition of an object throughout its volume. We image a planar slice of the object in a single snapshot by illuminating it with a fan beam and placing a coded aperture between the object and the detectors. We characterize the system and demonstrate a resolution of 13 mm in range and 2 mm in cross-range and a fractional momentum transfer resolution of 15%. In addition, we show that this technique allows a 100x speedup compared to previously-studied pencil beam systems using the same components. Finally, by scanning an object through the beam, we image the full 4 dimensional data cube (3 spatial and 1 material dimension) for complete volumetric molecular imaging. PMID- 27505792 TI - Ghost imaging with different frequencies through non-degenerated four-wave mixing. AB - As a novel imaging method, ghost imaging has been widely explored in various fields of research, such as lensless ghost imaging, computational ghost imaging, turbulence-free ghost imaging. Recently, ghost imaging in non-degenerated system with pseudo-thermal light has been discussed theoretically, however, to our best knowledge, no experimental evidence has been proven yet. In this paper, we propose a new approach to realize ghost imaging with different frequencies, which are generated through a non-degenerated four-wave mixing(FWM) process in Rb vapor. In our experiment, by employing pseudo-thermal light as the probe beam, we found that the generated FWM signal has a strong second-order correlation with the original thermal light. On basis of that, we successfully implement non degenerate ghost imaging, and reconstruct highly similar images of objects. PMID- 27505793 TI - Digital polarization holography advancing geometrical phase optics. AB - Geometrical phase or the fourth generation (4G) optics enables realization of optical components (lenses, prisms, gratings, spiral phase plates, etc.) by patterning the optical axis orientation in the plane of thin anisotropic films. Such components exhibit near 100% diffraction efficiency over a broadband of wavelengths. The films are obtained by coating liquid crystalline (LC) materials over substrates with patterned alignment conditions. Photo-anisotropic materials are used for producing desired alignment conditions at the substrate surface. We present and discuss here an opportunity of producing the widest variety of "free form" 4G optical components with arbitrary spatial patterns of the optical anisotropy axis orientation with the aid of a digital spatial light polarization converter (DSLPC). The DSLPC is based on a reflective, high resolution spatial light modulator (SLM) combined with an "ad hoc" optical setup. The most attractive feature of the use of a DSLPC for photoalignment of nanometer thin photo-anisotropic coatings is that the orientation of the alignment layer, and therefore of the fabricated LC or LC polymer (LCP) components can be specified on a pixel-by-pixel basis with high spatial resolution. By varying the optical magnification or de-magnification the spatial resolution of the photoaligned layer can be adjusted to an optimum for each application. With a simple "click" it is possible to record different optical components as well as arbitrary patterns ranging from lenses to invisible labels and other transparent labels that reveal different images depending on the side from which they are viewed. PMID- 27505794 TI - Experimental demonstration of an adaptive architecture for direct spectral imaging classification. AB - Spectral imaging is a powerful tool for providing in situ material classification across a spatial scene. Typically, spectral imaging analyses are interested in classification, though often the classification is performed only after reconstruction of the spectral datacube. We present a computational spectral imaging system, the Adaptive Feature-Specific Spectral Imaging Classifier (AFSSI C), which yields direct classification across the spatial scene without reconstruction of the source datacube. With a dual disperser architecture and a programmable spatial light modulator, the AFSSI-C measures specific projections of the spectral datacube which are generated by an adaptive Bayesian classification and feature design framework. We experimentally demonstrate multiple order-of-magnitude improvement of classification accuracy in low signal to-noise (SNR) environments when compared to legacy spectral imaging systems. PMID- 27505795 TI - Analysis of optical directional couplers using shortcuts to adiabaticity. AB - In this paper, we propose the use of the invariant based shortcuts to adiabaticity for the analysis of directional couplers. By describing the dynamical evolution of the system using the eigenstates of the invariant through new parameterizations, the system stability against errors in coupling coefficient and propagation constants mismatch is connected with the new parameters, which can be linked back to system parameters through inverse engineering. The merits and limitations of the conventional tapered directional coupler designs with various window functions are obtained through the analysis. We then propose an optimal design of compact directional couplers that is stable against errors in input wavelength and coupling coefficient simultaneously. The designed directional coupler has better tolerance, as compared to the conventional resonant couplers with smooth shape functions of Hamming and Blackman. These results are verified by beam propagation simulations. PMID- 27505796 TI - Optical Bloch oscillations and Zener tunneling of Airy beams in ionic-type photonic lattices. AB - We report on the existence of optical Bloch oscillations (OBOs) and Zener tunneling (ZT) of Airy beams in ionic-type photonic lattices with a refractive index ramp. Different from their counterparts in uniform lattices, Airy beams undergoing OBOs show an alternatively switched concave and convex trajectory as well as a periodical revival of input beam profiles. Moreover, the ionic-type photonic lattice established in photorefractive crystal exhibits a reconfigurable lattice structure, which provides a flexible way to tune the amplitude and period of the OBOs. Remarkably, it is demonstrated that the band gap of the lattice can be readily controlled by rotating the lattice inducing beam, which forces the ZT rate to follow two significant different decay curves amidst decreasing index gradient. Our results open up new possibilities for all-optical switching, routing and manipulation of Airy beams. PMID- 27505797 TI - Bulk magnetic terahertz metamaterials based on dielectric microspheres. AB - Rigid metamaterials were prepared by embedding TiO2 microspheres into polyethylene. These structures exhibit a series of Mie resonances where the lowest-frequency one is associated with a strong dispersion in the effective magnetic permeability. Using time-domain terahertz spectroscopy, we experimentally demonstrated the magnetic nature of the observed resonance. The presented approach shows a way for low-cost massive fabrication of mechanically stable terahertz metamaterials based on dielectric microresonators. PMID- 27505798 TI - Membrane distributed-reflector laser integrated with SiOx-based spot-size converter on Si substrate. AB - We demonstrate monolithic integration of a 50-MUm-long-cavity membrane distributed-reflector laser with a spot-size converter, consisting of a tapered InP wire waveguide and an SiOx waveguide, on SiO2/Si substrate. The device exhibits 9.4-GHz/mA0.5 modulation efficiency with a 2.2-dB fiber coupling loss. We demonstrate 25.8-Gbit/s direct modulation with a bias current of 2.5 mA, resulting in a low energy cost of 132 fJ/bit. PMID- 27505799 TI - Periodic nonlinear Fourier transform for fiber-optic communications, Part I: theory and numerical methods. AB - In this work, we introduce the periodic nonlinear Fourier transform (PNFT) method as an alternative and efficacious tool for compensation of the nonlinear transmission effects in optical fiber links. In the Part I, we introduce the algorithmic platform of the technique, describing in details the direct and inverse PNFT operations, also known as the inverse scattering transform for periodic (in time variable) nonlinear Schrodinger equation (NLSE). We pay a special attention to explaining the potential advantages of the PNFT-based processing over the previously studied nonlinear Fourier transform (NFT) based methods. Further, we elucidate the issue of the numerical PNFT computation: we compare the performance of four known numerical methods applicable for the calculation of nonlinear spectral data (the direct PNFT), in particular, taking the main spectrum (utilized further in Part II for the modulation and transmission) associated with some simple example waveforms as the quality indicator for each method. We show that the Ablowitz-Ladik discretization approach for the direct PNFT provides the best performance in terms of the accuracy and computational time consumption. PMID- 27505800 TI - Periodic nonlinear Fourier transform for fiber-optic communications, Part II: eigenvalue communication. AB - In this paper we propose the design of communication systems based on using periodic nonlinear Fourier transform (PNFT), following the introduction of the method in the Part I. We show that the famous "eigenvalue communication" idea [A. Hasegawa and T. Nyu, J. Lightwave Technol. 11, 395 (1993)] can also be generalized for the PNFT application: In this case, the main spectrum attributed to the PNFT signal decomposition remains constant with the propagation down the optical fiber link. Therefore, the main PNFT spectrum can be encoded with data in the same way as soliton eigenvalues in the original proposal. The results are presented in terms of the bit-error rate (BER) values for different modulation techniques and different constellation sizes vs. the propagation distance, showing a good potential of the technique. PMID- 27505801 TI - Lambertian thermal emitter based on plasmonic enhanced absorption. AB - In this paper, a narrow band thermal emission at 10 MUm is demonstrated using a one dimensional metasurface. The proposed metasurface structure provides magnetic resonance mode that enhances the phonon absorption of SiO2. The proposed metasurface thermal emitter shows a Lambertian distribution. Additionally, 5.8-folds enhancement of emissivity is achieved by optimizing the cavity thickness of the metasurfaces. This type of thermal emitter will be useful for IR sensing applications. PMID- 27505802 TI - Complete hyperentangled Bell state analysis for polarization and time-bin hyperentanglement. AB - We present a complete hyperentangled Bell state analysis protocol for two-photon four-qubit states that are simultaneously entangled in the polarization and time bin degrees of freedom. The 16 hyperentangled states can be unambiguously distinguished via two steps. In the first step, the polarization entangled state is distinguished deterministically and nondestructively with the help of the cross-Kerr nonlinearity. Then, in the second step, the time-bin state is analyzed with the aid of the polarization entanglement. We also discuss the applications of our protocol for quantum information processing. Compared with hyperentanglement in polarization and spatial-mode degrees of freedom, the polarization and time-bin hyperentangled states provide savings in quantum resources since there is no requirement for two spatial modes for each photon. This is the first complete hyperentangled Bell state analysis scheme for polarization and time-bin hyperentangled states, and it can provide new avenues for high-capacity, long-distance quantum communication. PMID- 27505803 TI - High-quality-factor planar optical cavities with laterally stopped, slowed, or reversed light. AB - In a planar optical cavity, the resonance frequencies increase as a function of in-plane wavevector according to a standard textbook formula. This has well-known consequences in many different areas of optics, from the shifts of etalon peaks at non-normal angles, to the properties of transverse modes in laser diodes, to the effective mass of microcavity photons, and so on. However, this standard formula is valid only when the reflection phase of each cavity mirror is approximately independent of angle. There is a certain type of mirror-a subwavelength dielectric grating near a guided mode resonance-with not only a strongly angle-dependent reflection phase, but also very high reflectance and low losses. Simulations show that by using such mirrors, high-quality-factor planar cavities can be designed that break all these textbook rules, leading to resonant modes that are slow, stopped or even backward-propagating in the in-plane direction. In particular, we demonstrate experimentally high-Q planar cavities whose resonance frequency is independent of in-plane wavevector-i.e., the resonant modes have zero in-plane group velocity, for one polarization but both in-plane directions. We discuss potential applications in various fields including lasers, quantum optics, and exciton-polariton condensation. PMID- 27505804 TI - Dual-wavelength digital holography with a single low-coherence light source. AB - We propose a measurement system using dual-wavelength digital holography and low coherence interferometry to measure micro- and nanostructure surface heights. To achieve an extended axial step-measurement range and better image quality, a single light-emitting diode generates two distinct light sources by filtering different center wavelengths and narrower bandwidths. The system can measure surface profile with higher step heights and lower speckle noise in a large field of-view. Using single-source lighting and a simple configuration, the method supports compactly configured and lower-cost surface-topography measurement systems applicable in various fields. Experimental results for a standard step sample verify the system's performance. PMID- 27505805 TI - Light coupling between vertical III-As nanowires and planar Si photonic waveguides for the monolithic integration of active optoelectronic devices on a Si platform. AB - We present a new concept for the optical interfacing between vertical III-As nanowires and planar Si waveguides. The nanowires are arranged in a two dimensional array which forms a grating structure on top of the waveguide. This grating enables light coupling in both directions between the components made from the two different material classes. Numerical simulations show that this concept permits a light extraction efficiency from the waveguide larger than 45% and a light insertion efficiency larger than 35%. This new approach would allow the monolithic integration of nanowire-based active optoelectronics devices, like photodetectors and light sources, on the Si photonics platform. PMID- 27505806 TI - Direct modulation of 1.3 MUm quantum dot lasers on silicon at 60 degrees C. AB - We demonstrate direct modulation of an InAs/GaAs quantum dot (QD) laser on Si. A Fabry-Perot QD laser was integrated on Si by an ultraviolet-activated direct bonding method, and a cavity was formed using cleaved facets without HR/AR coatings. The bonded laser was operated under continuous-wave pumping at room temperature with a threshold current of 41 mA and a maximum output power of 30 mW (single facet). Even with such a simple device structure and fabrication process, our bonded laser is directly modulated using a 10 Gbps non-return-to-zero signal with an extinction ratio of 1.9 dB at room temperature. Furthermore, 6 Gbps modulation with an extinction ratio of 4.5 dB is achieved at temperatures up to 60 degrees C without any current or voltage adjustment. These results of device performances indicate an encouraging demonstration on III-V QD lasers on Si for the applications of the photonic integrated circuits. PMID- 27505807 TI - Optical pulling using evanescent mode in sub-wavelength channels. AB - Optical evanescent wave in total internal reflection has been widely used in efficient optical manipulation, where the object is trapped by the intrinsic intensity gradient of the evanescent wave while transported by the scattering force along the orthogonal direction. Here, we propose a distinct optical manipulation scheme using the attenuated modes in subwavelength optical channels, where both the trapping and transportation forces are along the channel direction. We create such a mode in a sub-wavelength photonic crystal waveguide and quantitatively obtain the net pushing and pulling forces, which can overcome the Brownian motion within a critical length. Due to the presence of the physical channel, subwavelength trapping on the transverse direction is natural, and manipulation along bend trajectories is also possible without the assistance of the self-acceleration beams provided a channel is adopted. This optical manipulation method can be extended to any other channels that support attenuation mode, and may provide an alternate way for flexible optical manipulation. PMID- 27505808 TI - Pixel-wise absolute phase unwrapping using geometric constraints of structured light system. AB - This paper presents a method to unwrap phase pixel by pixel by solely using geometric constraints of the structured light system without requiring additional image acquisition or another camera. Specifically, an artificial absolute phase map, Phimin, at a given virtual depth plane z = zmin, is created from geometric constraints of the calibrated structured light system; the wrapped phase is pixel by-pixel unwrapped by referring to Phimin. Since Phimin is defined in the projector space, the unwrapped phase obtained from this method is absolute for each pixel. Experimental results demonstrate the success of this proposed novel absolute phase unwrapping method. PMID- 27505809 TI - Linearly chirped microwave waveform generation with large time-bandwidth product by optically injected semiconductor laser. AB - A scheme for photonic generation of linearly chirped microwave waveforms (LCMWs) with a large time-bandwidth product (TBWP) is proposed and demonstrated based on an optically injected semiconductor laser. In the proposed system, the optically injected semiconductor laser is operated in period-one (P1) oscillation state. After optical-to-electrical conversion, a microwave signal can be generated with its frequency determined by the injection strength. By properly controlling the injection strength, an LCMW with a large TBWP can be generated. The proposed system has a simple and compact structure. Besides, the center frequency, bandwidth, as well as the temporal duration of the generated LCMWs can be easily adjusted. An experiment is carried out. LCMWs with TBWPs as large as 1.2x105 (bandwidth 12 GHz; temporal duration 10 MUs) are successfully generated. The flexibility for tuning the center frequency, bandwidth and temporal duration is also demonstrated. PMID- 27505810 TI - High efficiency double-wavelength dielectric metasurface lenses with dichroic birefringent meta-atoms. AB - Metasurfaces are ultrathin optical structures that manipulate optical wavefronts. Most metasurface devices which deflect light are designed for operation at a single wavelength, and their function changes as the wavelength is varied. Here we propose and demonstrate a double-wavelength metasurface based on polarization dependent dielectric meta-atoms that control the phases of two orthogonal polarizations independently. Using this platform, we design lenses that focus light at 915 and 780 nm with perpendicular linear polarizations to the same focal distance. Lenses with numerical apertures up to 0.7 and efficiencies from 65% to above 90% are demonstrated. In addition to the high efficiency and numerical aperture, an important feature of this technique is that the two operation wavelengths can be chosen to be arbitrarily close. These characteristics make these lenses especially attractive for fluorescence microscopy applications. PMID- 27505811 TI - Super-resolving angular rotation measurement using binary-outcome homodyne detection. AB - There has been much recent interest in high precision angular rotation measurement using photon orbital angular momentum to realize super-resolving angular rotation measurement. It is well known that quantum detection strategies can obtain a quantum-enhanced performance. Here, we prove that binary-outcome homodyne detection method can obtain a narrower signal peak, showing better resolution compared with the existing data processing method. Since the photon loss is unavoidable in the actual non-ideal optical system, this paper further discusses the impact of photon loss on the resolution and sensitivity of angular rotation measurement with binary-outcome homodyne detection method. PMID- 27505812 TI - Rectilinear lattices of polarization vortices with various spatial polarization distributions. AB - In this paper, we propose a type of rectilinear lattices of polarization vortices, each spot in which has mutually independent, and controllable spatial polarization distributions. The lattices are generated by two holograms under special design. In the experiment, the holograms are encoded on two spatial light modulators, and the results fit very well with theory. Our scheme makes it possible to generate multiple polarization vortices with various polarization distributions simultaneously, for instance, radially and azimuthally polarized beams, and can be used in the domains as polarization-based data transmission system, optical manufacture, polarization detection and so on. PMID- 27505813 TI - Design of universal fiber with demonstration of full system reaches over 100G SR4, 40G sWDM, and 100G CWDM4 transceivers. AB - Universal fiber has an LP01 mode field diameter approximately matched to that of standard single mode fiber, while being a multimode fiber. We analyzed the dependence of the mode field diameter on the core diameter for different core delta values. Guided by the analysis, a universal fiber having a delta of 1.2% was fabricated, showing significantly reduced coupling loss of ~2.3 dB with conventional multimode fiber. We demonstrated that the fiber can transmit with full system reach in both single mode and VCSEL-based multimode transmissions, including 100G SR4, 40G sWDM, and 100G CWDM4 for the first time. PMID- 27505814 TI - Aberrations of the point spread function of a multimode fiber due to partial mode excitation. AB - We investigate the point spread function of a multimode fiber. The distortion of the focal spot created on the fiber output facet is studied for a variety of the parameters. We develop a theoretical model of wavefront shaping through a multimode fiber and use it to confirm our experimental results and analyze the nature of the focal distortions. We show that aberration-free imaging with a large field of view can be achieved by using an appropriate number of segments on the spatial light modulator during the wavefront-shaping procedure. The results describe aberration limits for imaging with multimode fibers as in, e.g., microendoscopy. PMID- 27505815 TI - Massively parallel femtosecond laser processing. AB - Massively parallel femtosecond laser processing with more than 1000 beams was demonstrated. Parallel beams were generated by a computer-generated hologram (CGH) displayed on a spatial light modulator (SLM). The key to this technique is to optimize the CGH in the laser processing system using a scheme called in system optimization. It was analytically demonstrated that the number of beams is determined by the horizontal number of pixels in the SLM NSLM that is imaged at the pupil plane of an objective lens and a distance parameter pd obtained by dividing the distance between adjacent beams by the diffraction-limited beam diameter. A performance limitation of parallel laser processing in our system was estimated at NSLM of 250 and pd of 7.0. Based on these parameters, the maximum number of beams in a hexagonal close-packed structure was calculated to be 1189 by using an analytical equation. PMID- 27505816 TI - Mapping the energy density of shaped waves in scattering media onto a complete set of diffusion modes. AB - We study the energy density of shaped waves inside a quasi-1D disordered waveguide. We find that the spatial energy density of optimally shaped waves, when expanded in the complete set of eigenfunctions of the diffusion equation, is well described by considering only a few of the lowest eigenfunctions. Taking into account only the fundamental eigenfunction, the total internal energy inside the sample is underestimated by only 2%. The spatial distribution of the shaped energy density is very similar to the fundamental eigenfunction, up to a cosine distance of about 0.01. We obtain the energy density of transmission eigenchannels inside the sample by numerical simulation of the scattering matrix. Computing the transmission-averaged energy density over all transmission channels yields the ensemble averaged energy density of shaped waves. From the averaged energy density, we reconstruct its spatial distribution using the eigenfunctions of the diffusion equation. The results of our study have exciting applications in controlled biomedical imaging, efficient light harvesting in solar cells, enhanced energy conversion in solid-state lighting, and low threshold random lasers. PMID- 27505817 TI - Quantification of the fluorescence sensing performance of microstructured optical fibers compared to multi-mode fiber tips. AB - Microstructured optical fibers, particularly those with a suspended-core geometry, have frequently been argued as efficient evanescent-field fluorescence based sensors. However, to date there has not been a systematic comparison between such fibers and the more common geometry of a multi-mode fiber tip sensor. In this paper we make a direct comparison between these two fiber sensor geometries both theoretically and experimentally. Our results confirm that suspended-core fibers provide a significant advantage in terms of total collected fluorescence signal compared to multi-mode fibers using an equivalent experimental configuration. PMID- 27505818 TI - Discrete dispersion scanning as a simple method for broadband femtosecond pulse characterization. AB - A simple and easy to implement technique for femtosecond pulse characterization is proposed and experimentally verified. It is based on the introduction of a known amount of dispersion (by controlling the number of passes through dispersive material) and subsequent recording of the spectral positions of second harmonic peaks obtained in a non-linear crystal. Such dependence allows for direct retrieval of the pulse spectral phase. The presented pulse characterization method is beneficial especially for broadband pulses, where the second harmonic spectrum exceeds the detection bandwidth of a single spectrometer. PMID- 27505819 TI - Sensitivity analysis of volume scattering phase functions. AB - To solve the radiative transfer equation and relate inherent optical properties (IOPs) to apparent optical properties (AOPs), knowledge of the volume scattering phase function is required. Due to the difficulty of measuring the phase function, it is frequently approximated. We explore the sensitivity of derived AOPs to the phase function parameterization, and compare measured and modeled values of both the AOPs and estimated phase functions using data from Monterey Bay, California during an extreme "red tide" bloom event. Using in situ measurements of absorption and attenuation coefficients, as well as two sets of measurements of the volume scattering function (VSF), we compared output from the Hydrolight radiative transfer model to direct measurements. We found that several common assumptions used in parameterizing the radiative transfer model consistently introduced overestimates of modeled versus measured remote-sensing reflectance values. Phase functions from VSF data derived from measurements at multiple wavelengths and a single scattering single angle significantly overestimated reflectances when using the manufacturer-supplied corrections, but were substantially improved using newly published corrections; phase functions calculated from VSF measurements using three angles and three wavelengths and processed using manufacture-supplied corrections were comparable, demonstrating that reasonable predictions can be made using two commercially available instruments. While other studies have reached similar conclusions, our work extends the analysis to coastal waters dominated by an extreme algal bloom with surface chlorophyll concentrations in excess of 100 mg m-3. PMID- 27505820 TI - Low-bias current 10 Gbit/s direct modulation of GaInAsP/InP membrane DFB laser on silicon. AB - Low-power consumption directly-modulated lasers are a key device for on-chip optical interconnection. We fabricated a GaInAsP/InP membrane DFB laser that exhibited a low-threshold current of 0.21 mA and single-mode operation with a sub mode suppression ratio of 47 dB at a bias current of 2 mA. A high modulation efficiency of 11 GHz/mA1/2 was obtained. A 10 Gbit/s direct modulation using a non-return-to-zero 231-1 pseudo-random bit sequence signal was performed with a bias current of 1 mA, which is the lowest bias current ever reported for direct modulation of a DFB laser. A bit-error rate of 10 9 was successfully achieved. PMID- 27505821 TI - Topological description for gaps of one-dimensional symmetric all-dielectric photonic crystals. AB - We propose a topological description for gaps of one-dimensional symmetric all dielectric photonic crystals (PCs). It is shown that, in the propagating direction, the effective electromagnetic parameters of PCs can be derived from one unit cell with mirror symmetry. Besides, at the frequencies of gaps, these symmetric PCs can be described as photonic insulators with effective negative permittivity or negative permeability. Moreover, based on the mapping of Maxwell's equations to the Dirac equation and the band inversion achieved by tuning the material and structural parameters, we demonstrate that the gaps of PCs with effective negative permittivity or negative permeability possess different topological orders. Lastly, we show that a bound state is robust against the disorder under a zero-average-effective-mass condition in a heterostructure made of two PCs with different topological orders. PMID- 27505822 TI - Metal clad active fibres for power scaling and thermal management at kW power levels. AB - We present a new approach to high power fibre laser design, consisting of a polymer-free all-glass optical fibre waveguide directly overclad with a high thermal conductivity metal coating. This metal clad active fibre allows a significant reduction in thermal resistance between the active fibre and the laser heat-sink as well as a significant increase in the operating temperature range. In this paper we show the results of a detailed thermal analysis of both polymer and metal coated active fibres under thermal loads typical of kW fibre laser systems. Through several different experiments we present the first demonstration of a cladding pumped aluminium-coated fibre laser and the first demonstration of efficient operation of a cladding-pumped fibre laser at temperatures of greater than 400 degrees C. Finally, we highlight the versatility of this approach through operation of a passively (radiatively) cooled ytterbium fibre laser head at an output power of 405 W in a compact and ultralight package weighing less than 100 g. PMID- 27505823 TI - Design methodology for micro-discrete planar optics with minimum illumination loss for an extended source. AB - Recently, studies have examined techniques for modeling the light distribution of light-emitting diodes (LEDs) for various applications owing to their low power consumption, longevity, and light weight. The energy mapping technique, a design method that matches the energy distributions of an LED light source and target area, has been the focus of active research because of its design efficiency and accuracy. However, these studies have not considered the effects of the emitting area of the LED source. Therefore, there are limitations to the design accuracy for small, high-power applications with a short distance between the light source and optical system. A design method for compensating for the light distribution of an extended source after the initial optics design based on a point source was proposed to overcome such limits, but its time-consuming process and limited design accuracy with multiple iterations raised the need for a new design method that considers an extended source in the initial design stage. This study proposed a method for designing discrete planar optics that controls the light distribution and minimizes the optical loss with an extended source and verified the proposed method experimentally. First, the extended source was modeled theoretically, and a design method for discrete planar optics with the optimum groove angle through energy mapping was proposed. To verify the design method, design for the discrete planar optics was achieved for applications in illumination for LED flash. In addition, discrete planar optics for LED illuminance were designed and fabricated to create a uniform illuminance distribution. Optical characterization of these structures showed that the design was optimal; i.e., we plotted the optical losses as a function of the groove angle, and found a clear minimum. Simulations and measurements showed that an efficient optical design was achieved for an extended source. PMID- 27505824 TI - Hyper-parallel Toffoli gate on three-photon system with two degrees of freedom assisted by single-sided optical microcavities. AB - Encoding qubits in multiple degrees of freedom (DOFs) of a quantum system allows less-decoherence quantum information processing with much less quantum resources. We present a compact and scalable quantum circuit to determinately implement a hyper-parallel controlled-controlled-phase-flip (hyper-C2PF) gate in a three-photon system in both the polarization and spatial DOFs. In contrast with the one with many qubits encoding on one DOF only, our hyper-C2PF gate operating two independent C2PF gates on a three-photon system with less decoherence, and reduces the quantum resources required in quantum information processing by a half. Additional photons, necessary for many approaches, are not required in the present scheme. Our calculation shows that this hyper-C2PF gate is feasible in experiment. PMID- 27505825 TI - Intensity-only measurement of partially uncontrollable transmission matrix: demonstration with wave-field shaping in a microwave cavity. AB - Transmission matrices (TMs) have become a powerful and widely used tool to describe and control wave propagation in complex media. In certain scenarios the TM is partially uncontrollable, complicating its identification and use. In standard optical wavefront shaping experiments, uncontrollable reflections or imperfect illumination may be the cause; in reverberating cavities, uncontrollable reflections off the walls have that effect. Here we employ phase retrieval techniques to identify such a partially uncontrollable TM solely based on random intensity-only reference measurements. We demonstrate the feasibility of our method by focusing both on a single target as well as on multiple targets in a microwave cavity, using a phase-binary Spatial-Microwave-Modulator. PMID- 27505826 TI - Aperiodic Mo/Si multilayers for hard x-rays. AB - In this work we have developed aperiodic Molybdenum/Silicon (Mo/Si) multilayers (MLs) to reflect 16.25 keV photons at a grazing angle of incidence of 0.6 degrees +/- 0.05 degrees . To the best of our knowledge this is the first time this material system has been used to fabricate aperiodic MLs for hard x-rays. At these energies new hurdles arise. First of all a large number of bilayers is required to reach saturation. This poses a challenge from the manufacturing point of view, as thickness control of each ML period becomes paramount. The latter is not well defined a priori, due to the thickness of the interfacial silicide layers which has been observed to vary as a function of Mo and Si thickness. Additionally an amorphous-to-crystalline transition for Mo must be avoided in order maintain reasonably low roughness at the interfaces. This transition is well within the range of thicknesses pertinent to this study. Despite these difficulties our data demonstrates that we achieved reasonably flat ML response across the angular acceptance of +/- 0.05 degrees , with an experimentally confirmed average reflectivity of 28%. Such a ML prescription is well suited for applications in the field of hard x-ray imaging of highly diverging sources. PMID- 27505827 TI - Unusual anti-thermal degradation of bismuth NIR luminescence in bismuth doped lithium tantalum silicate laser glasses. AB - For application of bismuth laser glasses in either fiber amplifier or laser, their performance stability in long run should be understood especially in extreme conditions. However, so far, there are few reports on it. Here, we found, after the cycle experiments on heating and cooling, that the proper increase of lithium content in lithium tantalum silicate laser glass can lead to unusual anti thermal degradation of bismuth NIR luminescence, which completely differs from the scenario in germanate glass. FTIR, 29Si MAS NMR spectra, absorption and dynamic photoluminescence spectra are employed to unravel how this happens. The results illustrate that it should be due to the decrease of polymerization of silicate glass network, which in turn allows the regeneration at 250 degrees C, and therefore, the content increase of bismuth NIR emission centers. In the meanwhile, we noticed though Bi luminescence can be thermally quenched its peak does not shift along with temperature, which seldom appears in laser materials. The unique property might guarantee the unshift of Bi fiber laser wavelength once such glass was made into fiber devices even as the environmental temperature changes. The role of lithium is discussed in the evolution of glass structures, the suppression of glass heterogeneity, and the thermal stability of Bi luminescence, and it should be helpful to design homogeneous silicate laser glass with outstanding thermal stability. PMID- 27505828 TI - Tunable bandpass microwave photonic filter with ultrahigh stopband attenuation and skirt selectivity. AB - we propose and demonstrate a bandpass microwave photonic filter (MPF) with ultrahigh stopband attenuation and skirt selectivity based on a simple signal cancellation technique. By injecting two phase modulated signals located on opposite sides of two resonant gain peaks of a Fabry-Perot semiconductor optical amplifier (FP-SOA), two microwave frequency responses can be generated by the two input signals, respectively. The two frequency responses will add together within the passband but cancel each other out within the stopband, thus generating a MPF with simultaneous ultrahigh stopband attenuation and skirt selectivity. In the experiment the obtained MPF exhibits single passband in the range from 0 to 18 GHz and is tunable from 4 to 16 GHz by adjusting the laser wavelengths. During the tuning process the maximum stopband attenuation is 76.3 dB and the minimum 30 dB to 3-dB bandwidth shape factor is 3.5. PMID- 27505829 TI - Experimental comparison between speckle and grating-based imaging technique using synchrotron radiation X-rays. AB - X-ray phase contrast and dark-field imaging techniques provide important and complementary information that is inaccessible to the conventional absorption contrast imaging. Both grating-based imaging (GBI) and speckle-based imaging (SBI) are able to retrieve multi-modal images using synchrotron as well as lab based sources. However, no systematic comparison has been made between the two techniques so far. We present an experimental comparison between GBI and SBI techniques with synchrotron radiation X-ray source. Apart from the simple experimental setup, we find SBI does not suffer from the issue of phase unwrapping, which can often be problematic for GBI. In addition, SBI is also superior to GBI since two orthogonal differential phase gradients can be simultaneously extracted by one dimensional scan. The GBI has less stringent requirements for detector pixel size and transverse coherence length when a second or third grating can be used. This study provides the reference for choosing the most suitable technique for diverse imaging applications at synchrotron facility. PMID- 27505830 TI - Ultrathin zoom telescopic objective. AB - We report an ultrathin zoom telescopic objective that can achieve continuous zoom change and has reduced compact volume. The objective consists of an annular folded lens and three electrowetting liquid lenses. The annular folded lens undertakes the main part of the focal power of the lens system. Due to a multiple fold design, the optical path is folded in a lens with the thickness of ~1.98mm. The electrowetting liquid lenses constitute a zoom part. Based on the proposed objective, an ultrathin zoom telescopic camera is demonstrated. We analyze the properties of the proposed objective. The aperture of the proposed objective is ~15mm. The total length of the system is ~18mm with a tunable focal length ~48mm to ~65mm. Compared with the conventional zoom telescopic objective, the total length has been largely reduced. PMID- 27505831 TI - Frequency modulation of high-order harmonic generation in an orthogonally polarized two-color laser field. AB - We have experimentally investigated the frequency modulation of high-order harmonics in an orthogonally polarized two-color laser field consisting of a mid infrared 1800nm fundamental pulse and its second harmonic pulse. It is demonstrated that the high harmonic spectra can be fine-tuned as we slightly change the relative delay of the two-color laser pulses. By analyzing the relative frequency shift of each harmonic at different two-color delays, the nonadiabatic spectral shift induced by the rapid variation of the intensity dependent intrinsic dipole phase can be distinguished from the blueshift induced by the change of the refractive index during self-phase modulation (SPM). Our comprehensive analysis shows that the frequency modulation pattern is a reflection of the average emission time of high-order harmonic generation (HHG), thus offering a simple method to fine-tune the spectra of the harmonics on a sub cycle time scale. PMID- 27505832 TI - Two-frame phase-shifting interferometry for testing optical surfaces. AB - Standard phase-shifting interferometry (PSI) generally requires collecting at least three phase-shifted interferograms to extract the physical quantity being measured. Here, we propose the application of a simple two-frame PSI for the testing of a range of optical surfaces, including flats, spheres, and aspheres. The two-frame PSI extracts modulated phase from two randomly phase-shifted interferograms using a Gram-Schmidt algorithm, and can work in either null testing or non-null testing modes. Since only two interferograms are used for phase demodulation and the phase shift amount can be random, requirements on environmental conditions and phase shifter calibration are greatly relaxed. Experimental results of three different mirrors suggest that the two-frame PSI can achieve comparable measurement precision with conventional multi-frame PSI, but has faster data acquisition speed and less stringent hardware requirements. The proposed two-frame PSI expands the flexibility of PSI and holds great potential in many applications. PMID- 27505833 TI - Fabrication of europium-doped silica optical fiber with high Verdet constant. AB - A europium-doped (Eu-doped) silica optical fiber is fabricated using modified chemical vapor deposition (MCVD) technology. Europium fluoride (EuF3) material is introduced into the fiber core with a high temperature vaporizing technique. Its concentration is approximately 0.11 at %. The outer and core diameters of doped fiber are approximately 122 and 9 MUm, respectively. Refractive index difference (RID) between core and cladding is approximately 2%. A magneto-optical effect measurement system, which is based on the Stokes polarization parameters method, is set up to analyze its magneto-optical properties. The Verdet constant of the Eu-doped optical fiber is -4.563 rad T-1m-1, which is approximately double than that of single mode fiber (SMF) at 660 nm. PMID- 27505834 TI - Group velocity locked vector dissipative solitons in a high repetition rate fiber laser. AB - Vectorial nature of dissipative solitons (DSs) with high repetition rate is studied for the first time in a normal-dispersion fiber laser. Despite the fact that the formed DSs are strongly chirped and the repetition rate is greater than 100 MHz, polarization locked and polarization rotating group velocity locked vector DSs can be formed under 129.3 MHz fundamental mode-locking and 258.6 MHz harmonic mode-locking of the fiber laser, respectively. The two orthogonally polarized components of these vector DSs possess distinctly different central wavelengths and travel together at the same group velocity in the laser cavity, resulting in a gradual spectral edge and small steps on the optical spectrum, which can be considered as an auxiliary indicator of the group velocity locked vector DSs. Moreover, numerical simulations well confirm the experimental observations and further reveal the impact of the net cavity birefringence on the properties of the formed vector DSs. PMID- 27505835 TI - Mode structure of planar optical antennas on dielectric substrates. AB - We report a numerical study, supported by photoemission electron microscopy (PEEM), of sub-micron planar optical antennas on transparent substrate. We find these antennas generate intricate near-field spatial field distributions with odd and even numbers of nodes. We show that the field distributions are primarily superpositions of planar surface plasmon polariton modes confined to the metal/substrate interface. The mode structure provides opportunities for coherent switching and optical control in sub-micron volumes. PMID- 27505836 TI - Free-space to few-mode-fiber coupling under atmospheric turbulence. AB - High speed free space optical communication (FSOC) has taken advantages of components developed for fiber-optic communication systems. Recently, with the rapid development of few-mode-fiber based fiber communication systems, few-mode fiber components might further promote their applications in FSOC system. The coupling efficiency between free space optical beam and few-mode fibers under atmospheric turbulence effect are investigated in this paper. Both simulation and experimental results show that, compared with single-mode fiber, the coupling efficiencies for a 2-mode fiber and a 4-mode fiber are improved by ~4 dB and ~7 dB respectively in the presence of medium moderate and strong turbulence. Compared with single-mode fiber, the relative standard deviation of received power is restrained by 51% and 66% respectively with a 4-mode and 2-mode fiber. PMID- 27505837 TI - Ptychographic hyperspectral spectromicroscopy with an extreme ultraviolet high harmonic comb. AB - We report a proof-of-principle demonstration of a new scheme of spectromicroscopy in the extreme ultraviolet (EUV) spectral range, where the spectral response of the sample at different wavelengths is imaged simultaneously. This scheme is enabled by combining ptychographic information multiplexing (PIM) with a tabletop EUV source based on high harmonic generation, where four spectrally narrow harmonics near 30 nm form a spectral comb structure. Extending PIM from previously demonstrated visible wavelengths to the EUV/X-ray wavelengths promises much higher spatial resolution and a more powerful spectral contrast mechanism, making PIM an attractive spectromicroscopy method in both microscopy and spectroscopy aspects. In addition to spectromicroscopy, this method images the multicolor EUV beam in situ, making this a powerful beam characterization technique. In contrast to other methods, the techniques described here use no hardware to separate wavelengths, leading to efficient use of the EUV radiation. PMID- 27505838 TI - Generation of Q-switched mode locking controlled rectangular noise-like soliton bunching in a Tm-doped fiber laser. AB - We report on an interesting phenomenon of the combination of Q-switched mode locked pulses (QSMLP) and rectangular noise-like pulses (RNLP) as a unit in a Tm doped ring fiber laser which contains a Fabry-Perot (F-P) subcavity based on the nonlinear polarization evolution (NPE) technique. The RNLP and QSMLP are independently generated in the ring cavity and F-P subcavity, respectively. A notable characteristic is that the physical parameters of RNLP, e.g. repetition rate and pulse duration, are controlled by QSMLP. Thus, they form as a composite bunching, which is termed as "Q-switched mode locking controlled rectangular noise-like soliton bunching (QRNSB)". Further investigation shows that the existence of QRNSB only occurs in high pumping conditions, while both fundamental mode-locking pulses and the coexistence of QSMLP and solitons are achieved in low pumping ones. Our work can enrich the understanding of the nonlinear dynamics in fiber lasers. PMID- 27505839 TI - Scalar-vector soliton fiber laser mode-locked by nonlinear polarization rotation. AB - We report a passively mode-locked fiber laser by nonlinear polarization rotation (NPR), where both vector and scalar soliton can co-exist within the laser cavity. The mode-locked pulse evolves as a vector soliton in the strong birefringent segment and is transformed into a regular scalar soliton after the polarizer within the laser cavity. The existence of solutions in a polarization-dependent cavity comprising a periodic combination of two distinct nonlinear waves is first demonstrated and likely to be applicable to various other nonlinear systems. For very large local birefringence, our laser approaches the operation regime of vector soliton lasers, while it approaches scalar soliton fiber lasers under the condition of very small birefringence. PMID- 27505840 TI - Scalable screen-size enlargement by multi-channel viewing-zone scanning holography. AB - Viewing-zone scanning holographic displays can enlarge both the screen size and the viewing zone. However, limitations exist in the screen size enlargement process even if the viewing zone is effectively enlarged. This study proposes a multi-channel viewing-zone scanning holographic display comprising multiple projection systems and a planar scanner to enable the scalable enlargement of the screen size. Each projection system produces an enlarged image of the screen of a MEMS spatial light modulator. The multiple enlarged images produced by the multiple projection systems are seamlessly tiled on the planar scanner. This screen size enlargement process reduces the viewing zones of the projection systems, which are horizontally scanned by the planar scanner comprising a rotating off-axis lens and a vertical diffuser to enlarge the viewing zone. A screen size of 7.4 in. and a viewing-zone angle of 43.0 degrees are demonstrated. PMID- 27505841 TI - Experimental verification of epsilon-near-zero plasmon polariton modes in degenerately doped semiconductor nanolayers. AB - We investigate optical polariton modes supported by subwavelength-thick degenerately doped semiconductor nanolayers (e.g. indium tin oxide) on glass in the epsilon-near-zero (ENZ) regime. The dispersions of the radiative (R, on the left of the light line) and non-radiative (NR, on the right of the light line) ENZ polariton modes are experimentally measured and theoretically analyzed through the transfer matrix method and the complex-frequency/real-wavenumber analysis, which are in remarkable agreement. We observe directional near-perfect absorption using the Kretschmann geometry for incidence conditions close to the NR-ENZ polariton mode dispersion. Along with field enhancement, this provides us with an unexplored pathway to enhance nonlinear optical processes and to open up directions for ultrafast, tunable thermal emission. PMID- 27505842 TI - Spatial optical phase-modulating metadevice with subwavelength pixelation. AB - Dynamic control over optical wavefronts enables focusing, diffraction and redirection of light on demand, however, sub-wavelength resolution is required to avoid unwanted diffracted beams that are present in commercial spatial light modulators. Here we propose a realistic metadevice that dynamically controls the optical phase of reflected beams with sub-wavelength pixelation in one dimension. Based on reconfigurable metamaterials and nanomembrane technology, it consists of individually moveable metallic nanowire actuators that control the phase of reflected light by modulating the optical path length. We demonstrate that the metadevice can provide on-demand optical wavefront shaping functionalities of diffraction gratings, beam splitters, phase-gradient metasurfaces, cylindrical mirrors and mirror arrays - with variable focal distance and numerical aperture - without unwanted diffraction. PMID- 27505843 TI - Room temperature continuous wave operation of InAs-based quantum cascade lasers at 15 um. AB - We report low threshold InAs/AlSb quantum cascade lasers emitting near 15 um. The devices are based on a vertical design similar to those employed previously in far infrared InAs-based QCLs, whereas the doping level of the active core is considerably decreased. The lasers exhibit a threshold current density as low as 730 A/cm2 in pulsed mode at room temperature and can operate in this regime up to 410K. The continuous wave regime of operation has been achieved in these devices at temperatures up to 20 degrees C. The cw regime is demonstrated for InAs-based QCLs for the first time at room temperature. PMID- 27505844 TI - Differential refractive index sensor based on photonic molecules and defect cavities. AB - We present a novel differential refractive index sensor prototype based on a matrix of photonic molecules (PM) of soda-lime glass cylinders (epsilonc = 4.5) and two defect cavities. The measured and simulated spectra in the microwave range (8-12 GHz) show a wide photonic stop band with two localized states: the reference state, bound to a decagonal ring of cylinders and the sensing state, bound to the defect cavities. The defect mode is very sensitive to the permittivity of the material inserted in the cavity while the state in the PM remains unperturbed. We find that the response of the sensor is linear. These results can be extrapolated to the visible range due to scale invariance of Maxwell equations. PMID- 27505845 TI - Evaluation of endometrial natural killer cell expression of CD4, CD103, and CD16 cells in women with unexplained infertility. AB - OBJECTIVE: To determine whether natural killer cell (NK) concentrations in the mid-secretory endometrial tissue of women with unexplained infertility differ from those in the mid-secretory endometrial tissue of fertile women. METHODS: This study was conducted with 22 patients with unexplained infertility caused by unsuccessful ovulation induced with gonadotrophins and 12 healthy fertile women, who formed a control group. Mid-secretory endometrial tissue samples were obtained with a Pipelle catheter, and the endometrial NK cell phenotypes were determined by flow cytometry. RESULTS: The median number of CD4+ cells in the endometrium was significantly lower in women with unexplained infertility compared with in the fertile controls (3.31 vs. 5.81; p=0.02). The CD4(+)/CD8(+) cell ratio in the unexplained-infertility group was significantly lower than that in the control group (0.42 vs. 0.76, p=0.01). The median number of CD103(+) cells in the endometrium of the infertile group was significantly lower than that in the endometrium of the control group (4.40 vs. 6.73, p=0.02). The median number of CD16(+) cells was significantly higher in infertile women than in control women (0.12 vs. 0.001, p=0.01). CONCLUSIONS: Significant reductions in the numbers of CD4(+) and CD103(+) cells as well as in the CD4(+)/CD8(+) ratio but an increased number of CD16(+) cells in the endometrium of infertile women suggest that disordered NK cell activity may be a contributor to the etiology of unexplained infertility. PMID- 27505846 TI - Distribution of HLA DRB1 and DQB1 alleles and DRB1-DQB1 haplotypes among Bahraini women with polycystic ovary syndrome. AB - OBJECTIVE: This study investigated the association between HLA-DRB1 and -DQB1 alleles and DRB1-DQB1 haplotypes, and polycystic ovary syndrome (PCOS) in Bahraini women. DESIGN: Case-control, retrospective study. METHODS: Study subjects comprised 80 women with PCOS, and 169 age- and ethnically-matched control women. DRB1 and DQB1 genotyping was done by PCR-SSP. RESULTS: Of the 13 DRB1 alleles and 5 DQB1 alleles identified, DRB1*10 (14.3% vs. 4.4%) and DRB1*14 (8.7% vs. 1.1%), along with DQB1*05 (35.0% vs. 23.9%), were the most frequent alleles in cases, while DRB1*11 (15.3% vs. 6.8%) was the frequent allele found in controls. The association of PCOS with DRB1*10 (Pc<0.001), DRB1*14 (Pc<0.001), DQB1*05 (Pc=0.040), but not DRB1*11 (Pc=0.076) persisted after correcting for multiple comparisons. DRB1-DQB1 haplotype analysis identified nine common shared haplotypes in women with PCOS and control women, with a frequency exceeding 1%. Significantly higher frequency of DRB1*10-DQB1*05 (12.4% vs. 3.1%) and DRB1*14 DQB1*03 (5.6% vs. 1.0%), and reduced frequency of DRB1*11-DQB1*03 (4.1% vs. 14.1%) haplotypes were seen in women with PCOS vs. control women, thus assigning PCOS-susceptible and -protective nature to these haplotypes, respectively. This association persisted after controlling for multiple comparisons. CONCLUSION: Our results confirm an association of HLA-DRB1 and -DQB1 alleles and haplotypes with PCOS susceptibility in Bahraini Arabs, further underscoring the immunological/inflammatory nature of this disorder. PMID- 27505847 TI - Lysophosphatidic acid-induced RhoA signaling and prolonged macrophage infiltration worsens fibrosis and fatty infiltration following rotator cuff tears. AB - Previous studies have suggested that macrophage-mediated chronic inflammation is involved in the development of rotator cuff muscle atrophy and degeneration following massive tendon tears. Increased RhoA signaling has been reported in chronic muscle degeneration, such as muscular dystrophy. However, the role of RhoA signaling in macrophage infiltration and rotator muscle degeneration remains unknown. Using a previously established rat model of massive rotator cuff tears, we found RhoA signaling is upregulated in rotator cuff muscle following a massive tendon-nerve injury. This increase in RhoA expression is greatly potentiated by the administration of a potent RhoA activator, lysophosphatidic acid (LPA), and is accompanied by increased TNFalpha and TGF-beta1 expression in rotator cuff muscle. Boosting RhoA signaling with LPA significantly worsened rotator cuff muscle atrophy, fibrosis, and fatty infiltration, accompanied with massive monocytic infiltration of rotator cuff muscles. Co-staining of RhoA and the tissue macrophage marker CD68 showed that CD68+ tissue macrophages are the dominant cell source of increased RhoA signaling in rotator cuff muscles after tendon tears. Taken together, our findings suggest that LPA-mediated RhoA signaling in injured muscle worsens the outcomes of atrophy, fibrosis, and fatty infiltration by increasing macrophage infiltraion in rotator cuff muscle. Clinically, inhibiting RhoA signaling may represent a future direction for developing new treatments to improve muscle quality following massive rotator cuff tears. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1539-1547, 2017. PMID- 27505848 TI - Synthesis and Antileukemic Activities of Piperlongumine and HDAC Inhibitor Hybrids against Acute Myeloid Leukemia Cells. AB - Synergistic-to-additive antileukemic interactions of piperlongumine (PL) and HDAC inhibitor (HDACi) SAHA (Vorinostat) provide a compelling rationale to construct PL-HDACi hybrids, such as 1-58, which recapitulated the synergism between the parental compounds in high-risk and chemoresistant AML cells. Both PL and HDACi components, either in combination or in hybrid molecules, are essential for inducing significant DNA damage and apoptosis. Introducing C2-chloro substituent to 1-58 yielded 3-35 with increased cytotoxicity but decreased selectivity in noncancerous MCF-10A cells; eliminating C7-C8 olefin of PL obtained 3-31/3-98 scaffolds which were still more active than PL or SAHA in AML and were well tolerated by MCF-10A cells. The HDACi function was crucial for modulating expression of DNA repair and apoptosis-related proteins. Collectively, PL and SAHA hybrids are potent, multifunctional anti-AML agents, acting in part, by interfering cellular GSH defense, suppressing expression of DNA repair and pro survival proteins, and inducing expression of pro-apoptotic proteins. PMID- 27505849 TI - [Not Available]. PMID- 27505850 TI - [Not Available]. PMID- 27505851 TI - [Not Available]. AB - Bee and wasp stings can cause allergic reactions. Although the local reactions are more frequent, anaphylaxis due to insect stings can be potentially fatal. Rapid recognition of anaphylaxis is therefore critical and reactions should immediately be treated with i.m. adrenaline. Patients having experienced anaphylaxis should be referred to an allergist for diagnostic evaluation and possible venom-immunotherapy (VIT). The clinical history is essential in diagnosis of venom allergy as the test results are not always reliable. Diagnostic testing with venom components might be beneficial in appropriate patients. The analysis of serum tryptase from the acute episode can be crucial. Mastocytosis is associated in about 8 percent of patients with severe anaphylaxis from insect stings and should be considered in the differential diagnosis. VIT is indicated for patients with a history of anaphylaxis and is effective in preventing future anaphylaxis from Hymenoptera stings. PMID- 27505852 TI - [Not Available]. PMID- 27505853 TI - [Not Available]. PMID- 27505854 TI - N-pentyl-nitrofurantoin induces apoptosis in HL-60 leukemia cell line by upregulating BAX and downregulating BCL-xL gene expression. AB - BACKGROUND: Nitrofurantoin is a nitroderivative antibiotic that has bactericidal activity against pathogens causing urinary tract infection. A few studies have reported that nitrofurantoin has cytotoxic activity against cancer cells; however, nitrofurans remain a poorly explored class of compounds with respect to their anticancer potential. The aim of this study was to investigate the anticancer effects of a nitrofurantoin derivative, n-pentyl-nitrofurantoin (NFP), on HL-60 leukemia cells. METHODS: Cytotoxicity was assayed by the MTT assay. Cell morphology and phosphatidylserine externalization were visualized after Giemsa May-Grunwald and annexin V staining, respectively. DNA content and mitochondrial depolarization were measured by flow cytometry. BAX and BCL-xL expression was examined by RT-PCR. RESULTS: NFP was 3.8-fold more cytotoxic against HL-60 leukemia cells than against normal cells. NFP reduced the number of viable cells 24h after the treatment with a concomitant increase in the number of apoptotic cells indicated by the externalization of phosphatidylserine, DNA fragmentation, and mitochondrial depolarization. The mRNA levels of BAX increased, whereas the mRNA levels of BCL-xL decreased. CONCLUSION: The results indicate that NFP induces apoptosis in HL-60 cells by upregulating BAX and downregulating BCL-xL. PMID- 27505855 TI - Puerarin inhibits the inflammatory response in atherosclerosis via modulation of the NF-kappaB pathway in a rabbit model. AB - BACKGROUND: The isoflavone puerarin [7-hydroxy-3-(4-hydroxyphenyl)-1-benzopyran-4 one 8-(beta-D-glucopyranoside)] possesses many biological activities. In this study, we investigated the effects of puerarin on adhesion molecules (AMs), including serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin), and the activation of nuclear factor kappa B (NF-kappaB) in rabbits with experimental atherosclerosis. METHODS: In total, 24 rabbits were divided into control (standard diet), high-lipid diet (HLD), and PUE (HLD supplemented with puerarin) groups. At the end of weeks 0, 8, and 16, serum levels of AMs were measured. At the end of week 16, the thickness of the intima was detected. Protein and mRNA levels of AMs were checked by immunohistochemistry and RT-PCR, respectively. Protein levels of p65 NF-kappaB and phosphorylation of inhibitor kappaB (I-kappaB) were investigated by Western blotting. RESULTS: Atherosclerotic lesions in the thoracic arch were found in the HLD and PUE groups, but not in the control group. Compared with the HLD group, the thickness of the intima in the PUE group was reduced. Our results indicate that puerarin reduced the protein and mRNA levels of AMs in this rabbit model. We also found that the reduced AM levels were due to inhibition of the phosphorylation and degradation of I-kappaB, resulting in reduced p65 NF-kappaB nuclear translocation. CONCLUSIONS: This study indicates that the effect of puerarin on the suppression of atherosclerosis was connected with an inhibited inflammatory response and reduced NF-kappaB activation. PMID- 27505856 TI - Evaluation of the Substrate Scope of Benzoic Acid (De)carboxylases According to Chemical and Biochemical Parameters. AB - The enzymatic carboxylation of phenolic compounds has been attracting increasing interest in recent years, owing to its regioselectivity and technical potential as a biocatalytic equivalent for the Kolbe-Schmitt reaction. Mechanistically the reaction was demonstrated to occur through electrophilic aromatic substitution/water elimination with bicarbonate as a cosubstrate. The effects of the substituents on the phenolic ring have not yet been elucidated in detail, but this would give detailed insight into the substrate-activity relationship and would provide predictability for the acceptance of future substrates. In this report we show how the kinetic and (apparent) thermodynamic behavior can be explained through the evaluation of linear free energy relationships based on electronic, steric, and geometric parameters and through the consideration of enzyme-ligand interactions. Moreover, the similarity between the benzoic acid decarboxylases and the amidohydrolases superfamily is investigated, and promiscuous hydrolytic activity of the decarboxylase in the context of the hydrolysis of an activated ester bond has been established. PMID- 27505857 TI - Impact of renal transplantation on glucose tolerance in Japanese recipients with impaired glucose tolerance. AB - AIMS: To investigate changes in glucose tolerance, insulin secretion and insulin sensitivity in Japanese recipients before and 1 year after renal transplantation. METHODS: We conducted a study of Japanese recipients without diabetes who underwent renal transplantation at Hokkaido University Hospital. A 75-g oral glucose tolerance test was performed before and 1 year after renal transplantation in these recipients. Insulin sensitivity was estimated using the Matsuda index and homeostasis model assessment of insulin resistance (HOMA-IR). Insulin secretion was evaluated based on the insulin secretion sensitivity index 2 (ISSI-2). RESULTS: Of the 62 renal transplant recipients, 31 were diagnosed as having impaired glucose tolerance before transplantation. Among these 31 recipients, after 1 year, four had developed new-onset diabetes after transplantation, and nine had impaired glucose tolerance. Unexpectedly, 18 changed from impaired to normal glucose tolerance. When these recipients with impaired glucose tolerance were classified into a non-amelioration group and an amelioration group, the ISSI-2 was significantly reduced, with no significant changes in the Matsuda index or HOMA-IR, in the non-amelioration group 1 year after renal transplantation. By contrast, ISSI-2 and Matsuda index values were significantly increased, with no significant changes in HOMA-IR values in the amelioration group. CONCLUSIONS: More than half of Japanese renal transplant recipients with impaired glucose tolerance had normal glucose tolerance 1 year after renal transplantation. These results suggest that an increase in insulin secretion and whole insulin sensitivity was associated with improvement in glucose tolerance in these recipients. PMID- 27505858 TI - The use of Zymosan A and bacteria anchored to tumor cells for effective cancer immunotherapy: B16-F10 murine melanoma model. AB - The idea of using killed microorganisms or their parts for a stimulation of immunity in the cancer immunotherapy is very old, but the question of interactions and binding of these preparations to tumor cells has not been addressed so far. The attachment of Zymosan A and both Gram-positive and Gram negative bacteria to tumor cells was tested in in vivo experiments. This binding was accomplished by charge interactions, anchoring based on hydrophobic chains and covalent bonds and proved to be crucial for a strong immunotherapeutic effect. The establishment of conditions for simultaneous stimulation of both Toll like and phagocytic receptors led to very strong synergy. It resulted in tumor shrinkage and its temporary or permanent elimination. The role of neutrophils in cancer immunotherapy was demonstrated and the mechanism of their action (frustrated phagocytosis) was proposed. Finally, therapeutic approaches applicable for safe human cancer immunotherapy are discussed. Heat killed Mycobacterium tuberculosis covalently attached to tumor cells seems to be promising tool for this therapy. PMID- 27505859 TI - A Comprehensive Study of Copper Guanidine Quinoline Complexes: Predicting the Activity of Catalysts in ATRP with DFT. AB - Copper complexes of the hybrid guanidine ligands 1,3-dimethyl-N-(quinolin-8-yl) imidazolidin-2-imine (DMEGqu) and 1,1,3,3-tetramethyl-2-(quinolin-8-yl)-guanidine (TMGqu) have been studied comprehensively with regard to their structural and electrochemical properties and their activity in atom transfer radical polymerization (ATRP). A simple analysis of the molecular structures of the complexes gives no indication about their activity in ATRP; however, with the help of DFT and NBO analysis the influence of particular coordinating donors on the electrochemical properties could be fully elucidated. With an adequate DFT methodology and newly applied theoretical isodesmic reactions it was possible to predict the relative position of the redox potentials of copper complexes containing DMEGqu and TMGqu ligands. In addition, predictions could be made as to whether the complexes of DMEGqu or TMGqu are more active in ATRP. Four new Cu(I) complexes were tested in standard ATRP reactions and kinetically investigated both in bulk and in solution. It could be proven that complexes featuring DMEGqu possess a lower redox potential and are more active in ATRP, although the tetramethylguanidine moiety represents the stronger donor. PMID- 27505860 TI - Slip length measurement of gas flow. AB - In this paper, we present a review of the most important techniques used to measure the slip length of gas flow on isothermal surfaces. First, we present the famous Millikan experiment and then the rotating cylinder and spinning rotor gauge methods. Then, we describe the gas flow rate experiment, which is the most widely used technique to probe a confined gas and measure the slip. Finally, we present a promising technique using an atomic force microscope introduced recently to study the behavior of nanoscale confined gas. PMID- 27505862 TI - MiR-139-3p induces cell apoptosis and inhibits metastasis of cervical cancer by targeting NOB1. AB - MicroRNAs (miRNAs) play an important role in the development of various cancers, including cervical cancer (CC). The dysregulation of miRNA expression is associated with oncogenic transformation and miRNA often act as tumor suppressors. In this study, we aimed to analyze the effect on and mechanism of miR-139-3p in the progression of CC. The result of real-time PCR showed that miR 139-3p was down-regulated in CC tissues and cell lines. Overexpression of miR-139 3p significantly suppressed HeLa cell proliferation, migration and invasion and induced cell apoptosis. Bioinformatics analysis and luciferase reporter gene assay confirmed that NOB1 was targeted by miR-139-3p at the 3'-untranslated region (3'UTR) of its mRNA sequence. Furthermore, overexpression of NOB1 counteracted the effects of miR-139-3p suppression. Our results suggest that miR 139-3p may act as a tumor suppressor that can inhibit CC cell proliferation, migration and invasion and induce cell apoptosis through down-regulation of NOB1 expression. Taken together, this study provides a novel potential therapeutic strategy for the treatment of CC. PMID- 27505861 TI - 4-Biphenylalanine- and 3-Phenyltyrosine-Derived Hydroxamic Acids as Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A. AB - Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50 value of 25.4 MUm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell-permeable derivatives clearly showed a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells. PMID- 27505863 TI - Genetic and functional analyses do not explain the association of high PRC1 expression with poor survival of breast carcinoma patients. AB - Microtubules are vitally important for eukaryotic cell division. Therefore, we evaluated the relevance of mitotic kinesin KIF14, protein-regulating cytokinesis 1 (PRC1), and citron kinase (CIT) for the prognosis of breast carcinoma patients. Transcript levels were assessed by quantitative real-time PCR in tissues from two independent groups of breast carcinoma patients and compared with clinical data. Tissue PRC1 protein levels were estimated using immunoblotting, and the PRC1 tagged haplotype was analyzed in genomic DNA. A functional study was performed in MDA-MB-231 cells in vitro. KIF14, PRC1, and CIT transcripts were overexpressed in tumors compared with control tissues. Tumors without expression of hormonal receptors or high-grade tumors expressed significantly higher KIF14 and PRC1 levels than hormonally-positive or low-grade tumors. Patients with high intra tumoral PRC1 levels had significantly worse disease-free survival than patients with low levels. PRC1 rs10520699 and rs11852999 polymorphisms were associated with PRC1 transcript levels, but not with patients survival. Paclitaxel-induced PRC1 expression, but PRC1 knockdown did not modify the paclitaxel cytotoxicity in vitro. PRC1 overexpression predicts poor disease-free survival of patients with breast carcinomas. Genetic variability of PRC1 and the protein interaction with paclitaxel cytotoxicity do not explain this association. PMID- 27505864 TI - Antidiabetic assessment; in vivo study of gold and core-shell silver-gold nanoparticles on streptozotocin-induced diabetic rats. AB - Recently, we have published a pioneering work on green biosynthesis and complete characterization of gold and core shell silver-gold nanoparticles (AuNPs and Ag@AuNPs). Herein, the so obtained nanoparticles are assessed for their antidiabetic activity in streptozotocin-induced diabetic rats. Thus, sixty-four male albino rats were divided into eight groups: control untreated; diabetic rats; diabetic rats received standard drug; diabetic rats received carrier only; diabetic rats received 0.5ml AuNPs; diabetic rats received 1ml AuNPs; diabetic rats received 0.5ml Ag@AuNPs and diabetic rats received 1ml Ag@AuNPs for twenty one days. Results revealed that diabetic rats treated with AuNPs or Ag@AuNPs restored normal glucose level. In particular, Ag@AuNPs was found to significantly induce a reduction in blood glucose and restore both the high serum insulin level and glucokinase activity compared to the control normal rats. The results obtained disclose the effectual role of Ag@AuNPs in reducing the lipid profile, an anti-inflammatory effect in diabetic rats assessed using inflammatory markers IL-alpha and C-reactive protein (CRP). Histopathological examination of diabetic rats signifies distortion in the arrangement of cells around the central vein, inflammatory cells, pyknotic and apoptotic nuclei. Kidney of diabetic rat appears with vacuolation and pyknotic nuclei of some tubules. On the other hand, the liver of diabetic rat treated with Ag@AuNPs displayed normal hepatic cells with only few necrosis of hepatocytes. Ag@AuNPs restored the increased number of caspase-3 stained cells in the liver and kidney tissue in diabetic rats. In conclusion, Ag@AuNPs was observed to improve diabetic condition by limiting prolonged inflammation, suppressing oxidative stress and elevating the antioxidant defense system in diabetic rats which subsequently evoke the potential impact of AuNPs as a cost effective therapeutic cure in diabetic treatments and its complications. PMID- 27505865 TI - When the woman gets violent: the construction of domestic abuse experience from heterosexual men's perspective. AB - AIMS AND OBJECTIVES: To promote a critical approach on the conceptualisation of domestic violence by investigating the experience of abuse on the part of men who are victims of domestic violence by their female partners. BACKGROUND: Media attention and prevention programmes relating to domestic violence have mainly focused on women as the victims and men as the perpetrators. The underlying idea is that violence is predominantly physical and a prerogative of men. This conceptualisation of violence reduces the opportunities for the consideration of different modalities of abuse. DESIGN: Discourse analysis within a qualitative approach. METHODS: Semistructured interviews with 20 Italian men who claimed to have been abused by their female partners were conducted via Skype and analysed with the software atlas.ti. The grounded theory methodology was used to avoid imposing external points of view. Personal data were collected; in particular, their occupational level was compared to their partners' to assess the social power within the couple. RESULTS: Because of their strong endorsement of social and cultural values, participants showed a protective attitude towards their partners and imputed their violent acts to fragility or an external condition. Emotional distress emerged due to the isolation and subsequent inability to seek help. Although the physical violence reported is severe, the psychological violence was indicated as more damaging. CONCLUSION: Gaining an understanding of how men experience domestic abuse offers an opportunity to provide better prevention and intervention for them and other family members at risk of abuse. RELEVANCE TO CLINICAL PRACTICE: The study identifies gaps in service provision generated by a lack of information or perceived prejudice towards abused men. The role of the nurse in supporting male victims is discussed, and future applications for treatments and prevention plans are proposed. PMID- 27505866 TI - Natural Constraints to Species Diversification. AB - Identifying modes of species diversification is fundamental to our understanding of how biodiversity changes over evolutionary time. Diversification modes are captured in species phylogenies, but characterizing the landscape of diversification has been limited by the analytical tools available for directly comparing phylogenetic trees of groups of organisms. Here, we use a novel, non parametric approach and 214 family-level phylogenies of vertebrates representing over 500 million years of evolution to identify major diversification modes, to characterize phylogenetic space, and to evaluate the bounds and central tendencies of species diversification. We identify five principal patterns of diversification to which all vertebrate families hold. These patterns, mapped onto multidimensional space, constitute a phylogenetic space with distinct properties. Firstly, phylogenetic space occupies only a portion of all possible tree space, showing family-level phylogenies to be constrained to a limited range of diversification patterns. Secondly, the geometry of phylogenetic space is delimited by quantifiable trade-offs in tree size and the heterogeneity and stem to-tip distribution of branching events. These trade-offs are indicative of the instability of certain diversification patterns and effectively bound speciation rates (for successful clades) within upper and lower limits. Finally, both the constrained range and geometry of phylogenetic space are established by the differential effects of macroevolutionary processes on patterns of diversification. Given these properties, we show that the average path through phylogenetic space over evolutionary time traverses several diversification stages, each of which is defined by a different principal pattern of diversification and directed by a different macroevolutionary process. The identification of universal patterns and natural constraints to diversification provides a foundation for understanding the deep-time evolution of biodiversity. PMID- 27505867 TI - To the Editor: Prescribing opioids. PMID- 27505868 TI - Trust the thyroid thermostat. PMID- 27505869 TI - In Reply: Prescribing opioids. PMID- 27505870 TI - To the Editor: Measles: More than the rash. PMID- 27505871 TI - In Reply: Measles: More than the rash. PMID- 27505872 TI - To the Editor: Acute liver failure. PMID- 27505873 TI - In Reply: Acute liver failure. PMID- 27505874 TI - Advanced-stage calciphylaxis: Think before you punch. PMID- 27505875 TI - Geographic tongue. PMID- 27505876 TI - Should patients with stable ischemic heart disease undergo revascularization? PMID- 27505877 TI - Is a serum TSH measurement sufficient to monitor the treatment of primary hypothyroidism? PMID- 27505878 TI - Your patient has chronic leukemia: Now what? AB - Although still in their infancy, biologic therapies for hematologic cancers are making rapid strides, diminishing the role of chemotherapy and offering long-term remission. More patients are surviving cancer and therefore are increasingly being seen by primary care physicians, who must be aware of complications of standard and newer treatments and how to manage them. PMID- 27505879 TI - Renal failure in HCV cirrhosis. PMID- 27505880 TI - Information management for clinicians. AB - Clinicians are bombarded with information daily by social media, mainstream television news, e-mail, and print and online reports. They usually do not have much control over these information streams and thus are passive recipients, which means they get more noise than signal. Accessing, absorbing, organizing, storing, and retrieving useful medical information can improve patient care. The authors outline how to create a personalized stream of relevant information that can be scanned regularly and saved so that it is readily accessible. PMID- 27505881 TI - Thrombotic thrombocytopenic purpura: The role of ADAMTS13. AB - Thrombotic thrombocytopenic purpura (TTP) is an uncommon, life-threatening disease requiring prompt diagnosis and initiation of therapeutic plasma exchange to improve patient survival. However, diagnosis is often difficult because of atypical presentations and signs and symptoms that resemble other conditions. Measurements of ADAMTS13 activity, ADAMTS13 inhibitor, and ADAMTS13 autoantibody are useful for diagnosing TTP, guiding therapy, and predicting relapse. PMID- 27505882 TI - Is there a time limit for systemic menopausal hormone therapy? AB - In deciding whether it is time to stop hormone therapy, in addition to the patient's age we need to consider her preferences, symptoms, quality of life, time since menopause, hysterectomy status, and personal risks of osteoporosis, breast cancer, heart disease, stroke, and venous thromboembolism. This article presents the evidence for and against extending hormone therapy and a guide for making this highly individualized and shared decision. PMID- 27505883 TI - Anemia of chronic kidney disease: Treat it, but not too aggressively. AB - Anemia of renal disease is common and is associated with significant morbidity and death. It is mainly caused by a decrease in erythropoietin production in the kidneys and can be partially corrected with erythropoiesis-stimulating agents (ESAs). However, randomized controlled trials have shown that using ESAs to target normal hemoglobin levels can be harmful, and have called into question any benefits of ESA treatment other than avoidance of transfusions. PMID- 27505884 TI - Electrospun-Technology-Derived High-Performance Electrochemical Energy Storage Devices. AB - Electrospinning, as a novel nontextile filament technology, is an important method to prepare continuous nanofibers and has shown its remarkable advantages, such as a broadly applicable material system, controllable fiber size and structure, and simple process. Electrospun nanofiber membranes prepared by electrospinning have shown promising applications in many fields, such as supercapacitors, lithium-ion batteries, and sodium-ion batteries, owing to their large specific surface area and adjustable network pore structure. The principle of electrospinning and key points relevant to its usage in the preparation of high-performance electrochemical energy storage materials are reviewed herein based on recent publications, particularly focusing on research progress of relative materials. Also, this review describes a distinctive conclusion and perspective on the future challenges and opportunities in electrospun nanomaterials. PMID- 27505885 TI - Kinesin-1 sorting in axons controls the differential retraction of arbor terminals. AB - The ability of neurons to generate multiple arbor terminals from a single axon is crucial for establishing proper neuronal wiring. Although growth and retraction of arbor terminals are differentially regulated within the axon, the mechanisms by which neurons locally control their structure remain largely unknown. In the present study, we found that the kinesin-1 (Kif5 proteins) head domain (K5H) preferentially marks a subset of arbor terminals. Time-lapse imaging clarified that these arbor terminals were more stable than others, because of a low retraction rate. Local inhibition of kinesin-1 in the arbor terminal by chromophore-assisted light inactivation (CALI) enhanced the retraction rate. The microtubule turnover was locally regulated depending on the length from the branching point to the terminal end, but did not directly correlate with the presence of K5H. By contrast, F-actin signal values in arbor terminals correlated spatiotemporally with K5H, and inhibition of actin turnover prevented retraction. Results from the present study reveal a new system mediated by kinesin-1 sorting in axons that differentially controls stability of arbor terminals. PMID- 27505886 TI - Tensin 3 is a new partner of Dock5 that controls osteoclast podosome organization and activity. AB - Bone resorption by osteoclasts is mediated by a typical adhesion structure called the sealing zone or actin ring, whose architecture is based on a belt of podosomes. The molecular mechanisms driving podosome organization into superstructures remain poorly understood to date, in particular at the osteoclast podosome belt. We performed proteomic analyses in osteoclasts and found that the adaptor protein tensin 3 is a partner of Dock5, a Rac exchange factor necessary for podosome belt formation and bone resorption. Expression of tensin 3 and Dock5 concomitantly increase during osteoclast differentiation. These proteins associate with the osteoclast podosome belt but not with individual podosomes, in contrast to vinculin. Super-resolution microscopy revealed that, even if they colocalize in the x-y plane of the podosome belt, Dock5 and tensin 3 differentially localize relative to vinculin in the z-axis. Tensin 3 increases Dock5 exchange activity towards Rac, and suppression of tensin 3 in osteoclasts destabilizes podosome organization, leading to delocalization of Dock5 and a severe reduction in osteoclast activity. Our results suggest that Dock5 and tensin 3 cooperate for osteoclast activity, to ensure the correct organization of podosomes. PMID- 27505887 TI - Shear-wave elasticity measurements of three-dimensional cell cultures for mechanobiology. AB - Studying mechanobiology in three-dimensional (3D) cell cultures better recapitulates cell behaviors in response to various types of mechanical stimuli in vivo Stiffening of the extracellular matrix resulting from cell remodeling potentiates many pathological conditions, including advanced cancers. However, an effective tool for measuring the spatiotemporal changes in elastic properties of such 3D cell cultures without directly contacting the samples has not been reported previously. We describe an ultrasonic shear-wave-based platform for quantitatively evaluating the spatiotemporal dynamics of the elasticity of a matrix remodeled by cells cultured in 3D environments. We used this approach to measure the elasticity changes of 3D matrices grown with highly invasive lung cancer cells and cardiac myoblasts, and to delineate the principal mechanism underlying the stiffening of matrices remodeled by these cells. The described approach can be a useful tool in fields investigating and manipulating the mechanotransduction of cells in 3D contexts, and also has potential as a drug screening platform. PMID- 27505888 TI - Cellular functions of the ADF/cofilin family at a glance. AB - The actin depolymerizing factor (ADF)/cofilin family comprises small actin binding proteins with crucial roles in development, tissue homeostasis and disease. They are best known for their roles in regulating actin dynamics by promoting actin treadmilling and thereby driving membrane protrusion and cell motility. However, recent discoveries have increased our understanding of the functions of these proteins beyond their well-characterized roles. This Cell Science at a Glance article and the accompanying poster serve as an introduction to the diverse roles of the ADF/cofilin family in cells. The first part of the article summarizes their actions in actin treadmilling and the main mechanisms for their intracellular regulation; the second part aims to provide an outline of the emerging cellular roles attributed to the ADF/cofilin family, besides their actions in actin turnover. The latter part discusses an array of diverse processes, which include regulation of intracellular contractility, maintenance of nuclear integrity, transcriptional regulation, nuclear actin monomer transfer, apoptosis and lipid metabolism. Some of these could, of course, be indirect consequences of actin treadmilling functions, and this is discussed. PMID- 27505889 TI - Proplatelet formation is selectively inhibited by collagen type I through Syk independent GPVI signaling. AB - Collagen receptors GPVI (also known as GP6) and integrin alpha2beta1 are highly expressed on blood platelets and megakaryocytes, their immediate precursors. After vessel injury, subendothelial collagen becomes exposed and induces platelet activation to prevent blood loss. Collagen types I and IV are thought to have opposite effects on platelet biogenesis, directing proplatelet formation (PPF) towards the blood vessels to prevent premature release within the marrow cavity. We used megakaryocytes lacking collagen receptors or treated megakaryocytes with blocking antibodies, and could demonstrate that collagen-I-mediated inhibition of PPF is specifically controlled by GPVI. Other collagen types competed for binding and diminished the inhibitory signal, which was entirely dependent on receptor proximal Src family kinases, whereas Syk and LAT were dispensable. Adhesion assays indicate that megakaryocyte binding to collagens is mediated by alpha2beta1, and that collagen IV at the vascular niche might displace collagen I from megakaryocytes and thus contribute to prevention of premature platelet release into the marrow cavity and thereby directionally promote PPF at the vasculature. PMID- 27505890 TI - 3D electron tomography of brain tissue unveils distinct Golgi structures that sequester cytoplasmic contents in neurons. AB - Macroautophagy is morphologically characterized by autophagosome formation. Autophagosomes are double-membraned vesicles that sequester cytoplasmic components for further degradation in the lysosome. Basal autophagy is paramount for intracellular quality control in post-mitotic cells but, surprisingly, the number of autophagosomes in post-mitotic neurons is very low, suggesting that alternative degradative structures could exist in neurons. To explore this possibility, we have examined neuronal subcellular architecture by performing three-dimensional (3D) electron tomography analysis of mouse brain tissue that had been preserved through high-pressure freezing. Here, we report that sequestration of neuronal cytoplasmic contents occurs at the Golgi complex in distinct and dynamic structures that coexist with autophagosomes in the brain. These structures are composed of several concentric double-membraned layers that appear to be formed simultaneously by the direct bending and sealing of discrete Golgi stacks. These structures are labelled for proteolytic enzymes, and lysosomes and late endosomes are found in contact with them, leading to the possibility that the sequestered material could be degraded inside them. Our findings highlight the key role that 3D electron tomography, together with tissue rapid-freezing techniques, will have in gaining new knowledge about subcellular architecture. PMID- 27505891 TI - Seeing is believing - multi-scale spatio-temporal imaging towards in vivo cell biology. AB - Life is driven by a set of biological events that are naturally dynamic and tightly orchestrated from the single molecule to entire organisms. Although biochemistry and molecular biology have been essential in deciphering signaling at a cellular and organismal level, biological imaging has been instrumental for unraveling life processes across multiple scales. Imaging methods have considerably improved over the past decades and now allow to grasp the inner workings of proteins, organelles, cells, organs and whole organisms. Not only do they allow us to visualize these events in their most-relevant context but also to accurately quantify underlying biomechanical features and, so, provide essential information for their understanding. In this Commentary, we review a palette of imaging (and biophysical) methods that are available to the scientific community for elucidating a wide array of biological events. We cover the most recent developments in intravital imaging, light-sheet microscopy, super resolution imaging, and correlative light and electron microscopy. In addition, we illustrate how these technologies have led to important insights in cell biology, from the molecular to the whole-organism resolution. Altogether, this review offers a snapshot of the current and state-of-the-art imaging methods that will contribute to the understanding of life and disease. PMID- 27505892 TI - Visualizing red blood cell sickling and the effects of inhibition of sphingosine kinase 1 using soft X-ray tomography. AB - Sickle cell disease is a destructive genetic disorder characterized by the formation of fibrils of deoxygenated hemoglobin, leading to the red blood cell (RBC) morphology changes that underlie the clinical manifestations of this disease. Using cryogenic soft X-ray tomography (SXT), we characterized the morphology of sickled RBCs in terms of volume and the number of protrusions per cell. We were able to identify statistically a relationship between the number of protrusions and the volume of the cell, which is known to correlate to the severity of sickling. This structural polymorphism allows for the classification of the stages of the sickling process. Recent studies have shown that elevated sphingosine kinase 1 (Sphk1)-mediated sphingosine 1-phosphate production contributes to sickling. Here, we further demonstrate that compound 5C, an inhibitor of Sphk1, has anti-sickling properties. Additionally, the variation in cellular morphology upon treatment suggests that this drug acts to delay the sickling process. SXT is an effective tool that can be used to identify the morphology of the sickling process and assess the effectiveness of potential therapeutics. PMID- 27505893 TI - The membrane trafficking and functionality of the K+-Cl- co-transporter KCC2 is regulated by TGF-beta2. AB - Functional activation of the neuronal K(+)-Cl(-) co-transporter KCC2 (also known as SLC12A5) is a prerequisite for shifting GABAA responses from depolarizing to hyperpolarizing during development. Here, we introduce transforming growth factor beta2 (TGF-beta2) as a new regulator of KCC2 membrane trafficking and functional activation. TGF-beta2 controls membrane trafficking, surface expression and activity of KCC2 in developing and mature mouse primary hippocampal neurons, as determined by immunoblotting, immunofluorescence, biotinylation of surface proteins and KCC2-mediated Cl(-) extrusion. We also identify the signaling pathway from TGF-beta2 to cAMP-response-element-binding protein (CREB) and Ras associated binding protein 11b (Rab11b) as the underlying mechanism for TGF-beta2 mediated KCC2 trafficking and functional activation. TGF-beta2 increases colocalization and interaction of KCC2 with Rab11b, as determined by 3D stimulated emission depletion (STED) microscopy and co-immunoprecipitation, respectively, induces CREB phosphorylation, and enhances Rab11b gene expression. Loss of function of either CREB1 or Rab11b suppressed TGF-beta2-dependent KCC2 trafficking, surface expression and functionality. Thus, TGF-beta2 is a new regulatory factor for KCC2 functional activation and membrane trafficking, and a putative indispensable molecular determinant for the developmental shift of GABAergic transmission. PMID- 27505894 TI - The polarity protein Scribble positions DLC3 at adherens junctions to regulate Rho signaling. AB - The spatial regulation of cellular Rho signaling by GAP proteins is still poorly understood. By performing mass spectrometry, we here identify the polarity protein Scribble as a scaffold for the RhoGAP protein DLC3 (also known as StarD8) at cell-cell adhesions. This mutually dependent interaction is mediated by the PDZ domains of Scribble and a PDZ ligand (PDZL) motif in DLC3. Both Scribble depletion and PDZL deletion abrogated DLC3 junctional localization. Using a RhoA biosensor and a targeted GAP domain, we demonstrate that DLC3 activity locally regulates RhoA-ROCK signaling at and Scribble localization to adherens junctions, and is required for their functional integrity. In a 3D model of cyst development, we furthermore show that DLC3 depletion impairs polarized morphogenesis, phenocopying the effects observed upon Scribble knockdown. We thus propose a new function for Scribble in Rho regulation that entails positioning of DLC3 GAP activity at cell junctions in polarized epithelial cells. PMID- 27505895 TI - Galpha12 is required for renal cystogenesis induced by Pkd1 inactivation. AB - Mutation of PKD1, encoding the protein polycystin-1 (PC1), is the main cause of autosomal dominant polycystic kidney disease (ADPKD). The signaling pathways downstream of PC1 in ADPKD are still not fully understood. Here, we provide genetic evidence for the necessity of Galpha12 (encoded by Gna12, hereafter Galpha12) for renal cystogenesis induced by Pkd1 knockout. There was no phenotype in mice with deletion of Galpha12 (Galpha12-/-). Polyinosine-polycytosine (pI:pC) induced deletion of Pkd1 (Mx1Cre+Pkd1f/fGalpha12+/+) in 1-week-old mice resulted in multiple kidney cysts by 9 weeks, but the mice with double knockout of Pkd1 and Galpha12 (Mx1Cre+Pkd1f/fGalpha12-/-) had no structural and functional abnormalities in the kidneys. These mice could survive more than one year without kidney abnormalities except multiple hepatic cysts in some mice, which indicates that the effect of Galpha12 on cystogenesis is kidney specific. Furthermore, Pkd1 knockout promoted Galpha12 activation, which subsequently decreased cell-matrix and cell-cell adhesion by affecting the function of focal adhesion and E cadherin, respectively. Our results demonstrate that Galpha12 is required for the development of kidney cysts induced by Pkd1 mutation in mouse ADPKD. PMID- 27505897 TI - Local Ras activation, PTEN pattern, and global actin flow in the chemotactic responses of oversized cells. AB - Chemotactic responses of eukaryotic cells require a signal processing system that translates an external gradient of attractant into directed motion. To challenge the response system to its limits, we increased the size of Dictyostelium discoideum cells by using electric-pulse-induced fusion. Large cells formed multiple protrusions at different sites along the gradient of chemoattractant, independently turned towards the gradient and competed with each other. Finally, these cells succeeded to re-establish polarity by coordinating front and tail activities. To analyse the responses, we combined two approaches, one aimed at local responses by visualising the dynamics of Ras activation at the front regions of reorientating cells, the other at global changes of polarity by monitoring front-to-tail-directed actin flow. Asymmetric Ras activation in turning protrusions underscores that gradients can be sensed locally and translated into orientation. Different to cells of normal size, the polarity of large cells is not linked to an increasing front-to-tail gradient of the PIP3 phosphatase PTEN. But even in large cells, the front communicates with the tail through an actin flow that might act as carrier of a protrusion inhibitor. PMID- 27505896 TI - Deep nuclear invaginations are linked to cytoskeletal filaments - integrated bioimaging of epithelial cells in 3D culture. AB - The importance of context in regulation of gene expression is now an accepted principle; yet the mechanism by which the microenvironment communicates with the nucleus and chromatin in healthy tissues is poorly understood. A functional role for nuclear and cytoskeletal architecture is suggested by the phenotypic differences observed between epithelial and mesenchymal cells. Capitalizing on recent advances in cryogenic techniques, volume electron microscopy and super resolution light microscopy, we studied human mammary epithelial cells in three dimensional (3D) cultures forming growth-arrested acini. Intriguingly, we found deep nuclear invaginations and tunnels traversing the nucleus, encasing cytoskeletal actin and/or intermediate filaments, which connect to the outer nuclear envelope. The cytoskeleton is also connected both to other cells through desmosome adhesion complexes and to the extracellular matrix through hemidesmosomes. This finding supports a physical and/or mechanical link from the desmosomes and hemidesmosomes to the nucleus, which had previously been hypothesized but now is visualized for the first time. These unique structures, including the nuclear invaginations and the cytoskeletal connectivity to the cell nucleus, are consistent with a dynamic reciprocity between the nucleus and the outside of epithelial cells and tissues. PMID- 27505899 TI - Editorial: Evidence-Informed Reviews-Moving Occupational Therapy Practice and Science Forward. PMID- 27505900 TI - Does a Falls Prevention Program Impact Perceived Participation in Everyday Occupations? A Pilot Randomized Controlled Trial. AB - This study aimed to evaluate the effectiveness of a multi-disciplinary, client centered, fall prevention program on the experiences of participation and autonomy in everyday occupations among community-dwelling older adults. In total, 131 older adults (65+) were included and randomly allocated into two groups. Intention-to-treat analysis was used. Results of this pilot study showed that the program had a limited effect on the subjective experiences of participation and autonomy in everyday occupations among the participants. However, a trend of increased perceived participation and a decrease in the experience of perceived problems with participation among the participants in the intervention group was shown. Perceived participation and autonomy seem to be subjective experiences, and they seem to vary depending on the individual. To properly understand the impact of fall prevention interventions on participation and autonomy, measurements that capture both subjective and objective experiences are essential to use. PMID- 27505898 TI - Persistent nuclear actin filaments inhibit transcription by RNA polymerase II. AB - Actin is abundant in the nucleus and it is clear that nuclear actin has important functions. However, mystery surrounds the absence of classical actin filaments in the nucleus. To address this question, we investigated how polymerizing nuclear actin into persistent nuclear actin filaments affected transcription by RNA polymerase II. Nuclear filaments impaired nuclear actin dynamics by polymerizing and sequestering nuclear actin. Polymerizing actin into stable nuclear filaments disrupted the interaction of actin with RNA polymerase II and correlated with impaired RNA polymerase II localization, dynamics, gene recruitment, and reduced global transcription and cell proliferation. Polymerizing and crosslinking nuclear actin in vitro similarly disrupted the actin-RNA-polymerase-II interaction and inhibited transcription. These data rationalize the general absence of stable actin filaments in mammalian somatic nuclei. They also suggest a dynamic pool of nuclear actin is required for the proper localization and activity of RNA polymerase II. PMID- 27505901 TI - Clinical Assessments as Predictors of Primary On-Road Outcomes in Parkinson's Disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder that affects fitness to drive. Research that has examined clinical predictors of fitness to drive in PD, using the on-road assessment as the gold standard, has generally used a dichotomous pass/fail decision. However, on-road assessments may also result in one of two additional outcomes (pass with recommendations, or fail-remediable). Individuals within these subgroups may benefit from interventions to improve their fitness to drive abilities. This study investigated clinical predictors that could be indicative of the pass, pass with recommendations, or fail remediable categories for drivers with PD (N = 99). Trails B, Left Finger to Nose Test, and contrast sensitivity measures were identified as significant predictors for the pass, and pass with recommendations subgroups. No significant predictors were identified for the fail-remediable subgroup. Results from this study provide a foundation for clinicians to identify drivers who can benefit from recommendations to preserve their driving abilities. PMID- 27505902 TI - Development of the Adolescent and Young Adult Activity Card Sort. AB - Emerging adulthood defines transition to employment, higher education, and domestic life. This study describes the development of an assessment of self reported participation in a range of age-appropriate activities. Item selection was established from literature review, feedback from youth and professionals, the former Adolescent Activity Card Sort (AACS), and the original Activity Card Sort (ACS). Iterative item selection occurred with three separate samples of emerging adults and six professionals. Test-retest reliability was evaluated. The Adolescent and Young Adult Activity Card Sort (AYA-ACS) consists of chores (11 items), leisure (13), social (10), health and fitness (9), work (10), education (8), and parenting (9). Test-retest reliability showed significant moderate to substantial Kappa agreement (.48-.85) for all domains except parenting (kappa = .15). This preliminary study describes the development of the AYA-ACS to be used with individuals who encounter challenges when transitioning to young adulthood. PMID- 27505903 TI - Meaningful Components of Exercise and Active Recreation for Spinal Cord Injuries. AB - This qualitative study used focus groups to identify meaningful components of exercise and active recreation (E/AR) related to consistent participation for those with spinal cord injury (SCI). Transcripts from each focus group were analyzed with classical content analysis, grounded theory coding, and meaning condensation using the International Classification of Function, Disability and Health (ICF). Variables within each of the ICF domains (body structures and functions, activities/participation, and environment) were indicated as meaningful components leading to increased participation, independence, and reasons why people consistently participated in E/AR. Occupational therapists can utilize these components to implement therapeutic intervisions, which provide clients with a sense of purpose and being, thus improving outcomes in meaningful occupations. PMID- 27505904 TI - Occupational Therapists' Views of Nussbaum's Life Capability: An Exploratory Study. AB - Life Capability is the first and most fundamental of Nussbaum's 10 Central Human Functional Capabilities (CHFCs). This capability refers to a person having a quality life of normal duration. The purpose of this study was to explore the views' of occupational therapists about Life Capability, specifically, their perspectives of this capability and its perceived relevance to practice. Semi structured interviews with 14 occupational therapists in British Columbia, Canada, were conducted and thematically analyzed. Within this Canadian context, three themes emerged regarding occupational therapists' views about Life Capability: basic human right, quality of life, and longevity. Occupational therapists appear to view Life Capability as being consistent with the values of the occupational therapy profession. Nussbaum's other CHFCs warrant study to explore the degree to which the Capabilities Approach could complement existing occupational therapy theories, science, and practice. PMID- 27505905 TI - Comment on "Efficacy of an Occupational Therapy Driving Intervention for Returning Combat Veterans". PMID- 27505907 TI - ANTI-INFLAMMATORY, ANALGESIC AND ANTIPYRETIC ACTIVITIES OF THE AQUEOUS METHANOLIC EXTRACT OF BERBERIS CALLIOBOTRYS IN ALBINO MICE. AB - The aqueous methanolic extract of stem part of Berberis calliobotiys (AMEBC) was evaluated for anti-inflammatory, analgesic and antipyretic activities in albino mice. Anti-inflammatory activity was evaluated by using carrageenan and albumin induced paw edema, while the analgesic effect was assessed by using formalin induced paw licking and acetic acid induced abdominal writhing in mice. The brewer's yeast-induced pyrexia model was used for antipyretic investigation. Ibuprofen (40 mg/kg) was used as a standard drug in all the three models. The aqueous methanolic extract at both (250 mg/kg and 500 mg/kg) doses, showed highly significant (p < 0.001) reduction in paw edema induced by carrageenan and albumin. Moreover, the aqueous methanolic extract also highly significantly (p < 0.001) reduced (87%) the formalin-induced paw licking at 500 mg/kg. The highly significant (p < 0.001) reductions (24.48% and 37.9%) was also observed in the number of writhings. Furthermore, aqueous methanolic extract also demonstrated significant (p < 0.001) antipyretic activity against yeast induced pyrexia. The maximum effect was observed in all the three parameters at 500 mg/kg dose. The results suggest a potential benefit of the aqueous methanolic extract of Berbeis calliobotrys in treating conditions associated with inflammation, pain and fever. PMID- 27505908 TI - Parenting in practice. PMID- 27505909 TI - Sentinel node biopsy should not be the standard of care for patients with intermediate and thick melanomas. PMID- 27505910 TI - MSLT-I: Comparing apples to antelopes. PMID- 27505911 TI - MSLT-I: Comparing apples to antelopes--Reply. PMID- 27505912 TI - Sentinel node biopsy for melanoma: The medical oncology perspective. PMID- 27505913 TI - Sentinel node biopsy in patients with intermediate and thick melanomas - A balanced view. PMID- 27505914 TI - Training for general practice: How Australia's programs compare to other countries. AB - BACKGROUND: General practice in Australia and internationally has undergone a dramatic transformation over the past half century in terms of recognition, academic status, organisation and funding. Training pathways have also evolved in response to this changing environment. OBJECTIVES: This paper compares some of the features of Australian and international general practice training using the educational standards developed by the World Organization of Family Doctors' (WONCA) Working Party on Education as a framework. DISCUSSION: General practice training in Australia, particularly rural training, is strong by international standards, but more lessons can still be learnt from other settings. Local contextual factors mean there are substantial differences in training across jurisdictions, but there are a number of similarities. There is increasing attention being paid to the many roles of a general practitioner, and the importance of a formalised, structured and well-resourced training program. More needs to be done internationally to ensure high-level primary care is available to all people, particularly the underserved. PMID- 27505915 TI - Global family medicine and Australian general practice. PMID- 27505916 TI - Adult-onset asthma. PMID- 27505917 TI - Not to attend a pharmaceutical company function is a moral not an ethical decision. PMID- 27505918 TI - Not to attend a pharmaceutical company function is a moral not an ethical decision--Reply. PMID- 27505919 TI - Considering domestic violence in clinical practice. PMID- 27505921 TI - Reply. PMID- 27505920 TI - Sleep problems in children. PMID- 27505922 TI - Higher education in New South Wales for permanent wheelchair users. PMID- 27505923 TI - What general practitioners need to know about veterans' health. PMID- 27505924 TI - Food insecurity. PMID- 27505925 TI - Reply. PMID- 27505926 TI - THORACOSTOMY PHILOSOPHY. PMID- 27505927 TI - OUT-OF-SIGHT AIRWAY. PMID- 27505928 TI - NOT SO 'COMMON'. PMID- 27505929 TI - DEXTROSE DOSING. PMID- 27505930 TI - ALTITUDE ILLNESS. PMID- 27505931 TI - INTO THE WILD. PMID- 27505932 TI - No other option. PMID- 27505934 TI - LEADING THE WAY TO SAVES. PMID- 27505935 TI - LEARNING TO DANCE WITH AN ELEPHANT. PMID- 27505933 TI - Lifesaving Field Amputations. PMID- 27505936 TI - BEYOND BLOOD SUGAR. AB - Because POC testing has been shown to alter prehospital care in up to 30% of its uses, it may be logical for prehospital systems to consider implementing a POC testing system. Information gleaned from the i-STAT data can be used to treat electrolyte imbalances, adjust medications and ventilator settings, and even change IV fluid use. MIH providers can also use the data from POC testing to provide important feedback to physicians about enrolled patients. All of these uses support critical clinical decision making by field EMS providers, and will perhaps even help promote the value proposition we're all striving for in our EMS delivery models. PMID- 27505937 TI - BREAKING GLASS. PMID- 27505938 TI - DRIVER'S ED. PMID- 27505939 TI - THE POWER OF ZAMBIKES. PMID- 27505940 TI - We never stop learning. PMID- 27505941 TI - Celebrating nurses' contributions. PMID- 27505942 TI - Leaders recognized and celebrated. PMID- 27505943 TI - Validity of psychometric instruments. PMID- 27505944 TI - Transitions: Adjusting to Working Life. PMID- 27505945 TI - If I Knew Then What I Know Now.... PMID- 27505946 TI - Cardiology and oncology care providers join forces. PMID- 27505947 TI - Medical assistance in dying: What can nurses expect after June 6? PMID- 27505949 TI - The globalization of Paisly Symenuk. PMID- 27505948 TI - Walking side by side on a journey of reconciliation. PMID- 27505950 TI - Making her career her own. PMID- 27505951 TI - Blood and plasma collection shouldn't be privatized. PMID- 27505952 TI - [Comparative study on the clinic effects of arthroscopic reconstructions of single-bundle and double-bundle anterior cruciate ligament]. PMID- 27505953 TI - [Case-control study on Chinese medicine fumigation and massage therapy for the treatment of knee stability and func tional recovery after anterior cruciate ligament reconstruction operation]. AB - OBJECTIVE: To study clinical outcomes of Chinese medidine fumigation and massage therapy for the treatment of knee stability and functional recovery after anterior cruciate ligament reconstruction operation,and to explore the effect on tendon-bone healing. METHODS: Total 50 patients were divided into two groups: the control group (normal rehabilitation therapy group),the treatment group (Chinese medicine fumigation and manipulation group). There were 25 patients in the control group, including 16 males and 9 females, who were treated with isometric muscle training, with the gradually enlarging amplitude of flexion and progressive loading of bearing training for knee recovery. There were 25 patients in the treatment group, including 15 males and 10 females,who were treated with the conventional rehabilitation therapy combined with Chinese medicine fumigation and massage therapy. The Chinese herbs named as Haitongpi decoction was steamed by a special equipment to fumigate the knee after operation; Based on the biomechanical parameters of the ligament reconstruction, the massage therapy was designed to control the degree of the knee flexion and release the adhesion for early recovery of knee functions. The Lysholm knee function evaluation system was used, and MRI examination was performed to measure the change in width of ligament tunnel in femur and tibia to evaluate the safety and stability of the treatment. RESULTS: Lysholm system showed that two groups both had improving results from the 1st month after operation to the 3rd month (treatment group, F=36.54, P<0.05; the control group, F=28.12, P<0.05), and the results of the treatment group was better than that of the control group at the observation point (the 1st month, t=0.105, P<0.05; the 3rd month, t=5.361, P<0.01). There was no difference between the two groups when evaluating the bone and tendon healing 3 and 12 months after operation (P>0.05), indicating that Chinese rehabilitation therapy was a safety treatment without the influence on the loosing of tendon. CONCLUSION: Chinese medicine fumigation and massage therapy can early improve the knee function after the anterior cruciate ligament reconstruction operation without the disturbance of the knee stability. PMID- 27505954 TI - [Clinical effect of staged repair and reconstruction of multiple ligament injuries in knee joints]. AB - OBJECTIVE: To evaluate clinical outcomes of anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) reconstruction under arthroscopy combined with limited open repair of medial collateral ligament (MCL) for the treatment of multiple ligament injuries of knee joints. METHODS: From March 2006 and June 2012,the data of 14 patients (14 knees) with multiple injuries of ACL, PCL, and MCL were collected. There were 8 males and 6 females with an average age of (31.8 +/- 8.1) years old (ranged, 20 to 49 years old). All the patients were performed with X-ray and MRI examination, and the results showed that 10 patients had combined with injuries of anterior cruciate ligament (ACL), posterior cruciate ligament (PCL) and medial collateral ligament (MCL); 4 patients had ALC,PCL and posterolateral corner (PLC) injuries. Four patients had medial meniscus injuries and 2 patients had lateral meniscus injuries. The MCL,PLC and meniscus injuries were treated with operation on the first stage, and functional exercises were performed 3 weeks after fixation. The reconstruction operation of ACL and (or) PCL was performed at the second stage under arthroscopy 3 to 6 months later when the movement range of knee joint recovered to the normal level with obvious relaxation. RESULTS: All incisions healed by primary intention. All the patients were followed up with a mean duration of 48.9 months (ranged, 24 to 80 months). The Lysholm score was improved from preoperative 19.6 +/- 0.9 to the latest follow-up 87.1 +/- 2.8 (t=12.3, P<0.01). The International Knee Documentation Committee (IKDC) rating: 9 cases nearly recovered to normal, 5 cases were abnormal. CONCLUSION: For multiple ligament injuries in the knee, staged repair and reconstruction can effectively restore knee joint stability and function. PMID- 27505955 TI - [Case-control study on two suturing methods for the repairing of complete rupture of the deltoid ligament]. AB - OBJECTIVE: To compare clinical outcomes between two suturing methods using non absorbable materials through drilling the bone and suturing anchors for the treatment of complete rupture of the deltoid ligament. METHODS: From January 2009 to January 2013, 58 hospitalized patients with ankle fracture combined with complete rupture of the deltoid ligament were treated with suturing using non absorbable materials through drilling the bone or suturing anchors. There were 29 patients who received suturing treatments using non absorbable materials through drilling the bone (Group A), including 18 males and 11 females, with an average age of (39.76 +/- 11.81) years old. According to the Lauge-Hansen classification, 12 patients had supination external rotation (SER) injuries with IV degree, 5 patients had pronation external rotation (PER) injuries with III degree, 10 patients had PER injuries with IV degrss, and 2 patients had pronation abduction injuries with III degree. There were 29 patients who received treatments with suturing using anchors (Group B), including 14 males and 15 females, with an average age of (41.79 +/- 13.28) years old. According to the Lauge-Hansen classification,9 patients had SER injuries with IV degree, 6 patients had PER injuries with III degree,13 patients had PER injuries with IV degree, and 1 patient had pronation abduction injuries with III degree. All the patients were treated with open reduction and internal fixation, as well as reconstruction of deltoid ligaments to restore the stability of the medial ankle structures. The clinical examination, imaging evaluation, American society for ankle surgery (AOFAS) ankle-hindfoot score and visual analogue scale (VAS) were used to evaluate the clinical results after operation, and the results of the two groups were compared and analyzed statistically. RESULTS: The follow-up duration of the 58 patients ranged from 23 to 40 months,with an average of 27.3 months. All the patients had fracture union, and the mean healing time was 12.3 weeks (ranged, 10 to 17 weeks). There were no incision complications and ankle instability. There were no significant differences between two groups in AOFAS (P=0.666) and the VAS (P=0.905). CONCLUSION: Treatments of complete rupture of the deltiod ligaments with the two suturing methods get similar good clinical effects, but the suturing using non absorbable materials through drilling the bone has several advantages such as reducing the financial burden of patients, saving social medical resources and avoiding the shortcoming in difficult removal of anchor suture. PMID- 27505956 TI - [Relationship between screw numbers and severity of tibial bone defect in primary total knee arthroplasty]. AB - OBJECTIVE: To summarize experience of using screws and cement to rebuild tibial bone defect in primary total knee arthroplasty (TKA) and to discuss the relationship between the number of required screws and the severity of tibial bone defects. METHODS: From July 2009 to May 2015, 34 patients (40 knees) with varus knees underwent TKA, and the screw and cement technique was used to rebuild medial tibia plateau during operation. There were 8 males (8 knees) and 26 females (32 knees), and the average age was (65.00 +/- 7.25) years old (ranged,55 to 82 years old). One to 6 screws were used in each case. Extension stems were used in 2 cases (4 and 5 screws was used respectively). The area percentages of the bone defects measured as defect area/tibia plateau area, depth of each defect, the number of screws needed in each case, were all used to determine the relationship between the number of screws and the area percentage in certain depth of bone defect by statistic methods, as well as the relationship between screw number and defect depth. RESULTS: All the patients were followed up and the average duration was 24 months (ranged, 1 to 72 months). The average preoperative HSS score was 43.33 +/- 6.11 (ranged, 32 to 51 scores). Whereas the average postoperative HSS score was 92.15 +/- 4.64 (ranged,83 to 96 scores). The preoperative individual scores including pain, function, activity, nuscle strength, flexion deformity and stability were all improved compared with preoperation,and the differences were statistically significant. All the patients received normal alignment postoperatively, femoraltibial angle was improved from (167.00 +/- 6.39) degrees preoperatively to (175.00 +/- 2.69) degrees postoperatively, the tibial angle was improved from (78.09 +/- 4.51) degrees preoperatively to (88.75 +/- 1.24) degrees postoperatively. Both area percentage and depth of bone defect in a fitting Ologistic model had a significant statistical relationship with the screw number, and a rectangular coordinate system could be formed according to the relationship. CONCLUSION: Screws and cement technique is a simple, safe and convenient method to rebuild tibial bone defects in primary TKA and its short-term and midterm effect are both reliable. During opera- tion, according to the rectangular coordinate system, the screw number needed in the operation can be inferred form th area and depth of tibia defect, which could have a guiding function in surgery. PMID- 27505957 TI - [Clinical efficacy of cannulated screw fixation with percutaneous Poking reduction for the treatment of calcaneal fracture]. AB - OBJECTIVE: To investigate the clinical efficacy of cannulated screw fixation with percutaneous Poking reduction for the treatment of Sanders II, III calcaneal fracture. METHODS: From January 2012 to January 2014, 19 patients with Sanders II, III calcaneal fracture were treated with cannulated screw fixation with percutaneous Poking reduction. There were 14 males and 5 females, ranging in age from 19 to 58 years old, with an average age of (38.3 +/- 4.1) years old. The changes of Bohler angle and Gissane angle were measured and compared preoperatively and postoperatively to observe the recovery of the articular surface. The Maryland Foot Score was used to evaluate operation outcomes. RESULTS: All the patients were followed up, and the duration ranged from 12 to 28 months with a mean of (22.3 +/- 5.3) months. The Bohler angle and Gissane angle were improved significantly after operation compared with those before operation (P < 0.05). The Maryland score was 83.2 +/- 8.4. CONCLUSION: Treatment of calcaneal fractures with screw fixation with percutaneous Poking reduction has several advantages such as satisfactory outcome,less damage, fewer complications, quicker recovery, and shorter hospital stay,and it is one of the effective treatments for Sanders II and III calcaneal fractures. PMID- 27505958 TI - [Unilateral fixation combined with interbody fusion for the treatment of lumbar degenerative instability via a paraspinal intermuscular approach under MAST Quadrant retractor]. AB - OBJECTIVE: To study clinical effects of unilateral pedicle screw-rod system fixation combined with the single the cage of interbody fusion in the treatment of lumbar degenerative instability via paraspinal intermuscular approach under MAST Quadrant retractor. METHODS: From February 2010 to December 2011, 39 patients with lumbar degenerative instability after invalid conservative treatment were treated with unilateral fixation combined with interbody fusion via the paraspinal intermuscular approach under MAST Quadrant retractor. The indexes such as the operative time, blood loss, complications, VAS pain scores, JOA (subjective symptoms of low back pain,lower limb pain and numbness, sensory disturbance, movement disorders) scores, modified Macnab criteria for curative effect evaluation were observed before treatment, at the 1st month after treatment and the latest follow-up. The intervertebral fusion was studied on the X-ray at the latest follow-up. RESULTS: All the patients were followed up, and the mean during was (22.3 +/- 8.6) months. The operation time was (138 +/- 46) min, and the amount of bleeding was (335 +/- 152) ml. There were no complications such as cerebrospinal fluid leakage and spinal nerve injury during operation, and no incision infection after operation. The VAS pain score was reduced from preoperative 7.93 +/- 1.27 to 2.05 +/- 1.18 on the 1st month after operation and 1.89 +/- 0.42 at the latest follow-up. The JOA total score was improved from preoperative 1.59 +/- 0.42 to 8.86 +/- 0.37 on the 1st month and 9.02 +/- 0.29 at the latest follow-up. According to modified Macnab criteria, there were 17 cases got an excellent result, 19 good, 3 case fair. Thirty-five patients got intervertebral bony fusion at the latest follow-up. CONCLUSION: Unilateral pedicle screw-rod system fixation combined with single cage interbody fusion in the treatment of lumbar degenerative instability via paraspinal intermuscular approach under MAST Quadrant retractor is a safe, minimally invasive, satisfactorily effective methods to treat lumbar degenerative instability. PMID- 27505959 TI - [Analysis and comparison about musculoskeletal ultrasonoLranhv and x-rav of knee osteoarthritis]. AB - OBJECTIVE: To analyze and compare the characteristics of musculoskeletal ultrasonography and X-ray of knee osteoarthritis, and to investigate the advantages of them. METHODS: According to the inclusion and exclusion criteria, 57 cases (66 knees) were collected from February 2015 to May 2015. Among them, there were 48 females and 9 males with an average age of (58.9 +/- 9.8) years old (ranged, 41 to 78 years old). The main symptoms included unilateral or bilateral knee pain and locked joints explicit areas of tender points. The mean course of disease was (13.6 +/- 3.0) months. The results of musculoskeletal ultrasound and X-ray examinations were analyzed. RESULTS: According to Kellgren-Lawrence classification of knee joint on the X-ray: the musculoskeletal ultrasound results of patients with I degree synovial hyperplasia in 9 cases, joint effusion in 20 cases, meniscal disease in 13 cases, patellar pad inflammation in 5 cases, and patellar lesion in 8 cases. The musculoskeletal ultrasound results of patients with III degree: synovial hyperplasia in 20 cases,joint effusion in 31 cases, meniscal disease in 22 cases, patellar pad inflammation in 16 cases and patellar lesion in 17 cases. The musculoskeletal ultrasound results of patients with III degree: synovial hyperplasia in 6 cases,joint effusion in 6 cases, meniscal disease in 7 cases, patellar pad inflammation in 7 cases and patellar lesion in 5 cases. CONCLUSION: The musculoskeletal ultrasound can detect the pathological changes of knee soft tissue sensitively, provide an accurate location of lesions,and find lesions early. The musculoskeletal ultrasound should be applicated in the diagnosis of knee osteoarthritis. PMID- 27505960 TI - [Clinical research on the efficiency of physical examinations used for diagnosis of subacromial impingement syndrome]. AB - OBJECTIVE: To evaluate the reliability and diagnosis accuracy of 5 special tests used for the diagnosis of subacromial impingement syndrome (SAIS). METHODS: A prospective blinded cohort study was taken,in which 105 patients with shoulder pain were reviewed. All the patients took 5 special syndrome tests including Neer syndrome, Hawkins-Kennedy syndrome, painful arc empty can test and external rotation resistance test, also underwent arthroscopic surgical examination. The Nikolaus's criterion was regarded as a golden standard for SAIS. Data accuracy analysis was calculated through a receiver operating characteristic (ROC) curve, sensitivity, specificity, positive likelihood ratio (+LR) and negative likelihood ratio (-LR). The binary Logistic regression analysis was used to find out the best test combination for ruling in or out SAIS. The interrater reliability was assessed by the Kappa coefficient and percent agreement. RESULTS: The ROC analysis indicated a significant area under the curve (AUC) (AUC=0.62 to 0.73, P<0.05) for all tests except the Hawkins-Kennedy. Tests with a +LR greater or equal to 2.0 were the painful arc,empty can,external rotation resistance, Tests with a-LR less than 0.5 were Neer,painful are ,external rotation resistance. The regression analysis found the painful arc, empty can and external rotation resistance made the best combination for diagnosis SAIS,while the painful are and external rotation resistance made the best combination for ruling out SAIS. The difference of ROC analysis was significant with a cut-off of 3 positive tests out of 5 tests. All tests had moderate to good agreement (Kappa=0.42 to 0.71). CONCLUSION: The single test of painful arc, empty can and external rotation resistance, as well as 3 or more positive tests of the 5 tests can help confirm the diagnosis of SAIS, while the single test of Neer, painful arc and external rotation resistance are help rule out the diagnisis of SAIS. The tests of painful arc, empty can and ex ternal rotation resistance are the best combination for the diagnosis of SAIS (when 2 or more are positive), while the tests of painful arc and external rotation resistance are the best combination for ruling out SAIS (when both are negative) PMID- 27505961 TI - [Biomechanical analysis on the correlation between iliac rotation displacement and L(4,5) disc degeneration]. AB - OBJECTIVE: To study the biomechanical relationship between iliac rotation displacement and L(4,5) disc degeneration, and to provide clinical evidences for the prevention and treatment of L(4,5) disc degeneration and herniation. METHODS: From March 2012 to February 2014,68 patients with lumbar disc herniation combined with sacroiliac joint disorders were selected. Among them, 42 patients with L(4,5) disc herniation combined with sacroiliac joint disorders included 22 males and 20 females, ranging in age from 19 to 63 years old, with an average of (51.78 +/- 20.18) years old, and the duration of the disease ranged from 1 to 126 months with an average of (11.18 +/- 9.23) months. Twenty-six patients with L5S1 disc herniation combined with sacroiliac joint disorders included 11 males and 15 females, ranging in age from18 to 65 years old with an average of (45.53 +/- 27.23) years old, and the duration of the disease ranged from 0.5 to 103 months with an average of (11.99 +/- 12.56) months. Sixty-eight anteroposterior lumbar radiographs, 68 lateral lumbar radiographs,and 68 pelvic plain films were taken. The degree of lumbar scoliosis, pelvic tilt,and disc thickness were measured. The correlation between pelvic tilt and lumbar scoliosis ,lumbar scoliosis and disc thickness were studied by using linear and regression methods. The hiomechanical analysis was performed. RESULTS: There was a positive correlation between pelvic tilt and lumbar scoliosis in patients with L(4,5) disk herniation (R=0.49, P=0.00). There was a causal relationship and good linear proportional relationship (Y=3.05+1.07X, P=0.00) in the two variables. There was a negative correlation between lumbar scoliosis and intervertebral space in male patients with L (4,5) disk herniation (R = -0.50, P=0.01). There was a causal relationship and good linear proportional relationship in the two variables (Y=13.09-0.27X, P=0.02). But there was a positive correlation between lumbar scoliosis and intervertebral space in male patients with L5S1 disk herniation (R=0.46, P=0.04). CONCLUSION: Iliac rotational displacement are closely related with L(4,5) disc degeneration and herniation in biomechanics. A new concepts and therapeutic approach is provided for clinical treatment of chronic and refractory herniation of L(4,5) disc in patients PMID- 27505962 TI - [Case-control study on three spinal rotation manipulations for the treatment of lumbar disc herniation]. AB - OBJECTIVE: To evaluate the efficacy and safety of three different spinal rotation manipulations for the treatment of lumbar disc herniation. METHODS: From September 2011 to April 2013,180 patients diagnosed as lumbar disc herniation were randomly divided into seat fixed rotation group (A), lateral position rotation group (B) and supine position rotation group (C) by using a digital table. Finally 10 patients were excluded and dropped, 170 patients were included in the study. There were 57 patients in group A, 57 patients in group B and 56 patients in group C. Baseline demographic characteristics of patients, clinical findings and indexes of health status had no statistically differences among three groups (P > 0.05). The manipulation was performed every other day, and the treatment duration for all patients was 3 weeks. Body pain (BP), Physical function (PF) in SF-36, Oswestry Disability Index (ODI) and adverse reactions were observed statistically 6 weeks, 3 months, 6 months, one year and two years after finishing treatment. RESULTS: BP, PF scores in 3 groups were significantly improved and ODI scores were significantly lower than those before treatment and the differences were statistically significant (P < 0.05); However, there was no significant difference among three groups in the BP, PF and ODI scores (P > 0.05). There were no obvious and serious adverse reactions among these groups. CONCLUSION: Based on the theory of dislocation of bone joints in TCM, three kinds of spinal rotation manipulations can be used safely for the treatment of lumbar disc herniation, and the efficacy was similar. PMID- 27505963 TI - [Effect of acupuncture therapy on patients with low back pain: a Meta-analysis]. AB - OBJECTIVE: To systematically review the clinical efficacy of acupuncture on the patients with low back pain (LBP). METHODS: Randomized controlled trials (RCTs) about pure acupuncture therapy versus other treatments in treating LBP were electronically searched in PubMed, CBM, EMbase, The Cochrane Library, CNKI, VIP and Wanfang Data from January 2004 to May 2014. The observed index on the results were the changed scores of VAS, ODI, JOA and RMDQ. Two reviewers independently screened the literatures according to the inclusion and exclusion criteria, as well as the extracted data, and assessed the methodological quality. The results of Meta-analysis was conducted by RevMan 5.2 software. RESULTS: Ten RCTs involved 751 patients were finally included. The results of Meta-analysis indicated that the role of pure acupuncture group in improving the VAS score was better than that of the control group, and the combined effect size was RR = -.32, 95% CI ( 1.41, -1.22); Z=27.28, P<0.00001; the role of pure acupuncture group in improving the ODI score was better than that of the control group, and the combined effect size was RR = -5.07, 95% CI (-7.50, -2.65); Z=4.10, P<0.0001; the role of pure acupuncture group on improved JOA score was better than that of the control group and the combined effect size was RR=2.83, 95% CI (2.02, 3.63), Z=6.90, P<0.00001. The role of pure acupuncture group in improving the RMDQ score was better than that of the control group, and the combined effect size was RR = -2.80, 95% CI ( 3.49, -2.11), Z=7.95, P<0.00001. CONCLUSION: The result of meta-analysis demonstrates that pure acupuncture may have a favorable effect on self-reported pain and functional limitations in LBP patients. PMID- 27505964 TI - [Surgical treatment of multiple ligament injuries of knee joints]. AB - OBJECTIVE: To study operative effects for the treatment of multiple ligament injuries of knee joints. METHODS: From 2008 to 2013, 26 patients (17 males and 9 females) with multiple ligament injuries of knee joints were treated surgically. The average age was 40.7 years old, ranging from 29 to 55 years old. All the patients were treated with arthroscopic reconstruction of cruiate ligament with autogenous or allogeneic hamstrings and tendon, and at the same time received repair of medial collateral ligament and lateral collateral ligament, as well as the treatment of exterior and interior complex injuries. Nine patients received second stage operation after the initial operation for mistake or missed diagnosis, and other patients were treated at the first stage. The Lysholm scoring system was used to evaluate function and stability of knee joints before and after operation. RESULTS: All the patients were followed up for an average duration of 1.6 years (ranged, 0.8 to 3.2 years). The mean awaiting time for operation was 1.2 months. The Lysholm score was improved from preoperative 42.5 +/- 4.5 (ranged, 33 to 48) to the latest follow-up 78.1 +/- 3.9 (ranged, 57 to 95). The function of knee joint was improved obviously in the arthroscopic reconstruction patients, with joint range of motion exceeding 900 and with Varus & Valgus tests near to normal. All the patients had negative findings in the Lachman test at 70 degrees of flexion. CONCLUSION: Arthroscopic reconstruction should be the first choice in treating multiple ligament injuries of knee joints. If the anterior and posterior cruciate ligament injuries can't be treated simultaneously, the posterior cruciate ligament injuries should be treated preferentially at the first stage and the anterior cruciate ligament injuries should be treated at the second stage. The diagnosis of posterior cruciate ligament is easy to be missed. PMID- 27505965 TI - [Diagnostic analysis of the radiologic characteristics in osteoporotic Kiinmmel's disease]. AB - OBJECTIVE: To explore the diagnostic value of the radiologic characteristics of osteoporotic Kummell's disease. METHODS: Total 16 patients with pathologically confirmed osteoporotic Kummell's diseases were reviewed from May 2010 to May 2012, including 4 males and 12 females with the mean age of 73.4 years (ranged, 67 to 83 years old). Radiologic imagings of all patients, including X-ray, CT and MRI, were analyzed retrospectively. RESULTS: Intravertebral linear clefts could be seen on the AP and lateral X-ray films of vertebrae. Sagittal and axial CT scans demonstrated the vacuum cleft phenomenon with liquid and air was identified within the vertebral body. Sagittal MRI showed the callapsed vertebral segment and the area of fluid signal with clear and intact border within the vertebral body. The fluid signal was low on T1-weighted images and high on T2-weighted images and stir images, which was corresponding to an intravertebral vacuum cleft. CONCLUSION: The radiologic characteristics of Kurmmell's diseases can provide valuable evidences for the early diagnosis. PMID- 27505966 TI - [Clinical effects of arthroscopic reconstruction of anterior cruciate ligament and minimally invasive reconstruction of posteromedial corner]. AB - OBJECTIVE: To evaluate the clinical effects of arthroscopic reconstruction of anterior cruciate ligament (ACL) and minimally invasive reconstruction of posteromedial corner (PMC). METHODS: There were 22 cases of ACL and PMC tear were performed with reconstruction from March 2012 to February 2014. The patients were 29.4 years old on average, including 8 males and 14 females. ACL reconstruction was performed under arthroscopy and PMC reconstruction was performed minimally invasively through the ACL incision. The stability of knee was assessed by anterior drawer test,Lachman test,vulgus stress test and Slocum test. The function of knee was assessed by Lysholm score and Tegner activity rating. MRI of knee was checked 12 months after operation. RESULTS: The stability tests of all patients were negative at 2 and 6 months after operation, and there was one positive case in anterior drawer test and another positive case in vulgus stress test at 12 months after operation. Lysholm score of all patients 12 months after operation was 96.8 +/- 6.8, which was significantly better than 32.0 +/- 11.2 before operation. Tegner activity rating of all patients at 12 months postoperatively was 6.1 +/- 0.9, which was significantly better than 0.9 +/- 0.5 before operation. It showed the grafts were very well in the MRI 12 months postoperatively. CONCLUSION: Arthroscopic ACL reconstruction and minimally invasive PMC reconstruction can restore the stability of knee. PMID- 27505967 TI - [Application of a self-made steel wire guide in the treatment of avulsion fractures of tibial posterior cruciate ligament]. AB - OBJECTIVE: To explore the effect of a self-made guiding needle of steel wire in guiding the wire through the tibial tunnel for the treatment of avulsion fractures of tibial posterior cruciate ligament with open reduction and wire fixation. METHODS: From February 2011 to June 2014, a total of 22 patients with avulsion fractures of tibial posterior cruciate ligament underwent surgical treatments were analyzed, including 14 males and 8 females with an average age of 35.6 years old (ranged, 17 to 63 years old). According to Meyers classification, 9 patients were classified as type II, 13 patients were classified as type III. All the patients underwent open reduction and wire fixation with medial knee "L" shape approach. A wire guiding needle was used to guide the wire through the tibial tunnel during operation. RESULTS: With the assistance of wire guidance needles, wires passed through the tibial tunnel rapidly during the operation in all the 22 patients. All the patients were followed up, X-ray imagings 6 months after operation showed the fractures healed well. The average follow-up time in all patients was 6 months (ranged, 6 to 12 months). The averaged Lysholm knee score in 22 knee was 92.7 +/- 3.4. All patients' posterior drawer test were negative. CONCLUSION: Self-made wire guiding needle can simplify the operation procedures in which the wires pass through the tibial tunnel, shorten the operation time, reduce the surgical trauma and complications, and be worthy of clinical application. PMID- 27505968 TI - [Reconstruction of complex proximal tibial defects using the long-stem tibial component combined with metallic wedge]. AB - OBJECTIVE: To investigate results of total knee arthroplasty using the long-stem tibial component combined with metallic wedge of knee prosthesis for the treatment of proximal defects. METHODS: From January 2011 to May 2013, 10 patients (11 knees) were treated with total knee arthroplasties using the long stem tibial component with metallic tibial wedge of knee prosthesis. All the patients were female and the average age was 67 years old (ranged, 60 to 77 years old). All the patients were osteoarthritis. All the patients were classified as T2A style. The patients were evaluated according to knee score system (KSS). RESULTS: All the patients were followed up for 12 months on average (ranged 3 to 29 months). The clinical outcome was assessed using KSS score, including knee pain score, knee stability score, knee range of motion score and knee walking score, knee stairs score. There were significantly differences at 6 weeks, 3 months, 6 months and 12 months between pre-and postoperative KSS score. CONCLUSION: The mechanical stability of tibial fixation in primary TKA is significantly increased by using the long-stem tibial component with metallic wedge of knee prosthesis, even in the presence of poor proximal bone. PMID- 27505969 TI - [A case report in entrapment of the ulnar nerve by forearm deep flexor tendon ganglion cyst]. PMID- 27505970 TI - [Microdecompression for intraforaminal lumbar disc herniations]. AB - OBJECTIVE: To summarize clinical results of the microdecompression for the treatment of intraforaminal lumbar disc herniations. METHODS: From September 2005 to May 2013,16 patients( 12 males, 4 females)with intraforaminal lumbar disc herniations underwent microdecompression, ranging in age from 32 to 56 years old with a mean of 38.6 years old. The lumbar disc herniations were located at L(3,4). in one patient, L(4,5) in 10 cases and L5S1 in 5 cases. RESULTS: All the patients were followed up, and the duration ranged from 20 to 48 months, with a mean period of 36 months. According to Macnab evaluation, 12 cases got an excellent result, 4 good. No apparent complications related to the technique occurred. Satisfactory clinical results were obtained in this series. CONCLUSION: Microdecompression may be particularly useful in the treatment of intraforaminal lumbar disc herniations. The microdecompression procedures are more likely to be well tolerated by older patients. PMID- 27505971 TI - [A review of research on the application of small intestinal submucosa in repairing osteoarticular injury]. AB - The ideal treatment and recovery of osteoarticular injury remain to be resolved. Small intestinal submucosa (SIS), a naturally-occurring decellularized extracellular matrix, has been recognized as an ideal scaffold for tissue engineering and widely used in repairing various tissues and organs. Nowadays its application has also been gradually increased in the field of orthopedics. We reviewed laboratorial studies and clinical trails about the application of SIS in bone and joint repair, aiming to evaluate its effects on the repair of bone, cartilage, meniscus, ligament and tendon. SIS has showed promising results in repairing bone, meniscus, ligament or tendon. However, additional studies will be required to further evaluate its effects on articular cartilage and tendon-bone healing. How to optimize SIS material,is also a focused problem concerned with making SIS a potential therapeutic option with high value for orthopedic tissue repair. PMID- 27505972 TI - 11 STRATEGIES FOR A SUCCESSFUL MERGER. PMID- 27505973 TI - USE DATA IN DIGITAL MARKETING. PMID- 27505974 TI - PEERS BENEFIT FROM ADVANCED TRAINING. PMID- 27505976 TI - 5 SKILLS EVERY EXECUTIVE MUST HAVE. PMID- 27505975 TI - ROSECRANCE AT 100. PMID- 27505977 TI - 5 WAYS TO MODERNIZE THE BUSINESS SIDE OF YOUR BUSINESS. PMID- 27505978 TI - HOW TO REDUCE WORKPLACE VIOLENCE. PMID- 27505979 TI - MENTAL HEALTH FIRST-AID TOOLS IN DEMAND. PMID- 27505980 TI - RESEARCHER UNCOVERS TRENDS IN MENTAL HEALTH DISPARITIES. PMID- 27505981 TI - IT'S TIME TO MOBILIZE mHEALTH IN BEHAVIORAL HEALTHCARE. PMID- 27505982 TI - WHAT WORKS: CLOUD COMPUTING. PMID- 27505983 TI - WHAT TO DO IF A BREACH HAPPENS TO YOU. PMID- 27505984 TI - WHY YOUR CLAIMS ARE BEING REJECTED. PMID- 27505985 TI - NORTH TAMPA BEHAVIORAL HEALTH. Wesley Chapel, Florida. PMID- 27505986 TI - Prevention of caries with probiotic bacteria during early childhood. Promising but inconsistent findings. AB - PURPOSE: This review summarized the available literature on the prevention of childhood caries through biofilm engineering with probiotic bacteria in early childhood. METHODS: Three databases (PubMed, Cochrane Library and Trip) were searched through January, 2016 for randomized controlled trials published in English. Out of 144 abstracts, seven studies fulfilled the predetermined inclusion criteria and were quality assessed with respect to risk of bias independently by two examiners. Due to the paucity and heterogeneity, a narrative synthesis was performed. The effect size was estimated from the caries prevalence and expressed as prevented fraction and number needed to treat. RESULTS: Probiotic supplements were better than placebo in preventing early childhood caries in all seven studies although the difference was statistically significant in only four of them. The prevented fraction ranged from 11% to 61% with a median of 48%. However, the quality of the evidence was low or very low and further translational research is needed to investigate this preventive approach in the clinic. PMID- 27505987 TI - A spectroscopic and surface microhardness study of enamel exposed to beverages supplemented with ferrous fumarate and ferrous sulfate. A randomized in vitro trial. AB - PURPOSE: To compare the efficacy between supplementing ferrous fumarate and ferrous sulfate to carbonated beverages by recording the in vitro mineral loss and surface microhardness (SMH) changes in human enamel. METHODS: 120 enamel blocks each (from primary and permanent teeth) were uniformly prepared and the initial SMH was recorded. These enamel specimens were equally divided (n = 60) for their respective beverage treatment in Group 1 (2 mmol/L ferrous sulfate) and Group 2 (2 mmol/L ferrous fumarate). Each group was further divided into three subgroups as Coca-Cola, Sprite and mineral water (n= 10). The specimens were subjected to three repetitive cycles of respective treatment for a 5-minute incubation period, equally interspaced by 5-minute storage in artificial saliva. The calcium and phosphate released after each cycle were analyzed spectrophotometrically and the final SMH recorded. RESULTS: The results were tested using student's t-test, one-way ANOVA and Wilcoxon signed rank test (P < 0.05). The spectrophotometric assessment of calcium and phosphate withdrawal found more loss with the supplementation of 2 mmol/L ferrous sulfate than ferrous fumarate (P < 0.005). Similarly, the mean surface microhardness reduction was less with the supplementation of 2 mmol/L ferrous fumarate than with ferrous sulfate (P < 0.005). Statistical comparisons revealed the maximum surface microhardness and mineral loss with primary enamel and the maximum loss produced in all groups by Coca-Cola (P < 0.005). PMID- 27505988 TI - Health concerns of heterotrophic plate count (HPC) bacteria in dental equipment water lines. AB - There is an unsubstantiated concern as to the health relevance of HPC (heterotrophic plate count) bacteria in dental equipment waterlines. The American Dental Association (ADA) web site includes guidelines for controlling HPC populations and implies that HPC populations >500 CFU/mL as a "health" benchmark. The world-wide published literature including the United Nations fully examined this situation and concluded that HPC bacteria are not a health risk, but merely a general water quality parameter for all waters including dental water lines. This review provides documentation that the standard measurement of HPC bacteria in waters alone do not pose a health risk and the ADA already provides appropriate practices to minimize HPC bacteria in dental equipment water. PMID- 27505989 TI - Potential of desensitizing toothpastes to reduce the hydrogen peroxide diffusion in teeth with cervical lesions. AB - PURPOSE: To evaluate the occlusive potential of four toothpastes by atomic force microscopy (AFM) before and after bleaching and quantify the hydrogen peroxide (HP) diffusion into the pulp chamber after application of desensitizing toothpastes in teeth with cervical lesions. METHODS: In 52 human extracted premolars, 2-mm deep artificial cervical lesions (ACL) were prepared and rinsed with EDTA for 10 seconds. Then teeth were adapted in a brushing machine and brushed with one of the following toothpastes [Regular toothpaste with no occlusive compounds Colgate Cavity Protection (CP), Oral-B Pro Health (OB), Colgate ProRelief (PR) and Sensodyne Rapid Relief (RR)] under constant loading (250 g; 4.5 cycles/seconds; 3 minutes). In 13 teeth (control group), no artificial cervical lesion was prepared. After that, the teeth were bleached with 35% HP with three 15-minute applications. The HP diffusion was measured spectrophotometrically as a stable red product based on HP reaction with 4 aminoanthipyrine and phenol in presence of peroxidase, at a wavelength of 510 nm and the dentin surfaces of ACL were evaluated before and after bleaching by AFM. Data was statistically analyzed by one-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: In the AFM images, some modifications of the dentin surface were observed after application of OB and RR. However, only for RR the formation of a surface deposit was produced, which occluded the majority of the dentin tubules. Also, only for RR, this deposit was not modified/removed by bleaching. Despite this, all groups with ACL showed higher HP penetration than sound teeth, regardless of the toothpaste used (P < 0.001). PMID- 27505990 TI - Consumption of baked nuts or seeds reduces dental plaque acidogenicity after sucrose challenge. AB - PURPOSE: To assess the acidogenic potential of eight different types of baked nuts or seeds eaten alone and after a sucrose challenge using in-dwelling electrode telemetry. METHODS: Six participants wearing a mandibular partial prosthesis incorporated with a miniature glass pH electrode were enrolled. The plaque pH was measured after 5 or 6 days of plaque accumulation. To establish a control, the subjects were instructed to rinse with sucrose, without any subsequent treatment, at the first visit. At each subsequent test visit, the subjects were asked to chew sugar free xylitol gum or consume 10 g of baked (180 degrees C, 5 minutes) peanuts, walnuts, pistachios, cashews, almonds, sunflower seeds, pumpkin seeds, or watermelon seeds alone and 10 minutes after a sucrose rinse. The minimum plaque pH value and area of plaque pH curve under 5.7 (AUC5.7) during and after nut/seed consumption or gum chewing alone, the plaque pH value at 10 minutes after the sucrose rinse, the time required for the pH to return to >5.7 and AUC5.7 after the sucrose rinse with or without nut/seed consumption or gum chewing were calculated from the telemetric curves. RESULTS: The sucrose rinse induced a rapid decrease in the plaque pH to 4.32 +/- 0.17 at 10 minutes; this value remained below 5.7 for the measurement period. The AUC5.7 values were 34.58 +/- 7.27 and 63.55 +/- 15.17 for 40 and 60 minutes after the sucrose challenge, respectively. With the exception of cashews and pumpkin seeds (minimum pH, 5.42 and 5.63 respectively), the nuts or seeds did not decrease the plaque pH to below 5.7 when consumed alone, with the AUC5.7 values during and after consumption (total 40 minutes) ranging from 0.24 to 2.5 (8.44 for cashews), which were significantly lower than those after the sucrose challenge. Furthermore, nut/seed consumption or gum chewing after the sucrose challenge significantly reversed the sucrose-induced decrease in the plaque pH, and the time required for the pH to return to >5.7 and the AUC5.7 values for 60 minutes after the sucrose challenge were much less than that of the sucrose challenge without subsequent interference. PMID- 27505991 TI - Antimicrobial efficacy of complete denture cleansers. AB - PURPOSE: To evaluate the in vitro antimicrobial efficacy of alkaline peroxides against microbial biofilms on acrylic resin surfaces. METHODS: Denture base acrylic resin (Lucitone 550; n= 360) circular specimens (15 x 3 mm) were obtained from a circular metal matrix and sterilized with microwave irradiation (650 W, 6 minutes). The specimens were then contaminated with suspensions [106 colony forming units (CFU)/mL] of Candida albicans (Ca), Candida glabrata (Cg), Staphylococcus aureus (Sa), Streptococcus mutans (Sm), Bacillus subtilis (Bs), Enterococcus faecalis (Ef), Escherichia coli (Ec), and Pseudomonas aeruginosa (Pa). After contamination, the specimens were incubated at 37 degrees C for 48 hours and then placed in a stainless steel basket, which was immersed in a beaker with one of the following solutions prepared and used according to the manufacturers' instructions (n= 10 per group): Group PC (positive control), phosphate-buffered saline (PBS) solution; Group MI, NitrAdine, Medical Interporous; Group EF, Efferdent Plus; Group CT, Corega Tabs; and Group NC (negative control; n= 5), no contamination and immersed in PBS. After incubation (37 degrees C, 24 hours), the number of colonies with characteristic morphology was counted, and CFU/mL values were calculated. The data were processed following the transformation into the formula log" (CFU + 1) and statistically analyzed by the Kruskal-Wallis and Dunn's tests (alpha = 0.05). RESULTS: There were significant differences between the groups for the evaluated microorganisms with a significant reduction in the CFU/mL. MI was effective for Ca, Cg, Sa, Sm, Ef, Ec and Pa; EF was effective for Cg, Sm, Ef, Ec and Pa; and CT was effective for Sa, Bs and Ec, when compared with the PC group. PMID- 27505992 TI - Effect of mechanical toothbrushing combined with different denture cleansers in reducing the viability of a multispecies biofilm on acrylic resins. AB - PURPOSE: To investigate the efficacy of immersion and brushing with different cleansing agents in reducing the viability of multispecies biofilm on acrylic resins. METHODS: Lucitone 550 (L) and Tokuyama Rebase Fast II (T) specimens (10 x 2 mm) were prepared, sterilized, and inoculated with a suspension of Candida albicans, Candida glabrata, and Streptococcus mutans. Specimens were incubated for 48 hours at 37 degrees C for biofilm formation. Then, they were divided into groups (n = 12) and subjected to brushing or immersion for 10 seconds in distilled water (W), 0.2% peracetic acid-Sterilife (Ac), 1% chlorhexidine digluconate (CHX), 1:1 water/dentifrice solution (D), 1% sodiumhypochlorite (NaOCl), and sodium perborate/Corega Tabs (Pb). Viable microorganisms were evaluated by the XTT assay and colony counts (cfu/mL). Data were performed by ANOVA and Tukey test with 5% significance level. RESULTS: The multispecies biofilm on L and T were killed by brushing or immersion in Ac, CHX, and NaOCl for only 10 seconds. PMID- 27505993 TI - Headache and jaw locking comorbidity with daytime sleepiness. AB - PURPOSE: To investigate the relationship between craniofacial pain symptoms (painful conditions present in the cranium and face, including jaw joint-related pathology and primary headache conditions) and daytime sleepiness, determined by the Epworth sleepiness scale (ESS), to correlate comorbidity as well as potential predictive factors. METHODS: 1,171 patients seeking care for chronic pain and/or sleep-related breathing disorders (SRBDs) at 11 international treatment centers were included in the study. Patients completed the ESS and identified their primary craniofacial pain and sleep pathology symptoms. Descriptive statistics and regression analysis were performed to determine comorbidities between craniofacial pain symptoms and daytime sleepiness, and factors predictive of higher ESS scores. RESULTS: There was high comorbidity of some craniofacial pain symptoms and high ESS scores, including headaches. In addition, for the first time to our knowledge, orthopedic craniofacial dysfunction (i.e., jaw locking) was correlated with, and predictive of, high ESS scores. PMID- 27505994 TI - An ion extract obtained from mineral trioxide aggregate induced dentin remineralization and dentin tubule occlusion in artificially demineralized bovine dentin. AB - PURPOSE: To investigate the ability of a mineral trioxide aggregate (MTA) extract mixed with a phosphate buffered saline (PBS) system to induce remineralization and dentin tubule occlusion in artificially demineralized bovine dentin. METHODS: The MTA extract solution was prepared by mixing white ProRoot MTA with distilled water (1:2) for 48 hours, before subjecting it to centrifugation. The elemental composition of the MTA extract solution was analyzed with inductively coupled plasma atomic emission spectrometry. The deposits produced by the MTA extract-PBS mixture were chemically analyzed using electron probe microanalysis (EPMA) and X ray diffraction (XRD). The effects of the two-step application of the mixture (MTA extract solution followed by PBS) to bovine dentin samples that had been artificially demineralized with phosphoric acid (10%, 10 seconds) were investigated with scanning electron microscopy and EPMA after the specimens had been stored in PBS for 1 or 7 days. RESULTS: The MTA extract solution contained calcium, silicone, and aluminum (Ca>Si>Al), and the deposits produced by the MTA extract-PBS mixture contained calcium, phosphorous, sodium, silicone, and aluminum (Ca>P>Na>Si>Al) as major mineral elements. XRD also revealed that the deposits contained hydroxyapatite. The two-step application process resulted in the formation of a 2-3 microm-thick "mineral infiltration layer", together with mineral tag-like structures in the dentin tubules. The MTA extract-treated specimens exhibited a significantly higher dentin tubule occlusion rate than the untreated specimens (P < 0.05). PMID- 27505995 TI - Wear of an enhanced resin-modified glass-ionomer restorative material. AB - PURPOSE: To compare the wear of an enhanced resin-modified glass-ionomer (RMGI) restorative material (ACTIVA BioACTIVE Restorative) to a resin composite (Filtek Supreme Ultra), RMGI (Fuji II LC), and glass-ionomer (GI) (Fuji IX) material. METHODS: Specimens of each material (n = 8) were prepared in a silicone mold. All specimens other than the GI material were light polymerized for 40 seconds. After 24-hour storage (H2O, 37 degrees C), the specimens were loaded into the modified Alabama wear testing device. Freshly extracted cusps of human premolars were prepared as antagonists. Specimens were loaded with 20N for 100,000 cycles at 1 Hz. A 33% glycerin lubricant was cycled throughout testing. Specimens and enamel antagonists were scanned before and after wear testing with a non-contact optical profilometer and volumetric wear was measured with superimposition software. Representative specimens were examined with scanning electron microscopy. Data were analyzed with a 1-way ANOVA and Tukey post-hoc analysis (alpha = 0.05). RESULTS: Significant differences were found between materials. Materials ranked in order of increasing wear: Filtek Supreme Ultra and ACTIVA BioACTIVE Restorative < Fuji II LC < Fuji IX. Micrographs revealed that Filtek Supreme Ultra and ACTIVA BioACTIVE Restorative underwent abrasive wear whereas Fuji II LC and Fuji IX underwent fatigue wear. PMID- 27505996 TI - Bond strength of resin cements to dentin using universal bonding agents. AB - PURPOSE: To determine the effect of new universal bonding agents on the bond strength of dual-cure resin cements to dentin. METHODS: 140 extracted human third molars were mounted in dental stone and sectioned with a saw to remove coronal tooth structure. The teeth were randomly divided into seven groups of 20, based on the use of five universal bonding agents (All-Bond Universal; FuturaBond U; Prime&Bond Elect; Scotchbond Universal; Clearfil Universal) compared to two self etch bonding agents (Clearfil SE Bond and Clearfil SE Bond 2). Each group was further divided into two equal subgroups of 10 specimens each with each subgroup tested with either self- or light-cure activation of the dual-cure resin cement (Calibra). The bonding agent was applied per manufacturers' instructions to the dentin surface of each specimen. The specimens were placed into a jig and resin cement was inserted into the mold to a height of 3-4 mm and light cured. Specimens were stored for 24 hours in 37 degrees C distilled water and tested in shear in a universal testing machine. A mean shear bond strength value (MPa) and standard deviation was determined per group. RESULTS: Except for Clearfil Universal, the new simplified universal bonding agents resulted in significantly lower shear bond strength of the resin cement to dentin than the two-step, self etching bonding agents Clearfil SE Bond or Clearfil SE Bond 2. PMID- 27505997 TI - Intratubular penetration in post cementing: A comparative study between a total etching system and a self-etching cement. AB - PURPOSE: To analyze the penetration depth and percentage perimeter with penetration of two fiber post cementing systems using confocal laser scanning microscopy (CLSM). METHODS: 20 maxillary incisors were shaped with the Mtwo system and filled using lateral condensation and TopSeal mixed with fluorescein. Fiber posts were cemented. The samples were divided into two groups of 10 teeth each, according to the post cementing technique used: Prime&Bond NT combined with Rebilda DC using a total dentin etching technique (Group 1); or BisCem a self adhesive cement (Group 2). Rhodamine B was incorporated in the adhesive systems. Cross-sections were prepared, with the selection of three sections (coronal, middle and apical thirds). CLSM was used to measure the percentage perimeter of the root canal showing penetration of the endodontic cement and of the adhesive system in the dentin tubules, together with the maximum penetration depth. The nonparametric Mann-Whitney U-test was used to compare the data referred to each of the three tooth sections between the two study groups. The Friedman test was used to compare the variables by coronal, middle and apical thirds within each group. RESULTS: Greater penetration was recorded with the BisCem system in all thirds, with statistically significant differences in the case of the middle and apical thirds (P = 0.001). The percentage perimeter with penetration was also greater in all thirds with the BisCem system, though without significant differences between the two groups. Penetration depth and percentage were found to decrease in the coronal to apical direction in both groups. PMID- 27505998 TI - PUBLIC FUNDING FOR DENTAL CARE. PMID- 27505999 TI - Knowledge, opinions and factors influencing practices regarding sugar in oral paediatric medications: a survey of Dunedin pharmacy staff. AB - BACKGROUND AND OBJECTIVES: Sugar, a known aetiological factor in dental decay, has been used in paediatric medications as a bulking agent, preservative and to improve taste. Although artificial sweeteners have largely replaced sugar, some prescribed and over-the-counter (OTC) paediatric medications and supplements containing sugar are still available in New Zealand. Little is currently known about the knowledge, opinions and practices of staff in NZ pharmacies regarding sugar-containing paediatric medications. This study was carried out to investigate these factors. METHODS: After ethical approval was obtained, questionnaires were delivered to all staff members at pharmacies in the greater Dunedin area. Quantitative statistical analysis was carried out using SPSS version 22.0 with the alpha value set at 0.05. Qualitative data were analysed using a general inductive technique. RESULTS: A total of 58 questionnaires were returned giving a pharmacy response rate of 63.0%. Some 29.9% of respondents thought the inclusion of sugar in medications necessary and 77.6% agreed that sugar in paediatric medications can contribute to dental decay. Most of the 67.2% who reported that they do not give advice to customers regarding sugar in medications and oral health, felt it was not a priority. Parental request was the main factor determining provision or recommendations regarding sugar-free options (87.9%). CONCLUSION: Although choice of a sugar-free medication can be limited by many factors, inter-professional collaboration and knowledge sharing on this topic would be advantageous. In addition, the provision of more formalised education, either as part of undergraduate pharmacy curricula or as part of continuing education, should be considered. PMID- 27506000 TI - A review of occupationally-linked suicide for dentists. AB - BACKGROUND AND OBJECTIVES: Suicide rates among dentists and a perceived elevated risk for suicide have been debated in the academic literature. It has filtered into the public psyche that dentists have the highest suicide rate of any occupation. The present review seeks support for both protagonist and antagonist positions from multidisciplinary perspectives. Contemporary risk factors and strategies for intervention and the prevention of suicide in dentistry are explored. METHODS: An online database search for articles and reports, with selected target words, was conducted for peer reviewed publications on suicide in the dental profession, and for factors contributing to dentist suicide. Review guidelines from the American Psychological Association were used to clarify concepts, identify where most work was focussed, and to explore the superiority of any approach to the emotive topic over another. RESULTS: Findings suggest the dominant belief that dentists have an elevated risk of suicide may be historically, but not currently, accurate. Although dentists' suicide is trending down, diversity in methodology means no current consensus is possible. Factors found to be influencing dentists' suicide ranged from known occupational stressors, to toxins and substance abuse, and untreated mental health problems. CONCLUSION: The contemporary position in New Zealand shows dentists per se are not more likely than other health professionals to commit suicide although they may have been in the past. Dentists should be aware of individual susceptibility to burnout and mental health problems. Future directions are outlined to address this including peer intervention, and programmes available for dentists to cope better with risks leading to suicide. PMID- 27506001 TI - Dental implant use in New Zealand: A 10-year update. AB - OBJECTIVE: The aim of this study was to explore changes in dentists' promotion and use of implants in New Zealand over the past 10 years. METHODS: A postal survey was conducted of a random sample of 807 New Zealand registered dentists, using a 23-item questionnaire adapted from one used in a similar survey in 2004. RESULTS: The participation rate was 54.3%. In the past 10 years, the percentage of dentists providing an implant service has increased from 49.4% to 68.0%, with an equal proportion of females now providing this service. Single missing teeth (56.9%) and trauma (51.5%) are the most common clinical situations in which implants are provided. Patient enquiries about implants have slightly increased. A need for continuing education, particularly in the area of implant prosthetic procedures, was noted by 76.5%. Despite more proprietary implant systems now being available, the most commonly used system has remained unchanged. Cost is still the primary barrier to implementing implant treatment. CONCLUSIONS: Although dental implant use in New Zealand has increased, it appears that a need exists for continuing education, particularly for implant prosthetic procedures. The perceived expense of treatment continues to hinder optimal utilisation. PMID- 27506002 TI - Ethnic and socioeconomic inequalities in dental treatment at a school of dentistry. AB - BACKGROUND AND OBJECTIVES: Health services should be targeted toward those most in need of health care. Poor oral health disproportionately affects Maori, Pacific Island, and socioeconomically deprived New Zealanders of all ages, and oral health care services should be prioritised to such groups. In New Zealand, free oral health care is available for all children up to the age of 17. On the other hand, adult dental services are provided on a user-pays basis, except for a limited range of basic services for some adults, access to which varies regionally. This study investigated the extent of dental treatment inequalities among patients at New Zealand's only School of Dentistry. METHODS: Data were audited for all treatments provided at the University of Otago Faculty of Dentistry from 2006 to 2011 for patients born prior to 1990. Ethnic and socioeconomic inequalities in the provision of dental extractions, endodontic treatment, crowns, and preventive care were investigated. Differences were expressed as the odds of having received one or more treatments of that type during the six-year period 2006 to 2011. RESULTS: Data were analysed for 23,799 individuals, of whom 11,945 (50.2%) were female, 1,285 (5.4%) were Maori and 479 (2.0%) were Pacific, 4,040 (17.0%) were of low socioeconomic status (SES), and 2,681 (11.3%) were beneficiaries or unemployed. After controlling for SES, age, and sex, Maori had 1.8 times greater odds of having had a tooth extracted than NZ European patients, while Pacific Islanders had 2.1 times the odds. Furthermore, after controlling for ethnicity, age, and sex, low-SES patients had 2.4 times greater odds of having had a tooth extracted than high-SES patients, and beneficiaries had 2.9 times the odds. Conversely, these groups were less likely to have had a tooth treated with a crown or endodontics or receive preventive care. CONCLUSIONS: Existing policies call for the reduction of inequalities. There is a need for a strategy to monitor changes in treatment inequality over time which includes improving equity in service care provision. The observed treatment inequalities are likely to be an underestimate of those occurring in private dental practice in New Zealand. PMID- 27506003 TI - LAWRENCE J CROXSON, ONZM. PMID- 27506004 TI - Eliminating Leprosy in India--Is it a Dream? AB - In recent years there have been considerable discussions on the current leprosy situation in India and the status of the country's attempts to eliminate or eradicate the disease. In this connection it is very important to analyze the background and various developments relevant to leprosy elimination in India. PMID- 27506005 TI - Study of 35 Cases of Hansen's Disease, which Required Treatment beyond Fixed Duration--Multi Drug Therapy. AB - Multi Drug Therapy (MDT) is the main weapon against leprosy since its inception in 1981. India achieved the level of elimination (< 1 case/10,000) on 31st December 2005. It has been proved in few studies that despite 2 years of regular therapy 10% of the patients continue to harbour viable persisters. There are many problems related with FD-MDT. Many cases have residual disease activity after completion of treatment. Aims of the present study was to study the profile of RFT cases in leprosy treated with FD-MDT, who required extended MDT, duration between completion of FD -MDT and clinical presentation, Acid Fast Bacilli (AFB) status, histopathology and type of leprosy at the time of presentation. A prospective study of 35 RFT (Released FromTreatment) cases with signs of activity were recruited in period betveen May 2007 to November 2001. All cases were diagnosed clinically and investigations were done for AFB smear, histopathological examination and Fite Faraco staining. We found that all the 35 cases, which required extended MDT, age group ranged from 10 to 65 years. Majority (71.4%) had taken previous Multi-Bacillary (MB) treatment for 1 year duration. Eleven (31.42%) of cases came within one year, 17 (48.57%) between one to two years and 7 (20%) cases after two years of stopping FD-MDT. AFB smear was positive in 36.84% of cases in which done. Majority of previously diagnosed MB cases presented as BT/TT in histopathology. Thus there is need to search for reliable prognostic markers for therapeutic purposes. PMID- 27506006 TI - A Rare Combination of Pure Neuritic Leprosy with Morphea Leading to Diagnostic Confusion. AB - A circumscribed sclerotic plaque of morphea can sometimes be mistaken for tuberculoid leprosy and vice versa can also happen. However, the co-existence of a patch of morphea mimicking as Leprosy patch in an underlying case of neuriticleprosy, can be very misleading. We present a case with glove and stocking anaesthesia and peripheral nerve enlargement with a single large hypopigmented, non-anaesthetic macule on trunk, clinically diagnosed as Hansen's disease (Borderline Tuberculoid - BT). Slit skin smears proved to be negative for AFB and histopathology of the skin lesion was consistent with morphea, which lead us to do a nerve biopsy. Sural nerve biopsy proved it to be Hansen's neuritis with occasional bacilli. The patient was started on MDT-MB and followed up. This is a rare case of co-existing morphea with Hansen's disease. It would have been easily misclassified if we had presumed the cutaneous lesion to be a case of Hansen's (BT) patch and not done a cutaneous nerve biopsy which led to diagnosis of multibacillary leprosy. PMID- 27506007 TI - Bone Changes in an Italian Ancient Human Skeleton--Possibly Caused by Leprosy. AB - Leprosy is an infectious disease caused by Mycobacterium leprae and Mycobacterium lepromatosis. In the last stage it can afflict the skeleton with a series of specific and non-specific bone changes. The possibility of studyingthe skeleton of an individual who lived in the pre-antibiotic era (Roman period) with skeletal changes in the rhino-maxillary region and hand and foot bones, permitted skeletal lesions to be analyzed directly. In addition, the localization and the complexity of the bony lesions could be attributed to the presence of leprosy. The importance of this approach was the possibility to verify the nature and typology of the primary and secondary bone changes in leprosy in absence of clinical therapy. PMID- 27506008 TI - Histopathological Diagnosis of Leprosy Type 1 Reaction with Emphasis on Interobserver Variation. AB - Upgrading typel lepra reaction or reversal reaction (RR) is an acute inflammatory complication of leprosy and a disparity exists between clinicians and pathologists for diagnosing a RR. Inter-observer variations among pathologists also compound this problem as no universally agreed diagnostic criteria exist. 120 biopsies and H&E stained slides were assessed by 3 pathologists. The pathologists were blinded to the clinical diagnosis and to each other's observations. Each pathologist assigned a likelihood of reaction by their histopathological observations as definitely reaction, probable reaction and no reaction. Clinicopathological correlation and interobserver agreement was analyzed statistically. Discordance between clinical and histopathological diagnosis was seen in 30.8% by pathologist 1 (P1), 23.7% by pathologist 2 (P2) and 34.5% bythe pathologist 3 (P3). Dermal edema, intragranuloma edema and epidermal erosion were consistent findings by all observers. Definite reaction was seen in 54.2% of cases by P1, 53.3% by P2 and 34.5% by P3. Kappa statistics for strength of agreement showed good agreement between 3 pathologists with P1 (kappa = 0.83), P2 (kappa = 0.61), P3 (kappa = 0.62). RR are underdiagnosed on histopathological examination but this study shows that dermal edema, edema within the granuloma and partial obliteration of grenz zone by granuloma are reliable clues to diagnose a RR on histopathology. PMID- 27506009 TI - [Exploring the Severe Haze in Beijing During December, 2015: Pollution Process and Emissions Variation]. AB - Severe haze episodes shrouded Beijing and its surrounding regions again during December, 2015, causing major environmental and health problems. Beijing authorities had launched two red alerts for atmospheric heavy pollution in this period, adopted a series of emergency control measures to reduce the emissions from major pollution sources. To better understand the pollution process and emissions variation during these extreme pollution events, we performed a model assisted analysis of the hourly observation data of PM2.5, and meteorological parameters combined with the emissions variation of pollution sources. The synthetic analysis indicated that: (1) Compared with the same period of last year, the emissions of atmospheric pollution sources decreased in December 2015. However, the emission levels of primary pollutants were still rather high, which were the main intrinsic causes for haze episodes, and the unfavorable diffusion conditions represented the important external factor. High source emissions and meteorological factors together led to this heavy air pollution process. (2) Emergency control measures taken by the red alert for heavy air pollution could decrease the pollutants emission by about 36% and the PM2.5 concentrations by 11% to 21%. Though the implementation of red alert could not reverse the evolution trend of heavier pollution, it indeed played an active role in mitigation of PM2.5 pollution aggravating. (3) Under the heavy pollution weather conditions, air pollutants continued to accumulate in the atmosphere, and the maximum effect by taking emergency measures occurred 48-72 hours after starting the implementation; therefore, the best time for executing emergency measures should be 36-48 hours before the rapid rise of PM2.5 concentration, which requires a more powerful demand on the accuracy of air quality forecast. PMID- 27506010 TI - [Pollution Characteristics and Source of HULIS in the Fine Particle During the Beijing APEC]. AB - In order to investigate the influence of the emission reduction measure during the Beijing APEC on the concentrations and pollution characteristics of humic like substances (HULIS) in atmospheric fine particles, PM2.5 samples were collected and analyzed for OCEC, WSOC, HULIS and water-soluble ions. The concentration of HULIS in PM2.5 ranged 1 ug . m-3-15 ug . m-3. HULIS concentrations were 7.99 ug . m-3, 5.83 ug . m-3 and 7.06 ug . m-3 before, during and after APEC, which indicated emission reduction measure had important effect on the reduction of HULlS. The decrease of HULIS during the APEC was significantly faster than those of EC and WSOC, while the increase of HULIS turned out to be much slower than OC, EC, WSOC and PM2.5 after the meeting. The proportions of HULIS to PM2.5 were 13.60%, 13.59%, 14.02% and 12.22% at four different stages, i. e., whole sampling period, before, during and after the APEC, while HULIS-C/OC and HULIS-C/WSOC were 28.95%, 35.51%, 28.37%, 19.93%; and 52.75%, 59.58%, 51.54%, 45.39%, respectively. HULlS was significantly positively correlated with humidity, while significantly negatively correlated with wind speed. Biomass burning and secondary transformation of VOCs might be two important sources of HULlS in Beijing. PMID- 27506011 TI - [Seasonal Variation Characteristics and Potential Source Contribution of Sulfate, Nitrate and Ammonium in Beijing by Using Single Particle Aerosol Mass Spectrometry]. AB - Single particle aerosol mass spectrometry (SPAMS) was deployed to continuously observe the aerosol particles of Beijing urban area from 2013-12 to 2014-11, and the hourly average data of sulfate, nitrate and ammonium (SNA) were obtained using the characteristic ion tracer method. The mixing state and size distribution of SNA were analyzed. In addition, based on Hysplit 48 h back air mass trajectory results in combination with Concentration Weighted Trajectory method (CWT), we obtained the seasonal potential source contribution area of SNA. The results showed that the mixture of sulfate, nitrate and ammonium in spring and summer was more stable than that in autumn and winter. The size distribution of sulfate and nitrate was very similar. The size distribution characteristics of SNA followed the order of autumn > summer > spring > winter. The potential source region of SNA had similar spatial distribution characteristics, and the potential source region of SNA was mainly located in Beijing and south areas, especially at Tianjin, Langfang, Hengshui, Baoding and Shijiazhuang. PMID- 27506012 TI - [Pollution Characteristics and Source Apportionment of PM2.5, in Lanzhou City]. AB - In order to understand the characteristics and sources of PM2.5 pollutant in Lanzhou City, two PM2.5 sampling sites were set up in Chengguan district and Xigu district, respectively. Samples were sampled during October (non-heating period) and December (heating period) 2013, and mass concentrations of PM2.5 and its 16 kinds of chemical components were analyzed. The results showed that the average mass concentration of PM2.5 during the sampling period was 129 ug . m-3. The sequence of mass concentrations of inorganic elements was: S > Ca > Fe > Al > Mg > Pb > Zn > Mn > Ti > Cu, while the mass concentrations of S, Ca, Fe, and Al, which were the major element compositions, exceeded 1 ug . m-3. The mass concentration of inorganic elements during heating period was higher than that during non-heating period, meanwhile, the mass concentration in Chengguan district was higher than that in Xigu district. The sequence of mass concentrations of water-soluble ions was: SO42- > NO3- > NH4+ > Cl- > K+ > Na+, while the mass concentrations of SO42-, NO3-, NH4+, which were the main ion components, exceeded 10 ug . m-3. The mass concentration of water- soluble ions during heating period was higher than that during non-heating period, meanwhile, the mass concentration in Xigu district was higher than that in Chengguan district. The result of enrichment factor (EF) analysis showed that the EF values of Al, Ca, Mg and Ti were lower than 1, indicating the contribution of natural source, while the EF values of Cu, Pb, S and Zn were higher than 10, indicating the contribution of anthropogenic pollution. The result of principal component analysis showed that the sources of PM2.5 were mainly derived from traffic emission, biomass burning, soil and secondary particles. PMID- 27506013 TI - [Pollution Level and Source Apportionment of Atmospheric Particles PM2.5 in Southwest Suburb of Chengdu in Spring]. AB - In order to understand the characteristics of PM2.5 pollution in the atmosphere of Chengdu southwest suburb, PM2.5 particles in Chengdu southwest suburb were collected and analyzed from March 18 to March 31st, 2015. The results showed that the daily average concentration of PM2.5 in the southwest suburb of Chengdu reached 121.21 ug . m-3, and the average daily concentration of 24 samples in 31 PM2.5 samples was over 75 ug . m-3, the daily excessive rate was 77%, indicating the PM2.5 pollution in the study area was serious in March. When studying the relationship between atmospheric and meteorological factors, it was found that there was a significant index correlation between PM2.5 concentration and atmospheric visibility, and it had a positive correlation with temperature and humidity, but the correlation was not obvious. NH4+ (16.24%), SO42- (12.58%) and NO3- (9.91%) were dominant in PM2.5 The ratio of NO3-/SO42- was 0.77, which indicated that the pollution of stationary sources in the southwest suburb was more severe than that of mobile sources. Organic carbon (OC)/elemental carbon (EC) ratios were higher than 2, which indicated the existence of second organic carbon (SOC). Using OC/EC ratio method to estimate the concentration of SOC, it was found that the average concentration of SOC in the southwest suburb of Chengdu in March was 3.49 u . m-3, and the contribution rate of OC was 20.6%, which showed that the main source of OC in the southwest suburb of Chengdu was primary discharge. The correlation analysis of OC and EC showed that the correlation coefficient reached 0.95, indicating that the OC and EC sources were similar and relatively stable, and there was a great impact of local source emissions on Chengdu southwest suburb in spring, and primary discharge played a dominant role, while the contribution of SOC to OC was relatively small, which was consistent with the SOC characteristics obtained by estimation. Using principal component analysis method to analyze the sources of PM2.5 in the southwest of Chengdu, it was found that the main pollution sources of PM2.5 in southwest suburb of Chengdu were coal burning and biomass burning, secondary nitrate/sulfate, soil and dust, vehicle emissions, electronic production source, and mechanical processing source. PMID- 27506014 TI - [Variation Characteristics of Total Gaseous Mercury at Simian Mountain Background Station in Mid-subtropical Region]. AB - Total gaseous mercury (TGM) was continuously monitored at the Simian Mountain Forest Nature Reserve in Chongqing, a representative of the mid-subtropical region, using high-resolution automatic atmospheric mercury vapor analyzer (Tekran 2537X) from March 2012 to February 2013. The results showed that the average concentration of TGM during the monitoring was (2.88 +/- 1.54) ng . m-3, which was much higher than the background TGM on north hemisphere but lower than those at most of the other monitoring sites in China. These results suggested that the TGM level in Simian Mountain was still in the normal range on regional scale, but had an increasing tendency globally. The TGM level exhibited a distinct seasonal variation, following the order of winter (3.68 +/- 2.43) ng . m 3 > summer (3.29 +/- 0.79) ng . m-3 > spring (2.44 +/- 0.69) ng . m-3 > autumn (2.13 +/- 0.97) ng . m-3, and the TGM concentration varied to a greater extent in winter. The diurnal variation of TGM concentration characterized as being higher at the nighttime in spring, while higher during the daytime in other seasons. The concentration variation of TGM had a positive correlation to temperature and light intensity. The result of backward trajectory analysis using HYSPLIT showed that the main source of the TGM in Simian Mountain was the local coal combustion, and long distance transportation by the Indian monsoon might also play a role in the increasing TGM level. PMID- 27506015 TI - [Establishment of Method for Health Risk Assessment of Pollutants from Fixed Sources]. AB - A health risk assessment method of pollutants from fixed sources was developed by applying AERMOD model in the health risk assessment. The method could directly forecast the health risks of toxic pollutants from source by some exposure pathway. Using the established method, in combination with the data of sources and traditional health risk assessment method as well as the measured data of PAHs in inhalation particle matter (PM10) in Lanzhou, the health risk of polycyclic aromatic hydrocarbons (PAHs) and benzo [a] pyrene (BaP) in PM10 from the three fire power plants and the health risk of PAHs and BaP in PM10 at the receptor point by inhalation exposure in heating and non-heating seasons was calculated, respectively. Then the contribution rates of the health risk caused by the three fire power plants to the health risk at the receptor point were calculated. The results showed that the contribution rates were not associated with sex and age, but were associated with time period and risk types. The contribution rates in the non-heating seasons were greater than those in heating seasons, and the contribution rates of the carcinogenic risk index were greater than those of the cancer risk value. The reliability of the established method was validated by comparing with the traditional method. This method was applicable to health risk assessment of toxic pollutants from all fixed sources and environmental risk assessment of environmental impact assessment. PMID- 27506016 TI - [Testing of Concentration and Characteristics of Particulate Matters Emitted from Stationary Combustion Sources in Beijing]. AB - A self-built monitoring sampling system on particulate matters and water soluble ions emitted from stationary combustion sources and a size separated sampling system on particulate matters based on FPS4000 and ELPI + were applied to test particulate matters in fumes of typical stationary combustion sources in Beijing. The results showed that the maximum concentration of total particulate matters in fumes of stationary combustion sources in Beijing was 83.68 mg . m-3 in standard smoke oxygen content and the minimum was 0.12 mg . m-3. And particle number concentration was in the 104-106 cm-3 number of grade. Both mass and number concentration ranking order of particulate matters emitted from stationary combustion sources in Beijing was: heating gas fired boilers < power plant coal fired boilers < heating coal fired boilers. And two or three peaks existed under 1 um of particulate size for both number size distribution and mass size distribution. The number concentration for PM2.5 accounted for over 99.8% of that for PM10 and that for PM0.1 accounted for over 83% of that for PM2.5. But the proportions of PM0.1, and PM2.5 in PM10 were significantly lower in quality analysis,the proportion of PM2.5 in PM10 was about 82%, and that of PM0.1 in PM2.5 was about 27%-33%. PMID- 27506017 TI - [Pollution Evaluation and Risk Assessment of Heavy Metals from Atmospheric Deposition in the Parks of Nanjing]. AB - Contents of heavy metals involving As, Cd, Cr, Cu, Ni, Pb and Zn from atmospheric deposition in 10 parks of Nanjing were analyzed. The pollution level, ecological risk and health risk were evaluated using Geoaccumulation Index, Potential Ecological Risk Index and the US EPA Health Risk Assessment Model, respectively. The results showed that the pollution levels of heavy metals in Swallow Rock Park, Swallow Rock Park and Mochou Lake Park were higher than the others. Compared to other cities such as Changchun, Wuhan and Beijing, the contents of heavy metals in atmospheric deposition of parks in Nanjing were higher. The evaluation results of Geoaccumulation Index showed that Pb was at moderate pollution level, Zn and Cu were between moderate and serious levels, while Cd was between serious and extreme levels. The ecological risk level of Cd was high. The assessment results of Health Risk Assessment Model indicated that there was no non-carcinogenic risk for all the seven heavy metals. For carcinogenic risk, the risks of Cd, Cr and Ni were all negligible (Risk < 1 x 10-6), whereas As had carcinogenic risk possibility but was considered to be acceptable (10-6 < Risk < 10-4). PMID- 27506018 TI - [CoCuMnOx Photocatalyzed Oxidation of Multi-component VOCs and Kinetic Analysis]. AB - Solar energy absorption coating CoCuMnOx was prepared by co-precipitation method and applied to photodegrade multi- component VOCs including toluene, ethyl acetate and acetone under visible light irradiation. The photocatalytic oxidation performance of toluene, ethyl acetate and acetone was analyzed and reaction kinetics of VOCs were investigated synchronously. The research indicated that removal rates of single-component toluene, ethyl acetate and acetone were 57%, 62% and 58% respectively under conditions of 400 mg . m-3 initial concentration, 120 mm illumination distance, 1 g/350 cm2 dosage of CoCuMnOx and 6 h of irradiation time by 100 W tungsten halogen lamp. Due to the competition among different VOCs, removal efficiencies in three-component mixture were reduced by 5%-26% as compared with single VOC. Degradation processes of single-component VOC and three-component VOCs both fitted pseudo first order reaction kinetics, and kinetic constants of toluene, ethyl acetate and acetone were 0.002, 0.002 8 and 0.002 33 min-1 respectively under single-component condition. Reaction rates of VOCs in three-component mixture were 0.49-0.88 times of single components. PMID- 27506019 TI - [Distribution of Nitrogen and Phosphorus in the Tidal Reach and Estuary of the Daliao River and Analysis of Potential Eutrophication]. AB - Based on the monitoring data in the tidal reach and estuary of the Daliao river in August and November, 2013, the seasonal and spatial distribution of the nitrogen and phosphorus forms were studied, and the degree of eutrophication was evaluated. The results showed that nitrate nitrogen was the main chemical species and occupied about fifty-five percent of inorganic nitrogen, and the particulate phosphorus was the main chemical species and occupied about fifty percent of total phosphorus in the tidal reach and estuary of the Daliao river in wet and dry seasons, 2013. The concentrations of nitrogen and phosphorus nutrients decreased in the direction from tidal reach to estuary of the Daliao river. Correlation analysis showed that there was a significant negative correlation between the nitrogen and phosphorus forms and salinity in most of the water body, which illustrated that physical dilution of seawater played a major role in the spatial distribution of nitrogen and phosphorus forms. The concentrations of nitrogen and phosphorus nutrients in the dry season were higher than those in the wet season, this was mainly related to the seasonal terrestrial input of the tidal reach. The concentration of the dissolved inorganic nitrogen was higher than 0.30 mg . L-1, and the value of N/P was higher than 60, which indicated that PO43--P was the nutrient limiting phytoplankton growth in the tidal reach and estuary of the Daliao river in August and November, 2013. PMID- 27506020 TI - [Spatial Distribution of Stable Isotope from the Lakes in Typical Temperate Glacier Region]. AB - We focused mainly on the spatial variation and influencing factors of hydrogen and oxygen stable isotopes between water samples collected at the surface and different depths in the Lashi Lake in August, 2014. Hydrological supply characteristics of the lake in typical temperate glacier region were discussed. The results showed that the values of delta18O and deltaD in the Lashi Lake ranged from -12.98 per thousand to -8.16 per thousand with the mean of -9.75 per thousand and from -99.42 per thousand to -73.78 per thousand with the mean of 82.23 per thousand, respectively. There was a reversed spatial variation between delta18O and d. Relatively low values of delta18O with high values of d were found at the edge of the lake where the rivers drained into. Meanwhile, the values of d in the vertical profile varied little with depth, suggesting that the waters mixed sufficiently in the vertical direction. The d values increased at first and then decreased from east to west at different layers, but both increase and decrease exhibited different velocities, which were related to the river distribution, the locality of the lake and environmental conditions etc. River water and atmospheric precipitation were the main recharge sources of the Lashi Lake, and the melt-water of snow and ice might also be the supply resource. The delta18O values of lake water in glacier region decreased along the elevation (except for Lashi Lake), generally, this phenomenon was called "altitude effect". Moreover, high isotopic values of the lake water from non-glacier region were due to the evaporation effect. PMID- 27506021 TI - [delta15N-NO3- and delta18O-NO3- Tracing of Nitrate Sources in Beijing Urban Rivers]. AB - In order to quantitatively identify sources of nitrate pollution in Beijing urban area and provide effective guidance for relevant departments to control the pollution of Beijing rivers, delta15N-NO3- and delta18O-NO3- isotope tracing method was used to analyze the composition of nitrogen and oxygen stable isotopes from nitrate in Beijing urban river. Besides, stable isotope mixing model was adopted to track nitrogen sources of nitrate in Beijing urban rivers and the contribution rates of respective pollution sources were evaluated. The results showed that: (1) NO3--N pollution was the main inorganic nitrogen pollution in Beijing rivers and pollution of downstream was more serious than that of upstream. (2) delta15N-NO3- in Beijing urban surface rivers was in range of 6.26 per thousand-24.94 per thousand, while delta18O-NO3- ranged -0.41 per thousand 11.74 per thousand; delta15N-NO3- increased from upstream to downstream along the flow of the surface water. (3) The nitrate pollution composition of Beijing rivers could be gained from the stable isotope mixing model. The average contribution rates of manure and sewage, soil nitrate and atmospheric deposition were 61.2%, 31.5% and 7.3%, respectively. PMID- 27506022 TI - [Distribution Characteristics and Influencing Factors of Nitrate Pollution in Shallow Groundwater of Liujiang Basin]. AB - Taking the nitrate in shallow groundwater of Liujiang basin as the research object, a total of 215 groups of shallow groundwater samples were collected during the wet period in July 2014 and the drought period in April 2015 on the basis of groundwater pollution investigation. The characteristics of spatial and temporal variability and the account of nitrate pollution were analyzed based on the model of semivariogram, the geostatistics of ArcGIS and factor analysis, respectively. The results showed that the study region in the southeast was the main nitrate-polluted area, with concentrations of up to 30-120 mg . L-1, in both wet and drought periods, while the nitrate-contaminated area in drought period was about 1. 4 times higher than that in wet period. The spatial distribution of nitrate was primarily influenced by human activities and the geological conditions, and secondarily by Eh, DO, pH and landform conditions. The nitrate concentration was less than 20 mg . L-1 in north. Pollution in local middle area was rather serious, due to human activities and the loss of nitrogen fertilizer in agricultural cultivation; the area to the south, which was confined by impervious boundary, was seriously contaminated, as indicated by the nitrate accumulation effects. PMID- 27506023 TI - [Nitrogen Losses Under the Action of Different Land Use Types of Small Catchment in Three Gorges Region]. AB - As an independent water-collecting area, small catchment is the source of non point source pollution in Three Gorges Region. Choosing 3 kinds of the most representative land-use types and using them to lay monitoring points of overland runoff within the small catchment of Wangjiagou in Fuling of Three Gorges Region, the author used the samples of surface runoff collected through the twelve natural rainfalls from May to December to analyze the feature of spatial-temporal change of Nitrogen's losses concentrations under the influence of different land use types and the hillslopes and small catchments composed by those land use types, revealing the relation between different land-use types and Nitrogen's losses of small catchments in Three Gorges Region. The result showed: the average losses concentration of TN showed the biggest difference for different land use types during the period of spring crops, and the average value of dry land was 1. 61 times and 6.73 times of the values of interplanting field of mulberry and paddy field, respectively; the change of the losses concentration of TN was most conspicuous in the 3 periods of paddy field. The main element was NO3--N, and the relation between TN and NO3--N showed a significant linear correlation. TN's and NO3--N's losses concentrations were significantly and positively correlated with the area ratio of corn and mustard, but got a significant negative correlation with the area ratio of paddy and mulberry; NH4+-N's losses concentrations got a significant positive correlation with the area ratio of mustard. Among all the hillslopes composed by different land use types, TN's average losses concentration of surface runoff of the hillslope composed by interplantating field of mulberry and paddy land during the three periods was the lowest, and the values were 2.55, 11.52, 8.58 mg . L-1, respectively; the hillslope of rotation plough land of corn and mustard had the maximum value, and the values were 27.51, 25.11, 27.11 mg . L-1, respectively; different land use types and spatial combination ways of subcatchment had a greater influence on TN's losses concentrations, so using a reasonable way to adjust land use structure and spatial arrangement of whole catchment was an effective measure to control the source of non-point source pollution of Three Gorges Region. PMID- 27506024 TI - [Interception Effect of Ecological Ditch on Nitrogen Transport in Agricultural Runoff in Subtropical China]. AB - Interception effects of an ecological ditch, used to control agricultural non point source pollution in subtropical China, on nitrogen transport in surface runoff were studied by monthly measuring the runoff volume and concentrations of ammonium nitrogen (NH4+-N), nitrate nitrogen (NO3--N) and total nitrogen (TN) at the ditch inlet and outlet from 2013 to 2014. In addition, differences of NH4+-N, NO3--N and TN removal were compared between 2013 and 2014. The results showed that the study ecological ditch worked effectively in N removal with average NH4+ N, NO3--N and TN removal rates of 77.8%, 58.3%, and 48.7%; and their interception rates were 38.4, 59.6, and 171.1 kg . a-1, respectively. The average proportion of NH4+-N and NO3--N in TN was 47.5% at inlet, and 33.6% at outlet, which was significantly lower than that at inlet (P < 0.01). All hydrophytes in the ecological ditch were replaced by Myriophyllum aquaticum in 2014, which led to the increased average NO3--N and TN removal rates of 30.5% and 18.2%, respectively, Compared to in 2013. The vegetation of Myriophyllum aquaticum was beneficial to the improvement of N interception in ecological ditch. These findings clearly demonstrated that ecological ditch can substantially reduce N loss from surface runoff and be used as an important technique to prevent agricultural non-point N pollution. PMID- 27506025 TI - [Biodegradation Coefficients of Typical Pollutants in the Plain Rivers Network]. AB - Biodegradation is a significant part of pollutant integrated degradation, the process rate of which is represented by the biodegradation coefficient. To investigate the biodegradation law of typical pollutants in the plain rivers network located in the upstream of the Lake Taihu, experiments were conducted in site in September 2015, one order kinetics model was used to measure the biodegradation coefficients for permanganate index, ammonia, total nitrogen and total phosphorus, and influencing factors of the biodegradation coefficients were also analyzed. The results showed that the biodegradation coefficients for permanganate index, ammonia, total nitrogen and total phosphorus were 0.008 3 0.126 4 d-1, 0.002 1-0.213 8 d-1, 0.002 1-0.090 5 d-1 and 0.011 0- 0.152 8 d-1, respectively. The influencing factors of the biodegradation coefficients for permanganate index were permanganate index and pH; those for ammonia were ammonia concentration and pH; those for total nitrogen were inorganic nitrogen concentration, total dissolved solid concentration and nitrite concentration; and those for total phosphorus were background concentration and pH. The research results were of important guiding significance for pollutants removal and ecological restoration of the plain rivers network located in the unstream of the Lake Taihu. PMID- 27506026 TI - [Influence of Submerged Plants on Microbial Community Structure in Sediment of Hongze Lake]. AB - Phospholipid fatty acids (PLFAs) method was applied to analyze the influence of submerged plants on sediment microbial community structure, in order to investigate the changes of sediment microbial community structure for different kinds of the submerged plants in different growth periods. Particularly, Potamogeton crispus L., Potamogeton pectinatus L and the mixed group were chosen as the typical submerged plants in Hongze Lake for investigation in this paper. The results indicated that the change of total PLFAs in different periods was significant, on the contrary, the PLFA change for different groups in the same period was insignificant. The values of G+ PLFA/G- PLFA in the submerged plant group were also highly related to the different growth periods, which demonstrated that the root function of the submerged plant had a severe impact on the microbial community in sediment. Furthermore, some environmental factors, such as Temperature, pH, TOC and DO, were correlated to characteristic phospholipid of PLFAs in sediment, which means the environmental factors could also affect the microbial community structure. PMID- 27506027 TI - [Community Structure Characteristics of Diatom in Reservoirs Located in the South of Jiangsu Province, China and Its Control Factors]. AB - In order to understand the community structure characteristics of Bacillariophyta and its controlling factors in reservoirs located in the Southeast, China, in the geographic background of hills landscape and humid climate, 18 reservoirs were investigated in June, 2015, during the period with high risk of diatom bloom, covering water quality, and the community structures of phytoplankton. The correlations between Bacillariophyta and other planktons with nutrients, water depth, storage capacity, etc. were analyzed. The results showed that, 10 reservoirs reached the light extent of diatom bloom ( density between 100 x 104 1,000 x 104 cells . L-1 reservoirs in this area were generally in mesotrophic or eutrophic state with considerably high total nitrogen concentrations; total phosphorus and trophic level index were both closely correlated with Bacillariophyta biomass. Phormidium in Cyanophyta was the dominating generus among phytoplankton in terms of density; with respect to biomass, Bacillariophyta, Chlorophyta and Cyanophyta were the top three phylum, and Bacillariophyta accounted for 46. 8% of the total phytoplankton biomass, becoming the most important one resulting in abnormal propagation of algae; Synedra (51.5%) and Cyclotella (21.4%) were the main dominating genera in Bacillariophyta, together with Achnanthes and Melosira. Deep water was favored by Bacillariophyta to dominate among different phyla. Larger ratio between catchment and reservoir storage capacity, on the other hand, caused the increase of trophic level and chlorophyll, and benefited the shift of dominating phytoplankton from Bacillariophyta to Chlorophyta and Cyanophyta, by which, the risk of algae bloom would be increased. It reveals that to alleviate the risk of algae bloom and protect drinking water resources, catchment management is crucial for the studied reservoirs. And the establishment of nutrient reduction strategies needs to consider the features of each individual reservoir, i. e. water depth, ratio between catchment and capacity. PMID- 27506028 TI - [Contamination and Ecological Risk Assessment of Mercury in Hengshuihu Wetland, Hebei Province]. AB - Investigation on the concentrations and the distribution characteristics of total mercury in atmosphere, water surface and soil/ sediments of Hengshuihu wetland was carried out based on a uniform set point sampling method. The geoaccumulation index and potential ecological risk index methods were simultaneously used to assess the mercury pollution in Hengshuihu wetland ecosystem. The results showed that: the total mercury content in Hengshuihu wetland atmosphere ranged from 1.0 to 5.0 ng . m-3, with an average of (2.9 +/- 0.85) ng . m-3; the total mercury content in water surface ranged from 0.010 to 0.57 ug . L-1, with the average value of (0.081 +/- 0.053) ug . L-1; the total mercury content in soil/sediment ranged from 0.001 0 to 0.058 mg . kg-1, with an average of (0.027 +/- 0.013) mg . kg-1. The distribution features of total mercury in Hengshuihu wetland were as follows: the total mercury concentration in surface water of the shore was significantly higher than that in the center (P < 0.05), but the total mercury concentration of sediments in the center of the lake was significantly higher than that at the shore (P < 0.05); the total mercury in the soil of shore had a consistent trend with that in the atmosphere; high concentrations of total mercury pollution were accompanied by severe human activities. The geoaccumulation index showed that mercury pollution in Hengshuihu wetland was at clean level; potential ecological risk index showed mercury contamination had a low ecological risk in Hengshuihu wetland. PMID- 27506029 TI - [Spatial Distribution and Potential Ecological Risk Assessment of Heavy Metals in Soils and Sediments in Shunde Waterway, Southern China]. AB - Environmental quality of soils and sediments around water source area can influence the safety of potable water of rivers. In order to study the pollution characteristics, the sources and ecological risks of heavy metals Zn, Cr, Pb, Cu, Ni and Cd in water source area, surface soils around the waterway and sediments in the estuary of main tributaries were collected in Shunde, and ecological risks of heavy metals were assessed by two methods of potential ecological risk assessment. The mean contents of Zn, Cr, Pb, Cu, Ni and Cd in the surface soils were 186.80, 65.88, 54.56, 32.47, 22.65 and 0.86 mg . kg-1 respectively, and they were higher than their soil background values except those of Cu and Ni. The mean concentrations of Zn, Cr, Pb, Cu, Ni and Cd in the sediments were 312.11, 111.41, 97.87, 92.32, 29.89 and 1.72 mg . kg-1 respectively, and they were higher than their soil background values except that of Ni. The results of principal component analysis illustrated that the main source of Cr and Ni in soils was soil parent materials, and Zn, Pb, Cu and Cd in soils mainly came from wastewater discharge of local manufacturing industry. The six heavy metals in sediments mainly originated from industry emissions around the Shunde waterway. The results of potential ecological risk assessment integrating environmental bioavailability of heavy metals showed that Zn, Cu, Pb and Ni had a slight potential ecological risk. Cd had a slight potential ecological risk in surface soils, but a moderate potential ecological risk in surfaces sediments. Because the potential ecological risk assessment integrating environmental bioavailability of heavy metals took the soil properties and heavy metal forms into account, its results of risks were lower than those of Hakanson methods, and it could avoid overestimating the potential risks of heavy metals. PMID- 27506030 TI - [Pollution Characteristics and Ecological Risk of PBDEs in Water and Sediment from an Electronic Waste Dismantling Area in Taizhou]. AB - An e-waste dismantling industrial park of Taizhou was selected as the sampling center, within a radius of 16 km, and a total of 30 sampling sites were designed in three circles as follows: C (3 km), S (5-10 km) and R (10-16 km). Pollution characteristics and ecological risk of polybrominated diphenyl ethers (PBDEs) in water and sediments were investigated. The concentrations of PBDEs in water ranged from 9.4 to 57.2 ng . L-1, with a mean value of 25.9 ng . L-1; and 3.7 to 38,775 ng . g-1, with an average of 2 779 ng . g-1 in sediments. BDE-209 was the predominant congener. The spatial distribution patterns of PBDE levels in water and sediment were both in the following order: C > S > R. Furthermore, the concentrations of PBDEs in sediments showed significant negative correlation against the distance from the industrial park (P < 0.01). Compared with other regions around the world, the PBDEs contamination was more serious in the area, which indicated that e-waste dismantling activity was one of the significant sources for PBDEs pollution. It was estimated that a total of 30. 7 t PBDEs (including 28. 9 t BDE- 209) was discharged into surrounding environment as a result of dismantling industrial activities in last 40 years. A preliminary ecological risk assessment for PBDEs in water and sediments was conducted by hazard quotient method. The results demonstrated that the Penta-BDEs in the center of e-waste dismantling area ( a radius of 1.5 km) was at particularly high risk level and could cause serious influence on the ecological safety and human health. PMID- 27506031 TI - [Major Ionic Features and Their Controlling Factors in the Upper-Middle Reaches of Wujiang River]. AB - The Wujing River, the largest river in Guizhou Province, is one of the most important water resources for social and economical development. Recently, with the fast population proliferation and rapid economic growth, the drainage basin is intensively interfered by anthropogenic activities. The hydrochemistry of surface water was analyzed from the upper-middle reaches of Wujiang River for investigating the hydrochemical characteristics and their main influencing factors. The results showed that the major cations of the four rivers were Ca2+ and Mg2+, accounting for more than 70%, and the main anions were HCO3- and SO42-, occupying more than 85%. The hydrochemical characteristics in the four rivers were found to be of HCO3-Ca type, and mainly determined by the carbonate rock dissolution, while only a small proportion of them were of HCO3 . SO4-Ca type, reflecting the influence of SO42- from anthropogenic activities. Compared to hydrochemical data in 1999, there was an obvious increase in cations and anions concentrations, majorly in NO3-, SO2- ion concentrations, which were significantly affected by human activities. The Na+, K+ , Cl- in the river mainly came from atmospheric precipitation, and Ca2+, HCO3-, Mg2+, mainly came from carbonate rocks dissolution, while NO3- and SO42- mainly came from human activities. According to principal component analysis and correlation analysis, hydrochemical composition of Liuchong River was affected by human activity, and that in the upstream of Sancha River was controlled by atmospheric precipitation and the dissolution of carbonate rocks, that to the downstream was enhanced by human activities. The main ion of Maotiao River was controlled by atmospheric precipitation and carbonate rocks dissolution, and also affected by human activity. The Nanming River, the Qingshui river's tributary, was mainly affected by human activity, while the middle and lower reaches of Qingshui River were affected by both the atmospheric precipitation and human activity. PMID- 27506032 TI - [Export of Total Organic Carbon (TOC) from Karst Watershed and Its Influencing Factors: An Example from Xueyudong Underground River System, Chongqing]. AB - High time-resolution auto-monitoring techniques were used to obtain the data for TOC and hydrogeochemistry of groundwater, and air temperature and precipitation from August 2014 to September 2015 in Xueyu Cave karst watershed, Southwest China, and then the principal component regression model was used to reveal the variation of TOC in groundwater and its influencing factors. The results indicated that there were significant variations of the TOC and hydrogeochemistry of groundwater in seasonal timescale. The temperature and specific conductance (SpC) of groundwater showed higher values in summer and lower values in winter; while an opposite variation pattern for pH in groundwater was observed, and the TOC and turbidity of groundwater showed higher values in winter and summer seasons and lower values in spring and autumn seasons. Meanwhile, high time resolution data revealed that the TOC of groundwater responded quickly to rainfall events with different intensities. Generally, an increasing trend for TOC in groundwater was observed during raining and a decreasing trend for TOC in groundwater was shown after rainfall events, especially after storm events due to the dilution effect of rainfall. The export and variations of the TOC in groundwater were mainly controlled by the precipitation and discharge of underground river in the study area, as revealed by the principal component regression model. The TOC increased with the increase of the precipitation, discharge and turbidity of groundwater, and declined with the increase of air temperature and pH of groundwater. PMID- 27506033 TI - [Seasonal Variations and Controlling Factors of the Element Contents in Drip Waters Collected from the Baojinggong Cave in Guangdong Province]. AB - Geochemical dynamics of cave water were monitored to unveil its seasonal variation and controlling factors from December 2011 to May 2013 in Baojinggong cave, north of Guangdong Province. Concentrations of elements such as Ba, Sr, Ca and Mg of three drips in the cave were analyzed. The results showed that: (1) All these elements of three drips displayed significant seasonal variations, but the trends of seasonal variation of different elements or different drips were not the same, which reflected that each element in different drips might be controlled by different effects; (2) The low element contents of Drip1 and Drip2 during the heavy rainfall month showed that heavy rainfall could dilute the concentrations of elements; (3) Mg/Ca had a positive relationship with Sr/Ca ratio in three drips, and was higher in dry season and lower in rainy season. It implied that the two proxies might be mainly controlled by precipitation, karst water source, leaching effect and prior calcite precipitation (PCP), and reflected the climate change. PMID- 27506034 TI - [Tracing the Fecal Contamination Sources Based on Bacteroides 16S rRNA PCR- DGGE in Karst Groundwater: Taking Laolongdong Underground River System, Nanshan, Chongqing as an Example]. AB - Microbial contamination in karst groundwater continually increases and tracing the source researches has become a hot topic for international researchers. In this study, Laolongdong underground river at Nanshan, Chongqing was chosen as an example to adopt filter membrane methods to monitor the fecal microbial contaminations including the total bacterial concentration (TB), the total E. coli concentration (TE), the total fecal coliform (FC) and the total fecal Streptocoocci (FS). Bacteriodes was used as an indicator and PCR-DGGE analysis was used to trace fecal contamination sources in karst groundwater. The results suggested that groundwater in this area was seriously polluted by microbes from feces. The concentrations of microbial parameters exceeded limited levels greatly and the total bacterial amounts ranged 10-2.9 x 107 CFU . mL-1, the concentrations of E. coli were between 4.3-4.0 x 105 CFU . mL-1, the max concentration of FC was 1.1 x 106 CFU . (100 mL)-1 and the max concentration of FS was 1.1 x 105 CFU . (100 mL)-1. The FC/FS ratios were mostly over 2 which suggested that the main fecal source in groundwater was human feces. In addition, PCR-DGGE contrastive analysis of Bacteroides communities showed that the similarities between groundwater samples and human feces were in range of 7. 1% 69. 1% , and the similarity of the groundwater sample from Laolongdong underground river outlet was 69.1% . Bacteroides community similarities between groundwater samples and swine feces were in range of 1.1%-53.4%, and the similarity of Laolongdong underground river outlet was merely 1.5%. The similarity data implied that groundwater contamination resulted mainly from human feces, swine feces contamination composed part of animals' fecal contamination, and other animals' feces participated too. Furthermore, sequencing results of PCR DGGE products revealed that most Bacteroides in groundwater originated from human intestinal tract and human feces. PMID- 27506035 TI - [Sources and Variation Characteristics of Dissolved Lipid Biomarkers in a Typical Karst Underground River]. AB - Water samples in Qingmuguan underground river were collected to determine the concentration of dissolved lipids, and their sources, composition and migration characteristics in underground river were studied. The results were obtained as follows. (1) The average content of various dissolved lipids decreased with increasing distance of migration in Qingmuguan underground river, and the most distinctive was dissolved saturated straight chain fatty acids with its content decreasing by about 81.71%, from the initial 5,704 ng . L-1 to 1,043 ng . L-1. (2) N-alkane could indicate the sources of dissolved organic matter in underground river, but saturated straight chain fatty acid and fatty alcohol had the advantage in indicating algae, bacteria and other microorganisms. (3) With the increasing migration distance of Qingmuguan underground river, the input type of dissolved organic matter in underground river was different, which might be resulted from the heterogeneity of karst surface. (4) In ternary plot of alkane sources, aquatic plants constituted the major contribution of dissolved organic matter in Qingmuguan underground river, followed by higher plant, algae/ bacteria. Unlike higher plants and algae/bacteria, the contribution from aquatic plants decreased with increasing migration distance of underground river. (5) To a certain extent, TAR (alkane) values could reflect the rainfall, and the values of CPI, L/H in saturated straight chain fatty acids might indicate the degradation activities of bacteria. PMID- 27506036 TI - [Formation of Halogenated By-products in Co2+ Activated Peroxymonosulfate Oxidation Process]. AB - Sulfate radicals (SO4.-) generated by Co2+ catalyzed activation of peroxymonosulfate (PMS) are highly oxidative and can be applied to degrade various organic pollutants. It was revealed in this research that bromide could be transformed in this process to reactive bromine species which reacted with phenol subsequently, leading to the formation of bromophenols and brominated by products such as bromoform and dibromoacetic acid. The formation of the brominated by-products first increased and then decreased. The maximum yields of bromoform (10.3 umol . L-1) and dibromoacetic acid (14.6 umol . L-1) occurred at approximately 8 h with initial phenol, PMS, Br-, Co2+, concentrations of 0.05, 1.0, 0.2, and 5 umol . L-1, respectively. Formation of the brominated by-products decreased with increasing pH. With constant total halides, increasing Cl-/Br- ratio decreased the total formation of halogenated by- products but generated more chlorinated byproducts. The findings of this research can provide valuable information in assessing the feasibility of SO4.- based oxidation technologies in real practice. PMID- 27506037 TI - [Aspartic Acid Generated in the Process of Chlorination Disinfection By-product Dichloroacetonitrile]. AB - In this study, a method was developed for the determination of dichloroacetonitrile (DCAN) in drinking water by liquid- liquid micro-extraction and gas chromatography/mass spectrometry ( LLE-GC/MS), which used 1,2 dibromopropane as the internal standard and methyl tertiary butyl ether (MTBE) as the extractant for high accuracy. The aspartic acid was used as the precursor of the DCAN formation during chlorination and the influencing factors were evaluated. The formation mechanism of DCAN was also discussed. The results showed that the DCAN amount increased with the increase of pH value under the neutral and acidic conditions, however, the amount of DCAN decreased with the increase of pH value under the alkali condition. And the final amount of DCAN under the alkali condition was much less than that under the neutral and acidic conditions. It was also found that the DCAN amount increased with the increase of chlorine addition, while the temperature in the range of 10-30 degrees C had little influence on the DCAN formation. The formation process of the DCAN from aspartic acid by chlorination included seven steps, such as substitution, decarboxylation, oxidation, etc and ultimately formed DCAN. PMID- 27506038 TI - [Influencing Factors of Assimilable Organic Carbon (AOC) Formation in Drinking Water During Ozonation Process]. AB - The influences of ozone dosage, pH and ionic strength on the formation of Assimilable Organic Carbon (AOC) during ozonation were investigated. The result demonstrated that within the range of 1-5 mg . L-1 O3, the formation of AOC increased with increasing ozone dosage, but higher ozone dosage (9 mg . L-1) resulted in reduction of AOC formation. AOC formation increased with higher pH but decreased with increasing ionic strength. The result also showed that AOC formation with hydrophobic fraction (HPO) was the most, followed by transphilic fraction (TPI), and charged hydrophilic fraction (CHPI), while neutral hydrophilic fraction (NHPI) was the least. It was found that AOC formation related closely with SUVA of small molecular weight organics, and the lower SUVA produced more AOC. PMID- 27506039 TI - [Wastewater Quantity and Quality Fluctuation Characteristics of Typical Area of Hybrid Sewage System]. AB - The inflow and infiltration problems cause large fluctuation in wastewater quantity and quality in hybrid sewage system. This seriously challenges the operation and management of sewage system. A multi-point on-line simultaneous monitoring system was established in a typical hybrid sewage system. The key characteristic parameters and their variation features under different circumstances were studied. The result indicated that the daily variation rule was obvious and appeared synchronous among multiple points at normal water level under dry weather flow, but there was no synchronization in conductivity variation among multiple points at high water level under dry weather flow. The statistical distribution range of water level and conductivity was significantly impacted by the seasonal rainfall change under dry weather. The statistical distribution ranges of water level variation rate and conductivity variation rate in specific time were significantly impacted by the rainfall. The response features of water level and conductivity to rainfall intensity and pattern were significantly different under different circumstances. The response sensitivity of conductivity was higher than water level at normal water level and lower at high water level. The database which could support the optimization of operation and management in the hybrid sewage system was proposed based on the distribution law of wastewater quality and quantity fluctuation under dry and wet weather, as well as the variation rate features of wastewater quality and quantity during rainfall obtained using the multi-point on-line simultaneous monitoring system. PMID- 27506040 TI - [Preparation of HDTMA-modified Zeolite and Its Performance in Nitro-phenol Adsorption from Wastewaters]. AB - In this study, natural zeolite was modified by HDTMA. Effects of the modified conditions, HDTMA-modified zeolite doses, solution pH values, and reaction time on nitro-phenol removal were investigated, and the adsorption kinetics and isotherms were discussed. Compared with natural zeolite, HDTMA-modified zeolite showed better performance in nitro-phenol removal. An adsorption capacity of 2.53 mg . g-1 was achieved when the concentration of HDTMA solution (pH = 10) was 1.2% in preparation of modified zeolite. This adsorption capacity was higher than that obtained by natural zeolite (0.54 mg . g-1). In adsorption tests, when HDTMA- modified zeolite dose was adjusted to 8 g . L-1, the removal efficiency of nitro phenol reached 93.9% after 90 min reaction, with wastewater pH of 6. Furthermore, the nitro-phenol adsorption process could be well fitted to the pseudo-first order kinetics model (R2 > 0.90), whereas the adsorption isotherm results indicated that Langmuir model provided the best fitting for the equilibrium data at different temperatures, with R2 of higher than 0.90. PMID- 27506041 TI - [Selection of Suitable Microalgal Species for Sorption of Uranium in Radioactive Wastewater Treatment]. AB - The amount of radioactive wastewater discharge was increasing year by year, with the quick development of nuclear industry. Therefore, the proper treatment and disposal of radioactive wastewater are essentially important for environmental safety and human health. Microalgal biosorption of nuclide has drawn much attention in the area of radioactive wastewater treatment recently, and the selection of a proper microalgal species for uranium biosorption is the basis for the research and application of this technology. The selection principle was set up from the view of practical application, and 11 species of microalgae were prepared for the selection work. Scenedesmus sp. LX1 has the highest biosorption capacity of 40.7 mg . g-1 for uranium; and its biomass production in mBG11 medium (simulating the nitrogen and phosphorus limits in the first-class A discharge standard of pollutants for municipal wastewater treatment plant) was 0.32 g . L 1, which was relatively high among the 11 microalgal species; when grown into stable phase it also showed a good precipitation capability with the precipitation ratio of 45.3%. Above all, in our selection range of the 11 microalgal species, Scenedesmus sp. LX1 could be considered as the suitable species for uranium biosorption in radioactive wastewater treatment. PMID- 27506042 TI - [Magnetic Fe3O4Microparticles Conditioning-Pressure Electro-osmotic Dewatering (MPEOD) of Sewage Sludge]. AB - For magnetic Fe3O4 microparticles conditioning--pressure electro-osmotic dewatering (MPEOD) process of activated sludge (AS), the effects of operating parameters (optimal dosage of Fe3O4, electric field duration, mechanical pressure and voltage) on the dewatering efficiency and energy consumption were investigated, and the optimal conditions were determined. Moreover, the properties of supernatant and sludge along MPEOD process were studied as well as the interaction force between the sludge biosolids. Taking the energy consumption into consideration, the results showed that the optimal dewatering effect for AS could be achieved with a magnetic Fe3O4 microparticles dosage of 0.15 g . g-1, an electric field duration of 2 h, a mechanical pressure of 400-600 kPa and a voltage of 30-50 V. When MPEOD was conducted at 400 kPa and 50 V for 2 h, the sludge reduction rate reached 98.30%, the percentage of water removal was 99.34% and the moisture content of AS decreased from 99.18% to 44.46%. The corresponding consumption of energy was 0.013 3 kW . h . kg-1. The coagulation mechanism played a slight role in the AS conditioning with magnetic Fe3O4 micro-particles. In fact, magnetic Fe3O4micro-particles could greatly decrease the acid-base interaction (WA) between AS biosolids, cause floc growth and enlarge pores in AS aggregates, which will be beneficial to AS dewatering. Compared to DLVO theory, the extended DLVO theory could accurately describe the aggregation and dispersion behavior of sludge particles. PMID- 27506043 TI - [Stability of Short-cut Nitrification Nitrogen Removal in Digested Piggery Wastewater with an Intermittently Aerated Sequencing Batch Reactor]. AB - Stability of short-cut nitrification nitrogen removal performance was studied in a step-feeding, intermittently aerated sequencing batch reactor (IASBR) at 30 degrees C to treat digested piggery wastewater. Results showed that the nitrogen removal was greatly influenced by the ratio of chemical oxygen demand (COD) to total nitrogen (TN) in the influent. Nitrite nitrogen kept accumulating up to 800 mg . L-1 when the influent COD/TN ratio was 0.8 +/- 0.2, and the removal rates of TN, ammonium nitrogen and total organic carbon (TOC) were only 18.3% +/- 12.2%, 84.2% +/- 10.3% and 60.7% +/- 10.7%, respectively. By contrast, as the influent COD/ TN ratio was increased to 2.4 +/- 0.5, the accumulated concentration of nitrite nitrogen sharply decreased from 800 mg . L-1 to below 10 mg-L-1, and the removal rates of TN, ammonium nitrogen and TOC were increased to over 90%, 95% and 85%, respectively. Gradually shortened hydraulic retention time ( HRT) reveales that the ammonia load is a restricting factor for nitrogen removal. The ammonia load should be controlled at no more than 0.30 kg . (m3 . d) -1, or else, the removal rates of TN, ammonium and TOC would be greatly decreased. The nitrite accumulation rate over the whole run was 74.6%-97.8% and the TN removal rate in the stable phase was over 90%. With efficient and stable short-cut nitrification denitrification in a low COD/TN, moreover, and unnecessary for addition of alkaline, IASBR shows great advantage for treating wastewater with high concentration of ammonia while low COD/TN ratio. PMID- 27506044 TI - [Effect of Irrigation Patterns on Soil CO2 and N2O Emissions from Winter Wheat Field in North China Plain]. AB - The water-saving irrigation is the trend of modernized agriculture. This paper aimed to study the effect of water-saving irrigation on soil CO2 and N2O emissions. The field experiments were conducted under micro sprinkler irrigation of integrated water and fertilizer (MSI) and conventional flooding irrigation (FI) in winter wheat growth season in the west of North China Plain during 2013- 2014 using the static chamber method. This paper analyzed the seasonal variation of soil CO2and N2O emissions under MSI and FI, and then compared the soil CO2 and N2O emissions from treatments located in different vertical distance away from micro sprinkler pipe. Root exclusion was used to estimate the components of soil respiration and agricultural carbon sequestration intensity under MSI and FI in winter wheat field. The results indicated that: (1) The average soil CO2 emissions under MSI and FI were 418.19 mg (m2 . h)-1 and 372.14 mg . (m2 . h)-1 respectively with no significant difference, and cumulative CO2 emissions under MSI and FI were 2 150.6 g . m-2 and 1 904.6 g . m-2, respectively. (2) During returning green stage to harvest stage of winter wheat, the highest soil CO2 cumulative emissions were found at the closest site to the micro sprinkler irrigated pipes under MSI. However, there were no significant differences among spatial treatments. (3) Under MSI and FI, soil heterotrophic respiration (C) was 468.49 g . m-2 and 427.31 g . m-2, and the net primary productivity (3) was 1988.21 g . m-2 and 1770.54 g . m-2; the carbon sink (C) during winter wheat growing season was 1 519.72 g . m-2 and 1 343.24 g . m-2, respectively. (4) The average N2O emissions under MSI and FI were 50.77 ug . (m2 . h)-1 and 28.81 ug . (m2 . h)-1 respectively with no significant difference. Cumulative N2O emission under MSI and FI was 272.67 mg . m-2 and 154.08 mg . m-2, respectively. (5) During returning green stage to harvest stage of winter wheat, the farther the distance away from the micro sprinkler irrigated pipes, the smaller the soil N2O emissions. Moreover, there were no significant differences among sptial treatment under MSI. Therefore, despite of the increase of soil CO2and N2O emissions, the intensity of carbon sink increased during the transformation from traditional flood irrigation to micro sprinkler irrigation in winter wheat fields. PMID- 27506045 TI - [Characteristics of Dissolved CH4 and N2O Concentrations of Weihe River in Xinxiang Section in Spring]. AB - Distributions of CH4 and N2O concentrations in Weihe River in Xinxiang City were monitored in spring of 2015, and their influencing factors were discussed. The result showed that CH4 and N2O were super-saturated in surface water of Weihe River. The variation ranges of two gases' saturations in the surface water of Weihe River were 147.59-2667.85 (CH4) and 4.06-188.25 (N2O). In the urban area, significant correlation existed between N2O and NH4+-N concentrations (P < 0.01), but in the new district, dissolved N2O concentration showed sharp increase because of the water input from the urban sewage plants, illustrating that the controlling mechanism on N2O production varied as pollutant characteristics changed. Stepwise regression analysis showed that CH4 concentrations could be explained by NH4+-N concentrations and water temperature, and CH4 concentrations in the surface water of Weihe River was significantly correlated with NH4+-N concentrations (R2 = 0.70, P < 0.01), suggesting that NH4+-N was the key factor in regulating the production and assumption of CH4oxidation in Weihe River in spring. Besides, this study showed that when there was less NO3--N but more NH4+ N in river water, CH4and N2O concentrations would be positively correlated, indicating that different nitrogen sources would impact the coupling mechanism of CH4and N2O productions. PMID- 27506046 TI - [Effect of Stimulated N Deposition on N2O Emission from a Stipa krylovii Steppe in Inner Mongolia, China]. AB - With fast development of industry, agriculture and society, very high N deposition occurs in China. N deposition has exceeded 3 g . (m2 . a)-1 in some areas of temperate steppes, which is a significant part of the Eurasia grassland, but may possibly be sensitive to N deposition. To study the effect of N deposition on N cycling in typical temperate steppe, N2O emissions were measured in a Stipa krylovii steppe in Inner Mongolia for a whole year. A field control experiment of simulated N deposition (by NaNO3 addition) was also carried out at 6 dose levels, CK (control), N2 [2 g . (m2 . a)-1], N5 [5 g . (m2 . a)-1], N10 [10 g . (m2 . a)-1], N25 [25 g . (m2 . a)-1], and N50 [50 g . (m2 . a)-1]. The results showed that the natural N2O-N emission flux was 0.10 g . (m2 . a)-1, accounting for about 3% of the total N deposition, and much depended on soil water content and soil temperature under ambient N deposition. In addition, enhanced N deposition might significantly increase N2O emission, especially at very high N doses (N25 and N50 treatments). The annual N2 0 emission flux showed a linear relationship with the N addition. Greater attention should therefore be paid to the relatively high N2O emission in the typical temperate steppe in China. PMID- 27506047 TI - [Response of Soil Respiration and Organic Carbon to Returning of Different Agricultural Straws and Its Mechanism]. AB - Soybean, maize and rice straws were selected as raw materials to study the response of the soil respiration (SR) and soil organic carbon (SOC) to returning of different straws in the Chongming Dongtan area. The results showed that all of SR, SOC and the plant biomass of the lands with returning of different straws were higher than those of the controls. The soil with soybean straw returning possessed the lowest SR and highest SOC among the three kinds of straws, meaning its higher soil organic carbon sequestration capability than corn and maize straws returning. Straw returning significantly enhanced soil dehydrogenase, beta glycosidase activities and microbial biomass, and soil dehydrogenase activity was significantly correlated with soil respiration. The dehydrogenase activity of the soil with soybean straw returning was the lowest, thus, the lowest SR and highest SOC. Soybean straw had the highest cellulose and lignin contents and the lowest N content among the three kinds of straws, resulting in its lowest biodegradability. Therefore, when soybean straw was returned to soil, it was difficult to degrade completely by soil microorganisms, thus the lowest soil microbial activity, eventually leading to the lowest SR and highest SOC. PMID- 27506048 TI - [Spatial Variability and Distribution Pattern of Soil Organic Matter in a Mollisol Watershed of China]. AB - Spatial variability of soil organic matter and its distribution pattern are the hot issues of soil scientific research. Selecting Haigouhe watershed as the study area, this paper mainly focused on the spatial variability, distribution pattern and its impact factors of SOM in the surface soil by classical statistics, Geo statistics and "3S" technology. The results showed that: compared with the other black soil areas, the SOM content in Haigouhe watershed was a little lower, there was a spatial autocorrelation, and a moderate variability. Random factors, such as human activities, cultivation measures and so on, had little impact on the spatial variation, while the structural factors had a dominant function, and there was a remarkable spatial anisotropy of SOM. The SOM content reduced gradually from east to west with the familiar changes of height, so the co kriging interpolation, selecting elevation as the co-variate, was employed to improve the accuracy. The spatial variability of SOM and its distribution pattern in Haigouhe watershed were greatly affected by topography and land use but weakly influenced by traffic, villages and other social factors. The surrounding environment of the samples would increase the uncertainty of spatial variability and interpolation of SOM and it cannot be ignored in future studies. In summary, it was a significant scientific research to analyze the spatial variability, distribution pattern of SOM and its main impact factors in a mollisol hilly watershed of China. PMID- 27506049 TI - [Effects of Tillage on Distribution of Heavy Metals and Organic Matter Within Purple Paddy Soil Aggregates]. AB - A long-term experiment was utilized to study the effects of tillage methods on the contents and distribution characteristics of organic matter and heavy metals (Cu, Zn, Pb, Cd, Fe and Mn) in aggregates with different sizes (including 1-2, 0.25-1, 0.05-0.25 mm and < 0.05 mm) in a purple paddy soil under two tillage methods including flooded paddy field (FPF) and paddy-upland rotation (PR). The relationship between heavy metals and organic matter in soil aggregates was also analyzed. The results showed that the aggregates of two tillage methods were dominated by 0.05-0.25 mm and < 0.05 mm particle size, respectively. The contents of organic matter in each aggregate decreased with the decrease of aggregate sizes, however, compared to PR, FPF could significantly increase the contents of organic matter in soils and aggregates. The tillage methods did not significantly affect the contents of heavy metals in soils, but FPF could enhance the accumulation and distribution of aggregate, organic matter and heavy metals in aggregates with diameters of 1-2 mm and 0.25-1 mm. Correlation analysis found that there was a negative correlation between the contents of heavy metals and organic matter in soil aggregates, but a positive correlation between the amounts of heavy metal and organic matter accumulated in soil aggregates. From the slope of the correlation analysis equations, we could found that the sensitivities of heavy metals to the changes of soil organic matters followed the order of Mn > Zn > Pb > Cu > Fe > Cd under the same tillage. When it came to the same heavy metal, it was more sensitive in PR than in FPF. PMID- 27506050 TI - [Distribution Characteristics and Potential Ecological Hazards Assessment of Soil Heavy Metals in Typical Soil Profiles in Southeast Suburb of Beijing]. AB - To investigate the distribution characteristics and the potential ecology risk of different types of heavy metals, soil samples were collected from various stratigraphic sections in the southeastern suburb of Beijing, where soil heavy metal (Cu, Pb, Cr, As) contents were measured and analyzed using multivariate statistical analysis and the potential ecological risk index method. The results showed that the concentrations of the four heavy metals followed the order of Cr > Cu > As > Pb with variable coefficients ranging from 59.60% to 159.33% at 3-6 m stratum, which all displayed a high degree of variability. The concentrations of Cu and Pb were positively correlated with soil organic matter (SOM), cation exchange capacity (CEC), etc, with higher eigenvalues in Factor 1 and 2, demonstrating the impact of organic colloid on the occurrence of heavy metals. The risk level of the specific heavy metal followed the order of As > Cu > Pb > Cr, where As already showed a medium potential ecological risk in the studied area. PMID- 27506051 TI - [Contamination Assessment and Sources Analysis of Soil Heavy Metals in Opencast Mine of East Junggar Basin in Xinjiang]. AB - The opencast mine of East Junggar Basin in Xinjiang is the largest self-contained coalfield in China, and the ecological environment of the opencast is very fragile because of its arid climate and poor soil. In this study, 50 soil samples (from 0 to 30 cm depth soil at intervals of 10 cm) in opencast Mine of East Junggar Basin in Xinjiang were collected in order to explore the heavy metals contamination of the coal mining. The contents of zinc (Zn), copper (Cu), cadmium (Cr), lead (Pb), mercury (Hg) and arsenic (As) were measured and the degree of pollution was assessed by Nemerow index, geo-accumulation (Igeo) index and potential ecological risk index. In addition, the layered comparison, dust fall and the distance between coal mine and samples location were used to analyze the source of heavy metals contamination. The results showed that value of As surpassed the Chinese soil quality standard class I (GB 15618-1995) mostly severely, followed by Cr, a relatively lower surpass was obtained by Hg and Cu, while Zn and Pb did not surpass the standard. According to the standard, the soil heavy metals content of research region was in light pollution status and the pollution index for each heavy metal followed the order of As (2.07) > Cr (0.95) > Cu (0.55) > Zn (0.48) > Hg (0.45) > Pb (0.38), which demonstrated a heavy pollution of As and clean status of others. Additionally, an Igeo value of 1.14 for Hg reflected a moderated pollution. The major contribution factor was Hg with a risk index of 251.40. The source analysis showed that the content of Pb in the surface soil (10-20 cm) was different from that in the deep layer (20-30 cm), which may be caused by coal combustion and other human activities. The sources of Hg and As were similar and may come from coal combustion. The distance to the mining area was not the major factor affecting the diffusion of heavy metals, other candidate factors included terrain, aspect and wind direction, etc. PMID- 27506052 TI - [Effect of Nano-TiO2 on Release and Speciation Changes of Heavy Metals in Soil]. AB - The effects of nano-TiO2 on migration and transformation of heavy metals in soil were investigated by outdoor flooding simulation experiments. Cr, Pb, Zn, Cd and Cu contents of different forms were determined in soil of typical fluctuating zone of Three Gorges Reservoir. The results showed that, after flooding months, both addition of 4 g . kg-1 of rutile and anatase particles resulted in the release of about 30% Cr into the water. Nano-TiO2 particles mainly promoted the dissolution of oxidizable residual Cr, and elevated its ecological risk. Thus nano-TiO2promoted the activation of chromium and improved the mobility of chromium in soil. 4 g . kg-1 of rutile particles caused the decrease of acid exchangeable lead by 25.92% and oxidizable lead by 33.09%, and enhanced the mobility of Pb. However, anatase particles caused the increase of oxidizable zinc by 30% in soil, which facilitated fixing of zinc. In addition, two types of nano TiO2particles had no significant effect on the speciation changes of Cu and Cd. Therefore, the effect of nano-TiO2 on release and transformation of Cr in soil was the largest, followed by Pb and Zn. This needs special attention when using nano-TiO2 to remediate heavy metals contaminated soil and assessing its environmental risk. PMID- 27506053 TI - [Reduction Kinetics of Cr (VI) in Chromium Contaminated Soil by Nanoscale Zerovalent Iron-copper Bimetallic]. AB - Nanoscale zerovalent iron-copper bimetallic (nZVI/Cu) was produced by liquid phase reduction and characterized by SEM and XRD. The remediation of Cr (VI) contaminated soil was conducted with nZVI/Cu, and the affecting factors and reduction kinetics were investigated. The results indicated that nZVI/Cu was effective in the degradation of Cr(VI) in soil at an initial pH of 7 at 30'C.After 10 min of reaction, Cr(VI) in the soil was completely degraded when the. concentration of nZVI/Cu was 2 g . L-' and the concentration of Cr(VI) in contaminated soil was 88 mg . kg-1. nZVI/Cu amount, pH value, reaction temperature, and the concentration of humic acid affected the degradation of Cr(VI). The removal efficiency of Cr(VI)--increased with increasing reaction temperature and decreased with increasing initial pH value. Humic acid had a certain impact on the degradation of Cr(W) in soil. The removal of Cr (VI) followed the pseudo first order reduction kinetics model, and the relationship between the reduction rate and the reaction temperature accorded with Arrhenius law, and the reaction activation energy (Ea) was 104.26 kJ . mol-1. PMID- 27506054 TI - [Inhibition of Low Molecular Organic Acids on the Activity of Acidithiobacillus Species and Its Effect on the Removal of Heavy Metals from Contaminated Soil]. AB - Application of organic fertilizer can reduce the solubility and bioavailability of heavy metals in contaminated soil, but in the flooded anaerobic environment, organic fertilizer will be decomposed to produce a large number of low molecular organic acids, which can inhibit the biological activity of Acidithiobacillus species. Batch cultures studies showed that the monocarboxylic organic acids including formic acid, acetic acid, propionic acid, and butyric acid exhibited a marked toxicity to Acidithiobacillus species, as indicated by that 90% of inhibitory rate for Fe2 and So oxidation in 72 h were achieved at extremely low concentrations of 41.2 mg . L-1, 78.3 mg . L-1, 43.2 mg . L-1, 123.4 mg . L-1 and 81.9 mg 230. 4 mg . L-1, 170.1 mg . L-1, 123.4 mg . L-1 respectively. Of these organic acids, formic acid was the most toxic one as indicated by that Fe2 and So oxidation was almost entirely inhibited at a low concentration. In addition, it was found that Acidithiobacillus ferrooxidans was more sensitive to low molecular organic acids than Acidithiobacillus thiooxidans. What's more, there was little effect on biological acidification process of heavy metal contaminated soil when organic acids were added at initial stage (Oh), but it was completely inhibited when these acids were added after 12 h of conventional biological acidification, thus decreasing the efficiency of heavy metals dissolution from soil. PMID- 27506055 TI - [Contribution of Particle Size and Surface Coating of Silver Nanoparticles to Its Toxicity in Marine Diatom Skeletonema costatum]. AB - Due to the unique antibacterial properties, silver nanoparticles (AgNPs) have been widely used in commercial applications. In this study, the toxicity of three kinds of AgNPs with different sizes and surface coatings to marine diatom Skeletonema costatum (S. costatum) was studied, which was one of the dominant species in estuarine and coastal areas. All three kinds of tested AgNPs inhibited the growth of exposed S. costatum under acute exposure condition, and the order of toxicity was 10 nm-OA > 10 nm-PVP > 20 nm-PVP. Given the condition of similar particle size, oil amine surface coated AgNPs were more toxic than polyvinyl pyrrolidone (PVP) surface coated AgNPs in S. costatum in term of cytotoxicity. With the same surface coating, the toxicity of AgNPs in S. costatum was affected by its hydrodynamic diameter and exposure concentrations. When the concentration of AgNPs was less than 500 ug . L-1, larger sized AgNPs showed greater toxicity; When the concentration was greater than or equal to 500 ug . L-1, smaller AgNPs exhibited greater toxicity. At molecular level, 50 ug . L-1 10nm-PVP significantly upregulated expression level of 3HfcpA (P < 0.05) and significantly downregulated expression level of Dl (P < 0.05), and 500 ug . L-1 10nm-OA significantly upregulated 3HfcpA expression (P < 0.05), while 20 nm-PVP treatment group didn't show any significant change. Exposed diatom demonstrated sensitive photosynthesis response to small size and PVP coated silver nanoparticles at molecular level. This study suggested that the toxicity of AgNPs to marine microalgae was largely controlled by the particle size, surface coating, exposure medium, exposure concentration and other factors. The smaller the particle size, the greater the toxicity of AgNPs, and the particle size of AgNPs played an important role in the toxicity of AgNPs in marine diatom S. costatum. PMID- 27506056 TI - [Rhizospheric Mechanisms of Hemerocallis middendorfii Trautv. et Mey. Remediating Petroleum-contaminated Soil and Metabonomic Analyses of the Root Systems]. AB - The effects of a special ornamental plant Hemerocallis middendorfii Trautv. et Mey. on remediating petroleum-contaminated soil from the Dagang Oilfield in Tianjin, China, was studied by a greenhouse pot-culture experiment and the gradients of TPHs were 0, 10,000 and 40,000 mg . kg-1. The results suggested that H. middendorfii had a high tolerance to TPHs (<= 40,000 mg . kg-1). And H. middendorfii significantly (P < 0.05) promoted the removal rate of TPHs (53.7% and 33.4%) compared with corresponding controls (31.8% and 12.0%) by natural degradation, respectively. The relative abundance of amino acids, organic acids and sugars and others in soil were analyzed by gas chromatography-mass spectrometry (GC-MS), and PCA and PLS-DA models were to investigate the rhizospheric mechanisms. The results suggested that H. middendorfii changed the distribution characteristics of each component in soil, and the glucopyranoside played a key role in the removal of TPHs. Furthermore, the results about comparative metabolic profile showed that some special metabolites were only found in the contaminated groups, including alanine, tetradecanoic acid, hexadecanoic acid and 9,12-octadecadienoic acid. Additionally, the exposure of TPHs changed the primary metabolic flux of roots, and caused the significant (P < 0.01) change of metabolites. In conclusion, H. middendorfii might be an enduring ornamental plant for effective remediating TPHs (<= 40,000 mg . kg-1) in soil. But the exposure of TPHs had changed the metabolic profile of H. middendorfii in roots, which might be the metabolic response of H. middendorfii to petroleum contaminated soil. PMID- 27506057 TI - [Effects of Thermophilic Composting on Antibiotic Resistance Genes (ARGs) of Swine Manure Source]. AB - To investigate the effects of thermophilic composting process on antibiotic resistance genes (ARGs) of swine manure source at a field scale, the abundance of four erythromycin resistance genes (ermA, ermB, ermC and ermF), three beta-lactam resistance genes (blaTEM, blaCTX and blaSHV) and two quinolone resistance genes (qnrA and qnrS) were quantified by quantitative PCR ( qPCR) during the composting process. The results suggested that the erm genes' copy numbers were significantly higher than those of the bla and qnr genes in the early stage of composting (P < 0.01). The maximum abundance of erm genes was ermB (9.88 x 108 copies . g-1), following by ermF (9.4 x 108 copies . g-1). At the end of the composting process, bla and qnr genes were at low levels, while erm genes were still at high levels. Even through ermF was proliferated comparing with the initial copies. These results indicated that thermophilic composting process could not effectively remove all ARGs. For some ARGs, compost may be a good bioreactor resulting in their proliferation. Application of composting products on farmland may cause transference of ARGs. PMID- 27506058 TI - [Interaction Between Sulfonamide Antibiotics Fates and Chicken Manure Composting]. AB - Based on aerobic manure composting with or without the addition of a mixture of sulfadimethoxine SM2 and sulfamonomethoxine SMM (1:1, m/m), changes in the physic chemical properties of manure compost, the microbial community physiological profiles, the antibiotics concentration and the abundances of five antibiotic resistance genes (ARGs) during the composting were tracked. The results indicated that the introduction of sulfonamide antibiotics led to inhibition on the basal respiration of manure compost during the early composting period, delayed the formation of thermophilic temperature and reduced the conversion of nutrients such as organic matter, ammonia nitrogen and nitrate nitrogen. Meanwhile, the introduction of sulfonamide antibiotics dramatically affected the physiological profile of microbial community in manure in the middle stage of composting. HPLC MS/MS results showed that both SMM and SM2 in manure were completely degraded within 14 days, while the degradation rate of SMM was faster than that of SM2. For both composting treatments with or without addition of exogenous antibiotics, the relative abundance of sull and sul2 showed an initial decline in the first 14 or 21 days and a slight increase thereafter. The addition of exogenous antibiotics showed insignificant enhancement on increasing the relative abundance of sul1 and IntI1 in manure, but resulted in an apparent increase in sul2 relative abundance. Although the fates of tetQ and tetW during composting were different from that of sulfonamide ARGs, the introduction of sulfonamide antibiotics into manure increased the relative abundance of tetracycline ARGs. Redundancy analysis indicated that composting temperature correlated negatively with sul1, sul2 and IntI1 relative abundance in manure but had no obvious relationship with tetQ and tetW relative abundance. All the ARGs detected in this work correlated negatively with C/N ratio and the nitrate nitrogen concentration of manure compost but positively correlated with pH, moisture and ammonia nitrogen concentration of manure compost. PMID- 27506059 TI - Are You a Victim of Identity Theft? PMID- 27506060 TI - Example of Coordinated Effort between Behavioral Health and Primary Health Care. PMID- 27506061 TI - Osteogenesis Imperfecta. PMID- 27506062 TI - Be Prepared: Phase 2 HIPAA Audits Set to Begin. PMID- 27506063 TI - [Not Available]. PMID- 27506064 TI - [Migraine: from generic recommendations to practical taking in charge]. AB - Although with an 11% prevalence migraine is a major public health problem, many patients are not satisfied with its handling by medical professionals. Migraine is a clinical diagnosis based on typically lateralized throbbing headache with nausea and/or photo- and phonophobia. It can in some be preceded by an aura with transient focal neurological symptoms. There are several "red flags" of clinical presentation, however, that should induce further examination with brain imaging studies. Treatment is based on identifying and avoiding provoking factors, on treating attacks with rescue medication (simple pain killers or triptans), on identifying conditions for a prophylactic treatment by one of several possible substance classes, and most importantly, on establishing a solid therapeutic relationship with the patient. PMID- 27506065 TI - [The dark side of facet joint]. AB - Low back pain (LBP) is a major medical and economical problem, because of its high incidence. Indeed, 70-85% of adult people will suffer from this kind of pain once in their life. We will focus in this article on chronic LBP, which represent an annual prevalence of 30% and more specifically on mechanical pain, with our without radiation into the legs. In case of failure of traditional analgesia combining drugs and physical therapies, we can propose interventional pain relief. This involves a series of diagnostic blocks (medial branch blocks), followed by the treatment (radiofrequency ablation). This treatment remains purely symptomatic. A multidisciplinary approach with patient's physical reconditioning is therefore very important. PMID- 27506066 TI - [Chronic postoperative pain]. AB - Chronic postoperative pain remains a frequent pathology whose global impact approximates 20 and 30% and accounts for 20% of the consultations in a pain center. Risk factors consider firstly each patient's feature and comorbidity and also different surgical procedures with their technical approach. Neuropathic pain compared to nociceptive pain is a great component in the postoperative period and needs to be recognized by specific tests (DN4). Pain prevention involves risk factors' detection, appropriate anesthetic support and effective postoperative pain management. Treatment is based on the type of pain and includes a multimodal analgesia with interventional pain therapy. PMID- 27506067 TI - [It is not only about cost ... when it comes to generic medication]. AB - The aim of this qualitative study was to explore patients' representations regarding generics in patients suffering from non-specific disabling chronic musculoskeletal pain, as these patients are confronted with the issue of the prescription and/or substitution of original formulations with generics. Patients' representations suggest that they might be confident in taking a generic medication: when the generic medication is prescribed by the physician and each prescription is discussed, i.e., the patient is prescribed the generic version of a given medication and not a generic medication. Economic arguments are not sufficient to accept substitution. Negative representations require attention and need be considered. PMID- 27506068 TI - [Spinal cord stimulation for the management of chronic pain]. AB - Neuromodulation techniques modify the activity of the central or peripheral nervous system. Spinal cord stimulation is a reversible and minimally invasive treatment whose efficacy and cost effectiveness are recognized for the treatment of chronic neuropathic pain or ischemic pain. Spinal cord stimulation is not the option of last resort and should be considered among other options before prescribing long-term opioids or considering reoperation. The selection and regular follow-up of patients are crucial to the success of the therapy. PMID- 27506069 TI - [Psychosomatic posttraumatic resonances in refugees]. AB - The recent flow of refugees in our countries connects the clinician to new challenges: posttraumatic consequences, exile pathologies, cultural differences. Moreover, the psychic pains express themselves often through the body in more or less qualified ways, making a clear understanding of them difficult. From the therapist's side, the confrontation to war violences and cultural differences might create difficulties in establishing an empathic and fruitful therapeutic alliance. PMID- 27506070 TI - [Abiotrophia defectiva: an unusual cause of endocarditis]. AB - This article reports one of the rare cases of Abiotrophia defectiva endocarditis with no underlying valvular condition. A sixty-three years old man was hospitalized because of complicated respiratory sepsis with acute heart failure. Hemocultures and echocardiogram enabled the diagnosis of A. defectiva endocarditis. The clinical course was favorable under combined aminoglycoside and cephalosporin. The patient ultimately required valvular replacement. A. defectiva is a micro-organism part of the Nutritionnaly Variant Streptococci (NVS) associated with a high mortality rate and often resistant to antibiotics. Although A. defectiva is a rare cause of endocarditis, prompt recognition and appropriate antibiotic treatment are essential to clinical course. PMID- 27506071 TI - [Not Available]. PMID- 27506072 TI - [Not Available]. PMID- 27506073 TI - [Not Available]. PMID- 27506074 TI - [Not Available]. PMID- 27506075 TI - [Not Available]. PMID- 27506076 TI - [Not Available]. PMID- 27506077 TI - [Not Available]. PMID- 27506078 TI - [Not Available]. PMID- 27506079 TI - [Not Available]. PMID- 27506080 TI - [Not Available]. PMID- 27506081 TI - [Biological review of completed suicide]. AB - Family, twin and adoption studies have revealed genetic factors involved in suicide, while the accumulation of stress and mental illnesses are major contributing factors of suicide. Since higher lethality of suicidal behavior is considered to increase familial liability to suicidal behavior, we believe biological research of completed suicide is most important for a better understanding of the pathophysiology in suicide. Dysregulated hypothalamic pituitary-adrenal axis has gained a special interest in the neurobiology of suicide, mostly because of the findings using a dexamethasone suppression test (DST), in which DST non-suppressors show a nearly 10-fold higher risk of completed suicide than DST suppressors in a depressed cohort. Other data mainly from postmortem brain studies indicate abnormalities of the noradrenergic-locus coeruleus system, serotonergic system, endogenous opioid system, brain-derived neurotrophic factor, inflammatory cytokines and omega-3 fatty acid in completed suicide. However, genetic research of complete suicide is behind other mental problems because it is extremely difficult to obtain tissue samples of completed suicide. Under the difficult situation, we now retain over 800 blood samples of suicide completers thanks to bereaved families' cooperation. We are actively working on the research of suicide, for instance, by performing a GWAS using 500 samples of suicide completers. PMID- 27506082 TI - [Pharmacokinetics and safety of aripiprazole long-acting injection, following multiple deltoid administrations in schizophrenia patients in Japan]. AB - Aripiprazole once-monthly (AOM) was previously approved for treatment of schizophrenia as monthly injections in the gluteal muscle. The deltoid muscle provides a more accessible injection site. The present study was conducted in Japanese schizophrenia patients as a 24-week, open-label trial that assessed the pharmacokinetics and safety of 5 sequential doses of AOM 400 mg (AOM 400) once every 4 weeks administered in the deltoid muscle. Patients treated with an oral atypical antipsychotic (other than aripiprazole) continued to receive their pre study medication up to 14 days after the first AOM 400 injection. The completion rate was 76.5% (n = 13/17). Mean aripiprazole plasma C(min) almost reached steady state by the fourth AOM 400 injection. After the fifth AOM 400 injection, mean aripiprazole AUC(28d), C(max) and C(min) were 165 MUg x h/ml, 331 ng/ml and 201 ng/ml, respectively, which were similar to previously published pharmacokinetic parameters after the fifth gluteal injection of AOM 400. The most common treatment-emergent adverse event (TEAE) was injection site pain (35.3%). Most TEAEs were classified as mild in intensity. In conclusion, the deltoid injection of AOM can be considered an alternative route of administration, as deltoid and gluteal injections are interchangeable in terms of aripiprazole plasma concentrations, with no additional safety issues. PMID- 27506083 TI - [Newly developed nomenclature (Neuroscience-based Nomenclature)]. AB - The current nomenclature is based on clinical indications; for example, drugs used for mania and psychosis are classified as "mood stabilizers" and "antipsychotic drugs", respectively. This discrepancy between their names and indications often confuses patients and their caregivers and sometimes leads to a misunderstanding of the effects of prescribed medications. In addition, up-to date scientific knowledge on these drugs has not been reflected in the current nomenclature. To overcome these limitations of the current nomenclature, following an initiative of the European Congress of Neuropsychopharmacology (ECNP), a taskforce for psychotropic nomenclature was established with representatives from 5 international organizations, including the Asian College of Neuropsychopharmacology (AsCNP). The mission of this taskforce is to provide a pharmacologically-driven (rather than indication-based) nomenclature, which is now referred to as Neuroscience-based Nomenclature (NbN). The NbN project has just started. Since it always takes time to change the culture, we understand the transition will likely involve some expected and unexpected responses from the field. However, we believe that such responses and feedback will surely improve the quality of the NbN, which in turn will be beneficial for clinicians, researchers, and patients as well as their caregivers. PMID- 27506084 TI - Canine osteosarcoma cell lines contain stem-like cancer cells: biological and pharmacological characterization. AB - Cancer stem cells (CSCs) represent a small subpopulation of cells responsible for tumor formation and progression, drug resistance, tumor recurrence and metastasization. CSCs have been identified in many human tumors including osteosarcoma (OSA). CSC distinctive properties are the expression of stem cell markers, sustained growth, self-renewal and tumorigenicity. Here we report the isolation of stem-like cells from two canine OSA cultures, characterized by self renewal, evaluated by sphere formation ability, differential marker expression, and in vitro proliferation when cultured in a medium containing EGF and bFGF. Current therapies for OSA increased survival time, but prognosis remains poor, due to the development of drug resistance and metastases. Chemotherapy shrinks the tumor mass but CSCs remain unaffected, leading to tumor recurrence. Metformin, a drug for type 2 diabetes, has been shown to possess antitumor properties affecting CSC survival in different human and animal cancers. Here we show that metformin has a significant antiproliferative effect on canine OSA stem like cells, validating this in vitro model for further pre-clinical drug evaluations. In conclusion, our results demonstrate the feasibility of obtaining CSC-enriched cultures from primary canine OSA cells as a promising model for biological and pharmacological studies of canine and human OSAs. PMID- 27506085 TI - Application of next-generation sequencing to investigation of norovirus diversity in shellfish collected from two coastal sites in Japan from 2013 to 2014. AB - A better understanding of the role played by shellfish regarding the manner of pathogen contamination, persistence, and selection may help considering epidemiology of noroviruses. Thus, norovirus genotype profiles in shellfish (Crassostrea gigas and Mitilus galloprovincialis) were investigated by using Next generation sequencing (NGS) technology. In genogroup I (GI), 7 genotypes (abbreviated as GI.2 to GI.7, and GI.9) were detected from C. gigas, whereas 9 genotypes (GI.1 to GI.9) were detected from M. galloprovincialis. The genotype with the highest proportion found in both C. gigas and M. galloprovincialis was GI.4, and the second highest was GI.3. In genogroup II (GII), 17 genotypes (GII.1 to GII.9, GII.11 to GII.17, GII.21 and GI.22) were detected from C. gigas, whereas 16 genotypes (GII.1 to GII.8, GII.11 to GII.17, GII.21 and GI.22) were detected from M. galloprovincialis. The genotype with the highest proportion in both C. gigas and M. galloprovincialis was GII.4, the next highest differed between C. gigas and M. galloprovincialis. To our knowledge, this study may be the first trial to utilize the latest technology in this field, and reveal the diversity of norovirus genotypes present in shellfish. PMID- 27506086 TI - Elevated cortisol content in dog hair with atopic dermatitis. AB - Canine atopic dermatitis (CAD) is a chronic relapsing inflammatory skin disease occurring in 10% of the canine population. Although most studies have focused on the pathophysiological mechanism involved in CAD, the detrimental impact of CAD on quality of life has received only little attention. Hair cortisol analysis is becoming a valuable tool in monitoring chronic stress. To further validate this approach in CAD, we compared the hair cortisol concentration of atopic dogs with that of healthy conditioned dogs. The extent and severity of cutaneous lesions of atopic dermatitis were assessed according to modified CADESI-03 scores. In addition, skin barrier function was evaluated by measuring transepidermal water loss (TEWL) and stratum corneum conductance. The correlation between CAD severity and hair cortisol concentration was evaluated. The level of hair cortisol evaluated by ELISA assay showed that the atopic dermatitis group had significantly increased cortisol levels compared to that of the healthy control group. A significant positive correlation was identified between hair cortisol level and the CADESI score in CAD patients. The TEWL value of the cubital flexor of the forelimb in the atopic group was significantly higher compared to the healthy controls. These findings imply that the hair cortisol analysis can be an effective and objective biomarker in assessment of long-term stress of CAD patients. PMID- 27506087 TI - Evaluation of a combination of alfaxalone with medetomidine and butorphanol for inducing surgical anesthesia in laboratory mice. AB - The anesthetic effects of alfaxalone were investigated in mice. Mice were administered alfaxalone (100 mg/kg) alone or the combinations of 0.3 mg/kg of medetomidine and 5 mg/kg of butorphanol with alfaxalone at doses of 20 mg/kg (M/B/A20), 40 mg/kg (M/B/A40), 60 mg/kg (M/B/A60), or 80 mg/kg (M/B/A80). Control mice received 0.3 mg/kg of medetomidine, 4 mg/kg of midazolam, and 5 mg/kg of butorphanol (M/M/B). Each drug was administrated by intraperitoneal (IP) or subcutaneous (SC) routes. M/M/B IP did not achieve surgical anesthesia but M/M/B SC achieved surgical anesthesia within 10 min after administration and maintained anesthesia for 45 min. The anesthetic scores were very low after IP or SC administration of alfaxalone alone. M/B/A20 IP and SC did not achieve surgical anesthesia. M/B/A40 IP did not achieve surgical anesthesia but M/B/A40 SC achieved surgical anesthesia within 10 min after administration and maintained anesthesia for 35 min. M/B/A60 SC achieved surgical anesthesia within 5 min after administration and maintained anesthesia for 75 min. By contrast, M/B/A60 IP did not achieve surgical anesthesia. M/B/A80 SC achieved surgical anesthesia within 5 min after administration and maintained anesthesia for 85 min. By contrast, M/B/A80 IP did not achieve surgical anesthesia and one mouse died about 10 min after drug administration. Administration of atipamezole rapidly reversed anesthesia induced by M/B/A60 in mice. These results suggest that M/B/A60 SC, an alfaxalone-based combination, is suitable for inducing surgical anesthesia in laboratory mice. PMID- 27506088 TI - Surgical stabilization of the atlanto-occipital overlap with atlanto-axial instability in a dog. AB - The atlanto-occipital (AO) overlap in combination with atlanto-axial (AA) instability was found in a dog. We hypothesized that ventral fixation of the AA junction can stabilize the atlas and prevent AO overlap by reviewing our past cases with AA instability. A standard ventral fixation of the AA junction using stainless k-wires and polymethyl methacrylate (PMMA) was performed. The dog fully recovered, and no complication was noted. The results of the postoperative CT imaging supported our hypothesis. The ventral fixation of the AA junction is a feasible treatment option for similar cases, although craniocervical junction abnormalities (CJA) including AA instability are varied, and careful consideration is required for each case. PMID- 27506089 TI - Complex malformations of the urogenital tract in a female dog: Gartner duct cyst, ipsilateral renal agenesis, and ipsilateral hydrometra. AB - A 10-month-old female toy poodle was referred to the University of Tokyo Veterinary Medical Center with a urogenital anomaly found during sterilization. An exploratory laparotomy revealed a cyst adhering to the cervix and a unilateral renal agenesis. Histopathology and immunohistochemical analysis of the cyst was consistent with remnants of the Wolffian duct or a Gartner duct cyst. This is a rare case of a canine Gartner duct cyst with renal agenesis and uterine anomaly. We discuss the similarity of this case to that of humans and introduce a classification in the literature for these complex urogenital malformations for further clinical research into the precise diagnosis and appropriate surgical planning. PMID- 27506090 TI - Evaluation of weekly bathing in allergic dogs with methicillin-resistant Staphylococcal colonization. AB - We evaluated the efficacy of weekly bathing in reducing methicillin-resistant Staphylococcus (MRS) colonization in canine allergic dermatitis in a pilot clinical trial. Six dogs with allergic dermatitis controlled by prescription medications were treated with weekly bathing for 1 month. The Canine Atopic Dermatitis Extent and Severity Index version 3 (CADESI-03) and pruritus scores and frequency of mecA-positive Staphylococcus spp. isolated from three body sites between weeks 0 and 4 were compared. There was no significant difference in CADESI-03 scores with bathing, whereas the pruritus scores were significantly reduced (p < 0.05). Furthermore, MRS frequency was decreased in four of the six dogs (p < 0.05). In conclusion, weekly bathing should be considered for reducing MRS colonization in canine allergic dermatitis. PMID- 27506091 TI - Water intoxication in adult cattle. AB - Water intoxication is a common disorder in calves and is usually characterized by transient hemoglobinuria. In contrast, the condition is very rare in adult cattle, with few reports on naturally occurring cases. In the present report, four female Japanese Black cattle, aged 16-25 months, showed neurological signs when they drank water following a water outage. Hemoglobinuria was not grossly observed, while severe hyponatremia was revealed by laboratory tests. Autopsy indicated cerebral edema with accumulation of serous fluid in expanded Virchow Robin spaces. These results indicate the possibility of water intoxication associated with cerebral edema due to severe dilutional hyponatremia in adult cattle. PMID- 27506092 TI - An unusual case of thoracic ectopia cordis in a Toggenburg Goat and its three dimensional images constructed with X-ray computed tomography. AB - A two-day-old female Toggenburg goat with thoracic ectopia cordis (EC) was diagnosed via radiography and computed tomography. The goat was born with EC, defects of the sternum and a supra-umbilical abdominal wall, but without the presence of Cantrell's syndrome. Necropsy and histopathological findings indicated the affected kid had malformation of the heart with an enlarged left ventricle. The findings showed the heart (9 x 5 x 5 cm) stayed outside the thorax, and was covered by a semitransparent membrane. This report is the first to describe a case of thoracic EC in a goat whose sternum was not developed fully and was not connected to the ribs. It is also the first paper to describe three dimensional images of this condition constructed from computed tomography scans. PMID- 27506093 TI - VALUE OF PROTECTIVE STOMA IN RECTAL CANCER SURGERY. AB - INTRODUCTION: Anastomotic leakage is the most serious surgical complication in rectal surgery. The aim of this study was to find out whether a protective stoma was capable of lowering the rate of clinical anastomotic leakage and to evaluate the rate of anastomotic leakages requiring resurgery. MATERIAL AND METHODS: A retrospective study included a sample of 149 consecutive patients with rectal cancer who had undergone elective rectal resection with primary anastomosis. After total mesorectal excision, the anastomosis was created using either the single stapling or double stapling anastomotic technique. Anastomotic integrity was verified by transanal air insufflations with the pelvis filled with saline. A protective covering colostomy was added in selected cases and according to the surgeon's preference. RESULTS: A protective stoma was created in 31% of patients. Clinical anastomotic leakage occurred in 6.7% of patients (10/149). Anastomotic leakage occurred in 8.5% of the patients with a protective stoma (4/47) and in 5.9% of those without a protective stoma (6/102), which was not statistically significant. Surgery lasted significantly longer when a stoma had to be created than in case when it was not needed (p=0.024). The overall rate of resurgery due to postoperative surgical complications was 5.3% and in three cases this happened because of anastomotic leakage. All patients with a protective stoma and clinical anastomotic leakage were treated conservatively, compared to 50% of patients without a protective stoma who suffered anastomotic leakage and had to be operated. CONCLUSION: A stoma cannot prevent but it can surely minimize surgical complications related to anastomotic leakage and it does reduce the rate of resurgery. PMID- 27506094 TI - POSTOPERATIVE VISUAL RECOVERY FOLLOWING SURGICAL TREATMENT OF CRANIOPHARYGIOMAS. AB - INTRODUCTION: Craniopharyngiomas are rare tumors which are typically focused in the sellar and suprasellar region. Secondary to mass effect, these tumors commonly mediate neurologic, endocrinologic or visual functions. The purpose of this study was to investigate the pre and postoperative visual acuity in patients with a craniopharyngioma in the area of the optic chiasm. MATERIAL AND METHODS: This retrospective study included 42 patients with a craniopharyngioma demonstrated by computerized tomography or magnetic resonance imaging. The visual status was analyzed both before and after surgery (10 days, one month and six months after surgery). RESULTS: Progressive loss of visual acuity was a typical initial eye symptom. Postoperatively, improvement in visual acuity was seen in 47.2% of eyes. Normal vision was attained in the majority of eyes (from 27% preoperatively to 40% six months after surgery). The percentage of eyes with heavily reduced visual acuity decreased as well (from 38% preoperatively to 11% six months after surgery). Visual acuity improved at least in one eye in 36.58% of patients, and 28% of patients achieved normal visual acuity in both eyes, six months after surgery. The improvement of 0.5 and better at least in one eye was observed in 33% of patients. The majority of eyes showed immediate improvement after surgical decompression, during first ten postoperative days. CONCLUSIONS: The majority of patients with craniopharyngioma show a significant improvement of visual function, particularly in the first ten postoperative days. PMID- 27506095 TI - ANTIVIRAL TREATMENT OF HEPATITIS C IN SERBIAN PRISON SETTING: MEDICAL TREATMENT OUTCOMES AND PATIENTS' ADHERENCE. AB - INTRODUCTION: Seroprevlence of chronic hepatitis C viral infection in correctional facilities ranges from 16% to 49%. However, there are only very limited data available on the course of hepatitis C viral infection and outcomes oftreatment with pegylated interferon plus ribavirin in correctional settings. The aim ofthis study was to assess the feasibility and effectiveness of use of pegylated interferon plus ribavirin treatment in the Serbian correctional setting. MATERIAL AND METHODS: The study sample consisted of the patients with hepatitis C hospitalized in the Special Hospital for Prisoners in Belgrade (Serbia) during 2007-2013. Health authorities approved treatment for 32 patients out of 76 treatment-naive patients referred to this institution. The patients (N=32) received 180 mcg pegylated interferon alfa-2a once a week plus oral ribavirin in dosage of 800 mg or 1000/1200 mg/day for 24 or 48-week treatment. All patients who completed therapy were assessed at the end of an additional 24 week treatment-free period for a sustained virological response. RESULTS: Sustained virological response was achieved in 53.8% of hepatitis C viral infection genotype I patients and in 73.3% and 66.6% of patients with hepatitis C viral infection genotype 3 and 4, respectively. One patient with mixed genotype (1, 2) did not achieve sustained virological response. The overall safety profile of the treatment regimen was very good. The incidence of influenza-like symptoms and depression were low A serious adverse event was recorded only in 6.4% of patients. CONCLUSION: The results showed that pegylated interferon alfa-2a plus ribavirin given once a week was well tolerated among prisoners and the regimen had the same adherence and effectiveness as in general population. PMID- 27506096 TI - TICK-BORNE ENCEPHALITIS VIRUS INFECTION IN HUMANS. AB - INTRODUCTION: Tick-borne meningoencephalitis virus is a flavivirus that causes the most important vector-borne central nervous system infection in many countries of Europe and Asia. There are three subtypes of tick-borne encephalitis virus: European, Siberian and the Far-Eastern subtype. TRANSMISSION: In endemic areas, the virus remains in transmissive cycles between Ixodes ticks and small rodents. CLINICAL PICTURE: In most cases (70-98%) infection goes asymptomatically. In about one-third of meningitis cases, meningoencephalitis or meningomyelitis is developed. Postencephalytic syndrome may be the complication of the infection, presenting with neurological symptoms. DIAGNOSIS: Etiologic diagnosis of tick-borne meningoencephalitis is only made on basis of laboratory analyses. Reverse transcription-polymerase chain reaction is used for determining the presence of virus in the blood and cerebrospinal fluid. Antibodies in blood and cerebrospinal fluid can be detected by serological tests. PREVENTION: The most efficient way to control this potentially severe disease with possible serious long-term consequences is vaccination. It should be recommended to persons who live or travel to endemic areas. CONCLUSION: In Serbia, tick-borne encephalitis virus infection belongs to the list of reportable diseases; however, there are no reported cases because the diagnostics is not performed routinely. We believe that the significance of this zoonosis must be examined in our country and some of its parts because of preliminary positive serological findings found out in Vojvodina as well as because of reported cases in neighboring countries such as Hungary and Croatia and its worldwide distribution. PMID- 27506097 TI - THE TIBIAL APERTURE SURFACE ANALYSIS IN ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION PROCESS. AB - INTRODUCTION: The tibial tunnel aperture in the anterior cruciate ligament reconstruction is usually analyzed as an ellipse, generated as an intersection between a tibial plateau and a tibial bone tunnel. The aim of this study is to show that the tibial tunnel aperture, which utilizes 3D tibial surface bone model, differs significantly from common computations which present the tibial tunnel anterior cruciate ligament aperture surface as an ellipse. MATERIAL AND METHODS: An interactive program system was developed for the tibial tunnel aperture analysis which included the real tibia 3D surface bone model generated from a series of computed tomography images of ten male patients, their mean age being 25 years. In aperture calculation, the transverse drill angle of 10 degrees was used, whereas sagittal drill angles of 40 degrees, 50 degrees and 60 degrees were used with the drill-bit diameter set to 10 mm. The real 3D and 2D tibial tunnel aperture surface projection was calculated and compared with an ellipse. RESULTS: According to the calculations, generated 3D aperture surfaces were different for every patient even though the same drill parameters were used. For the sagittal drill angles of 40 degrees, 50 degrees and 60 degrees, the mean difference between the projected 3D and 2D area on the tibial plateau was 19.6 +/ 5.4%, 21.1 +/- 8.0% and 21.3 +/- 9.6%, respectively. The difference between the projected 3D area on the tibial plateau and ellipse surface was 54.8 +/- 16.3%, 39.6 +/- 10.4% and 25.0 +/- 8.0% for sagittal drill angles of 40 degrees, 50 degrees and 60 degrees, respectively. CONCLUSION: The tibial tunnel aperture surface area differs significantly from the ellipse surface area, which is commonly used in the anterior cruciate ligament reconstruction analysis. Inclusion of the 3D shape of the tibial attachment site in the preoperative anterior cruciate ligament reconstruction planning process can lead to a more precise individual anatomic anterior cruciate ligament reconstruction on the tibial bone. Both tibial aperture area generated in 3D and its projection on a tibial plateau are larger than the ellipse surface; therefore, individual characteristics of each patient have to be taken into consideration. PMID- 27506098 TI - VARIATIONS IN TIMING OF ELECTIVE ORCHIDOPEXY. AB - INTRODUCTION: Undescended testis or cryptorchidism is detected in 3% of full-term male newborns, and inup to 33% of preemies. As the testicular descent may sometimes resolve spontaneously during first months of life, cryptorchidism is found in 1% of boys one year old. According to Consensus of Nordic experts in. pediatric urology regarding cryptorchidism the optimal period for surgery is 12 18 months of age. The goal of this study was to identify the age of patients with congenital undescended testis at the time of surgery. MATERIAL AND METHODS: A retrospective study included all the cases of cryptorchid patients who had undergone orchidopexy in the period from 2007 to 2014. The patients'. age and the place of residence were analyzed. RESULTS: A total of 637 patients (722 orchidopexies) underwent the elective operative treatment of undescended testis during the observed period. The analysis revealed that only 144 (22.60%) of cryptorchid infants were operated on within their first 18 months of life. In the group of 359 patients from* the urban environment, 101 (28.13%) were operated under the age of 18 months. Among the 278 patients from the rural enviornment, 43 (15.46%) were 18 months and younger at the time of surgery. CONCLUSION: The timing of surgical treatment of undescended testis in the study period was far from the recommended optimal time. It is evidently necessary to plan and provide additional information for pediatricians and parents about the current view on cryptorchidism and consequences of the late treatment. PMID- 27506099 TI - SUSCEPTIBILITY OF RESPIRATORY ISOLATES OF STREPTOCOCCUS PNEUMONIAE ISOLATED FROM CHILDREN HOSPITALIZED IN THE CLINICAL CENTER NIS. AB - INTRODUCTION: Streptococcus pneumoniae is one of the most common causes of respiratory infections. The aim was to study the susceptibility to antimicrobial agents of respiratory isolates ofStreptococcus pneumoniae obtained from hospitalized children. MATERIAL AND METHODS: A total of 190 respiratory pneumococcal isolates obtained from children aged from 0 to 14 years were isolated and identified by using standard microbiological methods. Susceptibility to oxacillin, erythromycin, clindamycin, tetracycline, cotrimoxazole, ofloxacin and rifampicin was tested by disc diffusion method. Minimal inhibitory concentrations for amoxicillin and ceftriaxone were determined by means of E test. The macrolide-resistant phenotype was detected by double disc diffusion test. RESULTS: All tested isolates were susceptible to amoxicillin and ceftriaxone. The minimal amoxicillin concentration inhibiting the growth of 50% of isolates and of 90% of isolates was 0.50 microg/ml and 1.0 microg/ml, respectively and the minimal ceftriaxone concentration inhibiting the growth of 50% of isolates and of 90% of isolates was 0.25 microg/ml and 0.50 microg/ml, respectively. Susceptibility to erythromycin and clindamycin was observed in 21.6% and 29.47% of isolates, respectively. The resistence to macrolides-M phenotype was detected in 10.07% of isolates and constitutive macrolide lincosamide-streptogramin phenotype (constitutive MLS phenotype) was found in 89.93% of isolates. All tested isolates were susceptible to ofloxacin and rifampicin. CONCLUSION: Amoxicillin could be the therapy of choice in pediatric practice. The macrolides should not be recommended for the empirical therapy of pneumococcal respiratory tract infection in our local area. PMID- 27506100 TI - LOWER BACK PAIN--SILENT SYMPTOM OF CHRONIC INFRARENAL ABDOMINAL ANEURYSM RUPTURE. AB - INTRODUCTION: The rupture of infrarenal abdominal aortic aneurysm is a surgical emergency condition with a high rate of mortality before the patients arrive at hospital. The signs and symptoms of abdominal aortic aneurysm rupture into the retroperitoneal cavity are pulsatile mass, abdominal pain, hypotension and shock, but sometimes silent symptoms also hide a dangerous and life threatening condition, such as chronic aneurysm rupture of abdominal aorta into the retroperitoneal cavity. CASE REPORT: We present a patient having had the lower back pain for 4 months, which had been recognized and treated as lumbar ischialgia but which was eventually diagnosed to be chronic infrarenal abdominal aortic aneurysm rupture by computed tomography angiography. The surgical intervention was successful and the patient was discharged from hospital after 6 days without any clinical complications. Preoperative imaging by computed tomography angiography of ruptured abdominal aortic aneurysm is highly sensitive for detection of several specific signs for rupture. This condition leads to urgent vascular surgery. PMID- 27506101 TI - TRANEXAMIC ACID IN SURGICAL TREATMENT OF SCOLIOSIS IN CHILDREN: A CASE REPORT. AB - INTRODUCTION: Children who are subjected to surgical treatment for scoliosis usually end up receiving a lot of blood transfusions since they tend to lose one or more blood volumes during the surgery. Tranexamic acid is an antifibrinolytic agent, increasingly used in children to reduce perioperative blood loss in various settings, including corrective surgery of scoliosis. CASE REPORT: A 12 year-old girl, weighing 44 kg, was admitted to our hospital for scoliosis correction. She had congenital scoliosis caused by congenital malformation of vertebrae. The surgery was performed under balanced general anesthesia. Two central and one peripheral line were cannulated in case massive transfusion would be required. Invasive monitoring was used, as well as prevention of hypothermia. Since massive blood loss was expected, bolus of tranexamic acid had been administered prior to the surgery. Tranexamic acid was given continuously in an intravenous infusion during the surgery. Blood loss was only 10 ml/kg, and since the hemoglobin value was orderline (89 g/l) during the surgery, the patient received 10 ml/kg of packed red blood cells. The child was hemodynamically stable throughout the surgery. After the completion of surgery, which lasted for 5 hours, the patient was extubated in the operating room. Postoperatively, the patient was transferred to the surgical ward. Hemoglobin values were stable and there was no need for additional blood replacement. CONCLUSION: Extensive blood loss is common in pediatric scoliosis correction surgery, transfusion being unavoidable in the majority of cases. In our patient, tranexamic acid proved safe and effective in reducing perioperative blood loss and transfusion requirement. PMID- 27506102 TI - VALPROATE, BIPOLAR DISORDER AND POLYCYSTIC OVARIAN SYNDROME. AB - INTRODUCTION: Polycystic ovarian syndrome is a syndrome of ovarian dysfunction with the principal features of hyperandrogenism and polycystic ovary morphology. A large number of studies conducted on this topic have suggested a possible role of anticonvulsants, particularly valproate, in the pathogenesis or risk factors associated with polycystic ovarian syndrome. Bipolar treatment guidelines from Canada and the United States of America recommend valproate as the first line strategy in the acute treatment of bipolar disorder. DISCUSSION: Most persons with bipolar disorder require maintenance treatment. Long-term administration of valproate in women with bipolar disorder or epilepsy is believed to result in the increased risk of hyperandrogenism, menstrual abnormalities and polycystic ovaries. Valproate may also increase the risk of infertility and other associated symptoms of polycystic ovarian syndrome. Therefore, particular caution is indicated in the use of valproate in women of reproductive age. CONCLUSION: The treatment of the female patients with bipolar disorder presents various challenges for the clinician. Every woman of reproductive age needs to know the risk and benefits of her pharmacologic treatment options. Bipolar disorder should be considered chronic disorder, whose development is largely affected by hormonal changes and reproductive cycle in women. These issues should be researched more thoroughly in order to opt for the most appropriate treatment in women with bipolar disorder. PMID- 27506103 TI - [THE EVOLUTION OF MARKERS OF PROSTATE CANCER]. AB - The implementation of biochemical laboratory tests in oncology practice increased exponentially during last decades and continues to be in progress nowadays. The application of modern molecular genetic technologies permits using diagnostic systems with greater diagnostic sensitivity and specificity. The new tests are actively implemented permitting to diagnose physical presence of tumor systemic manifestations of malignant neoplasm (cachexia, pyrexia), paraneoplastic syndromes and also to detect tumor markers. The oncomarker permits to differentiate malignant from benign tumor on the basis of quantitative differences in content of corresponding antigene-tumor marker in blood serum independently of localization of tumor nidus. The prostate cancer is a medical social problem of male population. On initial stages, this disease can take its course asymptomatically or with symptomatic conditioned by such concomitant and more prevalent pathologies as chronic prostatitis and prostate benign hyperplasia. The early diagnostic ofprostate cancer permits implementing timely radical treatment frequently contributing to total recovery of patients. The article presents detailed description of evolutionary conception of markers using in diagnostic, staging and prognostication of course of prostate cancer. The acid phosphatase was applied for the first time in early diagnostic of staging of prostate cancer in 1974. Nowadays, in century of "OMX"-technologies, in common clinical practice detection of RNA in urine of patient is used for staging diagnostic and prognostication of progression of process of tissue neotransformation. PMID- 27506104 TI - [THE MARKERS OF BONE TISSUE METABOLISM. THE REFERENCE VALUES FOR THE KHANTY-MANSI AUTONOMOUS OKRUG-YUGRA]. AB - The article defines reference values of particular markers of metabolism of bone tissue common to residents of the Khanty-Mansi Autonomous Okrug-Yugra. The enzyme linked immunosorbent assay was applied to analyze blood serum of 86 patients (43 males, 43 females) detecting concentration of C-tailed telopeptide of collagen type I, osteocalcin, calcitonin, parathyroid hormone and 1.25(OH)2 vitamin D. The following reference values were derived. The C-tailed telopeptide (ng/ml): 0.111 (0.071-0.162) for females and 0.146 (0.066-0.255) for males. The osteocalcin (ng/ml): 20.6 (12.9-33.0) for females and 27.6 (12.0-61.9) for males. Calcitonin (pg/ml) - 2.55 (1.90-3.76); parathyroid hormone (pg/ml) - 39 (13-88); 1.25(OH)2 vitamin D (pg/ml) - 10.5 (3.9-46.4). It was also noted that decreasing of average indicators of vitamin D level and increasing of level of parathyroid hormone among residents of the Khanty-Mansi Autonomous Okrug-Yugra can cause increasing of intensity of accumulation of minerals in bone tissue as compared with residents of middle latitudes. PMID- 27506105 TI - [THE DIFFERENTIAL DIAGNOSTIC POSSIBILITIES IN EVALUATION OF IRON-DEFICIENT CONDITION UNDER ANEMIAS]. AB - The article presents data concerning differential diagnostic possibilities of evaluation of genuine iron-deficient anemia and anemia of chronic diseases. The variety of mechanisms of development of anemia of chronic diseases is demonstrated, including effect of humoral inhibitors of erythropoiesis, disorder of iron metabolism at the expense of its redistribution into cells of macrophage system, suppression of erythropoiesis resulted in redistributed or functional iron deficiency. The data is presented concerning significance in diagnostic of anemia of chronic diseases of such factors as content of ferritin, dissolving receptors of transferrin and role of hepcidin protein in pathogenesis of anemia of chronic diseases. The analysis of scientific publications demonstrated that hepcidin is a negative regulator of iron metabolism. Under iron-deficient anemia its level in blood decreases that contribute to extensive absorption of iron in gastrointestinal tract. On the contrary, under anemia of chronic diseases its content drastically increases and results in blocking of iron transport everywhere, including internal epithelium, macrophages, placenta and other types of cells. The hyper-production of hepcidin during infection and inflammation is responsible for anemia of chronic diseases. The perspectives of development of pharmaceuticals decreasing level of hepcidin for treatment of anemia of chronic diseases is demonstrated. PMID- 27506106 TI - [THE METHODICAL APPROACHES TO DIAGNOSTIC OF NIGHT PAROXYSMAL HEMOGLOBINURIA]. AB - The article presents diagnostic of night paroxysmal hemoglobinuria. The night paroxysmal hemoglobinuria is an orphan disease characterized by absence of GPI anchor on blood cells as a result of mutation of PIG-A gene on the short arm of X chromosome. The particular proteins bounded with GPI-anchor implement function of defense from activation of components of complement and development of membrane attacking complex. The erythrocytes exposed to destruction in bloodstream are among the most impacted. Therefore, one of the main signs of night paroxysmal hemoglobinuria is complement-depending intravascular hemolysis which indicators for a long time played a key role in diagnostic of night paroxysmal hemoglobinuria. The actual technique of diagnostic of night paroxysmal hemoglobinuria is flow cytometry. The analysis of night paroxysmal hemoglobinuria clone is recommended to patients with hemolysis of unclear genesis, thrombosis of cerebral and abdominal veins, thrombocytopenia and macrocytosis and also patients with AA, myelodysplastic syndrome, myelofibrosis. The international protocol recommended by the International Society of Clinical Cytometry (2010) is implemented to diagnose night paroxysmal hemoglobinuria. The original technique of evaluation of reticulocytes was developed with purpose to detect night paroxysmal hemoglobinuria clone. The high correlation was substantiated between size of night paroxysmal hemoglobinuria clone measured among reticulocytes according to proposed mode and night paroxysmal hemoglobinuria clone measured among granulocytes and monocytes detected according international standardized approach. PMID- 27506107 TI - [THE PHYSICAL CHEMICAL, BIOLOGICAL BASICS OF CELLS ABSORPTION OF UNESTERIFIED FATTY ACIDS; ALBUMIN, CAVEOLIN, CLATHRIN AND LIPID-BINDING PROTEINS OF CYTOPLASM (THE LECTURE)]. AB - From aposition of phylogenetic theory of general pathology, obesity and metabolic syndrome are pathology of fatty cells. However, the first is a pathology of phylogenetically early visceral fatty cells of omentum. They supply with substratum of energy realization of biologic function of trophology, homeostasis, endoecology and adaptation. The visceral fatty cells of omentum have no receptors to insulin and synthesize adaptively insulin and they are not characterized by biologic reaction of proliferation. The obesity is a pathology of late in phylogenesis subcutaneous adpocytes. They are insulin-dependent and supply with substratum of energy realization of one biologic function of locomotion--movement at the expense of constriction of cross-striated miocytes. The adipocytes in terms of adaptation synthesize humoral mediator adponectin and actively implement biologic function of proliferation. Under both aphysiologic conditions increases passive by gradient of concentration, absorption by cells albumin-unbound free fatty acids in unionized form in micellae's composition. The passive aphysiologic absorption of free fatty acids by cells which under intracellular compartmentalization don't oxidize mitochondria results in synthesis, accumulation of triglycerides in cytoplasm of cells which don't implement it physiologically. The aphysiologic absorption of free fatty acids by cells, their etherification in triglyceride, in particular, in phylogenetically late beta cells of islets and either late cardiomyocytes which fatty acids don't synthesize de novo results in development of aphysiologic processes and disorder of function. From position of biology, these cells in vivo are subjected to loss similar to apoptosis. The formation of corpuscles of apoptosis compromise biologic function of endoecology activating biologic reaction of inflammation. PMID- 27506108 TI - [THE CYTOMETRIC TECHNIQUE OF BINDING OF EOSIN-5-MALEIMIDE IN DIAGNOSTIC OF INHERENT SPHEROCYTOSIS]. AB - The laboratory diagnostic of inherent spherocytosis is based on detection of spherocytes in peripheral blood, decreasing of index of sphericity, decreasing of osmotic resistance of erythrocytes. The new test of diagnostic of hereditary spherocytosis build on molecular defect was developed on the basis of binding extracellular fragments of protein of band 3 with eosin-5-maleimide (EMA-test). The study was carried out to implement comparative analysis of sensitivity and specificity of techniques applied to diagnose inherent spherocytosis. The sampling of 94 patients with various forms of anemias was analyzed All patients were applied complex clinical laboratory examination including analysis of osmotic resistance of erythrocytes, erythrocytometry and EMA-test as specific techniques of diagnostic of inherent spherocytosis. In 51 out of 94 patients (54%) decreasing of values of EMA-test was detected and in 47 patients diagnosis of inherent spherocytosis was confirmed. The standard values of EMA-test were established in 43 patients (46%) and 12 patients out of them with established diagnosis of inherent spherocytosis. Therefore, sensitivity of EMA-test made up to 79% and specificity - 80%. The most sensitive techniques of diagnostic remain osmotic resistance of erythrocytes (91%) and index of sphericity (up to 96%). But the highest specificity in this respect has EMA-test (80%). Nowadays, none of implemented techniques of diagnostic of inherent spherocytosis can be applied as a universal one. The implementation of complex examination is needed for proper diagnostic of disease. PMID- 27506109 TI - [THE DEVICE REGISTRATION OF IMMUNE CHROMATOGRAPHIC EXPRESS-TESTS]. AB - The development of sector of "fast-testing" i.e. test-systems permitting carrying out analysis during home visit of doctor or at primary examination of patient without any additional devices and reagents is predominant tendency in international practice. The immunochromatography is an effective technical solution in out-laboratory diagnostic, which nowadays is actively applied in controlling hundreds of diagnostically significant markers of infectious diseases, metabolic and functional disorders. However, common immunochromatography is focused on qualitative visual evaluation of results of study i.e. conclusion on presence or absence of coloration of particular zones of test-band. Therefore, the technical solutions retaining such merits of immunochromatography as expressness and technical simplicity and at the same time providing objectivity of diagnostic and increasing its informativeness are extremely in demand. The review considers main methodical solutions and tendencies of their practical implementation targeted at device documentation, processing and interpretation of results of immunochromatography analysis. The optical systems of registration in visible area of spectrum dominating in assortment of modern detectors are presented. The new solutions oriented on working with fluorescent, magnetic and electroconductive markers are presented too. The perspectives of further development of this direction are characterized including application as detectors of domestic communication devices and formation of cloud data bases for storage and processing of information concerning results of examinations. PMID- 27506110 TI - [THE STANDARD VALUES OF SUB-POPULATIONS OF T-HELPERS OF DIFFERENT LEVEL OF DIFFERENTIATION IN PERIPHERAL BLOOD]. AB - The study was carried out to develop standard indicators of relative and absolute content of main populations of T-helpers in peripheral blood of conditionally healthy donors. The examination was implemented to sampling of 52 healthy individuals (29 males and 23 females) aged 18-65 years (median is 30 years). The multicolor cytofluorimetric analysis was applied using panel of following antibodies: CD45RA-FITC, CD62L-PE, CCR4-PerCP/Cy5.5; CCR6-PE/Cy7, CXCR3-APC, CD3 APC-AF750, CD4-Pacific Blue and CXCR5-Brilliant Violet 510TM. The T-helpers 1 were distributed in populations of cells with phenotypes CXCR5-CXCR3+CCR6-CCR4-, also containing Th9, and CXCR5-CXCR3+CCR6+CCR4- referred as Thl/Thl7. The Th2 were detected an the basis of availability of CCR4 at the absence of all other chemokin receptors. The Thi7, besides Thl/Thi7 mentioned above, were detected in composition of CXCR5-CXCR3-CCR6+CCR4- and CXCR5-CXCR3-CCR6+CCR4+. The last population also contained Th22. The follicular Th which expressed at their surface CXCR5, formed six cellular populations with following phenotypes: CXCR5+CXCR3-CCR6-CCR4- (Tfh/Tfh2), CXCR5+CXCR3-CCR6-CCR4+ (Tfh2), CXCR5+CXCR3 CCR6+CCR4- (Tfh17), CXCR5+CXCR3-CCR6+CCR4+ (Tfh17), CXCR5+CXCR3+CCR6-CCR4- (Tfh1) and CXCR5+CXCR3+CCR6+CCR4- (Tfh1/Tfh17). The relative and absolute content of T helpers of mentioned phenotypes was established both within the framework of total population CD3+CD4+ of lymphocytes and among "naive" T-helpers (CD45RA CD62L+), T-helpers of central (CD45RA-CD62L+) and effector (CD45RA- CD62L-) memory and also "terminal-differentiated" CD45RA-positive cells of effector memory with phenotype CD45RA+CD62L-. The study results can be applied as standard indicators under diagnostic of pathologic conditions of immune system. PMID- 27506111 TI - [THE DEVELOPMENT OF IMMUNE ENZYME AND IMMUNE CHROMATOGRAPHIC MONOCLONAL TEST SYSTEM FOR DETECTING TULAREMIA AGENT]. AB - The immune enzyme and immunochromatographic test-systems for detecting tularemia agent were developed on the basis of selected set of monoclonal antibodies having immunochemical activity to antigens Francisella tularensis. The evaluation of sensitivity and specificity of developed test-systems demonstrated that samples provided detection of strains of F. tularensis in concentration from 5.0 x 105 mkxcm-3 to 1.0 x 106 mkxcm-3 and gave no false positive results in analysis of heterologous microorganisms in concentration of 1.0 x 108 mkxcm-3. PMID- 27506112 TI - [FROM THEORY TO PRACTICE. THE ROLE OF QUALITY CONTROL OF ANALYTICAL STAGE OF STUDIES IN INCREASING CLINICAL INFORMATIVENESS OF LABORATORY TESTS]. AB - Nowadays, improving accuracy and clinical informativeness of results of studies is one of main directions of development of laboratory. The article presents originally developed algorithm of evaluation of quality of immunochemical studies in part related to analytical stage. The case of application in practice of the results of such evaluation is presented. PMID- 27506113 TI - The hubris hypothesis: The downside of comparative optimism displays. AB - According to the hubris hypothesis, observers respond more unfavorably to individuals who express their positive self-views comparatively than to those who express their positive self-views non-comparatively, because observers infer that the former hold a more disparaging view of others and particularly of observers. Two experiments extended the hubris hypothesis in the domain of optimism. Observers attributed less warmth (but not less competence) to, and showed less interest in affiliating with, an individual displaying comparative optimism (the belief that one's future will be better than others' future) than with an individual displaying absolute optimism (the belief that one's future will be good). Observers responded differently to individuals displaying comparative versus absolute optimism, because they inferred that the former held a gloomier view of the observers' future. Consistent with previous research, observers still attributed more positive traits to a comparative or absolute optimist than to a comparative or absolute pessimist. PMID- 27506114 TI - Structural Covariance Networks and Their Association with Age, Features of Cerebral Small-Vessel Disease, and Cognitive Functioning in Older Persons. AB - Recently, cerebral structural covariance networks (SCNs) have been shown to partially overlap with functional networks. However, although for some of these SCNs a strong association with age is reported, less is known about the association of individual SCNs with separate cognition domains and the potential mediation effect in this of cerebral small vessel disease (SVD). In 219 participants (aged 75-96 years) with mild cognitive deficits, 8 SCNs were defined based on structural covariance of gray matter intensity with independent component analysis on 3DT1-weighted magnetic resonance imaging (MRI). Features of SVD included volume of white matter hyperintensities (WMH), lacunar infarcts, and microbleeds. Associations with SCNs were examined with multiple linear regression analyses, adjusted for age and/or gender. In addition to higher age, which was associated with decreased expression of subcortical, premotor, temporal, and occipital-precuneus networks, the presence of SVD and especially higher WMH volume was associated with a decreased expression in the occipital, cerebellar, subcortical, and anterior cingulate network. The temporal network was associated with memory (p = 0.005), whereas the cerebellar-occipital and occipital-precuneus networks were associated with psychomotor speed (p = 0.002 and p < 0.001). Our data show that a decreased expression of specific networks, including the temporal and occipital lobe and cerebellum, was related to decreased cognitive functioning, independently of age and SVD. This indicates the potential of SCNs in substantiating cognitive functioning in older persons. PMID- 27506115 TI - Buccal mucosal irritation studies of sublingual apomorphine film (APL-130277) in Syrian golden hamsters. AB - AIM: Determine the potential for cheek pouch buccal mucosa irritation in hamsters following administration of apomorphine hydrochloride film (APL-130277). METHODS: Three studies were conducted with Syrian golden hamsters. (First study, four hamsters received APL-130277 three times a day [TID] for 7 days. Second study, four hamsters received APL-130277 once a day [QD] for days 1-3, twice a day [BID] for days 4-7 and TID for days 8-21. Third study, 32 hamsters received either a placebo strip or APL-130277-dosed TID for 28 days). For all the studies, the macroscopic appearance of the buccal cavities was evaluated throughout the study. In the third study, all animals were necropsied on day 29, and macroscopic and histopathological examinations were performed. RESULTS: In the first and second studies, the buccal mucosa of the cheek pouch did not show any signs of irritation. In the third study, administration of APL-130277-dosed TID for 28 consecutive days did not result in observable local irritation of the buccal mucosa. CONCLUSION: In all the studies, APL-130277 produced no irritation of the cheek pouch buccal mucosa. PMID- 27506117 TI - Editorial overview: Cancer immunology: genomics & biomarkers: Cancer immunity through the prism of genomics and proteomics. PMID- 27506116 TI - Nuclear receptor corepressors Ncor1 and Ncor2 (Smrt) are required for retinoic acid-dependent repression of Fgf8 during somitogenesis. AB - Retinoic acid (RA) repression of Fgf8 is required for many different aspects of organogenesis, however relatively little is known about how endogenous RA controls gene repression as opposed to gene activation. Here, we show that nuclear receptor corepressors NCOR1 and NCOR2 (SMRT) redundantly mediate the ability of RA to repress Fgf8. Ncor1;Ncor2 double mutants generated by CRISPR/Cas9 gene editing exhibited a small somite and distended heart phenotype similar to that of RA-deficient Raldh2-/- embryos, associated with increased Fgf8 expression and FGF signaling in caudal progenitors and heart progenitors. Embryo chromatin immunoprecipitation studies revealed that NCOR1/2 but not coactivators are recruited to the Fgf8 RA response element (RARE) in an RA-dependent manner, whereas coactivators but not NCOR1/2 are recruited RA-dependently to a RARE near Rarb that is activated by RA. CRISPR/Cas9-mediated genomic deletion of the Fgf8 RARE in mouse embryos often resulted in a small somite defect with Fgf8 derepression caudally, but no defect was observed in heart development or heart Fgf8 expression. This suggests the existence of another DNA element whose function overlaps with the Fgf8 RARE to mediate Fgf8 repression by RA and NCOR1/2. Our studies support a model in which NCOR1/2 mediates direct RA dependent repression of Fgf8 in caudal progenitors in order to control somitogenesis. PMID- 27506118 TI - Did Amendments to the Ontario Highway Traffic Act in 2009-2010 Affect the Proportion of Alcohol-Related Motor Vehicle Collisions Seen at a Level I Trauma Centre over a 10-year Period? AB - OBJECTIVES: To determine if changes to the Ontario Highway Traffic Act (OHTA) in 2009 and 2010 had an effect on the proportion of alcohol-related motor vehicle collisions (MVCs) presenting to a trauma centre over a 10-year period. METHODS: A retrospective review of the trauma registry at a Level I trauma centre in southwestern Ontario was undertaken. The trauma registry is a database of all trauma patients with an injury severity score (ISS) >=12 and/or who had trauma team activation. Descriptive statistics were calculated. Interrupted time series analyses with ARIMA modeling were performed on quarterly data from 2004-2013. RESULTS: A total of 377 drivers with a detectable serum ethanol concentration (SEC) were treated at our trauma centre over the 10-year period, representing 21% of all MVCs. The majority (330; 88%) were male. The median age was 31 years, median SEC was 35.3 mmol/L, and median ISS was 21. A total of 29 (7.7%) drinking drivers died from their injuries after arriving to hospital. There was no change in the proportion of drinking drivers after the 2009 amendment, but there was a significant decline in the average SEC of drinking drivers after changes to the law. There was no difference in the proportion of drinking drivers <=21 years after introduction of the 2010 amendment for young and novice drivers. CONCLUSIONS: There was a significance decline in the average SEC of all drinking drivers after the 2009 OHTA amendment, suggesting that legislative amendments may have an impact on drinking before driving behaviour. PMID- 27506119 TI - Toxicity study of food-grade carboxymethyl cellulose synthesized from maize husk in Swiss albino mice. AB - Food-grade carboxymethyl cellulose was prepared from maize husk agro-waste and was evaluated sub-chronic oral toxicity in Swiss albino mice. 40 male mice were divided into 4 groups and fed diets with 0 (control) - 10% CMC for a period of 3 months. Daily oral doses were 5 - 20mg/g body weight to the mice/day. Animal care and handling were conformed according to internationally accepted standard guidelines. Haematological and biochemical parameters were monitored during this period. At the end of the study, tissues and organs were studied for histopathological changes. Repeat-dose oral toxicity study was carried out according to OECD guideline 408. The result did not show any treatment related abnormalities in terms of haematological and biochemical parameters. However, water intake, urine production and urinary sodium excretion increased with increasing doses of CMC. The weekly body weight showed no significant differences between control and mice treated with different doses of CMC. In mice of the treated groups, no abnormalities in the histopathology of liver, heart, lung and kidney were detected. This indicated the prepared CMC has no toxic effect at different doses on cellular structure, and support the safety use of CMC as food additives and an excipient for pharmaceuticals. PMID- 27506120 TI - Design and development of Albizia stipulata gum based controlled-release matrix tablets in cancer therapeutics. AB - The present study deals with the development of natural macromolecule gum Albizia stipulata (AS) based novel pharmaceutical excipient for the controlled-release of paracetamol (PC). Central composite design (CCD) two-factor, five-level was used for the optimization of independent variables AS gum and compression force (CF) based on desired response variable drug release (DR) of paracetamol matrix tablets (PCMT). The optimized PCMT was prepared by wet granulation method and screened for pre- and post- compression parameters, and were characterized. The optimized PCMT (F14) formulation showed favorable in vitro release of PC (65%) in 12h, and the release kinetics followed zero order anomalous diffusion mechanism. AS gum exerted significant (p<0.001) anticancer activity with 98.25% inhibition at 2000MUg/mL (IC50=179.12MUg/mL) against A549 cell line. PC and PCMT showed 78.56% inhibition (IC50 value=856.58MUg/mL) and 93.68% inhibition (IC50 value=396.35MUg/mL) respectively, symbolizing that the gum remarkably potentiated the anticancer effect of PC in formulation after 24h treatment by inducing apoptosis. This is the first report on A. stipulata gum as a promising biopolymer for drug delivery application in cancer therapeutics. PMID- 27506121 TI - Radiation formation of functionalized polysaccharide-protein based skin mimicking semi- inter penetrating network for biomedical application. AB - Radiation treatment of chitosan, gelatin, polyvinyl alcohol (PVA) and polyacrylamide [poly(AAm)] will form the sterile hydrogel wound dressings which can mimic the artificial skin function in wound therapy. These polymers have been characterized by cryo-scanning electron micrographs (cryo-SEMs), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR) and 13C solid state nuclear magnetic resonance (NMR) spectroscopy and swelling studies. Some important properties of hydrogel wound dressings like drug delivery, blood compatibility, wound fluid absorption, antioxidant activity, oxygen permeability, water vapour permeability, microbial penetration, mucoadhesion and mechanical properties have also been determined. The release profile of moxifloxacin from the polyacrylamide functionalized chitosan-gelatin matrix followed Fickian diffusion mechanism and release profile best fitted in Korsmeyer-Peppas kinetic model. The hydrogel films are permeable to O2 and H2O vapour and impermeable to microbes in open environment and showed high wound absorption, good mucoadhesion and antioxidant activity. Beside release of antibiotic, the inherent wound healing potential of chitosan, adhesion capacity of gelatin, film forming ability of PVA and wound fluid absorption of poly(AAm), may enhance wound healing potential of these hydrogel wound dressings. PMID- 27506122 TI - Cold-adapted organic solvent tolerant alkalophilic family I.3 lipase from an Antarctic Pseudomonas. AB - Lipolytic enzymes with cold adaptation are gaining increasing interest due to their biotechnological prospective. Previously, a cold adapted family I.3 lipase (AMS8 lipase) was isolated from an Antarctic Pseudomonas. AMS8 lipase was largely expressed in insoluble form. The refolded His-tagged recombinant AMS8 lipase was purified with 23.0% total recovery and purification factor of 9.7. The purified AMS8 lipase migrated as a single band with a molecular weight approximately 65kDa via electrophoresis. AMS8 lipase was highly active at 30 degrees C at pH 10. The half-life of AMS8 lipase was reported at 4 and 2h under the incubation of 30 and 40 degrees C, respectively. The lipase was stable over a broad range of pH. It showed enhancement effect in its relative activity under the presence of Li+, Na+, K+, Rb+ and Cs+ after 30min treatment. Heavy metal ions such as Cu2+, Fe3+ and Zn2+ inhibited AMS8 activity. This cold adapted alkalophilic AMS lipase was also active in various organic solvent of different polarity. These unique properties of this biological macromolecule will provide considerable potential for many biotechnological applications and organic synthesis at low temperature. PMID- 27506123 TI - Resveratrol induces thermal stabilization of human serum albumin and modulates the early aggregation stage. AB - Several phenolic compounds bind to proteins and show the ability to interfere with their aggregation process. The impact of the natural polyphenol resveratrol on the stability and heat induced aggregation of human serum albumin (HSA) was investigated by differential scanning calorimetry (DSC), attenuated total reflectance Fourier transform infrared (ATR-FTIR), UV-vis absorbance, ThT fluorescence, atomic force microscopy (AFM) and molecular modeling. The binding of resveratrol to HSA improves the stability of the protein to thermal unfolding, particularly for the energetic domain containing the ligand binding site, as modeled by computational techniques. The thermal unfolding is irreversible and after the melting the protein aggregates, either with or without the ligand. The kinetics of HSA aggregation between 70 and 80 degrees C shows an exponential growth of the absorbance change and it slows down when resveratrol is added. The aggregates have fibril-like morphology and resveratrol attenuates the formation of beta-structured species. The overall results suggest that resveratrol stabilizes the protein structure and modulates the formation of fibrils along the initial stage of the HSA aggregation pathway. PMID- 27506124 TI - Enhanced removal of cationic dye by calcium alginate/organobentonite beads: Modeling, kinetics, equilibriums, thermodynamic and reusability studies. AB - In this study, acid-activated organobentonite (OAB), calcium alginate (A) and calcium alginate/acid-activated organobentonite composite beads (A-OAB) were prepared and applied for the removal of methylene blue from solutions in batch system. The zero point charge of pH (pHpzc), Scanning electron microscopy (SEM) and Fourier transformed infrared spectroscopy (FTIR) analysis were carried out. The effects of pH solution (2-11), temperature (15, 25, 35 and 45 degrees C), initial concentration (20-500mg/L), and contact time were investigated. The adsorption processes fitted well with the pseudo-second-order kinetic model and both models Langmuir and Chapman isotherms. Results showed that the maximum adsorption capacities of (OAB), (A) and (A-OAB) for the adsorption of MB were 263.80, 483.6 and 799.43mg/g at 25 degrees C, respectively. Thermodynamic studies showed spontaneous and endothermic nature of the overall adsorption process. Desorption tests showed that the removal efficiency of MB decreased from 95 to 89.7% after six regeneration cycles for (A-OAB). From this, (A-OAB) can be utilized as an economical adsorbent for the removal of basic dyes from the contaminated waste water. PMID- 27506125 TI - Attenuation of thrombosis and bacterial infection using dual function nitric oxide releasing central venous catheters in a 9day rabbit model. AB - Two major problems with implanted catheters are clotting and infection. Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion/activation and an antimicrobial agent, and NO-releasing polymers are expected to have similar properties. Here, NO-releasing central venous catheters (CVCs) are fabricated using Elast-eonTM E2As polymer with both diazeniumdiolated dibutylhexanediamine (DBHD/NONO) and poly(lactic-co-glycolic acid) (PLGA) additives, where the NO release can be modulated and optimized via the hydrolysis rate of the PLGA. It is observed that using a 10% w/w additive of a PLGA with ester end group provides the most controlled NO release from the CVCs over a 14d period. The optimized DBHD/NONO-based catheters are non-hemolytic (hemolytic index of 0%) and noncytotoxic (grade 0). After 9d of catheter implantation in the jugular veins of rabbits, the NO-releasing CVCs have a significantly reduced thrombus area (7 times smaller) and a 95% reduction in bacterial adhesion. These results show the promise of DBHD/NONO-based NO releasing materials as a solution to achieve extended NO release for longer term prevention of clotting and infection associated with intravascular catheters. STATEMENT OF SIGNIFICANCE: Clotting and infection are significant complications associated with central venous catheters (CVCs). While nitric oxide (NO) releasing materials have been shown to reduce platelet activation and bacterial infection in vitro and in short term animal models, longer-term success of NO-releasing materials to further study their clinical potential has not been extensively evaluated to date. In this study, we evaluate diazeniumdiolate based NO-releasing CVCs over a 9d period in a rabbit model. The explanted NO-releasing CVCs were found to have significantly reduced thrombus area and bacterial adhesion. These NO-releasing coatings can improve the hemocompatibility and bactericidal activity of intravascular catheters, as well as other medical devices (e.g., urinary catheters, vascular grafts). PMID- 27506126 TI - Macroporous biohybrid cryogels for co-housing pancreatic islets with mesenchymal stromal cells. AB - Intrahepatic transplantation of allogeneic pancreatic islets offers a promising therapy for type 1 diabetes. However, long-term insulin independency is often not achieved due to severe islet loss shortly after transplantation. To improve islet survival and function, extrahepatic biomaterial-assisted transplantation of pancreatic islets to alternative sites has been suggested. Herein, we present macroporous, star-shaped poly(ethylene glycol) (starPEG)-heparin cryogel scaffolds, covalently modified with adhesion peptides, for the housing of pancreatic islets in three-dimensional (3D) co-culture with adherent mesenchymal stromal cells (MSC) as accessory cells. The implantable biohybrid scaffolds provide efficient transport properties, mechanical protection, and a supportive extracellular environment as a desirable niche for the islets. MSC colonized the cryogel scaffolds and produced extracellular matrix proteins that are important components of the natural islet microenvironment known to facilitate matrix-cell interactions and to prevent cellular stress. Islets survived the seeding procedure into the cryogel scaffolds and secreted insulin after glucose stimulation in vitro. In a rodent model, intact islets and MSC could be visualized within the scaffolds seven days after subcutaneous transplantation. Overall, this demonstrates the potential of customized macroporous starPEG heparin cryogel scaffolds in combination with MSC to serve as a multifunctional islet supportive carrier for transplantation applications. STATEMENT OF SIGNIFICANCE: Diabetes results in the insufficient production of insulin by the pancreatic beta-cells in the islets of Langerhans. Transplantation of pancreatic islets offers valuable options for treating the disease; however, many transplanted islets often do not survive the transplantation or die shortly thereafter. Co-transplanted, supporting cells and biomaterials can be instrumental for improving islet survival, function and protection from the immune system. In the present study, islet supportive hydrogel sponges were explored for the co-transplantation of islets and mesenchymal stromal cells. Survival and continued function of the supported islets were demonstrated in vitro. The in vivo feasibility of the approach was shown by transplantation in a mouse model. PMID- 27506127 TI - Low, but not too low, oxygen tension and macromolecular crowding accelerate extracellular matrix deposition in human dermal fibroblast culture. AB - A key challenge of in vitro organogenesis is the development in timely manner tissue equivalents. Herein, we assessed the simultaneous effect of oxygen tension (0.5%, 2% and 20%), foetal bovine serum concentration (0.5% and 10%) and macromolecular crowding (75MUg/ml carrageenan) in human dermal fibroblast culture. Our data demonstrate that cells cultured at 2% oxygen tension, in the presence of carrageenan and at 0.5% serum concentration deposited within 3days in culture more extracellular matrix than cells grown for 14days, at 20% oxygen tension, 10% serum concentration and in the absence of carrageenan. These data suggest that optimal oxygen tension coupled with macromolecular crowding are important in vitro microenvironment modulators for accelerated development of tissue-like modules in vitro. STATEMENT OF SIGNIFICANCE: To enable clinical translation and commercialisation of in vitro organogenesis therapies, we cultured human dermal fibroblast at 2% oxygen tension, under macromolecular crowding conditions (75MUg/ml carrageenan) and at low foetal bovine serum concentration (0.5%). Within 3days in culture, more extracellular matrix was deposited under these conditions than cells grown for 14days, at 20% oxygen tension, 10% FBS concentration and in the absence of crowding agents. These data bring us closer to the development of more clinically relevant tissue-like modules. PMID- 27506128 TI - On the early diagnosis of Alzheimer's Disease from multimodal signals: A survey. AB - INTRODUCTION: The number of Alzheimer's Disease (AD) patients is increasing with increased life expectancy and 115.4 million people are expected to be affected in 2050. Unfortunately, AD is commonly diagnosed too late, when irreversible damages have been caused in the patient. OBJECTIVE: An automatic, continuous and unobtrusive early AD detection method would be required to improve patients' life quality and avoid big healthcare costs. Thus, the objective of this survey is to review the multimodal signals that could be used in the development of such a system, emphasizing on the accuracy that they have shown up to date for AD detection. Some useful tools and specific issues towards this goal will also have to be reviewed. METHODS: An extensive literature review was performed following a specific search strategy, inclusion criteria, data extraction and quality assessment in the Inspec, Compendex and PubMed databases. RESULTS: This work reviews the extensive list of psychological, physiological, behavioural and cognitive measurements that could be used for AD detection. The most promising measurements seem to be magnetic resonance imaging (MRI) for AD vs control (CTL) discrimination with an 98.95% accuracy, while electroencephalogram (EEG) shows the best results for mild cognitive impairment (MCI) vs CTL (97.88%) and MCI vs AD distinction (94.05%). Available physiological and behavioural AD datasets are listed, as well as medical imaging analysis steps and neuroimaging processing toolboxes. Some issues such as "label noise" and multi-site data are discussed. CONCLUSIONS: The development of an unobtrusive and transparent AD detection system should be based on a multimodal system in order to take full advantage of all kinds of symptoms, detect even the smallest changes and combine them, so as to detect AD as early as possible. Such a multimodal system might probably be based on physiological monitoring of MRI or EEG, as well as behavioural measurements like the ones proposed along the article. The mentioned AD datasets and image processing toolboxes are available for their use towards this goal. Issues like "label noise" and multi-site neuroimaging incompatibilities may also have to be overcome, but methods for this purpose are already available. PMID- 27506129 TI - On the development of conjunctival hyperemia computer-assisted diagnosis tools: Influence of feature selection and class imbalance in automatic gradings. AB - OBJECTIVE: The sudden increase of blood flow in the bulbar conjunctiva, known as hyperemia, is associated to a red hue of variable intensity. Experts measure hyperemia using levels in a grading scale, a procedure that is subjective, non repeatable and time consuming, thus creating a need for its automatisation. However, the task is far from straightforward due to data issues such as class imbalance or correlated features. In this paper, we study the specific features of hyperemia and propose various approaches to address these problems in the context of an automatic framework for hyperemia grading. METHODOLOGY: Oversampling, undersampling and SMOTE approaches were applied in order to tackle the problem of class imbalance. 25 features were computed for each image and regression methods were then used to transform them into a value on the grading scale. The values and relationships among features and experts' values were analysed, and five feature selection techniques were subsequently studied. RESULTS: The lowest mean square error (MSE) for the regression systems trained with individual features is below 0.1 for both scales. Multi-layer perceptron (MLP) obtains the best values, but is less consistent than the random forest (RF) method. When all features are combined, the best results for both scales are achieved with MLP. Correlation based feature selection (CFS) and M5 provide the best results, MSE=0.108 and MSE=0.061 respectively. Finally, the class imbalance problem is minimised with the SMOTE approach for both scales (MSE<0.006). CONCLUSIONS: Machine learning methods are able to perform an objective assessment of hyperemia grading, removing both intra- and inter-expert subjectivity while providing a gain in computation time. SMOTE and oversampling approaches minimise the class imbalance problem, while feature selection reduces the number of features from 25 to 3-5 without worsening the MSE. As the differences between the system and a human expert are similar to the differences between experts, we can therefore conclude that the system behaves like an expert. PMID- 27506130 TI - Detecting signals of detrimental prescribing cascades from social media. AB - MOTIVATION: Prescribing cascade (PC) occurs when an adverse drug reaction (ADR) is misinterpreted as a new medical condition, leading to further prescriptions for treatment. Additional prescriptions, however, may worsen the existing condition or introduce additional adverse effects (AEs). Timely detection and prevention of detrimental PCs is essential as drug AEs are among the leading causes of hospitalization and deaths. Identifying detrimental PCs would enable warnings and contraindications to be disseminated and assist the detection of unknown drug AEs. Nonetheless, the detection is difficult and has been limited to case reports or case assessment using administrative health claims data. Social media is a promising source for detecting signals of detrimental PCs due to the public availability of many discussions regarding treatments and drug AEs. OBJECTIVE: In this paper, we investigate the feasibility of detecting detrimental PCs from social media. METHODS: The detection, however, is challenging due to the data uncertainty and data rarity in social media. We propose a framework to mine sequences of drugs and AEs that signal detrimental PCs, taking into account the data uncertainty and data rarity. RESULTS: We conduct experiments on two real world datasets collected from Twitter and Patient health forum. Our framework achieves encouraging results in the validation against known detrimental PCs (F1=78% for Twitter and 68% for Patient) and the detection of unknown potential detrimental PCs (Precision@50=72% and NDCG@50=95% for Twitter, Precision@50=86% and NDCG@50=98% for Patient). In addition, the framework is efficient and scalable to large datasets. CONCLUSION: Our study demonstrates the feasibility of generating hypotheses of detrimental PCs from social media to reduce pharmacists' guesswork. PMID- 27506132 TI - Predicting overlapping protein complexes from weighted protein interaction graphs by gradually expanding dense neighborhoods. AB - OBJECTIVE: Proteins are vital biological molecules driving many fundamental cellular processes. They rarely act alone, but form interacting groups called protein complexes. The study of protein complexes is a key goal in systems biology. Recently, large protein-protein interaction (PPI) datasets have been published and a plethora of computational methods that provide new ideas for the prediction of protein complexes have been implemented. However, most of the methods suffer from two major limitations: First, they do not account for proteins participating in multiple functions and second, they are unable to handle weighted PPI graphs. Moreover, the problem remains open as existing algorithms and tools are insufficient in terms of predictive metrics. METHOD: In the present paper, we propose gradually expanding neighborhoods with adjustment (GENA), a new algorithm that gradually expands neighborhoods in a graph starting from highly informative "seed" nodes. GENA considers proteins as multifunctional molecules allowing them to participate in more than one protein complex. In addition, GENA accepts weighted PPI graphs by using a weighted evaluation function for each cluster. RESULTS: In experiments with datasets from Saccharomyces cerevisiae and human, GENA outperformed Markov clustering, restricted neighborhood search and clustering with overlapping neighborhood expansion, three state-of-the-art methods for computationally predicting protein complexes. Seven PPI networks and seven evaluation datasets were used in total. GENA outperformed existing methods in 16 out of 18 experiments achieving an average improvement of 5.5% when the maximum matching ratio metric was used. Our method was able to discover functionally homogeneous protein clusters and uncover important network modules in a Parkinson expression dataset. When used on the human networks, around 47% of the detected clusters were enriched in gene ontology (GO) terms with depth higher than five in the GO hierarchy. CONCLUSIONS: In the present manuscript, we introduce a new method for the computational prediction of protein complexes by making the realistic assumption that proteins participate in multiple protein complexes and cellular functions. Our method can detect accurate and functionally homogeneous clusters. PMID- 27506131 TI - Clinical phenotyping in selected national networks: demonstrating the need for high-throughput, portable, and computational methods. AB - OBJECTIVE: The combination of phenomic data from electronic health records (EHR) and clinical data repositories with dense biological data has enabled genomic and pharmacogenomic discovery, a first step toward precision medicine. Computational methods for the identification of clinical phenotypes from EHR data will advance our understanding of disease risk and drug response, and support the practice of precision medicine on a national scale. METHODS: Based on our experience within three national research networks, we summarize the broad approaches to clinical phenotyping and highlight the important role of these networks in the progression of high-throughput phenotyping and precision medicine. We provide supporting literature in the form of a non-systematic review. RESULTS: The practice of clinical phenotyping is evolving to meet the growing demand for scalable, portable, and data driven methods and tools. The resources required for traditional phenotyping algorithms from expert defined rules are significant. In contrast, machine learning approaches that rely on data patterns will require fewer clinical domain experts and resources. CONCLUSIONS: Machine learning approaches that generate phenotype definitions from patient features and clinical profiles will result in truly computational phenotypes, derived from data rather than experts. Research networks and phenotype developers should cooperate to develop methods, collaboration platforms, and data standards that will enable computational phenotyping and truly modernize biomedical research and precision medicine. PMID- 27506133 TI - Medicines optimisation in older people: Taking age and sex into account. AB - There are a number of complex and seemingly ignored issues around prescribing safely and effectively for older people, particularly for very old women. These issues include polypharmacy, possible compliance issues and communication barriers between patient, specialists and general practitioners (GPs). There are specific pharmacokinetic (PK) and pharmacodynamic (PD) parameters that change in older age generally, and in women more specifically, which if ignored are likely to cause symptoms and to impair quality of life when drug dosage is unchanged. These changed PK and PD parameters are not all-or-nothing processes, but a continuum across age, sex and comorbidity. Very old people also have less 'reserve' when drugs are used in 'standard' doses, are more likely to have multiple concurrent therapies, and the risk of adverse effects of drugs in this group is very high. Doctors need to consider these issues when providing therapy for this group, or when trying to unravel the complex prescribing cascade here. This review outlines general principles to consider when prescribing for older people, focusing on age- and sex-related changes in both PK and PD processes. PMID- 27506134 TI - On the permanence of tooth bleaching. AB - OBJECTIVE: Bleaching (alias whitening) is increasingly the chosen means of modifying the appearance of teeth for cosmetic reasons. Behbehani et al. (2012) acquired the largest known data set for the effects of bleaching over time (300 patients for ~1year), but the analysis then was rather superficial and did not exploit the full depth of information available in it. METHODS: Data collected by Behbehani et al. (2012) were re-analysed to explore in detail the variation in outcome between patients and over time. RESULTS: There is a distinct regression in shade scale value with time, taking something over 1year to approach stability. There appears to be an intrinsic shade that cannot be altered, at around 1 unit (0.5M1 on the Vita 3D bleached shade guide). Some patients (11/300 at 1year) appear to be worse-off after treatment, especially those with lighter starting shades, while many get no real benefit, with a change <=2 units. SIGNIFICANCE: The effects of bleaching are often transient, but the reversion to a darker shade than the original may be due to the cumulative damage done to the organic matrix of enamel. The ethics of the treatment are questioned, as are over the-counter products and whitening toothpastes. It might be appropriate to suggest to a patient that there is no point unless the shade is darker than some (Vita) shade value, say ~1M2, but in any case informed consent is in need of improvement. All observations of the effects of bleaching ought to be made on timescales longer than 1year to be meaningful. PMID- 27506135 TI - Protein expression of preferred human codon-optimized Gaussia luciferase genes with an artificial open-reading frame in mammalian and bacterial cells. AB - The protein expressions of three preferred human codon-optimized Gaussia luciferase genes (pGLuc, EpGLuc, and KpGLuc) were characterized in mammalian and bacterial cells by comparing them with those of wild-type Gaussia luciferase gene (wGLuc) and human codon-optimized Gaussia luciferase gene (hGLuc). Two synthetic genes of EpGLuc and KpGLuc containing the complete preferred human codons have an artificial open-reading frame; however, they had the similar protein expression levels to those of pGLuc and hGLuc in mammalian cells. In bacterial cells, the protein expressions of pGLuc, EpGLuc, and KpGLuc with approximately 65% GC content were the same and showed approximately 60% activities of wGLuc and hGLuc. The artificial open-reading frame in EpGLuc and KpGLuc did not affect the protein expression in mammalian and bacterial cells. PMID- 27506136 TI - Traffic safety in China: Challenges and countermeasures. PMID- 27506137 TI - Half molecular exchange of IgGs in the blood of healthy humans: chimeric lambda kappa-immunoglobulins containing HL fragments of antibodies of different subclasses (IgG1-IgG4). AB - In the classic paradigm, immunoglobulins represent products of clonal B cell populations, each producing antibodies recognizing a single antigen (monospecific). There is a common belief that IgGs in mammalian biological fluids are monospecific molecules having stable structures and two identical antigen binding sites. But the issue concerning the possibility of exchange by HL fragments between the antibody molecules in human blood is still unexplored. Different physico-chemical and immunological methods for analysis of half molecule exchange between human blood IgGs were used. Using eighteen blood samples of healthy humans we have shown unexpected results for the first time: blood antibodies undergo extensive post-transcriptional half-molecule exchange and IgG pools on average consist of 62.4 +/- 6.5% IgGs containing kappa light chains (kappa-kappa-IgGs), 29.8.6 +/- 5.4% lambda light chains (lambda-lambda IgGs), and 8.8 +/- 2.7% (range 2.6-16.8%) IgGs containing both kappa- and lambda light chains. Kappa-kappa-IgGs and lambda-lambda-IgGs contained on average (%): IgG1 (36.0 and 32.3), IgG2 (50.9 and 51.4), IgG3 (9.7 and 9.9), and IgG4 (6.5 and 5.7), while chimeric kappa-lambda-IgGs consisted of (%): 25.5 +/- 4.2 IgG1, 50.8 +/- 3.9 IgG2, 9.1 +/- 2.1 IgG3, and 14.5 +/- 2.2 IgG4. Our unexpected data are indicative of the possibility of half-molecule exchange between blood IgGs of various subclasses, raised against different antigens. The existence of blood chimeric bifunctional IgGs with different binding sites destroys the classic paradigm. Due to the phenomenon of polyspecificity and cross-reactivity of bifunctional IgGs containing HL-fragments of different types to different antigens, such IgGs may be important in human blood for widening their different biological functions. PMID- 27506138 TI - Evaluation of serum levels of IL-9 and IL-17 in human Schistosoma mansoni infection and their relationship with periportal fibrosis. AB - Serum levels of IL-9 and IL-17 cytokines were evaluated in patients in the acute, chronic phases and clinical forms of human schistosomiasis and in different classifications of periportal fibrosis. No significant differences between the groups of the disease with serum levels of cytokine were found. However, this study discusses the results of some cytokines that have not fully defined roles in the pathology of human schistosomiasis. Furthermore, an examination was made of subjects in the acute phase. This is an important group that is difficult to identify in areas where the disease is endemic. More studies are being undertaken to study the role of IL-9 and IL-17 in human Schistosoma mansoni infection and their relationship with the immunopathogenesis of disease. PMID- 27506139 TI - Plasma enhanced vortex fluidic device manipulation of graphene oxide. AB - A vortex fluid device (VFD) with non-thermal plasma liquid processing within dynamic thin films has been developed. This plasma-liquid microfluidic platform facilitates chemical processing which is demonstrated through the manipulation of the morphology and chemical character of colloidal graphene oxide in water. PMID- 27506140 TI - Alternative to Ph. Eur. pour-plate method for detection of microbial contamination in non-sterile pharmaceutical preparations. AB - The current European Pharmacopoeia (Ph. Eur.) texts for Interferon (IFN)-alfa-2 include a nonspecific photometric protein assay using albumin as calibrator and a highly variable cell-based assay for the potency determination of the protective effects. A request was expressed by the Official Medicines Control Laboratories (OMCLs) for improved methods for the batch control of recombinant interferon alfa 2 bulk and market surveillance testing of finished products, including those formulated with Human Serum Albumin (HSA). A HPLC method was developed at the Medical Products Agency (MPA, Sweden) for the testing of IFN-alfa-2 products. An initial collaborative study run under the Biological Standardisation Programme (BSP; study code BSP039) revealed the need for minor changes to improve linearity of the calibration curves, assay reproducibility and robustness. The goal of the collaborative study, coded BSP071, was to transfer and further validate this improved HPLC method. Ten laboratories participated in the study. Four marketed IFN-alfa-2 preparations (one containing HSA) together with the Ph. Eur. Chemical Reference Substance (CRS) for IFN-alfa-2a and IFN-alfa-2b, and in-house reference standards from two manufacturers were used for the quantitative assay. The modified method was successfully transferred to all laboratories despite local variation in equipment. The resolution between the main and the oxidised forms of IFN-alfa-2 was improved compared to the results from the BSP039 study. The improved method even allowed partial resolution of an extra peak after the principal peak. Symmetry of the main IFN peak was acceptable for all samples in all laboratories. Calibration curves established with the Ph. Eur. IFN-alfa-2a and IFN-alfa-2b CRSs showed excellent linearity with intercepts close to the origin and coefficients of determination greater than 0.9995. Assay repeatability, intermediate precision and reproducibility varied with the tested sample within acceptable ranges. Test accuracy estimated by comparing the values obtained by the participants to the declared contents determined by the manufacturers was good despite the absence of a common reference preparation. In conclusion, the present study showed that the new method is suitable, reproducible and transferable. Proposals for the revision of Ph. Eur. texts are presented. PMID- 27506141 TI - Characterization of gray matter atrophy following 6-hydroxydopamine lesion of the nigrostriatal system. AB - BACKGROUND: The unilaterally-lesioned 6-hydroxydopamine (6-OHDA) rat is one of the most commonly used experimental models of Parkinson's disease (PD). Here we investigated whether magnetic resonance imaging (MRI) that is widely used in human PD research, has the potential to non-invasively detect macroscopic structural brain changes in the 6-OHDA rat in ways translatable to humans. METHODS: We measured the gray matter (GM) composition in the unilateral 6-OHDA rat in comparison to sham animals using whole-brain voxel-based morphometry (VBM) - an unbiased MR image analysis technique. The number of nigral dopamine (DA) neurons and the density of their cortical projections were examined post-mortem using immunohistochemistry. RESULTS: VBM revealed widespread bilateral changes in gray matter volume (GMV) on a topographic scale in the brains of 6-OHDA rats, compared to sham-operated rats. The greatest changes were in the lesioned hemisphere, which displayed reductions of GMV in motor, cingulate and somatosensory cortex. Histopathological results revealed dopaminergic cell loss in the substantia nigra (SN) and a denervation in the striatum, as well as in the frontal, somatosensory and cingulate cortices. CONCLUSION: Unilateral nigrostriatal 6-OHDA lesioning leads to widespread GMV changes, which extend beyond the nigrostriatal system and resemble advanced Parkinsonism. This study highlights the potential of structural MRI, and VBM in particular, for the system level phenotyping of rodent models of Parkinsonism and provides a methodological framework for future studies in novel rodent models as they become available to the research community. PMID- 27506142 TI - Building brains in a dish: Prospects for growing cerebral organoids from stem cells. AB - The recent development of organoid techniques, in which embryonic brain-like tissue can be grown from human or mouse stem cells in vitro offers the potential to transform the way in which brain development is studied. In this review, we summarize key aspects of the embryonic development of mammalian forebrains, focussing in particular on the cerebral cortex and highlight significant differences between mouse and primates, including human. We discuss recent work using cerebral organoids that has revealed key similarities and differences between their development and that of the brain in vivo. Finally, we outline the ways in which cerebral organoids can be used in combination with CRISPR/Cas9 genome editing to unravel genetic mechanisms that control embryonic development of the cerebral cortex, how this can help us understand the causes of neurodevelopmental disorders and some of the key challenges which will have to be resolved before organoids can become a mainstream tool to study brain development. PMID- 27506143 TI - Rapid CO breath test screening of drugs for protective effects on ribavirin induced hemolysis in a rabbit model: a pilot study. AB - Hemolytic anemia is a major side effect of ribavirin antiviral treatment for chronic hepatitis C. Ribavirin dose reduction may compromise the antiviral response and erythropoietin can take several weeks to alleviate anemia. The purpose of the present study was to screen potentially protective drugs against ribavirin-induced hemolytic anemia in a rabbit model, using our modified CO breath test for measuring erythrocyte (RBC) lifespan, the gold standard diagnostic index of hemolysis. Fifteen rabbits were divided randomly into five groups (N = 3/group): one vehicle control group, one ribavirin (only)-treated (RBV) group, and three groups initially treated with ribavirin only, followed by a combination of ribavirin with prednisone (RBV + Pred), polyene phosphatidyl choline (RBV + PPC), or reduced glutathione (RBV + GSH). RBC lifespan was calculated from accumulated CO measured in a closed rebreath apparatus, blood volume measured by the Evan's blue dye (EBD) dilution test, and hemoglobin concentration data. The RBC lifespan was normal in the vehicle control group (44 60 d), but reduced significantly in all of the ribavirin-treated groups before the addition of screened drugs (17-35 d). RBC lifespan rebounded significantly with the addition of glutathione, but not with the addition of prednisone or polyene phosphatidyl choline. A similar overall drug effect pattern was seen in the hemoglobin concentration and reticulocyte count data. In conclusion, the results of this pilot study indicate that reduced glutathione can attenuate ribavirin-induced hemolytic anemia, and that the RBC lifespan measured with our modified rapid CO breath test is feasible and reliable for use in animal studies. PMID- 27506144 TI - Validating the extract, transform, load process used to populate a large clinical research database. AB - BACKGROUND: Informaticians at any institution that are developing clinical research support infrastructure are tasked with populating research databases with data extracted and transformed from their institution's operational databases, such as electronic health records (EHRs). These data must be properly extracted from these source systems, transformed into a standard data structure, and then loaded into the data warehouse while maintaining the integrity of these data. We validated the correctness of the extract, load, and transform (ETL) process of the extracted data of West Virginia Clinical and Translational Science Institute's Integrated Data Repository, a clinical data warehouse that includes data extracted from two EHR systems. METHODS: Four hundred ninety-eight observations were randomly selected from the integrated data repository and compared with the two source EHR systems. RESULTS: Of the 498 observations, there were 479 concordant and 19 discordant observations. The discordant observations fell into three general categories: a) design decision differences between the IDR and source EHRs, b) timing differences, and c) user interface settings. After resolving apparent discordances, our integrated data repository was found to be 100% accurate relative to its source EHR systems. CONCLUSION: Any institution that uses a clinical data warehouse that is developed based on extraction processes from operational databases, such as EHRs, employs some form of an ETL process. As secondary use of EHR data begins to transform the research landscape, the importance of the basic validation of the extracted EHR data cannot be underestimated and should start with the validation of the extraction process itself. PMID- 27506145 TI - Epigenetic regulation of redox state mediates persistent cardiorespiratory abnormalities after long-term intermittent hypoxia. AB - KEY POINTS: The effects of short-term (ST; 10 days) and long-term (LT; 30 days) intermittent hypoxia (IH) on blood pressure (BP), breathing and carotid body (CB) chemosensory reflex were examined in adult rats. ST- and LT-IH treated rats exhibited hypertension, irregular breathing with apnoea and augmented the CB chemosensory reflex, with all these responses becoming normalized during recovery from ST- but not from LT-IH. The persistent cardiorespiratory responses to LT-IH were associated with elevated reactive oxygen species (ROS) levels in the CB and adrenal medulla, which were a result of DNA methylation-dependent suppression of genes encoding anti-oxidant enzymes (AOEs). Treating rats with decitabine either during LT-IH or during recovery from LT-IH prevented DNA methylation of AOE genes, normalized the expression of AOE genes and ROS levels, reversed the heightened CB chemosensory reflex and hypertension, and also stabilized breathing. ABSTRACT: Rodents exposed to chronic intermittent hypoxia (IH), simulating blood O2 saturation profiles during obstructive sleep apnoea (OSA), have been shown to exhibit a heightened carotid body (CB) chemosensory reflex and hypertension. CB chemosensory reflex activation also results in unstable breathing with apnoeas. However, the effect of chronic IH on breathing is not known. In the present study, we examined the effects of chronic IH on breathing along with blood pressure (BP) and assessed whether the autonomic responses are normalized after recovery from chronic IH. Studies were performed on adult, male, Sprague-Dawley rats exposed to either short-term (ST; 10 days) or long-term (LT, 30 days) IH. Rats exposed to either ST- or LT-IH exhibited hypertension, irregular breathing with apnoeas, an augmented CB chemosensory reflex as indicated by elevated CB neural activity and plasma catecholamine levels, and elevated reactive oxygen species (ROS) levels in the CB and adrenal medulla (AM). All these effects were normalized after recovery from ST-IH but not from LT-IH. Analysis of the molecular mechanisms underlying the persistent effects of LT-IH revealed increased DNA methylation of genes encoding anti-oxidant enzymes (AOEs). Treatment with decitabine, a DNA methylation inhibitor, either during LT-IH or during recovery from LT-IH, prevented DNA methylation, normalized the expression of AOE genes, ROS levels, CB chemosensory reflex and BP, and also stabilized breathing. These results suggest that persistent cardiorespiratory abnormalities caused by LT-IH are mediated by epigenetic re-programming of the redox state in the CB chemosensory reflex pathway. PMID- 27506147 TI - Metallic-like bonding in plasma-born silicon nanocrystals for nanoscale bandgap engineering. AB - Based on ab initio molecular dynamics simulations, we show that small nanoclusters of about 1 nm size spontaneously generated in a low-temperature silane plasma do not possess tetrahedral structures, but are ultrastable. Apparently small differences in the cluster structure result in substantial modifications in their electric, magnetic, and optical properties, without the need for any dopants. Their non-tetrahedral geometries notably lead to electron deficient bonds that introduce efficient electron delocalization that strongly resembles the one of a homogeneous electron gas leading to metallic-like bonding within a semiconductor nanocrystal. As a result, pure hydrogenated silicon clusters that form by self-assembly in a plasma reactor possess optical gaps covering most of the solar spectrum from 1.0 eV to 5.2 eV depending simply on their structure and, in turn, on their degree of electron delocalization. This feature makes them ideal candidates for future bandgap engineering not only for photovoltaics, but also for many nano-electronic devices employing nothing else but silicon and hydrogen atoms. PMID- 27506146 TI - CCBE1 promotes GIST development through enhancing angiogenesis and mediating resistance to imatinib. AB - Gastrointestinal stromal tumor (GIST) is the most major mesenchymal neoplasm of the digestive tract. Up to now, imatinib mesylate has been used as a standard first-line treatment for irresectable and metastasized GIST patients or adjuvant treatment for advanced GIST patients who received surgical resection. However, secondary resistance to imatinib usually happens, resulting in a major obstacle in GIST successful therapy. In this study, we first found that collagen and calcium binding EGF domains 1 (CCBE1) expression gradually elevated along with the risk degree of NIH classification, and poor prognosis emerged in the CCBE1 positive patients. In vitro experiments showed that recombinant CCBE1 protein can enhance angiogenesis and neutralize partial effect of imatinib on the GIST-T1 cells. In conclusion, these data indicated that CCBE1 may be served as a new predictor of prognosis in post-operative GIST patients and may play an important role in stimulating GIST progression. PMID- 27506148 TI - Incorporating Novel Mobile Health Technologies Into Management of Knee Osteoarthritis in Patients Treated With Intra-Articular Hyaluronic Acid: Rationale and Protocol of a Randomized Controlled Trial. AB - BACKGROUND: Osteoarthritis (OA) of the knee is one of the leading causes of disability in the United States. One relatively new strategy that could be helpful in the management of OA is the use of mHealth technologies, as they can be used to increase physical activity and promote exercise, which are key components of knee OA management. OBJECTIVE: Currently, no published data on the use of a mHealth approach to comprehensively monitor physical activity in patients with OA are available, and similarly, no data on whether mHealth technologies can impact outcomes are available. Our objective is to evaluate the effectiveness of mHealth technology as part of a tailored, comprehensive management strategy for patients with knee OA. METHODS: The study will assess the impact of a smartphone app that integrates data from a wearable activity monitor (thereby both encouraging changes in mobility as well as tracking them) combined with education about the benefits of walking on patient mobility. The results from the intervention group will be compared with data from a control group of individuals who are given the same Arthritis Foundation literature regarding the benefits of walking and wearable activity monitors but who do not have access to the data from those monitors. Activity monitors will capture step count estimates and will compare those with patients' step goals, calories burned, and distance walked. Patients using the novel smartphone app will be able to enter information on their daily pain, mood, and sleep quality. The relationships among activity and pain, activity and mood, and sleep will be assessed, as will patient satisfaction with and adherence to the mobile app. RESULTS: We present information on an upcoming trial that will prospectively assess the ability of a mobile app to improve mobility for knee OA patients who are treated with intra articular hyaluronic acid. CONCLUSIONS: We anticipate the results of this study will support the concept that mHealth technologies provide continuous, real-time feedback to patients with OA on their overall level of activity for a more proactive, personalized approach to treatment that may help modify behavior and assist with self-management through treatment support in the form of motivational messages and reminders. PMID- 27506151 TI - Skin prick test and development of tolerance in egg allergy. PMID- 27506149 TI - Phytochrome B and REVEILLE1/2-mediated signalling controls seed dormancy and germination in Arabidopsis. AB - Seeds maintain a dormant state to withstand adverse conditions and germinate when conditions become favourable to give rise to a new generation of flowering plants. Seed dormancy and germination are tightly controlled by internal and external signals. Although phytochrome photoreceptors are proposed to regulate primary seed dormancy, the underlying molecular mechanism remains elusive. Here we show that the REVEILLE1 (RVE1) and RVE2 transcription factors promote primary seed dormancy and repress red/far-red-light-reversible germination downstream of phytochrome B (phyB) in Arabidopsis thaliana. RVE1 and RVE2 expression is downregulated after imbibition and by phyB. RVE1 directly binds to the promoter of GIBBERELLIN 3-OXIDASE 2, inhibits its transcription and thus suppresses the biosynthesis of bioactive gibberellins. In addition, DELAY OF GERMINATION 1 also acts downstream of phyB. This study identifies a signalling pathway that integrates environmental light input with internal factors to control both seed dormancy and germination. PMID- 27506150 TI - Amylose engineering: phosphorylase-catalyzed polymerization of functional saccharide primers for glycobiomaterials. AB - Interest in amylose and its hybrids has grown over many decades, and a great deal of work has been devoted to developing methods for designing functional amylose hybrids. In this context, phosphorylase-catalyzed polymerization shows considerable promise as a tool for preparing diverse amylose hybrids. Recently, advances have been made in the chemoenzymatic synthesis and characterization of amylose-block-polymers, amylose-graft-polymers, amylose-modified surfaces, hetero oligosaccharides, and cellodextrin hybrids. Many of these saccharides provide clear opportunities for advances in biomaterials because of their biocompatibility and biodegradability. Important developments in bioapplications of amylose hybrids have also been made, and such newly developed amylose hybrids will help promote the development of new generations of glyco materials. WIREs Nanomed Nanobiotechnol 2017, 9:e1423. doi: 10.1002/wnan.1423 For further resources related to this article, please visit the WIREs website. PMID- 27506152 TI - Optical characterization of Tm(3+) doped Bi2O3-GeO2-Ga2O3 glasses in absence and presence of BaF2. AB - In this paper, Two new Bi2O3-GeO2-Ga2O3 glasses (one presence of BaF2) doped with 1mol% Tm2O3 were prepared by melt-quenching technique. Differential thermal analysis (DTA), the absorption, Raman, IR spectra and fluorescence spectra were measured. The Judd-Ofelt intensity parameters, emission cross section, absorption cross section, and gain coefficient of Tm(3+) ions were comparatively investigated. After the BaF2 introduced, the glass showed a better thermal stability, lower phonon energy and weaker OH(-) absorption coefficient, meanwhile, a larger ~1.8 MUm emission cross section sigmaem (7.56 * 10(-21) cm(2)) and a longer fluorescence lifetime taumea (2.25 ms) corresponding to the Tm(3+): (4)F3 -> (3)H6 transition were obtained, which is due to the addition of fluoride in glass could reduce the quenching rate of hydroxyls and raise the cross-relaxation ((3)H6 + (3)H4 -> (3)F4 + (3)F4) rate. Our results suggest that the Tm(3+) doped Bi2O3-GeO2-Ga2O3 glass with BaF2 might be potential to the application in efficient ~1.8 MUm lasers system. PMID- 27506153 TI - Custom Map Projections for Regional Groundwater Models. AB - For regional groundwater flow models (areas greater than 100,000 km2 ), improper choice of map projection parameters can result in model error for boundary conditions dependent on area (recharge or evapotranspiration simulated by application of a rate using cell area from model discretization) and length (rivers simulated with head-dependent flux boundary). Smaller model areas can use local map coordinates, such as State Plane (United States) or Universal Transverse Mercator (correct zone) without introducing large errors. Map projections vary in order to preserve one or more of the following properties: area, shape, distance (length), or direction. Numerous map projections are developed for different purposes as all four properties cannot be preserved simultaneously. Preservation of area and length are most critical for groundwater models. The Albers equal-area conic projection with custom standard parallels, selected by dividing the length north to south by 6 and selecting standard parallels 1/6th above or below the southern and northern extent, preserves both area and length for continental areas in mid latitudes oriented east-west. Custom map projection parameters can also minimize area and length error in non-ideal projections. Additionally, one must also use consistent vertical and horizontal datums for all geographic data. The generalized polygon for the Floridan aquifer system study area (306,247.59 km2 ) is used to provide quantitative examples of the effect of map projections on length and area with different projections and parameter choices. Use of improper map projection is one model construction problem easily avoided. PMID- 27506154 TI - Mycotic Aneurysm of the Abdominal Aorta Complicated With Iliopsoas Abscess and Infectious Spondylodiscitis in a Long-Term Hemodialyzed Patient: A Rare but Serious Complication of Staphylococcus Aureus Bacteremia. PMID- 27506155 TI - Crude oil exposures reveal roles for intracellular calcium cycling in haddock craniofacial and cardiac development. AB - Recent studies have shown that crude oil exposure affects cardiac development in fish by disrupting excitation-contraction (EC) coupling. We previously found that eggs of Atlantic haddock (Melanogrammus aeglefinus) bind dispersed oil droplets, potentially leading to more profound toxic effects from uptake of polycyclic aromatic hydrocarbons (PAHs). Using lower concentrations of dispersed crude oil (0.7-7 MUg/L ?PAH), here we exposed a broader range of developmental stages over both short and prolonged durations. We quantified effects on cardiac function and morphogenesis, characterized novel craniofacial defects, and examined the expression of genes encoding potential targets underlying cardiac and craniofacial defects. Because of oil droplet binding, a 24-hr exposure was sufficient to create severe cardiac and craniofacial abnormalities. The specific nature of the craniofacial abnormalities suggests that crude oil may target common craniofacial and cardiac precursor cells either directly or indirectly by affecting ion channels and intracellular calcium in particular. Furthermore, down regulation of genes encoding specific components of the EC coupling machinery suggests that crude oil disrupts excitation-transcription coupling or normal feedback regulation of ion channels blocked by PAHs. These data support a unifying hypothesis whereby depletion of intracellular calcium pools by crude oil derived PAHs disrupts several pathways critical for organogenesis in fish. PMID- 27506156 TI - Variability in the number of abdominal leucokinergic neurons in adult Drosophila melanogaster. AB - Developmental plasticity allows individuals with the same genotype to show different phenotypes in response to environmental changes. An example of this is how neuronal diversity is protected at the expense of neuronal number under sustained undernourishment during the development of the Drosophila optic lobe. In the development of the Drosophila central nervous system, neuroblasts go through two phases of neurogenesis separated by a period of mitotic quiescence. Although during embryonic development much evidence indicates that both cell number and the cell fates generated by each neuroblast are very precisely controlled in a cell autonomous manner, after quiescence extrinsic factors control the reactivation of neuroblast proliferation in a fashion that has not yet been elucidated. Moreover, there is very little information about whether environmental changes affect lineage progression during postembryonic neurogenesis. Using as a model system the pattern of abdominal leucokinergic neurons (ABLKs), we have analyzed how changes in a set of environmental factors affect the number of ABLKs generated during postembryonic neurogenesis. We describe the variability in ABLK number between individuals and between hemiganglia of the same individual and, by genetic analysis, we identify the bithorax-complex genes and the ecdysone hormone as critical factors in these differences. We also explore the possible adaptive roles involved in this process. J. Comp. Neurol. 525:639-660, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27506157 TI - Immune tolerance in pediatric solid organ transplant through allogeneic hematopoietic stem cell transplant and a solid organ/liver transplant from the same donor. PMID- 27506158 TI - PGE2 /EP4 Signaling Controls the Transfer of the Mammary Stem Cell State by Lipid Rafts in Extracellular Vesicles. AB - Prostaglandin E2 (PGE2 )-initiated signaling contributes to stem cell homeostasis and regeneration. However, it is unclear how PGE2 signaling controls cell stemness. This study identifies a previously unknown mechanism by which PGE2 /prostaglandin E receptor 4 (EP4 ) signaling regulates multiple signaling pathways (e.g., PI3K/Akt signaling, TGFbeta signaling, Wnt signaling, EGFR signaling) which maintain the basal mammary stem cell phenotype. A shift of basal mammary epithelial stem cells (MaSCs) from a mesenchymal/stem cell state to a non basal-MaSC state occurs in response to prostaglandin E receptor 4 (EP4 ) antagonism. EP4 antagonists elicit release of signaling components, by controlling their trafficking into extracellular vesicles/exosomes in a lipid raft/caveolae-dependent manner. Consequently, EP4 antagonism indirectly inactivates, through induced extracellular vesicle/exosome release, pathways required for mammary epithelial stem cell homeostasis, e.g. canonical/noncanonical Wnt, TGFbeta and PI3K/Akt pathways. EP4 antagonism causes signaling receptors and signaling components to shift from non-lipid raft fractions to lipid raft fractions, and to then be released in EP4 antagonist induced extracellular vesicles/exosomes, resulting in the loss of the stem cell state by mammary epithelial stem cells. In contrast, luminal mammary epithelial cells can acquire basal stem cell properties following ingestion of EP4 antagonist-induced stem cell extracellular vesicles/exosomes, and can then form mammary glands. These findings demonstrate that PGE2 /EP4 signaling controls homeostasis of mammary epithelial stem cells through regulating extracellular vesicle/exosome release. Reprogramming of mammary epithelial cells can result from EP4 -mediated stem cell property transfer by extracellular vesicles/exosomes containing caveolae-associated proteins, between mammary basal and luminal epithelial cells. Stem Cells 2017;35:425-444. PMID- 27506159 TI - Voltage controlled core reversal of fixed magnetic skyrmions without a magnetic field. AB - Using micromagnetic simulations we demonstrate core reversal of a fixed magnetic skyrmion by modulating the perpendicular magnetic anisotropy of a nanomagnet with an electric field. We can switch reversibly between two skyrmion states and two ferromagnetic states, i.e. skyrmion states with the magnetization of the core pointing down/up and periphery pointing up/down, and ferromagnetic states with magnetization pointing up/down, by sequential increase and decrease of the perpendicular magnetic anisotropy. The switching between these states is explained by the fact that the spin texture corresponding to each of these stable states minimizes the sum of the magnetic anisotropy, demagnetization, Dzyaloshinskii-Moriya interaction (DMI) and exchange energies. This could lead to the possibility of energy efficient nanomagnetic memory and logic devices implemented with fixed skyrmions without using a magnetic field and without moving skyrmions with a current. PMID- 27506160 TI - Photolysis of a bola-type supra-amphiphile promoted by water-soluble pillar[5]arene-induced assembly. AB - A bola-type supra-amphiphile assembled from a water-soluble pillar[5]arene host (WP5) and a rod-coil guest molecule (G) containing a photoactive 9,10 dialkoxyanthracene group was successfully constructed, which could further assemble into a monolayer supramolecular vesicle. Interestingly, the photodecomposition rate of G was remarkably promoted after its aggregation with WP5, accompanied by the disassembly of the formed supramolecular vesicle, especially with the coassembly of a photosensitizer eosin Y, which has potential applications in phototherapy. PMID- 27506161 TI - Sauropsids Cornification is Based on Corneous Beta-Proteins, a Special Type of Keratin-Associated Corneous Proteins of the Epidermis. AB - The evolution of the process of cornification in amniote epidermis from the general process of keratinization present in simple epithelia of anamniotes took place through the evolution of specialized intermediate filament (alpha) keratins, keratin-associated proteins (KAPs) and corneous proteins (CPs). The scanty information on the three-dimensional conformation of known KAPs and CPs indicate these proteins contain alpha-helix, random coiled, or beta sheets with different lengths and organizations. CP genes originated in a chromosome locus indicated as epidermal differentiation complex (EDC), and transformed the epidermal keratinization of anamniotes into the cornified epidermis and skin appendages of amniotes (claws, beaks, and feathers). In particular, peculiar genes encoding for small proteins with a central region of 34 amino acids conformed as beta sheets were originated in the EDC of sauropsids (reptiles and birds). These proteins were traditionally indicated as beta-keratins because they form filaments of 3-4 nm in diameter and show an X-ray beta pattern. Different from other proteins of the EDC, dimers of these corneous beta-proteins associate into long polymers of filamentous proteins utilized in sauropsids skin appendages, such as scales and feathers. Future challenges in this area of research will be the study on gene regulation and expression for these proteins, their origin and evolution in different lineages of sauropsids, and their role in determining the material properties of sauropsid scales and other skin appendages. PMID- 27506162 TI - (1)H NMR spectroscopic elucidation in solution of the kinetics and thermodynamics of spin crossover for an exceptionally robust Fe(2+) complex. AB - A series of Fe(2+) spin crossover (SCO) complexes [Fe(5/6)](2+) employing hexadentate ligands (5/6) with cis/trans-1,2-diamino cyclohexanes (4) as central building blocks were synthesised. The ligands were obtained by reductive amination of 4 with 2,2'-bipyridyl-6-carbaldehyde or 1,10-phenanthroline-2 carbaldehyde 3. The chelating effect and the rigid structure of the ligands 5/6 lead to exceptionally robust Fe(2+) and Zn(2+) complexes conserving their structure even in coordinating solvents like dmso at high temperatures. Their solution behavior was investigated using variable temperature (VT) (1)H NMR spectroscopy and VT Vis spectroscopy. SCO behavior was found for all Fe(2+) complexes in this series centred around and far above room temperature. For the first time we have demonstrated that the thermodynamics as well as kinetics for SCO can be deduced by using VT (1)H NMR spectroscopy. An alternative scheme using a linear correction term C(1) to model chemical shifts for Fe(2+) SCO complexes is presented. The rate constant for the SCO of [Fe(rac-trans-5)](2+) obtained by VT (1)H NMR was validated by Laser Flash Photolysis (LFP), with excellent agreement (1/(kHL + kLH) = 33.7/35.8 ns for NMR/LFP). The solvent dependence of the transition temperature T1/2 and the solvatochromism of complex [Fe(rac-trans 5)](2+) were ascribed to hydrogen bond formation of the secondary amine to the solvent. Enantiomerically pure complexes can be prepared starting with R,R- or S,S-1,2-diaminocyclohexane (R,R-trans-4 or S,S-trans-4). The high robustness of the complexes reduces a possible ligand scrambling and allows preparation of quasiracemic crystals of [Zn(R,R-5)][Fe(S,S-5)](ClO4)4.(CH3CN) composed of a 1 : 1 mixture of the Zn and Fe complexes with inverse chirality. PMID- 27506163 TI - Interaction of Staphylococcus aureus persister cells with the host when in a persister state and following awakening. AB - Persister cells, a tolerant cell sub-population, are commonly associated with chronic and recurrent infections. However, little is known about their ability to actually initiate or establish an infection, become virulent and cause pathogenicity within a host. Here we investigated whether Staphylococcus aureus persister cells initiate an infection and are recognized by macrophages, while in a persister cell status, and upon awakening due to exposure to cis-2-decenoic acid (cis-DA). Our results show that S. aureus persister cells are not able to initiate infections in A. thaliana and present significantly reduced virulence towards C. elegans compared to total populations. In contrast, awakened S. aureus persister cells are able to initiate infections in A. thaliana and in C. elegans albeit, with lower mortality than total population. Furthermore, exposure of S. aureus persister cells to cis-DA led to a loss of tolerance to ciprofloxacin, and an increase of the bacterial fluorescence to levels found in total population. In addition, macrophage engulfment of persister cells was significantly lower than engulfment of total population, both before and following awakening. Overall our findings indicate that upon awakening of a persister population the cells regain their ability to infect hosts despite the absence of an increased immune response. PMID- 27506164 TI - Preliminary Data on a Care Coordination Program for Home Care Recipients. AB - Home care recipients are often hospitalized for potentially avoidable reasons. A pilot program (Intervention in Home Care to Improve Health Outcomes (In-Home)) was designed to help home care providers identify acute clinical changes in condition and then manage the condition in the home and thereby avoid a costly hospitalization. Caregivers answer simple questions about the care recipient's condition during a telephone-based "clock-out" at the end of each shift. Responses are electronically captured in the agency management software that caregivers use to "clock-in," manage care, and "clock-out" on every shift. These are transmitted to the agency's care manager, who follows up on the change in condition and escalates appropriately. A description of the In-Home model is presented, and pilot data from 22 home care offices are reported. In the pilot, caregivers reported a change in condition after 2% of all shifts, representing an average of 1.9 changes per care recipient in a 6-month period. Changes in behavior and skin condition were the most frequently recorded domains. Interviews with participating caregivers and care managers suggested positive attitudes regarding the intervention; challenges included resistance to change on the part of home care staff and difficulties in applying a uniform intervention to individuals with varying needs in home care offices with varying capacities. In an ongoing randomized trial, the success of the overall program will be measured primarily according to the potential reduction in avoidable hospitalizations of home care recipients and the effect this potential reduction has on spending and healthcare outcomes. PMID- 27506165 TI - Are oxidative stress markers associated with unexplained male infertility? AB - Male infertility can be responsible for up to 20% of the cases attending fertility consultation facilities; nonetheless, the underlying molecular mechanisms that could explain it are still elusive. Therefore, we aimed to evaluate conventional and functional parameters of semen samples from patients who presented with male infertility of unknown origin. Conventional semen parameters and functional parameters (i.e. intracellular reactive oxygen species production, mitochondrial membrane potential, sperm chromatin structure assay, sperm membrane lipid peroxidation and antioxidant capacity of seminal plasma) were evaluated on semen samples from 54 healthy donors, 23 patients with idiopathic infertility and 34 fertile controls. No significant differences were observed in the conventional seminal parameters between the fertile and infertile men. However, increased intracellular reactive oxygen species (ROS) production and DNA fragmentation were observed in the infertile patients compared to the fertile group. Alterations in intracellular ROS production and DNA fragmentation could be associated with male idiopathic infertility. These parameters could eventually distinguish both groups more accurately than the conventional parameters. Our current results are encouraging, and the efficacy of these parameters in the clinical settings needs to be further assessed to establish their predictive potential as a marker of unexplained male infertility. PMID- 27506166 TI - Renal Doppler Indices in Children with Nephrotic Syndrome: Findings from a Tertiary Hospital in Nigeria. AB - The resistive and pulsatility indices are known tools for assessing renal function in kidney diseases, especially in proteinuric conditions like Paediatric Nephrotic syndrome (NS) which is a glomerular disease. However, there is a limited knowledge in the use of Doppler Resistive and pulsatility indices in the management of this disease condition. This was a case control study involving 53 cases and 57 controls. The Doppler parameters, resistive index (RI) and pulsatility index (PI) of the renal interlobar arteries were determined for the upper, middle, and lower poles bilaterally for both controls and cases. The mean RI on the right and left were 0.59 +/- 0.06 and 0.58 +/- 0.06 respectively for the NS cases whereas for the controls it was 0.61 +/- 0.05 and 0.60 +/- 0.04 on the right and left respectively. The mean PI on the right and left measured 0.96 +/- 0.16 and 0.94 +/- 0.15 respectively for the NS cases while that for the control cases measured 0.98 +/- 0.13.and 0.95 +/- 0.12 on the right and left respectively. Although, the interlobar arteries mean RIs were generally less than that for the controls, but only the left middle pole showed statistically significant mean difference (p= 0.004). There was also statistically significant mean difference (p= 0.048) between the cases and controls in the left middle pole PI. However, no correlation was found when the renal RI and PI are compared with the serum albumin and creatinine. Although there was no statistical significance between the mean RI and PI of the NS cases and controls, except in the left middle pole RI, it is recommended that Doppler ultrasound should still be part of management of Nephrotic syndrome patients especially those who have developed end stage renal disease in order to monitor their renal function. PMID- 27506167 TI - Spinal Cord Studies in the African Giant Rat (Cricetomys gambianus, Waterhouse). AB - The African giant rat, AGR, is known for advantageous behavioural patterns among which are cognition and dexterous locomotion. This study investigated the morphological, morphometric and possible functional aspects of the AGR spinal cord (SC) anatomy. Ten adult (5 males and 5 females) AGR were used to determine the gross and histological features of the SC which were typically of rodent features. The mean SC weight and length given as 2.50+/-0.24g and 15.87+/-0.24cm respectively for the male and 2.32+/-0.16g and 15.40+/-0.61cm for the female showed no sexual dimorphism. A positive linear relationship between the tail length and SC weight were found in both sexes (r =0.81 males; r =0.95 females) suggesting significant contribution of the filum terminale to SC weight. Forty three internal structures including nuclear aggregations and tracts were traced. Eight nuclear aggregations of neurons involved in nociception and limb coordination were observed to be prominent and larger than in laboratory rats. Same was noted for the dorsal, ventral and lateral funicular tracts which control the limbic system. This study provides morphometric baseline research information and delineates the functional aspects of the AGR SC anatomy. The information provided further strengthens the drive proposing the AGR as an indigenous research model for regional anaesthesia and locomotor disease. PMID- 27506168 TI - Anti-Gastric Ulcer Effect of Betulinic Acid in Male Albino Rats. AB - Betulinic acid (BA) is a lupane-type triterpene that has been identified and isolated from various plant species used in ethnomedicine in various cultures across the world. This study was undertaken to elucidate the mechanisms underlying the anti-ulcer effect of Betulinic acid. The effect of BA on indomethacin-induced ulcer, gastric mucus secretion, gastric mucus cells count, basal and histamine-induced gastric acid secretion and levels of malondialdehyde formation were studied using dose of 0.5, 1.5, and 3.0 mg/kg. The results showed that BA reduced indomethacin-induced ulceration significantly and significantly increased gastric mucus secretion in the 1.5 mg/kg and 3.0 mg/kg BA treated rats compared to the control rats. There was a significant increase in the mucus cells count in all the treated groups which is in a dose- dependent manner compared to the control group. There was significant decrease in gastric acid secretion in each of the BA treated groups compared to the control. Malondialdehyde concentration significantly decrease in all the treated groups compared to the control. The anti-gastric ulcer effect of BA may be mediated via decreasing gastric acid secretion, increasing gastric mucus secretions, increasing the number of gastric mucus cells and also by reducing the level of MDA concentration. PMID- 27506169 TI - Antinociceptive and anti-arthritic properties of hydroethanolic leaf extract of Clausena anisata (Willd.) Hook. f. ex Benth (Rutaceae) in Rodents: possible mechanism of actions. AB - The leaves of Clausena anisata (Willd.) Hook. f. ex Benth (Rutaceae) is used in Traditional African medicine for the treatment of various ailments including arthritis. The present study sought to investigate the antinociceptive and anti arthritic properties of hydroethanolic leaf extract of Clausena anisata (HeCA). HeCA (100, 200 or 400 mg/kg, p.o.) was administered 1 h before intraplantar injection of formalin 1%v/v in saline to evaluate antinociceptive effect. Moreover, its possible mechanism of antinociceptive action was investigated through pretreatment of mice with antagonists of receptors implicated in nociception. Anti!inflammatory effect of the extract was investigated using the carrageenan-induced paw oedema and complete Freund's adjuvant (CFA)-induced arthritis models in rats. HeCA (400 mg/kg) treatment significantly reduced the duration of paw licking/biting during both in the early (42.12%) and late (75.79%) phases of formalin-induced nociception. However, the antinociceptive effect elicited by HeCA was reverse by pretreatment of mice with naloxone, prazosin, yohimbine, ketanserin, L-arginine, and parachlorophenylalanine (PCPA). HeCA produced dose-dependent and time course decrease in carrageenan-induced paw oedema. Pre- and post-treatment of rats with HeCA ameliorated CFA-induced arthritis evidenced in the significant decrease in arthritic index comparatively similar to the effect of celecoxib. CFA- induced oxidative and nitrosative stress were attenuated by subchronic treatment with HeCA. Findings from this study shows that C. anisata possesses antinociceptive activity through possible interaction with opioidergic, noradrenergic, L-arginine-nitric oxide and serotonergic pathways as well as anti-arthritic property which could be attributed to its ability to prevent the release of inflammatory mediators and oxidative stress. PMID- 27506170 TI - Effects of Oral Maternal Administration of Caffeine on Reproductive Functions of Male Offspring of Wistar Rats. AB - Caffeine was investigated for its possible fetal programming effects on reproductive function of male offspring. Sixty-five pregnant Wistar rats were grouped into four. Group 1 was control and received distilled water. Groups 2, 3 and 4 were treated orally with 1.14, 3.42 and 5.70 mg/kg body weight of caffeine respectively. Each group was subdivided into four based on gestation days (GD) 1 7, 8-14, 15-21 and 1-21. The day of parturition was taken as postnatal day zero (0). Male offspring were sacrificed on postnatal day 70. Parameters determined were: weight at birth, body weight at postnatal day 21 and 70, anogenital distance (AGD) index, sperm parameters, reproductive organ weight, histology and hormonal profile (testosterone, FSH and LH). Data were analyzed using Analysis of Variance. Level of significance was taken at P<0.05. Male offspring belonging to caffeine treated dams showed dose dependent significant decreases in birth weight. Male offspring from dams treated with caffeine during GD 1-7 and GD 1-21 had a significant increase in their AGD index. Also, male offspring from dams treated with 1.14 and 5.70 mg/kg body weight of caffeine during GD 8-14 had a significant increase in AGD index. Dams treated with 3.42 mg/kg body weight of caffeine during GD 15-21, had a significant increase in the AGD index of their male offspring. The sperm motility of offspring from dams treated with 5.70 mg/kg body weight of caffeine during GD 1-7 and GD 1-21 were significantly increased. Offspring of GD 8-14 and GD 15-21 dams treated with 3.42 and 5.70 mg/kg body weight of caffeine respectively, showed significantly reduced serum testosterone level. There was a significant decrease in the weight of testes of offspring from dams treated with caffeine during GD 8-14. Histological sections of testes of offspring from caffeine treated dams showed interstitial congestions, edema, reduced germinal epithelial height and detached basal membrane. Maternal caffeine exposure during different gestational periods adversely affected birth weight and some reproductive indices in male offspring of Wistar rats. PMID- 27506171 TI - Effects of Hypothyroidism and Exogenous Thyroxine on Gastrointestinal Organs of Rat. AB - Thyroxine (T4) is important in gut development and maturation, and its use in treating hypothyroidism is becoming more popular. This study was conducted to evaluate the effect of thyroidectomy and thyroxine replacement on some gastrointestinal organs. Ten out of 20 thyroidectomised rats received 100pg/kgbw of T4 for five weeks to become euthyroid while the rest were left to become hypothyroid. Ten sham operated rats were made hyperthyroid by giving 100pg/kg.bw of T4 for five weeks, while the other ten sham operated rats served as control. 10mg/kg.bw intraperitoneal injection of ketamine was given as anesthesia for thyroidectomy and sham operation. At the end of the fifth week, the animals were sacrificed. Liver, stomach and small intestine were harvested and their morphological dimensions measured. Everted sacs were made from the small intestine for glucose transfer studies and slides for histomorphometry. There was no significant difference in the weights of the liver and stomach of the groups when compared with the control group. There was significant increase in length and diameter but reduced wall thickness in the hyperthyroid small intestine; unlike that of hypothyroid which had significant shorter length, decreased diameter but increased wall thickness. Villi length and crypt depth was higher in hyperthyroid but smallest in the hypothyroid. Glucose transfer was lesser in the hypothyroid but greater in the hyperthyroid intestine. These findings show that hypothyroidism diminishes the morphological variables of absorption in the small intestine as a mechanism to reducing its transfer capacity, while thyroxine replacement increases these variables as mechanism to increasing intestinal transfer capacity. PMID- 27506172 TI - Acute Administration of Methionine Affects Performance of Swiss Mice in Learning and Memory Paradigms. AB - Methionine, an essential amino acid, plays an essential role in the central nervous system CNS development. It serves as a crucial intermediate in the methylation, trans-sulfuration and amino- phosphorylationpathways,necessary for the synthesis of nucleic acids, phospholipids, hormones, neurotransmitters, antioxidants, polyamines, catecholamines and other biogenic amines. The effect of methionine on learning and memory in mice was investigated using Morris water maze (MWM), Elevated plus maze(EPM) and Y maze (YM). Animals were administered with distilled water (control), methionine (1,700mg/kg); folate (3mg/kg) or methionine (1700mg/kg) plus folate (3mg/kg) for 14 days. Escape latency and time spent in target quadrants; transfer latency and percentage spontaneous alternations were measured in the MWM, EPM and YM respectively. The animals were anaesthetized with inhalational chloroform and their brains subsequently harvested, homogenized and assayed for acetylcholinesterase24 hours after the experiment.Folate significantly(p<0.05) increased transfer latency (53.33 +/- 12.62) as compared to control (20.1 +/- 5.01) and reduced spontaneous alternations significantly (25.0 +/- 8.9) when compared to control (44.33 +/- 3.07). When folate was combined with methionine there was also a significant increase in transfer latency (43.0 +/- 14.39) when compared with control (20.1 +/ 5.01). Folate-methionine combination also significantly reduced spontaneous alternations (20.4 +/- 8.4) as compared to the control (44.33 +/- 3.07) much more than folate alone. Acetylcholinesterase activities in all groups were not statistically significant. It can be concluded that acute methionine administration has some benefits in memory enhancement. However, a short course folate supplementation impairslearning and working memory especially when combined with methioninewhich may be as a result of sudden overwhelming of the methylation cycle, leading to homocysteinemia which is pro-dementia. PMID- 27506173 TI - Effects of Telfairia Occidentalis Seed Oil on Female Reproductive Functions in Wistar Rats. AB - The effects of T. occidentalis seed oil on some female reproductive indices were investigated in Wistar rats. The study was divided into two phases: (estrous cycle and pregnancy). Animals were grouped into four: group A received distilled water (control), groups B, C and D received 400, 600 and 800 mg/kg bw of T. occidentalis seed oil respectively. The pattern of estrous cycle was determined for three weeks before and during the treatment. Thereafter, each group was sub- divided into two. The sub-group-1 rats were mated with male breeders, the litter size and birth weight of their offsprings was determined. Sub-group-2 rats were sacrificed and histology of organs and serum levels of LH, FSH and estrogen were assayed. There was no significant difference between the pre-treatment and post treatment estrous cycle length. However, there was a significant decrease in the frequency of diestrus phase during treatment in all the experimental groups when compared with pre-treatment period but there was no significant difference in the diestrus phase when compared with the control group. Serum estrogen concentration was significantly reduced in the group that was treated with 800 mg/kg bw of T. occidentalis seed oil. Histology of the ovary and uterus in the experimental groups were similar to that of the control group. Birth weight of pups was significantly increased in the group treated with 600 mg/kg bw of T. occidentalis seed oil when compared with the control group. The results of this study suggest that T. occidentalis seed oil does not alter estrous cycle in Wistar rats. PMID- 27506174 TI - Safety Evaluation of Osun River Water Containing Heavy Metals and Volatile Organic Compounds (VOCs) in Rats. AB - This study evaluated the pH, heavy metals and volatile organic compounds (VOCs) in Osun river water. It also evaluated its safety in rats. Heavy metals were determined by atomic absorption spectrophotometry (AAS) while VOCs were determined by gas chromatography coupled with flame ionization detector (GC-FID). Male and female rats were exposed to Osun river water for three weeks and then sacrificed. The abundance of heavy metals in Osun river followed the trend Pb > Cd > Zn > Fe > Cr > Cu while VOCs followed the trend benzene < ethylbenzene < toluene < xylene. The concentrations of Pb, Cd and benzene were higher than the permissible limits of Standards Organization of Nigeria (SON) and World Health Organization (WHO) respectively. Rats exposed to Osun river water for three weeks had increased WBC, thiobarbituric acid reactive substances (TBARS), serum proteins and serum aminotransferases. There were also significant decreases in HCT, PLT, liver aminotransferases and liver glutathione compared to the control. These results show that the pollutants in Osun river water are capable of inducing hematological imbalance and liver cell injury. The toxicity induced in blood was sex-dependent affecting female rats more than male rats. PMID- 27506175 TI - Baseline Haematology and Erythrocyte Morphological Changes of Apparently Normal Dogs Raised in Ibadan, Oyo State. AB - This study evaluates the haematological parameters and the observed erythrocytes morphological changesin dogs raised in Ibadan, Oyo State in the south western part of Nigeria. Blood samples were collected from sixty-four apparently healthy dogs. The haematological parameters of the blood samples collected were evaluated with the quantification of the percentage erythrocyte morphological abnormalities. The result of the quantitative count of the erythrocyte morphological abnormalities were also converted using reference guide to give the numerical/descriptive clinical grade of the associated morphological abnormalities. There was a significant difference between the haematological parameters reported in this study and the commonly used dog haematological reference ranges from temperate regions used in laboratories in Nigeria. Some of the morphological abnormalities observed in this study include echinocyte (4.12+/ 0.35%), macrocyte (2.61+/-0.22%) and spherocyte (2.17+/-0.29%) and eccentrocyte (0.39+/-0.06%) while other such as acanthocyte (1.39+/-0.19), leptocyte (0.71+/ 0.13), schizocyte (0.703+/-0.104) and codocyte (0.50+/-0.11) were also seen. These study findings show that the associated morphological changes were all not significant and fall within the acceptable range using the reference guide for erythrocyte morphological abnormalities even when the haematological values differ significantly fromthe reference value. This study provides baseline information on the haematological parameters and the novel correlation ofthe associated erythrocyte abnormalities seen as a corresponding proof of the apparently healthy status of the dogs raised in Ibadan used for this study. The study while serving as an important means of verification of the reference range of haematological parameters also shows that clinical case interpretation using haematological baseline data from the temperate region should be used with caution in our tropical environment. This thus necessitates the need for an advocacy to build a reference range of haematological parameters that can be used as a working baseline value for the tropical environment. PMID- 27506176 TI - Salivary Secretion and Composition in Malaria: A Case-control Study. AB - No previous studies have documented changes in salivary secretion in patients with malaria. This study aimed to compare salivary secretion and composition in malaria positive and malaria negative individuals. Ninety participants composed of 40 malaria parasite positive and 50 malaria parasite negative individuals (age and gender matched) were included. Malaria diagnosis was achieved by microscopic examination of Giemsa stained thick and thin film of blood smears. A self administered questionnaire was used to assess presence or absence of oral symptoms in the malaria parasite positive individuals. Whole saliva samples were collected and analyzed for flow rate, pH, total protein and concentrations of electrolytes (K+, Na+, Ca2+, Cl-, PO42-and HCO32-). Data were analysed using Independent-Samples t-test and Spearman's correlation test. The salivary flow rate was significantly reduced in malaria parasite positive individuals (P = 0.001). Oral symptoms were present in 82.5% of the malaria parasite positive individuals. There was no significant difference in the salivary pH, total protein and electrolyte ion concentrations between the two groups. Also, Spearman's correlation test showed no significant relationship between the presence of oral symptom and the salivary parameters. Salivary flow rates are reduced in the individuals with malaria. However, presence of oral symptoms in these individuals may not be attributed to the reduced salivary flow rate. Further studies are needed to validate our findings and elucidate mechanisms involved. PMID- 27506177 TI - A Survey of ABO, Rhesus (D) Antigen and Haemoglobin Genes Variants in Oyo State, Nigeria. AB - A survey of ABO and Rhesus (Rh D) antigens and variants of haemoglobin genes (HbGen) in Oyo state was carried out. This longitudinal study involved the determination of ABO and Rh(D) antigens in 3241 and HbGen in 2622 male and female adults (aged 26-65years) respectively using standard methods. 94.5% of the subjects were Rh(D) positive while 5.5% were Rh(D) negative respectively based on the detection (Positive) or absence (Negative) of Rh(D) antigen. 22.8% of the subjects had ABO blood group A, 26.4% were group B, 4.1% were group AB while 46.7% were group O. Further analysis revealed that 695 (21.4%) of the group A were Apositive while 44 (1.4%) were Anegative. 800 of these subjects (24.7%) were Bpositive while 56 (1.7%) were group Bnegative. 133 (4.1%) showed group AB out of which 125 (3.8%) were ABpositive and 8 (0.3%) were ABnegative. 1513 (46.7%) were group O out of which 1444 (44.6%) were Opositive while 69 (2.1%) were Onegative. HbGen determination showed that 1933 of the subjects (73.7%) had HbGen AA; 553 (21.1%) were AS; 119 (4.5%) were AC; 11 (0.4%) were SC while 3 subjects representing 0.1% and 0.2% each had HbGen SS and CC respectively. Although the results were similar to earlier ones; however, the need for sustained counselling towards eradication of SS genes and increased research towards identifying artificial blood substitutes was highlighted in this work. The increasing need for blood transfusion especially with the increase in various politically/communally motivated emergency situations underscores this fact. PMID- 27506178 TI - Effects of Maternal Dexamethasone Exposure During Lactation on Metabolic Imbalance and Oxidative Stress in the Liver of Male Offsprings of Wistar Rats. AB - It has been reported in human and animal studies that early exposure to glucocorticoids could retard growth and subsequent development of cardio metabolic diseases. Chronic exposure to glucocorticoids induced oxidative stress. Therefore, the role of oxidative stress in some of the observed metabolic imbalance needs to be elucidated. This study examined the effects of lactational dexamethasone exposure on metabolic imbalance and oxidative stress marker in the liver of male offspring of exposed mother. Twenty lactating dams were divided into 4 groups of 5 animals each. Group 1 was administered 0.02 ml/100gbwt/day normal saline through lactation days 1-21. Group 2, 3, and 4 were administered 100 ug/kgbwt/day dexamethasone for lactation days 1-7, 1-14, and 1-21 respectively. The male offspring were thereafter separated and sacrificed at 12weeks of age for evaluation of lipid profile and oxidative stress marker in the liver. Results from this study indicate that Total Cholesterol (TC), Triglycerides (TAG) and LDL- cholesterol (LDL-C) were significantly higher in the Dex 1-7, Dex 1-14 and Dex 1-21 groups when compared with the control. HDL Cholesterol (HDL-C) was significantly reduced in the Dex 1-7, Dex 1-14 and Dex 1 21 groups relative to the control. Basal Fasting Blood Sugar (FBS) was also significantly higher in the Dex 1-14 and Dex 1-21 groups when compared with the control. Liver malondialdehyde was significantly higher in the Dex1-14 and Dex1 21 group compared to the control. However, liver catalase and SOD activity were all significantly lower in Dex 1-7, Dex 1-14 and Dex 1-21 groups relative to control. Liver protein was significantly lower in the Dex1-14 and Dex1-21 treatment groups when compared with the control. Findings from this study suggest that there is possible increase in metabolic imbalance in the offspring of mother exposed to dexamethasone during lactation and these effects may be secondary to increase oxidative stress in the liver. PMID- 27506179 TI - A Novel Annotation Technique During Mapping to Facilitate the Termination of Atrial Tachycardia Following Ablation for Atrial Fibrillation. AB - INTRODUCTION: The treatment of atrial tachycardia (AT) occurring after ablation for atrial fibrillation (AF) is challenging. The most common ablation strategy relies on entrainment, and electroanatomic activation mapping (EAM) using a conventional window of interest (WOI), centered on the easily detectable atrial signal on the coronary sinus catheter. We describe a novel EAM annotation technique that uses a WOI starting 40 milliseconds prior to the P wave in order to detect the reentrant AT exit site. This WOI timing is based on the similarity between scar-related reentrant AT and scar-related ventricular tachycardia. METHODS: Patients with AT after prior ablation for AF were included. The EAM of the AT was performed using the novel mapping annotation technique. The ablation was considered successful if the AT terminated during ablation at the site identified by this strategy. RESULTS: Twenty-eight patients with 36 ATs were included. The ATs were classified as follows: mitral annulus (13/36), roof (11/36), anterior/posterior/lateral left atrial wall (10/36), and RA (2/36). A complete EAM using the novel annotation technique was achieved in 34 of 36 AT's, encompassing 94 +/- 6.5% of the cycle length. Low amplitude pre-P fractionated electrograms were found in 34 of 36 (94%) ATs and these occurred at a mean distance of 1.8 +/- 1.2 mm from the "early-meets-late" line. Ablation at these areas resulted in termination of 34 of 36 ATs (94%). CONCLUSION: The novel EAM annotation allows the accurate detection of the critical isthmus of post-AF ablation AT. Ablation of these isthmuses results in termination of the AT in the vast majority of patients. PMID- 27506180 TI - Ants exhibit asymmetric hybridization in a mosaic hybrid zone. AB - Research on hybridization between species provides unparalleled insights into the pre- and postzygotic isolating mechanisms that drive speciation. In social organisms, colony-level incompatibilities may provide additional reproductive barriers not present in solitary species, and hybrid zones offer an opportunity to identify these barriers. Here, we use genotyping-by-sequencing to sequence hundreds of markers in a hybrid zone between two socially polymorphic ant species, Formica selysi and Formica cinerea. We characterize the zone, determine the frequency of hybrid workers, infer whether hybrid queens or males are produced and investigate whether hybridization is influenced by colony social organization. We also compare cuticular hydrocarbon profiles and aggression levels between the two species. The hybrid zone exhibits a mosaic structure. The asymmetric distribution of hybrids skewed towards F. cinerea suggests a pattern of unidirectional nuclear gene flow from F. selysi into F. cinerea. The occurrence of backcrossed individuals indicates that hybrid queens and/or males are fertile, and the presence of the F. cinerea mitochondrial haplotype in 97% of hybrids shows that successful F1 hybrids will generally have F. cinerea mothers and F. selysi fathers. We found no evidence that social organization contributes to speciation, because hybrids occur in both single-queen and multiple-queen colonies. Strongly differentiated cuticular hydrocarbon profiles and heightened interspecific aggression further reveal that species recognition cues are both present and perceived. The discovery of fertile hybrids and asymmetrical gene flow is unusual in ants, and this hybrid zone will therefore provide an ideal system with which to investigate speciation in social insects. PMID- 27506181 TI - Reference intervals for biochemical and haematological analytes of juvenile captive-bred long-tailed macaques (Macaca fascicularis) from Mauritius with examination of the effects of individual characteristics using principal component analysis. AB - BACKGROUND: The Mauritian cynomolgus macaque (Macaca fascicularis) is widely used in biomedical research. Determining reference intervals for biochemical and haematological analytes provides an important tool for clinical diagnosis and pre clinical research. METHODS: Blood samples from 736 Mauritian long-tailed macaques were analysed to determine reference intervals of 13 biochemical and 10 haematological analytes. The need for partitioning the reference interval between males and females was determined. To examine the variation associated with age, body weight and sex on the analytes, our correlating, multivariate data set was first reduced using principal component analysis, and then the effect of these characteristics on factor scores was examined using GLM analysis. RESULTS: Partitioning of reference intervals, based on sex, was recommended for albumin, alkaline phosphatase and mean corpuscular haemoglobin. Sex significantly influenced the concentration of lymphocytes, granulocytes and white blood cells. CONCLUSION: These findings provide useful reference data for research involving Mauritian long-tailed macaques. PMID- 27506182 TI - Effectiveness and tolerability of simeprevir and sofosbuvir in nontransplant and post-liver transplant patients with hepatitis C genotype 1. AB - BACKGROUND: Hepatitis C virus genotype 1a (HCV-1a), prior treatment, cirrhosis and post-transplant status are historically associated with poor treatment responses. The new oral direct-acting agents appear to be effective and safe in these patients. AIMS: To evaluate the effectiveness and tolerability of simeprevir and sofosbuvir in a diverse real-life cohort of patients, including difficult-to-treat patients. METHODS: We conducted a retrospective cohort study in 198 consecutive patients with hepatitis C genotype 1 (148 nontransplant, 50 post transplant), who were treated with simeprevir and sofosbuvir for 12 weeks between December 2013 and December 2014. Primary outcome was sustained virological response with undetectable HCV RNA 12 weeks after completion of therapy (SVR12). Risk factors evaluated for lack of SVR12 included HCV 1a (vs. 1b), prior treatment (vs. none), and cirrhosis (vs. no cirrhosis). RESULTS: SVR12 rates were similar in non- and post-transplant settings, 82% and 88%, respectively. There were no significant differences in adverse events in patients regardless of cirrhosis or transplant status. On multivariate analysis also inclusive of gender and liver transplant status, negative predictors of SVR12 were having at least 2 or 3 risk factors (OR 0.30, 95% CI 0.10-0.87, P = 0.027 or 0.29, 95% CI 0.09-0.85, P = 0.025, respectively). CONCLUSION: Simeprevir and sofosbuvir combination is a safe and effective regimen for the treatment of non- and post-transplant patients with traditional risk factors for poor treatment response, unless more than 2 difficult-to-treat risk factors are present. PMID- 27506183 TI - Chain conformations and phase behavior of conjugated polymers. AB - Conjugated polymers may play an important role in various emerging optoelectronic applications because they combine the chemical versatility of organic molecules and the flexibility, stretchability and toughness of polymers with semiconducting properties. Nevertheless, in order to achieve the full potential of conjugated polymers, a clear description of how their structure, morphology, and macroscopic properties are interrelated is needed. We propose that the starting point for understanding conjugated polymers includes understanding chain conformations and phase behavior. Efforts to predict and measure the persistence length have significantly refined our intuition of the chain stiffness, and have led to predictions of nematic-to-isotropic transitions. Exploring mixing between conjugated polymers and small molecules or other polymers has demonstrated tremendous advancements in attaining the needed properties for various optoelectronic devices. Current efforts continue to refine our knowledge of chain conformations and phase behavior and the factors that influence these properties, thereby providing opportunities for the development of novel optoelectronic materials based on conjugated polymers. PMID- 27506184 TI - Quality of life and national pension receipt after retirement among older adults. AB - AIM: As the aging population (including baby boomers) retires, its members face the problem of retirement security. Social security, including the national pension, is the most important source of retirement security and thus directly affects the well-being of retired older adults. We investigated the relationship between national pension receipt and quality of life (QoL) among Koreans aged 60 years or older. METHODS: We used data from the Korean Longitudinal Study of Aging obtained in 2006-2012 from 340 baseline individuals who had retired. We measured QoL using a visual analog scale. A generalized estimating equations model was used to carry out a longitudinal regression analysis on longitudinal data. RESULTS: When participants who received a national pension were used as the reference group, those participants who did not receive a national pension had a QoL of -4.40 (SE = 1.73; P = 0.0109). Additionally, individuals without a national pension and with a low household income showed the most drastic decrease in QoL (-10.42; SE = 4.53; P = 0.0214). Individuals without a national pension and with a low wealth level showed a considerable decrease in QoL compared with individuals with national pension and with a low wealth level (-8.34; SE = 4.14; P = 0.0438). CONCLUSIONS: National pension receipt among retired older adults influences QoL, and the present results suggest that guaranteed income is very important to retired older adults with a low economic status. Thus, we require national pension schemes that aim to address retirement security for these individuals. Geriatr Gerontol Int 2017; 17: 1205-1213. PMID- 27506185 TI - Surgical treatment of stress urinary incontinence-trans-obturator tape compared with tension-free vaginal tape-5-year follow up: an economic evaluation. AB - OBJECTIVE: To conduct an economic evaluation of the use of trans-obturator tape (TOT) compared with tension-free vaginal tape (TVT) in the surgical treatment of stress urinary incontinence in women. DESIGN: Cost-utility and cost-effectiveness analyses from a public-payer perspective, conducted alongside a randomised clinical trial. SETTING: Health services provided in Alberta, Canada. SAMPLE: A total of 195 women participated in the randomised clinical trial, followed to 5 years postsurgery. METHODS: Comparisons were undertaken between study groups for cost and two health-outcome measures. Multiple imputation was used to estimate the 14% of missing data. Bootstrapping was used to account for sampling uncertainty. Sensitivity analyses were based on complete case analyses and the removal of a TVT patient with extreme health service cost. MAIN OUTCOME MEASURES: The 15D instrument was used to calculate quality-adjusted life-years (QALYs) for the primary analysis. Absence of serious adverse events was also analysed. Costs were based on inpatient and outpatient hospital use data and practitioner fee-for service claims data. RESULTS: The TOT group had a nonsignificant average saving of $2368 (95% CI -$7166 to $2548) and incremental gain of 0.04 QALYs (95% CI 0.06 to 0.14) compared with TVT. TOT was dominant in over 71% of bootstrap replications and cost-effective over a wide range of willingness-to-pay. Cost effectiveness analysis using the absence of an serious adverse events provided similar results. CONCLUSION: The results suggest that TOT is cost-effective compared with TVT in the treatment of stress urinary incontinence. TWEETABLE ABSTRACT: The results of a 5-year cost-effectiveness analysis suggest that trans obturator tape is cost-effective compared with tension-free vaginal tape in the treatment of stress urinary incontinence. PMID- 27506186 TI - Synthesis of substituted benzooxaborinin-1-ols via palladium-catalysed cyclisation of alkenyl- and alkynyl-boronic acids. AB - Two new palladium-catalysed reactions have been developed for the synthesis of stable 4-substituted benzooxaborinin-1-ols. A palladium-catalysed cyclisation of ortho-alkenylbenzene boronic acids can be used to access 4-chlorobenzooxaborinin 1-ols via a Wacker-type oxidation and chlorination. Alternatively, ortho alkynylbenzene boronic acids undergo a palladium-catalysed oxyallylation reaction to provide 4-allylbenzooxaborinin-1-ols. PMID- 27506187 TI - Size dependence of structural parameters in fcc and hcp Ru nanoparticles, revealed by Rietveld refinement analysis of high-energy X-ray diffraction data. AB - To reveal the origin of the CO oxidation activity of Ruthenium nanoparticles (Ru NPs), we structurally characterized Ru NPs through Rietveld refinement analysis of high-energy X-ray diffraction data. For hexagonal close-packed (hcp) Ru NPs, the CO oxidation activity decreased with decreasing domain surface area. However, for face-centered cubic (fcc) Ru NPs, the CO oxidation activity became stronger with decreasing domain surface area. In comparing fcc Ru NPs with hcp Ru NPs, we found that the hcp Ru NPs of approximately 2 nm, which had a smaller domain surface area and smaller atomic displacement, showed a higher catalytic activity than that of fcc Ru NPs of the same size. In contrast, fcc Ru NPs larger than 3.5 nm, which had a larger domain surface area, lattice distortion, and larger atomic displacement, exhibited higher catalytic activity than that of hcp Ru NPs of the same size. In addition, the fcc Ru NPs had larger atomic displacements than hcp Ru NPs for diameters ranging from 2.2 to 5.4 nm. Enhancement of the CO oxidation activity in fcc Ru NPs may be caused by an increase in imperfections due to lattice distortions of close-packed planes and static atomic displacements. PMID- 27506188 TI - President's Report. PMID- 27506189 TI - Discuss the role of microorganisms in the aetiology and pathogenesis of periapical disease. AB - The literature indicates that microorganisms have a critical role in the aetiology and pathogenesis of apical periodontitis. The advancement in microbiological study methods has allowed for the identification of newer species associated with the disease process. At our current understanding, however, the exact roles of specific microorganisms in apical periodontitis are not fully understood but the poly-microbial aetiology of the disease appears to be supported by the literature. The endodontic microbiota is comprised of a subset of microbiota present in the oral cavity, consisting of predominantly anaerobic bacterial species, some fungal and viral species. The pathogenesis of apical periodontitis is essentially the result of a complex interplay between bacterial and host factors, giving rise to a range of presentations depending on the balance of the interaction. The role of endodontic microbiota in the initiation and persistence of apical periodontitis means that the mainstay of endodontic treatment is the elimination of such bacteria. A challenge to the resolution of apical periodontitis after treatment lies in the inadequacy of treatment protocol in completely eradicating the pathogenic species and the inherent ability of certain species to survive the treatment. This issue should be the focus of future research as we continually search for more predictable treatment methods of achieving the resolution of apical periodontitis. PMID- 27506190 TI - Report on the 10th IFEA World Congress, June 03-06, 2016, Cape Town, South Africa. PMID- 27506192 TI - ASE (NSW) Report June 2016. PMID- 27506191 TI - Queensland Newsletter Report May 2016. PMID- 27506193 TI - Western Australia. PMID- 27506194 TI - Victoria. PMID- 27506195 TI - Elucidating tissue specific genes using the Benford distribution. AB - BACKGROUND: The RNA-seq technique is applied for the investigation of transcriptional behaviour. The reduction in sequencing costs has led to an unprecedented trove of gene expression data from diverse biological systems. Subsequently, principles from other disciplines such as the Benford law, which can be properly judged only in data-rich systems, can now be examined on this high-throughput transcriptomic information. The Benford law, states that in many count-rich datasets the distribution of the first significant digit is not uniform but rather logarithmic. RESULTS: All tested digital gene expression datasets showed a Benford-like distribution when observing an entire gene set. This phenomenon was conserved in development and does not demonstrate tissue specificity. However, when obedience to the Benford law is calculated for individual expressed genes across thousands of cells, genes that best and least adhere to the Benford law are enriched with tissue specific or cell maintenance descriptors, respectively. Surprisingly, a positive correlation was found between the obedience a gene exhibits to the Benford law and its expression level, despite the former being calculated solely according to first digit frequency while totally ignoring the expression value itself. Nevertheless, genes with low expression that exhibit Benford behavior demonstrate tissue specific associations. These observations were extended to predict the likelihood of tissue specificity based on Benford behaviour in a supervised learning approach. CONCLUSIONS: These results demonstrate the applicability and potential predictability of the Benford law for gleaning biological insight from simple count data. PMID- 27506196 TI - Prader-Willi syndrome in neonates: twenty cases and review of the literature in Southern China. AB - BACKGROUND: Prader-Willi syndrome is a rare genetic abnormality that can be challenging to diagnose early, but for which early interventions improve prognosis. METHODS: To improve understanding of Prader-Willi syndrome in neonates in Asia, we retrospectively analyzed the clinical records of 20 affected newborns diagnosed in the Department of Neonatology, Guangzhou Women and Children's Medical Center, Guangzhou, China from January 2007 to December 2014 and performed a review of the relevant literature. RESULTS: Fourteen boys and six girls presented with hypotonia, poor responsiveness, feeding difficulty, and infrequent, weak crying. Different from western patients, the 20 Asian patients exhibited at least five of the following typical features: prominent forehead, narrow face, almond-shaped eyes, small mouth, downturned mouth, thin upper lip, and micromandible. All 14 boys had a small scrotum, including nine with cryptorchidism. Diagnoses were made with microarray comparative genomic hybridization. All 20 infants required feeding tubes. Fifteen received swallowing training immediately after admission; the period of continuous tube feeding for these patients ranged from 8 to 22 days (mean, 14 +/- 5.3 days). For the five patients who did not receive swallowing training, the period of continuous tube feeding ranged from 15 to 35 days (mean, 18 +/- 4.3 days). Comprehensive care measures included: giving parents detailed health education and basic information about this disease, teaching skills to promote feeding and prevent suffocation, increasing children's passive activity, providing nutrition management for normal development, and preventing excessive or inadequate nutrient intake. CONCLUSIONS: Neonates with Prader-Willi syndrome in Asia have hypotonia, poor responsiveness, feeding difficulty, infrequent and weak crying, genital hypoplasia, and characteristic facial features. Recognition of the syndrome in neonates with confirmation by genetic testing is essential, because early diagnosis allows early intervention. Treatment measures including swallowing training can improve prognosis, prevent growth retardation and obesity, and elevate quality of life in individuals with Prader-Willi syndrome. PMID- 27506197 TI - Transcriptomic analysis of the autophagy machinery in crustaceans. AB - BACKGROUND: The giant freshwater prawn, Macrobrachium rosenbergii, is a decapod crustacean that is commercially important as a food source. Farming of commercial crustaceans requires an efficient management strategy because the animals are easily subjected to stress and diseases during the culture. Autophagy, a stress response process, is well-documented and conserved in most animals, yet it is poorly studied in crustaceans. RESULTS: In this study, we have performed an in silico search for transcripts encoding autophagy-related (Atg) proteins within various tissue transcriptomes of M. rosenbergii. Basic Local Alignment Search Tool (BLAST) search using previously known Atg proteins as queries revealed 41 transcripts encoding homologous M. rosenbergii Atg proteins. Among these Atg proteins, we selected commonly used autophagy markers, including Beclin 1, vacuolar protein sorting (Vps) 34, microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B), p62/sequestosome 1 (SQSTM1), and lysosomal-associated membrane protein 1 (Lamp-1) for further sequence analyses using comparative alignment and protein structural prediction. We found that crustacean autophagy marker proteins contain conserved motifs typical of other animal Atg proteins. Western blotting using commercial antibodies raised against human Atg marker proteins indicated their presence in various M. rosenbergii tissues, while immunohistochemistry localized Atg marker proteins within ovarian tissue, specifically late stage oocytes. CONCLUSIONS: This study demonstrates that the molecular components of autophagic process are conserved in crustaceans, which is comparable to autophagic process in mammals. Furthermore, it provides a foundation for further studies of autophagy in crustaceans that may lead to more understanding of the reproduction- and stress-related autophagy, which will enable the efficient aquaculture practices. PMID- 27506198 TI - Panx3 links body mass index and tumorigenesis in a genetically heterogeneous mouse model of carcinogen-induced cancer. AB - BACKGROUND: Body mass index (BMI) has been implicated as a primary factor influencing cancer development. However, understanding the relationship between these two complex traits has been confounded by both environmental and genetic heterogeneity. METHODS: In order to gain insight into the genetic factors linking BMI and cancer, we performed chemical carcinogenesis on a genetically heterogeneous cohort of interspecific backcross mice ((Mus Spretus * FVB/N) F1 * FVB/N). Using this cohort, we performed quantitative trait loci (QTL) analysis to identify regions linked to BMI. We then performed an integrated analysis incorporating gene expression, sequence comparison between strains, and gene expression network analysis to identify candidate genes influencing both tumor development and BMI. RESULTS: Analysis of QTL linked to tumorigenesis and BMI identified several loci associated with both phenotypes. Exploring these loci in greater detail revealed a novel relationship between the Pannexin 3 gene (Panx3) and both BMI and tumorigenesis. Panx3 is positively associated with BMI and is strongly tied to a lipid metabolism gene expression network. Pre-treatment Panx3 gene expression levels in normal skin are associated with tumor susceptibility and inhibition of Panx function strongly influences inflammation. CONCLUSIONS: These studies have identified several genetic loci that influence both BMI and carcinogenesis and implicate Panx3 as a candidate gene that links these phenotypes through its effects on inflammation and lipid metabolism. PMID- 27506199 TI - Factors influencing place of delivery for pastoralist women in Kenya: a qualitative study. AB - BACKGROUND: Kenya's high maternal mortality ratio can be partly explained by the low proportion of women delivering in health facilities attended by skilled birth attendants (SBAs). Many women continue to give birth at home attended by family members or traditional birth attendants (TBAs). This is particularly true for pastoralist women in Laikipia and Samburu counties, Kenya. This paper investigates the socio-demographic factors and cultural beliefs and practices that influence place of delivery for these pastoralist women. METHODS: Qualitative data were collected in five group ranches in Laikipia County and three group ranches in Samburu County. Fifteen in-depth interviews were conducted: seven with SBAs and eight with key informants. Nineteen focus group discussions (FGDs) were conducted: four with TBAs; three with community health workers (CHWs); ten with women who had delivered in the past two years; and two with husbands of women who had delivered in the past two years. Topics discussed included reasons for homebirths, access and referrals to health facilities, and strengths and challenges of TBAs and SBAs. The data were translated, transcribed and inductively and deductively thematically analysed both manually and using NVivo. RESULTS: Socio-demographic characteristics and cultural practices and beliefs influence pastoralist women's place of delivery in Laikipia and Samburu counties, Kenya. Pastoralist women continue to deliver at home due to a range of factors including: distance, poor roads, and the difficulty of obtaining and paying for transport; the perception that the treatment and care offered at health facilities is disrespectful and unfriendly; lack of education and awareness regarding the risks of delivering at home; and local cultural values related to women and birthing. CONCLUSIONS: Understanding factors influencing the location of delivery helps to explain why many pastoralist women continue to deliver at home despite health services becoming more accessible. This information can be used to inform policy and program development aimed at increasing the proportion of facility-based deliveries in challenging settings. PMID- 27506201 TI - Isolation and characterization of a novel Rickettsia species (Rickettsia asembonensis sp. nov.) obtained from cat fleas (Ctenocephalides felis). AB - A novel rickettsial agent, 'Candidatus Rickettsia asembonensis' strain NMRCiiT, was isolated from cat fleas, Ctenocephalides felis, from Kenya. Genotypic characterization of the new isolate based on sequence analysis of five rickettsial genes, rrs, gltA, ompA, ompB and sca4, indicated that this isolate clustered with Rickettsia felis URRWXCal2. The degree of nucleotide similarity demonstrated that isolate NMRCiiT belongs within the genus Rickettsia and fulfils the criteria for classification as a representative of a novel species. The name Rickettsia asembonensis sp. nov. is proposed, with NMRCiiT (=DSM 100172T=CDC CRIRC RAS001T=ATCC VR-1827T) as the type strain. PMID- 27506202 TI - Guillaine-barre syndrome; a rare complication of melioidosis. a case report. AB - BACKGROUND: Melioidosis caused by Burkholderia pseudomellei is an infection with protean clinical manifestations. Guillain-Barre syndrome [GBS] associated with melioidosis is very rare. CASE PRESENTATION: A 42-year-old woman with diabetes presented with abdominal pain, vomiting and intermittent fever for one month. Six months before presentation she had recurrent skin abscesses. Three months before presentation she had multiple liver abscesses which were aspirated in a local hospital. The aspirate grew "coliforms" resistant to gentamicin and sensitive to ceftazidime. On presentation she had high fever and tender hepatomegaly. Ultra Sound Scan of abdomen showed multiple liver and splenic abscesses. Based on the suggestive history and sensitivity pattern of the previous growth melioidosis was suspected and high dose meropenem was started. Antibodies to melioidin were raised at a titre of 1:10240. The growth from the aspirate of liver abscess was confirmed as Burkholderia pseudomellei by polymerase chain reaction [PCR]. After a week of treatment, patient developed bilateral lower limb weakness. Deep tendon reflexes were absent. There was no sensory loss or bladder/bowel involvement. Analysis of the cerebro-spinal fluid showed elevated proteins with no cells. There was severe peripheral neuropathy with axonal degeneration. A diagnosis of GBS was made and she was treated with plasmapharesis with marked improvement of neurological deficit. Continuation of intravenous antibiotics lead to further clinical improvement with normalization of inflammatory markers and resolution of liver and splenic abscess. Eradication therapy with oral co-trimoxazole and co amoxyclav was started on the seventh week. Patient was discharged to outpatient clinic with a plan to continue combination of oral antibiotics for 12 weeks. At the end of 12 weeks she was well with complete neurological resolution and no evidence of a relapse. CONCLUSIONS: Guillaine Barre syndrome is a rare complication of melioidosis and should be suspected in a patient with melioidosis who develop lower limb weakness. Plasmapharesis can be successfully used to treat GBS associated with active melioidosis. PMID- 27506200 TI - A tissue-specific protein purification approach in Caenorhabditis elegans identifies novel interaction partners of DLG-1/Discs large. AB - BACKGROUND: Affinity purification followed by mass spectrometry (AP/MS) is a widely used approach to identify protein interactions and complexes. In multicellular organisms, the accurate identification of protein complexes by AP/MS is complicated by the potential heterogeneity of complexes in different tissues. Here, we present an in vivo biotinylation-based approach for the tissue specific purification of protein complexes from Caenorhabditis elegans. Tissue specific biotinylation is achieved by the expression in select tissues of the bacterial biotin ligase BirA, which biotinylates proteins tagged with the Avi peptide. RESULTS: We generated N- and C-terminal tags combining GFP with the Avi peptide sequence, as well as four BirA driver lines expressing BirA ubiquitously and specifically in the seam and hyp7 epidermal cells, intestine, or neurons. We validated the ability of our approach to identify bona fide protein interactions by identifying the known LGL-1 interaction partners PAR-6 and PKC-3. Purification of the Discs large protein DLG-1 identified several candidate interaction partners, including the AAA-type ATPase ATAD-3 and the uncharacterized protein MAPH-1.1. We have identified the domains that mediate the DLG-1/ATAD-3 interaction, and show that this interaction contributes to C. elegans development. MAPH-1.1 co-purified specifically with DLG-1 purified from neurons, and shared limited homology with the microtubule-associated protein MAP1A, a known neuronal interaction partner of mammalian DLG4/PSD95. A CRISPR/Cas9 engineered GFP::MAPH-1.1 fusion was broadly expressed and co-localized with microtubules. CONCLUSIONS: The method we present here is able to purify protein complexes from specific tissues. We uncovered a series of DLG-1 interactors, and conclude that ATAD-3 is a biologically relevant interaction partner of DLG-1. Finally, we conclude that MAPH-1.1 is a microtubule-associated protein of the MAP1 family and a candidate neuron-specific interaction partner of DLG-1. PMID- 27506203 TI - Counteracting learned non-use in chronic stroke patients with reinforcement induced movement therapy. AB - BACKGROUND: After stroke, patients who suffer from hemiparesis tend to suppress the use of the affected extremity, a condition called learned non-use. Consequently, the lack of training may lead to the progressive deterioration of motor function. Although Constraint-Induced Movement Therapies (CIMT) have shown to be effective in treating this condition, the method presents several limitations, and the high intensity of its protocols severely compromises its adherence. We propose a novel rehabilitation approach called Reinforcement Induced Movement Therapy (RIMT), which proposes to restore motor function through maximizing arm use. This is achieved by exposing the patient to amplified goal oriented movements in VR that match the intended actions of the patient. We hypothesize that through this method we can increase the patients self-efficacy, reverse learned non-use, and induce long-term motor improvements. METHODS: We conducted a randomized, double-blind, longitudinal clinical study with 18 chronic stroke patients. Patients performed 30 minutes of daily VR-based training during six weeks. During training, the experimental group experienced goal-oriented movement amplification in VR. The control group followed the same training protocol but without movement amplification. Evaluators blinded to group designation performed clinical measurements at the beginning, at the end of the training and at 12-weeks follow-up. We used the Fugl-Meyer Assessment for the upper extremities (UE-FM) (Sanford et al., Phys Ther 73:447-454, 1993) as a primary outcome measurement of motor recovery. Secondary outcome measurements included the Chedoke Arm and Hand Activity Inventory (CAHAI-7) (Barreca et al., Arch Phys Med Rehabil 6:1616-1622, 2005) for measuring functional motor gains in the performance of Activities of Daily Living (ADLs), the Barthel Index (BI) for the evaluation of the patient's perceived independence (Collin et al., Int Disabil Stud 10:61-63, 1988), and the Hamilton scale (Knesevich et al., Br J Psychiatr J Mental Sci 131:49-52, 1977) for the identification of improvements in mood disorders that could be induced by the reinforcement-based intervention. In order to study and predict the effects of this intervention we implemented a computational model of recovery after stroke. RESULTS: While both groups showed significant motor gains at 6-weeks post-treatment, only the experimental group continued to exhibit further gains in UE-FM at 12-weeks follow-up (p<.05). This improvement was accompanied by a significant increase in arm-use during training in the experimental group. CONCLUSIONS: Implicitly reinforcing arm-use by augmenting visuomotor feedback as proposed by RIMT seems beneficial for inducing significant improvement in chronic stroke patients. By challenging the patients' self-limiting believe system and perceived low self-efficacy this approach might counteract learned non-use. TRIAL REGISTRATION: Clinical Trials NCT02657070 . PMID- 27506204 TI - Neuroprotective, Neurotrophic and Anti-oxidative Role of Bacopa monnieri on CUS Induced Model of Depression in Rat. AB - Major depression is a life threatening neuropsychiatric disorder that produces mental illness and major cause of morbidity. The present study was conducted to evaluate the neuroprotective, neurotrophic and antioxidant potential of Bacopa monnieri extract (BME) on chronic unpredictable stress (CUS) induced behavioral depression in rats. Behavioral tests were carried out for investigation of antidepressant like effects of BME, and potential mechanism was assessed by determining neurotrophin level and hippocampal neurogenesis. Depressive-like behavior was assessed by shuttle-box escape test, forced swim test and tail suspension test. Effect of BME on hypothalamic-pituitary-adrenal (HPA) axis was evaluated by measuring the plasma level of adrenocorticotropic hormone (ACTH) and corticosterone. The expression of brain derived neurotrophic factor (BDNF), neuronal marker doublecortin (DCX) in the hippocampus were measured and hippocampal neurogenesis was investigated by 5-bromo-2-deoxyuridine/neuronal nuclei (BrdU/NeuN). In addition, effects of BME on oxidative stress markers were also measured in the hippocampus of CUS exposed rats. The results indicated that BME significantly able to attenuate the depressive-like behaviors, normalized the levels of ACTH, corticosterone, and up-regulate the expression of BDNF, DCX and BrdU/NeuN in CUS induced rats compared to BME treated rats. It is also found that BME significantly increased the activity of antioxidant enzymes on CUS induced rats. These findings revealed that BME exerted neuroprotective effects possibly by promoting hippocampal neurogenesis with elevation of BDNF level and antioxidant defense against oxidative stress. PMID- 27506205 TI - Structural Effects of Solvation by 18-Crown-6 on Gaseous Peptides and TrpCage after Electrospray Ionization. AB - Significant effort is being employed to utilize the inherent speed and sensitivity of mass spectrometry for rapid structural determination of proteins; however, a thorough understanding of factors influencing the transition from solution to gas phase is critical for correct interpretation of the results from such experiments. It was previously shown that combined use of action excitation energy transfer (EET) and simulated annealing can reveal detailed structural information about gaseous peptide ions. Herein, we utilize this method to study microsolvation of charged groups by retention of 18-crown-6 (18C6) in the gas phase. In the case of GTP (CEGNVRVSRE LAGHTGY), solvation of the 2+ charge state leads to reduced EET, whereas the opposite result is obtained for the 3+ ion. For the mini-protein C-Trpcage, solvation by 18C6 leads to dramatic increase in EET for the 3+ ion. Examination of structural details probed by molecular dynamics calculations illustrate that solvation by 18C6 alleviates the tendency of charged side chains to seek intramolecular solvation, potentially preserving native-like structures in the gas phase. These results suggest that microsolvation may be an important tool for facilitating examination of native-like protein structures in gas phase experiments. Graphical Abstract ?. PMID- 27506206 TI - Native Mass Spectrometry Characterizes the Photosynthetic Reaction Center Complex from the Purple Bacterium Rhodobacter sphaeroides. AB - Native mass spectrometry (MS) is an emerging approach to study protein complexes in their near-native states and to elucidate their stoichiometry and topology. Here, we report a native MS study of the membrane-embedded reaction center (RC) protein complex from the purple photosynthetic bacterium Rhodobacter sphaeroides. The membrane-embedded RC protein complex is stabilized by detergent micelles in aqueous solution, directly introduced into a mass spectrometer by nano electrospray (nESI), and freed of detergents and dissociated in the gas phase by collisional activation. As the collision energy is increased, the chlorophyll pigments are gradually released from the RC complex, suggesting that native MS introduces a near-native structure that continues to bind pigments. Two bacteriochlorophyll a pigments remain tightly bound to the RC protein at the highest collision energy. The order of pigment release and their resistance to release by gas-phase activation indicates the strength of pigment interaction in the RC complex. This investigation sets the stage for future native MS studies of membrane-embedded photosynthetic pigment-protein and related complexes.Graphical Abstract. PMID- 27506207 TI - Characterization of N-Succinylation of L-Lysylphosphatidylglycerol in Bacillus subtilis Using Tandem Mass Spectrometry. AB - Phospholipids generally dominate in bacterial lipids. The negatively charged nature of phospholipids renders bacteria susceptible to cationic antibiotic peptides. In comparison with Gram-negative bacteria, Gram-positive bacteria in general have much less zwitterionic phosphatidylethanolamine. However, they are known for producing aminoacylated phosphatidylglycerol (PG), especially positively charged L-lysyl-PG, which is catalyzed by lysyl-PG synthase MprF, which appears to have a broad range of specificity for L-aminoacyl transfer RNAs. In addition, many Gram-positive bacteria also have a dlt-gene-coded D-alanylation pathway for lipoteichoic acids and wall teichoic acids covalently attached to a glycolipid or peptidoglycan. D-Alanylation also masks the dominant negative charge of the phosphate-rich polymers of teichoic acids. Using mass spectrometry, we have recently observed that precursor scans in negative mode for deprotonated amino acid fragments were most sensitive for ester-linked amino acids. Such a scan for precursors generating an m/z 145 lysyl anion revealed lysyl-PG as well as an additional species 100 m/z units greater than lysyl-PG. This unexpected species corresponded precisely to the expected mass of N-succinylated lysyl-PG. Tandem mass spectrometry revealed a precise match to the fragmentation pattern of this putative new species. PG, lysyl-PG, and N-succinyl-lysyl-PG may form a complete loop of charge reversal from -1 to +1 and then back to -1. Analogous charge reversal by N-succinylation of lysine residues in the bacterial as well as eukaryotic proteomes has been recently discovered as a major posttranslational modification. Such modification in bacterial lipids is possibly catalyzed by an enzyme homologous to the enzymes that modify lysine residues in proteins. Graphical Abstract ?. PMID- 27506208 TI - Action-FRET of a Gaseous Protein. AB - Mass spectrometry is an extremely powerful technique for analysis of biological molecules, in particular proteins. One aspect that has been contentious is how much native solution-phase structure is preserved upon transposition to the gas phase by soft ionization methods such as electrospray ionization. To address this question-and thus further develop mass spectrometry as a tool for structural biology-structure-sensitive techniques must be developed to probe the gas-phase conformations of proteins. Here, we report Forster resonance energy transfer (FRET) measurements on a ubiquitin mutant using specific photofragmentation as a reporter of the FRET efficiency. The FRET data is interpreted in the context of circular dichroism, molecular dynamics simulation, and ion mobility data. Both the dependence of the FRET efficiency on the charge state-where a systematic decrease is observed-and on methanol concentration are considered. In the latter case, a decrease in FRET efficiency with methanol concentration is taken as evidence that the conformational ensemble of gaseous protein cations retains a memory of the solution phase conformational ensemble upon electrospray ionization. Graphical Abstract ?. PMID- 27506209 TI - Erdheim-Chester disease with bilateral Achilles tendon involvement. AB - Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis with a broad spectrum of organ manifestations, presenting with characteristic radiological and histological findings. Soft tissue manifestations (xanthogranulomas) have been reported to be most commonly found in the region of the orbits. We report bilateral Achilles tendon xanthogramlomas in a 36-year-old male with biopsy-proven and B-RAF V600E-positive ECD. Although rare, ECD should be considered in the differential diagnosis of intratendinous masses. PMID- 27506210 TI - Anterior Versus Conventional Approach for Resection of Large Right Lobe Hepatocellular Carcinoma. AB - PURPOSE: In this study, we aim to report the efficacy of using the anterior approach (AA) versus the conventional approach (CA), in surgical resection for large hepatocellular carcinoma (HCC) (>=7 cm) of the right hepatic lobe in terms of surgical and long-term outcomes. MATERIALS AND METHODS: Between 2000 and 2006, 138 consecutive patients who underwent hepatic resection with curative intent for large right lobe HCC >=7 cm were identified from a retrospective database. The 40 patients who had AA were compared with the remaining 98 patients who had CA. Clinicopathological features and surgical results were analyzed and prognostic factors were evaluated by multivariate analysis. RESULTS: There was no significant difference between the two groups as regards clinical, laboratory, and pathological parameters. The operative results had shown a comparable proportion of patients who experienced massive operative blood loss and postoperative complications in the two groups. The AA group had a lower recurrence rate (P = 0.015), better disease-free survival (DFS) (P = 0.001), and overall survival than the CA group. Our study identified that AA is a prognostic factor of both overall survival and disease-free survival for large HCC >=7 cm. CONCLUSION: The AA is a safe and effective technique for right hepatic resection for large HCC and achieves more advantageous long survival outcome over the CA. PMID- 27506211 TI - Identification, characterization of selenoprotein W and its mRNA expression patterns in response to somatostatin 14, cysteamine hydrochloride, 17beta estradiol and a binary mixture of 17beta-estradiol and cysteamine hydrochloride in topmouth culter (Erythroculter ilishaeformis). AB - In this study, a selenoprotein W cDNA was cloned from topmouth culter (Erythroculter ilishaeformis), and it was designated as EISelW. The EISelW open reading frame was composed of 261 base pairs (bp), encoding 86-amino-acid protein. The 5' untranslated region (UTR) consisted of 104 bp, and the 3'-UTR was composed of 365 bp. A selenocysteine insertion sequence (SECIS) element was found in the 3'-UTR of EISelW mRNA. The SECIS element was classified as form II because of a small additional apical loop presented in SECIS element of EISelW mRNA. Bioinformatic approaches showed that the secondary structure of EISelW was a beta1-alpha1-beta2-beta3-beta4-alpha2 pattern from amino-terminal to carboxy terminal. Real-time PCR analysis of EISelW mRNAs expression in 17 tissues showed that the EISelW mRNA was predominantly expressed in liver, ovary, pituitary, various regions of the brain, spinal cord and head kidney. Study of intraperitoneal injection showed that the levels of EISelW mRNA in brain, liver, ovary and spleen were regulated by somatostatin 14 (SS14), 17beta-estradiol (E2), cysteamine hydrochloride (CSH) and a binary mixture of E2 and CSH, dependent on the dosage. These results suggest that E2, SS14 and CSH status may affect tissues of selenium metabolism by regulating the expression of SelW mRNA, as SelW plays a central role in selenium metabolism. PMID- 27506212 TI - Late-onset hypertrophic pyloric stenosis with gastric outlet obstruction: case report and review of the literature. AB - We report late-onset hypertrophic pyloric stenosis in a 17-year-old female. She presented with abdominal pain and an episode of upper gastrointestinal hemorrhage and subsequently developed gastric outlet obstruction. Work-up revealed circumferential pyloric thickening, delayed gastric emptying, and a stenotic, elongated pyloric channel. Biopsies showed benign gastropathy, negative for Helicobacter pylori, without eosinophilic infiltrates. Botulinum toxin injection provided limited relief. Diagnostic laparoscopy confirmed the hypertrophic pylorus and we performed laparoscopic pyloromyotomy. The patient tolerated the procedure well and had complete symptom resolution at 1-year follow-up. Hypertrophic pyloric stenosis is a rare cause of gastric outlet obstruction in adolescents and may be managed successfully with laparoscopic pyloromyotomy. PMID- 27506213 TI - Do Korean Doctors Think a Palliative Consultation Team Would Be Helpful to Their Terminal Cancer Patients? AB - PURPOSE: Hospice and palliative care services (HPC) are not commonly utilized in Korea; however, palliative care teams (PCTs) have been found to be effective at addressing the shortcomings in HPC. In this study, we attempted to outline unmet palliative care needs of terminal cancer patients and the potential benefits of PCTs as perceived by doctors in Korea. MATERIALS AND METHODS: We surveyed 474 doctors at 10 cancer-related academic conferences from June to November 2014 with a self-report questionnaire to assess their perceptions of end-of-life care needs and the expected effects of PCTs on caring for terminal cancer patients. Among those surveyed, 440 respondents who completed the entire questionnaire were analyzed. RESULTS: In all domains, fewer participants reported satisfaction with palliative care services than those reporting needs (p < 0.001). The surveyed participants also reported difficulties with a shortage of time for treatment, psychological burden, lack of knowledge regarding hospice care, lengths of stay, and palliative ward availability. Multivariate logistic regression analysis revealed that female doctors (odds ratio [OR], 2.672; 95% confidence interval [CI], 1.035 to 6.892), doctors who agreed that referring my patients to a HPC means I must give up on my patient (OR, 3.075; 95% CI, 1.324 to 7.127), and doctors who had no experience with HPC education (OR, 3.337; 95% CI, 1.600 to 7.125) were associated with higher expected effectiveness of PCT activities. CONCLUSION: The PCT activities were expected to fill the doctor's perceived unmet HPC needs of terminal cancer patients and difficulties in communications. PMID- 27506214 TI - Outcome and Prognostic Factors for ETV6/RUNX1 Positive Pediatric Acute Lymphoblastic Leukemia Treated at a Single Institution in Korea. AB - PURPOSE: ETV6/RUNX1 (+) acute lymphoblastic leukemia (ALL), which is the most common genetic subtype of pediatric ALL, has a favorable prognosis. In this study, we analyzed the outcome of ETV6/RUNX1 (+) ALL patients treated at our institution with the aim of identifying significant prognostic variables. MATERIALS AND METHODS: Sixty-three patients were diagnosed with ETV6/RUNX1 (+) ALL from 2005 to 2011. Prognostic variables studied included minimal residual disease (MRD) as detected by ETV6/RUNX1 (+) fusion, and the presence of additional cytogenetic abnormalities. RESULTS: The 5-year event-free survival was 84.1+/-4.6%, with 10 patients relapsing at a median of 28.3 months from diagnosis for a 5-year cumulative incidence of relapse of 15.9+/-4.6%. Multivariate analysis revealed that the presence MRD, as detected by real-time quantitative polymerase chain reaction or fluorescence in situ hybridization for ETV6/RUNX1 fusion at end of remission induction, and the presence of additional structural abnormalities of 12p (translocations or inversions) negatively affected outcome. Despite treatment such as allogeneic hematopoietic cell transplantation, eight of the 10 relapsed patients died from disease progression for overall survival of 82.5+/-6.9%. CONCLUSION: ETV6/RUNX1 (+) ALL may be heterogeneous in terms of prognosis, and variables such as MRD at end ofremission induction or additional structural abnormalities of 12p could define a subset of patients who are likely to have poor outcome. PMID- 27506215 TI - [Coronary interventions : Current developments for improved long-term results]. AB - Based on solid scientific evidence, new generation drug-eluting stents (DES) have become established as the standard of care in interventional cardiology. With at least similar safety and superior efficacy over uncoated bare metal stents (BMS) in various scenarios and including patients with increased bleeding risk, there are probably no remaining indications favoring the use of BMS. Additional developments regarding the platform, drug elution characteristics and polymer design were aimed at optimizing DES with even better outcomes. Although there is no lack of new variations, none has proven to be superior and several non inferiority trials lacked statistical power, which precludes the label third generation (over second generation or new generation DES). While it is recognized that potential long-term advantages of bioresorbable scaffolds cannot be expected at this stage from the current ABSORB III trial, the safety and efficacy are encouraging. Beyond procedural aspects, such as intracoronary imaging, variations in duration of antiplatelet therapy should help to improve outcomes but still require careful individual weighting of ischemic vs. bleeding risk. PMID- 27506216 TI - The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas. AB - Carcinoma-associated fibroblasts (CAFs) constitute a substantial proportion of the non-neoplastic mesenchymal cell compartment in various human tumors. These fibroblasts are phenotypically converted from their progenitors via interactions with nearby cancer cells during the course of tumor progression. The resulting CAFs, in turn, support the growth and progression of carcinoma cells. These fibroblasts have a major influence on the hallmarks of carcinoma and promote tumor malignancy through the secretion of tumor-promoting growth factors, cytokines and exosomes, as well as through the remodeling of the extracellular matrix. Coevolution of CAFs and carcinoma cells during tumorigenesis is therefore essential for progression into fully malignant tumors. Recent studies have revealed the molecular mechanisms underlying CAF functions, especially in tumor invasion, metastasis and drug resistance and have highlighted the significant heterogeneity among these cells. In this review, we summarize the impacts of recently identified roles of tumor-promoting CAFs and discuss the therapeutic implications of targeting the heterotypic interactions of these fibroblasts with carcinoma cells. Graphical Abstract ?. PMID- 27506217 TI - Evaluation of the characteristics of leucyl-tRNA synthetase (LeuRS) inhibitor AN3365 in combination with different antibiotic classes. AB - Aminoacyl tRNA synthetases are enzymes involved in the key process of coupling an amino acid to its cognate tRNA. AN3365 is a novel antibiotic that specifically targets leucyl-tRNA synthetase, whose development was halted after evaluation in phase II clinical trials owing to the rapid selection of resistance. In an attempt to bring AN3365 back into the developmental pipeline we have evaluated the efficacy of AN3365 in combination with different classes of antibiotic and characterized its mechanism of action. Although we detect no synergy or antagonism in combination with a range of antibiotic classes, a combination of AN3365 with colistin reduces the accumulation of AN3365-resistant and colistin resistance mutations. We also demonstrate that treatment with AN3365 results in the dramatic accumulation of the alarmone (p)ppGpp, the effector of the stringent response-a key player in antibiotic tolerance. PMID- 27506218 TI - Resilience of cassava (Manihot esculenta Crantz) to salinity: implications for food security in low-lying regions. AB - Rising sea levels are threatening agricultural production in coastal regions due to inundation and contamination of groundwater. The development of more salt tolerant crops is essential. Cassava is an important staple, particularly among poor subsistence farmers. Its tolerance to drought and elevated temperatures make it highly suitable for meeting global food demands in the face of climate change, but its ability to tolerate salt is unknown. Cassava stores nitrogen in the form of cyanogenic glucosides and can cause cyanide poisoning unless correctly processed. Previous research demonstrated that cyanide levels are higher in droughted plants, possibly as a mechanism for increasing resilience to oxidative stress. We determined the tolerance of cassava to salt at two different stages of development, and tested the hypothesis that cyanide toxicity would be higher in salt-stressed plants. Cassava was grown at a range of concentrations of sodium chloride (NaCl) at two growth stages: tuber initiation and tuber expansion. Established plants were able to tolerate 100mM NaCl but in younger plants 40mM was sufficient to retard plant growth severely. Nutrient analysis showed that plants were only able to exclude sodium at low concentrations. The foliar cyanogenic glucoside concentration in young plants increased under moderate salinity stress but was lower in plants grown at high salt. Importantly, there was no significant change in the cyanogenic glucoside concentration in the tubers. We propose that the mechanisms for salinity tolerance are age dependent, and that this can be traced to the relative cost of leaves in young and old plants. PMID- 27506219 TI - Pooling-Based Genome-Wide Association Study Identifies Risk Loci in the Pathogenesis of Ovarian Endometrioma in Chinese Han Women. AB - Endometriosis, regarded as a complex disease, is influenced by multiple genetic factors. Recent genome-wide association studies (GWASs) in endometriosis have identified several susceptibility loci in Caucasian and Japanese populations. However, the overlapped susceptible loci were few. This case-control study tried to identify risk loci-related genes for ovarian endometrioma in Chinese Han women from central China using DNA pooling-based GWAS. Genome DNA samples were extracted from 3038 participants in central China. Pooling-based genome-wide scan and individual genotyping were performed using Affymetrix Genome-Wide Human SNP Array 6.0 and IPLEX Gold system, which demonstrated 10 ovarian endometrioma related novel risk loci. There were 3 of them with P value < 5 * 10-06, separately locating in intron of insulin-like growth factor 1 receptor, chromosome 7 open reading frame 50, and Meis homeobox 1. In conclusion, the pooling-based GWAS for ovarian endometrioma identified some novel single nucleotide polymorphisms in Chinese Han women of central China. Further assessment in other samples will be crucial to confirm the susceptibility of these results and explore the mechanisms of the related genes in the pathogenesis of ovarian endometrioma. PMID- 27506220 TI - Medication, rehabilitation and health care consumption in adults with cerebral palsy: a population based study. AB - OBJECTIVE: To evaluate medication, rehabilitation and healthcare consumption in adults with CP as a function of Gross Motor Function Classification System (GMFCS) level. DESIGN: Questionnaire-based cross-sectional study. SETTING: Brittany, a French county. SUBJECTS: Adults with cerebral palsy. INTERVENTIONS: Questionnaires relating to drugs, orthotic devices, mobility aids, rehabilitation and medical input were sent to 435 members of a unique regional French network dedicated to adults with cerebral palsy. The questionnaire was completed by the participant or a helper if necessary. RESULTS: Of the 282 responders, 7.8% had a GMFCS level of I, 14.2% II, 17.7% III, 29.1% IV and 31.2% V. Participants consumed a large amount of healthcare. Almost three-quarters took orally administered drugs, of which antispastic and antiepileptic drugs were among the most frequent. Nearly all patients had at least one type of rehabilitation, 87.2% had physiotherapy, 78% used at least one mobility aid and 69.5% used at least one orthotic device. The frequency of numerous inputs increased with GMFCS level. Specificities were found for each GMFCS level, e.g. participants with GMFCS level IV and V had a high level of medical input and a greater use of trunk-supporting devices, antireflux and laxative. Profiles could be established based on GMFCS levels. CONCLUSIONS: Adults with cerebral palsy use a large amount of drugs, mobility aids, orthotic devices, rehabilitation and medical input. Healthcare is targeted at cerebral palsy-related issues. GMFCS is a determinant of healthcare consumption and thus a useful tool for clinical practice to target care appropriately. PMID- 27506221 TI - Is the Association Between Sweet and Bitter Perception due to Genetic Variation? AB - Perceived intensities of sweetness and bitterness are correlated with one another and each is influenced by genetics. The extent to which these correlations share common genetic variation, however, remains unclear. In a mainly adolescent sample (n = 1901, mean age 16.2 years), including 243 monozygotic (MZ) and 452 dizygotic (DZ) twin pairs, we estimated the covariance among the perceived intensities of 4 bitter compounds (6-n-propylthiouracil [PROP], sucrose octa-acetate, quinine, caffeine) and 4 sweeteners (the weighted mean ratings of glucose, fructose, neohesperidine dihydrochalcone, aspartame) with multivariate genetic modeling. The sweetness factor was moderately correlated with sucrose octa-acetate, quinine, and caffeine (rp = 0.35-0.40). This was mainly due to a shared genetic factor (rg = 0.46-0.51) that accounted for 17-37% of the variance in the 3 bitter compounds' ratings and 8% of the variance in general sweetness ratings. In contrast, an association between sweetness and PROP only became evident after adjusting for the TAS2R38 diplotype (rp increased from 0.18 to 0.32) with the PROP genetic factor accounting for 6% of variance in sweetness. These genetic associations were not inflated by scale use bias, as the cross-trait correlations for both MZ and DZ twins were weak. There was also little evidence for mediation by cognition or behavioral factors. This suggests an overlap of genetic variance between perceptions of sweetness and bitterness from a variety of stimuli, which includes PROP when considering the TAS2R38 diplotype. The most likely sources of shared variation are within genes encoding post-receptor transduction mechanisms common to the various taste G protein-coupled receptors. PMID- 27506222 TI - Efficacy and Safety of Liraglutide Added to Insulin Treatment in Type 1 Diabetes: The ADJUNCT ONE Treat-To-Target Randomized Trial. AB - OBJECTIVE: To investigate whether liraglutide added to treat-to-target insulin improves glycemic control and reduces insulin requirements and body weight in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A 52-week, double blind, treat-to-target trial involving 1,398 adults randomized 3:1 to receive once-daily subcutaneous injections of liraglutide (1.8, 1.2, or 0.6 mg) or placebo added to insulin. RESULTS: HbA1c level was reduced 0.34-0.54% (3.7-5.9 mmol/mol) from a mean baseline of 8.2% (66 mmol/mol), and significantly more for liraglutide 1.8 and 1.2 mg compared with placebo (estimated treatment differences [ETDs]: 1.8 mg liraglutide -0.20% [95% CI -0.32; -0.07]; 1.2 mg liraglutide 0.15% [95% CI -0.27; -0.03]; 0.6 mg liraglutide -0.09% [95% CI -0.21; 0.03]). Insulin doses were reduced by the addition of liraglutide 1.8 and 1.2 mg versus placebo (estimated treatment ratios: 1.8 mg liraglutide 0.92 [95% CI 0.88; 0.96]; 1.2 mg liraglutide 0.95 [95% CI 0.91; 0.99]; 0.6 mg liraglutide 1.00 [95% CI 0.96; 1.04]). Mean body weight was significantly reduced in all liraglutide groups compared with placebo ETDs (1.8 mg liraglutide -4.9 kg [95% CI -5.7; 4.2]; 1.2 mg liraglutide -3.6 kg [95% CI -4.3; -2.8]; 0.6 mg liraglutide -2.2 kg [95% CI -2.9; -1.5]). The rate of symptomatic hypoglycemia increased in all liraglutide groups (estimated rate ratios: 1.8 mg liraglutide 1.31 [95% CI 1.07; 1.59]; 1.2 mg liraglutide 1.27 [95% CI 1.03; 1.55]; 0.6 mg liraglutide 1.17 [95% CI 0.97; 1.43]), and hyperglycemia with ketosis increased significantly for liraglutide 1.8 mg only (event rate ratio 2.22 [95% CI 1.13; 4.34]). CONCLUSIONS: Liraglutide added to insulin therapy reduced HbA1c levels, total insulin dose, and body weight in a population that was generally representative of subjects with type 1 diabetes, accompanied by increased rates of symptomatic hypoglycemia and hyperglycemia with ketosis, thereby limiting clinical use in this group. PMID- 27506223 TI - A Smartphone Application to Deliver a Treat-to-Target Insulin Titration Algorithm in Insulin-Naive Patients With Type 2 Diabetes: A Pilot Randomized Controlled Trial. PMID- 27506224 TI - Toxicity Evaluation of Bisphenol A Administered by Gavage to Sprague Dawley Rats From Gestation Day 6 Through Postnatal Day 90. PMID- 27506225 TI - Alternatives to HIST for acellular pertussis vaccines: progress and challenges in replacement. AB - The 'International Workshop on Alternatives to the Murine Histamine Sensitization Test for Acellular Pertussis Vaccines: Progress and Challenges in the Replacement of HIST' was held on 24 August 2014, in Prague, Czech Republic, as a satellite meeting to the 9th World Congress on Alternatives and Animal Use in the Life Sciences. Participants discussed the progress and challenges associated with the development, validation, and implementation of in vitro assays as replacements for the histamine sensitisation test (HIST) for acellular pertussis vaccines. Discussions focused on the consistency approach, the necessary framework for regulatory acceptance of a harmonised method, and recent international efforts towards the development of in vitro assays to replace the HIST. Workshop participants agreed that acceptable alternatives to the HIST should be based on ADP ribosylation-mediated cell intoxication and therefore that the CHO cell clustering assay, which measures cell intoxication, should be further pursued and developed as a possible replacement for the HIST. Participants also agreed to continue ongoing multinational discussions involving national and international standardisation authorities to reach consensus and to organise collaborative studies in this context for assay characterisation and calibration of reference materials. PMID- 27506226 TI - DTMiner: identification of potential disease targets through biomedical literature mining. AB - MOTIVATION: Biomedical researchers often search through massive catalogues of literature to look for potential relationships between genes and diseases. Given the rapid growth of biomedical literature, automatic relation extraction, a crucial technology in biomedical literature mining, has shown great potential to support research of gene-related diseases. Existing work in this field has produced datasets that are limited both in scale and accuracy. RESULTS: In this study, we propose a reliable and efficient framework that takes large biomedical literature repositories as inputs, identifies credible relationships between diseases and genes, and presents possible genes related to a given disease and possible diseases related to a given gene. The framework incorporates name entity recognition (NER), which identifies occurrences of genes and diseases in texts, association detection whereby we extract and evaluate features from gene-disease pairs, and ranking algorithms that estimate how closely the pairs are related. The F1-score of the NER phase is 0.87, which is higher than existing studies. The association detection phase takes drastically less time than previous work while maintaining a comparable F1-score of 0.86. The end-to-end result achieves a 0.259 F1-score for the top 50 genes associated with a disease, which performs better than previous work. In addition, we released a web service for public use of the dataset. AVAILABILITY AND IMPLEMENTATION: The implementation of the proposed algorithms is publicly available at http://gdr web.rwebox.com/public_html/index.php?page=download.php The web service is available at http://gdr-web.rwebox.com/public_html/index.php CONTACT: jenny.wei@astrazeneca.com or kzhu@cs.sjtu.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 27506227 TI - Support vector machine model of developmental brain gene expression data for prioritization of Autism risk gene candidates. AB - MOTIVATION: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with clinical heterogeneity and a substantial polygenic component. High throughput methods for ASD risk gene identification produce numerous candidate genes that are time-consuming and expensive to validate. Prioritization methods can identify high-confidence candidates. Previous ASD gene prioritization methods have focused on a priori knowledge, which excludes genes with little functional annotation or no protein product such as long non-coding RNAs (lncRNAs). RESULTS: We have developed a support vector machine (SVM) model, trained using brain developmental gene expression data, for the classification and prioritization of ASD risk genes. The selected feature model had a mean accuracy of 76.7%, mean specificity of 77.2% and mean sensitivity of 74.4%. Gene lists comprised of an ASD risk gene and adjacent genes were ranked using the model's decision function output. The known ASD risk genes were ranked on average in the 77.4th, 78.4th and 80.7th percentile for sets of 101, 201 and 401 genes respectively. Of 10,840 lncRNA genes, 63 were classified as ASD-associated candidates with a confidence greater than 0.95. Genes previously associated with brain development and neurodevelopmental disorders were prioritized highly within the lncRNA gene list. CONTACT: liangjw@clemson.eduSupplementary information: Supplementary data are available at Bioinformatics online. PMID- 27506229 TI - Skills for Healthy Adult Relationships at the University of Maryland, Baltimore County: Program Development and Preliminary Data. AB - The present study examines the development and preliminary pilot findings of Skills for Healthy Adult Relationships at the University of Maryland, Baltimore County (SHARe@UMBC)-an intimate partner violence prevention program for college students. SHARe@UMBC is based on an integrative cognitive-behavioral model of communication and emotion regulation in close interpersonal relationships. There were four aims of the present study: first, to describe program development; second, to examine program acceptability and participant satisfaction; third, to examine the extent to which participants acquired relationship skills and their level of confidence in using those skills; and fourth, to examine perpetration and victimization of physical, sexual, and psychological aggression. These aims utilized data collected before program initiation, immediately after program completion, and at a follow-up 9 to 15 months after program completion. Findings from two pilot groups (15 students in total; eight women and seven men) indicated high ratings of program acceptability and satisfaction, reductions in negative communication, improvements in confidence using conflict management strategies with romantic partners and peers, and confidence initiating new romantic relationships. In addition, large effect sizes were observed for confidence providing emotional support to a romantic partner and self-disclosure with peers. Participants reported no incidents of physical, sexual, or psychological aggression perpetration or victimization at follow-up. Pilot implementation and initial uncontrolled results are encouraging and provide support for initiating a more extensive controlled investigation of program efficacy. PMID- 27506228 TI - Acute Precipitants of Physical Elder Abuse: Qualitative Analysis of Legal Records From Highly Adjudicated Cases. AB - Elder abuse is a common phenomenon with potentially devastating consequences for older adults. Although researchers have begun to identify predisposing risk factors for elder abuse victims and abusers, little is known about the acute precipitants that lead to escalation to physical violence. We analyzed legal records from highly adjudicated cases to describe these acute precipitants for physical elder abuse. In collaboration with a large, urban district attorney's office, we qualitatively evaluated legal records from 87 successfully prosecuted physical elder abuse cases from 2003 to 2015. We transcribed and analyzed narratives of the events surrounding physical abuse within victim statements, police reports, and prosecutor records. We identified major themes using content analysis. We identified 10 categories of acute precipitants that commonly triggered physical elder abuse, including victim attempting to prevent the abuser from entering or demanding that he or she leave, victim threatening or attempting to leave/escape, threat or perception that the victim would involve the authorities, conflict about a romantic relationship, presence during/intervention in ongoing family violence, issues in multi-generational child rearing, conflict about the abuser's substance abuse, confrontation about financial exploitation, dispute over theft/destruction of property, and disputes over minor household issues. Common acute precipitants of physical elder abuse may be identified. Improved understanding of these acute precipitants for escalation to physical violence and their contribution to elder abuse may assist in the development of prevention and management strategies. PMID- 27506230 TI - Implementing a Systematic Screening Procedure for Older Adult Mistreatment Within Individual Clinical Supervision: Is It Feasible? AB - Home care professionals are well positioned to witness or prevent older adult mistreatment in the community. Screening efforts are important because most victims will not easily come forth. Two Canadian local community service centers implemented a systematic screening procedure within preexisting individual clinical supervision sessions to support social workers and improve detection of mistreatment. The aim of this pilot project was to assess fidelity, acceptability, and feasibility of the new procedure. Qualitative data was collected using individual interviews with two clinical supervisors, one focus group with eight social workers and content transcribed from 15 supervision sessions. It was estimated that 400 clients were screened for older adult mistreatment using this new procedure. Results showed the procedure was judged acceptable because it sensitized social workers to risk factors, gave them time to reflect upon and discuss probable cases with their clinical supervisor. Nonetheless, participants did not use the designated statistical code in the new procedure to document mistreatment situations. Feasibility was mainly challenged by the fact that screening for older adult mistreatment competes with other organizational priorities. Future initiatives must develop strategies to counteract those barriers. PMID- 27506231 TI - Microbial Activation of Bacillus subtilis-Immobilized Microgel Particles for Enhanced Oil Recovery. AB - Microbially enhanced oil recovery involves the use of microorganisms to extract oil remaining in reservoirs. Here, we report fabrication of microgel particles with immobilized Bacillus subtilis for application to microbially enhanced oil recovery. Using B. subtilis isolated from oil-contaminated soils in Myanmar, we evaluated the ability of this microbe to reduce the interfacial tension at the oil-water interface via production of biosurfactant molecules, eventually yielding excellent emulsification across a broad range of the medium pH and ionic strength. To safely deliver B. subtilis into a permeable porous medium, in this study, these bacteria were physically immobilized in a hydrogel mesh of microgel particles. In a core flooding experiment, in which the microgel particles were injected into a column packed with silica beads, we found that these particles significantly increased oil recovery in a concentration-dependent manner. This result shows that a mesh of microgel particles encapsulating biosurfactant producing microorganisms holds promise for recovery of oil from porous media. PMID- 27506232 TI - Differentiation of pulmonary bacterial pathogens in cystic fibrosis by volatile metabolites emitted by their in vitro cultures: Pseudomonas aeruginosa, Staphylococcus aureus, Stenotrophomonas maltophilia and the Burkholderia cepacia complex. AB - As a contribution to the continuing search for breath biomarkers of lung and airways infection in patients with cystic fibrosis, CF, we have analysed the volatile metabolites released in vitro by Pseudomonas aeruginosa and other bacteria involved in respiratory infections in these patients, i.e. those belonging to the Burkholderia cepacia complex, Staphylococcus aureus or Stenotrophomonas maltophilia. These opportunistic pathogens are generally harmless to healthy people but they may cause serious infections in patients with severe underlying disease or impaired immunity such as CF patients. Volatile organic compounds emitted from the cultures of strains belonging to the above mentioned four taxa were analysed by selected ion flow tube mass spectrometry. In order to minimize the effect of differences in media composition all strains were cultured in three different liquid media. Multivariate statistical analysis reveals that the four taxa can be well discriminated by the differences in the headspace VOC concentration profiles. The compounds that should be targeted in breath as potential biomarkers of airway infection were identified for each of these taxa of CF pathogens. PMID- 27506233 TI - Single Figure Publications: Towards a novel alternative format for scholarly communication. AB - The single figure publication is a novel, efficient format by which to communicate scholarly advances. It will serve as a forerunner of the nano publication, a modular unit of information critical for machine-driven data aggregation and knowledge integration. PMID- 27506234 TI - Changes in Functional Connectivity of Default Mode Network with Auditory and Right Frontoparietal Networks in Poststroke Aphasia. AB - To evaluate the influence of poststroke aphasia on the functional association of widespread large-scale neuronal networks, we analyzed functional connectivity (FC) between resting-state brain networks (RSNs) in aphasic patients (N = 15) and in healthy volunteers (N = 17) of the same age using resting-state functional connectivity magnetic resonance imaging. As a result, six RSNs were isolated and cross-correlation matrices were computed for their time courses. Aphasic patients showed decreased correlations between posterior part of the default mode (pDMN) and both auditory (AUD) and right frontoparietal (RFP) networks. Additionally, we calculated regions of interest-based FC (ROI-FC), gray and white matter volumes in the ROIs overlapping with pDMN, AUD, and RFP. ROI-FC analysis showed decreased FC between the right pars triangularis and both right middle frontal and right superior frontal gyri. The decreased pDMN-RFP connectivity in patients is likely to reflect changes in FC of these nodes. The lesion in the regions overlapping with pDMN and AUD networks leads to the significantly decreased pDMN-AUD connectivity. Our results suggest that abnormal FC in stroke patients may reflect the impairment of activity not only in the regions directly affected by stroke lesion in the left hemisphere but also in the homotopic regions of the intact right hemisphere. The increase of gray and white matter volume in the right supramarginal gyrus, the functional hub of pDMN, AUD, and RFP networks, correlated with less speech impairment. This increase might reflect a right hemisphere neuroplasticity process to compensate the impaired function of the homotopic region of left frontoparietal network (LFP), pDMN, and AUD in the left hemisphere. The presented results contribute to the hypothesized compensative role of the transfer of attention and executive functions from the damaged areas in the left hemisphere to the right homotopic areas, accompanied by more preserved language skills at the chronic stroke stage. PMID- 27506236 TI - Relative and Absolute Reliabilities of the Conners' Continuous Performance Test II in Schizophrenia. AB - OBJECTIVE: The Conners' Continuous Performance Test II (CCPT-II) is one of the most commonly used tests of sustained attention in schizophrenia. To manage and monitor sustained attention deficits in schizophrenia, clinicians have to reliably assess the degree of attention impairment. The purpose of our study was to determine the relative and absolute reliability of the CCPT-II in schizophrenia. METHOD: The final sample was a total of 108 patients with schizophrenia. The primary measures in this study were the CCPT-II and the Clinical Global Impression-Severity (CGI-S). The CCPT-II was administered twice, 1 month apart, by a specially trained occupational therapist. We assessed two types of reliability: relative and absolute reliability. Relative reliability was determined with the intra-class correlation coefficient (ICC). Absolute reliability was quantified with standard error of measurement (SEM), minimal detectable change (MDC), and Bland-Altman's 95% limits of agreement (LOA). RESULTS: The ICCs for the five CCPT-II indexes (Omissions, Commissions, Hit RT, Hit RT Std Error, and Variability) ranged from 0.66 to 0.79. The MDCs (MDC%) of the five indices were 13.53 (156.78), 10.67 (47.85), 122.10 (34.16), 8.15 (106.82), and 25.81 (162.63), respectively. CONCLUSIONS: According to the results, the CCPT-II has limited reliability in monitoring the sustained attention function of patients with schizophrenia. Our results can be used as a reference for the measurement error of CCPT-II to help clinicians and researchers determine the true change between successive assessments of patients with schizophrenia. PMID- 27506235 TI - Conceptual Models and Guidelines for Clinical Assessment of Financial Capacity. AB - The ability to manage financial affairs is a life skill of critical importance, and neuropsychologists are increasingly asked to assess financial capacity across a variety of settings. Sound clinical assessment of financial capacity requires knowledge and appreciation of applicable clinical conceptual models and principles. However, the literature has presented relatively little conceptual guidance for clinicians concerning financial capacity and its assessment. This article seeks to address this gap. The article presents six clinical models of financial capacity : (1) the early gerontological IADL model of Lawton, (2) the clinical skills model and (3) related cognitive psychological model developed by Marson and colleagues, (4) a financial decision-making model adapting earlier decisional capacity work of Appelbaum and Grisso, (5) a person-centered model of financial decision-making developed by Lichtenberg and colleagues, and (6) a recent model of financial capacity in the real world developed through the Institute of Medicine. Accompanying presentation of the models is discussion of conceptual and practical perspectives they represent for clinician assessment. Based on the models, the article concludes by presenting a series of conceptually oriented guidelines for clinical assessment of financial capacity. In summary, sound assessment of financial capacity requires knowledge and appreciation of clinical conceptual models and principles. Awareness of such models, principles and guidelines will strengthen and advance clinical assessment of financial capacity. PMID- 27506237 TI - The Wayfinding Questionnaire as a Self-report Screening Instrument for Navigation related Complaints After Stroke: Internal Validity in Healthy Respondents and Chronic Mild Stroke Patients. AB - OBJECTIVE: In current stroke care, cognitive problems are usually diagnosed in a stepwise manner. More specifically, screening instruments are first applied to support healthcare professionals in deciding whether a second step (an extensive assessment) would be appropriate. None of the existing screening instruments, however, takes navigation ability into account. This is problematic, as navigation impairment after stroke has been shown to be common, more so than previously thought. The Wayfinding Questionnaire (WQ) is therefore presented as a screening instrument for navigation-related complaints after stroke. The internal validity of the WQ was investigated in two samples of participants to establish the final version. METHOD AND RESULTS: In Study 1, the WQ was administered in a representative sample of 356 healthy participants. Its factor structure was investigated using a principal component analysis. This procedure resulted in deletion of four items and revealed a three-factor structure: "Navigation and Orientation," "Spatial Anxiety," and "Distance Estimation". In Study 2, a confirmatory analysis was performed to directly verify the factor structure as obtained in Study 1 based on data of 158 chronic mild stroke patients. Fit indices of the confirmatory analysis indicated acceptable model fit. The reliability of the three subscales was found to be very good in both healthy participants and patients. CONCLUSIONS: These studies allowed us to determine the final version of the WQ. The results indicated that the WQ is an internally valid and reliable instrument that can be interpreted using a three-factor structure in both healthy respondents and chronic mild stroke patients. PMID- 27506238 TI - The Allelochemical MDCA Inhibits Lignification and Affects Auxin Homeostasis. AB - The phenylpropanoid 3,4-(methylenedioxy)cinnamic acid (MDCA) is a plant-derived compound first extracted from roots of Asparagus officinalis and further characterized as an allelochemical. Later on, MDCA was identified as an efficient inhibitor of 4-COUMARATE-CoA LIGASE (4CL), a key enzyme of the general phenylpropanoid pathway. By blocking 4CL, MDCA affects the biosynthesis of many important metabolites, which might explain its phytotoxicity. To decipher the molecular basis of the allelochemical activity of MDCA, we evaluated the effect of this compound on Arabidopsis thaliana seedlings. Metabolic profiling revealed that MDCA is converted in planta into piperonylic acid (PA), an inhibitor of CINNAMATE-4-HYDROXYLASE (C4H), the enzyme directly upstream of 4CL. The inhibition of C4H was also reflected in the phenolic profile of MDCA-treated plants. Treatment of in vitro grown plants resulted in an inhibition of primary root growth and a proliferation of lateral and adventitious roots. These observed growth defects were not the consequence of lignin perturbation, but rather the result of disturbing auxin homeostasis. Based on DII-VENUS quantification and direct measurement of cellular auxin transport, we concluded that MDCA disturbs auxin gradients by interfering with auxin efflux. In addition, mass spectrometry was used to show that MDCA triggers auxin biosynthesis, conjugation, and catabolism. A similar shift in auxin homeostasis was found in the c4h mutant ref3 2, indicating that MDCA triggers a cross talk between the phenylpropanoid and auxin biosynthetic pathways independent from the observed auxin efflux inhibition. Altogether, our data provide, to our knowledge, a novel molecular explanation for the phytotoxic properties of MDCA. PMID- 27506239 TI - Effects of Auxins on PIN-FORMED2 (PIN2) Dynamics Are Not Mediated by Inhibiting PIN2 Endocytosis. AB - By using the photoconvertible fluorescence protein Dendra2 as a tag we demonstrated that neither the naturally occurring auxins indole-3-acetic acid and indole-3-butyric acid, nor the synthetic auxin analogs 1-naphthaleneacetic acid and 2,4-dichlorophenoxyacetic acid nor compounds inhibiting polar auxin transport such as 2,3,5-triiodobenzoic acid and 1-N-naphthylphthalamic acid, were able to inhibit endocytosis of the putative auxin transporter PIN-FORMED2 (PIN2) in Arabidopsis (Arabidopsis thaliana) root epidermis cells. All compounds, except Indole-3-butyric acid, repressed the recovery of the PIN2-Dendra2 plasma membrane pool after photoconversion when they were used in high concentrations. The synthetic auxin analogs 1-naphthaleneacetic acid and 2,4-dichlorophenoxyacetic acid showed the strongest inhibition. Auxins and auxin transport inhibitors suppressed also the accumulation of both newly synthesized and endocytotic PIN2 pools in Brefeldin A compartments (BFACs). Furthermore, we demonstrated that all compounds are also interfering with BFAC formation. The synthetic auxin analogs caused the highest reduction in the number and size of BFACs. We concluded that auxins and inhibitors of auxin transport do affect PIN2 turnover in the cells, but it is through the synthetic rather than the endocytotic pathway. The study also confirmed inappropriateness of the BFA-based approach to study PIN2 endocytosis because the majority of PIN2 accumulating in BFACs is newly synthesized and not derived from the plasma membrane. PMID- 27506240 TI - The DEK1 Calpain Linker Functions in Three-Dimensional Body Patterning in Physcomitrella patens. AB - The DEFECTIVE KERNEL1 (DEK1) calpain is a conserved 240-kD key regulator of three dimensional body patterning in land plants acting via mitotic cell plane positioning. The activity of the cytosolic C-terminal calpain protease is regulated by the membrane-anchored DEK1 MEM, which is connected to the calpain via the 600-amino acid residue Linker. Similar to the calpain and MEM domains, the Linker is highly conserved in the land plant lineage, the similarity dropping sharply compared with orthologous charophyte sequences. Using site-directed mutagenesis, we studied the effect on Physcomitrella patens development by deleting the Linker and two conserved Linker motifs. The results show that removal of the Linker has nearly the same effect as removal of the entire DEK1 gene. In contrast, deletion of the conserved Laminin_G3 (LG3) domain had a milder effect, perturbing leafy gametophore patterning and archegonia development. The LG3 domain from Marchantia polymorpha is fully functional in P. patens, whereas angiosperm sequences are not functional. Deletion of a C-terminal Linker subsegment containing a potential calpain autolytic site severely disturbs gametophore development. Finally, changing one of the three calpain active-site amino acid residues results in the same phenotype as deleting the entire DEK1 gene. Based on the conserved nature of animal and DEK1 calpains, we propose that the DEK1 MEM-Linker complex inactivates the calpain by forcing apart the two calpain subunits carrying the three amino acids of the active site. PMID- 27506241 TI - ORM Expression Alters Sphingolipid Homeostasis and Differentially Affects Ceramide Synthase Activity. AB - Sphingolipid synthesis is tightly regulated in eukaryotes. This regulation in plants ensures sufficient sphingolipids to support growth while limiting the accumulation of sphingolipid metabolites that induce programmed cell death. Serine palmitoyltransferase (SPT) catalyzes the first step in sphingolipid biosynthesis and is considered the primary sphingolipid homeostatic regulatory point. In this report, Arabidopsis (Arabidopsis thaliana) putative SPT regulatory proteins, orosomucoid-like proteins AtORM1 and AtORM2, were found to interact physically with Arabidopsis SPT and to suppress SPT activity when coexpressed with Arabidopsis SPT subunits long-chain base1 (LCB1) and LCB2 and the small subunit of SPT in a yeast (Saccharomyces cerevisiae) SPT-deficient mutant. Consistent with a role in SPT suppression, AtORM1 and AtORM2 overexpression lines displayed increased resistance to the programmed cell death-inducing mycotoxin fumonisin B1, with an accompanying reduced accumulation of LCBs and C16 fatty acid-containing ceramides relative to wild-type plants. Conversely, RNA interference (RNAi) suppression lines of AtORM1 and AtORM2 displayed increased sensitivity to fumonisin B1 and an accompanying strong increase in LCBs and C16 fatty acid-containing ceramides relative to wild-type plants. Overexpression lines also were found to have reduced activity of the class I ceramide synthase that uses C16 fatty acid acyl-coenzyme A and dihydroxy LCB substrates but increased activity of class II ceramide synthases that use very-long-chain fatty acyl-coenzyme A and trihydroxy LCB substrates. RNAi suppression lines, in contrast, displayed increased class I ceramide synthase activity but reduced class II ceramide synthase activity. These findings indicate that ORM mediation of SPT activity differentially regulates functionally distinct ceramide synthase activities as part of a broader sphingolipid homeostatic regulatory network. PMID- 27506243 TI - A Cost Analysis of Salbutamol Administration by Metered-Dose Inhalers with Spacers versus Nebulization for Patients with Wheeze in the Pediatric Emergency Department: Evidence from Observational Data in Nova Scotia. AB - BACKGROUND: Despite evidence demonstrating the advantages of metered-dose inhalers with spacers (MDI-s), nebulization (NEB) remains the primary method of asthma treatment in some pediatric emergency departments (PEDs). There is a perception that delivering salbutamol by MDI-s is more costly than by NEB. This research evaluates the relative costs of MDI-s and NEB using local, hospital specific, patient-level data. METHODS: Regression models estimated associations between the salbutamol inhalation method and costs, length of stay (LOS) in the PED and hospital, and the probability of admission. Our population was a random sample of 822 patients presenting with wheeze to the PED in 2008/2009. Control variables included age, sex, triage acuity, time of PED visit, other medications, and vitals. Costs were calculated using the prices and quantities of medical resources used per treatment. Probabilistic sensitivity analysis was used. RESULTS: Treatment with MDI-s versus NEB was associated with an absolute decrease in hospitalization of 4.4% (p<0.05) and a 25-hour (p<0.001) reduction in average inpatient stay, after controlling for triage acuity and patient characteristics. This resulted in savings of $24/patient in the PED and $180/patient overall (p<0.001). Inpatient care accounted for more than 90% of total patient costs. CONCLUSIONS: Our results suggest economic gains associated with MDI-s for salbutamol inhalation in PEDs. Sensitivity analyses show that this conclusion is not affected by changes in model parameters that may differ by jurisdiction. Since most facilities already collect the data used for this study, our methods could be adopted for a cross-jurisdictional account of the cost effectiveness of MDI-s. PMID- 27506244 TI - Palladium nanoparticles supported on a nickel pyrazolate metal organic framework as a catalyst for Suzuki and carbonylative Suzuki couplings. AB - Methanolic reduction of [PdCl2(CH3CN)2] on a [Ni(2,5-di(1H-pyrazol-4 yl)benzenesulfonate)2] metal organic framework gives rise to Pd(2+)/Pd(0) nanocomposites with Suzuki and carbonylative Suzuki heterogeneous catalytic activities. PMID- 27506242 TI - d-Lactate Dehydrogenase Links Methylglyoxal Degradation and Electron Transport through Cytochrome c. AB - Glycolysis generates methylglyoxal (MGO) as an unavoidable, cytotoxic by-product in plant cells. MGO scavenging is performed by the glyoxalase system, which produces d-lactate as an end product. d-Lactate dehydrogenase (d-LDH) is encoded by a single gene in Arabidopsis (Arabidopsis thaliana; At5g06580). It catalyzes in vitro the oxidation of d-lactate to pyruvate using flavin adenine dinucleotide as a cofactor; knowledge of its function in the context of the plant cell remains sketchy. Blue native-polyacrylamide gel electrophoresis of mitochondrial extracts combined with in gel activity assays using different substrates and tandem mass spectrometry allowed us to definitely show that d-LDH acts specifically on d lactate, is active as a dimer, and does not associate with respiratory supercomplexes of the inner mitochondrial membrane. The combined use of cytochrome c (CYTc) loss-of-function mutants and respiratory complex III inhibitors showed that CYTc acts as the in vivo electron acceptor of d-LDH. CYTc loss-of-function mutants, as well as the d-LDH mutants, were more sensitive to d lactate and MGO, indicating that they function in the same pathway. In addition, overexpression of d-LDH and CYTc increased tolerance to d-lactate and MGO Together with fine-localization of d-LDH, the functional interaction with CYTc in vivo strongly suggests that d-lactate oxidation takes place in the mitochondrial intermembrane space, delivering electrons to the respiratory chain through CYTc These results provide a comprehensive picture of the organization and function of d-LDH in the plant cell and exemplify how the plant mitochondrial respiratory chain can act as a multifunctional electron sink for reductant from cytosolic pathways. PMID- 27506245 TI - Lithium ion solvation by ethylene carbonates in lithium-ion battery electrolytes, revisited by density functional theory with the hybrid solvation model and free energy correction in solution. AB - Complex formation between lithium (Li(+)) ions and electrolyte molecules would affect the ionic conductivity through the electrolyte in lithium-ion batteries (LIBs). We hence revisit the solvation number of Li(+) in the most commonly used ethylene carbonate (EC) electrolyte. The solvation number n of Li(+)(EC)n in the first solvation shell of Li(+) is estimated on the basis of the free energy calculated by the density functional theory combined with a hybrid solvation model where the explicit solvation shell of Li(+) is immersed in a free volume of an implicit bulk solvent. This new hybrid solvation (implicit and explicit) model predicts the most probable solvation number (n = 4) and solvation free energy ( 91.3 kcal mol(-1)) of Li(+) in a good agreement with those predicted by calculations employing simpler solvation models (either implicit or explicit). The desolvation (n = 2) of Li(0)(EC)n upon reduction near anodes is also well described with this new hybrid model. PMID- 27506246 TI - Self-assembly and the hemolysis effect of monodisperse N,N diethylacrylamide/acrylic acid nanogels with high contents of acrylic acid. AB - Monodisperse temperature/pH sensitive poly(N,N-diethylacrylamide/acrylic acid) (P(DEA/AAc)) nanogels with high contents of AAc up to 40 wt% have been prepared. In this study, it was unexpectedly found that the polydispersity of the nanogels with 40 wt% AAc strongly depended on the initiator concentration. Monodisperse P(DEA/AA) nanogels were synthesized only at a very low concentration of initiator. The phase transition behavior of the nanogels in water can be tuned by pH and temperature. Due to low polydispersity, the nanogels self-assembled into colloidal crystals at different temperatures below the volume phase transition temperature (VPTT). The sharp Bragg peaks of the crystals were significantly blue shifted as the concentration of the nanogels was increased. In contrast, the condensed suspensions without crystals still exhibited clear colours resulting from a short-range order structure. The reflection spectra of the coloured suspensions showed that the peak wavelength became a bit longer and much broader. And the reflection intensity of the coloured suspensions was much weaker. Elastic and coloured crosslinked nanogel networks prepared by a one-pot and rapid light initiated crosslinking method showed responses to pH and temperature. Furthermore, the interaction between the nanogels and peptide melittin was investigated. The results showed that an increasing AAc composition led to more efficient inhibition of the hemolytic activity of melittin. The nanogels with 40 wt% AAc composition completely inhibited hemolytic activity at a nanogel concentration of 400 ug ml(-1). Thus, monodisperse P(DEA/AAc) nanogels of high AAc composition may be developed as efficient substitutes for antibody-based antidotes. Owing to the combined influence of the periodic structure of the crystals of the nanogels and an efficient neutralization effect, the P(DEA/AAc) nanogels show promise to become an integral step for preparing valuable naked-eye biosensors as simple, cheap and stable substitutes for antibody-based antidotes. PMID- 27506247 TI - Binding-responsive catalysis of Taq DNA polymerase for the sensitive and selective detection of cell-surface proteins. AB - Here we develop a new method for the sensitive and selective detection of cell surface proteins with an aptamer probe designed for binding-responsive catalysis of Taq DNA polymerase. Taking the biotin receptor as a model, the method allows the detection of target protein on surfaces of different types of cancer cells. PMID- 27506248 TI - The role of confinement and corona crystallinity on the bending modulus of copolymer micelles measured directly by AFM flexural tests. AB - We present an approach which makes it possible to directly determine the bending modulus of single elongated block copolymer micelles. This is done by forming arrays of suspended micelles onto microfabricated substrates and by performing three-point bending flexural tests, using an atomic force microscope, on their suspended portions. By coupling the direct atomic force microscopy measurements with differential scanning calorimetry data, we show that the presence of a crystalline corona strongly increases the modulus of the copolymer elongated micelles. This large increase suggests that crystallites in the corona are larger and more uniformly oriented due to confinement effects. Our findings together with this hypothesis open new interesting avenues for the preparation of core templated polymer fibres with enhanced mechanical properties. PMID- 27506249 TI - Towards ALD thin film stabilized single-atom Pd1 catalysts. AB - Supported precious metal single-atom catalysts have shown interesting activity and selectivity in recent studies. However, agglomeration of these highly mobile mononuclear surface species can eliminate their unique catalytic properties. Here we study a strategy for synthesizing thin film stabilized single-atom Pd1 catalysts using atomic layer deposition (ALD). The thermal stability of the Pd1 catalysts is significantly enhanced by creating a nanocavity thin film structure. In situ infrared spectroscopy and Pd K-edge X-ray absorption spectroscopy (XAS) revealed that the Pd1 was anchored on the surface through chlorine sites. The thin film stabilized Pd1 catalysts were thermally stable under both oxidation and reduction conditions. The catalytic performance in the methanol decomposition reaction is found to depend on the thickness of protecting layers. While Pd1 catalysts showed promising activity at low temperature in a methanol decomposition reaction, 14 cycle TiO2 protected Pd1 was less active at high temperature. Pd L3 edge XAS indicated that the low reactivity compared with Pd nanoparticles is due to the strong adsorption of carbon monoxide even at 250 degrees C. These results clearly show that the ALD nanocavities provide a basis for future design of single-atom catalysts that are highly efficient and stable. PMID- 27506250 TI - Selenazolidine: a selenium containing proline surrogate in peptide science. AB - In the search for new peptide ligands containing selenium in their sequences, we investigated l-4-selenazolidine-carboxylic acid (selenazolidine, Sez) as a proline analog with the chalcogen atom in the gamma-position of the ring. In contrast to proteinogenic selenocysteine (Sec) and selenomethionine (SeMet), the incorporation within a peptide sequence of such a non-natural amino acid has never been studied. There is thus a great interest in increasing the possibility of selenium insertion within peptides, especially for sequences that do not possess a sulfur containing amino acid (Cys or Met), by offering other selenated residues suitable for peptide synthesis protocols. Herein, we have evaluated selenazolidine in Boc/Bzl and Fmoc/tBu strategies through the synthesis of a model tripeptide, both in solution and on a solid support. Special attention was paid to the stability of the Sez residue in basic conditions. Thus, generic protocols have been optimized to synthesize Sez-containing peptides, through the use of an Fmoc-Xxx-Sez-OH dipeptide unit. As an example, a new analog of the vasopressin receptor-1A antagonist was prepared, in which Pro was replaced with Sez [3-(4-hydroxyphenyl)-propionyl-d-Tyr(Me)-Phe-Gln-Asn-Arg-Sez-Arg-NH2]. Both proline and such pseudo-proline containing peptides exhibited similar pharmacological properties and endopeptidase stabilities indicating that the presence of the selenium atom has minimal functional effects. Taking into account the straightforward handling of Sez as a dipeptide building block in a conventional Fmoc/tBu SPPS strategy, this result suggested a wide range of potential uses of the Sez amino acid in peptide chemistry, for instance as a viable proline surrogate as well as a selenium probe, complementary to Sec and SeMet, for NMR and mass spectrometry analytical purposes. PMID- 27506252 TI - Transferability study of CHO cell clustering assays for monitoring of pertussis toxin activity in acellular pertussis vaccines. AB - Current regulations for acellular pertussis (aP) vaccines require that they are tested for the presence of residual or reversion-derived pertussis toxin (PTx) activity using the mouse histamine sensitisation test (HIST). Although a CHO cell clustering assay can be used by manufacturers to verify if sufficient inactivation of the substance has occurred in-process, this assay cannot be used at present for the final product due to the presence of aluminium adjuvants which interfere with mammalian cell cultures. Recently, 2 modified CHO cell clustering assays which accommodate for the adjuvant effects have been proposed as alternatives to the HIST. These modified assays eliminate the adjuvant-induced cytotoxicity either through dilution of the vaccine (called the Direct Method) or by introducing a porous barrier between the adjuvant and the cells (the Indirect Method). Transferability and suitability of these methods for testing of products present on the European market were investigated during a collaborative study organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM). Thirteen laboratories participated in this study which included 4 aP containing vaccines spiked by addition of PTx. This study also assessed the transferability of a standardised CHO cell clustering assay protocol for use with non-adjuvanted PTx preparations. Results showed that the majority of laboratories were able to detect the PTx spike in all 4 vaccines at concentrations of 4 IU/mL or lower using the Indirect Method. This sensitivity is in the range of the theoretical sensitivity of the HIST. The Direct Method however did not show the expected results and would need additional development work. PMID- 27506253 TI - Effects of Aspect Ratio on Water Immersion into Deep Silica Nanoholes. AB - Understanding the influence of aspect ratio on water immersion into silica nanoholes is of significant importance to the etching process of semiconductor fabrication and other water immersion-related physical and biological processes. In this work, the processes of water immersion into silica nanoholes with different height/width aspect ratios (phi = 0.87, 1.92, 2.97, 4.01, 5.06) and different numbers of water molecules (N = 9986, 19972, 29958, 39944) were studied by molecular dynamics simulations. A comprehensive analysis has been conducted about the detailed process of water immersion and the influence of aspect ratios on water immersion rates. Five distinguishable stages were identified for the immersion process with all studied models. The results reveal that water can easily immerse into the silica nanoholes with larger phi and smaller N. The calculation also suggests that aspect ratios have a greater effect on water immersion rates for larger N numbers. The mechanism of the water immersion process is discussed in this work. We also propose a mathematical model to correlate the complete water immersion process for different aspect ratios. PMID- 27506254 TI - Electronic properties of embedded graphene: doped amorphous silicon/CVD graphene heterostructures. AB - Large-area graphene film is of great interest for a wide spectrum of electronic applications, such as field effect devices, displays, and solar cells, among many others. Here, we fabricated heterostructures composed of graphene (Gr) grown by chemical vapor deposition (CVD) on copper substrate and transferred to SiO2/Si substrates, capped by n- or p-type doped amorphous silicon (a-Si:H) deposited by plasma-enhanced chemical vapor deposition. Using Raman scattering we show that despite the mechanical strain induced by the a-Si:H deposition, the structural integrity of the graphene is preserved. Moreover, Hall effect measurements directly on the embedded graphene show that the electronic properties of CVD graphene can be modulated according to the doping type of the a-Si:H as well as its phase i.e. amorphous or nanocrystalline. The sheet resistance varies from 360 Omega sq(-1) to 1260 Omega sq(-1) for the (p)-a-Si:H/Gr (n)-a-Si:H/Gr, respectively. We observed a temperature independent hole mobility of up to 1400 cm(2) V(-1) s(-1) indicating that charge impurity is the principal mechanism limiting the transport in this heterostructure. We have demonstrated that embedding CVD graphene under a-Si:H is a viable route for large scale graphene based solar cells or display applications. PMID- 27506251 TI - Brain Reward Circuits in Morphine Addiction. AB - Morphine is the most potent analgesic for chronic pain, but its clinical use has been limited by the opiate's innate tendency to produce tolerance, severe withdrawal symptoms and rewarding properties with a high risk of relapse. To understand the addictive properties of morphine, past studies have focused on relevant molecular and cellular changes in the brain, highlighting the functional roles of reward-related brain regions. Given the accumulated findings, a recent, emerging trend in morphine research is that of examining the dynamics of neuronal interactions in brain reward circuits under the influence of morphine action. In this review, we highlight recent findings on the roles of several reward circuits involved in morphine addiction based on pharmacological, molecular and physiological evidences. PMID- 27506255 TI - Temporal Sensing Platform Based on Bipolar Electrode for the Ultrasensitive Detection of Cancer Cells. AB - We report a bipolar electrode (BPE) sensing platform for the temporal detection of cancer cells. Combining the advantages of anodic dissolution and electrochemiluminescence (ECL), this strategy shows an ultralow detection limit down to 5 cells/cm(2). At the anode working as the reporting pole, Au NPs were assembled through DNA double strand, which served as both catalyzer for the ECL reaction of luminol/H2O2 and seeds for the chemical reduction of Ag, the anodic dissolution probe. The duration of Ag layer dissolution was positively correlated with the amount of Ag but negatively related to the controlled potential and the conductivity of the circuit. Therefore, it was possible to amplify a slight conductivity change through tuning the other two factors. As the formation of Ag@Au completely quenched the ECL emission of luminol, the ECL emission recovery reflected the extent of anodic dissolution. Through monitoring the ECL recovery time before and after the incubation of cells on the cathode, a few number of cells could be quantified due to slight difference of the conductivity. This method shows several merits. First, the combination of anodic dissolution and ECL significantly increases the detection sensitivity of BPE device. In addition, this strategy broadens the application of BPE for the ultrasensitive monitoring of cancer cells, which was applied to investigate the capture efficiencies of antibodies and aptamers toward MCF-7 and A549. PMID- 27506256 TI - Bridging the Gap: Dynamic Causal Modeling and Granger Causality Analysis of Resting State Functional Magnetic Resonance Imaging. AB - Granger causality (GC) and dynamic causal modeling (DCM) are the two key approaches used to determine the directed interactions among brain areas. Recent discussions have provided a constructive account of the merits and demerits. GC, on one side, considers dependencies among measured responses, whereas DCM, on the other, models how neuronal activity in one brain area causes dynamics in another. In this study, our objective was to establish construct validity between GC and DCM in the context of resting state functional magnetic resonance imaging (fMRI). We first established the face validity of both approaches using simulated fMRI time series, with endogenous fluctuations in two nodes. Crucially, we tested both unidirectional and bidirectional connections between the two nodes to ensure that both approaches give veridical and consistent results, in terms of model comparison. We then applied both techniques to empirical data and examined their consistency in terms of the (quantitative) in-degree of key nodes of the default mode. Our simulation results suggested a (qualitative) consistency between GC and DCM. Furthermore, by applying nonparametric GC and stochastic DCM to resting state fMRI data, we confirmed that both GC and DCM infer similar (quantitative) directionality between the posterior cingulate cortex (PCC), the medial prefrontal cortex, the left middle temporal cortex, and the left angular gyrus. These findings suggest that GC and DCM can be used to estimate directed functional and effective connectivity from fMRI measurements in a consistent manner. PMID- 27506257 TI - Stent Removal in 200 Kidney Transplant Recipients: Nonoperative Versus Endoscopic Removal. AB - OBJECTIVES: Inserting a double J stent during kidney transplant has reduced the rate of urologic complications. Traditionally, a double J stent is removed via endoscopic intervention. Here, we assessed the safety and efficacy of a nonoperative method for double J stent removal. MATERIALS AND METHODS: Our study group included 200 consecutive patients who underwent kidney transplant from January 2013 to April 2014. Group A consisted of 100 recipients who had a double J stent that was tied to a Foley catheter with 2-0 silk suture. The stent was simply removed by taking out the Foley catheter after 3 weeks. Patients in group A were compared with a second group of 100 kidney transplant patients whose stents were removed endoscopically 3 weeks later (group B). RESULTS: Patients were matched between the 2 groups regarding age distribution, male-to-female patient ratio, deceased versus living donor graft, prevalence of type 2 diabetes mellitus, and body mass index. The incidence of urinary fistula (3% in group A and 4% in group B; P = .7), ureteral stenosis (1% in group A and 2% in group B; P = .56), wound infection (1% in group A and 2% in group B; P = .56), and positive urine culture (20% in group A and 29% in group B; P = .14) after stent removal were not significantly different between the 2 groups. CONCLUSIONS: This study shows that nonoperative removal of a double J stent is a safe and effective method. This approach is simple, and there is no need for a surgical procedure or any outpatient surgical intervention. PMID- 27506258 TI - Modeling of Tacrolimus Exposure in Kidney Transplant According to Posttransplant Time Based on Routine Trough Concentration Data. AB - OBJECTIVES: The aim of this study was to develop a pharmacokinetics model allowing the description of the evolution of tacrolimus exposure in kidney transplant patients over the first months after transplant, using trough concentrations of routinely collected blood. MATERIALS AND METHODS: The authors performed a retrospective analysis of trough concentration data collected from adult kidney transplant recipients (from 2008 to 2013). The total data set was divided into a building data set, used to build the structural model, and a validation data set, used to validate the structural model. (C0 = 133; 26 patients). A pharmacokinetics analysis was carried out by applying a nonparametric adaptive grid approach. The structural model parameters were tacrolimus clearance and volume of distribution. RESULTS: In patients in the building set group, estimated clearance was 3.6 +/- 0.57 L/h and estimated volume of distribution was 9.9 +/- 1.14 L. No covariate was significantly associated with tacrolimus clearance or volume of distribution. The model adequately described tacrolimus dose-normalized trough concentration evolution after transplant (the plot of individual model predicted versus observed concentrations resulted in r = 0.84). The prediction performance in the validation group yielded 2.3% mean prediction error and 21.4% root mean squared error. CONCLUSIONS: This model could be highly useful in the optimization of tacrolimus prescription at any posttransplant time in kidney transplant patients. PMID- 27506259 TI - Preoperative Clinical Characteristics That Identify Potential Low-Volume Transfusion Candidates Among Orthotopic Liver Transplant Patients. AB - OBJECTIVES: The primary aim of this study was to determine whether specific preoperative clinical characteristics were associated with low-volume transfusion in liver transplant recipients. Low-volume transfusion was defined as transfusion of < 2100 mL of packed red blood cells intraoperatively during liver transplant. The ability to accurately predict low-volume transfusion could increase patient safety, decrease complications associated with transfusion, improve blood management, and decrease transplant case cost. MATERIALS AND METHODS: Data were retrieved by retrospective chart review of 266 patients who received a liver transplant at the Mayo Clinic (Jacksonville, FL, USA). The primary outcome was low-volume transfusion. Associations of preoperative information with low-volume transfusion were explored using single-variable and multivariable logistic regression models; missing data were imputed with the sample median for continuous data and the most frequent category for categorical variables. RESULTS: Low-volume transfusion occurred in 23% of first-time liver transplant recipients (62/266 patients; 95% confidence interval, 18%-29%). History of hepatitis C virus infection (P = .048), history of hepatocellular carcinoma (P = .050), short cold ischemia time (P = .006), and low international normalized ratio (P = .002) were independently associated with low-volume transfusion during liver transplant in a multivariable logistic regression model. CONCLUSIONS: Multiple studies have shown increased morbidity and mortality after orthotopic liver transplant when more than 6 U of packed red blood cells are administered within 24 hours of surgical incision. A method to identify low-volume transfusion candidates could help predict patient outcomes, decrease blood handling, and reduce costs. If patients with low-volume transfusion could be identified, fewer blood products would need to be prepared in advance. Although elevated preoperative coagulation parameters decrease the probability of low-volume transfusion, a definitive profile of a low-volume transfusion liver transplant recipient was not established. PMID- 27506260 TI - Cytomegalovirus Treatment Strategy After a Liver Transplant: Preemptive Therapy or Prophylaxis for Cytomegalovirus Seropositive Donor and Recipient. AB - OBJECTIVES: Cytomegalovirus infections cause the most frequent infection after solid-organ transplant. While Cytomegalovirus prophylaxis is established in high risk patients (donor+/ recipient-), data on Cytomegalovirus prophylaxis in other serostatus constellation are rare. The aim of this study was to evaluate the influence of Cytomegalovirus treatment strategy after a liver transplant (preemptive therapy vs general prophylaxis) in the largest group of patients: Cytomegalovirus seropositive donor and recipient. MATERIALS AND METHODS: Forty seven seropositive recipients of seropositive donor liver transplants (D+/R+, 2005-2012) were included in this retrospective study. Twenty-one patients received oral valganciclovir as Cytomegalovirus prophylaxis 100 days after transplant. Cytomegalovirus infection and Cytomegalovirus disease were monitored during the first 6 months. RESULTS: A Cytomegalovirus infection could be detected in 4 out of 47 patients (8.5%), including Cytomegalovirus disease in 2 patients (Cytomegalovirus pneumonia and Cytomegalovirus-CNS disease). Three of these patients received no Cytomegalovirus prophylaxis (P = .408). Eight patients developed a graft failure; this occurred more frequently among patients without Cytomegalovirus prophylaxis (P = .044). Patients receiving Cytomegalovirus prophylaxis more often developed leukopenia. No difference was seen regarding the number of platelets, hemoglobin, and creatinine. CONCLUSIONS: Cytomegalovirus prophylaxis can minimize the risk of Cytomegalovirus reactivation and graft failure. However, disadvantages of the prophylaxis as leukopenia should be considered. PMID- 27506261 TI - Graft-Versus-Lymphoma Effect Can Be Rapid and Potent in Diffuse Large B-Cell Lymphoma. PMID- 27506262 TI - Changes in milk performance and hepatic metabolism in mid-lactating dairy goats after being fed a high concentrate diet for 10 weeks. AB - Feeding a high concentrate (HC) diet is a widely used strategy for supporting high milk yields, yet it may cause certain metabolic disorders. This study aimed to investigate the changes in milk production and hepatic metabolism in goats fed different proportions of concentrate in the diet for 10 weeks. In total, 12 mid lactating goats were randomly assigned to an HC diet (65% concentrate of dry matter, n=6) or a low concentrate (LC) diet (35% concentrate of dry matter, n=6). Compared with LC, HC goats produced greater amounts of volatile fatty acids and produced more milk and milk lactose, fat and protein (P<0.01). HC goats showed a greater concentration of ATP, NAD, plasma non-esterified fatty acids and hepatic triglycerides than LC goats (P<0.05). Real-time PCR results showed that messenger RNA (mRNA) expression of gluconeogenic genes, namely, glucose-6-phosphatase, pyruvate carboxylase and phosphoenolpyruvate carboxykinase were significantly up regulated and accompanied greater gluconeogenic enzyme activities in the liver of HC goats. Moreover, the expression of hepatic lipogenic genes including sterol regulatory element-binding protein 1c, fatty acid synthase and diacylglycerol acyltransferase mRNA was also up-regulated by the HC diet (P<0.05). HC goats had greater hepatic phosphorylation of AMP-activated protein kinase than LC (P<0.05). Furthermore, histone-3-lysine-27-acetylation contributed to this elevation of gluconeogenic gene expression. These results indicate that lactating goats fed an HC diet for 10 weeks produced more milk, which was associated with up-regulated gene expression and enzyme activities involved in hepatic gluconeogenesis and lipogenesis. PMID- 27506264 TI - The importance of bone shortening in digital replantation. PMID- 27506263 TI - IFPA meeting 2015 workshop report IV: placenta and obesity; stem cells of the feto-maternal interface; placental immunobiology and infection. AB - Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialised topics. At the 2015 IFPA annual meeting there were 12 themed workshops, three of which are summarized in this report. These workshops related to various aspects of placental biology and collectively covered areas of obesity and the placenta, stem cells of the feto-maternal interface, and placental immunobiology and infection. PMID- 27506265 TI - Perforator-based propeller flaps for leg reconstruction in pediatric patients. AB - BACKGROUND: Perforator-based propeller flaps provide adequate soft tissue coverage for leg reconstruction. The aim of this study was to assess the versatility and reliability of the use of propeller flaps for leg reconstruction in pediatric patients. METHOD: Seven male pediatric patients ranging in age from 2 to 13 years with a mean age of 6.7 underwent perforator-based propeller flap surgery over a four-year period. The defects resulted from burn injuries (n = 4) and traffic accidents (n = 3). The injuries were located on the ankles of four patients and on the knee, anterior lower tibia, and foot dorsum of the other three patients, respectively. RESULTS: The flap sizes ranged from 5 * 3 to 10 * 6 cm with a mean flap size of 7.6 * 4.3 cm. Flap harvesting time ranged from 38 to 56 m with a mean of 46 m. The rotation degree range of the flaps was from 90 degrees to 180 degrees . The propeller flaps were based on the posterior tibial artery (n = 4), anterior tibial artery (n = 2), and the descending branch of the lateral circumflex femoral artery (n = 1). All flaps survived completely without surgical complication; however, one patient developed disseminated intravascular coagulation syndrome two days post-surgery and died within four days. CONCLUSION: Perforator-based propeller flap reconstruction is a safe, reliable, and versatile method for lower extremities in pediatric patients; however, it requires meticulous surgical dissection and extreme patience during the surgical procedure. PMID- 27506266 TI - Neurobiological degeneracy: A key property for functional adaptations of perception and action to constraints. AB - A crucial aspect of understanding human behavior relates to how perception and action sub-systems are integrated during coordinated and controlled movement in goal-directed activity. Here we discuss how a neurobiological system property, degeneracy (i.e., many coordinative structures to achieve one function), can help us understand how skilled individuals functionally adapt perception and action to interacting constraints during performance. Since most research investigating degeneracy has been conducted in neuroanatomy, genetics and theoretical neurobiology, here we clarify how degeneracy is exhibited in perceptual-motor systems. Using an ecological dynamics framework, we highlight how degeneracy underpins the functional role of movement coordination variability in performance of multi-articular tasks. Following that, we discuss how degenerate neurobiological systems are able to exploit system stability and flexibility in their movement coordination. Third, we show how better coupling of information and movement could lead individuals to explore functionally degenerate behaviors. Last, we explore how degeneracy can support pluri-potentiality (i.e., one coordinative structure for many perceptual-motor functions) as a way toward innovation or refinement in performance. PMID- 27506267 TI - Understanding metastable phase transformation during crystallization of RDX, HMX and CL-20: experimental and DFT studies. AB - Multiphase growth during crystallization severely affects deliverable output of explosive materials. Appearance and incomplete transformation of metastable phases are a major source of polymorphic impurities. This article presents a methodical and molecular level understanding of the metastable phase transformation mechanism during crystallization of cyclic nitramine explosives, viz. RDX, HMX and CL-20. Instantaneous reverse precipitation yielded metastable gamma-HMX and beta-CL-20 which undergo solution mediated transformation to the respective thermodynamic forms, beta-HMX and epsilon-CL-20, following 'Ostwald's rule of stages'. However, no metastable phase, anticipated as beta-RDX, was evidenced during precipitation of RDX, which rather directly yielded the thermodynamically stable alpha-phase. The gamma->beta-HMX and beta->epsilon-CL-20 transformations took 20 and 60 minutes respectively, whereas formation of alpha RDX was instantaneous. Density functional calculations were employed to identify the possible transition state conformations and to obtain activation barriers for transformations at wB97XD/6-311++G(d,p)(IEFPCM)//B3LYP/6-311G(d,p) level of theory. The computed activation barriers and lattice energies responsible for transformation of RDX, HMX and CL-20 metastable phases to thermodynamic ones conspicuously supported the experimentally observed order of phase stability. This precise result facilitated an understanding of the occurrence of a relatively more sensitive and less dense beta-CL-20 phase in TNT based melt-cast explosive compositions, a persistent and critical problem unanswered in the literature. The crystalline material recovered from such compositions revealed a mixture of beta- and epsilon-CL-20. However, similar compositions of RDX and HMX never showed any metastable phase. The relatively long stability with the highest activation barrier is believed to restrict complete beta->epsilon-CL-20 transformation during processing. Therefore a method is suggested to overcome this issue. PMID- 27506268 TI - 2D nanostructures for water purification: graphene and beyond. AB - Owing to their atomically thin structure, large surface area and mechanical strength, 2D nanoporous materials are considered to be suitable alternatives for existing desalination and water purification membrane materials. Recent progress in the development of nanoporous graphene based materials has generated enormous potential for water purification technologies. Progress in the development of nanoporous graphene and graphene oxide (GO) membranes, the mechanism of graphene molecular sieve action, structural design, hydrophilic nature, mechanical strength and antifouling properties and the principal challenges associated with nanopore generation are discussed in detail. Subsequently, the recent applications and performance of newly developed 2D materials such as 2D boron nitride (BN) nanosheets, graphyne, molybdenum disulfide (MoS2), tungsten chalcogenides (WS2) and titanium carbide (Ti3C2Tx) are highlighted. In addition, the challenges affecting 2D nanostructures for water purification are highlighted and their applications in the water purification industry are discussed. Though only a few 2D materials have been explored so far for water treatment applications, this emerging field of research is set to attract a great deal of attention in the near future. PMID- 27506269 TI - A Physiologically Based Pharmacokinetic Model to Describe Artemether Pharmacokinetics in Adult and Pediatric Patients. AB - Artemether is co-administered with lumefantrine as part of a fixed-dose combination therapy for malaria in both adult and pediatric patients. However, artemether exposure is higher in younger infants (1-3 months) with a lower body weight (<5 kg) as compared to older infants (3-6 months) with a higher body weight (>=5 to <10 kg), children, and adults. In contrast, lumefantrine exposure is similar in all age groups. This article describes the clinically observed artemether exposure data in pediatric populations across various age groups (1 month to 12 years) and body weights (<5 or >=5 kg) using physiologically based pharmacokinetic (PBPK) mechanistic models. A PBPK model was developed using artemether physicochemical, biopharmaceutic, and metabolic properties together with known enzyme ontogeny and pediatric physiology. The model was verified using clinical data from adult patients after multiple doses of oral artemether, and was then applied to simulate the exposure in children and infants. The simulated PBPK concentration-time profiles captured observed clinical data. Consistent with the clinical data, the PBPK model simulations indicated a higher artemether exposure for younger infants with lower body weight. A PBPK model developed for artemether reliably described the clinical data from adult and pediatric patients. PMID- 27506270 TI - Mannitol/l-Arginine-Based Formulation Systems for Freeze Drying of Protein Pharmaceuticals: Effect of the l-Arginine Counter Ion and Formulation Composition on the Formulation Properties and the Physical State of Mannitol. AB - Previous studies have shown that protein storage stability in freeze-dried l arginine-based systems improved in the presence of chloride ions. However, chloride ions reduced the glass transition temperature of the freeze concentrate (Tg') and made freeze drying more challenging. In this study, l-arginine was freeze dried with mannitol to obtain partially crystalline solids that can be freeze dried in a fast process and result in elegant cakes. We characterized the effect of different l-arginine counter ions on physicochemical properties of mannitol compared with mannitol/sucrose systems. Thermal properties of formulations with different compositions were correlated to thermal history during freeze drying and to physicochemical properties (cake appearance, residual moisture, reconstitution time, crystallinity). Partially crystalline solids were obtained even at the highest l-arginine level (mannitol:l-arginine of 2:1) used in this study. All l-arginine-containing formulations yielded elegant cakes. Only cakes containing l-arginine chloride and succinate showed a surface "crust" formed by phase separation. X-ray powder diffraction showed that inhibition of mannitol crystallization was stronger for l-arginine compared with sucrose and varied with the type of l-arginine counter ion. The counter ion affected mannitol polymorphism and higher levels of mannitol hemi-hydrate were obtained at high levels of l-arginine chloride. PMID- 27506271 TI - Influence of Adsorption on Proteins and Amyloid Detection by Silicon Nitride Nanopore. AB - For the past 2 decades, emerging single-nanopore technologies have opened the route to multiple sensing applications. Besides DNA sensing, the identification of proteins and amyloids is a promising field for early diagnosis. However, the influence of the interactions between the nanopore surface and proteins should be taken into account. In this work, we have selected three proteins (avidin, lysozyme, and IgG) that exhibit different affinities with the SiNx surface, and we have also examined lysozyme amyloid. Our results show that the piranha treatment of SiNx significantly decreases protein adsorption. Moreover, we have successfully detected all proteins (pore diameter 17 nm) and shown the possibility of discriminating between denatured lysozyme and its amyloid. For all proteins, the capture rates are lower than expected, and we evidence that they are correlated with the affinity of proteins to the surface. Our result confirms that proteins interacting only with the nanopore surface wall stay long enough to be detected. For lysozyme amyloid, we show that the use of the nanopore is suitable for determining the number of monomer units even if only the proteins interacting with the nanopore are detected. PMID- 27506272 TI - Hepaticoplasty prevents cholangitis after pancreaticoduodenectomy in patients with small bile ducts. AB - BACKGROUND: To reduce cholangitis after pancreaticoduodenectomy (PD), we perform 'hepaticoplasty', in which the left side of the bile duct is cut to widen the diameter of the bile duct wall before hepaticojejunostomy. The aim of this study was to clarify the usefulness of hepaticoplasty to reduce cholangitis after PD. METHODS: From January 2002 through December 2010, 161 patients underwent PD and were enrolled in this study. Patient demographics, surgical factors, and clinical and biochemical parameters were evaluated to examine the factors predictive of cholangitis after PD and confirm the usefulness of hepaticoplasty. RESULTS: Cholangitis after PD occurred in 13 patients (8.1%). Multivariate analysis revealed that the ratio of the postoperative bile duct diameter to that before surgery was the only independent risk factor for cholangitis after PD (p = 0.0012). In the small bile duct group, in which the diameter was <=15 mm before surgery (n = 99), hepaticoplasty reduced the narrowing of the bile duct after PD, and no cholangitis occurred. There were no complications related to hepaticoplasty. CONCLUSIONS: The ratio of postoperative reduction of the bile duct diameter to that before surgery was found to be the only risk factor for cholangitis after PD. Patients with a small bile duct of <=15 mm in diameter preoperatively might benefit from hepaticoplasty to widen the bile duct diameter and prevent cholangitis after PD. PMID- 27506274 TI - Purification and characterization of xylitol dehydrogenase with l-arabitol dehydrogenase activity from the newly isolated pentose-fermenting yeast Meyerozyma caribbica 5XY2. AB - Meyerozyma caribbica strain 5XY2, which was isolated from an alcohol fermentation starter in Thailand, was found to catabolize l-arabinose as well as d-glucose and d-xylose. The highest production amounts of ethanol from d-glucose, xylitol from d-xylose, and l-arabitol from l-arabinose were 0.45 g/g d-glucose, 0.60 g/g d xylose, and 0.61 g/g l-arabinose with 21.7 g/L ethanol, 20.2 g/L xylitol, and 30.3 g/l l-arabitol, respectively. The enzyme with l-arabitol dehydrogenase (LAD) activity was purified from the strain and found to exhibit broad specificity to polyols, such as xylitol, d-sorbitol, ribitol, and l-arabitol. Xylitol was the preferred substrate with Km=16.1 mM and kcat/Km=67.0 min-1mM-1, while l-arabitol was also a substrate for the enzyme with Km=31.1 mM and kcat/Km=6.5 min-1 mM-1. Therefore, this enzyme from M. caribbica was named xylitol dehydrogenase (McXDH). McXDH had an optimum temperature and pH at 40 degrees C and 9.5, respectively. The McXDH gene included a coding sequence of 1086 bp encoding a putative 362 amino acid protein of 39 kDa with an apparent homopentamer structure. Native McXDH and recombinant McXDH exhibited relative activities toward l-arabitol of approximately 20% that toward xylitol, suggesting the applicability of this enzyme with the functions of XDH and LAD to the development of pentose-fermenting Saccharomyces cerevisiae. PMID- 27506275 TI - Nucleophilic reactivity and electrocatalytic reduction of halogenated organic compounds by nickel o-phenylenedioxamidate complexes. AB - A growing number of halogenated organic compounds have been identified as hazardous pollutants. Although numerous advanced oxidative processes have been developed to degrade organohalide compounds, reductive and nucleophilic molecular approaches to dehalogenate organic compounds have rarely been reported. In this manuscript, we employ nickel(ii)-ate complexes bearing the o-phenylenebis(N methyloxamide) (Me2opba) tetraanionic ligand as nucleophilic reagents that can react with alkyl halides (methyl up to the bulky isobutyl) by O-alkylation to give their respective imidate products. Four new nickel(ii) complexes have been characterized by X-ray crystallography, and the salient structural parameters and FT-IR vibrational bands (~1655 cm(-1)) concur with their assignment as the imidate tautomeric form. To the best of our knowledge, this is the first report on the nucleophilic reactivity of Ni(II)(Me2opba) with halogenated organic compounds. The parent nickel(ii) Me2opba complex exhibits reversible electrochemical oxidation and reduction behavior. As a proof of concept, Ni(II)(Me2opba) and its alkylated congeners were utilized for the electrocatalytic reduction of chloroform, as a representative, simple polyhalogenated organic molecule that could arise from the oxidative treatment of organic compounds by chlorination. Modest turnover numbers of up to 6 were recorded, with dichloromethane identified as one of the possible products. Future efforts are directed towards bulkier -ate complexes that possess metal-centered instead of ligand-centered nucleophilic activity to create more effective electrocatalysts for the reduction of halogenated organic compounds. PMID- 27506276 TI - Effects of dietary Spirulina platensis on growth performance, humoral and mucosal immune responses and disease resistance in juvenile great sturgeon (Huso huso Linnaeus, 1754). AB - Dietary supplementation of Spirulina platensis at different levels (0% control, 2.5%, 5% and 10%) was evaluated to find out the effects on growth performance, digestive enzyme activities, humoral and skin innate immune responses and disease resistance in the great sturgeon (Huso huso). After 8 weeks of experimental trial, growth parameters, intestinal lactic acid bacteria count, protease and lipase activities were significantly high in 10% S. platensis fed group (P < 0.05). Similarly, in this group, respiratory burst activity of leucocytes and total protein of serum were also significantly high. Furthermore, supplementation of S. platensis at 5 or 10% exhibited higher serum IgM and lysozyme activity than the other experimental groups (P < 0.05). On the contrary, serum triglycerides and number of blood lymphocytes were lower in experimental groups than that of control group. Total proteins, lysozyme, protease and esterase, as well as in vitro bactericidal activity (against Streptococcus iniae, Yersinia ruckeri, Aeromonas hydrophila and Lactococcus garviea) were significantly high in skin mucus from fish fed 5% and 10% S. platensis, while, alkaline phosphatase was significantly high in fish fed 10% S. platensis (P < 0.05). Further, fish infected with Streptococcus iniae bacteria increased mortality, but it was alleviated by a diet supplemented with S. platensis. The present results demonstrate that this dietary supplementation with S. platensis (mainly at 10% level) could be useful for maintaining the overall health status of great sturgeon. PMID- 27506277 TI - Identification and characterization of an 18.4kDa antimicrobial truncation from shrimp Litopenaeus vannamei hemocyanin upon Vibrio parahaemolyticus infection. AB - Hemocyanin (HMC) is a multifunctional protein which plays many essential roles in invertebrate organism. Recently more and more immune-related functions have been discovered on this protein. Here the shrimp was infected with Vibrio parahaemolyticus and the shrimp sera were analyzed by two-dimensional gel electrophoresis. Totally 15 spots were identified as significantly up-regulated spots and further analyzed by MALDI-TOF/TOF mass spectrometry (MS). Four of them were identified as HMC derived truncations (HMCS1, HMCS3, HMCS4 and HMCS5). The HMCS4 primary sequence was further determined via Edman N terminal sequencing, MALDI-TOF MS and amino acid sequence alignment. The result indicated that the HMCS4 was a 165aa fragment from shrimp HMC small subunit C-terminal. The HMCS4 immunological activities were further analyzed by agglutination experiment and antibacterial assay in vitro. The results showed that the recombinant HMCS4 (rHMCS4) had strong agglutination and antibacterial activities against pathogenic bacteria at the optimum bacteriostasis concentration. In addition, the HMCS4 immunological activities were explored via mortality assay in vivo. The shrimp was challenged with V. parahaemolyticus and rHMCS4 V. parahaemolyticus mixture separately. The shrimp mortality rate was significantly decreased at 96 h post infection with rHMCS4 injection. Our data showed that shrimp HMC truncation generation upon infection was an effective immune response against invaded pathogens. Moreover, these findings may have some potential applications in shrimp industry. PMID- 27506278 TI - Disparities in Provider Recommendation of Human Papillomavirus Vaccination for U.S. Adolescents. AB - PURPOSE: To determine the prevalence of and examine factors associated with provider recommendation of human papillomavirus vaccination for U.S. adolescents. METHODS: Multivariable logistic regression analyses were performed using data from the National Immunization Survey-Teen 2014 on 34,478 adolescents aged 13-17 years. RESULTS: Overall prevalence of vaccine recommendation was 72.6% for girls and 51.8% for boys. Lower rates were observed among girls aged 13 years, living below poverty line, adolescents of lesser educated mothers, and those residing in the South. Overall, girls had higher odds of vaccine recommendation (odds ratio [OR] = 2.57; 95% confidence interval [CI] = 2.35-2.82). Correlates of higher vaccine recommendation for girls were: older age-17 versus 13 (OR = 1.51; 95% CI = 1.20-1.89), living above versus below poverty line, and residing in Northeast (OR = 1.45; 95% CI = 1.21-1.73) and Midwest (OR = 1.29; 95% CI = 1.11-1.50) versus South. For boys, correlates of higher vaccine recommendation were: non Hispanic black (OR = 1.30; 95% CI = 1.07-1.58) and Hispanic (OR = 1.24; 95% CI = 1.03-1.48) versus non-Hispanic white race and residing in Northeast (OR = 1.79; 95% CI = 1.54-2.08) and West (OR = 1.41; 95% CI = 1.17-1.70) versus South. Other factors associated with vaccine recommendation were having a college-educated mother and frequent doctor visits in the past 12 months. CONCLUSIONS: This study highlights significant disparities in provider recommendation of human papillomavirus vaccination for U.S. adolescents. Findings suggest possible areas for tailored interventions to bridge the gap in vaccine recommendation and uptake in high-risk populations. PMID- 27506279 TI - A Cross-Sectional Study on the Perceptions and Practices of Teenagers With Inflammatory Bowel Disease About Repeated Stool Sampling. AB - PURPOSE: Repeated stool sampling to monitor disease activity is increasingly used in teenagers with inflammatory bowel disease (IBD). Knowledge about their perceptions and practices regarding collection of feces will increase the success rate of this monitoring strategy. METHODS: We sent a survey to teenagers with IBD treated in an academic center. RESULTS: Seventy-two of 122 invited teenagers completed the survey (response rate 59%; median age 15 years (interquartile range, 13-17). Eighty-five percent reported that stool sampling is normally initiated with help of their parents or caretakers. Seventy-eight percent of respondents say that their parents assist with the placement of stool in the container. CONCLUSIONS: Teenagers do not feel embarrassed by the idea of stool sampling, but an active role of the parents or caretakers is an important prerequisite for maintaining a stool-based disease monitoring system. Autonomy in stool sampling is an essential skill required for a successful transition to adult-centered IBD care. PMID- 27506280 TI - Special issue on 'Cytoskeletal proteins in health and neurodegenerative disease'. AB - The cytoskeleton is the major intracellular structure that determines the morphology of neurons and maintains their structural integrity. It is therefore not surprising that a disturbance of cytoskeletal structure and functionunderlies many neurodegenerative diseases. This special issue brings together current information on the three majorneuronal cytoskeletal filament systems, microtubules, microfilaments and neurofilaments, and aims to provide a comprehensive overview of the role of the key components of these three systems under both physiological and pathological conditions. It therefore also addresses the role of microtubule-associated proteins (with a focus on tau) and motor proteins (with a focus on kinesin). PMID- 27506281 TI - Heterodinuclear Pt(iv)-Ru(ii) anticancer prodrugs to combat both drug resistance and tumor metastasis. AB - A novel approach to design bimetallic anticancer drug candidates with the capability to combat both drug resistance and tumor metastasis is reported. These water-soluble bifunctional Pt(iv)-Ru(ii) heterodinuclear complexes with a unique mode of action display up to 2-orders of magnitude enhanced cytotoxicity in cisplatin-resistant cells and significantly impede cancer cell migration. PMID- 27506282 TI - Epilepsy-associated tumours: what epileptologists should know about neuropathology, terminology, and classification systems. AB - Brain tumours are an ever-challenging issue in neurology and related medical disciplines. This applies in particular to brain tumours associated with childhood-onset epilepsies, in which seizures are the presenting and only neurological symptom, as our current understanding of the biology and clinical behaviour of an individual tumour is far from being evidence-based. Prospective and randomized clinical trials are lacking in the field of epilepsy-associated tumours and a review of the current literature evokes more questions than provides answers. In this review, current areas of controversy in neuropathology, as well as terminology and classification, are discussed from an epileptologist's perspective. An illustrative case report exemplifies this controversy to further promote interdisciplinary discussion and novel research avenues towards comprehensive patient management in the near future. PMID- 27506283 TI - Local lateral environment of the molecules at the surface of DMSO-water mixtures. AB - Molecular dynamics simulations of the liquid-vapour interface of dimethyl sulphoxide (DMSO)-water mixtures of 11 different compositions, including two neat systems are performed on the canonical (N, V, T) ensemble at 298 K. The molecules constituting the surface layer of these systems are selected by means of the identification of the truly interfacial molecules (ITIM) method, and their local lateral environment at the liquid surface is investigated by performing Voronoi analysis. The obtained results reveal that both molecules prefer to be in a mixed local environment, consisting of both kinds of molecules, at the liquid surface, and this preference is even stronger here than in the bulk liquid phase. Neat like patches, in which a molecule is surrounded by like neighbours, are not found. However, vacancies that are surrounded solely by water molecules are observed at the liquid surface. Our results show that strongly hydrogen bonded DMSO.H2O complexes, known to exist in the bulk phase of these mixtures, are absent from the liquid surface. PMID- 27506284 TI - Dipyrrolylpyrimidines as anion-responsive pi-electronic systems. AB - Dipyrrolylpyrimidines synthesized by coupling reactions exhibited anion-binding abilities with the inversion of pyrrole rings. In the solid state, anion complexes of dipyrrolylpyrimidines formed charge-by-charge columnar structures in combination with counter cations. PMID- 27506285 TI - Acute calcific tendinitis of the longus colli muscle. PMID- 27506286 TI - Chemical composition and methane potential of commercial food wastes. AB - There is increasing interest in anaerobic digestion in the U.S. However, there is little information on the characterization of commercial food waste sources as well as the effect of waste particle size on methane yield. The objective of this research was to characterize four commercial food waste sources: (1) university dining hall waste, (2) waste resulting from prepared foods and leftover produce at a grocery store, (3) food waste from a hotel and convention center, and (4) food preparation waste from a restaurant. Each sample was tested in triplicate 8L batch anaerobic digesters after shredding and after shredding plus grinding. Average methane yields for the university dining, grocery store, hotel, and restaurant wastes were 363, 427, 492, and 403mL/dry g, respectively. Starch exhibited the most complete consumption and particle size did not significantly affect methane yields for any of the tested substrates. Lipids represented 59-70% of the methane potential of the fresh substrates. PMID- 27506287 TI - Special Issue 7th International Granulation Workshop, June 2015. PMID- 27506288 TI - Wafer-scale high-resolution patterning of reduced graphene oxide films for detection of low concentration biomarkers in plasma. AB - Given that reduced graphene oxide (rGO)-based biosensors allow disposable and repeatable biomarker detection at the point of care, we developed a wafer-scale rGO patterning method with mass productivity, uniformity, and high resolution by conventional micro-electro-mechanical systems (MEMS) techniques. Various rGO patterns were demonstrated with dimensions ranging from 5 MUm up to several hundred MUm. Manufacture of these patterns was accomplished through the optimization of dry etching conditions. The axis-homogeneity and uniformity were also measured to verify the uniform patternability in 4-inch wafer with dry etching. Over 66.2% of uniform rGO patterns, which have deviation of resistance within range of +/-10%, formed the entire wafer. We selected amyloid beta (Abeta) peptides in the plasma of APP/PS1 transgenic mice as a study model and measured the peptide level by resistance changes of highly uniform rGO biosensor arrays. Abeta is a pathological hallmark of Alzheimer's disease and its plasma concentration is in the pg mL(-1) range. The sensor detected the Abeta peptides with ultra-high sensitivity; the LOD was at levels as low as 100 fg mL(-1). Our results provide biological evidences that this wafer-scale high-resolution patterning method can be used in rGO-based electrical diagnostic devices for detection of low-level protein biomarkers in biofluids. PMID- 27506289 TI - Non-absorbable apple procyanidins prevent obesity associated with gut microbial and metabolomic changes. AB - Several studies have suggested that flavan-3-ols/procyanidins are associated with a reduced risk of developing obesity and metabolic syndrome. However, the role of highly polymeric procyanidins (PP), which are major non-absorbable flavonoids, in the biological effects, is not completely understood. Here, we show that 0.5% PP administration for 20 weeks alleviated obesity and regulate expression of genes related to lipid metabolism in C57BL/6J mice fed a high-fat/high-sucrose diet. PP treatment attenuated weight gain and inflammatory effects including lipopolysaccharide and gut permeability. Additionally, metabolic urine profiling using high-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry demonstrated that PP-treatment decreased the levels of endogenous metabolites associated with insulin resistance. Furthermore, microbial 16S rRNA gene sequencing of the cecum demonstrated that PP administration markedly decreased the Firmicutes/Bacteroidetes ratio and increased eight times the proportion of Akkermansia. These data suggest that PPs influence the gut microbiota and the intestinal metabolome to produce beneficial effects on metabolic homeostasis. PMID- 27506290 TI - Turning the respiratory flexibility of Mycobacterium tuberculosis against itself. AB - The Mycobacterium tuberculosis (Mtb) electron transport chain (ETC) has received significant attention as a drug target, however its vulnerability may be affected by its flexibility in response to disruption. Here we determine the effect of the ETC inhibitors bedaquiline, Q203 and clofazimine on the Mtb ETC, and the value of the ETC as a drug target, by measuring Mtb's respiration using extracellular flux technology. We find that Mtb's ETC rapidly reroutes around inhibition by these drugs and increases total respiration to maintain ATP levels. Rerouting is possible because Mtb rapidly switches between terminal oxidases, and, unlike eukaryotes, is not susceptible to back pressure. Increased ETC activity potentiates clofazimine's production of reactive oxygen species, causing rapid killing in vitro and in a macrophage model. Our results indicate that combination therapy targeting the ETC can be exploited to enhance killing of Mtb. PMID- 27506291 TI - Scalable hybrid chemical manufacture to photothermal therapy: PEG-capped phototransducers. AB - Ag-TiO2@polyethylene glycol (PEG) nanoparticles were continuously obtained in a single-pass configuration by appropriately reacting freshly flame-synthesized TiO2 with Ag formed in an ultrasonic aqueous medium containing PEG. When the proposed synthesis was kept constant, the production rate for Ag-TiO2@PEG nanoparticles reached approximately 3 g/h while only using a combination of a lab scale inverse-diffusion flame (16 mm head diameter) and an ultrasonic Ag(I) cell (50 mL). The synthesized nanoparticles were employed as inducers for in vitro photoinduced therapy to kill cancer cells at different light wavelengths. Measurements of the nanoparticle cytotoxicity revealed that PEG incorporation with the Ag-TiO2 particles significantly decreased the cytotoxicity (cell viability of more than ~91% at 200 MUg mL(-1) particle concentration) of Ag, and this was comparable with that of TiO2 particles (cell viability of more than ~90%). When 632 nm and 808 nm light was applied to the nanoparticles in the HeLa cells, the viability of the cells was significantly affected [decreased to ~4% (632 nm) and ~26% (808 nm) at 200 MUg mL(-1), 5 min irradiation time] by surface plasmon resonance heating and photothermal therapy. PMID- 27506292 TI - The influence of distance and quality of care on place of delivery in rural Ghana. AB - Facility delivery is an important aspect of the strategy to reduce maternal and newborn mortality. Geographic access to care is a strong determinant of facility delivery, but few studies have simultaneously considered the influence of facility quality, with inconsistent findings. In rural Brong Ahafo region in Ghana, we combined surveillance data on 11,274 deliveries with quality of care data from all 64 delivery facilities in the study area. We used multivariable multilevel logistic regression to assess the influence of distance and several quality dimensions on place of delivery. Women lived a median of 3.3 km from the closest delivery facility, and 58% delivered in a facility. The probability of facility delivery ranged from 68% among women living 1 km from their closest facility to 22% among those living 25 km away, adjusted for confounders. Measured quality of care at the closest facility was not associated with use, except that facility delivery was lower when the closest facility provided substandard care on the EmOC dimension. These results do not imply, however, that we should increase geographic accessibility of care without improving facility quality. While this may be successful in increasing facility deliveries, such care cannot be expected to reduce maternal and neonatal mortality. PMID- 27506294 TI - The secret life of Pickering emulsions: particle exchange revealed using two colours of particle. AB - Emulsion droplets stabilised by colloidal particles (Pickering emulsions) can be highly stable, so it is unsurprising that they are beginning to be exploited industrially. The individual colloidal particles have interfacial attachment energies that are vastly larger than the thermal energy, hence they are usually thought of as being irreversibly adsorbed. Here we show, for the first time, particles being exchanged between droplets in a Pickering emulsion. This occurs when the emulsion contains droplets that share particles, often called bridging. By starting with two emulsions showing bridging, each stabilised by a different colour of particle, the dynamics can be studied as they are gently mixed together on a roller bank. We find that particle exchange occurs by two routes: firstly, during a period of unbridging and rebridging whose duration can be tuned by varying the wettability of the particles, and secondly, during very rare events when particles are ejected from one droplet and re-adsorbed onto another. PMID- 27506293 TI - Exosome-mediated Delivery of Hydrophobically Modified siRNA for Huntingtin mRNA Silencing. AB - Delivery represents a significant barrier to the clinical advancement of oligonucleotide therapeutics for the treatment of neurological disorders, such as Huntington's disease. Small, endogenous vesicles known as exosomes have the potential to act as oligonucleotide delivery vehicles, but robust and scalable methods for loading RNA therapeutic cargo into exosomes are lacking. Here, we show that hydrophobically modified small interfering RNAs (hsiRNAs) efficiently load into exosomes upon co-incubation, without altering vesicle size distribution or integrity. Exosomes loaded with hsiRNAs targeting Huntingtin mRNA were efficiently internalized by mouse primary cortical neurons and promoted dose dependent silencing of Huntingtin mRNA and protein. Unilateral infusion of hsiRNA loaded exosomes, but not hsiRNAs alone, into mouse striatum resulted in bilateral oligonucleotide distribution and statistically significant bilateral silencing of up to 35% of Huntingtin mRNA. The broad distribution and efficacy of hsiRNA loaded exosomes delivered to brain is expected to advance the development of therapies for the treatment of Huntington's disease and other neurodegenerative disorders. PMID- 27506295 TI - Epidermal growth factor gene is a newly identified candidate gene for gout. AB - Chromosome 4q25 has been identified as a genomic region associated with gout. However, the associations of gout with the genes in this region have not yet been confirmed. Here, we performed two-stage analysis to determine whether variations in candidate genes in the 4q25 region are associated with gout in a male Chinese Han population. We first evaluated 96 tag single nucleotide polymorphisms (SNPs) in eight inflammatory/immune pathway- or glucose/lipid metabolism-related genes in the 4q25 region in 480 male gout patients and 480 controls. The SNP rs12504538, located in the elongation of very-long-chain-fatty-acid-like family member 6 gene (Elovl6), was found to be associated with gout susceptibility (Padjusted = 0.00595). In the second stage of analysis, we performed fine mapping analysis of 93 tag SNPs in Elovl6 and in the epidermal growth factor gene (EGF) and its flanking regions in 1017 male patients gout and 1897 healthy male controls. We observed a significant association between the T allele of EGF rs2298999 and gout (odds ratio = 0.77, 95% confidence interval = 0.67-0.88, Padjusted = 6.42 * 10(-3)). These results provide the first evidence for an association between the EGF rs2298999 C/T polymorphism and gout. Our findings should be validated in additional populations. PMID- 27506296 TI - Ultrasonographically locating the mental foramen and its soft tissue relations. AB - OBJECTIVES: This ultrasound-based cross-sectional study aimed to visualize, locate and compare the position of the mental foramen with regard to its relationship to various soft tissue landmarks. METHODS: 100 Black and Caucasian subjects were included. An ultrasound transducer was used to locate the mental foramina. Distances to various landmarks were measured and compared. RESULTS: All mental foramina were visualized. The mean soft tissue distance of the entire group from the mental foramen on the right and left sides, respectively, were as follows: (a) 3.4 mm [standard deviation (SD) 1.7 mm] and 3.4 mm (SD 1.5 mm) lateral to a vertical line passing through the chelion; (b) 20.1 mm (SD 2.6 mm) and 20.1 mm (SD 2.6 mm) distal to a horizontal line bisecting the chelions; (c) 15.1 mm (SD 2.4 mm) and 15.0 mm (SD 2.4 mm) proximal to the inferior border of the mandible. We found no statistically significant differences between race groups, between gender group and between age categories with regard to the horizontal soft tissue distance from a vertical line passing through the chelion to the mental foramen on the right or left sides. There were statistically significant (but not clinically significant) differences between race groups and between gender groups but not between age groups with regard to the vertical soft tissue distance from a horizontal line bisecting the chelions to the mental foramen as well as from the inferior border of the mandible to the mental foramen on both the right and left sides. CONCLUSIONS: This study suggests that ultrasound is a feasible imaging modality that can be utilized to locate the mental foramen. Differences in the position of the mental foramen with regard to various soft tissue landmarks are minor and clinically insignificant. PMID- 27506297 TI - Reaction of Oxidized Polysialic Acid and a Diaminooxy Linker: Characterization and Process Optimization Using Nuclear Magnetic Resonance Spectroscopy. AB - Native polysialic acid (natPSA) is a high-molecular-weight glycan composed of repeat units of alpha-(2 -> 8) linked N-acetylneuraminic acid (Neu5Ac). Mild periodate oxidation of PSA selectively targets the end sialic acid ring containing three adjacent alcohols generating a putative aldehyde, which can be used, after attachment of a linker molecule, for terminal attachment of PSA to protein. Previously, we showed that the oxidized PSA (oxoPSA) contained a hemiacetal at the oxidation site and can react with a linker containing an aminooxy group in a conjugation reaction to form a stable oxime linkage. Thus, reagents containing an aminooxy group may be prepared for conjugation of PSA to the carbohydrate moiety of therapeutic proteins, thereby increasing their half life. These aminooxy-PSA reagents can selectively react with aldehyde groups generated by mild NaIO4 oxidation of glycans on the surface of the target protein. To comprehend the conjugation, unoxidized tetrasialic acid and Neu5Ac were reacted in model reactions with a diaminooxy linker to define the nuclear magnetic resonance (NMR) chemical shifts. Based on these data, we were able to show that, in the case of PSA, the reaction with the linker occurs not only at the expected oxidized end to form an aldoxime but also at the end distal to the oxidation to form a ketoxime. We determined that, in aged solutions, both oxoPSA and PSA aldoxime were hydrolyzed. PSA aldoxime was also shown to disproportionate to form a dimer (PSA-linker-PSA), which then could react further with the released linker at one of its PSA termini. Furthermore, NMR was used to monitor the effects of deliberate process changes so that conditions could be optimized for attachment of linker at the desired end of the PSA chain, which led to a well defined product. PMID- 25060184 TI - Aggressive primary thyroid lymphoma: imaging features of two elderly patients. AB - We report two cases of aggressive thyroid lymphoma in elderly patients that presented as large infiltrative thyroid masses with extensive invasion to adjacent structures including trachea, esophagus, and common carotid artery. Ultrasonography displayed irregular shaped, heterogeneous hypoechoic mass, mimicking anaplastic carcinoma. Computed tomography showed heterogeneously enhancing mass compared to surrounding muscles without calcification and hemorrhage. After biopsy, the masses were histopathologically diagnosed as lymphoma. Aggressive primary thyroid lymphoma is rare; therefore, here we report its image features, with emphasis on ultrasonographic findings, and discuss its differential diagnosis. PMID- 27506299 TI - Pancreatic Premalignant Lesions Secrete Tissue Inhibitor of Metalloproteinases-1, Which Activates Hepatic Stellate Cells Via CD63 Signaling to Create a Premetastatic Niche in the Liver. AB - BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) metastasizes to liver at early stages, making this disease highly lethal. Tissue inhibitor of metalloproteinases-1 (TIMP1) creates a metastasis-susceptible environment in the liver. We investigated the role of TIMP1 and its receptor CD63 in metastasis of early-stage pancreatic tumors using mice and human cell lines and tissue samples. METHODS: We obtained liver and plasma samples from patients in Germany with chronic pancreatitis, pancreatic intra-epithelial neoplasia, or PDAC, as well as hepatic stellate cells (HSCs). We performed studies with Ptf1a+/Cre;Kras+/LSL G12D;Trp53loxP/loxP (CPK) mice, Pdx-1+/Cre;Kras+/LSL-G12D;Trp53+/LSL-R172H (KPC) mice, and their respective healthy littermates as control, and Cd63-/- mice with their wild-type littermates. KPC mice were bred with Timp1-/- mice to produce KPCxTimp1-/- mice. TIMP1 was overexpressed and CD63 was knocked down in mice using adenoviral vectors AdTIMP1 or AdshCD63, respectively. Hepatic susceptibility to metastases was determined after intravenous inoculation of syngeneic 9801L pancreas carcinoma cells. Pancreata and liver tissues were collected and analyzed by histology, immunohistochemical, immunoblot, enzyme linked immunosorbent assay, and quantitative polymerase chain reaction analyses. We analyzed the effects of TIMP1 overexpression or knockdown and CD63 knockdown in transduced human primary HSCs and HSC cell lines. RESULTS: Chronic pancreatitis, pancreatic intra-epithelial neoplasia, and PDAC tissues from patients expressed higher levels of TIMP1 protein than normal pancreas. The premalignant pancreatic lesions that developed in KPC and CPK mice expressed TIMP1 and secreted it into the circulation. In vitro and in vivo, TIMP1 activated human or mouse HSCs, which required interaction between TIMP1 and CD63 and signaling via phosphatidylinositol 3-kinase, but not TIMP1 protease inhibitor activity. This signaling pathway induced expression of endogenous TIMP1. TIMP1 knockdown in HSCs reduced their activation. Cultured TIMP1-activated human and mouse HSCs began to express stromal-derived factor-1, which induced neutrophil migration, a marker of the premetastatic niche. Mice with pancreatic intra epithelial neoplasia-derived systemic increases in TIMP1 developed more liver metastases after injections of pancreatic cancer cells than mice without increased levels of TIMP1. This increase in formation of liver metastases from injected pancreatic cancer cells was not observed in TIMP1 or CD63 knockout mice. CONCLUSIONS: Expression of TIMP1 is increased in chronic pancreatitis, pancreatic intra-epithelial neoplasia, and PDAC tissues from patients. TIMP1 signaling via CD63 leads to activation of HSCs, which create an environment in the liver that increases its susceptibility to pancreatic tumor cells. Strategies to block TIMP1 signaling via CD63 might be developed to prevent PDAC metastasis to the liver. PMID- 27506300 TI - Domoic acid disrupts the activity and connectivity of neuronal networks in organotypic brain slice cultures. AB - Domoic acid is a neurotoxin produced by algae and is found in seafood during harmful algal blooms. As a glutamate agonist, domoic acid inappropriately stimulates excitatory activity in neurons. At high doses, this leads to seizures and brain lesions, but it is unclear how lower, asymptomatic exposures disrupt neuronal activity. Domoic acid has been detected in an increasing variety of species across a greater geographical range than ever before, making it critical to understand the potential health impacts of low-level exposure on vulnerable marine mammal and human populations. To determine whether prolonged domoic acid exposure altered neuronal activity in hippocampal networks, we used a custom-made 512 multi-electrode array with high spatial and temporal resolution to record extracellular potentials (spikes) in mouse organotypic brain slice cultures. We identified individual neurons based on spike waveform and location, and measured the activity and functional connectivity within the neuronal networks of brain slice cultures. Domoic acid exposure significantly altered neuronal spiking activity patterns, and increased functional connectivity within exposed cultures, in the absence of overt cellular or neuronal toxicity. While the overall spiking activity of neurons in domoic acid-exposed cultures was comparable to controls, exposed neurons spiked significantly more often in bursts. We also identified a subset of neurons that were electrophysiologically silenced in exposed cultures, and putatively identified those neurons as fast-spiking inhibitory neurons. These results provide evidence that domoic acid affects neuronal activity in the absence of cytotoxicity, and suggest that neurodevelopmental exposure to domoic acid may alter neurological function in the absence of clinical symptoms. PMID- 27506302 TI - C2H4 adsorption on Cu(210), revisited: bonding nature and coverage effects. AB - With the aid of density functional theory (DFT)-based calculations, we investigate the adsorption of C2H4 on Cu(210). We found two C2H4 adsorption sites, viz., the top of the step-edge atom (S) and the long bridge between two step-edge atoms (SS) of Cu(210). The step-edge atoms on Cu(210) block the otherwise active terrace sites found on copper surfaces with longer step sizes. This results in the preference for pi-bonded over di-sigma-bonded C2H4. We also found two stable C2H4 adsorption orientations on the S- and SS-sites, viz., with the C2H4 C[double bond, length as m-dash]C bond parallel (fit) and perpendicular (cross) to [001]. Furthermore, we found that the three peaks observed in previous temperature programmed desorption (TPD) experiment [Surf. Sci., 2011, 605, 934 940] could be attributed to C2H4 in the S-fit or S-cross, S-fit and S-cross-fit (S-cross and S-fit configurations that both exist in the same unit cell) configurations on Cu(210). PMID- 27506301 TI - A quasi-cyclic RNA nano-scale molecular object constructed using kink turns. AB - k-Turns are widespread RNA architectural elements that mediate tertiary interactions. We describe a double-kink-turn motif comprising two inverted k turns that forms a tight horse-shoe structure that can assemble into a variety of shapes by coaxial association of helical ends. Using X-ray crystallography we show that these assemble with two (dumbell), three (triangle) and four units (square), with or without bound protein, within the crystal lattice. In addition, exchange of a single basepair can almost double the pore radius or shape of a molecular assembly. On the basis of this analysis we synthesized a 114 nt self complementary RNA containing six k-turns. The crystal structure of this species shows that it forms a quasi-cyclic triangular object. These are randomly disposed about the three-fold axis in the crystal lattice, generating a circular RNA of quasi D3 symmetry with a shape reminiscent of that of a cyclohexane molecule in its chair conformation. This work demonstrates that the k-turn is a powerful building block in the construction of nano-scale molecular objects, and illustrates why k-turns are widely used in natural RNA molecules to organize long range architecture and mediate tertiary contacts. PMID- 27506303 TI - Sampling effort of periphytic diatoms for bioassessment research using taxonomic distinctness in marine ecosystems: A case study in coastal waters. AB - The sampling effort for detecting taxonomic distinctness of periphytic diatom communities was studied in coastal waters of the Yellow Sea, northern China, from May to June 2014. Samples with different sizes (microscopy glass slides) were collected at two depths of 1m and 3m. To obtain the communities with dissimilarities of <10%, 2 slide replicates were sufficient for sampling at a depth of 1m, while 4 were required for the those at a depth of 3m. The values of four taxonomic distinctness indices represented a low sensitivity to sample sizes over all exposure period ages: at a coefficient of variation of <10%, 2 and 9 slide replicates were required at a depth of 1m and 3m, respectively. We suggest that the sampling strategy of the diatoms for detecting taxonomic distinctness might be better at 1m than at a deeper layer in coastal waters. PMID- 27506304 TI - Experimental study of oil plume stability: Parametric dependences and optimization. AB - Oil plume is known to interact with density layer in spilled oil. Previous studies mainly focused on tracking oil plumes and predicting their impact on marine environment. Here, simulated experiments are presented that investigated the conditions inducing the formation of oil plume, focusing especially on the effects of oil/water volume ratio, oil/dispersant volume rate, ambient stratification and optimal conditions of oil plume on determining whether a plume will trap or escape. Scenario simulations showed that OWR influences the residence time most, dispersants dosage comes second and salinity least. The optimum residence time starts from 2387s, occurred at approximately condition (OWR, 0.1, DOR, 25.53% and salinity, 32.38). No change in the relative distribution under the more scale tank was observed, indicating these provide the time evolution of the oil plumes. PMID- 27506305 TI - Phosphate Ions Affect the Water Structure at Functionalized Membrane Surfaces. AB - Antifouling surfaces improve function, efficiency, and safety in products such as water filtration membranes, marine vehicle coatings, and medical implants by resisting protein and biofilm adhesion. Understanding the role of water structure at these materials in preventing protein adhesion and biofilm formation is critical to designing more effective coatings. Such fouling experiments are typically performed under biological conditions using isotonic aqueous buffers. Previous studies have explored the structure of pure water at a few different antifouling surfaces, but the effect of electrolytes and ionic strength (I) on the water structure at antifouling surfaces is not well studied. Here sum frequency generation (SFG) spectroscopy is used to characterize the interfacial water structure at poly(ether sulfone) (PES) and two surface-modified PES films in contact with 0.01 M phosphate buffer with high and low salt (Ionic strength, I= 0.166 and 0.025 M, respectively). Unmodified PES, commonly used as a filtration membrane, and modified PES with a hydrophobic alkane (C18) and with a poly(ethylene glycol) (PEG) were used. In the low ionic strength phosphate buffer, water was strongly ordered near the surface of the PEG-modified PES film due to exclusion of phosphate ions and the creation of a surface potential resulting from charge separation between phosphate anions and sodium cations. However, in the high ionic strength phosphate buffer, the sodium and potassium chloride (138 and 3 mM, respectively) in the phosphate buffered saline screened this charge and substantially reduced water ordering. A much smaller water ordering and subsequent reduction upon salt addition was observed for the C18 modified PES, and little water structure change was seen for the unmodified PES. The large difference in water structuring with increasing ionic strength between widely used phosphate buffer and phosphate buffered saline at the PEG interface demonstrates the importance of studying antifouling coatings in the same aqueous environment for which they are designed. These results further suggest that strong long-range water structuring is limited in high ionic strength environments, such as within cells, facilitating chemical and biological reactions and processes. PMID- 27506307 TI - An unprecedented one-step synthesis of octahedral Cu(ii)-bis(iminoquinone) complexes and their reactivity with NaBH4. AB - A new non-innocent ligand, H2L(AP(o-NO2-OPh)), was synthesized. The ligand H2L(AP(o-NO2-OPh)) reacted with 0.5 equivalents of CuCl2.2H2O and provided the corresponding mononuclear four-coordinate [Cu(ii)-bis(iminosemiquinone)] complex (1). Interestingly, the ligand upon reacting with 2 equivalents of CuCl2.2H2O in the presence of Et3N and air provided the corresponding trans-dichloride-bound six-coordinate mononuclear Cu(ii)-complex (2) in one step. To extend the validity of the newly developed one-step synthesis of the trans-dichloride-bound Cu(ii) bis(iminoquinone) complex using a non-innocent ligand and 2 equivalents of CuCl2.2H2O, the previously reported non-innocent ligand H2L(AP) was further examined. Thus the formed trans-dichloride-bound Cu(ii)-bis(iminoquinone) complex was designated as complex 3. The complexes were characterized by IR, mass, UV Vis/NIR, X-band EPR, and X-ray single crystal diffraction techniques. Molecular structure analysis confirmed that in 1 the oxidation state of the coordinating ligands was [L(ISQ(o-NO2-OPh))](1-), i.e., one-electron oxidized iminosemiquinone. In 2 and 3.CH2Cl2, both the coordinated-ligands were present in their two-electron oxidized iminoquinone form. The iminoquinone-complex formation was found to proceed with the generation of CuCl salt. X-band EPR spectrum measurement confirmed that both the iminoquinone-complexes were paramagnetic and the unpaired electron was located at the 3dx(2)-y(2) orbital of Cu(ii) ions. When the Cu(ii)-bis(iminoquinone) complex 3 was subjected to react with NaBH4 in dry CH3CN, H2 gas was formed along with the generation of the corresponding Cu(ii) bis(iminosemiquinone) complex. GC analyses were performed for the identification of H2 gas. PMID- 27506308 TI - Commentary to "Determinants of practice patterns in pediatric UTI". PMID- 27506309 TI - Unexpected reductions in regional cerebral perfusion during prolonged hypoxia. AB - KEY POINTS: Cognitive performance is impaired by hypoxia despite global cerebral oxygen delivery and metabolism being maintained. Using arterial spin labelled (ASL) magnetic resonance imaging, this is the first study to show regional reductions in cerebral blood flow (CBF) in response to decreased oxygen supply (hypoxia) at 2 h that increased in area and became more pronounced at 10 h. Reductions in CBF were seen in brain regions typically associated with the 'default mode' or 'task negative' network. Regional reductions in CBF, and associated vasoconstriction, within the default mode network in hypoxia is supported by increased vasodilatation in these regions to a subsequent hypercapnic (5% CO2 ) challenge. These results suggest an anatomical mechanism through which hypoxia may cause previously reported deficits in cognitive performance. ABSTRACT: Hypoxia causes an increase in global cerebral blood flow, which maintains global cerebral oxygen delivery and metabolism. However, neurological deficits are abundant under hypoxic conditions. We investigated regional cerebral microvascular responses to acute (2 h) and prolonged (10 h) poikilocapnic normobaric hypoxia. We found that 2 h of hypoxia caused an expected increase in frontal cortical grey matter perfusion but unexpected perfusion decreases in regions of the brain normally associated with the 'default mode' or 'task negative' network. After 10 h in hypoxia, decreased blood flow to the major nodes of the default mode network became more pronounced and widespread. The use of a hypercapnic challenge (5% CO2 ) confirmed that these reductions in cerebral blood flow from hypoxia were related to vasoconstriction. Our findings demonstrate steady-state deactivation of the default network under acute hypoxia, which become more pronounced over time. Moreover, these data provide a unique insight into the nuanced localized cerebrovascular response to hypoxia that is not attainable through traditional methods. The observation of reduced perfusion in the posterior cingulate and cuneal cortex, which are regions assumed to play a role in declarative and procedural memory, provides an anatomical mechanism through which hypoxia may cause deficits in working memory. PMID- 27506310 TI - Treatment discontinuation of oral hypoglycemic agents and healthcare utilization among patients with diabetes. AB - AIMS: To investigate the discontinuation of oral antihyperglycemic agents (OHA), and examine factors associated with OHA discontinuation, and the effect of OHA discontinuation on glycemic control and healthcare utilization among diabetes patients prescribed dual OHA therapy. METHODS: We identified 23,612 adult patients aged >18years with a diagnosis of type 2 diabetes who initiated dual OHA therapy between 1/1/2005 and 6/30/2010. The date of initiation of the second OHA was defined as the index date. Discontinuation was defined as a gap >1.5 times the last days' supply without subsequent reinitiation. RESULTS: Over 24months, 16.9% discontinued 1 OHA and 9.2% discontinued both. Patients who discontinued were more likely to be female, younger, Black or of Hispanic ethnicity, have more comorbidities, higher medication co-pays, start both OHAs together, have higher healthcare utilization before the index date and less likely to use prescription mail order compared with patients who did not discontinue. In multivariable regression models, patients who discontinued were more likely to be hospitalized or have emergency department visits during follow-up. CONCLUSIONS: Discontinuation of OHAs is common among patients with diabetes and is associated with several patient factors and increased healthcare utilization. Future research should further examine reasons for OHA discontinuation. PMID- 27506311 TI - Development and optimization of psychological stress model in mice using 2 level full factorial design. AB - INTRODUCTION: Psychological stress has long been a silent killer, impairing normal physiological functions and leading to a variety of diseased conditions. However, the existing animal models for studying psychological stress have been marred by their inherent limitations warranting further research in their development and optimization. METHODS: In this study 25 full factorial design was utilized for the development and optimization of psychological stress model in mice by applying different stressors viz., slanted cage(X1), restraint(X2), no bedding(X3), dirty bedding(X4) and isolation(X5) at two time duration levels of 30 and 60min. The development of behavioral changes like depression, anxiety and anhedonia was taken as criteria for development of stress. These responses were analyzed using Design Expert 7.1.6. (Stat-Ease, Inc., USA). The maximum effective responses obtained were taken as a criterion for optimization. The optimized model was applied to measure the change in serum cortisol level to confirm the stress development. RESULTS: The statistical data showed that a quadratic model was fitted to the data obtained. All the factors were found to have a significant role in the development of stress among which restraint, slanted cage and dirty bedding were found to be more causal (p<0.05). Serum cortisol level was increased significantly in the stressed mice of optimized model (p<0.05). DISCUSSION: Utilizing the magnitude of responses from the quadratic equations, it can be concluded that slanted cage, restraint and dirty bedding stressors should be applied for longer duration than other stressors for psychological stress development in mice. The study could lay a strong platform for the use of quality by design approach in the development of robust, efficient and resourceful animal models. PMID- 27506312 TI - Epidermal growth factor-induced stimulation of proliferation and gene expression changes in the hypotrichous ciliate, Stylonychia lemnae. AB - Epidermal growth factor (EGF) induces proliferation of epidermal and epithelial tissues in mammals. However, the effect of EGF on the single-celled eukaryotes is not well characterized, especially in the protists. Ciliates, an important group of protists, are well characterized as both pollution indicators and model organisms for research. Stylonychia lemnae, is one of the most common free-living ciliates, widely distributed in ponds, rivers and marshes. Here, we report the role of EGF on cell proliferation stimulation in S. lemnae. The growth curve of S. lemnae was established, and the stimulation effect of EGF on the proliferation of S. lemnae was investigated. Based on the results, potential EGF receptors were identified in S. lemnae according to the conserved domains and gene expression. Differential gene expression revealed that EGF-induced genes in other organisms (e.g. antioxidant) also up-regulated in S. lemnae cells at propagation stages. In addition, our results showed that EGF could up-regulate the signal transduction related processes in the decline stage of S. lemnae cells, indicating its potential function in apoptosis inhibition. In summary, this study reports findings of the first investigation of EGF effects in hypotrich ciliates, and establishes an additional system for the study of the molecular mechanisms of EGF actions in eukaryotic cell division and proliferation. PMID- 27506313 TI - miR-490-3p inhibits the growth and invasiveness in triple-negative breast cancer by repressing the expression of TNKS2. AB - Identification of key genes driving the aggressiveness of triple-negative breast cancer (TNBC) is important to develop effective therapies. In this study, we examined the expression and biological roles of microRNA (miR)-490-3p in TNBC. Our data showed that miR-490-3p-3p was underexpressed in TNBC compared with non TNBC tissues (P=0.0021). Similarly, this miRNA was expressed at lower levels in TNBC cell lines than in non-TNBC cell lines. Gain-of-function studies revealed that miR-490-3p-3p overexpression inhibited cell growth and invasion in both MDA MB-231 and MDA-MB-436 TNBC cells and impaired tumorigenesis of MDA-MB-231 cells in nude mice. Mechanistically, we found that miR-490-3p negatively regulated the expression of tankyrase 2 (TNKS2) via binding to its 3'-untranslated region and then blocked the activation of beta-catenin signaling. Importantly, overexpression of a miR-490-3p-resistant form of TNKS2 reversed miR-490-3p mediated suppression of TNBC cell proliferation and invasion. Knockdown of TNKS2 via small interfering RNA technology was found to mimic the suppressive activity of miR-490-3p in MDA-MB-231 cells. Taken together, miR-490-3p is downregulated in TNBC and plays a suppressive role in cancer cell proliferation, invasion, and tumorigenesis. The tumor suppressive activity of miR-490-3p is largely mediated through downregulation of TNKS2 and inactivation of beta-catenin signaling. Thus, miR-490-3p may represent a potential therapeutic target for TNBC. PMID- 27506314 TI - Systematic analyses of key genes and pathways in the development of invasive breast cancer. AB - BACKGROUND: Ductal carcinoma in situ (DCIS) is a common type of non-invasive breast cancer and can sometimes progress into invasive breast cancer (IBC). Identification of the critical genes and biological processes specifically and/or commonly changed in DCIS or IBC can help us understand more about breast cancer development and provide more critical targets and signal transduction pathways for the diagnosis and treatments for breast cancer patients. AIM AND METHODS: We aimed to gain more understanding about the whole process of IBC development, especially in the early stage. Here we systematically analyzed an online breast cancer patient database to identify those significantly changed genes and biological processes in epithelium from normal stage to DCIS stage or from DCIS stage to IBC stage. RESULTS: 344 specific genes, such as FN1, AURKA and HSPA8, were found to be significantly changed (both upregulated and downregulated) in DCIS group in comparison with normal tissue group, which represents the gene profile changes in early stage of breast cancer development. Meanwhile, 304 specific genes were significantly changed (both upregulated and downregulated) in IBC group in comparison with normal tissue group, which represents the gene profile changes in late stage of breast cancer development. Importantly, seven genes were identified to have consistent changes in both early stage and late stage, indicating they might play "driving" roles in the breast cancer development. Of these 7 genes, 5 have been shown to be involved in breast cancer progression by previous studies, which demonstrates the validity of our analyses. Notably, DNAPTP3 was identified for the first time to play an oncogenic role in breast cancer development. In the GO term analyses, cell cycle genes was found to play more important roles in the early stage while biological adhesion was indicated to be more specifically involved in late stage of breast cancer development. SIGNIFICANCE: Our systematic analyses provide better understanding of the unique gene profiles and biological processes during the breast cancer development and identify more potentially important targets for future studies, such as DNAPTP3. PMID- 27506316 TI - Determination of metabolic profile of novel triethylamine containing thiophene S006-830 in rat, rabbit, dog and human liver microsomes. PMID- 27506315 TI - Transcriptional regulation of the canine carbonyl reductase 1 gene (cbr1) by the specificity protein 1 (Sp1). AB - The clinical use of anthracyclines to treat various canine cancers is limited by the development of cardiotoxicity. The intra-cardiac synthesis of anthracycline C 13 alcohol metabolites (e.g. daunorubicinol) contributes to the development of cardiotoxicity. Canine carbonyl reductase 1 (cbr1) catalyzes the reduction of daunorubicin into daunorubicinol. Recent mapping of the cbr1 locus by sequencing DNA samples from dogs from various breeds revealed a cluster of conserved motifs for the transcription factor Sp1 in the putative promoter region of cbr1. We hypothesized that the variable number of Sp1 motifs could impact the transcription of canine cbr1. In this study, we report the functional characterization of the canine cbr1 promoter. Experiments with reporter constructs and chromatin immunoprecipitation show that cbr1 transcription depends on the binding of Sp1 to the proximal promoter. Site-directed mutagenesis experiments suggest that the variable number of Sp1 motifs impacts the transcription of canine cbr1. Inhibition of Sp1-DNA binding decreased canine cbr1 mRNA levels by 54% in comparison to controls, and also decreased enzymatic carbonyl reductase activity for the substrates daunorubicin (16%) and menadione (23%). The transactivation of Sp1 increased the expression of cbr1 mRNA (67%), and increased carbonyl reductase activity for daunorubicin (35%) and menadione (27%). These data suggest that the variable number of Sp1 motifs in the canine cbr1 promoter may impact the pharmacodynamics of anthracyclines in canine cancer patients. PMID- 27506317 TI - Improvement in symptoms of obstructive sleep apnoea in children following tonsillectomy versus tonsillotomy: a systematic review and meta-analysis. AB - BACKGROUND: Tonsillotomy (or intracapsular tonsillectomy) is a modern technique which is seen by some as potentially superior to traditional (extracapsular) tonsillectomy for the removal of tonsillar tissue to treat obstructive sleep apnoea in children. It has been suggested that peri-operative pain and haemorrhage and postoperative haemorrhage are reduced with the tonsillotomy technique. However, no systematic reviews have been carried out to assess its efficacy in treating obstructive sleep apnoea compared to tonsillectomy. OBJECTIVE OF REVIEW: To assess whether subjective improvement in symptoms of obstructive sleep apnoea following tonsillotomy is comparable to that following tonsillectomy, measured using a standardised questionnaire, the Obstructive sleep apnoea-18 (OSA-18) tool. TYPE OF REVIEW: Systematic review of the literature and meta-analysis. SEARCH STRATEGY: PubMed (MEDLINE), followed by Ovid (MEDLINE), Cochrane Database of Systematic Reviews, American College of Physicians Journal Club, and the British Medical Journal were searched for articles published in English between 1995 and 2015 inclusive. EVALUATION METHOD: Literature search, systematic review and meta-analysis. Studies examining improvement in mean OSA-18 score following tonsillotomy, improvement in mean OSA-18 score following tonsillectomy, and examining both were selected, examined and used for meta analysis. Studies with and without concurrent adenoidectomy were included. RESULTS: Four studies examining tonsillotomy and 16 studies examining tonsillectomy were included in the analysis. Using a random effects model, the pooled improvement in OSA-18 score for tonsillotomy was 2.46 (95% CI 1.92-2.99), and for tonsillectomy, it was 2.10 (95% CI 1.91-2.30). There was no significant difference between the methods. CONCLUSION: That there is no significant difference in subjective outcome between tonsillotomy and tonsillectomy may support wider use of tonsillotomy over tonsillectomy for the treatment of obstructive sleep apnoea in children. PMID- 27506318 TI - Introducing the Wiley Transplant Peer Review Network. PMID- 27506319 TI - Erratum. PMID- 27506320 TI - Interaction between migration behaviour and estuarine mortality in cultivated Atlantic salmon Salmo salar smolts. AB - Migration behaviour and estuarine mortality of cultivated Atlantic salmon Salmo salar smolts in a 16 km long estuary were studied using two methods: (1) acoustic telemetry and (2) group tagging in combination with trap nets. Progression rates of surviving individuals through the estuary were relatively slow using both methods [0.38 LT (total length) s-1 v. 0.25 LT s-1 ]. In 2012, the progression rate was slow from the river to the estuary (0.55 LT s-1 ) and the first part of the estuary (0.31 LT s-1 ), but increased thereafter (1.45-2.21 LT s-1 ). In 2013, the progression rate was fast from the river to the estuary (4.31 LT s-1 ) but was slower thereafter (0.18-0.91 LT s-1 ). Survival to the fjord was higher in 2012 (47%) compared to 2013 (6%). Fast moving individuals were more likely to migrate successfully through the estuary compared to slower moving individuals. Adult recapture of coded-wire-tagged S. salar was generally low (0.00-0.04%). Mortality hot spots were related to topographically distinct areas such as the river outlet (in 2012) or the sill separating the estuary and the fjord (in 2013). At the sill, an aggregation of cod Gadus morhua predating on cultivated smolts was identified. The results indicate that slow progression rates through the estuary decreases the likelihood of smolts being detected outside the estuary. The highly stochastic and site-specific mortality patterns observed in this study highlight the complexity in extrapolating mortality patterns of single release groups to the entire smolt run of wild S. salar. PMID- 27506321 TI - Spectral Analysis of Baseline Electrocardiogram During Atrial Fibrillation Predicts Response to Antiarrhythmic Drug Therapy in Patients With Persistent Atrial Fibrillation. AB - BACKGROUND: We evaluated the ability of spectral analysis of the baseline ECG during atrial fibrillation (AF) to predict the response of persistent AF to antiarrhythmic drug therapy. METHODS: Patients with persistent AF who were admitted for dofetilide loading were prospectively enrolled in the study. Atrial activity was extracted from the ECG using an Independent Component Analysis method and then subjected to a Modified Periodogram. The regularity index was computed as the ratio of the power in the dominant frequency and all its harmonics to the total power in the spectrum. Patients were followed at 1 month, 3 months and every 3 months thereafter. RESULTS: Of 28 patients enrolled in the study, 14 (50%) converted acutely to sinus rhythm during the 3-day hospital loading period. The clinical and echocardiographic characteristics of patients with and without acute pharmacologic conversion were similar. The regularity index was significantly higher in those who converted to sinus rhythm compared to those who did not (0.71 +/- 0.20 vs. 0.38 +/- 0.13, respectively; P < 0.0001). A regularity index >=0.44 had a 79% sensitivity and 93% specificity to predict acute conversion and was associated with a nearly 5-fold increase in the acute conversion rate (odds ratio = 4.89; 95% confidence interval 1.74-13.75; P = 0.003). The regularity index was the only independent predictor of acute conversion. Neither acute conversion, nor the regularity index predicted sinus rhythm maintenance, after a median follow-up of 10 months. CONCLUSION: Increased regularity index predicts acute conversion of persistent AF during dofetilide loading, but does not predict long-term sinus rhythm maintenance. PMID- 27506322 TI - Relationship between the cranial base and the mandible in artificially deformed skulls. AB - OBJECTIVES: There is controversy regarding the relationship between mandibular position and alterations of the cranial base that provoke a more anterior location of the glenoid fossa. Artificially deformed skulls display marked alterations of the cranial base. This study evaluates mandibular changes as function of the morphology of the cranial base in these skulls. MATERIAL AND METHODS: A geometric morphometric study was performed on lateral cephalometric X rays of three groups of skulls: 32 with anteroposterior deformity, 17 with circumferential deformity and 39 with no apparent deformity. RESULTS: In artificially deformed skulls, the cranial base was deformed causing the mandibular condyle to be in a more anterior position. There was a complete remodelling of the mandible involving narrowing and elongation of the mandibular ramus, rotation of the corpus of the mandible and increased vertical height of the symphysis. Forward displacement did not occur. Integration between mandible and cranial base is not altered by deformation of the skull. CONCLUSIONS: Deformity of the cranial vault exerts an influence on the mandible, supporting the theory of modular units in complete integration. This also supports the theory that mandibular prognathism is a multifactorial result and not a direct effect of displacement of the cranial base. PMID- 27506323 TI - Short-term storage of salmonids semen in a sodium alginate-based extender. AB - Short-term storage of semen is a useful strategy for preservation of fish spermatozoa. However, there is a significantly decrease on sperm function mainly due to oxidative stress. In this way, sodium alginate plays an important role as free radical scavenger compound. Accordingly, the aim of our study was to analyse the effect of a sodium alginate-based extender on sperm function in the short term storage of salmonids semen. Samples of Salmo salar, Oncorhynchus kisutch, and Oncorhynchus mykiss were stored in Storfish(r) (Ext-C) and Storfish(r) supplemented with sodium alginate (Ext-A) during 10 days at 4 degrees C. After storage, motility, viability, mitochondrial membrane potential (DeltaPsimit), superoxide anion (O2- ) level and DNA fragmentation (DNA Frag) were assessed. Ext A had positive effect in preservation of sperm motility, viability, DeltaPsimit, O2- level and DNA integrity in the three species analysed compared to control samples. In Ext-A, the spermatozoa of S. salar and O. mykiss showed significantly higher motility, viability and DeltaPsimit than O. kisutch. However, O. kisutch and O. mykiss had significantly lower O2- level than S. salar, and DNA fragmentation in O. kisutch and S. salar was significantly lower than in samples of O. mykiss (p < 0.05). Dilution of salmonids semen in a sodium alginate-based extender is effective for protecting sperm quality during 10 days of short-term storage. PMID- 27506324 TI - Women with intellectual disability are at a higher risk of adverse maternal and offspring outcomes. PMID- 27506325 TI - Thermally induced recrystallization of MAPbI3 perovskite under methylamine atmosphere: an approach to fabricating large uniform crystalline grains. AB - A liquid to solid phase transition of methylammonium lead triiodide (MAPbI3) under methylamine (MA) atmosphere at elevated temperatures was discovered, and used to form high quality and uniform thin films containing large, low defect crystal grains tens of microns in size. PMID- 27506326 TI - Effects of intra-operative maintenance of general anaesthesia with propofol on postoperative pain outcomes - a systematic review and meta-analysis. AB - Propofol is used both for induction and maintenance of anaesthesia. Recent evidence shows that propofol has analgesic properties. This meta-analysis evaluated differences in postoperative analgesia between general anaesthetic maintenance with intravenous propofol and inhalational anaesthetics. Fourteen trials met inclusion criteria and were included. Our outcomes were pain scores 2 and 24 h after surgery. No significant difference in pain scores was found at 2 h after surgery (Hedge's g (95% CI) -0.120 (-0.415-0.175) (p = 0.425). Propofol was associated with a statistically significant, albeit marginal, reduction in pain scores 24 h after surgery (Hedge's g (95% CI) -0.134 (-0.248 to -0.021) (p = 0.021). Data were insufficient to allow a meaningful analysis regarding 24-h morphine-equivalent consumption. Propofol was associated with reduced postoperative nausea and vomiting (relative risk (95%CI) 0.446 (0.304-0.656) (p < 0.0001). In conclusion, this meta-analysis suggests that propofol improves postoperative analgesia compared with inhalational anaesthesia 24 h after surgery, with a lower incidence of nausea and vomiting. PMID- 27506327 TI - Evaluation of successful aging among older people in China: Results from China health and retirement longitudinal study. AB - AIM: China faces a "time-bomb" of the aging population. Successful aging has long been a goal in the field of gerontology. The present study aimed to evaluate successful aging among Chinese older adults. METHODS: Data on a total of 7102 people in the China Health and Retirement Study aged >=60 years were analyzed in the present study. Successful aging is defined by the model of Rowe and Kahn including the following five indicators: "no major diseases," "no disability," "high cognitive functioning," "high physical functioning" and "active engagement with life." Using logistic regression analysis, crude and adjusted odds ratios with 95% confidence intervals were calculated to evaluate the relationship between sociodemographic parameters and successful aging. RESULTS: The prevalence of successful aging was 13.2% among Chinese older people. The percentage of older people with the five indicators, "no major diseases," "no disability," "high cognitive functioning," "high physical functioning," and "active engagement with life" was 41.7%, 92.1%, 54.2%, 70.2% and 46.0%, respectively. Multiple logistic regression showed people who had received education of high/vocational school or above had significantly greater odds of successful aging compared with those with less than primary school education (P < 0.05). The effect of education to college level or above on cognitive functioning was 2.51-fold higher in women than men (P = 0.006). Older people from a non-agricultural Hukou had 1.85-fold higher odds of successful aging than those from an agricultural Hukou. Older people living in the central, northeast or western regions had lower odds of successful aging relative to those living in the east coast region (0.72, 0.72 and 0.56, respectively). CONCLUSIONS: The prevalence of successful aging is low among Chinese older people, and is affected by sociodemographic factors, such as education, Hukou and regions. Geriatr Gerontol Int 2017; 17: 1183-1190. PMID- 27506328 TI - Comparison of models for genetic evaluation of number of inseminations to conception in Danish Holstein cows. AB - Number of inseminations to conception (NINS), an important fertility trait, requires appropriate approaches for genetic evaluation due to its non-normal distribution and censoring records. In this study, we analyzed NINS in 474 837 Danish Holstein cows at their first lactation by using seven models which deal with the categorical phenotypes and censored records in different manners, further assessed these models with regard to stability, lack of bias and accuracy of prediction. The estimated heritability from four models based on original NINS specified as a linear Gaussian model, categorical threshold model, threshold linear model and survival model were similar (0.031-0.037). While for the other three models based on the binary response derived from NINS, referred as threshold model (TM), logistic and probit models (LOGM and PROM), the heritability were estimated as 0.027, 0.063 and 0.027, respectively. The model comparison concluded that different models could lead to slightly different sire rankings in terms of breeding values; a more complicated model led to less stability of prediction; the models based on the binary response derived from NINS (TM, LOGM and PROM) had slightly better performances in terms of unbiased and accurate prediction of breeding values. PMID- 27506329 TI - Ancient DNA reveals differences in behaviour and sociality between brown bears and extinct cave bears. AB - Ancient DNA studies have revolutionized the study of extinct species and populations, providing insights on phylogeny, phylogeography, admixture and demographic history. However, inferences on behaviour and sociality have been far less frequent. Here, we investigate the complete mitochondrial genomes of extinct Late Pleistocene cave bears and middle Holocene brown bears that each inhabited multiple geographically proximate caves in northern Spain. In cave bears, we find that, although most caves were occupied simultaneously, each cave almost exclusively contains a unique lineage of closely related haplotypes. This remarkable pattern suggests extreme fidelity to their birth site in cave bears, best described as homing behaviour, and that cave bears formed stable maternal social groups at least for hibernation. In contrast, brown bears do not show any strong association of mitochondrial lineage and cave, suggesting that these two closely related species differed in aspects of their behaviour and sociality. This difference is likely to have contributed to cave bear extinction, which occurred at a time in which competition for caves between bears and humans was likely intense and the ability to rapidly colonize new hibernation sites would have been crucial for the survival of a species so dependent on caves for hibernation as cave bears. Our study demonstrates the potential of ancient DNA to uncover patterns of behaviour and sociality in ancient species and populations, even those that went extinct many tens of thousands of years ago. PMID- 27506331 TI - The impact of delayed biliary decompression and anti-microbial therapy in 260 patients with cholangitis-associated septic shock. AB - BACKGROUND: Cholangitis-associated septic shock carries significant mortality. There is uncertainty regarding the most appropriate time to achieve biliary decompression. AIM: To determine whether the timing of biliary decompression and anti-microbial therapy affect the survival in cholangitis patients with septic shock. METHODS: Nested retrospective cohort study of all cholangitis-associated septic shock patients (hypotension requiring vasopressors) from an international, multi-centre database between 1996 and 2011. RESULTS: Among 260 patients (mean age 69 years, 57% male), overall mortality was 37%. Compared to nonsurvivors (n = 96), survivors (n = 164) had lower mean admission Acute Physiology And Chronic Health Evaluation (APACHE) II (22 vs. 28, P < 0.001) and lower median serum lactate on admission (3.4 vs. 4.6 mmol/L, P < 0.001). Survivors were more likely to receive appropriate anti-microbial therapy earlier (median 2.6 vs. 6.8 h from shock, P < 0.001). Survivors were also more likely to undergo successful biliary decompression earlier (median 8.8 vs. 22 h, P < 0.001). After adjusting for co variates, APACHE II (odds ratio, OR 1.21 per increment (1.11-1.32), time delay to appropriate anti-microbial therapy [OR 1.15 per hour (1.07-1.25)] and delayed biliary decompression >12 h [OR 3.40 (1.12-10.31)] were all significantly associated with increased mortality (P < 0.04 for all; c-statistic 0.896). CONCLUSIONS: Patients with septic shock secondary to acute cholangitis have significant mortality. Endoscopic biliary decompression >12 h after the onset of shock and delayed receipt of appropriate anti-microbial therapy were both significantly associated with adverse hospital outcome. This might suggest that early initiation of anti-microbial therapy and urgent biliary decompression (within 12 h) could potentially improve outcomes in this high-risk patient population. PMID- 27506330 TI - Pauci-immune glomerulonephritis in a captive chimpanzee (Pan troglodytes), and a review of spontaneous cases in animals. AB - BACKGROUND: Crescentic glomeruli are the hallmark finding in rapidly progressive glomerulonephritis (RPGN) and are characterized by disruption and proliferation of the glomerular capsule and an influx of cells into Bowman's space. Pauci immune-type RPGN is identified by a lack of immunoglobulins and immune complexes in the glomerular basement membrane. METHODS: Complete necropsy and histology were performed on the affected chimpanzee. Electron microscopy was performed on kidney sections. A search of the literature was performed to identify spontaneous RPGN in animals. RESULTS: We report a case of crescentic glomerulonephritis of the pauci-immune-type in a hepatitis C virus-infected 28-year-old male chimpanzee (Pan troglodytes) who was humanely euthanized for a cardiac-related decline in health. CONCLUSION: To our knowledge, this is the first report describing pauci immune crescentic glomerulonephritis in a non-human primate. PMID- 27506332 TI - Echocardiographic Evaluation of Hemodynamic Changes in Left-Sided Heart Valves in Pregnant Women With Valvular Heart Disease. AB - Physiologic changes during pregnancy can deteriorate or improve patients' hemodynamic status in the setting of valvular heart disease. There are sparse data regarding the effect of pregnancy on valve hemodynamics in normal pregnant women with known valvular heart disease. In a prospective study from July 2014 to January 2016, a total of 52 normal pregnant women who had mitral stenosis, aortic stenosis, or a history of mitral valve or aortic valve replacements were assessed. All patients underwent echocardiographic examinations and hemodynamic parameters were measured for both the mitral valve and aortic valve at first, second, and third trimesters. The parameters included mean gradient, peak gradient, mean gradient/heart rate, peak gradient/heart rate, pressure halftime, dimensionless velocity index, and valve area. Although most hemodynamic parameters (i.e., mean gradient, peak gradient, mean gradient/heart rate, and peak gradient/heart rate) increased approximately 50% from first to second trimester and first to third trimester (p <0.05) but those remained stable at third compared with second trimester (p >0.05). The ratio of changes between trimesters for valve area and dimensionless velocity index were comparable. No clinical decompensations were observed except for 3 and 7 cases of deterioration to functional class II at second and third trimesters, respectively. In conclusion, during a full-term and uncomplicated pregnancy, mitral and aortic valve gradients increase without significant changes in valve area that are more marked between the second and first trimester than between the third and second trimester. PMID- 27506333 TI - Identification of distinctive molecular traits that are characteristic of the phylum "Deinococcus-Thermus" and distinguish its main constituent groups. AB - The phylum "Deinococcus-Thermus" contains two heavily researched groups of extremophilic bacteria: the highly radioresistant order Deinococcales and the thermophilic order Thermales. Very few characteristics are known that are uniquely shared by members of the phylum "Deinococcus-Thermus". Comprehensive phylogenetic and comparative analyses of >65 "Deinococcus-Thermus" genomes reported here have identified numerous molecular signatures in the forms of conserved signature insertions/deletions (CSIs) and conserved signature proteins (CSPs), which provide distinguishing characteristics of the phylum "Deinococcus Thermus" and its main groups. We have identified 58 unique CSIs and 155 unique CSPs that delineate different phylogenetic groups within the phylum. Of these identified traits, 24 CSIs and 29 CSPs are characteristic of the phylum "Deinococcus-Thermus" and they provide novel and reliable means to circumscribe/describe this phylum. An additional 3 CSIs and 3 CSPs are characteristic of the order Deinococcales, and 6 CSIs and 51 CSPs are characteristic of the order Thermales. The remaining 25 CSIs and 72 CSPs identified in this study are distinctive traits of genus level groups within the phylum "Deinococcus-Thermus". The molecular characteristics identified in this work provide novel and independent support for the common ancestry of the members of the phylum "Deinococcus-Thermus" and provide a new means to distinguish the main constituent clades of the phylum. Additionally, the CSIs and CSPs identified in this work may play a role in the unique extremophilic adaptations of the members of this phylum and further functional analyses of these characteristics could provide novel biochemical insights into the unique adaptations found within the phylum "Deinococcus-Thermus". PMID- 27506334 TI - Impact of androgen-deprivation therapy on the outcome of dose-escalation prostate cancer radiotherapy without elective pelvic irradiation. AB - The benefit of androgen-deprivation therapy (ADT) in combination with dose escalated radiotherapy (DERT) for localized prostate cancer has not been determined in randomized studies. In this study, the benefit of ADT was assessed in patients uniformly treated with dose-escalated intensity-modulated radiation therapy (IMRT) to the prostate and seminal vesicles but not pelvis. In all, 419 patients with localized prostate adenocarcinoma underwent definitive IMRT (cumulative dose 78 Gy), with 32.6%, 33.1%, 32.1%, and 2.1% having T1 through T4 disease, respectively, and 51.2% having high-risk disease. ADT was given to 76.1% of patients. With a median follow-up of 60 months, 5-year biochemical failure free, disease-free, and overall survival rates were 87%, 86%, and 87%, respectively. T stage was an independent predictor of all three rates. Five-year pelvic nodal recurrence rate was 2.9%. ADT improved biochemical failure-free and disease-free survival but not overall survival. ADT showed benefit in high-risk disease but not intermediate-risk disease. Late gastrointestinal and genitourinary toxicities >= grade 2 occurred in 11.0% and 6.7%, respectively. In conclusion, DERT with 78 Gy yields good disease control and low rate of pelvic nodal recurrence. ADT improves disease-free survival in patients with high-risk but not intermediate-risk disease. PMID- 27506335 TI - Quantity versus quality: the sperm war. PMID- 27506336 TI - Duodenal metastases from sarcomatoid renal cell carcinoma: Case report. PMID- 27506337 TI - A novel 384-multiwell microelectrode array for the impedimetric monitoring of Tau protein induced neurodegenerative processes. AB - Over the last decades, countless bioelectronic monitoring systems were developed for the analysis of cells as well as complex tissues. Most studies addressed the sensitivity and specificity of the bioelectronic detection method in comparison to classical molecular biological assays. In contrast, the up scaling as a prerequisite for the practical application of these novel bioelectronic monitoring systems is mostly only discussed theoretically. In this context, we developed a novel 384-multiwell microelectrode array (MMEA) based measurement system for the sensitive label-free real-time monitoring of neurodegenerative processes by impedance spectroscopy. With respect to the needs of productive screening systems for robust and reproducible measurements on high numbers of plates, we focused on reducing the critical contacting of more than 400 electrodes for a 384-MMEA. Therefore, we introduced an on top array of immersive counter electrodes that are individually addressed by a multiplexer and connected all measurement electrodes on the 384-MMEA to a single contact point. More strikingly, our novel approach provided a comparable signal stability and sensitivity similar to an array with integrated counter electrodes. Next, we optimized a SH-SY5Y cell based tauopathy model by introducing a novel 5-fold Tau mutation eliminating the need of artificial tauopathy induction. In combination with our novel 384-MMEA based measurement system, the concentration and time dependent neuroregenerative effect of the kinase inhibitor SRN-003-556 could be quantitatively monitored. Thus, our novel screening system could be a useful tool to identify and develop potential novel therapeutics in the field of Tau-related neurodegenerative diseases. PMID- 27506338 TI - Organic-resistant screen-printed graphitic electrodes: Application to on-site monitoring of liquid fuels. AB - This work presents the potential application of organic-resistant screen-printed graphitic electrodes (SPGEs) for fuel analysis. The required analysis of the antioxidant 2,6-di-tert-butylphenol (2,6-DTBP) in biodiesel and jet fuel is demonstrated as a proof-of-concept. The screen-printing of graphite, Ag/AgCl and insulator inks on a polyester substrate (250 MUm thickness) resulted in SPGEs highly compatible with liquid fuels. SPGEs were placed on a batch-injection analysis (BIA) cell, which was filled with a hydroethanolic solution containing 99% v/v ethanol and 0.1 mol L(-1) HClO4 (electrolyte). An electronic micropipette was connected to the cell to perform injections (100 MUL) of sample or standard solutions. Over 200 injections can be injected continuously without replacing electrolyte and SPGE strip. Amperometric detection (+1.1 V vs. Ag/AgCl) of 2,6 DTBP provided fast (around 8 s) and precise (RSD = 0.7%, n = 12) determinations using an external calibration curve. The method was applied for the analysis of biodiesel and aviation jet fuel samples and comparable results with liquid and gas chromatographic analyses, typically required for biodiesel and jet fuel samples, were obtained. Hence, these SPGE strips are completely compatible with organic samples and their combination with the BIA cell shows great promise for routine and portable analysis of fuels and other organic liquid samples without requiring sophisticated sample treatments. PMID- 27506339 TI - Magnetic ionic liquids in analytical chemistry: A review. AB - Magnetic ionic liquids (MILs) have recently generated a cascade of innovative applications in numerous areas of analytical chemistry. By incorporating a paramagnetic component within the cation or anion, MILs exhibit a strong response toward external magnetic fields. Careful design of the MIL structure has yielded magnetoactive compounds with unique physicochemical properties including high magnetic moments, enhanced hydrophobicity, and the ability to solvate a broad range of molecules. The structural tunability and paramagnetic properties of MILs have enabled magnet-based technologies that can easily be added to the analytical method workflow, complement needed extraction requirements, or target specific analytes. This review highlights the application of MILs in analytical chemistry and examines the important structural features of MILs that largely influence their physicochemical and magnetic properties. PMID- 27506340 TI - The management and exploitation of naturally light-emitting bacteria as a flexible analytical tool: A tutorial. AB - Conventional detection of toxic contaminants on surfaces, in food, and in the environment takes time. Current analytical approaches to chemical detection can be of limited utility due to long detection times, high costs, and the need for a laboratory and trained personnel. A non-specific but easy, rapid, and inexpensive screening test can be useful to quickly classify a specimen as toxic or non toxic, so prompt appropriate measures can be taken, exactly where required. The bioluminescent bacteria-based tests meet all these characteristics. Bioluminescence methods are extremely attractive because of their high sensitivity, speed, ease of implementation, and statistical significance. They are usually sensitive enough to detect the majority of pollutants toxic to humans and mammals. This tutorial provides practical guidelines for isolating, cultivating, and exploiting marine bioluminescent bacteria as a simple and versatile analytical tool. Although mostly applied for aqueous phase sample and organic extracts, the test can also be conducted directly on soil and sediment samples so as to reflect the true toxicity due to the bioavailability fraction. Because tests can be performed with freeze-dried cell preparations, they could make a major contribution to field screening activity. They can be easily conducted in a mobile environmental laboratory and may be adaptable to miniaturized field instruments and field test kits. PMID- 27506341 TI - A novel photoelectrochemical biosensor for protein kinase activity assay based on phosphorylated graphite-like carbon nitride. AB - Protein kinases are general and significant regulators in the cell signaling pathway, and it is still greatly desired to achieve simple and quick kinase detection. Herein, we develop a simple and sensitive photoelectrochemical strategy for the detection of protein kinase activity based on the bond between phosphorylated peptide and phosphorylated graphite-like carbon nitride (P-g-C3N4) conjugates triggered by Zr(4+) ion coordination. Under optimal conditions, the increased photocurrent is proportional to the protein kinase A (PKA) concentration ranging from 0.05 to 50 U/mL with a detection limit of 0.077 U/mL. Moreover, this photoelectrochemical assay can be also applied to quantitative analysis of kinase inhibition. The results indicated that the IC50 value (inhibitor concentration producing 50% inhibitor) for ellagic acid was 9.1 MUM. Moreover, the developed method is further applied to detect PKA activity in real samples, which contains serum from healthy person and gastric cancer patients and breast tissue from healthy person and breast cancer patients. Therefore, the established protocol provides a new and simple tool for assay of kinase activity and its inhibitors with low cost and high sensitivity. PMID- 27506342 TI - Phosphomolybdic acid functionalized graphene loading copper nanoparticles modified electrodes for non-enzymatic electrochemical sensing of glucose. AB - A sensitive non-enzymatic glucose electrochemical biosensor (Cu/PMo12-GR/GCE) was developed based on the combination of copper nanoparticles (CuNPs) and phosphomolybdic acid functionalized graphene (PMo12-GR). PMo12-GR films were modified on the surface of glassy carbon electrode (GCE) through electrostatic self-assembly with the aid of poly diallyl dimethyl ammonium chloride (PDDA). Then CuNPs were successfully decorated onto the PMo12-GR modified GCE through electrodeposition. The morphology of Cu/PMo12-GR/GCE was characterized by scanning electron microscope (SEM). Cyclic voltammetry (CV) and chronoamperometry were used to investigate the electrochemical performances of the biosensor. The results indicated that the modified electrode displayed a synergistic effect of PMo12-GR sheets and CuNPs towards the electro-oxidation of glucose in the alkaline solution. At the optimal detection potential of 0.50 V, the response towards glucose presented a linear response ranging from 0.10 MUM to 1.0 mM with a detection limit of 3.0 * 10(-2) MUM (S/N = 3). In addition, Cu/PMo12-GR/GCE possessed a high selectivity, good reproducibility, excellent stability and acceptable recovery, which indicating the potential application in clinical field. PMID- 27506343 TI - Ultrasensitive electrochemical biosensor for specific detection of DNA based on molecular beacon mediated circular strand displacement polymerization and hyperbranched rolling circle amplification. AB - Using a cascade signal amplification strategy, an ultrasensitive electrochemical biosensor for specific detection of DNA based on molecular beacon (MB) mediated circular strand displacement polymerization (CSDP) and hyperbranched rolling circle amplification (HRCA) was proposed. The hybridization of MB probe to target DNA resulted in a conformational change of the MB and triggered the CSDP in the presence of bio-primer and Klenow fragment (KF exo(-)), leading to multiple biotin-tagged DNA duplex. Furthermore, the HRCA was implemented to product amounts of double-stranded DNA (ds-DNA) fragments using phi29 DNA polymerase via biotin-streptavidin interaction. After the product of HRCA binded numerous biotinylated detection probes, an ultrasensitive electrochemical readout by further employing the streptavidin-alkaline phosphatase. The proposed biosensor exhibited excellent detection sensitivity and specificity with a log-linear response to target DNA from 0.01 fM to 10 pM as low as 8.9 aM. The proposed method allowed DNA detection with simplicity, rapidness, low cost and high specificity, which might have the potential for application in clinical molecular diagnostics and environmental monitoring. PMID- 27506344 TI - Amplified electrochemical detection of nucleic acid hybridization via selective preconcentration of unmodified gold nanoparticles. AB - The common drawback of optical methods for rapid detection of nucleic acid by exploiting the differential affinity of single-/double-stranded nucleic acids for unmodified gold nanoparticles (AuNPs) is its relatively low sensitivity. In this article, on the basis of selective preconcentration of AuNPs unprotected by single-stranded DNA (ssDNA) binding, a novel electrochemical strategy for nucleic acid sequence identification assay has been developed. Through detecting the redox signal mediated by AuNPs on 1, 6-hexanedithiol blocked gold electrode, the proposed method is able to ensure substantial signal amplification and a low background current. This strategy is demonstrated for quantitative analysis of the target microRNA (let-7a) in human breast adenocarcinoma cells, and a detection limit of 16 fM is readily achieved with desirable specificity and sensitivity. These results indicate that the selective preconcentration of AuNPs for electrochemical signal readout can offer a promising platform for the detection of specific nucleic acid sequence. PMID- 27506345 TI - Electrochemical DNA sensor-based strategy for sensitive detection of DNA demethylation and DNA demethylase activity. AB - DNA demethylation and demethylase activity play important roles in DNA self repair, and their detection is key to early diagnosis of fatal diseases. Herein, a facile electrochemical DNA (E-DNA) sensor was developed for the sensitive detection of DNA demethylation and demethylase activity based on an enzyme cleavage strategy. The thiol modified hemi-methylated hairpin probe DNA (pDNA) was self-assembled on a Au electrode surface through the formation of AuS bonds. The hemi-methylated pDNA served as the substrate of DNA demethylase (using methyl CpG-binding domain protein 2 (MBD2) as an example). Following demethylation, the hairpin stem was then recognized and cleaved by BstUI endonuclease. The ferrocene carboxylic acid (FcA)-tagged pDNA strands were released into the buffer solution from the electrode surface, resulting in a significant decrease of electrochemical signal and providing a means to observe DNA demethylation. The activity of DNA demethylase was analyzed in the concentration ranging from 0.5 to 500 ng mL(-1) with a limit of detection as low as 0.17 ng mL(-1). With high specificity and sensitivity, rapid response, and low cost, this simple E-DNA sensor provides a unique platform for the sensitive detection of DNA demethylation, DNA demethylase activity, and related molecular diagnostics and drug screening. PMID- 27506346 TI - Aberrant sialylation of a prostate-specific antigen: Electrochemical label-free glycoprofiling in prostate cancer serum samples. AB - Electrochemical detection method allowing to detect prostate-specific antigen (PSA), a biomarker of prostate cancer (PCa), with PSA glycoprofiling was applied in an analysis of PCa serum samples for the first time. Electrochemical impedance spectroscopy (EIS) as a label-free method with immobilized anti-PSA was applied for PSA detection and lectins to glycoprofile captured PSA on the same surface. A proper choice of blocking agent providing high selectivity of biosensor detection with the immobilized anti-PSA antibody was done. The biosensor could detect PSA down to 100 ag/mL with a linear concentration working range from 100 ag/mL up to 1 MUg/mL, i.e. 10 orders of concentration magnitude and the sensitivity of (5.5 +/- 0.2)%/decade. The results showed that a commercial carbo-free blocking solution was the best one, reducing non-specific binding 55-fold when compared to the immunosensor surface without any blocking agent applied, while allowing to detect PSA. The biosensor response obtained after addition of lectin (i.e. proportional to the amount of a particular glycan on PSA) divided by the biosensor response obtained after incubation with a sample (i.e. proportional to the PSA level in the sample) was applied to distinguish serum samples of PCa patients from those of healthy individuals. The results showed that Maackia amurensis agglutinin (MAA) recognizing alpha-2,3-terminal sialic acid can be applied to distinguish between these two sets of samples since the MAA/PSA response obtained from the analysis of the PCa samples was significantly higher (5.3-fold) compared to the MAA/PSA response obtained by the analysis of samples from healthy individuals. Thus, combined analysis of serological PSA levels together with PSA glycoprofiling of aberrant glycosylation of PSA (i.e. increase in the level of alpha-2,3-terminal sialic acid) has a potential to improve detection of PCa. PMID- 27506347 TI - Electromembrane extraction of polar basic drugs from plasma with pure bis(2 ethylhexyl) phosphite as supported liquid membrane. AB - Electromembrane extraction (EME) of polar basic drugs from human plasma was investigated for the first time using pure bis(2-ethylhexyl) phosphite (DEHPi) as the supported liquid membrane (SLM). The polar basic drugs metaraminol, benzamidine, sotalol, phenylpropanolamine, ephedrine, and trimethoprim were selected as model analytes, and were extracted from 300 MUL of human plasma, through 10 MUL of DEHPi as SLM, and into 100 MUL of 10 mM formic acid as acceptor solution. The extraction potential across the SLM was 100 V, and extractions were performed for 20 min. After EME, the acceptor solutions were analyzed by high performance liquid chromatography-ultraviolet detection (HPLC-UV). In contrast to other SLMs reported for polar basic drugs in the literature, the SLM of DEHPi was highly stable in contact with plasma, and the system-current across the SLM was easily kept below 50 MUA. Thus, electrolysis in the sample and acceptor solution was kept at an acceptable level with no detrimental consequences. For the polar model analytes, representing a log P range from -0.40 to 1.32, recoveries in the range 25-91% were obtained from human plasma. Strong hydrogen bonding and dipole interactions were probably responsible for efficient transfer of the model analytes into the SLM, and this is the first report on efficient EME of highly polar analytes without using any ionic carrier in the SLM. PMID- 27506348 TI - Magnetic field assisted MU-solid phase extraction of anti-inflammatory and loop diuretic drugs by modified polybutylene terephthalate nanofibers. AB - A magnetic nanocomposite consisting of nanoparticles-polybutylene terephthalate (MNPs-PBT) was electrospun and used as an extracting medium for an on-line MU solid phase extraction (MU-SPE)-high performance liquid chromatography (HPLC) set up with an ultraviolet (UV) detection system. Due to the magnetic property of the prepared nanofibers, the whole extraction procedure was implemented under an external magnetic field to enhance the extraction efficiencies. The developed method along with the synthesized nanocomposite were found to be appropriate for the determination of trace levels of selected drugs including furosemide, naproxen, diclofenac and clobetasol propionate in the urine sample. The prepared MNPs-PBT electrospun nanocomposite was characterized using the scanning electron microscopy (SEM), energy dispersive spectroscopy (EDX) and Fourier transform infrared (FT-IR) spectroscopy. The prepared magnetic fibers showed high porosity, which was another driving force for the extraction efficiency enhancement. Major parameters affecting the extraction efficiency of the selected drugs were optimized. The limits of detections (LOD) of the studied drugs were in the range of 0.4-1.6 MUg L(-1) and the limits of quantification (LOQ) were 1-4 MUg L(-1) under the optimized conditions. Relative standard deviation (RSD%) for three replicates at three concentration levels of 6, 100 and 400 MUg L(-1) were 5.9 8.0% while acceptable linear range with two orders of magnitude was obtained (R(2) = 0.99). The method was validated by the determination of the selected drugs in urine samples and the results indicated that this method has sufficient potential for enrichment and determination of the desired drugs in the urine sample. The relative recovery values were found to be in the range of 78-91%. Implementing the developed on-line MU-SPE method under the external magnetic field induction, led to higher extraction efficiencies for the selected drugs with various diamagnetic properties. PMID- 27506349 TI - Impedometric monitoring of the behavior of the supported liquid membrane in electromembrane extraction systems: An insight into the origin of optimized experimental parameters. AB - Electromembrane extraction (EME) was carried out using a novel instrumentation capable of impedometric monitoring of the system during the extraction. This instrumentation involves a classical two-electrode assembly fed by two time resolved potential functions, the first for the extraction of analyte and the second for obtaining the impedance information. The impedometric analysis of the system was achieved by Laplace transformation of the current recorded during the extraction. It has been shown that the obtained impedance information can be converted to very useful knowledge about time dependence of double layer capacitance, kinetics of analyte depletion, total permeability of the SLM and the effect of experimental parameters on system behavior. It has also been shown that the impedance analysis is a powerful tool for the estimation of optimum experimental parameters without determination of analyte in the acceptor phase. PMID- 27506350 TI - Magnetic ionic liquids as non-conventional extraction solvents for the determination of polycyclic aromatic hydrocarbons. AB - This work describes the applicability of magnetic ionic liquids (MILs) in the analytical determination of a group of heavy polycyclic aromatic hydrocarbons. Three different MILs, namely, benzyltrioctylammonium bromotrichloroferrate (III) (MIL A), methoxybenzyltrioctylammonium bromotrichloroferrate (III) (MIL B), and 1,12-di(3-benzylbenzimidazolium) dodecane bis[(trifluoromethyl)sulfonyl)]imide bromotrichloroferrate (III) (MIL C), were designed to exhibit hydrophobic properties, and their performance examined in a microextraction method for hydrophobic analytes. The magnet-assisted approach with these MILs was performed in combination with high performance liquid chromatography and fluorescence detection. The study of the extraction performance showed that MIL A was the most suitable solvent for the extraction of polycyclic aromatic hydrocarbons and under optimum conditions the fast extraction step required ~20 MUL of MIL A for 10 mL of aqueous sample, 24 mmol L(-1) NaOH, high ionic strength content of NaCl (25% (w/v)), 500 MUL of acetone as dispersive solvent, and 5 min of vortex. The desorption step required the aid of an external magnetic field with a strong NdFeB magnet (the separation requires few seconds), two back-extraction steps for polycyclic aromatic hydrocarbons retained in the MIL droplet with n-hexane, evaporation and reconstitution with acetonitrile. The overall method presented limits of detection down to 5 ng L(-1), relative recoveries ranging from 91.5 to 119%, and inter-day reproducibility values (expressed as relative standard derivation) lower than 16.4% for a spiked level of 0.4 MUg L(-1) (n = 9). The method was also applied for the analysis of real samples, including tap water, wastewater, and tea infusion. PMID- 27506351 TI - Facile synthesis of multifunctional attapulgite/Fe3O4/polyaniline nanocomposites for magnetic dispersive solid phase extraction of benzoylurea insecticides in environmental water samples. AB - In this study, the superparamagnetic attapulgite/Fe3O4/polyaniline (ATP/Fe3O4/PANI) nanocomposites were successfully synthesized by a one-pot method. Fe (III) was applied as both the oxidant for the oxidative polymerization of aniline and the single iron source of Fe3O4 formed by the redox reaction between aniline and Fe (III). The ATP/Fe3O4/PANI was used as sorbent for magnetic dispersive solid phase extraction (MDSPE) of benzoylurea insecticides (BUs) in environmental water samples. The as-prepared nanocomposite sorbents were characterized by Fourier transform infrared spectra (FT-IR), X Ray diffraction (XRD), scanning electron microscopy(SEM), transmission electron microscopy (TEM), and vibrating sample magnetometry. Various experimental parameters affecting the ATP/Fe3O4/PANI-based MDSPE procedure, including the composition of the nanocomposite sorbents, amount of ATP/Fe3O4/PANI nanocomposites, vortex time, pH, and desorption conditions were investigated. Under the optimal conditions, a good linearity was observed for all target analytes, with correlation coefficients (r(2)) ranging from 0.9985 to 0.9997; the limits of detection (LOD) were in the range of 0.02-0.43 MUg L(-1), and the recoveries of analytes using the proposed method ranged between 77.37% and 103.69%. The sorbents exhibited an excellent reproducibility in the range of 1.52-5.27% in extracting the five target analytes. In addition, the intra-day and inter-day precision values were found to be in the range of 0.78-6.86% and 1.66-8.41%, respectively. Finally, the proposed ATP/Fe3O4/PANI-based MDSPE method was successfully applied to analyze river water samples by rapid preconcentration of BUs. PMID- 27506352 TI - In situ hydrothermal growth of ZnO/g-C3N4 nanoflowers coated solid-phase microextraction fibers coupled with GC-MS for determination of pesticides residues. AB - In this paper, Zinc oxide (ZnO) hybridized with graphite-like C3N4 (ZnO/g-C3N4) nanoflowers based solid phase microextraction (SPME) coating was prepared on fiber using in situ hydrothermal growth method for gas chromatographic -mass spectrum (GC- MS) separation and analysis target analytes in complex matrixes for the first time. The proposed hybrid ZnO/g-C3N4 fiber exhibited wide linearity for the pesticide residues in range of 0.003-5.0 ng mL(-1). The limits of detection (LOD) were 0.001-0.0025 ng mL(-1). The relative standard deviation (RSD) for three replicate extractions using one fiber was ranged from 2.3% to 7.6%. The fiber to fiber RSD was 5.3-11.3% (n = 3). This method was successfully used for simultaneous determination of nine pesticide residues in cucumber, pear, Green tea and Minjiang water with satisfactory recoveries of 79.1-103.5%. These results indicated that the ZnO/g-C3N4 composite provided a promising alternative in sample pretreatment and analysis. PMID- 27506353 TI - A novel approach to Lab-In-Syringe Head-Space Single-Drop Microextraction and on drop sensing of ammonia. AB - A novel approach to the automation technique Lab-In-Syringe, also known as In Syringe Analysis, is proposed which utilizes a secondary inlet into the syringe void, used as a size-adaptable reaction chamber, via a channel passing through the syringe piston. This innovative approach allows straightforward automation of head-space single-drop microextraction, involving accurately controlled drop formation and handling, and the possibility of on-drop analyte quantification. The syringe was used in upside-down orientation and in-syringe magnetic stirring was carried out, which allowed homogenous mixing of solutions, promotion of head space analyte enrichment, and efficient syringe cleaning. The superior performance of the newly developed system was illustrated with the development of a sensitive method for total ammonia determination in surface waters. It is based on head-space extraction of ammonia into a single drop of bromothymol blue indicator created inside the syringe at the orifice of the syringe piston channel and on-drop sensing of the color change via fiber optics. The slope of the linear relationship between absorbance and time was used as the analytical signal. Drop formation and performance of on-drop monitoring was further studied with rhodamine B solution to give a better understanding of the system's performance. A repeatability of 6% RSD at 10 MUmol L(-1) NH3, a linear range of up to 25 MUmol L(-1) NH3, and a limit of detection of 1.8 MUmol L(-1) NH3 were achieved. Study of interferences proved the high robustness of the method towards humic acids, high sample salinity, and the presence of detergents, thus demonstrating the method superiority compared to the state-of-the-art gas-diffusion methods. A mean analyte recovery of 101.8% was found in analyzing spiked environmental water samples. PMID- 27506354 TI - Highly specific purification of N-glycans using phosphate-based derivatization as an affinity tag in combination with Ti(4+)-SPE enrichment for mass spectrometric analysis. AB - N-linked protein glycosylation is involved in regulation of a wide variety of cellular processes and associated with numerous diseases. Highly specific identification of N-glycome remains a challenge while its biological significance is acknowledged. The relatively low abundance of glycan in complex biological mixtures, lack of basic sites for protonation, and suppression by other highly abundant proteins/peptides lead to the particularly poor detection sensitivity of N-glycans in the MS analysis. Therefore, the highly specific purification procedure becomes a crucial step prior to MS analysis of the N-glycome. Herein, a novel N-glycans enrichment approach based on phosphate derivatization combined with Ti(4+)-SPE (solid phase extraction) was developed. Briefly, in this strategy, N-glycans were chemically labeled with a phospho-group at their reducing ends, such that the Ti(4+)-SPE microspheres were able to capture the phospho-containing glycans. The enrichment method was developed and optimized using model oligosaccharides (maltoheptaose DP7 and sialylated glycan A1) and also glycans from a standard glycoprotein (asialofetuin, ASF). This method experimentally showed high derivatization efficiency (almost 100%), excellent selectivity (analyzing DP7 in the digests of bovine serum albumin at a mass ratio of 1:100), high enriching recovery (90%), good reproducibility (CV<15%) as well as high sensitivity (LOD at fmol level). At last, the proposed method was successfully applied in the profiling of N-glycome in human serum, in which a total of 31 N-glycan masses were identified. PMID- 27506355 TI - Direct glycan structure determination of intact N-linked glycopeptides by low energy collision-induced dissociation tandem mass spectrometry and predicted spectral library searching. AB - Intact glycopeptide MS analysis to reveal site-specific protein glycosylation is an important frontier of proteomics. However, computational tools for analyzing MS/MS spectra of intact glycopeptides are still limited and not well-integrated into existing workflows. In this work, a new computational tool which combines the spectral library building/searching tool, SpectraST (Lam et al. Nat. Methods2008, 5, 873-875), and the glycopeptide fragmentation prediction tool, MassAnalyzer (Zhang et al. Anal. Chem.2010, 82, 10194-10202) for intact glycopeptide analysis has been developed. Specifically, this tool enables the determination of the glycan structure directly from low-energy collision-induced dissociation (CID) spectra of intact glycopeptides. Given a list of possible glycopeptide sequences as input, a sample-specific spectral library of MassAnalyzer-predicted spectra is built using SpectraST. Glycan identification from CID spectra is achieved by spectral library searching against this library, in which both m/z and intensity information of the possible fragmentation ions are taken into consideration for improved accuracy. We validated our method using a standard glycoprotein, human transferrin, and evaluated its potential to be used in site-specific glycosylation profiling of glycoprotein datasets from LC MS/MS. In addition, we further applied our method to reveal, for the first time, the site-specific N-glycosylation profile of recombinant human acetylcholinesterase expressed in HEK293 cells. For maximum usability, SpectraST is developed as part of the Trans-Proteomic Pipeline (TPP), a freely available and open-source software suite for MS data analysis. PMID- 27506356 TI - Rapid and reliable species identification of wild mushrooms by matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). AB - Mushrooms are a favourite natural food in many countries. However, some wild species cause food poisoning, sometimes lethal, due to misidentification caused by confusing fruiting bodies similar to those of edible species. The morphological inspection of mycelia, spores and fruiting bodies have been traditionally used for the identification of mushrooms. More recently, DNA sequencing analysis has been successfully applied to mushrooms and to many other species. This study focuses on a simpler and more rapid methodology for the identification of wild mushrooms via protein profiling based on matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF MS). A preliminary study using 6 commercially available cultivated mushrooms suggested that a more reproducible spectrum was obtained from a portion of the cap than from the stem of a fruiting body by the extraction of proteins with a formic acid-acetonitrile mixture (1 + 1). We used 157 wild mushroom-fruiting bodies collected in the centre of Hokkaido from June to November 2014. Sequencing analysis of a portion of the ribosomal RNA gene provided 134 identifications of mushrooms by genus or species, however 23 samples containing 10 unknown species that had lower concordance rate of the nucleotide sequences in a BLAST search (less than 97%) and 13 samples that had unidentifiable poor or mixed sequencing signals remained unknown. MALDI-TOF MS analysis yielded a reproducible spectrum (frequency of matching score >= 2.0 was >=6 spectra from 12 spectra measurements) for 114 of 157 samples. Profiling scores that matched each other within the database gave correct species identification (with scores of >=2.0) for 110 samples (96%). An in-house prepared database was constructed from 106 independent species, except for overlapping identifications. We used 48 wild mushrooms that were collected in autumn 2015 to validate the in-house database. As a result, 21 mushrooms were identified at the species level with scores >=2.0 and 5 mushrooms at the genus level with scores >=1.7, although the signals of 2 mushrooms were insufficient for analysis. The remaining 20 samples were recognized as "unreliable identification" with scores <1.7. Subsequent DNA analysis confirmed that the correct species or genus identifications were achieved by MALDI-TOF MS for the 26 former samples, whereas the 18 mushrooms with poorly matched scores were species that were not included in the database. Thus, the proposed MALDI-TOF MS coupled with our database could be a powerful tool for the rapid and reliable identification of mushrooms; however, continuous updating of the database is necessary to enrich it with more abundant species. PMID- 27506357 TI - Bioanalysis of dried saliva spot (DSS) samples using detergent-assisted sample extraction with UHPLC-MS/MS detection. AB - Dried saliva spot (DSS) sampling is a non-invasive sample collection technique for bioanalysis that can be potentially implemented at the patient's home. A UHPLC-MS/MS assay was developed using detergent-assisted sample extraction to quantify BMS-927711, a drug candidate in development for the treatment of migraines, in human DSS. By implementing DSS sampling at the patients' home, the bioanalytical sample collection for pharmacokinetic evaluation can be done at the time of the acute migraine attack without the need for clinical visits. DSS samples were prepared by spotting 15 MUL of liquid saliva onto regular Whatman FTATM DMPK-C cards and verified with a UV lamp (at lambda 254 nm or 365 nm) during DSS punching. The 4-mm DSS punches in a 96-well plate were sonicated with 200 MUL of [(13)C2, D4]-BMS-927711 internal standard (IS) solution in 20/80 MeOH/water for 10 min, followed by sonication with 50 MUL of 100 mM NH4OAc with 1.0% Triton-X-100 (as detergent) prior to liquid-liquid extraction with 600 MUL EtOAc/Hexane (90:10). UHPLC-MS/MS was performed with an Aquity((r)) UPLC BEH C18 Column (2.1 * 50 mm, 1.7 MUm) on a Triple QuadTM 5500 mass spectrometer. The assay was linear with a concentration range from 2.00 to 1000 ng mL(-1) for BMS 927711 in human saliva. The intra- and inter-assay precision was within 8.8% CV, and the accuracy was within +/-6.7% Dev of the nominal concentration values. This UHPLC-MS/MS assay has been successfully applied to determine the drug's pharmacokinetics within a clinical study. For the first time, we observed BMS 927711 exposure in human DSS, confirming the suitability of this sampling technique for migraine patients to use at home. Detergent-assisted extraction with Triton-X-100 could be very useful in DSS or other dried matrix spot (DMS) assays to overcome low or inconsistent analyte recovery issues. PMID- 27506358 TI - A new sample preparation and separation combination for precise, accurate, rapid, and simultaneous determination of vitamins B1, B2, B3, B5, B6, B7, and B9 in infant formula and related nutritionals by LC-MS/MS. AB - An improved method was developed for simultaneous determination of the fortified forms of thiamine (B1), riboflavin (B2), nicotinamide and nicotinic acid (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), and folic acid (B9) in infant formulas and related nutritionals. The method employed a simple, effective, and rapid sample preparation followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). It improved upon previous methodologies by offering facile and rugged sample preparation with improved chromatographic conditions, which culminated in a highly accurate and precise method for water-soluble vitamin determination in a wide range of formulas. The method was validated over six days in ten unique matrices with two analysts and on instruments in two different labs. Intermediate precision averaged 3.4 +/- 2.6% relative standard deviation and over-spike recovery averaged 100.2 +/- 2.4% (n = 160). Due to refinements in sample preparation, the method had high sample throughput capacity. PMID- 27506359 TI - Development of a blood-brain barrier model in a membrane-based microchip for characterization of drug permeability and cytotoxicity for drug screening. AB - Since most of the central nervous system (CNS) drug candidates show poor permeability across the blood-brain barrier (BBB), development of a reliable platform for permeability assay will greatly accelerate drug discovery. Herein, we constructed a microfluidic BBB model to mimic drug delivery into the brain to induce cytotoxicity at target cells. To reconstitute the in vivo BBB properties, human cerebral microvessel endothelial cells (hCMEC/D3) were dynamically cultured in a membrane-based microchannel. Sunitinib, a model drug, was then delivered into the microchannel and forced to permeate through the BBB model. The permeated amount was directly quantified by an electrospray ionization quadrupole time-of flight mass spectrometer (ESI-Q-TOF MS) after on-chip SPE (MUSPE) pretreatment. Moreover, the permeated drug was incubated with glioma cells (U251) cultured inside agarose gel in the downstream to investigate drug-induced cytotoxicity. The resultant permeability of sunitinib was highly correlated with literature reported value, and it only required 30 min and 5 MUL of sample solution for each permeation experiment. Moreover, after 48 h of treatment, the survival rate of U251 cells cultured in 3D scaffolds was nearly 6% higher than that in 2D, which was in accordance with the previously reported results. These results demonstrate that this platform provides a valid tool for drug permeability and cytotoxicity assays which have great value for the research and development of CNS drugs. PMID- 27506360 TI - Software-assisted serum metabolite quantification using NMR. AB - The goal of metabolomics is to analyze a whole metabolome under a given set of conditions, and accurate and reliable quantitation of metabolites is crucial. Absolute concentration is more valuable than relative concentration; however, the most commonly used method in NMR-based serum metabolic profiling, bin-based and full data point peak quantification, provides relative concentration levels of metabolites and are not reliable when metabolite peaks overlap in a spectrum. In this study, we present the software-assisted serum metabolite quantification (SASMeQ) method, which allows us to identify and quantify metabolites in NMR spectra using Chenomx software. This software uses the ERETIC2 utility from TopSpin to add a digitally synthesized peak to a spectrum. The SASMeQ method will advance NMR-based serum metabolic profiling by providing an accurate and reliable method for absolute quantification that is superior to bin-based quantification. PMID- 27506361 TI - Exploiting multi-function Metal-Organic Framework nanocomposite Ag@Zn-TSA as highly efficient immobilization matrixes for sensitive electrochemical biosensing. AB - A novel multi-function Metal-Organic Framework composite Ag@Zn-TSA (zinc thiosalicylate, Zn(C7H4O2S), Zn-TSA) was synthesized as highly efficient immobilization matrixes of myoglobin (Mb)/glucose oxidase (GOx) for electrochemical biosensing. The electrochemical biosensors based on Ag@Zn-TSA composite and ionic liquid (IL) modified carbon paste electrode (CPE) were fabricated successfully. Furthermore, the properties of the sensors were discussed by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and amperometric current-time curve, respectively. The results showed the proposed biosensors had wide linear response to hydrogen peroxide (H2O2) in the range of 0.3-20,000 MUM, to nitrite (NO2(-)) for 1.3 MUM-1660 MUM and 2262 MUM 1,33,000 MUM, to glucose for 2.0-1022 MUM, with a low detection limit of 0.08 MUM for H2O2, 0.5 MUM for NO2(-), 0.8 MUM for glucose. The values of the apparent heterogeneous electron transfer rate constant (ks) for Mb and GOx were estimated as 2.05 s(-1) and 2.45 s(-1), respectively. Thus, Ag@Zn-TSA was a kind of ideal material as highly efficient immobilization matrixes for sensitive electrochemical biosensing. In addition, this work indicated that MOF nanocomposite had a great potential for constructing wide range of sensing interface. PMID- 27506362 TI - Three dimensional graphene transistor for ultra-sensitive pH sensing directly in biological media. AB - In this work, pH sensing directly in biological media using three dimensional liquid gated graphene transistors is presented. The sensor is made of suspended network of graphene coated all around with thin layer of hafnium oxide (HfO2), showing high sensitivity and sensing beyond the Debye-screening limit. The performance of the pH sensor is validated by measuring the pH of isotonic buffered, Dulbecco's phosphate buffered saline (DPBS) solution, and of blood serum derived from Sprague-Dawley rat. The pH sensor shows high sensitivity of 71 +/- 7 mV/pH even in high ionic strength media with molarities as high as 289 +/- 1 mM. High sensitivity of this device is owing to suspension of three dimensional graphene in electrolyte which provides all around liquid gating of graphene, leading to higher electrostatic coupling efficiency of electrolyte to the channel and higher gating control of transistor channel by ions in the electrolyte. Coating graphene with hafnium oxide film (HfO2) provides binding sites for hydrogen ions, which results in higher sensitivity and sensing beyond the Debye screening limit. The 3D graphene transistor offers the possibility of real-time pH measurement in biological media without the need for desaltation or sample preparation. PMID- 27506363 TI - Rhodamine-based chemodosimeter for fluorescent determination of Hg(2+) in 100% aqueous solution and in living cells. AB - A rhodamine spirolactam derivative (1) bearing a hydrophilic carboxylic acid group is developed as a fluorescent chemodosimeter for bivalent mercury ions (Hg(2+)) in 100% aqueous solution. It exhibits a highly sensitive "turn-on" fluorescent response toward Hg(2+) with a 42-fold fluorescence intensity enhancement under 1 equiv. of Hg(2+) added. The chemodosimeter can be applied to the quantification of Hg(2+) with a linear range covering from 3.0 * 10(-7) to 1.0 * 10(-5) M and a detection limit of 9.7 * 10(-8) M. Most importantly, the fluorescence changes of the chemodosimeter are remarkably specific for Hg(2+) in the presence of other metal ions, which meet the selective requirements for practical application. Moreover, the experiment results show that the response behavior of 1 towards Hg(2+) is pH independent in neutral condition (pH 5.0-8.0) and the response is fast (response time less than 3 min). Furthermore, the ring opening mechanism of the rhodamine spirolactam induced by Hg(2+) was supported by NMR, MS, and DFT theoretical calculations. In addition, the proposed chemodosimeter has been used to detect Hg(2+) in water samples and image Hg(2+) in living cells with satisfying results. PMID- 27506364 TI - A redox-mediated chromogenic reaction and application in immunoassay. AB - A novel redox-mediated chromogenic reaction was demonstrated based on the reaction between HAuCl4 and 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), which generate various color responses from red to green in the resulting solutions. Various redox substance could be used to mediate the reaction and trigger a distinct color response. We established a sensitive hydrogen peroxide colorimetric sensor based on the redox-mediated chromogenic reaction and depicted the application both in detection of enzyme and in an immunoassay. Combining the traditional chromogenic reagent with gold nanoparticles, our assay has the advantage in short response time (within three minutes), high sensitivity (10( 12) g mL(-1) for HBsAg) and stability. PMID- 27506365 TI - One step derivatization with British Anti-Lewsite in combination with gas chromatography coupled to triple-quadrupole tandem mass spectrometry for the fast and selective analysis of inorganic arsenic in rice. AB - We developed a new fast and selective analytical method for the determination of inorganic arsenic (iAs) in rice by a gas chromatography - tandem mass spectrometry (GC-MS/MS) in combination with one step derivatization of inorganic arsenic (iAs) with British Anti-Lewsite (BAL). Two step derivatization of iAs with BAL has been previously performed for the GC-MS analysis. In this paper, the quantitative one step derivatization condition was successfully established. The GC-MS/MS was carried out with a short nonpolar capillary column (0.25 mm * 10 m) under the conditions of fast oven temperature ramp rate (4 degrees C/s) and high linear velocity (108.8 cm/s) of the carrier gas. The established GC-MS/MS method showed an excellent linearity (r(2) > 0.999) in a tested range (0.2-100.0 MUg L( 1)), ultra-low limit of detection (LOD, 0.08 pg), and high precision and accuracy. The GC-MS/MS technique showed far greater selectivity (22.5 fold higher signal to noise ratio in rice sample) on iAs than GC-MS method. The gas chromatographic running time was only 2.5 min with the iAs retention time of 1.98 min. The established method was successfully applied to quantify the iAs contents in polished rice. The mean iAs content in the Korean polished rice (n = 27) was 66.1 MUg kg(-1) with the range of 37.5-125.0 MUg kg(-1). This represents the first report on the GC-tandem mass spectrometry in combination with the one step derivatization with BAL for the iAs speciation in rice. This GC-MS/MS method would be a simple, useful and reliable measure for the iAs analysis in rice in the laboratories in which the expensive and element specific HPLC-ICP-MS is not available. PMID- 27506366 TI - Enantioselective simultaneous analysis of selected pharmaceuticals in environmental samples by ultrahigh performance supercritical fluid based chromatography tandem mass spectrometry. AB - In order to assess the true impact of each single enantiomer of pharmacologically active compounds (PACs) in the environment, highly efficient, fast and sensitive analytical methods are needed. For the first time this paper focuses on the use of ultrahigh performance supercritical fluid based chromatography coupled to a triple quadrupole mass spectrometer to develop multi-residue enantioselective methods for chiral PACs in environmental matrices. This technique exploits the advantages of supercritical fluid chromatography, ultrahigh performance liquid chromatography and mass spectrometry. Two coated modified 2.5 MUm-polysaccharide based chiral stationary phases were investigated: an amylose tris-3,5 dimethylphenylcarbamate column and a cellulose tris-3-chloro-4 methylphenylcarbamate column. The effect of different chromatographic variables on chiral recognition is highlighted. This novel approach resulted in the baseline resolution of 13 enantiomers PACs (aminorex, carprofen, chloramphenicol, 3-N-dechloroethylifosfamide, flurbiprofen, 2-hydroxyibuprofen, ifosfamide, imazalil, naproxen, ofloxacin, omeprazole, praziquantel and tetramisole) and partial resolution of 2 enantiomers PACs (ibuprofen and indoprofen) under fast gradient conditions (<10 min analysis time). The overall performance of the methods was satisfactory. The applicability of the methods was tested on influent and effluent wastewater samples. To the best of our knowledge, this is the first feasibility study on the simultaneous separation of chemically diverse chiral PACs in environmental matrices using ultrahigh performance supercritical fluid based chromatography coupled with tandem mass spectrometry. PMID- 27506367 TI - Development and optimization of ultra-high performance supercritical fluid chromatography mass spectrometry method for high-throughput determination of tocopherols and tocotrienols in human serum. AB - The goal of this study was to develop an effective supercritical fluid chromatography method using single quadrupole MS for analysis of all isomeric forms of vitamin E. Finally, two fast and effective methods, the high resolution one and the high speed one, for the determination of 8 vitamin E isomers in human serum were developed. Rapid high-throughput liquid-liquid extraction was selected as a sample preparation step. Sample pretreatment of 100 MUL human serum was consisted of protein precipitation with 200 MUL ethanol and liquid-liquid extraction by 400 MUL hexane/dichloromethane (80/20, v/v). The separation was performed on BEH 2-EP (3.0 * 100 mm, 1.7 MUm) stationary phase, using isocratic elution with carbon dioxide and 10 mM ammonium formate in methanol in the ratio 98:2 for high resolution method with run time 4.5 min and in the ratio 95:5 for high speed method, where the run time was 2.5 min. The method development included optimization of key parameters: the choice of the suitable stationary phase and the composition of mobile phase, where an influence of various modifiers, their ratio and additives were tested, and optimization of fine tunning parameters including BPR pressure, flow-rate and column temperature. Quantification of all isomeric forms was performed using SIM (single ion monitoring) experiments in ESI positive ion mode. Both high speed and high resolution chromatographic methods were validated in terms of precision, accuracy, range, linearity, LOD, LOQ and matrix effects using the same LLE procedure. The high resolution method provided more sensitive results (LOD: 0.017 0.083 MUg mL(-1)) and better linearity (r(2) > 0.9930) than the high speed one (LOD: 0.083-0.25 MUg mL(-1), r(2) > 0.9877) at the cost of double time of analysis. PMID- 27506368 TI - Ictal asystole mimicking seizure deterioration in temporal lobe epilepsy. PMID- 27506369 TI - Functional lignocellulosic materials prepared by ATRP from a wood scaffold. AB - Wood, a natural and abundant source of organic polymers, has been used as a scaffold to develop novel wood-polymer hybrid materials. Through a two-step surface-initiated Atom Transfer Radical Polymerization (ATRP), the porous wood structure can be effectively modified with polymer chains of various nature. In the present study, polystyrene and poly(N-isopropylacrylamide) were used. As shown with various characterization techniques including confocal Raman microscopy, FTIR, and SEM/EDX, the native wood ultrastructure and features are retained and the polymer chains can be introduced deep within the wood, i.e. inside the wood cell walls. The physical properties of the new materials have been studied, and results indicate that the insertion of polymer chains inside the wood cell wall alters the intrinsic properties of wood to yield a hybrid composite material with new functionalities. This approach to the functionalization of wood could lead to the fabrication of a new class of interesting functional materials and promote innovative utilizations of the renewable resource wood. PMID- 27506370 TI - Template-mediated Synthesis of Hollow Microporous Organic Nanorods with Tunable Aspect Ratio. AB - Hollow microporous organic nanorods (HMORs) with hypercrosslinked polymer (HCPs) shells were synthesized through emulsion polymerization followed by hypercrosslinking. The HMORs have tunable aspect ratios, high BET surface areas and monodispersed morphologies, showing good performance in gas adsorpion. PMID- 27506371 TI - Purely electronic mechanism of electrolyte gating of indium tin oxide thin films. AB - Epitaxial indium tin oxide films have been grown on both LaAlO3 and yttria stabilized zirconia substrates using RF magnetron sputtering. Electrolyte gating causes a large change in the film resistance that occurs immediately after the gate voltage is applied, and shows no hysteresis during the charging/discharging processes. When two devices are patterned next to one another and the first one gated through an electrolyte, the second one shows no changes in conductance, in contrast to what happens in materials (like tungsten oxide) susceptible to ionic electromigration and intercalation. These findings indicate that electrolyte gating in indium tin oxide triggers a pure electronic process (electron depletion or accumulation, depending on the polarity of the gate voltage), with no electrochemical reactions involved. Electron accumulation occurs in a very thin layer near the film surface, which becomes highly conductive. These results contribute to our understanding of the electrolyte gating mechanism in complex oxides and may be relevant for applications of electric double layer transistor devices. PMID- 27506373 TI - Expediting Viral Therapies For Cancers To the Clinic. PMID- 27506372 TI - Tsr Chemoreceptor Interacts With IL-8 Provoking E. coli Transmigration Across Human Lung Epithelial Cells. AB - Bacterial colonization of epithelial surfaces and subsequent transmigration across the mucosal barrier are essential for the development of infection. We hypothesized that the methyl-accepting proteins (MCPs), known as chemoreceptors expressed on Escherichia coli (E. coli) bacterial surface, play an important role in mediating bacterial transmigration. We demonstrated a direct interaction between human interleukin-8 (IL-8) and Tsr receptor, a major MCP chemoreceptor. Stimulation of human lung epithelial cell monolayer with IL-8 resulted in increased E. coli adhesion and transmigration of the native strain (RP437) and a strain expressing only Tsr (UU2373), as compared to a strain (UU2599) with Tsr truncation. The augmented E. coli adhesion and migration was associated with a higher expression of carcinoembryonic antigen-related cell adhesion molecule 6 and production of inflammatory cytokines/chemokines, and a lower expression of the tight junction protein claudin-1 and the plasma membrane protein caveolin-1 in lung epithelial cells. An increased E. coli colonization and pulmonary cytokine production induced by the RP437 and UU2373 strains was attenuated in mice challenged with the UU2599 strain. Our results suggest a critical role of the E. coli Tsr chemoreceptor in mediating bacterial colonization and transmigration across human lung epithelium during development of pulmonary infections. PMID- 27506376 TI - The Role of Nonhuman Primate Animal Models in the Clinical Development of Pluripotent Stem Cell Therapies. PMID- 27506377 TI - Socializing Individualized T-Cell Cancer Immunotherapy. PMID- 27506378 TI - Rethinking the Regulatory Infrastructure for Human Gene Transfer Clinical Trials. PMID- 27506379 TI - Effects of long-term continuous cropping on soil nematode community and soil condition associated with replant problem in strawberry habitat. AB - Continuous cropping changes soil physiochemical parameters, enzymes and microorganism communities, causing "replant problem" in strawberry cultivation. We hypothesized that soil nematode community would reflect the changes in soil conditions caused by long-term continuous cropping, in ways that are consistent and predictable. To test this hypothesis, we studied the soil nematode communities and several soil parameters, including the concentration of soil phenolic acids, organic matter and nitrogen levels, in strawberry greenhouse under continuous-cropping for five different durations. Soil pH significantly decreased, and four phenolic acids, i.e., p-hydroxybenzoic acid, ferulic acid, cinnamic acid and p-coumaric acid, accumulated with time under continuous cropping. The four phenolic acids were highly toxic to Acrobeloides spp., the eudominant genus in non-continuous cropping, causing it to reduce to a resident genus after seven-years of continuous cropping. Decreased nematode diversity indicated loss of ecosystem stability and sustainability because of continuous cropping practice. Moreover, the dominant decomposition pathway was altered from bacterial to fungal under continuous cropping. Our results suggest that along with the continuous-cropping time in strawberry habitat, the soil food web is disturbed, and the available plant nutrition as well as the general health of the soil deteriorates; these changes can be indicated by soil nematode community. PMID- 27506380 TI - Solvent-driven electron trapping and mass transport in reduced graphites to access perfect graphene. AB - Herein, we report on a significant discovery, namely, the quantitative discharging of reduced graphite forms, such as graphite intercalation compounds, graphenide dispersions and graphenides deposited on surfaces with the simple solvent benzonitrile. Because of its comparatively low reduction potential, benzonitrile is reduced during this process to the radical anion, which exhibits a red colour and serves as a reporter molecule for the quantitative determination of negative charges on the carbon sheets. Moreover, this discovery reveals a very fundamental physical-chemical phenomenon, namely a quantitative solvent reduction induced and electrostatically driven mass transport of K(+) ions from the graphite intercalation compounds into the liquid. The simple treatment of dispersed graphenides suspended on silica substrates with benzonitrile leads to the clean conversion to graphene. This unprecedented procedure represents a rather mild, scalable and inexpensive method for graphene production surpassing previous wet-chemical approaches. PMID- 27506381 TI - Correlation between the lateral pterygoid muscle attachment type and temporomandibular joint disc position in magnetic resonance imaging. AB - OBJECTIVES: The aim of this study was to investigate the correlation between the lateral pterygoid muscle (LPM) attachment type and temporomandibular joint (TMJ) disc position on sagittal and coronal MR scans. METHODS: 191 patients (148 females, 43 males), aged 14-60 years, underwent MR investigations of the TMJs in the intercuspal position (IP) and open-mouth position (OMP). The disc position was evaluated on oblique sagittal and coronal images in the IP and OMP on many MRI sections showing all portions of the joint. Relationships between the LPM attachment patterns and articular disc positions were evaluated by z and chi2 tests. RESULTS: Three types of the LPM attachment were found. There was a statistically significant correlation between the LPM attachment type and the disc position in IP (chi2 = 24.29; p < 0.01). The type of muscle attachment did not determine the prevalence of normal, lateral and medial disc positions. There were differences between the muscle attachment types in the anterior, anteromedial and anterolateral disc positions. There was a statistically significant association between TMJ disc position in OMP and particular attachment types in the sagittal plane (chi2 = 9.702; p < 0.01). CONCLUSIONS: Certain types of the LPM insertion are correlated with TMJ disc position. PMID- 27506382 TI - Contribution of prostanoid signaling to the evolution of spreading depolarization and the associated cerebral blood flow response. AB - The significance of prostanoid signaling in neurovascular coupling during somatosensory stimulation is increasingly more appreciated, yet its involvement in mediating the cerebral blood flow (CBF) response to spreading depolarization (SD) has remained inconclusive. Selective cyclooxygenase (COX) enzyme inhibitors (NS-398, SC-560) or an antagonist (L161,982) of the EP4 type prostaglandin E2 receptor were applied topically to a cranial window over the parietal cortex of isoflurane-anesthetized Sprague-Dawley rats (n = 60). Global forebrain ischemia was induced by occlusion of both common carotid arteries in half of the animals. SDs were triggered by the topical application of 1M KCl. SD occurrence was confirmed by the acquisition of DC potential, and CBF variations were recorded by laser-Doppler flowmetry. EP4 receptor antagonism significantly decreased peak hyperemia and augmented post-SD oligemia in the intact but not in the ischemic cortex. COX-1 inhibition and EP4 receptor blockade markedly delayed repolarization after SD in the ischemic but not in the intact brain. COX-2 inhibition achieved no significant effect on any of the end points taken. The data suggest, that activation of EP4 receptors initiates vasodilation in response to SD in the intact brain, and - together with COX-1 derived prostanoids - shortens SD duration in the acute phase of ischemia. PMID- 27506383 TI - Artificial Control of Gene Silencing Activity Based on siRNA Conjugation with Polymeric Molecule Having Coil-Globule Transition Behavior. AB - A new strategy for controlling gene silencing activity of siRNA in the cell was developed in the present study. siRNA was linearly conjugated with PNIPAAm, where coil-globule transition of the conjugated PNIPAAm allows thermoresponsive exposure of the vicinal siRNA molecule; a coil form of PNIPAAm (T < LCST) inhibits siRNA interaction with gene silencing-related proteins due to the steric hindrance effect, while a globule form of PNIPAAm (T > LCST) allows a ready access of siRNA to gene silencing pathway. As a result, at T > LCST, PNIPAAm siRNA elicited effective association of siRNA with a gene silencing-related protein of Ago2, while siRNA recruitment into the gene silencing pathway was significantly suppressed at T < LCST. Ultimately, gene silencing efficacy of PNIPAAm-siRNA was close to unconjugated siRNA at T > LCST (~80%), while it was dramatically decreased to ~20% at T < LCST, suggesting that coil-globule transition of the conjugated polymer can control the bioactivity of the vicinal siRNA molecule. PMID- 27506385 TI - Predicting gene targets from integrative analyses of summary data from GWAS and eQTL studies for 28 human complex traits. AB - Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with complex traits and diseases. However, elucidating the causal genes underlying GWAS hits remains challenging. We applied the summary data-based Mendelian randomization (SMR) method to 28 GWAS summary datasets to identify genes whose expression levels were associated with traits and diseases due to pleiotropy or causality (the expression level of a gene and the trait are affected by the same causal variant at a locus). We identified 71 genes, of which 17 are novel associations (no GWAS hit within 1 Mb distance of the genes). We integrated all the results in an online database ( http://www.cnsgenomics/shiny/SMRdb/ ), providing important resources to prioritize genes for further follow-up, for example in functional studies. PMID- 27506384 TI - The neurobiology of the emotional adolescent: From the inside out. AB - Adolescents are commonly portrayed as highly emotional, with their behaviors often hijacked by their emotions. Research on the neural substrates of adolescent affective behavior is beginning to paint a more nuanced picture of how neurodevelopmental changes in brain function influence affective behavior, and how these influences are modulated by external factors in the environment. Recent neurodevelopmental models suggest that the brain is designed to promote emotion regulation, learning, and affiliation across development, and that affective behavior reciprocally interacts with age-specific social demands and different social contexts. In this review, we discuss current findings on neurobiological mechanisms of adolescents' affective behavior and highlight individual differences in and social-contextual influences on adolescents' emotionality. Neurobiological mechanisms of affective processes related to anxiety and depression are also discussed as examples. As the field progresses, it will be critical to test new hypotheses generated from the foundational empirical and conceptual work and to focus on identifying more precisely how and when neural networks change in ways that promote or thwart adaptive affective behavior during adolescence. PMID- 27506386 TI - Once a clinician, always a clinician: a systematic review to develop a typology of clinician-researcher dual-role experiences in health research with patient participants. AB - BACKGROUND: Many health researchers are clinicians. Dual-role experiences are common for clinician-researchers in research involving patient-participants, even if not their own patients. To extend the existing body of literature on why dual role is experienced, we aimed to develop a typology of common catalysts for dual role experiences to help clinician-researchers plan and implement methodologically and ethically sound research. METHODS: Systematic searching of Medline, CINAHL, PsycINFO, Embase and Scopus (inception to 28.07.2014) for primary studies or first-person reflexive reports of clinician-researchers' dual role experiences, supplemented by reference list checking and Google Scholar scoping searches. Included articles were loaded in NVivo for analysis. The coding was focused on how dual-role was evidenced for the clinician-researchers in research involving patients. Procedures were completed by one researcher (MB) and independently cross-checked by another (JHS). All authors contributed to extensive discussions to resolve all disagreements about initial coding and verify the final themes. RESULTS: Database searching located 7135 records, resulting in 29 included studies, with the addition of 7 studies through reference checks and scoping searches. Two overarching themes described the most common catalysts for dual-role experiences - ways a research role can involve patterns of behaviour typical of a clinical role, and the developing connection that starts to resemble a clinician-patient relationship. Five subthemes encapsulated the clinical patterns commonly repeated in research settings (clinical queries, perceived agenda, helping hands, uninvited clinical expert, and research or therapy) and five subthemes described concerns about the researcher-participant relationship (clinical assumptions, suspicion and holding back, revelations, over-identification, and manipulation). Clinician-researchers use their clinical skills in health research in ways that set up a relationship resembling that of clinician-patient. Clinicians' ingrained orientation to patients' needs can be in tension with their research role, and can set up ethical and methodological challenges. CONCLUSION: The typology we developed outlines the common ways dual-role is experienced in research involving clinician researchers and patient-participants, and perhaps the inevitability of the experience given the primacy accorded to patient well-being. The typology offers clinician-researchers a framework for grappling with the ethical and methodological implications of dual-role throughout the research process, including planning, implementation, monitoring and reporting. PMID- 27506387 TI - Personality differences in early versus late suicide attempters. AB - BACKGROUND: Suicidality is an individual behaviour caused by a complex framework of internal and external factors. The predictive values of personality traits for a suicide attempt have been demonstrated, especially in conjunction with Cloninger's TCI and impulsivity. Two issues remain unsolved, namely whether these traits alter over time after a suicide attempt, and how they may be influenced by depressive symptoms. METHODS: We studied two patient cohorts: one sample of 81 patients after a suicide attempt no longer than 3 months previously (SA early) and another sample of 32 patients whose attempt had taken place more than 6 months previously (SA late). We carried out structured interviews with these subjects addressing diagnosis (MINI), suicidality (Scale for suicide ideation), depression (HAMD-17), temperament and character inventory (TCI), and impulsivity (BIS-10). Data analysis was done using SPSS 16.0. RESULTS: Our two groups did not differ significantly in sociodemographics or suicidality. However, patients in the SA early group were significantly more depressed (p < 0.001), and scored lower in reward dependence (p < 0.001) and persistence (p = 0.005) but higher in harm avoidance (p < 0.001); they did not differ significantly in impulsivity (p < 0.01). Reward dependence, persistence, and harm avoidance remained significantly different between the two groups after controlling for depressive symptoms. CONCLUSIONS: Our findings suggest that some personality traits vary after a suicide attempt. Further investigations are necessary to verify our results, ideally in longitudinal studies with larger, carefully-described cohorts. It would be also clinically important to investigate the influence of therapeutic strategies on the variability of personality traits and their impact on suicidal behavior. PMID- 27506388 TI - Grape compounds suppress colon cancer stem cells in vitro and in a rodent model of colon carcinogenesis. AB - BACKGROUND: We have previously shown that the grape bioactive compound resveratrol (RSV) potentiates grape seed extract (GSE)-induced colon cancer cell apoptosis at physiologically relevant concentrations. However, RSV-GSE combination efficacy against colon cancer stem cells (CSCs), which play a key role in chemotherapy and radiation resistance, is not known. METHODS: We tested the anti-cancer efficacy of the RSV-GSE against colon CSCs using isolated human colon CSCs in vitro and an azoxymethane-induced mouse model of colon carcinogenesis in vivo. RESULTS: RSV-GSE suppressed tumor incidence similar to sulindac, without any gastrointestinal toxicity. Additionally, RSV-GSE treatment reduced the number of crypts containing cells with nuclear beta-catenin (an indicator of colon CSCs) via induction of apoptosis. In vitro, RSV-GSE suppressed - proliferation, sphere formation, nuclear translocation of beta-catenin (a critical regulator of CSC proliferation) similar to sulindac in isolated human colon CSCs. RSV-GSE, but not sulindac, suppressed downstream protein levels of Wnt/beta-catenin pathway, c-Myc and cyclin D1. RSV-GSE also induced mitochondrial mediated apoptosis in colon CSCs characterized by elevated p53, Bax/Bcl-2 ratio and cleaved PARP. Furthermore, shRNA-mediated knockdown of p53, a tumor suppressor gene, in colon CSCs did not alter efficacy of RSV-GSE. CONCLUSION: The suppression of Wnt/beta-catenin signaling and elevated mitochondrial-mediated apoptosis in colon CSCs support potential clinical testing/application of grape bioactives for colon cancer prevention and/or therapy. PMID- 27506389 TI - Molecular features of biguanides required for targeting of mitochondrial respiratory complex I and activation of AMP-kinase. AB - BACKGROUND: The biguanides are a family of drugs with diverse clinical applications. Metformin, a widely used anti-hyperglycemic biguanide, suppresses mitochondrial respiration by inhibiting respiratory complex I. Phenformin, a related anti-hyperglycemic biguanide, also inhibits respiration, but proguanil, which is widely used for the prevention of malaria, does not. The molecular structures of phenformin and proguanil are closely related and both inhibit isolated complex I. Proguanil does not inhibit respiration in cells and mitochondria because it is unable to access complex I. The molecular features that determine which biguanides accumulate in mitochondria, enabling them to inhibit complex I in vivo, are not known. RESULTS: Here, a family of seven biguanides are used to reveal the molecular features that determine why phenformin enters mitochondria and inhibits respiration whereas proguanil does not. All seven biguanides inhibit isolated complex I, but only four of them inhibit respiration in cells and mitochondria. Direct conjugation of a phenyl group and bis-substitution of the biguanide moiety prevent uptake into mitochondria, irrespective of the compound hydrophobicity. This high selectivity suggests that biguanide uptake into mitochondria is protein mediated, and is not by passive diffusion. Only those biguanides that enter mitochondria and inhibit complex I activate AMP kinase, strengthening links between complex I and the downstream effects of biguanide treatments. CONCLUSIONS: Biguanides inhibit mitochondrial complex I, but specific molecular features control the uptake of substituted biguanides into mitochondria, so only some biguanides inhibit mitochondrial respiration in vivo. Biguanides with restricted intracellular access may be used to determine physiologically relevant targets of biguanide action, and for the rational design of substituted biguanides for diverse clinical applications. PMID- 27506390 TI - The genome of the emerging barley pathogen Ramularia collo-cygni. AB - BACKGROUND: Ramularia collo-cygni is a newly important, foliar fungal pathogen of barley that causes the disease Ramularia leaf spot. The fungus exhibits a prolonged endophytic growth stage before switching life habit to become an aggressive, necrotrophic pathogen that causes significant losses to green leaf area and hence grain yield and quality. RESULTS: The R. collo-cygni genome was sequenced using a combination of Illumina and Roche 454 technologies. The draft assembly of 30.3 Mb contained 11,617 predicted gene models. Our phylogenomic analysis confirmed the classification of this ascomycete fungus within the family Mycosphaerellaceae, order Capnodiales of the class Dothideomycetes. A predicted secretome comprising 1053 proteins included redox-related enzymes and carbohydrate-modifying enzymes and proteases. The relative paucity of plant cell wall degrading enzyme genes may be associated with the stealth pathogenesis characteristic of plant pathogens from the Mycosphaerellaceae. A large number of genes associated with secondary metabolite production, including homologs of toxin biosynthesis genes found in other Dothideomycete plant pathogens, were identified. CONCLUSIONS: The genome sequence of R. collo-cygni provides a framework for understanding the genetic basis of pathogenesis in this important emerging pathogen. The reduced complement of carbohydrate-degrading enzyme genes is likely to reflect a strategy to avoid detection by host defences during its prolonged asymptomatic growth. Of particular interest will be the analysis of R. collo-cygni gene expression during interactions with the host barley, to understand what triggers this fungus to switch from being a benign endophyte to an aggressive necrotroph. PMID- 27506391 TI - Molecular epidemiology of Mycobacterium africanum in Ghana. AB - BACKGROUND: Mycobacterium africanum comprises two phylogenetic lineages within the M. tuberculosis complex (MTBC) and is an important cause of human tuberculosis (TB) in West Africa. The reasons for this geographic restriction of M. africanum remain unclear. Here, we performed a prospective study to explore associations between the characteristics of TB patients and the MTBC lineages circulating in Ghana. METHOD: We genotyped 1,211 MTBC isolates recovered from pulmonary TB patients recruited between 2012 and 2014 using single nucleotide polymorphism typing and spoligotyping. Associations between patient and pathogen variables were assessed using univariate and multivariate logistic regression. RESULTS: Of the 1,211 MTBC isolates analysed, 71.9 % (871) belonged to Lineage 4; 12.6 % (152) to Lineage 5 (also known as M. africanum West-Africa 1), 9.2 % (112) to Lineage 6 (also known as M. africanum West-Africa 2) and 0.6 % (7) to Mycobacterium bovis. Univariate analysis revealed that Lineage 6 strains were less likely to be isoniazid resistant compared to other strains (odds ratio = 0.25, 95 % confidence interval (CI): 0.05-0.77, P < 0.01). Multivariate analysis showed that Lineage 5 was significantly more common in patients from the Ewe ethnic group (adjusted odds ratio (adjOR): 2.79; 95 % CI: 1.47-5.29, P < 0.001) and Lineage 6 more likely to be found among HIV-co-infected TB patients (adjOR = 2.2; 95 % confidence interval (CI: 1.32-3.7, P < 0.001). CONCLUSION: Our findings confirm the importance of M. africanum in Ghana and highlight the need to differentiate between Lineage 5 and Lineage 6, as these lineages differ in associated patient variables. PMID- 27506392 TI - Obstructive sleep apnea is associated with an increased risk of colorectal neoplasia. AB - BACKGROUND AND AIMS: A recent meta-analysis showed that obstructive sleep apnea (OSA) is associated with a higher prevalence of cancer and cancer-related mortality; however, little information is available on the association between OSA and colorectal neoplasia. METHODS: We identified consecutive patients who underwent overnight polysomnography (PSG) and subsequent colonoscopy. We compared the prevalence of colorectal neoplasia between patients with or without OSA according to the results of PSG. For each patient with OSA, 1 or 2 controls matched for age (+/-5 years), sex, body mass index (BMI), and smoking who had undergone first-time screening colonoscopy were selected. RESULTS: Of the 163 patients, 111 patients were diagnosed with OSA and 52 patients were within the normal range of the Apnea-Hypopnea Index. Of the 111 patients with OSA, 18 patients (16.2%) had advanced colorectal neoplasia, including 4 (3.6%) colorectal cancers. In the multivariate analyses, OSA was associated with an increased risk of advanced colorectal neoplasia after adjusting for factors including age and sex (mild: odds ratio [OR], 14.09; 95% confidence interval [CI], 1.55-127.83; P = .019; moderate or severe: OR, 14.12; 95% CI, 1.52-131.25; P = .020). Our case control study revealed that the odds of detecting advanced colorectal neoplasia among patients with OSA were approximately 3.03 times greater than in the controls matched for age, sex, BMI, and smoking (OR, 3.03; 95% CI, 1.44-6.34; P = .002). CONCLUSION: Physicians should be aware of the association between OSA and the development of colorectal neoplasia and explain the need for colonoscopy to patients with OSA. PMID- 27506393 TI - Non-adherence to the rule of 3 does not increase the risk of adverse events in esophageal dilation. AB - BACKGROUND AND AIMS: Although the rule of 3 is recommended to minimize the risk of perforation when esophageal dilation is performed using bougie dilators, there are no data to validate its use. Our aim was to investigate the association between the rule of 3 and adverse events (AEs) in esophageal dilation. METHODS: A retrospective chart review in patients who underwent esophageal bougie or balloon dilation between December 1991 and February 2013 at a tertiary hospital was performed. Data collection included patient demographics, stricture and procedural characteristics, AEs, and follow-up. Univariate logistic regression models were used to assess the risk of AEs and perforations. RESULTS: A total of 297 patients (median age, 63 years; 60% men) underwent 2216 esophageal bougie or balloon dilations. Major AEs occurred in 22 (1%) dilation sessions, including 11 (0.5%) perforations, 4 (0.2%) fistulas, 3 (0.1%) hospitalizations for pain management, 2 (0.09%) clinically significant hemorrhages, 1 (0.04%) fever, and 1 (0.04%) tracheoesophageal voice prosthesis leak. Mean duration of treatment was 43.2 months (standard deviation, 47.7 months). Most strictures were benign (n = 275; 93%) and complex in nature (n = 198; 67%). Non-adherence to the rule of 3 occurred in 190 (13%) dilations with bougie dilators. Non-adherence was not associated with a higher rate of major AEs (1/190, 0.5% vs 15/953, 1.6%; P = .18) and perforations (0/190, 0% vs 7/952, 0.7%; P = .18). Gender, complex strictures, location of the stricture, type of dilator, and additional interventions were also not associated with major AEs or perforations. However, malignant strictures were associated with an increased risk of major AEs (odds ratio, 3.5; 95% confidence interval, 1.1-12.0) and perforations (odds ratio, 8.3; 95% confidence interval, 2.2-31.9). CONCLUSIONS: Non-adherence to the rule of 3 does not appear to increase the risk of AEs, particularly perforation, after esophageal dilation using bougie dilators. Caution is needed with the dilation of malignant strictures, as there is an increased risk of perforations and AEs. However, large prospective studies are needed to verify the results of this study. PMID- 27506394 TI - A personalised approach is needed for the management of non-tuberculous mycobacterial cervicofacial lymphadenitis. PMID- 25475648 TI - Acute diverticulitis of the terminal ileum: ultrasonography and CT findings. AB - We describe a rare case of terminal ileal diverticulitis in a 68-year-old female with a day of history of right lower quadrant pain and tenderness, mimicking acute appendicitis. Ultrasonography revealed small sac-like out-pouching lesions with increased echogenicity of surrounding fat in thickened terminal ileum, suggesting inflamed diverticula. We diagnosed terminal ileal diverticulitis primarily by ultrasonography. The diagnosis was confirmed by subsequent computed tomography. PMID- 27506395 TI - Pneumonia presenting with organ dysfunctions: Causative microorganisms, host factors and outcome. AB - Community-acquired pneumonia (CAP) is a serious infection that may occasionally rapidly evolve provoking organ dysfunctions. We aimed to characterize CAP presenting with organ dysfunctions at the emergency room, with regard to host factors and causative microorganisms, and its impact on 30-day mortality. 460 of 4070 (11.3%) CAP patients had >=2 dysfunctions at diagnosis, with a 30-day mortality of 12.4% vs. 3.4% in those with one or no dysfunctions. Among them, the most frequent causative microorganisms were Streptococcus pneumoniae, gram negatives and polymicrobial etiology. Independent host risk factors for presenting with >=2 dysfunctions were: liver (OR 2.97) and renal diseases (OR 3.91), neurological disorders (OR 1.86), and COPD (OR 1.30). Methicillin resistant Staphylococcus aureus (OR 6.41) and bacteraemic episodes (OR 1.68) had the higher independent risk among microorganisms. The number of organ dysfunctions vs. none increased at 30-day mortality: three organs (OR 11.73), two organs (OR 4.29), and one organ (OR 2.42) whereas Enterobacteria (OR 3.73) were also independently related to mortality. The number of organ dysfunctions was the strongest 30-day mortality risk factor while Enterobacteriaceae was also associated with poorer outcome. The assessment of organ dysfunctions in CAP should be implemented for management, allocation and treatment decisions on initial evaluation. PMID- 27506397 TI - Characterization of the excited states of DNA building blocks: a coupled cluster computational study. AB - DNA building blocks consisting of up to four nucleobases are investigated using the EOM-CCSD and CC2-LR methods in two B-DNA-like arrangements of a poly adenine:poly-thymine (poly-A:poly-T) system. Excitation energies and oscillator strengths are presented and the characteristics of the excited states are discussed. Excited states of single-stranded poly-A systems are highly delocalized, especially the spectroscopically bright states, where delocalization over up to four fragments can be observed. In the case of poly-T systems, the states are somewhat less delocalized, extending to maximally about three fragments. A single A:T Watson-Crick pair has highly localized states, while delocalization over base pairs can be observed for some excited states of the (A)2:(T)2 system, but intrastrand delocalization is more pronounced in this case, as well. As for the characteristics of the simulated UV absorption spectra, a significant decrease of intensity can be observed in the case of single strands with increasing chain length; this is due to the stacking interactions and is in accordance with previous results. On the other hand, the breaking of H-bonds between the two strands does not alter the spectral intensity considerably, it only causes a redshift of the absorption band, thus it is unable to explain the experimentally observed DNA hyperchromism on its own, and stacking interactions need to be considered for the description of this effect as well. PMID- 27506398 TI - Fluorination methods in drug discovery. AB - Fluorination reactions of medicinal and biologically-active compounds will be discussed. Late stage fluorination strategies of medicinal targets have recently attracted considerable attention on account of the influence that a fluorine atom can impart to targets of medicinal importance, such as modulation of lipophilicity, electronegativity, basicity and bioavailability, the latter as a consequence of membrane permeability. Therefore, the recourse to late-stage fluorine substitution on compounds with already known and relevant biological activity can provide the pharmaceutical industry with new leads with improved medicinal properties. The fluorination strategies will take into account different fluorinating reagents, either of nucleophilic or electrophilic, and of radical nature. Diverse families of organic compounds such as (hetero)aromatic rings, and aliphatic substrates (sp(3), sp(2), and sp carbon atoms) will be studied in late-stage fluorination reaction strategies. PMID- 27506399 TI - Evaporation of Binary Sessile Drops: Infrared and Acoustic Methods To Track Alcohol Concentration at the Interface and on the Surface. AB - Evaporation of droplets of three pure liquids (water, 1-butanol, and ethanol) and four binary solutions (5 wt % 1-butanol-water-based solution and 5, 25, and 50 wt % ethanol-water-based solutions) deposited on hydrophobic silicon was investigated. A drop shape analyzer was used to measure the contact angle, diameter, and volume of the droplets. An infrared camera was used for infrared thermal mapping of the droplet's surface. An acoustic high-frequency echography technique was, for the first time, applied to track the alcohol concentration in a binary-solution droplet. Evaporation of pure alcohol droplets was executed at different values of relative humidity (RH), among which the behavior of pure ethanol evaporation was notably influenced by the ambient humidity as a result of high hygrometry. Evaporation of droplets of water and binary solutions was performed at a temperature of 22 degrees C and a mean humidity of approximately 50%. The exhaustion times of alcohol in the droplets estimated by the acoustic method and the visual method were similar for the water-1-butanol mixture; however, the time estimated by the acoustic method was longer when compared with that estimated by the visual method for the water-ethanol mixture due to the residual ethanol at the bottom of the droplet. PMID- 27506400 TI - A Novel Less Invasive Technique for the Excision of Large Intradural and Extradural Dumbbell Lumbar Schwannomas: The "Dual Approach". AB - OBJECTIVE: Large schwannomas with intradural and extradural extensions are often challenging surgical lesions. A variety of approaches, usually requiring large exposures, removal of facets and pars interarticularis, and spinal stabilization, have been described. The aim of this study is to describe the "dual approach," a less invasive technique for the excision of these lesions. METHODS: A large intradural and extradural schwannoma with paraspinal extension (Eden type II) was removed by a unilateral approach-midline, pars and facet sparing and no supplemental instrumentation. RESULTS: Complete excision was achieved through the described approach, with minimal removal of bone and soft tissue disruption. There were no intraoperative or perioperative complications and no evidence of residual tumor or instability/deformity. CONCLUSIONS: The dual approach is a novel and unique technique that allows complete and safe removal of large intradural and extradural dumbbell tumors through a less invasive approach and no need for instrumentation. PMID- 27506401 TI - Standalone Anterior Cervical Discectomy and Fusion Versus Combination with Foraminotomy for the Treatment of Cervical Spondylotic Radiculopathy Secondary to Bony Foraminal Stenosis. AB - OBJECTIVE: To compare the results of anterior cervical discectomy and fusion (ACDF) combined with anterior cervical foraminotomy (ACF) and standalone ACDF for the treatment of cervical spondylotic radiculopathy (CSR). METHODS: The data of 24 consecutive patients who underwent ACDF combined with ACF for significant bony foraminal stenosis were reviewed. The clinical outcomes, including visual analog scale (VAS) scores for neck pain and arm pain and Neck Disability Index, were evaluated by questionnaires. Radiologic outcomes as manifested by C2-7 angle and surgical segmental angle were recorded. The outcomes were compared with outcomes of standalone ACDF for CSR secondary to posterolateral spurs. RESULTS: At the final follow-up evaluation, all patients obtained bone fusion. No patient developed adjacent segment disease. Operative time was longer and blood loss was more in the ACDF combined with ACF group than in the ACDF group (all P < 0.05). However, in both groups, the neck VAS score, arm VAS score, and Neck Disability Index were significantly reduced postoperatively (all P < 0.05). The segmental curve and C2-7 lordosis were significantly improved postoperatively (all P < 0.05). There was no significant difference between the 2 groups in clinical and radiologic outcomes (P > 0.05). CONCLUSIONS: For CSR with foraminal stenosis secondary to significant bony pathology that cannot be managed with standalone ACDF, ACDF combined with ACF is an effective and safe treatment strategy. PMID- 27506402 TI - Choroid Plexus Papillomas of the Cerebellopontine Angle. AB - OBJECTIVE: Choroid plexus papillomas (CPPs) of the cerebellopontine angle (CPA) are extremely rare. We present a series of 21 cases operated on in the last 7 years at our institution. METHODS: During the period from January 2008 to October 2015, we encountered 102 histologically established cases of CPPs, of which 21 were located in the CPA region. Clinical profiles, radiologic features, surgical procedures, intraoperative findings, and outcomes were extracted from the patient records and neuroimaging data. RESULTS: The 21 CPPs in the CPA region accounted for 20.5% of all CPPs. Two of the tumors occurred in pediatric patients. Tumor size was 2.5-4.7 cm. The rate of calcification was higher in the CPPs in the CPA region. Peritumoral cysts and cysts with small nodules were observed in our cases. A far lateral suboccipital approach was chosen for CPPs protruding inferiorly into the foramen magnum region (n = 14), and a suboccipital retrosigmoid approach was chosen for the other tumors. Total resection was achieved in 18 patients, and subtotal resection was achieved in 3 patients. During the follow-up period, only 1 patient experienced recurrence 32 months after the first operation. The recurrence turned out to be an atypical CPP. CONCLUSIONS: CPPs in the CPA region cannot be easily differentiated from other tumors preoperatively. Cysts and calcifications appear on neuroimaging. CPPs in the CPA region usually protrude inferiorly into the foramen magnum region. As much tumor should be removed as possible to avoid recurrence and malignant transition. PMID- 27506403 TI - Risk Factors for Dysphagia After Single-Level Anterior Cervical Decompression with Arthroplasty or Fusion: A Prospective Study Comparing 2 Zero-Profile Implants. AB - OBJECTIVE: To determine any differences in self-reported dysphagia in patients treated with single-level anterior cervical decompression with different zero profile implants (arthroplasty vs. arthrodesis) and identify risk factors for postoperative dysphagia. METHODS: A total of 112 patients with 1-level cervical degenerative disc disease were included in the prospective study. The dysphagia conditions and radiologic results were assessed using Bazar dysphagia scoring system, the Swallowing Quality of Life scores, cervical alignment (CA), segmental angle, and prevertebral soft tissues swelling (PSTS). All these parameters were compared before and after surgery in the respective group, which were also compared between the 2 groups. Correlations between the confounding factors and postoperative dysphagia were analyzed. RESULTS: No significant differences existed in preoperative or initially postoperative dysphagia rate and scores between the 2 groups (P > 0.05). However, the dysphagia rate and scores of cervical disc arthroplasty was better than those of fusion at postoperative day 7. Heavy smoker, PSTS change (>=5 mm), or CA change (>=5 degrees) was prone to have postoperative dysphagia. CONCLUSIONS: Postoperative dysphagia remains a common incidence, despite advances in instrumentation technologies. However, cervical disc arthroplasty is superior to anterior cervical discectomy and fusion in ameliorating the symptom of dysphagia in the early postoperative term. Heavy smoker, PSTS change (>=5 mm), and CA change (>=5 degrees) were important predictors of postoperative dysphagia. PMID- 27506404 TI - Open Surgery for Recurrent Intracranial Aneurysms: Techniques and Long-Term Outcomes. AB - BACKGROUND: After occlusion of an aneurysm, a patient may experience aneurysm regrowth at the same site or develop de novo aneurysms. We present our experience in microsurgery of recurrent aneurysms with analysis of long-term results. METHODS: The senior authors (R. T. and H. K.) performed recurrent aneurysm clipping on 44 patients at Teishinkai Hospital and Asahikawa Red Cross Hospital in Sapporo, Japan. Operative techniques included clipping only, clipping and protective bypass, trapping of aneurysm with bypass, proximal occlusion, and bypass. Postoperative outcome was analyzed retrospectively using the modified Rankin Scale. RESULTS: Our series included 10 men (23%) and 34 women (77%), with a mean patient age of 63 years (range, 7-82 years). Before primary treatment, 11 patients (25%) had a ruptured aneurysm, while 33 patients (75%) had an unruptured aneurysm. The mean follow-up time after primary surgery was 7.6 years (range, 0.8 25 years). At our department the treatment of recurrent aneurysm included the clipping in 19 patients (43%), clipping with bypass in 6 patients (14%), aneurysm trapping with bypass in 10 patients (23%), and proximal occlusion and bypass in 9 patients (20%). The mean follow-up time after surgical treatment of recurrent aneurysms stood at 3.5 years (range 0.1-9 years). Altogether, 37 patients (84%) experienced favorable outcomes at last follow-up examination (modified Rankin Scale scores 0 and 1). CONCLUSIONS: Microsurgery of recurrent aneurysms may be performed safely and effectively, as shown by our study, in which 84% of patients experienced favorable results. PMID- 27506405 TI - Management Strategy of a Transorbital Penetrating Pontine Injury by a Wooden Chopstick. AB - BACKGROUND: Transorbital penetrating pontine injuries from small spear-like objects, which are extremely rare, provide neurosurgeons with life-threatening and challenging conditions to manage. CASE DESCRIPTION: We present an unusual case of transorbital penetrating pontine injury and discuss imaging, diagnosis, management strategy, and anatomy-injury correlation. A 23-year-old man sustained a penetrating cranial injury from a bamboo chopstick that extended from the right orbit to the pons and cerebellum. Using a frontotemporal approach, we successfully removed the chopstick. Follow-up studies confirmed a good outcome. CONCLUSIONS: Preoperative imaging, correct diagnosis, and surgical treatment are necessary to manage transorbital penetrating pontine injuries caused by spear like objects, with specific attention paid to effective exposure and inventive means with total removal of the foreign object without causing further injury. A trajectory through the superior orbital fissure and paralateral to the cavernous sinus and into the pons seems to be the most prevalent and influences management of removal and injuries. PMID- 27506406 TI - Differences in Dural Penetration of Clival Chordomas Are Associated with Different Prognosis and Expression of Platelet-Derived Growth Factor Receptor beta. AB - OBJECTIVE: We sought to compare the prognosis of clival chordomas with different dural penetration and establish the relationship between dural penetration and platelet-derived growth factor receptor (PDGFR)-beta signaling pathway. METHODS: Tumors in Type I (33 cases) showed limited dural penetration, while those in Type II (34 cases) had more serious dural penetration. Cox multivariate regression analysis was used to analyze risk factors affecting survival. Kaplan-Meier analysis measured overall survival (OS) and progression-free survival (PFS). To determine the relationship between dural penetration and PDGFR-beta signaling, expression of PDGFR-beta, Akt, mammalian target of rapamycin (mTOR), and phosphatase and tensin homolog (PTEN) expression was compared using immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and Western blotting. RESULTS: Total resection was achieved in 9 cases in Type I and 11 in Type II. There were significant correlations between OS and dural penetration (P = 0.032) and age (P = 0.034). PFS correlated significantly with dural penetration (P = 0.022), gender (P = 0.001), and degree of resection (P = 0.001). Mean OS in Type I was significantly longer than in Type II (P = 0.046). Patients aged <55 years had longer OS than those aged >=55 years (P = 0.004). Total resection was correlated with longer PFS (P = 0.011). Among patients with tumors totally resected, mean PFS in Type I was significantly longer than in Type II (P = 0.007). Expression of PDGFR-beta in Type II was higher than in Type I. CONCLUSIONS: Clival chordomas have different degrees of dural penetration. Patients with chordomas with serious dural penetration have poorer prognosis. Higher expression of PDGFR-beta is related to more serious dural penetration of clival chordomas. PMID- 27506407 TI - Barriers to Neurosurgical Training in Sub-Saharan Africa: The Need for a Phased Approach to Global Surgery Efforts to Improve Neurosurgical Care. AB - BACKGROUND: Neurosurgery in low-income countries is faced with multiple challenges. Although the most common challenges include infrastructure and physical resource deficits, an underemphasized barrier relates to the methods and components of surgical training. The role of important aspects, including didactic surgical training, surgical decision-making, workshops, conferences, and assessment methods, has not been duly studied. Knowledge of these issues is a crucial step to move closer to strengthening surgical capacity in low-income countries. METHODS: We designed an online survey to assess self-perceived and objectively measured barriers to neurosurgical training in various Sub-Saharan African countries. Key outcomes included perception toward adequacy of neurosurgery training and barriers to neurosurgical training at each individual site. RESULTS: Only 37% of responders felt that their training program adequately prepared them for handling incoming neurosurgical cases. Top perceived limitations of neurosurgery training included lack of physical resources (25% of all responses), lack of practical workshops (22%), lack of program structure (18%), and lack of topic-specific lectures (10%). CONCLUSIONS: Our results show that most responders believe their training program is inadequate and are interested in improving it through international collaborations. This implies that activities directed at strengthening surgical capacity must address this important necessity. One important strategy is the use of online educational tools. In consideration of the observed limitations in care, resources, and training, we recommend a phased approach to neurosurgical growth in low-income settings. PMID- 27506408 TI - Powder Topical Rifampin for Reducing Infections After Neural Tube Defect Surgery in Infants. AB - OBJECTIVE: The correct timing and technique of neural tube defect (NTD) repairs significantly decrease the morbidity and mortality of NTD cases. However, infections related to the surgery are still common. We investigated the effects of topical rifampin combined with routine prophylaxis in newborns with open NTDs. METHODS: This retrospective study included 86 patients who had undergone NTD surgery. The experimental group comprised 30 patients who were started on topical rifampin before surgery, and the control group comprised 56 patients who were not administered topical rifampin. Surgical site infections (SSIs) and meningitis/ventriculoperitoneal (VP) shunt infections that developed within 6 months after the surgical intervention were evaluated. RESULTS: In the postoperative period, meningitis/VP shunt infections and SSIs were observed in 6.7% and 3.3%, respectively, of the experimental group treated with topical rifampin. Meningitis/VP shunt infections and SSIs were observed in 37.5% and 21.4%, respectively, of the control group. External ventricular drainage and not using topical rifampin were identified as important relative risk (RR) factors for meningitis/VP shunt infections (RR 19.28, 95% confidence interval [CI] [3.53, 105.33], P = 0.001; RR 18.10, 95% CI [2.38, 137.68], P = 0.005). A flap transposition, cerebrospinal fluid leaks, and not using topical rifampin were identified as RR factors for SSIs (RR 22.21, 95% CI [4.81, 102.47], P < 0.001; RR 13.04, 95% CI [1.22, 139.33], P = 0.034; RR 7.09, 95% CI [1.12, 53.99], P = 0.042). We did not observe any local or systemic side effects resulting from the use of rifampin. CONCLUSIONS: The use of topical rifampin is an easy and effective method for reducing SSIs and meningitis/VP shunt infections related to NTD surgery. PMID- 27506409 TI - Assessing Barriers to Neurosurgical Care in Sub-Saharan Africa: The Role of Resources and Infrastructure. AB - BACKGROUND: Quantitative estimates of surgical capacity and infrastructure and perceived care limitations in low-resource countries are essential baseline measures that can provide strategies for improving access to surgical care. Information about these barriers in Africa is scarce, particularly with respect to neurosurgery. We conducted a survey to better understand the unmet surgical need and resources available for the care of neurosurgery patients in Sub-Saharan Africa. METHODS: Using SurveyMonkey, we administered a neurosurgery-specific survey to neurosurgery attending surgeons and residents in Sub-Saharan African countries. Key outcome measures included workforce, access to imaging modalities and instruments, volume and breakdown of neurosurgical cases, and perceived limitations of care. RESULTS: We obtained a 41% survey response (129/314 sent). In addition to the expected large gap in workforce between low- and high-income countries, we found a dramatic paucity of neurosurgical resources in Central Africa, whereas specific pockets in West and South Africa have better neurosurgical care. Access to neuroimaging was not a major limitation in Sub Saharan African countries. The most commonly perceived limitations of care included infrastructure, anesthesia/nursing availability, wait times, and strength of training. CONCLUSIONS: This large survey defines important self perceived limitations to care within neurosurgery and highlights the importance of infrastructure and allied professions in this role. A clear understanding of areas of focus will enable a more efficient and sustainable response to the limitations in surgical care in low-resource areas. PMID- 27506410 TI - When the Infection Hits the Wound: Matched Case-Control Study in a Neurosurgical Patient Collective Including Systematic Literature Review and Risk Factors Analysis. AB - BACKGROUND: To avoid surgical site infections (SSIs) by identifying patients at high risk for infectious complications, a better understanding of relevant risk factors is required. This manuscript describes a matched case-control study of patients undergoing cranial neurosurgery with postoperative surgical site infections and a systematic literature review. METHODS: From January 2012 to March 2015, 70 patients (2.47%) with SSIs (out of 2819 patients) and 185 controls were identified. Statistical analyses were performed using univariate and multivariate models to identify risk factors associated with SSIs. RESULTS: The time of the onset of SSIs ranged from 8 to 854 days after surgery (median: 42 days). American Society of Anesthesiologists score (P = 0.003), surgical drain (P <0.001), number of previous operations (P <0.001), and implantation of foreign material (P <0.001) were significant risk factors for SSIs in multivariate analysis. In a systematic literature review, the authors identified 20 independent risk factors. CONCLUSIONS: This article provides information to ease the prospective assessment of patients at risk of SSI based on preoperative and postoperative risk factors. Lowering the incidence of SSIs will improve the patient outcomes and the overall quality of the healthcare delivered. To our knowledge, this is the first systemic literature review of SSIs in cranial neurosurgery and analysis of own cases in a wide spectrum. PMID- 27506412 TI - Why do maternal and newborn deaths continue to occur? AB - According to estimates in 2015, there were 303,000 maternal deaths, 2.7 million newborn deaths and 2.6 million stillbirths. A wide range of factors, from health system dynamics to social determinants of health and underlying health conditions, contribute to this outcome. The highest mortality risk for mothers and their babies is on the day of birth, and most of these deaths are preventable. The largest burden of deaths occurs in low-income countries, particularly in sub-Saharan Africa and South Asia, due to their young population and high fertility. Substantial reductions in maternal and newborn mortality have been achieved between 1990 and 2015, but it has not been fast enough and stillbirths continue to remain uncounted in many national vital statistics systems. Lack of a universal definition and classification system for stillbirths is an obstacle for preventing stillbirths, hindering the design of effective interventions. PMID- 27506414 TI - Chelating bis-N-heterocyclic carbene complexes of iron(ii) containing bipyridyl ligands as catalyst precursors for oxidation of alcohols. AB - Chelating bis-N-heterocyclic carbene (bis-NHC) complexes of iron(ii) containing pyridyl ligands have been prepared by the reaction of [FeCl2L] [L = bipy (1), phen (2)] with [LiN(SiMe3)2] and a bis(imidazolium) salt. The [Fe(bis-NHC)L(I)2] complexes were active pre-catalysts in the oxidation of 1-phenylethanol with tert butyl hydroperoxide in neat conditions, affording a quantitative yield of acetophenone in 4.5 h. The catalyst could be reused up to six cycles giving a turnover number (TON) of 1500. Various secondary alcohols, both aromatic and aliphatic were selectivity oxidised to the corresponding ketones in excellent yields. Compound 1 is stable in acetonitrile solution for ca. 4 h, although after 16 h, it evolves to a mixture of [Fe(bis-NHC)(bipy)2]I2 (3), [Fe(bipy)3](2+) and bis-imidazolium salt. The molecular structure of 3 has been determined by X-ray diffraction studies. PMID- 27506413 TI - Sequence determinants of subtype-specific actions of KCNQ channel openers. AB - KEY POINTS: Retigabine is a KCNQ voltage-gated potassium channel opener that was recently approved as an add-on therapeutic for patients with drug-resistant epilepsy. Retigabine exhibits very little specificity between most KCNQ channel subtypes, and there is interest in generating more potent and specific KCNQ channel openers. The present study describes the marked specificity of ICA069673 for KCNQ2 vs. KCNQ3, and exploits this property to investigate determinants of KCNQ subtype specificity. ICA069673 acts on a binding site in the voltage-sensing domain that is distinct from the putative retigabine site in the channel pore. ICA069673 has two separable effects on KCNQ channel activity. We identify two channel residues required for subtype specificity of KCNQ channel openers and show that these are sufficient to generate ICA069673 sensitivity in KCNQ3. ABSTRACT: Retigabine (RTG) is the first approved anti-epileptic drug that acts via activation of voltage-gated potassium channels, targeting KCNQ channels that underlie the neuronal M-current. RTG exhibits little specificity between KCNQ2-5 as a result of conservation of a Trp residue in the pore domain that binds to the drug. The RTG analogue ICA-069673 ('ICA73') exhibits much stronger effects on KCNQ2 channels, including a large hyperpolarizing shift of the voltage-dependence of activation, an ~2-fold enhancement of peak current and pronounced subtype specificity for KCNQ2 over KCNQ3. Based on ICA73 sensitivity of chimeric constructs of the transmembrane segments of KCNQ2 and KCNQ3, this drug appears to interact with the KCNQ2 voltage sensor (S1-S4) rather than the pore region targeted by RTG. KCNQ2 point mutants in the voltage sensor were generated based on KCNQ2/KCNQ3 sequence differences, and screened for ICA73 sensitivity. These experiments reveal that KCNQ2 residues F168 and A181 in the S3 segment are essential determinants of ICA73 subtype specificity. Mutations at either position in KCNQ2 abolish the ICA73-mediated gating shift, but preserve RTG sensitivity. Interestingly, A181P mutant channels show little ICA73-mediated gating shift but retain current potentiation by the drug. Mutations (L198F and P211A), which introduce these critical KCNQ2 residues at corresponding positions in KCNQ3, transplant partial ICA73 sensitivity. These findings demonstrate that RTG and ICA73 act via distinct mechanisms, and also reveal specific residues that underlie subtype specificity of KCNQ channel openers. PMID- 27506415 TI - Short-term versus longer duration of glucocorticoid therapy for exacerbations of chronic obstructive pulmonary disease. AB - BACKGROUND: Systemic glucocorticoid has been shown to improve the outcome of acute exacerbation of chronic obstructive pulmonary disease (COPD). However, the optimal duration remains controversial. OBJECTIVES: To investigate whether a short-term (seven days or fewer) systemic glucocorticoid treatment in patients with COPD exacerbation is non inferior to longer duration (more than seven days) treatment in clinical outcome. METHODS: We searched PubMed, EMBASE, CENTRAL databases, China Clinical Trials, CNKI, The Chinese biomedical literature database (CBM) and wanfang database to identify randomized controlled trials using systemic glucocorticoid in COPD. At least two review authors independently assessed each potentially eligible trial for its inclusion in the review and its quality. Glucocorticoid is given for a period of seven days or fewer versus systemic given for more than seven days. We retrieved time from building to Apr 20, 2016, and supplemented by manual retrieval into literature references. By adopting the combination of keywords and free word retrieval methods, we performed a routine meta-analysis to evaluate the effects of glucocorticoid on FEV1, FEV1/FVC, PaO2, clinical symptoms, relapse, treatment failure, mortality and side-effects between the two treatment groups. RESULTS: Our search yielded 9 studies involving 874 patients. Six studies were fully published and three were published as abstracts. We obtained data for one study published as abstracts from authors. Short-term treatment varied between three and seven days and longer duration 10-15 days, at equivalent daily doses of glucocorticoid. Mean ages of participants ranged from 60 to 90 years. The FEV1, FEV1/FVC, PaO2 and clinical symptoms between the two treatment groups did not differ significantly by treatment duration. There was no significant difference of relapse, treatment failure, mortality and side-effects between the two treatment groups. CONCLUSION: These data show that short-term glucocorticoid is as effective as and possibly safer than longer duration. PMID- 27506416 TI - Extracellular vesicle-driven information mediates the long-term effects of particulate matter exposure on coagulation and inflammation pathways. AB - BACKGROUND: Continuous exposure to particulate air pollution (PM) is a serious worldwide threat to public health as it coherently links with increased morbidity and mortality of cardiorespiratory diseases (CRD), and of type 2 diabetes (T2D). Extracellular vesicles (EVs) are circular plasma membrane fragments released from human cells that transfer microRNAs between tissues. In the present work it was explored the hypothesis that EVs with their encapsulated microRNAs (EVmiRNAs) contents might mediate PM effects by triggering key pathways in CRD and T2D. METHODS: Expression of EVmiRNAs analyzed by real-time PCR was correlated with oxidative stress, coagulation and inflammation markers, from healthy steel plant workers (n=55) with a well-characterized exposure to PM and PM-associated metals. All p-values were adjusted for multiple comparisons. In-silico Ingenuity Pathway Analysis (IPA) was performed to identify biological pathways regulated by PM associated EVmiRNAs. RESULTS: Increased expression in 17 EVmiRNAs is associated with PM and metal exposure (p<0.01). Mir-196b that tops the list, being related to 9 different metals, is fundamental in insulin biosynthesis, however three (miR 302b, miR-200c, miR-30d) out of these 17 EVmiRNAs are in turn also related to disruptions (p<0.01) in inflammatory and coagulation markers. CONCLUSIONS: The study's findings support the hypothesis that adverse cardiovascular and metabolic effects stemming from inhalation exposures in particular to PM metallic component may be mediated by EVmiRNAs that target key factors in the inflammation, coagulation and glucose homeostasis pathways. PMID- 27506417 TI - Neonatal isoflavone exposure interferes with the reproductive system of female Wistar rats. AB - There is increasing concern about possible adverse effects of soy based infant formulas (SBIF) due to their high amount of isoflavones (ISO). The aim of the present study was to investigate effects of neonatal exposure to ISO on reproductive system of female Wistar rats. Animals were exposed to an ISO depleted diet or a diet enriched with an ISO extract (IRD; 508mg ISO/kg) during embryogenesis and adolescence. Pups of each group were fed daily by pipette with ISO-suspension (ISO+; 32mg ISO/kg bw) or placebo from postnatal day (PND) 1 until PND23 resulting in plasma concentrations similar to levels reported in infants fed SBIF. The visceral fat mass was reduced by long-term IRD. Vaginal epithelial height was increased at PND23 and vaginal opening was precocious in ISO+ groups. Later in life, more often irregular estrus cycles were observed in rats of ISO+ groups. In addition, FSH levels and uterine epithelial heights were increased at PND80 in ISO+ groups. In summary, the results indicate that neonatal ISO intake, resulting in plasma concentrations achievable through SBIF, has an estrogenic effect on prepubertal rats and influences female reproductive tract later in life. PMID- 27506418 TI - Paradoxical effect of methimazole on liver mitochondria: In vitro and in vivo. AB - Methimazole is the most frequently prescribed antithyroid agent. On the other hand, several cases of liver injury are attributed to this drug. The mechanism of methimazole-induced liver injury is obscure. Hepatocytes mitochondria seem to be a target for methimazole cytotoxicity. Current investigation aimed to evaluate the effects of methimazole on the hepatocytes mitochondria in different experimental models. In the in vivo model, methimazole (100, 200 and 400mg/kg, i.p) was administered to mice and liver mitochondria were isolated and assessed. In the in vitro experiments, intact isolated liver mitochondria were incubated with increasing methimazole concentrations (10MUM-100mM). It was found that methimazole decreased liver mitochondrial ATP and glutathione, increased mitochondrial swelling, lipid peroxidation and reactive oxygen species (ROS), and collapsed mitochondrial membrane potential when administered to mice. Paradoxically, methimazole not only caused no significant injury toward isolated liver mitochondria in vitro but improved mitochondrial function and protected this organelle. The differences between two investigated models in the current study might be associated with drug bioactivation and reactive metabolites formation. These findings suggest mitochondrial dysfunction as a mechanism for methimazole-induced liver injury. Moreover, methimazole seems to be a novel mitochondrial protecting agent in vitro. PMID- 27506419 TI - New brominated flame retardants and their metabolites as activators of the pregnane X receptor. AB - The present study investigated the activities on different nuclear receptors of the new brominated flame retardants 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (TBB) and bis(2-ethylhexyl) 2,3,4,5-tetrabromophthalate (TBPH), and their main carboxylic acid metabolites 2,3,4,5-tetrabromobenzoic acid (TBBA) and mono(2 ethylhexyl) tetrabromophthalate (TBMEPH). None of selected chemicals exhibited marked activity towards PPARalpha and PPARgamma by the use of transactivation assays in HepG2 cells transfected with peroxisome proliferator-activated receptors. In contrast, selected flame retardants all exhibited potent agonist activity on pregnane X receptor (PXR), with EC50 values of 5.5MUM for TBPH and 2.0MUM for its metabolite TBMEPH. Molecular docking of TBPH and TBMEPH to the PXR ligand binding site revealed similar interactions, with differences only for conformation and orientation of the alkyl chains. Additionally, TBPH showed antagonist activity on PXR (IC50, 13.9MUM). Moreover, there was significant up regulation of CYP3A4 expression via PXR activation for TBB and TBPH and their metabolites. Induction of CYP3A4 might cause undesired drug-drug interactions, lower bioavailability of pharmaceutical drugs, higher formation of reactive toxic metabolites, or enhanced elimination of endogenous hormones, such as T3/T4, to lead to endocrine disruption. These data provide new and important insights into the toxicity of these new polybrominated flame retardants, TBB and TBPH, and their metabolites. PMID- 27506420 TI - Diabetes induction by total pancreatectomy in minipigs with simultaneous splenectomy: a feasible approach for advanced diabetes research. AB - BACKGROUND: Safe and reliable diabetes models are a key prerequisite for advanced preclinical studies on diabetes. Chemical induction is the standard model of diabetes in rodents and also widely used in large animal models of non-human primates and minipigs. However, uncertain efficacy, the potential of beta-cell regeneration, and relevant side effects are debatable aspects particularly in large animals. Therefore, we aimed to evaluate a surgical approach of total pancreatectomy combined with splenectomy for diabetes induction in an exploratory study in Goettingen minipigs. METHODS: Total pancreatectomy was performed in Goettingen minipigs (n = 4) under general anesthesia and endotracheal intubation. Prior to surgery, a central venous line was established for drug application and blood sampling. After median laparotomy, splenectomy was performed and the lobular pancreas was carefully dissected with particular attention to the duodenal vascular arcade. Close monitoring of blood glucose was initiated immediately after surgery by standard glucometer measurement or continuous glucose monitoring systems (CGMS). Exogenous insulin was given by multiple daily subcutaneous (s.c.) injections or via insulin pump systems (CSII). Complete endogenous insulin deficiency was confirmed by intravenous glucose tolerance test (ivGTT) and measurement of c-peptide. For establishing a suitable regimen for diabetes management, the animals were followed for 4-6 weeks. RESULTS: Following pancreatectomy and splenectomy, the animals showed a quick recovery from surgery and initial analgetic medication and volume substitution could be terminated within 24 h. A rapid increase in blood glucose was observed immediately following pancreatectomy necessitating insulin therapy. The induced exocrine insufficiency did not cause any clinical symptoms. Complete insulin deficiency could be confirmed in all animals by determination of negative c-peptide during glucose challenge. The two regimen of insulin treatment (multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII)) were both feasible with respect to acceptable glycemic control whereas CSII was considerably advantageous in comfort and popularity for both animals and care takers. CONCLUSIONS: Surgical pancreatectomy in combination with splenectomy to facilitate access to the pancreas is a feasible model for efficient diabetes induction in minipigs. The procedure itself and postoperative animal care could be performed without complications in this exploratory study. Nevertheless, this approach requires well-equipped infrastructure, experienced and skilled surgeons and anesthesiologists and dedicated animal care takers. The impact of total pancreatectomy in combination with splenectomy on the digestive and immune system must be considered in the design and definition of end points of experimental diabetes and transplantation studies. PMID- 27506422 TI - Microbial Biotechnology 2020; microbiology of fossil fuel resources. AB - This roadmap examines the future of microbiology research and technology in fossil fuel energy recovery. Globally, the human population will be reliant on fossil fuels for energy and chemical feedstocks for at least the medium term. Microbiology is already important in many areas relevant to both upstream and downstream activities in the oil industry. However, the discipline has struggled for recognition in a world dominated by geophysicists and engineers despite widely known but still poorly understood microbially mediated processes e.g. reservoir biodegradation, reservoir souring and control, microbial enhanced oil recovery. The role of microbiology is even less understood in developing industries such as shale gas recovery by fracking or carbon capture by geological storage. In the future, innovative biotechnologies may offer new routes to reduced emissions pathways especially when applied to the vast unconventional heavy oil resources formed, paradoxically, from microbial activities in the geological past. However, despite this potential, recent low oil prices may make industry funding hard to come by and recruitment of microbiologists by the oil and gas industry may not be a high priority. With regards to public funded research and the imperative for cheap secure energy for economic growth in a growing world population, there are signs of inherent conflicts between policies aimed at a low carbon future using renewable technologies and policies which encourage technologies which maximize recovery from our conventional and unconventional fossil fuel assets. PMID- 27506421 TI - The differential impact of natural killer (NK) cell education via KIR2DL3 and KIR3DL1 on CCL4 secretion in the context of in-vitro HIV infection. AB - Carriage of certain inhibitory natural killer (NK) cell receptor (iNKR)/HLA ligand pairs is associated with protection from infection and slow time to AIDS implicating NK cells in HIV control. NK cells acquire functional potential through education, which requires the engagement of iNKRs by their human leucocyte antigen (HLA) ligands. HIV infection down-regulates cell surface HLA A/B, but not HLA-C/E. We investigated how NK cell populations expressing combinations of the iNKRs NKG2A, KIR2DL3 (2DL3) and KIR3DL1 (3DL1) responded to autologous HIV infected CD4 (iCD4) cells. Purified NK cells from HIV-uninfected individuals were stimulated with autologous HIV iCD4 or uninfected CD4 T cells. Using flow cytometry we gated on each of the 8 NKG2A+/- 2DL3+/- 3DL1+/- populations and analysed all possible combinations of interferon (IFN)-gamma, CCL4 and CD107a functional subsets responding to iCD4 cells. Infected CD4 cells induced differential frequencies of NKG2A+/- 2DL3+/- 3DL1+/- populations with total IFN-gamma+ , CCL4+ and CD107a+ functional profiles. 2DL3+ NKG2A+ NK cells had a higher frequency of responses to iCD4 than other populations studied. A higher frequency of 2DL3+ NK cells responded to iCD4 from individuals that were not HLA-C1 homozygotes. These results show that 2DL3+ NK cells are mediators of HIV-specific responses. Furthermore, responses of NK cell populations to iCD4 are influenced not only by NK cell education through specific KIR/HLA pairs, but also by differential HIV-mediated changes in HLA expression. PMID- 27506424 TI - A Lower Temperature FDM 3D Printing for the Manufacture of Patient-Specific Immediate Release Tablets. AB - PURPOSE: The fabrication of ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing. METHODS: Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of the drugs and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus. RESULTS: Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication of immediate release tablets at temperatures as low as 110 degrees C. The integrity of two model drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in batch variability and an immediate in vitro release pattern. CONCLUSIONS: Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms. PMID- 27506425 TI - Genetic Studies in Autism: Correspondence. PMID- 27506426 TI - Do sudden onsets need to be perceived as new objects to capture attention? The interplay between sensory transients and display configuration. AB - Yantis and Jonides (1984) and Jonides and Yantis (1988) reported robust involuntary attentional capture by sudden-onsets, the origin of which has been debated. Prominent accounts have highlighted aspects that include the "new object" status of a sudden-onset (Yantis & Hillstrom, 1994) and the substantial luminance changes accompanying their appearance (Gellatly, Cole & Blurton, 1999; Franconeri, Hollingworth & Simons, 2005), including relative differences in the amount of sensory change between target and nontarget items (Pinto, Olivers & Theeuwes, 2008). In this research we dissociate the amount of sensory change accompanying sudden onsets from the extent to which they appear as newly created objects in search displays. We attempted to determine the relative contribution of local sensory changes and display configuration to attentional capture by sudden-onsets. We showed that the display configuration of old objects modulates the impact of capture caused by sudden-onsets. PMID- 27506427 TI - The ticking time bomb: Using eye-tracking methodology to capture attentional processing during gradual time constraints. AB - Many decisions are made under suboptimal circumstances, such as time constraints. We examined how different experiences of time constraints affected decision strategies on a probabilistic inference task and whether individual differences in working memory accounted for complex strategy use across different levels of time. To examine information search and attentional processing, we used an interactive eye-tracking paradigm where task information was occluded and only revealed by an eye fixation to a given cell. Our results indicate that although participants change search strategies during the most restricted times, the occurrence of the shift in strategies depends both on how the constraints are applied as well as individual differences in working memory. This suggests that, in situations that require making decisions under time constraints, one can influence performance by being sensitive to working memory and, potentially, by acclimating people to the task time gradually. PMID- 27506428 TI - Target object moderation of attentional orienting by gazes or arrows. AB - Recent studies have attempted to demonstrate the importance of the characteristics of directional cues and observers' traits in attentional orienting. This study investigated how attentional orienting is influenced by target processing. Two experiments showed the critical role played by target processing in attentional orienting that relies on eye-gaze and arrow cues. In Experiment 1, stronger attentional orienting was observed under the object-target condition compared with the scrambled-display condition, irrespective of whether gaze or arrow cues were used. The results indicated that meaningful targets produced stronger attentional orienting than did meaningless targets, regardless of the social characteristics of the target. Experiment 2, which investigated whether attentional orienting was influenced by differences in the meaningfulness of targets regardless of their perceptual features, used participants' own faces and the faces of others as target stimuli; one's own face is typically more meaningful than the face of another. The results showed stronger attentional orienting in response to one's own face than in response to another's face under both gaze and arrow conditions. These findings suggest that the use of task irrelevant meaningful information as targets may be effective in enhancing attention, regardless of perceptual features. PMID- 27506429 TI - Measurement of global DNA methylation levels by flow cytometry in mouse fibroblasts. AB - DNA Methylation, 5meC, is an epigenetic modification that acts as an important regulator of genomic stability and gene expressivity. Genome-wide changes in methylation have been associated with lineage-specific changes in gene expression profiles during development and in some cell-based pathologies, including oncogenesis. Cost-effective and rapid platforms for the detection of changes in the global levels of methylation are of value for the investigation of the processes that regulate methylation. Flow cytometry allows rapid and quantitative analysis of epitopes within a large number of cells. We have recently optimised the conditions required for valid detection of 5meC by immunofluorescence microscopy. These studies showed that immunological detection of 5meC requires the sequential denaturation of chromatin by a brief period of acidification followed by a partial tryptic digestion step. We have assessed the reliability of flow cytometry for the detection of changes in 5meC when coupled with this optimised epitope retrieval strategy. This study provides support for the use of high throughput screening of 5meC by flow cytometry for the analysis of the epigenetic regulation of important cell transitions. PMID- 27506430 TI - A Unified Approach for the Enantioselective Synthesis of the Brominated Chamigrene Sesquiterpenes. AB - The brominated chamigrene sesquiterpenes constitute a large subclass of bromocyclohexane-containing natural products, yet no general enantioselective strategy for the synthesis of these small molecules exists. Herein we report a general strategy for accessing this family of secondary metabolites, including the enantioselective synthesis of (-)-alpha- and (-)-ent-beta-bromochamigrene, ( )-dactylone, and (+)-aplydactone. Access to these molecules is enabled by a stereospecific bromopolyene cyclization initiated by the solvolysis of an enantiomerically enriched vicinal bromochloride. PMID- 27506432 TI - Self-reported wellbeing and body image after abdominoperineal excision for rectal cancer. AB - PURPOSE: Patients with low rectal cancer are often operated with an abdominoperineal excision (APE) rendering them a permanent stoma. The surgical procedure itself, the cancer diagnosis, and the permanent stoma might all affect quality of life. The aim of this study was to explore wellbeing and body image 3 years after APE in a population-based cohort of patients. METHODS: All patients with rectal cancer operated with an APE between 2007 and 2009 were identified using the Swedish ColoRectal Cancer Registry. A total of 545 patients answered a questionnaire 3 years after surgery. Two open-ended questions were analyzed with a mixed method design using both qualitative and quantitative content analysis. Main themes and sub-themes on wellbeing and body image were identified. RESULTS: Three main themes were identified: bodily limitations, mental suffering, and acceptance. Bodily limitations included other symptoms than stoma-related problems. A majority of patients expressed acceptance to their situation regardless of bodily limitations and mental suffering. However, 18 % did not describe any acceptance of their current situation. CONCLUSIONS: Most patients expressed acceptance reflecting wellbeing 3 years after APE for rectal cancer. There is, however, a subset of patients (18 %) who describe bodily limitations and mental suffering without acceptance and who require further support. Many aspects of the portrayed bodily limitations and mental suffering could be prevented or treated. TRIAL REGISTRATION: NCT01296984. PMID- 27506431 TI - 177Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment. AB - PURPOSE: The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, 177Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC). METHODS: Thirty-one mCRPC patients with progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic68Ga PSMA-HBED-CCPET/CT, prior to inclusion for therapy. Included patients then underwent quarterly 177Lu-DKFZ-PSMA-617 therapy. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels. Metabolic response was assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score (VASmax) analgesic score (AS), Karanofsky performance status (KPS), and ttoxicity and response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria. RESULTS: The mean age of patients was 65.93 +/- 9.77 years (range: 38-81 years). The mean activity administered in the 31 patients was 5069 +/- 1845 MBq ranging from one to four cycles. There was a decline in the mean serum PSA levels from the baseline (baseline: 275 ng/mL, post 1st cycle therapy: 141.75 ng/mL). Based on biochemical response criteria 2/31, 20/31, 3/31, and 6/31 had complete response (CR), partial response(PR), stable disease (SD), and progressive disease (PD), respectively. Metabolic response revealed 2/6 patients with CR, and the remaining 3/6 patients with PR and 1/6 patients with SD. The mean VASmax score decreased from 7.5 to 3. The mean analgesic score decreased from 2.5 to 1.8 after therapy. The mean KPS score improved from 50.32 to 65.42 after therapies. The mean ECOG performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity. CONCLUSION: 177Lu-DKFZ PSMA-617 radionuclide therapy is a safe and effective approach in the treatment of mCRPC patients. PMID- 27506434 TI - Erratum to: Picosecond pulsed infrared laser tuned to amide I band dissociates polyglutamine fibrils in cells. PMID- 27506433 TI - Clinical and surgical factors associated with organ/space surgical site infection after laparoscopic gastrectomy for gastric cancer. AB - BACKGROUND: Surgical site infection (SSI), particularly organ/space SSI, remains a clinically important issue even after laparoscopic gastrectomy (LG) for gastric cancer (GC). This study aimed to identify specific clinical and surgical factors associated with organ/space SSI after LG. METHODS: This was a retrospective study of 407 patients who underwent LG for clinical stage I GC. SSI was defined according to the National Nosocomial Infection Surveillance System. The incidence and treatment outcomes of either incisional or organ/space SSI after LG were examined, and the risk factors for each type of SSI were identified using univariate and multivariate analyses. RESULTS: Organ/space SSI was observed in 21 patients (5.2 %), while incisional SSI was detected in 18 patients (4.4 %). Although no mortality was observed, the occurrence of either incisional or organ/space SSI significantly prolonged postoperative hospital stays (p = 0.000 and 0.000, respectively); however, organ/space SSI required more re-operations and re-admissions, and eventually longer total hospital stays than incisional SSI (p = 0.036). Intra-abdominal abscess around the pancreas was the main cause of organ/space SSI, while no anastomotic leakage was observed. Multivariate analyses identified male gender (odds ratio (OR) 3.385; 95 % confidence interval (CI) 1.073-15.07, p = 0.037), chronic liver disease (OR 8.897; 95 % CI 2.502-28.99, p = 0.001), and total gastrectomy (TG) (OR 3.817; 95 % CI 1.380-10.24, p = 0.011) as independent risk factors for organ/space SSI, while TG (OR 3.130; 95 % CI 1.102-8.768, p = 0.033) and operation time >=320 min (OR 3.732; 95 % CI 1.109 16.98, p = 0.033) were independently associated with incisional SSI. CONCLUSIONS: Male gender, chronic liver disease, and TG are independent risk factors for organ/space SSI after LG for GC; thus, meticulous surgical procedures need to be performed among patients with these specific risk factors. PMID- 27506435 TI - [Rank of outcome parameters in the treatment of depression : Results of a Delphi panel survey]. AB - BACKGROUND: In the context of new drug benefit assessments a list of outcome parameter are evaluated. Currently it is unclear, how different outcome parameters are weighed in the overall assessment. OBJECTIVES: The objective of the survey is to rank relevant outcome parameters in the treatment of depression, which may be considered in benefit the assessment of new antidepressants. MATERIALS AND METHODS: In 2015 a Delphi panel survey with 30 general practitioners and specialists in Germany was performed regarding the benefit assessment of antidepressants. On the basis of two fictive casuistics (patients with depressive disorders) the physicians weighed a range of relevant outcome parameters regarding efficacy, quality of life, safety and tolerability according to their relevance to clinical practice. RESULTS: Regarding efficacy, response, remission and recovery were rated as the most important outcomes. Regarding quality of life, handling of the daily household activities and mental performance were rated as most important. Suicidality was rated as the most important outcome regarding safety and tolerability. CONCLUSIONS: Individual outcome parameters were rated differently by the physicians regarding their relevance to clinical practice. The results indicate that outcome parameters should be weighed differently when assessing the overall benefit of new antidepressants. PMID- 27506436 TI - Managing player load in professional rugby union: a review of current knowledge and practices. AB - BACKGROUND: The loads to which professional rugby players are subjected has been identified as a concern by coaches, players and administrators. In November 2014, World Rugby commissioned an expert group to identify the physical demands and non physical load issues associated with participation in professional rugby. OBJECTIVE: To describe the current state of knowledge about the loads encountered by professional rugby players and the implications for their physical and mental health. FINDINGS: The group defined 'load' as it relates to professional rugby players as the total stressors and demands applied to the players. In the 2013 2014 seasons, 40% of professional players appeared in 20 matches or more, and 5% of players appeared in 30 matches or more. Matches account for ~5-11% of exposure to rugby-related activities (matches, team and individual training sessions) during professional competitions. The match injury rate is about 27 times higher than that in training. The working group surmised that players entering a new level of play, players with unresolved previous injuries, players who are relatively older and players who are subjected to rapid increases in load are probably at increased risk of injury. A mix of 'objective' and 'subjective' measures in conjunction with effective communication among team staff and between staff and players was held to be the best approach to monitoring and managing player loads. While comprehensive monitoring holds promise for individually addressing player loads, it brings with it ethical and legal responsibilities that rugby organisations need to address to ensure that players' personal information is adequately protected. CONCLUSIONS: Administrators, broadcasters, team owners, team staff and the players themselves have important roles in balancing the desire to have the 'best players' on the field with the ongoing health of players. In contrast, the coaching, fitness and medical staff exert significant control over the activities, duration and intensity of training sessions. If load is a major risk factor for injury, then managing training loads should be an important element in enabling players to perform in a fit state as often as possible. PMID- 27506437 TI - Measuring water fluxes in forests: the need for integrative platforms of analysis. PMID- 27506438 TI - Simple and Sensitive Quantification of Ghrelin Hormone in Human Plasma Using SBSE HPLC/DAD-MS. AB - During a decade and more since its discovery, the emerging physiological roles of ghrelin in mammalian are increasingly being introduced, proposing a critical need for its quantification in biological milieu. Here in, a simple and sensitive single-step method for extraction and quantification of ghrelin in human plasma was developed and validated using stir bar sorptive extraction (SBSE) followed by high-performance liquid chromatography (HPLC) with diode array detection (DAD) coupled to mass spectrometry (MS). Influential parameters of SBSE procedure were optimized including extraction and desorption times of 45 and 30 min, respectively; pH of 4; no addition of salt. The sum of peak heights of three most intense selected ions in mass spectrum (844, 1125 and 1686 m/z) related to 4-, 3- and 2-fold-charged ions of ghrelin was used for quantification. Validation parameters containing linear dynamic range, limit of quantification and limit of detection were 0.02-80, 0.02 and 0.007 ug L-1, respectively, and calculated relative standard deviation for peak heights was 6.5% (0.7 ug L-1 standard solution). Mean recovery for ghrelin in spiked plasma samples was 96% +/- 3. The efficiency of the SBSE-HPLC/DAD-MS procedure was proved by analysis of plasma samples from obese patients undergoing gastric plication surgery. The suggested methodology would contribute to simple and fast analysis of ghrelin levels in obesity and related diseases and also biochemical cycles in which gherlin is present. PMID- 27506439 TI - Sphingomonas naphthae sp. nov., isolated from oil-contaminated soil. AB - During the study of hydrocarbon-degrading bacteria in the oil-contaminated soil of Gunsan, North Jeolla Province, South Korea, a yellow, Gram-stain-negative, aerobic, motile, rod-shaped bacterium, designated strain DKC-5-1T, was isolated. This strain was non-sporulating, catalase-negative and oxidase-positive. It was able to grow at 10-33 degrees C, pH 6.0-8.5 and at an NaCl concentration of 0 1.5 % (w/v). This strain was characterized taxonomically using a polyphasic approach. Based on 16S rRNA gene sequence analysis, strain DKC-5-1T belongs to the genus Sphingomonas and is closely related to Sphingomonas laterariae LNB2T (96.65 % sequence similarity), Sphingomonas haloaromaticamans A175T (96.63 % sequence similarity), Sphingomonas histidinilytica UM2T (96.63 % sequence similarity), and Sphingomonas wittichii RW1T (96.43 % sequence similarity). The only respiratory quinone was ubiquinone-10 and the major polyamine was homospermidine. The polar lipid profile revealed the presence of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, sphingoglycolipid and phosphatidyldimethylethanolamine. The predominant fatty acids of strain DKC-5-1T were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), C16 : 0, C14 : 0 2-OH, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), C17 : 1omega6c and C14 : 0. The genomic DNA G+C content of this novel strain was 65.9 mol%. Morphological, physiological, chemotaxonomic and phylogenetic analyses clearly distinguished this strain from its closest phylogenetic neighbours. Thus, strain DKC-5-1T represents a novel species of the genus Sphingomonas, for which the name Sphingomonasnaphthae sp. nov. is proposed. The type strain is DKC-5-1T (=KEMB 9005-380T=KACC 18716T=JCM 31294T). PMID- 27506440 TI - Experiences of Japanese aged care: the pursuit of optimal health and cultural engagement. AB - Japan is a super-ageing society that faces pressures on its aged care system from a growing population of older adults. Naturalistic observations were undertaken at eight aged care facilities in central and northern Japan to explore how aged care is configured. Four aspects of contemporary provision were identified that offer potential gains in quality of life and health. The Japanese government mandates that aged care facilities must employ a qualified nutritionist to oversee meal preparation, fostering optimal dietary intake. A concept of life rehabilitation seeks to maximise physical and cognitive performance, with possible longevity gains. Low staff to resident ratios are also mandated by the Japanese government to afford residents high levels of interpersonal care. Finally, Japanese facilities prioritise experiences of seasonality and culture, connecting frail older people to the world beyond their walls. PMID- 27506442 TI - Attitudes of Primary Care Physicians Toward Sickle Cell Disease Care, Guidelines, and Comanaging Hydroxyurea With a Specialist. AB - BACKGROUND: Sickle cell disease (SCD) is a complex chronic disease requiring multidisciplinary care that involves primary care physicians (PCPs) working with a hematologist or SCD specialists. However, PCPs often lack access to SCD specialists and are unaware of SCD guidelines or efficacious treatment. METHODS: We partnered with Community Care of North Carolina (CCNC) to identify assigned PCPs for SCD patients with Medicaid across North Carolina. CCNC network administrators distributed a web-based questionnaire for completion. The questionnaire involved 12 self-reported items on a yes-no or a 1 to 5 Likert-type scale that assessed PCP attitudes toward SCD care, awareness of recent guidelines, and comanaging hydroxyurea. RESULTS: Of the 53 PCPs who completed the electronic survey, 73% felt they were comfortable with the number of SCD patients in their practice. Most PCPs reported having infrequent communications with an SCD specialist (67%) and most were also not aware of the 2014 SCD guidelines (66%). Many reported that they would frequently use the new SCD guidelines if provided to them (76%). Furthermore, 51% of PCPs expressed comfort with using mobile apps to access SCD guidelines and provided email contact to receive further information. The majority also reported being comfortable comanaging hydroxyurea with an SCD specialist (65%). CONCLUSION: Few PCPs in North Carolina were aware of the new SCD guidelines or had regular communication with an SCD specialist. The majority of PCPs, however, demonstrated a favorable attitude toward receiving the SCD guidelines and comanaging hydroxyurea with a specialist. In response to this gap in care, we have developed a mobile-based SCD toolbox specifically for PCPs to provide guidelines, algorithms, and a method to communicate with local SCD specialists. With the interest in receiving these guidelines, we are confident the toolbox will provide an easy to use platform to assist PCPs to utilize the SCD guidelines. PMID- 27506443 TI - Reaching Urban Poor Hypertensive Patients: A Novel Model of Chronic Disease Care Versus a Traditional Fee-for-Service Approach. AB - BACKGROUND: There is a significant disparity in hypertensive treatment rates between those with and without health insurance. If left untreated, hypertension leads to significant morbidity and mortality. The uninsured face numerous barriers to access chronic disease care. We developed the Community-based Chronic Disease Management (CCDM) clinics specifically for the uninsured with hypertension utilizing nurse-led teams, community-based locations, and evidence based clinical protocols. All services, including laboratory and medications, are provided on-site and free of charge. METHODS: In order to ascertain if the CCDM model of care was as effective as traditional models of care in achieving blood pressure goals, we compared CCDM clinics' hypertensive care outcomes with 2 traditional fee-for-service physician-led clinics. All the clinics are located near one another in poor urban neighborhoods of Milwaukee, Wisconsin. RESULTS: Patients seen at the CCDM clinics and at 1 of the 2 traditional clinics showed a statistically significant improvement in reaching blood pressure goal at 6 months ( P < .001 and P < .05, respectively). Logistic regression analysis found no difference in attaining blood pressure goal at 6 months for either of the 2 fee for-service clinics when compared with the CCDM clinics. CONCLUSION: The CCDM model of care is at least as effective in controlling hypertension as more traditional fee-for-service models caring for the same population. The CCDM model of care to treat hypertension may offer another approach for engaging the urban poor in chronic disease care. PMID- 27506444 TI - Publicly funded postpartum contraception use is associated with a reduction in the rate of subsequent preterm birth. PMID- 27506445 TI - Ultrasound-based IOTA simple rules allow accurate malignancy risk estimation for adnexal masses. PMID- 27506446 TI - Effects of addition of Aspergillus oryzae culture and 2-hydroxyl-4-(methylthio) butanoic acid on milk performance and rumen fermentation of dairy cows. AB - To investigate effects of Aspergillus oryzae culture (AOC) and 2-hydroxy-4 (methylthio) butanoic acid (HMB) on milk performance and rumen fermentation of dairy cows. Sixty-four multiparous Chinese Holstein cows were randomly allocated into four experimental diets: (i) Control diet; (ii) AOC diet: 5 g AOC/day per head; (iii) HMB diet: 25 g HMB/day; and (iv) AH diet: 5 g AOC plus 25 g HMB/day. Added HMB tended to increase the yield of milk protein (P = 0.06) and 3.5% fat corrected milk (P = 0.08) and milk fat content (P = 0.09). Milk fat yield (P = 0.03) and the contents of milk protein (P = 0.05) were increased by adding HMB. The cows fed on AOC diet had a tendency for higher body weight (BW) gain (P = 0.08). Addition of AOC, HMB and AH increased content of microbial protein (MCP) and total volatile fatty acids (VFA) (P < 0.01) in rumen fluid. Populations of rumen fungi, Fibrobacter succinogenes and Ruminococcus flavefaciens relative to total bacterial 16S rDNA (P <= 0.03) and activity of carboxymethylcellulase (CMCase) (P < 0.01) were increased with added AOC or HMB. It is inferred that added AOC or HMB can increase the contents of MCP and total VFA potentially by stimulating rumen microbe populations and CMCase activity. PMID- 27506448 TI - Sexual Assault: What Every Emergency Provider Needs to Know. PMID- 27506447 TI - Transcriptional regulation of the proto-oncogene Zfp521 by SPI1 (PU.1) and HOXC13. AB - The mouse zinc-finger gene Zfp521 (also known as ecotropic viral insertion site 3; Evi3; and ZNF521 in humans) has been identified as a B-cell proto-oncogene, causing leukemia in mice following retroviral insertions in its promoter region that drive Zfp521 over-expression. Furthermore, ZNF521 is expressed in human hematopoietic cells, and translocations between ZNF521 and PAX5 are associated with pediatric acute lymphoblastic leukemia. However, the regulatory factors that control Zfp521 expression directly have not been characterized. Here we demonstrate that the transcription factors SPI1 (PU.1) and HOXC13 synergistically regulate Zfp521 expression, and identify the regions of the Zfp521 promoter required for this transcriptional activity. We also show that SPI1 and HOXC13 activate Zfp521 in a dose-dependent manner. Our data support a role for this regulatory mechanism in vivo, as transgenic mice over-expressing Hoxc13 in the fetal liver show a strong correlation between Hoxc13 expression levels and Zfp521 expression. Overall these experiments provide insights into the regulation of Zfp521 expression in a nononcogenic context. The identification of transcription factors capable of activating Zfp521 provides a foundation for further investigation of the regulatory mechanisms involved in ZFP521-driven cell differentiation processes and diseases linked to Zfp521 mis-expression. PMID- 27506449 TI - Dual Therapeutic Action of a Neutralizing Anti-FGF2 Aptamer in Bone Disease and Bone Cancer Pain. AB - Fibroblast growth factor 2 (FGF2) plays a crucial role in bone remodeling and disease progression. However, the potential of FGF2 antagonists for treatment of patients with bone diseases has not yet been explored. Therefore, we generated a novel RNA aptamer, APT-F2, specific for human FGF2 and characterized its properties in vitro and in vivo. APT-F2 blocked binding of FGF2 to each of its four cellular receptors, inhibited FGF2-induced downstream signaling and cells proliferation, and restored osteoblast differentiation blocked by FGF2. APT-F2P, a PEGylated form of APT-F2, effectively blocked the bone disruption in mouse and rat models of arthritis and osteoporosis. Treatment with APT-F2P also exerted a strong analgesic effect, equivalent to morphine, in a mouse model of bone cancer pain. These findings demonstrated dual therapeutic action of APT-F2P in bone diseases and pain, providing a promising approach to the treatment of bone diseases. PMID- 27506450 TI - Type I Interferons Interfere with the Capacity of mRNA Lipoplex Vaccines to Elicit Cytolytic T Cell Responses. AB - Given their high potential to evoke cytolytic T cell responses, tumor antigen encoding messenger RNA (mRNA) vaccines are now being intensively explored as therapeutic cancer vaccines. mRNA vaccines clearly benefit from wrapping the mRNA into nano-sized carriers such as lipoplexes that protect the mRNA from degradation and increase its uptake by dendritic cells in vivo. Nevertheless, the early innate host factors that regulate the induction of cytolytic T cells to mRNA lipoplex vaccines have remained unresolved. Here, we demonstrate that mRNA lipoplexes induce a potent type I interferon (IFN) response upon subcutaneous, intradermal and intranodal injection. Regardless of the route of immunization applied, these type I IFNs interfered with the generation of potent cytolytic T cell responses. Most importantly, blocking type I IFN signaling at the site of immunization through the use of an IFNAR blocking antibody greatly enhanced the prophylactic and therapeutic antitumor efficacy of mRNA lipoplexes in the highly aggressive B16 melanoma model. As type I IFN induction appears to be inherent to the mRNA itself rather than to unique properties of the mRNA lipoplex formulation, preventing type I IFN induction and/or IFNAR signaling at the site of immunization might constitute a widely applicable strategy to improve the potency of mRNA vaccination. PMID- 27506451 TI - Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy is an inherited fatal genetic disease characterized by mutations in dystrophin gene, causing membrane fragility leading to myofiber necrosis and inflammatory cell recruitment in dystrophic muscles. The resulting environment enriched in proinflammatory cytokines, like IFN-gamma and TNF-alpha, determines the transformation of myofiber constitutive proteasome into the immunoproteasome, a multisubunit complex involved in the activation of cell mediate immunity. This event has a fundamental role in producing peptides for antigen presentation by MHC class I, for the immune response and also for cytokine production and T-cell differentiation. Here, we characterized for the first time the presence of T-lymphocytes activated against revertant dystrophin epitopes, in the animal model of Duchenne muscular dystrophy, the mdx mice. Moreover, we specifically blocked i-proteasome subunit LMP7, which was up regulated in dystrophic skeletal muscles, and we demonstrated the rescue of the dystrophin expression and the amelioration of the dystrophic phenotype. The i proteasome blocking lowered myofiber MHC class I expression and self-antigen presentation to T cells, thus reducing the specific antidystrophin T cell response, the muscular cell infiltrate, and proinflammatory cytokine production, together with muscle force recovery. We suggest that i-proteasome inhibition should be considered as new promising therapeutic approach for Duchenne muscular dystrophy pathology. PMID- 27506452 TI - Adaptive Immune Response Impairs the Efficacy of Autologous Transplantation of Engineered Stem Cells in Dystrophic Dogs. AB - Duchenne muscular dystrophy is the most common genetic muscular dystrophy. It is caused by mutations in the dystrophin gene, leading to absence of muscular dystrophin and to progressive degeneration of skeletal muscle. We have demonstrated that the exon skipping method safely and efficiently brings to the expression of a functional dystrophin in dystrophic CD133+ cells injected scid/mdx mice. Golden Retriever muscular dystrophic (GRMD) dogs represent the best preclinical model of Duchenne muscular dystrophy, mimicking the human pathology in genotypic and phenotypic aspects. Here, we assess the capacity of intra-arterial delivered autologous engineered canine CD133+ cells of restoring dystrophin expression in Golden Retriever muscular dystrophy. This is the first demonstration of five-year follow up study, showing initial clinical amelioration followed by stabilization in mild and severe affected Golden Retriever muscular dystrophy dogs. The occurrence of T-cell response in three Golden Retriever muscular dystrophy dogs, consistent with a memory response boosted by the exon skipped-dystrophin protein, suggests an adaptive immune response against dystrophin. PMID- 27506454 TI - Conidiobolus macrosporus (Entomophthorales), a mosquito pathogen in Central Brazil. AB - A new fungal pathogen of Culicinae (Diptera: Culicidae) adults, Conidiobolus macrosporus (Entomophthorales: Ancylistaceae), was detected and isolated during a survey of mosquito pathogens close to the city of Aruana, Goias State, in December 2014. The morphological characteristics of C. macrosporus are presented, and reasons for some uncertainty about this identification are discussed. The pathogenicity and high virulence of this fungus for Aedes aegypti were confirmed in laboratory conditions. Mortality of adults exposed to conidia was observed within 24h of exposure to the pathogen, and increased to 100% as quickly as 3days after inoculation (with the highest conidial concentration tested, 8.3*10(4)conidia/cm(2)). Repeated attempts to obtain genomic sequence data failed despite confirmations that the DNA extraction methods were themselves successful. PMID- 27506453 TI - Enriched retinal ganglion cells derived from human embryonic stem cells. AB - Optic neuropathies are characterised by a loss of retinal ganglion cells (RGCs) that lead to vision impairment. Development of cell therapy requires a better understanding of the signals that direct stem cells into RGCs. Human embryonic stem cells (hESCs) represent an unlimited cellular source for generation of human RGCs in vitro. In this study, we present a 45-day protocol that utilises magnetic activated cell sorting to generate enriched population of RGCs via stepwise retinal differentiation using hESCs. We performed an extensive characterization of these stem cell-derived RGCs by examining the gene and protein expressions of a panel of neural/RGC markers. Furthermore, whole transcriptome analysis demonstrated similarity of the hESC-derived RGCs to human adult RGCs. The enriched hESC-RGCs possess long axons, functional electrophysiological profiles and axonal transport of mitochondria, suggestive of maturity. In summary, this RGC differentiation protocol can generate an enriched population of functional RGCs from hESCs, allowing future studies on disease modeling of optic neuropathies and development of cell therapies. PMID- 27506455 TI - Substitution of outpatient care with primary care: a feasibility study on the experiences among general practitioners, medical specialists and patients. AB - BACKGROUND: Reinforcing the gatekeeping role of general practitioners (GPs) by embedding specialist knowledge into primary care is seen as a possibility for stimulating a more sustainable healthcare system and avoiding unnecessary referrals to outpatient care. An intervention called Primary Care Plus (PC+) was developed to achieve these goals. The objective of this study is to gain insight into: (1) the content and added value of PC+ consultations according to stakeholders, and (2) patient satisfaction with PC+ compared to outpatient care. METHODS: A feasibility study was conducted in the southern part of the Netherlands between April 2013 and January 2014. Data was collected using GP, medical specialist and patient questionnaires. Patient characteristics and medical specialty data were collected through the data system of a GP referral department. RESULTS: GPs indicated that they would have referred 85.4 % of their PC+ patients to outpatient care in the hypothetical case that PC+ was not available. Medical specialists indicated that about one fifth of the patients needed follow-up in outpatient care and 75.9 % of the consultations were of added value to patient care. The patient satisfaction results appear to be in favour of PC+. CONCLUSION: PC+ seems to be a feasible intervention to be implemented on a larger scale, because it has the potential to prevent unnecessary hospital referrals. PC+ will be evaluated on a larger scale regarding the effects on health outcomes, quality of care and costs (Triple Aim principle). PMID- 27506457 TI - Application of Mycobacterium Leprae-specific cellular and serological tests for the differential diagnosis of leprosy from confounding dermatoses. AB - Mycobacterium leprae-specific serological and cell-mediated-immunity/CMI test were evaluated for the differential diagnosis of multibacillary/MB, and paucibacillary/PB leprosy from other dermatoses. Whole-blood assay/WBA/IFNgamma stimulated with LID-1 antigen and ELISA tests for IgG to LID-1 and IgM to PGL-I were performed. WBA/LID-1/IFNgamma production was observed in 72% PB, 11% MB leprosy, 38% dermatoses, 40% healthy endemic controls/EC. The receiver operating curve/ROC for WBA/LID-1 in PB versus other dermatoses showed 72.5% sensitivity, 61.5% specificity and an area-under-the-curve/AUC=0.75; 74% positive predictive value/PPV, 59% negative predictive value/NPV. Anti PGL-I serology was positive in 67% MB, 8% PB leprosy, 6% of other dermatoses; its sensitivity for MB=66%, specificity=93%, AUC=0.89; PPV=91%, NPV=72%. Anti-LID-1 serology was positive in 87% MB, 7% PB leprosy, all other participants were seronegative; 87.5% sensitivity for MB, 100% specificity, AUC=0.97; PPV=100%, NPV=88%. In highly endemic areas anti-LID-1/PGL-I serology and WBA/LID-1-represent useful tools for the differential diagnosis of leprosy from other confounding dermatoses. PMID- 27506456 TI - Assessment of sedentary behaviors and transport-related activities by questionnaire: a validation study. AB - BACKGROUND: Comprehensive assessment of sedentary behavior (SB) and physical activity (PA), including transport-related activities (TRA), is required to design innovative PA promotion strategies. There are few validated instruments that simultaneously assess the different components of human movement according to their context of practice (e.g. work, transport, leisure). We examined test retest reliability and validity of the Sedentary, Transportation and Activity Questionnaire (STAQ), a newly developed questionnaire dedicated to assessing context-specific SB, TRA and PA. METHODS: Ninety six subjects (51 women) kept a contextualized activity-logbook and wore a hip accelerometer (Actigraph GT3X + (TM)) for a 7-day or 14-day period, at the end of which they completed the STAQ. Activity-energy expenditure was measured in a subgroup of 45 subjects using the double labeled water (DLW) method. Test-retest reliability was assessed using intra-class-coefficients (ICC) in a subgroup of 32 subjects who filled the questionnaire twice one month apart. Accelerometry was annotated using the logbook to obtain total and context-specific objective estimates of SB. Spearman correlations, Bland-Altman plots and ICC were used to analyze validity with logbook, accelerometry and DLW data validity criteria. RESULTS: Test-retest reliability was fair for total sitting time (ICC = 0.52), good to excellent for work sitting time (ICC = 0.71), transport-related walking (ICC = 0.61) and car use (ICC = 0.67), and leisure screen-related SB (ICC = 0.64-0.79), but poor for total sitting time during leisure and transport-related contexts. For validity, compared to accelerometry, significant correlations were found for STAQ estimates of total (r = 0.54) and context-specific sitting times with stronger correlations for work sitting time (r = 0.88), and screen times (TV/DVD viewing: r = 0.46; other screens: r = 0.42) than for transport (r = 0.35) or leisure-related sitting times (r = 0.19). Compared to contextualized logbook, STAQ estimates of TRA was higher for car (r = 0.65) than for active transport (r = 0.41). The questionnaire generally overestimated work- and leisure-related SB and sitting times, while it underestimated total and transport-related sitting times. CONCLUSIONS: The STAQ showed acceptable reliability and a good ranking validity for assessment of context-specific SB and TRA. This instrument appears as a useful tool to study SB, TRA and PA in context in adults. PMID- 27506458 TI - ZSM-5 with controllable acidity as an efficient catalyst for a highly adjustable propene/ethene ratio in the 1-butene cracking. AB - A facile strategy was proposed to realize the precise control of zeolitic acidity by selective cracking of a silane with an acid site. Modified ZSM-5 with controllable acidity brought about a highly adjustable propene/ethene (P/E) ratio in the 1-butene cracking. PMID- 27506459 TI - Different lines of evidence used to delimit species in ticks: A study of the South American populations of Amblyomma parvum (Acari: Ixodidae). AB - The goal of this work was to combine different lines of evidence besides that of molecular markers to delimit species in ticks when the molecular data are not totally congruent. Two groups (Argentina, Brazil) of South American populations of Amblyomma parvum were compared to test whether the splitting of these two lineages suggested by genetic analyses is complete. Comparative studies of reproductive compatibility, morphological analyses of fixed characters, and comparison of population distributions in spatially defined ecological niches were performed.The morphological comparisons of both discrete and morphometric characters showed no differences among A. parvum ticks from Argentina and Brazil. The intercrosses and backcrosses showed evidence of pre- and post-zygotic compatibility between the two groups. No significant differences in environmental traits were found which would justify the separation of the records of A. parvum in distinct groups. Although the gene flow between the two groups of populations is limited, the absence of reproductive barriers, the lack of significant morphological differences, and the absence of significant differences in the niche preferences indicate that populations of A. parvum from Argentina and Brazil should be treated as a single species. The speciation conjectures suggested by some analyses of mitochondrial DNA sequences were not supported when different lines of evidences were compared. PMID- 27506460 TI - Role of sonography in the diagnosis and treatment of a ganglion cyst compressing the lateral branch of deep peroneal nerve. AB - Selective compression neuropathy of the lateral branch of the deep peroneal nerve is rare. A 55-year-old woman with ankle instability and mild weakness of extension of the toes was examined with sonography (US), which revealed the presence of a ganglion cyst compressing selectively the lateral branch of the deep peroneal nerve. US-guided aspiration of the cyst resulted in nerve decompression and progressive resolution of symptoms. This case demonstrates the importance of examining the deep peroneal nerve and its branches when performing US in the clinical setting of ankle instability. (c) 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:108-111, 2017. PMID- 27506461 TI - Peer-instructed seminar attendance is associated with improved preparation, deeper learning and higher exam scores: a survey study. AB - BACKGROUND: Active engagement in education improves learning outcomes. To enhance active participation in seminars, a student-centered course design was implemented and evaluated in terms of self-reported preparation, student motivation and exam scores. We hypothesized that small group learning with intensive peer interaction, using buzz-groups followed by plenary discussion, would motivate students to prepare seminar assignments at home and to actively engage in the seminars. Active engagement involved discussion of the preparatory assignments until consensus was reached. METHODS: In total seven seminars were scheduled in a 10-week physiology course of an undergraduate Biomedical Sciences program. After each seminar, students were asked to fill out their perceptions of preparation and quality of the seminar (deepening of knowledge and confidence in answers) on a five-point scale using electronic questionnaires. Student motives were first collected using open questions. In the final questionnaire students were asked to indicate on a five-point scale how each motive was perceived. Students overall explanations why they had learned from seminars were collected via open questions in the final questionnaire. One hundred and twenty-four students of the cohort from November 2012 to February 2013 (82.6 %) voluntarily participated. Students' motives to prepare and attend seminars were analyzed by inspection of descriptive statistics. Linear regression analysis was conducted to relate student preparation to the quality of seminars, seminar attendance to exam scores, and exam scores to the quality of seminars. Answers to open questions were deductively clustered. RESULTS: Studying the material, training for exams and comparing answers with peers motivated students to prepare the seminars. Students were motivated to participate actively because they wanted to keep track of correct answers themselves, to better understand the content and to be able to present their findings in plenary discussions. Perceived preparation of peers was positively associated with the perceived quality of seminars. Also, seminar attendance was positively associated with exam scores. Students' overall explanations suggest that discussing with peers and applying knowledge in pathophysiology cases underlies this association. CONCLUSION: Discussion with well-prepared peers during seminars improves student perceptions of deeper learning and peer-instructed seminar attendance was associated with higher exam scores. PMID- 27506462 TI - Impact of Three-Dimensional Printed Pelvicaliceal System Models on Residents' Understanding of Pelvicaliceal System Anatomy Before Percutaneous Nephrolithotripsy Surgery: A Pilot Study. AB - OBJECTIVE: To investigate the impact of three-dimensional (3D) printed pelvicaliceal system models on residents' understanding of pelvicaliceal system anatomy before percutaneous nephrolithotripsy (PCNL). MATERIALS AND METHODS: Patients with unilateral complex renal stones indicating PCNL were selected. Usable data of patients were obtained from CT-scans in Digital Imaging and Communications in Medicine (DICOM) format. Mimics software version 16.0 (Materialise, Belgium) was used for segmentation and extraction of pelvicaliceal systems (PCSs). All DICOM-formatted files were converted to the stereolithography file format. Finally, fused deposition modeling was used to create plasticine 3D models of PCSs. A questionnaire was designed so that residents could assess the 3D models' effects on their understanding of the anatomy of the pelvicaliceal system before PCNL (Fig. 3). RESULTS: Five patients' anatomically accurate models of the human renal collecting system were effectively generated (Figs. 1 and 2). After presentation of the 3D models, residents were 86% and 88% better at determining the number of anterior and posterior calices, respectively, 60% better at understanding stone location, and 64% better at determining optimal entry calix into the collecting system (Fig. 5). CONCLUSION: Generating kidney models of PCSs using 3D printing technology is feasible, and the models were accepted by residents as aids in surgical planning and understanding of pelvicaliceal system anatomy before PCNL. PMID- 27506463 TI - Drug delivery into the cochlear apex: Improved control to sequentially affect finely spaced regions along the entire length of the cochlear spiral. AB - BACKGROUND: Administering pharmaceuticals to the scala tympani of the inner ear is a common approach to study cochlear physiology and mechanics. We present here a novel method for in vivo drug delivery in a controlled manner to sealed ears. NEW METHOD: Injections of ototoxic solutions were applied from a pipette sealed into a fenestra in the cochlear apex, progressively driving solutions along the length of scala tympani toward the cochlear aqueduct at the base. Drugs can be delivered rapidly or slowly. In this report we focus on slow delivery in which the injection rate is automatically adjusted to account for varying cross sectional area of the scala tympani, therefore driving a solution front at uniform rate. RESULTS: Objective measurements originating from finely spaced, low to high-characteristic cochlear frequency places were sequentially affected. Comparison with existing methods(s): Controlled administration of pharmaceuticals into the cochlear apex overcomes a number of serious limitations of previously established methods such as cochlear perfusions with an injection pipette in the cochlear base: The drug concentration achieved is more precisely controlled, drug concentrations remain in scala tympani and are not rapidly washed out by cerebrospinal fluid flow, and the entire length of the cochlear spiral can be treated quickly or slowly with time. CONCLUSIONS: Controlled administration of solutions into the cochlear apex can be a powerful approach to sequentially effect objective measurements originating from finely spaced cochlear regions and allows, for the first time, the spatial origin of CAPs to be objectively defined. PMID- 27506464 TI - Pseudomonas aeruginosa colonization enhances ventilator-associated pneumonia induced lung injury. AB - BACKGROUND: Pseudomonas aeruginosa (PA) is the single-most common pathogen of ventilator-associated pneumonia (VAP). Large quantities of PA in the trachea of ventilated patients are associated with an increased risk of death. However, the role of PA colonization in PA VAP-induced lung injury remains elusive. This study examined the effect and mechanism of PA colonization in VAP-induced lung injury. METHODS: C57BL/6 wild-type (WT) and c-Jun N-terminal kinase knockout (JNK1(-/-)) mice received mechanical ventilation for 3 h at 2 days after receiving nasal instillation of PA (1 * 10(6) colony forming unit) or normal saline. RESULTS: Intranasal instillation of PA or mechanical ventilation induced the expression of interleukin-6 (IL-6) in the lungs. Phospho-JNK protein expression in the lungs was significantly increased in mice receiving mechanical ventilation after PA instillation as compared with those receiving ventilation alone. Mechanical ventilation after PA instillation significantly increased the expression of tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and macrophage inflammatory protein 2 (MIP-2) proteins; neutrophil sequestration; and TNF-alpha, IL-1beta, and IL-6 levels in the lungs of WT mice, but not in JNK1(-/-) mice. CONCLUSION: PA colonization plays an important role in PA VAP-induced lung injury through the induction of JNK1-mediated inflammation. PA-induced VAP causes lung injury through JNK signaling pathway in the lungs. JNK inhibition in ICU patients with higher percentages of PA colonization may reduce VAP-induced lung injury and mortality. PMID- 27506465 TI - Maturation toward neuronal tissue in a Ewing sarcoma of bone after chemotherapy. AB - BACKGROUND: Ewing sarcoma is the second most common bone tumor, occurring mainly in children and young adults. It shows a typical primitive, small round cell morphology and a characteristic fusion oncogene involving EWSR1 and members of the ETS family in most of the cases. Neuronal maturation after chemotherapy is a rare phenomenon and we herein describe such an exceptional case. CASE PRESENTATION: An 8-year old boy was diagnosed with a Ewing sarcoma in the left femur. On biopsy the morphology was typical and there was an EWSR1-FLI1 gene fusion. He underwent neo-adjuvant chemotherapy and resection of the tumor. On microscopic evaluation, part of the tumor showed ganglioneuroblastoma-like differentiation with expression of neuronal markers. The continued presence of EWSR1 rearrangement in both the blue round cell component and the ganglioneuroblastoma-like component was shown by FISH analysis. CONCLUSIONS: In conclusion, this case describes the possibility of a Ewing sarcoma to differentiate into a ganglioneuroblastoma-like lesion after neo-adjuvant chemotherapy treatment; the prognostic value of this phenomenon remains questionable. PMID- 27506467 TI - Realizing controllable graphene nucleation by regulating the competition of hydrogen and oxygen during chemical vapor deposition heating. AB - Oxygen can passivate Cu surface active sites when graphene nucleates. Thus, the nucleation density is decreased. The CuO/Cu substrate was chosen for graphene domain synthesis in our study. The results indicate that the CuO/Cu substrate is beneficial for large-scale, single-crystal graphene domain synthesis. Graphene grown on the CuO/Cu substrate exhibits fewer nucleation sites than on Cu foils, suggesting that graphene follows an oxygen-dominating growth. Hydrogen treatment via a heating process could weaken the surface oxygen's role in limiting graphene nucleation under the competition of hydrogen and oxygen and could transfer the synthesis of graphene into a hydrogen-dominating growth. However, the competition only exists during the chemical vapor deposition heating process. For non hydrogen heated samples, oxygen-dominating growth is experienced even though the samples are annealed in hydrogen for a long time after the heating process. With the temperature increases, the role of hydrogen gradually decreases. The balance of hydrogen and oxygen is adjusted by introducing hydrogen gas at a different heating temperatures. The oxygen concentration on the substrate surface is believed to determine the reactions mechanisms based on the secondary ion mass spectrometry test results. This study provides a new method for the controllable synthesis of graphene nucleation during a heating process. PMID- 27506466 TI - Menopause-induced uterine epithelium atrophy results from arachidonic acid/prostaglandin E2 axis inhibition-mediated autophagic cell death. AB - Women experience menopause later in life. Menopause is characterized by dramatically decreased circulating estrogen level secondary to loss of ovarian function and atrophic state of genital organs. However, the molecular mechanisms for this process are not fully understood. In this study, we aimed to investigate the potential molecular mechanisms that underlie menopause-induced uterine endometrial atrophy. Our data showed that autophagy was activated in the uterine epithelial cells of both ovariectomized rats and peri-menopausal females. Endoplasmic reticulum (ER) stress occurred even prior to autophagy induction. Integrated bioinformatics analysis revealed that ER stress induced downstream decreased release of arachidonic acid (AA) and downregulation of AA/prostaglandin E2 (PGE2) axis, which led to Akt/mTOR signaling pathway inactivation. Consequently, autophagosomes were recruited and LC3-dependent autophagy was induced in uterine epithelial cells. Treatment with exogenous E2, PGE2, salubrinal or RNAi-mediated silencing of key autophagy genes could effectively counteract estrogen depletion-induced autophagy. Collectively, autophagy is a critical regulator of the uterine epithelium that accounts for endometrial atrophy after menopause. PMID- 27506468 TI - Needs among persons with human immunodeficiency virus and intellectual and developmental disabilities in community mental health care: a cross-sectional study. AB - BACKGROUND: The experience of having human immunodeficiency virus (HIV) is often associated with co-occurring mental health issues. Community mental health services are an important source of support for persons with HIV living in the community. Persons with intellectual disability (ID) are vulnerable to HIV and may have unique support needs beyond those without ID receiving community care. This study compared support needs of men with HIV in community mental health programmes, with and without ID. METHODS: The sample was composed of 138 HIV positive men with and without ID receiving mental health case management from one community organisation in Ontario, Canada, on 31 March 2013. Staff-rated needs across 16 domains grouped into four clusters were measured using the Camberwell Assessment of Need: Basic needs (accommodation, food, public transportation, money and benefits); self-care/functional needs (looking after the home, self care and daytime activities); health/safety needs (physical health, psychological distress, psychotic symptoms, safety to self and safety to others); and social needs (company, intimate relationships and sexual expression). Adjusted logistic regression models examined the association between ID and each need domain. RESULTS: One-quarter of the sample (n = 34/138, 24.6%) had co-occurring ID. Those with ID were more likely to have needs in the basic cluster [odds ratios: food 4.05 (1.14, 14.44), P:0.031; benefits 2.58 (1.05, 6.32), P:0.038)] and self care/functional cluster [looking after the home (2.75 (1.17, 6.49), P:0.021); self-care (2.72 (1.18, 6.27), P:0.019)], but were less likely to have need for sexual expression: 0.35 (0.14,0.90), P:0.030) (social cluster). There were no differences in the domains in the health/safety cluster. CONCLUSION: Despite elevated cognitive needs in the basic and self-care/functional clusters for the ID group, limited other differences suggest that with moderate additional targeting, community mental health programmes for persons with HIV may be appropriate for men with ID. PMID- 27506469 TI - IPMiner: hidden ncRNA-protein interaction sequential pattern mining with stacked autoencoder for accurate computational prediction. AB - BACKGROUND: Non-coding RNAs (ncRNAs) play crucial roles in many biological processes, such as post-transcription of gene regulation. ncRNAs mainly function through interaction with RNA binding proteins (RBPs). To understand the function of a ncRNA, a fundamental step is to identify which protein is involved into its interaction. Therefore it is promising to computationally predict RBPs, where the major challenge is that the interaction pattern or motif is difficult to be found. RESULTS: In this study, we propose a computational method IPMiner (Interaction Pattern Miner) to predict ncRNA-protein interactions from sequences, which makes use of deep learning and further improves its performance using stacked ensembling. One of the IPMiner's typical merits is that it is able to mine the hidden sequential interaction patterns from sequence composition features of protein and RNA sequences using stacked autoencoder, and then the learned hidden features are fed into random forest models. Finally, stacked ensembling is used to integrate different predictors to further improve the prediction performance. The experimental results indicate that IPMiner achieves superior performance on the tested lncRNA-protein interaction dataset with an accuracy of 0.891, sensitivity of 0.939, specificity of 0.831, precision of 0.945 and Matthews correlation coefficient of 0.784, respectively. We further comprehensively investigate IPMiner on other RNA-protein interaction datasets, which yields better performance than the state-of-the-art methods, and the performance has an increase of over 20 % on some tested benchmarked datasets. In addition, we further apply IPMiner for large-scale prediction of ncRNA-protein network, that achieves promising prediction performance. CONCLUSION: By integrating deep neural network and stacked ensembling, from simple sequence composition features, IPMiner can automatically learn high-level abstraction features, which had strong discriminant ability for RNA-protein detection. IPMiner achieved high performance on our constructed lncRNA-protein benchmark dataset and other RNA-protein datasets. IPMiner tool is available at http://www.csbio.sjtu.edu.cn/bioinf/IPMiner . PMID- 27506470 TI - Colonization of toxigenic Clostridium difficile among ICU patients: a prospective study. AB - BACKGROUND: A prospective study was performed to investigate the prevalence of colonization among ICU patients and to examine whether asymptomatic carriers were the source of subsequent C. difficile infection (CDI) and acquisition of toxigenic C. difficile. METHODS: Rectal swabs were collected from adult patients on admission to and at discharge from a 50-bed medical ICU of a major referral hospital in western China, from August to November 2014. Stools were collected from patients who developed ICU-onset diarrhea. Both swabs and stools were screened for tcdB (toxin B gene) by PCR. Samples positive to tcdB were cultured for C. difficile and isolates recovered were screened for tcdB and the binary toxin genes by PCR. Strain typing was performed using multilocus sequence typing and isolates belonging to the same sequence type (ST) were further typed using multiple-locus variable number tandem repeat analysis (MLVA). RESULTS: During the 4-month period, rectal swabs were collected from 360 (90.9 %) out of 396 patients who were admitted to the ICU. Among the 360 patients, 314 had stayed in the ICU more than 3 days, of which 213 (73.6 %) had a rectal swab collected within the 3 days prior to discharge from ICU. The prevalence of toxigenic C. difficile colonization was 1.7 % (6 cases) and 4.3 % (10 cases) on admission and discharge, respectively. Only four (1.1 %) out of 360 patients had CDI, corresponding to 10.7 cases per 10,000 ICU days. None of the four cases had toxigenic C. difficile either on admission or at discharge. Toxigenic C. difficile isolates were recovered from all swabs and stool samples positive for tcdB by PCR and belonged to 7 STs (ST2, 3, 6, 37, 54, 103 and 129). None of the isolates belonging to the same ST had identical MLVA patterns. Binary toxin genes were detected in one ST103 isolate that caused colonization. CONCLUSION: The prevalence of colonization with toxigenic C. difficile among patients on admission to ICU was low in our setting. ICU-acquired toxigenic C. difficile were not linked to those detected on admission. Active screening for toxigenic C. difficile may not be a resource-efficient measure in settings with a low prevalence of colonization. PMID- 27506471 TI - Academic nursing administrators' workplace satisfaction and intent to stay. AB - BACKGROUND: In nursing education, the academic administrator is critical given the multitude of challenges associated with program delivery (e.g., shortages of faculty, strict and changing regulations for program accreditation, and the sheer demand for more nurses). Unfortunately, with the focus on recruiting and retaining new novice faculty to teach students, academic nursing administrators have been overlooked in recent studies. PURPOSE: As such, this study aims to explore the workplace satisfaction and intent to stay of academic nursing administrators by considering their relation to a variety of demographic and work related variables. METHODS: A secondary data source was used from the Collaborative on Academic Careers in Higher Education (COACHE). One-way Analysis of Variance (ANOVA) with post hoc Fisher's Least Significant Difference tests and t-tests were used in the analysis. DISCUSSION/CONCLUSION: Results indicate that several modifiable work factors positively relate to both job satisfaction and intent to stay. PMID- 27506472 TI - Analysis Method for Quantifying the Morphology of Nanotube Networks. AB - While atomic force microscopy (AFM) is a powerful technique for imaging assemblies and networks of nanoscale materials, approaches for quantitative assessment of the morphology of these materials are lacking. Here we present a volume-based approach for analyzing AFM images of assemblies of nano-objects that enables the extraction of relevant parameters describing their morphology. Random networks of single-walled carbon nanotubes (SWCNTs) deposited via solution-phase processing are used as an example to develop the method and demonstrate its utility. AFM imaging shows that the morphology of these networks depends on details of processing and is influenced by choice of substrate, substrate cleaning method, and postdeposition rinsing protocols. A method is outlined to analyze these images and extract relevant parameters describing the network morphology such as the density of SWCNTs and the degree to which tubes are bundled. Because this volume-based approach depends on accurate measurements of the height of individual tubes and their networks, a procedure for obtaining reliable height measurements is also discussed. Obtaining quantitative parameters that describe the network morphology allows going beyond qualitative descriptions of images and will facilitate optimizing network preparation methods based on measurable criteria and correlating performance with morphology. PMID- 27506473 TI - In vitro selection and evolution. PMID- 27506474 TI - Fatty acid alterations in the detritivorous Prochilodus lineatus promoted by opportunistic feeding on sewage discharges in the Rio de la Plata estuary. AB - Muscle fatty acid profiles and PCB contents of the detritivorous species Prochilodus lineatus and its diet (stomach contents, settling particles and sediments) were analysed from reference and polluted areas of the Parana-Rio de la Plata basin, to evaluate the alterations produced by opportunistic feeding on sewage discharges. Overall muscle fatty acid composition was dominated by saturated and monounsaturated 16 and 18 carbon (18 C-FA) components with reduced long-chain polyunsaturated fatty acids (LC-PUFA). Compared to sediments, settling particles and stomach contents were enriched in lipids and had a similar fatty acid composition. Opportunistic feeding on sewage detritus at Buenos Aires resulted in enhanced PCB and triglyceride accumulation, with higher proportions of 18 C-FA and lower proportions of 16:1 and LC-PUFA compared to fish from northern pristine reaches of the basin. Mid-Parana showed intermediate values reflecting mixing of the North stock with migrating Buenos Aires P. lineatus identified by their lipid and contaminant profile. According to multivariate analyses, this geographical variation of fatty acid composition was strongly influenced by PCB concentration. Prochilodus lineatus assimilates the energy subsidy of sewage inputs through enhanced lipogenesis with dominant 18 C-FA and significant amounts of valuable LC-PUFA. This lipid alteration facilitates the bioaccumulation of PCBs which in turn may reinforce the adipogenic effect of sewage feeding. PMID- 27506475 TI - GSH Induced Controlled Release of Levofloxacin from a Purpose-Built Prodrug: Luminescence Response for Probing the Drug Release in Escherichia coli and Staphylococcus aureus. AB - Fluoroquinolones are third-generation broad spectrum bactericidal antibiotics and work against both Gram-positive and Gram-negative bacteria. Levofloxacin (L), a fluoroquinolone, is widely used in anti-infective chemotherapy and treatment of urinary tract infection and pneumonia. The main pathogen for urinary tract infections is Escherichia coli, and Streptococcus pneumoniae is responsible for pneumonia, predominantly a lower respiratory tract infection. Poor permeability of L leads to the use of higher dose of this drug and excess drug in the outer cellular fluid leads to central nervous system (CNS) abnormality. One way to counter this is to improve the lipophilicity of the drug molecule, and accordingly, we have synthesized two new Levofloxacin derivatives, which participated in the spatiotemporal release of drug via disulfide bond cleavage induced by glutathione (GSH). Recent studies with Streptococcus mutants suggest that it is localized in epithelial lining fluid (ELF) of the normal lower respiratory tract and the effective [GSH] in ELF is ~430 MUM. E. coli typically cause urinary tract infections and the concentration of GSH in porcine bladder epithelium is reported as 0.6 mM for a healthy human. Thus, for the present study we have chosen two important bacteria (Gram + ve and Gram - ve), which are operational in regions having high extracellular GSH concentration. Interestingly, this supports our design of new lipophilic Levofloxacin based prodrugs, which released effective drug on reaction with GSH. Higher lipophilicity favored improved uptake of the prodrugs. Site specific release of the drug (L) could be achieved following a glutathione mediated biochemical transformation process through cleavage of a disulfide bond of these purpose built prodrugs. Further, appropriate design helped us to demonstrate that it is possible also to control the kinetics of the drug release from respective prodrugs. Associated luminescence enhancement helps in probing the release of the drug from the prodrug in bacteria and helps in elucidating the mechanistic pathway of the transformation. Such an example is scarce in the contemporary literature. PMID- 27506476 TI - Casein glycomacropeptide-derived peptide IPPKKNQDKTE ameliorates high glucose induced insulin resistance in HepG2 cells via activation of AMPK signaling. AB - SCOPE: Recently, casein glycomacropeptide (GMP)-derived peptide was found to possess potent antioxidant and anti-inflammatory activities. In this study, the improvement effects and underlying molecular mechanisms of GMP-derived peptide on hepatic insulin resistance were investigated. METHODS AND RESULTS: The peptide IPPKKNQDKTE was identified from GMP papain hydrolysates by LC-ESI-MS/MS. Effects of IPPKKNQDKTE on glucose metabolism and expression levels of the hepatic insulin signaling proteins in high glucose-induced insulin-resistant HepG2 cells were evaluated. Results showed that IPPKKNQDKTE dose-dependently increased glucose uptake and intracellular glycogen in insulin-resistant HepG2 cells without affecting cell viability. IPPKKNQDKTE increased the phosphorylation of Akt and GSK3beta and decreased the expression levels of p-GS, G6Pase and PEPCK. These IPPKKNQDKTE-mediated protection effects were reversed by PI3K/Akt inhibitor LY294002, showing the mediatory role of PI3K/Akt. Moreover, treatment with IPPKKNQDKTE reduced IRS-1 Ser307 phosphorylation and increased phosphorylation of AMPK. Knockdown AMPK using siRNA in HepG2 cells increased Ser307 phosphorylation of IRS-1 and reduced Akt phosphorylation in IPPKKNQDKTE-treated insulin-resistant cells. CONCLUSION: IPPKKNQDKTE prevents high glucose-induced insulin resistance in HepG2 cells by modulating the IRS-1/PI3K/Akt signaling pathway through AMPK activation, indicating that IPPKKNQDKTE plays a potential role in the prevention and treatment of hepatic insulin resistance and type 2 diabetes. PMID- 27506478 TI - Prevalence of potentially inappropriate prescribing among older adults: A comparison of the Beers 2012 and Screening Tool of Older Person's Prescriptions criteria version 2. AB - AIM: To date, there is no study comparing the Beers 2012 and Screening Tool of Older Person's Prescriptions (STOPP) version 2 criteria, nor reporting a comparison of the prevalence of potentially inappropriate Prescribing (PIM) with STOPP version 2. We aimed to evaluate the prescriptions of patients admitted to a geriatric outpatient clinic with these tools, and to document the factors related to PIM use. METHODS: Older patients (aged >=65 years) admitted to the outpatient clinic of a university hospital were retrospectively evaluated for PIM with Beers 2012 and STOPP version 2 criteria. Age; sex; chronic disease and number of drugs; and functional, depression and nutritional statuses were studied with regression analysis as possible factors related to PIM. RESULTS: The study included 667 participants (63.1% women, mean age 77.6 +/- 6.3 years). The mean number of drugs was 6.1 +/- 3.4. PIM prevalence detected by STOPP version 2 was higher than that of the Beers 2012 criteria (39.1% vs 33.3%, respectively; P < 0.001; Z = -3.5) with moderate agreement in between (kappa = 0.44). Antipsychotics, over-the counter vitamin/supplements, aspirin, selective-serotonin-reuptake-inhibitors and anticholinergics were the leading drug classes for PIM. The extent of polypharmacy (P < 0.001, OR 1.29, 95% CI 1.20-1.38) was the most important variable related to PIM, along with the multiple comorbidities (P = 0.005, OR 1.16, 95% CI 1.05-1.30). Higher level of functionality was inversely associated with PIM (P = 0.009, OR 0.90, 95% CI 0.83-0.97). CONCLUSIONS: Inappropriate prescription prevalence of ~40% by STOPP version 2 was similar to the global worldwide prevalence - yet at the upper end. STOPP version 2 was more successful than Beers 2012 to detect PIM. Patients with multiple drug use, multiple comorbidities and more dependency were more likely to have PIM requiring special attention during prescription. Geriatr Gerontol Int 2017; 17: 1245-1251. PMID- 27506479 TI - Birthweight percentiles for twin birth neonates by gestational age in China. AB - Localized birthweight references for gestational ages serve as an essential tool in accurate evaluation of atypical birth outcomes. Such references for twin births are currently not available in China. The aim of this study was to construct up-to-data sex specific birth weight references by gestational ages for twin births in China. We conducted a population-based analysis on the data of 22,507 eligible living twin infants with births dated between 8/01/2006 and 8/31/2015 from all 95 hospitals within the Wuhan area. Gestational ages in complete weeks were determined using a combination of last-menstrual-period based (LMP) estimation and ultrasound examination. Smoothed percentile curves were created by the Lambda Mu Sigma (LMS) method. Reference of the 3(rd), 10(th), 25(th), 50(th), 75(th), 90(th), 97(th) percentiles birth weight by sex and gestational age were made using 11,861 male and 10,646 female twin newborns with gestational age 26-42 weeks. Separate birthweight percentiles curves for male and female twins were constructed. In summary, our study firstly presents percentile curves of birthweight by gestational age for Chinese twin neonates. Further research is required for the validation and implementation of twin birthweight curves into clinical practice. PMID- 27506481 TI - Sufficient dimension reduction for censored predictors. AB - Motivated by a study conducted to evaluate the associations of 51 inflammatory markers and lung cancer risk, we propose several approaches of varying computational complexity for analyzing multiple correlated markers that are also censored due to lower and/or upper limits of detection, using likelihood-based sufficient dimension reduction (SDR) methods. We extend the theory and the likelihood-based SDR framework in two ways: (i) we accommodate censored predictors directly in the likelihood, and (ii) we incorporate variable selection. We find linear combinations that contain all the information that the correlated markers have on an outcome variable (i.e., are sufficient for modeling and prediction of the outcome) while accounting for censoring of the markers. These methods yield efficient estimators and can be applied to any type of outcome, including continuous and categorical. We illustrate and compare all methods using data from the motivating study and in simulations. We find that explicitly accounting for the censoring in the likelihood of the SDR methods can lead to appreciable gains in efficiency and prediction accuracy, and also outperformed multiple imputations combined with standard SDR. PMID- 27506482 TI - Enemas, suppositories and rectal stimulation are not effective in accelerating enteral feeding or meconium evacuation in low-birthweight infants: a systematic review. AB - : Early full enteral feeding in preterm infants decreases morbidity and mortality. Our systematic review covered the effectiveness of rectal stimulation, suppositories and enemas on stooling patterns and feeding tolerance in low birthweight infants born at up to 32 weeks. It comprised seven studies published between 2007 and 2014 and covered 495 infants. CONCLUSION: Suppositories were ineffective in shortening the time to reach full enteral feeding, and the evidence on enemas was contradictory. Enemas and rectal stimulation did not shorten the time until complete meconium evacuation was reached. Further research into safe, effective interventions to accelerate meconium excretion is needed. PMID- 27506483 TI - Alterations of the Lamina Cribrosa Are Associated with Peripapillary Retinoschisis in Glaucoma and Pachychoroid Spectrum Disease. AB - PURPOSE: To describe the findings of enhanced depth imaging (EDI) optical coherence tomography (OCT) of the lamina cribrosa (LC) in glaucoma and pachychoroid spectrum diseases associated with peripapillary retinoschisis. DESIGN: Retrospective, observational case series. PARTICIPANTS: A total of 16 patients from 1 institution. METHODS: Detailed medical case histories, optic disc and retinal imaging with EDI using the Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany), and clinical course were reviewed for patients with peripapillary retinoschisis without a known predisposing condition. MAIN OUTCOME MEASURES: Clinical features and findings of the EDI OCT. RESULTS: Among the 16 eyes with peripapillary retinoschisis that had abnormal findings on EDI of the LC, 8 had glaucoma and 8 had pachychoroid spectrum diseases, including chronic central serous chorioretinopathy (CSC) (6 eyes), small pigment epithelium detachment (1 eye), and polypoidal choroidal vasculopathy (PCV) (1 eye). The abnormal LC findings were central or peripheral focal LC defects in eyes with glaucoma and LC disinsertions or peripheral focal LC defects in eyes with pachychoroid spectrum diseases. Central LC defects were related to inner layer retinoschisis, whereas LC disinsertions and peripheral LC defects were related to outer layer retinoschisis. The peripapillary retinoschisis did not show a topographic association with the underlying chronic CSC- or PCV-associated lesions. In 6 treated eyes with pachychoroid, peripapillary retinoschisis resolved along with subretinal fluid after anti-vascular endothelial growth factor injection in 4 eyes, whereas retinoschisis persisted after the resolution of subretinal fluid in 2 eyes. CONCLUSIONS: Enhanced depth imaging OCT of the LC demonstrated alterations associated with peripapillary retinoschisis, pachychoroid spectrum diseases, and glaucoma. PMID- 27506484 TI - Chronic Vascular Arrest as a Predictor of Bevacizumab Treatment Failure in Retinopathy of Prematurity. AB - PURPOSE: To describe a pattern of retinopathy of prematurity (ROP) disease regression and chronic vascular arrest after intravitreal bevacizumab treatment that is not observed after peripheral laser ablation. DESIGN: Single-institution retrospective cohort study. PARTICIPANTS: Consecutive sample of 58 eyes in 30 patients treated for type 1 ROP. METHODS: Initial treatment with either a single intravitreal injection of bevacizumab in off-label use (n = 33 eyes) or peripheral laser ablation (n = 25 eyes) as part of standard clinical care. There was bias in recommending off-label bevacizumab for smaller infants with type 1 ROP. MAIN OUTCOME AND MEASURES: Reactivation or persistence of ROP, as determined by clinical examination, fundus photography, and fluorescein angiography. RESULTS: All eyes treated initially with bevacizumab demonstrated irregular progression of the leading vascular edge in a stereotyped pattern, suggestive of scalloped regression. Recurrence, based on angiographic demonstration of leakage, or chronic vascular arrest, confirmed based on angiographic demonstration of peripheral ischemia, was noted in 30 eyes (91%) in the bevacizumab group, at a median interval of 14.9 weeks after injection (corrected gestational age, 49.3 weeks). Univariate logistic regression indicated that the need for rescue treatment was associated with decreased birth weight (odds ratio [OR], -0.007; P = 0.04) and age of initial treatment (OR, -0.35; P = 0.05), but not gender, race, or gestational age. Multivariate logistic regression indicated that only decreased birth weight (OR, -0.018; P = 0.04) was associated with need for rescue treatment. CONCLUSIONS: Treating ROP with intravitreal bevacizumab results in a characteristic scalloped regression pattern that is highly associated with treatment using biologic anti-vascular endothelial growth factor agents. The presence of this pattern in conjunction with chronic vascular arrest and peripheral retinal ischemia persisting beyond standard screening timelines has significant implications for the management of ROP. Fluorescein angiography is important in assessing vascular maturation in these infants. PMID- 27506485 TI - A Randomized Trial Evaluating Short-term Effectiveness of Overminus Lenses in Children 3 to 6 Years of Age with Intermittent Exotropia. AB - PURPOSE: To evaluate the short-term effectiveness of overminus spectacles in improving control of childhood intermittent exotropia (IXT). DESIGN: Randomized, clinical trial. PARTICIPANTS: A total of 58 children aged 3 to <7 years with IXT. Eligibility criteria included a distance control score of 2 or worse (mean of 3 measures during a single examination) on a scale of 0 (exophoria) to 5 (constant exotropia) and spherical equivalent refractive error between -6.00 diopters (D) and +1.00 D. METHODS: Children were randomly assigned to overminus spectacles ( 2.50 D over cycloplegic refraction) or observation (non-overminus spectacles if needed or no spectacles) for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome was distance control score for each child (mean of 3 measures during a single examination) assessed by a masked examiner at 8 weeks. Outcome testing was conducted with children wearing their study spectacles or plano spectacles for the children in the observation group who did not need spectacles. The primary analysis compared mean 8-week distance control score between treatment groups using an analysis of covariance model that adjusted for baseline distance control, baseline near control, prestudy spectacle wear, and prior IXT treatment. Treatment side effects were evaluated using questionnaires completed by parents. RESULTS: At 8 weeks, mean distance control was better in the 27 children treated with overminus spectacles than in the 31 children who were observed without treatment (2.0 vs. 2.8 points, adjusted difference = -0.75 points favoring the overminus group; 2-sided 95% confidence interval, -1.42 to -0.07 points). Side effects of headaches, eyestrain, avoidance of near activities, and blur appeared similar between treatment groups. CONCLUSIONS: In a pilot randomized clinical trial, overminus spectacles improved distance control at 8 weeks in children aged 3 to <7 years with IXT. A larger and longer randomized trial is warranted to assess the effectiveness of overminus spectacles in treating IXT, particularly the effect on control after overminus treatment has been discontinued. PMID- 27506486 TI - Two-Year COMPASS Trial Results: Supraciliary Microstenting with Phacoemulsification in Patients with Open-Angle Glaucoma and Cataracts. AB - PURPOSE: We evaluated 2-year safety and efficacy of supraciliary microstenting (CyPass Micro-Stent; Transcend Medical, Inc., Menlo Park, CA) for treating mild to-moderate primary open-angle glaucoma (POAG) in patients undergoing cataract surgery. DESIGN: Multicenter (24 US sites), interventional randomized clinical trial (RCT) (ClinicalTrials.gov identifier, NCT01085357). PARTICIPANTS: Subjects were enrolled beginning July 2011, with study completion in March 2015. Subjects had POAG with mean diurnal unmedicated intraocular pressure (IOP) 21-33 mmHg and were undergoing phacoemulsification cataract surgery. METHODS: After completing cataract surgery, subjects were intraoperatively randomized to phacoemulsification only (control) or supraciliary microstenting with phacoemulsification (microstent) groups (1:3 ratio). Microstent implantation via an ab interno approach to the supraciliary space allowed concomitant cataract and glaucoma surgery. MAIN OUTCOME MEASURES: Outcome measures included percentage of subjects achieving >=20% unmedicated diurnal IOP lowering versus baseline, mean IOP change and glaucoma medication use, and ocular adverse event (AE) incidence through 24 months. RESULTS: Of 505 subjects, 131 were randomized to the control group and 374 were randomized to the microstent group. Baseline mean IOPs in the control and microstent groups were similar: 24.5+/-3.0 and 24.4+/-2.8 mmHg, respectively (P > 0.05); mean medications were 1.3+/-1.0 and 1.4+/-0.9, respectively (P > 0.05). There was early and sustained IOP reduction, with 60% of controls versus 77% of microstent subjects achieving >=20% unmedicated IOP lowering versus baseline at 24 months (P = 0.001; per-protocol analysis). Mean IOP reduction was ?7.4 mmHg for the microstent group versus ?5.4 mmHg in controls (P < 0.001), with 85% of microstent subjects not requiring IOP medications at 24 months. Mean 24-month medication use was 67% lower in microstent subjects (P < 0.001); 59% of control versus 85% of microstent subjects were medication free. Mean medication use in controls decreased from 1.3+/-1.0 drugs at baseline to 0.7+/-0.9 and 0.6+/-0.8 drugs at 12 and 24 months, respectively, and in the microstent group from 1.4+/-0.9 to 0.2+/-0.6 drugs at both 12 and 24 months (P < 0.001 for reductions in both groups at both follow-ups vs. baseline). No vision threatening microstent-related AEs occurred. Visual acuity was high in both groups through 24 months; >98% of all subjects achieved 20/40 best-corrected visual acuity or better. CONCLUSIONS: This RCT demonstrated safe and sustained 2 year reduction in IOP and glaucoma medication use after microinterventional surgical treatment for mild-to-moderate POAG. PMID- 27506487 TI - Risk Alleles Associated with Neovascularization in a Pachychoroid Phenotype. PMID- 27506488 TI - Clinical and Genetic Features of Choroideremia in Childhood. AB - PURPOSE: To review the functional and anatomic characteristics of choroideremia in the pediatric population, aiming to describe the earliest features of the disease and to identify biomarkers useful for monitoring disease progression. DESIGN: Retrospective case series. PARTICIPANTS: Children diagnosed with choroideremia at a single institution. METHODS: Patients were identified using an electronic patient record system. Case notes and retinal imaging (color fundus photography [CFP], spectral-domain [SD] optical coherence tomography [OCT], and fundus autofluorescence [FAF]) then were reviewed. The results of genetic testing also were recorded. MAIN OUTCOME MEASURES: Presenting symptoms, visual acuity, fundus changes (CFP, SD OCT, FAF), and CHM sequencing results. RESULTS: Twenty nine patients were identified with a mean age at referral of 9 years (range, 3-16 years). CHM mutations were identified in 15 of 19 patients tested. Nyctalopia was the predominant symptom (66%). Five of 29 patients were asymptomatic at presentation. At the final follow-up visit (mean age, 16 years; range, 7-26 years), most maintained excellent visual acuity (mean, 0.98+/-0.13 decimalized Snellen acuity). The first sign of retinopathy was widespread pigment clumping at the level of the retinal pigment epithelium (RPE). This later evolved to chorioretinal atrophy, most marked in the mid-peripheral retina. Peripapillary atrophy also was an early feature and was progressive in nature. Three different zones of FAF change were visible. Persistence of the inner retinal layers, detected by SD OCT, was visible at presentation in 15 of 27 patients. Subfoveal choroidal thickness decreased with age, whereas central retinal thickness increased over a similar interval. Four patients in whom visual acuity decreased over the follow-up period recorded a reduction in central retinal thickness. CONCLUSIONS: Progressive structural changes occur at a time when central visual function is maintained. Pigmentary changes at the level of the RPE occur early in the disease course. Peripapillary chorioretinal atrophy, central retinal thickness, and subfoveal choroidal thickness are likely to be valuable in monitoring disease progression and should be considered as potential biomarkers in future therapeutic trials. PMID- 27506489 TI - Phase II Study of the EGFR-TKI Rechallenge With Afatinib in Patients With Advanced NSCLC Harboring Sensitive EGFR Mutation Without T790M: Okayama Lung Cancer Study Group Trial OLCSG 1403. AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line therapy for patients with EGFR-mutated non-small-cell lung cancer (NSCLC) have shown a significantly better objective response rate and progression free survival than platinum doublet therapy. However, acquired resistance often occurs within 12 months. One of the potential strategies for treating acquired resistance in NSCLC is the readministration of EGFR-TKIs, a strategy that has mainly been evaluated using gefitinib or erlotinib. The aim of the present study is to investigate the efficacy and safety of EGFR-TKI readministration with afatinib in patients with advanced NSCLC harboring activating EGFR mutations without T790M. The primary endpoint is progression-free survival. The secondary endpoints include the objective response rate, disease control rate, overall survival, toxicity, and quality of life. A total of 12 patients will be enrolled in this trial. PMID- 25754364 TI - Photoacoustic imaging platforms for multimodal imaging. AB - Photoacoustic (PA) imaging is a hybrid biomedical imaging method that exploits both acoustical and optical properties and can provide both functional and structural information. Therefore, PA imaging can complement other imaging methods, such as ultrasound imaging, fluorescence imaging, optical coherence tomography, and multi-photon microscopy. This article reviews techniques that integrate PA with the above imaging methods and describes their applications. PMID- 27506491 TI - Understanding the Correlates of Face-to-Face and Cyberbullying Victimization Among U.S. Adolescents: A Social-Ecological Analysis. AB - Using a national sample of 7,533 U.S. adolescents in grades 6-10, this study compares the social-ecological correlates of face-to-face and cyberbullying victimization. Results indicate that younger age, male sex, hours spent on social media, family socioeconomic status (SES; individual context), parental monitoring (family context), positive feelings about school, and perceived peer support in school (school context) were negatively associated with both forms of victimization. European American race, Hispanic/Latino race (individual), and family satisfaction (family context) were all significantly associated with less face-to-face victimization only, and school pressure (school context) was significantly associated with more face-to-face bullying. Peer groups accepted by parents (family context) were related to less cyberbullying victimization, and calling/texting friends were related to more cyberbullying victimization. Research and practice implications are discussed. PMID- 27506493 TI - Seasonal immunohistochemical reactivity of S-100 and alpha-smooth muscle actin proteins in the epididymis of dromedary camel, Camelus dromedarius. AB - The S-100 and alpha smooth muscle actin (alpha-SMA) proteins have been localised in epididymal tissue of several mammalian species, but there have been no data for a seasonal work in camel. The aim of this study was to investigate the immunoreactivities of S-100 and alpha-SMA proteins in the epididymis of dromedary camel during breeding and nonbreeding seasons. The immunopositive signals for both proteins were observed in different regions of camel epididymis. S-100 immunopositive signals were noted in both the epididymal epithelium and the intertubular connective tissue, while alpha-SMA signals were confined to the intertubular connective tissue, especially in the peritubular smooth muscle coat and the blood vessels. This study showed an increase in the intensity of S-100 and alpha-SMA immunoreactions during the breeding season in different regions of camel epididymis than that seen in the nonbreeding season. In conclusion, epididymis might be considered as a source of S-100 and alpha-SMA proteins in the camel and the secretion of these proteins showed distinct seasonal variations. Further, S-100 and alpha-SMA may affect the structural and physiological states of the epididymal duct. PMID- 27506492 TI - KV 7/M channels as targets for lipopolysaccharide-induced inflammatory neuronal hyperexcitability. AB - KEY POINTS: Neuroinflammation associated with CNS insults leads to neuronal hyperexcitability, which may culminate in epileptiform discharges. Application of the endotoxin lipopolysaccharide (LPS) to brain tissue initiates a neuroinflammatory cascade, providing an experimental model to study the mechanisms of neuroinflammatory neuronal hyperexcitability. Here we show that LPS application to hippocampal slices markedly enhances the excitability of CA1 pyramidal cells by inhibiting a specific potassium current, the M-current, generated by KV 7/M channels, which controls the excitability of almost every neuron in the CNS. The LPS-induced M-current inhibition is triggered by sequential activation of microglia, astrocytes and pyramidal cells, mediated by metabotropic purinergic and glutamatergic transmission, leading to blockade of KV 7/M channels by calcium released from intracellular stores. The identification of the downstream molecular target of neuroinflammation, namely the KV 7/M channel, potentially has far reaching implications for the understanding and treatment of many acute and chronic brain disorders. ABSTRACT: Acute brain insults and many chronic brain diseases manifest an innate inflammatory response. The hallmark of this response is glia activation, which promotes repair of damaged tissue, but also induces structural and functional changes that may lead to an increase in neuronal excitability. We have investigated the mechanisms involved in the modulation of neuronal activity by acute inflammation. Initiating inflammatory responses in hippocampal tissue rapidly led to neuronal depolarization and repetitive firing even in the absence of active synaptic transmission. This action was mediated by a complex metabotropic purinergic and glutamatergic glia to-neuron signalling cascade, leading to the blockade of neuronal KV 7/M channels by Ca2+ released from internal stores. These channels generate the low voltage activating, non-inactivating M-type K+ current (M-current) that controls intrinsic neuronal excitability, and its inhibition was the predominant cause of the inflammation-induced hyperexcitability. Our discovery that the ubiquitous KV 7/M channels are the downstream target of the inflammation-induced cascade, has far reaching implications for the understanding and treatment of many acute and chronic brain disorders. PMID- 27506494 TI - In vitro Characterization of Phenylacetate Decarboxylase, a Novel Enzyme Catalyzing Toluene Biosynthesis in an Anaerobic Microbial Community. AB - Anaerobic bacterial biosynthesis of toluene from phenylacetate was reported more than two decades ago, but the biochemistry underlying this novel metabolism has never been elucidated. Here we report results of in vitro characterization studies of a novel phenylacetate decarboxylase from an anaerobic, sewage-derived enrichment culture that quantitatively produces toluene from phenylacetate; complementary metagenomic and metaproteomic analyses are also presented. Among the noteworthy findings is that this enzyme is not the well-characterized clostridial p-hydroxyphenylacetate decarboxylase (CsdBC). However, the toluene synthase under study appears to be able to catalyze both phenylacetate and p hydroxyphenylacetate decarboxylation. Observations suggesting that phenylacetate and p-hydroxyphenylacetate decarboxylation in complex cell-free extracts were catalyzed by the same enzyme include the following: (i) the specific activity for both substrates was comparable in cell-free extracts, (ii) the two activities displayed identical behavior during chromatographic separation of cell-free extracts, (iii) both activities were irreversibly inactivated upon exposure to O2, and (iv) both activities were similarly inhibited by an amide analog of p hydroxyphenylacetate. Based upon these and other data, we hypothesize that the toluene synthase reaction involves a glycyl radical decarboxylase. This first time study of the phenylacetate decarboxylase reaction constitutes an important step in understanding and ultimately harnessing it for making bio-based toluene. PMID- 27506495 TI - Absorber modeling for NGCC carbon capture with aqueous piperazine. AB - A hybrid system combining amine scrubbing with membrane technology for carbon capture from natural gas combined cycle (NGCC) power plants is proposed in this paper. In this process, the CO2 in the flue gas can be enriched from 4% to 18% by the membrane, and the amine scrubbing system will have lower capture costs. Aqueous piperazine (PZ) is chosen as the solvent. Different direct contact cooler (DCC) options, multiple absorber operating conditions, optimal intercooling designs, and different cooling options have been evaluated across a wide range of inlet CO2. Amine scrubbing without DCC is a superior design for NGCC carbon capture. Pump-around cooling at the bottom of the absorber can effectively manage the temperature of the hot flue gas, and still be effective for CO2 absorption. The absorber gas inlet must be designed to avoid excessive localized temperature and solvent evaporation. When the inlet CO2 increases from 4% to 18%, total absorber CAPEX decreases by 60%; another 10% of the total absorber CAPEX can be saved by eliminating the DCC. In-and-out intercooling works well for high CO2, while pump-around intercooling is more effective for low CO2. Dry cooling requires more packing and energy but appears to be technically and economically feasible if cooling water availability is limited. PMID- 27506496 TI - A Functional Polymorphism (rs937283) in the MDM2 Promoter Region is Associated with Poor Prognosis of Retinoblastoma in Chinese Han Population. AB - The effect of single nucleotide polymorphisms (SNPs) at MDM2 has been investigated in several cancer types. Three MDM2 SNPs(rs937283, rs2270744 and rs769412) have previously been suggested to be positively correlated with cancer. In this study, we aimed to explore the association of rs937283, rs2270744 and rs769412 polymorphisms with retinoblastoma (RB) risk, clinicopathological characteristics, and prognosis. Compared with wild-type genotype AA at rs937283, individuals carrying AG and GG genotype had a significantly increased risk for developing RB (OR = 1.86, 95% CI 1.13-3.08; OR = 2.48, 95% CI 1.10-5.62, respectively). RB patients with allele G at rs937283 were more susceptible to invasion and high tumor aggression (OR = 2.42, 95% CI 1.43-4.11; OR = 2.15, 95% CI 1.27-3.64, respectively). Kaplan-Meier curves and log-rank results revealed that RB patients harboring genotype GG and G allele at rs937283 had worse survival (P < 0.02 and P < 0.01, respectively). In addition, the A to G substitution at rs937283 significantly enhanced the transcription activity of the MDM2 gene in vitro. In vivo, we found that MDM2 mRNA and protein were overexpressed in individuals who carried the G allele at rs937283. This study suggested that the MDM2 rs937283 polymorphism is a novel functional SNP both in vitro and in vivo as well as a biomarker for poor prognosis in RB. PMID- 27506497 TI - Challenges and successes for the grantees and the Technical Advisory Group of WHO's influenza vaccine technology transfer initiative. AB - One of the aims of the WHO Global Action Plan for Influenza Vaccines (GAP) was to transfer influenza vaccine production technology to interested manufacturers and governments in developing countries, to enable greater influenza vaccine manufacturing capacity against any pandemic threat or pandemic. For this objective, the GAP was supported by an independent Technical Advisory Group (TAG) to assist WHO to select vaccine manufacturing proposals for funding and to provide programmatic support for successful grantees. While there were many challenges, for both the TAG and grantees, there were also notable successes with an additional capacity of 338-600 million pandemic vaccine doses being made possible by the programme between 2007 and 2015, and a potential capacity of more than 600 million by 2016/17 with up to one billion doses expected by 2018/19. Seasonal vaccine production was also developed in 4 countries with another 4-5 countries expected to be producing seasonal vaccine by 2018/19. The relatively small WHO investments - in time and funding - made in these companies to develop their own influenza vaccine production facilities have had quite dramatic results. PMID- 27506498 TI - Preventing further misuse of the ELISA technique and misinterpretation of serological antibody assay data. AB - The indirect ELISA is a widely utilized method to assay serum antibodies. However, a common and critical problem when analyzing serum antibodies is the disregard for the background noise reaction caused by the hydrophobic binding of immunoglobulin components in serum components to plastic. Unfortunately, current blocking agents cannot prevent this background noise reaction. To prevent further misuse of the ELISA technique, it is important to openly discuss the fundamental problems involved in the ELISA system. PMID- 27506499 TI - Keloidectomy with core fillet flap and intralesional verapamil injection for recurrent earlobe keloids. AB - BACKGROUND: Earlobe keloids are usually recalcitrant to treatment and have a high rate of recurrence. Verapamil is a calcium channel antagonist that has been shown to inhibit the synthesis/secretion of extracellular matrix molecules and increase collagenase. OBJECTIVES: This prospective study was designed to evaluate the results of treatment of recurrent earlobe keloids using keloidectomy with core fillet flap and intralesional verapamil injection. METHODS: Nineteen keloids in 16 patients were treated using this technique with intralesional verapamil injection given intraoperatively, then every 2 weeks for 3 months, with postoperative follow-up for 18 months. RESULTS: Fourteen patients completed the study. Ten patients (71.4%) showed response to treatment. Four (28.6%) cases showed recurrence, two (14.2%) at the wound bed and another two (14. 2%) at the incision line. Eighty percent of responders were highly satisfied with their treatment. CONCLUSION: Keloidectomy with core fillet flap and intralesional verapamil injection is a reliable and cost-effective method in the treatment of recurrent earlobe keloids with a low rate of recurrence and high patient satisfaction. PMID- 27506500 TI - Chronic subcutaneous nodules, plaques and ulcers of the hand. PMID- 27506501 TI - Progressive Nagashima-type palmoplantar keratosis in a Chinese patient with recurrent c.796C>T mutation in SERPINB7. PMID- 27506503 TI - A retrospective study of the utility of targeted phototherapy in vitiligo. AB - BACKGROUND: Targeted phototherapy is a recent advance in the treatment of vitiligo, involving selective treatment of vitiligo patches with no effect on surrounding areas. Although it has been in use for a few years, little data is available regarding its safety and efficacy. AIMS: A retrospective study to determine efficacy and safety of targeted phototherapy in vitiligo. METHODS: One hundred and thirty four patients (male: 53, female: 81) who received targeted phototherapy and completed 11 or more sittings were included. Treatment was given once a week using the Lumera phototherapy system, a broadband ultraviolet B source, starting at 150 mJ/spot and after excluding a sunburn reaction, with increments of 50 mJ every week up to a maximum of 1000 mJ/patch. Chi-square test for linear trends was used for statistical analysis. RESULTS: The most common sites involved were the legs and a majority (70.9%) had non-segmental vitiligo. Response was mild in 78 (58.2%) patients, moderate in 50 (37.3%) and excellent in 6 (4.5%) patients. Response was directly proportional to the number of sittings with more patients showing moderate and excellent responses with an increase in the number of sittings. The most common site for an excellent response was the trunk while the lower limbs were involved in most cases with a moderate or mild response. Side effects were seen in 27 (20.2%) patients, the commonest being erythema. LIMITATIONS: This is a retrospective uncontrolled study. Further, the effects of adjuvant treatment were not assessed. CONCLUSIONS: Targeted phototherapy is a useful treatment for vitiligo with mild adverse effects, though response is mild or moderate and appears to be directly proportional to the number of treatments received. PMID- 27506502 TI - Paronychia and onychomadesis due to pemphigus vulgaris. PMID- 27506504 TI - Tinea pseudoimbricata. PMID- 27506505 TI - A study of the free radical scavenging effects of Piper betle leaf extract in patients with vitiligo. AB - BACKGROUND: Vitiligo is an idiopathic skin disease manifested by depigmented macules. It is characterised by melanocyte destruction, and redox imbalance is proposed to play a contributory role. AIM: The aim of this study was to analyze the effects of an ethanolic extract of Piper betle leaves on the generation of reactive oxygen species in erythrocytes sourced from vitiligo patients. METHODS: The effect of Piper betle on the generation of reactive oxygen species in erythrocytes was measured by flow cytometry in patients with active and stable vitiligo versus healthy controls, using 5-(and-6)-chloromethyl-2'-7' dichlorodihydrofluorescein diacetate. RESULTS: The generation of reactive oxygen species in erythrocytes was higher in patients with vitiligo (n = 23) compared to healthy controls (n = 18). The geometrical mean fluorescence channel was 23.05 +/ 2.11 in patients versus 17.77 +/- 1.79 in controls, P = 0.039. The levels of reactive oxygen species were higher in patients with active vitiligo. Treatment of erythrocytes with Piper betle in concentrations of 0.5 and 1.0 MUg/ml significantly decreased the baseline levels of reactive oxygen species by 31.7% in healthy controls, and 47.6% and 44.3% in patients with active vitiligo, respectively. Piper betle effectively scavenged hydrogen peroxide, which was evident by a decrease in the geometrical mean fluorescence channel by 52.4% and 62.9% in healthy controls, and 45.0% and 57.0% in patients with active vitiligo. LIMITATIONS: The study had a small sample size. Future studies should focus on evaluation of the antioxidant role of Piper betle at the lesional site. CONCLUSION: This pilot study indicates that patients with active vitiligo demonstrate enhanced generation of reactive oxygen species in erythrocytes, which was significantly reduced following ex vivo treatment with Piper betle. PMID- 27506506 TI - Familial eyelash trichomegaly: The case of a sister and a brother. PMID- 27506507 TI - Pagetoid Bowen's disease of vulva: Excellent response to imiquimod. PMID- 27506508 TI - Current molecular methods for the detection of hepatitis B virus quasispecies. AB - Chronic HBV infection affects more than 240 million people worldwide and is associated with a broad range of clinical manifestations including liver cirrhosis, liver failure and hepatocellular carcinoma. Because of the lack of an efficient cure for chronic hepatitis B, the main goal of antiviral therapy is the prevention of liver disease progression coupled with prolonged survival of patients. Because HBV viral load has been shown to be a crucial determinant of the progression of liver damage, these goals can be achieved as long as HBV replication can be suppressed. Unfortunately, long-term therapy with the low-to moderate genetic barrier drugs, which are still recommended in a majority of developing countries, are strongly associated with HBV resistance development and treatment failure. In such cases, the precise and accurate determination of drug resistant variants in an individual patient before treatment is important for a proper choice of first-line potent therapy. Nowadays, a number of techniques are available to study HBV quasispecies evolution. This review describes the advantages and limitations of various assays detecting drug-resistant HBV variants. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27506509 TI - Antimicrobial resistance in zoonotic nontyphoidal Salmonella: an alarming trend? AB - Zoonotic bacteria of the genus Salmonella have acquired various antimicrobial resistance properties over the years. The corresponding resistance genes are commonly located on plasmids, transposons, gene cassettes, or variants of the Salmonella Genomic Islands SGI1 and SGI2. Human infections by nontyphoidal Salmonella isolates mainly result from ingestion of contaminated food. The two predominantly found Salmonella enterica subsp. enterica serovars in the USA and in Europe are S. Enteritidis and S. Typhimurium. Many other nontyphoidal Salmonella serovars have been implicated in foodborne Salmonella outbreaks. Summary reports of the antimicrobial susceptibility patterns of nontyphoidal Salmonella isolates over time suggest a moderate to low level of antimicrobial resistance and multidrug-resistance. However, serovar-specific analyses showed in part a steady state, a continuous decline, or a recent increase in resistance to certain antimicrobial agents. Resistance to critically important antimicrobial agents, e.g. third-generation cephalosporins and (fluoro)quinolones is part of many monitoring programmes and the corresponding results confirm that extended spectrum beta-lactamases are still rarely found in nontyphoidal Salmonella serovars, whereas resistance to (fluoro)quinolones is prevalent at variable frequencies among different serovars from humans and animals in different countries. Although it is likely that nontyphoidal Salmonella isolates from animals represent a reservoir for resistance determinants, it is mostly unknown where and when Salmonella isolates acquired resistance properties and which exchange processes have happened since then. PMID- 27506510 TI - Small lesion size measured by colposcopy may predict absence of cervical intraepithelial neoplasia in a large loop excision of the transformation zone specimen. AB - OBJECTIVE: To evaluate whether colposcopic measurement of the lesion size at diagnosis and/or human papillomavirus (HPV) genotyping can predict the absence of dysplasia in a large loop excision of the transformation zone (LLETZ) specimen in women treated for squamous intraepithelial lesions/cervical intraepithelial neoplasia (SIL/CIN). DESIGN: Prospective observational study. SETTING: Tertiary university hospital. POPULATION: A cohort of 116 women who underwent LLETZ because of biopsy-proven low-grade SIL/CIN that had persisted for 2 years, or because of a high-grade SIL/CIN diagnosed in the referral visit and squamocolumnar junction completely visible (types 1 or 2, according to the International Federation of Cervical Pathology and Colposcopy, IFCPC). METHODS: After LLETZ the women were classified by histology into the study group (absence of SIL/CIN in the surgical specimen, 28/116, 24.1%) and the control group (SIL/CIN in the LLETZ specimen, 88/116, 75.9%). MAIN OUTCOME MEASURES: The size of the lesion determined in the diagnostic colposcopy and the HPV genotype were evaluated in all women. RESULTS: The lesion size was significantly smaller in the study group (25.7 +/- 37.8 versus 84.5 +/- 81.7 mm2 ; P < 0.001). A lesion size of <=12 mm2 and HPV types other than 16 or 18 were associated with an absence of SIL/CIN in the LLETZ specimen (P < 0.001 and P = 0.016, respectively). On multivariate analysis only a lesion size of <=12 mm2 predicted the absence of SIL/CIN (odds ratio, OR 10.6; 95% confidence interval, 95% CI 3.6-30.6; P < 0.001). A lesion size of <=12 mm2 had a specificity of 90.9% (95% CI 83.0-95.3%) and a negative predictive value of 86.0% (95% CI 77.5-91.6%) to predict the absence of SIL/CIN in the surgical specimen. CONCLUSIONS: Small lesion size in diagnostic colposcopy could predict the absence of SIL/CIN in the LLETZ specimen. Colposcopy measurement of lesion size prior to LLETZ may avoid unnecessary treatment. TWEETABLE ABSTRACT: Small lesion size in colposcopic evaluation might predict the absence of SIL/CIN in an LLETZ specimen. PMID- 27506511 TI - Unexpected solvent impact in the crystallinity of praziquantel/poly(vinylpyrrolidone) formulations. A solubility, DSC and solid state NMR study. AB - The saturation solubility of PVP:PZQ physical mixtures (PMs) and solid dispersions (SDs) prepared from ethanol (E/E) or ethanol/water (E/W) by the solvent evaporation method at 1:1, 2:1 and 3:1 ratio (w/w) was determined. The presence of PVP improves the solubility of PZQ (0.31+/-0.01mg/mL). A maximum of 1.29+/-0.03mg/mL of PZQ in solution was achieved for the 3:1 SD (E/E). The amount of PZQ in solution depends on the amount of polymer and on the preparation method. Solid-state NMR (ssNMR) and DSC were used to understand this behavior. Results show that PMs are a mixture of crystalline PZQ with the polymer, while SDs show different degrees of drug amorphization depending on the solvent used. For E/W SDs, PZQ exists in amorphous and crystalline states, with no clear correlation between the amount of crystalline PZQ and the amount of PVP. For E/E SDs, formulations with a higher percentage of PZQ are amorphous with the components miscible in domains larger than 3nm ((1)H ssNMR relaxation measurements). Albeit its higher saturation solubility, the 3:1 E/E PVP:PZQ sample has a significant crystalline content, probably due to the water introduced by the polymer. High PVP content and small crystal size account for this result. PMID- 27506512 TI - Controlled drug release from lung-targeted nanocarriers via chemically mediated shell permeabilisation. AB - Nanocarriers can aid therapeutic agent administration to the lung, but controlling drug delivery from these systems after deposition in the airways can be problematic. The aim of this study was to evaluate if chemically mediated shell permeabilisation could help manipulate the rate and extent of nanocarrier drug release. Rifampicin was loaded into lipid shell (loading efficiency 41.0+/ 11.4%, size 50nm) and polymer shell nanocarriers (loading efficiency 25.9+/-2.3%, size 250nm). The drug release at pH 7.4 (lung epithelial pH) and 4.2 (macrophage endosomal pH) with and without the chemical permeabilisers (Pluronic L62D - lipid nanocarriers; H(+)- polymer nanocarriers) was then tested. At pH 7.4 the presence of the permeabilisers increased nanocarrier drug release rate (from 3.2MUg/h to 6.8MUg/h for lipid shell nanocarriers, 2.3MUg/h to 3.4MUg/h for polymer shell nanocarriers) and drug release extent (from 50% to 80% for lipid shell nanocarriers, from 45% to 76% for polymer shell nanocarriers). These effects were accompanied by lipid nanocarrier distension (from 50 to 240nm) and polymer shell hydrolysis. At pH 4.2 the polymer nanocarriers did not respond to the permeabiliser, but the lipid nanocarrier maintained a robust drug release enhancement response and hence they demonstrated that the manipulation of controlled drug release from lung-targeted nanocarriers was possible through chemically mediated shell permeabilisation. PMID- 27506513 TI - Challenges in the first seizure clinic for adult patients with epilepsy. AB - AIMS: (1) To delineate the challenges in seizure diagnosis in the first seizure clinic setting for adult patients of a teaching hospital, and (2) quantify the diagnostic accuracy of the referral source and the yield of routine investigations, including blood tests, EEGs, and neuroimaging. METHODS: We retrospectively reviewed medical records of patients referred by the emergency department to the adult first seizure clinic and seen by the same epilepsy specialist between June 2007 and June 2011. The diagnostic accuracy in the emergency department was calculated by comparing with the final diagnosis made by an epilepsy specialist. RESULTS: In total, 219 patients were referred to the first seizure clinic. Median age was 45 and 60% of patients were male. From the cohort, 38 (17%) patients presented with seizure mimickers; the most common were reflex syncope (74%) and psychogenic non-epileptic seizures (16%). From the remaining 181 patients presenting with seizures, only 110 (61%) of these patients were diagnosed with true first seizures, and 71 (39%) patients had evidence of previous seizures. Nineteen (17%) of true first-ever seizures were provoked. The most frequent cause of provoked seizures was alcohol and illicit drugs (65%). In the emergency department, sensitivity and specificity in seizure diagnosis were 0.74 and 0.32, respectively. In our true first seizure patients, the EEG demonstrated epileptiform discharges in 22 (21%) patients. In the same cohort, computed tomography and magnetic resonance neuroimaging conferred 16% and 20% probability of finding a potentially epileptogenic structural abnormality, respectively. The most common epileptogenic abnormality found on magnetic resonance neuroimaging was cortical infarct. CONCLUSIONS: The diagnosis and management of first seizure remains challenging due to the variety of seizure mimickers and low yield of investigations. Our data highlight the potential pitfalls and practical challenges in this process, as well as the need for these patients to be assessed in dedicated first seizure clinics. PMID- 27506514 TI - Photonic Weyl degeneracies in magnetized plasma. AB - Weyl particles are elusive relativistic fermionic particles with vanishing mass. While not having been found as an elementary particle, they are found to emerge in solid-state materials where three-dimensional bands develop a topologically protected point-like crossing, a so-called Weyl point. Photonic Weyl points have been recently realised in three-dimensional photonic crystals with complex structures. Here we report the presence of a novel type of plasmonic Weyl points in a naturally existing medium-magnetized plasma, in which Weyl points arise as crossings between purely longitudinal plasma modes and transverse helical propagating modes. These photonic Weyl points are right at the critical transition between a Weyl point with the traditional closed finite equifrequency surfaces and the newly proposed 'type II' Weyl points with open equifrequency surfaces. Striking observable features of plasmon Weyl points include a half k plane chirality manifested in electromagnetic reflection. Our study introduces Weyl physics into homogeneous photonic media, which could pave way for realizing new topological photonic devices. PMID- 27506515 TI - Influence of dentin pretreatment with synthetic hydroxyapatite application on the bond strength of fiber posts luted with 10-methacryloyloxydecyl dihydrogen phosphate-containing luting systems. AB - The aim of this in vitro study was evaluate the effect of application of synthetic hydroxyapatite on fiber post bond strength to radicular dentine. Forty, single-root teeth were endodontically treated and an 8 mm post space was prepared. Specimens were randomly placed in four groups (n = 10 in each) and treated using the following fiber post luting procedures: group 1, 17% EDTA + Panavia SA; group 2, 17% EDTA + Teethmate Desensitizer + Panavia SA; group 3, All Bond Universal + Duo-Link Universal; and group 4, All-Bond Universal + Teethmate Desensitizer + Duo-Link Universal. Fiber posts were luted in the post space and light-cured for 120 s using a light-emitting diode (LED) lamp. After 7 d of storage at 37 degrees C, the teeth were cut into 1-mm-thick slices, which were subjected to a push-out test until failure using a universal testing machine. Two specimens per group were prepared for scanning electron microscopy analysis. An energy-dispersive X-ray spectroscopy detector was used for elemental analysis of the specimen surface. The results were statistically analyzed using one-way anova. The fiber post bond strength was statistically significantly increased after the application of Teethmate Desensitizer to post space walls, either with a 10-MDP-containing self-adhesive cement or with a universal adhesive. Scanning electron microscopy and EDAX analysis showed that Teethmate Desensitizer created a calcium phosphate precipitate over post space dentinal tubules, which significantly improved the bond strength of the fiber post luted with 10 methacryloyloxydecyl dihydrogen phosphate (10-MDP)-containing adhesive systems. PMID- 27506516 TI - Nasopharyngeal teratoma, congenital diaphragmatic hernia and Dandy-Walker malformation - a yet uncharacterized syndrome. AB - An association of congenital diaphragmatic hernia, dandy walker malformation and nasopharyngeal teratoma is very rare. Here, we report a fourth case with this association where chromosomal microarray and whole exome sequencing (WES) was performed to understand the underlying genetic basis. Findings of few variants especially a novel variation in HIRA provided some insights. An association of congenital diaphragmatic hernia, dandy walker malformation and nasopharyngeal teratoma is very rare. Here, we report a fourth case with this association where chromosomal microarray and whole exome sequencing (WES) was performed to understand the underlying genetic basis. Findings of few variants especially a novel variation in HIRA provided some insights. PMID- 27506517 TI - Electromicrobiology: realities, grand challenges, goals and predictions. AB - Electromicrobiology is a subdiscipline of microbiology that involves extracellular electron transfer (EET) to (or from) insoluble electron active redox compounds located outside the outer membrane of the cell. These interactions can often be studied using electrochemical techniques which have provided novel insights into microbial physiology in recent years. The mechanisms (and variations) of outward EET are well understood for two model systems, Shewanella and Geobacter, both of which employ multihaem cytochromes to provide an electron conduit to the cell exterior. In contrast, little is known of the intricacies of inward EET, even in these model systems. Given the number of labs now working on EET, it seems likely that most of the mechanistic details will be understood in a few years for the model systems, and the many applications of electromicrobiology will continue to move forward. But emerging work, using electrodes as electron acceptors and donors is providing an abundance of new types of microbes capable of EET inward and/or outward: microbes that are clearly different from our known systems. The extent of this very diverse, and perhaps widely distributed and biogeochemically important ability needs to be determined to understand the mechanisms, importance, and raison d'etre of EET for microbial biology. PMID- 27506518 TI - Promotion of Organic Reactions by Non-Benzenoid Carbocyclic Aromatic Ions. AB - The first three primary members of the non-benzenoid carbocyclic aromatic ion family, namely cyclopropenium, cyclopentadienide, and cycloheptatrienium (tropylium) ions, have planar cyclic structures with (4n+2)pi electrons in fully conjugated systems. They fulfill Huckel's rule for aromaticity and hence possess extraordinary stability. Since the historic discovery of tropylium bromide in the late 19th Century, these non-benzenoid aromatic ions have attracted a lot of attention because of their unique combination of stability and reactivity. The charge on the aromatic ions makes them more prone to nucleophilic/electrophilic reactions than the neutral benzenoid counterparts. Within the last seven years, there has been a large number of investigations in utilizing aromatic ions to mediate organic reactions. This Review highlights these recent developments and discusses the potential of aromatic ions in promoting synthetically useful organic transformations. PMID- 27506521 TI - Resumes dans ce numero. PMID- 27506519 TI - The use of T-DNA insertional mutagenesis to improve cellulase production by the thermophilic fungus Humicola insolens Y1. AB - Humicola insolens is an excellent producer of pH-neutral active, thermostable cellulases that find many industrial applications. In the present study, we developed an efficient Agrobacterium tumefaciens-mediated transformation system for H. insolens. We transformed plasmids carrying the promoter of the glyceraldehyde-3-phosphate dehydrogenase gene of H. insolens driving the transcription of genes encoding neomycin phosphotransferase, hygromycin B phosphotransferase, and enhanced green fluorescent protein. We optimized transformation efficiency to obtain over 300 transformants/10(6) conidia. T-DNA insertional mutagenesis was employed to generate an H. insolens mutant library, and we isolated a transformant termed T4 with enhanced cellulase and hemicellulase activities. The FPase, endoglucanase, cellobiohydrolase, beta glucosidase, and xylanase activities of T4, measured at the end of fermentation, were 60%, 440%, 320%, 41%, and 81% higher than those of the wild-type strain, respectively. We isolated the sequences flanking the T-DNA insertions and thus identified new genes potentially involved in cellulase and hemicellulase production. Our results show that it is feasible to use T-DNA insertional mutagenesis to identify novel candidate genes involved in cellulase production. This will be valuable when genetic improvement programs seeking to enhance cellulase production are planned, and will also allow us to gain a better understanding of the genetics of the thermophilic fungus H. insolens. PMID- 27506522 TI - Resumenes en esta edicion. PMID- 27506523 TI - Invasive liver abscess syndrome predisposed by Klebsiella pneumoniae related prostate abscess in a nondiabetic patient: a case report. AB - BACKGROUND: Prostate abscess is usually a complication of acute urinary tract infection. Invasive liver abscess syndrome is characterized with Klebsiella pneumoniae related multiple organ metastasis. Concomitant pyogenic liver abscess and prostate abscess have rarely been reported. Recurrent episode of liver abscess is even rarer. CASE PRESENTATION: We report a 71-year-old male with acute bacterial prostate abscess and urinary tract infection caused by K. pneumoniae associated with multiple liver abscess, psoas muscle abscess and osteomyelitis. Blood culture and urine culture yielded K. pneumoniae, which confirmed the diagnosis of invasive liver abscess syndrome caused by K. pneumoniae. The patient was successfully treated with empirical antibiotics for 6 weeks. CONCLUSIONS: This case emphasizes the importance of timely and accurate diagnosis followed by appropriate treatment in disseminated K. pneumoniae infection to prevent significant morbidity and mortality. PMID- 27506524 TI - Responsiveness and minimal important change for the ProFitMap-neck questionnaire and the Neck Disability Index in women with neck-shoulder pain. AB - PURPOSE: The aim was to determine the responsiveness and minimal important change (MIC) of the questionnaire ProFitMap-neck that measures symptoms and functional limitations in women with neck pain. The same measurement properties were determined for Neck Disability Index (NDI) for comparison purposes. METHODS: Longitudinal data were derived from two randomized controlled trials, including 103 and 120 women with non-specific neck pain, with questionnaire measurements performed before and after interventions. Sensitivity and specificity to discriminate between improved and not or little changed participants, based on categorization of a global rating of change scale (GRCS), were determined for the ProFitMap-neck indices and NDI by using area under receiver operating characteristic curves (AUC). Correlations between the GRCS anchor and change scores of the questionnaires were also used to assess responsiveness. The change score that showed the highest combination of sensitivity and specificity was set for MIC. RESULTS: The ProFitMap-neck indices showed similar responsiveness as NDI with AUC exceeding 0.70 (Range: ProFitMap-neck, 0.74-0.83; NDI, 0.75-0.86). The MIC in the two samples ranged between 6.6 and 13.6 % for ProFitMap-neck indices and 5.2 and 6.3 % for NDI. Both questionnaires had significant correlations with GRCS (Spearman's rho 0.47-0.72). CONCLUSIONS: Validity of change scores was endorsed for the ProFitMap-neck indices and NDI with adequate ability to discriminate between improved and not or little changed participants. Values of minimal important change were presented. PMID- 27506525 TI - Validation of World Health Organization Assessment Schedule 2.0 in specialized somatic rehabilitation services in Norway. AB - PURPOSE: The World Health Organization Disability Assessment Schedule (WHODAS) 2.0 is a generic instrument to assess disability covering six domains. The purpose of this study was to investigate the potential of the instrument for monitoring disability in specialized somatic rehabilitation by testing reliability, construct validity and responsiveness of WHODAS 2.0, Norwegian version, among patients with various health conditions. METHODS: For taxonomy, terminology and definitions, the Consensus-based Standards for the Selection of Health Measurement Instruments were followed. Reproducibility was investigated by the intra-class correlation coefficient (ICC) in a randomly selected sample. Internal consistency was assessed by Cronbach's alpha. Construct validity was evaluated by correlations between WHODAS 2.0 and the Medical Outcomes Study 36 item Short Form, and fit of the hypothesized structure using confirmatory factor analysis (CFA). Responsiveness was evaluated in another randomly selected sample by testing a priori formulated hypotheses. RESULTS: Nine hundred seventy patients were included in the study. Reproducibility and responsiveness were evaluated in 53 and 104 patients, respectively. The ICC for the WHODAS 2.0 domains ranged from 0.63 to 0.84 and was 0.87 for total score. Cronbach's alpha for domains ranged from 0.75 to 0.94 and was 0.93 for total score. For construct validity, 6 of 12 expected correlations were confirmed and CFA did not achieve satisfactory fit indices. For responsiveness, 3 of 8 hypotheses were confirmed. CONCLUSION: The Norwegian version of WHODAS 2.0 showed moderate to satisfactory reliability and moderate validity in rehabilitation patients. However, the present study indicated possible limitations in terms of responsiveness. PMID- 27506527 TI - STORMy Interactions: Gaze and the Modulation of Mimicry in Adults on the Autism Spectrum. AB - Mimicry involves unconsciously imitating the actions of others and is a powerful and ubiquitous behavior in social interactions. There has been a long debate over whether mimicry is abnormal in people with autism spectrum conditions (ASC) and what the causes of any differences might be. Wang and Hamilton's (2012) social top-down response modulation (STORM) model proposed that people with ASC can and do mimic but, unlike neurotypical participants, fail to modulate their mimicry according to the social context. This study used an established mimicry paradigm to test this hypothesis. In neurotypical participants, direct gaze specifically enhanced congruent hand actions as previously found; in the ASC sample, direct gaze led to faster reaction times in both congruent and incongruent movements. This result shows that mimicry is intact in ASC, but is not socially modulated by gaze, as predicted by STORM. PMID- 27506526 TI - Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation. AB - It is envisaged that application of mechanistic models will improve prediction of changes in renal disposition due to drug-drug interactions, genetic polymorphism in enzymes and transporters and/or renal impairment. However, developing and validating mechanistic kidney models is challenging due to the number of processes that may occur (filtration, secretion, reabsorption and metabolism) in this complex organ. Prediction of human renal drug disposition from preclinical species may be hampered by species differences in the expression and activity of drug metabolising enzymes and transporters. A proposed solution is bottom-up prediction of pharmacokinetic parameters based on in vitro-in vivo extrapolation (IVIVE), mediated by recent advances in in vitro experimental techniques and application of relevant scaling factors. This review is a follow-up to the Part I of the report from the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25th 29th October 2015) which focuses on IVIVE and mechanistic prediction of renal drug disposition. It describes the various mechanistic kidney models that may be used to investigate renal drug disposition. Particular attention is given to efforts that have attempted to incorporate elements of IVIVE. In addition, the use of mechanistic models in prediction of renal drug-drug interactions and potential for application in determining suitable adjustment of dose in kidney disease are discussed. The need for suitable clinical pharmacokinetics data for the purposes of delineating mechanistic aspects of kidney models in various scenarios is highlighted. PMID- 27506528 TI - Anti-inflammatory effect of AMPK signaling pathway in rat model of diabetic neuropathy. AB - Diabetic neuropathy (DN) is characterized as Hyperglycemia activates thdisturbed nerve conduction and progressive chronic pain. Inflammatory mediators, particularly cytokines, have a determinant role in the pathogenesis of neuropathic pain. The activity of adenosine monophosphate protein kinase (AMPK), an energy charge sensor with neuroprotective properties, is decreased in diabetes. It has been reported that activation of AMPK reduces the systemic inflammation through inhibition of cytokines. In this study, we aimed to investigate the probable protective effects of AMPK on DN in a rat of diabetes. DN was induced by injection of streptozotocin (65 mg/kg, i.p.). Motor nerve conduction velocities (MNCV) of the sciatic nerve, as an electrophysiological marker for peripheral nerve damage, were measured. Plasma levels of IL-6, TNF alpha, CRP were assessed as relevant markers for inflammatory response. Also, the expression of phosphorylated AMPK (p-AMPK) and non-phosphorylated (non-p-AMPK) was evaluated by western blotting in the dorsal root ganglia. Histopathological assessment was performed to determine the extent of nerve damage in sciatic nerve. Our findings showed that activation of AMPK by metformin (300 mg/kg) significantly increased the MNCV and reduced the levels of inflammatory cytokines. In addition, we showed that administration of metformin increased the expression of p-AMPK as well as decline in the level of non p-AMPK. Our results demonstrated that co-administration of dorsomorphin with metformin reversed the beneficial effects of metformin. In conclusion, the results of this study demonstrated that the activation of AMPK signaling pathway in diabetic neuropathy might be associated with the anti-inflammatory response. PMID- 27506529 TI - The HB22.7-vcMMAE antibody-drug conjugate has efficacy against non-Hodgkin lymphoma mouse xenografts with minimal systemic toxicity. AB - In this study, HB22.7, an anti-CD22 monoclonal antibody, was used for specific, targeted delivery of monomethyl auristatin E (MMAE) to non-Hodgkin lymphoma (NHL). MMAE was covalently coupled to HB22.7 through a valine-citrulline peptide linker (vc). Maleimide-functionalized vcMMAE (mal-vcMMAE) was reacted with thiols of the partially reduced mAb. Approximately 4 molecules of MMAE were conjugated to HB22.7 as determined by residual thiol measurement and hydrophobic interaction chromatography-HPLC (HIC-HPLC). HB22.7-vcMMAE antibody-drug conjugate (ADC) retained its binding to Ramos NHL cells and also exhibited potent and specific in vitro cytotoxicity on a panel of B cell NHL cell lines with IC50s of 20-284 ng/ml. HB22.7-vcMMAE also showed potent efficacy in vivo against established NHL xenografts using the DoHH2 and Granta 519 cell lines. One dose of the ADC induced complete and persistent response in all DoHH2 xenografts and 90 % of Granta xenografts. Minimal toxicity was observed. In summary, HB22.7-vcMMAE is an effective ADC that should be evaluated for clinical translation. PMID- 27506530 TI - Optical Properties of Silicon Nanowires Fabricated by Environment-Friendly Chemistry. AB - Silicon nanowires (SiNWs) were fabricated by metal-assisted chemical etching (MACE) where hydrofluoric acid (HF), which is typically used in this method, was changed into ammonium fluoride (NH4F). The structure and optical properties of the obtained SiNWs were investigated in details. The length of the SiNW arrays is about 2 MUm for 5 min of etching, and the mean diameter of the SiNWs is between 50 and 200 nm. The formed SiNWs demonstrate a strong decrease of the total reflectance near 5-15 % in the spectral region lambda < 1 MUm in comparison to crystalline silicon (c-Si) substrate. The interband photoluminescence (PL) and Raman scattering intensities increase strongly for SiNWs in comparison with the corresponding values of the c-Si substrate. These effects can be interpreted as an increase of the excitation intensity of SiNWs due to the strong light scattering and the partial light localization in an inhomogeneous optical medium. Along with the interband PL was also detected the PL of SiNWs in the spectral region of 500-1100 nm with a maximum at 750 nm, which can be explained by the radiative recombination of excitons in small Si nanocrystals at nanowire sidewalls in terms of a quantum confinement model. So SiNWs, which are fabricated by environment-friendly chemistry, have a great potential for use in photovoltaic and photonics applications. PMID- 27506531 TI - Oxidation Resistance of Materials Based on Ti3AlC2 Nanolaminate at 600 degrees C in Air. AB - The oxidation behavior of Ti3AlC2-based materials had been investigated at 600 degrees C in static air for 1000 h. It was shown that the intense increase of weight gain per unit surface area for sintered material with porosity of 22 % attributed to oxidation of the outer surface of the specimen and surfaces of pores in the bulk material. The oxidation kinetics of the hot-pressed Ti3AlC2 based material with 1 % porosity remarkably increased for the first 15 h and then slowly decreased. The weight gain per unit surface area for this material was 1.0 mg/cm(2) after exposition for 1000 h. The intense initial oxidation of Ti3AlC2 based materials can be eliminated by pre-oxidation treatment at 1200 degrees C in air for 2 h. As a result, the weight gain per unit surface area for the pre oxidized material did not exceed 0.11 mg/cm(2) after 1000 h of exposition at 600 degrees C in air. It was demonstrated that the oxidation resistance of Ti3AlC2 based materials can be significantly improved by niobium addition. PMID- 27506533 TI - Localization of the Reflection Sources of Stimulus-Frequency Otoacoustic Emissions. AB - The generation of stimulus-frequency otoacoustic emission (SFOAE) residuals in humans is analyzed both theoretically and experimentally to investigate the relation between the frequency difference between the probe and the suppressor tone and the localization of the residual source. Experimental measurements of the SFOAE residual were performed using suppressors of increasing frequency to separate the otoacoustic response from the probe stimulus. From the response to the probe alone, the SFOAE response was also estimated, using spectral smoothing, and compared with the residuals obtained for different frequency suppressors. A nonlinear delayed-stiffness active cochlear model was used to compute the spatial distribution of the residual sources according to a recent model of the local reflectivity from roughness, as a function of the suppressor frequency. The simulations clarified the role of high-frequency suppressors, showing that in humans, with increasing suppressor frequency, the generation region of the residual is only slightly basally shifted with respect to the case of a near frequency suppressor, near the basal edge of the peak of the resonant basilar membrane response. As a consequence, the hierarchy among different-delay components correspondingly changes, gradually favoring short-delay components, with increasing suppressor frequency. Good agreement between the experimental and theoretical dependence of the level of otoacoustic components of different delay on the frequency shift between probe and suppressor confirms the validity of this interpretation. PMID- 27506532 TI - Aberrant sialylation causes dilated cardiomyopathy and stress-induced heart failure. AB - Dilated cardiomyopathy (DCM), the third most common cause of heart failure, is often associated with arrhythmias and sudden cardiac death if not controlled. The majority of DCM is of unknown etiology. Protein sialylation is altered in human DCM, with responsible mechanisms not yet described. Here we sought to investigate the impact of clinically relevant changes in sialylation on cardiac function using a novel model for altered glycoprotein sialylation that leads to DCM and to chronic stress-induced heart failure (HF), deletion of the sialyltransferase, ST3Gal4. We previously reported that 12- to 20-week-old ST3Gal4 (-/-) mice showed aberrant cardiac voltage-gated ion channel sialylation and gating that contribute to a pro-arrhythmogenic phenotype. Here, echocardiography supported by histology revealed modest dilated and thinner-walled left ventricles without increased fibrosis in ST3Gal4 (-/-) mice starting at 1 year of age. Cardiac calcineurin expression in younger (16-20 weeks old) ST3Gal4 (-/-) hearts was significantly reduced compared to WT. Transverse aortic constriction (TAC) was used as a chronic stressor on the younger mice to determine whether the ability to compensate against a pathologic insult is compromised in the ST3Gal4 (-/-) heart, as suggested by previous reports describing the functional implications of reduced cardiac calcineurin levels. TAC'd ST3Gal4 (-/-) mice presented with significantly reduced systolic function and ventricular dilation that deteriorated into congestive HF within 6 weeks post-surgery, while constricted WT hearts remained well-adapted throughout (ejection fraction, ST3Gal4 (-/-) = 34 +/ 5.2 %; WT = 53.8 +/- 7.4 %; p < 0.05). Thus, a novel, sialo-dependent model for DCM/HF is described in which clinically relevant reduced sialylation results in increased arrhythmogenicity and reduced cardiac calcineurin levels that precede cardiomyopathy and TAC-induced HF, suggesting a causal link among aberrant sialylation, chronic arrhythmia, reduced calcineurin levels, DCM in the absence of a pathologic stimulus, and stress-induced HF. PMID- 27506534 TI - Genetics and mapping of seedling resistance to Ug99 stem rust in winter wheat cultivar Triumph 64 and differentiation of SrTmp, SrCad, and Sr42. AB - KEY MESSAGE: Resistance to Ug99 stem rust in Triumph 64 was conferred by SrTmp on chromosome arm 6DS and was mapped to the same position as SrCad and Sr42 , however, the three genes show functional differences. Stem rust, caused by Puccinia graminis f. sp. tritici (Pgt), is an important disease of wheat that can be controlled by effective stem rust resistance (Sr) genes. The emergence of virulent Pgt races in Africa, namely Ug99 and its variants, has stimulated the search for new Sr genes and genetic characterization of known sources of resistance. Triumph 64 is a winter wheat cultivar that carries gene SrTmp, which confers resistance to Ug99. The goals of this study were to genetically map SrTmp and examine its relationship with other Sr genes occupying a similar chromosome location. A doubled haploid (DH) population from the cross LMPG-6S/Triumph 64 was inoculated with Ug99 at the seedling stage. A single gene conditioning resistance to Ug99 segregated in the population. Genetic mapping with SSR markers placed SrTmp on chromosome arm 6DS in a region similar to SrCad and Sr42. SNP markers developed for SrCad were used to further map SrTmp and were also added to a genetic map of Sr42 using a DH population (LMPG-6S/Norin 40). Three SNP markers that co-segregated with SrTmp also co-segregated with SrCad and Sr42. The SNP markers showed no difference in the map locations of SrTmp, SrCad, and Sr42. Multi-race testing with DH lines from the Triumph 64 and Norin 40 populations and a recombinant inbred-line population from the cross LMPG-6S/AC Cadillac showed that SrTmp, SrCad, and Sr42 confer different spectra of resistance. Markers closely linked to SrTmp are suitable for marker-assisted breeding and germplasm development. PMID- 27506535 TI - Falcatimonas natans gen. nov., sp. nov., a strictly anaerobic, amino-acid decomposing bacterium isolated from a methanogenic reactor of cattle waste. AB - A strictly anaerobic bacterial strain (WN011T) was isolated from a methanogenic reactor treating waste from cattle farms. Cells of the strain were Gram-stain negative curved rods with a polar flagellum. Spores were not produced. The optimum temperature for growth was 35-37 degrees C and the optimum pH was 6.7. The strain did not utilize carbohydrates as growth substrates. The strain grew in PY medium and produced acetate, butyrate, isovalerate and H2 as well as propionate and isobutyrate as minor products. Amino acids (l-isoleucine, l leucine, l-lysine, l-serine, l-threonine and l-valine) added to PY medium enhanced growth of the strain and increased the amounts of fermentation products. Oxidase, catalase and nitrate-reducing activities were negative. Hydrogen sulfide was produced. The genomic DNA G+C content was 38.8 mol%. Compounds related to iso C15 : 0 (fatty acid, dimethylacetal and aldehyde) were detected as predominant components by the cellular fatty acids analysis. The diagnostic diamino acid of the cell-wall peptidoglycan was meso-diaminopimelic acid. On the basis of 16S rRNA gene sequences, three clones from wastewater were very closely related to strain WN011T (up to 99.9 % sequence similarity). The most closely related described species were those in cluster XIVa of the class Clostridia such as Ruminococcus gauvreauii (93.8 % 16S rRNA gene sequence similarity), Clostridium fimetarium (93.5 %) and Clostridium bolteae(93.5 %). Based on the distinct differences in phylogenetic and phenotypic characteristics of strain WN011T from those of related species, it is concluded that strain WN011T represents a novel species of a new genus in the family Lachnospiraceae, for which the name Falcatimonas natans gen. nov., sp. nov. is proposed. The type strain of the type species is WN011T (=JCM 16476T=DSM 22923T). PMID- 27506536 TI - An evaluation of the experiences of guide dog owners visiting Scottish veterinary practices. AB - Guide dogs and their owners will visit a veterinary practice at least twice a year. The aim of this study was to evaluate what guide dog owners thought about these visits, in order to identify areas of good practice which could be incorporated into the undergraduate curriculum. Nine guide dog owners volunteered to take part in the study and were interviewed by the primary researcher. Thematic analysis was carried out and several themes were identified: good experiences were highlighted where staff had an understanding of visual impairment and the work of a guide dog; the importance of good communication skills involving the owner in the consultation; the need for veterinary professionals to understand the bond between an owner and guide dog; how medication and information could be provided in a user-friendly format for someone affected by a visual impairment and concerns about costs and decision making for veterinary treatment. This work highlights the importance for veterinary staff to talk to, empathise with and understand the individual circumstances of their clients and identifies areas that should be included in veterinary education to better prepare students for the workplace. PMID- 27506537 TI - What Are the Top 10 Research Questions in the Treatment of Inflammatory Bowel Disease? A Priority Setting Partnership with the James Lind Alliance. AB - BACKGROUND AND AIMS: Many uncertainties remain regarding optimal therapies and strategies for the treatment of inflammatory bowel disease. Setting research priorities addressing therapies requires a partnership between health care professionals, patients and organisations supporting patients. We aimed to use the structure of the James Lind Alliance Priority Setting Partnership, which has been used in other disease areas, to identify and prioritise unanswered questions about treatments for inflammatory bowel disease. METHODS: The James Lind Priority Setting Partnership uses methods agreed and adopted in other disease areas to work with patients and clinicians: to identify uncertainties about treatments; to agree by consensus a prioritised list of uncertainties for research; then to translate these uncertainties into research questions which are amenable to hypothesis testing; and finally to take results to research commissioning bodies to be considered for funding. RESULTS: A total of 1636 uncertainties were collected in the initial survey from 531 respondents, which included 22% health care professionals and 78% patients and carers. Using the rigorously applied processes of the priority setting partnership, this list was distilled down to the top 10 research priorities for inflammatory bowel disease. The top priorities were: identifying treatment strategies to optimise efficacy, safety and cost effectiveness; and stratifying patients with regard to their disease course and treatment response. Diet and symptom control [pain, incontinence and fatigue] were also topics which were prioritised. CONCLUSIONS: A partnership involving multidisciplinary clinicians, patients and organisations supporting patients has identified the top 10 research priorities in the treatment of patients with inflammatory bowel disease. PMID- 27506538 TI - Epigenetic modulation on cat-cow interspecies somatic cell nuclear transfer embryos by treatment with trichostatin A. AB - This study aimed to determine the acetylation at lysine 9/18/23 of histone H3 (H3K9ac/H3K18ac/H3K23ac; H3K9/18/23 ac) and the di-methylation at lysine 9 of histone H3 (H3K9me2) during early embryogenesis among trichostatin A (TSA) treated interspecies somatic cell nuclear transfer (iSCNT) cat-cow (TSA-iSCNT) embryos, TSA-untreated iSCNT cat-cow control (control) embryos and bovine in vitro fertilization (IVF) embryos, because TSA-iSCNT embryos can develop to blastocysts. Compared to the control embryos, higher expressions of H3K9/18/23 ac were observed in TSA-iSCNT embryos and IVF embryos at most following stages (2 h post-fusion / post-insemination (PF/PI) to eight-cell stage). At 6 h PF/PI the expression of H3K9/23 ac in TSA-iSCNT embryos and IVF embryos were lower than those in control embryos, and the expression of H3K18ac was no difference among the three groups. The expression of H3K9/23 ac increased in TSA-iSCNT embryos and IVF embryos at pronuclear (PN) stages. The expression of H3K9me2 in TSA-iSCNT embryos resembled that of IVF embryos at 2 h PF/PI to PN stages, and these expression levels were greater than those of control embryos. These results suggest that treatment of iSCNT embryos with TSA modifies the patterns of histone modification at certain lysine residues in a manner that is comparable with that seen in IVF during early embryogenesis. PMID- 27506539 TI - Community perceptions of health and rodent-borne diseases along the Inter-Oceanic Highway in Madre de Dios, Peru. AB - BACKGROUND: Madre de Dios is located in the southeastern Amazonian region of Peru. Rodents have been estimated to be the reservoirs for up to 50 % of emerging zoonotic pathogens, including a host of viruses, bacteria, and parasites. As part of a larger study involving both human and animal research, this study serves to obtain a broader understanding of the key challenges and concerns related to health and rodent-borne illnesses from the perspective of the people living in these communities. METHODS: We used a mixed methods approach, which comprised of 12 focus group discussions, 34 key informant interviews and the application of a survey (n = 522) in four communities along the Inter-Oceanic Highway (IOH) in Madre de Dios, Peru over a two-year period. RESULTS: Although 90 % of survey respondents answered that rodents can transmit diseases and had seen rodents in their homes and immediate surroundings, most could not name specific rodent-borne diseases and, when probed, described rodents as pests or nuisance animals, but were not concerned about acquiring illnesses from them. Key informant interview data suggests that there has been a perceived increase in the amount of rodents in the communities since the construction of the IOH, however this potential increase was not coupled with increased knowledge about diseases or perceived risks among these key informants. Health providers also mentioned a lack of diagnostic tools specific for rodent-borne illnesses. This may be related to the fact that although a common rodent-borne disease like leptospirosis is frequently detected in the region, it is not routinely and readily diagnosed, therefore the real burden of the disease and exposure risk can be underestimated. If rodent borne diseases are not on the radar of health professionals, they may not consider presumptive treatment, which could result in unnecessary morbidity and mortality. CONCLUSION: Awareness of rodent-borne diseases is still lacking in the area, even among health care professionals within the communities, despite the known burden of diseases like leptospirosis. We expect to report further findings as we obtain more information from all the study components. PMID- 27506540 TI - The immunotherapy era of myeloma: monoclonal antibodies, vaccines, and adoptive T cell therapies. AB - The treatment of multiple myeloma has evolved significantly over the last decades from primarily alkylator-based chemotherapeutic agents with minimal efficacy to the introduction of more effective agents including immune modulators and proteasome inhibitors, which have changed the landscape of therapy for this disease. We are now entering a new era that will increasingly integrate immunotherapy into standard treatment. This review discusses the current immune based strategies currently approved, as well as various immune approaches being actively investigated including monoclonal antibodies, checkpoint inhibitors, vaccines, and adoptive T-cell therapies. PMID- 27506541 TI - Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells. AB - Therapeutic CD4(+)Foxp3(+) natural regulatory T cells (Tregs) can control experimental graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) by suppressing conventional T cells (Tconvs). Treg-based therapies are currently tested in clinical trials with promising preliminary results in allo-HCT. Here, we hypothesized that as Tregs are capable of modulating Tconv response, it is likely that the inflammatory environment and particularly donor T cells are also capable of influencing Treg function. Indeed, previous findings in autoimmune diabetes revealed a feedback mechanism that renders Tconvs able to stimulate Tregs by a mechanism that was partially dependent on tumor necrosis factor (TNF). We tested this phenomenon during alloimmune response in our previously described model of GVHD protection using antigen specific Tregs. Using different experimental approaches, we observed that control of GVHD by Tregs was fully abolished by blocking TNF receptor type 2 (TNFR2) or by using TNF-deficient donor T cells or TNFR2-deficient Tregs. Thus, our results show that Tconvs exert a powerful modulatory activity on therapeutic Tregs and clearly demonstrate that the sole defect of TNF production by donor T cells was sufficient to completely abolish the Treg suppressive effect in GVHD. Importantly, our findings expand the understanding of one of the central components of Treg action, the inflammatory context, and support that targeting TNF/TNFR2 interaction represents an opportunity to efficiently modulate alloreactivity in allo-HCT to either exacerbate it for a powerful antileukemic effect or reduce it to control GVHD. PMID- 27506543 TI - Tadalafil Treatment Delays the Onset of Cardiomyopathy in Dystrophin-Deficient Hearts. AB - BACKGROUND: Cardiomyopathy is a leading cause of mortality among Duchenne muscular dystrophy patients and lacks effective therapies. Phosphodiesterase type 5 is implicated in dystrophic pathology, and the phosphodiesterase type 5 inhibitor tadalafil has recently been studied in a clinical trial for Duchenne muscular dystrophy. METHODS AND RESULTS: Tadalafil was evaluated for the prevention of cardiomyopathy in the mdx mouse and golden retriever muscular dystrophy dog models of Duchenne muscular dystrophy. Tadalafil blunted the adrenergic response in mdx hearts during a 30-minute dobutamine challenge, which coincided with cardioprotective signaling, reduced induction of MU-calpain levels, and decreased sarcomeric protein proteolysis. Dogs with golden retriever muscular dystrophy began daily tadalafil treatment prior to detectable cardiomyopathy and demonstrated preserved cardiac function, as assessed by echocardiography and magnetic resonance imaging at ages 18, 21, and 25 months. Tadalafil treatment improved golden retriever muscular dystrophy histopathological features, decreased levels of the cation channel TRPC6, increased total threonine phosphorylation status of TRPC6, decreased m-calpain levels and indicators of calpain target proteolysis, and elevated levels of utrophin. In addition, we showed that Duchenne muscular dystrophy patient myocardium exhibited increased TRPC6, m-calpain, and calpain cleavage products compared with control human myocardium. CONCLUSIONS: Prophylactic use of tadalafil delays the onset of dystrophic cardiomyopathy, which is likely attributed to modulation of TRPC6 levels and permeability and inhibition of protease content and activity. Consequently, phosphodiesterase type 5 inhibition is a candidate therapy for slowing the development of cardiomyopathy in Duchenne muscular dystrophy patients. PMID- 27506542 TI - Socioeconomic status as a moderator between frailty and mortality at old ages. AB - BACKGROUND: Despite the well-established power of frailty to predict mortality, and the known associations of socioeconomic status (SES) with mortality, it is largely unknown whether the linkage between frailty and mortality varies across different SES groups. This study aims to investigate whether SES moderates the association between frailty and mortality. METHODS: We relied on the 2008/2009 and 2011/2012 waves of the Chinese Longitudinal Healthy Longevity Survey, a nationwide sample of 13,731 adults aged 65 or older in China. Frailty was constructed using a cumulative index of 38 items (with 39 deficits) reflecting different dimensions of health; the index or the proportion of deficits ranges from 0 to 1, with greater scores indicating poorer health condition. SES was measured by a socioeconomic vulnerability index (SEVI) also from a similar cumulative approach consisting of 6 deficits; the proportion of deficits ranges from 0 to 1 with higher scores indicating lower SES. Eight Weibull hazard regression models were performed to examine how SES moderates the linkage between frailty and mortality. RESULTS: We found that a one percentage point increase in the frailty index was associated with an increased hazard ratio (HR) by 2.7 % (HR = 1.027, 95 % CI: 1.025-1.027); a one percentage point increase in SEVI score was associated with an increased hazard ratio by 0.6 % (HR = 1.006, 95 % CI: 1.004 1.008) controlling for demographics. When interactions between SEVI and frailty index were modeled, the increased mortality risk associated with frailty was weaker among people with lower SES than among people with higher SES (HR = 0.983, 95 % CI: 0.967-0.992). However, the moderating role of SES was diminished when interactions between SES and age and between frailty and age were modeled. With increasing age, the increased mortality risks associated with frailty and socioeconomic vulnerability weakened. CONCLUSIONS: Frailty was a stronger predictor of mortality among individuals with higher SES than those with lower SES. The increased mortality risks associated with socioeconomic vulnerability and frailty weakened with age. Public health programs aimed at improving SES and promoting healthy longevity should start early in old age, or even earlier, and target poor and frail older adults for maximum impact. PMID- 27506544 TI - In-Hospital Vital Status and Heart Transplants After Intervention for Congenital Heart Disease in the Pediatric Cardiac Care Consortium: Completeness of Ascertainment Using the National Death Index and United Network for Organ Sharing Datasets. AB - BACKGROUND: The long-term outcomes of patients undergoing interventions for congenital heart disease (CHD) remain largely unknown. We linked the Pediatric Cardiac Care Consortium (PCCC) with the National Death Index (NDI) and the United Network for Organ Sharing Dataset (UNOS) registries to study mortality and transplant occurring up to 32 years postintervention. The objective of the current analysis was to determine the sensitivity of this linkage in identifying patients who are known to have died or undergone heart transplant. METHODS AND RESULTS: We used direct identifiers from 59 324 subjects registered in the PCCC between 1982 and 2003 to test for completeness of case ascertainment of subjects with known vital and heart transplant status by linkage with the NDI and UNOS registries. Of the 4612 in-hospital deaths, 3873 were identified by the NDI as "true" matches for a sensitivity of 84.0% (95% CI, 82.9-85.0). There was no difference in sensitivity across 25 congenital cardiovascular conditions after adjustment for age, sex, race, presence of first name, death year, and residence at death. Of 455 known heart transplants in the PCCC, there were 408 matches in the UNOS registry, for a sensitivity of 89.7% (95% CI, 86.9-92.3). An additional 4851 deaths and 363 transplants that occurred outside the PCCC were identified through 2014. CONCLUSIONS: The linkage of the PCCC with the NDI and UNOS national registries is feasible with a satisfactory sensitivity. This linkage provides a conservative estimate of the long-term death and heart transplant events in this cohort. PMID- 27506545 TI - High resolution metabolomics to discriminate compounds in serum of male lung cancer patients in South Korea. AB - BACKGROUND: The cancer death rate escalated during 20th century. In South Korea, lung cancer is expected to contribute 12,736 deaths in men, the highest amount among all cancers. Several risk factors may increase the chance to acquiring lung cancer, with mostly related to exogenous compounds found in cigarette smoke and synthetic manufacturing materials. As the mortality rate of lung cancer increases, deeper understanding is necessary to explore risk factors that may lead to this malignancy. In this regard, this study aims to apply high resolution metabolomics (HRM) using LC-MS to detect significant compounds that might contribute in inducing lung cancer and find the correlation of these compounds to the subjects' smoking habit. METHODS: The comparison was made between healthy control and lung cancer groups for metabolic differences. Further analyses to determine if these differences are related to tobacco-induced lung cancer (past smoker control vs. past-smoker lung cancer patients (LCPs) and non-smoker control vs. current-smoker LCPs) were selected. The univariate analysis was performed, including a false discovery rate (FDR) of q = 0.05, to determine the significant metabolites between the analyses. Hierarchical clustering analysis (HCA) was done to discriminate metabolites between the control and case subjects. Selected compounds based on significant m/z features of human serum then experienced MS/MS examination, showing that for many m/z, the patterns of ion dissociation matched with standards. Then, the significant metabolites were identified using Metlin database and features were mapped on the human metabolic pathway mapping tool of the Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: Using metabolomics wide association studies, metabolic changes were observed among control group and lung cancer patients. Bisphenol A (211.11, [M + H-H2O](+)), retinol (287.23, [M + H](+)) and L-proline (116.07, [M + H](+)) were among the significant compounds found to have contributed in the discrimination between these groups, suggesting that these compounds might be related in the development of lung cancer. Retinol has been seen to have a correlation with smoking while both bisphenol A and L proline were found to be unrelated. CONCLUSIONS: Two potential biomarkers, retinol and L-proline, were identified and these findings may create opportunities for the development of new lung cancer diagnostic tools. PMID- 27506546 TI - Expression of aryl hydrocarbon receptor in rat brain lesions following traumatic brain injury. AB - BACKGROUND: Aryl Hydrocarbon Receptor (AhR) is a ligand-activated transcription factor with multiple functions operating in a variety of organs, including the brain. Recent studies have revealed that AhR played a functional role in traumatic injuries. This paper aims to study the expression of AhR during the early phase following a traumatic brain injury (TBI) in rat brains by immunohistochemistry. METHODS: Weight-drop induced TBI was performed in rats. The expression of AhR in brain of TBI rats were examined by immunohistochemistry. RESULTS: Neuron expression of AhR in the rat brains of experiment group had been upregulated since day 3 in lesional hemisphere compared to that of the control group and mainly located in the cytoplasm, indicating an inactivated state. Interestingly, the accumulation of AhR(+) non-neuron cells became significant as early as 18 h after injury, which had kept increasing until 24 h post injury and then decreased slowly. For AhR(+) non-neuron cells, the AhR mainly located in cell nucleus, indicating a reactive status. Furthermore, double staining showed that most AhR(+) non-neuron cells co-localized with W3/13, a marker for T lymphocytes, but not with ED-1 (for activated microglia/macrophages) or GFAP (for activated astrocytes), suggesting that most AhR(+) non-neuron cells were T lymphocytes. CONCLUSION: This is the first study concerning AhR expression in brains following TBI, and our data demonstrated that AhR was upregulated and activated in T lymphocytes following TBI. More research is needed to make a more conclusive conclusion. PMID- 27506547 TI - Understanding clinical prediction models as 'innovations': a mixed methods study in UK family practice. AB - BACKGROUND: Well-designed clinical prediction models (CPMs) often out-perform clinicians at estimating probabilities of clinical outcomes, though their adoption by family physicians is variable. How family physicians interact with CPMs is poorly understood, therefore a better understanding and framing within a context-sensitive theoretical framework may improve CPM development and implementation. The aim of this study was to investigate why family physicians do or do not use CPMs, interpreting these findings within a theoretical framework to provide recommendations for the development and implementation of future CPMs. METHODS: Mixed methods study in North West England that comprised an online survey and focus groups. RESULTS: One hundred thirty eight respondents completed the survey, which found the main perceived advantages to using CPMs were that they guided appropriate treatment (weighted rank [r] = 299; maximum r = 414 throughout), justified treatment decisions (r = 217), and incorporated a large body of evidence (r = 156). The most commonly reported barriers to using CPMs were lack of time (r = 163), irrelevance to some patients (r = 161), and poor integration with electronic health records (r = 147). Eighteen clinicians participated in two focus groups (i.e. nine in each), which revealed 13 interdependent themes affecting CPM use under three overarching domains: clinician factors, CPM factors and contextual factors. Themes were interdependent, indicating the tensions family physicians experience in providing evidence-based care for individual patients. CONCLUSIONS: The survey and focus groups showed that CPMs were valued when they supported clinical decision making and were robust. Barriers to their use related to their being time-consuming, difficult to use and not always adding value. Therefore, to be successful, CPMs should offer a relative advantage to current working, be easy to implement, be supported by training, policy and guidelines, and fit within the organisational culture. PMID- 27506548 TI - Transcriptome profiling of the rumen epithelium of beef cattle differing in residual feed intake. AB - BACKGROUND: Feed efficient cattle consume less feed and produce less environmental waste than inefficient cattle. Many factors are known to contribute to differences in feed efficiency, however the underlying molecular mechanisms are largely unknown. Our study aimed to understand how host gene expression in the rumen epithelium contributes to differences in residual feed intake (RFI), a measure of feed efficiency, using a transcriptome profiling based approach. RESULTS: The rumen epithelial transcriptome from highly efficient (low (L-) RFI, n = 9) and inefficient (high (H-) RFI, n = 9) Hereford x Angus steers was obtained using RNA-sequencing. There were 122 genes differentially expressed between the rumen epithelial tissues of L- and H- RFI steers (p < 0.05) with 85 up-regulated and 37 down-regulated in L-RFI steers. Functional analysis of up regulated genes revealed their involvement in acetylation, remodeling of adherens junctions, cytoskeletal dynamics, cell migration, and cell turnover. Additionally, a weighted gene co-expression network analysis (WGCNA) identified a significant gene module containing 764 genes that was negatively correlated with RFI (r = -0.5, p = 0.03). Functional analysis revealed significant enrichment of genes involved in modulation of intercellular adhesion through adherens junctions, protein and cell turnover, and cytoskeletal organization that suggest possible increased tissue morphogenesis in the L-RFI steers. Additionally, the L RFI epithelium had increased expression of genes involved with the mitochondrion, acetylation, and energy generating pathways such as glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. Further qPCR analysis of steers with different RFI (L-RFI, n = 35; M-RFI, n = 34; H-RFI, n = 35) revealed that the relative mitochondrial genome copy number per cell of the epithelium was positively correlated with RFI (r = 0.21, p = 0.03). CONCLUSIONS: Our results suggest that the rumen epithelium of L-RFI (efficient) steers may have increased tissue morphogenesis that possibly increases paracellular permeability for the absorption of nutrients and increased energy production to support the energetic demands of increased tissue morphogenesis compared to those of H-RFI (inefficient) animals. Greater expression of mitochondrial genes and lower relative mitochondrial genome copy numbers suggest a greater rate of transcription in the rumen epithelial mitochondria of L-RFI steers. Understanding how host gene expression profiles are associated with RFI could potentially lead to identification of mechanisms behind this trait, which are vital to develop strategies for the improvement of cattle feed efficiency. PMID- 27506550 TI - Introduction to the Special Series on Fraction Learning. PMID- 27506549 TI - Prevention of mother-to-child transmission of hepatitis B virus: a phase III, placebo-controlled, double-blind, randomized clinical trial to assess the efficacy and safety of a short course of tenofovir disoproxil fumarate in women with hepatitis B virus e-antigen. AB - BACKGROUND: Chronic hepatitis B virus (HBV) infection is complicated by cirrhosis and liver cancer. In Thailand, 6-7 % of adults are chronically infected with HBV. The risk of mother-to-child transmission (MTCT) of HBV has been estimated to be about 12 % when mothers have a high hepatitis B viral load, even if infants receive passive-active prophylaxis with HBV immunoglobulin (HBIg) and initiate the hepatitis B vaccine series at birth. We designed a study to assess the efficacy and safety of a short course of maternal tenofovir disoproxil fumarate (TDF) among women with a marker of high viral load for the prevention of MTCT of HBV. METHODS: The study is a phase III, multicenter (17 sites in Thailand), placebo-controlled, double-blind, randomized 1:1, two-arm clinical trial of TDF 300 mg once daily versus placebo among pregnant women from 28 weeks' gestation through 2-month post-partum. All infants receive HBIg at birth, and a hepatitis B (HB) vaccination series according to Thai guidelines: birth, and age 1, 2, 4 and 6 months. Participant women at study entry must be age >=18 years, hepatitis B surface antigen (HBsAg) and e-antigen (HBeAg) positive, have alanine aminotransferase (ALT) level < 30 IU/L at screening (confirmed < 60 IU/L pre entry), negative hepatitis C serology, creatinine clearance >50 mL/min, and no history of anti-HBV antiviral treatment. The target sample size of 328 mother/infant pairs assumed 156 evaluable cases per arm to detect a >=9 % difference in MTCT transmission (3 % experimental arm versus 12 % placebo arm) with 90 % power. Mothers and infants are followed until 12 months after delivery. The primary infant endpoint is detection of HBsAg, confirmed by detection of HBV DNA at six months of age. Secondary endpoints are maternal and infant adverse events, acute exacerbations of maternal hepatitis B disease (ALT >300 IU/L, defined as a "flare") following discontinuation of study treatment, infant HBV infection status and growth up to 12 months of age. DISCUSSION: The results of this randomized trial will clarify the efficacy and safety of a short course of antiviral treatment to prevent mother-to-child transmission of HBV and inform international guidelines. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01745822 . PMID- 27506551 TI - Delaware Longitudinal Study of Fraction Learning: Implications for Helping Children With Mathematics Difficulties. AB - The goal of the present article is to synthesize findings to date from the Delaware Longitudinal Study of Fraction Learning. The study followed a large cohort of children ( N = 536) between Grades 3 and 6. The findings showed that many students, especially those with diagnosed learning disabilities, made minimal growth in fraction knowledge and that some showed only a basic grasp of the meaning of a fraction even after several years of instruction. Children with low growth in fraction knowledge during the intermediate grades were much more likely to fail to meet state standards on a broad mathematics measure at the end of Grade 6. Although a range of general and mathematics-specific competencies predicted fraction outcomes, the ability to estimate numerical magnitudes on a number line was a uniquely important marker of fraction success. Many children with mathematics difficulties have deep-seated problems related to whole number magnitude representations that are complicated by the introduction of fractions into the curriculum. Implications for helping students with mathematics difficulties are discussed. PMID- 27506552 TI - Fraction Sense: Foundational Understandings. AB - The intent of this commentary is to identify elements of fraction sense and note how the research studies provided in this special issue, in related but somewhat different ways, validate the importance of such understandings. Proficiency with fractions serves as a prerequisite for student success in higher level mathematics, as well as serving as a gateway to many occupations and varied contexts beyond the mathematics classroom. Fraction sense is developed through instructional opportunities involving fraction equivalence and magnitude, comparing and ordering fractions, using fraction benchmarks, and computational estimation. Such foundations are then extended to operations involving fractions and decimals and applications involving proportional reasoning. These components of fraction sense are all addressed in the studies provided in this issue, with particular consideration devoted to the significant importance of the use of the number line as a central representational tool for conceptually understanding fraction magnitude. PMID- 27506555 TI - Myocardial dysfunction in diabetes: Another epidemic? PMID- 27506554 TI - Matrix Metalloproteinase-8 Augments Bacterial Clearance in a Juvenile Sepsis Model. AB - Genetic ablation or pharmacologic inhibition of matrix metalloproteinase-8 (MMP8) improves survival in an adult murine sepsis model. Because developmental age influences the host inflammatory response, we hypothesized that developmental age influences the role of MMP8 in sepsis. First, we compared sepsis survival between wild type (WT, C57BL/6) and MMP8 null juvenile-aged mice (12-14 days) after intraperitoneal injection of a standardized cecal slurry. Second, peritoneal lavages collected at 6 and 18 hours after cecal slurry injection were analyzed for bacterial burden, leukocyte subsets, and inflammatory cytokines. Third, juvenile WT mice were pretreated with an MMP8 inhibitor prior to cecal slurry injection; analysis of their bacterial burden was compared to vehicle-injected animals. Fourth, the phagocytic capacity of WT and MMP8 null peritoneal macrophages was compared. Finally, peritoneal neutrophil extracellular traps (NETs) were compared using immunofluorescent imaging and quantitative image analysis. We found that juvenile MMP8 null mice had greater mortality and higher bacterial burden than WT mice. Leukocyte counts and cytokine concentrations in the peritoneal fluid were increased in the MMP8 null mice, relative to the wild type mice. Peritoneal macrophages from MMP8 null mice had reduced phagocytic capacity compared to WT macrophages. There was no quantitative difference in NET formation, but fewer bacteria were adherent to NETs from MMP8 null animals. In conclusion, in contrast to septic adult mice, genetic ablation of MMP8 increased mortality following bacterial peritonitis in juvenile mice. The increase in mortality in MMP8 null juvenile mice was associated with reduced bacterial clearance and reduced NET efficiency. We conclude that developmental age influences the role of MMP8 in sepsis. PMID- 27506553 TI - The Spectrum of Mitochondrial Ultrastructural Defects in Mitochondrial Myopathy. AB - Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus provide insight into the underlying pathogenesis of inherited and acquired mitochondrial diseases. Following a systematic literature review on ultrastructural defects in mitochondrial myopathy, we investigated skeletal muscle biopsies from seven subjects with genetically defined mtDNA mutations. Mitochondrial ultrastructure and morphology were characterized using two complimentary approaches: transmission electron microscopy (TEM) and serial block face scanning EM (SBF-SEM) with 3D reconstruction. Six ultrastructural abnormalities were identified including i) paracrystalline inclusions, ii) linearization of cristae and abnormal angular features, iii) concentric layering of cristae membranes, iv) matrix compartmentalization, v) nanotunelling, and vi) donut-shaped mitochondria. In light of recent molecular advances in mitochondrial biology, these findings reveal novel aspects of mitochondrial ultrastructure and morphology in human tissues with implications for understanding the mechanisms linking mitochondrial dysfunction to disease. PMID- 25971900 TI - Current status of automated breast ultrasonography. AB - Breast ultrasonography (US) is currently considered the first-line examination in the detection and characterization of breast lesions. However, conventional handheld US (HHUS) has several limitations such as operator dependence and the requirement of a considerable amount of radiologist time for whole-breast US. Automated breast US (ABUS), recently approved by the United States Food and Drug Administration for screening purposes, has several advantages over HHUS, such as higher reproducibility, less operator dependence, and less required physician time for image acquisition. In addition, ABUS provides both a coronal view and a relatively large field of view. Recent studies have reported that ABUS is promising in US screening for women with dense breasts and can potentially replace handheld second-look US in a preoperative setting. PMID- 25971901 TI - Postoperative ultrasonography of the musculoskeletal system. AB - Ultrasonography of the postoperative musculoskeletal system plays an important role in the accurate diagnosis of abnormal lesions in the bone and soft tissues. Ultrasonography is a fast and reliable method with no harmful irradiation for the evaluation of postoperative musculoskeletal complications. In particular, it is not affected by the excessive metal artifacts that appear on computed tomography or magnetic resonance imaging. Another benefit of ultrasonography is its capability to dynamically assess the pathologic movement in joints, muscles, or tendons. This article discusses the frequent applications of musculoskeletal ultrasonography in various postoperative situations including those involving the soft tissues around the metal hardware, arthroplasty, postoperative tendons, recurrent soft tissue tumors, bone unions, and amputation surgery. PMID- 27506558 TI - Design, synthesis and antimicrobial activity of 6-N-substituted chitosan derivatives. AB - Three novel 6-N-substituted chitosan derivatives were designed and synthesised and characterized by FTIR and NMR. The degree of substitution was calculated by elemental analysis results. The antimicrobial activities of the target compounds were evaluated by twofold serial broth dilution method and poisoned food technique. The antifungal activities of 6-aminoethylamino-6-deoxy chitosan (3), 6 butylamino-6-deoxy chitosan (4) and 6-pyridyl-6-deoxy chitosan (5) were significantly increased against Rhizoctonia cerealis, Fusarium oxysporum and Botrytis cinerea, and the inhibition rate ranged from 22.48% to 63.56% at the concentration of 0.2mg/mL. The compound 3 had better antibacterial activities than chitosan, and the minimum inhibition concentration of which ranged between 6.25 and 25mg/L against gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis and Bacillus anthracis) and gram-negative bacteria (Escherichia coli, Salmonella typhi). The antibacterial activities of 6-N-substituted chitosan tended to increase with the increase of the number of -NH2 group. PMID- 27506559 TI - Discovery of ravidasvir (PPI-668) as a potent pan-genotypic HCV NS5A inhibitor. AB - This Letter describes the synthesis, representative structure activity relationship (SAR), activity and PK profiles of a series of functionalized benzimidazole-naphthylene-imidazole derivatives as HCV NS5A inhibitors. This effort successfully led to the discovery of ravidasvir (PPI-668), which has been well tolerated and shown high sustained viral response rates as a key component in all-oral combination regimens in multiple human clinical trials. PMID- 27506560 TI - The contribution of adenines in the catalytic core of 10-23 DNAzyme improved by the 6-amino group modifications. AB - In the catalytic core of 10-23 DNAzyme, its five adenine residues are moderate conservative, but with highly conserved functional groups like 6-amino group and 7-nitrogen atom. It is this critical conservation that these two groups could be modified for better contribution. With 2'-deoxyadenosine analogues, several functional groups were introduced at the 6-amino group of the five adenine residues. 3-Aminopropyl substituent at 6-amino group of A15 resulted in a five fold increase of kobs. More efficient DNAzymes are expected by delicate design of the linkage and the external functional groups for this 6-amino group of A15. With this modification approach, other functional groups or residues could be optimized for 10-23 DNAzyme. PMID- 27506561 TI - Novel pentapeptide, PALAL, derived from a bony fish elicits contraction of the muscle in starfish Patiria pectinifera. AB - A bioactive peptide mimicking peptide-signaling molecules has been isolated from the skin extract of fish Channa argus which caused contraction of the apical muscle of a starfish Patiria pectinifera, a deuterostomian invertebrate. The primary structure of the isolated pentapeptide comprises amino acid sequence of H Pro-Ala-Leu-Ala-Leu-OH (PALAL) with a molecular mass of 483.7 Da. Pharmacological activity of PALAL, dosage ranging from 10-9 to 10-5 M, revealed concentration dependent contraction of the apical muscles of P. pectinifera and Asterias amurensis. However, PALAL was not active on the intestinal smooth muscle of the goldfish Carassius auratus and has presumably other physiological roles in fish skin. Investigation of structure-activity relationship using truncated and substituted analogs of PALAL demonstrated that H-Ala-Leu-Ala-Leu-OH was necessary and should be sufficient to constrict apical muscle of P. pectinifera. Furthermore, the second alanine residue was required to display the activity, and the fifth leucine residue was responsible for its potency. Comparison with PALAL's primary structure with those of other known bioactive peptides from fish and starfish revealed that PALAL does not have any significant homology. Consequently, PALAL is a bioactive peptide that elicits a muscle contraction in starfish, and the isolation of PALAL may lead to develop other bioactive peptides sharing its similar sequence and/or activity. Copyright (c) 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID- 27506562 TI - Acute pancreatitis and pneumonia due to Mycoplasma pneumoniae: a case report. AB - BACKGROUND: Mycoplasma pneumoniae is a bacterium responsible for 15 to 40 % of acute community-acquired pneumonia in children and 20 % of adult cases. Several extrapulmonary manifestations have been reported. We report a rare case of an adult patient suffering from pneumonia associated with an acute pancreatitis in the setting of Mycoplasma pneumoniae infection. CASE PRESENTATION: A 28-year-old Caucasian woman was referred for anorexia lasting for 1 week. Her past medical history was notable for congenital hydrocephalus with consecutive ventriculo peritoneal shunt, epilepsia and paraparesis. The patient rapidly deteriorated, presenting with dyspnea, tachypnea, productive cough, abdominal pain, and onset of fever. C-reactive protein was at 270 mg/L, with a rise in serum lipase (670 UI/L, N: 13-60). A computed-tomography scan showed an acute interstitial edematous pancreatitis without necrosis, consistent with grade C on the Balthazar score. Thoracic sections revealed diffuse parenchymal consolidations combined with ground glass opacities. Calcium and triglyceride levels were normal. There was no history of recent trauma, alcoholic intake or drug intoxication. Mycoplasma pneumoniae serological assay showed an elevated IgM titer (22 UA/mL), compatible with recent infection, and cold agglutinins were present. A diagnosis of acute pancreatitis and diffuse interstitial pneumonia caused by an infection with Mycoplasma pneumoniae was considered. Respiratory and abdominal evolution was quickly favorable after initiation of clarithromycin 500 mg bid. CONCLUSIONS: The relationship between Mycoplasma pneumoniae infection and acute pancreatitis has been debated in the literature for many years. This observation, supported by clinical, biological and radiological features, is an additional argument in favor of a non-fortuitous association. PMID- 27506563 TI - Poor validity of the routine diagnosis of necrotising enterocolitis in preterm infants at discharge. AB - AIM: Necrotising enterocolitis contributes considerably to the mortality of preterm infants, but most questions remain unsolved after decades of extensive research. This Danish study investigated the validity of necrotising enterocolitis diagnoses at discharge according to Bell's staging system. METHODS: We conducted a retrospective single-centre cohort study of 714 preterm infants with a gestational age of less than 30 weeks born in 2006-2013. The infants were diagnosed with necrotising enterocolitis according to Bell's stages 2-3 at discharge and in retrospect by an expert panel, which served as our gold standard. RESULTS: The sensitivity of necrotising enterocolitis diagnosed at discharge was 0.72-0.75 depending on whether spontaneous intestinal perforation was included as necrotising enterocolitis or not. The positive predictive value of the diagnosis was 0.49-0.61. The incidence was significantly higher when diagnosed at discharge than when diagnosed by the expert panel (11.1 versus 9.0%, p = 0.03). The mortality rate for infants who were underdiagnosed at discharge was 50.0%, and it was 25.8% for infants who were overdiagnosed (p = 0.10). CONCLUSION: We found poor validity for the discharge diagnosis of necrotising enterocolitis. In future, a better way of defining the disease is needed for large-scale epidemiologic research. PMID- 27506564 TI - Enhanced Solubility and Dissolution Rate of Lacidipine Nanosuspension: Formulation Via Antisolvent Sonoprecipitation Technique and Optimization Using Box-Behnken Design. AB - Lacidipine (LCDP) is a highly lipophilic calcium channel blocker of poor aqueous solubility leading to poor oral absorption. This study aims to prepare and optimize LCDP nanosuspensions using antisolvent sonoprecipitation technique to enhance the solubility and dissolution of LCDP. A three-factor, three-level Box Behnken design was employed to optimize the formulation variables to obtain LCDP nanosuspension of small and uniform particle size. Formulation variables were as follows: stabilizer to drug ratio (A), sodium deoxycholate percentage (B), and sonication time (C). LCDP nanosuspensions were assessed for particle size, zeta potential, and polydispersity index. The formula with the highest desirability (0.969) was chosen as the optimized formula. The values of the formulation variables (A, B, and C) in the optimized nanosuspension were 1.5, 100%, and 8 min, respectively. Optimal LCDP nanosuspension had particle size (PS) of 273.21 nm, zeta potential (ZP) of -32.68 mV and polydispersity index (PDI) of 0.098. LCDP nanosuspension was characterized using x-ray powder diffraction, differential scanning calorimetry, and transmission electron microscopy. LCDP nanosuspension showed saturation solubility 70 times that of raw LCDP in addition to significantly enhanced dissolution rate due to particle size reduction and decreased crystallinity. These results suggest that the optimized LCDP nanosuspension could be promising to improve oral absorption of LCDP. PMID- 27506565 TI - Influence of Hydroalcoholic Vehicle on In Vitro Transport of 4-Hydroxy Tamoxifen Through the Mammary Papilla (Nipple). AB - Majority of breast cancers originate from epithelial cells in the duct and lobules in the breast. Current systemic treatments for breast cancer are associated with significant systemic side effects, thus warranting localized drug delivery approaches. The aim of this study was to investigate the influence of hydroalcoholic vehicle on topical delivery of 4-hydroxy tamoxifen (4-HT) through the mammary papilla (nipple). The in vitro permeability of 4-HT through porcine mammary papilla was studied using different hydroalcoholic vehicles (0, 33.33, and 66.66% alcohol). Nile red was used as a model lipophilic dye to characterize the drug transport pathway in the mammary papilla. The penetration of 4-HT through the mammary papilla increased with increase in alcohol concentration in the vehicle. The solubility of 4-HT was enhanced by increasing alcohol concentration in the vehicle. On the other hand, the epidermis/vehicle partition coefficient decreased with increase in alcohol concentration. The mammary papilla served as a depot and slowly released 4-HT into the receptor medium. Highest drug penetration was observed with saturated drug solution in 66.66% alcohol, and 4-HT levels were comparable to IC50 value of 4-HT. Results from this study demonstrate the possibility of using mammary papilla as a potential route for direct delivery of 4-HT to the breast. PMID- 27506566 TI - Letter to the editor of infection in response to de Francesco et al., a cluster of invasive listeriosis in Brescia, Italy. PMID- 27506568 TI - Advances in the development of catalytic tethering directing groups for C-H functionalization reactions. AB - Transition metal-catalyzed C-H bond insertion is one of the most straightforward strategies to introduce functionalities within a hydrocarbon microenvironment. For the past two decades, selective activation and functionalization of certain inert C-H bonds have been made possible with the help of directing groups (DGs). Despite the enormous advances in the field, an overwhelming majority of systems require two extra steps from their simple precursors: installation and removal of the DGs. Recently, traceless and multitasking groups were invented as a partial solution to DG release. However, installation remains largely unsolved. Ideally, a transient, catalytic DG would circumvent this problem and increase the step- and atom-economy of C-H functionalization processes. In this review, we summarize the recent development of the transient tethering strategy for C-H activation reactions. PMID- 27506567 TI - Does the intraocular pressure-lowering effect of prostaglandin analogues continue over the long term? AB - The purpose of the study is to assess the changes in the long-term effects of prostaglandin analogues (PGAs) on intraocular pressure (IOP) reduction in patients with primary open-angle glaucoma (POAG). Data of POAG patients treated with latanoprost (0.005 %), travoprost (0.004 %), or bimatoprost (0.03 %) as the first line treatment for 5 years or more were retrospectively evaluated. Baseline ophthalmic assessment values were recorded together with the IOP at the 6th month, 1st year, and then annually. The 79 patients included 33 (41.8 %) men and 46 (58.2 %) women. There were 34 (43.0 %) patients using latanoprost (0.005 %), 23 (29.1 %) patients using bimatoprost (0.03 %), and 22 (27.8 %) patients using travoprost (0.004 %). There was no difference between the groups in terms of age, gender, or baseline IOP levels. IOP levels at the 6th month were significantly lower than baseline IOP levels in all groups (p < 0.01, Friedman test). The IOP decrease was maintained after the 6th month in all three group with no statistically significant difference compared to the 6th month IOP value (p > 0.05, Friedman test) and no statistically significant difference between the groups during follow-up (Kruskal-Wallis test, p > 0.05). IOP reductions with PGAs were adequate and stable in the 5-year follow-up period with no decrease in effectiveness over time. PMID- 27506569 TI - Complications of elastic stable intramedullary nailing of femoral shaft fractures in children weighing fifty kilograms (one hundred and ten pounds) and more. AB - AIM: The purpose of this study was to assess treatment outcomes in children weighing 50 kg (110 pounds) or more with displaced femur shaft fractures treated by elastic stable intramedullary nailing (ESIN) and to identify potential correlations between nail size/medullary canal diameter ratio and outcome. METHODS: Twenty out of 117 consecutive children surgically treated by ESIN for displaced fractures of the femoral shaft with no associated neurovascular injury weighed 50 kg (110 pounds) or more. All patients underwent regular clinical and radiographic follow-up for at least one year after their index surgery. RESULTS: The average patient age at the time of injury was 13.1 years (25th and 75th interquartile range [IQR] = 11.7-14.5). The mean follow-up was 27.4 months (IQR = 18.4-36.8). Overall, nine (45 %) adverse events were observed. The rate of complications was higher among children weighting 55 kg and over (67 %) than in children weighing less than 55 kg (35 %) and among children aged 13 years old or older (72 %) than among children younger than 13 years old (11 %). DISCUSSION: Femoral shaft fractures in children and adolescents weighing 50 kg (110 pounds) and over and older than ten years of age have an increased rate of complications. CONCLUSION: Heavier patients have a greater chance of complications. In particular, patients younger than 13 years old and weighing less than 55 kg can be safely managed with ESIN, but older and heavier patients should preferably be treated with rigid fixation systems due to a greater complication rate. However, further studies are needed to consolidate the conclusions. PMID- 27506570 TI - Treatment of displaced supracondylar humeral fractures in children by humero ulnar external fixation. AB - PURPOSE: Humero-ulnar external fixation has been proposed to treat complex supracondylar humeral fractures in children. It facilitates fracture reduction and reduces the risk of ulnar nerve lesion, which can occur after cross pinning. METHODS: In a ten year period, 28 children have been operated on in our centre by humero-ulnar external fixation, for Lagrange-Rigault stages III and IV supracondylar humeral fractures. The data about fracture management and early follow-up were obtained from our medical database. The long-term evaluation was done at a minimum six months' follow-up. The range of motion and carrying angle measurements were classified according to Flynn. The final X-rays were evaluated for quality of reduction, presence of malunion, late infection signs, osteo arthritis and myositis ossificans. The elbow function was evaluated by Mayo Elbow Performance Index (MEPI), Disabilities of the Arm, Shoulder and Hand (DASH) or modified DASH scores. RESULTS: The treatment was well tolerated by children and parents. There was no neurological complication related to the insertion of the pins, and no Volkmann syndrome. The median duration of external fixation was 33.5 days. Twelve patients were reviewed after a median follow-up duration of seven years (mean, 7.5 years; range, 3-21 years). One child had a refracture, three years after his original fracture, which was treated non-operatively. This case ended up in a cubitus varus deformity with a pronation deficit. All other patients had excellent clinical and radiological results. CONCLUSIONS: For the treatment of complex supracondylar humeral fractures in children, humero-ulnar external fixation is a good alternative to lateral or crossed pinning. The advantages are the ease to obtain the reduction, the absence of neurological risk to the ulnar nerve and the possibility to obtain good stabilisation of the fracture with moderate elbow flexion. PMID- 27506571 TI - Early aseptic loosening of cementless monoblock acetabular components. AB - PURPOSE: Early aseptic loosening of cementless monoblock acetabular components is a rare complication of total hip arthroplasty (THA) and hip resurfacing arthroplasty (HRA). The purpose of this study was to evaluate the incidence and risk factors for early aseptic loosening of the cementless monoblock acetabular components. METHODS: This retrospective analysis consisted of 4,043 cementless hip devices (3,209 THAs and 834 HRAs). We identified 41 patients with early aseptic loosening of the acetabular component. A control group of 123 patients without acetabular component loosening was randomly selected. The demographic data and risk factors for loosening of the acetabular component were evaluated. The mean follow-up time was 4.6 years (range, 1.7-7.8). The end-point was acetabular revision. RESULTS: The incidence of early acetabular component loosening was 1.0 %. Mean time to revision was 1.2 years (SD 1.6, range 0.0-5.4). There was significantly more Dorr type A and C acetabular morphology in patients with early loosening (P = 0.014). The loosened components were implanted to more vertical (P < 0.001) and less anteverted (P = 0.001) position than those of the control group. Presence of acetabular dysplasia or acetabular component type did not associate to early loosening. CONCLUSIONS: Acetabular morphology (Dorr type A and C) and component positioning vertically and less anteverted were more common in patients with early aseptic loosening of cementless acetabular components. Suboptimal cup position most likely reflects challenges to obtain sufficient stability during surgery. We hypothesize that errors in surgical technique are the main reason for early loosening of monoblock acetabular components. PMID- 27506572 TI - Total shoulder replacement using a bone ingrowth central peg polyethylene glenoid component: a prospective clinical and computed tomography study with short- to mid-term follow-up. AB - AIM OF THE STUDY: To assess the clinical and computed tomography (CT) outcomes of shoulder replacement with a novel bone ingrowth all-polyethylene glenoid component (APGC). METHODS: Twenty-eight patients (30 shoulders) with osteoarthritis, mean age 62.3 years (range, 45-75), were implanted with the novel component between 2011 and 2013. Patients were evaluated by active range of motion (ROM), Constant-Murley score (CMS), simple shoulder test (SST), X-rays, and multidetector CT at two months and at a mean follow-up of 31 months (range, 24-39). Early and late follow-up CT scans were available for 21/30 shoulders. RESULTS: Median ROM increased from 105 to 160 degrees for anterior elevation, from 100 to 160 degrees for lateral elevation, from 20 to 40 degrees for external rotation, and from 2 to 10 points for internal rotation (all p < 0.001). CMS rose from 30 to 80.5 points and SST from 2.5 to 11 (both p < 0.0001). None of the glenoid components migrated. Progressive radiolucency was seen in 28/30 shoulders. There was a strong correlation between greater bone ingrowth (median Arnold score: 7) and lower radiolucency score (median Yian score: 2) at the last follow-up (p < 0.001). Osteolysis around the central peg was seen in two shoulders. There was no correlation between clinical scores and CT findings (p >0.05). DISCUSSION: The partially cemented glenoid component for TSR assessed in this study resulted in satisfactory shoulder function at an early follow-up. The glenoid prosthesis was stable, with few radiolucent lines and good central peg bone ingrowth. CONCLUSIONS: The satisfactory bone ingrowth documented on CT is encouraging and supports the use of the new prosthesis. Long-term follow-up studies can confirm if this device represents a rational alternative to fully cemented polyethylene glenoids. PMID- 27506573 TI - Eudesmane-type sesquiterpenoids from Salvia plebeia inhibit IL-6-induced STAT3 activation. AB - Seven eudesmane-type sesquiterpenoid lactones and the known plebeiolide C were isolated from an ethanol-soluble extract of the aerial parts of Salvia plebeia R. Br. Their structures were determined via NMR and MS, and their absolute configurations were elucidated using ECD, and X-ray crystallographic analysis, as well as the modified Mosher ester method. All isolates were evaluated for their inhibitory effects on IL6-induced STAT3 promoter activation in stably transfected Hep3B cells. Of these isolates, eudebeiolide D exhibited an inhibitory effect with the IC50 value of 1.1 MUM. PMID- 27506574 TI - Features and Application in Asymmetric Catalysis of Chiral Phosphine-Phosphite Ligands. AB - Chiral phosphine-phosphites are a class of ligands for asymmetric catalysis characterized by two coordinating functionalities with different electronic properties. These ligands also possess a highly modular structure and, due to versatile synthetic processes, they can be tuned precisely in the catalyst optimization process. Research regarding the application of these ligands in several enantioselective catalytic processes has provided outstanding results in a good number of them. These processes include not only Rh catalyzed reactions, such as olefin hydrogenation and hydroformylation, but also other reactions, such as hydrogenation of olefins and imines by Ru complexes, of imines and N heterocycles by Ir derivatives, allyl alkylation or conjugate addition by Cu catalysts, or hydrocyanation of olefins by Ni ones. Overall, the use of these ligands has led to the preparation of a wide variety of chiral building blocks with high enantiomeric excess. Therefore, phosphine-phosphites have become in an important class of ligands in asymmetric catalysis. PMID- 27506575 TI - Free-Radical-Assisted Rapid Synthesis of Graphene Quantum Dots and Their Oxidizability Studies. AB - This work reports a modified electrochemical method for rapid and large-scale preparing graphene quantum dots (GQDs) by introduction of active free radicals, which were produced by hydrogen peroxide or ultraviolet radiation. These free radicals can deepen the oxidized or reduced level of working electrode in electrochemical process and thus lead to GQDs with high concentration and small size, but different surface oxidized degree. The improved oxidation and reduction mechanism were analyzed in this work. Meanwhile, the optical properties and oxidizability of GQDs with different surface oxidized degree were investigated. It is found that these GQDs can be used as an oxidizing agent and their oxidizability is related to the degree being oxidized. PMID- 27506576 TI - Citation for the 2015 Down Surgical Prize: Professor Velupillai Ilankovan. PMID- 27506577 TI - Aerobic metabolism on muscle contraction in porcine iris sphincter. AB - Eyes are supplied O2 through the cornea and vessels of the retina and iris, which are tissues characterized by aerobic metabolism. Meanwhile, there are no reports on the association between iris sphincter contraction and aerobic metabolism. In this paper, we studied the aforementioned association. Eyes from adult pigs of either sex were obtained from a local abattoir. A muscle strip was connected to a transducer to isometrically record the tension. O2 consumption was measured using a Clark-type polarograph connected to a biological oxygen monitor. Creatine phosphate (PCr) and adenosine triphosphate (ATP) contents were measured in the muscle strips by high-performance liquid chromatography (HPLC). Iris sphincter muscles were measured in resting, contractile or hypoxic phases. Contraction was induced by hyperosmotic 65 mM KCl (H-65K+) or carbachol (CCh), and hypoxia was induced by aeration with N2 instead of O2 or by addition of sodium cyanide (NaCN). H-65K+- and CCh-induced muscle contraction, involved increasing O2 consumption. Hypoxia and NaCN significantly decreased H-65K+- and CCh-induced muscle contraction and/or O2 consumption and PCr contents. Our results suggest that the contractile behavior in porcine iris sphincter highly depends on mitogen oxidative metabolism. PMID- 27506578 TI - TRPV4 ion channel as important cell sensors. AB - This review provides a summary of the physiological significance of the TRPV4 ion channel. Although TRPV4 was initially characterized as an osmosensor, we found that TRPV4 can also act as a thermosensor or a mechanosensor in brain neurons or epithelial cells in the urinary bladder. Here, we summarize the newly characterized functions of TRPV4, including the research progress that has been made toward our understanding of TRPV4 physiology, and discuss other recent data pertaining to TRPV4. It is thought that TRPV4 may be an important drug target based on its broad expression patterns and important physiological functions. Possible associations between diseases and TRPV4 are also discussed. PMID- 27506579 TI - Variation in primary site resection practices for advanced colon cancer: a study using the National Cancer Data Base. AB - BACKGROUND: Treatment of metastatic colon cancer may be driven as much by practice patterns as by features of disease. To optimize management, there is a need to better understand what is determining primary site resection use. METHODS: We evaluated all patients with stage IV cancers in the National Cancer Data Base from 2002 to 2012 (50,791 patients, 1,230 hospitals). We first identified patient characteristics associated with primary tumor resection. Then, we assessed nationwide variation in hospital resection rates. RESULTS: Overall, 27,387 (53.9%) patients underwent primary site resection. Factors associated with resection included younger age, having less than 2 major comorbidities, and white race (P < .001). Nationwide, hospital-adjusted primary tumor resection rates ranged from 26.0% to 87.8% with broad differences across geographical areas and hospital accreditation types. CONCLUSIONS: There is statistically significant variation in hospital rates of primary site resection. This demonstrates inconsistent adherence to guidelines in the presence of conflicting evidence regarding resection benefit. PMID- 27506580 TI - Using fundamental frequency of cancer survivors' speech to investigate emotional distress in out-patient visits. AB - OBJECTIVE: Emotions, are in part conveyed by varying levels of fundamental frequency of voice pitch (f0). This study tests the hypothesis that patients display heightened levels of emotional arousal (f0) during Verona Coding Definitions of Emotional Sequences (VR-CoDES) cues and concerns versus during neutral statements. METHODS: The audio recordings of sixteen head and neck cancer survivors' follow-up consultations were coded for patients' emotional distress. Pitch (f0) of coded cues and concerns, including neutral statements was extracted. These were compared using a hierarchical linear model, nested for patient and pitch range, controlling for statement speech length. Utterance content was also explored. RESULTS: Clustering by patient explained 30% of the variance in utterances f0. Cues and concerns were on average 13.07Hz higher than neutral statements (p=0.02). Cues and concerns in these consultations contained content with a high proportion of recurrence fears. CONCLUSION: The present study highlights the benefits and challenges of adding f0 and potential other prosodic features to the toolkit of coding emotional distress in the health communication setting. PRACTICE IMPLICATIONS: The assessment of f0 during clinical conversations can provide additional information for research into emotional expression. PMID- 27506581 TI - Cancer patients' understanding of longitudinal EORTC QLQ-C30 scores presented as bar charts. AB - OBJECTIVE: To investigate cancer patients' understanding of graphical presentations of longitudinal EORTC QLQ-C30 scores. METHODS: We conducted semi structured interviews with brain tumour patients participating in routine patient reported outcome (PRO) monitoring. We assessed understanding of longitudinal quality of life (QOL) profiles, presented as bar charts objectively and with self ratings. In addition, patients' opinions on congruency of the QOL scores with their self-perceived health status were evaluated. RESULTS: We recruited 40 brain tumour patients (57.5% female; mean age 52.7, SD 13.7). In total, 90% of patients rated the graphs as easy to understand. Accordingly, almost all questions on assessing understanding objectively were answered correctly by at least 80% of the patients. More than 95% indicated that the displayed QOL scores matched their personal perception of symptom burden and functional health in the observed period. CONCLUSION: Patients are able to understand their QOL results when presented graphically and are able to interpret important changes. Displayed QOL scores obtained with the EORTC QLQ-C30 are consistent with the patients' personal perception of physical and emotional functioning, pain and fatigue. PRACTICE IMPLICATIONS: Knowledge about patients' understanding of graphically displayed QOL results contributes to creation of optimal evidence-based feedback on the patients' present QOL and its trajectory. PMID- 27506582 TI - A multiplex real-time PCR panel assay for simultaneous detection and differentiation of 12 common swine viruses. AB - Mixed infection with different pathogens is common in swine production systems especially under intensive production conditions. Quick and accurate detection and differentiation of different pathogens are necessary for epidemiological surveillance, disease management and import and export controls. In this study, we developed and validated a panel of multiplex real-time PCR/RT-PCR assays composed of four subpanels, each detects three common swine pathogens. The panel detects 12 viruses or viral serotypes, namely, VSV-IN, VSV-NJ, SVDV, CSFV, ASFV, FMDV, PCV2, PPV, PRV, PRRSV-NA, PRRSV-EU and SIV. Correlation coefficients (R(2)) and PCR amplification efficiencies of all singular and triplex real-time PCR reactions are within the acceptable range. Comparison between singular and triplex real-time PCR assays of each subpanel indicates that there is no significant interference on assay sensitivities caused by multiplexing. Specificity tests on 226 target clinical samples or 4 viral strains and 91 non target clinical samples revealed that the real-time PCR panel is 100% specific, and there is no cross amplification observed. The limit of detection of each triplex real-time PCR is less than 10 copies per reaction for DNA, and less than 16 copies per reaction for RNA viruses. The newly developed multiplex real-time PCR panel also detected different combinations of co-infections as confirmed by other means of detections. PMID- 27506583 TI - Biomass and productivity of fishes in estuaries: a South African case study. AB - Estuaries are well known for their role as nutrient and detrital sinks that stimulate high levels of both primary and secondary production which, in turn, support a large biomass of fishes per unit area. This study reviews available information on coastal fish biomasses (g m-2 wet mass) and productivity (g m-2 wet mass year-1 ) in order to place South African data on these topics into a global perspective. Using biogeographic fish productivity estimates, together with estuarine water area, the approximate annual teleost production in South African estuaries was calculated at 585, 1706 and 13 904 t in the cool temperate, warm temperate and subtropical regions, respectively. Total annual fish production in estuaries on the subcontinent is conservatively estimated at 16 195 t, but this figure is likely to fluctuate widely, depending on recruitment success and annual environmental conditions pertaining to these systems. Approximately 2000 t of fish are estimated to be harvested by fishing activities in South African estuaries each year, which represents c. 12% of annual fish production. Although this figure may appear sustainable, the reality is that there are a few heavily targeted estuary-associated marine species at the top of the food chain that are being overexploited by both anglers and subsistence fishermen. Natural mortalities due to piscivorous fish and bird predation has been estimated at c. 3% of total fish biomass per month in the East Kleinemonde Estuary, but this figure will vary considerably depending on bird abundance and foraging patterns along the coast. In contrast to catches made by the fishermen, piscivorous fishes and birds are targeting mainly juvenile marine fish and small estuarine resident species that are very abundant and generally low down in the food web. PMID- 27506584 TI - Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. AB - AIMS/HYPOTHESIS: Human pancreatic beta cells may be complicit in their own demise in type 1 diabetes, but how this occurs remains unclear. One potentially contributing factor is hyperexpression of HLA class I antigens. This was first described approximately 30 years ago, but has never been fully characterised and was recently challenged as artefactual. Therefore, we investigated HLA class I expression at the protein and RNA levels in pancreases from three cohorts of patients with type 1 diabetes. The principal aims were to consider whether HLA class I hyperexpression is artefactual and, if not, to determine the factors driving it. METHODS: Pancreas samples from type 1 diabetes patients with residual insulin-containing islets (n = 26) from the Network for Pancreatic Organ donors with Diabetes (nPOD), Diabetes Virus Detection study (DiViD) and UK recent-onset type 1 diabetes collections were immunostained for HLA class I isoforms, signal transducer and activator of transcription 1 (STAT1), NLR family CARD domain containing 5 (NLRC5) and islet hormones. RNA was extracted from islets isolated by laser-capture microdissection from nPOD and DiViD samples and analysed using gene-expression arrays. RESULTS: Hyperexpression of HLA class I was observed in the insulin-containing islets of type 1 diabetes patients from all three tissue collections, and was confirmed at both the RNA and protein levels. The expression of beta2-microglobulin (a second component required for the generation of functional HLA class I complexes) was also elevated. Both 'classical' HLA class I isoforms (i.e. HLA-ABC) as well as a 'non-classical' HLA molecule, HLA-F, were hyperexpressed in insulin-containing islets. This hyperexpression did not correlate with detectable upregulation of the transcriptional regulator NLRC5. However, it was strongly associated with increased STAT1 expression in all three cohorts. Islet hyperexpression of HLA class I molecules occurred in the insulin containing islets of patients with recent-onset type 1 diabetes and was also detectable in many patients with disease duration of up to 11 years, declining thereafter. CONCLUSIONS/INTERPRETATION: Islet cell HLA class I hyperexpression is not an artefact, but is a hallmark in the immunopathogenesis of type 1 diabetes. The response is closely associated with elevated expression of STAT1 and, together, these occur uniquely in patients with type 1 diabetes, thereby contributing to their selective susceptibility to autoimmune-mediated destruction. PMID- 27506585 TI - Leukocyte-poor platelet-rich plasma is more effective than the conventional therapy with acetaminophen for the treatment of early knee osteoarthritis. AB - INTRODUCTION: Knee osteoarthritis (OA) is a degenerative and progressive articular cartilage disease. Infiltration of autologous platelet-rich plasma (PRP) has been proposed as a therapeutic alternative due to the content of biologically active cytokines in PRP. We aimed to compare the clinical response of acetaminophen and intra-articular leukocyte-poor PRP (LP-PRP) in early knee OA. MATERIALS AND METHODS: A total of 65 patients with clinically and radiographically documented knee OA (grade 1-2) were analyzed. Patients were randomized into two groups: 32 were treated with acetaminophen (500 mg/8 h) over 6 weeks, and 33 received three intra-articular injections of autologous LP-PRP (once every 2 weeks). All patients were evaluated by the Visual Analogue Scale (VAS), the Western Ontario and McMaster Universities (WOMAC) score, and the SF-12 health survey at baseline and 6, 12, and 24 weeks of follow-up. All LP-PRP preparations were analyzed for the platelet, leukocyte, IL-1ra, and TGF-beta concentrations. RESULTS: The decrease in the VAS pain level in the LP-PRP group was greater than that in the acetaminophen group (p < 0.05). Patients treated with LP-PRP showed a sustained improvement in knee function at week 24 (p < 0.01). The SF-12 results only indicated an improvement in quality-of-life in the LP-PRP group at 6, 12, and 24 weeks of follow-up (p < 0.01). Both IL-1ra and TGF beta were detected in the LP-PRP samples (313.8 +/- 231.6 and 21,183.8 +/- 8556.3 pg/mL, respectively). CONCLUSIONS: Treatment with LP-PRP injections resulted in a significantly better clinical outcome than did treatment with acetaminophen, with sustained lower EVA and WOMAC scores and improvement in quality-of-life (higher SF-12 score). Therapy with LP-PRP may positively modify the inflammatory joint environment by counteracting IL-1beta action. PMID- 27506586 TI - Differentiating acute ischemic lesions from mitochondrial stroke-like lesions on 3D pseudo-continuous arterial spin labelling. PMID- 27506588 TI - In vitro effects of different sources of fibrinogen supplementation on clot initiation and stability in a model of dilutional coagulopathy. AB - OBJECTIVES: To analyse which fibrinogen source may improve coagulation using an in vitro 33% dilutional coagulopathy model. BACKGROUND: Uncritical volume resuscitation in the context of trauma haemorrhage contributes to the iatrogenic arm of the acute trauma-induced coagulopathy through dilution and depletion of coagulation factors, with fibrinogen reaching critical levels first. MATERIALS AND METHODS: By using an experimental model of 33% dilutional coagulopathy, we have analysed which fibrinogen source may exert superior effects on improving haemocoagulative capacities and correcting depleted fibrinogen levels. As fibrinogen sources, we supplemented (i) fresh frozen plasma (FFP), (ii) fibrinogen concentrate low-dose (Fiblow ) and (iii) fibrinogen concentrate high dose (Fibhigh ), the latter both in the presence and absence of additional FXIII. RESULTS: The dilution was associated with decreased haemoglobin and haematocrit levels. Fibrinogen supplementation with fibrinogen-containing formulations led to increased fibrinogen levels (FFP: 172.2 +/- 17.4 mg dL-1 ; Fiblow : 211.5 +/- 20.61 mg dL-1 ; Fibhigh : 255.8 +/- 21.4 mg dL-1 ) than in a diluted-only sample (155.5 +/- 19.7 mg dL-1 ). Extrinsically activated assay with tissue factor (EXTEM) clot formation times, alpha-angles and maximum clot firmness significantly improved in the groups of Fiblow + FXIII (79 +/- 12.2 s; 74.3 +/- 2.4 degrees ; 62 +/- 2.3 mm), Fibhigh (70.8 +/- 10.6 s; 76.2 +/- 2.7 degrees ; 64.3 +/- 2.3 mm) and Fibhigh + FXIII (69.8 +/- 11.5 s; 77.5 +/- 2.7 degrees ; 64.33 +/- 2.5 mm) compared with the dilution groups (104.2 +/- 19 s; 69.7 +/- 2.9 degrees ; 56.5 +/- 3.1 mm). In contrast, rotational thromboelastometric trace (ROTEM) measures of samples supplemented with FFP largely remained unchanged. CONCLUSION: Fibrinogen concentrates corrected and improved haemodilution-induced changes in blood clotting in vitro. High-dose fibrinogen supplementation was associated with correction and improvement in clot dynamics and stability. PMID- 27506587 TI - Melanoma Expression Genes Identified through Genome-Wide Association Study of Breslow Tumor Thickness. PMID- 27506589 TI - Sympathetic neural and cardiovascular responses during static handgrip exercise in women with a history of hypertensive pregnancy. AB - PURPOSE: Women with a history of hypertensive pregnancy are at greater risk for future cardiovascular events; however, the mechanisms for this increased risk are unknown. Evidence suggests that an exercise stimulus unmasks latent hypertensive tendencies, identifying individuals at the greatest risk for developing cardiovascular disease. The current study examined the hypothesis that women with a hypertensive pregnancy history exhibit an augmented exercise pressor response. METHODS: Normotensive women with a history of healthy pregnancy (CON; n = 9) and hypertensive pregnancy (HP+; n = 12) were studied during the mid-luteal phase of the menstrual cycle. Heart rate (HR), systolic and diastolic blood pressure (SBP, DBP), and muscle sympathetic nerve activity (MSNA) were measured during a cold pressor test (CPT), and, following a sufficient period of recovery, during static handgrip to fatigue (SHG) and post-exercise circulatory arrest (PECA). RESULTS: The BP, HR, and MSNA responses to the CPT were similar between groups. The SBP response to SHG and PECA was similar between groups, but DBP and HR were significantly greater in HP+ women (both p < 0.05). MSNA burst frequency, but not burst incidence or total activity, tended to be elevated in HP+ women during the stressor (peak Delta from baseline 31 +/- 13 vs. 23 +/- 13 bursts/min; p for group = 0.06). CONCLUSION: Despite no clinical signs of cardiovascular disease or hypertension, women with a history of hypertensive pregnancy display an enhanced cardiovascular reactivity to an exercise stimulus compared to women with a healthy pregnancy history. This response may be indicative of impaired cardiovascular control that precedes the clinical manifestation of hypertension or cardiovascular events. PMID- 27506590 TI - Microbacterium aureliae sp. nov., a novel actinobacterium isolated from Aurelia aurita, the moon jellyfish. AB - The taxonomic position of a lemon-yellow-pigmented actinobacterium, strain JF-6T, isolated from Aurelia aurita, the moon jellyfish, collected from the Bay of Bengal coast, Kanyakumari, India, was determined using a polyphasic approach. The strain had phenotypic and chemotaxonomic properties that were consistent with its classification in the genus Microbacterium. Alignment of the 16S rRNA gene sequence of strain JF-6T with sequences from Microbacterium arthrosphaerae CC-VM YT, Microbacterium yannicii G72T, Microbacterium trichothecenolyticum IFO 15077T, Microbacterium flavescens DSM 20643T, Microbacterium insulae DS-66T, Microbacterium resistens DMMZ 1710T and Microbacterium thalassium IFO 16060T revealed similarities of 98.95, 98.76, 98.43, 98.41, 98.41, 98.26 and 98.22 %, respectively. However, the levels of DNA-DNA relatedness with its closest phylogenetic neighbours confirmed that it represents a novel species within the genus. The major polar lipids were phosphatidylglycerol, diphosphatidylglycerol and an unknown glycolipid. The major menaquinones detected for strain JF-6T were MK-13 and MK-12. The diamino acid in the cell-wall peptidoglycan was ornithine and the peptidoglycan was type B2beta (Glu/Hyg-Gly-d-Orn). The DNA G+C content was 69.4 mol%. Based on these differences, strain JF-6T (=MTCC 11843T=JCM 30060T=KCTC 39828T) should be classified as the type strain of a novel species of Microbacterium, for which the name Microbacterium aureliae sp. nov. is proposed. PMID- 27506591 TI - M1 polarization and the effect of PGE2 on TNF-alpha production by lymph node cells from dogs with visceral leishmaniasis. AB - Canine visceral leishmaniasis (CVL) is caused by the intracellular parasite Leishmania infantum. Increased levels of arginase, nitric oxide (NO2 ) and prostaglandin E2 (PGE2 ) can play a regulatory role regarding the immune response in CVL cases. This study aimed to evaluate the arginase activity in adherent macrophages cultured from the lymph nodes of healthy and naturally infected dogs and to examine the NO2 and PGE2 levels in the supernatant of these cultures. In addition, the regulatory effect of PGE2 on the production of tumour necrosis factor (TNF-alpha) and interleukin-10 (IL-10) in supernatants from the total lymph node was observed in leucocyte cultures. The arginase activity was lower in the adherent macrophages cultured from the lymph nodes of naturally infected dogs and there were higher concentrations of NO2 and PGE2 in the supernatants of these cultures. Higher TNF-alpha and IL-10 concentrations were observed in supernatants from total lymph node leucocytes cultures, from infected dogs, and the presence of indomethacin only decreased TNF-alpha in the supernatant of these cultures. We conclude that the low arginase activity in macrophages suggested that M1 polarization and PGE2 were participating in the immune response and were increasing TNF-alpha in CVL. PMID- 27506592 TI - An efficient hydrogenation catalyst in sulfuric acid for the conversion of nitrobenzene to p-aminophenol: N-doped carbon with encapsulated molybdenum carbide. AB - The transfer of catalytic function from molybdenum carbide to N-doped carbon has been tested by encapsulating molybdenum carbide with N-doped carbon using a one pot preparation process. The outer layer of N-doped carbon, inert itself, exhibits high activity and excellent selectivity with molybdenum carbide as the catalyst for the hydrogenation of nitrobenzene to p-aminophenol in sulfuric acid. PMID- 27506593 TI - The burden of disease of dental anxiety: generic and disease-specific quality of life in patients with and without extreme levels of dental anxiety. AB - The aim of this study was to compare disease-specific (oral health-related) quality of life (OHRQoL), assessed using the Oral Health Impact Profile-14 (OHIP 14), and generic (health-related) quality of life (HRQoL), assessed using the EuroQol5D (EQ-5D-5L), in patients with severe dental anxiety (who were visiting a centre for special care dentistry) with a control group from the general population. Seventy-six patients with severe dental anxiety [Dental Anxiety Scale (DAS) score >= 13] were matched, according to age, gender, and socio-economic status, to a control group of 76 participants in a larger epidemiological study on oral health in the Netherlands (n = 1,125). The Wilcoxon signed-rank test was used to compare levels of HRQoL and OHRQoL in both groups. The total OHIP score (indicating lower OHRQoL) was higher for the patient group (10th percentile = 30.5; 90th percentile = 46.0) than for the control group (10th percentile = 1.0; 90th percentile = 14.5). The patient group showed higher scores on all seven OHIP domains. Lower utility scores were found in patients with severe dental anxiety (HRQOL: 10th percentile = 0.7; 90th percentile = 0.9) relative to the control group (HRQOL: 10th percentile = 0.9; 90th percentile = 1.0). A disease burden of 74,000 disability-adjusted life years (DALYs) was calculated for the Netherlands. The findings of this study show differences between patients visiting a dental fear clinic and matched controls from the general population for both OHRQoL and HRQoL, indicating that having severe dental anxiety generates a significant burden of disease. PMID- 27506594 TI - Combining fibroblast isolation with lentiviral gene transfer to validate transgene expression in mice following pronucleus injection. AB - The binary tetracycline-based expression system in transgenic mice relies on the expression of the tetracycline transactivator (tTA or rtTA) in a particular cell type together with a transcription unit encoding the gene of interest under a tetracycline or doxycycline-responsive promoter. Transgenic mice containing this transcription unit are produced via pronucleus injection. As the chromosomal integration site of the injected DNA influences transgene expression, several founder lines have to be crossed with (r)tTA-expressing mice to find a line showing low background and high transgene expression following doxycycline stimulation. Here, we describe a method to analyze primary fibroblasts derived from the founder lines to quickly test transgene expression and inducibility. Fibroblasts isolated from a small piece of mouse ear were infected with a recombinant lentivirus expressing rtTA. Transgene expression was verified by both RT-PCR and western blot, following stimulation with doxycycline. Transgene expression could easily be detected on the RNA and protein levels in primary fibroblasts derived from transgenic founder lines. An enzymatic function of the transgene was not required for the identification of transgene expression. Thus, the method allows a quick and easy discrimination of transgenic founder lines according to transgene expression and inducibility. PMID- 27506595 TI - Effect of DNA on the conformational dynamics of the endonucleases I-DmoI as provided by molecular dynamics simulations. AB - The conformational behavior of the wild-type endonucleases I-DmoI and two of its mutants has been studied in the presence and in the absence of DNA target sequences by means of extended molecular dynamics simulations. Our results show that in the absence of DNA, the three protein forms explore a similar essential conformational space, whereas when bound to the same DNA target sequence of 25 base pairs, they diversify and restrain the subspace explored. In addition, the differences in the essential subspaces explored by the residues near the catalytic site for both the bound and unbound forms are discussed in background of the experimental protein activity. PMID- 27506596 TI - Enhancing quantum sensing sensitivity by a quantum memory. AB - In quantum sensing, precision is typically limited by the maximum time interval over which phase can be accumulated. Memories have been used to enhance this time interval beyond the coherence lifetime and thus gain precision. Here, we demonstrate that by using a quantum memory an increased sensitivity can also be achieved. To this end, we use entanglement in a hybrid spin system comprising a sensing and a memory qubit associated with a single nitrogen-vacancy centre in diamond. With the memory we retain the full quantum state even after coherence decay of the sensor, which enables coherent interaction with distinct weakly coupled nuclear spin qubits. We benchmark the performance of our hybrid quantum system against use of the sensing qubit alone by gradually increasing the entanglement of sensor and memory. We further apply this quantum sensor-memory pair for high-resolution NMR spectroscopy of single (13)C nuclear spins. PMID- 27506597 TI - Roadmap for cardiovascular circulation model. AB - Computational models of many aspects of the mammalian cardiovascular circulation have been developed. Indeed, along with orthopaedics, this area of physiology is one that has attracted much interest from engineers, presumably because the equations governing blood flow in the vascular system are well understood and can be solved with well-established numerical techniques. Unfortunately, there have been only a few attempts to create a comprehensive public domain resource for cardiovascular researchers. In this paper we propose a roadmap for developing an open source cardiovascular circulation model. The model should be registered to the musculo-skeletal system. The computational infrastructure for the cardiovascular model should provide for near real-time computation of blood flow and pressure in all parts of the body. The model should deal with vascular beds in all tissues, and the computational infrastructure for the model should provide links into CellML models of cell function and tissue function. In this work we review the literature associated with 1D blood flow modelling in the cardiovascular system, discuss model encoding standards, software and a model repository. We then describe the coordinate systems used to define the vascular geometry, derive the equations and discuss the implementation of these coupled equations in the open source computational software OpenCMISS. Finally, some preliminary results are presented and plans outlined for the next steps in the development of the model, the computational software and the graphical user interface for accessing the model. PMID- 27506598 TI - Frameshift variant FANCL*c.1096_1099dupATTA is not associated with high breast cancer risk. PMID- 27506599 TI - What do I need to know about aminoglycoside antibiotics? AB - The aminoglycosides are broad-spectrum, bactericidal antibiotics that are commonly prescribed for children, primarily for infections caused by Gram negative pathogens. The aminoglycosides include gentamicin, amikacin, tobramycin, neomycin, and streptomycin. Gentamicin is the most commonly used antibiotic in UK neonatal units. Aminoglycosides are polar drugs, with poor gastrointestinal absorption, so intravenous or intramuscular administration is needed. They are excreted renally. Aminoglycosides are concentration-dependent antibiotics, meaning that the ratio of the peak concentration to the minimum inhibitory concentration of the pathogen is the pharmacokinetic-pharmacodynamic index best linked to their antimicrobial activity and clinical efficacy. However, due to their narrow therapeutic index, the patient's renal function should be monitored to avoid toxicity, and therapeutic drug monitoring is often required. Here we provide a review of aminoglycosides, with a particular focus on gentamicin, considering their pharmacokinetics and pharmacodynamics, and also practical issues associated with prescribing these drugs in a paediatric clinical setting. PMID- 27506601 TI - Altered lipid metabolism in Drosophila model of Huntington's disease. AB - Huntington's disease (HD) is late-onset, progressive neurodegenerative disorder caused by expansion of polyglutamine (polyQ) repeat within Huntingtin (Htt) protein. In HD patients, energy-related manifestations such as modulation of weight during entire course of disease with energy deficit at terminal stage have been reported, however, underlying reason remains elusive till date. Lipids, carbohydrate and protein constitute a predominant fraction of body's energy reservoir and perturbation in their homeostasis may influence weight. To discern role of these energy molecules in weight alteration, we quantified them in an in vivo transgenic Drosophila model of HD. We document that diseased flies exhibit change in weight due to an altered lipid metabolism, as evident from considerably high lipid levels at the time of disease onset followed by a pathologic decline at end-stage. An alteration in intracellular lipid droplet size suggested altered cellular lipid turnover. Furthermore, diseased flies displayed substantial changes in carbohydrate and protein content. Interestingly, alteration in weight and lipid levels are independent of the feeding pattern in diseased condition and exhibit weak correlation with insulin-like peptide or adipokinetic hormone producing cells. We propose that therapeutic intervention aimed at restoring lipid levels and associated metabolic pathways may improve longevity and quality of patient's life. PMID- 27506600 TI - Prevalence of hardcore smoking in the Netherlands between 2001 and 2012: a test of the hardening hypothesis. AB - BACKGROUND: Hardcore smokers are smokers who have smoked for many years and who do not intend to quit smoking. The "hardening hypothesis" states that light smokers are more likely to quit smoking than heavy smokers (such as hardcore smokers). Therefore, the prevalence of hardcore smoking among smokers would increase over time. If this is true, the smoking population would become harder to reach with tobacco control measures. In this study we tested the hardening hypothesis. METHODS: We calculated the prevalence of hardcore smoking in the Netherlands from 2001 to 2012. Smokers were 'hardcore' if they a) smoked every day, b) smoked on average 15 cigarettes per day or more, c) had not attempted to quit in the past 12 months, and d) had no intention to quit within 6 months. We used logistic regression models to test whether the prevalence changed over time. We also investigated whether trends differed between educational levels. RESULTS: Among smokers, the prevalence of hardcore smoking decreased from 40.8 % in 2001 to 32.2 % in 2012. In the general population, it decreased from 12.2 to 8.2 %. Hardcore smokers were significantly lower educated than non-hardcore smokers. Among the general population, the prevalence of hardcore smoking decreased more among higher educated people than among lower educated people. CONCLUSIONS: We found no support for the hardening hypothesis in the Netherlands between 2001 and 2012. Instead, the decrease of hardcore smoking among smokers suggests a 'softening' of the smoking population. PMID- 27506602 TI - Peripheral brain-derived neurotrophic factor in autism spectrum disorder: a systematic review and meta-analysis. AB - Brain-derived neurotrophic factor (BDNF) regulates neuronal survival and growth and promotes synaptic plasticity. Recently, researchers have begun to explore the relationship between peripheral BDNF levels and autism spectrum disorder (ASD), but the findings are inconsistent. We undertook the first systematic review and meta-analysis of studies examining peripheral BDNF levels in ASD compared with healthy controls. The PubMed, Embase, and Cochrane Library databases were searched for studies published before February 2016. Fourteen studies involving 2,707 participants and 1,131 incident cases were included. The meta-analysis provided evidence of higher peripheral BDNF levels in ASD compared with controls [standardized mean difference (SMD) = 0.63, 95% confidence interval (95% CI) = 0.18-1.08; P = 0.006]. Subgroup analyses revealed higher BDNF levels in ASD compared with controls for both serum [SMD = 0.58, 95% CI = 0.11-1.04; P = 0.02] and plasma [SMD = 1.27, 95% CI = 0.92-1.61; P < 0.001]. Studies of childhood yielded similar cumulative effect size [SMD = 0.78, 95% CI = 0.31-1.26; P = 0.001], while this was not true for the studies of adulthood [SMD = 0.04, 95% CI = -1.72-1.80; P = 0.97]. This meta-analysis suggests that peripheral BDNF levels are a potential biomarker of ASD. PMID- 27506603 TI - Criteria for assigning laboratory measurands to models for analytical performance specifications defined in the 1st EFLM Strategic Conference. AB - This paper, prepared by the EFLM Task and Finish Group on Allocation of laboratory tests to different models for performance specifications (TFG-DM), is dealing with criteria for allocating measurands to the different models for analytical performance specifications (APS) recognized in the 1st EFLM Strategic Conference Consensus Statement. Model 1, based on the effect of APS on clinical outcome, is the model of choice for measurands that have a central role in the decision-making of a specific disease or clinical situation and where cut off/decision limits are established for either diagnosing, screening or monitoring. Total cholesterol, glucose, HbA1c, serum albumin and cardiac troponins represent practical examples. Model 2 is based on components of biological variation and should be applied to measurands that do not have a central role in a specific disease or clinical situation, but where the concentration of the measurand is in a steady state. This is best achieved for measurands under strict homeostatic control in order to preserve their concentrations in the body fluid of interest, but it can also be applied to other measurands that are in a steady state in biological fluids. In this case, it is expected that the "noise" produced by the measurement procedure will not significantly alter the signal provided by the concentration of the measurand. This model especially applies to electrolytes and minerals in blood plasma (sodium, potassium, chloride, bicarbonate, calcium, magnesium, inorganic phosphate) and to creatinine, cystatin C, uric acid and total protein in plasma. Model 3, based on state-of-the-art of the measurement, should be used for all the measurands that cannot be included in models 1 or 2. PMID- 27506604 TI - Review of Disintegrants and the Disintegration Phenomena. AB - Disintegrant is one of the most important components in a typical tablet dosage form. It is responsible for ensuring the break-up of the tablet matrix upon ingestion. Disintegrants act by different mechanisms, and a number of factors may affect their performance. It is important for formulators to understand how disintegrants function so as to be able to judiciously use disintegrants to develop optimized formulations. If the formulator is required to implement the quality by design paradigm while developing a tablet formulation, it would be important to determine the impact of component ranges and process variations on tablet performance and of particular importance, tablet disintegration. Thus, a better understanding of the mechanisms of disintegrants and the tablet disintegration processes can be critical to product design success. This review aims to provide an overview of tablet disintegrants and the disintegration processes with particular focus on the factors affecting the functionalities of disintegrants. An updated compendium of different techniques employed to evaluate disintegrant action and measure disintegration time is also provided. The objective of this review is to assemble the knowledge about disintegrants and the measurement of tablet disintegratability so that the information provided could be of help to tablet formulation development. PMID- 27506605 TI - Molecular epidemiology of drug-resistant Neisseria gonorrhoeae in Russia (Current Status, 2015). AB - BACKGROUND: The widespread distribution of Neisseria gonorrhoeae strains that are resistant to previously used and clinically implemented antibiotics is a significant global public health problem. In line with WHO standards, the national Gonococcal Antimicrobial Surveillance Programme (RU-GASP) has been in existence in Russia since 2004; herein, the current status (2015) is described, including associations between N. gonorrhoeae antimicrobial susceptibility, primary genetic resistance determinants and specific strain sequence types. METHODS: A total of 124 N. gonorrhoeae strains obtained from 9 regions in Russia in 2015 were examined using N. gonorrhoeae Multi-Antigen Sequence Typing (NG MAST), an antimicrobial susceptibility test according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria and an oligonucleotide microarray for the identification of mutations in the penA, ponA, rpsJ, gyrA and parC genes responsible for penicillin G, tetracycline, and fluoroquinolone resistance. Genogroup (G) isolates were evaluated based on their porB and tbpB sequence types (STs). RESULTS: NG-MAST analysis showed a diversified population of N. gonorrhoeae in Russia with 58 sequence types, 35 of which were described for the first time. The STs 807, 1544, 1993, 5714, 9476 and 12531, which were typical for some Russian Federation regions and several countries of the former Soviet Union, were represented by five or more isolates. The internationally widespread ST 1407 was represented by a single strain in the present study. Division into genogroups facilitated an exploration of the associations between N. gonorrhoeae sequence type, antimicrobial resistance spectra and genetic resistance determinant contents. Preliminarily susceptible (G-807, G-12531) and resistant (G-5714, G-9476) genogroups were revealed. The variability in the most frequently observed STs and genogroups in each participating region indicated geographically restricted antimicrobial susceptibility in N. gonorrhoeae populations. CONCLUSIONS: Resistance or intermediate susceptibility to previously recommended antimicrobials, such as penicillin G (60.5 %), ciprofloxacin (41.1 %) and tetracycline (25 %), is common in the N. gonorrhoeae population. Based on previous reports and current data, ceftriaxone and spectinomycin should be recommended for first-line empiric antimicrobial monotherapy for gonorrhoea in Russia. PMID- 27506606 TI - Impact of Expression of Vimentin and Axl in Breast Cancer. AB - BACKGROUND: The association between Axl and vimentin protein expression has been observed in several cell lines. However, the clinical importance of Axl and vimentin expression in breast cancer have not been fully determined. PATIENTS AND METHODS: The expressions of Axl and vimentin were evaluated by immunohistochemistry in a total of 343 patients with invasive ductal carcinoma. The relationships between expression of Axl and vimentin and clinicopathologic characteristics and prognosis were analyzed. RESULTS: Axl expression was classified into high (n = 170) and low (n = 173) expression groups. Axl expression alone was not associated with any clinicopathologic factor or prognosis. Coexistence of vimentin-positive and Axl-high expression was observed in 10.5% (n = 36). Vimentin-positive and Axl-high tumors were associated with triple-negative breast cancers (P = .0396) and with poor prognosis in terms of both recurrence-free survival (P = .0126) and overall survival (P = .0005) compared to the other groups, including vimentin-positive and Axl-low tumors, vimentin-negative and Axl-high tumors, and vimentin-negative and Axl-low tumors. Multivariate analysis showed that coexistence of vimentin-positive and Axl-high expression was an independent poor prognostic factor for recurrence-free survival (hazard ratio, 2.78; 95% confidence interval, 1.23-5.68; P = .0158) and overall survival (hazard ratio, 3.72; 95% confidence interval, 1.51-8.47; P = .0059). CONCLUSION: Coexistence of vimentin-positive and Axl-high expression is a poor prognostic factor for primary breast cancer. Vimentin and Axl expression might contribute to the aggressive phenotype in breast cancer. PMID- 27506607 TI - Characterizing internet health information seeking strategies by socioeconomic status: a mixed methods approach. AB - BACKGROUND: The Internet is valuable for those with limited access to health care services because of its low cost and wealth of information. Our objectives were to investigate how the Internet is used to obtain health-related information and how individuals with differing socioeconomic resources navigate it when presented with a health decision. METHODS: Study participants were recruited from public settings and social service agencies. Participants listened to one of two clinical scenarios - consistent with influenza or bacterial meningitis - and then conducted an Internet search. Screen-capture video software captured the Internet search. Participant Internet search strategies were analyzed and coded for pre- and post-Internet search guess at diagnosis and information seeking patterns. Individuals who did not have a college degree and were recruited from locations offering social services were categorized as "lower socioeconomic status" (SES); the remainder was categorized as "higher SES." Participants were 78 Internet health information seekers, ranging from 21-35 years of age, who experienced barriers to accessing health care services. RESULTS: Lower-SES individuals were more likely to use an intuitive, rather than deliberative, approach to Internet health information seeking. Lower- and higher-SES participants did not differ in the tendency to make diagnostic guesses based on Internet searches. Lower-SES participants were more likely than their higher-SES counterparts to narrow the scope of their search. CONCLUSIONS: Our findings suggest that individuals with different levels of socioeconomic status vary in the heuristics and search patterns they rely upon to direct their searches. The influence and use of credible information in the process of making a decision is associated with education and prior experiences with healthcare services. Those with limited resources may be disadvantaged when turning to the Internet to make a health decision. PMID- 27506608 TI - Adequacy of initial evaluation of fever in long-term care facilities. AB - AIM: Febrile residents in long-term care facilities (LTCF) might be inadequately evaluated by caregivers. The present study aimed to examine the factors associated with inadequacy of initial fever evaluations by caregivers at night in LTCF. METHODS: We carried out a cross-sectional study among a convenience sample of caregivers employed at 11 LTCF in Japan using a vignette-based questionnaire. The respondents were randomly assigned to one of two scenarios describing a mild or severe febrile episode in an LTCF resident at night. The respondents' thinking patterns were classified based on influential factors in their fever evaluation. Associations between adequacy of evaluation and respondents' characteristics were evaluated using generalized linear mixed models. RESULTS: A total of 34% of fever evaluations among caregivers were considered to be inadequate regarding the necessity for examination by a physician, due in most cases to underestimating the severity of the fever. Respondents' thinking patterns in fever evaluation were significantly associated with the adequacy of the evaluation. Caregivers who placed particular importance on the preferences of residents and families versus other factors including the resident's febrile condition, were more likely to make an inadequate evaluation than those who did not. CONCLUSIONS: Our findings here suggest that eagerness to comply with residents' preference in fever evaluation could prompt caregivers not to call for an appropriate diagnostic procedure. Geriatr Gerontol Int 2017; 17: 1294-1299. PMID- 27506609 TI - The challenge of using intermittent preventive therapy with sulfadoxine/pyrimethamine among pregnant women in Uganda. AB - BACKGROUND: The Uganda National Malaria Control Programme recommends the use of intermittent preventive therapy in pregnancy with sulfadoxine/pyrimethamine (SP) to prevent malaria, however, there is overwhelming evidence of low uptake of this intervention. This study, therefore, sought to examine the factors associated with taking two or more doses of therapy among women who had had the most recent live birth. METHODS: This was a secondary data analysis of the 2014 Malaria Indicator Survey dataset. The outcome was the use of two or more doses of SP for the most recent live birth while independent variables included; age, highest education attained, residence (rural and urban), use of radio and community health teams for malaria related messages, knowledge of taking SP and use of LLINS to prevent malaria, household wealth, skilled attendant seen at ANC and number of children the woman has. RESULTS: Of the 1820 women included in the final analysis, 822 (45.16 %) women took two or more doses of SP. Women who knew that this therapy was used to prevent malaria and those who had been seen by a skilled attendant were 10.72 times [Adjusted OR (95 % CI): 10.72 (7.62-15.08), p value = 0.001] and 3.19 times [Adjusted OR (95 % CI): 3.19 (1.26-8.07), p-value = 0.015] more likely to take at least two doses as compared to those who did not know about this therapy and those seen by unskilled attendants, respectively. CONCLUSION: This study shows that knowledge among women that SP is a medication used for malaria prevention during pregnancy increases the uptake of two or more doses of this therapy among pregnant women. This highlights the importance of behaviour change communication focused on IPTp uptake that can be complemented by having skilled personnel attending to pregnant women at the antenatal clinic. PMID- 27506610 TI - Angiomatous pleomorphic xanthoastrocytoma: a case report and literature review. AB - BACKGROUND: Pleomorphic xanthoastrocytoma is rare, accounting for <1 % of all central nervous system (CNS) neoplasms. Angiomatous pleomorphic xanthoastrocytoma is an extremely rare variant of pleomorphic xanthoastrocytoma, with only six cases reported thus far. CASE PRESENTATION: A 24-year-old Chinese female patient who presented with seizure and loss of consciousness for 15 min underwent computed tomography and magnetic resonance imaging, which revealed a mass in the left parietal lobe. Histologically, the tumor was characterized by pleomorphic tumor cells and prominent vascularity. The angiomatous region varied, ranging from a sinusoidal pattern to a venous malformation. Focal fibrinoid necrosis, hyalinization, and a moderate infiltration by lymphocytes and plasma cells were visible in the vessel wall. The tumor cells were in close proximity with adjacent small vessels. Capillaries adjacent to or extending between tumor cells were focally observed. Most tumor cells were positive for glial fibrillary acidic protein and oligodendrocyte lineage transcription factor 2. The Ki-67 index was low. Based on the patient's history, clinical data, and pathological findings, she was diagnosed with angiomatous pleomorphic xanthoastrocytoma (WHO grade II). CONCLUSIONS: This case serves as a reminder to pathologists of the need to be aware of this rare variant of pleomorphic xanthoastrocytoma to avoid a misdiagnosis of this indolent CNS tumor and therefore inappropriate treatment. PMID- 27506611 TI - A Dynamical Analysis of the Suitability of Prehistoric Spheroids from the Cave of Hearths as Thrown Projectiles. AB - Spheroids are ball-shaped stone objects found in African archaeological sites dating from 1.8 million years ago (Early Stone Age) to at least 70,000 years ago (Middle Stone Age). Spheroids are either fabricated or naturally shaped stones selected and transported to places of use making them one of the longest-used technologies on record. Most hypotheses about their use suggest they were percussive tools for shaping or grinding other materials. However, their size and spherical shape make them potentially useful as projectile weapons, a property that, uniquely, humans have been specialised to exploit for millions of years. Here we show (using simulations of projectile motions resulting from human throwing) that 81% of a sample of spheroids from the late Acheulean (Bed 3) at the Cave of Hearths, South Africa afford being thrown so as to inflict worthwhile damage to a medium-sized animal over distances up to 25 m. Most of the objects have weights that produce optimal levels of damage from throwing, rather than simply being as heavy as possible (as would suit other functions). Our results show that these objects were eminently suitable for throwing, and demonstrate how empirical research on behavioural tasks can inform and constrain our theories about prehistoric artefacts. PMID- 27506612 TI - Curative hepatitis C treatment is effective in drug users, trial shows. PMID- 27506613 TI - Prevalence and antimicrobial susceptibility pattern of methicillin resistant Staphylococcus aureus isolated from clinical samples at Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia. AB - BACKGROUND: Staphylococcus aureus particularly MRSA strains are one of the major causes of community and hospital acquired bacterial infections. They are also becoming increasingly multi-drug resistant and have recently developed resistance to vancomycin, which has been used successfully to treat MRSA for many years. In vitro determination of drug resistance patterns of S. aureus is critical for the selection of effective drugs for the treatment of staphylococci infections. The main aim of this study was to determine the prevalence of methicillin resistant S. aureus strains from different clinical specimens from patients referred for routine culture and sensitivity testing. METHOD: A cross sectional study was conducted among 1360 participants at Yekatit 12 Hospital Medical College in Ethiopia from September 2013 to April 2014. Clinical samples from various anatomical sites of study participants were cultured on blood agar and mannitol salt agar and identified to be S. aureus by using catalase, coagulase and DNAse tests. S. aureus isolates then were screened for MRSA using 30 MUg cefoxitin disc and other 11 antimicrobial drugs by disc diffusion procedure, and agar dilution and E tests for vancomycin. All S. aureus isolates examined for beta-lactamase production by employing nitrocefin. Data were analyzed using SPSS version 20 software and logistic regressions were applied to assess any association between dependent and independent variables. RESULTS: Of 1360 clinical specimens analyzed S. aureus was recovered from (194, 14.3 %). Rate of isolation of S. aureus with regard to clinical specimens was the highest in pus (118, 55.4 %).No S. aureus was isolated from CSF and urethral discharge. Out of 194 S. aureus isolates, (34, 17.5 %) were found out to be MRSA and the remaining (160, 82.5 %) were MSSA. Ninety eight (50.5 %) S. aureus were multi drug resistant and the highest isolates were resistant to penicillin (187, 96.4 %) and least resistant for clindamycin (23, 11.9 %) and vancomycin (10, 5.1 %). MRSA strains were 100 % resistant to penicillin G, erythromycin, trimethoprim-sulfamethoxazole and least resistant to vancomycin (10, 29.4 %). Out of 194 S. aureus isolates (153, 79.0 %) were beta-lactamase producers. CONCLUSION: In this study S. aureus isolates exhibited very high degree of resistance to different antibiotics. The isolates were also multidrug resistant to several combinations of the tested antibiotics. The emergence of vancomycin resistant S. aureus highlights the value of prudent prescribing of antibiotics and avoiding their irrational use. PMID- 27506614 TI - Overexpression of diacylglycerol acyltransferase in Yarrowia lipolytica affects lipid body size, number and distribution. AB - In the oleaginous yeast Yarrowia lipolytica, the diacylglycerol acyltransferases (DGATs) are major factors for triacylglycerol (TAG) synthesis. The Q4 strain, in which the four acyltransferases have been deleted, is unable to accumulate lipids and to form lipid bodies (LBs). However, the expression of a single acyltransferase in this strain restores TAG accumulation and LB formation. Using this system, it becomes possible to characterize the activity and specificity of an individual DGAT. Here, we examined the effects of DGAT overexpression on lipid accumulation and LB formation in Y. lipolytica Specifically, we evaluated the consequences of introducing one or two copies of the Y. lipolytica DGAT genes YlDGA1 and YlDGA2 Overall, multi-copy DGAT overexpression increased the lipid content of yeast cells. However, the size and distribution of LBs depended on the specific DGAT overexpressed. YlDGA2 overexpression caused the formation of large LBs, while YlDGA1 overexpression generated smaller but more numerous LBs. This phenotype was accentuated through the addition of a second copy of the overexpressed gene and might be linked to the distinct subcellular localization of each DGAT, i.e. YlDga1 being localized in LBs, while YlDga2 being localized in a structure strongly resembling the endoplasmic reticulum. PMID- 27506616 TI - Factors Associated With Gastrostomy Tube Removal in Patients With Dysphagia After Stroke. AB - Gastrostomy feeding tubes are commonly placed in patients with dysphagia after stroke. The subsequent removal of the tube is a primary goal during rehabilitation. The purpose of our review was to identify predictors and factors associated with gastrostomy tube removal in patients with dysphagia after stroke. We conducted a literature review following the PRISMA statement and included the search databases PubMed, Scopus, Web of Science, and CINAHL. Articles were included in the final analysis per predefined inclusion and exclusion criteria. Our search retrieved a total of 853 results consisting of 416 articles (after eliminating duplicates). Six articles met our final eligibility criteria. The following factors were identified in at least 1 article as being significantly associated with gastrostomy tube removal: reduced age, decreased number of comorbidities, prolonged inpatient rehabilitation stay, absence of bilateral stroke, nonhemorrhagic stroke, reduced dysphagia severity, absence of aspiration, absence of premature bolus loss, and timely initiation of pharyngeal swallow. Aspiration was the only factor that was investigated by 2 studies-both using multiple regression and both showing stable results, with absence of aspiration increasing the chances for tube removal. In conclusion, little is known about factors associated with gastrostomy tube removal in patients with dysphagia after stroke. Most of the identified factors are associated with stroke or disease severity; however, the role of the individual factors remains unclear. The strongest predictor appears to be absence of aspiration on modified barium swallow studies emphasizing the importance of instrumental swallow studies in this patient population. PMID- 27506617 TI - Microscopic mechanistic study on the multiferroic of R2CoMnO6/La2CoMnO6 (R = Ce, Pr, Nd, Pm, Sm, Gd, Tb, Dy, Ho, Er, Tm) by chemical and hydrostatic pressures: a first-principles calculation. AB - A specific class of multiferroic superlattices R2CoMnO6/La2CoMnO6 (R = Ce, Pr, Nd, Pm, Sm, Gd, Tb, Dy, Ho, Er, Tm), which displayed observable electric polarizations and considerable magnetization, were investigated based on density functional theory. The multiferroic behavior was induced by both of the a(-)a( )c(+) Glazer rotation patterns of BO6 (CoO6 and MnO6) octahedra and ferromagnetic coupling in the magnetic ordered superlattices. In addition, the ferroelectric and ferromagnetic properties of R2CoMnO6/La2CoMnO6 superlattices can be tuned by chemical pressure and hydrostatic pressure, with the former being more effective in tuning magnetoelectric properties than the latter. For chemical pressure, the incorporation of lanthanide ions promoted an increase of BO6 octahedral tilting, reflected by the sharp decrease of Co-O3-Mn bond angles in the R-layer along the c axis. By contrast, the hydrostatic pressure acts on all three directions of the superlattice so that the change in Co-O-Mn bond angles is relatively small, therefore the octahedral distortion is much smaller than that caused by chemical pressure. Consequently, the electric polarization and magnetization changed more slowly. Our first-principles simulations proposed a series of rational multiferroic superlattices with tunable ferromagnetism and ferroelectricity by chemical and hydrostatic pressures, with expectation to be applied as novel spintronic materials. PMID- 27506615 TI - Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria. AB - Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre-and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria naive Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naive Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria. PMID- 27506618 TI - Nuclear receptors as pharmacological targets, where are we now? AB - Knowledge of integrative physiology is a major challenge for scientists, as even small deregulation could lead to diseases. Cells communicate with each other to control many processes such as growth, migration, survival, or differentiation. Such interaction could be achieved via several mechanisms either through cell cell interactions and/or through the signaling of molecules that bind to receptors on the membrane or in the target cells. The produced molecules could have either autocrine, paracrine stimulations, or even act on distant organs (endocrine signaling). PMID- 27506619 TI - CDK5 downregulation enhances synaptic plasticity. AB - CDK5 is a serine/threonine kinase that is involved in the normal function of the adult brain and plays a role in neurotransmission and synaptic plasticity. However, its over-regulation has been associated with Tau hyperphosphorylation and cognitive deficits. Our previous studies have demonstrated that CDK5 targeting using shRNA-miR provides neuroprotection and prevents cognitive deficits. Dendritic spine morphogenesis and forms of long-term synaptic plasticity-such as long-term potentiation (LTP)-have been proposed as essential processes of neuroplasticity. However, whether CDK5 participates in these processes remains controversial and depends on the experimental model. Using wild type mice that received injections of CDK5 shRNA-miR in CA1 showed an increased LTP and recovered the PPF in deficient LTP of APPswe/PS1Delta9 transgenic mice. On mature hippocampal neurons CDK5, shRNA-miR for 12 days induced increased dendritic protrusion morphogenesis, which was dependent on Rac activity. In addition, silencing of CDK5 increased BDNF expression, temporarily increased phosphorylation of CaMKII, ERK, and CREB; and facilitated calcium signaling in neurites. Together, our data suggest that CDK5 downregulation induces synaptic plasticity in mature neurons involving Ca2+ signaling and BDNF/CREB activation. PMID- 27506622 TI - Erratum to: Outcome and prognosis of hypoxic brain damage patients undergoing neurological early rehabilitation. PMID- 27506620 TI - Cell-cell junctional mechanotransduction in endothelial remodeling. AB - The vasculature is one of the most dynamic tissues that encounter numerous mechanical cues derived from pulsatile blood flow, blood pressure, activity of smooth muscle cells in the vessel wall, and transmigration of immune cells. The inner layer of blood and lymphatic vessels is covered by the endothelium, a monolayer of cells which separates blood from tissue, an important function that it fulfills even under the dynamic circumstances of the vascular microenvironment. In addition, remodeling of the endothelial barrier during angiogenesis and trafficking of immune cells is achieved by specific modulation of cell-cell adhesion structures between the endothelial cells. In recent years, there have been many new discoveries in the field of cellular mechanotransduction which controls the formation and destabilization of the vascular barrier. Force induced adaptation at endothelial cell-cell adhesion structures is a crucial node in these processes that challenge the vascular barrier. One of the key examples of a force-induced molecular event is the recruitment of vinculin to the VE cadherin complex upon pulling forces at cell-cell junctions. Here, we highlight recent advances in the current understanding of mechanotransduction responses at, and derived from, endothelial cell-cell junctions. We further discuss their importance for vascular barrier function and remodeling in development, inflammation, and vascular disease. PMID- 27506621 TI - Chromosome doubling to overcome the chrysanthemum cross barrier based on insight from transcriptomic and proteomic analyses. AB - BACKGROUND: Cross breeding is the most commonly used method in chrysanthemum (Chrysanthemum morifolium) breeding; however, cross barriers always exist in these combinations. Many studies have shown that paternal chromosome doubling can often overcome hybridization barriers during cross breeding, although the underlying mechanism has seldom been investigated. RESULTS: In this study, we performed two crosses: C. morifolium (pollen receptor) * diploid C. nankingense (pollen donor) and C. morifolium * tetraploid C. nankingense. Seeds were obtained only from the latter cross. RNA-Seq and isobaric tags for relative and absolute quantitation (iTRAQ) were used to investigate differentially expressed genes and proteins during key embryo development stages in the latter cross. A previously performed cross, C. morifolium * diploid C. nankingense, was compared to our results and revealed that transcription factors (i.e., the agamous-like MADS-box protein AGL80 and the leucine-rich repeat receptor protein kinase EXS), hormone responsive genes (auxin-binding protein 1), genes and proteins related to metabolism (ATP-citrate synthase, citrate synthase and malate dehydrogenase) and other genes reported to contribute to embryo development (i.e., LEA, elongation factor and tubulin) had higher expression levels in the C. morifolium * tetraploid C. nankingense cross. In contrast, genes related to senescence and cell death were down-regulated in the C. morifolium * tetraploid C. nankingense cross. CONCLUSIONS: The data resources helped elucidate the gene and protein expression profiles and identify functional genes during different development stages. When the chromosomes from the male parent are doubled, the genes contributing to normal embryo developmentare more abundant. However, genes with negative functions were suppressed, suggesting that chromosome doubling may epigenetically inhibit the expression of these genes and allow the embryo to develop normally. PMID- 27506623 TI - Cerebral collateral circulation and acute ischaemic stroke. PMID- 25971898 TI - Prenatal diagnosis of hypophosphatasia congenita using ultrasonography. AB - Congenital hypophosphatasia is a rare fatal skeletal dysplasia. Antenatal determinants of lethality include small thoracic circumference with pulmonary hypoplasia and severe micromelia. These features were present in the fetus of a 25-year-old female who came for an anomaly scan in her second trimester of pregnancy. Additional findings of generalized demineralization and osteochondral spurs led to the diagnosis of hypophosphatasia congenita. The pregnancy was terminated, and the findings were confirmed on autopsy. Common differential diagnoses with clues to diagnose the above mentioned condition have been discussed here. Early and accurate detection of this medical condition is important as no treatment has been established for this condition. Therefore, antenatal ultrasonography helps in diagnosing and decision making with respect to the current pregnancy and lays the foundation for the genetic counseling of the couple. PMID- 27506626 TI - Taming contact line instability for pattern formation. AB - Coating surfaces with different fluids is prone to instability producing inhomogeneous films and patterns. The contact line between the coating fluid and the surface to be coated is host to different instabilities, limiting the use of a variety of coating techniques. Here we take advantage of the instability of a receding contact line towards cusp and droplet formation to produce linear patterns of variable spacings. We stabilize the instability of the cusps towards droplet formation by using polymer solutions that inhibit this secondary instability and give rise to long slender cylindrical filaments. We vary the speed of deposition to change the spacing between these filaments. The combination of the two gives rise to linear patterns into which different colloidal particles can be embedded, long DNA molecules can be stretched and particles filtered by size. The technique is therefore suitable to prepare anisotropic structures with variable properties. PMID- 27506627 TI - What makes intersectoral partnerships for health promotion work? A review of the international literature. AB - A Health in All Policies approach requires creating and sustaining intersectoral partnerships for promoting population health. This scoping review of the international literature on partnership functioning provides a narrative synthesis of findings related to processes that support and inhibit health promotion partnership functioning. Searching a range of databases, the review includes 26 studies employing quantitative (n = 8), qualitative (n = 10) and mixed method (n = 8) designs examining partnership processes published from January 2007 to June 2015. Using the Bergen Model of Collaborative Functioning as a theoretical framework for analyzing the findings, nine core elements were identified that constitute positive partnership processes that can inform best practices: (i) develop a shared mission aligned to the partners' individual or institutional goals; (ii) include a broad range of participation from diverse partners and a balance of human and financial resources; (iii) incorporate leadership that inspires trust, confidence and inclusiveness; (iv) monitor how communication is perceived by partners and adjust accordingly; (v) balance formal and informal roles/structures depending upon mission; (vi) build trust between partners from the beginning and for the duration of the partnership; (vii) ensure balance between maintenance and production activities; (viii) consider the impact of political, economic, cultural, social and organizational contexts; and (ix) evaluate partnerships for continuous improvement. Future research is needed to examine the relationship between these processes and how they impact the longer term outcomes of intersectoral partnerships. PMID- 27506628 TI - Difference in DNA-binding abilities of Fur-homolog DNA binding protein from Neisseria gonorrhoeae. AB - Gonorrhea is a severe disease infecting both men and women worldwide. The causative agent of the disease is Neisseria gonorrhoeae. The organism mostly affects human beings in iron restricted environments. In such an environment the organism produces a set of proteins which are mostly absent in iron rich environments. The expressions of the genes for the proteins are regulated by the transcription factor (TF) belonging to the Fur family. Interestingly, the same TF acts as the activator and repressor of genes. In this present work, an attempt has been made to analyze the molecular details of the differential DNA-binding activities of the TF from Neisseria gonorrhoeae to come up with a plausible molecular reason behind the difference DNA binding activities of the same TF. Computational modelling technique was used to build the three dimensional structure of the TF. Molecular docking and molecular dynamics simulations were employed to determine the binding interactions between the TF and the promoter DNA. With the help of the computational techniques, the biochemical reason behind the different modes of DNA binding by the TF was analyzed. Results from this analysis may be useful to future drug development endeavours to curtail the spread of Gonorrhea. PMID- 27506629 TI - NaGd(MoO4)2 nanocrystals with diverse morphologies: controlled synthesis, growth mechanism, photoluminescence and thermometric properties. AB - Pure tetragonal phase, uniform and well-crystallized sodium gadolinium molybdate (NaGd(MoO4)2) nanocrystals with diverse morphologies, e.g. nanocylinders, nanocubes and square nanoplates have been selectively synthesized via oleic acid mediated hydrothermal method. The phase, structure, morphology and composition of the as-synthesized products are studied. Contents of both sodium molybdate and oleic acid of the precursor solutions are found to affect the morphologies of the products significantly, and oleic acid plays a key role in the morphology controlled synthesis of NaGd(MoO4)2 nanocrystals with diverse morphologies. Growth mechanism of NaGd(MoO4)2 nanocrystals is proposed based on time-dependent morphology evolution and X-ray diffraction analysis. Morphology-dependent down shifting photoluminescence properties of NaGd(MoO4)2: Eu(3+) nanocrystals, and upconversion photoluminescence properties of NaGd(MoO4)2: Yb(3+)/Er(3+) and Yb(3+)/Tm(3+) nanoplates are investigated in detail. Charge transfer band in the down-shifting excitation spectra shows a slight blue-shift, and the luminescence intensities and lifetimes of Eu(3+) are decreased gradually with the morphology of the nanocrystals varying from nanocubes to thin square nanoplates. Upconversion energy transfer mechanisms of NaGd(MoO4)2: Yb(3+)/Er(3+), Yb(3+)/Tm(3+) nanoplates are proposed based on the energy level scheme and power dependence of upconversion emissions. Thermometric properties of NaGd(MoO4)2: Yb(3+)/Er(3+) nanoplates are investigated, and the maximum sensitivity is determined to be 0.01333 K(-1) at 285 K. PMID- 27506630 TI - Effects of yuja peel extract and its flavanones on osteopenia in ovariectomized rats and osteoblast differentiation. AB - SCOPE: Yuja (Citrus junos Tanaka) possesses various health benefits, but its effects on bone health are unknown. In this study, the preventative effects of yuja peel ethanol extract (YPEE) on osteopenia were determined in ovariectomized (OVX) rats, and the mechanisms by which YPEE and its flavanones regulate osteoblastogenesis were examined in vitro. METHODS AND RESULTS: The effects of YPEE on osteoblastogenesis were investigated in MC3T3-E1 cells. YPEE promoted alkaline phosphatase (ALP) activity, mineralization, and the expression of osteoblast differentiation marker genes, such as ALP, runt-related transcription factor 2 (Runx2), and osteocalcin. YPEE and its flavanones promoted osteoblast differentiation via BMP-2-mediated p38 and the Smad1/5/8 signaling pathway. YPEE supplementation significantly decreased body weight and increased uterine weight and bone mineral density in OVX rats. Based on a micro-CT analysis of femurs, YPEE significantly attenuated osteopenia and increased trabecular volume fraction, trabecular separation, and trabecular number (p < 0.05). CONCLUSION: Dietary YPEE has a protective effect on OVX-induced osteopenia. YPEE and its flavanones promote osteoblastogenesis via the activation of the BMP/p38/Smad/Runx2 pathways. These results extend our knowledge of the beneficial effects of YPEE and provide a basis for the development of novel therapies for osteoporosis. PMID- 27506631 TI - Characterization of complex, heterogeneous lipid A samples using HPLC-MS/MS technique I. Overall analysis with respect to acylation, phosphorylation and isobaric distribution. AB - We established a new reversed phase-high performance liquid chromatography method combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry for the simultaneous determination and structural characterization of different lipid A types in bacteria (Escherichia coli O111, Salmonella adelaide O35 and Proteus morganii O34) showing serological cross-reactivity. The complex lipid A mixtures (obtained by simple extraction and acid hydrolysis of the outer membrane lipopolysaccharides) were separated and detected without phosphate derivatization. Several previously unidentified ions were detected, which differed in the number and type of acyl chains and number of phosphate groups. In several cases, we observed the different retention of isobaric lipid A species, which had different secondary fatty acyl distribution at the C2' or the C3' sites. The fragmentation of the various, C4' monophosphorylated lipid A species in deprotonated forms provided structural assignment for each component. Fragmentation pathways of the tri-acylated, tetra-acylated, penta-acylated, hexa acylated and hepta-acylated lipid A components and of the lipid A partial structures are suggested. As standards, the hexa-acylated ion at m/z 1716 with the E. coli-type acyl distribution and the hepta-acylated ion at m/z 1954 with the Salmonella-type acyl distribution were used. The results confirmed the presence of multiple forms of lipid A in all strains analyzed. In addition, the negative-ion mode MS permitted efficient detection for non-phosphorylated lipid A components, too. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27506632 TI - Epileptic spasms in epilepsy with myoclonic-atonic seizures (Doose syndrome). AB - AIM: To describe the occurrence of epileptic spasms in epilepsy with myoclonic atonic seizures (EMAS) or Doose syndrome. METHODS: Case descriptions of patients with EMAS and epileptic spasms. Diagnosis of EMAS was performed according to the following criteria: (1) onset of myoclonic, myoclonic-atonic, or atonic seizures at between 7 months and 6 years of age; (2) normal development before onset of epilepsy; (3) absence of structural cerebral abnormalities on MRI; (4) presence of generalized spike-waves or polyspike-waves on EEG; and (5) exclusion of other myoclonic epilepsies. RESULTS: Four patients with EMAS were included. For each of them, epileptic spasms were documented by video interpretation, or video-EEG when available. CONCLUSIONS: Our description of epileptic spasms in four patients with EMAS enlarges the spectrum of seizures that may be observed in this syndrome, as well as the number of epilepsy syndromes which may involve epileptic spasms. This evidence suggests that the presence of epileptic spasms is consistent with a diagnosis of EMAS; epileptic spasms should therefore not be considered a seizure type that excludes diagnosis of this epilepsy syndrome. The prognostic significance of epileptic spasms associated with EMAS remains unknown. PMID- 27506633 TI - A 6-month, randomized, double-blind, placebo-controlled study evaluating the ability of a marine complex supplement to promote hair growth in men with thinning hair. AB - BACKGROUND: Male pattern baldness, or androgenetic alopecia, affects approximately 50% of the adult population and can cause poor self-image, low self esteem and have a significant negative impact on the quality of life. An oral nutraceutical supplement based on a marine complex formulation has previously been reported to significantly increase the number of terminal hairs in women with thinning hair. AIMS: The objective of this double-blind, placebo-controlled study was to confirm the beneficial effects of a similar marine complex supplement in adult male subjects with thinning hair (Viviscal(r) Man; Lifes2good, Inc., Chicago, IL, USA). PATIENTS/METHODS: Healthy adult male subjects with thinning hair associated with clinically diagnosed male pattern hair loss were enrolled and randomized to receive study drug or placebo twice daily. RESULTS: At Day 90, subjects indicated a significant improvement in three of six quality of life measures as well as a significant overall improvement in quality of life. After 180 days, significant increases were observed for total hair count, total hair density, and terminal hair density (for each, P = 0.001). The investigator assessments revealed significant improvements in terminal and vellus hair count and terminal hair density. Hair pull test results were significantly lower (fewer hairs removed) for study drug vs. placebo at Days 90 (P < 0.05) and 180 (P < 0.01). There were no reports of treatment-emergent adverse events. CONCLUSION: The results of this study showed for the first time that a dietary supplement containing a marine complex and other ingredients can decrease hair shedding and promote hair growth in men with thinning hair. PMID- 27506634 TI - High density genome wide genotyping-by-sequencing and association identifies common and low frequency SNPs, and novel candidate genes influencing cow milk traits. AB - High-throughput sequencing technologies have increased the ability to detect sequence variations for complex trait improvement. A high throughput genome wide genotyping-by-sequencing (GBS) method was used to generate 515,787 single nucleotide polymorphisms (SNPs), from which 76,355 SNPs with call rates >85% and minor allele frequency >=1.5% were used in genome wide association study (GWAS) of 44 milk traits in 1,246 Canadian Holstein cows. GWAS was accomplished with a mixed linear model procedure implementing the additive and dominant models. A strong signal within the centromeric region of bovine chromosome 14 was associated with test day fat percentage. Several SNPs were associated with eicosapentaenoic acid, docosapentaenoic acid, arachidonic acid, CLA:9c11t and gamma linolenic acid. Most of the significant SNPs for 44 traits studied are novel and located in intergenic regions or introns of genes. Novel potential candidate genes for milk traits or mammary gland functions include ERCC6, TONSL, NPAS2, ACER3, ITGB4, GGT6, ACOX3, MECR, ADAM12, ACHE, LRRC14, FUK, NPRL3, EVL, SLCO3A1, PSMA4, FTO, ADCK5, PP1R16A and TEP1. Our study further demonstrates the utility of the GBS approach for identifying population-specific SNPs for use in improvement of complex dairy traits. PMID- 27506636 TI - Clinical-pathological features and treatment modalities associated with recurrence in DCIS and micro-invasive carcinoma: Who to treat more and who to treat less. AB - The primary aim in the management of DCIS is the prevention of recurrence and contralateral tumor. Risk factors for DCIS recurrence and appropriate treatments are still widely debated. Adjuvant therapies after surgical resection reduce recurrences and contralateral disease, but these treatments have significant financial costs, side effects and there is a group of low-risk patients who would not gain additional benefit. The aim of our analysis was to identify clinical pathological features and treatment modalities associated with recurrence in DCIS and microinvasive carcinoma. In the Thomas Jefferson University Cancer Registry of Philadelphia, we identified 865 patients with DCIS or micro-invasive carcinoma treated between 2003 and 2013. Associations between recurrence and demographic factors (age at diagnosis, ethnicity), biological features (ER, PR and HER2) and treatment modalities (surgery, radiotherapy and endocrine treatment) were assessed. Our single institution register-based study showed that distribution of age at diagnosis and biological features did not significantly differ among ethnic groups. Younger women and micro-invasive carcinoma patients were more likely to undergo mastectomy, while African Americans were more likely to take endocrine therapy and undergo radiotherapy. In our sample only ER/PR negative DCIS were associated with significantly higher recurrence rate. Moreover, we reported a high rate of HER2 positive recurrences, suggesting that expression of this oncogene may represent a potential biomarker for DCIS at high risk of recurrence. To better define the molecular profile of the subgroup at worse prognosis might help to identify biomarkers predictive of recurrence or second tumors, identifying patients candidates for more appropriate treatments. PMID- 27506637 TI - Functions of the basal ganglia-paradox or no paradox? PMID- 27506635 TI - Effect of fixed-dose combinations of ezetimibe plus rosuvastatin in patients with primary hypercholesterolemia: MRS-ROZE (Multicenter Randomized Study of ROsuvastatin and eZEtimibe). AB - AIM: We aimed to compare the effects of fixed-dose combinations of ezetimibe plus rosuvastatin to rosuvastatin alone in patients with primary hypercholesterolemia, including a subgroup analysis of patients with diabetes mellitus (DM) or metabolic syndrome (MetS). METHOD: This multicenter eight-week randomized double blind phase III study evaluated the safety and efficacy of fixed-dose combinations of ezetimibe 10 mg plus rosuvastatin, compared with rosuvastatin alone in patients with primary hypercholesterolemia. Four hundred and seven patients with primary hypercholesterolemia who required lipid-lowering treatment according to the ATP III guideline were randomized to one of the following six treatments for 8 weeks: fixed-dose combinations with ezetimibe 10 mg daily plus rosuvastatin (5, 10, or 20 mg daily) or rosuvastatin alone (5, 10, or 20 mg daily). RESULTS: Fixed-dose combination of ezetimibe plus rosuvastatin significantly reduced LDL cholesterol, total cholesterol, and triglyceride levels compared with rosuvastatin alone. Depending on the rosuvastatin dose, these fixed dose combinations of ezetimibe plus rosuvastatin provided LDL cholesterol, total cholesterol, and triglyceride reductions of 56%-63%, 37%-43%, and 19%-24%, respectively. Moreover, the effect of combination treatment on cholesterol levels was more pronounced in patients with DM or MetS than in non-DM or non-MetS patients, respectively, whereas the effect of rosuvastatin alone did not differ between DM vs non-DM or MetS vs non-MetS patients. CONCLUSION: Fixed-dose combinations of ezetimibe and rosuvastatin provided significantly superior efficacy to rosuvastatin alone in lowering LDL cholesterol, total cholesterol, and triglyceride levels. Moreover, the reduction rate was greater in patients with DM or MetS. PMID- 27506639 TI - Corrigendum to "The redox-active drug metronidazole and thiol-depleting garlic compounds act synergistically in the protist parasite Spironucleus vortens" [Mol. Biochem. Parasitol. 206 (1-2) (2016) 20-28]. PMID- 27506638 TI - Cost-effectiveness of neurostimulation in Parkinson's disease with early motor complications. AB - BACKGROUND: Recent research efforts have focused on the effects of deep brain stimulation of the subthalamic nucleus (STN DBS) for selected patients with mild to-moderate PD experiencing motor complications. OBJECTIVES: We assessed the cost utility of subthalamic DBS compared with the best medical treatment for German patients below the age of 61 with early motor complications of PD. METHODS: We applied a previously published Markov model that integrated health utilities based on EuroQoL and direct costs over patients' lifetime adjusted to the German health care payer perspective (year of costing: 2013). Effectiveness was evaluated using the Parkinson's Disease Questionnaire 39 summary index. We performed sensitivity analyses to assess uncertainty. RESULTS: In the base-case analysis, the incremental cost-utility ratio for STN DBS compared to best medical treatment was 22,700 Euros per quality-adjusted life year gained. The time to, and costs for, battery exchange had a major effect on the incremental cost utility ratios, but never exceeded a threshold of 50,000 Euros per quality adjusted life year. CONCLUSIONS: Our decision analysis supports the fact that STN DBS at earlier stages of the disease is cost-effective in patients below the age of 61 when compared with the best medical treatment in the German health care system. This finding was supported by detailed sensitivity analyses reporting robust results. Whereas the EARLYSTIM study has shown STN DBS to be superior to medical therapy with respect to quality of life for patients with early motor complications, this further analysis has shown its cost-effectiveness. (c) 2016 International Parkinson and Movement Disorder Society. PMID- 27506640 TI - Indoor tanning: bringing the sun inside? PMID- 27506641 TI - Gender differences on the interacting effects of marital status and health insurance on long-term colon cancer survival in California, 1995-2014. PMID- 27506642 TI - Effects of mimic of manganese superoxide dismutase on 2,4,6-trinitrobenzene sulfonic acid-induced colitis in rats. AB - The mimic of manganese superoxide dismutase (MnSODm) has been synthesized and reported to have anti-inflammatory properties. However, whether MnSODm has anti inflammatory effects on colitis and any underlying mechanisms are poorly understood. This study was to investigate therapeutic effects and mechanism of MnSODm on 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced colitis model in rats. Rats were intragastrically administered MnSODm (10, 20, and 40 mg/kg) per day for 7 days after colitis was induced by TNBS. After treated with MnSODm, the colonic macroscopic and microscopic damage scores and colonic weight/length ratios were significantly decreased compared with colitis model group. Myeloperoxidase (MPO) activity, malonyldialdehyde (MDA), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-8 levels in colon tissues were also significantly decreased in MnSODm treatment groups. However, superoxide dismutase (SOD) activity significantly increased and phosphorylated inhibitory kappa B-alpha (IkappaBalpha), inhibitor kappa B kinase (IKKalpha/beta), and nuclear factor-kappa Bp65 (NF-kappaBp65) as well as Toll-like receptor 4 (TLR4) and myeloid differentiation actor 88 (MyD88) in the colonic mucosa were significantly inhibited by MnSODm treatment. Thus, MnSODm was protective against colitis via antioxidant activity and by inhibiting inflammatory mediators by down regulating TLR4/MyD88/NF-kappaB signaling pathways. These data suggest a potential therapeutic effect of MnSODm in colitis. PMID- 27506643 TI - Triply Halide-Bridged Dinuclear Iridium(III) Complexes with Chiral Diphosphine Ligands as New Easy-to-Handle Iridium Catalysts for Asymmetric Hydrogenation of Imines and N-Heteroaromatics. AB - Iridium(III) complexes bearing chiral ligands have proved to be active species in asymmetric hydrogenation of C=N bonds, though there are only a few iridium(III) precursors. We prepared triply halide-bridged dinuclear iridium complexes bearing chiral diphosphine ligands by simple treatment of the iridium(I) precursor, chiral diphosphine, and aqueous hydrogen halide. The strong advantage of these dinuclear iridium complexes is that they are air and moisture stable, leading to easy handling in asymmetric synthesis. The dinuclear iridium complexes exhibited high catalytic activity toward asymmetric hydrogenation of imines and N heteroaromatics. Moreover, we demonstrated the application of triply halide bridged dinuclear ruthenium(II) and rhodium(III) catalyst precursors for the asymmetric hydrogenation of ketonic substrates and simple olefins, respectively. PMID- 27506644 TI - Parent and Self-Report Ratings on the Perceived Levels of Social Vulnerability of Adults with Williams Syndrome. AB - The current study took a multi-informant approach to compare parent to self report ratings of social vulnerability of adults with Williams syndrome (WS). Participants included 102 pairs of adults with WS and their parents. Parents completed the Social Vulnerability Questionnaire and adults with WS completed an adapted version of the questionnaire. Parents consistently reported higher levels of social vulnerability for their son/daughter than the individual with WS reported, with the exception of emotional abuse. The lower ratings of social vulnerability by adults with WS, compared to their parents, offer new information about their insight into their own vulnerability. These findings highlight the importance of teaching self-awareness as a part of a multi-informant approach to interventions designed to target social vulnerability. PMID- 27506646 TI - Editor's perspectives - August 2016. PMID- 27506645 TI - Supportive Dyadic Coping and Psychological Adaptation in Couples Parenting Children with Autism Spectrum Disorder: The Role of Relationship Satisfaction. AB - In couples parenting children with Autism Spectrum Disorder (ASD), the partner becomes a primary source of support for addressing the additional parenting demands. The purpose of this study was to examine the associations between supportive dyadic coping and parental adaptation, and to assess the mediating role of relationship satisfaction between them. Seventy-six couples parenting children with ASD participated. Data were gathered through self-report questionnaires and an Actor-Partner Interdependence Mediation Model was used. Mothers' and fathers' supportive dyadic coping was related to both their own and partner's relationship satisfaction and parental adaptation. Findings also revealed the mediation role of relationship satisfaction, in the association between supportive dyadic coping and parental adaptation. The implications for research and clinical practice are discussed. PMID- 27506647 TI - The "Superior Ledge": a Modification of the Standard Superomedial Pedicle Reduction Mammoplasty to Accentuate Nipple-Areola Complex Projection. AB - BACKGROUND: The superomedial pedicle parenchymal excision pattern for reduction mammaplasty has the benefits of a reproducible breast shape and improved superomedial fullness, but is limited by a susceptibility to nipple retraction. The senior author of this paper has formalized the "superior ledge" modification of the superomedial pedicle technique (SL-SMP) to address these limitations. OBJECTIVE: To describe the technical details of the SL-SMP breast reduction technique and to analyze patient outcomes. METHODS: The technique involves only partial-thickness parenchymal excision superolateral to the pedicle, thereby leaving a "superior ledge" of parenchyma on top of which the nipple-areola complex (NAC) rests in a tension-free manner. Postoperative photographs were recorded; and patient demographics, intraoperative details, complications, and outcomes were recorded and analyzed. RESULTS: One hundred seven patients underwent SL-SMP reduction mammaplasty between 2007 and 2013. Complications included wound-healing complications (9.3 %), infection (2.8 %), seroma (1.9 %), and hematoma (1.9 %). Mean follow-up was 44.6 months (Range: 17-72), and during that period no incidence of clinically relevant NAC retraction was noted by either the patient or surgical team. CONCLUSIONS: Maintenance of a distinct superior ledge underlying the final position of the NAC is an important modification to stress, to prevent nipple retraction. Importantly, the height of the ledge can be personalized for each patient. We feel it is a valuable addition to the plastic surgeon's armamentarium to optimize outcomes for patients seeking relief from excessive breast tissue. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27506648 TI - Early life stages of an arctic keystone species (Boreogadus saida) show high sensitivity to a water-soluble fraction of crude oil. AB - Increasing anthropogenic activities in the Arctic represent an enhanced threat for oil pollution in a marine environment that is already at risk from climate warming. In particular, this applies to species with free-living pelagic larvae that aggregate in surface waters and under the sea ice where hydrocarbons are likely to remain for extended periods of time due to low temperatures. We exposed the positively buoyant eggs of polar cod (Boreogadus saida), an arctic keystone species, to realistic concentrations of a crude oil water-soluble fraction (WSF), mimicking exposure of eggs aggregating under the ice to oil WSF leaking from brine channels following encapsulation in ice. Total hydrocarbon and polycyclic aromatic hydrocarbon levels were in the ng/L range, with most exposure concentrations below the limits of detection throughout the experiment for all treatments. The proportion of viable, free-swimming larvae decreased significantly with dose and showed increases in the incidence and severity of spine curvature, yolk sac alterations and a reduction in spine length. These effects are expected to compromise the motility, feeding capacity, and predator avoidance during critical early life stages for this important species. Our results imply that the viability and fitness of polar cod early life stages is significantly reduced when exposed to extremely low and environmentally realistic levels of aqueous hydrocarbons, which may have important implications for arctic food web dynamics and ecosystem functioning. PMID- 27506649 TI - Oil spills and their impacts on sand beach invertebrate communities: A literature review. AB - Sand beaches are highly dynamic habitats that can experience considerable impacts from oil spills. This review provides a synthesis of the scientific literature on major oil spills and their impacts on sand beaches, with emphasis on studies documenting effects and recoveries of intertidal invertebrate communities. One of the key observations arising from this review is that more attention has generally been given to studying the impacts of oil spills on invertebrates (mostly macrobenthos), and not to documenting their biological recovery. Biological recovery of sand beach invertebrates is highly dynamic, depending on several factors including site-specific physical properties and processes (e.g., sand grain size, beach exposure), the degree of oiling, depth of oil burial, and biological factors (e.g., species-specific life-history traits). Recovery of affected communities ranges from several weeks to several years, with longer recoveries generally associated with physical factors that facilitate oil persistence, or when cleanup activities are absent on heavily oiled beaches. There are considerable challenges in quantifying impacts from spills on sand beach invertebrates because of insufficient baseline information (e.g., distribution, abundance and composition), knowledge gaps in their natural variability (spatial and temporal), and inadequate sampling and replication during and after oil spills. Thus, environment assessments of impacts and recovery require a rigorous experimental design that controls for confounding sources of variability. General recommendations on sampling strategies and toxicity testing, and a preliminary framework for incorporating species-specific life history traits into future assessments are also provided. PMID- 27506650 TI - Partners' Ongoing Treatment for Chronic Disease and the Risk of Psychological Distress after the Great East Japan Earthquake. AB - Several studies have reported that not only patients with chronic diseases but also their partners are likely to face major psychosocial problems. This study examined the association between a partner's ongoing treatment for chronic disease and the risk of psychological distress after the Great East Japan Earthquake (GEJE). In 2012, a questionnaire was distributed as part of a cross sectional study of participants aged 20 years or older living in a municipality that had been severely inundated by the tsunami following the GEJE. We identified couples using the household numbers of the municipality and collected self reported information on ongoing chronic disease treatment for stroke, cancer, myocardial infarction, and angina. Psychological distress was evaluated using the Kessler 6 scale (K6) and was defined as a score >= 5/24 points. Among 1,246 couples (2,492 participants) thus identified, 2,369 completed the K6. The number of participants whose partners were under treatment for chronic diseases was 209 (9%). Overall, participants with partners who were receiving treatment for chronic diseases (odds ratio [OR] = 1.3, 95% confidence interval [CI] = 0.95-1.8, P = 0.09) did not show a significantly higher risk of psychological distress using logistic regression analysis. Women, but not men, whose partners were receiving treatment for chronic diseases, had a higher risk of psychological distress (women: OR = 1.6, P = 0.02; men: OR = 1.0, P = 0.92). After the GEJE, only in women the presence of partners under treatment for chronic diseases appears to be a risk factor for psychological distress. PMID- 27506651 TI - Activation of the trigeminal alpha2-adrenoceptor produces sex-specific, estrogen dependent thermal antinociception and antihyperalgesia using an operant pain assay in the rat. AB - Higher prevalence of several pain disorders in women and sexual dimorphism in G protein coupled receptor-induced analgesia has been reported. We have previously shown that alpha2-adrenoceptor-induced antinociception is sex-specific and attenuated by estrogen in the female rat. However, this evidence was obtained using reflexive withdrawal-based nociceptive assays conducted on restrained animals that may not involve cerebral processing. Hence, we evaluated whether activation of the trigeminal alpha2-adrenoceptor produces sex-specific antinociceptive and antihyperalgesic effects in the orofacial region of the rat using a reward conflict-based operant paradigm in which animals must tolerate nociceptive thermal stimulation to be rewarded. Male and ovariectomized (OVX) Sprague-Dawley rats were implanted intracisternally with a PE10 cannula for drug injections. A group of OVX rats (OVX+E) was administered subcutaneously with estradiol 48h before the test. Effect of clonidine, an alpha2-adrenoceptor agonist, was determined on the operant pain assay using a fully automated Orofacial Pain Assessment Device. Number of spout licks, thermode contacts, and amount of reward intake were automatically recorded by the ANY-maze software. Using acute pain modeling, clonidine produced a dose-dependent increase in all three parameters in male and OVX groups, however, it was ineffective in the OVX+E group. Similarly, using inflammatory pain modeling, clonidine significantly increased these parameters in carrageenan-treated male and OVX groups but not in the OVX+E group. Thus, alpha2-adrenoceptor activation produces sex-specific antinociception and antihyperalgesia and estrogen attenuates these effects in female rats using an operant pain assay. These findings may help the discovery of effective analgesics for each sex. PMID- 27506652 TI - Nicotine evokes kinetic tremor by activating the inferior olive via alpha7 nicotinic acetylcholine receptors. AB - Nicotinic acetylcholine (nACh) receptors are implicated in the pathogenesis of movement disorders (e.g., tremor) and epilepsy. Here, we performed behavioral and immunohistochemical studies using mice and rats to elucidate the mechanisms underlying nicotine-induced tremor. Treatments of animals with nicotine (0.5 2mg/kg, i.p.) elicited kinetic tremor, which was completely suppressed by the nACh receptor antagonist mecamylamine (MEC). The specific alpha7 nACh receptor antagonist methyllycaconitine (MLA) also inhibited nicotine-induced tremor, whereas the alpha4beta2 nACh antagonist dihydro-beta-erythroidine (DHbetaE) or the peripheral alpha3beta4 nACh antagonist hexamethonium showed no effects. Mapping analysis of Fos protein expression, a biological marker of neural excitation, revealed that a tremorgenic dose (1mg/kg) of nicotine region specifically elevated Fos expression in the piriform cortex (PirC), medial habenula, solitary nucleus and inferior olive (IO) among 44 brain regions examined. In addition, similarly to the tremor responses, nicotine-induced Fos expression in the PirC and IO was selectively antagonized by MLA, but not by DHbetaE. Furthermore, an electrical lesioning of the IO, but not the PirC, significantly suppressed the induction of nicotine tremor. The present results suggest that nicotine elicits kinetic tremor in rodents by activating the IO neurons via alpha7 nACh receptors. PMID- 27506653 TI - Ritanserin-sensitive receptors modulate the prosocial and the anxiolytic effect of MDMA derivatives, DOB and PMA, in zebrafish. AB - Little is known about the pharmacological effects of amphetamine derivatives. In the present study, the effect on social preference and anxiety-like behavior of 2,5-dimetoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA), in comparison with 3,4 methylenedioxymethamphetamine (MDMA) was investigated in zebrafish, an emerging model to study emotional behavior in an inexpensive and quick manner. DOB (0.05-2mg/kg), PMA (0.0005-2mg/kg) or MDMA (0.25-20mg/kg), given i.m. to adult zebrafish, progressively increased the time spent in the proximity of nacre fish picture in a social preference test. However, high doses were ineffective. Similarly, in the novel tank diving and light-dark tests the compounds elicited a progressive anxiolytic effect in terms of time spent in the upper half of the tank and in the light compartment, respectively. All the above effects were interpolated by symmetrical parabolas. The 5-HT2A/C antagonist ritanserin (0.025-2.5mg/kg) in association with the maximal effective dose of MDMA, DOB and PMA blocked both the social and anxiolytic effect. Taken together these findings demonstrate for the first time the prosocial and anxiolytic properties of DOB and PMA and focus on the mechanisms of their action through the serotonergic-like system suggesting a potential clinical application. PMID- 27506654 TI - Altered consolidation of extinction-like inhibitory learning in genotype-specific dysfunctional coping fostered by chronic stress in mice. AB - Genetic and stress-related factors interact to foster mental disorders, possibly through dysfunctional learning. In a previous study we reported that a temporary experience of reduced food availability increases forced swim (FS)-induced helplessness tested 14days after a first experience in mice of the standard inbred C57BL/6(B6) strain but reduces it in mice of the genetically unrelated DBA/2J (D2) strain. Because persistence of FS-induced helplessness influences adaptive coping with stress challenge and involve learning processes the present study tested whether the behavioral effects of restricted feeding involved altered consolidation of FS-related learning. First, we demonstrated that restricted feeding does not influence behavior expressed on the first FS experience, supporting a specific effect on persistence rather then development of helplessness. Second, we found that FS-induced c-fos expression in the infralimbic cortex (IL) was selectively enhanced in food-restricted (FR) B6 mice and reduced in FR D2 mice, supporting opposite alterations of consolidation processes involving this brain area. Third, we demonstrated that immediate post FS inactivation of IL prevents 24h retention of acquired helplessness by continuously free-fed mice of both strains, indicating the requirement of a functioning IL for consolidation of FS-related learning in either mouse strain. Finally, in line with the known role of IL in consolidation of extinction memories, we found that restricted feeding selectively facilitated 24h retention of an acquired extinction in B6 mice whereas impairing it in D2 mice. These findings support the conclusion that an experience of reduced food availability strain-specifically affects persistence of newly acquired passive coping strategies by altering consolidation of extinction-like inhibitory learning. PMID- 27506656 TI - NMDA antagonist MK 801 in nucleus accumbens core but not shell disrupts the restraint stress-induced reinstatement of extinguished cocaine-conditioned place preference in rats. AB - Relapse is a common feature of cocaine addiction. In rodents, it can be elicited by cues, stress or the drug. Restraint stress-induced reinstatement of cocaine conditioned place preference (CPP) is a useful model to study the mechanisms involved in stress-induced relapse of drug-seeking behavior. There is evidence that the glutamate NMDA receptors are critically involved in drug- and cue induced reinstatement of seeking behavior and drug-CPP responses. The aim of this study was to investigate the contribution of NMDA receptors within core vs. shell nucleus accumbens (NAc) subregions to restraint stress-induced reinstatement of extinguished cocaine-CPP. After extinction of cocaine-conditioned preference, animals were administered MK 801 systemically or directly into intra-core or intra-shell, and restrained for 30min or left undisturbed in their home-cages. First, we demonstrated that restraint stress-induced reinstatement of extinguished cocaine-CPP depends on the duration of restraint as well as on the context in which it is applied. Second, this effect was blocked by systemic MK 801 administration either before or after restraint. Third, intra-core but not intra-shell administration abrogated the restraint stress-induced reinstatement. These findings show that NMDA receptors within NAc core, but not shell, play a critical role in restraint stress-induced reinstatement of cocaine-CPP. PMID- 27506655 TI - The role of genes involved in stress, neural plasticity, and brain circuitry in depressive phenotypes: Convergent findings in a mouse model of neglect. AB - Early life neglect increases risk for the development of psychopathologies during childhood and adulthood, including depression and anxiety disorders. We recently reported epigenetic changes in DNA derived from saliva in three genes predicted depression in a cohort of maltreated children: DNA-binding protein inhibitor ID-3 (ID3), Glutamate NMDA Receptor (GRIN1), and Tubulin Polymerization Promoting Protein (TPPP). To validate the role of these genes in depression risk, secondary analyses were conducted of gene expression data obtained from medial prefrontal cortex (mPFC) tissue of mice subjected to a model of maternal neglect which included maternal separation and early weaning (MSEW). Anxiety and depression like phenotype data derived using the elevated plus maze (EPM) and forced swimming test (FST), respectively, were also available for secondary analyses. Behavioral tests were conducted in MSEW and control adult male mice when they were between 65 and 80days old. ID3, GRIN1 and TPPP gene expression in the mPFC were found to significantly predict behavioral differences in the EPM and FST. These results further support the role of these genes in the etiology of depressive and anxiety phenotypes following early life stress. PMID- 27506657 TI - Reactive hypoglycaemia with seizure following intraduodenal glucose infusion in a patient with type 2 diabetes. PMID- 27506658 TI - Differences in fat accumulation between immature male and female Atlantic salmon Salmo salar after dietary administration of tetradecylthioacetic acid. AB - This study provoked sex-specific differences in fat metabolism in Atlantic salmon Salmo salar, by dietary administration of tetradecylthioacetic acid (TTA) during their first spring and winter in the sea. The effects of TTA were evaluated in June of the first spring and May of the second spring in the sea, by analysing white muscle-fat content. Muscle fat in males and females differed significantly as a result of TTA in their diet and diet interacted with the sex of the fish. The fat content during the first spring after dietary TTA was lowered by a greater amount in females than in males, 3.1-4.3%, respectively (P < 0.05). In contrast, during the second spring, fat content was lowered by a greater amount in males than in females, 15.8-16.7%, respectively (P < 0.01). Condition factor followed a similar pattern to the muscle fat. The results indicate that the difference in male and female fat accumulation dynamics is related to sex specific reproduction biology of S. salar. In addition, the findings show that it is important to consider the sex of the fish and the season of the year when studying fat dynamics and reproductive biology of S. salar. PMID- 27506659 TI - Exam preparation course in obstetrics and gynecology for the German Medical State Examination: proof of concept and implications for the recruitment of future residents. AB - OBJECTIVES: Today's written part of the medical state examination requires students to retrieve a comprehensive amount of knowledge in a limited period of time. Therefore, the main study objectives were to implement and to evaluate a two-day exam preparation course for the German Medical State Examination in obstetrics and gynecology. The project evaluation focused on acceptability, satisfaction and the gain of knowledge for the participants of such a face-to face course. STUDY DESIGN: The two-day intensive training for senior medical students offered a review of the entire exam-relevant content in the field of obstetrics and gynecology in combination with interactive discussions along selected exam questions. Skill gains were assessed using pre- and post-course multiple choice tests. In addition, a qualitative questionnaire assessed attitudes and satisfaction of course participants. RESULTS: A total of 101 fifth year senior medical students from Heidelberg University Medical School participated in the two pilot courses (summer 2014 and winter 2015). Pre- and post-course tests showed a significant skill-gain from 14.9 to 18.0 points [of a maximum of 20; pre-post difference 95 % CI (2.21; 3.98), t test: p < 0.001]. Furthermore, the qualitative results showed high satisfaction with the course, with an average Likert scale grading of 5.63 (2014) and 5.44 (2015) on a scale from 1 ("extraordinary bad") to 6 ("extraordinary good"). CONCLUSIONS: This study shows that a two-day intensive course in obstetrics and gynecology is feasible, effective and highly appreciated by senior medical students preparing for the Second German Medical State Examination. It further suggests surplus value for academic clinical departments to recruit future residents. Methods and tools presented in this paper are intended to inspire and guide clinical colleagues in implementing the format at their respective universities. PMID- 27506660 TI - Erratum to: Hard to Believe: Produced by Ken Stone and Irene Silber, 2015, Swoop Films and Stone Soup Productions (New York, 56 minutes, unrated). PMID- 27506661 TI - Effects of Neoadjuvant Laparoscopic Hyperthermic Intraperitoneal Chemotherapy and Neoadjuvant Intraperitoneal/Systemic Chemotherapy on Peritoneal Metastases from Gastric Cancer. AB - BACKGROUND: The Peritoneal Cancer Index (PCI) is the most important prognostic factor following comprehensive treatment for peritoneal metastasis (PM) from gastric cancer (GCPM); however, 70 % of patients with GCPM showed a PCI score above the cut-off level at the time of diagnosis. Furthermore, neoadjuvant chemotherapy may reduce the PCI score to lower than the cut-off levels. In this study, the effects of neoadjuvant laparoscopic hyperthermic intraperitoneal chemoperfusion (NLHIPEC) and neoadjuvant intraperitoneal/systemic chemotherapy (NIPS) were investigated. MATERIALS AND METHODS: In group A, NLHIPEC was performed twice in 53 patients with GCPM, separated by a 1-month rest interval. Changes in the PCI were studied at the time of first and second laparoscopy. In group B, after NLHIPEC, a series of 3-week cycles of NIPS were performed over three courses in 52 patients. A laparotomy for cytoreductive surgery (CRS) was then carried out and the PCI changes were studied. RESULTS: In group A, the PCI score at the time of the second session (11.8 +/- 11.0) was significantly lower than at the time of the first session (14.2 +/- 10.7), while in group B, the PCI at the time of laparotomy (9.9 +/- 11.3) was significantly lower than at the time of NLHIPEC (14.8 +/- 11.4). After NLHIPEC plus NIPS, complete cytoreduction was achieved in 30 (57.6 %) patients. CONCLUSIONS: NLHIPEC and NIPS are effective methods of reducing PCI levels before CRS. PMID- 27506662 TI - Impact of Flap Reconstruction on Radiotoxicity After Salvage Surgery and Reirradiation for Recurrent Head and Neck Cancer. AB - BACKGROUND: Recurrent head and neck malignancies remain a therapeutic challenge. Tissue transfer, in addition to defect coverage and prevention of wound complications, may potentially decrease radiotoxicity. We evaluated radiation toxicity and survival outcomes of patients who underwent salvage surgery with reirradiation, comparing primary closure to flap reconstruction. METHODS: Retrospective outcomes analysis of recurrent head and neck squamous cell carcinoma (HNSCC) patients treated with curative intent by salvage surgery (+/- flap reconstruction) and reirradiation from 1996 to 2011. Recurrent stage, reirradiation modality, chemotherapy use, and toxicities were evaluated. RESULTS: Of 96 patients, 59 had primary closure, whereas 37 underwent flap reconstruction (26 free, 11 pedicled). Median radiation and reirradiation doses were 66 Gy and 60 Gy, respectively. Comparing nonflap and flap patients, there was no significant difference in acute mild toxicities (100 vs. 100 %, p = 1.0) or acute severe toxicities (33.9 vs. 37.8 %, p = 0.83). Nonflap patients experienced significantly greater incidence of both late mild toxicities (81.4 vs. 54.1 %, p = 0.006) and late severe toxicities (47.5 vs. 21.6 %, p = 0.02). Overall survival at 5 years was equivalent (33.1 vs. 34.7 %, p = 0.88). Free flap patients had greater delays to postoperative reirradiation and treatment package times compared with pedicled flap patients but no meaningful difference in survival outcomes. CONCLUSIONS: Vascularized tissue potentially helps offset late toxicities associated with a second radiation course in recurrent head and neck cancer patients. In these selected patients, flap coverage may confer functional benefits and improve the long-term radiotoxicity profile. PMID- 27506663 TI - Pseudoduganella danionis sp. nov., isolated from zebrafish (Danio rerio). AB - One beige-pigmented, Gram-staining-negative, rod-shaped bacterium, strain E3/2T, was isolated from a zebrafish, Daniorerio. Phylogenetic analysis based on nearly full-length 16S rRNA gene sequences showed that the isolate shared 97.7 % 16S rRNA gene sequence similarity to the species Pseudoduganella violaceinigra and between 97.4 to 97.0 % to some species of the genera Duganella and Massilia, including Duganella radicis, Duganella phyllosphaerae, Massilia dura, Massilia lutea, Duganella sacchari, Duganella zoogloeoides, Massiliaalbidiflava and Massilia umbonata. Sequence similarities to all other species were below 97 %. The main cellular fatty acids of the strain were summed feature 3 fatty acids (C16 : 1omega7c/iso-C15 : 0 2-OH), C10 : 0 3-OH, C16 : 0 and C12 : 0. The polyamine pattern of strain E3/2T contained predominantly putrescine and 2 hydroxyputrescine. The major quinone was ubiquinone Q-8. Major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Based on phylogenetic, chemotaxonomic, genomic and phenotypic analyses we propose a novel species of the genus Pseudoduganella named Pseudoduganella danionis sp. nov., with strain E3/2T (=LMG 29678T=CCM 8698T) as the type strain. PMID- 27506664 TI - Entanglement revive and information flow within the decoherent environment. AB - In this paper, the dynamics of entanglement is investigated in the presence of a noisy environment. We reveal its revival behavior and probe the mechanisms of this behavior via an information-theoretic approach. By analyzing the correlation distribution and the information flow within the composite system including the qubit subsystem and a noisy environment, it has been found that the subsystem environment coupling can induce the quasi-periodic entanglement revival. Furthermore, the dynamical relationship among tripartite correlations, bipartite entanglement and local state information is explored, which provides a new insight into the non-Markovian mechanisms during the evolution. PMID- 27506665 TI - Early clinical experience utilizing scintillator with optical fiber (SOF) detector in clinical boron neutron capture therapy: its issues and solutions. AB - BACKGROUND: Real-time measurement of thermal neutrons in the tumor region is essential for proper evaluation of the absorbed dose in boron neutron capture therapy (BNCT) treatment. The gold wire activation method has been routinely used to measure the neutron flux distribution in BNCT irradiation, but a real-time measurement using gold wire is not possible. To overcome this issue, the scintillator with optical fiber (SOF) detector has been developed. The purpose of this study is to demonstrate the feasibility of the SOF detector as a real-time thermal neutron monitor in clinical BNCT treatment and also to report issues in the use of SOF detectors in clinical practice and their solutions. MATERIAL AND METHODS: Clinical measurements using the SOF detector were carried out in 16 BNCT clinical trial patients from December 2002 until end of 2006 at the Japanese Atomic Energy Agency (JAEA) and Kyoto University Research Reactor Institute (KURRI). RESULTS: The SOF detector worked effectively as a real-time thermal neutron monitor. The neutron fluence obtained by the gold wire activation method was found to differ from that obtained by the SOF detector. The neutron fluence obtained by the SOF detector was in better agreement with the expected fluence than with gold wire activation. The estimation error for the SOF detector was small in comparison to the gold wire measurement. In addition, real-time monitoring suggested that the neutron flux distribution and intensity at the region of interest (ROI) may vary due to the reactor condition, patient motion and dislocation of the SOF detector. CONCLUSION: Clinical measurements using the SOF detector to measure thermal neutron flux during BNCT confirmed that SOF detectors are effective as a real-time thermal neutron monitor. To minimize the estimation error due to the displacement of the SOF probe during treatment, a loop-type SOF probe was developed. PMID- 27506668 TI - Caution is urged over "game changing" asthma drug. PMID- 27506666 TI - A microdeletion at Xq22.2 implicates a glycine receptor GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies. AB - BACKGROUND: Among the 21 annotated genes at Xq22.2, PLP1 is the only known gene involved in Xq22.2 microdeletion and microduplication syndromes with intellectual disability. Using an atypical microdeletion, which does not encompass PLP1, we implicate a novel gene GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies. CASE PRESENTATION: We report a female patient (DGDP084) with a de novo Xq22.2 microdeletion of at least 110 kb presenting with intellectual disability, motor delay, behavioral problems and craniofacial anomalies. While her phenotypic features such as cognitive impairment and motor delay show overlap with Pelizaeus-Merzbacher disease (PMD) caused by PLP1 mutations at Xq22.2, this gene is not included in our patient's microdeletion and is not dysregulated by a position effect. Because the microdeletion encompasses only three genes, GLRA4, MORF4L2 and TCEAL1, we investigated their expression levels in various tissues by RT-qPCR and found that all three genes were highly expressed in whole human brain, fetal brain, cerebellum and hippocampus. When we examined the transcript levels of GLRA4, MORF4L2 as well as TCEAL1 in DGDP084's family, however, only GLRA4 transcripts were reduced in the female patient compared to her healthy mother. This suggests that GLRA4 is the plausible candidate gene for cognitive impairment, behavioral problems and craniofacial anomalies observed in DGDP084. Importantly, glycine receptors mediate inhibitory synaptic transmission in the brain stem as well as the spinal cord, and are known to be involved in syndromic intellectual disability. CONCLUSION: We hypothesize that GLRA4 is involved in intellectual disability, behavioral problems and craniofacial anomalies as the second gene identified for X-linked syndromic intellectual disability at Xq22.2. Additional point mutations or intragenic deletions of GLRA4 as well as functional studies are needed to further validate our hypothesis. PMID- 27506667 TI - Effect of vitamin D3 supplementation on iron status: a randomized, double-blind, placebo-controlled trial among ethnic minorities living in Norway. AB - BACKGROUND: Both vitamin D and iron deficiencies are widespread globally, and a relationship between these deficiencies has been suggested. However, there is a paucity of randomised controlled trials assessing the effect of vitamin D supplementation on iron status. PURPOSE: We aimed to investigate whether 16 weeks of daily vitamin D3 supplementation had an effect on serum ferritin, haemoglobin, serum iron and transferrin saturation. METHODS: Overall, 251 participants from South Asia, Middle East and Africa aged 18-50 years who were living in Norway were randomised to receive daily oral supplementation of 10 MUg vitamin D3, 25 MUg vitamin D3, or placebo for 16 weeks during the late winter. Blood samples from baseline and after 16 weeks were analysed for serum 25-hydroxyvitamin D (s 25(OH) D), serum ferritin, haemoglobin and serum iron. In total, 214 eligible participants completed the intervention (86 % of those randomised). Linear regression analysis were used to test the effect of vitamin D3 supplementation combined (10 or 25 MUg) and separate doses 10 or 25 MUg compared to placebo on change (T2-T1) in each outcome variable adjusted for baseline s-25(OH)D values. RESULTS: There was no difference in change in the levels of s-ferritin (1.9 MUg/L, 95 % CI: -3.2, 7.0), haemoglobin (-0.02 g/dL, 95 % CI: -0.12, 0.09), s iron (0.4 MUg/L, 95 % CI: -0.5, 1.3) or transferrin saturation (0.7 %, 95 % CI: 0.6.1, 2.0) between those receiving vitamin D3 or those receiving placebo. Serum 25-hydroxyvitamin D increased from 29 nmol/L at baseline to 49 nmol/L after the intervention, with little change in the placebo group. CONCLUSIONS: In this population of healthy ethnic minorities from South Asia, the Middle East and Africa who had low vitamin D status, 16 weeks of daily supplementation with 10 or 25 MUg of vitamin D3 did not significantly affect the haemoglobin levels or other markers of iron status. PMID- 27506669 TI - Pretreatment quality-of-life score is a better discriminator of oesophageal cancer survival than performance status. AB - OBJECTIVES: Performance status [Eastern Cooperative Oncology Group (ECOG)] is a physician-assigned score indicating a patient's fitness for treatment. Functional assessment of cancer therapy-esophagus (FACT-E) is a patient-reported, health related quality-of-life (HRQOL) instrument containing an oesophageal cancer subscale (ECS). Our objective was to assess the discriminative ability of pretreatment FACT-E and ECS when compared with performance status in predicting survival in patients with Stage II-III oesophageal cancer. METHODS: Patient data from four prospective studies were pooled together. These four studies included oesophageal patients who received chemoradiation either as neoadjuvant therapy or as definitive therapy. Three separate Cox regressions were performed considering FACT-E, ECS and ECOG as the main predictors, respectively. Receiver-operating characteristics analyses were performed. RESULTS: Of the 120 curative intent patients, 39.8% (n = 51), 58.6% (n = 75) and 1.6% (n = 2) had ECOG 0, 1 and 2, respectively. On Cox regression analysis, pretreatment FACT-E (P = 0.04) and ECS (P = 0.004) but not ECOG (P = 0.27) were independently associated with overall survival. ECOG could not discriminate between survivors and non-survivors (P = 0.28) with an area under the curve (AUC) of 0.56 [95% confidence interval (CI): 0.45-0.66], whereas FACT-E (P = 0.02) and ECS (P < 0.001) were discriminative with AUC = 0.63 (95% CI: 0.52-0.73) and AUC = 0.69 (95% CI: 0.60-0.79), respectively. CONCLUSIONS: In patients with Stage II-III oesophageal cancer being considered for curative therapy, pretreatment FACT-E and ECS have better discrimination for survival than does ECOG. The majority of patients were ECOG 0/1. Thus, these patient-derived scores were able to discriminate survivors from non-survivors even within this constrained range of clinician-assigned performance status. This highlights the potential utility of FACT-E and ECS as prognostic tools. PMID- 27506671 TI - 'Rare' manifestation of 'rare' disease: sarcoidosis presenting as pancreatitis, duodenal ulcer and severe acute kidney injury. PMID- 27506672 TI - Transluminal angioplasty and stenting versus conservative treatment in patients with symptomatic basilar artery stenosis : Perspective for future clinical trials. AB - PURPOSE: Two recent randomized controlled trials (RCT) consistently showed superiority of aggressive medical treatment versus percutaneous transluminal angioplasty and stenting (PTAS) in patients with intracranial artery stenosis. Patients with symptomatic basilar stenosis have a higher long-term risk of recurrent stroke compared to patients with anterior circulation stenosis but no study has specifically focused on the role of PTAS in this subgroup. The aim of our study was to investigate the subgroup of patients with symptomatic basilar artery stenosis to find evidence for the feasibility of a future clinical trial. METHODS: Patients with ischemic stroke caused by a symptomatic basilar stenosis and admitted to five German tertiary care hospitals were included in this multicenter effectiveness study. Primary outcome was a composite endpoint of stroke recurrence, clinically relevant restenosis, progression and death. Shared frailty Cox regression models were used to compare outcome rates between groups. RESULTS: Of the 139 patients included in the study 79 (57 %) underwent PTAS and 60 (43 %) conservative treatment alone. The median follow-up period was 300 (IQR 18-738) days. Risks of the primary composite outcome (hazard ratio HR 0.49, 95 % confidence interval CI 0.25-0.97, p = 0.039) and of the key secondary outcomes recurrent stroke (HR 0.42, 95 % CI 0.19-0.95, p = 0.037) and clinically relevant restenosis/progression (HR 0.12, 95 % CI 0.03-0.59, p = 0.009) were lower in patients with PTAS compared to conservative treatment. There was no difference in all-cause mortality between groups (HR 0.98, 95 % CI 0.19-5.09, p = 0.979). CONCLUSION: In this retrospective study we could not reproduce the findings from large RCTs on intracranial stenting. Our data could be considered as a basis for a prospective study on patient selection for PTAS in the basilar artery. PMID- 27506673 TI - Transorbital Cavernous Sinus Direct Puncture : Alternative to treat dural arteriovenous fistula. AB - INTRODUCTION: The authors present a retrospective series of their clinical experience in the treatment of cavernous dural arteriovenous fistulas (DAVF) by direct transorbital puncture of the cavernous sinus as an alternative to the endovascular approach. METHODS: Between October 2012 and September 2014, eight patients harboring cavernous DAVF underwent percutaneous treatment by direct transorbital puncture of the cavernous sinus at three institutions. All patients presented with ocular symptoms. Standard endovascular approaches, including transvenous and transarterial routes, were primarily attempted without success in all cases. Direct puncture was performed through two different approaches, namely inferolateral and superomedial. The entry point was the inferior and superior eyelid, respectively. Embolization was performed with coils or Onyx (Covidien, Irvine, CA). Immediate and late angiographies were used to evaluate the occlusion of the fistula. RESULTS: Of the patients seven had complete occlusion of the cavernous DAVFs noted on the immediate and follow-up angiograms and one patient had residual filling but reduction of the shunt resulted in clinical improvement. None of the patients had worsening of neurological function. One case was complicated by inadvertent internal carotid puncture but without clinical manifestations. One patient experienced postoperative superior ophthalmic vein thrombosis. CONCLUSION: In very specific cases, when endovascular access is not possible or fails to occlude cavernous DAVF, direct transorbital puncture of the cavernous sinus was shown to be feasible, safe and very effective. PMID- 27506674 TI - Differential expression of skeletal muscle genes following administration of clenbuterol to exercised horses. AB - BACKGROUND: Clenbuterol, a beta2-adrenergic receptor agonist, is used therapeutically to treat respiratory conditions in the horse. However, by virtue of its mechanism of action it has been suggested that clenbuterol may also have repartitioning affects in horses and as such the potential to affect performance. Clenbuterol decreases the percent fat and increases fat-free mass following high dose administration in combination with intense exercise in horses. In the current study, microarray analysis and real-time PCR were used to study the temporal effects of low and high dose chronic clenbuterol administration on differential gene expression of several skeletal muscle myosin heavy chains, genes involved in lipid metabolism and the beta2-adrenergic receptor. The effect of clenbuterol administration on differential gene expression has not been previously reported in the horse, therefore the primary objective of the current study was to describe clenbuterol-induced temporal changes in gene expression following chronic oral administration of clenbuterol at both high and low doses. RESULTS: Steady state clenbuterol concentrations were achieved at approximately 50 h post administration of the first dose for the low dose regimen and at approximately 18-19 days (10 days post administration of 3.2 MUg/kg) for the escalating dosing regimen. Following chronic administration of the low dose (0.8 MUg/kg BID) of clenbuterol, a total of 114 genes were differentially expressed, however, none of these changes were found to be significant following FDR adjustment of the p-values. A total of 7,093 genes were differentially expressed with 3,623 genes up regulated and 3,470 genes down regulated following chronic high dose administration. Of the genes selected for further study by real-time PCR, down-regulation of genes encoding myosin heavy chains 2 and 7, steroyl CoA desaturase and the beta2-adrenergic receptor were noted. For most genes, expression levels returned towards baseline levels following cessation of drug administration. CONCLUSION: This study showed no evidence of modified gene expression following chronic low dose administration of clenbuterol to horses. However, following chronic administration of high doses of clenbuterol alterations were noted in transcripts encoding various myosin heavy chains, lipid metabolizing enzymes and the beta2-adrenergic receptor. PMID- 27506675 TI - Evaluation of cellular and molecular impact of zearalenone and Escherichia coli co-exposure on IPEC-1 cells using microarray technology. AB - BACKGROUND: The gastrointestinal tract is the primary site of toxin interaction, an interface between the organism and its surroundings. In this study, we assessed the alteration of intestinal mRNA profile in the case of co-occurrence of zearalenone (ZEA), a secondary Fusarium metabolite, and Escherichia coli (E. coli), on the intestinal porcine epithelial cells IPEC-1. We chose this model since the pig is a species which is susceptible to pathogen and mycotoxin co exposure. RESULTS: After treating the cells with the two contaminants, either separately or in combination, the differential gene expression between groups was assessed, using the microarray technology. Data analysis identified 1691 upregulated and 797 downregulated genes as a response to E. coli exposure, while for ZEA treated cells, 303 genes were upregulated and 49 downregulated. The co contamination led to 991 upregulated and 800 downregulated genes. The altered gene expression pattern was further classified into 8 functional groups. In the case of co-exposure to ZEA and E.coli, a clear increase of proinflammatory mechanisms. CONCLUSIONS: These results demonstrate the complex effect of single or multiple contaminants exposure at cellular and molecular level, with significant implications that might lead to the activation of pathological mechanisms. A better understanding of the effects of co-contamination is mandatory in developing novel exposure regulations and prevention measures. PMID- 27506676 TI - Follow-up of young patients after acute poisoning by substances of abuse: a comparative cohort study at an emergency outpatient clinic. AB - BACKGROUND: Young patients with acute poisoning by substances of abuse have increased mortality rates in the long term. In Oslo, Norway, most of these patients are treated at the Oslo Accident and Emergency Outpatient Clinic. The majority were discharged without follow-up. In 2010, the clinic implemented an intervention program for patients under the age of 23 presenting with acute poisoning by substances of abuse. The intervention was a brief motivational interview with a social worker before discharge, followed by a telephone consultation. Patients in need of further follow-up were identified and referred. Our objective was to study short-term effects of the intervention program on referrals to follow-up and repetition rates of acute poisoning. METHODS: Comparative cohorts were derived from studies of acute poisoning at the Oslo Accident and Emergency Outpatient Clinic in 2003, 2008 and 2012. Two age groups of patients presenting with acute poisoning by substances of abuse were included: 16-22 years and 23-27 years. Patients in the pre-intervention cohorts of 2003 and 2008 were compared with patients of the same age in the post-intervention cohort of 2012. Repetition rates were estimated using survival analysis. In total, 1323 patients were included; 422 in the younger pre-intervention group, 366 in the younger post-intervention group, 288 in the older pre-intervention group, and 247 in the older post-intervention group. Overall, the major toxic agents were ethanol 823/1323 (62 %) and opioids 215/1323 (16 %). 719/1323 (54 %) patients were male. RESULTS: In the younger groups referrals to follow-up increased from 86/317 (27 %) to 156/366 (43 %) (p < 0.001) after the implementation of the program. Among the older patients, who were not included in the program, there was no significant change in referrals. There was no change in the repetition rate of acute poisoning in either age group. The program established contact with 225/366 (61 %) of the eligible patients. CONCLUSION: More patients were referred to follow-up after the intervention. We expect this to have a beneficial effect on their substance use and reduce excess morbidity and mortality in the long term. There was no change in the repetition rate of poisoning. PMID- 27506677 TI - Constraint-Induced Aphasia Therapy in the Acute Stage: What Is the Key Factor for Efficacy? A Randomized Controlled Study. AB - BACKGROUND: Constraint-induced aphasia therapy (CIAT) has proven effective in patients with subacute and chronic forms of aphasia. It has remained unclear, however, whether intensity of therapy or constraint is the relevant factor. Data about intensive speech and language therapy (SLT) are conflicting. OBJECTIVE: To identify the effective component of CIAT and assess the feasibility of SLT in the acute stage after stroke. METHOD: A total of 60 patients with aphasia (68.2 +/- 11.7 years) were enrolled 18.9 days after first-ever stroke. They were randomly distributed into 3 groups: (1) CIAT group receiving therapy for 3 hours per day (10 workdays, total 30 hours); (2) conventional communication treatment group, with same intensity without constraints; and (3) control group receiving individual therapy twice a day as well as group therapy (total 14 hours). Patients were assessed pretreatment and posttreatment using the Aachener Aphasia Test (primary end point: token test) and the Communicative Activity Log (CAL). RESULTS: Pretreatment, there were no between-group differences. Posttreatment, all groups showed significant improvements without between-group differences. CONCLUSION: It was found that 14 hours of aphasia therapy administered within 2 weeks as individual therapy, focusing on individual deficits, combined with group sessions has proven to be most efficient. This approach yielded the same outcome as 30 hours of group therapy, either in the form of CIAT or group therapy without constraints. SLT in an intensive treatment schedule is feasible and was well tolerated in the acute stage after stroke. PMID- 27506678 TI - Perceptions of diet, physical activity, and obesity-related health among black daughter-mother pairs in Soweto, South Africa: a qualitative study. AB - BACKGROUND: The prevalence of overweight and obesity is on the rise in South Africa, particularly among females living in urban environments. The purpose of this qualitative study was to explore the emic perspectives of black young adult daughter and mother pairs living in Soweto, South Africa on diet, physical activity, and obesity-related health within their social and cultural context. METHODS: Purposeful sampling was used to recruit daughters with a normal body mass index (BMI) who have obese mothers. Individual semi-structured in-depth interviews were conducted with 17 daughters (age 24 years) and 15 of their mothers in Soweto, South Africa. Interview questions related to: a) eating and physical activity behaviors and perceptions, b) perceptions of social and community level factors, c) cultural beliefs about diet and body image, and d) intergenerational relationships. Data were analyzed using four-phases of thematic analysis and the constant comparison approach. RESULTS: Daughters and mothers had similar ideas of the definition of healthy food and the importance of eating healthy, but mothers were more likely to report eating healthy because of their age, adverse health experiences, and a desire to live longer. Daughters and mothers engaged in physical activity for reasons related to weight maintenance and feeling better, but mothers reported being more likely to start exercising as a result of a health concern. Daughters and mothers had comparable views of what makes a person healthy. Daughters and mothers relied on each other for food purchasing and food preparation. CONCLUSION: Daughters and mothers shared some similar perceptions of diet, physical activity, and health that were rooted in their daily life in Soweto. However, mothers generally reported being more likely to exhibit healthy eating and physical activity behaviors despite being obese. The mothers may have adopted these perceptions and behaviors later in life linked to ageing and ill-health. It is possible that through exposure, their daughters have assimilated these perceptions earlier in childhood or adolescence. It is important to focus health promotion efforts around preventing the otherwise expected increase of obesity among the young adult generation. PMID- 27506679 TI - Clinical efficacy and safety of multidrug therapy including thrice weekly intravenous amikacin administration for Mycobacterium abscessus pulmonary disease in outpatient settings: a case series. AB - BACKGROUND: Mycobacterium abscessus (M. abscessus) pulmonary disease is a refractory chronic infectious disease. Options for treating M. abscessus pulmonary disease are limited, especially in outpatient settings. Among parenteral antibiotics against M. abscessus, intravenous amikacin (AMK) is expected to be an effective outpatient antimicrobial therapy. This study evaluated the clinical efficacy and safety of intravenous AMK therapy in outpatients with M. abscessus pulmonary disease. METHODS: This retrospective chart review of cases of M. abscessus pulmonary disease evaluated patient background data, AMK dosage and duration, sputum conversion, clinical symptoms radiological findings, and adverse events. M. massiliense was excluded on the basis of multiplex PCR assay. RESULTS: Thirteen patients (2 men and 11 women) with M. abscessus pulmonary disease were enrolled at 2 hospitals. The median age at the initiation of intravenous AMK treatment was 65 years (range: 50-86 years). Patients received a median AMK dose of 12.5 mg/kg (range: 8.3-16.2 mg/kg) for a median duration of 4 months (range: 3-9 months). The addition of intravenous AMK led to sputum conversion in 10 of 13 patients, and 8 patients continued to have negative sputum status 1 year after treatment. Approximately half of the patients showed improvement on chest high-resolution computed tomography. There were no severe adverse events such as ototoxicity, vestibular toxicity, and renal toxicity. CONCLUSIONS: Thrice weekly intravenous AMK administration in outpatient settings is effective and safe for patients with M. abscessus pulmonary disease. PMID- 27506680 TI - High T2-weighted signal intensity is associated with elevated troponin T in hypertrophic cardiomyopathy. AB - OBJECTIVE: Areas of high signal intensity (HighT2) on T2-weighted cardiovascular magnetic resonance (CMR) imaging have been demonstrated in hypertrophic cardiomyopathy (HCM). It has been hypothesised that HighT2 may indicate active tissue injury in HCM. In this context, we studied HighT2 in relation to cardiac troponin. METHODS: Outpatient HCM patients without a history of coronary artery disease underwent CMR imaging at 1.5 T using T2-weighted, cine and late gadolinium enhancement (LGE) imaging to assess HighT2, left ventricular (LV) function, LV mass and the presence and extent of LGE. Highly sensitive cardiac troponin T (hs-cTnT) was assessed as a marker of injury, with hs-cTnT >=14 and >3 ng/L defined as an elevated and detectable troponin. RESULTS: HighT2 was present in 28% of patients (28/101). An elevated hs-cTnT was present in 54% of patients with HighT2 (15/28) compared with 14% of patients without HighT2 (10/73) (p<0.001). Hs-cTnT was detectable in 96% of patients with HighT2 (27/28) compared with 66% of patients without HighT2 (48/73) (p=0.002). In case of an undetectable hs-cTnT, HighT2 was only seen in 4% (1/26). In addition, the extent of HighT2 was related with increasing hs-cTnT concentrations (Spearman's rho: 0.42, p<0.001). CONCLUSIONS: In this CMR study of patients with HCM, we observed HighT2 in a quarter of patients, and demonstrated that HighT2 was associated with an elevated hs-cTnT. This observation, combined with the very high negative predictive value of an undetectable hs-cTnT for HighT2, provides supportive evidence for the hypothesis that HighT2 is indicative of recently sustained myocyte injury. PMID- 27506681 TI - Transmission of HCV NS5A Inhibitor-Resistant Variants Among HIV-Infected Men Who Have Sex With Men. PMID- 27506683 TI - Reply to Skowronski et al. PMID- 27506684 TI - Editorial Commentary: End-Stage Liver Disease in HIV Infection: An Avoidable Burden? PMID- 27506685 TI - Coexistence of MCR-1 and NDM-1 in Clinical Escherichia coli Isolates. PMID- 27506686 TI - Repeat Influenza Vaccination and High-Dose Efficacy. PMID- 27506687 TI - Treatment of Hospital or Ventilator-Associated Pneumonia Due to Carbapenem Resistant Enterobacteriaceae: Leveraging Molecular Resistance Testing and Combination Therapy to Improve Outcomes. PMID- 27506682 TI - Risk of End-Stage Liver Disease in HIV-Viral Hepatitis Coinfected Persons in North America From the Early to Modern Antiretroviral Therapy Eras. AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected patients coinfected with hepatitis B (HBV) and C (HCV) viruses are at increased risk of end-stage liver disease (ESLD). Whether modern antiretroviral therapy has reduced ESLD risk is unknown. METHODS: Twelve clinical cohorts in the United States and Canada participating in the North American AIDS Cohort Collaboration on Research and Design validated ESLD events from 1996 to 2010. ESLD incidence rates and rate ratios according to hepatitis status adjusted for age, sex, race, cohort, time updated CD4 cell count and HIV RNA were estimated in calendar periods corresponding to major changes in antiretroviral therapy: early (1996-2000), middle (2001-2005), and modern (2006-2010) eras. RESULTS: Among 34 119 HIV infected adults followed for 129 818 person-years, 380 incident ESLD outcomes occurred. ESLD incidence (per 1000 person-years) was highest in triply infected (11.57) followed by HBV- (8.72) and HCV- (6.10) coinfected vs 1.27 in HIV monoinfected patients. Adjusted incidence rate ratios (95% confidence intervals) comparing the modern to the early antiretroviral era were 0.95 (.61-1.47) for HCV, 0.95 (.40-2.26) for HBV, and 1.52 (.46-5.02) for triply infected patients. Use of antiretrovirals dually activity against HBV increased over time. However, in the modern era, 35% of HBV-coinfected patients were not receiving tenofovir. There was little use of HCV therapy. CONCLUSIONS: Despite increasing use of antiretrovirals, no clear reduction in ESLD risk was observed over 15 years. Treatment with direct-acting antivirals for HCV and wider use of tenofovir-based regimens for HBV should be prioritized for coinfected patients. PMID- 27506688 TI - The Burden of Hepatitis C Infection-Related Liver Fibrosis in the United States. AB - BACKGROUND: Knowledge of the estimated proportion of hepatitis C virus (HCV) infected persons with advanced fibrosis or cirrhosis is critical to estimating healthcare needs. METHODS: We analyzed HCV-related testing conducted by Quest Diagnostics from January 2010 through December 2013. Tests included hepatitis C antibody, HCV RNA, HCV genotype (nucleic acid tests [NAT]), liver function tests, and platelet counts; patient age was also determined. Aspartate aminotransferase (AST)-to-platelet ratio (APRI) was calculated as = 100*(aspartate aminotransferase [AST]/upper limit of AST)/platelet. Fibrosis-4 (FIB-4) was calculated as (age * AST)/(platelet *? alanine aminotransferase [ALT]). Persons were "currently infected" if they had >=1 positive HCV NAT; "in care" if a positive RNA test was followed <6 months by >=1 additional NAT(s), or ALT, AST, and platelets <90 days, or any test ordered by an infectious diseases or gastroenterology specialist; and "evaluated for treatment" if they had a genotype test. RESULTS: Approximately 10 million HCV test results were analyzed, representing 5.6 million unique patients. Of the 2.6 million patients with data to estimate liver disease, 5% were currently infected. Among those currently infected, APRI and FIB-4 scores indicated that 23% overall-and 27% among the cohort born during 1945-1965-had advanced fibrosis or cirrhosis at first diagnosis. A total of 54% of infected were in care and 51% of infected with advanced fibrosis or cirrhosis were evaluated for treatment. CONCLUSIONS: Testing from a large US commercial laboratory indicates that about 1 in 4 HCV-infected persons have levels of liver disease put them at highest risk for complications and could benefit from immediate antiviral therapy. PMID- 27506690 TI - Elections, scare campaigns and Medicare: Towards a balanced scorecard. PMID- 27506689 TI - Effect of a Dengue Clinical Case Management Course on Physician Practices in Puerto Rico. AB - BACKGROUND: Prior to 2010, the clinical management of dengue in Puerto Rico was inconsistent with World Health Organization guidelines. A 4-hour classroom-style course on dengue clinical management was developed in 2009 and mandated for Puerto Rico medical licensure in 2010. Fifty physicians were trained as "master trainers" and gave this course to 7638 physicians. This study evaluated the effect of the course on the clinical management of hospitalized dengue patients. METHODS: Pre- and post-course test responses were compared. Changes in physician practices were assessed by reviewing medical records of 430 adult and 1075 pediatric dengue patients at the 12 hospitals in Puerto Rico that reported the most cases during 2008-2009 (pre-intervention) and 2011 (post-intervention). Mixed-effects logistic regression was used to compare key indicators of dengue management. RESULTS: Physician test scores increased from 48% to 72% correct. Chart reviews showed that the percentage of adult patients who did not receive corticosteroids increased from 30% to 68% (odds ratio [OR], 5.9; 95% confidence interval [CI], 3.7-9.5) and from 91% to 96% in pediatric patients (OR, 2.7; 95% CI, 1.5-4.9). Usage of isotonic intravenous saline during the critical period increased from 57% to 90% in adult patients (OR, 6.2; 95% CI, 1.9-20.4) and from 25% to 44% in pediatric patients (OR, 3.4; 95% CI, 2.2-5.3). CONCLUSIONS: Management of dengue inpatients significantly improved following implementation of a classroom-style course taught by master trainers. An online version of the course was launched in 2014 to expand its reach and sustainability. PMID- 27506691 TI - Prognostic Features for Objectively Defined Urinary Continence after Radical Cystectomy and Ileal Orthotopic Neobladder in a Contemporary Cohort. AB - PURPOSE: We objectively quantified daytime and nocturnal continence rates, and defined predictive features for favorable continence outcomes after radical cystectomy and orthotopic ileal neobladder creation. MATERIALS AND METHODS: At 1 institution 1,012 cystectomies were performed between 2004 and 2015. Questionnaires evaluating the continence status were sent to 244 patients. To objectify postoperative urine loss daytime and nocturnal pad tests were performed. Continence was defined as the need for up to 1 safety pad and urine loss 10 gm or less per test. Predefined associative features were tested for an influence on continence outcomes. Statistical analysis was done with the Fisher exact and Mann-Whitney U tests, and linear logistic regression models. Significance was considered at p <0.05. RESULTS: A total of 188 patients (77.0%) returned the questionnaires. Median followup was 61 months. Median daytime pad use was 1 pad per day (range 0 to 9). Median daily urine loss based on standardized pad testing was 8 gm (range 0 to 2,400). During the night a median of 1 pad (range 0 to 7) was used and median nocturnal urine loss was 28.5 gm (range 0 to 1,220). The continence rate was 54.3% during the day and 36.3% at night. On multivariate analysis good preoperative ECOG (Eastern Cooperative Oncology Group) status (OR 2.987, p = 0.010), retained sensation of bladder filling (OR 6.462, p = 0.003) and preoperative coronary heart disease (OR 0.036, p = 0.002) were independent predictors of daytime success. Based on preoperative risk factors a simple predictive score for daytime continence was created (AUC 0.725, p <0.001). CONCLUSIONS: Continence rates after orthotopic ileal neobladder creation are lower than previously described when objective continence definitions are applied. Patients with good performance status, without coronary heart disease and with retained sensation of orthotopic ileal neobladder filling have better daytime continence outcomes. PMID- 27506692 TI - Epidemiology of Genitourinary Injuries among Male U.S. Service Members Deployed to Iraq and Afghanistan: Early Findings from the Trauma Outcomes and Urogenital Health (TOUGH) Project. AB - PURPOSE: In this study we report the number, nature and severity of genitourinary injuries among male U.S. service members deployed to Operations Iraqi Freedom and Enduring Freedom. MATERIALS AND METHODS: This retrospective cross-sectional study of the Department of Defense Trauma Registry used ICD-9-CM codes to identify service members with genitourinary injuries, and used Abbreviated Injury Scale codes to determine injury severity, genitourinary organs injured and comorbid injuries. RESULTS: From October 2001 to August 2013, 1,367 male U.S. service members sustained 1 or more genitourinary injuries. The majority of injuries involved the external genitalia (1,000, 73.2%), including the scrotum (760, 55.6%), testes (451, 33.0%), penis (423, 31%) and/or urethra (125, 9.1%). Overall more than a third of service members with genitourinary injury sustained at least 1 severe genitourinary injury (502, 36.7%). Loss of 1 or both testes was documented in 146 men, including 129 (9.4%) unilateral orchiectomies and 17 (1.2%) bilateral orchiectomies. Common comorbid injuries included traumatic brain injury (549, 40.2%), pelvic fracture (341, 25.0%), colorectal injury (297, 21.7%) and lower extremity amputations (387, 28.7%). CONCLUSIONS: An unprecedented number of U.S. service members sustained genitourinary injury while deployed to Operation Iraqi Freedom/Operation Enduring Freedom. Further study is needed to describe the long-term impact of genitourinary injury and determine the potential need for novel treatments to improve sexual, urinary and/or reproductive function among service members with severe genital injury. PMID- 27506693 TI - The Impact of Repeat Prostate Biopsies on Oncologic, Pathological and Perioperative Outcomes after Radical Prostatectomy. AB - PURPOSE: The impact of repeat biopsy sessions on radical prostatectomy remains controversial regarding perioperative, pathological and oncologic outcome. MATERIALS AND METHODS: We analyzed the records of 12,624 patients who underwent radical prostatectomy from 2007 to 2013. The association of the number of biopsy sessions (range 1 to 3 or more) with pathological outcomes and perioperative complications was analyzed using the Wilcoxon matched pair test. To test the association between biopsy sessions and biochemical recurrence-free survival we used Kaplan-Meier curves and multivariable Cox regression analysis. RESULTS: Of the patients 89.2% had 1 biopsy session, 7.4% had 2 sessions and 3.4% had 3 or more sessions. Median followup was 36.6 months. In patients with 1, 2 and 3 or more biopsy sessions prostate volume (38, 44 and 45 ml) and prostate specific antigen (6.7, 7.6 and 10.1 ng/ml, respectively) were greater (each p <0.001). The perioperative outcome was more favorable. Patients with 1, 2 and 3 or more biopsy sessions more often had organ confined tumors (67.6%, 72.1% and 72.9%, p = 0.003) and higher tumor volume (3.1, 3.0 and 3.6 ml, p <0.001) but a lower tumor percent (7.5%, 3.7% and 2.4%, respectively, p <0.001). More biopsy sessions were associated with fewer lymph node metastases (1, 2 and 3 sessions 0.23, 0.13 and 0.17, respectively, p <0.001). Gleason score and surgical margin status did not differ. The overall biochemical recurrence rate was 18.9% and it was comparable among the biopsy groups. No association was found between the number of biopsies and biochemical recurrence. CONCLUSIONS: Patients with multiple biopsy sessions experience a slightly more favorable pathological outcome without an impact on the oncologic outcome. The perioperative outcome was more favorable in patients with multiple biopsies. PMID- 27506694 TI - Emotional Distress Increases the Likelihood of Undergoing Surgery among Men with Localized Prostate Cancer. AB - PURPOSE: We determined whether among men with clinically localized prostate cancer, particularly men with low risk disease, greater emotional distress increases the likelihood of undergoing surgery vs radiation or active surveillance. MATERIALS AND METHODS: Participants were 1,531 patients recruited from 2 academic and 3 community facilities (nonHispanic white 83%, nonHispanic black 11% and Hispanic 6%; low risk 36%, intermediate risk 49% and high risk 15%; choice of active surveillance 24%, radiation 27% and surgery 48%). Emotional distress was assessed shortly after diagnosis and after men made a treatment decision with the Distress Thermometer. We used multinomial logistic regression with robust standard errors to test if emotional distress at either point predicted treatment choice in the sample as a whole and after stratifying by D'Amico risk score. RESULTS: In the sample as a whole the participants who were more emotionally distressed at diagnosis were more likely to choose surgery over active surveillance (RRR 1.07; 95% CI 1.01, 1.14; p=0.02). Men who were more distressed close to the time they made a treatment choice were more likely to have chosen surgery over active surveillance (RRR 1.16; 95% CI 1.09, 1.24; p <0.001) or surgery over radiation (RRR 1.12; 95% CI 1.05, 1.19; p=0.001). This pattern was also found in men with low risk disease. CONCLUSIONS: Emotional distress may motivate men with low risk prostate cancer to choose more aggressive treatment. Addressing emotional distress before and during treatment decision making may reduce a barrier to the uptake of active surveillance. PMID- 27506695 TI - Linkage of Lower Urinary Tract Symptoms to Sleep Quality in Elderly Men with Nocturia: A Community Based Study Using Home Measured Electroencephalogram Data. AB - PURPOSE: We objectively investigated the relationship between sleep quality/efficiency and factors associated with micturition using at-home electroencephalogram assessment. MATERIALS AND METHODS: Participants were recruited from among those enrolled in the Fujiwara-kyo Study, a community based longitudinal evaluation that began in Nara Prefecture, Japan, in 2007. Included participants were men at least 65 years old who woke up in the middle of the night/early morning at least 3 times per week with the urge to void. We evaluated lower urinary tract symptoms using the I-PSS and subjective sleep quality using the Pittsburgh Sleep Quality Index. Uroflowmetry and 3-day frequency volume charting measurements were also obtained. Electroencephalogram recordings were obtained during sleep to evaluate objective sleep quality. RESULTS: Final analysis included data from 47 participants. I-PSS-quality of life score and slow wave sleep time were independent predictors of good subjective sleep quality as determined by Pittsburgh Sleep Quality Index scores. Nocturnal urinary volume was an independent predictor of greater sleep efficiency. Maximum flow rate was an independent predictor of longer slow wave sleep time. CONCLUSIONS: In elderly men with nocturia, sleep quality is associated with lower urinary tract function. Higher subjective sleep quality is associated with longer slow wave sleep time and less severe lower urinary tract symptoms. Higher objective sleep quality is further associated with a higher urinary flow rate and lower nocturnal urinary volume. PMID- 27506696 TI - Suppressed Recurrent Bladder Cancer after Androgen Suppression with Androgen Deprivation Therapy or 5alpha-Reductase Inhibitor. AB - PURPOSE: We determined whether intravesical recurrence is affected by inhibition of androgen signaling among men with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: We examined the intravesical recurrence rate among men treated with or without androgen suppression therapy by androgen deprivation therapy for prostate cancer or 5alpha-reductase inhibitor dutasteride for benign prostatic hyperplasia. RESULTS: We studied 228 men, including 32 with and 196 without androgen suppression therapy. During a median followup of 3.6 and 3.0 years intravesical recurrence developed in 4 (12.5%) and 59 men (30.1%) with and without androgen suppression therapy, respectively. On multivariate analysis multiple tumors (HR 1.82, p = 0.027), a large tumor (HR 2.13, p = 0.043) and ever smoking (HR 2.45, p = 0.020) as well as the presence of androgen suppression therapy (HR 0.36, p = 0.024) were independent risk factors for intravesical recurrence. Notably, tumor progressed to muscle invasive bladder cancer in 6 men (3.1%) without androgen suppression therapy. No man with androgen suppression therapy progressed to muscle invasive bladder cancer. CONCLUSIONS: Our study suggests the possibility of androgen suppression therapy as prophylaxis for intravesical recurrence of bladder cancer. Further explorations are warranted of the prophylactic effect of androgen suppression therapy on bladder cancer pathogenesis. PMID- 27506697 TI - Circadian Rhythms in Water and Solute Handling in Adults with a Spinal Cord Injury. AB - PURPOSE: We evaluated nocturnal urine production and circadian rhythms of renal function (glomerular filtration, and water and solute diuresis) in adults with spinal cord injury compared to controls. MATERIALS AND METHODS: This prospective observational study was done at Ghent University Hospital, Belgium. Participants were asked to perform a 24-hour urine collection. A blood sample was taken to calculate the diuresis rate and the renal clearance of creatinine, free water, solutes, sodium and urea. RESULTS: A total of 119 patients were divided into 32 with spinal cord injury, and 68 controls with and 19 without nocturnal polyuria. Spinal cord injured patients showed no circadian rhythms in the diuresis rate or in the renal clearance of creatinine, free water, solutes, sodium or urea. Controls without nocturnal polyuria reported a lower nighttime diuresis rate and lower nighttime clearance of creatinine, solutes, sodium and urea compared to daytime levels. Controls with nocturnal polyuria had no circadian rhythms in the diuresis rate or creatinine clearance and a significant increase in nocturnal free water clearance compared to daytime levels. CONCLUSIONS: Comparing the mechanisms underlying nocturnal urine production between patients with spinal cord injury and controls revealed important differences. Spinal cord injured patients showed absent circadian rhythms in the renal clearance of creatinine (glomerular filtration), free water (water diuresis) and solutes such as sodium and urea (solute diuresis). Future research must be done to evaluate the role of patient stratification to find the most effective and safe treatment or combination of treatments for spinal cord injured patients with complaints or complications related to nocturnal polyuria. PMID- 27506698 TI - Priority of Treatment Outcomes for Caregivers and Patients with Mild Cognitive Impairment: Preliminary Analyses. AB - INTRODUCTION: The patient-centered movement advocates for greater attention to the outcomes that matter most to patients and their families. In neurodegenerative disease, determination of patient and caregiver priorities has received scant attention in part because dementia patients are deemed unreliable reporters. However, people with mild cognitive impairment (MCI) likely retain capacity to report their preferences. METHODS: In two separate MCI cohorts, we conducted preliminary analyses of patient and caregiver priorities among seven patient and five caregiver outcomes of the HABIT(r) Healthy Action to Benefit Independence & Thinking program (Mayo Clinic, Rochester, MN, USA). RESULTS: Via interview and paper-and-pencil reporting both patient and caregiver respondents' ranked patient and caregiver quality of life and patient self-efficacy as highest priorities, ranking them ahead of patient and caregiver mood, patient functional status, patient distressing behaviors and caregiver burden. Patients and caregivers tended to value the outcomes for their loved ones higher than their own outcomes. CONCLUSION: Caregivers appeared to be reasonable, but not perfect, proxies for patient reports. Additional research with larger cohorts and a more comprehensive range of outcomes is needed. PMID- 27506699 TI - What is this image? 2016: Image 3. PMID- 27506701 TI - Cardiac sarcoidosis: An important niche for PET, but a journey just begun. PMID- 27506700 TI - The radiation dose to overweighted patients undergoing myocardial perfusion SPECT can be significantly reduced: validation of a linear weight-adjusted activity administration protocol. AB - BACKGROUND: Large body size can cause a higher proportion of emitted photons being attenuated within the patient. Therefore, clinical myocardial perfusion SPECT (MPS) protocols often include unproportionally higher radioisotope activity to obese patients. The aim was to evaluate if a linear weight-adjusted low-dose protocol can be applied to obese patients and thereby decrease radiation exposure. METHODS AND RESULT: Two hundred patients (>110 kg, BMI 18-41, [n = 69], <= 110 kg, BMI 31-58, [n = 131]) underwent 99mTc-tetrofosmin stress examination on a Cadmium Zinc Telluride or a conventional gamma camera using new generations of reconstruction algorithm (Resolution Recovery). Patients <110 kg were administered 2.5 MBq/kg, patients between 110 and 120 kg received 430 MBq and patients >120 kg received 570 MBq according to clinical routine. Patients >110 kg had 130% total number of counts in the images compared to patients <110 kg. Recalculating the counts to correspond to an administered activity of 2.5 MBq/kg resulted in similar number of counts across the groups. Image analyses in a subgroup with images corresponding to high activity and 2.5 MBq/kg showed no difference in image quality or ischemia quantification. CONCLUSION: Linear low dose weight-adjusted protocol of 2.5 MBq/kg in MPS can be applied over a large weight span without loss of counts or image quality, resulting in a significant reduction in radiation exposure to obese patients. PMID- 27506702 TI - Prognostic value of one millisievert exercise myocardial perfusion imaging in patients without known coronary artery disease. AB - : The aim of this study was to assess the prognostic value of normal ultra-low dose exercise MPI with a CZT camera. METHODS: 1901 consecutive patients without known CAD referred for exercise MPI with 1.8 MBq/kg (0.05 mCi) of Tc99m sestamibi or tetrofosmin and a CZT camera were included prospectively. Patients with an abnormal scan requiring an additional resting image (230) or a submaximal exercise test (271) were excluded. The 1400 remaining patients were followed for 39 months. The primary end-point was cardiac events (cardiac death, nonfatal myocardial infarction, and revascularization). The secondary end-point was noncardiac death. RESULTS: The mean injected activity was 145 +/- 37 MBq (3.9 +/- 1 mCi), the mean acquisition duration was 10 +/- 0.7 minutes, and the mean effective dose was 0.91 +/- 0.13 mSv. 1288 patients (92%) achieved full follow up. We observed 22 cardiac events and 16 noncardiac deaths. The annualized rates were equivalent to 0.55% for cardiac events and 0.37% for noncardiac mortality. CONCLUSIONS: Normal ultra-low-dose exercise MPI with a CZT camera has a high negative predictive value. The effective dose was less than 1 mSv, and the study thus allays concerns about radiation burden. PMID- 27506703 TI - [18F]-Sodium fluoride uptake in Takayasu arteritis. AB - BACKGROUND: While 18F-fluorodeoxyglucose and 18F-sodium fluoride with positron emission tomography relate with inflammation and calcification, their role in the assessment of patients with Takayasu arteritis has not yet been studied. METHODS: We present 5 patients with suspected active metabolic disease who underwent PET with 18F-fluorodeoxyglucose and 18F-sodium fluoride in order to explore the locations and correlations of 18F-fluorodeoxyglucose and 18F-sodium fluoride uptakes. Diagnosis of metabolic active disease was based on 18F fluorodeoxyglucose uptake. RESULTS: We studied 3 female patients and 2 male patients. Median age was 29 years (min: 19 max: 63). In areas with atherosclerotic plaques, we found a negative correlation between 18F-sodium fluoride and 18F-fluorodeoxyglucose uptakes (r = -0.78) (P = .001). Meanwhile, in areas with only metabolic active disease, we found a positive correlation between 18F-sodium fluoride and 18F-fluorodeoxyglucose uptakes (r = 0.94) (P = .019). CONCLUSIONS: In Takayasu arteritis, 18F-sodium fluoride uptake can document different stages of metabolic disease, even in the absence of active metabolic disease or symptoms. PMID- 27506704 TI - The Utility of Cannabidiol in the Treatment of Refractory Epilepsy. AB - Cannabis-derived cannabinoids such as cannabidiol (CBD) have anticonvulsant properties. Recently, there has been an emerging interest in the use of CBD enriched products for treatment of drug-resistant epilepsy. Some pilot trials of CBD have proved beneficial for refractory epilepsy, but its efficacy is yet to be confirmed by standard placebo-controlled trials. However, the mechanisms underlying the seizure protection efficacy claims of CBD remain unclear. This review briefly describes the clinical utility of CBD in the treatment of refractory epilepsy. PMID- 27506705 TI - 3,3',5,5'-Tetramethylbenzidine Oxidation on Paper Devices for Horseradish Peroxidase-based Assays. AB - We report on the colorimetric oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by hydrogen peroxide using horseradish peroxidase on photolithography-fabricated (P-PAD) and wax-printed (W-PAD) paper-based analytical devices. Fabricating PADs via photolithography exposes the hydrophilic areas to polymers (photoresists) and solvents, not only reducing the hydrophilicity, but also affecting the TMB-H2O2 assay system with an unavoidable incomplete elimination of photoresist during fabrication. Detection signals are then observed in the presence of photoresist residues on the P-PAD, even at a blank HRP concentration. PMID- 27506706 TI - A Simple and Sensitive Method for Auramine O Detection Based on the Binding Interaction with Bovin Serum Albumin. AB - A simple, rapid and effective method for auramine O (AO) detection was proposed by fluorescence and UV-Vis absorption spectroscopy. In the BR buffer system (pH 7.0), AO had a strong quenching ability to the fluorescence of bovin serum albumin (BSA) by dynamic quenching. In terms of the thermodynamic parameters calculated as DeltaH > 0 and DeltaS > 0, the resulting binding of BSA and AO was mainly attributed to the hydrophobic interaction forces. The linearity of this method was in the concentration range from 0.16 to 50 MUmol L(-1) with a detection limit of 0.05 MUmol L(-1). Based on fluorescence resonance energy transfer (FRET), the distance r (1.36 nm) between donor (BSA) and acceptor (AO) was obtained. Furthermore, the effects of foreign substances and ionic strength were evaluated under the optimum reaction conditions. BSA as a selective probe could be applied to the analysis of AO in medicines with satisfactory results. PMID- 27506707 TI - New Electrochemical Evaluation of the Antioxidant Capacity of Beverages with Polyoxometalates as Redox Probes. AB - A new method was developed to evaluate antioxidant activity based on the redox properties of polyoxometalates, which are partially reduced by antioxidants to generate a limiting potential. The polyoxometalates [PMo12O40](3-), [PVW11O40](4 ) and [SV2W10O40]4- formed in situ were used as electrochemical probes for the new evaluation method, and their formation conditions were optimized to evaluate the antioxidant activities of gallic acid, ellagic acid, catechin, quercetin, morin, trans-ferulic acid, sesamol, alpha-tocopherol, delta-tocopherol and L ascorbic acid. The observed difference between initial potential and limiting potential (DeltaE) were compared with spectrophotometrically evaluated antioxidant activities. In addition, the antioxidant capacities of five beverages (Japanese green tea, concentrated catechin-containing green tea, grapefruit juice, red wine and Japanese sake) were evaluated. PMID- 27506708 TI - Differentiation of the Isomers of N-Alkylated Cathinones by GC-EI-MS-MS and LC PDA. AB - Synthetic compounds structurally derived from the mild stimulant 2-amino-1-phenyl 1-propanone, known as cathinone derivatives, are one of the largest growing class of synthetic designer drugs. The characterization of these drugs is complicated by the structural diversity and similarity of compounds in the ever-growing cathinone family. This paper demonstrates the successful application of gas chromatography-electron ionization-tandem mass spectrometry (GC-EI-MS-MS) and liquid chromatography-photodiode array (LC-PDA) analysis to differentiate structurally similar derivatives including regioisomers of cathinones. Product ion spectrometry of iminium ions allows for an univocal differentiation of the studied cathinones with the same aminoalkyl moiety. Furthermore, the product ion spectrometry of acylium ions and ultraviolet spectra obtained by LC-PDA enabled differentiation of regioisomers resulting from different substitution patterns on the aromatic ring. The validity of the method was demonstrated by the analysis of N-alkylated ortho-, meta-, and para-alkylcathinones along with the scaffolds of buphedrones and pentiophenones. PMID- 27506709 TI - Determination of Iodide, Iodate and Total Iodine in Natural Water Samples by HPLC with Amperometric and Spectrophotometric Detection, and Off-line UV Irradiation. AB - We developed a rapid, simple method for the iodine speciation analysis of water and applied it to natural water samples. Simultaneous determinations of I(-) and IO3(-) were achieved with an HPLC system with amperometric detection for I(-) and spectrophotometric detection after a postcolumn reaction for IO3(-). We determined the I(-) and IO3(-) concentrations in 20-MUL water samples within 10 min. Total I concentrations in water samples were determined after the decomposition of organics by off-line UV irradiation for 30 min, followed by reduction to I(-). The analytical conditions were optimized by using test solutions rich in organic matter extracted from soils. We tested the new method with samples of groundwater, spring water, precipitation, soil percolate, stream water, and seawater as well as solutions extracted from soil. The method worked well, although the concentrations of some I species were below detection. This method is suitable for routine speciation analysis, which is important for studies of I behavior in the environment. PMID- 27506710 TI - Development of Sensitive Analytical Approach for the Quantification of alpha Lipoic Acid Using Boron Doped Diamond Electrode. AB - A boron doped diamond (BDD) electrode was investigated for use as an electrochemical sensor for alpha-lipoic acid (LA) using amperometric and differential pulse voltammetric detection. LA displays a well expressed oxidation peak at +0.9 V vs. Ag/AgCl in solutions with a pH value of 3. It was found that signals obtained are linearly related to the concentration range from 0.3 to 105 MUM with detection limit of 0.088 MUM. Interferences by common compounds such as ascorbic acid, uric acid and dopamine were tested and the method was successfully applied to the determination of LA in human body fluids where it gave recoveries in the range from 95 to 97%. PMID- 27506711 TI - Electrochemical Sensing of Casein Based on the Interaction between Its Phosphate Groups and a Ruthenium(III) Complex. AB - A reaction to casein, along with beta-lactoglobulin, is a main cause of milk allergies, and also is a useful indicator of protein in allergic analyses. In the present study, a simple casein sensor was developed based on the interaction between a phosphate group of casein and electroactive [Ru(NH3)6](3+). We evaluated the voltammetric behavior of a casein-[Ru(NH3)6](3+) complex using a glassy carbon electrode. When the ruthenium(III) complex was combined with the phosphate groups of casein, the structure of the casein was changed. Since the hydrophobicity of casein was increased due to the binding, the casein was adsorbed onto the electrode. Furthermore, we modified an electrode with a ruthenium(III) ions/collagen film. When the sensor was applied to the detection of the casein contained in milk, the values coincided with those indicated by the manufacturer. Accordingly, this electrode could be a powerful sensor for the determination of casein in several foods. PMID- 27506712 TI - Raman Spectral Analysis of Low-content Benzene Concentration in Gasoline with Partial Least Squares Based on Interference Peak Subtraction. AB - Raman spectroscopy is adopted to detect the low-content benzene concentrations in gasoline products. Due to the peak overlap of benzene and other species in the gasoline spectrum, the associated statistical regression methods cannot make stable predictions unless there are enough training samples. To extend their extrapolation to small-size training sets, we propose the method of partial least squares based on a spectral pretreatment of interference peak subtraction (IPS PLS). During the analysis, after spectral interpolation and baseline removal, we extract the benzene peak by interference peak subtraction (IPS), and then partial least squares (PLS) is applied to make a prediction. The experimental results demonstrate that, IPS can extract benzene information effectively, and help to decrease principal components needed by PLS, thus IPS-PLS is superior to direct PLS with small-size training sets, and depends less on the training sample distribution. Meanwhile, IPS-PLS can reach the standard of ASTM 3606-10 with the least of 9 training samples, while keeping its max predictive error less than 0.1254% (v/v), which shows promising prospects in gasoline quality test. PMID- 27506713 TI - Use of Ni/NixB Nanoparticles as a Novel Adsorbent for the Preconcentration of Mercury Species prior to Cold Vapor-Atomic Fluorescence Spectrometric Determination. AB - A selective matrix separation/enrichment method, utilizing a simple batch procedure with nickel/nickel boride (Ni/NixB) nanoparticles was proposed for the determination of inorganic mercury(II), Hg(2+) and methyl mercury(I), CH3Hg(+) in waters prior to cold vapor-atomic fluorescence spectrometry (CV-AFS). The Ni/NixB nanoparticles, were synthesized by the chemical reduction of Ni(II) to Ni/NixB. The novel adsorbent was selective to Hg(2+) and CH3Hg(+) species between pH values of 4 - 10. Both of the mercury species were recovered from the adsorbent using 1.0 mol L(-1) hot HNO3 with high efficiency. It was observed that the adsorbent selectively removed Hg(2+) and CH3Hg(+) from the bulk solution in the presence of several competitor ions (As(3+), Sb(3+), Pb(2+), Zn(2+), Cu(2+), Cd(2+) and Fe(3+)) with >=96% adsorption. The limit of detection (3sigma above blank) was found to be 1.8 ng L(-1) with a preconcentration factor of 20. The validation of the method was tested through spike recovery experiments with several water samples (tap and seawater) at MUg L(-1) concentration levels, and all recovery values were found to vary between 95 and 105%. PMID- 27506714 TI - Stepwise Preparation of Spherical Gold Nanoparticles Passivated with Cationic Amphiphiles. AB - Spherical gold nanoparticles with cationic surfaces were prepared in hexadecyltrimethylammonium (CTA(+)) chloride (CTAC) and CTA(+) bromide (CTAB) solutions. In a CTAC solution, ascorbic acid reduction of gold ions (AuCl4(-)) induced spontaneous nucleation of gold clusters, which resulted in the formation of small gold nanoparticles (<5 nm). In a CTAB solution, the combination of ascorbic acid and AuBr4(-) induced low spontaneous nucleation, and therefore controllable crystal growth of seed particles was possible. To obtain uniform gold nanoparticles, seed particles (<5 nm) were first prepared in a CTAC solution using NaBH4 as a reducing agent. Subsequent growth reactions of the seeds in CTAB solutions were controllable to obtain gold nanoparticles with diameters ranging from 7 to 60 nm. PMID- 27506715 TI - Electrochemical Determination of Bisphenol A with Pencil Graphite Electrodes Modified with Co(II), Ni(II), Cu(II) and Fe(II) Phthalocyaninetetrasulfonates. AB - Pencil graphite electrodes modified with Co(II), Ni(II), Cu(II) and Fe(II) metallophthalocyaninetetrasulfonates (MePcTSs) were investigated for an electrochemical determination of bisphenol A (BPA). The electrochemical performances of the modified electrodes for different pH values in phosphate and the Britton-Robinson buffers were determined by cyclic voltammetry; the electrode performances were better in the Britton-Robinson buffer. NiPcTS and CoPcTS modifications of the electrodes had remarkable enhancements on their performances. The differential pulse voltammetry parameters for the electrodes were optimized, and we found that the electrochemical response versus the concentration of BPA is linear from 5.0 * 10(-7) to 1.0 * 10(-5) M for the NiPcTS and CoPcTS modified electrodes. The detection limits of these modified electrodes are 2.9 * 10(-7) and 4.3 * 10(-7) M, respectively, and the effects of interfering species are less than 5%. The results show that NiPcTS and CoPcTS modified pencil graphite electrodes could be used for electrochemical determinations of BPA for analytical purposes. PMID- 27506716 TI - A Label-free, Highly Sensitive and Selective Detection of Hemin Based on the Competition between Hemin and Protoporphyrin IX Binding to G-Quadruplexes. AB - Herein is reported a simple and label-free fluorescent detection method for hemin based on using protoporphyrin IX (PPIX) as a fluorescent signal reporter. PPIX emits weak fluorescence in an aqueous solution. When PPIX binds to G quadruplexes, the fluorescence intensity of PPIX is greatly increased. While in the presence of target hemin, hemin competes with PPIX toward G-quadruplexes because its affinity to G-quadruplexes is higher than that of PPIX. With the formation of the hemin-G-quadruplex complex, PPIX is released to the solution from the G-quadruplex accompanied by quenching of the fluorescence of the system. This fluorescence change of the system can be used to monitor hemin with a low detection limit of 36 nM. In addition, the possible binding sites for PPIX binding to the G-quadruplex are discussed based on competition between hemin and PPIX. What is more, this method might pave the way for applying G-quadruplexes and PPIX to more sensing systems. PMID- 27506717 TI - Amino Acid Metabolomics Using LC-MS/MS: Assessment of Cancer-Cell Resistance in a Simulated Tumor Microenvironment. AB - We performed a comprehensive quantification of 20 amino acids in RPMI 1640 medium cultured human colorectal adenocarcinoma cells to evaluate the efficacy of 5 fluorouracil treatment under hypoxic and hypoglycemic conditions, which mimic the tumor microenvironment. In this study, we developed a simple and comprehensive analytical method by using LC-MS/MS connected to the Intrada amino acid column, which eluted amino acids within 9 min. The present method covered a linearity range of 3.6 - 1818 MUM, except for Gly (227 - 1818 MUM), Ala, Asp, His (7.1 - 1818 MUM each), and Trp (3.6 - 909 MUM). The limits of detection were in the range of 0.02 - 38.0 pmol per injection in a standard solution. Amino acid concentration data were analyzed using principal-component analysis to represent samples on two-dimensional graphs. Linear discriminant analysis was used to classify samples on the score plots. Using this approach, the effect of 5 fluorouracil treatment could be successfully discriminated at high discrimination rates. Moreover, several amino acids were extracted from corresponding loading plots as candidate markers for distinguishing the effects of the 5-fluorouracil treatment or tumor microenvironmental conditions. These results suggest that our proposed method might be a useful tool for evaluating the efficacy of anticancer drugs in the tumor microenvironment. PMID- 27506718 TI - Colorimetric Coupled Enzyme Assay for Cystathionine beta-Synthase. AB - A colorimetric coupled enzyme assay for the determination of cystathionine beta synthase activity is described. The method exploits cystathionine gamma-lyase as an ancillary enzyme capable of transforming cystathionine, produced by cystathionine beta-synthase, into cysteine. The cysteine is then spectrophotometrically detected at 560 nm, after its specific complexation with ninhydrin. This method was used to detect cystathionine beta-synthase in crude extracts, and for the kinetic characterization of the enzyme partially purified from bovine kidney. A rapid two-step protocol is described for the partial purification of cystathionine gamma-lyase from bovine kidney, aimed at a suitable and stable ancillary enzyme preparation. PMID- 27506719 TI - Investigation of 5-(3-Trifluoromethylbenzylidene)thiazolidine-2,4-dione as a Matrix for Analyses of Biogenic Monoamine Transmitters Using MALDI-MS. AB - In order to discover new matrices suitable for the analyses of low molecular weight compounds using positive-ion mode matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry (MS), 5-(3 trifluoromethylbenzylidene)thiazolidine-2,4-dione (3-CF3-BTD) was synthesized, and its effectiveness was compared with that when commercially available alpha cyano-4-hydroxycinnamic acid was used. 3-CF3-BTD was sufficiently sensitive to analyze neurotransmitters, i.e., dopamine, serotonin, histamine, and epinephrine, in amounts of several picomoles. Similar to vacuum MALDI experiments, atmospheric pressure MALDI-MS measurements using 3-CF3-BTD as a matrix also detected dopamine. PMID- 27506720 TI - Fast Determination of Toxic Arsenic Species in Food Samples Using Narrow-bore High-Performance Liquid-Chromatography Inductively Coupled Plasma Mass Spectrometry. AB - A new method for the speciation analysis of arsenic in food using narrow-bore high-performance liquid-chromatography inductively coupled plasma mass spectrometry (HPLC-ICP-MS) has been developed. Fast separation of arsenite, arsenate, monomethylarsonic acid and dimethylarsinic acid was carried out in 7 min using an anion-exchange narrow-bore Nucleosil 100 SB column and 12 mM ammonium dihydrogen phosphate of pH 5.2 as the mobile phase, at a flow rate of 0.3 mL min(-1). A PFA-ST micronebulizer jointed to a cyclonic spray chamber was used for HPLC-ICP-MS coupling. Compared with standard-bore HPLC-ICP-MS, the new method has provided higher sensitivity, reduced mobile-phase consumption, a lower matrix plasma load and a shorter analysis time. The achieved instrumental limits of detection were in the 0.3 - 0.4 ng As mL(-1) range, and the precision was better than 3%. The arsenic compounds were efficiently (>80%) extracted from various food samples using a 1:5 methanol/water solution, with additional ultrasonic treatment for rice products. The applicability of this method was demonstrated by the analysis of several samples, such as seafood (fish, mussels, shrimps, edible algae) and rice-based products (Jasmine and Arborio rice, spaghetti, flour, crackers), including three certified reference materials. PMID- 27506722 TI - Retrospective Descriptive Study of an Intensive Care Unit at a Ugandan Regional Referral Hospital. AB - BACKGROUND: We describe delivery and outcomes of critical care at Mbarara Regional Referral Hospital, a Ugandan secondary referral hospital serving a large, widely dispersed rural population. METHODS: Retrospective observational study of ICU admissions was performed from January 2008 to December 2011. RESULTS: Of 431 admissions, 239 (55.4 %) were female, and 142 (33.2 %) were children (<18 years). The median length of stay was 2 (IQR 1-4) days, with 365 patients (85 %) staying less than 8 days. Indications for admission were surgical 49.3 % (n = 213), medical/pediatric 27.4 % (n = 118), or obstetrical/gynecological 22.3 % (n = 96). The overall mortality rate was 37.6 % (162/431) [adults 39.3 % (n = 113/287), children 33.5 % (n = 48/143), unspecified age 100 % (n = 1/1)]. Of the 162 deaths, 76 (46.9 %) occurred on the first, 20 (12.3 %) on the second, 23 (14.2 %) on the third, and 43 (26.5 %) on a subsequent day of admission. Mortality rates for common diagnoses were surgical abdomen 31.9 % (n = 29/91), trauma 45.5 % (n = 30/66), head trauma 59.6 % (n = 28/47), and poisoning 28.6 % (n = 10/35). The rate of mechanical ventilation was 49.7 % (n = 214/431). The mortality rate of ventilated patients was 73.5 % (n = 119/224). The multivariate odd ratio estimates of mortality were significant for ventilation [aOR 6.15 (95 % CI 3.83-9.87), p < 0.0001] and for length of stay beyond seven days [aOR 0.37 (95 % CI 0.19-0.70), p = 0.0021], but not significant for decade of age [aOR 1.06 (95 % CI 0.94-1.20), p = 0.33], gender [aOR 0.61(95 % CI 0.38 0.99), p = 0.07], or diagnosis type [medical vs. surgical aOR 1.08 (95 % CI 0. 63 1.84), medical vs. obstetric/gynecology aOR 0.73 (95 % CI 0.37-1.43), p = 0.49]. CONCLUSIONS: The ICU predominantly functions as an acute care unit for critically ill young patients, with most deaths occurring within the first 48 h of admission. Expansion of critical care capacity in low-income countries should be accompanied by measurement of the nature and impact of this intervention. PMID- 27506723 TI - A New Prediction Model for Patient Satisfaction After Total Knee Arthroplasty. AB - BACKGROUND: Total knee arthroplasty (TKA) is a proven and cost-effective treatment for osteoarthritis. Despite the good to excellent long-term results, some patients remain dissatisfied. Our study aimed at establishing a predictive model to aid patient selection and decision-making in TKA. METHODS: Using data from our prospective arthroplasty outcome database, 113 patients were included. Preoperatively and postoperatively, the patients completed 107 questions in 5 questionnaires: Knee Injury and Osteoarthritis Outcome Score, Oxford Knee Score, Pain Catastrophizing Scale, Euroqol questionnaire, and Knee Scoring System. First, outcome parameters were compared between the satisfied and dissatisfied group. Second, we developed a new prediction tool using regression analysis. Each outcome score was analyzed with simple regression. Subsequently, the predictive weight of individual questions was evaluated applying multiple linear regression. Finally, 10 questions were retained to construct a new prediction tool. RESULTS: Overall satisfaction rate in this study was found to be 88%. We identified a significant difference between the satisfied and dissatisfied group when looking at the preoperative questionnaires. Dissatisfied patients had more preoperative symptoms (such as stiffness), less pain, and a lower quality of life. They were more likely to ruminate and had a lower preoperative Knee Scoring System satisfaction score. The developed prediction tool consists of 10 simple but robust questions. Sensitivity was 97% with a positive-predictive value of 93%. CONCLUSIONS: Based upon preoperative parameters, we were able to partially predict satisfaction and dissatisfaction after TKA. After further validation, this new prediction tool for patient satisfaction following TKA may allow surgeons and patients to evaluate the risks and benefits of surgery on an individual basis and help in patient selection. PMID- 27506724 TI - Socioeconomic Risk Adjustment Models for Reimbursement Are Necessary in Primary Total Joint Arthroplasty. AB - BACKGROUND: Alternative payment models, such as bundled payments, aim to control rising costs for total knee arthroplasty (TKA) and total hip arthroplasty (THA). Without risk adjustment for patients who may utilize more resources, concerns exist about patient selection and access to care. The purpose of this study was to determine whether lower socioeconomic status (SES) was associated with increased resource utilization following TKA and THA. METHODS: Using the Michigan Arthroplasty Registry Collaborative Quality Initiative database, we reviewed a consecutive series of 4168 primary TKA and THA patients over a 3-year period. We defined lowest SES based upon the median household income of the patient's ZIP code. Demographics, medical comorbidities, length of stay, discharge destination, and readmission rates were compared between patients of lowest SES and higher SES. RESULTS: Patients in the lowest SES group had a longer hospital length of stay (2.79 vs 2.22 days, P < .001), were more likely to be discharged to a rehabilitation facility (27% vs 18%, P < .001), and be readmitted to the hospital within 90 days (11% vs 8%, P = .002) than the higher SES group. Multivariate analysis revealed that lowest SES was an independent risk factor for all 3 outcome variables (all P < .001). CONCLUSION: Patients in the lowest SES group utilize more resources in the 90-day postoperative period. Therefore, risk adjustment models, including SES, may be necessary to fairly compensate hospitals and surgeons and to avoid potential problems with access to joint arthroplasty care. PMID- 27506725 TI - Total Knee Arthroplasty After Failed Unicompartmental Knee Arthroplasty. Clinical Results, Radiologic Findings, and Technical Tips. AB - BACKGROUND: The loss of anatomic references and bone stock turns unicompartmental knee arthroplasty (UKA) revision surgery difficult, and according to some authors, it is technically as challenging as a total knee arthroplasty (TKA) revision surgery. METHODS: A retrospective review of 559 Oxford medial UKA was performed between 2007 and 2013. Nineteen knees were revised to TKA for reasons other than infection, most commonly for osteoarthritis progression. RESULTS: The most frequent cause of failure in our series was osteoarthritis progression (10 cases, 52.63%). In 15 patients (78.95%), tibial stems were needed, and in 10 (55.5%), metallic blocks for augmentation of tibial plateau were used. Postoperative radiographic studies showed a correct implant alignment, preserving adequate joint line (24.8 mm), and patellar (1.1 mm) height (according to Insall Salvati). After a mean follow-up of 21 months (range 6-51) mean values of 78.8 (standard deviation [SD] = 16.8) and 62.3 (SD = 19.6) were obtained for the physical and mental scores of the Knee Society Score test. In the SF-36 tests mean values of 45.2 (SD = 7.6) and 53 (SD = 5.2) were obtained for the physical and mental scores respectively. In one case, a varus/valgus instability occurred intraoperatively and it required revision with a prosthesis with higher constriction. No thromboembolic or infectious events were observed during postoperative follow-up. CONCLUSION: Following a standardized technique, UKA revision surgery can be achieved with TKA in almost every case despite bone stock loss and lack of anatomic landmarks. PMID- 27506726 TI - Highly conductive, printable pastes from capillary suspensions. AB - We have used the capillary suspension phenomenon to design conductive pastes for printed electronic applications, such as front side metallization of solar cells, without non-volatile, organic additives that often deteriorate electrical properties. Adding a small amount of a second, immiscible fluid to a suspension creates a network of liquid bridges between the particles. This capillary force controlled microstructure allows for tuning the flow behavior in a wide range. Yield stress and low-shear viscosity can be adjusted such that long-term stability is provided by inhibiting sedimentation, and, even more importantly, narrow line widths and high aspect ratios are accessible. These ternary mixtures, called capillary suspensions, exhibit a strong degree of shear thinning that allows for conventional coating or printing equipment to be used. Finally, the secondary fluid, beneficial for stability and processing of the wet paste, completely evaporates during drying and sintering. Thus, we obtained high purity silver and nickel layers with a conductivity two times greater than could be obtained with state-of-the-art, commercial materials. This revolutionary concept can be easily applied to other systems using inorganic or even organic conductive particles and represents a fundamental paradigm change to the formulation of pastes for printed electronics. PMID- 27506727 TI - Effective axillary malodour reduction by polyquaternium-16-containing deodorants. AB - OBJECTIVE: Worldwide, individuals apply deodorants to combat malodour formation originating from the axillary vault. Considering the globally increasing demand for efficacious, safe deodorants, we investigated the antimicrobial effectiveness of a polymeric quaternary ammonium compound (PQ-16) as a new active in a roll-on formulation against microbial growth and axillary malodour. METHODS: We utilized an in vivo microbiological assessment to determine antimicrobial effects of the PQ-16-containing deodorant formulation (DEO1) (i) in comparison with a commercially available deodorant roll-on claiming a 24-h protection against body odour (DEO2) and (ii) in comparison with a roll-on containing the same formulation as DEO1 but comprising aluminium chlorohydrate instead of PQ-16 (DEO3) 1, 4, 8, 24 and 48 h after treatment. Also, the axillary malodour intensity 24 and 48 h after application of deodorants was investigated in a controlled in vivo study performed by a trained sniffer panel using direct sniffing. RESULTS: Treatment with DEO1 in comparison with application of DEO2 significantly reduced the log 10 bacterial count at all points in time. After 24 and 48 h, sniffers rated malodour production in the DEO1-treated axillae significantly lower than in the DEO2-treated armpits. Application of DEO1 in comparison with DEO3 decreased the log 10 bacterial count after 1, 4, 8 and 24 h (significant for 4 and 8 h). After 48 h, the log 10 bacterial count showed similar values for both DEO1 and DEO3. The sniffer panel reported no significant differences between axillary malodour in DEO1-treated compared to DEO3-treated armpits after 24 and 48 h. CONCLUSION: We identified polyquaternium-16 (PQ-16, copolymers of 1-vinyl-2-pyrrolidone and 1-vinyl-3-methylimidazolium chloride) as a highly effective deodorant active. Results showed that a newly developed PQ-16 containing deodorant roll-on formulation (i) significantly reduced axillary malodour 24 and 48 h after treatment, (ii) significantly decreased the amount of axillary bacteria, (iii) compared to a commercially available deodorant claiming a 24-h odour protection significantly lowered axillary malodour 24 h and 48 h after application, and (iv) was well tolerated by the study population. PQ-16 represents an innovative and skin-friendly deodorant active. PMID- 27506728 TI - Subclinical hypothyroidism causing hypertension in pregnancy. AB - This is a case of a 25-year-old primigravida who was referred to the hypertension specialist for elevated blood pressures. The patient had an elevated thyroid stimulating hormone with normal free thyroxine (T4) levels and was positive for thyroid peroxidase antibodies resulting in a diagnosis of subclinical hypothyroidism. The patient was successfully treated with levothyroxine which normalized the blood pressure without the need for antihypertensive treatment. This case illustrates a cause of secondary hypertension that is not always considered in the differential diagnosis of a patient with hypertension in pregnancy. PMID- 27506729 TI - Acute metabolic amplification of insulin secretion in mouse islets: Role of cytosolic acetyl-CoA. AB - OBJECTIVE: Stimulation of the beta-cell metabolism by glucose and other fuels triggers insulin release by enhancing the mitochondrial ATP production and acutely amplifies the secretory response by increase in mitochondrial export of metabolites. We aimed to narrow down the uniform final reaction steps mediating fuel-induced acute amplification of insulin secretion. MATERIAL/METHODS: Insulin secretion and metabolic parameters were measured in isolated mouse islets exposed to the sulfonylurea glipizide in high concentration (closing all ATP-sensitive K(+) channels) during the entire experiment. Fuel-induced effects were examined after treating the islets for one hour with medium devoid of fuels. This experimental design prevented acute amplification, but only when glucose was the sole fuel. RESULTS: Strong amplification of insulin secretion by alpha ketoisocaproate or glucose combined with alpha-ketoisovalerate (supplying mitochondrial oxaloacetate) was abolished within 14min after transition to medium devoid of fuels. After transition from medium containing glucose plus alpha ketoisovalerate to medium containing solely glucose or alpha-ketoisovalerate, amplification (strong or weak, respectively) occurred until the end of the experiment. Glucose (alone or combined with alpha-ketoisovalerate) increased the total acetyl-CoA content as intensely as alpha-ketoisocaproate. Low concentrations of alpha-ketoisovalerate or alpha-ketoisocaproate were sufficient for saturation of acetyl-CoA increase, but caused no or only weak amplification, respectively. No acetyl-CoA increases occurred in the absence of glipizide. CONCLUSIONS: Glucose and other fuels regulate acute amplification of insulin secretion by controlling the supply of acetyl-CoA to the beta-cell cytosol. Cytosolic acetyl-CoA does not amplify by serving as substrate for syntheses of metabolic intermediates, but amplifies by acting as substrate for cytosolic protein acetylation. PMID- 27506730 TI - Deep subcutaneous adipose tissue lipid unsaturation associates with intramyocellular lipid content. AB - BACKGROUND: Obese twins have lower saturated and higher long-chain polyunsaturated fatty acids (FA) in subcutaneous adipose tissue (SAT) compared to their lean monozygotic (MZ) co-twin. Whether this holds for metabolically distinct deep (DSAT) and superficial (SSAT) depots is unknown. Here we use non invasive magnetic resonance spectroscopy (MRS) to measure the FA unsaturation in body mass index (BMI) discordant MZ twins in DSAT and SSAT and their relationship to ectopic fat content and body fat distribution. The main finding is further confirmed in an independent cohort using standardized measurement times. METHODS: MRS and magnetic resonance imaging were used to measure DSAT and SSAT unsaturation and their relationship to intramyocellular lipids (IMCL), hepatocellular lipids (HCL) and the amount of subcutaneous (SAT) and visceral adipose tissue (VAT) in 16 pairs of healthy monozygotic twins (MZ) discordant for BMI. A second independent cohort of 12 healthy volunteers was used to measure DSAT unsaturation and IMCL with standardized measurement time. One volunteer also underwent repeated random measurements of DSAT unsaturation and IMCL. RESULTS: In accordance with biopsy studies SSAT unsaturation was higher in the heavier twins (15.2+/-1.0% vs. 14.4+/-1.5%, P=0.024) and associated with SAT volume (R=0.672, P=0.001). DSAT unsaturation did not differ between twins (11.4+/-0.8 vs. 11.0+/ 1.0, P=0.267) and associated inversely with IMCL content (R=-0.462, P=0.001). The inverse association between DSAT unsaturation and IMCL was also present in the participants of the second cohort (R=-0.641, P=0.025) and for the repeated sampling at random of one person (R=-0.765, P=0.027). CONCLUSIONS: DSAT and SSAT FA unsaturation shows distinct associations with obesity and IMCL in MZ twins, reflecting compartment-specific metabolic activities. The FA unsaturation in the DSAT depot associates inversely with IMCL content, which raises the possibility of cross talk between the DSAT depot and the rapid turnover IMCL depot. PMID- 27506732 TI - Apolipoprotein D deficiency is associated to high bone turnover, low bone mass and impaired osteoblastic function in aged female mice. AB - BACKGROUND: Apolipoprotein D (ApoD) is a member of the lipocalin family known to transport small hydrophobic ligands. A major site of ApoD expression in mice is the central nervous system where evidence suggests that it plays a protective role. Gene expression of ApoD was reported in bone-forming osteoblasts but its impact on bone metabolism remains undocumented. METHODS: We compared basic bone parameters of ApoD(-/-) (null) and transgenic (tg) mice to wild-type (wt) littermates through microCT and histochemistry, as well as ApoD expression and secretion in osteoblasts under various culture conditions through real-time PCR and immunoblotting. RESULTS: ApoD-null females displayed progressive bone loss with aging, resulting in a 50% reduction in trabecular bone volume and a 23% reduction in cortical bone volume by 9months of age. Only cortical bone volume was significantly reduced in ApoD-null males by an average of 24%. Histochemistry indicated significantly higher osteoblast surface and number of osteoclasts in femora from ApoD-null females. ApoD gene expression was confirmed in primary cultures of bone marrow mesenchymal cells (MSC), with higher expression levels in MSC from females compared to males. ApoD-null MSC exhibited impaired proliferation and differentiation potentials. Moreover, exogenous ApoD partially rescued the osteogenic potential of null MSC, which were shown to readily uptake the protein from media. ApoD expression was upregulated under low proliferation conditions, by contact inhibition and osteoblastic differentiation in MC3T3-E1 osteoblast-like cells. CONCLUSION: Our results indicate that ApoD influences bone metabolism in mice in a gender-specific manner, potentially through an auto /paracrine pathway. PMID- 27506731 TI - Endoplasmic reticulum stress in obesity and obesity-related disorders: An expanded view. AB - The endoplasmic reticulum (ER) is most notable for its central roles in calcium ion storage, lipid biosynthesis, and protein sorting and processing. By virtue of its extensive membrane contact sites that connect the ER to most other organelles and to the plasma membrane, the ER can also regulate diverse cellular processes including inflammatory and insulin signaling, nutrient metabolism, and cell proliferation and death via a signaling pathway called the unfolded protein response (UPR). Chronic UPR activation has been observed in liver and/or adipose tissue of dietary and genetic murine models of obesity, and in human obesity and non-alcoholic fatty liver disease (NAFLD). Activation of the UPR in obesity and obesity-related disorders likely has two origins. One linked to classic ER stress involving the ER lumen and one linked to alterations to the ER membrane environment. This review discusses both of these origins and also considers the role of post-translational protein modifications, such as acetylation and palmitoylation, and ER-mitochondrial interactions to obesity-mediated impairments in the ER and activation of the UPR. PMID- 27506733 TI - Influences of body size phenotype on the incidence of gestational diabetes needing prescription; analysis by Korea National Health Insurance (KNHI) claims and the National Health Screening Examination (NHSE) database. AB - OBJECTIVES: Although growing evidence has emphasized the pivotal role of metabolic status irrespective of body mass index (BMI), there has been no study to examine the association of body size phenotype with development of gestational diabetes that requires treatment with oral hypoglycemic agent or insulin (GDM+T) in primiparas. METHODS: Data from a total of 216,961 women who participated in the National Health Screening Examination (NHSE) between January 2007 and December 2011 and delivered their first babies within two years of the NHSE were analyzed. Body size phenotypes were classified according to body mass index (BMI) and the presence/absence of metabolic syndrome according to the results of the NHSE. GDM+T was identified using the International Classification of Diseases 10th Revision (ICD-10) and prescription codes using Korea National Health Insurance (KNHI) claims. RESULTS: Approximately 0.39% of primiparas developed GDM+T. Compared to metabolically healthy normal weight (MHNW) women, both metabolically unhealthy normal weight (MUNW) and metabolically healthy obese (MHO) women had a significantly increased risk for developing GDM+T (odds ratio, OR: 9.53, 95% confidence interval, CI: 5.64-16.09 and OR: 3.30, 95% CI: 2.56 4.25, respectively). Specifically, MUNW individuals had a significantly higher risk of GDM+T when directly compared to MHO women even after adjusting for other GDM risk factors (OR: 2.92, 95% CI: 1.67-5.10). Furthermore, underweight women with metabolic syndrome showed a significantly increased frequency of GDM+T compared to MHNW subjects (OR: 8.87, 95% CI: 1.19-66.32). CONCLUSIONS: Pre pregnant metabolic status is critical for development of GDM+T, regardless of their BMI. Therefore, intensive intervention for the components of metabolic syndrome may be helpful for the prevention of GDM+T even in low or normal weight women. PMID- 27506735 TI - Immune therapy in type 1 diabetes mellitus - Attempts to untie the Gordian knot? PMID- 27506734 TI - Beyond knockout: A novel homodimerization-targeting MyD88 inhibitor prevents and cures type 1 diabetes in NOD mice. AB - INTRODUCTION AND AIMS: Studies have reported that myeloid differentiation factor 88 (MyD88) plays an important role in the development of type 1 diabetes (T1D). The aim of this study was to determine the effects of the self-created MyD88 inhibitor, TJ-M2010-6, in preventing and treating T1D. METHODS: Molecule docking and co-immunoprecipitation were used to determine the suppressing capability of TJ-M2010-6 on the homodimerization of MyD88. The preventive and therapeutic effects of TJ-M2010-6 were tested in NOD mice. RESULTS: TJ-M2010-6 interacted with amino acid residues of the MyD88 TIR domain and inhibited MyD88 homodimerization. Continuous administration of TJ-M2010-6 significantly reduced the onset of diabetes during the observation period in NOD mice (36.4% vs. 80%, P<0.01). Although the immediate TJ-M2010-6 treatment group showed a retardation in the rise of their blood glucose level, the delayed treatment group did not show this effect. Mechanism studies have shown that TJ-M2010-6 treatment significantly inhibits insulitis in vivo. In vitro, TJ-M2010-6 inhibited the maturation of DCs, leading to the suppression of T cell activation and inflammatory cytokine secretion. CONCLUSIONS: These results demonstrated that the strategy targeted at the innate immune system using the MyD88 inhibitor had a profound significance in preventing and treating T1D. PMID- 27506736 TI - Clinical correlates of sex hormones in women: The study of health in Pomerania. AB - BACKGROUND: Despite associations of sex hormones in women with increased cardiometabolic risk and mortality, the clinical correlates of altered sex hormone concentrations in women are less clearly understood. We investigated a broad range of clinical correlates of sex hormones in women from a large population-based sample. METHODS: Data from 2560 women from two cohorts of the Study of Health in Pomerania were used. Stepwise multivariable regression models were implemented to investigate a broad range of behavioral, socio-demographic, and cardiometabolic clinical correlates related to total testosterone (TT), free testosterone (fT), androstenedione (ASD), dehydroepiandrosterone-sulfate (DHEAS), estrone (E1), estradiol (E2), and sex hormone-binding globulin (SHBG). RESULTS: Waist circumference and BMI (beta-coefficient: -0.03; 95% CI: -0.04; 0.03) were inversely related to SHBG, and BMI was positively related to TT (beta coefficient: 0.005; 95% CI: 0.001; 0.009), fT, E1, and E2. Smoking was positively related to TT (beta-coefficient: 0.04; 95% CI: 0.01; 0.06), ASD, and fT. Systolic blood pressure (TT: beta-coefficient: 0.002; 95% CI: 0.001; 0.003), hypertension (TT: beta-coefficient: 0.05; 95% CI: 0.003; 0.11), low-density lipoprotein (LDL) cholesterol (TT: beta-coefficient: 0.02; 95% CI: 0.01; 0.05), and total cholesterol (TT: beta-coefficient: -0.03; 95% CI: 0.01; 0.05) were positively related to TT and ASD. Finally, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS) were positively related to fT, but inversely related to SHBG. CONCLUSIONS: Our population-based study, with sex hormone concentrations measured by liquid chromatography tandem mass spectrometry, revealed associations between clinical correlates including waist circumference, smoking, cohabitation, systolic blood pressure, cholesterol, and MetS with sex hormones. Thus, sex hormones and SHBG may play a role in the cardiovascular risk profile of women. PMID- 27506737 TI - Adiponectin as a target for the treatment of nonalcoholic steatohepatitis with thiazolidinediones: A systematic review. AB - Thiazolidinediones (TZDs; pioglitazone and rosiglitazone) have provided promising results in clinical trials for nonalcoholic steatohepatitis (NASH). The main purpose of this systematic review was to summarize evidence on circulating adiponectin levels in relation to histological changes following TZD treatment in patients with histologically confirmed NASH. We performed a systematic search in PubMed, Scopus and Cochrane Library. We included four studies, published between 2006 and 2012, providing data for 187 histologically confirmed NASH adult patients (105 on TZD and 82 controls) treated for 6-12months. Significant increase in adiponectin (80-178%) after TZD treatment was observed in all included studies. Improvement in steatosis following treatment was observed in all studies. A trend towards improvement in lobular inflammation was observed in all studies after pioglitazone, but not after rosiglitazone. Trends toward improvement in ballooning and fibrosis were observed in the two studies after pioglitazone using either the highest doses or the longest duration of therapy. Overall disease activity score was improved in all studies after pioglitazone, but not after rosiglitazone. Insulin resistance and liver function tests were also improved after treatment. Despite weight gain, circulating leptin was not increased after treatment. In conclusion, parallel increases in circulating adiponectin levels and histological improvement were observed in this systematic review. These results warrant further consideration of TZDs, but even more importantly point to a key role for novel potential treatments for NASH patients such as the newer selective peroxisome proliferator activated receptor-gamma modulators, which increase adiponectin without significant weight gain. PMID- 27506738 TI - Autophagy protects human podocytes from high glucose-induced injury by preventing insulin resistance. AB - OBJECTIVE: Insulin resistance is correlated with the progress of albuminuria in diabetic patients, and podocytes are crucial for maintaining the normal function of the glomerular filtration barrier. In the present study, we aimed to investigate the high glucose-induced insulin resistance and cell injury in human podocytes and the putative role of autophagy in this process. METHODS: Human podocytes were cultured in high glucose-supplemented medium and low glucose and high osmotic conditions were used for the controls. Autophagy in the podocytes was regulated using rapamycin or 3-methyladenine stimulation. Next, autophagy markers including LC3B, Beclin-1, and p62 were investigated using western blot and qPCR, and the insulin responsiveness was analyzed based on glucose uptake and by using the phosphorylation of the insulin receptor with Nephrin as a podocyte injury marker. RESULTS: The basal autophagy level decreased under the high glucose conditions, which was accompanied by a decrease in the glucose uptake and phosphorylation of the insulin receptor in the human podocytes. More interestingly, the glucose uptake and the phosphorylation of the insulin receptor were decreased by 3-MA stimulation and increased by rapamycin, illustrating that the responsiveness of insulin was regulated by autophagy. The activation of autophagy by rapamycin also ameliorated cell injury in the human podocytes. CONCLUSIONS: The presence or activation of autophagy was found to play a protective role in human podocytes against high glucose-induced insulin resistance and cell injury, which indicates a novel cellular mechanism and provides a potential therapeutic target for diabetic nephropathy (DN). PMID- 27506739 TI - The effects of interval- vs. continuous exercise on excess post-exercise oxygen consumption and substrate oxidation rates in subjects with type 2 diabetes. AB - BACKGROUND: For unknown reasons, interval training often reduces body weight more than energy-expenditure matched continuous training. We compared the acute effects of time-duration and oxygen-consumption matched interval- vs. continuous exercise on excess post-exercise oxygen consumption (EPOC), substrate oxidation rates and lipid metabolism in the hours following exercise in subjects with type 2 diabetes (T2D). METHODS: Following an overnight fast, ten T2D subjects (M/F: 7/3; age=60.3+/-2.3years; body mass index (BMI)=28.3+/-1.1kg/m(2)) completed three 60-min interventions in a counterbalanced, randomized order: 1) control (CON), 2) continuous walking (CW), 3) interval-walking (IW - repeated cycles of 3min of fast and 3min of slow walking). Indirect calorimetry was applied during each intervention and repeatedly for 30min per hour during the following 5h. A liquid mixed meal tolerance test (MMTT, 450kcal) was consumed by the subjects 45min after completion of the intervention with blood samples taken regularly. RESULTS: Exercise interventions were successfully matched for total oxygen consumption (CW=1641+/-133mL/min; IW=1634+/-126mL/min, P>0.05). EPOC was higher after IW (8.4+/-1.3l) compared to CW (3.7+/-1.4l, P<0.05). Lipid oxidation rates were increased during the MMTT in IW (1.03+/-0.12mg/kg per min) and CW (0.87+/ 0.04mg/kg per min) compared with CON (0.73+/-0.04mg/kg per min, P<0.01 and P<0.05, respectively), with no difference between IW and CW. Moreover, free fatty acids and glycerol concentrations, and glycerol kinetics were increased comparably during and after IW and CW compared to CON. CONCLUSIONS: Interval exercise results in greater EPOC than oxygen-consumption matched continuous exercise during a post-exercise MMTT in subjects with T2D, whereas effects on substrate oxidation and lipid metabolism are comparable. PMID- 27506740 TI - Serum uric acid and mortality in chronic kidney disease: A systematic review and meta-analysis. AB - BACKGROUND: Studies have shown inconsistent results about the association between serum uric acid levels and mortality in patients with chronic kidney disease (CKD). METHODS: A systematic literature search in MEDLINE, Web of Science and bibliographies of retrieved articles was performed to identify studies investigating the association between serum uric acid and mortality in patients with CKD. Pooled hazard ratios (HR) and corresponding 95% confidence intervals (CIs) were calculated using random-effects models. RESULTS: A total of 24 studies with 25,453 patients with CKD were included. By meta-analysis, patients with the highest serum uric acid level were associated with a significantly higher risk for mortality (14 studies; HR, 1.52; 95% CI, 1.33-1.73) compared with patients with the lowest serum uric acid level. For dose-response analysis, a linear relationship (8 studies; Pfor non-linearity=0.14) between serum uric acid levels and risk of mortality was found. Overall, an increase of 1mg/dl in serum uric acid level was associated with an 8% increased risk of mortality (21 studies; HR, 1.08; 95% CI, 1.04-1.11). CONCLUSIONS: Elevated serum uric acid levels are significantly associated with risk of mortality in patients with CKD. Further randomized controlled trials should attempt to determine whether it improves survival to target serum uric acid in patients with CKD. PMID- 27506741 TI - The novel mineralocorticoid receptor antagonist finerenone in diabetic kidney disease: Progress and challenges. PMID- 27506742 TI - Effects of lifestyle intervention on left ventricular regional myocardial function in metabolic syndrome patients from the RESOLVE randomized trial. AB - AIMS: The purpose of our study was to determine the effect of lifestyle intervention on left ventricular (LV) regional myocardial function in patients with metabolic syndrome (MetS) and investigate the relationships of the changes in myocardial function to changes in epicardial adipose tissue (EAT), inflammatory profile and MetS components. METHODS: Eighty-seven MetS patients were enrolled in a 6month lifestyle intervention program based on dietary management and increased physical activity, and compared with 44 aged and sex matched healthy controls. MetS individuals were allocated to different groups randomized (computer-generated randomization) on exercise modalities (high intensity dominant resistance or aerobic training, and moderate-intensity of both modes). EAT was measured by transthoracic echocardiography and LV longitudinal strains and strain rates were obtained using vector velocity imaging. Blood chemistry allowed assessments of adipocytokines (TNF-alpha: tumor necrosis factor alpha, PAI active: active plasminogen activator inhibitor-1 and adiponectin) and glucose tolerance markers. RESULTS: Regardless of exercise training modalities, lifestyle intervention improved significantly LV strains and strain rates (p<0.001) as well as metabolic and inflammatory profiles. Stepwise multiple regression analyses revealed EAT (beta=0.73, p<0.01), log adiponectin (beta= 0.13, p<0.05) and log TNF-alpha (beta=0.15, p<0.05) as independent predictors of LV longitudinal strain (R(2)=0.74, p<0.001) while myocardial function improvement consecutive to lifestyle intervention was explained by EAT changes only (R(2)=0.54, p<0.001). CONCLUSION: The mechanisms through which regional myocardial function is impaired in MetS and improved consecutive to intervention involved EAT, possibly via paracrine effects of adipocytokines. EAT should be considered as a future therapeutic target of interest in the treatment of metabolic-related cardiac diseases. PMID- 27506743 TI - Imbalance of plasma amino acids, metabolites and lipids in patients with lysinuric protein intolerance (LPI). AB - BACKGROUND: Lysinuric protein intolerance (LPI [MIM 222700]) is an aminoaciduria with defective transport of cationic amino acids in epithelial cells in the small intestine and proximal kidney tubules due to mutations in the SLC7A7 gene. LPI is characterized by protein malnutrition, failure to thrive and hyperammonemia. Many patients also suffer from combined hyperlipidemia and chronic kidney disease (CKD) with an unknown etiology. METHODS: Here, we studied the plasma metabolomes of the Finnish LPI patients (n=26) and healthy control individuals (n=19) using a targeted platform for analysis of amino acids as well as two analytical platforms with comprehensive coverage of molecular lipids and polar metabolites. RESULTS: Our results demonstrated that LPI patients have a dichotomy of amino acid profiles, with both decreased essential and increased non-essential amino acids. Altered levels of metabolites participating in pathways such as sugar, energy, amino acid and lipid metabolism were observed. Furthermore, of these metabolites, myo-inositol, threonic acid, 2,5-furandicarboxylic acid, galactaric acid, 4 hydroxyphenylacetic acid, indole-3-acetic acid and beta-aminoisobutyric acid associated significantly (P<0.001) with the CKD status. Lipid analysis showed reduced levels of phosphatidylcholines and elevated levels of triacylglycerols, of which long-chain triacylglycerols associated (P<0.01) with CKD. CONCLUSIONS: This study revealed an amino acid imbalance affecting the basic cellular metabolism, disturbances in plasma lipid composition suggesting hepatic steatosis and fibrosis and novel metabolites correlating with CKD in LPI. In addition, the CKD-associated metabolite profile along with increased nitrite plasma levels suggests that LPI may be characterized by increased oxidative stress and apoptosis, altered microbial metabolism in the intestine and uremic toxicity. PMID- 27506744 TI - Role of metabolism in neurodegenerative disorders. AB - Along with the increase in life expectancy over the last century, the prevalence of age-related disorders, such as neurodegenerative diseases continues to rise. This is the case of Alzheimer's, Parkinson's, Huntington's diseases and Multiple sclerosis, which are chronic disorders characterized by neuronal loss in motor, sensory or cognitive systems. Accumulating evidence has suggested the presence of a strong correlation between metabolic changes and neurodegeneration. Indeed epidemiologic studies have shown strong associations between obesity, metabolic dysfunction, and neurodegeneration, while animal models have provided insights into the complex relationships between these conditions. In this context, hormones such as leptin, ghrelin, insulin and IGF-1 seem to play a key role in the regulation of neuronal damage, toxic insults and several other neurodegenerative processes. This review aims to presenting the most recent evidence supporting the crosstalk linking energy metabolism and neurodegeneration, and will focus on metabolic manipulation as a possible therapeutic tool in the prevention and treatment of neurodegenerative diseases. PMID- 27506745 TI - Lipid phenotypes in patients with nonalcoholic fatty liver disease. AB - OBJECTIVE: There has been conflicting evidence regarding the role of single lipid species in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We aimed to explore the associations between dyslipidemia phenotypes (combinations of lipid parameters) and the risk of NAFLD. METHODS: We conducted a cross-sectional analysis using a cohort of 9560 apparently healthy Chinese adults who underwent comprehensive health checkups including abdominal ultrasonography. RESULTS: Of 3709 participants with NAFLD, 41.8% were classified as normolipemia (NL), 3.8% as combined hyperlipidemia, 3.2% as hypercholesterolemia, 17.7% as dyslipidemia of metabolic syndrome (MetS), 10.2% as isolated low high-density lipoprotein cholesterol (HDL-C), and 23.3% as isolated hypertriglyceridemia. The multivariable-adjusted odds ratios (ORs) (with 95% confidence intervals) for NAFLD in those with combined hyperlipidemia, those with hypercholesterolemia, those with MetS dyslipidemia, those with low HDL-C, and those with hypertriglyceridemia compared with those with NL were 4.79 (3.19-7.20), 1.26 (0.94-1.69), 3.31 (2.74-3.99), 1.13 (0.95-1.34), and 2.63 (2.26-3.08), respectively. The associations between combined hyperlipidemia, MetS dyslipidemia, or hypertriglyceridemia and risk of NAFLD were consistently seen in various evaluated subgroups. The interactions between lipid phenotypes and sex, body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), or uric acid (UA) were not significant for NAFLD (all P>0.05). CONCLUSIONS: There were diverse dyslipidemia phenotypes in patients with NAFLD. Combined hyperlipidemia, MetS dyslipidemia, and hypertriglyceridemia were strongly and independently associated with increased risk of NAFLD. Gender, BMI, BP, FPG, and UA status did not modify the associations between dyslipidemia phenotypes and NAFLD. PMID- 27506746 TI - Validation of a metabolite panel for early diagnosis of type 2 diabetes. AB - BACKGROUND: Accurate, early diagnosis of type 2 diabetes (T2D) would enable more effective clinical management and a reduction in T2D complications. Therefore, we sought to identify plasma metabolite and protein biomarkers that, in combination with glucose, can better predict future T2D compared with glucose alone. METHODS: In this case-control study, we used plasma samples from the Bavarian Red Cross Blood Transfusion Center study (61 T2D cases and 78 non-diabetic controls) for discovering T2D-associated metabolites, and plasma samples from the Personalized Medicine Research Project in Wisconsin (56 T2D cases and 445 non-diabetic controls) for validation. All samples were obtained before or at T2D diagnosis. We tested whether the T2D-associated metabolites could distinguish incident T2D cases from controls, as measured by the area under the receiver operating characteristic curve (AUC). Additionally, we tested six metabolic/pro inflammatory proteins for their potential to augment the ability of the metabolites to distinguish cases from controls. RESULTS: A panel of 10 metabolites discriminated better between T2D cases and controls than glucose alone (AUCs: 0.90 vs 0.87; p=2.08*10(-5)) in Bavarian samples, and associations between these metabolites and T2D were confirmed in Wisconsin samples. With use of either a Bayesian network classifier or ridge logistic regression, the metabolites, with or without the proteins, discriminated incident T2D cases from controls marginally better than glucose in the Wisconsin samples, although the difference in AUCs was not statistically significant. However, when the metabolites and proteins were added to two previously reported T2D prediction models, the AUCs were higher than those of each prediction model alone (AUCs: 0.92 vs 0.87; p=3.96*10(-2) and AUCs: 0.91 vs 0.71; p=1.03*10(-5), for each model, respectively). CONCLUSIONS: Compared with glucose alone or with previously described T2D prediction models, a panel of plasma biomarkers showed promise for improved discrimination of incident T2D, but more investigation is needed to develop an early diagnostic marker. PMID- 27506747 TI - Physical exercise alleviates ER stress in obese humans through reduction in the expression and release of GRP78 chaperone. AB - BACKGROUND AND OBJECTIVES: Perturbation of the endoplasmic reticulum (ER) homeostasis has emerged as one of the prominent features of obesity and diabetes. This occurs when the adaptive unfolded protein response (UPR) fails to restore ER function in key metabolic tissues. We previously reported increased inflammation and impaired heat shock response (HSR) in obese human subjects that were restored by physical exercise. Here, we investigated the status of ER stress chaperone; glucose-regulated protein 78 (GRP78) and its downstream UPR pathways in human obese, and their modulation by a supervised 3-month physical exercise. METHODS: Subcutaneous adipose tissue (SAT) and blood samples were collected from non diabetic adult human lean (n=40) and obese (n=40, at baseline and after 3months of physical exercise). Transcriptomic profiling was used as a primary screen to identify differentially expressed genes and it was carried out on SAT samples using the UPR RT(2) Profiler PCR Array. Conventional RT-PCR, immunohistochemistry, immunofluorescence, Western blot and ELISA were used to validate the transcriptomic data. Correlation analyses with the physical, clinical and biochemical outcomes were performed using Pearson's rank correlation coefficient. RESULTS: Levels of GRP78 and its three downstream UPR arms; activating transcription factor-6 (ATF6), inositol-requiring enzyme-1alpha (IRE1alpha) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) were increased in obese subjects. More interestingly, higher levels of circulating GRP78 protein were found in obese compared to lean subjects which correlated negatively with maximum oxygen uptake (VO2 Max) but positively with high sensitivity C-reactive protein (hsCRP) and obesity indicators such as BMI, percentage body fat (PBF) and waist circumference. GRP78 increased secretion in obese was further confirmed in vitro using 3T3-L1 preadipocyte cells under ER stress. Finally, we showed that physical exercise significantly attenuated the expression and release of GRP78 with a concomitant reduction in the phosphorylation of IRE1alpha and eukaryotic initiation factor-2alpha (eIF2alpha). CONCLUSION: Our results suggest that physical exercise alleviates ER stress in human obese through attenuation of GRP78 signaling network. PMID- 27506748 TI - Functional and proteomic alterations of plasma high density lipoproteins in type 1 diabetes mellitus. AB - OBJECTIVE: Higher HDL-cholesterol (HDL-C) is linked to lower cardiovascular risk but individuals with type 1 diabetes mellitus (T1DM) with normal or high HDL-C have higher cardiovascular events compared to age matched non-diabetic controls (ND). We determined whether altered HDL functions despite having normal HDL-C concentration may explain increased cardiovascular risk in T1DM individuals. We also determined whether irreversible posttranslational modifications (PTMs) of HDL bound proteins occur in T1DM individuals with altered HDL functions. METHODS: T1DM with poor glycemic control (T1D-PC, HbA1c>=8.5%, n=15) and T1DM with good glycemic control (T1D-GC, HbA1c<=6.6%, n=15) were compared with equal numbers of NDs, ND-PC and ND-GC respectively, matched for age, sex and body mass index (BMI). We measured cholesterol efflux capacity (CEC) of HDL in the serum using J774 macrophages, antioxidant function of HDL as the ability to reverse the oxidative damage of LDL and PON1 activity using commercially available kit. For proteomic analysis, HDL was isolated by density gradient ultracentrifugation and was analyzed by mass spectrometry and shotgun proteomics method. RESULTS: Plasma HDL-C concentrations in both T1DM groups were similar to their ND. However, CEC (%) of T1D-PC (16.9+/-0.8) and T1D-GC (17.1+/-1) were lower than their respective ND (17.9+/-1, p=0.01 and 18.2+/-1.4, p=0.02). HDL antioxidative function also was lower (p<0.05). The abundance of oxidative PTMs of apolipoproteins involved in CEC and antioxidative functions of HDL were higher in T1D-PC (ApoA4, p=0.041) and T1D-GC (ApoA4, p=0.025 and ApoE, p=0.041) in comparison with ND. Both T1D-PC and T1D-GC groups had higher abundance of amadori modification of ApoD (p=0.002 and p=0.041 respectively) and deamidation modification of ApoA4 was higher in T1D-PC (p=0.025). CONCLUSIONS: Compromised functions of HDL particles in T1DM individuals, irrespective of glycemic control, could be explained by higher abundance of irreversible PTMs of HDL proteins. These results lend mechanistic support to the hypothesis that HDL quality rather than quantity determines HDL function in T1DM and suggest that measurements of concentrations of HbA1c and HDL C are not sufficient as biomarkers of effective treatment to lower cardiovascular risk in T1DM individuals. PMID- 27506749 TI - Predictive ability of a simple subjective memory complaints scale for incident dementia: Evaluation of Japan's national checklist, the "Kihon Checklist". AB - AIM: Subjective memory complaints scales are expected to be useful for the prediction of future cognitive decline. In Japan, the "Kihon Checklist-Cognitive Function" (KCL-CF), which consists of three items, is used for primary screening of high-risk older adults. However, the predictive validity of the KCL-CF remains unknown. The aim of the present cohort study was to examine whether the KCL-CF can predict the incidence of dementia. METHODS: Information on the KCL-CF score (0-3 points) was collected from community-dwelling older adults (>=65 years) through a questionnaire. Data on incident dementia were retrieved from the Long term Care Insurance database. The Cox model and receiver operating characteristic curve analysis were used. RESULTS: Among 13 974 participants, the 5.7-year rate of incident dementia was 8.8%. All KCL-CF items significantly predicted the risk of incident dementia even after adjustment for age and sex (P-trend < 0.0001). A higher KCL-CF score was associated with a higher risk of dementia; the age- and sex-adjusted hazard ratios (95% confidence interval) were 1.00 (reference) for a KCL-CF score of 0 points, 1.89 (1.65-2.15) for 1 point, 3.01 (2.59-3.50) for 2 points, and 6.20 (4.87-7.90) for 3 points (P-trend < 0.0001). A cut-off score of >=1 points had a specificity of 65.1% and a sensitivity of 60.2%, and the area under the receiver operating characteristic curve was 0.65 (95% confidence interval 0.63-0.66). CONCLUSIONS: The KCL-CF was able to predict incident dementia. However, because a false-negativity rate of approximately 40% would be expected, the KCL-CF score alone might not be sufficient for screening of dementia incidence. Geriatr Gerontol Int 2017; 17: 1300-1305. PMID- 27506750 TI - Palliative care for a patient with Lambert-Eaton myasthenic syndrome: role of 3,4 diaminopyridine. AB - Lambert-Eaton myasthenic syndrome (LEMS) is an uncommon autoimmune idiopathic or paraneoplastic syndrome producing antibodies against voltage presynaptic calcium channels. According to previous studies, many patients with LEMS experience remission in both the clinical symptoms of muscle weakness and the electrophysiologic abnormalities after successful treatment of lung SCC. However, some patients might not respond to conventional therapy and eventually require palliative care. Hereby, we reported a LEMS patient with advanced lung malignancy was referred for palliative care. He was benefited from multidisciplinary approach even with limited survival. In this case, use of 3,4-diaminopyridine (3,4-DAP) had other roles apart from symptomatic treatment. PMID- 27506751 TI - Superior mesenteric artery (SMA) syndrome: an unusual cause of intestinal obstruction in palliative care. AB - Superior mesenteric artery (SMA) syndrome is an uncommon cause of intestinal obstruction and seldom been mentioned in palliative care. Hereby, we reported a case of SMA syndrome who presented with symptoms of upper intestinal obstruction in a 68-year-old patient; subsequent CT findings were classical of SMA syndrome. The patient's history of poliomyelitis and recent significant weight loss were the predisposing factors for SMA syndrome. It also highlights the importance of monitoring signs and symptoms of intestinal obstruction in such patients before considering switching to oral feeding. PMID- 27506752 TI - Association between the age and the development of colorectal cancer in patients with familial adenomatous polyposis: a multi-institutional study. AB - PURPOSE: To investigate the incidence of colorectal cancer among familial adenomatous polyposis (FAP) patients by phenotype using the latest modalities. METHODS: We collected data on 303 patients who underwent surgery for FAP at one of 23 institutions between 2000 and 2012. The incidence of colorectal cancer was investigated by phenotype. RESULTS: Colorectal cancer was diagnosed in 115 (38.0 %) of the 303 patients. Overall, colorectal cancer with the attenuated, sparse, and profuse phenotypes was diagnosed at 30, 31, and 28 years of age, respectively, in 10 % of the patients and at 59, 48, and 41 years of age, respectively, in 50 % of the patients (P = 0.013). The patients with colorectal cancer were older than those without colorectal cancer for all phenotypes. The optimal cut-off age for predicting the development of colorectal cancer in the attenuated, sparse, and profuse phenotypes was 46, 31, and 27 years, respectively. CONCLUSIONS: Patients with profuse and sparse phenotypes should undergo prophylactic proctocolectomy before their mid-to-late 20 s. On the other hand, the timing and type of surgery for patients with attenuated FAP (AFAP) should be decided individually with reference to the colonoscopic findings. PMID- 27506753 TI - A novel transanal tube designed to prevent anastomotic leakage after rectal cancer surgery: the WING DRAIN. AB - PURPOSE: We introduce a novel transanal tube (TAT), named the "WING DRAIN", designed to prevent anastomotic leakage after rectal cancer surgery, and report the fundamental experiments that led to its development. MATERIALS AND METHODS: We performed the basic experiments to evaluate the effect of TATs on intestinal decompression, the changes they make in patterns of watery fluid drainage, the changes in their decompression effect when the extension tube connecting the TAT to the collection bag fills with watery drainage fluid, and the variations in intestinal contact and crushing pressure made by some types of TAT. RESULTS: Any type of TAT contributed to decompression in the intestinal tract. Watery drainage commenced from when the water level first rose to the hole in the tip of drain. The intestinal pressure increased with the length of the vertical twist in an extension tube. The crushing pressures of most types of TAT were high enough to cause injury to the intestine. CONCLUSIONS: We resolved the problems using an existing TAT for the purpose of intestinal decompression and by creating the first specialized TAT designed to prevent anastomotic leakage after rectal cancer surgery in Japan. PMID- 27506754 TI - Short- and long-term results of radial artery and saphenous vein grafts in the right coronary system: a propensity-matched study. AB - PURPOSE: The selection of optimal grafts for the right coronary artery remains controversial. This study aims to evaluate the short- and long-term results of radial artery (RA) grafts and saphenous vein grafts (SVGs) to the right coronary artery. METHODS: We reviewed, retrospectively, isolated coronary artery bypass grafts, placed between 1997 and 2007, and compared the long-term results of patients who received RA (n = 110) grafts with those of patients who received SVGs (n = 264) using propensity-score matching for risk. The preoperative predictors of graft occlusion were investigated on a per case basis. RESULTS: Superior survival was noted in the unmatched RA group, but late outcomes after propensity-score matching yielded 91 patient pairs that were similar in the two groups. Graft failure was not correlated with mortality, but showed strong correlation with cardiac events in all patients. The predictors of graft occlusion in the RA group were mild proximal stenosis and low indexing glomerular filtration rates for body surface area, whereas those in the SVG were female gender and off-pump coronary artery bypass grafting. CONCLUSIONS: There were no significant differences in long-term outcomes between the RA and SVG groups. Predictors of graft occlusion differed between the groups. Notably, renal dysfunction impaired radial patency, emphasizing the importance of careful graft selection. PMID- 27506755 TI - Whole blood microRNAs as a prognostic classifier for acute respiratory distress syndrome 28-day mortality. PMID- 27506756 TI - Ten key points about ICU palliative care. PMID- 27506759 TI - Corrigendum. PMID- 27506757 TI - Impaired executive control and reward circuit in Internet gaming addicts under a delay discounting task: independent component analysis. AB - This study utilized independent component analysis to explore the abnormal functional connectivity (FC) in male participants with Internet gaming disorder (IGD). Functional magnetic resonance imaging and behavioral data were collected from 21 healthy controls (HC) and 18 IGD patients when they were performing a delay discounting task. Behavioral results revealed that the IGD patients showed higher delay discounting rates than HC. Two networks were found to be associated with IGD: (1) the executive control network containing the anterior cingulate cortex and the medial and superior frontal gyrus, and (2) the basal ganglia network containing the lentiform nucleus. Comparing to HC, IGD exhibited stronger FC when selecting small and now options. In addition, the delay discounting rates were positively correlated with the modulation of the two networks and the reaction time. The results suggested that the IGD patients have enhanced sensitivity to reward and decreased ability to control their impulsivity effectively, which leads to myopic decision making. PMID- 27506760 TI - Clinical and endocrine characteristics and genetic analysis of Korean children with McCune-Albright syndrome: a retrospective cohort study. AB - BACKGROUND: McCune-Albright syndrome (MAS) is a rare disease defined by the triad of fibrous dysplasia (FD), cafe au lait spots, and peripheral precocious puberty (PP). Because of the rarity of this disease, only a few individuals with MAS have been reported in Korea. We describe the various clinical and endocrine manifestations and genetic analysis of 14 patients with MAS in Korea. METHODS: Patients' clinical data-including peripheral PP, FD, and other endocrine problems were reviewed retrospectively. In addition, treatment experiences of letrozole in five patients with peripheral PP were described. Mutant enrichment with 3' modified oligonucleotides - polymerase chain reaction (MEMO-PCR) was performed on eight patients to detect mutation in GNAS using blood. MEMO-PCR is a simple and practical method that enables the nondestructive selection and enrichment of minor mutant alleles in blood. RESULTS: The median age at diagnosis was 5 years 2 months (range: 18 months to 16 years). Eleven patients were female, and three were male. Thirteen patients showed FD. All female patients showed peripheral PP at onset, and three patients subsequently developed central PP. There was a significant decrease in estradiol levels after two years of letrozole treatment. However, bone age was advanced in four patients. Two patients had clinical hyperthyroidism, and two patients had growth hormone (GH) excess with pituitary microadenoma. c.602G > A (p.Arg201His) in GNAS was detected in two patients in blood, and c.601C > T (p.Arg201Cys) in GNAS was detected in one patient in pituitary adenoma. CONCLUSIONS: This study described the various clinical manifestations of 14 patients with MAS in a single center in Korea. This study first applied MEMO-PCR on MAS patients to detect GNAS mutation. Because a broad spectrum of endocrine manifestations could be found in MAS, multiple endocrinopathies should be monitored in MAS patients. Better treatment options for peripheral PP with MAS are needed. PMID- 27506762 TI - Cash strapped CCG plans to halt non-urgent referrals. PMID- 27506761 TI - Applied multimodal diagnostics in a case of presenile dementia. AB - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The possibility of disease-modifying strategies has evoked a need for early and accurate diagnosis. To improve the accuracy of the clinical diagnosis of AD, biomarkers like cerebrospinal fluid (CSF) and neuroimaging techniques like magnetic resonance imaging (MRI) and positron emission tomography (PET) have been incorporated into the diagnostic guidelines of AD. CASE PRESENTATION: In this case report we outline in reference to one of our patients with presenile dementia the current approaches to the diagnosis of AD. The patient was a 59-year old woman presenting with progressive memory decline. CSF-Abeta42 was normal while P-tau was slightly increased. FDG-PET indicated a pattern typical for AD, amyloid-PET showed an extensive global amyloid load, and tau-PET depicted a pronounced hippocampal tracer accumulation. The MRI scan was rated as normal at routine diagnostics, however quantitative volumetric analysis revealed significant atrophy especially of the parietal lobe. The combination of biomarkers and neuroimaging techniques was therefore suggestive of an underlying AD pathology. CONCLUSIONS: To enable early and accurate diagnosis of AD and thereby also patient recruitment for anti-tau or anti-beta-amyloid therapeutic trials, a combination of biomarkers and neuroimaging techniques seems useful. PMID- 27506763 TI - Reversibly tuning the mechanical properties of a DNA hydrogel by a DNA nanomotor. AB - By integrating a DNA motor based on an i-motif sequence that undergoes a pH dependent conformational transition into a DNA hydrogel network, such microscopic transition leads to a macroscopic change in mechanical properties. This strategy allows reversible tuning of the mechanical strength of the hydrogel ranging from 250 Pa to 1000 Pa. PMID- 27506764 TI - Coupling of mitochondrial function and skeletal muscle fiber type by a miR 499/Fnip1/AMPK circuit. AB - Upon adaption of skeletal muscle to physiological and pathophysiological stimuli, muscle fiber type and mitochondrial function are coordinately regulated. Recent studies have identified pathways involved in control of contractile proteins of oxidative-type fibers. However, the mechanism for coupling of mitochondrial function to the muscle contractile machinery during fiber type transition remains unknown. Here, we show that the expression of the genes encoding type I myosins, Myh7/Myh7b and their intronic miR-208b/miR-499, parallels mitochondrial function during fiber type transitions. Using in vivo approaches in mice, we found that miR-499 drives a PGC-1alpha-dependent mitochondrial oxidative metabolism program to match shifts in slow-twitch muscle fiber composition. Mechanistically, miR-499 directly targets Fnip1, an AMP-activated protein kinase (AMPK)-interacting protein that negatively regulates AMPK, a known activator of PGC-1alpha. Inhibition of Fnip1 reactivated AMPK/PGC-1alpha signaling and mitochondrial function in myocytes. Restoration of the expression of miR-499 in the mdx mouse model of Duchenne muscular dystrophy (DMD) reduced the severity of DMD Thus, we have identified a miR-499/Fnip1/AMPK circuit that can serve as a mechanism to couple muscle fiber type and mitochondrial function. PMID- 27506765 TI - Combination analysis of genome-wide association and transcriptome sequencing of residual feed intake in quality chickens. AB - BACKGROUND: Residual feed intake (RFI) is a powerful indicator for energy utilization efficiency and responds to selection. Low RFI selection enables a reduction in feed intake without affecting growth performance. However, the effective variants or major genes dedicated to phenotypic differences in RFI in quality chickens are unclear. Therefore, a genome-wide association study (GWAS) and RNA sequencing were performed on RFI to identify genetic variants and potential candidate genes associated with energy improvement. RESULTS: A lower average daily feed intake was found in low-RFI birds compared to high-RFI birds. The heritability of RFI measured from 44 to 83 d of age was 0.35. GWAS showed that 32 of the significant single nucleotide polymorphisms (SNPs) associated with the RFI (P < 10(-4)) accounted for 53.01 % of the additive genetic variance. More than half of the effective SNPs were located in a 1 Mb region (16.3-17.3 Mb) of chicken (Gallus gallus) chromosome (GGA) 12. Thus, focusing on this region should enable a deeper understanding of energy utilization. RNA sequencing was performed to profile the liver transcriptomes of four male chickens selected from the high and low tails of the RFI. One hundred and sixteen unique genes were identified as differentially expressed genes (DEGs). Some of these genes were relevant to appetite, cell activities, and fat metabolism, such as CCKAR, HSP90B1, and PCK1. Some potential genes within the 500 Kb flanking region of the significant RFI related SNPs detected in GWAS (i.e., MGP, HIST1H110, HIST1H2A4L3, OC3, NR0B2, PER2, ST6GALNAC2, and G0S2) were also identified as DEGs in chickens with divergent RFIs. CONCLUSIONS: The GWAS findings showed that the 1 Mb narrow region of GGA12 should be important because it contained genes involved in energy consuming processes, such as lipogenesis, social behavior, and immunity. Similar results were obtained in the transcriptome sequencing experiments. In general, low-RFI birds seemed to optimize energy employment by reducing energy expenditure in cell activities, immune responses, and physical activity compared to eating. PMID- 27506766 TI - A computational docking study on the pH dependence of peptide binding to HLA-B27 sub-types differentially associated with ankylosing spondylitis. AB - A single amino acid difference (Asp116His), having a key role in a pathogenesis pathway, distinguishes HLA-B*27:05 and HLA-B*27:09 sub-types as associated and non-associated with ankylosing spondylitis, respectively. In this study, molecular docking simulations were carried out with the aim of comprehending the differences in the binding behavior of both alleles at varying pH conditions. A library of modeled peptides was formed upon single point mutations aiming to address the effect of 20 naturally occurring amino acids at the binding core peptide positions. For both alleles, computational docking was applied using Autodock 4.2. Obtained free energies of binding (FEB) were compared within the peptide library and between the alleles at varying pH conditions. The amino acid preferences of each position were studied enlightening the role of each on binding. The preferred amino acids for each position of pVIPR were found to be harmonious with experimental studies. Our results indicate that, as the pH is lowered, the capacity of HLA-B*27:05 to bind peptides in the library is largely lost. Hydrogen bonding analysis suggests that the interaction between the main anchor positions of pVIPR and their respective binding pocket residues are affected from the pH the most, causing an overall shift in the FEB profiles. PMID- 27506767 TI - Associations between access to recreational physical activity facilities and body mass index in Scottish adults. AB - BACKGROUND: The aim of this country-wide study was to link individual health and behavioural data with area-level spatial data to examine whether the body mass index (BMI) of adults was associated with access to recreational physical activity (PA) facilities by different modes of transport (bus, car, walking, cycling) and the extent to which any associations were mediated by PA participation. METHODS: Data on individual objectively-measured BMI, PA (number of days of (a) >=20 min of moderate-to-vigorous PA, and (b) >=15 min of sport or exercise, in previous 4 weeks), and socio-demographic characteristics were obtained from a nationally representative sample of 6365 adults. The number of accessible PA facilities per 1,000 individuals in each small area (data zones) was obtained by mapping a representative list of all fixed PA facilities throughout mainland Scotland. A novel transport network was developed for the whole country, and routes on foot, by bike, by car and by bus from the weighted population centroid of each data zone to each facility were calculated. Separate multilevel models were fitted to examine associations between BMI and each of the 24 measures of accessibility of PA facilities and BMI, adjusting for age, gender, longstanding illness, car availability, social class, dietary quality and urban/rural classification. RESULTS: We found associations (p < 0.05) between BMI and 7 of the 24 accessibility measures, with mean BMI decreasing with increasing accessibility of facilities-for example, an estimated decrease of 0.015 BMI units per additional facility within a 20-min walk (p = 0.02). None of these accessibility measures were found to be associated with PA participation. CONCLUSIONS: Our national study has shown that some measures of the accessibility of PA facilities by different modes of transport (particularly by walking and cycling) were associated with BMI; but PA participation, as measured here, did not appear to play a part in this relationship. Understanding the multi-factorial environmental influences upon obesity is key to developing effective interventions to reduce it. PMID- 27506769 TI - Erratum to: The dominance of the private sector in the provision of emergency obstetric care: studies from Gujarat, India. PMID- 27506768 TI - Flavihumibacter stibioxidans sp. nov., an antimony-oxidizing bacterium isolated from antimony mine soil. AB - A Gram-stain-positive, strictly aerobic, non-motile and rod-shaped bacterial strain, designated YS-17T, was isolated from soil in the Lengshuijiang antimony mine, Hunan Province, China. Comparative 16S rRNA gene sequencing analysis clustered it with Flavihumibacter strains, and strain YS-17T was most closely related to Flavihumibacter cheonanensis WS16T (97.2 % similarity), Flavihumibacter petaseus T41T (96.6 %) and Flavihumibacter solisilvae 3-3T (96.5 %). The level of DNA-DNA relatedness between strain YS-17T and F. cheonanensis JCM 19322T was 35.5+/-0.1 % (n=2). The major respiratory quinone of strain YS-17T was menaquinone-7 and the major polar lipids were phosphatidylethanolamine, two unidentified lipids, two unidentified amino lipids and phospholipid. The major fatty acids (>=5 %) were iso-C15 : 0, iso-C15 : 1 G, unknown ECL 13.565, iso-C17 : 0 3-OH, C15 : 0, C16 : 1omega5c and anteiso-C15 : 0. The DNA G+C content was 47.8 mol%. Compared with other Flavihumibacter strains, strain YS-17T showed major biophysical and biochemical differences, with the ability to hydrolyse gelatin and to assimilate salicin and l-proline. The results demonstrated that strain YS-17T belongs to the genus Flavihumibacter and represents a novel species, for which the name Flavihumibacter stibioxidans sp. nov. is proposed. The type strain is YS-17T (=CCTCC AB 2016053T=KCTC 52205T). PMID- 27506770 TI - Inhibition of ANXA7 GTPase activity by a small molecule promotes HMBOX1 translation of vascular endothelial cells in vitro and in vivo. AB - Homeobox containing 1 (HMBOX1) is essential for the survival of human umbilical vein endothelial cells (HUVECs). However, the regulatory mechanism of HMBOX1 expression is still unclear. We recently found that a small molecule 6-amino-2,3 dihydro-3-hydroxymethyl-1,4-benzoxazine (ABO) directly targeted annexin A7 (ANXA7) and inhibited its GTPase activity. In addition, both HMBOX1 and ANXA7 participated in the autophagy and apoptosis of HUVECs. But, their relationship in the regulation of HMBOX1 expression is unknown. In this study, we found that ABO could elevate HMBOX1 at translation level through inhibiting ANXA7 GTPase activity. ABO failed to increase HMBOX1 protein level in ANXA7-deficient HUVECs. TGFB2 overlapping transcript 1 (TGFB2-OT1) that was increased by ABO facilitated HMBOX1 expression by increasing La-related protein 1 (LARP1) expression. Furthermore, the protein level of HMBOX1 was decreased under oxidized low-density lipoprotein (oxLDL) treatment in HUVECs and in the aortic endothelium of apolipoprotein E-deficient (apoE-/-) mice, which could be reversed by ABO in vitro and in vivo. In conclusion, ANXA7 was an endogenous regulator of HMBOX1, and ABO promoted HMBOX1 translation by inhibiting ANXA7 GTPase activity and enhancing TGFB2-OT1 expression. Besides, our data suggested that HMBOX1 might be a novel diagnostic marker and therapeutic target of atherosclerosis. PMID- 27506771 TI - Prenatal high-dose vitamin D3 supplementation has balanced effects on cord blood Th1 and Th2 responses. AB - BACKGROUND: Antenatal vitamin D3 (vitD3) supplementation significantly increases maternal and neonatal 25-hydroxyvitamin D3 (25(OH)D3) concentration, yet the effect of an improvement in maternal-fetal vitamin D status on the neonatal immune response is unclear. METHOD: To assess the effect of prenatal vitD3 supplementation on cord blood T cell function, healthy pregnant Bangladeshi women (n = 160) were randomized to receive either oral 35,000 IU/week vitD3 or placebo from 26 to 29 weeks of gestation to delivery. In a subset of participants (n = 80), cord blood mononuclear cells (CBMC) were cultured, non-adherent lymphocytes were isolated to assess T cell cytokine responses to phytohemagglutinin (PHA) and anti-CD3/anti-CD28 (iCD3/iCD28), measured by multiplex assay. In 12 participants, lymphocyte gene expression profiles were analyzed by PCR array. RESULT: In supplemented group, increased concentrations of IL-10 (P < 0.000) and TNF-alpha (P = 0.05) with iCD3/iCD28 stimulation and IFN-gamma (p = 0.05) with PHA stimulation were obtained compared to placebo group. No differences in the gene expression profile were noted between the two groups. However, PHA stimulation significantly induced the expression of genes encoding Th1 and Th2 cytokines and down-regulated a number of genes involved in T-cell development, proliferation and differentiation of B cells, signal transduction pathway, transcriptional regulation and pattern recognition receptors (PRRs) in the vitamin D group (vitD group). CONCLUSION: Third-trimester high-dose vitD3 supplementation in healthy pregnant women had balanced effects on biomarkers of cord blood Th1 and Th2 responses. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01126528 ). PMID- 27506772 TI - Reply to Letter Regarding "Amplatzer Vascular Plugs Versus Coils for Embolization of Pulmonary Arteriovenous Malformations in Patients with Hereditary Hemorrhagic Telangiectasia". PMID- 27506773 TI - Routine Use of Surgical Retrograde Transtibial Endovascular Approach for Failed Attempts at Antegrade Recanalization of Chronic Peripheral Artery Total Occlusions. AB - PURPOSE: Our aim was to describe the technical aspects and clinical outcomes of an open surgical approach to retrograde transtibial endovascular therapy for recanalization of chronic total occlusions (CTOs) of peripheral arteries because of inability to acquire antegrade intravascular access across the occlusion. MATERIALS AND METHODS: Between January 2011 and May 2014, conventional antegrade revascularization failed in 15 limbs of 15 patients (11 males, 4 females) with complex CTOs. The mean age of the patients was 74 years (range 48-83 years). Five patients had severe claudication (Rutherford Category 3), and 10 patients had critical limb-threatening ischemia (Rutherford Categories 4-5). For each of these cases of antegrade failure, an open surgical exposure of the tibial or dorsalis pedis artery was used to allow a safe retrograde transtibial endovascular approach to recanalize the CTO. RESULTS: Surgical retrograde access from the tibial artery was achieved successfully in 14 of the 15 patients. In the 14 successful retrograde endovascular approaches, surgical retrograde transtibial access was achieved from the dorsalis pedis artery in 8 patients and from the posterior tibial artery in 6. The average time to obtain retrograde access was 5 min (range 2-11 min). No stenosis or occlusion occurred in the tibial or dorsalis pedis arteries used for the retrograde access sites during follow-up. CONCLUSIONS: Routine surgical exposure can be a safe and an effective method for retrograde transtibial access to the more proximal occluded arterial segments in selected patients with CTO. PMID- 27506774 TI - [Positioning therapy and early mobilization in intensive care units : Findings from the current 2015 guidelines]. AB - The 2007 guidelines "Positioning for prophylaxis and therapy of pulmonary disorders" were completely revised in 2015 on behalf of the German Society of Anaesthesiology and Intensive Care Medicine. With regard to practical and scientific relevance, early mobilization of patients in critical care has been included in the guidelines for the first time. Furthermore, the recommendations for prone positioning have been updated, based on current evidence in medicine and nursing. In addition, recommendations regarding unsuitable positions that may actually harm patients were made. As such, the flat supine position should only be used in cases of urgent medical or nursing needs. This underlines the importance of a moderately elevated head of bed position (20(o)-45(o)) in mechanically ventilated patients. PMID- 27506775 TI - [Epidemiology and mortality of extracorporeal life support in Germany between 2007 and 2014]. PMID- 27506776 TI - Spontaneous splenic rupture associated with apixaban: a case report. AB - BACKGROUND: Spontaneous splenic rupture associated with anticoagulant use is a rare but potentially lethal disorder. Lack of prompt recognition can be associated with poor patient outcomes. The use of novel oral anticoagulants is becoming more common and thus consideration of this disorder while evaluating a patient who presents with abdominal pain while using these agents is extremely important. This is the first reported case of spontaneous splenic rupture associated with apixaban. CASE PRESENTATION: We describe the clinical case of an 83-year-old white man who complained of sudden severe abdominal pain 5 days into a hospital stay for acute-on-chronic congestive heart failure and exacerbation of chronic obstructive pulmonary disease. Neither he nor his wife reported any significant trauma for the past 6 months prior to his admission. His medical history included chronic atrial fibrillation treated with medications including apixaban 2.5 mg twice daily. An urgent abdominal computed tomography scan demonstrated a large splenic hematoma and evidence of intraperitoneal bleeding from which he rapidly declined, developing hypovolemic shock. An emergency splenic arteriogram displayed a patent splenic artery and an embolization was successful in stabilizing him. Due to evidence of recurrent bleeding, an exploratory laparotomy and splenectomy was subsequently performed the following day. CONCLUSIONS: The diagnosis of spontaneous splenic rupture is important to consider in a patient using apixaban who presents with abdominal pain and associated signs of hypotension and anemia. For hemodynamically unstable patients, prompt treatment to stop significant bleeding through splenic artery embolization or splenectomy is warranted and may be lifesaving. PMID- 27506777 TI - The transposable element environment of human genes is associated with histone and expression changes in cancer. AB - BACKGROUND: Only 2 % of the human genome code for proteins. Among the remaining 98 %, transposable elements (TEs) represent millions of sequences. TEs have an impact on genome evolution by promoting mutations. Especially, TEs possess their own regulatory sequences and can alter the expression pattern of neighboring genes. Since they can potentially be harmful, TE activity is regulated by epigenetic mechanisms. These mechanisms participate in the modulation of gene expression and can be associated with some human diseases resulting from gene expression deregulation. The fact that the TE silencing can be removed in cancer could explain a part of the changes in gene expression. Indeed, epigenetic modifications associated locally with TE sequences could impact neighboring genes since these modifications can spread to adjacent sequences. RESULTS: We compared the histone enrichment, TE neighborhood, and expression divergence of human genes between a normal and a cancer conditions. We show that the presence of TEs near genes is associated with greater changes in histone enrichment and that differentially expressed genes harbor larger histone enrichment variation related to the presence of particular TEs. CONCLUSIONS: Taken together, these results suggest that the presence of TEs near genes could favor important variation in gene expression when the cell environment is modified. PMID- 27506778 TI - Changes in enterovirus serotype constituent ratios altered the clinical features of infected children in Guangdong Province, China, from 2010 to 2013. AB - BACKGROUND: Enterovirus (EV)-related hand, foot, and mouth disease/herpangina (HFMD/HA) has been prevalent in Guangdong Province, China, since 2010. METHODS: Clinical data for EV-related HFMD/HA inpatients admitted to the Department of Paediatrics of Zhujiang Hospital from 2010 to 2013 were retrospectively reviewed. The corresponding EV serotypes were also determined by reverse transcription polymerase chain reaction or BLAST analysis of the sequenced partial lengths of the viral protein1/5'-untranslated region. RESULTS: A total of 867 eligible inpatients admitted during 2010-2013 were included in the study. Of these, the serotype of the responsible EV was successfully identified in 824 cases. The incidence of enterovirus 71 (EV71) infection amongst pediatric HFMD/HA inpatients decreased dramatically from 55.5 % in 2010 to 8.1 % in 2013, with a similar decrease recorded for coxsackievirus A16 (CVA16). However, the incidence of non EV71/CVA16 infection increased from 30.0 % in 2010 to 83.8 % in 2013. We noted that the types of infection caused by different EV serotypes varied: EV71 was responsible for 100 % of the paralysis cases (26/26), 84.6 % of the deaths (11/13), and 84.1 % of cases with severe central nervous system involvement (SCNSI) (74/88); echovirus contributed to 16.4 % of the deaths (2/13) and 4.4 % of the SCNSI cases; and coxsackievirus accounted for only 2.2 % of the SCNSI cases (2/90). The clinical features of HFMD/HA cases varied greatly during the time period examined, with drastic changes in the hospitalization rates (45.1, 63.7, 36.4, and 19.1 % for 2010, 2011, 2012, and 21013, respectively), mortality rates (2.3, 0.9, 2.5, and 0.0 %, respectively), paralysis (5.1, 1.2, 5.4, and 0.0 %, respectively), SCNSI (16.8, 7.1, 12.7, and 2.2 %, respectively), and acute respiratory infection (21.1, 22.0, 45.9, and 59.0 %, respectively). CONCLUSIONS: The incidences of infection caused by different EV serotypes, along with the clinical features of HFMD/HA cases, changed drastically in Guangdong Province, China, from 2010 to 2013, with the biggest changes observed in 2013. The changed constituent ratios of the different EV serotypes might therefore be responsible for the differences in the observed clinical features of HFMD/HA during this period. PMID- 27506779 TI - Acute stroke with major intracranial vessel occlusion: Characteristics of cardioembolism and atherosclerosis-related in situ stenosis/occlusion. AB - Acute ischemic stroke with major intracranial vessel occlusion is commonly due to cardioembolic or atherosclerosis-related in situ stenosis/occlusion, and immediate identification of these subtypes is important to establish the optimal treatment strategy. The aim of this study was to clarify the differences in clinical presentation, radiological findings, neurological temporal courses, and outcomes between these etiologies, which have not been fully evaluated. Consecutive emergency patients with acute ischemic stroke were retrospectively reviewed. Among them, patients with stroke with major intracranial vessel occlusion were analyzed with a focus on clinical and radiological findings, and a comparison was performed for those with cardioembolic or atherosclerosis-related in situ stenosis/occlusion. Of 1053 patients, 80 had stroke with acute major intracranial vessel occlusion (45 with cardioembolic and 35 with atherosclerosis related in situ stenosis/occlusion). Interestingly, the susceptibility vessel sign (SVS) on T2-weighted MR angiography was more frequently detected in cardioembolic stroke (80.0%) than in atherosclerosis (in situ stenosis: 5.9%, chronic occlusion: 14.3%). Moreover, the proximal intra-arterial signal (IAS) on arterial spin labeling MRI and the distal IAS on fluid attenuated inversion recovery MRI was less frequently detected in chronic occlusion (27.3% and 50.0%, respectively) than in acute occlusion due to cardioembolic or in situ stenosis. Multivariate regression analysis showed that the SVS was significantly related to cardioembolism (adjusted odds ratio (OR): 21.68, P=0.004). Clinical characteristics of acute stroke with major intracranial vessel occlusion differ depending on the etiology. The SVS and proximal/distal IAS on MRI are useful to distinguish between cardioembolic and atherosclerotic-related in situ stenosis/occlusion. PMID- 27506780 TI - Minimally invasive surgery through the interlaminar approach in the treatment of spinal tuberculosis: A retrospective study of 31 patients. AB - The aim of this study was to evaluate the efficacy of minimally invasive spinal decompression combined with local chemotherapy in treating patients with thoracic/lumbar tuberculosis (TB) and abscess compression of the spinal canal. Clinical data of 31 patients with thoracic/lumbar TB and spinal epidural abscess, admitted to our hospital between December 2005 and June 2014 were retrospectively analyzed. All patients received initial conservative treatment but achieved unsatisfactory results and then underwent minimally invasive spinal canal decompression, focus debridement and catheter drainage through a posterior interlaminar approach. Postoperatively, a short-course (1-2months) of local chemotherapy was given. The patients were followed up on a regular basis. The neurologic status was graded according to the American Spinal Injury Association (ASIA) score system. Kyphotic deformity was evaluated using Cobb angle measurement. Patients were followed up for an average of 37months (range: 12 96months). At the last follow-up, ASIA scores were improved in all patients, and there was a mild increase in the Cobb angle, but satisfactory spinal stabilization was achieved. Hepatorenal function, erythrocyte sedimentation rate and C-reactive protein levels all returned to normal. One complication was observed, where the patient had worsened deficit postoperatively but achieved a satisfactory recovery (from Grade C to Grade E) one year after a second surgery. Minimally invasive spinal canal decompression combined with local chemotherapy appears to be an effective treatment for patients with thoracic/lumbar TB and abscess compression in the spinal canal. PMID- 27506781 TI - Five-year experience of 101 adult patients with moyamoya disease at a single institution in Eastern China. AB - This retrospective study included 101 adult moyamoya disease (MMD) patients of whom 58 were females and 43 were males in Wenzhou, China. Clinical and diagnostic features, surgical treatment, follow-up information and outcomes constitute this review. The modified Rankin Scale (mRS) was used to determine the neurological functional outcome. The Kaplan-Meier method was used to estimate recurrent stroke and mortality risk based on drug treatment alone or in combination with revascularization. The mean age at symptom onset was 43.3 (range, 18-64)years. The initial symptom was either hemorrhage, ischemia or transient ischemic attack (TIA) in 90, 6 and 5 patients, respectively. The median follow-up time in 84 patients was 26.5 (range, 6-62)months. Ten patients were treated with revascularization. In the remaining drug-treated group, the 5-year risk of recurrent stroke and death was 8% following onset of initial symptoms, while it was 25% in the revascularization group. However, the difference between these two groups was not significant (p>0.05). There was also no difference in mRS between these two groups upon patient discharge, but in the revascularization group was lower than that in the drug-treated group at their last follow-up (p<0.05). Adult MMD patients were most ikely to present with hemorrhage and had a better neurological functional outcome after revascularization than from medical therapy. However, revascularization did not decrease the recurrent stroke incidence or mortality risk. These results are different from those reported by other Chinese and foreign institutions. PMID- 27506782 TI - Decrease of aquaporin-4 and excitatory amino acid transporter-2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV-associated neurocognitive disorders. AB - Human immunodeficiency virus (HIV) encephalitis and degeneration of cerebral cortex are established histopathologies of HIV-associated neurocognitive disorders (HAND). We previously reported decreased excitatory amino acid transporter-2 (EAAT-2) and astrocytic apoptosis in cortical degeneration using SIVmac239 and simian-human immunodeficiency virus (SHIV)-infected macaques and human AIDS autopsy cases. In the present study, we added highly pathogenic SIVsm543-3-infected macaques. These animals showed similar degenerative changes in the frontal cortex. Using 11 SIV-infected macaques, three SIVsm543-3, five SIVmac239 and three SHIV, we compared brain pathology caused by three different viruses and further analyzed the pathogenic process of HAND. We noticed vacuolar changes in perivascular processes of astrocytes by electron microscopy, and examined expression of astrocyte-specific protein aquaporin-4 (AQP4) by immunohistochemistry. APQ4 was diffusely positive in the neuropil and perivascular area in control brains. There was patchy or diffuse decrease of AQP4 staining in the neuropil of SIV-infected macaques, which was associated with EAAT 2 staining by double immunostaining. A quantitative analysis demonstrated significant positive correlation between areas of AQP4 and EAAT-2. Some astrocytes express EAAT-2 but not AQP4, and decrease of EAAT-2 expression tended to be less than the decrease of AQP4. Active-caspase-3 immunostaining demonstrated apoptosis of neurons and astrocytes in the area of AQP4/EAAT-2 reduction. These results suggest that AQP4 is damaged first and decrease of EAAT 2 may follow in pathogenesis of cortical degeneration. This is the first demonstration of decrease of AQP4 and its association with EAAT-2 decrease in AIDS brain, suggesting a role in the pathogenesis of HAND. PMID- 27506783 TI - QnAs with Christine Jacobs-Wagner. PMID- 27506784 TI - Bioelectronic neural pixel: Chemical stimulation and electrical sensing at the same site. AB - Local control of neuronal activity is central to many therapeutic strategies aiming to treat neurological disorders. Arguably, the best solution would make use of endogenous highly localized and specialized regulatory mechanisms of neuronal activity, and an ideal therapeutic technology should sense activity and deliver endogenous molecules at the same site for the most efficient feedback regulation. Here, we address this challenge with an organic electronic multifunctional device that is capable of chemical stimulation and electrical sensing at the same site, at the single-cell scale. Conducting polymer electrodes recorded epileptiform discharges induced in mouse hippocampal preparation. The inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), was then actively delivered through the recording electrodes via organic electronic ion pump technology. GABA delivery stopped epileptiform activity, recorded simultaneously and colocally. This multifunctional "neural pixel" creates a range of opportunities, including implantable therapeutic devices with automated feedback, where locally recorded signals regulate local release of specific therapeutic agents. PMID- 27506785 TI - Histone arginine methylation in cocaine action in the nucleus accumbens. AB - Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase 6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction. PMID- 27506786 TI - Auditory-induced neural dynamics in sensory-motor circuitry predict learned temporal and sequential statistics of birdsong. AB - Predicting future events is a critical computation for both perception and behavior. Despite the essential nature of this computation, there are few studies demonstrating neural activity that predicts specific events in learned, probabilistic sequences. Here, we test the hypotheses that the dynamics of internally generated neural activity are predictive of future events and are structured by the learned temporal-sequential statistics of those events. We recorded neural activity in Bengalese finch sensory-motor area HVC in response to playback of sequences from individuals' songs, and examined the neural activity that continued after stimulus offset. We found that the strength of response to a syllable in the sequence depended on the delay at which that syllable was played, with a maximal response when the delay matched the intersyllable gap normally present for that specific syllable during song production. Furthermore, poststimulus neural activity induced by sequence playback resembled the neural response to the next syllable in the sequence when that syllable was predictable, but not when the next syllable was uncertain. Our results demonstrate that the dynamics of internally generated HVC neural activity are predictive of the learned temporal-sequential structure of produced song and that the strength of this prediction is modulated by uncertainty. PMID- 27506787 TI - Implications for Alzheimer's disease of an atomic resolution structure of amyloid beta(1-42) fibrils. PMID- 27506788 TI - Glycoengineering of plants yields glycoproteins with polysialylation and other defined N-glycoforms. PMID- 27506789 TI - QnAs with James Allison. PMID- 27506790 TI - Peptide- and proton-driven allosteric clamps catalyze anthrax toxin translocation across membranes. AB - Anthrax toxin is an intracellularly acting toxin in which sufficient information is available regarding the structure of its transmembrane channel, allowing for detailed investigation of models of translocation. Anthrax toxin, comprising three proteins-protective antigen (PA), lethal factor (LF), and edema factor translocates large proteins across membranes. Here we show that the PA translocase channel has a transport function in which its catalytic active sites operate allosterically. We find that the phenylalanine clamp (phi-clamp), the known conductance bottleneck in the PA translocase, gates as either a more closed state or a more dilated state. Thermodynamically, the two channel states have >300-fold different binding affinities for an LF-derived peptide. The change in clamp thermodynamics requires distant alpha-clamp and phi-clamp sites. Clamp allostery and translocation are more optimal for LF peptides with uniform stereochemistry, where the least allosteric and least efficiently translocated peptide had a mixed stereochemistry. Overall, the kinetic results are in less agreement with an extended-chain Brownian ratchet model but, instead, are more consistent with an allosteric helix-compression model that is dependent also on substrate peptide coil-to-helix/helix-to-coil cooperativity. PMID- 27506791 TI - Disruption of promoter memory by synthesis of a long noncoding RNA. AB - The yeast HO endonuclease is expressed in late G1 in haploid mother cells to initiate mating-type interconversion. Cells can be arrested in G1 by nutrient deprivation or by pheromone exposure, but cells that resume cycling after nutrient deprivation or cyclin-dependent kinase (CDK) inactivation express HO in the first cell cycle, whereas HO is not expressed until the second cycle after release from pheromone arrest. Here, we show that transcription of a long noncoding RNA (lncRNA) mediates this differential response. The SBF and Mediator factors remain bound to the inactive promoter during arrest due to CDK inactivation, and these bound factors allow the cell to remember a transcriptional decision made before arrest. If the presence of mating pheromone indicates that this decision is no longer appropriate, a lncRNA originating at 2700 upstream of the HO gene is induced, and the transcription machinery displaces promoter-bound SBF, preventing HO transcription in the subsequent cell cycle. Further, we find that the displaced SBF is blocked from rebinding due to incorporation of its recognition sites within nucleosomes. Expressing the pHO lncRNA in trans is ineffective, indicating that transcription in cis is required. Factor displacement during lncRNA transcription could be a general mechanism for regulating memory of previous events at promoters. PMID- 27506792 TI - Crystallographic snapshots of sulfur insertion by lipoyl synthase. AB - Lipoyl synthase (LipA) catalyzes the insertion of two sulfur atoms at the unactivated C6 and C8 positions of a protein-bound octanoyl chain to produce the lipoyl cofactor. To activate its substrate for sulfur insertion, LipA uses a [4Fe 4S] cluster and S-adenosylmethionine (AdoMet) radical chemistry; the remainder of the reaction mechanism, especially the source of the sulfur, has been less clear. One controversial proposal involves the removal of sulfur from a second (auxiliary) [4Fe-4S] cluster on the enzyme, resulting in destruction of the cluster during each round of catalysis. Here, we present two high-resolution crystal structures of LipA from Mycobacterium tuberculosis: one in its resting state and one at an intermediate state during turnover. In the resting state, an auxiliary [4Fe-4S] cluster has an unusual serine ligation to one of the irons. After reaction with an octanoyllysine-containing 8-mer peptide substrate and 1 eq AdoMet, conditions that allow for the first sulfur insertion but not the second insertion, the serine ligand dissociates from the cluster, the iron ion is lost, and a sulfur atom that is still part of the cluster becomes covalently attached to C6 of the octanoyl substrate. This intermediate structure provides a clear picture of iron-sulfur cluster destruction in action, supporting the role of the auxiliary cluster as the sulfur source in the LipA reaction and describing a radical strategy for sulfur incorporation into completely unactivated substrates. PMID- 27506793 TI - Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. AB - Ferroptosis is form of regulated nonapoptotic cell death that is involved in diverse disease contexts. Small molecules that inhibit glutathione peroxidase 4 (GPX4), a phospholipid peroxidase, cause lethal accumulation of lipid peroxides and induce ferroptotic cell death. Although ferroptosis has been suggested to involve accumulation of reactive oxygen species (ROS) in lipid environments, the mediators and substrates of ROS generation and the pharmacological mechanism of GPX4 inhibition that generates ROS in lipid environments are unknown. We report here the mechanism of lipid peroxidation during ferroptosis, which involves phosphorylase kinase G2 (PHKG2) regulation of iron availability to lipoxygenase enzymes, which in turn drive ferroptosis through peroxidation of polyunsaturated fatty acids (PUFAs) at the bis-allylic position; indeed, pretreating cells with PUFAs containing the heavy hydrogen isotope deuterium at the site of peroxidation (D-PUFA) prevented PUFA oxidation and blocked ferroptosis. We further found that ferroptosis inducers inhibit GPX4 by covalently targeting the active site selenocysteine, leading to accumulation of PUFA hydroperoxides. In summary, we found that PUFA oxidation by lipoxygenases via a PHKG2-dependent iron pool is necessary for ferroptosis and that the covalent inhibition of the catalytic selenocysteine in Gpx4 prevents elimination of PUFA hydroperoxides; these findings suggest new strategies for controlling ferroptosis in diverse contexts. PMID- 27506794 TI - RNF122 suppresses antiviral type I interferon production by targeting RIG-I CARDs to mediate RIG-I degradation. AB - The activation of retinoic acid-inducible gene 1 (RIG-I), a cytoplasmic innate sensor for viral RNA, is tightly regulated to maintain immune homeostasis properly and prevent excessive inflammatory reactions other than initiation of antiviral innate response to eliminate RNA virus effectively. Posttranslational modifications, particularly ubiquitination, are crucial for regulation of RIG-I activity. Increasing evidence suggests that E3 ligases play important roles in various cellular processes, including cell proliferation and antiviral innate signaling. Here we identify that E3 ubiquitin ligase RING finger protein 122 (RNF122) directly interacts with mouse RIG-I through MS screening of RIG-I interacting proteins in RNA virus-infected cells. The transmembrane domain of RNF122 associates with the caspase activation and recruitment domains (CARDs) of RIG-I; this interaction effectively triggers RING finger domain of RNF122 to deliver the Lys-48-linked ubiquitin to the Lys115 and Lys146 residues of RIG-I CARDs and promotes RIG-I degradation, resulting in a marked inhibition of RIG-I downstream signaling. RNF122 is widely expressed in various immune cells, with preferential expression in macrophages. Deficiency of RNF122 selectively increases RIG-I-triggered production of type I IFNs and proinflammatory cytokines in macrophages. RNF122-deficient mice exhibit more resistance against lethal RNA virus infection, with increased production of type I IFNs. Thus, we demonstrate that RNF122 acts as a selective negative regulator of RIG-I-triggered antiviral innate response by targeting CARDs of RIG-I and mediating proteasomal degradation of RIG-I. Our study outlines a way for E3 ligase to regulate innate sensor RIG-I for the control of antiviral innate immunity. PMID- 27506795 TI - Assembly scaffold NifEN: A structural and functional homolog of the nitrogenase catalytic component. AB - NifEN is a biosynthetic scaffold for the cofactor of Mo-nitrogenase (designated the M-cluster). Previous studies have revealed the sequence and structural homology between NifEN and NifDK, the catalytic component of nitrogenase. However, direct proof for the functional homology between the two proteins has remained elusive. Here we show that, upon maturation of a cofactor precursor (designated the L-cluster) on NifEN, the cluster species extracted from NifEN is spectroscopically equivalent and functionally interchangeable with the native M cluster extracted from NifDK. Both extracted clusters display nearly indistinguishable EPR features, X-ray absorption spectroscopy/extended X-ray absorption fine structure (XAS/EXAFS) spectra and reconstitution activities, firmly establishing the M-cluster-bound NifEN (designated NifEN(M)) as the only protein other than NifDK to house the unique nitrogenase cofactor. Iron chelation experiments demonstrate a relocation of the cluster from the surface to its binding site within NifEN(M) upon maturation, which parallels the insertion of M cluster into an analogous binding site in NifDK, whereas metal analyses suggest an asymmetric conformation of NifEN(M) with an M-cluster in one alphabeta-half and an empty cluster-binding site in the other alphabeta-half, which led to the proposal of a stepwise assembly mechanism of the M-cluster in the two alphabeta dimers of NifEN. Perhaps most importantly, NifEN(M) displays comparable ATP independent substrate-reducing profiles to those of NifDK, which establishes the M-cluster-bound alphabeta-dimer of NifEN(M) as a structural and functional mimic of one catalytic alphabeta-half of NifDK while suggesting the potential of this protein as a useful tool for further investigations of the mechanistic details of nitrogenase. PMID- 27506796 TI - Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L. AB - The seed oil of Euphorbia lathyris L. contains a series of macrocyclic diterpenoids known as Euphorbia factors. They are the current industrial source of ingenol mebutate, which is approved for the treatment of actinic keratosis, a precancerous skin condition. Here, we report an alcohol dehydrogenase-mediated cyclization step in the biosynthetic pathway of Euphorbia factors, illustrating the origin of the intramolecular carbon-carbon bonds present in lathyrane and ingenane diterpenoids. This unconventional cyclization describes the ring closure of the macrocyclic diterpene casbene. Through transcriptomic analysis of E. lathyris L. mature seeds and in planta functional characterization, we identified three enzymes involved in the cyclization route from casbene to jolkinol C, a lathyrane diterpene. These enzymes include two cytochromes P450 from the CYP71 clan and an alcohol dehydrogenase (ADH). CYP71D445 and CYP726A27 catalyze regio specific 9-oxidation and 5-oxidation of casbene, respectively. When coupled with these P450-catalyzed monooxygenations, E. lathyris ADH1 catalyzes dehydrogenation of the hydroxyl groups, leading to the subsequent rearrangement and cyclization. The discovery of this nonconventional cyclization may provide the key link to complete elucidation of the biosynthetic pathways of ingenol mebutate and other bioactive macrocyclic diterpenoids. PMID- 27506797 TI - Acinetobacter baumannii phenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis. AB - Innate cellular immune responses are a critical first-line defense against invading bacterial pathogens. Leukocyte migration from the bloodstream to a site of infection is mediated by chemotactic factors that are often host-derived. More recently, there has been a greater appreciation of the importance of bacterial factors driving neutrophil movement during infection. Here, we describe the development of a zebrafish infection model to study Acinetobacter baumannii pathogenesis. By using isogenic A. baumannii mutants lacking expression of virulence effector proteins, we demonstrated that bacterial drivers of disease severity are conserved between zebrafish and mammals. By using transgenic zebrafish with fluorescent phagocytes, we showed that a mutation of an established A. baumannii global virulence regulator led to marked changes in neutrophil behavior involving rapid neutrophil influx to a localized site of infection, followed by prolonged neutrophil dwelling. This neutrophilic response augmented bacterial clearance and was secondary to an impaired A. baumannii phenylacetic acid catabolism pathway, which led to accumulation of phenylacetate. Purified phenylacetate was confirmed to be a neutrophil chemoattractant. These data identify a previously unknown mechanism of bacterial-guided neutrophil chemotaxis in vivo, providing insight into the role of bacterial metabolism in host innate immune evasion. Furthermore, the work provides a potentially new therapeutic paradigm of targeting a bacterial metabolic pathway to augment host innate immune responses and attenuate disease. PMID- 27506798 TI - Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2. AB - The circadian clock has a profound effect on gene regulation, controlling rhythmic transcript accumulation for up to half of expressed genes in eukaryotes. Evidence also exists for clock control of mRNA translation, but the extent and mechanisms for this regulation are not known. In Neurospora crassa, the circadian clock generates daily rhythms in the activation of conserved mitogen-activated protein kinase (MAPK) pathways when cells are grown in constant conditions, including rhythmic activation of the well-characterized p38 osmosensing (OS) MAPK pathway. Rhythmic phosphorylation of the MAPK OS-2 (P-OS-2) leads to temporal control of downstream targets of OS-2. We show that osmotic stress in N. crassa induced the phosphorylation of a eukaryotic elongation factor-2 (eEF-2) kinase, radiation sensitivity complementing kinase-2 (RCK-2), and that RCK-2 is necessary for high-level phosphorylation of eEF-2, a key regulator of translation elongation. The levels of phosphorylated RCK-2 and phosphorylated eEF-2 cycle in abundance in wild-type cells but not in cells deleted for OS-2 or the core clock component FREQUENCY (FRQ). Translation extracts from cells grown in constant conditions show decreased translational activity in the late subjective morning, coincident with the peak in eEF-2 phosphorylation, and rhythmic translation of glutathione S-transferase (GST-3) from constitutive mRNA levels in vivo is dependent on circadian regulation of eEF-2 activity. In contrast, rhythms in phosphorylated eEF-2 levels are not necessary for rhythms in accumulation of the clock protein FRQ, indicating that clock control of eEF-2 activity promotes rhythmic translation of specific mRNAs. PMID- 27506799 TI - Lyme disease and relapsing fever Borrelia elongate through zones of peptidoglycan synthesis that mark division sites of daughter cells. AB - Agents that cause Lyme disease, relapsing fever, leptospirosis, and syphilis belong to the phylum Spirochaetae-a unique lineage of bacteria most known for their long, spiral morphology. Despite the relevance to human health, little is known about the most fundamental aspects of spirochete growth. Here, using quantitative microscopy to track peptidoglycan cell-wall synthesis, we found that the Lyme disease spirochete Borrelia burgdorferi displays a complex pattern of growth. B. burgdorferi elongates from discrete zones that are both spatially and temporally regulated. In addition, some peptidoglycan incorporation occurs along the cell body, with the notable exception of a large region at the poles. Newborn cells inherit a highly active zone of peptidoglycan synthesis at midcell that contributes to elongation for most of the cell cycle. Concomitant with the initiation of nucleoid separation and cell constriction, second and third zones of elongation are established at the 1/4 and 3/4 cellular positions, marking future sites of division for the subsequent generation. Positioning of elongation zones along the cell is robust to cell length variations and is relatively precise over long distances (>30 um), suggesting that cells "sense" relative, as opposed to absolute, cell length to establish zones of peptidoglycan synthesis. The transition from one to three zones of peptidoglycan growth during the cell cycle is also observed in relapsing fever Borrelia. However, this mode of growth does not extend to representative species from other spirochetal genera, suggesting that this distinctive growth mode represents an evolutionary divide in the spirochete phylum. PMID- 27506801 TI - Endocrine disorders in women with complex regional pain syndrome type I. AB - BACKGROUND: The question of hormonal dysregulation in patients with CRPS I in whole was investigated very scantily. There are only a few studies concerning catecholamines, oestrogens and endorphins independently. Other hormones were studied in patients with different other chronic pain conditions. Considering the accumulation of sufficient knowledge about the role of disadaptation processes in CRPS I pathogenesis and the role of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-ovarian systems in the process of adaptation it was logical and consistent to define the role of hormonal dysregulation of these systems in patients with CRPS I. OBJECTIVES: Our objective was to determine the role of hypothalamic-pituitary-adrenal and hypothalamic-pituitary-ovarian systems in pathogenesis of complex regional pain syndrome type I (CRPS I) in women. METHODS: We investigated the pituitary gonadotropic function and the function of sex glands in women with CRPS I and healthy volunteers by measuring the plasma levels of estradiol (E2 ), follicle-stimulating hormone, luteinizing hormone, prolactin, adrenocorticotropic hormone, and cortisol, and urinary excretion of 17 ketosteroids, 17-oxycocorticosteroids, epinephrine and norepinephrine. RESULTS: Women with CRPS I were characterized by the decreased content of oestrogens in the blood plasma and increased pituitary gonadotrophic function. The disturbed ratio of anabolic and catabolic steroids in women with CRPS I was detected due to lower adrenal cortex function. CONCLUSIONS: In patients with CRPS I endocrine status is characterized by hormonal imbalances of the hypothalamic-pituitary adrenal and hypothalamic-pituitary-gonadal systems. The changes in reproductive and adaptation homeostasis characterize CRPS I as a form of the disease of disadaptation. SIGNIFICANCE: This study determined the role of hypothalamic pituitary-adrenal and hypothalamic-pituitary-ovarian systems in pathogenesis of CRPS I. PMID- 27506800 TI - Midgut microbiota and host immunocompetence underlie Bacillus thuringiensis killing mechanism. AB - Bacillus thuringiensis is a widely used bacterial entomopathogen producing insecticidal toxins, some of which are expressed in insect-resistant transgenic crops. Surprisingly, the killing mechanism of B. thuringiensis remains controversial. In particular, the importance of the septicemia induced by the host midgut microbiota is still debated as a result of the lack of experimental evidence obtained without drastic manipulation of the midgut and its content. Here this key issue is addressed by RNAi-mediated silencing of an immune gene in a lepidopteran host Spodoptera littoralis, leaving the midgut microbiota unaltered. The resulting cellular immunosuppression was characterized by a reduced nodulation response, which was associated with a significant enhancement of host larvae mortality triggered by B. thuringiensis and a Cry toxin. This was determined by an uncontrolled proliferation of midgut bacteria, after entering the body cavity through toxin-induced epithelial lesions. Consequently, the hemolymphatic microbiota dramatically changed upon treatment with Cry1Ca toxin, showing a remarkable predominance of Serratia and Clostridium species, which switched from asymptomatic gut symbionts to hemocoelic pathogens. These experimental results demonstrate the important contribution of host enteric flora in B. thuringiensis-killing activity and provide a sound foundation for developing new insect control strategies aimed at enhancing the impact of biocontrol agents by reducing the immunocompetence of the host. PMID- 27506802 TI - Psychometric Testing of the Chinese-Version Glover-Nilsson Smoking Behavioral Questionnaire (GN-SBQ-C) for the Identification of Nicotine Dependence in Adult Smokers in Taiwan. AB - PURPOSE: The purposes of this study were to evaluate the psychometric properties, reliability, and validity of the Chinese-version Glover-Nilsson Smoking Behavioral Questionnaire (GN-SBQ-C) and assess the behavioral nicotine dependence among community-dwelling adult smokers in Taiwan. METHOD: The methods used were survey design, administration, and validation. A total of 202 adult smokers completed a survey to assess behavioral dependence, nicotine dependence, depression, social support, and demographic and smoking characteristics. Data analysis included descriptive statistics, internal consistency reliability, t test, exploratory factor analysis, independent t test, and Pearson product moment correlation. RESULTS: The results showed that (1) the GN-SBQ-C has good internal consistency reliability and stability (2-week test-retest reliability); (2) the extracted one factor explained 41.80 % of the variance, indicating construct validity; (3) the scale has acceptable concurrent validity, with significant positive correlation between the GN-SBQ-C and nicotine dependence, depression, and time smoking and negative correlation between the GN-SBQ-C and age and exercise habit; and (4) the instrument has discriminant validity, supported by significant differences between those with high and low-to-moderate nicotine dependence, smokers greater than 43 years old and those 43 years old and younger, and those who smoked 10 years or less and those smoking more than 10 years. CONCLUSION: The 11-item GN-SBQ-C has satisfactory psychometric properties when applied in a sample of Taiwanese adult smokers. The scale is feasible and valid to use to assess smoking behavioral dependence. PMID- 27506803 TI - Two-Year Outcomes of Vagal Nerve Blocking (vBloc) for the Treatment of Obesity in the ReCharge Trial. AB - BACKGROUND: The ReCharge Trial demonstrated that a vagal blocking device (vBloc) is a safe and effective treatment for moderate to severe obesity. This report summarizes 24-month outcomes. METHODS: Participants with body mass index (BMI) 40 to 45 kg/m2, or 35 to 40 kg/m2 with at least one comorbid condition were randomized to either vBloc therapy or sham intervention for 12 months. After 12 months, participants randomized to vBloc continued open-label vBloc therapy and are the focus of this report. Weight loss, adverse events, comorbid risk factors, and quality of life (QOL) will be assessed for 5 years. RESULTS: At 24 months, 123 (76 %) vBloc participants remained in the trial. Participants who presented at 24 months (n = 103) had a mean excess weight loss (EWL) of 21 % (8 % total weight loss [TWL]); 58 % of participants had >=5 % TWL and 34 % had >=10 % TWL. Among the subset of participants with abnormal preoperative values, significant improvements were observed in mean LDL (-16 mg/dL) and HDL cholesterol (+4 mg/dL), triglycerides (-46 mg/dL), HbA1c (-0.3 %), and systolic (-11 mmHg) and diastolic blood pressures (-10 mmHg). QOL measures were significantly improved. Heartburn/dyspepsia and implant site pain were the most frequently reported adverse events. The primary related serious adverse event rate was 4.3 %. CONCLUSIONS: vBloc therapy continues to result in medically meaningful weight loss with a favorable safety profile through 2 years. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01327976. PMID- 27506804 TI - Cost-comparativeness of proton versus photon therapy. AB - Proton beam radiotherapy (PBT) offers great promise in the treatment of a wide variety of cancers owing to the sharp drop-off in radiation dose at a defined point, known as the Bragg peak, beyond which there is no appreciable dose. However, it is also well-understood that PBT is associated with large economic costs, including both capital investment and operating costs. From a medical as well as societal perspective, therefore, it is important to be aware of the economic implications of new technologies such as PBT, and to evaluate the cost effectiveness based on different clinical and treatment scenarios. This review examines PBT from a health economics perspective, evaluating both the design and results of costeffectiveness (CE) studies that have been performed previously. We further examine several salient variables that can affect CE of PBT, including patient, tumor, treatment, and logistical factors. We discuss the implication of technological advances on PBT delivery, and its impact on overall healthcare delivery costs. Additionally, we evaluate the status of economic analyses for PBT and discuss the role of ongoing and future CE studies in better defining the economic role of PBT as part of modern cancer therapy. PMID- 27506805 TI - Treatment of common pediatric CNS malignancies with proton therapy. AB - Radiation therapy plays an important role in the management of pediatric CNS malignancies. With the improving outcomes of these patients, the potential risk of late toxicities present with current radiation therapy techniques (i.e., 3D CRT, IMRT, VMAT) has become apparent. Proton therapy (PRT), due to its unique physical characteristics, provides an advantage in reducing unintended dose to normal tissue structures, and the resultant acute and late side effects of this dose "bath". In this review we will highlight the current standards of care, and the benefits achieved with using PRT in treating common childhood CNS tumors. PMID- 27506806 TI - Molecular features of response to anti-PD-1 therapy. PMID- 27506807 TI - Chromodomain-helicase-DNA-binding protein 4: a novel therapeutic target in liver cancer stem cells. PMID- 27506808 TI - Reduced acute toxicity and improved efficacy from intensity-modulated proton therapy (IMPT) for the management of head and neck cancer. AB - Cancers in the head and neck area are usually close to several critical organ structures. Traditional external-beam photon radiation therapy unavoidably exposes these structures to significant doses of radiation, which can lead to serious acute and chronic toxicity. Intensity-modulated proton therapy (IMPT), however, has dosimetric advantages that allow it to deposit high doses within the target while largely sparing surrounding structures. Because of this advantage, IMPT has the potential to improve both tumor control and toxicity. To determine the degree to which IMPT can reduce toxicity and improve tumor control, more randomized trials are needed that directly compare IMPT with intensity-modulated photon therapy. Here we examine the existing evidence on the efficacy and toxicity of IMPT for treating cancers at several anatomic subsites of the head and neck. We also report on the ability of IMPT to reduce malnutrition, and gastrostomy tube dependence and improve patient-reported outcomes (PROs). PMID- 27506809 TI - Arthroscopic treatment of global pincer-type femoroacetabular impingement. AB - PURPOSE: Few studies have evaluated the role of hip arthroscopy in patients with coxa profunda. The purposes of this study are to (1) report functional hip outcomes after arthroscopic treatment of patients with femoroacetabular impingement (FAI) associated with radiographic coxa profunda and (2) evaluate factors associated with poor hip function at minimum 2 years following surgery in this specific cohort. METHODS: This retrospective review included patients with radiographic sign of coxa profunda who underwent hip arthroscopy to treat FAI. Preoperative and post-operative radiographs were reviewed to determine changes in lateral centre-edge angle (CEA), the presence and correction of Cam deformity, and Tonnis grade of osteoarthritis. Hip functional scores, including modified Harris Hip Score, Hip Outcome Score, and IHOT score, were obtained at a minimum of 2 years following surgery. RESULTS: The study cohort included 46 patients with a mean preoperative CEA of 39.9 (+/-2.4) degrees which decreased to a mean of 30.8 (+/-1.8) degrees post-operatively. At a mean follow-up of 2.5 years (+/ 0.5), the mean mHHS and IHOT scores were 79.5 (+/-20.2) and of 69.7 (+/-28.3), respectively. Increased preoperative (p = 0.02) and post-operative (p = 0.001) Tonnis Osteoarthritis Grade was associated with a lower mHHS. CONCLUSIONS: Patients with coxa profunda can achieve similar functional scores to more traditional FAI cohorts after arthroscopic treatment. Baseline osteoarthritis is predictive of lower hip function after hip arthroscopy. This study demonstrates that patients with global over-coverage can benefit from hip arthroscopy and may influence surgeons to treat these patients with less invasive arthroscopic techniques which avoid the morbidity of open surgical procedures. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 27506810 TI - Remaining mild varus limb alignment leads to better clinical outcome in total knee arthroplasty for varus osteoarthritis. AB - PURPOSE: Postoperative neutral limb alignment [femorotibial mechanical axis (FTMA) 180 degrees +/- 3 degrees ] is generally considered to be one of the prerequisites for successful total knee arthroplasty (TKA). However, the influence of residual malalignment on clinical and functional outcomes after TKA is unknown. Therefore, the purpose of this study was to investigate the relationship between postoperative limb alignment and clinical outcomes in Asian patients who underwent primary TKA. METHODS: The study included 220 knees with a mean age of 73.5 years who underwent primary TKA for varus-type osteoarthritis; the mean follow-up period was 3.6 years. Patients were divided into four groups based on postoperative FTMA: severe varus (FTMA < 174 degrees , n = 15), mild varus (FTMA >177 degrees and <=174 degrees , n = 61), neutral (FTMA 180 degrees +/- 3 degrees , n = 128), and valgus (FTMA > 183 degrees , n = 16). Knee Society Knee Score (KSKS) and Knee Society Functional Score (KSFS) were compared among the 4 groups. RESULTS: KSKS and KSFS showed significant improvement in all groups. There were no statistically significant differences for postoperative KSKS among the four groups. For KSFS, however, the severe varus and valgus groups exhibited significantly lower values compared with the mild varus and neutral groups. CONCLUSION: Postoperative mild varus alignment as well as neutral mechanical alignment of the lower limb led to excellent functional outcomes. For the clinical relevance, postoperative mild varus alignment of the lower limb is acceptable following TKA for varus-type osteoarthritis. LEVEL OF EVIDENCE: IV. PMID- 27506811 TI - Optimizing the process of fertility preservation in pediatric female cancer patients - a multidisciplinary program. AB - BACKGROUND: Current evidence indicates sub-optimal incidence of fertility preservation (FP) in eligible patients. We present herein our designated multidisciplinary program for FP in pediatric and adolescent population and present our data on FP in female patients. METHODS: Pediatric patients (age 0-18) who were candidate for highly gonadotoxic treatments were referred to FP program for a multidisciplinary discussion and gonadal risk-assessment followed by either oocyte cryopreservation or ovarian cryopreservation (OCP) for female patients, and sperm banking for male patients. The OCP protocol consists of aspiration of oocytes from small antral follicles and in-vitro maturation followed by cryopreservation, as well as ovarian tissue cryopreservation. RESULTS: The establishment of a designated FP program resulted in a significant increase in referral and subsequent FP procedures of all eligible patients. Sixty-two female patients were referred for FP discussion during a period of 36 months; 41 underwent OCP; 11 underwent oocyte cryopreservation and six were declined due to parental decision. The median age was 13.2y (range 18 months-18y). Thirty-two (51.6 %) were chemotherapy-naive. Seventeen patients (27 %) had sarcoma, 16 patients (26 %) had acute leukemia. The mean number of mature oocytes that were eventually vitrified was significantly higher in chemotherapy-naive patients compared with chemotherapy-exposed patients (mean 12 oocytes (1-42) versus 2 (0 7)). CONCLUSION: Multidisciplinary programs that encompass experts of all relevant fields, skilled laboratory resources and a facilitated path appear to maximize the yield. We observed a considerable higher referral rates following launching a designated program and earlier OCP in chemo-naive patients that culminated in a better fertility preservation procedure. PMID- 27506812 TI - Antibiotic dosing in obesity: a BIG challenge. PMID- 27506813 TI - Morphine enhances IL-1beta release through toll-like receptor 4-mediated endocytic pathway in microglia. AB - Morphine creates a neuroinflammatory response and enhances release of the proinflammatory cytokines like interleukin-1beta (IL-1beta), which compromises morphine analgesia as well as induces morphine tolerance. In this study, we attempted to investigate the mechanisms of morphine induced IL-1beta synthesis and release. Microglial cells were treated with morphine (100 MUM) once daily for 3 days. Control groups underwent the same procedure but received sterile saline injection instead of morphine. Toll-like receptor 4 (TLR4) and P2X4 receptor (P2X4R) signaling were analyzed using Western blot; immunofluorescence was used to detect the signaling of CD68; real-time RT-PCR and ELISA kit was used to measure the messenger RNA and protein synthesis and release level of IL-1beta. Morphine enhanced IL-1beta synthesis and P2X4R protein expression. TLR4 were responsible for morphine-induced IL-1beta synthesis, while morphine-induced IL 1beta release was via P2X4R. Morphine-induced IL-1beta release is mediated by endocytosis of TLR4. These results indicated that TLR4 and P2X4R pathways mediated IL-1beta synthesis and release in microglia followed chronic morphine. TLR4 internalization is the main mechanism of morphine-induced microglia activation and IL-1beta release. PMID- 27506814 TI - Computed tomography in the investigation and management of obturator hernia. AB - INTRODUCTION: Obturator hernias are a rare groin hernia. They are most commonly found incidentally during laparoscopic inguinal hernia repair. We investigated our experience with obturator hernias in the elective and emergency setting. METHODS: Cases of obturator hernia were identified from a hospital database and reviewed retrospectively over the last 10 years. There were no exclusions. There were a number of surgeons involved with an interest in groin hernia surgery. RESULTS: Twenty-one patients were included. The mean age was 66 years old. Eleven were male. There were four emergency presentations. One emergency case presented with small bowel obstruction, while the other three cases presented with groin pain. Two patients had a preoperative computed tomography, which showed an obturator hernia confirmed at surgery. The patient with small bowel obstruction had an open bowel resection alone with no hernia repair. They were discharged with no complications or recurrence on follow-up. The other three cases had a mesh repair (one laparoscopic, one laparotomy, one pre-peritoneal). One patient who underwent a laparotomy died of a post-operative pneumonia. The others were discharged uneventfully. In the elective group of 17 patients, 8 patients were taken for an elective laparoscopic inguinal hernia repair but found to actually have an obturator hernia alone. An obturator hernia was found incidentally with an inguinal hernia in three patients. Five patients were expected to have an obturator hernia on clinical examination alone. At surgery, an obturator hernia was found in three cases. In the other two cases, no hernia was found. One patient had a pre-operative computed tomography, which showed an obturator hernia confirmed at surgery. CONCLUSIONS: Computed tomography would be recommended in cases of diagnostic uncertainty. It may avoid unnecessary surgery in the elective setting and allow a focused procedure in the emergency setting. Laparoscopic repair is feasible in the emergency and elective setting with excellent results. PMID- 27506815 TI - Effective treatment of spasticity using dronabinol in pediatric palliative care. AB - BACKGROUND: Cannabis extracts have a wide therapeutic potential but in many countries they have not been approved for treatment in children so far. OBJECTIVE: We conducted an open, uncontrolled, retrospective study on the administration of dronabinol to determine the value, efficacy, and safety of cannabis-based medicines in the treatment of refractory spasticity in pediatric palliative care. DESIGN AND PARTICIPANTS: Sixteen children, adolescents and young adults having complex neurological conditions with spasticity (aged 1.3-26.6 years, median 12.7 years) were treated with dronabinol by our specialized pediatric palliative care team between 01.12.2010 and 30.04.2015 in a home-care setting. Therapeutic efficacy and side effects were closely monitored. RESULTS: Drops of the 2.5% oily tetrahydrocannabinol solution (dronabinol) were administered. A promising therapeutic effect was seen, mostly due to abolishment or marked improvement of severe, treatment resistant spasticity (n = 12). In two cases the effect could not be determined, two patients did not benefit. The median duration of treatment was 181 days (range 23-1429 days). Dosages to obtain a therapeutic effect varied from 0.08 to 1.0 mg/kg/d with a median of 0.33 mg/kg/d in patients with a documented therapeutic effect. When administered as an escalating dosage scheme, side effects were rare and only consisted in vomiting and restlessness (one patient each). No serious and enduring side effects occurred even in young children and/or over a longer period of time. CONCLUSIONS: In the majority of pediatric palliative patients the treatment with dronabinol showed promising effects in treatment resistant spasticity. PMID- 27506816 TI - Is genotyping of single isolates sufficient for population structure analysis of Pseudomonas aeruginosa in cystic fibrosis airways? AB - BACKGROUND: The primary cause of morbidity and mortality in cystic fibrosis (CF) patients is lung infection by Pseudomonas aeruginosa. Therefore much work has been done to understand the adaptation and evolution of P. aeruginosa in the CF lung. However, many of these studies have focused on longitudinally collected single isolates, and only few have included cross-sectional analyses of entire P. aeruginosa populations in sputum samples. To date only few studies have used the approach of metagenomic analysis for the purpose of investigating P. aeruginosa populations in CF airways. RESULTS: We analysed five metagenomes together with longitudinally collected single isolates from four recently chronically infected CF patients. With this approach we were able to link the clone type and the majority of SNP profiles of the single isolates to that of the metagenome(s) for each individual patient. CONCLUSION: Based on our analysis we find that when having access to comprehensive collections of longitudinal single isolates it is possible to rediscover the genotypes of the single isolates in the metagenomic samples. This suggests that information gained from genome sequencing of comprehensive collections of single isolates is satisfactory for many investigations of adaptation and evolution of P. aeruginosa to the CF airways. PMID- 27506818 TI - Slobodan Lang. PMID- 27506817 TI - Social Network Influence on HIV Testing Among Urban Men in Tanzania. AB - Men in sub-Saharan Africa have low HIV testing rates. Social networks exert an important influence on men's HIV-related behavior. We examined associations between network factors and HIV testing among men in Dar es Salaam, Tanzania. Data are from the baseline assessment of an HIV prevention trial with 48 primarily male networks. Among 923 sexually active men, 52 % had ever tested for HIV. In a random effects logistic regression model, men in the network core were 1.50 times more likely (p < .05) to test than those in the periphery. Percentage of women in the network was associated with men's increased HIV testing (AOR 4.24, p < .05). Perception of network HIV stigma was negatively associated with HIV testing (AOR 0.92, p < .01). Thinking at least one close friend tested for HIV was associated with increased testing (AOR 2.66, p < .001). Social network interventions are a promising approach for scaling up men's HIV testing. PMID- 27506820 TI - Incidence, Treatment Intensity, and Incremental Annual Expenditures for Patients Experiencing a Cardiac Implantable Electronic Device Infection: Evidence From a Large US Payer Database 1-Year Post Implantation. AB - BACKGROUND: Because of the increasing use of cardiac implantable electronic devices (CIEDs), it is important to estimate the incidence and annual healthcare expenditures associated with CIED infections. METHODS AND RESULTS: Patients with a record of an initial or replacement (full implant or generator only) CIED implant during the calendar years 2009 to 2012 in MarketScan Commercial Claims and Medicare Supplemental database were identified. CIED infections were classified into 4 categories: (1) infection not managed by inpatient admission nor implant removal, (2) infection managed by inpatient admission but no implant removal, (3) infection managed by an implant removal either in an inpatient or in an outpatient setting, and (4) infection with severe sepsis and managed in an inpatient setting with implant removal. Using separate models for initial and replacement cohorts, annualized incidence of infection and incremental annual expenditures by treatment intensity were estimated. Cumulative incidence of infection at 1 year post implant was 1.18% for initial CIED implants and 2.37% for replacement. Median time to infection was 35 days for initial and 23 days for replacement. Incremental healthcare expenditures by treatment intensity categories for initial implant patients at 1 year were $16 651, $104 077, $45 291, and $279 744. For replacement patients, incremental expenditures at 1 year by treatment intensity categories were $26 857, $43 541, $48 759, and $362 606. CONCLUSIONS: The management of CIED infections results in a substantial healthcare burden with a significant increase in annual expenditures the year after implant when device infection occurs. PMID- 27506819 TI - Association between perceived neighbourhood characteristics, physical activity and diet quality: results of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - BACKGROUND: The study explores associations between perceived neighbourhood characteristics, physical activity and diet quality, which in Latin America and Brazil have been scarcely studied and with inconsistent results. METHODS: We conducted a cross-sectional analysis of 14,749 individuals who participated in the Brazilian Longitudinal Study of Adult Health (Estudo Longitudinal de Saude do Adulto, ELSA-Brasil) baseline. The study included current and retired civil servants, aged between 35 and 74 years, from universities and research institutes in six Brazilian states. The International Physical Activity Questionnaire (IPAQ) long form was used to characterize physical activity during leisure time and commuting; additional questions assessed how often fruit and vegetables were consumed, as a proxy for diet quality. Neighbourhood characteristics were evaluated by the "Walking Environment" and "Availability of Healthy Foods" scales originally used in the Multi-Ethnic Study of Atherosclerosis (MESA). Associations were examined using multinomial logistic regression. RESULTS: Perceiving a more walkable neighbourhood was positively associated with engaging in leisure time physical activity and doing so for longer weekly. Compared with those who saw their neighbourhood as less walkable, those who perceived it as more walkable had 1.69 (95 % CI 1.57-1.83) and 1.39 (1.28-1.52) greater odds of engaging in leisure time physical activity for more than 150 min/week or up to 150 min/week (vs. none), respectively. Perceiving a more walkable neighbourhood was also positively associated with transport-related physical activity. The same pattern was observed for diet: compared with participants who perceived healthy foods as less available in their neighbourhood, those who saw them as more available had odds 1.48 greater (1.31-1.66) of eating fruits, and 1.47 greater (1.30-1.66) of eating vegetables, more than once per day. CONCLUSIONS: Perceived walkability and neighbourhood availability of healthy food were independently associated with the practice of physical activity and diet quality, respectively, underlining the importance of neighbourhood-level public policies to changing and maintaining health-related habits. PMID- 27506822 TI - Toward an absolute NMR shielding scale using the spin-rotation tensor within a relativistic framework. AB - One of the most influential articles showing the best way to get the absolute values of NMR magnetic shieldings, sigma (non-measurables) from both accurate measurements and theoretical calculations, was published a long time ago by Flygare. His model was shown to break down when heavy atoms are involved. This fact motivated the development of new theories of nuclear spin-rotation (SR) tensors, which consider electronic relativistic effects. One was published recently by some of us. In this article we take another step further and propose three different models that generalize Flygare's model. All of them are written using four-component relativistic expressions, though the two-component relativistic SO-S term also appears in one. The first clues for these developments were built from the relationship among sigma and the SR tensors within the two-component relativistic LRESC model. Besides, we had to introduce a few other well defined assumptions: (i) relativistic corrections must be included in a way to best reproduce the relationship among the (e-e) term (called "paramagnetic" within the non-relativistic domain) of sigma and its equivalent part of the SR tensor, (ii) as happens in Flygare's rule, the shielding of free atoms shall be included to improve accuracy. In the highest accurate model, a new term known as Spin-orbit due to spin, SO-S (in this mechanism the spin-Zeeman Hamiltonian replaces the orbital-Zeeman Hamiltonian), is included. We show the results of the application of those models to halogen containing linear molecules. PMID- 27506821 TI - Multicenter Experience With Catheter Ablation for Ventricular Tachycardia in Lamin A/C Cardiomyopathy. AB - BACKGROUND: Lamin A/C (LMNA) cardiomyopathy is a genetic disease with a proclivity for ventricular arrhythmias. We describe the multicenter experience with percutaneous catheter ablation of sustained monomorphic ventricular tachycardia (VT) in LMNA cardiomyopathy. METHODS AND RESULTS: Twenty-five consecutive LMNA mutation patients from 4 centers were included (mean age, 55+/-9 years; ejection fraction, 34+/-12%; VT storm in 36%). Complete atrioventricular block was present in 11 patients; 3 patients were on mechanical circulatory support for severe heart failure. A median of 3 VTs were inducible per patient; in 82%, mapping was consistent with origin from scar in the basal left ventricle, particularly the septum, but also basal inferior wall and subaortic mitral continuity. After multiple procedures (median 2/patient; transcoronary alcohol in 6 and surgical cryoablation in 2 patients), acute success (noninducibility of any VT) was achieved in only 25% of patients. Partial success (inducibility of a nonclinical VT only: 50%) and failure (persistent inducibility of clinical VT: 12.5%) was attributed to intramural septal substrate in 13 of 18 patients (72%). Complications occurred in 25% of patients. After a median follow-up of 7 months after the last procedure, 91% experienced >=1 VT recurrence, 44% received or were awaiting mechanical circulatory support or transplant for end-stage heart failure, and 26% died. CONCLUSIONS: Catheter ablation of VT associated with LMNA cardiomyopathy is associated with poor outcomes including high rate of arrhythmia recurrence, progression to end-stage heart failure, and high mortality. Basal septal scar and intramural VT origin makes VT ablation challenging in this population. PMID- 27506823 TI - Reversed-phase separation parameters for intact proteins using liquid chromatography with triple quadrupole mass spectrometry. AB - The separation of intact proteins is inherently more complex than that of small molecules using reversed-phase liquid chromatography. The goal of this work was to determine a reasonable set of operational parameters (a recommended starting point for other analysts) for the separation of intact proteins and their detection by triple quadrupole mass spectrometry. Although protein separations have been studied for many years, the direct detection of intact proteins with mass spectrometry requires special considerations of mobile phase additives to achieve efficient separation and sensitive detection. Myoglobin, cytochrome c, lactalbumin, lysozyme, and ubiquitin were used as model analytes to investigate chromatographic method development using a triple quadrupole mass spectrometer and detection by multiple reaction monitoring. Chromatographic parameters including the concentration of trifluoroacetic acid, flow rate, gradient slope, temperature, mobile phase composition, and stationary phase chemistry were evaluated. Protein charge state profiles were also monitored for temperature and modifier effects. An optimized method using 0.2 mL/min flow rate, 15% gradient slope, and 75 degrees C with a combined trifluoroacetic acid and formic acid modified mobile phase was developed. PMID- 27506824 TI - Litorisediminivivensgilvus gen. nov., sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, non-flagellated, aerobic and coccoid, ovoid or rod-shaped bacterium, designated YSM-17T, was isolated from tidal flat sediment collected from the South Sea, South Korea, and subjected to a polyphasic taxonomic study. The novel strain grew optimally at 30 degrees C, at pH 6.5-8.0 and in the presence of 2.0-3.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences showed that strain YSM-17T forms a distinct evolutionary lineage independent of other taxa in the family Rhodobacteraceae. Strain YSM-17T exhibited 16S rRNA gene sequence similarity values of 96.8 and 96.6 % to the type strains of Pseudopelagicola gijangensis and Pelagicola litoralis, respectively, and of less than 96.5 % to the type strains of other recognized taxa. Strain YSM 17T contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the major fatty acid. The major polar lipids detected in strain YSM-17T were phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and one unidentified aminolipid. The fatty acid and polar lipid profiles of strain YSM 17T were distinguished from those of the genera Pseudopelagicola and Pelagicola. The DNA G+C content of strain YSM-17T was 64.6+/-0.04 mol%. On the basis of the phylogenetic, chemotaxonomic and other phenotypic properties, strain YSM-17T is considered to represent a novel species of a new genus within the family Rhodobacteraceae, for which the name Litorisediminivivensgilvus gen. nov., sp. nov., is proposed. The type strain of Litorisediminivivensgilvus is YSM-17T (=KCTC 52249T=NBRC 112330T). PMID- 27506825 TI - Age and sex differences in immune response following LPS treatment in mice. AB - Puberty is an important developmental event that is marked by the reorganizing and remodeling of the brain. Exposure to stress during this critical period of development can have enduring effects on both reproductive and non-reproductive behaviors. The purpose of this study was to investigate age and sex differences in immune response by examining sickness behavior, body temperature changes, and serum cytokine levels following an immune challenge. The effects of circulating gonadal hormones on age and sex differences in immune response were also examined. Results showed that male mice display more sickness behavior and greater fluctuations in body temperature following LPS treatment than female mice. Moreover, adult male mice display more sickness behavior and a greater drop in body temperature following LPS treatment compared to pubertal male mice. Following gonadectomy, pubertal and adult males displayed steeper and prolonged drops in body temperature compared to sham-operated counterparts. Gonadectomy did not eliminate sex differences in LPS-induced body temperature changes, suggesting that additional factors contribute to the observed differences. LPS treatment increased cytokine levels in all mice. However, the increase in pro-inflammatory cytokines was higher in adult compared to pubertal mice, while the increase in anti-inflammatory cytokines was greater in pubertal than in adult mice. Our findings contribute to a better understanding of age and sex differences in acute immune response following LPS treatment and possible mechanisms involved in the enduring alterations in behavior and brain function following pubertal exposure to LPS. PMID- 27506826 TI - Erratum to: The short-term association of selected components of fine particulate matter and mortality in the Denver Aerosol Sources and Health (DASH) study. PMID- 27506827 TI - Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer. AB - Interleukin 12 (IL-12) is a powerful immunostimulatory cytokine with a strong antitumoural activity. In this work, the immunological, anti-angiogenic and clinical effects of three consecutive intratumoural IL-12 electrogene therapy (EGT) treatments were evaluated in nine dogs with spontaneous cancer. In all the dogs, tumour biopsies and blood samples were taken prior, during and after the intratumoural IL-12 EGT (on days 1, 8, 35 and 1, 3, 8, 15, 35, respectively). An initial decrease in immune cells was followed by an increase above baseline 1-3 weeks after treatment initiation. Interestingly, the decrease in peripheral leukocytes 2 days after the first intratumoural IL-12 EGT coincided with erythema and tumour swelling. Transient increases of IL-12 and interferon gamma were measured in the serum and the tumour tissue, whereas IL-10 transiently increased only in the serum. The effect of intratumoural IL-12 EGT on the levels of IL-24 and vascular endothelial growth factor in the sera and tumour biopsies differed per dog. Via contrast-enhanced ultrasound (US) (on days 1, 8 and 35), we demonstrated that intratumoural IL-12 EGT resulted in a significant decrease of the relative blood volume and blood flow speed in the tumour compared with baseline. Metastases were present in two dogs. In one of these dogs, IL-12 EGT of the primary tumour caused a transient partial regression of the metastases, but not of the primary tumour. The second dog with metastases did not survive long enough to complete the entire treatment cycle. Despite encouraging immunostimulatory and anti-angiogenic effects after intratumoural IL-12 EGT, no clinically relevant outcomes were observed in this study, as persistent tumour regression could not be obtained. On the other hand, the laboratory and US results hold great promise for combinatorial strategies of intratumoural IL-12 EGT with conventional antitumour (immuno)therapies. PMID- 27506828 TI - An unusual course of aortic arch through an accessory fissure of left upper lobe of the lung: extramediastinal aortic arch. AB - In this case report, we present an unexpected, extramediastinal course of aortic arch through an accessory fissure of left upper lobe of the lung in a 19-year-old healthy man. PMID- 27506830 TI - Structure and Modification of Electrode Materials for Protein Electrochemistry. AB - The interactions between proteins and electrode surfaces are of fundamental importance in bioelectrochemistry, including photobioelectrochemistry. In order to optimise the interaction between electrode and redox protein, either the electrode or the protein can be engineered, with the former being the most adopted approach. This tutorial review provides a basic description of the most commonly used electrode materials in bioelectrochemistry and discusses approaches to modify these surfaces. Carbon, gold and transparent electrodes (e.g. indium tin oxide) are covered, while approaches to form meso- and macroporous structured electrodes are also described. Electrode modifications include the chemical modification with (self-assembled) monolayers and the use of conducting polymers in which the protein is imbedded. The proteins themselves can either be in solution, electrostatically adsorbed on the surface or covalently bound to the electrode. Drawbacks and benefits of each material and its modifications are discussed. Where examples exist of applications in photobioelectrochemistry, these are highlighted. PMID- 27506829 TI - Visualization of the olfactory nerve using constructive interference in steady state magnetic resonance imaging. AB - PURPOSE: The olfactory nerve (OlfN) is a small neural structure with inconsistent visualization on neuroimages. The aim of this study was to delineate the intracranial course of the OlfN using constructive interference in steady state magnetic resonance (MR) imaging. METHODS: A total of 168 patients were enrolled in this study. Following initial examinations with conventional MR sequences, constructive interference in steady-state sequence (CISS) was performed in coronal and axial sections. RESULTS: On coronal sections, the OlfN was entirely visualized in 90 % of patients on the right and 92 % on the left, coursing along the olfactory sulcus. Complete visualization of the OlfN occurred in 100 % of patients on serial axial images. The OlfN was classified into four portions based on the topographical differences and surrounding structures. The olfactory fossa exhibited considerable variability at the midlevel of the olfactory bulb on coronal images. Characteristic appearance of the OlfN with respect to age range or gender was not observed. CONCLUSIONS: The OlfN follows a highly consistent course along the olfactory sulcus. Thin-sliced, CISS sequences are useful for consistent visualization of the OlfN. PMID- 27506831 TI - In Vitro-In Vivo Carcinogenicity. AB - The evaluation of the carcinogenic potential of chemicals constitutes an essential step in assessing the risk that the chemicals pose to human health. The "gold standard" method to evaluate the carcinogenic potential of chemicals is the carcinogenicity test in laboratory animals. However, because carcinogenicity studies in vivo are extremely time-consuming, expensive, make use of a high number of animals, and cannot be used to screen a high number of compounds at the same time, various different in vitro cell transformation assays have been developed. In this report, procedures to test the carcinogenicity in vivo and in vitro are described, whereby in the latter case three extensively evaluated test systems (the BALB/c 3T3 cell transformation assay, the Bhas 42 cell transformation assay, and the Syrian hamster embryo assay) are presented. Their performance shows that they are a useful complement to in vitro genotoxicity test batteries, can be used to identify non-genotoxic carcinogens, and as screening assays may significantly limit the number of chemicals to undergo an in vivo carcinogenicity testing, thereby strongly reducing the number of laboratory animals to be used. In the future, the development of human cell line-based transformation assays may contribute to increase further their relevance and the willingness to incorporate them into existing in vitro toxicity test batteries. PMID- 27506832 TI - Hazardous drinking among young adults seeking outpatient mental health services. AB - BACKGROUND: Alcohol use can have a significant negative impact on young adults in mental health treatment. This cross-sectional study examined prevalence and factors associated with hazardous drinking among young adults seeking outpatient mental health services, rate of alcohol use disorders (AUDs), and the relationship between hazardous drinking and other types of substance use. METHODS: Participants were 487 young adults ages 18-25 who completed self administered computerized screening questions for alcohol and drug use. Alcohol use patterns were assessed and predictors of hazardous drinking (>=5 drinks on one or more occasions in the past year) were identified using logistic regression. RESULTS: Of the 487 participants, 79.8 % endorsed prior-year alcohol use, 52.3 % reported one or more episodes of hazardous drinking in the prior year and 8.2 % were diagnosed with an AUD. Rates of recent and lifetime alcohol, tobacco and marijuana use were significantly greater in those with prior-year hazardous drinking. In logistic regression, prior-year hazardous drinking was associated with lifetime marijuana use (OR 3.30, p < 0.001; 95 % CI 2.05, 5.28), lifetime tobacco use (OR 1.88, p = 0.004; 95 % CI 1.22, 2.90) and older age (OR 1.18 per year, p < 0.001; 95 % CI 1.08, 1.29). CONCLUSIONS: In an outpatient mental health setting, high rates of hazardous drinking were identified, and drinking was associated with history of other substance use. Results highlight patient characteristics associated with hazardous drinking that mental health providers should be aware of in treating young adults, especially older age and greater use of tobacco and marijuana. PMID- 27506834 TI - Insights on stock structure of round sardinella Sardinella aurita off north-west Africa based on otolith shape analysis. AB - This study examines the geographic variability in otolith shape of round sardinella Sardinella aurita as a tool for stock discrimination. Fish were analysed from six sampling locations from Senegal to the Mediterranean coast of Morocco. A combination of otolith shape indices and elliptic Fourier descriptors was investigated by multivariate statistical procedures. Within the studied area, three distinct groups were identified with an overall correct classification of 78%. Group A: Nador (Alboran Sea), group B: Casablanca (northern Morocco) and group C: Senegalese-Mauritanian. The results of this study confirm the absence of an Atlantic Ocean-Mediterranean Sea transition for this species, the Gibraltar Strait acting as an efficient barrier for S. aurita population separation. Off north-west Africa, fish from northern Morocco form a single group which is clearly isolated from Senegalese-Mauritanian waters, confirming the existence of a distinct stock in this area. Among group C, some discontinuity exists and suggests the existence of a sedentary fraction of S. aurita in northern Mauritania (Arguin Bank). The results are discussed in relation to oceanographic features and physical barriers to dispersal and fish management strategy in the study area. PMID- 27506833 TI - Transcriptional analysis of the conidiation pattern shift of the entomopathogenic fungus Metarhizium acridum in response to different nutrients. AB - BACKGROUND: Most fungi, including entomopathogenic fungi, have two different conidiation patterns, normal and microcycle conidiation, under different culture conditions, eg, in media containing different nutrients. However, the mechanisms underlying the conidiation pattern shift are poorly understood. RESULTS: In this study, Metarhizium acridum undergoing microcycle conidiation on sucrose yeast extract agar (SYA) medium shifted to normal conidiation when the medium was supplemented with sucrose, nitrate, or phosphate. By linking changes in nutrients with the conidiation pattern shift and transcriptional changes, we obtained conidiation pattern shift libraries by Solexa/Illumina deep-sequencing technology. A comparative analysis demonstrated that the expression of 137 genes was up-regulated during the shift to normal conidiation, while the expression of 436 genes was up-regulated at the microcycle conidiation stage. A comparison of subtractive libraries revealed that 83, 216, and 168 genes were related to sucrose-induced, nitrate-induced, and phosphate-induced conidiation pattern shifts, respectively. The expression of 217 genes whose expression was specific to microcycle conidiation was further analyzed by the gene expression profiling via multigene concatemers method using mRNA isolated from M. acridum grown on SYA and the four normal conidiation media. The expression of 142 genes was confirmed to be up-regulated on standard SYA medium. Of these 142 genes, 101 encode hypothetical proteins or proteins of unknown function, and only 41 genes encode proteins with putative functions. Of these 41 genes, 18 are related to cell growth, 10 are related to cell proliferation, three are related to the cell cycle, three are related to cell differentiation, two are related to cell wall synthesis, two are related to cell division, and seven have other functions. These results indicate that the conidiation pattern shift in M. acridum mainly results from changes in cell growth and proliferation. CONCLUSIONS: The results indicate that M. acridum shifts conidiation pattern from microcycle conidiation to normal conidiation when there is increased sucrose, nitrate, or phosphate in the medium during microcycle conidiation. The regulation of conidiation patterning is a complex process involving the cell cycle and metabolism of M. acridum. This study provides essential information about the molecular mechanism of the induction of the conidiation pattern shift by single nutrients. PMID- 27506835 TI - Functional and structural brain connectivity of young binge drinkers: a follow-up study. AB - Adolescence is a period of ongoing brain maturation characterized by hierarchical changes in the functional and structural networks. For this reason, the young brain is particularly vulnerable to the toxic effects of alcohol. Nowadays, binge drinking is a pattern of alcohol consumption increasingly prevalent among adolescents. The aim of the present study is to evaluate the evolution of the functional and anatomical connectivity of the Default Mode Network (DMN) in young binge drinkers along two years. Magnetoencephalography signal during eyes closed resting state as well as Diffusion Tensor Imaging (DTI) were acquired twice within a 2-year interval from 39 undergraduate students (22 controls, 17 binge drinkers) with neither personal nor family history of alcoholism. The group comparison showed that, after maintaining a binge drinking pattern along at least two years, binge drinkers displayed an increased brain connectivity of the DMN in comparison with the control group. On the other hand, the structural connectivity did not show significant differences neither between groups nor over the time. These findings point out that a continued pattern of binge drinking leads to functional alterations in the normal brain maturation process, even before anatomical changes can be detected. PMID- 27506836 TI - Long-term Effects on Cognitive Trajectories of Postmenopausal Hormone Therapy in Two Age Groups. AB - Background: Postmenopausal hormone therapy may have long-term effects on cognitive function depending on women's age. Methods: Postintervention follow-up was conducted with annual cognitive assessments of two randomized controlled clinical trial cohorts, beginning an average of 6-7 years after study medications were terminated: 1,376 women who had enrolled in the Women's Health Initiative when aged 50-54 years and 2,880 who had enrolled when aged 65-79 years. Women had been randomly assigned to 0.625mg/d conjugated equine estrogens (CEE) for those with prior hysterectomy (mean 7.1 years), CEE with 2.5mg/d medroxyprogesterone acetate for those without prior hysterectomy (mean 5.4 years), or matching placebos. Results: Hormone therapy, when prescribed to women aged 50-54 years, had no significant long-term posttreatment effects on cognitive function and on changes in cognitive function. When prescribed to older women, it was associated with long-term mean (SE) relative decrements (standard deviation units) in global cognitive function of 0.081 (0.029), working memory of 0.070 (0.025), and executive function of 0.054 (0.023), all p < .05. These decrements were relatively stable over time. Findings did not vary depending on the hormone therapy regimen, prior use, or years from last menstrual period. Mean intervention effects were small; however, the largest were comparable in magnitude to those seen during the trial's active intervention phase. Conclusions: CEE-based hormone therapy delivered near the time of menopause provides neither cognitive benefit nor detriment. If administered in older women, it results in small decrements in several cognitive domains that remain for many years. PMID- 27506837 TI - Pneumonia hospitalisations in Scotland following the introduction of pneumococcal conjugate vaccination in young children. AB - BACKGROUND: Scotland introduced PCV7 and PCV13 immunisation in young children in 2006 and 2010 respectively. One recent study from the United States reported a decrease in hospitalisation rates for all-cause pneumonia most notably in adults older than 75 years of age following PCV7 introduction in the US child population. We aimed to examine the effect of PCV7 and PCV13 on hospitalisation rates for all-cause pneumonia across all age groups in Scotland. METHODS: We linked hospital records and death certification datasets for the entire Scottish population for the period 2000 to 2012. We included all cases where the primary / secondary diagnosis was pneumonia. Differences in hospital admission rates for pneumonia by age group were calculated using the difference in average annual rates for each period. RESULTS: We estimated that all-cause pneumonia hospitalisation rates in children <2 years decreased by about 30 % in the post PCV-13 period compared with the pre-PCV period. However, in adults aged 75-84 years and >=85 years, all-cause pneumonia hospitalisation rates increased by 63 and 46 % respectively in the post-PCV 13 period compared to the pre-PCV period. This resulted in an additional 7000 hospitalisations across all age groups in Scotland in 2012 about half of which were in adults >75 years. At the same time, the median length of hospital stay decreased by a third in children <2 years and by about 20 % in adults >75 years in the post-PCV13 period compared to the pre PCV period. Additionally, there was an 11 % reduction in deaths due to all-cause pneumonia, and 30 % reduction in pneumococcal hospitalisations across all age groups in the post-PCV13 period compared with pre-PCV period. DISCUSSION: The modest and sustained decline in the rates of hospitalisation for all-cause pneumonia in children and the reduction in proportion of pneumonia hospitalisations in children coded as pneumococcal disease in the post-PCV period should alleviate concerns that pneumococcal serotype replacement may have resulted in an increased pneumonia burden in this age group. The indirect impact of child PCV immunisation in those not vaccinated (in terms of reduction in all cause pneumonia hospitalisations in the elderly) has not been seen in Scotland. Our results are likely to be confounded by changes in clinical coding and healthcare practices over the same period. CONCLUSIONS: Our results illustrate that health care planners cannot, with confidence, predict indirect PCV vaccine impacts on hospitalisations. IPD surveillance across all age groups is needed to assess the indirect effects of PCV in the community. PMID- 27506839 TI - Hierarchical Mesoporous 3D Flower-like CuCo2O4/NF for High-Performance Electrochemical Energy Storage. AB - Ternary spinel CuCo2O4 nanostructure clenches great potential as high-performance electrode material for next-generation energy storage systems because of its higher electrical conductivity and electrochemical activity. Carbon free and binder free 3D flower-like CuCo2O4 structure are grown on nickel foam (NF) via a facile hydrothermal synthesis method followed by annealing. The obtained CuCo2O4/NF is directly used as electrode for lithium ion batteries (LIBs) and supercapacitors (SCs) application. The electrochemical study of 3D flower-like CuCo2O4 as an electrode for LIB and SC shows highly mesoporous unique architecture plays important role in achieving high capacity/capacitance with superior cycle life. The high surface area and mesoporous nature not only offer sufficient reaction sites, but also can accelerate the liquid electrolyte to penetrate electrode and the ions to reach the reacting sites. In outcome, it exhibits highest capacity of 1160 mA h g(-1) after 200 cycles when used as an anode for LIB and specific capacitance of 1002 F g(-1) after 3000 cycles. The superior electrochemical of synthesized material is attributed to direct contact of electrode active material with good intrinsic electrical conductivity to the underneath conductive NF substrate builds up an express path for fast ion and electron transfer. PMID- 27506838 TI - Writing of H3K4Me3 overcomes epigenetic silencing in a sustained but context dependent manner. AB - Histone modifications reflect gene activity, but the relationship between cause and consequence of transcriptional control is heavily debated. Recent developments in rewriting local histone codes of endogenous genes elucidated instructiveness of certain marks in regulating gene expression. Maintenance of such repressive epigenome editing is controversial, while stable reactivation is still largely unexplored. Here we demonstrate sustained gene re-expression using two types of engineered DNA-binding domains fused to a H3K4 methyltransferase. Local induction of H3K4me3 is sufficient to allow re-expression of silenced target genes in various cell types. Maintenance of the re-expression is achieved, but strongly depends on the chromatin microenvironment (that is, DNA methylation status). We further identify H3K79me to be essential in allowing stable gene re expression, confirming its role in epigenetic crosstalk for stable reactivation. Our approach uncovers potent epigenetic modifications to be directly written onto genomic loci to stably activate any given gene. PMID- 27506840 TI - [Revised WHO Classification of Tumours of the Central Nervous System:Summary of the Revision and Perspective]. PMID- 27506841 TI - [Diagnosis and Treatment of Osteoporotic Thoracolumbar Vertebral Fracture]. PMID- 27506842 TI - [Rapid 3-Dimensional Models of Cerebral Aneurysm for Emergency Surgical Clipping]. AB - We developed a method for manufacturing solid models of cerebral aneurysms, with a shorter printing time than that involved in conventional methods, using a compact 3D printer with acrylonitrile-butadiene-styrene(ABS)resin. We further investigated the application and utility of this printing system in emergency clipping surgery. A total of 16 patients diagnosed with acute subarachnoid hemorrhage resulting from cerebral aneurysm rupture were enrolled in the present study. Emergency clipping was performed on the day of hospitalization. Digital Imaging and Communication in Medicine(DICOM)data obtained from computed tomography angiography(CTA)scans were edited and converted to stereolithography(STL)file formats, followed by the production of 3D models of the cerebral aneurysm by using the 3D printer. The mean time from hospitalization to the commencement of surgery was 242 min, whereas the mean time required for manufacturing the 3D model was 67 min. The average cost of each 3D model was 194 Japanese Yen. The time required for manufacturing the 3D models shortened to approximately 1 hour with increasing experience of producing 3D models. Favorable impressions for the use of the 3D models in clipping were reported by almost all neurosurgeons included in this study. Although 3D printing is often considered to involve huge costs and long manufacturing time, the method used in the present study requires shorter time and lower costs than conventional methods for manufacturing 3D cerebral aneurysm models, thus making it suitable for use in emergency clipping. PMID- 27506843 TI - [Repeated Rupture of Bilateral Internal Carotid Artery Aneurysms in a Short Period in Association with Polyarteritis Nodosa:A Case Report]. AB - Cerebral involvement is rare in polyarteritis nodosa(PAN);furthermore, secondary intracranial hemorrhage due to cerebral aneurysm is extremely rare. We describe an unusual case of repeated subarachnoid hemorrhage(SAH)in a 64-year-old woman with a history of PAN. Initially, she developed severe headache(probable first SAH, day 0), and presented at our hospital with second severe headache with disturbed consciousness on day 6. Computed tomography(CT)revealed that SAH was mainly distributed in the right basal cistern and sylvian fissure(second SAH). Three aneurysms were detected using CT angiography on the bilateral internal carotid arteries. An intentionally delayed surgery was planned because of the high risk period of cerebral vasospasm and takotsubo cardiomyopathy. On day 15, she complained of headache and had a convulsion. CT revealed a third SAH in the left sylvian fissure;cerebral angiography revealed enlargement of the left internal carotid-posterior communicating artery(IC-PC)aneurysm. Coil embolization of the aneurysm was performed on day 16, and she was treated using prednisolone(20mg/day)for PAN. However, on day 20, the patient became comatose, and CT revealed a fourth SAH in the right sylvian fissure. Cerebral angiography revealed enlargement of the right IC-PC aneurysm. Clipping of the aneurysm was successfully performed in spite of ventricular dysfunction, and the dose of prednisolone was increased to 40mg/day. After treatment, the ventricular dysfunction gradually resolved. Cerebral aneurysms with PAN are candidates for intervention because of their strong tendency to rupture. In our case, takotsubo cardiomyopathy might have been associated with impairment of the coronary microcirculation due to PAN. We suggest that aggressive immunosuppressive treatment for PAN and curative treatments for cerebral aneurysms should be considered with careful radiological examination and follow-up monitoring. PMID- 27506844 TI - [Treatment of Non-Traumatic Spinal Epidural Hematoma:A Report of Five Cases and a Systematic Review of the Literature]. AB - Objective:Non-traumatic spinal epidural hematoma(SEH)is relatively rare. We report five cases of SEH, review the relevant literature, and discuss the current treatment strategies for non-traumatic SEH in Japan. Methods:Clinical data of cases with non-traumatic SEH treated at our institute from 2008 to 2015 were retrospectively analyzed. In addition, we identified the relevant literature using the Japan Medical Abstracts Society databases for peer-reviewed articles published from Jan 1, 1995 to Aug 31, 2015. The search terms "spinal", "epidural hematoma", and "non-traumatic OR spontaneous" were used. Treatment strategies were summarized according to the treatment criteria. Results:Five patients(1 man and 4 women;age, 59-86 years;mean age, 74 years)were treated for SEH. Hematomas were located in the cervical(n=1), cervicothoracic(n=2), thoracic(n=1), and thoracolumbar(n=1)regions. All patients suffered sudden neck and/or back pain followed by subsequent neurological deterioration. Four patients were under antithrombotic treatment, and underwent laminectomy and drainage of the hematoma due to severe and progressive neurological deficits. All patients demonstrated significant neurological recovery. Seventy-seven articles from domestic institutes and hospitals were identified. Their criteria for conservative and surgical treatments differed based on the time from the onset and severity. Conclusion:Five cases of non-traumatic SEH were treated successfully. Patients with moderate to severe neurological deficit need timely surgical management, while non-surgical treatment may be indicated in mild deficits. To standardize the optimal treatment for non-traumatic SEH, an appropriate assessment system incorporating the time from onset and severity of neurological impairment should be established. PMID- 27506845 TI - [A Surgical Case of Tuberculoma with Visual Disturbance]. AB - We herein report a surgical case of multiple cerebral calculi located within the chiasmatic cistern resulting in visual disturbance. A 61-year-old man experienced homonymous lower right quadrantanopsia a few years prior. Non-enhanced head CT revealed multiple calcified lesions of about 7-mm within the basal cistern. MRI showed the lesion compressing the left optic tract. We could not remove the entire lesion because of severe adhesion to the optic tract. A pathological test showed calcified lesions with lymphocyte infiltration. We diagnosed tuberculoma caused by tuberculous meningitis with degeneration of the calcified lesion because of a history of tuberculosis at a fetal age. After the surgery, the patient was discharged without improvement of the visual disturbance. PMID- 27506846 TI - [Intramedullary Abscess of the Cervical Spinal Cord Caused by Advanced Periodontitis:Case Report]. AB - We describe the case of a 60-year-old man with an intramedullary abscess of the cervical spinal cord caused by advanced periodontitis. He suddenly developed severe neck pain and rapidly progressive palsy of the left upper arm. T2-weighted sagittal magnetic resonance imaging(MRI)revealed a hyperintense area extending from C1 to C6. Gadolinium-enhanced T1-weighted MRI showed a ring-enhanced lesion at the C3-4 level that was hyperintense on diffusion-weighted MRI. The patient underwent drainage of the abscess through laminectomy. Cultures of the abscess contents revealed Fusobacterium nucleatum and Peptostreptococcus micros. Antibiotics administered to the patient to treat the infection with these anaerobic bacteria improved the neurological deficit eight weeks after surgery. The patient was also diagnosed with advanced periodontitis due to Fusobacterium nucleatum that might have caused the intramedullary abscess of the cervical spinal cord. PMID- 27506848 TI - [Update Knowledge for Brain Tumors(9)Peripheral Nerve Tumor]. PMID- 27506847 TI - [Radiation-Induced Malignant Peripheral Nerve Sheath Tumor of the High Cervical Spine]. AB - CASE: A 30-year-old woman presented with posterior cervical pain and left sided omalgia. The patient had a history of non-Hodgkin's lymphoma for which she had received prophylactic whole-brain irradiation(including at the upper cervical level)17 years previously. A magnetic resonance imaging(MRI)scan obtained 1 month previously showed an intradural extramedullary mass lesion at the left C1/2 level. We initially considered the tumor to be a benign schwannoma, but the patient subsequently developed left hemiparesis and was consequently admitted 2 days after her first visit. A second MRI scan showed that the tumor had progressed markedly. Hence, the patient underwent emergency surgical excision of the tumor. However, the tumor could only be partially removed because it had strongly adhered to the ventral aspect of the spinal cord. The tumor was pathologically diagnosed as a malignant peripheral nerve sheath tumor(MPNST). The residual tumor was subjected to local irradiation and surgery, but the treatment was unsuccessful, and the patient died on the 91st day of her illness. Conclusion:We report a case of radiation-induced high cervical MPNST arising from a benign schwannoma. All 9 previously reported cases of radiation induced spinal MPNST were reviewed. Intraspinal MPNST of the high cervical region are extremely rare and are associated with a very poor prognosis. The 5-year survival rate of such tumors is markedly worse than that of other types of MPNST, and no standard treatment has been established for this condition. PMID- 27506849 TI - SARAF modulates TRPC1, but not TRPC6, channel function in a STIM1-independent manner. AB - Canonical transient receptor potential-1 (TRPC1) is an almost ubiquitously expressed channel that plays a relevant role in cell function. As other TRPC members, TRPC1 forms receptor-operated cation channels that exhibit both STIM1 dependent and store-independent behaviour. The STIM1 inhibitor SARAF (for store operated Ca2+ entry (SOCE)-associated regulatory factor) modulates SOCE by interaction with the STIM1 region responsible for Orai1 activation (SOAR). Furthermore, SARAF modulates Ca2+ entry through the arachidonate-regulated Ca2+ (ARC) channels, consisting of Orai1 and Orai3 heteropentamers and plasma membrane resident STIM1. While a role for STIM1-Orai1-mediated signals has been demonstrated, the possible role of SARAF in TRPC1 function remains unknown. Here, we provide evidence for the interaction of SARAF with TRPC1, independently of STIM1 both in STIM1-deficient NG115-401L cells and SH-SY5Y cells endogenously expressing STIM1. Silencing of SARAF expression in STIM1-deficient cells demonstrated that SARAF plays a negative regulatory role in TRPC1-mediated Ca2+ entry. The interaction of SARAF with TRPC1 in STIM1-deficient cells, as well as with the TRPC1 pool not associated with STIM1 in STIM1-expressing cells was enhanced by stimulation with the physiological agonist ATP. In contrast with TRPC1, we found that the interaction between SARAF and TRPC6 was constitutive rather than inducible by agonist stimulation. Furthermore, we found that SARAF expression silencing was without effect on Ca2+ entry evoked by agonists in TRPC6 overexpressing cells, as well as in Ca2+ influx evoked by the TRPC6 activator Hyp9. These findings provide evidence for a new regulator of TRPC1 channel function and highlight the relevance of SARAF in intracellular Ca2+ homeostasis. PMID- 27506850 TI - Purely endoscopic resection of pineal region tumors using infratentorial supracerebellar approach: How I do it. AB - BACKGROUND: Infratentorial supracerebellar approach via microscope still has some limitations in resection of pineal region tumors. METHODS: The authors describe a purely endoscopic infratentorial supracerebellar approach for resection of pineal region tumors with matched air-driven arm and navigation. The lateral oblique position is adopted. The same bimanual microsurgical techniques are utilized in this endoscopic approach with panoramic view and satisfying comfort. CONCLUSIONS: Purely endoscopic resection of pineal region tumors using infratentorial supracerebellar approach is feasible. It may be considered as an alternative approach for certain pineal region tumors. PMID- 27506851 TI - Therapeutic Monoclonal Antibodies for the Treatment of Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is a disorder characterized by a complex chronic inflammatory response that is largely poorly responsive to treatment with corticosteroids. Consequently, there is a huge need to find effective anti-inflammatory agents for the treatment of patients with this disease. Inhibition of cytokines and chemokines or their receptors using monoclonal antibodies (mAbs) could be a potential strategy to treat the inflammatory component of COPD. In this article, we review the therapeutic potential of some of these mAbs; however, to date there has been little or no therapeutic effect of any mAb directed against cytokines or chemokines in patients with COPD. This may reflect the complexity of COPD in which there is no dominant role for any single cytokine or chemokine. It is also likely that since the umbrella term COPD covers many endotypes having different underlying mechanisms, mAbs directed towards specific cytokines or chemokines should be tested in restricted and focused populations. PMID- 27506853 TI - Mutuality, mobilization, and messaging for health promotion: Toward collective cultural change. PMID- 27506854 TI - The role of DOG1 immunohistochemistry in dermatopathology. AB - BACKGROUND: This study was designed to evaluate the immunoexpression of DOG1, a specific marker expressed in gastrointestinal stromal tumors, in normal skin tissues and cutaneous epithelial tumors. METHODS: DOG1 immunostaining extent, intensity and pattern were evaluated in 69 cutaneous apocrine/eccrine tumors, 11 sebaceous tumors, 46 follicular tumors, 52 keratinocytic tumors and perilesional normal tissues. RESULTS: In normal tissues, DOG1 was expressed strongly in the intercellular canaliculi of eccrine glands, moderately in the myoepithelial cells of mammary and anogenital mammary-like glands, and weakly or not at all in the periphery of sebaceous lobules and the lower layer of epidermis and follicular infundibulum. All apocrine-type cutaneous mixed tumors showed apical-luminal positivity for DOG1, and 4/9 of these tumors included intercellular canaliculi highlighted by DOG1 immunostaining. Other sweat gland tumors, including hidrocystadenoma, spiradenoma, cylindroma and apocrine carcinoma, also expressed DOG1 focally with an apical-luminal pattern. Although slight membranous positivity for DOG1 was observed in various tumor types, hidradenoma papilliferum exhibited diffuse membranous DOG1 staining in the myoepithelial cells. CONCLUSIONS: DOG1 is a novel marker for identifying intercellular canaliculi and is a potential immunomarker of myoepithelial cells specific to mammary glands, anogenital mammary-like glands and tumors originating therein. PMID- 27506852 TI - Tetravalent Dengue Vaccine: A Review in the Prevention of Dengue Disease. AB - Tetravalent, live-attenuated, dengue vaccine (Dengvaxia((r)); CYD-TDV) is the first vaccine approved for the prevention of dengue disease caused by dengue virus (DENV) serotypes 1-4 in individuals aged 9-45 or 9-60 years living in high dengue endemic areas. This narrative review discusses the immunogenicity, protective efficacy, reactogenicity and safety of CYD-TDV in the prevention of dengue disease. In Latin American and Asian phase 3 trials in children and adolescents (n > 30,000), the recommended three-dose CYD-TDV regimen was efficacious in preventing virologically-confirmed dengue (VCD) during the period from 28 days after the last dose (month 13) to month 25, meeting the primary endpoint criteria. Protective efficacy against VCD in the respective individual trials was 60.8 and 56.5 % (primary analysis). During the 25-month active surveillance phase, CYD-TDV also provided protective efficacy against VCD, severe dengue, any grade of dengue haemorrhagic fever and VCD-related hospitalization in children aged 9 years and older. CYD-TDV was generally well tolerated, with no safety concerns identified after up to 4 years' follow-up (i.e. from post dose 1) in ongoing long-term studies. Based on evidence from the dengue clinical trial program, the WHO SAGE recommended that countries with high dengue endemicity consider introducing CYD-TDV as part of an integrated disease prevention strategy to lower disease burden. Pharmacoeconomic considerations will be pivotal to implementing dengue vaccination prevention strategies in these countries. The availability of a dengue vaccine is considered essential if the 2012 WHO global strategy targets for reducing the burden of dengue disease by 2020 are to be attained. Hence, CYD-TDV represents a major advance for the prevention of dengue disease in high dengue endemic regions. PMID- 27506855 TI - Enemies with benefits: parasitic endoliths protect mussels against heat stress. AB - Positive and negative aspects of species interactions can be context dependant and strongly affected by environmental conditions. We tested the hypothesis that, during periods of intense heat stress, parasitic phototrophic endoliths that fatally degrade mollusc shells can benefit their mussel hosts. Endolithic infestation significantly reduced body temperatures of sun-exposed mussels and, during unusually extreme heat stress, parasitised individuals suffered lower mortality rates than non-parasitised hosts. This beneficial effect was related to the white discolouration caused by the excavation activity of endoliths. Under climate warming, species relationships may be drastically realigned and conditional benefits of phototrophic endolithic parasites may become more important than the costs of infestation. PMID- 27506857 TI - Prognostic factors of status epilepticus in adults. AB - AIM: Status epilepticus (SE) can lead to sequelae or even death. Identifying characteristics associated with poor outcome is crucial in guiding patient treatment. Based on our retrospective patient cohorts, potential prognostic factors were analysed. METHODS: Patients consecutively treated for refractory convulsive status epilepticus (CSE) between 2001 and 2010 and non-convulsive status epilepticus (NCSE) between 2004 and 2009 were studied. Outcome was compared to prognostic variables. Index SE episodes were used for the statistical analyses. Crosstabs and independent samples t-test were applied. Due to sample size, logistic regression was performed for the combined groups. RESULTS: In total, 50% (9/18) of index refractory CSE and 42% (16/38) of index NCSE episodes led to sequelae. Refractory CSE requiring narcosis for >20 hours was associated with poor outcome (p=0.05). De novo presentation (p=0.0001), long-lasting SE (>2 hours) (p=0.014), age >65 years (p=0.002), and refractory SE (p=0.047) were predictors of poor outcome following NCSE. Based on logistic regression for combined refractory CSE and NCSE, de novo presentation was identified as the strongest predictor of sequelae. CONCLUSIONS: Older age and de novo SE are predictors of sequelae following NCSE. Prolonged SE is a risk factor for poor outcome, both for refractory CSE and NCSE. Aggressive initial treatment to terminate seizures during the early phase is therefore essential. PMID- 27506856 TI - Marine and giant viruses as indicators of a marine microbial community in a riverine system. AB - Viral communities are important for ecosystem function as they are involved in critical biogeochemical cycles and controlling host abundance. This study investigates riverine viral communities around a small rural town that influences local water inputs. Myoviridae, Siphoviridae, Phycodnaviridae, Mimiviridae, Herpesviridae, and Podoviridae were the most abundant families. Viral species upstream and downstream of the town were similar, with Synechoccocus phage, salinus, Prochlorococcus phage, Mimivirus A, and Human herpes 6A virus most abundant, contributing to 4.9-38.2% of average abundance within the metagenomic profiles, with Synechococcus and Prochlorococcus present in metagenomes as the expected hosts for the phage. Overall, the majority of abundant viral species were or were most similar to those of marine origin. At over 60 km to the river mouth, the presence of marine communities provides some support for the Baas Becking hypothesis "everything is everywhere, but, the environment selects." We conclude marine microbial species may occur more frequently in freshwater systems than previously assumed, and hence may play important roles in some freshwater ecosystems within tens to a hundred kilometers from the sea. PMID- 27506858 TI - Can knowledge-based N management produce more staple grain with lower greenhouse gas emission and reactive nitrogen pollution? A meta-analysis. AB - Knowledge-based nitrogen (N) management, which is designed for a better synchronization of crop N demand with N supply, is critical for global food security and environmental sustainability. Yet, a comprehensive assessment on how these N management practices affect food production, greenhouse gas emission (GHG), and N pollution in China is lacking. We compiled the results of 376 studies (1166 observations) to evaluate the overall effects of seven knowledge based N management practices on crop productivity, nitrous oxide (N2 O) emission, and major reactive N (Nr) losses (ammonia, NH3 ; N leaching and runoff), for staple grain (rice, wheat, and corn) production in China. These practices included the application of controlled-release N fertilizer, nitrification inhibitor (NI) and urease inhibitor (UI), higher splitting frequency of fertilizer N application, lower basal N fertilizer (BF) proportion, deep placement of N fertilizer, and optimal N rate based on soil N test. Our results showed that, compared to traditional N management, these knowledge-based N practices significantly increased grain yields by 1.3-10.0%, which is attributed to the higher aboveground N uptake (5.1-12.1%) and N use efficiency in grain (8.0 48.2%). Moreover, these N management practices overall reduced GHG emission and Nr losses, by 5.4-39.8% for N2 O emission, 30.7-61.5% for NH3 emission (except for the NI application), 13.6-37.3% for N leaching, and 15.5-45.0% for N runoff. The use of NI increased NH3 emission by 27.5% (9.0-56.0%), which deserves extra attention. The cost and benefit analysis indicated that the yield profit of these N management practices exceeded the corresponding input cost, which resulted in a significant increase of the net economic benefit by 2.9-12.6%. These results suggest that knowledge-based N management practice can be considered an effective way to ensure food security and improve environmental sustainability, while increasing economic return. PMID- 27506859 TI - Discussion. PMID- 27506860 TI - Rural risk: Geographic disparities in trauma mortality. AB - BACKGROUND: Barriers to trauma care for rural populations are well documented, but little is known about the magnitude of urban-rural disparities in injury mortality. This study sought to quantify differences in injury mortality comparing rural and nonrural residents with traumatic injuries. METHODS: Using data from the 2009-2010 Nationwide Emergency Department Sample, multiple logistic regression analyses were conducted to estimate odds of death after traumatic injury for rural residents compared with nonrural residents, while controlling for age, sex, injury type and severity, comorbidities, trauma designation, and Census region. RESULTS: Rural residents were 14% more likely to die after traumatic injury compared with nonrural residents (P < .001). Increased odds of death for rural residents were observed at level I (odds ratio = 1.20, P < .001), level II (odds ratio = 1.34, P < .001), and level IV/nontrauma centers (odds ratio = 1.23, P < .001). The disparity was greatest for injuries occurring in the South and Midwest (odds ratio = 1.54, P < .001 and odds ratio = 2.06, P < .001, respectively) and for cases with an injury severity score <9 or unknown severity (odds ratio = 2.09, P < .001 and odds ratio = 1.31, P < .001, respectively). CONCLUSION: Rural residents are significantly more likely than nonrural residents to die after traumatic injury. This disparity varies by trauma center designation, injury severity, and US Census region. Distance and time to treatment likely play a role in rural injury outcomes, along with regional differences in prehospital care and trauma system organization. PMID- 27506861 TI - An unusual, life-threatening camel bite to the abdomen of a young man. PMID- 27506862 TI - Discussion. PMID- 27506864 TI - Discussion. PMID- 27506863 TI - Comparative characteristics of primary hyperparathyroidism in pediatric and young adult patients. AB - BACKGROUND: Primary hyperparathyroidism is rare in pediatric patients. Our study aim was to compare primary hyperparathyroidism in pediatric (<19 years) and young adult (19-29 years) patients. METHODS: A prospectively collected database from a single, high-volume institution was queried for all patients age <30 years who had initial parathyroidectomy for primary hyperparathyroidism yielding 126/4,546 (2.7%) primary hyperparathyroidism patients representing 39 pediatric and 87 young adult patients. Presenting symptoms, operative data, and postoperative course were compared for patients age 0-19 years and 20-29 years. RESULTS: Sporadic primary hyperparathyroidism was present in 81.7% and occurred less often in pediatric patients than young adult patients (74.4% vs 86.2%, P = .12). Among patients with hereditary primary hyperparathyroidism, multiple endocrine neoplasia type 1 was the most common type. Multiglandular disease was common in both pediatric (30.7%) and young adult (21.8%) patients. Following parathyroidectomy, 3 (2.3%) patients had permanent hypoparathyroidism and none had permanent recurrent laryngeal nerve paralysis. Biochemical cure at 6 months was equally likely in pediatric and young adult patients (97.1% vs 93.6%, P = .44) with comparable follow-up (78.4 months vs 69.1 months, P = .66) and rates of recurrent disease (5.9% vs 10.3%, P = .46). Recurrence was due to multiple endocrine neoplasia 1-related primary hyperparathyroidism in all cases. CONCLUSION: Although primary hyperparathyroidism is sporadic in most patients <19 years, they are more likely to have multiple endocrine neoplasia type 1 associated primary hyperparathyroidism (23%). Parathyroidectomy for primary hyperparathyroidism can be performed safely in pediatric patients with a high rate of cure. Follow-up for patients with hereditary disease is necessary. PMID- 27506865 TI - MiR-30c-2* negative regulated MTA-1 expression involved in metastasis and drug resistance of HPV-infected non-small cell lung cancer. AB - BACKGROUND: MiR-30c-2* is considered to be a tumor suppressor microRNA in various cancers and is associated with gemcitabine sensitivity of lung cancer cells. Downregulation of miR-30c-2* promotes tumor invasion via increased expression of metastasis-associated protein-1. We hypothesized that downregulated expression of miR-30c-2* was involved in human papillomavirus-associated lung tumorigenesis and drug resistance. METHODS: We examined whether expression of human papillomavirus 16/18 oncoprotein and miR-30c-2*-associated genes could be linked to patient outcome by collecting 319 lung tumors from patients with non-small cell lung cancer to determine expression of human papillomavirus 16/18 E6 protein, miR-30c 2*, and miR-30c-2* downstream metastasis-associated protein-1 mRNA by immunohistochemical and real-time polymerase chain reaction analysis. RESULTS: Our results showed that miR-30C-2* levels were increased 45-fold in the E6 knockdown TL-1 cells when compared with levels in the parental cells. More interestingly, metastasis-associated protein-1 expression correlated negatively with miR-30C-2* and positively with human papillomavirus 16 E6 protein expression in lung tumors from lung cancer patients. Metastasis-associated protein-1 expression levels in the tumor tissues correlated positively with tumor stage and nodal metastasis. Patients with high metastasis-associated protein-1 expression, and especially patients infected with human papillomavirus, experienced a poor clinical outcome, tumor recurrence, and a poor therapeutic response compared with those with low metastasis-associated protein-1 expression. CONCLUSION: These results showed that miR-30C-2* and levels of downstream metastasis-associated protein-1 gene expression in the tumor tissues of patients could be useful in predicting clinical outcome and therapeutic response and in selecting useful therapeutic drugs for lung cancer patients, especially patients with human papillomavirus infection. PMID- 27506866 TI - Live tissue versus simulation training for emergency procedures: Is simulation ready to replace live tissue? AB - BACKGROUND: Training of emergency procedures is challenging and application is not routine in all health care settings. The debate over simulation as an alternative to live tissue training continues with legislation before Congress to banish live tissue training in the Department of Defense. Little evidence exists to objectify best practice. We sought to evaluate live tissue and simulation based training practices in 12 life-saving emergency procedures. METHODS: In the study, 742 subjects were randomized to live tissue or simulation-training. Assessments of self-efficacy, cognitive knowledge, and psychomotor performance were completed pre- and post-training. Affective response to training was assessed through electrodermal activity. Subject matter experts gap analysis of live tissue versus simulation completed the data set. RESULTS: Subjects demonstrated pre- to post-training gains in self-efficacy, cognitive knowledge, psychomotor performance, and affective response regardless of training modality (P < .01 each). With the exception of fluid resuscitation in the psychomotor performance domain, no statistically significant differences were observed based on training modality in the overall group. Risk estimates on the least pretest performance subgroup favored simulation in 7 procedures. Affective response was greatest in live tissue training (P < .01) and varied by species and model. Subject matter experts noted significant value in live tissue in 7 procedures. Gap analysis noted shortcomings in all models and synergy between models. CONCLUSION: Although simulation has made significant gains, no single modality can be identified definitively as superior. Wholesale abandonment of live tissue training is not warranted. We maintain that combined live tissue and simulation based training add value and should be continued. Congressional mandates may accelerate simulation development and improve performance. PMID- 27506867 TI - Fifteen-year experience with renal cell carcinoma with associated venous tumor thrombus. AB - BACKGROUND: For patients with renal cell carcinoma with venous tumor thrombus (VTT), the importance of the extent of the VTT on survival has inconsistent published results. The aim of the study was to evaluate the prognostic value of the VTT on morbidity and mortality of our patients with renal cell carcinoma. METHODS: This was a single institution review of all patients who underwent resection of renal cell carcinoma with VTT over a 15-year period. RESULTS: Thirty seven patients (26 men, 11 women) with a mean age of 61 years were analyzed. The majority of the cohort were of Neves level II (n = 19), while 8 were of Neves 0 (only renal vein) or I, and 10 were of Neves III (extending into retrohepatic cava) or IV (extending supradiaphragmatically). When compared with Neves 0-II patients, there were more Neves III-IV patients with operative time >3 hours (70% vs 30%), blood loss >2,000 mL (70% vs 33%), and intensive care unit stay longer than one day (60% vs 30%) (P <= .05 each). Mean follow-up was 58 months. The overall 5-year survival was 71%, and all 10 patients with Neves III-IV had survived since the operation. CONCLUSION: We found advanced tumor thrombus involvement did not impact long-term survival; however, cases with suprahepatic VTT had increased operative time, blood loss, and duration of hospital stay. PMID- 27506868 TI - Leptospirosis Presenting with Rapidly Progressing Acute Renal Failure and Conjugated Hyperbilirubinemia: A Case Report. AB - BACKGROUND Unexplained renal insufficiency combined with hepatic failure is a common problem encountered by clinicians. As with many disease processes involving multi-organ systems, reversible causes are usually not readily identifiable, and for many patients their health deteriorates rapidly. We present a rare cause of acute renal failure and hyperbilirubinemia occurring simultaneously, with leptospirosis presenting as Weil's disease. CASE REPORT A 53 year-old male presented to our clinic with complaints of anuria over the past two days. His symptoms started with dark urine, severe cramps in the thighs, and chills. The patient was a visitor to the United States from Guyana. Positive physical examination findings included mild tachycardia and hypotension, scleral icterus, and tenderness over abdomen, costovertebral angles, and thighs. The patient had a high white blood cell count, thrombocytopenia, renal/hepatic insufficiency, and an urinary tract infection (UTI). The patient was initially treated under the suspicion of acute kidney injury secondary to rhabdomyolysis and pyelonephritis. The patient continued to deteriorate with decreasing platelet counts, worsening renal function, hyperbilirubinemia, and respiratory distress, with no improvement with hemodialysis. Broad-spectrum antibiotics were administered, including doxycycline, due to a high suspicion of leptospirosis. The patient's condition drastically improved after initiation of doxycycline. On subsequent days, the patient's Leptospira antibody results were available, showing titers of more than 1:3200. Hemodialysis was discontinued as the patient started producing urine with improved kidney function. CONCLUSIONS As world travel becomes more economically feasible, we will continue to encounter foreign endemic diseases. Leptospirosis presenting as Weil's disease is a common cause of renal and hyperbilirubinemia in endemic areas. Often, as was the case for our patient where the time from presentation to acute respiratory distress syndrome (ARDS) was 72 hours, the diagnosis evolves over the course of several days. Antibody testing often takes time and delays in treatment can cause rapid clinical deterioration. In such cases, we recommend beginning empiric treatment before confirmation of laboratory tests. PMID- 27506869 TI - Analysis of the efficiency of recombinant Escherichia coli strain cultivation in a gas-vortex bioreactor. AB - The levels of aeration and mass transfer are critical parameters required for an efficient aerobic bioprocess, and directly depend on the design features of exploited bioreactors. A novel apparatus, using gas vortex for aeration and mass transfer processes, was constructed in the Center of Vortex Technologies (Novosibirsk, Russia). In this paper, we compared the efficiency of recombinant Escherichia coli strain cultivation using novel gas-vortex technology with conventional bioprocess technologies such as shake flasks and bioreactors with mechanical stirrers. We demonstrated that the system of aeration and agitation used in gas-vortex bioreactors provides 3.6 times higher volumetric oxygen transfer coefficient in comparison with mechanical bioreactor. The use of gas vortex bioreactor for recombinant E. coli strain cultivation allows to increase the efficiency of target protein expression at 2.2 times for BL21(DE3)/pFK2 strain and at 3.5 times for auxotrophic C600/pRT strain (in comparison with stirred bioreactor). PMID- 27506870 TI - Introduction: Metal Hydrides. PMID- 27506871 TI - Multi-target therapeutics for neuropsychiatric and neurodegenerative disorders. AB - Historically, neuropsychiatric and neurodegenerative disease treatments focused on the 'magic bullet' concept; however multi-targeted strategies are increasingly attractive gauging from the escalating research in this area. Because these diseases are typically co-morbid, multi-targeted drugs capable of interacting with multiple targets will expand treatment to the co-morbid disease condition. Despite their theoretical efficacy, there are significant impediments to clinical success (e.g., difficulty titrating individual aspects of the drug and inconclusive pathophysiological mechanisms). The new and revised diagnostic frameworks along with studies detailing the endophenotypic characteristics of the diseases promise to provide the foundation for the circumvention of these impediments. This review serves to evaluate the various marketed and nonmarketed multi-targeted drugs with particular emphasis on their design strategy. PMID- 27506872 TI - Recent advances in cancer drug discovery targeting RAS. AB - Mutated RAS is present in 30% of human tumors, appearing in 90% of pancreatic, 45% of colon and 35% of lung cancers. These high occurrences make RAS one of the most important drug targets in oncology. Three decades of effort to target RAS have been unsuccessful in generating drug therapies suggesting that it might represent an 'undruggable' target. However, recent reports highlighting new approaches for targeting RAS have uncovered more information on protein structure and identified new binding pockets. Efforts to target the KRAS G12C mutation specifically have shown promising results whereas other approaches have targeted various protein complexes. These advances could lead to development of new effective cancer drugs targeting RAS. PMID- 27506873 TI - Structural features of subtype-selective EP receptor modulators. AB - Prostaglandin E2 is a potent endogenous molecule that binds to four different G protein-coupled receptors: EP1-4. Each of these receptors is a valuable drug target, with distinct tissue localisation and signalling pathways. We review the structural features of EP modulators required for subtype-selective activity, as well as the structural requirements for improved pharmacokinetic parameters. Novel EP receptor subtype selective agonists and antagonists appear to be valuable drug candidates in the therapy of many pathophysiological states, including ulcerative colitis, glaucoma, bone healing, B cell lymphoma, neurological diseases, among others, which have been studied in vitro, in vivo and in early phase clinical trials. PMID- 27506874 TI - Predisposing factors, pathogenesis and therapeutic intervention of Kawasaki disease. AB - Kawasaki disease (KD) is an acute febrile childhood inflammatory disease, associated with coronary artery abnormalities. The disease is believed to result from an aberrant inflammatory response to an infectious trigger in a genetically predisposed individual. KD is associated with an endothelial cell injury as a consequence of T cell activation and cytotoxic effects of various proinflammatory cytokines. Intravenous immunoglobulin (IVIG) infusion and aspirin are the standard treatment of acute KD. However, 10-20% of patients show resistance to IVIG therapy and present higher risk of coronary vasculitis. The relative roles of second IVIG infusion, corticosteroids, calcineurin inhibitors, interleukin-1 antagonists and anti-tumor necrosis factor agents remain uncertain. In this review, we highlight the predisposing factors, pathogenesis and therapeutic intervention of KD, particularly new therapeutics for IVIG-resistant patients. PMID- 27506875 TI - Unprecedented Disease-Related Coral Mortality in Southeastern Florida. AB - Anomalously high water temperatures, associated with climate change, are increasing the global prevalence of coral bleaching, coral diseases, and coral mortality events. Coral bleaching and disease outbreaks are often inter-related phenomena, since many coral diseases are a consequence of opportunistic pathogens that further compromise thermally stressed colonies. Yet, most coral diseases have low prevalence (<5%), and are not considered contagious. By contrast, we document the impact of an extremely high-prevalence outbreak (61%) of white plague disease at 14 sites off southeastern Florida. White-plague disease was observed near Virginia Key, Florida, in September 2014, and after 12 months had spread 100 km north and 30 km south. The disease outbreak directly followed a high temperature coral-bleaching event and affected at least 13 coral species. Eusmilia fastigiata, Meandrina meandrites, and Dichocoenia stokesi were the most heavily impacted coral species, and were reduced to <3% of their initial population densities. A number of other coral species, including Colpophyllia natans, Pseudodiploria strigosa, Diploria labyrinthiformis, and Orbicella annularis were reduced to <25% of their initial densities. The high prevalence of disease, the number of susceptible species, and the high mortality of corals affected suggests this disease outbreak is arguably one of the most lethal ever recorded on a contemporary coral reef. PMID- 27506876 TI - NanoSIMS chemical imaging combined with correlative microscopy for biological sample analysis. AB - Nano-scale Secondary Ion Mass Spectrometry (NanoSIMS) is one of the most powerful in situ elemental and isotopic analysis techniques available to biologists. The combination of stable isotope probing with NanoSIMS (nanoSIP) has opened up new avenues for biological studies over the past decade. However, due to limitations inherent with any analytical methodology, additional information from correlative techniques is usually required to address real biological questions. Here we review recent developments in correlative analysis applied to complex biological systems: first, high-resolution tracking of molecules (e.g. peptides, lipids) by correlation with electron microscopy and atomic force microscopy; second, identification of a specific microbial taxon with fluorescence in situ hybridization and quantification of its metabolic capacities; and, third, molecular specific imaging with new probes. PMID- 27506879 TI - N-Hydroxyphthalimide: a new photoredox catalyst for [4+1] radical cyclization of N-methylanilines with isocyanides. AB - The first utilization of N-hydroxyphthalimide (NHPI) as an organophotoredox catalyst is demonstrated by the [4+1] radical cyclization reaction of N methylanilines with isocyanides. The protocol offers an operationally simple one pot synthesis of 3-iminodihydroindoles at room temperature. PMID- 27506878 TI - Association between angiotensin converting enzyme gene insertion/deletion polymorphism and renal scar risk in children vesicoureteral reflex: a reappraise meta-analysis. AB - Vesicoureteral reflex(VUR) is a common disease in children. Some studies indicated that the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism associated with the renal scar in VUR, but not all researchers agreed with it. To clarify the effect of ACE I/D polymorphism on renal scar risk in children with VUR, we performed the present meta-analysis. PubMed, CNKI, CBM, and Embase databases were searched for studies that examined the relationship between ACE I/D polymorphism and renal scar risk in children with VUR. The Stata 12.0 software was used for statistical analyses. 11 case-control studies with 1,032 VUR patients were analyzed. The results showed that the DD genotype and D allele were associated with renal scar risk in overall VUR patients, DD vs. DI + II: OR = 1.61, 95% CI = 1.04-2.49, P = 0.03; DD vs. II: OR = 1.78, 95% CI = 1.20 2.65, P < 0.01; D vs. I: OR = 1.38, 95% CI = 1.02-1.86, P = 0.04. Similar results were revealed in Turks, but not in Caucasians and Asians. Our meta-analysis indicated that the ACE DD genotype may increase the risk of renal scar in children with VUR. PMID- 27506880 TI - Epicardial Adipose Tissue Contributes to the Development of Non-Calcified Coronary Plaque: A 5-Year Computed Tomography Follow-up Study. AB - AIM: Epicardial adipose tissue (EAT) has been suggested as a contributing factor for coronary atherosclerosis based on the previous cross-sectional studies and pathophysiologic background. However, a causal relationship between EAT and the development of non-calcified coronary plaque (NCP) has not been investigated. METHODS: A total of 122 asymptomatic individuals (age, 56.0+/-7.6 years; male, 80.3%) without prior history of coronary artery disease (CAD) or metabolic syndrome and without NCP or obstructive CAD at baseline cardiac computed tomography (CT) were enrolled. Repeat cardiac CT was performed with an interval of more than 5 years. Epicardial fat volume index (EFVi; cm3/m2) was assessed in relation to the development of NCP on the follow-up CT where the results were classified into "calcified plaque (CP)," "no plaque," and "NCP" groups. RESULTS: On the follow-up CT performed with a median interval of 65.4 months, we observed newly developed NCP in 24 (19.7%) participants. Baseline EFVi was significantly higher in the NCP group (79.9+/-30.3 cm3/m2) than in the CP group (63.7+/-22.7 cm3/m2; P=0.019) and in the no plaque group (62.5+/-24.7 cm3/m2; P=0.021). Multivariable logistic regression analysis demonstrated that the presence of diabetes (OR, 9.081; 95% CI, 1.682-49.034; P=0.010) and the 3rd tertile of EFVi (OR, 4.297; 95% CI, 1.040-17.757; P=0.044 compared to the 1st tertile) were the significant predictors for the development of NCP on follow-up CT. CONCLUSIONS: Greater amount of EAT at baseline CT independently predicts the development of NCP in asymptomatic individuals. PMID- 27506881 TI - The plasma membrane monoamine transporter (PMAT): Structure, function, and role in organic cation disposition. AB - Plasma membrane monoamine transporter (PMAT) is a new polyspecific organic cation transporter that transports a variety of biogenic amines and xenobiotic cations. Highly expressed in the brain, PMAT represents a major uptake2 transporter for monoamine neurotransmitters. At the blood-cerebrospinal fluid (CSF) barrier, PMAT is the principal organic cation transporter for removing neurotoxins and drugs from the CSF. Here I summarize our latest understanding of PMAT and its roles in monoamine uptake and xenobiotic disposition. PMID- 27506884 TI - Adult Neurology Training Schedule is Important, Not Just the Length. PMID- 27506882 TI - Serum Autotaxin is a Marker of the Severity of Liver Injury and Overall Survival in Patients with Cholestatic Liver Diseases. AB - Autotaxin (ATX) is involved in the synthesis of lysophosphatidic acid. Both have recently been linked to cholestatic pruritus and liver injury. We aimed to investigate whether ATX is an indicator of cholestatic liver injury, health related quality of life (HRQoL) and prognosis based on a group of 233 patients, 118 with primary biliary cholangitis (PBC) and 115 with primary sclerosing cholangitis (PSC). Patients were followed for 1-60 months, cumulative survival rates were calculated. ATX activity was significantly higher in both groups than in the 103 controls, particularly in patients with cirrhosis and in patients with longer disease duration. Ursodeoxycholic acid (UDCA) non-responders with PBC exhibited increased ATX activity. ATX activity was correlated with liver biochemistry, MELD, Mayo Risk scores and was associated with worse disease specific HRQoL aspects. In both groups, Cox model analysis indicated that ATX was a negative predictor of survival. Increased ATX levels were associated with a 4 fold higher risk of death/liver transplantation in patients with PBC and a 2.6 fold higher risk in patients with PSC. We conclude that in patients with cholestatic conditions, ATX is not only associated with pruritus but also indicates impairment of other HRQoL aspects, liver dysfunction, and can serve as a predictor of survival. PMID- 27506885 TI - Purification and identification of amylases released by the human pathogen Trichomonas vaginalis that are active towards glycogen. AB - The parasitic protist Trichomonas vaginalis is the causative agent of the sexually transmitted infection trichomoniasis. In the laboratory, T. vaginalis is typically cultured in a serum-containing medium with maltose or glucose as the carbon source. The nature of the carbohydrates used by the organism in the environment of its host is unclear. However, the vagina contains substantial amounts of glycogen, which is believed to provide a growth substrate for the vaginal microbiota. We have shown previously that T. vaginalis releases glucosidases that are active towards glycogen into its environment. Here we purify and identifying these glucosidases. Using ammonium sulfate precipitation and precipitation with ethanol/glycogen, we purified glucosidase activity from conditioned growth medium, achieving over 300-fold enrichment. Maltose was released when glycogen was incubated with the glucosidase preparation, indicating that a beta-amylase was present. However, after prolonged incubation, small quantities of larger products including maltotriose were obtained. Liquid chromatography and tandem mass spectrometry showed that the glucosidase preparation contained three proteins, the major component being a putative beta amylase encoded by the TVAG_080000 open reading frame. Lesser amounts of two putative alpha-amylases, encoded by the TVAG_178580 and TVAG_205920 open reading frames, were also present. We cloned and expressed the TVAG_080000 open reading frame and found that the recombinant protein was capable of digesting glycogen, releasing exclusively maltose. We conclude that T. vaginalis releases a variety of amylases into its growth environment and is well equipped to utilize the glycogen found in the vagina as a source of essential carbohydrates. PMID- 27506886 TI - Antioxidant activity in vitro and in vivo of the polysaccharides from different varieties of Auricularia auricula. AB - In this study, five different kinds of polysaccharides (AAP1, AAP2, AAP3, AAP4, and AAP5) were extracted from different varieties of Auricularia auricula through an alkali extraction process. Furthermore, the crude polysaccharides were deproteinized by the Sevag method. Auricularia auricula produced in the Shanxi province had the highest content of polysaccharide, 53.02%. The monosaccharide composition was determined by the GC method. Their antioxidant capacities in vitro were assessed by radical-scavenging capacity (DPPH, superoxide, and hydroxyl radicals), metal chelating ability and reducing-power methods. In addition, the evaluation of their antioxidant effects in vivo was performed using the C. elegans model. The yield of crude polysaccharides, monosaccharide composition and antioxidant activity of Auricularia auricula polysaccharides (AAPs) were different among samples from various sources. Among them, the strongest antioxidant activity was shown for AAP1, consisting of arabinose, xylose, 2-deoxy-d-glucose, mannose, glucose, and N-acetyl-d-glucosamine with the molar ratio of 1 : 0.44 : 0.33 : 1.67 : 1 : 0.17. It could scavenge free radicals, up-regulate stress-resistance-related enzymes including superoxide dismutase (SOD) by 70.04 +/- 8.75% and CAT by 117.32 +/- 8.06% and reduce the level of reactive oxygen species (ROS) in C. elegans under oxidative stress. The present results suggested that variety was an important factor that affects the antioxidant activity of A. auricula polysaccharides. PMID- 27506887 TI - Fresh Perspectives from Emerging Experts. PMID- 27506888 TI - Primary percutaneous coronary intervention in octogenarians. AB - BACKGROUND: Limited data are available on the outcome of primary percutaneous coronary intervention (PCI) in octogenarian patients, as the elderly are under represented in randomized trials. This study aims to provide insights on clinical characteristics, management and outcome of the elderly and very elderly presenting with STEMI. METHODS: 2225 STEMI patients >=70years old (mean age 76.8+/-5.1years and 53.8% men) were admitted into the network of the ISACS-TC registry. Of these patients, 72.8% were >=70 to 79years old (elderly) and 27.2% were >=80years old (very-elderly). The primary end-point was 30-day mortality. RESULTS: Thirty-day mortality rates were 13.4% in the elderly and 23.9% in the very-elderly. Primary PCI decreased the unadjusted risk of death both in the elderly (OR: 0.32, 95% CI: 0.24-0.43) and very-elderly patients (OR: 0.45, 95% CI 0.30-0.68), without significant difference between groups. In the very-elderly hypertension and Killip class >=2 were the only independent factors associated with mortality; whereas in the elderly female gender, prior stroke, chronic kidney disease and Killip class >=2 were all factors independently associated with mortality. Factors associated with the lack of use of reperfusion were female gender and atypical chest pain in the very-elderly and in the elderly; in the elderly, however, there were some more factors, namely: history of diabetes, current smoking, prior stroke, Killip class >=2 and history chronic kidney disease. CONCLUSIONS: Age is relevant in the prognosis of STEMI, but its importance should not be considered secondary to other major clinical factors. Primary PCI appears to have beneficial effects in the octogenarian STEMI patients. PMID- 27506889 TI - High glycaemia and low uptake of insulin treatment among remote Torres Strait Islanders with diabetes: Implications for service delivery. PMID- 27506890 TI - Close encounters of the type-six kind: injected bacterial toxins modulate gut microbial composition. PMID- 27506892 TI - Bmal1 induces osteoblast differentiation via regulation of BMP2 expression in MC3T3-E1 cells. AB - AIMS: Mammalian circadian rhythms regulate many metabolic processes. Recent studies suggest that brain and muscle Arnt-like 1 (BMAL1), an important component of mammalian circadian rhythm, is associated with insulin signaling. Several studies have shown that insulin is associated with bone metabolism; however, the relationship between BMAL1 and osteoblasts remains unclear. MAIN METHODS: Expression of osteogenic markers and Bmal1 in MC3T3-E1 cells was measured by RT PCR and Western blotting. Alizarin red S staining was performed to assess matrix mineralization in MC3T3-E1 cells. KEY FINDINGS: mRNA levels of osteogenic genes and Bmal1 were up-regulated in MC3T3-E1 cells upon insulin treatment. In addition, Bmal1 overexpression increased the expression of osteogenic genes including inhibitor of DNA binding (Id1), Runt-related transcription factor 2 (Runx2), and osteocalcin (OC). Interestingly, expression of Bone morphogenetic protein-2 (BMP2), an important upstream factor of Id1, Runx2, and OC, was markedly increased by Bmal1. Finally, we confirmed that insulin-induced BMP2 expression was attenuated in Bmal1 knockout (KO) cells. PCR analysis and alizarin red S staining showed that insulin-mediated increases gene expression and calcium deposition were reduced in Bmal1 KO cells compared to wild-type cells. SIGNIFICANCE: Taken together, these results demonstrate that Bmal1 promotes osteoblast differentiation by regulating BMP2 expression in MC3T3-E1 cells. PMID- 27506891 TI - Capture-C reveals preformed chromatin interactions between HIF-binding sites and distant promoters. AB - Hypoxia-inducible factor (HIF) directs an extensive transcriptional cascade that transduces numerous adaptive responses to hypoxia. Pan-genomic analyses, using chromatin immunoprecipitation and transcript profiling, have revealed large numbers of HIF-binding sites that are generally associated with hypoxia-inducible transcripts, even over long chromosomal distances. However, these studies do not define the specific targets of HIF-binding sites and do not reveal how induction of HIF affects chromatin conformation over distantly connected functional elements. To address these questions, we deployed a recently developed chromosome conformation assay that enables simultaneous high-resolution analyses from multiple viewpoints. These assays defined specific long-range interactions between intergenic HIF-binding regions and one or more promoters of hypoxia inducible genes, revealing the existence of multiple enhancer-promoter, promoter enhancer, and enhancer-enhancer interactions. However, neither short-term activation of HIF by hypoxia, nor long-term stabilization of HIF in von Hippel Lindau (VHL)-defective cells greatly alters these interactions, indicating that at least under these conditions, HIF can operate on preexisting patterns of chromatin-chromatin interactions that define potential transcriptional targets and permit rapid gene activation by hypoxic stress. PMID- 27506893 TI - Epigenetic suppression of potassium-chloride co-transporter 2 expression in inflammatory pain induced by complete Freund's adjuvant (CFA). AB - BACKGROUND: Multiple mechanisms contribute to the stimulus-evoked pain hypersensitivity that may be experienced after peripheral inflammation. Persistent pathological stimuli in many pain conditions affect the expression of certain genes through epigenetic alternations. The main purpose of our study was to investigate the role of epigenetic modification on potassium-chloride co transporter 2 (KCC2) gene expression in the persistence of inflammatory pain. METHODS: Persistent inflammatory pain was induced through the injection of complete Freund's adjuvant (CFA) in the left hind paw of rats. Acetyl-histone H3 and H4 level was determined by chromatin immunoprecipitation in the spinal dorsal horn. Pain behaviour and inhibitory synaptic function of spinal cord were determined before and after CFA injection. KCC2 expression was determined by real time RT-PCR and Western blot. Intrathecal KCC2 siRNA (2 MUg per 10 MUL per rat) or HDAC inhibitor (10 MUg per 10 MUL per rat) was injected once daily for 3 days before CFA injection. RESULTS: Persistent inflammatory pain epigenetically suppressed KCC2 expression through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in decreased inhibitory signalling efficacy. KCC2 knock-down caused by intrathecal administration of KCC2 siRNA in naive rats reduced KCC2 expression in the spinal cord, leading to sensitized pain behaviours and impaired inhibitory synaptic transmission in their spinal cords. Moreover, intrathecal HDAC inhibitor injection in CFA rats increased KCC2 expression, partially restoring the spinal inhibitory synaptic transmission and relieving the sensitized pain behaviour. CONCLUSION: These findings suggest that the transcription of spinal KCC2 is regulated by histone acetylation epigenetically following CFA. SIGNIFICANCE: Persistent pain suppresses KCC2 expression through HDAC-mediated histone hypoacetylation and consequently impairs the inhibitory function of inhibitory interneurons. Drugs such as HDAC inhibitors that suppress the influences of persistent pain on the expression of KCC2 may serve as a novel analgesic. PMID- 27506894 TI - Gutmann's Donor Numbers Correctly Assess the Effect of the Solvent on the Kinetics of SN Ar Reactions in Ionic Liquids. AB - We report an experimental study on the effect of solvents on the model SN Ar reaction between 1-chloro-2,4-dinitrobenzene and morpholine in a series of pure ionic liquids (IL). A significant catalytic effect is observed with reference to the same reaction run in water, acetonitrile, and other conventional solvents. The series of IL considered include the anions, NTf2 (-) , DCN(-) , SCN(-) , CF3 SO3 (-) , PF6 (-) , and FAP(-) with the series of cations 1-butyl-3-methyl imidazolium ([BMIM](+) ), 1-ethyl-3-methyl-imidazolium ([EMIM](+) ), 1-butyl-2,3 dimethyl-imidazolium ([BM2 IM](+) ), and 1-butyl-1-methyl-pyrrolidinium ([BMPyr](+) ). The observed solvent effects can be attributed to an "anion effect". The anion effect appears related to the anion size (polarizability) and their hydrogen-bonding (HB) abilities to the substrate. These results have been confirmed by performing a comparison of the rate constants with Gutmann's donicity numbers (DNs). The good correlation between rate constants and DN emphasizes the major role of charge transfer from the anion to the substrate. PMID- 27506895 TI - Relationships between intramuscular fat, muscle strength and gait independence in older women: A cross-sectional study. AB - AIM: The objectives of the present study were to examine the relationships between intramuscular fat, muscle strength and gait independence, as well as to clarify the intramuscular fat characteristics of dependent older women. METHODS: A total of 25 older women who were unable to walk with or without assistance (dependent group), 22 frail older women (frail group) and 22 healthy older women (healthy group) participated in the present study. The frail participants could walk independently, but showed three or more of the following characteristics: slowness, weakness, weight loss, exhaustion and low physical activity. Outcome measures were quadriceps intramuscular fat determined by ultrasound echo intensity, and quadriceps muscle strength of the dependent, frail and healthy groups. In addition, the degree of gait independence (functional independence measures gait score) was assessed in the dependent and frail groups. RESULTS: Echo intensity in the dependent group was significantly negatively correlated with muscle strength and the functional independence measure gait score (correlation coefficients -0.635 and -0.344, respectively). Furthermore, echo intensity in the dependent group was significantly higher than in the healthy group. There was no significant difference in echo intensity between the dependent and frail groups. CONCLUSIONS: The present results suggest negative relationships between intramuscular fat and muscle strength, and intramuscular fat and degree of gait independence in dependent older women. In addition, dependent older women have more intramuscular fat than healthy older women. Geriatr Gerontol Int 2017; 17: 1683-1688. PMID- 27506896 TI - The diversity of the human hair colour assessed by visual scales and instrumental measurements. A worldwide survey. AB - OBJECTIVES: To study (i) the diversity of the natural colour of the human hair through both visual assessment of hair tone levels and colorimetric measurements of hair strands collected from 2057 human male and female volunteers, from 23 regions of the world and (ii) the correlation between visual assessments and colorimetric measurements. METHODS: Hair strands were analysed by a spectrocolorimeter under the L*, a*, b* referential system and scored in vivo by experts before sampling, through standardized visual reference scales based on a 1-10 range. RESULTS: Results show that from a typological aspect, black or dark brown hairs largely predominate among studied ethnic groups, whereas Caucasian or derived populations exhibit the widest palette of medium to fair shades, partly explaining some past interbreeding among populations. Instrumental measurements clearly confirm that a given colour of a pigmented hair, at the exclusion of red hairs, is mostly governed by two components, L* and b*, from the L*, a*, b* reference system. CONCLUSION: The comparisons between visual assessments and instrumental data show that these appear closely linked. Darker hairs show close or subtle variations in L*, a*, b* parameters, making their individual colour differentiation calling for technical improvements in colorimetric measurements. The latter are likely governed by other physical factors such as shape, diameter and shine. PMID- 27506897 TI - In reply: Monitoring recovery from neuromuscular block using acceleromyography at the trapezius muscle: problems that must be considered. PMID- 27506898 TI - A Combinatorial Investigation of the Response to Anti-angiogenic Therapy in Breast Cancer: New Strategies for Patient Selection and Opportunities for Reconsidering Anti-VEGF, Anti-PI3K and Checkpoint Inhibition. PMID- 27506899 TI - Fetal programming of blood pressure in a transgenic mouse model of altered intrauterine environment. AB - KEY POINTS: Nitric oxide is essential in the vascular adaptation to pregnancy, as knockout mice lacking nitric oxide synthase (NOS3) have abnormal utero-placental perfusion, hypertension and growth restriction. We previously showed with ex vivo studies on transgenic animals lacking NOS3 that adverse intrauterine environment alters fetal programming of vascular reactivity in adult offspring. The current research shows that altered vascular reactivity correlates with higher blood pressure in vivo. Our data suggest that higher blood pressure depends on both genetic background (NOS3 deficiency) and uterine environment, becomes more evident with age (> 7 postnatal weeks), activity and stress, is gender specific (preponderant among males), and can be affected by the sleep-awake cycle. In utero or early postnatal life (< 7 weeks), before onset of hypertension, may represent a potential window for intervention to prevent future cardiovascular disorders. ABSTRACT: Nitric oxide is involved in the vascular adaptation to pregnancy. Using transgenic animals, we previously showed that adverse intrauterine environment alters vascular reactivity in adult offspring. The aim of our study was to determine if altered vascular programming is associated with abnormal blood pressure (BP) profiles in vivo. Mice lacking a functional endothelial nitric oxide synthase (KO, NOS3-/- ) and wild-type mice (WT, NOS3+/+ ) were crossbred to generate homozygous NOS3-/- (KO), maternally derived heterozygous NOS3+/- (KOM: mother with adverse intrauterine environment from NOS3 deficiency), paternally derived heterozygous NOS3+/- (KOP: mother with normal in utero milieu) and NOS3+/+ (WT) litters. BP was measured in vivo at 7, 14 and 21 weeks of age. After univariate analysis, multivariate population-averaged linear regression models were used to identify factors affecting BP. When compared to WT offspring, systolic (SBP), diastolic (DBP) and mean (MAP) BP progressively increased from KOP, to KOM, and peaked among KO (P < 0.001), although significance was not reached for KOP. Higher BP was also associated with male gender, older age (> 7 postnatal weeks), higher locomotor activity, daytime recordings, and recent blood pressure transducer insertion (P < 0.001). Post hoc analysis showed that KOM had higher SBP than KOP (P < 0.05). Our study indicates that adverse intrauterine environment contributes, along with multiple other factors, to account for hypertension; moreover, in utero or early postnatal life may represent a possible therapeutic window for prevention of cardiovascular disease later in life. PMID- 27506900 TI - INFORMEG, a new evaluation system for family medicine trainees: feasibility in an Italian rural setting. AB - INTRODUCTION: In Italy the course to become a general practitioner (GP) lasts 3 years and includes both theoretical and practical study. Different from the theoretical part, until recently the practical activity has not been assessed at all. The Emilia Romagna Regional Health Authority has developed a special program called INFORMEG (Management of Tutoring during the Triennial Specific Training in General Practice), aimed at assessing primary doctor trainees' practical skills. INFORMEG includes a list of pre-defined cases of specific diseases, conditions or health problem, a web application and a smartphone app, aimed at assisting trainee self-management and helping the tutor in the assessment of trainee performance. The Emilia Romagna Regional Health Authority divided the pre-defined cases into three categories (A, B and C) according to their relevance to a trainee's education and coded them using the International Classification of Primary Care (ICPC). The aim of this project report is to illustrate the implementation of INFORMEG in a rural setting. METHODS: Program evaluation took place from 2 May to 31 October 2013 during GPs' routine clinical activities. The following steps were accomplished during every meeting: (1) consultation recording; (2) identification of the reason for the encounter (RfE); (3) classification of the diagnostic procedure(s) performed (diagnostic/therapeutic/test results/administrative/advice); (4) classification of special procedures called 'practical clinical skills' and (5) elaboration of the final diagnosis after the encounter. RESULTS: The number of cases of specific disease or condition encountered by the trainee were 98 for type A, 57 for type B and 22 for type C. A total of 605 RfEs were collected: 376 for type A cases, 147 for type B cases and 82 for type C cases. A total of 976 procedures were performed during the 6 months: 590 procedures for the type A cases, 271 for type B and 115 for type C. CONCLUSIONS: The pre-selected health problems were almost all addressed, thus confirming the good degree of representativeness of these clinical cases even in a rural setting. The ICPC coding helped the trainee in the construction of the case according to the logical process of family medicine. Two things to amend in INFORMEG are the absence of common arrhythmic conditions such as atrial fibrillation and the absence of means to assess the patient-trainee relationship. PMID- 27506901 TI - Mangrovimonas xylaniphaga sp. nov. isolated from estuarine mangrove sediment of Matang Mangrove Forest, Malaysia. AB - A Gram-staining-negative, aerobic, rod-shaped, yellow-orange-pigmented, gliding bacterium, designated as strain ST2L12T, was isolated from estuarine mangrove sediment from Matang Mangrove Forest, Perak, Malaysia. Strain ST2L12T grew at 15 39 degrees C, pH 6-8 and in 1-6 % (w/v) NaCl. This strain was able to degrade xylan and casein. 16S rRNA gene sequence analysis showed 95.3-92.8 % similarity to members of the genera Mangrovimonas, Meridianimaribacter, Sediminibacter, Gaetbulibacter and Hoppeia. Phylogenetic analysis indicated that it belonged to the family Flavobacteriaceae. Respiratory quinone present was menaquinone-6 (MK 6), and the DNA G+C content was 38.3 mol%. The predominant fatty acids were iso C15:0, iso-C15:1, C15:0 and iso-C17:0 3-OH. Moreover, previous genome comparison study showed that the genome of ST2L12T is 1.4 times larger compared to its closest relative, Mangrovimonas yunxiaonensis LYYY01T. Phenotypic, fatty acid, 16S rRNA gene sequence and previous genome data indicate that strain ST2L12T represents a novel species of the genus Mangrovimonas in the family Flavobacteriaceae, for which the name Mangrovimonas xylaniphaga sp. nov. is proposed. The type strain of Mangrovimonas xylaniphaga is ST2L12T (=LMG 28914T=JCM 30880T). PMID- 27506903 TI - Systematic Review of Randomized Controlled Trials of Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension. AB - BACKGROUND: There are currently three Food and Drug Administration approved endothelin receptor antagonists (ERAs): bosentan, ambrisentan, and macitentan. There is a growing body of evidence that demonstrates the beneficial effects of ERAs in patients with pulmonary arterial hypertension (PAH). OBJECTIVES: To compare the available evidence from randomized clinical trials for specific outcomes of different endothelin antagonists for the treatment of PAH. METHODS: A multi-database search of randomized controlled trials up to March 15, 2016 was conducted for those that would measure functional parameters of patients with PAH treated with ERA monotherapy versus placebo. Studies that analyzed 6-min walking distance, pulmonary vascular resistance, pulmonary arterial pressure, or WHO functional status were incorporated for analysis. A total of 15 trials and 2 subanalyses were compiled and quality and abovementioned outcomes were compared among studies. RESULTS: A constant decrease in pulmonary vascular resistance and pulmonary arterial pressure was globally reported among the different studies, resulting in increased 6-min walking distance and functional status compared to placebo. CONCLUSIONS: Although this evidence clearly shows the benefit of ERAs, studies, which compare ERAs against one another and with other therapies for progressive PAH, have been lacking. Larger and longer studies are necessary to define the role of ERAs as standalone agents and in combination therapies. PMID- 27506902 TI - Respiratory Muscle Assessment in Acute Guillain-Barre Syndrome. AB - PURPOSE: Guillain-Barre Syndrome (GBS) is a life-threatening disease due to respiratory muscle involvement. This study aimed at objectively assessing the course of respiratory muscle function in GBS subjects within the first week of admission to an intensive care unit. METHODS: Medical Research Council Sum Score (MRC-SS), vigorimetry, spirometry, and respiratory muscle function tests (inspiratory/expiratory muscle strength: PImax/PEmax, sniff nasal pressure: SnPna) were assessed twice daily. GBS Disability Score (GBS-DS) was assessed once daily. On days one (d1) and seven (d7), blood gases and twitch mouth pressure during magnetic phrenic nerve stimulation (Pmo,tw) were additionally evaluated. RESULTS: Nine subjects were included. MRC-SS, vigorimetry, PImax, and SnPna increased between d1 and d7. GBS-DS, spirometry and Pmo,tw remained unaltered. Only SnPna correlated closely with the MRC-SS on both d1 (r = 0.77, p = 0.02) and d7 (r = 0.74, p = 0.02). CONCLUSION: SnPna was the only parameter that correlated with MRC-SS, while the current gold standard of spirometry measurement did not. PMID- 27506904 TI - HDAC 1 and 6 modulate cell invasion and migration in clear cell renal cell carcinoma. AB - BACKGROUND: Class I histone deacetylases (HDACs) have been reported to be overexpressed in clear cell renal cell carcinoma (ccRCC), whereas the expression of class II HDACs is unknown. METHODS: Four isogenic cell lines C2/C2VHL and 786 O/786-OVHL with differential VHL expression are used in our studies. Cobalt chloride is used to mimic hypoxia in vitro. HIF-2alpha knockdowns in C2 and 786-O cells is used to evaluate the effect on HDAC 1 expression and activity. Invasion and migration assays are used to investigate the role of HDAC 1 and HDAC 6 expression in ccRCC cells. Comparisons are made between experimental groups using the paired T-test, the two-sample Student's T-test or one-way ANOVA, as appropriate. ccRCC and the TCGA dataset are used to observe the clinical correlation between HDAC 1 and HDAC 6 overexpression and overall and progression free survival. RESULTS: Our analysis of tumor and matched non-tumor tissues from radical nephrectomies showed overexpression of class I and II HDACs (HDAC6 only in a subset of patients). In vitro, both HDAC1 and HDAC6 over-expression increased cell invasion and motility, respectively, in ccRCC cells. HDAC1 regulated invasiveness by increasing matrix metalloproteinase (MMP) expression. Furthermore, hypoxia stimulation in VHL-reconstituted cell lines increased HIF isoforms and HDAC1 expression. Presence of hypoxia response elements in the HDAC1 promoter along with chromatin immunoprecipitation data suggests that HIF-2alpha is a transcriptional regulator of HDAC1 gene. Conversely, HDAC6 and estrogen receptor alpha (ERalpha) were co-localized in cytoplasm of ccRCC cells and HDAC6 enhanced cell motility by decreasing acetylated alpha-tubulin expression, and this biological effect was attenuated by either biochemical or pharmacological inhibition. Finally, analysis of human ccRCC specimens revealed positive correlation between HIF isoforms and HDAC. HDAC1 mRNA upregulation was associated with worse overall survival in the TCGA dataset. CONCLUSIONS: Taking together, these results suggest that HDAC1 and HDAC6 may play a role in ccRCC biology and could represent rational therapeutic targets. PMID- 27506905 TI - Full-length autonomous transposable elements are preferentially targeted by expression-dependent forms of RNA-directed DNA methylation. AB - BACKGROUND: Chromatin modifications such as DNA methylation are targeted to transposable elements by small RNAs in a process termed RNA-directed DNA methylation (RdDM). In plants, canonical RdDM functions through RNA polymerase IV to reinforce pre-existing transposable element silencing. Recent investigations have identified a "non-canonical" form of RdDM dependent on RNA polymerase II expression to initiate and re-establish silencing of active transposable elements. This expression-dependent RdDM mechanism functions through RNAi degradation of transposable element mRNAs into small RNAs guided by the RNA dependent RNA polymerase 6 (RDR6) protein and is therefore referred to as RDR6 RdDM. RESULTS: We performed whole-genome MethylC-seq in 20 mutants that distinguish RdDM mechanisms when transposable elements are either transcriptionally silent or active. We identified a new mechanism of expression dependent RdDM, which functions through DICER-LIKE3 (DCL3) but bypasses the requirement of both RNA polymerase IV and RDR6 (termed DCL3-RdDM). We found that RNA polymerase II expression-dependent forms of RdDM function on over 20 % of transcribed transposable elements, including the majority of full-length elements with all of the domains required for autonomous transposition. Lastly, we find that RDR6-RdDM preferentially targets long transposable elements due to the specificity of primary small RNAs to cleave full-length mRNAs. CONCLUSIONS: Expression-dependent forms of RdDM function to critically target DNA methylation to full-length and transcriptionally active transposable elements, suggesting that these pathways are key to suppressing mobilization. This targeting specificity is initiated on the mRNA cleavage-level, yet manifested as chromatin level silencing that in plants is epigenetically inherited from generation to generation. PMID- 27506906 TI - Quantitative [18F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer. AB - PURPOSE: Evaluation of [18F]fluoromisonidazole ([18F]FMISO)-positron emission tomography (PET) imaging as a metric for evaluating early response to trastuzumab therapy with histological validation in a murine model of HER2+ breast cancer. PROCEDURES: Mice with BT474, HER2+ tumors, were imaged with [18F]FMISO-PET during trastuzumab therapy. Pimonidazole staining was used to confirm hypoxia from imaging. RESULTS: [18F]FMISO-PET indicated significant decreases in hypoxia beginning on day 3 (P < 0.01) prior to changes in tumor size. These results were confirmed with pimonidazole staining on day 7 (P < 0.01); additionally, there was a significant positive linear correlation between histology and PET imaging (r 2 = 0.85). CONCLUSIONS: [18F]FMISO-PET is a clinically relevant modality which provides the opportunity to (1) predict response to HER2+ therapy before changes in tumor size and (2) identify decreases in hypoxia which has the potential to guide subsequent therapy. PMID- 27506908 TI - The role of web sharing, species recognition and host-plant defence in interspecific competition between two herbivorous mite species. AB - When competing with indigenous species, invasive species face a problem, because they typically start with a few colonizers. Evidently, some species succeeded, begging an answer to the question how they invade. Here, we investigate how the invasive spider mite Tetranychus evansi interacts with the indigenous species T. urticae when sharing the solanaceous host plant tomato: do they choose to live together or to avoid each other's colonies? Both species spin protective, silken webs on the leaf surfaces, under which they live in groups of con- and possibly heterospecifics. In Spain, T. evansi invaded the non-crop field where native Tetranychus species including T. urticae dominated. Moreover, T. evansi outcompetes T. urticae when released together on a tomato plant. However, molecular plant studies suggest that T. urticae benefits from the local down regulation of tomato plant defences by T. evansi, whereas T. evansi suffers from the induction of these defences by T. urticae. Therefore, we hypothesize that T. evansi avoids leaves infested with T. urticae whereas T. urticae prefers leaves infested by T. evansi. Using wild-type tomato and a mutant lacking jasmonate mediated anti-herbivore defences, we tested the hypothesis and found that T. evansi avoided sharing webs with T. urticae in favour of a web with conspecifics, whereas T. urticae more frequently chose to share webs with T. evansi than with conspecifics. Also, T. evansi shows higher aggregation on a tomato plant than T. urticae, irrespective of whether the mites occur on the plant together or not. PMID- 27506907 TI - High-throughput sequencing and degradome analysis reveal altered expression of miRNAs and their targets in a male-sterile cybrid pummelo (Citrus grandis). AB - BACKGROUND: G1 + HBP is a male sterile cybrid line with nuclear genome from Hirado Buntan pummelo (C. grandis Osbeck) (HBP) and mitochondrial genome from "Guoqing No.1" (G1, Satsuma mandarin), which provides a good opportunity to study male sterility and nuclear-cytoplasmic cross talk in citrus. High-throughput sRNA and degradome sequencing were applied to identify miRNAs and their targets in G1 + HBP and its fertile type HBP during reproductive development. RESULTS: A total of 184 known miRNAs, 22 novel miRNAs and 86 target genes were identified. Some of the targets are transcription factors involved in floral development, such as auxin response factors (ARFs), SQUAMOSA promoter binding protein box (SBP-box), MYB, basic region-leucine zipper (bZIP), APETALA2 (AP2) and transport inhibitor response 1 (TIR1). Eight target genes were confirmed to be sliced by corresponding miRNAs using 5' RACE technology. Based on the sequencing abundance, 42 differentially expressed miRNAs between sterile line G1 + HBP and fertile line HBP were identified. Differential expression of miRNAs and their target genes between two lines was validated by quantitative RT-PCR, and reciprocal expression patterns between some miRNAs and their targets were demonstrated. The regulatory mechanism of miR167a was investigated by yeast one-hybrid and dual-luciferase assays that one dehydrate responsive element binding (DREB) transcription factor binds to miR167a promoter and transcriptionally repress miR167 expression. CONCLUSION: Our study reveals the altered expression of miRNAs and their target genes in a male sterile line of pummelo and highlights that miRNA regulatory network may be involved in floral bud development and cytoplasmic male sterility in citrus. PMID- 27506909 TI - Expectations affect psychological and neurophysiological benefits even after a single bout of exercise. AB - The study investigated whether typical psychological, physiological, and neurophysiological changes from a single exercise are affected by one's beliefs and expectations. Seventy-six participants were randomly assigned to four groups and saw different multimedia presentations suggesting that the subsequent exercise (moderate 30 min cycling) would result in more or less health benefits (induced expectations). Additionally, we assessed habitual expectations reflecting previous experience and beliefs regarding exercise benefits. Participants with more positive habitual expectations consistently demonstrated both greater psychological benefits (more enjoyment, mood increase, and anxiety reduction) and greater increase of alpha-2 power, assessed with electroencephalography. Manipulating participants' expectations also resulted in largely greater increases of alpha-2 power, but not in more psychological exercise benefits. On the physiological level, participants decreased their blood pressure after exercising, but this was independent of their expectations. These results indicate that habitual expectations in particular affect exercise-induced psychological and neurophysiological changes in a self-fulfilling manner. PMID- 27506910 TI - Assessment of factors associated with the quality of life of patients living with HIV/HCV co-infection. AB - This study compared the quality of life (QoL) of HIV-infected patients with and without hepatitis C and examined the sociodemographic, HIV-related and psychological symptoms associated with the QoL domains in patients with HIV/HCV co-infection. The sample consisted of 248 HIV/HCV co-infected patients (18-74 years, 81.5 % male) and 482 patients only with HIV (24-78 years, 62.7 % male). Participants completed the WHOQOL-HIV-Bref questionnaire and the Brief Symptom Inventory. The HIV/HCV co-infected patients reported significantly lower QoL in all domains, as well as significantly lower scores in 10 of the 17 specific facets. Overall, among the co-infected patients, male gender, employment, combination antiretroviral therapy use and fewer depressive and anxiety symptoms were significantly associated with higher QoL. Symptoms of psychological distress accounted for significant variability in the QoL scores of co-infected patients. These data reinforce the need for tailored interventions to improve the overall well-being of HIV/HCV co-infected patients. PMID- 27506912 TI - Binary and ternary recombination of H2D(+) and HD2(+) ions with electrons at 80 K. AB - The recombination of deuterated trihydrogen cations with electrons has been studied in afterglow plasmas containing mixtures of helium, argon, hydrogen and deuterium. By monitoring the fractional abundances of H3(+), H2D(+), HD2(+) and D3(+) as a function of the [D2]/[H2] ratio using infrared absorption observed in a cavity ring down absorption spectrometer (CRDS), it was possible to deduce effective recombination rate coefficients for H2D(+) and HD2(+) ions at a temperature of 80 K. From pressure dependences of the measured effective recombination rate coefficients the binary and the ternary recombination rate coefficients for both ions have been determined. The inferred binary and ternary recombination rate coefficients are: alphabinH2D(80 K) = (7.1 +/- 4.2) * 10(-8) cm(3) s(-1), alphabinHD2(80 K) = (8.7 +/- 2.5) * 10(-8) cm(3) s(-1), KH2D(80 K) = (1.1 +/- 0.6) * 10(-25) cm(6) s(-1) and KHD2(80 K) = (1.5 +/- 0.4) * 10(-25) cm(6) s(-1). PMID- 27506913 TI - [Kondylomer viste sig at vaere peniscancer]. PMID- 27506914 TI - [Multidisciplinary teams in cancer care]. AB - Multidisciplinary teams (MDTs) are considered a core component of cancer care worldwide. It is commonly believed that MDTs ensure higher-quality decision making and improved outcomes for the patients. However, the evidence underpinning MDTs is weak and the degree to which they have been absorbed into clinical practice varies widely. Based on a literature review this article explores effects, barriers and potentials for improving MDTs in cancer care. A stronger focus is needed on how MDTs can be optimized to achieve the best possible results in cancer care. PMID- 27506911 TI - Pain beliefs and problems in functioning among people with arthritis: a meta analytic review. AB - In this meta-analysis, we evaluated overall strengths of relation between beliefs about pain, health, or illness and problems in functioning (i.e., functional impairment, affective distress, pain severity) in osteoarthritis and rheumatoid arthritis samples as well as moderators of these associations. In sum, 111 samples (N = 17,365 patients) met inclusion criteria. On average, highly significant, medium effect sizes were observed for associations between beliefs and problems in functioning but heterogeneity was also inflated. Effect sizes were not affected by arthritis subtype, gender, or age. However, pain belief content emerged as a significant moderator, with larger effect sizes for studies in which personal incapacity or ineffectiveness in controlling pain was a content theme of belief indices (i.e., pain catastrophizing, helplessness, self-efficacy) compared to those examining locus of control and fear/threat/harm beliefs. Furthermore, analyses of longitudinal study subsets supported the status of pain beliefs risk factors for later problems in functioning in these groups. PMID- 27506915 TI - [Individualized treatment of colon cancer]. AB - The treatment of colon cancer has undergone a rapid development with improved surgical and medical regimes and the introduction of targeted treatments. This review offers insight into the current available tailored treatment of colon cancer, and some of the new tailored treatment possibilities with focus on preoperative-, surgical- and post-operative treatment are presented. PMID- 27506916 TI - [Systemic lupus erythematosus and pregnancy]. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease which most often affects women of childbearing age. Pregnancy is therefore an important issue for the patient and the responsible physician. Pregnancy outcomes in women with SLE has improved significantly over the latest decades, and current research initiatives aim towards further improvement. Pregnant women with SLE are still considered being at various levels of risk. In order to achieve the best possible outcomes for mother and child, joint care in specialised multidisciplinary teams including rheumatologists and obstetricians is recommended. PMID- 27506917 TI - Overview of online two-dimensional liquid chromatography based on cell membrane chromatography for screening target components from traditional Chinese medicines. AB - Cell membrane chromatography is a simple, specific, and time-saving technique for studying drug-receptor interactions, screening of active components from complex mixtures, and quality control of traditional Chinese medicines. However, the short column life, low sensitivity, low column efficiency (so cannot resolve satisfactorily mixture of compounds), low peak capacity, and inefficient in structure identification were bottleneck in its application. Combinations of cell membrane chromatography with multidimensional chromatography such as two dimensional liquid chromatography and high sensitivity detectors like mass have significantly reduced many of the above-mentioned shortcomings. This paper provides an overview of the current advances in online two-dimensional-based cell membrane chromatography for screening target components from traditional Chinese medicines with particular emphasis on the instrumentation, preparation of cell membrane stationary phase, advantages, and disadvantages compared to alternative approaches. The last section of the review summarizes the applications of the online two-dimensional high-performance liquid chromatography based cell membrane chromatography reported since its emergence to date (2010-June 2016). PMID- 27506918 TI - Clinical and non-clinical safety of artemisinin derivatives in pregnancy. AB - Malaria in pregnancy is a clinically wasting infectious disease, where drug therapy has to be promptly initiated. Currently, the treatment of this infection depends on the use of artemisinin derivatives. The World Health Organization does not recommend the use of these drugs in the first trimester of pregnancy due to non-clinical findings that have shown embryolethality and teratogenic effects. Nevertheless, until now, this toxicity has not been proved in humans. Artemisinin derivatives mechanisms of embryotoxicity are related to depletion of circulating embryonic primitive erythroblasts. Species differences in this sensitive period for toxicity and the presence of malaria infection, which could reduce drug distribution to the fetus, are significant to the risk assessment of artemisinin derivatives treatment to pregnant women. In this review we aimed to assess the results of non-clinical and clinical studies with artemisinin derivatives, their mechanisms of embryotoxicity and discuss the safety of their use during pregnancy. PMID- 27506919 TI - 5-Position-selective C-H trifluoromethylation of 8-aminoquinoline derivatives. AB - We developed a copper-catalyzed 5-position-selective C-H trifluoromethylation of 8-aminoquinoline derivatives. The reaction proceeded with high functional group tolerance under mild conditions. In the case of quinolines with an amide, carbamate, urea, or sulfonamide group at the 8-position of quinoline moieties, a radical scavenger experiment indicated that the reaction proceeded via a radical pathway. The protecting group of an 8-amidoquinoline derivative could be removed by hydrolysis. On the other hand, the trifluoromethylation of 8-aminoquinolines was also promoted by other Lewis acids as well as a copper catalyst and proceeded even in the presence of a radical scavenger. These results indicated that the trifluoromethylation of 8-aminoquinolines proceeded via a Friedel-Crafts-type reaction. Interestingly, the copper salt works as either a catalyst for the formation of a CF3 radical or a Lewis acid to promote a Friedel-Crafts-type reaction, depending on the substrate. PMID- 27506920 TI - A novel canine B-cell leukaemia cell line. Establishment, characterisation and sensitivity to chemotherapeutics. AB - We established a new B-cell leukaemia cell line CLB70 from a dog with chronic lymphocytic leukaemia. This cell line is positive for CD20, CD45, CD79a, MHC class II, IgG, IgM; weakly positive for CD21; and negative for CD3, CD4, CD5, CD8, CD14, CD34, CD117. PCR for antigen receptor gene rearrangement (PARR) analysis revealed a biclonal immunoglobulin heavy chain (IgH) gene rearrangement and negative result for TCRgamma. Western blot analysis of anti- and pro apoptotic proteins showed increased expression of Bcl-2, Mcl-1, NF-kB, and Ras, and decreased expression of p53. CLB70 cells grow rapidly in vitro and are tumourigenic in nude mice. The CLB70 line is highly sensitive to doxorubicin, less sensitive to etoposide and imatinib, and resistant to piroxicam, celecoxib and dexamethasone. Our results indicate that CLB70 cells are derived from mature B-cells and they may be a useful tool for the development of new therapeutic strategies for both dogs and humans. PMID- 27506921 TI - Trusts spend 25 times more on locum fees than on recruiting for permanent posts. PMID- 27506922 TI - Population levels of sport participation: implications for sport policy. AB - BACKGROUND: Participation in sport can contribute to health-enhancing levels of leisure-time physical activity. There are recent reports that participation in sport in Australia is decreasing. However, these studies are limited to ages 15 years and over. METHODS: This study integrates sports club membership data from five popular team sports and investigates sport participation across the lifespan (4-100 years) by sex and region (metropolitan/non-metropolitan). RESULTS: Overall participant numbers per annum increased from 414,167 in 2010 to 465,403 in 2012 corresponding to a rise in the proportion of Victorian's participating in these sports from 7.5 % in 2010 to 8.3 % in 2012. The highest proportion of participants was in the 10-14 year age range, with participation rates of 36 % in 2010 and 40 % in 2012. There was a considerably lower participation rate in the 15-19 year age group compared to the 10-14 age group, in all three years studied, and the decline continued progressively with increasing age. Male and female age profiles of participation were generally similar in shape, but the female peak at age 10-14 was sharper than for the males, and conversely there were very few 4 year old female participants. Participation rates were generally higher in non metropolitan than metropolitan areas; the difference increased with increasing age from 4 to 34 years, then steadily declined, reaching parity at around 60 years of age. CONCLUSIONS: It is a positive sign that participation in these popular sports increased by over 50,000 participants from 2010 to 2012. Large proportions of the population aged 5-14 participate in club based sport. Participation rates decline sharply in late adolescence, particularly for females, and while this may not be a concern from a broad health perspective so long as they transition into other forms of physical activity, it is certainly a matter of concern for the sport sector. It is recommended that sport policy places a higher priority on grass-roots participation and that sporting organisations are supported to prioritise the retention issues occurring during adolescence, particularly for females so as to maximise the potential for sport to maintain its positive contribution to population wellbeing. PMID- 27506923 TI - Improving access for community health and sub-acute outpatient services: protocol for a stepped wedge cluster randomised controlled trial. AB - BACKGROUND: Waiting lists for treatment are common in outpatient and community services, Existing methods for managing access and triage to these services can lead to inequities in service delivery, inefficiencies and divert resources from frontline care. Evidence from two controlled studies indicates that an alternative to the traditional "waitlist and triage" model known as STAT (Specific Timely Appointments for Triage) may be successful in reducing waiting times without adversely affecting other aspects of patient care. This trial aims to test whether the model is cost effective in reducing waiting time across multiple services, and to measure the impact on service provision, health-related quality of life and patient satisfaction. METHODS/DESIGN: A stepped wedge cluster randomised controlled trial has been designed to evaluate the impact of the STAT model in 8 community health and outpatient services. The primary outcome will be waiting time from referral to first appointment. Secondary outcomes will be nature and quantity of service received (collected from all patients attending the service during the study period and health-related quality of life (AQOL-8D), patient satisfaction, health care utilisation and cost data (collected from a subgroup of patients at initial assessment and after 12 weeks). Data will be analysed with a multiple multi-level random-effects regression model that allows for cluster effects. An economic evaluation will be undertaken alongside the clinical trial. DISCUSSION: This paper outlines the study protocol for a fully powered prospective stepped wedge cluster randomised controlled trial (SWCRCT) to establish whether the STAT model of access and triage can reduce waiting times applied across multiple settings, without increasing health service costs or adversely impacting on other aspects of patient care. If successful, it will provide evidence for the effectiveness of a practical model of access that can substantially reduce waiting time for outpatient and community services with subsequent benefits for both efficiency of health systems and patient care. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12615001016527 . Approved 15/9/2015. PMID- 27506924 TI - Baicalein suppresses the proliferation of acute T-lymphoblastic leukemia Jurkat cells by inhibiting the Wnt/beta-catenin signaling. AB - Although the response rates of chemotherapy in patients with acute T lymphoblastic leukemia (T-ALL) have improved significantly, the outcome of these patients is still poor. Previous studies suggested that baicalein could inhibit the growth of several cancers, while its effect on T-ALL cells remains unclear. We used Jurkat cells as an in vitro model of T-ALL. Cell counting kit-8 assay and cytometric analysis with Annexin V-FITC/PI double staining were used to investigate the proliferation and apoptosis of Jurkat cells treated with increasing concentration of baicalein for indicated time. RT-PCR and western blotting was used to test the expression of Wnt/beta-catenin associated genes and proteins. In cell viability assay, baicalein could inhibit the proliferation of Jurkat cells both in dose- and time-dependent manners. In cell apoptosis assay, baicalein could stimulate apoptosis of Jurkat cells both in dose- and time dependent manners. Moreover, we demonstrated that baicalein could down-regulated the mRNA and protein levels of beta-catenin and its widely accepted downstream targets (c-Myc, cyclin D1, and Axin2) in dose-dependent manners. These results proved that baicalein might be a potential choice for the treatment of T-ALL. PMID- 27506925 TI - ? PMID- 27506926 TI - Randomized Comparison of High-Sensitivity Troponin Reporting in Undifferentiated Chest Pain Assessment. AB - BACKGROUND: High-sensitivity troponin T (hs-TnT) assays promise greater discrimination of evolving myocardial infarction, but the impact of unguided implementation on the effectiveness of care is uncertain. METHODS AND RESULTS: We evaluated the impact of hs-TnT reporting on care and outcome among chest pain patients presenting to 5 emergency departments within a multicenter randomized trial. Patients were allocated to hs-TnT reporting (hs-report) or standard reporting (std-report; Roche Elecys). The primary end point was death and new or recurrent acute coronary syndrome by 12 months. A total of 1937 patients without ST-segment elevation were enrolled between July 2011 and March 2013. The median age was 61 (interquartile range, 48-74) years, and 46.3% were women. During the index hospitalization, 1466 patients (75.7%) had maximal troponin <30 ng/L within 24 hours. Randomization to hs-report format did not alter the admission rate (hs report: 57.7% versus std-report: 58.0%; P=0.069). There was no difference in angiography (hs-report: 11.9% versus std-report: 10.9%; P=0.479). The hs reporting did not reduce 12-month death or new/recurrent acute coronary syndrome in the overall population (hs-report: 9.7% versus std-report: 7.2% [hazard ratio, 0.83 (0.57-1.22); P=0.362]). However, among those with troponin levels <30 ng/L, a modest reduction in the primary end point was observed (hs-report: 2.6% versus std-report: 4.4%, [hazard ratio, 0.58; 95% confidence interval, 0.34-0.1.00; P=0.050). CONCLUSIONS: High-sensitivity troponin reporting alone is associated with only modest changes in practice. Clinical effectiveness in the adoption of high-sensitivity troponin may require close coupling with protocols that guide interpretation and care. CLINICAL TRIAL REGISTRATION: URL: http://www.ANZCTR.org.au. Unique identifier: ACTRN12611000879965. PMID- 27506927 TI - Nitrogen can improve the rapid response of photosynthesis to changing irradiance in rice (Oryza sativa L.) plants. AB - To identify the effect of nitrogen (N) nutrition on the dynamic photosynthesis of rice plants, a pot experiment was conducted under two N conditions. The leaf N and chlorophyll levels, as well as steady-state photosynthesis, were significantly increased under high N. After the transition from saturating to low light levels, decreases in the induction state (IS%) of leaf photosynthesis (A) and stomatal conductance (gs) were more severe under low than under high N supply. After the transition from low to flecked irradiance, the times to 90% of maximum A (T90%A) were significantly longer under low than under high N supply. Under flecked irradiance, the maximum A under saturating light (Amax-fleck) and the steady-state A under low light (Amin-fleck) were both lower than those under uniform irradiance (Asat and Ainitial). Under high N supply, Amax-fleck was 14.12% lower than Asat, while it was 22.80% lower under low N supply. The higher IS%, shorter T90%A, and the lower depression of Amax-fleck from Asat under high N supply led to a less carbon loss compared with under a low N supply. Therefore, we concluded that N can improve the rapid response of photosynthesis to changing irradiance. PMID- 27506928 TI - The annual marine feeding aggregation of Atlantic sturgeon Acipenser oxyrinchus in the inner Bay of Fundy: population characteristics and movement. AB - Atlantic sturgeon Acipenser oxyrinchus aggregate to feed from May to October in Minas Basin (45 degrees N; 64 degrees W), a large, cul-de-sac embayment of the inner Bay of Fundy. The aggregation consists mainly of migrants from the Saint John, NB and Kennebec Rivers, ME (99%). During 2004-2015, 4393 A. oxyrinchus were taken as by-catch by commercial fish trawlers or at intertidal fishing weirs, and 1453 were marked and/or sampled and released. Fork length (LF ) ranged from 458 to 2670 mm, but 72.5% were <1500 mm. Mass (M) ranged from 0.5 to 58.0 kg. The mass-length relationship for fish <=50 kg was log10 M = 3.32log10 LF - 5.71. Observed growth of unsexed A. oxyrinchus recaptured after 1-8 years indicated fish of 90-179 cm LF grew c. 2-4 cm a year. Ages obtained from pectoral spines were from 4 to 54 years. The Von Bertalanffy growth model predicted K = 0.01 and Linfinity = 5209 mm LF . Estimated annual mortality was 9.5-10.9%. Aggregation sizes in 2008 and 2013 were 8804 and 9244 individuals, respectively. Fish exhibited high fidelity for yearly return to Minas Basin and population estimates indicated the total at-sea number utilizing the Basin increased from c. 10 700 in 2010 to c. 37 500 in 2015. Abundance in the Basin was greatest along the north shore in spring and along the south shore in summer, suggesting clockwise movement following the residual current structure. Marked individuals were recaptured in other bays of the inner Bay of Fundy, north to Gaspe, Quebec, and south to New Jersey, U.S.A., with 26 recoveries from the Saint John River, NB, spawning run. Fish marked at other Canadian and U.S. sites were also recovered in Minas Basin. Since all A. oxyrinchus migrate into and out of the Basin annually they will be at risk of mortality if planned tidal power turbines are installed in Minas Passage. PMID- 27506929 TI - Novel educational interventions in residency increase knowledge of chronic liver disease and career interest in hepatology. AB - : There is an increasing burden of chronic liver disease (CLD) in the United States but a significant shortage of hepatologists. Thus, it is necessary to develop new recruitment strategies to the field of hepatology as well as ensure that non-gastroenterology-trained physicians are able to capably assist in the care of CLD. We established a novel, nonelective, inpatient hepatology rotation that uses required modules in the American Association for the Study of Liver Diseases Curriculum and Training-First Hepatitis B and C curriculums as well as in LiverLearning. A paper-based anonymous assessment was distributed to the inaugural 25 postgraduate years 2 and 3 internal medicine residents before and after the 2-week rotation over the course of 1 year. Both the prerotation and postrotation assessments included validated multiple-choice questions and Likert type questions, which evaluated self-perceived knowledge and comfort with managing CLD. The mean comfort level (1 = not at all comfortable/strongly disagree, 5 = very comfortable/strongly agree) of managing several common liver diseases increased significantly after completion of the rotation (i.e., cirrhosis 2.8 versus 3.8, P < 0.001; hepatitis B 2.4 versus 3.4, P = 0.001; hepatitis C 2.6 versus 3.7, P = 0.002; nonalcoholic steatohepatitis 3.0 versus 4.0, P < 0.001; liver transplant care 2.1 versus 3.4, P < 0.001). There was also a significantly increased interest in hepatology as a career (2.6 versus 3.0, P = 0.03). Finally, the mean percentage of multiple-choice questions answered correctly on the pretest was 62% and posttest was 77% (P = 0.02). CONCLUSION: Our novel curriculum and nonelective hepatology rotation has effectively demonstrated improvement in internal medicine residents' comfort with and knowledge of CLD, and increased career interest in hepatology was also observed after completion of the curriculum, which suggests that more exposure to CLD could positively impact recruitment to the workforce; larger, multicenter studies are needed to validate these results. (Hepatology 2016;64:2210-2218). PMID- 27506931 TI - Corrigendum: Conformational heterogeneity of the calmodulin binding interface. PMID- 27506930 TI - Reduced interfacial recombination in dye-sensitized solar cells assisted with NiO:Eu(3+),Tb(3+) coated TiO2 film. AB - Eu(3+),Tb(3+) doped and undoped NiO films were deposited on TiO2 by a sol-gel spin-coating method as the photoanodes of dye sensitized solar cells (DSSCs). A comparative study with different structures including TiO2, TiO2/NiO and TiO2/NiO:Eu(3+),Tb(3+) as the photoanodes was carried out to illustrate the photovoltaic performance of solar cells. NiO could enhance the performance of DSSCs ascribed to acting as a barrier for the charge recombination from the fluorine doped tin oxide (FTO) to electrolyte and forming a p-n junction (NiO/TiO2). Moreover, Eu(3+), Tb(3+) co-doped NiO could accelerate the electron transfer at TiO2/dye/electrolyte interface, which further benefited the performance of solar cells. The solar cells assembled with the photoelectrodes consisting of NiO:Eu(3+),Tb(3+) and TiO2 exhibited short-circuit current density (JSC) of 17.4 mA cm(-2), open-circuit voltage (VOC) of 780 mV and conversion efficiency of 8.8%, which were higher than that with TiO2/NiO and pure TiO2. The mechanisms of the influence of NiO and NiO:Eu(3+),Tb(3+) on the photovoltaic performance of DSSCs were discussed. PMID- 27506932 TI - Design and application of a target capture sequencing of exons and conserved non coding sequences for the rat. AB - BACKGROUND: Target capture sequencing is an efficient approach to directly identify the causative mutations of genetic disorders. To apply this strategy to laboratory rats exhibiting various phenotypes, we developed a novel target capture probe set, TargetEC (target capture for exons and conserved non-coding sequences), which can identify mutations not only in exonic regions but also in conserved non-coding sequences and thus can detect regulatory mutations. RESULTS: TargetEC covers 1,078,129 regions spanning 146.8 Mb of the genome. We applied TargetEC to four inbred rat strains (WTC/Kyo, WTC-swh/Kyo, PVG/Seac, and KFRS4/Kyo) maintained by the National BioResource Project for the Rat in Japan, and successfully identified mutations associated with these phenotypes, including one mutation detected in a conserved non-coding sequence. CONCLUSIONS: The method developed in this study can be used to efficiently identify regulatory mutations, which cannot be detected using conventional exome sequencing, and will help to deepen our understanding of the relationships between regulatory mutations and associated phenotypes. PMID- 27506933 TI - NUMB negatively regulates the epithelial-mesenchymal transition of triple negative breast cancer by antagonizing Notch signaling. AB - Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with higher rates of early relapse and metastasis, is frequently associated with aberrant activation of epithelial-mesenchymal transition (EMT). Nonetheless, how EMT is initiated and regulated during TNBC progression is not well understood. Here, we report that NUMB is a negative regulator of EMT in both human mammary epithelial cells and breast cancer cells. Reduced NUMB expression was significantly associated with elevated EMT in TNBC. Conversely, overexpression of NUMB strongly attenuated the EMT program and metastasis of TNBC cell lines. Interestingly, we showed that NUMB employs different molecular mechanisms to regulate EMT. In normal mammary epithelial cells and breast cancer cells expressing wild-type p53, NUMB suppressed EMT by stabilizing p53. However, in TNBC cells, loss of NUMB facilitated the EMT program by activating Notch signaling. Consistent with these findings, low NUMB expression and high Notch activity were significantly correlated with the TNBC subtype in patients. Collectively, these findings reveal novel molecular mechanisms of NUMB in the regulation of breast tumor EMT, especially in TNBC. PMID- 27506934 TI - Acute myeloid leukemia stem cell markers in prognosis and targeted therapy: potential impact of BMI-1, TIM-3 and CLL-1. AB - Acute myeloid leukemia (AML) patients show high relapse rates and some develop conventional chemotherapy resistance. Leukemia Stem Cells (LSCs) are the main player for AML relapses and drug resistance. LSCs might rely on the B-cell specific Moloney murine leukemia virus integration site-1 (BMI-1) in promoting cellular proliferation and survival. Growth of LSCs in microenvironments that are deprived of nutrients leads to up-regulation of the signaling pathways during the progression of the disease, which may illustrate the sensitivity of LSCs to inhibitors of those signaling pathways as compared to normal cells. We analyzed the expression of LSC markers (CD34, CLL-1, TIM-3 and BMI-1) using quantitative RT-PCR in bone marrow samples of 40 AML patients of different FAB types (M1, M2, M3, M4, M5, and M7). We also studied the expression of these markers in 2 AML cell lines (Kasumi-1 and KG-1a) using flow cytometry and quantitative RT-PCR. The overexpression of TIM-3, CLL-1, and BMI-1 was markedly correlated with poor prognosis in these patients. Our in vitro findings demonstrate that targeting BMI 1, which markedly increased in the leukemic cells, was associated with marked decrease in leukemic burden. This study also presents results for blocking LSCs' surface markers CD44, CLL-1, and TIM-3. These markers may play an important role in elimination of AML. Our study indicates a correlation between the expression of markers TIM-3, CLL-1, and especially of BMI-1 and the aggressiveness of AML and thus the potential impact of prognosis and therapies that target LSCs on improving the cure rates. PMID- 27506935 TI - RWCFusion: identifying phenotype-specific cancer driver gene fusions based on fusion pair random walk scoring method. AB - While gene fusions have been increasingly detected by next-generation sequencing (NGS) technologies based methods in human cancers, these methods have limitations in identifying driver fusions. In addition, the existing methods to identify driver gene fusions ignored the specificity among different cancers or only considered their local rather than global topology features in networks. Here, we proposed a novel network-based method, called RWCFusion, to identify phenotype specific cancer driver gene fusions. To evaluate its performance, we used leave one-out cross-validation in 35 cancers and achieved a high AUC value 0.925 for overall cancers and an average 0.929 for signal cancer. Furthermore, we classified 35 cancers into two classes: haematological and solid, of which the haematological got a highly AUC which is up to 0.968. Finally, we applied RWCFusion to breast cancer and found that top 13 gene fusions, such as BCAS3 BCAS4, NOTCH-NUP214, MED13-BCAS3 and CARM-SMARCA4, have been previously proved to be drivers for breast cancer. Additionally, 8 among the top 10 of the remaining candidate gene fusions, such as SULF2-ZNF217, MED1-ACSF2, and ACACA-STAC2, were inferred to be potential driver gene fusions of breast cancer by us. PMID- 27506936 TI - PTEN expression is a prognostic marker for patients with non-small cell lung cancer: a systematic review and meta-analysis of the literature. AB - Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a known tumor suppressor in non-small cell lung cancer (NSCLC). By performing a systematic review and meta-analysis of the literature, we determined the prognostic value of decreased PTEN expression in patients with NSCLC. We comprehensively and systematically searched through multiple online databases up to May 22, 2016 for NSCLC studies reporting on PTEN expression and patient survival outcome. Several criteria, including the Newcastle-Ottawa Quality Assessment Scale (NOS), were used to discriminate between studies. In total, 23 eligible studies with a total of 2,505 NSCLC patients were included in our meta-analysis. Our results demonstrated that decreased expression of PTEN correlated with poor overall survival in NSCLC patients and was indicative of a poor prognosis for disease free survival and progression-free survival in patients with NSCLC. PMID- 27506937 TI - Deletion of epidermal Rac1 inhibits HPV-8 induced skin papilloma formation and facilitates HPV-8- and UV-light induced skin carcinogenesis. AB - Overexpression and increased activity of the small Rho GTPase Rac1 has been linked to squamous cell carcinoma of the epidermis and mucosa in humans. Targeted deletion of Rac1 or inhibition of Rac1 activity in epidermal keratinocytes reduced papilloma formation in a chemical skin carcinogenesis mouse model. However, a potential role of Rac1 in HPV- and UV-light induced skin carcinogenesis has not been investigated so far, solar UV radiation being an important carcinogen to the skin.To investigate this, we deleted Rac1 or modulated its activity in mice with transgenic expression of Human papilloma virus type-8 (HPV-8) in epidermal keratinocytes. Our data show that inhibition or deletion of Rac1 results in reduced papilloma formation upon UV-irradiation with a single dose, whereas constitutive activation of Rac1 strongly increases papilloma frequency in these mice. Surprisingly, we observed that, upon chronic UV-irradiation, the majority of mice with transgenic expression of HPV-8 and epidermis specific Rac1 deletion developed squamous cell carcinomas. Taken together, our data show that Rac1 exerts a dual role in skin carcinogenesis: its activation is, on one hand, required for HPV-8- and UV-light induced papilloma formation but, on the other, suppresses the development of squamous cell carcinomas. PMID- 27506938 TI - C23 promotes tumorigenesis via suppressing p53 activity. AB - C23 is an abundant and multi-functional protein, which plays an important role in various biological processes, including ribosome biogenesis and maturation, cell cycle checkpoints and transcriptional regulation [1, 2]. However, the role of C23 in controlling tumorigenesis has not been well defined. Here we report that C23 is highly expressed in cancer cells and the elevated expression of C23 facilitates cancer cell proliferation in vitro and tumor xenograft growth in vivo. Notably, C23 binds to p53 through its GAR domain and suppresses the transcriptional activity of p53 under DNA damage and hypoxia. Moreover, the GAR domain is critical for C23-mediated tumor cell proliferation both in vitro and in vivo. Our findings reveal a novel role of C23 in tumorigenesis and suggest that C23 may represent a potential therapeutic target for treating malignancy. PMID- 27506939 TI - Inhibition of PlexA1-mediated brain tumor growth and tumor-associated angiogenesis using a transmembrane domain targeting peptide. AB - The neuropilin-plexin receptor complex regulates tumor cell migration and proliferation and thus is an interesting therapeutic target. High expression of neuropilin-1 is indeed associated with a bad prognosis in glioma patients. Q RTPCR and tissue-array analyses showed here that Plexin-A1 is highly expressed in glioblastoma and that the highest level of expression correlates with the worse survival of patients. We next identified a developmental and tumor-associated pro angiogenic role of Plexin-A1. Hence, by using molecular simulations and a two hybrid like assay in parallel with biochemical and cellular assays we developed a specific Plexin-A1 peptidic antagonist disrupting transmembrane domain-mediated oligomerization of the receptor and subsequent signaling and functional activity. We found that this peptide exhibits anti-tumor activity in vivo on different human glioblastoma models including glioma cancer stem cells. Thus, screening Plexin-A1 expression and targeting Plexin-A1 in glioblastoma patients exhibit diagnostic and therapeutic value. PMID- 27506940 TI - Aberrant DR5 transport through disruption of lysosomal function suggests a novel mechanism for receptor activation. AB - To examine reciprocal or unilateral implications between two cell destruction processes, autophagy and apoptosis, in 5-Fluorouracil (5-FU)-treated tumor cells, a combination of chemical inhibitors, RNAi and genetic approaches were used. In contrast to cancer cells harboring obstructed apoptosis, either at the DISC or the mitochondrial level, p53-deficiency generated signs of autophagy deregulation upon chemotherapy. On the other, hand disruption of lysosomal function by chloroquine, caused a profound decrease in apoptotic markers appearing in response to 5-FU. DR5, which is essential for 5-FU-induced apoptosis, accumulated in lysosomes and autophagosomes upon chloroquine treatment. Since neither 3-MA, RNAi of critical autophagy regulators or inhibition of cathepsins reversed apoptosis in a similar manner, it is likely that not autophagy per se but rather correct receptor transport is an important factor for 5-FU cytotoxicity. We found that apoptosis generated by TRAIL, the cognate ligand for DR5, remained unchanged upon chloroquine lysosomal interference, indicating that 5-FU activates the receptor by a discrete mechanism. In support, depletion of membrane cholesterol or hampering cholesterol transport drastically reduced 5-FU cytotoxicity. We conclude that targeting of lysosomes by chloroquine deregulates DR5 trafficking and abrogates 5-FU- but not TRAIL-stimulated cell elimination, hence suggesting a novel mechanism for receptor activation. PMID- 27506941 TI - KDM4B plays an important role in mitochondrial apoptosis by upregulating HAX1 expression in colorectal cancer. AB - Histone methyltransferases and demethylases regulate transcription by altering the epigenetic marks on histones in tumorigenesis. Members of the histone lysine(K)-specific demethylase 4 (KDM4) family are dysregulated in several types of cancer. Here, we report a novel role for KDM4B in mitochondrial apoptosis. In this study, we demonstrate that KDM4B is overexpressed in colorectal cancer (CRC) tissues. Decreased expression of KDM4B significantly promoted apoptosis of CRC cell lines. Moreover, our data indicate that HAX1 is required for KDM4B-mediated mitochondrial apoptosis. The transcription of HAX1 was directly activated by KDM4B. We also show that HAX1 is overexpressed in CRC tissues and is positively correlated with KMD4B expression. Collectively, we demonstrate that KDM4B may play an important role in mitochondrial apoptosis and represent a potential therapeutic cancer target in CRC. PMID- 27506942 TI - Prognostic nomogram for post-surgical treatment with adjuvant TACE in hepatitis B virus-related hepatocellular carcinoma. AB - OBJECTIVE: This study sought to establish an effective and reliable prognostic nomogram to guide the decision for post-surgical adjuvant transarterial chemoembolization (PA-TACE) in patients with hepatitis B virus-related (HBV) hepatocellular carcinoma (HCC). RESULTS: The 1, 3, 5-year overall survival rates were, respectively, 87.7%, 52.1% and 28.3% in the patients from the derivation set and 91.7%, 57.1% and 34.1% in those from the validation set. Five risk factors (HBV-DNA level, platelet count, vascular invasion, change of Child-Pugh score, and tumor diameter) in the multivariate analysis were significantly associated with prognosis. The statistical nomogram incorporated these five factors achieved good calibration and discriminatory abilities with c-index of 0.75 (95% CI 0.67 to 0.83). The findings were supported by the independent external validation set (c-index, 0.69; 95% CI 0.56 to 0.83). Patients who had a nomogram score of less than 180 was considered to have higher survival benefit from PA-TACE. METHODS: The nomogram was established based on data obtained from a retrospective study on 235 consecutive patients with HBV HCC who received PA-TACE as an initial therapy from 2006 to 2010 in our center. 84 patients who were collected at another institution between 01/2008 and 12/2010 served as an external validation set. The prognostic nomogram was developed based on the data obtained before the PA-TACE procedure. Predictive accuracy and discriminative ability of the nomogram were assessed by concordance index (C-index), calibration curves, and validation set. CONCLUSIONS: The novel nomogram may achieve an optimal prognostic prediction for PA-TACE in HBV-related HCC. PMID- 27506945 TI - Sunitinib as salvage treatment including potent anti-tumor activity in carcinomatous ulcers for patients with multidrug-resistant metastatic breast cancer. AB - OBJECTIVE: To evaluate the efficacy and safety of single-agent sunitinib as salvage treatment in Chinese patients with multidrug-resistant metastatic breast cancer (MBC). RESULTS: 37 patients were enrolled with median age of 48 years. 17 had hormone receptor (HR)-positive tumors, 7 had HER2-positive tumors, and 10 had triple-negative tumors. Among 32 evaluable patients with follow-up, 6 (18.8%) achieved partial response, 14 (43.8%) achieved stable disease, and 11 (34.4%) exhibited tumor shrinkage. The response rate in 9 patients with carcinomatous ulcers was 77.8%. The median progression free survival (PFS) was 8.6 weeks. Patients with a better response had improved overall survival and PFS relative to patients with a worse response (p = 0.007, p < 0.001). Compared with HR-negative tumor, HR-positive tumor had significantly better response to sunitinib (p = 0.035). The most frequent non-hematologic adverse events were fatigue (82.8%) and hypertension (34.5%). Grade 3/4 hematologic toxicity included neutropenia (82.8%) and thrombocytopenia (79.3%). There was no correlation between the clinical response and IHC findings. MATERIALS AND METHODS: Patients with MBC who were resistant to multiple salvage regimens (>= 3 previous chemotherapy lines) were enrolled to receive sunitinib monotherapy. Dosage adjustment was allowed depending on adverse events. 14 patients underwent immunohistochemistry (IHC) testing for VEGF, PDGFR, EGFR and c-KIT. CONCLUSIONS: Sunitinib salvage treatment provided modest antitumor effect to patients with refractory multidrug-resistant MBC, especially to those with troublesome carcinomatous ulcers. The treatment related adverse events of sunitinib were manageable through dosage adjustment. PMID- 27506944 TI - RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors. AB - The factors triggering pancreatic neuroendocrine tumor (PanNET) progression are largely unknown. Here we investigated the role and mechanisms of the sumoylation enhancing protein RSUME in PanNET tumorigenesis. Immunohistochemical studies showed that RSUME is strongly expressed in normal human pancreas, in particular in beta-cells. RSUME expression is reduced in insulinomas and is nearly absent in other types of PanNETs suggesting a role in PanNET tumorigenesis. In human pancreatic neuroendocrine BON1 cells, RSUME stimulates hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor-A (VEGF-A), which are key components of tumor neovascularisation. In contrast, RSUME suppresses nuclear factor-kappaB (NF-kappaB) and its target interleukin-8 (IL-8). Correspondingly, PanNET cells with RSUME knockdown showed decreased HIF-1alpha activity and increased NF-kappaB and IL-8 production leading to a moderate reduction of VEGF-A release as reduced HIF-1alpha/VEGF-A production is partly compensated by NF kappaB/IL-8-induced VEGF-A. Notably, RSUME stabilizes the tumor suppressor PTEN, which is frequently lost in PanNETs and whose absence is associated with metastasis formation. In vivo orthotopic transplantation of PanNET cells with or without RSUME expression into nude mice showed that PanNETs without RSUME have reduced PTEN expression, grow faster and form multiple liver metastases. In sum, RSUME differentially regulates key components of PanNET formation suggesting that the observed loss of RSUME in advanced PanNETs is critically involved in PanNET tumorigenesis, particularly in metastasis formation. PMID- 27506946 TI - A general strategy to optimize immunogenicity of HLA-B*0702 restricted cryptic peptides from tumor associated antigens: Design of universal neo-antigen like tumor vaccines for HLA-B*0702 positive patients. AB - Tumor Associated Antigens (TAAs) are the privileged targets of almost all the cancer vaccines tested to date. Unfortunately all these vaccines failed to show a clinical efficacy. The main reason for this failure is the immune tolerance to TAAs that are self-proteins expressed by normal and cancer cells. Self-tolerance to TAAs is directed against their dominant rather than against their cryptic epitopes. The best way to overcome self-tolerance to TAAs would therefore be to target their cryptic epitopes. However, because of their low HLA-I affinity, cryptic peptides are non-immunogenic and cannot be used to stimulate an antitumor immune response unless their immunogenicity has been previously enhanced. In this paper we describe a general approach to enhance immunogenicity of almost all the HLA-B*0702 restricted cryptic peptides derived from TAAs. It consists in substituting residues at position 1 or 9 of low HLA-B*0702 affinity cryptic peptides by an Alanine or a Leucine respectively. These substitutions increase affinity of peptides for HLA-B*0702. These optimized cryptic peptides are strongly immunogenic and very importantly CTL they stimulate recognize their native counterparts.TAAs derived optimized cryptic peptides can be considered as universal antitumor vaccine since they escape self-tolerance, are immunogenic and are not patient specific. PMID- 27506948 TI - Acinetobacter spp. are associated with a higher mortality in intensive care patients with bacteremia: a survival analysis. AB - BACKGROUND: It has been challenging to determine the true clinical impact of Acinetobacter spp., due to the predilection of this pathogen to colonize and infect critically ill patients, who often have a poor prognosis. The aim of this study was to assess whether Acinetobacter spp. bacteremia is associated with lower survival compared with bacteremia caused by other pathogens in critically ill patients. METHODS: This study was performed at Hospital das Clinicas, University of Sao Paulo, Brazil. There are 12 intensive care units (ICUs) in the hospital: five Internal Medicine ICUs (emergency, nephrology, infectious diseases and respiratory critical care), three surgical ICU (for general surgery and liver transplantion), an Emergency Department ICU for trauma patients, an ICU for burned patients, a neurosurgical ICU and a post-operative ICU. A retrospective review of medical records was conducted for all patients admitted to any of the ICUs, who developed bacteremia from January 2010 through December 2011. Patients with Acinetobacter spp. were compared with those with other pathogens (Klebsiella pneumoniae, Staphylococcus aureus, Enterobacter spp., Enterococcus spp., Pseudomonas aeruginosa). We did a 30-day survival analysis. The Kaplan-Meier method and log-rank test were used to determine the overall survival. Potential prognostic factors were identified by bivariate and multivariate Cox regression analysis. RESULTS: One hundred forty-one patients were evaluated. No differences between patients with Acinetobacter spp. and other pathogens were observed with regard to age, sex, APACHE II score, Charlson Comorbidity Score and type of infection. Initial inappropriate antimicrobial treatment was more frequent in Acinetobacter bacteremia (88 % vs 51 %). Bivariate analysis showed that age > 60 years, diabetes mellitus, and Acinetobacter spp. infection were significantly associated with a poor prognosis. Multivariate model showed that Acinetobacter spp. infection (HR = 1.93, 95 % CI: 1.25-2.97) and age > 60 years were independent prognostic factors. CONCLUSION: Acinetobacter is associated with lower survival compared with other pathogens in critically ill patients with bacteremia, and is not merely a marker of disease severity. PMID- 27506947 TI - G-protein-coupled receptors mediate omega-3 PUFAs-inhibited colorectal cancer by activating the Hippo pathway. AB - Colorectal cancer (CRC) is one of the most common cancers leading to high mortality. However, long-term administration of anti-tumor therapy for CRC is not feasible due to the side effects. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs), particularly DHA and EPA, exert protection against CRC, but the mechanisms are unclear. Here, we show that omega-3 PUFAs inhibit proliferation and induce apoptosis of CRC cells in vitro and alleviate AOM/DSS-induced mice colorectal cancer in vivo. Moreover, omega-3 PUFAs promote phosphorylation and cytoplasmic retention of YAP and this effect was mediated by MST1/2 and LATS1, suggesting that the canonical Hippo Pathway is involved in omega-3 PUFAs function. We further confirmed that increase of pYAP by omega-3 PUFAs was mediated by GPRs, including GPR40 and GPR120, which subsequently activate PKA via Galphas, thus inducing the Hippo pathway activation. These data provide a novel DHA/EPA-GPR40/120-Galphas-PKA-MST1/2-LATS1-YAP signaling pathway which is linked to omega-3 PUFAs-induced inhibition of cell proliferation and promotion of apoptosis in CRC cells, indicating a mechanism that could explain the anti-cancer action of omega-3 PUFAs. PMID- 27506949 TI - ETV6 rearrangement in a case of mammary analogue secretory carcinoma of the skin. AB - Mammary analog secretory carcinoma of salivary glands is a relatively recently recognized entity that harbors the ETV6-NTRK3 fusion transcript. To date, only rare cases of mammary analog secretory carcinoma of the skin have been reported. A 57-year-old man presented with a 6.0 cm cystic mass in the axilla, involving the dermis and superficial subcutis. Microscopically, the tumor exhibited nodular aggregation of tubular and microcystic structures embedded in the dense fibrotic and hyalinized stroma. Characteristic 'colloid-like' eosinophilic secretory material was present within intraluminal spaces. Tumor cells were largely characterized by vesicular nuclei with inconspicuous nucleoli and pink vacuolated cytoplasm. With respect to immunohistochemistry, tumor cells were intensely positive for AE1/AE3, Cam 5.2, and CK7, whereas Ber-EP4 and CEA were completely negative. A dual color break-apart fluorescence in situ hybridization probe identified rearrangement of the ETV6 gene locus on chromosome 12. The patient is alive with no evidence of recurrent disease or metastasis 3 years after the initial surgery. In conclusion, we report a rare example of mammary analog secretory carcinoma of the skin with ETV6 rearrangement. Awareness of this unique cutaneous tumor and subsequent reporting of additional cases is necessary for better characterization of its completely clinicopathologic spectrum. PMID- 27506950 TI - Re: Alexander Kutikov, Marc C. Smaldone, Robert G. Uzzo, Miki Haifler, Gennady Bratslavsky, Bradley C. Leibovich. Renal Mass Biopsy: Always, Sometimes, or Never? Eur Urol 2016;70:403-6. PMID- 27506951 TI - Medical Expulsive Therapy for Ureterolithiasis: The EAU Recommendations in 2016. AB - Medical expulsive therapy (MET), in particular alpha-blockers, have been recommended as supportive medication if observational treatment of a ureteral stone was an option. Over the years, a considerable number of randomized controlled trials (RCT) as well as several meta-analyses have been published on MET, supporting the use of alpha-blockers. However, several recently published high quality, large, placebo-controlled randomized trials raised serious doubts about the effectiveness of alpha-blockers. The contradictory results of meta analyses of small RCTs versus the findings of large, well conducted multicenter trials show the methodological vulnerability of meta-analyses, in particular if small single center, lower quality, papers have been included. Small single center trials, for instance, tend to show larger treatment effects compared to multicenter RCTs. It also shows the responsibility of careful planning when conducting a RCT. Trial registration as a prerequisite for approval by ethics committees could in addition minimize publication bias. Weighting the current evidence on whether to use MET, or not, it seems that in distal ureteral stones larger than 5mm, there may be a potential therapeutic benefit for the use of alpha-blockers. Patients should be informed about the possible, but as yet unproven benefit of using alpha-blockers in this situation, as well as their off label use and potential side effects. PMID- 27506952 TI - Fine mapping of a dominant gene conferring chlorophyll-deficiency in Brassica napus. AB - Leaf colour regulation is important in photosynthesis and dry material production. Most of the reported chlorophyll-deficient loci are recessive. The dominant locus is rarely reported, although it may be more important than the recessive locus in the regulation of photosynthesis efficiency. During the present study, we mapped a chlorophyll-deficient dominant locus (CDE1) from the ethyl methanesulfonate-mutagenized Brassica napus line NJ7982. Using an F2 population derived from the chlorophyll-deficient mutant (cde1) and the canola variety 'zhongshuang11', a high-density linkage map was constructed, consisting of 19 linkage groups with 2,878 bins containing 13,347 SNP markers, with a total linkage map length of 1,968.6 cM. Next, the CDE1 locus was mapped in a 0.9-cM interval of chromosome C08 of B. napus, co-segregating with nine SNP markers. In the following fine-mapping of the gene using the inherited F2:3 populations of 620 individuals, the locus was identified in an interval with a length of 311 kb. A bioinformatics analysis revealed that the mapping interval contained 22 genes. These results produced a good foundation for continued research on the dominant locus involved in chlorophyll content regulation. PMID- 27506953 TI - Influence of HLA-DR polymorphism and allergic sensitization on humoral immune responses to intact pneumococcus in a transgenic mouse model. AB - Asthma is independently associated with HLA-DR3 and increased risks of pneumococcal diseases. We aimed to determine whether HLA-DR polymorphism (HLA DRB1*03), sensitization to house dust mite (HDM), or their interaction affects humoral immune responses to pneumococcal polysaccharide and protein antigens of intact pneumococci. Induction of serum titers of anti-pneumococcal polysaccharide and anti-surface protein IgM and IgG in response to immunization with intact pneumococci (Pn) serotype 14 was determined using humanized HLA-DR3 and DR2 transgenic mice. Transgenic mice were sensitized by injecting HDM and challenged with intranasal HDM. Mice were subsequently immunized with heat-killed Pn14 at day 24. Serum titers of anti-phosphorylcholine (PC) IgM and IgG, anti pneumococcal polysaccharide, capsular type 14 (PPS14) IgM and IgG, and anti pneumococcal surface protein A (PspA) IgG were measured. We included a total of 44 mice (22 DR3 and 22 DR2 mice) and half of mice in each group were sensitized with HDM (i.e. 22 HDM-sensitized and 22 control mice). HDM-sensitized mice, irrespective of HLA-DR polymorphism, had significantly lower humoral immune responses. HLA-DR3 mice, irrespective of HDM sensitization, elicited a significantly lower anti-PC IgG response. In contrast, the anti-PspA IgG response was higher in DR3 relative to DR2 mice. The effect of HDM sensitization on lowering humoral immune responses to Pn14 was observed in DR3 mice regardless of the nature of the antigen, whereas such decreases were observed only for the anti PPS14 IgG and anti-PC IgM responses in DR2 mice. HDM sensitization lowered humoral immune responses to intact pneumococcus and this effect was significantly modified by the HLA-DR polymorphism. PMID- 27506954 TI - Olaparib for Maintenance Treatment of BRCA 1 or 2 Mutated, Relapsed, Platinum Sensitive Ovarian, Fallopian Tube and Peritoneal Cancer in People Whose Relapsed Disease has Responded to Platinum-Based Chemotherapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - As part of its Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of olaparib (AstraZeneca) to submit evidence on the clinical and cost effectiveness of olaparib for the maintenance treatment of BRCA1/2 mutated (BRCAm), platinum sensitive relapsed (PSR) ovarian, fallopian tube and peritoneal cancer in people whose relapsed disease has responded to platinum-based chemotherapy. The Evidence Review Group (ERG) produced a critical review of the evidence contained within the company's submission (CS) to NICE. The clinical evidence related to one phase II, double-blind randomised controlled trial that recruited 265 patients with PSR serous ovarian cancer (OC) regardless of BRCAm status. Patients received olaparib 400 mg twice daily (b.i.d.) or matched placebo. In the whole population, the primary endpoint of progression-free survival (PFS) was met (hazard ratio [HR] 0.35; 95 % confidence interval [CI] 0.25-0.49, p < 0.01) for olaparib versus placebo. The BRCAm subgroup analysis (added after the study commenced but 1 month before the primary analysis was undertaken) reported an HR for PFS of 0.18 (95 % CI 0.10-0.31, p < 0.0001) for olaparib versus placebo, though interaction tests appeared inconclusive. Overall survival was not statistically significant in the whole group (HR 0.88; 95 % CI 0.64-1.21; p = 0.44) or the BRCAm subgroup (0.73; 95 % CI 0.45-1.17; p = 0.19), though treatment switching may have confounded results. The exclusion of data from sites allowing crossover resulted in an HR for overall survival (OS) of 0.52 (95 % CI 0.28-0.97, p = 0.039) in the BRCAm group. Health-related quality-of-life measures were not significantly different between groups. All post hoc exploratory outcomes (time to treatment discontinuation/death, time to first subsequent therapy/death, and time to second subsequent therapy/death) were statistically significantly better in the olaparib arm in the whole population and the BRCAm subgroup analyses. Adverse events were more frequent for olaparib but were largely minor or manageable. The company's semi-Markov model assessed the cost effectiveness of olaparib versus routine surveillance in patients with BRCAm PSR OC from a National Health Service (NHS) and Personal Social Services (PSS) perspective over a lifetime horizon. The model suggests that the incremental cost-effectiveness ratio (ICER) for olaparib versus routine surveillance is expected to be approximately L49,146 per quality-adjusted life-year (QALY) gained. The ERG did not consider the company's cost effectiveness estimates to be credible. Additional ERG analyses suggested that the ICER is likely to be more than L92,214 per QALY gained. Additional analyses provided by the company in patients who received three or more lines of chemotherapy suggested a more favourable cost-effectiveness profile for olaparib. The NICE Appraisal Committee recommended olaparib for this subgroup provided the cost of olaparib for people who continue to receive treatment after 15 months will be met by the company. PMID- 27506956 TI - Letter to the Editor. PMID- 27506955 TI - Antinociceptive action of botulinum toxin type A in carrageenan-induced mirror pain. AB - "Mirror pain" or mirror-image pain (MP) is pain opposite to the side of injury. Mechanism and frequency in humans are not known. There is no consent on therapy. Here we report that unilaterally injected botulinum toxin type A (BT-A) has bilateral effect in experimental MP, thus deserves to be investigated as therapy for this condition. We examined the localization of BT-A's bilateral antinociceptive action in MP induced by 3 % carrageenan intramuscular injection in Wistar rats. BT-A was applied peripherally (5 U/kg), into ipsilateral or contralateral hind paw pad (i.pl.) and centrally (1 U/kg), at spinal (intrathecally, i.t.) or supraspinal (intracisternally, i.c.) level. Additionally, we examined the involvement of central opioid and GABAergic systems, as well as the contribution of peripheral capsaicin-sensitive neurons to BT-A's bilateral antinociceptive effect. Ipsilateral i.pl. and i.t. BT-A reduced the bilateral mechanical sensitivity to von Frey filaments, while contralateral i.pl. and i.c. treatments had no effect on either tested side. Bilateral antinociceptive effect of ipsilateral i.pl. BT-A was prevented by MU-opioid antagonist naloxonazine (1.5 MUg/10 MUl) and GABAA antagonist bicuculline (1 MUg/10 MUl) if applied at the spinal level, in contrast to supraspinal application of the same doses. Local treatment of sciatic nerve with 2 % capsaicin 5 days following BT-A i.pl. injection caused desensitization of sciatic capsaicin-sensitive fibers, but did not affect bilateral antinociceptive effect of BT-A and the presence of cleaved SNAP-25 at the spinal cord slices. Present experiments suggest segmental actions of peripheral BT-A at spinal level, which are probably not solely dependent on capsaicin-sensitive neurons. PMID- 27506957 TI - Correlations of Promoter Methylation in WIF-1, RASSF1A, and CDH13 Genes with the Risk and Prognosis of Esophageal Cancer. AB - BACKGROUND This study was designed to explore the correlations of promoter methylation in Wnt inhibitory factor-1 (WIF-1), ras-association domain family member 1A (RASSF1A), and Cadherin 13 (CDH13) genes with the risk and prognosis of esophageal cancer (EC). MATERIAL AND METHODS A total of 71 EC tissues from resection and 35 adjacent normal tissues were collected. Methylation status in the promoter region was detected by methylation- and non-methylation-specific primers. Corresponding mRNA levels were detected by reverse transcriptase polymerase chain reaction (RT-PCR). Correlations between the methylations of these 3 genes and clinicopathologic characteristics were analyzed. Kaplan-Meier method and Cox regression model were used to investigate the relationships between WIF-1, RASSF1A, and CDH13 promoter methylations and the prognosis of EC. RESULTS Compared with adjacent normal tissues, the methylation frequencies of WIF 1, RASSF1A, and CDH13 genes were significantly higher but the mRNA levels of these 3 genes were significantly lower in EC tissues (all P<0.05). WIF-1 and CDH13 promoter methylations were associated with the degree of tumor differentiation and WIF-1 and RASSF1A promoter methylations were associated with age (all P<0.05). The survival rates of patients with WIF-1, RASSF1A, and CDH13 methylations were significantly lower than those of patients without methylation (all P<0.05). WIF-1, RASSF1A, and CDH13 promoter methylations were independent risk factors affecting the prognosis of EC (all P<0.05). CONCLUSIONS WIF-1, RASSF1A, and CDH13 promoter methylations are associated with EC. The methylation levels are negatively related with the prognosis in EC. PMID- 27506958 TI - Barren-ground caribou (Rangifer tarandus groenlandicus) behaviour after recent fire events; integrating caribou telemetry data with Landsat fire detection techniques. AB - Fire regimes are changing throughout the North American boreal forest in complex ways. Fire is also a major factor governing access to high-quality forage such as terricholous lichens for barren-ground caribou (Rangifer tarandus groenlandicus). Additionally, fire alters forest structure which can affect barren-ground caribou's ability to navigate in a landscape. Here, we characterize how the size and severity of fires are changing across five barren-ground caribou herd ranges in the Northwest Territories and Nunavut, Canada. Additionally, we demonstrate how time since fire, fire severity, and season result in complex changes in caribou behavioural metrics estimated using telemetry data. Fire disturbances were identified using novel gap-free Landsat surface reflectance composites from 1985 to 2011 across all herd ranges. Burn severity was estimated using the differenced normalized burn ratio. Annual area burned and burn severity were assessed through time for each herd and related to two behavioural metrics: velocity and relative turning angle. Neither annual area burned nor burn severity displayed any temporal trend within the study period. However, certain herds, such as the Ahiak/Beverly, have more exposure to fire than other herds (i.e. Cape Bathurst had a maximum forested area burned of less than 4 km2 ). Time since fire and burn severity both significantly affected velocity and relative turning angles. During fall, winter, and spring, fire virtually eliminated foraging focused behaviour for all 26 years of analysis while more severe fires resulted in a marked increase in movement-focused behaviour compared to unburnt patches. Between seasons, caribou used burned areas as early as 1-year postfire, demonstrating complex, nonlinear reactions to time since fire, fire severity, and season. In all cases, increases in movement-focused behaviour were detected postfire. We conclude that changes in caribou behaviour immediately postfire are primarily driven by changes in forest structure rather than changes in terricholous lichen availability. PMID- 27506959 TI - A regioselective double Stille coupling reaction of bicyclic stannolanes. AB - A regioselective double Stille coupling reaction was explored using bicyclic stannolanes that were easily prepared from the radical cascade reaction of beta amino-alpha-methylene esters. Various 1-bromo-2-iodoarenes underwent the double coupling reaction to afford benzoisoindole derivatives in a regioselective manner, where the carbon attached to the iodine selectively coupled with the vinylic carbon, and then the carbon attached to bromine coupled with the alkyl carbon. The combination of intra- and intermolecular coupling reactions provided hexahydroindeno[1,2-b]pyrrole derivatives in good yields. The yields were further improved in the presence of excess amounts of CsF. An attempt to identify the reaction intermediate was made wherein the decomposition of the stannolanes with aqueous HCl and HBr afforded trigonal bipyramidal (TBP) pentacoordinated tin complexes, as confirmed by microanalyses and (119)Sn NMR. Using DCl for the decomposition selectively introduced a deuterium to the E-position of the exomethylene unit. The complexes smoothly underwent the intramolecular Stille coupling reaction in the presence of both a palladium catalyst and DABCO, affording hexahydroindeno[1,2-b]pyrroles in good yields. These results suggest that the double coupling reaction progresses through a TBP tin complex, promoting the second intramolecular coupling reaction between the aryl halide and Csp(3) tin bond. PMID- 27506960 TI - Wide dynamic range of surface-plasmon-resonance-based assay for hepatitis B surface antigen antibody optimal detection in comparison with ELISA. AB - Limit of detection (LOD), limit of quantification, and the dynamic range of detection of hepatitis B surface antigen antibody (anti-HBs) using a surface plasmon resonance (SPR) chip-based approach with Pichia pastoris-derived recombinant hepatitis B surface antigen (HBsAg) as recognition element were established through the scouting for optimal conditions for the improvement of immobilization efficiency and in the use of optimal regeneration buffer. Recombinant HBsAg was immobilized onto the sensor surface of a CM5 chip at a concentration of 150 mg/L in sodium acetate buffer at pH 4 with added 0.6% Triton X-100. A regeneration solution of 20 mM HCl was optimally found to effectively unbind analytes from the ligand, thus allowing for multiple screening cycles. A dynamic range of detection of ~0.00098-0.25 mg/L was obtained, and a sevenfold higher LOD, as well as a twofold increase in coefficient of variance of the replicated results, was shown as compared with enzyme-linked immunosorbent assay (ELISA). Evaluation of the assay for specificity showed no cross-reactivity with other antibodies tested. The ability of SPR chip-based assay and ELISA to detect anti-HBs in human serum was comparable, indicating that the SPR chip-based assay with its multiple screening capacity has greater advantage over ELISA. PMID- 27506961 TI - An altered gut microbiota may trigger autoimmune-mediated acquired bone marrow failure syndromes. PMID- 27506962 TI - Laboratory testing for the diagnosis, evaluation, and management of systemic lupus erythematosus: Still more questions for the next generations: A Tribute and Thanks and in Memory of my mentor: Henry G. Kunkel. AB - This paper is a review, personal memoir, a tribute to Henry Kunkel, and a critique regarding laboratory tests used for the evaluation, diagnosis, and understanding Autoimmune Rheumatic Diseases, in particular systemic lupus erythematosus (SLE). PMID- 27506964 TI - A Quick-responsive DNA Nanotechnology Device for Bio-molecular Homeostasis Regulation. AB - Physiological processes such as metabolism, cell apoptosis and immune responses, must be strictly regulated to maintain their homeostasis and achieve their normal physiological functions. The speed with which bio-molecular homeostatic regulation occurs directly determines the ability of an organism to adapt to conditional changes. To produce a quick-responsive regulatory system that can be easily utilized for various types of homeostasis, a device called nano-fingers that facilitates the regulation of physiological processes was constructed using DNA origami nanotechnology. This nano-fingers device functioned in linked open and closed phases using two types of DNA tweezers, which were covalently coupled with aptamers that captured specific molecules when the tweezer arms were sufficiently close. Via this specific interaction mechanism, certain physiological processes could be simultaneously regulated from two directions by capturing one biofactor and releasing the other to enhance the regulatory capacity of the device. To validate the universal application of this device, regulation of the homeostasis of the blood coagulant thrombin was attempted using the nano-fingers device. It was successfully demonstrated that this nano-fingers device achieved coagulation buffering upon the input of fuel DNA. This nano device could also be utilized to regulate the homeostasis of other types of bio molecules. PMID- 27506965 TI - AdoMet analog synthesis and utilization: current state of the art. AB - S-Adenosyl-l-methionine (AdoMet) is an essential enzyme cosubstrate in fundamental biology with an expanding range of biocatalytic and therapeutic applications. In recent years, technologies enabling the synthesis and utilization of novel functional AdoMet surrogates have rapidly advanced. Developments highlighted within this brief review include improved syntheses of AdoMet analogs, unique S-adenosyl-l-methionine isosteres with enhanced stability, and corresponding applications in epigenetics, proteomics and natural product/small molecule diversification ('alkylrandomization'). PMID- 27506966 TI - Microstructural, mechanical, and histological evaluation of modified alginate based scaffolds. AB - Scaffolds are three-dimensional structures used for tissue regeneration being the base in tissue engineering. These scaffolds are obtained from natural and/or synthetic polymers and they should satisfy some specific requirements such as biocompatibility, suitable mechanical, and microstructural properties to favor cellular adhesion and neovascularization. This work shows a preclinic study about the production of low and medium molecular weight alginate through the use of calcium salts (calcium glutamate). The results showed prove that better structures, distribution, and pore sizes as well as better mechanical properties correspond to medium molecular weight alginate and higher calcium salts concentration. This type of scaffold, after muscular cells cultivation, has been proved as an excellent material for muscle growth. The histopathological analysis shows a low inflammatory response, without a foreign body reaction, suitable neovascularization and good fibroblasts incorporation. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3107-3114, 2016. PMID- 27506967 TI - Clinical Faceoff: Slightly Displaced, Isolated, Partial Articular Fracture of the Radial Head. PMID- 27506968 TI - CORR Insights(r): What Factors are Predictive of Patient-reported Outcomes? A Prospective Study of 337 Shoulder Arthroplasties. PMID- 27506969 TI - Cochrane in CORR (r): Surgical Versus Non-surgical Interventions for Treating Patellar Dislocation (Review). PMID- 27506970 TI - T1rho Hip Cartilage Mapping in Assessing Patients With Cam Morphology: How Can We Optimize the Regions of Interest? AB - BACKGROUND: T1rho MRI has been shown feasible to detect the biochemical status of hip cartilage, but various region-of-interest strategies have been used, compromising the reproducibility and comparability between different institutions and studies. QUESTIONS/PURPOSES: The purposes of this study were (1) to determine representative regions of interest (ROIs) for cartilage T1rho mapping in hips with a cam deformity; and (2) to assess intra- and interobserver reliability for cartilage T1rho mapping in hips with a cam deformity. METHODS: The local ethics committee approved this prospective study with written informed consent obtained. Between 2010 and 2013, in 54 hips (54 patients), T1rho 1.5-T MRI was performed. Thirty-eight hips (38 patients; 89% male) with an average age of 35 +/- 7.5 years (range, 23-51 tears) were diagnosed with a cam deformity; 16 hips (16 patients; 87% male) with an average age of 34 +/- 7 years (range, 23-47 years) were included in the control group. Of the 38 patients with a cam deformity, 20 were pain-free and 18 symptomatic patients underwent surgery after 6 months of failed nonsurgical management of antiinflammatories and physical therapy. Exclusion criteria were radiologic sings of osteoarthritis with Tonnis Grade 2 or higher as well as previous hip surgery. Three region-of-interest (ROI) selections were analyzed: Method 1: as a whole; Method 2: as 36 to 54 small ROIs (sections of 30 degrees in the sagittal plane and 3 mm in the transverse plane); Method 3a: as six ROIs (sections of 90 degrees in the sagittal plane and one-third of the acetabular depth in the transverse plane: the anterosuperior and posterosuperior quadrants, divided into lateral, intermediate, and medial thirds); and Method 3b: as the ratio (anterosuperior over posterosuperior quadrant). ROIs in Method 3 represent the region of macroscopic cartilage damage, described in intraoperative findings. To asses interobserver reliability, 10 patients were analyzed by two observers (HA, GM). For intraobserver reliability, 20 hip MRIs were analyzed twice by one observer (HA). To assess interscan reliability, three patients underwent two scans within a time period of 2 weeks and were analyzed twice by one observer (HA). T1rho values were compared using Student's t test. Interclass correlation coefficient (ICC) and root mean square coefficient of variation (RMS CV) were used to analyze intraobserver, interobserver, and interscan reliability. RESULTS: Patients with a cam deformity showed increased T1rho values in the whole hip cartilage (mean: 34.0 +/- 3.8 ms versus 31.4 +/- 3.0 ms; mean difference: 2.5; 95% confidence interval [CI], 4.7-0.4; p = 0.019; Method 1), mainly anterolateral (2), in the lateral and medial thirds of the anterosuperior quadrant (mean: 32.3 +/- 4.9 ms versus 29.4 +/- 4.1 ms; mean difference: 3.0; 95% CI, 5.8-0.2; p = 0.039 and mean 36.5 +/- 5.6 ms versus 32.6 +/- 3.8 ms; mean difference: 3.8; 95% CI, 6.9-0.8; p = 0.014), and in the medial third of the posterosuperior quadrant (mean: 34.4 +/- 5.5 ms versus 31.1 +/- 3.9 ms; mean difference: 3.1; 95% CI, 6.2-0.1; p = 0.039) (3a). The ratio was increased in the lateral third (mean: 1.00 +/- 0.12 versus 0.90 +/- 0.15; mean difference: 0.10; 95% CI, 0.18-0.2; p = 0.018) (3b). ICC and RMS-CV were 0.965 and 4% (intraobserver), 0.953 and 4% (interobserver), and 0.988 (all p < 0.001) and 9% (inter-MR scan), respectively. CONCLUSIONS: Cartilage T1rho MRI mapping in hips is feasible at 1.5 T with strong inter-, intraobserver, and inter-MR scan reliability. The six ROIs (Method 3) showed a difference of T1rho values anterolateral quadrant, consistent with the dominant area of cartilage injury in cam femoroacetabular impingement, and antero- and posteromedial, indicating involvement of the entire hip cartilage health. The six ROIs (Method 3) have been shown feasible to assess cartilage damage in hips with a cam deformity using T1rho MRI. We suggest applying this ROI selection for further studies using quantitative MRI for assessment of cartilage damage in hips with a cam deformity to achieve better comparability and reproducibility between different studies. The application of this ROI selection on hips with other deformities (eg, pincer deformity, developmental dysplasia of the hip, and acetabular retroversion) has to be analyzed and potentially adapted. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 27506971 TI - Is Botulinum Toxin Type A a Valuable Adjunct During Femoral Lengthening? A Randomized Trial. AB - BACKGROUND: Reduced joint ROM and distraction-induced pain are common complaints of patients who have undergone gradual femoral lengthening. Attempts to reduce the effects of lengthening on joint motion have included the use of botulinum toxin to reduce the muscle forces that restrict motion. The benefits of this approach during femoral lengthening, however, have not been conclusively established. QUESTIONS/PURPOSES: We wished to evaluate the effects of botulinum toxin type A (BtX-A) injection in the anterior thigh muscles during femoral distraction osteogenesis on adjacent joint ROM and distraction-induced pain. We asked: (1) Does injection of BtX-A in the quadriceps muscles lead to improved knee and hip motion during femoral lengthening? (2) Does injection of BtX-A reduce pain during femoral lengthening? METHODS: A single-center, double-blind, randomized placebo-controlled trial was conducted. Forty-four patients (88 femurs) undergoing bilateral femoral lengthening for familial short stature were included in the study. BtX-A (200 IU) was injected intraoperatively in the quadriceps muscles of one thigh. An equal volume of sterile normal saline was injected in the other thigh as a control. Selection of the limb receiving the toxin was randomized. Clinical evaluation included a VAS score for pain measurement, ROM evaluation of the hips and knees, and measurement of thigh circumference. Side-to-side differences were analyzed throughout the entire consolidation phase. No patients were lost to followup, leaving 44 patients (88 femurs). The mean followup was 26 months (range, 14-40 months). The distraction rate and final length of gain were similar between treated and control limbs. A priori power analysis suggested that 44 legs were required in each group to achieve statistical significance of 0.05 with 90% power to detect a 50% difference in treatment effect between treatment and control groups. RESULTS: There were no differences in hip ROM, knee ROM, or maximal thigh circumference between the two lower extremities at any time during the study period. VAS scores were no different between the patients who received BtX-A and those who received saline. CONCLUSIONS: Local injection of 200 IU BtX-A in the quadriceps muscles does not appear to reduce distraction-induced pain nor enhance ROM in the hip or knee during femoral lengthening. Additional studies are needed to evaluate the effect of larger doses or different injection methods. Based on our findings, we do not recommend routine use of botulinum injections during limb lengthening and believe any further use of this drug should only be in the context of a controlled trial. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 27506972 TI - CORR Insights(r): Two- to 4-year Followup of a Short Stem THA Construct: Excellent Fixation, Thigh Pain a Concern. PMID- 27506973 TI - What is the Prevalence of Radiographic Hip Findings Associated With Femoroacetabular Impingement in Asymptomatic Asian Volunteers? AB - BACKGROUND: Morphologic features of the proximal femur reminiscent of those seen in patients with femoroacetabular impingement (FAI) have been reported among asymptomatic individuals in Western populations, but whether this is the case in Asian populations is unknown. QUESTIONS/PURPOSES: The purpose of this study was to determine the prevalence of radiographic findings in the proximal femur that are consistent with FAI in asymptomatic Korean volunteers. METHODS: Two hundred asymptomatic volunteers with no prior hip surgery or childhood hip problems underwent three-view plain radiographs (pelvis AP view, Sugioka view, and 45 degrees Dunn view) of both hips. There were 146 hips from male volunteers and 254 hips from female volunteers in the study. The mean age of all participants was 34.7 years (range, 21-49 years). Cam-type morphologic features were defined as the presence of the following on one or more of the three views: pistol-grip morphologic features, an osseous bump at the femoral head-neck junction, flattening of the femoral head-neck offset, or alpha angle greater than 55 degrees . Pincer-type morphologic features were determined by radiographic signs, including crossover sign, deficient posterior wall sign, or lateral center-edge angle greater than 40 degrees . RESULTS: The prevalence of cam-type morphologic features seen on at least one radiograph was 38% (male, 57%; female, 26%). The prevalence of cam-type features (at least one positive cam-type feature) was 2.0% (male, 6%; female, 0%) on the pelvic AP view, 24% (male, 36%; female, 17%) on the Sugioka view, and 30% (male, 47%; female, 20%) on the 45 degrees Dunn view. The prevalence of pincer-type morphologic features (at least one positive pincer-type feature) was 23% (male, 27%; female, 21%) on the pelvic AP view. CONCLUSION: The prevalence of FAI-related morphologic features in asymptomatic Asian populations was comparable to the prevalence in Western populations. Considering the high prevalence of radiographic hip findings reminiscent of FAI in asymptomatic Asian populations, it will be important to determine whether FAI-related morphologic features are a cause of hip pain when considering surgery in Asian patients. PMID- 27506974 TI - Is the detection of accelerated sea level rise imminent? AB - Global mean sea level rise estimated from satellite altimetry provides a strong constraint on climate variability and change and is expected to accelerate as the rates of both ocean warming and cryospheric mass loss increase over time. In stark contrast to this expectation however, current altimeter products show the rate of sea level rise to have decreased from the first to second decades of the altimeter era. Here, a combined analysis of altimeter data and specially designed climate model simulations shows the 1991 eruption of Mt Pinatubo to likely have masked the acceleration that would have otherwise occurred. This masking arose largely from a recovery in ocean heat content through the mid to late 1990 s subsequent to major heat content reductions in the years following the eruption. A consequence of this finding is that barring another major volcanic eruption, a detectable acceleration is likely to emerge from the noise of internal climate variability in the coming decade. PMID- 27506975 TI - Global or Granulosa Cell-Specific Pten Mutations in Combination with Elevated FSH Levels Fail to Cause Ovarian Tumours in Mice. AB - Phosphatase and tensin homologue (PTEN) is a known tumour suppressor. To explore the role of Pten in ovarian tumorigenesis, we used transgenic (Tg) SOX2. Cre and AMH. Cre mouse models to direct global Pten haploinsufficiency (Pten +/-) or ovary-specific granulosa cell (GC) Pten disruption (Pten GC ). Pten mutant models were combined with progressively rising Tg-follicle-stimulating hormone (TgFSH) levels to study the tumorigenic potential of combined genetic/endocrine modification in vivo. Global Pten +/- mice exhibited grossly detectable tumours in multiple organs including uterine and mammary tissue and displayed reduced survival. Despite extra-ovarian tumorigenesis, Pten +/- females had no detectable ovarian tumours, although elevated corpus luteum numbers increased ovary size and estrous cycling was altered. Combined TgFSH/Pten +/- mice also had no ovarian tumours, but early survival was reduced in the presence of TgFSH. Ovary-specific Pten GC +/- TgFSH females exhibited no detectable ovarian or uterine tumours, and corpus luteum numbers and estrous cycling remained unchanged. The non tumorigenic ovarian phenotypes in Pten +/- and Pten GC +/- TgFSH mice support the proposal that multi-hit genetic mutations (including ovarian and extra ovarian tissue) initiate ovarian tumours. Our findings suggest that elevated FSH may reduce early cancer survival; however, the ovary remains remarkably resistant to Pten-induced tumorigenic changes even in the presence of uterine and reproductive cancers. PMID- 27506976 TI - Selective mitochondrial depletion, apoptosis resistance, and increased mitophagy in human Charcot-Marie-Tooth 2A motor neurons. AB - Charcot-Marie-Tooth 2A (CMT2A) is an inherited peripheral neuropathy caused by mutations in MFN2, which encodes a mitochondrial membrane protein involved in mitochondrial network homeostasis. Because MFN2 is expressed ubiquitously, the reason for selective motor neuron (MN) involvement in CMT2A is unclear. To address this question, we generated MNs from induced pluripotent stem cells (iPSCs) obtained from the patients with CMT2A as an in vitro disease model. CMT2A iPSC-derived MNs (CMT2A-MNs) exhibited a global reduction in mitochondrial content and altered mitochondrial positioning without significant differences in survival and axon elongation. RNA sequencing profiles and protein studies of key components of the apoptotic executioner program (i.e. p53, BAX, caspase 8, cleaved caspase 3, and the anti-apoptotic marker Bcl2) demonstrated that CMT2A MNs are more resistant to apoptosis than wild-type MNs. Exploring the balance between mitochondrial biogenesis and the regulation of autophagy-lysosome transcription, we observed an increased autophagic flux in CMT2A-MNs that was associated with increased expression of PINK1, PARK2, BNIP3, and a splice variant of BECN1 that was recently demonstrated to be a trigger for mitochondrial autophagic removal. Taken together, these data suggest that the striking reduction in mitochondria in MNs expressing mutant MFN2 is not the result of impaired biogenesis, but more likely the consequence of enhanced mitophagy. Thus, these pathways represent possible novel molecular therapeutic targets for the development of an effective cure for this disease. PMID- 27506977 TI - Transcriptome-wide effects of a POLR3A gene mutation in patients with an unusual phenotype of striatal involvement. AB - RNA polymerase III is essential for the transcription of non-coding RNAs, including tRNAs. Mutations in the genes encoding its largest subunits are known to cause hypomyelinating leukodystrophies (HLD7) with pathogenetic mechanisms hypothesised to involve impaired availability of tRNAs. We have identified a founder mutation in the POLR3A gene that leads to aberrant splicing, a premature termination codon and partial deficiency of the canonical full-length transcript. Our clinical and imaging data showed no evidence of the previously reported white matter or cerebellar involvement; instead the affected brain structures included the striatum and red nuclei with the ensuing clinical manifestations. Our transcriptome-wide investigations revealed an overall decrease in the levels of Pol III-transcribed tRNAs and an imbalance in the levels of regulatory ncRNAs such as small nuclear and nucleolar RNAs (snRNAs and snoRNAs). In addition, the Pol III mutation was found to exert complex downstream effects on the Pol II transcriptome, affecting the general regulation of RNA metabolism. PMID- 27506979 TI - HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia. AB - Mutations that cause increased and/or inappropriate activation of FGFR3 are responsible for a collection of short-limbed chondrodysplasias. These mutations can alter receptor trafficking and enhance receptor stability, leading to increased receptor accumulation and activity. Here, we show that wildtype and mutant activated forms of FGFR3 increase expression of the cytoplasmic deacetylase HDAC6 (Histone Deacetylase 6) and that FGFR3 accumulation is compromised in cells lacking HDAC6 or following treatment of fibroblasts or chondrocytes with small molecule inhibitors of HDAC6. The reduced accumulation of FGFR3 was linked to increased FGFR3 degradation that occurred through a lysosome dependent mechanism. Using a mouse model of Thanatophoric Dysplasia Type II (TDII) we show that both HDAC6 deletion and treatment with the small molecule HDAC6 inhibitor tubacin reduced FGFR3 accumulation in the growth plate and improved endochondral bone growth. Defective endochondral growth in TDII is associated with reduced proliferation and poor hypertrophic differentiation and the improved bone growth was associated with increased chondrocyte proliferation and expansion of the differentiation compartment within the growth plate. These findings further define the mechanisms that control FGFR3 accumulation and contribute to skeletal pathology caused by mutations in FGFR3. PMID- 27506978 TI - Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused by NPHP5 mutation. AB - Ciliary defects can result in severe disorders called ciliopathies. Mutations in NPHP5 cause a ciliopathy characterized by severe childhood onset retinal blindness, Leber congenital amaurosis (LCA), and renal disease. Using the canine NPHP5-LCA model we compared human and canine retinal phenotypes, and examined the early stages of photoreceptor development and degeneration, the kinetics of photoreceptor loss, the progression of degeneration and the expression profiles of selected genes. NPHP5-mutant dogs recapitulate the human phenotype of very early loss of rods, and relative retention of the central retinal cone photoreceptors that lack function. In mutant dogs, rod and cone photoreceptors have a sensory cilium, but develop and function abnormally and then rapidly degenerate; L/M cones are more severely affected than S-cones. The lack of outer segments in mutant cones indicates a ciliary dysfunction. Genes expressed in mutant rod or both rod and cone photoreceptors show significant downregulation, while those expressed only in cones are unchanged. Many genes in cell-death and survival pathways also are downregulated. The canine disease is a non-syndromic LCA-ciliopathy, with normal renal structures and no CNS abnormalities. Our results identify the critical time points in the pathogenesis of the photoreceptor disease, and bring us closer to defining a potential time window for testing novel therapies for translation to patients. PMID- 27506982 TI - Cytokine genes as potential biomarkers for muscle weakness in OPMD. AB - Molecular biomarkers emerge as an accurate diagnostic tool, but are scarce for myopathies. Lack of outcome measures sensitive to disease onset and symptom severity hamper evaluation of therapeutic developments. Cytokines are circulating immunogenic molecules, and their potential as biomarkers has been exploited in the last decade. Cytokines are released from many tissues, including skeletal muscles, but their application to monitor muscle pathology is sparse. We report that the cytokine functional group is altered in the transcriptome of oculopharyngeal muscular dystrophy (OPMD). OPMD is a dominant, late-onset myopathy, caused by an alanine-expansion mutation in the gene encoding for poly(A) binding protein nuclear 1 (expPABPN1). Here, we investigated the hypothesis that cytokines could mark OPMD disease state. We determined cytokines levels the vastus lateralis muscle from genetically confirmed expPABPN1 carriers at a symptomatic or a presymptomatic stage. We identified cytokine-related genes candidates from a transcriptome study in a mouse overexpressing exp PABPN1 Six cytokines were found to be consistently down-regulated in OPMD vastus lateralis muscles. Expression levels of these cytokines were highly correlated in controls, but this correlation pattern was disrupted in OPMD. The levels of these 6 cytokines were not altered in expPABPN1 carriers at a pre-symptomatic stage, suggesting that this group of cytokines is a potential biomarker for muscle weakness in OPMD. Correlation pattern of expression levels could be a novel measurer for disease state. PMID- 27506985 TI - Lineage tracing reveals conversion of liver sinusoidal endothelial cells into hepatocytes. AB - Although liver sinusoidal endothelial cells (LSECs) have long been known to contribute to liver regeneration following injury, the exact role of these cells in liver regeneration remains poorly understood. In this work, we performed lineage tracing of LSECs in mice carrying Tie2-Cre or VE-cadherin-Cre constructs to facilitate fate-mapping of LSECs in liver regeneration. Some YFP-positive LSECs were observed to convert into hepatocytes following a two-thirds partial hepatectomy (PH). Furthermore, human umbilical vein endothelial cells (HUVECs) could be triggered to convert into cells that closely resembled hepatocytes when cultured with serum from mice that underwent an extended PH. These findings suggest that mature non-hepatocyte LSECs play an essential role in mammalian liver regeneration by converting to hepatocytes. The conversion of LSECs to hepatocyte-like (iHep) cells may provide a new approach to tissue engineering. PMID- 27506986 TI - Berberine Reduces Uremia-Associated Intestinal Mucosal Barrier Damage. AB - Berberine is one of the main active constituents of Rhizoma coptidis, a traditional Chinese medicine, and has long been used for the treatment of gastrointestinal disorders. The present study was designed to investigate the effects of berberine on the intestinal mucosal barrier damage in a rat uremia model induced by the 5/6 kidney resection. Beginning at postoperative week 4, the uremia rats were treated with daily 150 mg/kg berberine by oral gavage for 6 weeks. To assess the intestinal mucosal barrier changes, blood samples were collected for measuring the serum D-lactate level, and terminal ileum tissue samples were used for analyses of intestinal permeability, myeloperoxidase activity, histopathology, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity. Berberine treatment resulted in significant decreases in the serum D-lactate level, intestinal permeability, intestinal myeloperoxidase activity, and intestinal mucosal and submucosal edema and inflammation, and the Chiu's scores assessed for intestinal mucosal injury. The intestinal MDA level was reduced and the intestinal SOD activity was increased following berberine treatment. In conclusion, berberine reduces intestinal mucosal barrier damage induced by uremia, which is most likely due to its anti-oxidative activity. It may be developed as a potential treatment for preserving intestinal mucosal barrier function in patients with uremia. PMID- 27506987 TI - Blackberry, raspberry and black raspberry polyphenol extracts attenuate angiotensin II-induced senescence in vascular smooth muscle cells. AB - Activation of angiotensin II (Ang II) signaling during aging increases reactive oxygen species (ROS) leading to vascular senescence, a process linked to the onset and progression of cardiovascular diseases (CVD). Consumption of fruits and vegetables, particularly berries, is associated with decreased incidence of CVD, which has mainly been attributed to the polyphenol content of these foods. Thus, the objective of this study was to investigate the role of blackberry (BL), raspberry (RB), and black raspberry (BRB) polyphenol extracts in attenuating Ang II-induced senescence in vascular smooth muscle cells (VSMCs) and to determine the molecular mechanisms involved. BL, RB and BRB polyphenol extracts (200 MUg ml 1) attenuated Ang II-induced senescence, denoted by decreased number of cells positive for senescence associated beta-galactosidase (SA-beta-gal) and down regulation of p21 and p53 expression, which were associated with decreased ROS levels and Ang II signaling. BL polyphenol extract increased superoxide dismutase (SOD) 1 expression, attenuated the up-regulation of Nox1 expression and the phosphorylation of Akt, p38MAPK and ERK1/2 induced by Ang II, and reduced senescence in response to Nox1 overexpression. In contrast, RB and BRB polyphenol extracts up-regulated the expression of SOD1, SOD2, and glutathione peroxidase 1 (GPx1), but exerted no effect on Nox1 expression nor on senescence induced by Nox1 overexpression. BRB reduced signaling similar to BL, while RB was unable to reduce Akt phosphorylation. Furthermore, we demonstrated that inhibition of Akt, p38MAPK and ERK1/2 as well as down-regulation of Nox1 by siRNA prevented senescence induced by Ang II. Our findings indicate that Ang II-induced senescence is attenuated by BL polyphenols through a Nox1-dependent mechanism and by RB and BRB polyphenols in a Nox1-independent manner, likely by increasing the cellular antioxidant capacity. PMID- 27506988 TI - Survivorship and clinical outcome of the minimally invasive Uniglide medial fixed bearing, all-polyethylene tibia, unicompartmental knee arthroplasty at a mean follow-up of 7.3years. AB - BACKGROUND: Medial UKA performed in England and Wales represents seven to 11% of all knee arthroplasty procedures, and is most commonly performed using mobile bearing designs. Fixed bearing eliminates the risk of bearing dislocation, however some studies have shown higher revision rates for all-polyethylene tibial components compared to those that utilize metal-backed implants. The aim of the study is to analyse survivorship and maximum eight-year clinical outcome of medial fixed bearing, Uniglide unicompartmental knee arthroplasty performed using an all-polyethylene tibial component with a minimal invasive approach. METHODS: Between 2002 and 2009, 270 medial fixed UKAs were performed in our unit. Patients were reviewed pre-operatively, five and eight years post-operatively. Clinical and radiographic reviews were carried out. Patients' outcome scores (Oxford, WOMAC and American Knee Score) were documented in our database and analysed. RESULTS: Survival and clinical outcome data of 236 knees with a mean of 7.3years follow-up are reported. Every patient with less than 4.93years of follow-up underwent a revision. The patients' average age at the time of surgery was 69.5years. The American Knee Society Pain and Function scores, the Oxford Knee Score and the WOMAC score all improved significantly. The five-year survival rate was 94.1% with implant revision surgery as an end point. The estimated 10years of survival rate is 91.3%. Fourteen patients were revised before the five-year follow-up. CONCLUSION: Fixed bearing Uniglide UKA with an all-polyethylene tibial component is a valuable tool in the management of a medial compartment osteoarthritis, affording good short-term survivorship. Level of evidence IV. PMID- 27506989 TI - Proposal for a new T-stage classification system for distal cholangiocarcinoma: a 10-institution study from the U.S. Extrahepatic Biliary Malignancy Consortium. AB - BACKGROUND: Seventh AJCC distal cholangiocarcinoma T-stage classification inadequately separates patients by survival. This retrospective study aimed to define a novel T-stage system to better stratify patients after resection. METHODS: Curative-intent pancreaticoduodenectomies for distal cholangiocarcinoma (1/2000-5/2015) at 10 US institutions were included. Relationships between tumor characteristics and overall survival (OS) were assessed and incorporated into a novel T-stage classification. RESULTS: 176 patients (median follow-up: 24mo) were included. Current AJCC T-stage was not associated with OS (T1: 23mo, T2: 20mo, T3: 25mo, T4: 12mo; p = 0.355). Tumor size >=3 cm and presence of lymphovascular invasion (LVI) were associated with decreased OS on univariate and multivariable analyses. Patients were stratified into 3 groups [T1: size <3 cm and (-)LVI (n = 69; 39.2%); T2: size >=3 cm and (-)LVI or size <3 cm and (+)LVI (n = 82; 46.6%); and T3: size >=3 cm and (+)LVI (n = 25; 14.2%)]. Each progressive proposed T stage was associated with decreased median OS (T1: 35mo; T2: 20mo; T3: 8mo; p = 0.002). CONCLUSION: Current AJCC distal cholangiocarcinoma T-stage does not adequately stratify patients by survival. This proposed T-stage classification, based on tumor size and LVI, better differentiates patient outcomes after resection and could be considered for incorporation into the next AJCC distal cholangiocarcinoma staging system. PMID- 27506990 TI - Optimal use of hepatobiliary scintigraphy before liver resection. PMID- 27506991 TI - Validation of the peak bilirubin criterion for outcome after partial hepatectomy. AB - INTRODUCTION: Postoperative liver failure (PLF) is a dreaded complication after partial hepatectomy. The peak bilirubin criterion (>7.0 mg/dL or >=120 MUmol/L) is used to define PLF. This study aimed to validate the peak bilirubin criterion as postoperative risk indicator for 90-day liver-related mortality. METHODS: Characteristics of 956 consecutive patients who underwent partial hepatectomy at the Maastricht University Medical Centre or Royal Free London between 2005 and 2012 were analyzed by uni- and multivariable analyses with odds ratios (OR) and 95% confidence intervals (95%CI). RESULTS: Thirty-five patients (3.7%) met the postoperative peak bilirubin criterion at median day 19 with a median bilirubin level of 183 [121-588] MUmol/L. Sensitivity and specificity for liver-related mortality after major hepatectomy were 41.2% and 94.6%, respectively. The positive predictive value was 22.6%. Predictors of liver-related mortality were the peak bilirubin criterion (p < 0.001, OR = 15.9 [95%CI 5.2-48.7]), moderate severe steatosis and fibrosis (p = 0.013, OR = 8.5 [95%CI 1.6-46.6]), ASA 3-4 (p = 0.047, OR = 3.0 [95%CI 1.0-8.8]) and age (p = 0.044, OR = 1.1 [95%CI 1.0-1.1]). CONCLUSION: The peak bilirubin criterion has a low sensitivity and positive predictive value for 90-day liver-related mortality after major hepatectomy. PMID- 27506992 TI - Robotic and open distal pancreatectomy with celiac axis resection for locally advanced pancreatic body tumors: a single institutional assessment of perioperative outcomes and survival. AB - BACKGROUND: Distal pancreatectomy with celiac axis resection (DP-CAR) is an option for T4 tumors of the pancreatic body. We examined the perioperative and oncologic outcomes of open and robotic DP-CAR at a high-volume pancreatic center. METHODS: Retrospective review of all consecutive DP-CARs. Patient demographics, 90-day perioperative outcomes, and disease specific survival were collected. RESULTS: 30 DP-CARs were performed (11 Robotic, 19 Open). Both groups had similar preoperative/tumor characteristics, and 27 of 28 PDA patients received neoadjuvant chemotherapy. Robotic DP-CAR was associated with decreased OT (316 vs. 476 min), reduced EBL (393 vs. 1736 ml) and lower rates of blood transfusion (0% vs. 54%) (all p < 0.05). No robotic DP-CAR required conversion. Both groups had similar rates of 90-day mortality, major morbidity, LOS, readmission, and receipt of adjuvant therapy. Similarly, both approaches were associated with high R0 resection rates (82% vs. 79%). At a median follow-up of 33 months, median overall survival for the PDA cohort was 35 months, with no difference in the robotic and open approach (33 and 40 months, p = 0.310). CONCLUSIONS: With a median survival approaching 3 years, DP-CAR represents an effective treatment for select patients with locally advanced pancreatic body cancer, regardless of approach. PMID- 27506994 TI - Classification and techniques of en bloc venous reconstruction for pancreaticoduodenectomy. AB - BACKGROUND: Surgical resection is the only cure for hepato-pancreato-biliary (HPB) malignancy. In the era of multidisciplinary approaches and neoadjuvant therapies for locally advanced, borderline resectable tumors, the feasibility and efficacy of en bloc vascular resection has been validated across multiple studies. However, the variability of venous anatomy within the perihepatic and peri-portal regions necessitates familiarity with alternative resection and reconstruction techniques appropriate to the specific region of tumor invasion. METHODS: To organize these paradigms, the venous system has been divided into five zones: 1) hepatic hilum; 2) hepatoduodenal ligament; 3) portal vein/splenic vein confluence, which is further subdivided into right (3a) and left (3b); 4) infra-confluence; and 5) splenic vein. RESULTS: This study systematically analyzes the anatomic considerations and clinical scenarios specific to each zone to organize the necessary preparative maneuvers, surgical procedures, and vascular reconstruction techniques to achieve an R0 resection. The anatomic and tumor-specific factors which deem a specimen unresectable are also explored. Surgical videos demonstrating these techniques are presented. DISCUSSION: Preparation and familiarity with venous reconstruction maneuvers is essential for an oncologically effective operation, and can be safely achieved by utilizing this logical anatomic and procedural framework. PMID- 27506993 TI - Outcome of surgery for recurrent pyogenic cholangitis: a single center experience. AB - BACKGROUND: Although, recurrent pyogenic cholangitis (RPC) is prevalent in several parts of India, there is paucity of published literature from India. The aim of this study was to report on the short and long-term outcomes of surgery for RPC. METHODS: All the patients, who underwent surgery for RPC between August 2007 and February 2016 in the Department of Surgical gastroenterology, Institute of Postgraduate Medical Education and Research, Kolkata, India were retrospectively reviewed. RESULTS: Of the total 94 patients, 66 (70%) were women. The median age at presentation was 40 years. Left lobe was solely involved in 49% of patients. Left hepatectomy was performed in 23/44 (52%) patients who underwent liver resection. Thirty two postoperative complications developed in 27 patients (29%). Complete stone clearance was possible in 83% of patients after primary surgery. Over a median follow up of 36 months, seventy one of 87 patients (81%) remained free of stones. Recurrent cholangitis occurred 10 of 87 patients (11%). CONCLUSIONS: Surgery plays an important role in the management of RPC achieving excellent short and long-term outcomes. PMID- 27506995 TI - Patterns of hepatic resections in North America: use of concurrent partial resections and ablations. AB - BACKGROUND: National registries have not adequately captured concurrent partial hepatic resections or ablations. Therefore, the aim of this analysis was to describe the patterns of concurrent partial resections and ablations in North America. METHODS: Patients undergoing a hepatic resection were identified using the American College of Surgeons-National Surgical Quality Improvement Program Targeted Hepatectomy database. Perioperative outcomes were compared for patients undergoing concurrent "wedge" resections and/or ablations and other subsets. RESULTS: A total of 2714 patients were identified who met inclusion criteria. Major hepatectomy was performed in 1037 patients (38.2%) while partial lobectomy was performed in 1677 (61.8%) patients. Concurrent "wedge" hepatic resections and ablations were undertaken in 56.0% and 14.2% of patients, respectively, and were more frequently performed among patients undergoing a partial lobectomy and among patients undergoing surgery for colorectal liver metastasis (both p < 0.001). While associated with a decreased incidence of postoperative complications (p = 0.027) and liver failure (p = 0.031) among patients undergoing a major hepatectomy, concurrent therapies were associated with comparable 30-day outcomes for patients undergoing partial lobectomy. CONCLUSION: Concurrent "wedge" hepatic resections and ablations are performed in 56.0% and 14.2%, respectively of patients undergoing hepatectomy. Concurrent procedures were not associated with worse clinical outcomes. PMID- 27506996 TI - Erratum to: The continuous performance test (rCPT) for mice: a novel operant touchscreen test of attentional function. PMID- 27506997 TI - Cannabinoid-induced depression of synaptic transmission is switched to stimulation when dopaminergic tone is increased in the globus pallidus of the rodent. AB - Because activation of D2 receptors reverses the neurochemical effects of cannabinoids, we examined whether increasing dopaminergic tone in the globus pallidus (GPe) switches cannabinoid induced depression of synaptic transmission. GABAergic synaptic currents evoked in pallidal neurons by stimulation of striatal projections (IPSCs) were depressed by perfusion with the CB1R agonist ACEA. Coactivation of D2Rs with quinpirole converted the depression into stimulation. Pretreatment with pertussis toxin (PTX) to limit Gi/o protein coupling also switched the CB1R-induced depression of IPSCs. The stimulation of IPSCs was blocked by the selective PKA blocker H89. Changes in the paired pulse ratio during both inhibitory and stimulatory responses indicate that the effects are due to changes in transmitter release. Postsynaptic depolarization induces endocannabinoid release that inhibits transmitter release (DSI). When D2Rs were activated with quinpirole, depolarization increased transmission instead of depressing it. This increase was blocked by AM251. We also examined the effects of CB1R/D2R coactivation on cAMP accumulation in the GPe to further verify that the AC/PKA cascade is involved. CB1R/D2R coactivation converted the inhibition of cAMP seen when each receptor is stimulated alone into a stimulation. We also determined the effects on turning behavior of unilateral injection of ACEA into the GPe of awake animals and its modification by dopamine antagonists. Blockade of D2 family receptors with sulpiride antagonized the motor effects of ACEA. We show, for the first time, that cannabinoid-inhibition of synaptic transmission in the GPe becomes a stimulation after D2Rs or PTX treatment and that the switch is probably relevant for the control of motor behavior. PMID- 27506998 TI - Concurrent exercise training: do opposites distract? AB - Specificity is a core principle of exercise training to promote the desired adaptations for maximising athletic performance. The principle of specificity of adaptation is underpinned by the volume, intensity, frequency and mode of contractile activity and is most evident when contrasting the divergent phenotypes that result after undertaking either prolonged endurance or resistance training. The molecular profiles that generate the adaptive response to different exercise modes have undergone intense scientific scrutiny. Given divergent exercise induces similar signalling and gene expression profiles in skeletal muscle of untrained or recreationally active individuals, what is currently unclear is how the specificity of the molecular response is modified by prior training history. The time course of adaptation and when 'phenotype specificity' occurs has important implications for exercise prescription. This context is essential when attempting to concomitantly develop resistance to fatigue (through endurance-based exercise) and increased muscle mass (through resistance-based exercise), typically termed 'concurrent training'. Chronic training studies provide robust evidence that endurance exercise can attenuate muscle hypertrophy and strength but the mechanistic underpinning of this 'interference' effect with concurrent training is unknown. Moreover, despite the potential for several key regulators of muscle metabolism to explain an incompatibility in adaptation between endurance and resistance exercise, it now seems likely that multiple integrated, rather than isolated, effectors or processes generate the interference effect. Here we review studies of the molecular responses in skeletal muscle and evidence for the interference effect with concurrent training within the context of the specificity of training adaptation. PMID- 27506999 TI - miR-489 inhibits silica-induced pulmonary fibrosis by targeting MyD88 and Smad3 and is negatively regulated by lncRNA CHRF. AB - Silicosis is an incurable occupational disease associated with inflammation, fibroblast proliferation and the accumulation of extracellular matrix in lung tissues. The dysregulation of lncRNAs and miRNAs has been implicated in many complex diseases; however, the current understanding of their roles in fibrotic lung diseases, especially silicosis, remains limited. Our previous microRNA (miRNA, miR) microarray data have indicated decreased expression levels of miR 489 in lung tissues of silica-induced pulmonary fibrosis. Here, we further explored the role of miR-489 in a mouse model of silicosis. Interestingly, miR 489 levels were reduced in both macrophages that were exposed to silica and fibroblasts that were exposed to TGF-beta1. Additionally, the overexpressed miR 489 carried out its anti-fibrotic role by attenuating inflammation and fibrotic progression in vivo. Our molecular study further demonstrated that miR-489 inhibited silica-induced pulmonary fibrosis primarily by repressing its target genes MyD88 and Smad3. Moreover, the up-regulated lncRNA cardiac hypertrophy related factor (CHRF) reversed the inhibitory effect of miR-489 on MyD88 and Smad3 and then triggered the inflammation and fibrotic signaling pathways. Overall, our data indicate that the CHRF-miR-489-MyD88 Smad3 signaling axis exerts key functions in silica-induced pulmonary fibrosis and may represent a therapeutic target for silicosis. PMID- 27507000 TI - Structure and function of methanogenic microbial communities in sediments of Amazonian lakes with different water types. AB - Tropical lake sediments are a significant source for the greenhouse gas methane. We studied function (pathway, rate) and structure (abundance, taxonomic composition) of the microbial communities (Bacteria, Archaea) leading to methane formation together with the main physicochemical characteristics in the sediments of four clear water, six white water and three black water lakes of the Amazon River system. Concentrations of sulfate and ferric iron, pH and delta13 C of organic carbon were usually higher, while concentrations of carbon, nitrogen and rates of CH4 production were generally lower in white water versus clear water or black water sediments. Copy numbers of bacterial and especially archaeal ribosomal RNA genes also tended to be relatively lower in white water sediments. Hydrogenotrophic methanogenesis contributed 58 +/- 16% to total CH4 production in all systems. Network analysis identified six communities, of which four were comprised mostly of bacteria found in all sediment types, while two were mostly in clear water sediment. Terminal restriction fragment length polymorphism (T RFLP) and pyrosequencing showed that the compositions of the communities differed between the different sediment systems, statistically related to the particular physicochemical conditions and to CH4 production rates. Among the archaea, clear water, white water, and black water sediments contained relatively more Methanomicrobiales, Methanosarcinaceae and Methanocellales, respectively, while Methanosaetaceae were common in all systems. Proteobacteria, Deltaproteobacteria (Myxococcales, Syntrophobacterales, sulfate reducers) in particular, Acidobacteria and Firmicutes were the most abundant bacterial phyla in all sediment systems. Among the other important bacterial phyla, clear water sediments contained relatively more Alphaproteobacteria and Planctomycetes, whereas white water sediments contained relatively more Betaproteobacteria, Firmicutes, Actinobacteria, and Chloroflexi than the respective other sediment systems. The data showed communities of bacteria common to all sediment types, but also revealed microbial groups that were significantly different between the sediment types, which also differed in physicochemical conditions. Our study showed that function of the microbial communities may be understood on the basis of their structures, which in turn are determined by environmental heterogeneity. PMID- 27507001 TI - Boosting oxygen reduction/evolution reaction activities with layered perovskite catalysts. AB - Layered PrBaMn2O5+delta (H-PBM) was simply prepared by annealing pristine Pr0.5Ba0.5MnO3-delta in H2. The oxygen reduction/evolution reaction activities are remarkably enhanced by employing H-PBM. The improvement can be ascribed to the introduction of additional oxygen vacancies, an optimized eg filling of Mn ions, and the facile incorporation of oxygen into layered H-PBM. PMID- 27507002 TI - Associations between body composition, nutrition, and physical activity in young adults. AB - OBJECTIVE: The aim of the present study is to investigate the associations between total energy, macronutrient intakes, and physical activity (PA) and body composition by assessing body fat mass, fat-free mass, and BMI in a population of young adults. METHODS: The study population consisted of 605 young Spanish adults (median age 20.38 +/- 2.67). Body composition, including fat mass and fat-free mass, was calculated with body composition analyzer. Daily energy and macronutrient intakes were measured using a 72-h recall method. The International PA Questionnaire was used to assess PA and sedentary time. Linear regression analyses were performed to test the possible associations between nutrition, PA factors, and body composition. RESULTS: Linear regression analyses revealed that BMI has a significant positive association with protein intake (P = .004, B = 0.088, 95% CI 0.028-0.149) and an inverse association with carbohydrate intake (P = 0.034, B = -0.027, 95% CI -0.053 - -0.002). Protein intake also demonstrated a significant association with fat-free mass, but the size of the effect was smaller (P = .027, B = 96.965, 95% CI 11.250-182.679). There was evidence of a positive association between total PA and moderate-to-vigorous PA (P < .001, B = 15.630, 95% CI 6.989 -24.270) and fat-free mass (P < .001, B = 20.208, 95% CI 9.694 -30.723). When fat mass was used as the outcome variable, there was no evidence of any association with the PA, total energy, and macronutrient intakes variables analyzed. CONCLUSIONS: Our findings suggest that PA variables were consistently associated with body composition, specifically fat-free mass. Dietary factors also have influence over body composition; we showed that protein intake is significantly associated with fat-free mass and BMI. PMID- 27507003 TI - The effect of the neural activity on topological properties of growing neural networks. AB - The connectivity structure in cortical networks defines how information is transmitted and processed, and it is a source of the complex spatiotemporal patterns of network's development, and the process of creation and deletion of connections is continuous in the whole life of the organism. In this paper, we study how neural activity influences the growth process in neural networks. By using a two-dimensional activity-dependent growth model we demonstrated the neural network growth process from disconnected neurons to fully connected networks. For making quantitative investigation of the network's activity influence on its topological properties we compared it with the random growth network not depending on network's activity. By using the random graphs theory methods for the analysis of the network's connections structure it is shown that the growth in neural networks results in the formation of a well-known "small world" network. PMID- 27507004 TI - ADAMTS13-von Willebrand factor axis is involved in the pathophysiology of kidney ischaemia-reperfusion injury. AB - AIM: The ADAMTS13-von Willebrand factor (vWF) axis has been suggested to play a critical role in the pathophysiology of ischaemia-reperfusion injury (IRI) in the heart or brain. Therefore, we aimed to investigate whether this axis was involved in the pathophysiology of IRI-induced acute kidney injury. METHODS: We performed renal IRI in ADAMTS13 knockout (KO) or wild type (WT) mice. Functional and histological kidney damage, and inflammation were compared and the effect of anti vWF antibodies in ADAMTS13 KO mice was assessed. RESULTS: Following IRI, the blood and kidney ADAMTS13 levels were significantly decreased. vWF expression was significantly upregulated in both the medulla and cortex of injured kidneys as shown by immunohistochemistry and western blot analyses. There was also an increased level of vWF dimers after IRI. In ADAMTS13 KO mice, kidney vWF levels were further increased and this was associated with greater endothelial and epithelial injury compared to WT mice, suggesting an important role of vWF in renal IRI. In addition, the number of Gr-1+ neutrophils was significantly higher in the kidneys of ADAMTS13 KO mice compared to WT mice, whereas F4/80 macrophage numbers were unchanged. In ADAMTS13 KO mice, administration of anti-vWF antibodies after IRI partially reversed renal injury. CONCLUSION: Our data show that the ADAMTS13-vWF axis is partially involved in the pathophysiology of kidney IRI, suggesting that regulating ADAMTS13- and vWF-dependent mechanisms could have therapeutic potential to limit renal IRI. PMID- 27507005 TI - Pubertal status, pre-meal drink composition, and later meal timing interact in determining children's appetite and food intake. AB - Puberty is a period of development that alters energy intake patterns. However, few studies have examined appetite and food intake (FI) regulation during development of puberty in children and adolescents. Therefore, the objective was to measure the effect of pubertal status on FI and subjective appetite after pre meal glucose and whey protein drinks in 9- to 14-year-old boys and girls. In a within-subject, randomized, repeated-measures design, children (21 pre-early pubertal, 15 mid-late pubertal) received equally sweetened drinks containing Sucralose (control), glucose, or whey protein (0.75 g/kg body weight) in 250 mL of water 2 h after a standardized breakfast on 6 separate mornings. Ad libitum FI was measured either 30 or 60 min later and appetite was measured over time. In pre-early and mid-late pubertal boys and girls there was no effect of sex on total FI (kcal). Glucose and whey protein drinks reduced calorie intake similarly at 30 min. But at 60 min, whey protein reduced FI (p < 0.001) compared with control and glucose in pre-early pubertal children, but not in mid-late pubertal children. However, sex was a factor (p = 0.041) when FI was expressed per kilogram body weight. Pubertal status did not affect FI/kilogram body weight in boys, but it was 32% lower in mid-late pubertal girls than at pre-early puberty (p = 0.010). Appetite was associated with FI in mid-late pubertal children only. In conclusion, pubertal development affects appetite and FI regulation in children. PMID- 27507006 TI - Food avoidance in athletes: FODMAP foods on the list. AB - We surveyed 910 athletes to assess behaviours towards self-selected food/ingredient avoidance to minimize gastrointestinal distress. Fifty-five percent eliminated at least 1 high fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) food/category, with up to 82.6% reporting symptom improvement. In athletes indicating that high FODMAP foods trigger gastrointestinal symptoms, lactose (86.5%) was most frequently eliminated, followed by galactooligosaccharides (23.9%), fructose (23.0%), fructans (6.2%), and polyols (5.4%). Athletes avoid predominantly lactose and to a lesser extent other high FODMAP foods to reduce gastrointestinal distress. PMID- 27507007 TI - Association between exercise-induced change in body composition and change in cardiometabolic risk factors in postmenopausal South Asian women. AB - The South Asian population suffers from a high prevalence of type 2 diabetes and cardiovascular disease (CVD). A unique obesity phenotype of elevated visceral adipose tissue (VAT) is associated with CVD risk among South Asians. Exercise induced reduction in VAT and body fat is an effective mechanism to improve cardiometabolic risk factors but this has not been shown in South Asians. Whether exercise-induced changes in measurements such as waist circumference (WC) are independently related to changes in cardiometabolic risk factors in South Asians is unknown. Multi-slice computed tomography scanning was used to assess VAT, cardiometabolic risk factors through a fasting blood sample, and body fat using dual-energy X-ray absorptiometry. Forty- nine postmenopausal South Asian women who participated in two 12-week aerobic exercise programs were included. Bivariate correlations were used to assess associations between change in cardiometabolic risk factors and change in body composition. Regression analyses were conducted with change in glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) as dependent variables and change in body composition as independent variables of interest. There were significant associations between changes in fasting insulin, glucose, and HOMA-IR with change in VAT. The association between change in VAT and these cardiometabolic risk factors was independent of change in other body composition variables of interest. South Asian women should be encouraged to engage in aerobic activity to reduce their risk of type 2 diabetes and CVD, and physicians should be aware of improvements in glucose regulation with exercise training not observed through reductions in WC. PMID- 27507008 TI - Compartmentalization in PVC super-phylum: evolution and impact. AB - BACKGROUND: The PVC super-phylum gathers bacteria from seven phyla (Planctomycetes, Verrucomicrobiae, Chlamydiae, Lentisphaera, Poribacteria, OP3, WWE2) presenting different lifestyles, cell plans and environments. Planctomyces and several Verrucomicrobiae exhibit a complex cell plan, with an intracytoplasmic membrane inducing the compartmentalization of the cytoplasm into two regions (pirellulosome and paryphoplasm). The evolution and function of this cell plan is still subject to debate. In this work, we hypothesized that it could play a role in protection of the bacterial DNA, especially against Horizontal Genes Transfers (HGT). Therefore, 64 bacterial genomes belonging to seven different phyla (whose four PVC phyla) were studied. We reconstructed the evolution of the cell plan as precisely as possible, thanks to information obtained by bibliographic study and electronic microscopy. We used a strategy based on comparative phylogenomic in order to determine the part occupied by the horizontal transfers for each studied genomes. RESULTS: Our results show that the bacteria Simkania negevensis (Chlamydiae) and Coraliomargarita akajimensis (Verrucomicrobiae), whose cell plan were unknown before, are compartmentalized, as we can see on the micrographies. This is one of the first indication of the presence of an intracytoplasmic membrane in a Chlamydiae. The proportion of HGT does not seems to be related to the cell plan of bacteria, suggesting that compartmentalization does not induce a protection of bacterial DNA against HGT. Conversely, lifestyle of bacteria seems to impact the ability of bacteria to exchange genes. CONCLUSIONS: Our study allows a best reconstruction of the evolution of intracytoplasmic membrane, but this structure seems to have no impact on HGT occurrences. REVIEWERS: This article was reviewed by Mircea Podar and Olivier Tenaillon. PMID- 27507009 TI - Pseudorabies virus can escape from CRISPR-Cas9-mediated inhibition. AB - The CRISPR-Cas9 system is a newly developed genome-engineering tool used to inhibit virus infection by targeting the conserved regions of the viral genomic DNA. In the present study, we constructed a cell line stably expressing Cas9 endonuclease and sgRNA targeting the conserved UL30 gene of pseudorabies virus (PRV). During the PRV infection, the CRISPR-Cas9 system was efficient in cleaving the UL30 gene in each passage. However, deletions and insertions occurred at low passages, while substitutions were frequently observed at high passages. Furthermore, copy numbers and virus titers of PRV were significantly increased in a passage-dependent manner, indicating that viral genomic replication and assembly were more effective at the high passages than at low passages. These results demonstrated that PRV could escape from CRISPR-Cas9-mediated inhibition. Therefore, whether the CRISPR-Cas9 system is suitable for antiviral application should be considered and carefully verified. PMID- 27507010 TI - ZnO nanorods prepared via ablation of Zn with millisecond laser in liquid media. AB - ZnO nanomaterials with controlled size, shape and surface chemistry are required for applications in diverse areas, such as optoelectronics, photocatalysis, biomedicine and so on. Here, we report on ZnO nanostructures with rod-like and spherical shapes prepared via laser ablation in liquid using a laser with millisecond-long pulses. By changing laser parameters (such as pulse width and peak power), the size or aspect ratio of such nanostructures could be tuned. The surface chemistry and defects of the products were also strongly affected by applied laser conditions. The preparation of different structures is explained by the intense heating of liquid media caused by millisecond-long pulses and secondary irradiation of already-formed nanostructures. PMID- 27507011 TI - Imaging mass spectrometry of elements in forensic cases by LA-ICP-MS. AB - Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) was performed to map elements in thin formalin-fixed paraffin-embedded tissue sections of two forensic cases with firearm and electrocution injuries, respectively. In both cases, histological examination of the wounded tissue regions revealed the presence of exogenous aggregates that may be interpreted as metallic depositions. The use of imaging LA-ICP-MS allowed us to unambiguously determine the elemental composition of the observed aggregates assisting the pathologist in case assessments. To the best of our knowledge, we demonstrate for the first time the use of imaging LA-ICP-MS as a complementary tool for forensic pathologists and toxicologists in order to map the presence of metals and other elements in thin tissue sections of post-mortem cases. PMID- 27507012 TI - [Ingestion of castor seeds in attempting suicide]. PMID- 27507013 TI - [New recommendations of 2016 European Guidelines on cardiovascular disease prevention]. PMID- 27507014 TI - Efficacy and safety of Dexrazoxane (DRZ) in sarcoma patients receiving high cumulative doses of anthracycline therapy - a retrospective study including 32 patients. AB - BACKGROUND: Anthracyclines, as the most effective therapy, are the cornerstone of advanced stage sarcoma treatment. However, anthracyclines can also contribute to myocardial dysfunction and congestive heart failure, ultimately limiting the therapeutic potential of the drug. Coadministration of Dexrazoxane has been shown to effectively reduce cardiotoxicity, however primarily in patients suffering in diseases other than sarcoma. METHODS: The aim of this retrospective analysis was to evaluate safety and efficacy of chemotherapy with high cumulative doses of anthracyclines in combination with Dexrazoxane. The medical charts of 32 patients treated in four institutions were analyzed. Reasons for coadministration were rechallenge, reaching the cumulative anthracycline dose and preexisting heart failure. RESULTS: The median age was 54 years [18-68 years]. The median cumulative anthracycline dose before adding DRZ was 450 mg/m(2) and after administration of last anthracycline containing therapy 750 mg/m(2). Either during treatment or follow up, 2/27 patients (7 %) without preexisting major cardiac findings developed anthracycline-induced cardiotoxicity. The median overall survival (OS) from start of the first anthracycline containing chemotherapy was 46 months and 17 months from the initial coadministration of DRZ. At rechallenge, the median progression free survival (PFS) with DRZ was 7 months. In continuous therapy, the median PFS was 13 months from beginning of chemotherapy and 9 months from the addition of DRZ. CONCLUSION: Chemotherapy with high cumulative doses of anthracyclines in addition with DRZ demonstrated a remarkable OS in these advanced disease patients. Cardiac side-effects due to high cumulative doses of anthracyclines requiring discontinuation of anthracycline treatment were rare. A PFS of 9 months from the beginning of the coadministration of DRZ indicates that continuing anthracycline therapy beyond established cumulative doses is a promising therapeutic option. PMID- 27507015 TI - Production of hemolysin BL by Bacillus cereus group isolates of dairy origin is associated with whole-genome phylogenetic clade. AB - BACKGROUND: Bacillus cereus group isolates that produce diarrheal or emetic toxins are frequently isolated from raw milk and, in spore form, can survive pasteurization. Several species within the B. cereus group are closely related and cannot be reliably differentiated by established taxonomical criteria. While B. cereus is traditionally recognized as the principal causative agent of foodborne disease in this group, there is a need to better understand the distribution and expression of different toxin and virulence genes among B. cereus group food isolates to facilitate reliable characterization that allows for assessment of the likelihood of a given isolate to cause a foodborne disease. RESULTS: We performed whole genome sequencing of 22 B. cereus group dairy isolates, which represented considerable genetic diversity not covered by other isolates characterized to date. Maximum likelihood analysis of these genomes along with 47 reference genomes representing eight validly published species revealed nine phylogenetic clades. Three of these clades were represented by a single species (B. toyonensis -clade V, B. weihenstephanensis - clade VI, B. cytotoxicus - VII), one by two dairy-associated isolates (clade II; representing a putative new species), one by two species (B. mycoides, B. pseudomycoides - clade I) and four by three species (B. cereus, B. thuringiensis, B. anthracis - clades III-a, b, c and IV). Homologues of genes encoding a principal diarrheal enterotoxin (hemolysin BL) were distributed across all, except the B. cytotoxicus clade. Using a lateral flow immunoassay, hemolysin BL was detected in 13 out of 18 isolates that carried hblACD genes. Isolates from clade III-c (which included B. cereus and B. thuringiensis) consistently did not carry hblACD and did not produce hemolysin BL. Isolates from clade IV (B. cereus, B. thuringiensis) consistently carried hblACD and produced hemolysin BL. Compared to others, clade IV was significantly (p = 0.0001) more likely to produce this toxin. Isolates from clade VI (B. weihenstephanensis) carried hblACD homologues, but did not produce hemolysin BL, possibly due to amino acid substitutions in different toxin encoding genes. CONCLUSIONS: Our results demonstrate that production of diarrheal enterotoxin hemolysin BL is neither inclusive nor exclusive to B. cereus sensu stricto, and that phylogenetic classification of isolates may be better than taxonomic identification for assessment of B. cereus group isolates risk for causing a diarrheal foodborne disease. PMID- 27507016 TI - Calcinosis cutis universalis. PMID- 27507017 TI - Excess long-term mortality in outpatient deep venous thrombosis patients managed in an ambulatory care setting. AB - Background: Deep venous thrombosis (DVT) is increasingly being managed in the outpatient setting, particularly patients deemed low-risk at presentation. The long-term outcomes of these patients remain unclear. Aim: To determine the long term outcomes of patients with DVT and those with raised D-dimer without DVT managed exclusively by an ambulatory care pathway. Design: Retrospective cohort analysis. Methods: 828 consecutive patients assessed at the Ambulatory Care Clinic of a tertiary care university hospital between 1 January and 31 December 2008 for potential lower limb DVT were analysed. Primary and secondary outcome was all-cause mortality and new diagnosis of cancer, respectively. Median follow up was 6.4 years. Results: The final cohort comprised 131 patients with DVT, 396 with raised D-dimer without DVT and 165 with normal D-dimer without DVT. Long term survival was 72.5% for DVT, 75.3% for elevated D-dimer without thrombosis and 93.3% for those with normal D-dimer ( P < 0.0001). The risk of death with DVT remained significant after adjusting for age, gender, previous cancer, recent surgery and previous thromboembolism (HR 2.17, 95% CI [1.07, 4.38]). Cancer accounted for 44.4 and 37.8% of deaths within the first and second groups, respectively. 50% of cancers in the former group were diagnosed during follow-up vs. 95.1% in the latter. Conclusion: The 5-year survival of patients with DVT managed via ambulatory care was worse than expected. An algorithm is urgently needed to identify predictors of adverse outcomes for both these patients as well as those with raised D-dimer without thrombosis. PMID- 27507018 TI - Third nerve palsy and internal carotid aneurysm. PMID- 27507019 TI - Hydroa vacciniforme-like lymphoma. PMID- 27507021 TI - Genetic and Environmental Influences on Traits of Gender Identity Disorder: A Study of Japanese Twins Across Developmental Stages. AB - The present study examined: (1) gender and age differences of mean gender identity disorder (GID) trait scores in Japanese twins; (2) the validity of the prenatal hormone transfer theory, which predicts that, in dizygotic (DZ) twin pairs, twins with an opposite-gender co-twin more frequently exhibit GID traits than twins with a same-gender co-twin; and (3) the magnitude of genetic and environmental influences on GID traits as a function of age and gender. Data from 1450 male twin pairs, 1882 female twin pairs, and 1022 DZ male-female pairs ranging from 3 to 26 years of age were analyzed. To quantify individual variances in GID traits, each participant completed four questionnaire items based on criteria for GID from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). Our most important findings were: (1) Japanese females exhibited GID traits more frequently than males and Japanese children exhibited GID traits less frequently than adolescents and adults (among females, the prevalence was 1.6 % in children, 10 % in adolescents, and 12 % in adults; among males, the prevalence was 0.5, 2, and 3 %, respectively); (2) the data did not support the prenatal hormone transfer theory for GID traits; and (3) a large part of the variance for GID traits in children was accounted for by familial factors; however, the magnitude was found to be greater in children than in adolescents or adults, particularly among females. This study suggests that although the prevalence is likely to increase, familial effects are likely to decrease as individuals age. PMID- 27507020 TI - A Qualitative Investigation of the Impact of a Livelihood Intervention on Gendered Power and Sexual Risk Behaviors Among HIV-Positive Adults in Rural Kenya. AB - Despite the recognized links between food insecurity, poverty, and the risk of HIV/AIDS, few randomized trials have evaluated the impact of livelihood interventions on HIV risk behaviors. The current study draws upon data collected from a qualitative process evaluation that was embedded into a pilot randomized controlled trial that tested whether a multisectoral agricultural intervention (Shamba Maisha) affected the HIV-related health of HIV-positive adults in rural Kenya. In the current study, we drew upon longitudinal, in-depth interviews with 45 intervention participants and nine control participants (N = 54) in order to examine the impacts of the intervention on gendered power and sexual risk reduction among both women and men. Female and male participants in the intervention described positive changes in sexual practices and gendered power dynamics as a result of intervention participation. Changes included reduced sexual risk behaviors, improved gender-related power dynamics, and enhanced quality of intimate relationships. These findings illuminate how a multisectoral agricultural intervention may affect inequitable gender relations and secondary transmission risk. Further research is needed to explore how to best leverage agricultural interventions to address the important intersections between poverty and inequitable gender relations that shape HIV risks. PMID- 27507022 TI - Chronic Physical Illness Burden and Suicidal Ideation Among Dominicans in New York City. AB - Little is known about the association between chronic illness and suicidal ideation (SI) among Dominicans living in the United States. This study used data from a community survey of 2753 Dominican adults in New York City. SI included thoughts of self-harm or being better off dead in the past month. Chronic physical illness burden was categorized as having 0, 1, or 2+ diagnosed conditions. Adjusted logistic regressions evaluated the association between number of conditions and SI, overall and stratified by sex and age. Adjusted models yielded a strong association between chronic illness burden and SI among men [odds ratio (OR) 5.57, 95 % confidence interval (CI) 2.19-14.18] but not women (OR 0.80, 95 % CI 0.50-1.29; interaction p = 0.011). The association of interest did not differ significantly between younger and older adults. Screening for SI in health care practice, particularly among Dominican men with multiple chronic health conditions, may be warranted. PMID- 27507023 TI - Establishment and application of an analytical in-house database (IHDB) for rapid discrimination of Bacillus subtilis group (BSG) using whole-cell MALDI-TOF MS technology. AB - Members of the Bacillus subtilis group (BSG) possess industrial applicability; unfortunately, B. subtilis and its phylogenetically closest species are indistinguishable from one another using 16S rDNA sequencing, physiological and biochemical tests. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is a relatively novel technique for the fast and reliable identification of microorganisms. The aim of this study was to construct a unique analytical in-house database (IHDB) for BSG discrimination based on whole-cell protein fingerprinting using MALDI-TOF MS, as well as to discover biomarkers from the MS peaks to generate a classification model for further differentiation using the ClinProTools software. Type strains of 12 species (included five subspecies) of the BSG were used to build a main spectrum profile (MSP) to create an IHDB under the optimized parameters. The BSG isolates obtained from partial recA gene sequencing were used for IHDB validation. A total of 84 (100%) isolates were correctly identified to the species level and had high score values (mean score: 2.52). However, the IHDB had ambiguous identification at the subspecies level of Bacillus amyloliquefaciens. After implementation of the classification models, the strains could be clearly differentiated. We have successfully developed a rapid, accurate and cost-effective platform for the species- and subspecies-level discrimination of BSG based on the implementation of the IHDB and coupled with ClinProTools, which can be employed as an alternative technology to DNA sequencing and applied for efficient quality control of the microbial agent. PMID- 27507024 TI - [Not Available]. PMID- 27507025 TI - [Not Available]. PMID- 27507026 TI - [Not Available]. PMID- 27507027 TI - [Fluordeoxyglukose-PET/CT af angiosarkom i aorta]. PMID- 27507028 TI - [Dermatological laser- and light treatments of scars]. AB - Many patients struggle with tender, rigid and erythematous scars. Various modalities are used to treat cutaneous scars and in recent years, laser treatments are emerging as promising procedures. This article describes laser systems used for scar treatment according to scar type, evaluates the highest available level of evidence from randomized controlled trials (RCTs) and introduces a guideline for laser treatment of scars. Twelve RCTs documented effect on acne, burn and surgical scars. It is recommended that laser- and light based treatments are considered according to the scar type. PMID- 27507029 TI - [Clinical trial informed consent information for participants can be improved]. AB - Informed consent has been a legal right for patients participating in clinical research and an obligation for health professionals for a long time. A growing body of literature suggests that a considerable share of research participants do not read or understand the information they are given, or do not base their decisions on trial participation on the information. This article points out the challenges for health professionals arising from this situation and offers suggestions for how professionals can deal with the challenges. PMID- 27507030 TI - [An ordinary condom can be used for removing encircling metallic objects around penis]. AB - We describe a new method for removing encircling objects from penis. A 69-year old male was admitted with a ratchet spanner stuck at the penile base. A condom was applied to the penile shaft and manoeuvred in between the ratchet spanner and the penis. A lot of lubrication was applied, and the ratchet spanner was removed. Later the same method was tried when a 66-year-old male had a tap aerator stuck under glans penis. However, the method was unsuccessful because of a very narrow diameter of the tap aerator. Instead, the tap aerator was cut in two by using an angle grinder. PMID- 27507031 TI - [Therapeutic management of poorly differentiated neuroendocrine lung tumors and neuroendocrine carcinomas of the digestive system]. AB - Poorly differentiated neuroendocrine tumors are rare but their incidence is rising. High-grade neuroendocrine lung tumors, including small-cell lung cancer, are part of this group. Outside of the lung, they most often arise within the gastrointestinal tract (oesophagus, guts and pancreas) and are called neuroendocrine carcinomas. Due to their rarity, very little is known about neuroendocrine carcinomas of the pancreas and the gastrointestinal tract and few studies have been done. Therefore, most therapeutic recommendations are issued from studies on small-cell lung cancers. Histological scores have grown more accurate these past few years: poorly differentiated neuroendocrine tumors regroup various entities such as small-cells, large-cells and mix tumors, which seem to have different prognosis. They are diagnosed at a metastatic state in more than 50 % of cases. In localised disease, surgery is performed on selected patients. Adjuvant chemotherapy is administered in poorly differentiated neuroendocrine tumors of the lung and is an option in neuroendocrine carcinomas, without proof of efficacy. If not operable, radiochemotherapy is done for tumors of the lung, rectum, and eosophagus. If the disease is diagnosed at a metastatic state, chemotherapy is administered with a combination of platin salts (cisplatin or carboplatin) and etoposide. In poorly differentiated neuroendocrine tumors of the lung, prophylactic cranial irradiation is performed in localized disease if there is a good response to chemotherapy. Even if these therapies have improved the overall survival, no improvement has been made during the past four decades and the prognosis remains low. PMID- 27507032 TI - Use of routine histopathology and factor VIII-related antigen/von Willebrand factor immunohistochemistry to differentiate primary hemangiosarcoma of bone from telangiectatic osteosarcoma in 54 dogs. AB - Hemangiosarcoma (HSA) of bone and telangiectatic osteosarcoma (tOSA) can appear similar histologically, but differ in histogenesis (malignant endothelial cells versus osteoblasts), and may warrant different treatments. Immunohistochemistry (IHC) for endothelial cell marker factor VIII-related antigen/von Willebrand factor (FVIII-RAg/vWF) is a well-documented ancillary test to confirm HSA diagnoses in soft tissues, but its use in osseous HSA is rarely described. Archived samples of 54 primary appendicular bone tumours previously diagnosed as HSA or tOSA were evaluated using combination routine histopathology (RHP) and IHC. Approximately 20% of tumours were reclassified on the basis of FVIII-RAg/vWF immunoreactivity, typically from an original diagnosis of tOSA to a reclassified diagnosis of HSA. No sample with tumour osteoid clearly identified on RHP was immunopositive for FVIII-RAg/vWF. RHP alone was specific but not sensitive for diagnosis of HSA, compared with combination RHP and IHC. Routine histopathological evaluation in combination with FVIII-RAg/vWF IHC can help differentiate canine primary appendicular HSA from tOSA. PMID- 27507033 TI - Drug retention and safety of TNF inhibitors in elderly patients with rheumatoid arthritis. AB - BACKGROUND: The concerns about the development of adverse events (AEs) in elderly RA patients as a result of age-related changes in drug metabolism and the presence of comorbid illnesses are emphasizing due to increasing prevalence of rheumatoid arthritis (RA) in old age. However, they tend to be inadequately represented in RA clinical trials because of the exclusion criteria that are commonly applied. The tolerability and safety of TNF inhibitors in elderly patients have not been also evaluated in clinical practice. This study aimed to evaluate the retention rate and safety of TNF inhibitors (TNFI) in elderly RA patients. METHODS: Total 429 RA patients (838 person-years [PYs]) treated with TNFI from a retrospective biologic DMARDs registry. Patients were divided into an elderly (age >=60 years) and a younger group (<60 years). The drug retention rates of both groups were compared using Kaplan-Meier curves. Potential predictors of TNFI discontinuation in the elderly were examined using Cox regression analysis. The incidence rate (IR) of serious adverse events (SAEs) in the elderly group was compared to that of the young group. RESULTS: Of the patients, 24.9 % (n = 107, 212 PYs) were in the elderly group. Regarding the retention rates of TNFI in 3 years, there was no significant difference between the elderly and younger group (p = 0.33). The major cause of discontinuation in elderly patients was AE (34.3 %), whereas that was drug ineffectiveness (41.7 %) in younger patients. Age (HR 1.09, CI 1.02-1.16) was a predictor of discontinuation, while the presence of comorbidity (HR 0.37, CI 0.15-0.91) had a protective effect against drug discontinuation in the elderly. The IR of SAEs in the elderly (6.13/100 PYs) was higher than in the younger group (5.11/100 PYs). CONCLUSIONS: The retention rate of TNFI in the elderly was comparable with that in younger patients. The major cause of discontinuation in the elderly patients was AEs, while it was drug ineffectiveness in younger patients. The IR of SAEs in the elderly was higher than in the younger patients. PMID- 27507034 TI - Measuring and understanding motivation among community health workers in rural health facilities in India-a mixed method study. AB - BACKGROUND: Motivated human resource is the key to improve health system performance and retention of health workers. There is scanty literature on measuring motivation of health workers in India. Thus, the objective of this study was to measure and identify important aspects of health workers' motivation in North India. METHODS: A mixed method study design was adopted. Under the quantitative component, we interviewed randomly selected 62 community health workers (CHWs) in 18 sub-centres in two blocks of District Ambala, Haryana, India using a structured motivation scale. In-depth interviews were also carried out with 18 CHWs to explore the sources of motivation. RESULTS: The age of respondents and training in the past 12 months were found to be significantly associated with motivation. Job burnout, poor personal health, job insecurity and less career development opportunities were the individual level de-motivators, whereas not being able to fulfil family roles and poor supportive supervision were identified as environmental factors for poor motivation. Love for work, and financial incentives were individual level motivators, while community support and recognition, organizational commitment and pride, regular training were identified as environmental level motivators. CONCLUSION: Non-financial motivators such as interpersonal relations, family support, skill and career development opportunities require more attention. Regular need-based training is essential to maintain high levels of motivation. PMID- 27507035 TI - Five boosts to GP funding. PMID- 27507036 TI - Association of rs10811656 on 9P21.3 with the risk of coronary artery disease in a Chinese population. AB - BACKGROUND: Genome-wide association studies have reported that the 9p21.3 locus confers risk for coronary artery disease (CAD). However, it is not known whether rs10811656 is linked with CAD in a Chinese population. Thus, the purpose of this study was to investigate the potential association between rs10811656 and the risk of CAD in a Chinese population. METHODS: We conducted a hospital-based, case control study with 251 CAD patients and 304 controls to examine the potential association of rs10811656 with CAD. RESULTS: The frequencies of the TT genotypes in CAD cases were significantly different from those in controls (adjusted OR: 1.96, 95 % CI: 1.09-3.505, P = 0.024). Compared to controls, rs10811656 was significantly associated with the stable angina pectoris (adjusted OR: 1.42, 95 % CI: 1.06-1.90, P = 0.017), but not with acute coronary syndrome. There was also a highly significant association of rs10811656 with double-vessel and triple-vessel disease when patients were divided into subgroups based on the number of diseased vessels (adjusted OR: 1.68 and 1.60, 95 % CI: 1.14-2.44 and 1.10-2.33, P = 0.009 and 0.02, respectively). CONCLUSION: Our results suggest that the rs10811656 locus might be associated with CAD in a Chinese Han population. PMID- 27507037 TI - Lack of pharmacokinetic drug-drug interaction between ramucirumab and irinotecan in patients with advanced solid tumors. AB - PURPOSE: The objective of this phase II study was to evaluate the potential of pharmacokinetic (PK) drug-drug interactions between ramucirumab and irinotecan or its metabolite, SN-38, when administered with folinic acid and 5-fluorouracil (FOLFIRI). METHODS: Patients received intravenous infusions of FOLFIRI and ramucirumab 8 mg/kg on Day 1 of a 2-week cycle. FOLFIRI was administered alone in Cycle 1; ramucirumab followed by FOLFIRI was administered in all subsequent cycles. Blood was collected at regular intervals after infusions in Cycles 1 and 2 to determine irinotecan, SN-38, and ramucirumab concentrations. PK parameters were derived by noncompartmental analysis. RESULTS: Twenty-nine patients received treatment. The dose-normalized area under the concentration versus time curve from zero to infinity [AUC(0-infinity)] and the maximum observed concentration (C max) of irinotecan and SN-38 were comparable between Cycle 1 (FOLFIRI alone) and Cycle 2 (ramucirumab + FOLFIRI). The ratios of geometric least squares (LS) means for irinotecan were 0.93 (90 % CI 0.83-1.05) for AUC(0-infinity) and 1.04 (90 % CI 0.97-1.12) for C max. The ratios of geometric LS means for SN-38 were 0.95 (90 % CI 0.88-1.04) for AUC(0-infinity) and 0.97 (90 % CI 0.85-1.12) for C max. The most common treatment-emergent adverse events, regardless of grade, were fatigue (19 patients, 65.5 %), diarrhea, (16 patients, 55.2 %), and neutropenia (15 patients, 51.7 %). Grade >=3 neutropenia was reported in 7 (24.1 %) patients. CONCLUSIONS: There was no PK drug-drug interaction between ramucirumab and irinotecan or its metabolite, SN-38. Ramucirumab with FOLFIRI was well tolerated in this study, with no new safety concerns. PMID- 27507038 TI - Systematic assessment of pharmaceutical prescriptions in association with cancer risk: a method to conduct a population-wide medication-wide longitudinal study. AB - It is a public health priority to identify the adverse and non-adverse associations between pharmaceutical medications and cancer. We search for and evaluate associations between all prescribed medications and longitudinal cancer risk in participants of the Swedish Cancer Register (N = 9,014,975). We associated 552 different medications with incident cancer risk (any, breast, colon, and prostate) during 5.5 years of follow-up (7/1/2005-12/31/2010) in two types of statistical models, time-to-event and case-crossover. After multiple hypotheses correction and replication, 141 (26%) drugs were associated with any cancer in a time-to-event analysis constraining drug exposure to 1 year before first cancer diagnosis and adjusting for history of medication use. In a case crossover analysis, 36 drugs (7%) were associated with decreased cancer risk. 12 drugs were found in common in both analyses with concordant direction of association. We found 14, 10, 7% of all drugs associated with colon, prostate, and breast cancers in time-to-event models. We only found 1, 2%, and 0% for these cancers, respectively, in case-crossover analyses. Pharmacoepidemiologic analyses of cancer risk are sensitive to modeling choices and false-positive findings are a threat. Medication-wide analyses using different analytical models may help suggest consistent signals of increased cancer risk. PMID- 27507039 TI - [The ReWiKs project : Current results of research into participation opportunities for adults with disabilities in the area of sexual self determination]. AB - Several studies point to various barriers in achieving sexual self-determination for people with disabilities as well as a high degree of thematic uncertainty among staff in residential homes. In addition, women with disabilities and people in institutions are especially at risk in a particular way, to be victims of sexual violence. The ReWiKs project develops, based on evaluated guidelines for sexual self-determination, materials in order to reflect the institutional handling of the subject. Training modules and recommendations are also developed. In addition, extracts of materials are created in simple language. All materials are evaluated before their publication in an intensive theory-practice dialogue. PMID- 27507040 TI - Lunar influence on prey availability, diet shifts and niche overlap between Engraulidae larvae in tropical mangrove creeks. AB - The influence of the lunar cycle on prey availability, diet shifts and overlap between larval Anchovia clupeoides and Cetengraulis edentulus was evaluated in mangrove creeks of the Goiana Estuary. Copepod eggs were highly abundant in the first and last quarter, at the full moon and zoea of Ucides cordatus (Ocypodidae) in the new moon. The Engraulidae larvae fed on microcrustaceans, algae and early planktonic stages of benthic organisms. The relative importance of prey varied according to prey availability in all moon phases. Larval diets were more even in the full and new moons, when the relative importance of calanoid copepods and zoeae of U. cordatus as food items increased (index of relative importance, >80% IRI ). Mangrove creeks were very important feeding grounds for engraulid larvae during spring tides. Larval diets were more diverse in the first and last-quarter moon and included protozoeae of Caridean shrimp, larvae of Anomalocardia brasiliana (Veneridae), Isopoda, Gastropoda, ephippium of Daphnia sp. and nauplii of Cirripedia, Harpacticoidia and cyclopoid Copepoda. The last five items were not found in the creeks, suggesting feeding in the main channel. During neap tides, mangrove creeks were probably also used as refugia. These larvae are opportunistic and feed on highly available prey and both species feed on the same items, leading to high dietary overlap in all moon phases. The lunar cycle, which is related to the spring-neap tidal cycle, was the major driver of quantitative and qualitative changes in feeding of engraulid larvae on a short time scale. PMID- 27507042 TI - Cytoskeletal impairment during isoamyl alcohol-induced cell elongation in budding yeast. AB - Isoamyl alcohol (IAA) induces pseudohyphae including cell elongation in the budding yeast Saccharomyces cerevisiae. Detailed regulation of microtubules and actin in developmental transition during cell elongation is poorly understood. Here, we show that although IAA did not affect the intracellular actin level, it reduced the levels of both alpha- and beta-tubulins. In budding yeast, cytoplasmic microtubules are linked to actin via complexes consisting of at least Kar9, Bim1, and Myo2, and reach from the spindle pole body to the cortical attachment site at the bud tip. However, IAA did not affect migration of Myo2 to the bud tip and kept Kar9 in the interior portion of the cell. In addition, bud elongation was observed in Kar9-overexpressing cells in the absence of IAA. These results indicate that impairment of the link between cytoplasmic microtubules and actin is possibly involved in the lowered interaction of Myo2 with Kar9. Our study might explain the reason for delayed cell cycle during IAA-induced cell elongation. PMID- 27507043 TI - Evaluation of the effects of multiple providers in complex surgical interventions. AB - In contrast to new medicinal products, surgical interventions have many features that complicate their formal assessment through Randomised Clinical Trials. For example, surgery is delivered by multidisciplinary teams; hence, differential effects on the outcome are not solely caused by differences in the leading operator's skill but are also induced by surgical team differences and patient characteristics. This study focuses on how statistical methods can be used to accommodate the multicomponent nature of the delivery of surgical interventions. Hierarchical models with cross-classifications between components of surgery, applied to historic datasets, can be used during the trial planning phase to establish the effects and interactions between different components. Methods are illustrated using two influential components of the intervention, the surgeon and the anaesthetist, in a cohort of cardiac surgery cases. The statistical implications for trial design and analysis are presented. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27507044 TI - Early programming of the oocyte epigenome temporally controls late prophase I transcription and chromatin remodelling. AB - Oocytes are arrested for long periods of time in the prophase of the first meiotic division (prophase I). As chromosome condensation poses significant constraints to gene expression, the mechanisms regulating transcriptional activity in the prophase I-arrested oocyte are still not entirely understood. We hypothesized that gene expression during the prophase I arrest is primarily epigenetically regulated. Here we comprehensively define the Drosophila female germ line epigenome throughout oogenesis and show that the oocyte has a unique, dynamic and remarkably diversified epigenome characterized by the presence of both euchromatic and heterochromatic marks. We observed that the perturbation of the oocyte's epigenome in early oogenesis, through depletion of the dKDM5 histone demethylase, results in the temporal deregulation of meiotic transcription and affects female fertility. Taken together, our results indicate that the early programming of the oocyte epigenome primes meiotic chromatin for subsequent functions in late prophase I. PMID- 27507045 TI - Sebaceous mantleoma (mantle adenoma): reappraisal of the myth of the problematic benign neoplasm with sebaceous mantle differentiation. AB - Few cases of a true benign neoplasm with sebaceous mantle differentiation have been reported, and little is known about this tumor. Herein, we present a rare case of the neoplasm called sebaceous mantleoma, along with a comparison of the histology and immunoprofile with those of normal sebaceous mantles. A pedunculated polyp occurred on the scalp of a 51-year-old woman. Histopathologically, the tumor showed lobulated epithelial-mesenchymal units that were separated from the normal dermis by clefts. The lesion was composed of cords and columns of basaloid cells containing a few mature sebocytes, with a focal connection to infundibulocystic structures as well as dense fibrotic or fibromyxoid stroma. Immunohistochemically, androgen receptor, estrogen receptor, and CD117 were partially positive for the tumor, and CD8 (C8/144B) and epithelial membrane antigen were focally positive. Additionally, cytokeratin 20-positive Merkel cells were individually admixed in the tumor nests as well as in normal sebaceous mantles. This case report reveals the characteristic histology and immunoprofile of this problematic benign neoplasm and helps to understand this entity. PMID- 27507046 TI - RAD51 inhibition in triple negative breast cancer cells is challenged by compensatory survival signaling and requires rational combination therapy. AB - The molecular rationale to induce synthetic lethality, by targeting defective homologous recombination repair in triple negative breast cancer (TNBC), has proven to have several shortcomings. Not meeting the expected minimal outcomes in clinical trials has highlighted common clinical resistance mechanisms including; increased expression of the target gene PARP1, increased expression or reversion mutation of BRCA1, or up-regulation of the compensatory homologous recombination protein RAD51. Indeed, RAD51 has been demonstrated to be an alternative synthetic lethal target in BRCA1-mutated cancers. To overcome selective pressure on DNA repair pathways, we examined new potential targets within TNBC that demonstrate synthetic lethality in association with RAD51 depletion. We confirmed complementary targets of PARP1/2 and DNA-PK as well as a new synthetic lethality combination with p38. p38 is considered a relevant target in breast cancer, as it has been implicated in resistance to chemotherapy, including tamoxifen. We show that the combination of targeting RAD51 and p38 inhibits cell proliferation both in vitro and in vivo, which was further enhanced by targeting of PARP1. Analysis of the molecular mechanisms revealed that depletion of RAD51 increased ERK1/2 and p38 signaling. Our results highlight a potential compensatory mechanism via p38 that limits DNA targeted therapy. PMID- 27507047 TI - UHRF1 regulates global DNA hypomethylation and is associated with poor prognosis in esophageal squamous cell carcinoma. AB - BACKGROUND: Global DNA hypomethylation contributes to oncogenesis through various mechanisms. The level of long interspersed nucleotide element-1 (LINE- 1) methylation is considered a surrogate marker of global DNA methylation, and is attracting interest as a good predictor of cancer prognosis. However, the mechanism how LINE-1 (global DNA) methylation is controlled in cancer cells remains to be fully elucidated. Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) plays a crucial role in DNA methylation. UHRF1 is overexpressed in many cancers, and UHRF1 overexpression may be a mechanism underlying DNA hypomethylation in cancer cells. Nonetheless, the relationship between UHRF1, LINE-1 methylation level, and clinical outcome in esophageal squamous cell carcinoma (ESCC) remains unclear. RESULTS: In ESCC cell lines, vector-mediated UHRF1 overexpression caused global DNA (LINE-1) hypomethylation and, conversely, UHRF1 knockdown using siRNA increased the global DNA methylation level. In ESCC tissues, UHRF1 expression was significantly associated with LINE-1 methylation levels. Furthermore, UHRF1 overexpression correlated with poor prognosis in our cohort of 160 ESCC patients. MATERIALS AND METHODS: The relationships between UHRF1 expression and LINE-1 methylation level (i.e., global DNA methylation level) were investigated using ESCC tissues and cell lines. In addition, we examined the correlation between UHRF1 expression, LINE-1 methylation, and clinical outcome in patients with ESCC. CONCLUSIONS: Our results suggest that UHRF1 is a key epigenetic regulator of DNA methylation and might be a potential target for cancer treatment. PMID- 27507050 TI - The truncated somatostatin receptor sst5TMD4 stimulates the angiogenic process and is associated to lymphatic metastasis and disease-free survival in breast cancer patients. AB - The truncated somatostatin receptor sst5TMD4 is associated with poor prognosis in breast cancer and increases breast cancer cell malignancy. Here, we examined the cellular/molecular mechanisms underlying this association, aiming to identify new molecular tools to improve diagnosis, prognosis or therapy. A gene expression array comparing sst5TMD4 stably-transfected MCF-7 cells and their controls (empty plasmid) revealed the existence of profound alterations in the expression of genes involved in key tumoral processes, such as cell survival or angiogenesis. Moreover, sst5TMD4-overexpressing MCF-7 and MDA-MB-231 cells demonstrated increased expression/production of pro-angiogenic factors and enhanced capacity to form mammospheres. Consistently, sst5TMD4-expressing MCF-7 cells induced xenografted tumors with higher VEGF levels and elevated number of blood vessels. Importantly, sst5TMD4 was expressed in a subset of breast cancers, where it correlated with angiogenic markers, lymphatic metastasis, and reduced disease free survival. These results, coupled to our previous data, support a relevant role of sst5TMD4 in the angiogenic process and reinforce the role of sst5TMD4 in breast cancer malignancy and metastatic potential, supporting its possible utility to develop new molecular biomarkers and drug therapies for these tumors. PMID- 27507052 TI - Long non-coding RNA ANRIL promotes the invasion and metastasis of thyroid cancer cells through TGF-beta/Smad signaling pathway. AB - OBJECTIVE: To investigate the effect of antisense non-coding RNA in the INK4 locus (ANRIL) on invasion and metastasis of thyroid cancer (TC). RESULTS: ANRIL expression was significantly up-regulated in TC tissues and cells (P < 0.001), and ANRIL expression was significantly different regarding histological grade and LNM (both P < 0.01). The siRNA-mediated ANRIL silencing inhibits proliferation, invasion, and metastasis of TPC-1 and SW579 cells, and lung metastasis, which can be reversed by TGF-beta1 siRNA. The mRNA levels of p15INK4b, p14ARF and p16INK4a in TPC-1 and SW579 cells increased significantly after silencing ANRIL (all P < 0.001), and TGF-beta1 siRNA could reverse the ANRIL siRNA induced increase of p15INK4b; expressions of TGF-beta1 and p-Smad2/3 were increased after silencing ANRIL (both P < 0.05). MATERIALS AND METHODS: TC and adjacent normal tissues were collected from 105 TC patients. LncRNA ANRIL expressions were detected by qRT PCR. The siRNA ANRIL and siRNA TGF-beta1 were constructed for TPC-1 and SW579 cell line transfection: si-ANRIL group, si-TGF-beta1 group, si-ANRIL + si-TGF beta1 group, negative control group and blank group. Effects of ANRIL silencing on proliferation, invasion and metastasis of TC cells was detected by MTT assay, Transwell assay and tail vein injection of nude mice in vitro and in vivo. TGF beta1 and p-Smad2/3 expressions in TGF-beta/Smad signaling pathway were detected by western blot. CONCLUSIONS: ANRIL may reduce p15INK4B expression through inhibiting TGF-beta/Smad signaling pathway, promoting invasion and metastasis of TC cells, and the silencing of ANRIL inhibits the invasion and metastasis of TPC 1 cells. PMID- 27507053 TI - The Fanconi anemia pathway controls oncogenic response in hematopoietic stem and progenitor cells by regulating PRMT5-mediated p53 arginine methylation. AB - The Fanconi anemia (FA) pathway is involved in DNA damage and other cellular stress responses. We have investigated the role of the FA pathway in oncogenic stress response by employing an in vivo stress-response model expressing the Gadd45beta-luciferase transgene. Using two inducible models of oncogenic activation (LSL-K-rasG12D and MycER), we show that hematopoietic stem and progenitor cells (HSPCs) from mice deficient for the FA core complex components Fanca or Fancc exhibit aberrant short-lived response to oncogenic insults. Mechanistic studies reveal that FA deficiency in HSPCs impairs oncogenic stress induced G1 cell-cycle checkpoint, resulting from a compromised K-rasG12D-induced arginine methylation of p53 mediated by the protein arginine methyltransferase 5 (PRMT5). Furthermore, forced expression of PRMT5 in HSPCs from LSL-K rasG12D/CreER-Fanca-/- mice prolongs oncogenic response and delays leukemia development in recipient mice. Our study defines an arginine methylation dependent FA-p53 interplay that controls oncogenic stress response. PMID- 27507054 TI - GDF11 administration does not extend lifespan in a mouse model of premature aging. AB - GDF11 has recently emerged as a powerful anti-aging candidate, found in young blood, capable of rejuvenating a number of aged tissues, such as heart, skeletal muscle and brain. However, recent reports have shown contradictory data questioning its capacity to reverse age-related tissue dysfunction. The availability of a mouse model of accelerated aging, which shares most of the features occurring in physiological aging, gives us an excellent opportunity to test in vivo therapies aimed at extending lifespan both in pathological and normal aging. On this basis, we wondered whether the proposed anti-aging functions of GDF11 would have an overall effect on longevity. We first confirmed the existence of a reduction in GDF11/8 levels in our mouse model of accelerated aging compared with wild-type littermates. However, we show herein that GDF11 daily administration does not extend lifespan of premature-aged mice. PMID- 27507055 TI - Incidence and relative risk of hemorrhagic events associated with ramucirumab in cancer patients: a systematic review and meta-analysis. AB - The purpose of this study was to investigate the overall incidence and relative risk (RR) of hemorrhagic events in cancer patients treated with ramucirumab. 298 potentially relevant citations on ramucirumab from Pubmed, Web of Science and the Cochrane Database, as well as abstracts presented at conferences (all up to March 2016) were identified through our initial search. Only phase II and III prospective clinical trials of ramucirumab among cancer patients with toxicity records on hemorrhagic events were selected for final analysis. Data was extracted from the original studies by two independent reviewers. The overall incidence, RR, and 95% confidence intervals (CI) were calculated using fixed or random effects models according to the heterogeneity of the enrolled studies. The statistical analysis was performed by STATA version 11.0 (Stata Corporation, College Station, TX). 4963 patients with a variety of solid tumors from eleven eligible studies were selected into our analysis. The results demonstrated that the overall incidences of all-grade and high-grade hemorrhagic events in cancer patients were 27.6% (95% CI, 18.7-36.5%) and 2.3% (95% CI, 1.3-3.2%), respectively. The RR of hemorrhagic events of ramucirumab compared to control was significantly increased for low-grade (RR, 2.06; 95% CI, 1.85-2.29, p < 0.001), but not for high-grade (RR, 1.19, 95% CI, 0.80-1.76, p=0.39) hemorrhagic events. Hemorrhagic events associated with ramucirumab are modest and manageable while patients could continue to receive ramucizumab treatment to achieve their maximum clinical benefits. PMID- 27507056 TI - First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors. AB - Transmembrane glycoprotein CD44 is overexpressed in various malignancies. Interactions between CD44 and hyaluronic acid are associated with poor prognosis, making CD44 an attractive therapeutic target. We report results from a first-in human phase I trial of RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, in patients with advanced CD44-expressing solid malignancies.Sixty-five heavily pretreated patients not amenable to standard therapy were enrolled and received RG7356 intravenously biweekly (q2w) or weekly (qw) in escalating doses from 100 mg to 2,250 mg. RG7356 was well tolerated. Most frequent adverse events were fever, headache and fatigue. Dose-limiting toxicities included headache (1,500 mg q2w and 1,350 mg qw) and febrile neutropenia (2,250 mg q2w). The maximum tolerated dose with q2w dosing was 1,500 mg, but was not defined for qw dosing due to early study termination. Clinical efficacy was modest; 13/61 patients (21%) experienced disease stabilization lasting a median of 12 (range, 6-35) weeks. No apparent dose- or dose schedule dependent changes in biological activity were reported from blood or tissue analyses. Tumor-targeting by positron emission tomography (PET) using 89Zr labeled RG7356 was observed for doses >=200 mg (q2w) warranting further investigation of this agent in combination regimens. PMID- 27507057 TI - Glypican-3 induces a mesenchymal to epithelial transition in human breast cancer cells. AB - Breast cancer is the disease with the highest impact on global health, being metastasis the main cause of death. To metastasize, carcinoma cells must reactivate a latent program called epithelial-mesenchymal transition (EMT), through which epithelial cancer cells acquire mesenchymal-like traits.Glypican-3 (GPC3), a proteoglycan involved in the regulation of proliferation and survival, has been associated with cancer. In this study we observed that the expression of GPC3 is opposite to the invasive/metastatic ability of Hs578T, MDA-MB231, ZR-75-1 and MCF-7 human breast cancer cell lines. GPC3 silencing activated growth, cell death resistance, migration, and invasive/metastatic capacity of MCF-7 cancer cells, while GPC3 overexpression inhibited these properties in MDA-MB231 tumor cell line. Moreover, silencing of GPC3 deepened the MCF-7 breast cancer cells mesenchymal characteristics, decreasing the expression of the epithelial marker E Cadherin. On the other side, GPC3 overexpression induced the mesenchymal epithelial transition (MET) of MDA-MB231 breast cancer cells, which re-expressed E-Cadherin and reduced the expression of vimentin and N-Cadherin. While GPC3 inhibited the canonical Wnt/beta-Catenin pathway in the breast cancer cells, this inhibition did not have effect on E-Cadherin expression. We demonstrated that the transcriptional repressor of E-Cadherin - ZEB1 - is upregulated in GPC3 silenced MCF-7 cells, while it is downregulated when GPC3 was overexpressed in MDA-MB231 cells. We presented experimental evidences showing that GPC3 induces the E Cadherin re-expression in MDA-MB231 cells through the downregulation of ZEB1.Our data indicate that GPC3 is an important regulator of EMT in breast cancer, and a potential target for procedures against breast cancer metastasis. PMID- 27507058 TI - Chemoprevention of intestinal tumorigenesis by the natural dietary flavonoid myricetin in APCMin/+ mice. AB - Myricetin is a natural dietary flavonoid compound. We evaluated the efficacy of myricetin against intestinal tumorigenesis in adenomatous polyposis coli multiple intestinal neoplasia (APCMin/+) mice. Myricetin was given orally once a day for 12 consecutive weeks. APCMin/+ mice fed with myricetin developed fewer and smaller polyps without any adverse effects. Histopathological analysis showed a decreased number of dysplastic cells and degree of dysplasia in each polyp. Immunohistochemical and western blot analysis revealed that myricetin selectively inhibits cell proliferation and induces apoptosis in adenomatous polyps. The effects of myricetin were associated with a modulation the GSK-3beta and Wnt/beta catenin pathways. ELISA analysis showed a reduced concentration of pro inflammatory cytokines IL-6 and PGE2 in blood, which were elevated in APCMin/+ mice. The effect of myricetin treatment was more prominent in the adenomatous polyps originating in the colon. Further studies showed that myricetin downregulates the phosphorylated p38 MAPK/Akt/mTOR signaling pathways, which may be the mechanisms for the inhibition of adenomatous polyps by myricetin. Taken together, our data show that myricetin inhibits intestinal tumorigenesis through a collection of biological activities. Given these results, we suggest that myricetin could be used preventatively to reduce the risk of developing colon cancers. PMID- 27507059 TI - Superior efficacy of co-treatment with the dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A against NSCLC. AB - Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. NSCLC development and progression have recently been correlated with the heightened activation of histone deacetylases (HDACs) and PI3K/Akt signaling pathways. Targeted inhibition of these proteins is promising approach for the development of novel therapeutic strategies to treat patients with advanced NSCLC. For this reason, we combined a dual PI3K and mTOR inhibitor, BEZ235 with the HDAC inhibitor Trichostatin A (TSA), to determine their combined effects on human NSCLC. In this study, we initially discovered that co-treatment with BEZ235 and TSA showed a synergistic effect on inhibition of NSCLC cell proliferation and induction of apoptosis. The combination treatment also synergistically suppressed NSCLC migration, invasion and the NSCLC epithelial-mesenchymal transition (EMT) in vitro. The synergistic effect was also evidenced by declines in xenograft growth and metastasis rates and in ki-67 protein expression in vivo. Together, these results indicated that BEZ235 and TSA combination treatment significantly increased anti-tumor activities compared with BEZ235 and TSA alone, supporting a further evaluation of combination treatment for NSCLC. PMID- 27507060 TI - Targeting antisense mitochondrial ncRNAs inhibits murine melanoma tumor growth and metastasis through reduction in survival and invasion factors. AB - We reported that knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, suggesting this approach for selective therapy against different types of cancer. In order to translate these results to a preclinical scenario, we characterized the murine noncoding mitochondrial RNAs (ncmtRNAs) and performed in vivo knockdown in syngeneic murine melanoma models. Mouse ncmtRNAs display structures similar to the human counterparts, including long double-stranded regions arising from the presence of inverted repeats. Knockdown of ASncmtRNAs with specific antisense oligonucleotides (ASO) reduces murine melanoma B16F10 cell proliferation and induces apoptosis in vitro through downregulation of pro survival and metastasis markers, particularly survivin. For in vivo studies, subcutaneous B16F10 melanoma tumors in C57BL/6 mice were treated systemically with specific and control antisense oligonucleotides (ASO). For metastasis studies, tumors were resected, followed by systemic administration of ASOs and the presence of metastatic nodules in lungs and liver was assessed. Treatment with specific ASO inhibited tumor growth and metastasis after primary tumor resection. In a metastasis-only assay, mice inoculated intravenously with cells and treated with the same ASO displayed reduced number and size of melanoma nodules in the lungs, compared to controls. Our results suggest that ASncmtRNAs could be potent targets for melanoma therapy. To our knowledge, the ASncmtRNAs are the first potential non-nuclear targets for melanoma therapy. PMID- 27507061 TI - A novel approach to assessing bisphenol-A hazards using an in vitro model system. AB - BACKGROUND: Although the toxicological impacts of the xenoestrogen bisphenol-A (BPA) have been studied extensively, but the mechanism of action is poorly understood. Eventually, no standard method exists for evaluating the possible health hazards of BPA exposure. Considering mice spermatozoa as a potential in vitro model, we investigated the effects of BPA exposure (0.0001, 0.01, 1, and 100 MUM for 6 h) on spermatozoa and the related mechanisms of action. The same doses were also employed to evaluate protein profiles of spermatozoa as a means to monitor their functional affiliation to diseases. RESULTS: Our results demonstrated that high concentrations of BPA negatively affect sperm motility, viability, mitochondrial functions, and intracellular ATP levels by activating the mitogen-activated protein kinase, phosphatidylinositol 3-kinase, and protein kinase-A pathways. Moreover, short-term exposure of spermatozoa to high concentrations of BPA induced differential expressions of 24 proteins. These effects appeared to be caused by protein degradation and phosphorylation in spermatozoa. Proteins differentially expressed in spermatozoa from BPA treatment groups are putatively involved in the pathogenesis of several diseases, mainly cancer, carcinoma, neoplasm, and infertility. CONCLUSIONS: Based on these results, we propose that BPA adversely affects sperm function by the activation of several kinase pathways in spermatozoa. In addition, BPA-induced changes in the sperm proteome might be partly responsible for the observed effects in spermatozoa, subsequently involve in the pathogenesis of many diseases. Therefore, we anticipated that current strategy might broadly consider for the health hazards assessment of other toxicological agents. PMID- 27507063 TI - Diagnostic utility of arborizing stromal meshwork fragments in mucinous tumors. AB - INTRODUCTION: Arborizing stromal meshwork fragments (ASMFs) have been proposed as a useful clue to differentiate mucin associated with mucinous adenocarcinoma from contaminating mucus during endobronchial ultrasound-guided transbronchial needle aspiration. Our aim was to retrospectively review cytology cases with mucinous material to determine the utility of ASMFs in diagnosing mucinous tumors. MATERIAL AND METHODS: Diff-Quik stained smears from archival cytology cases (N = 40) were reviewed, including adenocarcinomas with mucinous features, cystic mucinous neoplasms, and control cases with mucin contamination. Specimens were procured by image-guided fine needle aspiration (FNA) (16 cases), endoscopic ultrasound-guided FNA (22 cases), pathologist-performed FNA (1 case), and fluid drainage (1 case). All cases were reviewed for ASMFs, which were defined as metachromatic, spidery extensions with frayed edges within a background of mucinous material. RESULTS: ASMFs were identified in 4 (10% of cases, 14% of adenocarcinomas) cases of metastatic gastrointestinal mucinous adenocarcinomas in various locations (liver, lymph node, lung, and bone), but absent in mucin contamination. ASMFs in Diff-Quik stained smears were magenta-colored and corresponded to intervening stroma between dissecting mucin in the tumor. Nonarborizing desmoplastic stroma, inspissated mucus, cartilage fragments, transgressing vessels in renal cell carcinoma, and mucus-like material in pancreatic pseudocysts can morphologically mimic ASMFs. CONCLUSION: These data show that ASMFs may be encountered in some (14%) cases of adenocarcinoma with mucinous differentiation. When present, ASMFs can be diagnostically helpful to differentiate adenocarcinoma with mucinous features from contaminating mucus, if reliably distinguished from mimics. Diagn. Cytopathol. 2016;44:805-810. (c) 2016 Wiley Periodicals, Inc. PMID- 27507064 TI - Bleeding complications with oral anticoagulants in the elderly: an observational study. AB - Over recent years, new oral anticoagulant agents (NOAC) have been commercialized as a new treatment in order to prevent or treat thromboembolic events. Although the use of NOACs is easier than for vitamin K antagonists (VKA), their risk benefit balance still raises concerns, especially in the elderly. To evaluate bleeding complications with anticoagulants agents (NOAC and VKA) among a geriatric population. A retrospective study performed in the four units of the acute geriatric department of CHU Charleroi (116 beds). All the patients who received at least one dose of oral anticoagulant (NOAC or VKA) during their hospitalization between January 1st 2013 and May 31th 2014 were enrolled. Medical files of 242 patients were analyzed, and the type and severity of bleeding were recorded. Mean age was 84 +/- 5.4 years old. Seventy-three percent were prescribed VKA. Rivaroxaban was the most prescribed NOAC among this population. Atrial fibrillation was the primary indication of oral anticoagulation in 73% with VKA and 94% with NOAC. Fourty-six patients presented a bleeding (38 patients (22% of patients with VKA) with VKA and 8 patients with NOAC (12% of patients with NOAC)). We found 13 major bleedings with VKA and only one with NOAC. The results of this study are encouraging concerning the utilization of NOACs in the geriatric population. However, larger studies are needed to confirm this. PMID- 27507062 TI - Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn's disease and leprosy. AB - Genetic polymorphism within the 9q32 locus is linked with increased risk of several diseases, including Crohn's disease (CD), primary biliary cholangitis (PBC) and leprosy. The most likely disease-causing gene within 9q32 is TNFSF15, which encodes the pro-inflammatory cytokine TNF super-family member 15, but it was unknown whether these disparate diseases were associated with the same genetic variance in 9q32, and how variance within this locus might contribute to pathology. Using genetic data from published studies on CD, PBC and leprosy we revealed that bearing a T allele at rs6478108/rs6478109 (r(2) = 1) or rs4979462 was significantly associated with increased risk of CD and decreased risk of leprosy, while the T allele at rs4979462 was associated with significantly increased risk of PBC. In vitro analyses showed that the rs6478109 genotype significantly affected TNFSF15 expression in cells from whole blood of controls, while functional annotation using publicly-available data revealed the broad cell type/tissue-specific regulatory potential of variance at rs6478109 or rs4979462. In summary, we provide evidence that variance within TNFSF15 has the potential to affect cytokine expression across a range of tissues and thereby contribute to protection from infectious diseases such as leprosy, while increasing the risk of immune-mediated diseases including CD and PBC. PMID- 27507065 TI - The role of hand hygiene in controlling norovirus spread in nursing homes. AB - BACKGROUND: Norovirus, the leading cause of gastroenteritis, causes higher morbidity and mortality in nursing homes (NHs) than in the community. Hence, implementing infection control measures is crucial. However, the evidence on the effectiveness of these measures in NH settings is lacking. Using an innovative data-driven modeling approach, we assess various interventions to control norovirus spread in NHs. METHODS: We collected data on resident and staff characteristics and inter-human contacts in a French NH. Based on this data, we developed a stochastic compartmental model of norovirus transmission among the residents and staff of a 100-bed NH. Using this model, we investigated how the size of a 100-day norovirus outbreak changed following three interventions: increasing hand hygiene (HH) among the staff or residents and isolating symptomatic residents. RESULTS: Assuming a baseline staff HH compliance rate of 15 %, the model predicted on average 19 gastroenteritis cases over 100 days among the residents, which is consistent with published incidence data in NHs. Isolating symptomatic residents was highly effective, leading to an 88 % reduction in the predicted number of cases. The number of expected cases could also be reduced significantly by increasing HH compliance among the staff; for instance, by 75 % when assuming a 60 % HH compliance rate. While there was a linear reduction in the predicted number of cases when HH practices among residents increased, the achieved impact was less important. CONCLUSIONS: This study shows that simple interventions can help control the spread of norovirus in NHs. Modeling, which has seldom been used in these settings, may be a useful tool for decision makers to design optimal and cost-effective control strategies. PMID- 27507066 TI - Evolution of hypothalamic lipoma after Roux-en-Y gastric bypass. AB - Severe obesity is a common consequence of hypothalamic region diseases and their treatment. Only two previous case reports have described hypothalamic lipomas in children with obesity. We described a case of an adult with severe obesity associated with hypothalamic lipoma attached to the third ventricle floor who underwent Roux-en-Y gastric bypass. He lost 38 and 59 kg at 6 and 12 months after surgery, respectively. Weight loss after bariatric surgery was as expected in this patient with severe obesity. At 6 and 12 months, brain magnetic resonance imaging (MRI) showed stability in lipoma's size. PMID- 27507067 TI - Trends in vitamin, mineral and dietary supplement use in Switzerland. The CoLaus study. AB - BACKGROUND/OBJECTIVES: Vitamin/mineral (VMS) and dietary supplements (DS) use is common in Switzerland, but nothing is known regarding the factors associated with their initiation, discontinuation or continuation of intake. SUBJECTS/METHODS: Prospective study conducted between 2003-2006 and 2009-2012 in Lausanne, Switzerland among 4676 participants (2525 women, age range 35-75 years). VMS were defined as single or multivitamin/multimineral preparations; DS were defined as any dietary supplement. RESULTS: VMS use was 20.6% at baseline and 20.3% at follow-up (P=0.69): 559 (12.0%) participants discontinued; 545 (11.7%) initiated and 404 (8.6%) continued VMS use. On multivariable analysis, men had a lower relative risk ratio (RRR) of discontinuing, initiation or continuing; older age and being physically active were associated with a higher RRR of initiation or continuing; lower education and higher body mass index were associated with a lower RRR of discontinuing or continuing of VMS. DS use decreased from 10.4 to 6.8% (P<0.001): 405 (8.7%) participants discontinued; 239 (5.1%) initiated and 81 (1.7%) continued DS use. On multivariable analysis, men had a lower RRR of discontinuing, initiation or continuing; older age had a higher RRR of initiation, discontinuing or continuing; being physically active was associated with a higher RRR of initiation or continuing; Swiss citizens and former smokers had a higher RRR of discontinuing. CONCLUSIONS: VMS use is stable in the Lausanne population, whereas DS use appears to be decreasing. Individuals can be categorized either as users or non-users depending on the study period, and consistent users are only a small fraction of prevalent users. PMID- 27507068 TI - The prevalence of sarcopenia before and after correction for DXA-derived fat-free adipose tissue. AB - The literature suggests that the estimate of lean mass may be overestimated in the obese using dual-energy X-ray absorptiometry (DXA), as ~15% of adipose tissue is composed of fat-free tissue. The purpose of this study was to investigate how the DXA-derived fat-free adipose influences appendicular lean mass and prevalence of sarcopenia across a range of body fat % in both men and women using a national sample (n=1946). The appendicular lean mass/m2 went from 7.0 kg/m2 (confidence interval (CI): 6.9, 7.2) to 5.9 kg/m2 (CI: 5.8, 6.1) following correction in those with ?35% body fat, whereas it only went from 7.5 kg/m2 (CI: 7.2, 7.8) to 7.1 kg/m2 (CI: 6.8, 7.4) following correction in those with <25% body fat. Fat free adipose tissue may need to be accounted for when estimating appendicular lean mass and failure to account for fat-free adipose tissue may underestimate the prevalence of sarcopenia. PMID- 27507069 TI - Assessment of drug administration via feeding tube and the knowledge of health care professionals in a university hospital. AB - BACKGROUND/OBJECTIVES: The use of drugs via feeding tube is problematic. Appropriate techniques must be used during the administration to prevent obstruction of a feeding tube, to avoid inadequate drug effects and to minimize the risk of toxicity of the given pharmaceuticals. SUBJECTS/METHODS: In this study, medications of all the patients in a University Hospital with 1100 beds were monitored to identify the appropriateness of administration. The study was performed on 5 days each in 5 consecutive weeks to observe the current practice. After evaluation of practice, a questionnaire was given to doctors, nurses and pharmacists to determine the health-care professionals' attitudes on drug administration through a feeding tube. RESULTS: A total of 225 drugs (out of 13 935) were administered via feeding tube during the study period and 40.5% (n=91) were not administered in appropriate dosage forms. Only 86% of the doctors and 98% of the nurses stated that they pay attention to the suitability of drugs when they prescribe or administer drugs via feeding tube. Only 58% of pharmacists, 17% of nurses and 24% of doctors were aware of the fact that enteric-coated tablets should not be crushed owing to the risk of tube occlusion and lack of efficacy when they are administered via feeding tube. CONCLUSIONS: This study demonstrated the discordance between the theoretical knowledge and the practical performance of the health-care professionals in drug administration. In patients with feeding tubes, assessment of drug dosage forms by a pharmacist would be beneficial for appropriate administration and to prevent drug interactions. PMID- 27507070 TI - Associations between body composition, physical capabilities and pulmonary function in healthy older adults. AB - BACKGROUND/OBJECTIVES: There are positive associations between pulmonary function (PF) and fat-free mass as well as muscle strength. Contrarily, negative associations were found with indirect measures of visceral adipose tissue (VAT). We aimed to differentiate between associations of body composition and PF by assessing mediating and moderating effects of physical capabilities. SUBJECTS/METHODS: Cross-sectional data were assessed among 40 healthy, free living elderly (20 males) aged 65.1-81.2 years (mean+/-s.d. age: 72.2+/-4.3 years; body mass index: 25.6+/-3.7 kg/m2). Total and regional skeletal muscle (SM), and adipose tissue (AT) were measured using whole-body magnetic resonance imaging. Muscle strength by handgrip dynamometry, physical activity (PA) by questionnaire, and physical performance by gait speed and sit-to-stand test (STS). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were assessed by spirometry. RESULTS: Positive associations between height standardized FVC (FVCI) as well as FEV1 (FEVI), and SM (r=0.435-0.520, P<0.05) were found; subcutaneous AT (SAT) and FVCI correlated negatively (r=-0.374; P<0.05). HGS and PA correlated positively with FEVI (r=0.456-0.608, P<0.05), HGS also with FVCI (r=0.595, P<0.05). Stepwise multiple regression using FVCI and FEVI as dependent variables, and total/thoracic SM, VAT, SAT, HGS, PA and physical performance as independent variables showed that (i) only HGS entered the regression for predicting FVCI (R2=0.351; standard error of estimation (SEE)=0.32 l), and (ii) HGS and PA explained 50% of FEVI (SEE=0.23 l). HGS mediated the relationship between SM and PF; the STS moderated the relationship between SM and FVCI. CONCLUSIONS: In healthy elderly, PF is positively associated with SM; physical capabilities mediate and moderate these relationships. PMID- 27507071 TI - A tailored automated nutrition screening tool for rapid identification of risk in acute-care hospital settings. AB - Malnourishment is prevalent in hospitalized patients and associated with adverse medical outcomes. Thus, nutrition screening to identify high-risk patients is widespread. However, no single universal tool has been shown to be suitable for all hospital departments. To address this challenge, a novel, tailored, electronic tool for nutritional screening was developed and evaluated. The Rambam Automated Nutrition Computerized Screening tool efficiently screens all newly admitted patients and does not rely on self-reported height and weight estimates. Validation was carried out in medical wards (n=94), and compared to the Malnutrition Universal Screening Tool, length of stay and an independent assessment by a professional dietician. Results from this research support the use of automated, flexible tools that instantaneously incorporate relevant available data from the electronic health record. Tools that are adaptable to meet the needs of individual hospital departments, can save valuable time and ensure full screening of all admitted patients. PMID- 27507072 TI - The gluten-free basic food basket: a problem of availability, cost and nutritional composition. AB - The basic food basket (BFB), formed by the more economical products available, is used by less-affluent countries to establish the minimum daily food consumption to satisfy nutritional requirements in less-privileged individuals. There is no information about groups that depend on the BFB and in addition follow gluten free diet (GF/BFB). We measured availability, cost, main ingredients and nutritional composition of GF/BFB. Data were collected in the area that was first in the social priority list in the capital city, matching BFB components with gluten-free equivalents (GF/BFB). GF/BFB characterized by being 42% less available, three times more costly (>500% higher for bread), with up to 69% lower protein content and with no fortifications, leaving at nutritional risk celiac individuals that depend on GF/BFB. Results raise concerns on the capacity of the GF/BFB to encourage adherence, maintain adequate nutritional status and quality of life in celiac patients. PMID- 27507073 TI - A Mediterranean-style diet, its components and the risk of heart failure: a prospective population-based study in a non-Mediterranean country. AB - BACKGROUND/OBJECTIVES: Growing evidence emerged about the role of diet in heart failure (HF) development, but data are sparse and inconclusive. We examined the association between a Mediterranean-style diet, its components and HF risk. SUBJECTS/METHODS: Analyses were carried out in 24 008 middle-aged participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam (Germany), including 209 incident HF cases within 8.2 years. The traditional Greek Mediterranean diet score (tMED) was used to assess dietary adherence. Cox's proportional hazards regression was applied to estimate the relationship between the adherence to the Mediterranean-style diet, its components and HF risk. RESULTS: After adjustment for age, sex and energy intake, a 2-unit increment in the tMED was associated with 26% lower risk of HF (HR (95% confidence interval (CI)): 0.76 (0.60-0.97)). After multivariable adjustment, this association was slightly attenuated and lost significance [HR (95%CI): 0.82 (0.64-1.05)]. Interestingly, we observed a significant association in multivariable adjusted models when milk products were excluded from the score (HR (95% CI): 0.75 (0.59 0.96)). Three score components were significantly associated with HF risk: alcohol (HR (95%CI): 0.73 (0.55-0.97) for moderate versus low/high intakes), meat: 2.04 (1.17-3.55) and fish: 0.59 (0.36-0.95), both for the highest versus the lowest quintile. CONCLUSIONS: The tMED was not significantly associated with HF risk, but low meat, high fish and moderate alcohol intake were inversely associated with HF risk in our non-Mediterranean population. Minor dietary changes could be valuable primary prevention measures, particularly the increase of fish consumption while reducing the intake of meat. PMID- 27507074 TI - Comparison of fatty acid intakes assessed by a cardiovascular-specific food frequency questionnaire with red blood cell membrane fatty acids in hyperlipidaemic Australian adults: a validation study. AB - BACKGROUND/OBJECTIVES: Limited dietary intake tools have been validated specifically for hyperlipidaemic adults. The Australian Eating Survey (AES) Food Frequency Questionnaire (FFQ) was adapted to include foods with cardio-protective properties (CVD-AES). The aims were to estimate dietary fatty acid (FA) intakes derived from the CVD-AES and AES and compare them with red blood cell (RBC) membrane FA content. SUBJECTS/METHODS: Dietary intake was measured using the semi quantitative 120-item AES and 177-item CVD-AES. Nutrient intakes were calculated using AUSNUT 2011-2013. Fasting RBC membrane FAs were assessed using gas chromatography. Extent of agreement between intakes estimated by AES or CVD-AES and RBC membrane composition (% of total FAs) for linoleic acid (LA), alpha linolenic acid (ALA), eicosapentanoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) were assessed using Spearman's correlation coefficients, adjusted linear regressions and Kappa statistics. RESULTS: Data from 39 participants (72% female, 59.3+/-11.1 years) indicate stronger positive correlations between RBC membrane FAs and CVD-AES dietary estimates compared with the AES. Significant (P<0.05) moderate-strong correlations were found between CVD AES FAs and FA proportions in RBC membranes for EPA (r=0.62), DHA (r=0.53) and DPA (r=0.42), with a moderate correlation for LA (r=0.39) and no correlation with ALA. Significant moderate correlations were found with the AES for DHA (r=0.39), but not for LA, ALA, EPA or DPA. CONCLUSIONS: The CVD-AES provides a more accurate estimate of long chain FA intakes in hyperlipidaemic adults, compared with AES estimates. This indicates that a CVD-specific FFQ should be used when evaluating FA intakes in this population. PMID- 27507075 TI - Consumption of sugar-sweetened beverages and discretionary foods among US adults by purchase location. AB - BACKGROUND/OBJECTIVES: Excess calorie intake from sugar-sweetened beverages (SSBs) and energy-dense, nutrient-poor foods occupies a significant proportion of Western diet. The aim of this study was to examine consumption of SSBs and discretionary foods in US adults by purchase location. SUBJECTS/METHODS: Nationally representative 24-h dietary recall data came from the 2011-2012 National Health and Nutrition Examination Survey. The discretionary food category identifies energy-dense, nutrient-poor foods that do not necessarily contain essential nutrients but may add variety and enjoyment. Linear regressions were performed to estimate daily calorie intake from SSBs and discretionary foods by purchase location (supermarket/grocery store, convenience store, vending machine, fast-food restaurant, full-service restaurant and other source), adjusting for individual characteristics and sampling design. RESULTS: During 2011-2012, 46.3% and 88.8% of US adults consumed SSBs and discretionary foods on any given day, respectively. SSB consumers on average consumed 213.0 kcal from SSBs daily, of which 111.6 kcal (52.4%) were purchased from supermarkets/grocery stores, 33.0 kcal (15.5%) from fast-food restaurants, 23.9 kcal (11.2%) from convenience stores, 17.1 kcal (8.0%) from full-service restaurants, 8.5 kcal (4.0%) from vending machines and 19.0 kcal (8.9%) from other sources. Discretionary food consumers on average consumed 439.0 kcal from discretionary foods daily, of which 280.1 kcal (63.8%) were purchased from supermarkets/grocery stores, 45.8 kcal (10.4%) from fast-food restaurants, 30.0 kcal (6.8%) from full-service restaurants, 21.1 kcal (4.8%) from convenience stores, 4.1 kcal (0.9%) from vending machines and 58.0 kcal (13.2%) from other sources. CONCLUSIONS: Supermarkets/grocery stores were by far the single largest source for SSB and discretionary food purchases in US adults. PMID- 27507076 TI - A 7-day intravenous toxicity study and neurotoxicity assessment of pyridorin in Sprague-Dawley rats. AB - Pyridorin(r), a naturally occurring metabolite of vitamin B6 that inhibits and scavenges reactive oxygen species, is being developed as a potential therapeutic for acute kidney injury. An investigational new drug application (IND) was opened for Pyridorin in support of its ongoing oral drug clinical development program. Currently, a Pyridorin intravenous (IV) formulation is being developed for use in surgical patients. To support the IND for Pyridorin, a full battery of nonclinical Good Laboratory Practice compliant studies was performed with no neurological or behavioral signs of toxicity seen following oral or IV administration of pyridoxine dihydrochloride (the active ingredient in Pyridorin). However, excessive ingestion of vitamin B6 has been reported to cause neurotoxic syndrome in humans. Therefore, under Food and Drug Administration recommendation, a 7-day IV study in rats was conducted to further evaluate the drug's potential to cause neurotoxicity. Blood plasma samples indicated that exposure to pyridoxamine dihydrochloride and its metabolites, pyridoxal, pyridoxine, and 4-pyridoxic acid was linearly dose proportional and independent of gender. At doses of up to 200 mg/kg/day pyridoxine dihydrochloride, no treatment-related effects were seen in rats, providing further evidence for the absence of pyridoxine dihydrochloride-related changes in the nervous system. A no observed adverse effect level of 200 mg/kg/day was identified for this study. PMID- 27507077 TI - Incorporating climate change into ecosystem service assessments and decisions: a review. AB - Climate change is having a significant impact on ecosystem services and is likely to become increasingly important as this phenomenon intensifies. Future impacts can be difficult to assess as they often involve long timescales, dynamic systems with high uncertainties, and are typically confounded by other drivers of change. Despite a growing literature on climate change impacts on ecosystem services, no quantitative syntheses exist. Hence, we lack an overarching understanding of the impacts of climate change, how they are being assessed, and the extent to which other drivers, uncertainties, and decision making are incorporated. To address this, we systematically reviewed the peer-reviewed literature that assesses climate change impacts on ecosystem services at subglobal scales. We found that the impact of climate change on most types of services was predominantly negative (59% negative, 24% mixed, 4% neutral, 13% positive), but varied across services, drivers, and assessment methods. Although uncertainty was usually incorporated, there were substantial gaps in the sources of uncertainty included, along with the methods used to incorporate them. We found that relatively few studies integrated decision making, and even fewer studies aimed to identify solutions that were robust to uncertainty. For management or policy to ensure the delivery of ecosystem services, integrated approaches that incorporate multiple drivers of change and account for multiple sources of uncertainty are needed. This is undoubtedly a challenging task, but ignoring these complexities can result in misleading assessments of the impacts of climate change, suboptimal management outcomes, and the inefficient allocation of resources for climate adaptation. PMID- 27507078 TI - When Will Physical Activity be Routinely Measured in the Clinical Setting? The Case for Bariatric Surgery. PMID- 27507079 TI - Response to "When will physical activity be routinely measured in the clinical setting? The case for bariatric surgery". PMID- 27507082 TI - Hypothyroidism and hyponatremia: data from a series of patients with iatrogenic acute hypothyroidism undergoing radioactive iodine therapy after total thyroidectomy for thyroid cancer. AB - PURPOSE: The aim of the present study was to evaluate the role of hypothyroidism as a cause of hyponatremia in a clinical model of iatrogenic acute hypothyroidism due to thyroid hormone withdrawal prior to ablative radioactive iodine (RAI) therapy after total thyroidectomy. METHODS: The study group consisted of 101 differentiated thyroid cancer (DTC) patients (77 women and 24 men). Plasma concentration of thyroid-stimulating hormone ([TSH]) and sodium ([Na+]) was evaluated before total thyroidectomy (pre[TSH] and pre[Na+]) and on the day of RAI therapy (post[TSH] and post[Na+]). RESULTS: The frequency of hypothyroidism associated hyponatremia was 4 % (4/101). Pre[Na+] was significantly higher than post[Na+] (140.7 +/- 1.6 vs 138.7 +/- 2.3 mEq/L, p = 0.012). Moreover, a linear correlation was identified between pre[Na+] and post[Na+]. CONCLUSIONS: Iatrogenic acute hypothyroidism-related hyponatremia is uncommon. However, because of the significant reduction of [Na+] in the transition from euthyroidism to iatrogenic hypothyroidism, the value of pre[Na+] should be viewed as a parameter to be considered. Since it acts as an independent risk factor for the development of hyponatremia, patients with a pre[Na+] close to the lower limit of normal range may deserve a closer monitoring of [Na+]. PMID- 27507083 TI - Experimental and DFT characterization, antioxidant and anticancer activities of a Cu(II)-irbesartan complex: structure-antihypertensive activity relationships in Cu(II)-sartan complexes. AB - The coordination compound of the antihypertensive ligand irbesartan (irb) with copper(II) (CuIrb) was synthesized and characterized by FTIR, FT-Raman, UV visible, reflectance and EPR spectroscopies. Experimental evidence allowed the implementation of structural and vibrational studies by theoretical calculations made in the light of the density functional theory (DFT). This compound was designed to induce structural modifications on the ligand. No antioxidant effects were displayed by both compounds, though CuIrb behaved as a weak 1,1-diphenyl-2 picrylhydrazyl radical (DPPH(.)) scavenger (IC50 = 425 MUM). The measurements of the contractile capacity on human mesangial cell lines showed that CuIrb improved the antihypertensive effects of the parent medication. In vitro cell growth inhibition against prostate cancer cell lines (LNCaP and DU 145) was measured for CuIrb, irbesartan and copper(II). These cell lines have been selected since the angiotensin II type 1 (AT1) receptor (that was blocked by the angiotensin receptor blockers, ARB) has been identified in them. The complex exerted anticancer behavior (at 100 MUM) improving the activity of the ligand. Flow cytometry determinations were used to determine late apoptotic mechanisms of cell death. Experimental and DFT characterization of an irbesartan copper(II) complex has been performed. The complex exhibits low scavenging activity against DPPH(.) and significant growth inhibition of LNCaP and DU 145 prostate cancer cell lines. Flow cytometry determinations were used to determine late apoptotic mechanisms of cell death. This compound improved the antihypertensive effect of irbesartan. This effect was observed earlier for the mononuclear Cu-candesartan complex, but not in structurally modified sartans forming dinuclear or octanuclear Cu-sartan compounds. PMID- 27507084 TI - The association between particulate air pollution and respiratory admissions among young children in Hanoi, Vietnam. AB - While the effects of ambient air pollution on health have been studied extensively in many developed countries, few studies have been conducted in Vietnam, where the population is exposed to high levels of airborne particulate matter. The aim of our study was to examine the short-term effects of PM10, PM2.5, and PM1 on respiratory admissions among young children in Hanoi. Data on daily admissions from the Vietnam National Hospital of Paediatrics and daily records of PM10, PM2.5, PM1 and other confounding factors as NO2, SO2, CO, O3 and temperature were collected from September 2010 to September 2011. A time stratified case-crossover design with individual lag model was applied to evaluate the associations between particulate air pollution and respiratory admissions. Significant effects on daily hospital admissions for respiratory disease were found for PM10, PM2.5 and PM1. An increase in 10MUg/m3 of PM10, PM2.5 or PM1 was associated with an increase in risk of admission of 1.4%, 2.2% or 2.5% on the same day of exposure, respectively. No significant difference between the effects on males and females was found in the study. The study demonstrated that infants and young children in Hanoi are at increased risk of respiratory admissions due to the high level of airborne particles in the city's ambient air. PMID- 27507085 TI - A tool box strategy using Bacteroides genetic markers to differentiate human from non-human sources of fecal contamination in natural water. AB - Bacteroides genetic markers have been widely used to identify fecal pollution of water originating from human and animal sources. Many of the assays currently used for detecting human-specific Bacteroides produce false positive results. The focus of this study was to develop a microbial source tracking (MST) tool box strategy for differentiating Bacteroides from human and animal sources. Bacteroides 16S rRNA gene sequences from fish and selected animals were aligned against human fecal Bacteroides isolates to compare and characterize the variable regions within the 16S rRNA gene sequence. Conserved sequences between 4 variable regions were deleted and the truncated sequences were combined to develop a hyper variable genomic segment (HVGS). The cladogram created from truncated sequences show a clear separation of Bacteroides from human feces and those from animal sources. The proposed strategy was field tested by collecting water samples from central Arizona source waters and three different recreational ponds. PCR using HF134 and HF183 primer sets was performed and sequences from positive reactions were aligned against human Bacteroides sequences to identify the source of contamination. Based on PCR results, the source of fecal contamination was presumptively identified as either human or from another source. For samples testing positive using the HF183 primer set (8/13), fecal contamination was presumed to be from human sources, but to confirm the results, PCR products were sequenced and aligned against the four variable regions and then incorporated within the truncated cladogram. As expected, the sequences from water samples with human fecal contamination grouped in a separate clade. A variability matrix, developed after exclusion of conserved sequences among the four regions, was utilized to establish discrete groupings for sequences within the truncated cladogram, generally differentiating Bacteroides isolates from varying host animals, but most importantly, separating Bacteroides from human feces from Bacteroides from other animals. The proposed strategy offers a new tool box method for MST and a step-wise methodology essential for identifying human sources of fecal pollution. PMID- 27507086 TI - Phosphorus in the catchment of high sediment load river: A case of the Yellow River, China. AB - Surface sediment samples concurrently collected in the catchment of the Ningxia Inner Mongolian reach of Yellow River (NIMYR) were analyzed to determine the phosphorus and correlated physiochemical properties of sediments. Samples were obtained from three main areas: the riverbed surface sediment (RSS), the floodplain surface sediment (FSS) and the desert surface sediment (DSS). The sequence of phosphorus-contamination level in this catchment, determined by a cumulative distribution function and multivariate statistical analysis, were FSS>RSS>DSS. Moreover, because of the impacts of anthropogenic activities, the sampling site with the highest and lowest phosphorus concentration (mgkg-1) of this catchment appeared in RSS (749.40) and DSS (200.10) respectively. In addition, this is the first study to present a qualification of the effect of the sediment's physicochemical properties on phosphorus by the multivariate regression tree analysis. Co-precipitation of phosphate with calcite [i], phosphate absorbed onto ferric hydroxides [ii] and grain-size effect [iii] were the three main mechanisms for phosphorus distribution in the sediment of NIMYR. The contributions of these three mechanisms to RSS and FSS were, respectively, [i]>[iii]>[ii] and [i]>[ii]>[iii]. The heaviest phosphorus-contaminated group of RSS was primarily controlled by [i], whereas the heaviest phosphorus-contaminated group of FSS was controlled by [i] and [ii], indicating that the FSS had a higher potential risk of releasing phosphorus from the sediment to overlying water. PMID- 27507087 TI - Enhancing microbial production of biofuels by expanding microbial metabolic pathways. AB - Fatty acid, isoprenoid, and alcohol pathways have been successfully engineered to produce biofuels. By introducing three genes, atfA, adhE, and pdc, into Escherichia coli to expand fatty acid pathway, up to 1.28 g/L of fatty acid ethyl esters can be achieved. The isoprenoid pathway can be expanded to produce bisabolene with a high titer of 900 mg/L in Saccharomyces cerevisiae. Short- and long-chain alcohols can also be effectively biosynthesized by extending the carbon chain of ketoacids with an engineered "+1" alcohol pathway. Thus, it can be concluded that expanding microbial metabolic pathways has enormous potential for enhancing microbial production of biofuels for future industrial applications. However, some major challenges for microbial production of biofuels should be overcome to compete with traditional fossil fuels: lowering production costs, reducing the time required to construct genetic elements and to increase their predictability and reliability, and creating reusable parts with useful and predictable behavior. To address these challenges, several aspects should be further considered in future: mining and transformation of genetic elements related to metabolic pathways, assembling biofuel elements and coordinating their functions, enhancing the tolerance of host cells to biofuels, and creating modular subpathways that can be easily interconnected. PMID- 27507088 TI - Analysis of high-order SNP barcodes in mitochondrial D-loop for chronic dialysis susceptibility. AB - OBJECTIVES: Positively identifying disease-associated single nucleotide polymorphism (SNP) markers in genome-wide studies entails the complex association analysis of a huge number of SNPs. Such large numbers of SNP barcode (SNP/genotype combinations) continue to pose serious computational challenges, especially for high-dimensional data. METHODS: We propose a novel exploiting SNP barcode method based on differential evolution, termed IDE (improved differential evolution). IDE uses a "top combination strategy" to improve the ability of differential evolution to explore high-order SNP barcodes in high-dimensional data. RESULTS: We simulate disease data and use real chronic dialysis data to test four global optimization algorithms. In 48 simulated disease models, we show that IDE outperforms existing global optimization algorithms in terms of exploring ability and power to detect the specific SNP/genotype combinations with a maximum difference between cases and controls. In real data, we show that IDE can be used to evaluate the relative effects of each individual SNP on disease susceptibility. CONCLUSION: IDE generated significant SNP barcode with less computational complexity than the other algorithms, making IDE ideally suited for analysis of high-order SNP barcodes. PMID- 27507089 TI - Correlation between videogame mechanics and executive functions through EEG analysis. AB - This paper addresses a different point of view of videogames, specifically serious games for health. This paper contributes to that area with a multidisciplinary perspective focus on neurosciences and computation. The experiment population has been pre-adolescents between the ages of 8 and 12 without any cognitive issues. The experiment consisted in users playing videogames as well as performing traditional psychological assessments; during these tasks the frontal brain activity was evaluated. The main goal was to analyse how the frontal lobe of the brain (executive function) works in terms of prominent cognitive skills during five types of game mechanics widely used in commercial videogames. The analysis was made by collecting brain signals during the two phases of the experiment, where the signals were analysed with an electroencephalogram neuroheadset. The validated hypotheses were whether videogames can develop executive functioning and if it was possible to identify which kind of cognitive skills are developed during each kind of typical videogame mechanic. The results contribute to the design of serious games for health purposes on a conceptual level, particularly in support of the diagnosis and treatment of cognitive-related pathologies. PMID- 27507090 TI - Automated population of an i2b2 clinical data warehouse from an openEHR-based data repository. AB - BACKGROUND: Detailed Clinical Model (DCM) approaches have recently seen wider adoption. More specifically, openEHR-based application systems are now used in production in several countries, serving diverse fields of application such as health information exchange, clinical registries and electronic medical record systems. However, approaches to efficiently provide openEHR data to researchers for secondary use have not yet been investigated or established. METHODS: We developed an approach to automatically load openEHR data instances into the open source clinical data warehouse i2b2. We evaluated query capabilities and the performance of this approach in the context of the Hanover Medical School Translational Research Framework (HaMSTR), an openEHR-based data repository. RESULTS: Automated creation of i2b2 ontologies from archetypes and templates and the integration of openEHR data instances from 903 patients of a paediatric intensive care unit has been achieved. In total, it took an average of ~2527s to create 2.311.624 facts from 141.917 XML documents. Using the imported data, we conducted sample queries to compare the performance with two openEHR systems and to investigate if this representation of data is feasible to support cohort identification and record level data extraction. DISCUSSION: We found the automated population of an i2b2 clinical data warehouse to be a feasible approach to make openEHR data instances available for secondary use. Such an approach can facilitate timely provision of clinical data to researchers. It complements analytics based on the Archetype Query Language by allowing querying on both, legacy clinical data sources and openEHR data instances at the same time and by providing an easy-to-use query interface. However, due to different levels of expressiveness in the data models, not all semantics could be preserved during the ETL process. PMID- 27507097 TI - Structural basis of unique ligand specificity of KAI2-like protein from parasitic weed Striga hermonthica. AB - The perception of two plant germination inducers, karrikins and strigolactones, are mediated by the proteins KAI2 and D14. Recently, KAI2-type proteins from parasitic weeds, which are possibly related to seed germination induced by strigolactone, have been classified into three clades characterized by different responses to karrikin/strigolactone. Here we characterized a karrikin-binding protein in Striga (ShKAI2iB) that belongs to intermediate-evolving KAI2 and provided the structural bases for its karrikin-binding specificity. Binding assays showed that ShKAI2iB bound karrikins but not strigolactone, differing from other KAI2 and D14. The crystal structures of ShKAI2iB and ShKAI2iB-karrikin complex revealed obvious structural differences in a helix located at the entry of its ligand-binding cavity. This results in a smaller closed pocket, which is also the major cause of ShKAI2iB's specificity of binding karrikin. Our structural study also revealed that a few non-conserved amino acids led to the distinct ligand-binding profile of ShKAI2iB, suggesting that the evolution of KAI2 resulted in its diverse functions. PMID- 27507099 TI - A genomic view of the peopling of the Americas. AB - Whole-genome studies have documented that most Native American ancestry stems from a single population that diversified within the continent more than twelve thousand years ago. However, this shared ancestry hides a more complex history whereby at least four distinct streams of Eurasian migration have contributed to present-day and prehistoric Native American populations. Whole genome studies enhanced by technological breakthroughs in ancient DNA now provide evidence of a sequence of events involving initial migrations from a structured Northeast Asian source population with differential relatedness to present-day Australasian populations, followed by a divergence into northern and southern Native American lineages. During the Holocene, new migrations from Asia introduced the Saqqaq/Dorset Paleoeskimo population to the North American Arctic ~4500 years ago, ancestry that is potentially connected with ancestry found in Athabaskan speakers today. This was then followed by a major new population turnover in the high Arctic involving Thule-related peoples who are the ancestors of present-day Inuit. We highlight several open questions that could be addressed through future genomic research. PMID- 27507098 TI - Insights into human evolution from ancient and contemporary microbiome studies. AB - Over the past decade, human microbiome research has energized the study of human evolution through a complete shift in our understanding of what it means to be human. The microbiome plays a pivotal role in human biology, performing key functions in digestion, mood and behavior, development and immunity, and a range of acute and chronic diseases. It is therefore critical to understand its evolution and changing ecology through time. Here we review recent findings on the microbiota of diverse human populations, non-human primates, and past human populations and discuss the implications of this research in formulating a deeper evolutionary understanding of the human holobiont. PMID- 27507100 TI - Biomimetic nucleus pulposus scaffold created from bovine caudal intervertebral disc tissue utilizing an optimal decellularization procedure. AB - Intervertebral disc (IVD) degeneration (IDD) and herniation (IDH) can result in low back pain and impart significant socioeconomic burden. These pathologies involve detrimental alteration to the nucleus pulposus (NP) either via biochemical degradation or extrusion from the IVD, respectively. Thus, engineering living NP tissue utilizing biomaterial scaffolds that recapitulate native NP microarchitecture, biochemistry, mechanical properties, and which support cell viability represents an approach to aiding patients with IDD and IDH. To date, an ideal biomaterial to support NP regeneration has yet to be developed; however, one promising approach to generating biomimetic materials is to employ the decellularization (decell) of xenogeneic NP tissue to remove host DNA while maintaining critical native extracellular matrix (ECM) components. Herein, 13 different procedures were evaluated in an attempt to decell bovine caudal IVD NP tissue. An optimal method was identified which was confirmed to effectively remove bovine DNA, while maintaining physiologically relevant amounts of glycosaminoglycan (GAG) and type II collagen. Unconfined static and dynamic compressive mechanical properties of scaffolds approached values reported for human NP and viability of human amniotic stem cells (hAMSCs) was maintained on noncrosslinked and EDC/NHS treated scaffolds for up to 14 days in culture. Taken together, NP tissue obtained from bovine caudal IVDs can be successfully decelled in order to generate a biomimetic scaffold for NP tissue regeneration. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 3093-3106, 2016. PMID- 27507101 TI - Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization. AB - Recent reports have brought back the acetylcholine synthesizing enzyme, choline acetyltransferase in the mainstream research in dementia and the cholinergic anti inflammatory pathway. Here we report, a specific strategy for the design of novel ChAT ligands based on molecular docking, Hologram Quantitative Structure Activity Relationship (HQSAR) and lead optimization. Molecular docking was performed on a series of ChAT inhibitors to decipher the molecular fingerprint of their interaction with the active site of ChAT. Then robust statistical fragment HQSAR models were developed. A library of novel ligands was generated based on the pharmacophoric and shape similarity scoring function, and evaluated in silico for their molecular interactions with ChAT. Ten of the top scoring invented compounds are reported here. We confirmed the activity of alpha-NETA, the only commercially available ChAT inhibitor, and one of the seed compounds in our model, using a new simple colorimetric ChAT assay (IC50 ~ 88 nM). In contrast, alpha-NETA exhibited an IC50 of ~30 MUM for the ACh-degrading cholinesterases. In conclusion, the overall results may provide useful insight for discovering novel ChAT ligands and potential positron emission tomography tracers as in vivo functional biomarkers of the health of central cholinergic system in neurodegenerative disorders, such as Alzheimer's disease. PMID- 27507102 TI - Gut microbiota: D-amino acids employed against gut pathogens. PMID- 27507103 TI - IBD: A timely diagnosis of primary sclerosing cholangitis in IBD. PMID- 27507105 TI - Left-Sided Catamenial Pneumothorax with Thoracic Endometriosis and Bullae in the Alveolar Wall. AB - Catamenial pneumothorax (CP) is generally caused by intraperitoneal air leaking from the uterus into the thoracic cavity via a defect in the endometrial tissue of the diaphragm and is usually detected in the right thorax. We report a case of left-sided CP caused by endometriosis in the visceral pleura and with no abnormal findings in the diaphragm. A 33-year-old female patient presented at the end of a course of low-dose contraceptive pills for pelvic endometriosis, with spontaneous pneumothorax in the left chest. Chest CT revealed a bulla in the left upper lung lobe. The patient underwent partial resection of the lung. Immunohistochemistry confirmed the presence of endometrial stromal tissue in the visceral pleura and confirmed this as the cause of pneumothorax since there were no observable abnormalities in the diaphragm. This case suggests that immunohistochemical examination of patients with spontaneous pneumothorax can detect alternative endometrial lesions. PMID- 27507106 TI - Long-Term Quality of Life after Cardiac and Thoracic Aortic Surgery for Very Elderly Patients 85 Years or Older. AB - PURPOSE: We evaluated the outcomes of open heart surgery and long-term quality of life for patients 85 years and older. METHODS: We enrolled 46 patients 85 years and older who underwent cardiac and thoracic aortic surgery between May 1999 and November 2012. Long-term assessment was performed for 43 patients; three patients who died in the hospital were excluded. Patient conditions were assessed before surgery, 6 months and 12 months after surgery, and during the late period regarding the need for nursing care, degree of independent living, and living willingness. RESULTS: Three patients (6.5%) died during hospitalization and 22 (51%) died during the follow-up period. The 1-, 3-, 5-year survival rates were 74%, 49%, and 36%. During the late period, of 21 surviving patients, 18 patients (85%) were living at home. The need for nursing care was comparable before and after surgery. The degree of independent living decreased after surgery. Living willingness was similar before and after surgery. CONCLUSION: Among patients 85 years or older who underwent open heart surgery, 85% were living at home. All patients could perform activities of daily living without any assistance while maintaining living willingness. PMID- 27507104 TI - Bioengineering the gut: future prospects of regenerative medicine. AB - Functions of the gastrointestinal tract include motility, digestion and absorption of nutrients. These functions are mediated by several specialized cell types including smooth muscle cells, neurons, interstitial cells and epithelial cells. In gastrointestinal diseases, some of the cells become degenerated or fail to accomplish their normal functions. Surgical resection of the diseased segments of the gastrointestinal tract is considered the gold-standard treatment in many cases, but patients might have surgical complications and quality of life can remain low. Tissue engineering and regenerative medicine aim to restore, repair, or regenerate the function of the tissues. Gastrointestinal tissue engineering is a challenging process given the specific phenotype and alignment of each cell type that colonizes the tract - these properties are critical for proper functionality. In this Review, we summarize advances in the field of gastrointestinal tissue engineering and regenerative medicine. Although the findings are promising, additional studies and optimizations are needed for translational purposes. PMID- 27507107 TI - Lymph Node Dissection in Surgery for Lung Cancer: Comparison of Open vs. Video Assisted vs. Robotic-Assisted Approaches. AB - PURPOSE: We compared open, video-assisted and robotic-assisted thoracoscopic surgical techniques in the dissection of N1 and N2-level lymph nodes during surgery for lung cancer. METHODS: This retrospective analysis is based on prospectively collected data of patients (excluding those with N2 or N3 diseases, and sleeve resections) undergoing mediastinal lymph node dissection via open (n = 96), video-assisted thoracoscopy (n = 68), and robotic-assisted thoracoscopy (n = 106). The groups are compared according to the number of lymph node stations dissected, the number of lymph nodes dissected, and the number of lymph nodes dissected by stations. RESULTS: Three techniques had similar results based on the number of the dissected N1 and N2-level lymph node stations. Robotic-assisted thoracoscopic surgery yielded significantly more lymph nodes in total (p = 0.0007), and in the number of dissected N1-level nodes (p <0.0001). All techniques yielded similar number of mediastinal lymph nodes, whereas robotic assisted thoracic surgery (RATS) yielded more station #11 and #12 lymph nodes compared to the other groups. CONCLUSIONS: In this study, robotic-assisted thoracoscopic surgery has been shown to dissect more lymph nodes at N1 level. However, taking the open approach as standard, we could claim that both currently robotic and video-assisted techniques may provide similar number of dissected N1 and N2-level lymph node stations. PMID- 27507108 TI - Role of phytochemicals in the inhibition of epithelial-mesenchymal transition in cancer metastasis. AB - Epithelial-mesenchymal transition (EMT) is the process by which epithelial cells become mesenchymal cells, gaining fibroblast-like properties and displaying reduced intercellular adhesion and increased motility. EMT plays an important role in cancer metastasis. Suppressing or reversing EMT is therefore an important way of controlling various cancers. Phytochemicals are important sources of anticancer lead molecules. Natural products have been shown to safely suppress or reverse EMT via the inhibition of associated signalling pathways in various cancer cells. In the present review, we discuss the relevant factors and the role of EMT in cancer metastasis. We then present examples of phytochemicals with a role in the inhibition and reversal of EMT in various cancers, focusing on reports from 2012 to 2016. PMID- 27507109 TI - Design, synthesis and biological evaluation of novel hamamelitannin analogues as potentiators for vancomycin in the treatment of biofilm related Staphylococcus aureus infections. AB - Staphylococcus aureus is a frequent cause of biofilm-related infections. Bacterial cells within a biofilm are protected from attack by the immune system and conventional antibiotics often fail to penetrate the biofilm matrix. The discovery of hamamelitannin as a potentiator for antibiotics, recently led to the design of a more drug-like lead. In the present study, we want to gain further insight into the structure-activity relationship (S.A.R.) of the 5-position of the molecule, by preparing a library of 21 hamamelitannin analogues. PMID- 27507110 TI - Discovery of a new type of scaffold for the creation of novel tyrosinase inhibitors. AB - Tyrosinase is known as the key enzyme for melanin biosynthesis, which is effective in preventing skin injury by ultra violet (UV). In past decades, tyrosinase has been well studied in the field of cosmetics, medicine, agriculture and environmental sciences, and a lot of tyrosinase inhibitors have been developed for their needs. Here, we searched for new types of tyrosinase inhibitors and found phenylbenzoic acid (PBA) as a unique scaffold. Among three isomers of PBA, 3-phenylbenzoic acid (3-PBA) was revealed to be the most potent inhibitor against mushroom tyrosinase (IC50=6.97MUM, monophenolase activity; IC50=36.3MUM, diphenolase activity). The kinetic studies suggested that the apparent inhibition modes for the monophenolase and diphenolase activities were noncompetitive and mixed type inhibition, respectively. Analyses by in silico docking studies using the crystallographic structure of mushroom tyrosinase indicated that the carboxylic acid group of the 3-PBA could adequately bind to two cupric ions in the tyrosinase. To prove this hypothesis, we examined the effect of modification of the carboxylic acid group of the 3-PBA on its inhibitory activity. As expected, the esterification abrogated the inhibitory activity. These observations suggest that 3-PBA is a useful lead compound for the generation of novel tyrosinase inhibitors and provides a new insight into the molecular basis of tyrosinase catalytic mechanisms. PMID- 27507111 TI - Frequency of Poor Outcome (Death or Poor Quality of Life) After Left Ventricular Assist Device for Destination Therapy: Results From the INTERMACS Registry. AB - BACKGROUND: A left ventricular assist device (LVAD) improves survival and quality of life for many, but not all, patients with end-stage heart failure who are ineligible for transplantation. We sought to evaluate the frequency of poor outcomes using a novel composite measure that integrates quality of life with mortality. METHODS AND RESULTS: Within the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) national registry, poor outcome was defined as death or an average Kansas City Cardiomyopathy Questionnaire <45 during the year after LVAD (persistently limiting heart failure symptoms and poor quality of life). Among 1638 patients with LVAD, 29.7% had a poor outcome, with death in 22.4% and persistently poor quality of life in 7.3%. Patients who had a poor outcome were more likely to have higher body mass indices (29.3 versus 28.2 kg/m(2); P=0.007), lower hemoglobin levels (11.1 versus 11.4 g/dL; P=0.005), previous cardiac surgery (47.8% versus 39.8%; P=0.004), history of cancer (13.8% versus 9.7%; P=0.025), severe diabetes mellitus (15.6% versus 11.5%; P=0.038), and poorer quality of life preimplant (Kansas City Cardiomyopathy Questionnaire scores: 29.8 versus 35.3; P<0.001). CONCLUSIONS: Nearly one third of patients die or have a persistently poor quality of life during the year after LVAD. We identified several factors associated with a poor outcome, which may inform discussions before LVAD implantation to enable more realistic expectations of recovery. PMID- 27507112 TI - Hypochloremia, Diuretic Resistance, and Outcome in Patients With Acute Heart Failure. AB - BACKGROUND: Chloride plays a role in renal salt sensing, neurohormonal activation, and regulation of diuretic targets, and hypochloremia predicts mortality in acute heart failure (AHF). AHF therapies, such as diuretics, alter chloride homeostasis. We studied the association between (changes in) chloride levels and diuretic responsiveness, decongestion, and mortality in patients with AHF. METHODS AND RESULTS: Patients hospitalized for AHF in the PROTECT trial (n=2033) with serum chloride levels within 24 hours of admission and 14 days later were studied (n=1960). Hypochloremia was defined as serum chloride <96 mEq/L. Mean baseline chloride was 100.8+/-5.0 mEq/L. Low baseline chloride was associated with high bicarbonate, poor diuretic response, less hemoconcentration, and worsening heart failure (all P<0.01). Newly developed hypochloremia at day 14 was common and associated with a decline in renal function and an increase in blood urea nitrogen (P<0.01). In multivariable analyses, chloride measured at day 14, but not baseline chloride, was strongly and independently associated with mortality through 180 days (hazard ratio per unit decrease: 1.07 [1.03-1.10]; P<0.001). In comparison, sodium was not significantly associated with mortality after multivariable adjustment at any time point. Hypochloremia at baseline that resolved was not associated with mortality (P=0.55), but new or persistent hypochloremia at day 14 was associated with increased mortality (hazard ratio: 3.11 [2.17-4.46]; P<0.001). CONCLUSIONS: Low serum chloride at AHF hospital admission was strongly associated with impaired decongestion. New or persistent hypochloremia 14 days later was independently associated with reduced survival, whereas hypochloremia that resolved by day 14 was not. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00354458. PMID- 27507114 TI - Putting Life in the Years: Incorporating Quality of Life Into Left Ventricular Assist Devices Outcomes. PMID- 27507113 TI - Hypochloremia and Diuretic Resistance in Heart Failure: Mechanistic Insights. AB - BACKGROUND: Recent epidemiological studies have implicated chloride, rather than sodium, as the driver of poor survival previously attributed to hyponatremia in heart failure. Accumulating basic science evidence has identified chloride as a critical factor in renal salt sensing. Our goal was to probe the physiology bridging this basic and epidemiological literature. METHODS AND RESULTS: Two heart failure cohorts were included: (1) observational: patients receiving loop diuretics at the Yale Transitional Care Center (N=162) and (2) interventional pilot: stable outpatients receiving >=80 mg furosemide equivalents were studied before and after 3 days of 115 mmol/d supplemental lysine chloride (N=10). At the Yale Transitional Care Center, 31.5% of patients had hypochloremia (chloride <=96 mmol/L). Plasma renin concentration correlated with serum chloride (r=-0.46; P<0.001) with no incremental contribution from serum sodium (P=0.49). Hypochloremic versus nonhypochloremic patients exhibited renal wasting of chloride (P=0.04) and of chloride relative to sodium (P=0.01), despite better renal free water excretion (urine osmolality 343+/-101 mOsm/kg versus 475+/-136; P<0.001). Hypochloremia was associated with poor diuretic response (odds ratio, 7.3; 95% confidence interval, 3.3-16.1; P<0.001). In the interventional pilot, lysine chloride supplementation was associated with an increase in serum chloride levels of 2.2+/-2.3 mmol/L, and the majority of participants experienced findings such as hemoconcentration, weight loss, reduction in amino terminal, pro B-type natriuretic peptide, increased plasma renin activity, and increased blood urea nitrogen to creatinine ratio. CONCLUSIONS: Hypochloremia is associated with neurohormonal activation and diuretic resistance with chloride depletion as a candidate mechanism. Sodium-free chloride supplementation was associated with increases in serum chloride and changes in several cardiorenal parameters. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02031354. PMID- 27507115 TI - Endoluminal application of glass-capped diffuser for ex vivo endovenous photocoagulation. AB - Endovenous laser ablation (EVLA) has frequently been used to treat varicose veins for 20 years. In spite of 90~95% occlusion rates, clinical complications such as burn and ecchymosis still occur due to excessive thermal injury to perivenous tissue. In the current study, a glass-capped diffusing applicator is designed to validate the feasibility of EVLA as an effective therapeutic device by applying circumferential light distribution. The proposed device is evaluated with a flat fiber as a reference in terms of temperature elevation, fiber degradation, and degree of coagulative necrosis after 532 nm-assisted EVLA at 100 J/cm. The diffusing fiber generates a 40% lower maximum temperature with a 90% lower transient temperature change in blood, compared to the flat fiber. Due to low irradiance (13.5 kW/cm2 ) and wide light distribution, the diffuser tip experiences no significant thermal degradation while severe carbonization occurs at the flat fiber tip. Ex vivo tissue tests verify that the diffusing fiber induces circumferential and consistent tissue denaturation to the vein wall (107.8 +/- 7.8 um) along with 19% vessel shrinkage. The proposed glass-capped diffusing applicator can be a feasible therapeutic device for EVLA with minimal complications by entailing low maximum temperatures and uniform tissue denaturation in the venous tissue. PMID- 27507116 TI - Saffron (Crocus sativus) pretreatment confers cardioprotection against ischemia reperfusion injuries in isolated rabbit heart. AB - Restoration of blood flow to the ischemic myocardium is imperative to avoid demise of cardiomyocytes, but is paradoxically associated with irreversible damage to cardiac tissues due to the excessive generation of reactive oxygen species (ROS). We have previously reported that saffron, a natural antioxidant, attenuated ischemia-reperfusion (IR) injuries in vitro; however, its role in a meaningful cardiac recovery remains unknown. Here, we show that saffron supplement (oral administration for 6 weeks) reduced myocardial damage and restored cardiac function in an IR model of rabbit hearts. This was evidenced by improved left ventricle pressure, heart rate and coronary flow, and left ventricle end diastolic pressure (LVEDP) in IR hearts (isolated from rabbits pre exposed to saffron (S/IR)). Electrophysiological recordings revealed a significant decline in both premature ventricle contraction and ventricle tachycardia/fibrillation in S/IR compared to IR hearts. This was paralleled by increased expression of the contractile proteins alpha-actinin and Troponin C in the myocardium of S/IR hearts. Histological examination combined to biochemical analysis indicated that hearts pre-exposed to saffron exhibited reduced infarct size, lower lipid peroxidation, with increased glutathione peroxidase activity, and oxidation of nitro blue tetrazolium (by reactive oxygen species). Furthermore, in contrast with IR hearts, saffron pretreatment induced restoration of the phosphorylation level of the survival proteins Akt and 4EBP1 and reduced activity of p38. Collectively, our data demonstrate that the natural antioxidant saffron plays a pivotal role in halting IR-associated cardiac injuries and emerges as a novel preventive tool for ischemic heart disease. PMID- 27507117 TI - Fluorescent cyanine dyes for the quantification of low amounts of dsDNA. AB - In this research six cyanine fluorophores for the quantification of dsDNA in the pg-ng range, without amplification, are compared under exactly identical conditions: EvaGreen, SYBR Green, PicoGreen, AccuClear, AccuBlue NextGen and YOYO 1. The fluorescence intensity as a function of the amount of dsDNA is measured at the optimal wavelengths for excitation and emission and for each dye the limit of detection and the response linearity at low levels of dsDNA are determined. No linear range was found for SYBR Green and YOYO-1 for pg-ng quantities of dsDNA. EvaGreen, PicoGreen, AccuClear and AccuBlue NextGen show good linearity in the pg ng range. AccuClear exhibits the widest linear range of 3 pg-200 ng, whereas AccuBlue NextGen turned out to have the highest sensitivity of the tested dyes with a limit of detection of 50 pg. PMID- 27507118 TI - Payer Formulary Alerts as a Cause of Patient Harm and the Journey to Change Them. AB - BACKGROUND AND OBJECTIVES: A safety event drew attention to unsafe and inappropriate payer formulary alerts. These alerts display formulary, coverage, and eligibility data from the pharmacy benefits manager in response to an electronic prescription. They are intended to redirect prescribers to medications that are covered by insurance; however, these alerts were found to be inaccurate and contribute to potentially harmful alerts. Our objective was to reduce inappropriate payer formulary alerts by 30% within 1 year and to change the ePrescribing certification requirements to prevent future instances of harm. METHODS: Using process mapping we identified the changes that were required both locally and nationally through our electronic health record (EHR) vendor and ePrescribing transaction broker. We partnered with vendors to show the safety risk and to suggest modifications to the payer formulary alert content and ePrescribing certification criteria. On the basis of the new criteria, we modified and deactivated inappropriate alerts. Rates were followed weekly for 13 months and a control chart was used to track progress. RESULTS: From January 2014 to January 2015, we reviewed 59 325 payer formulary alerts from ambulatory care and 11 630 from the emergency department and inpatient wards. Both local and national modifications resulted in significant and sustained decreases in inappropriate alerts. CONCLUSIONS: Enduring and meaningful change required partnership with multiple stakeholders, including EHR vendors, ePrescribing vendors, and pharmacy benefits managers. Improving drug alerts, reducing alert fatigue, and promoting value-based prescribing in the EHR will likely require similar partnerships. PMID- 27507119 TI - Coarse and fine N1 tuning for print in younger and older Chinese children: Orthography, phonology, or semantics driven? AB - Visual expertise in distinguishing words from objects and word-like stimuli is a fundamental skill that is important for children to become proficient readers. This expertise can be indexed by the N1 component of ERPs at the neural level. However, the nature of N1 tuning for print is controversial in terms of onset of the latency, lateralization and the neural mechanism of the N1. This study aimed to investigate whether two groups of Chinese children could discriminate characters/character-like stimuli from visual controls (i.e., coarse N1 tuning) and distinguish characters from character-like stimuli (i.e., fine N1 tuning). We also explored the cognitive-linguistic correlates of N1 tuning. Seventeen children in the younger group (M=7.7 years) and 13 in the older group (M=9.4 years) were all required to finish a character decision task with character, pseudocharacter, noncharacter, and stroke combination conditions using ERP testing. Both the pseudocharacters and noncharacters were unpronounceable, and the main difference between the two conditions was in orthographic presentation (i.e., radical position). Children were also administered measures of reading fluency, reading accuracy, RAN, phonological skill and vocabulary knowledge. ERP results showed that a significantly larger N1 was observed in the characters, pseudocharacters, and noncharacters as compared to the stroke combinations in both groups. The N1 for characters and pseudocharacters was also significantly larger than that for noncharacters in both groups. Both coarse and fine N1s were larger for younger children than for older children, and the N1 was bilateral in younger children, but left lateralized in older children. Correlational analyses showed that the coarse N1 tuning of real characters versus visual controls was moderately correlated with reading fluency and accuracy but not RAN, phonology, or vocabulary. Taken together, our study suggests that both coarse and fine N1 tuning occurs in both younger and older children, when performing character decisions. Under such task demands, orthography, rather than phonology or semantics, seems to be the driver of coarse N1 tuning for print in Chinese children. PMID- 27507120 TI - Effects of packaging materials on the aroma stability of Thai 'tom yam' seasoning powder as determined by descriptive sensory analysis and gas chromatography-mass spectrometry. AB - BACKGROUND: Changes in the aroma characteristics of Thai 'tom yam' seasoning powder, containing lemongrass, galangal and kaffir lime leaf, as affected by different packaging materials were assessed using quantitative descriptive analysis (QDA) and gas chromatography-mass spectrometry (GC-MS). The descriptive aroma attributes for lemongrass, galangal and kaffir lime leaf powders were developed by the QDA panel. The mixed herb and spice seasoning powder was kept in glass jars closed with different packaging materials (Nylon 6, polyethylene terephthalate (PET) and polylactic acid (PLA)) stored at 38 degrees C (accelerated storage condition), and evaluated by the trained QDA panel during storage for 49 days. RESULTS: The descriptive words for Thai 'tom yam' seasoning powder developed by the trained panelists were lemongrass, vinegary and leafy for lemongrass, galangal and kaffir lime leaf dried powder, respectively. The aroma intensities significantly (P <= 0.05) decreased with increased storage time. However, the intensity scores for aroma attributes were not significantly (P > 0.05) different among the packaging materials studied. The major components in Thai 'tom yam' seasoning powder, quantified by GC-MS, were estragole, bicyclo[3.1.1]heptane, beta-bisabolene, benzoic acid and 2-ethylhexyl salicylate. The concentrations of major aroma compounds significantly (P <= 0.05) decreased with storage time. CONCLUSION: Aroma stability of Thai 'tom yam' powder can be determined by descriptive sensory evaluation and GC-MS analysis. Nylon, PET and PLA exhibited similar aroma barrier properties against key aroma compounds in Thai 'tom yam'. This information can be used for prediction of aroma loss through packaging materials during storage of Thai 'tom yam'. (c) 2016 Society of Chemical Industry. PMID- 27507121 TI - Progress to extinction: increased specialisation causes the demise of animal clades. AB - Animal clades tend to follow a predictable path of waxing and waning during their existence, regardless of their total species richness or geographic coverage. Clades begin small and undifferentiated, then expand to a peak in diversity and range, only to shift into a rarely broken decline towards extinction. While this trajectory is now well documented and broadly recognised, the reasons underlying it remain obscure. In particular, it is unknown why clade extinction is universal and occurs with such surprising regularity. Current explanations for paleontological extinctions call on the growing costs of biological interactions, geological accidents, evolutionary traps, and mass extinctions. While these are effective causes of extinction, they mainly apply to species, not clades. Although mass extinctions is the undeniable cause for the demise of a sizeable number of major taxa, we show here that clades escaping them go extinct because of the widespread tendency of evolution to produce increasingly specialised, sympatric, and geographically restricted species over time. PMID- 27507122 TI - Rhizobia: tractable models for bacterial evolutionary ecology. PMID- 27507123 TI - From discrete molecule, to polymer, to MOF: mapping the coordination chemistry of Cd(II) using (113)Cd solid-state NMR. AB - Studies of three related Cd(II) systems (a discrete [Cd(II)2] unit, a one dimensional [Cd(II)2]n coordination polymer and a Cd(II)-based MOF) all derived from the ligand 2,4,6-tris(2-pyrimidyl)-1,3,5-triazine, reveal an exceptionally rare example of (113)Cd-(113)Cd J coupling in the polymer that is detectable by solid-state NMR ((2)JCd-Cd = ~65 Hz). PMID- 27507124 TI - Predisposing factors for poor prognosis of angiosarcoma of the scalp and face: Systematic review and meta-analysis. AB - BACKGROUND: Angiosarcoma of the scalp and face is an aggressive tumor with a high rate of local recurrence. Although many previous studies have demonstrated risk factors for poor prognosis, debate remains. We identified the predisposing factors for poor prognosis through comprehensive review of selected studies with meta-analysis. METHODS: A systematic literature review and meta-analysis were performed using MEDLINE, EMBASE, and Cochrane databases. Nine variables were extracted from the included studies and evaluated based on a 5-year survival rate. The Newcastle-Ottawa scale was used to assess the quality of the studies. RESULTS: The search strategy identified 89 publications. After screening, 11 articles were selected for review. Age, size, site of tumor, margin status, and surgery associated with poor angiosarcoma prognosis were identified. CONCLUSION: Although further investigation of long-term and prospective studies is needed, we identified 5 variables as predisposing factors for poor prognosis of angiosarcoma through meta-analysis. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 380-386, 2017. PMID- 27507125 TI - [Early diagnosis of anal intraepithelial neoplasia associated with human papillomavirus. What is the best strategy?]. PMID- 27507126 TI - Stressors and expectations of undergraduate nursing students during clinical practice in Singapore. AB - Nursing students have experienced stress because they need to focus on academic performance while being exposed to a clinical environment. The study aimed to identify the contributing factors of stress and the clinical environment expectations of undergraduate nursing students during their clinical practice at a university in Singapore. A cross-sectional descriptive study design using validated surveys was adopted. The Stressors in Nursing Students and the Clinical Learning Environment Inventory questionnaires were used to collect the data in January 2014. A total of 285 nursing students participated in this study. The results showed that third year nursing students had higher stress levels than first year and second year students. Satisfaction in terms of fulfilment among nursing students during clinical practice was found to be the most influential factor in predicting stress. The study suggests that the nursing faculty needs to be more concerned about nursing students' stress level and provide more support to third year students. In addition, students' satisfaction should be considered when developing a clinical curriculum. PMID- 27507127 TI - Comparing the effects of Essix and Hawley retainers on the acoustics of speech. AB - Objective: The aim of this study was to compare the effects of two retainer types (Essix and Hawley) on speech performance. Subjects and methods: The speech articulation of 30 patients was evaluated prospectively. Five patients did not appear during the follow-up periods. The patients were randomly divided into retention groups by treatment allocation cards as Essix and Hawley. The Essix group included 13 participants with a mean age of 15.3+/-2.4 years; the Hawley group included 12 participants with a mean age of 16.3+/-2.56 years. Speech sound assessments were performed on the first day and 1 week, 4 weeks, and 3 months later. On the first day, the assessments were conducted prior to inserting the retainers, immediately after maxillary and mandibular retainer application, individually, and with both retainers applied. The acoustic analyses were obtained using spectral and temporal parameters. Results: Statistical analyses were performed with IBM SPSS for Windows, version 20. A P value less than 0.05 was considered statistically significant. The most apparent changes were found in the [a] vowel in the Hawley group, the [e] vowel in the Essix group, and the [u] vowel in both groups (P < 0.05). While the number of affected consonant-vowel couples in the Essix group was low, alterations were common in the Hawley group. There was a statistically significant difference (P < 0.05) in voice onset time of the [d] sound between the groups. Limitations: The trial had a small sample size and a short follow-up period. Conclusions: The Hawley retainer affected articulatory movements in consonant-vowel combinations more prominently than the Essix retainer did. Voice onset time of the consonant [d] in the Hawley group was shorter than normal, indicating rapid articulatory movement in the alveolar region. PMID- 27507128 TI - A Phase II Study of XELOX and Cetuximab as First-Line Therapy in Patients With KRAS Wild Type Metastatic Colorectal Cancer (FLEET2 Study). AB - BACKGROUND: Despite the comparable clinical benefit of XELOX (capecitabine with oxaliplatin) and FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin), the value of XELOX treatment in combination with cetuximab for metastatic colorectal cancer (mCRC) remains largely unknown. PATIENTS AND METHODS: In this clinical trial we evaluated the efficacy and safety of weekly/biweekly cetuximab administration combined with biweekly XELOX in patients with previously untreated v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type mCRC. The primary end point was response rate (RR) with confirmation, and the secondary end points included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), dose intensity, and the safety of the protocol treatment. RESULTS: Forty patients who fulfilled the inclusion criteria participated in this study. The median treatment cycle number was 8 and the median dose intensities were 218 mg/m2/wk for cetuximab, 34 mg/m2/wk for oxaliplatin, and 821 mg/m2/d for capecitabine. One patient showed complete response and partial response was observed in 19 patients, giving an overall RR of 50% (95% confidence interval [CI], 33.8%-66.2%). Stable disease was obtained in 13 patients, resulting in a DCR of 82.5% (95% CI, 67.2%-92.7%). The PFS was 6.5 months (95% CI, 3.5-9.6 months), and the OS was 24.3 months (95% CI, 14.9-33.7 months). The safety profile revealed the common Grade 3/4 adverse events to be acneiform eruption (12.5%), peripheral neuropathy (7.5%), and elevated alanine transaminase levels (7.5%). Grade 3/4 thrombocytopenia and neutropenia occurred only in 5.0% and 2.5% of the patients, respectively. Grade 1 hand-foot syndrome (HFS) was not uncommon (20%), whereas Grade 2/3 HFS occurred in only 3 patients (7.5%). No deaths were reported within 30 days of the last dose. CONCLUSION: Cetuximab with XELOX showed a confirmed overall RR of 50%, which was within the previously reported range of RR. The safety profile showed an acceptable rate and severity of adverse events. In light of the several advantages of XELOX, including convenience and the reported cost-saving aspects, further study of this combination therapy is warranted. PMID- 27507129 TI - Reporting of Resting-State Functional Magnetic Resonance Imaging Preprocessing Methodologies. AB - There has been a rapid increase in resting-state functional magnetic resonance imaging (rs-fMRI) literature in the past few years. We aim to highlight the variability in the current reporting practices of rs-fMRI acquisition and preprocessing parameters. The PubMed database was searched for the selection of appropriate articles in the rs-fMRI literature and the most recent 100 articles were selected based on our criteria. These articles were evaluated based on a checklist for reporting of certain preprocessing steps. All of the studies reported the temporal resolution for the scan and the software used for the analysis. Less than half of the studies reported physiologic monitoring, despiking, global signal regression, framewise displacement, and volume censoring. A majority of the studies mentioned the scanning duration, eye status, and smoothing kernel. Overall, we demonstrate the wide variability in reporting of preprocessing methods in rs-fMRI studies. Although there might be potential variability in reporting across studies due to individual requirements for a study, we suggest the need for standardizing reporting guidelines to ensure reproducibility. PMID- 27507130 TI - Not merely a question of self-control: The longitudinal effects of overeating behaviors, diet quality and physical activity on dieters' perceived diet success. AB - This longitudinal study was conducted between 2010 (T1) and 2014 (T2) on a random sample from the general Swiss population (N = 2781, 46% male). Results showed that dieters (restrained eaters) who reported lack of success in T2 were overweight in T1, had higher levels of emotional and external eating, overeating, and ambivalence toward eating palatable food in T1, and a significantly increased body mass index (BMI) in the period between T1 and T2. Dieters who reported success in T2 had maintained a normal BMI between T1 and T2, had a higher diet quality in T1 and had maintained regular physical activity for at least one year before T2. The logistic regression revealed that high levels of dispositional self-control provided the most important predictor of being a successful dieter. When controlling for dispositional self-control, high levels of emotional eating, overeating, and ambivalence in T1, together with increases in these levels between T1 and T2, were associated with a decreased likelihood of being a successful dieter in T2. High levels of diet quality in T1 and the maintenance of regular physical activity were associated with an increased likelihood of being a successful dieter in T2. Results suggest that diet success and failure is a long term phenomenon, partly but not fully explained by dispositional self-control. Independent of self-control persistent patterns of overeating due to emotional eating and ambivalent feelings toward eating palatable food, also explain long term diet failure. A high diet quality and maintenance of regular physical activity accounted for dieters' long-term success. This is the first study that examined the long-term psychological and behavioral characteristics of successful and unsuccessful restrained eaters. PMID- 27507131 TI - Subjective mood and energy levels of healthy weight and overweight/obese healthy adults on high-and low-glycemic load experimental diets. AB - Emerging evidence suggests a positive association of diet and obesity with depression. Researchers have examined several diet-mood hypotheses, including investigating the extent to which carbohydrates may impact mood. There is limited research on how glycemic load, a characteristic of carbohydrates, impacts mood in healthy adults. Eighty-two healthy weight and overweight/obese, but otherwise healthy, adults enrolled in a randomized, crossover controlled feeding study testing low-compared to high-glycemic load diets. All participants completed self report mood and energy level questionnaires during each arm of the intervention. Diets were isocaloric and were matched by macronutrient content as a percent of total energy. Mood was assessed with the Profile of Mood States (POMS) subscales; tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue inertia, and confusion-bewilderment, total mood disturbance (TMD), and negative affect (NA) in addition to the Center for Epidemiological Studies - Depression (CES-D) scale at baseline and end of both 28-day feeding periods. Linear mixed models tested the intervention effect on mood, controlling for baseline POMS and CES-D scores, diet type, diet sequence, feeding period, sex, and percent body fat classification. The consumption of the high-glycemic load diet resulted in a 38% higher score for depressive symptoms on the CES-D (P = 0.002) compared to the low glycemic load diet as well as 55% higher score for TMD (P = 0.05), and 26% higher score for fatigue/inertia (P = 0.04). In subgroup analyses, the overweight/obese participants had 40% higher scores on the CES-D scale compared to healthy weight participants (P = 0.05). In conclusion, a high-glycemic load diet was associated with higher depression symptoms, total mood disturbance, and fatigue compared to a low-glycemic load diet especially in overweight/obese, but otherwise healthy, adults. This trial was registered at clinicaltrials.gov: NCT00622661. PMID- 27507132 TI - Examining the relationship between selective attentional bias for food- and body related stimuli and purging behaviour in bulimia nervosa. AB - Previous research exploring cognitive biases in bulimia nervosa suggests that attentional biases occur for both food-related and body-related cues. Individuals with bulimia were compared to non-bulimic controls on an emotional-Stroop task which contained both food-related and body-related cues. Results indicated that bulimics (but not controls) demonstrated a cognitive bias for both food-related and body-related cues. However, a discrepancy between the two cue-types was observed with body-related cognitive biases showing the most robust effects and food-related cognitive biases being the most strongly associated with the severity of the disorder. The results may have implications for clinical practice as bulimics with an increased cognitive bias for food-related cues indicated increased bulimic disorder severity. PMID- 27507133 TI - Direct phase coexistence molecular dynamics study of the phase equilibria of the ternary methane-carbon dioxide-water hydrate system. AB - Molecular dynamics simulation is used to predict the phase equilibrium conditions of a ternary hydrate system. In particular, the direct phase coexistence methodology is implemented for the determination of the three-phase coexistence temperature of the methane-carbon dioxide-water hydrate system at elevated pressures. The TIP4P/ice, TraPPE-UA and OPLS-UA forcefields for water, carbon dioxide and methane respectively are used, in line with our previous studies of the phase equilibria of the corresponding binary hydrate systems. The solubility in the aqueous phase of the guest molecules of the respective binary and ternary systems is examined under hydrate-forming conditions, providing insight into the predictive capability of the methodology as well as the combination of these forcefields to accurately describe the phase behavior of the ternary system. The three-phase coexistence temperature is calculated at 400, 1000 and 2000 bar for two compositions of the methane-carbon dioxide mixture. The predicted values are compared with available calculations with satisfactory agreement. An estimation is also provided for the fraction of the guest molecules in the mixed hydrate phase under the conditions examined. PMID- 27507134 TI - The role of qualitative research in adding value to a randomised controlled trial: lessons from a pilot study of a guided e-learning intervention for managers to improve employee wellbeing and reduce sickness absence. AB - BACKGROUND: Despite the growing popularity of mixed-methods studies and considerable emphasis on the potential value of qualitative research to the trial endeavour, there remains a dearth of published studies reporting on actual contribution. This paper presents a critically reflective account of our experience of the actual value of undertaking qualitative research alongside a pilot cluster randomised controlled trial of a guided e-learning intervention for managers in an NHS Mental Health Trust to improve employee wellbeing and reduce sickness absence. For the qualitative study we undertook 36 in-depth interviews with key informants, managers and employees. We observed and took in-depth field notes of 10 meetings involving managers and employees at the Trust, and the two qualitative researchers acted as participant observers at steering committee and monthly research team meetings. We adopted a narrative methodological orientation alongside a thematic approach to data analysis, eliciting a rich account of the complexities of managing stress at work. RESULTS: We identified two key overarching roles played by the qualitative research: 'problematising' and 'contextualising'. Specifically, the qualitative data revealed and challenged assumptions embedded in the trial about the nature of the learning process, and exposed the slippery and contested nature of abstracted variables, on which a trial depends. The qualitative data challenged the trial's logic model, and provided a rich understanding of the context within which the trial and intervention took place. CONCLUSIONS: While acknowledging the ever-present tension in mixed-methods research between the requirements of quantitative research to represent the social world as abstracted variables, and the goal of qualitative research to explore and document the complexity of social phenomena, we adopted a pragmatic position that enabled us to engage with this tension in a productive and partially integrative way. Our critically reflective account of the praxis of integration illuminated opportunities and challenges for maximising the value of qualitative research to a trial. This paper sets out tangible illustrative lessons for other mixed-methods researchers endeavouring to get the most from qualitative research. TRIAL REGISTRATION: This study is registered as ISRCTN58661009 . Registration was submitted on 22 April 2013 and completed on 17 June 2013. PMID- 27507135 TI - Adherence partners are an acceptable behaviour change strategy to support calcium and iron-folic acid supplementation among pregnant women in Ethiopia and Kenya. AB - Antenatal calcium and iron-folic acid (IFA) supplementation can reduce maternal mortality and morbidity. Yet, even when pregnant women have a stable supply of supplements, forgetting is often a barrier to adherence. We assessed the acceptability of adherence partners to support calcium and IFA supplementation among pregnant women in Kenya and Ethiopia. Adherence partners are a behaviour change strategy to improve adherence, where pregnant women are counselled to select a partner (e.g. spouse, relative) to remind them to take their supplements. We conducted trials of improved practices, a formative research method that follows participants over time as they try a new behaviour. We provided pregnant women in Ethiopia (n = 50) and Kenya (n = 35) with calcium and IFA supplements and counselling, and suggested selecting an adherence partner. For each participant, we conducted semi-structured interviews about acceptability and adherence during four interviews over six weeks. We analysed interview transcripts thematically and tallied numerical data. In Kenya, 28 of 35 women agreed to try an adherence partner; almost all selected their husbands. In Ethiopia, 42 of 50 women agreed to try an adherence partner; half asked their husbands, others asked children or relatives. Most women who did not select adherence partners reported not needing help or not having anyone to ask. Participants reported adherence partners reminded and encouraged them, brought supplements, provided food and helped address side-effects. Almost all women with adherence partners would recommend this strategy to others. Adherence partners are an acceptable, low-cost strategy with the potential to support antenatal micronutrient supplementation adherence. PMID- 27507136 TI - Reply to the comment on "Outcomes of transconjunctival sutureless 27-gauge vitrectomy with silicone oil infusion". PMID- 27507137 TI - Comments on outcomes of transconjunctival sutureless 27-gauge vitrectomy with silicone oil infusion. PMID- 27507138 TI - Impact of food model (micro)structure on the microbial inactivation efficacy of cold atmospheric plasma. AB - The large potential of cold atmospheric plasma (CAP) for food decontamination has recently been recognized. Room-temperature gas plasmas can decontaminate foods without causing undesired changes. This innovative technology is a promising alternative for treating fresh produce. However, more fundamental studies are needed before its application in the food industry. The impact of the food structure on CAP decontamination efficacy of Salmonella Typhimurium and Listeria monocytogenes was studied. Cells were grown planktonically or as surface colonies in/on model systems. Both microorganisms were grown in lab culture media in petri dishes at 20 degrees C until cells reached the stationary phase. Before CAP treatment, cells were deposited in a liquid carrier, on a solid(like) surface or on a filter. A dielectric barrier discharge reactor generated helium-oxygen plasma, which was used to treat samples up to 10min. Although L. monocytogenes is more resistant to CAP treatment, similar trends in inactivation behavior as for S. Typhimurium are observed, with log reductions in the range [1.0-2.9] for S. Typhimurium and [0.2-2.2] for L. monocytogenes. For both microorganisms, cells grown planktonically are easily inactivated, as compared to surface colonies. More stressing growth conditions, due to cell immobilization, result in more resistant cells during CAP treatment. The main difference between the inactivation support systems is the absence or presence of a shoulder phase. For experiments in the liquid carrier, which exhibit a long shoulder, the plasma components need to diffuse and penetrate through the medium. This explains the higher efficacies of CAP treatment on cells deposited on a solid(like) surface or on a filter. This research demonstrates that the food structure influences the cell inactivation behavior and efficacy of CAP, and indicates that food intrinsic factors need to be accounted when designing plasma treatment. PMID- 27507139 TI - Prognostic relevance of caspase 8 -652 6N InsDel and Asp302His polymorphisms for breast cancer. AB - BACKGROUND: The minor allele of two caspase 8 polymorphisms, namely CASP8 -652 6N InsDel (rs3834129) and CASP8 Asp302His (rs1045485), were repeatedly associated with reduced breast cancer susceptibility. Contrarily, the presence of the -652 6N Del or the CASP8 302His variant was reported to be an unfavorable prognostic factor in colorectal cancer or neuroblastoma. However, prognostic relevance of these genetic variants for breast cancer is completely unknown and is therefore adressed by the current study. METHODS: Genotyping was performed by pyrosequencing. Caspase 8 mRNA expression was quantified by comparative RT-qPCR. RESULTS: We observed an allele-dose dependent association between CASP8 -652 6N InsDel and caspase 8 mRNA expression in breast cancer tissue, with homozygous deletion carriers showing lowest relative caspase 8 expression (p = 0.0131). Intriguingly, the presence of the -652 6N Del or the 302His variant was shown to be a negative prognostic factor for breast cancer in terms of an allele-dose dependent influence on overall survival (OS, p = 0.0018, p = 0.0150, respectively). Moreover, both polymorphisms were independent predictors of OS after adjusting for co-variats (p = 0.007, p = 0.037, respectively). Prognostic relevance of both polymorphisms were confirmed to be independent from each other and combined analysis of diplotypes revealed an additive influence upon OS (p = 0.0002). CONCLUSION: This is the first report, showing negative and independent prognostic impact of the CASP8 -652 6N Del and the 302His variant for breast cancer. Our data provide rationale to further validate clinical utility of these polymorphisms for breast cancer and to extend this investigation to a broad scope of other malignancies. PMID- 27507140 TI - Genome-wide variation in recombination rate in Eucalyptus. AB - BACKGROUND: Meiotic recombination is a fundamental evolutionary process. It not only generates diversity, but influences the efficacy of natural selection and genome evolution. There can be significant heterogeneity in recombination rates within and between species, however this variation is not well understood outside of a few model taxa, particularly in forest trees. Eucalypts are forest trees of global economic importance, and dominate many Australian ecosystems. We studied recombination rate in Eucalyptus globulus using genetic linkage maps constructed in 10 unrelated individuals, and markers anchored to the Eucalyptus reference genome. This experimental design provided the replication to study whether recombination rate varied between individuals and chromosomes, and allowed us to study the genomic attributes and population genetic parameters correlated with this variation. RESULTS: Recombination rate varied significantly between individuals (range = 2.71 to 3.51 centimorgans/megabase [cM/Mb]), but was not significantly influenced by sex or cross type (F1 vs. F2). Significant differences in recombination rate between chromosomes were also evident (range = 1.98 to 3.81 cM/Mb), beyond those which were due to variation in chromosome size. Variation in chromosomal recombination rate was significantly correlated with gene density (r = 0.94), GC content (r = 0.90), and the number of tandem duplicated genes (r = -0.72) per chromosome. Notably, chromosome level recombination rate was also negatively correlated with the average genetic diversity across six species from an independent set of samples (r = -0.75). CONCLUSIONS: The correlations with genomic attributes are consistent with findings in other taxa, however, the direction of the correlation between diversity and recombination rate is opposite to that commonly observed. We argue this is likely to reflect the interaction of selection and specific genome architecture of Eucalyptus. Interestingly, the differences amongst chromosomes in recombination rates appear stable across Eucalyptus species. Together with the strong correlations between recombination rate and features of the Eucalyptus reference genome, we maintain these findings provide further evidence for a broad conservation of genome architecture across the globally significant lineages of Eucalyptus. PMID- 27507141 TI - Environmental implications of high metal content in soils of a titanium mining zone in Kenya. AB - Mining activities contribute to an increase of specific metal contaminants in soils. This may adversely affect plant life and consequently impact on animal and human health. The objective of this study was to obtain the background metal concentrations in soils around the titanium mining in Kwale County for monitoring its environmental impacts. Forty samples were obtained with half from topsoils and the other from subsoils. X-ray fluorescence spectrometry was used to determine the metal content of the soil samples. High concentrations of Ti, Mn, Fe, and Zr were observed where Ti concentrations ranged from 0.47 to 2.8 %; Mn 0.02 to 3.1 %; Fe 0.89 to 3.1 %; and Zr 0.05 to 0.85 %. Using ratios of elemental concentrations in topsoil to subsoil method and enrichment factors concept, the metals were observed to be of geogenic origin with no anthropogenic input. The high concentrations of Mn and Fe may increase their concentration levels in the surrounding agricultural lands through deposition, thereby causing contamination on the land and the cultivated food crops. The latter can cause adverse human health effects. In addition, titanium mining will produce tailings containing low level titanium concentrations, which will require proper disposal to avoid increasing titanium concentrations in the soils of the region since it has been observed to be phytotoxic to plants at high concentrations. The results of this study will serve as reference while monitoring the environmental impact by the titanium mining activities. PMID- 27507142 TI - Effects of dispersed oil exposure on biomarker responses and growth in juvenile wolfish Anarhichas denticulatus. AB - This study evaluated the sensitivity of the wolfish Anarhichas denticulatus exposed to crude oil, comparing the effects of mechanically dispersed versus chemically dispersed oil using sub-lethal endpoints. To test the toxicity of this controversial technique, two experiments involving exposure of the organisms for 48 h were conducted. The first experiment assessed the effects of oil exposure on biomarker responses. The second experiment monitored the growth of juveniles over 5 weeks after exposure. Overall, this study demonstrated that polycyclic aromatic hydrocarbon (PAH) biliary metabolites, ethoxyresorufin-O-deethylase (EROD), and acetylcholinesterase (AChE) are appropriate biomarkers to assess exposure of A. denticulatus. Growth rate, both in length and weight, was significantly higher in control compared to oil exposure treatments. The lack of differences between chemically and mechanically dispersed oils in biomarker response and growth suggests that dispersant application is no more toxic than the natural oil dispersion. The results indicate the potential for population-level effects resulting from exposure to oil. PMID- 27507143 TI - No-tillage effects on grain yield, N use efficiency, and nutrient runoff losses in paddy fields. AB - The effect of no-tillage (NT) on rice yield and nitrogen (N) behavior often varies considerably from individual studies. A meta-analysis was performed to assess quantitatively the effect of NT on rice yield and N uptake by rice, N use efficiency (NUE, i.e., fertilizer N recovery efficiency), and nutrient runoff losses. We obtained data from 74 rice-field experiments reported during the last three decades (1983-2013). Results showed the NT system brought a reduction of 3.8 % in the rice yield compared with conventional tillage (CT). Soil pH of 6.5 7.5 was favorable for the improvement of rice yield with the NT system, while a significant negative NT effect on rice yield was observed in sandy soils (p < 0.05). N rate, ranging from 120 to 180 kg N ha-1, for at least 3 years was necessary for NT to enable rice yield comparable with that of CT. Furthermore, the observations indicated NT reduced N uptake and NUE of the rice by 5.4 and 16.9 %, while increased the N and P exports via runoff by 15.4 and 40.1 % compared with CT, respectively. Seedling cast transplantation, N rate within the range 120-180 kg N ha-1, and employing NT for longer than 3 years should be encouraged to compromise between productivity and environmental effects of NT implementation in rice fields. PMID- 27507144 TI - Influences of anthropogenic activities and topography on water quality in the highly regulated Huai River basin, China. AB - Our study analyzed the spatio-temporal trends of four major water quality parameters (i.e., dissolved oxygen (DO), ammonium nitrogen (NH3-N), total phosphorus (TP) and permanganate index (CODMn)) at 17 monitoring stations in one of the most polluted large river basins, Huai River Basin, in China during 2005 to 2014. More concerns were emphasized on the attributions, e.g., anthropogenic actives (land cover, pollution load, water temperature, and regulated flow) and natural factors (topography) to the changes in the water quality. The seasonal Mann-Kendall test indicated that water quality conditions were significantly improved during the study period. The results given by the Moran's I methods demonstrated that NH3-N and CODMn existed a weak and moderate positive spatial autocorrelation. Two cluster centers of significant high concentrations can be detected for DO and TP at the Mengcheng and Huaidian station, respectively, while four cluster centers of significant low concentrations for DO at Wangjiaba and Huaidian station in the 2010s. Multiple linear regression analysis suggested that water temperature, regulated flow, and load of water quality could significantly influence the water quality variations. Additionally, urban land cover was the primary predictor for NH3-N and CODMn at large scale. The predictive ability of regression models for NH3-N and CODMn declined as the scale decreases or the period ranges from the 2000s to the 2010s. Topography variables of elevation and slope, which can be treated as the important explanatory variables, exhibited positive and negative correlations to NH3-N and CODMn, respectively. This research can help us identify the water quality variations from the scale-process interactions and provide a scientific basis for comprehensive water quality management and decision making in the Huai River Basin and also other river basins over the world. PMID- 27507145 TI - Voice Outcomes following a Single Office-Based Steroid Injection for Vocal Fold Scar. AB - OBJECTIVE: Persistent dysphonia from vocal fold scar remains a clinical challenge, with current therapies providing inconsistent outcomes. We evaluated voice outcomes after a single office-based steroid injection. STUDY DESIGN: Case series with chart review. SETTING: Academic medical center. SUBJECTS AND METHODS: This study was based on pre- and postoperative analysis of patient-reported, perceptual, acoustic, aerodynamic, and videostroboscopic parameters. The sample comprised 25 patients undergoing office-based dexamethasone injection into the superficial lamina propria for mild/moderate vocal fold scar. Average follow-up was 13.7 +/- 4.4 weeks; patients completed 3.5 +/- 2.3 sessions of voice therapy between assessments. Complete data sets were not available for each parameter; sample size is noted with results. RESULTS: Voice handicap index (n = 24; P < .001) and glottal function index (n = 22; P < .001) decreased after injection. Total GRBAS score (grade, roughness, breathiness, asthenia, strain) decreased (n = 25; P < .001). Fundamental frequency range increased (n = 24; P = .024). Phonation threshold pressure decreased (n = 14; P = .017). Videostroboscopic parameters of vocal fold edge (P = .004), glottic closure (P = .003), and right mucosal wave (P = .016) improved after injection. CONCLUSIONS: Office-based steroid injection combined with voice therapy for mild/moderate vocal fold scar is associated with improved patient-reported and functional voice measures. These findings provide preliminary support for this approach. Importantly, the procedure is low risk and can be performed in the office, thus offering a simple treatment alternative to patients with a disorder that has traditionally been difficult to manage. Prospective studies evaluating the effects of multiple injections are warranted. PMID- 27507146 TI - Genetic Associations Between Personality Traits and Lifetime Reproductive Success in Humans. AB - Personality has been associated with reproductive success in humans and other animals, suggesting potential evolutionary selection pressures. However, studies to date have only examined these associations on a phenotypic level, which may be inadequate in estimating evolutionary change. Using a large longitudinal twin dataset of contemporary Finns, we compared the phenotypic (breeder's equation) and genetically informed (the Robertson-Price identity) associations between lifetime reproductive success (LRS) and two personality traits-neuroticism and extraversion. Neuroticism was not associated with LRS at the phenotypic nor genetic level, while extraversion was associated with higher LRS in men both phenotypically and genetically. Compared to the univariate phenotypic analysis, the genetic analysis suggested a larger selection response of extraversion, and a selection response of neuroticism due to indirect selection. We estimated that neuroticism decreases by .05 standard deviations and extraversion increases by .11 standard deviations by one generation. Our results highlight the importance of considering genetic associations between personality and fitness and investigating several inter-related personality traits and their covariance with each other to predict responses to selection more accurately. PMID- 27507147 TI - Measuring Metasyntactic Abilities: On a Classification of Metasyntactic Tasks. AB - Researchers working on metasyntactic abilities (i.e., the metalinguistic ability associated with syntax) face the problem of defining and measuring them. Metasyntactic abilities is a multifaceted concept, which encompasses various types of behaviours, from being able to intentionally manipulate syntactic structures to being able to state syntactic rules, and the way in which it is defined and measured varies greatly from one study to another. The present paper proposes a theoretically informed classification of syntax related tasks. The first part presents previous research defining and distinguishing various types of syntactic and metasyntactic abilities and their interrelations. In the second part, commonly used tasks are described and analyzed in terms of the framework presented, with the aim of better pinpointing the type of ability measured by each task. Ultimately, with this analysis of commonly used tasks, we hope to offer criteria for discriminating between the various measures of metasyntactic abilities. PMID- 27507148 TI - Are Vocal Pitch Changes in Response to Facial Expressions of Emotions Potential Cues of Empathy? A Preliminary Report. AB - Previous research has demonstrated that even brief exposures to facial expressions of emotions elicit facial mimicry in receivers in the form of corresponding facial muscle movements. As well, vocal and verbal patterns of speakers converge in conversations, a type of vocal mimicry. There is also evidence of cross-modal mimicry in which emotional vocalizations elicit corresponding facial muscle activity. Further, empathic capacity has been associated with enhanced tendency towards facial mimicry as well as verbal synchrony. We investigated a type of potential cross-modal mimicry in a simulated dyadic situation. Specifically, we examined the influence of facial expressions of happy, sad, and neutral emotions on the vocal pitch of receivers, and its potential association with empathy. Results indicated that whereas both mean pitch and variability of pitch varied somewhat in the predicted directions, empathy was correlated with the difference in the variability of pitch while speaking to the sad and neutral faces. Discussion of results considers the dimensional nature of emotional vocalizations and possible future directions. PMID- 27507149 TI - Ethnic difference in the prevalence of pre-diabetes and diabetes mellitus in regions with Sami and non-Sami populations in Norway - the SAMINOR1 study. AB - OBJECTIVE: The aim of this study was to measure the prevalence of pre-diabetes and diabetes mellitus in rural populations of Norway, as well as to explore potential ethnic disparities with respect to dysglycaemia in Sami and non-Sami populations. DESIGN: Cross-sectional population-based study. METHODS: The SAMINOR1 study was performed in 2003-2004. The study took place in regions with both Sami and non-Sami populations and had a response rate of 60.9%. Information in the SAMINOR1 study was collected using two self-administered questionnaires, clinical examination and laboratory tests. The present analysis included 15,208 men and women aged 36-79 years from the SAMINOR1 study. RESULTS: Age-standardised prevalence of pre-diabetes and diabetes mellitus among Sami men was 3.4 and 5.5%, respectively. Corresponding values for non-Sami men were 3.3 and 4.6%. Age standardised prevalence of pre-diabetes and diabetes mellitus for Sami women was 2.7 and 4.8%, respectively, while corresponding values for non-Sami women were 2.3 and 4.5%. Relative risk ratios for dysglycaemia among Sami participants compared with non-Sami participants were significantly different in different geographical regions, with the southern region having the highest prevalence of pre-diabetes and diabetes mellitus among Sami participants. CONCLUSION: We observed a heterogeneity in the prevalence of pre-diabetes and diabetes mellitus in different geographical regions both within and between different ethnic groups. PMID- 27507150 TI - Musical preferences and learning outcome of medical students in cadaver dissection laboratory: A Nigerian survey. AB - Background music has been reported to enhance learning in the cadaver dissection laboratory. This study was designed to determine the impact of various forms of musical genre and some of their characteristics on students' learning outcome in the dissection laboratory. Some selected musical genre in vocal and non-vocal forms and at different tempi and volume were played as background music (BM) to 253 Medical and Dental students during various sessions of cadaver dissection. Psychological Stress assessment was done using Psychological stress measure-9. Participants love for music, preferred musical genre and other musical characteristics were assessed. The impact of the various musical genre and their characteristics on learning was done via written examination on the region dissected during each musical session. A positive relationship was noted between students' preference for musical genre during leisure with their preference for BM during private study time (P<0.01). Statistically significant differences (P<0.01) were established in the impacts of the selected musical genre on some selected learning factors. Country and Classical music gave the highest positive impact on the various learning factors in CDL followed by R&B. No significant difference was noted between the cognitive values of vocal and non-vocal music. Classical music most effectively reduced the stress induced by dissection in the CDL while Reggae and High life musical genre created a more stressful environment than regular background noise (P<0.01). Moderate volume level and Tempo were most preferred during both cadaver dissection activity and leisure hours. This study shows statistically significant differences in the cognitive values of some of the studied musical genre and their various characteristics. The inability to isolate the particular musical genre with these desired properties could account for the controversies in the reports of the role of music in academic environment. PMID- 27507151 TI - Influence of the wording of evaluation items on outcome-based evaluation results for large-group teaching in anatomy, biochemistry and legal medicine. AB - Student learning outcome is an important dimension of teaching quality in undergraduate medical education. Measuring an increase in knowledge during teaching requires repetitive objective testing which is usually not feasible. As an alternative, student learning outcome can be calculated from student self ratings. Comparative self-assessment (CSA) gain reflects the performance difference before and after teaching, adjusted for initial knowledge. It has been shown to be a valid proxy measure of actual learning outcome derived from objective tests. However, student self-ratings are prone to a number of confounding factors. In the context of outcome-based evaluation, the wording of self-rating items is crucial to the validity of evaluation results. This randomized trial assessed whether including qualifiers in these statements impacts on student ratings and CSA gain. First-year medical students self-rated their initial (then-test) and final (post-test) knowledge for lectures in anatomy, biochemistry and legal medicine, respectively, and 659 questionnaires were retrieved. Six-point scales were used for self-ratings with 1 being the most positive option. Qualifier use did not affect then-test ratings but was associated with slightly less favorable post-test ratings. Consecutively, mean CSA gain was smaller for items containing qualifiers than for items lacking qualifiers (50.6+/-15.0% vs. 56.3+/-14.6%, p=0.079). The effect was more pronounced (Cohen's d=0.82) for items related to anatomy. In order to increase fairness of outcome-based evaluation and increase the comparability of CSA gain data across subjects, medical educators should agree on a consistent approach (qualifiers for all items or no qualifiers at all) when drafting self-rating statements for outcome-based evaluation. PMID- 27507152 TI - Variations in brachial plexus with respect to concomitant accompanying aberrant arm arteries. AB - INTRODUCTION: Variations in the brachial plexus are the rule rather than the exception. This fact is of special interest for the anesthetist when planning axillary block of brachial plexus. MATERIAL AND METHODS: 167 cadaver arms were evaluated for variations in brachial plexus, with focus on the cords of the plexus, the loop of the median nerve, and the course of the median, musculocutaneous, ulnar, axillary and radial nerves. In addition, concomitant arterial variations were recorded. RESULTS: In 167 arms, variations were detected in 60 cases (36%). With 46 arms (28%) most variations concern the median nerve, followed by 13 cases (8%) which involved the musculocutaneous nerve. Ulnar, axillary and radial nerve variations were rare, amounting to 1.2% for each nerve. In median nerve conditions with a shifted loop of median nerve (12%), a hidden position of the loop or a hidden course of the beginning median nerve (8%) and a doubled loop of median nerve (17%) were observed. In musculocutaneous nerve conditions with a non-perforated coracobrachialis (1.8%), a doubled origin of the nerve (1.2%) and a giving back of branches to the median nerve (1.8%) were noted. Variations in ulnar, axillary and radial nerves concerned lower than normal diameters. CONCLUSIONS: It must be stressed that cases which showed a hidden position or a doubled expression of the loop of the median nerve, a hidden course of its beginning and variable interconnections between musculocutaneous and median nerves are of special interest for anesthetists and surgeons. Hence, it is important to note that variations of arm arteries can be associated with brachial plexus variations. For example, a common trunk of axillary artery followed by a hidden loop and course of the median nerve may result in incomplete axillary block of brachial plexus. PMID- 27507153 TI - A silver carp skin derived collagen in bone defect treatment-A histological study in a rat model. AB - In recent years, there has been increasing interest in elaboration of novel therapeutic strategies, such as the use of the marine collagen products. Biochemical properties of marine collagen are different from those of mammalian collagen; e.g., its extremely high solubility in diluted acid. Extracts produced using low temperature techniques contain a number of small proteins and collagen with preserved triple helix structure. The aim of the study was to evaluate the influence of a new marine product Collgel(r) obtained with a unique method from a silver carp (Hypophthalmichthys molitrix) on bone defect healing in a rat study. For this purpose bone defects with diameters of 5mm were created in 15 animals and subsequently filled with Collgel combined with another commercially available material. Samples were processed for histological evaluation and a Micro-CT study was performed. Histological analysis showed new bone formation in all groups after 8 weeks. The bone formation was significantly increased in treated bone lesions compared to untreated bone tissue. However no significant difference was noted between the healing of the defects filled with xenogenic bovine derived bone substitute alone and xenogenic, bovine derived bone substitute combined with a marine delivered collagen. Finding from the histological examination was confirmed in a Micro-CT study. The study has shown that the new marine product can be used instead of conventional porcine or bovine collagen membranes in guided bone regeneration. PMID- 27507154 TI - Protective Effects of Arginine on Saccharomyces cerevisiae Against Ethanol Stress. AB - Yeast cells are challenged by various environmental stresses in the process of industrial fermentation. As the currently main organism for bio-ethanol production, Saccharomyces cerevisiae suffers from ethanol stress. Some amino acids have been reported to be related to yeast tolerance to stresses. Here the relationship between arginine and yeast response to ethanol stress was investigated. Marked inhibitions of ethanol on cell growth, expression of genes involved in arginine biosynthesis and intracellular accumulation of arginine were observed. Furthermore, extracellular addition of arginine can abate the ethanol damage largely. To further confirm the protective effects of arginine on yeast cells, yeast strains with different levels of arginine content were constructed by overexpression of ARG4 involved in arginine biosynthesis or CAR1 encoding arginase. Intracellular arginine was increased by 18.9% or 13.1% respectively by overexpression of ARG4 or disruption of CAR1, which enhanced yeast tolerance to ethanol stress. Moreover, a 41.1% decrease of intracellular arginine was observed in CAR1 overexpressing strain, which made yeast cells keenly sensitive to ethanol. Further investigations indicated that arginine protected yeast cells from ethanol damage by maintaining the integrity of cell wall and cytoplasma membrane, stabilizing the morphology and function of organellae due to low ROS generation. PMID- 27507155 TI - IL-4 downregulates expression of the target receptor CD30 in neoplastic canine mast cells. AB - CD30 is a novel therapeutic target in human mast cell (MC) neoplasms. In this 'comparative oncology' study, we examined CD30 expression and regulation in neoplastic canine MC using a panel of immunomodulatory cytokines [interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-13 and stem cell factor (SCF)] and the canine mastocytoma cell lines NI-1 and C2. Of all cytokines tested IL-4 was found to downregulate expression of CD30 in NI-1 and C2 cells. We also found that the CD30 targeting antibody-conjugate brentuximab vedotin induces growth inhibition and apoptosis in both MC lines. Next, we asked whether IL-4-induced downregulation of CD30 interferes with brentuximab vedotin-effects. Indeed, pre-incubation of NI-1 cells with IL-4 decreased responsiveness towards brentuximab vedotin. To overcome IL-4-mediated resistance, we applied drug combinations and found that brentuximab vedotin synergizes with the Kit-targeting drugs masitinib and PKC412 in inhibiting growth of NI-1 and C2 cells. In summary, CD30 is a new marker and IL-4 regulated target in neoplastic canine MC. PMID- 27507156 TI - Hypophosphatasia and the risk of atypical femur fractures: a case-control study. AB - BACKGROUND: Case reports have linked adult hypophosphatasia as a possible cause of atypical femur fractures (AFF) associated with bisphosphonate use. Adult hypophosphatasia is an asymptomatic genetic condition which results in low alkaline phosphatase and elevated pyridoxal phosphate. We conducted a case control study to assess the role of hypophosphatasia and atypical femur fracture. METHODS: We recruited 13 control patients who took long term bisphosphonates without complication and 10 patients who sustained atypical femur fractures (mean bisphosphonate use, 9 years both cohorts). Patients underwent clinical exam and measurement of alkaline phosphatase and pyridoxal phosphate (PLP) levels. In addition, DNA was extracted and the ALPL gene was sequenced in both cohorts. RESULTS: Low alkaline phosphatase levels (<55 U/L) were seen in 5/10 AFF patients and 5/13 control patients. Two control patients demonstrated low alkaline phosphatase levels and elevated PLP. The alkaline phosphatase (ALPL) gene exons and intron splice sites were sequenced in the atypical femur fracture and control cohorts and no coding mutations were identified in any subjects. Atypical femur fracture patients demonstrated more varus hip alignment (p < 0.048) with no significant difference in mechanical axis. CONCLUSIONS: We found no evidence of hypophosphatasia as a risk factor for atypical femur fractures. Laboratory findings of mildly low alkaline phosphatase activity were equally common in atypical and control cohorts and may be due to long term bisphosphonate use. TRIAL REGISTRATION: Clinicaltrials.gov number NCT01360099 . Prospectively registered May 20, 2011. First patient enrolled June 14, 2011. PMID- 27507157 TI - Using systems thinking to identify workforce enablers for a whole systems approach to urgent and emergency care delivery: a multiple case study. AB - BACKGROUND: Overcrowding in emergency departments is a global issue, which places pressure on the shrinking workforce and threatens the future of high quality, safe and effective care. Healthcare reforms aimed at tackling this crisis have focused primarily on structural changes, which alone do not deliver anticipated improvements in quality and performance. The purpose of this study was to identify workforce enablers for achieving whole systems urgent and emergency care delivery. METHODS: A multiple case study design framed around systems thinking was conducted in South East England across one Trust consisting of five hospitals, one community healthcare trust and one ambulance trust. Data sources included 14 clinical settings where upstream or downstream pinch points are likely to occur including discharge planning and rapid response teams; ten regional stakeholder events (n = 102); a qualitative survey (n = 48); and a review of literature and analysis of policy documents including care pathways and protocols. RESULTS: The key workforce enablers for whole systems urgent and emergency care delivery identified were: clinical systems leadership, a single integrated career and competence framework and skilled facilitation of work based learning. CONCLUSIONS: In this study, participants agreed that whole systems urgent and emergency care allows for the design and implementation of care delivery models that meet complexity of population healthcare needs, reduce duplication and waste and improve healthcare outcomes and patients' experiences. For this to be achieved emphasis needs to be placed on holistic changes in structures, processes and patterns of the urgent and emergency care system. Often overlooked, patterns that drive the thinking and behavior in the workplace directly impact on staff recruitment and retention and the overall effectiveness of the organization. These also need to be attended to for transformational change to be achieved and sustained. Research to refine and validate a single integrated career and competence framework and to develop standards for an integrated approach to workplace facilitation to grow the capacity of facilitators that can use the workplace as a resource for learning is needed. PMID- 27507158 TI - Detection of Diatoms by a Combination of Membrane Filtration and Transparentness. AB - Diagnosis of drowning remains a difficult issue in current forensic sciences. A large number of diatoms were lost by removing the supernatant after centrifugation in the conventional forensic diatom test. We developed a novel membrane filtration method to enrich diatoms from samples. A new solution using different ratios of acetic acid and eugenol is prepared to make the membrane transparent. These processes allow the diatom-containing membrane to be visualized and identified easily by light microscopy. The tissues contaminated by water rich in diatoms were detected by the new method for the recovery of diatoms. Eleven drowning cases were analyzed by both the new method and the conventional method to compare the sensitivity of both methods. The recovery of the novel diatom test method was 54.2 +/- 23.1%. The positive rate of the novel method has been proven to be superior to the conventional method in the diagnosis of drowning. PMID- 27507159 TI - Impact of degradable nanowires on long-term brain tissue responses. AB - BACKGROUND: A promising approach to improve the performance of neural implants consists of adding nanomaterials, such as nanowires, to the surface of the implant. Nanostructured interfaces could improve the integration and communication stability, partly through the reduction of the cell-to-electrode distance. However, the safety issues of implanted nanowires in the brain need to be evaluated and understood before nanowires can be used on the surface of implants for long periods of time. To this end we here investigate whether implanted degradable nanowires offer any advantage over non-degradable nanowires in a long-term in vivo study (1 year) with respect to brain tissue responses. RESULTS: The tissue response after injection of degradable silicon oxide (SiOx) coated gallium phosphide nanowires and biostable hafnium oxide-coated GaP nanowires into the rat striatum was compared. One year after nanowire injection, no significant difference in microglial or astrocytic response, as measured by staining for ED1 and glial fibrillary acidic protein, respectively, or in neuronal density, as measured by staining for NeuN, was found between degradable and biostable nanowires. Of the cells investigated, only microglia cells had engulfed the nanowires. The SiOx-coated nanowire residues were primarily seen in aggregated hypertrophic ED1-positive cells, possibly microglial cells that have fused to create multinucleated giant cells. Occasionally, degradable nanowires with an apparently intact shape were found inside single, small ED1-positive cells. The biostable nanowires were found intact in microglia cells of both phenotypes described. CONCLUSION: The present study shows that the degradable nanowires remain at least partly in the brain over long time periods, i.e. 1 year; however, no obvious bio-safety issues for this degradable nanomaterial could be detected. PMID- 27507160 TI - [Mediastinal lymphomas]. AB - Lymphomas infiltrating the mediastinum are a challenge for the treating physician as well as for the pathological diagnostics. The clinical scenario is often an emergency situation, while the pathologist is usually confronted only with small biopsy samples. Classical Hodgkin's lymphoma is by far the most frequently occurring lymphoma in the mediastinum and predominantly the nodular sclerosis subtype. In small and very sclerotic specimens it can be difficult to morphologically detect Hodgkin and Reed-Sternberg cells and to identify the characteristic phenotype by immunohistochemistry. Primary mediastinal large B cell lymphomas should be distinguished from classical Hodgkin's lymphomas as the treatment is different. This is characterized by the detection of sheets of blast cells, which immunohistochemically show a strong B-cell phenotype (positivity for CD20 and CD79a), while CD30 can also often be expressed. The intimate biological relationship between classical Hodgkin's lymphomas and mediastinal large B-cell lymphomas is illustrated by the existence of B-cell lymphomas with intermediate features (so-called mediastinal grey zone lymphomas). It is important to recognize and diagnose these lymphomas as they are associated with a slightly inferior prognosis. Extranodal thymic marginal zone lymphomas of the mucosa associated lymphoid tissue (MALT) type are a rare form of lymphoma encountered in the mediastinum, which can be associated with autoimmune diseases. T lymphoblastic lymphomas and leukemia, which occur predominantly in children and young adults, represent a rapidly growing precursor cell neoplasia and must be distinguished from thymomas in the differential diagnostics as well as from normal and hyperplastic thymus glands. PMID- 27507162 TI - [Not Available]. PMID- 27507161 TI - [Neuroendocrine neoplasms of the mediastinum]. AB - Primary neuroendocrine tumors (NET) in the mediastinum are very rare and among them thymic NETs are the most common. They represent 5 % of all thymic and mediastinal tumors. The WHO classification from 2015 subdivides thymic NETs into three groups; low grade (typical carcinoid), intermediate grade (atypical carcinoid) and high grade (large cell neuroendocrine carcinoma and small cell carcinoma). Through this change of mediastinal/thymic NET classification into three groups of malignancy, the nomenclature was adapted to that of the lungs, while the histological criteria for each entity remained the same. Thymic NETs typically occur in middle-aged adults and predominantly in males. Approximately 30 % are asymptomatic and the rest present with symptoms caused by local tumor growth, distant metastases and/or endocrine manifestations. Carcinoids can also occur as a part of multiple endocrine neoplasia type 1 (MEN1) and at the time of diagnosis commonly present with regional lymph node or distant metastases, which most often affect the lungs and bones. For the correct diagnosis tumor cell morphology, mitotic count and/or necrosis are crucial. Patients with typical carcinoids have the best prognosis, whereas the prognosis is slightly worse for atypical carcinoids but very poor for large cell neuroendocrine carcinomas. Small cell carcinomas have the worst prognosis and the shortest median survival time of approximately 14 months. PMID- 27507163 TI - Malaria control along China-Myanmar Border during 2007-2013: an integrated impact evaluation. AB - BACKGROUND: Implementing effective interventions remain a lot of difficulties along all border regions. The emergence of artemisinin resistance of Plasmodium falciparum strains in the Greater Mekong Subregion is a matter of great concern. China has effectively controlled cross-border transmission of malaria and artemisinin resistance of P. falciparum along the China-Myanmar border. METHODS: A combined quantitative and qualitative study was used to collect data, and then an integrated impact evaluation was conducted to malaria control along the China Myanmar border during 2007-2013. RESULTS: The parasite prevalence rate (PPR) in the five special regions of Myanmar was decreased from 13.6 % in March 2008 to 1.5 % in November 2013. Compared with the baseline (PPR in March 2008), the risk ratio was only 0.11 [95 % confidence interval (CI), 0.09-0. 14) in November 2013, which is equal to an 89 % reduction in the malaria burden. Annual parasite incidence (API) across 19 Chinese border counties was reduced from 19.6 per 10 000 person-years in 2006 to 0.9 per 10 000 person-years in 2013. Compared with the baseline (API in 2006), the API rate ratio was only 0.05(95 % CI, 0.04-0.05) in 2013, which equates to a reduction of the malaria burden by 95.0 %. Meanwhile, the health service system was strengthened and health inequity of marginalized populations reduced along the international border. CONCLUSION: The effective collaboration between China, Myanmar and the international non-governmental organization promptly carried out the core interventions through simplified processes. The integrated approaches dramatically decreased malaria burden of Chinese-Myanmar border. PMID- 27507164 TI - What's the hospitalisation's impact on background treatments of patients over 65 years. AB - As our population aging increases, it requires a particular attention from the health system. Indeed, elderly are often frail, with several diseases and presenting high risk of adverse drug accident. Prescribing appropriately to the elderly has become an important matter. Hospitalization and consultation with the general practitioner are key moments for drug prescription. However, their real impact on background treatments of this population has been barely evaluated. A retrospective descriptive study was conducted with 300 patients over 65 years old, hospitalized at the Laveran military hospital in Marseille. Treatment modifications, consecutive to hospitalization and to the first consultation with the general practitioner, were identified and analyzed. We found an average prescription of 5.93 drugs in prehospital period and 66% of the patients with polypharmacy. Drugs for cardiovascular system were the most prescribed and the most modified. Hospitalization generated a rate of modification by prescription of 28.5% and the consultation with the general practitioner following this hospitalization led to further change in 48% of cases. Beside the important prevalence of patients with polypharmacy, this study shows that hospitalization entails a significant change in background treatments in that population at risk. Therefore, it is important to have a consensus in the re-evaluation of these treatments, in order to prevent the iatrogenic risk. PMID- 27507165 TI - Wiring up pre-characterized single-photon emitters by laser lithography. AB - Future quantum optical chips will likely be hybrid in nature and include many single-photon emitters, waveguides, filters, as well as single-photon detectors. Here, we introduce a scalable optical localization-selection-lithography procedure for wiring up a large number of single-photon emitters via polymeric photonic wire bonds in three dimensions. First, we localize and characterize nitrogen vacancies in nanodiamonds inside a solid photoresist exhibiting low background fluorescence. Next, without intermediate steps and using the same optical instrument, we perform aligned three-dimensional laser lithography. As a proof of concept, we design, fabricate, and characterize three-dimensional functional waveguide elements on an optical chip. Each element consists of one single-photon emitter centered in a crossed-arc waveguide configuration, allowing for integrated optical excitation and efficient background suppression at the same time. PMID- 27507166 TI - Modifying a generic postoperative recovery profile instrument to an instrument specifically targeting coronary artery bypass grafting. AB - Patients may suffer from a wide range of postoperative symptoms after coronary artery bypass grafting. In-depth knowledge of the recovery process is a prerequisite for nursing interventions. However, we found no specific instrument covering the entire range and duration of postoperative symptoms related to this procedure. We therefore modified and extended the 19 items, generic Postoperative Recovery Profile questionnaire for the specific evaluation of the recovery after coronary artery bypass grafting. We here report on the development process of the new questionnaire. Procedure-specific symptoms were identified by a literature review and by experts. The content validity was assessed by healthcare professionals (n = 15), inpatients (n = 12) and outpatients (n = 4). A test run was done with inpatients (n = 10), which was followed by a test-retest reliability evaluation with inpatients (n = 24). We identified 15 new symptoms in the literature review and six in the content validity assessment. Only three of the 35 items had an acceptable content validity index, but all 35 items in the test run were reported by at least two patients. The questionnaire took 4-9 minutes to complete and was considered easy to use. The final instrument used in the reliability test included 22 new items, and 25 of the 35 items were satisfactory stable. To conclude, we developed a 35 items, procedure-specific questionnaire that was easy to use and may aid systematic assessment of the recovery after coronary artery bypass grafting. PMID- 27507167 TI - Reaction Times to Consecutive Automation Failures: A Function of Working Memory and Sustained Attention. AB - OBJECTIVE: This study explored whether working memory and sustained attention influence cognitive lock-up, which is a delay in the response to consecutive automation failures. BACKGROUND: Previous research has demonstrated that the information that automation provides about failures and the time pressure that is associated with a task influence cognitive lock-up. Previous research has also demonstrated considerable variability in cognitive lock-up between participants. This is why individual differences might influence cognitive lock-up. The present study tested whether working memory-including flexibility in executive functioning-and sustained attention might be crucial in this regard. METHOD: Eighty-five participants were asked to monitor automated aircraft functions. The experimental manipulation consisted of whether or not an initial automation failure was followed by a consecutive failure. Reaction times to the failures were recorded. Participants' working-memory and sustained-attention abilities were assessed with standardized tests. RESULTS: As expected, participants' reactions to consecutive failures were slower than their reactions to initial failures. In addition, working-memory and sustained-attention abilities enhanced the speed with which participants reacted to failures, more so with regard to consecutive than to initial failures. CONCLUSION: The findings highlight that operators with better working memory and sustained attention have small advantages when initial failures occur, but their advantages increase across consecutive failures. APPLICATION: The results stress the need to consider personnel selection strategies to mitigate cognitive lock-up in general and training procedures to enhance the performance of low ability operators. PMID- 27507168 TI - Influence of proximal box elevation technique on marginal integrity of adhesively luted Cerec inlays. AB - OBJECTIVES: This in vitro study evaluated the marginal quality of Lava Ultimate inlays in deep proximal cavities with and without proximal box elevation (PBE) before and after thermomechanical loading (TML). MATERIALS AND METHODS: Mesio occluso-distal cavities with proximal boxes beneath the cementoenamel junction (CEJ) were prepared in 24 human molars. Then, one of the proximal boxes was elevated with Filtek Supreme above the CEJ. The specimens were divided into three groups (n = 8). The inlays of group A were adhesively luted to the cavities with Scotchbond Universal and Rely X Ultimate, the inlays of group B with Monobond Plus, Syntac, and Variolink II, and the inlays of group C with Clearfil Ceramic Primer and Panavia SA Cement. Epoxy resin replicas were taken before and after thermomechanical loading (1,200,000 cycles, 55 degrees C/5 degrees C, max. load 50 N). Marginal integrity at the different interfaces tooth/PBE, tooth/dentine, inlay/PBE, inlay/dentine was evaluated with scanning electron microscopy (*200). The percentage of continuous margin (% of total proximal margin length) was compared between the groups before and after TML. STATISTICS: Mann-Whitney U test (p = 0.05). RESULTS: No significant differences (p > 0.05) before and after TML were found between the three groups for bonding the inlay to dentine or to PBE composite. CONCLUSIONS: The marginal integrities of bonding inlays directly to dentine are not different from bonding inlays to a proximal box, which has been elevated by a composite filling material. For deep proximal cavities, the PBE technique could be an alternative technique to conventional methods. Clinical research is needed to confirm. PMID- 27507169 TI - An integrative and applicable phylogenetic footprinting framework for cis regulatory motifs identification in prokaryotic genomes. AB - BACKGROUND: Phylogenetic footprinting is an important computational technique for identifying cis-regulatory motifs in orthologous regulatory regions from multiple genomes, as motifs tend to evolve slower than their surrounding non-functional sequences. Its application, however, has several difficulties for optimizing the selection of orthologous data and reducing the false positives in motif prediction. RESULTS: Here we present an integrative phylogenetic footprinting framework for accurate motif predictions in prokaryotic genomes (MP(3)). The framework includes a new orthologous data preparation procedure, an additional promoter scoring and pruning method and an integration of six existing motif finding algorithms as basic motif search engines. Specifically, we collected orthologous genes from available prokaryotic genomes and built the orthologous regulatory regions based on sequence similarity of promoter regions. This procedure made full use of the large-scale genomic data and taxonomy information and filtered out the promoters with limited contribution to produce a high quality orthologous promoter set. The promoter scoring and pruning is implemented through motif voting by a set of complementary predicting tools that mine as many motif candidates as possible and simultaneously eliminate the effect of random noise. We have applied the framework to Escherichia coli k12 genome and evaluated the prediction performance through comparison with seven existing programs. This evaluation was systematically carried out at the nucleotide and binding site level, and the results showed that MP(3) consistently outperformed other popular motif finding tools. We have integrated MP(3) into our motif identification and analysis server DMINDA, allowing users to efficiently identify and analyze motifs in 2,072 completely sequenced prokaryotic genomes. CONCLUSION: The performance evaluation indicated that MP(3) is effective for predicting regulatory motifs in prokaryotic genomes. Its application may enhance progress in elucidating transcription regulation mechanism, thus provide benefit to the genomic research community and prokaryotic genome researchers in particular. PMID- 27507171 TI - Tunneling-injection in vertical quasi-2D heterojunctions enabled efficient and adjustable optoelectronic conversion. AB - The advent of 2D materials integration has enabled novel heterojunctions where carrier transport proceeds thrsough different ultrathin layers. We here demonstrate the potential of such heterojunctions on a graphene/dielectric/semiconductor vertical stack that combines several enabling features for optoelectronic devices. Efficient and stable light emission was achieved through carrier tunneling from the graphene injector into prominent states of a luminescent material. Graphene's unique properties enable fine control of the band alignment in the heterojunction. This advantage was used to produce vertical tunneling-injection light-emitting transistors (VtiLET) where gating allows adjustment of the light emission intensity independent of applied bias. This device was shown to simultaneously act as a light detecting transistor with a linear and gate tunable sensitivity. The presented development of an electronically controllable multifunctional light emitter, light detector and transistor open up a new route for future optoelectronics. PMID- 27507170 TI - Factors related to outcome of bloodstream infections due to Candida parapsilosis complex. AB - BACKGROUND: Although Candida albicans is the most common cause of fungal blood stream infections (BSIs), infections due to Candida species other than C. albicans are rising. Candida parapsilosis complex has emerged as an important fungal pathogen and became one of the main causes of fungemia in specific geographical areas. We analyzed the factors related to outcome of candidemia due to C. parapsilosis in a single tertiary referral hospital over a five-year period. METHODS: A retrospective observational study of all cases of candidemia was carried out at a 980-bedded University Hospital in Italy. Data regarding demographic characteristics and clinical risk factors were collected from the patient's medical records. Antifungal susceptibility testing was performed and MIC results were interpreted according to CLSI species-specific clinical breakpoints. RESULTS: Of 270 patients diagnosed with Candida BSIs during the study period, 63 (23 %) were infected with isolates of C. parapsilosis complex which represented the second most frequently isolated yeast after C. albicans. The overall incidence rate was 0.4 episodes/1000 hospital admissions. All the strains were in vitro susceptible to all antifungal agents. The overall crude mortality at 30 days was 27 % (17/63), which was significantly lower than that reported for C. albicans BSIs (42 % [61/146], p = 0.042). Being hospitalized in ICU resulted independently associated with a significant higher risk of mortality (HR 4.625 [CI95% 1.015-21.080], p = 0.048). Conversely, early CVC removal was confirmed to be significantly associated with a lower risk of mortality (HR 0.299 [CI95% 0.102-0.874], p = 0.027). Finally, the type of primary antifungal therapy did not influence the outcome of infection. CONCLUSIONS: Candidemia due to C. parapsilosis complex, the second most commonly causative agent of yeast BSIs in our center, is characterized by a non-negligible mortality at 30 days. An early CVC removal is associated with a significant reduced mortality. PMID- 27507173 TI - A Systematic Review of the Respiratory Effects of Inhalational Marijuana. AB - This systematic review focuses on respiratory effects of inhalational marijuana. The systematic review of the literature was conducted using a comparative method between 2 researchers. Abstracts were reviewed for inclusion of respiratory effects related to inhalational marijuana. Relevant abstracts were collected, and full text articles were retrieved for review. Articles were removed if they did not contain burning marijuana; were animal studies; or were editorials, systematic reviews, commentaries, non-English language, or non-respiratory related articles. Forty-eight articles were collected and categorized by respiratory effects. In particular, lung cancer, bullous emphysema/COPD, and other respiratory symptoms were the primary categories. Articles were noted by study population country, sample size, age distribution, and findings that were pertinent to respiratory health. The research indicates that there is a risk of lung cancer from inhalational marijuana as well as an association between inhalational marijuana and spontaneous pneumothorax, bullous emphysema, or COPD. A variety of symptoms have been reported by inhalational marijuana smokers, including wheezing, shortness of breath, altered pulmonary function tests, cough, phlegm production, bronchodilation, and other symptoms. It is important to stay current with research findings to educate patients on this smoking behavior. PMID- 27507172 TI - The severity of hereditary porphyria is modulated by the porphyrin exporter and Lan antigen ABCB6. AB - Hereditary porphyrias are caused by mutations in genes that encode haem biosynthetic enzymes with resultant buildup of cytotoxic metabolic porphyrin intermediates. A long-standing open question is why the same causal porphyria mutations exhibit widely variable penetrance and expressivity in different individuals. Here we show that severely affected porphyria patients harbour variant alleles in the ABCB6 gene, also known as Lan, which encodes an ATP binding cassette (ABC) transporter. Plasma membrane ABCB6 exports a variety of disease-related porphyrins. Functional studies show that most of these ABCB6 variants are expressed poorly and/or have impaired function. Accordingly, homozygous disruption of the Abcb6 gene in mice exacerbates porphyria phenotypes in the Fech(m1Pas) mouse model, as evidenced by increased porphyrin accumulation, and marked liver injury. Collectively, these studies support ABCB6 role as a genetic modifier of porphyria and suggest that porphyrin-inducing drugs may produce excessive toxicities in individuals with the rare Lan(-) blood type. PMID- 27507174 TI - Effectiveness of Intraoral Chlorhexidine Protocols in the Prevention of Ventilator-Associated Pneumonia: Meta-Analysis and Systematic Review. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is common in critical patients and related with increased morbidity and mortality. We conducted a systematic review and meta-analysis, with intention-to-treat analysis, of randomized controlled clinical trials that assessed the effectiveness of different intraoral chlorhexidine protocols for the prevention of VAP. METHODS: Search strategies were developed for the MEDLINE, EMBASE, and LILACS databases. MeSH terms were combined with Boolean operators and used to search the databases. Eligible studies were randomized controlled trials of mechanically ventilated subjects receiving oral care with chlorhexidine or standard oral care protocols consisting of or associated with the use of a placebo or no chemicals. Pooled estimates of the relative risk and corresponding 95% CIs were calculated with random effects models, and heterogeneity was assessed with the Cochran Q statistic and I(2). RESULTS: The 13 included studies provided data on 1,640 subjects that were randomly allocated to chlorhexidine (n = 834) or control (n = 806) treatments. A preliminary analysis revealed that oral application of chlorhexidine fails to promote a significant reduction in VAP incidence (relative risk 0.80, 95% CI 0.59 1.07, I(2) = 45%). However, subgroup analyses showed that chlorhexidine prevents VAP development when used at 2% concentration (relative risk 0.53, 95% CI 0.31 0.91, I(2) = 0%) or 4 times/d (relative risk 0.56, 95% CI 0.38-0.81, I(2) = 0%). CONCLUSIONS: We found that oral care with chlorhexidine is effective in reducing VAP incidence in the adult population if administered at 2% concentration or 4 times/d. PMID- 27507176 TI - Respiratory Care Received by Individuals With Duchenne Muscular Dystrophy From 2000 to 2011. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) causes progressive respiratory muscle weakness and decline in function, which can go undetected without monitoring. DMD respiratory care guidelines recommend scheduled respiratory assessments and use of respiratory assist devices. To determine the extent of adherence to these guidelines, we evaluated respiratory assessments and interventions among males with DMD in the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet) from 2000 to 2011. METHODS: MD STARnet is a population-based surveillance system that identifies all individuals born during or after 1982 residing in Arizona, Colorado, Georgia, Hawaii, Iowa, and western New York with Duchenne or Becker muscular dystrophy. We analyzed MD STARnet respiratory care data for non-ambulatory adolescent males (12-17 y old) and men (>=18 y old) with DMD, assessing whether: (1) pulmonary function was measured twice yearly; (2) awake and asleep hypoventilation testing was performed at least yearly; (3) home mechanical insufflation-exsufflation, noninvasive ventilation, and tracheostomy/ventilators were prescribed; and (4) pulmonologists provided evaluations. RESULTS: During 2000-2010, no more than 50% of both adolescents and men had their pulmonary function monitored twice yearly in any of the years; 67% or fewer were assessed for awake and sleep hypoventilation yearly. Although the use of mechanical insufflation-exsufflation and noninvasive ventilation is probably increasing, prior use of these devices did not prevent all tracheostomies, and at least 18 of 29 tracheostomies were performed due to acute respiratory illnesses. Fewer than 32% of adolescents and men had pulmonologist evaluations in 2010-2011. CONCLUSIONS: Since the 2004 publication of American Thoracic Society guidelines, there have been few changes in pulmonary clinical practice. Frequencies of respiratory assessments and assist device use among males with DMD were lower than recommended in clinical guidelines. Collaboration of respiratory therapists and pulmonologists with clinicians caring for individuals with DMD should be encouraged to ensure access to the full spectrum of in-patient and out-patient pulmonary interventions. PMID- 27507177 TI - New Predictor of Atherosclerosis in Subjects With COPD: Atherogenic Indices. AB - BACKGROUND: We aimed to investigate the predictor role of the plasma levels of lipid parameters and atherogenic indices on development of atherosclerosis in subjects with COPD. METHODS: We retrospectively analyzed 104 male subjects diagnosed with stable COPD in hospital records. We excluded subjects with exacerbation, with known cardiovascular diseases and other chronic diseases, receiving anti-hyperlipidemic treatment, without sufficient past medical history, and lacking needed laboratory data. Additionally, 40 age-matched male healthy controls were also enrolled. C-reactive protein, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels of COPD and the control group were analyzed. Atherogenic indices (atherogenic index of plasma, cardiogenic risk ratio, and atherogenic coefficient) were calculated. RESULTS: C-reactive protein, triglyceride, atherogenic index of plasma, cardiogenic risk ratio, and atherogenic coefficient values were significantly higher in subjects with stable COPD than in control subjects (P < .05 for all). High-density lipoprotein cholesterol level was significantly lower in subjects with COPD than in the control group (P < .001). C reactive protein, lipid profiles, and atherogenic indices were similar in lower risk (stage A and B) and higher-risk (stage C and D) subjects with COPD. Cardiogenic risk ratio and atherogenic coefficient were negatively correlated with FEV1 in all stable subjects with COPD and in higher-risk subjects with COPD (r = -0.27, P = .01 and r = -0.35, P = .01, respectively). CONCLUSIONS: We concluded that atherogenic indices (atherogenic index of plasma, cardiogenic risk ratio, atherogenic coefficient) could be considered as a useful predictor for atherosclerosis and cardiovascular diseases in stable COPD patients. Nevertheless, further prospective investigations on this issue are warranted. PMID- 27507178 TI - Use of multivitamin, acidifier and Azolla in the diet of broiler chickens. AB - OBJECTIVE: The experiments were carried out to measure the effect of multivitamin, acidifier and Azolla on growth performance, profitability and lipid profiles of blood of broiler chickens to produce safe and cost effective broilers. METHODS: In experiment 1, 240 day-old Cobb-500 broiler chicks were fed diets; D1 (control), D2 (D1 with 1 mL multivitamin/liter water), D3 (D1 with 1 mL acidifier/liter water), D4 (D1 with 1 mL multivitamin and 2 mL acidifier/liter water) having 3 replications in each, and 20 chicks/replication. In experiment 2, 150 day-old Cobb-500 broiler chicks were fed diets; T1 (control), T2 (5% Azolla in the diet), T3 (7% Azolla in the diet) and T4 (T1 with 1 mL multivitamin and 1 mL acidifier/liter water) having 3 replications in each, and 20 chicks/replication in control, and 10 chicks/replication in the remaining dietary treatment groups for 35 days. RESULTS: In experiment 1, the highest live weight was observed in D4 (p<0.05), however, feed intake was statistically similar between diets (p>0.05). The lowest feed conversion ratio (FCR) (p<0.001) and mortality (p<0.05) were observed in D2 followed by D4, D1, and D3, respectively. There were no significant differences between diets for feed cost and net profit (p>0.05). However, evidently but not significantly, the highest net profit was obtained in D2 followed by D4, D1, and D3, respectively. In experiment 2, the highest live weight (p<0.05) and feed intake (p<0.001) were observed in T4. Mortality (p<0.01), FCR (p<0.01), feed cost (p<0.05) and net profit (p<0.05) were significantly different among diets. Considering net profit, T2 was the best performing dietary group followed by T3, T1, and T4, respectively. The lowest lipid profiles were observed in D3 followed by D1, D4, and D2, respectively (p<0.05). In experiment 2, the lowest total cholesterol, TG, and the highest amount of high density lipoprotein were observed in T2, followed by T3, T1, and T4, respectively (p<0.05). Evidently but not significantly, low density lipoprotein was the highest in T2 followed by T3, T4, and T1, respectively (p>0.05). CONCLUSION: In conclusion, Azolla and acidifier reduced lipid profiles of broiler chickens. Considering net profit and lipid profiles, 5% Azolla may be the suitable dietary group for producing safe and profitable broilers. However, more studies are needed to confirm this study prior to suggesting using Azolla in the poultry industry. PMID- 27507179 TI - In vitro stability evaluation of coated lipase. AB - OBJECTIVE: The study was conducted to evaluate the stability of commercial coated lipase (CT-LIP) in vitro. METHODS: The capsules were tested under different conditions with a range of temperature, pH, dry heat treatment and steaming treatment, simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) in this work, respectively. Free lipase (uncoated lipase, UC-LIP) was the control group. Lipase relative activities measured in various treatments were used as a reference frame to characterize the stability. RESULTS: The lipase activities were decreased with increasing temperatures (p<0.05), and there was a markedly decline (p<0.01) in lipase comparative activities of UC-LIP at 80 degrees C compared with CT-LIP group. Higher relative activities of lipase were observed in CT-LIP group compared with the free one under acidic ambient (pH 3 to 7) and an alkaline medium (pH 8 to 12). Residual lipase activities of CT-LIP group were increased (p<0.05) by 5.67% and 35.60% in dry heat and hydrothermal treatments, respectively. The lipase relative activity profile of CT-LIP was raised at first and dropped subsequently (p<0.05) compared with constantly reduced tendency of UC LIP exposed to both SGF and SIF. CONCLUSION: The results suggest that the CT-LIP possesses relatively higher stability in comparison with the UC-LIP in vitro. The CT-LIP could retain the potential property to provide sustained release of lipase and thus improved its bioavailability in the gastrointestinal tract. PMID- 27507180 TI - The impact of diet on the composition and relative abundance of rumen microbes in goat. AB - OBJECTIVE: This experiment was conducted to explore the impact of diet on the ruminal microbial community in goats. METHODS: Twelve goats were divided into two groups and fed complete feed (CF) or all forage (AF) diet. The total microbial DNAs in the rumen liquid were extracted. The V4 region of microbial 16S rRNA genes was amplified and sequenced using high-throughput. Information of sequences was mainly analyzed by QIIME 1.8.0. RESULTS: The results showed that Bacteroidetes and Firmicutes were the most predominant microbial phyla in the rumen of all goats. At genus level, the abundance of fiber-digesting bacteria such as Ruminococcus and Lachnospiracea incertae sedis was significantly higher in AF than that in CF, while the levels of fat-degrading bacterium Anaerovibrio and protein-degrading bacterium Pseudomonas were opposite. The core shared genera, Prevotella and Butyrivibrio were widespread in the rumen of goats and no significant difference was observed in relative abundance between groups. CONCLUSION: We concluded that the richness of fiber-, protein-, and fat-digesting bacteria was affected by diet and tended to increase with the rise of their corresponding substrate contents in the ration; some bacteria shared by all goats maintained stable despite the difference in the ration, and they might be essential in maintaining the normal function of rumen. PMID- 27507181 TI - Validation of selection accuracy for the total number of piglets born in Landrace pigs using genomic selection. AB - OBJECTIVE: This study was to determine the relationship between estimated breeding value and phenotype information after farrowing when juvenile selection was made in candidate pigs without phenotype information. METHODS: After collecting phenotypic and genomic information for the total number of piglets born by Landrace pigs, selection accuracy between genomic breeding value estimates using genomic information and breeding value estimates of best linear unbiased prediction (BLUP) using conventional pedigree information were compared. RESULTS: Genetic standard deviation (sigmaa ) for the total number of piglets born was 0.91. Since the total number of piglets born for candidate pigs was unknown, the accuracy of the breeding value estimated from pedigree information was 0.080. When genomic information was used, the accuracy of the breeding value was 0.216. Assuming that the replacement rate of sows per year is 100% and generation interval is 1 year, genetic gain per year is 0.346 head when genomic information is used. It is 0.128 when BLUP is used. CONCLUSION: Genetic gain estimated from single step best linear unbiased prediction (ssBLUP) method is by 2.7 times higher than that the one estimated from BLUP method, i.e., 270% more improvement in efficiency. PMID- 27507182 TI - Relationships between Single Nucleotide Polymorphism Markers and Meat Quality Traits of Duroc Breeding Stocks in Korea. AB - This study was conducted to determine the relationships of five intragenic single nucleotide polymorphism (SNP) markers (protein kinase adenosine monophosphate activated gamma3 subunit [PRKAG3], fatty acid synthase [FASN], calpastatin [CAST], high mobility group AT-hook 1 [HMGA1], and melanocortin-4 receptor [MC4R]) and meat quality traits of Duroc breeding stocks in Korea. A total of 200 purebred Duroc gilts from 8 sires and 40 dams at 4 pig breeding farms from 2010 to 2011 reaching market weight (110 kg) were slaughtered and their carcasses were chilled overnight. Longissimus dorsi muscles were removed from the carcass after 24 h of slaughter and used to determine pork properties including carcass weight, backfat thickness, moisture, intramuscular fat, pH24h, shear force, redness, texture, and fatty acid composition. The PRKAG3, FASN, CAST, and MC4R gene SNPs were significantly associated with the meat quality traits (p<0.003). The meats of PRKAG3 (A 0.024/G 0.976) AA genotype had higher pH, redness and texture than those from PRKAG3 GG genotype. Meats of FASN (C 0.301/A 0.699) AA genotype had higher backfat thickness, texture, stearic acid, oleic acid and polyunsaturated fatty acid than FASN CC genotype. While the carcasses of CAST (A 0.373/G 0.627) AA genotype had thicker backfat, and lower shear force, palmitoleic acid and oleic acid content, they had higher stearic acid content than those from the CAST GG genotype. The MC4R (G 0.208/A 0.792) AA genotype were involved in increasing backfat thickness, carcass weight, moisture and saturated fatty acid content, and decreasing unsaturated fatty acid content in Duroc meat. These results indicated that the five SNP markers tested can be a help to select Duroc breed to improve carcass and meat quality properties in crossbred pigs. PMID- 27507183 TI - Effects of particle size of processed barley grain, enzyme addition and microwave treatment on in vitro disappearance and gas production for feedlot cattle. AB - OBJECTIVE: The effects of particle size of processed barley grain, enzyme addition and microwave treatment on in vitro dry matter (DM) disappearance (DMD), gas production and fermentation pH were investigated for feedlot cattle. METHODS: Rumen fluid from four fistulated feedlot cattle fed a diet of 860 dry-rolled barley grain, 90 maize silage and 50 supplement g/kg DM was used as inoculum in 3 batch culture in vitro studies. In Experiment 1, dry-rolled barley and barley ground through a 1-, 2-, or 4-mm screen were used to obtain four substrates differing in particle size. In Experiment 2, cellulase enzyme (ENZ) from Acremonium cellulolyticus Y-94 was added to dry-rolled and ground barley (2-mm) at 0, 0.1, 0.5, 1, and 2 mg/g, while Experiment 3 examined the interactions between microwaving (0, 30, and 60 s microwaving) and ENZ addition (0, 1, and 2 mg/g) using dry-rolled barley and 2-mm ground barley. RESULTS: In Experiment 1, decreasing particle size increased DMD and gas production, and decreased fermentation pH (p<0.01). The DMD (g/kg DM) of the dry-rolled barley after 24 h incubation was considerably lower (p<0.05) than that of the ground barley (119.1 dry-rolled barley versus 284.8 for 4-mm, 341.7 for 2-mm; and 358.6 for 1-mm). In Experiment 2, addition of ENZ to dry-rolled barley increased DMD (p<0.01) and tended to increase (p = 0.09) gas production and decreased (p<0.01) fermentation pH, but these variables were not affected by ENZ addition to ground barley. In Experiment 3, there were no interactions between microwaving and ENZ addition after microwaving for any of the variables. Microwaving had minimal effects (except decreased fermentation pH), but consistent with Experiment 2, ENZ addition increased (p<0.01) DMD and gas production, and decreased (p<0.05) fermentation pH of dry-rolled barley, but not ground barley. CONCLUSION: We conclude that cellulase enzymes can be used to increase the rumen disappearance of barley grain when it is coarsely processed as in the case of dry-rolled barley. However, microwaving of barley grain offered no further improvements in ruminal fermentation of barley grain. PMID- 27507184 TI - Sex change and effective population size: implications for population genetic studies in marine fish. AB - Large variance in reproductive success is the primary factor that reduces effective population size (Ne) in natural populations. In sequentially hermaphroditic (sex-changing) fish, the sex ratio is typically skewed and biased towards the 'first' sex, while reproductive success increases considerably after sex change. Therefore, sex-changing fish populations are theoretically expected to have lower Ne than gonochorists (separate sexes), assuming all other parameters are essentially equal. In this study, we estimate Ne from genetic data collected from two ecologically similar species living along the eastern coast of South Africa: one gonochoristic, the 'santer' sea bream Cheimerius nufar, and one protogynous (female-first) sex changer, the 'slinger' sea bream Chrysoblephus puniceus. For both species, no evidence of genetic structuring, nor significant variation in genetic diversity, was found in the study area. Estimates of contemporary Ne were significantly lower in the protogynous species, but the same pattern was not apparent over historical timescales. Overall, our results show that sequential hermaphroditism may affect Ne differently over varying time frames, and that demographic signatures inferred from genetic markers with different inheritance modes also need to be interpreted cautiously, in relation to sex-changing life histories. PMID- 27507185 TI - Reducing beef consumption might not reduce emissions: response to Phalan et al. (2016). PMID- 27507186 TI - Early warning score: An indicator of adverse outcomes in postoperative patients on a gynecologic oncology service. AB - OBJECTIVE: In 2014, our hospital implemented an early warning score (EWS) to identify inpatients at risk for clinical deterioration. EWS>=8 is associated with >=10% mortality in medical admissions. Since postoperative hemodynamic changes may alter EWS, we evaluated EWS in post-laparotomy patients. METHODS: Gynecologic oncology patients admitted for laparotomy from 9/1/2014 to 7/31/2015 were categorized by highest EWS during admission: <5, 5-7, and >=8. The primary outcome was a composite including death, ICU transfer, rapid response team activation, pulmonary embolus, sepsis, and reoperation. For patients with the composite, highest EWS prior to that outcome was evaluated. Secondary outcomes were length of stay (LOS), readmission, and transfusion. Groups were compared using chi-square test for trend, analysis of variance, and Kruskal-Wallis tests. A receiver operating characteristic (ROC) curve estimated the association between EWS and the composite outcome. RESULTS: 411 patients were included: 217 (52.8%) with EWS<5, 151 (36.7%) with EWS 5-7, and 43 (10.5%) with EWS>=8. The composite occurred in 32.6% of patients with EWS>=8, 7.3% with EWS 5-7, and 0% with EWS<5 (p<0.01). EWS>=8 was associated with longer LOS, higher readmission rate, and more transfusions. For the composite, the area under the ROC curve was 0.89 (95% CI 0.84-0.94). EWS>=5 had 100% sensitivity and 56.2% specificity for the primary outcome; EWS>=8 had 56.0% sensitivity and 92.5% specificity for the primary outcome. CONCLUSIONS: EWS>=5 after laparotomy is associated with adverse outcomes. Future studies should evaluate the ability of EWS to predict and prevent these outcomes. PMID- 27507187 TI - Teaching multiply controlled intraverbals to children and adolescents with autism spectrum disorders. AB - Reciprocal conversations, instructional activities, and other social interactions are replete with multiply controlled intraverbals, examples of which have been conceptualized in terms of conditional discriminations. Although the acquisition of conditional discriminations has been examined extensively in the behavior analytic literature, little research has evaluated procedures to establish multiply controlled intraverbals. Thus, the purpose of this investigation was to evaluate the effects of procedures based on conditional discrimination training on the acquisition of multiply controlled intraverbals with 7 participants who had been diagnosed with autism spectrum disorders. We evaluated the effects of prompt delay with error correction, a differential observing response (DOR), and a DOR plus blocked trials on the acquisition of intraverbals using a multiple baseline design. Accuracy of intraverbal performance increased for at least 1 set of stimuli for all participants under prompt delay with error correction conditions; however, 4 participants required additional teaching (i.e., DOR, modified DOR, modified prompt delay with error correction). Based on these findings, when prompt delay with error correction is not sufficient to establish multiply controlled intraverbals, prompted DORs may be an effective alternative. PMID- 27507188 TI - From Clothing to Laundry Water: Investigating the Fate of Phthalates, Brominated Flame Retardants, and Organophosphate Esters. AB - The accumulation of phthalate esters, brominated flame retardants (BFRs) and organophosphate esters (OPEs) by clothing from indoor air and transfer via laundering to outdoors were investigated. Over 30 days cotton and polyester fabrics accumulated 3475 and 1950 ng/dm(2) ?5phthalates, 65 and 78 ng/dm(2) ?10BFRs, and 1200 and 310 ng/dm(2) ?8OPEs, respectively. Planar surface area concentrations of OPEs and low molecular weight phthalates were significantly greater in cotton than polyester and similar for BFRs and high molecular weight phthalates. This difference was significantly and inversely correlated with KOW, suggesting greater sorption of polar compounds to polar cotton. Chemical release from cotton and polyester to laundry water was >80% of aliphatic OPEs (log KOW < 4), < 50% of OPEs with an aromatic structure, 50-100% of low molecular weight phthalates (log KOW 4-6), and < detection-35% of higher molecular weight phthalates (log KOW > 8) and BFRs (log KOW > 6). These results support the hypothesis that clothing acts an efficient conveyer of soluble semivolatile organic compounds (SVOCs) from indoors to outdoors through accumulation from air and then release during laundering. Clothes drying could as well contribute to the release of chemicals emitted by electric dryers. The results also have implications for dermal exposure. PMID- 27507189 TI - Biobrane versus topical agents in the treatment of adult scald burns. AB - BACKGROUND: Limited data is available for treatment of scald lesions in adults. The use of the biosynthetic matrix Biobrane(r) has been suggested as treatment option with more benefits over topical dressings. Application of Biobrane(r) in scalds in our center led to a perceived increase of infection, secondary deepening, surgery and length of stay. We therefore assessed the effect of different treatment options in adult scalds in our center. METHODS: We performed a retrospective cohort study of adult patients that have been admitted with scalds in our center between 2011 and 2014. We assessed two groups, group 1 with Biobrane(r) as initial treatment and group 2 with topical treatment using polyhexanid hydrogel and fatty gauze. Primary outcome variables were rate of secondary deepening, surgery, infection (defined as positive microbiological swabs and antibiotic treatment) and length of stay. Total body surface area (TBSA) as well as diabetes mellitus (DM), hypertension, smoking and alcohol consumption as potential confounders were included. RESULTS: A total of 52 patients were included in this study. 36 patients received treatment with Biobrane(r) and 16 with ointment and fatty gauze. No significant differences were found for age and TBSA whereas gender ratio was different (25/11 male/female in group 1 vs 4/12 in group 2, p=0.003). Rate of secondary deepening, surgery, infection as well as days of hospital stay (DOHS) were comparable. Logistic and multilinear regression showed TBSA to be a predictive factor for infection (p=0.041), and TBSA and age for length of stay (age p=0.036; TBSA p=0.042) in group 1. CONCLUSION: The use of Biobrane(r) in adult scald lesions is safe and non-inferior to topical treatment options. In elder patients and larger TBSA Biobrane(r) may increase the risk of infection or a prolonged stay in hospital. LEVEL OF EVIDENCE: Level 3 - retrospective cohort study. PMID- 27507190 TI - Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma. AB - Uveal melanoma (UM) is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified. Novel therapeutic approaches are therefore urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to the use of PKC inhibitors as a rational strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents. Employing a large panel of UM patient derived xenograft models (PDXs), several PKC inhibitor-based combinations were tested in vivo using the PKC inhibitor AEB071. The most promising approaches were further investigated in vitro using our unique panel of UM cell lines. When combined with AEB071, the two agents CGM097 (p53-MDM2 inhibitor) and RAD001 (mTORC1 inhibitor) demonstrated greater activity than single agents, with tumor regression observed in several UM PDXs. Follow-up studies in UM cell lines on these two drug associations confirmed their combination activity and ability to induce cell death. While no effective treatment currently exists for metastatic uveal melanoma, we have discovered using our unique panel of preclinical models that combinations between PKC/mTOR inhibitors and PKC/p53-MDM2 inhibitors are two novel and very effective therapeutic approaches for this disease. Together, our study reveals that combining PKC and p53-MDM2 or mTORC1 inhibitors may provide significant clinical benefit for UM patients. PMID- 27507191 TI - Anxiety symptoms bias memory assessment in older adults. AB - BACKGROUND: Older adults with anxiety and/or depression experience additional memory dysfunction beyond that of the normal aging process. However, few studies have examined test bias in memory assessments due to anxiety and/or depressive symptoms. The current study investigated the influence of self-reported symptoms of anxiety and depression on the measurement equivalence of memory tests in older adults. METHOD: This is a secondary analysis of the Advanced Cognitive Training for Independent and Vital Elderly dataset, a randomized controlled trial of community-dwelling older adults. Baseline data were included in this study (n = 2802). Multiple indicators multiple causes modeling was employed to assess for measurement equivalence, differential item functioning (DIF), in memory tests. RESULTS: The DIF was present for anxiety symptoms but not for depressive symptoms, such that higher anxiety placed older adults at a disadvantage on measures of memory performance. Analysis of DIF impact showed that compared with participants scoring in the bottom quartile of anxious symptoms, participants in the upper quartile exhibited memory performance scores that were 0.26 standard deviation lower. CONCLUSION: Anxious but not depressive symptoms introduce test bias into the measurement of memory in older adults. This indicates that memory models for research and clinical purposes should account for the direct relationship between anxiety symptoms and memory tests in addition to the true relationship between anxiety symptoms and memory construct. These findings support routine assessments of anxiety symptoms among older adults in settings in which cognitive testing is being conducted. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27507192 TI - Expanded Circulating Tumor Cells from a Patient with ALK-Positive Lung Cancer Present with EML4-ALK Rearrangement Along with Resistance Mutation and Enable Drug Sensitivity Testing: A Case Study. AB - The emergence of liquid biopsy using circulating tumor cells (CTCs) as a resource to identify genomic alterations in cancer presents new opportunities for diagnosis, therapy, and surveillance. We identified EML4-ALK gene rearrangement in expanded CTCs from a patient with ALK-positive lung adenocarcinoma. At the time of radiographic progression, CTCs obtained from the patient revealed a drug resistance mutation (i.e., L1196M on the ALK gene). CTCs were expanded ex vivo and drug sensitivity testing was performed using two ALK inhibitors, crizotinib and ceritinib. The half maximal inhibitory concentration of ceritinib was 1664 nM compared with crizotinib (2268 nM), showing that ceritinib was a more potent ALK inhibitor. We show that it is feasible to detect serial genetic alterations in expanded CTCs and perform in vitro drug screening. These findings support the clinical utility of CTCs not only for diagnosis, but also a potential tool for drug sensitivity testing in distinct subsets of lung cancer and for personalized precision medicine. PMID- 27507193 TI - A method for nondestructive mechanical testing of tissues and implants. AB - Numerous tests have been used to elucidate mechanical properties of tissues and implants including tensile, compressive, shear, hydrostatic compression, and three-point bending in one or more axial directions. The development of a nondestructive test that could be applied to tissues and materials in vivo would promote the analysis of tissue pathology as well as the design of implant materials. The purpose of this article is to present the results of preliminary studies demonstrating nondestructive in vitro testing of a tissue model, decellularized human dermis, and a model implant, silicone rubber, using a combination of optical coherence tomography (OCT), and vibrational analysis. The results presented suggest that nondestructive vibrational testing of tissues and materials can be used to determine the modulus of polymeric materials and the results are similar to those found using tensile stress-strain measurements. The advantage of this method is that the modulus can be obtained from vibrational methods without having to approximate the tangent to the stress-strain curve, which is difficult for nonlinear materials that have a rapidly changing slope. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 15-22, 2017. PMID- 27507194 TI - Atomic force microscopy for the investigation of molecular and cellular behavior. AB - The present review details the methods used for the measurement of cells and their exudates using atomic force microscopy (AFM) and outlines the general conclusions drawn by the mechanical characterization of biological materials through this method. AFM is a material characterization technique that can be operated in liquid conditions, allowing its use for the investigation of the mechanical properties of biological materials in their native environments. AFM has been used for the mechanical investigation of proteins, nucleic acids, biofilms, secretions, membrane bilayers, tissues and bacterial or eukaryotic cells; however, comparison between studies is difficult due to variances between tip sizes and morphologies, sample fixation and immobilization strategies, conditions of measurement and the mechanical parameters used for the quantification of biomaterial response. Although standard protocols for the AFM investigation of biological materials are limited and minor differences in measurement conditions may create large discrepancies, the method is nonetheless highly effective for comparatively evaluating the mechanical integrity of biomaterials and can be used for the real-time acquisition of elasticity data following the introduction of a chemical or mechanical stimulus. While it is currently of limited diagnostic value, the technique is also useful for basic research in cancer biology and the characterization of disease progression and wound healing processes. PMID- 27507195 TI - Blood-borne miRNA profile-based diagnostic classifier for lung adenocarcinoma. AB - Accumulated evidence indicates that various types of miRNA are aberrantly expressed in lung cancer and secreted into the bloodstream. For this study, we constructed a serum diagnostic classifier based on detailed bioinformatics analysis of miRNA profiles from a training cohort of 143 lung adenocarcinoma patients and 49 healthy subjects, resulting in a 20 miRNA-based classifier. Validation performed with an independent cohort of samples from lung adenocarcinoma patients (n = 110), healthy subjects (n = 52), and benign pulmonary disease patients (n = 47) showed a sensitivity of 89.1% and specificity of 94.9%, with an area under the curve value of 0.958. Notably, 90.8% of Stage I lung adenocarcinoma cases were correctly diagnosed. Interestingly, this classifier also detected squamous and large cell lung carcinoma cases at relatively high rates (70.4% and 70.0%, respectively), which appears to be consistent with organ site-dependent miRNA expression in cancer tissues. In contrast, we observed significantly lower rates (0-35%) using samples from 96 cases of cancer in other major organs, with breast cancer the lowest. These findings warrant a future study to realize its clinical application as a part of diagnostic procedures for lung cancers, for which early detection and surgical removal is presently the only hope for eventual cure. PMID- 27507196 TI - Creation of artificial skyrmions and antiskyrmions by anisotropy engineering. AB - Topologically non-trivial spin textures form a fundamental paradigm in solid state physics and present unique opportunities to explore exciting phenomena such as the topological Hall effect. One such texture is a skyrmion, in which the spins can be mapped to point in all directions wrapping around a sphere. Understanding the formation of these spin textures, and their energetic stability, is crucial in order to control their behavior. In this work, we report on controlling the perpendicular anisotropy of continuous Co/Pt multilayer films with ion irradiation to form unique spin configurations of artificial skyrmions and antiskyrmions that are stabilized by their demagnetization energy. We elucidate their behavior using aberration-corrected Lorentz transmission electron microscopy. We also discuss the energetic stability of these structures studied through in-situ magnetizing experiments performed at room temperature, combined with micromagnetic simulations that successfully reproduce the spin textures and behavior. This research offers new opportunities towards creation of artificial skyrmion or antiskyrmion lattices that can be used to investigate not only fundamental properties of their interaction with electron currents but also technological applications such as artificial magnonic crystals. PMID- 27507197 TI - Wound healing effects of Bambusa vulgaris leaves. PMID- 27507199 TI - Phytochemistry and pharmacology of Allii Macrostemonis Bulbus, a traditional Chinese medicine. AB - Allii Macrostemonis Bulbus (Xiebai in Chinese), as a famous traditional Chinese medicine, has great medicinal and dietary values since ancient times. In China, the dry bulbs of Allium macrostemon and Allium chinense are both used as its original plants. Pharmacological studies have revealed that both of them could increase plasminogen activator activity and prolong the effect of coagulation to achieve antiplatelet aggregation which validates their traditional uses for the treatment of thoracic obstruction and cardialgia in clinics. Besides, several other significant activities, including lipid-lowering, anti-atherosclerosis, antitumor, antispasmodic, antibacterial, antioxidant, and insecticidal activities, have already been reported. The volatile oils, nitrogenous compounds, and steroidal saponins are the major beneficial compounds. Among them, steroidal saponins are considered as the characteristic constituents. In this review, the current information concerning the phytochemistry and pharmacology of Allii Macrostemonis Bulbus is summarized comprehensively. In addition, several research future perspectives are presented, especially the mechanism of bioactive components and fraction from the bulbs of Allium macrostemon and Allium chinense. PMID- 27507200 TI - Siwu decoction attenuates oxonate-induced hyperuricemia and kidney inflammation in mice. AB - The aim of the study was to investigate the effects of Siwu decoction on hyperuricemia, kidney inflammation, and dysfunction in hyperuricemic mice. Siwu decoction at 363.8, 727.5, and 1 455 mg.kg(-1) was orally administered to potassium oxonate-induced hyperuricemic mice for 7 days. Serum urate, creatinine, and blood urea nitrogen levels and hepatic xanthine oxidase (XOD) activity were measured. The protein levels of hepatic XOD and renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporters 1 (OAT1), ATP binding cassette subfamily G member 2 (ABCG2), organic cation transporter 1 (OCT1), OCT2, organic cation/carnitine transporter 1 (OCTN1), OCNT2, Nod-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck like protein (ASC), Caspase-1, and interleukin-1beta (IL-1beta) were determined by Western blotting. Renal histopathology change was obtained following hematoxylin-eosin staining. Our results indicated that Siwu decoction significantly reduced serum urate, creatinine and blood urea nitrogen levels and increased fractional excretion of uric acid in hyperuricemic mice. It effectively reduced hepatic XOD activity and protein levels in this animal model. Furthermore, Siwu decoction down-regulated URAT1 and GLUT9 protein levels, and up regulated the protein levels of OAT1, ABCG2, OCT1, OCT2, OCTN1, and OCTN2 in the kidney of the hyperuricemic mice. Additionally, Siwu decoction remarkably reduced renal protein levels of NLRP3, ASC, Caspase-1, and IL-1beta in the hyperuricemic mice. These results suggested that Siwu decoction exhibited anti-hyperuricemic and anti-inflammatory effects by inhibiting hepatic XOD activity, regulating renal organic ion transporter expression, and suppressing renal NLRP3 inflammasome activation, providing the evidence for its use in the treatment of hyperuricemia and associated kidney inflammation. PMID- 27507201 TI - A combination of four effective components derived from Sheng-mai san attenuates hydrogen peroxide-induced injury in PC12 cells through inhibiting Akt and MAPK signaling pathways. AB - The present study was designed to investigate whether a combination of four effective components derived from Sheng-mai san (SMXZF; ginsenoside Rb1: ginsenoside Rg1: DT-13: Schizandrol A as 6 : 9 : 4 : 5) could attenuate hydrogen peroxide (H2O2)-induced injury in PC12 cells, focusing on the Akt and MAPK pathways . The PC12 cells were exposed to H2O2 (400 MUmol.L(-1)) for 1 h in the presence or absence of SMXZF pre-treatment for 24 h. Cell viability was measured by MTT assay. The efflux of lactate dehydrogenase (LDH), the intracellular content of malondialdehyde (MDA), the activities of superoxide dismutase (SOD), and caspase-3 were also determined. Cell apoptosis was measured by Hoechst 33342 staining and Annexin V-FITC/PI staining method. The expression of Bcl-2, Bax, cleaved caspase-3, Akt, and MAPKs were detected by Western blotting analyses. SMXZF pretreatment significantly increased the cell viability and SOD activity and improved the cell morphological changes, while reduced the levels of LDH and MDA at the concentrations of 0.1, 1 and 10 MUg.mL(-1). SMXZF also inhibited H2O2 induced apoptosis in PC12 cells. Moreover, SMXZF reduced the activity of caspase 3, up-regulated the protein ratio of Bcl-2 and Bax and inhibited the expression of cleaved caspase-3, p-Akt, p-p38, p-JNK and p-ERK1/2 in H2O2-induced PC12 cells. Co-incubation of Akt inhibitor or p38 inhibitor partly attenuated the protection of SMXZF against H2O2-injured PC12 cells. In conclusion, our findings suggested that SMXZF attenuated H2O2-induced injury in PC12 cells by inhibiting Akt and MAPKs signaling pathways, which might shed insights on its neuroprotective mechanism. PMID- 27507202 TI - Berberine enhances antidiabetic effects and attenuates untoward effects of canagliflozin in streptozotocin-induced diabetic mice. AB - The present study aimed at determining whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus. Streptozotocin-induced diabetic mice were introduced, and the combined effects of berberine and canagliflozin on glucose metabolism and kidney functions were investigated. Our results showed that berberine combined with canagliflozin (BC) increased reduction of fasting and postprandial blood glucose, diet, and water intake compared with berberine or canagliflozin alone. Interestingly, BC showed greater decrease in blood urea nitrogen and creatinine levels and lower total urine glucose excretion than canagliflozin alone. In addition, BC showed increased phosphorylated 5' AMP-activated protein kinase (pAMPK) expression and decreased tumor necrosis factor alpha (TNFalpha) levels in kidneys, compared with berberine or canagliflozin alone. These results indicated that BC was a stronger antidiabetic than berberine or canagliflozin alone with less negative side effects on the kidneys in the diabetic mice. The antidiabetic effect was likely to be mediated by synergically promoting the expression of pAMPK and reducing the expression of TNFalpha in kidneys. The present study represented the first report that canagliflozin combined with berberine was a promising treatment for diabetes mellitus. The exact underlying mechanisms of action should be investigated in future studies. PMID- 27507203 TI - Anti-proliferative and apoptotic effects of S1, a tetrandrine derivative, in human gastric cancer BGC-823 cells. AB - The aim of the study was to investigate the anti-proliferation and apoptosis inducing effects of S1, a novel tetrandrine derivative, in human gastric cancer BGC-823 cells and explore the possible mechanism of action. The anti proliferative activity was determined by MTT assay; the induction of cell cycle arrest and apoptosis were detected by flow cytometry. Quantitative real time RT PCR and Western blotting were used to evaluate the mRNA and protein expression levels in mitochondrial pathway. S1 significantly reduced cell viability and induced a G2/M phase arrest and apoptosis in dose- and time-dependent manner. Further studies showed that S1 increased mRNA and protein expression of Bax and the Bax/Bcl-2 ratio. Moreover, S1 decreased the protein expression of procaspase 9 and procaspase-3, suggesting that the induction of apoptosis may be related to the alteration of the ratio of Bax/Bcl-2 and the activation of caspases. These findings suggested that S1 merits further investigation as a novel therapeutic agent for the treatment of human gastric cancer. PMID- 27507204 TI - Effects of diammonium glycyrrhizinate on hepatic and intestinal UDP Glucuronosyltransferases in rats: Implication in herb-drug interactions. AB - Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil (MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases (UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s (CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate (GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid (GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs. PMID- 27507205 TI - EPSAH, an exopolysaccharide from Aphanothece halophytica GR02, improves both cellular and humoral immunity as a novel polysaccharide adjuvant. AB - EPSAH is an exopolysaccharide from Aphanothece halophytica GR02. The present study was designed to evaluate its toxicity and adjuvant potential in the specific cellular and humoral immune responses in ovalbumin (OVA) in mice. EPSAH did not cause any mortality and side effects when the mice were administered subcutaneously twice at the dose of 50 mg.kg(-1). Hemolytic activity in vitro indicated that EPSAH was non-hemolytic. Splenocyte proliferation in vitro was assayed with different concentrations of EPSAH. The mice were immunized subcutaneously with OVA 0.1 mg alone or with OVA 0.1 mg dissolved in saline containing Alum (0.2 mg) or EPSAH (0.2, 0.4, or 0.8 mg) on Day 1 and 15. Two weeks later, splenocyte proliferation, natural killer (NK) cell activity, production of cytokines IL-2 from splenocytes, and serum OVA-specific antibody titers were measured. Phagocytic activity, production of pro-inflammatory cytokines IL-1 and IL-12 in mice peritoneal macrophages were also determined. EPSAH showed a dose-dependent stimulating effect on mitogen-induced proliferation. The Con A-, LPS-, and OVA-induced splenocyte proliferation and the serum OVA-specific IgG, IgG1, and IgG2a antibody titers in the immunized mice were significantly enhanced. EPSAH also significantly promoted the production of Th1 cytokine IL-2. Besides, EPSAH remarkably increased the killing activities of NK cells from splenocytes in the immunized mice. In addition, EPSAH enhanced phagocytic activity and the generation of pro-inflammatory cytokines IL-1 and IL 12 in macrophages. These results indicated that EPSAH had a strong potential to increase both cellular and humoral immune responses, particularly promoting the development of Th1 polarization. PMID- 27507206 TI - Screening and verifying potential NTCP inhibitors from herbal medicinal ingredients using the LLC-PK1 cell model stably expressing human NTCP. AB - NTCP is specifically expressed on the basolateral membrane of hepatocytes, participating in the enterohepatic circulation of bile salts, especially conjugated bile salts, to maintain bile salts homeostasis. In addition, recent studies have found that NTCP is a functional receptor of HBV and HDV. Therefore, it is important to study the interaction between drugs and NTCP and identify the inhibitors/substrates of NTCP. In the present study, a LLC-PK1 cell model stably expressing human NTCP was established, which was simple and suitable for high throughput screening, and utilized to screen and verify the potential inhibitors of NTCP from 102 herbal medicinal ingredients. The results showed that ginkgolic acid (GA) (13 : 0), GA (15 : 1), GA (17 : 1), erythrosine B, silibinin, and emodin have inhibitory effects on NTCP uptake of TCNa in a concentration dependent manner. Among them, GA (13 : 0) and GA (15 : 1) exhibited the stronger inhibitory effects, with IC50 values being less than 8.3 and 13.5 MUmol.L(-1), respectively, than the classical inhibitor, cyclosporin A (CsA) (IC50 = 20.33 MUmol.L(-1)). Further research demonstrated that GA (13 : 0), GA (15 : 1), GA (17 : 1), silibinin, and emodin were not substrates of NTCP. These findings might contribute to a better understanding of the disposition of the herbal ingredients in vivo, especially in biliary excretion. PMID- 27507207 TI - Cell signalling: The motif behind PP2A-B56 specificity. PMID- 27507208 TI - Cell signalling: Signalling to cell cycle arrest. PMID- 27507210 TI - Translation: Profiling ribosome dynamics. PMID- 27507209 TI - Notch signalling in context. AB - The highly conserved Notch signalling pathway functions in many different developmental and homeostatic processes, which raises the question of how this pathway can achieve such diverse outcomes. With a direct route from the membrane to the nucleus, the Notch pathway has fewer opportunities for regulation than do many other signalling pathways, yet it generates exquisitely patterned structures, including sensory hair cells and branched arterial networks. More confusingly, its activity promotes tissue growth and cancers in some circumstances but cell death and tumour suppression in others. Many different regulatory mechanisms help to shape the activity of the Notch pathway, generating functional outputs that are appropriate for each context. These mechanisms include the receptor-ligand landscape, the tissue topology, the nuclear environment and the connectivity of the regulatory networks. PMID- 27507211 TI - Nonadaptive radiation: Pervasive diet specialization by drift in scale insects? AB - At least half of metazoan species are herbivorous insects. Why are they so diverse? Most herbivorous insects feed on few plant species, and adaptive host specialization is often invoked to explain their diversification. Nevertheless, it is possible that the narrow host ranges of many herbivorous insects are nonadaptive. Here, we test predictions of this hypothesis with comparative phylogenetic analyses of scale insects, a group for which there appear to be few host-use trade-offs that would select against polyphagy, and for which passive wind-dispersal should make host specificity costly. We infer a strong positive relationship between host range and diversification rate, and a marked asymmetry in cladogenetic changes in diet breadth. These results are consonant with a system of pervasive nonadaptive host specialization in which small, drift- and extinction-prone populations are frequently isolated from persistent and polyphagous source populations. They also contrast with the negative relationship between diet breadth and taxonomic diversification that has been estimated in butterflies, a disparity that likely stems from differences in the average costs and benefits of host specificity and generalism in scale insects versus butterflies. Our results indicate the potential for nonadaptive processes to be important to diet-breadth evolution and taxonomic diversification across herbivorous insects. PMID- 27507212 TI - Embryogenesis and early skeletogenesis in the antarctic bullhead notothen, Notothenia coriiceps. AB - BACKGROUND: Environmental temperature influences rates of embryonic development, but a detailed staging series for vertebrate embryos developing in the subzero cold of Antarctic waters is not yet available from fertilization to hatching. Given projected warming of the Southern Ocean, it is imperative to establish a baseline to evaluate potential effects of changing climate on fish developmental dynamics. RESULTS: We studied the Bullhead notothen (Notothenia coriiceps), a notothenioid fish inhabiting waters between -1.9 and +2 degrees C. In vitro fertilization produced embryos that progressed through cleavage, epiboly, gastrulation, segmentation, organogenesis, and hatching. We compared morphogenesis spatially and temporally to Zebrafish and medaka. Experimental animals hatched after about 6 months to early larval stages. To help understand skeletogenesis, we analyzed late embryos for expression of sox9 and runx2, which regulate chondrogenesis, osteogenesis, and eye development. Results revealed that, despite their prolonged developmental time course, N. coriiceps embryos developed similarly to those of other teleosts with large yolk cells. CONCLUSIONS: Our studies set the stage for future molecular analyses of development in these extremophile fish. Results provide a foundation for understanding the impact of ocean warming on embryonic development and larval recruitment of notothenioid fish, which are key factors in the marine trophic system. Developmental Dynamics 245:1066-1080, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27507213 TI - Beam and tissue factors affecting Cherenkov image intensity for quantitative entrance and exit dosimetry on human tissue. AB - This study's goal was to determine how Cherenkov radiation emission observed in radiotherapy is affected by predictable factors expected in patient imaging. Factors such as tissue optical properties, radiation beam properties, thickness of tissues, entrance/exit geometry, curved surface effects, curvature and imaging angles were investigated through Monte Carlo simulations. The largest physical cause of variation of the correlation ratio between of Cherenkov emission and dose was the entrance/exit geometry (~50%). The largest human tissue effect was from different optical properties (~45%). Beyond these, clinical beam energy varies the correlation ratio significantly (~20% for X-ray beams), followed by curved surfaces (~15% for X-ray beams and ~8% for electron beams), and finally, the effect of field size (~5% for X-ray beams). Other investigated factors which caused variations less than 5% were tissue thicknesses and source to surface distance. The effect of non-Lambertian emission was negligible for imaging angles smaller than 60 degrees. The spectrum of Cherenkov emission tends to blue-shift along the curved surface. A simple normalization approach based on the reflectance image was experimentally validated by imaging a range of tissue phantoms, as a first order correction for different tissue optical properties. PMID- 27507214 TI - Blockade of FLT4 suppresses metastasis of melanoma cells by impaired lymphatic vessels. AB - The metastatic spread of tumor cells via lymphatic vessels affects the relapse of tumor patients. New lymphatic vessel formation, including lymphangiogenesis, is promoted in the tumor environment. The lymphangiogenic factor VEGF-C can mediate lymphatic vessel formation and induce tumor metastasis by binding with FLT4. In melanoma, metastasis via lymphatics such as lymph nodes is one of the main predictors of poor outcome. Thus, we investigated whether blockade of FLT4 can reduce metastasis via the suppression of lymphatic capillaries. Proliferative lymphatic capillaries in melanoma were estimated by immunohistochemistry using FLT4 antibody after the injection of the FLT4 antagonist MAZ51. The numbers of tumor modules in metastasised lungs were calculated by gross examination and lymphatic related factors were examined by qRT-PCR. MAZ51 injection resulted in the suppression of tumor size and module number and the inhibition of proliferative lymphatic vessels in the intratumoral region in the lung and proliferating melanoma cells in the lung compared to those of untreated groups. Additionally, high FLT4 and TNF-alpha were detected in melanoma-induced tissue, while lymphatic markers such as VEGF-C, FLT4 and Prox-1 were significantly decreased in MAZ51 treated groups, implying that anti-lymphangiogenesis by MAZ51 may provide a potential strategy to prevent tumor metastasis in melanoma and high number of lymphatic capillaries could be used diagnosis for severe metastasis. PMID- 27507215 TI - PDGF-D/PDGFRbeta promotes tongue squamous carcinoma cell (TSCC) progression via activating p38/AKT/ERK/EMT signal pathway. AB - Platelet-derived growth factor D (PDGF-D) signaling plays significant roles during the development and progression of human malignancies via interacting with the receptor of PDGF-D (PDGFR). Meanwhile, the majority of human tumor metastasis is closely associated with epithelial-mesenchymal transition (EMT). However, the underlying mechanism between PDGF-D/PDGFR signaling and EMT which involved in tumor metastasis remain dismal. This study aimed to investigate the role of PDGF D signaling during EMT process of tongue squamous cell carcinoma (TSCC). In our study, the expression of PDGF-D and PDGFR were examined in primary TSCC samples and the expression of PDGF-D was also determined in TSCC cell lines. In addition, the correlation between PDGF-D expression and TSCC aggressive histopathological features was analyzed. Our results implied that upregulation of PDGFRbeta in UM1 cells induced with exogenous PDGF-D can remarkably promote tumor cells invasiveness; conversely, when using small interfering RNA (siRNA), the invasiveness can be severely prohibited. Furthermore, PDGF-D downstream signal molecules p38, AKT, ERK and EMT biomarkers (E-cadherin, N-cadherin, Vimentin and snail) were measured using Western blot. Our results showed that PDGF-D can induce p38, AKT and ERK phosphorylation; downregulate epithelial markers and upregulate mesenchymal markers. On the contrary, PDGFRbeta siRNA significantly prohibited p38, AKT and ERK phosphorylation; inhibited EMT process. Function analysis revealed that PDGFRbeta siRNA obviously interfered with UM1 cell migration and invasion, according to transwell and wound healing assay. In conclusion, this study suggested that EMT process can be triggered by the PDGF D/PDGFRbeta axis in TSCC, and then involved in the tumor cell invasion via activation of p38/AKT/ERK/EMT pathway. PMID- 27507216 TI - Roles of N287 in catalysis and product formation of amylomaltase from Corynebacterium glutamicum. AB - Amylomaltase catalyzes intermolecular and intramolecular transglucosylation reactions to form linear and cyclic oligosaccharides, respectively. The aim of this work is to investigate the structure-function relationship of amylomaltase from a mesophilic Corynebacterium glutamicum (CgAM). Site-directed mutagenesis was performed to substitute Tyr for Asn287 (N287Y) to determine its role in controlling amylomaltase activity and product formation. Expression of the wild type (WT) and N287Y was achieved by cultivating recombinant cells in the medium containing lactose at 16 degrees C for 14 h. The purified mutated enzyme showed a significant decrease in all transglucosylation activities while hydrolysis activity was not changed. Optimum temperature and pH for disproportionation reaction were slightly changed upon mutation while those for cyclization reaction were not changed. Interestingly, N287Y showed a change in large-ring cyclodextrin (LR-CD) product profile in which the larger size was observed together with an increase in thermostability and substrate preference for G5 in addition to G3. The secondary structure of the mutated enzyme was slightly changed in related to the WT as evidenced from circular dichroism analysis. This work thus demonstrates that N287 is required for transglucosylation activities of CgAM. Having an aromatic residue in this position increased thermostability, changed product profile and substrate preference but demolished most enzyme activities. PMID- 27507217 TI - SCAMP 3 is a novel regulator of endosomal morphology and composition. AB - Secretory Carrier Membrane Proteins (SCAMPs) are transmembrane proteins that function in the plasma membrane, endosomes, and trans-Golgi network. Here we show that SCAMP 3 is a novel regulator of endosomal morphology and composition. Under certain nutrient-starved conditions, SCAMP 3 concentrates in enlarged early endosomes. The enlarged contain ubiquitylated and non-ubiquitylated SCAMP 3 as well as other SCAMPs, EEA1, and the ESCRT-0 protein Hrs. We demonstrate that SCAMP 3 is sufficient to recruit Hrs to the enlarged endosomes. Taken together, our results suggest a novel role for SCAMP 3 in modifying endosome structure through interactions that involve its ubiquitylation and ESCRT proteins. PMID- 27507218 TI - Potential application of microalga Spirulina platensis as a protein source. AB - The high protein level of various microalgal species is one of the main reasons to consider them an unconventional source of this compound. Spirulina platensis stands out for being one of the richest protein sources of microbial origin (460 630 g kg-1 , dry matter basis), having similar protein levels when compared to meat and soybeans. The use of S. platensis in food can bring benefits to human health owing to its chemical composition, since it has high levels of vitamins, minerals, phenolics, essential fatty acids, amino acids and pigments. Furthermore, the development of new protein sources to supply the shortage of this nutrient is an urgent need, and protein from S. platensis plays an important role in this scenario. In this sense, extraction processes that allow maximum protein yield and total utilization of biomass is an urgent need, and ultrasonic waves have proven to be an effective extraction technique. The number of scientific papers related to protein fraction from S. platensis is still limited; thus further studies on its functional and technological properties are needed. (c) 2016 Society of Chemical Industry. PMID- 27507220 TI - Hexanuclear tin(ii) and mixed valence tin(ii,iv) oxide clusters within polyoxometalates. AB - A hexanuclear mixed valence tin oxide cluster [Sn3(2+)Sn3(4+)O15](12-) was successfully synthesized by the solution-state selective oxidation of a tin oxide cluster [Sn6(2+)O12](12-) within trivacant lacunary polyoxometalates, where lone pairs on the Sn(2+) species acted as stereochemically active sites. PMID- 27507219 TI - Normal tissue radioprotection by amifostine via Warburg-type effects. AB - The mechanism of Amifostine (WR-2721) mediated radioprotection is poorly understood. The effects of amifostine on human basal metabolism, mouse liver metabolism and on normal and tumor hepatic cells were studied. Indirect calorimetric canopy tests showed significant reductions in oxygen consumption and of carbon dioxide emission in cancer patients receiving amifostine. Glucose levels significantly decreased and lactate levels increased in patient venous blood. Although amifostine in vitro did not inhibit the activity of the prolyl hydroxylase PHD2, experiments with mouse liver showed that on a short timescale WR-1065 induced expression of the Hypoxia Inducible Factor HIF1alpha, lactate dehydrogenase LDH5, glucose transporter GLUT2, phosphorylated pyruvate dehydrogenase pPDH and PDH-kinase. This effect was confirmed on normal mouse NCTC hepatocytes, but not on hepatoma cells. A sharp reduction of acetyl-CoA and ATP levels in NCTC cells indicated reduced mitochondrial usage of pyruvate. Transient changes of mitochondrial membrane potential and reactive oxygen species ROS production were evident. Amifostine selectively protects NCTC cells against radiation, whilst HepG2 neoplastic cells are sensitized. The radiation protection was correlates with HIF levels. These findings shed new light on the mechanism of amifostine cytoprotection and encourage clinical research with this agent for the treatment of primary and metastatic liver cancer. PMID- 27507221 TI - Radiotherapy in early-stage tongue squamous cell carcinoma with minor adverse features. AB - BACKGROUND: Treatment for early-stage tongue squamous cell carcinoma (SCC) is usually surgery alone. There is ambiguity regarding the impact of minor adverse features (MAFs) on outcome and the role of postoperative radiotherapy (PORT) in tongue SCC. METHODS: A retrospective analysis was performed on 48 patients diagnosed with tongue SCC treated in our center. Patients with MAFs received adjuvant PORT. Disease outcome in patients with MAFs, and the effect of PORT were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Thirty-one patients had T1 and 17 had T2 disease. PORT was given to 7 patients with MAFs. Mean follow-up time was 70 months. The 2-year overall survival (OS) rate was 86%. Perineural invasion had a significant impact on disease-free survival (DFS; p =.05). There was an improved DFS in patients with MAFs treated with PORT (p =.01). CONCLUSION: MAFs may have an impact on outcome in tongue SCC, and PORT can improve disease outcome in these patients. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 147-150, 2017. PMID- 27507223 TI - The global prevalence of Huntington's disease: a systematic review and discussion. AB - The ascertained prevalence of Huntington's disease (HD) increased significantly following the provision of diagnostic testing. A systematic review was conducted to estimate the prevalence of HD in the post-diagnostic testing era. 22 studies with original data pertaining to the prevalence of HD (1993-2015) were included and analyzed. A global meta-analysis was not performed due to heterogeneity in study methods and geographical variation. The prevalence of HD is significantly lower in Asian populations compared with western Europe, North America and Australia. The global variation in HD prevalence is partly explained by the average CAG repeat lengths and frequency of different HTT gene haplotypes in the general population. Understanding the prevalence of HD has significant implications for healthcare resource planning. PMID- 27507222 TI - Gut Microbiome Associates With Lifetime Cardiovascular Disease Risk Profile Among Bogalusa Heart Study Participants. AB - RATIONALE: Few studies have systematically assessed the influence of gut microbiota on cardiovascular disease (CVD) risk. OBJECTIVE: To examine the association between gut microbiota and lifetime CVD risk profile among 55 Bogalusa Heart Study participants with the highest and 57 with the lowest lifetime burdens of CVD risk factors. METHODS AND RESULTS: 16S ribosomal RNA sequencing was conducted on microbial DNA extracted from stool samples of the Bogalusa Heart Study participants. alpha Diversity, including measures of richness and evenness, and individual genera were tested for associations with lifetime CVD risk profile. Multivariable regression techniques were used to adjust for age, sex, and race (model 1), along with body mass index (model 2) and both body mass index and diet (model 3). In model 1, odds ratios (95% confidence intervals) for each SD increase in richness, measured by the number of observed operational taxonomic units, Chao 1 index, and abundance-based coverage estimator, were 0.62 (0.39-0.99), 0.61 (0.38-0.98), and 0.63 (0.39-0.99), respectively. Associations were consistent in models 2 and 3. Four genera were enriched among those with high versus low CVD risk profile in all models. Model 1 P values were 2.12*10(-3), 7.95*10(-5), 4.39*10(-4), and 1.51*10(-4) for Prevotella 2, Prevotella 7, Tyzzerella, and Tyzzerella 4, respectively. Two genera were depleted among those with high versus low CVD risk profile in all models. Model 1 P values were 2.96*10(-6) and 1.82*10(-4) for Alloprevotella and Catenibacterium, respectively. CONCLUSIONS: The current study identified associations of overall microbial richness and 6 microbial genera with lifetime CVD risk. PMID- 27507224 TI - Patient participation in patient safety still missing: Patient safety experts' views. AB - The aim of this study was to elicit patient safety experts' views of patient participation in promoting patient safety. Data were collected between September and December in 2014 via an electronic semi-structured questionnaire and interviews with Finnish patient safety experts (n = 21), then analysed using inductive content analysis. Patient safety experts regarded patients as having a crucial role in promoting patient safety. They generally deemed the level of patient safety as 'acceptable' in their organizations, but reported that patient participation in their own safety varied, and did not always meet national standards. Management of patient safety incidents differed between organizations. Experts also suggested that patient safety training should be increased in both basic and continuing education programmes for healthcare professionals. Patient participation in patient safety is still lacking in clinical practice and systematic actions are needed to create a safety culture in which patients are seen as equal partners in the promotion of high-quality and safe care. PMID- 27507225 TI - UVB exposure enhanced benzanthrone-induced inflammatory responses in SKH-1 mouse skin by activating the expression of COX-2 and iNOS through MAP kinases/NF kappaB/AP-1 signalling pathways. AB - This study was conducted to explore the role of UVB on benzanthrone (BA)-induced skin inflammation and its mechanism/s. SKH-1 hairless mice were topically exposed with BA (25 and 50 mg/kg b.wt) either alone or along with UVB (50 mJ/cm(2)) for 24 h and estimation of ROS, histopathological analysis, myeloperoxidase (MPO) activity, mast cell staining, immunohistochemistry for COX-2 and iNOS as well as western blotting for MAPKs, p-NF-kappaB, c-jun, c-fos COX-2 and iNOS were carried out. Enhanced ROS generation, increased epidermal thickness, mast cell number, MPO activity, enhanced expression of COX-2 and iNOS, MAPKs, c-jun, c-fos, NF kappaB were found in BA either alone or when followed by UVB treatment, compared to the control groups. Expression of COX-2, iNOS and phosphorylation of ERK1/2 were found to be more enhanced in BA and UVB- exposed group compared to BA and UVB only group, while phosphorylation of JNK1/2, p38, NF-kappaB and expression of c-jun and c-fos were comparable with BA and UVB only groups. In summary, we suggest that UVB exposure enhanced BA-induced SKH-1 skin inflammation possibly via oxidative stress-mediated activation of MAPKs-NF-kappaB/AP-1 signalling, which subsequently increased the expression of COX-2 and iNOS and led to inflammation in SKH-1 mouse skin. PMID- 27507226 TI - A report on emergent uranyl binding phenomena by an amidoxime phosphonic acid co polymer. AB - The development of technology to harvest the uranium dissolved in seawater would enable access to vast quantities of this critical metal for nuclear power generation. Amidoxime polymers are the most promising platforms for achieving this separation, yet the design of advanced adsorbents is hindered by uncertainty regarding the uranium binding mode. In this work we use XAFS to investigate the uranium coordination environment in an amidoxime-phosphonic acid copolymer adsorbent. In contrast to the binding mode predicted computationally and from small molecule studies, a cooperative chelating model is favoured, attributable to emergent behavior resulting from inclusion of amidoxime in the polymer. Samples exposed to seawater also display a feature consistent with a MU(2)-oxo bridged transition metal, suggesting the formation of an in situ specific binding site. These findings challenge long held assumptions and provide new opportunities for the design of advanced adsorbent materials. PMID- 27507227 TI - Implicit motor sequence learning in schizophrenia and in old age: reduced performance only in the third session. AB - Although there still is conflicting evidence whether schizophrenia is a neurodegenerative disease, cognitive changes in schizophrenia resemble those observed during normal aging. In contrast to extensively demonstrated deficits in explicit learning, it remains unclear whether implicit sequence learning is impaired in schizophrenia and normal aging. Implicit sequence learning was investigated using a computerized drawing task, the 'implicit pattern learning task (IPLT)' in 30 stable patients with schizophrenia, 30 age-matched controls and 30 elderly subjects on two consecutive days and after 1 week (sessions 1, 2 and 3). Fixed sequence trials were intermixed with random trials, and sequence learning was assessed by subtraction of the response time in fixed sequence trials from random trials. Separate analyses of response times and movement accuracy (i.e., directional errors) were performed. Explicit sequence knowledge was assessed using three different awareness tasks. All groups learned equally during sessions 1 and 2. In session 3, control subjects showed significantly larger learning scores than patients with schizophrenia (p = .012) and elderly subjects (p = .021). This group difference is mainly expressed in movement time and directional errors. Patients with schizophrenia demonstrated less subjective sequence awareness, and both patients with schizophrenia and elderly subjects had less explicit sequence recall. Explicit recall was positively correlated with task performance in all groups. After a short 24 h interval, all subjects showed similar improvements in implicit sequence learning. However, no benefit of prior task exposure 1 week later was observed in patients with schizophrenia and elderly subjects compared to controls. As patients with schizophrenia and elderly both display less explicit sequence recall, the control group superiority after 1 week could be explained by an explicit learning component. The few patients with schizophrenia and elderly subjects who had some sequence recall could possibly utilize this explicit knowledge to improve their task performance but did this by distinct mechanisms. PMID- 27507228 TI - Long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with severe uncontrolled asthma. AB - BACKGROUND: Omalizumab is effective and well-tolerated in children with moderate to severe allergic asthma. However, the effects of long-term treatment with omalizumab in this population haven't been well investigated. The objective of this study is to evaluate the long-term safety, efficacy, pharmacokinetics and pharmacodynamics of omalizumab in children with uncontrolled severe asthma. METHODS: Thirty-eight Japanese children (aged 7-16 years) who completed the 24 week treatment core study were included in an uncontrolled extension study, in which treatment with omalizumab continued until the pediatric indication was approved in Japan (ClinicalTrials.gov number: NCT01328886). RESULTS: Thirty-five patients (92.1%) completed the extension study. The median exposure throughout the core and extension studies was 116.6 weeks (range, 46.9-151.1 weeks). The most common adverse events were nasopharyngitis, influenza, upper respiratory tract infection, and asthma. Serious adverse events developed in 10 patients (26.3%), but resolved completely with additional treatments. Incidence of adverse events didn't increase with extended exposure with omalizumab. Twenty-nine patients (76.3%) achieved completely- or well-controlled asthma compared with 9 patients (23.7%) at the start of the extension study. QOL scores, the rates (per year) of hospitalizations and ER visits were significantly improved compared with the baseline of the core study [39.0 vs 48.0 (median), p < 0.001 for QOL, 1.33 vs 0.16, p < 0.001 for hospitalization, 0.68 vs 0.15, p = 0.002 for ER visits]. Remarkably, the mean total IgE level showed a decreasing trend while exposure to omalizumab remained at steady-state. CONCLUSIONS: Long-term treatment with omalizumab is well-tolerated and effective in children with uncontrolled severe allergic asthma. No new safety findings were identified. PMID- 27507229 TI - Re-evaluation of progenitor thresholds and expectations for haematopoietic recovery based on an analysis of 810 autologous transplants: Implications for quality assurance. AB - Haematological engraftment was assessed in 804 autologous transplants. Neutrophil recovery occurred in over 99% within 14 d but platelet recovery was delayed beyond this time in 14.8%. Time to recovery was dependent on the progenitor cell dose infused. The minimum CD34+ cell threshold adopted in this study (2 * 106 /kg) was safe although recovery was faster with a dose >5 * 106 /kg. CD34+ cell doses of between 1 and 2 * 106 /kg were also acceptable if either the granulocyte macrophage colony-forming cell dose exceeded 2 * 105 /kg or this dose was due to splitting a higher yield harvest. Prompt neutrophil recovery affords important quality assurance for laboratory processing. PMID- 27507230 TI - The association between food insecurity and depressive symptoms severity among pregnant women differs by social support category: a cross-sectional study. AB - Common mental disorders, such as depression and anxiety, affect approximately 16% of pregnant women in low- and middle-income countries. Food insecurity (FI) has been shown to be associated with depressive symptoms. It has also been suggested that the association between FI and depressive symptoms is moderated by social support (SS); however, there is limited evidence of these associations among pregnant women living in low-income and middle-income countries. We studied the association between FI and depressive symptoms severity and assessed whether such an association varied among Ugandan pregnant women with low vs. high SS. Cross sectional data were collected among 403 pregnant women in northern Uganda. SS was assessed using an eight-item version of the Duke-UNC functional SS scale. FI and depressive symptoms were assessed by, respectively, the individually focused FI scale and the Center for Epidemiologic Studies-Depression scale. Women were categorized into two SS groups, based on scoring < or >= to the median SS value. Multivariate linear regression models indicated an independent association between FI and depressive symptoms severity. The association between FI and depressive symptoms severity was moderated by SS i.e. was stronger among women in the low SS category (adjusted beta (95%CI): 0.91 (0.55; 1.27)) than for women belonging to the high SS group (0.53 (0.28; 0.78)) (adjusted p value for interaction = 0.026). There is need for longitudinal or interventional studies among pregnant women living in northern Uganda or similar contexts to examine the temporal sequence of the associations among food insecurity, depressive symptoms severity and social support. (c) 2016 John Wiley & Sons Ltd. PMID- 27507231 TI - Refining Ovarian Cancer Test accuracy Scores (ROCkeTS): protocol for a prospective longitudinal test accuracy study to validate new risk scores in women with symptoms of suspected ovarian cancer. AB - INTRODUCTION: Ovarian cancer (OC) is associated with non-specific symptoms such as bloating, making accurate diagnosis challenging: only 1 in 3 women with OC presents through primary care referral. National Institute for Health and Care Excellence guidelines recommends sequential testing with CA125 and routine ultrasound in primary care. However, these diagnostic tests have limited sensitivity or specificity. Improving accurate triage in women with vague symptoms is likely to improve mortality by streamlining referral and care pathways. The Refining Ovarian Cancer Test Accuracy Scores (ROCkeTS; HTA 13/13/01) project will derive and validate new tests/risk prediction models that estimate the probability of having OC in women with symptoms. This protocol refers to the prospective study only (phase III). METHODS AND ANALYSIS: ROCkeTS comprises four parallel phases. The full ROCkeTS protocol can be found at http://www.birmingham.ac.uk/ROCKETS. Phase III is a prospective test accuracy study. The study will recruit 2450 patients from 15 UK sites. Recruited patients complete symptom and anxiety questionnaires, donate a serum sample and undergo ultrasound scored as per International Ovarian Tumour Analysis (IOTA) criteria. Recruitment is at rapid access clinics, emergency departments and elective clinics. Models to be evaluated include those based on ultrasound derived by the IOTA group and novel models derived from analysis of existing data sets. Estimates of sensitivity, specificity, c-statistic (area under receiver operating curve), positive predictive value and negative predictive value of diagnostic tests are evaluated and a calibration plot for models will be presented. ROCkeTS has received ethical approval from the NHS West Midlands REC (14/WM/1241) and is registered on the controlled trials website (ISRCTN17160843) and the National Institute of Health Research Cancer and Reproductive Health portfolios. PMID- 27507232 TI - Evaluation of dietary cholesterol intake in elderly Chinese: a longitudinal study from the China Health and Nutrition Survey. AB - OBJECTIVE: This study aimed to evaluate daily cholesterol intake across demographic factors and its food sources in elderly Chinese. DESIGN: A longitudinal study was conducted using demographic and dietary data for elders aged 60 and above from eight waves (1991-2011) of the China Health and Nutrition Survey. SETTING: The data were derived from urban and rural communities of nine provinces (autonomous regions) in China. PARTICIPANTS: There were 16 274 participants (7657 male and 8617 female) in this study. OUTCOMES: The primary outcome was daily cholesterol intake, which was calculated by using the Chinese Food Composition Table, based on dietary data. RESULTS: Daily consumption of cholesterol in the elderly significantly increased by 34% from 1991 to 2011 (p<0.0001) and reached 253.9 mg on average in 2011. Secular trends in the proportion of subjects with an intake of >300 mg/day increased significantly during 1991-2011 (p<0.0001). The major food sources of cholesterol by ranked order were eggs, pork, and fish and shellfish in 1991 and 2011, while organ meats which ranked fourth in the contribution to total intake in 1991 was replaced by poultry in 2011. Moreover, younger elders, male elders and elders from a high income family or a highly urbanised community had higher cholesterol intakes and larger proportions of subjects with excessive cholesterol consumption in each survey year. CONCLUSIONS: The large growth in daily cholesterol intake may pose major challenges for the health of elders in China. Reduced exposure to food enriched in cholesterol is required for elderly Chinese. PMID- 27507233 TI - Do university hospitals perform better than general hospitals? A comparative analysis among Italian regions. AB - OBJECTIVE: The aim of this research was to investigate how university hospitals (UHs) perform compared with general hospitals (GHs) in the Italian healthcare system. DESIGN AND SETTING: 27 indicators of overall performance were selected and analysed for UHs and GHs in 10 Italian regions. The data refer to 2012 and 2013 and were selected from two performance evaluation systems based on hospital discharge administrative data: the Inter-Regional Performance Evaluation System developed by the Management and Health Laboratory of the Scuola Superiore Sant'Anna of Pisa and the Italian National Outcome Evaluation Programme developed by the National Agency for Healthcare Services. The study was conducted in 2 stages and by combining 2 statistical techniques. In stage 1, a non-parametric Mann-Whitney U test was carried out to compare the performance of UHs and GHs on the selected set of indicators. In stage 2, a robust equal variance test between the 2 groups of hospitals was carried out to investigate differences in the amount of variability between them. RESULTS: The overall analysis gave heterogeneous results. In general, performance was not affected by being in the UH rather than the GH group. It is thus not possible to directly associate Italian UHs with better results in terms of appropriateness, efficiency, patient satisfaction and outcomes. CONCLUSIONS: Policymakers and managers should further encourage hospital performance evaluations in order to stimulate wider competition aimed at assigning teaching status to those hospitals that are able to meet performance requirements. In addition, UH facilities could be integrated with other providers that are responsible for community, primary and outpatient services, thereby creating a joint accountability for more patient-centred and integrated care. PMID- 27507234 TI - Impact of omalizumab on treatment of severe allergic asthma in UK clinical practice: a UK multicentre observational study (the APEX II study). AB - OBJECTIVE: To describe the impact of omalizumab on asthma management in patients treated as part of normal clinical practice in the UK National Health Service (NHS). DESIGN: A non-interventional, mixed methodology study, combining retrospective and prospective data collection for 12 months pre-omalizumab and post-omalizumab initiation, respectively. SETTING: Data were collected in 22 UK NHS centres, including specialist centres and district general hospitals in the UK. PARTICIPANTS: 258 adult patients (aged >=16 years; 65% women) with severe persistent allergic asthma treated with omalizumab were recruited, of whom 218 (84.5%) completed the study. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was change in mean daily dose of oral corticosteroids (OCS) between the 12-month pre-omalizumab and post-omalizumab initiation periods. A priori secondary outcome measures included response to treatment, changes in OCS dosing, asthma exacerbations, lung function, employment/education, patient reported outcomes and hospital resource utilisation. RESULTS: The response rate to omalizumab at 16 weeks was 82.4%. Comparing pre-omalizumab and post-omalizumab periods, the mean (95% CIs) daily dose of OCS decreased by 1.61 (-2.41 to -0.80) mg/patient/day (p<0.001) and hospital exacerbations decreased by 0.97 (-1.19 to 0.75) exacerbations/patient (p<0.001). Compared with baseline, lung function, assessed by percentage of forced expiratory volume in 1 s, improved by 4.5 (2.7 to 6.3)% at 16 weeks (p<0.001; maintained at 12 months) and patient quality of life (Asthma Quality of Life Questionnaire) improved by 1.38 (1.18 to 1.58) points at 16 weeks (p<0.001, maintained at 12 months). 21/162 patients with complete employment data gained employment and 6 patients lost employment in the 12-month post-omalizumab period. The mean number of A&E visits, inpatient hospitalisations, outpatient visits (excluding for omalizumab) and number of bed days/patient decreased significantly (p<0.001) in the 12-month post-omalizumab period. CONCLUSIONS: These data support the beneficial effects of omalizumab on asthma-related outcomes, quality of life and resource utilisation in unselected patients treated in 'real-world' clinical practice. PMID- 27507235 TI - Principal components analysis to identify influences on research communication and engagement during an environmental disaster. AB - OBJECTIVES: To discern community attitudes towards research engagement in Libby, Montana, the only Superfund site for which a public health emergency has been declared. STUDY DESIGN: Survey study of convenience samples of residents near the Libby, Montana Superfund site. PARTICIPANTS: Residents of the Libby, Montana area were recruited from a local retail establishment (N=120, survey 1) or a community event (N=127, survey 2). MEASURES: Two surveys were developed in consultation with a Community Advisory Panel. RESULTS: Principal components of survey 1 showed four dimensions of community members' attitudes towards research engagement: (1) researcher communication and contributions to the community, (2) identity and affiliation of the researchers requesting participation, (3) potential personal barriers, including data confidentiality, painful or invasive procedures and effects on health insurance and (4) research benefits for the community, oneself or family. The score on the first factor was positively related to desire to participate in research (r=0.31, p=0.01). Scores on factors 2 and 3 were higher for those with diagnosis of asbestos-related disease (ARD) in the family (Cohen's d=0.41, 0.57). Survey 2 also found more positive attitudes towards research when a family member had ARD (Cohen's d=0.48). CONCLUSIONS: Principal components analysis shows different dimensions of attitudes towards research engagement. The different dimensions are related to community members' desire to be invited to participate in research, awareness of past research in the community and having been screened or diagnosed with a health condition related to the Superfund contaminant. PMID- 27507237 TI - Hypoxia Tolerance and Metabolic Suppression in Oxygen Minimum Zone Euphausiids: Implications for Ocean Deoxygenation and Biogeochemical Cycles. AB - The effects of regional variations in oxygen and temperature levels with depth were assessed for the metabolism and hypoxia tolerance of dominant euphausiid species. The physiological strategies employed by these species facilitate prediction of changing vertical distributions with expanding oxygen minimum zones and inform estimates of the contribution of vertically migrating species to biogeochemical cycles. The migrating species from the Eastern Tropical Pacific (ETP), Euphausia eximia and Nematoscelis gracilis, tolerate a Partial Pressure (PO2) of 0.8 kPa at 10 degrees C (~15 uM O2) for at least 12 h without mortality, while the California Current species, Nematoscelis difficilis, is incapable of surviving even 2.4 kPa PO2 (~32 uM O2) for more than 3 h at that temperature. Euphausia diomedeae from the Red Sea migrates into an intermediate oxygen minimum zone, but one in which the temperature at depth remains near 22 degrees C. Euphausia diomedeae survived 1.6 kPa PO2 (~22 uM O2) at 22 degrees C for the duration of six hour respiration experiments. Critical oxygen partial pressures were estimated for each species, and, for E. eximia, measured via oxygen consumption (2.1 kPa, 10 degrees C, n = 2) and lactate accumulation (1.1 kPa, 10 degrees C). A primary mechanism facilitating low oxygen tolerance is an ability to dramatically reduce energy expenditure during daytime forays into low oxygen waters. The ETP and Red Sea species reduced aerobic metabolism by more than 50% during exposure to hypoxia. Anaerobic glycolytic energy production, as indicated by whole-animal lactate accumulation, contributed only modestly to the energy deficit. Thus, the total metabolic rate was suppressed by ~49-64%. Metabolic suppression during diel migrations to depth reduces the metabolic contribution of these species to vertical carbon and nitrogen flux (i.e., the biological pump) by an equivalent amount. Growing evidence suggests that metabolic suppression is a widespread strategy among migrating zooplankton in oxygen minimum zones and may have important implications for the economy and ecology of the oceans. The interacting effects of oxygen and temperature on the metabolism of oceanic species facilitate predictions of changing vertical distribution with climate change. PMID- 27507238 TI - Hypoxia and Anoxia Tolerance in the Annual Killifish Austrofundulus limnaeus. AB - Embryos of the annual killifish Austrofundulus limnaeus are routinely exposed to oxygen limitation during development and are extremely tolerant of anoxia. Importantly, tolerance of anoxia is not strictly associated with entrance into metabolic dormancy associated with diapause II, but rather any embryo will respond to anoxia by entering into a state of anoxia-induced quiescence. Hypoxia causes a reduction in the rate of development, reduced heart rates, and reduced capacities for metabolic enzyme activity in both aerobic and anaerobic pathways. Embryos of A. limnaeus begin life as oxyconformers, and transition into oxyregulators near the completion of embryonic development. As this transition occurs, extreme anoxia tolerance is lost. The rate of early development is independent of oxygen partial pressure, despite the fact that the embryos are oxyconformers. This suggests a contribution from anaerobic pathways to support early development. However, the specific pathways supporting this metabolism are unknown. The response of A. limnaeus embryos to hypoxia and anoxia is unique compared to other fishes and most other vertebrates, and thus future studies on this species may lend insight into novel mechanisms that support survival during prolonged oxygen limitation. PMID- 27507236 TI - Counteracting Age-related Loss of Skeletal Muscle Mass: a clinical and ethnological trial on the role of protein supplementation and training load (CALM Intervention Study): study protocol for a randomized controlled trial. AB - BACKGROUND: Aging is associated with decreased muscle mass and functional capacity, which in turn decrease quality of life. The number of citizens over the age of 65 years in the Western world will increase by 50 % over the next four decades, and this demographic shift brings forth new challenges at both societal and individual levels. Only a few longitudinal studies have been reported, but whey protein supplementation seems to improve muscle mass and function, and its combination with heavy strength training appears even more effective. However, heavy resistance training may reduce adherence to training, thereby attenuating the overall benefits of training. We hypothesize that light load resistance training is more efficient when both adherence and physical improvement are considered longitudinally. We launched the interdisciplinary project on Counteracting Age-related Loss of Skeletal Muscle Mass (CALM) to investigate the impact of lifestyle changes on physical and functional outcomes as well as everyday practices and habits in a qualitative context. METHODS: We will randomize 205 participants older than 65 years to be given 1 year of two daily nutrient supplements with 10 g of sucrose and 20 g of either collagen protein, carbohydrates, or whey. Further, two groups will perform either heavy progressive resistance training or light load training on top of the whey supplement. DISCUSSION: The primary outcome of the CALM Intervention Study is the change in thigh cross-sectional area. Moreover, we will evaluate changes in physical performance, muscle fiber type and acute anabolic response to whey protein ingestion, sensory adaptation, gut microbiome, and a range of other measures, combined with questionnaires on life quality and qualitative interviews with selected subjects. The CALM Intervention Study will generate scientific evidence and recommendations to counteract age-related loss of skeletal muscle mass in elderly individuals. TRIAL REGISTRATION: ClinicalTrials.gov NCT02034760 . Registered on 10 January 2014. ClinicalTrials.gov NCT02115698 . Registered on 14 April 2014. Danish regional committee of the Capital Region H-4-2013-070. Registered on 4 July 2013. Danish Data Protection Agency 2012-58-0004 - BBH-2015 001 I-Suite 03432. Registered on 9 January 2015. PMID- 27507239 TI - A novel blue-light phototropic response is revealed in roots of Arabidopsis thaliana in microgravity. AB - MAIN CONCLUSION: Blue-light positive phototropism in roots is masked by gravity and revealed in conditions of microgravity. In addition, the magnitude of red light positive phototropic curvature is correlated to the magnitude of gravity. Due to their sessile nature, plants utilize environmental cues to grow and respond to their surroundings. Two of these cues, light and gravity, play a substantial role in plant orientation and directed growth movements (tropisms). However, very little is currently known about the interaction between light- (phototropic) and gravity (gravitropic)-mediated growth responses. Utilizing the European Modular Cultivation System on board the International Space Station, we investigated the interaction between phototropic and gravitropic responses in three Arabidopsis thaliana genotypes, Landsberg wild type, as well as mutants of phytochrome A and phytochrome B. Onboard centrifuges were used to create a fractional gravity gradient ranging from reduced gravity up to 1g. A novel positive blue-light phototropic response of roots was observed during conditions of microgravity, and this response was attenuated at 0.1g. In addition, a red light pretreatment of plants enhanced the magnitude of positive phototropic curvature of roots in response to blue illumination. In addition, a positive phototropic response of roots was observed when exposed to red light, and a decrease in response was gradual and correlated with the increase in gravity. The positive red-light phototropic curvature of hypocotyls when exposed to red light was also confirmed. Both red-light and blue-light phototropic responses were also shown to be affected by directional light intensity. To our knowledge, this is the first characterization of a positive blue-light phototropic response in Arabidopsis roots, as well as the first description of the relationship between these phototropic responses in fractional or reduced gravities. PMID- 27507240 TI - Climate change increases the risk of herbicide-resistant weeds due to enhanced detoxification. AB - MAIN CONCLUSION: Global warming will increase the incidence of metabolism-based reduced herbicide efficacy on weeds and, therefore, the risk for evolution of non target site herbicide resistance. Climate changes affect food security both directly and indirectly. Weeds are the major biotic factor limiting crop production worldwide, and herbicides are the most cost-effective way for weed management. Processes associated with climatic changes, such as elevated temperatures, can strongly affect weed control efficiency. Responses of several grass weed populations to herbicides that inhibit acetyl-CoA carboxylase (ACCase) were examined under different temperature regimes. We characterized the mechanism of temperature-dependent sensitivity and the kinetics of pinoxaden detoxification. The products of pinoxaden detoxification were quantified. Decreased sensitivity to ACCase inhibitors was observed under elevated temperatures. Pre-treatment with the cytochrome-P450 inhibitor malathion supports a non-target site metabolism-based mechanism of herbicide resistance. The first 48 h after herbicide application were crucial for pinoxaden detoxification. The levels of the inactive glucose-conjugated pinoxaden product (M5) were found significantly higher under high- than low-temperature regime. Under high temperature, a rapid elevation in the level of the intermediate metabolite (M4) was found only in pinoxaden-resistant plants. Our results highlight the quantitative nature of non-target-site resistance. To the best of our knowledge, this is the first experimental evidence for temperature-dependent herbicide sensitivity based on metabolic detoxification. These findings suggest an increased risk for the evolution of herbicide-resistant weeds under predicted climatic conditions. PMID- 27507241 TI - CpG site methylation in CRYAA promoter affect transcription factor Sp1 binding in human lens epithelial cells. AB - BACKGROUND: Age-related cataract (ARC) is the leading cause of visual impairment worldwide, and alpha-crystallin (CRYAA) is the predominant structural protein involved in the maintenance of lens clarity and refractive properties. We previously demonstrated that CRYAA genes undergo epigenetic repression in the lens epithelia in ARC. We further analyze the underlying mechanism in the current study. METHODS: The transcription factor binding sites of the CpG island of CRYAA promoter were predicted by TESS website. An electrophoretic mobility shift assay (EMSA) was used to analyze the impact of the methylation of CpG sites on transcription factors. Human lens epithelial B-3 (HLE B-3) Cells were treated with demethylation agent zebularine in the concentrations of 0 (PBS as control), 10 MUM, 20 MUM, 50 MUM, 100 MUM and 200 MUM, respectively. After treatment in the above concentrations for 24 h, 48 h and 72 h, respectively, CRYAA mRNA expression levels were detected by Quantitative Real-Time RT-PCR. RESULTS: The methylation of the CpG site of the CRYAA promoter decreased the DNA-binding capacity of transcription factor Sp1. Zebularine increased CRYAA expression in HLE B-3 Cells in a dose- dependent and time- dependent pattern. CONCLUSIONS: The evidence presented suggests that the methylation of the CpG sites of the CRYAA promotor directly affect Sp1 binding, leading to down expression of CRYAA in human lens epithelial cells. Zebularine treatment could restore CRYAA expression in a dose- dependent and time- dependent pattern. PMID- 27507242 TI - When the brain goes diving: transcriptome analysis reveals a reduced aerobic energy metabolism and increased stress proteins in the seal brain. AB - BACKGROUND: During long dives, the brain of whales and seals experiences a reduced supply of oxygen (hypoxia). The brain neurons of the hooded seal (Cystophora cristata) are more tolerant towards low-oxygen conditions than those of mice, and also better survive other hypoxia-related stress conditions like a reduction in glucose supply and high concentrations of lactate. Little is known about the molecular mechanisms that support the hypoxia tolerance of the diving brain. RESULTS: Here we employed RNA-seq to approach the molecular basis of the unusual stress tolerance of the seal brain. An Illumina-generated transcriptome of the visual cortex of the hooded seal was compared with that of the ferret (Mustela putorius furo), which served as a terrestrial relative. Gene ontology analyses showed a significant enrichment of transcripts related to translation and aerobic energy production in the ferret but not in the seal brain. Clusterin, an extracellular chaperone, is the most highly expressed gene in the seal brain and fourfold higher than in the ferret or any other mammalian brain transcriptome. The largest difference was found for S100B, a calcium-binding stress protein with pleiotropic function, which was 38-fold enriched in the seal brain. Notably, significant enrichment of S100B mRNA was also found in the transcriptomes of whale brains, but not in the brains of terrestrial mammals. CONCLUSION: Comparative transcriptomics indicates a lower aerobic capacity of the seal brain, which may be interpreted as a general energy saving strategy. Elevated expression of stress-related genes, such as clusterin and S100B, possibly contributes to the remarkable hypoxia tolerance of the brain of the hooded seal. Moreover, high levels of S100B that possibly protect the brain appear to be the result of the convergent adaptation of diving mammals. PMID- 27507243 TI - Gender Differences in Perceived Unmet Treatment Needs Among Persons With and Without Co-occurring Disorders. AB - This study examined gender differences in perceived unmet treatment needs among persons with and without co-occurring substance use disorders and serious mental health conditions. Data were drawn from the 2008-2013 National Survey on Drug Use and Health (unweighted N = 37,187) to test the hypothesis that the relationships between diagnosis and perceived unmet treatment needs differ as a function of gender. Compared to individuals with a substance use disorder or severe mental illness, those with co-occurring disorders were more likely to report perceived unmet needs for substance abuse and mental health treatment. Gender significantly moderated the relationship between diagnosis and unmet needs, suggesting that men with co-occurring disorders might be more adversely affected. Findings highlight the need for better understanding of gender-diagnosis differences with respect to unmet needs for substance abuse and mental health care. PMID- 27507244 TI - Overexpression of jumu induces melanotic nodules by activating Toll signaling in Drosophila. AB - Melanotic nodules are commonly assumed to be caused by an abnormal immune response. Several hematopoietic mutants and signaling pathways, including the Toll, JAK/STAT, Ras and JNK pathways, can cause melanotic nodules to develop when specifically activated in hemocytes. Here, we used the UAS-Gal4 system to overexpress jumeaux (jumu) in the fly immune response system. Jumeaux (Jumu) is a new member of the winged-helix/forkhead (WH/FKH) gene family of transcription factors, which plays an important role in the growth and morphogenesis of Drosophila and participates in the proliferation and differentiation of hemocytes. Overexpressing jumu in both hemocytes and the fat body generated many melanotic nodules in larvae and adult flies. The nodules observed in the fat body were surrounded by large numbers of blood cells through a process that appeared similar to foreign body encapsulation. This phenomenon is caused by Toll pathway activation and leads to blood cells deposited in the fat body. In addition, we also report the dissociation of fat cells and the abnormal proliferation and differentiation of blood cells. These results suggest a Jumu-mediated crosstalk between hematopoiesis and the fat body, especially during the Toll-dependent formation of melanotic nodules. PMID- 27507245 TI - 21-Gene recurrence score decreases receipt of chemotherapy in ER+ early-stage breast cancer: an analysis of the NCDB 2010-2013. AB - The purpose of this study was to determine if receipt of chemotherapy was associated with utilization of the 21-gene recurrence score assay (RS assay) or with recurrence score (RS) in eligible patients. Using the National Cancer Data Base (NCDB), we identified female patients eligible for RS assay based on National Comprehensive Cancer Network (NCCN) guidelines: age 18-70, ER-positive and HER2-negative early-stage breast cancer diagnosed during 2010-2013. We excluded patients not meeting testing guidelines. Inclusion required result of RS in patients who underwent RS assay and status for receipt of chemotherapy. Multivariable logistic regression models and propensity matched analysis were used to determine associations between RS assay and RS with receipt of chemotherapy. Among 129,765 patients who were eligible, 74,778 underwent RS assay and had results available. Of these, 59.5 % (44,505) had low-risk, 32.0 % (23,920) had intermediate-risk, and 8.5 % (6353) had high-risk RS. Patients with intermediate- and high-risk RS were more likely to receive chemotherapy [OR 12.9 (CI 12.2-13.6), p <0.001 and OR 87.2 (CI 79.6-95.6), p <0.0001], respectively. In both low- and intermediate-risk groups, increasing RS score was significantly associated with increasing odds of receiving chemotherapy [OR 1.10 (CI 1.09 1.12), p <0.0001 and OR 1.26 (CI 1.25-1.27), p <0.0001, respectively, for each point increase in RS]. Receipt of chemotherapy was more likely in patients who did not undergo RS assay compared to those who did, OR 1.21 (CI 1.175-1.249) p <0.0001. The utilization of RS assay and the RS were both strongly associated with chemotherapy receipt. Patients eligible for chemotherapy, based on NCCN criteria, were more likely to receive chemotherapy if they did not undergo RS assay or they had a high RS. PMID- 27507246 TI - Tyrosine kinase inhibition reverses TDP-43 effects on synaptic protein expression, astrocytic function and amino acid dis-homeostasis. AB - The trans-activating response of DNA/RNA-binding protein (TDP)-43 pathology is associated with many neurodegenerative diseases via unknown mechanisms. Here, we use a transgenic mouse model over-expressing human wild-type neuronal TDP-43 to study the effects of TDP-43 pathology on glutamate metabolism and synaptic function. We found that neuronal TDP-43 over-expression affects synaptic protein expression, including Synapsin I, and alters surrounding astrocytic function. TDP 43 over-expression is associated with an increase in glutamate and gamma-amino butyric acid and reduction of glutamine and aspartate levels, indicating impairment of presynaptic terminal. TDP-43 also decreases tricarboxylic acid cycle metabolism and induces oxidative stress via lactate accumulation. Neuronal TDP-43 does not alter microglia activity or significantly changes systemic and brain inflammatory markers compared to control. We previously demonstrated that brain-penetrant tyrosine kinase inhibitors (TKIs), nilotinib and bosutinib, reduce TDP-43-induced cell death in transgenic mice. Here, we show that TKIs reverse the effects of TDP-43 on synaptic proteins, increase astrocytic function and restore glutamate and neurotransmitter balance in TDP-43 mice. Nilotinib, but not bosutinib, reverses mitochondrial impairment and oxidative metabolism. Taken together, these data suggest that TKIs can attenuate TDP-43 toxicity and improve synaptic and astrocytic function, independent of microglial or other inflammatory effects. In conclusion, our data demonstrate novel mechanisms of the effects of neuronal TDP-43 over-expression on synaptic protein expression and alteration of astrocytic function. PMID- 27507247 TI - The Power of Being Vulnerable in Christian Soul Care: Common Humanity and Humility. AB - Soul caregivers often hesitate to be vulnerable in their pastoral practices. Jesus, however, embraced his vulnerabilities as a human to redeem humanity even though he was the Son of God. This paper first explores the dynamics of shame and power that make soul caregivers reluctant to accept their vulnerabilities and then describes the contributions of sharing caregiver's vulnerabilities in a soul care practice. This article argues that being vulnerable allows a soul caregiver to imitate Jesus by sharing in the client's common humanity, initiating an authentic relationship between the client and the soul caregiver; it is also a practice of humility, inviting God's cure in soul care. This study proposes the necessity of embracing vulnerability in soul care ministry, instead of hiding it. PMID- 27507248 TI - Prediction of Quantum Anomalous Hall Insulator in half-fluorinated GaBi Honeycomb. AB - Using first-principles electronic structure calculations, we predict half fluorinated GaBi honeycomb under tensile strain to harbor a quantum anomalous Hall (QAH) insulator phase. We show that this QAH phase is driven by a single inversion in the band structure at the Gamma point. Moreover, we have computed the electronic spectrum of a half-fluorinated GaBi nanoribbon with zigzag edges, which shows that only one edge band crosses the Fermi level within the band gap. Our results suggest that half-fluorination of the GaBi honeycomb under tensile strain could provide a new platform for developing novel spintronics devices based on the QAH effect. PMID- 27507249 TI - Interventions to improve the rate or timing of initiation of antiretroviral therapy for HIV in sub-Saharan Africa: meta-analyses of effectiveness. AB - INTRODUCTION: As global policy evolves toward initiating lifelong antiretroviral therapy (ART) regardless of CD4 count, initiating individuals newly diagnosed with HIV on ART as efficiently as possible will become increasingly important. To inform progress, we conducted a systematic review of pre-ART interventions aiming to increase ART initiation in sub-Saharan Africa. METHODS: We searched PubMed, Embase and the ISI Web of Knowledge from 1 January 2008 to 1 March 2015, extended in PubMed to 25 May 2016, for English language publications pertaining to any country in sub-Saharan Africa and reporting on general adult populations. We included studies describing interventions aimed at increasing linkage to HIV care, retention in pre-ART or uptake of ART, which reported ART initiation as an outcome. We synthesized the evidence on causal intervention effects in meta analysis of studies belonging to distinct intervention categories. RESULTS AND DISCUSSION: We identified 22 studies, which evaluated 25 interventions and included data on 45,393 individual patients. Twelve of twenty-two studies were observational. Rapid/point-of-care (POC) CD4 count technology (seven interventions) (relative risk, RR: 1.26; 95% confidence interval, CI: 1.02-1.55), interventions within home-based testing (two interventions) (RR: 2.00; 95% CI: 1.36-2.92), improved clinic operations (three interventions) (RR: 1.36; 95% CI: 1.25-1.48) and a package of patient-directed services (three interventions) (RR: 1.54; 95% CI: 1.20-1.97) were all associated with increased ART initiation as was HIV/TB service integration (three interventions) (RR: 2.05; 95% CI: 0.59-7.09) but with high imprecision. Provider-initiated testing (three interventions) was associated with reduced ART initiation (RR: 0.91; 95% CI: 0.86-0.97). Counselling and support interventions (two interventions) (RR 1.08; 95% CI: 0.94-1.26) had no impact on ART initiation. Overall, the evidence was graded as low or moderate quality using the GRADE criteria. CONCLUSIONS: The literature on interventions to increase uptake of ART is limited and of mixed quality. POC CD4 count and improving clinic operations show promise. More implementation research and evaluation is needed to identify how best to offer treatment initiation in a manner that is both efficient for service providers and effective for patients without jeopardizing treatment outcomes. PMID- 27507250 TI - The evaluation of a healthcare passport to improve quality of care and communication for people living with dementia (EQuIP): a protocol paper for a qualitative, longitudinal study. AB - BACKGROUND: There is an urgent need for the development of simple communication tools that convey the strengths, assets, and healthcare needs of people living with dementia. A Healthcare Passport may improve communication with range of health and social support services, enhancing quality and continuity of care, and to permit a consideration of the challenges and how these might be managed effectively and compassionately. This study aims to evaluate the acceptability and use of this type of intervention for people living with dementia and their carers. METHODS/DESIGN: This is a qualitative longitudinal study informed by a critical realist review. The participants will be individuals identified as having mild-moderate dementia and informal carers. The in-depth interviews will occur at three points over the course of 18 months as they use the passport. This will be supplemented by analysis of the content of the passports and information from health and social care providers on the daily practicalities of using the passport in a range of healthcare settings. DISCUSSION: By using a critical realist review and a qualitative, longitudinal approach, the study allows for the assessment of a complex intervention in a manner which goes beyond evaluating the basic efficacy of the passport, but looking more deeply at how it worked, for whom, and in what context. It has the potential to develop new data on how interventions improve communication across a range of service providers, while encouraging health and social care professionals to respect and encourage the development of self-management and retention of personhood throughout the progression of life-limiting illnesses. PMID- 27507251 TI - Rifaximin for the prevention of readmissions for patients with hepatic encephalopathy - the price is right. PMID- 27507252 TI - Nonselective beta blockers in patients with ascites: implications of a nationwide study. PMID- 27507253 TI - Response to Successful liver transplantation for hepatocellular carcinoma following down-staging using sorafenib single therapy by Borentain et al. PMID- 27507254 TI - Surgical spacer placement prior carbon ion radiotherapy (CIRT): an effective feasible strategy to improve the treatment for sacral chordoma. AB - BACKGROUND: Sacral chordoma (SC) is a neoplasm arising from residual notochordal cells degeneration. SC is difficult to manage mainly because of anatomic location and tendency to extensive spread. Carbon ion radiotherapy (CIRT) is highly precise to selectively deliver high biological effective dose to the tumor target sparing the anatomical structure on its path even if when SC is contiguous to the intestine, and a surgical spacer might be an advantageous tool to create a distance around the target volume allowing radical curative dose delivery with a safe dose gradient to the surrounding organs. This paper describes a double approach-open and hand-assisted laparoscopic-for a silicon spacer placement in patients affected by sacral chordoma undergoing carbon ion radiotherapy. METHODS: Six consecutive patients have been enrolled for surgical spacer placement-open (three) or hand-assisted (three)-prior carbon ion radiotherapy treatment in order to increase efficacy of carbon ion radiotherapy minimizing its side effects. RESULTS: Results showed that silicon spacer placement for SC treatment is feasible both via laparoscopic and laparotomic approach. CONCLUSIONS: Its use might improve CIRT safety and thus efficacy for SC treatment. PMID- 27507255 TI - Differentiation and description of aromatic short grain rice landraces of eastern Indian state of Odisha based on qualitative phenotypic descriptors. AB - BACKGROUND: Speciality rice, in general, and aromatic rice in particular, possess enormous market potential for enhancing farm profits. However, systematic characterization of the diversity present in this natural wealth is a major pre requisite for using it in the breeding programs. This study reports qualitative phenotypic trait based characterization of 126 short grain aromatic rice genotypes, collected from different areas of the state of Odisha, India. RESULTS: Out of the 24 descriptors employed, highest variability (8 different types) was observed for lemma-palea colour with a genetic diversity index (He) of 0.696. The principal component analysis reveals that the tip colour of lemma, colour of awn and colour of stigma, cumulatively explain 74 % of the total variation. The Population STRUCTURE analysis classified the population into two subpopulations which were subdivided further into four distinct groups. The western and southern districts of Odisha are endowed with maximum diversity in comparison to eastern and northern districts and at district level comparisons, Koraput and Puri districts are rich with a genetic diversity values of 0.324 and 0.303 respectively. With this set of morphological qualitative traits, based on 'phenoprinting', a newly proposed bar coding system, unique fingerprints of each genotype can be effectively generated that can help in easy identification of these genotypes. CONCLUSION: Though aromatic rices represent a tiny fraction of the total rice germplasm, a small collection of 126 land races did exhibit rich diversity for all the qualitative traits. For lemma-palea colour, eight different types were detected while for tip colour of lemma, six different types were recorded, suggesting the presence of rich variability in short grain aromatic rices that are conserved in this region. The proposed 'phenoprinting' can be an effective descriptor with the unique finger prints generated for each genotype and coupled with molecular (DNA) finger printing, we can discriminate and identify each and every aromatic short grain rice genotype. The proposed system not only help in conservation but also can confer IPR protection to these specialty rices. PMID- 27507256 TI - Comparison of Updated Weight and Height Percentiles with Previous References in 6 17-Year-Old Children in Kayseri, Turkey. AB - OBJECTIVE: To compare updated weight and height percentiles of 6-17-year-old children from all socio-economic levels in Kayseri with previous local references and other national/international data. METHODS: The second study "Determination of Anthropometric Measurements of Turkish Children and Adolescents study (DAMTCA II)" was conducted in Kayseri, between October 2007 and April 2008. Weight and height measurements from 4321 (1926 boys, 2395 girls) school children aged between 6 to 17 years were included in this cross-sectional study. Using these data, weight and height percentile curves were produced with generalized additive models for location, scale and shape (GAMLSS) and compared with the most recent references. RESULTS: Smoothed percentile curves including the 3rd, 5th, 10th, 15th, 25th, 50th, 75th, 85th, 90th, 95th, and 97th percentiles were obtained for boys and girls. These results were compared with DAMTCA I study and with two national (Istanbul and Ankara) and international data from Asia and from Europe. CONCLUSION: This study provides updated weight and height references for Turkish school children aged between 6 and 17 years residing in Kayseri. PMID- 27507257 TI - On characterizing protein spatial clusters with correlation approaches. AB - Spatial aggregation of proteins might have functional importance, e.g., in signaling, and nano-imaging can be used to study them. Such studies require accurate characterization of clusters based on noisy data. A set of spatial correlation approaches free of underlying cluster processes and input parameters have been widely used for this purpose. They include the radius of maximal aggregation ra obtained from Ripley's L(r) - r function as an estimator of cluster size, and the estimation of various cluster parameters based on an exponential model of the Pair Correlation Function(PCF). While convenient, the accuracy of these methods is not clear: e.g., does it depend on how the molecules are distributed within the clusters, or on cluster parameters? We analyze these methods for a variety of cluster models. We find that ra relates to true cluster size by a factor that is nonlinearly dependent on parameters and that can be arbitrarily large. For the PCF method, for the models analyzed, we obtain linear relationships between the estimators and true parameters, and the estimators were found to be within +/-100% of true parameters, depending on the model. Our results, based on an extendable general framework, point to the need for caution in applying these methods. PMID- 27507258 TI - The role of ICT in nursing practice: an integrative literature review of the Swedish context. AB - BACKGROUND: The Swedish healthcare system employs information and communication technologies (ICT) in nursing practice to meet quality-, security- and efficiency related demands. Although ICT is integrated with nursing practices, nurses do not always feel that they are convenient to use it. We need to improve our knowledge of the role of ICT in healthcare environments and so we decided to complement existing experience of how ICT influences nursing practice. AIM: This study aimed to review and synthesise the available literature on the role of ICT in nursing practice in Swedish healthcare settings. METHOD: To consolidate previous studies based on diverse methodologies, an integrative literature review was carried out. Three databases were used to search for literature, 20 articles met the inclusion criteria. RESULTS: The literature review indicates that ICT integration into nursing practice is a complex process that impacts nurses' communication and relationships in patient care, working conditions, and professional identities and development. Nurses are found to express ambiguous views on ICT as a usable service in their everyday practice since it impacts both positively and negatively. DISCUSSION AND CONCLUSION: Although ICT cannot replace physical presence, it can be considered a complementary service that gives rise to improved patient care. However, nonverbal communication cues may be missed when ICT is used as mediating tool and ICT can be limiting because it is not always designed to meet nurse and patient needs. The meaning of an encounter appears to change when ICT is used in nursing practice, not only for patient relationships but also for interpersonal communication. PMID- 27507259 TI - Anti-CCP status determines the power Doppler oscillation pattern in rheumatoid arthritis: a prospective study. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction. Serologically, it can be differentiated according to rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (anti-CCP), or both. This differentiation is prognostically and therapeutically relevant. No method has been described to separate the two forms phenotypically. We hypothesize that a differentiation is possible by evaluating oscillation patterns in power Doppler sonography (PDS). In a prospective study, 20 patients with anti-CCP-positive RA and 20 patients with anti-CCP-negative RA with active wrist synovitis were examined. A PDS scan was performed, and perfusion maxima (P max) and minima (P min) as well as the amplitude (DeltaP) were determined by a blinded study member. The amplitude was standardized (sDeltaP) by dividing by P max, and the anti-CCP positive and anti-CCP-negative patients as well as the RF-positive and RF negative were compared to each other. In the ultrasonographic evaluation, we found a highly significant difference in sDeltaP between CCPp and CCPn patients (median 19.0 vs. 42.9 %, p < 0.0001). sDeltaP is independent of disease activity. The absolute amplitude DeltaP did not differ between the groups. Also, in anti CCP-positive patients there was a completely linear correlation between P max and P min, and this was far less marked in anti-CCP-negative patients. Anti-CCP positive and anti-CCP-negative RA display different PDS oscillation patterns. This constitutes a nonserological parameter to differentiate between the two forms. The difference in PDS oscillation patterns suggests that the underlying pathological process differs between the forms. PMID- 27507260 TI - Needs of adolescents and young adults after cancer treatment: a systematic review. AB - The aim of this study was to conduct a systematic review of the literature on the needs of adolescents and young adults (AYAs) who have survived cancer. PRISMA recommendations for systematic reviews were followed, and the quality of the studies reviewed was also assessed with a specific checklist. The following databases were searched from their inception to May 2016: ERIC, EMBASE, MEDLINE, PILOTS, ProQuest, PsycARTICLES, PsycBOOKS, psycCRITIQUES, PsycINFO, Social Services Abstracts and Sociological Abstracts. Fourteen studies were identified and analysed. The results show that the most common needs for AYA cancer survivors are as follows: "individualised information and advice," "counselling and psychological support" and "social support, and social relationships." These results are different from those reported in studies on adults, which shows the importance of specifically addressing the needs of this population. In order to advance in this emerging area of study and facilitate the work of health professionals, it is crucial to reach a consensus on two central issues: how the needs of AYA survivors should be conceptualised and what the most valid and reliable procedure for assessing patient's needs is. PMID- 27507262 TI - An Exploration of the Interaction Between Touch Avoidance and the Pleasant Touch (C-Tactile Afferent) System. AB - C-tactile (CT) afferent fibers are optimally stimulated by slow gentle stroking, and an inverted U-shaped relationship exists between stroking velocity and pleasantness ratings of this type of touch. This study investigated whether an additional and potentially important variable, touch avoidance, interacts with this relationship. While a typical U-shaped velocity-pleasantness relationship was expected, those high in touch avoidance were expected to rate CT-targeted touch (1-10 cm/s) as less pleasant than those low in touch avoidance. Thirty-five participants rated the pleasantness of a brush stroked across their forearm at five velocities (0.3, 1, 3, 10, 30 cm/s) administered by a custom-built touch stimulator ("the touch device"). Participants also completed two self-report measures of touch avoidance. There was an inverted U-shaped relationship between velocity and pleasantness ratings, and high touch avoidance resulted in a downward shift of this curve. The downward shift was across all velocities, including those that do not maximally engage CT afferents. It appears that touch avoidance reduces the pleasantness of all kinds of touch in a similar way, and it is unlikely to be specifically related to CT afferent functioning. Other potential mechanisms leading to touch avoidance are discussed. PMID- 27507261 TI - Overweight/obese status associates with favorable outcome in patients with metastatic nasopharyngeal carcinoma: a 10-year retrospective study. AB - BACKGROUND: Although the prognostic impact of body mass index (BMI) in patients with non-metastatic nasopharyngeal carcinoma (NPC) had been extensively studied, its effect among metastatic NPC patients remains unknown. The purpose of this study was to evaluate the prognostic effect of BMI in patients with metastatic NPC. METHODS: We retrospectively studied 819 patients who were diagnosed with distant metastasis from NPC and received treatment between 1998 and 2007. The patients were divided into three subgroups according to the World Health Organization classifications for Asian populations: underweight (BMI <18.5 kg/m(2)), normal weight (BMI 18.5-22.9 kg/m(2)), and overweight/obese (BMI >=23.0 kg/m(2)). The associations of BMI with overall survival (OS) and progression-free survival (PFS) were determined by Cox regression analysis. RESULTS: Of the 819 patients, 168 (20.5%) were underweight, 431 (52.6%) were normal weight, and 220 (26.9%) were overweight/obese. Multivariate analysis adjusted for covariates showed that overweight/obese patients had a longer OS than underweight patients [hazard ratio (HR), 0.64; 95% confidence interval (CI), 0.49-0.84] and normal weight patients (HR, 0.72; 95% CI, 0.57-0.90); no significant difference in PFS was observed among these three groups (P = 0.407). Moreover, in stratified analysis, no statistically significant differences in the effect of overweight/obese status among different subgroups were observed. CONCLUSION: For patients with metastatic NPC, overweight/obese status was associated with longer OS but not longer PFS compared with underweight or normal weight status. PMID- 27507263 TI - Aging and the Haptic Perception of Material Properties. AB - The ability of 26 younger (mean age was 22.5 years) and older adults (mean age was 72.6 years) to haptically perceive material properties was evaluated. The participants manually explored (for 5 seconds) 42 surfaces twice and placed each of these 84 experimental stimuli into one of seven categories: paper, plastic, metal, wood, stone, fabric, and fur/leather. In general, the participants were best able to identify fur/leather and wood materials; in contrast, recognition performance was worst for stone and paper. Despite similar overall patterns of performance for younger and older participants, the younger adults' recognition accuracies were 26.5% higher. The participants' tactile acuities (assessed by tactile grating orientation discrimination) affected their ability to identify surface material. In particular, the Pearson r correlation coefficient relating the participants' grating orientation thresholds and their material identification performance was -0.8: The higher the participants' thresholds, the lower the material recognition ability. While older adults are able to effectively perceive the solid shape of environmental objects using the sense of touch, their ability to perceive surface materials is significantly compromised. PMID- 27507265 TI - The Feasibility of an eLearning Nutrition Education Program for Low-Income Individuals. AB - BACKGROUND: Online eLearning may be an innovative, efficient, and cost-effective method of providing nutrition education to a diverse low-income audience. AIMS: The intent of this project is to examine perceptions of nutrition educators regarding the feasibility of an eLearning nutrition education program tailored to low-income Georgians. METHOD: Semistructured individual interviews were conducted, guided by the constructivist theory. The interview guide focused on three themes: accessibility, literacy, and content. A prototype of the program also served as a talking point. Interviews were conducted in two urban Georgian counties in a location chosen by each participant. We recruited a convenience sample of Georgian nutrition educators ( n = 10, 100% female, 50% Black). Interviews were transcribed and analyzed using constant comparative method. RESULTS AND DISCUSSION: Motivation is considered the primary barrier to program feasibility. Neither access to the Internet nor literacy are considered significant barriers. Inclusion of skill-based, visual education methods such as cooking videos, recipes, and step-by-step teaching tools was highlighted. Nutrition educators perceived this program would be a feasible form of nutrition education for the priority audience. CONCLUSIONS: Findings from this study will inform the user-centered development of the program. PMID- 27507264 TI - Symbiosis with Francisella tularensis provides resistance to pathogens in the silkworm. AB - Francisella tularensis, the causative agent of tularemia, is a highly virulent facultative intracellular pathogen found in a wide range of animals, including arthropods, and environments. This bacterium has been known for over 100 years, but the lifestyle of F. tularensis in natural reservoirs remains largely unknown. Thus, we established a novel natural host model for F. tularensis using the silkworm (Bombyx mori), which is an insect model for infection by pathogens. F. tularensis established a symbiosis with silkworms, and bacteria were observed in the hemolymph. After infection with F. tularensis, the induction of melanization and nodulation, which are immune responses to bacterial infection, were inhibited in silkworms. Pre-inoculation of silkworms with F. tularensis enhanced the expression of antimicrobial peptides and resistance to infection by pathogenic bacteria. These results suggest that silkworms acquire host resistance via their symbiosis with F. tularensis, which may have important fitness benefits in natural reservoirs. PMID- 27507266 TI - In silico analyses of mitochondrial ORFans in freshwater mussels (Bivalvia: Unionoida) provide a framework for future studies of their origin and function. AB - BACKGROUND: Many species of bivalves exhibit a unique system of mtDNA transmission named Doubly Uniparental Inheritance (DUI). Under this system, species have two distinct, sex-linked mitochondrial genomes: the M-type mtDNA, which is transmitted by males to male offspring and found in spermatozoa, and the F-type mtDNA, which is transmitted by females to all offspring, and found in all tissues of females and in somatic tissues of males. Bivalves with DUI also have sex-specific mitochondrial ORFan genes, (M-orf in the M mtDNA, F-orf in the F mtDNA), which are open reading frames having no detectable homology and no known function. DUI ORFan proteins have previously been characterized in silico in a taxonomically broad array of bivalves including four mytiloid, one veneroid and one unionoid species. However, the large evolutionary distance among these taxa prevented a meaningful comparison of ORFan properties among these divergent lineages. The present in silico study focuses on a suite of more closely-related Unionoid freshwater mussel species to provide more reliably interpretable information on patterns of conservation and properties of DUI ORFans. Unionoid species typically have separate sexes, but hermaphroditism also occurs, and hermaphroditic species lack the M-type mtDNA and possess a highly mutated version of the F-orf in their maternally transmitted mtDNA (named H-orf in these taxa). In this study, H-orfs and their respective proteins are analysed for the first time. RESULTS: Despite a rapid rate of evolution, strong structural and functional similarities were found for M-ORF proteins compared among species, and among the F-ORF and H-ORF proteins across the studied species. In silico analyses suggest that M-ORFs have a role in transport and cellular processes such as signalling, cell cycle and division, and cytoskeleton organisation, and that F ORFs may be involved in cellular traffic and transport, and in immune response. H ORFs appear to be structural glycoproteins, which may be involved in signalling, transport and transcription. Our results also support either a viral or a mitochondrial origin for the ORFans. CONCLUSIONS: Our findings reveal striking structural and functional similarities among proteins encoded by mitochondrial ORFans in freshwater mussels, and strongly support a role for these genes in the DUI mechanism. Our analyses also support the possibility of DUI systems with elements of different sources/origins and different mechanisms of action in the distantly-related DUI taxa. Parallel situations to the novel mitochondrially encoded functions of freshwater mussel ORFans present in some other eukaryotes are also discussed. PMID- 27507267 TI - Epidemiology of hepatitis C virus in Ghana: a systematic review and meta analysis. AB - BACKGROUND: To fully understand the burden of hepatitis C (HCV) infection in Ghana towards informing appropriate preventive measures, accurate prevalence estimates are needed. In this study, we estimate the prevalence of chronic HCV infection by systematically reviewing primary studies published between 1995 and 2015. METHODS: A systematic review and meta-analysis was conducted as per the PRISMA guidelines. Comprehensive searches for hepatitis C prevalence studies for the years 1995-2015 were conducted in PubMed, ScienceDirect, Google Scholar, Africa Journals Online (AJOL) and the WHO African Index Medicus databases. We also searched the websites of the ministry of health and Ghana Health service for non-indexed studies or reports on the subject. Further systematic reference screening of published reviews and retrieved studies were also conducted to identify additional publications not captured through the online searches. RESULTS: Twenty-Four (24) studies from nine regions of Ghana with a combined sample size of 100,782 were analyzed. No study involving participants from Upper West region was retrieved. The national prevalence of chronic HCV was estimated as 3.0 % (95 % CI = 2.6 % to 3.5 %; I(2) = 97.61 %, p < 0. 001). Prevalence rates of chronic HCV infection among blood donors was 2.6 % (95 % CI = 2.1 % to 3.1 %; I(2) = 98.33 %, p < 0.001) with higher prevalence rate estimated for replacement blood donors (RBDs) than voluntary blood donors (RBDs). Among pregnant women and parturients, anti-HCV seroprevalence was estimated as 4.6 % (95 % CI = 1.8 % to 7.5 %; I(2) = 75.74 %, p = 0.016). The national prevalence of HIV/HCV co infection was also estimated as 2.8 % (95 % CI = 0.4-6 %; I(2) = 65.86 %, p = 0.0053). Regional prevalence of chronic HCV infection were determined for Ashanti (1.5 %, 95 % CI = 1.2 % to 1.9 %; I(2) = 96.24 %, p < 0.001) and Greater Accra (6.4 %, 95 % CI = 4.2 % to 8.6 %; I(2) = I(2) = 88.5 %, P < 0. 001) regions but no estimates were available for the other eight regions. The ascending order of HCV prevalence rates according to years in which studies were conducted was 2006 2010 < 2011-2015 < 1995-2002 < 2001-2005. Higher prevalence of chronic HCV infection was estimated for rural (5.7; 95 % CI 5.0-6.3 %; I(2) = 0, p = 0.804) than urban (2.6 %, 95 % CI = 2.1 % to 3.0 %; I(2) = 97.3 %, p = 0.0001) settings. CONCLUSION: Our study demonstrates a high prevalence of chronic hepatitis C infection in Ghana. This highlights the urgent need for stronger commitments from government and all stakeholders within the country to outline efficient preventive and curative measures towards reducing the overall burden of the disease. PMID- 27507269 TI - Effect of Hippophae rhamnoides Extract on Oxidative Oropharyngeal Mucosal Damage Induced in Rats Using Methotrexate. AB - OBJECTIVES: The objective of this study is to investigate and evaluate the effect of Hippophae rhamnoides extract (HRE) on oropharyngeal mucositis induced in rats with methotrexate (MTX) through biochemical, gene expression, and histopathological examinations. METHODS: Experimental animals were divided into a healthy group (HG), a HRE+MTX (HREM) group, HRE group (HREG), and a control group that received MTX (MTXG). The HREM and HREG groups of rats was administered 50 mg/kg HRE, while the MTXG and HG groups were given an equal volume distilled water with gavage. Then, the HREM and MTXG rat groups were given oral MTX at a dose of 5 mg/kg 1 hour after HRE and distilled water was administered. This procedure was repeated for 1 month. At the end of this period, all of the animals were sacrificed with a high dose of anesthesia. Then, the amounts of malondialdehyde (MDA) and total glutathione (tGSH) were determined in the removed oropharyngeal tissues. Interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) gene expressions were measured, and all the tissues were studied histopathologically. RESULTS: The amount of MDA was significantly increased in the MTXG group compared to the HREM, HREG, and HG groups (P<0.001). MTX significantly decreased the amount of tGSH in the MTXG group compared to the HREM, HREG, and HG groups (P<0.001). In this study, there were no visible ulcers in the animal group in which the levels of MDA, IL-1beta, and TNF-alpha were high and the level of tGSH was low. However, histopathologic examination revealed mucin pools in wide areas due to ruptured oropharynx glands, and proliferated, dilated, and congested blood vessels and dilated ductal structures in some areas. CONCLUSION: HRE protected oropharyngeal oxidative damage induced by MTX. As an inexpensive and natural product, HRE has important advantages in the prevention of oropharyngeal damage induced by MTX. PMID- 27507270 TI - A Trainable Hearing Aid Algorithm Reflecting Individual Preferences for Degree of Noise-Suppression, Input Sound Level, and Listening Situation. AB - OBJECTIVES: In an effort to improve hearing aid users' satisfaction, recent studies on trainable hearing aids have attempted to implement one or two environmental factors into training. However, it would be more beneficial to train the device based on the owner's personal preferences in a more expanded environmental acoustic conditions. Our study aimed at developing a trainable hearing aid algorithm that can reflect the user's individual preferences in a more extensive environmental acoustic conditions (ambient sound level, listening situation, and degree of noise suppression) and evaluated the perceptual benefit of the proposed algorithm. METHODS: Ten normal hearing subjects participated in this study. Each subjects trained the algorithm to their personal preference and the trained data was used to record test sounds in three different settings to be utilized to evaluate the perceptual benefit of the proposed algorithm by performing the Comparison Mean Opinion Score test. RESULTS: Statistical analysis revealed that of the 10 subjects, four showed significant differences in amplification constant settings between the noise-only and speech-in-noise situation (P<0.05) and one subject also showed significant difference between the speech-only and speech-in-noise situation (P<0.05). Additionally, every subject preferred different beta settings for beamforming in all different input sound levels. CONCLUSION: The positive findings from this study suggested that the proposed algorithm has potential to improve hearing aid users' personal satisfaction under various ambient situations. PMID- 27507271 TI - Purification of Two Novel Sugar Acid-binding Lectins from Haplomitrium Mnioides (bryophyte, Plantae) and their Preliminary Characterization. AB - Two novel sugar acid-binding lectins were purified from Haplomitrium mnioides (Lindb.) Schust. using a procedure consisting of ammonium sulfate precipitation, G-50 gel filtration, hydroxyapatite chromatography, and HW-50 gel filtration. We reported their partial physicochemical properties: molecular weight, affinity for carbohydrates and organic acids, pH stability, and dependence of their hemagglutination activity on metal ions. We also determined their N-terminal amino acid sequences. H. mnioides lectins (HMLs) were monomers (one with a molecular weight of approximately 27 kDa, and the other with a molecular weight of approximately 105 kDa) under both nonreducing and reducing conditions. They were named HML27 and HML105, respectively. Both HMLs had an affinity for N acetylneuraminic acid, D-glucuronic acid, D-glucaric acid, bovine submaxillary mucin, heparin, and organic acids, such as citrate, 2-oxoglutaric acid, and D-2 hydroxyglutarate. Furthermore, HML27 had an affinity for alpha-D-galacturonic acid, D-malate, L-malate, and pyruvate, while HML105 had an affinity for D gluconic acid. HML27 and HML105 are novel plant lectins: they have an affinity for sugar acids and organic acids and specifically recognize the carboxyl group, and there is no homology between their N-terminal amino acid sequences and those of the previously described lectins and agglutinins. PMID- 27507268 TI - Schizophrenia and Infections: The Eyes Have It. AB - The visual tract is prominently involved in schizophrenia, as evidenced by perceptual distortions and a type of nystagmus found in many individuals affected. Genetic explanations for these abnormalities have been suggested. This study proposes an alternate explanation based on infection. Several infectious agents thought to be associated with some cases of schizophrenia are known to cause both infection of the fetus and abnormalities of the eye. Toxoplasma gondii is examined in detail, and rubella, cytomegalovirus, varicella-zoster virus, and herpes simplex virus more briefly. Careful ophthalmic assessments, including funduscopy and direct examination of tissues for infectious agents, will clarify the role of such agents in ocular aspects of schizophrenia. PMID- 27507272 TI - Simultaneous Hydrogen and Methane Production Through Multi-Phase Anaerobic Digestion of Paperboard Mill Wastewater Under Different Operating Conditions. AB - Multi-phase anaerobic reactor for H2 and CH4 production from paperboard mill wastewater was studied. The reactor was operated at hydraulic retention times (HRTs) of 12, 18, 24, and 36 h, and organic loading rates (OLRs) of 2.2, 1.5, 1.1, and 0.75 kg chemical oxygen demand (COD)/m3 day, respectively. HRT of 12 h and OLR of 2.2 kg COD/m3 day provided maximum hydrogen yield of 42.76 +/- 14.5 ml/g CODremoved and volumetric substrate uptake rate (-rS) of 16.51 +/- 4.43 mg COD/L h. This corresponded to the highest soluble COD/total COD (SCOD/TCOD) ratio of 56.25 +/- 3.3 % and the maximum volatile fatty acid (VFA) yield (YVFA) of 0.21 +/- 0.03 g VFA/g COD, confirming that H2 was mainly produced through SCOD conversion. The highest methane yield (18.78 +/- 3.8 ml/g CODremoved) and -rS of 21.74 +/- 1.34 mgCOD/L h were achieved at an HRT of 36 h and OLR of 0.75 kg COD/m3 day. The maximum hydrogen production rate (HPR) and methane production rate (MPR) were achieved at carbon to nitrogen (C/N) ratio of 47.9 and 14.3, respectively. This implies the important effect of C/N ratio on the distinction between the dominant microorganism bioactivities responsible for H2 and CH4 production. PMID- 27507279 TI - Development and validation of a climate-based ensemble prediction model for West Nile Virus infection rates in Culex mosquitoes, Suffolk County, New York. AB - BACKGROUND: West Nile Virus (WNV) is an endemic public health concern in the United States that produces periodic seasonal epidemics. Underlying these outbreaks is the enzootic cycle of WNV between mosquito vectors and bird hosts. Identifying the key environmental conditions that facilitate and accelerate this cycle can be used to inform effective vector control. RESULTS: Here, we model and forecast WNV infection rates among mosquito vectors in Suffolk County, New York using readily available meteorological and hydrological conditions. We first validate a statistical model built with surveillance data between 2001 and 2009 (m09) and specify a set of new statistical models using surveillance data from 2001 to 2012 (m12). This ensemble of new models is then used to make predictions for 2013-2015, and multimodel inference is employed to provide a formal probabilistic interpretation across the disparate individual model predictions. The findings of the m09 and m12 models align; with the ensemble of m12 models indicating an association between warm, dry early spring (April) conditions and increased annual WNV infection rates in Culex mosquitoes. CONCLUSIONS: This study shows that real-time climate information can be used to predict WNV infection rates in Culex mosquitoes prior to its seasonal peak and before WNV spillover transmission risk to humans is greatest. PMID- 27507281 TI - Reduction enthalpy and charge distribution of substituted ferrites and doped ceria for thermochemical water and carbon dioxide splitting with DFT+U. AB - The thermal reduction step of substituted ferrites (MFe2O4 where M = Fe, Ni, Co, Gd) and doped ceria (MxCe1-xO2, where M = Ce, Zr, Hf and x = 0.25) in two-step thermochemical cycles for H2O and CO2 splitting is investigated within the DFT+U framework. This thermal reduction step is described as the oxygen vacancy formation energy (reduction enthalpy), i.e. the energy required to create an oxygen vacancy in the crystal lattice. Oxides with a lower oxygen vacancy creation energy are easier to reduce. A Bader charge analysis of the reduction mechanism is carried out providing the charge distribution of the bulk and reduced ions, enabling interrelations of the substitute ions and the resulting reduction energies. Based on the approach presented here, interesting solar fuels producing materials are CoFe2O4, NiFe2O4 and Hf0.25Ce0.75O2. PMID- 27507280 TI - Biomechanical Behavior of Bioprosthetic Heart Valve Heterograft Tissues: Characterization, Simulation, and Performance. AB - The use of replacement heart valves continues to grow due to the increased prevalence of valvular heart disease resulting from an ageing population. Since bioprosthetic heart valves (BHVs) continue to be the preferred replacement valve, there continues to be a strong need to develop better and more reliable BHVs through and improved the general understanding of BHV failure mechanisms. The major technological hurdle for the lifespan of the BHV implant continues to be the durability of the constituent leaflet biomaterials, which if improved can lead to substantial clinical impact. In order to develop improved solutions for BHV biomaterials, it is critical to have a better understanding of the inherent biomechanical behaviors of the leaflet biomaterials, including chemical treatment technologies, the impact of repetitive mechanical loading, and the inherent failure modes. This review seeks to provide a comprehensive overview of these issues, with a focus on developing insight on the mechanisms of BHV function and failure. Additionally, this review provides a detailed summary of the computational biomechanical simulations that have been used to inform and develop a higher level of understanding of BHV tissues and their failure modes. Collectively, this information should serve as a tool not only to infer reliable and dependable prosthesis function, but also to instigate and facilitate the design of future bioprosthetic valves and clinically impact cardiology. PMID- 27507282 TI - Multimodal US-gamma imaging using collaborative robotics for cancer staging biopsies. AB - PURPOSE: The staging of female breast cancer requires detailed information about the level of cancer spread through the lymphatic system. Common practice to obtain this information for patients with early-stage cancer is sentinel lymph node (SLN) biopsy, where LNs are radioactively identified for surgical removal and subsequent histological analysis. Punch needle biopsy is a less invasive approach but suffers from the lack of combined anatomical and nuclear information. We present and evaluate a system that introduces live collaborative robotic 2D gamma imaging in addition to live 2D ultrasound to identify SLNs in the surrounding anatomy. METHODS: The system consists of a robotic arm equipped with both a gamma camera and a stereoscopic tracking system that monitors the position of an ultrasound probe operated by the physician. The arm cooperatively places the gamma camera parallel to the ultrasound imaging plane to provide live multimodal visualization and guidance. We validate the system by evaluating the target registration errors between fused nuclear and US image data in a phantom consisting of two spheres, one of which is filled with radioactivity. Medical experts perform punch biopsies on agar-gelatine phantoms with complex configurations of hot and cold lesions to provide a qualitative and quantitative evaluation of the system. RESULTS: The average point registration error for the overlay is [Formula: see text] mm. The time of the entire procedure was reduced by 36 %, with 80v of the biopsies being successful. The users' feedback was very positive, and the system was deemed to be very intuitive, with handling similar to classic US-guided needle biopsy. CONCLUSION: We present and evaluate the first medical collaborative robotic imaging system. Feedback from potential users for SLN punch needle biopsy is encouraging. Ongoing work investigates the clinical feasibility with more complex and realistic phantoms. PMID- 27507285 TI - Reducing the width of confidence intervals for the difference between two population means by inverting adaptive tests. AB - In the last decade, it has been shown that an adaptive testing method could be used, along with the Robbins-Monro search procedure, to obtain confidence intervals that are often narrower than traditional confidence intervals. However, these confidence interval limits require a great deal of computation and some familiarity with stochastic search methods. We propose a method for estimating the limits of confidence intervals that uses only a few tests of significance. We compare these limits to those obtained by a lengthy Robbins-Monro stochastic search and find that the proposed method is nearly as accurate as the Robbins Monro search. Adaptive confidence intervals that are produced by the proposed method are often narrower than traditional confidence intervals when the distributions are long-tailed, skewed, or bimodal. Moreover, the proposed method of estimating confidence interval limits is easy to understand, because it is based solely on the p-values from a few tests of significance. PMID- 27507283 TI - Ordered chromatin changes and human X chromosome reactivation by cell fusion mediated pluripotent reprogramming. AB - Erasure of epigenetic memory is required to convert somatic cells towards pluripotency. Reactivation of the inactive X chromosome (Xi) has been used to model epigenetic reprogramming in mouse, but human studies are hampered by Xi epigenetic instability and difficulties in tracking partially reprogrammed iPSCs. Here we use cell fusion to examine the earliest events in the reprogramming induced Xi reactivation of human female fibroblasts. We show that a rapid and widespread loss of Xi-associated H3K27me3 and XIST occurs in fused cells and precedes the bi-allelic expression of selected Xi-genes by many heterokaryons (30 50%). After cell division, RNA-FISH and RNA-seq analyses confirm that Xi reactivation remains partial and that induction of human pluripotency-specific XACT transcripts is rare (1%). These data effectively separate pre- and post mitotic events in reprogramming-induced Xi reactivation and reveal a complex hierarchy of epigenetic changes that are required to reactivate the genes on the human Xi chromosome. PMID- 27507284 TI - Sexual orientation identity disparities in human papillomavirus vaccination initiation and completion among young adult US women and men. AB - PURPOSE: To examine the association between sexual orientation identity and human papillomavirus (HPV) vaccination initiation and completion among both women and men. METHODS: Using data from the 2013 and 2014 National Health Interview Survey, we estimated logistic regression models for the association between sexual orientation identity and HPV vaccination initiation (>=1 dose) and completion (>=3 doses) among US women and men in relation to sociodemographic and healthcare factors. Analyses were restricted to individuals for whom the HPV vaccine was recommended at some point in their lives, namely women aged 18-34 years (n = 9,734) and men aged 18-31 years (n = 6,812). RESULTS: Among all women, bisexual women had higher adjusted odds of HPV vaccination initiation [(odds ratio) 1.71; (95 % confidence interval) 1.20-2.45] and completion (1.59; 1.05-2.42) than heterosexual women. No difference was observed in the odds of HPV vaccination initiation or completion between lesbian and heterosexual women. Among women who had initiated HPV vaccination, lesbians had lower adjusted odds of completion than heterosexual women (0.41; 0.19-0.90). Among all men, gay men had higher adjusted odds of initiating (2.07; 1.17-3.52) and completing (3.90; 1.68-9.06) HPV vaccination than heterosexual men. No difference was observed in the odds of HPV vaccination initiation or completion between bisexual and heterosexual men. Among men who had initiated HPV vaccination, gay (4.36; 1.28-14.83) and bisexual (20.92; 2.34-186.73) men had higher adjusted odds of completion than heterosexual men, although these results are unreliable and should be interpreted with caution. CONCLUSIONS: Interventions are needed to promote HPV vaccination among all US women and men, regardless of sexual orientation identity. PMID- 27507286 TI - Sample size and classification error for Bayesian change-point models with unlabelled sub-groups and incomplete follow-up. AB - Many medical (and ecological) processes involve the change of shape, whereby one trajectory changes into another trajectory at a specific time point. There has been little investigation into the study design needed to investigate these models. We consider the class of fixed effect change-point models with an underlying shape comprised two joined linear segments, also known as broken-stick models. We extend this model to include two sub-groups with different trajectories at the change-point, a change and no change class, and also include a missingness model to account for individuals with incomplete follow-up. Through a simulation study, we consider the relationship of sample size to the estimates of the underlying shape, the existence of a change-point, and the classification error of sub-group labels. We use a Bayesian framework to account for the missing labels, and the analysis of each simulation is performed using standard Markov chain Monte Carlo techniques. Our simulation study is inspired by cognitive decline as measured by the Mini-Mental State Examination, where our extended model is appropriate due to the commonly observed mixture of individuals within studies who do or do not exhibit accelerated decline. We find that even for studies of modest size ( n = 500, with 50 individuals observed past the change point) in the fixed effect setting, a change-point can be detected and reliably estimated across a range of observation-errors. PMID- 27507287 TI - Calibration of medical diagnostic classifier scores to the probability of disease. AB - Scores produced by statistical classifiers in many clinical decision support systems and other medical diagnostic devices are generally on an arbitrary scale, so the clinical meaning of these scores is unclear. Calibration of classifier scores to a meaningful scale such as the probability of disease is potentially useful when such scores are used by a physician. In this work, we investigated three methods (parametric, semi-parametric, and non-parametric) for calibrating classifier scores to the probability of disease scale and developed uncertainty estimation techniques for these methods. We showed that classifier scores on arbitrary scales can be calibrated to the probability of disease scale without affecting their discrimination performance. With a finite dataset to train the calibration function, it is important to accompany the probability estimate with its confidence interval. Our simulations indicate that, when a dataset used for finding the transformation for calibration is also used for estimating the performance of calibration, the resubstitution bias exists for a performance metric involving the truth states in evaluating the calibration performance. However, the bias is small for the parametric and semi-parametric methods when the sample size is moderate to large (>100 per class). PMID- 27507288 TI - A multi-locus genetic association test for a dichotomous trait and its secondary phenotype. AB - Genetic association studies often collect information on secondary phenotypes related to the primary disease status. In many situations, the secondary phenotypes are only measured in subjects with the disease condition. It would be advantageous to model the primary trait and the secondary phenotype together if they share certain level of genetic heritability. We propose a family of multi locus testing procedures to detect the composite association between a set of genetic markers and two traits (the primary trait and a secondary phenotype), in order to identify genes influencing both traits. The proposed test is derived from a random effect model with two variance components, with each presenting the genetic effect on one trait, and incorporates a model selection procedure for seeking the optimal model to represent the two sources of genetic effects. We conduct simulation studies to evaluate performance of the proposed procedure and apply the method to a genome-wide association study of prostate cancer with the Gleason score as the secondary phenotype. PMID- 27507289 TI - A new parsimonious model for ordinal longitudinal data with application to subjective evaluations of a gastrointestinal disease. AB - In this paper, a new discrete statistical model for ordered categorical data is proposed via fixed-point discretization of a beta latent variable. The resulting discretized beta distribution has a highly flexible shape and it can be either over-dispersed or under-dispersed with respect to the binomial distribution. It has only two parameters, which may therefore parsimoniously depend on covariates and on random effects, providing new tools for the analysis of structured, clustered or longitudinal ordinal data. Practical examples and advices are given and an application of the new model to subjective evaluations of a gastrointestinal disease is shown. PMID- 27507290 TI - Efficient Monte Carlo evaluation of resampling-based hypothesis tests with applications to genetic epidemiology. AB - Monte Carlo evaluation of resampling-based tests is often conducted in statistical analysis. However, this procedure is generally computationally intensive. The pooling resampling-based method has been developed to reduce the computational burden but the validity of the method has not been studied before. In this article, we first investigate the asymptotic properties of the pooling resampling-based method and then propose a novel Monte Carlo evaluation procedure namely the n-times pooling resampling-based method. Theorems as well as simulations show that the proposed method can give smaller or comparable root mean squared errors and bias with much less computing time, thus can be strongly recommended especially for evaluating highly computationally intensive hypothesis testing procedures in genetic epidemiology. PMID- 27507291 TI - Successful completion of a semi-automated enzyme-free cloning method. AB - Nowadays, in scientific fields such as Structural Biology or Vaccinology, there is an increasing need of fast, effective and reproducible gene cloning and expression processes. Consequently, the implementation of robotic platforms enabling the automation of protocols is becoming a pressing demand. The main goal of our study was to set up a robotic platform devoted to the high-throughput automation of the polymerase incomplete primer extension cloning method, and to evaluate its efficiency compared to that achieved manually, by selecting a set of bacterial genes that were processed either in the automated platform (330) or manually (94). Here we show that we successfully set up a platform able to complete, with high efficiency, a wide range of molecular biology and biochemical steps. 329 gene targets (99 %) were effectively amplified using the automated procedure and 286 (87 %) of these PCR products were successfully cloned in expression vectors, with cloning success rates being higher for the automated protocols respect to the manual procedure (93.6 and 74.5 %, respectively). PMID- 27507293 TI - Materials in the vitreous during standard cataract surgery: concept not verified yet. PMID- 27507292 TI - The economic burden of urinary tract infections in women visiting general practices in France: a cross-sectional survey. AB - BACKGROUND: Urinary tract infections (UTIs) are among the most common bacterial infections. Despite this burden, there are few studies of the costs of UTIs. The objective of this study was to determine the costs of UTIs in women over 18 years of age who visit general practitioners in France. METHODS: The direct and indirect costs of clinical UTIs were estimated from societal, French National Health Insurance and patient perspectives. The study population was derived from a national cross-sectional survey entitled the Drug-Resistant Urinary Tract Infection (Druti). The Druti included every woman over 18 years of age who presented with symptoms of UTI and was conducted in France in 2012 and 2013 to estimate the annual incidence of UTIs due to antibiotic-resistant Enterobacteriaceae in women visiting general practitioners (GPs) for suspected UTIs. RESULTS: Of the 538 women included in Druti, 460 were followed over 8 weeks and included in the cost analysis. The mean age of the women was 46 years old. The median cost of care for one episode of a suspected UTI was ?38, and the mean cost was ?70. The annual societal cost was ?58 million, and ?29 million of this was reimbursed by the French National Health Insurance system. In 25 % of the cases, the suspected UTIs were associated with negative urine cultures. The societal cost of these suspected UTIs with negative urine cultures was ?13.5 million. No significant difference was found between the costs of the UTIs due to antibiotic-resistant E. coli and those due to wild E. coli (p = 0.63). CONCLUSION: In the current context in which the care costs are continually increasing, the results of this study suggests that it is possible to decrease the cost of UTIs by reducing the costs of suspected UTIs and unnecessary treatments, as well as limiting the use of non-recommended tests. PMID- 27507295 TI - Reusable sanitary towels: promoting menstrual hygiene in post-earthquake Nepal. AB - It is a normal human tendency to 'run for your life' when an earthquake occurs. Adolescent girls and women of reproductive age leave their homes with only the clothes they are wearing to save their own and their families' lives. Immediate disaster relief aid with its (unintentional) lack of gender sensitivity has little or no materials for the appropriate management of menstrual hygiene. The biological needs of disaster-affected women will not change despite the dire need for basic food, shelter and security. Timely identification and preparation beforehand with appropriate and culturally sensitive techniques and locally available materials that are reusable can help introduce sustainable and acceptable means of managing menstrual hygiene in a crisis. The use of reusable sanitary towels is well accepted for menstrual hygiene management in non-disaster situations and is appropriate in post-earthquake relief in Nepal. PMID- 27507296 TI - Brain atlas of the Mongolian gerbil (Meriones unguiculatus) in CT/MRI-aided stereotaxic coordinates. AB - A new stereotaxic brain atlas of the Mongolian gerbil (Meriones unguiculatus), an important animal model in neurosciences, is presented. It combines high-quality histological material for identification of brain structures with reliable stereotaxic coordinates. The atlas consists of high-resolution images of frontal sections alternately stained for cell bodies (Nissl) and myelinated fibers (Gallyas) of 62 rostro-caudal levels at intervals of 350 MUm. Brain structures were named according to the Paxinos nomenclature for rodents. The accuracy of the stereotaxic coordinate system was improved substantially by comparing and matching the series of histological sections to in vivo brain images of the gerbil obtained by magnetic resonance imaging (MRI). The skull outlines corresponding to the MR images were acquired using X-ray computerized tomography (CT) and were used to establish the relationship between coordinates of brain structures and skull. Landmarks such as lambda, bregma, ear canals and occipital crest can be used to line up skull and brain in standard atlas coordinates. An easily reproducible protocol allows sectioning of experimental brains in the standard frontal plane of the atlas. PMID- 27507297 TI - Investigation of avian haemosporidian parasites from raptor birds in Turkey, with molecular characterisation and microscopic confirmation. AB - Avian haemosporidians are common vector-borne blood parasites that have been reported in birds all over the world. Investigations of avian haemosporidian parasites are conducted mainly on passerine birds. However, studies that focus on non-passerine avian hosts are important for our understanding of the true diversity, host specificity and genetic variability among these widespread parasites. In the present study, blood samples from a total of 22 raptor birds belonging to two orders, two families and six species from the Central Anatolia Region of Turkey were investigated for three genera of avian haemosporidians (Plasmodium Marchiafava et Celli, 1885, Haemoproteus Kruse, 1890 and Leucocytozoon Sambon, 1908) using a combination of microscopic examination of blood films and nested PCR targeting the parasite mitochondrial cytochrome b gene (cyt-b). In total, six individual raptor birds identified positive for species of Plasmodium or Leucocytozoon and one individual was found co-infected with all three haemosporidian genera. We identified five parasite cyt-b haplotypes, three of which were reported for the first time. Among these, one Plasmodium haplotype is linked to a corresponding morphospecies (P-TURDUS1, Plasmodium circumflexum Kikuth, 1931). All haplotypes were clearly distinguishable in phylogenetic analyses. As one of the first studies to investigate blood parasites from non passerine birds in the Central Anatolia Region of Turkey, this study provides important new information on the phylogenetic relationships and genetic diversity of avian haemosporidian parasites from raptor birds. We discuss these findings in the context of avian haemosporidian host-parasite relationships and we draw attention to the need for microscopy to detect parasite sexual development stages in surveys of avian haemosporidians. PMID- 27507298 TI - Estimation of the need for bilateral intravitreal anti-VEGF injections in clinical practice. AB - BACKGROUND: To estimate the need for bilateral intravitreal anti-VEGF injections in patients treated for neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), retinal vein occlusion, choroidal neovascularization (CNV) in high myopia, and other causes of CNV. METHODS: All consecutive patients treated with intravitreal anti-VEGF injection over a 1-month period were included in a prospective multicenter survey. The reason for intravitreal anti-VEGF injection and the involvement of the fellow eye in the pathology requiring a treatment with intravitreal anti-VEGF were recorded. A time interval between bilateral injections longer than 1 month, within a 1-month period, and same-day bilateral injections were recorded. RESULTS: A total of 1335 patients were included, corresponding to 1024 (76.7 %) patients treated for nAMD, 167 (12.5 %) for DME, and 144 (10.8 %) for other reasons. Four hundred and fifty nine (34.4 %) patients were treated bilaterally with a time interval between injections longer than 1 month, 170 (12.7 %) were treated bilaterally within a 1 month interval, and 87 (6.6 %) had same-day bilateral injections. Bilateral injections were more frequent in diabetic patients than in nAMD patients (respectively 48 % vs. 36 %, p = 0.0033). CONCLUSIONS: Patients with DME are more likely to be treated bilaterally with anti-VEGF injections. As the rate of second eye involvement requiring treatment increases progressively over time, a same-day bilateral injection strategy will become more common as it decreases the administrative burden on the healthcare system and treatment burden experienced by patients. PMID- 27507299 TI - Impact of chemotherapy on the outcome of osteosarcoma of the head and neck in adults. AB - BACKGROUND: There is an ongoing debate about the value of (neo-)adjuvant chemotherapy in high- and intermediate-grade osteosarcoma of the head and neck. METHODS: All records of patients older than 16 years diagnosed with osteosarcoma of the head and neck in the Netherlands between 1993 and 2013 were reviewed. RESULTS: We identified a total of 77 patients with an osteosarcoma of the head and neck; the 5-year overall survival (OS) was 55%. In 50 patients with surgically resected high- or intermediate-grade osteosarcoma of the head and neck younger than 75 years, univariate and multivariable analysis, adjusting for age and resection margins, showed that patients who had not received chemotherapy had a significantly higher risk of local recurrence (hazard ratio [HR] = 3.78 and 3.66, respectively). CONCLUSION: In patients younger than 75 years of age with surgically resected high- and intermediate-grade osteosarcoma of the head and neck, treatment with (neo-)adjuvant chemotherapy resulted in a significantly smaller risk of local recurrence. Therefore, we suggest (neo-)adjuvant chemotherapy in patients amenable to chemotherapy. (c) 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 39: 140-146, 2017. PMID- 27507300 TI - An approach to measuring and encouraging research translation and research impact. AB - BACKGROUND: Research translation, particularly in the biomedical area, is often discussed but there are few methods that are routinely used to measure it or its impact. Of the impact measurement methods that are used, most aim to provide accountability - to measure and explain what was generated as a consequence of funding research. This case study reports on the development of a novel, conceptual framework that goes beyond measurement. The Framework To Assess the Impact from Translational health research, or FAIT, is a platform designed to prospectively measure and encourage research translation and research impact. A key assumption underpinning FAIT is that research translation is a prerequisite for research impact. METHODS: The research impact literature was mined to understand the range of existing frameworks and techniques employed to measure and encourage research translation and research impact. This review provided insights for the development of a FAIT prototype. A Steering Committee oversaw the project and provided the feedback that was used to refine FAIT. RESULTS: The outcome of the case study was the conceptual framework, FAIT, which is based on a modified program logic model and a hybrid of three proven methodologies for measuring research impact, namely a modified Payback method, social return on investment, and case studies or narratives of the process by which research translates and generates impact. CONCLUSION: As funders increasingly seek to understand the return on their research investments, the routine measurement of research translation and research impact is likely to become mandatory rather than optional. Measurement of research impact on its own is insufficient. There should also be a mechanism attached to measurement that encourages research translation and impact - FAIT was designed for this task. PMID- 27507301 TI - MicroRNA 101b Is Downregulated in the Prefrontal Cortex of a Genetic Model of Depression and Targets the Glutamate Transporter SLC1A1 (EAAT3) in Vitro. AB - BACKGROUND: MicroRNAs (miRNAs) are small regulatory molecules that cause translational repression by base pairing with target mRNAs. Cumulative evidence suggests that changes in miRNA expression may in part underlie the pathophysiology and treatment of neuropsychiatric disorders, including major depressive disorder (MDD). METHODS: A miRNA expression assay that can simultaneously detect 423 rat miRNAs (miRBase v.17) was used to profile the prefrontal cortex (PFC) of a genetic rat model of MDD (the Flinders Sensitive Line [FSL]) and the controls, the Flinders Resistant Line (FRL). Gene expression data from the PFC of FSL/FRL animals (GEO accession no. GSE20388) were used to guide mRNA target selection. Luciferase reporter assays were used to verify miRNA targets in vitro. RESULTS: We identified 23 miRNAs that were downregulated in the PFC of the FSL model compared with controls. Interestingly, one of the identified miRNAs (miR-101b) is highly conserved between rat and human and was recently found to be downregulated in the PFC of depressed suicide subjects. Using a combination of in silico and in vitro analyses, we found that miR-101b targets the neuronal glutamate transporter SLC1A1 (also known as EAAC1 or EAAT3). Accordingly, both mRNA and protein levels of SLC1A1 were found to be upregulated in the PFC of the FSL model. CONCLUSIONS: Besides providing a list of novel miRNAs associated with depression-like states, this preclinical study replicated the human association of miR-101 with depression. In addition, since one of the targets of miR-101b appears to be a glutamate transporter, our preclinical data support the hypothesis of a glutamatergic dysregulation being implicated in the etiology of depression. PMID- 27507302 TI - Clinical Interpretation of Genomic Variations. AB - Novel high-throughput sequencing technologies generate large-scale genomic data and are used extensively for disease mapping of monogenic and/or complex disorders, personalized treatment, and pharmacogenomics. Next-generation sequencing is rapidly becoming routine tool for diagnosis and molecular monitoring of patients to evaluate therapeutic efficiency. The next-generation sequencing platforms generate huge amounts of genetic variation data and it remains a challenge to interpret the variations that are identified. Such data interpretation needs close collaboration among bioinformaticians, clinicians, and geneticists. There are several problems that must be addressed, such as the generation of new algorithms for mapping and annotation, harmonization of the terminology, correct use of nomenclature, reference genomes for different populations, rare disease variant databases, and clinical reports. PMID- 27507303 TI - Benefits of interventions for respiratory secretion management in adult palliative care patients-a systematic review. AB - BACKGROUND: Respiratory secretions impact negatively on palliative patients. Unfortunately, a gold standard therapy is not yet available. The purpose of this study was to identify which interventions are in use to control respiratory secretions in patients with chronic disease with a poor prognosis and verify their effects on outcomes relevant for palliative care patients. METHODS: A systematic review of the literature with narrative summary was conducted. We searched eight electronic databases in April (6th), 2016. Citation-tracking and reference list searches were conducted. We included randomized controlled trials, crossover trials, observational and qualitative studies regarding interventions for respiratory secretion management in adult patients with chronic diseases that met inclusion criteria indicating short prognosis. RESULTS: Six randomized controlled trials, 11 observational studies, ten crossover trials and one qualitative study were found. Interventions included mechanical insufflation exsufflation (MIE), expiratory muscle training, manually-assisted cough, tracheotomy, chest physiotherapy, suctioning, air stacking, electrical stimulation of abdominal muscles, nebulized saline, positive expiratory pressure masks, percussive ventilation, high frequency chest wall oscillations. The interventions with most promising benefits to patients in palliative care were manually-assisted cough and mechanical insufflation-exsufflation to promote expectoration and percussive ventilation to improve mucous clearance. CONCLUSION: Therapies, such as manually assisted cough, mechanical insufflation-exsufflation and percussive ventilation, which aim to deal with respiratory secretion, were the most promising treatment for use in palliative care for specific diseases. Nevertheless, the evidence still needs to improve in order to identify which treatment is the best. PMID- 27507304 TI - Compression of the superior mesenteric vein-a sign of acute internal herniation in patients with antecolic laparoscopic Roux-en-Y gastric bypass. AB - OBJECTIVES: To investigate whether compression of the superior mesenteric vein (SMV) on computed tomography (CT) can serve as a valid sign of internal herniation (IH) in patients with antecolic laparoscopic Roux-en-Y gastric bypass (LRYGBP). MATERIALS AND METHODS: With institutional review board approval, we performed a retrospective analysis of 41 patients with antecolic LRYGBP referred for acute CT of the abdomen with suspicion of IH or another cause of acute abdomen. CT scans were randomly reviewed for signs of IH by two radiologists in a blinded manner, and the findings were correlated with the results of the patients' bariatric workup. Sensitivity, specificity, and inter-observer agreement were calculated for each sign. RESULTS: Five patients were classified as having intermittent IH and were excluded. Eighteen patients were found to have IH at laparoscopy and served as the study group; 18 patients served as the control group. SMV compression had the best sensitivity (67 % for both reviewers) and inter-observer agreement (kappa = 0.82) of all investigated signs. The swirl sign showed a lower sensitivity (39 and 50 % respectively) and kappa (0.37). CONCLUSION: SMV compression is a reliable sign of IH in patients with antecolic LRYGBP. KEY POINTS: * CT can help detect internal herniation after laparoscopic Roux-en-Y gastric bypass. * Compression of the superior mesenteric vein is a sign of internal herniation. * This sign has a high inter-observer-agreement. * A diagnosis of internal herniation can be made with greater confidence. PMID- 27507305 TI - Analysis of thulium fiber laser induced bubble dynamics for ablation of kidney stones. AB - The Thulium fiber laser (TFL) is being explored as an alternative to the Holmium : YAG laser for lithotripsy. TFL parameters differ in several fundamental ways from Holmium laser, including smaller fiber delivery, more strongly absorbed wavelength, low pulse energy/high pulse rate operation, and more uniform temporal pulse structure. High speed imaging of laser induced bubbles was performed at 105,000 frames per second and 10 MUm spatial resolution to determine influence of these laser parameters on bubble formation and needle hydrophone data was also used to measure pressure transients. The TFL was operated at 1908 nm with pulse energies of 5-65 mJ, and pulse durations of 200-1000 MUs, delivered through 105 MUm-core and 270-MUm-core silica optical fibers. Bubble dynamics using Holmium laser at a wavelength of 2100 nm with pulse energies of 200-1000 mJ and pulse duration of 350 MUs was studied, for comparison. A single, 500 MUs TFL pulse produced a bubble stream extending 1200 +/- 90 MUm and 1070 +/- 50 MUm from fiber tip, with maximum bubble widths averaging 650 +/- 20 MUm and 870 +/- 40 MUm (n = 4), for 105 MUm and 270 MUm fibers, respectively. These observations are consistent with previous studies which reported TFL ablation stallout at working distances beyond 1.0 mm. TFL bubble dimensions were four times smaller than for Holmium laser due to lower peak power and smaller fiber diameter used. The maximum pressure transients measured 0.6 bars at 35 mJ pulse energy for TFL and 7.5 bars at 600 mJ pulse energy for Holmium laser. These fundamental studies of bubble dynamics as a function of specific laser and fiber parameters may assist with optimization of the TFL parameters for safe and efficient lithotripsy in the clinic. Image of bubble formation during fiber optic delivery of Thulium fiber laser energy in saline (35 mJ, 500 MUs). PMID- 27507306 TI - Is it better to overtreat or undertreat? PMID- 27507307 TI - Do we end life well? PMID- 27507308 TI - Iron deficiency anemia: like mother, like child. PMID- 27507309 TI - Nonsteroidal anti-inflammatory drugs: risks outweigh benefits. PMID- 27507310 TI - A severity score in PGM-1 deficiency. PMID- 27507312 TI - Blunted response: smoke, illicit substances, and how babies breathe. PMID- 27507311 TI - Hypothermia at NICU admission in very preterm infants. PMID- 27507313 TI - 50 Years Ago in TheJournal ofPediatrics: Legislation and Advances in Medical Knowledge-Acceleration or Inhibition? PMID- 27507314 TI - 50 Years Ago in TheJournal ofPediatrics: Nutritional and Antigenic Effects of 2 Bovine Milk Preparations in Infants. PMID- 27507315 TI - 50 Years Ago in TheJournal ofPediatrics: The Sweat Test in Cystic Fibrosis: A Comparison of Overnight Sweat Collection versus the Pilocarpine Iontophoresis Method. PMID- 27507317 TI - Correction. PMID- 27507316 TI - 50 Years Ago in TheJournal ofPediatrics: An Outbreak of Coxsackie B-5 Virus Infection in a Newborn Nursery. PMID- 27507318 TI - Correction. PMID- 27507319 TI - Vaccine Hesitancy and Refusal. PMID- 27507320 TI - The SAGES telephone neuropsychological battery: correlation with in-person measures. AB - OBJECTIVE: Neuropsychological test batteries are administered in person to assess cognitive function in both clinical and research settings. However, in-person administration holds a number of logistical challenges that makes it difficult to use in large or remote populations or for multiple serial assessments over time. The purpose of this descriptive study was to determine whether a telephone administered neuropsychological test battery correlated well with in-person testing. METHODS: Fifty English-speaking patients without dementia, over 70 years old, and part of a cohort of patients in a prospective cohort study examining cognitive outcomes following elective surgery were enrolled in this study. Five well-validated neuropsychological tests were administered by telephone to each participant by a trained interviewer within 2-4 weeks of the most recent in person interview. Tests included the Hopkins Verbal Learning Test-Revised, Digit Span, Category Fluency, Phonemic Fluency, and Boston Naming Test. A General Cognitive Performance composite score was calculated from individual subtest scores as a Z-score. RESULTS: Mean age was 74.9 years (SD = 4.1), 66% female, and 4% non-White. Mean and interquartile distributions of telephone scores were similar to in-person scores. Correlation analysis of test scores revealed significant correlations between telephone and in-person results for each individual subtest, as well as for the overall composite score. A Bland-Altman plot revealed no bias or trends in scoring for either test administration type. CONCLUSIONS: In this descriptive study, the telephone version of a neuropsychological test battery correlated well with the in-person version and may provide a feasible supplement in clinical and research applications. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27507321 TI - Global synthesis suggests that food web connectance correlates to invasion resistance. AB - Biological invasions are a key component of global change, and understanding the drivers of global invasion patterns will aid in assessing and mitigating the impact of invasive species. While invasive species are most often studied in the context of one or two trophic levels, in reality species invade communities comprised of complex food webs. The complexity and integrity of the native food web may be a more important determinant of invasion success than the strength of interactions between a small subset of species within a larger food web. Previous efforts to understand the relationship between food web properties and species invasions have been primarily theoretical and have yielded mixed results. Here, we present a synthesis of empirical information on food web connectance and species invasion success gathered from different sources (estimates of food web connectance from the primary literature and estimates of invasion success from the Global Invasive Species Database as well as the primary literature). Our results suggest that higher-connectance food webs tend to host fewer invaders and exert stronger biotic resistance compared to low-connectance webs. We argue that while these correlations cannot be used to infer a causal link between food web connectance and habitat invasibility, the promising findings beg for further empirical research that deliberately tests for relationships between food web connectance and invasion. PMID- 27507322 TI - A fully automated microfluidic micellar electrokinetic chromatography analyzer for organic compound detection. AB - An integrated microfluidic chemical analyzer utilizing micellar electrokinetic chromatography (MEKC) is developed using a pneumatically actuated Lifting-Gate microvalve array and a capillary zone electrophoresis (CZE) chip. Each of the necessary liquid handling processes such as metering, mixing, transferring, and washing steps are performed autonomously by the microvalve array. In addition, a method is presented for automated washing of the high resistance CZE channel for device reuse and periodic automated in situ analyses. To demonstrate the functionality of this MEKC platform, amino acids and thiols are labeled and efficiently separated via a fully automated program. Reproducibility of the automated programs for sample labeling and periodic in situ MEKC analysis was tested and found to be equivalent to conventional sample processing techniques for capillary electrophoresis analysis. This platform enables simple, portable, and automated chemical compound analysis which can be used in challenging environments. PMID- 27507323 TI - Immunological characterization of de novo and recall alloantibody suppression by CTLA4Ig in a mouse model of allosensitization. AB - It is well known that CTLA4Ig inhibits allogenic T-cell activation in transplantation. The immunological features and mechanisms associated with alloantibody suppression by CTLA4Ig, however, are poorly understood. Here, we used a mouse model of allosensitization to evaluate the efficacy of CTLA4Ig (abatacept) in suppression of donor-specific antibody (DSA) during de novo and recall alloantibody responses. We found that abatacept inhibited de novo DSA IgM and IgG responses to HLA-A2 expressing skin grafts. Abatacept administered during primary T cell priming also reduced recall IgG responses induced by re immunization. Suppression of de novo DSA responses by abatacept is associated with a reduction in splenic expression of the germinal center activation marker GL7 and a reduction of CD4(+)PD1(+)CXCR5(+) follicular T helper (Tfh) subset in splenic lymphocytes detected by flow cytometry. The efficacy of abatacept on recall DSA suppression is moderate. In vitro experiments demonstrated that abatacept inhibited DSA IgG secretion by CD138(+) plasma cells isolated from allograft recipients. Additional experiments using an IgG1 secreting mouse hybridoma cell line showed that abatacept binds to CD80 expressed on these cells with subsequent inhibition of cell proliferation and reduction in IgG ELISpot formation. In conclusion, CTLA4Ig is a potent suppressor of de novo DSA responses and also affects recall responses. The data suggests modification of recall DSA responses is due to a direct suppressive effect on plasma cells. PMID- 27507324 TI - Ensemble based adaptive over-sampling method for imbalanced data learning in computer aided detection of microaneurysm. AB - Diabetic retinopathy (DR) is a progressive disease, and its detection at an early stage is crucial for saving a patient's vision. An automated screening system for DR can help in reduce the chances of complete blindness due to DR along with lowering the work load on ophthalmologists. Among the earliest signs of DR are microaneurysms (MAs). However, current schemes for MA detection appear to report many false positives because detection algorithms have high sensitivity. Inevitably some non-MAs structures are labeled as MAs in the initial MAs identification step. This is a typical "class imbalance problem". Class imbalanced data has detrimental effects on the performance of conventional classifiers. In this work, we propose an ensemble based adaptive over-sampling algorithm for overcoming the class imbalance problem in the false positive reduction, and we use Boosting, Bagging, Random subspace as the ensemble framework to improve microaneurysm detection. The ensemble based over-sampling methods we proposed combine the strength of adaptive over-sampling and ensemble. The objective of the amalgamation of ensemble and adaptive over-sampling is to reduce the induction biases introduced from imbalanced data and to enhance the generalization classification performance of extreme learning machines (ELM). Experimental results show that our ASOBoost method has higher area under the ROC curve (AUC) and G-mean values than many existing class imbalance learning methods. PMID- 27507325 TI - Incorporation of gradient vector flow field in a multimodal graph-theoretic approach for segmenting the internal limiting membrane from glaucomatous optic nerve head-centered SD-OCT volumes. AB - The internal limiting membrane (ILM) separates the retina and optic nerve head (ONH) from the vitreous. In the optical coherence tomography volumes of glaucoma patients, while current approaches for the segmentation of the ILM in the peripapillary and macular regions are considered robust, current approaches commonly produce ILM segmentation errors at the ONH due to the presence of blood vessels and/or characteristic glaucomatous deep cupping. Because a precise segmentation of the ILM surface at the ONH is required for computing several newer structural measurements including Bruch's membrane opening-minimum rim width (BMO-MRW) and cup volume, in this study, we propose a multimodal multiresolution graph-based method to precisely segment the ILM surface within ONH-centered spectral-domain optical coherence tomography (SD-OCT) volumes. In particular, the gradient vector flow (GVF) field, which is computed from a multiresolution initial segmentation, is employed for calculating a set of non overlapping GVF-based columns perpendicular to the initial segmentation. The GVF columns are utilized to resample the volume and also serve as the columns to the graph construction. The ILM surface in the resampled volume is fairly smooth and does not contain the steep slopes. This prior shape knowledge along with the blood vessel information, obtained from registered fundus photographs, are incorporated in a graph-theoretic approach in order to identify the location of the ILM surface. The proposed method is tested on the SD-OCT volumes of 44 subjects with various stages of glaucoma and significantly smaller segmentation errors were obtained than that of current approaches. PMID- 27507326 TI - Volumetric image classification using homogeneous decomposition and dictionary learning: A study using retinal optical coherence tomography for detecting age related macular degeneration. AB - Three-dimensional (3D) (volumetric) diagnostic imaging techniques are indispensable with respect to the diagnosis and management of many medical conditions. However there is a lack of automated diagnosis techniques to facilitate such 3D image analysis (although some support tools do exist). This paper proposes a novel framework for volumetric medical image classification founded on homogeneous decomposition and dictionary learning. In the proposed framework each image (volume) is recursively decomposed until homogeneous regions are arrived at. Each region is represented using a Histogram of Oriented Gradients (HOG) which is transformed into a set of feature vectors. The Gaussian Mixture Model (GMM) is then used to generate a "dictionary" and the Improved Fisher Kernel (IFK) approach is used to encode feature vectors so as to generate a single feature vector for each volume, which can then be fed into a classifier generator. The principal advantage offered by the framework is that it does not require the detection (segmentation) of specific objects within the input data. The nature of the framework is fully described. A wide range of experiments was conducted with which to analyse the operation of the proposed framework and these are also reported fully in the paper. Although the proposed approach is generally applicable to 3D volumetric images, the focus for the work is 3D retinal Optical Coherence Tomography (OCT) images in the context of the diagnosis of Age-related Macular Degeneration (AMD). The results indicate that excellent diagnostic predictions can be produced using the proposed framework. PMID- 27507327 TI - Salvianolic acid B protects against paraquat-induced pulmonary injury by mediating Nrf2/Nox4 redox balance and TGF-beta1/Smad3 signaling. AB - The present study was aimed at exploring the protective effects of Salvianolic acid B (SalB) against paraquat (PQ)-induced lung injury in mice. Lung fibrotic injuries were induced in mice by a single intragastrical administration of 300mg/kg PQ, then the mice were administrated with 200mg/kg, 400mg/kg SalB, 100mg/kg vitamin C (Vit C) and dexamethasone (DXM) for 14days. PQ-triggered structure distortion, collagen overproduction, excessive inflammatory infiltration, pro-inflammatory cytokine release, and oxidative stress damages in lung tissues and mortality of mice were attenuated by SalB in a dose-dependent manner. Furthermore, SalB was noted to enhance the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and reduce expression of the reactive oxygen species-generating enzyme Nox4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-4]. SalB also inhibited the increasing expression of transforming growth factor (TGF)-beta1 and the phosphorylation of its downstream target Smad3 which were enhanced by PQ. These results suggest that SalB may exert protective effects against PQ-induced lung injury and pulmonary fibrosis. Its mechanisms involve the mediation of Nrf2/Nox4 redox balance and TGF-beta1/Smad3 signaling. PMID- 27507329 TI - Restriction Endonuclease Analysis Typing of Clostridium difficile Isolates. AB - Restriction endonuclease analysis (REA) typing using HindIII enzyme is a highly discriminatory, reproducible, and consistent method of genetic typing of Clostridium difficile (CD) isolates. REA typing analyzes CD whole cellular DNA on two levels of discrimination: REA Group designation and REA Type designation, which distinguishes specific subtypes within the REA Group. This methodology has enabled the tracking of epidemiologically significant CD strains over time and in some cases has allowed documentation of the evolution of previously rare REA Group strains that have subsequently become epidemic. The chapter details the methods used to isolate and purify CD colonies from stool samples, to obtain intact, full-length whole cellular DNA from CD isolates by use of guanidine-EDTA solution, and to analyze the HindIII-digested DNA after electrophoretic separation on agarose gels. PMID- 27507328 TI - Environmental variables and definitive host distribution: a habitat suitability modelling for endohelminth parasites in the marine realm. AB - Marine nematodes of the genus Anisakis are common parasites of a wide range of aquatic organisms. Public interest is primarily based on their importance as zoonotic agents of the human Anisakiasis, a severe infection of the gastro intestinal tract as result of consuming live larvae in insufficiently cooked fish dishes. The diverse nature of external impacts unequally influencing larval and adult stages of marine endohelminth parasites requires the consideration of both abiotic and biotic factors. Whereas abiotic factors are generally more relevant for early life stages and might also be linked to intermediate hosts, definitive hosts are indispensable for a parasite's reproduction. In order to better understand the uneven occurrence of parasites in fish species, we here use the maximum entropy approach (Maxent) to model the habitat suitability for nine Anisakis species accounting for abiotic parameters as well as biotic data (definitive hosts). The modelled habitat suitability reflects the observed distribution quite well for all Anisakis species, however, in some cases, habitat suitability exceeded the known geographical distribution, suggesting a wider distribution than presently recorded. We suggest that integrative modelling combining abiotic and biotic parameters is a valid approach for habitat suitability assessments of Anisakis, and potentially other marine parasite species. PMID- 27507330 TI - Direct PCR-Ribotyping of Clostridium difficile. AB - PCR-ribotyping, a method based on heterogeneity of ribosomal intergenic spacer region, is the preferred method for genotyping of Clostridium difficile. Standardly used procedure for PCR-ribotyping is culturing of C. difficile from fecal samples and subsequent typing. In this chapter, we describe a modified PCR ribotyping method for direct detection of PCR-ribotypes directly in total stool DNA extract, without prior need to isolate C. difficile. PMID- 27507331 TI - From FASTQ to Function: In Silico Methods for Processing Next-Generation Sequencing Data. AB - This chapter presents a method to process C. difficile whole-genome next generation sequencing data straight from the sequencer. Quality control processing and de novo assembly of these data enable downstream analyses such as gene annotation and in silico multi-locus strain-type identification. PMID- 27507332 TI - Clostridium difficile Genome Editing Using pyrE Alleles. AB - Precise manipulation (in-frame deletions and substitutions) of the Clostridium difficile genome is possible through a two-stage process of single-crossover integration and subsequent isolation of double-crossover excision events using replication-defective plasmids that carry a counterselection marker. Use of a codA (cytosine deaminase) or pyrE (orotate phosphoribosyltransferase) as counter selection markers appears equally effective, but there is considerable merit in using a pyrE mutant as the host as, through the use of allele-coupled exchange (ACE) vectors, mutants created (by whatever means) can be rapidly complemented concomitant with restoration of the pyrE allele. This avoids the phenotypic effects frequently observed with high-copy-number plasmids and dispenses with the need to add antibiotic to ensure plasmid retention. PMID- 27507333 TI - Use of mCherryOpt Fluorescent Protein in Clostridium difficile. AB - Here we describe protocols for using the red fluorescent protein mCherryOpt in Clostridium difficile. The protocols can be readily adapted to similar fluorescent proteins (FPs), such as green fluorescent protein (GFP) and cyan fluorescent protein (CFP). There are three critical considerations for using FPs in C. difficile. (1) Choosing the right color: Blue and (especially) red are preferred because C. difficile exhibits considerable yellow-green autofluorescence. (2) Codon optimization: Most FP genes in general circulation have a GC content of ~60 %, so they are not well expressed in low-GC bacteria. (3) Fixing anaerobically grown cells prior to exposure to O2: The FPs under consideration here are non-fluorescent when produced anaerobically because O2 is required to introduce double bonds into the chromophore. Fixation prevents C. difficile cells from becoming degraded during the several hours required for chromophore maturation after cells are exposed to air. Fixation can probably be omitted for studies in which maintaining cellular architecture is not important, such as using mCherryOpt to monitor gene expression. PMID- 27507334 TI - A Fluorescent Reporter for Single Cell Analysis of Gene Expression in Clostridium difficile. AB - Genetically identical cells growing under homogeneous growth conditions often display cell-cell variation in gene expression. This variation stems from noise in gene expression and can be adaptive allowing for division of labor and bet hedging strategies. In particular, for bacterial pathogens, the expression of phenotypes related to virulence can show cell-cell variation. Therefore, understanding virulence-related gene expression requires knowledge of gene expression patterns at the single cell level. We describe protocols for the use of fluorescence reporters for single cell analysis of gene expression in the human enteric pathogen Clostridium difficile, a strict anaerobe. The reporters are based on modified versions of the human DNA repair enzyme O ( 6)-alkylguanine DNA alkyltransferase, called SNAP-tag and CLIP-tag. SNAP becomes covalently labeled upon reaction with O ( 6)-benzylguanine conjugated to a fluorophore, whereas CLIP is labeled by O ( 6)-benzylcytosine conjugates. SNAP and CLIP labeling is orthogonal allowing for dual labeling in the same cells. SNAP and CLIP cassettes optimized for C. difficile can be used for quantitative studies of gene expression at the single cell level. Both the SNAP and CLIP reporters can also be used for studies of protein subcellular localization in C. difficile. PMID- 27507335 TI - Clostridium difficile Adhesins. AB - Clostridium difficile is responsible for a large spectrum of intestinal diseases ranging from mild diarrhea to fatal colitis depending on the one hand on the strain virulence and on the other on the host. The pathogenesis of C. difficile infection could be seen as a three-step process that takes place after disruption of the digestive microbiota by antibiotics: (1) contamination by and germination of spores; (2) multiplication of vegetative cells in the colonic niche using colonization factors; (3) production of the two toxins TcdA and TcdB and for some strains an additional toxin, the binary toxin CDT. Several studies have been performed to characterize the bacterial factors involved in the colonization step and particularly adhesins.Here, we describe first the methods used to study C. difficile adherence in vitro to epithelial cells and in vivo in animal model intestinal tract, and second the methods used to demonstrate the adhesive properties of surface proteins using Cwp66, GroEL, and FbpA as examples. PMID- 27507336 TI - Intestinal Epithelial Cell Response to Clostridium difficile Flagella. AB - Clostridium difficile is the bacterium responsible for most antibiotic-associated diarrhea in North America and Europe. This bacterium, which colonizes the gut of humans and animals, produces toxins that are known to contribute directly to damage of the gut. It is known that bacterial flagella are involved in intestinal lesions through the inflammatory host response. The C. difficile flagellin recognizes TLR5 and consequently activates the NF-kappaB and the MAPK signaling pathways which elicit the synthesis of pro-inflammatory cytokines. Increasing interest on the role of C. difficile flagella in eliciting this cell response was recently developed and the development of tools to study cell response triggered by C. difficile flagella will improve our understanding of the pathogenesis of C. difficile. PMID- 27507337 TI - Isolating and Purifying Clostridium difficile Spores. AB - The ability for the obligate anaerobe, Clostridium difficile to form a metabolically dormant spore is critical for the survival of this organism outside of the host. This spore form is resistant to a myriad of environmental stresses, including heat, desiccation, and exposure to disinfectants and antimicrobials. These intrinsic properties of spores allow C. difficile to survive long-term in an oxygenated environment, to be easily transmitted from host-to-host, and to persist within the host following antibiotic treatment. Because of the importance of the spore form to the C. difficile life cycle and treatment and prevention of C. difficile infection (CDI), the isolation and purification of spores are necessary to study the mechanisms of sporulation and germination, investigate spore properties and resistances, and for use in animal models of CDI. Here we provide basic protocols, in vitro growth conditions, and additional considerations for purifying C. difficile spores for a variety of downstream applications. PMID- 27507338 TI - Inducing and Quantifying Clostridium difficile Spore Formation. AB - The Gram-positive nosocomial pathogen Clostridium difficile induces sporulation during growth in the gastrointestinal tract. Sporulation is necessary for this obligate anaerobe to form metabolically dormant spores that can resist antibiotic treatment, survive exit from the mammalian host, and transmit C. difficile infections. In this chapter, we describe a method for inducing C. difficile sporulation in vitro. This method can be used to study sporulation and maximize spore purification yields for a number of C. difficile strain backgrounds. We also describe procedures for visualizing spore formation using phase-contrast microscopy and for quantifying the efficiency of sporulation using heat resistance as a measure of functional spore formation. PMID- 27507339 TI - Characterization of Functional Prophages in Clostridium difficile. AB - Bacteriophages (phages) are present in almost, if not all ecosystems. Some of these bacterial viruses are present as latent "prophages," either integrated within the chromosome of their host, or as episomal DNAs. Since prophages are ubiquitous throughout the bacterial world, there has been a sustained interest in trying to understand their contribution to the biology of their host. Clostridium difficile is no exception to that rule and with the recent release of hundreds of bacterial genome sequences, there has been a growing interest in trying to identify and classify these prophages. Besides their identification in bacterial genomes, there is also growing interest in determining the functionality of C. difficile prophages, i.e., their capacity to escape their host and reinfect a different strain, thereby promoting genomic evolution and horizontal transfer of genes through transduction, for example of antibiotic resistance genes. There is also some interest in using therapeutic phages to fight C. difficile infections.The objective of this chapter is to share with the broader C. difficile research community the expertise we developed in the study of C. difficile temperate phages. In this chapter, we describe a general "pipeline" comprising a series of experiments that we use in our lab to identify, induce, isolate, propagate, and characterize prophages. Our aim is to provide readers with the necessary basic tools to start studying C. difficile phages. PMID- 27507341 TI - Phage Transduction. AB - Bacteriophages mediate horizontal gene transfer through a mechanism known as transduction. Phage transduction carried out in the laboratory involves a bacterial donor and a recipient, both of which are susceptible to infection by the phage of interest. Phage is propagated in the donor, concentrated, and exposed transiently to recipient at different multiplicity of infection ratios. Transductants are selected for the desired phenotype by culture on selective medium. Here we describe transduction of ermB conferring resistance to erythromycin by the C. difficile phage phiC2. PMID- 27507340 TI - Induction and Purification of C. difficile Phage Tail-Like Particles. AB - Due to the inherent limitations of conventional antibiotics for the treatment of C. difficile infection (CDI), there is a growing interest in the development of alternative treatment strategies. Both bacteriophages and R-type bacteriocins, also known as phage tail-like particles (PTLPs), show promise as potential antibacterial alternatives for treating CDI. Similar to bacteriophages, but lacking a viral capsid and genome, PTLPs remain capable of killing target bacteria. Here we describe our experience in the induction and purification of C. difficile PTLPs. These methods have been optimized to allow production of concentrated, non-contractile, and non-aggregated samples for both sensitivity testing and structural electron microscopy studies. PMID- 27507343 TI - Methods for Determining Transfer of Mobile Genetic Elements in Clostridium difficile. AB - Horizontal gene transfer by mobile genetic elements plays an important role in the evolution of bacteria, allowing them to rapidly acquire new traits, including antibiotic resistance. Mobile genetic elements such as conjugative and mobilizable transposons make up a considerable part of the C. difficile genome. While sequence analysis has identified a large number of these elements, experimental analysis is required to demonstrate mobility and function. This chapter describes the experimental methods utilized for determining function and transfer of mobile genetic elements in C. difficile including detection of the circular transfer intermediate and the analysis and confirmation of mobile genetic element transfer to recipient cells. PMID- 27507342 TI - Transfer of Clostridium difficile Genetic Elements Conferring Resistance to Macrolide-Lincosamide-Streptogramin B (MLSB) Antibiotics. AB - Molecular analysis is an important tool to investigate Clostridium difficile resistance to macrolide-lincosamide-streptogramin B (MLSB). In particular, the protocols described in this chapter have been designed to investigate the genetic organization of erm(B)-containing elements and to evaluate the capability of these elements to transfer in C. difficile recipient strains using filter mating assay. PMID- 27507344 TI - Investigating Transfer of Large Chromosomal Regions Containing the Pathogenicity Locus Between Clostridium difficile Strains. AB - The genomes of all sequenced Clostridium difficile isolates contain multiple mobile genetic elements. The chromosomally located pathogenicity locus (PaLoc), encoding the cytotoxins TcdA and TcdB, was previously hypothesized to be a mobile genetic element; however, mobility was not demonstrated. Here we describe the methods used to facilitate and detect the transfer of the PaLoc from a toxigenic strain into non-toxigenic strains of C. difficile. Although the precise mechanism of transfer has not yet been elucidated, a number of controls are described which indicate transfer occurs via a cell-to-cell-mediated conjugation-like transfer mechanism. Importantly, transfer of the PaLoc was shown to occur on large chromosomal fragments of variable sizes, indicating that homologous recombination is likely to be responsible for the insertion events. PMID- 27507345 TI - An In Vitro Model of the Human Colon: Studies of Intestinal Biofilms and Clostridium difficile Infection. AB - The in vitro gut model is an invaluable research tool to study indigenous gut microbiota communities, the behavior of pathogenic organisms, and the therapeutic and adverse effect of antimicrobial administration on these communities. The model has been validated against the intestinal contents of sudden death victims to reflect the physicochemical and microbiological conditions of the proximal to distal colon, and has been extensively used to investigate the interplay between gut microbiota populations, antibiotic exposure, and Clostridium difficile infection. More recently the gut model has been adapted to additionally model intestinal biofilm. Here we describe the structure, assembly, and application of the biofilm gut model. PMID- 27507346 TI - MiniBioReactor Arrays (MBRAs) as a Tool for Studying C. difficile Physiology in the Presence of a Complex Community. AB - The commensal microbiome plays an important role in the dynamics of Clostridium difficile infection. In this chapter, we describe minibioreactor arrays (MBRAs), an in vitro cultivation system that we developed that allows for C. difficile physiology to be assayed in the presence of complex fecal microbial communities. The small size of the bioreactors within the MBRAs allows for dozens of reactors to be run simultaneously and therefore several different variables can be tested with limited time and cost. When coupled with experiments in animal models of C. difficile infection, MBRAs can provide important insights into C. difficile physiology and pathogenesis. PMID- 27507347 TI - A Practical Method for Preparation of Fecal Microbiota Transplantation. AB - Clostridium difficile is a challenging infection that can be difficult to treat with antibiotic therapy. This chapter outlines the processing material for fecal microbiota transplantation (FMT), also known as stool transplant. Fecal transplantations are effective in treating recurrent C. difficile infection (CDI). FMT uses a stool sample collected from a healthy, screened donor to restore healthy microbiota in the colon of a patient with CDI for symptom resolution. Here, we describe a rapid method for FMT preparation that uses inexpensive and disposable materials. PMID- 27507348 TI - Ion-Exchange Chromatography to Analyze Components of a Clostridium difficile Vaccine. AB - Ion-exchange (IEX) chromatography is one of many separation techniques that can be employed to analyze proteins. The separation mechanism is based on a reversible interaction between charged amino acids of a protein to the charged ligands attached to a column at a given pH. This interaction depends on both the pI and conformation of the protein being analyzed. The proteins are eluted by increasing the salt concentration or pH gradient. Here we describe the use of this technique to characterize the charge variant heterogeneities and to monitor stability of four protein antigen components of a Clostridium difficile vaccine. Furthermore, the IEX technique can be used to monitor reversion to toxicity for formaldehyde-treated Clostridium difficile toxins. PMID- 27507350 TI - Highly enantioselective construction of carbazole derivatives via [4+2] cycloaddition of silyloxyvinylindoles and beta,gamma-unsaturated alpha ketoesters. AB - A highly efficient catalytic asymmetric [4+2] cycloaddition of silyloxyvinylindoles with beta,gamma-unsaturated alpha-ketoesters has been accomplished by an available chiral N,N'-dioxide/yttrium triflate complex. A widespread range of carbazole derivatives were obtained in 47-98% yield with 86 99% ee under mild reaction conditions. PMID- 27507349 TI - A Size-Exclusion Chromatography Method for Analysis of Clostridium difficile Vaccine Toxins. AB - High-performance size-exclusion chromatography (HPSEC or SEC) is a method that can be applied to measure size distribution of proteins, including aggregates, monomers, and fragments. In the biopharmaceutical industry the quantitation of aggregates contained in biotherapeutics and protein-based vaccines is critical given the potential impact on safety, immunogenicity, and efficacy. Hence, aggregation analysis of therapeutic proteins or protein-based vaccine products is almost always a requirement of regulatory agencies. SEC, also referred to as gel filtration chromatography, separates molecules by size through a porous resin stationary phase. Under isocratic flow small molecules are retained on the column longer than large molecules. Here we describe the use of this SEC technique to characterize aggregation levels for four different protein antigens for a Clostridium difficile vaccine. PMID- 27507351 TI - Annual charade makes a mockery of the pay process. AB - Imagine if someone paid you for some expert advice, but before you had the chance to say anything they told you what that advice should be. Pointless? I would say so. You might be inclined to take the money, but would be entitled to question the sanity or motives of the person handing over their cash. PMID- 27507352 TI - Nursing Standard letter to PM: don't scrap bursary. AB - Nursing Standard has urged prime minister Theresa May to rethink scrapping the student bursary, warning that the move threatens the future of the profession. PMID- 27507353 TI - Memories online. AB - Nurses past and present are being encouraged to share their stories and memorabilia for an online project charting the history of the NHS. PMID- 27507354 TI - Unions censure Jeremy Hunt's rigid insistence on public sector pay restraint. AB - Unions have condemned health secretary Jeremy Hunt's views that pay restraint for nurses and other public sector workers continue. PMID- 27507355 TI - Nurses urged to lobby NHS to fund HIV drug. AB - Staff should lobby NHS England to fund a drug that can prevent HIV transmission, according to a leading sexual health nurse. PMID- 27507357 TI - Wales Safe Staffing Levels Act due in 2018. AB - Hospitals in Wales will be legally obliged to implement safe nurse staffing levels from April 2018, the Welsh Assembly has announced. PMID- 27507359 TI - Nurses who faked blood sugar readings struck off. AB - Three nurses who faked patients' blood sugar readings have been removed from the Nursing and Midwifery Council register. PMID- 27507360 TI - nursing.standard.com. AB - 1 Nurses who have taken part in Widening Access Training scheme courses may be eligible for national insurance and tax rebates. One nurse received a rebate of L6,000, according to Moneysavingexpert.com . Read more: rcni.com/tax-rebate. PMID- 27507361 TI - Revalidation renewal figures 'positive so far'. AB - Nine out of ten nurses and midwives have renewed their Nursing and Midwifery Council registration in the first 3 months of revalidation, figures reveal. PMID- 27507362 TI - Former RCN Nurse of the Year to be honoured for her victim abuse training. AB - Award-winning nurse Amanda Burston, pictured, will be feted for her work supporting victims of domestic abuse at the Women of the Year lunch in October, an event celebrating women's achievements. 'I am delighted to to be invited on behalf of every victim of abuse,' she said. 'I accept every opportunity to keep this vital conversation going.' PMID- 27507363 TI - Nurses' tax rebate claims on the rise. AB - Last week Nursing Standard reported on how potentially thousands of nurses and other healthcare staff could be in line for rebates if they overpaid contributions while studying on Widening Access Training (WAT) scheme courses. PMID- 27507366 TI - Morning sickness. AB - Essential facts Eight out of ten pregnant women are affected by nausea and vomiting in pregnancy. It is one of the most common reasons for pregnant women being admitted to hospital. Despite being known as morning sickness, symptoms can occur at any time of the day or night. The severe form of nausea and vomiting in pregnancy, hyperemesis gravidarum, is much rarer and affects up to 3% of pregnant women. For most women, their symptoms improve or disappear by around week 14, although for some it can last longer. PMID- 27507367 TI - Call for guidance for women choosing C-sections. AB - A study has highlighted the need for appropriate advice to be given to women choosing to have a caesarean birth for non-medical reasons. PMID- 27507368 TI - Too much TV causes lung blood clot deaths. AB - Lung blood clots - also known as pulmonary embolisms - usually stem from clots in the leg or pelvis after inactivity has slowed blood flow. It is particularly dangerous if the clot travels to the lung and lodges in a small blood vessel. PMID- 27507369 TI - Study calls for thyroid cancer test review. AB - A study has called for a review of thyroid cancer follow-up practices following concerns that unnecessary imaging tests are being carried out after primary treatment. PMID- 27507371 TI - Smoking less does not equal drinking more. AB - The common conception that people giving up smoking drink more alcohol to compensate has been questioned by a study. PMID- 27507372 TI - Meet the school health pioneer. AB - Nineteen years after becoming a school nurse I won the child health category in the RCNi Nurse Awards for creating and developing a website called Health Matters. Since becoming a school nurse in 1987, I have been challenged by how difficult it is to engage young people in health and well-being. Young people want a health service that is visible, accessible and confidential. But how can we achieve that with the resources we have?' PMID- 27507373 TI - Nurses join pollution fight. AB - Most of us are aware of outdoor air pollution: spend time in any traffic-clogged street, and you can taste the chemicals. Even spring days in the countryside can be spoiled by ozone haze. But a report published earlier this year by the Royal College of Physicians (RCP) and the Royal College of Paediatrics and Child Health (RCPCH) revealed that air pollution is much more than an inconvenience - it is a major health risk. PMID- 27507374 TI - Sex, PrEP and the moral backlash. AB - The news last week that the National AIDS Trust had won its High Court challenge for Pre-exposure Prophylaxis (PrEP) to be provided by NHS England has made the headlines. PMID- 27507375 TI - Three approaches to safe staffing levels. AB - We have a natural experiment emerging, with different UK countries looking at different approaches to NHS nurse staffing. For example, in June, Scotland first minister Nicola Sturgeon announced that Scotland will enshrine the use of existing local nurse workforce planning tools in law. This was misrepresented in some media coverage as being about legislated staffing levels, but it actually legislates what was already common local practice: flexibility framed by tested workforce tools, underpinned by professional judgement. PMID- 27507376 TI - Mary Seacole statue campaign epitomises the strength of nursing. AB - On the morning of 30 June in the grounds of St Thomas's Hospital in London, overlooking the Thames and the Houses of Parliament, the statue of Mary Seacole was unveiled. PMID- 27507377 TI - Using folic acid-fortified flour should be mandatory policy. AB - Research published last month states that pregnancy multivitamins do not contribute anything towards boosting the health of mothers and babies. PMID- 27507379 TI - Thanks for your help. AB - On behalf of myself and the Mary Seacole Memorial Statue Appeal's Trustees, thanks for your help and support in achieving our dream of a fitting monument to Mary Seacole. PMID- 27507381 TI - Key workers deserve better. AB - Key workers 'affordable' housing is shocking treatment. PMID- 27507382 TI - We need a full-scale campaign. AB - I was glad you highlighted the housing crisis facing nursing. The situation has never been this dire. PMID- 27507383 TI - Readers' panel - Will expenses payments take the sting out of student loans? AB - Our experts consider a hot topic of the day. PMID- 27507387 TI - A Walk Through Dementia. AB - Developed by charity Alzheimer's Research UK, and guided by people living with different forms of dementia, this app aims to give an insight into the everyday life of people suffering from dementia. PMID- 27507384 TI - Nurses are leading the way in changing attitudes to dementia. AB - My father and I had a pact - we would never repeat the daft things my grandmother said. We just couldn't bear people laughing at her. My granny had always been warm, witty and wise. Now in her eighties, she was in good form physically, but her memory had left the building. PMID- 27507388 TI - Student life - Role of neurodiverse nurses. AB - Students and practitioners who are 'neurodiverse' - encompassing people who are dyslexic and dyspraxic - make a positive contribution to patient care, and should be celebrated. PMID- 27507389 TI - In at the deep end with a drug-related wound. AB - My first second-year placement was in the community, where I helped care for a patient with an open wound on his inner thigh caused by repeated trauma from intravenous drug use. PMID- 27507390 TI - How to leave your job. AB - 'Leaving a job is never a decision you should take lightly,' says Nick Simpson, CEO of health recruitment agency MSI Group. 'Every nursing professional has things about their job they find frustrating and daily tasks they may not necessarily enjoy doing, but it's important to consider the positive aspects of your current role before you make a decision.' PMID- 27507391 TI - Clinical leaders of the future. AB - Putting ideas for management improvement into practice is one of the core tenets of the RCN's clinical leadership programme It's a transformational experience,' says RCN interim head of education Anne Corrin. 'The change is personal and professional.' PMID- 27507392 TI - 'Don't wait, look for opportunities'. AB - Steve Jamieson qualified as a nurse in 1986, and worked for the RCN for 17 years. He was deputy director of nursing, managing a team of professional leads across all areas of nursing, then chief executive of The Hospice of St Francis Berkhamsted. PMID- 27507393 TI - Effect of poverty on eye health and implications for nursing practice. AB - Poverty is a global issue that affects the health and quality of life of millions of people. It predisposes people to many health conditions, including sight loss or blindness as a result of the immune system becoming compromised. Blindness is common in areas of the world where there is extreme poverty. In the UK, poverty has become a major social issue, contributing to many health problems, including eye conditions. These eye conditions can result in sight loss if they are not managed effectively. Psychosocial care is an essential aspect of patient care, because poverty and sight loss are interrelated. Healthcare practitioners have a significant role in the management and prevention of blindness. Blindness caused by poverty is largely preventable, and health promotion is an important strategy in care management. PMID- 27507394 TI - Adverse drug reactions: classification, susceptibility and reporting. AB - Adverse drug reactions (ADRs) are increasingly common and are a significant cause of morbidity and mortality. Historically, ADRs have been classified as type A or type B. Type A reactions are predictable from the known pharmacology of a drug and are associated with high morbidity and low mortality. Type B reactions are idiosyncratic, bizarre or novel responses that cannot be predicted from the known pharmacology of a drug and are associated with low morbidity and high mortality. Not all ADRs fit into type A and type B categories; therefore, additional categories have been developed. These include type C (continuing), type D (delayed use), and type E (end of use) reactions. Susceptibility to ADRs is influenced by age, gender, disease states, pregnancy, ethnicity and polypharmacy. Drug safety is reliant on nurses and other healthcare professionals being alert to the possibility of ADRs, working with patients to optimise medicine use and exercising vigilance in the reporting of ADRs through the Yellow Card Scheme. PMID- 27507395 TI - Systematic reviews. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The CPD article discussed the purpose of systematic reviews in nursing practice. It outlined the process of undertaking a systematic review, and how this can benefit future research and clinical practice. PMID- 27507397 TI - Big picture. AB - Joan Myers introduces her trust's BME strategy. Since its implementation, 71% of BME staff at the trust believe career progression is possible. PMID- 27507398 TI - Noisy nursing in the nick. AB - 'It was interesting to see how the police and NHS staff work alongside each other; two agencies with quite different agendas working under one roof'. PMID- 27507396 TI - Matthew made my mum feel she wasn't 'just another patient'. AB - Matthew Ridout gave outstanding care to my 85-year-old mother during her stay at Ysbyty Ystrad Fawr hospital in Ystrad Mynach, south Wales following a stroke. PMID- 27507399 TI - The great outdoors. AB - Can a yearly camping trip help nurses improve their relationships with patients with mental health problems? Emma Dorn and Danielle Hitch, writing in Mental Health Practice, discuss the positive effect of a three-day annual camp organised by mental health services. PMID- 27507400 TI - The 'S' word. AB - Sarah Cubbin, writing in Cancer Nursing Practice, notes that healthcare staff found it difficult to bring up smoking cessation with patients with cancer who were receiving palliative care and found it to be inappropriate when the patient had limited life expectancy. The author notes that a solution for healthcare professionals is to address the issue of smoking soon after diagnosis. PMID- 27507401 TI - The value of e-rostering. AB - Jacqueline Price, in Emergency Nurse, discusses her experience of an American e rostering system. The system saved time for senior staff and provided an easier way to manage leave and yet the author's colleagues viewed it unfavourably, leading some to pursue jobs with more consistent shift systems. The author argues that the systems must offer shift patterns that encourage work-life happiness and better productivity. PMID- 27507402 TI - Patients With Short Bowel on Narcotics During 2 Randomized Trials Have Abdominal Complaints Independent of Teduglutide. AB - BACKGROUND: Narcotic agents are frequently administered to manage increased intestinal motility in patients with short bowel syndrome, but long-term use is associated with gastrointestinal (GI) complaints. This analysis evaluated the incidence of narcotic use and abdominal adverse events among patients with short bowel syndrome receiving teduglutide. MATERIALS AND METHODS: Pooled data from patients who received >=1 dose of teduglutide 0.05 mg/kg/d (n = 77) or placebo (n = 59) in either of 2 randomized, double-blind, phase III studies were analyzed. RESULTS: Of 136 patients, 52 (38%) received narcotics. GI adverse events occurred more often among patients who received narcotics than among those who did not (abdominal pain, 51% vs 21%; nausea, 42% vs 11%; abdominal distension, 17% vs 8%; vomiting, 19% vs 6%). Logistic regression analysis indicated that the probability of GI adverse events was significantly increased in patients with narcotic use ( P = .0009). In contrast, teduglutide treatment, as well as the interaction between teduglutide and narcotic use, did not affect the probability of GI adverse events. CONCLUSIONS: These results suggest that patients with short bowel syndrome receiving narcotics have chronic GI complaints independent of teduglutide treatment. Data included in this analysis were derived from ClinicalTrials.gov NCT00081458 and NCT00798967 (EudraCT 2004-000438-35 and 2008 006193-15). PMID- 27507403 TI - Polypropylene-based composite mesh versus standard polypropylene mesh in the reconstruction of complicated large abdominal wall hernias: a prospective randomized study. AB - PURPOSE: To compare polypropylene mesh positioned onlay supported by omentum and/or peritoneum versus inlay implantation of polypropylene-based composite mesh in patients with complicated wide-defect ventral hernias. METHODS: This was a prospective randomized study carried out on 60 patients presenting with complicated large ventral hernia in the period from January 2012 to January 2016 in the department of Gastrointestinal Surgery unit and Surgical Emergency of the Main Alexandria University Hospital, Egypt. Large hernia had an abdominal wall defect that could not be closed. Patients were divided into two groups of 30 patients according to the type of mesh used to deal with the large abdominal wall defect. RESULTS: The study included 38 women (63.3 %) and 22 men (37.7 %); their mean age was 46.5 years (range, 25-70). Complicated incisional hernia was the commonest presentation (56.7 %).The operative and mesh fixation times were longer in the polypropylene group. Seven wound infections and two recurrences were encountered in the propylene group. Mean follow-up was 28.7 months (2-48 months). CONCLUSIONS: Composite mesh provided, in one session, satisfactory results in patients with complicated large ventral hernia. The procedure is safe and effective in lowering operative time with a trend of low wound complication and recurrence rates. PMID- 27507404 TI - Resolvin D2 Enhances Postischemic Revascularization While Resolving Inflammation. AB - BACKGROUND: Resolvins are lipid mediators generated by leukocytes during the resolution phase of inflammation. They have been shown to regulate the transition from inflammation to tissue repair; however, it is unknown whether resolvins play a role in tissue revascularization following ischemia. METHODS: We used a murine model of hind limb ischemia (HLI), coupled with laser Doppler perfusion imaging, microcomputed tomography, and targeted mass spectrometry, to assess the role of resolvins in revascularization and inflammation resolution. RESULTS: In mice undergoing HLI, we identified resolvin D2 (RvD2) in bone marrow and skeletal muscle by mass spectrometry (n=4-7 per group). We also identified RvD2 in skeletal muscle biopsies from humans with peripheral artery disease. Monocytes were recruited to skeletal muscle during HLI and isolated monocytes produced RvD2 in a lipoxygenase-dependent manner. Exogenous RvD2 enhanced perfusion recovery in HLI and microcomputed tomography of limb vasculature revealed greater volume, with evidence of tortuous arterioles indicative of arteriogenesis (n=6-8 per group). Unlike other treatment strategies for therapeutic revascularization that exacerbate inflammation, RvD2 did not increase vascular permeability, but reduced neutrophil accumulation and the plasma levels of tumor necrosis factor-alpha and granulocyte macrophage colony-stimulating factor. In mice treated with RvD2, histopathologic analysis of skeletal muscle of ischemic limbs showed more regenerating myocytes with centrally located nuclei. RvD2 enhanced endothelial cell migration in a Rac-dependent manner, via its receptor, GPR18, and Gpr18 deficient mice had an endogenous defect in perfusion recovery following HLI. Importantly, RvD2 rescued defective revascularization in diabetic mice. CONCLUSIONS: RvD2 stimulates arteriogenic revascularization during HLI, suggesting that resolvins may be a novel class of mediators that both resolve inflammation and promote arteriogenesis. PMID- 27507405 TI - Predictors and Prognostic Significance of Right Ventricular Ejection Fraction in Patients With Ischemic Cardiomyopathy. AB - BACKGROUND: Decreased right ventricular (RV) ejection fraction (RVEF) portends poor prognosis in patients with ischemic cardiomyopathy, and previous studies have suggested an association between mitral regurgitation (MR) and RVEF. We sought to evaluate this association and whether mitral valve repair or replacement affects the relationship between RV function and mortality. METHODS: We included 588 patients (mean age, 63+/-11 years; 75% male) with ischemic cardiomyopathy who underwent cardiac magnetic resonance imaging between 2002 and 2008. Baseline characteristics, left ventricular ejection fraction, MR severity, treatment modality, scar burden, and RVEF were assessed. Multivariable linear regression and Cox proportional hazards models were used to assess the association between MR and RVEF and between RVEF and mortality, respectively. RESULTS: After adjustment for age, sex, left ventricular ejection fraction, right bundle-branch block, and RV scar, MR severity was found to be associated independently with RVEF. There were a total of 240 deaths during a median follow up time of 5.7 years. After multivariable adjustment, every 10% decrease in RVEF was associated with a 17% increased risk of death (P=0.008). Although decreasing RVEF was associated with a poor prognosis in the nonrepair group (hazard ratio, 1.28; 95% confidence interval, 1.12-1.47; P<0.001), it was not associated with death in the mitral valve repair or replacement group (P for interaction=0.046). CONCLUSIONS: MR severity was found to be an independent predictor of RVEF, as were right bundle-branch block, left ventricular ejection fraction, and the presence of RV scar. Decreasing RVEF is associated with increased mortality in patients with ischemic cardiomyopathy; however, this association may be mitigated in patients who undergo mitral valve repair or replacement. PMID- 27507406 TI - Return to the Workforce After First Hospitalization for Heart Failure: A Danish Nationwide Cohort Study. AB - BACKGROUND: Return to work is important financially, as a marker of functional status and for self-esteem in patients developing chronic illness. We examined return to work after first heart failure (HF) hospitalization. METHODS: By individual-level linkage of nationwide Danish registries, we identified 21 455 patients of working age (18-60 years) with a first HF hospitalization in the period from 1997 to 2012. Of these patients, 11 880 (55%) were in the workforce before HF hospitalization and comprised the study population. We applied logistic regression to estimate odds ratios for associations between age, sex, length of hospital stay, level of education, income, comorbidity, and return to work. RESULTS: One year after first HF hospitalization, 8040 (67.7%) returned to the workforce, 2981 (25.1%) did not, 805 (6.7%) died, and 54 (0.5%) emigrated. Predictors of return to work included younger age (18-30 versus 51-60 years; odds ratio [OR], 3.12; 95% confidence interval [CI], 2.42-4.03), male sex (OR, 1.22; 95% CI, 1.12-1.34), and level of education (long-higher versus basic school; OR, 2.06; 95% CI, 1.63-2.60). Conversely, hospital stay >7 days (OR, 0.56; 95% CI, 0.51-0.62) and comorbidity including history of stroke (OR, 0.55; 95% CI, 0.45 0.69), chronic kidney disease (OR, 0.46; 95% CI, 0.36-0.59), chronic obstructive pulmonary disease (OR, 0.62; 95% CI, 0.52-0.75), diabetes mellitus (OR 0.76; 95% CI, 0.68-0.85), and cancer (OR, 0.49; 95% CI, 0.40-0.61) were all significantly associated with lower chance of return to work. CONCLUSIONS: Patients in the workforce before HF hospitalization had low mortality but high risk of detachment from the workforce 1 year later. Young age, male sex, and a higher level of education were predictors of return to work. PMID- 27507407 TI - Development and characterization of chromosome segment substitution lines derived from Oryza rufipogon in the genetic background of O. sativa spp. indica cultivar 9311. AB - BACKGROUND: Wild rice (Oryza rufipogon) constitutes a primary gene source for rice breed improvement. Chromosome segment substitution line (CSSL) for O. rufipogon is a powerful tool for fine mapping of quantitative traits, new gene discovery, and marker-assisted breeding. Thus, they provide a basis for a wide range of genomic and genetic studies. RESULTS: In this study, a set of 198 CSSLs were developed from a cross between recurrent parent indica var. 9311 and an O. rufipogon donor parent; these were then genotyped using 313 polymorphic SSR markers evenly distributed across the 12 rice chromosomes. On average, each CSSL carried 2.16 introgressed segments, and the genetic distance of each segment was about 6 cM. The segments collectively covered 84.9 % of the wild rice genome. Based on these CSSLs, 25 QTLs involved in 10 agronomic traits were identified. Seven CSSLs were subjected to a whole-genome single nucleotide polymorphism chip assay and two QTLs, qSH4-1 and qDTH10-1, detected. In addition, a new QTL associated with the heading date was detected in a 78-Kb region on chromosome 10, thus proving the ability of these CSSLs to identify new QTLs and genes. CONCLUSIONS: The newly developed CSSL population proved a useful tool for both gene identification and whole-genome research of wild rice. These CSSL materials will provide a foundation for rice variety improvement. PMID- 27507408 TI - Phrenology between anthropology and neurology in a nineteenth-century collection of skulls. AB - The University of Padua has many legends about its cultural heritage. One of these concerns a collection of eight skulls still preserved in the Hall of Medicine at Bo Palace, near the old anatomy theatre built in 1545. It is said that some famous professors of the University donated their bodies to medical science, and the skulls were from these bodies. From multidisciplinary research, both historical and anthropological, we have discovered that Francesco Cortese, Professor of Medicine and Rector of the University, started this personal collection of colleagues' skulls, although they had not donated their bodies to science, so that he could make his own detailed phrenology study. PMID- 27507409 TI - Effects of different fluid shear stress patterns on the in vitro degradation of poly(lactide-co-glycolide) acid membranes. AB - The applications of poly (lactide-co-glycolide) acid (PLGA) for coating or fabricating polymeric biodegradable stents (BDSs) have drawn more attention. The fluid shear stress has been proved to affect the in vitro degradation process of PLGA membranes. During the maintenance, BDSs could be suffered different patterns of fluid shear stress, but the effect of these different patterns on the whole degradation process is unclear. In this study, in vitro degradation of PLGA membranes was examined with steady, sinusoid, and squarewave fluid shear stress patterns in 150 mL deionized water at 37 degrees C for 20 days, emphasizing on the changes in the viscosity of the degradation solution, mechanical, and morphological properties of the samples. The unsteady fluid shear stress with the same average magnitude as the steady one accelerate the in vitro degradation process of PLGA membranes in terms of maximum fluid shear stress and "window" of effectiveness. Maximum fluid shear stress accelerates the in vitro degradation of molecular fragments that diffused out in the solution while the "window" of effectiveness affects too in the early stage. Besides, maximum fluid shear stress and "window" of effectiveness accelerates the in vitro loss of tensile modulus and ultimate strength of the PLGA membranes while the maximum fluid shear stress plays the leading role in the decrease of tensile modulus at the early degradation stage. This study could help advance the degradation design of PLGA membranes under different fluid shear stress patterns for biomedical applications like stents and drug release systems. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 23-30, 2017. PMID- 27507411 TI - [Pseudoxanthoma elasticum: A disorder with different manifestations]. AB - BACKGROUND: Pseudoxanthoma elasticum (PXE) is a rare, autosomal recessive inheritable disorder characterized by progressive elastic fibre calcification. CASE DESCRIPTION: Here we describe two patients with different presentations of PXE. Patient A, an 11-year-old girl, visited the dermatologist because of yellow papules (pseudoxanthomas) on the side of her neck. With the aid of a skin biopsy, the dermatologist diagnosed PXE. Some years later, patient A developed symptoms of intermittent claudication due to arterial calcifications. Supervised exercise training diminished these symptoms. Patient B, a 55-year-old man, visited the ophthalmologist due to recent onset of metamorphopsia. The ophthalmologist discovered a subretinal haemorrhage and observed changes in the retina consistent with PXE. Severe loss of vision was prevented by intraocular anti-VEGF injections. Upon further investigation, pseudoxanthomas and arterial calcifications were found. CONCLUSION: PXE is a rare monogenetic disorder with dermatological, ocular and vascular manifestations. With these two case reports we have illustrated how the initial clinical presentation and symptomatology may vary widely. PMID- 27507410 TI - Durable Responses with Brentuximab Vedotin in cHL. AB - According to survival results from a phase II trial of brentuximab vedotin, 34 patients with relapsed or refractory classic Hodgkin lymphoma had a complete response with this CD30-targeting antibody-drug conjugate; 13 remain in remission 5 years later. PMID- 27507412 TI - [Infection prevention in newborns through maternal vaccination: current insights and developments]. AB - - In the first few months of life, newborns are vulnerable to infections.- Vaccination of the pregnant mother leads to transplacental antibody transfer, resulting in the best possible protection of the newborn.- Maternal vaccination has long been given for the prevention of tetanus in developing countries, and for the prevention of pertussis and influenza in developed countries, such as the United States, England and Belgium. These vaccinations give newborns good protection and, to date, no adverse effects are known for the foetus or the pregnancy.- Currently, phase 3 trials during pregnancy are ongoing following maternal vaccination against group B streptococci and respiratory syncytial virus. Here, again, no risks to mother or child have been reported.- Recently, the Dutch Health Council advised that all pregnant women in the Netherlands be vaccinated against pertussis in a vaccination programme.- This paper gives an overview of effectiveness, safety and practicalities of maternal vaccination. PMID- 27507413 TI - [Trends in suicidal behaviour in Dutch general practice, 1983-2013]. AB - OBJECTIVE: We investigated trends in suicidal behaviour as reported by Dutch general practices from 1983 to 2013. Also, we analysed the relationship with patient characteristics and with the financial crisis of 2008. DESIGN: Retrospective observational study. METHOD: We estimated age-adjusted and gender specific trends in suicides (342) and attempted suicides (1614), as registered in 1983-2013 under ICPC code P77 by 40 Dutch general practices participating in the NIVEL Primary Care Database sentinel station. Secondary outcomes, on the basis of supplementary questions in the GP Information System (Huisartsen Informatie Systeem), were the relationship between suicidal behaviour, earlier treatments and patient characteristics. Also, we analysed separate frequencies for the periods 1983-2007 and 2008-2013. RESULTS: Join-point analyses revealed a significant rise in male suicides from 2008 (b = 0.32, SE = 0.1, p = 0.008), and an increase in male suicide attempts since 2009 (b = 0.19, SE = 0.04, p < 0.001). Female suicidal behaviour showed a steady decrease in 1989-2013: b = -0.03, SE = 0.007, p < 0.0001 for female suicide, b = -0.02, SE = 0.002, p < 0.001 for female attempts. Almost half of the suicidal patients had visited their GP one month before the event. In 31% of these patients, the GP had recognized suicidal behaviour. CONCLUSIONS: Since 2008, there was a rise in the male suicide rate while female suicide behaviour has continued to decline. Training in the early recognition of suicide ideation in depressive patients might improve suicide prevention in primary care. PMID- 27507414 TI - [Psychiatric manifestations due to abnormal glucocorticoid levels]. AB - This clinical case presentation describes the disease trajectory in two patients who presented with psychiatric symptoms as a result of abnormal serum glucocorticoid levels. One case involves a 58-year-old man with hypercortisolism, the other case concerns a 55-year-old woman with hypocortisolism. In both cases there was a considerable diagnostic delay in recognizing the underlying adrenal gland pathology. Abnormal glucocorticoid levels, caused by endocrine disorders, often results in psychiatric symptoms. Delay in diagnosis may have adverse consequences. Hyper- or hypocortisolism should be considered in patients who present with an atypical presentation of psychiatric symptoms. Moreover, the absence of specific physical signs or symptoms at first presentation in such patients does not exclude an underlying endocrinological cause. Therefore, physical and psychiatric reassessment of such patients should be considered at regular intervals. PMID- 27507416 TI - Application of Deep Eutectic Solvent Modified Cotton as a Sorbent for Online Solid-Phase Extraction and Determination of Trace Amounts of Copper and Nickel in Water and Biological Samples. AB - Deep eutectic solvent (DES) was used as the extractant to improve the extraction properties of cotton. DES of choline chloride-urea (ChCl-urea) was prepared and immobilized on the surface of cotton fibers. The resulting sorbent was packed on a microcolumn, and a flow injection flame atomic absorption spectrometry was designed for the online separation and determination of trace amounts of copper and nickel. Various parameters affecting the extraction recovery of analytes such as pH, sample volume, sample loading rate, nature, volume, concentration, and flow rate of eluent were investigated and optimized. Under the optimum conditions, the method showed good linearity in the concentration range of 0.25 50.0 and 4.0-125.0 MUg L-1 with the coefficient of determination (r 2) of 0.9991 and 0.9990 for copper and nickel, respectively. The method was very sensitive with the detection limits (defined as 3Sb/m) of 0.05 and 0.60 MUg L-1 for Cu and Ni, respectively. It was successfully applied for the determination of Cu and Ni in water and biological samples. The accuracy of the method was evaluated through the recovery experiments and independent analysis by electrothermal atomic absorption spectrometry. PMID- 27507417 TI - Facilitators and barriers to treatment with haemodialysis among persons in mid adulthood: an interpretative phenomenological analysis. AB - BACKGROUND: The quality of life of persons on haemodialysis (HD) is often limited by the restrictions imposed by their medical regimen. These restrictions may negatively influence patients' adherence to their treatment. Therefore, in an effort to improve patients' adherence to treatment, there is the need to explore the patients' perceptions of facilitators and barriers in relation to their experience of HD. AIM: The purpose of the study was to explore the perceived barriers and facilitators of the HD experience of persons in mid-adulthood. PARTICIPANTS AND DESIGN: A qualitative design was used. Semistructured interviews were conducted with seven participants in the mid-adulthood phase (40-65 years). The transcribed texts were analysed using an Interpretative Phenomenological Analysis approach. RESULTS: Three main themes were identified from the analysis: 'social network outside the renal unit', 'the renal setting as a context' and 'qualities relating to staff'. Facilitators identified include: support from family and work colleagues, caring and knowledgeable staff and consultation with patients when planning out the treatment schedule. Barriers to treatment include: discomfort with the needling process, intrusion of HD on family time, lack of privacy in the renal unit and staff that do not take their concerns seriously. CONCLUSION: This study demonstrated the need for healthcare professionals to allocate time and space, where persons on HD may discuss personal issues that relate to their care experience in a private care setting. By identifying and exploring the barriers and facilitators of patients on haemodialysis, healthcare professionals may formulate individualised care plans which may improve patients' adherence to their HD treatment. PMID- 27507415 TI - Time to antibiotic therapy and outcome in bacterial meningitis: a Danish population-based cohort study. AB - BACKGROUND: Community-acquired bacterial meningitis (CABM) is a life-threatening disease and timing of antibiotic therapy remains crucial. We aimed to analyse the impact of antibiotic timing on the outcome of CABM in a contemporary cohort. METHODS: We conducted a population-based cohort study based on chart reviews of all adult cases (>16 years of age) of CABM in North Denmark from 1998 to 2014 excluding patients given pre-hospital parenteral antibiotics. We used modified Poisson regression analyses to compute the adjusted risk ratio (adj. RR) with 95 % confidence intervals (CIs) for in-hospital mortality and unfavourable outcome at discharge by time after arrival to hospital to adequate antibiotic therapy. RESULTS: We identified 195 adults with CABM of whom 173 patients were eligible for further analyses. The median door-to-antibiotic time was 2.0 h (interquartile range (IQR) 1.0-5.5). We observed increased adjusted risk ratios for in-hospital mortality of 1.6 (95 % CI 0.8-3.2) and an unfavourable outcome at discharge of 1.5 (95 % CI 1.0-2.2, p = 0.03) when treatment delays exceeded 6 h versus treatment within 2 h of admission. These findings corresponded to adjusted risk ratios of in-hospital mortality of 1.1 per hour of delay (95 % CI 0.8-1.5) and an unfavourable outcome at discharge of 1.1 per hour of delay (95 % CI 1.0-1.3) within the first 6 h of admission. Some patients (31 %) were diagnosed after admission and had more delays in antibiotic therapy and correspondingly increased in-hospital mortality (30 vs 14 %, p = 0.01) and unfavourable outcome (62 vs 37 %, p = 0.002). CONCLUSIONS: Delay in antibiotic therapy was associated with unfavourable outcome at discharge. PMID- 27507418 TI - Effects of Antibiotics on the Growth and Physiology of Chlorophytes, Cyanobacteria, and a Diatom. AB - The occurrence of antibiotics in surface waters has been reported worldwide with concentrations ranging from ng L-1 to low ug L-1 levels. During environmental risk assessments, effects of antibiotics on algal species are assessed using standard test protocols (e.g., the OECD 201 guideline), where the cell number endpoint is used as a surrogate for growth. However, the use of photosynthetic related endpoints, such as oxygen evolution rate, and the assessment of effects on algal pigments could help to inform our understanding of the impacts of antibiotics on algal species. This study explored the effects of three major usage antibiotics (tylosin, lincomycin, and trimethoprim) on the growth and physiology of two chlorophytes (Desmodesmus subspicatus and Pseudokirchneriella subcapitata), a cyanobacteria (Anabaena flos-aquae), and a diatom (Navicula pelliculosa) using a battery of parameters, including cell density, oxygen evolution rate, total chlorophyll content, carotenoids, and the irradiance photosynthesis relationship. The results indicated that photosynthesis of chlorophytes was a more sensitive endpoint than growth (i.e., EC50 derived based on the effects of tylosin on the growth of D. subspicatus was 38.27 umol L-1 compared with an EC50 of 17.6 umol L-1 based on photosynthetic rate), but the situation was reversed when testing cyanobacteria and the diatom (i.e., EC50 derived based on the effects of tylosin on the growth of A. flos-aquae was 0.06 umol L-1; EC50 0.33 umol L-1 based on photosynthetic rate). The pigment contents of algal cells were affected by the three antibiotics for D. subspicatus. However, in some cases, pigment content was stimulated for P. subcapitata, N. pelliculosa, and A. flos-aquae. The light utilization efficiency of chlorophytes and diatom was decreased markedly in the presence of antibiotics. The results demonstrated that the integration of these additional endpoints into existing standardised protocols could provide useful insights into the impacts of antibiotics on algal species. PMID- 27507419 TI - Breath analysis for colorectal cancer screening. PMID- 27507420 TI - Base-Biased Evolution of Disease-Associated Mutations in the Human Genome. AB - Understanding the evolution of disease-associated mutations is fundamental to analyze pathogenetics of diseases. Mutation, recombination (by GC-biased gene conversion, gBGC), and selection have been known to shape the evolution of disease-associated mutations, but how these evolutionary forces work together is still an open question. In this study, we analyzed several human large-scale datasets (1000 Genomes, ESP6500, ExAC and ClinVar), and found that base-biased mutagenesis generates more GC->AT than AT->GC mutations, while gBGC promotes the fixation of AT->GC mutations to balance the impact of base-biased mutation on genome. Due to this effect of gBGC, purifying selection removes more deleterious AT->GC mutations than GC->AT from population, but many high-frequency (fixed and nearly fixed) deleterious AT->GC mutations are remained possibly due to high genetic load. As a special subset, disease-associated mutations follow this evolutionary rule, in which disease-associated GC->AT mutations are more enriched in rare mutations compared with AT->GC, while disease-associated AT->GC are more enriched in mutations with high frequency. Thus, we presented a base-biased evolutionary framework that explains the base-biased generation and accumulation of disease-associated mutations in human populations. PMID- 27507421 TI - Isolation and genotyping of Acanthamoeba spp. from Acanthamoeba meningitis/ meningoencephalitis (AME) patients in India. AB - BACKGROUND: Acanthamoeba spp. are free-living ubiquitous protozoans capable of causing Acanthamoeba meningitis/meningoencephalitis (AME) of the central nervous system in humans. Acanthamoeba spp. are divided into 20 different genotypes (T1 T20) on the basis of variation in nucleotide sequences of the 18S rRNA gene. The objective of this study was to identify the genotypes of Acanthamoeba spp. in patients of Acanthamoeba meningitis/meningoencephalitis (AME) using 18S rRNA gene based PCR assay. The present study provides information regarding the involvement of the most prevalent and predominant genotype of Acanthamoeba spp. in Acanthamoeba meningitis/meningoencephalitis infections in India. METHODS: Cerebrospinal fluid (CSF) was collected from 149 clinically suspected Acanthamoeba meningitis/meningoencephalitis (AME) patients reporting to the outpatient department/causality services of the Neurosciences Centre, AIIMS, New Delhi, India during the past five years. Samples were inoculated onto 2 % non nutrient agar plates overlaid with E. coli and incubated at 30 degrees C for 14 days. Among 149 suspected patients, ten were found culture-positive for Acanthamoeba spp. out of which six isolates were established in axenic culture for molecular analysis. DNA was isolated and a PCR assay was performed for amplification of the Diagnostic fragment 3 (DF3) (~280 bp) region of the 18S rRNA gene from axenic culture of six Acanthamoeba spp. isolates. Rns genotyping was performed on the basis of the variation in nucleotide sequences of DF3 region of the 18S rRNA gene. RESULTS: In the phylogenetic analysis, all of the six Acanthamoeba spp. isolates were found to belong to genotype T4. The sequence homology search for these six isolates in the NCBI databank showed homology with the available strains of Acanthamoeba spp. The newly generated sequences are available in the GenBank database under accession numbers KT004416-KT004421. CONCLUSIONS: In the present study, genotype T4 was found as the most prevalent and predominant genotype in Acanthamoeba meningitis/ meningoencephalitis infections. Hence further studies are needed to develop optimal therapeutic strategy against Acanthamoeba spp. of genotype T4 to combat against the infections. PMID- 27507422 TI - Neural modulation of directed forgetting by valence and arousal: An event-related potential study. AB - Intentional forgetting benefits memory by removing no longer needed information and promoting processing of more relevant materials. This study sought to understand how the behavioural and neurophysiological representation of intentional forgetting would be impacted by emotion. We took a novel approach by examining the unique contribution of both valence and arousal on emotional directed forgetting. Participants completed an item directed forgetting task for positive, negative, and neutral words at high and lower levels of arousal while brain activity was recorded using electroencephalography (EEG). Behaviourally, recognition of to-be-remembered (TBR) and to-be-forgotten (TBF) items varied as a function of valence and arousal with reduced directed forgetting for high arousing negative and neutral words. In the brain, patterns of frontal and posterior activation in response to TBF and TBR cues respectively replicated prior EEG evidence to support involvement of inhibitory and selective rehearsal mechanisms in item directed forgetting. Interestingly, emotion only impacted cue related posterior activity, which varied depending on specific interactions between valence and arousal. Together, results suggest that the brain handles valence and arousal differently and highlights the importance of considering in a collective manner the multidimensional nature of emotion in experimentation. PMID- 27507423 TI - Activation of the prefrontal cortex by unilateral transcranial direct current stimulation leads to an asymmetrical effect on risk preference in frames of gain and loss. AB - Previous brain imaging and brain stimulation studies have suggested that the dorsolateral prefrontal cortex may be critical in regulating risk-taking behavior, although its specific causal effect on people's risk preference remains controversial. This paper studied the independent modulation of the activity of the right and left dorsolateral prefrontal cortex using various configurations of transcranial direct current stimulation. We designed a risk-measurement table and adopted a within-subject design to compare the same participant's risk preference before and after unilateral stimulation when presented with different frames of gain and loss. The results confirmed a hemispheric asymmetry and indicated that the right dorsolateral prefrontal cortex has an asymmetric effect on risk preference regarding frames of gain and loss. Enhancing the activity of the right dorsolateral prefrontal cortex significantly decreased the participants' degree of risk aversion in the gain frame, whereas it increased the participants' degree of risk aversion in the loss frame. Our findings provide important information regarding the impact of transcranial direct current stimulation on the risk preference of healthy participants. The effects observed in our experiment compared with those of previous studies provide further evidence of the effects of hemispheric and frame-dependent asymmetry. These findings may be helpful in understanding the neural basis of risk preference in humans, especially when faced with decisions involving possible gain or loss relative to the status quo. PMID- 27507424 TI - Rats showing low and high sensitization of frequency-modulated 50-kHz vocalization response to amphetamine differ in amphetamine-induced brain Fos expression. AB - Individuals predisposed to addiction constitute a minority of drug users, in both humans and animal models of the disorder, but there are no established characteristics that would allow identifying them beforehand. Our studies demonstrate that sensitization of rat 50-kHz ultrasonic vocalization (USV) response to amphetamine shows marked inter-individual diversity but substantial intra-individual stability. Low sensitization of the response shows relevance to the acquisition of self-administration of this drug and hence might be of predictive value regarding the risk of addiction. We compared amphetamine-induced Fos expression in 16 brain regions considered important for the development of addiction between rats preselected for low and high sensitization of the response and next given nine daily amphetamine doses followed by a 2-week withdrawal and final amphetamine challenge. Ventral tegmental area and nucleus accumbens shell Fos-positive nuclei counts correlated positively with 50-kHz USV response to the challenge in high-sensitized rats. Compared to those in amphetamine-untreated controls, Fos-positive nuclei counts were significantly and markedly (2-6 times) higher in 12 regions in high-sensitized rats, whereas in low-sensitized rats they were significantly higher in the cingulate cortex and dorsomedial striatum only. The difference in the counts between the latter two subsets reached statistical significance in dorsomedial and dorsolateral striatum and three out of four cortical regions studied. The fact that the diversification was most distinct in dorsal striatum that plays a critical role in the transition from controlled to compulsive drug intake suggests that the USV-based categorization may be related to divergent vulnerability of rats to AMPH addiction. PMID- 27507425 TI - Structural basis for cytokinin production by LOG from Corynebacterium glutamicum. AB - "Lonely guy" (LOG) has been identified as a cytokinin-producing enzyme in plants and plant-interacting fungi. The gene product of Cg2612 from the soil-dwelling bacterium Corynebacterium glutamicum was annotated as an LDC. However, the facts that C. glutamicum lacks an LDC and Cg2612 has high amino acid similarity with LOG proteins suggest that Cg2612 is possibly an LOG protein. To investigate the function of Cg2612, we determined its crystal structure at a resolution of 2.3 A. Cg2612 functions as a dimer and shows an overall structure similar to other known LOGs, such as LOGs from Arabidopsis thaliana (AtLOG), Claviceps purpurea (CpLOG), and Mycobacterium marinum (MmLOG). Cg2612 also contains a "PGGXGTXXE" motif that contributes to the formation of an active site similar to other LOGs. Moreover, biochemical studies on Cg2612 revealed that the protein has phosphoribohydrolase activity but not LDC activity. Based on these structural and biochemical studies, we propose that Cg2612 is not an LDC family enzyme, but instead belongs to the LOG family. In addition, the prenyl-binding site of Cg2612 (CgLOG) comprised residues identical to those seen in AtLOG and CpLOG, albeit dissimilar to those in MmLOG. The work provides structural and functional implications for LOG-like proteins from other microorganisms. PMID- 27507427 TI - Genetic gradient of a host-parasite pair along a river persisted ten years against physical mobility: Baltic Salmo salar vs. Gyrodactylus salaris. AB - The Atlantic salmon, Salmo salar L., in the Tornio River in the Northern Baltic Sea basin accommodates a monogenean ectoparasite, Gyrodactylus salaris. The aim of the study was to understand the population structure of apparently co-adapted host-parasite system: no parasite-associated mortality has been reported. The parasite burden among salmon juveniles (parr) was monitored along 460km of the river in 2000-2009. Among the parr, 33.0% were infected (nfish=1913). The genetic structure of the parasite population was studied by sequencing an anonymous nuclear DNA marker (ADNAM1, three main genotypes) and mitochondrial CO1 (three clades, six haplotypes). During the ten years, the parasite population was strongly and stably genetically differentiated among up- and downstream nurseries (nADNAM1=411, FST=0.579; nCO1=443, FST=0.534). Infection prevalence among the smolts migrating to sea was higher than in the sedentary parr populations (82.2%, nfish=129). The spatial differentiation observed among the sedentary juveniles was reflected temporally in the smolt run: parasite genotypes dominating the upper part of the river arrived later than downstream dwellers (medians June 4 and June 2) to the trap 7km from the river mouth. The nuclear and mitochondrial markers were in stable disequilibrium which was not relaxed in the contact zone or among the smolts where the parasite clones often met on individual fish. Only five parasite specimens on smolts (nworms=217) were putative recent sexual recombinants. The contribution of extant salmon hatcheries into the infection was negligible. The host salmon population in Tornio River is known to show significant spatial differentiation (FST=0.022). The stable spatial genetic structure of the parasite against the high physical mobility suggested a possibility of local co-adaptation of the host-parasite subpopulations. PMID- 27507428 TI - The CD4(+) T cell methylome contributes to a distinct CD4(+) T cell transcriptional signature in Mycobacterium bovis-infected cattle. AB - We hypothesised that epigenetic regulation of CD4(+) T lymphocytes contributes to a shift toward a dysfunctional T cell phenotype which may impact on their ability to clear mycobacterial infection. Combined RNA-seq transcriptomic profiling and Reduced Representation Bisulfite Sequencing identified 193 significantly differentially expressed genes and 760 differentially methylated regions (DMRs), between CD4(+) T cells from M. bovis infected and healthy cattle. 196 DMRs were located within 10 kb of annotated genes, including GATA3 and RORC, both of which encode transcription factors that promote TH2 and TH17 T helper cell subsets respectively. Gene-specific DNA methylation and gene expression levels for the TNFRSF4 and Interferon-gamma genes were significantly negatively correlated suggesting a regulatory relationship. Pathway analysis of DMRs identified enrichment of genes involved in the anti-proliferative TGF-beta signaling pathway and TGFB1 expression was significantly increased in peripheral blood leukocytes from TB-infected cattle. This first analysis of the bovine CD4(+) T cell methylome suggests that DNA methylation directly contributes to a distinct gene expression signature in CD4(+) T cells from cattle infected with M. bovis. Specific methylation changes proximal to key inflammatory gene loci may be critical to the emergence of a non-protective CD4(+) T cell response during mycobacterial infection in cattle. PMID- 27507429 TI - Carbon nanorings with inserted acenes: breaking symmetry in excited state dynamics. AB - Conjugated cycloparaphenylene rings have unique electronic properties being the smallest segments of carbon nanotubes. Their conjugated backbones support delocalized electronic excitations, which dynamics is strongly influenced by cyclic geometry. Here we present a comparative theoretical study of the electronic and vibrational energy relaxation and redistribution in photoexcited cycloparaphenylene carbon nanorings with inserted naphthalene, anthracene, and tetracene units using non-adiabatic excited-state molecular dynamics simulations. Calculated excited state structures reflect modifications of optical selection rules and appearance of low-energy electronic states localized on the acenes due to gradual departure from a perfect circular symmetry. After photoexcitation, an ultrafast electronic energy relaxation to the lowest excited state is observed on the time scale of hundreds of femtoseconds in all molecules studied. Concomitantly, the efficiency of the exciton trapping in the acene raises when moving from naphthalene to anthracene and to tetracene, being negligible in naphthalene, and ~60% and 70% in anthracene and tetracene within the first 500 fs after photoexcitation. Observed photoinduced dynamics is further analyzed in details using induced molecular distortions, delocatization properties of participating electronic states and non-adiabatic coupling strengths. Our results provide a number of insights into design of cyclic molecular systems for electronic and light-harvesting applications. PMID- 27507430 TI - Large-scale molecular dynamics simulation: Effect of polarization on thrombin ligand binding energy. AB - Molecular dynamics (MD) simulations lasting 500 ns were performed in explicit water to investigate the effect of polarization on the binding of ligands to human alpha-thrombin based on the standard nonpolarizable AMBER force field and the quantum-derived polarized protein-specific charge (PPC). The PPC includes the electronic polarization effect of the thrombin-ligand complex, which is absent in the standard force field. A detailed analysis and comparison of the results of the MD simulation with experimental data provided strong evidence that intra protein, protein-ligand hydrogen bonds and the root-mean-square deviation of backbone atoms were significantly stabilized through electronic polarization. Specifically, two critical hydrogen bonds between thrombin and the ligand were broken at approximately 190 ns when AMBER force field was used and the number of intra-protein backbone hydrogen bonds was higher under PPC than under AMBER. The thrombin-ligand binding energy was computed using the molecular mechanics Poisson Boltzmann surface area (MM/PBSA) method, and the results were consistent with the experimental value obtained using PPC. Because hydrogen bonds were unstable, it was failed to predict the binding affinity under the AMBER force field. Furthermore, the results of the present study revealed that differences in the binding free energy between AMBER and PPC almost comes from the electrostatic interaction. Thus, this study provides evidence that protein polarization is critical to accurately describe protein-ligand binding. PMID- 27507431 TI - Assessing cardiac and liver iron overload in chronically transfused patients with sickle cell disease. AB - Transfusional iron overload represents a substantial challenge in the management of patients with sickle cell disease (SCD) who receive chronic or episodic red blood cell transfusions. Iron-induced cardiomyopathy is a leading cause of death in other chronically transfused populations but rarely seen in SCD. Study objectives were to: (i) examine the extent of myocardial and hepatic siderosis using magnetic resonance imaging (MRI) in chronically transfused SCD patients, and (ii) evaluate the relationship between long-term (over the 5 years prior to enrolment) mean serum ferritin (MSF), spot-ferritin values and liver iron content (LIC) measured using MRI and liver biopsy. Thirty-two SCD patients (median age 15 years) with transfusional iron overload were recruited from two U.S. institutions. Long-term MSF and spot-ferritin values significantly correlated with LIC by MRI-R2* (r = 0.77, P < 0.001; r = 0.82, P < 0.001, respectively). LIC by MRI-R2* had strong positive correlation with LIC by liver biopsy (r = 0.98, P < 0.001) but modest inverse correlation with cardiac MRI-T2* (r = -0.41, P = 0.02). Moderate to severe transfusional iron overload in SCD was not associated with aberrations in other measures of cardiac function based on echocardiogram or serum biomarkers. Our results suggest that SCD patients receiving chronic transfusions may not demonstrate significant cardiac iron loading irrespective of ferritin trends, LIC and erythropoiesis suppression. PMID- 27507433 TI - Controlled creation and displacement of charged domain walls in ferroelectric thin films. AB - Charged domain walls in ferroelectric materials are of high interest due to their potential use in nanoelectronic devices. While previous approaches have utilized complex scanning probe techniques or frustrative poling here we show the creation of charged domain walls in ferroelectric thin films during simple polarization switching using either a conductive probe tip or patterned top electrodes. We demonstrate that ferroelectric switching is accompanied - without exception - by the appearance of charged domain walls and that these walls can be displaced and erased reliably. We ascertain from a combination of scanning probe microscopy, transmission electron microscopy and phase field simulations that creation of charged domain walls is a by-product of, and as such is always coupled to, ferroelectric switching. This is due to the (110) orientation of the tetragonal (Pb,Sr)TiO3 thin films and the crucial role played by the limited conduction of the LSMO bottom electrode layer used in this study. This work highlights that charged domain walls, far from being exotic, unstable structures, as might have been assumed previously, can be robust, stable easily-controlled features in ferroelectric thin films. PMID- 27507432 TI - "A novel highly stable and injectable hydrogel based on a conformationally restricted ultrashort peptide". AB - Nanostructures including hydrogels based on peptides containing non protein amino acids are being considered as platform for drug delivery because of their inherent biocompatibility and additional proteolytic stability. Here we describe instantaneous self-assembly of a conformationally restricted dipeptide, LeuDeltaPhe, containing an alpha,beta-dehydrophenylalanine residue into a highly stable and mechanically strong hydrogel, under mild physiological aqueous conditions. The gel successfully entrapped several hydrophobic and hydrophilic drug molecules and released them in a controlled manner. LeuDeltaPhe was highly biocompatible and easily injectable. Administration of an antineoplastic drug entrapped in the gel in tumor bearing mice significantly controlled growth of tumors. These characteristics make LeuDeltaPhe an attractive candidate for further development as a delivery platform for various biomedical applications. PMID- 27507434 TI - Impact of a standardized rapid response system on outcomes in a large healthcare jurisdiction. AB - AIM: To assess the impact of a standardized rapid response system (RRS) implemented across a large health care jurisdiction on reducing serious adverse events, hospital mortality and unexpected deaths. METHOD: We conducted an interrupted time series (2007-2013) population-based study in the state of New South Wales (NSW), Australia to evaluate the impact of introducing a statewide standardized RRS (the between-the-flags [BTF] system) which employed a five component intervention strategy. We studied 9,799,081 admissions in all 232 public hospitals in NSW. We studied changes in trends for annual rates of multiple key patient-centered outcomes before and after its introduction. RESULTS: Before the BTF system (2007-2009), there was a progressive decrease in mortality, cardiac arrest rates, cardiac arrests related mortality, and failure to rescue rates, but no changes in mortality rate among low mortality diagnostic related group (LMDRGs) patients. After the BTF program (2010-2013), the same trends continued for all outcomes with an overall (2013 vs 2007) 46% reduction in cardiac arrest rates; a 54% reduction in cardiac arrest related mortality rates; a 19% reduction in hospital mortality; a 35% decrease in failure to rescue rates (all Ps<0.001) over seven-years. In addition, there was a new 20% (p<0.001) mortality reduction among LMDRG patients (2013 vs 2007). CONCLUSIONS: The BTF program was associated with continued decrease in the overall cardiac arrests rates, deaths after cardiac arrest, hospital mortality and failure to rescue. In addition, among patients in the LMDRC group, it induced a new and significant post-intervention reduction in mortality which was never reported before. PMID- 27507436 TI - Sexual rights and the public health: why moral judgements matter. PMID- 27507435 TI - Mechanistic characterization of nitrite-mediated neuroprotection after experimental cardiac arrest. AB - Nitrite acts as an ischemic reservoir of nitric oxide (NO) and a potent S nitrosating agent which reduced histologic brain injury after rat asphyxial cardiac arrest (ACA). The mechanism(s) of nitrite-mediated neuroprotection remain to be defined. We hypothesized that nitrite-mediated brain mitochondrial S nitrosation accounts for neuroprotection by reducing reperfusion reactive oxygen species (ROS) generation. Nitrite (4 MUmol) or placebo was infused IV after normothermic (37 degrees C) ACA in randomized, blinded fashion with evaluation of neurologic function, survival, brain mitochondrial function, and ROS. Blood and CSF nitrite were quantified using reductive chemiluminescence and S-nitrosation by biotin switch. Direct neuroprotection was verified in vitro after 1 and 4 h neuronal oxygen glucose deprivation measuring neuronal death with inhibition studies to examine mechanism. Mitochondrial ROS generation was quantified by live neuronal imaging using mitoSOX. Nitrite significantly reduced neurologic disability after ACA. ROS generation was reduced in brain mitochondria from nitrite- versus placebo-treated rats after ACA with congruent preservation of brain ascorbate and reduction of ROS in brain sections using immuno-spin trapping. ATP generation was maintained with nitrite up to 24 h after ACA. Nitrite rapidly entered CSF and increased brain mitochondrial S-nitrosation. Nitrite reduced in vitro mitochondrial superoxide generation and improved survival of neurons after oxygen glucose deprivation. Protection was maintained with inhibition of soluble guanylate cyclase but lost with NO scavenging and ultraviolet irradiation. Nitrite therapy results in direct neuroprotection from ACA mediated by reductions in brain mitochondrial ROS in association with protein S-nitrosation. Neuroprotection is dependent on NO and S-nitrosothiol generation, not soluble guanylate cyclase. PMID- 27507437 TI - Why take part in personalised cancer research? Patients' genetic misconception, genetic responsibility and incomprehension of stratification-an empirical-ethical examination. AB - Therapeutic misconception is a well-known challenge for informed decision-making for cancer research participants. What is still missing, is a detailed understanding of the impact of "personalised" treatment research (e.g. biomarkers for stratification) on research participants. For this, we conducted the first longitudinal empirical-ethical study based on semi-structured interviews with colorectal cancer patients (n = 40) enrolled in a biomarker trial for (neo)adjuvant treatment, analysing the patients' understanding of and perspectives on research and treatment with qualitative methods. In addition to therapeutic misconception based on patients' confusion of research and treatment, and here triggered by misled motivation, information paternalism or incomprehension, we identified genetic misconception and genetic responsibility as new problematic issues. Patients mainly were not aware of the major research aim of future stratification into responders and non-responders nor did they fully acknowledge this as the aim for personalised cancer research. Thus, ethical and practical reflection on informed decision-making in cancer treatment and research should take into account the complexity of lay interpretations of modern personalised medicine. Instead of very formalistic, liability-oriented informed consent procedures, we suggest a more personalised communication approach to inform and motivate patients for cancer research. PMID- 27507438 TI - Charge-based separation of particles and cells with similar sizes via the wall induced electrical lift. AB - The separation of particles and cells in a uniform mixture has been extensively studied as a necessity in many chemical and biomedical engineering and research fields. This work demonstrates a continuous charge-based separation of fluorescent and plain spherical polystyrene particles with comparable sizes in a psi-shaped microchannel via the wall-induced electrical lift. The effects of both the direct current electric field in the main-branch and the electric field ratio in between the inlet branches for sheath fluid and particle mixture are investigated on this electrokinetic particle separation. A Lagrangian tracking method based theoretical model is also developed to understand the particle transport in the microchannel and simulate the parametric effects on particle separation. Moreover, the demonstrated charge-based separation is applied to a mixture of yeast cells and polystyrene particles with similar sizes. Good separation efficiency and purity are achieved for both the cells and the particles. PMID- 27507439 TI - Reaction pathway mechanism of thermally induced isomerization of 9,12-linoleic acid triacylglycerol. AB - BACKGROUND: To clarify the formation mechanism of trans linoleic acid isomers in edible oils during the heating process, trilinolein and trilinoelaidin, as representative oils, were placed in glass ampoules and sealed before heating at 180, 240 and 320 degrees C. The glass ampoules were removed at regular time intervals, and the contents were analyzed by infrared spectroscopy. The samples were then subjected to derivatization into their methyl esters for gas chromatographic analysis. RESULTS: Analysis results show that 9c,12c and 9t,12t fatty acids from trilinolein and trilinoelaidin molecules undergo chemical bond rotation, migration and degradation, leading to the formation of non-conjugated linoleic acids (NLAs), conjugated linoleic acids (CLAs) and aldehydes. The formation rate of isomers from the 9c,12c fatty acid is higher than that of the 9t,12t fatty acid. The production of aldehydes increases with heating temperature and time. The isomerization pathways involved in the formation of NLAs and CLAs during heating are clearly presented. CONCLUSION: These findings suggest possible pathways of NFA and CFA formation from heated trilinolein and trilinoelaidin, complement the mechanistic studies previously published in the literature, and provide a theoretical basis for future control of the quality and safety of fats and oils. (c) 2016 Society of Chemical Industry. PMID- 27507440 TI - Complex enzyme hydrolysis releases antioxidative phenolics from rice bran. AB - In this study, phenolic profiles and antioxidant activity of rice bran were analyzed following successive treatment by gelatinization, liquefaction and complex enzyme hydrolysis. Compared with gelatinization alone, liquefaction slightly increased the total amount of phenolics and antioxidant activity as measured by ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays. Complex enzyme hydrolysis significantly increased the total phenolics, flavonoids, FRAP and ORAC by 46.24%, 79.13%, 159.14% and 41.98%, respectively, compared to gelatinization alone. Furthermore, ten individual phenolics present in free or soluble conjugate forms were also analyzed following enzymatic processing. Ferulic acid experienced the largest release, followed by protocatechuic acid and then quercetin. Interestingly, a major proportion of phenolics existed as soluble conjugates, rather than free form. Overall, complex enzyme hydrolysis releases phenolics, thus increasing the antioxidant activity of rice bran extract. This study provides useful information for processing rice bran into functional beverage rich in phenolics. PMID- 27507441 TI - Pressurized water extraction of isoflavones by experimental design from soybean flour and Soybean Protein Isolate. AB - A Doehlert experimental design was conducted and surface response methodology was used to determine the effect of temperature, contact time and solid liquid ratio on isoflavone extraction from soybean flour or Soybean Protein Isolate in pressurized water system. The optimal conditions conducted gave an extraction yield of 85% from soybean flour. For Soybean Protein Isolate compared to soybean flour, the isoflavone extraction yield is 61%. This difference could be explained by higher aglycon content, while aglycon appears to be the least extracted isoflavone by pressurized water. The solid liquid ratio in the ASE cell was the overriding factor in obtaining high yields with both soybean products, while temperature has less influence. A high temperature causes conversion of the malonyls-glucosides and glucosides isoflavone derivatives into glucosides or aglycons forms. pressurized water extraction showed a high solubilization of protein material up to 95% of inserted Soybean Protein Isolate. PMID- 27507442 TI - Textural and cargo release attributes of trisodium citrate cross-linked starch hydrogel. AB - An alkaline starch suspension was charged with citric acid and incubated for different durations (0, 8.5 or 17h). The suspension was then supplemented with caffeine and gelatinized to fabricate hydrogels which were subsequently stored for varying periods (0, 24 or 48h). Charging of the well-dissolved alkaline starch suspension with citric acid decreased at first both the flow index and consistency coefficient (K); however, starch cross-linking over time by the generated trisodium citrate increased the K value. The latter also inhibited gel syneresis and increased its water-holding capacity. Trisodium citrate did not nonetheless influence the gel hardness except for the sample incubated for maximum duration and stored for the longest period. The amount of the caffeine released from hydrogel decreased by citrate cross-linking and was higher at neutral pH than pH 2.0. Fourier-transform infra-red spectroscopy suggested that caffeine was enclosed within the gel network via non-covalent interactions. PMID- 27507443 TI - Highly sensitive determination of antimony in food by resonance Rayleigh scattering-energy transfer between grapheme oxide and I3(.). AB - Sb(III) was reduced to SbH3 gas and introduced to the I3(-)-grapheme oxide (GO) or I3(-)-silver nanorod (AgNR)-Victoria blue B (VBB) solutions. Resonance Rayleigh scattering energy transfer (RRS-ET) occurred between the donor GO and the acceptor I3(-) due to the overlap between the absorption peak of I3(-) and RRS peak of GO. When I3(-) was reduced by SbH3, RRS-ET weakened and the RRS intensity enhanced. The increased RRS intensity was linear to Sb concentration in the range of 2.1-376.6MUg/L. In the I3(-)-AgNR-VBB solution, I3(-) combined with VBB to form VBB-I3 and there was a weak surface-enhanced Raman scattering (SERS) effect. When SbH3 reduced I3(-), the SERS intensity increased due to the release of SERS active VBB. The enhanced SERS intensity was linear for Sb concentration in the range of 8.4-292.9MUg/L. The RRS-ET method was applied for determination of Sb in food with satisfactory results. PMID- 27507444 TI - Antioxidant, nutritional and functional characteristics of wheat bread enriched with ground flaxseed hulls. AB - Antioxidant capacity, nutritional and functional quality of wheat bread supplemented with 1-5% flaxseed hull (FH) were studied. Analyses of the chemically-extractable fraction show that supplementation with 5% of FH increased (compared to control) phenolics content (by 93%), radicals scavenging ability (by 176%) and reducing power (by 220%). Furthermore, phenolic antioxidants were bioaccessible in vitro (samples after simulated digestion). Fortification had no significant influence on rapidly and slowly digestible starch, in vitro starch digestibility and values of expected glycemic index; however, a decrease (up to 8%) of relative proteins digestibility was determined. Enrichment decreased loaf volume and increased crumb hardness. The results from sensory evaluation show that the incorporation of FH had a slightly unfavorable effect on bread sensory properties but ensured satisfactory consumer acceptability. In view of these facts, it is concluded that flaxseed hulls may be a beneficial food additive. PMID- 27507445 TI - Purification and characterization of a naringinase from a newly isolated strain of Bacillus amyloliquefaciens 11568 suitable for the transformation of flavonoids. AB - An intracellular naringinase from Bacillus amyloliquefaciens 11568 isolated from soil was purified, identified, and characterized. The sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of the purified enzyme gave a single protein band corresponding to a molecular mass of 32kDa. The optimum pH and temperature for naringinase and its alpha-l-rhamnosidase and beta d-glucosidase activities were pH 7.5 and 45 degrees C, respectively. The enzymes were stable below 45 degrees C between pH 3.5 and 8.5. The Km and the Vmax of the isolated naringinase were 0.95mmol/L and 3847.3mmol/(L.min), respectively. The isolated naringinase was capable of hydrolyzing naringin, neohesperidin, and other glycosides. Additionally, a concentration of 4U/mL of the enzyme in citrus juice was sufficient to remove the naringin and alleviate the bitterness of the juice. These results provide an in-depth insight into the structure of the naringinase and the hydrolysis of naringin and other flavonoids. PMID- 27507446 TI - Polyvinylpolypyrrolidone reduces cross-reactions between antibodies and phenolic compounds in an enzyme-linked immunosorbent assay for the detection of ochratoxin A. AB - Ochratoxin A (OTA) is a fungal metabolite and putative carcinogen which can contaminate a variety of foods such as cereals, wine, and nuts. Commercial ELISA kits are known to give false-positive results for OTA concentrations when phenolic compounds are present. Pistachios represent a food matrix rich in phenolic compounds potentially contaminated with OTA, and were used to model OTA cross-reactivity. Polyvinylpolypyrrolidone (PVPP) was incorporated during extraction of OTA using a commercial ELISA protocol. HPLC methods were used to confirm that PVPP does not interact with OTA and levels of gallic acid and catechin remaining in pistachio extracts decreased with increasing PVPP application. Cross-reactivity of extracts also decreased with increasing PVPP application, and color loss was used as an indicator of anthocyanin removal. Incorporating PVPP into ELISA protocols allows for the continued use of rapid immunological methods in food matrices containing phenolic compounds. PMID- 27507447 TI - Impact of acid and oxidative modifications, single or dual, of sorghum starch on biodegradable films. AB - The objective of this study was to evaluate the effects of acid and oxidation modifications on sorghum starch, as well as the effect of dual modification of starch on the physical, morphological, mechanical, and barrier properties of biodegradable films. The acid modification was performed with 3% lactic acid and the oxidation was performed with 1.5% active chlorine. For dual modification, the acid modification was performed first, followed by oxidation under the same conditions as above. Both films of the oxidized starches, single and dual, had increased stiffness, providing a higher tensile strength and lower elongation when compared to films based on native and single acid modified starches. However, the dual modification increased the water vapor permeability of the films without changing their solubility. The increase in sorghum starch concentration in the filmogenic solution increased the thickness, water vapor permeability, and elongation of the films. PMID- 27507449 TI - Development of a workflow for screening and identification of alpha-amylase inhibitory peptides from food source using an integrated Bioinformatics-phage display approach: Case study - Cumin seed. AB - The main objective of this study was to develop an efficient workflow to discover alpha-amylase inhibitory peptides from cumin seed. A total of 56 unknown peptides was initially found in the cumin seed protein hydrolysate. They were subjected to 2 different in silico screenings and 6 peptides were shortlisted. The peptides were then subjected to in vitro selection using phage display technique and 3 clones (CSP3, CSP4 and CSP6) showed high affinity in binding alpha-amylase. These clones were subjected to the inhibitory test and only CSP4 and CSP6 exhibited high inhibitory activity. Therefore, these peptides were chemically synthesized for validation purposes. CSP4 exhibited inhibition of bacterial and human salivary alpha-amylases with IC50 values of 0.11 and 0.04MUmol, respectively, whereas CSP6 was about 0.10 and 0.15MUmol, respectively. Results showed that the strength of each protocol has been successfully combined as deemed fit to enhance the alpha-amylase inhibitor peptide discovery. PMID- 27507448 TI - Green extraction of polyphenols from whole pomegranate fruit using cyclodextrins. AB - Pomegranate is a source of bioactive phytochemicals. The objective of this study was the derivation of a sustainable method to exploit the whole fruit, both edible and non-edible parts, as a source of polyphenols. Pomegranate peel contains a 10-fold higher phenolic content than the pulp. The fruit was freeze dried and the resulting dry matter was extracted with solid-liquid percolation equipment using non-toxic and eco-friendly extraction solvents: either deionized water or aqueous solutions of cyclodextrins. Cyclodextrins (CDs) are known molecular encapsulators and our results prove enhancement of the extraction of pomegranate polyphenols by 20%. In order to examine the formation of inclusion complexes between CD's and polyphenols of the extract, polyphenols were isolated using solid-phase extraction. NMR studies with the purified extracts and the individual CDs confirmed inclusion complex formation in water. Pomegranate liquid extracts may be used as raw materials for several end-users in the food, cosmetic and pharmaceutical industries. PMID- 27507450 TI - Determination of metrafenone in vegetables by matrix solid-phase dispersion and HPLC-UV method. AB - A simple method for determination of metrafenone in vegetables by matrix solid phase dispersion (MSPD) and HPLC was developed. All vegetable samples were extracted with dichloromethane, and then the extracts were directly separated on a reversed-phase column with isocratic elution without a cleanup step. The linearity of metrafenone was good with the concentration between 0.005 and 5mg/kg, and the limit of detection (LOD) of the metrafenone was 0.002mg/kg. The recoveries ranged from 86.5% to 104.8% with the relative standard deviations (RSDs) in the range of 2.1-7.9% (n=6). The results indicated that the method was simple, rapid, highly sensitive and suitable for the determination of metrafenone in vegetables. PMID- 27507451 TI - Amplified electrochemical determination of maltol in food based on graphene oxide wrapped tin oxide@carbon nanospheres. AB - The study presents a new approach for rapid and ultrasensitive detection of maltol using a glassy carbon electrode (GCE) modified with graphene oxide-wrapped tin oxide@carbon nanospheres (SnO2@C@GO). The morphological and components properties of SnO2@C@GO nanocomposites were investigated by means of X-ray diffraction spectroscopy, Raman spectroscopy, field emission scanning electron microscopy, high resolution transmission electron microscopy, and electrochemical impedance spectroscopy. SnO2@C@GO nanocomposite on a GCE had a synergetic effect on the electrochemical oxidation of maltol by means of square wave voltammetry. Under the optimum conditions, anodic peak current response of maltol was linear with its concentration in the range of 80nM-10MUM, and a detection limit of 12nM was achieved for maltol. The experiment results presented that the method showed good selectivity, sensitivity, reproducibility, and long-term stability, as well as excellent potential for use as an ideal inexpensive voltammetric method applicable for complex food matrices. PMID- 27507452 TI - Structure and pasting properties of alkaline-treated phosphorylated cross-linked waxy maize starches. AB - The objectives of this study were to determine the stability of cross-linked bonds of starch at different pH values and their effects on the pasting property of waxy maize starch cross-linked by 0.05% and 3% sodium trimetaphosphate/sodium tripolyphosphate. The cross-linked waxy maize starch (CLWMS) was slurried (40%, w/w) and subjected to alkali treatments of pH 9, 10, 11, and 12 at 40 degrees C for 4h. The phosphorus in 3% CLWMS decreased with increasing pH and remained unchanged in 0.05% CLWMS for all pH treatments. Decreased settling volumes indicated the reduction of swelling power for the alkali-treated CLWMS at pH 11 and 12. The (31)P NMR spectra of 3% CLWMS at pH 12 showed decreased cyclic monostarch phosphate, monostarch monophosphate, and monostarch diphosphate, but significantly increased distarch monophosphate. Alkali treatments of phosphorylated cross-linked starches offer a way to manipulate the rheological properties of cross-linked starch for desired food applications. PMID- 27507453 TI - Mercury accumulation of three Lactarius mushroom species. AB - Accumulation, distribution and potential dietary intake of mercury accumulated by mushrooms of Lactarius species L. delicious, L. volemus and L. deterrimus were studied in the Pomerania region of Poland. In total, 212 fruiting bodies and 106 underlying topsoil samples were analyzed. Analysis indicated that the concentrations of Hg were at low levels both in mushrooms and forest topsoils for a majority of the locations investigated. L. volemus that grew in soils with only a slightly elevated contamination (0.11+/-0.07mgkg(-1) of dried soil), very efficiently accumulated Hg in fruiting bodies and concentration levels were at 3.7+/-1.3mgkg(-1) of dry biomass in caps and at 1.9+/-0.9mgkg(-1) of dry biomass in stipes. Consumption of mushrooms foraged from the Sobowidz forest, which is close to a foundry using ferrous and non-ferrous metals could result in a Hg intake that exceeds the current statutory limits. PMID- 27507454 TI - Leptosperin is a distinct and detectable fluorophore in Leptospermum honeys. AB - New Zealand manuka (Leptospermum scoparium) honey exhibits two unique fluorescence signatures that distinguish it from other honey types. One of these is the MM1 fluorescence marker (270-365nm excitation-emission) which we show is due to a Leptospermum nectar-derived compound, leptosperin. Synthetic or honey purified leptosperin not only displayed an identical fluorescence spectrum, but supplementation of leptosperin into clover or artificial honeys generated the MM1 fluorescence signature. There was a quenching effect of the honey matrix on leptosperin fluorescence but otherwise leptosperin was chemically stable over prolonged storage at 37 degrees C. Leptosperin was also present in the woody fruited Australian Leptospermum species at elevated concentrations but virtually absent in Leptospermum subtenue suggesting its elevated expression developed following the mid-Miocene separation of the genus. These findings suggest that fluorescence spectroscopy could offer a rapid and high-throughput screening method for identification of Leptospermum honeys using the MM1 fluorescence marker. PMID- 27507455 TI - Analyses of effects of alpha-cembratrien-diol on cell morphology and transcriptome of Valsa mali var. mali. AB - The objective of this work was to study the underlying mechanisms of growth inhibition of Valsa mali var. mali, the causative pathogen of apple tree canker disease, by alpha-cembratrien-diol. The half maximal inhibitory concentration of alpha-cembratrien-diol against V. mali var. mali is 18.0mg/L. Treatment of V. mali var. mali with alpha-cembratrien-diol resulted in various mycelial and cellular abnormalities, and the up- and down-regulation of 94 and 170 differentially expressed genes, respectively. Gene Ontology term enrichment analysis revealed that alpha-cembratrien-diol substantially altered the expression of genes involved in the redox process, tetrapyrrole binding, coenzyme binding, heme binding, and iron binding. Kyoto Encyclopedia of Genes and Genomes enrichment analysis also showed significant enrichment of specific metabolic pathways involving the set of differentially expressed genes. The present study will assist in the development of alternative alpha-cembratrien-diol-based biological control agents and ultimately facilitate organic apple production. PMID- 27507456 TI - Stability-increasing effects of anthocyanin glycosyl acylation. AB - This review comprehensively summarizes the existing knowledge regarding the chemical implications of anthocyanin glycosyl acylation, the effects of acylation on the stability of acylated anthocyanins and the corresponding mechanisms. Anthocyanin glycosyl acylation commonly refers to the phenomenon in which the hydroxyl groups of anthocyanin glycosyls are esterified by aliphatic or aromatic acids, which is synthetically represented by the acylation sites as well as the types and numbers of acyl groups. Generally, glycosyl acylation increases the in vitro and in vivo chemical stability of acylated anthocyanins, and the mechanisms primarily involve physicochemical, stereochemical, photochemical, biochemical or environmental aspects under specific conditions. Additionally, the acylation sites as well as the types and numbers of acyl groups influence the stability of acylated anthocyanins to different degrees. This review could provide insight into the optimization of the stability of anthocyanins as well as the application of suitable anthocyanins in food, pharmaceutical and cosmetic industries. PMID- 27507457 TI - Salinity effect on nutritional value, chemical composition and bioactive compounds content of Cichorium spinosum L. AB - Soil salinization is an increasing problem for many areas throughout the world that renders prohibitive vegetables and crop production in general. In the present study, Cichorium spinosum L. plants were grown under saline conditions in order to evaluate chemical composition and bioactive compounds content of their leaves. Salinity increase resulted in significant changes of macro and micro nutrients content (nutritional value, sugars, fatty acids, minerals, ascorbic acid and tocopherols), whereas the concentration of phenolic compounds was not significantly affected. Chicoric and 5-O-caffeoylquinic acid were the most abundant phenolic acids. In contrast, antioxidant activity and mineral composition were beneficially affected by mid-to-high and high salinity levels. In conclusion, C. spinosum can be cultivated under saline conditions without compromising the quality of the final product, especially in semi-arid areas where irrigation water is scarce and/or of low quality due to high content of NaCl (coastal areas or areas where underground water is saline). PMID- 27507458 TI - Accumulation of carotenoids and expression of carotenogenic genes in peach fruit. AB - To understand better the regulatory mechanism of the carotenoid accumulation, the expression profile of relevant carotenoid genes and metabolites were compared between two peach cultivars with different colors during fruit development. Meanwhile, the change pattern of carotenoid content and expression of carotenoid metabolic genes in peaches after harvest in response to blue light were also investigated. As compared to the yellow fleshed-cultivar 'Jinli', lower carotenoid levels were observed in skin and pulp in white peach cultivar 'Hujing', which might be explained by differentially expression of PpCCD4 gene. With respect to 'Jinli', the carotenoid accumulation during fruit development in fruit skin was partially linked with the transcriptional regulation of PpFPPS, PpGGPS, PpLCYB and PpCHYB. However, in the pulp, the accumulation might be also associated with the increased transcriptions of PpPDS, along with the above four genes. Blue light treatment induced carotenoid accumulation in 'Jinli' peaches during storage. In addition, the treated-fruit displayed higher expression of all the eight genes analysed with a lesser extent on PpCCD4, which suggested that the much more increased carotenoid synthesis rate could result in the higher carotenoid content in blue light-treated fruit. The results presented herein contribute to further elucidating the regulatory mechanism of carotenoid accumulation in peach fruit. PMID- 27507459 TI - A rapid method for the simultaneous quantification of the major tocopherols, carotenoids, free and esterified sterols in canola (Brassica napus) oil using normal phase liquid chromatography. AB - A normal phase high performance liquid chromatography (HPLC) method was developed to simultaneously quantify several prominent bioactive compounds in canola oil vis. alpha-tocopherol, gamma-tocopherol, delta-tocopherol, beta-carotene, lutein, beta-sitosterol, campesterol and brassicasterol. The use of sequential diode array detection (DAD) and tandem mass spectrometry (MS/MS) allowed direct injection of oils, diluted in hexane without derivatisation or saponification, greatly reducing sample preparation time, and permitting the quantification of both free sterols and intact sterol esters. Further advantages over existing methods included increased analytical selectivity, and a chromatographic run time substantially less than other reported normal phase methods. The HPLC-DAD-MS/MS method was applied to freshly extracted canola oil samples as well as commercially available canola, palm fruit, sunflower and olive oils. PMID- 27507460 TI - Continuous method to determine the trypsin inhibitor activity in soybean flour. AB - The determination of trypsin inhibitor (TI) activity is of importance to evaluate the nutritional value of soybean flours. An analytical method, which involves a continuous spectrophotometric rate determination for trypsin activity against the substrate N-benzoyl-DL-arginine p-nitroanilide, is proposed as an alternative to the standard discontinuous assay. Stopping the reaction with acetic acid and a centrifugation/filtration step to decrease turbidity are not required, thus reducing costs and sample preparation time. The TI activity of different flour samples, determined by both assays, demonstrated to be statistically comparable, irrespective of the TI concentration level. The coefficients of variation of the novel method did not exceed 8% at any concentration level. The curves of progress reaction showed a non-linear behavior in samples without TI. A reduction of incubation time from 10min to 2min increased the method sensitivity and extended its linear range. A more economical, faster and simpler assay was developed. PMID- 27507461 TI - Evaluation of health potential of nutritionally enriched Kodo millet (Eleusine coracana) grown in Himachal Pradesh, India. AB - In this study, Kodo millet grains were phytochemically investigated for their nutritional and antioxidant potential for their use as functional foods. Methanolic extracts of grains showed higher phenolic content and antioxidant activity. TLC studies of the extracted polyphenols from kodo millet showed the predominant presence of ferulic acid and cinnamic acid in the millet. Further quantification of these polyphenols was done by using HPLC, analysing ferulic acid and cinnamic acid. Antagonistic spectrum of the polyphenols extracted showed inhibition against four bacterial test indicators viz. Staphylococcus aureus, Leuconostoc mesenteroides, Bacillus cereus and Enterococcus faecalis proving its antimicrobial action. The grains of kodo millet grains taken under study were found to posses' high protein, carbohydrates, minerals, crude fibers, polyphenols and antioxidants thus can be used as a good source of nutrition with additional health benefits. PMID- 27507462 TI - One-step competitive lateral flow biosensor running on an independent quantification system for smart phones based in-situ detection of trace Hg(II) in tap water. AB - In this study, a one-step lateral flow biosensor (LFB) has been developed, optimized and validated for quantitative detection of Hg(II) in water. In the measurement principle, just one T-rich ssDNA probe (TSP) for the specific binding process was successfully employed in the competitive LFB based methods. The concept of an independent quantification system was realized using a cresol red dot as an external standard, which effectively eliminates false negative results. Under optimized conditions, the limit of detection for Hg(II) was 4nM; high selectivity towards Hg(II) and extraordinary device-to-device repeatability of the LFB were achieved. Furthermore, Hg(II) from tap water samples was analyzed, and the results were confirmed by ICP-MS. The interference from other components in the real samples could be neglected during the analysis. The approach provides a simple, sensitive, and practical tool for the detection of trace Hg(II) in tap water, showing great promise for in-situ applications. PMID- 27507463 TI - Validation of a high-performance size-exclusion chromatography method to determine and characterize beta-glucans in beer wort using a triple-detector array. AB - Beer wort beta-glucans are high-molecular-weight non-starch polysaccharides of that are great interest to the brewing industries. Because glucans can increase the viscosity of the solutions and form gels, hazes, and precipitates, they are often related to poor lautering performance and beer filtration problems. In this work, a simple and suitable method was developed to determine and characterize beta-glucans in beer wort using size exclusion chromatography coupled with a triple-detector array, which is composed of a light scatterer, a viscometer, and a refractive-index detector. The method performances are comparable to the commercial reference method as result from the statistical validation and enable one to obtain interesting parameters of beta-glucan in beer wort, such as the molecular weight averages, fraction description, hydrodynamic radius, intrinsic viscosity, polydispersity and Mark-Houwink parameters. This characterization can be useful in brewing science to understand filtration problems, which are not always explained through conventional analysis. PMID- 27507464 TI - Rapid identification of the botanical and entomological sources of honey using DNA metabarcoding. AB - Honey is generated by various bee species from diverse plants, and because the value of different types of honey varies more than 100-fold, it is a target for fraud. This paper describes a protocol that employs DNA metabarcoding of three gene regions (ITS2, rbcLa, and COI) to provide an inexpensive tool to simultaneously deliver information on the botanical and entomological origins of honey. This method was used to examine seven varieties of honey: light, medium, dark, blended, pasteurized, creamed, and meliponine. Plant and insect sources were identified in five samples, but only the botanical or insect source could be identified in the other two. Two samples were found to be misrepresented. Although this method was generally successful in determining both plant and insect sources, honeys rich in polyphenolic compounds or subject to crystallization were recalcitrant to analysis, so further research is required to combat honey adulteration and mislabeling. PMID- 27507465 TI - A novel method for the synthesis of glyceryl monocaffeate by the enzymatic transesterification and kinetic analysis. AB - A novel enzymatic method for glyceryl monocaffeate (GMC) preparation by the transesterification of ethyl caffeate (EC) was investigated. The effects of reaction variables (reaction pressure, temperature, reaction time, enzyme load, and substrate ratio) on the enzymatic transesterification were studied and optimized using response surface methodology. HPLC-ESI-MS and HPLC-UV were used to monitor the transesterification. Thermodynamics, kinetic analyses and reaction mechanism were also evaluated. Results showed that, GMC can be successfully prepared by the enzymatic transesterification of EC with glycerol. Under the optimal conditions (enzyme load 22.54%, EC:glycerol=1:12.75 (mol/mol), 72.5 degrees C, and 10.5h), EC conversion and GMC yield were 97.9+/-0.7% and 95.8+/ 1.0%, respectively. The activation energies (Ea) for EC conversion and GMC formation were 44.23 and 46.51kJ/mol, respectively. The kinetic values for Vmax, Km(') and KIA were 2.18*10(-3)mol/(Lmin), 0.086mol/L, and 0.52mol/L, respectively. The transesterification mechanism with EC inhibition was also proposed. PMID- 27507466 TI - Changes in whole grain polyphenols and antioxidant activity of six sorghum genotypes under different irrigation treatments. AB - Sorghum grain containing elevated polyphenolic antioxidant content may provide foods with benefits to human health. A study was undertaken to determine the potential role of irrigation on the content of polyphenols and antioxidant levels in sorghum grain. Bound, free and total polyphenols were investigated in six diverse sorghum genotypes grown under either full irrigation or a deficit irrigation regime. Results showed genotype, irrigation and their interaction had a significant effect on polyphenols and antioxidant activity (P?0.05). The deficit irrigation treatment significantly increased polyphenol content and antioxidant activity compared to the full irrigation treatment. Of the six genotypes Shawaya black short 1 and IS1311C (brown) showed the highest polyphenols levels and antioxidant activity. Therefore, both irrigation treatments and genotype need to be considered by sorghum breeders and farmers during sorghum production to produce grain with the required levels of polyphenolics and antioxidant activity for targeted end-use. PMID- 27507467 TI - Enzymatic hydrolysis of phytate and effects on soluble oxalate concentration in foods. AB - Soluble oxalate in foods is major concern for kidney stone formers due to its tendency to increase urinary oxalate concentration. Phytate forms complexes with cations, which increases soluble oxalate by making cations unavailable to precipitate oxalate. Thus, in order to reduce soluble oxalate, bran samples (wheat, oat and barley) and bean samples (red kidney bean and white bean) were treated with phytase. Release of phosphate after phytate degradation and its association with calcium was determined. Phosphate concentration increased after application of phytase in all samples, but effect on soluble oxalate concentration varied. Wheat and oat bran showed significant reduction (P<0.05) in soluble oxalate compared to bean samples. Wheat bran, oat bran and white bean had a lower calcium:phosphate ratio than barley bran and red kidney beans. Correlation of the calcium:phosphate molar ratio with release of phosphate depends on concentration of calcium ions and this influences soluble oxalate concentration. PMID- 27507468 TI - Stabilization of starch-based microgel-lysozyme complexes using a layer-by-layer assembly technique. AB - The layer-by-layer assembly of polyelectrolyte multilayers of chitosan (CS) and carboxymethyl starch (CMS) on soft and porous pH- and ionic strength-response microgels was determined by confocal laser scanning microscopy (CLSM) and zeta potential measurements. In vitro release of lysozyme from the stabilized microgels under simulated gastric and intestinal fluids was also investigated. The distribution of CS in the microgels was identified by CLSM, and the optimal molecular weight of CS was 100kDa, which could only be absorbed on the microgel surface. The CS was used as the first layer, while the CMS was used as the second layer, and the zeta potential revealed that the optimal weight ratios of CS and CMS to microgels in the complexes were 0.1 and 0.06, respectively. The in vitro release experiments suggested that the stabilized double-layer microgel complexes could potentially be applied as a carrier system to prevent early release in the stomach to target intestinal delivery. PMID- 27507469 TI - Coffee aroma: Chemometric comparison of the chemical information provided by three different samplings combined with GC-MS to describe the sensory properties in cup. AB - This study is part of a wider project aiming to correlate the chemical composition of the coffee volatile fraction to its sensory properties with the end-goal of developing an instrumental analysis approach complementary to human sensory profiling. The proposed investigation strategy compares the chemical information concerning coffee aroma and flavor obtained with HS-SPME of the ground coffee and in-solution SBSE/SPME sampling combined with GC-MS to evaluate their compatibility with the cupping evaluation for quality control purposes. Roasted coffee samples with specific sensory properties were analyzed. The chemical results obtained by the three samplings were compared through multivariate analysis, and related to the samples' sensory attributes. Despite the differences between the three sampling approaches, data processing showed that the three methods provide the same kind of chemical information useful for sample discrimination, and that they could be used interchangeably to sample the coffee aroma and flavor. PMID- 27507470 TI - Comparison of phytochemical profiles and health benefits in fiber and oil flaxseeds (Linum usitatissimum L.). AB - Flaxseed (Linum usitatissimum L.) is a rich source of nutritive and bioactive compounds. The research evaluated the disparity in phytochemical profiles along with total and cellular antioxidant activities between oil and fiber flaxseeds. There were significant differences in total phenolics, total flavonoids and antioxidant activities among the six cultivars of fiber and oil flaxseed, respectively. Four phytochemical compounds including caffeic acid, p-coumaric acid and ferulic acid, and secoisolariciresinol diglucoside (SDG) were identified and quantified in the cultivars of oil and fiber flaxseed by HPLC analysis. Notably, the average of total phenolic and flavonoid contents, along with total antioxidant activities between fiber and oil flaxseeds were not different significantly; even the cellular antioxidant activity of fiber flaxseed was superior to oil flaxseed. These results suggest that fiber flaxseeds would be valuable candidates as functional products and dietary supplements production owing to the higher bioactive values as well as oil flaxseeds. PMID- 27507471 TI - Anthocyanins degradation during storage of Hibiscus sabdariffa extract and evolution of its degradation products. AB - Degradation parameters of two main anthocyanins from roselle extract (Hibiscus sabdariffa L.) stored at different temperatures (4-37 degrees C) over 60days were determined. Anthocyanins and some of their degradation products were monitored and quantified using HPLC-MS and DAD. Degradation of anthocyanins followed first order kinetics and reaction rate constants (k values), which were obtained by non linear regression, showed that the degradation rate of delphinidin 3-O sambubioside was higher than that of cyanidin 3-O-sambubioside with k values of 9.2.10(-7)s(-1) and 8.4.10(-7)s(-1) at 37 degrees C respectively. The temperature dependence of the rate of anthocyanin degradation was modeled by the Arrhenius equation. Degradation of delphinidin 3-O-sambubioside (Ea=90kJmol(-1)) tended to be significantly more sensitive to an increase in temperature than cyanidin 3-O sambubioside (Ea=80kJmol(-1)). Degradation of these anthocyanins formed scission products (gallic and protocatechuic acids respectively) and was accompanied by an increase in polymeric color index. PMID- 27507472 TI - A method for producing superfine black tea powder with enhanced infusion and dispersion property. AB - Tea is rich in healthy components including polyphenols, caffeine, gallic acids, and others. Current technology of tea infusion and extraction leads to more than 40% soluble solids wasted in spent leaf. To increase the bioaccessibility of black tea, we report a method of pulverization treatments including general and superfine grinding to reduce the particle size. In comparison with coarsely ground black tea powders (BTPs), the superfine ground BTP with medium diameter 6.9MUm resulted in significant higher infusion yield of total polyphenols (TPP), caffeine, and water-soluble carbohydrate (WSC). The total water-soluble solids (WSS) of superfine BTP infusion increased markedly by twice due to the accelerated diffusion and enhanced solubility. High correlation between particle size and sedimentation ratio suggested improved dispersion stability of superfine BTP. The optimal dispersion of 0.1% superfine BTP in water was obtained by combination of homogenization and 0.08% CMC-Na formulation with 27.05% centrifugal sedimentation ratio. PMID- 27507473 TI - Seed coat color and seed weight contribute differential responses of targeted metabolites in soybean seeds. AB - The distribution and variation of targeted metabolites in soybean seeds are affected by genetic and environmental factors. In this study, we used 192 soybean germplasm accessions collected from two provinces of Korea to elucidate the effects of seed coat color and seeds dry weight on the metabolic variation and responses of targeted metabolites. The effects of seed coat color and seeds dry weight were present in sucrose, total oligosaccharides, total carbohydrates and all measured fatty acids. The targeted metabolites were clustered within three groups. These metabolites were not only differently related to seeds dry weight, but also responded differentially to seed coat color. The inter-relationship between the targeted metabolites was highly present in the result of correlation analysis. Overall, results revealed that the targeted metabolites were diverged in relation to seed coat color and seeds dry weight within locally collected soybean seed germplasm accessions. PMID- 27507474 TI - Comparison of alpha-amylase, alpha-glucosidase and lipase inhibitory activity of the phenolic substances in two black legumes of different genera. AB - Antioxidant-rich plant foods can inhibit starch and lipid digestions that are relevant to diabetes management. Two high-antioxidant black legumes, black soybean (Glycine max) and black turtle bean (Phaseolus vulgaris), belonging to two different genera were used to investigate their capacity against digestive enzymes. Phenolic substances were compared in crude, semi-purified extracts (semi purified by XAD-7 column), and fractions (fractionationed by Sephadex LH-20 column) from these two legumes. In addition, their antioxidant capacities and abilities to inhibit digestive enzymes were characterized. Results showed that Fraction V from black soybean was the most effective (IC50: 0.25mg/mL) against alpha-amylase; Fraction V from black turtle bean was the most potent (IC50: 0.25MUg/mL) against alpha-glucosidase; Fraction IV from black turtle bean was the most powerful (IC50: 76MUg/mL) against lipase. Of the pure phenolic compounds tested, myricetin showed the highest inhibition of alpha-amylase, alpha glucosidase and lipase (IC50: 0.38mg/mL, 0.87MUg/mL and 15MUg/mL, respectively). PMID- 27507475 TI - Oxyresveratrol and ascorbic acid O/W microemulsion: Preparation, characterization, anti-isomerization and potential application as antibrowning agent on fresh-cut lotus root slices. AB - The purpose of this study is to prepare an oxyresveratrol (Oxy) microemulsion (ME) with improved Oxy's solubility and stability and to investigate its antibrowning effects on fresh-cut lotus root slices. The formula of OxyME consisted of ethyl butyrate, Tween 80, PEG400, and water with w/w of 4%, 10.67%, 5.33%, and 80%, respectively. Encapsulating Oxy into OxyME greatly increased its solubility and stability compared with that of in water. Strong antibrowning effects were observed on fresh-cut lotus root slices treated with OxyME, even better than 4-hexylresorcinol. The addition of ascorbic acid (VC) into OxyME greatly improved the Oxy stability in long-term storage and antibrowning effects on fresh-cut lotus root slices. However, the simultaneous addition of calcium chloride and VC did not obviously improve the antibrowning effects compared with the addition of VC alone. These results indicated that Oxy+VCME may be suitable as an antibrowning agent for fresh-cut vegetables. PMID- 27507476 TI - Effect of polyglycerol esters additive on palm oil crystallization using focused beam reflectance measurement and differential scanning calorimetry. AB - The effect of 0.1-0.7% (w/w) of polyglycerol esters (PGEmix-8) on palm oil crystallization was studied using focused beam reflectance measurement (FBRM) to analyze the in-line changes of crystal size distribution during the crystallization. FBRM results show that 0.1-0.5% (w/w) of PGEmix-8 did not significantly affect nucleation but slightly retarded crystal growth. The use of 0.7% (w/w) additive showed greater heterogeneous nucleation compared to those with lower dosages of additive. Crystal growth was also greatly reduced when using 0.7% (w/w) dosage. The morphological study indicated that the palm oil crystals were smaller and more even in size than when more additive was added. Isothermal crystallization studies using differential scanning calorimetry (DSC) showed increased inhibitory effects on palm oil crystal growth with increasing concentration of PGEmix-8. These results imply that PGEmix-8 is a nucleation enhancing and crystal growth retarding additive in palm oil crystallization at 0.7% (w/w) dosage. PMID- 27507477 TI - Effect of parboiling on phytochemical content, antioxidant activity and physicochemical properties of germinated red rice. AB - In order to improve functional properties and palatability of germinated red rice, this study investigated differences in phytochemicals and physicochemical properties of germinated red rice at 2, 5, 10, 15min of parboiling. Total free phenolic content and antioxidant activity of germinated red rice parboiled for 5 and 15min was higher than that of germinated red rice. Free p-coumaric acid increased from 0.20 to 0.67mg/100g with parboiling time increasing from 5 to 15min. Bound vanillic (0.17-0.27mg/100g) and p-coumaric acid (6.56-8.59mg/100g) had higher levels at 0, 2, or 5min. During 15min of parboiling, color difference (DeltaE) increased from 0.58 to 9.09, heat enthalpy (DeltaH) decreased from 4.69 to 1.94J/g, and internal structure of rice was destroyed. Overall, parboiling time of less than 5min was suitable to improve the quality of germinated red rice. PMID- 27507478 TI - Phenolic compound in beans as protection against mycotoxins. AB - Phenolic compounds, their inhibitory activity against fungal amylase and the occurrence of aflatoxins were determined in edible beans. The free, conjugated and bounded phenolic compounds and their phenolic acid profiles were determined in ten bean varieties. A method for aflatoxin B1, B2, G1 and G2 determination and confirmation by LC-MS/MS was validated. The red and carioca beans presented the highest total phenolic content (1.8 and 1.2mg.g(-1), respectively); the fradinho and white beans the lowest (0.18 and 0.19mg.g(-1), respectively). In the free and conjugated forms, chlorogenic acid was present in 60% of the samples, while in the bounded phenolic, ferulic acid was in 90% of the samples. The phenolic extracts were able to inhibit fungal amylase, and the PCA analysis confirmed that the relation between the chlorogenic and gallic acids is important to this effect. The absence of aflatoxins in samples confirm the protector effects of these phenolic compounds. PMID- 27507479 TI - Capillary electrophoresis method with UV-detection for analysis of free amino acids concentrations in food. AB - Simple and inexpensive capillary electrophoresis with UV-detection method (CE-UV) was optimized and validated for determination of six amino acids namely (alanine, asparagine, glutamine, proline, serine and valine) for Sudanese food. Amino acids in the samples were derivatized with 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD Cl) prior to CE-UV analysis. Labeling reaction conditions (100mM borate buffer at pH 8.5, labeling reaction time 60min, temperature 70 degrees C and NBD-Cl concentration 40mM) were systematically investigated. The optimal conditions for the separation were 100mM borate buffer at pH 9.7 and detected at 475nm. The method was validated in terms of linearity, limit of detection (LOD), limit of quantification (LOQ), precision (repeatability) (RSD%) and accuracy (recovery). Good linearity was achieved for all amino acids (r(2)>0.9981) in the concentration range of 2.5-40mg/L. The LODs in the range of 0.32-0.56mg/L were obtained. Recoveries of amino acids ranging from 85% to 108%, (n=3) were obtained. The validated method was successfully applied for the determination of amino acids for Sudanese food samples. PMID- 27507480 TI - Storage stability of phenolic compounds in powdered BRS Violeta grape juice microencapsulated with protein and maltodextrin blends. AB - The stabilities of the phenolic compounds, antioxidant activity and colour parameters of microencapsulated powdered BRS Violeta red grape juice were evaluated throughout storage at 5, 25 and 35 degrees C for up to 150days. Different soy protein (S) or whey protein (W) blends with maltodextrin (M) were used as carrier agents, added at diverse concentrations and proportions. The treatment combining S and M with the highest carrier agent concentration (1SM) preserved almost all the anthocyanins. Except for 1SM, the proportion of p coumaroylated anthocyanins increased during storage, and the flavonol content of the 1SM powder decreased after 150days. The hydroxycinnamate content decreased for all treatments, independent of storage temperature, and flavan-3-ols were lost at 35 degrees C. The time and temperature did not influence the antioxidant activity of the powder or the colour of the reconstituted grape juice after 150days. PMID- 27507481 TI - Effects of salts on the gelatinization and retrogradation properties of maize starch and waxy maize starch. AB - The objective of this study was to evaluate the effects of salts on the gelatinization and retrogradation of maize and waxy maize starch. Experimental results showed that the salting-out or structure-making ions, such as F(-) and SO4(2-), decreased the swelling power, solubility and transparency of both starches, but increased the gelatinization temperature, enthalpy, and syneresis, due to the tendency of these ions to protect the hydrogen bond links among starch molecules. On the other hand, the salting-in or structure-breaking ions, such as I(-) and SCN(-), exhibited the opposite effects. Microscopic observations confirmed such effects of salts on both starches. Furthermore, the effects of salts were more significant on waxy maize and on normal maize starch. Generally, salts could significantly influence on the gelatinization and retrogradation of maize and waxy maize starch, following the order of the Hofmeister series. PMID- 27507482 TI - Study on the metabolites of isoalantolactone in vivo and in vitro by ultra performance liquid chromatography combined with Triple TOF mass spectrometry. AB - Isoalantolactone (IAL) is an active sesquiterpene naturally present in many vegetables, condiments and medicinal plants. In this study, an efficient strategy was developed for the identification of metabolites following the in vivo metabolism and in vitro biotransformation of IAL with rat intestinal bacteria utilizing ultra performance liquid chromatography combined with Triple TOF mass spectrometry (UPLC-Triple TOF-MS/MS). As a result, 46 metabolites including 34 novel sulfur-containing products were identified. The results demonstrated that IAL could undergo general metabolic reactions, including oxidation, hydration, hydrogenation, demethylation, cysteine conjugation and N-acetylcysteine conjugation, but the most noticeable characteristic of IAL metabolism was the H2S addition to the double bond between C-11 and C-13 and subsequent reactions to produce a series of novel sulfur-containing dimers. This is the first study of IAL metabolism in vivo, whose results provide novel and useful data for a better understanding of the safety and efficacy of IAL. PMID- 27507483 TI - Optimisation of selective alkaline extraction for Cr(VI) determination in dairy and cereal products by HPIC-ICPMS using an experimental design. AB - This study presents the optimisation through an experimental design then the validation of a method to determine Cr(VI) in certain foodstuffs by high performance ionic chromatography with inductively coupled plasma mass spectrometry. This method is free from interferences possibly associated with chloride and organic or inorganic carbon. Analytical performances assessed by the accuracy profile method were satisfactory in terms of linearity, specificity, sensitivity, accuracy, repeatability and intermediate precision. Limits of quantification ranged from 0.6MUg.kg(-1) in dairy products to 0.8MUg.kg(-1) in cereal products. The method was applied to the determination of Cr(VI) in dairy and cereal products from different brands and origins. Despite the method's very high sensitivity, Cr(VI) was not found in all the studied samples. This confirms the results of the most recent studies using an on-line speciation method, and invalidates older studies that found traces of Cr(VI) in food by using a less specific off-line speciation method. PMID- 27507484 TI - Characterization of a salt-tolerant aminopeptidase from marine Bacillus licheniformis SWJS33 that improves hydrolysis and debittering efficiency for soy protein isolate. AB - An aminopeptidase was isolated from the marine Bacillus licheniformis SWJS33 (BLAP) and purified. According to the tandem mass spectrometry, the enzyme displayed 11% amino acid identity with the aminopeptidase from Bacillus (gi|496687392). BLAP exhibited maximum activity at 60 degrees C and pH 8.0-8.5 and had a molecular mass of 100kDa. The presence of NaCl enabled 50% improvement of enzyme activity with 10-15% NaCl being the best. The observed inactivation by EDTA and bestatin and activation by Co(2+) and Ag(+) indicated that the obtained enzyme was a metalloaminopeptidase. Such an aminopeptidase could further improve the hydrolysis degree of soy protein isolate hydrolysates catalyzed by papain, Alcalase 2.4L or Flavourzyme 500MG from 8.5%, 9.5% or 14.4-18.8%, 18.7% or 20.1%, respectively, while decreasing the bitter intensity score of the SPI hydrolysates catalyzed by Alcalase 2.4L from 3.6 to 0.4. PMID- 27507485 TI - Direct activation of GABAA receptors by substances in the organic acid fraction of Japanese sake. AB - We investigated the effect of substances present in Japanese sake on the response of ionotropic gamma-aminobutyric acid (GABA)A receptors expressed in Xenopus oocytes. Sake was fractionated by ion-exchange chromatography. The fraction containing organic acids (OA fraction) showed agonist activities on the GABAA receptor. OA fractions from sake were analyzed by capillary electrophoresis time of-flight mass spectrometry (CE-TOFMS). Of the 64 compounds identified, 13 compounds showed GABAA receptor agonist activities. Especially, l-lactic acid showed high agonist activity and its EC50 value was 37MUM. Intraperitoneal injections of l-lactic acid, gluconic acid, and pyruvic acid (10, 10, and 5mg/kg BW, respectively), which showed agonistic activity on the GABAA receptor, led to significant anxiolytic effects during an elevated plus-maze test in mice. PMID- 27507486 TI - Methylmercury varies more than one order of magnitude in commercial European rice. AB - Rice is known to accumulate methylmercury (MeHg) in the rice grains. MeHg as a neurotoxin impacts on the human central nervous systems and especially on the developing brain. In this exploratory study, 87 commercial rice products sold in Europe, including nine baby-rice products, were analyzed for total Hg and MeHg content. MeHg concentration in all rice products investigated range from 0.11 to 6.45MUgkg(-1) with an average value of 1.91+/-1.07MUgkg(-1) and baby-rice is not significantly different from other rice products. Total Hg ranges from 0.53 to 11.1MUgkg(-1) with an average of 3.04+/-2.07MUgkg(-1). MeHg concentrations in all rice products studied in this work would not exceed the provisional tolerable weekly intake (PTWI). 30% of all commercial market rice products exceeded 10% of the PTWI calculated for toddlers or 13% of products for adults with rice based diet. PMID- 27507487 TI - Facile preparation of water soluble curcuminoids extracted from turmeric (Curcuma longa L.) powder by using steviol glucosides. AB - Curcuminoids from rhizomes of Curcuma longa possess various biological activities. However, low aqueous solubility and consequent poor bioavailability of curcuminoids are major limitations to their use. In this study, curcuminoids extracted from turmeric powder using stevioside (Ste), rebaudioside A (RebA), or steviol glucosides (SG) were solubilized in water. The optimum extraction condition by Ste, RebA, or SG resulted in 11.3, 9.7, or 6.7mg/ml water soluble curcuminoids. Curcuminoids solubilized in water showed 80% stability at pH from 6.0 to 10.0 after 1week of storage at 25 degrees C. The particle sizes of curcuminoids prepared with Ste, RebA, and SG were 110.8, 95.7, and 32.7nm, respectively. The water soluble turmeric extracts prepared with Ste, RebA, and SG showed the 2,2-diphenyl-1-picrylhydrazyl radical scavenging (SC50) activities of 127.6, 105.4, and 109.8MUg/ml, and the inhibition activities (IC50) against NS2B NS3(pro) from dengue virus type IV of 14.1, 24.0 and 15.3MUg/ml, respectively. PMID- 27507489 TI - DNA barcoding for identification of consumer-relevant mushrooms: A partial solution for product certification? AB - One challenge in the dietary supplement industry is confirmation of species identity for processed raw materials, i.e. those modified by milling, drying, or extraction, which move through a multilevel supply chain before reaching the finished product. This is particularly difficult for samples containing fungal mycelia, where processing removes morphological characteristics, such that they do not present sufficient variation to differentiate species by traditional techniques. To address this issue, we have demonstrated the utility of DNA barcoding to verify the taxonomic identity of fungi found commonly in the food and dietary supplement industry; such data are critical for protecting consumer health, by assuring both safety and quality. By using DNA barcoding of nuclear ribosomal internal transcribed spacer (ITS) of the rRNA gene with fungal specific ITS primers, ITS barcodes were generated for 33 representative fungal samples, all of which could be used by consumers for food and/or dietary supplement purposes. In the majority of cases, we were able to sequence the ITS region from powdered mycelium samples, grocery store mushrooms, and capsules from commercial dietary supplements. After generating ITS barcodes utilizing standard procedures accepted by the Consortium for the Barcode of Life, we tested their utility by performing a BLAST search against authenticate published ITS sequences in GenBank. In some cases, we also downloaded published, homologous sequences of the ITS region of fungi inspected in this study and examined the phylogenetic relationships of barcoded fungal species in light of modern taxonomic and phylogenetic studies. We anticipate that these data will motivate discussions on DNA barcoding based species identification as applied to the verification/certification of mushroom-containing dietary supplements. PMID- 27507488 TI - Selenium-enriched durum wheat improves the nutritional profile of pasta without altering its organoleptic properties. AB - Two field experiments were conducted over three growing seasons (2006-07, 2008-09 and 2009-10) to evaluate Se-enriched pasta through foliar fertilization at various rates and timing of application on 4 durum wheat varieties. Our findings confirm the effectiveness of foliar Se fertilization to increase Se concentrations in durum wheat grain, even at high Se rates (120gSeha(-1)). Se fortification was significant across different genotypes, with greater Se accumulation in landraces ('Timilia') and obsolete varieties ('Cappelli'), with respect to modern varieties. The Se content in the grain was increased by up to 35-fold that of the untreated control. The Se concentration decreased during milling (11%), while processing and cooking of pasta did not show significant decreases. This biofortification stategy had no effects on grain quality parameters, except for reduced gluten index in the high-gluten variety PR22D89, as well as for the sensorial properties of the spaghetti. PMID- 27507490 TI - Changes in chemical interactions and protein conformation during heat-induced wheat gluten gel formation. AB - In order to elucidate the heat-induced wheat gluten gel formation mechanism, changes in chemical interactions and protein conformation were investigated during gelation. The contribution of ionic and hydrogen bonds were found to decrease from 0.746 and 4.133g/L to 0.397 and 2.733g/L, respectively, as the temperature increased from 25 to 90 degrees C. Moreover, the free SH content remarkably decreased from 37.91 to 19.79MUmol/g during gelation. Ultraviolet absorption spectra and intrinsic fluorescence spectra suggested that wheat gluten unfolded during the heating process. In addition, wheat gluten gels treated at 80 and 90 degrees C exhibited a "steric hindrance" effect, which can be attributed to the formation of aggregates. Fourier transform infrared spectra suggested that the random coil content increased at low temperatures (40 and 50 degrees C), whereas the content of intermolecular beta-sheets due to protein aggregation increased from 38.10% to 44.28% when the gelation temperature was 90 degrees C. PMID- 27507491 TI - Mineral content of sorghum genotypes and the influence of water stress. AB - Sorghum is a source of several minerals whose content may vary depending on the genotype and the production environment. The objective of this study was to screen sorghum genotypes for mineral content and to investigate the effect of water stress on it. A large variability was observed in the mineral content of 100 sorghum genotypes grown in environments without (WoWS) and with water stress (WthWS). The water stress decreased Mn, P, Mg and S contents in 100, 96, 93 and 56% of genotypes, respectively. The genotypes and other factors seemed to have more impact than water stress on K, Ca, Cu, Fe and Zn levels. In 100 sorghum genotypes, 2 were classified as excellent sources of Fe and 25 of Zn, in both environments. The best two genotypes to Fe content were SC21 and SC655 and to Zn were SC320 and SHAN-QUI-RED which showed great potential for use in biofortification. PMID- 27507492 TI - Transcriptional regulation of lycopene metabolism mediated by rootstock during the ripening of grafted watermelons. AB - Rootstocks have comprehensive effects on lycopene accumulation in grafted watermelon fruits. However, little is known about lycopene metabolic regulation in grafted watermelon. To address this problem, parallel changes in lycopene contents and the expression of its metabolic genes were analyzed during the fruit ripening of nongrafted watermelon and watermelon grafted onto bottle gourd, pumpkin, and wild watermelon. Results showed that rootstocks mediated the transcriptional regulations of lycopene accumulation in different ways. Bottle gourd and wild watermelon promoted lycopene accumulation in grafted watermelon fruits by upregulating the biosynthetic genes phytoene synthase (PSY) and zeta carotene desaturase (ZDS), and downregulating the catabolic genes beta-carotene hydroxylase (CHYB), zeaxanthin epoxidase (ZEP), 9-cis-epoxycarotenoid dioxygenase (NCED), and carotenoid cleavage dioxygenase (CCD). However, pumpkin did not affect lycopene accumulation by upregulating both biosynthetic and catabolic genes. The rootstock-dependent characteristic of lycopene accumulation in grafted watermelon fruits provided an alternative model for investigating lycopene metabolic regulation. PMID- 27507493 TI - Hydrothermal changes in wheat starch monitored by two-dimensional NMR. AB - The temperature-dependent changes in wheat starch powder and wheat starch-water mixtures were monitored in real-time throughout the heating/cooling program using a classical one-dimensional T1 method and a novel bi-dimensional approach to correlate spin-lattice and spin-spin relaxation times (T1-T2) including acquisition of the FID signal. The influence of two controlling factors (i.e. water content (11%, 35-50%, wet basis) and temperature (20-90 degrees C and back to 20 degrees C)) on water distribution and starch transformation was investigated. Quantitative analysis of 2D T1-T2 maps greatly facilitated the interpretation of T1 relaxation times, which have been interpreted rather narrowly in the literature when classically measured in one-dimension. Application of the new IR-FID-CPMG sequence allowed distinction between different proton pools with different T1 relaxation times, particularly when the starch gelatinization occurred. The quantification of each T1 component permitted to assign the short T1 to slow cross relaxation phenomena, highlighting proton chemical and/or diffusional exchanges between water and starch. PMID- 27507494 TI - Aggregation and conformational change of mushroom (Agaricus bisporus) polyphenoloxidase subjected to thermal treatment. AB - This study investigated changes in the activity, conformation and microstructure of mushroom polyphenoloxidase (PPO) subjected to thermal treatment. The inactivation of PPO can be achieved by high temperature-short time or mild temperature-long time treatment. Circular dichroism and fluorescence spectra suggested that heating process induced the rearrangement of secondary structure and the disruption of tertiary structure. Red shifts of fluorescence spectra showed positive correlations with the inactivation rate of PPO. There were significant differences in the conformation and molecular microstructure among PPO samples with the same relative activity, which were obtained by treating PPO at 45, 55 and 65 degrees C for different times. In summary, PPO molecules were deformed at mild temperature, while higher temperature induced the formation of large aggregates. PPO with the same relative activity might exist in different forms. PMID- 27507495 TI - Effects of clove essential oil and eugenol on quality and browning control of fresh-cut lettuce. AB - This study confirmed the inhibitory effects of clove essential oil (CEO) and eugenol (EUG) on the browning and relevant enzymes of fresh-cut lettuce, and examined associated mechanisms by inhibition kinetics and computational docking analysis. Fresh-cut lettuce was treated with 0.05% CEO and 0.05% EUG solutions, resulting in inhibition of the deterioration of texture quality and browning of the lettuce surface and interior. Compared with the controls, CEO and EUG significantly inhibited the activities of phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO), and peroxidase (POD, all p<0.05). EUG suppressed PAL, PPO, and POD in vitro in a dose-dependent manner, with IC50 values of 5.4+/-0.9, 29.5+/-3.5, and 61.9+/-6.7mM, respectively. The binding and inhibition effects of EUG on PAL, PPO, and POD, determined by inhibition kinetics and computational docking analysis, established EUG as a competitive inhibitor of these browning relevant enzymes. PMID- 27507496 TI - Multi-mycotoxin contamination of couscous semolina commercialized in Morocco. AB - The multi-mycotoxin contamination of ninety-eight (98) couscous semolina samples collected from various areas in Morocco was investigated in this study. Samples were surveyed for the presence of 22 mycotoxins (four aflatoxins, ochratoxin A, diacetoxiscyrpenol (DAS), three fumonisins, beauvericin (BEA), deoxynivalenol (DON), 15-acetyl-deoxynivalenol (15-ADON), 3-acetyl-deoxynivalenol (3-ADON), nivalenol (NIV), sterigmatocystin (STG), zearalenone (ZEA), four enniatins, T-2 and HT-2 toxins). Results showed that 96 out of 98 total couscous samples (98%) were contaminated by at least one mycotoxin. Enniatin B (ENB), Enniatin B1 (ENB1), Enniatin A1 (ENA1) and zearalenone (ZEA) have shown the highest incidences in contaminated samples. The dietary exposure was estimated to be 1.02, 0.57, 0.06, 0.57 and 0.3MUg/kgbw/day for the sum of (DON+3-ADON+15-ADON), fumonisins (FB1+FB2+FB3), the sum of (T2+HT-2), NIV and ZEA, respectively. PMID- 27507497 TI - Contribution of trans-aconitic acid to DPPH scavenging ability in different media. AB - The antioxidant properties of trans-aconitic acid (TAA) alone or in the presence of usual antioxidants were assessed by DPPH assay. The IC50 value equal to 70mM was very high compared to usual antioxidants (vitamin C and trolox). A joint experimental/theoretical study suggested that hydrogen atom abstraction in TAA by DPPH was located on -CH2- methylene bridge because the corresponding radical was more stabilized than COO(.) and CC(.) radicals. In combination with antioxidants (vitamin C, gallic acid, caffeic acid, trolox), synergy or additivity effects were noticed. The magnitude of the synergistic effect varied between 1.06 and 1.24 depending on the type and concentration of antioxidant for a concentration of TAA equal to 22.3mM. Especially, the addition of TAA at a concentration below 32mM to a solution containing 20MUM of vitamin C had a synergy effect. Beyond this concentration, TAA showed an additive effect. PMID- 27507498 TI - The whole grain content of foods consumed in the UK. AB - This study aimed to assess the whole grain (WG) content of foods consumed in the UK which include ingredients that retain all three structural components of the grain, and contained ?10% WG. Dietary data from seven studies with 10,474 UK subjects were examined for foods containing WG. The WG content was then determined from ingredient lists, manufacturers' information and recipes. 372 food descriptors from nine food groups (4.4% of all food codes) contained ?10% WG. Of these 372 foods, 31.5% contained ?51%, 30.6% 25-50%, and 37.9% 10-24% WG dry matter as eaten. The relatively small number of WG foods identified in the total number of foods consumed confirms the low contribution of WG foods to the overall pattern of foods consumed in the UK. Since foods containing <51% WG accounted for the majority of WG food codes identified, recognising the importance of these foods to WG intake is essential. PMID- 27507499 TI - Black bean (Phaseolus vulgaris L.) protein hydrolysates: Physicochemical and functional properties. AB - Black bean protein hydrolysates obtained from pepsin and alcalase digestions until 120min of hydrolysis were evaluated by gel electrophoresis, relative fluorescence intensity, emulsifying properties, light micrograph of emulsions and in vitro antioxidant activity. The emulsion stability of the bean protein hydrolysates were evaluated during 30days of storage. The pepsin-treated bean protein hydrolysates presented higher degree of hydrolysis than the alcalase treated protein hydrolysates. The alcalase-treated bean protein hydrolysates showed higher surface hydrophobicity. Moreover, the protein hydrolysates obtained with alcalase digestion presented higher emulsion stability during 30-days than those obtained from pepsin digestion. The protein concentrate and especially the hydrolysates obtained from alcalase digestion had good emulsion stability and antioxidant activity. Thus, they could be exploited as protein supplements in the diet as nutritional and bioactive foods. PMID- 27507500 TI - Fatty acids and fat-soluble vitamins in ewe's milk predicted by near infrared reflectance spectroscopy. Determination of seasonality. AB - The aim of the present work was to determine the fatty acid and fat-soluble vitamin composition and the season of ewe's milk production using NIR spectroscopy. 219 ewe's milk samples from different breeds and feeding regimes were taken each month over one year. Fatty acids were analyzed by gas chromatography, and retinol and alpha-, and gamma-tocopherol by liquid chromatography. The results showed that the quantification was more accurate for the milk dried on paper, except for vitamins. Calibration statistical descriptors on milk dried on paper were good for capric, lauric, myristic, palmitoleic, stearic and oleic acids, and acceptable for caprilic, undecanoic, 9c, 11tCLA, SigmaCLA, PUFA, omega3, omega6, retinol and alpha-tocopherol. The equations for the discrimination of seasonality was obtained using the partial least squares discriminant analysis (PLSDA) algorithm. 93% of winter samples and 89% of summer samples were correctly classified using the NIR spectra of milk dried on paper. PMID- 27507501 TI - Evaluation studies of persimmon plant (Diospyros kaki) for physiological benefits and bioaccessibility of antioxidants by in vitro simulated gastrointestinal digestion. AB - This study aims to analyze the antioxidant benefits from persimmon leaf tea, fruit and fibres taking into account their changes along gastrointestinal digestion. The evolution of polyphenols, flavonoids and antioxidant capacity was studied using the recent harmonized in vitro protocol published by Minekus et al. (2014). The digestion was performed with and without digestive enzymes. Results showed aqueous leaf extract was richer in antioxidants than the fruit or the extracted fibres. Nevertheless, persimmon-leaf antioxidants were more sensitive to the digestive environment. In general, the oral conditions greatly affected the antioxidants, while gastric digestion led to slight additional losses. The intestinal step enhanced polyphenols and flavonoids solubility coming from the fruit and fibres. Additionally, the presence of digestive enzymes positively contributed to antioxidant release throughout digestion. Finally, the bioaccessibility of polyphenols, flavonoids and antioxidant activity of persimmon fruit were 1.4, 1.0 and 3.8 times higher than in aqueous leaf extract. PMID- 27507502 TI - The food matrix affects the anthocyanin profile of fortified egg and dairy matrices during processing and in vitro digestion. AB - The aim of the present study was to understand to what extent the inclusion of anthocyanins into dairy and egg matrices could affect their stability after processing and their release and solubility during digestion. For this purpose, individual and total anthocyanin content of four different enriched matrices, namely custard dessert, milkshake, pancake and omelettete, was determined after their manufacturing and during in vitro digestion. Results showed that anthocyanin recovery after processing largely varied among matrices, mainly due to the treatments applied and the interactions developed with other food components. In terms of digestion, the present study showed that the inclusion of anthocyanins into food matrices could be an effective way to protect them against intestinal degradation, and also the incorporation of anthocyanins into matrices with different compositions and structures could represent an interesting and effective method to control the delivery of anthocyanins within the different compartments of the digestive tract. PMID- 27507503 TI - Crystallization kinetics of cocoa butter in the presence of sorbitan esters. AB - Cocoa butter crystallization in the presence of sorbitan mono- and triesters or canola oil was investigated. Solid-state surfactant esters accelerated early stage cocoa butter solidification while suppressing later growth. Sorbitan tristearate showed the strongest effect, followed by sorbitan monostearate and sorbitan monopalmitate. Liquid-state surfactants suppressed cocoa butter crystallization at all time points, with sorbitan trioleate showing a stronger effect than sorbitan monooleate, which behaved in a similar fashion to canola oil. Via DSC, the palmitic and stearic-based surfactants only associated with cocoa butter's high-melting fraction, with the oleic acid-based surfactants and canola oil showing little influence. All sorbitan esters had little effect on polymorphism, whereas canola oil accelerated the form II-to-III-to-IV transition. The palmitic and stearic-based surfactants greatly reduced cocoa butter crystal size whereas the oleic acid-based surfactants and canola showed no notable effect. Overall, sorbitan esters impacted cocoa butter crystallization kinetics, though this depended on surfactant structure and concentration. PMID- 27507504 TI - Secondary structure and conformational change of mushroom polyphenol oxidase during thermosonication treatment by using FTIR spectroscopy. AB - To understand the conformational changes of mushroom PPO, the secondary structural change of the enzyme during thermosonication treatment at different power (60, 80 and 100%), temperature (20-60 degrees C) and time (0-30min) combinations was investigated by using FTIR spectroscopy and compared with the change in enzyme activity. The enzyme inactivation higher than 99% was obtained at 100% amplitude at 60 degrees C for 10min. FTIR studies showed that marked spectral changes were noted after ultrasound treatment at 20 degrees C. The alpha helix and beta-sheet contents decreased, while aggregated beta-sheet, turns and random coil contents increased as temperature increased up to 60 degrees C during thermosonication treatment for 10min indicating protein denaturation. Aggregated bands located at 1683 and 1616cm(-1) became evident after ultrasound treatment at 40 degrees C. When temperature was lowered back to 25 degrees C, from ultrasound treatment at 60 degrees C, these bands were still observed, indicating the irreversible change in the structure. PMID- 27507505 TI - High-throughput assay comparison and standardization for metal chelating capacity screening: A proposal and application. AB - Aiming to standardize the experimental protocols to assess the ability to chelate Fe(2+) and Cu(2+) using 96-well microplates, we analyzed Brazilian coffees (n=20) as a study-case in relation to their antioxidant activity using conventional methods (DPPH and FRAP assays) and correlated the results with the total phenolic content (TPC) using bivariate and multivariate statistical approaches. Complementarily, we assessed the repeatability, reproducibility, recovery, and linearity of both methods. Data showed that the proposed assays presented a good repeatability and reproducibility (<7% RSD) and mean recovery values of 96.66% and 98.91% for the iron and copper assays, respectively. Both methods were linear in the range of 0-100mg EDTA equivalents/L. Cu(2+)-chelating ability was significantly correlated to FRAP, DPPH, and TPC, while sparse (p<0.05) correlations were obtained with Fe(2+)-chelating ability. Overall, both micro assays can be used to assess the ability of plant-based extracts to chelate Fe(2+) and Cu(2+)in vitro. PMID- 27507506 TI - Determination of oligomeric proanthocyanidins and their antioxidant capacity from different chocolate manufacturing stages using the NP-HPLC-online-DPPH methodology. AB - Cocoa beans are a well-known source of antioxidant polyphenols. Especially individual oligomeric proanthocyanidins demonstrated a significant contribution to the total antioxidant activity of cocoa compared to monomeric compounds. An NP HPLC-online-DPPH assay was developed for separating the homologous series of oligomeric proanthocyanidins and the simultaneous assessment of their antioxidant capacity in relation to the degree of polymerization (DP). The present study describes the influence of the different stages of a lab-scale chocolate manufacturing process on the content of oligomeric proanthocyanidins and their antioxidant capacity. The sum of the total proanthocyanidin content (? DP1-DP13) decreased from 30mg epicatechin equivalents per gram non-fat dry matter in raw fresh cocoa beans to 6mg epicatechin equivalents per gram in the final chocolate. The antioxidant capacity decreased accordingly from 25mg epicatechin equivalents per gram non-fat dry matter in raw fresh cocoa beans to 4mg/g in the final chocolate product. PMID- 27507507 TI - Effects of germination and high hydrostatic pressure processing on mineral elements, amino acids and antioxidants in vitro bioaccessibility, as well as starch digestibility in brown rice (Oryza sativa L.). AB - The effects of germination and high hydrostatic pressure (HHP) processing on the in vitro bioaccessibility of mineral elements, amino acids (AAs), antioxidants and starch in brown rice (BR) were investigated. Germinated BR (GBR) was obtained by incubating at 37 degrees C for 36h and then subjected to HHP treatments at 0.1, 100, 300 and 500MPa for 10min. The in vitro bioaccessibility of calcium and copper was increased by 12.59-52.17% and 2.87-23.06% after HHP, respectively, but bioaccessible iron was decreased. In addition, HHP significantly improved individual AAs, particularly indispensable AAs and gama-aminobutyric acid, as well as bioaccessible total antioxidant activities and starch resistance to enzymatic hydrolysis. However, germination greatly increased starch digestibility. Atomic force microscopy characterization suggested an obvious structural change in bran fraction at pressures above 300MPa. These results can help to understand the effects of germination and HHP technologies on nutrients bioaccessibility and develop appropriate processing conditions. PMID- 27507508 TI - Effects of chitin nano-whiskers on the gelatinization and retrogradation of maize and potato starches. AB - Starch is very prone to retrogradation after gelatinization. Inhibition of starch retrogradation has been an important factor in improving the quality of food. For the first time, we investigated the effect of nano-materials, represented by chitin nano-whiskers (CNWs), on the short- and long-term retrogradation of maize and potato starches. Rapid Visco-Analyser results showed that the addition of CNWs significantly decreased the setback values of maize and potato starches, which suggested that CNWs could retard the short-term retrogradation of starch. Differential scanning calorimetry and X-ray diffraction results showed that the percentage of retrogradation of maize and potato starches significantly decreased (P<0.05), suggesting the inhibition of long-term retrogradation. The CNWs could be used as a new inhibitor of starch retrogradation to develop starch-based food with longer shelf life. PMID- 27507509 TI - Biochemical composition and antioxidant activities of Arthrospira (Spirulina) platensis in response to gamma irradiation. AB - Arthrospira (Spirulina) platensis is a blue-green alga, rich with bioactive components and nutrients. To evaluate effect of gamma irradiation, A. platensis was exposed to different doses of 0.0, 0.5, 1.0, 1.5, 2.0 and 2.5kGy. The data showed that the phenolic and proline contents significantly increased with the increase of gamma irradiation doses up to 2.0kGy, above which a reduction was observed. The soluble proteins and malondialdehyde (MDA) contents were stimulated by all tested irradiation doses. Furthermore, the vitamins (A, K and B group) and mineral contents (N, P, Na, K, Ca, Mg and Fe) were stimulated by the irradiation doses compared with the control. The activities of some N-assimilating and antioxidant enzymes were significantly increased with the irradiation doses up to 2.0kGy. This study suggests the possible use of gamma irradiation as a stimulatory agent to raise the nutritive value and antioxidant activity of A. platensis. PMID- 27507510 TI - Synthesis of some glucose-fatty acid esters by lipase from Candida antarctica and their emulsion functions. AB - The synthesis of glucose esters with palmitic acid, lauric acid and hexanoic acid using lipase enzyme was studied and their emulsion functionality in oil-in-water system were compared. Reactions at 3:1M ratio of fatty acids-to-glucose had the highest conversion percentages (over 90% for each of the fatty acid). Initial conversion rate increased as substrate solubility increased. Ester bond formation was confirmed by nuclear magnetic resonance technique that the chemical shifts of glucose H-6 and alpha-carbon protons of fatty acids in the ester molecules shifted to the higher fields. Contact angle of water on esters' pelleted surface increased as the hydrophobicity increased. Glucose esters' and commercial sucrose esters' functionality as emulsifiers were compared. Glucose esters delayed, but did not prevent coalescence, because the oil droplets diameter doubled during 7days. Sucrose esters prevented coalescence during 7days since the droplets diameter did not have significant change. PMID- 27507511 TI - Pressurized liquid extraction of anthocyanins and biflavonoids from Schinus terebinthifolius Raddi: A multivariate optimization. AB - Response surface methodology was employed to investigate the effects of pressurized liquid extraction (PLE) parameters on the recovery of phenolic compounds (anthocyanins, biflavonoids) from Brazilian pepper (Schinus terebinthifolius Raddi) fruits. The effects of temperature, static time, and ethanol as well as acid concentration on the polyphenol yield were described well by quadratic models (p<0.0001). A significant influence of the ethanol concentration (p<0.0001) and several interactions (p<0.05) were identified. Identification of the biflavonoid I3',II8-binaringenin in drupes of S. terebinthifolius was achieved by UHPLC-MS(2). Interestingly, at high extraction temperatures (>75 degrees C), an artifact occurred and was tentatively identified as a diastereomer of I3',II8-binaringenin. Multivariate optimization led to high yields of phenolic compounds from the exocarp/drupes at 100/75 degrees C, 10/10min, 54.5/54.2% ethanol, and 5/0.03% acetic acid. This study demonstrates that PLE is well suited for the extraction of phenolic compounds from S. terebinthifolius and can efficiently be optimized by response surface methodology. PMID- 27507512 TI - Antidiabetic activity and chemical constituents of the aerial parts of Heracleum dissectum Ledeb. AB - Heracleum dissectum Ledeb. has long been used as a wild edible vegetable by local people in China. The purpose of this study is to investigate the antidiabetic potential of aerial part of H. dissectum methanol extract (HdME) and the chemical constituents. Ten compounds including eight coumarins were isolated and four of them were found from H. dissectum for the first time. HdME potently inhibited the elevation of plasma glucose after its oral administration to glucose-loaded mice, and its petroleum ether (PE) fraction exerted the greatest inhibitory activities. Meanwhile, HdME (125 and 250mg/kg) also significantly decreased the blood glucose level in STZ-induced diabetic mice, but had no effect in normoglycemic mice. Additionally, HdME showed weak inhibitory effects on alpha-glucosidase activity and DPPH free radicals scavenging. In conclusion, HdME has antidiabetic action and PE fraction is the active part where coumarins possibly play an important role in antidiabetic activity. PMID- 27507513 TI - Sulforaphane formation and bioaccessibility are more affected by steaming time than meal composition during in vitro digestion of broccoli. AB - Broccoli is a rich source of the glucosinolate glucoraphanin (GR). After hydrolysis of GR by the endogenous enzyme myrosinase, sulforaphane (SF) or sulforaphane nitrile (SFN) are produced, depending on environmental conditions. How the conversion of GR and bioaccessibility of released breakdown products are affected by steaming (raw, 1min, 2min and 3min steamed) and meal composition (protein or lipid addition) was studied with an in vitro digestion model (mouth, stomach, intestine, but not colonic digestion). The main formation of SF and SFN occurred during in vitro chewing. The contents of GR, SF and SFN did not change after further digestion, as the irreversible inactivated myrosinase under gastric conditions caused no further GR hydrolysis. SF concentrations were up to 10 times higher in raw and 1min steamed broccoli samples after digestion compared to longer-steamed broccoli. Protein or lipid addition had no influence on the formation and bioaccessibility of SF or SFN. PMID- 27507514 TI - Simultaneous determination of individual isothiocyanates in plant samples by HPLC DAD-MS following SPE and derivatization with N-acetyl-l-cysteine. AB - The procedure for the isothiocyanates (ITCs) determination that involves derivatization with N-acetyl-l-cysteine (NAC) and separation by HPLC was developed. Prior to derivatization, plant ITCs were isolated and purified using solid-phase extraction (SPE). The optimum conditions of derivatization are: 500MUL of isopropanolic eluate obtained by SPE combined with 500MUL of derivatizing reagent (0.2M NAC and 0.2M NaHCO3 in water) and reaction time of 1h at 50 degrees C. The formed dithiocarbamates are directly analyzed by HPLC coupled with diode array detector and mass spectrometer if required. The method was validated for nine common natural ITCs. Calibration curves were linear (R(2)?0.991) within a wide range of concentrations and limits of detection were below 4.9nmol/mL. The recoveries were in the range of 83.3-103.7%, with relative standard deviations <5.4%. The developed method has been successfully applied to determine ITCs in broccoli, white cabbage, garden cress, radish, horseradish and papaya. PMID- 27507515 TI - Oxidation of proline decreases immunoreactivity and alters structure of barley prolamin. AB - Elimination of celiac-toxic prolamin peptides and proteins is essential for Triticeae products to be gluten-free. Instead of enzymatic hydrolysis, in this study we investigated metal-catalyzed oxidation of two model peptides, QQPFP, and PQPQLPY, together with a hordein isolate from barley (Hordeum vulgare L.). We established a multiple reaction monitoring (MRM) LC-MS method to detect and quantify proline oxidation fragments. In addition to fragmentation, aggregation and side chain modifications were identified, including free thiol loss, carbonyl formation, and dityrosine formation. The immunoreactivity of the oxidized hordein isolate was considerably decreased in all metal-catalyzed oxidation systems. Cleavage of peptides or protein fragments at the numerous proline residues partially accounts for the decrease. Metal-catalyzed oxidation can thus be used in the modification and elimination of celiac-toxic peptides and proteins. PMID- 27507516 TI - Comparing the calcium bioavailability from two types of nano-sized enriched milk using in-vivo assay. AB - Calcium bioavailability from two types of enriched (calcium citrate and calcium carbonate) milks homogenized to a nano-sized particle distribution has been studied among 48 female Sprauge-dawley rats. Skim milk powder was enriched with some essential nutrients (Inulin, DHA & EPA, vitamins B6, K1, and D3) as enhancers of calcium bioavailability according to recommended dietary allowances of the West European and North American. Ovariectomized and ovariectomized osteoporosis rats were used as a menopause and menopause-osteoporosis model, respectively. Although, nano-sized enriched milk powders had the greatest calcium bioavailability among the groups, but bioavailability of nano-sized calcium carbonate-enriched-milk was significantly (P<0.05) better than nano-sized calcium citrate-enriched-milk. Moreover, the trends were similar for bone calcium, strength and morphology. Therefore, based on the current results the calcium carbonate nano-sized enriched milk could be an effective enriched milk powder in ovariectomized-osteoporosis and ovariectomized rats as a model of menopause osteoporosis and menopause women. PMID- 27507517 TI - Characterization and emulsifying properties of beta-lactoglobulin-gum Acacia Seyal conjugates prepared via the Maillard reaction. AB - Gum Acacia Seyal (ASY) is less valued than is gum Acacia Senegal, due to its poor emulsifying ability. The present study investigated the Maillard reaction between ASY and beta-lactoglobulin (BLG) and its impact on the emulsifying properties of ASY. The reaction products of BLG/ASY mixture (r=1/4), prepared by dry-heating at 60 degrees C and a relative humidity of 79%, as a function of incubation time, were characterized by SDS-PAGE, GPC-MALLS and DSC. The results showed that 12-24h of dry-heating under the given conditions was sufficient for conjugation, meanwhile avoiding the formation of deeply coloured and insoluble melanoidins. More than 64% of the protein was incorporated into ASY, resulting in a two-fold increase in arabinogalactan-protein (AGP) content and 3.5 times increase in weight-average molecular mass of ASY. The conjugation with BLG markedly improved the stability of ASY-stabilized emulsions and their resistance against severe conditions, such as low pH and high saline conditions. PMID- 27507518 TI - Extraction of espresso coffee by using gradient of temperature. Effect on physicochemical and sensorial characteristics of espresso. AB - Espresso extraction is generally carried out at a fixed temperature within the range 85-95 degrees C. In this work the extraction of the espressos was made in a new generation coffee machine that enables temperature profiling of the brewing water. The effect of using gradient of temperature to brew espressos on physicochemical and sensorial characteristics of the beverage has been investigated. Three different extraction temperature profiles were tested: updrawn gradient (88-93 degrees C), downdrawn gradient (93-88 degrees C) and fixed temperature (90 degrees C). The coffee species investigated were Robusta, Arabica natural and Washed Arabica. Results proved that the use of gradient temperature for brewing espressos allows increasing or decreasing the extraction of some chemical compounds from coffee grounds. Moreover an appropriate gradient of temperature can highlight or hide some sensorial attributes. In conclusion, the possibility of programming gradient of temperature in the coffee machines recently introduced in the market opens new expectations in the field of espresso brewing. PMID- 27507519 TI - NGS tools for traceability in candies as high processed food products: Ion Torrent PGM versus conventional PCR-cloning. AB - The Next Generation Sequencing methodologies are considered the next step within DNA-based methods and their applicability in different fields is being evaluated. Here, we tested the usefulness of the Ion Torrent Personal Genome Machine (PGM) in food traceability analyzing candies as a model of high processed foods, and compared the results with those obtained by PCR-cloning-sequencing (PCR-CS). The majority of samples exhibited consistency between methodologies, yielding more information and species per product from the PGM platform than PCR-CS. Significantly higher AT-content in sequences of the same species was also obtained from PGM. This together with some taxonomical discrepancies between methodologies suggest that the PGM platform is still pre-mature for its use in food traceability of complex highly processed products. It could be a good option for analysis of less complex food, saving time and cost per sample. PMID- 27507520 TI - A food waste utilization study for removing lead(II) from drinks. AB - This is the first study about removal of lead (Pb(II)) from energy drinks. In this paper, food waste, namely eggshell (hydroxyapatite) utilization, was used to remove Pb(II) from mineral water and energy drinks. Mineral water and energy drinks were chosen for removal of lead since the latter is severely hazardous to human health even in small amounts. Response Surface Methodology (RSM) was performed to optimize the application process by practice of the quadratic model united with the Central Composite Design (CCD) and quadratic combined program was utilized to study the most effective parameters on aforementioned liquids. Through the application of variance analysis (ANOVA) factors critical to removing of lead were identified for each experimental design response. Maximum adsorption capacity of eggshell was achieved as 923mgg(-1) for Pb(II). The obtained optimum conditions were applied to drinks. Results showed that used adsorbent was quite effective in removing Pb(II) from drinks. PMID- 27507521 TI - Polyphenols from wolfberry and their bioactivities. AB - Nine new phenylpropanoids, one new coumarin, and 43 known polyphenols were isolated from wolfberry. Their structures were determined by spectroscopic analyses, chemical methods, and comparison of NMR data. Polyphenols, an important type of natural products, are notable constituents in wolfberry. 53 polyphenols, including 28 phenylpropanoids, four coumarins, eight lignans, five flavonoids, three isoflavonoids, two chlorogenic acid derivatives, and three other constituents, were identified from wolfberry. Lignans and isoflavonoids were firstly reported from wolfberry. 22 known polyphenols were the first isolates from the genus Lycium. This research presents a systematic study on wolfberry polyphenols, including their bioactivities. All these compounds exhibited oxygen radical absorbance capacity (ORAC), and some compounds displayed DPPH radical scavenging activity. One compound had acetylcholinesterase inhibitory activity. The discovery of new polyphenols and their bioactivities is beneficial for understanding the scientific basis of the effects of wolfberry. PMID- 27507522 TI - Effects of micronisation and dehulling of pre-soaked bambara groundnut seeds on microstructure and functionality of the resulting flours. AB - Functional properties of flours from pre-soaked and micronised (130 degrees C) whole and dehulled bambara seeds (5, 10 and 15min) were determined. An increase in micronisation time significantly reduced the pasting viscosity of the flours. Significant reductions in the differential scanning calorimetry endothermic peak enthalpies and loss of birefringence in the starch were found, indicating starch pre-gelatinisation when micronised. The low viscous paste of resultant flours seems to be related to protein denaturation as shown by decrease in nitrogen solubility index. Starch was embedded in a protein matrix as shown by confocal laser scanning microscopy. This denatured protein matrixes could be in part preventing starch hydration and dispersion during pasting and thus reduced viscosity. Dehulling reduced the pasting viscosity suggesting higher effect of micronisation for dehulled than whole samples. Resulting flours can be useful ingredients in protein energy-dense foods due to low viscosity. PMID- 27507523 TI - Chip-based molecularly imprinted monolithic capillary array columns coated GO/SiO2 for selective extraction and sensitive determination of rhodamine B in chili powder. AB - A novel solid-phase extraction chip embedded with array columns of molecularly imprinted polymer-coated silanized graphene oxide (GO/SiO2-MISPE) was established to detect trace rhodamine B (RB) in chili powder. GO/SiO2-MISPE monolithic columns for RB detection were prepared by optimizing the supporting substrate, template, and polymerizing monomer under mild water bath conditions. Adsorption capacity and specificity, which are critical properties for the application of the GO/SiO2-MISPE monolithic column, were investigated. GO/SiO2-MIP was examined by scanning electron microscopy (SEM) and Fourier transform-infrared spectroscopy. The recovery and the intraday and interday relative standard deviations for RB ranged from 83.7% to 88.4% and 2.5% to 4.0% and the enrichment factors were higher than 110-fold. The chip-based array columns effectively eliminated impurities in chili powder, indicating that the chip-based GO/SiO2 MISPE method was reliable for RB detection in food samples using high-performance liquid chromatography. Accordingly, this method has direct applications for monitoring potentially harmful dyes in processed food. PMID- 27507524 TI - A comprehensive evaluation of three microfluidic chemiluminescence methods for the determination of the total phenolic contents in fruit juices. AB - Three recently reported microfluidic chemiluminescence (MF-CL) methods (based on reactions with acidic permanganate enhanced by formaldehyde (KMnO4-COH), acidic cerium (IV) and rhodamine B (Ce-RB), and acidic cerium (IV) and rhodamine 6G (Ce R6G) enhanced by SDS) for the determination of the total phenolic content (TPC) in juices were critically evaluated in terms of their selectivity. The evaluation was carried out using 86 analytes, including 22 phenolic compounds (phenolic acids and polyphenols), 6 known non-phenolic antioxidants, 9 amino acids and a number of proteins, carbohydrates, nucleotide bases, inorganic salts and other compounds. Each method was sensitive toward phenolic compounds (PCs). However, the KMnO4-COH CL system showed a higher sensitivity toward phenolic acids and also responded to non-phenolic antioxidants. The other two systems showed higher sensitivity toward polyphenolic compounds than to phenolic acids and did not responded to all other compounds including non-phenolic antioxidants. PMID- 27507525 TI - HPLC-DAD-ESI/MS(n) profiling of phenolic compounds from Lathyrus cicera L. seeds. AB - Lathyrus cicera L. seeds are of interest for food and feed purposes. Despite the recognized antioxidant activity of the seeds, arising from the phenolic fraction, their phenolic compounds have not been studied in depth yet. Therefore, to determine the phenolics profile of these seeds, a target analysis was performed using high-performance liquid chromatography coupled to photodiode-array detection and electrospray ionization/ion trap mass spectrometry (HPLC-DAD ESI/MS(n)). Thirty-seven glycosylated flavonoids were identified for the first time in the seeds of this species and, according to their MS fragmentation, clustered in flavonol-3-O-di-/tri-glycosides-7-O-rhamnosides and other flavonol glycosides, and flavonol-3-O-(cinnamoyl)glycoside-7-O-rhamnosides, flavonol-3-O (dihydrophaseoyl, cinnamoyl)glycoside-7-O-rhamnosides and flavonol-3-O (malonyl)glycoside-7-O-rhamnosides. Glycosides of kaempferol were the main flavonoids found (10 non-acylated and 21 acylated), followed by those of quercetin (3) and those of isorhamnetin, apigenin and luteolin (1). The most abundant flavonols were identified as kaempferol-3-O-(2-hexosyl)hexoside-7-O rhamnosides. The methodology used allowed to increase the knowledge on a relevant phytochemical class of seeds from L. cicera. PMID- 27507526 TI - A fast and environment-friendly MEPSPEP/UHPLC-PDA methodology to assess 3-hydroxy 4,5-dimethyl-2(5H)-furanone in fortified wines. AB - Sotolon is widely associated with the quality of fortified aged wines, and has also been linked to premature oxidative aging (premox). Here we developed a single, fast and environmental-friendly microextraction by packed sorbent ultra high pressure liquid chromatography analysis (MEPS/UHPLC-PDA) for sotolon quantification in different wines. The best extraction conditions (loading three times 250MUL samples through the MEPSPEP sorbent and elution with 100MUL of 50% MeOH) were combined with a fast UHPLC separation (5min separation using acidified 10% MeOH isocratic flow in a CORTECS C18 column) to allow unparalleled minimum sample and solvents volumes usage. The validated methodology showed good linearity (r(2)>0.993) and precision (<5.6%); high recovery (>81%) and detection limits (0.45-2.51MUg/L) far below sotolon odor threshold for any type of wine. The methodology was successfully applied to selected white table and Madeira wines, encompassing therefore a wide range of alcohol and sugar contents. Furthermore, as far we may know, this is the first time a single methodology can be used to assess both wine aging or premox according to the type of wine. PMID- 27507527 TI - Quality assessment of 178 cultivars of plum regarding phenolic, anthocyanin and sugar content. AB - In this study assessment of total phenolic, individual anthocyanin and total sugar content (TSC) of wide range of plum cultivars was done in order to select cultivars with high health benefiting compounds for potential breeding purposes. Total phenolics varied between 38.45 and 841.50mg GAE 100g(-1) FW. Cyaniding-3 rutinoside, cyaniding-3- glucoside and its equivalents were identified in anthocyanin measurement by HPLC with different ranges. TSC differed between 9.63 and 29.47%. Besides, evaluation of the effect of cultivar and year on phenolic content of 23 randomly selected cultivars over two following years (2013 & 2014) showed significant effect of both factors on phenolic content of plum cultivars. Overall, cultivars "Cacaks Spaete" which had high amount of total phenolics with stability over time, as well as "Hohenheim breed 4894" as a cultivar which contained high amounts of total phenolics, anthocyanins and TSC were selected for further breeding purposes to provide high nutritional quality plum to consumers. PMID- 27507528 TI - Effect of pullulan on the water distribution, microstructure and textural properties of rice starch gels during cold storage. AB - The effects of pullulan on the water distribution, microstructure and textural properties of rice starch gels during cold storage were investigated by low field nuclear magnetic resonance (LF-NMR), scanning electron microscope (SEM), and texture profile analysis (TPA). The addition of pullulan reduced the transversal relaxation time of rice starch gels during cold storage. The microstructure of rice starch gel with 0.5% pullulan was denser and more uniform compared with that of rice starch without pullulan in each period of storage time. With regard to textural properties, 0.01% pullulan addition did not significantly change the texture of rice starch gels, while 0.5% pullulan addition appeared to reduce the hardness and retain the springiness of rice starch gels (P?0.05). The restriction effects of pullulan on water mobility and starch retrogradation were hypothesized to be mainly responsible for the water retention, gel structure maintenance, and modification of the textural attributes of rice starch gels. PMID- 27507529 TI - Effect of trypsin treatments on the structure and binding capacity of volatile compounds of myosin. AB - In order to investigate the mechanism between flavor binding and proteins degradation during meat processing, the influence of different trypsin contents on the structure of myosin and the adsorption capacity on aldehydes and ketones was determined. The 1% treatment produced subfragment 2 (S2), light meromyosin (LMM) and decreased 18 and 16kDa light chains; 5% and 10% treatments produced 100 and 65kDa new bands and more S2, LMM and cleaned light chains. With the rising trypsin contents, beta-sheet, beta-turn, random coil, hydrophobicity and total sulfydryl content increased; solubility, alpha-helix and free percentages of aldehydes and ketones decreased. The increase of absorbing capacity could be attributed to the increased hydrophobicity and total sulphydryl and the unfolding of secondary structures by exposing reactive amino and thiol groups and hydrophobic sites; the decreased solubility was related to the increased hydrophobicity. The trypsin-dose dependent proteolysis of myosin increased the retention of volatile compounds. PMID- 27507530 TI - Chemical profiling of the major components in natural waxes to elucidate their role in liquid oil structuring. AB - Elucidating the composition of waxes is of utmost importance to explain their behavior in liquid oil structuring. The chemical components (hydrocarbons - HCs, free fatty acids - FFAs, free fatty alcohols - FALs and wax esters - WEs) of natural waxes were analyzed using HPLC-ELSD and GC-MS followed by evaluation of their oil structuring properties. The gel strength, including the average storage modulus and oscillation yield stress, displayed a negative correlation with FALs and a positive correlation with HCs, FFAs and WEs. The components dictating the gel strength are HCs, FFAs and WEs in a descending order of importance. The consistency of the oleogels increased with the increasing amount of FFAs and HCs and the decreasing amount of WEs and FALs. The presence of more WEs results in a strong but brittle gel with a high initial flow yield stress. We believe these results might be useful in selecting the right waxes to combine in certain fat based food products. PMID- 27507531 TI - Chemo-enzymatic synthesis of vinyl and l-ascorbyl phenolates and their inhibitory effects on advanced glycation end products. AB - This study successfully established the feasibility of a two-step chemo-enzymatic synthesis of l-ascorbyl phenolates. Intermediate vinyl phenolates were first chemically produced and then underwent trans-esterification with l-ascorbic acid in the presence of Novozyme 435(r) (Candida Antarctica lipase B) as a catalyst. Twenty vinyl phenolates and 11 ascorbyl phenolates were subjected to in vitro bioassays to investigate their inhibitory activity against advanced glycation end products (AGEs). Among them, vinyl 4-hydroxycinnamate (17VP), vinyl 4-hydroxy-3 methoxycinnamate (18VP), vinyl 4-hydroxy-3,5-dimethoxycinnamate (20VP), ascorbyl 4-hydroxy-3-methoxycinnamate (18AP) and ascorbyl 3,4-dimethoxycinnamate (19AP) showed 2-10 times stronger inhibitory activities than positive control (aminoguanidine and its precursors). These results indicated that chemo enzymatically synthesized compounds have AGE inhibitory effect and thus are effective in either preventing or retarding glycation protein formation. PMID- 27507532 TI - Pinot noir wine volatile and anthocyanin composition under different levels of vine fruit zone leaf removal. AB - The impacts of fruit zone leaf removal on volatile and anthocyanin compositions of Pinot noir wine were investigated over two growing seasons. Wine volatiles were analyzed by multiple techniques, including headspace solid phase microextraction-GC-MS (HS-SPME-GC-MS), headspace-GC-FID (HS-GC-FID) and stir bar sorptive extraction-GC-MS (SBSE-GC-MS). Fruit zone leaf removal affected the concentration of many grape-derived volatile compounds such as terpene alcohols and C13-norisoprenoids in wine, although the degree of impact depended on the vintage year and severity of leaf removal. Fruit zone leaf removal resulted in greater concentrations of linalool, alpha-terpineol and beta-damascenone but had no impact on other terpene alcohols or beta-ionone. Fruit zone leaf removal had no consistent impact on C6 alcohols, volatile phenols, lactones, fermentation derived alcohols, acids, or most esters. Fruit zone leaf removal increased anthocyanins in final wine. PMID- 27507533 TI - Corrigendum to "New steroidal saponins and antiulcer activity from Solanum paniculatum L." [Food Chem. 186 (2015) 160-167]. PMID- 27507535 TI - Investigation of Ca substitution on the gas sensing potential of LaFeO3 nanoparticles towards low concentration SO2 gas. AB - The present work investigates the superior ability of LaFeO3 (LaFeO) and La0.8Ca0.2FeO2.95 (LaCaFeO) nanoparticles to detect 3 ppm SO2 gas. The influence of calcium substitution on the sensing behaviour of LaFeO has been studied. High resolution TEM images show that the particle sizes of LaFeO and LaCaFeO are less than 100 nm and SEM images show the agglomeration of interconnected nanoparticles. Both LaFeO and LaCaFeO crystallize in the orthorhombic crystal system with the space group Pbnm. Rietveld analysis of neutron diffraction data showed that LaCaFeO has lattice oxygen vacancies. In addition, magnetic refinements on both the samples have been carried out. The presence of lattice oxygen vacancies in LaCaFeO is qualitatively supported by Raman and XPS measurements. Electrical characterization showed increased conductivity for the LaCaFeO sample, influencing their sensing performance significantly. The LaCaFeO nanoparticles exhibit higher sensitivity, faster response time, rapid recovery time and good recyclability for sensing 3 ppm SO2 gas. This enhanced sensing behaviour is attributed to the increased oxygen vacancies in the lattice as well as the surface. As a consequence, increased active sites are created in LaCaFeO, promoting redox reaction between the analyte and the sensing material. The results demonstrated that while LaFeO is a good gas sensor, p-type substitution by Ca(2+) renders this material an improved resistivity based gas sensor to detect low concentration SO2. PMID- 27507534 TI - Diagnostic imaging and cataloguing of female genital malformations. AB - To help physicians and radiologists in the diagnosis of female genito-urinary malformations, especially of complex cases, the embryology of the female genital tract, the basis for Mullerian development anomalies, the current classifications for such anomalies and the comparison for inclusion and cataloguing of female genital malformations are briefly reviewed. The use of the embryological system to catalogue female genito-urinary malformations may ultimately be more useful in correlations with clinical presentations and in helping with the appropriate diagnosis and treatment. Diagnostic imaging of the different genito-urinary anomalies are exposed, placing particular emphasis on the anomalies within group II of the embryological and clinical classification (distal mesonephric anomalies), all of them associated with unilateral renal agenesis or dysplasia. Similarly, emphasis is placed on cases of cervico-vaginal agenesis, cavitated noncommunicated uterine horns, and cloacal and urogenital sinus anomalies and malformative combinations, all of them complex malformations. Diagnostic imaging for all these anomalies is essential. The best imaging tools and when to evaluate for other anomalies are also analysed in this review. TEACHING POINTS: * The appropriate cataloguing of female genital malformations is controversial. * An embryological classification system suggests the best diagnosis and appropriate management. * The anomalies most frequently diagnosed incorrectly are the distal mesonephric anomalies (DMAs). * DMAs are associated with unilateral renal agenesis or renal dysplasia with ectopic ureter. * We analyse other complex malformations. Diagnostic imaging for these anomalies is essential. PMID- 27507536 TI - Fruits and vegetables are incorporated into home cuisine in different ways that are relevant to promoting increased consumption. AB - Fruits and vegetables are essential for healthy life. We examined the fruits and vegetables consumption by 240 caregivers and their children aged 1-17 years in peri-urban Lima, and the ways that they were incorporated into local cuisine. A randomized cross-sectional household survey collected information on the weight of all foods eaten the previous day (24 h) including fruits and vegetables, their preparation and serving sizes. Fruit and vegetable consumption was low and very variable: fruit intake was mean 185.2 +/- 171.5 g day-1 , median 138 g day-1 for caregivers and 203.6 +/- 190.6 g day-1 and 159 g day-1 for children, vegetable intake was mean 116.9 +/- 94.0 g day-1 median 92 g day-1 for caregivers, mean 89.3 +/- 84.7 g day-1 median 60 g day-1 for children. Only 23.8% of children and 26.2% of caregivers met the recommended >=400 g of fruit or vegetable/day. Vegetables were mainly eaten either as ingredients of the main course recipe, eaten by about 80% of caregivers and children, or as salads eaten by 47% of caregivers and 42% of children. Fruits were most commonly eaten as whole fresh fruits eaten by 68% of caregivers and 75% of children. In multivariate analysis of the extent to which different presentations contributed to daily fruit and vegetable consumption, main courses contributed most to determining vegetable intake for caregivers, and for children, main course and salads had similar contributions. For fruit intake, the amount eaten as whole fruit determined total fruit and total fruit plus vegetable intake for both caregivers and children. Local cuisine should be considered in interventions to promote fruit and vegetable consumption. (c) 2016 John Wiley & Sons Ltd. PMID- 27507537 TI - Characterization of a re-engineered, mesothelin-targeted Pseudomonas exotoxin fusion protein for lung cancer therapy. AB - Mesothelin overexpression in lung adenocarcinomas correlates with the presence of activating KRAS mutations and poor prognosis. Hence SS1P, a mesothelin-targeted immunotoxin, could offer valuable treatment options for these patients, but its use in solid tumor therapy is hampered by high immunogenicity and non-specific toxicity. To overcome both obstacles we developed RG7787, a de-immunized cytotoxic fusion protein comprising a humanized SS1 Fab fragment and a truncated, B-cell epitope silenced, 24 kD fragment of Pseudomonas exotoxin A (PE24). Reactivity of RG7787 with sera from immunotoxin-treated patients was >1000 fold reduced. In vitro RG7787 inhibited cell viability of lung cancer cell lines with picomolar potency. The pharmacokinetic properties of RG7787 in rodents were comparable to SS1P, yet it was tolerated up to 10 fold better without causing severe vascular leak syndrome or hepatotoxicity. A pharmacokinetic/pharmacodynamic model developed based on NCI-H596 xenograft studies showed that for RG7787 and SS1P, their in vitro and in vivo potencies closely correlate. At optimal doses of 2-3 mg/kg RG7787 is more efficacious than SS1P. Even large, well established tumors (600 mm(3)) underwent remission during three treatment cycles with RG7787. Also in two patient-derived lung cancer xenograft models, Lu7336 and Lu7187, RG7787 showed anti-tumor efficacy. In monotherapy two treatment cycles were moderately efficacious in the Lu7336 model but showed good anti-tumor activity in the KRAS mutant Lu7187 model (26% and 80% tumor growth inhibition, respectively). Combination of RG7787 with standard chemotherapies further enhanced efficacy in both models achieving near complete eradication of Lu7187 tumors. PMID- 27507539 TI - Structural basis for Myf and Psa fimbriae-mediated tropism of pathogenic strains of Yersinia for host tissues. AB - Three pathogenic species of the genus Yersinia assemble adhesive fimbriae via the FGL-chaperone/usher pathway. Closely related Y. pestis and Y. pseudotuberculosis elaborate the pH6 antigen (Psa), which mediates bacterial attachment to alveolar cells of the lung. Y. enterocolitica, instead, assembles the homologous fimbriae Myf of unknown function. Here, we discovered that Myf, like Psa, specifically recognizes beta1-3- or beta1-4-linked galactose in glycosphingolipids, but completely lacks affinity for phosphatidylcholine, the main receptor for Psa in alveolar cells. The crystal structure of a subunit of Psa (PsaA) complexed with choline together with mutagenesis experiments revealed that PsaA has four phosphatidylcholine binding pockets that enable super-high-avidity binding of Psa fibres to cell membranes. The pockets are arranged as six tyrosine residues, which are all missing in the MyfA subunit of Myf. Conversely, the crystal structure of the MyfA-galactose complex revealed that the galactose-binding site is more extended in MyfA, enabling tighter binding to lactosyl moieties. Our results suggest that during evolution, Psa has acquired a tyrosine-rich surface that enables it to bind to phosphatidylcholine and mediate adhesion of Y. pestis/pseudotuberculosis to alveolar cells, whereas Myf has specialized as a carbohydrate-binding adhesin, facilitating the attachment of Y. enterocolitica to intestinal cells. PMID- 27507538 TI - MiR-31 and miR-128 regulates poliovirus receptor-related 4 mediated measles virus infectivity in tumors. AB - Oncolytic measles virus strains are currently being evaluated in several clinical trials, as a promising novel oncolytic platform. Poliovirus receptor-related 4 (PVRL4) was recently identified as a potent measles virus (MV) receptor; however, its regulation is not yet understood. Increased levels of PVRL4 protein were observed in cell membrane, cytoplasm and nuclei of glioblastoma, breast and ovarian tumor clinical samples with no significant change in PVRL4 mRNA levels in glioblastoma and breast cancer compared with their corresponding control samples, suggesting that PVRL4 is likely post-transcriptionally regulated. Therefore, we sought to investigate the potential role of miRNAs in PVRL4 regulation and thus MV infectivity. We demonstrated that miR-31 and miR-128 can bind to the 3'UTR of PVRL4 and decrease PVRL4 levels while anti-miR-31/128 increase PVRL4 levels suggesting that PVRL4 is miRNA targeted. Furthermore, miR-31/128 expression levels were down-regulated in glioblastoma and breast tumor samples and showed significant negative correlations with PVRL4 levels. Infection with an MV strain that exclusively utilizes PVRL4 as its receptor showed that over-expression of miR-31/128 decreases MV infectivity while inhibition of the respective miRNAs via anti-miRs increase MV infectivity and reduce tumor size in mouse xenograft models of glioblastoma, breast and ovarian cancer. Additionally, miR-128 levels showed significant correlations with MV infection and in vivo anti-tumor effect, while MV infection increased miR-31 expression and thereby contributed to the observed decrease in PVRL4 levels. This study suggests that PVRL4 is post transcriptionally regulated by miR-128 and miR-31 and harbors possible miRNA targets that could modulate MV infectivity and in turn enhance MV based oncolytic therapeutic strategies. PMID- 27507540 TI - Lifestyle medicine curriculum for a preventive medicine residency program: implementation and outcomes. AB - BACKGROUND: The vast majority of the healthcare problems burdening our society today are caused by disease-promoting lifestyles (e.g., physical inactivity and unhealthy eating). Physicians report poor training and lack of confidence in counseling patients on lifestyle changes. OBJECTIVE: To evaluate a new curriculum and rotation in lifestyle medicine for preventive medicine residents. METHODS: Training included didactics (six sessions/year), distance learning, educational conferences, and newly developed lifestyle medicine rotations at the Institute of Lifestyle Medicine, the Yale-Griffin Prevention Research Center, and the Integrative Medicine Center. We used a number of tools to assess residents' progress including Objective Structured Clinical Examinations (OSCEs), self assessments, and logs of personal health habits. RESULTS: A total of 20 residents participated in the lifestyle medicine training between 2010 and 2013. There was a 15% increase in residents' discussions of lifestyle issues with their patients based on their baseline and follow-up surveys. The performance of preventive medicine residents on OSCEs increased each year they were in the program (average OSCE score: PGY1 73%, PGY2 83%, PGY3 87%, and PGY4 91%, p=0.01). Our internal medicine and preliminary residents served as a control, since they did participate in didactics but not in lifestyle medicine rotations. Internal medicine and preliminary residents who completed the same OSCEs had a slightly lower average score (76%) compared with plural for resident, preventive medicine residents (80%). However, this difference did not reach statistical significance (p=0.11). CONCLUSION: Incorporating the lifestyle medicine curriculum is feasible for preventive medicine training allowing residents to improve their health behavior change discussions with patients as well as their own personal health habits. PMID- 27507541 TI - Starting a new residency program: a step-by-step guide for institutions, hospitals, and program directors. AB - Although our country faces a looming shortage of doctors, constraints of space, funding, and patient volume in many existing residency programs limit training opportunities for medical graduates. New residency programs need to be created for the expansion of graduate medical education training positions. Partnerships between existing academic institutions and community hospitals with a need for physicians can be a very successful means toward this end. Baylor College of Medicine and The Children's Hospital of San Antonio were affiliated in 2012, and subsequently, we developed and received accreditation for a new categorical pediatric residency program at that site in 2014. We share below a step-by-step guide through the process that includes building of the infrastructure, educational development, accreditation, marketing, and recruitment. It is our hope that the description of this process will help others to spur growth in graduate medical training positions. PMID- 27507542 TI - Probiotic-derived ferrichrome inhibits colon cancer progression via JNK-mediated apoptosis. AB - Previous reports have suggested that some probiotics inhibit tumorigenesis and cancer progression. However, the molecules involved have not yet been identified. Here, we show that the culture supernatant of Lactobacillus casei ATCC334 has a strong tumour-suppressive effect on colon cancer cells. Using mass spectrometry, we identify ferrichrome as a tumour-suppressive molecule produced by L. casei ATCC334. The tumour-suppressive effect of ferrichrome is greater than that of cisplatin and 5-fluorouracil, and ferrichrome has less of an effect on non cancerous intestinal cells than either of those agents. A transcriptome analysis reveals that ferrichrome treatment induces apoptosis, which is mediated by the activation of c-jun N-terminal kinase (JNK). Western blotting indicates that the induction of apoptosis by ferrichrome is reduced by the inhibition of the JNK signalling pathway. This we demonstrate that probiotic-derived ferrichrome exerts a tumour-suppressive effect via the JNK signalling pathway. PMID- 27507543 TI - Surgical management of spinal fractures and neurological involvement in patients with myeloma. AB - INTRODUCTION: Multiple Myeloma (MM) typically involves the spine and causes bone pain, pathological fractures and spinal cord compression with possible consequent neurological deficits. This retrospective study reports the results of surgery on a selected population of patients who underwent surgery for symptomatic spinal myeloma. MATERIALS AND METHODS: A total of 26 patients who underwent surgery for spinal myeloma with neurological involvement were studied retrospectively. Neurological evaluation was performed according to the Frankel grade. Characteristics of this population, reconstructive techniques and surgery-related complications were reviewed. RESULTS: The tumours involved the thoracic spine in 13 patients, the lumbar spine in 10 patients, and the cervical spine in three patients. The most common approach was a posterior-only approach (70%), followed by a staged, combined approach (20%), and an anterior-only approach (10%). The mean postoperative survival time was 43 months (range: 8-60 months). A significant improvement in neurological function was observed in the study population after surgery (p=0.001). There were seven early postoperative complications, two late complications and five surgery-related complications. DISCUSSION: Surgery in selected patients affected by spinal myeloma with neurological involvement is associated with good clinical outcomes and neurological recovery and an acceptable rate of complications. Neurological deficit and segmental instability can be treated sufficiently in most cases by the implementation of a posterior-only approach; however, the final treatment should, when possible, include adjuvant chemotherapy and radiotherapy and rigorous bracing. PMID- 27507544 TI - Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets. AB - Recalcitrant humeral non-union is a disabling condition that is extremely difficult to treat. The use of BMP-7 has been proposed to improve bone healing. This is a report of the results obtained in 12 patients with recalcitrant humeral non-union treated using stable fixation with a long locking compression plate and BMP-7, autologous bone graft and hydroxyapatite pellets applied at the non-union site. Patients had up to three surgical attempts at non-union healing prior to our treatment. The average time from the initial fracture to our surgery was 5.2 years. Average follow-up was 5.3 years. At follow-up, non-union had healed in all patients by an average of 7.3 months. All the patients were very satisfied with their final results, despite a restricted range of motion of the elbow and a moderate muscular atrophy, which was frequently observed. Our study shows that BMP-7 associated with autologous bone grafting and hydroxyapatite pellets after stable fixation is an effective adjuvant to stimulate bone healing in the treatment of recalcitrant humeral non-union. PMID- 27507545 TI - Revision of ceramic fracture with ceramic-on-polyethylene in total hip arthroplasty: Medium-term results. AB - There is no consensus on the bearing of choice in revision for ceramic fracture after total hip arthroplasty (THA). The aim of this study was to evaluate the outcomes using ceramic-on-polyethylene (CoP) articulation in revision for ceramic breakage. Twelve patients who underwent revision hip surgery between 2002 and 2013 were followed-up. Appropriate surgical technique, including accurate synoviectomy, was used. The cup and the head were changed in four patients and only the liner and the head were replaced in the remaining eight patients. At the final follow-up there were no cases of re-revision due to tribological reasons, and only one case of polyethylene (PE) wear and osteolysis was scheduled for a new revision because of clear cup malposition. Complications were four cases of dislocation, one case of loosening and one case of infection. Revision of fractured ceramic is a challenging situation with a high risk of early complications. Using CoP liners with accurate synoviectomy and correction of misalignment can be considered a valuable bearing option at medium-term follow up. PMID- 27507546 TI - Long endomedullary nail in proximal third humeral shaft fractures. AB - INTRODUCTION: Proximal humeral fractures with a spiral line of fracture extending from the humeral head to the diaphyseal region are increasing. Treatment for these fractures is comparable to that for shaft fractures. The purpose of this study was to evaluate the use of a new "Long" humeral nail for this type of lesion and identify the best distal locking. MATERIALS AND METHODS: Forty-three patients treated with a Long Diphos Nail(r) were selected for this study: main exclusion criteria were poor cognitive and responsive ability to physical therapy, four-part fracture requiring humeral head replacement, an isolated greater or lesser tubercle fracture and a head-splitting fracture. All patients were divided into two groups according to the distal locking (single or double) and clinically evaluated at 1, 3, 6 and 12 months after surgery. The following parameters were evaluated: fracture healing on radiographic images every month; level of pain with Visual Analogue Scale (VAS); recovery of shoulder function or ability to resume normal daily activities according to the Constant Scoring System (CSS); patient satisfaction; and complications, like fracture consolidation defect or delay. A statistical analysis was performed. RESULTS: Improvements in pain, satisfaction and shoulder functional recovery were recorded. Patients reached fracture healing in two to six months. The mean healing time was better for double distal locking (p=0.04).There was a clinically greater difference (p=0.006) between the groups for the mean Constant score at 3 months follow-up, with better results for the double distal locking group. Complications were: one patient with a consolidation delay with a single distal locking screw breakage; it was necessary to remove the nail and perform a second treatment. CONCLUSIONS: The results of the study indicate the efficacy of Long Diphos Nail(r) in the treatment of fractures with a line of fracture extending to the proximal diaphyseal region. The features of a multiplane stabilisation above the fracture and a distal double locking may represent the key for a good fixation for 11-A2, A3 or B2 fractures with a long spiral line. A double distal locking reduces fracture micro-instability and so patients recover function and strength quicker because of less pain at the fracture site. STUDY DESIGN: retrospective, cohort of cases. LEVEL OF EVIDENCE: IV. PMID- 27507547 TI - Outcomes and complications of triceps tendon repair following acute rupture in American military personnel. AB - INTRODUCTION: Triceps tendon ruptures are uncommon injuries primarily occurring in young, active males or elderly individuals with various systemic diseases. Relatively little is known about the epidemiology of this injury, or the results of surgical management in high-demand populations. The purpose of this study was to define the incidence and outcomes of surgical treatment in active duty American military personnel. PATIENTS AND METHODS: The Military Data Repository (MDR) was queried for all active duty military personnel undergoing surgical repair or reconstruction of a triceps tendon rupture between January 2012 and December 2014. The electronic health records of all patients with at least 12 months clinical follow-up were searched for demographic information, injury details, preoperative imaging findings, post-operative complications, and ability to return to duty following surgical repair. Incidence was calculated based on total active duty population in the MDR over the study period. Risk factors for postoperative complication and inability to return to duty following surgical repair were assessed using univariate analyses. RESULTS: A total of 54 acute triceps tendon ruptures were identified in the search, of which 48 had at least 12 months follow-up and complete post-operative records. The incidence of acute triceps tendon rupture was 1.1 per 100,000 person-years. Twelve patients experienced post-operative complications, six of which were traumatic re-ruptures within four months of the index surgery. No patient had a post-operative infection or atraumatic repair failure. 94% of patients were able to return to active military service following surgical repair. Enlisted rank was a significant risk factor for a post-operative complication, but no factor predicted inability to return to active duty service. CONCLUSIONS: Surgical repair of acute triceps tendon ruptures reliably restores strength and function even in high-demand individuals. In our population, traumatic rerupture was the most common complication. PMID- 27507548 TI - Emergency Nurse Transport of Telemetry Patients: Benefits and Drawbacks. AB - PROBLEM: Emergency nurse-accompanied telemetry transport on admission to the hospital is a common practice. Potential drawbacks include inefficient use of nursing resources, unnecessary telemetry transports, and disruption of care for remaining ED patients. METHODS: This was a 2-part descriptive quality improvement study using retrospective chart review and prospective documentation of patient transports. Charts were selected by American Heart Association Practice Standards for ECG Monitoring to classify transported telemetry patients into 3 categories. Patient characteristics and adverse events were assessed. Prospectively, the length of transport time and the number and severity of patients the transport nurse left in the emergency department were also recorded. RESULTS: Zero adverse events occurred during any transport. Transport time ranged from 5 to 38 minutes, with a mean of 16.5 minutes. The normal patient ratio increased for nursing staff remaining in the emergency department for the period of the transport, with 74% of patients left in the emergency department classified into high-risk Emergency Severity Index categories 1 and 2. IMPLICATIONS FOR PRACTICE: Findings provided evidence that low-risk telemetry patients had minimal chance of adverse events during transport and highlighted added risks for the remaining emergency patients. Alternative models and interventions are needed to identify appropriate patients for telemetry transport, assign appropriate staff such as licensed paramedics for transport, and evaluate alternative models of nursing care and teamwork in the emergency department. PMID- 27507549 TI - What Qualitative Research Can Do for You: Deriving Solutions and Interventions from Qualitative Findings. PMID- 27507550 TI - Understanding the Experience of Miscarriage in the Emergency Department. AB - INTRODUCTION: Up to 20% of pregnancies end in miscarriage, which can be a significant life event for women with psychological implications. Because the only preventative measure for a miscarriage is risk factor modification, the treatment focuses on confirming the miscarriage has occurred and medical management of symptoms. Although women experiencing a miscarriage are frequently directed to seek medical care in emergency departments, the patients are often triaged as nonemergent patients unless they are unstable, which exposes women to potentially prolonged wait times. Research about miscarriages and emergency departments predominantly focus on medical management with little understanding of how emergency care shapes the experience of miscarriage for women. METHODS: Seeking to describe the experiences of women coming to the emergency department for care while having a miscarriage, interpretive phenomenology-a form of qualitative research-guided this study. Eight women were recruited to participate in semi-structured face-to-face interviews of 60 to 90 minutes in length. Data were analyzed using hermeneutics and thematic analysis. RESULTS: Five themes emerged: "Pregnant/Life: Miscarriage/Death"; "Deciding to go to the emergency department: Something's wrong"; "Not an illness: A different kind of trauma"; "Need for acknowledgement"; and "Leaving the emergency department: What now?". Participants believed their losses were not acknowledged but instead dismissed. These experiences, combined with a perceived lack of discharge education and clarity regarding follow-up, created experiences of marginalization. DISCUSSION: This study describes the experience of miscarrying in emergency departments and provides insights regarding how nursing and physician care may affect patient perceptions of marginalization. PMID- 27507551 TI - Materials in the vitreous demonstrated under the operating microscope during cataract surgery and confirmed histologically. PMID- 27507552 TI - Muscle expression of a malonyl-CoA-insensitive carnitine palmitoyltransferase-1 protects mice against high-fat/high-sucrose diet-induced insulin resistance. AB - Impaired skeletal muscle mitochondrial fatty acid oxidation (mFAO) has been implicated in the etiology of insulin resistance. Carnitine palmitoyltransferase 1 (CPT1) is a key regulatory enzyme of mFAO whose activity is inhibited by malonyl-CoA, a lipogenic intermediate. Whereas increasing CPT1 activity in vitro has been shown to exert a protective effect against lipid-induced insulin resistance in skeletal muscle cells, only a few studies have addressed this issue in vivo. We thus examined whether a direct modulation of muscle CPT1/malonyl-CoA partnership is detrimental or beneficial for insulin sensitivity in the context of diet-induced obesity. By using a Cre-LoxP recombination approach, we generated mice with skeletal muscle-specific and inducible expression of a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA inhibition. When fed control chow, homozygous CPT1mt transgenic (dbTg) mice exhibited decreased CPT1 sensitivity to malonyl-CoA inhibition in isolated muscle mitochondria, which was sufficient to substantially increase ex vivo muscle mFAO capacity and whole body fatty acid utilization in vivo. Moreover, dbTg mice were less prone to high fat/high-sucrose (HFHS) diet-induced insulin resistance and muscle lipotoxicity despite similar body weight gain, adiposity, and muscle malonyl-CoA content. Interestingly, these CPT1mt-protective effects in dbTg-HFHS mice were associated with preserved muscle insulin signaling, increased muscle glycogen content, and upregulation of key genes involved in muscle glucose metabolism. These beneficial effects of muscle CPT1mt expression suggest that a direct modulation of the malonyl-CoA/CPT1 partnership in skeletal muscle could represent a potential strategy to prevent obesity-induced insulin resistance. PMID- 27507553 TI - Hepatic functions of GLP-1 and its based drugs: current disputes and perspectives. AB - GLP-1 and its based drugs possess extrapancreatic metabolic functions, including that in the liver. These direct hepatic metabolic functions explain their therapeutic efficiency for subjects with insulin resistance. The direct hepatic functions could be mediated by previously assumed "degradation" products of GLP-1 without involving canonic GLP-1R. Although GLP-1 analogs were created as therapeutic incretins, extrapancreatic functions of these drugs, as well as native GLP-1, have been broadly recognized. Among them, the hepatic functions are particularly important. Postprandial GLP-1 release contributes to insulin secretion, which represses hepatic glucose production. This indirect effect of GLP-1 is known as the gut-pancreas-liver axis. Great efforts have been made to determine whether GLP-1 and its analogs possess direct metabolic effects on the liver, as the determination of the existence of direct hepatic effects may advance the therapeutic theory and clinical practice on subjects with insulin resistance. Furthermore, recent investigations on the metabolic beneficial effects of previously assumed "degradation" products of GLP-1 in the liver and elsewhere, including GLP-128-36 and GLP-132-36, have drawn intensive attention. Such investigations may further improve the development and the usage of GLP-1 based drugs. Here, we have reviewed the current advancement and the existing controversies on the exploration of direct hepatic functions of GLP-1 and presented our perspectives that the direct hepatic metabolic effects of GLP-1 could be a GLP-1 receptor-independent event involving Wnt signaling pathway activation. PMID- 27507554 TI - Restitution of Tumor Suppressor MicroRNA-145 Using Magnetic Nanoformulation for Pancreatic Cancer Therapy. AB - INTRODUCTION: The functional significance of lost microRNAs has been reported in several human malignancies, including pancreatic cancer (PC). Our prior work has identified microRNA-145 (miR-145) as a tumor suppressor microRNA (miRNA) in pancreatic cancer. The restoration of miR-145 downregulates a number of oncogenes including mucin MUC13, a transmembrane glycoprotein that is aberrantly expressed in pancreatic cancer, thus efficiently inhibiting tumor growth in mice. However, lack of an effective tumor-specific delivery system remains an unmet clinical challenge for successful translation of microRNAs. METHODS: We developed a miRNA 145-based magnetic nanoparticle formulation (miR-145-MNPF) and assessed its anti cancer efficacy. Physico-chemical characterization (dynamic light scattering (DLS), transmission electron microscopy (TEM) and miR-binding efficiency), cellular internalization (Prussian blue and confocal microscopy), miR-145 restitution potential (quantitative reverse-transcription PCR (qRT-PCR), and anti cancer efficacy (proliferation, colony formation, cell migration, cell invasion assays) of this formulation were performed using clinically relevant pancreatic cancer cell lines (HPAF-II, AsPC-1). RESULTS: miR-145-MNPF exhibited optimal particle size and zeta potential which effectively internalized and restituted miR-145 in pancreatic cancer cells. miR-145 re-expression resulted in downregulation of MUC13, HER2, pAKT, and inhibition of cell proliferation, clonogenicity, migration, and invasion of pancreatic cancer cells. CONCLUSIONS: miR-145-MNPF is an efficient system for miR-145 delivery and restitution in pancreas cancer that may offer a potential therapeutic treatment for PC either alone or in conjunction with conventional treatment. PMID- 27507555 TI - Does Diverting Loop Ileostomy Improve Outcomes Following Open Ileo-Colic Anastomoses? A Nationwide Analysis. AB - BACKGROUND: Anastomotic leak is one of the most feared complications of gastrointestinal surgery. Surgeons routinely perform a diverting loop ileostomy (DLI) to protect high-risk colo-rectal anastomoses. STUDY DESIGN: The NSQIP database was queried from 2012 to 2013 for patients undergoing open ileo-colic resection with and without a DLI. The primary outcome was the development of any anastomotic leak-including those managed operatively and non-operatively. Secondary outcomes included overall complication rate, return to the OR, readmission, and 30-day mortality. RESULTS: Four thousand one hundred fifty-nine patients underwent open ileo-colic resection during the study period. One hundred eighty-six (4.5 %) underwent a DLI. Factors associated with the addition of a DLI included emergency surgery, pre-operative sepsis, and IBD. There were 197 anastomotic leaks (4.7 %) with 100 patients requiring reoperation (2.4 %). DLI was associated with a decrease in anastomotic leaks requiring reoperation (DLI vs no DLI: 0 (0 %) vs 100 (2.5 %); p = 0.02) and with increased readmission (OR 1.93; 95 % CI 1.30-2.85; p = 0.001). CONCLUSION: DLI is rarely used for open ileo colic resection. There were no serious leaks requiring reoperation in the DLI group. A DLI was associated with an almost two-fold increase in the odds of readmission. Surgeons must weigh the reduction in serious leak rate with postoperative morbidity when considering a DLI for open ileo-colic resection. PMID- 27507556 TI - IL-33 inhibits the differentiation and immunosuppressive activity of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. AB - Myeloid-derived suppressor cells (MDSCs) contribute to tumor-mediated immune escape by suppressing antitumor immune responses. Interleukin-33 (IL-33) is capable of regulating various immune cell populations; however, the effects of IL 33 on the differentiation of MDSCs have not been well characterized. In this study, we evaluated the effects of IL-33 on MDSCs and found that IL-33 significantly reduced the differentiation of lineage-negative bone marrow progenitor cells into granulocytic MDSCs (G-MDSCs). IL-33-treated MDSCs exhibited diminished immunosuppressive capacity; reduced inhibition on T-cell proliferation and interferon-gamma production, and diminished production of reactive oxygen species. However, IL-33 treatment did not affect the frequency of monocytic MDSCs (M-MDSCs) or their production of nitric oxide and expression of arginase-1. Additionally, compared with control MDSCs, IL-33-treated MDSCs had reduced capacity to induce the differentiation or expansion of Treg cells. Moreover, in vivo IL-33 administration significantly decreased MDSCs and G-MDSCs accumulation in the spleen and tumor microenvironment. Also, despite increasing CD4+ and CD8+ T-cell infiltration, IL-33 administration markedly decreased Treg-cell population in tumor microenvironment. Taken together, our findings indicate that IL-33 reduces the frequency and immunosuppressive activity of G-MDSCs and ultimately the extent of tumor growth. PMID- 27507558 TI - Long-term result of autologous cultivated oral mucosal epithelial transplantation for severe ocular surface disease. AB - The present study aimed to investigate the clinical outcomes of autologous cultivated oral mucosal epithelial transplantation (COMET) on human amniotic membrane (AM) for corneal limbal stem cell deficiency (LSCD). In this prospective, noncomparative case series, 20 eyes (18 patients) with bilateral severe ocular surface disease were chosen to undergo COMET on human AM. The primary outcome was clinical success, and the secondary outcomes were the best corrected visual acuity difference, corneal opacification, symblepharon formation, and complications. The mean patient age was 48.2 +/- 15.5 years. The mean follow-up time was 31.9 +/- 12.1 months (range 8-50 months). All except one eye exhibited complete epithelialization within the first postoperative week. A successful clinical outcome, defined as a stable ocular surface without epithelial defects, a clear cornea without fibrovascular tissue invasion at the pupillary area, and no or mild ocular surface inflammation, was obtained in 15 of 20 eyes (75 %). The clinical success rate at 1 year was 79.3 %, and that at 4 years (end of follow-up) was 70.5 %. Fourteen of 20 (70 %) eyes exhibited improvement in visual acuity after COMET, and some required subsequent cataract surgery (2 eyes), penetrating keratoplasty (3 eyes), or keratoprosthesis implantation (1 eye). Preoperative symblepharon was eliminated in most eyes (8 of 13, 61.5 %) after COMET combined with eyelid reconstruction when needed. The only complication was corneal perforation (1 eye) induced by a severe eyelid abnormality; treatment with a tectonic corneal graft was successful. COMET can successfully restore ocular surface damage in most eyes with corneal LSCD. PMID- 27507557 TI - Maintenance of the EBV-specific CD8+ TCRalphabeta repertoire in immunosuppressed lung transplant recipients. AB - Epstein-Barr virus (EBV) is one of the most common viruses in humans, capable of causing life-threatening infections and cancers in immunocompromised individuals. Although CD8+ T cells provide key protection against EBV, the persistence and dynamics of specific T-cell receptor (TCR) clones during immunosuppression in transplant patients is largely unknown. For the first time, we used a novel single-cell TCRalphabeta multiplex-nested reverse transcriptase PCR to dissect TCRalphabeta clonal diversity within GLCTLVAML (GLC)-specific CD8+ T cells in healthy individuals and immunocompromised lung transplant recipients. The GLC peptide presented by HLA-A*02:01 is one of the most immunogenic T-cell targets from the EBV proteome. We found that the GLC-specific TCRalphabeta repertoire was heavily biased toward TRAV5 and encompassed five classes of public TCRalphabetas, suggesting that these clonotypes are preferentially utilized following infection. We identified that a common TRAV5 was diversely paired with different TRAJ and TRBV/TRBJ genes, in both immunocompetent and immunocompromised individuals, with an average of 12 different TCRalphabeta clonotypes/donor. Moreover, pre transplant GLC-specific TCRalphabeta repertoires were relatively stable over 1 year post transplant under immunosuppression in the absence or presence of EBV reactivation. In addition, we provide the first evidence of early GLC-specific CD8+ T cells at 87 days post transplant, which preceded clinical EBV detection at 242 days in an EBV-seronegative patient receiving a lung allograft from an EBV seropositive donor. This was associated with a relatively stable TCRalphabeta repertoire after CD8+ T-cell expansion. Our findings provide insights into the composition and temporal dynamics of the EBV-specific TCRalphabeta repertoire in immunocompromised transplant patients and suggest that the early detection of EBV specific T cells might be a predictor of ensuing EBV blood viremia. PMID- 27507559 TI - The increased level of COX-dependent arachidonic acid metabolism in blood platelets from secondary progressive multiple sclerosis patients. AB - Platelet activation is increasingly postulated as a possible component of the pathogenesis of multiple sclerosis (MS), especially due to the increased risk of cardiovascular events in MS. Arachidonic acid cascade metabolized by cyclooxygenase (COX) is a key pathway of platelet activation. The aim of our study was to investigate the COX-dependent arachidonic acid metabolic pathway in blood platelets from secondary progressive multiple sclerosis (SP MS) patients. The blood samples were obtained from 50 patients (man n = 22; female n = 28), suffering from SP MS, diagnosed according to the revised McDonald criteria. Platelet aggregation was measured in platelet-rich plasma after arachidonic acid stimulation. The level of COX activity and thromboxane B2 concentration were determined by ELISA method. Lipid peroxidation was assessed by measuring the level of malondialdehyde. The results were compared with a control group of healthy volunteers. We found that blood platelets obtained from SP MS patients were more sensitive to arachidonic acid and their response measured as platelet aggregation was stronger (about 14 %) relative to control. We also observed a significantly increased activity of COX (about 40 %) and synthesis of thromboxane B2 (about 113 %). The generation of malondialdehyde as a marker of lipid peroxidation was about 10 % higher in SP MS than in control. Cyclooxygenase dependent arachidonic acid metabolism is significantly increased in blood platelets of patients with SP MS. Future clinical studies are required to recommend the use of low-dose aspirin, and possibly other COX inhibitors in the prevention of cardiovascular risk in MS. PMID- 27507561 TI - Prevalence and intensity of Streblidae in bats from a Neotropical savanna region in Brazil. AB - Bats of the family Phyllostomidae are common hosts to streblids known as bat flies. Here, we discuss the component community, prevalence and intensity of infection with species of Streblidae on an assemblage of phyllostomid bats in the Cafuringa Environmental Protection Area (APA Cafuringa) in the core area of the Cerrado in Central Brazil. A total of 1 841 streblid individuals of 24 species occurred on 752 bats of 14 species. Ten species of streblids infected Glossophaga soricina (Pallas), whereas seven or fewer streblid species infected the other bat species. Nine bat fly species presented a prevalence of more than 50%, whereas some differences in the abundance of bat flies among hosts were observed. Strebla wiedemanni Kolenati, 1856 and Trichobius furmani Wenzel, 1966 were more host specific compared to the other streblids, and they occurred in greater abundance on their preferred hosts. Trichobius uniformis Curran, 1935 and Strebla mirabilis (Waterhouse, 1879) were the least host-specific, occurring on five and six hosts, respectively. PMID- 27507560 TI - Trends and area variations in Potentially Preventable Admissions for COPD in Spain (2002-2013): a significant decline and convergence between areas. AB - BACKGROUND: Potentially Preventable Hospitalizations (PPH) are hospital admissions for conditions which are preventable with timely and appropriate outpatient care being Chronic Obstructive Pulmonary Disease (COPD) admissions one of the most relevant PPH. We estimate the population age-sex standardized relative risk of admission for COPD-PPH by year and area of residence in the Spanish National Health System (sNHS) during the period 2002-2013. METHODS: The study was conducted in the 203 Hospital Service Areas of the sNHS, using the 2002 to 2013 hospital admissions for a COPD-PPH condition of patients aged 20 and over. We use conventional small area variation statistics and a Bayesian hierarchical approach to model the different risk structures of dependence in both space and time. RESULTS: COPD-PPH admissions declined from 24.5 to 15.5 per 10,000 persons-year (Men: from 40.6 to 25.1; Women: from 9.1 to 6.4). The relative risk declined from 1.19 (19 % above 2002-2013 average) in 2002 to 0.77 (30 % below average) in 2013. Both the starting point and the slope were different for the different regions. Variation among admission rates between extreme areas dropped from 6.7 times higher in 2002 to 4.6 times higher in 2013. CONCLUSIONS: COPD-PPH conditions in Spain have undergone a strong decline and a reduction in geographical variation in the last 12 years, suggesting a general improvement in health policies and health care over time. Variability among areas still remains, with a substantial room for improvement. PMID- 27507562 TI - Combination of phosphotidylinositol-3-kinase targeting with cetuximab and irradiation: A preclinical study on an orthotopic xenograft model of head and neck cancer. AB - BACKGROUND: The purpose of this study was to investigate the effects of combining the phosphotidylinositol-3-kinase (PI3K) inhibitor buparlisib (BKM)120 with the anti-epidermal growth factor receptor (EGFR) agent cetuximab and radiotherapy (RT) on an orthotopic model of head and neck squamous cell carcinoma (HNSCC). METHODS: We evaluated the antitumor efficacy of BKM120, cetuximab, and RT, administered alone or in combination, using the human PIK3CA-mutated HNSCC cell line, CAL33, injected into the floor of the mouth of nude mice. RESULTS: Compared with control, the BKM120-cetuximab and the BKM120-cetuximab-RT combinations led to the highest tumor inhibition (p < .001). The highest inhibitory effect of treatments on cell proliferation, mitogen-activated protein kinase (MAPK) and PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways were found with the BKM120-cetuximab association. The association of BKM120 and cetuximab with RT inhibited RT-induced activation of the MAPK pathway. CONCLUSION: These results can serve as a preclinical rationale for innovative treatments combining PI3K inhibition with anti-EGFR therapies and irradiation in patients with HNSCC. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 151-159, 2017. PMID- 27507563 TI - The Importance of Debiasing Social Media Data to Better Understand E-Cigarette Related Attitudes and Behaviors. PMID- 27507564 TI - Social Contact and Cognitive Functioning: The Role of Personality. AB - Objectives: Social contact has been shown to be positively associated with cognitive functioning. It is unclear, however, whether all individuals can equally benefit from social contact with regard to their cognitive functioning. The goal of this study was to examine whether the beneficial effects of social contact are affected by individual differences in personality. Method: We examined the Big Five personality traits as moderators of the associations between social contact and episodic memory and executive functioning using the second wave of the Midlife in the U.S. study (N = 3,524, M(age) = 55.8). Results: High levels of Extraversion and low levels of Openness to Experience strengthened the association between social contact and memory and executive functioning. High levels of Neuroticism and Agreeableness weakened the association of social contact with memory but not with executive functioning. The results are consistent across adulthood. Discussion: Personality modifies the social contact cognition association. Whereas extraverts may need social contact for cognitive stimulation, those who are high on Openness gain their stimulations elsewhere. The highly neurotic might experience contact as stressful and hence as less beneficial. Emotional rather than cognitive motivation might be the reason that the highly agreeable benefit less from social contact with regard to their cognitive functioning. PMID- 27507565 TI - The Associations Between Dispositional Mindfulness, Sense of Control, and Affect in a National Sample of Adults. AB - Objectives: The present study examined factors associated with better affective experiences across the life span, extending existing research to older adults. Specifically, we investigated dispositional mindfulness and sense of control as predictors of affect and sense of control as a potential mediator of the mindfulness-affect associations. Method: We hypothesized that dispositional mindfulness mediated by sense of control would predict affective outcomes. An archival analysis of a sample of 4,962 adults, aged 28 to 84 years, was conducted using the Midlife in the U.S. national survey (MIDUS-II). Exploratory analyses were conducted with age as a moderator in all associations. Results: Greater dispositional mindfulness predicted more positive and negative affect irrespective of age. Dispositional mindfulness did not predict sense of control. Greater sense of control predicted more positive and less negative affect, and these associations were significantly moderated by age. Sense of control did not mediate the dispositional mindfulness-affect associations. Discussion: The present study extends existing research on the dispositional mindfulness-positive affect association to older ages. The sense of control and positive and negative affect associations are enhanced and buffered, respectively, at older ages, indicating that the association between control and affect differs by age. PMID- 27507566 TI - Missing the mark: ongoing missed opportunities for HIV diagnosis at an urban medical center despite universal screening recommendations. AB - BACKGROUND: Despite established recommendations from the Centers for Disease Control (CDC) to scale up testing efforts in the USA, this study shows full scale implementation of these recommendations may still be lacking. We hypothesize that patients experience ongoing missed opportunities for earlier diagnosis of HIV, despite frequent encounters to Montefiore Medical Center (MMC), an integrated hospital system in the Bronx, NY. METHODS: Retrospective chart review via electronic medical records of patients newly diagnosed with HIV in 2012 and 2013 at varied MMC clinical sites. Missed opportunities were defined as > 1 prior health care encounter at MMC within three calendar years of diagnosis, in which HIV testing was not offered for those who had a prior negative test or no prior test. RESULTS: There were 218 patients newly diagnosed with HIV at MMC during the study period; 31% presented with a CD4 <200 cells/mm3; 22% were asymptomatic at diagnosis. Patients (56%) without a prior HIV test had an average 4.72 clinical encounters at MMC within the 3 years prior to their HIV diagnosis. Over 95% of visits prior to diagnosis occurred in emergency departments (EDs) or primary care outpatient department (OPDs) and accounted for the vast majority of missed opportunities. CONCLUSIONS: HIV infected patients continue to present late to care, with low CD4 and commonly utilize OPDs and EDs, where missed opportunities for earlier diagnosis are common. Practices that address augmentation of current HIV testing strategies are needed, especially in outpatient and first-contact acute care settings. PMID- 27507567 TI - Screening the low molecular weight fraction of human serum using ATR-IR spectroscopy. AB - Vibrational spectroscopic techniques can detect small variations in molecular content, linked with disease, showing promise for screening and early diagnosis. Biological fluids, particularly blood serum, are potentially valuable for diagnosis purposes. The so-called Low Molecular Weight Fraction (LMWF) contains the associated peptidome and metabolome and has been identified as potentially the most relevant molecular population for disease-associated biomarker research. Although vibrational spectroscopy can deliver a specific chemical fingerprint of the samples, the High Molecular Weight Fraction (HMWF), composed of the most abundant serum proteins, strongly dominates the response and ultimately makes the detection of minor spectral variations a challenging task. Spectroscopic detection of potential serum biomarkers present at relatively low concentrations can be improved using pre-analytical depletion of the HMWF. In the present study, human serum fractionation by centrifugal filtration was used prior to analysis by Attenuated Total Reflection infrared spectroscopy. Using a model sample based on glycine spiked serum, it is demonstrated that the screening of the LMWF can be applied to quantify blinded concentrations up to 50 times lower. Moreover, the approach is easily transferable to different bodily fluids which would support the development of more efficient and suitable clinical protocols exploring vibrational spectroscopy based ex-vivo diagnostic tools. Revealing serum LMWF for spectral serological diagnostic applications. PMID- 27507568 TI - Risk factors for choroidal detachment following rhegmatogenous retinal detachment in a chinese population. AB - BACKGROUD: Choroidal detachment (CD) following primary rhegmatogenous retinal detachment (RRD) is a special type of RRD. The purpose of this study is to investigate the potential risk factors of RRD with CD in a Chinese population. METHODS: All of 201 consecutive RRD with CD patients and 210 RRD without CD patients were enrolled in this case-control retrospective study. The clinical data from these cases were reviewed here. Patients were undergone scleral buckling or encircling or both, or pars plana vitrectomy with or without scleral buckling or encircling or both according the patients' condition. The incidence of RRD with CD in this Chinese population was measured, and the potential risk factors for the development of RRD with CD were investigated by multivariate logistic regression analysis. RESULTS: In this population, the incidence of RRD with CD was 8.6 %. The incidence of RRD with CD was significantly higher in patients with macular hole (P < 0.05), retinal breaks located posterior to the equator (P < 0.05), and total detachment (P < 0.05). Furthermore, the incidence of RRD with CD was significantly higher in patients with longer axial length (P < 0.05) only when ages, IOP, AL and duration time was set for categorical variables. CONCLUSIONS: Hypotony, retinal breaks located posteriorly especially macular hole, longer axial length, and the whole retinal detachment might be the potential risk factors for the development of CD in RRD patients. PMID- 27507569 TI - User involvement in the implementation of clinical guidelines for common mental health disorders: a review and compilation of strategies and resources. AB - BACKGROUND: There is now broad consensus regarding the importance of involving users in the process of implementing guidelines. Few studies, however, have addressed this issue, let alone the implementation of guidelines for common mental health disorders. The aim of this study is to compile and describe implementation strategies and resources related to common clinical mental health disorders targeted at service users. METHODS: The literature was reviewed and resources for the implementation of clinical guidelines were compiled using the PRISMA model. A mixed qualitative and quantitative analysis was performed based on a series of categories developed ad hoc. RESULTS: A total of 263 items were included in the preliminary analysis and 64 implementation resources aimed at users were analysed in depth. A wide variety of types, sources and formats were identified, including guides (40%), websites (29%), videos and leaflets, as well as instruments for the implementation of strategies regarding information and education (64%), self-care, or users' assessment of service quality. CONCLUSIONS: The results reveal the need to establish clear criteria for assessing the quality of implementation materials in general and standardising systems to classify user targeted strategies. The compilation and description of key elements of strategies and resources for users can be of interest in designing materials and specific actions for this target audience, as well as improving the implementation of clinical guidelines. PMID- 27507570 TI - Antenatal immunoglobulin for prevention of neonatal hemochromatosis. AB - Neonatal hemochromatosis (NH) is a rare disease with a poor prognosis, particularly prior to 2008. Antenatal maternal high-dose immunoglobulin (Ig) is effective in preventing NH recurrence, but the adverse effects of this treatment have not been documented as yet. Here, we report on a patient who underwent high dose Ig treatment to prevent NH recurrence. The patient was a 31-year-old pregnant Japanese woman. Her first child died of NH after receiving living donor liver transplantation. The patient received high-dose Ig treatment to prevent recurrence of NH from gestational weeks 16 to 35. During the treatment, platelet count gradually decreased, and cesarean section was required at 35 gestational weeks. The child did not develop liver failure. High-dose Ig prevented the recurrence of NH. Caution should be exercised due to possible adverse effects of this treatment. PMID- 27507572 TI - A dose-response estimate for acute alcohol use and risk of suicide attempt. AB - This study reports dose-response estimates for the relative risk and population attributable risk (PAR) between acute alcohol use and serious suicide attempt. Data were analyzed on 272 suicide attempters arriving at 38 emergency departments within 6 hours of the event in 17 countries. Case-crossover analysis, pair matching the number of standard drinks consumed within the 6 hours prior to the suicide attempt with that consumed during the same 6-hour period of the previous week, was performed using fractional polynomial analysis for dose-response. Every drink increased the risk of a suicide attempt by 30 percent; even one-two drinks was associated with a sizable increase in the risk of a serious suicide attempt, and a dose-response was found for the relationship between drinking 6 hours prior and the risk of a suicide attempt up to 20 drinks. Acute use of alcohol was responsible for 35 percent PAR of all suicide attempts. While very high levels of drinking were associated with larger relative risk s of suicide attempt, the control and reduction of smaller quantities of acute alcohol use also had an impact on population levels of suicide attempt, as showed here for the first time with our PAR estimates. Interventions to stop drinking or at least decrease levels of consumption could reduce the risk of suicide attempt. Screening people more at risk to suffer these acute effects of ethanol and offering interventions that work to these high-risk groups are a matter of urgent new research in the area. PMID- 27507573 TI - Thrombotic mass traversing a patent foramen ovale. PMID- 27507574 TI - Iodine 125 Seed for Localization in Primary Hyperparathyroidism. AB - Background Preoperative localization of the parathyroid gland prior to a minimally invasive parathyroidectomy (MIP) is important because of varying locations of the parathyroid gland. Several methods have been described to localize the affected gland. One novel technique is the use of an iodine 125 (I 125) seed as a marker. The aim of this study is to evaluate the feasibility of using an I-125 seed in localizing the diseased parathyroid gland prior to MIP. Materials and methods This is a pilot study of 10 patients performed in the Amphia Hospital, the Netherlands. Patients in whom primary hyperparathyroidism (PHPT) was diagnosed in combination with 1 enlarged parathyroid gland on ultrasound (US) and scintigraphy and who were eligible for MIP were included in this study. These patients underwent a preoperative US-guided I-125 seed placement in the affected parathyroid gland. The main study parameters were the feasibility of the placement, intraoperative localization of the diseased gland and complications. Results A total of 10 patients were included. The US-guided I 125 placement in the affected parathyroid gland was technically feasible in the majority of cases. Because of the anatomical location of the gland, the placement was difficult in 2 patients, resulting in suboptimal position and possible misplacement of the marker. MIP was uncomplicated in most cases. Complications during surgery were mainly intraoperative bleeding. Conclusions The use of an I 125 seed for preoperative localization in PHPT is a relatively safe technique in parathyroid surgery. More research is needed to compare this technique with other preoperative localization techniques. PMID- 27507575 TI - Variation and Acquisition of Complex Techniques: Pancreaticoduodenectomy. AB - Background Complex procedures often have numerous acceptable approaches; it is unclear how surgical fellows choose between techniques. We used pancreaticoduodenectomy as a model to catalogue variability between surgeons and investigate factors that affect fellows' acquisition of techniques. Materials and methods Semistructured interviews and operative note analysis were conducted to determine techniques of 5 attending surgeons, and these data were mapped to identify variations. Identical interviews and questioning were completed with 4 fellowship graduates whose practice includes pancreaticoduodenectomy. Results All surgeons performed a different operation, both in order and techniques employed. Based on minor variations, there were 21 surgical step data points that differed. Of 5 surgeons, 4 were unable to identify colleagues' techniques. Fellows reported adopting techniques from mentors who had regimented techniques, teaching styles they related to, and with whom they frequently operated. Residency training did not strongly influence their choice of technique; however, senior partners after fellowship did influence technique. Conclusions The number of variants of pancreaticoduodenectomy based on granular, step-by-step differences is larger than previously described. Results hint that variation may be furthered by the fact that surgeons are not aware of the techniques used by colleagues. Fellows choose techniques based on factors not directly related to their own outcomes but rather mentor factors. Whether fellows adopt techniques that will be optimal given their abilities is worthy of further investigation, as are changes in technique over time. Better codification of variation is needed to facilitate these investigations as well as matching of technical variations to patient outcomes. PMID- 27507576 TI - [Possibilities, limitations, and perspectives in diagnosis and treatment of glaucoma : Tried and tested procedures in a new light]. PMID- 27507577 TI - Revealing complex function, process and pathway interactions with high-throughput expression and biological annotation data. AB - The biological relationships both between and within the functions, processes and pathways that operate within complex biological systems are only poorly characterized, making the interpretation of large scale gene expression datasets extremely challenging. Here, we present an approach that integrates gene expression and biological annotation data to identify and describe the interactions between biological functions, processes and pathways that govern a phenotype of interest. The product is a global, interconnected network, not of genes but of functions, processes and pathways, that represents the biological relationships within the system. We validated our approach on two high-throughput expression datasets describing organismal and organ development. Our findings are well supported by the available literature, confirming that developmental processes and apoptosis play key roles in cell differentiation. Furthermore, our results suggest that processes related to pluripotency and lineage commitment, which are known to be critical for development, interact mainly indirectly, through genes implicated in more general biological processes. Moreover, we provide evidence that supports the relevance of cell spatial organization in the developing liver for proper liver function. Our strategy can be viewed as an abstraction that is useful to interpret high-throughput data and devise further experiments. PMID- 27507579 TI - Reduced saccadic inhibition of return to moving eyes in autism spectrum disorders. AB - Inhibition of Return (IOR) refers to slower reaction time to a target presented at the same location as a preceding stimulus. Here, we examine reflexive attention orienting via the saccadic IOR using a shift in gaze direction (i.e. from averted to direct) in faces presented as a peripheral cue, in upright and inverted orientations, in adults with Autism Spectrum Disorder (ASD) and typically developed comparison participants. While both groups showed an IOR in the inverted face condition, this effect was reduced in participants with ASD in the upright face condition, as compared to comparison participants, suggesting that moving eyes do not trigger reflexive exogenous orienting in individuals with ASD. Impaired reflexive orienting to eye gaze might severely compromise the later development of social functions in ASD, such as joint attention, face emotion recognition and mindreading. PMID- 27507578 TI - HNO suppresses LPS-induced inflammation in BV-2 microglial cells via inhibition of NF-kappaB and p38 MAPK pathways. AB - Both hydrogen sulfide (H2S) and nitric oxide (NO) are important gaseous mediators. We and others previously reported that these two gases react with each other to generate a new mediator, nitroxyl (HNO), and regulate cardiovascular functions. In this study, we demonstrated for the first time that the interaction between the two gases also existed in microglia. The biological functions of HNO in microglial cells were further studied with Angeli's salt (AS), an HNO donor. We found that AS attenuated lipopolysaccharide (LPS)-evoked production of reactive oxygen species (ROS) and pro-inflammatory cytokines (e.g. IL-1beta and TNFalpha) through downregulating the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). HNO significantly reduced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and the activation of nuclear factor-kappaB (NF-kappaB) through suppression of phosphorylation p65 and IkappaBalpha. The above effects were abolished by l-cysteine, an HNO scavenger, but were not mimicked by nitrite, another product of AS during generating HNO. A Cys-179-to-Ala mutation in inhibitory kappaB kinase beta (IKKbeta) mimicked the effect of HNO on LPS-induced NF-kappaB activation. Interestingly, AS abolished the inflammation in cells overexpressing WT-IKKbeta, but had no significant effect in cells overexpressing C179A-IKKbeta. These data suggest that HNO may act on C179 to prevent IKKbeta-dependent inflammation. Taken together, our data demonstrated for the first time that H2S interacts with NO to generate HNO in microglial cells. HNO produces anti-inflammatory effects through suppressing the IKKbeta dependent NF-kappaB activation and p38 MAPK pathways. PMID- 27507580 TI - Outlining face processing skills of portrait artists: Perceptual experience with faces predicts performance. AB - Most humans seem to demonstrate astonishingly high levels of skill in face processing if one considers the sophisticated level of fine-tuned discrimination that face recognition requires. However, numerous studies now indicate that the ability to process faces is not as fundamental as once thought and that performance can range from despairingly poor to extraordinarily high across people. Here we studied people who are super specialists of faces, namely portrait artists, to examine how their specific visual experience with faces relates to a range of face processing skills (perceptual discrimination, short- and longer term recognition). Artists show better perceptual discrimination and, to some extent, recognition of newly learned faces than controls. They are also more accurate on other perceptual tasks (i.e., involving non-face stimuli or mental rotation). By contrast, artists do not display an advantage compared to controls on longer term face recognition (i.e., famous faces) nor on person recognition from other sensorial modalities (i.e., voices). Finally, the face inversion effect exists in artists and controls and is not modulated by artistic practice. Advantages in face processing for artists thus seem to closely mirror perceptual and visual short term memory skills involved in portraiture. PMID- 27507581 TI - Southward autumn migration of waterfowl facilitates cross-continental transmission of the highly pathogenic avian influenza H5N1 virus. AB - The highly pathogenic avian influenza subtype H5N1 (HPAI H5N1) is a worldwide zoonotic infectious disease, threatening humans, poultry and wild birds. The role of wild birds in the spread of HPAI H5N1 has previously been investigated by comparing disease spread patterns with bird migration routes. However, the different roles that the southward autumn and northward spring migration might play in virus transmission have hardly been explored. Using direction analysis, we analyze HPAI H5N1 transmission directions and angular concentration of currently circulating viral clades, and compare these with waterfowl seasonal migration directions along major waterfowl flyways. Out of 22 HPAI H5N1 transmission directions, 18 had both a southward direction and a relatively high concentration. Differences between disease transmission and waterfowl migration directions were significantly smaller for autumn than for spring migration. The four northward transmission directions were found along Asian flyways, where the initial epicenter of the virus was located. We suggest waterfowl first picked up the virus from East Asia, then brought it to the north via spring migration, and then spread it to other parts of world mainly by autumn migration. We emphasize waterfowl autumn migration plays a relatively important role in HPAI H5N1 transmission compared to spring migration. PMID- 27507582 TI - Transversus abdominis plane block or intravenous lignocaine in open prostate surgery: a randomized controlled trial. AB - BACKGROUND AND OBJECTIVES: Transversus abdominis plane block (TAP) and intravenous lignocaine are two analgesic techniques frequently used after abdominal surgery. We hypothesized that these two techniques improve post operative analgesia after open prostate surgery and sought to compare their efficacy on immediate post-operative outcome after open prostate surgery. METHODS: After ethics committee approval, 101 patients were enrolled in this prospective study and randomly allocated to receive bilateral ultrasound-guided TAP (n = 34), intravenous lignocaine (n = 33) or placebo (n = 34). In addition, intravenous paracetamol was given every 6 h. The primary endpoint was the cumulative opioid consumption during the first 48 post-operative hours (median[IQR]). Secondary endpoints included pain scores at rest and upon coughing, need for rescue tramadol, incidence of post-operative nausea and vomiting (PONV), recovery of bowel function and incidence of bladder catheter related discomfort. RESULTS: Cumulative piritramide consumption after 48 h was 28 [23] mg in the control group, 21 [29] mg in the TAP group and 21 [31] mg in the lignocaine group (P = 0.065). There was no significant difference in post operative pain scores between groups. The proportions of patients requiring rescue tramadol, experiencing PONV or bladder catheter-related discomfort were similar in each group. Recovery of bowel function was also similar in the three groups. CONCLUSIONS: Our study suggests that TAP block and intravenous lignocaine do not improve the post-operative analgesia provided by systematic administration of paracetamol after open prostatectomy. PMID- 27507583 TI - Rh-Catalyzed annulations of N-methoxybenzamides with ketenimines: synthesis of 3 aminoisoindolinones and 3-diarylmethyleneisoindolinones with strong aggregation induced emission properties. AB - Rhodium-catalyzed C-H activation/annulation reactions of ketenimines with N methoxybenzamides furnished 3-aminoisoindolin-1-ones and 3 (diarylmethylene)isoindolin-1-ones. The synthesized 3-(diarylmethylene)isoindolin 1-ones exhibited aggregation induced emissions in aqueous tetrahydrofuran solution and strong green-yellow emissions in solids. PMID- 27507584 TI - Alterations of Glycosphingolipids in Embryonic Stem Cell Differentiation and Development of Glycan-Targeting Cancer Immunotherapy. AB - All mammalian cells display an array of surface glycans that can modulate cellular interactions and regulate the development of an organism. In spite of their important implications in health and disease, investigations of glycans pose a great challenge given their inherent heterogeneity and the frequently observed cross-reactivities of antibodies against glycosphingolipids (GSLs) with multiple glycans, which may lead to erroneous interpretation and conclusion. We employed matrix-assisted laser desorption-ionization mass spectrometry and tandem MS/MS analyses to systematically delineate changes in GSLs during differentiation of human embryonic stem (ES) and induced pluripotent stem cells into various derivatives. In addition to the well-known human ES-specific markers, stage specific embryonic antigen (SSEA)-3 and SSEA-4 and several globo- and lacto series GSLs (Gb4Cer, Lc4Cer, fucosyl-Lc4Cer, Globo H, and disialyl-Gb5Cer) not reported previously were identified. A close association of the switching of core structures of GSLs from globo- and lacto- to ganglio-series during ES differentiation was revealed, consistent with the observed changes in GSL expression during murine embryonic development. Such switching was accompanied with the concerted changes in the expression of glycosyltransferases during differentiation. Finally, since aberrant glycosylation is a general feature of cancer, targeting tumor-associated surface glycans for cancer immunotherapy is gaining international attention. While GD2-targeted immunotherapy of neuroblastoma represents the first antiglycan monoclonal antibody to obtain FDA approval for standard medical care, Globo H-targeted immunotherapy of breast cancer has generated promising results in the ongoing multinational clinical trials. In this study, we also describe the studies of the scientific rationales for the use of glycans as anticancer immunotherapeutics. PMID- 27507585 TI - Successful management of apical abscess after Nipro left ventricular assisted device explantation by removal of apical cuff and omentopexy. AB - Nipro-Toyobo-paracorporeal pulsatile flow VAD (Nipro VAD; Nipro, Osaka, Japan) has been used most commonly as a paracorporeal VAD (p-VAD) in Japan. There are few reports describing clinical course of post LVAD explantation and its complication. We herein present two cases of apical abscess after the explantation of the device. SSI is a main risk factor of formation of the apical abscess at the time of LVAD explantation. It is mandatory to perform sufficient debridement and closure of the layers including abdominal muscle and anterior abdominal fascia at exit sites in the explantation surgery. Omentopexy is also helpful for prevention from infection. Routine removal of apical cuff and outflow graft could be considered as one of the options when LVAD is explanted as bridge to recovery. PMID- 27507586 TI - Infection control in healthcare settings: perspectives for mfDNA analysis in monitoring sanitation procedures. AB - BACKGROUND: Appropriate sanitation procedures and monitoring of their actual efficacy represent critical points for improving hygiene and reducing the risk of healthcare-associated infections. Presently, surveillance is based on traditional protocols and classical microbiology. Innovation in monitoring is required not only to enhance safety or speed up controls but also to prevent cross infections due to novel or uncultivable pathogens. In order to improve surveillance monitoring, we propose that biological fluid microflora (mf) on reprocessed devices is a potential indicator of sanitation failure, when tested by an mfDNA based approach. The survey focused on oral microflora traces in dental care settings. METHODS: Experimental tests (n = 48) and an "in field" trial (n = 83) were performed on dental instruments. Conventional microbiology and amplification of bacterial genes by multiple real-time PCR were applied to detect traces of salivary microflora. Six different sanitation protocols were considered. A monitoring protocol was developed and performance of the mfDNA assay was evaluated by sensitivity and specificity. RESULTS: Contaminated samples resulted positive for saliva traces by the proposed approach (CT < 35). In accordance with guidelines, only fully sanitized samples were considered negative (100 %). Culture-based tests confirmed disinfectant efficacy, but failed in detecting incomplete sanitation. The method provided sensitivity and specificity over 95 %. CONCLUSIONS: The principle of detecting biological fluids by mfDNA analysis seems promising for monitoring the effectiveness of instrument reprocessing. The molecular approach is simple, fast and can provide a valid support for surveillance in dental care or other hospital settings. PMID- 27507587 TI - Quorum-sensing in yeast and its potential in wine making. AB - This mini-review synthesises the present knowledge of microbial quorum-sensing, with a specific focus on quorum-sensing in yeast, and especially in wine yeast. In vine and wine ecosystems, yeast co-interact with a large variety of microorganisms, thereby affecting the fermentation process and, consequently, the flavour of the wine. The precise connections between microbial interactions and quorum-sensing remain unclear, but we describe here how and when some species start to produce quorum-sensing molecules to synchronously adapt their collective behaviour to new conditions. In Saccharomyces cerevisiae, the quorum-sensing molecules were identified as 2-phenylethanol and tryptophol. However, it was recently shown that also a quorum-sensing molecule formerly identified only in Candida albicans, tyrosol, appears to be regulated in S. cerevisiae according to cell density. This review describes the methods for detection and quantification of those quorum-sensing molecules, their underlying mechanisms of action, and their genetic background. It also examines the external stimuli that evoke the quorum-sensing mechanism in the wine-processing environment. The review closes with insight into the biotechnological applications that are already making use of the advantages of quorum-sensing systems and indicates the important questions that still need to be addressed in future research into quorum-sensing. PMID- 27507588 TI - Integrated analyses using RNA-Seq data reveal viral genomes, single nucleotide variations, the phylogenetic relationship, and recombination for Apple stem grooving virus. AB - BACKGROUND: Next-generation sequencing (NGS) provides many possibilities for plant virology research. In this study, we performed integrated analyses using plant transcriptome data for plant virus identification using Apple stem grooving virus (ASGV) as an exemplar virus. We used 15 publicly available transcriptome libraries from three different studies, two mRNA-Seq studies and a small RNA-Seq study. RESULTS: We de novo assembled nearly complete genomes of ASGV isolates Fuji and Cuiguan from apple and pear transcriptomes, respectively, and identified single nucleotide variations (SNVs) of ASGV within the transcriptomes. We demonstrated the application of NGS raw data to confirm viral infections in the plant transcriptomes. In addition, we compared the usability of two de novo assemblers, Trinity and Velvet, for virus identification and genome assembly. A phylogenetic tree revealed that ASGV and Citrus tatter leaf virus (CTLV) are the same virus, which was divided into two clades. Recombination analyses identified six recombination events from 21 viral genomes. CONCLUSIONS: Taken together, our in silico analyses using NGS data provide a successful application of plant transcriptomes to reveal extensive information associated with viral genome assembly, SNVs, phylogenetic relationships, and genetic recombination. PMID- 27507589 TI - Curcumin improves atorvastatin-induced myotoxicity in rats: Histopathological and biochemical evidence. AB - Atorvastatin is considered to be one of the most commonly used of all statins anti-hyperlipidemic drugs despite the fact that there is much controversy about its safety. Its therapeutic use becomes severely limited by the hazards of inducing myotoxicity. Curcumin is one of the safe spices that have chemoprotection and cytoprotection effects against endogenous and exogenous noxious stimuli. This study investigates the effect of curcumin on atorvastatin sub-chronic use-induced myotoxicity in rats by the assessment of serum creatinine phosphokinase, lactic acid dehydrogenase, myoglobin, troponin, potassium, creatinine, and histopathological changes of skeletal, smooth, and cardiac muscles by light and electron microscope examination. Eighty adult albino rats were divided into four groups; each group consists of 20 rats. The control group received water, the second group received atorvastatin, the third group received curcumin, and the fourth group received curcumin with atorvastatin for 90 days by gastric gavage. The prolonged use of atorvastatin induced significant abnormalities of all myotoxicity biomarkers associated with histopathological and ultrastructural changes in the different types of the muscles. Co-administration of curcumin with sub-chronic use of atorvastatin led to an improvement in myotoxicity manifestations. PMID- 27507590 TI - Subjective and clinical assessment criteria suggestive for five clinical patterns discernible in nonspecific neck pain patients. A Delphi-survey of clinical experts. AB - BACKGROUND: Nonspecific neck pain patients form a heterogeneous group with different musculoskeletal impairments. Classifying nonspecific neck pain patients into subgroups based on clinical characteristics might lead to more comprehensive diagnoses and can guide effective management. OBJECTIVE: To establish consensus among a group of experts regarding the clinical criteria suggestive of a clinical dominance of 'articular', 'myofascial', 'neural', 'central' and 'sensorimotor control' dysfunction patterns distinguishable in patients with nonspecific neck pain. STUDY DESIGN: Delphi study. METHODS: A focus group with 10 academic experts was organized to elaborate on the different dysfunction patterns discernible in neck pain patients. Consecutively, a 3-round online Delphi-survey was designed to obtain consensual symptoms and physical examination findings for the 5 distinct dysfunction patterns resulting from the focus group. RESULTS: A total of 21 musculoskeletal physical therapists from Belgium and the Netherlands experienced in assessing and treating neck pain patients completed the 3-round Delphi-survey. Respectively, 33 (response rate, 100.0%), 27 (81.8%) and 21 (63.6%) respondents replied to rounds 1, 2 and 3. Eighteen 'articular', 16 'myofascial', 20 'neural', 18 'central' and 10 'sensorimotor control' clinical indicators reached a predefined >=80% consensus level. CONCLUSION: These indicators suggestive of a clinical dominance of 'articular', 'myofascial', 'neural', 'central', and 'sensorimotor control' dysfunction patterns may help clinicians to assess and diagnose patients with nonspecific neck pain. Future validity testing is needed to determine how these criteria may help to improve the outcome of physical therapy interventions in nonspecific neck pain patients. PMID- 27507592 TI - Topological spin and valley pumping in silicene. AB - We propose to realize adiabatic topological spin and valley pumping by using silicene, subject to the modulation of an in-plane ac electric field with amplitude Ey and a vertical electric field consisting of an electrostatic component and an ac component with amplitudes and . By tuning and , topological valley pumping or spin-valley pumping can be achieved. The low-noise valley and spin currents generated can be useful in valleytronic and spintronic applications. Our work also demonstrates that bulk topological spin or valley pumping is a general characteristic effect of two-dimensional topological insulators, irrelevant to the edge state physics. PMID- 27507591 TI - Environmental NO2 and CO Exposure: Ignored Factors Associated with Uremic Pruritus in Patients Undergoing Hemodialysis. AB - Uremic pruritus (UP), also known as chronic kidney disease-associated pruritus, is a common and disabling symptom in patients undergoing maintenance hemodialysis (MHD). The pathogenesis of UP is multifactorial and poorly understood. Outdoor air pollution has well-known effects on the health of patients with allergic diseases through an inflammatory process. Air pollution-induced inflammation could occur in the skin and aggravate skin symptoms such as pruritus or impair epidermal barrier function. To assess the role of air pollutants, and other clinical variables on uremic pruritus (UP) in HD patients, we recruited 866 patients on maintenance HD. We analyzed the following variables for association with UP: average previous 12-month and 24-month background concentrations for nitrogen dioxide (NO2) and carbon monoxide (CO), and suspended particulate matter of <2.5 MUm (PM2.5). In a multivariate logistic regression, hemodialysis duration, serum ferritin levels, low-density lipoprotein levels, and environmental NO2/CO levels were positively associated with UP, and serum albumin levels were negatively associated with UP. This cross-sectional study showed that air pollutants such as NO2 and CO might be associated with UP in patients with MHD. PMID- 27507593 TI - Nutraceuticals in Neurodegeneration and Aging. PMID- 27507594 TI - Phytochemicals in animal health: diet selection and trade-offs between costs and benefits. AB - Many plant tissues contain plant secondary compounds (PSC), which have long been recognised as defensive chemicals that deter herbivory via their toxic effects. However, herbivores may also benefit from including PSC into their diets. Plant derived phenolics, terpenes and alkaloids have antiparasitic properties and sesquiterpene lactones have antibacterial, antifungal and antiparasitic properties. These actions are in part a consequence of the negative actions that PSC exert across several trophic levels, including the bacteria, parasites and fungi that inhabit herbivores' bodies. Given the dual action, toxin and medicine, it is possible to hypothesise that self-selection of PSC by herbivores should occur when the benefits outweigh the costs of PSC ingestion. Recent research suggests that sheep and goats self-medicate against parasitic infections. They increase preference for condensed tannin-containing foods when experiencing a parasitic burden. This behaviour improves health; it is triggered by parasitism and weakens when parasitism subsides. However, the causes underlying these responses are not straightforward when viewed under a unidimensional cost-benefit analysis. This is because the intensity of antinutritional/toxic and medicinal effects of PSC is not static or just dependent upon the isolated post-ingestive effects of single PSC. Nutrient-PSC and PSC-PSC interactions, social models, as well as feeding patterns, all influence the perceived net benefit of incorporating medicines into a diet. A better understanding of the net benefit of self-medication in complex feeding environments will allow for the development of innovative managing strategies aimed at providing the food alternatives and conditions for improving the nutrition, health and welfare of grazing animals. PMID- 27507596 TI - Competing amination and C-H arylation pathways in Pd/xantphos-catalyzed transformations of binaphthyl triflates: switchable routes to chiral amines and helicene derivatives. AB - A Pd(OAc)2/xantphos catalyst system was found effective for benzylaminations of binaphthyl 2-triflates bearing a variety of alkyl, benzyl, and substituted phenyl substituents at the 2'-position. With 2'-aryl substituents, an intramolecular Pd catalyzed C-H arylation was observed as a competing side reaction under some conditions. By adjusting the solvent and quantity of the amine, the reaction was optimized to favor either the amination or the C-H arylation pathway, affording two distinct and potentially useful sets of products. The amines represent tunable chiral ligand precursors, while the C-H arylation pathway affords a series of benzofused [5]helicene derivatives. Kinetic studies and activation parameters for the C-H arylation pathway, supported by DFT calculations, are consistent with a concerted metalation-deprotonation (CMD) mechanism involving a Pd-bound carbonate as the base. Xantphos is proposed to facilitate the turnover limiting inner-sphere CMD step by acting as a hemilabile ligand, while its wide bite angle engenders a low reductive elimination barrier. PMID- 27507595 TI - The interaction of fasting, caloric restriction, and diet-induced obesity with 17beta-estradiol on the expression of KNDy neuropeptides and their receptors in the female mouse. AB - Arcuate neurons that coexpress kisspeptin (Kiss1), neurokinin B (Tac2), and dynorphin (Pdyn) mediate negative feedback of 17beta-estradiol (E2) on the HPG axis. Previous studies report that fasting and caloric restriction reduce arcuate Kiss1 expression. The objective of this study was to determine the interactions of E2 with fasting, caloric restriction, and diet-induced obesity on KNDy gene and receptor expression. Ovariectomized female mice were separated into control and estradiol benzoate (E2B)-treated groups. E2B decreased Kiss1 and the tachykinin 2 receptor, Tac3r, in ARC tissue and Tac2 in Tac2 neurons. Diet induced obesity decreased Kiss1 in oil-treated animals and the kisspeptin receptor, Kiss1r and Tac3r in the ARC of E2B-treated animals. Chronic caloric (30%) restriction reduced all three neuropeptides in oil-treated females and Kiss1r by E2B in CR animals. Taken together, our experiments suggest that steroidal environment and energy state negatively regulate KNDy gene expression in both ARC and Tac2 neurons. PMID- 27507597 TI - Label-free optical detection of age-related and diabetic oxidative damage in human aqueous humors. AB - In this study, we investigate the biochemical characteristics of oxidative stress in age-related macular degeneration (AMD) and diabetic retinopathy (DR) by analyzing aqueous humors. Nondiabetic cataract aqueous humor was used as the control. The level of oxidative damage was evaluated based on changes in Raman spectral intensity. Seven prominent peaks were detected at 1002, 1043, 1062, 1352, 1419, 1454, and 1656 cm-1 . We proposed four multimodal biomarkers to distinguish these peaks based on the ratios of Raman intensities in two wavelengths, including CHO (C-O stretching or C-O-H bending modes), AG (adenine and guanine), PRO-AG (protein and AG), and PHEalpha (phenylalanine symmetric ring breath and amide I alpha-helix) markers. The presence of oxidative damage was detected by CHO and AG markers associated with C-O stretching, C-O-H bending modes in carbohydrates (1043 cm-1 ), and the nucleic acids adenine and guanine (1352 cm-1 ), respectively. DR-related oxidative damage was identified by PRO-AG and PHEalpha markers associated with adenine, guanine, and protein components (1419 and 1454 cm-1 ) and amide I alpha-helix protein structure (1656 cm-1 ), respectively. AMD-related oxidative damage was identified by four biomarkers. Four multimodal biomarkers with simple linear threshold values achieved high sensitivity of 100% and high specificity of 100% for classifying oxidative stress induced AMD and DR diseases. Therefore, Raman-based label-free optical detection is effective for detecting the presence of age-related or diabetic oxidative damage in aqueous humor. PMID- 27507598 TI - Neuroprotective effects of antibodies on retinal ganglion cells in an adolescent retina organ culture. AB - Glaucoma, a neurodegenerative disease, is characterized by a progressive loss of retinal ganglion cells (rgc). Up- and down-regulated autoantibody immunoreactivities in glaucoma patients have been demonstrated. Previous studies showed protective effects of down-regulated antibodies [gamma (gamma)-synuclein and glial fibrillary acidic protein [GFAP]) on neuroretinal cells. The aim of this study was to test these protective antibody effects on rgc in an organ culture model and to get a better understanding of cell-cell interactions of the retina in the context of the protective effect. We used an adolescent retinal organ culture (pig) with an incubation time of up to 4 days. Retinal explants were incubated with different antibodies for 24 h (anti-GFAP, anti-gamma synuclein and anti-myoglobin antibody as a control). Brn3a and TUNEL staining were performed. We also conducted glutamine synthetase staining and quantification of the retinal explants. Mass spectrometry analyses were performed as well as protein analyses via microarray. We detected a continuous decrease of rgc/mm in the retinal explants throughout the 4 days of incubation with increased TUNEL rgc staining. Immunohistochemical analyses showed a protective effect of anti-gamma-synuclein (increased rgc/mm of 41%) and anti-GFAP antibodies (increased rgc/mm of 37%). Mass spectrometric, microarray and immunohistochemical analyses demonstrated Muller cell involvement and decreased endoplasmic reticulum stress response in the antibody-treated retinae. We could detect that the tested antibodies have a protective effect on rgc which seems to be the result of reduced stress levels in the retina as well as a shift of glutamine synthetase localization in the endfeet of the Muller cells towards the inner retinal layer. Loss of retinal ganglion cells (rgc) in glaucoma leads to blindness. Several antibodies are down-regulated in glaucoma patients. Our aim was to test if these antibodies have a protective effect of rgc in a retinal organ culture. This could be shown with an increase of rgc numbers. This effect results through reduced stress levels and the shift of glutamine synthetase localization. PMID- 27507599 TI - Remodeling of injectable, low-viscosity polymer/ceramic bone grafts in a sheep femoral defect model. AB - Ceramic/polymer composite bone grafts offer the potential advantage of combining the osteoconductivity of ceramic component with the ductility of polymeric component, resulting in a graft that meets many of the desired properties for bone void fillers (BVF). However, the relative contributions of the polymer and ceramic components to bone healing are not well understood. In this study, we compared remodeling of low-viscosity (LV) ceramic/poly(ester urethane) composites to a ceramic BVF control in a sheep femoral condyle plug defect model. LV composites incorporating either ceramic (LV/CM) or allograft bone (LV/A) particles were evaluated. We hypothesized that LV/CM composites which have the advantageous handling properties of injectability, flowability, and settability would heal comparably to the CM control, which was evaluated for up to 2 years to study its long-term degradation properties. Remodeling of LV/CM was comparable to that observed for the CM control, as evidenced by new bone formation on the surface of the ceramic particles. At early time points (4 months), LV/CM composites healed similar to the ceramic clinical control, while LV/A components showed more variable healing due to osteoclast-mediated resorption of the allograft particles. At longer time points (12-15 months), healing of LV/CM composites was more variable due to the nonhomogeneous distribution and lower concentration of the ceramic particles compared to the ceramic clinical control. Resorption of the ceramic particles was almost complete at 2 years. This study highlights the importance of optimizing the loading and distribution of ceramic particles in polymer/ceramic composites to maximize bone healing. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2333-2343, 2017. PMID- 27507600 TI - Expectations and perspectives of ovarian cancer patients about cancer management in Romania. The international NOGGO-ENGOT trial: EXPRESSION III. AB - We have investigated a relational model of expectations and preferences among ovarian cancer patients centred on physician-patient communication, treatment approach, and the need for information. Consecutive patients anonymously filled in the EXPRESSION III questionnaire between 2009 and 2012. Following descriptive statistics, structural equation modelling was used to analyse the relationships between physician's evaluation by the patient (PEP), result of therapy (RT), need for changes in treatment (NCT) and patient's desire to be informed (PD). From a total of 108 patients, 53 (49.1%) knew their disease stage, 103 (95.4%) underwent surgery, 91 (84.3%) had chemotherapy and 51 (46.3%) relapsed. The final model demonstrated a good fit of data with fit indices >0.90. There was a significant positive effect of PEP on RT and a significant negative effect of PEP on NCT, with the final model explaining 84% of the NCT variance. Physicians represent the main point of contact, not only as a source of information about the disease and various treatment options, but also in the coping processes. As patients benefit from completeness of medical consultations, their awareness of the treatment outcome increases, while a negative perception of the physician leads to a desire to make changes in therapy. PMID- 27507601 TI - Acetylcholine-hydrolyzing activities in soluble brain fraction: Characterization with reversible and irreversible inhibitors. AB - Some effects of organophosphorus compounds (OPs) esters cannot be explained through actions on currently recognized targets acetylcholinesterase or neuropathy target esterase (NTE). In soluble chicken brain fraction, three components (Ealpha, Ebeta and Egamma) of pheny lvalerate esterase activity (PVase) were kinetically discriminated and their relationship with acetylcholine hydrolyzing activity (cholinesterase activity) were studied in previous works. In this work, four enzymatic components (CS1, CS2, CS3 and CS4) of cholinesterase activity have been discriminated in soluble fraction, according to their sensitivity to irreversible inhibitors mipafox, paraoxon, PMSF and iso-OMPA and to reversible inhibitors ethopropazine and BW284C51. Cholinesterase component CS1 can be related to the Ealpha component of PVase activity and identified as butyrylcholinesterase (BuChE). No association and similarities can be stablished among the other PVase component (Ebeta and Egamma) with the other cholinesterase components (CS2, CS3, CS4). The kinetic analysis has allowed us to stablish a method for discriminating the enzymatic component based on a simple test with two inhibitors. It can be used as biomarker in toxicological studies and for monitoring these cholinesterase components during isolation and molecular identification processes, which will allow OP toxicity to be understood by a multi-target approach. PMID- 27507602 TI - N-phenylmaleimides affect adipogenesis and present antitumor activity through reduction of FASN expression. AB - In light of the evidence that in contrast to most healthy tissues, several neoplasms overexpress fatty acid synthase (FASN) upon their dependence on increased lipogenesis; targeting of this protein is being considered as a valuable strategy in anticancer drug development. This can be particularly relevant for aggressive tumors such as melanoma in which FASN overexpression has been associated with increased depth of invasion and worse prognosis. We have previously shown that a sub-class of cyclic imides, the N-phenylmaleimides, presented antitumor activity against L1210 leukemia and B16F10 melanoma with evidences of interference in the energetic metabolism. Here, we aimed to investigate if some selected N-phenylmaleimides (M1 and M5) interfere with fatty acids metabolism and its relation with cancer. For that, a model of pre adipocytes differentiation (3T3-L1 cells) and also human melanoma cells (SK-Mel 147) were used. As results, when 3T3-L1 cells were exposed to non-cytotoxic concentrations of M1 and M5 in the presence of an adipogenic cocktail, intracellular lipid content decreased by 26-36%, marking the inhibition of adipocyte differentiation. High selectivity indexes were obtained for both compounds for tumoral cells. Cell cycle phases analysis revealed a remarkable proportion of cells with DNA fragmentation after their exposure to M1 and M5. This was correlated to both apoptosis and necrosis, showed by Annexin-V/PI assay. Furthermore, M1 and M5 reduced FASN expression by 19-39%, respectively. In conclusion, M1 and M5 presented antiadipogenic and antitumoral activities. The antitumoral activity that was associated to apoptosis and necrosis is a possible consequence of the FASN reduction, which in turn, might result in a fuel decrease to cell proliferation. As it happens with antiangiogenic activity, reduction of fatty acid synthesis might be a potential target for cancer treatment in a strategy of hunger-strike, which valorizes these N-phenylmaleimides as candidates for drug development. PMID- 27507603 TI - Controllable in-situ cell electroporation with cell positioning and impedance monitoring using micro electrode array. AB - This paper reports a novel microarray chip for in-situ, real-time and selective electroporation on individual cells integrated with cell positioning and impedance monitoring. An array of quadrupole-electrode units (termed positioning electrodes) and pairs of planar center electrodes located at the centers of each quadrupole-electrode unit were fabricated on the chip. The positioning electrodes are used to trap and position living cells onto the center electrodes based on negative dielectrophoresis (nDEP). The center electrodes are used for in-situ cell electroporation, and also used to measure cell impedance for monitoring cellular dynamics in real time. Controllably selective electroporation and electrical measurement on the cells in array are realized. We present an evidence of selective electroporation through use of fluorescent dyes. Subsequently we use in-situ and real-time impedance measurement to monitor the process, which demonstrates the dynamic behavior of the cell electroporation. Finally, we show the use of this device to perform successful transfection onto individual HeLa cells with vector DNA encoding a green fluorescent. PMID- 27507604 TI - Salicylic acid confers salt tolerance in potato plants by improving water relations, gaseous exchange, antioxidant activities and osmoregulation. AB - BACKGROUND: Potato is an important vegetable; however, salt stress drastically affects its growth and yield. A pot experiment was therefore conducted to assess salicylic acid efficacy in improving performance of potato cultivars, grown under salt stress (50 mmol L-1 ). Salicylic acid at 0.5 mmol L-1 was sprayed on to potato plants after 1 week of salinity application. RESULTS: Salt stress effects were ameliorated by salicylic acid effectively in both the studied cultivars. N-Y LARA proved more responsive to salicylic acid application than 720-110 NARC, which confirmed genetic variation between cultivars. Salicylic acid scavenged reactive oxygen species by improving antioxidant enzyme activities (superoxide dismutase, catalase, peroxidases) and regulating osmotic adjustment (proline, phenolic contents), which led to enhanced water relation and gaseous exchange attributes, and thereby increased potassium availability and reduced sodium content in potato leaves. Moreover, potato tuber yield showed a positive correlation with potassium content, photosynthesis and antioxidant enzyme activities. CONCLUSION: Salt tolerance efficacy of salicylic acid is authenticated in improving potato crop performance under salt stress. Salicylic acid effect was more pronounced in N-Y LARA, reflecting greater tolerance than 720-110 NARC, which was confirmed as a susceptible cultivar. Hence salicylic acid at 0.5 mmol L-1 and cultivation of N-Y LARA may be recommended in saline soil. (c) 2016 Society of Chemical Industry. PMID- 27507606 TI - The Correlation of Increased CRP Levels with NFKB1 and TLR2 Polymorphisms in the Case of Morbid Obesity. AB - Morbid obesity (MO) is associated with an increase in circulating levels of systemic acute phase proteins such as C-reactive protein (CRP). Toll-like receptor is possible candidate for inflammatory responses which is mainly mediated by NFKB1. The aim of this study was to investigate the relationship between NFKB1 and Toll-like receptor (TLR) 2 polymorphisms and the risk of MO in a Turkish population in the context of CRP serum levels which may contribute to susceptibility to the disease. We analysed the distribution of NFKB1-94 ins/del ATTG rs28362491 and TLR2 Arg753Gln rs5743708 polymorphisms using PCR-RFLP method and CRP serum levels using ELISA method in 213 MO and 200 healthy controls. The frequency of the ins/ins genotype and ins allele of rs28362491 was significantly higher in the patients compared to control group (P: 0.0309; P: 0.0421, respectively). Additionally, the frequency of GG genotype and G allele of rs5743708 was found to be statistically higher in the patient group (P: 0.0421; P < 0.0001, respectively). In addition, serum CRP levels (>20 mg/l) in MO patients with ins/ins genotype were significantly higher than in patients with del/ins genotype (P: 0.0309). Serum CRP levels were also higher in MO patients with GG genotype and G allele (P: 0.0001). According to combined analysis, the wild type of rs28362491 and rs5743708 polymorphisms (ins/ins/GG genotype) was also significantly higher in the patient group versus the control group when compared with the combined ins/ins/GA and del/ins/GA genotype (P < 0.0001). Therefore, our findings suggest that rs28362491 and rs5743708 polymorphisms were significantly associated with MO disease through acting by modulating serum CRP levels. PMID- 27507607 TI - How Are Short Exons Flanked by Long Introns Defined and Committed to Splicing? AB - The splice sites (SSs) delimiting an intron are brought together in the earliest step of spliceosome assembly yet it remains obscure how SS pairing occurs, especially when introns are thousands of nucleotides long. Splicing occurs in vivo in mammals within minutes regardless of intron length, implying that SS pairing can instantly follow transcription. Also, factors required for SS pairing, such as the U1 small nuclear ribonucleoprotein (snRNP) and U2AF65, associate with RNA polymerase II (RNAPII), while nucleosomes preferentially bind exonic sequences and associate with U2 snRNP. Based on recent publications, we assume that the 5' SS-bound U1 snRNP can remain tethered to RNAPII until complete synthesis of the downstream intron and exon. An additional U1 snRNP then binds the downstream 5' SS, whereas the RNAPII-associated U2AF65 binds the upstream 3' SS to facilitate SS pairing along with exon definition. Next, the nucleosome associated U2 snRNP binds the branch site to advance splicing complex assembly. This may explain how RNAPII and chromatin are involved in spliceosome assembly and how introns lengthened during evolution with a relatively minimal compromise in splicing. PMID- 27507609 TI - Recognizing Plant Defense Priming. AB - Defense priming conditions diverse plant species for the superinduction of defense, often resulting in enhanced pest and disease resistance and abiotic stress tolerance. Here, we propose a guideline that might assist the plant research community in a consistent assessment of defense priming in plants. PMID- 27507610 TI - Bone mineral density in anorexia nervosa: Only weight and menses recovery? AB - INTRODUCTION: The study objectives were to analyze the presence of reduced bone mass in a sample of patients with anorexia nervosa (AN) and amenorrhea, to assess Bone Mineral Density (BMD) recovery after having a normal weight is reached and regular menses are resumed, and to predict BMD after a treatment period considering different variables (baseline BMD, baseline and final body mass index (BMI), treatment duration). MATERIAL & METHODS: 35 patients with AN (mean age 20.57+/-5.77) were studied at treatment start (T0) and after they had recovered their normal weight and regular menses (T1) in order to measure their BMD using quantitative computed tomography (QCT) of the lumbar spine (L2-L4). RESULTS: At T0, 2.86% of patients had normal BMD, while a reduced bone mass consistent with osteopenia or with osteoporosis was found in 22.86% and 74.28% of patients respectively. At T1, the percentages were 20%, 20%, and 60% respectively. No significant differences were seen in L2-L3 and mean BMD (L2-L4). A significant difference was however found for L4 (p<0.05). A positive relationship was seen between final body mass index (BMI) and final BMD in patients with T0-T1>11 months, but not when the time period was <=11 months. CONCLUSIONS: This follow-up study of changes not only in BMD but also in BMI and recovery of menses has clinical relevance from the viewpoint of the day-by-day treatment process. Use of QCT makes the study more relevant because this is a more advanced technique that allows for differentiating trabecular and cortical bone. PMID- 27507608 TI - Cockayne syndrome: Clinical features, model systems and pathways. AB - Cockayne syndrome (CS) is a disorder characterized by a variety of clinical features including cachectic dwarfism, severe neurological manifestations including microcephaly and cognitive deficits, pigmentary retinopathy, cataracts, sensorineural deafness, and ambulatory and feeding difficulties, leading to death by 12 years of age on average. It is an autosomal recessive disorder, with a prevalence of approximately 2.5 per million. There are several phenotypes (1-3) and two complementation groups (CSA and CSB), and CS overlaps with xeroderma pigmentosum (XP). It has been considered a progeria, and many of the clinical features resemble accelerated aging. As such, the study of CS affords an opportunity to better understand the underlying mechanisms of aging. The molecular basis of CS has traditionally been ascribed to defects in transcription and transcription-coupled nucleotide excision repair (TC-NER). However, recent work suggests that defects in base excision DNA repair and mitochondrial functions may also play key roles. This opens up the possibility for molecular interventions in CS, and by extrapolation, possibly in aging. PMID- 27507611 TI - Effects of dietary supplementation with EPA and/or alpha-lipoic acid on adipose tissue transcriptomic profile of healthy overweight/obese women following a hypocaloric diet. AB - In obesity, the increment of adiposity levels disrupts the whole body homeostasis, promoting an over production of oxidants and inflammatory mediators. The current study aimed to characterize the transcriptomic changes promoted by supplementation with eicosapentaenoic acid (EPA, 1.3 g/day), alpha-lipoic acid (0.3 g/day), or both (EPA + alpha-lipoic acid, 1.3 g/day + 0.3 g/day) in subcutaneous abdominal adipose tissue from overweight/obese healthy women, who followed a hypocaloric diet (30% of total energy expenditure) during ten weeks, by using a microarray approach. At the end of the intervention, a total of 33,297 genes were analyzed using Affymetrix GeneChip arrays. EPA promoted changes in extracellular matrix remodeling gene expression, besides a rise of genes associated with either chemotaxis or wound repair. alpha-Lipoic acid decreased expression of genes related with cell adhesion and inflammation. Furthermore, alpha-lipoic acid, especially in combination with EPA, upregulated the expression of genes associated with lipid catabolism while downregulated genes involved in lipids storage. Together, all these data suggest that some of the metabolic effects of EPA and alpha-lipoic acid could be related to their regulatory actions on adipose tissue metabolism. (c) 2016 BioFactors, 43(1):117-131, 2017. PMID- 27507612 TI - "Non-Toxic" Proteins of the Botulinum Toxin Complex Exert In-vivo Toxicity. AB - The botulinum neurotoxin (BoNT) causes muscle paralysis and is the most potent toxin in nature. BoNT is associated with a complex of auxiliary "Non-Toxic" proteins, which constitute a large-sized toxin complex (L-TC). However, here we report that the "Non-Toxic" complex of serotype D botulinum L-TC, when administered to rats, exerts in-vivo toxicity on small-intestinal villi. Moreover, Serotype C and D of the "Non-Toxic" complex, but not BoNT, induced vacuole-formation in a rat intestinal epithelial cell line (IEC-6), resulting in cell death. Our results suggest that the vacuole was formed in a manner distinct from the mechanism by which Helicobacter pylori vacuolating toxin (VacA) and Vibrio cholerae haemolysin induce vacuolation. We therefore hypothesise that the serotype C and D botulinum toxin complex is a functional hybrid of the neurotoxin and vacuolating toxin (VT) which arose from horizontal gene transfer from an ancestral BoNT-producing bacterium to a hypothetical VT-producing bacterium. PMID- 27507613 TI - The secondary frame in spider orb webs: the detail that makes the difference. AB - Spider orb webs are multifunctional structures, the main function of which is to dissipate the kinetic energy of the impacting prey, while minimizing structural damage. There is no single explanation for their remarkable strength and ductility. However, it is clear that topology is decisive in the structural performance upon impact, and the arrangement of the different silk threads in the web must also exert an effect. The aim of this study is to show how a slight variation in the geometry markedly affects the prey-capture ability of spider orb webs. The study is focused on the secondary frame, a thread interposed between radial and primary frame strands, the importance of which has not been examined until now. The simulation of the impact performance of webs using different lengths of the secondary frame clarifies its structural role, which has proven to be decisive. Furthermore, the study explains why secondary frame threads of moderate length, as commonly encountered, enable the capture of prey with higher energy without a marked increase in the volume of silk used. PMID- 27507614 TI - NKD1 correlates with a poor prognosis and inhibits cell proliferation by inducing p53 expression in hepatocellular carcinoma. AB - Naked cuticle 1 (NKD1), a negative regulator of the Wnt signaling pathway, is abnormally expressed in many types of malignant tumors. Yet the role and mechanism of NKD1 in hepatocellular carcinoma (HCC) cell proliferation and its relationship with HCC patients' prognosis have been poorly characterized. In the present study, real-time polymerase chain reaction (PCR) was used to examine the mRNA expression patterns of NKD1 in the tissues of 60 patients with HCC and corresponding adjacent non-tumor tissues and found that NKD1 mRNA expression in HCC tissues was relatively lower than that in non-tumor tissues and negatively correlated with tumor size. Kaplan-Meier survival curves uncovered that patients with lower NKD1 expression had a poorer post-operative prognosis than those with higher expression. In addition, over-expression of NKD1 inhibited the HCC cell proliferation ability, whereas knockdown of NKD1 had the opposite effect. In vivo assays showed that mice injected with SMMC-7721 + control cells had bigger tumor nodules than those injected with SMMC-7721 + NKD1. Mechanism studies demonstrated that NKD1 repressed HCC cell proliferation by inducing p53 expression. Taken together, our study revealed that NKD1 mRNA expression was downregulated in HCC tissues and correlated with a poor prognosis. NKD1 inhibited HCC cell proliferation by inducing p53 expression. PMID- 27507616 TI - Integrated Epigenomics Analysis Reveals a DNA Methylation Panel for Endometrial Cancer Detection Using Cervical Scrapings. AB - PURPOSE: Endometrial cancer is a common gynecologic cancer whose incidence is increasing annually worldwide. Current methods to detect endometrial cancer are unreliable and biomarkers are unsatisfactory for screening. Cervical scrapings were reported as a potential source of material for molecular testing. DNA methylation is a promising cancer biomarker, but limited use for detecting endometrial cancer. EXPERIMENTAL DESIGN: We analyzed two methylomics databases of endometrioid-type endometrial cancer. Using nonnegative matrix factorization algorithm clustered the methylation pattern and reduced the candidate genes. We verified in pools DNA from endometrial cancer tissues and cervical scrapings, and validated in 146 cervical scrapings from patients with endometrioid-type endometrial cancer (n = 50), uterine myoma (n = 40), and healthy controls (n = 56) using quantitative methylation-specific PCR (QMSP). The logistic regression was used to evaluate the performance of methylation signal and gene combination. RESULTS: We filtered out 180 methylated genes, which constituted four consensus clusters. Serial testing of tissues and cervical scrapings detected 14 genes that are hypermethylated in endometrial cancer. Three genes, BHLHE22, CDO1, and CELF4, had the best performance. Individual genes were sensitivity of 83.7%-96.0% and specificity of 78.7%-96.0%. A panel comprising any two of the three hypermethylated genes reached a sensitivity of 91.8%, specificity of 95.5%, and odds ratio of 236.3 (95% confidence interval, 56.4-989.6). These markers were also applied to cervical scrapings of type II endometrial cancer patients, and detected in 13 of 14 patients. CONCLUSIONS: This study demonstrates the potential use of methylated BHLHE22/CDO1/CELF4 panel for endometrial cancer screening of cervical scrapings. Clin Cancer Res; 23(1); 263-72. (c)2016 AACR. PMID- 27507615 TI - Characterization of cancer stem cells from different grades of human colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common solid tumors worldwide. Recent evidence suggests that a population of cancer cells, called cancer stem cells (CSCs), is responsible for tumor heterogeneity, invasion, metastasis, therapeutic resistance, and recurrence of CRC. The isolation and characterization of CSCs using cell surface markers have been reported previously with varying results. In this study, we investigated a panel of four putative CSC markers, CD44, CD24, CD166, and EpCAM, to define CRC-CSC. Paraffin embedded tissue samples from different grades of primary, untreated CRC were analyzed for the expression of four CSC markers CD44, CD326, CD24, and CD166, using immunohistochemistry. Flow cytometric analysis of CRC-CSC from HT29 (low grade) and HCT116 (high grade) human colorectal cancer cell lines was done. Marker-based isolation of CSC and non-CSC-bulk-tumor cells from HT29 was done using FACS, and tumor sphere assay was performed. There was a statistically significant difference (p < 0.05) in the expression of CD44, CD326, and CD166 between cases and controls. A novel cutoff distribution of CD44 and CD166 was suggested to help for better immunohistochemical analysis of CRC. Higher prevalence of CSC was seen in high grade CRC as compared to low-grade CRC. Sorted and cultured CD44 + CD166+ cells formed tumor spheres, suggesting that these cells, having properties of self renewal and anchorage independent proliferation, were in fact CSC. Hence, CD44 and CD166 may serve as good CRC-CSC markers when used together with novel cutoff immunohistochemistry (IHC) expression levels. PMID- 27507617 TI - Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer. AB - Purpose:UGT1A1*28 confers a higher risk of toxicity in patients treated with irinotecan. Patients with *1/*1 and *1/*28 genotypes might tolerate higher than standard doses of irinotecan. We aimed to identify the MTD of irinotecan in patients with metastatic colorectal cancer (mCRC) with *1/*1 and *1/*28 genotypes treated with FOLFIRI plus bevacizumab, and to determine whether bevacizumab alters irinotecan pharmacokinetics.Experimental Design: Previously untreated patients with mCRC (25 *1/*1; 23 *1/*28) were given FOLFIRI plus bevacizumab every 2 weeks. The irinotecan dose was escalated using a 3 + 3 design in each genotype group as follows: 260, 310, and 370 mg/m2 The MTD was the highest dose at which <4/10 patients had a dose-limiting toxicity (DLT). Pharmacokinetics of irinotecan and SN-38 were measured on days 1 to 3 (without bevacizumab) and 15 to 17 (with bevacizumab).Results: For *1/*1 patients, 2 DLTs were observed among 10 patients at 310 mg/m2, while 370 mg/m2 was not tolerated (2 DLTs in 4 patients). For *1/*28 patients, 2 DLTs were observed among 10 patients at 260 mg/m2, while 310 mg/m2 was not tolerated (4 DLTs in 10 patients). Neutropenia and diarrhea were the most common DLTs. Changes in the AUCs of irinotecan and SN-38 associated with bevacizumab treatment were marginal.Conclusions: The MTD of irinotecan in FOLFIRI plus bevacizumab is 310 mg/m2 for UGT1A1 *1/*1 patients and 260 mg/m2 for *1/*28 patients. Bevacizumab does not alter the pharmacokinetics of irinotecan. The antitumor efficacy of these genotype-guided doses should be tested in future studies of patients with mCRC treated with FOLFIRI plus bevacizumab. Clin Cancer Res; 23(4); 918-24. (c)2016 AACR. PMID- 27507618 TI - Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung. AB - PURPOSE: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations. EXPERIMENTAL DESIGN: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases). RESULTS: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60% 100%). CONCLUSIONS: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. Clin Cancer Res; 23(3); 757-65. (c)2016 AACR. PMID- 27507619 TI - Collaborative study for the validation of an improved HPLC assay for recombinant IFN-alfa-2. AB - The current European Pharmacopoeia (Ph. Eur.) texts for Interferon (IFN)-alfa-2 include a nonspecific photometric protein assay using albumin as calibrator and a highly variable cell-based assay for the potency determination of the protective effects. A request was expressed by the Official Medicines Control Laboratories (OMCLs) for improved methods for the batch control of recombinant interferon alfa 2 bulk and market surveillance testing of finished products, including those formulated with Human Serum Albumin (HSA). A HPLC method was developed at the Medical Products Agency (MPA, Sweden) for the testing of IFN-alfa-2 products. An initial collaborative study run under the Biological Standardisation Programme (BSP; study code BSP039) revealed the need for minor changes to improve linearity of the calibration curves, assay reproducibility and robustness. The goal of the collaborative study, coded BSP071, was to transfer and further validate this improved HPLC method. Ten laboratories participated in the study. Four marketed IFN-alfa-2 preparations (one containing HSA) together with the Ph. Eur. Chemical Reference Substance (CRS) for IFN-alfa-2a and IFN-alfa-2b, and in-house reference standards from two manufacturers were used for the quantitative assay. The modified method was successfully transferred to all laboratories despite local variation in equipment. The resolution between the main and the oxidised forms of IFN-alfa-2 was improved compared to the results from the BSP039 study. The improved method even allowed partial resolution of an extra peak after the principal peak. Symmetry of the main IFN peak was acceptable for all samples in all laboratories. Calibration curves established with the Ph. Eur. IFN-alfa-2a and IFN-alfa-2b CRSs showed excellent linearity with intercepts close to the origin and coefficients of determination greater than 0.9995. Assay repeatability, intermediate precision and reproducibility varied with the tested sample within acceptable ranges. Test accuracy estimated by comparing the values obtained by the participants to the declared contents determined by the manufacturers was good despite the absence of a common reference preparation. In conclusion, the present study showed that the new method is suitable, reproducible and transferable. Proposals for the revision of Ph. Eur. texts are presented. PMID- 27507620 TI - Dynamics of flexible fibers and vesicles in Poiseuille flow at low Reynolds number. AB - The dynamics of flexible fibers and vesicles in unbounded planar Poiseuille flow at low Reynolds number is shown to exhibit similar basic features, when their equilibrium (moderate) aspect ratio is the same and vesicle viscosity contrast is relatively high. Tumbling, lateral migration, accumulation and shape evolution of these two types of flexible objects are analyzed numerically. The linear dependence of the accumulation position on relative bending rigidity, and other universal scalings are derived from the local shear flow approximation. PMID- 27507621 TI - Assessing the temporal stability of surface functional groups introduced by plasma treatments on the outer shells of carbon nanotubes. AB - Plasma treatments are emerging as superior efficiency treatment for high surface to volume ratio materials to tune functional group densities and alter crystallinity due to their ability to interact with matter at the nanoscale. The purpose of this study is to assess for the first time the long term stability of surface functional groups introduced across the surface of carbon nanotube materials for a series of oxidative, reductive and neutral plasma treatment conditions. Both plasma duration dose matrix based exposures and time decay experiments, whereby the surface energy of the materials was evaluated periodically over a one-month period, were carried out. Although only few morphological changes across the graphitic planes of the carbon nanotubes were found under the uniform plasma treatment conditions, the time dependence of pertinent work functions, supported by Raman analysis, suggested that the density of polar groups decreased non-linearly over time prior to reaching saturation from 7 days post treatment. This work provides critical considerations on the understanding of the stability of functional groups introduced across high specific surface area nano-materials used for the design of nano-composites, adsorptive or separation systems, or sensing materials and where interfacial interactions are key to the final materials performance. PMID- 27507622 TI - Effects of confinement on pattern formation in two dimensional systems with competing interactions. AB - Template-assisted pattern formation in monolayers of particles with competing short-range attraction and long-range repulsion interactions (SALR) is studied by Monte Carlo simulations in a simple generic model [N. G. Almarza et al., J. Chem. Phys., 2014, 140, 164708]. We focus on densities corresponding to formation of parallel stripes of particles and on monolayers laterally confined between straight parallel walls. We analyze both the morphology of the developed structures and the thermodynamic functions for broad ranges of temperature T and the separation L2 between the walls. At low temperature stripes parallel to the boundaries appear, with some corrugation when the distance between the walls does not match the bulk periodicity of the striped structure. The stripes integrity, however, is rarely broken for any L2. This structural order is lost at T = TK(L2) depending on L2 according to a Kelvin-like equation. Above the Kelvin temperature TK(L2) many topological defects such as breaking or branching of the stripes appear, but a certain anisotropy in the orientation of the stripes persists. Finally, at high temperature and away from the walls, the system behaves as an isotropic fluid of elongated clusters of various lengths and with various numbers of branches. For L2 optimal for the stripe pattern the heat capacity as a function of temperature takes the maximum at T = TK(L2). PMID- 27507624 TI - Ultrafast formation of air-processable and high-quality polymer films on an aqueous substrate. AB - Polymer solar cells are attracting attention as next-generation energy sources. Scalable deposition techniques of high-quality organic films should be guaranteed to realize highly efficient polymer solar cells in large areas for commercial viability. Herein, we introduce an ultrafast, scalable, and versatile process for forming high-quality organic films on an aqueous substrate by utilizing the spontaneous spreading phenomenon. This approach provides easy control over the thickness of the films by tuning the spreading conditions, and the films can be transferred to a variety of secondary substrates. Moreover, the controlled Marangoni flow and ultrafast removal of solvent during the process cause the films to have a uniform, high-quality nanomorphology with finely separated phase domains. Polymer solar cells were fabricated from a mixture of polymer and fullerene derivatives on an aqueous substrate by using the proposed technique, and the device exhibited an excellent power conversion efficiency of 8.44 %. Furthermore, a roll-to-roll production system was proposed as an air-processable and scalable commercial process for fabricating organic devices. PMID- 27507623 TI - Sustained treatment of sickle cell mice with haptoglobin increases HO-1 and H ferritin expression and decreases iron deposition in the kidney without improvement in kidney function. AB - There is growing evidence that extracellular haemoglobin and haem mediate inflammatory and oxidative damage in sickle cell disease. Haptoglobin (Hp), the scavenger for free haemoglobin, is depleted in most patients with sickle cell disease due to chronic haemolysis. Although single infusions of Hp can ameliorate vaso-occlusion in mouse models of sickle cell disease, prior studies have not examined the therapeutic benefits of more chronic Hp dosing on sickle cell disease manifestations. In the present study, we explored the effect of Hp treatment over a 3-month period in sickle mice at two dosing regimens: the first at a moderate dose of 200 mg/kg thrice weekly and the second at a higher dose of 400 mg/kg thrice weekly. We found that only the higher dosing regimen resulted in increased haem-oxygenase-1 and heavy chain ferritin (H-ferritin) expression and decreased iron deposition in the kidney. Despite the decreased kidney iron deposition following Hp treatment, there was no significant improvement in kidney function. However, there was a nearly significant trend towards decreased liver infarction. PMID- 27507625 TI - The influence of the test setup on knee joint kinematics - A meta-analysis of tibial rotation. AB - The human knee is one of the most investigated joints in the human body. Various test setups exist to measure and analyse knee kinematics in vitro which differ in a wide range of parameters. The purpose of this article is to find an answer to the question if the test setup influences the kinematic outcome of studies and to what extend the results can be compared. To answer this question, we compared the tibial rotation as a function of flexion angle presented in 19 published studies. Raw data was extracted via image segmentation from the graphs depicted in these publications and the differences between the publications was analysed. Additionally, all test setups were compared regarding four aspects: method for angle calculation, system for data acquisition, loading condition and testing rig design. The resulting correlation matrix shows the influence of the test setup on the study outcome. Our results indicate that each study needs to collect its own reference data. Finally, we provide a mean internal rotation as a function of flexion angle based on more than 140 specimens tested in 14 different studies. PMID- 27507626 TI - Cost-effectiveness of Single- Versus Multistep Root Canal Treatment. AB - INTRODUCTION: Single-visit root canal treatment requires fewer visits and reduces treatment time and material use compared with multiple-visit treatment. However, it might result in a higher risk of complications. We aimed to assess the long term cost-effectiveness of single- versus multivisit root canal treatment using a model-based approach. METHODS: A mixed public-private-payer perspective in German health care was adopted. Permanent teeth were simulated over the lifetime of 40 year-old patients. Different tooth types and preoperative conditions were modeled. Teeth could experience endodontic and nonendodontic complications. The risk of endodontic complications after single- versus multiple-visit treatment was estimated based on systematically collected data and adjusted depending on the preoperative conditions. The health outcome was tooth retention time. Costs were calculated based on the German dental fee catalogs and the Monte Carlo microsimulations were performed for analysis. RESULTS: For nonvital molars without periapical lesions, single-visit treatment was minimally less costly (1703 Euro vs 1729 Euro) and more effective (19.9 vs 19.8 years) than multiple visit treatment. This cost-effectiveness ranking also applied to vital molars or those with periapical lesions. In single-rooted teeth, multiple-visit treatment was less costly (1667 vs 1770 Euro) and more effective (18.9 vs 15.1 years). CONCLUSIONS: The overall cost-effectiveness difference between treatments seems limited. The resulting cost-effectiveness differs in subgroups of teeth, whereas data supporting such subgroup analyses are scarce. Practical aspects in scheduling treatments as well as patients' and dentists' preferences should be considered for decision making. PMID- 27507627 TI - Effect of Sodium Bicarbonate Buccal Infiltration on the Success of Inferior Alveolar Nerve Block in Mandibular First Molars with Symptomatic Irreversible Pulpitis: A Prospective, Randomized Double-blind Study. AB - INTRODUCTION: The purpose of this prospective, randomized, double-blind study was to evaluate the effect of a buccal infiltration of sodium bicarbonate on the anesthetic success of the inferior alveolar nerve block (IANB) for mandibular first molars in patients with symptomatic irreversible pulpitis. METHODS: One hundred patients diagnosed with symptomatic irreversible pulpitis of a mandibular first molar were selected. The patients randomly received a buccal infiltration injection of either 0.7 mL 8.4% sodium bicarbonate with 0.3 mL 2% lidocaine containing 1:80,000 epinephrine or 0.7 mL sterile distilled water with 0.3 mL 2% lidocaine containing 1:80,000 epinephrine in a double-blind manner. After 15 minutes, all the patients received conventional IANB injection using 3.6 mL 2% lidocaine with 1:80,000 epinephrine. Access cavity preparation was initiated 15 minutes after the IANB injection. Lip numbness was a requisite for all the patients. Success was determined as no or mild pain on the basis of Heft-Parker visual analog scale recordings upon access cavity preparation or initial instrumentation. Data were analyzed using the t, chi-square and Mann-Whitney U tests. RESULTS: The success rate after the buccal infiltration of sodium bicarbonate was 78%, whereas without the buccal infiltration of sodium bicarbonate it was 44% (P < .001). CONCLUSIONS: A buccal infiltration of 0.7 mL 8.4% sodium bicarbonate increased the success rate of IANBs in mandibular first molars with symptomatic irreversible pulpitis. PMID- 27507628 TI - The Assessment and Management of External Cervical Resorption with Periapical Radiographs and Cone-beam Computed Tomography: A Clinical Study. AB - INTRODUCTION: This in vivo study assessed whether there was a difference between periapical radiographs (PRs) and cone-beam computed tomographic (CBCT) imaging in the detection, assessment, and management of external cervical resorption (ECR). The secondary aim was to determine if parallax radiographs were of any further benefit compared with a single PR. METHODS: PR and CBCT data were gathered for 115 teeth (98 patients) consecutively diagnosed with ECR. The diagnosis and treatment plan of each tooth were determined with PRs and CBCT imaging. Sensitivity, specificity, positive predictive values, negative predictive values, and receiver operator characteristic values were determined. RESULTS: The overall sensitivity (0.86) and specificity (0.89) of PRs was significantly lower than CBCT imaging (P < .001). PRs had a limited ability to accurately detect the size (0.75), circumferential spread (0.60), and location of ECR compared with CBCT imaging (P < .001). PRs also underestimated the size of the ECR lesion. Significant differences (P < .001) were apparent in the treatment plans formed when PRs were assessed versus CBCT imaging. Parallax radiographs were shown to be of no additional benefit compared with a single radiograph. CONCLUSIONS: PRs have significant limitations in the detection, assessment, and treatment planning of ECR when compared with CBCT imaging. A CBCT scan should be considered before the management of a potentially restorable ECR lesion. PMID- 27507629 TI - Benefit from cytoreductive nephrectomy and the prognostic role of neutrophil-to lymphocyte ratio in patients with metastatic renal cell carcinoma. AB - BACKGROUND: The role of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of targeted therapies is currently undefined. In recent years, neutrophil-to-lymphocyte ratio (NLR) has emerged as a prognostic marker in several cancers, including mRCC. In this multicentre retrospective study, we aim to assess the impact of CN in mRCC and the value of NLR in risk stratification and patient selection. METHODS: Retrospective data from patients with de novo mRCC from four large Australian hospitals were collected. Survival analyses were performed using the Kaplan-Meier method and compared using the log rank test. Multivariate analyses were performed using the Cox proportional hazards method. RESULTS: Our study identified 91 de novo mRCC patients. Patients who underwent CN (n = 46, 51%) were more likely to be younger (59.0 years vs 64.6 years, P = 0.019) and to have received systemic therapy (91% vs 76%, P = 0.043). Median overall survival (mOS) was significantly improved in patients who underwent CN (23.0 months vs 10.9 months, hazard ratios (HR) 0.33, 95% confidence interval (CI) 0.20-0.55, P < 0.0001). Patients with NLR >= 5 also had inferior mOS (6.2 months vs 16.7 months, HR 1.94, 95% CI 1.14-3.29, P = 0.014). CN was associated with substantially improved survival in patients with both NLR < 5 (mOS 31.1 months vs 7.0 months, HR 0.41, 95% CI, 0.18-0.64, P = 0.0009) and NLR >= 5 (mOS 10.9 months vs 2.3 months, HR 0.33, 95% CI, 0.11-0.69, P = 0.009). Significant survival benefits associated with CN were maintained in multivariate analyses (HR 0.39, 95% CI 0.22-0.70, P = 0.0014). CONCLUSIONS: CN is associated with significantly improved overall survival in de novo mRCC. The incremental survival benefit associated with CN was seen irrespective of NLR. PMID- 27507630 TI - Current Knowledge on Genetic Biofortification in Lentil. AB - Micronutrient deficiency in the human body, popularly known as "hidden hunger", causes many health problems. It presently affects >2 billion people worldwide, especially in South Asia and sub-Saharan Africa. Biofortification of food crop varieties is one way to combat the problem of hidden hunger using conventional plant breeding and transgenic methods. Lentils are rich sources of protein, micronutrients, and vitamins including iron, zinc, selenium, folates, and carotenoids. Lentil genetic resources including germplasm and wild species showed genetic variability for these traits. Studies revealed that a single serving of lentils could provide a significant amount of the recommended daily allowance of micronutrients and vitamins for adults. Therefore, lentils have been identified as a food legume for biofortification, which could provide a whole food solution to the global micronutrient malnutrition. The present review discusses the current ongoing efforts toward genetic biofortification in lentils using classical breeding and molecular marker-assisted approaches. PMID- 27507631 TI - CD101, a novel echinocandin with exceptional stability properties and enhanced aqueous solubility. AB - : The echinocandins are an important class of antifungal agents. However, instability and, in some cases, lack of solubility have restricted their use to situations in which daily infusions are acceptable. CD101 is a novel echinocandin in development for topical and weekly i.v. administration that exhibits prolonged stability in plasma and aqueous solutions up to 40 degrees C. After incubation for 44 h in rat, dog, monkey and human plasma at 37 degrees C, the percent of CD101 remaining (91%, 79%, 94% and 93%, respectively) was consistently greater than that of anidulafungin (7%, 15%, 14% and 7%, respectively). Similarly, after incubation in phosphate-buffered saline at 37 degrees C, the CD101 remaining (96%) was greater than that of anidulafungin (42%). CD101 exhibited <2% degradation after long-term storage at 40 degrees C as a lyophilized powder (9 months) and at room temperature in 5% dextrose (15 months), 0.9% saline (12 months) and sterile water (18 months). Degradation was <7% at 40 degrees C in acetate and lactate buffers (6 to 9 months at pH 4.5-5.5). The chemical stability and solubility of CD101 contribute to dosing, pharmacokinetic, formulation and safety advantages over other echinocandins and should expand utility beyond daily i.v. THERAPY: PMID- 27507632 TI - Germicidins H-J from Streptomyces sp. CB00361. PMID- 27507633 TI - Allantopyrone A activates Keap1-Nrf2 pathway and protects PC12 cells from oxidative stress-induced cell death. AB - Keap1-Nrf2 system is known as a sensor of electrophilic compounds, and protects cells from oxidative stress through induction of various antioxidant enzymes. We found by proteomic analysis that allantopyrone A, a metabolite isolated from an endophytic fungus, upregulates the expression of proteins that are regulated by the transcription factor Nrf2. Indeed, allantopyrone A increased the antioxidant enzyme heme oxygenase-1 in PC12 cells. Moreover, it induced localization of Nrf2 in the nucleus. Affinity purification of allantopyrone A-binding protein showed that this compound could bind directly to Keap1. Allantopyrone A suppressed intracellular reactive oxygen species level and cell death induced by H2O2 in PC12 cells. These results indicate that allantopyrone A protects PC12 cells from oxidative stress-induced cell death through direct binding with Keap1 and activation of the Keap1-Nrf2 pathway. PMID- 27507634 TI - Feasibility of assessing patients' acceptable pain in a randomized controlled trial on a patient pain education program. AB - BACKGROUND: For patients with cancer-related pain, the numeric rating scale is the most frequently used instrument to measure pain intensity. In the literature, it has been suggested to interpret patient-reported ratings of pain in relation to the pain intensity which is acceptable to the individual patient. AIM: We aimed to examine the feasibility and course of acceptable pain intensity. DESIGN: A secondary analysis of a randomized controlled trial that tested the effectiveness of standard care versus standard care supplemented by a pain consultation combined with a patient pain education program. SETTING: A total of 72 patients were included from an outpatient oncology clinic of a university hospital. They were diagnosed with cancer-related nociceptive pain with an average pain intensity ?4. RESULTS: Most patients (97%) were able to give a score for acceptable pain. Almost half of the patients scored their acceptable pain in the range of moderate to severe. Patients' ratings of acceptable pain were stable; after 8 weeks, 69% of patients had a variation of up to 1 point compared to baseline. However, the mean acceptable pain intensity remained equal in the standard care group (from 4.6 (range: 0-8) to 5.0 (range: 2-8)) and decreased in the intervention group (from 4.6 (range: 2-8) to 3.8 (range: 0-7, p < 0.01), difference between groups p < 0.05). CONCLUSION: Measurement of acceptable pain intensity is feasible. Patients with additional pain treatment became more critical and accepted less pain. More research is needed before we can use acceptable pain intensity as a reference for the interpretation of pain ratings. PMID- 27507635 TI - Palliative homecare is associated with reduced high- and low-acuity emergency department visits at the end of life: A population-based cohort study of cancer decedents. AB - BACKGROUND: Prior work shows that palliative homecare services reduce the subsequent need for hospitalizations and emergency services; however, no study has investigated whether this association is present for emergency department visits of high acuity or whether it only applies to low-acuity emergency department visits. AIM: To examine the association between palliative versus standard homecare nursing and the rate of high-acuity and low-acuity emergency department visits among cancer decedents during their last 6 months of life. DESIGN: This is a retrospective cohort study of end-of-life homecare patients in Ontario, Canada, who had confirmed cancer cause of death from 2004 to 2009. A multivariable Poisson regression analysis was implemented to examine the association between the receipt of palliative homecare nursing (vs standard homecare nursing) and the rate of high- and low-acuity emergency department visits, separately. RESULTS: There were 54,743 decedents who received homecare nursing in the last 6 months of life. The receipt of palliative homecare nursing decreased the rate of low-acuity emergency department visits (relative rate = 0.53, 95% confidence interval = 0.50-0.56) and was significantly associated with a larger decrease in the rate of high-acuity emergency department visits (relative rate = 0.37, 95% confidence interval = 0.35-0.38). CONCLUSION: Receiving homecare nursing with palliative intent may decrease the need for dying cancer patients to visit the emergency department, for both high and low-acuity visits, compared to receiving general homecare nursing. Policy implications include building support for additional training in palliative care to generalist homecare nurses and increasing access to palliative homecare nursing. PMID- 27507636 TI - Electronic palliative care coordination systems: Devising and testing a methodology for evaluating documentation. AB - BACKGROUND: The need to improve coordination of care at end of life has driven electronic palliative care coordination systems implementation across the United Kingdom and internationally. No approaches for evaluating electronic palliative care coordination systems use in practice have been developed. AIM: This study outlines and applies an evaluation framework for examining how and when electronic documentation of advance care planning is occurring in end of life care services. DESIGN: A pragmatic, formative process evaluation approach was adopted. The evaluation drew on the Project Review and Objective Evaluation methodology to guide the evaluation framework design, focusing on clinical processes. SETTING/PARTICIPANTS: Data were extracted from electronic palliative care coordination systems for 82 of 108 general practices across a large UK city. All deaths ( n = 1229) recorded on electronic palliative care coordination systems between April 2014 and March 2015 were included to determine the proportion of all deaths recorded, median number of days prior to death that key information was recorded and observations about routine data use. RESULTS: The evaluation identified 26.8% of all deaths recorded on electronic palliative care coordination systems. The median number of days to death was calculated for initiation of an electronic palliative care coordination systems record (31 days), recording a patient's preferred place of death (8 days) and entry of Do Not Attempt Cardiopulmonary Resuscitation decisions (34 days). Where preferred and actual place of death was documented, these were matching for 75% of patients. Anomalies were identified in coding used during data entry on electronic palliative care coordination systems. CONCLUSION: This study reports the first methodology for evaluating how and when electronic palliative care coordination systems documentation is occurring. It raises questions about what can be drawn from routine data collected through electronic palliative care coordination systems and outlines considerations for future evaluation. Future evaluations should consider work processes of health professionals using electronic palliative care coordination systems. PMID- 27507637 TI - The Edmonton Symptom Assessment Scale remains useful for depression screening. PMID- 27507638 TI - Capsule Commentary on Battistone et al., "Mini-Residency" in Musculoskeletal Care: a National Continuing Professional Development Program for Primary Care Providers. PMID- 27507639 TI - Development of an ELISA using anti-idiotypic antibody for diagnosis of opisthorchiasis. AB - Monoclonal antibody specific for an epitope of cretory-secretory antigen protein of Opisthorchis felineus (Rivolta, 1884) (Trematoda: Opisthorchiidae) with a molecular weight of 28 kDa was used in a sandwich enzyme-linked immunosorbent assay (ELISA) for immobilisation of liver fluke specific antigen to the solid phase. Examination of human sera by this ELISA compared with commercial assays demonstrated that the monoclonal antibody epitope is located within this significant parasite protein. Anti-idiotypic antibody specific for the paratope of this monoclonal antibody was obtained by a hybridoma technique. Mimicking an epitope of excretory-secretory antigen of O. felineus, it had the capacity to bind specific antibody and elicit an antibody response. The value of anti idiotypic antibody as a substitute for the liver fluke antigen was tested by ELISA using serum samples of infected dogs. Anti-idiotypic antibody proved to be of value in both an indirect-ELISA and a competitive-ELISA for diagnosis of opisthorchiasis. Mature trematodes were isolated from all infected animals. The faecal egg counts were negative in dogs with a relatively small number of parasites, despite finding antibodies in serum by ELISA. Substitution of parasite antigen with anti-idiotype avoids the use of experimental animals and also reduces time-consuming steps of antigen preparation. PMID- 27507640 TI - DNA-PkCS expression in oropharyngeal squamous cell carcinoma: Correlations with human papillomavirus status and recurrence after transoral robotic surgery. AB - BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) has improved clinical outcomes compared to HPV-negative disease. However, the biology underlying differences in prognosis remains unclear. METHODS: We characterized the expression of DNA-protein kinase catalytic subunit (DNA-PkCS ), a key DNA repair protein also associated with tumor progression, in 29 cases of oropharyngeal SCCs and correlated our findings with HPV status and disease recurrence. In addition, we assessed therapeutic response, migration, and invasion in head and neck cancer cell lines upon DNA-PkCS knockdown. RESULTS: DNA PkCS expression was significantly decreased in HPV-positive compared to HPV negative oropharyngeal SCC samples. Within the HPV-positive subgroup, DNA-PkCS expression was inversely related to HPV E6 and E7 expression and trended toward significance as a predictor of recurrence. DNA-PkCS knockdown in cell lines resulted in increased sensitivity to cisplatin and radiotherapy and reduced cell migration and invasion. CONCLUSION: These results suggest DNA-PkCS should be further studied as a potential marker of tumor progression in HPV-positive oropharyngeal SCCs. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 206-214, 2017. PMID- 27507641 TI - Quantifying App Store Dynamics: Longitudinal Tracking of Mental Health Apps. AB - BACKGROUND: For many mental health conditions, mobile health apps offer the ability to deliver information, support, and intervention outside the clinical setting. However, there are difficulties with the use of a commercial app store to distribute health care resources, including turnover of apps, irrelevance of apps, and discordance with evidence-based practice. OBJECTIVE: The primary aim of this study was to quantify the longevity and rate of turnover of mental health apps within the official Android and iOS app stores. The secondary aim was to quantify the proportion of apps that were clinically relevant and assess whether the longevity of these apps differed from clinically nonrelevant apps. The tertiary aim was to establish the proportion of clinically relevant apps that included claims of clinical effectiveness. We performed additional subgroup analyses using additional data from the app stores, including search result ranking, user ratings, and number of downloads. METHODS: We searched iTunes (iOS) and the Google Play (Android) app stores each day over a 9-month period for apps related to depression, bipolar disorder, and suicide. We performed additional app specific searches if an app no longer appeared within the main search RESULTS: On the Android platform, 50% of the search results changed after 130 days (depression), 195 days (bipolar disorder), and 115 days (suicide). Search results were more stable on the iOS platform, with 50% of the search results remaining at the end of the study period. Approximately 75% of Android and 90% of iOS apps were still available to download at the end of the study. We identified only 35.3% (347/982) of apps as being clinically relevant for depression, of which 9 (2.6%) claimed clinical effectiveness. Only 3 included a full citation to a published study. CONCLUSIONS: The mental health app environment is volatile, with a clinically relevant app for depression becoming unavailable to download every 2.9 days. This poses challenges for consumers and clinicians seeking relevant and long-term apps, as well as for researchers seeking to evaluate the evidence base for publicly available apps. PMID- 27507642 TI - Activation-induced cytidine deaminase selectively catalyzed active DNA demethylation in pluripotency gene and improved cell reprogramming in bovine SCNT embryo. AB - DNA methylation in mammals is an epigenetic marker and necessary for normal embryogenesis. The global genomic demethylation of 5-methylcytosine occurs during the first cell cycle following fertilization. Activation-induced cytidine deaminase (AID), which is well-known for the function in antibody diversification, has been implicated to play a role in active demethylation, but its role in cell reprogramming and its crosstalk with other DNA demethylation mechanism need to be clarified. In this study, the dynamic epigenetic regulation of cell pluripotency and embryo development by AID in bovine preimplantation embryos was investigated. The analysis of an AID overexpressing transgenic cell line showed that AID overexpression did not change the global genomic methylation but did change the methylation status of the promoters of the OCT4, NANOG and SOX2 genes, thereby causing changes in their expression. The siRNA-mediated AID knockdown in early embryonic development indicated that AID interference did not affect oocyte maturation or the following embryo development after in vitro fertilization but influenced the DNA methylation status of OCT4 and NANOG. To clarify the role of AID in preimplantation embryos, SCNT embryos were obtained using AID-overexpressing cells as nuclear donors. Compared to the control group, the cleavage and blastocyst rates were both significantly improved in the AID overexpression group. The expression of OCT4 and NANOG was increased in the SCNT embryos, whereas the methylation levels of their promoters were reduced. In conclusion, this study demonstrated that AID selectively catalyzes DNA demethylation of pluripotency genes to play a role in regulation their expression, improves bovine SCNT embryo development by increased expression levels. PMID- 27507643 TI - Promoting differentiation of cultured myoblasts using biomimetic surfaces that present alpha-laminin-2 peptides. AB - Traditionally, muscle cell lines are cultured on glass coverslips and differentiated to investigate myoblast fusion and differentiation. Efficient differentiation of myoblasts produces a dense network of myotubes with the correct organisation for contraction. Here we have tested the ability of artificially generated, precisely controlled peptide surfaces to enhance the efficiency of myoblast differentiation. We focused on specific short peptides from alpha-laminin-2 (IKVSV, VQLRNGFPYFSY and GLLFYMARINHA) as well as residues 15-155 from FGF1. We tested if these peptides in isolation, and/or in combination promoted muscle differentiation in culture, by promoting fusion and/or by improving sarcomere organisation. The majority of these peptides promoted fusion and differentiation in two different mouse myogenic cell lines and in primary human myoblasts. The additive effects of all four peptides gave the best results for both mouse cell lines tested, while primary human cell cultures differentiated equally well on most peptide surfaces tested. These data show that a mixture of short biomimetic peptides can reliably promote differentiation in mouse and human myoblasts. PMID- 27507644 TI - In silico analysis of novel mutations in maple syrup urine disease patients from Iran. AB - Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism. The disease is mainly caused by mutations either in the BCKDHA, BCKDHB, DBT or DLD genes encoding components of the E1alpha, E1beta, E2 and E3 subunits of branched-chain alpha-keto acid dehydrogenase complex (BCKDC), respectively. BCKDC is a mitochondrial enzyme which is responsible for the normal breakdown of BCAA. The rate of consanguineous marriage in Iran is 38.6 %, so the prevalence of autosomal recessive disorders is higher in comparison to other countries. Consanguinity increases the chance of the presence of pathogenic mutations in a homoallelic state. This phenomenon has made homozygosity mapping a powerful tool for finding the probable causative gene in heterogeneous disorders like IEM (Inborn Errors of Metabolism). In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above-mentioned genes were selected to identify the probable pathogenic gene in the studied families. The families who showed a homozygous haplotype for the STR markers of the BCKDHB gene were subsequently sequenced. Four novel mutations including c.633 + 1G > A, c.988G > A, c.833_834insCAC, and a homozygous deletion of whole exon 3 c. (274 + 1_275-1) _(343 + 1_344-1), as well as one recently reported (c. 508G > T) mutation have been identified. Interestingly, three families shared a common haplotype structure along with the c. 508G > T mutation. Also, four other families revealed another similar haplotype with c.988G > A mutation. Founder effect can be a suggestive mechanism for the disease. Additionally, structural models of MSUD mutations have been performed to predict the pathogenesis of the newly identified variants. PMID- 27507646 TI - Enteromyxum leei (Myxosporea: Bivalvulida) as the cause of myxosporean emaciation disease of farmed olive flounders (Paralichthys olivaceus) and a turbot (Scophthalmus maximus) on Jeju Island, Korea. AB - A life-threatening emaciation disease of unknown cause(s) is affecting the farming of olive flounders (Paralichthys olivaceus) and turbots (Scophthalmus maximus) on Jeju Island, Korea. As this is one of the major industries in the region, it is of great concern to local farmers trying to develop successful and sustainable aquaculture. We examined 16 olive flounders and one turbot cultured at three farms located in the southern part of Jeju Island, which manifested moderate to severe emaciation such as thinning of the body with notable appearance of bony ridges of the skull on heads. Fresh mucosal scrapings of the intestinal mucosa contained many myxosporean vegetative stages at various developments but not fully grown spores. Histological examination of gastrointestinal and other visceral organs revealed striking changes in the intestinal mucosa such as detachment and loss of the epithelium due to intensive parasitism of the myxosporean vegetative stages, accompanied by considerable leukocyte infiltration in the lamina propria, and at the final stage villus atrophy with no epithelial lining. Specific polymerase chain reaction using a pair of primers targeting a fragment of the 18S ribosomal RNA gene (rDNA) of Enteromyxum leei, a known pathogen causing myxosporean emaciation disease in a variety of cultured fish in Mediterranean countries and Japan, amplified 433-bp products in almost all diseased fish samples, particularly the gastrointestinal tract. Nearly the whole length of the 18S rDNA, 1672-bp long excluding primer aligning sequences, of the present Korean isolate was comparable to those of E. leei isolates from Japan and Europe, particularly those from the former region. Taking the heavy load of various developmental stages of E. leei in the gastrointestinal mucosa into account, we ascribe the emaciation disease of the fish examined in the present study to this well-known myxosporean species and not to another unknown pathogen(s). PMID- 27507645 TI - Questionnaire survey on work motivations of gastrointestinal and hepatobiliary pancreatic surgeons enrolled in a Japanese national interdisciplinary program. AB - BACKGROUND: Among young residents, there seems to be a decreasing desire to become surgeons, resulting in a decrease in the number of surgeons. There is concern regarding a shortage of hepatobiliary pancreatic (HBP) surgery residents in Japan. A questionnaire survey was designed to assess the work motivations of Japanese gastrointestinal (GI) and HBP surgeons. METHODS: Questionnaires assessing seven domains related to motivation (aptitude, satisfaction/dissatisfaction, knowledge/skill, evaluation/approval, self management, community/expectation from other parties, and emotion) were sent to GI and HBP surgeons throughout Japan. Differences between HBP and GI surgeons were analyzed. RESULTS: Responses were received from 27 institutions in Japan between May and August 2014. Mid-career and senior HBP surgeons (11-20 years after graduation) working in university hospitals were significantly less satisfied with their work than GI surgeons (P = 0.036). Evaluation/approval factors were significantly lower in senior HBP surgeons than in GI surgeons 16-20 years after graduation (P = 0.048). CONCLUSIONS: The future satisfaction of young residents seeking to become HBP surgeons should be enhanced, providing an appealing workplace for young residents and preventing discontinuation by mid career and senior surgeons. PMID- 27507647 TI - Characteristics of hepatocellular carcinoma in Egyptian patients with primary Budd-Chiari syndrome. AB - BACKGROUND & AIM: Budd-Chiari syndrome (BCS) is caused by hepatic venous outflow obstruction. This work aimed at analyzing characteristics and factors associated with development of hepatocellular carcinoma (HCC) in patients with primary BCS. METHODS: A total of 348 Egyptian BCS patients were included. They were presented to the Budd-Chiari Study Group of Ain Shams University Hospital. BCS was confirmed using abdominal Doppler US. Abdominal magnetic resonance imaging (MRI), MR venography and/or multislice computed tomography (CT) were performed to confirm all diagnoses and to assess vascular anatomy. Hepatic focal lesions detected during the study period (2005-2011) were evaluated using serum alpha foetoprotein (AFP) level, imaging features and histopathological examination. RESULTS: Diagnosis of HCC was confirmed in 15/348 patients (4.3%). Imaging studies showed that 60% had multiple hepatic focal lesions ranging from 2 to 6.3 cm in size. The median level of serum AFP in BCS with HCC was 300 ng/mL vs 11 ng/mL in those without HCC (P<.001). A cut-off level >24.5 ng/mL for serum AFP showed sensitivity 80%, specificity 97.9%, positive predictive value 93.18% and negative predictive value 99.1% for detection of HCC in BCS patients. Male gender, older age, cigarette smoking, serum AFP (>24.5 ng/mL) and shrunken liver by ultrasonography were independent factors associated with HCC development. CONCLUSION: Male gender, older age and cigarette smoking are independent risk factors for development of HCC in BCS. Serum AFP is a good screening test in BCS. PMID- 27507648 TI - Tissue-infiltrating mucosal-associated invariant T cells play an important role against Mycobacterium tuberculosis infection in tuberculosis pleurisy. AB - Control of infection with Mycobacterium tuberculosis (M.tb) requires effective antigen-specific immune response, including CD4+ and CD8+ T-cell responses; however, the local immune response of mucosal-associated invariant T (MAIT) cells at the site of infection is unclear. MAIT cells are a prevalent and unique, innate T-cell population that expresses the semi-invariant T-cell receptor TCRValpha7.2. Our direct ex vivo analysis demonstrates that the frequency of MAIT cells in pleural fluid was much higher than that in peripheral blood from healthy donors, but much lower than that in peripheral blood from patients with tuberculosis. M.tb-reactive MAIT cells highly expressed tissue-specific chemokine receptors (CXCR3hiCXCR4hiCCR5hiCXCR6hi) and displayed an effector memory T-cell phenotype (CD45RO+CCR7-CD62L-), which indicates preferential homing to mucosal associated lymphoid tissues. Furthermore, the majority of MAIT cells in pleurisy fluid express tissue-resident makers (CD69+) that were only marginally present on MAIT cells from normal peripheral blood mononuclear cells. In addition, MAIT cells produce cytokines IFN-gamma and TNF-alpha and exhibit cytotoxic activity molecules, CD107a/b and granzyme B, in response to tuberculosis-specific antigens, which suggests that MAIT cells played a significant role in immune response to M.tb in local lesions. Here, we address the potential roles for M.tb reactive MAIT cells at the site of tuberculosis infection.-Li, J., Yu, S., Zhang, Y., Shen, J., Lao, S., Li, B., Yang, B., Wu, C. Tissue-infiltrating mucosal associated invariant T cells play an important role against Mycobacterium tuberculosis infection in tuberculosis pleurisy. PMID- 27507650 TI - Long-term potentiation modulates synaptic phosphorylation networks and reshapes the structure of the postsynaptic interactome. AB - The postsynaptic site of neurons is composed of more than 1500 proteins arranged in protein-protein interaction complexes, the composition of which is modulated by protein phosphorylation through the actions of complex signaling networks. Components of these networks function as key regulators of synaptic plasticity, in particular hippocampal long-term potentiation (LTP). The postsynaptic density (PSD) is a complex multicomponent structure that includes receptors, enzymes, scaffold proteins, and structural proteins. We triggered LTP in the mouse hippocampus CA1 region and then performed large-scale analyses to identify phosphorylation-mediated events in the PSD and changes in the protein-protein interactome of the PSD that were associated with LTP induction. Our data indicated LTP-induced reorganization of the PSD. The dynamic reorganization of the PSD links glutamate receptor signaling to kinases (writers) and phosphatases (erasers), as well as the target proteins that are modulated by protein phosphorylation and the proteins that recognize the phosphorylation status of their binding partners (readers). Protein phosphorylation and protein interaction networks converged at highly connected nodes within the PSD network. Furthermore, the LTP-regulated phosphoproteins, which included the scaffold proteins Shank3, Syngap1, Dlgap1, and Dlg4, represented the "PSD risk" for schizophrenia and autism spectrum disorder, such that without these proteins in the analysis, the association with the PSD and these two psychiatric diseases was not present. These data are a rich resource for future studies of LTP and suggest that the PSD holds the keys to understanding the molecular events that contribute to complex neurological disorders that affect synaptic plasticity. PMID- 27507651 TI - Comment on "SUMO deconjugation is required for arsenic-triggered ubiquitylation of PML". AB - Fasci et al proposed that a SENP1-mediated switch from SUMO2 to SUMO1 conjugation on Lys(65) in promyelocytic leukemia protein (PML) is required for arsenic induced PML degradation, the basis for the antileukemic activity of arsenic. We found that PML or PML/RARA (retinoic acid receptor alpha) mutants that cannot be SUMO-conjugated on this specific site nevertheless underwent immediate arsenic triggered SUMO modification. Moreover, these mutants were efficiently degraded in cells and even in vivo, demonstrating that SUMOylation of Lys(65) was dispensable for arsenic response. The existence and putative role of a SUMO switch on PML should thus be reassessed. PMID- 27507652 TI - Response to Comment on "SUMO deconjugation is required for arsenic-triggered ubiquitylation of PML". AB - Arsenic trioxide chemotherapy cures acute promyelocytic leukemia by inducing the ubiquitylation of an oncogenic fusion protein containing promyelocytic leukemia protein (PML) subsequent to modification of PML by SUMO1 and SUMO2. We proposed that the SUMO switch at Lys(65) of PML enhanced subsequent SUMO2 conjugation to Lys(160) and consequent RNF4-dependent ubiquitylation of PML. Ferhi et al note differences between their experimental system and ours regarding the outcome and mechanisms of SUMO-dependent PML signaling. When confronted by apparently contradictory data, it is appropriate to drill down to where the differences could lie. PMID- 27507649 TI - Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling. AB - Histone deacetylase (HDAC) inhibitors are efficacious epigenetic-based therapies for some cancers and neurological disorders; however, each of these drugs inhibits multiple HDACs and has detrimental effects on the skeleton. To better understand how HDAC inhibitors affect endochondral bone formation, we conditionally deleted one of their targets, Hdac3, pre- and postnatally in type II collagen alpha1 (Col2alpha1)-expressing chondrocytes. Embryonic deletion was lethal, but postnatal deletion of Hdac3 delayed secondary ossification center formation, altered maturation of growth plate chondrocytes, and increased osteoclast activity in the primary spongiosa. HDAC3-deficient chondrocytes exhibited increased expression of cytokine and matrix-degrading genes (Il-6, Mmp3, Mmp13, and Saa3) and a reduced abundance of genes related to extracellular matrix production, bone development, and ossification (Acan, Col2a1, Ihh, and Col10a1). Histone acetylation increased at and near genes that had increased expression. The acetylation and activation of nuclear factor kappaB (NF-kappaB) were also increased in HDAC3-deficient chondrocytes. Increased cytokine signaling promoted autocrine activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and NF-kappaB pathways to suppress chondrocyte maturation, as well as paracrine activation of osteoclasts and bone resorption. Blockade of interleukin-6 (IL-6)-JAK-STAT signaling, NF-kappaB signaling, and bromodomain extraterminal proteins, which recognize acetylated lysines and promote transcriptional elongation, significantly reduced Il-6 and Mmp13 expression in HDAC3-deficient chondrocytes and secondary activation in osteoclasts. The JAK inhibitor ruxolitinib also reduced osteoclast activity in Hdac3 conditional knockout mice. Thus, HDAC3 controls the temporal and spatial expression of tissue-remodeling genes and inflammatory responses in chondrocytes to ensure proper endochondral ossification during development. PMID- 27507653 TI - Automated identification of antibiotic overdoses and adverse drug events via analysis of prescribing alerts and medication administration records. AB - Objectives: Electronic trigger detection tools hold promise to reduce Adverse drug event (ADEs) through efficiencies of scale and real-time reporting. We hypothesized that such a tool could automatically detect medication dosing errors as well as manage and evaluate dosing rule modifications. Materials and Methods: We created an order and alert analysis system that identified antibiotic medication orders and evaluated user response to dosing alerts. Orders associated with overridden alerts were examined for evidence of administration and the delivered dose was compared to pharmacy-derived dosing rules to confirm true overdoses. True overdose cases were reviewed for association with known ADEs. Results: Of 55 546 orders reviewed, 539 were true overdose orders, which lead to 1965 known overdose administrations. Documentation of loose stools and diarrhea was significantly increased following drug administration in the overdose group. Dosing rule thresholds were altered to reflect clinically accurate dosing. These rule changes decreased overall alert burden and improved the salience of alerts. Discussion: Electronic algorithm-based detection systems can identify antibiotic overdoses that are clinically relevant and are associated with known ADEs. The system also serves as a platform for evaluating the effects of modifying electronic dosing rules. These modifications lead to decreased alert burden and improvements in response to decision support alerts. Conclusion: The success of this test case suggests that gains are possible in reducing medication errors and improving patient safety with automated algorithm-based detection systems. Follow up studies will determine if the positive effects of the system persist and if these changes lead to improved safety outcomes. PMID- 27507655 TI - Proposed mechanism for reviewing the coverage of National Health Insurance benefits: New mission for the National Health Insurance Committee. PMID- 27507654 TI - Overexpression of Histone Deacetylase and Amyloid Precursor Protein in Hepatocellular Carcinoma. AB - Epigenetic modifications are involved in the pathogenesis of cancer, and histone deacetylase inhibitors are considered potential therapeutic agents. Histone tails undergo acetylation at lysine residues, which is associated with transcriptional activation. However, previous studies indicated that as histone deacetylase inhibitors, both (-)-epigallocatechin-3-gallate and valproic acid presented the effects of downregulation of amyloid precursor protein expression, which resulted in the induction of apoptosis. The downregulation of amyloid precursor protein, instead of conventionally activating gene expression as histone deacetylase inhibitor, was attractive. However, there was no relevant report on the correlation of the expression of amyloid precursor protein and histone deacetylase 1 in cancer. In the present study, we detected the expression of amyloid precursor protein and histone deacetylase 1 in hepatocellular carcinoma and adjacent tissues, as well as the correlations among histone deacetylase 1, amyloid precursor protein, and tumor stage. The results showed that the expressions of amyloid precursor protein and histone deacetylase 1 were significantly higher in hepatocellular carcinoma tissues than that in adjacent tissues ( P < .05), however, there was no statistical difference between amyloid precursor protein and histone deacetylase 1 with tumor stages. The present findings provided more foundation for the study on amyloid precursor protein metabolism in cancer, especially on the regulation of amyloid precursor protein by histone deacetylases. PMID- 27507656 TI - Entropy analysis of stable isotopes in precipitation: tracing the monsoon systems in China. AB - Due to the complexity of monsoon systems and random behaviors of isotope tracers, conventional methods are not adequate for uncovering detailed information about monsoon activities from typically limited precipitation isotope data. We developed a new approach based on the entropy theory to analyze such data with a focus on the monsoon systems in China, dealing with the complexity of these systems and data deficiency. Using precipitation isotope data from 42 selected stations in and around China within the GNIP network, we computed entropies associated with D and (18)O. These entropies were found to relate linearly to each other with a proportionality factor close to unity. The spatial variations of the D and (18)O entropy in the study area revealed the origins, extents and pathways of the Chinese monsoon systems, as well as their interactions. While further investigation is needed at a greater (global) scale, this study has demonstrated how the entropy theory enables an in-depth analysis of precipitation isotope data to trace the pathway and determine the range of a monsoon system. PMID- 27507659 TI - Birth order and hospitalization for alcohol and narcotics use in Sweden. AB - BACKGROUND: Previous studies have shown that birth order is an important predictor of later life health as well as socioeconomic attainment. In this study, we examine the relationship between birth order and hospitalization for alcohol and narcotics use in Sweden. METHODS: We study the relationship between birth order and hospitalization related to alcohol and narcotics use before and after the age of 20 using Swedish register data for cohorts born 1987-1994. We apply Cox proportional hazard models and use sibling fixed effects, eliminating confounding by factors shared by the siblings. RESULTS: Before age 20 we find that later born siblings are hospitalized for alcohol use at a higher rate than first-borns, and there is a monotonic increase in the hazard of hospitalization with increasing birth order. Second-borns are hospitalized at a rate 47% higher than first-borns, and third-borns at a rate 65% higher. Similar patterns are observed for hospitalization for narcotics use. After age 20 the pattern is similar, but the association is weaker. These patterns are consistent across various sibling group sizes. CONCLUSIONS: Later born siblings are more likely to be hospitalized for both alcohol and narcotics use in Sweden. These birth order effects are substantial in size, and larger than the estimated sex differences for the risk of hospitalization related to alcohol and drug use before age 20, and previous estimates for socioeconomic status differences in alcohol and drug abuse. PMID- 27507657 TI - What is abnormal about addiction-related attentional biases? AB - BACKGROUND: The phenotype of addiction includes prominent attentional biases for drug cues, which play a role in motivating drug-seeking behavior and contribute to relapse. In a separate line of research, arbitrary stimuli have been shown to automatically capture attention when previously associated with reward in non clinical samples. METHODS AND RESULTS: Here, I argue that these two attentional biases reflect the same cognitive process. I outline five characteristics that exemplify attentional biases for drug cues: resistant to conflicting goals, robust to extinction, linked to dorsal striatal dopamine and to biases in approach behavior, and can distinguish between individuals with and without a history of drug dependence. I then go on to describe how attentional biases for arbitrary reward-associated stimuli share all of these features, and conclude by arguing that the attentional components of addiction reflect a normal cognitive process that promotes reward-seeking behavior. PMID- 27507658 TI - Recognition and response to opioid overdose deaths-New Mexico, 2012. AB - PURPOSE: Drug overdose deaths are epidemic in the U.S. Prescription opioid pain relievers (OPR) and heroin account for the majority of drug overdoses. Preventing death after an opioid overdose by naloxone administration requires the rapid identification of the overdose by witnesses. This study used a state medical examiner database to characterize fatal overdoses, evaluate witness-reported signs of overdose, and identify opportunities for intervention. METHODS: We reviewed all unintentional drug overdose deaths that occurred in New Mexico during 2012. Data were abstracted from medical examiner records at the New Mexico Office of the Medical Investigator. We compared mutually exclusive groups of OPR and heroin-related deaths. RESULTS: Of the 489 overdose deaths reviewed, 49.3% involved OPR, 21.7% involved heroin, 4.7% involved a mixture of OPR and heroin, and 24.3% involved only non-opioid substances. The majority of OPR-related deaths occurred in non-Hispanic whites (57.3%), men (58.5%), persons aged 40-59 years (55.2%), and those with chronic medical conditions (89.2%). Most overdose deaths occurred in the home (68.7%) and in the presence of bystanders (67.7%). OPR and heroin deaths did not differ with respect to paramedic dispatch and CPR delivery, however, heroin overdoses received naloxone twice as often (20.8% heroin vs. 10.0% OPR; p<0.01). CONCLUSION: OPR overdose deaths differed by age, health status, and the presence of bystanders, yet received naloxone less often when compared to heroin overdose deaths. These findings suggest that naloxone education and distribution should be targeted in future prevention efforts. PMID- 27507660 TI - Quantitative assays for measuring human telomerase activity and DNA binding properties. AB - Telomerase is the ribonucleoprotein enzyme that catalyzes the processive addition of the telomeric DNA repeat 5'-TTAGGG-3' onto chromosome ends. In addition to its fascinating biochemical and enzymatic properties, clinical interest in telomerase stems from its dysregulated expression in ~90% of human cancers, representing a broad spectrum of diseases. Exploiting telomerase as a therapeutic target and hence identifying and/or evaluating potential inhibitors requires quantitative measurement of its activity. This article presents procedures for measuring multiple aspects of telomerase enzymology that are relevant to both fundamental biochemistry and drug discovery: direct activity assays, DNA binding affinity, DNA dissociation, and cell-based over-expression of the active enzyme complex. PMID- 27507662 TI - Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi Sakurai reaction. AB - The synthesis of dehaloperophoramidine, a non-halogenated derivative of the marine natural product perophoramidine, and its biological activity towards HCT116, HT29 and LoVo colorectal carcinoma cells is reported. A [3,3]-Claisen rearrangement and an epoxide opening/allylsilylation reaction installed the contiguous all-carbon quaternary stereocentres with the required relative stereochemistry. PMID- 27507661 TI - Association between rheumatoid arthritis and systemic mastocytosis: a case report and literature review. AB - Classically, mast cells (MC) are considered as important actors of the innate immune response playing a pivotal role in IgE-mediated allergic and antiparasite responses. In the last two decades, many experimental evidences demonstrated that these hematopoietic-derived cells present in both connective and mucosal tissues are also key modulators of the adaptive immune response and could contribute to autoimmune disease notably in rheumatoid arthritis (RA). Recently, Bader-Meunier et al. reported a series of 31 patients suffering from inflammatory joint diseases associated with mastocytosis, suggesting that mastocytosis was associated with a higher prevalence in spondyloarthritis. We discuss here the possible link between chronic inflammatory arthritis and mastocytosis through the report of a clinical case describing a patient developing RA after a long history of mastocytosis. Of great interest, antihistamine treatment alone was sufficient to treat RA in this patient. PMID- 27507663 TI - A comparative analysis reveals the dosage sensitivity and regulatory patterns of lncRNA in prostate cancer. AB - Although the key roles of long non-coding RNAs (lncRNAs) in multiple diseases are well documented, the relationship between the lncRNA copy number and expression is unknown. Here, we present a comprehensive study that demonstrates the impact of miRNA-TF co-regulatory motifs on the dosage effects of protein-coding genes (PCGs) and lncRNAs in prostate cancer. By integrating copy number profiles, expression profiles and regulatory relationships with miRNAs and transcription factors, we reveal that lncRNAs and PCGs correlate with distinct dosage sensitivity and regulatory pattern characteristics. We also show that lncRNAs from different genomic regions have different features. Using a custom-built framework, we identified 24 candidate prostate cancer-related lncRNAs based on the known properties of established prostate-related lncRNAs. Our method will enable the identification of cancer-related lncRNAs, which will provide new insights into cancer lncRNA biology. PMID- 27507664 TI - Alignment between values of dryland pastoralists and conservation needs for small mammals. AB - Policies for conservation outside protected areas, such as those designed to address the decline in Australian mammals, will not result in net improvements unless they address barriers to proenvironmental behavior. We used a mixed methods approach to explore potential value-action gaps (disconnects between values and subsequent action) for small mammal conservation behaviors among pastoralists in dryland Australia. Using semistructured surveys and open-ended interviews (n = 43), we explored values toward small mammals; uptake of a range of current and intended actions that may provide benefit to small mammals; and potential perceived barriers to their uptake. Pastoralists assigned great conservation value to small mammals; over 80% (n = 36) agreed to strongly agreed that small mammals on their property were important. These values did not translate into stated willingness to engage in voluntary cessation of wild-dog control (r2 = 0.187, p = 0.142, n = 43). However, assigning great conservation value to small mammals was strongly related to stated voluntary willingness to engage in the proenvironmental behavior most likely to result in benefits to small mammals: cat and fox control (r2 = 0.558, p = 0.000, n = 43). There was no significant difference between stated voluntarily and incentivized willingness to engage in cat and fox control (p = 0.862, n = 43). The high levels of willingness to engage in voluntary cat and fox control highlight a potential entry point for addressing Australia's mammal declines because the engagement of pastoralists in conservation programs targeting cat and fox control is unlikely to be prevented by attitudinal constraints. Qualitative data suggest there is likely a subpopulation of pastoralists who value small mammals but do not wish to engage in formal conservation programs due to relational barriers with potential implementers. A long-term commitment to engagement with pastoralists by implementers will thus be necessary for conservation success. On-property cat and fox control programs that build and leverage trust, shared goals, collaboration, and shared learning experiences between stakeholders and that explicitly recognize the complexity of small mammal dynamics and the property-level ecological knowledge of pastoralists are more likely to gain traction. PMID- 27507665 TI - Gradient moduli lens models: how material properties and application of forces can affect deformation and distributions of stress. AB - The human lens provides one-third of the ocular focussing power and is responsible for altering focus over a range of distances. This ability, termed accommodation, defines the process by which the lens alters shape to increase or decrease ocular refractive power; this is mediated by the ciliary muscle through the zonule. This ability decreases with age such that around the sixth decade of life it is lost rendering the eye unable to focus on near objects. There are two opponent theories that provide an explanation for the mechanism of accommodation; definitive support for either of these requires investigation. This work aims to elucidate how material properties can affect accommodation using Finite Element models based on interferometric measurements of refractive index. Gradients of moduli are created in three models from representative lenses, aged 16, 35 and 48 years. Different forms of zonular attachments are studied to determine which may most closely mimic the physiological form by comparing stress and displacement fields with simulated shape changes to accommodation in living lenses. The results indicate that for models to mimic accommodation in living eyes, the anterior and posterior parts of the zonule need independent force directions. Choice of material properties affects which theory of accommodation is supported. PMID- 27507666 TI - A highly sensitive HPLC-MS/MS method for quantification of 20(S)-protopanaxadiol in human plasma and its application in phase IIa clinical trial of a novel antidepressant agent. AB - A highly sensitive HPLC-MS/MS assay method was established to quantify 20(S) protopanaxadiol (PPD) in human plasma with dexamethasone as an internal standard. The electrospray ion mass spectrometry (ESI-MS) was operated under the multiple reactions monitoring mode (MRM) using positive ion mode. PPD was extracted from 500MUL plasma samples by liquid-liquid extraction then separated by a C18 analytical column with gradient elution. The concentration of PPD could be determined by this HPLC-MS/MS method over the range of 0.05-20ng/mL with the lower limit of quantification (LLOQ) of 0.05ng/mL. The method was successfully applied to phase IIa clinical trial of Yuxintine (PPD capsule) in which plasma samples of 87 subjects were analyzed following 6 weeks of oral administration of placebo or PPD capsules in 5 different doses. In this study, the measured concentration was linearly related to the oral dosage with R=0.9901. The minimum and maximum values of measured concentration were 0.06 and 11.60ng/mL, respectively. In addition, plasma concentrations of PPD in depression patients were reported for the first time in our study. PMID- 27507667 TI - An improvement of separation and response applying post-column compensation and one-step acetone protein precipitation for the determination of coenzyme Q10 in rat plasma by SFC-MS/MS. AB - Coenzyme Q10 (CoQ10) solid dispersion was prepared to improve its oral bioavailability due to the poor solubility of CoQ10. To evaluate the pharmacokinetic behaviors of CoQ10 solid dispersion, a simple, rapid, sensitive and environment friendly method for the determination of CoQ10 in rat plasma was developed. In this study, samples were prepared by one-step protein precipitation with acetone and then the supercritical fluid chromatography-electrospray ionization tandem mass spectrometry (SFC-ESI-MS/MS) method was used. The separation was achieved by an ACQUITY UPC(2)TM BEH 2-EP column (100mm*3mm, 1.7MUm) maintained at 35 degrees C, using carbon dioxide (>=99.99%) and methanol (85:15, v/v) as the mobile phase at a flow rate of 1.0ml/min. To improve the response and sensitivity, the compensation solvent of methanol with 2mM ammonium acetate at a flow rate of 0.2ml/min was used and the total analysis time was only 1.5min for each sample. The detection was carried out on a tandem mass spectrometer with electrospray ionization (ESI) source and the mass transition ion pair was m/z 881.0->197.0 and 285.1->193.0 for CoQ10 and diazepam, internal standard (IS), respectively. Calibration curve was linear over the concentration range of 2.00-500.00ng/ml (r(2)>=0.998) with a lower limit of quantification of 2.00ng/ml. The intra- and inter-day accuracy and precision were below 15% for all quality control samples. The proposed method was rapid, accurate and reproducible, which was suitable to compare the pharmacokinetic behaviors in rats after a single oral dose of 100mg/kg CoQ10 solid dispersion or tablets. PMID- 27507668 TI - Multifunctional metal-polymer nanoagglomerates from single-pass aerosol self assembly. AB - In this study, gold (Au)-iron (Fe) nanoagglomerates were capped by a polymer mixture (PM) consisting of poly(lactide-co-glycolic acid), protamine sulfate, and poly-l-lysine via floating self-assembly in a single-pass aerosol configuration as multibiofunctional nanoplatforms. The Au-Fe nanoagglomerates were directly injected into PM droplets (PM dissolved in dichloromethane) in a collison atomizer and subsequently heat-treated to liberate the solvent from the droplets, resulting in the formation of PM-capped Au-Fe nanoagglomerates. Measured in vitro, the cytotoxicities of the nanoagglomerates (>98.5% cell viability) showed no significant differences compared with PM particles alone (>98.8%), thus implying that the nanoagglomerates are suitable for further testing of biofunctionalities. Measurements of gene delivery performance revealed that the incorporation of the Au-Fe nanoagglomerates enhanced the gene delivery performance (3.2 * 10(6) RLU mg(-1)) of the PM particles alone (2.1 * 10(6) RLU mg(-1)), which may have been caused by the PM structural change from a spherical to a hairy structure (i.e., the change followed the agglomerated backbone). Combining the X-ray-absorbing ability of Au and the magnetic property of Fe led to magnetic resonance (MR)-computed tomography (CT) contrast ability in a phantom; and the signal intensities [which reached 64 s(-1) T2-relaxation in MR and 194 Hounsfield units (HUs) in CT at 6.0 mg mL(-1)] depended on particle concentration (0.5-6.0 mg mL(-1)). PMID- 27507670 TI - A new function for the yeast trehalose-6P synthase (Tps1) protein, as key pro survival factor during growth, chronological ageing, and apoptotic stress. AB - Looking back to our recent work that challenged the paradigm of trehalose in stress resistance in yeast, our objective was to revisit the role of this disaccharide in chronological life span (CLS), and in the control of apoptosis. Using a catalytically dead variant of the trehalose-6-phosphate synthase (Tps1) protein, (the first enzyme in the trehalose biosynthetic pathway), and by manipulating intracellular trehalose independently of this pathway, we demonstrated that trehalose has no role in CLS or in the inhibition of acetic acid or H202-triggered cell death. We showed instead that, in the absence of any apoptotic stimulus, the Tps1 protein itself was necessary in preventing massive, spontaneous commitment of yeast cells to apoptosis during growth. Without Tps1p, the life span was shortened and cells were sensitized to acetic acid (AA) and H202, whereas the overexpression of the inactive variant of Tps1p almost abolished AA-triggered apoptosis. Genetic interaction analysis of TPS1 and genes such as YCA1, NUC1 and AIF1 indicated that these key executioners of cell death partially relayed tps1Delta-triggered signaling. Our results suggested that the pro-survival role of Tps1p could be connected with its ability to preserve ATP levels in yeast cells. PMID- 27507669 TI - ER fatalities-The role of ER-mitochondrial contact sites in yeast life and death decisions. AB - Following extracellular stress signals, all eukaryotic cells choose whether to elicit a pro-survival or pro-death response. The decision over which path to take is governed by the severity and duration of the damage. In response to mild stress, pro-survival programs are initiated (unfolded protein response, autophagy, mitophagy) whereas severe or chronic stress forces the cell to abandon these adaptive programs and shift towards regulated cell death to remove irreversibly damaged cells. Both pro-survival and pro-death programs involve regulated communication between the endoplasmic reticulum (ER) and mitochondria. In yeast, recent data suggest this inter-organelle contact is facilitated by the endoplasmic reticulum mitochondria encounter structure (ERMES). These membrane contacts are not only important for the exchange of cellular signals, but also play a role in mitochondrial tethering during mitophagy, mitochondrial fission and mitochondrial inheritance. This review focuses on recent findings in yeast that shed light on how ER-mitochondrial communication mediates critical cell fate decisions. PMID- 27507671 TI - Preoperative urinary tract obstruction in scoliosis patients. AB - BACKGROUND: While the association between scoliosis and cardiac and respiratory function impairments has been well characterized in clinical practice and research, the potential effect of scoliosis on urinary tract structure and renal function has received little attention. Therefore, the purpose of this study was to evaluate the preoperative clinical characteristics of urinary tract structure and renal function in pediatric patients with idiopathic scoliosis, using a combination of blood tests, urinalysis, and imaging. METHODS: Preoperative measures of urinary tract structure and renal function were obtained for 16 patients, 13-17 years old, scheduled for corrective surgery for idiopathic scoliosis. Preoperative assessment included blood test and urinalysis, combined with structural imaging on ultrasound (US), magnetic resonance imaging (MRI), magnetic resonance urography (MRU), and radioisotope tracing (RI), using technetium-99 m mercaptoacetyltriglycine (99m Tc-MAG3). Differences in blood and urine tests between patients with and without urinary tract obstruction (UTO) were evaluated for significance using Mann-Whitney U test. RESULTS: For all 16 patients, blood tests and MRU were within normal limits. Dilatation of the renal pelvis was identified on US in eight patients (50.0%). UTO was identified on RI in six patients (37.5%). UTO was associated with elevated beta2-microglobulin concentration. Urinary beta2-microglobulin concentration >0.7 MUg/mg Cr differentiated patients with UTO from those without UTO, with a sensitivity of 100% and specificity of 70%. CONCLUSIONS: beta2-Microglobulin concentration may be a useful marker to screen for asymptomatic UTO in patients with idiopathic scoliosis. PMID- 27507672 TI - Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta. AB - Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. The objective of this study was to investigate the relationships between cerebral amyloid production and both blood and cerebrospinal fluid (CSF) markers of the homocysteine metabolism. We assessed CSF concentrations of soluble APPalpha, soluble APPbeta, and amyloid beta1-42 (Abeta1-42), as well as plasma levels of homocysteine (Hcys), total vitamin B12, and folate, and CSF concentrations of homocysteine (Hcys-CSF), 5-methyltetrahydrofolate (5-MTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) in 59 subjects with normal cognition. Linear regression analyses were performed to assess associations between homocysteine metabolism parameters and amyloid production. The study was approved by the Ethical Committee of the University of Bonn. After controlling for age, gender, APOEe4 status, and albumin ratio (Qalb), higher Abeta1-42 CSF levels were associated with high Hcys and low vitamin B12 plasma levels as well as with high Hcys, high SAH, and low 5-MTHF CSF levels. Higher CSF concentrations of sAPPalpha and sAPPbeta were associated with high SAH levels. The results suggest that disturbed homocysteine metabolism is related to increased CSF levels of sAPP forms and Abeta1-42, and may contribute to the accumulation of amyloid pathology in the brain. Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. We found associations between CSF levels of soluble APP forms and Abeta1-42, and markers of the homocysteine metabolism in both plasma and CSF in adults with normal cognition. Disturbed homocysteine metabolism may represent a target for preventive and early disease-modifying interventions in Alzheimer's disease. PMID- 27507673 TI - Polymorphism of the renalase gene in gestational diabetes mellitus. AB - Renalase is considered as a novel candidate gene for type 2 diabetes. In this study, we aimed to investigate the relationship of serum renalase and two single nucleotide polymorphisms with gestational diabetes mellitus. One hundred and ninety-eight normotensive pregnant females (n = 99 gestational diabetes mellitus; n = 99 euglycemic pregnant controls) were classified according to the International Association of the Diabetes and Pregnancy Study criteria. Fasting and 2-h post glucose load blood levels and anthropometric assessment was performed. Serum renalase was measured using enzyme-linked immunosorbent assay, whereas DNA samples were genotyped for renalase single nucleotide polymorphisms rs2576178 and rs10887800 using Polymerase chain reaction-Restriction fragment length polymorphism method. In an age-matched case control study, no difference was observed in the serum levels of renalase (p > 0.05). The variant rs10887800 showed an association with gestational diabetes mellitus and remained significant after multiple adjustments (p < 0.05), whereas rs2576178 showed weak association (p = 0.030) that was lost after multiple adjustments (p = 0.09). We inferred a modest association of the rs10887800 polymorphism with gestational diabetes. Although gestational diabetes mellitus is self-reversible, yet presence of this minor G allele might predispose to metabolic syndrome phenotypes in near the future. PMID- 27507675 TI - Discordance Between Intraoperative Consultation by Frozen Section and Final Diagnosis. AB - Discrepancies between intraoperative consultations with frozen section diagnosis and the final pathology report have the potential to alter treatment decisions and affect patient care. Monitoring these correlations is a key component of laboratory quality assurance, however identifying specific areas for improvement can be difficult to attain. Our goal is to develop a standardized method utilizing root cause analysis and a modified Eindhoven classification schematic to identify the source of discrepancies and deferrals and subsequently to guide performance improvement initiatives. A retrospective review of intraoperative consultations performed at a tertiary level hospital and cancer center over a 6 month period identified deferrals and discrepancies between the intraoperative consult report and the final pathology report. We developed and applied a classification tool to identify the process errors and cognitive errors leading to discrepant results. A total of 48 (4.6%) discrepancies and 24 (2.3%) deferrals were identified from the 1042 frozen sections. Within the entire data set of frozen sections, the process errors (n = 26, 54.2%) were due to gross sampling (n = 16, 33.3%), histologic sampling (n = 8, 16.7%), and surgical sampling (n = 2, 4.2%). Interpretation errors (n = 22, 45.8%) included undercalls/false negatives (n=8, 16.7%), overcalls/false positives (n = 10, 20.8%), and misclassification errors (n = 4, 8.3%). Application of our classification tool demonstrated that the root cause of discrepancies and deferrals varied both between organ systems and by specific organs and that classification models may be utilized as a standardized method to identify focused areas for improvement. PMID- 27507674 TI - Initial experience with endocrinology e-consults. PMID- 27507676 TI - Pregnenolone sulfate regulates prolactin production in the rat pituitary. AB - Pregnenolone sulfate (PS) is a neuroactive steroid hormone produced in the brain. In this study, the effects of PS on synthesis and secretion of rat pituitary prolactin (PRL) were examined. To accomplish this, GH3 rat pituitary adenoma cells were treated with PS, which showed significantly increased mRNA and protein levels of PRL compared with the control. The mechanism of action responsible for the effects of PS on PRL synthesis and secretion was investigated by pretreating cells with inhibitors of traditional PRL- or the PS-related signaling pathway. PS stimulated PRL transcription was significantly reduced by inhibitors of PKA, PKC and MAPK, but unchanged by GABAAR and NMDAR inhibitors. Western blotting analysis revealed that the total ERK1/2 level was upregulated in a time-dependent manner following PS treatment. An approximate 10% increase in GH3 cell proliferation was also observed in response to PS relative to the control. In the animal study, levels of PRL in the pituitary and in serum were elevated by PS. PS-stimulated PRL synthesis was also found to be associated with decreased expression of PRL target genes such as GNRH1, FSHB and LHB. These findings show that PS upregulates PRL synthesis and secretion in vivo and in vitro via MAPK signaling, suggesting that it has the potential for use as a therapeutic hormone to treat PRL-related disorders such as hypoprolactinemia and low milk supply. PMID- 27507677 TI - Acceleration of wound healing by ultrasound activation of TiO2 in Escherichia coli-infected wounds in mice. AB - Surgical site infections continue to be a common complication affecting surgical prognosis. Reactive oxygen species (ROS) are generated by ultrasound-irradiated titanium dioxide (TiO2 ) (UIT). Although excessive ROS production can cause cell damage, ROS at physiological levels mediate beneficial cellular responses, including angiogenesis. This study investigated whether UIT can promote healing of Escherichia coli-infected wounds. We used TiO2 and ultrasound irradiation using an ultrasonography machine at a frequency of 1.0 MHz and intensity of 0.4 W cm-2 . These levels are not bactericidal in vitro; therefore, we could study the effect of UIT on E. coli survival without interference of ultrasound effects. The number of cluster of differentiation 31-positive blood vessels, which are indicative of angiogenesis, was decreased by bacterial infection, and increased at the wound edges in the UIT-treated infected wounds, suggesting upregulation of neovascularization by UIT. Although UIT treatment did not decrease E. coli survival in vivo, it promoted healing of the infected wounds as evidenced by a significant decrease in the wound area in the UIT-treated mice. Our findings demonstrate that UIT promotes wound healing in surgical site infections and suggest beneficial use of the UIT-based approach as a novel therapeutic method to treat infected surgical wounds. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2344-2351, 2017. PMID- 27507679 TI - Cultural Attunement in Therapy With Mexican-Heritage Couples: A Grounded Theory Analysis of Client and Therapist Experience. AB - There is a need for culturally attuned approaches for couple therapy with Mexican/Mexican-Americans. This qualitative grounded theory study utilized interviews with 11 client couples of Mexican heritage and 14 marital and family therapists to shed light on how Latino and non-Latino therapists co-construct positive experiences of cultural attunement with Mexican and Mexican-American couple clients. Analysis identified a model of cultural connection through personal engagement with four interrelated phases: (a) mutual invitation, (b) shared engagement, (c) expanding personal connection, and (d) creating cultural connections. Clients in this study valued professionalism and expertise of the therapist, but felt attuned to and respected when therapists demonstrated humility, shared personal stories and emotion, and engaged in a collaborative process. PMID- 27507678 TI - Bridging the gap between guidelines and practice in the management of emerging infectious diseases: a qualitative study of emergency nurses. AB - AIMS AND OBJECTIVES: To explore the difficulties and strategies regarding guideline implementation among emergency nurses. BACKGROUND: Emerging infectious diseases remain an underlying source of global health concern. Guidelines for accident and emergency departments would require adjustments for infectious disease management. However, disparities between guidelines and nurses' practice are frequently reported, which undermines the implementation of these guidelines into practice. This article explores the experience of frontline emergency nurses regarding guideline implementation and provides an in-depth account of their strategies in bridging guideline-practice gaps. DESIGN: A qualitative descriptive design was used. METHODS: Semi-structured, face-to-face, individual interviews were conducted between November 2013-May 2014. A purposive sample of 12 frontline emergency nurses from five accident and emergency departments in Hong Kong were recruited. The audio-recorded interviews were transcribed verbatim and analysed with a qualitative content analysis approach. RESULTS: Four key categories associated with guideline-practice gaps emerged, including getting work done, adapting to accelerated infection control measures, compromising care standards and resolving competing clinical judgments across collaborating departments. The results illustrate that the guideline-practice gaps could be associated with inadequate provision of corresponding organisational supports after guidelines are established. CONCLUSIONS: The nurses' experiences have uncovered the difficulties in the implementation of guidelines in emergency care settings and the corresponding strategies used to address these problems. The nurses' experiences reflect their endeavour in adjusting accordingly and adapting themselves to their circumstances in the face of unfeasible guidelines. RELEVANCE TO CLINICAL PRACTICE: It is important to customise guidelines to the needs of frontline nurses. Maintaining cross-departmental consensus on guideline interpretation and operation is also indicated as an important component for effective guideline implementation. PMID- 27507681 TI - Metabolic pathways regulated by abscisic acid, salicylic acid and gamma aminobutyric acid in association with improved drought tolerance in creeping bentgrass (Agrostis stolonifera). AB - Abscisic acid (ABA), salicylic acid (SA) and gamma-aminobutyric acid (GABA) are known to play roles in regulating plant stress responses. This study was conducted to determine metabolites and associated pathways regulated by ABA, SA and GABA that could contribute to drought tolerance in creeping bentgrass (Agrostis stolonifera). Plants were foliar sprayed with ABA (5 MUM), GABA (0.5 mM) and SA (10 MUM) or water (untreated control) prior to 25 days drought stress in controlled growth chambers. Application of ABA, GABA or SA had similar positive effects on alleviating drought damages, as manifested by the maintenance of lower electrolyte leakage and greater relative water content in leaves of treated plants relative to the untreated control. Metabolic profiling showed that ABA, GABA and SA induced differential metabolic changes under drought stress. ABA mainly promoted the accumulation of organic acids associated with tricarboxylic acid cycle (aconitic acid, succinic acid, lactic acid and malic acid). SA strongly stimulated the accumulation of amino acids (proline, serine, threonine and alanine) and carbohydrates (glucose, mannose, fructose and cellobiose). GABA enhanced the accumulation of amino acids (GABA, glycine, valine, proline, 5 oxoproline, serine, threonine, aspartic acid and glutamic acid) and organic acids (malic acid, lactic acid, gluconic acid, malonic acid and ribonic acid). The enhanced drought tolerance could be mainly due to the enhanced respiration metabolism by ABA, amino acids and carbohydrates involved in osmotic adjustment (OA) and energy metabolism by SA, and amino acid metabolism related to OA and stress-defense secondary metabolism by GABA. PMID- 27507680 TI - Detection of inflammatory cell function using (13)C magnetic resonance spectroscopy of hyperpolarized [6-(13)C]-arginine. AB - Myeloid-derived suppressor cells (MDSCs) are highly prevalent inflammatory cells that play a key role in tumor development and are considered therapeutic targets. MDSCs promote tumor growth by blocking T-cell-mediated anti-tumoral immune response through depletion of arginine that is essential for T-cell proliferation. To deplete arginine, MDSCs express high levels of arginase, which catalyzes the breakdown of arginine into urea and ornithine. Here, we developed a new hyperpolarized (13)C probe, [6-(13)C]-arginine, to image arginase activity. We show that [6-(13)C]-arginine can be hyperpolarized, and hyperpolarized [(13)C] urea production from [6-(13)C]-arginine is linearly correlated with arginase concentration in vitro. Furthermore we show that we can detect a statistically significant increase in hyperpolarized [(13)C]-urea production in MDSCs when compared to control bone marrow cells. This increase was associated with an increase in intracellular arginase concentration detected using a spectrophotometric assay. Hyperpolarized [6-(13)C]-arginine could therefore serve to image tumoral MDSC function and more broadly M2-like macrophages. PMID- 27507682 TI - Receptor Antagonist of IL-13 Exerts a Potential Negative Regulation During Early Infection of Human Schistosomiasis. AB - The pathology of schistosomiasis is associated with the formation of granulomas, and this process is associated with liver fibrosis. Studies indicate that Th1 cytokines reduce fibrosis in schistosomiasis, while Th2 cytokines play a part in the progression of fibrosis, and IL-13 has a critical role in this process. The IL-13Ralpha2 receptor, known as a 'receptor antagonist' binds with high affinity to IL-13, and studies have identified that this plays a part in reducing fibrosis and the size of granulomas. The objective of this study was to evaluate the function of IL-13Ralpha2 and cellular immune response in hepatic fibrosis. A negative correlation between IL-13Ralpha2 and IL-13 was found, suggesting an increase in cytokine in early fibrosis. Initially, a negative correlation between IFN-gamma and IL-13 was found in patients without fibrosis, and subsequently, this correlation was found to be positive in patients with severe fibrosis, thereby highlighting a new mechanism for regulating the progress of periportal fibrosis. There was a positive correlation between the profiles of Th1 and Th2 cytokines, suggesting the presence of both responses, thus regulating the disease. The results contribute to a better understanding of the immune mechanisms that control the process of hepatic fibrogenesis in schistosomiasis in humans. PMID- 27507683 TI - Migratory Birds as Global Dispersal Vectors. AB - Propagule dispersal beyond local scales has been considered rare and unpredictable. However, for many plants, invertebrates, and microbes dispersed by birds, long-distance dispersal (LDD) might be regularly achieved when mediated by migratory movements. Because LDD operates over spatial extents spanning hundreds to thousands of kilometers, it can promote rapid range shifts and determine species distributions. We review evidence supporting this widespread LDD service and propose a conceptual framework for estimating LDD by migratory birds. Although further research and validation efforts are still needed, we show that current knowledge can be used to make more realistic estimations of LDD mediated by regular bird migrations, thus refining current predictions of its ecological and evolutionary consequences. PMID- 27507684 TI - Meeting the Self at the Crossroads: Thoughts on Aging as a Young Cancer Survivor. AB - PURPOSE OF THE STUDY: With nearly 14.5 million cancer survivors currently alive in the United States, it is expected this will rise to roughly 19 million by 2024. As more people will age with a history of cancer than ever before, it is important to consider how experiences of cancer affect the life course through the bending of time and its interpretation. As such, aging as a cancer survivor must be at the forefront of health maintenance across the life course. DESIGN AND METHODS: Through reference to my own cancer experiences in an auto-ethnographic format, this article interprets the illness experience as co-occurring in a young, aging body. This enhances our understanding of biographical reconstruction and individual liminality through descriptions of wisdom imparted by the cancer experience itself. Knowledge and wisdom are further interpreted as enhancing researchers' understandings of cancer and cancer survivorship. RESULTS: In this article, I use my illness experiences as a young person to describe evolving interpretations of the life course, the aging body, and the self. IMPLICATIONS: Concepts presented in this article aid researchers' understanding of how wisdom might be achieved through the experience of protracted illness over time. Such knowledge has important implications for the management of cancer as chronic, which may be most clearly described through the lens of the ill person. PMID- 27507685 TI - It's Interpersonal: Family Relationships, Genetic Risk, and Caregiving. AB - My research program considers family relationships across the life course: in early life, with a focus on disease prevention-leveraging genetic risk information and relationships to motivate health-promoting behaviors-and in later life, with a focus on informal caregiving-identifying characteristics of those most vulnerable to, or resilient from, caregiver stress. It is fortuitous, if not tragic, then, that my research and personal worlds collided during my mother's final 8 months of life. Here, I discuss how this experience has shifted my thinking within both arms of my research program. First, I consider the state of the science in family health history, arguing that the current approach which focuses on an individual's first- and second-degree relatives does not take us far enough into the relational landscape to activate communal coping with disease risk. Second, I discuss caregiving from a family systems perspective. My family's experience confirmed the importance of using a systems approach and highlighted a need to identify underlying variability in members' expectations of caregiving roles. In so doing, I capture the significance of understanding the multiple perspectives that frame a context in which families adapt and cope with risk and disease diagnoses. PMID- 27507686 TI - Reflections on Women's Retirement. AB - Popular literature often claims that baby boom women will "redefine" retirement, and there is some evidence in the gerontological literature that this may be true. However, considerably more research needs to be done on this generation of retirees. The author, a baby boomer herself, draws on recent research on retirement and her own experiences in early retirement to examine what a "good retirement" might mean, considering the diversity of baby boomers, the range of their experiences, and their relationship to work. PMID- 27507687 TI - Rationales for Anti-aging Activities in Middle Age: Aging, Health, or Appearance? AB - Purpose: We explore the motivations of middle-aged consumers of anti-aging products and services in relation to aging, health, and appearance. Admission of use of anti-aging products and services could align a respondent with a stigmatized group, old people, and also connotes a feminine concern with aesthetics. For these reasons, people, particularly men, will be unlikely to report using them for this purpose. Design and Methods: Semi-structured, in-depth interviews were conducted among 19 men and women aged 42-61 years. Topics included their perceptions of bodily changes and their responses to these. We analyzed data qualitatively. Results: Respondents frame their uses of anti-aging products in terms of health and appearance, not anti-aging per se. Both men and women see anti-aging as related to beautiful appearance and thus as a feminized activity. Both are concerned about appearance, but in gendered ways. Overall, respondents conflate bodily appearance, health, and aging in their constructions of anti-aging. Implications: This conflation maintains inequality by stigmatizing old age as unhealthy and unseemly. Our results point to the limits of studying the consumption of anti-aging products and services if researchers ask only about anti-aging uses per se. They also point to the ways that discourses of health and appearance naturalize ageism, as they suggest that old age inheres in bodies that "naturally" decline and thus should be excluded. PMID- 27507688 TI - New Love/Older Adults. PMID- 27507689 TI - Diabetic ketoacidosis and severe hypertriglyceridaemia as a consequence of an atypical antipsychotic agent. AB - The atypical antipsychotic agent clozapine, although an effective treatment for schizophrenia, is linked with metabolic adverse effects. We report a case of diabetic ketoacidosis and very severe hypertriglyceridaemia associated with clozapine use, in a patient with type 2 diabetes mellitus, who was successfully treated with continuous insulin infusion and fluids. As clozapine proved to be the most efficacious in controlling the patient's psychotic symptoms, the patient has been continued on clozapine despite its known metabolic side effects. Importantly the patient has achieved satisfactory long-term lipid and glycaemic control. The current recommendations related to the metabolic care for patients treated with atypical antipsychotic agents as well as the mechanisms behind abnormal glucose and lipid regulation with clozapine therapy are discussed. PMID- 27507690 TI - Isolated brain metastasis from a small renal mass. AB - The identification of small renal masses is increasing. Active surveillance is a guideline-approved management strategy for select patients with small renal masses. Metastases during the observation of small renal masses are uncommon, and no cases of brain metastasis have been reported. We report the case of a 73-year old man who presented with tonic-clonic seizures as the result of a brain metastasis from a small renal mass (3.5 cm in maximal dimension). Treatment with whole brain radiotherapy was undertaken successfully. The patient will undergo surveillance with consideration for systemic therapy at the time of progression. PMID- 27507691 TI - Small cell neuroendocrine carcinoma of tracheostomy site in a patient with a history of juvenile laryngeal papillomatosis. AB - Juvenile laryngeal papillomatosis is the commonest cause of benign epithelial tumours of the larynx. Following diagnostic biopsy, surgical debulking is the mainstay of therapy. The condition is often recurrent with further papillomas forming after debridement, requiring serial procedures and occasionally demanding tracheostomy. Rarely, the disease can undergo malignant transformation; most commonly to squamous cell carcinoma. We describe the first reported case of small cell neuroendocrine carcinoma occurring in the previous tracheostomy site of a 29 year-old male with a history of juvenile laryngeal papillomatosis. The patient, with a background of multiple treatments for juvenile papillomas, presented with voice change, breathing difficultly and erythema at the site of previous tracheostomy. Induction chemotherapy followed by chemoradiation was used to treat the lesion with a good response to initial therapy. PMID- 27507692 TI - Rare case of iridofundal coloboma with buried optic nerve head drusen in a paediatric patient. PMID- 27507693 TI - Meckel's diverticular perforation presenting as acute abdomen in the second trimester of pregnancy. AB - Meckel's diverticular perforation is a rare cause of acute abdomen during pregnancy. We report the case of a 24-year-old woman at 24 weeks of gestation who presented with abdominal pain for 4 days accompanied with abdominal distension, tenderness and guarding in right lower quadrant. Ultrasonography was inconclusive. The patient underwent exploratory laparotomy with the clinical suspicion of appendicular perforation peritonitis. Intraoperatively, a perforated Meckel's diverticulum was detected. Owing to gross contamination of the peritoneal cavity, a diverticulectomy with ileostomy was performed. She had a normal full-term vaginal delivery, and ileostomy was reversed 1 month after delivery. The physiological and anatomical changes in pregnancy can make a straightforward clinical diagnosis difficult. A high index of suspicion is required to prevent delay in diagnosis and surgical intervention, which could prove detrimental to the mother and fetus. PMID- 27507694 TI - Calciphylaxis of the breast: a rare metabolic complication of kidney disease. PMID- 27507695 TI - Pulmonary cavitary lesion and haemoptysis: rare aetiology on biopsy. AB - Pleomorphic carcinoma of the lung is a rare form of malignancy that can present similarly to other necrotising cavitary lung diseases. We present a case of a Caucasian woman who presented with recurrent haemoptysis and a right upper lobe cavitary lesion on CT scan. She underwent selective embolisation of the right bronchial artery by interventional radiology to control her haemoptysis. Positron emission tomography/CT scan was performed which showed significant fluorodeoxyglucose uptake in the right upper lobe cavitary lesion. There was a discussion among her providers about the aetiology of this lesion including infection and malignancy. Cultures from bronchoalveolar lavage and blood were negative for infection as the patient underwent right upper lobectomy which showed invasive sarcomatoid pleomorphic carcinoma with a minor component of acinar adenocarcinoma. She was diagnosed with stage IB (T2aN0M0) sarcomatoid pleomorphic carcinoma and underwent adjuvant chemotherapy after her lobectomy with recurrence and metastasis to her stomach and pancreas. PMID- 27507696 TI - Asymptomatic posthaemodialysis femoral arteriovenous fistula: multidetector computed tomography (MDCT) evaluation and management. PMID- 27507697 TI - Annexin A10 is involved in the development and maintenance of neuropathic pain in mice. AB - ANXA10 (annexin A10) is a member of the annexin family, and its biological effects are mediated primarily through the calcium-dependent phospholipid-binding and calcium ion binding. We examined the gene expressions of the L5 spinal cord after spinal nerve ligation (SNL)-induced neuropathic pain in mice by gene chip. The results showed that Anxa10 mRNA was the most upregulated gene in annexin family with 73.7-fold increase. Although previous studies have reported that several annexins are involved in nociceptive pain, the role of Anxa10 in pain remains undefined. We aimed to evaluate the role of ANXA10 in mediating injury induced heat hyperalgesia and mechanical allodynia. We found that SNL induced persistent upregulation of Anxa10 mRNA and protein in the spinal cord of mice. Moreover, ANXA10 was colocalized with the neuronal marker MAP2 and astrocytic marker glial fibrillary acidic protein (GFAP), but not with microglial marker CD11b. Finally, pretreatment with Anxa10 siRNA partially prevented SNL-induced mechanical allodynia and heat hyperalgesia. Posttreatment with Anxa10 siRNA attenuated SNL-induced neuropathic pain. These findings suggest that ANXA10 might be a novel target in the treatment of neuropathic pain. PMID- 27507698 TI - Association between MKL1 rs6001946 and schizophrenia in a Han Chinese population. AB - Megakaryoblastic leukemia 1 (MKL1) is highly expressed in the nervous system and plays a potentially principal role in neuronal migration and morphology. A recent study showed that some genetic loci within the MKL1 gene, especially single nucleotide polymorphism (SNP) rs6001946, may increase schizophrenia susceptibility. Here, we sought to determine whether the polymorphism rs6001946 was associated with schizophrenia in a Han Chinese population using the ligase detection reaction-polymerase chain reaction method to genotype SNP rs6001946 in the MKL1 gene. We observed that there was a marginally significant association between SNP rs6001946 and the risk of schizophrenia (P=0.077). Our results indicated that SNP rs6001946 of the MKL1 gene is likely a risk factor for schizophrenia, but the role of SNP rs6001946 in the development of schizophrenia in Han Chinese should be interpreted cautiously. Further studies with larger sample sizes are needed to determine the involvement of the MKL1 polymorphism in schizophrenia susceptibility. PMID- 27507699 TI - Silencing strategies for therapy of SOD1-mediated ALS. AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset, lethal, paralytic disorder caused by the degeneration of motor neurons. Our understanding of this disease has been greatly facilitated by studies of familial ALS caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Evidence indicates that misfolded wild-type SOD1 may also be pathogenic in sporadic ALS. Mutant SOD1 is neurotoxic through multiple mechanisms. Because the pathogenicity of mutant SOD1 is proportional to the dose of the toxic protein, a rational approach to treating SOD1-related ALS is to reduce levels of the toxic SOD1 species. An advantage of this strategy is that it potentially obviates intervening in multiple, downstream pathological cascades. In recent years, several strategies to silence gene expression have been developed. The most clinically promising are predicated on approaches that enhance degradation of RNA, such as anti-sense oligonucleotides (ASO) and RNA interference (RNAi); the latter include small inhibitory RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miR). Agents such as shRNA and either native or synthetic miR are capable of permeating the central nervous system (CNS) and efficiently silencing genes in the brain and spinal cord. Here we review recent progress in silencing SOD1, focusing on studies using artificial shRNA or miRNA in combination with potent viral vector delivery systems to mediate SOD1 silencing within the CNS in transgenic SOD1G93A mice and non-human primates. PMID- 27507700 TI - Determination of Recent Growth Hormone Abuse Using a Single Dried Blood Spot. AB - BACKGROUND: Although it is being increasingly applied, blood collection for drug testing in sport presents some logistic issues that complicate full applicability on a large scale. The use of dried blood spots (DBS) could benefit compliant blood testing considerably owing to its simplicity, minimal invasiveness, analyte stability, and reduced costs. The aim of this study was to evaluate the applicability of DBS to the methodology approved by the World Anti-Doping Agency (WADA) for detection of doping by recombinant human growth hormone (rhGH) in serum. METHODS: A protocol for a single DBS analysis using the hGH isoforms differential immunoassays (kit 1 and kit 2) was developed and validated. A clinical study with healthy volunteers injected for 3 consecutive days with a low subcutaneous dose (0.027 mg . kg(-1) . day(-1) . person(-1)) of rhGH was conducted. Finger prick DBS and paired-time serum samples from arm venipuncture were compared. RESULTS: The analysis of the DBS-based protocol indicated that with only a single blood spot it was possible to detect positivity for growth hormone abuse. In spite of the low rhGH dose administered and independently of the kit used, the window of detection for DBS was confirmed in all analyzed samples up to 8 h after rhGH administration and extended up to 12 h in 50% of the cases. Serum positivity was detected in all studied samples for 12 h after administration. CONCLUSIONS: These results support the usefulness of DBS as a biological matrix for testing recent growth hormone abuse. PMID- 27507701 TI - Genetic differentiation and population structure of five ethnic groups of Punjab (North-West India). AB - The state of Punjab in the North-West part of India has acted as the main passage for all the major human invasions into the Indian subcontinent. It has resulted in the mixing of foreign gene pool into the local populations, which led to an extensive range of genetic diversity and has influenced the genetic structure of populations in Punjab, North-West India. The present study was conducted to examine the genetic structure, relationships, and extent of genetic differentiation in five Indo-European speaking ethnic groups of Punjab. A total of 1021 unrelated samples belonging to Banias, Brahmins, Jat Sikhs, Khatris, and Scheduled castes were analyzed for four human-specific Ins/Del polymorphic loci (ACE, APO, PLAT, and D1) and three restriction fragment length polymorphisms ESR (PvuII), LPL (PvuII), and T2 (MspI) using Polymerase chain reaction (PCR). All the loci were found to be polymorphic among the studied populations. The frequency of the Alu insertion at APO locus was observed to exhibit the highest value (82.6-96.3 %), whereas D1 exhibited the lowest (26.5-45.6 %) among all the ethnic groups. The average heterozygosity among the studied populations ranged from 0.3816 in Banias to 0.4163 in Khatris. The FST values ranged from 0.0418 to 0.0033 for the PLAT and LPL loci, respectively, with an average value being 0.0166. Phylogenetic analysis revealed that Banias and Khatris are genetically closest to each other. The Jat Sikhs are genetically close to Brahmins and are distant from the Banias. The Jat Sikhs, Banias, Brahmins, and Khatris are genetically very distant from the Scheduled castes. Overall, Uniform allele frequency distribution patterns, high average heterozygosity values, and a small degree of genetic differentiation in this study suggest a genetic proximity among the selected populations. A low level of genetic differentiation was observed in the studied population groups indicating that genetic drift might have been small or negligible in shaping the genetic structure of North-West Indian Populations. PMID- 27507703 TI - Examining dynamics in a polymer matrix by single molecule fluorescence probes of different sizes. AB - Rotational motion of single fluorescence probes with different sizes doped inside films of polyvinylacetate is investigated by defocused single molecule fluorescence microscopy. Discrete vibration modes in the rotational motion of individual probes are clearly exposed in the power spectra of the rotation trajectories, reflecting multiple relaxation dynamics and also the difference in dynamics among separate locations. The power spectra show a strong dependence on the probe size and temperature. By sampling the rotation of a large number of probes, the averaged power spectra show that the activated rotation of the probes falls into the frequency range of the alpha-relaxation and data analysis shows that activation of the vibration modes with all probes corresponds to the maximum population of rotating probes, and this made the comparison between single molecule data and the ensemble data meaningful (differential scanning calorimetry, as an example). Such an analysis shows a coincidence between the temperature of a significant occurrence of glass transition and the activation of rotational motion of all probes with one specific size, indicating that such a dimension correlates with the size of the cooperative rearrangement region - a volume of approximately 1.0 nm(3). PMID- 27507702 TI - Transcriptome sequencing and de novo characterization of Korean endemic land snail, Koreanohadra kurodana for functional transcripts and SSR markers. AB - The Korean endemic land snail Koreanohadra kurodana (Gastropoda: Bradybaenidae) found in humid areas of broadleaf forests and shrubs have been considered vulnerable as the number of individuals are declining in recent years. The species is poorly characterized at the genomic level that limits the understanding of functions at the molecular and genetics level. In the present study, we performed de novo transcriptome sequencing to produce a comprehensive transcript dataset of visceral mass tissue of K. kurodana by the Illumina paired end sequencing technology. Over 234 million quality reads were assembled to a total of 315,924 contigs and 191,071 unigenes, with an average and N50 length of 585.6 and 715 bp and 678 and 927 bp, respectively. Overall, 36.32 % of the unigenes found matches to known protein/nucleotide sequences in the public databases. The direction of the unigenes to functional categories was determined using COG, GO, KEGG, and InterProScan protein domain search. The GO analysis search resulted in 22,967 unigenes (12.02 %) being categorized into 40 functional groups. The KEGG annotation revealed that metabolism pathway genes were enriched. The most prominent protein motifs include the zinc finger, ribonuclease H, reverse transcriptase, and ankyrin repeat domains. The simple sequence repeats (SSRs) identified from >1 kb length of unigenes show a dominancy of dinucleotide repeat motifs followed with tri- and tetranucleotide motifs. A number of unigenes were putatively assessed to belong to adaptation and defense mechanisms including heat shock proteins 70, Toll-like receptor 4, AMP-activated protein kinase, aquaporin-2, etc. Our data provide a rich source for the identification and functional characterization of new genes and candidate polymorphic SSR markers in K. kurodana. The availability of transcriptome information ( http://bioinfo.sch.ac.kr/submission/ ) would promote the utilization of the resources for phylogenetics study and genetic diversity assessment. PMID- 27507704 TI - Prediction of kinase-specific phosphorylation sites through an integrative model of protein context and sequence. AB - Identifying kinase substrates and the specific phosphorylation sites they regulate is an important factor in understanding protein function regulation and signalling pathways. Computational prediction of kinase targets - assigning kinases to putative substrates, and selecting from protein sequence the sites that kinases can phosphorylate - requires the consideration of both the cellular context that kinases operate in, as well as their binding affinity. This consideration enables investigation of how phosphorylation influences a range of biological processes. We report here a novel probabilistic model for classifying kinase-specific phosphorylation sites from sequence across three model organisms: human, mouse and yeast. The model incorporates position-specific amino acid frequencies, and counts of co-occurring amino acids from kinase binding sites. We show how this model can be seamlessly integrated with protein interactions and cell-cycle abundance profiles. When evaluating the prediction accuracy of our method, PhosphoPICK, on an independent hold-out set of kinase-specific phosphorylation sites, it achieved an average specificity of 97%, with 32% sensitivity. We compared PhosphoPICK's ability, through cross-validation, to predict kinase-specific phosphorylation sites with alternative methods, and show that at high levels of specificity PhosphoPICK obtains greater sensitivity for most comparisons made. We investigated the relationship between kinase-specific phosphorylation sites and nuclear localisation signals. We show that kinases PKA, Akt1 and AurB have an over-representation of predicted binding sites at particular positions downstream from predicted nuclear localisation signals, demonstrating an important role for these kinases in regulating the nuclear import of proteins. PhosphoPICK is freely available as a web-service at http://bioinf.scmb.uq.edu.au/phosphopick. PMID- 27507705 TI - Collaborative study for the calibration of replacement batches for the heparin low-molecular-mass for assay biological reference preparation. AB - The European Pharmacopoeia (Ph. Eur.) prescribes the control of the activity of low molecular mass heparins by assays for anti-Xa and anti-IIa activities (monograph 0828), using a reference standard calibrated in International Units (IU). An international collaborative study coded BSP133 was launched in the framework of the Biological Standardisation Programme (BSP) run under the aegis of the Council of Europe and the European Commission to calibrate replacement batches for the dwindling stocks of the Heparin low-molecular-mass for assay Biological Reference Preparation (BRP) batch 8. Thirteen official medicines control and manufacturers laboratories from European and non-European countries took part in this study to calibrate two freeze-dried candidate batches against the 3rd International Standard (IS) for heparin, low molecular weight (11/176; 3rd IS). The Heparin low-molecular-mass for assay BRP (batch 8) was also included in the test panel to check the continuity between subsequent BRP batches. Taking into account the stability data, the results of this collaborative study and on the basis of the central statistical analysis performed at the European Directorate for the Quality of Medicines & HealthCare (EDQM), the 2 candidate batches were officially adopted by the Commission of the European Pharmacopoeia as Heparin low-molecular-mass for assay BRP batches 9 and 10 with assigned anti Xa activities of 102 and 100 IU/vial and anti-IIa activities of 34 and 33 IU/vial respectively. PMID- 27507706 TI - miRNA profiles in livers with different mass deficits after partial hepatectomy and miR-106b~25 cluster accelerating hepatocyte proliferation in rats. AB - Partial hepatectomy (PH) promotes the reentry of quiescent hepatocytes into cell cycle for regrowth. miRNA profiles in livers with different mass deficits after PH have not been investigated and miRNAs implicated in liver regeneration remain unclear. We generated miRNA profiles from normal and remnant livers at 6, 12, 24, and 36 hours after 1/3 or 2/3PH using microarrays. Compared with normal livers, the proportion of altered miRNAs decreased with time after 1/3PH, but increased after 2/3PH. Most of altered miRNAs between 1/3 and 2/3PH exhibited similar up- or down-regulation, but lower expression magnitude for 1/3PH. Among differentially expressed miRNAs between 2/3PH with robust DNA replication and 1/3PH with a minimal replicative response, we identified miR-101a, miR-92a, miR 25, miR-93 and miR-106b as key regulators of cell cycle. In 2/3PH model, overexpression of miR-106b~25 cluster tended to accelerate liver regeneration, while inhibition of miR-106b~25 cluster markedly repressed regenerative response and delayed recovery of liver function. Mechanistically, RB1 and KAT2B with cell cycle arrest activity were identified as novel targets of miR-106b/93 and miR-25, respectively. Overall, we featured miRNA profiles and dynamics after 1/3 and 2/3PH, and identified miR-106b~25 cluster as being involved in timely cell cycle entry of hepatocytes after PH. PMID- 27507708 TI - Telemedicine for Gestational Diabetes Mellitus (TeleGDM): A Mixed-Method Study Protocol of Effects of a Web-Based GDM Support System on Health Service Utilization, Maternal and Fetal Outcomes, Costs, and User Experience. AB - BACKGROUND: Women with insulin-treated gestational diabetes mellitus (GDM) require close monitoring and support to manage their diabetes. Recent changes to the diagnostic criteria have implications for service provision stemming from increased prevalence, suggesting an increased burden on health services in the future. Telemedicine may augment usual care and mitigate service burdens without compromising clinical outcomes but evidence in GDM is limited. OBJECTIVE: The Telemedicine for Gestational Diabetes Mellitus (TeleGDM) trial aims to explore the use of telemedicine in supporting care and management of women with GDM treated with insulin. METHODS: The TeleGDM is a mixed-methods study comprising an exploratory randomized controlled trial (RCT) and a qualitative evaluation using semistructured interviews. It involves women with insulin-treated GDM who are up to 35 weeks gestation. Participating patients (n=100) are recruited face-to-face in outpatient GDM clinics at an outer metropolitan tertiary hospital with a culturally diverse catchment and a regional tertiary hospital. The second group of participants (n=8) comprises Credentialed Diabetes Educator Registered Nurses involved in routine care of the women with GDM at the participating clinics. The RCT involves use of a Web-based patient-controlled personal health record for GDM data sharing between patients and clinicians compared to usual care. Outcomes include service utilization, maternal and fetal outcomes (eg, glycemic control, 2nd and 3rd trimester fetal size, type of delivery, baby birth weight), diabetes self-efficacy, satisfaction, and costs. Semistructured interviews will be used to examine user experiences and acceptability of telemedicine. RESULTS: The trial recruitment is currently underway. Results are expected by the end of 2016 and will be reported in a follow-up paper. CONCLUSIONS: Innovative use of technology in supporting usual care delivery in women with GDM may facilitate timely access to GDM monitoring data and mitigate care burdens without compromising maternal and fetal outcomes. The intervention may potentially reduce health service utilization. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12614000934640; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366740 (Archived by WebCite(r) at http://www.webcitation.org/6jRiqzjSv). PMID- 27507707 TI - Microfabric Vessels for Embryoid Body Formation and Rapid Differentiation of Pluripotent Stem Cells. AB - Various scalable three-dimensional culture systems for regenerative medicine using human induced pluripotent stem cells (hiPSCs) have been developed to date. However, stable production of hiPSCs with homogeneous qualities still remains a challenge. Here, we describe a novel and simple embryoid body (EB) formation system using unique microfabricated culture vessels. Furthermore, this culture system is useful for high throughput EB formation and rapid generation of differentiated cells such as neural stem cells (NSCs) from hiPSCs. The period of NSC differentiation was significantly shortened under high EB density culture conditions. Simultaneous mass production of a pure population of NSCs was possible within 4 days. These results indicate that the novel culture system might not only become a unique tool to obtain new insights into developmental biology based on human stem cells, but also provide an important tractable platform for efficient and stable production of NSCs for clinical applications. PMID- 27507709 TI - A morphological and genetic description of pentastomid infective nymphs belonging to the family Sebekidae Sambon, 1922 in fish in Australian waters. AB - Infective nymphal stages of the family Sebekidae Sambon, 1922 are reported from four species of fish in Australian waters for the first time. Infected fish were collected from locations in Western Australia, the Northern Territory and north Queensland. The infective nymphs of Alofia merki Giglioli in Sambon, 1922 and Sebekia purdieae Riley, Spratt et Winch, 1990 are reported and described for the first time. The remaining specimens were identified as belonging to the genus Sebekia Sambon, 1922 based on the combination of buccal cadre shape, shape and size of hooks, and overall body size, but could not be attributed to any of the other species of Sebekia already reported due to missing required morphological features. DNA sequences of members of the family Sebekidae are presented for the first time. The lack of knowledge on the pentastome fauna of wild crocodiles, and any potential intermediate hosts, in northern Australia, is also outlined. PMID- 27507710 TI - Recombinant overexpression of camel hepcidin cDNA in Pichia pastoris: purification and characterization of the polyHis-tagged peptide HepcD-His. AB - Hepcidin, a liver-expressed antimicrobial peptide, has been demonstrated to act as an iron regulatory hormone as well as to exert a wide spectrum of antimicrobial activity. The aim of this work was the expression, as secreted peptide, purification, and characterization of a new recombinant polyHis-tagged camel hepcidin (HepcD-His) in yeast Pichia pastoris. The use of this eukaryotic expression system, for the production of HepcD-His, having 6 histidine residues at its C terminus, was simpler and more efficient compared with the use of the prokaryotic system Escherichia coli. Indeed, a single purification step was required to isolate the soluble hepcidin with purity estimated more that 94% and a yield of 2.8 against 0.2 mg/L for the E coli system. Matrix-assisted laser desorption/ionization time-of-flight (TOF)/TOF mass spectrometry of the purified HepcD-His showed 2 major peaks at m/z 4524.64 and 4634.56 corresponding to camel hepcidin with 39 and 40 amino acids. Evaluation of disulfide bond connectivity with the Ellman method showed an absence of free thiol groups, testifying that the 8 cysteine residues in the peptide are displayed, forming 4 disulfide bridges. Circular dichroism spectroscopy showed that camel hepcidin structure was significantly modified at high temperature of 90 degrees C and returns to its original structure when incubation temperature drops back to 20 degrees C. Interestingly, this peptide showed also a greater bactericidal activity, at low concentration of 9.5MUM, against E coli, than the synthetic analog DH3. Thus, the production, at a large scale, of the recombinant camel hepcidin, HepcD-His, may be helpful for future therapeutic applications including bacterial infection diseases. PMID- 27507711 TI - Worldwide impact of aerosol's time scale on the predicted long-term concentrating solar power potential. AB - Concentrating solar technologies, which are fuelled by the direct normal component of solar irradiance (DNI), are among the most promising solar technologies. Currently, the state-of the-art methods for DNI evaluation use datasets of aerosol optical depth (AOD) with only coarse (typically monthly) temporal resolution. Using daily AOD data from both site-specific observations at ground stations as well as gridded model estimates, a methodology is developed to evaluate how the calculated long-term DNI resource is affected by using AOD data averaged over periods from 1 to 30 days. It is demonstrated here that the use of monthly representations of AOD leads to systematic underestimations of the predicted long-term DNI up to 10% in some areas with high solar resource, which may result in detrimental consequences for the bankability of concentrating solar power projects. Recommendations for the use of either daily or monthly AOD data are provided on a geographical basis. PMID- 27507712 TI - Survival outcomes in elderly patients with untreated upper aerodigestive tract cancer. AB - BACKGROUND: This study is an evaluation of survival in patients with upper aerodigestive tract (UADT) cancer who did not receive guideline-directed therapy. METHODS: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was examined to identify patients with invasive cancer of the UADT. Patients were classified as "untreated" if they received neither surgery nor radiotherapy. Kaplan-Meier observed survival estimates were computed and stage-specific actuarial estimates of relative survival were computed. RESULTS: Of 3589 untreated patients, 13.7% were black, compared to 9.5% white, and 9.2% all other races (p <.0001). Patients with stage IV disease were more likely to be untreated than those with stage I disease (11.9% vs 3.8%; p <.0001). Median survival was 39 months for treated patients and 4 months for untreated patients. CONCLUSION: The median survival for untreated patients was 4 months. Stage, race, and primary site were independently associated with untreated status. (c) 2016 Wiley Periodicals, Inc. Head Neck 39: 215-218, 2017. PMID- 27507713 TI - Three-dimensional facial analysis of Chinese children with repaired unilateral cleft lip and palate. AB - We analyzed the facial features of Chinese children with repaired unilateral cleft lip and palate (UCLP) and compared them with a normal control group using a three-dimensional (3D) stereophotogrammetry camera. This cross-sectional study examined 3D measurements of the facial surfaces of 20 Chinese children with repaired UCLP and 40 unaffected Chinese children aged 7 to 12 years old, which were captured using the VECTRA 3D five-pod photosystem and analyzed using Mirror software. Twenty-five variables and two ratios were compared between both groups using independent t-test. Intra- and inter-observer reliability was determined using ten randomly selected images and analyzed using intra-class correlation coefficient test (ICC). The level of significance was set at p < 0.0018. Intra- and inter-observers' reliability was considered fair to excellent with an ICC value ranging from 0.54 to 0.99. Statistically significant differences (p < 0.0018) were found mainly in the nasolabial region. The cleft group exhibited wider alar base root width, flattened nose and broader nostril floor width on the cleft side. They tended to have shorter upper lip length and thinner upper vermillion thickness. Faces of Chinese children with repaired UCLP displayed meaningful differences when compared to the normal group especially in the nasolabial regions. PMID- 27507715 TI - Randomized clinical trial of single-incision versus multiport laparoscopic colectomy. AB - BACKGROUND: The efficacy and safety of single-incision laparoscopic colectomy (SILC) for colonic cancer remain unclear. The aim of this study was to determine the outcomes of SILC compared with multiport laparoscopic colectomy (MPLC) for colonic cancer. METHODS: Patients with histologically proven colonic carcinoma located in the caecum, ascending, sigmoid or rectosigmoid colon, clinically diagnosed as stage 0-III by CT, were eligible for this study. Patients were randomized before surgery and underwent tumour dissection with complete mesocolic excision. Safety analyses were conducted according to randomization groups. RESULTS: A total of 200 patients were enrolled and randomized to the MPLC (100 patients) or SILC (100 patients) arm. Surgical outcomes were similar between the MPLC and SILC arms, including duration of operation (mean 162 versus 156 min respectively; P = 0.273), blood loss (mean 8.8 versus 21.4 ml; P = 0.102), conversion to open laparotomy (2.0 versus 1.0 per cent; P = 0.561), reoperation (3.0 versus 3.0 per cent; P = 1.000), time to first flatus (both median 1 day; P = 0.155) and postoperative hospital stay (both median 6; P = 0.372). The total skin incision length was significantly shorter in the SILC arm (mean 4.4 cm versus 6.8 cm in the MPLC arm; P < 0.001). The median duration of analgesia use was 5 days in the MPLC and 4 days in the SILC arm (P = 0.485). Overall complication rates were equivalent (15.0 versus 12.0 per cent respecitvely; P = 0.680). CONCLUSION: SILC is not superior to MPLC. REGISTRATION NUMBER: UMIN000007220 (http://www.umin.ac.jp/ctr/index.htm). PMID- 27507716 TI - Making the next steps the right ones: progress towards the Smokefree Aotearoa 2025 Goal. PMID- 27507714 TI - MEF2C protects bone marrow B-lymphoid progenitors during stress haematopoiesis. AB - DNA double strand break (DSB) repair is critical for generation of B-cell receptors, which are pre-requisite for B-cell progenitor survival. However, the transcription factors that promote DSB repair in B cells are not known. Here we show that MEF2C enhances the expression of DNA repair and recombination factors in B-cell progenitors, promoting DSB repair, V(D)J recombination and cell survival. Although Mef2c-deficient mice maintain relatively intact peripheral B lymphoid cellularity during homeostasis, they exhibit poor B-lymphoid recovery after sub-lethal irradiation and 5-fluorouracil injection. MEF2C binds active regulatory regions with high-chromatin accessibility in DNA repair and V(D)J genes in both mouse B-cell progenitors and human B lymphoblasts. Loss of Mef2c in pre-B cells reduces chromatin accessibility in multiple regulatory regions of the MEF2C-activated genes. MEF2C therefore protects B lymphopoiesis during stress by ensuring proper expression of genes that encode DNA repair and B-cell factors. PMID- 27507717 TI - Pregnant women lack accurate knowledge of their BMI and recommended weight gain during pregnancy. PMID- 27507718 TI - Smoking prevalence in New Zealand from 1996-2015: a critical review of national data sources to inform progress toward the Smokefree 2025 goal. AB - AIM: The New Zealand Government has committed to a goal of becoming a smokefree nation by 2025. This study analysed recent smoking trends using three national data sets to: i) assess progress towards the smokefree goal; and ii) critically evaluate New Zealand's main national-level data sources on smoking prevalence for measuring progress towards the Smokefree 2025 goal. METHODS: Trends in adult (age 15+) daily smoking prevalence from 1996 to 2015 were compiled from three data sources: the New Zealand Census, the New Zealand Health Survey (NZHS), and the Health and Lifestyles Survey (HLS). We compared key features of the surveys (eg, sample size, ethnicity classification), examined composite trends across surveys, and analysed differences between and within surveys over time. RESULTS: Both the Census and the NZHS show a decline in adult (age 15+) daily smoking over the past 18 years, from 23-25% in 1996/97, to around 15% in 2014/15, with broadly consistent findings from the HLS since it began in 2008. However, recent NZHS findings do not suggest substantive reductions in daily smoking prevalence, particularly for Maori and Pacific populations, with 2014/15 rates of 35.5% and 22.4% in these populations respectively, and no statistically significant change since 2006/07. NZHS has advantages over the New Zealand Census and the HLS for the purposes of monitoring annual progress towards to the Smokefree 2025 goal. CONCLUSION: These data collectively suggest that recent declines in smoking prevalence are modest and clearly inadequate for achieving the Smokefree 2025 and interim 2018 goals, particularly for Maori and Pacific peoples. Continuation and improvement of tobacco-related surveillance is crucial for monitoring progress toward the 2025 goal. PMID- 27507719 TI - The All New Zealand Acute Coronary Syndrome Quality Improvement Programme: Implementation, Methodology and Cohorts (ANZACS-QI 9). AB - The All New Zealand Acute Coronary Syndrome Quality Improvement programme (ANZACS QI) uses a web-based system to create a clinical registry of patients with acute coronary syndrome (ACS) and other cardiac problems admitted to hospitals across New Zealand. This detailed clinical registry is complemented by parallel analyses of, and individual linkage to, New Zealand's multiple routine health information datasets. The programme is primarily designed to support secondary care clinicians to implement evidence based guidelines and to meet national performance targets for New Zealand cardiac patients. ANZACS-QI simultaneously generates a large-scale research database and provides an electronic data infrastructure for clinical registry studies. ANZACS-QI has been successfully implemented in all the 41 public hospitals across New Zealand where acute cardiac patients are admitted. By June 2015 25,273 patients with suspected ACS and 30,696 referred for coronary angiography were registered in ANZACS-QI. In this report we describe the development and national implementation of ANZACS-QI, its governance, the data collection processes and the current ANZACS-QI cohorts and available outputs. PMID- 27507720 TI - Pregnant women lack accurate knowledge of their BMI and recommended gestational weight gain. AB - AIM: To investigate pregnant women's knowledge of their body mass index (BMI) and their knowledge of gestational weight gain guidelines. METHODS: Participants were recruited when attending their nuchal translucency scan at between 11 and 13 weeks, 6-days gestation in Dunedin or Christchurch, New Zealand. Recruitment staff measured participants' weight and height. By way of a self-administered, paper-based survey, participants were asked to identify their body size (including: underweight (BMI <18.5 kg/m2); normal weight (18.5-24.9); overweight (25-29.9); and obese (>=30)), and recommended gestational weight gain (including the 2009 Institute of Medicine guidelines for healthy weight gain in pregnancy, along with the options: "I should not gain any weight in my pregnancy", plus "It does not matter how much weight I gain"). Participant-measured BMI was compared to responses for perceived BMI and recommended gestational weight gain to assess accuracy. Demographic predictors of accuracy were also investigated. RESULTS: In total, 644 women were included. Sixty-six percent of these correctly identified their BMI category, however only 31% identified their correct gestational weight gain recommendation. Overweight and obese women were much more likely to underestimate their BMI than normal weight women (p<0.001 for both). Overweight and obese women were also more likely to overestimate their weight gain recommendation (OR=4, p<0.001; OR=18, p<0.001, respectively) while normal weight women were more likely to underestimate their weight gain recommendation (p<0.001). Independent of BMI, women of New Zealand European ethnicity were less likely to underestimate their recommended gestational weight gain compared to other women of non-Maori/non-Pacific Island ethnicity (p=0.001), whereas younger women (p=0.012) were more likely to underestimate recommended gestational weight gain. CONCLUSION: The present study indicates that New Zealand women, particularly those who are overweight and obese, lack accurate knowledge of their own body size, and this may lead to an under- or over-estimation of appropriate gestational weight gain, which may in turn lead to increased risk of poor health outcomes in pregnancy. Education strategies related to healthy weight gain in pregnancy are urgently required. PMID- 27507721 TI - Smoking in cars: knowledge, behaviours and support for smokefree cars legislation among New Zealand smokers and recent quitters. AB - AIM: Exposure to second-hand smoke (SHS) poses serious health consequences to non smokers, and normalises smoking. Currently, there is no legislation restricting smoking in private cars in New Zealand. This paper supplements previous New Zealand studies on exposure to SHS in cars by examining smokers and recent quitters' knowledge and behaviours towards smoking in cars, and their support for two possible smokefree cars policy options. METHOD: The New Zealand Smoking Monitor is a fortnightly survey that uses a self-refreshing panel approach. The questionnaire contains smoking- and cessation-related questions, including eight non-core questions addressing smoking in homes or cars. These questions were answered by 364 respondents in 2014. Responses were compared by socio-demographic variables and recent quit attempt status. RESULTS: Smoking in cars was common among the respondents in our sample: 63% had recently smoked in a car when they were the only person in it, and 27% had done so when there were other people present. Some groups of respondents exhibited information gaps around the harms (eg, compared with males, females had reduced odds of agreeing with the false statement: "it's OK to smoke inside cars if there are windows open", OR=0.41, 0.21-0.78); however, support for banning smoking in cars if there are children in them was consistently high across different sub-groups (92% overall). CONCLUSION: Our data show the importance of providing specific information around the danger of smoking in cars, and strategies to enforce a complete smokefree rule in cars. Legislation may be required to further protect children from SHS exposure. PMID- 27507722 TI - Improved scores for observed teamwork in the clinical environment following a multidisciplinary operating room simulation intervention. AB - AIMS: We ran a Multidisciplinary Operating Room Simulation (MORSim) course for 20 complete general surgical teams from two large metropolitan hospitals. Our goal was to improve teamwork and communication in the operating room (OR). We hypothesised that scores for teamwork and communication in the OR would improve back in the workplace following MORSim. We used an extended Behavioural Marker Risk Index (BMRI) to measure teamwork and communication, because a relationship has previously been documented between BMRI scores and surgical patient outcomes. METHODS: Trained observers scored general surgical teams in the OR at the two study hospitals before and after MORSim, using the BMRI. RESULTS: Analysis of BMRI scores for the 224 general surgical cases before and 213 cases after MORSim showed BMRI scores improved by more than 20% (0.41 v 0.32, p<0.001). Previous research suggests that this improved teamwork score would translate into a clinically important reduction in complications and mortality in surgical patients. CONCLUSIONS: We demonstrated an improvement in scores for teamwork and communication in general surgical ORs following our intervention. These results support the use of simulation-based multidisciplinary team training for OR staff to promote better teamwork and communication, and potentially improve outcomes for general surgical patients. PMID- 27507723 TI - Key design features of a new smokefree law to help achieve the Smokefree Aotearoa. AB - AIM: To design new tobacco control legislation to achieve the New Zealand Government's 2025 smokefree goal. METHOD: An original analysis of the legislative options for New Zealand tobacco control. RESULTS: 'Business as usual' is most unlikely to achieve smoking prevalence that is less than 5% by 2025. Key components of a new Act would ideally include plans and targets with teeth, a focus on the industry, a focus on the product, reduction of supply, and a whole of-society approach to promote consistency in policy implementation through: i) a public duty on government agencies to act consistently with smokefree law; ii) a general duty on those associated with the tobacco/nicotine industry in relation to tobacco control objectives; and iii) a principle requiring international treaties to be interpreted consistently with tobacco control objectives. CONCLUSION: Strategies such as those identified in this Viewpoint should be explored further as part of urgently needed planning to achieve the New Zealand Government's goal for Smokefree Aotearoa by 2025. PMID- 27507724 TI - 'Poorly defined': unknown unknowns in New Zealand Rural Health. AB - There is a considerable mismatch between the population that accesses rural healthcare in New Zealand and the population defined as 'rural' using the current statistics New Zealand rural and urban categorisations. Statistics New Zealand definitions (based on population size or density) do not accurately identify the population of New Zealanders who actually access rural health services. In fact, around 40% of people who access rural health services are classified as 'urban' under the Statistics New Zealand definition, while a further 20% of people who are currently classified as 'rural' actually have ready access to urban health services. Although there is some recognition that current definitions are suboptimal, the extent of the uncertainty arising from these definitions is not widely appreciated. This mismatch is sufficient to potentially undermine the validity of both nationally-collated statistics and also any research undertaken using Statistics New Zealand data. Under these circumstances it is not surprising that the differences between rural and urban health care found in other countries with similar health services have been difficult to demonstrate in New Zealand. This article explains the extent of this mismatch and suggests how definitions of rural might be improved to allow a better understanding of New Zealand rural health. PMID- 27507725 TI - Alcohol consumption by youth: Peers, parents, or prices? AB - Using data from the National Longitudinal Survey of Adolescent to Adult Health, we estimate the effect of peers' alcohol consumption and alcohol prices on the drinking habits of high-school-age youth. We use the two-stage residual inclusion method to account for the endogeneity of peer drinking in nonlinear models. For our sample of high school students, we find that peer effects are statistically and economically significant regarding the choice to participate in drinking but are not significant for the frequency of drinking, including binge drinking. Regarding alcohol prices, even though we have good price variation in our sample, alcohol prices are not found to be significant. The results are important for policymakers who are considering policies to reduce underage drinking, as we conclude that no significant impact on underage drinking will result from low-tax states' increasing excise taxes on alcohol so they are similar to those of high tax states. Policymakers may choose to focus instead on the influence of peers and changing the social norm behavior. PMID- 27507726 TI - Automated multi-plug filtration cleanup for liquid chromatographic-tandem mass spectrometric pesticide multi-residue analysis in representative crop commodities. AB - An automated multi-plug filtration cleanup (m-PFC) method on modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) extracts was developed. The automatic device was aimed to reduce labor-consuming manual operation workload in the cleanup steps. It could control the volume and the speed of pulling and pushing cycles accurately. In this work, m-PFC was based on multi-walled carbon nanotubes (MWCNTs) mixed with other sorbents and anhydrous magnesium sulfate (MgSO4) in a packed tip for analysis of pesticide multi-residues in crop commodities followed by liquid chromatography with tandem mass spectrometric (LC MS/MS) detection. It was validated by analyzing 25 pesticides in six representative matrices spiked at two concentration levels of 10 and 100MUg/kg. Salts, sorbents, m-PFC procedure, automated pulling and pushing volume, automated pulling speed, and pushing speed for each matrix were optimized. After optimization, two general automated m-PFC methods were introduced to relatively simple (apple, citrus fruit, peanut) and relatively complex (spinach, leek, green tea) matrices. Spike recoveries were within 83 and 108% and 1-14% RSD for most analytes in the tested matrices. Matrix-matched calibrations were performed with the coefficients of determination >0.997 between concentration levels of 10 and 1000MUg/kg. The developed method was successfully applied to the determination of pesticide residues in market samples. PMID- 27507727 TI - Determination of pesticides in edible oils by liquid chromatography-tandem mass spectrometry employing new generation materials for dispersive solid phase extraction clean-up. AB - The goal of this work was to evaluate the efficiency of several sorbents on removal fats from edible oils (olive, soya and sunflower) during the clean-up step for posterior determination of 165 pesticides by UHPLC-QqQ-MS/MS system. The extraction procedure employed in this work was the citrate version of QuEChERS method followed by a step of freezing out with dry ice and clean-up evaluation using i) PSA with magnesium sulfate (d-SPE); ii) magnesium sulfate and Z-sep sorbent (d-SPE); iii) Z-sep (column SPE) and iv) Agilent Bond Elut QuEChERS Enhanced Matrix Removal-Lipid (EMR-Lipid). After evaluation of the recovery results at 10, 20 and 50MUgkg(-1), the EMR-Lipid showed important advantages comparing to the other sorbents evaluated, such as better recovery rates and RSD%. The method was validated at the three concentrations described above. Analytical curves linearity was evaluated by spiking blank oil samples at 10, 20, 50, 100 and 500MUgkg(-1). The method demonstrated good recoveries values between the acceptable range of 70-120% and RSD%<20 for most of evaluated pesticides. In order to evaluate the performance of the method, this same procedure was employed to other oils such as soya and sunflower with very good results. PMID- 27507728 TI - Dealing with the ubiquity of phthalates in the laboratory when determining plasticizers by gas chromatography/mass spectrometry and PARAFAC. AB - Determining plasticizers and other additives migrated from plastic materials becomes a hard task when these substances are already present in the laboratory environment. This work dealt with this drawback in the multiresidue determination of four plasticizers (2,6-di-tert-butyl-4-methyl-phenol (BHT), diisobutyl phthalate (DiBP), bis(2-ethylhexyl) adipate (DEHA) and diisononyl phthalate (DiNP)) and a UV stabilizer (benzophenone (BP)) by gas chromatography/mass spectrometry (GC/MS) using DiBP-d4 as internal standard. The ubiquity of DiBP by a non-constant leaching process in the laboratory was detected, which could not guarantee the achievement of a trustworthy quantification. To handle this, the assessment of the level of DiBP in solvent blanks having fixed the probabilities of false non-compliance (alpha) and false compliance (beta) at 0.01 was performed. On the other hand, another special case was that of DiNP, in whose chromatogram finger peaks appear because of an array of possible C9 isomers. PARAFAC, used for the identification and quantification of all the substances, is a useful chemometric tool that enabled a more reliable determination of this analyte since no peak areas were considered but chromatographic and spectral loadings. Since phthalates may migrate from rubber latex items, an evaluation of the existence of matrix effects on the determination of the five analytes was conducted prior to an extraction with hexane from a dummy for infants. As matrix effects were present, the quantification of the compounds under study was performed following the standard addition method using PARAFAC sample loadings as response variable. As a result, the presence of BHT was confirmed, being its concentration equal to 37.87MUgL(-1). Calibrations based on PARAFAC yielded the following values for the decision limit (CCalpha): 1.16MUgL(-1) for BHT, 1.34MUgL(-1) for BP, 1.84MUgL(-1) for DEHA and 51.42MUgL(-1) for DiNP(for alpha=0.05 and two replicates). PMID- 27507729 TI - Magnetic solid-phase extraction using nanoporous three dimensional graphene hybrid materials for high-capacity enrichment and simultaneous detection of nine bisphenol analogs from water sample. AB - The synthesis of a magnetic nanoporous three dimensional graphene (3DG)/ZnFe2O4 composite has been achieved. Through formation of graphene hydrogel, ZnFe2O4 magnetic particles was successfully introduced into the nanoporous 3DG, resulting in a magnetic porous carbon material. The morphology, structure, and magnetic behavior of the as-prepared 3DG/ZnFe2O4 were characterized by using the techniques of SEM, XRD, BET, VSM, FTIR, Raman and TGA. The 3DG/ZnFe2O4 has a high specific surface area and super paramagnetism. Its performance was evaluated by the magnetic solid-phase extraction of nine bisphenol analogs (BPs) from water samples followed by HPLC analysis, and showed excellent adsorption capability for the nine target compounds. Under optimized condition, the lower method detection limits (0.05-0.18ngmL(-1)), the higher enrichment factors (800 fold) and good recoveries (95.1-103.8%) with relative standard deviation (RSD) values less than 6.2% were achieved. The results indicated that the developed method based on the use of 3DG/ZnFe2O4 as the magnetic adsorbent has the advantages of convenience and high efficiency, and can be successfully applied to detect the nine BPs in real water samples. PMID- 27507730 TI - Corrigendum to "In vitro cytotoxicity of Nicotiana gossei leaves, used in the Australian Aboriginal smokeless tobacco known as pituri or mingkulpa" [Toxicol. Lett. 254 (2016) 45-51]. PMID- 27507731 TI - Determining the efficacy of the chronic disease self-management programme and readability of 'living a healthy life with chronic conditions' in a New Zealand setting. AB - BACKGROUND: Self-management programmes are an increasingly popular way of treating chronic diseases. AIMS: This study aims to determine the efficacy of the Stanford Chronic Disease Self-Management Programme (CDSMP) in a New Zealand context by assessing course outcomes and readability of the accompanying reference guide Living a Healthy Life with Chronic Conditions, 4th Edition. METHODS: This is a cross-sectional pre-post study conducted in Auckland between August 2009 and September 2015, using CDSMP participants' baseline and follow-up Health Education Intervention Questionnaire (heiQTM ) data. Readability of the guide was assessed using the Gunning Fog Index, Coleman Liau, Flesch Reading Ease, Flesch Kincaid Grade Level and Simplified Measure of Gobbledygook scores. RESULTS: Significant evidence of improvement (P <= 0.001) was observed in seven of the eight domains measured by the heiQTM (Deakin University, Centre for Population Health Research, Melbourne, Vic., Australia). The greatest improvements were seen in skill and technique acquisition (mean change score 0.25, P <= 0.001) and self-monitoring and insight (0.18, P <= 0.001). There was little evidence of improvement in health service navigation (0.04, P = 0.17). Readability analyses indicate that a person needs to be reading at a minimum of U.S. 8th grade level in order to understand the text, and possibly up to 11th grade. CONCLUSIONS: The CDSMP is effective for improving patient self-efficacy in the New Zealand setting. However, adaptation of the programme to support better health service navigation is warranted. The readability of the reference guide is not suitable for this setting and requires further improvement. PMID- 27507732 TI - Survey of eye practitioners' preference of diagnostic tests and treatment modalities for dry eye in Ghana. AB - PURPOSE: This study sought to provide an evidence-based profile of the diagnosis, treatment and knowledge or opinions on dry eye among optometrists and ophthalmologists in Ghana. METHODS: This was a cross-sectional survey RESULTS: The responses of 162 participants are included in the analysis. The most commonly used test to diagnosed dry eye disease was tear break-up time followed by patient history. The most common symptom doctors heard from dry eye patients were burning sensation followed by foreign body sensation. The most often prescribed first- line treatment for dry eye was aqueous-based artificial tears followed by lipid based artificial tears. Most practitioners considered meibomian gland dysfunction as the most common cause of dry eye followed by pterygium. The most often used test to guide or gauge therapeutic effect is patient history followed closely by tear break-up time. Most practitioners reported that 10%-20% of all their patients they see in a day are diagnosed of dry eye. CONCLUSION: This study showed tear break up time was the main test majority of practitioners in Ghana used to diagnose dry eye but patient history was the main test used to gauge therapeutic effect over time. Burning sensation was the commonest symptom practitioners heard from dry eye patients whilst artificial tears was their main and first-line treatment for dry eye. PMID- 27507733 TI - Oral food challenge with a mixture of 'at risk' foods in children with FPIES. PMID- 27507734 TI - Defective DNA repair increases susceptibility to senescence through extension of Chk1-mediated G2 checkpoint activation. AB - Susceptibility to senescence caused by defective DNA repair is a major hallmark of progeroid syndrome patients, but molecular mechanisms of how defective DNA repair predisposes to senescence are largely unknown. We demonstrate here that suppression of DNA repair pathways extends the duration of Chk1-dependent G2 checkpoint activation and sensitizes cells to senescence through enhancement of mitosis skipping. Extension of G2 checkpoint activation by introduction of the TopBP1 activation domain and the nondegradable mutant of Claspin sensitizes cells to senescence. In contrast, a shortening of G2 checkpoint activation by expression of SIRT6 or depletion of OTUB2 reduces susceptibility to senescence. Fibroblasts from progeroid syndromes tested shows a correlation between an extension of G2 checkpoint activation and an increase in the susceptibility to senescence. These results suggest that extension of G2 checkpoint activation caused by defective DNA repair is critical for senescence predisposition in progeroid syndrome patients. PMID- 27507735 TI - Factors associated with Internet addiction: Cross-sectional study of Turkish adolescents. AB - BACKGROUND: The aim of this study was to investigate the prevalence of Internet addiction (IA), and the relationship between sociodemographic characteristics, depression, anxiety, attention-deficit-hyperactivity disorder (ADHD) symptoms and IA in adolescents. METHODS: This was a cross-sectional school-based study with a representative sample of 468 students aged 12-17 years at the first trimester of the 2013-2014 academic year. The students were assessed using Young's Internet Addiction Scale, Children's Depression Inventory, Beck Anxiety Inventory, Conners' Parent Rating Scale, Conners' Teacher Rating Scale, Hollingshead-Redlich Scale, and the information form including characteristics of Internet use and socioeconomic status (SES). The relationship between these factors and Internet use was examined. RESULTS: Approximately 1.6% of students were identified as having IA, whereas 16.2% had possible IA. There were significant correlations between IA and depression, anxiety, attention disorder and hyperactivity symptoms in adolescents. Smoking was also related to IA. There was no significant relationship between IA and age, sex, body mass index, school type, and SES. CONCLUSIONS: Depression, anxiety, ADHD and smoking addiction are associated with PIU in adolescent students. Preventive public health policies targeting the psychological wellbeing of young people are needed. PMID- 27507736 TI - Carotid Stenting Versus Carotid Endarterectomy: What Did the Carotid Revascularization Endarterectomy Versus Stenting Trial Show and Where Do We Go From Here? AB - Although rapidly expanding in its use, carotid artery stenting remains a relatively new procedure. Its growth is due, at least in part, to the perceived advantages of a less invasive technique. However, the clinical effectiveness and specific role for stenting in the treatment of carotid occlusive disease are still under evaluation. The primary aim of the randomized clinical trial, Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), was to contrast the relative efficacy of carotid stenting versus carotid endarterectomy in preventing stroke, myocardial infarction, or death during a 30-day periprocedural period or ipsilateral stroke over the follow-up period in patients with symptomatic and asymptomatic extracranial carotid stenosis. The secondary goals were to describe the differential efficacy of the 2 procedures in men and women, contrast periprocedural (30-day) morbidity and postprocedural morbidity and mortality, estimate and contrast the restenosis rates of the 2 procedures, evaluate differences in measures of health-related quality of life and cost effectiveness, and identify subgroups of participants at differential risk of stenting or surgery. This report summarizes the results obtained from CREST with respect to its primary and secondary aims. PMID- 27507738 TI - Schizoxylon as an experimental model for studying interkingdom symbiosis. AB - Experiments to re-synthesise lichens so far focused on co-cultures of fungal and algal partners. However, recent studies have revealed that bacterial communities colonise lichens in a stable and host-specific manner. We were therefore interested in testing how lichenised fungi and algae interact with selected bacteria in an experimental setup. We selected the symbiotic system of Schizoxylon albescens and the algal genera Coccomyxa and Trebouxia as a suitable model. We isolated bacterial strains from the naturally occurring bacterial fraction of freshly collected specimens and established tripartite associations under mixed culture experiments. The bacteria belong to Actinobacteria, Firmicutes and Proteobacteria and corresponded to groups already found associated with fungi including lichens. In mixed cultures with Coccomyxa, the fungus formed a characteristic filamentous matrix and tightly contacted the algae; the bacteria distributed in small patches between the algal cells and attached to the cell walls. In mixed cultures with Trebouxia, the fungus did not develop the filamentous matrix, but bacterial cells were observed to be tightly adhering to the fungal hyphae. Our experiments show that this tripartite fungal-algal bacterial model system can be maintained in culture and can offer multiple opportunities for functional studies based on experiments under controlled conditions in the laboratory. PMID- 27507737 TI - Quiescent Bone Lining Cells Are a Major Source of Osteoblasts During Adulthood. AB - The in vivo origin of bone-producing osteoblasts is not fully defined. Skeletal stem cells, a population of mesenchymal stem cells resident in the bone marrow compartment, are thought to act as osteoprogenitors during growth and adulthood. Quiescent bone lining cells (BLCs) have been suggested as a population capable of activation into mature osteoblasts. These cells were defined by location and their morphology and studies addressing their significance have been hampered by their inaccessibility, and lack of markers that would allow for their identification and tracing. Using lineage tracing models, we have observed labeled osteoblasts at time points extending beyond the reported lifespan for this cell type, suggesting continuous reactivation of BLCs. BLCs also make a major contribution to bone formation after osteoblast ablation, which includes the ability to proliferate. In contrast, mesenchymal progenitors labeled by Gremlin1 or alpha smooth muscle actin do not contribute to bone formation in this setting. BLC activation is inhibited by glucocorticoids, which represent a well established cause of osteoporosis. BLCs express cell surface markers characteristic of mesenchymal stem/progenitors that are largely absent in osteoblasts including Sca1 and Leptin Receptor. BLCs also show different gene expression profiles to osteoblasts, including elevated expression of Mmp13, and osteoclast regulators RANKL and macrophage colony stimulating factor, and retain osteogenic potential upon transplantation. Our findings provide evidence that bone lining cells represent a major source of osteoblasts during adulthood. Stem Cells 2016;34:2930-2942. PMID- 27507739 TI - Hydraulic fracturing offers view of microbial life in the deep terrestrial subsurface. AB - Horizontal drilling and hydraulic fracturing are increasingly used for recovering energy resources in black shales across the globe. Although newly drilled wells are providing access to rocks and fluids from kilometer depths to study the deep biosphere, we have much to learn about microbial ecology of shales before and after 'fracking'. Recent studies provide a framework for considering how engineering activities alter this rock-hosted ecosystem. We first provide data on the geochemical environment and microbial habitability in pristine shales. Next, we summarize data showing the same pattern across fractured shales: diverse assemblages of microbes are introduced into the subsurface, eventually converging to a low diversity, halotolerant, bacterial and archaeal community. Data we synthesized show that the shale microbial community predictably shifts in response to temporal changes in geochemistry, favoring conservation of key microorganisms regardless of inputs, shale location or operators. We identified factors that constrain diversity in the shale and inhibit biodegradation at the surface, including salinity, biocides, substrates and redox. Continued research in this engineered ecosystem is required to assess additive biodegradability, quantify infrastructure biocorrosion, treat wastewaters that return to the surface and potentially enhance energy production through in situ methanogenesis. PMID- 27507740 TI - Deep into the Aristolochia Flower: Expression of C, D, and E-Class Genes in Aristolochia fimbriata (Aristolochiaceae). AB - Aristolochia fimbriata (Aristolochiaceae) is a member of an early diverging lineage of flowering plants and a promising candidate for evo-devo studies. Aristolochia flowers exhibit a unique floral synorganization that consists of a monosymmetric and petaloid calyx formed by three congenitally fused sepals, and a gynostemium formed by the congenital fusion between stamens and the stigmatic region of the carpels. This floral ground plan atypical in the magnoliids can be used to evaluate the role of floral organ identity MADS-box genes during early flower evolution. In this study, we present in situ hybridization experiments for the homologs of the canonical C-, D-, and E-class genes. Spatiotemporal expression of the C-class gene AfimAG is restricted to stamens, ovary, and ovules, suggesting a conserved stamen and carpel identity function, consistent with that reported in core-eudicots and monocots. The D-class gene AfimSTK is detected in the anthers, the stigmas, the ovary, the ovules, the fruit, and the seeds, suggesting conserved roles in ovule and seed identity and unique roles in stamens, ovary, and fruit development. In addition, AfimSTK expression patterns in areas of organ abscission and dehiscence zones suggest putative roles linked to senescence processes. We found that both E-class genes are expressed in the anthers and the ovary; however, AfimSEP2 exhibits higher expression compared to AfimSEP1. These findings provide a comprehensive picture of the ancestral expression patterns of the canonical MADS-box floral organ identity genes and the foundations for further comparative analyses in other magnoliids. PMID- 27507741 TI - Halting the Olympics-Zika virus bandwagon. PMID- 27507742 TI - HPV vaccination: a decade on. PMID- 27507743 TI - Evidence-based policy for salt reduction is needed. PMID- 27507744 TI - End-of-life care across the world: a global moral failing. PMID- 27507745 TI - Sitting on the FENSA: WHO engagement with industry. PMID- 27507747 TI - The Zika virus public health emergency: 6 months on. PMID- 27507748 TI - US presidential candidates far apart on environmental health. PMID- 27507750 TI - Impact of proposal to extend charging for NHS in England. PMID- 27507749 TI - UK surgical trainees will continue to support European research collaboration. PMID- 27507751 TI - The need for global R&D coordination for infectious diseases with epidemic potential. PMID- 27507752 TI - A call for transparency in the evaluation of global maternal health projects. PMID- 27507753 TI - The neglect of eating disorders. PMID- 27507754 TI - The neglect of eating disorders - Authors' reply. PMID- 27507755 TI - Preventing bloodstream infection in children: What's the CATCH? PMID- 27507756 TI - Preventing bloodstream infection in children: What's the CATCH? - Authors' reply. PMID- 27507758 TI - Department of Error. PMID- 27507757 TI - Health diplomacy to tackle the crisis in Nepal. PMID- 27507759 TI - An exploration of screening protocols for intimate partner violence in healthcare facilities: a qualitative study. AB - AIMS AND OBJECTIVES: Explore different methods by which intimate partner violence screening practices are implemented in clinic and emergency settings and better understand barriers and facilitators. BACKGROUND: Healthcare visits provide an opportunity for providers to identify and provide assistance to victims of intimate partner violence. However, wide variation exists in the implementation of screening and response protocols. In addition, providers experience barriers and facilitators to intimate partner violence screening and response. A comprehensive understanding of these factors is necessary to improve the role that providers play in detection and intervention of intimate partner violence. DESIGN: Qualitative descriptive research design. METHODS: Sixteen healthcare facilities were recruited from a large metropolitan area in the USA. Data were collected through semi-structured, in-depth interviews with individuals knowledgeable about intimate partner violence screening and response within their facility. Data were analysed using directive content analysis. RESULTS: Major themes and patterns concerning intimate partner violence screening and response were identified within the following areas: procedural characteristics, barriers, facilitators and additional needs. Patient-provider communication and operational/facility characteristics emerged as critical aspects that impact the successful implementation of intimate partner violence screening and response programmes. Differences were found between clinic and emergency settings stemming from variations in health delivery models. CONCLUSIONS: Results provide important information on how healthcare facilities implement intimate partner violence screening and response, suggestions for practice improvement and directions for future interventions. Additional guidance is needed to ensure intimate partner violence identification, and response procedures are effective and tailored to needs of patients, providers and the facility. RELEVANCE TO CLINICAL PRACTICE: Nurses are in a strategic position to play a pivotal role in identification of and response to intimate partner violence. It is essential that nurses are cognizant of this, and understand the actions they can take to assist patients who have been victims of intimate partner violence. Recommendations on how to do this are provided. PMID- 27507760 TI - A Xhosa language translation of the CORE-OM using South African university student samples. AB - The translation of well established psychometric tools from English into Xhosa may assist in improving access to psychological services for Xhosa speakers. The aim of this study was to translate the Clinical Outcomes in Routine Evaluation - Outcome Measure (CORE-OM), a measure of general distress and dysfunction developed in the UK, into Xhosa for use at South African university student counselling centres. The CORE-OM and embedded CORE-10 were translated into Xhosa using a five-stage translation design. This design included (a) forward translation, (b) back-translation, (c) committee approach, (d) qualitative piloting, and (e) quantitative piloting on South African university students. Clinical and general samples were drawn from English-medium South African universities. Clinical samples were generated from university student counselling centres. General student samples were generated through random stratified cluster sampling of full-time university students. Qualitative feedback from the translation process and results from quantitative piloting of the 34-item CORE-OM English and Xhosa versions supported the reduction of the scale to 10 items. This reduced scale is referred to as the South African CORE-10 (SA CORE-10). A measurement and structural model of the SA CORE-10 English version was developed and cross-validated using an English-speaking university student sample. Equivalence of this model with the SA CORE-10 Xhosa version was investigated using a first-language Xhosa-speaking university sample. Partial measurement equivalence was achieved at the metric level. The resultant SA CORE-10 Xhosa and English versions provide core measures of distress and dysfunction. Additional, culture- and language-specific domains could be added to increase sensitivity and specificity. PMID- 27507761 TI - Contextualizing Afghan refugee views of depression through narratives of trauma, resettlement stress, and coping. AB - This qualitative study explored how Afghan refugees conceptualize frames of mind that may reflect depression in general and as it relates to trauma they experienced. We performed in-depth interviews with 18 Afghans residing in the San Diego area. Views regarding the causes, symptoms, and perceived treatments of depression were gathered through free-listing techniques, and supplemented with narratives relating to pre- and post-resettlement stressors and coping mechanisms. Data were analyzed with standard qualitative content analysis methods. Items endorsed with relation to depression causality included pre migration war traumas, notably separation from family, and post-migration stressors including status dissonance and cultural conflicts that ranged from linguistic challenges to intergenerational problems. Depressive symptoms were viewed as highly debilitating, and included changes in temperament, altered cognitions, avoidance and dissociative behaviors, and somatic complaints. Relief was sought through family reunification and community support, reliance on prayer, and the academic success of their children in the US. The findings underscore the need for practitioners to take into account situational stressors, cultural aspects of mourning and symptomatology, and existing coping mechanisms in developing interventions that are based on refugees' articulated needs. PMID- 27507762 TI - Connection of the Posterior Occipital Muscle and Dura Mater of the Siamese Crocodile. AB - The myodural bridge was proposed initially in 1995. The myodural bridge is a connective tissue bridge that connects a pair of deep muscles at the suboccipital region to the dura mater. There have been numerous studies concerning the morphology and function of the myodural bridge. To determine whether a myodural bridge exists in reptiles, six Siamese crocodiles were investigated using gross anatomy dissection and P45 sheet plastination technologies. As a result, we demonstrated that the posterior occipital muscles of the Siamese crocodile are directly or indirectly connected to the proatlas, atlas, and intermembrane between them. Multiple trabeculae existing in the posterior epidural space extended from the ventral surface of the proatlas, atlas, and intermembrane between them to the dorsal surface of the spinal dura mater. This study showed that the posterior occipital muscle in the suboccipital region of the Siamese crocodile is connected to the spinal dura mater through the proatlas, atlas, and the trabeculae. In conclusion, a myodural bridge-like structure exists in reptiles. This connection may act as a pump to provide cerebrospinal fluid (CSF) circulation at the occipitocervical junction. We hypothesize that a physiologic role of the Siamese crocodile's myodural bridge may be analogous to the human myodural bridge. Anat Rec, 299:1402-1408, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27507763 TI - Inhibition of VEGF165/VEGFR2-dependent signaling by LECT2 suppresses hepatocellular carcinoma angiogenesis. AB - Hepatocellular carcinoma (HCC) relies on angiogenesis for growth and metastasis. Leukocyte cell-derived chemotaxin 2 (LECT2) is a cytokine and preferentially expressed in the liver. Previous studies have found that LECT2 targets to both immune and tumor cells to suppress HCC development and vascular invasion. Although LECT2 did not affect HCC cells growth in vitro, it still suppressed HCC xenografts growth in immune-deficient mice, suggesting other cells such as stroma cells may also be targeted by LECT2. Here, we sought to determine the role of LECT2 in tumor angiogenesis in HCC patients. We found that LECT2 expression inhibited tumor growth via angiogenesis in the HCC xenograft model. Specifically, we demonstrated that recombinant human LECT2 protein selectively suppressed vascular endothelial growth factor (VEGF)165-induced endothelial cell proliferation, migration, and tube formation in vitro and in vivo. Mechanistically, LECT2 reduced VEGF receptor 2 tyrosine phosphorylation and its downstream extracellular signal-regulated kinase and AKT phosphorylation. Furthermore, LECT2 gene expression correlated negatively with angiogenesis in HCC patients. Taken together, our findings demonstrate that LECT2 inhibits VEGF165 induced HCC angiogenesis through directly binding to VEGFR2 and has broad applications in treating VEGF-mediated solid tumors. PMID- 27507764 TI - HPA axis dysregulation, NR3C1 polymorphisms and glucocorticoid receptor isoforms imbalance in metabolic syndrome. AB - CONTEXT: Metabolic syndrome (MetS) shares several similarities with hypercortisolism. OBJECTIVES: To evaluate hypothalamic-pituitary-adrenal (HPA) axis sensitivity to dexamethasone (DEX), NR3C1 single nucleotide polymorphisms (SNPs), and expression of glucocorticoid receptor (GR) isoforms and cytokines in peripheral immune cells of MetS patients and controls. DESIGN: Prospective study with 40 MetS patients and 40 controls was conducted at the Ribeirao Preto Medical School University Hospital. METHODS: Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5, and 1 mg of DEX given at 2300 h. In addition, p.N363S (rs6195), p.ER22/23EK (rs6189-6190), and BclI (rs41423247) SNPs were evaluated by quantitative polymerase chain reaction allelic discrimination. Exons 3 to 9 and exon/intron boundaries of NR3C1 were sequenced. GR isoforms and cytokines (IL1B, IL2, IL4, IL6, IL8, IL10, IFNgamma, TNFalpha) expression were assessed by quantitative polymerase chain reaction. RESULTS: Plasma and salivary cortisol (nmol/L) after 1-mg DEX were higher in MetS patients compared with controls (PF: 70.2 +/- 17.3 vs 37.9 +/- 2.6, P = .02, and SF: 4.9 +/- 1.7 vs 2.2 +/- 0.3, P < .0001). After all DEX doses, a lower number of MetS patients suppressed plasma and salivary cortisol compared with controls. The BclI genotypic frequencies (%) differed between patients (CC:56/CG:44) and controls (CC:50/CG:32.5/GG:17.5) (P = .03). The GRbeta was overexpressed (fold = 100.0; P = .002) and IL4 (fold = -265.0; P < .0001) was underexpressed in MetS. CONCLUSION: MetS patients exhibited decreased HPA sensitivity to glucocorticoid feedback. Moreover, the BclI polymorphism lower frequency, GRbeta overexpression, and IL4 underexpression might underlie the molecular mechanism of glucocorticoid resistance in MetS. Thus, HPA axis dysregulation might contribute to MetS pathogenesis. PMID- 27507765 TI - Comparative transcriptome analysis reveals a global insight into molecular processes regulating citrate accumulation in sweet orange (Citrus sinensis). AB - Citrate, the predominant organic acid in citrus, determines the taste of these fruits. However, little is known about the synergic molecular processes regulating citrate accumulation. Using 'Dahongtiancheng' (Citrus sinensis) and 'Bingtangcheng' (C. sinensis) with significant difference in citrate, the objectives of this study were to understand the global mechanisms of high-citrate accumulation in sweet orange. 'Dahongtiancheng' and 'Bingtangcheng' exhibit significantly different patterns in citrate accumulation throughout fruit development, with the largest differences observed at 50-70 days after full bloom (DAFB). Comparative transcriptome profiling was performed for the endocarps of both cultivars at 50 and 70 DAFB. Over 34.5 million clean reads per library were successfully mapped to the reference database and 670-2630 differentially expressed genes (DEGs) were found in four libraries. Among the genes, five transcription factors were ascertained to be the candidates regulating citrate accumulation. Functional assignments of the DEGs indicated that photosynthesis, the citrate cycle and amino acid metabolism were significantly altered in 'Dahongtiancheng'. Physiological and molecular analyses suggested that high photosynthetic efficiency and partial impairment of citrate catabolism were crucial for the high-citrate trait, and amino acid biosynthesis was one of the important directions for citrate flux. The results reveal a global insight into the gene expression changes in a high-citrate compared with a low-citrate sweet orange. High accumulating efficiency and impaired degradation of citrate may be associated with the high-citrate trait of 'Dahongtiancheng'. Findings in this study increase understanding of the molecular processes regulating citrate accumulation in sweet orange. PMID- 27507766 TI - Melatonin abrogates nonylphenol-induced testicular dysfunction in Wistar rats. AB - Endocrine-disrupting chemicals present in the environment can bring about hormonal imbalance and be potentially harmful to the human health. Alkylphenols are omnipresent in the environment as they are constituents of several products. The aim of this study was to evaluate the effect of exogenous melatonin treatment on nonylphenol (NP)-induced oxidative stress and testicular toxicity in Wistar rats using biochemical and histopathological parameters. The oxidative stress biomarkers, activities of enzymatic and non-enzymatic antioxidants and histopathological evaluation were performed in testicular tissues. NP caused elevated TBARS levels and marked alteration of both nonenzymatic and enzymatic biomarkers. Furthermore, severe histopathological alterations were observed in the testis of NP-exposed animals as compared with that of the control rats. Melatonin supplementation ameliorated the alterations in these biochemical and histopathological variables in rats. In conclusion, our results demonstrated that melatonin through its antioxidant activity effectively protected against the NP induced testicular toxicity. PMID- 27507767 TI - Childhood-Diagnosed ADHD, Symptom Progression, and Reversal Learning in Adulthood. AB - OBJECTIVE: ADHD persists in up to 60% into adulthood, and the reasons for persistence are not fully understood. The objective of this study was to characterize the neurofunctional basis of decision making in those with a childhood diagnosis of ADHD with either persistent or remitted symptoms in adulthood versus healthy control participants. METHOD: Thirty-two adults diagnosed with ADHD as children were split into persistent ( n = 18) or remitted ( n = 14) ADHD groups. Their neural activity and neurofunctional connectivity during a probabilistic reversal learning task were compared with 32 healthy controls. RESULTS: Remitters showed significantly higher neural connectivity in final reversal error and probabilistic error conditions, and persisters depict higher neural connectivity in reversal errors than controls at a family-wise error (FWE) corrected whole-brain corrected threshold. CONCLUSION: Remitters may have utilized higher neural connectivity than controls to make successful decisions. Also, remitters may have utilized compensatory strategies to override any potential underlying ADHD deficits. PMID- 27507768 TI - Creating Virtual Integration and Improved Oncology Care Quality Through a Co Management Services Agreement. AB - PURPOSE: Implementation of a co-management services agreement (Co-MSA) creates agreed-upon cancer care delivery quality metrics, a forum for discussion of service line oversight, and virtually integrated care without institutional employment of oncologists. The goal of this project was to demonstrate that a Co MSA improved predefined quality metrics and provided enhanced communications between a health system's oncology service line and a group of independent oncologists. METHODS: Iterative planning discussions were scheduled biweekly over an 18-month period. Contractual, quality, and clinical data with benchmarking were considered in the creation of the Co-MSA. Review of the first year's implementation occurred through examination of the metric achievements and qualitative themes that arose through committee meetings, clinical implementation processes, and cross-organizational discussions. RESULTS: Metrics designed for the Co-MSA included improved adherence to the breast cancer, colon cancer, and non-small-cell lung cancer level I pathways; improvement of the medical oncology physician communication component of the hospital system's Hospital Consumer Assessment of Healthcare Providers and Systems survey scores; and increased delivery of survivorship care plans to appropriate patients. Nonquantifiable themes from the first year of implementation included the need for technology to collect data, both organizations needing a wider understanding of quality improvement techniques, and a need for greater executive leadership involvement. CONCLUSION: In its first year, the Co-MSA resulted in improvement of the delivery of survivorship care plans and adherence to value pathways powered by the National Comprehensive Cancer Network. Improvement of Hospital Consumer Assessment of Healthcare Providers and Systems scores did not occur. PMID- 27507769 TI - Population-Based Precision Cancer Screening: A Symposium on Evidence, Epidemiology, and Next Steps. AB - Precision medicine, an emerging approach for disease treatment that takes into account individual variability in genes, environment, and lifestyle, is under consideration for preventive interventions, including cancer screening. On September 29, 2015, the National Cancer Institute sponsored a symposium entitled "Precision Cancer Screening in the General Population: Evidence, Epidemiology, and Next Steps". The goal was two-fold: to share current information on the evidence, practices, and challenges surrounding precision screening for breast, cervical, colorectal, lung, and prostate cancers, and to allow for in-depth discussion among experts in relevant fields regarding how epidemiology and other population sciences can be used to generate evidence to inform precision screening strategies. Attendees concluded that the strength of evidence for efficacy and effectiveness of precision strategies varies by cancer site, that no one research strategy or methodology would be able or appropriate to address the many knowledge gaps in precision screening, and that issues surrounding implementation must be researched as well. Additional discussion needs to occur to identify the high priority research areas in precision cancer screening for pertinent organs and to gather the necessary evidence to determine whether further implementation of precision cancer screening strategies in the general population would be feasible and beneficial. Cancer Epidemiol Biomarkers Prev; 25(11); 1449-55. (c)2016 AACR. PMID- 27507770 TI - Use of Electronic Health Data to Estimate Heart Failure Events in a Population Based Cohort with CKD. AB - BACKGROUND AND OBJECTIVES: Studies that use electronic health data typically identify heart failure (HF) events from hospitalizations with a principal diagnosis of HF. This approach may underestimate the total burden of HF among persons with CKD. We assessed the accuracy of algorithms for identifying validated HF events from hospitalizations and outpatient encounters, and we used this validation information to estimate the rate of HF events in a large CKD population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We identified a cohort of 15,141 adults age 18-89 years with an eGFR<60 ml/min per 1.73 m2 from 2008 to 2011. Potential HF events during follow-up were randomly sampled for validation with medical record review. Positive predictive values from the validation study were used to estimate the rate of validated HF events in the full cohort. RESULTS: A total of 1864 participants had at least one health care encounter that qualified as a potential HF event during 2.7 years of mean follow-up. Among 313 potential events that were randomly sampled for validation, positive predictive values were 92% for hospitalizations with a principal diagnosis of HF, 32% for hospitalizations with a secondary diagnosis of HF, and 70% for qualifying outpatient HF encounters. Through use of this validation information in the full cohort, the rate of validated HF events estimated from the most comprehensive algorithm that included principal and secondary diagnosis hospitalizations and outpatient encounters was 35.2 events/1000 person-years (95% confidence interval, 33.1 to 37.4), compared with 9.5 events/1000 person-years (95% confidence interval, 8.7 to 10.5) from the algorithm that included only principal diagnosis hospitalizations. Outpatient encounters accounted for 20% of the total number of validated HF events. CONCLUSIONS: In studies that rely on electronic health data, algorithms that include hospitalizations with a secondary diagnosis of HF and outpatient HF encounters more fully capture the burden of HF, although validation of HF events may be necessary with this approach. PMID- 27507771 TI - A simple scoring system to assess the need for an endoscopic intervention in suspected upper gastrointestinal bleeding: A prospective cohort study. AB - BACKGROUND: Assessment of the emergent endoscopy for upper gastrointestinal bleeding (UGIB) patients has important clinical implications. There is no validated criterion to triage. AIMS: To develop a simple score predicting an endoscopic intervention. METHODS: A prospective cohort study was conducted at a tertiary care centre. Primary outcome was the high-risk stigmata which were well established endoscopic findings to determine the need for an endoscopic intervention. We created a simple score by multivariable logistic regression and compared with the Glasgow Blatchford Score (GBS). External validation was performed in a second cohort. RESULTS: 284 of consecutive 568 patients with suspected UGIB had the high-risk stigmata. Three variables were selected: "no daily use of proton pump inhibitors during one week before examination (+1 point)", "shock index (heart rate/systolic blood pressure)>=1 (+1 point)" and "urea/creatinine>=140 (blood urea nitrogen/creatinine>=30) (+1 point)". The accumulating score (range 0-3) achieved an area under the receiver-operating characteristic curve (AUC) of 0.74 (95% confidence interval [CI], 0.70-0.78), which was superior to the GBS (AUC, 0.63; 95% CI, 0.59-0.68; p<0.001). Validation in an external cohort demonstrated superiority to the GBS (AUC, 0.78 vs. 0.59; p<0.001). CONCLUSIONS: The simple score has greater accuracy than the GBS for assessing the need for an endoscopic intervention in cases of suspected UGIB. Further external validation should be performed to verify generalizability. PMID- 27507772 TI - Localization of glutamatergic, GABAergic, and cholinergic neurons in the brain of the African cichlid fish, Astatotilapia burtoni. AB - Neural communication depends on release and reception of different neurotransmitters within complex circuits that ultimately mediate basic biological functions. We mapped the distribution of glutamatergic, GABAergic, and cholinergic neurons in the brain of the African cichlid fish Astatotilapia burtoni using in situ hybridization to label vesicular glutamate transporters (vglut1, vglut2.1, vglut3), glutamate decarboxylases (gad1, gad2), and choline acetyltransferase (chat). Cells expressing the glutamatergic markers vgluts 1-3 show primarily nonoverlapping distribution patterns, with the most widespread expression observed for vglut2.1, and more restricted expression of vglut1 and vglut3. vglut1 is prominent in granular layers of the cerebellum, habenula, preglomerular nuclei, and several other diencephalic, mesencephalic, and rhombencephalic regions. vglut2.1 is widely expressed in many nuclei from the olfactory bulbs to the hindbrain, while vglut3 is restricted to the hypothalamus and hindbrain. GABAergic cells show largely overlapping gad1 and gad2 expression in most brain regions. GABAergic expression dominates nuclei of the subpallial ventral telencephalon, while glutamatergic expression dominates nuclei of the pallial dorsal telencephalon. chat-expressing cells are prominent in motor cranial nerve nuclei, and some scattered cells lie in the preoptic area and ventral part of the ventral telencephalon. A localization summary of these markers within regions of the conserved social decision-making network reveals a predominance of either GABAergic or glutamatergic cells within individual nuclei. The neurotransmitter distributions described here in the brain of a single fish species provide an important resource for identification of brain nuclei in other fishes, as well as future comparative studies on circuit organization and function. J. Comp. Neurol. 525:610-638, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27507773 TI - Application of compound mixture of caprylic acid, iron and mannan oligosaccharide against Sparicotyle chrysophrii (Monogenea: Polyopisthocotylea) in gilthead sea bream, Sparus aurata. AB - We have evaluated the therapeutic effect of a compound mixture of caprylic acid (200 mg/kg fish), organic iron (0.2% of diet) and mannan oligosaccharide (0.4% of diet) in gilthead sea bream, Sparus aurata Linnaeus, infected with Sparicotyle chrysophrii Beneden et Hesse, 1863 in controlled conditions. One hundred and ten reared and S. chrysophrii-free fish (197 g) located in a cement tank were infected by the parasite two weeks following the addition of 150 S. chrysophrii infected fish (70 g). Growth parameters and gill parasitic load were measured in treated against control fish after a ten-week-period. Differences in final weight, feed conversion ratio, specific growth rate and feed efficiency were not statistically significant between the experimental groups, suggesting no evident effect with respect to fish growth during the study period. Although the prevalence of S. chrysophrii was not affected by the mixture at the end of the experiment, the number of adults and larvae was significantly lower. The mean intensity encompassing the number of adults and larvae was 8.1 in treated vs 17.7 in control fish. Individual comparisons of gill arches showed that the preferred parasitism site for S. chrysophrii it the outermost or fourth gill arch, consistently apparent in fish fed the modified diet and in control fish. In conclusion, the combined application of caprylic acid, organic iron and mannan oligosaccharide can significantly affect the evolution of infection with S. chrysophrii in gilthead sea bream, being capable of reducing adult and larval stages of the monogenean. However, no difference in growth improvement was observed after the trial period, potentially leaving space for further optimisation of the added dietary compounds. PMID- 27507774 TI - The costs and benefits of brain dopamine for cognitive control. AB - Cognitive control helps us attain our goals by resisting distraction and temptations. Dopaminergic drugs are well known to enhance cognitive control. However, there is great variability in the effects of dopaminergic drugs across different contexts, with beneficial effects on some tasks but detrimental effects on other tasks. The mechanisms underlying this variability across cognitive task demands remain unclear. I aim to elucidate this across-task variability in dopaminergic drug efficacy by going beyond classic models that emphasize the importance of dopamine in the prefrontal cortex for cognitive control and working memory. To this end, I build on recent advances in cognitive neuroscience that highlight a role for dopamine in cost-benefit decision making. Specifically, I reconceptualize cognitive control as involving not just prefrontal dopamine but also modulation of cost-benefit decision making by striatal dopamine. This approach will help us understand why we sometimes fail to (choose to) exert cognitive control while also identifying mechanistic factors that predict dopaminergic drug effects on cognitive control. WIREs Cogn Sci 2016, 7:317-329. doi: 10.1002/wcs.1401 For further resources related to this article, please visit the WIREs website. PMID- 27507775 TI - The Clinical Significance of N-terminal Pro-brain Natriuretic Peptide in Detecting the Residual Cardiovascular Risk in Hypertension and Other Clinical Conditions and in Predicting Future Cardiovascular Events. PMID- 27507777 TI - Ternary dendritic nanowires as highly active and stable multifunctional electrocatalysts. AB - Multimetallic nanocatalysts with a controlled structure can provide enhanced catalytic activity and durability by exploiting electronic, geometric, and strain effects. Herein, we report the synthesis of a novel ternary nanocatalyst based on Mo doped PtNi dendritic nanowires (Mo-PtNi DNW) and its bifunctional application in the methanol oxidation reaction (MOR) at the anode and the oxygen reduction reaction (ORR) at the cathode for direct methanol fuel cells. An unprecedented Mo PtNi DNW structure can combine multiple structural attributes of the 1D nanowire morphology and dendritic surfaces. In the MOR, Mo-PtNi DNW exhibits superior activity to Pt/C and Mo doped Pt dendritic nanowires (Mo-Pt DNW), and excellent durability. Furthermore, Mo-PtNi DNW demonstrates excellent activity and durability for the ORR. This work highlights the important role of compositional and structural control in nanocatalysts for boosting catalytic performances. PMID- 27507776 TI - Sodium MRI in Multiple Sclerosis is Compatible with Intracellular Sodium Accumulation and Inflammation-Induced Hyper-Cellularity of Acute Brain Lesions. AB - The cascade of inflammatory pathogenetic mechanisms in multiple sclerosis (MS) has no specific conventional MRI correlates. Clinicians therefore stipulate improved imaging specificity to define the pathological substrates of MS in vivo including mapping of intracellular sodium accumulation. Based upon preclinical findings and results of previous sodium MRI studies in MS patients we hypothesized that the fluid-attenuated sodium signal differs between acute and chronic lesions. We acquired brain sodium and proton MRI data of N = 29 MS patients; lesion type was defined by the presence or absence of contrast enhancement. N = 302 MS brain lesions were detected, and generalized linear mixed models were applied to predict lesion type based on sodium signals; thereby controlling for varying numbers of lesions among patients and confounding variables such as age and medication. Hierarchical model comparisons revealed that both sodium signals average tissue (chi(2)(1) = 27.89, p < 0.001) and fluid attenuated (chi(2)(1) = 5.76, p = 0.016) improved lesion type classification. Sodium MRI signals were significantly elevated in acute compared to chronic lesions compatible with intracellular sodium accumulation in acute MS lesions. If confirmed in further studies, sodium MRI could serve as biomarker for diagnostic assessment of MS, and as readout parameter in clinical trials promoting attenuation of chronic inflammation. PMID- 27507778 TI - Vitamin C Prevents Sleep Deprivation-induced Elevation in Cortisol and Lipid Peroxidation in the Rat Plasma. AB - Sleep deprivation (SD) is biological stressor that alters metabolic parameters, induced oxidative stress and lipid peroxidation. Previous studies have shown that antioxidants substances such as melatonin, tryptophan, vitamin E and vitamin C improved stress tolerance in laboratory animals. In this study, we examined the potential protective effects of administration of vitamin C on acute and chronic sleep deprivation-induced metabolic derangement. In addition, possible processes involved in vitamin C effects on acute and chronic sleep deprivation-induced metabolic derangement were determined. Thirty-five rats (120-250g) were used. The rats were divided into 7 groups of 5 rats each as Control (CTRL), Acute sleep deprived untreated with vitamin C (AC), Acute sleep deprived treated with vitamin C (AWC), Chronic sleep deprived untreated with vitamin C (CC), Chronic sleep deprived treated with vitamin C (CWC), Chronic sleep deprived + Recovery untreated with vitamin C (RC), and Chronic sleep deprived + Recovery treated with vitamin C (RWC). The SD was carried out for 20h for 1 day on the acute groups, and for 20h/day for 5 days on the chronic group, using the Multiple Modified Platforms (MMP) after oral administration of 300mg/kg of vitamin C to all vitamin C-treated groups. The recovery groups were further observed for five days after SD. The control group were treated with vitamin C and without stress in their home cages. At the end of the experiment, the animals were sacrificed and blood was collected for estimation of plasma glucose, insulin, cortisol and malondialdehyde (MDA). The results showed that acute and chronic SDs significantly increased MDA and cortisol levels, while significantly reduced the levels of insulin. Treatment with vitamin C reversed the changes in the MDA, cortisol and plasma insulin levels. Additionally, allowing the rats to recover for 5 days after sleep deprivation corrected the observed changes. Plasma glucose was significantly reduced in all the sleep deprived groups compared to the control. In conclusion, sleep deprivation induced metabolic, hormonal and lipid peroxidation derangement, and treatment with vitamin C prevented these impairments. Thus, the effects of vitamin C could improve stress tolerance in rats. PMID- 27507779 TI - Honey Attenuates the Detrimental Effects of Nicotine on Testicular Functions in Nicotine Treated Wistar Rats. AB - Effect of honey on reproductive functions of male rats exposed to nicotine was examined in this study. Thirty-two adult male wistar rats (n=8/Group) were grouped as Control (distilled water), Nicotine (1.0mg/kg bwt), Honey (100mg/kg bwt) and Nicotine with Honey. The animals were orally treated for 35 days consecutively. Epididymis sperm motility, viability, morphology and counts were estimated, serum Follicle Stimulating Hormone (FSH), Leutinizing Hormone (LH) and Testosterone were assayed using ELISA method and testicular histology were also assessed. Significant reduction in percentage sperm motility, viability, morphology and counts were observed in nicotine group compared to control. Serum FSH, LH and testosterone levels were significantly reduced in nicotine group when compared with the control. There was significant improvement in sperm motility, viability, morphology, counts, FSH, LH and Testosterone in group co-treated with nicotine and honey relative to nicotine group. Also, the degenerative seminiferous tubule architecture due to nicotine was improved by honey. In conclusion, honey may suppress nicotine toxic effect on reproductive functions in male Wistar rats. PMID- 27507780 TI - Healing Potentials of Oral Moringa Oleifera Leaves Extract and Tetracycline on Methicillin Resistant Staphylococcus Aureus Infected Wounds of Wistar rats. AB - The effects of oral dose of aqueous extract of Moringa oleifera and tetracycline antibiotics on cutaneous wounds infected with Staphylococcus aureus were studied in eighteen adult wistar rats (159+/-31.5g) randomized into three groups: Group A, n = 6, Moringa oleifera-(300 mg/kg). Group B, n = 6, tetracycline (9.4 mg/kg) and Group C, n = 6, Sterile water (control). Six millimetres diameter nape wound, created on each rat under 2% xylazine (5 mg/kg) and 5% ketamine (35 mg/kg), was contaminated with Staphylococcus aureus (108 Colony Forming Unit (CFU). Following infection, treatment was commenced with daily oral dose of test preparations and the wounds were evaluated every other day i.e., day 3, 5, 7, 9, 11, 13 and 15 for wetness (wound exudation), wound edge oedema, hyperaemia, granulation tissues and contraction (diameter). Severe wound exudation existed in all the groups between days 0-3 (p = 1.00). A significantly less wound exudation was observed at days 3 5 (p = 0.000) and 5-9 (p = 0.003) (Control< Tetracycline Moringa> Tetracycline). Differences in wound diameter was not significant except at days 5-9 (p = 0.013) (Control> Moringa >Tetracycline). Oral doses of Moringa oleifera extract (300mg/kg) and tetracycline (9.4mg/kg) are not effective as antimicrobial or immune-boosting agents to enhance healing of wounds infected with Staphylococcus aureus and hence not recommended for rapid clearance of Staphylococcus aureus infected wounds. PMID- 27507781 TI - Genistein Precipitated Hypothyroidism, Altered Leptin and C-Reactive Protein Synthesis in Pregnant Rats. AB - Genistein is an isoflavone constituent of soya. This study examined the mechanism by which genistein produced adverse effects in pregnant laboratory rats. Pregnant rats were divided into control (Con) and genistein (Gen) force fed (2 mg/kg) groups. At terminal gestation day (GD) ranging from 0-20, the rats were sacrificed, and blood samples and amniotic fluids were collected. Thyroid hormone, C-reactive protein (CRP) and leptin assay was carried using the blood samples. Leptin was also assayed in the placenta and amniotic fluid supernatant. Oral exposure of pregnant rats to genistein significantly altered maternal T3, (GD18; Con 1.65 +/- 0.01, Gen 1.03 +/- 0.04 nmol/L), T4 (GD6; Con 29.60 +/- 0.00, Gen 36.04 +/- 1.29 nmol/L), Leptin (Placenta GD20; Con 0.08 +/- 0.01, Gen 0.31 +/ 0.02 ng/ml, amniotic fluid ;GD 20; Con 0.02 +/- 0.00, Gen 0.35 +/- 0.05 ng/ml) in genistein group. These changes were accompanied with loss of embryonic implants and a decrease in fetal and placental weights. The CRP level was significantly decreased and increased at the onset and toward late pregnancy respectively. Oral exposure of pregnant rats to genistein precipitated hypothyroidism, altered some metabolic hormones with a reduction in fetal and placental growth and increased resorption of embryonic implants. PMID- 27507782 TI - Effect of Ethanolic Leaf Extract of Senna Fistula on some Haematological Parameters, Lipid Profile and Oxidative Stress in Alloxan-induced Diabetic Rats. AB - Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus. The disease is also known to adversely affect some haematological parameters and cause dyslipidemia. This study was designed to investigate the effect of chronic administration of ethanolic leave extract of Senna fistula on haematological values, oxidative stress and dyslipidemia in experimental diabetic rats. Twenty-four albino rats weighing 120-150 g were divided into 4 experimental groups of six rats each; control, diabetic untreated, diabetic treated with glibenclamide and diabetic treated with 100 mg/kg b.w of Senna fistula. Diabetes was induced by 100 mg/kg b.w. of alloxan monohydrates. The control and diabetic groups received normal saline while the diabetic treated groups were administered with 5mg/kg and 100mg/kg body weight of glibenclamide and ethanolic leaves extract of Senna fistula respectively for 28 days. At the end of experimental period blood samples were taken from the animals for the determination of Red blood cells (RBC), packed cell volume (PCV), Haemoglobin concentration (Hb), total cholesterol, triglycerides (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and malondialdehyde (MDA), marker of lipid peroxidation. The result showed that in diabetic rats, PCV, RBC and Hb were decreased but the application of the extract increased the parameters. Similarly, the result showed a significant increase in total cholesterol, TG and LDL level of the diabetic group when compared with the control, glibenclamide and extract treated diabetic groups, however, there was no significant difference in HDL level in all the groups. The result also showed a significant decrease in elevated MDA of diabetic treated rats. These findings suggest that ethanolic leaves extract of Senna fistula might improve the diabetic induced disturbances of some haematological parameters, reduces the plasma lipid imbalances and decreases the production of free radicals associated with diabetes. PMID- 27507783 TI - An evidence-based system for health surveillance of occupational divers. AB - BACKGROUND: The value of the commonly required routine annual medical examination of occupational divers has been questioned, and there is a need for a robust, evidence-based system of health surveillance for this group of workers. AIMS: To determine whether the medical examination and investigation component of occupational divers' routine comprehensive health surveillance adds significantly to the information gained from the questionnaire component in determining fitness for diving. METHODS: An occupational diver database was interrogated to identify divers issued with a 'limited' medical clearance or considered 'unfit' for diving over a 5-year period. Reasons for the 'unfit' or 'limited' designation and the source of the critical information, whether the annual health questionnaire or the medical examination or questionnaire component (or both) of the initial or 5 yearly comprehensive medical evaluation, was recorded. For divers completing the 5-yearly repeat comprehensive medical evaluation, the sensitivity and specificity of the questionnaire alone for determining unfitness for diving was compared with that of a nominal 'gold standard'. RESULTS: Of 5178 certificates issued to 2187 divers over a 5-year period, 158 (3%) were provisionally designated as either 'limited' or 'unfit'. Of nine divers identified by the examination component of the 5-yearly comprehensive medical evaluation, four were eventually designated 'fit', two 'limited', and three were lost to follow up. None who had completed subsequent investigations remained 'unfit'. The sensitivity and specificity of the questionnaire to detect unfit divers compared with the gold standard were 84.6 and 99.3%, respectively, and its accuracy was 98.9%. CONCLUSION: The current New Zealand occupational diver medical certification process, comprising annual health questionnaires and 5-yearly full examinations, detects all health issues critical to the determination of fitness to dive. PMID- 27507784 TI - Activation of p38 Mitogen-Activated Protein Kinase by Clotrimazole Induces Multidrug Resistance-Associated Protein 3 Activation through a Novel Transcriptional Element. AB - Multidrug resistance-associated protein 3 (MRP3) is a basolaterally localized transporter in the liver and contributes to the transport of various metabolites such as conjugates of endogenous compounds and drugs from hepatocytes. MRP3 expression in the human liver is low under normal physiologic conditions but is induced by drug treatment. Although several studies have identified a region necessary for the basal transcription of MRP3, no region that responds to drugs has been reported. To identify the xenobiotic-responsive elements of MRP3, we constructed a luciferase reporter plasmid containing the MRP3 5'-flanking region up to -10 kb upstream from the transcription start site. Among typical nuclear receptor ligands, clotrimazole dramatically enhanced MRP3 reporter activity in HepG2 cells, whereas rifampicin had no effect. We then conducted MRP3 reporter assays with deletion or mutation constructs to identify a clotrimazole-responsive element. The element was located approximately -6.8 kb upstream from the MRP3 transcription start site. Overexpression of the pregnane X receptor did not enhance clotrimazole-mediated transcription. We found that clotrimazole was toxic to HepG2 cells and we therefore investigated whether mitogen-activated protein kinase (MAPK) activation is involved in the transactivation of MRP3 by clotrimazole. p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4 methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] suppressed MRP3 mRNA expression induced by clotrimazole, whereas c-Jun N-terminal kinase inhibitor SP600125 (1,9 pyrazoloanthrone) and extracellular signal-regulated kinase inhibitor PD98059 [2 (2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] did not. Phosphorylated p38 MAPK was detected in HepG2 cells treated with clotrimazole. These results suggest that activation of the p38 MAPK pathway induces the transcriptional activation of MRP3. PMID- 27507785 TI - Intercellular ultrafast Ca(2+) wave in vascular smooth muscle cells: numerical and experimental study. AB - Vascular smooth muscle cells exhibit intercellular Ca(2+) waves in response to local mechanical or KCl stimulation. Recently, a new type of intercellular Ca(2+) wave was observed in vitro in a linear arrangement of smooth muscle cells. The intercellular wave was denominated ultrafast Ca(2+) wave and it was suggested to be the result of the interplay between membrane potential and Ca(2+) dynamics which depended on influx of extracellular Ca(2+), cell membrane depolarization and its intercel- lular propagation. In the present study we measured experimentally the conduction velocity of the membrane depolarization and performed simulations of the ultrafast Ca(2+) wave along coupled smooth muscle cells. Numerical results reproduced a wide spectrum of experimental observations, including Ca(2+) wave velocity, electrotonic membrane depolarization along the network, effects of inhibitors and independence of the Ca(2+) wave speed on the intracellular stores. The numerical data also provided new physiological insights suggesting ranges of crucial model parameters that may be altered experimentally and that could significantly affect wave kinetics allowing the modulation of the wave characteristics experimentally. Numerical and experimental results supported the hypothesis that the propagation of membrane depolarization acts as an intercellular messenger mediating intercellular ultrafast Ca(2+) waves in smooth muscle cells. PMID- 27507787 TI - Allogeneic Mesenchymal Stem Cells Stimulate Cartilage Regeneration and Are Safe for Single-Stage Cartilage Repair in Humans upon Mixture with Recycled Autologous Chondrons. AB - Traditionally, mesenchymal stem cells (MSCs) isolated from adult bone marrow were described as being capable of differentiating to various lineages including cartilage. Despite increasing interest in these MSCs, concerns regarding their safety, in vivo behavior and clinical effectiveness have restrained their clinical application. We hypothesized that MSCs have trophic effects that stimulate recycled chondrons (chondrocytes with their native pericellular matrix) to regenerate cartilage. Searching for a proof of principle, this phase I (first in-man) clinical trial applied allogeneic MSCs mixed with either 10% or 20% recycled autologous cartilage-derived cells (chondrons) for treatment of cartilage defects in the knee in symptomatic cartilage defect patients. This unique first in man series demonstrated no treatment-related adverse events up to one year postoperatively. At 12 months, all patients showed statistically significant improvement in clinical outcome compared to baseline. Magnetic resonance imaging and second-look arthroscopies showed completely filled defects with regenerative cartilage tissue. Histological analysis on biopsies of the grafts indicated hyaline-like regeneration with a high concentration of proteoglycans and type II collagen. Short tandem repeat analysis showed the regenerative tissue only contained patient-own DNA. These findings support the novel insight that the use of allogeneic MSCs is safe and opens opportunities for other applications. Stem cell-induced paracrine mechanisms may play an important role in the chondrogenesis and successful tissue regeneration found. Stem Cells 2017;35:256-264. PMID- 27507788 TI - Psychometric Analysis of the Multidimensional State Boredom Scale and Its Condensed Versions. AB - The Multidimensional State Boredom Scale (MSBS) is a promising new self-report measure of state boredom. Two condensed versions of the scale have also been introduced. This study helped explore the psychometric qualities of these scales, using a large sample of Australian adults ( N = 1,716), as well as two smaller samples ( N = 199 and N = 422). Data analyses indicated strong convergent validity and very high internal consistency for the scales. Test-retest reliability over a 6- to 8-day period was moderately high. Confirmatory factor analyses of the MSBS authors' suggested factor structure indicated good fit for this model. However, some of the data analyses raise questions as to whether the scale includes meaningful subfactors. Overall, the MSBS (and Short Form) is recommended for researchers who wish to assess state boredom. PMID- 27507786 TI - Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome. AB - A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus - within the current protocols - the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression. PMID- 27507789 TI - Assessing Context-Specific Attributions During Couples' Conflict Interactions. AB - Two studies were conducted to develop and validate a six-item scale for measuring context-specific attributions regarding the extent to which people either blame or exonerate partners during couples' conflicts. Context-specific attributions pertain to appraisals made during a single episode of relationship conflict, and the scale was expected to be distinct from existing attribution scales measuring people's schemas regarding the types of attributions they typically make. Study 1 included 2,452 people in marriage or cohabitating relationships; Study 2 included 172 people in dating relationships, and participants in both studies completed Internet questionnaires. Item response theory was used to create an attribution scale using the fewest number of items to discriminate reliably across the full range of attribution levels. The resulting scale produced an expected pattern of convergent and divergent correlations with other context-specific measures, including two types of underlying concerns and three types of emotion. The context-specific attribution scale explained variance in these criterion variables that could not be explained by other existing scales that assess attributions at the schematic level. PMID- 27507790 TI - Proactive therapeutic drug monitoring of infliximab: a comparative study of a new point-of-care quantitative test with two established ELISA assays. AB - BACKGROUND: Therapeutic drug monitoring is a powerful strategy known to improve the clinical outcomes and to optimise the healthcare resources in the treatment of autoimmune diseases. Currently, most of the methods commercially available for the quantification of infliximab (IFX) are ELISA-based, with a turnaround time of approximately 8 h, and delaying the target dosage adjustment to the following infusion. AIM: To validate the first point-of-care IFX quantification device available in the market - the Quantum Blue Infliximab assay (Buhlmann, Schonenbuch, Switzerland) - by comparing it with two well-established methods. METHODS: The three methods were used to assay the IFX concentration of spiked samples and of the serum of 299 inflammatory bowel diseases (IBD) patients undergoing IFX therapy. RESULTS: The point-of-care assay had an average IFX recovery of 92%, being the most precise among the tested methods. The Intraclass Correlation Coefficients of the point-of-care IFX assay vs. the two ELISA-based established methods were 0.889 and 0.939. Moreover, the accuracy of the point-of care IFX compared with each of the two reference methods was 77% and 83%, and the kappa statistics revealed a substantial agreement (0.648 and 0.738). CONCLUSIONS: The Quantum Blue IFX assay can successfully replace the commonly used ELISA-based IFX quantification kits. This point-of-care IFX assay is able to deliver the results within 15 min makes it ideal for an immediate target concentration adjusted dosing. Moreover, it is a user-friendly desktop device that does not require specific laboratory facilities or highly specialised personnel. PMID- 27507792 TI - Efficient CRISPR-Mediated Post-Transcriptional Gene Silencing in a Hyperthermophilic Archaeon Using Multiplexed crRNA Expression. AB - CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-mediated RNA degradation is catalyzed by a type III system in the hyperthermophilic archaeon Sulfolobus solfataricus Earlier work demonstrated that the system can be engineered to target specifically mRNA of an endogenous host reporter gene, namely the beta-galactosidase in S. solfataricus Here, we investigated the effect of single and multiple spacers targeting the mRNA of a second reporter gene, alpha-amylase, at the same, and at different, locations respectively, using a minimal CRISPR (miniCR) locus supplied on a viral shuttle vector. The use of increasing numbers of spacers reduced mRNA levels at progressively higher levels, with three crRNAs (CRISPR RNAs) leading to ~ 70-80% reduction, and five spacers resulting in an alpha-amylase gene knockdown of > 90% measured on both mRNA and protein activity levels. Our results indicate that this technology can be used to increase or modulate gene knockdown for efficient post-transcriptional gene silencing in hyperthermophilic archaea, and potentially also in other organisms. PMID- 27507791 TI - Glucose or Altered Ceramide Biosynthesis Mediate Oxygen Deprivation Sensitivity Through Novel Pathways Revealed by Transcriptome Analysis in Caenorhabditis elegans. AB - Individuals with type 2 diabetes display metabolic abnormalities, such as hyperglycemia, increased free fatty acids, insulin resistance, and altered ceramide levels, that contribute to vascular dysfunctions and compromised oxygen delivery. Caenorhabditis elegans fed a glucose-supplemented diet or with altered ceramide metabolism, due to a hyl-2 mutation, are sensitive to oxygen deprivation (anoxia). Our experiments showed that the combination of these factors further decreased the anoxia survival. RNA-sequencing analysis was performed to assess how a glucose-supplemented diet and/or a hyl-2 mutation altered the transcriptome. Comparison analysis of transcripts associated with anoxia sensitive animals [hyl-2(tm2031) mutation or a glucose diet] revealed 199 common transcripts encoded by genes with known or predicted functions involving innate immunity, cuticle function (collagens), or xenobiotic and endobiotic phase I and II detoxification system. Use of RNA interference (RNAi) to target gene products of the xenobiotic and endobiotic phase I and II detoxification system (UDP glycosyltransferase and Cytochrome p450 genes; ugt-15, ugt-18, ugt-19, ugt-41, ugt-63, cyp-13A12, cyp-25A1, and cyp-33C8) increased anoxia survival in wild-type animals fed a standard diet. Anoxia sensitivity of the hyl-2(tm2031) animals was suppressed by RNAi of cyp-25A1 or cyp-33C8 genes. A glucose diet fed to the P0 hermaphrodite decreased the anoxia survival of its F1 embryos; however, the RNAi of ugt-63 and cyp-33C8 suppressed anoxia sensitivity. These studies provide evidence that the detoxification system impacts oxygen deprivation responses and that C. elegans can be used to model the conserved detoxification system. PMID- 27507793 TI - Response of the Pacific inter-tropical convergence zone to global cooling and initiation of Antarctic glaciation across the Eocene Oligocene Transition. AB - Approximately 34 million years ago across the Eocene-Oligocene transition (EOT), Earth's climate tipped from a largely unglaciated state into one that sustained large ice sheets on Antarctica. Antarctic glaciation is attributed to a threshold response to slow decline in atmospheric CO2 but our understanding of the feedback processes triggered and of climate change on the other contents is limited. Here we present new geochemical records of terrigenous dust accumulating on the sea floor across the EOT from a site in the central equatorial Pacific. We report a change in dust chemistry from an Asian affinity to a Central-South American provenance that occurs geologically synchronously with the initiation of stepwise global cooling, glaciation of Antarctica and aridification on the northern continents. We infer that the inter-tropical convergence zone of intense precipitation extended to our site during late Eocene, at least four degrees latitude further south than today, but that it migrated northwards in step with global cooling and initiation of Antarctic glaciation. Our findings point to an atmospheric teleconnection between extratropical cooling and rainfall climate in the tropics and the mid-latitude belt of the westerlies operating across the most pivotal transition in climate state of the Cenozoic Era. PMID- 27507794 TI - Efficacy of a footbath for post-partum fatigue in South Korea: A quasi experimental study. AB - AIM: The purpose of this study was to identify the effects of a footbath on post partum fatigue. METHODS: This study used a quasi-experimental design by using an unequivalent control group, pre-post-test design. The participants were divided into experimental and control groups. Fifty post-partum women who were admitted to an obstetrics and gynecology ward of a general hospital were the experimental group and 50 post-partum women who were admitted to an obstetrics and gynecology ward of a women's hospital were the control group. Two hospitals were providing similar postnatal care to their patients and they were located in the same city. The experimental group received a footbath along with postnatal care at the hospital, while the control group received only postnatal care from the hospital. Each group completed the Fatigue Continuum Form at a specified time. RESULTS: The general characteristics and pretest dependent variables were homogenous between the two groups. The hypothesis was supported post-test as the Fatigue Continuum Form scores differed significantly between the experimental and the control groups. CONCLUSION: This study showed that a footbath helps to decrease fatigue among post-partum women. In addition, it is a good preventative strategy for post partum women who should initiate it in the early post-partum period. PMID- 27507795 TI - A Case Indistinguishable Between Indeterminate Cell Histiocytosis and Cutaneous Rosai-Dorfman Disease. PMID- 27507796 TI - Prognostic significance of lymph node yield in ypN0 rectal cancer. AB - BACKGROUND: Neoadjuvant radiation therapy for locally advanced rectal adenocarcinoma decreases lymph node yield. This study investigated the association between survival and number of lymph nodes evaluated in patients with pathologically negative nodes after neoadjuvant therapy. METHODS: Patients with locally advanced rectal adenocarcinoma who underwent neoadjuvant therapy and had pathologically negative lymph nodes were included from the Surveillance, Epidemiology, and End Results (SEER) database over a 7-year interval (January 2004 to December 2010). Systematic dichotomization for optimal cut-off point identification was performed using statistical modelling. RESULTS: A total of 3995 patients met the inclusion criteria. The majority had T3 (66.7 per cent) and moderately differentiated (71.5 per cent) tumours. The median number of lymph nodes retrieved was 12 (i.q.r. 7-16). An optimal cut-off of nine lymph nodes was identified. Increasing age (P < 0.001), increasing T category (T4 versus T1, P < 0.001; T3 versus T1, P = 0.010), response to neoadjuvant therapy (P < 0.001) and number of nodes evaluated (P < 0.001) were significant factors for overall survival in univariable analysis. After adjustment in the multivariable model, the group with nine or more nodes examined had significantly better overall survival (hazard ratio (HR) 0.76, 95 per cent c.i. 0.65 to 0.88, P < 0.001; 5 year survival 83.2 versus 78.0 per cent) and cancer-specific survival (HR 0.76, 0.64 to 0.92, P = 0.004; 5-year survival 87.9 versus 85.1 per cent) than the group with one to eight nodes examined. CONCLUSION: Overall and cancer-specific survival were worse where fewer than nine lymph nodes were identified after neoadjuvant therapy for locally advanced rectal cancer. PMID- 27507797 TI - Terpene metabolic engineering via nuclear or chloroplast genomes profoundly and globally impacts off-target pathways through metabolite signalling. AB - The impact of metabolic engineering on nontarget pathways and outcomes of metabolic engineering from different genomes are poorly understood questions. Therefore, squalene biosynthesis genes FARNESYL DIPHOSPHATE SYNTHASE (FPS) and SQUALENE SYNTHASE (SQS) were engineered via the Nicotiana tabacum chloroplast (C), nuclear (N) or both (CN) genomes to promote squalene biosynthesis. SQS levels were ~4300-fold higher in C and CN lines than in N, but all accumulated ~150-fold higher squalene due to substrate or storage limitations. Abnormal leaf and flower phenotypes, including lower pollen production and reduced fertility, were observed regardless of the compartment or level of transgene expression. Substantial changes in metabolomes of all lines were observed: levels of 65-120 unrelated metabolites, including the toxic alkaloid nicotine, changed by as much as 32-fold. Profound effects of transgenesis on nontarget gene expression included changes in the abundance of 19 076 transcripts by up to 2000-fold in CN; 7784 transcripts by up to 1400-fold in N; and 5224 transcripts by as much as 2200 fold in C. Transporter-related transcripts were induced, and cell cycle associated transcripts were disproportionally repressed in all three lines. Transcriptome changes were validated by qRT-PCR. The mechanism underlying these large changes likely involves metabolite-mediated anterograde and/or retrograde signalling irrespective of the level of transgene expression or end product, due to imbalance of metabolic pools, offering new insight into both anticipated and unanticipated consequences of metabolic engineering. PMID- 27507798 TI - Erratum. PMID- 27507799 TI - Erratum. PMID- 27507800 TI - Effects of host genetics and environment on egg-associated microbiotas in brown trout (Salmo trutta). AB - Recent studies found fish egg-specific bacterial communities that changed over the course of embryogenesis, suggesting an interaction between the developing host and its microbiota. Indeed, single-strain infections demonstrated that the virulence of opportunistic bacteria is influenced by environmental factors and host immune genes. However, the interplay between a fish embryo host and its microbiota has not been studied yet at the community level. To test whether host genetics affects the assemblage of egg-associated bacteria, adult brown trout (Salmo trutta) were sampled from a natural population. Their gametes were used for full-factorial in vitro fertilizations to separate sire from dam effects. In total, 2520 embryos were singly raised under experimental conditions that differently support microbial growth. High-throughput 16S rRNA amplicon sequencing was applied to characterize bacterial communities on milt and fertilized eggs across treatments. Dam and sire identity influenced embryo mortality, time until hatching and composition of egg-associated microbiotas, but no link between bacterial communities on milt and on fertilized eggs could be found. Elevated resources increased embryo mortality and modified bacterial communities with a shift in their putative functional potential. Resource availability did not significantly affect any parental effects on embryo performance. Sire identity affected bacterial diversity that turned out to be a significant predictor of hatching time: embryos associated with high bacterial diversity hatched later. We conclude that both host genetics and the availability of resources define diversity and composition of egg-associated bacterial communities that then affect the life history of their hosts. PMID- 27507801 TI - The Role of Hox in Pisiform and Calcaneus Growth Plate Formation and the Nature of the Zeugopod/Autopod Boundary. AB - The mesopodium forms at the boundary between the zeugopod and autopod and is composed of short nodular bones that typically lack growth plates. Hoxa11 and Hoxa13 are expressed in mutually exclusive proximal-distal domains that demarcate the zeugopod/autopod boundary. Similarly, Hoxd genes are deployed in two distinct phases during limb development. The early phase corresponds to proximal segments including the zeugopod, and a late phase occurs in the digits. This arrangement produces a gap of low Hoxd expression that is traditionally viewed to correspond to the mesopodium. In contrast to the other mesopodials, the mammalian pisiform and calcaneus form true growth plates. We show that these bones, along with other proximal mesopodials, develop within the Hoxa11 and Hoxd11 expression domains. We also observe that the pisiform growth plate becomes disorganized with Hoxa11 or Hoxd11 loss of function, indicating a direct role for Hox11 in its development. Hoxa13 loss of function has minimal effect on the pisiform and proximal calcaneus as these bones still form secondary centers and undergo longitudinal growth. Consideration of the phenotypes resulting from hypodactyly (Hd) and synpolydactyly homolog (spdh) mutations, which result from altered HOXA13 and HOXD13 proteins, respectively, confirms that Hox13 plays a limited role in the development of the pisiform and calcaneus and suggests that they lie within the early phase of Hox expression. Therefore, with respect to patterns of ossification and gene expression, these bones share much more in common with the zeugopod than the autopod. Such an interpretation fits with the timing of autopod origins during tetrapod evolution. PMID- 27507802 TI - Testosterone-dependent sex differences in red blood cell hemolysis in storage, stress, and disease. AB - BACKGROUND: Red blood cell (RBC) hemolysis represents an intrinsic mechanism for human vascular disease. Intravascular hemolysis releases hemoglobin and other metabolites that inhibit nitric oxide signaling and drive oxidative and inflammatory stress. Although these pathways are important in disease pathogenesis, genetic and population modifiers of hemolysis, including sex, have not been established. STUDY DESIGN AND METHODS: We studied sex differences in storage or stress-induced hemolysis in RBC units from the United States and Canada in 22 inbred mouse strains and in patients with sickle cell disease (SCD) using measures of hemolysis in 315 patients who had homozygous SS hemoglobin from the Walk-PHASST cohort. A mouse model also was used to evaluate posttransfusion recovery of stored RBCs, and gonadectomy was used to determine the mechanisms related to sex hormones. RESULTS: An analysis of predisposition to hemolysis based on sex revealed that male RBCs consistently exhibit increased susceptibility to hemolysis compared with females in response to routine cold storage, under osmotic or oxidative stress, after transfusion in mice, and in patients with SCD. The sex difference is intrinsic to the RBC and is not mediated by plasmatic factors or female sex hormones. Importantly, orchiectomy in mice improves RBC storage stability and posttransfusion recovery, whereas testosterone repletion therapy exacerbates hemolytic response to osmotic or oxidative stress. CONCLUSION: Our findings suggest that testosterone increases susceptibility to hemolysis across human diseases, suggesting that male sex may modulate clinical outcomes in blood storage and SCD and establishing a role for donor genetic variables in the viability of stored RBCs and in human hemolytic diseases. PMID- 27507803 TI - Expanding the donor pool: regional variation in pediatric organ donation rates. AB - There are limited published data on pediatric organ donation rates. The aim of this study was to describe the trends in pediatric organ donation over time and to assess the regional variation in pediatric deceased organ donation. OPTN data were utilized to assess the trends in pediatric organ donation over time. The number of deceased pediatric organ donors was indexed using regional mortality data obtained from the National Center for Health Statistics and compared across UNOS regions and two different eras. The number of pediatric deceased organ donors has declined in the recent era, largely driven by fewer adolescent donors. For all age groups, there is significant regional variation in organ donation rates, with identifiable high- and low-performing regions. Expansion of the donor pool may be possible by optimizing organ donation in regions demonstrating lower recruitment of pediatric donors. Using the region with the highest donation rate for each age group as the gold standard, we estimate a potential 24% increase in the number of donors if all regions performed comparably, equating to 215 new pediatric donors annually. PMID- 27507804 TI - Reduced asthma susceptibility from early childhood exposure to residing in developing country. PMID- 27507806 TI - Spontaneous Lung Lesions in Aging Laboratory Rabbits ( Oryctolagus cuniculus). AB - Spontaneous age-related lesions of laboratory rabbits are not well documented in the contemporary scientific literature. A retrospective study of diagnostic necropsies of 36 rabbits >2 years of age found a number of common lung lesions. Fibromuscular intimal hyperplasia affected medium and to a lesser extent large pulmonary arteries and was present to a variable extent in all 36 rabbits >2 years of age. The lesions were characterized by fragmentation and/or reduplication of the internal elastic lamina (IEL), proliferation of smoothelin+/alpha-smooth muscle actin (alpha-SMA)+/vimentin- smooth muscle cells and fewer smoothelin-/alpha-SMA+/vimentin+ myofibroblasts, and intimal deposition of collagen without thrombosis, embolism, or evidence of pulmonary hypertension. Pulmonary emphysema, present in 30/36 rabbits, was characterized by the loss of alveolar septa; most affected rabbits did not have clinical signs of respiratory disease. In 8/13 rabbits of the inbred EIII/JC audiogenic strain, we identified a unique syndrome of granulomatous pneumonia containing hyaline brown to gray, globular to ring-like acellular material that was Alcian blue and periodic acid Schiff positive. The material was immunoreactive for surfactant protein-A and had the ultrastructural appearance of multilamellar vesicles, suggesting a genetic defect in surfactant metabolism. Additionally, we found small benign primary lung tumors (fibropapillomas, 5 rabbits) not previously described. Other findings included heterotopic bone (5 rabbits), subacute to chronic suppurative bronchopneumonia, pyogranulomatous pneumonia with plant material, and pulmonary artifacts from barbiturate euthanasia solution. PMID- 27507805 TI - Nomenclature for factors of the HLA system, update June 2016. PMID- 27507807 TI - Care-Seeking Behavior After Notification Among Young Women With Recurrent Sexually Transmitted Infections After Pelvic Inflammatory Disease. AB - Objective To determine the level of nurse case management and outreach required to notify young women with sexually transmitted infection (STI) positive test results after pelvic inflammatory disease (PID) and percent seeking treatment. METHODS: Participants (N = 153) were enrolled in a clinical trial of young women diagnosed with PID and followed for 3 months for recurrent STIs. Vaginal swabs were obtained at 1 and 3 months. All participants were notified of positive STIs at 1 and 3 months and treatment arranged. Data were analyzed with logistic regression for comparison of treatment status by number of nurse contacts. Results Over the 3-month period, 59 participants (38.6%) tested positive for one or more STIs and all received notification. Only 50% (19/38) of participants with STI at 1 month and 43% (16/37) at 3 months received treatment. Conclusions Despite the high notification rate of positive test results for young adults with recurrent STIs, many failed to seek treatment. PMID- 27507808 TI - Understanding the Use of Whole Milk and Flavored Powders in Children of Low Income, Immigrant Latina Mothers: A Descriptive Study. PMID- 27507809 TI - Pregnancy outcomes, reproductive history and cardiovascular disease risk in women: What do we know and what is needed? PMID- 27507810 TI - Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth. AB - EGF receptor (EGFR) in tumor cells serves as a tumor promoter. However, information about EGFR activation in macrophages in regulating M2 polarization and tumor development is limited. This study aimed to investigate the effects of EGFR activation in macrophages on M2 polarization and development of gastrointestinal tumors. IL-4, a cytokine to elicit M2 polarization, stimulated release of an EGFR ligand, HB-EGF, and transactivation and down-regulation of EGFR in Raw 264.7 cells and peritoneal macrophages from WT mice. Knockdown of HB EGF in macrophages inhibited EGFR transactivation by IL-4. IL-4-stimulated STAT6 activation, Arg1 and YM1 gene expression, and HB-EGF production were further enhanced by inhibition of EGFR activity in Raw 264.7 cells using an EGFR kinase inhibitor and in peritoneal macrophages from Egfr(wa5) mice with kinase inactive EGFR and by knockdown of EGFR in peritoneal macrophages from Egfr(fl/fl) LysM-Cre mice with myeloid cell-specific EGFR deletion. Chitin induced a higher level of M2 polarization in peritoneal macrophages in Egfr(fl/fl) LysM-Cre mice than that in Egfr(fl/fl) mice. Accordingly, IL-4-conditioned medium stimulated growth and epithelial-to-mesenchymal transition in gastric epithelial and colonic tumor cells, which were suppressed by that from Raw 264.7 cells with HB-EGF knockdown but promoted by that from Egfr(wa5) and Egfr(fl/fl) LysM-Cre peritoneal macrophages. Clinical assessment revealed that the number of macrophages with EGFR expression became less, indicating decreased inhibitory effects on M2 polarization, in late stage of human gastric cancers. Thus, IL-4-stimulated HB EGF-dependent transactivation of EGFR in macrophages may mediate inhibitory feedback for M2 polarization and HB-EGF production, thereby inhibiting gastrointestinal tumor growth. PMID- 27507811 TI - Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor kappaB (RANK) Signaling Complex Enhances Osteoclastogenesis. AB - The signaling pathway downstream of stimulation of receptor activator of nuclear factor kappaB (RANK) by RANK ligand is crucial for osteoclastogenesis. RANK recruits TNF receptor-associated factor 6 (TRAF6) to TRAF6-binding sites (T6BSs) in the RANK cytoplasmic tail (RANKcyto) to trigger downstream osteoclastogenic signaling cascades. RANKcyto harbors an additional highly conserved domain (HCR) that also activates crucial signaling during RANK-mediated osteoclastogenesis. However, the functional cross-talk between T6BSs and the HCR in the RANK signaling complex remains unclear. To characterize the cross-talk between T6BSs and the HCR, we screened TRAF6-interacting proteins using a proteomics approach. We identified Vav3 as a novel TRAF6 binding partner and evaluated the functional importance of the TRAF6-Vav3 interaction in the RANK signaling complex. We demonstrated that the coiled-coil domain of TRAF6 interacts directly with the Dbl homology domain of Vav3 to form the RANK signaling complex independent of the TRAF6 ubiquitination pathway. TRAF6 is recruited to the RANKcyto mutant, which lacks T6BSs, via the Vav3 interaction; conversely, Vav3 is recruited to the RANKcyto mutant, which lacks the IVVY motif, via the TRAF6 interaction. Finally, we determined that the TRAF6-Vav3 interaction resulting from cross-talk between T6BSs and the IVVY motif in RANKcyto enhances downstream NF-kappaB, MAPK, and NFATc1 activation by further strengthening TRAF6 signaling, thereby inducing RANK mediated osteoclastogenesis. Thus, Vav3 is a novel TRAF6 interaction partner that functions in the activation of cooperative signaling between T6BSs and the IVVY motif in the RANK signaling complex. PMID- 27507812 TI - Suppressor of Cytokine Signaling (SOCS)1 Regulates Interleukin-4 (IL-4)-activated Insulin Receptor Substrate (IRS)-2 Tyrosine Phosphorylation in Monocytes and Macrophages via the Proteasome. AB - Allergic asthma is a chronic lung disease initiated and driven by Th2 cytokines IL-4/-13. In macrophages, IL-4/-13 bind IL-4 receptors, which signal through insulin receptor substrate (IRS)-2, inducing M2 macrophage differentiation. M2 macrophages correlate with disease severity and poor lung function, although the mechanisms that regulate M2 polarization are not understood. Following IL-4 exposure, suppressor of cytokine signaling (SOCS)1 is highly induced in human monocytes. We found that siRNA knockdown of SOCS1 prolonged IRS-2 tyrosine phosphorylation and enhanced M2 differentiation, although siRNA knockdown of SOCS3 did not affect either. By co-immunoprecipitation, we found that SOCS1 complexes with IRS-2 at baseline, and this association increased after IL-4 stimulation. Because SOCS1 is an E3 ubiquitin ligase, we examined the effect of proteasome inhibitors on IL-4-induced IRS-2 phosphorylation. Proteasomal inhibition prolonged IRS-2 tyrosine phosphorylation, increased ubiquitination of IRS-2, and enhanced M2 gene expression. siRNA knockdown of SOCS1 inhibited ubiquitin accumulation on IRS-2, although siRNA knockdown of SOCS3 had no effect on ubiquitination of IRS-2. Monocytes from healthy and allergic individuals revealed that SOCS1 is induced by IL-4 in healthy monocytes but not allergic cells, whereas SOCS3 is highly induced in allergic monocytes. Healthy monocytes displayed greater ubiquitination of IRS-2 and lower M2 polarization than allergic monocytes in response to IL-4 stimulation. Here, we identify SOCS1 as a key negative regulator of IL-4-induced IRS-2 signaling and M2 differentiation. Our findings provide novel insight into how dysregulated expression of SOCS increases IL-4 responses in allergic monocytes, and this may represent a new therapeutic avenue for managing allergic disease. PMID- 27507813 TI - Leucine Carboxyl Methyltransferase 1 (LCMT-1) Methylates Protein Phosphatase 4 (PP4) and Protein Phosphatase 6 (PP6) and Differentially Regulates the Stable Formation of Different PP4 Holoenzymes. AB - The protein phosphatase 2A (PP2A) subfamily of phosphatases, PP2A, PP4, and PP6, are multifunctional serine/threonine protein phosphatases involved in many cellular processes. Carboxyl methylation of the PP2A catalytic subunit (PP2Ac) C terminal leucine is regulated by the opposing activities of leucine carboxyl methyltransferase 1 (LCMT-1) and protein phosphatase methylesterase 1 (PME-1) and regulates PP2A holoenzyme formation. The site of methylation on PP2Ac is conserved in the catalytic subunits of PP4 and PP6, and PP4 is also methylated on that site, but the identities of the methyltransferase enzyme for PP4 are not known. Whether PP6 is methylated is also not known. Here we use antibodies specific for the unmethylated phosphatases to show that PP6 is carboxyl methylated and that LCMT-1 is the major methyltransferase for PP2A, PP4, and PP6 in mouse embryonic fibroblasts (MEFs). Analysis of PP2A and PP4 complexes by blue native polyacrylamide gel electrophoresis (BN-PAGE) indicates that PP4 holoenzyme complexes, like those of PP2A, are differentially regulated by LCMT-1, with the PP4 regulatory subunit 1 (PP4R1)-containing PP4 complex being the most dramatically affected by the LCMT-1 loss. MEFs derived from LCMT-1 knock-out mouse embryos have reduced levels of PP2A B regulatory subunit and PP4R1 relative to control MEFs, indicating that LCMT-1 is important for maintaining normal levels of these subunits. Finally, LCMT-1 homozygous knock-out MEFs exhibited hyperphosphorylation of HDAC3, a reported target of the methylation-dependent PP4R1-PP4c complex. Collectively, our data suggest that LCMT-1 coordinately regulates the carboxyl methylation of PP2A-related phosphatases and, consequently, their holoenzyme assembly and function. PMID- 27507814 TI - Allostery Wiring Map for Kinesin Energy Transduction and Its Evolution. AB - How signals between the kinesin active and cytoskeletal binding sites are transmitted is an open question and an allosteric question. By extracting correlated evolutionary changes within 700+ sequences, we built a model of residues that are energetically coupled and that define molecular routes for signal transmission. Typically, these coupled residues are located at multiple distal sites and thus are predicted to form a complex, non-linear network that wires together different functional sites in the protein. Of note, our model connected the site for ATP hydrolysis with sites that ultimately utilize its free energy, such as the microtubule-binding site, drug-binding loop 5, and necklinker. To confirm the calculated energetic connectivity between non-adjacent residues, double-mutant cycle analysis was conducted with 22 kinesin mutants. There was a direct correlation between thermodynamic coupling in experiment and evolutionarily derived energetic coupling. We conclude that energy transduction is coordinated by multiple distal sites in the protein rather than only being relayed through adjacent residues. Moreover, this allosteric map forecasts how energetic orchestration gives rise to different nanomotor behaviors within the superfamily. PMID- 27507815 TI - Smoking history can influence the epigenetic and gene expression profile. PMID- 27507816 TI - Response to comments by Emma et al. PMID- 27507817 TI - Corrigendum. PMID- 27507818 TI - Role of the mobility of antigen binding site in high affinity antibody elucidated by surface plasmon resonance. AB - Antibody is known to exhibit conformational change in the antigen recognition site after forming the initial complex. This structural change, which is widely known as "induced fit", is believed to be critical for high affinity (Kd of nM range) of antigen-antibody interaction. Elucidation of this 'induced fit' process is essential for rational design of high affinity antibody, while it is prevented by limitation of the available biophysical and biochemical data of the initial complex. Here, we performed kinetic and thermodynamic analysis of the interaction between single-chain variable fragment (denoted as scFv) of 64M5 antibody and a (6-4) photoproduct by using surface plasmon resonance (denoted as SPR). It revealed that the 64M5scFv associates the (6-4) photoproduct at initial step by hydrophobic interactions, and enthalpy-driving interactions, hydrogen bonds and van der Waals interactions, were formed by second step structural rearrangement. Furthermore, mutational analysis revealed that the mobility of the antigen binding site is critical for the second step. It could be assumed that optimization of the mobility of the antigen recognition site is a clue for rational design of high affinity antibody. PMID- 27507819 TI - Derivation of a valid momentary first-order rate constant for kinetic and energetic analyses of enzymatic reactions. AB - To analyze enzymatic reactions energetically for comparison with non-enzymatic reactions (first order) under the same dimension, a method to derive valid momentary first-order rate constants for enzymatic reactions was developed. The momentary first-order rate constant, k enz0 = k cat[E'S']e,0/[S]0, was derived for an enzymatic reaction under a certain condition. It was shown that this rate constant is applicable for a wide range of enzymatic reactions. Utilizing this constant, one can conduct reliable kinetic and energetic analyses of enzymatic reactions. PMID- 27507820 TI - Substance Abuse and Addiction Among Ex-Service Personnel: Forces in Mind Trust Issues Call for Research Proposals. PMID- 27507821 TI - Trends in Alcohol Use among Adolescents from 2000 to 2011: The Role of Socioeconomic Status and Depression. AB - AIMS: To assess temporal trends of adolescent alcohol use in Finland from 2000 to 2011, according to socio-economic status and depression. METHODS: Classroom self administered questionnaires concerning health, health behaviours and school experiences were administered biennially from 2000-2001 to 2010-2011 to nationwide samples of 14- to 16-year-olds (n = 618,084). Alcohol use was measured as the frequencies of drinking and drunkenness. Socioeconomic status was measured using parental education and unemployment. Depression was measured using a Finnish modification of the Beck Depression Inventory. Cross-tabulations and a logistic regression analysis were applied. RESULTS: Over the study period, rates of frequent drinking and frequent drunkenness decreased among both boys and girls. Low levels of parental education and unemployment as well as adolescent depression increased the likelihoods of frequent drinking and drunkenness. Unlike the general decreasing trend observed for alcohol use, the likelihoods of frequent drinking and drunkenness increased among adolescents who were depressed and had unemployed parents with low levels of education. The prevalence of frequent drunkenness was 75.8% among the boys in this group during 2008-2011, whereas the corresponding prevalence was 2.3% for boys without depression and with highly educated, employed parents. The corresponding figures for girls were 41.7% and 1.4%, respectively. CONCLUSIONS: The overall decreasing trend in frequent alcohol use was not observed among socioeconomically deprived adolescents with depression. Thus, alcohol prevention programmes should treat these youth as special targets. PMID- 27507822 TI - Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis: Higher Dosages Are Required for Maximal Efficacy. AB - Each year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic (PK) and pharmacodynamic (PD) study in young children comparing dosing. Sixty Ugandan children aged 3 to 8 years old with egg patent Schistosoma mansoni received PZQ at either 40 mg/kg or 60 mg/kg. PK parameters of PZQ racemate and enantiomers (R and S) were quantified. PD outcomes were assessed by standard fecal egg counts and novel schistosome-specific serum (circulating anodic antigen [CAA]) and urine (circulating cathodic antigen [CCA]) antigen assays. Population PK and PD analyses were performed to estimate drug exposure in individual children, and the relationship between drug exposure and parasitological cure was estimated using logistic regression. Monte Carlo simulations were performed to identify better, future dosing regimens. There was marked PK variability between children, but the area under the concentration-time curve (AUC) of PZQ was strongly predictive of the parasitological cure rate (CR). Although no child achieved antigenic cure, which is suggestive of an important residual adult worm burden, higher AUC was associated with greater CAA antigenic decline at 24 days. To optimize the performance of PZQ, analysis of our simulations suggest that higher doses (>60 mg/kg) are needed, particularly in smaller children. IMPORTANCE: Schistosomiasis is a neglected tropical disease, typically associated with chronic morbidity, and its control is a global health priority. Praziquantel (PZQ) is the only available antiparasitic drug and is often given out, as a single oral dose (40 mg/kg), to school-aged children by mass drug administration (MDA) schemes operating within preventive chemotherapy campaigns as endorsed by the World Health Organization (WHO). This current strategy has several limitations. (i) It excludes preschool children who can be patently infected. (ii) It delivers PZQ at a dose directly extrapolated from adult pharmacological studies. To address these problems, we conducted the first pharmacokinetic and pharmacodynamic study of young children within an area of Uganda where Schistosoma mansoni is hyperendemic. Our results demonstrate that a higher dose (>60 mg/kg) is required, especially in smaller children, and draw attention to the need for further optimization of PZQ treatment based on schistosome antigenic assays, which are more sensitive to pharmacodynamic markers. PMID- 27507823 TI - A Diguanylate Cyclase Acts as a Cell Division Inhibitor in a Two-Step Response to Reductive and Envelope Stresses. AB - Cell division arrest is a universal checkpoint in response to environmental assaults that generate cellular stress. In bacteria, the cyclic di-GMP (c-di-GMP) signaling network is one of several signal transduction systems that regulate key processes in response to extra-/intracellular stimuli. Here, we find that the diguanylate cyclase YfiN acts as a bifunctional protein that produces c-di-GMP in response to reductive stress and then dynamically relocates to the division site to arrest cell division in response to envelope stress in Escherichia coli YfiN localizes to the Z ring by interacting with early division proteins and stalls cell division by preventing the initiation of septal peptidoglycan synthesis. These studies reveal a new role for a diguanylate cyclase in responding to environmental change, as well as a novel mechanism for arresting cell division. IMPORTANCE: While the major role of c-di-GMP signaling is to control the decision to move freely or settle in a biofilm, recent studies show a broader range of output functions for c-di-GMP signaling. This work reports an unexpected second role for YfiN, a conserved diguanylate cyclase in Gram-negative bacteria, known to contribute to persistence in the host. We find that YfiN acts as a cell division inhibitor in response to envelope stress. Unlike known cell division inhibitors, the interaction of YfiN with cell division proteins retains the Z ring at the midcell but prevents septal invagination. The new function of YfiN not only emphasizes the versatility of c-di-GMP signaling but describes a novel mechanism for a cell division checkpoint. PMID- 27507824 TI - ATP-Dependent C-F Bond Cleavage Allows the Complete Degradation of 4 Fluoroaromatics without Oxygen. AB - Complete biodegradation of the abundant and persistent fluoroaromatics requires enzymatic cleavage of an arylic C-F bond, probably the most stable single bond of a biodegradable organic molecule. While in aerobic microorganisms defluorination of fluoroaromatics is initiated by oxygenases, arylic C-F bond cleavage has never been observed in the absence of oxygen. Here, an oxygen-independent enzymatic aryl fluoride bond cleavage is described during the complete degradation of 4 fluorobenzoate or 4-fluorotoluene to CO2 and HF in the denitrifying Thauera aromatica: the ATP-dependent defluorination of 4-fluorobenzoyl-coenzyme A (4-F BzCoA) to benzoyl-coenzyme A (BzCoA) and HF, catalyzed by class I BzCoA reductase (BCR). Adaptation to growth with the fluoroaromatics was accomplished by the downregulation of a promiscuous benzoate-CoA ligase and the concomitant upregulation of 4-F-BzCoA-defluorinating/dearomatizing BCR on the transcriptional level. We propose an unprecedented mechanism for reductive arylic C-F bond cleavage via a Birch reduction-like mechanism resulting in a formal nucleophilic aromatic substitution. In the proposed anionic 4-fluorodienoyl-CoA transition state, fluoride elimination to BzCoA is favored over protonation to a fluorinated cyclic dienoyl-CoA. IMPORTANCE: Organofluorides are produced as pesticides, pharmaceuticals, and other chemicals and comprise approximately one quarter of all organic compounds in the pharmaceutical and agricultural sectors; they are considered a growing class of environmentally relevant persistent pollutants. Especially in the case of fluoroaromatics, biodegradation is hampered by the extreme stability of the arylic C-F bond. In aerobic microorganisms, degradation proceeds via oxygenase-dependent C-F bond cleavage reactions, whereas the enzymes involved in the degradation of fluoroaromatics at anoxic sites are unknown. Here we report a strategy for the complete biodegradation of a fluoroaromatic to CO2 and HF in a denitrifying bacterium via activation to a CoA ester, followed by oxygen-independent arylic C-F bond cleavage catalyzed by an ATP-dependent enzyme. This reaction, in conjunction with a transcriptional adaptation to fluorinated growth substrates, is essential for the anoxic biodegradation of 4 fluorobenzoate/4-F-toluene and probably other fluoroaromatics. PMID- 27507825 TI - Localization of the Houdinisome (Ejection Proteins) inside the Bacteriophage P22 Virion by Bubblegram Imaging. AB - The P22 capsid is a T=7 icosahedrally symmetric protein shell with a portal protein dodecamer at one 5-fold vertex. Extending outwards from that vertex is a short tail, and putatively extending inwards is a 15-nm-long alpha-helical barrel formed by the C-terminal domains of portal protein subunits. In addition to the densely packed genome, the capsid contains three "ejection proteins" (E-proteins [gp7, gp16, and gp20]) destined to exit from the tightly sealed capsid during the process of DNA delivery into target cells. We estimated their copy numbers by quantitative SDS-PAGE as approximately 12 molecules per virion of gp16 and gp7 and 30 copies of gp20. To localize them, we used bubblegram imaging, an adaptation of cryo-electron microscopy in which gaseous bubbles induced in proteins by prolonged irradiation are used to map the proteins' locations. We applied this technique to wild-type P22, a triple mutant lacking all three E proteins, and three mutants each lacking one E-protein. We conclude that all three E-proteins are loosely clustered around the portal axis, in the region displaced radially inwards from the portal crown. The bubblegram data imply that approximately half of the alpha-helical barrel seen in the portal crystal structure is disordered in the mature virion, and parts of the disordered region present binding sites for E-proteins. Thus positioned, the E-proteins are strategically placed to pass down the shortened barrel and through the portal ring and the tail, as they exit from the capsid during an infection. IMPORTANCE: While it has long been appreciated that capsids serve as delivery vehicles for viral genomes, there is now growing awareness that viruses also deliver proteins into their host cells. P22 has three such proteins (ejection proteins [E proteins]), whose initial locations in the virion have remained unknown despite their copious amounts (total of 2.5 MDa). This study succeeded in localizing them by the novel technique of bubblegram imaging. The P22 E-proteins are seen to be distributed around the orifice of the portal barrel. Interestingly, this barrel, 15 nm long in a crystal structure, is only about half as long in situ: the remaining, disordered, portion appears to present binding sites for E-proteins. These observations document a spectacular example of a regulatory order-disorder transition in a supramolecular system and demonstrate the potential of bubblegram imaging to map the components of other viruses as well as cellular complexes. PMID- 27507826 TI - Erratum for Fu et al., Ubiquitin-Like Proteasome System Represents a Eukaryotic Like Pathway for Targeted Proteolysis in Archaea. PMID- 27507827 TI - Glycomics for Microbes and Microbiologists. AB - The recent article "Lectin-Glycan Interaction Network-Based Identification of Host Receptors of Microbial Pathogenic Adhesins" by Ielasi et al. describes a new development in microbial carbohydrate analysis [Ielasi FS, Alioscha-Perez M, Donohue D, Claes S, Sahli H, Schols D, Willaert RG, mBio 7(4):e00584-16, 2016, http://dx.doi.org/10.1128/mbio.00584-16]. Specific carbohydrate ligands have been identified from the patterns of lectin binding to oligosaccharides printed on a chip. The new technique links the output to a comprehensive glycan database and offers a number of data visualization options. The graphs highlight the occurrence of potential ligands, organized by organism, tissue, and patterns of association with disease states. The analysis has successfully predicted novel glycoprotein ligands for microbial lectins, including an interaction of E. coli FimH with HIV gp120. PMID- 27507828 TI - The Cell Wall Polymer Lipoteichoic Acid Becomes Nonessential in Staphylococcus aureus Cells Lacking the ClpX Chaperone. AB - Lipoteichoic acid (LTA) is an important cell wall component of Gram-positive bacteria and a promising target for the development of vaccines and antimicrobial compounds against Staphylococcus aureus Here we demonstrate that mutations in the conditionally essential ltaS (LTA synthase) gene arise spontaneously in an S. aureus mutant lacking the ClpX chaperone. A wide variety of ltaS mutations were selected, and among these, a substantial portion resulted in premature stop codons and other changes predicted to abolish LtaS synthesis. Consistent with this assumption, the clpX ltaS double mutants did not produce LTA, and genetic analyses confirmed that LTA becomes nonessential in the absence of the ClpX chaperone. In fact, inactivation of ltaS alleviated the severe growth defect conferred by the clpX deletion. Microscopic analyses showed that the absence of ClpX partly alleviates the septum placement defects of an LTA-depleted strain, while other phenotypes typical of LTA-negative S. aureus mutants, including increased cell size and decreased autolytic activity, are retained. In conclusion, our results indicate that LTA has an essential role in septum placement that can be bypassed by inactivating the ClpX chaperone. IMPORTANCE: Lipoteichoic acid is an essential component of the Staphylococcus aureus cell envelope and an attractive target for the development of vaccines and antimicrobials directed against antibiotic-resistant Gram-positive bacteria such as methicillin-resistant S. aureus and vancomycin-resistant enterococci. In this study, we showed that the lipoteichoic acid polymer is essential for growth of S. aureus only as long as the ClpX chaperone is present in the cell. Our results indicate that lipoteichoic acid and ClpX play opposite roles in a pathway that controls two key cell division processes in S. aureus, namely, septum formation and autolytic activity. The discovery of a novel functional connection in the genetic network that controls cell division in S. aureus may expand the repertoire of possible strategies to identify compounds or compound combinations that kill antibiotic-resistant S. aureus. PMID- 27507829 TI - Host Physiologic Changes Induced by Influenza A Virus Lead to Staphylococcus aureus Biofilm Dispersion and Transition from Asymptomatic Colonization to Invasive Disease. AB - Staphylococcus aureus is a ubiquitous opportunistic human pathogen and a major health concern worldwide, causing a wide variety of diseases from mild skin infections to systemic disease. S. aureus is a major source of severe secondary bacterial pneumonia after influenza A virus infection, which causes widespread morbidity and mortality. While the phenomenon of secondary bacterial pneumonia is well established, the mechanisms behind the transition from asymptomatic colonization to invasive staphylococcal disease following viral infection remains unknown. In this report, we have shown that S. aureus biofilms, grown on an upper respiratory epithelial substratum, disperse in response to host physiologic changes related to viral infection, such as febrile range temperatures, exogenous ATP, norepinephrine, and increased glucose. Mice that were colonized with S. aureus and subsequently exposed to these physiologic stimuli or influenza A virus coinfection developed pronounced pneumonia. This study provides novel insight into the transition from colonization to invasive disease, providing a better understanding of the events involved in the pathogenesis of secondary staphylococcal pneumonia. IMPORTANCE: In this study, we have determined that host physiologic changes related to influenza A virus infection causes S. aureus to disperse from a biofilm state. Additionally, we report that these same host physiologic changes promote S. aureus dissemination from the nasal tissue to the lungs in an animal model. Furthermore, this study identifies important aspects involved in the transition of S. aureus from asymptomatic colonization to pneumonia. PMID- 27507830 TI - Salmonella Rapidly Regulates Membrane Permeability To Survive Oxidative Stress. AB - The outer membrane (OM) of Gram-negative bacteria provides protection against toxic molecules, including reactive oxygen species (ROS). Decreased OM permeability can promote bacterial survival under harsh circumstances and protects against antibiotics. To better understand the regulation of OM permeability, we studied the real-time influx of hydrogen peroxide in Salmonella bacteria and discovered two novel mechanisms by which they rapidly control OM permeability. We found that pores in two major OM proteins, OmpA and OmpC, could be rapidly opened or closed when oxidative stress is encountered and that the underlying mechanisms rely on the formation of disulfide bonds in the periplasmic domain of OmpA and TrxA, respectively. Additionally, we found that a Salmonella mutant showing increased OM permeability was killed more effectively by treatment with antibiotics. Together, these results demonstrate that Gram-negative bacteria regulate the influx of ROS for defense against oxidative stress and reveal novel targets that can be therapeutically targeted to increase bacterial killing by conventional antibiotics. IMPORTANCE: Pathogenic bacteria have evolved ways to circumvent inflammatory immune responses. A decrease in bacterial outer membrane permeability during infection helps protect bacteria from toxic molecules produced by the host immune system and allows for effective colonization of the host. In this report, we reveal molecular mechanisms that rapidly alter outer membrane pores and their permeability in response to hydrogen peroxide and oxidative stress. These mechanisms are the first examples of pores that are rapidly opened or closed in response to reactive oxygen species. Moreover, one of these mechanisms can be targeted to artificially increase membrane permeability and thereby increase bacterial killing by the antibiotic cefotaxime during in vitro experiments and in a mouse model of infection. We envision that a better understanding of the regulation of membrane permeability will lead to new targets and treatment options for multidrug-resistant infections. PMID- 27507831 TI - Tidal volume during mouthpiece non-invasive home ventilation: When the choice is the right answer. PMID- 27507832 TI - Antibiotic therapy for stable non-CF bronchiectasis in adults - A systematic review. AB - To provide an update on efficacy and safety of antibiotic treatments for stable non-cystic fibrosis (CF) bronchiectasis (BE). Systematic review based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines was done. Twenty-six studies (1.898 patients) fulfilled the inclusion criteria. Studies of inhaled tobramycin have revealed conflicting results regarding quality of life (QoL), exacerbations and admissions, but may result in sputum cultures negative for Pseudomonas aeruginosa, whereas studies investigating the effect of inhaled gentamycin have shown positive effects on sputum bacterial density, decrease in sputum cultures positive for P. aeruginosa, QoL and exacerbation rate, but no improvement in forced expiratory volume in first second (FEV1). Oral azithromycin can reduce exacerbations, together with minor improvements in QoL and FEV1. Furthermore, oral erythromycin reduces exacerbations, but has no effect on lung function, symptoms or QoL. Inhaled ciprofloxacin may reduce P. aeruginosa in sputum cultures, but without changes in lung function, exacerbations or QoL. Although with limited evidence, inhaled colistin may have effects on P. aeruginosa density, exacerbations and QoL, whereas studies on aztreonam revealed no significant clinical improvements in the outcomes of interest, including exacerbation rate. Adverse events, including bronchospasm, have been reported in association with tobramycin and aztreonam. Several antibiotic treatment regimens have been shown to improve QoL and exacerbation rate, whereas findings regarding sputum production, lung function and admissions have been conflicting. Evidence based treatment algorithms for antibiotic treatment of stable non-CF BE will have to await large-scale, long-term controlled studies. PMID- 27507833 TI - Managing fatigue in sarcoidosis - A systematic review of the evidence. AB - Fatigue is a common manifestation of sarcoidosis, often persisting without evidence of disease activity. First-line therapies for sarcoidosis have limited effect on fatigue. This review aimed to assess the treatment options targeting sarcoidosis-associated fatigue. Medline and Web of Science were searched in November 2015; the bibliographies of these papers, and relevant review papers, were also searched. Studies were included if they reported on the efficacy of interventions (both pharmacological and non-pharmacological) on fatigue scores in sarcoidosis patients. Eight studies were identified that fulfilled the inclusion criteria. These studies evaluated six different interventions (infliximab, adalimumab, ARA 290, methylphenidate, armodafinil and exercise programmes). There is evidence to support a treatment effect of anti-tumour necrosis factor (TNF) alphatherapies (adalimumab and infliximab) and neurostimulants (methylphenidate and armodafinil), but within five of the studies, the risk of bias was high within most domains and the remaining three studies included only small numbers of participants and were short in duration. Trial evidence for treating fatigue as a manifestation of sarcoidosis is limited and requires further investigation. Anti-TNF-alpha therapies may be beneficial in patients with organ-threatening disease. Neurostimulants have some trial evidence supporting improvements in fatigue but further investigation is needed before they can be recommended. PMID- 27507834 TI - Mouthpiece ventilation: Individualized patient care is the key to success. PMID- 27507835 TI - Does the COPD assessment test reflect functional status in patients with COPD? AB - The aim of this study was to investigate whether the chronic obstructive pulmonary disease (COPD) assessment test (CAT) reflects the functional status of patients with COPD. Forty-seven patients underwent anthropometric assessment, spirometry, the 6-minute walk test (6MWT), the Glittre-activity of daily living (ADL) test (TGlittre), the London Chest ADL (LCADL) scale, and the CAT. The total score of the CAT correlated with 6MWT distance, TGlittre time spent, and LCADL%total ( r = -0.56, 0.52, and 0.78, respectively; p < 0.05 for all). There was significant difference in 6MWT distance (490 +/- 85.4 m vs. 387 +/- 56.8 m), TGlittre time spent (3.67 +/- 1.07 min vs. 5.03 +/- 1.32 min), and LCADL%total (24.2 +/- 3.02% vs. 44.4 +/- 13.3%) between the low and high impacts of COPD on health status (respectively, p < 0.05 for all) as well as in the LCADL%total between medium and high impact of COPD on health status (31.3 +/- 7.35% vs. 44.4 +/- 13.3%; p = 0.001). In conclusion, the CAT reflects the functional status of patients with COPD. PMID- 27507836 TI - Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer's and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies. AB - alpha-Synuclein (alphaSyn) is a major constituent of proteinaceous aggregates in neurodegenerative diseases such as Parkinson's disease (PD) and a potential biomarker candidate for diagnosis and treatment effects. However, studies about alphaSyn in cerebrospinal fluid (CSF) in diseases are inconsistent and mainly based on immunological assays. Quantitative information about beta-synuclein (betaSyn) and gamma-synuclein (gammaSyn) in CSF is not available.Here, we present an alternative method for the simultaneous quantification of alphaSyn, betaSyn and gammaSyn in CSF by multiple reaction monitoring (MRM) with a high sequence coverage (70%) of alphaSyn to validate previous, ELISA-based results and characterize synucleins in CSF in more detail.The MRM has high sensitivity in the low pg/ml range (3-30pg/ml full-length alphaSyn) using 200 MUl CSF. A high portion of CSF alphaSyn is present in the N-terminally acetylated form and the concentration of unmodified peptides in the nonamyloid component region is about 40% lower than in the N-terminal region. Synuclein concentrations show a high correlation with each other in CSF (r>0.80) and in contrast to alphaSyn and gammaSyn, betaSyn is not affected by blood contamination. CSF alphaSyn, betaSyn and gammaSyn concentrations were increased in Alzheimer's and Creutzfeldt-Jakob disease but not altered in PD, PD dementia (PDD), Lewy body dementia and atypical parkinsonian syndromes. The ratio betaSyn/alphaSyn was increased in PDD (1.49 +/- 0.38, p < 0.05) compared with PD (1.11 +/- 0.26) and controls (1.15 +/- 0.28). betaSyn shows a high correlation with CSF tau concentrations (r = 0.86, p < 0.0001, n = 125).In conclusion, we could not confirm previous observations of reduced alphaSyn in PD and our results indicate that CSF synuclein concentrations are rather general markers of synaptic degeneration than specific for synucleinopathies. betasyn is an attractive biomarker candidate that might be used as an alternative to or in combination with tau in AD and CJD diagnosis and in combination with alphaSyn it is a biomarker candidate for PDD. PMID- 27507838 TI - Niche divergence between diploid and autotetraploid Tolmiea. AB - PREMISE OF STUDY: Polyploidy is common in eukaryotes and is of major evolutionary importance over both short and long time-scales. Compared to allopolyploids, autopolyploids remain understudied; they are often morphologically cryptic and frequently remain taxonomically unrecognized, although there is increasing recognition of the high frequency of autopolyploidy in angiosperms. While autopolyploidy can serve as an instant speciation mechanism, little is known about the ecological consequences of this process. We describe the ecological divergence of a diploid-autotetraploid species pair in Tolmiea. METHODS: We investigated whether abiotic niche divergence has shaped the current allopatric distribution of diploid T. diplomenziesii and its autotetraploid derivative, T. menziesii, in the Pacific Northwest of North America. We employed field measures of light availability, as well as niche modeling and a principal component analysis of environmental space. Within a common garden, we also investigated physiological responses to changes in soil moisture. KEY RESULTS: Diploid and autotetraploid Tolmiea inhabit significantly different climatic niche spaces. The climatic niche divergence between these two species is best explained by a shift in precipitation availability, and we found evidence of differing physiological response to water availability between these species. CONCLUSIONS: We found that spatial segregation of T. diplomenziesii and T. menziesii was accompanied by adaptation to changes in climatic regime. Tolmiea menziesii is not a nascent autotetraploid, having persisted long enough to be established throughout the Pacific Northwest, and therefore both polyploidization and subsequent evolution have contributed to the observed differences between T. menziesii and T. diplomenziesii. PMID- 27507839 TI - Bet-hedging against larval herbivory and seed bank mortality in the evolution of heterocarpy. AB - PREMISE OF THE STUDY: Bet-hedging strategies maximize long-term geometric fitness at the cost of reduced arithmetic fitness by offsetting different mortality risks. Heterocarpic systems accomplish bet-hedging through the production of two or more fruit types that vary in dormancy and dispersal ability. It is unknown whether heterocarpy also offsets predispersal mortality risks. To address this question, we investigated whether heterocarpy in Grindelia ciliata (Asteraceae) also offsets mortality risks posed by a seed predator Schinia mortua (Noctuidae) to increase plant fitness. METHODS: We conducted two manipulative experiments to quantify critical life history components of this plant-insect interaction. We measured predispersal achene mortality from herbivory, postdispersal achene mortality in the seed bank, and seedling emergence. These measurements were then used in deterministic models to evaluate evolutionary consequences of predispersal seed mortality in G. ciliata. KEY RESULTS: Dormant achene types were less vulnerable to herbivory but more susceptible to mortality in the seed bank due to delayed seed emergence. Nondormant achene types experienced high predispersal mortality but low seed bank mortality due to rapid germination. Our herbivore-dependent model improved fit between observed and expected proportions of dormant and nondormant G. ciliata achenes and showed that heterocarpy could evolve in the absence of postgermination mortality. CONCLUSIONS: Our study provides empirical support of how predispersal herbivory can be equally important to postdispersal seed mortality risks in the evolution and maintenance of a heterocarpic reproductive system and expands understanding of how bet-hedging theory can be used to understand this unique reproductive strategy. PMID- 27507840 TI - Life History of the Oldest Lentivirus: Characterization of ELVgv Integrations in the Dermopteran Genome. AB - Endogenous retroviruses are genomic elements formed by germline infiltration by originally exogenous viruses. These molecular fossils provide valuable information about the evolution of the retroviral family. Lentiviruses are an extensively studied genus of retroviruses infecting a broad range of mammals. Despite a wealth of information on their modern evolution, little is known about their origins. This is partially due to the scarcity of their endogenous forms. Recently, an endogenous lentivirus, ELVgv, was discovered in the genome of the Malayan colugo (order Dermoptera). This represents the oldest lentiviral evidence available and promises to lead to further insights into the history of this genus. In this study, we analyzed ELVgv integrations at several genomic locations in four distinct colugo specimens covering all the extant dermopteran species. We confirmed ELVgv integrations in all the specimens examined, which implies that the virus originated before the dermopteran diversification. Using a locus specific dermopteran substitution rate, we estimated that the proviral integrations occurred 21-40 Ma. Using phylogenetic analysis, we estimated that ELVgv invaded an ancestor of today's Dermoptera in an even more distant past. We also provide evidence of selective pressure on the TRIM5 antiviral restriction factor, something usually taken as indirect evidence of past retroviral infections. Interestingly, we show that TRIM5 was under strong positive selection pressure only in the common dermopteran ancestor, where the ELVgv endogenization occurred. Further experiments are required to determine whether ELVgv participated in the TRIM5 selection. PMID- 27507841 TI - The Telltale Heart of Chordate Evolution: New Study Shows Model Organism Making Do with Less. PMID- 27507842 TI - Use of cefovecin in a UK population of cats attending first-opinion practices as recorded in electronic health records. AB - Objectives The objective was to use electronic health records to describe the use of cefovecin (Convenia; Zoetis UK), a third-generation long-acting injectable antimicrobial, in a UK population of cats attending first-opinion practices, and to compare the use of Convenia with the licensed uses described on the UK Convenia datasheet. Methods Data were obtained as an Excel database from the Small Animal Veterinary Surveillance Network for all feline consultations containing the word Convenia and/or cefovecin from 1 September 2012 to 23 September 2013 inclusive. Entries were classified according to body system treated, confirmation or suspicion of an abscess, evidence of microbiological evaluation being performed, any concurrent therapies given and whether any reason was given for use of Convenia over alternative antimicrobials. Data were exported to IBM SPSS Statistics and descriptive analysis performed. Results In total, 1148 entries were analysed. The most common body system treated was skin in 553 (48.2%) entries, then urinary (n = 157; 13.7%) and respiratory (n = 112; 9.8%). Microbiological evaluation was recorded in 193 (16.8%) entries, with visible purulent material most commonly cited (in 147 [12.8%] entries). A reason for prescribing Convenia over alternative antimicrobials was given in 138 (12.0%) entries; the most cited was an inability to orally medicate the cat in 77 (55.8%) of these entries. Excluding 131 entries where no body system or multiple body systems were described, the use of Convenia complied with a licensed use in the UK datasheet in 710 (69.8%) of 1017 entries. Conclusions and relevance Most administrations were licensed uses; however, most entries did not describe any microbiological evaluation, or a reason for prescribing Convenia over alternative antimicrobials. Further education of the public and the veterinary profession is needed to promote antimicrobial stewardship in the UK. Health records provide a valuable tool with which to monitor, both locally and at scale, the use of important therapeutics like antimicrobials. Information relevant to decision making should be recorded in individual animal health records. PMID- 27507843 TI - The Influence of Meniscal and Anterolateral Capsular Injury on Knee Laxity in Patients With Anterior Cruciate Ligament Injuries. AB - BACKGROUND: The role of the anterolateral capsule (ALC) as a secondary restraint to quantitative rotatory laxity of patients with an anterior cruciate ligament (ACL) injury is currently debated. PURPOSE/HYPOTHESIS: The purpose was to determine the influence of concomitant ALC injuries as well as injuries to other soft tissue structures on rotatory knee laxity in patients with an ACL injury. It was hypothesized that a concomitant ALC injury would be associated with increased rotatory knee laxity as measured during a quantitative pivot-shift test. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Forty-one patients with an ACL injury (average age, 23 +/- 6.9 years) were enrolled. Two blinded musculoskeletal radiologists reviewed magnetic resonance imaging (MRI) scans for the presence of ACL injuries and concomitant soft tissue injuries including the ALC, medial collateral ligament, lateral collateral ligament, posterolateral corner, medial meniscus, and lateral meniscus. A standardized pivot-shift test was performed under anesthesia, and rotatory laxity was quantified according to anterior translation of the lateral tibial compartment during the pivot-shift maneuver. The Student t test was used to analyze the data. Statistical significance was set at P < .05. RESULTS: A complete ACL rupture was confirmed in all of the patients. MRI evidence of an ALC injury was observed in 21 (51%) of the patients. Patients with MRI evidence of an ALC injury had significantly higher rotatory knee laxity (3.6 +/- 1.5 mm) compared with those without an ALC injury (2.7 +/- 1.5 mm; P = .04). Lateral and medial meniscus injuries were detected in 17 (41%) and 19 (46%) patients, respectively. Patients with MRI evidence of either a medial meniscus injury or lateral meniscus injury had significantly higher rotatory knee laxity compared with patients without these injuries (medial meniscus: 3.7 +/- 1.4 mm vs 2.7 +/- 1.6 mm, respectively; lateral meniscus: 3.7 +/- 1.7 mm vs 2.7 +/- 1.3 mm, respectively) (P = .03 for both). CONCLUSION: MRI evidence of a concomitant injury to the ALC, medial meniscus, or lateral meniscus is associated with increased knee rotatory laxity in patients with an ACL injury. These structures may function as important secondary stabilizers in an ACL-injured knee. Careful assessment and proper treatment of injuries to these secondary stabilizers should be considered, especially in knees with a high level of the pivot shift. PMID- 27507844 TI - Clinical and Ultrasonographic Evaluations of the Shoulders of Elite Swimmers. AB - BACKGROUND: Shoulder pain is a common problem in competitive swimmers, but the structural alterations in elite-level competitive swimmers are not well known. HYPOTHESIS: Adaptive changes are common in the rotator cuff, bursa, labrum, and capsule in elite swimmers, and such abnormalities are related to factors concerning training and correlate with symptoms. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: The study population was the 2008 United States Olympic swimming team. All athletes completed standardized scales on shoulder pain and function and provided data on their training history and history of shoulder pain or injuries. Each athlete also underwent a comprehensive physical examination of both shoulders, followed by an evaluation of the rotator cuff, biceps, and bursa using ultrasound with dynamic images to assess for subcoracoid impingement and subacromial impingement. RESULTS: A history of shoulder pain was reported by 29 of 42 (66%) athletes. Morphological changes consistent with tendinosis were common in the biceps (33/46 shoulders; 72%) and supraspinatus/infraspinatus (44/46 shoulders; 96%). Subcoracoid impingement was seen in 17 of 46 shoulders (37%), with subacromial impingement seen in 34 of 41 shoulders (83%). There was an increased odds ratio (OR) for biceps tendinosis in older swimmers (OR, 1.92; 95% CI, 1.23-3.00; P = .004) and in swimmers who had missed a competition because of shoulder pain (OR, 9.76; 95% CI, 1.13-84.3; P = .038). There was an increased OR for rotator cuff tendinosis in swimmers who reported worse scores for pain with activities (OR, 0.10; 95% CI, 0.01-0.78; P = .028) and in those with a positive sulcus sign (OR, 33.2; 95% CI, 3.09-355; P = .004). There was an increased OR for impingement in swimmers with a positive sulcus sign (OR, 5.40; 95% CI, 0.80-36.3; P = .083), worse pain scores (OR, 0.44; 95% CI, 0.22-0.87; P = .019), and a partial rotator cuff tear (OR, 31.2; 95% CI, 3.58-272; P = .002). CONCLUSION: We found a high prevalence of rotator cuff and biceps tendinopathy, which was associated with increased symptoms. Tendinosis was also more common in swimmers with a positive sulcus sign, suggesting a role for shoulder laxity. PMID- 27507845 TI - Effect of Changing the Joint Kinematics of Knees With a Ruptured Anterior Cruciate Ligament on the Molecular Biological Responses and Spontaneous Healing in a Rat Model. AB - BACKGROUND: The poor healing capacity of a completely ruptured anterior cruciate ligament (ACL) has been attributed to an insufficient vascular supply, cellular metabolism, and deficient premature scaffold formation because of the unique intra-articular environment. However, previous studies have focused on intra articular factors without considering extra-articular factors, including the biomechanical aspects of ACL-deficient knees. HYPOTHESIS: Changing the joint kinematics of an ACL-ruptured knee will improve cellular biological responses and lead to spontaneous healing through the mechanotransduction mechanism. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 66 skeletally mature Wistar rats were randomly assigned to a sham-operated group (SO), ACL-transection group (ACL-T), controlled abnormal movement group (CAM), and an intact group (IN). The ACL was completely transected at the midportion in the ACL-T and CAM groups, and the CAM group underwent extra-articular braking to control for abnormal tibial translation. The SO group underwent skin and joint capsule incisions and tibial drilling, without ACL transection and extra-articular braking. The animals were allowed full cage activity until sacrifice at 1, 2, 4, 6, and 8 weeks postoperatively for histological, molecular biological, and biomechanical assessment. RESULTS: All injured ACLs in the ACL-T group were not healed, but those in the CAM group healed spontaneously, showing a typical ligament healing response. Regarding the molecular biological response, there was an upregulation of anabolic factors (ie, transforming growth factor-beta) and downregulation of catabolic factors (ie, matrix metalloproteinase). Examination of the mechanical properties at 8 weeks after injury showed that >50% of the strength of the intact ACL had returned. CONCLUSION: Our results suggest that changing the joint kinematics of knees with a ruptured ACL alters the molecular biological responses and leads to spontaneous healing. These data support our hypothesis that the mechanotransduction mechanism mediates molecular responses and determines whether the ACL will heal. CLINICAL RELEVANCE: Elucidating the relationship between the mechanotransduction mechanism and healing responses in knees with completely ruptured ACLs may result in the development of novel nonsurgical treatment that enables the ACL to spontaneously heal in patients who are not suitable for reconstruction. PMID- 27507846 TI - Bridging the gap: the assessment and treatment of adolescent personality disorder in routine clinical care. AB - Despite a marked increase in research supporting the assessment, diagnosis and treatment of personality disorder (PD) in adolescence, clinicians continue to be reluctant to apply treatment guidelines and psychiatric nomenclature in routine clinical care. This gap arises from several beliefs: (1) psychiatric nomenclature does not allow the diagnosis of PD in adolescence; (2) certain features of PD are normative and not particularly symptomatic of personality disturbance; (3) the symptoms of PD are better explained by other psychiatric syndromes; (4) adolescents' personalities are still developing and therefore too unstable to warrant a PD diagnosis; and (5) because PD is long-lasting, treatment-resistant and unpopular to treat, it would be stigmatising to label an adolescent with borderline personality disorder (BPD). In this paper, the empirical evidence challenging each of these beliefs is evaluated in the hope of providing a balanced review of the validity of adolescent PD with a specific focus on BPD. The paper concludes with recommendations on how routine clinical care can integrate a PD focus. PMID- 27507847 TI - Does paracetamol in pregnancy cause ADHD and autism? PMID- 27507848 TI - Articulatory Suppression Effects on Short-term Memory of Signed Digits and Lexical Items in Hearing Bimodal-Bilingual Adults. AB - We can gain a better understanding of short-term memory processes by studying different language codes and modalities. Three experiments were conducted to investigate: (a) Taiwanese Sign Language (TSL) digit spans in Chinese/TSL hearing bilinguals (n = 32); (b) American Sign Language (ASL) digit spans in English/ASL hearing bilinguals (n = 15); and (c) TSL lexical sign spans in Chinese/TSL hearing bilinguals (n = 22). Articulatory suppression conditions were manipulated to determine if participants would use a speech- or sign-based code to rehearse lists of signed items. Results from all 3 experiments showed that oral suppression significantly reduced spans while manual suppression had no effect, revealing that participants were using speech-based rehearsal to retain lists of signed items in short-term memory. In addition, sub-vocal rehearsal using Chinese facilitated higher digit spans than English even though stimuli were perceived and recalled using signs. This difference was not found for lexical sign spans. PMID- 27507849 TI - Effects of EFL Individual Learner Variables on Foreign Language Reading Anxiety and Metacognitive Reading Strategy Use. AB - Past research has shown an association between foreign language reading anxiety and reading strategy. However, individual variables tend to affect foreign language anxiety and strategy use. The present study examined a hypothesized model that specified direct and indirect effects among English and foreign languages readers' distinct variables, including academic level; self-perceived English level; and satisfaction with reading proficiency, reading anxiety, and metacognitive awareness of reading strategies. A total of 523 volunteer Taiwanese college students provided 372 valid responses to a written questionnaire (281 women and 91 men; M age = 19.7 years, SD = 1.1) containing the translated versions of Foreign Language Reading Anxiety Scale, Survey of Reading Strategies Inventory, and self-assessment background questionnaire. The results showed that self-evaluation of reading proficiency did not correlate with academic level and readers' perceptions. Satisfaction had a direct effect on foreign language reading anxiety but not on metacognitive awareness of reading strategies. Results of path analysis demonstrated that the perception learners who had their own reading proficiency predicted their foreign language reading anxiety and was a mediating variable for metacognitive reading strategy use. PMID- 27507851 TI - Knockdown of Apolipoprotein E Enhanced Sensitivity of Hep3B Cells to Cardiac Steroids via Regulating Na+/K+-ATPase Signalosome. AB - This study compared the sensitivity of human hepatoma Hep3B, SK-HEP-1, SMMC-7721, and BEL-7402 cells to cardiac steroids, including bufalin (BF), a bufalin derivative (BF211), ouabain (OUA), and digitoxin (DIG). Hep3B cells exhibited relatively low sensitivity to cardiac steroids. Expression levels of subunits of Na+/K+-ATPase were high in Hep3B cells. However, colocalization of Na+/K+-ATPase and caveolin was nearly undetectable in Hep3B cells. By using RNA-Seq technology, we found a total of 36 genes to be differentially expressed between Hep3B cells and SK-HEP-1 cells, which are highly sensitive to cardiac steroids. Our bioinformatics analysis determined that these genes were mostly comprised of extracellular space, protein binding, and extracellular region. Among these 36 genes, apolipoprotein E (APOE) played a critical role, as knockdown APOE expression induced colocalization of Na+/K+-ATPase and caveolin and increased sensitivity of Hep3B cells to both proliferation-inhibiting and cytotoxic effects of BF or BF211. Also, the effects of BF on PI3K/AKT/GSK3beta and apoptosis signal cascades were enhanced in APOE knockdown cells. The results of our study confirmed the role of Na+/K+-ATPase signalosome in cytotoxicity of cardiac steroids and suggested that APOE regulated the sensitivity of cells to cardiac steroids by affecting formation and function of Na+/K+-ATPase signalosome. In addition, intercellular interaction with high level of Na+/K+-ATPase beta1 subunit may be also a factor in the low sensitivity of Hep3B cells to cardiac steroids. Mol Cancer Ther; 15(12); 2955-65. (c)2016 AACR. PMID- 27507850 TI - EGFR and RB1 as Dual Biomarkers in HPV-Negative Head and Neck Cancer. AB - Clinical decision making for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is predominantly guided by disease stage and anatomic location, with few validated biomarkers. The epidermal growth factor receptor (EGFR) is an important therapeutic target, but its value in guiding therapeutic decision making remains ambiguous. We integrated analysis of clinically annotated tissue microarrays with analysis of data available through the TCGA, to investigate the idea that expression signatures involving EGFR, proteins regulating EGFR function, and core cell-cycle modulators might serve as prognostic or drug response-predictive biomarkers. This work suggests that consideration of the expression of NSDHL and proteins that regulate EGFR recycling in combination with EGFR provides a useful prognostic biomarker set. In addition, inactivation of the tumor suppressor retinoblastoma 1 (RB1), reflected by CCND1/CDK6-inactivating phosphorylation of RB1 at T356, inversely correlated with expression of EGFR in patient HNSCC samples. Moreover, stratification of cases with high EGFR by expression levels of CCND1, CDK6, or the CCND1/CDK6 regulatory protein p16 (CDKN2A) identified groups with significant survival differences. To further explore the relationship between EGFR and RB1-associated cell-cycle activity, we evaluated simultaneous inhibition of RB1 phosphorylation with the CDK4/6 inhibitor palbociclib and of EGFR activity with lapatinib or afatinib. These drug combinations had synergistic inhibitory effects on the proliferation of HNSCC cells and strikingly limited ERK1/2 phosphorylation in contrast to either agent used alone. In summary, combinations of CDK and EGFR inhibitors may be particularly useful in EGFR and pT356RB1-expressing or CCND1/CDK6-overexpressing HPV-negative HNSCC. Mol Cancer Ther; 15(10); 2486-97. (c)2016 AACR. PMID- 27507852 TI - FTY720 (Fingolimod) Inhibits HIF1 and HIF2 Signaling, Promotes Vascular Remodeling, and Chemosensitizes in Renal Cell Carcinoma Animal Model. AB - Clear cell renal cell carcinoma (ccRCC) is characterized by intratumoral hypoxia and chemoresistance. The hypoxia-inducible factors HIF1alpha and HIF2alpha play a crucial role in ccRCC initiation and progression. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF1alpha and HIF2alpha under hypoxia in various cancer cell models. Here, we report that FTY720, an inhibitor of the S1P signaling pathway, inhibits both HIF1alpha and HIF2alpha accumulation in several human cancer cell lines. In a ccRCC heterotopic xenograft model, we show that FTY720 transiently decreases HIF1alpha and HIF2alpha intratumoral level and modifies tumor vessel architecture within 5 days of treatment, suggesting a vascular normalization. In mice bearing subcutaneous ccRCC tumor, FTY720 and a gemcitabine-based chemotherapy alone display a limited effect, whereas, in combination, there is a significant effect on tumor size without toxicity. Noteworthy, administration of FTY720 for 5 days before chemotherapy is not associated with a more effective tumor control, suggesting a mode of action mainly independent of the vascular remodeling. In conclusion, these findings demonstrate that FTY720 could successfully sensitize ccRCC to chemotherapy and establish this molecule as a potent therapeutic agent for ccRCC treatment, independently of drug scheduling. Mol Cancer Ther; 15(10); 2465-74. (c)2016 AACR. PMID- 27507853 TI - Genomic Landscape of Malignant Mesotheliomas. AB - Understanding the genomic landscape of malignant mesothelioma may identify novel molecular drivers of this ultra-rare disease, which can lead to an expanded roster of targeted therapies and clinical trial options for patients with mesothelioma. We examined the molecular profiles of 42 patients with malignant mesothelioma (including pleural, peritoneal, and pericardial) that were referred by clinicians to be tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory using next-generation sequencing (NGS; 182 or 236 genes). Among 42 patients, there were 116 alterations, with 92 being distinct. The number of genomic alterations per patient ranged from 1 to 5 (median = 3). No two patients had identical molecular portfolios. The most common aberrations were in BAP1 (BRCA1-associated protein 1; 47.6% [20/42]), NF2 (38.1% [16/42]), and CDKN2A/B (loss) (35.7% [15/42]). BAP1 alterations and CDKN2A/B loss were associated with pleural mesothelioma (OR 3.4, P = 0.059 [BAP1] [trend]; OR 5.8, P = 0.01 [CDKN2A/B]). All 42 patients had a molecular abnormality that was potentially actionable (median = three actionable alterations per patient; range, 1 to 5), and, in 40 patients (95.2%), a drug approved by the FDA was applicable. In conclusion, each individual with malignant mesothelioma harbored a unique set of genomic aberrations, suggesting that NGS-based profiling of patients will be needed if patients are to be optimally matched to cognate treatments. All 42 patients had at least one alteration that was, in theory, pharmacologically tractable. Mol Cancer Ther; 15(10); 2498-507. (c)2016 AACR. PMID- 27507854 TI - CREBH Couples Circadian Clock With Hepatic Lipid Metabolism. AB - The circadian clock orchestrates diverse physiological processes critical for health and disease. CREB, hepatocyte specific (CREBH) is a liver-enriched, endoplasmic reticulum (ER)-tethered transcription factor known to regulate the hepatic acute phase response and energy homeostasis under stress conditions. We demonstrate that CREBH is regulated by the circadian clock and functions as a circadian regulator of hepatic lipid metabolism. Proteolytic activation of CREBH in the liver exhibits typical circadian rhythmicity controlled by the core clock oscillator BMAL1 and AKT/glycogen synthase kinase 3beta (GSK3beta) signaling pathway. GSK3beta-mediated phosphorylation of CREBH modulates the association between CREBH and the coat protein complex II transport vesicle and thus controls the ER-to-Golgi transport and subsequent proteolytic cleavage of CREBH in a circadian manner. Functionally, CREBH regulates circadian expression of the key genes involved in triglyceride (TG) and fatty acid (FA) metabolism and is required to maintain circadian amplitudes of blood TG and FA in mice. During the circadian cycle, CREBH rhythmically regulates and interacts with the hepatic nuclear receptors peroxisome proliferator-activated receptor alpha and liver X receptor alpha as well as with the circadian oscillation activator DBP and the repressor E4BP4 to modulate CREBH transcriptional activities. In conclusion, these studies reveal that CREBH functions as a circadian-regulated liver transcriptional regulator that integrates energy metabolism with circadian rhythm. PMID- 27507855 TI - Adult Playfulness, Humor Styles, and Subjective Happiness. AB - Playfulness has been referred to as a disposition that involves reframing a situation to amuse others and to make the situation more stimulating and enjoyable. It may serve to shift one's perspective when dealing with environmental threats. Despite all the benefits of playfulness towards psychological well-being, it remains a largely understudied subject in psychology, particularly in Chinese societies. Hence, this study examined the association between adult playfulness, humor styles, and subjective happiness among a sample of 166 university students in Hong Kong and 159 students in Guangzhou, who completed a self-administered questionnaire, including the Short Measure for Adult Playfulness, the Chinese Humor Styles Questionnaire, and the Subjective Happiness Scale. Results showed that adult playfulness was positively correlated with affiliative humor, self-enhancing humor, and subjective happiness in both Hong Kong and Guangzhou samples. By its implication, highly playful Chinese students preferred using affiliative and self-enhancing humor to amuse themselves and others. PMID- 27507857 TI - Often Overlooked but Critical: Poststroke Cognitive Impairment in Right Hemispheric Ischemic Stroke. PMID- 27507856 TI - Effects of Alteplase for Acute Stroke on the Distribution of Functional Outcomes: A Pooled Analysis of 9 Trials. AB - BACKGROUND: Thrombolytic therapy with intravenous alteplase within 4.5 hours of ischemic stroke onset increases the overall likelihood of an excellent outcome (no, or nondisabling, symptoms). Any improvement in functional outcome distribution has value, and herein we provide an assessment of the effect of alteplase on the distribution of the functional level by treatment delay, age, and stroke severity. METHODS: Prespecified pooled analysis of 6756 patients from 9 randomized trials comparing alteplase versus placebo/open control. Ordinal logistic regression models assessed treatment differences after adjustment for treatment delay, age, stroke severity, and relevant interaction term(s). RESULTS: Treatment with alteplase was beneficial for a delay in treatment extending to 4.5 hours after stroke onset, with a greater benefit with earlier treatment. Neither age nor stroke severity significantly influenced the slope of the relationship between benefit and time to treatment initiation. For the observed case mix of patients treated within 4.5 hours of stroke onset (mean 3 hours and 20 minutes), the net absolute benefit from alteplase (ie, the difference between those who would do better if given alteplase and those who would do worse) was 55 patients per 1000 treated (95% confidence interval, 13-91; P=0.004). CONCLUSIONS: Treatment with intravenous alteplase initiated within 4.5 hours of stroke onset increases the chance of achieving an improved level of function for all patients across the age spectrum, including the over 80s and across all severities of stroke studied (top versus bottom fifth means: 22 versus 4); the earlier that treatment is initiated, the greater the benefit. PMID- 27507858 TI - Automated CT Perfusion Ischemic Core Volume and Noncontrast CT ASPECTS (Alberta Stroke Program Early CT Score): Correlation and Clinical Outcome Prediction in Large Vessel Stroke. AB - BACKGROUND AND PURPOSE: The semiquantitative noncontrast CT Alberta Stroke Program Early CT Score (ASPECTS) and RAPID automated computed tomography (CT) perfusion (CTP) ischemic core volumetric measurements have been used to quantify infarct extent. We aim to determine the correlation between ASPECTS and CTP ischemic core, evaluate the variability of core volumes within ASPECTS strata, and assess the strength of their association with clinical outcomes. METHODS: Review of a prospective, single-center database of consecutive thrombectomies of middle cerebral or intracranial internal carotid artery occlusions with pretreatment CTP between September 2010 and September 2015. CTP was processed with RAPID software to identify ischemic core (relative cerebral blood flow<30% of normal tissue). RESULTS: Three hundred and thirty-two patients fulfilled inclusion criteria. Median age was 66 years (55-75), median ASPECTS was 8 (7-9), whereas median CTP ischemic core was 11 cc (2-27). Median time from last normal to groin puncture was 5.8 hours (3.9-8.8), and 90-day modified Rankin scale score 0 to 2 was observed in 54%. The correlation between CTP ischemic core and ASPECTS was fair (R=-0.36; P<0.01). Twenty-six patients (8%) had ASPECTS <6 and CTP core <=50 cc (37% had modified Rankin scale score 0-2, whereas 29% were deceased at 90 days). Conversely, 27 patients (8%) had CTP core >50 cc and ASPECTS >=6 (29% had modified Rankin scale 0-2, whereas 21% were deceased at 90 days). Moderate correlations between ASPECTS and final infarct volume (R=-0.42; P<0.01) and between CTP ischemic core and final infarct volume (R=0.50; P<0.01) were observed; coefficients were not significantly influenced by the time from stroke onset to presentation. Multivariable regression indicated ASPECTS >=6 (odds ratio 4.10; 95% confidence interval, 1.47-11.46; P=0.01) and CTP core <=50 cc (odds ratio 3.86; 95% confidence interval, 1.22-12.15; P=0.02) independently and comparably predictive of good outcome. CONCLUSIONS: There is wide variability of CTP-derived core volumes within ASPECTS strata. Patient selection may be affected by the imaging selection method. PMID- 27507859 TI - Risk Stratification for Recurrence and Mortality in Embolic Stroke of Undetermined Source. AB - BACKGROUND AND PURPOSE: The risk of stroke recurrence in patients with Embolic Stroke of Undetermined Source (ESUS) is high, and the optimal antithrombotic strategy for secondary prevention is unclear. We investigated whether congestive heart failure, hypertension, age >=75 years, diabetes mellitus, and stroke or transient ischemic attack (TIA; CHADS2) and CHA2DS2-VASc scores can stratify the long-term risk of ischemic stroke/TIA recurrence and death in ESUS. METHODS: We pooled data sets of 11 stroke registries from Europe and America. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group. Cox regression analyses were performed to investigate if prestroke CHADS2 and congestive heart failure, hypertension, age >=75 years, diabetes mellitus, stroke or TIA, vascular disease, age 65-74 years, sex category (CHA2DS2-VASc) scores were independently associated with the risk of ischemic stroke/TIA recurrence or death. The Kaplan-Meier product limit method was used to estimate the cumulative probability of ischemic stroke/TIA recurrence and death in different strata of the CHADS2 and CHA2DS2-VASc scores. RESULTS: One hundred fifty-nine (5.6% per year) ischemic stroke/TIA recurrences and 148 (5.2% per year) deaths occurred in 1095 patients (median age, 68 years) followed-up for a median of 31 months. Compared with CHADS2 score 0, patients with CHADS2 score 1 and CHADS2 score >1 had higher risk of ischemic stroke/TIA recurrence (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.41-4.00 and HR, 2.72; 95% CI, 1.68-4.40, respectively) and death (HR, 3.58; 95% CI, 1.80-7.12, and HR, 5.45; 95% CI, 2.86 10.40, respectively). Compared with low-risk CHA2DS2-VASc score, patients with high-risk CHA2DS2-VASc score had higher risk of ischemic stroke/TIA recurrence (HR, 3.35; 95% CI, 1.94-5.80) and death (HR, 13.0; 95% CI, 4.7-35.4). CONCLUSIONS: The risk of recurrent ischemic stroke/TIA and death in ESUS is reliably stratified by CHADS2 and CHA2DS2-VASc scores. Compared with the low-risk group, patients in the high-risk CHA2DS2-VASc group have much higher risk of ischemic stroke recurrence/TIA and death, approximately 3-fold and 13-fold, respectively. PMID- 27507861 TI - Nonatheroscleotic Isolated Middle Cerebral Artery Disease May Be Early Manifestation of Moyamoya Disease. AB - BACKGROUND AND PURPOSE: Middle cerebral artery steno-occlusive disease (MCAD) is not an uncommon cause of ischemic stroke in young Asians. Aside from atherosclerosis, the pathogenesis of MCAD include various nonatherosclerotic vasculopathies, most of which are yet to be defined. This study investigated the pathogenesis of symptomatic isolated MCAD in young Asian patients using high resolution magnetic resonance imaging (HR-MRI) and mutation analysis of RNF213. METHODS: Patients aged <60 years with stroke or transient ischemic attack caused by MCAD were prospectively enrolled. Patients with a confirmed diagnosis of moyamoya disease, dissection, and vasculitis; with significant steno-occlusion in cerebral arteries other than the MCA; or with high-risk cardioembolic source were excluded. Using high-resolution MRI, patients were classified into an atherosclerosis group and a nonatherosclerosis group. RESULTS: Eighty-one patients were enrolled, 45 (56.6%) in the atherosclerosis and 36 (44.4%) in the nonatherosclerosis group. The nonatherosclerosis group was significantly younger (P=0.013), had a smaller number of vascular risk factors (P=0.001), showed a lower homocysteine level (P<0.001), thinner intima-media thickness (P=0.006), and had more frequent heterozygotes at RNF213 (P=0.045) than the atherosclerosis group. Diffusion-weighted image lesion pattern showed no significant differences in assumed stroke mechanisms between the 2 groups. CONCLUSIONS: Nonatherosclerotic pathogenesis are common in young Asians with symptomatic isolated MCAD. Clinical findings, high-resolution MRI features, and results of RNF213 mutation analysis suggest that moyamoya disease is responsible etiologically for a significant portion of nonatherosclerotic lesions. Symptomatic isolated MCAD may be an early manifestation of moyamoya disease in young Asian adults. PMID- 27507860 TI - Global Survey of the Frequency of Atrial Fibrillation-Associated Stroke: Embolic Stroke of Undetermined Source Global Registry. AB - BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is increasingly recognized as the single most important cause of disabling ischemic stroke in the elderly. We undertook an international survey to characterize the frequency of AF-associated stroke, methods of AF detection, and patient features. METHODS: Consecutive patients hospitalized for ischemic stroke in 2013 to 2014 were surveyed from 19 stroke research centers in 19 different countries. Data were analyzed by global regions and World Bank income levels. RESULTS: Of 2144 patients with ischemic stroke, 590 (28%; 95% confidence interval, 25.6-29.5) had AF-associated stroke, with highest frequencies in North America (35%) and Europe (33%) and lowest in Latin America (17%). Most had a history of AF before stroke (15%) or newly detected AF on electrocardiography (10%); only 2% of patients with ischemic stroke had unsuspected AF detected by poststroke cardiac rhythm monitoring. The mean age and 30-day mortality rate of patients with AF-associated stroke (75 years; SD, 11.5 years; 10%; 95% confidence interval, 7.6-12.6, respectively) were substantially higher than those of patients without AF (64 years; SD, 15.58 years; 4%; 95% confidence interval, 3.3-5.4; P<0.001 for both comparisons). There was a strong positive correlation between the mean age and the frequency of AF (r=0.76; P=0.0002). CONCLUSIONS: This cross-sectional global sample of patients with recent ischemic stroke shows a substantial frequency of AF-associated stroke throughout the world in proportion to the mean age of the stroke population. Most AF is identified by history or electrocardiography; the yield of conventional short-duration cardiac rhythm monitoring is relatively low. Patients with AF associated stroke were typically elderly (>75 years old) and more often women. PMID- 27507862 TI - Association Between Serum Phosphate Levels and Stroke Risk in Patients Undergoing Hemodialysis: The Q-Cohort Study. AB - BACKGROUND AND PURPOSE: The contribution of serum phosphate levels to stroke risk in dialysis patients remains unclear. The present study aimed to elucidate the respective association between serum phosphate levels and the risk of brain hemorrhage or infarction in patients undergoing hemodialysis. METHODS: A total of 3437 patients undergoing hemodialysis were followed up for a median of 3.9 years. The primary outcome was the occurrence of brain hemorrhage or infarction. Patients were divided into 4 groups based on their baseline serum phosphate levels (Q1-Q4). Stroke risk was estimated using a Cox proportional hazards model. RESULTS: During the follow-up period, 75 patients experienced brain hemorrhage and 139 experienced brain infarction. The risk of brain hemorrhage was significantly higher in the highest (Q4) compared with the lowest quartile (Q1) as the reference value (multivariate-adjusted hazard ratio [95% confidence intervals]: Q1, 1.00; Q2, 1.76 [0.79-4.18]; Q3, 1.99 [0.92-4.67]; and Q4, 2.74 [1.27-6.47]; P=0.077 for trend; hazard ratio for every 1 mmol/L increase in serum phosphate level, 2.07 [1.10-3.81]; P=0.025). In contrast, the risk of brain infarction was significantly higher in Q1 (P=0.045) compared with Q3 as the reference value (Q1, 1.65 [1.01-2.73]; Q2, 1.35 [0.82-2.25]; Q3, 1.00; and Q4, 1.30 [0.77-2.20]). CONCLUSIONS: Higher serum phosphate levels were associated with an increased risk of brain hemorrhage, whereas low levels were associated with an increased risk of brain infarction in hemodialysis patients. These results suggest the importance of managing serum phosphate levels within an appropriate range in hemodialysis patients. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/. Unique identifier: UMIN000000556. PMID- 27507863 TI - Cerebral Microbleeds and Cortical Superficial Siderosis in Patients Presenting With Minor Cerebrovascular Events. AB - BACKGROUND AND PURPOSE: Transient focal neurological episodes occur in cerebral amyloid angiopathy (CAA) and can mimic transient ischemic attack (TIA). Risk factors and outcomes of minor ischemic stroke or TIA might differ in patients with and without cerebral microbleeds (CMBs), including CAA-consistent lobar CMB. METHODS: Baseline magnetic resonance imaging (MRI) was analyzed for CMBs and cortical superficial siderosis in 416 patients in the prospective computed tomography and MRI in the CATCH study (Triage of TIA and Minor Cerebrovascular Events to Identify High Risk Patients). Clinical symptoms, baseline characteristics, recurrence, and 90-day modified Rankin Scale were prospectively collected. MRI white-matter hyperintensity was measured using the Fazekas scale. RESULTS: CMBs were detected in 65 (15.6%) and cortical superficial siderosis in 11 patients (2.6%). Lobar CMBs were present in 49 (11.8%). In multivariable logistic regression adjusted for risk factors and age, subcortical Fazekas score was associated with lobar CMB (odds ratio, 2.07; 95% confidence interval, 1.23 3.48; P=0.006). Forty-two patients (10.1%) had lobar-only CMBs with or without cortical superficial siderosis consistent with modified Boston criteria for possible/probable CAA. The possible/probable CAA pattern was not predictive of recurrent TIA (odds ratio, 0.42; 95% confidence interval, 0.05-3.31; P=0.41), stroke (odds ratio, 1.24; 95% confidence interval, 0.26-5.99; P=0.79), or 90-day modified Rankin Scale score >=2 (odds ratio, 1.38; 95% confidence interval, 0.62 3.07; P=0.42). CONCLUSIONS: CMBs in TIA and minor stroke are moderately common but do not predict recurrence or 90-day outcome. CAA-related transient focal neurological episodes and TIA have overlapping clinical symptoms, suggesting that MRI may be needed for differentiation. PMID- 27507864 TI - Comparison of Perfusion CT Software to Predict the Final Infarct Volume After Thrombectomy. AB - BACKGROUND AND PURPOSE: Computed tomographic perfusion represents an interesting physiological imaging modality to select patients for reperfusion therapy in acute ischemic stroke. The purpose of our study was to determine the accuracy of different commercial perfusion CT software packages (Philips (A), Siemens (B), and RAPID (C)) to predict the final infarct volume (FIV) after mechanical thrombectomy. METHODS: Single-institutional computed tomographic perfusion data from 147 mechanically recanalized acute ischemic stroke patients were postprocessed. Ischemic core and FIV were compared about thrombolysis in cerebral infarction (TICI) score and time interval to reperfusion. FIV was measured at follow-up imaging between days 1 and 8 after stroke. RESULTS: In 118 successfully recanalized patients (TICI 2b/3), a moderately to strongly positive correlation was observed between ischemic core and FIV. The highest accuracy and best correlation are shown in early and fully recanalized patients (Pearson r for A=0.42, B=0.64, and C=0.83; P<0.001). Bland-Altman plots and boxplots demonstrate smaller ranges in package C than in A and B. Significant differences were found between the packages about over- and underestimation of the ischemic core. Package A, compared with B and C, estimated more than twice as many patients with a malignant stroke profile (P<0.001). Package C best predicted hypoperfusion volume in nonsuccessfully recanalized patients. CONCLUSIONS: Our study demonstrates best accuracy and approximation between the results of a fully automated software (RAPID) and FIV, especially in early and fully recanalized patients. Furthermore, this software package overestimated the FIV to a significantly lower degree and estimated a malignant mismatch profile less often than other software. PMID- 27507865 TI - Affective Prosody and Depression After Stroke: A Pilot Study. AB - BACKGROUND AND PURPOSE: Poststroke depression (PSD) is a frequent complication of stroke with detrimental consequences in terms of quality of life and functional outcomes. In individuals with major depression, several studies have demonstrated an alteration of affective prosody. The aim of this study is to identify prosodic markers that may be predictive of PSD. METHODS: Patient voices were recorded at baseline and 3 months after stroke. We extracted prosodic parameters, including fundamental frequency, percentage of voice breaks, and shimmer. Depression and anxiety symptoms were assessed 3 months later. RESULTS: Among the 49 patients included in the study, 22.5% developed PSD 3 months after stroke. A significant decrease was observed concerning the fundamental frequency among patients who developed PSD. Discriminant analysis demonstrated that initial voice breaks coupled with shimmer are strongly predictive of subsequent PSD. CONCLUSIONS: Early alterations of affective prosody are associated with a higher risk of PSD 3 months after a stroke. This new physiological approach overcomes traditional barriers associated with clinical instruments and contributes to the prediction of this disorder. PMID- 27507866 TI - Does Admission to Hospital Affect Trends in Survival and Dependency After Stroke Using the South London Stroke Register? AB - BACKGROUND AND PURPOSE: Despite guidelines for specialist assessment in hospital for stroke, it is important to identify patient characteristics, trends, and outcome in patients not admitted to hospital compared with patients admitted to hospital. METHODS: Population-based stroke register of first in a life time strokes between 1995 and 2012 were examined. Baseline data included admission or nonadmission, case mix, stroke subtype, and risk factors before stroke. Survival curves were estimated with Kaplan-Meier methods. Logistic regression was used to determine factors associated with poor outcome (dead and dependency: Barthel index, <15) at 3 months and 1 year. RESULTS: Three thousand four hundred sixty four patients were admitted to hospital for stroke. Patients admitted were more likely have more severe impairments (P<0.001). There was a significant trend for increasing admission over time; 1995 to 2000 (82%), 2001 to 2006 (90%), and 2007 to 2012 (94%); P<0.001. When survival analysis was stratified according to Barthel index >=15 at day 7, there were no significant differences in survival curves between admission and nonadmission groups in 1995 to 2000 (P=0.15) or 2001 to 2006 (P=0.06), but there was a significant trend for higher survival rates for nonadmission in the 2007 to 2012 cohort (P=0.025). Admission to hospital (stroke unit) compared with nonadmission was also associated with poor outcome in the 2001 to 2006 time period (odds ratio, 2.66; confidence interval, 1.17-6.04) and the 2007 to 2012 time period (odds ratio, 5.26; confidence interval, 1.27-21.81). CONCLUSION: There is a survival advantage from 2007 onward and lower levels of dependency from 2001 onward after adjusting for case mix for those patients who are not admitted to hospital, which requires further explanation. PMID- 27507867 TI - Impact of Initial Diffusion-Weighted Imaging Lesion Growth Rate on the Success of Endovascular Reperfusion Therapy. AB - BACKGROUND AND PURPOSE: Initial diffusion-weighted imaging lesion growth rate (IGR) assessed by diffusion-weighted imaging lesion volume divided by the delay from onset to magnetic resonance imaging offers an estimate of early brain infarction progression. We investigated the impact of IGR on the rate of favorable outcome according to the occurrence of a successful endovascular revascularization within 6 hours after onset in patients experiencing an acute brain infarction complicating internal carotid artery terminus/middle cerebral artery M1 occlusion. METHODS: The primary study end point was a favorable outcome defined by a modified Rankin Scale score of <=2, 90 days after onset. A Thrombolysis in Cerebral Infarction score 2b/3 defined a successful recanalization. RESULTS: A total of 166 patients were included. Median IGR was 7 mL/h (interquartile range, 2-26). Sixty-eight patients (41%) experienced a favorable outcome. After adjustment on age, systolic blood pressure, vessel site occlusion, National Institutes of Health Stroke Scale, and antithrombotic medication, increase in IGR was associated with a decreased occurrence of favorable outcome with an odds ratio per SD increase of 0.60 (95% confidence interval, 0.38-0.94; P=0.03). A successful recanalization was achieved among 56% of the patients after a median delay of 251 minutes (interquartile range, 211-291 minutes). Increasing IGR was associated with a decreased favorable outcome only when a successful recanalization was not achieved (adjusted odds ratio, 0.32; 95% confidence interval, 0.12-0.85; P=0.02). CONCLUSIONS: Proximal internal carotid artery/M1 occlusion did result into a wide range of IGR within 6 hours after onset. Increasing IGR was associated with a lower rate of favorable outcome after endovascular treatment overall and when a successful recanalization was not achieved. PMID- 27507868 TI - Prescription of Guideline-Based Medical Therapies at Discharge After Carotid Artery Stenting and Endarterectomy: An NCDR Analysis. AB - BACKGROUND AND PURPOSE: Carotid artery revascularization was previously found to incrementally reduce stroke risk among patients with carotid stenosis treated with medical therapy. However, the frequency with which optimal medical therapies are used at discharge after carotid endarterectomy (CEA) and carotid artery stenting (CAS) is not known, and the influence of patient, operator, and hospital characteristics on the likelihood of prescription is poorly understood. METHODS: In a retrospective cohort study of 23 112 patients undergoing CAS or CEA between January 2007 and June 2012 at US hospitals participating in the CARE registry (Carotid Artery Revascularization and Endarterectomy), we examined antiplatelet therapy and statin utilization at discharge. Hierarchical multivariable logistic regression was used in adjusted analyses. RESULTS: Antiplatelet agents and statins were prescribed at discharge in 99% and 78%, respectively, after CAS and 93% and 75%, respectively, after CEA. After adjustment, antiplatelet therapy was more often prescribed after CAS than CEA (odds ratio 2.4 [95% confidence interval 1.68-3.45]), but statin prescription was equally likely (odds ratio 1.11 [95% confidence interval 0.84-1.49]). Operator specialty (medical>radiology/surgery) and hospital community setting (suburban>urban>rural) independently predicted antiplatelet and statin agent use at discharge, whereas hospital geographic location (Northeast>Midwest/South>West) predicted use of statins but not antiplatelet therapy at discharge. CONCLUSIONS: US antiplatelet agent and statin discharge prescription rates were suboptimal after both CAS and CEA and varied by revascularization modality, operating physician specialty, and hospital characteristics. Improved and more uniform utilization after these procedures will be critical to the success of comprehensive stroke risk reduction efforts. PMID- 27507869 TI - Large Capacity of Conscious Access for Incidental Memories in Natural Scenes. AB - When searching a crowd, people can detect a target face only by direct fixation and attention. Once the target is found, it is consciously experienced and remembered, but what is the perceptual fate of the fixated nontarget faces? Whereas introspection suggests that one may remember nontargets, previous studies have proposed that almost no memory should be retained. Using a gaze-contingent paradigm, we asked subjects to visually search for a target face within a crowded natural scene and then tested their memory for nontarget faces, as well as their confidence in those memories. Subjects remembered up to seven fixated, nontarget faces with more than 70% accuracy. Memory accuracy was correlated with trial-by trial confidence ratings, which implies that the memory was consciously maintained and accessed. When the search scene was inverted, no more than three nontarget faces were remembered. These findings imply that incidental memory for faces, such as those recalled by eyewitnesses, is more reliable than is usually assumed. PMID- 27507870 TI - Healthcare staff attitudes towards the use of electronic cigarettes ('e cigarettes') compared with a local trust policy. AB - BACKGROUND: E-cigarette use has risen dramatically in recent years, despite uncertainty over long-term health effects and concerns regarding efficacy as a smoking cessation device. Currently, there is no legislation prohibiting use in public, though many trusts have extended the NHS Smokefree policy to include e cigarettes. The successful implementation of such policy is, however, unclear. AIM: This study examined staff attitudes towards the use of e-cigarettes in a hospital environment with respect to enforcement of a local trust smoking policy. METHODS: A total of 79 healthcare professionals working at South Tyneside District Hospital, South Shields, completed a written questionnaire regarding use of e-cigarettes, particularly views on use in public and on hospital premises. Factors influencing the likelihood of individuals to challenge the use of e cigarettes were assessed. RESULTS: In all, 45% of respondents thought that e cigarettes should be allowed in public places, though a majority (62%) favoured use on hospital grounds compared to within hospital buildings (18%). Over 50% of respondents were unaware of trust policy relating to e-cigarettes and only 25% had ever challenged someone using a device. Roughly, one-third reported that they would still not challenge someone in future, despite being informed of trust policy. Fear of abuse was the most cited reason for not challenging. Expressed concerns of e-cigarette use related to fire risk, 'normalising' smoking behaviour and uncertainty of long-term effects. CONCLUSION: Most staff do not enforce trust policy regarding e-cigarette use. This reflects variation in opinion over use, poor awareness of the policy itself and perceived barriers to implementation, including fear of abuse. Addressing these issues through staff education sessions may help successful future implementation. PMID- 27507871 TI - Restricted Mean Survival Time: An Obligatory End Point for Time-to-Event Analysis in Cancer Trials? PMID- 27507872 TI - Critical Role of Iron in Epoetin Alfa Treatment of Chemotherapy-Associated Anemia. PMID- 27507873 TI - Intellectual Outcome in Molecular Subgroups of Medulloblastoma. AB - Purpose To evaluate intellectual functioning and the implications of limiting radiation exposure in the four biologically distinct subgroups of medulloblastoma: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Patients and Methods A total of 121 patients with medulloblastoma (n = 51, Group 4; n = 25, Group 3; n = 28, SHH; and n = 17, WNT), who were treated between 1991 and 2013 at the Hospital for Sick Children (Toronto, Ontario, Canada), Children's National Health System (Washington, DC), or the Lucile Packard Children's Hospital (Palo Alto, CA), had intellectual assessments. First, we compared intellectual trajectories between subgroups. Next, we evaluated the effect of treatment with reduced-dose craniospinal irradiation (CSI) plus a tumor bed boost versus treatments that deliver higher CSI doses and/or larger boost volumes to the brain (all other treatments) within subgroups. Linear mixed modeling was used to determine the stability or change in intelligence scores over time. Results Intellectual outcomes declined comparably in each subgroup except for processing speed; SHH declined less than Group 3 ( P = .04). SHH had the lowest incidence of cerebellar mutism and motor deficits. Treatment with reduced-dose CSI plus a tumor bed boost was associated with preserved intellectual functioning in WNT and Group 4 patients considered together (ie, subgroups containing patients who are candidates for therapy de-escalation), and not in Group 3 or SHH. Across all subgroups, patients in the all other treatments group declined over time (all P < .05). Conclusion SHH patients appear to have the most distinct functional (ie, motor deficits and mutism) outcomes and a unique processing speed trajectory. Only WNT and Group 4 patients seem to benefit from limiting radiation exposure. Our findings highlight the value of conducting subgroup-specific analyses, and can be used to inform novel biologically based treatment protocols for patients with medulloblastoma. PMID- 27507874 TI - Randomized Controlled Trial of Laparoscopic Versus Open D2 Distal Gastrectomy for Advanced Gastric Cancer: How Should We Define the Age of Included Patents? PMID- 27507875 TI - How to Summarize the Safety Profile of Epoetin Alfa Versus Best Standard of Care in Anemic Patients With Metastatic Breast Cancer Receiving Standard Chemotherapy? PMID- 27507876 TI - Randomized Phase II Trial of Gefitinib With and Without Pemetrexed as First-Line Therapy in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer With Activating Epidermal Growth Factor Receptor Mutations. AB - PURPOSE: To determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations. PATIENTS AND METHODS: Chemotherapy-naive for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2:1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m(2) on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-free-survival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65). RESULTS: PFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P = .014; two-sided P = .029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+G, but toxicities were manageable. CONCLUSION: P+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation-positive patients new treatment options and improved clinical outcomes compared with the current standard of care. PMID- 27507877 TI - Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia. AB - Purpose To characterize the toxicity, pharmacokinetics, and pharmacodynamics of selinexor, a selective inhibitor of nuclear export, when combined with fludarabine and cytarabine, in children with relapsed or refractory leukemia. Patients and Methods Eighteen patients with relapsed or refractory acute leukemia were enrolled in the SELHEM (Selinexor With Fludarabine and Cytarabine for Treatment of Refractory or Relapsed Leukemia or Myelodysplastic Syndrome) clinical trial (NCT02212561). Selinexor, initially at 30 mg/m2 per dose, was given orally on days 1, 3, 8, 10, 22, and 24 and was escalated according to a rolling-six design. Fludarabine 30 mg/m2 and cytarabine 2 g/m2 were administered on days 15 to 19. Pharmacokinetic and pharmacodynamic studies were performed on days 1 and 22. Response evaluations were performed on day 15 and at the completion of course 1. Results Among the 17 patients who were evaluable for toxicity, three were treated at 30 mg/m2, three at 40 mg/m2, six at 55 mg/m2, and five at 70 mg/m2. The most common grade 3 nonhematologic toxicity was asymptomatic hyponatremia. Two patients who were treated at 70 mg/m2 experienced reversible cerebellar toxicity, thereby defining the dose-limiting toxicity. Pharmacokinetic parameters demonstrated that plasma exposure was dose proportional. Fifteen of 16 patients demonstrated at least a twofold increase of XPO1 mRNA, indicating inhibition of the XPO1 protein. In this group of heavily pretreated, relapsed, and refractory patients, seven of 15 evaluable patients (47%) achieved complete response or complete response with incomplete count recovery. Conclusion Selinexor, in combination with fludarabine and cytarabine, is tolerable at doses up to 55 mg/m2 in pediatric patients with relapsed or refractory leukemia. All patients who received selinexor at >= 40 mg/m2 demonstrated XPO1 target inhibition. Response rates are promising and will be further explored in a phase II trial. PMID- 27507878 TI - Pretransplantation Anti-CCR4 Antibody Mogamulizumab Against Adult T-Cell Leukemia/Lymphoma Is Associated With Significantly Increased Risks of Severe and Corticosteroid-Refractory Graft-Versus-Host Disease, Nonrelapse Mortality, and Overall Mortality. AB - PURPOSE: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is one important treatment option for patients with aggressive adult T-cell leukemia/lymphoma (ATLL). Mogamulizumab (anti-CCR4 monoclonal antibody; Mog) was recently approved as a treatment for ATLL in Japan. Major concerns exist about the possible adverse effects of pretransplantation Mog because Mog depletes regulatory T cells for several months. We assessed the impact of pretransplantation Mog on clinical outcomes after allo-HSCT. PATIENTS AND METHODS: We included 996 allo-HSCT recipients age 70 years or younger with aggressive ATLL who were given the diagnosis between 2000 and 2013 and who received intensive chemotherapy by multiple chemotherapeutic drugs as first-line therapy. Before allo-HSCT, 82 patients received Mog with a median interval of 45 days from the last Mog to allo-HSCT. RESULTS: Pretransplantation Mog was associated with an increased risk of grade 3 to 4 acute graft-versus-host disease (GVHD; relative risk, 1.80; P < .01) and refractoriness to systemic corticosteroid for acute GVHD (relative risk, 2.09; P < .01). One-year cumulative incidence of nonrelapse mortality was significantly higher in patients with pretransplantation Mog compared with those without (43.7% v 25.1%; P < .01). The probability of 1-year overall survival was also significantly inferior in patients with pretransplantation Mog compared with those without (32.3% v 49.4%; P < .01). In particular, use of Mog with intervals < 50 days to allo-HSCT was associated with a dismal clinical outcome. CONCLUSION: Pretransplantation Mog was significantly associated with an increased risk of GVHD-related mortality, which supports the relevance of CCR4-expressing Tregs after allo-HSCT in humans. In clinical practice, Mog should be cautiously used for patients with ATLL who are eligible for allo-HSCT. PMID- 27507879 TI - Changes in Clinical Context for Kaposi's Sarcoma and Non-Hodgkin Lymphoma Among People With HIV Infection in the United States. AB - PURPOSE: The biology of HIV-associated cancers may differ depending on immunologic and virologic context during development. Therefore, an understanding of the burden of Kaposi's sarcoma (KS) and non-Hodgkin lymphoma (NHL) relative to antiretroviral therapy (ART), virologic suppression, and CD4 count is important. PATIENTS AND METHODS: KS and NHL diagnoses during 1996 to 2011 were identified among patients with HIV infection in eight clinical cohorts in the United States. Among patients in routine HIV clinical care, the proportion of cases in categories of ART use, HIV RNA, and CD4 count at diagnosis were described across calendar time. Person-time and incidence rates were calculated for each category. RESULTS: We identified 466 patients with KS and 258 with NHL. In recent years, KS was more frequently diagnosed after ART initiation (55% in 1996 to 2001 v 76% in 2007 to 2011; P-trend = .02). The proportion of patients with NHL who received ART was higher but stable over time (83% overall; P-trend = .81). An increasing proportion of KS and NHL occurred at higher CD4 counts (P < .05 for KS and NHL) and with undetectable HIV RNA (P < .05 for KS and NHL). In recent years, more person-time was contributed by patients who received ART, had high CD4 counts and had undetectable HIV RNA, whereas incidence rates in these same categories remained stable or declined. CONCLUSION: Over time, KS and NHL occurred at higher CD4 counts and lower HIV RNA values, and KS occurred more frequently after ART initiation. These changes were driven by an increasing proportion of patients with HIV who received effective ART, had higher CD4 counts, and had suppressed HIV RNA and not by increases in cancer risk within these subgroups. An improved understanding of HIV-associated cancer pathogenesis and outcomes in the context of successful ART is therefore important. PMID- 27507880 TI - Reply to T. Hasegawa et al and I. Gross et al. PMID- 27507881 TI - Reply to L. Zong et al. PMID- 27507882 TI - MEF2D-BCL9 Fusion Gene Is Associated With High-Risk Acute B-Cell Precursor Lymphoblastic Leukemia in Adolescents. AB - PURPOSE: Acute lymphoblastic leukemia (ALL) makes up a significant proportion of all pediatric cancers, and relapsed ALL is a leading cause of cancer-associated deaths in children. Identification of risk factors and druggable molecular targets in ALL can lead to a better stratification of treatments and subsequent improvement in prognosis. PATIENTS AND METHODS: We enrolled 59 children with relapsed or primary refractory ALL who were treated in our institutions. We primarily performed RNA sequencing (RNA-seq) using patients' leukemic cells to comprehensively detect gene fusions and analyze gene expression profiles. On the basis of results obtained by RNA-seq, we performed genetic validation, functional analysis, and in vitro drug sensitivity testing using patients' samples and an exogenous expression model. RESULTS: We identified a total of 26 gene fusions in 22 patients by RNA-seq. Among these, 19 were nonrandom gene fusions already described in ALL, and four of the remaining seven involved identical combination of MEF2D and BCL9. All MEF2D-BCL9-positive patients had B-cell precursor immunophenotype and were characterized as being older in age, being resistant to chemotherapy, having very early relapse, and having leukemic blasts that mimic morphologically mature B-cell leukemia with markedly high expression of HDAC9. Exogenous expression of MEF2D-BCL9 in a B-cell precursor ALL cell line promoted cell growth, increased HDAC9 expression, and induced resistance to dexamethasone. Using a primary culture of leukemic blasts from a patient, we identified several molecular targeted drugs that conferred inhibitory effects in vitro. CONCLUSION: A novel MEF2D-BCL9 fusion we identified characterizes a novel subset of pediatric ALL, predicts poor prognosis, and may be a candidate for novel molecular targeting. PMID- 27507883 TI - Talking to Children With Cancer: Sometimes Less Is More. PMID- 27507884 TI - Enhanced copy number variants detection from whole-exome sequencing data using EXCAVATOR2. AB - Copy Number Variants (CNVs) are structural rearrangements contributing to phenotypic variation that have been proved to be associated with many disease states. Over the last years, the identification of CNVs from whole-exome sequencing (WES) data has become a common practice for research and clinical purpose and, consequently, the demand for more and more efficient and accurate methods has increased. In this paper, we demonstrate that more than 30% of WES data map outside the targeted regions and that these reads, usually discarded, can be exploited to enhance the identification of CNVs from WES experiments. Here, we present EXCAVATOR2, the first read count based tool that exploits all the reads produced by WES experiments to detect CNVs with a genome-wide resolution. To evaluate the performance of our novel tool we use it for analysing two WES data sets, a population data set sequenced by the 1000 Genomes Project and a tumor data set made of bladder cancer samples. The results obtained from these analyses demonstrate that EXCAVATOR2 outperforms other four state-of-the art methods and that our combined approach enlarge the spectrum of detectable CNVs from WES data with an unprecedented resolution. EXCAVATOR2 is freely available at http://sourceforge.net/projects/excavator2tool/. PMID- 27507885 TI - ADPriboDB: The database of ADP-ribosylated proteins. AB - ADP-ribosylation refers to the addition of one or more ADP-ribose units onto proteins post-translationally. This protein modification is often added by ADP ribosyltransferases, commonly known as PARPs, but it can also be added by other enzymes, including sirtuins or bacterial toxins. While past literature has utilized a variety of methods to identify ADP-ribosylated proteins, recent proteomics studies bring the power of mass spectrometry to determine sites of the modification. To appreciate the diverse roles of ADP-ribosylation across the proteome, we have created ADPriboDB - a database of ADP-ribosylated proteins (http://ADPriboDB.leunglab.org). Each entry of ADPriboDB is annotated manually by at least two independent curators from the literature between January 1975 and July 2015. The current database includes over 12 400 protein entries from 459 publications, identifying 2389 unique proteins. Here, we describe the structure and the current state of ADPriboDB as well as the criteria for entry inclusion. Using this aggregate data, we identified a statistically significant enrichment of ADP-ribosylated proteins in non-membranous RNA granules. To our knowledge, ADPriboDB is the first publicly available database encapsulating ADP-ribosylated proteins identified from the past 40 years, with a hope to facilitate the research of both basic scientists and clinicians to better understand ADP ribosylation at the molecular level. PMID- 27507886 TI - Nuclear poly(A)-binding protein aggregates misplace a pre-mRNA outside of SC35 speckle causing its abnormal splicing. AB - A short abnormal polyalanine expansion in the polyadenylate-binding protein nuclear-1 (PABPN1) protein causes oculopharyngeal muscular dystrophy (OPMD). Mutated PABPN1 proteins accumulate as insoluble intranuclear aggregates in muscles of OPMD patients. While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice have been established, the molecular mechanisms which trigger pathological defects in OPMD and the role of aggregates remain to be determined. Using exon array, for the first time we have identified several splicing defects in OPMD. In particular, we have demonstrated a defect in the splicing regulation of the muscle-specific Troponin T3 (TNNT3) mutually exclusive exons 16 and 17 in OPMD samples compared to controls. This splicing defect is directly linked to the SC35 (SRSF2) splicing factor and to the presence of nuclear aggregates. As reported here, PABPN1 aggregates are able to trap TNNT3 pre-mRNA, driving it outside nuclear speckles, leading to an altered SC35-mediated splicing. This results in a decreased calcium sensitivity of muscle fibers, which could in turn plays a role in muscle pathology. We thus report a novel mechanism of alternative splicing deregulation that may play a role in various other diseases with nuclear inclusions or foci containing an RNA binding protein. PMID- 27507887 TI - The RNA-binding protein Gemin5 binds directly to the ribosome and regulates global translation. AB - RNA-binding proteins (RBPs) play crucial roles in all organisms. The protein Gemin5 harbors two functional domains. The N-terminal domain binds to snRNAs targeting them for snRNPs assembly, while the C-terminal domain binds to IRES elements through a non-canonical RNA-binding site. Here we report a comprehensive view of the Gemin5 interactome; most partners copurified with the N-terminal domain via RNA bridges. Notably, Gemin5 sediments with the subcellular ribosome fraction, and His-Gemin5 binds to ribosome particles via its N-terminal domain. The interaction with the ribosome was lost in F381A and Y474A Gemin5 mutants, but not in W14A and Y15A. Moreover, the ribosomal proteins L3 and L4 bind directly with Gemin5, and conversely, Gemin5 mutants impairing the binding to the ribosome are defective in the interaction with L3 and L4. The overall polysome profile was affected by Gemin5 depletion or overexpression, concomitant to an increase or a decrease, respectively, of global protein synthesis. Gemin5, and G5-Nter as well, were detected on the polysome fractions. These results reveal the ribosome binding capacity of the N-ter moiety, enabling Gemin5 to control global protein synthesis. Our study uncovers a crosstalk between this protein and the ribosome, and provides support for the view that Gemin5 may control translation elongation. PMID- 27507888 TI - Discharging tRNAs: a tug of war between translation and detoxification in Escherichia coli. AB - Translation is a central cellular process and is optimized for speed and fidelity. The speed of translation of a single codon depends on the concentration of aminoacyl-tRNAs. Here, we used microarray-based approaches to analyze the charging levels of tRNAs in Escherichia coli growing at different growth rates. Strikingly, we observed a non-uniform aminoacylation of tRNAs in complex media. In contrast, in minimal medium, the level of aminoacyl-tRNAs is more uniform and rises to approximately 60%. Particularly, the charging level of tRNA(Ser), tRNA(Cys), tRNA(Thr) and tRNA(His) is below 50% in complex medium and their aminoacylation levels mirror the degree that amino acids inhibit growth when individually added to minimal medium. Serine is among the most toxic amino acids for bacteria and tRNAs(Ser) exhibit the lowest charging levels, below 10%, at high growth rate although intracellular serine concentration is plentiful. As a result some serine codons are among the most slowly translated codons. A large fraction of the serine is most likely degraded by L-serine-deaminase, which competes with the seryl-tRNA-synthetase that charges the tRNAs(Ser) These results indicate that the level of aminoacylation in complex media might be a competition between charging for translation and degradation of amino acids that inhibit growth. PMID- 27507889 TI - Retraction: Long non-coding RNA INXS is a critical mediator of BCL-XS induced apoptosis. PMID- 27507890 TI - Exercise limitation in chronic kidney disease: deep seas and new shores. PMID- 27507891 TI - Urinary proteomics predict onset of microalbuminuria in normoalbuminuric type 2 diabetic patients, a sub-study of the DIRECT-Protect 2 study. AB - Background: Early prevention of diabetic nephropathy is not successful as early interventions have shown conflicting results, partly because of a lack of early and precise indicators of disease development. Urinary proteomics has shown promise in this regard and could identify those at high risk who might benefit from treatment. In this study we investigate its utility in a large type 2 diabetic cohort with normoalbuminuria. Methods: We performed a post hoc analysis in the Diabetic Retinopathy Candesartan Trials (DIRECT-Protect 2 study), a multi centric randomized clinical controlled trial. Patients were allocated to candesartan or placebo, with the aim of slowing the progression of retinopathy. The secondary endpoint was development of persistent microalbuminuria (three of four samples). We used a previously defined chronic kidney disease risk score based on proteomic measurement of 273 urinary peptides (CKD273-classifier). A Cox regression model for the progression of albuminuria was developed and evaluated with integrated discrimination improvement (IDI), continuous net reclassification index (cNRI) and receiver operating characteristic curve statistics. Results: Seven hundred and thirty-seven patients were analysed and 89 developed persistent microalbuminuria (12%) with a mean follow-up of 4.1 years. At baseline the CKD273 classifier predicted development of microalbuminuria during follow-up, independent of treatment (candesartan/placebo), age, gender, systolic blood pressure, urine albumin excretion rate, estimated glomerular filtration rate, HbA1c and diabetes duration, with hazard ratio 2.5 [95% confidence interval (CI) 1.4-4.3; P = 0.002] and area under the curve 0.79 (95% CI 0.75-0.84; P < 0.0001). The CKD273-classifier improved the risk prediction (relative IDI 14%, P = 0.002; cNRI 0.10, P = 0.043). Conclusions: In this cohort of patients with type 2 diabetes and normoalbuminuria from a large intervention study, the CKD273 classifier was an independent predictor of microalbuminuria. This may help identify high-risk normoalbuminuric patients for preventive strategies for diabetic nephropathy. PMID- 27507892 TI - Characterization of C3 in C3 glomerulopathy. AB - Background: C3 glomerulopathy (C3G) is caused by overactivity of the alternative pathway of complement that results in bright glomerular C3 staining with minimal or no deposition of immunoglobulins on immunofluorescence microscopy. Laser microdissection and mass spectrometry of the two subtypes, C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), have identified C3 as the predominant glomerular complement protein, although lesser amounts of C9, C5, C6, C7 and C8 are detectable. C3 plays a central role in complement activity, with its proteolytic cleavage first generating C3a and C3b, followed by inactivation of C3b generating iC3b (which includes C3alpha and C3beta), which undergoes further breakdown yielding C3c and terminal breakdown fragment C3dg. The composition of C3 breakdown products in C3G is not known. Methods: In this study, we chose six cases each of C3GN and DDD to analyze the composition of C3 deposits. We analyzed the amino acid sequence of C3 spectra detected by mass spectrometry to determine the relative abundance of C3 fragments in C3G. Thus we were able to determine the amino acid sequences mapping to the various C3 activation products including C3dg, C3alpha (C3alpha1 and alpha2), and C3beta that are part of C3b/iC3b/C3c. Results: C3dg is the predominant cleavage product detected with the highest amino acid coverage. The remaining amino acids map to C3alpha (C3alpha1 and alpha2) and C3beta. Amino acids mapping to C3a and C3f are absent. Taken together, the C3alpha and C3beta amino acids represent iC3b prior to or after C3c cleavage of C3dg. The C3 spectra for both C3GN and DDD are surprisingly similar. Conclusion: The finding of large amounts of C3dg suggests that C3b deposition in the glomerulus is an active process triggered by thioester binding of C3b to the glycocalyx overlying the glomerular endothelial cells and glomerular basement membrane. Regulatory protein-mediated inactivation of C3b results in the generation of iC3b. After additional cleavages, mostly C3dg remains. PMID- 27507893 TI - Effects of bioaerosol exposure on respiratory health in compost workers: a 13 year follow-up study. AB - OBJECTIVES: To determine the risk of German compost workers developing chronic respiratory effects from long-term exposure to bioaerosols. METHODS: Respiratory health was determined in 74 currently exposed compost workers and 37 non-exposed controls after 13 years of follow-up. In addition, 42 former compost workers (drop-outs) who left their work during the follow-up period were also examined. Respiratory symptoms and working conditions were assessed using identical questionnaires as at baseline. In addition, lung function was measured using the same spirometer as in the initial study. Sera from both surveys were tested for specific IgE and IgG antibodies to moulds and the risk of work-related symptoms was evaluated using regression approaches for prospective studies with binary data. RESULTS: In the follow-up period, the number of participants reporting cough significantly increased in compost workers and drop-outs compared to the controls. Working as a compost worker for at least 5 years increased the relative risk for cough (RR 1.28; 95% CI 1.2 to 1.4) and for cough with phlegm (RR 1.32; 95% CI 1.2 to 1.5). Current and former compost workers had slightly lower predicted percentage of forced expiratory volume in 1 s and predicted percentage of forced vital capacity than controls, but decrease in lung function during follow-up was not different among the 3 groups. In addition, no significant changes could be detected in antibody concentrations. CONCLUSIONS: Our results suggest that chronic exposure to bioaerosols in composting plants is related to a significantly higher risk for cough with phlegm, indicating chronic bronchitis. However, compost workers showed no higher incidence of deterioration of pulmonary function over the study. PMID- 27507894 TI - Barriers to Care Coordination and Medical Home Implementation. AB - BACKGROUND: Pediatricians are central in leading the family-centered medical home (FCMH), yet little is known about how provider-perceived barriers to and attitudes toward the FCMH affect implementation. This study aims to assess the relationship between pediatrician-perceived barriers to and attitudes toward FCMH and reported care coordination. METHODS: Pediatricians working in ambulatory care responded to the American Academy of Pediatrics Periodic Survey of Fellows #79 (N = 572, response rate, 59%). Our primary care coordination outcomes were whether pediatricians were: (1) leading a multidisciplinary team; (2) developing care plans; and (3) connecting with support services. Independent variables included barriers to FCMH implementation (lack of communication skills, support services, and time). Associations between outcomes and barriers were assessed by multivariate logistic regression, controlling for pediatrician and practice characteristics. RESULTS: Lack of sufficient personnel was significantly associated with fewer care coordination activities: leading a multidisciplinary team (odds ratio [OR], 0.53), developing care plans (OR, 0.51), and connecting with support services (OR, 0.42). Lacking communication skills was significantly associated with lower odds of development of care plans (OR, 0.56) and assistance with support services (OR, 0.64). Lack of time was significantly associated with lower odds of leading a multidisciplinary team (OR, 0.53). A pediatrician's belief that the FCMH encourages the use of preventive services was significantly associated with increased support services (OR, 2.06). CONCLUSIONS: Pediatricians report a need for sufficient personnel and communication skills to provide care coordination, a core component of the FCMH. Interventions to boost FCMH implementation should focus on providing resources to develop these characteristics. PMID- 27507895 TI - A 3-Day-Old Girl Referred From Her Pediatrician for Oral Ulcerations. AB - A 3-day-old girl was referred from her pediatrician for oral ulcerations. The patient was otherwise well appearing and afebrile. Her prenatal and antenatal courses were unremarkable, except for a failed routine hearing screen. The patient's examination was notable for several yellowish ulcers on erythematous bases located on her anterior tonsillar pillars. The patient also had a right coloboma and a II/VI systolic ejection murmur. Laboratory analyses revealed a traumatic lumbar puncture with 182 000 red blood cells and 808 white blood cells, as well as a complete blood count that showed thrombocytopenia and leukocytosis. During the patient's hospitalization, she developed a new facial rash. Her physical examination findings, along with her diagnostic evaluation and hospital course, ultimately led to 2 surprising diagnoses elaborated on in this case discussion. PMID- 27507896 TI - Reciprocal Regulation of 11beta-HSDs May Predict Steroid Sensitivity in Childhood Nephrotic Syndrome. AB - Childhood nephrotic syndrome, in which steroid-dependence occurs concurrently with steroid-resistance, requires aggressive therapy to prevent relapse. Predictive biomarkers that can be used to stratify treatment are urgently needed. Here we report that reciprocal regulation of the glucocorticoid metabolizing enzymes, 11beta-hydroxysteroid dehydrogenase types 1 and 2, is associated with steroid-responsiveness and disease remission in childhood nephrotic syndrome, potentially providing a marker to identify patients in which aggressive therapy is required. PMID- 27507897 TI - Urine 2-Hydroxyglutarate in Glioma. PMID- 27507898 TI - In Reply. PMID- 27507899 TI - Relieving dyspnoea by non-invasive ventilation decreases pain thresholds in amyotrophic lateral sclerosis. AB - BACKGROUND: Dyspnoea is a threatening sensation of respiratory discomfort that presents many similarities with pain. Experimental dyspnoea in healthy subjects induces analgesia. This 'dyspnoea-pain counter-irritation' could, in reverse, imply that relieving dyspnoea in patients with chronic respiratory diseases would lower their pain thresholds. METHODS: We first determined pressure pain thresholds in 25 healthy volunteers (22-31 years; 13 men; handheld algometer), during unloaded breathing (BASELINE) and during inspiratory threshold loading (ITL). Two levels of loading were used, adjusted to induce dyspnoea self-rated at 60% or 80% of a 10 cm visual analogue scale (ITL6 and ITL8). 18 patients with chronic respiratory failure due to amyotrophic lateral sclerosis (ALS) were then studied during unassisted breathing and after 30 and 60 min of non-invasive ventilation-NIV30 and NIV60-(same dyspnoea evaluation). RESULTS: In healthy volunteers, pressure pain thresholds increased significantly in the deltoid during ITL6 (p<0.05) and ITL8 (p<0.05) and in the trapezius during ITL8 (p<0.05), validating the use of pressure pain thresholds to study dyspnoea-pain counter irritation. In patients with ALS, the pressure pain thresholds measured in the deltoid during unassisted breathing decreased by a median of 24.5%-33.0% of baseline during NIV30 and NIV60 (p<0.05). CONCLUSION: Relieving dyspnoea by NIV in patients with ALS having respiratory failure is associated with decreased pressure pain thresholds. Clinical implications have yet to be determined, but this observation suggests that patients with ALS could become more susceptible to pain after the institution of NIV, hence the need for reinforced attention towards potentially painful diagnostic and therapeutic interventions. PMID- 27507900 TI - NIV for OHS without severe OSAS: is it worth it? PMID- 27507901 TI - Design and methods of the Population Assessment of Tobacco and Health (PATH) Study. AB - BACKGROUND: This paper describes the methods and conceptual framework for Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study data collection. The National Institutes of Health, through the National Institute on Drug Abuse, is partnering with the Food and Drug Administration's (FDA) Center for Tobacco Products to conduct the PATH Study under a contract with Westat. METHODS: The PATH Study is a nationally representative, longitudinal cohort study of 45 971 adults and youth in the USA, aged 12 years and older. Wave 1 was conducted from 12 September 2013 to 15 December 2014 using Audio Computer-Assisted Self Interviewing to collect information on tobacco-use patterns, risk perceptions and attitudes towards current and newly emerging tobacco products, tobacco initiation, cessation, relapse behaviours and health outcomes. The PATH Study's design allows for the longitudinal assessment of patterns of use of a spectrum of tobacco products, including initiation, cessation, relapse and transitions between products, as well as factors associated with use patterns. Additionally, the PATH Study collects biospecimens from consenting adults aged 18 years and older and measures biomarkers of exposure and potential harm related to tobacco use. CONCLUSIONS: The cumulative, population-based data generated over time by the PATH Study will contribute to the evidence base to inform FDA's regulatory mission under the Family Smoking Prevention and Tobacco Control Act and efforts to reduce the Nation's burden of tobacco-related death and disease. PMID- 27507902 TI - The inside and outside: topological issues in plant cell wall biosynthesis and the roles of nucleotide sugar transporters. AB - The cell wall is a complex extracellular matrix composed primarily of polysaccharides. Noncellulosic polysaccharides, glycoproteins and proteoglycans are synthesized in the Golgi apparatus by glycosyltransferases (GTs), which use nucleotide sugars as donors to glycosylate nascent glycan and glycoprotein acceptors that are subsequently exported to the extracellular space. Many nucleotide sugars are synthesized in the cytosol, leading to a topological issue because the active sites of most GTs are located in the Golgi lumen. Nucleotide sugar transporters (NSTs) overcome this problem by translocating nucleoside diphosphate sugars from the cytosol into the lumen of the organelle. The structures of the cell wall components synthesized in the Golgi are diverse and complex; therefore, transporter activities are necessary so that the nucleotide sugars can provide substrates for the GTs. In this review, we describe the topology of reactions involved in polysaccharide biosynthesis in the Golgi and focus on the roles of NSTs as well as their impacts on cell wall structure when they are altered. PMID- 27507903 TI - Full-spectrum (FUSE) versus standard forward-viewing colonoscopy in an organised colorectal cancer screening programme. AB - OBJECTIVE: Miss rate of polyps has been shown to be substantially lower with full spectrum endoscopy (FUSE) compared with standard forward-viewing (SFV) colonoscopy in a tandem study at per polyp analysis. However, there is uncertainty on whether FUSE is also associated with a higher detection rate of colorectal neoplasia, especially advanced lesions, in per patient analysis. METHODS: Consecutive subjects undergoing colonoscopy following a positive faecal immunochemical test (FIT) by experienced endoscopists and performed in the context of a regional colorectal cancer population-screening programme were randomised between colonoscopy with either FUSE or SFV colonoscopy in seven Italian centres. Randomisation was stratified by gender, age group and screening history. Primary outcomes included detection rates of advanced adenomas (A-ADR), adenomas (ADR) and sessile-serrated polyps (SSPDR). RESULTS: Of 741 eligible subjects, 658 were randomised to either FUSE (n=328) or SFV (n=330) colonoscopy and included in the analysis. Overall, 293/658 and 143/658 subjects had at least one adenoma (ADR 44.5%) and advanced adenoma (A-ADR 21.7%), respectively, while SSP was the most advanced lesion in 18 cases (SSPDR 2.7%). ADR and A-ADR were 43.6% and 19.5% in the FUSE arm, and 45.5% and 23.9% in the SFV arm, with no difference for both ADR (OR for FUSE: 0.96, 95% CI 0.81 to 1.14) and A-ADR (OR for FUSE: 0.82, 95% CI 0.61 to 1.09). No difference in SSPDR or multiplicity was detected between the two arms. In the per polyp analysis, the mean number of adenomas and proximal adenomas per patient was 0.81+/-1.25 and 0.47+/-0.93 in the FUSE arm, and 0.85+/-1.33 and 0.48+/-0.96 in the SFV colonoscopy arm (p=NS for both comparisons). CONCLUSIONS: No statistically significant difference in ADR and A-ADR between FUSE and SFV colonoscopy was detected in a per patient analysis in FIT-positive patients. TRIAL REGISTRATION NUMBER: ISRCTN10357435. PMID- 27507904 TI - Integrated genomic analysis of recurrence-associated small non-coding RNAs in oesophageal cancer. AB - OBJECTIVE: Oesophageal squamous cell carcinoma (ESCC) is a heterogeneous disease with variable outcomes that are challenging to predict. A better understanding of the biology of ESCC recurrence is needed to improve patient care. Our goal was to identify small non-coding RNAs (sncRNAs) that could predict the likelihood of recurrence after surgical resection and to uncover potential molecular mechanisms that dictate clinical heterogeneity. DESIGN: We developed a robust prediction model for recurrence based on the analysis of the expression profile data of sncRNAs from 108 fresh frozen ESCC specimens as a discovery set and assessment of the associations between sncRNAs and recurrence-free survival (RFS). We also evaluated the mechanistic and therapeutic implications of sncRNA obtained through integrated analysis from multiple datasets. RESULTS: We developed a risk assessment score (RAS) for recurrence with three sncRNAs (microRNA (miR)-223, miR 1269a and nc886) whose expression was significantly associated with RFS in the discovery cohort (n=108). RAS was validated in an independent cohort of 512 patients. In multivariable analysis, RAS was an independent predictor of recurrence (HR, 2.27; 95% CI, 1.26 to 4.09; p=0.007). This signature implies the expression of DeltaNp63 and multiple alterations of driver genes like PIK3CA. We suggested therapeutic potentials of immune checkpoint inhibitors in low-risk patients, and Polo-like kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase inhibitors in high-risk patients. CONCLUSION: We developed an easy-to-use prognostic model with three sncRNAs as robust prognostic markers for postoperative recurrence of ESCC. We anticipate that such a stratified and systematic, tumour-specific biological approach will potentially contribute to significant improvement in ESCC treatment. PMID- 27507905 TI - A randomised comparison of two faecal immunochemical tests in population-based colorectal cancer screening. AB - OBJECTIVE: Colorectal cancer screening programmes are implemented worldwide; many are based on faecal immunochemical testing (FIT). The aim of this study was to evaluate two frequently used FITs on participation, usability, positivity rate and diagnostic yield in population-based FIT screening. DESIGN: Comparison of two FITs was performed in a fourth round population-based FIT-screening cohort. Randomly selected individuals aged 50-74 were invited for FIT screening and were randomly allocated to receive an OC -Sensor (Eiken, Japan) or faecal occult blood (FOB)-Gold (Sentinel, Italy) test (March-December 2014). A cut-off of 10 ug haemoglobin (Hb)/g faeces (ie, 50 ng Hb/mL buffer for OC-Sensor and 59 ng Hb for FOB-Gold) was used for both FITs. RESULTS: In total, 19 291 eligible invitees were included (median age 61, IQR 57-67; 48% males): 9669 invitees received OC Sensor and 9622 FOB-Gold; both tests were returned by 63% of invitees (p=0.96). Tests were non-analysable in 0.7% of participants using OC-Sensor vs 2.0% using FOB-Gold (p<0.001). Positivity rate was 7.9% for OC-Sensor, and 6.5% for FOB-Gold (p=0.002). There was no significant difference in diagnostic yield of advanced neoplasia (1.4% for OC-Sensor vs 1.2% for FOB-Gold; p=0.15) or positive predictive value (PPV; 31% vs 32%; p=0.80). When comparing both tests at the same positivity rate instead of cut-off, they yielded similar PPV and detection rates. CONCLUSIONS: The OC-Sensor and FOB-Gold were equally acceptable to a screening population. However, FOB-Gold was prone to more non-analysable tests. Comparison between FIT brands is usually done at the same Hb stool concentration. Our findings imply that for a fair comparison on diagnostic yield between FIT's positivity rate rather than Hb concentration should be used. TRIAL REGISTRATION NUMBER: NTR5385; Results. PMID- 27507906 TI - Erratum: Are we meeting the standards set for endoscopy? Results of a large-scale prospective survey of endoscopic retrograde cholangio-pancreatograph practice. PMID- 27507908 TI - Efficacy of single serum cortisol reading obtained between 9 AM and 10 AM as an index of adrenal function in children treated with glucocorticoids or synthetic adrenocorticotropic hormone. AB - To find a simple method to screen for iatrogenic childhood adrenal insufficiency, we retrospectively examined the results of CRH stimulation tests performed 212 times on 111 subjects (68 males; age at commencement of initial treatment ranged 0.0-19.8 yr; median age, 5.8 yr). Before the commencement of this study, 97 subjects had been treated with glucocorticoids and 14 subjects with West syndrome had been treated with synthetic adrenocorticotropic hormone. Duration of the primary treatment ranged from 15 to 2150 days. CRH stimulation tests were conducted between 09:00 AM and 10:00 AM and peak cortisol values less than 15 ug/dL were considered indicative of adrenal insufficiency. The receiver operating characteristic curve showed that the optimal basal serum cortisol cut-off values when screening for adrenal suppression ranged from 5.35 to 5.80 ug/dL depending on the primary disease. All subjects having a serum cortisol value of less than 2.3 ug/dL had insufficient adrenal function while all subjects having greater than 11 ug/dL had intact adrenal function. We concluded that single serum cortisol values obtained between 09:00 AM and 10:00 AM had the potential to serve as an index of adrenal function in children treated with glucocorticoids or synthetic adrenocorticotropic hormone. PMID- 27507907 TI - Dry Eye Disease Incidence Associated with Chronic Graft-Host Disease: Nonconcurrent Cohort Study (An American Ophthalmological Society Thesis). AB - PURPOSE: To determine if chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with stable or progressive dry eye disease and to determine the true incidence in patients with no prior history of dry eye disease. METHODS: A nonconcurrent cohort study at a single institution with 136 patients who had no previous history of dry eye disease before HSCT. Survival analysis was used to estimate dry eye disease incidence. The incidence rate was calculated using life tables as the number of observed dry eye disease cases divided by the person-time at risk accumulated by the cohort. Transition probabilities were calculated from time of transplant to time of diagnosis, and then to last recorded visit. RESULTS: Incidence rate was 0.8 cases of dry eye disease per person-year, and half of the population at risk developed dry eye disease during the first 10 months post transplant. Time to develop dry eye disease was 2.5 months for mild dry eye disease, 9.6 months for moderate dry eye disease, and 13.2 months for severe dry eye disease. In terms of cumulative incidence, 73% of subjects developed dry eye disease (50% mild, 16% moderate, and 7% severe) at the time of diagnosis. CONCLUSIONS: Our findings suggest that dry eye disease associated with cGVHD is an extremely frequent event and shows a wide spectrum of severity, with a mild form presenting early and a moderate to severe form presenting later after HSCT. These findings need to be studied further to elucidate if these are two different pathophysiological entities or just different expressions of the same pathology. PMID- 27507909 TI - Potential utility of cinacalcet as a treatment for CDC73-related primary hyperparathyroidism: a case report. AB - We report a Japanese pedigree with familial primary hyperparathyroidism due to a CDC73 mutation. To our knowledge, this is the first report of cinacalcet as a treatment for CDC73-related primary hyperparathyroidism. The proband had severe psychomotor retardation and received laryngotracheal separation surgery. At 19 yr of age, he developed acute pancreatitis. Hypercalcemia (12.2-13.8 mg/dL), elevated levels of intact PTH (86-160 pg/mL), and a tumor detected upon neck ultrasonography led to the diagnosis of primary hyperparathyroidism. Family history and biochemical examinations revealed that three family members (the proband's mother, elder brother, and maternal grandfather) had primary hyperparathyroidism. We identified a novel heterozygous mutation, c.240delT, p.Glu81Lysfs*28, in the CDC73 gene in three affected family members, excluding the proband's elder brother who refused genetic testing. Parathyroidectomy for the proband was considered as high-risk, because the tumor was located close to the tracheostomy orifice. After receiving approval from the institutional review board and obtaining the consent, we initiated cinacalcet treatment. At 22 yr of age, treatment with 100 mg of cinacalcet maintained serum calcium levels below 11.0 mg/dL with no apparent side effects. Our report presents the potential efficacy of cinacalcet as a treatment for CDC73-related primary hyperparathyroidism, in particularly inoperative cases. PMID- 27507910 TI - Chromosome 6q24 methylation defects are uncommon in childhood-onset non autoimmune diabetes mellitus patients born appropriate- or large-for-gestational age. PMID- 27507911 TI - A Japanese familial case of hypochondroplasia with a novel mutation in FGFR3. PMID- 27507912 TI - A Japanese familial case of Schmid metaphyseal chondrodysplasia with a novel mutation in COL10A1. PMID- 27507913 TI - A novel NR3C2 mutation in a Japanese patient with the renal form of pseudohypoaldosteronism type 1. PMID- 27507914 TI - A novel frameshift mutation in the TRPS1 gene caused Tricho-rhino-phalangeal syndrome type I and III in a Japanese family. PMID- 27507915 TI - Comparative Evaluation of the Remineralizing Effects and Surface Micro hardness of Glass Ionomer Cements Containing Bioactive Glass (S53P4):An in vitro Study. AB - Dental cements including the glass ionomer cement (GIC) have found widespread use in restoring tooth structures. In this study, modifications of glass ionomer cements (GICs) were made by adding bioactive glass (BAG) to GIC to obtain bioactive restorative materials. This study used polarized light microscopy (PLM) to examine the remineralization effects of the study materials on dentin. It also evaluated the Vickers microhardness of the experimental materials. Experimental glass ionomer cement (GIC)-BAG materials were made by mixing 10 wt% of BAG particles with conventional cure and resin-modified GIC powders. Class V restorations were made in 80 extracted mandibular teeth which included 4 groups of 20 teeth each. 100 |jm sections of the teeth were examined under polarized light microscope after undergoing pH cycling. Materials were also processed into 80 cylindrical specimens and immersed in water for 7 and 30 days before mechanical tests. Resin-modified GIC containing BAG showed a thick uniform layer of mineralization on the restoration-dentin interface. The conventional cure GIC based materials had higher surface microhardness than the resin-modified materials. SIGNIFICANCE: The addition of BAG to GIC compromises the mechanical properties of the materials to some extent. Thus, their clinical use ought to be restricted to applications where their bioactivity can be beneficial, such as root surface fillings and liners in dentistry. PMID- 27507916 TI - Interrelationship among Dental, Skeletal and Chronological Ages in Urban and Rural Female Children. AB - AIM: This study was an attempt, to determine chronological age, dental age and skeletal age, and to establish interrelationship, amongst the dental, skeletal and chronological ages and their differences if any between rural and urban female children. The study included 80 girls aged 8 to 14 years from rural and urban areas. MATERIAL AND METHODS: The subjects were divided into 4 Groups: Group I, II, III, and IV. Group I and II comprising of rural female subjects, wherein Group I comprised of 8 to 11 years and Group II comprised of 11 to 14 years old females. Group III and IV comprising of urban females wherein Group III included 8 to 11 years and Group IV comprised of 11 to 14 years old females. Orthopantomograms and hand and wrist radiographs were taken. The calcification status of permanent teeth was evaluated from orthopantomograms, and dental age was calculated according to Demirjian's method. The stages of ossification of various carpal bones were evaluated from the hand-wrist radiograph using radiographic atlas of Greulich and Pyle and skeletal age was calculated. The chronological age was recorded from the actual date of birth. RESULTS: Data collected was statistically analyzed. CONCLUSION: Highly significant correlation was observed between dental and skeletal age (r=0.752, p-value < 0.01) in total sample. Strong correlation of chronological age with dental and skeletal age was also observed (r=0.650, r = 0.620, respectively). Out of all three correlations, dental age and skeletal age had the maximum correlation in total sample. While comparing rural and urban sample as regard to ages or correlations no significant difference was found (p-value < 0.01). PMID- 27507917 TI - Aloe-Vera: A Nature's Gift to Children. AB - (1)Aloe-Barbadensis Mill (Liliaceae) is used in the traditional medicine of Mexico and other countries for anti-inflammatory and cosmetic purposes (Diez Martinez 1981, Grindlay and Reynolds 1986). Two components are obtained from the fresh leaves of Aloe-Barbadensis, a bitter yellow juice (exudate), which drains from the transversally cut leaves used as a laxative (Ishii et al 1990) and a mucilaginous gel from leaf parenchyma, which has been used as a remedy for a variety of pathological states such as arthritis, gout, acne, dermatitis, burns and peptic ulcers induced by epithelial alterations (Cap-passo and Ganginella 1997, Reynolds and Dweek 1999). The aim of this study is to evaluate efficacy of Aloe-Vera gel as a healing agent in an endodontic procedure called pulpotomy. Fifteen primary molars were treated for pulpotomy using 'Aloe-Vera gel'. Patients were recalled after 1 month to check for any clinical symptoms. None of the patients reported with clinical symptoms of pain, mobility, abscess and histopathological evaluation done following extraction after 2 months showed positive signs of healing. PMID- 27507918 TI - Antibacterial Properties of Fluoride Releasing Glass lonomer Cements (GICs) and Pit and Fissure Sealants on Streptococcus Mutans. AB - TITLE: Antibacterial properties of fluoride releasing glass Ionomer cements (GICs) and pit and fissure sealants on Streptococcus mutans. BACKGROUND: Occlusal pit and fissures are the most susceptible sites for dental caries. The clinical effectiveness of GICs and fissure sealants in preventing caries is well documented, but there is some concern about bacteria left beneath sealants. OBJECTIVE: (1) Study the antibacterial activity of GICs and pit and fissure sealants. (2) Compare between these materials. METHODOLOGY: GICs (Fuji IX GP and Ketac molar) and pit and fissure sealants (Teethmate-F1 and Helioseal-F ). The strains was grown in the Brain Heart Infusion broth and was incubated anaerobically for 18 hours at 37 degrees C and subcultured in MSB agar.Four wells measuring 5 mm diameter was prepared on each agar plate and the prepared materials was placed and further incubated anaerobically for 48 hours at 37 degrees C. The zone of inhibition was measured. RESULTS: All the materials tested showed antibacterial properties to varying levels except; among pit and fissure sealants it is Teethmate-F which showed more antibacterial property. CONCLUSION: Teethmate-F1 sealant showed more antibacterial property compared to Fuji IX and Ketac molar. Helioseal-F did not show any antibacterial property. PMID- 27507919 TI - Fabrication of an Ocular Prosthesis for a Pediatric Retinoblastoma Patient by a Simplified Technique. AB - Retinoblastoma is one of the more highly invasive and common intraocular malignancies of childhood. Treatment in most of the cases consists of enucleation followed by placement of orbital implants. Prosthetic rehabilitation is especially challenging in younger and precooperative pediatric patients. The following case report describes the rehabilitation of a 4-year-old child with retinoblastoma, with an ocular prosthesis fabricated by a simplified technique. PMID- 27507920 TI - Bilateral Transverse Facial Cleft as an Isolated and Asyndromic Deformity. AB - Congenital macrostomia or transverse facial cleft is a rare congenital craniofacial anomaly, which affects the esthetics and functions of oral cavity. It is usually associated with deformities of other structures developed from the first and second branchial arches. Bilateral transverse cleft, occurring alone is uncommon. Since the deformity is rare, its treatment has not been commonly described in the literature. We report a case of congenital bilateral macrostomia as an isolated, asyndromic deformity to add one more case in the literature and surgical technique has been discussed here. PMID- 27507921 TI - Radix Entomolaris: A Clinical Challenge. AB - A major anatomical variant of the two-rooted mandibular first molar is a tooth with an additional distolingual third root: The radix entomolaris (RE). It is essential to anticipate and find all roots and canals during root canal treatment. Proper angulations and interpretation of radiographs help to identify pulp chamber and root anatomy. If present, an awareness and understanding of this unusual root and its root canal morphology can contribute to the successful outcome of root canal treatment. PMID- 27507922 TI - Management of Developing Anterior Malocclusion due to SupernumeraryTooth with Preventive and Intercep-tive Approach: A 11/2 Year Case Study. AB - Variety of clinical complications occurs due to the presence of supernumerary teeth, especially mesiodens. It may result in impaction of one or both central incisors which in turn may lead to a variety of malocclusions. Timely intervention not only prevents malocclusion but also the time taken for corrective orthodontics. A complete case report of developing mesiodens' tooth germ resulting in malocclusion including treatment in 11/2 year period is presented. PMID- 27507923 TI - Maxillary Growth Encircling the Central Incisor Crown. AB - During osteogenesis, mesenchymal tissues function to form fibrous matrix which changes into bone by ossification. In rare instances, fibrous matrix persists in which foci of immature bone is evident resulting in progressive enlargement. Such conditions are commonly benign in nature but few are anatomically benign and clinically destructive. Though recurrence and residual defects following surgical treatment are the challenging complications, fatal consequences are infrequent. We report a juvenile case of ossifying fibroma with an aim to highlight its clinical course and salient criteria to differentiate this entity from the common variants. PMID- 27507924 TI - Complex Composite Odontoma. AB - Odontomas are hamartomas composed of various dental tissues, i.e. enamel, dentin, cementum and sometimes pulp. They are slow-growing, benign tumors showing nonaggressive behavior. Most of the odontomes are asymptomatic with unknown etiology, although occasional signs and symptoms related to their presence do occur. Presented here is the case report of 10-year-old girl with impacted left central incisor. PMID- 27507925 TI - Conservative Management of Dens Evaginatus: Report of Two Unusual Cases. AB - Dens evaginatus (DE) is a rare developmental anomaly characterized by presence of an extra cusp arising from occlusal or lingual surfaces. Isolated occurrence or concomitant presence of DE with other dental anomalies has been reported. DE commonly affects permanent teeth and is rarely seen in primary dentition. Treatment may be conservative or radical. This article presents two unusual cases of concomitant occurrence of a supernumerary tooth and DE affecting maxillary deciduous lateral incisor and conservative management of DE occurring concurrently with a possible Oehler's type I invagination in maxillary permanent lateral incisor. PMID- 27507926 TI - Editorial. PMID- 27507927 TI - Nurse students' experiences with clinical placement in outpatient unit - a qualitative study. AB - BACKGROUND: The recent reforms in the health care sector have changed the requirements for professional nursing competence in the clinical field. The reforms have also required nursing education to consider different areas for clinical placements for their students, and outpatient units in hospitals have been increasingly formalized as clinical learning environments. The complex technologies in some of these units represent a challenge for students who have limited existing knowledge or experience. More focus on outpatient care has also led to fewer opportunities for studying the continuity of a patient's life situation. In order to meet these challenges, structured learning activities with special forms were developed by nursing educators and nurses at outpatient units. The aim of this study was to explore students' experiences of using structured learning activities as unit-specific learning outcomes and targeted reflection during clinical placements in an outpatient unit. METHODS: Two focus group interviews were conducted with a total of seven nursing students who had experienced structured learning activities during clinical placements in an outpatient unit. Data were analyzed by means of content analyses. RESULTS: This study shows that preparedness and guidance during placement were imperative for making the week in the outpatient unit meaningful. 'Being prepared', which was one of the categories, incorporated the subcategories 'being able to understand what to do', 'being at the right place at the right time' and 'being alert for new experiences'. The category 'being guided' which incorporated the subcategories 'from uncertainty to more confidence', 'from observer to seeking knowledge' and 'from focusing on technology to seeing the person' showed that the forms guided the students through the placement in the outpatient unit. DISCUSSION: Students take a more active approach to seeking knowledge when given structured learing activities during clinical placement in outpatient unit. CONCLUSIONS: This study shows that use of outpatient units for clinical placement in nursing studies has several challenges but also the potential for creating positive experiences for the students. PMID- 27507928 TI - Current tobacco use and its associated factors among adults in a country with comprehensive ban on tobacco: findings from the nationally representative STEPS survey, Bhutan, 2014. AB - BACKGROUND: Despite a comprehensive ban on cultivation, manufacture, distribution, and sale of tobacco products since 2004, two nationwide surveys conducted in 2012 and 2013 reported high tobacco use in Bhutan. National Health Survey 2012 reported that 4 % of the population aged 15-75 years used smoked tobacco and about 48 % used smokeless tobacco. Similarly, Global Youth Tobacco Survey (GYTS) of Bhutan reported tobacco use prevalence of 30.3 % in 2013. However, factors associated with this high tobacco use were not systematically studied. Hence, we assessed the prevalence of tobacco use and its associated sociodemographic, behavioral, and environmental factors. METHODS: This cross sectional analytical study used secondary data collected in a nationally representative Non-communicable Disease Risk Factors Surveillance STEPS Survey 2014 conducted among Bhutanese adults (18-69 years). The survey included a total of 2820 adults; selected using multistage stratified cluster sampling. Weighted analysis was done to calculate the prevalence of tobacco use. Unadjusted and adjusted prevalence ratios were calculated using log binomial regression. RESULTS: The prevalence of current overall tobacco use was 24.8 % (95 % CI: 21.4 28.3) and that of smoked, smokeless, and dual forms (smoked and smokeless forms) were 7.4 % (95 % CI: 5.8-9.0), 19.7 % (95 % CI: 16.5-22.9), and 2.3 % (95 % CI: 1.8-2.9), respectively. Significantly higher prevalence of tobacco use in all forms was found among males, younger age groups, and alcohol users. The prevalence of smoked form was higher in urban areas compared to rural areas (11 % vs 6 %; aPR 1.8, 95 % CI: 1.5-2.0). Among individuals who reported having a non communicable disease, the prevalence of smoked tobacco use was significantly lower than those who did not have disease (3.5 % vs. 8.3 %; aPR 0.5, 95 % CI: 0.3 0.9). Exposure to health warnings was protective for current tobacco use and smokeless tobacco use, while exposure to tobacco warnings through the media was helpful among smokers and overall tobacco users. CONCLUSIONS: Despite a comprehensive ban on tobacco, tobacco use was high in Bhutan, especially the smokeless form. Males, younger age groups, and alcohol users should be targeted with behavioral interventions along the stricter implementation of tobacco control measures. PMID- 27507930 TI - Effects of varenicline on sympatho-vagal balance and cue reactivity during smoking withdrawal: a randomised placebo-controlled trial. AB - BACKGROUND: Varenicline is an effective smoking cessation medication. Some concern has been raised that its use may precipitate adverse cardiovascular events although no patho-physiological mechanism potentially underlying such an effect has been reported. The aim of this study was to test the hypothesis that varenicline impacts on sympatho-vagal balance during smoking withdrawal. METHODS: In this randomised, placebo-controlled trial, muscle sympathetic nerve activity (MSNA), baroreflex sensitivity (BRS), heart rate, and blood pressure were assessed in 17 smokers four weeks before a quit attempt (baseline) and again on the third day of that quit attempt (acute smoking withdrawal). RESULTS: Regarding the primary endpoint of our study, we did not find a significant effect of varenicline compared to placebo on changes in MSNA burst incidence between baseline and acute smoking withdrawal (-3.0 +/- 3.3 vs.-3.9 +/- 5.0 bursts/100 heart beats; p = 0.308). However, heart rate and systolic blood pressure significantly decreased in the placebo group only, while no significant changes in these parameters were observed in the varenicline group. Exposure to smoking cues during acute withdrawal lead to a significant increase of heart rate in the placebo group, while heart rate decreased in the varenicline group, and the difference in these changes was significant between groups (+2.7 +/- 1.0 vs.-1.8 +/- 0.5 1/min; p = 0.002). In all 17 participants combined, a significant increase in heart rate during smoking cue exposure was detected in subjects who relapsed in the course of six weeks after the quit date compared to those who stayed abstinent (+2.5 +/- 1.2 vs.-1.1 +/- 0.7; p = 0.018). Six-week abstinence rates were higher in the varenicline group compared to placebo (88 vs. 22 % p = 0.015). CONCLUSION: We did not find evidence of adverse effects of varenicline on sympatho-vagal balance. Varenicline probably blunts the heart rate response to smoking cues, which may be linked to improved cessation outcome. PMID- 27507929 TI - Estrogen-related receptor beta (ERRbeta) - renaissance receptor or receptor renaissance? AB - Estrogen-related receptors (ERRs) are founding members of the orphan nuclear receptor (ONR) subgroup of the nuclear receptor superfamily. Twenty-seven years of study have yet to identify cognate ligands for the ERRs, though they have firmly placed ERRalpha and ERRgamma at the intersection of cellular metabolism and oncogenesis. The pace of discovery for novel functions of ERRbeta, however, has until recently been somewhat slower than that of its family members. ERRbeta has also been largely ignored in summaries and perspectives of the ONR literature. Here, we provide an overview of established and emerging knowledge of ERRbeta in mouse, man, and other species, highlighting unique aspects of ERRbeta biology that set it apart from the other two estrogen-related receptors, with a focus on the impact of alternative splicing on the structure and function of this receptor. PMID- 27507931 TI - Entire Sound Representations Are Time-Compressed in Sensory Memory: Evidence from MMN. AB - In order to examine the encoding of partial silence included in a sound stimulus in neural representation, time flow of the sound representations was investigated using mismatch negativity (MMN), an ERP component that reflects neural representation in auditory sensory memory. Previous work suggested that time flow of auditory stimuli is compressed in neural representations. The stimuli used were a full-stimulus of 170 ms duration, an early-gap stimulus with silence for a 20-50 ms segment (i.e., an omitted segment), and a late-gap stimulus with an omitted segment of 110-140 ms. Peak MMNm latencies from oddball sequences of these stimuli, with a 500 ms SOA, did not reflect time point of the physical gap, suggesting that temporal information can be compressed in sensory memory. However, it was not clear whether the whole stimulus duration or only the omitted segment duration is compressed. Thus, stimuli were used in which the gap was replaced by a tone segment with a 1/4 sound pressure level (filled), as well as the gap stimuli. Combinations of full-stimuli and one of four gapped or filled stimuli (i.e., early gap, late gap, early filled, and late filled) were presented in an oddball sequence (85 vs. 15%). If compression occurs only for the gap duration, MMN latency for filled stimuli should show a different pattern from those for gap stimuli. MMN latencies for the filled conditions showed the same pattern as those for the gap conditions, indicating that the whole stimulus duration rather than only gap duration is compressed in sensory memory neural representation. These results suggest that temporal aspects of silence are encoded in the same manner as physical sound. PMID- 27507932 TI - Evidence for a Role of Orexin/Hypocretin System in Vestibular Lesion-Induced Locomotor Abnormalities in Rats. AB - Vestibular damage can induce locomotor abnormalities in both animals and humans. Rodents with bilateral vestibular loss showed vestibular deficits syndrome such as circling, opisthotonus as well as locomotor and exploratory hyperactivity. Previous studies have investigated the changes in the dopamine system after vestibular loss, but the results are inconsistent and inconclusive. Numerous evidences indicate that the orexin system is implicated in central motor control. We hypothesized that orexin may be potentially involved in vestibular loss induced motor disorders. In this study, we examined the effects of arsanilate- or 3,3'-iminodipropionitrile (IDPN)-induced vestibular lesion (AVL or IVL) on the orexin-A (OXA) labeling in rat hypothalamus using immunohistochemistry. The vestibular lesion-induced locomotor abnormalities were recorded and verified using a histamine H4 receptor antagonist JNJ7777120 (20 mg/kg, i.p.). The effects of the orexin receptor type 1 antagonist SB334867 (16 MUg, i.c.v.) on these behavior responses were also investigated. At 72 h post-AVL and IVL, animals exhibited vestibular deficit syndrome and locomotor hyperactivity in the home cages. These responses were significantly alleviated by JNJ7777120 which also eliminated AVL-induced increases in exploratory behavior in an open field. The numbers of OXA-labeled neurons in the hypothalamus were significantly increased in the AVL animals at 72 h post-AVL and in the IVL animals at 24, 48, and 72 h post-IVL. SB334867 significantly attenuated the vestibular deficit syndrome and locomotor hyperactivity at 72 h post-AVL and IVL. It also decreased exploratory behavior in the AVL animals. These results suggested that the alteration of OXA expression might contribute to locomotor abnormalities after acute vestibular lesion. The orexin receptors might be the potential therapeutic targets for vestibular disorders. PMID- 27507933 TI - Analysis of Amyloid Precursor Protein Function in Drosophila melanogaster. AB - The Amyloid precursor protein (APP) has mainly been investigated in connection with its role in Alzheimer's Disease (AD) due to its cleavage resulting in the production of the Abeta peptides that accumulate in the plaques characteristic for this disease. However, APP is an evolutionary conserved protein that is not only found in humans but also in many other species, including Drosophila, suggesting an important physiological function. Besides Abeta, several other fragments are produced by the cleavage of APP; large secreted fragments derived from the N-terminus and a small intracellular C-terminal fragment. Although these fragments have received much less attention than Abeta, a picture about their function is finally emerging. In contrast to mammals, which express three APP family members, Drosophila expresses only one APP protein called APP-like or APPL. Therefore APPL functions can be studied in flies without the complication that other APP family members may have redundant functions. Flies lacking APPL are viable but show defects in neuronal outgrowth in the central and peripheral nervous system (PNS) in addition to synaptic changes. Furthermore, APPL has been connected with axonal transport functions. In the adult nervous system, APPL, and more specifically its secreted fragments, can protect neurons from degeneration. APPL cleavage also prevents glial death. Lastly, APPL was found to be involved in behavioral deficits and in regulating sleep/activity patterns. This review, will describe the role of APPL in neuronal development and maintenance and briefly touch on its emerging function in circadian rhythms while an accompanying review will focus on its role in learning and memory formation. PMID- 27507934 TI - Neuronal Actin Dynamics, Spine Density and Neuronal Dendritic Complexity Are Regulated by CAP2. AB - Actin remodeling is crucial for dendritic spine development, morphology and density. CAP2 is a regulator of actin dynamics through sequestering G-actin and severing F-actin. In a mouse model, ablation of CAP2 leads to cardiovascular defects and delayed wound healing. This report investigates the role of CAP2 in the brain using Cap2(gt/gt) mice. Dendritic complexity, the number and morphology of dendritic spines were altered in Cap2(gt/gt) with increased number of excitatory synapses. This was accompanied by increased F-actin content and F actin accumulation in cultured Cap2(gt/gt) neurons. Moreover, reduced surface GluA1 was observed in mutant neurons under basal condition and after induction of chemical LTP. Additionally, we show an interaction between CAP2 and n-cofilin, presumably mediated through the C-terminal domain of CAP2 and dependent on cofilin Ser3 phosphorylation. In vivo, the consequences of this interaction were altered phosphorylated cofilin levels and formation of cofilin aggregates in the neurons. Thus, our studies identify a novel role of CAP2 in neuronal development and neuronal actin dynamics. PMID- 27507935 TI - Sustained Exocytosis after Action Potential-Like Stimulation at Low Frequencies in Mouse Chromaffin Cells Depends on a Dynamin-Dependent Fast Endocytotic Process. AB - Under basal conditions the action potential firing rate of adrenal chromaffin cells is lower than 0.5 Hz. The maintenance of the secretory response at such frequencies requires a continuous replenishment of releasable vesicles. However, the mechanism that allows such vesicle replenishment remains unclear. Here, using membrane capacitance measurements on mouse chromaffin cells, we studied the mechanism of replenishment of a group of vesicles released by a single action potential-like stimulus (APls). The exocytosis triggered by APls (ETAP) represents a fraction (40%) of the immediately releasable pool, a group of vesicles highly coupled to voltage dependent calcium channels. ETAP was replenished with a time constant of 0.73 +/- 0.11 s, fast enough to maintain synchronous exocytosis at 0.2-0.5 Hz stimulation. Regarding the mechanism involved in rapid ETAP replenishment, we found that it depends on the ready releasable pool; indeed depletion of this vesicle pool significantly delays ETAP replenishment. On the other hand, ETAP replenishment also correlates with a dynamin-dependent fast endocytosis process (tau = 0.53 +/- 0.01 s). In this regard, disruption of dynamin function markedly inhibits the fast endocytosis and delays ETAP replenishment, but also significantly decreases the synchronous exocytosis during repetitive APls stimulation at low frequencies (0.2 and 0.5 Hz). Considering these findings, we propose a model in where both the transfer of vesicles from ready releasable pool and fast endocytosis allow rapid ETAP replenishment during low stimulation frequencies. PMID- 27507936 TI - Distinct Roles of SOM and VIP Interneurons during Cortical Up States. AB - During cortical network activity, recurrent synaptic excitation among pyramidal neurons is approximately balanced by synaptic inhibition, which is provided by a vast diversity of inhibitory interneurons. The relative contributions of different interneuron subtypes to inhibitory tone during cortical network activity is not well-understood. We previously showed that many of the major interneuron subtypes in mouse barrel cortex are highly active during Up states (Neske et al., 2015); while fast-spiking (FS), parvalbumin (PV)-positive cells were the most active interneuron subtype, many non-fast-spiking (NFS), PV negative interneurons were as active or more active than neighboring pyramidal cells. This suggests that the NFS cells could play a role in maintaining or modulating Up states. Here, using optogenetic techniques, we further dissected the functional roles during Up states of two major NFS, PV-negative interneuron subtypes: somatostatin (SOM)-positive cells and vasoactive intestinal peptide (VIP)-positive cells. We found that while pyramidal cell excitability during Up states significantly increased when SOM cells were optogenetically silenced, VIP cells did not influence pyramidal cell excitability either upon optogenetic silencing or activation. VIP cells failed to contribute to Up states despite their ability to inhibit SOM cells strongly. We suggest that the contribution of VIP cells to the excitability of pyramidal cells may vary with cortical state. PMID- 27507937 TI - Spatiotemporal Features of Retinal Waves Instruct the Wiring of the Visual Circuitry. AB - Coordinated spontaneous activity is present in different sensory systems during early stages of development. This activity is thought to play a critical role in the development of sensory representations before the maturation of sensory experience. In the visual system, the mechanisms by which spatiotemporal properties of retinal spontaneous activity, called retinal waves, drive developmental events has been well studied. Recent advancements in pharmacological, genetic, and optogenetic manipulations have provided further understanding of the contribution of specific spatiotemporal properties of retinal waves to eye-specific segregation and retinotopic refinement of retinofugal projections. Here we review some of the recent progress in understanding the role of retinal waves in the early stages of visual system development, prior to the maturation of vision. PMID- 27507938 TI - The Pointing Errors in Optic Ataxia Reveal the Role of "Peripheral Magnification" of the PPC. AB - Interaction with visual objects in the environment requires an accurate correspondence between visual space and its internal representation within the brain. Many clinical conditions involve some impairment in visuo-motor control and the errors created by the lesion of a specific brain region are neither random nor uninformative. Modern approaches to studying the neuropsychology of action require powerful data-driven analyses and error modeling in order to understand the function of the lesioned areas. In the present paper we carried out mixed-effect analyses of the pointing errors of seven optic ataxia patients and seven control subjects. We found that a small parameter set is sufficient to explain the pointing errors produced by unilateral optic ataxia patients. In particular, the extremely stereotypical errors made when pointing toward the contralesional visual field can be fitted by mathematical models similar to those used to model central magnification in cortical or sub-cortical structure(s). Our interpretation is that visual areas that contain this footprint of central magnification guide pointing movements when the posterior parietal cortex (PPC) is damaged and that the functional role of the PPC is to actively compensate for the under-representation of peripheral vision that accompanies central magnification. Optic ataxia misreaching reveals what would be hand movement accuracy and precision if the human motor system did not include elaborated corrective processes for reaching and grasping to non-foveated targets. PMID- 27507939 TI - Increased Functional Activation of Limbic Brain Regions during Negative Emotional Processing in Migraine. AB - Pain is both an unpleasant sensory and emotional experience. This is highly relevant in migraine where cortical hyperexcitability in response to sensory stimuli (including pain, light, and sound) has been extensively reported. However, migraine may feature a more general enhanced response to aversive stimuli rather than being sensory-specific. To this end we used functional magnetic resonance imaging to assess neural activation in migraineurs interictaly in response to emotional visual stimuli from the International Affective Picture System. Migraineurs, compared to healthy controls, demonstrated increased neural activity in response to negative emotional stimuli. Most notably in regions overlapping in their involvement in both nociceptive and emotional processing including the posterior cingulate, caudate, amygdala, and thalamus (cluster corrected, p < 0.01). In contrast, migraineurs and healthy controls displayed no and minimal differences in response to positive and neutral emotional stimuli, respectively. These findings support the notion that migraine may feature more generalized altered cerebral processing of aversive/negative stimuli, rather than exclusively to sensory stimuli. A generalized hypersensitivity to aversive stimuli may be an inherent feature of migraine, or a consequential alteration developed over the duration of the disease. This proposed cortical-limbic hypersensitivity may form an important part of the migraine pathophysiology, including psychological comorbidity, and may represent an innate sensitivity to aversive stimuli that underpins attack triggers, attack persistence and (potentially) gradual headache chronification. PMID- 27507941 TI - Neural Correlates of Fear of Movement in Patients with Chronic Low Back Pain vs. Pain-Free Individuals. AB - Fear of movement (FOM) can be acquired by a direct aversive experience such as pain or by social learning through observation and instruction. Excessive FOM results in heightened disability and is an obstacle for recovery from acute, subacute, and chronic low back pain (cLBP). FOM has further been identified as a significant explanatory factor in the Fear Avoidance (FA) model of cLBP that describes how individuals experiencing acute back pain may become trapped into a vicious circle of chronic disability and suffering. Despite a wealth of evidence emphasizing the importance of FOM in cLBP, to date, no related neural correlates in patients were found and this therefore has initiated a debate about the precise contribution of fear in the FA model. In the current fMRI study, we applied a novel approach encompassing: (1) video clips of potentially harmful activities for the back as FOM inducing stimuli; and (2) the assessment of FOM in both, cLBP patients (N = 20) and age- and gender-matched pain-free subjects (N = 20). Derived from the FA model, we hypothesized that FOM differentially affects brain regions involved in fear processing in patients with cLBP compared to pain free individuals due to the recurrent pain and subsequent avoidance behavior. The results of the whole brain voxel-wise regression analysis revealed that: (1) FOM positively correlated with brain activity in fear-related brain regions such as the amygdala and the insula; and (2) differential effects of FOM between patients with cLBP and pain-free subjects were found in the extended amygdala and in its connectivity to the anterior insula. Current findings support the FOM component of the FA model in cLBP. PMID- 27507940 TI - A Direct Cortico-Nigral Pathway as Revealed by Constrained Spherical Deconvolution Tractography in Humans. AB - Substantia nigra is an important neuronal structure, located in the ventral midbrain, that exerts a regulatory function within the basal ganglia circuitry through the nigro-striatal pathway. Although its subcortical connections are relatively well-known in human brain, little is known about its cortical connections. The existence of a direct cortico-nigral pathway has been demonstrated in rodents and primates but only hypothesized in humans. In this study, we aimed at evaluating cortical connections of substantia nigra in vivo in human brain by using probabilistic constrained spherical deconvolution (CSD) tractography on magnetic resonance diffusion weighted imaging data. We found that substantia nigra is connected with cerebral cortex as a whole, with the most representative connections involving prefrontal cortex, precentral and postcentral gyri and superior parietal lobule. These results may be relevant for the comprehension of the pathophysiology of several neurological disorders involving substantia nigra, such as parkinson's disease, schizophrenia, and pathological addictions. PMID- 27507942 TI - Visualizing Presynaptic Calcium Dynamics and Vesicle Fusion with a Single Genetically Encoded Reporter at Individual Synapses. AB - Synaptic transmission depends on the influx of calcium into the presynaptic compartment, which drives neurotransmitter release. Genetically encoded reporters are widely used tools to understand these processes, particularly pHluorin-based reporters that report vesicle exocytosis and endocytosis through pH dependent changes in fluorescence, and genetically encoded calcium indicators (GECIs) that exhibit changes in fluorescence upon binding to calcium. The recent expansion of the color palette of available indicators has made it possible to image multiple probes simultaneously within a cell. We have constructed a single molecule reporter capable of concurrent imaging of both presynaptic calcium influx and exocytosis, by fusion of sypHy, the vesicle associated protein synaptophysin containing a GFP-based pHluorin sensor, with the red-shifted GECI R-GECO1. Due to the fixed stoichiometry of the two probes, the ratio of the two responses can also be measured, providing an all optical correlate of the calcium dependence of release. Here, we have characterized stimulus-evoked sypHy-RGECO responses of hippocampal synapses in vitro, exploring the effects of different stimulus strengths and frequencies as well as variations in external calcium concentrations. By combining live sypHy-RGECO imaging with post hoc fixation and immunofluorescence, we have also investigated correlations between structural and functional properties of synapses. PMID- 27507943 TI - Age-Related Decrease in Heat Shock 70-kDa Protein 8 in Cerebrospinal Fluid Is Associated with Increased Oxidative Stress. AB - Age-associated declines in protein homeostasis mechanisms ("proteostasis") are thought to contribute to age-related neurodegenerative disorders. The increased oxidative stress which occurs with aging can activate a key proteostatic process, chaperone-mediated autophagy. This study investigated age-related alteration in cerebrospinal fluid (CSF) concentrations of heat shock 70-kDa protein 8 (HSPA8), a molecular chaperone involved in proteostatic mechanisms including chaperone mediated autophagy, and its associations with indicators of oxidative stress (8 hydroxy-2'-deoxyguanosine [8-OHdG] and 8-isoprostane) and total anti-oxidant capacity. We examined correlations between age, HSPA8, 8-OHdG, 8-isoprostane, and total antioxidant capacity (TAC) in CSF samples from 34 healthy subjects ranging from 20 to 75 years of age. Age was negatively associated with HSPA8 (rho = 0.47; p = 0.005). An age-related increase in oxidative stress was indicated by a positive association between age and 8-OHdG (rho = 0.61; p = 0.0001). HSPA8 was moderately negatively associated with 8-OHdG (rho = -0.58; p = 0.0004). Age and HSPA8 were weakly associated with 8-isoprostane and TAC (range of rho values: 0.15 to 0.16). Our findings in this exploratory study suggest that during healthy aging, CSF HSPA8 may decrease, perhaps due in part to an increase in oxidative stress. Our results also suggest that 8-OHdG may be more sensitive than 8 isoprostane for measuring oxidative stress in CSF. Further studies are indicated to determine if our findings can be replicated with a larger cohort, and if the age-related decrease in HSPA8 in CSF is reflected by a similar change in the brain. PMID- 27507944 TI - Mood Influences the Concordance of Subjective and Objective Measures of Sleep Duration in Older Adults. AB - OBJECTIVE/BACKGROUND: Sleep plays a central role in maintaining health and cognition. In most epidemiologic studies, sleep is evaluated by self-report questionnaires but several reports suggest that these evaluations might be less accurate than objective measures such as polysomnography or actigraphy. Determinants of the discrepancy between objective and subjective measures remain to be investigated. The aim of this pilot-study was to examine the role of mood states in determining the discrepancy observed between objective and subjective measures of sleep duration in older adults. PATIENTS/METHODS: Objective sleep quantity and quality were recorded by actigraphy in a sample of 45 elderly subjects over at least three consecutive nights. Subjective sleep duration and supplementary data, such as mood status and memory, were evaluated using ecological momentary assessment (EMA). RESULTS: A significant discrepancy was observed between EMA and actigraphic measures of sleep duration (p < 0.001). The magnitude of this difference was explained by the patient's mood status (p = 0.020). No association was found between the magnitude of this discrepancy and age, sex, sleep quality or memory performance. CONCLUSION: The discrepancy classically observed between objective and subjective measures of sleep duration can be explained by mood status at the time of awakening. These results have potential implications for epidemiologic and clinical studies examining sleep as a risk factor for morbidity or mortality. PMID- 27507945 TI - Cannabinoids As Potential Treatment for Chemotherapy-Induced Nausea and Vomiting. AB - Despite the advent of classic anti-emetics, chemotherapy-induced nausea is still problematic, with vomiting being somewhat better managed in the clinic. If post treatment nausea and vomiting are not properly controlled, anticipatory nausea-a conditioned response to the contextual cues associated with illness-inducing chemotherapy-can develop. Once it develops, anticipatory nausea is refractive to current anti-emetics, highlighting the need for alternative treatment options. One of the first documented medicinal uses of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was for the treatment of chemotherapy-induced nausea and vomiting (CINV), and recent evidence is accumulating to suggest a role for the endocannabinoid system in modulating CINV. Here, we review studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system in human patients and pre-clinical animal models of nausea and vomiting. PMID- 27507946 TI - Relationship between Age and the Ability to Break Scored Tablets. AB - BACKGROUND: Practical problems with the use of medicines, such as difficulties with breaking tablets, are an often overlooked cause for non-adherence. Tablets frequently break in uneven parts and loss of product can occur due to crumbling and powdering. Health characteristics, such as the presence of peripheral neuropathy, decreased grip strength and manual dexterity, can affect a patient's ability to break tablets. As these impairments are associated with aging and age related diseases, such as Parkinson's disease and arthritis, difficulties with breaking tablets could be more prevalent among older adults. The objective of this study was to investigate the relationship between age and the ability to break scored tablets. METHODS: A comparative study design was chosen. Thirty-six older adults and 36 young adults were systematically observed with breaking scored tablets. Twelve different tablets were included. All participants were asked to break each tablet by three techniques: in between the fingers with the use of nails, in between the fingers without the use of nails and pushing the tablet downward with one finger on a solid surface. It was established whether a tablet was broken or not, and if broken, whether the tablet was broken accurately or not. RESULTS: The older adults experienced more difficulties to break tablets compared to the young adults. On average, the older persons broke 38.1% of the tablets, of which 71.0% was broken accurately. The young adults broke 78.2% of the tablets, of which 77.4% was broken accurately. Further analysis by mixed effects logistic regression revealed that age was associated with the ability to break tablets, but not with the accuracy of breaking. CONCLUSIONS: Breaking scored tablets by hand is less successful in an elderly population compared to a group of young adults. Health care providers should be aware that tablet breaking is not appropriate for all patients and for all drugs. In case tablet breaking is unavoidable, a patient's ability to break tablets should be assessed by health care providers and instructions on the appropriate method of breaking should be provided. PMID- 27507947 TI - Scorpion Venom Heat-Resistant Peptide Protects Transgenic Caenorhabditis elegans from beta-Amyloid Toxicity. AB - Scorpion venom heat-resistant peptide (SVHRP) is a component purified from Buthus martensii Karsch scorpion venom. Our previous studies found SVHRP could enhance neurogenesis and inhibit microglia-mediated neuroinflammation in vivo. Here, we use the transgenic CL4176, CL2006, and CL2355 strains of Caenorhabditis elegans which express the human Abeta1-42 to investigate the effects and the possible mechanisms of SVHRP mediated protection against Abeta toxicity in vivo. The results showed that SVHRP-fed worms displayed remarkably decreased paralysis, less abundant toxic Abeta oligomers, reduced Abeta plaque deposition with respect to untreated animals. SVHRP also suppressed neuronal Abeta expression-induced defects in chemotaxis behavior and attenuated levels of ROS in the transgenic C. elegans. Taken together, these results suggest SVHRP could protect against Abeta induced toxicity in C. elegans. Further studies need to be conducted in murine models and humans to analyze the effectiveness of the peptide. PMID- 27507948 TI - Chronic Treatment with Ivabradine Does Not Affect Cardiovascular Autonomic Control in Rats. AB - A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine-a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels- has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. This study assessed the effects of chronic treatment with ivabradine on the modulatory, reflex and tonic cardiovascular autonomic control and on the renal sympathetic nerve activity (RSNA). Male Wistar rats were divided in 2 groups, receiving intraperitoneal injections of vehicle (VEH) or ivabradine (IVA) during 7 or 8 consecutive days. Rats were submitted to vessels cannulation to perform arterial blood pressure (AP) and HR recordings in freely moving rats. Time series of resting pulse interval and systolic AP were used to measure cardiovascular variability parameters. We also assessed the baroreflex, chemoreflex and the Bezold-Jarish reflex sensitivities. To better evaluate the effects of ivabradine on the autonomic control of the heart, we performed sympathetic and vagal autonomic blockade. As expected, ivabradine-treated rats showed a lower resting (VEH: 362 +/- 16 bpm vs. IVA: 260 +/- 14 bpm, p = 0.0005) and intrinsic HR (VEH: 369 +/- 9 bpm vs. IVA: 326 +/- 11 bpm, p = 0.0146). However, the chronic treatment with ivabradine did not change normalized HR spectral parameters LF (nu) (VEH: 24.2 +/- 4.6 vs. IVA: 29.8 +/- 6.4; p > 0.05); HF (nu) (VEH: 75.1 +/- 3.7 vs. IVA: 69.2 +/- 5.8; p > 0.05), any cardiovascular reflexes, neither the tonic autonomic control of the HR (tonic sympathovagal index; VEH: 0.91+/- 0.02 vs. IVA: 0.88 +/- 0.03, p = 0.3494). We performed the AP, HR and RSNA recordings in urethane-anesthetized rats. The chronic treatment with ivabradine reduced the resting HR (VEH: 364 +/- 12 bpm vs. IVA: 207 +/- 11 bpm, p < 0.0001), without affecting RSNA (VEH: 117 +/- 16 vs. IVA: 120 +/- 9 spikes/s, p = 0.9100) and mean arterial pressure (VEH: 70 +/- 4 vs. IVA: 77 +/- 6 mmHg, p = 0.3293). Our results suggest that, in health rats, the long-term treatment with ivabradine directly reduces the HR without changing the RSNA modulation and the reflex and tonic autonomic control of the heart. PMID- 27507949 TI - Development and Clinical Evaluation of an mHealth Application for Stress Management. AB - A large number of individuals experience mental health disorders, with cognitive behavioral therapy (CBT) emerging as a standard practice for reduction in psychiatric symptoms, including stress, anger, anxiety, and depression. However, CBT is associated with significant patient dropout and lacks the means to provide objective data regarding a patient's experience and symptoms between sessions. Emerging wearables and mobile health (mHealth) applications represent an approach that may provide objective data to the patient and provider between CBT sessions. Here, we describe the development of a classifier of real-time physiological stress in a healthy population (n = 35) and apply it in a controlled clinical evaluation for armed forces veterans undergoing CBT for stress and anger management (n = 16). Using cardiovascular and electrodermal inputs from a wearable device, the classifier was able to detect physiological stress in a non clinical sample with accuracy greater than 90%. In a small clinical sample, patients who used the classifier and an associated mHealth application were less likely to discontinue therapy (p = 0.016, d = 1.34) and significantly improved on measures of stress (p = 0.032, d = 1.61), anxiety (p = 0.050, d = 1.26), and anger (p = 0.046, d = 1.41) compared to controls undergoing CBT alone. Given the large number of individuals that experience mental health disorders and the unmet need for treatment, especially in developing nations, such mHealth approaches have the potential to provide or augment treatment at low cost in the absence of in-person care. PMID- 27507950 TI - A Deeper Look at the "Neural Correlate of Consciousness". AB - A main goal of the neuroscience of consciousness is: find the neural correlate to conscious experiences (NCC). When have we achieved this goal? The answer depends on our operationalization of "NCC." Chalmers (2000) shaped the widely accepted operationalization according to which an NCC is a neural system with a state which is minimally sufficient (but not necessary) for an experience. A deeper look at this operationalization reveals why it might be unsatisfactory: (i) it is not an operationalization of a correlate for occurring experiences, but of the capacity to experience; (ii) it is unhelpful for certain cases which are used to motivate a search for neural correlates of consciousness; (iii) it does not mirror the usage of "NCC" by scientists who seek for unique correlates; (iv) it hardly allows for a form of comparative testing of hypotheses, namely experimenta crucis. Because of these problems (i-iv), we ought to amend or improve on Chalmers's operationalization. Here, I present an alternative which avoids these problems. This "NCC2.0" also retains some benefits of Chalmers's operationalization, namely being compatible with contributions from extended, embedded, enacted, or embodied accounts (4E-accounts) and allowing for the possibility of non-biological or artificial experiencers. PMID- 27507951 TI - Production and Perception of Tone 3 Focus in Mandarin Chinese. AB - This study uses production and perception experiments to explore tone 3 focus in Mandarin Chinese. Overall, contrastive focus in Mandarin is clearly marked with increased duration, intensity, and pitch range: in the experiments, listeners identified focused syllables correctly more than 90% of the time. However, a tone 3 syllable offers a smaller capacity for pitch range expansion under focus, and also yields less intensity increase; in addition, local dissimilation increases the duration, intensity, and pitch range of adjacent syllables within the same phrase as a focused tone 3 syllable. As a result, tone 3 focus was less well identified by listeners (77.1%). We suggest that the relatively poor identification of tone 3 focus is due to the smaller capacity for pitch range expansion, the confusion from within-phrase local dissimilatory effects, and the relatively weak intensity of tone 3. This study demonstrates that even within a language where purely prosodic marking of focus is clear, the location of prosodic focus can be difficult to identify in certain circumstances. Our results underline the conclusion, established in other work, that prosodic marking of focus is not universal, but is expressed through the prosodic system of each language. PMID- 27507952 TI - How Changes in Psychosocial Job Characteristics Impact Burnout in Nurses: A Longitudinal Analysis. AB - AIMS: The main aim of this longitudinal study was to test the Job Demand-Control Support (JDCS) model and to analyze whether changes in psychosocial job characteristics are related to (changes in) burnout. BACKGROUND: Previous studies on the effects of JDCS variables on burnout dimensions have indicated that the iso-strain hypothesis (i.e., high job demands, low control, and low support additively predict high stress reactions) and the buffer hypotheses (i.e., high job control and/or social support is expected to moderate the negative impact of high demands on stress reactions) have hardly been examined concurrently in a longitudinal design; and that the effects of changes of psychosocial job variables on burnout dimensions have hardly been analyzed. DESIGN: This two wave study was carried out over a period of 14 months in a sample of 217 Italian nurses. METHOD: Hierarchical regression analyses were used to test the cross lagged main and interactive effects of JDCS variables, and to analyse the across time effects of changes in JDCS dimensions on burnout variables. RESULTS: The Time 1 job characteristics explained 2-8% of the variance in the Time 2 burnout dimensions, but no support for the additive, or the buffer hypothesis of the JDCS model was found. Changes in job characteristics explained an additional 3-20% of variance in the Time 2 burnout dimensions. Specifically, high levels of emotional exhaustion at Time 2 were explained by high levels of social support at Time 1, and unfavorable changes in demands, control, and support over time; high depersonalization at Time 2 was explained by high social support at time 1 and by an increase in demands over time; and high personal accomplishment at Time 2 was predicted by high demands, high control, interactive effect demands * control * social support, at Time 1, and by a decrease in demands over time. No reversed effects of burnout on work characteristics have been found. CONCLUSION: Our findings suggest that the work environment is subject to changes: the majority of employees experienced considerable changes in all job conditions over time. These changes impacted employee burnout. Limitations and implications of the study are discussed. PMID- 27507953 TI - Cultural Affordances: Scaffolding Local Worlds Through Shared Intentionality and Regimes of Attention. AB - In this paper we outline a framework for the study of the mechanisms involved in the engagement of human agents with cultural affordances. Our aim is to better understand how culture and context interact with human biology to shape human behavior, cognition, and experience. We attempt to integrate several related approaches in the study of the embodied, cognitive, and affective substrates of sociality and culture and the sociocultural scaffolding of experience. The integrative framework we propose bridges cognitive and social sciences to provide (i) an expanded concept of 'affordance' that extends to sociocultural forms of life, and (ii) a multilevel account of the socioculturally scaffolded forms of affordance learning and the transmission of affordances in patterned sociocultural practices and regimes of shared attention. This framework provides an account of how cultural content and normative practices are built on a foundation of contentless basic mental processes that acquire content through immersive participation of the agent in social practices that regulate joint attention and shared intentionality. PMID- 27507954 TI - The Effects of General System Justification on Corruption Perception and Intent. AB - Previous research stresses that system justifying belief can weaken corruption perception, by this possibly fostering unjust behaviors. However, general results of the effect of general system justification on corruption are ambiguous, indicating also a lessening impact. We conducted a line of studies trying to elucidate these circumstances by testing the effect of general system justification on corruption perception and intention. In addition, we explored institutional trust as a possible mediator in this process. For this purpose, we conducted three studies. The first two studies examined the association between general system justification and corruption. In Study 1, a correlational design was run using questionnaires to assess the relation between general system justification and corruption perception as well as corruption intention. In Study 2, an experimental design was conducted manipulating general system justification via exposure to high or low system threat condition, then measuring its effect on corruption perception and corrupt intention. In Study 3, two sub-studies using correlational and experimental designs were run to explore the mediating role of institutional trust, respectively. Results replicated former studies showing that general system justification is negatively associated with corruption perception. However, they also showed a negative correlation with corrupt intention. Furthermore, they showed that institutional trust mediated the relation between general system justification and corruption. We suggest to consider these findings to further elucidate the psychological basis underlying different effects of general system justification on human behaviors. PMID- 27507955 TI - Encouraging Realistic Expectations in STEM Students: Paradoxical Effects of a Motivational Intervention. AB - College students in STEM (science, technology, engineering, mathematics) disciplines are increasingly faced with highly competitive and demanding degree programs and are at risk of academic overconfidence. Following from theory and research highlighting the psychological and developmental risks of unrealistic expectations, the present exploratory study evaluated the longitudinal effects of a motivational intervention encouraging college students in STEM degree programs (N = 52) to consider the importance of downgrading one's expectations in response to academic setbacks. Contrary to study hypotheses, the results showed intervention participants to report significantly higher expectations and optimism on post-test measures administered 4 months later, no significant gains in emotional well-being or achievement goal orientations, and lower GPAs over five subsequent semesters. These paradoxical effects underscore the need for additional larger-scale research on the nature of students' responses to potentially ego-threatening motivational programs in STEM disciplines so as to minimize achievement deficits at the expense of preserving motivational resources. PMID- 27507956 TI - Implicit and Explicit Gender Beliefs in Spatial Ability: Stronger Stereotyping in Boys than Girls. AB - Sex differences in spatial ability are a seriously debated topic, given the importance of spatial ability for success in the fields of science, technology, engineering, and mathematics (STEM) and girls' underrepresentation in these domains. In the current study we investigated the presence of stereotypic gender beliefs on spatial ability (i.e., "spatial ability is for boys") in 10- and 12 year-old children. We used both an explicit measure (i.e., a self-report questionnaire) and an implicit measure (i.e., a child IAT). Results of the explicit measure showed that both sexes associated spatial ability with boys, with boys holding more male stereotyped attitudes than girls. On the implicit measure, boys associated spatial ability with boys, while girls were gender neutral. In addition, we examined the effects of gender beliefs on spatial performance, by experimentally activating gender beliefs within a pretest instruction-posttest design. We compared three types of instruction: boys are better, girls are better, and no sex differences. No effects of these gender belief instructions were found on children's spatial test performance (i.e., mental rotation and paper folding). The finding that children of this age already have stereotypic beliefs about the spatial capacities of their own sex is important, as these beliefs may influence children's choices for spatial leisure activities and educational tracks in the STEM domain. PMID- 27507957 TI - Neuroplasticity and Clinical Practice: Building Brain Power for Health. AB - The focus of this review is on driving neuroplasticity in a positive direction using evidence-based interventions that also have the potential to improve general health. One goal is to provide an overview of the many ways new neuroscience can inform treatment protocols to empower and motivate clients to make the lifestyle choices that could help build brain power and could increase adherence to healthy lifestyle changes that have also been associated with simultaneously enhancing vigorous longevity, health, happiness, and wellness. Another goal is to explore the use of a focus in clinical practice on helping clients appreciate this new evidence and use evolving neuroscience in establishing individualized goals, designing strategies for achieving them and increasing treatment compliance. The timing is urgent for such interventions with goals of enhancing brain health across the lifespan and improving statistics on dementia worldwide. PMID- 27507958 TI - Schizophrenia Spectrum Disorders Show Reduced Specificity and Less Positive Events in Mental Time Travel. AB - Mental time travel refers to the ability to recall past events and to imagine possible future events. Schizophrenia (SCZ) patients have problems in remembering specific personal experiences in the past and imagining what will happen in the future. This study aimed to examine episodic past and future thinking in SCZ spectrum disorders including SCZ patients and individuals with schizotypal personality disorder (SPD) proneness who are at risk for developing SCZ. Thirty two SCZ patients, 30 SPD proneness individuals, and 33 healthy controls participated in the study. The Sentence Completion for Events from the Past Test (SCEPT) and the Sentence Completion for Events in the Future Test were used to measure past and future thinking abilities. Results showed that SCZ patients showed significantly reduced specificity in recalling past and imagining future events, they generated less proportion of specific and extended events compared to healthy controls. SPD proneness individuals only generated less extended events compared to healthy controls. The reduced specificity was mainly manifested in imagining future events. Both SCZ patients and SPD proneness individuals generated less positive events than controls. These results suggest that mental time travel impairments in SCZ spectrum disorders and have implications for understanding their cognitive and emotional deficits. PMID- 27507959 TI - Analysis of Metagenomics Next Generation Sequence Data for Fungal ITS Barcoding: Do You Need Advance Bioinformatics Experience? AB - During the last few decades, most of microbiology laboratories have become familiar in analyzing Sanger sequence data for ITS barcoding. However, with the availability of next-generation sequencing platforms in many centers, it has become important for medical mycologists to know how to make sense of the massive sequence data generated by these new sequencing technologies. In many reference laboratories, the analysis of such data is not a big deal, since suitable IT infrastructure and well-trained bioinformatics scientists are always available. However, in small research laboratories and clinical microbiology laboratories the availability of such resources are always lacking. In this report, simple and user-friendly bioinformatics work-flow is suggested for fast and reproducible ITS barcoding of fungi. PMID- 27507960 TI - The Potential Role of Arbuscular Mycorrhizal Fungi in the Restoration of Degraded Lands. AB - Experiences worldwide reveal that degraded lands restoration projects achieve little success or fail. Hence, understanding the underlying causes and accordingly, devising appropriate restoration mechanisms is crucial. In doing so, the ever-increasing aspiration and global commitments in degraded lands restoration could be realized. Here we explain that arbuscular mycorrhizal fungi (AMF) biotechnology is a potential mechanism to significantly improve the restoration success of degraded lands. There are abundant scientific evidences to demonstrate that AMF significantly improve soil attributes, increase above and belowground biodiversity, significantly improve tree/shrub seedlings survival, growth and establishment on moisture and nutrient stressed soils. AMF have also been shown to drive plant succession and may prevent invasion by alien species. The very few conditions where infective AMF are low in abundance and diversity is when the soil erodes, is disturbed and is devoid of vegetation cover. These are all common features of degraded lands. Meanwhile, degraded lands harbor low levels of infective AMF abundance and diversity. Therefore, the successful restoration of infective AMF can potentially improve the restoration success of degraded lands. Better AMF inoculation effects result when inocula are composed of native fungi instead of exotics, early seral instead of late seral fungi, and are consortia instead of few or single species. Future research efforts should focus on AMF effect on plant community primary productivity and plant competition. Further investigation focusing on forest ecosystems, and carried out at the field condition is highly recommended. Devising cheap and ethically widely accepted inocula production methods and better ways of AMF in situ management for effective restoration of degraded lands will also remain to be important research areas. PMID- 27507961 TI - Comparison of Fusarium graminearum Transcriptomes on Living or Dead Wheat Differentiates Substrate-Responsive and Defense-Responsive Genes. AB - Fusarium graminearum is an opportunistic pathogen of cereals where it causes severe yield losses and concomitant mycotoxin contamination of the grains. The pathogen has mixed biotrophic and necrotrophic (saprophytic) growth phases during infection and the regulatory networks associated with these phases have so far always been analyzed together. In this study we compared the transcriptomes of fungal cells infecting a living, actively defending plant representing the mixed live style (pathogenic growth on living flowering wheat heads) to the response of the fungus infecting identical, but dead plant tissues (cold-killed flowering wheat heads) representing strictly saprophytic conditions. We found that the living plant actively suppressed fungal growth and promoted much higher toxin production in comparison to the identical plant tissue without metabolism suggesting that molecules signaling secondary metabolite induction are not pre existing or not stable in the plant in sufficient amounts before infection. Differential gene expression analysis was used to define gene sets responding to the active or the passive plant as main impact factor and driver for gene expression. We correlated our results to the published F. graminearum transcriptomes, proteomes, and secretomes and found that only a limited number of in planta- expressed genes require the living plant for induction but the majority uses simply the plant tissue as signal. Many secondary metabolite (SM) gene clusters show a heterogeneous expression pattern within the cluster indicating that different genetic or epigenetic signals govern the expression of individual genes within a physically linked cluster. Our bioinformatic approach also identified fungal genes which were actively repressed by signals derived from the active plant and may thus represent direct targets of the plant defense against the invading pathogen. PMID- 27507962 TI - Antibiotic Susceptibility Testing of the Gram-Negative Bacteria Based on Flow Cytometry. AB - Rapidly treating infections with adequate antibiotics is of major importance. This requires a fast and accurate determination of the antibiotic susceptibility of bacterial pathogens. The most frequently used methods are slow because they are based on the measurement of growth inhibition. Faster methods, such as PCR based detection of determinants of antibiotic resistance, do not always provide relevant information on susceptibility, particularly that which is not genetically based. Consequently, new methods, such as the detection of changes in bacterial physiology caused by antibiotics using flow cytometry and fluorescent viability markers, are being explored. In this study, we assessed whether Alexa Fluor(r) 633 Hydrazide (AFH), which targets carbonyl groups, can be used for antibiotic susceptibility testing. Carbonylation of cellular macromolecules, which increases in antibiotic-treated cells, is a particularly appropriate to assess for this purpose because it is irreversible. We tested the susceptibility of clinical isolates of Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa, to antibiotics from the three classes: beta-lactams, aminoglycosides, and fluoroquinolones. In addition to AFH, we used TO-PRO(r)-3, which enters cells with damaged membranes and binds to DNA, and DiBAC4 (3), which enters cells with depolarized membranes. We also monitored antibiotic-induced morphological alterations of bacterial cells by analyzing light scattering signals. Although all tested dyes and light scattering signals allowed for the detection of antibiotic-sensitive cells, AFH proved to be the most suitable for the fast and reliable detection of antibiotic susceptibility. PMID- 27507963 TI - Pea Broth Enhances the Biocontrol Efficacy of Lysobacter capsici AZ78 by Triggering Cell Motility Associated with Biogenesis of Type IV Pilus. AB - Bacterial cells can display different types of motility, due to the presence of external appendages such as flagella and type IV pili. To date, little information on the mechanisms involved in the motility of the Lysobacter species has been available. Recently, L. capsici AZ78, a biocontrol agent of phytopathogenic oomycetes, showed the ability to move on jellified pea broth. Pea broth medium improved also the biocontrol activity of L. capsici AZ78 against Plasmopara viticola under greenhouse conditions. Noteworthy, the quantity of pea residues remaining on grapevine leaves fostered cell motility in L. capsici AZ78. Based on these results, this unusual motility related to the composition of the growth medium was investigated in bacterial strains belonging to several Lysobacter species. The six L. capsici strains tested developed dendrite-like colonies when grown on jellified pea broth, while the development of dendrite like colonies was not recorded in the media commonly used in motility assays. To determine the presence of genes responsible for biogenesis of the flagellum and type IV pili, the genome of L. capsici AZ78 was mined. Genes encoding structural components and regulatory factors of type IV pili were upregulated in L. capsici AZ78 cells grown on the above-mentioned medium, as compared with the other tested media. These results provide new insight into the motility mechanism of L. capsici members and the role of type IV pili and pea compounds on the epiphytic fitness and biocontrol features of L. capsici AZ78. PMID- 27507965 TI - The FlgT Protein Is Involved in Aeromonas hydrophila Polar Flagella Stability and Not Affects Anchorage of Lateral Flagella. AB - Aeromonas hydrophila sodium-driven polar flagellum has a complex stator-motor. Consist of two sets of redundant and non-exchangeable proteins (PomA/PomB and PomA2/PomB2), which are homologs to other sodium-conducting polar flagellum stator motors; and also two essential proteins (MotX and MotY), that they interact with one of those two redundant pairs of proteins and form the T-ring. In this work, we described an essential protein for polar flagellum stability and rotation which is orthologs to Vibrio spp. FlgT and it is encoded outside of the A. hydrophila polar flagellum regions. The flgT was present in all mesophilic Aeromonas strains tested and also in the non-motile Aeromonas salmonicida. The A. hydrophila DeltaflgT mutant is able to assemble the polar flagellum but is more unstable and released into the culture supernatant from the cell upon completion assembly. Presence of FlgT in purified polar hook-basal bodies (HBB) of wild-type strain was confirmed by Western blotting and electron microscopy observations showed an outer ring of the T-ring (H-ring) which is not present in the DeltaflgT mutant. Anchoring and motility of proton-driven lateral flagella was not affected in the DeltaflgT mutant and specific antibodies did not detect FlgT in purified lateral HBB of wild type strain. PMID- 27507964 TI - Gut Microbiota Profiling: Metabolomics Based Approach to Unravel Compounds Affecting Human Health. AB - The gut microbiota is composed of a huge number of different bacteria, that produce a large amount of compounds playing a key role in microbe selection and in the construction of a metabolic signaling network. The microbial activities are affected by environmental stimuli leading to the generation of a wide number of compounds, that influence the host metabolome and human health. Indeed, metabolite profiles related to the gut microbiota can offer deep insights on the impact of lifestyle and dietary factors on chronic and acute diseases. Metagenomics, metaproteomics and metabolomics are some of the meta-omics approaches to study the modulation of the gut microbiota. Metabolomic research applied to biofluids allows to: define the metabolic profile; identify and quantify classes and compounds of interest; characterize small molecules produced by intestinal microbes; and define the biochemical pathways of metabolites. Mass spectrometry and nuclear magnetic resonance spectroscopy are the principal technologies applied to metabolomics in terms of coverage, sensitivity and quantification. Moreover, the use of biostatistics and mathematical approaches coupled with metabolomics play a key role in the extraction of biologically meaningful information from wide datasets. Metabolomic studies in gut microbiota related research have increased, focusing on the generation of novel biomarkers, which could lead to the development of mechanistic hypotheses potentially applicable to the development of nutritional and personalized therapies. PMID- 27507966 TI - Changes in the Structure of the Microbial Community Associated with Nannochloropsis salina following Treatments with Antibiotics and Bioactive Compounds. AB - Open microalgae cultures host a myriad of bacteria, creating a complex system of interacting species that influence algal growth and health. Many algal microbiota studies have been conducted to determine the relative importance of bacterial taxa to algal culture health and physiological states, but these studies have not characterized the interspecies relationships in the microbial communities. We subjected Nanochroloropsis salina cultures to multiple chemical treatments (antibiotics and quorum sensing compounds) and obtained dense time-series data on changes to the microbial community using 16S gene amplicon metagenomic sequencing (21,029,577 reads for 23 samples) to measure microbial taxa-taxa abundance correlations. Short-term treatment with antibiotics resulted in substantially larger shifts in the microbiota structure compared to changes observed following treatment with signaling compounds and glucose. We also calculated operational taxonomic unit (OTU) associations and generated OTU correlation networks to provide an overview of possible bacterial OTU interactions. This analysis identified five major cohesive modules of microbiota with similar co-abundance profiles across different chemical treatments. The Eigengenes of OTU modules were examined for correlation with different external treatment factors. This correlation-based analysis revealed that culture age (time) and treatment types have primary effects on forming network modules and shaping the community structure. Additional network analysis detected Alteromonadeles and Alphaproteobacteria as having the highest centrality, suggesting these species are "keystone" OTUs in the microbial community. Furthermore, we illustrated that the chemical tropodithietic acid, which is secreted by several species in the Alphaproteobacteria taxon, is able to drastically change the structure of the microbiota within 3 h. Taken together, these results provide valuable insights into the structure of the microbiota associated with N. salina cultures and how these structures change in response to chemical perturbations. PMID- 27507967 TI - Characterization of Outer Membrane Proteome of Akkermansia muciniphila Reveals Sets of Novel Proteins Exposed to the Human Intestine. AB - Akkermansia muciniphila is a common member of the human gut microbiota and belongs to the Planctomycetes-Verrucomicrobia-Chlamydiae superphylum. Decreased levels of A. muciniphila have been associated with many diseases, and thus it is considered to be a beneficial resident of the intestinal mucus layer. Surface exposed molecules produced by this organism likely play important roles in colonization and communication with other microbes and the host, but the protein composition of the outer membrane (OM) has not been characterized thus far. Herein we set out to identify and characterize A. muciniphila proteins using an integrated approach of proteomics and computational analysis. Sarkosyl extraction and sucrose density-gradient centrifugation methods were used to enrich and fractionate the OM proteome of A. muciniphila. Proteins from these fractions were identified by LC-MS/MS and candidates for OM proteins derived from the experimental approach were subjected to computational screening to verify their location in the cell. In total we identified 79 putative OM and membrane associated extracellular proteins, and 23 of those were found to differ in abundance between cells of A. muciniphila grown on the natural substrate, mucin, and those grown on the non-mucus sugar, glucose. The identified OM proteins included highly abundant proteins involved in secretion and transport, as well as proteins predicted to take part in formation of the pili-like structures observed in A. muciniphila. The most abundant OM protein was a 95-kD protein, termed PilQ, annotated as a type IV pili secretin and predicted to be involved in the production of pili in A. muciniphila. To verify its location we purified the His Tag labeled N-terminal domain of PilQ and generated rabbit polyclonal antibodies. Immunoelectron microscopy of thin sections immunolabeled with these antibodies demonstrated the OM localization of PilQ, testifying for its predicted function as a type IV pili secretin in A. muciniphila. As pili structures are known to be involved in the modulation of host immune responses, this provides support for the involvement of OM proteins in the host interaction of A. muciniphila. In conclusion, the characterization of A. muciniphila OM proteome provides valuable information that can be used for further functional and immunological studies. PMID- 27507968 TI - Engineering of Helicobacter pylori Dimeric Oxidoreductase DsbK (HP0231). AB - The formation of disulfide bonds that are catalyzed by proteins of the Dsb (disulfide bond) family is crucial for the correct folding of many extracytoplasmic proteins. Thus, this formation plays an essential, pivotal role in the assembly of many virulence factors. The Helicobacter pylori disulfide bond forming system is uncomplicated compared to the best-characterized Escherichia coli Dsb pathways. It possesses only two extracytoplasmic Dsb proteins named HP0377 and HP0231. As previously shown, HP0377 is a reductase involved in the process of cytochrome c maturation. Additionally, it also possesses disulfide isomerase activity. HP0231 was the first periplasmic dimeric oxidoreductase involved in disulfide generation to be described. Although HP0231 function is critical for oxidative protein folding, its structure resembles that of dimeric EcDsbG, which does not confer this activity. However, the HP0231 catalytic motifs (CXXC and the so-called cis-Pro loop) are identical to that of monomeric EcDsbA. To understand the functioning of HP0231, we decided to study the relations between its sequence, structure and activity through an extensive analysis of various HP0231 point mutants, using in vivo and in vitro strategies. Our work shows the crucial role of the cis-Pro loop, as changing valine to threonine in this motif completely abolishes the protein function in vivo. Functioning of HP0231 is conditioned by the combination of CXXC and the cis-Pro loop, as replacing the HP0231 CXXC motif by the motif from EcDsbG or EcDsbC results in bifunctional protein, at least in E. coli. We also showed that the dimerization domain of HP0231 ensures contact with its substrates. Moreover, the activity of this oxidase is independent on the structure of the catalytic domain. Finally, we showed that HP0231 chaperone activity is independent of its redox function. PMID- 27507969 TI - Flavoprotein-Mediated Tellurite Reduction: Structural Basis and Applications to the Synthesis of Tellurium-Containing Nanostructures. AB - The tellurium oxyanion tellurite (TeO3 (2-)) is extremely harmful for most organisms. It has been suggested that a potential bacterial tellurite resistance mechanism would consist of an enzymatic, NAD(P)H-dependent, reduction to the less toxic form elemental tellurium (Te(0)). To date, a number of enzymes such as catalase, type II NADH dehydrogenase and terminal oxidases from the electron transport chain, nitrate reductases, and dihydrolipoamide dehydrogenase (E3), among others, have been shown to display tellurite-reducing activity. This activity is generically referred to as tellurite reductase (TR). Bioinformatic data resting on some of the abovementioned enzymes enabled the identification of common structures involved in tellurite reduction including vicinal catalytic cysteine residues and the FAD/NAD(P)(+)-binding domain, which is characteristic of some flavoproteins. Along this line, thioredoxin reductase (TrxB), alkyl hydroperoxide reductase (AhpF), glutathione reductase (GorA), mercuric reductase (MerA), NADH: flavorubredoxin reductase (NorW), dihydrolipoamide dehydrogenase, and the putative oxidoreductase YkgC from Escherichia coli or environmental bacteria were purified and assessed for TR activity. All of them displayed in vitro TR activity at the expense of NADH or NADPH oxidation. In general, optimal reducing conditions occurred around pH 9-10 and 37 degrees C. Enzymes exhibiting strong TR activity produced Te-containing nanostructures (TeNS). While GorA and AhpF generated TeNS of 75 nm average diameter, E3 and YkgC produced larger structures (>100 nm). Electron-dense structures were observed in cells over expressing genes encoding TrxB, GorA, and YkgC. PMID- 27507970 TI - Regulatory RNAs in the Less Studied Streptococcal Species: From Nomenclature to Identification. AB - Streptococcal species are Gram-positive bacteria involved in severe and invasive diseases in humans and animals. Although, this group includes different pathogenic species involved in life-threatening infections for humans, it also includes beneficial species, such as Streptococcus thermophilus, which is used in yogurt production. In bacteria virulence factors are controlled by various regulatory networks including regulatory RNAs. For clearness and to develop logical thinking, we start this review with a revision of regulatory RNAs nomenclature. Previous reviews are mostly dealing with Streptococcus pyogenes and Streptococcus pneumoniae regulatory RNAs. We especially focused our analysis on regulatory RNAs in Streptococcus agalactiae, Streptococcus mutans, Streptococcus thermophilus and other less studied Streptococcus species. Although, S. agalactiae RNome remains largely unknown, sRNAs (small RNAs) are supposed to mediate regulation during environmental adaptation and host infection. In the case of S. mutans, sRNAs are suggested to be involved in competence regulation, carbohydrate metabolism, and Toxin-Antitoxin systems. A new category of miRNA size small RNAs (msRNAs) was also identified for the first time in this species. The analysis of S. thermophilus sRNome shows that many sRNAs are associated to the bacterial immune system known as CRISPR-Cas system. Only few of the other different Streptococcus species have been the subject of studies pointed toward the characterization of regulatory RNAs. Finally, understanding bacterial sRNome can constitute one step forward to the elaboration of new strategies in therapy such as substitution of antibiotics in the management of S. agalactiae neonatal infections, prevention of S. mutans dental caries or use of S. thermophilus CRISPR-Cas system in genome editing applications. PMID- 27507971 TI - Melanoma Affects the Composition of Blood Cell-Derived Extracellular Vesicles. AB - Extracellular vesicles (EVs) are specifically loaded with nucleic acids, lipids, and proteins from their parental cell. Therefore, the constitution of EVs reflects the type and status of the originating cell and EVs in melanoma patient's plasma could be indicative for the tumor. Likewise, EVs might influence tumor progression by regulating immune responses. We performed a broad protein characterization of EVs from plasma of melanoma patients and healthy donors as well as from T cells, B cells, natural killer (NK) cells, monocytes, monocyte derived dendritic cells (moDCs), and platelets using a multiplex bead-based platform. Using this method, we succeeded in analyzing 58 proteins that were differentially displayed on EVs. Hierarchical clustering of protein intensity patterns grouped EVs according to their originating cell type. The analysis of EVs from stimulated B cells and moDCs revealed the transfer of surface proteins to vesicles depending on the cell status. The protein profiles of plasma vesicles resembled the protein profiles of EVs from platelets, antigen-presenting cells and NK cells as shown by platelet markers, co-stimulatory proteins, and a NK cell subpopulation marker. In comparison to healthy plasma vesicles, melanoma plasma vesicles showed altered signals for platelet markers, indicating a changed vesicle secretion or protein loading of EVs by platelets and a lower CD8 signal that might be associated with a diminished activity of NK cells or T cells. As we hardly detected melanoma-derived vesicles in patient's plasma, we concluded that blood cells induced the observed differences. In summary, our results question a direct effect of melanoma cells on the composition of EVs in melanoma plasma, but rather argue for an indirect influence of melanoma cells on the vesicle secretion or vesicle protein loading by blood cells. PMID- 27507972 TI - Extracellular Release and Signaling by Heat Shock Protein 27: Role in Modifying Vascular Inflammation. AB - Heat shock protein 27 (HSP27) is traditionally viewed as an intracellular chaperone protein with anti-apoptotic properties. However, recent data indicate that a number of heat shock proteins, including HSP27, are also found in the extracellular space where they may signal via membrane receptors to alter gene transcription and cellular function. Therefore, there is increasing interest in better understanding how HSP27 is released from cells, its levels and composition in the extracellular space, and the cognate cell membrane receptors involved in effecting cell signaling. In this paper, the knowledge to date, as well as some emerging paradigms about the extracellular function of HSP27 is presented. Of particular interest is the role of HSP27 in attenuating atherogenesis by modifying lipid uptake and inflammation in the plaque. Moreover, the abundance of HSP27 in serum is an emerging new biomarker for ischemic events. Finally, HSP27 replacement therapy may represent a novel therapeutic opportunity for chronic inflammatory disorders, such as atherosclerosis. PMID- 27507974 TI - Cytogenetic Diversity of Simple Sequences Repeats in Morphotypes of Brassica rapa ssp. chinensis. AB - A significant fraction of the nuclear DNA of all eukaryotes is comprised of simple sequence repeats (SSRs). Although these sequences are widely used for studying genetic variation, linkage mapping and evolution, little attention had been paid to the chromosomal distribution and cytogenetic diversity of these sequences. In this paper, we report the distribution characterization of mono-, di-, and tri-nucleotide SSRs in Brassica rapa ssp. chinensis. Fluorescence in situ hybridization was used to characterize the cytogenetic diversity of SSRs among morphotypes of B. rapa ssp. chinensis. The proportion of different SSR motifs varied among morphotypes of B. rapa ssp. chinensis, with tri-nucleotide SSRs being more prevalent in the genome of B. rapa ssp. chinensis. We determined the chromosomal locations of mono-, di-, and tri-nucleotide repeat loci. The results showed that the chromosomal distribution of SSRs in the different morphotypes is non-random and motif-dependent, and allowed us to characterize the relative variability in terms of SSR numbers and similar chromosomal distributions in centromeric/peri-centromeric heterochromatin. The differences between SSR repeats with respect to abundance and distribution indicate that SSRs are a driving force in the genomic evolution of B. rapa species. Our results provide a comprehensive view of the SSR sequence distribution and evolution for comparison among morphotypes B. rapa ssp. chinensis. PMID- 27507973 TI - Proteometabolomic Study of Compatible Interaction in Tomato Fruit Challenged with Sclerotinia rolfsii Illustrates Novel Protein Network during Disease Progression. AB - Fruit is an assimilator of metabolites, nutrients, and signaling molecules, thus considered as potential target for pathogen attack. In response to patho-stress, such as fungal invasion, plants reorganize their proteome, and reconfigure their physiology in the infected organ. This remodeling is coordinated by a poorly understood signal transduction network, hormonal cascades, and metabolite reallocation. The aim of the study was to explore organ-based proteomic alterations in the susceptibility of heterotrophic fruit to necrotrophic fungal attack. We conducted time-series protein profiling of Sclerotinia rolfsii invaded tomato (Solanum lycopersicum) fruit. The differential display of proteome revealed 216 patho-stress responsive proteins (PSRPs) that change their abundance by more than 2.5-fold. Mass spectrometric analyses led to the identification of 56 PSRPs presumably involved in disease progression; regulating diverse functions viz. metabolism, signaling, redox homeostasis, transport, stress-response, protein folding, modification and degradation, development. Metabolome study indicated differential regulation of organic acid, amino acids, and carbohydrates paralleling with the proteomics analysis. Further, we interrogated the proteome data using network analysis that identified two significant functional protein hubs centered around malate dehydrogenase, T-complex protein 1 subunit gamma, and ATP synthase beta. This study reports, for the first-time, kinetically controlled patho-stress responsive protein network during post-harvest storage in a sink tissue, particularly fruit and constitute the basis toward understanding the onset and context of disease signaling and metabolic pathway alterations. The network representation may facilitate the prioritization of candidate proteins for quality improvement in storage organ. PMID- 27507975 TI - Characterization of Shikonin Derivative Secretion in Lithospermum erythrorhizon Hairy Roots as a Model of Lipid-Soluble Metabolite Secretion from Plants. AB - Shikonin derivatives are specialized lipophilic metabolites, secreted in abundant amounts from the root epidermal cells of Lithospermum erythrorhizon. Because they have anti-microbial activities, these compounds, which are derivatives of red naphthoquinone, are thought to serve as a chemical barrier for plant roots. The mechanism by which they are secreted from cells is, however, largely unknown. The shikonin production system in L. erythrorhizon is an excellent model for studying the mechanism by which lipophilic compounds are secreted from plant cells, because of the abundant amounts of these compounds produced by L. erythrorhizon, the 0 to 100% inducibility of their production, the light-specific inhibition of production, and the visibility of these products as red pigments. To date, many factors regulating shikonin biosynthesis have been identified, but no mechanism that regulates shikonin secretion without inhibiting biosynthesis has been detected. This study showed that inhibitors of membrane traffic strongly inhibit shikonin secretion without inhibiting shikonin production, suggesting that the secretion of shikonin derivatives into the apoplast utilizes pathways common to the ADP-ribosylation factor/guanine nucleotide exchange factor (ARF/GEF) system and actin filament polymerization, at least in part. These findings provide clues about the machinery involved in secreting lipid-soluble metabolites from cells. PMID- 27507976 TI - Natural Genetic Variation of Seed Micronutrients of Arabidopsis thaliana Grown in Zinc-Deficient and Zinc-Amended Soil. AB - The quality of edible seeds for human and animal nutrition is crucially dependent on high zinc (Zn) and iron (Fe) seed concentrations. The micronutrient bioavailability is strongly reduced by seed phytate that forms complexes with seed cations. Superior genotypes with increased seed Zn concentrations had been identified, but low micronutrient seed levels often prevail when the plants are grown in Zn-deficient soils, which are globally widespread and correlate with human Zn-deficiency. Here, seed Zn concentrations of Arabidopsis accessions grown in Zn-deficient and Zn-amended conditions were measured together with seed Fe and manganese (Mn), in a panel of 108 accessions. By applying genome-wide association, de novo candidate genes potentially involved in the seed micronutrient accumulation were identified. However, a candidate inositol 1,3,4 trisphosphate 5/6-kinase 3 gene (ITPK3), located close to a significant nucleotide polymorphism associated with relative Zn seed concentrations, was dispensable for seed micronutrients accumulation in Col-0. Loss of this gene in itpk3-1 did neither affect phytate seed levels, nor seed Zn, Fe, and Mn. It is concluded that large natural variance of micronutrient seed levels is identified in the population and several accessions maintain high seed Zn despite growth in Zn-deficient conditions. PMID- 27507977 TI - Identification of Drought Tolerant Mechanisms in Maize Seedlings Based on Transcriptome Analysis of Recombination Inbred Lines. AB - Zea mays is an important crop that is sensitive to drought stress, but survival rates and growth status remain strong in some drought-tolerant lines under stress conditions. Under drought conditions, many biological processes, such as photosynthesis, carbohydrate metabolism and energy metabolism, are suppressed, while little is known about how the transcripts of genes respond to drought stress in the genome-wide rang in the seedling stage. In our study, the transcriptome profiles of two maize recombination inbred lines (drought-tolerant RIL70 and drought-sensitive RIL93) were analyzed at different drought stages to elucidate the dynamic mechanisms underlying drought tolerance in maize seedlings during drought conditions. Different numbers of differentially expressed genes presented in the different stages of drought stress in the two RILs, for the numbers of RIL93 vs. RIL70 were: 9 vs. 358, 477 vs. 103, and 5207 vs. 152 respectively in DT1, DT2, and DT5. Gene Ontology enrichment analysis revealed that in the initial drought-stressed stage, the primary differentially expressed genes involved in cell wall biosynthesis and transmembrane transport biological processes were overrepresented in RIL70 compared to RIL93. On the contrary, differentially expressed genes profiles presented at 2 and 5 day-treatments, the primary differentially expressed genes involved in response to stress, protein folding, oxidation-reduction, photosynthesis and carbohydrate metabolism, were overrepresented in RIL93 compared to RIL70. In addition, the transcription of genes encoding key members of the cell cycle and cell division processes were blocked, but ABA- and programmed cell death-related processes responded positively in RIL93. In contrast, the expression of cell cycle genes, ABA- and programmed cell death-related genes was relatively stable in RIL70. The results we obtained supported the working hypothesis that signaling events associated with turgor homeostasis, as established by cell wall biosynthesis regulation- and aquaporin-related genes, responded early in RIL70, which led to more efficient detoxification signaling (response to stress, protein folding, oxidation reduction) during drought stress. This energy saving response at the early stages of drought should facilitate more cell activity under stress conditions and result in drought tolerance in RIL70. PMID- 27507978 TI - The Root Hair Specific SYP123 Regulates the Localization of Cell Wall Components and Contributes to Rizhobacterial Priming of Induced Systemic Resistance. AB - Root hairs are important for nutrient and water uptake and are also critically involved the interaction with soil inhabiting microbiota. Root hairs are tubular shaped outgrowths that emerge from trichoblasts. This polarized elongation is maintained and regulated by a robust mechanism involving the endomembrane secretory and endocytic system. Members of the syntaxin family of SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) in plants (SYP), have been implicated in regulation of the fusion of vesicles with the target membranes in both exocytic and endocytic pathways. One member of this family, SYP123, is expressed specifically in the root hairs and accumulated in the growing tip region. This study shows evidence of the SYP123 role in polarized trafficking using knockout insertional mutant plants. We were able to observe defects in the deposition of cell wall proline rich protein PRP3 and cell wall polysaccharides. In a complementary strategy, similar results were obtained using a plant expressing a dominant negative soluble version of SYP123 (SP2 fragment) lacking the transmembrane domain. The evidence presented indicates that SYP123 is also regulating PRP3 protein distribution by recycling by endocytosis. We also present evidence that indicates that SYP123 is necessary for the response of roots to plant growth promoting rhizobacterium (PGPR) in order to trigger trigger induced systemic response (ISR). Plants with a defective SYP123 function were unable to mount a systemic acquired resistance in response to bacterial pathogen infection and ISR upon interaction with rhizobacteria. These results indicated that SYP123 was involved in the polarized localization of protein and polysaccharides in growing root hairs and that this activity also contributed to the establishment of effective plant defense responses. Root hairs represent very plastic structures were many biotic and abiotic factors can affect the number, anatomy and physiology of root hairs. Here, we presented evidence that indicates that interactions with soil PGPR could be closely regulated by signaling involving secretory and/or endocytic trafficking at the root hair tip as a quick way to response to changing environmental conditions. PMID- 27507979 TI - Is the Invasive Species Listronotus bonariensis (Kuschel) (Coleoptera: Curculionidae) (Argentine Stem Weevil) a Threat to New Zealand Natural Grassland Ecosystems? AB - Listronotus bonariensis (Argentine stem weevil) is a stem-boring weevil that has become a major pasture pest in New Zealand, and cool climate turf grass in Australia. This species is also frequently found in native tussock grassland in New Zealand. Laboratory and field trials were established to determine the risk posed to both seedlings and established plants of three native grass species compared to what happens with a common host of this species, hybrid ryegrass (L. perenne X L. multiflorum). Adult weevil feeding damage scores were higher on Poa colensoi and Festuca novae-zelandiae than Chionochloa rigida. Oviposition was lower on P. colensoi than hybrid ryegrass, and no eggs were laid on F. novae zelandiae. In field trials using the same four species established as spaced plants L. bonariensis laid more eggs per tiller in ryegrass in a low altitude pasture site than in ryegrass in a higher altitude site. No eggs were found on the three native grass species at the tussock sites, and only low numbers were found on other grasses at the low altitude pasture site. Despite this, numbers of adult weevils were extracted from the plants in the field trials. These may have comprised survivors of the original weevils added to the plants, together with new generation weevils that had emerged during the experiment. Irrespective, higher numbers were recovered from the tussock site plants than from those from the pasture site. It was concluded that L. bonariensis is likely to have little overall impact, but a greater impact on native grass seedling survival than on established plants. PMID- 27507980 TI - Genetic Diversity of Cultivated Lentil (Lens culinaris Medik.) and Its Relation to the World's Agro-ecological Zones. AB - Assessment of genetic diversity and population structure of germplasm collections plays a critical role in supporting conservation and crop genetic enhancement strategies. We used a cultivated lentil (Lens culinaris Medik.) collection consisting of 352 accessions originating from 54 diverse countries to estimate genetic diversity and genetic structure using 1194 polymorphic single nucleotide polymorphism (SNP) markers which span the lentil genome. Using principal coordinate analysis, population structure analysis and UPGMA cluster analysis, the accessions were categorized into three major groups that prominently reflected geographical origin (world's agro-ecological zones). The three clusters complemented the origins, pedigrees, and breeding histories of the germplasm. The three groups were (a) South Asia (sub-tropical savannah), (b) Mediterranean, and (c) northern temperate. Based on the results from this study, it is also clear that breeding programs still have considerable genetic diversity to mine within the cultivated lentil, as surveyed South Asian and Canadian germplasm revealed narrow genetic diversity. PMID- 27507981 TI - Why Be a Shrub? A Basic Model and Hypotheses for the Adaptive Values of a Common Growth Form. AB - Shrubs are multi-stemmed short woody plants, more widespread than trees, important in many ecosystems, neglected in ecology compared to herbs and trees, but currently in focus due to their global expansion. We present a novel model based on scaling relationships and four hypotheses to explain the adaptive significance of shrubs, including a review of the literature with a test of one hypothesis. Our model describes advantages for a small shrub compared to a small tree with the same above-ground woody volume, based on larger cross-sectional stem area, larger area of photosynthetic tissue in bark and stem, larger vascular cambium area, larger epidermis (bark) area, and larger area for sprouting, and faster production of twigs and canopy. These components form our Hypothesis 1 that predicts higher growth rate for a small shrub than a small tree. This prediction was supported by available relevant empirical studies (14 publications). Further, a shrub will produce seeds faster than a tree (Hypothesis 2), multiple stems in shrubs insure future survival and growth if one or more stems die (Hypothesis 3), and three structural traits of short shrub stems improve survival compared to tall tree stems (Hypothesis 4)-all hypotheses have some empirical support. Multi-stemmed trees may be distinguished from shrubs by more upright stems, reducing bending moment. Improved understanding of shrubs can clarify their recent expansion on savannas, grasslands, and alpine heaths. More experiments and other empirical studies, followed by more elaborate models, are needed to understand why the shrub growth form is successful in many habitats. PMID- 27507982 TI - Molecular Characterization of the 14-3-3 Gene Family in Brachypodium distachyon L. Reveals High Evolutionary Conservation and Diverse Responses to Abiotic Stresses. AB - The 14-3-3 gene family identified in all eukaryotic organisms is involved in a wide range of biological processes, particularly in resistance to various abiotic stresses. Here, we performed the first comprehensive study on the molecular characterization, phylogenetics, and responses to various abiotic stresses of the 14-3-3 gene family in Brachypodium distachyon L. A total of seven 14-3-3 genes from B. distachyon and 120 from five main lineages among 12 species were identified, which were divided into five well-conserved subfamilies. The molecular structure analysis showed that the plant 14-3-3 gene family is highly evolutionarily conserved, although certain divergence had occurred in different subfamilies. The duplication event investigation revealed that segmental duplication seemed to be the predominant form by which the 14-3-3 gene family had expanded. Moreover, seven critical amino acids were detected, which may contribute to functional divergence. Expression profiling analysis showed that BdGF14 genes were abundantly expressed in the roots, but showed low expression in the meristems. All seven BdGF14 genes showed significant expression changes under various abiotic stresses, including heavy metal, phytohormone, osmotic, and temperature stresses, which might play important roles in responses to multiple abiotic stresses mainly through participating in ABA-dependent signaling and reactive oxygen species-mediated MAPK cascade signaling pathways. In particular, BdGF14 genes generally showed upregulated expression in response to multiple stresses of high temperature, heavy metal, abscisic acid (ABA), and salicylic acid (SA), but downregulated expression under H2O2, NaCl, and polyethylene glycol (PEG) stresses. Meanwhile, dynamic transcriptional expression analysis of BdGF14 genes under longer treatments with heavy metals (Cd(2+), Cr(3+), Cu(2+), and Zn(2+)) and phytohormone (ABA) and recovery revealed two main expression trends in both roots and leaves: up-down and up-down-up expression from stress treatments to recovery. This study provides new insights into the structures and functions of plant 14-3-3 genes. PMID- 27507983 TI - Validation of Suitable Reference Genes for Assessing Gene Expression of MicroRNAs in Lonicera japonica. AB - MicroRNAs (miRNAs), which play crucial regulatory roles in plant secondary metabolism and responses to the environment, could be developed as promising biomarkers for different varieties and production areas of herbal medicines. However, limited information is available for miRNAs from Lonicera japonica, which is widely used in East Asian countries owing to various pharmaceutically active secondary metabolites. Selection of suitable reference genes for quantification of target miRNA expression through quantitative real-time (qRT) PCR is important for elucidating the molecular mechanisms of secondary metabolic regulation in different tissues and varieties of L. japonica. For precise normalization of gene expression data in L. japonica, 16 candidate miRNAs were examined in three tissues, as well as 21 cultivated varieties collected from 16 production areas, using GeNorm, NormFinder, and RefFinder algorithms. Our results revealed combination of u534122 and u3868172 as the best reference genes across all samples. Their specificity was confirmed by detecting the cycling threshold (C t) value ranges in different varieties of L. japonica collected from diverse production areas, suggesting the use of these two reference miRNAs is sufficient for accurate transcript normalization with different tissues, varieties, and production areas. To our knowledge, this is the first report on validation of reference miRNAs in honeysuckle (Lonicera spp.). Restuls from this study can further facilitate discovery of functional regulatory miRNAs in different varieties of L. japonica. PMID- 27507984 TI - Crystal Structure Analysis and the Identification of Distinctive Functional Regions of the Protein Elicitor Mohrip2. AB - The protein elicitor MoHrip2, which was extracted from Magnaporthe oryzae as an exocrine protein, triggers the tobacco immune system and enhances blast resistance in rice. However, the detailed mechanisms by which MoHrip2 acts as an elicitor remain unclear. Here, we investigated the structure of MoHrip2 to elucidate its functions based on molecular structure. The three-dimensional structure of MoHrip2 was obtained. Overall, the crystal structure formed a beta barrel structure and showed high similarity to the pathogenesis-related (PR) thaumatin superfamily protein thaumatin-like xylanase inhibitor (TL-XI). To investigate the functional regions responsible for MoHrip2 elicitor activities, the full length and eight truncated proteins were expressed in Escherichia coli and were evaluated for elicitor activity in tobacco. Biological function analysis showed that MoHrip2 triggered the defense system against Botrytis cinerea in tobacco. Moreover, only MoHrip2M14 and other fragments containing the 14 amino acids residues in the middle region of the protein showed the elicitor activity of inducing a hypersensitive response and resistance related pathways, which were similar to that of full-length MoHrip2. These results revealed that the central 14 amino acid residues were essential for anti-pathogenic activity. PMID- 27507985 TI - Raffinose Family Oligosaccharides Act As Galactose Stores in Seeds and Are Required for Rapid Germination of Arabidopsis in the Dark. AB - Raffinose synthase 5 (AtRS5, At5g40390) was characterized from Arabidopsis as a recombinant enzyme. It has a far higher affinity for the substrates galactinol and sucrose than any other raffinose synthase previously reported. In addition raffinose synthase 5 is also working as a galactosylhydrolase, degrading galactinol, and raffinose under certain conditions. Together with raffinose synthase 4, which is predominantly a stachyose synthase, both enzymes contribute to the raffinose family oligosaccharide (RFO) accumulation in seeds. A double knockout in raffinose synthase 4 and raffinose synthase 5 (DeltaAtRS4,5) was generated, which is devoid of RFOs in seeds. Unstressed leaves of 4 week old DeltaAtRS4,5 plants showed drastically 23.8-fold increased concentrations of galactinol. Unexpectedly, raffinose appeared again in drought stressed DeltaAtRS4,5 plants, but not under other abiotic stress conditions. Drought stress leads to novel transcripts of raffinose synthase 6 suggesting that this isoform is a further stress inducible raffinose synthase in Arabidopsis. DeltaAtRS4,5 seeds showed a 5 days delayed germination phenotype in darkness and an elevated expression of the transcription factor phytochrome interacting factor 1 (AtPIF1) target gene AtPIF6, being a repressor of germination. This prolonged dormancy is not seen during germination in the light. Exogenous galactose partially promotes germination of DeltaAtRS4,5 seeds in the dark suggesting that RFOs act as a galactose store and repress AtPIF6 transcripts. PMID- 27507986 TI - Spatial and Temporal Variation in Selection of Genes Associated with Pearl Millet Varietal Quantitative Traits In situ. AB - Ongoing global climate changes imply new challenges for agriculture. Whether plants and crops can adapt to such rapid changes is still a widely debated question. We previously showed adaptation in the form of earlier flowering in pearl millet at the scale of a whole country over three decades. However, this analysis did not deal with variability of year to year selection. To understand and possibly manage plant and crop adaptation, we need more knowledge of how selection acts in situ. Is selection gradual, abrupt, and does it vary in space and over time? In the present study, we tracked the evolution of allele frequency in two genes associated with pearl millet phenotypic variation in situ. We sampled 17 populations of cultivated pearl millet over a period of 2 years. We tracked changes in allele frequencies in these populations by genotyping more than seven thousand individuals. We demonstrate that several allele frequencies changes are compatible with selection, by correcting allele frequency changes associated with genetic drift. We found marked variation in allele frequencies from year to year, suggesting a variable selection effect in space and over time. We estimated the strength of selection associated with variations in allele frequency. Our results suggest that the polymorphism maintained at the genes we studied is partially explained by the spatial and temporal variability of selection. In response to environmental changes, traditional pearl millet varieties could rapidly adapt thanks to this available functional variability. PMID- 27507987 TI - Genetic Diversity and Molecular Evolution of a Violaxanthin De-epoxidase Gene in Maize. AB - Violaxanthin de-epoxidase (VDE) has a critical role in the carotenoid biosynthesis pathway, which is involved in protecting the photosynthesis apparatus from damage caused by excessive light. Here, a VDE gene in maize, ZmVDE1, was cloned and shown to have functional domains in common with the gramineous VDE protein. Candidate gene association analysis indicated that no polymorphic sites in ZmVDE1 were significant association with any of the examined carotenoid-related traits at P = 0.05 in an association panel containing 155 maize inbred lines. Nucleotide diversity analysis of VDE1 in maize and teosinte indicated that its exon had less genetic variation, consistent with the conserved function of VDE1 in plants. In addition, dramatically reduced nucleotide diversity, fewer haplotypes and a significantly negative parameter deviation for Tajima's D test of ZmVDE1 in maize and teosinte suggested that a potential selective force had acted across the ZmVDE1 locus. We further identified a 4.2 Mb selective sweep with low recombination surrounding the ZmVDE1 locus that resulted in severely reduced nucleotide diversity on chromosome 2. Collectively, natural selection and the conserved domains of ZmVDE1 might show an important role in the xanthophyll cycle of the carotenoid biosynthesis pathway. PMID- 27507989 TI - Comparative Efficacy of Topical Curcumin and Triamcinolone for Oral Lichen Planus: A Randomized, Controlled Clinical Trial. AB - OBJECTIVES: Lichen planus (LP) is a chronic inflammatory mucocutaneous disease. Its treatment is often symptomatic and includes topical and systemic corticosteroids. Although corticosteroid therapy is usually successful, it has side effects and thus, an alternative treatment is favorable. The aim of this study was to compare the efficacy of topical curcumin and triamcinolone for treatment of oral lichen planus (OLP). MATERIALS AND METHODS: In this study, 50 patients (36 women and 14 men) in the age range of 38 to 73 years with OLP were randomly divided into two groups. Each group received 0.1% triamcinolone or 5% curcumin oral paste three times a day for four weeks. Assessment of the appearance score and severity of pain was done at baseline and at the end of two and four weeks and recorded in the patients' questionnaires. The data were analyzed by SPSS 17 software, using the Mann-Whitney and Spearman's tests. RESULTS: With respect to pain reduction, nine patients (36%) in the curcumin group and eight patients (32%) in the triamcinolone group showed complete remission. With respect to the appearance score, one patient (4%) in each group showed complete remission. No statistically significant difference was noted between the two groups. CONCLUSION: Application of curcumin is suggested for treatment of OLP because of its desirable anti-inflammatory effects and insignificant side effects. PMID- 27507988 TI - Spatial Genome Organization and Its Emerging Role as a Potential Diagnosis Tool. AB - In eukaryotic cells the genome is highly spatially organized. Functional relevance of higher order genome organization is implied by the fact that specific genes, and even whole chromosomes, alter spatial position in concert with functional changes within the nucleus, for example with modifications to chromatin or transcription. The exact molecular pathways that regulate spatial genome organization and the full implication to the cell of such an organization remain to be determined. However, there is a growing realization that the spatial organization of the genome can be used as a marker of disease. While global genome organization patterns remain largely conserved in disease, some genes and chromosomes occupy distinct nuclear positions in diseased cells compared to their normal counterparts, with the patterns of reorganization differing between diseases. Importantly, mapping the spatial positioning patterns of specific genomic loci can distinguish cancerous tissue from benign with high accuracy. Genome positioning is an attractive novel biomarker since additional quantitative biomarkers are urgently required in many cancer types. Current diagnostic techniques are often subjective and generally lack the ability to identify aggressive cancer from indolent, which can lead to over- or under-treatment of patients. Proof-of-principle for the use of genome positioning as a diagnostic tool has been provided based on small scale retrospective studies. Future large scale studies are required to assess the feasibility of bringing spatial genome organization-based diagnostics to the clinical setting and to determine if the positioning patterns of specific loci can be useful biomarkers for cancer prognosis. Since spatial reorganization of the genome has been identified in multiple human diseases, it is likely that spatial genome positioning patterns as a diagnostic biomarker may be applied to many diseases. PMID- 27507990 TI - Accuracy of Cone Beam Computed Tomography, Photostimulable Phosphor Plate Digital Radiography and Conventional Radiography for Detection of Artificial Cancellous Bone Defects. AB - OBJECTIVES: The optimal goal of radiography is to provide high-quality diagnostic images with the least patient radiation dose. The aim of this study was to evaluate the accuracy of cone-beam computed tomography (CBCT) and intraoral photostimulable phosphor plate (PSP) digital and film-based conventional radiography for detection of artificial cancellous bone defects. MATERIALS AND METHODS: Five dry human mandibles were used in this study. The mandibles were placed inside a water bath made of plexiglass plates; then PSP and CBCT scans were obtained. The mandibles were cut by a coping saw in buccolingual dimension and oval defects measuring 6.1*6.1 mm, 3*6.1 mm and 4*4 mm were created by a milling machine in the spongy bone. After fixing the two parts together (buccal and lingual), radiographs were repeated. Presence or absence of defects on images was evaluated and recorded by the two observers. Using SPSS 16, compatibility level, sensitivity, specificity and receiver operating curve (ROC) analysis were determined for each observer. RESULTS: The intraobserver agreement in all three imaging modalities was low to moderate (kappa<=0.613). The inter-observer agreement in all the three imaging modalities was moderate (kappa=0.406). The area under the curve (AUC) of the imaging modalities in each observation was not significantly different. The area under the curve based on defect size for the two observers was not significantly different either. CONCLUSION: Defects confined to spongy bone can be identified on film and PSP radiographs and CBCT scans. However, interpretation of PSP images and CBCT scans needs greater expertise and skills. PMID- 27507991 TI - Effect of a Desensitizing Varnish on Microleakage of Two Self-Etch Adhesives. AB - OBJECTIVES: The aim of this in-vitro experimental study was to assess the effect of application of a desensitizing varnish on the enamel and dentin marginal seal. MATERIALS AND METHODS: Seventy-two freshly extracted, intact human premolar teeth were divided into four groups (n=18). Class V cavities (3mm in length, 2mm in width and 2mm in depth) were prepared on the buccal surface of each tooth. The following sealing materials were applied in the four groups: One-step Clearfil S3 Bond (S3) self-etch adhesive, two-step Clearfil SE Bond (SE) self-etch adhesive, S3 Bond+ VivaSens desensitizing varnish (VS+S3) and Clearfil SE Bond + VivaSens (VS+SE). The cavities on the teeth were then incrementally filled with Z350 light cure composite. The teeth were stored in distilled water for 24 hours at 37 degrees C, and were then thermocycled for 1000 cycles. Then, all the specimens were prepared for dye penetration test and were immersed in 2% basic fuchsin dye and incubated at 37 degrees C for 24 hours. The teeth were then sectioned buccolingually along the center of restorations with a diamond disk. Microleakage at the tooth-restoration interface was assessed in the enamel and dentin margins blindly using dye penetration under a stereomicroscope at *20 magnification. RESULTS: There was significantly greater leakage at the enamel and dentin margins in group VS+SE than in group SE; also, these values were higher in group VS+S3 than in S3. CONCLUSION: Combined application of desensitizing varnish and self etch adhesives seems to increase microleakage in composite restorations. Thus, its application is not suggested. PMID- 27507992 TI - In Vitro Effect of Porcelain Firing Cycle and Different Thicknesses of IPS E.max CAD Core on Marginal Accuracy of All-Ceramic Restorations. AB - OBJECTIVES: Marginal adaptation is important for long-term success of full coverage restorations. The aim of this study was to determine the effect of porcelain firing cycle and different thicknesses of IPS e.max core on marginal accuracy of all-ceramic restorations. MATERIALS AND METHODS: A standard stainless steel die with 0.8 mm classic chamfer finish line and 10 degrees taper was used in this in vitro study. An impression was taken from the stainless steel die to fabricate 20 epoxy resin dies, which were then scanned and IPS e.max CAD cores were fabricated using computer-aided design/computer-aided manufacturing (CAD/CAM) technique in two groups of 10 with 0.7 mm (group A) and 0.4mm (group B) core thickness. Copings were then placed on their respective dies and randomly numbered. The amount of marginal gap was measured in 10 points under a stereomicroscope (*90 magnification) before and after porcelain veneering. RESULTS: The mean gap in 0.7mm and 0.4mm core thicknesses was 15.62+/-2.55MUm and 19.68+/-3.09MUm before porcelain firing and 32.01+/-3.19MUm and 35.24+/-3.8MUm after porcelain firing. The difference in marginal gap between the two thicknesses was significant before porcelain firing but not significant after veneering. Significant differences were also found in the marginal gap before and after porcelain veneering in each group. CONCLUSION: The porcelain firing cycle increases marginal gap in IPS e.max CAD restorations; 0.3 mm decrease in core thickness slightly increased marginal discrepancy, however it was not significant. PMID- 27507993 TI - Regenerative Effects of Three Types of Allografts on Rabbit Calvarium: An Animal Study. AB - OBJECTIVES: The aim of this study was to histologically compare the regenerative properties of two allografts manufactured by two Iranian companies. MATERIALS AND METHODS: In this study, four 8-mm defects were produced in the calvaria of 12 rabbits. In three defects, three types of allografts namely ITB, CenoBone and Grafton were placed and one defect served as control. Samples were prepared and histomorphometric evaluations were carried out after healing periods of four weeks (interval 1) and eight weeks (interval 2). Qualitative and quantities variables were compared and analyzed with SPSS software. RESULTS: Mild inflammation was observed in 45% and 12.5% of the samples in the first and second intervals, respectively. Foreign body reaction was observed in only 5% of the samples. The quality of regenerated bone was immature, mixed and lamellar in 54.5%, 15.9% and 4.5% of the samples, respectively. The rate of allograft resorption was the highest and lowest in the CenoBone and Grafton samples, respectively. The mean amount of regenerated bone was higher in areas containing Grafton; however, the differences were not statistically significant. CONCLUSION: Despite the differences in the numerical values of bone regeneration, there were no statistically significant differences in bone generation among the material groups, and allografts manufactured in Iran can be suitable alternatives to Grafton with the same good properties. Further studies are necessary to clarify the efficacy of these allografts. PMID- 27507994 TI - Assessment of IgG Antibodies Against HSV1, HSV2, CMV and EBV in Patients with Pemphigus Vulgaris Versus Healthy People. AB - OBJECTIVES: Regarding the implication of viruses particularly herpes in pemphigus vulgaris, we sought to assess and compare the level of immunoglobulin G (IgG) antibodies against herpes simplex virus types 1 and 2 (HSV1 and HSV2), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in patients with pemphigus vulgaris and healthy people. MATERIALS AND METHODS: In this cross-sectional study, 25 patients with pemphigus vulgaris and 27 healthy individuals comprised the experimental and control groups, respectively. Serum samples were taken from both groups; the levels of IgG antibodies against HSV1, HSV2, CMV and EBV were measured using ELISA. RESULTS: Immunoglobulin G titer was higher for all four viruses in the patient group in comparison to the control group. This difference was significant for anti-EBV (P= 0.005), anti-CMV (P=0.0001) and anti-HSV2 (P=0.001) but not significant for anti-HSV1 (P= 0.36). CONCLUSION: Viruses including EBV, CMV, and HSV2 probably play a role in the pathogenesis of pemphigus in addition to the effects of genetics, toxins and other predisposing factors. In this study, no statistically significant relationship was observed between HSV1 and pemphigus vulgaris, which was probably due to the high titer of anti-HSV1 IgG in healthy individuals in the community. More studies must be done in this regard. PMID- 27507995 TI - Comparison of Apical Sealing Ability of Two Phases of Gutta-Percha: A Bacterial Leakage Model. AB - OBJECTIVES: The aim of this study was to compare apical sealing ability of alpha and beta phases of gutta-percha by means of bacterial leakage model. MATERIALS AND METHODS: Fifty single-rooted human premolars were selected. The root canals were prepared with Mtwo rotary instruments up to apical #35.04. Forty teeth were randomly divided into two groups (n= 20). The root canals were obturated by alpha phase (G1) and beta phase (G2) of gutta-percha and AH26 sealer, respectively, with warm vertical compaction technique. Ten teeth served as positive (n=8) and negative (n=2) control groups. Then, the specimens were sterilized with ethylene oxide gas. Bacterial suspension of Enterococcus faecalis (E. faecalis) in 0.5 McFarland concentration was prepared. All teeth were mounted in plastic vial caps containing Muller Hinton broth and then exposed to bacterial suspension of E. faecalis every three days up to 31 days. The number of days required for the contamination of the entire root canals was recorded. The data were analyzed using Mann Whitney U test. RESULTS: There were no significant differences in bacterial leakage between the G1 and G2 groups (P>0.05). Negative controls revealed no microbial leakage; whereas positive controls showed gross microbial leakage. CONCLUSION: Despite better thermal conduction and adaptability of alpha phase of guttapercha, our study revealed no significant difference in bacterial leakage between alpha and beta phases of gutta-percha in warm vertical compaction. PMID- 27507996 TI - Immunohistochemical Evaluation of Angiogenesis and Cell Proliferation in Tongue Squamous Cell Carcinoma. AB - OBJECTIVES: Squamous cell carcinoma (SCC) is the most common malignant neoplasm of the oral cavity and a public health threat. Tumor progression is believed to be influenced by angiogenesis as well as tumor cell proliferation; however, the correlation of these two factors in tongue SCC still remains unclear. This study aimed to assess the correlation of these two factors in tongue SCC. MATERIALS AND METHODS: Twenty-four paraffin block sections of tongue SCC were stained with monoclonal antibodies against CD105 and Ki-67. In order to assess the expressions of CD105 and Ki-67 to evaluate CD105 microvessel density (MVD), positively stained microvessels were counted in a predominantly vascular area (hot spot) in each specimen at *400 magnification. The proliferation index was expressed as a percentage of Ki-67 positive cells. Data were analyzed by t-test and Pearson's correlation coefficient (P<0.05). RESULTS: The CD105 MVD was related to histological grading as well as Ki67 labeling index (LI; P= 0.045 and P=0.047, respectively). Both CD105 MVD and KI67 LI were unrelated to sex (P=0.41 and P=0.78, respectively) and age (P=0.20 and P=0.36, respectively) of the patients. No correlation was found between CD105 MVD and Ki67 LI (P=0.86). CONCLUSION: The mean CD105 MVD was significantly lower in poorly differentiated tumors. This finding suggests that CD105 MVD may serve as a valuable prognostic factor in tongue SCC. Absence of correlation between MVD and tumor cell proliferation indicates that these processes may be guided by unrelated mechanisms. PMID- 27507997 TI - Effects of Different Viewing Conditions on Radiographic Interpretation. AB - OBJECTIVES: Optimum viewing conditions facilitate identification of radiographic details and decrease the need for retakes, patients' costs and radiation dose. This study sought to evaluate the effects of different viewing conditions on radiographic interpretation. MATERIALS AND METHODS: This diagnostic study was performed by evaluating radiograph of a 7mm-thick aluminum block, in which 10 holes with 2mm diameters were randomly drilled with depths ranging from 0.05 mm to 0.50mm. The radiograph was viewed by four oral radiologists independently under four viewing conditions, including a white light viewing light box in a lit room, yellow light viewing light box in a lit room, white light viewing light box in a dark room and yellow light viewing light box in a dark room. Number of circular shadows observed on the film was recorded. The data were analyzed by two way ANOVA. RESULTS: The mean number of detected circular shadows was 6.75, 7.5, 7.25 and 7.75 in white light viewing light box in a lit room, white light viewing light box in a dark room, yellow light viewing light box in a lit room and yellow light viewing light box in a dark room, respectively. Although the surrounding illumination had statistically significant effect on the radiographic details (P<=0.03), the light color of the viewing light box had no significant effect on visibility of the radiographic details. CONCLUSION: White and yellow light of the viewing light box had no significant effect on visibility of the radiographic details but more information was obtained in a dark room. PMID- 27507998 TI - Effect of Bonding Application Time on Bond Strength of Composite Resin to Glass Ionomer Cement. AB - OBJECTIVES: This experimental study evaluated the effect of bonding application time on the microshear bond strength of composite resin to different types of glass ionomer cements (GICs). MATERIALS AND METHODS: One-hundred and sixty specimens (two conventional and two resin-modified GICs) were prepared and divided into 16 groups. The surface of all specimens was prepared using two different bonding systems (Frog and Stea) at three different times. After setting, the composite resin (Z100) was placed over the GICs. The specimens were then stored in distilled water for 24 hours (37 degrees C) and exposed to microshear stresses at a crosshead speed of 1 mm/min. The results were analyzed using three-way ANOVA and Tukey's test (P<0.05). RESULTS: In conventional GICs, bond strength was affected by the type of bonding system at different times, and bond strength was significantly higher in the Fuji II group compared to Riva Self Cure group. In the Riva Self Cure group, bond strength was significantly affected by time; whereas, the type of bonding system failed to exert a significant effect on bond strength. There was no significant correlation between the type of bonding system and the two brands of resin-modified GICs. Bond strength was not affected by the type of bonding agent; however, among the two brands of resin modified GICs, Fuji II LC yielded a significantly stronger bond. CONCLUSION: It appears that the type of bonding agent does not affect the microshear bond strength, and the bonding application time affects the microshear bond strength in Riva Self Cure GICs. PMID- 27507999 TI - Passive acoustic monitoring reveals group ranging and territory use: a case study of wild chimpanzees (Pan troglodytes). AB - BACKGROUND: Assessing the range and territories of wild mammals traditionally requires years of data collection and often involves directly following individuals or using tracking devices. Indirect and non-invasive methods of monitoring wildlife have therefore emerged as attractive alternatives due to their ability to collect data at large spatiotemporal scales using standardized remote sensing technologies. Here, we investigate the use of two novel passive acoustic monitoring (PAM) systems used to capture long-distance sounds produced by the same species, wild chimpanzees (Pan troglodytes), living in two different habitats: forest (Tai, Cote d'Ivoire) and savanna-woodland (Issa valley, Tanzania). RESULTS: Using data collected independently at two field sites, we show that detections of chimpanzee sounds on autonomous recording devices were predicted by direct and indirect indices of chimpanzee presence. At Tai, the number of chimpanzee buttress drums detected on recording devices was positively influenced by the number of hours chimpanzees were seen ranging within a 1 km radius of a device. We observed a similar but weaker relationship within a 500 m radius. At Issa, the number of indirect chimpanzee observations positively predicted detections of chimpanzee loud calls on a recording device within a 500 m but not a 1 km radius. Moreover, using just seven months of PAM data, we could locate two known chimpanzee communities in Tai and observed monthly spatial variation in the center of activity for each group. CONCLUSIONS: Our work shows PAM is a promising new tool for gathering information about the ranging behavior and habitat use of chimpanzees and can be easily adopted for other large territorial mammals, provided they produce long-distance acoustic signals that can be captured by autonomous recording devices (e.g., lions and wolves). With this study we hope to promote more interdisciplinary research in PAM to help overcome its challenges, particularly in data processing, to improve its wider application. PMID- 27508000 TI - Precipitating factors and targeted therapies in combating the perils of sickle cell disease--- A special nutritional consideration. AB - Nutritional research in sickle cell disease has been the focus in recent times owing to not only specific nutritional deficiencies, but also the improvements associated with less painful episodes. Though hydroxyurea remains the drug of choice, certain adverse health effects on long term supplementation makes room for researches of different compounds. Macro and micro nutrient deficiencies, along with vitamins, play an important role in not only meeting the calorific needs, but also reducing clinical complications and growth abnormalities. Symptoms of hyper protein metabolism, increased cell turnover, increased cardiac output, and appetite suppression due to enhanced cytokine production, might give us leads for better understanding of the mechanisms involved. Different nutritional approaches comprising of traditional herbal therapies, antioxidants, flavonoids, vitamins, minerals etc., reducing oxidative stress and blood aggregation, have been tried out to increase the health potential. Nutritional therapies may also serve complementary to the newer therapies using ozone, hematopoietic stem cell transplantation, antifungal medications, erythropoietin etc. Herein we try to present a holistic picture of the different patho physiological mechanisms, and nutritional strategies adopted. PMID- 27508001 TI - Relationship of suicide rates with climate and economic variables in Europe during 2000-2012. AB - BACKGROUND: It is well known that suicidal rates vary considerably among European countries and the reasons for this are unknown, although several theories have been proposed. The effect of economic variables has been extensively studied but not that of climate. METHODS: Data from 29 European countries covering the years 2000-2012 and concerning male and female standardized suicidal rates (according to WHO), economic variables (according World Bank) and climate variables were gathered. The statistical analysis included cluster and principal component analysis and categorical regression. RESULTS: The derived models explained 62.4 % of the variability of male suicidal rates. Economic variables alone explained 26.9 % and climate variables 37.6 %. For females, the respective figures were 41.7, 11.5 and 28.1 %. Male suicides correlated with high unemployment rate in the frame of high growth rate and high inflation and low GDP per capita, while female suicides correlated negatively with inflation. Both male and female suicides correlated with low temperature. DISCUSSION: The current study reports that the climatic effect (cold climate) is stronger than the economic one, but both are present. It seems that in Europe suicidality follows the climate/temperature cline which interestingly is not from south to north but from south to north-east. This raises concerns that climate change could lead to an increase in suicide rates. The current study is essentially the first successful attempt to explain the differences across countries in Europe; however, it is an observational analysis based on aggregate data and thus there is a lack of control for confounders. PMID- 27508002 TI - Pattern and predictors of mortality in necrotizing fasciitis patients in a single tertiary hospital. AB - BACKGROUND: Necrotizing fasciitis (NF) is a fatal aggressive infectious disease. We aimed to assess the major contributing factors of mortality in NF patients. METHODS: A retrospective study was conducted at a single surgical intensive care unit between 2000 and 2013. Patients were categorized into 2 groups based on their in-hospital outcome (survivors versus non-survivors). RESULTS: During a14 year period, 331 NF patients were admitted with a mean age of 50.8 +/- 15.4 years and 74 % of them were males Non-survivors (26 %) were 14.5 years older (p = 0.001) and had lower frequency of pain (p = 0.01) and fever (p = 0.001) than survivors (74 %) at hospital presentation. Diabetes mellitus, hypertension, and coronary artery disease were more prevalent among non-survivors (p = 0.001). The 2 groups were comparable for the site of infection; except for sacral region that was more involved in non-survivors (p = 0.005). On admission, non-survivors had lower hemoglobin levels (p = 0.001), platelet count (p = 0.02), blood glucose levels (p = 0.07) and had higher serum creatinine (p = 0.001). Non-survivors had greater median LRINEC (Laboratory Risk Indicator for NECrotizing fasciitis score) and Sequential Organ Failure Assessment (SOFA) scores (p = 0.001). Polybacterial and monobacterial gram negative infections were more evident in non-survivors group. Monobacterial pseudomonas (p = 0.01) and proteus infections (p = 0.005) were reported more among non-survivors. The overall mortality was 26 % and the major causes of death were bacteremia, septic shock and multiorgan failure. Multivariate analysis showed that age and SOFA score were independent predictors of mortality in the entire study population. CONCLUSION: The mortality rate is quite high as one quarter of NF patients died during hospitalization. The present study highlights the clinical and laboratory characteristics and predictors of mortality in NF patients. PMID- 27508003 TI - Mapping N-linked glycosylation of carbohydrate-active enzymes in the secretome of Aspergillus nidulans grown on lignocellulose. AB - BACKGROUND: The genus Aspergillus includes microorganisms that naturally degrade lignocellulosic biomass, secreting large amounts of carbohydrate-active enzymes (CAZymes) that characterize their saprophyte lifestyle. Aspergillus has the capacity to perform post-translational modifications (PTM), which provides an additional advantage for the use of these organisms as a host for the production of heterologous proteins. In this study, the N-linked glycosylation of CAZymes identified in the secretome of Aspergillus nidulans grown on lignocellulose was mapped. RESULTS: Aspergillus nidulans was grown in glucose, xylan and pretreated sugarcane bagasse (SCB) for 96 h, after which glycoproteomics and glycomics were carried out on the extracellular proteins (secretome). A total of 265 proteins were identified, with 153, 210 and 182 proteins in the glucose, xylan and SCB substrates, respectively. CAZymes corresponded to more than 50 % of the total secretome in xylan and SCB. A total of 182 N-glycosylation sites were identified, of which 121 were detected in 67 CAZymes. A prevalence of the N-glyc sequon N-X-T (72.2 %) was observed in N-glyc sites compared with N-X-S (27.8 %). The amino acids flanking the validated N-glyc sites were mainly composed of hydrophobic and polar uncharged amino acids. Selected proteins were evaluated for conservation of the N-glyc sites in Aspergilli homologous proteins, but a pattern of conservation was not observed. A global analysis of N-glycans released from the proteins secreted by A. nidulans was also performed. While the proportion of N-glycans with Hex5 to Hex9 was similar in the xylan condition, a prevalence of Hex5 was observed in the SCB and glucose conditions. CONCLUSIONS: The most common and frequent N-glycosylated motifs, an overview of the N-glycosylation of the CAZymes and the number of mannoses found in N-glycans were analyzed. There are many bottlenecks in protein production by filamentous fungi, such as folding, transport by vesicles and secretion, but N-glycosylation in the correct context is a fundamental event for defining the high levels of secretion of target proteins. A comprehensive analysis of the protein glycosylation processes in A. nidulans will assist with a better understanding of glycoprotein structures, profiles, activities and functions. This knowledge can help in the optimization of heterologous expression and protein secretion in the fungal host. PMID- 27508004 TI - Identification of small marker chromosomes using microarray comparative genomic hybridization and multicolor fluorescent in situ hybridization. AB - BACKGROUND: Marker chromosomes are small supernumerary chromosomes that cannot be unambiguously identified by chromosome banding techniques alone. However, the precise characterization of marker chromosomes is important for prenatal diagnosis and proper genetic counseling. In this study, we evaluated the chromosomal origin of marker chromosomes using a combination of banding cytogenetics and molecular cytogenetic techniques including diverse fluorescence in situ hybridization (FISH) assays and array comparative genomic hybridization (array CGH). RESULTS: In a series of 2871 patients for whom cytogenetic analysis was requested, 14 cases with small supernumerary marker chromosomes (sSMCs) were identified. Nine sSMCs were mosaic, and five nonmosaic. Of the nine cases with known parental origins, four were identified as de novo, and four and one were maternally and paternally inherited, respectively. Six sSMCs were identified by FISH using centromeric probes; three sSMCs were derived from chromosome 15, including two heterochromatic sSMC(15)s and a large sSMC(15) spanning 15q11.1q13.1, and three sSMCs originated from chromosome 14 or 22. Array CGH revealed two cases with derivatives of chromosome 2 and whole chromosome painting multicolor-FISH (M-FISH) identified three cases with derivatives of chromosome 6, 16, and 19, respectively. One maker chromosome in Turner syndrome was characterized as sSMC(X) by preferential application of a centromeric probe for X chromosome. In addition, one sSMC composed of genomic materials from chromosomes 12 and 18 was identified in parallel with parental karyotype analysis that revealed the reciprocal balanced translocation. CONCLUSIONS: This report is the largest study on sSMCs in Korea and expands the spectrum of sSMCs that are molecularly characterized. PMID- 27508005 TI - Sex chromosome loss after allogeneic hematopoietic stem cell transplant in patients with hematologic neoplasms: a diagnostic dilemma for clinical cytogeneticists. AB - BACKGROUND: Sex chromosome loss (SCL), including loss of an X chromosome (-X) in females and loss of the Y chromosome (-Y) in males, resulting in a karyotype of 45,X, rarely occurs in patients post an allogeneic hematopoietic stem cell transplant (alloHSCT). However, origin of this abnormal clone and its clinical significance remains unknown. RESULTS: We present 12 cases with SCL who underwent alloHSCT; 9 patients (4 men and 5 women with a median age of 56 years) developed isolated SCL after alloHSCT (Group I), and 3 patients (all women with a median age of 58 years) had a SCL before undergoing alloHSCT after which SCL disappeared (Group II). The primary neoplasms included chronic lymphocytic leukemia (n = 5), acute myeloid leukemia (n = 5), chronic myelogenous leukemia with nodal marginal zone lymphoma (n = 1) and Hodgkin lymphoma (n = 1). According to the donor/recipient relationship, their alloHSCT can be divided into sex-matched, HLA matched, unrelated donors (n = 2); sex-mismatched, HLA-matched, unrelated donors (n = 4); sex-mismatched, HLA-matched, related donors (2 HLA-identical and 2 HLA haploidentical cases) and sex-matched, HLA-matched, related donors (2 HLA haploidentical cases). In Group I, isolated SCL was first detected with a median interval of 3 months (range 1 to 42 months) after the alloHSCT. By the end of clinical follow-up in patients in Group I, 7 patients expired with a median overall survival of 45 months (range 3 to 108 months) after alloHSCT and 33 months (range 0 to 66 months) after SCL detection. In Group II, 1 patient expired with a survival time of 54 months after the alloHSCT. Detection of SCL after alloHSCT can be transient, intermittent or persistent. CONCLUSIONS: Interpretation of SCL is challenging in the context of alloHSCT. Chimerism testing is useful in determining the origin of SCL. In the case of SCL with donor/recipient chimerism, deduction of the SCL origin by all means and use of " ?X" or "-?Y" in the ISCN nomenclature are recommended. Clinical follow-up with closely monitoring the SCL by both cytogenetic and molecular analyses is needed. PMID- 27508006 TI - Evaluation, intervention, and follow-up of patients with diabetes in a primary health care setting in Brazil: the importance of a specialized mobile consultancy. AB - BACKGROUND: Studies show that educational interventions improve glycemic control in patients with diabetes mellitus (DM), reducing the occurrence of complications associated with the disease. OBJECTIVES: To evaluate the effects of a mobile DM consultancy on clinical and laboratory parameters, disease knowledge, and quality of life in patients with type 2 DM (T2DM) at a primary health care network in Brazil. METHODS: Randomized clinical trial conducted in a city in southern Brazil with 52 patients with T2DM receiving care at a primary health care setting. The intervention lasted for 6 months and consisted of a follow-up with an endocrinologist (five meetings), treatment adjustment based on clinical evaluation and laboratory tests, and educational activities with conversation maps in DM. The statistical analysis included comparison and association tests, considering p values <=0.05 as statistically significant. RESULTS: The mean age of the patients was 63.8 years. Most participants were female (63.5 %), had low educational level (59.6 %) and family history of T2DM (71.2 %), used only oral hypoglycemic agents to manage their DM (73.2 %), presented unfavorable anthropometric and laboratory parameters, a high or medium risk of complications (84.6 %), and inadequate glycemic control (67.3 %; with 71 % of the high-risk patients presenting a HbA1c level >9 %). Adjustment in pharmacological treatment was required in 63.5 % of the patients. After the intervention, we observed a significant 0.46 % decrease in mean HbA1c level (p = 0.0218), particularly among individuals with inadequate glycemic control (0.71 %; p = 0.0136). Additionally, there was an increase in disease knowledge scores and a significant decrease in mean body mass index, waist circumference, and disease impact scores. CONCLUSION: The intervention improved glycemic control and disease knowledge, reduced the values of body mass index and waist circumference, and the impact of the disease on patients' lives. This indicates that care and educational measures improve the experience of the patients with DM and control of the disease. PMID- 27508007 TI - Pedigree based DNA sequencing pipeline for germline genomes of cancer families. AB - BACKGROUND: In the course of our whole-genome sequencing efforts, we have developed a pipeline for analyzing germline genomes from Mendelian types of cancer pedigrees (familial cancer variant prioritization pipeline, FCVPP). RESULTS: The variant calling step distinguishes two types of genomic variants: single nucleotide variants (SNVs) and indels, which undergo technical quality control. Mendelian types of variants are assumed to be rare and variants with frequencies higher that 0.1 % are screened out using human 1000 Genomes (Phase 3) and non-TCGA ExAC population data. Segregation in the pedigree allows variants to be present in affected family members and not in old, unaffected ones. The effectiveness of variant segregation depends on the number and relatedness of the family members: if over 5 third-degree (or more distant) relatives are available, the experience has shown that the number of likely variants is reduced from many hundreds to a few tens. These are then subjected to bioinformatics analysis, starting with the combined annotation dependent depletion (CADD) tool, which predicts the likelihood of the variant being deleterious. Different sets of individual tools are used for further evaluation of the deleteriousness of coding variants, 5' and 3' untranslated regions (UTRs), and intergenic variants. CONLUSIONS: The likelihood of success of the present genomic pipeline in finding novel high- or medium-penetrant genes depends on many steps but first and foremost, the pedigree needs to be reasonably large and the assignments and diagnoses among the members need to be correct. PMID- 27508009 TI - SRT1720, a SIRT1 specific activator, protected H2O2-induced senescent endothelium. AB - Silent information regulator 1 (SIRT1) plays a critical role in maintaining vascular homeostasis via modulating senescent-related signal pathway, however, the molecular mechanism remains modest clarified. The purpose of this study was to examine whether SIRT1 specific activator SRT1720 would exhibit pro-angiogenic and anti-aging properties in response to hydrogen peroxide (H2O2)-induced endothelial senescence, and determine the underlying mechanisms. We pre-treated senescent human umbilical vein endothelial cells (HUVECs) with SRT1720, senescence-associated beta-galactosidase activity, apoptosis, migration, tube formation, proliferation and angiogenic factors were quantitatively examined. The results revealed that pharmacologic activation of SIRT1 by SRT1720 rescued apoptotic HUVECs and upregulated angiogenic response through reinforcing the protein expressions of angiogenic and survival factors in vitro. Furthermore, we confirmed that the expressions of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) and phosphoryl-Akt were augmented in SRT1720-treated senescent HUVECs. In conclusion, our data indicated that SRT1720 could protect against endothelial senescence and maintain cell function via Akt/eNOS/VEGF axis. PMID- 27508008 TI - Research progress of cardioprotective agents for prevention of anthracycline cardiotoxicity. AB - Anthracyclines, including doxorubicin, epirubicin, daunorubicin and aclarubicin, are widely used as chemotherapeutic agents in the treatment of hematologic and solid tumor, including acute leukemia, lymphoma, breast cancer, gastric cancer, soft tissue sarcomas and ovarian cancer. In the cancer treatment, anthracyclines also can be combined with other chemotherapies and molecular-targeted drugs. The combination of anthracyclines with other therapies is usually the first-line treatment. Anthracyclines are effective and potent agents with a broad antitumor spectrum, but may cause adverse reactions, including hair loss, myelotoxicity, as well as cardiotoxicity. We used hematopoietic stimulating factors to control the myelotoxicity, such as G-CSF, EPO and TPO. However, the cardiotoxicity is the most serious side effect of anthracyclines. Clinical research and practical observations indicated that the cardiotoxicity of anthracyclines is commonly progressive and irreversible. Especially to those patients who have the first time use of anthracyclines, the damage is common. Therefore, early detection and prevention of anthracyclines induced cardiotoxicity are particularly important and has already aroused more attention in clinic. By literature review, we reviewed the research progress of cardioprotective agents for prevention of anthracycline cardiotoxicity. PMID- 27508010 TI - Preliminary study of urine metabolism in type two diabetic patients based on GC MS. AB - OBJECTIVE: Comparative study of type 2 diabetes and healthy controls by metabolomics methods to explore the pathogenesis of Type II diabetes. METHODS: Gas chromatography - mass spectrometry (GC-MS) with a variety of multivariate statistical analysis methods to the healthy control group 58 cases, 68 cases of Type II diabetes group were analyzed. Chromatographic conditions: DB-5MS column; the carrier gas He; flow rate of 1 mL.min(-1), the injection volume 1 uL; split ratio is 100: 1. MS conditions: electron impact (EI) ion source, an auxiliary temperature of 280 degrees C, the ion source 230 degrees C, quadrupole 150 degrees C; mass scan range 30~600 mAu. RESULTS: Established analytical method based on urine metabolomics GC-MS of Type II diabetes, determine the urine succinic acid, L-leucine, L-isoleucine, tyrosine, slanine, acetoace acid, mannose, L-isoleucine, L-threonine, Phenylalanine, fructose, D-glucose, palmi acid, oleic acid and arachidonic acid were significantly were significantly changed. CONCLUSION: Based on metabolomics of GC-MS detection and analysis metabolites can be found differences between type 2 diabetes and healthy control group, PCA diagram can effectively distinguish Type II diabetes and healthy control group, with load diagrams and PLS-DA VIP value metabolite screening, the resulting differences in metabolic pathways involved metabolites, including amino acid metabolism, lipid metabolism, glucose metabolism and energy metabolism. PMID- 27508011 TI - Collateral development and spinal motor reorganization after nerve injury and repair. AB - Functional recovery is often unsatisfactory after severe extended nerve defects or proximal nerve trunks injuries repaired by traditional repair methods, as the long regeneration distance for the regenerated axons to reinnervate their original target end-organs. The proximal nerve stump can regenerate with many collaterals that reinnervate the distal stump after peripheral nerve injury, it may be possible to use nearby fewer nerve fibers to repair more nerve fibers at the distal end to shorten the regenerating distance. In this study, the proximal peroneal nerve was used to repair both the distal peroneal and tibial nerve. The number and location of motor neurons in spinal cord as well as functional and morphological recovery were assessed at 2 months, 4 months and 8 months after nerve repair, respectively. Projections from the intact peroneal and tibial nerves were also studied in normal animals. The changes of motor neurons were assessed using the retrograde neurotracers FG and DiI to backlabel motor neurons that regenerate axons into two different pathways. To evaluate the functional recovery, the muscle forces and sciatic function index were examined. The muscles and myelinated axons were assessed using electrophysiology and histology. The results showed that all labeled motor neurons after nerve repair were always confined within the normal peroneal nerve pool and nearly all the distribution of motor neurons labeled via distal different nerves was disorganized as compared to normal group. However, there was a significant decline in the number of double labeled motor neurons and an obvious improvement with respect to the functional and morphological recovery between 2 and 8 months. In addition, the tibial/peroneal motor neuron number ratio at different times was 2.11+/-0.05, 2.13+/-0.08, 2.09+/-0.12, respectively, and was close to normal group (2.21+/ 0.09). Quantitative analysis showed no significant morphological differences between myelinated nerve fibers regenerated along the two distal nerves except for the number of nerve fibers, which was higher in the tibial nerve. The ratio of distal regenerated axon numbers to proximal donor nerve axon numbers was about 3.95+/-0.10, 4.06+/-0.19 and 3.87+/-0.23, respectively. This study demonstrated that fewer nerve fibers can regenerate a large number of collaterals which successfully repopulate both distal nerves and lead to the partial recovery of lost functions. It may provide a new method to repair severe extended nerve defects or proximal nerve trunks injuries. PMID- 27508012 TI - Gax regulates human vascular smooth muscle cell phenotypic modulation and vascular remodeling. AB - Abnormal phenotypic modulation of vascular smooth muscle cells (VSMCs) is a hallmark of cardiovascular diseases such as atherosclerosis, hypertension and restenosis after angioplasty. Transcription factors have emerged as critical regulators for VSMCs function, and recently we verified inhibiting transcription factor Gax was important for controlling VSMCs proliferation and migration. This study aimed to determine its role in phenotypic modulation of VSMCs. Western blot revealed that overexpression of Gax increased expression of VSMCs differentiation marker genes such as calponin and SM-MHC 11. Then, Gax overexpression potently suppressed proliferation and migration of VSMCs with or without platelet-derived growth factor-induced-BB (PDGF-BB) stimuli whereas Gax silencing inhibited these processes. Furthermore, cDNA array analysis indicated that Rap1A gene was the downstream target of Gax in human VSMCs. And overexpression of Gax significantly inhibited expression of Rap1A in VSMCs with or without PDGF-BB stimuli. Moreover, overexpression of Rap1A decreased expression of VSMCs differentiation marker genes and increased proliferation and migration of VSMCs with or without PDGF-BB stimuli. Finally, Gax overexpression significantly inhibited the neointimal formation in carotid artery injury of mouse models, specifically through maintaining VSMCs contractile phenotype by decreasing Rap1A expression. In conclusion, these results indicated that Gax was a regulator of human VSMCs phenotypic modulation by targeting Rap1A gene, which suggested that targeting Gax or its downstream targets in human VSMCs may provide an attractive approach for the prevention and treatment of cardiovascular diseases. PMID- 27508013 TI - Follicular helper T cell exhaustion induced by PD-L1 expression in hepatocellular carcinoma results in impaired cytokine expression and B cell help, and is associated with advanced tumor stages. AB - Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is one of the most common cancers in HBV-endemic regions, with irreversible progression and poor prognosis. HBV-related HCC patients lack effective antiviral/antitumor B cell antibody responses. We hypothesize that dysregulation of PD-1-expressing follicular helper T (Tfh) cell, induced by intrahepatic/intratumoral PD-L1 expression in HCC, could contribute to the defects in B cell immunity. The Tfh responses in healthy control (HC) subjects, chronic hepatitis B (HepB) patients, and HBV-related HCC patients were examined. Compared to HC and HepB individuals, HCC patients showed reduced ICOS expression, IL-10 and IL-21 secretion, and proliferation in Tfh cells. Tfh cells from stage III patients demonstrated increased impairment than those from stage I and stage II patients. Compared to Tfh cells from HC and HepB subjects, those from stage III HCC patients were significantly less effective at inducing the differentiation of naive B cells toward plasmablasts. HCC is known to upregulate hepatic PD-L1 expression, which could suppress Tfh responses. Blocking PD-1 partially rescued the Tfh functions in stage I and stage II HCC subjects but not in stage III HCC patients, while treatment with recombinant PD-L1 strongly suppressed Tfh functions in all HCC stages. Moreover, the level of IL-10 and IL-21 expression by Tfh cells was inversely correlated with the intensity of PD-L1 expression in resected tumors. Together, our results demonstrated an HCC-specific Tfh exhaustion, which might have resulted from elevated PD-1 and PD-L1 signaling. PMID- 27508014 TI - Intervention effect of pinelliae decoction for purging stomach-fire on malignant transformation of bone marrow mesenchymal stem cells in the gastric cancer microenvironment. AB - OBJECTIVE: The study aimed to simulate the microenvironment of gastric cancer to promote the malignant transformation of bone marrow mesenchymal stem cells (BMSCs) and further evaluate the effect of Pinelliae Decoction for Purging Stomach-Fire and its disassembled prescriptions on BMSCs. METHODS: Transwell co culture was performed on the human gastric cancer cell strains BGC-823 and BMSCs to simulate the microenvironment of gastric cancer. The drug-containing serum prepared by Pinelliae Decoction for Purging Stomach-Fire and its disassembled prescriptions was used, and its influence on BMSCs with malignant transformation was observed. RESULTS: BMSCs were harvested successfully from the rat bone marrow, and flow cytometer identification indicated that CD44+/CD34- cells accounted for 70.64%. The co-culture of BGC-823 cells can induce malignant transformation of BMSCs. And the drug-containing serum can induce G2 phase arrest, inhibit cell proliferation, simultaneously inhibit TERT and c-myc expression, lower the cellular ability of chemotactic migration, inhibit the tumor-forming ability of BGC-823 in nude rats and promote the tumor apoptosis. CONCLUSION: The effective components of Pinelliae Decoction for Purging Stomach Fire in gastric cancer treatment are pinelliae and dried ginger, and the main acting mechanism is to inhibit tumor cell proliferation and chemotactic migration and promote apoptosis. PMID- 27508015 TI - Immunotherapy with dendritic cells and cytokine-induced killer cells for MDA-MB 231 breast cancer stem cells in nude mice. AB - OBJECTIVE: To compare the effects and safety of immunotherapy using different methods to load DC-CIK cells for MDA-MB-231 breast cancer stem cells. METHODS: A breast cancer model was established in BALB/c nude mice using breast cancer stem cells. All mice were randomly divided into six groups, and each group had three nude mice: the blank control group, the DC-CIK group (group D), the MDA-MB-231 CSC whole-cell lysate DC-CIK group (group L-D), the MDA-MB-231 CSC RNA DC-CIK group (group R-D), the THP DC-CIK group (group T-D) and group THP. Nude mice in groups D, L-D, R-D and T-D were injected with CSCs; 4 days later, the mice were inoculated with 1 * 10(6) DC-CIK cells via the tail vein. This injection was repeated 2 times a week for three weeks. The mice in groups THP and T-D were injected with a 5 mg/Kg dose of THP chemotherapeutic agents via the tail vein the day before DC-CIK injection, which was repeated one time a week for three weeks. Nude mice in the blank control group were injected with normal saline. The weights and sizes of the tumors were measured after the mice were euthanized. The expression of c-Myc, a key proto-oncogene associated with the Akt signaling pathway, was detected with RT-PCR. RESULTS: The tumor growth rates in each group were as follows: group L-D < group R-D < group D < group T-D < blank control group < group THP. The nude mice in groups L-D, R-D and D were normal, active and had a healthy appetite. The mice in groups T-D and THP were lethargic, less active and showed loss of appetite, and their caudal vein was easy to stimulate. The mice in the blank control group were sacrificed during the third week or when their tumors developed ulceration. Compared with the blank control group, c-Myc gene expression was reduced in the tumors of the five experimental groups. CONCLUSION: The results showed that DC-CIK cells stimulated by different methods were highly effect against MDA-MB-231 breast cancer stem cells in nude mice in all groups, especially in group L-D. DC-CIK immunotherapy may provide a new strategy for the clinical treatment of breast cancer. PMID- 27508016 TI - T helper 17 and T helper 1 cells are increased but regulatory T cells are decreased in subchondral bone marrow microenvironment of patients with rheumatoid arthritis. AB - OBJECTIVES: The present study is to investigate the profiles of Th17, Th1 and Treg cells in bone marrow of patients with rheumatoid arthritis (RA). METHODS: Flow cytometry was used to analyze the frequencies of Th17, Th1 and Treg cells in paired peripheral blood and bone marrow of 26 RA patients and 11 osteoarthritis (OA) patients, as well as 10 healthy controls. In addition, the disease activity was analyzed by the 28-joint disease activity score (DAS28). RESULTS: The frequencies of Th17 and Th1 cells were significantly elevated in bone marrow of RA patients. Importantly, Th17 and Th1 cells were significantly elevated in bone marrow compared with the matched peripheral blood from RA patients. However, Treg cells were significantly decreased in bone marrow of RA patients compared with the matched peripheral blood of RA patients and bone marrow of osteoarthritis patients and healthy controls. Moreover, the frequencies of tumor necrosis factor alpha-producing T cells were significantly elevated in bone marrow from RA patients. Additionally, Th17 and Th1 cells in bone marrow were positively correlated with DAS28, while Treg cells were negatively correlated with DAS28. CONCLUSIONS: The present study demonstrates that Th17 and Th1 cells are markedly increased in bone marrow from RA patients. By contrast, Treg cells are significantly decreased in bone marrow from RA patients. These results suggest that local abnormality of Th17, Th1 and Treg cells in bone marrow of RA patients may contribute to bone destruction in skeletal system. PMID- 27508017 TI - Wallichinine reverses ABCB1-mediated cancer multidrug resistance. AB - Overexpression of ABCB1 in cancer cells is one of the main reasons of cancer multidrug resistance (MDR). Wallichinine is a compound isolated from piper wallichii and works as an antagonist of platelet activiating factor receptor to inhibit the gathering of blood platelet. In this study, we investigate the effect of wallichinine on cancer MDR mediated by ABCB1 transporter. Wallichinine significantly potentiates the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in ABCB1 overexpressing cancer cells. Furthermore, wallichinine do not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, wallichinine blocks the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. The predicted binding mode shows the hydrophobic interactions of wallichinine within the large drug binding cavity of ABCB1. At all, our study of the interaction of wallichinine with ABCB1 presented herein provides valuable clues for the development of novel MDR reversal reagents from natural products. PMID- 27508018 TI - Tanshinol suppresses endothelial cells apoptosis in mice with atherosclerosis via lncRNA TUG1 up-regulating the expression of miR-26a. AB - Endothelial cell (EC) apoptosis is a crucial process for the development of atherosclerosis. Tanshinol is reported to protect vascular endothelia and attenuate the formation of atherosclerosis. However, the potential molecule mechanism of the protective role of tanshinol in atherosclerosis need to be further investigated. ApoE(-/-)mice were fed with a high-fat diet and treated with tanshinol to detect the effect of tanshinol on endothelial cells apoptosis with TUNEL staining assay. qRT-PCR and Western blot were performed to examine the expression of TUG1 and miR-26a in endothelial cells. RNA-binding protein immunoprecipitation assay was performed to verify the relationship between TUG1 and miR-26a. It has been shown that tanshinol reduced the aortic atherosclerotic lesion area in the entire aorta and aortic sinus in a concentration dependent manner, and suppressed the endothelial cells apoptosis in ApoE(-/-) mice. We further found that the mRNA level of TUG1 was reduced and the expression of miR 26a was up-regulated by tanshinol in endothelial cells. In addition, TUG1 down regulated the expression of miR-26a in ECV304 cells. Finally, it was shown that overexpression of TUG1 removed the reversed effect of tanshinol on oxidized low density lipoprotein (ox-LDL)-induced endothelial cells apoptosis. Taken together, our study reveals that tanshinol could attenuate the endothelial cells apoptosis in atherosclerotic ApoE(-/-) mice. Moreover, low TUG1 expression and high level of miR-26a are associated with the endothelial protecting effect of tanshinol. PMID- 27508019 TI - miR-144 reverses chemoresistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Chemoresistance occurrence is a major cause of treatment failure in HCC. Currently, extensive research has revealed diverse mechanisms for chemoresistance, but the molecular mechanisms underlying the role of miRNAs in resistance to 5-FU are not confirmed in HCC cells. By quantitative real-time polymerase chain reaction (qRT-PCR) analysis, we found that miR-144 was significantly decreased in HCC cell lines. It has been further demonstrated that miR-144 were significantly down-regulated in Bel-7402/5-FU cells compared with parental Bel-7402 cells by qRT-PCR and western blot. The expression of Nrf2 was reversely correlated to that of miR-144 in HCC cells. Moreover, Enhancement of 5 FU-induced cytotoxicity and apoptosis are resulted from the transfection with miR 144 mimics in Bel-7402/5-FU cells. Mechanically, miR-144 promoted nuclear factor erythroid-2-related factor-2 (Nrf2) mRNA degradation by directly targeting the Nrf2 3'untranslated region (3'UTR). In addition, ectopic expression of miR-144 in Bel-7402/5-FU cells reduced the levels of Nrf2 and inhibited the transcription of Nrf2-dependent HO-1 gene, thus contributing to 5-FU sensibilization. Conversely, re-expression of Nrf2 partly attenuated the chemosensibilization of miR-144. Our study showed that miR-144 serves as a potential chemoresistance-reversal agent in hepatocellular carcinoma cells, which is at least partly due to the down regulation of Nrf2-dependent antioxidant pathway. PMID- 27508020 TI - Targeting Btk with ibrutinib inhibit gastric carcinoma cells growth. AB - Bruton's tyrosine kinase (Btk) is a member of the Tec-family non-receptor tyrosine kinases family. It has previously been reported to be expressed in B cells and has an important role in B-cell malignancies. While the roles of Btk in the pathogenesis of certain B-cell malignancies are well established, the functions of Btk in gastric carcinoma have never been investigated. Herein, we found that Btk is over-expressed in gastric carcinoma tissues and gastric cancer cells. Knockdown of Btk expression selectively inhibits the growth of gastric cancer cells, but not that of the normal gastric mucosa epithelial cell, which express very little Btk. Inhibition of Btk by its inhibitor ibrutinib has an additive inhibitory effect on gastric cancer cell growth. Treatment of gastric cancer cells, but not immortalized breast epithelial cells with ibrutinib results in effective cell killing, accompanied by the attenuation of Btk signals. Ibrutinib also induces apoptosis in gastric carcinoma cells as well as is a chemo sensitizer for docetaxel (DTX), a standard of care for gastric carcinoma patients. Finally, ibrutinib markedly reduces tumor growth and increases tumor cell apoptosis in the tumors formed in mice inoculated with the gastric carcinoma cells. Given these promising preclinical results for ibrutinib in gastric carcinoma, a strategy combining Btk inhibitor warrants attention in gastric cancer. PMID- 27508021 TI - miR-448 suppresses proliferation and invasion by regulating IGF1R in colorectal cancer cells. AB - Accumulating evidence has demonstrated that miR-448 expression was downregulated, and exerted tumor suppressor roles in several types of cancer. However, the biological function and underlying mechanism of miR-448 in colorectal cancer (CRC) have not been elucidated. In this study, we detected the miR-448 expression in CRC tumor tissues and adjacent normal tissues (ANT) and five colorectal cancer cell lines by real time quantitative RT-PCR (qRT-PCR). Cell proliferation, colony formation, migration and invasion were investigated in CRC cells transfected miR 448 mimic or negative control mimic by MTT, colony forming, wound healing and transwell invasion assays, respectively. Target gene was identified by bioinformatic prediction, dual-luciferase reporter assay, qRT-PCR and Western blot. Our data proved that miR-448 expression was downregulated in CRC tissues and cell lines, and was inversely associated with advanced tumor-node-metastasis (TNM) stage (P < 0.01), and lymph node metastasis (P < 0.01). Overexpression of miR-448 suppressed CRC cell proliferation, colony formation, migration, and invasion. Moreover, we identified insulin-like growth factor 1 receptor (IGF1R) as a direct target gene of miR-448 in CRC cell. IGF1R expression was upregulated in CRC tissues and cell lines, and its expression was negatively correlated with the expression level of miR-448 in CRC tissues(r = -0.569, P = 0.002). In addition, IGF1R overexpression rescued the suppressive effect of miR-448-mediated CRC on cell proliferation, colony formation, migration and invasion. These results suggested that miR-448 might serve as a tumor suppressor in CRC partly through targeting IGF1R. PMID- 27508022 TI - MiR-497 enhances metastasis of oral squamous cell carcinoma through SMAD7 suppression. AB - SMAD7 is a key inhibitor of transforming growth factor beta (TGFbeta) receptor signaling, which regulates the alteration of cancer cell invasiveness through epithelial-mesenchymal cell conversion. Since microRNAs (miRNAs) play a potential role in the tumorigenesis, cancer cell growth and metastases of oral squamous cell carcinoma (OSCC), determination of the involved miRNAs that may regulate SMAD7-mediated OSCC cell invasion appears to be one important question. Here, we found that the levels of miR-497 were significantly increased and the levels of SMAD7 were significantly decreased in OSCC specimens, compared to the paired adjacent non-tumor tissue. Moreover, miR-497 and SMAD7 inversely correlated in OSCC specimens. The 5-year survival of the patients with higher miR-497 levels in the resected OSCC was worse than those high miR-497 levels. Bioinformatics analyses showed that miR-497 targeted the 3'-UTR of SMAD7 mRNA to inhibit its translation, which was proved by luciferase reporter assay. Furthermore, miR-497 overexpression increased SMAD7-suppressed cell invasion, while miR-497 depletion decreased SMAD7-suppressed cell invasion in OSCC cells, in both a transwell cell invasion assay and a scratch would healing assay. Together, our data suggest that suppression of miR-497 in OSCC cells may promote cancer cell invasion via suppression of SMAD7, and highlight miR-497 as an intriguing therapeutic target to prevent OSCC metastases. PMID- 27508023 TI - Effects of the extract of Ginkgo biloba on the differentiation of bone marrow mesenchymal stem cells in vitro. AB - The balance of osteogenesis and adipogenesis in bone marrow mesenchymal stem cells (BMSCs) is disrupted in osteoporosis. This study was designed to investigate the effects of extract of Ginkgo biloba (EGB) on proliferation, osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells in vitro. The effect of EGB on proliferation was evaluated by CCK-8 assay and flow cytometry. Osteogenic differentiation was evaluated by Alizarin Red S staining and Alkaline phosphatase assay. Adipogenic differentiation was evaluated by Oil Red O staining. Quantitative real-time polymerase chain reaction (Real time PCR) was used to detect the expression of osteogenic specific genes (BMP-2, Runx2 and Colla1) and adipogenic specific genes (ap2, PPARgamma). EGB did not significantly affect proliferation of BMSCs. However, it increased the calcium accumulation and significantly promoted the activity of alkaline phosphatase, especially when the concentration of EGB reached 150 ug/mL. EGB dose-dependently inhibited the adipogenic ability of BMSCs. The osteogenic-related genes (BMP-2, Runx2, Colla1) were overexpressed while the expression of genes involved in adipogenesis, such as PPAR-gamma and ap2, was decreasing with the increase of EGB concentration. Our data proves that EGB inhibited adipocyte differentiation and enhanced osteogenic differentiation in BMSCs, but had no effect on the proliferation of BMSCs. PMID- 27508024 TI - Inhibition of spinal UCHL1 attenuates pain facilitation in a cancer-induced bone pain model by inhibiting ubiquitin and glial activation. AB - The present study examined alterations of spinal ubiquitin C-terminal hydrolase L1 (UCHL1), ubiquitin expression and glial activation in the cancer-induced bone pain rats. Furthermore, whether inhibition of spinal UCHL1 could alleviate cancer induced bone pain was observed. The CIBP model was established by intrathecal Walker 256 mammary gland carcinoma cells in SD rats. The rats of CIBP developed significant pain facilitation in the Von Frey test. Double immunofluorescence analyses revealed that in the spines of CIBP rats, ubiquitin co-localized with NeuN, Iba-1 or GFAP; UCHL1 and NeuN were co-expressed and UCHL1 also co-localized with ubiquitin. The CIBP model induced up-regulation of ubiquitin and UCHL1 in the spines, as well as glial activation. Inhibition of spinal UCHL1 attenuated pain facilitation by down-regulation of ubiquitin expression and glial activation. in the CIBP rats. Our data suggests that UCHL1/ubiquitin distributed and increased in the spines of CIBP rats, that glial activation also increased in the CIBP model and that inhibition of spinal UCHL1 may be an effective method to alleviate cancer-induced bone pain. PMID- 27508025 TI - Effects of pterostilbene on treating hyperprolactinemia and related mechanisms. AB - Hyperprolactinemia (HPRL) frequently causes primary menopause and reproductive disorders. Pterostilbene is known to have anti-inflammation and modulation on cell apoptosis. However, its role in treating HPRL and potential mechanisms remain unclear yet. Healthy female virgin SD rats were randomly assigned into control, HPRL model group, bromocriptine treatment group, and low (20 mg/kg) and high (40 mg/kg) pterostilbene treatment groups. All groups except control ones received metoclopramide hydrochloride injection for generating HPRL model. Uterus and ovarian index in all animals were monitored. Prolactin (PRL), estradiol (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH) were quantified by ELISA. Caspase 3 activity was assayed, with real time PCR measuring Bcl-2 and Bax mRNA levels. HPRL rats had lower uterus and ovarian index, accompanied with elevated PRL, caspase 3 activity, Bax expression, and decreased FSH, LH, E2 and Bcl-2 expression as compared to control group (p<0.05). Pterostilbene treatment significantly increased uterus and ovarian index, FSH, LH, E2 and Bcl-2 expression, and decreased PRL, caspase 3 activity and Bax expression as compared to control group (p<0.05). 40 mg/kg pterostilbene had similar efficacy as those of bromocriptine. Pterostilbene exerts its function in the treatment of HPRL via modulating apoptosis-anti-apoptosis homeostasis, inhibiting serum PRL level, and regulating secretion of gonadotropin hormones. PMID- 27508026 TI - MiR-122 targets VEGFC in bladder cancer to inhibit tumor growth and angiogenesis. AB - Previous studies indicate that microRNA-122 (miR-122) is down-regulated in several cancer cells and regulates cell apoptosis, proliferation, metastasis, and tumor angiogenesis. However, the mount of miR-122 in bladder cancer and the pivotal molecular mechanisms of miR-122 used to regulate bladder carcinogenesis and angiogenesis remain to be clarified. Here, we reveal that miR-122 expression is down-regulated in human bladder cancer tissues and cell lines. MiR-122 represses vascular endothelial growth factor C (VEGFC) post-transcriptional expression by directly binding to its 3'-UTR. The protein kinase B (AKT) and mammalian target of rapamycin (mTOR), which are the most important downstream molecules of VEGFC, are also decreased in bladder cancer cell after miR-122 overexpression. Furthermore, miR-122 over-expression decreases bladder cancer cell migration, invasion, colony formation in vitro and slow bladder cancer growth and angiogenesis in vivo. Finally, miR-122 sensitizes bladder cancer cells to cisplatin-induced apoptosis. Taken together, these studies suggest that miR 122 serves as a tumor suppressor and down-regulating VEGFC expression, leading to the inhibition of bladder cancer growth and angiogenesis. PMID- 27508027 TI - Treatment of chronic ulcer in diabetic rats with self assembling nanofiber gel encapsulated-polydeoxyribonucleotide. AB - OBJECTIVE: This study aims to explore the treatment effects of chronic ulcer in diabetic rats with self assembling nanofiber gel encapsulated polydeoxyribonucleotide. METHODS: Diabetic skin ulcer mouse model was established in this study. They were divided into control group, common wound group and infectious wound group. Human embryonic fibroblast cells and vascular endothelial cells were treated with short poly-N-acetyl glucosamine nanofibers and polydeoxyribonucleotide. Their effects on cell proliferation, revascularization and inhibiting infection were detected by RT-PCR, western-blotting, HE staining and immunohistochemical methods respectively. RESULTS: The expression levels of cytokines and angiogenic factors increased in the treatment groups especially in sNAG encapsulated-PDRN group. HE staining results indicated that PDRN, sNAG and sNAG encapsulated-PDRN could improve the wound healing, immunohistochemical results showed that PDRN, sNAG and sNAG encapsulated-PDRN promoted cell proliferation and new vessel formation especially sNAG encapsulated-PDRN. CONCLUSIONS: sNAG encapsulated-PDRN may have a potential application in the treatment of diabetic ulcers and chronic wound healing. PMID- 27508028 TI - Erianin inhibits the proliferation of T47D cells by inhibiting cell cycles, inducing apoptosis and suppressing migration. AB - Erianin is a natural product extracted from Dendrobiumchrysotoxum. To investigate the antitumor activity of Erianin in estrogen receptor (ER) positive breast cancer, we treated T47D cells with Erianin and evaluated the effects of Erianin treatment on multiple cancer-associated pathways. Erianin inhibited the proliferation of T47D cells effectively. Erianin induced apoptosis in T47D cells through reducing Bcl-2 expression and activating caspase signaling. Furthermore, it also suppressed the expression of CDKs and caused cell cycle arrest. In addition, Erianin treatment suppressed the migration of T47D cells, most likely through regulating the homeostatic expression of MPP and TIMP. Meanwhile, Erianin did not affect the proliferation of normal breast epithelial cell line MCF10A. Together, these results demonstrated that Erianin might have the potential to be an effective drug to treat the ER positive breast cancer. PMID- 27508029 TI - Rescue of hypertension-related impairment of angiogenesis by therapeutic ultrasound. AB - We examined the hypothesis that therapeutic ultrasound (TUS) treatment would rescue the hypertension-related inhibition of ischemia-induced angiogenesis. TUS protects against endothelial dysfunction, but it is little known that the effect of TUS treatment on angiogenesis inhibited by hypertension. 20-week-old male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) were randomly allocated to 4 groups: SHR; TUS treated SHR (SHR-TUS); WKY and TUS treated WKY (WKY-TUS). After undergoing excision of the left femoral artery, the ischemic skeletal muscles were treated with extracorporeal TUS for 9 minutes of daily exposure (frequency of 1 MHz, intensity of 0.3 W/cm(2)) for 14 consecutive days. We found that TUS normalized the blood perfusion in SHR-TUS accompanied by elevated capillary density. Similar results were found in the protein expression of angiogenic factors. TUS treatment also enhanced peripheral capillary density in WKY rats and restored the capillary rarefaction in hypertension by elevating the protein levels of endothelial nitric oxide synthase (eNOS), hypoxic inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF) and phosphorylated Akt (p-Akt) in vivo. Our data demonstrated that TUS treatment ameliorated hypertension-related inhibition of ischemia-induced angiogenesis, at least in part, via an NO-dependent manner. PMID- 27508030 TI - Hypothalamic gastrin-releasing peptide receptor mediates an antidepressant-like effect in a mouse model of stress. AB - Evidence has shown that gastrin-releasing peptide receptor (GRPR) is involved in responses to stress and anxiety. The primary role of GRPR is to stimulate corticotrophin-releasing hormone (CRH) or adrenocorticotropic hormone (ACTH) secretion. Thus, the mechanisms of GRPR signaling should be elucidated to discover novel therapeutic targets for treating depression. This study aimed to investigate GRPR alterations in the C57 mouse hypothalamus after the animals were subjected to stress and fluoxetine treatments. Specifically, we subjected the mice to isolation and chronic unpredictable mild stress (CUMS) for three weeks to establish an experimental model of depression. These mice were subsequently treated with fluoxetine for three weeks. Then, we performed the sucrose preference test and the open field test and measured food intake and body weight to explore the effects of stress and fluoxetine on activity and anhedonia. After fluoxetine treatment, we also assessed changes in the levels of GRPR expression in the hypothalamus using immunohistochemistry, western blotting, and real-time quantitative PCR (RT-PCR). We found that stressed mice showed significant reductions in locomotion, food intake/body weight, and sucrose preference; these reduced parameters indicated a state of anhedonia. Marked increases in mRNA and protein expression of GRPR in the hypothalamus of CUMS-exposed mice were also observed, although treatment with fluoxetine reversed these stress-induced changes. Our results also demonstrated the feasibility and effectiveness of the C57 mouse model of depression established by CUMS and isolation. After fluoxetine treatment was administered, the animals' depression symptoms were alleviated, and these behavioral alterations were accompanied by specific changes in mRNA and protein expression of GRPR in the hypothalamus. These results suggest that GRPR may be implicated in depression; therefore, new therapeutic targets of depression focused on GRPR signaling should be explored. PMID- 27508031 TI - miR-145 suppresses breast cancer cell migration by targeting FSCN-1 and inhibiting epithelial-mesenchymal transition. AB - MicroRNAs (miRNAs), small non-coding RNAs, regulate fundamental cellular and developmental processes such as cell growth, apoptosis, migration, and invasion. In our present study, we investigated the inhibitory role of miR-145 on breast cancer cell migration as well as its underlying mechanism. Wound healing assay and transwell migration assay showed that ectopic expression of miR-145 significantly inhibited breast cancer cell migration. Bioinformatics analysis revealed that FSCN-1 was a putative target of miR-145. The expression of FSCN-1 varied among four different breast cancer cells, and inversely correlated with miR-145 levels. Moreover, miR-145 mimic transfection enhanced the expression of FSCN-1 in Bcap-37 and HCC-1937 cells. We also found that siRNA- mediated down regulation of FSCN-1 inhibited cell motility in breast cancer cells. In addition, we found that up-regulation of miR-145 blocked EMT and decreased the expression of MMP-2/9 in breast cancer cells. These results reveal a new link between miR 145, FSCN-1 and EMT in the regulation of breast cancer migration. PMID- 27508032 TI - MicroRNA-765 regulates neural stem cell proliferation and differentiation by modulating Hes1 expression. AB - Neural stem cells (NSCs) are multipotent, self-renewing and undifferentiated cells that have the ability to differentiate to both glial and neuronal lineages. miRNAs act a key role in regulating neuronal fate and self-renewal of NSCs. In this study, we found that ectopic expression of miR-765 promoted NSCs proliferation. Moreover, miR-765 overexpression increased the ki-67 and beta tubulin-III expression inNSCs. Overexpression of miR-765 inhibited the expression of GFAP in NSCs. Furthermore, Hes1 was identified as a direct target gene of miR 765 in NSCs. Overexpression of Hes1 decreased miR-765-induced proliferation of NSCs and inhibited NSCs differentiation to neurons in miR-765-treated NSCs. These results demonstrated that miR-765 acted a crucial role in NSCs differentiation and proliferation by inhibiting Hes1 expression. PMID- 27508033 TI - Tanshinone IIA inhibits apoptosis in the myocardium by inducing microRNA-152-3p expression and thereby downregulating PTEN. AB - Progressive loss of cardiac myocytes through apoptosis contributes to heart failure (HF). In this study, we tested whether tanshinone IIA, one of the most abundant constituents of the root of Salvia miltiorrhiza, protects rat myocardium derived H9C2 cells against apoptosis. Treatment of H9C2 cells with tanshinone IIA inhibited angiotensin II-induced apoptosis by downregulating the expression of PTEN (phosphatase and tensin homolog), a tumor suppressor that plays a critical role in apoptosis. Furthermore, tanshinone IIA was found to inhibit PTEN expression by upregulating the microRNA miR-152-3p, a potential PTEN regulator that is highly conserved in both rat and human. Notably, the antiapoptotic effect of tanshinone IIA was partially reversed when H9C2 cells were transfected with an inhibitor of miR-152-3p. Collectively, our findings reveal a previously unrecognized mechanism underlying the cardioprotective role of tanshinone IIA, and further suggest that tanshinone IIA could represent a promising drug candidate for HF therapy. PMID- 27508034 TI - Effects of osteoprotegerin, RANK and RANKL on bone destruction and collapse in avascular necrosis femoral head. AB - Avascular necrosis of femoral head (AVFH) is a clinically recalcitrant disease of hip that leads to joint destruction. Osteoprotegerin (OPG), receptor activator of nuclear factor kappa-B (RANK) and RANK ligand (RANKL) regulates the balance, maturation and function of osteoclast and bone remodeling. This study aims to investigate molecular pathways which leads to AVN by studying expression profile of OPG, RANK and RANKL genes. Quantitative Real Time-PCR is used to evaluate mRNA expression of OPG, RANK and RANKL. mRNA and protein level in normal and necrotic tissue from 42 samples of ANFH specimens were analyzed. OPG and RANKL protein levels are estimated by western blotting. The results indicated that OPG mRNA levels are higher but not significantly different in necrotic tissue than that in normal tissue (P>0.05). Although expression of RANK and RANKL is significantly lower than that of OPG, RANK and RANKL mRNA levels are higher in necrotic tissue than normal tissue (P<0.05). Protein levels of OPG and RANKL show no significant difference. In conclusion, OPG, RANK and RANKL play important role in progress of bone remodeling in necrotic area and in disturbance of bone homeostasis, which might have an effect on bone destruction and subsequent collapse of hip joint. PMID- 27508035 TI - Relationship between PI3K pathway and angiogenesis in CIA rat synovium. AB - To investigate the expression of hypoxia inducible factor (HIF-1alpha) and vascular endothelial growth factor (VEGF) in the synovium of collagen-induced arthritis (CIA) joint, and whether the PI3K pathway regulates angiogenesis in rheumatoid arthritis or not. A randomized controlled according to the principle of the rats were divided into normal control group (10 rats) and the experimental group (40 rats). The experimental group rats were established as type II collagen plus adjuvant Freund's complete adjuvant-induced arthritis model. HIF-1alpha and VEGF proteins' expression in serum of CIA rats group and normal control group were detected by ELISA. Microvessel density (MVD) in synovial tissue of CIA rats group and normal control group were detected by immunohistochemistry (IHC) staining. The protein expression of PTEN, PI3K, and AKT in synovial tissue were detected by Western Blot. Compared with normal control group, toes and ankle swelling and arthritis index (AI) of CIA rat increased, and the expression of VEGF and HIF-1alpha proteins in peripheral serum increased, IHC showed that MVD was significantly higher than that of the control group, and the difference was statistically significant (p<0.05). Western Blot results showed that PI3K and AKT proteins expression in CIA synovial tissue of rats increased, while the expression of PTEN protein decreased. Correlation analysis showed that VEGF and HIF-1 levels in the peripheral serum of CIA rats were positively correlated with arthritis index (AI); the contents of HIF-1alpha and VEGF in the peripheral serum of CIA rats were positively correlated with MVD in synovium tissue. The CIA rat model regulated the expression of HIF-1alpha and VEGF proteins in peripheral serum by PI3K signaling pathway, and then regulated neovascularization in RA. PMID- 27508036 TI - Effects of immobilizations stress with or without water immersion on the expression of atrial natriuretic peptide in the hearts of two rat strains. AB - Atrial natriuretic peptide (ANP) is produced and released by mammalian cardiomyocytes and induces natriuresis, diuresis, and lowering of blood pressure. The present study examined localization of ANP and a possible role of the hypothalamic-pituitary-adrenal axis (HPA) activity on the expression of proANP gene in the heart. The Sprague Dawley (SD) and Lewis (LE) rat strains were used. The animals were exposed to the two types of stress: immobilization and immobilization combined with water immersion for 1 hour. Localization of ANP was detected by immunohistochemistry and expression of the proANP mRNA by real-time qPCR in all heart compartments of control and stressed animals after 1 and 3 hours after stress termination (IS1, IS3, ICS1, and ICS3). Relatively high density of ANP-immunoreactivity was observed in both atria of both rat strains. In control rats of both strains, the expression of the proANP mRNA was higher in the atria than in ventricles. In SD rats with the intact HPA axis, an upregulation of ANP gene expression was observed in the right atrium after IS1, in both atria and the left ventricle after IS3 and in the left atrium and the left ventricle after ICS3. In LE rats with a blunted reactivity of the HPA axis, no increase or even a downregulation of the gene expression was observed. Thus, acute stress-induced increase in the expression of the proANP gene is related to the activity of the HPA axis. It may have relevance to ANP-induced protection of the heart. PMID- 27508037 TI - Calretinin, S100 and protein gene product 9.5 immunostaining of rectal suction biopsies in the diagnosis of Hirschsprung' disease. AB - Evaluation of rectal suction biopsies for the ganglion cells and neural hypertrophy is the basic modality for the diagnosis of Hirschsprung's disease (HD). However, the traditional hematoxylin and eosin staining coupled with acetylcholinesterase histochemistry remain challenging, especially in newborns. Thus we conducted a prospective study to evaluate the usefulness of calretinin combined with S100 and protein gene product 9.5 (PGP9.5) immunostaining of rectal suction biopsies for the diagnosis of HD. A total of 195 patients were enrolled in our study. Of the 195 patients 69% had ganglion cells on the initial diagnostic protocol. Sixty cases were devoid of ganglion cells, and of these, 90% and 91% showed submucosal neural hypertrophy on S-100 staining and PGP9.5 staining, respectively. Eighty-one patients underwent a colonic resection, and of these, 59 had confirmed aganglionic segment, the other 22 patients were diagnosed as intestinal neuronal dysplasia type B (n=13) and isolated hypoganglionosis (n=9). Of the rest 114 patients, 51 cases underwent a full-thickness biopsy, and HD was excluded; sixty-three patients were thoroughly followed-up with no evidence of HD. We encountered two false-negatives and they were proved to be short segment HD after the surgery. The sensitivity and specificity rates of our diagnostic protocol was 96.49% (95% CI, 0.88-0.99) and 100% (95% CI, 0.97-1.00), respectively, excluding 5 patients with inconclusive results. Our findings demonstrated that calretinin coupled with S100 and PGP9.5 immunostaining on suction rectal biopsies is sensitive and specific for diagnosing HD. PMID- 27508038 TI - Chidamide, a novel histone deacetylase inhibitor, inhibits the viability of MDS and AML cells by suppressing JAK2/STAT3 signaling. AB - Many studies have indicated that histone deacetylase (HDAC) activity is always increased in a lot of human tumors, and inhibition of HDAC activity is a promising new strategy in the treatment of cancers. Chidamide, a novel HDAC inhibitor of the benzamide class, is currently under clinical trials. In this study, we aimed to investigate the antitumor activity of Chidamide on myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) cell lines and explore the possible mechanism. Chidamide exhibited efficient anti-proliferative activity on MDS and AML cells in a time- and dose-dependent manner, accompanied by cell cycle arrest at G0/G1 phase and cell apoptosis. Importantly, Chidamide possessed potent HDAC inhibition property, as evaluated by HDAC activity analysis and acetylation of histone H3 and H4. Moreover, Chidamide significantly increased the expression of Suppressors of cytokine signaling 3 (SOCS3), reduced the expression of Janus activated kinases 2 (JAK2) and Signal transducer and activator of transcription 3 (STAT3), and inhibited STAT3 downstream genes, including c-Myc, Bcl-xL, and Mcl-1, which are involved in cell cycle progression and anti-apoptosis. Therefore, we demonstrate that Chidamide exhibits potent inhibitory effect on cell viability of MDS and AML cells, and the possible mechanism may lie in the downregulation of JAK2/STAT3 signaling through SOCS3 upregulation. Our data provide rationale for clinical investigations of Chidamide in MDS and AML. PMID- 27508039 TI - Effects of microRNA-21 and microRNA-24 inhibitors on neuronal apoptosis in ischemic stroke. AB - OBJECTIVES: The purpose of our study was aimed to investigate the effects of microRNA-21 (miR-21) and microRNA-24 (miR-24) inhibitors on ischemic stroke. METHODS: MiR-21 inhibitor or miR-24 inhibitor was delivered to Sprague Dawley (SD) rats by continuous intracerebroventricular infusion. Two days later, middle cerebral artery occlusion (MCAO) was performed to induce ischemic stroke. Quantitative real-time PCR was performed to confirm transfection efficiency. The number of apoptotic neurons was detected using TUNEL method. Besides, primary hippocampal or cortical neuronal cultures were prepared from embryonic day 16-18 C57BL/6 mice. These cells were transfected with miR-21 inhibitor, miR-24 inhibitor, or negative scramble RNA. Then the cell viability was detected after transfection, as well as the protein levels of Caspase-3, B-cell lymphoma (Bcl) xL, and heat shock protein (HSP) 70. RESULTS: Both the levels of miR-21 and miR 24 were significantly reduced by transfection with inhibitors compared to control group or scramble RNA group (both P < 0.05). The apoptosis was significantly reduced in both hippocampal neuron and cortical neuron by miR-24 inhibitor rather than miR-21 inhibitor (P < 0.05), while the cell viability was significantly increased compared to the control group or the scramble group (P < 0.05). In addition, the levels of Bcl-xL and HSP70 were significantly increased, and the levels of Caspase-3 were statistically decreased by transfection with miR-24 inhibitor. CONCLUSION: MiRNA-24 but not miR-21 inhibitor prevents apoptosis in ischemic stroke by regulation of Bcl-xL, Caspase-3 and HSP70. PMID- 27508040 TI - Interleukin-21 is associated with the severity of psoriasis vulgaris through promoting CD4+ T cells to differentiate into Th17 cells. AB - Interleukin-21 (IL-21) and T helper 17 (Th17) cells are known to be involved in the pathogenesis of psoriasis, but little is known about their relationship in psoriasis. Herein, we investigated whether IL-21 could regulate Th17 cell induction in patients with psoriasis vulgaris. 32 patients with psoriasis vulgaris and 13 healthy controls were recruited. Flow cytometry was used to detect the frequencies of cells mainly secreting IL-21 (including IL-21+CD4+ T and IL-21+ Th17 cells) and Th17 cells. An enzyme-linked immunosorbent assay (ELISA) was used to determine the serum content of IL-21. Severity of the psoriasis was evaluated by a Psoriasis Area and Severity Index (PASI) score. In addition, the differentiation of CD4+ T cells with IL-21 and the different frequencies of IL-21+CD4+ T cells, IL-21+ Th17 cells and Th17 cells were assessed, as were serum levels of IL-21 in patients with moderate to severe psoriasis before and after treatment. Our results showed that the levels of IL 21, IL-21+CD4+ T cells, IL-21+ Th17 cells and Th17 cells were significantly increased in patients and positively associated with PASI score (P < 0.01). Moreover, the levels of IL-21, IL-21+CD4+ T cells and IL-21+ Th17 cells were positively correlated with the frequency of Th17 cells (P < 0.01). In vitro experiments demonstrated that IL-21 could promote CD4+ T cells to differentiate into Th17 cells. After a 4-week treatment of acitretin and a topical therapy, all the immune markers observed in patients decreased significantly (P < 0.01), but the levels remained higher than those in healthy controls (P < 0.01). These findings indicate that IL-21 might promote Th17 cell induction in psoriasis and might be a potential immune marker for targeting this disease. PMID- 27508041 TI - MiR-338* suppresses fibrotic pathogenesis in pulmonary fibrosis through targeting LPA1. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease involving pulmonary injury associated with tissue repair, dysfunction and fibrosis. MicroRNAs (miRNAs), as gene regulators, are assumed to regulate about one third of genes and thus play important roles in cellular functions including proliferation, growth, differentiation and apoptosis. Recent studies have indicated that some miRNAs may play critical roles in the pathogenesis of pulmonary fibrosis. In this study, we found that miR-338*(miR-338-5p), which has been found to be associated with tumor progression, was down-regulated in fibroblasts and TGF-beta-induced lung fibrotic tissues. Over-expression of miR 338* can partly prevent the fibrotic process induced by TGF-beta. Moreover, LPA1 was proven to be a downstream target of miR-338*. Lentivirus-mediated over expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. Taken together, our results suggest that miR-338* attenuates the pathogenesis of pulmonary fibrosis through targeting LPA1. Thus, miR-338* can be a potential therapeutic target for the treatment of IPF. PMID- 27508042 TI - MiR-338* targeting smoothened to inhibit pulmonary fibrosis by epithelial mesenchymal transition. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease involving pulmonary injury associated with tissue repair, dysfunction and fibrosis. Recent studies indicate that some microRNAs (miRNAs) may play critical roles in the pathogenesis of pulmonary fibrosis. In this study, we aim to investigate whether miR-338* (miR 338-5p), which has been found to be associated with tumor progression, is associated with pathological process of pulmonary fibrosis. Balb/c mice were treated with bleomycin (BLM) to establish IPF models. Targtscan was used to predict the downstream target of miR-338*. Morphological changes were observed with light microscope and epithelial to mesenchymal transition (EMT) markers were detected by western blot. The expression of miR-338* or downstream target SMO was analyzed by real-time quantitative RT-PCR, northern blot or western blot. MiR 338* was down-regulated in the lung tissue from mice with bleomycin-induced pulmonary fibrosis. The smoothened (SMO) is a direct target of miR-338*, and knocking-down the expression of SMO could partially rescue the fibrotic phenotype of TGF-beta-induced NuLi-1 cells. Over-expression of SMO led to the fibrotic phenotype of NuLi-1 cells even without TGF-beta treatment. These findings showed that the over-expression of SMO contributed to the fibrotic phenotype of NuLi-1 cells by affecting the epithelial-to-mesenchymal transition (EMT) procedure. Furthermore, in vivo, lentivirus-mediated over-expression of miR-338* can alleviate lung fibrosis induced by bleomycin in mice. In conclusion, our results suggest that miR-338* can target SMO to reduce the EMT procedure and thus postpone the development of pulmonary fibrosis. PMID- 27508043 TI - Human papillomavirus infection correlates with inflammatory Stat3 signaling activity and IL-17 expression in patients with breast cancer. AB - OBJECTIVES: Microbiota has been suggested in promoting chronic inflammation in human tissues which, in turn, promotes tumor development. This study tests a hypothesis that high-risk human papillomavirus (HR-HPV) infection may correlate with proinflammatory Stat3 signaling activities and IL-17 levels in breast cancer (BC) patients. MATERIALS AND METHODS: This study examined HPV infection by GenChip technology, constitutively active Stat3 (p-Stat3) and IL-17 levels by immunohistochemistry (IHC) using specific antibodies in 379 BC patients, together with 245 paired adjacent breast adenosis (ABA) tissues and 100 unrelated breast adenosis (BA) tissues. RESULTS: We obtained four major findings: (1) HR-HPV16/18 infections existed in 10.5% (34/325) of BC issues, higher than control BA tissues (4%, 4/100, P = 0.047). (2) Using IHC methodology, BC tissues showed more overactive p-Stat3 (2+/3+, 38.5%, 146/379) than ABA tissues (27.3%, 67/245, P < 0.001); similarly, BC also had more tissues overexpressing IL-17 (2+/3+, 61.5%, 233/379) than ABA tissues (51.8%, 127/245, P < 0.001). (3) High levels (2+/3+) of both active p-Stat3 and IL-17 correlated with poor differentiation and lymph nodal metastasis in BC (both with P < 0.05), but not with patients' prognosis. (4) HR-HPV infections correlated with both active p-Stat3 (P = 0.018) and its downstream IL-17 levels (P = 0.021) in BC tissues. CONCLUSION: There may be a possible tri-lateral relationship among HPV infection, constitutive Stat3 activity and IL-17 level, whose collaborations could orchestrate a proinflammatory microenvironment in breast tissues by which promote carcinogenesis and/or facilitate progression of breast cancer. PMID- 27508044 TI - Role of nanobacteria in the pathogenesis of kidney stone formation. AB - OBJECTIVE: This study aimed to investigate the nanobacteria (NB) induced damage to human tubular epithelial HK-2 cells and the potential role of NB in the kidney stone formation. METHODS: Serum sample from 15 patients with kidney stone was collected. Four groups were included: control, NB group, nanograde hydroxyapatite (nHAP) and calcium oxalate monohydrate (COM) group. Catalase (CAT), malonaldehyde (MDA) and Na(+)/K(+) ATPase activity was detected in the supernatant at 12 and 24 h. At 12 and 24 h, COM was added. RESULTS: At 12 h and 24 h, the CAT in NB group was significantly higher than in control group and nHAP group (P<0.01). CAT at 24 h was significantly higher than in COM group (P<0.01). At 12 h and 24 h, the MDA in NB group was significantly higher than in control group and nHAP group (P<0.01) and significantly lower than in COM group (P<0.01). At 12 h, the Na(+)/K(+) ATPase activity in NB group and nHAP group was significantly lower than in control group, but dramatically increased as compared to COM group (P<0.01). At 24 h, the Na(+)/K(+) ATPase activity in NB group and nHAP group was significantly lower than in control group (P<0.01). CONCLUSION: NB may induce lipid peroxidation in HK-2 cells and cause adhesion of HK-2 cells to COM in a time-dependent manner, resulting in damage to HK-2 cells. This injury-causing capability of NB is more potent than nHAP and might be involved in the pathogenesis of kidney stone formation. PMID- 27508045 TI - Effect of hepatitis B virus infection on trophoblast cell line (HTR-8/SVneo) and choriocarcinoma cell line (JEG3) is linked to CD133-2 (AC141) expression. AB - Mother-to-infant transmission of hepatitis B virus (HBV) plays an important role in the chronic carrier state in China. In our studies, the response of trophoblast cell and choriocarcinoma cell to HBV infection regarding the expression of CD133-2 (AC141) was evaluated. Western blot and RT-PCR showed that a high level of CD133-2 protein and mRNA in HTR-8/SVneo cells, but a low level in JEG-3 cells. Lower proliferation and mobility, and higher apoptosis were observed in HTR-8/SVneo cells and JEG-3-CD133-2(+) cells after HBV infection than those in HTR-8-CD133-2(-) cells and JEG-3 cells. Our main finding is that CD133-negative cells (HTR-8-CD133-2(-) and JEG-3) are prone to HBV infection. In the last, our data indicated that the activation of Smad signaling pathway and the induction of epithelial-mesenchymal transition (EMT) in CD133-negative cells after HBV infection. In summary, our study demonstrated that CD133 is a key factor that mediated HBV infection to trophoblast cell and choriocarcinoma cell. PMID- 27508046 TI - Therapeutic effects of human umbilical cord mesenchymal stem cells transplantation on hypoxic ischemic encephalopathy. AB - OBJECTIVE: Human umbilical cord mesenchymal stem cells (hUC-MSCs) hold substantial promise for the treatment of ischemic neurological disease, but few clinical data are currently available about its therapeutic effects in hypoxic ischemic encephalopathy (HIE). This study is to evaluate the effects of hUC-MSCs transplantation on patients with HIE. Methods A total 22 patients with HIEwere randomly divided into hUC-MSCs transplantation group (n = 12) and control group (n = 10). After isolation, hUC-MSCs were cultured for 3 to 5 passages in vitro and then intravenously administered to HIE patients in the transplantation group, while the control group received routine treatment only. The outcomes of HIE patients were evaluated at designated time points by clinical assessment scales, including NIHSS, Barthel Index, MMSE, HAMA24, HAMD14 and UPDRS. RESULTS: hUC-MSCs were identified by morphological analysis and flow cytometry assays before clinic transplantation. No significant differences of demographic characteristics were observed between the two groups of subjects. Compared to the control group, hUC MSCs transplantation markedly improved the outcomes of HIE patients leading to better recovery of neurological function, cognition ability, emotional reaction and extrapyramidal function. No significant adverse effects were found in subjects with hUC-MSCs transplantation during a 180-day follow-up period. CONCLUSION: These data suggest that hUC-MSCs therapy markedly improves the outcomes of patients with HIE, which is potential for the routine treatment of ischemic neurological disease. PMID- 27508047 TI - Sauchinone augments cardiomyocyte viability by enhancing autophagy proteins PI3K, ERK(1/2), AMPK and Beclin-1 during early ischemia-reperfusion injury in vitro. AB - Background. Sauchinone has proved its anti-oxidant and anti-inflammatory properties in various animal tissues. This study sought to illustrate its regulatory nature on autophagy associated proteins (PI3K, ERK1/2, AMPK, and Beclin-1) during early cardiomyocyte ischemia and subsequent reperfusion. Methods. Cultured cardiomyocytes were subjected to simulated Ischemia/reperfusion with and without Sauchinone pretreatment and also in the presence of autophagy inhibitor (3-MA). Colorimetric analysis of CCK-8, LDH antibody assay as well as Western blot analysis were performed to observe the expressions of LC3B (II) and Beclin-1 protein (markers of autophagy), autophagy proteins (PI3K, ERK1/2 and AMPK) and apoptotic proteins (Bax and Bcl-2) and the results were quantified into their grey values and subjected to statistical analysis. Results. Sauchinone demonstrated cell survival enhancing properties with increase in CCK-8 (SD = 0.553+/-0.012) and decrease in LDH (SD = 0.183+/-0.054) expressions, both of which were best observed at test dose of 20 umol/L. At this dose, there was increment in cellular autophagy as demonstrated by peaking of autophagy markers LC3B-II (p<0.05) and Beclin-1 (p<0.05) with strong correlations (r = 0.99). Similarly, the autophagy proteins, compared to control and I/R model, also showed a significant increased level with PI3K (p<0.0001), total p-ERK1/2 (p<0.0001) and p-AMPKalpha (p<0.0001). Simultaneously, a decrease in expressions of pro apoptotic molecules Bax (r = 0.989, p<0.0001) with increment of in the anti apoptotic protein Bcl-2 (r = 0.996, p<0.0001) was observed. The observed effects on cell density, viability and autophagy was abrogated in presence of 3-MA. Conclusions. Sauchinone enhances cell survival by promoting autophagy and inhibiting apoptosis in cardiomyocytes during early stages of Ischemia/reperfusion injury. PMID- 27508048 TI - MiR-338-3p targets pyruvate kinase M2 and affects cell proliferation and metabolism of ovarian cancer. AB - MiR-338-3p is down-regulated in cancer, which inhibits cancer cell proliferation, metastasis, and increases chemosensitivity, but its functions in ovarian cancer remains unknown. The present study aims to identify the miR-338-3p targeted genes and to investigate the associated regulatory mechanisms in ovarian cancer cell proliferation and metabolism. Our results demonstrated miR-338-3p expression was down-regulated in most of ovarian cancer tissues and cell lines. Restoration of miR-338-3p expression in ovarian cancer cells could inhibit cell proliferation, lactate production and lactate production of ovarian cancer cells. PKM2 was verified as a target gene of miR-338-3p by luciferase assay. Further study indicated miR-338-3p controlled ovarian cancer cell metabolism by inhibiting PKM2 expression. It is summarized that the regulatory role of miR-338-3p on PKM2 expression in ovarian cancer may play important roles in cell metabolism. PMID- 27508049 TI - Expression of programmed death-1 ligand (PD-L1) in tumor-infiltrating lymphocytes is associated with favorable spinal chordoma prognosis. AB - Aberrant expression of programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) proteins alters human immunoresponse and promotes tumor development and progression. We assessed the expression status of PD-1 and PD-L1 in spinal chordoma tissue specimens and their association with clinicopathological characteristics of patients. Formalin-fixed paraffin-embedded tumor samples from 54 patients with spinal chordoma were collected for immunohistochemical analysis of PD-1 and PD-L1 expression. The association of the expression levels of PD-1 and PD-L1 with clinicopathological variables and survival data were statistically analyzed. Lymphocyte infiltrates were present in all 54 patient samples. Of 54 samples, 37 (68.5%) had both positive PD-1 and PD-L1 expression in tumor cell membrane. Moreover, 38 (70.4%) and 12 (22.2%) had positive PD-1 and PD-L1 expression in tumor-infiltrating lymphocytes (TILs), respectively. Tumors with positive PD-L1 expression were significantly associated with advanced stages of chordoma (p = 0.041) and TIL infiltration (p = 0.005), and had a borderline association with tumor grade (p = 0.051). However, positive tumor PD-L1 expression was not significantly associated with local recurrence-free survival (LRFS) or overall survival (OS). PD-1 expression in TILs was associated with poor LRFS (chi(2) = 10.051, p = 0.002, log-rank test). Multivariate analysis showed that PD-L1 expression only in TILs was an independent predictor for LRFS (HR = 0.298, 95% CI: 0.098-0.907, p = 0.033), and OS (HR = 0.188, 95% CI: 0.051-0.687, p = 0.011) in spinal chordoma patients. In conclusion, PD-L1 expression in TILs was an independent predictor for both LRFS and OS in spinal chordoma patients. Our findings suggest that the PD-1/PD-L1 pathway may be a novel therapeutic target for the immunotherapy of chordoma. PMID- 27508050 TI - Differential expression of miR-21 and miR-75 in esophageal carcinoma patients and its clinical implication. AB - In Xinjiang, China, esophageal carcinoma has a high incidence in Kazak and Uighur populations. MicroRNA (miR)-21 and miR-375 are related to esophageal carcinoma. This study thus investigated their potencials in early diagnosis and prognosis in Kazak and Uighur populations, to provide evidences for serum markers of esophageal cancer. A total of 126 Kazak or Uighur esophageal cancer patients were enrolled as the disease group, along with 86 local Han patients as disease control cohort, and 80 healthy Kazak or Uighur individuals. MiRNA expression was detected by in situ hybridization in tissues and by qRT-PCR in serum. ROC approach was used to evaluate the diagnostic value of miRNA on esophageal carcinoma. Cox analysis was performed to screen factors governing prognosis. MiR 21 level was significantly elevated in both tissue and serum samples of esophageal cancer patients, while miR-375 was down-regulated. Such difference was more potent in disease group compared to disease control group. MiR expression was correlated with infiltration depth, TNM stage, vascular invasion, and lymph node metastasis. Elevated expression of miR-21 reduced the sensitivity of radio therapy, and increased recurrence frequency. The diagnostic value of single assay for miR-21 or miR-375 was lower than the combined assay (AUC=0.812 or 0.739 vs. 0.858). They also affected patient prognosis (OR=1.53 or 0.652). MiR-21 and miR 375 presented abnormal expression in Kazak or Uighur esophageal carcinoma patients and were independent factors affecting prognosis. The combined assay of miR-21 and miR-375 may help to make early diagnosis of esophageal cancer. PMID- 27508051 TI - Ursolic acid attenuates temozolomide resistance in glioblastoma cells by downregulating O(6)-methylguanine-DNA methyltransferase (MGMT) expression. AB - The DNA-alkylating agent temozolomide (TMZ) is an effective chemotherapeutic agent against malignant glioma, including glioblastoma multiforme (GBM). However, the clinical efficacy of TMZ is limited in many patients because of O(6) methylguanine-DNA methyltransferase (MGMT)-driven resistance. Thus, new strategies to overcome TMZ resistance are urgently needed. Ursolic acid (UA) is a naturally derived pentacyclic triterpene acid that exerts broad anticancer effects, and shows capability to cross the blood-brain barrier. In this study, we evaluated the possible synergistic effect of TMZ and UA in resistant GBM cell lines. The results showed that UA prevented the proliferation of resistant GBM cells in a concentration-dependent manner. Compared with TMZ or UA treatment alone, the combination treatment of TMZ and UA synergistically enhanced cytotoxicity and senescence in TMZ-resistant GBM cells. This effect was correlated with the downregulation of MGMT. Moreover, experimental results with an in vivo mouse xenograft model showed that the combination treatment of UA and TMZ reduced tumor volumes by depleting MGMT. Therefore, UA as both a monotherapy and a resensitizer, might be a candidate agent for patients with refractory malignant gliomas. PMID- 27508052 TI - Mitochondrial DNA Damage and Diseases. AB - Various endogenous and environmental factors can cause mitochondrial DNA (mtDNA) damage. One of the reasons for enhanced mtDNA damage could be its proximity to the source of oxidants, and lack of histone-like protective proteins. Moreover, mitochondria contain inadequate DNA repair pathways, and, diminished DNA repair capacity may be one of the factors responsible for high mutation frequency of the mtDNA. mtDNA damage might cause impaired mitochondrial function, and, unrepaired mtDNA damage has been frequently linked with several diseases. Exploration of mitochondrial perspective of diseases might lead to a better understanding of several diseases, and will certainly open new avenues for detection, cure, and prevention of ailments. PMID- 27508053 TI - Biomarkers and recent advances in the management and therapy of sickle cell disease. AB - Although production of hemoglobin S, the genetic defect that causes sickle cell disease (SCD), directly affects only red blood cells, the manifestations of SCD are pervasive, and almost every cell type and organ system in the body can be involved. Today, the vast majority of patients with SCD who receive modern health care reach adulthood thanks to vaccine prophylaxis and improvements in supportive care, including transfusion. However, once patients reach adulthood, they commonly experience recurrent painful vaso-occlusive crises and frequently have widespread end-organ damage and severely shortened life expectancies. Over the last several decades, research has elucidated many of the mechanisms whereby abnormal red blood cells produce such ubiquitous organ damage. With these discoveries have come new ways to measure disease activity. In addition, new pharmaceutical interventions are now being developed to address what has been learned about disease mechanisms. PMID- 27508054 TI - Epigenetic and microRNA regulation during osteoarthritis development. AB - Osteoarthritis (OA) is a common degenerative joint disease, the pathological mechanism of which is currently unknown. Genetic alteration is one of the key contributing factors for OA pathology. Recent evidence suggests that epigenetic and microRNA regulation of critical genes may contribute to OA development. In this article, we review the epigenetic and microRNA regulations of genes related to OA development. Potential therapeutic strategies may be developed on the basis of novel findings. PMID- 27508055 TI - Bugs, genes, fatty acids, and serotonin: Unraveling inflammatory bowel disease? AB - The annual incidence of the inflammatory bowel diseases (IBDs) ulcerative colitis and Crohn's disease has increased at an alarming rate. Although the specific pathophysiology underlying IBD continues to be elusive, it is hypothesized that IBD results from an aberrant and persistent immune response directed against microbes or their products in the gut, facilitated by the genetic susceptibility of the host and intrinsic alterations in mucosal barrier function. In this review, we will describe advances in the understanding of how the interaction of host genetics and the intestinal microbiome contribute to the pathogenesis of IBD, with a focus on bacterial metabolites such as short chain fatty acids (SCFAs) as possible key signaling molecules. In particular, we will describe alterations of the intestinal microbiota in IBD, focusing on how genetic loci affect the gut microbial phylogenetic distribution and the production of their major microbial metabolic product, SCFAs. We then describe how enteroendocrine cells and myenteric nerves express SCFA receptors that integrate networks such as the cholinergic and serotonergic neural systems and the glucagon-like peptide hormonal pathway, to modulate gut inflammation, permeability, and growth as part of an integrated model of IBD pathogenesis. Through this integrative approach, we hope that novel hypotheses will emerge that will be tested in reductionist, hypothesis-driven studies in order to examine the interrelationship of these systems in the hope of better understanding IBD pathogenesis and to inform novel therapies. PMID- 27508056 TI - The effects of an editor serving as one of the reviewers during the peer-review process. AB - Background Publishing in scientific journals is one of the most important ways in which scientists disseminate research to their peers and to the wider public. Pre publication peer review underpins this process, but peer review is subject to various criticisms and is under pressure from growth in the number of scientific publications. Methods Here we examine an element of the editorial process at eLife, in which the Reviewing Editor usually serves as one of the referees, to see what effect this has on decision times, decision type, and the number of citations. We analysed a dataset of 8,905 research submissions to eLife since June 2012, of which 2,750 were sent for peer review, using R and Python to perform the statistical analysis. Results The Reviewing Editor serving as one of the peer reviewers results in faster decision times on average, with the time to final decision ten days faster for accepted submissions (n=1,405) and 5 days faster for papers that were rejected after peer review (n=1,099). There was no effect on whether submissions were accepted or rejected, and a very small (but significant) effect on citation rates for published articles where the Reviewing Editor served as one of the peer reviewers. Conclusions An important aspect of eLife's peer-review process is shown to be effective, given that decision times are faster when the Reviewing Editor serves as a reviewer. Other journals hoping to improve decision times could consider adopting a similar approach. PMID- 27508057 TI - The expanding regulatory universe of p53 in gastrointestinal cancer. AB - Tumor suppresser gene TP53 is one of the most frequently deleted or mutated genes in gastrointestinal cancers. As a transcription factor, p53 regulates a number of important protein coding genes to control cell cycle, cell death, DNA damage/repair, stemness, differentiation and other key cellular functions. In addition, p53 is also able to activate the expression of a number of small non coding microRNAs (miRNAs) through direct binding to the promoter region of these miRNAs. Many miRNAs have been identified to be potential tumor suppressors by regulating key effecter target mRNAs. Our understanding of the regulatory network of p53 has recently expanded to include long non-coding RNAs (lncRNAs). Like miRNA, lncRNAs have been found to play important roles in cancer biology. With our increased understanding of the important functions of these non-coding RNAs and their relationship with p53, we are gaining exciting new insights into the biology and function of cells in response to various growth environment changes. In this review we summarize the current understanding of the ever expanding involvement of non-coding RNAs in the p53 regulatory network and its implications for our understanding of gastrointestinal cancer. PMID- 27508058 TI - Can free open access resources strengthen knowledge-based emerging public health priorities, policies and programs in Africa? AB - Tackling emerging epidemics and infectious diseases burden in Africa requires increasing unrestricted open access and free use or reuse of regional and global policies reforms as well as timely communication capabilities and strategies. Promoting, scaling up data and information sharing between African researchers and international partners are of vital importance in accelerating open access at no cost. Free Open Access (FOA) health data and information acceptability, uptake tactics and sustainable mechanisms are urgently needed. These are critical in establishing real time and effective knowledge or evidence-based translation, proven and validated approaches, strategies and tools to strengthen and revamp health systems. As such, early and timely access to needed emerging public health information is meant to be instrumental and valuable for policy-makers, implementers, care providers, researchers, health-related institutions and stakeholders including populations when guiding health financing, and planning contextual programs. PMID- 27508059 TI - Early-childhood housing mobility and subsequent PTSD in adolescence: a Moving to Opportunity reanalysis. AB - In a 2014 report on adolescent mental health outcomes in the Moving to Opportunity for Fair Housing Demonstration (MTO), Kessler et al. reported that, at 10- to 15-year follow-up, boys from households randomized to an experimental housing voucher intervention experienced 12-month prevalence of post-traumatic stress disorder (PTSD) at several times the rate of boys from control households. We reanalyze this finding here, bringing to light a PTSD outcome imputation procedure used in the original analysis, but not described in the study report. By bootstrapping with repeated draws from the frequentist sampling distribution of the imputation model used by Kessler et al., and by varying two pseudorandom number generator seeds that fed their analysis, we account for several purely statistical components of the uncertainty inherent in their imputation procedure. We also discuss other sources of uncertainty in this procedure that were not accessible to a formal reanalysis. PMID- 27508060 TI - search.bioPreprint: a discovery tool for cutting edge, preprint biomedical research articles. AB - The time it takes for a completed manuscript to be published traditionally can be extremely lengthy. Article publication delay, which occurs in part due to constraints associated with peer review, can prevent the timely dissemination of critical and actionable data associated with new information on rare diseases or developing health concerns such as Zika virus. Preprint servers are open access online repositories housing preprint research articles that enable authors (1) to make their research immediately and freely available and (2) to receive commentary and peer review prior to journal submission. There is a growing movement of preprint advocates aiming to change the current journal publication and peer review system, proposing that preprints catalyze biomedical discovery, support career advancement, and improve scientific communication. While the number of articles submitted to and hosted by preprint servers are gradually increasing, there has been no simple way to identify biomedical research published in a preprint format, as they are not typically indexed and are only discoverable by directly searching the specific preprint server websites. To address this issue, we created a search engine that quickly compiles preprints from disparate host repositories and provides a one-stop search solution. Additionally, we developed a web application that bolsters the discovery of preprints by enabling each and every word or phrase appearing to with articles from preprint servers. This tool, search.bioPreprint, is publicly available at http://www.hsls.pitt.edu/resources/preprint. PMID- 27508061 TI - From reads to genes to pathways: differential expression analysis of RNA-Seq experiments using Rsubread and the edgeR quasi-likelihood pipeline. AB - In recent years, RNA sequencing (RNA-seq) has become a very widely used technology for profiling gene expression. One of the most common aims of RNA-seq profiling is to identify genes or molecular pathways that are differentially expressed (DE) between two or more biological conditions. This article demonstrates a computational workflow for the detection of DE genes and pathways from RNA-seq data by providing a complete analysis of an RNA-seq experiment profiling epithelial cell subsets in the mouse mammary gland. The workflow uses R software packages from the open-source Bioconductor project and covers all steps of the analysis pipeline, including alignment of read sequences, data exploration, differential expression analysis, visualization and pathway analysis. Read alignment and count quantification is conducted using the Rsubread package and the statistical analyses are performed using the edgeR package. The differential expression analysis uses the quasi-likelihood functionality of edgeR. PMID- 27508062 TI - Bioconductor workflow for microbiome data analysis: from raw reads to community analyses. AB - High-throughput sequencing of PCR-amplified taxonomic markers (like the 16S rRNA gene) has enabled a new level of analysis of complex bacterial communities known as microbiomes. Many tools exist to quantify and compare abundance levels or microbial composition of communities in different conditions. The sequencing reads have to be denoised and assigned to the closest taxa from a reference database. Common approaches use a notion of 97% similarity and normalize the data by subsampling to equalize library sizes. In this paper, we show that statistical models allow more accurate abundance estimates. By providing a complete workflow in R, we enable the user to do sophisticated downstream statistical analyses, including both parameteric and nonparametric methods. We provide examples of using the R packages dada2, phyloseq, DESeq2, ggplot2 and vegan to filter, visualize and test microbiome data. We also provide examples of supervised analyses using random forests, partial least squares and linear models as well as nonparametric testing using community networks and the ggnetwork package. PMID- 27508063 TI - Long noncoding RNAs in hematopoiesis. AB - Mammalian development is under tight control to ensure precise gene expression. Recent studies reveal a new layer of regulation of gene expression mediated by long noncoding RNAs. These transcripts are longer than 200nt that do not have functional protein coding capacity. Interestingly, many of these long noncoding RNAs are expressed with high specificity in different types of cells, tissues, and developmental stages in mammals, suggesting that they may have functional roles in diverse biological processes. Here, we summarize recent findings of long noncoding RNAs in hematopoiesis, which is one of the best-characterized mammalian cell differentiation processes. Then we provide our own perspectives on future studies of long noncoding RNAs in this field. PMID- 27508064 TI - Recent advances in understanding cardiac contractility in health and disease. AB - The aim of this review is to provide the reader with a synopsis of some of the emerging ideas and experimental findings in cardiac physiology and pathophysiology that were published in 2015. To provide context for the non specialist, a brief summary of cardiac contraction and calcium (Ca) regulation in the heart in health and disease is provided. Thereafter, some recently published articles are introduced that indicate the current thinking on (1) the Ca regulatory pathways modulated by Ca/calmodulin-dependent protein kinase II, (2) the potential influences of nitrosylation by nitric oxide or S-nitrosated proteins, (3) newly observed effects of reactive oxygen species (ROS) on contraction and Ca regulation following myocardial infarction and a possible link with changes in mitochondrial Ca, and (4) the effects of some of these signaling pathways on late Na current and pro-arrhythmic afterdepolarizations as well as the effects of transverse tubule disturbances. PMID- 27508065 TI - Transporting mitochondria in neurons. AB - Neurons demand vast and vacillating supplies of energy. As the key contributors of this energy, as well as primary pools of calcium and signaling molecules, mitochondria must be where the neuron needs them, when the neuron needs them. The unique architecture and length of neurons, however, make them a complex system for mitochondria to navigate. To add to this difficulty, mitochondria are synthesized mainly in the soma, but must be transported as far as the distant terminals of the neuron. Similarly, damaged mitochondria-which can cause oxidative stress to the neuron-must fuse with healthy mitochondria to repair the damage, return all the way back to the soma for disposal, or be eliminated at the terminals. Increasing evidence suggests that the improper distribution of mitochondria in neurons can lead to neurodegenerative and neuropsychiatric disorders. Here, we will discuss the machinery and regulatory systems used to properly distribute mitochondria in neurons, and how this knowledge has been leveraged to better understand neurological dysfunction. PMID- 27508067 TI - Homing in on the hepatic scar: recent advances in cell-specific targeting of liver fibrosis. AB - Despite the high prevalence of liver disease globally, there are currently no approved anti-fibrotic therapies to treat patients with liver fibrosis. A major goal in anti-fibrotic therapy is the development of drug delivery systems that allow direct targeting of the major pro-scarring cell populations within the liver (hepatic myofibroblasts) whilst not perturbing the homeostatic functions of other mesenchymal cell types present within both the liver and other organ systems. In this review we will outline some of the recent advances in our understanding of myofibroblast biology, discussing both the origin of myofibroblasts and possible myofibroblast fates during hepatic fibrosis progression and resolution. We will then discuss the various strategies currently being employed to increase the precision with which we deliver potential anti fibrotic therapies to patients with liver fibrosis. PMID- 27508066 TI - Genome-edited human stem cell-derived beta cells: a powerful tool for drilling down on type 2 diabetes GWAS biology. AB - Type 2 diabetes (T2D) is a disease of pandemic proportions, one defined by a complex aetiological mix of genetic, epigenetic, environmental, and lifestyle risk factors. Whilst the last decade of T2D genetic research has identified more than 100 loci showing strong statistical association with disease susceptibility, our inability to capitalise upon these signals reflects, in part, a lack of appropriate human cell models for study. This review discusses the impact of two complementary, state-of-the-art technologies on T2D genetic research: the generation of stem cell-derived, endocrine pancreas-lineage cells and the editing of their genomes. Such models facilitate investigation of diabetes-associated genomic perturbations in a physiologically representative cell context and allow the role of both developmental and adult islet dysfunction in T2D pathogenesis to be investigated. Accordingly, we interrogate the role that patient-derived induced pluripotent stem cell models are playing in understanding cellular dysfunction in monogenic diabetes, and how site-specific nucleases such as the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system are helping to confirm genes crucial to human endocrine pancreas development. We also highlight the novel biology gleaned in the absence of patient lines, including an ability to model the whole phenotypic spectrum of diabetes phenotypes occurring both in utero and in adult cells, interrogating the non coding 'islet regulome' for disease-causing perturbations, and understanding the role of other islet cell types in aberrant glycaemia. This article aims to reinforce the importance of investigating T2D signals in cell models reflecting appropriate species, genomic context, developmental time point, and tissue type. PMID- 27508068 TI - Neurobiology of opioid dependence in creating addiction vulnerability. AB - Opioid drugs are potent modulators of many physiological and psychological processes. When given acutely, they can elicit the signature responses of euphoria and analgesia that societies have coveted for centuries. Repeated, or chronic, use of opioids induces adaptive or allostatic changes that modify neuronal circuitry and create an altered normality - the "drug-dependent" state. This state, at least that exhibited by those maintained continuously on long acting opioid drugs such as methadone or buprenorphine, is generally indistinguishable from the drug-naive state for most overt behaviors. The consequences of the allostatic changes (cellular, circuit, and system adaptations) that accompany the drug-dependent state are revealed during drug withdrawal. Drug cessation triggers a temporally orchestrated allostatic re establishment of neuronal systems, which is manifested as opposing physiological and psychological effects to those exhibited by acute drug intoxication. Some withdrawal symptoms, such as physical symptoms (sweating, shaking, and diarrhea) resolve within days, whilst others, such as dysphoria, insomnia, and anxiety, can linger for months, and some adaptations, such as learned associations, may be established for life. We will briefly discuss the cellular mechanisms and neural circuitry that contribute to the opioid drug-dependent state, inferring an emerging role for neuroinflammation. We will argue that opioid addictive behaviors result from a learned relationship between opioids and relief from an existing or withdrawal-induced anxiogenic and/or dysphoric state. Furthermore, a future stressful life event can recall the memory that opioid drugs alleviate negative affect (despair, sadness, and anxiety) and thereby precipitate craving, resulting in relapse. A learned association of relief of aversive states would fuel drug craving in vulnerable people living in an increasingly stressful society. We suggest that this route to addiction is contributive to the current opioid epidemic in the USA. PMID- 27508069 TI - Regenerating the liver: not so simple after all? AB - Under normal homeostatic conditions, hepatocyte renewal is a slow process and complete turnover likely takes at least a year. Studies of hepatocyte regeneration after a two-thirds partial hepatectomy (2/3 PH) have strongly suggested that periportal hepatocytes are the driving force behind regenerative re-population, but recent murine studies have brought greater complexity to the issue. Although periportal hepatocytes are still considered pre-eminent in the response to 2/3 PH, new studies suggest that normal homeostatic renewal is driven by pericentral hepatocytes under the control of Wnts, while pericentral injury provokes the clonal expansion of a subpopulation of periportal hepatocytes expressing low levels of biliary duct genes such as Sox9 and osteopontin. Furthermore, some clarity has been given to the debate on the ability of biliary derived hepatic progenitor cells to generate physiologically meaningful numbers of hepatocytes in injury models, demonstrating that under appropriate circumstances these cells can re-populate the whole liver. PMID- 27508070 TI - Gallstones: new insights into an old story. AB - Gallstones, particularly cholesterol gallstones, are common in Western populations and may cause symptoms such as biliary colic or complications such as acute cholecystitis or gallstone pancreatitis. Recent studies have allowed for a better understanding of the risk of symptoms or complications in patients with gallstones. In addition, newer data suggest an association of gallstones with overall mortality, cardiovascular disease, gastrointestinal cancers, and non alcoholic fatty liver disease. Knowledge of appropriate indications and timing of cholecystectomy, particularly for mild biliary pancreatitis, has gradually accumulated. Lastly, there are exciting possibilities for novel agents to treat or prevent cholesterol stone disease. This review covers new advances in our understanding of the natural history, clinical associations, and management of gallstone disease. PMID- 27508071 TI - Varicocele - a case for early intervention. AB - Testicular varicocele, which is defined as the dilation of the veins draining the testicle, has long been associated with a detrimental effect on testicular function. Despite a lack of high-quality, prospective data, recent evidence has shed light on potential links between varicocele and male infertility and serum testosterone levels. Similarly, varicocele repair has increasingly been shown to have a beneficial impact on pregnancy rates, semen parameters, and on improving serum testosterone in adult men. Numerous studies have assessed the optimal technique for varicocele repair and the bulk of the evidence has shown the microsurgical inguinal/subinguinal approach to have the highest success rates, the lowest overall complication rates, and the lowest recurrence rates. The management of varicocele in adolescents remains a clinical conundrum, but contemporary evidence suggests early deleterious effects of varicocele on testicular function in some patients. Well-designed prospective trials are critical to delineate the true impact and role of varicocele repair on male infertility and hypogonadism in adult and adolescent men. PMID- 27508072 TI - Novel insights into mitotic chromosome condensation. AB - The fidelity of mitosis is essential for life, and successful completion of this process relies on drastic changes in chromosome organization at the onset of nuclear division. The mechanisms that govern chromosome compaction at every cell division cycle are still far from full comprehension, yet recent studies provide novel insights into this problem, challenging classical views on mitotic chromosome assembly. Here, we briefly introduce various models for chromosome assembly and known factors involved in the condensation process (e.g. condensin complexes and topoisomerase II). We will then focus on a few selected studies that have recently brought novel insights into the mysterious way chromosomes are condensed during nuclear division. PMID- 27508073 TI - Horizontal gene transfer: essentiality and evolvability in prokaryotes, and roles in evolutionary transitions. AB - The wide spread of gene exchange and loss in the prokaryotic world has prompted the concept of 'lateral genomics' to the point of an outright denial of the relevance of phylogenetic trees for evolution. However, the pronounced coherence congruence of the topologies of numerous gene trees, particularly those for (nearly) universal genes, translates into the notion of a statistical tree of life (STOL), which reflects a central trend of vertical evolution. The STOL can be employed as a framework for reconstruction of the evolutionary processes in the prokaryotic world. Quantitatively, however, horizontal gene transfer (HGT) dominates microbial evolution, with the rate of gene gain and loss being comparable to the rate of point mutations and much greater than the duplication rate. Theoretical models of evolution suggest that HGT is essential for the survival of microbial populations that otherwise deteriorate due to the Muller's ratchet effect. Apparently, at least some bacteria and archaea evolved dedicated vehicles for gene transfer that evolved from selfish elements such as plasmids and viruses. Recent phylogenomic analyses suggest that episodes of massive HGT were pivotal for the emergence of major groups of organisms such as multiple archaeal phyla as well as eukaryotes. Similar analyses appear to indicate that, in addition to donating hundreds of genes to the emerging eukaryotic lineage, mitochondrial endosymbiosis severely curtailed HGT. These results shed new light on the routes of evolutionary transitions, but caution is due given the inherent uncertainty of deep phylogenies. PMID- 27508074 TI - Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues. AB - There has been immense progress in our understanding of the factors driving cell migration in both two-dimensional and three-dimensional microenvironments over the years. However, it is becoming increasingly evident that even though most cells share many of the same signaling molecules, they rarely respond in the same way to migration cues. To add to the complexity, cells are generally exposed to multiple cues simultaneously, in the form of growth factors and/or physical cues from the matrix. Understanding the mechanisms that modulate the intracellular signals triggered by multiple cues remains a challenge. Here, we will focus on the molecular mechanism involved in modulating cell migration, with a specific focus on how cell contractility can mediate the crosstalk between signaling initiated at cell-matrix adhesions and growth factor receptors. PMID- 27508075 TI - Primary Hyperparathyroidism. AB - Over the past several generations, primary hyperparathyroidism (PHTP) has undergone a change in its clinical presentation in many countries from a symptomatic disease to an asymptomatic one. The reasons for this change in clinical presentation are related to the widespread use of biochemical screening tests, to the measurement of PTH more routinely in the evaluation of metabolic bone disease and to the status of vitamin D sufficiency in the population. Along with recognition of a broader clinical spectrum of disease, including a more recently recognized normocalcemic variant, has come an appreciation that the evaluation of classic target organs that can be affected in PHPT, such as the skeleton and the kidneys, require more advanced imaging technology for complete evaluation. It is clear that even in asymptomatic patients, evidence for microstructural disease in the skeleton and calcifications in the kidneys can be demonstrated often. Potential non-classical manifestations of PHPT related to neurocognition and the cardiovascular system continue to be of interest. As a result of these advances, revised guidelines for the management of asymptomatic PHPT have been recently published to help the clinician determine whether surgery is appropriate or whether a more conservative approach is acceptable. PMID- 27508076 TI - Advances of gene therapy for primary immunodeficiencies. AB - In the recent past, the gene therapy field has witnessed a remarkable series of successes, many of which have involved primary immunodeficiency diseases, such as X-linked severe combined immunodeficiency, adenosine deaminase deficiency, chronic granulomatous disease, and Wiskott-Aldrich syndrome. While such progress has widened the choice of therapeutic options in some specific cases of primary immunodeficiency, much remains to be done to extend the geographical availability of such an advanced approach and to increase the number of diseases that can be targeted. At the same time, emerging technologies are stimulating intensive investigations that may lead to the application of precise genetic editing as the next form of gene therapy for these and other human genetic diseases. PMID- 27508077 TI - Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation. AB - Inflammasomes are high-molecular-weight protein complexes that are formed in the cytosolic compartment in response to danger- or pathogen-associated molecular patterns. These complexes enable activation of an inflammatory protease caspase 1, leading to a cell death process called pyroptosis and to proteolytic cleavage and release of pro-inflammatory cytokines interleukin (IL)-1beta and IL-18. Along with caspase-1, inflammasome components include an adaptor protein, ASC, and a sensor protein, which triggers the inflammasome assembly in response to a danger signal. The inflammasome sensor proteins are pattern recognition receptors belonging either to the NOD-like receptor (NLR) or to the AIM2-like receptor family. While the molecular agonists that induce inflammasome formation by AIM2 and by several other NLRs have been identified, it is not well understood how the NLR family member NLRP3 is activated. Given that NLRP3 activation is relevant to a range of human pathological conditions, significant attempts are being made to elucidate the molecular mechanism of this process. In this review, we summarize the current knowledge on the molecular events that lead to activation of the NLRP3 inflammasome in response to a range of K (+) efflux-inducing danger signals. We also comment on the reported involvement of cytosolic Ca (2+) fluxes on NLRP3 activation. We outline the recent advances in research on the physiological and pharmacological mechanisms of regulation of NLRP3 responses, and we point to several open questions regarding the current model of NLRP3 activation. PMID- 27499850 TI - From hepatoprotection models to new therapeutic modalities for treating liver diseases: a personal perspective. AB - A variety of rodent models of hepatoprotection have been developed in which tolerance to acetaminophen-induced hepatotoxicity occurs. Autoprotection/heteroprotection is a phenomenon where prior exposure to a mildly toxic dose of toxicant confers protection against a subsequently administered higher dose of the same toxicant (as in the case of autoprotection) or to a different toxicant (referred to as heteroprotection). Multiple mechanisms regulate this adaptive response, including hepatocellular proliferation, proteostasis, enhanced expression of cytoprotective genes, and altered tissue immune response. In this review, we will discuss recent findings that highlight the complexity of these adaptive mechanisms and we also outline the usefulness of these findings to devise therapeutic and/or diagnostic tools for acetaminophen induced liver damage in patients. PMID- 27508079 TI - Higher reliability of triple-phase bone scintigraphy in cementless total hip arthroplasty compared to cementless bipolar hemiarthroplasty. AB - PURPOSE: Periprosthetic infection is one of the main reasons for revision surgery after hip arthroplasty. The purpose of the present study is to compare the reliability of triple-phase bone scintigraphy (TPBS) in the diagnosis of periprosthetic infection between cementless total hip arthroplasty (THA) and bipolar hemiarthroplasty (BHA). METHODS: In this retrospective study, 52 patients were analyzed; 33 of them were performed with THA and 19 of them were performed with BHA. The exclusion criteria were cementation in previous surgery, romatological joint disorders, periprosthetic fracture and malignancy history. C reactive protein (CRP) and erythrocyte sedimentation (ESR) rate results were recorded preoperatively. Tissue samples from the different areas periprosthetic tissue were obtained for histopathological examination and sample tissue culture. RESULTS: In the present study, the sensitivity, specificity and accuracy were 90.9%, 77.3% and 81.8%, respectively, for THA and 77.8%, 60.0% and 68.4%, respectively, for BHA. Positive predictive values for THA and BHA were 66.7% and 63.6%, and negative predictive values were 94.4% and 75.0%, respectively. CONCLUSIONS: Due to the higher sensitivity, specificity and accuracy, TPBS has a more reliable diagnostic value for cementless THA in the diagnosis of periprosthetic infection compared to cementless BHA. PMID- 27508080 TI - Extralevator abdominoperineal excision (Elape): A retrospective cohort study. AB - INTRODUCTION: Extralevator abdominoperineal excision (ELAPE) is relatively new surgical technique for low rectal cancers. It is a more radical approach than conventional abdominoperineal excision (APE) with potentially better oncological outcome. The aim of this study was to analyse short term results of ELAPE compared with conventional abdominoperineal excision. METHODS: Data were collected prospectively for 72 patients who underwent abdominoperineal excision (APE) for low rectal carcinomas from 2010 to 2014. Of these 24 patients underwent ELAPE with biological prosthetic mesh used to close the perineal defect. RESULTS: The median age of patients was 68 (37-87). Positive circumferential resection margin (1/24 vs. 8/48) and Intra operative perorations (0/24 vs. 6/48) compared favourably with ELAPE. CONCLUSIONS: Short term results from this study support that ELAPE has better oncological outcome. PMID- 27508081 TI - Anxiety and depression on an acute respiratory ward. AB - OBJECTIVES: Psychological difficulties are a common complication among patients with respiratory disease, and are associated with poorer health outcomes and increased use of healthcare. As prevalence studies typically sample patients from community settings, this study aimed to explore the extent and nature of psychological difficulties during acute hospital admission. METHODS: A case example of an acute respiratory ward is presented. In total, 41 acute respiratory inpatients completed standardised measures of depression, anxiety, and health anxiety. RESULTS: Rates of clinically significant depression, anxiety, and health anxiety were 71%, 40%, and 21%, respectively, with 76% of participants showing clinically significant scores on at least one measure. Comparison to existing literature suggests depression rates may be elevated in the acute inpatient context. The difficulties experienced encompassed both contextual factors related to being in hospital and broader health concerns. CONCLUSION: We suggest that psychological distress may be particularly prevalent in inpatient settings and that larger-scale studies are warranted. PMID- 27508082 TI - Optimization of DRASTIC method by artificial neural network, nitrate vulnerability index, and composite DRASTIC models to assess groundwater vulnerability for unconfined aquifer of Shiraz Plain, Iran. AB - BACKGROUND: Extensive human activities and unplanned land uses have put groundwater resources of Shiraz plain at a high risk of nitrate pollution, causing several environmental and human health issues. To address these issues, water resources managers utilize groundwater vulnerability assessment and determination of protection. This study aimed to prepare the vulnerability maps of Shiraz aquifer by using Composite DRASTIC index, Nitrate Vulnerability index, and artificial neural network and also to compare their efficiency. METHODS: The parameters of the indexes that were employed in this study are: depth to water table, net recharge, aquifer media, soil media, topography, impact of the vadose zone, hydraulic conductivity, and land use. These parameters were rated, weighted, and integrated using GIS, and then, used to develop the risk maps of Shiraz aquifer. RESULTS: The results indicated that the southeastern part of the aquifer was at the highest potential risk. Given the distribution of groundwater nitrate concentrations from the wells in the underlying aquifer, the artificial neural network model offered greater accuracy compared to the other two indexes. The study concluded that the artificial neural network model is an effective model to improve the DRASTIC index and provides a confident estimate of the pollution risk. CONCLUSIONS: As intensive agricultural activities are the dominant land use and water table is shallow in the vulnerable zones, optimized irrigation techniques and a lower rate of fertilizers are suggested. The findings of our study could be used as a scientific basis in future for sustainable groundwater management in Shiraz plain. PMID- 27508083 TI - A spectrum of CYP1B1 mutations associated with primary congenital glaucoma in families of Pakistani descent. AB - Glaucoma is the second leading cause of blindness, affecting ~65 million people worldwide. We identified and ascertained a large cohort of inbred families with multiple individuals manifesting cardinal symptoms of primary congenital glaucoma (PCG) to investigate the etiology of the disease at a molecular level. Ophthalmic examinations, including slit-lamp microscopy and applanation tonometry, were performed to characterize the causal phenotype and confirm that affected individuals fulfilled the diagnostic criteria for PCG. Subsequently, exclusion analysis was completed with fluorescently labeled short tandem repeat markers, followed by Sanger sequencing to identify pathogenic variants. Exclusion analysis suggested linkage to the CYP1B1 locus, with positive two-point logarithm of odds scores in 23 families, while Sanger sequencing identified a total of 11 variants, including two novel mutations, in 23 families. All mutations segregated with the disease phenotype in their respective families. These included the following seven missense mutations: p.Y81N, p.E229K, p.R368H, p.R390H, p.W434R, p.R444Q and p.R469W, as well as one nonsense mutation, p.Q37*, and three frameshift mutations, p.W246Lfs81*, p.T404Sfs30* and p.P442Qfs15*. In conclusion, we identified a total of 11 mutations, reconfirming the genetic heterogeneity of CYP1B1 in the pathogenesis of PCG. To the best of our knowledge, this is the largest study investigating the contribution of CYP1B1 to the pathogenesis of PCG in the Pakistani population. PMID- 27508084 TI - A novel nonsense mutation in the NOG gene causes familial NOG-related symphalangism spectrum disorder. AB - The human noggin (NOG) gene is responsible for a broad spectrum of clinical manifestations of NOG-related symphalangism spectrum disorder (NOG-SSD), which include proximal symphalangism, multiple synostoses, stapes ankylosis with broad thumbs (SABTT), tarsal-carpal coalition syndrome, and brachydactyly type B2. Some of these disorders exhibit phenotypes associated with congenital stapes ankylosis. In the present study, we describe a Japanese pedigree with dactylosymphysis and conductive hearing loss due to congenital stapes ankylosis. The range of motion in her elbow joint was also restricted. The family showed multiple clinical features and was diagnosed with SABTT. Sanger sequencing analysis of the NOG gene in the family members revealed a novel heterozygous nonsense mutation (c.397A>T; p.K133*). In the family, the prevalence of dactylosymphysis and hyperopia was 100% while that of stapes ankylosis was less than 100%. Stapes surgery using a CO2 laser led to a significant improvement of the conductive hearing loss. This novel mutation expands our understanding of NOG SSD from clinical and genetic perspectives. PMID- 27508085 TI - Tuberculosis in foreign students in Japan, 2010-2014: a comparison with the notification rates in their countries of origin. PMID- 27508086 TI - Profile of tuberculosis among the foreign-born population in Japan, 2007-2014. AB - The proportion of foreign-born people among the newly notified tuberculosis (TB) patients has been increasing in recent years and potentially poses a new challenge to TB control in Japan. In this report, we analysed the data from the Japan TB surveillance system between 2007 and 2014 to gain an overview of the trends and characteristics of foreign-born TB patients in Japan. We found that the proportion of foreign-born TB patients was especially high among the younger age groups - 44.1% among the 20-29 years age group in 2014. The largest groups of foreign-born patients were from China and the Philippines; however, the number of those from Nepal and Viet Nam was on the rise. Students comprised the second largest professional category group for TB after regular workers, and its proportion increased over the study period. Compared to Japan-born TB patients, foreign-born patients were more likely to be diagnosed through routine medical check-ups. Treatment successes and patients still on treatment were significantly lower among foreign-born patients than their Japan-born counterparts; and transferred-out and unknown outcomes were higher. Our results indicated that distinctive subgroups within the foreign-born population in Japan, especially students and regular workers, might have a higher risk of developing TB. Measures to ensure early diagnosis and treatment adherence should be adapted to such populations. PMID- 27508087 TI - Assessment of the risk posed to Singapore by the 2015 Middle East respiratory syndrome outbreak in the Republic of Korea. AB - OBJECTIVE: To assess the public health risk to Singapore posed by the Middle East respiratory syndrome (MERS) outbreak in the Republic of Korea in 2015. METHODS: The likelihood of importation of MERS cases and the magnitude of the public health impact in Singapore were assessed to determine overall risk. Literature on the epidemiology and contextual factors associated with MERS coronavirus infection was collected and reviewed. Connectivity between the Republic of Korea and Singapore was analysed. Public health measures implemented by the two countries were reviewed. RESULTS: The epidemiology of the 2015 MERS outbreak in the Republic of Korea remained similar to the MERS outbreaks in Saudi Arabia. In addition, strong infection control and response measures were effective in controlling the outbreak. In view of the air traffic between Singapore and MERS affected areas, importation of MERS cases into Singapore is possible. Nonetheless, the risk of a serious public health impact to Singapore in the event of an imported case of MERS would be mitigated by its strong health-care system and established infection control practices. DISCUSSION: The MERS outbreak was sparked by an exported case from the Middle East, which remains a concern as the reservoir of infection (thought to be camels) continues to exist in the Middle East, and sporadic cases in the community and outbreaks in health-care settings continue to occur there. This risk assessment highlights the need for Singapore to stay vigilant and to continue enhancing core public health capacities to detect and respond to MERS coronavirus. PMID- 27508088 TI - External quality assessment of dengue and chikungunya diagnostics in the Asia Pacific region, 2015. AB - OBJECTIVE: To conduct an external quality assessment (EQA) of dengue and chikungunya diagnostics among national-level public health laboratories in the Asia Pacific region following the first round of EQA for dengue diagnostics in 2013. METHODS: Twenty-four national-level public health laboratories performed routine diagnostic assays on a proficiency testing panel consisting of two modules. Module A contained serum samples spiked with cultured dengue virus (DENV) or chikungunya virus (CHIKV) for the detection of nucleic acid and DENV non-structural protein 1 (NS1) antigen. Module B contained human serum samples for the detection of anti-DENV antibodies. RESULTS: Among 20 laboratories testing Module A, 17 (85%) correctly detected DENV RNA by reverse transcription polymerase chain reaction (RT-PCR), 18 (90%) correctly determined serotype and 19 (95%) correctly identified CHIKV by RT-PCR. Ten of 15 (66.7%) laboratories performing NS1 antigen assays obtained the correct results. In Module B, 18/23 (78.3%) and 20/20 (100%) of laboratories correctly detected anti-DENV IgM and IgG, respectively. Detection of acute/recent DENV infection by both molecular (RT PCR) and serological methods (IgM) was available in 19/24 (79.2%) participating laboratories. DISCUSSION: Accurate laboratory testing is a critical component of dengue and chikungunya surveillance and control. This second round of EQA reveals good proficiency in molecular and serological diagnostics of these diseases in the Asia Pacific region. Further comprehensive diagnostic testing, including testing for Zika virus, should comprise future iterations of the EQA. PMID- 27508089 TI - Prevalence of resistance to second-line tuberculosis drug among multidrug resistant tuberculosis patients in Viet Nam, 2011. AB - INTRODUCTION: Extensively drug-resistant tuberculosis (XDR-TB) represents an emerging public health problem worldwide. According to the World Health Organization, an estimated 9.7% of multidrug-resistant TB (MDR-TB) cases are defined as XDR-TB globally. The objective of this study was to determine the prevalence of drug resistance to second-line TB drugs among MDR-TB cases detected in the Fourth National Anti-Tuberculosis Drug Resistance Survey in Viet Nam. METHODS: Eighty clusters of TB cases were selected using a probability-proportion to-size approach. To identify MDR-TB cases, drug susceptibility testing (DST) was performed for the four major first-line TB drugs. DST of second-line drugs (ofloxacin, amikacin, kanamycin, capreomycin) was performed on isolates from MDR TB cases to identify pre-XDR and XDR cases. RESULTS: A total of 1629 smear positive TB cases were eligible for culture and DST. Of those, DST results for first-line drugs were available for 1312 cases, and 91 (6.9%) had MDR-TB. Second line DST results were available for 84 of these cases. Of those, 15 cases (17.9%) had ofloxacin resistance and 6.0% were resistant to kanamycin and capreomycin. Five MDR-TB cases (6.0%) met the criteria of XDR-TB. CONCLUSION: This survey provides the first estimates of the proportion of XDR-TB among MDR-TB cases in Viet Nam and provides important information for local policies regarding second line DST. Local policies and programmes that are geared towards TB prevention, early diagnosis and treatment with effective regimens are of high importance. PMID- 27508090 TI - Epidemiology and control of tuberculosis in the Western Pacific Region: update with 2013 case notification data. AB - INTRODUCTION: Since the year 2000, tuberculosis (TB) prevalence in the World Health Organization (WHO) Western Pacific Region decreased 36%. However, there were an estimated 1.6 million TB cases in the Region in 2013. This study describes a regional analysis using the WHO global TB database data from 2000 to 2013. METHODS: TB surveillance data are annually collected from 36 countries and areas in the Western Pacific Region using a web-based system. TB case notifications, treatment outcomes and information on TB/HIV coinfection are analysed descriptively. Stratified analysis of the TB data by age, sex and countries and areas were conducted. RESULTS: Countries and areas in the Western Pacific Region notified 1.3 million new and relapse TB cases in 2013. TB notification rate increased in the early 2000s, stabilized for several years and declined recently. Country-specific TB notification rates declined over time for all age groups in most countries. TB treatment success rates remain high in the Region with 16 countries reaching or maintaining 85% (or higher) in 2013. HIV testing among TB cases has increased gradually with approximately 11 000 HIV positive TB cases diagnosed each year since 2009. DISCUSSION: The results suggest that true TB incidence is possibly declining. Treatment success rates have remained high for six of seven high-burden countries. TB surveillance data analysis is an important source of programmatic and epidemiological information. Careful interpretation of these findings can provide useful insight for programmatic decision-making. While the TB burden remains immense, national TB programmes must evolve and adapt to build upon previous efforts. PMID- 27508092 TI - Celecoxib-erlotinib combination delays growth and inhibits angiogenesis in EGFR mutated lung cancer. AB - Combination treatment for non-small cell lung cancer (NSCLC) is becoming more popular due to the anticipation that it may be more effective than single drug treatment. In addition, there are efforts to genetically screen patients for specific mutations in light of attempting to administer specific anticancer agents that are most effective. In this study, we evaluate the anticancer and anti-angiogenic effects of low dose celecoxib-erlotinib combination in NSCLC in vitro and in vivo. In NSCLC cells harboring epidermal growth factor receptor (EGFR) mutations, combination celecoxib-erlotinib treatment led to synergistic cell death, but there was minimal efficacy in NSCLC cells with wild-type EGFR. In xenograft models, combination treatment also demonstrated greater inhibition of tumor growth compared to individual treatment. The anti-tumor effect observed was secondary to the targeting of angiogenesis, evidenced by decreased vascular endothelial growth factor A (VEGFA) levels and decreased levels of CD31 and microvessel density. Combination treatment targets angiogenesis through the modulation of of the PI3K/AKT and ERK/Raf1-1 pathway in NSCLC with EGFR exon 19 deletions. These findings may have significant clinical implications in patients with tumors harboring EGFR exon 19 deletions as they may be particularly sensitive to this regimen. PMID- 27508091 TI - Extracellular MicroRNA in liquid biopsy: applicability in cancer diagnosis and prevention. AB - One of the goals of contemporary cancer research is the development of new markers that facilitate earlier and non-invasive diagnosis. MicroRNAs are non coding RNA molecules that regulate gene expression; studies have shown that their expression levels are altered in cancer. Recently, extra-cellular microRNAs have been detected in biological fluids and studied as possible cancer markers that can be detected by noninvasive procedures. In this review, we analyze the current understanding of extracellular miRNAs based on clinical studies to establish their possible use for the prevention of the most common tumors. Despite discrepancies among different studies of the same cancers, panels of specific extracellular microRNAs are emerging as a new tool for the secondary (selection of high-risk individuals to undergo screening) and tertiary (relapse) prevention of cancer. PMID- 27508093 TI - Circulating miR-21 as an independent predictive biomarker for chemoresistance in esophageal squamous cell carcinoma. AB - Only a few studies indentified the significance of circulating microRNAs in blood as a predictive biomarker for chemoresistance in esophageal squamous cell carcinoma (ESCC). In this study, we tested whether oncogenic miR-21 promoted chemoresistance in ESCC and served as a biomarker for predicting chemoresistance in plasma of patients with ESCC. All consecutive patients underwent the preoperative chemotherapy regimen (JCOG9907 trial) with cisplatin plus 5 fluorouracil. As a result, pretreatment plasma concentrations of miR-21 were significantly higher in ESCC patients with a low histopathological response than in those with a high histopathological response (P = 0.0416). Multivariate analysis revealed that a high pretreatment plasma concentration of miR-21 was an independent risk factor of chemoresistance (p = 0.0150; Odds Ratio 9.95 (range: 1.56-63.4)). The expression of miR-21 was also significantly higher in pretreatment ESCC tissues with a low histopathological response than in those with a high histopathological response (P = 0.0409). In vitro, although the growth of KYSE 170 ESCC cells transfected with the control mimics was markedly inhibited by the 5-fluorouracil or cisplatin treatment, the inhibitory effects of 5-FU (P < 0.05) or cisplatin (P < 0.05) were significantly reduced in KYSE170 cells that overexpressed miR-21. Taken together, the overexpression of miR-21 contributed to chemoresistance and circulating miR-21 in plasma of patients with ESCC could be a useful biomarker for predicting chemoresistance. PMID- 27508094 TI - TMEM45A, SERPINB5 and p16INK4A transcript levels are predictive for development of high-grade cervical lesions. AB - Women persistently infected with human papillomavirus (HPV) type 16 are at high risk for development of cervical intraepithelial neoplasia grade 3 or cervical cancer (CIN3+). We aimed to identify biomarkers for progression to CIN3+ in women with persistent HPV16 infection. In this prospective study, 11,088 women aged 20 29 years were enrolled during 1991-1993, and re-invited for a second visit two years later. Cervical cytology samples obtained at both visits were tested for HPV DNA by Hybrid Capture 2 (HC2), and HC2-positive samples were genotyped by INNO-LiPA. The cohort was followed for up to 19 years via a national pathology register. To identify markers for progression to CIN3+, we performed microarray analysis on RNA extracted from cervical swabs of 30 women with persistent HPV16 infection and 11 HPV-negative women. Six genes were selected and validated by quantitative PCR. Three genes were subsequently validated within a different and large group of women from the same cohort. Secondly, Kaplan-Meier and Cox regression analyses were used to investigate whether expression levels of those three genes predict progression to CIN3+. We found that high transcript levels of TMEM45A, SERPINB5 and p16INK4a at baseline were associated with increased risk of CIN3+ during follow-up. The hazard ratios of CIN3+ per 10-fold increase in baseline expression level were 1.6 (95% CI: 1.1-2.3) for TMEM45A, 1.6 (95% CI: 1.1-2.5) for p16INK4a, and 1.8 (95% CI: 1.2-2.7) for SERPINB5. In conclusion, high mRNA expression levels of TMEM45A, SERPINB5 and p16INK4a were associated with increased risk of CIN3+ in persistently HPV16-infected women. PMID- 27508095 TI - MicroRNAs-208b-3p, 204-5p, 129-2-3p and 3065-5p as predictive markers of oral leukoplakia that progress to cancer. AB - Leukoplakia is the most common precursor lesion of oral squamous cell carcinoma (OSCC). Currently, the risk of progression to OSCC is assessed based on histopathologic examination alone. However, this method fails to identify the subset of microscopically innocuous leukoplakia that ultimately transforms to OSCC. The aim of this study was to determine if microRNAs (miRNAs) can be utilized to identify non- and low-grade dysplastic oral lesions at risk for cancer progression. A retrospective study of genome-wide miRNA expression level analyses was performed in the training cohort (n=20) using deep sequencing formalin-fixed paraffin embedded incisional biopsy tissues from patients with oral leukoplakic lesions diagnosed with non- or low-grade dysplasia and known clinical outcome. The promising miRNA candidates were then evaluated in the validation cohort (n=80) using quantitative real-time PCR (qRT-PCR). Four promising miRNAs-208b-3p, 204-5p, 129-2-3p and 3065-5p were identified. Combining these four miRNAs as a panel with age and histologic diagnosis (p<0.004), our final model had a predictive value for the area under the receiver operating characteristic (ROC) curve (AUC) of 0.792, sensitivity of 76.9% and specificity of 73.7% to accurately identify non- and low-grade dysplastic lesions at risk of cancer progression, which is a significant improvement over histopathologic examination alone (AUC of 0.645). While further investigation is needed, discovery of predictive markers that can accurately identify histologically innocuous oral lesions at high risk for progression to OSSC will significantly improve clinical outcome by means of early intervention. PMID- 27508096 TI - Response to 'Dai W et al. Am J Cancer Res 2015;5(10):3270-3275' from the makers of nintedanib. PMID- 27508097 TI - MicroRNA-17/20a impedes migration and invasion via TGF-beta/ITGB6 pathway in esophageal squamous cell carcinoma. AB - Patients with esophageal squamous cell carcinoma (ESCC) have an overall poor prognosis due to invasion and metastasis. Although it has been studied extensively, the metastatic mechanisms of ESCC remains largely unclear. Here, we evaluated microRNA expression in ESCC cell sublines with distinct motility and found that microRNA-17 and microRNA-20a (miR-17/20a) dramatically impeded cell migration and invasion of ESCC in vitro and decreased pulmonary arrest in vivo. Furthermore, we identified that TGF-beta receptor 2 (TGFBR2) and Smad anchor for receptor activation (SARA) served as genuine miR-17/20a targets, which are both implicated in TGF-beta pathway. TGF-beta treatment promoted the motility of ESCC cells, and miR-17/20a could attenuate the activation of TGF-beta pathway by weakening the phosphorylation of Smad2/3 to reduce the expression of ITGB6, which was crucial in migration and invasion of ESCC cells. Moreover, evaluation of ESCC specimens revealed a close correlation between miR-17/20a, TGFBR2, SARA and lymph node metastasis. Together, our findings demonstrate that miR-17/20a suppresses cell migration and invasion of ESCC by modulating TGF-beta/ITGB6 pathway, suggesting a promising strategy for diagnosis and therapy of ESCC invasion and metastasis. PMID- 27508098 TI - MiR-153 promotes breast cancer cell apoptosis by targeting HECTD3. AB - Homologous to the E6-associated protein carboxyl terminus domain containing 3 (HECTD3) is an E3 ubiquitin ligase which ubiquitinates caspase-8, caspase-9 and promotes cancer cell survival. Aberrant HECTD3 expression is frequently involved in various types of cancer progression. However, to date, the regulation of HECTD3 remains unclear. Here, we demonstrated that miR-153 functions as a negative regulator of HECTD3 and sensitizes cisplatin-induced apoptosis in triple negative breast cancer cells MDA-MB-231 and BT-549. Luciferase reporter assay demonstrated that miR-153 suppresses HECTD3 expression through directly targeting its mRNA within the 3'-Untranslated Region (3'UTR). Additionally, the expression levels of miR-153 and HECTD3 are inversely correlated in breast cancer cell lines. Furthermore, ectopic expression of miR-153 promotes apoptosis in MDA-MB 231 and BT-549 cells treated with cisplatin or TNF-alpha, and miR-153 inhibitor treatment inhibits cisplatin induced apoptosis in MDA-MB-231 and BT-549 cells. Moreover, stable overexpression of HECTD3 abrogates the sensitization effect of miR-153 to cisplatin treatment in MDA-MB-231 cells, and miR-153 inhibitor protects cells against cisplatin cytotoxicity in control cells, but not in the stable knockdown HECTD3 MDA-MB-231 cells. More importantly, breast cancer patients with higher expression levels of miR-153 had significant higher 5-year survival rate in PROGmiR database (P<0.05). Taken together, our study indicated that miR-153 inhibits TNBC survival by targeting HECTD3 and functions as a potent tumor suppressor. PMID- 27508099 TI - Impacts of physically active and under-active on clinical outcomes of esophageal cancer patients undergoing esophagectomy. AB - Physical activity has been reported to positively influence quality of life and survival in certain cancers. However, the associations between them in esophageal cancer are previously undefined. The aims of this study are to investigate whether physically active esophageal cancer patients have improved quality of life and lower risk of recurrence as well as death compared with physically inactive patients. We evaluated the relationships between postoperative leisure time physical activity and quality of life and recurrence and death among patients diagnosed with esophageal cancer. We respectively used generalized estimating equations and Cox proportional regression to analysis quality of life and survival, adjusting for known potential confounding factors. Comparing esophageal cancer patients reporting more than 9 MET hours per week of postoperative leisure time physical activity with those reporting less, we found improved quality of life. Additionally, we also found that postoperative leisure time physical activity >=9 MET hours per week, compared with less, was associated with a 23% lower risk of all-cause mortality (HR, 0.666; 95% CI, 0.481-0.921; P=0.014) and a 53% lower risk of recurrence (HR, 0.306; 95% CI 0.218-0.429; P<0.001). Leisure time physical activity was significantly associated with quality of life and risk of recurrence and death of esophageal cancer patients. Clinicians should consider increasing physical activity, regardless of previous behaviors, as a part of primary cancer treatment. The ultimate goal is to improve quality of life and prolong survival of cancer survivors. PMID- 27508100 TI - Erratum: MicroRNA-338-3p suppresses metastasis of lung cancer cells by targeting the EMT regulator Sox4. AB - [This corrects the article on p. 127 in vol. 6, PMID: 27186391.]. PMID- 27508101 TI - Invasive Meningococcal Meningitis Serogroup C Outbreak in Northwest Nigeria, 2015 - Third Consecutive Outbreak of a New Strain. AB - BACKGROUND: In northwest Nigeria in 2013 and 2014, two sequential, localized outbreaks of meningitis were caused by a new strain of Neisseria meningitidis serogroup C (NmC). In 2015, an outbreak caused by the same novel NmC strain occurred over a wider geographical area, displaying different characteristics to the previous outbreaks. We describe cases treated by Medecins Sans Frontieres (MSF) in the 2015 outbreak. METHODS: From February 10 to June 8, 2015, data on cerebrospinal meningitis (CSM) cases and deaths were recorded on standardized line-lists from case management sites supported by MSF. Cerebrospinal fluid (CSF) samples from suspected cases at the beginning of the outbreak and throughout from suspected cases from new geographical areas were tested using rapid Pastorex(r) latex agglutination to determine causative serogroup. A subset of CSF samples was also inoculated into Trans-Isolate medium for testing by the WHO Collaborating Centre for Reference and Research on Meningococci, Oslo. Reactive vaccination campaigns with meningococcal ACWY polysaccharide vaccine targeted affected administrative wards. RESULTS: A total of 6394 (65 confirmed and 6329 probable) cases of CSM including 321 deaths (case fatality rate: 5.0%) were recorded. The cumulative attack rate was 282 cases per 100,000 population in the wards affected. The outbreak lasted 17 weeks, affecting 1039 villages in 21 local government areas in three states (Kebbi, Sokoto, Niger). Pastorex(r) tests were NmC positive for 65 (58%) of 113 CSF samples. Of 31 Trans-Isolate medium samples, 26 (84%) tested positive for NmC (14 through culture and 12 through PCR); all had the same rare PorA type P1.21-15,16 as isolates from the 2013 and 2014 outbreaks. All 14 culture-positive samples yielded isolates of the same genotype (ST-10217 PorA type P1.21-15,16 and FetA type F1-7). More than 222,000 targeted individuals were vaccinated relatively early in the outbreak (administrative coverage estimates 98% and 89% in Kebbi and Sokoto, respectively). CONCLUSIONS: The outbreak was the largest caused by NmC documented in Nigeria. Reactive vaccination in both states may have helped curtail the epidemic. A vaccination campaign against NmC with a long-lasting conjugate vaccine should be considered in the region. PMID- 27508102 TI - Long-term quality assurance of [(18)F]-fluorodeoxyglucose (FDG) manufacturing. AB - Nine years of experience with 2286 commercial synthesis allowed us to deliver comprehensive information on the quality of (18)F-FDG production. Semi-automated FDG production line using Cyclone 18/9 machine (IBA Belgium), TRACERLab MXFDG synthesiser (GE Health, USA) using alkalic hydrolysis, grade "A" isolator with dispensing robotic unit (Tema Sinergie, Italy), and automatic control system under GAMP5 (minus2, Slovakia) was assessed by TQM tools as highly reliable aseptic production line, fully compliant with Good Manufacturing Practice and just-in-time delivery of FDG radiopharmaceutical. Fluoride-18 is received in steady yield and of very high radioactive purity. Synthesis yields exhibited high variance connected probably with quality of disposable cassettes and chemicals sets. Most performance non-conformities within the manufacturing cycle occur at mechanical nodes of dispensing unit. The long-term monitoring of 2286 commercial synthesis indicated high reliability of automatic synthesizers. Shewhart chart and ANOVA analysis showed that minor non-compliances occurred were mostly caused by the declinations of less experienced staff from standard operation procedures, and also by quality of automatic cassettes. Only 15 syntheses were found unfinished and in 4 cases the product was out-of-specification of European Pharmacopoeia. Most vulnerable step of manufacturing was dispensing and filling in grade "A" isolator. Its cleanliness and sterility was fully controlled under the investigated period by applying hydrogen peroxide vapours (VHP). Our experience with quality assurance in the production of [(18)F]-fluorodeoxyglucose (FDG) at production facility of BIONT based on TRACERlab MXFDG production module can be used for bench-marking of the emerging manufacturing and automated manufacturing systems. PMID- 27508103 TI - A preliminary investigation into textural features of intratumoral metabolic heterogeneity in (18)F-FDG PET for overall survival prognosis in patients with bulky cervical cancer treated with definitive concurrent chemoradiotherapy. AB - We examined the role of intratumoral metabolic heterogeneity on (18)F-FDG PET during concurrent chemoradiotherapy (CCRT) in predicting survival outcomes for patients with cervical cancer. This prospective study consisted of 44 patients with bulky (>= 4 cm) cervical cancer treated with CCRT. All patients underwent serial (18)F-FDG PET studies. Primary cervical tumor standardized uptake values, metabolic tumor volume, and total lesion glycolysis (TLG) were measured in pretreatment and intra-treatment (2 weeks) PET scans. Regional textural features were analyzed using the grey level run length encoding method (GLRLM) and grey level size zone matrix. Associations between PET parameters and overall survival (OS) were tested by Kaplan-Meier analysis and Cox regression model. In univariate analysis, pretreatment grey-level nonuniformity (GLNU) > 48 by GLRLM textural analysis and intra-treatment decline of run length nonuniformity < 55% and the decline of TLG (?TLG) < 60% were associated with significantly worse OS. In multivariate analysis, only ?TLG was significant (P = 0.009). Combining pretreatment with intra-treatment factors, we defined the patients with a initial GLNU > 48 and a ?TLG <= 60% as the high-risk group and the other patients as the low-risk. The 5-year OS rate for the high-risk group was significantly worse than that for the low-risk group (42% vs. 81%, respectively, P = 0.001). The heterogeneity of intratumoral FDG distribution and the early temporal change in TLG may be an important predictor for OS in patients with bulky cervical cancer. This gives the opportunity to adjust individualized regimens early in the treatment course. PMID- 27508104 TI - Design, construction and testing of a low-cost automated (68)Gallium-labeling synthesis unit for clinical use. AB - The interest in (68)Gallium labeled PET probes continues to increase around the world. Widespread use in Europe and Asia has led to great interest for use at numerous sites in the US. One barrier to entry is the cost of the automated synthesis units for relatively simple labeling procedures. We describe the construction and testing of a relatively low-cost automated (68)Ga-labeling unit for human-use. We provide a guide for construction, including part lists and synthesis timelists to facilitate local implementation. Such inexpensive systems could help increase use around the globe and in the US in particular by removing one of the barriers to greater widespread availability. The developed automated synthesis unit reproducibly synthesized (68)Ga-DOTATOC with average yield of 71 +/- 8% and a radiochemical purity >= 95% in a synthesis time of 25 +/- 1 minutes. Automated product yields are comparable to that of manual synthesis. We demonstrate in-house construction and use of a low-cost automated synthesis unit for labeling of DOTATOC and similar peptides with (68)Gallium. PMID- 27508105 TI - Synthesis and pre-clinical evaluation of an (18)F-labeled single-chain antibody fragment for PET imaging of epithelial ovarian cancer. AB - Anti-CA125 antibodies have been used in immunoassays to quantify levels of shed antigen in the serum of patients who are under surveillance for epithelial ovarian cancer (EOC). However, there is currently no molecular imaging probe in the clinic for the assessment of CA125 expression in vivo. The present study describes the development of an (18)F-labeled single-chain variable fragment (scFv) for PET imaging of CA125 in preclinical EOC models. Anti-CA125 scFv was derived from MAb-B43.13 by recombinant expression of the fragment in E.coli. Fragment scFv-B43.13 was purified via immobilized metal affinity chromatography and characterized for antigen binding via immuno-staining and flow cytometry. Prosthetic group N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB) was used for radiolabeling of scFv-B43.13. Preclinical ovarian cancer models were developed based on ovarian cancer cell lines OVCAR3 (CA125-positive) and SKOV3 (CA125 negative) in NIH-III mice. The radiopharmacological profile of (18)F-labeled scFv B43.13 ([(18)F]FBz-scFv-B43.13) was studied with PET. [(18)F]FBz-scFv-B43.13 was prepared in radiochemical yields of 3.7 +/- 1.8% (n = 5) at an effective specific activity of 3.88 +/- 0.76 GBq/umol (n = 5). The radiotracer demonstrated selective uptake in CA125-positive OVCAR3 cells and virtually no uptake in CA125 negative SKOV3 cells. Standardized uptake values (SUV) of radioactivity uptake in OVCAR3 tumors was 0.5 (n = 3) and 0.3 (n = 2) in SKOV3 tumors after 60 min post injection (p.i.). PMID- 27508106 TI - Development of a novel linearly-filled Derenzo microPET phantom. AB - Positron emission tomography (PET) phantoms are used to calibrate PET scanners so that inter-scanner and inter-isotope comparison can be made between PET datasets. Hot rod style phantoms have a hole pattern, which is filled with a positron emitting isotope and typically involves using two radioisotope reservoirs with the pattern created with channels in between. However, this configuration is difficult to fill and requires an excess of activity and volume. Here we present an alternative design, a phantom that is linearly filled-one channel at a time. The process of fabrication of prototypes of the design is described and PET images of the prototyped phantom are also shown for a variety of commonly used radioisotopes ((52)Mn, (64)Cu, (76)Br, (124)I). This design allows for a large reduction in isotope volume and required filling time making a quality assurance (QA) protocol safer, more efficient and less costly. PMID- 27508107 TI - Novel melanoma therapy. AB - With the rapid succession of new effective agents for melanoma in the recent years, the paradigm for treatment of metastatic melanoma is changing. The success of combining multiple effective agents compared with outcomes of monotherapy also brings increasing complexity in the treatment algorithm for various subsets of metastatic melanoma patients. We reviewed the recent reports on novel melanoma therapy to shed light on rational decision-making in treating these patients. PMID- 27508109 TI - Fundamental role of pan-inflammation and oxidative-nitrosative pathways in neuropathogenesis of Alzheimer's disease [Retraction]. AB - [This retracts the article on p. 1 in vol. 5, PMID: 27073740.]. PMID- 27508108 TI - Non-invasive urine testing of EGFR activating mutation and T790M resistance mutation in non-small cell lung cancer. AB - BACKGROUND: The increasing understanding of non-small cell lung cancer (NSCLC) biology over the last two decades has led to the identification of multiple molecular targets. This led to the development of multiple targeted therapies in the primary and secondary resistance setting and the epidermal growth factor receptor (EGFR) gene remains the most frequently observed molecular target in NSCLC. Tissue biopsies remain the standard for the identification of such EGFR mutations. Obtaining serial tissue biopsies, especially in the secondary resistance setting is associated with multiple medical and logistical challenges. Utilizing circulating tumor DNA (ctDNA) fragments for molecular analysis can overcome these challenges and aid in therapeutic decision-making. CASE PRESENTATION: Here we present a present a 72-year-old Korean woman with metastatic, EGFR L858R mutated bronchogenic adenocarcinoma. She developed skeletal progression on treatment with first and second generation tyrosine kinase inhibitors (TKIs). Repeated biopsies failed to provide informative molecular test results. A novel urine ctDNA assay was utilized and confirmed T790M positive status. The patient was started on a third generation TKI, which led to a measurable clinical response. CONCLUSIONS: Utilization of urine liquid biopsies for EGFR diagnostics are feasible and provided critical clinical information in this patient's case. Urine liquid biopsy represents a viable alternative to tissue biopsy, particularly in the secondary resistance setting, when tissue is not available for molecular testing. PMID- 27508110 TI - Omental transplantation in a patient with mild ALS. AB - To demonstrate that amyotrophic lateral sclerosis (ALS) is not a neurodegenerative disease. The patient, a 33-year-old man began with symptoms of the bulbar form of ALS, characterized by burning pain in both feet during two months and then, he presented right crural monoparesis, fasciculations, slight dysarthria and he walked with help of orthopedic devices. A preoperative MRI scans showed atherosclerosis at the V4 segment of the left vertebral artery. On May 2012, he received an omental transplantation on the anterior, left lateral and posterior surface of the medulla oblongata. About 48 hours after surgery, the dysarthria disappeared and the voluntary movement of the right foot improved. Three days later, he walked without aid of orthopedic device. At present, four years after operation he present complete reversal of symptoms. In conclusion, this patient confirms that bulbar ALS is of ischemic origin and therefore, mild ALS can be cured. PMID- 27508111 TI - Effect of probiotic and prebiotic fermented milk on skin and intestinal conditions in healthy young female students. AB - Although persistent constipation is considered to be associated with skin problems, the supporting evidence is limited. Hence, this study investigated the effects of probiotic and prebiotic fermented milk on skin and intestinal conditions in an open-label trial. Among the 101 Japanese healthy young female students that participated, the 81 subjects in the intake group consumed a bottle of probiotic and prebiotic fermented milk containing Bifidobacterium breve strain Yakult and galactooligosaccharides daily for 4 weeks after a pre-intake period of 4 weeks, while the 20 subjects in the non-intake group did not consume the test beverage. Defecation patterns, skin conditions including hydration levels in the stratum corneum, and urinary phenol and p-cresol levels were evaluated before (baseline) and after intake. All subjects completed the study. No differences in dietary intake and body mass index were observed between both groups during the trial. In the intake group, hydration levels of the stratum corneum, defecation frequency, and feces quantity significantly increased, and urinary phenol and p cresol levels significantly decreased after intake compared with the corresponding baseline values. However, they did not significantly change in the non-intake group. A significant difference was observed between the intake group and non-intake group in regard to clearness of the skin as assessed by visual analogue scale. Therefore, consecutive intake of probiotic and prebiotic fermented milk might have beneficial effects on the skin that prevent dryness and beneficial effects on the intestinal conditions that stimulate defecation and decrease phenol production by gut bacteria in healthy young women. PMID- 27508112 TI - The production of S-equol from daidzein is associated with a cluster of three genes in Eggerthella sp. YY7918. AB - Daidzein (DZN) is converted to equol (EQL) by intestinal bacteria. We previously reported that Eggerthella sp. YY7918, which is found in human feces, is an EQL producing bacterium and analyzed its whole genomic sequence. We found three coding sequences (CDSs) in this bacterium that showed 99% similarity to the EQL producing enzymes of Lactococcus sp. 20-92. These identified CDSs were designated eqlA, eqlB, and eqlC and thought to encode daidzein reductase (DZNR), dihydrodaidzein reductase (DHDR), and tetrahydrodaidzein reductase (THDR), respectively. These genes were cloned into pColdII. Recombinant plasmids were then introduced into Escherichia coli BL21 (DE3) and DZNR, DHDR, and THDR were expressed and purified by 6*His-Tag chromatography. We confirmed that these three enzymes were involved in the conversion of DZN to EQL. Purified DZNR converted DZN to dihydrodaizein (DHD) in the presence of NADPH. DHDR converted DHD to tetrahydrodaizein (THD) in the presence of NADPH. Neither enzyme showed activities with NADH. THDR converted THD in the absence of cofactors, NAD(P)H, and also produced DHD as a by-product. Thus, we propose that THDR is not a reductase but a new type of dismutase. The GC content of these clusters was 64%, similar to the overall genomic GC content for Eggerthella and Coriobacteriaceae (56-60%), and higher than that for Lactococcus garvieae (39%), even though the gene cluster showed 99% similarity to that in Lactococcus sp. 20-92. Taken together, our results indicate that the gene cluster associated with EQL production evolved in high-GC bacteria including Coriobacteriaceae and was then laterally transferred to Lactococcus sp. 20-92. PMID- 27508113 TI - Safety and long-term effect of the probiotic FK-23 in patients with hepatitis C virus infection. AB - A clinical trial was conducted on 39 adult HCV-positive subjects to determine the safety and long-term effect of the probiotic FK-23 (heat-treated Enterococcus faecalis strain FK-23). Asymptomatic anti-HCV positive adults who fulfilled the selection criteria and gave voluntary consent were recruited from attendees of the Hepatitis Carrier Clinic, Department of Medical Research (Lower Myanmar). Each subject was given 2,700 mg of FK-23 per day by oral route. Blood samples were taken at enrollment and every 3 months and tested for alanine aminotransferase (ALT) and aspartate transaminase (AST). Viral load, urea, total protein, hemoglobin and platelet count were determined every 6 months. Among the subjects, 23 completed 36 months, 31 completed 24 months, 35 completed 12 months and 37 completed 6 months of probiotic therapy. Significant decreases in mean ALT levels were observed at 3 months (34. 9 +/- 15.1 IU/l) as compared with the initial level (64.8 +/- 17.5 IU/l) and persisted up to 36 months (43.7 +/- 25.2 IU/l). Decrease of AST was detected after 9 months (46.2 +/- 21.7 IU/l) of probiotic therapy as compared with the initial level (64.3 +/- 28.7 IU/l). FK-23 was safe based on the stable levels of biochemical and hematological parameters and the absence of untoward side effects. The FK-23 preparation was well tolerated and accepted by the subjects. PMID- 27508114 TI - Effect of consuming a purple-fleshed sweet potato beverage on health-related biomarkers and safety parameters in Caucasian subjects with elevated levels of blood pressure and liver function biomarkers: a 4-week, open-label, non comparative trial. AB - An open-label study with one treatment arm was conducted to investigate changes in health-related biomarkers (blood pressure and liver enzyme activity) and the safety of 4 weeks of consuming a purple-fleshed sweet potato beverage in Caucasian subjects. Twenty healthy adults, 18-70 years of age, with a body mass index >25 kg/m(2), elevated blood pressure and elevated levels of liver function biomarkers consumed two cartons of purple-fleshed sweet potato beverage (125 ml, including 117 mg anthocyanin per carton) daily for 4 weeks. Hematology, serum clinical profile, dipstick urinalysis and blood pressure were determined before consumption, at 2 and 4 weeks of consumption and after a 2-week washout period. A trend was found toward lowering systolic blood pressure during the treatment period (p=0.0590). No significant changes were found in diastolic blood pressure throughout the study period. Systolic blood pressure was significantly lower after 4 weeks of consumption compared with before consumption (p=0.0125) and was significantly higher after the 2-week washout period compared with after consumption (p=0.0496). The serum alanine aminotransferase level significantly increased over time, but aspartate aminotransferase and gamma-glutamyltransferase levels stayed within the normal range of reference values. Safety parameters of the blood and urine showed no clinically relevant changes. The consumption of a purple-fleshed sweet potato beverage for 4 weeks resulted in no clinically relevant changes in safety parameters of the blood and urine and showed a trend toward lowering systolic blood pressure. PMID- 27508115 TI - Protective effects of heat-killed Lactococcus lactis subsp. lactis BF3, isolated from the intestine of chum salmon, in a murine model of DSS-induced inflammatory bowel disease. AB - Oxidative stress is considered an etiological factor responsible for several symptoms of inflammatory bowel disease (IBD). In vitro anti-inflammatory activities of heat-killed Lactococcus lactis subsp. lactis BF3 have been reported. In this study, the anti-inflammatory effect of these cells was examined using a dextran sodium sulphate (DSS)-induced murine IBD model. Administration of heat-killed L. lactis BF3 via drinking water suppressed the IBD symptoms, such as shortening of colon length, damage to the colon mucosa as observed under the microscope, and spleen enlargement. This result suggests that heat-killed L. lactis BF3 has the potential to treat IBD. PMID- 27508116 TI - Effect of repeated oral administration of Bifidobacterium longum BB536 on apomorphine-induced rearing behavior in mice. AB - Schizophrenia is a chronic psychiatric illness. Disruption of the dopaminergic system has been suggested to be the pathogenic cause of this disease. The effect of Bifidobacterium longum BB536 (BB536) on schizophrenic behavior was investigated in an animal model. Daily administration of BB536 (10(9) CFU/mouse, p.o. for 2 weeks) was found to reduce rearing behavior augmented by the dopamine receptor agonist apomorphine and to decrease the resting level of plasma corticosterone and the ratio of kynurenine to tryptophan. These results suggest the potential of BB536 for supplemental treatment of the symptoms of schizophrenia. PMID- 27508117 TI - Ectoparasitism on deep-sea fishes in the western North Atlantic: In situ observations from ROV surveys. AB - A complete understanding of how parasites influence marine ecosystem functioning requires characterizing a broad range of parasite-host interactions while determining the effects of parasitism in a variety of habitats. In deep-sea fishes, the prevalence of parasitism remains poorly understood. Knowledge of ectoparasitism, in particular, is limited because collection methods often cause dislodgment of ectoparasites from their hosts. High-definition video collected during 43 remotely operated vehicle surveys (2013-2014) provided the opportunity to examine ectoparasitism on fishes across habitats (open slope, canyon, seamount, cold seep) and depths (494-4689 m) off the northeastern U.S., while providing high-resolution images and valuable observations of fish behavior. Only 9% (n = 125 individuals) of all observed fishes (25 species) were confirmed with ectoparasites, but higher percentages (~33%) were observed for some of the most abundant fish species (e.g., Antimora rostrata). Ectoparasites included two copepod families (Lernaeopodidae, Sphyriidae) that infected four host species, two isopod families (Cymothoidae, Aegidae) that infected three host species, and one isopod family (Gnathiidae) that infected 19 host species. Hyperparasitism was also observed. As host diversity declined with depth, ectoparasite diversity declined; only gnathiids were observed at depths down to 3260 m. Thus, gnathiids appear to be the most successful group to infect a diversity of fishes across a broad depth range in the deep sea. For three dominant fishes (A. rostrata, Nezumia bairdii, Synaphobranchus spp.), the abundance and intensity of ectoparasitism peaked in different depths and habitats depending on the host species examined. Notably, gnathiid infections were most intense on A. rostrata, particularly in submarine canyons, suggesting that these habitats may increase ectoparasite infections. Although ectoparasitism is often overlooked in deep-sea benthic communities, our results demonstrate that it occurs widely across a variety of habitats, depths, and locations and is a significant component of deep sea biodiversity. PMID- 27508118 TI - Haemosporidian parasite infections in grouse and ptarmigan: Prevalence and genetic diversity of blood parasites in resident Alaskan birds. AB - Projections related to future climate warming indicate the potential for an increase in the distribution and prevalence of blood parasites in northern regions. However, baseline data are lacking for resident avian host species in Alaska. Grouse and ptarmigan occupy a diverse range of habitat types throughout the northern hemisphere and are among the most well-known and important native game birds in North America. Information regarding the prevalence and diversity of haemosporidian parasites in tetraonid species is limited, with few recent studies and an almost complete lack of genetic data. To better understand the genetic diversity of haemosporidian parasites in Alaskan tetraonids and to determine current patterns of geographic range and host specificity, we used molecular methods to screen 459 tissue samples collected from grouse and ptarmigan species across multiple regions of Alaska for infection by Leucocytozoon, Haemoproteus, and Plasmodium blood parasites. Infections were detected in 342 individuals, with overall apparent prevalence of 53% for Leucocytozoon, 21% for Haemoproteus, and 9% for Plasmodium. Parasite prevalence varied by region, with different patterns observed between species groups (grouse versus ptarmigan). Leucocytozoon was more common in ptarmigan, whereas Haemoproteus was more common in grouse. We detected Plasmodium infections in grouse only. Analysis of haemosporidian mitochondrial DNA cytochrome b sequences revealed 23 unique parasite haplotypes, several of which were identical to lineages previously detected in other avian hosts. Phylogenetic analysis showed close relationships between haplotypes from our study and those identified in Alaskan waterfowl for Haemoproteus and Plasmodium parasites. In contrast, Leucocytozoon lineages were structured strongly by host family. Our results provide some of the first genetic data for haemosporidians in grouse and ptarmigan species, and provide an initial baseline on the prevalence and diversity of blood parasites in a group of northern host species. PMID- 27508119 TI - Draft genome sequence of Staphylococcus aureus KT/312045, an ST1-MSSA PVL positive isolated from pus sample in East Coast Malaysia. AB - Most of the efforts in elucidating the molecular relatedness and epidemiology of Staphylococcus aureus in Malaysia have been largely focused on methicillin resistant S. aureus (MRSA). Therefore, here we report the draft genome sequence of the methicillin-susceptible Staphylococcus aureus (MSSA) with sequence type 1 (ST1), spa type t127 with Panton-Valentine Leukocidin (pvl) pathogenic determinant isolated from pus sample designated as KT/314250 strain. The size of the draft genome is 2.86 Mbp with 32.7% of G + C content consisting 2673 coding sequences. The draft genome sequence has been deposited in DDBJ/EMBL/GenBank under the accession number AOCP00000000. PMID- 27508120 TI - Characterization of the replication timing program of 6 human model cell lines. AB - During the S-phase, the DNA replication process is finely orchestrated and regulated by two programs: the spatial program that determines where replication will start in the genome (Cadoret et al. (2008 Oct 14), Cayrou et al. (2011 Sep), Picard et al. (2014 May 1) [1], [2], [3]), and the temporal program that determines when during the S phase different parts of the genome are replicated and when origins are activated. The temporal program is so well conserved for each cell type from independent individuals [4] that it is possible to identify a cell type from an unknown sample just by determining its replication timing program. Moreover, replicative domains are strongly correlated with the partition of the genome into topological domains (determined by the Hi-C method, Lieberman Aiden et al. (2009 Oct 9), Pope et al. (2014 Nov 20) [5], [6]). On the one hand, replicative areas are well defined and participate in shaping the spatial organization of the genome for a given cell type. On the other hand, studies on the timing program during cell differentiation showed a certain plasticity of this program according to the stage of cell differentiation Hiratani et al. (2008 Oct 7, 2010 Feb) [7], [8]. Domains where a replication timing change was observed went through a nuclear re-localization. Thus the temporal program of replication can be considered as an epigenetic mark Hiratani and Gilbert (2009 Feb 16) [9]. We present the genomic data of replication timing in 6 human model cell lines: U2OS (GSM2111308), RKO (GSM2111309), HEK 293T (GSM2111310), HeLa (GSM2111311), MRC5-SV (GSM2111312) and K562 (GSM2111313). A short comparative analysis was performed that allowed us to define regions common to the 6 cell lines. These replication timing data can be taken into account when performing studies that use these model cell lines. PMID- 27508121 TI - Metagenomic analysis of fungal taxa inhabiting Mecca region, Saudi Arabia. AB - The data presented contains the sequences of fungal Internal Transcribed Spacer (ITS) and 18S rRNA gene from a metagenome of the Mecca region, Saudi Arabia. Sequences were amplified using fungal specific primers, which amplified the amplicon aligned between the 18S and 28S rRNA genes. A total of 460 fungal species belonging to 133 genera, 58 families, 33 orders, 13 classes and 4 phyla were identified in four contrasting locations. The raw sequencing data used to perform this analysis along with FASTQ file are located in the NCBI Sequence Read Archive (SRA) under accession numbers: SRR3150823, SRR3144873, SRR3150825 and SRR3150846. PMID- 27508122 TI - The draft genome sequence of Mangrovibacter sp. strain MP23, an endophyte isolated from the roots of Phragmites karka. AB - Till date, only one draft genome has been reported within the genus Mangrovibacter. Here, we report the second draft genome shotgun sequence of a Mangrovibacter sp. strain MP23 that was isolated from the roots of Phargmites karka (P. karka), an invasive weed growing in the Chilika Lagoon, Odisha, India. Strain MP23 is a facultative anaerobic, nitrogen-fixing endophytic bacteria that grows optimally at 37 degrees C, 7.0 pH, and 1% NaCl concentration. The draft genome sequence of strain MP23 contains 4,947,475 bp with an estimated G + C content of 49.9% and total 4392 protein coding genes. The genome sequence has provided information on putative genes that code for proteins involved in oxidative stress, uptake of nutrients, and nitrogen fixation that might offer niche specific ecological fitness and explain the invasive success of P. karka in Chilika Lagoon. The draft genome sequence and annotation have been deposited at DDBJ/EMBL/GenBank under the accession number LYRP00000000. PMID- 27508123 TI - Context based computational analysis and characterization of ARS consensus sequences (ACS) of Saccharomyces cerevisiae genome. AB - Genome-wide experimental studies in Saccharomyces cerevisiae reveal that autonomous replicating sequence (ARS) requires an essential consensus sequence (ACS) for replication activity. Computational studies identified thousands of ACS like patterns in the genome. However, only a few hundreds of these sites act as replicating sites and the rest are considered as dormant or evolving sites. In a bid to understand the sequence makeup of replication sites, a content and context based analysis was performed on a set of replicating ACS sequences that binds to origin-recognition complex (ORC) denoted as ORC-ACS and non-replicating ACS sequences (nrACS), that are not bound by ORC. In this study, DNA properties such as base composition, correlation, sequence dependent thermodynamic and DNA structural profiles, and their positions have been considered for characterizing ORC-ACS and nrACS. Analysis reveals that ORC-ACS depict marked differences in nucleotide composition and context features in its vicinity compared to nrACS. Interestingly, an A-rich motif was also discovered in ORC-ACS sequences within its nucleosome-free region. Profound changes in the conformational features, such as DNA helical twist, inclination angle and stacking energy between ORC-ACS and nrACS were observed. Distribution of ACS motifs in the non-coding segments points to the locations of ORC-ACS which are found far away from the adjacent gene start position compared to nrACS thereby enabling an accessible environment for ORC proteins. Our attempt is novel in considering the contextual view of ACS and its flanking region along with nucleosome positioning in the S. cerevisiae genome and may be useful for any computational prediction scheme. PMID- 27508124 TI - Endoscopic Excision of Non-embolized Juvenile Nasopharyngeal Angiofibroma: Our Technique. AB - To approach Juvenile nasopharyngeal angiofibroma extending to the sphenoid sinus, pterygoid wedge and minimal involvement of the pterygopalatine fossa (Radkowski Stage 2 A) with an endoscopic technique without embolization with no recurrence and minimal morbidity and mortality. This is a retrospective, descriptive study based on the medical records of 15 patients with histologically confirmed JNA who underwent endoscopic binostril four handed endoscopic excision in our centre without embolisation between 2010 and 2015. All 15 patients were young males with a mean age of 14.13 years who underwent endoscopic excision of JNA without embolisation. Nasal obstruction (100 %) and epistaxis (100 %) were the most common symptoms. Average surgery length was 1 h 41 min. Mean blood loss was 67.2 ml and none of patients required blood transfusion. All patients had crusting and septal defect postoperatively, only 3 (20 %) had synechiae. Mean hospitalization time was 3.66 days. 2 (13.33 %) of our patients had a residual tumor and one (6.66 %) had a relapse in pterygoid wedge. There were no cases of death or significant morbidity. The follow up period was 1 year. Endoscopic endo nasal bi nostril four handed technique can achieve complete resection without embolization in case of small to medium sized JNA s in the hands of an experienced surgeon with minimal blood loss, low rates of recurrence and morbidity. PMID- 27508125 TI - Presentations and Challenges in Tuberculosis of Head and Neck Region. AB - (1) To study the different patterns of presentations of tuberculosis in Head and Neck region. (2) To know the importance and reliability of ESR and Mantoux test as an aid in diagnosis of tuberculosis. This study was conducted at Department of ENT and Head and Neck Surgery, Gandhi Medical College, Bhopal, Madhya Pradesh from January 2014 to June 2015. Patients presenting with lesions in the Head and Neck region suspected of tuberculosis were subjected for cytological and histological investigations. Those cases confirmed to be tuberculosis on the basis of either of these tests were included in the study. Study comprised of 113 proven cases of tuberculosis of Head and Neck region. A female preponderance of 1:1.97 (M:F) ratio was noted. Most commonly involved structure was cervical lymph node (92.92 %) followed by larynx, skin and oral mucosa (1.76 %). It was also noted that Mantoux test was positive in 93.8 % of patients and ESR was >30 mm (first hour) in 95.5 % of patients with tuberculosis. Most common presentation of Tuberculosis in Head and Neck area was cervical lymphadenopathy. In a developing country like India the population is mostly in the lower socioeconomic strata. Access to various modern investigations is limited and diagnosis is challenging. Here ESR and Mantoux test are helpful in purusing the case for further evaluation. Based on these pointers cytologically negative cases can be taken up for biopsy. PMID- 27508126 TI - Comparative Study of Improvement of Nasal Symptoms Following Septoplasty with Partial Inferior Turbinectomy Versus Septoplasty Alone in Adults by NOSE Scale: A Prospective Study. AB - To compare the symptomatic improvement of nasal symptoms following septoplasty with partial inferior turbinectomy (groups A) versus septoplasty alone (groups B) and to assess the improvement of nasal symptoms in both surgical groups before and after surgery by NOSE scale. This Tertiary Hospital based study was carried out between August 2012 and April 2014. 60 cases with septal deviation and contralateral inferior turbinate hypertrophy. Nasal Obstruction Symptom Evaluation (NOSE) scale for evaluating nasal symptoms. Patients were alternatively divided into two surgical groups, group A. Septoplasty with partial inferior turbinectomy and group B septoplasty alone. Post-operative patient's symptoms evaluated by NOSE scale at 1, 3 and 6 months. Data analysed using tables, graph and percentage and test of significance like paired t test, Friedman test, Chi square test used. Post operative improvement following both group A septoplasty with partial inferior turbinectomy and group B in those undergoing septoplasty alone was highly significant (p < 0.001) at post-op 1, 3 and 6 months subjectively. When both groups were compared those undergoing partial inferior turbinectomy surgery with septoplasty had highly significant results (p < 0.001) for subjective assessment by NOSE scale. This study showed that hypertrophied turbinate need to be addressed in chronic cases of nasal obstruction with deviated nasal septum and contralateral turbinate hypertrophy. partial inferior turbinectomy should be done in addition to septoplasty, its highly effective modality for the treatment of nasal obstruction in patients with deviated nasal septum. NOSE score can be used as a subjective tool for symptomatic measurement of patients with nasal obstruction. PMID- 27508127 TI - An Innovative Operative Method for Correction of Tracheal Stenosis. AB - This is a case of failed attempt of hanging, resulted into cervical injury & injury to the trachea. Patient was put on the ventilator for respiratory support for long period. Poor recovery of the patient resulted into prolong tracheostomy tube. Combine effect of all resulted into suprastomal tracheal stenosis. Due to complexity of the problem a novel method was customized to correct the tracheal stenosis. Strap muscle (Sternohyoid & Sternothyroid) was raised as a flap; free cartilage was sandwiched in between and sutured to the created tracheal defect. Bovine collagen was placed over a stent and placed in the tracheal lumen. Good result was achieved post operatively in the form of adequate lumen, rigid anterior wall during respiration, good mucosal lining without fibrosis and normal speech. PMID- 27508128 TI - Effect of Septoplasty on Cepstral Analysis of Voice. AB - Resonance change is a common clinical symptom in individuals with deviated nasal septum. Often this anatomical deficit is surgically treated by septoplasty. Therefore monitoring resonance changes using acoustical tools is vital. Hence, the study investigated cepstral measure differences in subjects with deviated nasal septum compared to normals. A case-control study design involving 20 subjects within 18-40 years divided into Group I of 10 subjects with deviated nasal septum (DNS) and Group II of 10 normal subjects participated. All the subjects sustained nasalized vowel /a/ at 10 cm mouth-microphone distance for minimum of 5 seconds. For Group I, voice sample was recorded in 2 conditions, 2 days pre-septoplasty and 1 month post-septoplasty. Cepstral peak prominence (CPP) and smooth cepstral peak prominence (CPPS) values was extracted using the Hillenbrand algorithm. Mean values revealed increased CPP and CPPS measure post septoplasty when compared to pre-septoplasty. ANOVA showed statistically significant difference only for CPPS at p = 0.00. The higher cepstral values of post-septoplasty is due to widened nasal passage that leads to increased nasal volume, decreased acoustic damping and increased nasal patency. These changes in supraglottic chambers will result in a better acoustic space for good resonance. However, the CPPS values were not similar to normal subjects because of scarring or incomplete recovery of the outer mucosal layer of the nasal tract. Thus, we can conclude that cepstral analysis is a sensitive tool to detect resonance changes in the nasal patency. PMID- 27508129 TI - Challenges in the Management of Laryngeal Stenosis. AB - Laryngeal stenosis is one of the most complex and challenging problems in the field of head and neck surgery. The management involves a multidisciplinary approach with multiple complex procedures. In this study we discuss our experience of laryngeal stenosis with regards to patient characteristics, cause and management. A retrospective analysis of 35 patients of laryngeal stenosis treated at a tertiary care centre was evaluated. Inclusion criteria were all patients with laryngeal stenosis who required surgical intervention. Exclusion criteria were patients with associated tracheal stenosis and laryngeal stenosis due to cancer. Demographic data was recorded and findings relating to aetiology, characteristics of stenosis and the various aspects of therapeutic procedures performed are discussed with review of literature. Among 35 patients, 24 were males and 11 females of the age group 2-79 years. 2 (5.7 %) patients had supraglottic stenosis, 11 (31.4 %) had glottis stenosis, 16 (45.7 %) had subglottic stenosis and 6 (17.1 %) had combined multiple sites stenosis. Each patient underwent an average of 3.22 surgical procedures like microlaryngoscopy and excision with cold instrument, CO2 laser excision or open procedures like laryngofissure and excision and laryngoplasty. Montgomery t tube insertion was a common procedure in 17 patients (48.6 %). Of the total 35 patients with severe LS, 27 (77.1 %) patients were successfully decanulated. The results of glottic (100 %) and supraglottic stenosis (100 %) are excellent as compared to subglottic (68.8 %) and combined stenosis (50 %) of multiple sites. Laryngeal stenosis with airway compromise causes significant morbidity to the patients and is a difficult condition to treat in both adult and pediatric population. The need for multiple surgical procedures is common in the treatment of laryngeal stenosis with the t tube being an important aid in the management of this condition. Trauma especially post intubation trauma is the commonest cause of laryngeal stenosis and the involvement of subglottis has poor outcome as compared to other subsites. PMID- 27508130 TI - Functional Endoscopic Sinus Surgery Versus Balloon Sinuplasty with Ethmoidectomy: A 2-year Analysis in Pediatric Chronic Rhinosinusitis. AB - To evaluate the 2-year post-operative outcomes of pediatric patients with chronic rhinosinusitis (CRS) treated with balloon catheter sinuplasty (BCS) and ethmoidectomy compared to functional endoscopic sinus surgery (FESS). Two-group, retrospective cohort study of 28 children with CRS was performed. Of these 28 participants, 15 were treated with traditional FESS (53.6 %) and 13 (46.4 %) underwent traditional ethmoidectomy with balloon sinuplasty. Pre-operative and 2 year postoperative total symptom scores and medications were compared. To examine the potential long-term differences in surgical outcomes and surgical procedure on symptom outcome, one-tailed Chi square analyses were employed. The mean age of the children examined was 9.3 (SD = SD = 4.1; range 3-18) and 61.9 % were male. Pre-operative symptomatology, medication and Lund Mackay scores were evaluated for both groups and no significant differences were identified. Overall, 73.3 % of children that underwent traditional FESS and 76.9 % of those who had BCS with ethmoidectomy reported significant long-term improvement in at least one of their pre-operative sinus complaints. Our data suggests that both BCS with ethmoidectomy and traditional FESS are effective treatment options for uncomplicated CRS and result in long-term alleviation of core sinus complaints, as well as decreased sinus related medication use. Larger prospective studies are needed to further evaluate these procedures. PMID- 27508131 TI - Middle and Lower Face Soft Tissue Reconstruction: A 10-Year Retrospective Study. AB - Retrospectively analyze the reconstruction methods and surgical outcomes of patients with middle and lower face soft tissue defects treated at our hospital over the past 10 years. 200 patients with middle and lower face soft tissue defects were surgically reconstructed at our hospital. Medical charts were retrospectively reviewed and analyzed to abstract the pertinent information. The lesion was mainly at the eyelid, lips, chin and nasal-cheek region. There were 41 (63.08 %) men and 24 (36.92 %) women. In our study, male to female ratio = 1.7:1. We used direct closure for night patients, local flap for 141 patients, free flap for 38 patients, combined flap for 12 patients involving extensive mid face and lower face defects. Most patients had their tumor resected and reconstructed in single stage procedure mostly with local advancement flap, and no flap failure was presented post-operatively. Middle and lower face soft tissue defects can be successfully treated with local flap in a single stage approach and step-by-step approach. PMID- 27508132 TI - Questionable Necessity for Removing Submandibular Gland in Neck Dissection in Squamous Cell Carcinoma of Oral Cavity. AB - To assess whether submandibular gland is involved by metastasis in cases of oral cavity squamous cell carcinomas. It was a retrospective study, where we reviewed the records of the patients who underwent neck dissections for Squamous Cell Carcinoma of the oral cavity. It included 112 patients who had undergone 115 neck dissections (three patients had undergone bilateral neck dissection), either therapeutic or prophylactic. No pathologic evidence of metastasis to submandibular gland was seen in any of the case. Preservation of submandibular glands can be a good technique for reducing future complications in a patient undergoing Neck Dissection wherever feasible. Therefore, if there is no need to expose large oral cavity tumors through the submandibular triangle, or when there is no direct extension of the primary and/or regional lymph nodes into the submandibular gland, it may be safe to preserve the submandibular gland. PMID- 27508133 TI - Challenges During Baha Surgery: Our Experience. AB - Baha has proven performance and advantages for patients with aural atresia or chronic ear drainage. Being a per cutaneous osseo integrated implant the skin around the fixture is in contact with a foreign body that leads to chronic inflammatory reaction and complications such as skin irritation and overgrowth occur frequently. Challenges that are faced during Baha surgery include those during candidate selection, work up, anesthesia related as well as intra operative and post operative complications. Ours was a retrospective and observational study where case records of 10 patients who underwent Baha surgery in the Department of E.N.T during the time period from January 2010 to June 2013 were reviewed. Here, the candidates were advised Baha either for congenital external ear deformity or single sided deafness. Out of 10 patients, who underwent Baha implantation, 8 underwent single staged Baha implant and two patients had two staged implant owing to bone thickness <3 mm behind temporo parietal suture line on HRCT Temporal bone. The complications observed were skin infection (Holgers grade 2) around the site of implant in two patients, skin overgrowth due to more thickness of scalp (Holgers grade 4) in one of the patient. The patient had to undergo revision surgery to replace the abutment. And one of the patients underwent failure of osseointegration and was re-implanted later. Proper surgical technique and post operative wound care play an important role in avoiding complications. PMID- 27508135 TI - Comparative Study of Apo-Cetirizine Single Therapy and Intermittent Sequential Therapy with Cetirizine, Loratadine and Chlorpheniramine in Allergic Rhinitis. AB - There are limited numbers of articles, studying combined use of antihistamines. In this study, we compare single therapy of Apo-Cetirizine with a new regimen of intermittent sequential therapy with cetirizine, loratadine and chlorpheniramine in treatment of seasonal allergic rhinitis. This randomized clinical trial was performed between April and September at the peak prevalence of seasonal allergic rhinitis. Fifty-four eligible patients diagnosed clinically to have seasonal allergic rhinitis were randomized in two groups: 24 cases in single therapy arm, received Apo-Cetirizine 10 mg tablet daily and in other arm, 30 patients received sequential regimen of cetirizine 10 mg tablet, loratadine 10 mg tablet and chlorpheniramine 4 mg tablet, one tablet each day. Major Symptom Complex Score (MSCS) and Total Symptom Complex Score (TSCS) of patients were recorded before treatment and after 30 days of treatment in two groups. The average post treatment MSCS and TSCS in combination therapy group showed better improvement than single therapy group but difference was not statistically significant (p value = 0.053 and p value = 0.104 respectively). Combination therapy regimen was better in improvement of nasal congestion (p value = 0.006). There were no significant difference between two groups in efficacy, side effects and patient's satisfaction. Combination therapy would be effective on a wide spectrum of symptoms with lower price and theoretically offers lower chance of tolerance and re-appearance of complaints. PMID- 27508134 TI - Uses of Various Grafting Techniques in External Approach Rhinoplasty: An Overview. AB - The surgeons performing rhinoplasty found Graft selection the greatest challenge. To avoid an immune response the preferred choice thus far for nasal reconstruction would be autograft compared to allograft due to its lower rate of rejection. We have evaluated 30 patients who underwent open rhinoplasty and We used conchal and septal cartilaginous grafts in various forms by the open approach to correct various nasal deformities compared our experience regarding the operative technique, graft availability, indications, and limitations. No bony graft material or synthetic materials were used. Preoperative extensive evaluation of the patient was done in order to determine the type of deformity and the type of graft to be used in order to correct the deformity. Preoperative and postoperative photographs were taken in four basic views: frontal, lateral, lateral-oblique and basal in order to assess the results of the surgery. The study was done on 30 patients (20 male and 10 females) using the external rhinoplasty approach using the septal and conchal cartilages in different forms. Autologous septal cartilage was used in most of the patients (25 out of 30) and conchal cartilage was used in 5 patients. Multiple grafting techniques were used in some patients. Three patients had traumatic etiology. Columellar strut graft along with TIG technique was used in 16 patients, spreader graft was used in 8 patients, and septal extension graft was used in 5 patient and shield graft in 1 patient. Septorhinoplasty continues to evolve through various new techniques and modifications with the main goal to improve functional nasal airway and to restore cosmetic harmony to the face. Optimum result is very much dependent on the surgeon's attention to functional, aesthetic, and reconstructive principles and graft selection. PMID- 27508136 TI - Brainstem Evoked Response Audiometry (BERA) in Neonates with Hyperbillirubinemia. AB - (1) To study the BERA changes in neonates with unconjugated hyperbilirubinemia. (2) To compare the BERA changes in the neonates with unconjugated hyperbilirubinemia before and after therapy. Thirty consecutive term appropriate for gestational age (AGA) neonates presenting to NICU with total serum bilirubin requiring intervention (using the American Academy of Pediatrics guidelines) were included in the study as cases and thirty normal term AGA neonates with uneventful peri-natal period and a maximum measured serum bilirubin <12 mg/dl in case of term baby were included as controls after obtaining informed consent. Initial BERA was done within 3-24 h of hospitalization after obtaining informed consent from parents, at the time of discharge and at 3 month followup. Machine used for recording BERA was intelligent hearing system version 3.3. In our study out of the 30 cases 10 (33.3 %) cases were found to have BERA changes in the form of absent wave forms, raised threshold, prolonged latencies or prolonged inter peak latencies. In our study, it was observed that there was statistically significant correlation (p value < 0.005) between increasing bilirubin level and BERA changes. Correlation of the findings of this study with previous few studies indicates that BERA can be used as a useful non invasive tool to determine auditory functions in the neonate especially changes of early bilirubin toxicity. PMID- 27508137 TI - Boomerang-Shaped Chondro-Perichondral Graft Versus Temporalis Muscle Fascia Graft: Which One is to be Trusted? AB - The aim of this study was to compare anatomical and audiological results of boomerang-shaped chondroperichondrial graft (BSCPG) with temporal muscle fascia in type 1 tympanoplasties. Sixty-eight patients in BSCPG group and 54 patients in fascia group were evaluated. Otomicroscopic examination was done periodically till 24 months as for graft perforation, lateralization and retraction and mean air conduction threshold and airbone gap values were measured. At long term controls, in BSCPG group, rates of neomembrane, perforation, retraction and lateralization were 91.17 % (n = 62), 8.82 % (n = 6), 4.41 % (n = 3) and 0 % (n = 0), respectively. In fascia group, the corresponding rates were 79.62 % (n = 43), 20.37 % (n = 11), 12.96 % (n = 7) and 3.7 % (n = 2), respectively. In both groups, mean postoperative PTA and ABG values were significantly better while postoperative same values were significantly different between groups (p = 0.044 and 0.032, respectively). Compared to fascia, BSCPG is an ideal grafting technique in the repair of tympanic membrane perforations. PMID- 27508138 TI - Cervical Node Tuberculosis in Adults of an Urban Middle Class Community: Incidence and Management. AB - The aim of this study is to estimate the incidence of cervical node tuberculosis (TB) in an urban middle class population and to describe an effective protocol for management of cervical lymphadenopathy. The present study is a prospective observational study conducted over two years (2007-2009) in a community hospital in Mumbai, India. All adults (age >=14 years) presenting with cervical lymphadenopathy, not resolving were included and their details of history and examination were noted. All patients were subjected to fine needle aspiration cytology (FNAC) and biopsy was done selectively as indicated. The response at 1, 3 and 6 months of starting anti tuberculous treatment (ATT) were noted. A total of 191 patients were included in this study. The mean age was 41 years and male to female ratio was 1:1.1 in patients with cervical lymphadenopathy. A history of contact with a patient of TB was the most significantly associated history seen in patients diagnosed to have TB of cervical nodes (p < 0.001). TB (38.7%) followed by reactive nodes (37.6%) were the most common etiologies. A 90.6% response rate was seen in patients taking 6 months ATT for cervical node TB. The incidence of adult (>=14 years) cervical node TB was 52/100,000 people in an urban middle class community in Mumbai. A single swelling in the neck without other associated symptoms or signs was the commonest mode of presentation of TB of the neck nodes. A history of contact with TB, demonstrated an association with the final diagnosis of tuberculous lymphadenopathy. PMID- 27508139 TI - Sinonasal Anatomical Variants: CT and Endoscopy Study and Its Correlation with Extent of Disease. AB - To evaluate the incidence of anatomical variations in sinonasal area by nasal endoscopy and CT scan paranasal sinuses and to correlate the anatomical variations in sinonasal area with extent of disease. The present study was conducted on 40 patients of chronic sinusitis. All the patients underwent CT scan paranasal sinus axial and coronal view and nasal endoscopy. The most common anatomical variations were agger nasi cells (80 %), deviated nasal septum (72.5 %) and concha bullosa (47.5 %). Other anatomical variations seen in sinonasal region were uncinate process variations, paradoxical middle turbinate, haller cells, accessory ostia of maxillary sinus, multiseptated sphenoid. Osteomeatal unit (87.5 %) and maxillary sinuses (87.5 %) were the most commonly involved which was followed by anterior ethmoids (70 %), posterior ethmoids (50 %), frontal sinuses (32.5 %) and the sphenoids (20 %). Considering the results obtained, we believe that anatomical variations may increase the risk of sinus mucosal disease. We therefore, emphasize the importance of a careful evaluation of CT study in patients with persistent symptoms of chronic rhinosinusitis. PMID- 27508140 TI - Clinical Predictors of Streptomycin-Vestibulotoxicity. AB - The Global tuberculosis control is challenged with a growing resistance to antitubercular treatment (ATT) culminating in resistant (MDR/XDR) strains; an important factor being premature withdrawal of streptomycin owing to its morbidity particularly nephrotoxicity and cochleotoxicity as guidelines for their prevention exist. An attempt is made here to address the least recognized and most debilitating vestibular toxic effects of streptomycin and defining a vestibular-protocol for its early detection and progression. Thirty two prospective patients (treatment-failures, relapse and default cases) undergoing ATT (24 shots of IM streptomycin 15-20 mg/kg over 8 weeks) underwent complete vestibular workup including vestibulo-ocular and vestibulo-spinal reflex assessment with an attempt to closely follow them. Four categories (I: No-, II: Occult-, III: Delayed-Manifest- and IV: Manifest-vestibulotoxicity) were defined. The DHI and casual gait abnormality clearly differentiated III/IV from I/II. The occilopsia and head thrust tests significantly differentiated II from I. Rotation and bithermal calorics significantly differentiated I from II and II from III/IV. The Fukuda, Rhomberg, Tandem-Rhomberg and CTSIB were significant in differentiating I from II and II from III/IV. Dix-Hallpike and Positional tests were of no significance in the entire study. The Occilopsia and Head-Thrust tests that showed 100 % positivity for II to IV are more likely to better predict 'manifest' or 'occult' -vestibulotoxicity while DHI and casual gait assessment may be carried out by a paramedic at a peripheral center to suspect vestibulotoxicity. Since we found absolute compliance with our series we feel that vestibulotoxicity may not be a deciding factor for termination of streptomycin provided an in-built mechanism for patient support/counseling be incorporated in management schedule. PMID- 27508141 TI - An Intriguing Case of Ectasia of External Jugular Vein Presenting as Intermittent Neck Mass. AB - Ectasia of external jugular vein is a rare entity presenting as an intermittent neck swelling. High index of suspicion is required to diagnose the condition. Ultrasonography with Doppler before, during and after valsalva manoeuvre is the preferred method for diagnosis. The treatment is conservative for asymptomatic patients and surgery is reserved for patients with complications. PMID- 27508142 TI - Adenoid Cystic Carcinoma of Buccal Mucosa: A Rare Case Report. AB - Adenoid cystic carcinoma is a malignant neoplasm most commonly originating in salivary glands of head and neck region. Among intra oral adenoid cystic carcinoma, buccal mucosa is among the rarest sites. We report a case of adenoid cystic of buccal mucosa in a 40-year old female. We have discussed the clinical features, histopathology, diagnosis and treatment along with a brief review of the relevant literature. Although the buccal mucosa is an uncommon site for adenoid cystic carcinoma, the relatively indolent growth pattern of this case and its location which is rather atypical for this type of salivary gland malignancy primarily warrants the necessity behind reporting of this case. Secondly, adenoid cystic carcinoma should be considered in the differential diagnosis of mass of buccal mucosa. It is important to identify such cases rather early and surgical removal with adequate margins is the treatment of choice . PMID- 27508143 TI - Metastatic Renal Cell Carcinoma Presenting as Nasal Mass: Case Report and Review of Literature. AB - Sinonasal neoplasms are rare and exceptional site for metastatic tumours and comprising <3 % of all malignant aerodigestive tumours and <1 % of all malignancies. Renal cell carcinoma is known to metastasise to the most unusual sites, the sinonasal region being one of them. We here by present a case of 60 year old male patient who presented with epistaxis and nasal obstruction. Clinical examination and CT scan revealed a tumour in the right nasal cavity and maxillary sinus. The presence of primary renal cell carcinoma was recognized only after surgical removal of metastatic tumour. Very few reports have been presented in literature of metastatic renal cell carcinoma in the sinonasal region. We present this case to document its occurrence; highlight the rarity, presentation and difficulties in diagnosis and treatment along with review of literature. PMID- 27508144 TI - Leiomyoma of External Auditory Canal. AB - This article reports a case of piloleiomyoma of external auditory canal, which is the 7th case of leiomyoma of the external auditory canal being reported and the 2nd case of leiomyoma arising from arrectores pilorum muscles, all the other five cases were angioleiomyomas, arising from blood vessels. A 52 years old male presented with a mass in the right external auditory canal and decreased hearing of 6 months duration. Tumor excision done by end aural approach. Histopathological examination report was leiomyoma. It is extremely rare for leiomyoma to occur in the external auditory canal because of the non-availability of smooth muscles in the external canal. So it should be considered as a very rare differential diagnosis for any tumor or polyp in the ear canal. PMID- 27508145 TI - Unusual Presentation of Chordoma in Nose. AB - Chordomas are uncommon tumors of the bone representing 1-4 % of all primary bone tumors. These typically involve axial skeleton. Primary nasal presentation of chordoma is a rare occurrence and is usually misdiagnosed till the histopathological confirmation. We present a case of chordoma in nasal cavity treated by wide local resection and also present a review of literature discussing various facets in its presentation and management. PMID- 27508146 TI - Giant Sclerosing Oral Rhabdomyosarcoma-A Unique Case. AB - We present a case of oral Rhabdomyosarcoma in a 50 years old man presenting with a huge mass in the oral cavity. Pre operative investigations showed the mass to be Rhabdomyosarcoma. The mass was excised and subjected to histopathogical and immunohistochemical examinations which confirmed to be Rhabdomyosarcoma. PMID- 27508147 TI - Ultrasonography Guided Excision of Isolated Cysticercosis of the Temporalis Muscle Causing Intractable Headache: A Rare Case Report. AB - Cysticercosis cellulosae is a systemic parasitic infection caused by the larval stage of pork tapeworm, Taenia solium which involve humans as either a definitive or secondary hosts. The central nervous system is the most important primary site of involvement. Cases of cysticercosis presenting as an isolated muscle mass is an extremely rare entity and demands documentation. We report an extremely unusual case of isolated cysticercosis of the temporalis muscle causing intractable headache which presented a diagnostic challenge. The condition was surgically treated by ultrasonography guided excision of the cysticercosis swelling in the temporalis muscle. We also emphasize on the role of proper imaging modalities in the diagnosis and treatment of such unique cases. PMID- 27508148 TI - Interaction of ACTN3 gene polymorphism and muscle imbalance effects on kinematic efficiency in combat sports athletes. AB - PURPOSE: The purpose of this study was to determine the interaction of ACTN3 gene polymorphism and muscle imbalance effects on kinematic efficiency changes in combat sports athletes. METHODS: Six types of combat sports athletes (Judo, Taekwondo, boxing, kendo, wrestling, and Korean Ssi-reum) participated in the study. ATCN3 gene polymorphism and muscle imbalance in lower extremity were evaluated followed by analysis of differences of moment in hip, knee, and ankle joint during V-cut jumping and stop. To examine the moment difference due to an interaction of ATCN3 polymorphism and muscle imbalance, all participants were divided into 4 groups (R+MB, R+MIB, X+MB, and X+MIB). RESULTS: There was no significant difference of hip, knee, and ankle joint moment in R allele and X allele during V-cut jumping and stop based on ACTN3 gene polymorphism. Otherwise, muscle imbalance of knee moment in X-axis and ground reaction force of knee in Z axis showed a higher significance in muscle imbalance during V-cut jumping and stop compared to muscle balance (p<0.05). In addition, joint analysis showed that muscle imbalance in X allele group had significantly higher knee moment of V-cut ground reaction force in X-axis and higher ankle moment of jumping ground reaction force in X and Z-axis compared to muscle balance with R and/or X group (p <0.05). CONCLUSION: This study confirmed that muscle imbalance in lower extremity of combat athletes might induce higher risk factors of sports injury incidence than genetic factor and training might reduce the ratio of sports injury risk incidence. PMID- 27508149 TI - The effects of senior brain health exercise program on basic physical fitness, cognitive function and BDNF of elderly women - a feasibility study. AB - PURPOSE: This study was to investigate the impacts of senior brain heath exercise (SBHE) program for 12 weeks to basic active physical fitness, cognitive function and brain derived neurotrophic factor (BDNF) in elderly women. METHODS: Subject of this study is total of 24 women in the age of 65-79 who can conduct normal daily activity and communication but have not participated in regular exercise in recent 6 months. The study groups were divided into an exercise group (EG, n=13) and a control group (CG, n=11). The exercise program was consisted of SBHE, and training frequency was 4 times weekly, of which training time was a total of 50 minutes each time in level of intensity of 9-14 by rating of perceived exertion (RPE). RESULTS: First, 12-week SBHE program has shown statistical increase in basic physical fitness in the EG comparing with the CG, such as lower body strength, upper body strength and aerobic endurance, but not in flexibility, agility and dynamic balance. Second, in the case of Mini-mental state examination Korean version (MMSE-K) and BDNF, it showed that there was a statistically significant increase in the EG comparing with the CG. CONCLUSION: In this study, 12-week SBHE program has resulted in positive effect on change of basic physical fitness (strength and aerobic endurance), cognitive function and BDNF. If above program adds movements that can enhance flexibility, dynamic balance and agility, this can be practical exercise program to help seniors maintain overall healthy lifestyle. PMID- 27508150 TI - The effects of long-term whole-body vibration and aerobic exercise on body composition and bone mineral density in obese middle-aged women. AB - PURPOSE: The purpose of this study was to determine the effectiveness of whole body passive vibration exercise and its differences from aerobic exercise on body composition, bone mineral density (BMD) and bone mineral content (BMC). METHODS: Obese middle-aged women (n=33 out of 45) with 34+/-3% body fat completed the training protocol. They were randomly assigned into diet (n=9; control group), diet plus whole-body vibration exercise (n=13; vibration group), and diet plus aerobic exercise (n=11; aerobic group) groups and we compared their body composition, BMD, and BMC before and after 9 months of training. There were no significant differences in nutrient intake among groups during the training period. RESULTS: Relative body fat (%) decreased significantly (p < .05) in all three groups and the exercise groups showed a greater reduction in fat mass than the diet only group. BMD in the whole body, lumbar spine, hip and forearm were not significantly different among the three groups. Total body BMC increased significantly in the vibration group throughout the first 6 months of training. CONCLUSION: Results suggest that long- term vibration training when used in conjunction with a diet program is as effective as aerobic exercise with a diet program in improving body composition of obese middle-aged women without compromising BMC or BMD. Thus, it can be considered a novel and effective method for reducing body fat. PMID- 27508151 TI - Exercise and dietary change ameliorate high fat diet induced obesity and insulin resistance via mTOR signaling pathway. AB - PURPOSE: The purpose of this study was to investigate the effect of exercise and dietary change on obesity and insulin resistance and mTOR signaling protein levels in skeletal muscles of obese rats. METHODS: Sixty male Sprague-Dawley rats were divided into CO (Normal diet) and HF (High Fat diet) groups in order to induce obesity for 15 weeks. The rats were then subdivided into CO, COT (CO + Training), HF, HFT (HF + Training), HFND (Dietary change), and HFNDT (HFND + Training) groups (10 rats / group). The training groups underwent moderate intensity treadmill exercise for 8 weeks, after which soleus muscles were excised and analyzed. Data was statistically analyzed by independent t-test and One-way ANOVA tests with a 0.05 significance level. RESULTS: Fasting blood glucose, plasma insulin, and HOMA-IR in the HF group were significantly higher, as compared with other groups (p <.05). Protein levels of insulin receptor subunit-1 (IRS-1), IRS-2, and p-Akt were significantly higher in the HFT, HFND, and HFNDT groups, as compared with HF group. In addition, the protein levels of the mammalian target of rapamycin complex 1 (mTORC1) and ribosomal S6 protein kinase 1 were significantly decreased by exercise and dietary change (p <.05). However, mTORC2 and phosphoinositide 3-kinase were significantly increased (p <.05). CONCLUSION: In summary, despite the negative impact of continuous high fat intake, regular exercise and dietary change showed a positive effect on insulin resistance and mTOR signaling protein levels. PMID- 27508152 TI - Characterization of the metabolic effect of beta-alanine on markers of oxidative metabolism and mitochondrial biogenesis in skeletal muscle. AB - PURPOSE: beta-alanine is a common component of numerous sports supplements purported to improve athletic performance through enhanced carnosine biosynthesis and related intracellular buffering. To date, the effects of beta-alanine on oxidative metabolism remain largely unexplored. This work investigated the effects of beta-alanine on the expression of proteins which regulate cellular energetics. METHODS: C2C12 myocytes were cultured and differentiated under standard conditions followed by treatment with either beta-alanine or isonitrogenous non-metabolizable control D-alanine at 800MUM for 24 hours. Metabolic gene and protein expression were quantified by qRT-PCR and immunoblotting, respectively. Glucose uptake and oxygen consumption were measured via fluorescence using commercially available kits. RESULTS: beta-alanine-treated myotubes displayed significantly elevated markers of improved oxidative metabolism including elevated peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) and mitochondrial transcription factor a (TFAM) which led to increased mitochondrial content (evidenced by concurrent increases in cytochrome c content). Additionally, beta-alanine-treated cells exhibited significantly increased oxygen consumption compared to control in a PPARbeta/delta-dependent manner. beta-alanine significantly enhanced expression of myocyte enhancer factor 2 (MEF-2) leading to increased glucose transporter 4 (GLUT4) content. CONCLUSION: beta-alanine appears to increase cellular oxygen consumption as well as the expression of several cellular proteins associated with improved oxidative metabolism, suggesting beta-alanine supplementation may provide additional metabolic benefit (although these observations require in vivo experimental verification). PMID- 27508153 TI - The effect of exercise training combined with PPARgamma agonist on skeletal muscle glucose uptake and insulin sensitivity in induced diabetic obese Zucker rats. AB - PURPOSE: Exercise training with PPARgamma agonist is expected to increase glucose uptake and improve insulin sensitivity in skeletal muscle of patients with diabetes. However, its mechanisms to effect glucose uptake and insulin sensitivity in skeletal muscle are unclear. METHODS: The mechanism of action was determined by co-treatment with PPARgamma agonist- rosiglitazone and exercise training in streptozotocin induced-diabetic obese Zucker rats. Exercise training was carried out for 6 weeks (swimming, 1 h/day, 5 times/week, 5% weight/g, 32+/ 1C) with rosiglitazone treatment (3mg/kg/day, 6weeks). RESULTS: Glucose uptake and insulin sensitivity was decreased in diabetic than normal animals. Exercise training and rosiglitazone treatment respectively increased the expression of PPAR(peroxisome proliferators-activated receptor)-alpha, -beta/delta, -gamma, PGC 1alpha(PPAR-gamma coactivator-1alpha), adiponectin, GLUT-4(glucose transportor-4) and p-AMPK-alpha2(phospho-AMP activated protein kinase-alpha2) in EDL and SOL of diabetic, as compared to normal animals. Interestingly, training combined with rosiglitazone significantly increased glucose uptake and insulin sensitivity, which resulted in high expression of all molecules in diabetic than all other groups. CONCLUSION: These results indicated that exercise training combined with rosiglitazone might mediate regulation of glucose uptake and insulin sensitivity in skeletal muscle. Therefore, exercise training combined with rosiglitazone may be recommended as complementary therapies for diabetes. PMID- 27508154 TI - GLUT2 proteins and PPARgamma transcripts levels are increased in liver of ovariectomized rats: reversal effects of resistance training. AB - PURPOSE: This study investigated the effects of ovariectomy (Ovx) and 12 weeks of resistance training (RT) on gene expression of GLUT2, the main glucose transporter in the liver, and on PPARgamma, a transcription factor known to target GLUT2 expression. METHODS: Forty Holtzman rats were divided into 5 groups: Sham-sedentary (Sed), Sham- RT, Ovx-Sed, Ovx-RT, and Ovx-Sed with hormone replacement (E2). The RT protocol consisted of sessions held every 72 h for 12 weeks, during which the animals performed 4 to 9 vertical climbs (1.1 m) at 2 min intervals with progressively heavier weights (30 g after the fourth climb) tied to the tail. The E2 silastic capsule was inserted into the rats' backs 48 hours before the first RT session. RESULTS: In addition to liver fat, GLUT2 protein levels and PPARgamma transcripts were increased (P < 0.05) in Ovx compared to Sham-Sed animals, suggesting increased hepatic glucose uptake under estrogen deficient conditions. RT and E2 in Ovx rats decreased liver fat accumulation as well as GLUT2 and PPARgamma gene expression to the level of Sham- Sed animals. CONCLUSION: The results of this study suggest that liver GLUT2 as well as PPARgamma expression in Ovx rats are accompanied by increased fat accumulation and glucose uptake, thus providing a substrate for increased de novo lipogenesis. RT appears to be an appropriate exercise model to circumvent these effects. PMID- 27508156 TI - Criteria for clinical translucency evaluation of direct esthetic restorative materials. AB - The purpose of this review was to suggest practical criteria for the clinical translucency evaluation of direct esthetic restorative materials, and to review the translucency with these criteria. For the evaluation of reported translucency values, measuring instrument and method, specimen thickness, background color, and illumination should be scrutinized. Translucency parameter (TP) of 15 to 19 could be regarded as the translucency of 1 mm thick human enamel. Visual perceptibility threshold for translucency difference in contrast ratio (DeltaCR) of 0.07 could be transformed into DeltaTP value of 2. Translucency differences between direct and indirect resin composites were perceivable (DeltaTP > 2). Universal and corresponding flowable resin composites did not show perceivable translucency differences in most products. Translucency differed significantly by the product within each shade group, and by the shade group within each product. Translucency of human enamel and perceptibility threshold for translucency difference may be used as criteria for the clinical evaluation of translucency of esthetic restorative materials. PMID- 27508155 TI - Altered potassium ATP channel signaling in mesenteric arteries of old high salt fed rats. AB - PURPOSE: Both aging and the consumption of a high salt diet are associated with clear changes in the vascular system that can lead to the development of cardiovascular disease; however the mechanisms are not clearly understood. Therefore, we examined whether aging and the consumption of excess salt alters the function of potassium ATP-dependent channel signaling in mesenteric arteries. METHODS: Young (7 months) and old (29 months) Fischer 344 x Brown Norway rats were fed a control or a high salt diet (8% NaCl) for 12 days and mesenteric arteries were utilized for vascular reactivity measurements. RESULTS: Acetylcholine-induced endothelium relaxation was significantly reduced in old arteries (81 +/- 4%) when compared with young arteries (92 +/- 2%). Pretreatment with the potassium-ATP channel blocker glibenclamide reduced relaxation to acetylcholine in young arteries but did not alter dilation in old arteries. On a high salt diet, endothelium dilation to acetylcholine was significantly reduced in old salt arteries (60 +/- 3%) when compared with old control arteries (81 +/- 4%). Glibenclamide reduced acetylcholine-induced dilation in young salt arteries but had no effect on old salt arteries. Dilation to cromakalim, a potassium-ATP channel opener, was reduced in old salt arteries when compared with old control arteries. CONCLUSION: These findings demonstrate that aging impairs endothelium dependent relaxation in mesenteric arteries. Furthermore, a high salt diet alters the function of potassium-ATP-dependent channel signaling in old isolated mesenteric arteries and affects the mediation of relaxation stimuli. PMID- 27508157 TI - Cytotoxicity and biocompatibility of Zirconia (Y-TZP) posts with various dental cements. AB - OBJECTIVES: Endodontically treated teeth with insufficient tooth structure are often restored with esthetic restorations. This study evaluated the cytotoxicity and biological effects of yttria partially stabilized zirconia (Y-TZP) blocks in combination with several dental cements. MATERIALS AND METHODS: Pairs of zirconia cylinders with medium alone or cemented with three types of dental cement including RelyX U200 (3M ESPE), FujiCEM 2 (GC), and Panavia F 2.0 (Kuraray) were incubated in medium for 14 days. The cytotoxicity of each supernatant was determined using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays on L929 fibroblasts and MC3T3-E1 osteoblasts. The levels of interleukin-6 (IL-6) mRNA were evaluated by reverse transcription polymerase chain reaction (RT-PCR), and IL-6 protein was evaluated by enzyme-linked immunosorbent assays (ELISA). The data were analyzed using one-way ANOVA and Tukey post-hoc tests. A p < 0.05 was considered statistically significant. RESULTS: The MTT assays showed that MC3T3-E1 osteoblasts were more susceptible to dental cements than L929 fibroblasts. The resin based dental cements increased IL 6 expression in L929 cells, but reduced IL-6 expression in MC3T3-E1 cells. CONCLUSIONS: Zirconia alone or blocks cemented with dental cement showed acceptable biocompatibilities. The results showed resin-modified glass-ionomer based cement less produced inflammatory cytokines than other self-adhesive resin based cements. Furthermore, osteoblasts were more susceptible than fibroblasts to the biological effects of dental cement. PMID- 27508158 TI - Preference of undergraduate students after first experience on nickel-titanium endodontic instruments. AB - OBJECTIVES: This study aimed to compare two nickel-titanium systems (rotary vs. reciprocating) for their acceptance by undergraduate students who experienced nickel-titanium (NiTi) instruments for the first time. MATERIALS AND METHODS: Eighty-one sophomore dental students were first taught on manual root canal preparation with stainless-steel files. After that, they were instructed on the use of ProTaper Universal system (PTU, Dentsply Maillefer), then the WaveOne (WO, Dentsply Maillefer). They practiced with each system on 2 extracted molars, before using those files to shape the buccal or mesial canals of additional first molars. A questionnaire was completed after using each file system, seeking students' perception about 'Ease of use', 'Flexibility', 'Cutting-efficiency', 'Screwing-effect', 'Feeling-safety', and 'Instrumentation-time' of the NiTi files, relative to stainless-steel instrumentation, on a 5-point Likert-type scale. They were also requested to indicate their preference between the two systems. Data was compared between groups using t-test, and with Chi-square test for correlation of each perception value with the preferred choice (p = 0.05). RESULTS: Among the 81 students, 55 indicated their preferred file system as WO and 22 as PTU. All scores were greater than 4 (better) for both systems, compared with stainless-steel files, except for 'Screwing-effect' for PTU. The scores for WO in the categories of 'Flexibility', 'Screwing-effect', and 'Feeling-safety' were significantly higher scores than those of PTU. A significant association between the 'Screwing-effect' and students' preference for WO was observed. CONCLUSIONS: Novice operators preferred nickel-titanium instruments to stainless steel, and majority of them opted for reciprocating file instead of continuous rotating system. PMID- 27508159 TI - Proximity of the mandibular molar root apex from the buccal bone surface: a cone beam computed tomographic study. AB - OBJECTIVES: The purpose of this study was to evaluate the proximity of the mandibular molar apex to the buccal bone surface in order to provide anatomic information for apical surgery. MATERIALS AND METHODS: Cone-beam computed tomography (CBCT) images of 127 mandibular first molars and 153 mandibular second molars were analyzed from 160 patients' records. The distance was measured from the buccal bone surface to the root apex and the apical 3.0 mm on the cross sectional view of CBCT. RESULTS: The second molar apex and apical 3 mm were located significantly deeper relative to the buccal bone surface compared with the first molar (p < 0.01). For the mandibular second molars, the distance from the buccal bone surface to the root apex was significantly shorter in patients over 70 years of age (p < 0.05). Furthermore, this distance was significantly shorter when the first molar was missing compared to nonmissing cases (p < 0.05). For the mandibular first molars, the distance to the distal root apex of one distal-rooted tooth was significantly greater than the distance to the disto buccal root apex (p < 0.01). In mandibular second molar, the distance to the apex of C-shaped roots was significantly greater than the distance to the mesial root apex of non-C-shaped roots (p < 0.01). CONCLUSIONS: For apical surgery in mandibular molars, the distance from the buccal bone surface to the apex and apical 3 mm is significantly affected by the location, patient age, an adjacent missing anterior tooth, and root configuration. PMID- 27508160 TI - In vitro evaluation of a newly produced resin-based endodontic sealer. AB - OBJECTIVES: A variety of root canal sealers were recently launched to the market. This study evaluated physicochemical properties, biocompatibility, and sealing ability of a newly launched resin-based sealer (Dia-Proseal, Diadent) compared to the existing root canal sealers (AHplus, Dentsply DeTrey and ADseal, Metabiomed). MATERIALS AND METHODS: The physicochemical properties of the tested sealers including pH, solubility, dimensional change, and radiopacity were evaluated. Biocompatibility was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. For microleakage test, single-rooted teeth were instrumented, and obturated with gutta-percha and one of the sealers (n = 10). After immersion in 1% methylene blue solution for 2 weeks, the specimens were split longitudinally. Then, the maximum length of staining was measured. Statistical analysis was performed by one-way analysis of variance followed by Tukey test (p = 0.05). RESULTS: Dia-Proseal showed the highest pH value among the tested sealers (p < 0.05). ADseal showed higher dimensional change compared to AHplus and Dia-Proseal (p < 0.05). The solubility values of AHplus and Dia-Proseal were similar, whereas ADseal had the lowest solubility value (p < 0.05). The flow values of sealer in increasing order were AHplus, DiaProseal, and ADseal (p < 0.05). The radiopacity of AHplus was higher than those of ADseal and Dia-Proseal (p < 0.05). The cell viability of the tested materials was statistically similar throughout the experimental period. There were no significant differences in microleakage values among the tested samples. CONCLUSIONS: The present study indicates that Dia-Proseal has acceptable physicochemical properties, biocompatibility, and sealing ability. PMID- 27508161 TI - Effect of three nanobiomaterials on microhardness of bleached enamel. AB - OBJECTIVES: The aim of this in vitro study was to evaluate the effect of incorporating three different nanobiomaterials into bleaching material on microhardness of bleached enamel. MATERIALS AND METHODS: The crowns of 24 extracted sound human molars were sectioned. Sixty enamel specimens (2 * 3 * 4 mm) were selected and divided into five groups (n = 12): Group 1 received no bleaching procedure (control); Group 2 underwent bleaching with a 40% hydrogen peroxide (HP) gel; Groups 3, 4, and 5 were bleached with a 40% HP gel modified by incorporation of bioactive glass (BAG), amorphous calcium phosphate (ACP) and hydroxyapatite (HA), respectively. The enamel microhardness was evaluated. The differences in Knoop microhardness data of each group were analyzed by one-way ANOVA, followed by post hoc Tukey tests. RESULTS: Significant differences were observed between the study groups. The enamel microhardness changes in Groups 1, 3, 4, and 5 were significantly lower than that of Group 2 (p < 0.001). CONCLUSIONS: Within the limitations of this study, it can be concluded that incorporation of each one of the three tested biomaterials as remineralizing agents might be effective in decreasing enamel microhardness changes subsequent to in-office bleaching. PMID- 27508162 TI - Involvement of TRPA1 in the cinnamaldehyde-induced pulpal blood flow change in the feline dental pulp. AB - OBJECTIVES: The purpose of this study was to investigate the involvement of TRPA1 in the cinnamaldehyde-induced pulpal blood flow (PBF) change in the feline dental pulp. MATERIALS AND METHODS: Mandibles of eight cats were immobilized and PBF was monitored with a laser Doppler flowmetry at the mandibular canine tooth. To evaluate the effect of cinnamaldehyde on PBF, cinnamaldehyde was injected into the pulp through the lingual artery at a constant rate for 60 seconds. As a control, a mixture of 70% ethanol and 30% dimethyl sulfoxide (DMSO, vehicle) was used. To evaluate the involvement of transient receptor potential ankyrin 1 (TRPA1) in PBF change, AP18, a specific TRPA1 antagonist, was applied into the pulp through the Class V dentinal cavity followed by cinnamaldehyde administration 3 minutes later. The paired variables of experimental data were statistically analyzed using paired t-test. A p value of less than 0.05 was considered as statistically significant. RESULTS: Administration of cinnamaldehyde (0.5 mg/kg, intra-arterial [i.a.]) induced significant increases in PBF (p < 0.05). While administration of a TRPA1 antagonist, AP18 (2.5 - 3.0 mM, into the dentinal cavity [i.c.]) caused insignificant change of PBF (p > 0.05), administration of cinnamaldehyde (0.5 mg/kg, i.a.) following the application of AP18 (2.5 - 3.0 mM, i.c.) resulted in an attenuation of PBF increase from the control level (p < 0.05). As a result, a TRPA1 antagonist, AP18 effectively inhibited the vasodilative effect of cinnamaldehyde (p < 0.05). CONCLUSIONS: The result of the present study provided a functional evidence that TRPA1 is involved in the mechanism of cinnamaldehyde-induced vasodilation in the feline dental pulp. PMID- 27508163 TI - Esthetic enhancement of a traumatized anterior tooth with a combination of forced eruption and tooth alignment: a case report. AB - Exposing sound structure of a subgingivally fractured tooth using orthodontic extrusion is considered to be a conservative way to re-establish biologic width without sacrificing esthetics or jeopardizing periodontal support of neighboring teeth. When a misaligned tooth is traumatically involved, a more comprehensive approach combining tooth extrusion and re-alignment may be necessary for a successful restorative outcome. This case report describes a successful esthetic management of a patient with complicated crown-root fracture on the maxillary right central incisor and pre-existing malocclusion in the maxillary anterior region. Forced eruption along with re-alignment of teeth by orthodontic movement seems to allow re-positioning of the fracture line to a favorable position and correction of crowding, providing a better esthetic result. PMID- 27508164 TI - A combined approach to non-carious cervical lesions associated with gingival recession. AB - Non-carious cervical lesions (NCCLs) with gingival recession require specific consideration on both aspects of hard and soft tissue lesion. In the restorative aspect, careful finishing and polishing of the restorations prior to mucogingival surgery is the critical factor contributing to success. Regarding surgery, assessment of the configuration of the lesion and the choice of surgical technique are important factors. The precise diagnosis and the choice of the proper treatment procedure should be made on the basis of both restorative and surgical considerations to ensure the successful treatment of NCCLs. PMID- 27508165 TI - Application of quantitative light-induced fluorescence to determine the depth of demineralization of dental fluorosis in enamel microabrasion: a case report. AB - Enamel microabrasion has become accepted as a conservative, nonrestorative method of removing intrinsic and superficial dysmineralization defects from dental fluorosis, restoring esthetics with minimal loss of enamel. However, it can be difficult to determine if restoration is necessary in dental fluorosis, because the lesion depth is often not easily recognized. This case report presents a method for analysis of enamel hypoplasia that uses quantitative light-induced fluorescence (QLF) followed by a combination of enamel microabrasion with carbamide peroxide home bleaching. We describe the utility of QLF when selecting a conservative treatment plan and confirming treatment efficacy. In this case, the treatment plan was based on QLF analysis, and the selected combination treatment of microabrasion and bleaching had good results. PMID- 27508166 TI - Statistical notes for clinical researchers: Sample size calculation 3. Comparison of several means using one-way ANOVA. PMID- 27508167 TI - Introducing the GentleWave System. PMID- 27508168 TI - Nano-computed tomography: current and future perspectives. PMID- 27508169 TI - Effect of Akimbo versus Raised Arm Positioning on Breast and Cardiopulmonary Dosimetry in Pediatric Hodgkin Lymphoma. AB - PURPOSE: In pediatric Hodgkin lymphoma (HL), radiotherapy (RT)-related late toxicities are a prime concern during treatment planning. This is the first study to examine whether arm positioning (raised versus akimbo) result in differential cardiopulmonary and breast doses in patients undergoing mediastinal RT. METHODS: Two treatment plans were made for each patient (akimbo/arms raised); treatment was per Children's Oncology Group AHOD0031 protocol, including AP/PA fields. The anterior midline T6-T7 disk space was used as an anatomic reference of "midline." Heart/lungs were contoured for each setup. For females, breasts were also contoured and nipple positions identified. Volumetric centers of contoured organs were defined and three-dimensional distances from "midline" were computed. Analyzed dosimetric parameters included V5 (volume receiving >=5 Gy), V10, V15, V20, and mean dose. Statistics were performed using the Mann-Whitney test. RESULTS: Fifteen (6 females, 9 males) pediatric HL patients treated with mediastinal RT were analyzed. The median lateral distance from the breast center/nipple to "midline" with arms akimbo was larger than that with arms raised (8.6 vs. 7.7 cm left breast, p = 0.04; 10.7 vs. 9.2 cm left nipple, p = 0.04; 8.7 vs. 7.0 cm right breast, p = 0.004; 9.9 vs. 7.9 cm right nipple, p = 0.007). Raised arm position was associated with a median 2.8/3.0 cm decrease in breast/nipple separation, respectively. There were no significant differences in craniocaudal breast/nipple position based on arm positioning (p > 0.05). Increasing breast volume was correlated with larger arm position-related changes in breast/nipple separation (r = 0.74, p = 0.06/r = 0.85, p = 0.02). Akimbo positioning lowered median breast V5, V10, V15, and mean dose (p < 0.05), with no differences observed in patients with both mediastinal and axillary disease for any parameters (p > 0.05). Arm position had no significant effect on cardiopulmonary doses. CONCLUSION: Akimbo arm positioning may be advantageous to decrease breast doses in female pediatric HL patients undergoing mediastinal RT, especially in the absence of axillary disease. PMID- 27508170 TI - DNA methylation changes and TE activity induced in tissue cultures of barley (Hordeum vulgare L.). AB - BACKGROUND: In vitro plant regeneration via androgenesis or somatic embryogenesis is capable of inducing (epi)mutations that may affect sexual progenies. While epimutations are associated with DNA methylation, mutations could be due to the movement of transposons. The common notion is that both processes are linked. It is being assumed that demethylation activates transposable elements (TEs). Analysis of methylation changes and their relation with TEs activation in tissue cultures requires uniquely derived donor plants (Ds), their regenerants (Rs) and respective progeny (Ps) that would allow discrimination of processes not related to changes introduced via in vitro cultures. Moreover, a set of methods (RP-HPLC, SSAP, and MSTD) is needed to study whether different TEs families are being activated during in vitro tissue culture plant regeneration and whether their activity could be linked to DNA methylation changes or alternative explanations should be considered. RESULTS: The in vitro tissue culture plant regeneration in barley was responsible for the induction of DNA methylation in regenerants and conservation of the methylation level in the progeny as shown by the RP-HPLC approach. No difference between andro- and embryo-derived Rs and Ps was observed. The SSAP and MSTD approach revealed that Ds and Rs were more polymorphic than Ps. Moreover, Rs individuals exhibited more polymorphisms with the MSTD than SSAP approach. The differences between Ds, Rs and Ps were also evaluated via ANOVA and AMOVA. CONCLUSIONS: Stressful conditions during plant regeneration via in vitro tissue cultures affect regenerants and their sexual progeny leading to an increase in global DNA methylation of Rs and Ps compared to Ds in barley. The increased methylation level noted among regenerants remains unchanged in the Ps as indicated via RP-HPLC data. Marker-based experiments suggest that TEs are activated via in vitro tissue cultures and that, independently of the increased methylation, their activity in Rs is greater than in Ps. Thus, the increased methylation level may not correspond to the stabilization of TEs movement at least at the level of regenerants. The presence of TEs variation among Ds that were genetically and epigenetically uniform may suggest that at least some mobile elements may be active, and they may mask variation related to tissue cultures. Thus, tissue cultures may activate some TEs whereas the others remain intact, or their level of movement is changed. Finally, we suggest that sexual reproduction may be responsible for the stabilization of TEs. PMID- 27508171 TI - A review on the diagnosis and treatment of hepatocellular carcinoma with a focus on the role of Wnts and the dickkopf family of Wnt inhibitors. AB - Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. There are multiple etiologic factors including viral and environmental influences that can lead to HCC. Successful screening for early HCC is challenging due to the lack of well characterized and specific biomarkers. However, achieving successful screening is critically important as early diagnosis can potentially provide curative opportunities. Once HCC is advanced, there are multiple therapeutic venues, but most eventually fail, therefore developing new targeted therapies may provide greater chance for effective therapies. Along these lines, the Wnt pathway has been identified as contributing to the development and progression of HCC. Wnts can modify HCC growth and invasive ability. A key factor in the Wnt pathway is the dickkopf (DKK) family of Wnt inhibitors. DKKs have also been shown to modulate HCC progression. Additionally, several studies have suggested that DKK expression in tissue and serum has diagnostic and prognostic value. PMID- 27508172 TI - Emerging role of insulin-like growth factor-binding protein 7 in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a vicious and highly vascular cancer with a dismal prognosis. It is a life-threatening illness worldwide that ranks fifth in terms of cancer prevalence and third in cancer deaths. Most patients are diagnosed at an advanced stage by which time conventional therapies are no longer effective. Targeted molecular therapies, such as the multikinase inhibitor sorafenib, provide a modest increase in survival for advanced HCC patients and display significant toxicity. Thus, there is an immense need to identify novel regulators of HCC that might be targeted effectively. The insulin-like growth factor (IGF) axis is commonly abnormal in HCC. Upon activation, the IGF axis controls metabolism, tissue homeostasis, and survival. Insulin-like growth factor binding protein 7 (IGFBP7) is a secreted protein of a family of low-affinity IGF binding proteins termed "IGFBP-related proteins" that have been identified as a potential tumor suppressor in HCC. IGFBP7 has been implicated in regulating cellular proliferation, senescence, and angiogenesis. In this review, we provide a comprehensive discussion of the role of IGFBP7 in HCC and the potential use of IGFBP7 as a novel biomarker for drug resistance and as an effective therapeutic strategy. PMID- 27508173 TI - Micro-ribonucleic acids: potential noninvasive biomarkers for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies globally. Each year, more than 500,000 people worldwide are diagnosed with HCC. The onset of HCC is typically unnoticeable, and the prognosis is usually poor. The early diagnosis of HCC and dynamic monitoring of this disease can contribute to more effective therapeutic interventions and improve patient outcomes. To achieve early diagnosis, more sensitive, specific, and easily detectable biomarkers are necessary. Recently, scientists have focused on identifying novel, sensitive, and minimally invasive or noninvasive biomarkers. Micro-ribonucleic acids (miRNAs) are a class of endogenous noncoding single-stranded RNAs that regulate gene expression at the posttranscriptional level. By negatively regulating target-gene expression, miRNAs play a critical role in diverse biological processes, including apoptosis, proliferation, differentiation, and developmental timing. Unique changes in miRNA expression in serum or plasma samples from HCC patients have been reported, suggesting that miRNAs may serve as novel noninvasive biomarkers for diagnosing HCC and evaluating therapeutic responses or as potential therapeutic targets in HCC. This review focuses on recent progress in understanding the role of miRNAs in HCC pathogenesis and progression, and highlights their diagnostic and prognostic value for HCC patients. PMID- 27508174 TI - Critical analysis of the potential of targeting GPC3 in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. The treatment options for patients with advanced HCC are limited, and novel treatment strategies are required urgently. Glypican-3 (GPC3), a member of the glypican family of heparan sulfate proteoglycans, is overexpressed in 72%-81% of HCC cases, and is correlated with a poor prognosis. GPC3 regulates both stimulatory and inhibitory signals, and plays a key role in regulating cancer cell growth. GPC3 is released into the serum, and so might be a useful diagnostic marker for HCC. GPC3 is also used as an immunotherapeutic target in HCC. A Phase I study of a humanized anti-GPC3 monoclonal antibody, GC33, revealed a good safety profile and potential antitumor activity, and a Phase II trial is currently ongoing. In addition, the authors' investigator-initiated Phase I study of a GPC3-derived peptide vaccine showed good safety and tolerability, and demonstrated that the GPC3 peptide-specific cytotoxic T-lymphocyte frequency in peripheral blood correlated with overall survival in HCC patients. A sponsor initiated Phase I clinical trial of a three-peptide cocktail vaccine, which includes a GPC3-derived peptide, is also underway. GPC3 is currently recognized as a promising therapeutic target and diagnostic marker for HCC. This review introduces the recent progress in GPC3 research, from biology to clinical impact. PMID- 27508176 TI - Potential immunotherapeutic role of interleukin-2 and interleukin-12 combination in patients with hepatocellular carcinoma. AB - BACKGROUND: Many recent therapeutic interventions are necessary to improve the treatment of hepatocellular carcinoma (HCC), including immunotherapy, which seems to offer one of the new realistic therapeutic modalities. This study aims to investigate the optimization of immunotherapy for HCC patients by appraisal of both interferon (IFN)-gamma levels and phenotyping of lymphocytes obtained from peripheral blood and fine-needle aspirates. METHODS: The isolated lymphocytes were cultured in the presence of interleukins (IL)-2, IL-4, and IL-12. Enzyme linked immunosorbent assay and flow cytometric techniques were used for the assessment of human IFN-gamma production and the studied T-cell subpopulations, respectively. RESULTS: Mixed cell populations of peripheral blood lymphocytes and tumor infiltrating lymphocytes treated with IL-2 plus IL-12 showed a marked and significant elevation in IFN-gamma levels in their culture media, a significant decrease in the percentage of cluster of differentiation (CD)4(+)CD25(+) regulatory T-cells, and a nonsignificant increase in the percentage of CD8(+) cytotoxic T-cells. Meanwhile, IL-2 plus IL-4 treatment demonstrated nonsignificant effects. CONCLUSION: Our data suggested that IL-12 together with IL-2 caused a suppression of CD4(+)CD25(+) regulatory T-cells and an elevation of IFN-gamma levels, which play a crucial immunotherapeutic role in the management of HCC patients. PMID- 27508175 TI - Fibroblast growth factor family as a potential target in the treatment of hepatocellular carcinoma. AB - Hepatocellular cancer (HCC) is currently the third leading cause of cancer death worldwide. The prognosis of patients diagnosed with late-stage disease is dismal due to high resistance to conventional systemic therapies. The introduction of sorafenib, despite its limited efficacy, as the standard systemic therapy for advanced HCC has paved a way for targeted molecular therapies for HCC. Fibroblast growth factor (FGF) signaling plays an important role in the developing embryo and the adult. The FGF signaling pathway is often hijacked by cancer cells, including HCC. Several alterations in FGF signaling correlate with poor outcome in HCC patients, suggesting that this family of signaling molecules plays an important role in the development of HCC. Multikinase inhibitors targeting FGF signaling are currently under investigation in clinical trials. This review discusses the current understanding of the biological and clinical implications of aberrant FGF signaling in the prognosis, diagnosis, and treatment of HCC. PMID- 27508177 TI - New insights on the role of epigenetic alterations in hepatocellular carcinoma. AB - Emerging evidence assigns to epigenetic mechanisms heritable differences in gene function that come into being during cell development or via the effect of environmental factors. Epigenetic deregulation is strongly involved in the development of hepatocellular carcinoma (HCC). It includes changes in methionine metabolism, promoter hypermethylation, or increased proteasomal degradation of oncosuppressors, as well as posttranscriptional deregulation by microRNA or messenger RNA (mRNA) binding proteins. Alterations in the methylation of the promoter of methyl adenosyltransferase MAT1A and MAT2A genes in HCC result in decreased S-adenosylmethionine levels, global DNA hypomethylation, and deregulation of signal transduction pathways linked to methionine metabolism and methyl adenosyltransferases activity. Changes in S-adenosylmethionine levels may also depend on MAT1A mRNA destabilization associated with MAT2A mRNA stabilization by specific proteins. Decrease in MAT1A expression has also been attributed to miRNA upregulation in HCC. A complex deregulation of miRNAs is also strongly involved in hepatocarcinogenesis, with up-regulation of different miRNAs targeting oncosuppressor genes and down-regulation of miRNAs targeting genes involved in cell-cycle and signal transduction control. Oncosuppressor gene down regulation in HCC is also induced by promoter hypermethylation or posttranslational deregulation, leading to proteasomal degradation. The role of epigenetic changes in hepatocarcinogenesis has recently suggested new promising therapeutic approaches for HCC on the basis of the administration of methylating agents, inhibition of methyl adenosyltransferases, and restoration of the expression of tumor-suppressor miRNAs. PMID- 27508178 TI - Sorafenib in advanced hepatocellular carcinoma: current status and future perspectives. AB - The approval of sorafenib, a multikinase inhibitor targeting primarily Raf kinase and the vascular endothelial growth factor receptor, in 2007 for treating advanced hepatocellular carcinoma (HCC) has generated considerable enthusiasm in drug development for this difficult-to-treat disease. However, because several randomized Phase III studies testing new multikinase inhibitors failed, sorafenib remains the standard of first-line systemic therapy for patients with advanced HCC. Field practice studies worldwide have suggested that in daily practice, physicians are adopting either a preemptive dose modification or a ramp-up strategy to improve the compliance of their patients. In addition, accumulating data have suggested that patients with Child-Pugh class B liver function can tolerate sorafenib as well as patients with Child-Pugh class A liver function, although the actual benefit of sorafenib in patients with Child-Pugh class B liver function has yet to be confirmed. Whether sorafenib can be used as an adjunctive therapy to improve the outcomes of intermediate-stage HCC patients treated with transcatheter arterial chemoembolization or early-stage HCC patients after curative therapies is being investigated in several ongoing randomized Phase III studies. An increasing number of studies have reported that sorafenib exerts "off-target" effects, including the modulation of signaling pathways other than Raf/MEK/ERK pathway, nonapoptotic cell death mechanisms, and even immune modulation. Finally, although sorafenib in combination with chemotherapy or other targeted therapies has the potential to improve therapeutic efficacy in treating HCC, it also increases toxicity. Additional clinical studies are warranted to determine useful sorafenib-based combinations for the treatment of advanced HCC. PMID- 27508179 TI - Clinical utility of imaging for evaluation of hepatocellular carcinoma. AB - The hemodynamics of a hepatocellular nodule is the most important imaging parameter used to characterize various hepatocellular nodules in liver cirrhosis, because sequential changes occur in the feeding vessels and hemodynamic status during hepatocarcinogenesis. Therefore, the imaging criteria for hepatocellular carcinoma (HCC) are also usually based on vascular findings, eg, early arterial uptake followed by washout in the portal venous and equilibrium phases. Contrast enhanced ultrasonography, dynamic multidetector-row computed tomography (MDCT), and dynamic magnetic resonance (MR) imaging with gadopentetate dimeglumine (Gd DTPA) are useful for detecting hypervascular HCC on the basis of vascular criteria but are not as useful for hypovascular HCC. Contrast-enhanced MR imaging with gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), a hepatocyte-specific MR contrast agent, is superior to dynamic MDCT and dynamic MR imaging with Gd-DTPA in detecting both hypervascular and hypovascular HCC. Moreover, Gd-EOB-DTPA-enhanced MR imaging can display each histologically differentiated HCC as hypointense relative to the liver parenchyma. (18)F fluorodeoxyglucose positron emission tomography imaging might not be suitable for the screening and detection of HCC, given its lower diagnostic performance. However, this technique plays an important role in determining whether HCC has spread beyond the liver. PMID- 27508180 TI - Telaprevir-containing regimen for treatment of hepatitis C virus infection in patients with hepatocellular carcinoma awaiting liver transplantation: a case series. AB - In patients who undergo liver transplantation (LT), allograft failure secondary to hepatitis C virus (HCV) recurrence after LT accounts for two-thirds of graft failures and deaths. Achievement of sustained virologic response before LT eliminates the risk of HCV recurrence. Only a limited number of studies have evaluated the role of antiviral treatment before LT. No published data are available regarding the use of HCV protease inhibitors before LT. We report our experience using the combination of telaprevir, pegylated interferon alfa-2a (PegIFN alfa-2a), and ribavirin in three patients with HCV-associated hepatocellular carcinoma (HCC) awaiting LT. Two patients had not received, and one had had a partial response to HCV therapy (PegIFN alfa-2a plus ribavirin). All three patients had genotype 1b and were started on telaprevir and full doses of PegIFN alfa-2a and ribavirin. Treatment was planned to be continued until the day of LT or 48 weeks total, whichever came first. One patient still had detectable HCV RNA after 24 weeks of antivirals and was, therefore, excluded from further analysis. The other two patients had undetectable HCV RNA at the end of antiviral therapy. In one of these patients, HCV RNA remained undetectable after LT; the other patient experienced viral relapse. HCV therapy was tolerated by all patients; no patient required permanent discontinuation of therapy because of toxic effects. All three patients experienced hematologic toxic effects. Only one patient required treatment discontinuation, due to progression of HCC. The use of telaprevir-containing regimens appears to be safe in selected patients with HCV associated HCC awaiting LT, but more studies are warranted to evaluate the safety and efficacy of this treatment combination to prevent post-LT viral recurrence. PMID- 27508181 TI - Hepatocellular carcinoma: epidemiology and risk factors. AB - Hepatocellular carcinoma is one of the major malignant tumors in the world today. The number of new cases of the tumor increases year by year, and hepatocellular carcinoma almost always runs a fulminant course and carries an especially grave prognosis. It has a low resectability rate and a high recurrence rate after surgical intervention, and responds poorly to anticancer drugs and radiotherapy. Hepatocellular carcinoma does not have a uniform geographical distribution: rather, very high incidences occur in Eastern and Southeastern Asia and in sub Saharan Black Africans. In these regions and populations, the tumor shows a distinct shift in age distribution toward the younger ages, seen to greatest extent in sub-Saharan Black Africans. In all populations, males are more commonly affected. The most common risk factors for hepatocellular carcinoma in resource poor populations with a high incidence of the tumor are chronic hepatitis B virus infection and dietary exposure to the fungal hepatocarcinogen aflatoxin B1. These two causative agents act either singly or synergistically. Both the viral infection and exposure to the fungus occur from early childhood, and the tumor typically presents at an early age. Chronic hepatitis C virus infection is an important cause of hepatocellular carcinoma in resource-rich countries with a low incidence of the tumor. The infection is acquired in adulthood and hepatocellular carcinoma occurs later than it does with hepatitis B virus-induced tumors. In recent years, obesity and the metabolic syndrome have increased markedly in incidence and importance as a cause of hepatocellular carcinoma in some resource rich regions. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol induced cirrhosis. Excessive iron accumulation in hereditary hemochromatosis and dietary iron overload in the Black African population and membranous obstruction of the inferior cava cause the tumor in a few countries. PMID- 27508182 TI - Emerging role of the peroxisome proliferator-activated receptor-gamma in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the major leading cause of cancer death worldwide. Hepatitis B virus, hepatitis C virus, alcohol consumption, non alcoholic fatty liver disease, and diabetes are the major risks for developing HCC. Until now, recurrence and metastasis are the major cause of death in HCC patients. Therefore, identification of new effective molecular targets is an urgent need for treatment of HCC. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated nuclear receptor which could be activated by PPARgamma agonists such as thiazolidinediones, and natural PPARgamma ligand (such as 15-deoxy-Delta12,14-prostaglandin J2, 15d-PGJ2). Increasing in vitro and in vivo evidence has demonstrated that PPARgamma agonists exhibit an inhibitory role on tumor cell growth, migration, and invasion, suggesting that PPARgamma activation may play an important role in the regulation of growth of HCC. It has been reported that PPARgamma activation by thiazolidinediones or overexpression of PPARgamma by virus-mediated gene transfer has shown growth inhibitory effects in hepatoma cells, but the expression level of PPARgamma in HCC tissues still remains conflicting. Notably, a novel PPARgamma agonist, honokiol, has recently been found to activate the PPARgamma/RXR heterodimer, and has also exhibited significant anti-cancer effects in hepatoma cells. In the present review, we summarized studies on the role and the molecular regulation of PPARgamma in HCC development in vitro and in vivo. PPARgamma has the potential to be a therapeutic target for future treatment of HCC. PMID- 27508183 TI - Radiological diagnosis of hepatocellular carcinoma. AB - Diagnosis of hepatocellular carcinoma (HCC) still remains a challenging issue. In the setting of liver cirrhosis, international guidelines have set the noninvasive criteria for HCC diagnosis, represented by the detection of contrast hyperenhancement in the arterial phase (wash-in) and hypoenhancement in the portal or delayed phase (wash-out) with dynamic multi-detector computer tomography or magnetic resonance (MR) imaging. Although highly specific, this typical enhancement pattern has relatively low sensitivity, since approximately one-third of HCC nodules are characterized by atypical enhancement patterns. In atypical HCC nodules larger than 1 cm, the majority of international guidelines recommend liver biopsy. However, there is an increasing interest in exploiting new noninvasive diagnostic tools, to increase the sensitivity of radiological diagnosis of HCC. Diffusion-weighted MR imaging and MR hepatobiliary contrast agents may represent useful tools for the detection and characterization of borderline hypovascular lesions by providing functional information such as water molecule motion in diffusion-weighted imaging and residual hepatobiliary function, which can be impaired early during the course of hepatocarcinogenesis. Also, dual-energy computed tomography (CT) represents an interesting new CT technology that could increase detectability and conspicuity of hypervascular lesions, thus possibly improving CT sensitivity in small HCCs. However, more data and further developments are needed to verify the usefulness of these new technologies in the diagnosis of HCC and to translate these recent advances into clinical practice. PMID- 27508184 TI - Potent efficacy signals from systemically administered oncolytic herpes simplex virus (HSV1716) in hepatocellular carcinoma xenograft models. AB - Oncolytic herpes simplex virus (HSV1716), lacking the neurovirulence factor ICP34.5, has highly selective replication competence for cancer cells and has been used in clinical studies of glioma, melanoma, head and neck squamous cell carcinoma, pediatric non-central nervous system solid tumors, and malignant pleural mesothelioma. To date, 88 patients have received HSV1716 and the virus is well tolerated, with selective replication in tumor cells and no spread to surrounding normal tissue. We assessed the potential value of HSV1716 in preclinical studies with two human hepatocellular carcinoma cell lines, HuH7 and HepG2-luc. HSV1716 displayed excellent replication kinetics in vitro in HepG2-luc cells, a cell line engineered to express luciferase, and virus-mediated cell killing correlated with loss of light emissions from the cells. In vivo, the HepG2-luc cells readily formed light-emitting xenografts that were easily visualized by an in vivo imaging system and efficiently eliminated by HSV1716 oncolysis after intratumoral injection. HSV1716 also demonstrated strong efficacy signals in subcutaneous HuH7 xenografts in nude mice after intravenous administration of virus. In the HuH7 model, the intravenously injected virus replicated prolifically immediately after efficient tumor localization, resulting in highly significant reductions in tumor growth and enhanced survival. Our preclinical results demonstrate excellent tumor uptake of HSV1716, with prolific replication and potent oncolysis. These observations warrant a clinical study of HSV1716 in hepatocellular carcinoma. PMID- 27508186 TI - Emerging role of dual antiplatelet therapy in the prevention of hepatitis B virus associated hepatocellular carcinoma. AB - Platelets, the chief effectors of vascular homeostasis, have been identified as important players in the pathogenesis of both acute and chronic liver disease in preclinical models of hepatitis B viral infection. Platelets are thought to promote the accumulation of virus-specific T-cells into the liver parenchyma. Importantly, the inhibition of platelet activation by clinically relevant doses of aspirin and clopidogrel was able to reduce immune-mediated necroinflammatory liver disease, extracellular matrix deposition, and hepatocellular carcinoma development; the same treatment was able to improve overall survival. These results strongly support the design of clinical trials aiming to define the potential of antiplatelet therapy in the prevention of hepatitis B virus associated hepatocellular carcinoma. PMID- 27508185 TI - Transarterial radioembolization using yttrium-90 microspheres in the treatment of hepatocellular carcinoma: a review on clinical utility and developments. AB - A selective intra-arterial liver injection using yttrium-90-loaded microspheres as sources for internal radiation therapy is a form of transarterial radioembolization (TARE). Current data from the literature suggest that TARE is effective in hepatocellular carcinoma (HCC) and is associated with a low rate of adverse events; however, they are all based on retrospective series or non controlled prospective studies, since randomized controlled trials comparing the other liver-directed therapies for intermediate and locally advanced stages HCC are still ongoing. The available data show that TARE provides similar or even better survival rates. TARE is very well tolerated and has a low rate of complications; these complications do not result from the embolic effects but mainly from the unintended irradiation to non-target tissue, including the liver parenchyma. The complications can be further reduced by accurate patient selection and a strict pre-treatment evaluation, including dosimetry and assessment of the vascular anatomy. First-line TARE is best indicated for intermediate-stage patients (according to the Barcelona Clinic Liver Cancer [BCLC] staging classification) who are poor candidates for transarterial chemoembolization or patients having locally advanced disease with segmental or lobar branch portal vein thrombosis. Moreover, data are emerging regarding the use of TARE in patients classified slightly above the criteria for liver transplantation with the purpose of downstaging them. TARE can also be applied as a second-line treatment in patients progressing to transarterial chemoembolization or sorafenib; a large number of Phase II/III trials are in progress in order to evaluate the best association with systemic therapies. Given the complexity of a correct treatment algorithm for potential TARE candidates and the need for clinical guidance, a comprehensive review was carried out analyzing both the best selection criteria of patients who really benefit from TARE and the new advances of this therapy which add significant value to the therapeutic weaponry against HCC. PMID- 27508187 TI - Chemoembolization with drug-eluting microspheres (DEM-TACE) for hepatocellular carcinoma: single-center review of safety and efficacy. AB - PURPOSE: This study examines the safety and efficacy of transarterial chemoembolization using doxorubicin-loaded 30-60 um QuadraSphere microspheres (DEM-TACE) for the treatment of hepatocellular carcinoma. MATERIALS AND METHODS: Over 10 weeks, patients with hepatocellular carcinoma. (Child-Pugh A/B: 65%/35%) were embolized with 30-60 um QuadraSphere microspheres. Excluded patients had previous locoregional therapy, macrovascular invasion, extrahepatic disease, Child-Pugh score >B7, ECOG performance status >0, and total bilirubin >3 mg/dL. Technical success, minor and major complications, 30-day hospital readmission rate, and 30-day mortality were assessed. alpha-Fetoprotein levels before and after treatment were compared. Local response was evaluated by radiologic tumor response per modified Response Evaluation Criteria in Solid Tumors 1 month after treatment. RESULTS: Thirty tumors (mean size, 2.3 cm; range, 1.0-4.9 cm) were treated in 20 patients (16 male and 4 female; mean age, 64.7 years). There were no major complications. Thirty-day mortality was 0%. Minor complications included postembolization syndrome in 16.7% of cases and transient rise in liver enzymes requiring no therapy. Mean alpha-fetoprotein levels trended down following treatment (71.8+/-201.9 ng/mL vs 53.4+/-116.7 ng/mL), but were not statistically significant. Complete response was achieved in 30% of patients, partial response in 35%, stable disease in 30%, and progression of disease in 5%. Overall objective response was 65%. Mean follow-up was 10.4 months (range, 2-16.4 months). CONCLUSION: DEM-TACE with doxorubicin-loaded 30-60 um QuadraSpheres is feasible, well tolerated, and associated with promising tumor response in early and intermediate stage disease. PMID- 27508188 TI - Welcome to Journal of Hepatocellular Carcinoma. PMID- 27508189 TI - Untreated hepatocellular carcinoma in Egypt: outcome and prognostic factors. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer worldwide as well as in Egypt with hepatitis C and B, alcohol and aflatoxins being the commonest risk factors. AIM: The objective of this study was to assess the prognostic factors affecting overall survival (OS) of untreated HCC in Egypt. METHODS: This retrospective study was conducted at Tanta Cancer Center, Egypt where 288 HCC cases who received no specific therapy and were followed-up until death were identified. The impact of possible prognostic factors on OS was assessed using the log-rank test (univariate analyses) and Cox regression method (multivariate analysis). RESULTS: The median OS of untreated HCC was 2.3 months (95% confidence interval: 1.9-2.6). The 1, 3, 6, 12, 24 months OS rates were 84%, 42%, 21%, 9%, and 3%, respectively. All cases had died by 46 months. Male sex, advanced Child Pugh class, the clinical presentation of ascites, cough, fatigue, and the presence of metastases were associated with poor survival (P<0.05 for all). In multivariate analysis; cough, presence of ascites, and Child-Pugh class were independent predictors of poor survival. CONCLUSION: OS in untreated HCC in Egypt is very short. Many factors interact to produce this dismal survival. PMID- 27508190 TI - Emerging role of Toll-like receptor 4 in hepatocellular carcinoma. AB - Toll-like receptor (TLR) signaling has been implicated in inflammatory-related cancers. The upregulation of TLR signaling in hepatocellular carcinoma (HCC) suggests that it may play an essential role in the prognosis of chronic and inflammatory diseases that ultimately culminate in HCC. Here, we provide evidence about the involvement of the TLR pathway in the initiation, progression, and metastasis of HCC. The differential expression of TLR in epithelial cells has also been discussed. In particular, we emphasize the physiological role of TLR4 in the development and pathogenesis of HCC and propose novel and promising approaches for HCC therapeutics with the aid of TLR ligands. PMID- 27508191 TI - A clinical perspective of the link between metabolic syndrome and hepatocellular carcinoma. AB - Metabolic syndrome (MS), which is defined as a constellation of clinico biological features closely related to insulin-resistance has reached epidemic levels in Western Europe and Northern America. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of MS. As its incidence parallels that of MS, NAFLD is currently becoming one of the most frequent chronic liver diseases in Western countries. On one hand, MS favors the development of hepatocellular carcinoma (HCC) either through NAFLD liver parenchymal alterations (steatosis; steatohepatitis; fibrosis), or in the absence of significant underlying liver parenchyma changes. In this setting, HCC are often diagnosed incidentally, tend to be larger than in patients developing HCC on cirrhosis and therefore frequently require major liver resections. On the other hand, MS patients are at increased risk of both liver-related postoperative complications and increased cardiorespiratory events leading to non-negligible mortality rates following liver surgery. These deleterious effects seem to be related to the existence of impaired liver function even in the absence of severe fibrosis but also higher cardiorespiratory sensitivity in a setting of MS/NAFLD. Hence, specific medical and surgical improvements in the perioperative management of these patients are required. These include complete preoperative cardiorespiratory work-up and the wide use of preoperative liver volume modulation. Finally, the long-term prognosis after curative surgery for MS related HCC does not seem to be worse than for other HCC occurring on classical chronic liver diseases. This is probably related to less aggressive tumor behavior with lower micro vascular invasion and decreased rates of poorly differentiated lesions. In this setting, several medical therapies including metformin could be of value in the prevention of both occurrence and recurrence of HCC. PMID- 27508192 TI - c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma. AB - c-MET is the membrane receptor for hepatocyte growth factor (HGF), also known as scatter factor or tumor cytotoxic factor, a mitogenic growth factor for hepatocytes. HGF is mainly produced by cells of mesenchymal origin and it mainly acts on neighboring epidermal and endothelial cells, regulating epithelial growth and morphogenesis. HGF/MET signaling has been identified among the drivers of tumorigenesis in human cancers. As such, c-MET is a recognized druggable target, and against it, targeted agents are currently under clinical investigation. c-MET overexpression is a common event in a wide range of human malignancies, including gastric, lung, breast, ovary, colon, kidney, thyroid, and liver carcinomas. Despite c-MET overexpression being reported by a large majority of studies, no evidence for a c-MET oncogenic addiction exists in hepatocellular carcinoma (HCC). In particular, c-MET amplification is a rare event, accounting for 4%-5% of cases while no mutation has been identified in c-MET oncogene in HCC. Thus, the selection of patient subgroups more likely to benefit from c-MET inhibition is challenging. Notwithstanding, c-MET overexpression was reported to be associated with increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition. Here we summarize the role of activated HGF/MET signaling in HCC, its prognostic relevance, and the implications for therapeutic approaches in HCC. PMID- 27508193 TI - Early alpha-fetoprotein response predicts survival in patients with advanced hepatocellular carcinoma treated with sorafenib. AB - BACKGROUND: It is not clear whether tumor marker responses can predict survival during sorafenib treatment in hepatocellular carcinoma (HCC). We investigated whether the alpha-fetoprotein (AFP) response is associated with survival in patients with advanced HCC treated with sorafenib. METHODS: We retrospectively reviewed the records of 126 patients with advanced HCC treated with sorafenib between 2007 and 2012. An AFP response was defined as >20% decrease from baseline. At 6-8 weeks after commencing sorafenib, AFP and radiological responses were assessed by modified Response Evaluation Criteria in Solid Tumors. RESULTS: The median overall survival (OS) and progression-free survival (PFS) were 6.2 and 3.5 months, respectively. Of the study population, a partial response (PR) was identified in 5 patients (4.0%), stable disease (SD) in 65 patients (51.6%), and progressive disease (PD) in 57 patients (44.4%), respectively. AFP non-response was an independent prognostic factor for poor OS (median 10.9 months for AFP response vs 5.2 months for AFP non-response), together with Child-Pugh B, tumor diameter >=10 cm, and portal vein invasion (all P<0.05), and PFS (median 5.3 months for AFP response vs 2.9 months for AFP non-response), together with tumor diameter >=10 cm and portal vein invasion (all P<0.05). SD or PR was more frequently found in AFP responders than in non-responders (72.1% vs 47.0%, respectively; P=0.007). In a sub-group with SD, OS (median 12.7 vs 5.8 months, respectively) and PFS (median 9.1 vs 3.7 months, respectively) were significantly longer in AFP responders than in non-responders (all P<0.05). CONCLUSION: Early AFP response may be useful for predicting survival in patients with advanced HCC treated with sorafenib. PMID- 27508194 TI - Hepatocellular carcinoma ablation and possible immunity in the age of nanosecond pulsed electric fields. PMID- 27508195 TI - Hapten-enhanced overall survival time in advanced hepatocellular carcinoma by ultro-minimum incision personalized intratumoral chemoimmunotherapy. AB - PURPOSE: To compare the therapeutic effects of ultra-minimum incision personalized intratumoral chemoimmunotherapy (UMIPIC) with intratumoral chemotherapy (ITCT) in the treatment of advanced hepatocellular carcinomas and to analyze the effect of hapten as an immune booster. MATERIALS AND METHODS: Patients with advanced hepatocellular carcinomas were treated with UMIPIC or ITCT with the same therapeutic procedure; the UMIPIC method had a proprietary regimen including an oxidant, a cytotoxic drug, and hapten, while ITCT delivered the same drug excluding hapten. Of 339 patients in total, 119 of the UMIPIC patients (n=214) had response data and 214 had survival data, and of the ITCT patients (n=125), 61 had response data and 125 had survival data. Tumor response was assessed with a computed tomography scan 6-8 weeks after the initial treatment; the survival rate was evaluated by follow-up visits. Tumor size was classified as small (<5 cm), large (5-10 cm), or very large (>10 cm); tumor sizes with liver function categorized using Child-Pugh class (A and B) were analyzed by correlation with overall survival. RESULTS: The response rates (complete response + partial response + stable disease) were 78.68% and 81.52% in the UMIPIC and ITCT groups, respectively, with no statistically significant difference; however, the median overall survival was 7 months for UMIPIC (test) and 4 months for ITCT (control), respectively (P<0.01). The 6-month and 1-year survival rates for UMIPIC and ITCT were 58.88% vs 32.3% and 30.37% vs 13.6%, respectively (P<0.01). Single and multiple UMIPIC revealed significant improvement in overall survival compared to that of ITCT. Child-Pugh class A patients had a longer duration of survival compared to Child-Pugh class B patients in UMIPIC therapy. CONCLUSION: Hapten had enhanced therapeutic effect with improvement in the survival duration in UMIPIC compared to ITCT. After reexamination, the response rate was not different due to inflammation caused by hapten. Hapten has been found to play an important role in immunotherapy to improve patient survival. PMID- 27508196 TI - Emerging role of Hpo signaling and YAP in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related mortality worldwide. Due to the poor prognosis and limited therapeutic options, there is great interest in further understanding better the molecular underpinnings and potential molecular targets associated with HCC. The Hippo (Hpo) signaling pathway and YAP, its principal downstream effector, represent an innovative area of research in HCC. Pioneered in Drosophila melanogaster, the Hpo cascade controls tissue homeostasis including organ size, cell proliferation, apoptosis, as well as cell-cycle regulation and differentiation. This conserved kinase cascade in mammals depends on central control by the tumor suppressor mammalian sterile 20-like kinase 1/2 (Mst1/2). The Mst1/2 commences the downstream kinase cascade, ultimately activating the oncoprotein YAP and allowing its physical association with downstream targets to enhance the gene expression signatures that are involved in proliferation and survival. Alterations in YAP expression and defective regulation of other key Hpo pathway members, such as Mst1/2, Salvador, neurofibromatosis and Mer (Nf2/mer), large tumor suppressor homolog 1/2 (Lats1/2), and Mps one binder kinase activator like 1A and 1B (Mob1) drive carcinogenesis in animal models. The dysregulation of the Hpo pathway - resulting in an unchecked activation of YAP - culminates in the development of a broad range of human tumor types, including HCC. The abrogation of Mst1/2-mediated YAP phosphorylation permits YAP entry into the nucleus in murine models and functions similarly in human HCCs. Chemoresistance mechanisms displayed by HCC tumors occur in a YAP-dependent manner. The HCC specimens exhibit YAP overexpression, and YAP serves as an independent prognostic marker for disease-free survival and overall survival in patients with HCC. Recently, the small molecule inhibitor, verteporfin has been shown to attenuate YAP activity in murine models, perhaps offering a novel therapeutic approach for patients with advanced HCC. PMID- 27508197 TI - Ambovex((r)) as a novel immunological modulator drug for the treatment of hepatocellular carcinoma (HCC) in the liver: a Phase II clinical trial. AB - Hepatocellular carcinoma (HCC) is a global public health problem, based on it being the fifth most common cancer and third leading cause of cancer-related mortality worldwide. The approved conventional treatment methods for HCC have shown life-threatening side effects with limited or negligible success, especially in multifocal HCC. As a consequence, new therapeutic approaches are being explored, including immunoregulatory molecules that may have the potential to treat or delay the progression of HCC. A novel pharmaceutical botanical drug - Ambovex((r)), an immune-modulator molecule - was tested to treat or delay the progress of HCC. We conducted a 6-month randomized clinical trial with an additional 3-month washing period (no treatment) to evaluate the safety and efficacy of low-dose Ambovex oral spray in treating patients with HCC. The clinical study involved a total of 40 patients, with 33 in the treatment group and seven in the control group. The alpha-fetoprotein (AFP) levels were measured every month and ultrasound scans were performed at time zero and every 2 months thereafter. Computed tomography (CT) scans were performed for patients in the treatment group. Ambovex proved to be safe, as there were no significant side effects although some patients found that the drug has unpleasant taste. AFP analysis showed a significant decrease in its level (alpha=0.05; 95% confidence interval) in the treatment group when compared to the control group at 3 months (P=0.0031) and at 6 months (P=0.007). The ultrasound results showed improvement in the treated group, as evidenced by a significant decrease in the lesion numbers and sizes. The lesions in 38% of treated patients decreased from multiple to single with major improvements; 35% of patients exhibited a decrease from multiple lesions to multiple lesions with minor improvements, whereas 27% had stabilized lesions. CT scans in the treated group showed significant improvement, as there was complete disappearance of the lesions after 6 months of treatment with Ambovex in two patients. This clinical study showed the effective and promising results of Ambovex as an immunological modulator in treating HCC. Further exploration of Ambovex is recommended. PMID- 27508198 TI - The androgen receptor as an emerging target in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the male-dominant liver diseases with poor prognosis, although treatments for HCC have been progressing in the past decades. Androgen receptor (AR) is a member of the nuclear receptor superfamily. Previous studies reported that AR was expressed in human HCC and non-HCC tissues. AR is activated both ligand-dependently and ligand-independently. The latter is associated with a mitogen-activated protein kinase-, v-akt murine thymoma viral oncogene homolog 1-, or signal-transducer and activator of transcription signaling pathway, which has been implicated in the development of HCC. It has been reported that more than 200 RNA expression levels are altered by androgen treatment. In the liver, androgen-responsive genes are cytochrome P450s, transforming growth factor beta, vascular endothelial growth factor, and glucose regulated protein 78 kDa, which are also associated with human hepatocarcinogenesis. Recent studies also revealed that AR plays a role in cell migration and metastasis. It is possible that cross-talk among AR-signaling, endoplasmic reticulum stress, and innate immune response is important for human hepatocarcinogenesis and HCC development. This review shows that AR could play a potential role in human HCC and represent one of the important target molecules for the treatment of HCC. PMID- 27508200 TI - Whither alpha-FP in the diagnosis of hepatocellular carcinoma? PMID- 27508199 TI - State-of-the-art cross-sectional liver imaging: beyond lesion detection and characterization. AB - Cross-sectional imaging with computed tomography or magnetic resonance imaging is routinely used to detect and diagnose liver lesions; however, these examinations can provide additional important information. The improvement of equipment and techniques has allowed outstanding evaluation of the vascular and biliary anatomy, which is practicable in most routine examinations. Anatomical variants may exclude patients from certain therapeutic options and may be the cause of morbidity or mortality after surgery or interventional procedures. Diffuse liver disease, such as steatosis, hemochromatosis, or fibrosis, must be diagnosed and quantified. Usually these conditions are silent until the late stages, and imaging plays an important role in detecting them early. Additionally, a background of diffuse disease may interfere in a focal lesion systematic reasoning. The diagnostic probability of a particular nodule varies according to the background liver disease. Nowadays, most diffuse liver diseases can be easily and accurately quantified by imaging, which has allowed better understanding of these diseases and improved patient management. Finally, cross-sectional imaging can calculate total and partial liver volumes and estimate the future liver remnant after hepatectomy. This information helps to select patients for portal vein embolization and reduces postoperative complications. Use of a specific hepatic contrast agent on magnetic resonance imaging, in addition to improving detection and characterization of focal lesions, provides functional global and segmental information about the liver parenchyma. PMID- 27508201 TI - Transarterial chemoembolization for hepatocellular carcinoma: an evidence-based review of its place in therapy. AB - Transarterial chemoembolization (TACE) is the standard treatment for patients with Barcelona Clinic Liver Cancer-intermediate stage hepatocellular carcinoma (HCC). The concept of drug-eluting bead TACE builds on the rationale of intratumoral drug delivery, and drug-eluting bead TACE has been shown to provide consistent and reliable results and to significantly diminish systemic drug exposure, liver toxicity, and drug-related adverse events as compared with conventional TACE. Based on the belief that combinations of TACE and other local or systemic therapies have several theoretical advantages, many clinical trials have been conducted to evaluate the effectiveness of TACE in combination with local treatment such as radiofrequency ablation or radiotherapy, and systemic therapy such as sorafenib or another molecular therapy. TACE has also been used as a preoperative adjuvant chemotherapy in patients with HCC to improve survival and as a bridging therapy before liver transplantation to downstage HCC. In the present evidence-based review, the authors summarize the current status of these transcatheter arterial embolic therapies in HCC. PMID- 27508203 TI - Role of endoscopic ultrasound in diagnosis and management of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is an aggressive tumor and a leading cause of cancer-related deaths globally. The mortality rate remains high despite many advances in treatment. HCC is frequently diagnosed late in its course due to lack of classical symptoms at earlier stages. Endoscopic ultrasound (EUS) has emerged as an important diagnostic tool for the diagnostic evaluation, staging, and treatment of gastrointestinal tract disorders. EUS-guided fine needle aspiration has been a valuable addition to EUS by being able to obtain tissue under direct visualization. Here, we review the potential role of EUS in the diagnosis and management of HCC. EUS seems to be a safe and reliable alternative method for obtaining tissue for diagnosis of liver cancer, especially for lesions that are inaccessible by traditional methods. EUS could play an important role in the diagnosis and management of HCC. PMID- 27508202 TI - Type I insulin-like growth factor as a liver reserve assessment tool in hepatocellular carcinoma. AB - Chronic liver diseases (CLDs) encompass a wide range of illnesses, including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and viral hepatitis. Deterioration of liver capacity, with subsequent progression into cirrhosis and hepatocellular carcinoma (HCC), ultimately leads to a further decrease in the hepatic reserve. The Child-Turcotte-Pugh scoring system is the standard tool for assessing underlying liver reserve capacity in routine practice and in clinical trials of CLD and HCC. In this review, we highlight the clinical significance of insulin-like growth factor-I (IGF-I) and the growth hormone (GH) signaling pathway in HCC. IGF-I could be a marker for liver reserve capacity in CLDs and HCC in clinical practice. This approach could improve the risk assessment and stratifications of patients on the basis of their underlying liver reserve, either before active treatment in routine practice or before they are enrolled in clinical trials. PMID- 27508204 TI - Fibrolamellar hepatocellular carcinoma: current clinical perspectives. AB - Fibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC), which comprises ~1%-9% of all HCCs. Although FLC is a variant of HCC, it is distinct from HCC in that it most often affects younger patients (10-35 years of age) with no underlying liver disease. FLC often presents with vague abdominal pain, nausea, abdominal fullness, malaise, and weight loss. Surgery is the current mainstay of treatment for FLC and remains the only potentially curative option. While FLCs are considered less responsive to chemotherapy than their classic HCC counterparts, there have been suggestions that multimodality treatments may be effective, especially in advanced cases. Further research is necessary to determine effective systemic therapies as an adjunct to surgery for FLC. PMID- 27508205 TI - Comparing Outcomes of Two Types of Bariatric Surgery in an Adolescent Obese Population: Roux-en-Y Gastric Bypass vs. Sleeve Gastrectomy. AB - BACKGROUND: Obesity is prevalent among adolescents and is associated with serious health consequences. Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG) are bariatric procedures that cause significant weight loss in adults and are increasingly being performed in adolescents with morbid obesity. Data comparing outcomes of RYGB vs. SG in this age-group are scarce. This study aims to compare short-term (1-6 months) and longer-term (7-18 months) body mass index (BMI) and biochemical outcomes following RYGB and SG in adolescents/young adults. METHODS: A retrospective study using data extracted from medical records of patients 16-21 years who underwent RYGB or SG between 2012 and 2014 at a tertiary care academic medical center. RESULTS: Forty-six patients were included in this study: 24 underwent RYGB and 22 underwent SG. Groups did not differ for baseline age, sex, race, or BMI. BMI reductions were significant at 1-6 months and 7-18 months within groups (p < 0.0001), but did not differ by surgery type (p = 0.65 and 0.09, for 1-6 months and 7-18 months, respectively). Over 7-18 months, within group improvement in low-density lipoprotein (LDL) (-24 +/- 6 in RYGB, p = 0.003, vs. -7 +/- 9 mg/dl in SG, p = 0.50) and non-high-density lipoprotein (non-HDL) cholesterol (-23 +/- 8 in RYGB, p = 0.02, vs. -12 +/- 7 in SG, p = 0.18) appeared to be of greater magnitude following RYGB. However, differences between groups did not reach statistical significance. When divided by non-alcoholic steatohepatitis stages (NASH), patients with Stage II-III NASH had greater reductions in alanine aminotransferase levels vs. those with Stage 0-I NASH (-45 +/- 18 vs. -9 +/- 3, p = 0.01) after 7-18 months. RYGB and SG groups did not differ for the magnitude of post-surgical changes in liver enzymes. CONCLUSION: RYGB and SG did not differ for the magnitude of BMI reduction across groups, though changes trended higher following RYGB. Further prospective studies are needed to confirm these findings. PMID- 27508206 TI - New Insights into How Trafficking Regulates T Cell Receptor Signaling. AB - There is emerging evidence that exocytosis plays an important role in regulating T cell receptor (TCR) signaling. The trafficking molecules involved in lytic granule (LG) secretion in cytotoxic T lymphocytes (CTL) have been well-studied due to the immune disorder known as familial hemophagocytic lymphohistiocytosis (FHLH). However, the knowledge of trafficking machineries regulating the exocytosis of receptors and signaling molecules remains quite limited. In this review, we summarize the reported trafficking molecules involved in the transport of the TCR and downstream signaling molecules to the cell surface. By combining this information with the known knowledge of LG exocytosis and general exocytic trafficking machinery, we attempt to draw a more complete picture of how the TCR signaling network and exocytic trafficking matrix are interconnected to facilitate T cell activation. This also highlights how membrane compartmentalization facilitates the spatiotemporal organization of cellular responses that are essential for immune functions. PMID- 27508207 TI - Increased Ghrelin but Low Ghrelin-Reactive Immunoglobulins in a Rat Model of Methotrexate Chemotherapy-Induced Anorexia. AB - BACKGROUND AND AIMS: Cancer chemotherapy is commonly accompanied by mucositis, anorexia, weight loss, and anxiety independently from cancer-induced anorexia cachexia, further aggravating clinical outcome. Ghrelin is a peptide hormone produced in gastric mucosa that reaches the brain to stimulate appetite. In plasma, ghrelin is protected from degradation by ghrelin-reactive immunoglobulins (Ig). To analyze possible involvement of ghrelin in the chemotherapy-induced anorexia and anxiety, gastric ghrelin expression, plasma levels of ghrelin, and ghrelin-reactive IgG were studied in rats treated with methotrexate (MTX). METHODS: Rats received MTX (2.5 mg/kg, subcutaneously) for three consecutive days and were killed 3 days later, at the peak of anorexia and weight loss. Control rats received phosphate-buffered saline. Preproghrelin mRNA expression in the stomach was analyzed by in situ hybridization. Plasma levels of ghrelin and ghrelin-reactive IgG were measured by immunoenzymatic assays and IgG affinity kinetics by surface plasmon resonance. Anxiety- and depression-like behaviors in MTX-treated anorectic and in control rats were evaluated in the elevated plus maze and the forced-swim test, respectively. RESULTS: In MTX-treated anorectic rats, the number of preproghrelin mRNA-producing cells was found increased (by 51.3%, p < 0.001) as well were plasma concentrations of both ghrelin and des-acyl ghrelin (by 70.4%, p < 0.05 and 98.3%, p < 0.01, respectively). In contrast, plasma levels of total IgG reactive with ghrelin and des-acyl-ghrelin were drastically decreased (by 87.2 and 88.4%, respectively, both p < 0.001), and affinity kinetics of these IgG were characterized by increased small and big Kd, respectively. MTX-treated rats displayed increased anxiety- but not depression like behavior. CONCLUSION: MTX-induced anorexia, weight loss, and anxiety are accompanied by increased ghrelin production and by a decrease of ghrelin-reactive IgG levels and affinity binding properties. Such changes of ghrelin-reactive IgG may underlie their decreased ghrelin-transporting capacities compromising ghrelin orexigenic and anxiolytic effects and contributing to chemotherapy-induced loss of appetite. PMID- 27508208 TI - PLS-Based and Regularization-Based Methods for the Selection of Relevant Variables in Non-targeted Metabolomics Data. AB - Non-targeted metabolomics constitutes a part of the systems biology and aims at determining numerous metabolites in complex biological samples. Datasets obtained in the non-targeted metabolomics studies are high-dimensional due to sensitivity of mass spectrometry-based detection methods as well as complexity of biological matrices. Therefore, a proper selection of variables which contribute into group classification is a crucial step, especially in metabolomics studies which are focused on searching for disease biomarker candidates. In the present study, three different statistical approaches were tested using two metabolomics datasets (RH and PH study). The orthogonal projections to latent structures discriminant analysis (OPLS-DA) without and with multiple testing correction as well as the least absolute shrinkage and selection operator (LASSO) with bootstrapping, were tested and compared. For the RH study, OPLS-DA model built without multiple testing correction selected 46 and 218 variables based on the VIP criteria using Pareto and UV scaling, respectively. For the PH study, 217 and 320 variables were selected based on the VIP criteria using Pareto and UV scaling, respectively. In the RH study, OPLS-DA model built after correcting for multiple testing, selected 4 and 19 variables as in terms of Pareto and UV scaling, respectively. For the PH study, 14 and 18 variables were selected based on the VIP criteria in terms of Pareto and UV scaling, respectively. In the RH and PH study, the LASSO selected 14 and 4 variables with reproducibility between 99.3 and 100%, respectively. In the light of PLS-based models, the larger the search space the higher the probability of developing models that fit the training data well with simultaneous poor predictive performance on the validation set. The LASSO offers potential improvements over standard linear regression due to the presence of the constrain, which promotes sparse solutions. This paper is the first one to date utilizing the LASSO penalized logistic regression in untargeted metabolomics studies. PMID- 27508209 TI - Bilateral vertebral artery occlusion without headache in giant cell arteritis. PMID- 27508210 TI - Early indicators of relapses vs pseudorelapses in neuromyelitis optica spectrum disorder. AB - OBJECTIVE: The purpose of this study was to review cases of neuromyelitis optica spectrum disorder (NMOSD) relapses and pseudorelapses to identify early features that differentiate between them at onset of symptoms. METHODS: This was a retrospective analysis of 74 hospitalizations of patients with NMOSD who were admitted to the Johns Hopkins Hospital for workup and treatment of a presumed relapse. Standard workup included MRI and blood and urine testing for metabolic and infectious etiologies. The gold standard for a relapse was defined as new or worsening symptoms and a change in neurologic examination correlating with a new or enhancing MRI lesion. A pseudorelapse was a clinical exacerbation with similar symptoms and signs but the MRI was negative, and workup identified an alternative cause for the symptoms that, when treated, resulted in the improvement of neurologic symptoms. Factors considered to be early predictors of relapses vs pseudorelapses were analyzed using the Fisher test. RESULTS: Among 74 NMOSD hospitalizations for presumed relapse, 57 were confirmed relapses while 17 had a negative MRI and an identifiable cause of pseudorelapse. The most common causes of pseudorelapse were infection, pain, and dysautonomia. The only early predictor that reliably differentiated relapse from pseudorelapse among this NMOSD patient population was vision loss (p = 0.039). Race, sex, presentations of weakness, numbness, and bowel/bladder dysfunction, white blood cell count, and urinary tract infection were not different among patients with relapses vs pseudorelapses. CONCLUSIONS: Vision loss in NMOSD is strongly suggestive of a true relapse vs a pseudorelapse. Pseudorelapses localized to the spinal cord in patients with previous myelitis presented similarly to true relapses and could only be ruled out by a negative MRI. PMID- 27508211 TI - Low-Income First-Time Mothers: Effects of APN Follow-up Using Mobile Technology on Maternal and Infant Outcomes. AB - Background. Low-income mothers have greater challenges in accessing health care services due changes in the health care system and budget cuts. The purpose of this randomized clinical trial was to test a nurse practitioner (NP) intervention using cell phone and texting on maternal/infant outcomes. Methods. The sample included 129 mother-infant pairs. Intervention group mothers received NP 2-way cell phone follow-up intervention post-hospital discharge for 6 months. Results. Intervention mothers' perceived social support was significantly higher. Intervention infants received their first newborn follow-up visit significantly earlier (6 vs 9 days); significantly more infants were immunized at recommended times (2, 4, and 6 months of age); and there were fewer infant morbidities compared to controls. The intervention saved between $51 030 and $104 277 in health care costs averted. Conclusion. This easy-to-use, safe intervention is an effective way to reach a wide range of populations and demonstrated improved maternal/infant outcomes and decreased cost. PMID- 27508212 TI - Thrombosis of Kommerell's diverticulum with subclavian steal phenomenon in a patient with non-small cell lung carcinoma under chemotherapy. AB - Kommerell's diverticulum (KD) is defined as a bulbous dilatation of the origin of an aberrant subclavian artery due to a remnant of the left fourth aortic arch. We report the case of an asymptomatic woman in whom progressive thrombosis of the KD extending to the prevertebral tract of an aberrant right subclavian artery was detected at multidetector computed tomography imaging for lung cancer staging performed before and after the beginning of chemotherapy. Reversed blood flow in the ipsilateral vertebral artery due to subclavian steal phenomenon was also observed by color Doppler ultrasound examination. PMID- 27508213 TI - Data correlations between gender, cytomegalovirus infection and T cells, NK cells, and soluble immune mediators in elderly humans. AB - We describe a cohort of 50 elderly subjects, age at least 70 years. We present gender-specific findings in T lymphocyte markers and soluble immune mediators. We show the correlation between cytomegalovirus infection status with CD56(dim) NK cell responses to a variety of stimuli and with CD56(bright)/CD56(dim) NK cell ratio. We also present the correlation of retinol binding protein (RBP)-4 plasma levels with NK cell responses and we explore the relationship between gender and adiponectin, 25(OH)D (vitamin D), and RBP4 in affecting CD56(dim) NK cell responses. These data are discussed in Al-Attar et al. (2016) [1]. PMID- 27508214 TI - Large-scale gene expression profiling data of bone marrow stromal cells from osteoarthritic donors. AB - This data article contains data related to the research article entitled, "in vitro characterization of bone marrow stromal cells from osteoarthritic donors" [1]. Osteoarthritis (OA) represents the main indication for total joint arthroplasty and is one of the most frequent degenerative joint disorders. However, the exact etiology of OA remains unknown. Bone marrow stromal cells (BMSCs) can be easily isolated from bone marrow aspirates and provide an excellent source of progenitor cells. The data shows the identification of pivotal genes and pathways involved in osteoarthritis by comparing gene expression patterns of BMSCs from osteoarthritic versus healthy donors using an array-based approach. PMID- 27508215 TI - Phylodynamic analysis of porcine circovirus type 2: Methodological approach and datasets. AB - Since its first description, PCV2 has emerged as one of the most economically relevant diseases for the swine industry. Despite the introduction of vaccines effective in controlling clinical syndromes, PCV2 spread was not prevented and some potential evidences of vaccine immuno escape have recently been reported ("Complete genome sequence of a novel porcine circovirus type 2b variant present in cases of vaccine failures in the United States" (Xiao and Halbur, 2012) [1], "Genetic and antigenic characterization of a newly emerging porcine circovirus type 2b mutant first isolated in cases of vaccine failure in Korea" (Seo et al., 2014) [2]). In this article, we used a collection of PCV2 full genomes, provided in the present manuscript, and several phylogentic, phylodynamic and bioinformatic methods to investigate different aspects of PCV2 epidemiology, history and evolution (more thoroughly described in "PHYLODYNAMIC ANALYSIS of PORCINE CIRCOVIRUS TYPE 2 REVEALS GLOBAL WAVES of EMERGING GENOTYPES and the CIRCULATION of RECOMBINANT FORMS"[3]). The methodological approaches used to consistently detect recombiantion events and estimate population dymanics and spreading patterns of rapidly evolving ssDNA viruses are herein reported. Programs used are described and original scripts have been provided. Ensembled databases used are also made available. These consist of a broad collection of complete genome sequences (i.e. 843 sequences; 63 complete genomes of PCV2a, 310 of PCV2b, 4 of PCV2c, 217 of PCV2d, 64 of CRF01, 140 of CRF02 and 45 of CRF03.), divided in differnt ORF (i.e. ORF1, ORF2 and intergenic regions), of PCV2 genotypes and major Circulating Recombinat Forms (CRF) properly annotated with respective collection data and country. Globally, all of these data can be used as a starting point for further studies and for classification purpose. PMID- 27508216 TI - Clinical, neuropsychological, and pre-stimulus dorsomedial thalamic nucleus electrophysiological data in deep brain stimulation patients. AB - The data presented here comprise clinical, neuropsychological, and intrathalamic electrophysiological data from 7 patients with pharmacoresistant focal epilepsy and are related to the article "Pre-stimulus thalamic theta power predicts human memory formation" C.M. Sweeney-Reed, T. Zaehle, J. Voges, F.C. Schmitt, L. Buentjen, K. Kopitzki, et al. (2016) [1]. The patients participated in a memory paradigm after receiving electrodes implanted in the DMTN due to the surgical approach taken in electrode insertion for deep brain stimulation of the anterior thalamic nucleus. Epilepsy duration and pre-operative neuropsychological tests provide an indication of the profile of patients receiving intrathalamic electrode implantation and the memory capabilities in such a patient group. The electrophysiological data were recorded from the right DMTN preceding stimulus presentation during intentional memory encoding. The patients viewed a series of photographic scenes, which they judged as indoors or outdoors. The 900 ms epochs prior to stimulus presentation were labeled as preceding successful or unsuccessful subsequent memory formation according to a subsequent memory test for the items. The difference between theta power preceding successful versus unsuccessful subsequent memory formation is shown against time for each patient individually. PMID- 27508217 TI - NMR and computational data of two novel antimicrobial peptides. AB - Here we report details on the design and conformational analysis of two novel peptides showing antimicrobial properties, as reported in the research article, "New antimicrobial peptides against foodborne pathogens: from in silico design to experimental evidence" G. Palmieri, M. Balestrieri, Y.T.R. Proroga, L. Falcigno, A. Facchiano, A. Riccio, F. Capuano, R. Marrone, G. Campanile, A. Anastasio (2016) [1]. NMR data, such as chemical shifts in two different solvents as well as aCH protons deviations from random coil values and NOE patterns, are shown together with the statistics of structural calculations. Strategy and particulars of molecular design are presented. PMID- 27508218 TI - Human lung epithelial cell A549 proteome data after treatment with titanium dioxide and carbon black. AB - Here, we have described the dataset relevant to the A549 cellular proteome changes after exposure to either titanium dioxide or carbon black particles as compared to the non-exposed controls, "Proteomic changes in human lung epithelial cells (A549) in response to carbon black and titanium dioxide exposures" (Vuong et al., 2016) [1]. Detailed methodologies on the separation of cellular proteins by 2D-GE and the subsequent mass spectrometry analyses using MALDI-TOF-TOF-MS are documented. Particle exposure-specific protein expression changes were measured via 2D-GE spot volume analysis. Protein identification was done by querying mass spectrometry data against SwissProt and RefSeq protein databases using Mascot search engine. Two-way ANOVA analysis data provided information on statistically significant A549 protein expression changes associated with particle exposures. PMID- 27508219 TI - Dataset of milk whey proteins of two indigenous greek goat breeds. AB - Due to its rarity and unique biological traits, as well as its growing financial value, milk of dairy Greek small ruminants is continuously attracting interest from both the scientific community and industry. For the construction of the present dataset, cutting-edge proteomics methodologies were employed, in order to investigate and characterize, for the first time, the milk whey proteome from the two indigenous Greek goat breeds, Capra prisca and Skopelos. In total 822 protein groups were identified in milk whey of the two breeds, The present data are further discussed in the research article "Milk of Greek sheep and goat breeds; characterization by means of proteomics" [1]. PMID- 27508220 TI - The dataset of proteins specifically interacted with activated TICAM-1. AB - The presented data are related with our paper entitled "14-3-3-zeta participates in TLR3-mediated TICAM-1 signal-platform formation" (Funami et al., 2016) [1]. These data show the proteins which specifically bind to the activated (oligomerized) TICAM-1. Fifty-three proteins were identified as specifically interacted with oligomerized TICAM-1. Mutant TICAM-1 cannot form the active oligomer, so the proteins interacted with mutant TICAM-1 are dispensable for TICAM-1-signaling. Among 53 proteins, 14-3-3-zeta specifically interacts with oligomerized TICAM-1 to corroborate TICAM-1 signalosome. PMID- 27508221 TI - Dataset of cocoa aspartic protease cleavage sites. AB - The data provide information in support of the research article, "The cleavage specificity of the aspartic protease of cocoa beans involved in the generation of the cocoa-specific aroma precursors" (Janek et al., 2016) [1]. Three different protein substrates were partially digested with the aspartic protease isolated from cocoa beans and commercial pepsin, respectively. The obtained peptide fragments were analyzed by matrix-assisted laser-desorption/ionization time-of flight mass spectrometry (MALDI-TOF/TOF-MS/MS) and identified using the MASCOT server. The N- and C-terminal ends of the peptide fragments were used to identify the corresponding in-vitro cleavage sites by comparison with the amino acid sequences of the substrate proteins. The same procedure was applied to identify the cleavage sites used by the cocoa aspartic protease during cocoa fermentation starting from the published amino acid sequences of oligopeptides isolated from fermented cocoa beans. PMID- 27508222 TI - Data on green Spanish-style Manzanilla table olives fermented in salt mixtures. AB - This article contains processed data related to the research published in "Fermentation in nutrient salt mixtures affects green Spanish-style Manzanilla table olives" [1]. It displays information on the salt substitution by other nutrient salts (potassium chloride and calcium chloride) during fermentation of green Spanish-style Manzanilla table olives to produce healthier products. Particularly, it studies the relationship between the different colour parameters (L*, a*, b* and C i), firmness, and sensory attributes (saltiness, bitterness, hardness, and fibrousness), and the composition of the initial brine in NaCl, KCl, and CaCl2. The composition of the brines affected the characteristics of the product. In general, the higher was the proportion of CaCl2 in the initial brines the better was the colour. Also, the presence of this salt mitigated the saltiness perception but increment those of bitterness, hardness, fibrousness, and crunchiness. Besides, most of the sensory attribute scores could successfully be predicted as a function of the Na, K, and Ca concentrations in the fermented olive flesh. The work allows the production of table olives with specific characteristics and predetermined mineral nutrient composition. PMID- 27508223 TI - Data regarding association between serum osteoprotegerin level, numerous of circulating endothelial-derived and mononuclear-derived progenitor cells in patients with metabolic syndrome. AB - Metabolic syndrome (MetS) is defined as cluster of multiple metabolic and cardiovascular (CV) abnormalities included abdominal obesity, high-normal blood pressure, dyslipidaemia, and impaired fasting glucose tolerance that exhibits has a growing prevalence worldwide. We investigated whether an elevated level of osteoprotegerin (OPG) predicts imbalance between different phenotypes of circulating endothelial (EPCs) and mononuclear (MPCs) progenitor cells in MetS patients. We have analyzed data regarding dysmetabolic disorder subjects without known CV disease), as well as with known type two diabetes mellitus. All patients have given their informed written consent for participation in the study. This article contains data on the independent predictors of depletion in numerous of circulating EPCs and MPCs in MetS patients. The data are supplemental to our original research article describing detailed associations of elevated OPG level in MetS patients with numerous of EPCs and MPCs beyond traditional CV risk factors. PMID- 27508224 TI - Dataset for an analysis of tourism and economic growth: A study of Sri Lanka. AB - We use the sample from 1978 to 2014 for the paper (doi:10.1016/j.tmp.2016.05.005). The data on GDP at constant 2005 USD (US dollar), and the gross fixed capital formation at constant 2005 USD are extracted from the World Bank (2015). The labour stock which includes direct and indirect employment and the tourism receipts (in USD) are sourced from the Sri Lanka Tourism Development Authority (http://www.sltda.lk/statistics). Tourism receipts as a per cent of GDP is used to measure tourism demand. The capital stock data is computed using perpetual inventory method, where a depreciation rate of 8 per cent is assumed with the initial capital stock as 1.05 times the GDP of 1969 at constant 2005 USD. The output per worker and capital per worker is computed by dividing the GDP and capital stock by the labour stock, respectively. PMID- 27508225 TI - Data supporting functional diversity of the marine bacterium Cobetia amphilecti KMM 296. AB - Data is presented in support of functionality of hyper-diverse protein families encoded by the Cobetia amphilecti KMM 296 (formerly Cobetia marina KMM 296) genome ("The genome of the marine bacterium Cobetia marina KMM 296 isolated from the mussel Crenomytilus grayanus (Dunker, 1853)" [1]) providing its nutritional versatility, adaptability and biocontrol that could be the basis of the marine bacterium evolutionary and application potential. Presented data include the information of growth and biofilm-forming properties of the food-associated isolates of Pseudomonas, Bacillus, Listeria, Salmonella and Staphylococcus under the conditions of their co-culturing with C. amphilecti KMM 296 to confirm its high inter-species communication and anti-microbial activity. Also included are the experiments on the crude petroleum consumption by C. amphilecti KMM 296 as the sole source of carbon in the presence of sulfate or nitrate to ensure its bioremediation capacity. The multifunctional C. amphilecti KMM 296 genome is a promising source for the beneficial psychrophilic enzymes and essential secondary metabolites. PMID- 27508226 TI - Data for the co-expression and purification of human recombinant CaMKK2 in complex with calmodulin in Escherichia coli. AB - Calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) has been implicated in a range of conditions and pathologies from prostate to hepatic cancer. Here, we describe the expression in Escherichia coli and the purification protocol for the following constructs: full-length CaMKK2 in complex with CaM, CaMKK2 'apo', CaMKK2 (165-501) in complex with CaM, and the CaMKK2 F267G mutant. The protocols described have been optimized for maximum yield and purity with minimal purification steps required and the proteins subsequently used to develop a fluorescence-based assay for drug binding to the kinase, "Using the fluorescent properties of STO-609 as a tool to assist structure-function analyses of recombinant CaMKK2" [1]. PMID- 27508227 TI - Data on characterizing the gene expression patterns of neuronal ceroid lipofuscinosis genes: CLN1, CLN2, CLN3, CLN5 and their association to interneuron and neurotransmission markers: Parvalbumin and Somatostatin. AB - The article contains raw and analyzed data related to the research article "Neuronal ceroid lipofuscinosis genes, CLN2, CLN3, CLN5 are spatially and temporally co-expressed in a developing mouse brain" (Fabritius et al., 2014) [1]. The processed data gives an understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN1, CLN2, CLN3 and CLN5 genes in a murine model. The data shows relationship between the expression pattern of these genes during neural development. Immunohistochemistry was used to identify known interneuronal markers for neurotransmission and cell proliferation: parvalbumin, somatostatin subpopulations of interneurons. Non-radioactive in-situ hybridization detected CLN5 mRNA in the hippocampus. Throughout the development strong expression of CLN genes were identified in the germinal epithelium and in ventricle regions, cortex, hippocampus, and cerebellum. This provides supportive evidence that CLN1, CLN2, CLN3 and CLN5 genes may be involved in synaptic pruning. PMID- 27508228 TI - Data of fluorescence, UV-vis absorption and FTIR spectra for the study of interaction between two food colourants and BSA. AB - In this data article, the fluorescence, UV-vis absorption and FTIR spectra data of BSA-AR1/AG50 system were presented, which were used for obtaining the binding characterization (such as binding constant, binding distance, binding site, thermodynamics, and structural stability of protein) between BSA and AR1/AG50. PMID- 27508229 TI - Proteomic dataset of Paracentrotus lividus gonads of different sexes and at different maturation stages. AB - We report the proteomic dataset of gonads from wild Paracentrotus lividus related to the research article entitled "Proteomic changes occurring along gonad maturation in the edible sea urchin Paracentrotus lividus" [1]. Gonads of three individuals per sex in the recovery, pre-mature, mature, and spent stages were analyzed using a shotgun proteomics approach based on filter-aided sample preparation followed by tandem mass spectrometry, protein identification carried out using Sequest-HT as the search engine within the Proteome Discoverer informatics platform, and label-free differential analysis. The dataset has been deposited in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PRIDE: PXD004200. PMID- 27508230 TI - Time-course gene expression data on the transcriptional effects of Aminaphtone on ECV304 endothelial cells. AB - We previously showed that Aminaphtone, a drug used in the treatment of chronic venous insufficiency, modulates several vasoactive factors, such as endothelin-1 and adhesion molecules. Here, we provide data of time-course experiments about the effects of Aminaphtone on gene expression at the genome-wide level in human endothelial cells undergoing cytokine stimulation in vitro. ECV-304 endothelial cells were incubated with interleukin-1beta (IL-1beta) in the presence or absence of Aminaphtone for 1, 3, and 6 h. Gene expression profiles were analyzed by microarray. This article contains complete data on the genes significantly modulated by the drug over time. The data are supplemental to our original research article reporting detailed analysis of the actions of Aminaphtone on IL 1beta stimulated endothelial cells at the molecular level, "Gene expression profiling reveals novel protective effects of Aminaphtone on ECV304 endothelial cells" (Salazar et al., 2016) [1]. PMID- 27508231 TI - Datasets of genes coexpressed with FBN1 in mouse adipose tissue and during human adipogenesis. AB - This article contains data related to the research article entitled "Expression of FBN1 during adipogenesis: relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions" [1]. The article concerns the expression of FBN1, the gene encoding the extracellular matrix protein fibrillin-1, during adipogenesis in vitro and in relation to adipose tissue in vivo. The encoded protein has recently been shown to produce a short glucogenic peptide hormone, (Romere et al., 2016) [2], and this gene is therefore a key gene for regulating blood glucose levels. FBN1 and coexpressed genes were examined in mouse strains and in human cells undergoing adipogenesis. The data show the genes that were coexpressed with FBN1, including genes coding for other connective tissue proteins and the proteases that modify them and for the transcription factors that control their expression. Data analysed were derived from datasets available in the public domain and the analysis highlights the utility of such datasets for ongoing analysis and hence reduction in the use of experimental animals. PMID- 27508232 TI - Real-world datasets for portfolio selection and solutions of some stochastic dominance portfolio models. AB - A large number of portfolio selection models have appeared in the literature since the pioneering work of Markowitz. However, even when computational and empirical results are described, they are often hard to replicate and compare due to the unavailability of the datasets used in the experiments. We provide here several datasets for portfolio selection generated using real-world price values from several major stock markets. The datasets contain weekly return values, adjusted for dividends and for stock splits, which are cleaned from errors as much as possible. The datasets are available in different formats, and can be used as benchmarks for testing the performances of portfolio selection models and for comparing the efficiency of the algorithms used to solve them. We also provide, for these datasets, the portfolios obtained by several selection strategies based on Stochastic Dominance models (see "On Exact and Approximate Stochastic Dominance Strategies for Portfolio Selection" (Bruni et al. [2])). We believe that testing portfolio models on publicly available datasets greatly simplifies the comparison of the different portfolio selection strategies. PMID- 27508233 TI - Data on optimized production and characterization of alkaline proteases from newly isolated alkaliphiles from Lonar soda lake, India. AB - Alkaline proteases are one of the industrially important enzymes and generally preferred from alkaliphilic sources. Here we have provided the data on optimized production and characterization of alkaline proteases from five newly isolated and identified alkaliphiles from Lonar soda lake, India. The data provided for optimization of physicochemical parameters for maximum alkaline proteases production is based on OVAT (one variable at a time) approach. Alkaline protease production (U/mL) recorded by using different agro industrial residues is included in the given data. Further readers can find more information in our previously published research article where we have already described about the methods used and comparative analysis of the data recorded regarding optimized production, characterization and application of alkaline proteases isolated from Lonar soda lake isolates (http://dx.doi.org/10.1016/j.bcab.2016.06.002) [1]. The data provided here by us is useful to other researchers for setting up various suitable statistical models to perform optimization studies other than OVAT approach. PMID- 27508234 TI - Data on daily fluoride intake based on drinking water consumption prepared by household desalinators working by reverse osmosis process. AB - In this data article, we evaluated the daily fluoride contents in 20 household desalinators working by reverse osmosis (RO) process in Bushehr, Iran. The concentration levels of fluoride in inlet and outlet waters were determined by the standard SPADNS method using a spectrophotometer (M501 Single Beam Scanning UV/VIS, UK). The fluoride content in outlet waters were compared with EPA and WHO guidelines for drinking water. PMID- 27508235 TI - Data on the verification and validation of segmentation and registration methods for diffusion MRI. AB - The verification and validation of segmentation and registration methods is a necessary assessment in the development of new processing methods. However, verification and validation of diffusion MRI (dMRI) processing methods is challenging for the lack of gold-standard data. The data described here are related to the research article entitled "Surface-driven registration method for the structure-informed segmentation of diffusion MR images" [1], in which publicly available data are used to derive golden-standard reference-data to validate and evaluate segmentation and registration methods in dMRI. PMID- 27508236 TI - Dataset of milk whey proteins of three indigenous Greek sheep breeds. AB - The importance and unique biological traits, as well as the growing financial value, of milk from small Greek ruminants is continuously attracting interest from both the scientific community and industry. In this regard the construction of a reference dataset of the milk of the Greek sheep breeds is of great interest. In order to obtain such a dataset we employed cutting-edge proteomics methodologies to investigate and characterize, the proteome of milk from the three indigenous Greek sheep breeds Mpoutsko, Karagouniko and Chios. In total, more than 1300 protein groups were identified in milk whey from these breeds, reporting for the first time the most detailed proteome dataset of this precious biological material. The present results are further discussed in the research paper "Milk of Greek sheep and goat breeds; characterization by means of proteomics" (Anagnostopoulos et al. 2016) [1]. PMID- 27508237 TI - Bacterial clinical infectious diseases ontology (BCIDO) dataset. AB - This article describes the Bacterial Infectious Diseases Ontology (BCIDO) dataset related to research published in http:dx.doi.org/ 10.1016/j.jbi.2015.07.014 [1], and contains the Protege OWL files required to run BCIDO in the Protege environment. BCIDO contains 1719 classes and 39 object properties. PMID- 27508238 TI - Data from thermal testing of the Open Source Cryostage. AB - The data presented here is related to the research article "An open source cryostage and software analysis method for detection of antifreeze activity" (Buch and Ramlov, 2016) [1]. The design of the Open Source Cryostage (OSC) is tested in terms of thermal limits, thermal efficiency and electrical efficiency. This article furthermore includes an overview of the electrical circuitry and a flowchart of the software program controlling the temperature of the OSC. The thermal efficiency data is presented here as degrees per volt and maximum cooling capacity. PMID- 27508239 TI - Data for behavioral results and brain regions showing a time effect during pair association retrieval. AB - The current data article provides behavioral and neuroimaging data for the research article "Relatedness-dependent rapid development of brain activity in anterior temporal cortex during pair-association retrieval" (Jimura et al., 2016) [1]. Behavioral performance is provided in a table. Fig. 2 of the article is based on this table. Brain regions showing time effect are provided in a table. A statistical activation map for the time effect is shown in Fig. 3C of the article. PMID- 27508240 TI - Data on affected cancer-related genes in pediatric t(12;21)-positive acute lymphoblastic leukemia patients harboring unbalanced der(6)t(X;6) translocations. AB - The t(12;21)(p13;q22), leading to ETV6/RUNX1 fusion, is of importance for leukemogenesis in acute lymphoblastic leukemia but is not sufficient for the leukemic transformation. Acquired secondary chromosomal aberrations are necessary for overt leukemia but their complete nature and genes involved are still elusive. In our recent publication, "Oligo-based aCGH analysis reveals cryptic unbalanced der(6)t(X;6) in pediatric t(12;21)-positive acute lymphoblastic leukemia", we identified acquired common concurrent regions with 6q deletion and Xq duplication E. Kjeldsen (2016) [1]. The present article provides data on genes that are associated with hematological malignancy and other cancers located in these common regions of chromosomal aberrations. PMID- 27508241 TI - Data set demonstrating an absence of touch effects on social orienting in adults. AB - Forty-five women participated in a variant of the social orienting paradigm employed in "Maternal Touch Predicts Attentional Bias Towards Faces in Young Children" (Reece, in press) [1]. On a given trial, they saw a mathematical equation and indicated whether this equation was true or false. Equations were superimposed on face or house distractors. A female experimenter sat next to the participant. In separate blocks, she either rested her hand on the participants arm or refrained from touching. Performance was poorer on trials with face than house distractors. However, experimenter touch failed to modulate this effect. Here we present raw and analyzed data of this companion experiment. PMID- 27508242 TI - Data for default network reduced functional connectivity in meditators, negatively correlated with meditation expertise. AB - FMRI data described here was recorded during resting-state in Mindfulness Meditators (MM) and control participants (see "Task-induced activity and resting state fluctuations undergo similar alterations in visual and DMN areas of long term meditators" Berkovich-Ohana et al. (2016) [1] for details). MM participants were also scanned during meditation. Analyses focused on functional connectivity within and between the default mode network (DMN) and visual network (Vis). Here we show data demonstrating that: 1) Functional connectivity within the DMN and the Visual networks were higher in the control group than in the meditators; 2) Data show an increase for the functional connectivity between the DMN and the Visual networks in the meditators compared to controls; 3) Data demonstrate that functional connectivity both within and between networks reduces during meditation, compared to the resting-state; and 4) A significant negative correlation was found between DMN functional connectivity and meditation expertise. The reader is referred to Berkovich-Ohana et al. (2016) [1] for further interpretation and discussion. PMID- 27508243 TI - Dataset and standard operating procedure for newborn screening of six lysosomal storage diseases: By tandem mass spectrometry. AB - In this data article we provide a detailed standard operating procedure for performing a tandem mass spectrometry, multiplex assay of 6 lysosomal enzymes for newborn screening of the lysosomal storage diseases Mucopolysaccharidosis-I, Pompe, Fabry, Niemann-Pick-A/B, Gaucher, and Krabbe, (Elliott, et al., 2016) [1]. We also provide the mass spectrometry peak areas for the product and internal standard ions typically observed with a dried blood spot punch from a random newborn, and we provide the daily variation of the daily mean activities for all 6 enzymes. PMID- 27508244 TI - Data in support for the measurement of serum 25-hydroxyvitamin D (25OHD) by tandem mass spectrometry. AB - This article provides data and a method related to a research paper entitled "Assessing vitamin D nutritional status: is capillary blood adequate?" (Jensen et al., 2016) [1]. Circulating 25OHD, the accepted biomarker of the vitamin D nutritional status, is routinely measured by automated immunoassays, that although may be performed in hospital central laboratories, often suffer from a lack of specificity with regards to the different vitamin D metabolites, "Measurement of circulating 25-hydroxyvitamin D: a historical review" (Le Goff et al., 2015) [2]. Mass spectrometry offers this specificity. This article describes the performance of an in-house tandem mass spectrometry method for the individual measurement of 25OHD3, 25OHD2 and 3-epi-25OHD3. PMID- 27508245 TI - Vehicular crash data used to rank intersections by injury crash frequency and severity. AB - This article contains data on research conducted in "A double standard model for allocating limited emergency medical service vehicle resources ensuring service reliability" (Liu et al., 2016) [1]. The crash counts were sorted out from comprehensive crash records of over one thousand major signalized intersections in the city of Chicago from 2004 to 2010. For each intersection, vehicular crashes were counted by crash severity levels, including fatal, injury Types A, B, and C for major, moderate, and minor injury levels, property damage only (PDO), and unknown. The crash data was further used to rank intersections by equivalent injury crash frequency. The top 200 intersections with the highest number of crash occurrences identified based on crash frequency- and severity based scenarios are shared in this brief. The provided data would be a valuable source for research in urban traffic safety analysis and could also be utilized to examine the effectiveness of traffic safety improvement planning and programming, intersection design enhancement, incident and emergency management, and law enforcement strategies. PMID- 27508246 TI - Summary of high field diffusion MRI and microscopy data demonstrate microstructural aberration in chronic mild stress rat brain. AB - This data article describes a large, high resolution diffusion MRI data set from fixed rat brain acquired at high field strength. The rat brain samples consist of 21 adult rat brain hemispheres from animals exposed to chronic mild stress (anhedonic and resilient) and controls. Histology from amygdala of the same brain hemispheres is also included with three different stains: DiI and Hoechst stained microscopic images (confocal microscopy) and ALDH1L1 antibody based immunohistochemistry. These stains may be used to evaluate neurite density (DiI), nuclear density (Hoechst) and astrocytic density (ALDH1L1). This combination of high field diffusion data and high resolution images from microscopy enables comparison of microstructural parameters derived from diffusion MRI to histological microstructure. The data provided here is used in the article (Jespersen, 2016) [1]. PMID- 27508247 TI - 16S rRNA amplicon sequencing dataset for conventionalized and conventionally raised zebrafish larvae. AB - Data presented here contains metagenomic analysis regarding the sequential conventionalization of germ-free zebrafish embryos. Zebrafish embryos that underwent a germ-free sterilization process immediately after fertilization were promptly exposed to and raised to larval stage in conventional fish water. At 6 days postfertilization (dpf), these "conventionalized" larvae were compared to zebrafish larvae that were raised in conventional fish water never undergoing the initial sterilization process. Bacterial 16S rRNA amplicon sequencing was performed on DNA isolated from homogenates of the larvae revealing distinct microbiota variations between the two groups. The dataset described here is also related to the research article entitled "Microbial modulation of behavior and stress responses in zebrafish larvae" (Davis et al., 2016) [1]. PMID- 27508248 TI - Data on alteration of hormone and growth factor receptor profiles over progressive passages of breast cancer cell lines representing different clinical subtypes. AB - Human breast cancers are a highly heterogeneous group of tumours consisting of several molecular subtypes with a variable profile of hormone, growth factor receptors and cytokeratins [1]. Here, the data shows immunofluorescence profiling of four different cell lines belonging to distinct clinical subtypes of breast cancer. Post revival, the cell lines were passaged in culture and immunophenotyping was done for ER, HER-2, AR and EGFR. Data for the markers from early passage (5th) through passages as late as 25 for the different cell lines is presented. PMID- 27508250 TI - Data of the natural and pharmaceutical angiotensin-converting enzyme inhibitor isoleucine-tryptophan as a potent blocker of matrix metalloproteinase-2 expression in rat aorta. AB - The present data are related to the research article entitled "Whey peptide isoleucine-tryptophan inhibits expression and activity of matrix metalloproteinase-2 in rat aorta" [1]. Here we present data on removal of endothelium from aorta, endothelium dependent aortic relaxation and inhibition of expression of pro-MMP2 by di-peptide isoleucine-tryptophan (IW). Experiments were performed in rat aortic endothelial cells (EC) and smooth muscle cells (SMC) in vitro, along with isolated rat aorta ex vivo. The cells and isolated aorta were stimulated with angiotensin II (ANGII) or angiotensin I (ANGI). ACE activity was inhibited by treatment with either IW or captopril (CA). Losartan was used as a blocker of angiotensin type-1 receptor. IW inhibited MMP2 protein expression induced with ANGI in a dose-dependent manner. IW was effective both in ECs and SMCs, as well as in isolated aorta. Similarly, captopril (CA) inhibited ANGI induced MMP2 protein expression in both in vitro and ex vivo. Neither IW nor CA inhibited ANGII-induced MMP2 protein expression in contrast to losartan. The data also displays that removal of endothelium in isolated rat aorta abolished the endothelium-dependent relaxation induced with acetylcholine. However, SMC dependent relaxation induced with sodium nitroprusside remained intact. Finally, the data provides histological evidence of selective removal of endothelial cells from aorta. PMID- 27508251 TI - Data on metal contents (As, Ag, Sr, Sn, Sb, and Mo) in sediments and shells of Trachycardium lacunosum in the northern part of the Persian Gulf. AB - In this data article, by using inductively coupled plasma optical spectrometry (ICP-OES), we aimed to (1) determine the concentration levels of As, Ag, Sr, Sn, Sb, and Mo in the sediments and the shells of Trachycardium lacunosum simultaneously in two separated areas (unpolluted and polluted areas) (2) comparison between the metal contents of sediments in the unpolluted and polluted areas as well as shells. Analysis of data showed that sediment as well as shell samples in polluted area contained significantly higher concentration levels of all measured metals compared with unpolluted area. PMID- 27508249 TI - Data on publications, structural analyses, and queries used to build and utilize the AlloRep database. AB - The AlloRep database (www.AlloRep.org) (Sousa et al., 2016) [1] compiles extensive sequence, mutagenesis, and structural information for the LacI/GalR family of transcription regulators. Sequence alignments are presented for >3000 proteins in 45 paralog subfamilies and as a subsampled alignment of the whole family. Phenotypic and biochemical data on almost 6000 mutants have been compiled from an exhaustive search of the literature; citations for these data are included herein. These data include information about oligomerization state, stability, DNA binding and allosteric regulation. Protein structural data for 65 proteins are presented as easily-accessible, residue-contact networks. Finally, this article includes example queries to enable the use of the AlloRep database. See the related article, "AlloRep: a repository of sequence, structural and mutagenesis data for the LacI/GalR transcription regulators" (Sousa et al., 2016) [1]. PMID- 27508252 TI - Benchmark dataset for undirected and Mixed Capacitated Arc Routing Problems under Time restrictions with Intermediate Facilities. AB - In this article we present benchmark datasets for the Mixed Capacitated Arc Routing Problem under Time restrictions with Intermediate Facilities (MCARPTIF). The problem is a generalisation of the Capacitated Arc Routing Problem (CARP), and closely represents waste collection routing. Four different test sets are presented, each consisting of multiple instance files, and which can be used to benchmark different solution approaches for the MCARPTIF. An in-depth description of the datasets can be found in "Constructive heuristics for the Mixed Capacity Arc Routing Problem under Time Restrictions with Intermediate Facilities" (Willemseand Joubert, 2016) [2] and "Splitting procedures for the Mixed Capacitated Arc Routing Problem under Time restrictions with Intermediate Facilities" (Willemseand Joubert, in press) [4]. The datasets are publicly available from "Library of benchmark test sets for variants of the Capacitated Arc Routing Problem under Time restrictions with Intermediate Facilities" (Willemse and Joubert, 2016) [3]. PMID- 27508253 TI - Data on NAEP 2011 writing assessment prior computer use. AB - This data article contains information based on the 2011 National Assessment of Educational Progress in Writing Restricted-Use Data, available from the National Center for Education Statistics (NCES Pub. No. 2014476). https://nces.ed.gov/nationsreportcard/researchcenter/datatools.aspx. The data include the statistical relationships between survey reports of teachers and students regarding prior use of computers and other technology and writing achievement levels on the 2011 computer-based NAEP writing assessment. This data article accompanies "The Effects of Prior Computer Use on Computer-Based Writing: The 2011 NAEP Writing Assessment" [1]. PMID- 27508254 TI - Myelin contrast across lamina at 7T, ex-vivo and in-vivo dataset. AB - In this article we report the complete data obtained in-vivo for the paper: "Lines of Baillarger in vivo and ex-vivo: myelin contrast across lamina at 7T MRI and histology" (Fracasso et al., 2015) [1]. Single participant data (4 participants) from the occipital lobe acquisition are reported for axial, coronal and sagittal slices; early visual area functional localization and laminar profiles are reported. Data from whole brain images are reported and described (5 participants), for axial, coronal and sagittal slices. Laminar profiles from occipital, parietal and frontal lobes are reported. The data reported in this manuscript complements the paper (Fracasso et al., 2015) [1] by providing the full set of results from the complete pool of participants, on a single participant basis. Moreover, we provide histological images from the ex-vivo sample reported in Fracasso et al. (2015) [1]. PMID- 27508255 TI - A semi-simulated EEG/EOG dataset for the comparison of EOG artifact rejection techniques. AB - Artifact rejection techniques are used to recover the brain signals underlying artifactual electroencephalographic (EEG) segments. Although over the last few years many different artifact rejection techniques have been proposed (http://dx.doi.org/10.1109/JSEN.2011.2115236[1], http://dx.doi.org/10.1016/j.clinph.2006.09.003[2], http://dx.doi.org/10.3390/e16126553[3]), none has been established as a gold standard so far, because assessing their performance is difficult and subjective (http://dx.doi.org/10.1109/ITAB.2009.5394295[4], http://dx.doi.org/10.1016/j.bspc.2011.02.001[5], http://dx.doi.org/10.1007/978-3 540-89208-3_300. [6]). This limitation is mainly based on the fact that the underlying artifact-free brain signal is unknown, so there is no objective way to measure how close the retrieved signal is to the real one. This article solves the aforementioned problem by presenting a semi-simulated EEG dataset, where artifact-free EEG signals are manually contaminated with ocular artifacts, using a realistic head model. The significant part of this dataset is that it contains the pre-contamination EEG signals, so the brain signals underlying the EOG artifacts are known and thus the performance of every artifact rejection technique can be objectively assessed. PMID- 27508256 TI - Input data for inferring species distributions in Kyphosidae world-wide. AB - Input data files for inferring the relationship among the family Kyphosidae, as presented in (Knudsen and Clements, 2016) [1], is here provided together with resulting topologies, to allow the reader to explore the topologies in detail. The input data files comprise seven nexus-files with sequence alignments of mtDNA and nDNA markers for performing Bayesian analysis. A matrix of recoded character states inferred from the morphology examined in museum specimens representing Dichistiidae, Girellidae, Kyphosidae, Microcanthidae and Scorpididae, is also provided, and can be used for performing a parsimonious analysis to infer the relationship among these perciform families. The nucleotide input data files comprise both multiple and single representatives of the various species to allow for inference of the relationship among the species in Kyphosidae and between the families closely related to Kyphosidae. The '.xml'-files with various constrained relationships among the families potentially closely related to Kyphosidae are also provided to allow the reader to rerun and explore the results from the stepping-stone analysis. The resulting topologies are supplied in newick-file formats together with input data files for Bayesian analysis, together with '.xml'-files. Re-running the input data files in the appropriate software, will enable the reader to examine log-files and tree-files themselves. PMID- 27508257 TI - Data on cell growth inhibition induced by anti-VEGF siRNA delivered by Stealth liposomes incorporating G2 PAMAM-cholesterol versus Metafectene(r) as a function of exposure time and siRNA concentration. AB - In this data article, carboxyfluorescein-loaded liposomes were prepared and purified from free carboxyfluorescein using gel filtration chromatography in the first part. In the next part, following preparation of anti-VEGF siRNA loaded liposomes incorporating hydrophobically modified G2 PAMAM dendrimer (G2-Chol40%) (Golkar et al., 2016) [1], the cell growth inhibition induced by the formulations (siRNA/Metafectene complexes and siRNA loaded liposomes incorporating hydrophobic G2) was evaluated at two exposure times through MTT assay in a breast cancer cell (SKBR-3) and compared by two-way ANOVA. PMID- 27508258 TI - Single-leg landing neuromechanical data following load and land height manipulations. AB - Lower extremity sagittal kinematic and kinetic data are summarized alongside electrical muscle activities during single-leg landing trials completed in contrasting external load and landing height conditions. Nineteen subjects were analyzed during 9 landing trials in each of 6 experimental conditions computed as percentages of subject anthropometrics (bodyweight: BW and subject height: H; BW, BW+12.5%, BW+25%, and H12.5%, H25%). Twelve lower extremity variables (sagittal hip, knee, ankle angles and moments, vertical ground reaction force (GRFz), gluteus maximus, biceps femoris, vastus medials, medial gastrocnemius, and tibialis anterior muscles) were assessed using separate principal component analyses (PCA). Variable trends across conditions were summarized in "Neuromechanical synergies in single-leg landing reveal changes in movement control. Human Movement Science" (Nordin and Dufek, 2016) [1], revealing changes in landing biomechanics and movement control. PMID- 27508259 TI - Data on biochemical fluxes generated from biofabricated enzyme complexes assembled through engineered tags and microbial transglutaminase. AB - Data presented is related to an article titled "Modular construction of multi subunit protein complexes using engineered tags and microbial transglutaminase" (Bhokisham et al., 2016) [1]. In this article, we have presented western blot and flux data associated with assembly of Pfs-LuxS enzyme complexes on beads using uni-tagged and bi-tagged LuxS enzymes. We have also presented biochemical flux following changes in enzyme stoichiometries. We covalently coupled a Pfs-LuxS complex with Protein G, an antibody binding non-enzyme component and directed these complexes to the surfaces of bacterial cells via anti-Escherichia coli antibodies. Fluorescence microscopy images represented the altered behavior of bacterial cells in response to the autoinducer-2 that is synthesized by the Protein G-enzyme complexes. PMID- 27508260 TI - Data and programs in support of network analysis of genes and their association with diseases. AB - The network-based approaches that were employed in order to depict the relationships between human genetic diseases and their associated genes are described. Towards this direction, monopartite disease-disease and gene-gene networks were constructed from bipartite gene-disease association networks. The latter were created by collecting and integrating data from three diverse resources, each one with different content, covering from rare monogenic disorders to common complex diseases. Moreover, topological and clustering graph analyses were performed. The methodology and the programs presented in this article are related to the research article entitled "Network analysis of genes and their association with diseases" [1]. PMID- 27508261 TI - Data on the optimization of a GC-MS procedure for the determination of total plasma myo-inositol. AB - Myo-inositol (MI) is one of the stereoisomers of hexahydroxycyclohexane, which plays an important role in intracellular signal pathway. Derivatization is an indispensable step in both external and internal standard method during the chromatography-mass spectrometer (GC-MS) detection, as MI can't be ionized directly. It is valuable to optimize the derivative process and the detection volume for clinical detection. This article contains optimization data related to research publication "Quantification of plasma myo-inositol using gas chromatography-mass spectrometry" [1]. Here we introduce the data on the optimized derivatization volume, temperature, duration and the detection volume. PMID- 27508262 TI - Data on pro-inflammatory cytokines IL-1beta, IL-17, and IL-6 in the peripheral blood of HIV-infected individuals. AB - Our most recent data indicate differences in the levels of pro-inflammatory cytokines (IL-1beta, IL-17, and IL-6) and malondialdehyde (MDA), a stable end product of lipid peroxidation in the plasma samples between HIV positive individuals with low CD4 T cell counts <200 mm(3) and HIV positive individuals with CD4 T cell counts between 200 and 300 mm(3) (ee). The data lend support and provide valuable correlation between CD4 T cell counts and the levels of inflammatory cytokines in HIV positive individuals. PMID- 27508263 TI - Metagenomic and near full-length 16S rRNA sequence data in support of the phylogenetic analysis of the rumen bacterial community in steers. AB - Amplicon sequencing utilizing next-generation platforms has significantly transformed how research is conducted, specifically microbial ecology. However, primer and sequencing platform biases can confound or change the way scientists interpret these data. The Pacific Biosciences RSII instrument may also preferentially load smaller fragments, which may also be a function of PCR product exhaustion during sequencing. To further examine theses biases, data is provided from 16S rRNA rumen community analyses. Specifically, data from the relative phylum-level abundances for the ruminal bacterial community are provided to determine between-sample variability. Direct sequencing of metagenomic DNA was conducted to circumvent primer-associated biases in 16S rRNA reads and rarefaction curves were generated to demonstrate adequate coverage of each amplicon. PCR products were also subjected to reduced amplification and pooling to reduce the likelihood of PCR product exhaustion during sequencing on the Pacific Biosciences platform. The taxonomic profiles for the relative phylum level and genus-level abundance of rumen microbiota as a function of PCR pooling for sequencing on the Pacific Biosciences RSII platform were provided. For more information, see "Evaluation of 16S rRNA amplicon sequencing using two next generation sequencing technologies for phylogenetic analysis of the rumen bacterial community in steers" P.R. Myer, M. Kim, H.C. Freetly, T.P.L. Smith (2016) [1]. PMID- 27508264 TI - Hawai'i Coral Disease database (HICORDIS): species-specific coral health data from across the Hawaiian archipelago. AB - The Hawai'i Coral Disease database (HICORDIS) houses data on colony-level coral health condition observed across the Hawaiian archipelago, providing information to conduct future analyses on coral reef health in an era of changing environmental conditions. Colonies were identified to the lowest taxonomic classification possible (species or genera), measured and assessed for visual signs of health condition. Data were recorded for 286,071 coral colonies surveyed on 1819 transects at 660 sites between 2005 and 2015. The database contains observations for 60 species from 22 genera with 21 different health conditions. The goals of the HICORDIS database are to: i) provide open access, quality controlled and validated coral health data assembled from disparate surveys conducted across Hawai'i; ii) facilitate appropriate crediting of data; and iii) encourage future analyses of coral reef health. In this article, we describe and provide data from the HICORDIS database. The data presented in this paper were used in the research article "Satellite SST-based Coral Disease Outbreak Predictions for the Hawaiian Archipelago" (Caldwell et al., 2016) [1]. PMID- 27508265 TI - Data on the descriptive overview and the quality assessment details of 12 qualitative research papers. AB - This data article presents the supplementary material for the review paper "Role of acceptability barriers in delayed diagnosis of Tuberculosis: Literature review from high burden countries" (Barnabishvili et al., in press) [1]. General overview of 12 qualitative papers, including the details about authors, years of publication, data source locations, study objectives, overview of methods, study population characteristics, as well as the details of intervention and the outcome parameters of the papers are summarized in the first two tables included to the article. Quality assessment process of the methodological strength of 12 papers and the results of the critical appraisal are further described and summarized in the second part of the article. PMID- 27508266 TI - Human leukocyte antigen (HLA)-binding epitopes dataset for the newly identified T cell antigens of Mycobacterium immunogenum. AB - The dataset described herein is related to our article entitled "T-cell antigens of Mycobacterium immunogenum (MI), an etiological agent of occupational hypersensitivity pneumonitis'' (Chandra and Yadav, 2016) [1]. The data include in silico-predicted T-cell epitopes of the T-cell antigens AgA and AgD of MI predicted to bind to HLA-I or HLA-II alleles. Data on two reference T-cell antigens ESAT-6 and CFP-10 of Mycobacterium tuberculosis H37Rv are included for comparison. The data for each antigen include the predicted epitope's amino acid sequence, its first amino acid position, and its ability to bind HLA-I or HLA-II allele(s). PMID- 27508267 TI - CZTS x Se1-x nanocrystals: Composition dependent method of preparation, morphological characterization and cyclic voltammetry data analysis. AB - In this article, synthesis procedures of preparation of copper zinc tin sulpho selenide (CZTS x Se1-x ) alloy nanocrystals and the data acquired for the material characterization are presented. This data article is related to the research article doi: http://dx.doi.org/10.1016/j.solmat.2016.06.030 (Jadhav et al., 2016) [1]. FTIR data have been presented which helped in confirmation of adsorption of oleylamine on CZTS x Se1-x . Transmission electron microscopy (TEM), Field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) data have been presented which have been used to reveal the morphological details of the nanocrystals. The Energy dispersive X-ray analysis (EDAX) based elemental mapping data has been presented to confirm the elemental composition of nanocrystals. Procedure for the preparation of CZTS x Se1-x based working electrode for the CV measurements have been given. The summary table for the optical, electrochemical band gaps, valance and conduction band edges as a function of composition are listed for the ready reference. PMID- 27508268 TI - Single molecule force spectroscopy data and BD- and MD simulations on the blood protein von Willebrand factor. AB - We here give information for a deeper understanding of single molecule force spectroscopy (SMFS) data through the example of the blood protein von Willebrand factor (VWF). It is also shown, how fitting of rupture forces versus loading rate profiles in the molecular dynamics (MD) loading-rate range can be used to demonstrate the qualitative agreement between SMFS and MD simulations. The recently developed model by Bullerjahn, Sturm, and Kroy (BSK) was used for this demonstration. Further, Brownian dynamics (BD) simulations, which can be utilized to estimate the lifetimes of intramolecular VWF interactions under physiological shear, are described. For interpretation and discussion of the methods and data presented here, we would like to directly point the reader to the related research paper, "Mutual A domain interactions in the force sensing protein von Willebrand Factor" (Posch et al., 2016) [1]. PMID- 27508269 TI - A description of data sets to determine the innovative diversification capacity of farm households. AB - This data represents research activities carried out in Co. Offaly and Co. Mayo, Ireland, to identify farm household innovative diversification behavior and policy/institutional actor capacity roles in support. The data sets are overlain with household and agency data from the two study areas to describe levels of innovative diversification capacity by individual socio-economic farm household profile. The data sets summarize the public policy discussions on rural innovation and diversification and policy actor response requirements, and incorporate both qualitative and quantitative data set combinations. The data are used to assess policy/institutional actors' roles and farm households' capacity for innovation at the farm household/institution interface in support of sustainable rural business innovations on-farm and diversification. PMID- 27508270 TI - Data on morphometric analysis of the pancreatic islets from C57BL/6 and BALB/c mice. AB - The endocrine portion of the pancreas, which is characterized by pancreatic islets, has been widely investigated among different species. The BALB/c and C57BL/6 mice are extensively used in experimental research, and the morphometric differences in the pancreatic islets of these animals have not been evaluated so far. Thus, our data have a comparative perspective related to the morphometric analysis of area, diameters, circularity, and density of pancreatic islets from BALB/c and C57BL/6 mice. The data presented here are focused to evaluate the differences in morphology of pancreatic islets of two common laboratory mouse strains. PMID- 27508271 TI - Serous carcinoma of endometrium in combination with neuroendocrine small-cell: A case report and literature review. AB - Endometrial serous carcinomas are very clinically aggressive, which constitutes 40% of all deaths and recurrences associated with endometrial cancer. Small-cell carcinoma of the endometrium is relatively rare but aggressive, and often presents a component of endometrioid carcinoma, and is not generally associated with serous carcinoma. Herein, we report a case of 74-year-old African-American female, who presented with intermittent post-menopausal bleeding for > 1-month. She underwent robotic-assisted laparoscopic hysterectomy, bilateral salpingo oophorectomy, sentinel lymph node mapping, and pelvic-and-aortic lymphadenectomy. Final pathology was consistent with serous carcinoma of the endometrium in combination with neuroendocrine small-cell carcinoma. This extremely rare combination of tumors presents a challenge for treatment. The mainstay of treatment seems to be surgery followed by chemotherapy +/- radiation therapy. To our knowledge, it represents an under-reported area of gynecological medicine. PMID- 27508272 TI - Primary ovarian neuroendocrine tumor arising in association with a mature cystic teratoma: A case report. AB - Primary ovarian carcinoid tumors are exceptionally rare entities accounting for approximately 0.1% of all ovarian neoplasms. This report describes a primary ovarian neuroendocrine tumor arising in association with a mature cystic teratoma in a 65 year-old woman. Macroscopically, the unilateral adnexal tumor was composed of cystic, solid and mucinous elements which resolved into a dual component lesion histologically. The majority of the tumor displayed an organoid architecture with mild to moderate pleomorphism and no discernible mitotic activity, while approximately 10% consisted of sheets and groups of cells with highly pleomorphic nuclei, necrosis and occasional mitoses. Features of a mature cystic teratoma were seen very focally. Immunohistochemistry revealed strong, diffuse positivity for CD56 and synaptophysin. Chromogranin immunonegativity was noted and there was an absence of nuclear beta-catenin accumulation. Ki-67 index was 10-12%. Although there is no established diagnostic framework for primary ovarian carcinoid tumors, this case was diagnosed as a well-differentiated neuroendocrine tumor, Grade 2 (intermediate grade), arising in association with a mature cystic teratoma/dermoid cyst. This case highlights the need to develop ovarian diagnostic criteria in this area. PMID- 27508273 TI - Editorial: Preventive strategies in geriatric dental medicine. PMID- 27508274 TI - Impact of Chlorhexidine Pretreatment Followed by Probiotic Streptococcus salivarius Strain K12 on Halitosis in Children: A Randomised Controlled Clinical Trial. AB - PURPOSE: The aim of this study was to examine the effect of chlorhexidine disinfection, as a chemical method of oral hygiene practice, and subsequent use of probiotics on halitosis in children. The effects of mechanical and chemical oral hygiene practice methods on the severity of halitosis were also assessed. MATERIALS AND METHODS: 208 children with organoleptic test (OLT) scores of 2 or more were randomly assigned to four groups: A: conventional oral hygiene practices (COH) including toothbrushing and flossing; B: COH + tongue scraping (TS); C: COH + TS + chlorhexidine; D: COH + TS + chlorhexidine + probiotics. OLT was performed at 1-week and 3-month follow-ups. RESULTS: A significant and stable number of participants showed major and moderate levels of improvement in OLT scores in group D (p < 0.001). The improvement of OLT scores in group C was also significant (p < 0.001), but not stable over the follow-ups (p = 0.44). Neither significant nor stable improvements in the OLT scores were detected in groups A and B through follow-ups (p > 0.05). CONCLUSION: Probiotic therapy following oral disinfection with chlorhexidine may reduce the severity of halitosis over longer periods. PMID- 27508279 TI - Determination and prediction of the magnetic anisotropy of Mn ions. AB - This tutorial is dedicated to the investigation of magnetic anisotropy using both electron paramagnetic resonance (EPR) spectroscopy for its experimental determination and quantum chemistry for its theoretical prediction. Such an approach could lead to the definition of magneto-structural correlation essential for the rational design of complexes with targeted magnetic properties or for the identification of unknown reactive metallic species involved in catalysis. To illustrate this combined approach the high spin MnII, MnIII and MnIV ions have been taken as specific examples. The first part deals with the analysis of the EPR experiments as a function of the ions under investigation and the conditions of the measurements, specifically: (i) EPR spectra recorded under high vs. low frequency conditions with respect to magnetic anisotropy, (ii) EPR spectra of non integer (Kramers) vs. integer (non-Kramers) spin states and (iii) mono- vs. multi frequency EPR spectra. In the second part, two main quantum chemical approaches, which have proven their capability to predict magnetic anisotropy, are described. More importantly, these calculations give access to the different contributions of zero field splitting, key information for the full understanding of magnetic anisotropy. The last part demonstrates that such a combined experimental and theoretical approach allows for the definition of magneto-structural correlations. PMID- 27508280 TI - Changes in the volume phase transition temperature of hydrogels for detection of the DNA hybridization process. AB - A simple biosensing platform which involves the application of thermoresponsive hydrogels (p(NIPA-co-AA)) for detection of target DNA sequences is presented. For this aim the hydrogel based on N-isopropylacrylamide grafted with carboxyl groups was modified with H2N-ssDNA via the amide bond. The detection of target DNA sequences was achieved successfully by monitoring the volume phase transition temperature (VPTT). It was found that the dependence between the VPTT and the concentration of the target complementary DNA is linear in the concentration range from 10-12 to 10-6 M. The proposed DNA detection method is characterized by high sensitivity and good reproducibility. The detection limit obtained (~1 pM) is a substantial improvement over DNA biosensor labelling with tags, because the detection is based on a physical parameter (VPTT). Circular dichroism (CD) and inductively coupled plasma mass spectrometry with laser ablation (LA-ICP-MS) proved that the hybridization process took place in the hydrogel matrix without any restrictions. PMID- 27508281 TI - Advanced gas sensors based on substrate-integrated hollow waveguides and dual color ring quantum cascade lasers. AB - This study shows the first combination of a ring-shaped vertically emitting quantum cascade laser (riQCL) providing two distinct emission wavelengths combined with a substrate-integrated hollow waveguide (iHWG). This ultra-compact riQCL-iHWG gas sensing device enables the simultaneous detection of two vapor phase species - here, furan and 2-methoxyethanol - providing distinctive absorption features at the emission wavelengths of the riQCL (i.e., 1144 and 1170 cm-1). Hence, multianalyte gas sensing via a unique mid-infrared (MIR) sensor concept is demonstrated. PMID- 27508282 TI - Fluorescence recognition of double-stranded DNA based on the quenching of gold nanoparticles to a fluorophore labeled DNA probe. AB - An ultrasensitive fluorescent platform for sequence-specific recognition of double-stranded DNA (dsDNA) based on the quenching of gold nanoparticles (AuNPs) to a fluorophore labeled DNA probe was developed. The target dsDNA could hybridize with the loop portion of the molecular beacon (MB) to form a triplex DNA structure and opened the "stem-loop" structure of the MB; such triplex DNA was used as an assistant probe (AP). Meanwhile, a fluorophore labeled DNA-AuNP probe that contained a specific enzyme cleavage site was introduced and its fluorescence signal was efficiently quenched due to the vicinity of the fluorophore to the AuNP surface. Such a DNA-AuNP probe could hybridize with the 5' stem portion of the MB in the AP to form duplex DNA strands that contained a specific enzyme cleavage site for the nicking enzyme assisted cleavage reaction, and resulted in the release of the fluorophore from the AuNP surface and the recovery of the fluorescence signal. Because the AP remains intact during such a cleavage process, it could be reused to hybridize with the next DNA-AuNP probe and trigger the nicking nuclease assisted signal amplification. Under optimal conditions, a low detection limit of 3.8 pM was obtained for dsDNA detection, and the assay has high sequence specificity for dsDNA detection. PMID- 27508283 TI - Stimulated Raman photoacoustic spectroscopy for chemical-contrast imaging of a sample deeply buried in scattering media. AB - The development of a stimulated Raman scattering photoacoustic (SRS-PA) spectrometer is presented. In the apparatus, a molecular vibrational mode is excited by the SRS process. The vibrational excitation energy is converted to heat by vibrational relaxation. The volumes around the excited molecules including the surrounding solvent molecules expand by heating, resulting in the generation of an ultrasonic wave. The ultrasonic wave can be used as a molecular selective signal. Because the ultrasonic wave is scarcely scattered by media, SRS PA is expected to be applied for obtaining molecular-selective signals from deeply buried samples. In the present study, a SRS-PA spectrometer was developed and applied to obtain molecular-selective signals from test samples. The SRS-PA signals from water and lipid, which are important components in biological systems, were first obtained. The SRS-PA signal from a polystyrene film buried in a highly light-scattering intralipid suspension was also measured. We succeeded in obtaining the signal from the film when it was buried with a depth of up to 1.8 mm. The results indicate that SRS-PA can be effectively applied for the chemical-contrast imaging of deeply buried samples. PMID- 27508284 TI - Encapsulated feeder cells within alginate beads for ex vivo expansion of cord blood-derived CD34(+) cells. AB - A co-culture system based on encapsulated feeder cells within alginate beads was developed through optimizing the detailed aspects of the cell culture system to expand CD34-positive (CD34(+)) cells ex vivo. Mesenchymal stem cells isolated from different sources (human amniotic (hAMSCs) and umbilical cord (UCMSCs)), and human fibroblast cells (HFs) have been respectively chosen as feeder cells and the results showed that the hAMSCs were superior to UCMSCs and HFs in conventional two-dimensional (2D) co-cultures regarding the promotion of total nucleated cell (TNCs) expansion and the maintenance of the CD34(+) phenotype. Alginate beads were employed to limit the growth of hAMSCs, which could effectively restrict the proliferation of the encapsulated hAMSCs, while the cell viability of hAMSCs was still highly maintained. Intriguingly, only a few hAMSCs migrated out of the alginate beads, whereas secreted growth factors and cytokines could be easily released. Furthermore, the alginate beads supported CD34(+) cells/hAMSCs 2D indirect co-culture exhibited increased TNCs expansion, higher percentages of CD34(+) and CD34(+)CD38(-) cells, and better cell vitality when compared to the 2D co-culture. Therefore, the co-culture system based on encapsulated hAMSCs within alginate beads can effectively promote CD34(+) cells to expand ex vivo. PMID- 27508285 TI - Synthesis, characterization and in vitro biocompatibility assessment of a novel tripeptide hydrogelator, as a promising scaffold for tissue engineering applications. AB - We have synthesized and characterized a self-assembling tripeptide hydrogelator Ac-l-Phe-l-Phe-l-Ala-NH2. A series of experiments showed that the hydrogel material could serve as a stabile and biocompatible physical support as it improves the survival of HEK293T cells in vitro, thus being a promising biomaterial for use in tissue engineering applications. PMID- 27508286 TI - Isolated Parotid Gland Sarcoidosis Mimicking Parotid Tumor. PMID- 27508287 TI - Turning point: Kevin Esvelt. PMID- 27508288 TI - Introduction to Special Issue on Imaging of Plants and Fungi. PMID- 27508289 TI - WHO AND EXPERTS PRIORITIZE VACCINES, DIAGNOSTICS AND INNOVATIVE VECTOR CONTROL TOOLS FOR ZIKA R&D. PMID- 27508290 TI - WHO SUPPORTS CABO VERDE IN MANAGING ZIKA VIRUS. PMID- 27508291 TI - Recent, Innovative Approaches to Neural Therapy and Repair: Introduction to the ASNTR Special Issue From the 2015 Meeting. PMID- 27508292 TI - BLUE CROSS HEALTH PLANS COLLABORATE ON OPIOID PROTOCOLS. PMID- 27508293 TI - OBAMA UNDERLINES COLLECTIVE APPROACH TO ADDICTION CRISIS. PMID- 27508294 TI - Directed Chemical Evolution with an Outsized Genetic Code. AB - The first demonstration that macromolecules could be evolved in a test tube was reported twenty-five years ago. That breakthrough meant that billions of years of chance discovery and refinement could be compressed into a few weeks, and provided a powerful tool that now dominates all aspects of protein engineering. A challenge has been to extend this scientific advance into synthetic chemical space: to enable the directed evolution of abiotic molecules. The problem has been tackled in many ways. These include expanding the natural genetic code to include unnatural amino acids, engineering polyketide and polypeptide synthases to produce novel products, and tagging combinatorial chemistry libraries with DNA. Importantly, there is still no small-molecule analog of directed protein evolution, i.e. a substantiated approach for optimizing complex (>= 10^9 diversity) populations of synthetic small molecules over successive generations. We present a key advance towards this goal: a tool for genetically-programmed synthesis of small-molecule libraries from large chemical alphabets. The approach accommodates alphabets that are one to two orders of magnitude larger than any in Nature, and facilitates evolution within the chemical spaces they create. This is critical for small molecules, which are built up from numerous and highly varied chemical fragments. We report a proof-of-concept chemical evolution experiment utilizing an outsized genetic code, and demonstrate that fitness traits can be passed from an initial small-molecule population through to the great grandchildren of that population. The results establish the practical feasibility of engineering synthetic small molecules through accelerated evolution. PMID- 27508295 TI - Impact of Decreased Serum Insulin-Like Growth Factor-1 Levels on Central Aortic Compliance in Small-for-Gestational-Age Infants. AB - BACKGROUND: Intrauterine growth restriction is associated with arterial hypertension in adulthood; however, the underlying mechanism is unclear. OBJECTIVES: We hypothesized that serum insulin-like growth factor-1 (IGF-1) levels affect central aortic elastic properties and structure in small-for gestational-age (SGA) infants. METHODS: Eighteen SGA infants and 22 appropriate for-gestational-age (AGA) infants were enrolled in this study. The serum IGF-1 level within 1 h of birth and abdominal aortic echo parameters at 1 week of age were retrospectively compared. RESULTS: In the SGA infants, IGF-1 levels (27.6 +/ 17.7 vs. 42.6 +/- 15 ng/ml, p = 0.006), aortic strain (10.2 +/- 3.1 vs. 12.8 +/- 3.1%, p = 0.01), and aortic distensibility (0.73 +/- 0.19 vs. 0.92 +/- 0.34 cm2/dyn * 10-4, p = 0.05) were significantly lower compared with AGA infants. By contrast, blood pressure, aortic intima-media thickness (aIMT) in relation to body weight (383 +/- 163 vs. 256 +/- 43 MUm/kg, p < 0.001), aortic stiffness index in relation to body weight (2.0 +/- 1.7 vs. 1.1 +/- 0.4, p = 0.005), and arterial pressure-strain elastic modulus (293 +/- 72 vs. 242 +/- 78 mm Hg, p = 0.04) were higher compared with AGA infants. In the SGA infants, IGF-1 levels were significantly correlated with aortic strain (r = 0.49, p = 0.04), aIMT in relation to body weight (r = -0.61, p = 0.007), and aortic stiffness index in relation to body weight (r = -0.63, p = 0.005). CONCLUSIONS: Decreased serum IGF 1 levels in SGA infants may affect the vascular compliance and structure of the central aorta. PMID- 27508296 TI - Grape Cultivar and Sap Culture Conditions Affect the Development of Xylella fastidiosa Phenotypes Associated with Pierce's Disease. AB - Xylella fastidiosa is a xylem-limited bacterium in plant hosts and causes Pierce's disease (PD) of grapevines, which differ in susceptibility according to the Vitis species (spp.). In this work we compared X. fastidiosa biofilm formation and population dynamics when cultured in xylem saps from PD-susceptible and -resistant Vitis spp. under different conditions. Behaviors in a closed culture system were compared to those in different sap-renewal cultures that would more closely mimic the physicochemical environment encountered in planta. Significant differences in biofilm formation and growth in saps from PD susceptible and -resistant spp. were only observed using sap renewal culture. Compared to saps from susceptible V. vinifera, those from PD-resistant V. aestivalis supported lower titers of X. fastidiosa and less biofilm and V. champinii suppressed both growth and biofilm formation, behaviors which are correlated with disease susceptibility. Furthermore, in microfluidic chambers X. fastidiosa formed thick mature biofilm with three-dimensional (3-D) structures, such as pillars and mounds, in saps from all susceptible spp. In contrast, only small aggregates of various shapes were formed in saps from four out of five of the resistant spp.; sap from the resistant spp. V. mustangensis was an exception in that it also supported thick lawns of biofilm but not the above described 3-D structures typically seen in a mature biofilm from the susceptible saps. Our findings provide not only critical technical information for future bioassays, but also suggest further understanding of PD susceptibility. PMID- 27508297 TI - The Use of Antihypertensive Medication and the Risk of Breast Cancer in a Case Control Study in a Spanish Population: The MCC-Spain Study. AB - INTRODUCTION: The evidence on the relationship between breast cancer and different types of antihypertensive drugs taken for at least 5 years is limited and inconsistent. Furthermore, the debate has recently been fueled again with new data reporting an increased risk of breast cancer among women with a long history of use of antihypertensive drugs compared with nonusers. METHODS: In this case control study, we report the antihypertensive drugs-breast cancer relationship in 1,736 breast cancer cases and 1,895 healthy controls; results are reported stratifying by the women's characteristics (i.e., menopausal status or body mass index category) tumor characteristics and length of use of antihypertensive drugs. RESULTS: The relationship among breast cancer and use of calcium channel blockers (CCB) for 5 or more years had odds ratio (OR) = 1.77 (95% CI, 0.99 to 3.17). Stratifying by BMI, the OR increased significantly in the group with BMI >= 25 (OR 2.54, 95% CI, 1.24 to 5.22). CCBs were even more strongly associated with more aggressive tumors, (OR for invasive tumors = 1.96, 95% CI = 1.09 to 3.53; OR for non ductal cancers = 3.97, 95% CI = 1.73 to 9.05; OR for Erbb2+ cancer = 2.97, 95% CI: 1.20 to 7.32). On the other hand, premenopausal women were the only group in which angiotensin II receptor blockers may be associated with breast cancer (OR = 4.27, 95% CI = 1.32 to 13.84) but this could not be identified with any type or stage. Use of angiotensin-converting-enzyme inhibitors, beta blockers and diuretics were not associated with risk. CONCLUSIONS: In this large population-based study we found that long term use of calcium channel blockers is associated with some subtypes of breast cancer (and with breast cancer in overweight women). PMID- 27508298 TI - Competing Distractors Facilitate Visual Search in Heterogeneous Displays. AB - In the present study, we examine how observers search among complex displays. Participants were asked to search for a big red horizontal line among 119 distractor lines of various sizes, orientations and colours, leading to 36 different feature combinations. To understand how people search in such a heterogeneous display, we evolved the search display by using a genetic algorithm (Experiment 1). The best displays (i.e., displays corresponding to the fastest reaction times) were selected and combined to create new, evolved displays. Search times declined over generations. Results show that items sharing the same colour and orientation as the target disappeared over generations, implying they interfered with search, but items sharing the same colour and were 12.5 degrees different in orientation only interfered if they were also the same size. Furthermore, and inconsistent with most dominant visual search theories, we found that non-red horizontal distractors increased over generations, indicating that these distractors facilitated visual search while participants were searching for a big red horizontally oriented target. In Experiments 2 and 3, we replicated these results using conventional, factorial experiments. Interestingly, in Experiment 4, we found that this facilitation effect was only present when the displays were very heterogeneous. While current models of visual search are able to successfully describe search in homogeneous displays, our results challenge the ability of these models to describe visual search in heterogeneous environments. PMID- 27508299 TI - Does Economic Growth Reduce Childhood Undernutrition in Ethiopia? AB - BACKGROUND: Policy discussions and debates in the last couple of decades emphasized efficiency of development policies for translating economic growth to development. One of the key aspects in this regard in the developing world is achieving improved nutrition through economic development. Nonetheless, there is a dearth of literature that empirically verifies the association between economic growth and reduction of childhood undernutrition in low- and middle-income countries. Thus, the aim of the study is to assess the interplay between economic growth and reduction of childhood undernutrition in Ethiopia. METHODS: The study used pooled data of three rounds (2000, 2005 and 2010) from the Demographic and Health Surveys (DHS) of Ethiopia. A multilevel mixed logistic regression model with robust standard errors was utilized in order to account for the hierarchical nature of the data. The dependent variables were stunting, underweight, and wasting in children in the household. The main independent variable was real per capita income (PCI) that was adjusted for purchasing power parity. This information was obtained from World Bank. RESULTS: A total of 32,610 children were included in the pooled analysis. Overall, 11,296 (46.7%) [46.0%-47.3%], 8,197(33.8%) [33.2%-34.4%] and 3,175(13.1%) [12.7%-13.5%] were stunted, underweight, and wasted, respectively. We found a strong correlation between prevalence of early childhood undernutrition outcomes and real per capita income (PCI). The proportions of stunting (r = -0.1207, p<0.0001), wasting (r = -0.0338, p<0.0001) and underweight (r = -0.1035, p<0.0001) from the total children in the household were negatively correlated with the PCI. In the final model adjustment with all the covariates, economic growth substantially reduced stunting [beta = 0.0016, SE = 0.00013, p<0.0001], underweight [beta = -0.0014, SE = 0.0002, p<0.0001] and wasting [beta = -0.0008, SE = 0.0002, p<0.0001] in Ethiopia over a decade. CONCLUSION: Economic growth reduces child undernutrition in Ethiopia. This verifies the fact that the economic growth of the country accompanied with socio-economic development and improvement of the livelihood of the poor. Direct nutrition specific and nutrition sensitive interventions could also be recommended in order to have an impact on the massive reduction of childhood undernutrition in the country. PMID- 27508300 TI - Activated Protein C Resistance Does Not Increase Risk for Recurrent Stroke or Death in Stroke Patients. AB - BACKGROUND: Activated protein C (APC) resistance is the most common inherited prothrombotic disorder. The role of APC resistance in ischemic stroke is controversially discussed. OBJECTIVES: The aim of this single center follow up study was to investigate the effect of APC resistance on stroke recurrence and survival in stroke patients. PATIENTS/METHODS: We retrospectively identified 966 patients who had had an ischemic stroke or transitory ischemic attack (TIA) and in whom laboratory tests for APC resistance had been conducted. These patients were contacted to determine the primary outcomes of recurrent ischemic stroke or death. RESULTS: A total of 858 patients with an average follow up time of 8.48 years were included. APC resistance did not influence cumulative incidence functions for stroke free and total survival. In multivariate analyses, crude and adjusted hazard ratios for recurrent stroke as well as for death where not significantly increased in patients with APC resistance. This also applies to the subgroups of young patients, patients with cryptogenic stroke and patients with atrial fibrillation. CONCLUSION: APC-resistance is not a risk factor for subsequent stroke or death in patients with a first ischemic stroke or TIA. Testing for APC-resistance in stroke patients therefore cannot be routinely recommended. PMID- 27508301 TI - Incidence of Diabetes Mellitus and Obesity and the Overlap of Comorbidities in HIV+ Hispanics Initiating Antiretroviral Therapy. AB - BACKGROUND: Cardiovascular disease (CVD) is a leading health threat for HIV+ patients on antiretroviral therapy (ART); cardiometabolic comorbidities are key predictors of risk. Data are limited on incidence of metabolic comorbidities in HIV+ individuals initiating ART in low and middle income countries (LMICs), particularly for Hispanics. We examined incidence of diabetes and obesity in a prospective cohort of those initiating ART in the Dominican Republic. METHODS: Participants >=18 years, initiating ART <90 days prior to study enrollment, were examined for incidence of impaired fasting glucose (IFG), diabetes mellitus (DM), overweight, and obesity. Fasting plasma glucose (FPG) 100-125mg/dl defined IFG; FPG >=126 mg/dl, diagnosis per medical record, or use of hypoglycemic medication defined DM. Overweight and obesity were BMI 25-30 and >=30kg/m2, respectively. Dyslipidemia was total cholesterol >=240mg/dl or use of lipid-lowering medication. Framingham risk equation was used to determine ten-year CVD risk at the end of observation. RESULTS: Of 153 initiating ART, 8 (6%) had DM and 23 (16%) had IFG at baseline, 6 developed DM (28/1000 person-years follow up [PYFU]) and 46 developed IFG (329/1000 PYFU). At baseline, 24 (18%) were obese and 36 (27%) were overweight, 15 became obese (69/1000 PYFU) and 22 became overweight (163/1000 PYFU). Median observation periods for the diabetes and obesity analyses were 23.5 months and 24.3 months, respectively. Increased CVD risk (>=10% 10-year Framingham risk score) was present for 13% of the cohort; 79% of the cohort had >=1 cardiometabolic comorbidity, 48% had >=2, and 13% had all three. CONCLUSIONS: In this Hispanic cohort in an LMIC, incidences of IFG/DM and overweight/obesity were similar to or higher than that found in high income countries, and cardiometabolic disorders affected three-quarters of those initiating ART. Care models incorporating cardiovascular risk reduction into HIV treatment programs are needed to prevent CVD-associated mortality in this vulnerable population. PMID- 27508302 TI - Epitope Mapping of a Monoclonal Antibody Directed against Neisserial Heparin Binding Antigen Using Next Generation Sequencing of Antigen-Specific Libraries. AB - We explore here the potential of a newly described technology, which is named PROFILER and is based on next generation sequencing of gene-specific lambda phage displayed libraries, to rapidly and accurately map monoclonal antibody (mAb) epitopes. For this purpose, we used a novel mAb (designated 31E10/E7) directed against Neisserial Heparin-Binding Antigen (NHBA), a component of the anti-group B meningococcus Bexsero(r) vaccine. An NHBA phage-displayed library was affinity selected with mAb 31E10/E7, followed by massive sequencing of the inserts present in antibody-selected phage pools. Insert analysis identified an amino acid stretch (D91-A128) in the N-terminal domain, which was shared by all of the mAb enriched fragments. Moreover, a recombinant fragment encompassing this sequence could recapitulate the immunoreactivity of the entire NHBA molecule against mAb 31E10/E7. These results were confirmed using a panel of overlapping recombinant fragments derived from the NHBA vaccine variant and a set of chemically synthetized peptides covering the 10 most frequent antigenic variants. Furthermore, hydrogen-deuterium exchange mass-spectrometry analysis of the NHBA mAb 31E10/E7 complex was also compatible with mapping of the epitope to the D91 A128 region. Collectively, these results indicate that the PROFILER technology can reliably identify epitope-containing antigenic fragments and requires considerably less work, time and reagents than other epitope mapping methods. PMID- 27508303 TI - IRF1 Downregulation by Ras/MEK Is Independent of Translational Control of IRF1 mRNA. AB - Oncogenic activation of Ras/MEK downregulates the expression of interferon regulatory factor 1 (IRF1), which is a prerequisite for oncolytic viruses to replicate in cancer cells [1]. Moreover, restoration of IRF1 expression is essential to induce apoptosis of cancer cells treated with a MEK inhibitor [2]. However, the molecular mechanisms that underlie IRF1 downregulation by Ras/MEK remain unclear. In this study, we determined whether Ras/MEK activation modulates IRF1 expression at its translational level. MEK inhibition increased the activity of IRF1 promoter construct in Ras transformed NIH3T3 cells and wild type MEF, but not in IRF1 deficient MEF, indicating that IRF1 protein is required for the transcriptional activation of IRF1. By conducting reporter analysis using IRF1 5' and 3'- UTR constructs, we determined that cis elements on 5'- and 3'-UTR of IRF1 mRNA are not involved in the IRF1 regulation by Ras/MEK. We further compared the recruitment of ribosomes to IRF1 mRNA in RasV12 cells treated with or without the MEK inhibitor by conducting polysome analysis. No difference was observed in the polysomal distribution of IRF1 mRNA between RasV12 cells treated with and without the MEK inhibitor. These results suggest that regulation of IRF1 translation is independent of IRF1 downregulation by Ras/MEK. PMID- 27508306 TI - Heterometallic Co(III)-Gd(III) Clusters as Magnetic Refrigerants. AB - Two heterometallic Co(III)-Gd(III) nanomagnets (Co2Gd6 and Co2Gd9) with defective dicubane-like cores were isolated from the same set of reactants by varying the reaction conditions. These are the first examples of cobalt(III)-gadolinium(III) phosphonate compounds and a rare class of compounds with large 4f ratio among the reported 3d-4f complexes. Magnetic studies reveal large magnetic entropy changes for both complexes (-DeltaSm = 27.81 and 33.07 J kg(-1) K(-1), respectively at 3 K and 7 T). PMID- 27508305 TI - Determining the Effect of Natural Selection on Linked Neutral Divergence across Species. AB - A major goal in evolutionary biology is to understand how natural selection has shaped patterns of genetic variation across genomes. Studies in a variety of species have shown that neutral genetic diversity (intra-species differences) has been reduced at sites linked to those under direct selection. However, the effect of linked selection on neutral sequence divergence (inter-species differences) remains ambiguous. While empirical studies have reported correlations between divergence and recombination, which is interpreted as evidence for natural selection reducing linked neutral divergence, theory argues otherwise, especially for species that have diverged long ago. Here we address these outstanding issues by examining whether natural selection can affect divergence between both closely and distantly related species. We show that neutral divergence between closely related species (e.g. human-primate) is negatively correlated with functional content and positively correlated with human recombination rate. We also find that neutral divergence between distantly related species (e.g. human-rodent) is negatively correlated with functional content and positively correlated with estimates of background selection from primates. These patterns persist after accounting for the confounding factors of hypermutable CpG sites, GC content, and biased gene conversion. Coalescent models indicate that even when the contribution of ancestral polymorphism to divergence is small, background selection in the ancestral population can still explain a large proportion of the variance in divergence across the genome, generating the observed correlations. Our findings reveal that, contrary to previous intuition, natural selection can indirectly affect linked neutral divergence between both closely and distantly related species. Though we cannot formally exclude the possibility that the direct effects of purifying selection drive some of these patterns, such a scenario would be possible only if more of the genome is under purifying selection than currently believed. Our work has implications for understanding the evolution of genomes and interpreting patterns of genetic variation. PMID- 27508307 TI - Asymmetric Reduction of Lactam-Based beta-Aminoacrylates. Synthesis of Heterocyclic beta(2)-Amino Acids. AB - The ability to affect asymmetric reduction of heterocyclic beta-aminoacrylates 1 (n = 1-3) has been assessed with pyrrolidine and piperidone variants generating the corresponding N-heterocyclic beta(2)-amino acids 3b and 5b with high enantioselectivity (>=97% ee) using a Rh/WALPHOS catalyst combination. The use of the carboxylic acid substrate was essential; the corresponding esters do undergo reduction but led to racemic products. The seven-ring azepanone variant (as the carboxylic acid 9b) underwent reduction, but only a minimal level of asymmetric induction was observed. PMID- 27508308 TI - Boesenberols, Pimarane Diterpenes with TRAIL-Resistance-Overcoming Activity from Boesenbergia pandurata. AB - TRAIL is a potent and selective inducer of apoptosis in most cancer cells while sparing normal cells, which makes it an attractive target for the development of new cancer therapies. In a screening program on natural resources with the ability to abrogate TRAIL resistance, the bioassay-guided fractionation of Boesenbergia pandurata rhizomes resulted in the isolation of 17 pimarane diterpenes and a monoterpene. Among these, compounds 1-8, named boesenberols A-H, are new pimarane diterpenes. All compounds exhibited TRAIL-resistance-overcoming activity in TRAIL-resistant AGS cells. Subtoxic doses of the major compound 9 sensitized AGS cells to TRAIL-induced apoptosis by up-regulating apoptosis inducing proteins, such as DR4, DR5, p53, Fas, CHOP, Bak, and cleaved caspases-3, -8, and -9, and down-regulating the levels of cell survival proteins, such as Bcl 2, c-FLIP, and GSK-3beta, in TRAIL-resistant AGS cells. Furthermore, compound 9 did not decrease the viability of noncancerous (HEK293) cells at concentrations up to 30 MUM. PMID- 27508309 TI - Inoculation of Brassica oxyrrhina with plant growth promoting bacteria for the improvement of heavy metal phytoremediation under drought conditions. AB - The aim of this study was to investigate the effects of drought resistant serpentine rhizobacteria on plant growth and metal uptake by Brassica oxyrrhina under drought stress (DS) condition. Two drought resistant serpentine rhizobacterial strains namely Pseudomonas libanensis TR1 and Pseudomonas reactans Ph3R3 were selected based on their ability to stimulate seedling growth in roll towel assay. Further assessment on plant growth promoting (PGP) parameters revealed their ability to produce indole-3-acetic acid, siderophore and 1 aminocyclopropane-1-carboxylate deaminase. Moreover, both strains exhibited high resistance to various heavy metals, antibiotics, salinity and extreme temperature. Inoculation of TR1 and Ph3R3 significantly increased plant growth, leaf relative water and pigment content of B. oxyrrhina, whereas decreased concentrations of proline and malondialdehyde in leaves under metal stress in the absence and presence of DS. Regardless of soil water conditions, TR1 and Ph3R3 greatly improved organ metal concentrations, translocation and bioconcentration factors of Cu and Zn. The successful colonization and metabolic activities of P. libanensis TR1 and P. reactans Ph3R3 represented positive effects on plant development and metal phytoremediation under DS. These results indicate that these strains could be used as bio-inoculants for the improvement of phytoremediation of metal polluted soils under semiarid conditions. PMID- 27508310 TI - Solution Nuclear Magnetic Resonance Studies of Sterol Carrier Protein 2 Like 2 (SCP2L2) Reveal the Insecticide Specific Structural Characteristics of SCP2 Proteins in Aedes aegypti Mosquitoes. AB - Sterol carrier protein 2 like 2 from Aedes aegypti (AeSCP2L2) plays an important role in lipid transport in mosquitoes for its routine metabolic processes. Repeated unsuccessful attempts to crystallize ligand free SCP2L2 prompted us to undertake nuclear magnetic resonance (NMR) spectroscopy to determine its three dimensional structure. We report here the three-dimensional structures and dynamics of apo-AeSCP2L2 and its complex with palmitate. The (15)N heteronuclear single-quantum coherence spectrum of apo-AeSCP2L2 displayed multiple peaks for some of the amide resonances, implying the presence of multiple conformations in solution, which are transformed to a single conformation upon formation of the complex with plamitate. The three-dimensional structures of apo-AeSCP2L2 and palmitated AeSCP2L2 reveal an alpha/beta mixed fold, with five beta-strands and four alpha-helices, very similar to the other SCP2 protein structures. Unlike the crystal structure of palmitated AeSCP2L2, both solution structures are monomeric. It is further confirmed by the rotational correlation times determined by NMR relaxation times (T1 and T2) of the amide protons. In addition, the palmitated AeSCP2L2 structure contains two palmitate ligands, bound in the binding pocket, unlike the three palmitates bound in the dimeric form of AeSCP2L2 in the crystals. The relaxation experiments revealed that complex formation significantly reduces the dynamics of the protein in solution. PMID- 27508311 TI - Hypertension and Diabetic Nephropathy. PMID- 27508312 TI - Development of Nano-Sulfide Sorbent for Efficient Removal of Elemental Mercury from Coal Combustion Fuel Gas. AB - The surface area of zinc sulfide (ZnS) was successfully enlarged using nanostructure particles synthesized by a liquid-phase precipitation method. The ZnS with the highest surface area (named Nano-ZnS) of 196.1 m(2).g(-1) was then used to remove gas-phase elemental mercury (Hg(0)) from simulated coal combustion fuel gas at relatively high temperatures (140 to 260 degrees C). The Nano-ZnS exhibited far greater Hg(0) adsorption capacity than the conventional bulk ZnS sorbent due to the abundance of surface sulfur sites, which have a high binding affinity for Hg(0). Hg(0) was first physically adsorbed on the sorbent surface and then reacted with the adjacent surface sulfur to form the most stable mercury compound, HgS, which was confirmed by X-ray photoelectron spectroscopy analysis and a temperature-programmed desorption test. At the optimal temperature of 180 degrees C, the equilibrium Hg(0) adsorption capacity of the Nano-ZnS (inlet Hg(0) concentration of 65.0 MUg.m(-3)) was greater than 497.84 MUg.g(-1). Compared with several commercial activated carbons used exclusively for gas-phase mercury removal, the Nano-ZnS was superior in both Hg(0) adsorption capacity and adsorption rate. With this excellent Hg(0) removal performance, noncarbon Nano ZnS may prove to be an advantageous alternative to activated carbon for Hg(0) removal in power plants equipped with particulate matter control devices, while also offering a means of reusing fly ash as a valuable resource, for example as a concrete additive. PMID- 27508313 TI - The investigation of the cellular electrophysiological and antiarrhythmic effects of a novel selective sodium-calcium exchanger inhibitor, GYKB-6635, in canine and guinea-pig hearts. AB - The sodium-calcium exchanger (NCX) is considered as the major transmembrane transport mechanism that controls Ca2+ homeostasis. Its contribution to the cardiac repolarization has not yet been directly studied due to lack of specific inhibitors, so that an urgent need for more selective compounds. In this study, the electrophysiological effects of GYKB-6635, a novel NCX inhibitor, on the NCX, L-type calcium, and main repolarizing potassium currents as well as action potential (AP) parameters were investigated. Ion currents and AP recordings were investigated by applying the whole-cell patch clamp and standard microelectrode techniques in canine heart at 37 degrees C. Effects of GYKB-6635 were studied in ouabain-induced arrhythmias in isolated guinea-pig hearts. At a concentration of 1 MUmol/L, GYKB significantly reduced both the inward and outward NCX currents (57% and 58%, respectively). Even at a high concentration (10 MUmol/L), GYKB-6635 did not change the ICaL, the maximum rate of depolarization (dV/dtmax), the main repolarizing K+ currents, and the main AP parameters. GYKB-6635 pre-treatment significantly delayed the time to the development of ventricular fibrillation (by about 18%). It is concluded that GYKB-6635 is a potent and highly selective inhibitor of the cardiac NCX and, in addition, it is suggested to also contribute to the prevention of DAD-based arrhythmias. PMID- 27508314 TI - The effectiveness of a comprehensive reminder system in the secondary prevention of hypertensive ischaemic stroke: randomized controlled trial protocol. AB - AIM: The aim of this study was to determine whether the Comprehensive Reminder System based on the Health Belief Model improves health belief, health behaviours, medication adherence and blood pressure control as a means of decreasing the rate of stroke recurrence among hypertensive ischaemic stroke. BACKGROUND: Hypertensive patients having experienced recent ischaemic strokes are at high risk for stroke recurrence. Several trials attempted to improve secondary stroke prevention via patient education, however, patient outcomes remained poor. Long-term follow-up studies regarding secondary stroke prevention are limited. DESIGN: A multi-centre, 12-month, assessor-blinded, parallel-group, randomized controlled longitudinal trial. METHODS: Hypertensive patients having experienced an ischaemic stroke are the target population. The intervention consists of health belief education, a calendar handbook, a weekly automated short-message service and four telephone follow-up interviews. Outcomes will be assessed at baseline and at 3, 6 and 12 months following discharge. The primary outcome is blood pressure control. The secondary outcomes include health belief, health behaviours and medication adherence. The clinical endpoint is the rate of stroke recurrence. DISCUSSION: Although many efforts to improve secondary stroke prevention have been undertaken, research indicates that improvements remain possible and warranted. This research protocol based on the Health Belief Model will improve our understanding of stroke education and transitional care needed in China and with the world-wide target population. PMID- 27508315 TI - Effect of the Keto Group on Yields and Composition of Organic Aerosol Formed from OH Radical-Initiated Reactions of Ketones in the Presence of NOx. AB - Yields of secondary organic aerosol (SOA) were measured for OH radical-initiated reactions of the 2- through 6-dodecanone positional isomers and also n-dodecane and n-tetradecane in the presence of NOx. Yields decreased in the order n tetradecane > dodecanone isomer average > n-dodecane, and the dodecanone isomer yields decreased as the keto group moved toward the center of the molecule, with 6-dodecanone being an exception. Trends in the yields can be explained by the effect of carbon number and keto group presence and position on product vapor pressures, and by the isomer-specific effects of the keto group on branching ratios for keto alkoxy radical isomerization, decomposition, and reaction with O2. Most importantly, results indicate that isomerization of keto alkoxy radicals via 1,5- and 1,6-H shifts are significantly hindered by the presence of a keto group whereas decomposition is enhanced. Analysis of particle composition indicates that the SOA products are similar for all isomers, and that compared to those formed from the corresponding reactions of alkanes the presence of a pre existing keto group opens up additional heterogeneous/multiphase reaction pathways that can lead to the formation of new products. The results demonstrate that the presence of a keto group alters gas and particle phase chemistry and provide new insights into the potential effects of molecular structure on the products of the atmospheric oxidation of volatile organic compounds and subsequent formation of SOA. PMID- 27508316 TI - Stealthy role of size-driven stresses in biomechanics of breast implants capsular contracture. AB - Breast Capsular Contracture (BCC) is one of the adverse complications occurring with greater incidence in breast augmentation surgical procedures. Its formation can be interpreted as the conclusive result of the physiological process known as response to a foreign body. From a biochemical standpoint, the formation of the peri-prosthetic capsule is certainly a multifactorial process: many hypotheses concerning its etiology have been suggested in the literature and a number of related pharmacological protocols have been consequently proposed to clinically treat this pathology with the aim to prevent further complications and avoid future re-interventions. However, the vast majority of these theories seems to be only partially supported by clinical outcomes and thus a shared opinion on this matter is still absent among specialists. Within this framework, by starting from clinical observations which highlighted an unexpected correlation between histo morphological features of fibrotic capsules and overall size of breast implants, the present study investigates the hypothesis that the biomechanical interaction between prosthesis and host tissue may play a crucial role in the biological processes governing the pathological phenomenon at hand. Therefore, to shed light on the underlying mechanisms which could trigger the breast capsular contracture, both simple analytical solutions, in which elasticity and growth are simultaneously taken into account, and more accurate geometrically faithful Finite Element-based numerical simulations have been exploited. The theoretical findings demonstrate that somehow counter-intuitive radial and hoop stress fields occur at the capsula-implant interface in a way such that their combined action, independently from other possible concurrent factors, results significantly amplified for small-size breast prostheses, localized stress peaks in these cases promoting detaching and rippling phenomena actually observed in BCC clinical complications. PMID- 27508317 TI - Circulating Des-gamma-carboxy prothrombin is not associated with cardiovascular calcification or stiffness: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND AND AIMS: Vitamin K-dependent protein (VKDP) activity may have a role in preventing cardiovascular calcification, but has not previously been studied in large, generally healthy populations. METHODS: Using an elevated ankle brachial index (ABI) as a measure of medial vascular calcification, we performed a case-cohort analysis within the Multi-Ethnic Study of Atherosclerosis, measuring Des-gamma-carboxy prothrombin (DCP) to estimate VKDP activity. In secondary analyses of the weighted subcohort, we examined the cross-sectional associations between DCP and prevalent vascular calcification of the coronary vessels, aortic and mitral valves, and aortic wall, and with vascular stiffness. RESULTS: In adjusted analysis, cases (n = 104) had 0.21 ng/ml (-0.94-0.52) lower DCP concentrations than the subcohort (n = 613). Furthermore, amongst the 717 participants in the weighted cohort, VKDP activity was not associated with coronary artery, mitral valve, aortic valve or aortic wall calcification, nor was it associated with vascular stiffness. CONCLUSIONS: Our negative results do not support a role of circulating VKDP activity in cardiovascular calcification in community-dwelling adults. PMID- 27508318 TI - Association of serum mimecan with angiographic coronary collateralization in patients with stable coronary artery disease and chronic total occlusion. AB - BACKGROUND AND AIMS: Mimecan/osteoglycin is identified as an emerging biomarker of coronary atherosclerosis. We investigated whether and to what extent serum mimecan reflects angiographic coronary collateralization in patients with stable coronary artery disease and chronic total occlusion. METHODS: Serum levels of mimecan were determined in 559 consecutive patients with stable angina and angiographic total occlusion of at least one major coronary artery. The degree of collaterals supplying the distal aspect of a total occlusion from the contra lateral vessel was graded as poor (Rentrop score of 0 or 1) or good coronary collateralization (Rentrop score of 2 or 3). RESULTS: Serum mimecan was significantly higher in patients with poor collateralization than in those with good collateralization, and correlated inversely with Rentrop score (adjusted Spearmen's r = -0.443, p < 0.001). The prevalence of poor coronary collaterals increased stepwise from the lowest to the highest quartile of serum mimecan (OR 2.140, 95% CI 1.793-2.555; p for trend < 0.001). After adjusting for age, gender, traditional risk factors for coronary artery disease, history of myocardial infarction, severity of coronary artery disease, renal function and C-reactive protein, serum mimecan (per SD) remained an independent determinant for poor collateralization (OR 2.674, 95% CI 2.057-3.475, p < 0.001). The diagnostic value of mimecan (per SD) for detecting poor collateralization was consistent when the patients were specified by gender, age, body mass index, presence or absence of hypertension and diabetes, and status of renal function (OR 2.075-6.932, p interaction >= 0.059). CONCLUSION: Increased serum mimecan is associated with poor angiographic coronary collateralization in patients with chronic total occlusion. PMID- 27508319 TI - Angiographic progression of coronary atherosclerosis in patients with familial hypercholesterolaemia treated with non-statin therapy: Impact of a fat-modified diet and a resin. AB - BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) profoundly increases the risk of coronary artery disease (CAD). We investigated whether diet and a bile acid sequestrant decrease coronary atherosclerosis in patients with FH. METHODS: We identified 26 men with FH and CAD, participating in the St Thomas' Atherosclerosis Regression Study, who had been randomized to receive a fat modified diet plus cholestyramine (8 g twice daily) (DC, n = 12) or usual care (UC, n = 14), and investigated the relative effects of these treatments on the angiographic progression of coronary atherosclerosis over 39 months. FH was defined as probable/definite according to Dutch Lipid Clinic Network criteria; mean FH score was 8.7 (range 6-15) and mean baseline low-density lipoprotein cholesterol (LDL-Ch) concentration was 5.4 (SD 1.4) mmol/L. Coronary atherosclerosis was assessed by serial quantitative angiography as the global changes in mean and minimum absolute width of segments (MAWS and MinAWS, respectively). RESULTS: Mean plasma LDL-Ch concentration fell by 35% with DC and remained significantly (p < 0.001) lower during the trial at 3.78 (SD 0.98) mmol/L compared with UC at 4.89 (1.04). MAWS decreased by 0.252 (SEM 0.072) mm in the UC group and by 0.001 (0.065) mm in the DC group (p = 0.007), with corresponding reductions in MinAWS of 0.290 (0.087) mm and 0.013 (0.058) mm (p = 0.009); these changes were significant after adjusting for baseline variables, including coronary luminal dimensions and lipoprotein(a). Progression was observed in 7 patients (50%) on UC and 3 (25%) on DC (p = 0.19), with regression in no patients (0%) and 3 patients (25%) (p < 0.05), respectively. CONCLUSIONS: This investigation, carried out in the pre-statin era, demonstrates that a prudent diet and cholestyramine could improve the course of coronary atherosclerosis in men with phenotypic FH through sustained reductions in LDL-Ch. PMID- 27508320 TI - Altered relation of the renin-aldosterone system and vasoactive peptides in type 2 diabetes: The KORA F4 study. AB - BACKGROUND AND AIMS: The exact mechanism of premature atherosclerosis in diabetes is still unclear. Inappropriate activation of the renin-aldosterone-angiotensin system may be an important risk factor for cardiovascular disease. We investigated whether renin and aldosterone are associated with vasoactive peptides midregional-pro atrial natriuretic peptide (MR-proANP) and midregional pro adrenomedullin (MR-proADM), or with intima media thickness (IMT) as a marker for early atherosclerotic alterations in the general community and in subjects with type 2 diabetes. METHODS: In 1261 participants in the KORA F4 study, the associations of renin, aldosterone and aldosterone to renin ratio with MR-proANP, MR-proADM and IMT were assessed using linear regression models stratified for the presence of prediabetes and type 2 diabetes. RESULTS: After adjustment for confounding factors, an inverse association of MR-proANP with renin (p = 0.002) and aldosterone (p = 0.021) and a direct association of MR-proADM with renin (p < 0.001) and aldosterone (p = 0.019) were seen in nondiabetic individuals. In diabetic subjects, there was no significant correlation of MR-proANP or MR-proADM with renin or aldosterone. Renin and aldosterone were not directly associated with IMT in non-diabetic subjects and the total cohort, whereas aldosterone was associated with IMT in diabetic participants (p = 0.005). CONCLUSIONS: This study shows associations between renin, aldosterone and MR-proANP/MR-proADM plasma levels that are altered in type 2 diabetes. Plasma renin and aldosterone are not independent biomarkers for early atherosclerotic damages of the carotid arteries in the general community. PMID- 27508321 TI - Intralesional meglumine antimoniate for the treatment of localised cutaneous leishmaniasis: a retrospective review of a Brazilian referral centre. AB - Although intralesional meglumine antimoniate (MA) infiltration is considered an option for cutaneous leishmaniasis (CL) therapy and is widely used in the Old World, there have been few studies supporting this therapeutic approach in the Americas. This study aims to describe outcomes and adverse events associated with intralesional therapy for CL. This retrospective study reviewed the experience of a Brazilian leishmaniasis reference centre using intralesional MA to treat 31 patients over five years (2008 and 2013). The median age was 63 years (22-86) and the median duration time of the lesions up to treatment was 16 weeks. In 22 patients (71%), intralesional therapy was indicated due to the presence of contraindications or previous serious adverse events with systemic MA. Other indications were failure of systemic therapy or ease of administration. Intralesional treatment consisted of one-six infiltrations (median three) for a period of up to 12 weeks. The initial (three months) and definitive (six months) cure rates were 70.9% and 67.7%, respectively. Most patients reported mild discomfort during infiltration and no serious adverse events were observed. In conclusion, these results show that the intralesional MA efficacy rate was very similar to that of systemic MA treatment, and reinforce the need for further studies with adequate design to establish the efficacy and safety of this therapeutic approach. PMID- 27508322 TI - Comparative growth of spotted fever group Rickettsia spp. strains in Vero cells. AB - In Brazil, the spotted fever group (SFG) Rickettsia rickettsii and Rickettsia parkeri related species are the etiological agents of spotted fever rickettsiosis. However, the SFG, Rickettsia rhipicephali, that infects humans, has never been reported. The study of growth dynamics can be useful for understanding the infective and invasive capacity of these pathogens. Here, the growth rates of the Brazilian isolates R. rickettsii str. Taiacu, R. parkeri str. At#24, and R. rhipicephali HJ#5, were evaluated in Vero cells by quantitative polymerase chain reaction. R. rhipicephali showed different kinetic growth compared to R. rickettsii and R. parkeri. PMID- 27508323 TI - Single-Molecule Imaging of Iron-Phthalocyanine-Catalyzed Oxygen Reduction Reaction by in Situ Scanning Tunneling Microscopy. AB - We report herein an in situ electrochemical scanning tunneling microscopy (ECSTM) investigation of iron-phthalocyanine (FePc)-catalyzed oxygen reduction reaction (ORR). A highly ordered FePc adlayer is revealed on a Au(111) electrode. The center ions in the FePc adlayer show uniform high contrast in an oxygen-saturated electrolyte, which is attributed to the formation of an FePc-O2 complex. In situ STM results reveal the sharp contrast change upon shifting the electrode potential to trigger the ORR. Theoretical simulation has supplied further evidence for the contrast difference of the adsorbed FePc species. PMID- 27508324 TI - MicroRNA-19b Mediates Lung Epithelial-Mesenchymal Transition via Phosphatidylinositol-3,4,5-Trisphosphate 3-Phosphatase in Response to Mechanical Stretch. AB - Lung epithelial-mesenchymal transition (EMT) plays an important role in ventilation-associated lung fibrosis, which may contribute to the poor outcome of patients with acute respiratory distress syndrome. Because microRNAs control and modulate normal physiological and pathophysiological processes, we investigated the role of microRNAs in the development of acute respiratory distress syndrome associated EMT in response to mechanical stress. In the current study, primary human alveolar epithelial type II (AEII) cells were subjected to cyclic stretch that resulted in EMT profiles with decreased gene expression of cytokeratin-8, E cadherin, and surfactant protein B, and increased expression of vimentin, alpha smooth muscle actin, and N-cadherin. Microarray analysis revealed that the expression of microRNA-19b (miR-19b) was up-regulated in the AEII cells, and real time polymerase chain reaction showed that the expression of miR-19b increased in both the AEII cells and the primary human small-airway epithelial cells. Overexpression of miR-19b in small-airway epithelial cells promoted the mechanical stretch-induced EMT phenotypes, whereas inhibition of miR-19b attenuated it. The inhibitory effect of miR-19b was attributed to enhanced signaling of phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN), leading to inactivation of the AKT pathway. Restoration of PTEN expression or inhibition of AKT phosphorylation suppressed the mechanical stretch-induced EMT phenotypes. We further demonstrated that the mechanical stretch-induced miR19 expression was regulated by the focal adhesion kinase-Rho pathway. In conclusion, we found that miR-19b plays a key role in the development of the EMT phenotype through down-regulation of PTEN in human lung epithelial cells in response to mechanical stretch. The miR-19b-PTEN signaling pathway may serve as a novel therapeutic target in the context of ventilator-associated lung fibrosis. PMID- 27508325 TI - Therapeutic outcomes of endoscopic submucosal dissection for early gastric cancer: single-center study. AB - OBJECTIVES: Endoscopic submucosal dissection (ESD) has been widely accepted for selected patients with early gastric cancer (EGC). The aim of this study was to assess the therapeutic outcomes after ESD according to the pathological extent. PATIENTS AND METHODS: From January 2005 to December 2014, a total of 599 patients with 611 lesions were enrolled in this study. The tumors were categorized according to pathological results on the basis of absolute criteria (AC), expanded criteria (EC), EC with undifferentiated histology [(EC-U), mucosal cancer, ulcer (-), <=20 mm], or beyond EC (BEC). The therapeutic outcomes among the four groups were analyzed retrospectively. RESULTS: The number of patients in the AC, EC, EC-U, and BEC groups was 447, 91, 19, and 54. The complete resection rates of EGC were 97.8, 84.6, 94.4, and 45.5% (P=0.001) and en bloc resection rates in the AC, EC, EC-U, and BEC groups were 99.1, 98.9, 100, and 98.1% (P=0.833), respectively. The 5-year disease-free survival rate in the AC, EC, EC U, and BEC groups was 90.6, 88.7, 75.0, and 83.3% (P=0.394). In multivariate analysis, undifferentiated histology (P=0.001) and tumor size (>30 mm, P=0.017) were risk factors related to local recurrence. CONCLUSION: The efficacy of ESD for EGCs in EC is almost equal to that in AC when complete resection was achieved. However, the indication for ESD should be decided conservatively because the complete resection rate of EGC in the EC group was significantly lower than that in the AC group. Undifferentiated histology and tumor size over 30 mm were risk factors related to local recurrence. PMID- 27508326 TI - Detection of molecular bacterascites in decompensated cirrhosis defines a risk with decreased survival. AB - BACKGROUND: The prognostic relevance of bacterial DNA (bactDNA) detection in ascitic fluid of patients with cirrhosis is still under debate. Using quantitative real-time PCR with broad-range primers targeting the V3 and V4 variable region of the 16S rRNA gene, we measured bactDNA concentrations in patients with and without leukocytic ascites and evaluated the impact on short term survival. PATIENTS AND METHODS: Ascites samples from 173 patients with decompensated cirrhosis were consecutively collected between February 2011 and December 2012. BactDNA-positive ascites samples were sequenced and chromatograms were identified using RipSeq. Clinical data collection and survival analyses were carried out retrospectively and correlated with ascites bactDNA levels. RESULTS: BactDNA was detected qualitatively with a similar frequency in both nonleukocytic and leukocytic ascites [40% (57/144) and 43.5% (10/23), respectively; P=0.724]. However, the median bactDNA level was significantly higher in leukocytic ascites than in nonleukocytic ascites (1.2*10 vs. 5.7*10 copies/ml; P=0.008). Patients' survival was associated significantly with bactDNA level. The 30-day and 180-day survival was reduced if bactDNA was above the quantification limit of 520 copies/ml (84 and 63% vs. 72 and 43%, respectively; P<0.05) and worst if bactDNA was above 5000 copies/ml. The bacterial spectrum was dominated by Gram-positive strains as shown by direct sequencing. CONCLUSION: BactDNA quantification in ascitic fluid samples using culture-independent 16S rRNA gene-based methods seems to be an interesting approach to identify patients at risk of reduced survival. Our study warrants further evaluation of antibiotic treatment in patients with molecular bacterascites. PMID- 27508327 TI - A 1-year prospective study of the effect of infliximab on bone metabolism in inflammatory bowel disease patients. AB - OBJECTIVES: Infliximab (IFX) treatment has shown potentially beneficial effects on bone metabolism in inflammatory bowel disease (IBD) patients. We aimed to prospectively evaluate the impact of IFX treatment on bone metabolism in antitumour necrosis factor (TNF)-alpha-naive IBD patients using established bone metabolism markers and an in-vitro osteoblast model. MATERIALS AND METHODS: A total of 37 anti-TNFalpha-naive IBD patients and 20 healthy controls were included. All measurements were performed at baseline and repeated in IBD patients following IFX therapy. Bone mineral density was measured by dual-energy X-ray absorptiometry. Parathyroid hormone, vitamin D, osteoprotegerin, soluble receptor activator of nuclear factor B ligand and proinflammatory and anti inflammatory cytokines were measured. Bone formation was measured using osteocalcin (OC) and procollagen type 1N propeptide, and bone resorption was measured using serum type 1 collage c-telopeptide. The effect of control and IBD patient sera on human osteoblast viability and differentiation was analysed. RESULTS: OC level was higher in controls than IBD patients (P=0.018). After IFX, OC and procollagen type 1N propeptide increased significantly (P=0.002 and 0.011) and (P<0.001 and P=0.016) at weeks 6 and 30 after treatment, respectively. There was a nonsignificant decrease in serum type 1 collage c-telopeptide. After IFX therapy, proinflammatory cytokines TNF-alpha, interleukin-6 and interleukin-13 decreased significantly (P=0.016, week 54; P=0.005, week 6 and P=0.025, week 6), respectively. Sera from IBD patients before IFX showed increased osteoblast viability compared with the controls (P=0.003 to P<0.005), but induced reduced osteoblast differentiation. After IFX, viability reduced to control levels, but osteoblast differentiation increased (P=0.041). CONCLUSION: IFX treatment induced beneficial effects on bone metabolism. Osteoblast culture results suggest that IBD patients may have increased osteoblast viability, but reduced differentiation, which has implications for bone strength. PMID- 27508328 TI - Laparoscopic Approach for Thermoablation Microwave in the Treatment of Hepatocellular Carcinoma: A Single Center Experience. AB - BACKGROUND: The surgical therapy of choice for hepatocellular carcinoma (HCC) is liver transplantation (LT) or hepatic resection, although only a small percentage of patients can undergo these procedures. Microwave thermal ablation (MWTA) can be an effective alternative treatment for HCC that complicates a cirrhotic liver disease, either as a final procedure or for downstaging patients on the waiting list for LT, or in combination with resective surgery to achieve oncological radicality. OBJECTIVE: The purpose of this retrospective study was to evaluate experience with the laparoscopic approach of MWTA at our center. MATERIALS AND METHODS: In a cohort of 35 consecutive patients undergoing MWTA with laparoscopic approach between January, 2013 and May, 2016, we reviewed the demographic data, the Barcelona clinic liver cancer stage, the severity of cirrhotic liver disease, the size of the ablated lesion, the duration of the procedure, and complications occurring within 90 days of surgery. RESULTS: MWTA was performed by applying one to three hepatic parenchymal insertions (mean 1.8) per patient. The mean duration of surgery was 163 +/- 18 minutes. There was no blood loss in any of the procedures. Complete necrosis on CT scan was achieved in 26/35 patients (75%). The mean hospital stay was 4.6 (range 2-7) days; major complications were postablation syndrome in 2/35 (5.7%), peritoneal fluid in 4/35 (11.4%), and transient jaundice in 1/35 (2.8%) patients. There was no mortality. CONCLUSIONS: Laparoscopic MTWA is a safe and effective treatment for unresectable HCC and when a percutaneous procedure is not feasible. PMID- 27508329 TI - Connection Map for Compounds (CMC): A Server for Combinatorial Drug Toxicity and Efficacy Analysis. AB - Drug discovery and development is a costly and time-consuming process with a high risk for failure resulting primarily from a drug's associated clinical safety and efficacy potential. Identifying and eliminating inapt candidate drugs as early as possible is an effective way for reducing unnecessary costs, but limited analytical tools are currently available for this purpose. Recent growth in the area of toxicogenomics and pharmacogenomics has provided with a vast amount of drug expression microarray data. Web servers such as CMap and LTMap have used this information to evaluate drug toxicity and mechanisms of action independently; however, their wider applicability has been limited by the lack of a combinatorial drug-safety type of analysis. Using available genome-wide drug transcriptional expression profiles, we developed the first web server for combinatorial evaluation of toxicity and efficacy of candidate drugs named "Connection Map for Compounds" (CMC). Using CMC, researchers can initially compare their query drug gene signatures with prebuilt gene profiles generated from two large-scale toxicogenomics databases, and subsequently perform a drug efficacy analysis for identification of known mechanisms of drug action or generation of new predictions. CMC provides a novel approach for drug repositioning and early evaluation in drug discovery with its unique combination of toxicity and efficacy analyses, expansibility of data and algorithms, and customization of reference gene profiles. CMC can be freely accessed at http://cadd.tongji.edu.cn/webserver/CMCbp.jsp . PMID- 27508330 TI - Efficient Cellular Knockdown Mediated by siRNA Nanovectors of Gemini Cationic Lipids Having Delocalizable Headgroups and Oligo-Oxyethylene Spacers. AB - The use of small interfering RNAs (siRNAs) to silence specific genes is one of the most promising approaches in gene therapy, but it requires efficient nanovectors for successful cellular delivery. Recently, we reported liposomal gene carriers derived from a gemini cationic lipid (GCL) of the 1,2-bis(hexadecyl dimethyl imidazolium) oligo-oxyethylene series ((C16Im)2(C2H4O)nC2H4 with n = 1, 2, or 3) and 1,2-dioleyol phosphatidylethanolamine as highly efficient cytofectins for pDNA. On the basis of the satisfactory outcomes of the previous study, the present work focuses on the utility of coliposomes of these gemini lipids with the biocompatible neutral lipid mono oleoyl glycerol (MOG) as highly potent vectors for siRNA cellular transport in the presence of serum. The (C16Im)2(C2H4O)nC2H4/MOG-siRNA lipoplexes were characterized through (i) a physicochemical study (zeta potential, cryo-transmission electron microscopy, small-angle X-ray scattering, and fluorescence anisotropy) to establish the relationship between size, structure, fluidity, and the interaction between siRNA and the GCL/MOG gene vectors and (ii) a biological analysis (flow cytometry, fluorescence microscopy, and cell viability) to report the anti-GFP siRNA transfections in HEK 293T, HeLa, and H1299 cancer cell lines. The in vitro biological analysis confirms the cellular uptake and indicates that a short spacer, a very low molar fraction of GCL in the mixed lipid, and a moderate effective charge ratio of the lipoplex yielded maximum silencing efficacy. At these experimental conditions, the siRNA used in this work is compacted by the GCL/MOG nanovectors by forming two cubic structures (Ia3d and Pm3n) that are correlated with excellent silencing activity. These liposomal nanocarriers possess high silencing activity with a negligible cytotoxicity, which strongly supports their practical use for in vivo knockdown studies. PMID- 27508331 TI - Adaptation to an invasive host is driving the loss of a native ecotype. AB - Locally adapted populations are often used as model systems for the early stages of ecological speciation, but most of these young divergent populations will never become complete species. The maintenance of local adaptation relies on the strength of natural selection overwhelming the homogenizing effects of gene flow; however, this balance may be readily upset in changing environments. Here I show that soapberry bugs (Jadera haematoloma) have lost adaptations to their native host plant (Cardiospermum corindum) and are regionally specializing on an invasive host (Koelreuteria elegans), collapsing a classic and well-documented example of local adaptation. All populations that were adapted to the native host including those still found on that host today-are now better adapted to the invasive host in multiple phenotypes. Weak differentiation remains in two traits, suggesting that homogenization across the region is incomplete. This study highlights the potential for adaptation to invasive species to disrupt native communities by swamping adaptation to native conditions through maladaptive gene flow. PMID- 27508332 TI - Nonpuerperal Mastitis Acts as the Initial Presentation of Pituitary Prolactinoma. PMID- 27508333 TI - In vivo assessment of a new multifunctional coating architecture for improved Mg alloy biocompatibility. AB - Magnesium alloys are regarded as potential biodegradable load-bearing biomaterials for orthopedic applications due to their physico-chemical and biomechanical properties. However, their clinical applicability is restricted by their high degradation rate, which limits the physiological reconstruction of the neighbouring tissues. In this work, a multifunctional coating architecture was developed on an AZ31 alloy by conjoining an anodization process with the deposition of a polymeric-based layer consisting of polyether imine reinforced with hydroxyapatite nanoparticles, aiming at improved control of the corrosion activity and biological performance of the Mg substrate. Anodization and coating protocols were evaluated either independently or combined for corrosion resistance and biological behaviour, i.e. the irritation potential and angiogenic capability within a chicken chorioallantoic membrane assay, and bone tissue response following tibia implantation within a rabbit model. Electrochemical impedance spectroscopy (EIS) analysis showed that coated Mg constructs, particularly anodized plus coated with AZ31, exhibited excellent stability compared to the anodized alloy and, particularly, to the bare AZ31. Microtomographic evaluation of the implanted samples correlated with these degradation results. Mg constructs displayed a non-irritating behaviour, and were associated with high levels of vascular ingrowth. Bone ingrowth neighbouring the implanted constructs was observed for all samples, with coated and anodized plus coated samples presenting the highest bone formation. Gene expression analysis suggested that the enhanced bone tissue formation was associated with the boost in osteogenic activity through Runx2 upregulation, following the activation of PGC-1alpha/ERRalpha signaling. Overall, the developed multifunctional coatings appear to be a promising strategy to obtain safe and bioactive biodegradable Mg based implants with potential applications within bone tissue. PMID- 27508334 TI - Surgical Hand Antisepsis and Surgical Site Infections. AB - BACKGROUND: Surgical site infections (SSI) remain a significant problem to both the patients and the healthcare system. Value care and standardized quality measures continue to promote improvement in surgical asepsis, but certain debates remain unresolved in the field of surgical hand antisepsis. METHODS: Review of relevant accounts and literature. RESULTS: Controversy has existed regarding the U.S. Food and Drug Administration (FDA)'s 1994 Tentative Final Monograph (TFM), which defined how surgical hand antisepsis products are assessed. Issues involving neutralizers and demonstration of a cumulative effect were addressed in the FDA's Proposed Rule in 2015. Few studies have used SSI as a primary outcome and instead have used a surrogate marker (colony-forming units [CFU]). Quantitative microbiology studies suggest a minimum bacterial inoculum of 105-107 CFU/mL is necessary to cause a clinical infection. Outcomes of antisepsis likely are driven by both active ingredient(s) and overall product formulation. Povidone iodine aqueous scrubs are inferior to chlorhexidine gluconate (CHG) 4% aqueous scrubs and alcohol-based rubs (ABR). The SSI and CFU outcomes studies support the equivalence or superiority of ABR over CHG. CONCLUSIONS: Both ABRs and CHG 4% are preferred to povidone-iodine for surgical hand antisepsis. Well-powered randomized controlled trials measuring SSI as a primary outcome, as well as those designed according to either TFM or European methodology, with appropriate controls and neutralizers, are warranted. These trials should incorporate different ABR formulations and CHG 4%, as well as skin tolerance assessments and a cost analysis. PMID- 27508335 TI - Effects of Manganese Oxide on Arsenic Reduction and Leaching from Contaminated Floodplain Soil. AB - Reductive release of the potentially toxic metalloid As from Fe(III) (oxyhydr)oxides has been identified as an important process leading to elevated As porewater concentrations in soils and sediments. Despite the ubiquitous presence of Mn oxides in soils and their oxidizing power toward As(III), their impact on interrelated As, Fe, and Mn speciation under microbially reducing conditions remains largely unknown. For this reason, we employed a column setup and X-ray absorption spectroscopy to investigate the influence of increasing birnessite concentrations (molar soil Fe-to-Mn ratios: 4.8, 10.2, and 24.7) on As speciation and release from an As-contaminated floodplain soil (214 mg As/kg) under anoxic conditions. Our results show that birnessite additions significantly decreased As leaching. The reduction of both As and Fe was delayed, and As(III) accumulated in birnessite-rich column parts, indicating the passivation of birnessite and its transformation products toward As(III) oxidation and the precipitation of Fe(III)(oxyhydr)oxides. Microbial Mn reduction resulted in elevated soil pH values, which in turn lowered the microbial activity in the birnessite-enriched soil. We conclude that in Mn-oxide-rich soil environments undergoing redox fluctuations, the enhanced As adsorption to newly formed Fe(III) (oxyhydr)oxides under reducing conditions leads to a transient stabilization of As. PMID- 27508336 TI - Reports to FDA of fatal anaphylaxis associated with intravenous iron products. PMID- 27508338 TI - Use of CT to evaluate and compare intranasal features in brachycephalic and normocephalic dogs. AB - OBJECTIVES: To evaluate and compare nasal mucosal contact, septal deviation and caudal aberrant nasal turbinates in brachycephalic and normocephalic dogs using computed tomography. METHODS: Dogs without nasal disease and having undergone computed tomography scan of the head (plica alaris to the cribiform plate) were retrospectively selected and divided into brachycephalic and normocephalic groups. Eighteen brachycephalic and 32 normocephalic dogs were included. Anatomic criteria were used to locate predetermined pairs of intranasal structures and nasal mucosal contact was described as present or absent for each site. Septal deviations were identified and measured using angle of septal deviation. Caudal aberrant nasal turbinates were identified and categorised when present. RESULTS: Prevalence of nasal mucosal contact was significantly higher in brachycephalic dogs. No significant difference was seen in prevalence or in angle of septal deviation between groups. Prevalence of caudal aberrant nasal turbinates was significantly higher in brachycephalic dogs. CLINICAL SIGNIFICANCE: Nasal mucosal contact and caudal aberrant nasal turbinates were significantly more prevalent in brachycephalic dogs than in normocephalic dogs in our study. Computed tomography can be a valuable aid in obtaining data on nasal mucosal contact, caudal aberrant nasal turbinates and septal deviations. Combination of computed tomography with endoscopy and functional airway testing would be useful to further evaluate the correlation between intranasal features and symptoms of brachycephalic airway syndrome. PMID- 27508339 TI - Tailored Nanoparticle Codelivery of antimiR-21 and antimiR-10b Augments Glioblastoma Cell Kill by Temozolomide: Toward a "Personalized" Anti-microRNA Therapy. AB - Glioblastoma remains an aggressive brain malignancy with poor prognosis despite advances in multimodal therapy that include standard use of Temozolomide. MicroRNA-21 (miR-21) and microRNA-10b (miR-10b) are oncomiRs overexpressed in glioblastoma, promoting many aspects of cancer biology. We hypothesized that PLGA nanoparticles carrying antisense miR-21 (antimiR-21) and antisense miR-10b (antimiR-10b) might beneficially knockdown endogenous miR-21 and miR-10b function and reprogram cells prior to Temozolomide treatment. PLGA nanoparticles were effective in intracellular delivery of encapsulated oligonucleotides. Concentrations of delivered antimiR-21 and antimiR-10b were optimized and specifically tailored to copy numbers of intracellular endogenous microRNAs. Coinhibition of miR-21 and miR-10b significantly reduced the number of viable cells (by 24%; p < 0.01) and increased (2.9-fold) cell cycle arrest at G2/M phase upon Temozolomide treatment in U87 MG cells. Cell-tailored nanoparticle-assisted concurrent silencing of miR-21 and miR-10b prior to Temozolomide treatment is an effective molecular therapeutic strategy in cell culture, warranting the need for further studies prior to future in vivo "personalized" medicine applications. PMID- 27508341 TI - The Pitt Innovation Challenge (PInCh): Driving Innovation in Translational Research Through an Incentive-Based, Problem-Focused Competition. AB - PROBLEM: Translational research aims to move scientific discoveries across the biomedical spectrum from the laboratory to humans, and to ultimately transform clinical practice and public health policies. Despite efforts to accelerate translational research through national initiatives, several major hurdles remain. APPROACH: The authors created the Pitt Innovation Challenge (PInCh) as an incentive-based, problem-focused approach to solving identified clinical or public health problems at the University of Pittsburgh Clinical and Translational Science Institute in spring 2014. With input from a broad range of stakeholders, PInCh leadership arrived at the challenge question: How do we empower individuals to take control of their own health outcomes? The authors developed the PInCh's three-round proposal submission and review process as well as an online contest management tool to support the process. OUTCOMES: Ninety-two teams submitted video proposals in round one. Proposals included mobile applications (29; 32%), other information technology (19; 21%), and community program (22; 24%) solutions. Ten teams advanced to the final round, where three were awarded $100,000 to implement their solution over 12 months. In a 6-month follow-up survey, 6/11 (55%) team leaders stated the PInCh helped to facilitate connections outside their normal sphere of collaborators. NEXT STEPS: Additional educational training sessions related to problem-focused research will be developed. The PInCh will be expanded to engage investment and industry communities to facilitate the translation of solutions to clinical practice via commercialization pathways. External organizations and other universities will be engaged to use the PInCh as a mechanism to fuel innovation in their spaces. PMID- 27508337 TI - Early adverse experience and substance addiction: dopamine, oxytocin, and glucocorticoid pathways. AB - Substance addiction may follow a chronic, relapsing course and critically undermine the physical and psychological well-being of the affected individual and the social units of which the individual is a member. Despite the public health burden associated with substance addiction, treatment options remain suboptimal, with relapses often seen. The present review synthesizes growing insights from animal and human research to shed light upon developmental and neurobiological pathways that may increase susceptibility to addiction. We examine the dopamine system, the oxytocin system, and the glucocorticoid system, as they are particularly relevant to substance addiction. Our aim is to delineate how early adverse experience may induce long-lasting alterations in each of these systems at molecular, neuroendocrine, and behavioral levels and ultimately lead to heightened vulnerability to substance addiction. We further discuss how substance addiction in adulthood may increase the risk of suboptimal caregiving for the next generation, perpetuating the intergenerational cycle of early adverse experiences and addiction. PMID- 27508340 TI - Quantitative proteomics of rat livers shows that unrestricted feeding is stressful for proteostasis with implications on life span. AB - Studies in young mammals on the molecular effects of food restriction leading to prolong adult life are scares. Here, we used high-throughput quantitative proteomic analysis of whole rat livers to address the molecular basis for growth arrest and the apparent life-prolonging phenotype of the food restriction regimen. Over 1800 common proteins were significantly quantified in livers of ad libitum, restriction- and re-fed rats, which summed up into 92% of the total protein mass of the cells. Compared to restriction, ad libitum cells contained significantly less mitochondrial catabolic enzymes and more cytosolic and ER HSP90 and HSP70 chaperones, which are hallmarks of heat- and chemically-stressed tissues. Following re-feeding, levels of HSPs nearly reached ad libitum levels. The quantitative and qualitative protein values indicated that the restriction regimen was a least stressful condition that used minimal amounts of HSP chaperones to maintain optimal protein homeostasis and sustain optimal life span. In contrast, the elevated levels of HSP-chaperones in ad libitum tissues were characteristic of a chronic stress, which in the long term could lead to early aging and shorter life span. PMID- 27508342 TI - The Community Mentorship Program: Providing Community-Engagement Opportunities for Early-Stage Clinical and Translational Scientists to Facilitate Research Translation. AB - PROBLEM: A goal of the Southern California Clinical and Translational Science Institute (SC-CTSI) at the University of Southern California and Children's Hospital Los Angeles is to train early-stage clinical and translational scientists (CTSs) to conduct research that improves the health of diverse communities. This goal aligns well with the Institute of Medicine's recommendations emphasizing community engagement in biomedical research that facilitates research translation. The Community Mentorship Program (CMP), created to complement community-engaged research didactics, matches CTSs with community mentors who help them identify and complete community-engaged experiences that inform their research. APPROACH: The CMP was piloted in 2013-2015 by the SC-CTSI Workforce Development and Community Engagement cores. The CMP team matched three CTSs (assistant professors pursuing mentored career development awards) with mentors at community-based organizations (CBOs) aligned with their research interests. Each mentor-mentee pair signed a memorandum of understanding. The CMP team checked in regularly, monitoring progress and addressing challenges in CTSs' completion of their community-engaged experience. OUTCOMES: Each pair completed at least one community-engaged activity informing the CTS's research. In exit interviews, the CTSs and CBO mentors expressed satisfaction with the program and stated that they would continue to work together. The CTSs reported that the program provided opportunities to develop networks outside academia, build trust within the community, and receive feedback and learn from individuals in communities affected by their research. NEXT STEPS: The CMP will be expanded to include all eligible early-career CTSs and promoted for use in similar settings outside the SC-CTSI. PMID- 27508344 TI - Internationally Educated Health Professionals in Canada: Navigating Three Policy Subsystems Along the Pathway to Practice. AB - The integration of internationally educated health professionals (IEHPs) into the health workforces of their adopted countries is an issue that has challenged policy makers and policy scholars for decades. In this article, the authors explore the implications of the ideological underpinnings of the policy subsystems that IEHPs must navigate in seeking employment in Canada, with a focus on Ontario.Using a policy subsystem approach, in 2015 the authors analyzed a large preexisting data set composed of articles, governmental reports, Web sites, and transcripts of interviews and focus groups conducted in Ontario with IEHPs, health care executives, human resource managers, and job counselors to IEHPs. Through this analysis, they identified three policy subsystems-the immigration system, the educational and licensure/regulatory system, and the health human resources system-that conflict ideologically and, as a result, create barriers to IEHP integration.To make substantive progress on IEHP integration in Canada, four questions should be considered. First, how can researchers bring new research methods to bear to explore why no jurisdiction has been able to create an integrated pathway to practice for IEHPs? Second, how and to what end are the institutions within the three policy subsystems regulating the IEHP pathway to practice? Third, how might the educational and licensure/regulatory policy subsystem create alternative health care employment options for IEHPs? Finally, how might health professions educators pursue a leadership role in the creation of an overarching institution to manage the pathway to practice for IEHPs? PMID- 27508343 TI - Population Health Science: A Core Element of Health Science Education in Sub Saharan Africa. AB - Sub-Saharan Africa suffers an inordinate burden of disease and does not have the numbers of suitably trained health care workers to address this challenge. New concepts in health sciences education are needed to offer alternatives to current training approaches.A perspective of integrated training in population health for undergraduate medical and nursing education is advanced, rather than continuing to take separate approaches for clinical and public health education. Population health science educates students in the social and environmental origins of disease, thus complementing disease-specific training and providing opportunities for learners to take the perspective of the community as a critical part of their education.Many of the recent initiatives in health science education in sub Saharan Africa are reviewed, and two case studies of innovative change in undergraduate medical education are presented that begin to incorporate such population health thinking. The focus is on East Africa, one of the most rapidly growing economies in sub-Saharan Africa where opportunities for change in health science education are opening. The authors conclude that a focus on population health is a timely and effective way for enhancing training of health care professionals to reduce the burden of disease in sub-Saharan Africa. PMID- 27508345 TI - Hyperglycemia is associated with increased risk of patient delay in pulmonary tuberculosis in rural areas. AB - BACKGROUND: Excessive time between the first presentation of symptoms of pulmonary tuberculosis (PTB) and diagnosis contributes to ongoing transmission and increased risk of infection in the community, as well as to increased disease severity and higher mortality. People with type 2 diabetes mellitus (T2DM) have a higher risk of developing PTB. However, the effect of T2DM on delayed diagnosis of PTB is not fully understood. This study investigated the effects of hyperglycemia (diabetes and prediabetes) and other factors on PTB patient delay in a rural area of China. METHODS: In the present community-based investigation, PTB patients aged >=16 years newly diagnosed at county tuberculosis dispensaries were recruited consecutively between September 2011 and December 2013. Fasting blood glucose was determined in all subjects, and a structured questionnaire was used to collect basic information. RESULTS: Of the 2280 patients, 605 (26.5 %) had hyperglycemia. The median (interquartile range) time to seeking health care was 44 (59) days. Health care seeking was delayed in 1754 subjects, and hyperglycemia was independently associated with an increased probability (odds ratio 2.10; 95 % confidence interval 1.49-2.97) of patient delay in subjects aged >=30 years. Other factors associated with patient delay were cough, night sweats, and lack of knowledge regarding typical tuberculosis symptoms. The onset of hemoptysis was negatively correlated with patient delay. CONCLUSIONS: Patient delay appears to be a serious problem in this rural area with a high prevalence of tuberculosis. Hyperglycemia is independently associated with an increased probability of patient delay, which, in turn, may result in more serious clinical manifestations. PMID- 27508347 TI - Ultrafast Hole Transfer from (6,5) SWCNT to P3HT:PCBM Blend by Resonant Excitation. AB - Nowadays, SWCNTs are envisaged to enhance the charge separation or transport of conjugated polymer-fullerene derivatives blends. In this work we studied, by means of ultrafast transient absorption spectroscopy, three components blends in which commercially available SWCNTs are added to the standard bulk heterojunction. We explored three different configurations that give rise to diverse interfacing scenarios. We found strong evidence of a direct hole transfer from photoexcited SWCNTs to the P3HT polymer. The transfer efficiency depends on the interface configuration. It is the highest for the blend where we achieve closer contact between the (6,5) SWCNTs and the polymer. When the polymer blend is deposited on top of the nanotube film or the nanotube film is deposited onto the polymer blend, the process is slowed down due to less or missing interfacing of the carbon nanotubes with the polymer chains. Additionally we demonstrate a cascading effect in the electron path, which stabilizes charge separation by further transferring the electron left behind by hole transfer to the polymer to the adjacent (7,5) SWCNTs. Our results highlight the potential of semiconducting SWCNTs to improving the performance of organic solar cells. PMID- 27508346 TI - Unidirectional and sustained delivery of the proresolving lipid mediator resolvin D1 from a biodegradable thin film device. AB - Resolvin D1 (RvD1) belongs to a family of endogenously derived proresolving lipid mediators that have been shown to attenuate inflammation, activate proresolution signaling, and promote homeostasis and recovery from tissue injury. In this study we present a poly(lactic-co-glycolic acid) (PLGA) based thin-film device composed of layers of varying ratios of lactic and glycolic acid that elutes RvD1 unidirectionally to target tissues. The device demonstrated sustained release in vitro for 56 days with an initial burst of release over 14 days. The asymmetric design of the device released 98% of RvD1 through the layer with the lowest molar ratio of lactic acid to glycolic acid, and the remainder through the opposite side. We validated structural integrity of RvD1 released from the device by mass spectrometry and investigated its bioactivity on human vascular endothelial (EC) and smooth muscle cells (VSMC). RvD1 released from the device attenuated VSMC migration, proliferation, and TNF-alpha induced NF-kappaB activation, without evidence of cytotoxicity. Delivery of RvD1 to blood vessels was demonstrated ex vivo in a flow chamber system using perfused rabbit aortas and in vivo in a rat carotid artery model, with the devices applied as an adventitial wrap. Our results demonstrate a novel approach for sustained, local delivery of Resolvin D1 to vascular tissue at therapeutically relevant levels. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 31-41, 2017. PMID- 27508348 TI - Drugs for bipolar disorder. PMID- 27508349 TI - Sofosbuvir/velpatasvir (Epclusa) for hepatitis C. PMID- 27508350 TI - Criteria for designation of clinical substage in canine lymphoma: a survey of veterinary oncologists. AB - Clinical substage is frequently reported to be prognostic in dogs with lymphoma, yet formal criteria for defining this parameter are lacking. The World Health Organization TNM Classification of Tumors of Domestic Animals simply defines substage as the absence or presence of systemic signs (substages a and b, respectively). We designed a survey to query veterinary oncologists on the criteria they use to determine clinical substage in practice. Gastrointestinal, constitutional and respiratory signs were the most commonly identified clinical factors, with greater than 90% respondents indicating that inappetence, vomiting, diarrhoea, changes in attitude, weakness and dyspnea were integral in assigning clinical substage. Nevertheless, more than three-quarters of respondents also considered metabolic, neurologic and nutritional parameters when making this determination. For most factors, respondents reported mild-to-moderate severity of clinical signs was sufficient for substage b designation. PMID- 27508352 TI - Retraction Notice. AB - [This retracts the article on p. 65 in vol. 7, PMID: 26435620.]. PMID- 27508353 TI - Prehospital Application of the Canadian Triage and Acuity Scale by Emergency Medical Services. AB - OBJECTIVES: Triage is fundamental to emergency patient assessment. Effective triage systems accurately prioritize patients and help predict resource utilization. CTAS is a validated five-level triage score utilized in Emergency Departments (EDs) across Canada and internationally. Historically CTAS has been applied by triage nurses in EDs. Observational evidence suggests that the CTAS might be implemented reliably by paramedics in the prehospital setting. This is the first system-wide assessment of CTAS interrater reliability between paramedics and triage nurses during clinical practice. METHODS: Variables were extracted from hospital and EMS databases. EMS providers determined CTAS on scene, CTAS pre-transport, and CTAS on-arrival at hospital for each patient (N=14,378). The hospital arrival EMS CTAS (CTAS arrival ) score was compared to the initial nursing CTAS score (CTAS initial ) and the final nursing CTAS score (CTAS final ) incuding nursing overrides. Interrater reliability between ED CTAS initial and EMS CTAS arrival scores was assessed. Interrater reliability between ED CTAS final and EMS CTAS arrival scores, as well as proportion of patient encounters with perfect or near-perfect agreement, were evaluated. RESULTS: Our primary outcome, interrater reliability [kappa=0.437 (p<0.001, 95% CI 0.421 0.452)], indicated moderate agreement. EMS CTAS arrival and ED CTAS initial scores had an exact or within one point match 84.3% of the time. The secondary interrater reliability outcome between hospital arrival EMS CTAS (CTAS arrival ) score and the final ED triage CTAS score (CTAS final ) showed moderate agreement with kappa =0.452 (p<0.001, 95% CI 0.437-0.466). CONCLUSIONS: Interrater reliability of CTAS scoring between triage nurses and paramedics was moderate in this system-wide implementation study. PMID- 27508351 TI - White adipose tissue inflammation and cancer-specific survival in patients with squamous cell carcinoma of the oral tongue. AB - BACKGROUND: Obesity is associated with increased adipose tissue in the tongue. Chronic white adipose tissue (WAT) inflammation commonly occurs in the obese. We investigated whether WAT inflammation in the tongue impacts survival in patients with squamous cell carcinoma (SCC) of the oral tongue. METHODS: In a retrospective cohort study, patients with T1 and T2 SCC of the oral tongue who underwent curative-intent resection were included. Tongue WAT inflammation was defined by the presence of dead or dying adipocytes surrounded by macrophages forming crown-like structures. The primary and secondary endpoints were disease specific survival (DSS) and overall survival (OS), respectively. Subgroup analyses were carried out in patients without lymph node involvement for whom adjuvant therapies were not indicated. RESULTS: Archived tissue was available from 125 patients. The median follow-up was 55 months (range, 3-156 months). Overall, 49 of 125 patients (39%) had tongue WAT inflammation, which was associated with higher body mass index, increased tumor thickness, and vascular invasion (P < .05). The 3-year DSS rate for patients with tongue WAT inflammation was 59% (95% confidence interval [CI], 46%-76%) versus 82% (95% CI, 73%-92%) for those without inflammation. For patients without lymph node involvement for whom adjuvant therapy was not indicated (N = 70), tongue WAT inflammation was associated with shortened DSS and OS (P < .05). When adjusted for body mass index and potential prognostic covariates, the hazard ratio for DSS and OS was 5.40 (95% CI, 1.20-24.26) and 2.97 (95% CI, 1.02-8.65), respectively. CONCLUSIONS: Tongue WAT inflammation is associated with worse DSS and OS in patients who have early stage SCC of the oral tongue. Cancer 2016;122:3794-3802. (c) 2016 American Cancer Society. PMID- 27508354 TI - Rhizobial strains exert a major effect on the amino acid composition of alfalfa nodules under NaCl stress. AB - Specific amino acids have protective functions in plants under stress conditions. This study assessed the effects of rhizobial strains on the amino acid composition in alfalfa under salt stress. Two alfalfa cultivars (Medicago sativa L. cv Apica and salt-tolerant cv Halo) in association with two Sinorhizobium meliloti strains with contrasting growth under salt stress (strain A2 and salt tolerant strain Rm1521) were exposed to different levels of NaCl (0, 20, 40, 80 or 160 mM NaCl) under controlled conditions. We compared root and shoot biomasses, as well as root:shoot ratio for each association under these conditions as indicators of the salt tolerance of the symbiosis. Amino acid concentrations were analyzed in nodules, leaves and roots. The total concentration of free amino acids in nodules was mostly rhizobial-strain dependent while in leaves and roots it was mostly responsive to salt stress. For both cultivars, total and individual concentrations of amino acids including asparagine, proline, glutamine, aspartate, glutamate, gamma-aminobutyric acid (GABA), histidine and ornithine were higher in Rm1521 nodules than in A2 nodules. Conversely, lysine and methionine were more abundant in A2 nodules than in Rm1521 nodules. Proline, glutamine, arginine, GABA and histidine substantially accumulated in salt-stressed nodules, suggesting an enhanced production of amino acids associated with osmoregulation, N storage or energy metabolism to counteract salt stress. Combining the salt-tolerant strain Rm1521 and the salt tolerant cultivar Halo enhanced the root:shoot ratios and amino acid concentrations involved in plant protection which could be in part responsible for the enhancement of salt tolerance in alfalfa. PMID- 27508356 TI - LC-MS/MS analysis of metformin, saxagliptin and 5-hydroxy saxagliptin in human plasma and its pharmacokinetic study with a fixed-dose formulation in healthy Indian subjects. AB - A specific and rapid liquid chromatography-tandem mass spectrometry method is proposed for the simultaneous determination of metformin (MET), saxagliptin (SAXA) and its active metabolite, 5-hydroxy saxagliptin (5-OH SAXA) in human plasma. Sample preparation was accomplished from 50 MUL plasma sample by solid phase extraction using sodium dodecyl sulfate as an ion-pair reagent. Reversed phase chromatographic resolution of analytes was possible within 3.5 min on ACE 5CN (150 * 4.6 mm, 5 MUm) column using acetonitrile and10.0 mm ammonium formate buffer, pH 5.0 (80:20, v/v) as the mobile phase. Triple quadrupole mass spectrometric detection was performed using electrospray ionization in the positive ionization mode. The calibration curves showed good linearity (r2 >= 0.9992) over the established concentration range with limit of quantification of 1.50, 0.10 and 0.20 ng/mL for MET, SAXA and 5-OH SAXA respectively. The extraction recoveries obtained from spiked plasma samples were highly consistent for MET (75.12-77.84%), SAXA (85.90-87.84%) and 5-OH SAXA (80.32-82.69%) across quality controls. The validated method was successfully applied to a bioequivalence study with a fixed-dose formulation consisting of 5 mg SAXA and 500 mg MET in 18 healthy subjects. The reproducibility of the assay was demonstrated by reanalysis of 87 incurred samples. PMID- 27508355 TI - Hippocampal pattern completion is linked to gamma power increases and alpha power decreases during recollection. AB - How do we retrieve vivid memories upon encountering a simple cue? Computational models suggest that this feat is accomplished by pattern completion processes involving the hippocampus. However, empirical evidence for hippocampal pattern completion and its underlying mechanisms has remained elusive. Here, we recorded direct intracranial EEG as human participants performed an associative memory task. For each study (encoding) and test (retrieval) event, we derived time frequency resolved representational patterns in the hippocampus and compared the extent of pattern reinstatement for different mnemonic outcomes. Results show that successful associative recognition (AR) yields enhanced event-specific reinstatement of encoding patterns compared to non-associative item recognition (IR). Moreover, we found that gamma power (50-90 Hz) increases - in conjunction with alpha power (8-12 Hz) decreases not only distinguish AR from IR, but also correlate with the level of hippocampal reinstatement. These results link single shot hippocampal pattern completion to episodic recollection and reveal how oscillatory dynamics in the gamma and alpha bands orchestrate these mnemonic processes. PMID- 27508357 TI - Ultrafine TiO2 Decorated Carbon Nanofibers as Multifunctional Interlayer for High Performance Lithium-Sulfur Battery. AB - Although lithium-sulfur (Li-S) batteries deliver high specific energy densities, lots of intrinsic and fatal obstacles still restrict their practical application. Electrospun carbon nanofibers (CNFs) decorated with ultrafine TiO2 nanoparticles (CNF-T) were prepared and used as a multifunctional interlayer to suppress the volume expansion and shuttle effect of Li-S battery. With this strategy, the CNF network with abundant space and superior conductivity can accommodate and recycle the dissolved polysulfides for the bare sulfur cathode. Meanwhile, the ultrafine TiO2 nanoparticles on CNFs work as anchoring points to capture the polysulfides with the strong interaction, making the battery perform with remarkable and stable electrochemical properties. As a result, the Li-S battery with the CNF-T interlayer delivers an initial reversible capacity of 935 mA h g(-1) at 1 C with a capacity retention of 74.2% after 500 cycles. It is believed that this simple, low-cost and scalable method will definitely bring a novel perspective on the practical utilization of Li-S batteries. PMID- 27508358 TI - Cycled light in the intensive care unit for preterm and low birth weight infants. AB - BACKGROUND: Potential benefits and harms of different lighting in neonatal units have not been quantified. OBJECTIVES: * To determine effectiveness and safety of cycled light (CL) (approximately 12 hours of light on and 12 hours of light off) for growth in preterm infants at three and six months' corrected age (CA).* In separate analyses, to compare effects of CL with those of irregularly dimmed light (DL) or near darkness (ND), and effects of CL with those of continuous bright light (CBL), on growth in preterm infants at three and six months' CA.* To assess, in subgroup analyses, the effectiveness and safety of CL (vs control interventions (DL, ND and CBL)) introduced at different postmenstrual ages (PMAs) - before 32 weeks', at 32 weeks' and from 36 weeks' PMA - and to compare effectiveness and safety of CL for small for gestational age (GA) infants versus appropriately grown infants. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12), MEDLINE via PubMed (1966 to January 2016), Embase (1980 to January 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to January 2016). We searched clinical trials databases, conference proceedings and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised trials of CL versus ND or CBL in preterm and low birth weight infants. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses according to the methods of the Cochrane Neonatal Review Group. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. MAIN RESULTS: We identified one additional study enrolling 38 participants for inclusion in this update, for a total of nine studies reporting on 544 infants. In general, the quality of the studies was low, mainly owing to lack of blinding and small sample sizes.Six studies enrolling 424 infants compared CL versus ND. No study reported on weight at three or six months. One study (n = 40) found no statistically significant difference in weight at four months between CL and ND groups. In another study (n = 62), the ratio of day-night activity before discharge favoured the CL group (mean difference (MD) 0.18, 95% confidence interval (CI) 0.17 to 0.19), indicating 18% more activity during the day than during the night in the CL group compared with the ND group. Two studies (n = 189) reported on retinopathy of prematurity (stage >= 3) and reported no statistically significant differences between CL and ND groups (typical risk ratio (RR) 0.53, 95% CI 0.25 to 1.11, I(2) = 0%; typical risk difference (RD) -0.09, 95% CI -0.19 to 0.01, I(2) = 0%). Two studies (n = 77) reported length of hospital stay (days) and noted a significant reduction in length of stay between CL and ND groups favouring the CL group (weighted mean difference (WMD) -13 days, 95% CI -23 to 2, I(2) = 0%; no heterogeneity). The quality of the evidence according to GRADE was low for this outcome. One study (n = 37) reported less crying at 11 weeks' corrected age (CA) in the CL group compared with the ND group (MD -0.57 hours/24 h, 95% CI -1.09 to -0.05). Tests for heterogeneity were not applicable.Three studies enrolling 120 infants compared CL versus CBL. Two studies (n = 79) reported significantly shorter length of stay in the CL group compared with the CBL group (WMD -16.5 days, 95% CI -26.2 to -6.8, I(2) = 0%; no heterogeneity). The quality of the evidence according to GRADE was low for this outcome. One study (n = 41) reported higher mean weight at three months' CA among infants cared for in the CL nursery (P value < 0.02) and a lower mean number of hours spent awake in 24 hours at three months of age (P value < 0.005). Data could not be entered into RevMan or GRADE. One study (n = 41) reported shorter time on the ventilator in the CL compared with the CBL group (MD -18.2 days, 95% CI -31.40 to -5.0). One study (n = 41) reported a shorter time to first oral feeding in the CL group (MD -6.8 days, 95% CI -13.29 to -0.31). We identified no safety issues. AUTHORS' CONCLUSIONS: Trials assessing the effects of CL have enrolled 544 infants. No study reported on our primary outcome of weight at three or six months. Results from one additional study strengthen our findings that CL versus CBL shortens length of stay, as does CL versus ND. The quality of the evidence on both comparisons for this outcome according to GRADE was low. Future research should focus on comparing CL versus ND. PMID- 27508360 TI - CFD for wastewater treatment: an overview. AB - Computational fluid dynamics (CFD) is a rapidly emerging field in wastewater treatment (WWT), with application to almost all unit processes. This paper provides an overview of CFD applied to a wide range of unit processes in water and WWT from hydraulic elements like flow splitting to physical, chemical and biological processes like suspended growth nutrient removal and anaerobic digestion. The paper's focus is on articulating the state of practice and research and development needs. The level of CFD's capability varies between different process units, with a high frequency of application in the areas of final sedimentation, activated sludge basin modelling and disinfection, and greater needs in primary sedimentation and anaerobic digestion. While approaches are comprehensive, generally capable of incorporating non-Newtonian fluids, multiphase systems and biokinetics, they are not broad, and further work should be done to address the diversity of process designs. Many units have not been addressed to date. Further needs are identified throughout, but common requirements include improved particle aggregation and breakup (flocculation), and improved coupling of biology and hydraulics. PMID- 27508361 TI - Electrocoagulation and nanofiltration integrated process application in purification of bilge water using response surface methodology. AB - Marine pollution has been considered an increasing problem because of the increase in sea transportation day by day. Therefore, a large volume of bilge water which contains petroleum, oil and hydrocarbons in high concentrations is generated from all types of ships. In this study, treatment of bilge water by electrocoagulation/electroflotation and nanofiltration integrated process is investigated as a function of voltage, time, and initial pH with aluminum electrode as both anode and cathode. Moreover, a commercial NF270 flat-sheet membrane was also used for further purification. Box-Behnken design combined with response surface methodology was used to study the response pattern and determine the optimum conditions for maximum chemical oxygen demand (COD) removal and minimum metal ion contents of bilge water. Three independent variables, namely voltage (5-15 V), initial pH (4.5-8.0) and time (30-90 min) were transformed to coded values. The COD removal percent, UV absorbance at 254 nm, pH value (after treatment), and concentration of metal ions (Ti, As, Cu, Cr, Zn, Sr, Mo) were obtained as responses. Analysis of variance results showed that all the models were significant except for Zn (P > 0.05), because the calculated F values for these models were less than the critical F value for the considered probability (P = 0.05). The obtained R(2) and Radj(2) values signified the correlation between the experimental data and predicted responses: except for the model of Zn concentration after treatment, the high R(2) values showed the goodness of fit of the model. While the increase in the applied voltage showed negative effects, the increases in time and pH showed a positive effect on COD removal efficiency; also the most effective linear term was found as time. A positive sign of the interactive coefficients of the voltage-time and pH-time systems indicated synergistic effect on COD removal efficiency, whereas interaction between voltage and pH showed an antagonistic effect. PMID- 27508362 TI - Biosurfactant production and its effects on solubilization activity of phenanthrene: a longitudinal study. AB - Pseudomonas facilis and Pseudomonasspp., isolated on the basis of its ability to grow on polycyclic aromatic hydrocarbon, was assayed for biosurfactant production (BP) potentials by measuring the surface tension (ST) of the culture supernatant at different time intervals. The strains in three levels of initial inoculum size (OD600 nm = 0.5, 1, 1.5) were added to medium to determine if bacterial inoculum size affects solubilization of phenanthrene (PHE).The result showed that although the two strains reduced the mean ST to less than 34.12 mN m(-1) at the end of day 6, mean solubilization activity of PHE reached 77.05 mg L(-1) on the sixth day. There was a significant increase in BP over time (P = 0.008); reaching its peak, 157.84 mg L(-1), at the end of the sixth day. Mean solubilization activity of PHE was not significantly different for the two strains (P = 0.216). The time-course study revealed that the ST reduction and BP potential was enhanced as inoculation size increased, leading to higher PHE solubility during the incubation time. However, the trend of increase in PHE solubility was not totally in the same way to cell growth and BP. It may be suggested that more bacterial density needs to be inoculated for practical application of effective bioremediation. PMID- 27508363 TI - Treatment of leather industrial wastewater via combined advanced oxidation and membrane filtration. AB - The liming/unhairing operation is among the important processes of the leather industry. It generates large amounts of effluent that are highly loaded with organic hazard wastes. Such effluent is considered one of the most obnoxious materials in the leather industry, causing serious environmental pollution and health risks. The effluent is characterized by high concentrations of the pollution parameters. Conventional chemical and/or biological treatment of such wastewater is inefficient to meet the required limits of standard specifications, due to the presence of resistant and toxic compounds. The present investigation deals with an effective treatment approach for the lime/unhair effluent using the Fenton reaction followed by membrane filtration. The experiment was extended to a laboratory pilot-scale in a continuous treatment study. In this study the raw wastewater was treated with the predetermined Fenton's optimum dose followed by membrane filtration. The wastewater was efficiently treated and the final effluent met the standards for unrestricted water reuse. PMID- 27508364 TI - Influence of different anoxic time exposures on active biomass, protozoa and filamentous bacteria in activated sludge. AB - Medium-sized wastewater treatment plants are considered too small to implement anaerobic digestion technologies and too large for extensive treatments. A promising option as a sewage sludge reduction method is the inclusion of anoxic time exposures. In the present study, three different anoxic time exposures of 12, 6 and 4 hours have been studied to reduce sewage sludge production. The best anoxic time exposure was observed under anoxic/oxic cycles of 6 hours, which reduced 29.63% of the biomass production compared with the oxic control conditions. The sludge under different anoxic time exposures, even with a lower active biomass concentration than the oxic control conditions, showed a much higher metabolic activity than the oxic control conditions. Microbiological results suggested that both protozoa density and abundance of filamentous bacteria decrease under anoxic time exposures compared to oxic control conditions. The anoxic time exposures 6/6 showed the highest reduction in both protozoa density, 37.5%, and abundance of filamentous bacteria, 41.1%, in comparison to the oxic control conditions. The groups of crawling ciliates, carnivorous ciliates and filamentous bacteria were highly influenced by the anoxic time exposures. Protozoa density and abundance of filamentous bacteria have been shown as promising bioindicators of biomass production reduction. PMID- 27508365 TI - Stimulation of the hydrolytic stage for biogas production from cattle manure in an electrochemical bioreactor. AB - Electrical current in the hydrolytic phase of the biogas process might affect biogas yield. In this study, four 1,150 mL single membrane-less chamber electrochemical bioreactors, containing two parallel titanium plates were connected to the electrical source with voltages of 0, -0.5, -1 and -1.5 V, respectively. Reactor 1 with 0 V was considered as a control reactor. The trend of biogas production was precisely checked against pH, oxidation reduction potential and electrical power at a temperature of 37 +/- 0.5 degrees C amid cattle manure as substrate for 120 days. Biogas production increased by voltage applied to Reactors 2 and 3 when compared with the control reactor. In addition, the electricity in Reactors 2 and 3 caused more biogas production than Reactor 4. Acetogenic phase occurred more quickly in Reactor 3 than in the other reactors. The obtained results from Reactor 4 were indicative of acidogenic domination and its continuous behavior under electrical stimulation. The results of the present investigation clearly revealed that phasic electrical current could enhance the efficiency of biogas production. PMID- 27508366 TI - A novel PSB-EDI system for high ammonia wastewater treatment, biomass production and nitrogen resource recovery: PSB system. AB - A novel process coupling photosynthetic bacteria (PSB) with electrodeionization (EDI) treatment was proposed to treat high ammonia wastewater and recover bio resources and nitrogen. The first stage (PSB treatment) was used to degrade organic pollutants and accumulate biomass, while the second stage (EDI) was for nitrogen removal and recovery. The first stage was the focus in this study. The results showed that using PSB to transform organic pollutants in wastewater into biomass was practical. PSB could acclimatize to wastewater with a chemical oxygen demand (COD) of 2,300 mg/L and an ammonia nitrogen (NH4(+)-N) concentration of 288-4,600 mg/L. The suitable pH was 6.0-9.0, the average COD removal reached 80%, and the biomass increased by an average of 9.16 times. The wastewater COD removal was independent of the NH4(+)-N concentration. Moreover, the PSB functioned effectively when the inoculum size was only 10 mg/L. The PSB-treated wastewater was then further handled in an EDI system. More than 90% of the NH4(+)-N was removed from the wastewater and condensed in the concentrate, which could be used to produce nitrogen fertilizer. In the whole system, the average NH4(+)-N removal was 94%, and the average NH4(+)-N condensing ratio was 10.0. PMID- 27508367 TI - Application of lactic acid bacteria in removing heavy metals and aflatoxin B1 from contaminated water. AB - In this study selected lactic acid bacteria (LAB, Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus plantrium and Streptococcus thermophiles) and probiotic bacteria (Bifidobacterium angulatum) were tested for their ability in removing heavy metals (HM) including cadmium (Cd), lead (Pb) and arsenic (As) as well as aflatoxin B1 (AFB1) from contaminated water. The biosorption parameters (pH, bacterial concentration, contact time and temperature) of removal using individual as well as mixed LAB and probiotic bacteria were studied. Removal of HM and AFB1 depended on the strain, wherein the process was strongly pH-dependent with high removal ability at a pH close to neutral. The increase in bacterial concentration enhanced the removal of Cd, Pb and As. Also, increasing of contact time and temperature increased the ability of LAB to remove HM. The effect of contact time on Cd removal was slightly different when freshly cultured cells were used. The removal of Cd, Pb and As decreased with the increase in the initial metal concentration. The most effective HM removers were Lactobacillus acidophilus and Bifidobacterium angulatum. The system was found to be adequate for concentrations of HM under investigation. At the end of the operation, the concentration of HM reached the level allowed by the World Health Organization regulations. PMID- 27508368 TI - Pd/RGO modified carbon felt cathode for electro-Fenton removing of EDTA-Ni. AB - Ethylenediaminetetraacetic acid (EDTA) forms stable complexes with toxic metals such as nickel due to its strong chelation. The electro-Fenton (EF) process using a cathode made from palladium (Pd), reduced graphene oxide (RGO) and carbon felt, fed with air, exhibited high activities and stability for the removal of 10 mg L( 1) EDTA-Ni solution. Pd/RGO catalyst was prepared by one-pot synthesis; the scanning electron microscopy and X-ray diffraction analysis indicated nanoparticles and RGO were well distributed on carbon felt, forming three dimensional architecture with both large macropores and a mesoporous structure. The cyclic voltammetric results showed that the presence of RGO in Pd/RGO/carbon felt significantly increased the current response of two-electron reduction of O2 (0.45 V). The key factors influencing the removal efficiency of EDTA-Ni, such as pH, current and Fe(2+) concentration, were investigated. Under the optimum conditions, the removal efficiency of EDTA-Ni reached 83.8% after 100 min EF treatment. Mechanism analysis indicated that the introduction of RGO in Pd/RGO/carbon felt significantly enhanced the electrocatalytic activities by inducing *OH in the EF process; direct H2O2 oxidation still accounted for a large amount of EDTA-Ni removal efficiency. PMID- 27508369 TI - Characteristics and kinetics simulation of controlled-release KMnO4 for phenol remediation. AB - Controlled-release KMnO4 (CRP) technology has been recently developed as an improved, highly efficient technique in wastewater treatment. In this study, batch-style experiments were conducted to evaluate this technology. The release characteristics of CRP in distilled water and the reaction between CRP and phenol were studied and fitted using MATLAB software. Results indicated that in distilled water, temperature (T) and pH value had a larger effect than dissolved oxygen (DO) concentration on the release characteristics of KMnO4, and this relationship can be accurately described by the following kinetic equation: logQ = log[1.141T(0.152)(pH)(-1.0536)(DO)(0.4674)] + [0.0048T(0.3756)(pH)(1.8854)(DO)( 0.0509)]logt. KMnO4 released from CRP can effectively degrade phenol-contaminated water with different concentrations. A simulated equation (r = -dCA/dt = -15.1705 CA(0.6840)CP(-0.1406)) characterizing phenol degradation was developed using MATLAB software. Comparison between the theoretical phenol removal rates deduced by the above two equations and the initial phenol concentration as well as the CRP dosage with the experimental data indicates that the differences between them were less than 20%. The results indicate phenol can be effectively removed by CRP and smaller dosage of KMnO4 was required compared with literature values. The models can provide guidance for CRP application in real polluted sites, which can lower the cost for site remediation. PMID- 27508370 TI - Effects of the combination of aeration and biofilm technology on transformation of nitrogen in black-odor river. AB - Excess nitrogen in urban river networks leading to eutrophication has become one of the most urgent environmental problems. Combinations of different aeration and biofilm techniques was designed to remove nitrogen from rivers. In laboratory water tank simulation experiments, we assessed the removal efficiency of nitrogen in both the overlying water and sediments by using the combination of the aeration and biofilm techniques, and then analyzed the transformation of nitrogen during the experiments. Aeration (especially sediment aeration) combined with the biofilms techniques was proved efficient in removing nitrogen from polluted rivers. Results indicated that the combination of sediment aeration and biofilms, with the highest nitrogen removal rate from the overlying water and sediments, was the most effective combined process, which especially inhibited the potential release of nitrogen from sediments by reducing the enzyme activity. It was found that the content of dissolved oxygen in water could be restored on the basis of the application of aeration techniques ahead, and the biofilm technique would be effective in purifying water in black-odor rivers. PMID- 27508371 TI - Adsorption of the harmful hormone ethinyl estradiol inside hydrophobic cavities of CTA(+) intercalated montmorillonite. AB - Hydrophobic cavities produced by cetyltrimethylammonium cation (CTA(+)) exchanged and trapped in the interlayer space of montmorillonite were used to remove the harmful hormone contaminant ethinyl estradiol (EE2) from water. X-ray diffraction, thermogravimetry/derivative thermogravimetry, elemental analysis (carbon, hydrogen, nitrogen), Fourier transform infrared, scanning electron microscopy/energy dispersive spectroscopy, Brunauer-Emmett-Teller and contact angle analyses showed that the intercalation of 9, 16 and 34 wt% CTA(+) in the montmorillonite resulted in the d001 expansion from 1.37 to 1.58, 2.09 and 2.18 nm, respectively. EE2 adsorption experiments showed that the original clay montmorillonite does not remove EE2 from water whereas the intercalated composites showed high efficiency with adsorption capacities of 4.3, 8.8 and 7.3 mg g(-1) for M9CTA(+), M16CTA(+) and M34CTA(+), respectively. Moreover, experiments with montmorillonite simply impregnated with cetyltrimethylammonium bromide showed that the intercalation of CTA(+) to form the hydrophobic cavity is very important for the adsorption properties. Simple solvent extraction can be used to remove the adsorbed EE2 without significant loss of CTA(+), which allows the recovery and reuse of the adsorbent for at least five times. PMID- 27508372 TI - Energy recovery from thermal treatment of dewatered sludge in wastewater treatment plants. AB - Sewage sludge is a by-product generated from municipal wastewater treatment (WWT) processes. This study examines the conversion of sludge via energy recovery from gasification/combustion for thermal treatment of dewatered sludge. The present analysis is based on a chemical equilibrium model of thermal conversion of previously dewatered sludge with moisture content of 60-80%. Prior to combustion/gasification, sludge is dried to a moisture content of 25-55% by two processes: (1) heat recovered from syngas/flue gas cooling and (2) heat recovered from syngas combustion. The electricity recovered from the combined heat and power process can be reused in syngas cleaning and in the WWT plant. Gas temperature, total heat and electricity recoverable are evaluated using the model. Results show that generation of electricity from dewatered sludge with low moisture content (<= 70%) is feasible within a self-sufficient sludge treatment process. Optimal conditions for gasification correspond to an equivalence ratio of 2.3 and dried sludge moisture content of 25%. Net electricity generated from syngas combustion can account for 0.071 kWh/m(3) of wastewater treated, which is up to 25.4-28.4% of the WWT plant's total energy consumption. PMID- 27508373 TI - Optimization design of submerged propeller in oxidation ditch by computational fluid dynamics and comparison with experiments. AB - The operating condition of a submerged propeller has a significant impact on flow field and energy consumption of the oxidation ditch. An experimentally validated numerical model, based on the computational fluid dynamics (CFD) tool, is presented to optimize the operating condition by considering two important factors: flow field and energy consumption. Performance demonstration and comparison of different operating conditions were carried out in a Carrousel oxidation ditch at the Yingtang wastewater treatment plants in Anhui Province, China. By adjusting the position and rotating speed together with the number of submerged propellers, problems of sludge deposit and the low velocity in the bend could be solved in a most cost-effective way. The simulated results were acceptable compared with the experimental data and the following results were obtained. The CFD model characterized flow pattern and energy consumption in the full-scale oxidation ditch. The predicted flow field values were within -1.28 +/- 7.14% difference from the measured values. By determining three sets of propellers under the rotating speed of 6.50 rad/s with one located 5 m from the first curved wall, after numerical simulation and actual measurement, not only the least power density but also the requirement of the flow pattern could be realized. PMID- 27508374 TI - Estimation of the degree of soil P saturation from Brazilian Mehlich-1 P data and field investigations on P losses from agricultural sites in Minas Gerais. AB - The degree of phosphorus saturation (DPS) of agricultural soils is studied worldwide for risk assessment of phosphorus (P) losses. In previous studies, DPS could be reliably estimated from water-soluble P (WSP) for European and Brazilian soils. In the present study, we correlated measured WSP and Mehlich-1 P (M1P) from soils of Minas Gerais (MG) and Pernambuco (PE) (R(2) = 0.94, n = 59) to create a DPS map from monitoring data. The resulting DPS map showed high spatial variability and low values of DPS (54 +/- 22%, mean and standard deviation; n = 1,827). Measured soil DPS values amounted to 63 +/- 14% and resulted in relatively low dissolved P concentrations measured in a surface runoff study in MG. However, fertilizer grains on the soil surface led to high WSP values (>30 mg/kg) indicating high risks of dissolved P losses. We suppose that small Oxisol particles with Fe and Al hydroxides sorbed most of the dissolved fertilizer P in runoff so that P was mainly exported in particulate form. In soils with lower contents of P sorption and binding partners, e.g. Entisols in PE, this effect may be less dominant. Consequently, superficial fertilizer effects have to be considered in addition to DPS in risk assessment of P losses from agricultural areas in Brazil. PMID- 27508375 TI - Facile one pot synthesis of zinc oxide nanorods and statistical evaluation for photocatalytic degradation of a diazo dye. AB - In the present work zinc oxide nanorods (ZNRs) have been synthesized to estimate its photocatalytic degradation potential on an industrially used diazo dye and optimization of the total treatment process has been designed. Response surface methodology (RSM) has been used to model the operational parameters for this photocatalytic degradation. The crystallite size (101 plane) of the synthesized ZNR has been found to be 20.99 nm having a band gap energy of 3.45 eV. At elevated pH, the rate of degradation of the photocatalyst was found to be higher than that of acidic pH. The independent variables of the model are time (9.6-122 min), pH (2-12.2), catalyst dose (0.2-0.4 g/L) and dye concentration (88-512 mg/L). It was seen that the degradation efficiency was significantly affected by the initial dye concentration and the pH, the optimal values of the parameters being a pH of 10.67, an initial concentration of 150 mg/L and ZnO dose of 0.37 g/L, the time taken being 88.52 min. The actual degradation efficiency of the dye reached 96.9% at optimized condition, which is quite close to the predicted value of 98.07%. PMID- 27508376 TI - High performance of nitrogen and phosphorus removal in an electrolysis-integrated biofilter. AB - A novel electrolysis-integrated biofilter system was developed in this study to evaluate the intensified removal of nitrogen and phosphorus from contaminated water. Two laboratory-scale biofilter systems were established, one with electrolysis (E-BF) and one without electrolysis (BF) as control. The dynamics of intensified nitrogen and phosphorus removal and the changes of inflow and outflow water qualities were also evaluated. The total nitrogen (TN) removal rate was 94.4% in our newly developed E-BF, but only 74.7% in the control BF. Ammonium removal rate was up to 95% in biofilters with or without electrolysis integration with an influent ammonium concentration of 40 mg/L, and the accumulation of nitrate and nitrite was much lower in the effluent of E-BF than that of BF. Thus electrolysis plays an important role in TN removal especially the nitrate and nitrite removal. Phosphorus removal was significantly enhanced, exceeding 90% in E-BF by chemical precipitation, physical adsorption, and flocculation of phosphorus because of the in situ formation of ferric ions by the anodizing of sacrificial iron anodes. Results from this study indicate that the electrolysis integrated biofilter is a promising solution for intensified nitrogen and phosphorus removal. PMID- 27508377 TI - Longitudinal dispersion in open channel flow with suspended canopies. AB - Suspended canopies can cause flow disturbances such as reducing velocities within the canopy, and increasing flow beneath the canopy. Flow modifications by canopies dramatically affect the fate and transport of sediment, nutrients, contaminants, dissolved oxygen, and fauna in aquatic systems. A three-zone model is presented here to predict the longitudinal dispersion coefficient by simplifying Chikwendu's N-zone model. To validate the model, both flow field and tracer experiments were conducted using a straight rectangular Plexiglas flume, with rigid circular rods as the modeled suspended canopies. The result shows that velocities increased above the flume bed and maximized at a point between the canopies and flume bed. Above that point, streamwise velocities decreased into and within the canopies. Reynolds shear stresses were largest at the canopy interface and smallest (zero) at the velocity maximum point. Good agreement between the modeled results and experimental data shows that the model can effectively predict the longitudinal dispersion coefficient in open channels with suspended canopies. PMID- 27508378 TI - Effect of pH on the flocculation behaviors of kaolin using a pH-sensitive copolymer. AB - pH-sensitive copolymers have been widely introduced to achieve rapid dewatering and consolidation of solids in mining and oil sands processing wastes. But no more attention has been given to the flocculation efficiency of solid suspensions as a function of pH using pH-sensitive copolymer. In this study, a pH-sensitive copolymer was synthesized and employed to investigate the flocculation behaviors of kaolin by focused beam reflectance measurement (FBRM). A titration test was introduced to characterize the copolymer conformation transition. The results demonstrated that at pH ranging from 3 to 6, with the pH increase, the zeta potential magnitude of kaolin particles increased, resulting in the repulsive forces between particles increasing. However, the hydrophobicity of kaolin increased as the pH increased. Thus, the hydrophobic forces could neutralize a part of the repulsive forces between particles and result in good and similar flocculation performances. At the pH greater than 6, the zeta potential magnitude of kaolin particles and copolymer molecules increased significantly, and the repulsive force between kaolin particles increased after copolymer addition due to the kaolin particles being more negatively charged, which resulted in poor flocculation efficiency and cloudy supernatant. It was concluded that the pH sensitive copolymer could achieve both perfect flocculation efficiency and low moisture of filter cake at the isoelectric point of copolymer. PMID- 27508379 TI - Polyethersulfone/polyacrylonitrile blended ultrafiltration membranes: preparation, morphology and filtration properties. AB - Polyethersulfone (PES)/polyacrylonitrile (PAN) membranes have been paid attention among membrane research subjects. However, very few studies are included in the literature. In our study, asymmetric ultrafiltration (UF) membranes were prepared from blends of PES/PAN with phase inversion method using water as coagulation bath. Polyvinylpyrrolidone (PVP) with Mw of 10,000 Da was used as pore former agent. N,N-dimethylformamide was used as solvent. The effects of different percentage of PVP and PES/PAN composition on morphology and water filtration properties were investigated. Membrane performances were examined using pure water and lake water filtration studies. Performances of pure water were less with the addition of PAN into the PES polymer casting solutions. However, long term water filtration tests showed that PES/PAN blend membranes anti-fouling properties were much higher than the neat PES membranes. The contact angles of PES/PAN membranes were lower than neat PES membranes because of PAN addition in PES polymer casting solutions. Furthermore, it was found that PES/PAN blend UF membranes' dynamic mechanical analysis properties in terms of Young's modules were less than neat PES membrane because of decreasing amount of PES polymer. PMID- 27508380 TI - Microbial risk in wastewater irrigated lettuce: comparing Escherichia coli contamination from an experimental site with a laboratory approach. AB - This study assessed the contamination of Escherichia coli, in lettuce grown with treated domestic wastewater in four different irrigation configurations: open spray, spray under plastic sheet cover, open drip and drip under plastic sheet cover. Samples of lettuce from each irrigation configuration and irrigating wastewater were collected during the growing season. No E. coli was detected in lettuce from drip irrigated beds. All lettuce samples from spray beds were positive for E. coli, however, no statistical difference (p > 0.05) was detected between lettuces grown in open spray or covered spray beds. The results from the field experiment were also compared to a laboratory experiment which used submersion of lettuce in wastewater of known E. coli concentration as a surrogate method to assess contamination following irrigation. The microbial quality of spray bed lettuces was not significantly different from submersed lettuce when irrigated with wastewater containing 1,299.7 E. coli MPN/100 mL (p > 0.05). This study is significant since it is the first to validate that the microbial contamination of lettuce irrigated with wastewater in the field is comparable with a laboratory technique frequently applied in the quantitative microbial risk assessment of the consumption of wastewater irrigated salad crops. PMID- 27508381 TI - Impact of ozonation in removing organic micro-pollutants in primary and secondary municipal wastewater: effect of process parameters. AB - The study investigates the influence of process parameters on the effectiveness of ozonation in the removal of organic micro-pollutants from wastewater. Primary and secondary municipal wastewater containing phenol was treated. The effect of operating parameters such as initial pH, ozone dosage, and initial contaminant concentration was studied. An increase in contaminant decomposition with pH (3 11) was observed. The contaminant removal efficiencies increased with an increase in ozone dose rate (5.5-36.17 mg L(-1) min(-1)). Furthermore, the ultraviolet absorbance (UV 254 nm) of the wastewater decreased during ozonation indicating the breakdown of complex organic compounds into low molecular weight organics. Along the reaction, the pH of wastewater decreased from 11 to around 8.5 due to the formation of intermediate acidic species. Moreover, the biodegradability of wastewaters, measured as biological and chemical oxygen demand (BOD5/COD), increased from 0.22 to 0.53. High ozone utilization efficiencies of up to 95% were attained thereby increasing the process efficiency; and they were dependent on the ozone dosage and pH of solution. Ozonation of secondary wastewater attained the South African water standards in terms of COD required for wastewater discharge and dissolved organic carbon in drinking water and increased significantly the biodegradability of primary wastewater. PMID- 27508382 TI - Influences of electroosmosis and electrophoresis on permeate flux and membrane fouling in submerged membrane bioreactors (SMBRs). AB - The objective of this study was to investigate the influences of electroosmosis (EO) and electrophoresis (EP) on the permeate flux in submerged membrane bioreactors. When a polymeric membrane is placed in between an anode and a cathode, both EO and EP occur simultaneously, causing enhancement in flux. Results showed that after 150 min of filtration, the permeate fluxes were 60, 115, 175 and 260 L/m(2)/h at 0, 30, 40 and 50 V, respectively. It was shown that the EO was linearly changing with increasing voltage, reaching up to 54 L/m(2)/h at 50 V. EP was found to be a significant process in removing soluble microbial products from the membrane surface, resulting in an increase in permeate flux as the filtration progressed. About 20-fold of smaller protein and carbohydrate concentrations were found in the cake layer when the electrical field (EF) was applied. However, the EF application promoted pore fouling, because of the calcium and magnesium scaling. PMID- 27508383 TI - Erratum: Water Science and Technology 72 (7): Development of a new wastewater treatment process for resource recovery of carotenoids, H. Sato, H. Nagare, T. N. C. Huynh and H. Komatsu, doi: 10.2166/wst.2015.330. AB - A new wastewater treatment process that involves coagulation, ozonation, and microalgae cultivation has been developed. Here, two challenges are discussed. The first was minimizing phosphorus removal during coagulation in order to maximize algal production. The second was to optimize microalgae cultivation; algal species that grow rapidly and produce valuable products are ideal for selection. Haematococcus pluvialis, which produces the carotenoid astaxanthin, was used. Growth rate, nutrient removal ability, and astaxanthin production of H. pluvialis in coagulated wastewater were investigated. After coagulation with chitosan, the turbidity and suspended solids decreased by 89% +/- 8% and 73% +/- 16%, respectively. The nitrogen and phosphorus contents of the supernatant remained at 86% +/- 6% and 67% +/- 24%, respectively. These results indicate that coagulation with chitosan can remove turbidity and SS while preserving nutrients. H. pluvialis grew well in the supernatant of coagulated wastewater. The astaxanthin yield from coagulated wastewater in which microalgae were cultured was 3.26 mg/L, and total phosphorus and nitrogen contents decreased 99% +/- 1% and 90% +/- 8% (Days 31-35), respectively. PMID- 27508384 TI - Integration of Serum Protein Biomarker and Tumor Associated Autoantibody Expression Data Increases the Ability of a Blood-Based Proteomic Assay to Identify Breast Cancer. AB - Despite significant advances in breast imaging, the ability to accurately detect Breast Cancer (BC) remains a challenge. With the discovery of key biomarkers and protein signatures for BC, proteomic technologies are currently poised to serve as an ideal diagnostic adjunct to imaging. Research studies have shown that breast tumors are associated with systemic changes in levels of both serum protein biomarkers (SPB) and tumor associated autoantibodies (TAAb). However, the independent contribution of SPB and TAAb expression data for identifying BC relative to a combinatorial SPB and TAAb approach has not been fully investigated. This study evaluates these contributions using a retrospective cohort of pre-biopsy serum samples with known clinical outcomes collected from a single site, thus minimizing potential site-to-site variation and enabling direct assessment of SPB and TAAb contributions to identify BC. All serum samples (n = 210) were collected prior to biopsy. These specimens were obtained from 18 participants with no evidence of breast disease (ND), 92 participants diagnosed with Benign Breast Disease (BBD) and 100 participants diagnosed with BC, including DCIS. All BBD and BC diagnoses were based on pathology results from biopsy. Statistical models were developed to differentiate BC from non-BC (i.e., BBD and ND) using expression data from SPB alone, TAAb alone, and a combination of SPB and TAAb. When SPB data was independently used for modeling, clinical sensitivity and specificity for detection of BC were 74.7% and 77.0%, respectively. When TAAb data was independently used, clinical sensitivity and specificity for detection of BC were 72.2% and 70.8%, respectively. When modeling integrated data from both SPB and TAAb, the clinical sensitivity and specificity for detection of BC improved to 81.0% and 78.8%, respectively. These data demonstrate the benefit of the integration of SPB and TAAb data and strongly support the further development of combinatorial proteomic approaches for detecting BC. PMID- 27508385 TI - Prevalence, Risk Behaviors, and Virological Characteristics of Hepatitis B Virus Infection in a Group of Men Who Have Sex with Men in Brazil: Results from a Respondent-Driven Sampling Survey. AB - BACKGROUND: Men who have sex with men (MSM) are at increased risk of exposure to hepatitis B virus (HBV) compared with the general population. This study aims to assess the epidemiological and virological characteristics of HBV infection in a sample of MSM in Brazil, where data are scarce. METHODS: A cross-sectional study was conducted among MSM in the City of Goiania, Central Brazil, from March to November 2014, using Respondent-Driven Sampling (RDS). After signing the consent form, participants were interviewed and a blood sample collected. All samples were tested for HBV serological markers and HBV DNA. HBV nucleotide sequence analysis was also performed. RESULTS: A total of 522 MSM were recruited in the study. The prevalence of HBV infection (current or past [presence of anti-HBc marker]) was 15.4% (95% CI: 8.7-25.8) and the rate of HBsAg carriers was 0.6% (95% CI: 0.2-1.6). About 40% (95% CI: 32.3-48.8) of the participants had serological evidence of previous HBV vaccination (reactive for isolated anti HBs). In addition, 44.3% (95% CI: 36.1-52.9) were seronegative for all HBV markers. Age over 25 years old, receptive anal intercourse, previous sex with women, and history of sexually transmitted infections (STIs) were factors associated with HBV infection. HBV DNA was detected only in HBsAg-positive individuals. HBV isolates were classified into genotype A (subgenotypes A1 and A2), and some mutations were identified throughout the genome. Therefore, occult HBV infection was not observed in the study population. CONCLUSIONS: Public health strategies should be improved for the MSM population in order to prevent HBV and other STIs, as well as to provide appropriate management of patients with active infections. PMID- 27508386 TI - Explaining Lifelong Loyalty: The Role of Identity Fusion and Self-Shaping Group Events. AB - Pledging lifelong loyalty to an ingroup can have far-reaching behavioural effects, ranging from ordinary acts of ingroup kindness to extraordinary acts of self-sacrifice. What motivates this important form of group commitment? Here, we propose one especially potent answer to this question-the experience of a visceral sense of oneness with a group (i.e., identity fusion). In a sample of British football fans, a population in which high levels of lifelong loyalty are thought to be common, we first examined the hypothesised relationship between fusion and perceptions of lifelong loyalty to one's club. We further explored the hypothesis that fusion and lifelong loyalty are not merely a reflection of past time investment in a group, but also reflect a deeper, memory-based process of feeling personally shaped by key group events, both euphoric and dysphoric. We found broad support for these hypotheses. Results suggest that feeling personally self-shaped by club events (e.g., crucial wins and losses), rather than time invested in the club, leads to greater identity fusion to one's club. In turn, fusion engenders a sense of lifelong club loyalty. We discuss our findings in relation to the growing literature on the experiential origins of intense social cohesion. PMID- 27508387 TI - Phenotypic Plasticity through Transcriptional Regulation of the Evolutionary Hotspot Gene tan in Drosophila melanogaster. AB - Phenotypic plasticity is the ability of a given genotype to produce different phenotypes in response to distinct environmental conditions. Phenotypic plasticity can be adaptive. Furthermore, it is thought to facilitate evolution. Although phenotypic plasticity is a widespread phenomenon, its molecular mechanisms are only beginning to be unravelled. Environmental conditions can affect gene expression through modification of chromatin structure, mainly via histone modifications, nucleosome remodelling or DNA methylation, suggesting that phenotypic plasticity might partly be due to chromatin plasticity. As a model of phenotypic plasticity, we study abdominal pigmentation of Drosophila melanogaster females, which is temperature sensitive. Abdominal pigmentation is indeed darker in females grown at 18 degrees C than at 29 degrees C. This phenomenon is thought to be adaptive as the dark pigmentation produced at lower temperature increases body temperature. We show here that temperature modulates the expression of tan (t), a pigmentation gene involved in melanin production. t is expressed 7 times more at 18 degrees C than at 29 degrees C in female abdominal epidermis. Genetic experiments show that modulation of t expression by temperature is essential for female abdominal pigmentation plasticity. Temperature modulates the activity of an enhancer of t without modifying compaction of its chromatin or level of the active histone mark H3K27ac. By contrast, the active mark H3K4me3 on the t promoter is strongly modulated by temperature. The H3K4 methyl-transferase involved in this process is likely Trithorax, as we show that it regulates t expression and the H3K4me3 level on the t promoter and also participates in female pigmentation and its plasticity. Interestingly, t was previously shown to be involved in inter-individual variation of female abdominal pigmentation in Drosophila melanogaster, and in abdominal pigmentation divergence between Drosophila species. Sensitivity of t expression to environmental conditions might therefore give more substrate for selection, explaining why this gene has frequently been involved in evolution of pigmentation. PMID- 27508388 TI - Protein Profiles for Muscle Development and Intramuscular Fat Accumulation at Different Post-Hatching Ages in Chickens. AB - Muscle development and growth influences the efficiency of poultry meat production, and is closely related to deposition of intramuscular fat (IMF), which is crucial in meat quality. To clarify the molecular mechanisms underlying muscle development and IMF deposition in chickens, protein expression profiles were examined in the breast muscle of Beijing-You chickens at ages 1, 56, 98 and 140 days, using isobaric tags for relative and absolute quantification (iTRAQ). Two hundred and four of 494 proteins were expressed differentially. The expression profile at day 1 differed greatly from those at day 56, 98 and 140. KEGG pathway analysis of differential protein expression from pair-wise comparisons (day 1 vs. 56; 56 vs. 98; 98 vs. 140), showed that the fatty acid degradation pathway was more active during the stage from day 1 to 56 than at other periods. This was consistent with the change in IMF content, which was highest at day 1 and declined dramatically thereafter. When muscle growth was most rapid (days 56-98), pathways involved in muscle development were dominant, including hypertrophic cardiomyopathy, dilated cardiomyopathy, cardiac muscle contraction, tight junctions and focal adhesion. In contrast with hatchlings, the fatty acid degradation pathway was downregulated from day 98 to 140, which was consistent with the period for IMF deposition following rapid muscle growth. Changes in some key specific proteins, including fast skeletal muscle troponin T isoform, aldehyde dehydrogenase 1A1 and apolipoprotein A1, were verified by Western blotting, and could be potential biomarkers for IMF deposition in chickens. Protein-protein interaction networks showed that ribosome-related functional modules were clustered in all three stages. However, the functional module involved in the metabolic pathway was only clustered in the first stage (day 1 vs. 56). This study improves our understanding of the molecular mechanisms underlying muscle development and IMF deposition in chickens. PMID- 27508389 TI - Indoor Air Pollution and Delayed Measles Vaccination Increase the Risk of Severe Pneumonia in Children: Results from a Case-Control Study in Mwanza, Tanzania. AB - BACKGROUND: Mortality due to severe pneumonia during childhood in resource constrained settings is high, but data to provide basis for interventions to improve survival are limited. The objective of this study was to determine the risk factors for severe pneumonia in children aged under five years old in Mwanza, Tanzania. METHODS: We conducted a case-control study of children aged 2 to 59 months at Sekou-Toure regional hospital in Mwanza City, north-western, Tanzania from May 2013 to March 2014. Cases were children with severe pneumonia and controls were children with other illnesses. Data on demography, social economical status, nutritional status, environmental factors, vaccination status, vitamin A supplementation and deworming, and nasopharyngeal carriage were collected and analysed using logistic regression. RESULTS: 117 patients were included in the study. Of these, 45 were cases and 72 controls. Cases were younger than controls, but there were no differences in social-economic or nutritional status between the two groups. In multiple regression, we found that an increased risk of severe pneumonia was associated with cooking indoors (OR 5.5, 95% CI: 1.4, 22.1), and delayed measles vaccination (OR 3.9, 95% CI: 1.1, 14.8). The lack of vitamin A supplementation in the preceding six month and Enterobacter spp nasopharyngeal carriage were not associated with higher risk of severe pneumonia. Age >=24 months (OR 0.2, 95% CI: 0.04, 0.8) and not receiving antibiotics before referral (OR 0.3, 95% CI 0.1, 0.9) were associated with lower risk for severe pneumonia. CONCLUSIONS: Indoor air pollution and delayed measles vaccination increase the risk for severe pneumonia among children aged below five years. Interventions to reduce indoor air pollution and to promote timely administration of measles vaccination are urgently needed to reduce the burden of severe pneumonia in children in Tanzania. PMID- 27508390 TI - Bacterial Loads Measured by the Xpert MTB/RIF Assay as Markers of Culture Conversion and Bacteriological Cure in Pulmonary TB. AB - INTRODUCTION: Biomarkers are needed to monitor tuberculosis (TB) treatment and predict treatment outcomes. We evaluated the Xpert MTB/RIF (Xpert) assay as a biomarker for TB treatment during and at the end of the 24 weeks therapy. METHODS: Sputum from 108 HIV-negative, culture-positive pulmonary TB patients was analyzed using Xpert at time points before and during anti-TB therapy. Results were compared against culture. Direct Xpert cycle-threshold (Ct), a change in the Ct (delta Ct), or a novel "percent closing of baseline Ct deficit" (percent closing) were evaluated as classifiers of same-day and end-of-treatment culture and therapeutic outcomes. RESULTS: Xpert was positive in 29/95 (30.5%) of subjects at week 24; and positive one year after treatment in 8/64 (12.5%) successfully-treated patients who remained free of tuberculosis. We identified a relationship between initial bacterial load measured by baseline Xpert Ct and time to culture conversion (hazard ratio 1.06, p = 0.0023), and to the likelihood of being among the 8 treatment failures at week 24 (AUC = 72.8%). Xpert Ct was even more strongly associated with culture conversion on the day the test was performed with AUCs 96.7%, 99.2%, 86.0% and 90.2%, at Day 7, Week 4, 8 and 24, respectively. Compared to baseline Ct measures alone, a combined measure of baseline Ct plus either Delta Ct or percent closing improved the classification of treatment failure status to a 75% sensitivity and 88.9% specificity. CONCLUSIONS: Genome loads measured by Xpert provide a potentially-useful biomarker for classifying same day culture status and predicting response to therapy. PMID- 27508391 TI - Stimulus Statistics Change Sounds from Near-Indiscriminable to Hyperdiscriminable. AB - Objects and events in the sensory environment are generally predictable, making most of the energy impinging upon sensory transducers redundant. Given this fact, efficient sensory systems should detect, extract, and exploit predictability in order to optimize sensitivity to less predictable inputs that are, by definition, more informative. Not only are perceptual systems sensitive to changes in physical stimulus properties, but growing evidence reveals sensitivity both to relative predictability of stimuli and to co-occurrence of stimulus attributes within stimuli. Recent results revealed that auditory perception rapidly reorganizes to efficiently capture covariance among stimulus attributes. Acoustic properties per se were perceptually abandoned, and sounds were instead processed relative to patterns of co-occurrence. Here, we show that listeners' ability to distinguish sounds from one another is driven primarily by the extent to which they are consistent or inconsistent with patterns of covariation among stimulus attributes and, to a lesser extent, whether they are heard frequently or infrequently. When sounds were heard frequently and deviated minimally from the prevailing pattern of covariance among attributes, they were poorly discriminated from one another. In stark contrast, when sounds were heard rarely and markedly violated the pattern of covariance, they became hyperdiscriminable with discrimination performance beyond apparent limits of the auditory system. Plausible cortical candidates underlying these dramatic changes in perceptual organization are discussed. These findings support efficient coding of stimulus statistical structure as a model for both perceptual and neural organization. PMID- 27508392 TI - The Impact of Macronutrients on Retinal Microvasculature among Singapore Pregnant Women during the Mid-Late Gestation. AB - BACKGROUND: Imbalanced macronutrient intakes can induce impairment of endothelial and vascular function, and further lead to metabolic and cardiovascular disease. However, little is known about the influence of such diets on endothelial and vascular dysfunction in pregnant women, even though high-fat diet is a known risk for pregnancy complications such as gestational diabetes and pre-eclampsia. OBJECTIVE: We aimed to assess the association between maternal macronutrient intakes (protein, fat and carbohydrates), dietary quality and retinal microvascular changes in a multi-ethnic Asian mother-offspring cohort. METHODS: Pregnant women (n = 614) with singleton pregnancies were recruited during their first trimester from June 2009 to Sep 2010. Maternal diet quality and macronutrient intakes, expressed as a percentage of total energy during pregnancy, were ascertained using 24 hr recalls and 3 d food diaries at 26-28 weeks gestation. Retinal examination was completed at the same clinic visit. Dietary quality was assessed and scored using the Health Eating Index in Asian Pregnant women (HEI-AP), while macronutrients intakes ware expressed as percentages of total energy and further log transformed for analysis. Associations were examined cross-sectionally by substitution models with the use of multiple linear regression. RESULTS: In adjusted model, each 20 points decrease in HEI-AP score was associated with a significant increase of 1.70 MUm (p<0.05) in retinal venular calibre. Each 0.1 log increase in percentage of total fat intake was associated with a significant increment of 1.84 MUm (p<0.05) in retinal venular caliber. Additionally, each 0.1 log increase in percentage of mono-unsaturated fat intake was associated with an increment of 1.84 MUm (p<0.01) in retinal venular caliber. CONCLUSIONS: In this cross-sectional study, we found that women with higher fat and lower protein intakes, and lower diet quality tended to have wider retinal venular caliber, which is suggestive of suboptimal microvasculature. PMID- 27508393 TI - Phenome-Wide Association Study to Explore Relationships between Immune System Related Genetic Loci and Complex Traits and Diseases. AB - We performed a Phenome-Wide Association Study (PheWAS) to identify interrelationships between the immune system genetic architecture and a wide array of phenotypes from two de-identified electronic health record (EHR) biorepositories. We selected variants within genes encoding critical factors in the immune system and variants with known associations with autoimmunity. To define case/control status for EHR diagnoses, we used International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes from 3,024 Geisinger Clinic MyCode(r) subjects (470 diagnoses) and 2,899 Vanderbilt University Medical Center BioVU biorepository subjects (380 diagnoses). A pooled analysis was also carried out for the replicating results of the two data sets. We identified new associations with potential biological relevance including SNPs in tumor necrosis factor (TNF) and ankyrin-related genes associated with acute and chronic sinusitis and acute respiratory tract infection. The two most significant associations identified were for the C6orf10 SNP rs6910071 and "rheumatoid arthritis" (ICD-9 code category 714) (pMETAL = 2.58 x 10-9) and the ATN1 SNP rs2239167 and "diabetes mellitus, type 2" (ICD-9 code category 250) (pMETAL = 6.39 x 10-9). This study highlights the utility of using PheWAS in conjunction with EHRs to discover new genotypic-phenotypic associations for immune-system related genetic loci. PMID- 27508394 TI - Prevalence of psoriatic arthritis and its correlates among patients with psoriasis in Greece: results from a large retrospective study. AB - OBJECTIVES: To evaluate the prevalence and its clinical characteristics of psoriatic arthritis (PsA) in a specialized psoriasis clinic of a University Hospital. METHODS: In this retrospective study, 278 patients with psoriasis were evaluated between 2011 and 2013. RESULTS: The study included 278 patients with psoriasis: 144 (52%) were male and 134 (48%) female. Their median age was 51.41 with median psoriasis presenting age of 34.52 years. Referring to the type of psoriasis, 86% presented with plaque psoriasis, 5% guttate, 2% palms and soles, 2% inverse, 1% pustular and 4% with psoriasis of more than one type. Nail disease appeared in 121 patients (43.5%) and scalp disease in 175 (63%). Of these patients, 85 (30%) had PsA, whereas 51% of patients with PsA had psoriatic nail disease. With reference to the PsA type, 43 (51%) patients presented with polyarthritis, 10 (12%) with oligoarthritis, 7 (8%) with axial arthritis, whereas the rest 25 of them (31%) had PsA of more than one type. The subgroup of patients with PsA had significantly higher rates of comorbidities including arterial hypertension, diabetes and hypercholesterolaemia compared to non-PsA patients with 41% vs. 17% (P = 0.001), 20% vs. 8% (P = 0.021) and 41% vs. 19% (P = 0.004), respectively. CONCLUSION: The prevalence of PsA among patients with psoriasis was relatively higher in Greece compared to other ethnic-based studies. Comorbidities related to life expectancy were more frequent. As there is a high percentage of undiagnosed cases with active arthritis among patients with psoriasis, dermatologists should be aware of PsA clinical signs in order to recognize it earlier and provide successful treatment. PMID- 27508395 TI - Association between perceived social support and anxiety in pregnant adolescents. AB - Objective:: To evaluate the association between perceived social support and anxiety disorders in pregnant adolescents. Methods:: We conducted a cross sectional study with a sample of 871 pregnant women aged 10 to 19 years who received prenatal care in the national public health care system in the urban area of Pelotas, state of Rio Grande do Sul, southern Brazil. We assessed perceived social support and anxiety disorders using the Medical Outcomes Study Social Support Survey and the Mini International Neuropsychiatric Interview. A self-report questionnaire was used to obtain sociodemographic information. Results:: The prevalence of any anxiety disorder was 13.6%. Pregnant adolescents with an anxiety disorder reported less perceived social support in all domains (affectionate, emotional, tangible, informational, and positive social interaction). Older teenagers reported lower perceived support in the emotional, informational, and positive social interaction domains, whereas those with low socioeconomic status reported lower perceived social support in the material domain. Women who did not live with a partner had less perceived social support in the affectionate and positive social interaction domains. Conclusion:: Perceived social support seems to be a protective factor against anxiety disorders in pregnant adolescents, with a positive effect on mental health. PMID- 27508396 TI - Electroencephalographic findings in patients with major depressive disorder during cognitive or emotional tasks: a systematic review. AB - Objective:: Major depressive disorder (MDD) is a prevalent psychiatric condition characterized by multiple symptoms that cause great distress. Uncovering the brain areas involved in MDD is essential for improving therapeutic strategies and predicting response to interventions. This systematic review discusses recent findings regarding cortical alterations in depressed patients during emotional or cognitive tasks, as measured by electroencephalography (EEG). Methods:: A search of the MEDLINE/PubMed and Cochrane databases was carried out using the keywords EEG and depression, confined to article title. Results:: The studies identified reveal the frontal cortex as an important brain structure involved in the complex neural processes associated with MDD. Findings point to disorganization of right hemisphere activity and deficient cognitive processing in MDD. Depressed individuals tend to ruminate on negative information and respond with a pattern of relatively higher right frontal activity to emotional stimuli associated with withdrawal and isolation. Conclusion:: Patients with MDD may have altered dynamic patterns of activity in several neuroanatomical structures, especially in prefrontal and limbic areas involved in affective regulation. Identification of these alterations might help predict the response of patients to different interventions more effectively and thus maximize the effects both of pharmacotherapeutic and of psychotherapeutic strategies. PMID- 27508397 TI - Components of the metabolic syndrome and depressive symptoms in community dwelling older people: the Bambui Cohort Aging Study. AB - OBJECTIVE: To investigate the moderating effect of an increasing number of clustered metabolic syndrome (MetS) components on the association between MetS and depressive symptoms in a population-based cohort of older adults in Brazil. METHODS: This analysis used data from the Bambui Cohort Aging Study. Participants in this cross-sectional study comprised 1,469 community-dwelling older people aged >= 60 years. Analyses were performed to assess both the association between depressive symptoms and each individual MetS component and the association between depressive symptoms and clustering of an increasing number of MetS components. RESULTS: High triglyceride level was the individual component that showed the strongest association with depressive symptoms (odds ratio [OR]: 1.47; 95% confidence intervals [95%CI] 1.19-1.81; p < 0.0001). Only the presence of three MetS components was associated with depressive symptoms (OR = 1.53; 95%CI 1.05-2.23; p = 0.025). No graded association was detected between increasing number of clustered MetS components and depressive symptoms. CONCLUSIONS: Increasing the number of MetS components did not impact the association with depressive symptoms. The association between high triglyceride level and depressive symptoms highlights the relevance of lipid metabolism abnormalities for the emergence of depressive symptoms in older adults. PMID- 27508398 TI - Impairment of fine motor dexterity in mild cognitive impairment and Alzheimer's disease dementia: association with activities of daily living. AB - OBJECTIVE: Cognitive impairment is a hallmark of mild cognitive impairment (MCI) and Alzheimer's disease dementia (AD). Although the cognitive profile of these patients and its association with activities of daily living (ADLs) is well documented, few studies have assessed deficits in fine motor dexterity and their association with ADL performance. The objective of this research paper is to evaluate fine motor dexterity performance among MCI and AD patients and to investigate its association with different aspects of ADLs. METHODS: We assessed normal aging controls, patients with multiple- and single-domain amnestic MCI (aMCI), and patients with mild AD. Fine motor dexterity was measured with the Nine-Hole Peg Test and cognitive functioning by the Mattis Dementia Rating Scale. We analyzed the data using general linear models. RESULTS: Patients with AD or multiple-domain aMCI had slower motor responses when compared to controls. AD patients were slower than those with single-domain aMCI. We found associations between cognition and instrumental ADLs, and between fine motor dexterity and self-care ADLs. CONCLUSION: We observed progressive slowing of fine motor dexterity along the normal aging-MCI-AD spectrum, which was associated with autonomy in self-care ADLs. PMID- 27508399 TI - Strategies toward High-Temperature Lanthanide-Based Single-Molecule Magnets. AB - Lanthanide-based single-molecule magnets are leading materials for achieving magnetization blocking at the level of one molecule. In this paper, we examine the physical requirements for efficient magnetization blocking in single-ion complexes and identify the design principles for achieving very high magnetization blocking barriers in lanthanide-based compounds. The key condition is the preponderant covalent binding of the Ln ion to one of the ligand atoms, tremendously enhancing the axial crystal field. We also make an overview of practical schemes for the implementation of this principle. These are (1) the effective lowering of the coordination number via displacement of the Ln ion to one of the atoms in the coordination polyhedron, (2) the design of two coordinated complexes, and (3) the stabilization of diatomic compounds in cages and on surfaces. The last proposal is appealing in connection to spintronics applications, especially via the exploration of robust and highly anisotropic [LnX] units displaying multilevel blocking barriers of thousands of Kelvin and prospects for room-temperature magnetization blocking. PMID- 27508400 TI - Interplay of Specific Trans- and Juxtamembrane Interfaces in Plexin A3 Dimerization and Signal Transduction. AB - Plexins are transmembrane proteins that serve as guidance receptors during angiogenesis, lymphangiogenesis, neuronal development, and zebrafish fin regeneration, with a putative role in cancer metastasis. Receptor dimerization or clustering, induced by extracellular ligand binding but modulated in part by the plexin transmembrane (TM) and juxtamembrane (JM) domains, is thought to drive plexin activity. Previous studies indicate that isolated plexin TM domains interact through a conserved, small-x3-small packing motif, and the cytosolic JM region interacts through a hydrophobic heptad repeat; however, the roles and interplay of these regions in plexin signal transduction remain unclear. Using an integrated experimental and simulation approach, we find disruption of the small x3-small motifs in the Danio rerio Plexin A3 TM domain enhances dimerization of the TM-JM domain by enhancing JM-mediated dimerization. Furthermore, mutations of the cytosolic JM heptad repeat that disrupt dimerization do so even in the presence of TM domain mutations. However, mutations to the small-x3-small TM interfaces also disrupt Plexin A3 signaling in a zebrafish axonal guidance assay, indicating the importance of this TM interface in signal transduction. Collectively, our experimental and simulation results demonstrate that multiple TM and JM interfaces exist in the Plexin A3 homodimer, and these interfaces independently regulate dimerization that is important in Plexin A3 signal transduction. PMID- 27508401 TI - Air-Driven Potassium Iodide-Mediated Oxidative Photocyclization of Stilbene Derivatives. AB - A new method has been developed for the potassium iodide-mediated oxidative photocyclization of stilbene derivatives. Compared with conventional iodine mediated oxidative photocyclization reactions, this new method requires shorter reaction times and affords cyclized products in yields of 45-97%. This reaction proceeds with a catalytic amount of potassium iodide and works in an air-driven manner without the addition of an external scavenger. The radical-mediated oxidative photocyclization of stilbene derivatives using TEMPO was also investigated. PMID- 27508402 TI - Factors Associated with the Use of Gene Expression Profiles in Estrogen Receptor Positive Early-Stage Breast Cancer Patients: A Nationwide Study. AB - BACKGROUND: Breast cancer guidelines suggest the use of gene expression profiles (GEPs) in estrogen receptor-positive (ER+) breast cancer patients in whom controversy exists regarding adjuvant chemotherapy benefit based on traditional prognostic factors alone. We evaluated the current use of GEPs in these patients in the Netherlands. PATIENTS AND METHODS: Primary breast cancer patients treated between January 1, 2011 and December 31, 2014 and eligible for GEP use according to the Dutch national breast cancer guideline were identified in the Netherlands Cancer Registry: ER+ patients <70 years with grade 1 tumors >2 cm or grade 2 tumors 1-2 cm without overt lymph node metastases (pN0-Nmi). Mixed-effect logistic regression analysis was performed to associate characteristics of patients, tumors and hospitals with GEP use. RESULTS: GEPs were increasingly deployed: 12% of eligible patients received a GEP in 2011 versus 46% in 2014. Lobular versus ductal morphology (OR 0.58, 95% CI 0.47-0.72), pN1mi status (versus pN0, OR 0.52, 95% CI 0.40-0.68), and tumor size (>3 cm vs. >2 cm, OR 0.33, 95% CI 0.14-0.88) were inversely associated with GEP use. High socioeconomic status (SES) (OR 1.32, 95% CI 1.06-1.64) and younger age (OR 0.96/year increasing age, 95% CI 0.95-0.96) were positively associated with GEP use. GEP use per hospital did vary, but no predefined institutional factors remained independently associated with GEP use. CONCLUSION: GEP use increased over time and was influenced by patient- and tumor-associated factors as well as by SES. PMID- 27508403 TI - Characteristic Contrast in Deltafmin Maps of Organic Molecules Using Atomic Force Microscopy. AB - Scanning tunneling microscopy and atomic force microscopy can provide detailed information about the geometric and electronic structure of molecules with submolecular spatial resolution. However, an essential capability to realize the full potential of these techniques for chemical applications is missing from the scanning probe toolbox: chemical recognition of organic molecules. Here, we show that maps of the minima of frequency shift-distance curves extracted from 3D data cubes contain characteristic contrast. A detailed theoretical analysis based on density functional theory and molecular mechanics shows that these features are characteristic for the investigated species. Structurally similar but chemically distinct molecules yield significantly different features. We find that the van der Waals and Pauli interaction, together with the specific adsorption geometry of a given molecule on the surface, accounts for the observed contrast. PMID- 27508404 TI - Enhanced Bulk and Interfacial Charge Transfer Dynamics for Efficient Photoelectrochemical Water Splitting: The Case of Hematite Nanorod Arrays. AB - Charge transport in the bulk and across the semiconductor/electrolyte interface is one of the major issues that limits photoelectrochemical (PEC) performance in hematite photoelectrodes. Efficient charge transport in the entire hematite is of great importance to obtaining high photoelectrochemical properties. Herein, to reach this goal, we employed both TiO2 underlayer and overlayer deposition on hematite nanorod films, followed by a fast annealing treatment. The TiO2 underlayer and overlayer not only serve as dopant sources for carrier density increase but also reduce charge recombination at the fluorine-doped tin oxide (FTO)/hematite interface and accelerate charge transfer across the hematite/electrolyte interface. This synergistic doping and interface modifying effects give rise to an enhanced photoelectrochemical water oxidation performance of hematite nanorod arrays, generating an impressive photocurrent density of 1.49 mA cm(-2) at 1.23 V vs RHE. This is the first report on using both underlayer and overlayer modification with the same material to improve charge transport through the entire electron transport path in hematite, which provides a novel way to manipulate charge transfer across the semiconductor interface for a high performance photoelectrode. PMID- 27508405 TI - Direct Photolysis Rates and Transformation Pathways of the Lampricides TFM and Niclosamide in Simulated Sunlight. AB - The lampricides 3-trifluoromethyl-4-nitrophenol (TFM) and 2',5-dichloro-4' nitrosalicylanilide (niclosamide) are directly added to many tributaries of the Great Lakes that harbor the invasive parasitic sea lamprey. Despite their long history of use, the fate of lampricides is not well understood. This study evaluates the rate and pathway of direct photodegradation of both lampricides under simulated sunlight. The estimated half-lives of TFM range from 16.6 +/- 0.2 h (pH 9) to 32.9 +/- 1.0 h (pH 6), while the half-lives of niclosamide range from 8.88 +/- 0.52 days (pH 6) to 382 +/- 83 days (pH 9) assuming continuous irradiation over a water depth of 55 cm. Both compounds degrade to form a series of aromatic intermediates, simple organic acids, ring cleavage products, and inorganic ions. Experimental data were used to construct a kinetic model which demonstrates that the aromatic products of TFM undergo rapid photolysis and emphasizes that niclosamide degradation is the rate-limiting step to dehalogenation and mineralization of the lampricide. This study demonstrates that TFM photodegradation is likely to occur on the time scale of lampricide applications (2-5 days), while niclosamide, the less selective lampricide, will undergo minimal direct photodegradation during its passage to the Great Lakes. PMID- 27508406 TI - Supramolecular Thermo-Electrochemical Cells: Enhanced Thermoelectric Performance by Host-Guest Complexation and Salt-Induced Crystallization. AB - Thermo-electrochemical cells have potential to generate thermoelectric voltage 1 order higher than that given by semiconductor materials. To overcome the current issues in thermoelectric energy conversion, it is of paramount importance to grow and fulfill the full potential of thermo-electrochemical cells. Here we report a rational supramolecular methodology that yielded the highest Seebeck coefficient of ca. 2.0 mV K(-1) around ambient temperatures. This is based on the encapsulation of triiodide ions in alpha-cyclodextrin, whose equilibrium is shifted to the complexation at lower temperatures, whereas it is inverted at elevated temperatures. This temperature-dependent host-guest interaction provides a concentration gradient of redox ion pairs between two electrodes, leading to the eminent performance of the thermo-electrochemical cells. The figure of merit for this system, zT reached a high value of 5 * 10(-3). The introduction of host guest chemistry to thermoelectric cells thus provides a new perspective in thermoelectric energy conversion. PMID- 27508407 TI - Palladium-Catalyzed Intramolecular Dearomatization of Indoles via Decarboxylative Alkynyl Termination. AB - A highly diastereoselective dearomatization of indoles via palladium-catalyzed decarboxylative alkynyl termination was developed. This protocol provides dissimilar tetracyclic and tetrasubstituted indoline scaffolds bearing congested stereocenters, which led to operationally simple conditions, short time, and broad substrate scope. Additionally, this reaction system could be scaled to gram quantities in a satisfactory yield and diastereoselectivity. PMID- 27508408 TI - Transient Two-Dimensional Infrared Spectroscopy in a Vibrational Ladder. AB - We report on transient 2D Fourier transform infrared spectroscopy (2DIR) after vibrational ladder climbing induced in the CO-moiety longitudinal stretch of carboxyhemoglobin. The population distribution, spreading up to seven vibrational levels, results in a nonequilibrium 2DIR spectrum evidencing a large number of peaks that can be easily attributed to individual transitions thanks to the anharmonicity of the vibrational potential. We discuss the physical origin of the observed peaks as well as the qualitative behavior of the subsequent dynamics governed by population relaxation in the vibrational ladder. PMID- 27508409 TI - Use of the Coelomic Grafting Technique for Prolonged ex utero Cultivation of Late Preprimitive Streak-Stage Rabbit Embryos. AB - Due to its morphological similarity with the early human embryo, the pregastrulation-stage rabbit may represent an appropriate mammalian model for studying processes involved in early human development. The usability of mammalian embryos for experimental studies depends on the availability of whole embryo culture methods facilitating prolonged ex utero development. While currently used culture methods yield high success rates for embryos from primitive streak stages onward, the success rate of extended cultivation of preprimitive streak-stage mammalian embryos is low for all previously established methods and for all studied species. This limits the usability of preprimitive streak-stage rabbit embryos in experimental embryology. We have tested whether the extraembryonic coelom of 4-day-old chick embryos may be used for prolonged ex utero culture of preprimitive streak-stage rabbit embryos (stage 2, 6.2 days post coitum). We found that, within this environment, stage 2 rabbit blastocysts can be cultured at decreasing success rates (55% after 1 day, 35% after 2 days, 15% after 3 days) up to a maximum of 72 h. Grafted blastocysts can continue development from the onset of gastrulation to early organogenesis and thereby form all structures characterizing age-matched controls (e.g. neural tube, somites, beating heart). Compared to normal controls, successfully cultured embryos developed at a slower rate and finally showed some structural and gross morphological anomalies. The method presented here was originally developed for whole embryo culture of mouse embryos by Gluecksohn-Schoenheimer in 1941. It is a simple and inexpensive method that may represent a useful extension to presently available ex utero culture systems for rabbit embryos. PMID- 27508410 TI - Effects of Mulching on Soil Properties and Growth of Tea Olive (Osmanthus fragrans). AB - Different mulches have variable effects on soil physical properties and plant growth. This study aimed to compare the effects of mulching with inorganic (round gravel, RG), organic (wood chips, WC), and living (manila turf grass, MG) materials on soil properties at 0-5-cm and 5-10-cm depths, as well as on the growth and physiological features of Osmanthus fragrans L. 'Rixianggui' plants. Soil samples were collected at three different time points from field plots of O. fragrans plants treated with the different mulching treatments. Moisture at both soil depths was significantly higher after mulching with RG and WC than that in the unmulched control (CK) treatment. Mulching did not affect soil bulk density, pH, or total nitrogen content, but consistently improved soil organic matter. The available nitrogen in the soil increased after RG and WC treatments, but decreased after MG treatment during the experimental period. Mulching improved plant growth by increasing root activity, soluble sugar, and chlorophyll a content, as well as by providing suitable moisture conditions and nutrients in the root zone. Plant height and trunk diameter were remarkably increased after mulching, especially with RG and WC. However, while MG improved plant growth at the beginning of the treatment, the 'Rixianggui' plants later showed no improvement in growth. This was probably because MG competed with the plants for water and available nitrogen in the soil. Thus, our findings suggest that RG and WC, but not MG, improved the soil environment and the growth of 'Rixianggui' plants. Considering the effect of mulching on soil properties and plant growth and physiology, round gravel and wood chips appear to be a better choice than manila turf grass in 'Rixianggui' nurseries. Further studies are required to determine the effects of mulch quality and mulch-layer thickness on shoot and root growths. PMID- 27508411 TI - Accelerating Gene Discovery by Phenotyping Whole-Genome Sequenced Multi-mutation Strains and Using the Sequence Kernel Association Test (SKAT). AB - Forward genetic screens represent powerful, unbiased approaches to uncover novel components in any biological process. Such screens suffer from a major bottleneck, however, namely the cloning of corresponding genes causing the phenotypic variation. Reverse genetic screens have been employed as a way to circumvent this issue, but can often be limited in scope. Here we demonstrate an innovative approach to gene discovery. Using C. elegans as a model system, we used a whole-genome sequenced multi-mutation library, from the Million Mutation Project, together with the Sequence Kernel Association Test (SKAT), to rapidly screen for and identify genes associated with a phenotype of interest, namely defects in dye-filling of ciliated sensory neurons. Such anomalies in dye-filling are often associated with the disruption of cilia, organelles which in humans are implicated in sensory physiology (including vision, smell and hearing), development and disease. Beyond identifying several well characterised dye filling genes, our approach uncovered three genes not previously linked to ciliated sensory neuron development or function. From these putative novel dye filling genes, we confirmed the involvement of BGNT-1.1 in ciliated sensory neuron function and morphogenesis. BGNT-1.1 functions at the trans-Golgi network of sheath cells (glia) to influence dye-filling and cilium length, in a cell non autonomous manner. Notably, BGNT-1.1 is the orthologue of human B3GNT1/B4GAT1, a glycosyltransferase associated with Walker-Warburg syndrome (WWS). WWS is a multigenic disorder characterised by muscular dystrophy as well as brain and eye anomalies. Together, our work unveils an effective and innovative approach to gene discovery, and provides the first evidence that B3GNT1-associated Walker Warburg syndrome may be considered a ciliopathy. PMID- 27508412 TI - The Great Irish Famine: Identifying Starvation in the Tissues of Victims Using Stable Isotope Analysis of Bone and Incremental Dentine Collagen. AB - The major components of human diet both past and present may be estimated by measuring the carbon and nitrogen isotope ratios (delta13C and delta15N) of the collagenous proteins in bone and tooth dentine. However, the results from these two tissues differ substantially: bone collagen records a multi-year average whilst primary dentine records and retains time-bound isotope ratios deriving from the period of tooth development. Recent studies harnessing a sub-annual temporal sampling resolution have shed new light on the individual dietary histories of our ancestors by identifying unexpected radical short-term dietary changes, the duration of breastfeeding and migration where dietary change occurs, and by raising questions regarding factors other than diet that may impact on delta13C and delta15N values. Here we show that the dentine delta13C and delta15N profiles of workhouse inmates dating from the Great Irish Famine of the 19th century not only record the expected dietary change from C3 potatoes to C4 maize, but when used together they also document prolonged nutritional and other physiological stress resulting from insufficient sustenance. In the adults, the influence of the maize-based diet is seen in the delta13C difference between dentine (formed in childhood) and rib (representing an average from the last few years of life). The demonstrated effects of stress on the delta13C and delta15N values will have an impact on the interpretations of diet in past populations even in slow-turnover tissues such as compact bone. This technique also has applicability in the investigation of modern children subject to nutritional distress where hair and nails are unavailable or do not record an adequate period of time. PMID- 27508413 TI - Demography of the Early Neolithic Population in Central Balkans: Population Dynamics Reconstruction Using Summed Radiocarbon Probability Distributions. AB - The Central Balkans region is of great importance for understanding the spread of the Neolithic in Europe but the Early Neolithic population dynamics of the region is unknown. In this study we apply the method of summed calibrated probability distributions to a set of published radiocarbon dates from the Republic of Serbia in order to reconstruct population dynamics in the Early Neolithic in this part of the Central Balkans. The results indicate that there was a significant population growth after ~6200 calBC, when the Neolithic was introduced into the region, followed by a bust at the end of the Early Neolithic phase (~5400 calBC). These results are broadly consistent with the predictions of the Neolithic Demographic Transition theory and the patterns of population booms and busts detected in other regions of Europe. These results suggest that the cultural process that underlies the patterns observed in Central and Western Europe was also in operation in the Central Balkan Neolithic and that the population increase component of this process can be considered as an important factor for the spread of the Neolithic as envisioned in the demic diffusion hypothesis. PMID- 27508414 TI - Risk of Nephrotic Syndrome following Enteroviral Infection in Children: A Nationwide Retrospective Cohort Study. AB - PURPOSE: Nephrotic syndrome is a common chronic illness encountered during childhood. Infections have been identified as a cause of nephrotic syndrome. The aim of this study was to evaluate the association between enteroviral infection and nephrotic syndrome. METHODS: A nationwide retrospective cohort study was conducted by analyzing data from the National Health Insurance Research Database in Taiwan. Children aged <18 years with enteroviral infection were enrolled. Non enterovirus-infected children were randomly selected as the comparison cohort. The primary endpoint was the occurrence of nephrotic syndrome. METHODS: This study included 280,087 enterovirus-infected children and 280,085 non-enterovirus infected children. The mean age of the enterovirus-infected children was 2.38 years, and 53.7% of these children were boys. The overall incidence densities of nephrotic syndrome for enterovirus- and non-enterovirus-infected children were 2.65 and 2.21 per 10,000 person-years, respectively. The enterovirus-infected cohort had a higher cumulative incidence of nephrotic syndrome than did the non enterovirus-infected cohort (log-rank test, p = 0.01). Multivariable analyses revealed that children with enteroviral infection were significantly associated with an increased risk of nephrotic syndrome compared with those without enteroviral infection (adjusted hazard ratio, 1.20; 95% confidence interval, 1.04 1.39; p = 0.01), particularly in children infected with coxsackievirus. Subgroup analyses revealed that enterovirus-infected girls, children of blue-collar workers, and children without allergies had a higher risk of nephrotic syndrome than did children in the non-enterovirus-infected cohort. CONCLUSION: This study revealed a significant association between enteroviral infection and nephrotic syndrome. Additional studies elucidating the role and pathogenesis of enterovirus in nephrotic syndrome are warranted. PMID- 27508415 TI - Assumptions of Mixed Treatment Comparisons in Health Technology Assessments - Challenges and Possible Steps for Practical Application. AB - The validity of mixed treatment comparisons (MTCs), also called network meta analysis, relies on whether it is reasonable to accept the underlying assumptions on similarity, homogeneity, and consistency. The aim of this paper is to propose a practicable approach to addressing the underlying assumptions of MTCs. Using data from clinical studies of antidepressants included in a health technology assessment (HTA), we present a stepwise approach to dealing with challenges related to checking the above assumptions and to judging the robustness of the results of an MTC. At each step, studies that were dissimilar or contributed to substantial heterogeneity or inconsistency were excluded from the primary analysis. In a comparison of the MTC estimates from the consistent network with the MTC estimates from the homogeneous network including inconsistencies, few were affected by notable changes; that is, a change in effect size (factor 2), direction of effect or statistical significance. Considering the small proportion of studies excluded from the network due to inconsistency, as well as the number of notable changes, the MTC results were deemed sufficiently robust. In the absence of standard methods, our approach to checking assumptions in MTCs may inform other researchers in need of practical options, particularly in HTA. PMID- 27508416 TI - Integrative Inferences on Pattern Geometries of Grapes Grown under Water Stress and Their Resulting Wines. AB - Multiple datasets of two consecutive vintages of replicated grape and wines from six different deficit irrigation regimes are characterized and compared. The process consists of four temporal-ordered signature phases: harvest field data, juice composition, wine composition before bottling and bottled wine. A new computing paradigm and an integrative inferential platform are developed for discovering phase-to-phase pattern geometries for such characterization and comparison purposes. Each phase is manifested by a distinct set of features, which are measurable upon phase-specific entities subject to the common set of irrigation regimes. Throughout the four phases, this compilation of data from irrigation regimes with subsamples is termed a space of media-nodes, on which measurements of phase-specific features were recoded. All of these collectively constitute a bipartite network of data, which is then normalized and binary coded. For these serial bipartite networks, we first quantify patterns that characterize individual phases by means of a new computing paradigm called "Data Mechanics". This computational technique extracts a coupling geometry which captures and reveals interacting dependence among and between media-nodes and feature-nodes in forms of hierarchical block sub-matrices. As one of the principal discoveries, the holistic year-factor persistently surfaces as the most inferential factor in classifying all media-nodes throughout all phases. This could be deemed either surprising in its over-arching dominance or obvious based on popular belief. We formulate and test pattern-based hypotheses that confirm such fundamental patterns. We also attempt to elucidate the driving force underlying the phase-evolution in winemaking via a newly developed partial coupling geometry, which is designed to integrate two coupling geometries. Such partial coupling geometries are confirmed to bear causal and predictive implications. All pattern inferences are performed with respect to a profile of energy distributions sampled from network bootstrapping ensembles conforming to block-structures specified by corresponding hypotheses. PMID- 27508417 TI - The 4p16.3 Parkinson Disease Risk Locus Is Associated with GAK Expression and Genes Involved with the Synaptic Vesicle Membrane. AB - Genome-wide association studies (GWAS) have identified the GAK/DGKQ/IDUA region on 4p16.3 among the top three risk loci for Parkinson's disease (PD), but the specific gene and risk mechanism are unclear. Here, we report transcripts containing the 3' clathrin-binding domain of GAK identified by RNA deep sequencing in post-mortem human brain tissue as having increased expression in PD. Furthermore, carriers of 4p16.3 PD GWAS risk SNPs show decreased expression of one of these transcripts, GAK25 (Gencode Transcript 009), which correlates with the expression of genes functioning in the synaptic vesicle membrane. Together, these findings provide strong evidence for GAK clathrin-binding- and J domain transcripts' influence on PD pathogenicity, and for a role for GAK in regulating synaptic function in PD. PMID- 27508418 TI - Twelve-Month and Lifetime Prevalence of Mental Disorders in Cancer Patients. AB - BACKGROUND: Psychological problems are common in cancer patients. For the purpose of planning psycho-oncological interventions and services tailored to the specific needs of different cancer patient populations, it is necessary to know to what extent psychological problems meet the criteria of mental disorders. The purpose of this study was to estimate the 12-month and lifetime prevalence rates of mental disorders in cancer patients. METHODS: A representative sample of patients with different tumour entities and tumour stages (n = 2,141) in outpatient, inpatient and rehabilitation settings underwent the standardized computer-assisted Composite International Diagnostic Interview for mental disorders adapted for cancer patients (CIDI-O). RESULTS: The overall 12-month prevalence for any mental disorder was 39.4% (95% CI: 37.3-41.5), that for anxiety disorders was 15.8% (95% CI: 14.4-17.4), 12.5% (95% CI: 11.3-14.0) for mood disorders, 9.5% (95% CI: 8.3-10.9) for somatoform disorders, 7.3% (95% CI: 6.2-8.5) for nicotine dependence, 3.7% (95% CI: 3.0-4.6) for disorders due to general medical condition, and 1.1% (95% CI: 0.7-1.6) for alcohol abuse or dependence. Lifetime prevalence for any mental disorder was 56.3% (95% CI 54.1 58.6), that for anxiety disorders was 24.1% (95% CI: 22.3-25.9), 20.5% (95% CI: 18.9-22.3) for mood disorders, 19.9% (95% CI: 18.3-21.7) for somatoform disorders, 18.2% (95% CI: 16.6-20.0) for nicotine dependence, 6.4% (95% CI: 5.4 7.6) for alcohol abuse or dependence, 4.6% (95% CI: 3.8-5.6) for disorders due to general medical condition, and 0.2% (95% CI: 0.1-0.6) for eating disorders. CONCLUSIONS: Mental disorders are highly prevalent in cancer patients, indicating the need for provision of continuous psycho-oncological support from inpatient to outpatient care, leading to an appropriate allocation of direct personnel and other resources. PMID- 27508419 TI - Preservation Obscures Pelagic Deep-Sea Fish Diversity: Doubling the Number of Sole-Bearing Opisthoproctids and Resurrection of the Genus Monacoa (Opisthoproctidae, Argentiniformes). AB - The family Opisthoproctidae (barreleyes) constitutes one of the most peculiar looking and unknown deep-sea fish groups in terms of taxonomy and specialized adaptations. All the species in the family are united by the possession of tubular eyes, with one distinct lineage exhibiting also drastic shortening of the body. Two new species of the mesopelagic opisthoproctid mirrorbelly genus Monacoa are described based on pigmentation patterns of the "sole"-a unique vertebrate structure used in the reflection and control of bioluminescence in most short bodied forms. Different pigmentation patterns of the soles, previously noted as intraspecific variations based on preserved specimens, are here shown species specific and likely used for communication in addition to counter-illumination of down-welling sunlight. The genus Monacoa is resurrected from Opisthoproctus based on extensive morphological synaphomorphies pertaining to the anal fin and snout. Doubling the species diversity within sole-bearing opisthoproctids, including recognition of two genera, is unambiguously supported by mitogenomic DNA sequence data. Regular fixation with formalin and alcohol preservation is shown problematic concerning the retention of species-specific pigmentation patterns. Examination or photos of fresh material before formalin fixation is shown paramount for correct species recognition of sole-bearing opisthoproctids-a relatively unknown issue concerning species diversity in the deep-sea pelagic realm. PMID- 27508421 TI - Numerical Simulation and Experimental Validation of Calibrant-Loaded Extraction Phase Standardization Approach. AB - We present the kinetics of calibrant release and analyte uptake between the sample and calibrant-loaded extraction phase, CL-EP, with a finite-element analysis (FEA) using COMSOL Multiphysics software package. Effect of finite and infinite sample volume conditions, as well as various sample environment parameters such as fluid flow velocity, temperature, and presence of a binding matrix component were investigated in detail with the model in relation to the performance of the calibration. The simulation results supported by experimental data demonstrate the suitability of the CL-EP method for analysis of samples with variation of the sample environment parameters. The calibrant-loaded approach can provide both total and free concentrations from a single experiment based on whether the partition coefficient (Kes) value being used is measured in a matrix matched sample or in a matrix-free sample, respectively. Total concentrations can also be obtained by utilizing CL-EP in combination with external matrix-matched calibrations, which can be employed to automate the sampling process and provide corrections for variations in sample preparation, matrix effects, and detection processes. This approach is also suitable for very small volumes of sample, where addition of an internal standard in the sample is either troublesome or can change the sample characteristics. PMID- 27508420 TI - Number of Persistent Organic Pollutants Detected at High Concentrations in Blood Samples of the United States Population. AB - Human exposure to environmental chemicals as persistent organic pollutants (POPs) is usually assessed considering each pollutant individually, with little attention to concentrations of mixtures in individuals or social groups. Yet, it may be relatively common for humans to have low and high concentrations of numerous POPs. The study objectives were to analyze the number of POPs detected per person at high concentrations in the U.S. population, and the associations between such type of indicators and socioeconomic factors as gender, race / ethnicity, education, and poverty level. From 91 POPs analyzed in serum samples of 4,739 individuals in three subsamples of the National Health and Nutrition Examination Survey (NHANES) 2003-2004 (the last period with valid updated individual data for the compounds considered in the present study), we computed the number of POPs whose serum concentrations were above selected cutoff points. POPs included were 13 organochlorine compounds (OCs), 10 polybrominated diphenyl ethers (PBDEs), the polybrominated biphenyl (PBB) 153, 38 polychlorinated biphenyls (PCBs), 17 polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/Fs), and 12 perfluorinated compounds (PFCs). Over 13% of participants had >=10 of the 37 most detected POPs each at a concentration in the top decile (P90). Over 30% of subjects with total toxic equivalency (TEQ) >=P75, had >=10 of 24 POPs not included in TEQ calculations at concentrations >=P90. Compared to non Hispanic whites, the adjusted odds ratio of having >=10 of the 37 POPs at P90 was 9.2 for non-Hispanic blacks and 0.18 for Mexican Americans. Poverty, body mass index, age, and gender were also independently associated with having >=10 POPs in the top decile. More than one tenth of the US population may have >=10 POPs each at concentrations in the top decile. Such pattern is nine times more frequent in Non-Hispanic blacks and four times less frequent in Mexican Americans than in non-Hispanic whites. PMID- 27508422 TI - LARGE RETINAL PIGMENT EPITHELIAL RIP ASSOCIATED WITH BULLOUS RETINAL AND CHOROIDAL DETACHMENT. AB - PURPOSE: To report a giant retinal pigment epithelium rip in a patient with a bullous retinal and choroidal detachment. METHODS: Case report with widefield imaging, fundus autofluorescence, and optical coherence tomography of the retina. RESULTS: This 62-year-old patient had a history of advanced glaucoma, trabeculectomy, blebitis, and endophthalmitis. He had cataract surgery 6 weeks before presentation. He was found to have a large bullous retinal and choroidal detachment with a large retinal pigment epithelium tear at the limit of the choroidal detachment. After vitrectomy for retinal detachment repair, the tear was observed to extend inferiorly at the margins of the choroidal detachment. CONCLUSION: This case report demonstrates that large retinal pigment epithelium rips can be found associated with large bullous choroidal and retinal detachments. These tears seem similar to tears that have been observed after trabeculectomy. PMID- 27508423 TI - EN FACE OPTICAL COHERENCE TOMOGRAPHY (OCT) AND OCT ANGIOGRAPHY FINDINGS IN RETINAL ASTROCYTIC HAMARTOMAS. AB - PURPOSE: To report spectral-domain optical coherence tomography, en face optical coherence tomography (OCT), and optical coherence tomography angiography findings in retinal astrocytic hamartomas. METHODS: Four cases of retinal astrocytic hamartomas, with small white or yellowish typical retinal mass, were imaged with fundus photography, intravenous fluorescein angiography, fundus autofluorescence, spectral-domain OCT, en face OCT, and OCT angiography. RESULTS: The tumor was solitary in all cases and involved the posterior pole. It was idiopathic in three cases and was related to tuberous sclerosis complex in one case. The OCT findings included intralesional lucencies in two cases with no exudation. The tumor was within the retinal nerve fiber layer or deeper, usually overlying the inner plexiform layer providing a protusion in the vitreous cavity. Vitreous changes were present in all cases, corresponding to thickening and adhesion of the vitreous facing the lesion (two cases), apparent interdigitation with vitreous (one case), and marked condensation of the vitreous with interdigitations (one case). En face OCT imaging at the level of the retinal pigment epithelial zone showed a hyporeflective, round, well-delineated mass. A peripheral poorly defined hyperreflectivity with a central hyporeflectivity was observed at the level of mid-retina, likely because of shadowing effect. The OCT-A reveals a dense vascular network within the tumor. CONCLUSION: Retinal astrocytic hamartomas may be well characterized by non-invasive imaging using spectral-domain OCT, en face OCT, and OCT angiography. The OCT angiography seemed to show tumor vascularity, which may represent dilated disorganized and anastomotic superficial and deep plexus capillaries. The tumor is often unique, peripapillary, small in diameter, and dome-shaped on spectral-domain OCT protruding into the vitreous cavity, responsible for vitreous changes facing the lesion. PMID- 27508424 TI - QUIESCENT HERPES SIMPLEX KERATITIS REACTIVATION AFTER INTRAVITREAL INJECTION OF DEXAMETHASONE IMPLANT. AB - PURPOSE: To report reactivation of herpes simplex virus keratitis after the injection of dexamethasone implant (Ozurdex) and to raise the awareness of this potentially vision threatening side effect. METHODS: A 90-year-old man presented with ocular pain and tearing in the left eye 3 weeks after receiving a dexamethasone implant (Ozurdex) for the treatment of macular edema associated with branch retinal vein occlusion. The patient had a history of herpes simplex virus keratitis that was quiescent for more than 30 years. RESULTS: Clinical examination of the left eye showed arborizing epithelial ulcer with terminal bulbs consistent with herpes simplex virus keratitis. CONCLUSION: Quiescent herpes simplex virus keratitis can be reactivated after dexamethasone implant (Ozurdex). Prophylactic antiviral therapy might be indicated in individuals who have a high risk of recurrent herpetic disease. PMID- 27508425 TI - Insights into the Nature of the Chemical Bonding in Thiophene-2-thiol from X-ray Absorption Spectroscopy. AB - Thiophenes are the simplest aromatic sulfur-containing compounds; they are widespread in fossil fuels and a variety of natural products, and they have vital roles in determining characteristic aromas that are important in food chemistry. We used a combination of sulfur K-edge X-ray absorption spectroscopy and density functional theory to investigate the chemical bonding in the novel sulfur containing heterocycle thiophene-2-thiol. We show that solutions of thiophene-2 thiol contain significant quantities of the thione tautomer, which may be the energetically preferred 5H-thiophene-2-thione or the more accessible 3H-thiophene 2-thione. PMID- 27508426 TI - Learning Experiences of Nurses as Part of a European Union Project on Complementary Therapies: A Multinational Qualitative Study. AB - The objectives of this study were to investigate learning experiences of the nurses who participated in transnational and multinational occupational training. A qualitative descriptive methodology was used. Data are clustered into 3 categories "occupational training," "complementary care," and "intercultural interaction." This research has revealed many insights into the transnational training of nurses. PMID- 27508427 TI - Stabilization of membrane necks by adhesive particles, substrate surfaces, and constriction forces. AB - Membrane remodelling processes involving the formation and fission of small buds require the formation and closure of narrow membrane necks, both for biological membranes and for model membranes such as lipid bilayers. The conditions required for the stability of such necks are well understood in the context of budding of vesicles with bilayer asymmetry and/or intramembrane domains. In many cases, however, the necks form in the presence of an adhesive surface, such as a solid particle or substrate, or the cellular cortex itself. Examples of such processes in biological cells include endocytosis, exocytosis and phagocytosis of solid particles, the formation of extracellular and outer membrane vesicles by eukaryotic and prokaryotic cells, as well as the closure of the cleavage furrow in cytokinesis. Here, we study the interplay of curvature elasticity, membrane substrate adhesion, and constriction forces to obtain generalized stability conditions for closed necks which we validate by numerical energy minimization. We then explore the consequences of these stability conditions in several experimentally accessible systems such as particle-filled membrane tubes, supported lipid bilayers, giant plasma membrane vesicles, bacterial outer membrane vesicles, and contractile rings around necks. At the end, we introduce an intrinsic engulfment force that directly describes the interplay between curvature elasticity and membrane-substrate adhesion. PMID- 27508429 TI - Engineering platelets for tumour-targeting. PMID- 27508428 TI - Antibacterial ability and osteogenic activity of porous Sr/Ag-containing TiO2 coatings. AB - Implant-associated infection and poor osseointegration remains a major clinical challenge in Ti-based implant materials. A versatile strategy to endow Ti-based implants with long-term antibacterial ability as well as better osteogenic activity is highly desirable for high quality implantation. Strontium (Sr) has been shown to be a significant element to favor bone growth by promoting new bone formation and inhibiting bone resorption. In this study, a novel duplex-treatment technique encompassing magnetron sputtering with micro-arc oxidation is utilized to fabricate porous Sr/Ag-containing TiO2 coatings loaded with different concentrations of Ag and Sr. All coatings are porous with pore size less than 5 um. Ag is primarily distributed homogeneously inside the pores, and the concentrations of Ag in Sr/Ag-containing TiO2 coatings with low and high Ag contents are 0.40 at.% and 0.83 at.% respectively. We have demonstrated that this kind of coating displays long-lasting antibacterial ability even up to 28 d due to the incorporation of Ag. Further, Sr/Ag-containing TiO2 coatings with optimum Ag and Sr contents revealed good cytocompatibility, enhanced osteoblast spreading and osseointegration, which stemmed primarily from the synergistic effect exerted by the porous surface topography and the bioactive element Sr. However, this study has also identified, for the first time, that proper addition of Ag would further facilitate osteogenic effects. Besides, Sr may be able to alleviate the potential cytotoxic effect of excessive Ag. Thus, integration of optimum functional elements Ag and Sr into Ti-based implant materials would be expected to expedite osseointegration while simultaneously sustaining long-term antibacterial activity, which would provide new insights for relevant fundamental investigations and biomedical applications. PMID- 27508430 TI - A Case of Mutism in Noncatatonic Schizophrenia Responding to Small Dose of Fluvoxamine Addition to Clozapine. PMID- 27508431 TI - New Insights into How Cholesterol and Unsaturation Control Lipid Domain Formation. PMID- 27508432 TI - Quantitative Localization Microscopy Reveals a Novel Organization of a High-Copy Number Plasmid. AB - The maintenance of high-copy number plasmids within bacteria had been commonly thought to result from free diffusion and random segregation. Recent microscopy experiments, however, observed high-copy number plasmids clustering into discrete foci, which seemed to contradict this model, and hinted at an undiscovered active mechanism, as often found in low-copy number plasmids. We recently investigated the cellular organization of a ColE1-derivative plasmid in Escherichia coli bacteria using quantitative superresolved microscopy based on single-molecule localization in combination with single-molecule fluorescence in situ hybridization (smFISH). We observed that many of the plasmids aggregated into large clusters, although most of the plasmids were randomly distributed throughout the bacteria, minus an excluded volume about the chromosomal DNA. Our results indicate that neither of the previous models completely encompasses the behavior of high-copy number plasmids. We also found many plasmids within the chromosomal volume, providing further evidence that the nucleoid does not fully exclude DNA and RNA. PMID- 27508433 TI - Structure of an Intrinsically Disordered Stress Protein Alone and Bound to a Membrane Surface. AB - Dehydrins are a group of intrinsically disordered proteins that protect plants from damage caused by drought, cold, and high salinity. Like other intrinsically disordered proteins, dehydrins can gain structure when bound to a ligand. Previous studies have shown that dehydrins are able to protect liposomes from cold damage, but the interactions that drive membrane binding and the detailed structure of the bound and unbound forms are not known. We use an ensemble structure approach to generate models of a dehydrin known as K2 in the presence and absence of sodium dodecyl sulfate micelles, and we docked the bound structure to the micelle. The collection of residual dipolar coupling data, amide protection factors, and paramagnetic relaxation enhancement distances, in combination with chemical shifts and relaxation measurements, allows for determining plausible structures that are not otherwise visible in time-averaged structural data. The results show that in the bound structure, the conserved lysines are important for membrane binding, whereas the flanking hydrophobic residues play a lesser role. The unbound structure shows a high level of disorder and an extended structure. We propose that the structural differences between bound and unbound forms allow dehydrins to act as molecular shields in their unbound state and as membrane protectants in their bound state. Unlike alpha synuclein, the significant gain of alpha-helicity in K2 at low concentrations of sodium dodecyl sulfate is not due to a decrease in the critical micelle concentration. The study provides structural insight into how a disordered protein can interact with a membrane surface. PMID- 27508434 TI - RETRACTED: Protonation State-Dependent Communication in Cytochrome c Oxidase. AB - Proton transfer in cytochrome c oxidase from the cellular inside to the binuclear redox center (BNC) can occur through two distinct pathways, the D- and K channels. For the protein to function as both redox enzyme and proton pump, proton transfer out of either of the channels toward the BNC or into the protein toward a proton loading site, and ultimately through the membrane, must be highly regulated. The O->E intermediate of cytochrome c oxidase is the first redox state in its catalytic cycle, where proton transfer through the K-channel, from K362 to Y288 at the BNC, is important. Molecular dynamics simulations of this intermediate with 16 different combinations of protonation states of key residues in the D- and K-channel show the mutual impact of the two proton-conducting channels to be protonation state-dependent. Strength as well as means of communication, correlations in positions, or connections along the hydrogen bonded network, change with the protonation state of the K-channel residue K362. The conformational and hydrogen-bond dynamics of the D-channel residue N139 regulated by an interplay of protonation in the D-channel and K362. N139 thus assumes a gating function by which proton passage through the D-channel toward E286 is likely facilitated for states with protonated K362 and unprotonated E286, which would in principle allow proton transfer to the BNC, but no proton pumping until a proton has reached E286. PMID- 27508435 TI - Effects of Temperature on Heteromeric Kv11.1a/1b and Kv11.3 Channels. AB - Kv11.1 channels are crucial in cardiac physiology, and there is increasing evidence of physiological roles of different Kv11 channels outside the heart. The HERG (human Kv11.1a) channel has previously been shown to carry substantially more current at elevated temperatures, and we have now comparably investigated the temperature dependence of neuronal Kv11.3 channels and the more ubiquitous heteromeric Kv11.1a/1b channels. Transiently expressed rat Kv11 channels were studied at 21 degrees C, 30 degrees C, and 35 degrees C. At near-physiological temperature, the maximal sustained outward current density was almost three times the mean value obtained at room temperature for Kv11.1a/1b, and increased by ~150% for Kv11.3. For both channels, reduced inactivation contributed to the current increase at higher temperature. Elevated temperature moved Kv11.1a/1b isochronal activation curves to more negative potentials, but shifted the potential of half-maximal Kv11.3 channel activation to more depolarized values and reduced its voltage sensitivity. Thus, increased temperature stabilized the open state over the closed state of Kv11.1a/1b channels and exerted the opposite effect on Kv11.3 channel activation. Both Kv11 channels exhibited an overall high temperature sensitivity of most gating parameters, with remarkably high Q10 factors of ~5 for the rate of Kv11.1a/1b activation. The Q10 factors for Kv11.3 gating were more uniform, but still higher for activation than for inactivation kinetics. The results demonstrate that characteristic differences between Kv11.1a/1b and Kv11.3 determined at room temperature do not necessarily apply to physiological conditions. The data provided here can aid in the design of models that will enhance our understanding of the role of Kv11 currents in excitable cells. PMID- 27508436 TI - Human Pulmonary Surfactant Protein SP-A1 Provides Maximal Efficiency of Lung Interfacial Films. AB - Pulmonary surfactant is a lipoprotein complex that reduces surface tension to prevent alveolar collapse and contributes to the protection of the respiratory surface from the entry of pathogens. Surfactant protein A (SP-A) is a hydrophilic glycoprotein of the collectin family, and its main function is related to host defense. However, previous studies have shown that SP-A also aids in the formation and biophysical properties of pulmonary surfactant films at the air water interface. Humans, unlike rodents, have two genes, SFTPA1 and SFTPA2. The encoded proteins, SP-A1 and SP-A2, differ quantitatively or qualitatively in function. It has been shown that both gene products are necessary for tubular myelin formation, an extracellular structural form of lung surfactant. The goal of this study was to investigate potential differences in the biophysical properties of surfactants containing human SP-A1, SP-A2, or both. For this purpose, we have studied for the first time, to our knowledge, the biophysical properties of pulmonary surfactant from individual humanized transgenic mice expressing human SP-A1, SP-A2, or both SP-A1 and SP-A2, in the captive bubble surfactometer. We observed that pulmonary surfactant containing SP-A1 reaches lower surface tension after postexpansion interfacial adsorption than surfactants containing no SP-A or only SP-A2. Under interfacial compression-expansion cycling conditions, surfactant films containing SP-A1 also performed better, particularly with respect to the reorganization of the films that takes place during compression. On the other hand, addition of recombinant SP-A1 to a surfactant preparation reconstituted from the hydrophobic fraction of a porcine surfactant made it more resistant to inhibition by serum than the addition of equivalent amounts of SP-A2. We conclude that the presence of SP-A1 allows pulmonary surfactant to adopt a particularly favorable structure with optimal biophysical properties. PMID- 27508437 TI - Conditions that Stabilize Membrane Domains Also Antagonize n-Alcohol Anesthesia. AB - Diverse molecules induce general anesthesia with potency strongly correlated with both their hydrophobicity and their effects on certain ion channels. We recently observed that several n-alcohol anesthetics inhibit heterogeneity in plasma membrane-derived vesicles by lowering the critical temperature (Tc) for phase separation. Here, we exploit conditions that stabilize membrane heterogeneity to further test the correlation between the anesthetic potency of n-alcohols and effects on Tc. First, we show that hexadecanol acts oppositely to n-alcohol anesthetics on membrane mixing and antagonizes ethanol-induced anesthesia in a tadpole behavioral assay. Second, we show that two previously described "intoxication reversers" raise Tc and counter ethanol's effects in vesicles, mimicking the findings of previous electrophysiological and behavioral measurements. Third, we find that elevated hydrostatic pressure, long known to reverse anesthesia, also raises Tc in vesicles with a magnitude that counters the effect of butanol at relevant concentrations and pressures. Taken together, these results demonstrate that DeltaTc predicts anesthetic potency for n-alcohols better than hydrophobicity in a range of contexts, supporting a mechanistic role for membrane heterogeneity in general anesthesia. PMID- 27508438 TI - The Affinity of Cholesterol for Different Phospholipids Affects Lateral Segregation in Bilayers. AB - Saturated and unsaturated phospholipids (PLs) can segregate into lateral domains. The preference of cholesterol for saturated acyl chains over monounsaturated, and especially polyunsaturated ones, may also affect lateral segregation. Here we have studied how cholesterol influenced the lateral segregation of saturated and unsaturated PLs, for which cholesterol had a varying degree of affinity. The fluorescence lifetime of trans-parinaric acid reported the formation of ordered domains (gel or liquid-ordered (lo)) in bilayers composed of different unsaturated phosphatidylcholines, and dipalmitoyl-phosphatidylcholine or n palmitoyl-sphingomyelin, in the presence or absence of cholesterol. We observed that cholesterol facilitated lateral segregations and the degree of facilitation correlated with the relative affinity of cholesterol for the different PLs in the bilayers. Differential scanning calorimetry and (2)H nuclear magnetic resonance showed that cholesterol increased the thermostability of both the gel and lo domains. Increased number of double bonds in the unsaturated PL increased the order in the lo-domains, likely by enriching the ordered domains in saturated lipids and cholesterol. This supported the conclusions from the trans-parinaric acid experiments, and offers insight into how cholesterol facilitated lateral segregation. In conclusion, the relative affinity of cholesterol for different PLs appears to be an important determinant for the formation of ordered domains. Our data suggests that knowledge of the affinity of cholesterol for the different PLs in a bilayer allows prediction of the degree to which the sterol promotes lo domain formation. PMID- 27508439 TI - The Limiting Speed of the Bacterial Flagellar Motor. AB - Recent experiments on the bacterial flagellar motor have shown that the structure of this nanomachine, which drives locomotion in a wide range of bacterial species, is more dynamic than previously believed. Specifically, the number of active torque-generating complexes (stators) was shown to vary across applied loads. This finding brings under scrutiny the experimental evidence reporting that limiting (zero-torque) speed is independent of the number of active stators. In this study, we propose that, contrary to previous assumptions, the maximum speed of the motor increases as additional stators are recruited. This result arises from our assumption that stators disengage from the motor for a significant portion of their mechanochemical cycles at low loads. We show that this assumption is consistent with current experimental evidence in chimeric motors, as well as with the requirement that a processive motor driving a large load via an elastic linkage must have a high duty ratio. PMID- 27508441 TI - The Effect of Hematocrit on Platelet Adhesion: Experiments and Simulations. AB - The volume fraction of red blood cells (RBCs) in a capillary affects the degree to which platelets are promoted to marginate to near a vessel wall and form blood clots. In this work we investigate the relationship between RBC hematocrit and platelet adhesion activity. We perform experiments flowing blood samples through a microfluidic channel coated with type 1 collagen and observe the rate at which platelets adhere to the wall. We compare these results with three-dimensional boundary integral simulations of a suspension of RBCs and platelets in a periodic channel where platelets can adhere to the wall. In both cases, we find that the rate of platelet adhesion varies greatly with the RBC hematocrit. We observe that the relative decrease in platelet activity as hematocrit falls shows a similar profile for simulation and experiment. PMID- 27508440 TI - Association of Endophilin B1 with Cytoplasmic Vesicles. AB - Endophilins are SH3- and BAR domain-containing proteins implicated in membrane remodeling and vesicle formation. Endophilins A1 and A2 promote the budding of endocytic vesicles from the plasma membrane, whereas endophilin B1 has been implicated in vesicle budding from intracellular organelles, including the trans Golgi network and late endosomes. We previously reported that endophilins A1 and A2 exist almost exclusively as soluble dimers in the cytosol. Here, we present results of fluorescence fluctuation spectroscopy analyses indicating that, in contrast, the majority of endophilin B1 is present in multiple copies on small, highly mobile cytoplasmic vesicles. Formation of these vesicles was enhanced by overexpression of wild-type dynamin 2, but suppressed by expression of a catalytically inactive dynamin 2 mutant. Using dual-color heterospecies partition analysis, we identified the epidermal growth factor receptor on endophilin B1 vesicles. Moreover, a proportion of endophilin B1 vesicles also contained caveolin, whereas clathrin was almost undetectable on those vesicles. These results raise the possibility that endophilin B1 participates in dynamin 2 dependent formation of a population of transport vesicles distinct from those generated by A-type endophilins. PMID- 27508442 TI - Rheology of the Active Cell Cortex in Mitosis. AB - The cell cortex is a key structure for the regulation of cell shape and tissue organization. To reach a better understanding of the mechanics and dynamics of the cortex, we study here HeLa cells in mitosis as a simple model system. In our assay, single rounded cells are dynamically compressed between two parallel plates. Our measurements indicate that the cortical layer is the dominant mechanical element in mitosis as opposed to the cytoplasmic interior. To characterize the time-dependent rheological response, we extract a complex elastic modulus that characterizes the resistance of the cortex against area dilation. In this way, we present a rheological characterization of the cortical actomyosin network in the linear regime. Furthermore, we investigate the influence of actin cross linkers and the impact of active prestress on rheological behavior. Notably, we find that cell mechanics values in mitosis are captured by a simple rheological model characterized by a single timescale on the order of 10 s, which marks the onset of fluidity in the system. PMID- 27508443 TI - Glycoprotein Ib-IX-V Complex Transmits Cytoskeletal Forces That Enhance Platelet Adhesion. AB - Platelets bind to exposed vascular matrix at a wound site through a highly specialized surface receptor, glycoprotein (GP) Ib-IX-V complex, which recognizes von Willebrand factor (VWF) in the matrix. GPIb-IX-V is a catch bond for it becomes more stable as force is applied to it. After attaching to the wound site, platelets generate cytoskeletal forces to compact and reinforce the hemostatic plug. Here, we evaluated the role of the GPIb-IX-V complex in the transmission of cytoskeletal forces. We used arrays of flexible, silicone nanoposts to measure the contractility of individual platelets on VWF. We found that a significant proportion of cytoskeletal forces were transmitted to VWF through GPIb-IX-V, an unexpected finding given the widely held notion that platelet forces are transmitted exclusively through its integrins. In particular, we found that the interaction between GPIbalpha and the A1 domain of VWF mediates this force transmission. We also demonstrate that the binding interaction between GPIbalpha and filamin A is involved in force transmission. Furthermore, our studies suggest that cytoskeletal forces acting through GPIbalpha are involved in maintaining platelet adhesion when external forces are absent. Thus, the GPIb-IX-V/VWF bond is able to transmit force, and uses this force to strengthen the bond through a catch-bond mechanism. This finding expands our understanding of how platelets attach to sites of vascular injury, describing a new, to the best of our knowledge, mechanism in which the catch bonds of GPIb-IX-V/VWF can be supported by internal forces produced by cytoskeletal tension. PMID- 27508444 TI - Dopamine Receptor Signaling in MIN6 beta-Cells Revealed by Fluorescence Fluctuation Spectroscopy. AB - Insulin secretion defects are central to the development of type II diabetes mellitus. Glucose stimulation of insulin secretion has been extensively studied, but its regulation by other stimuli such as incretins and neurotransmitters is not as well understood. We investigated the mechanisms underlying the inhibition of insulin secretion by dopamine, which is synthesized in pancreatic beta-cells from circulating L-dopa. Previous research has shown that this inhibition is mediated primarily by activation of the dopamine receptor D3 subtype (DRD3), even though both DRD2 and DRD3 are expressed in beta-cells. To understand this dichotomy, we investigated the dynamic interactions between the dopamine receptor subtypes and their G-proteins using two-color fluorescence fluctuation spectroscopy (FFS) of mouse MIN6 beta-cells. We show that proper membrane localization of exogenous G-proteins depends on both the Gbeta and Ggamma subunits being overexpressed in the cell. Triple transfections of the dopamine receptor subtype and Gbeta and Ggamma subunits, each labeled with a different colored fluorescent protein (FP), yielded plasma membrane expression of all three FPs and permitted an FFS evaluation of interactions between the dopamine receptors and the Gbetagamma complex. Upon dopamine stimulation, we measured a significant decrease in interactions between DRD3 and the Gbetagamma complex, which is consistent with receptor activation. In contrast, dopamine stimulation did not cause significant changes in the interactions between DRD2 and the Gbetagamma complex. These results demonstrate that two-color FFS is a powerful tool for measuring dynamic protein interactions in living cells, and show that preferential DRD3 signaling in beta-cells occurs at the level of G-protein release. PMID- 27508445 TI - Phasor Analysis of Local ICS Detects Heterogeneity in Size and Number of Intracellular Vesicles. AB - Organelles represent the scale of organization immediately below that of the cell itself, and their composition, size, and number are tailored to their function. Monitoring the size and number of organelles in live cells is relevant for many applications but can be challenging due to their highly heterogeneous properties. Image correlation spectroscopy is a well-established analysis method capable of extracting the average size and number of particles in images. However, when image correlation spectroscopy is applied to a highly heterogeneous system, it can fail to retrieve, from a single correlation function, the characteristic size and the relative amount associated to each subspecies. Here, we describe a fast, unbiased, and fit-free algorithm based on the phasor analysis of multiple local image correlation functions, capable of mapping the sizes of elements contained in a heterogeneous system. The method correctly provides the size and number of separate subspecies, which otherwise would be hidden in the average properties of a single correlation function. We apply the method to quantify the spatial and temporal heterogeneity in the size and number of intracellular vesicles formed after endocytosis in live cells. PMID- 27508446 TI - Visualizing Flagella while Tracking Bacteria. AB - A complete description of the swimming behavior of a bacterium requires measurement of the displacement and orientation of the cell body together with a description of the movement of the flagella. We rebuilt a tracking microscope so that we could visualize flagellar filaments of tracked cells by fluorescence. We studied Escherichia coli (cells of various lengths, including swarm cells), Bacillus subtilis (wild-type and a mutant with fewer flagella), and a motile Streptococcus (now Enterococcus). The run-and-tumble statistics were nearly the same regardless of cell shape, length, and flagellation; however, swarm cells rarely tumbled, and cells of Enterococcus tended to swim in loops when moving slowly. There were events in which filaments underwent polymorphic transformations but remained in bundles, leading to small deflections in direction of travel. Tumble speeds were ~2/3 as large as run speeds, and the rates of change of swimming direction while running or tumbling were smaller when cells swam more rapidly. If a smaller fraction of filaments were involved in tumbles, the tumble intervals were shorter and the angles between runs were smaller. PMID- 27508447 TI - Collective Chemotaxis through Noisy Multicellular Gradient Sensing. AB - Collective cell migration in response to a chemical cue occurs in many biological processes such as morphogenesis and cancer metastasis. Clusters of migratory cells in these systems are capable of responding to gradients of <1% difference in chemical concentration across a cell length. Multicellular systems are extremely sensitive to their environment, and although the limits to multicellular sensing are becoming known, how this information leads to coherent migration remains poorly understood. We develop a computational model of multicellular sensing and migration in which groups of cells collectively measure noisy chemical gradients. The output of the sensing process is coupled to the polarization of individual cells to model migratory behavior. Through the use of numerical simulations, we find that larger clusters of cells detect the gradient direction with higher precision and thus achieve stronger polarization bias, but larger clusters also induce more drag on collective motion. The trade-off between these two effects leads to an optimal cluster size for most efficient migration. We discuss how our model could be validated using simple, phenomenological experiments. PMID- 27508448 TI - Mechanical Regulation of Three-Dimensional Epithelial Fold Pattern Formation in the Mouse Oviduct. AB - Epithelia exhibit various three-dimensional morphologies linked to organ function in animals. However, the mechanisms of three-dimensional morphogenesis remain elusive. The luminal epithelium of the mouse oviduct forms well-aligned straight folds along the longitudinal direction of the tubes. Disruption of the Celsr1 gene, a planar cell polarity-related gene, causes ectopically branched folds. Here, we evaluated the mechanical contributions of the epithelium to the fold pattern formation. In the mutant oviduct, the epithelium was more intricate along the longitudinal direction than in the wild-type, suggesting a higher ratio of the longitudinal length of the epithelial layer to that of the surrounding smooth muscle (SM) layer (L-Epi/SM ratio). Our mathematical modeling and computational simulations suggested that the L-Epi/SM ratio could explain the differences in fold branching between the two genotypes. Longitudinal epithelial tensions were increased in well-aligned folds compared with those in disorganized folds both in the simulations and in experimental estimations. Artificially increasing the epithelial tensions suppressed the branching in simulations, suggesting that the epithelial tensions can regulate fold patterning. The epithelial tensions could be explained by the combination of line tensions along the epithelial cell-cell boundaries with the polarized cell arrays observed in vivo. These results suggest that the fold pattern is associated with the polarized cell array through the longitudinal epithelial tension. Further simulations indicated that the L-Epi/SM ratio could contribute to fold pattern diversity, suggesting that the L-Epi/SM ratio is a critical parameter in the fold patterning in tubular organs. PMID- 27508449 TI - Durotaxis in Nematode Caenorhabditis elegans. AB - Durotaxis is a process where cells are able to sense the stiffness of substrates and preferentially migrate toward stiffer regions. Here, we show that the 1-mm long nematode, Caenorhabditis elegans are also able to detect the rigidity of underlying substrates and always migrate to regions of higher stiffness. Our results indicate that C. elegans are able to judiciously make a decision to stay on stiffer regions. We found that the, undulation frequency, and wavelength of worms, crawling on surfaces show nonmonotonic behavior with increasing stiffness. A number of control experiments were also conducted to verify whether C. elegans are really able to detect the rigidity of substrates or whether the migration to stiffer regions is due to other factors already reported in the literature. As it is known that bacteria and other single-celled organisms exhibit durotaxis toward stiffer surfaces, we conjecture that durotaxis in C. elegans may be one of the strategies developed to improve their chances of locating food. PMID- 27508450 TI - Phenotypic Diversity Using Bimodal and Unimodal Expression of Stress Response Proteins. PMID- 27508451 TI - Peer Review and bioRxiv. PMID- 27508453 TI - Retraction Notice. AB - [This retracts the article on p. 9 in vol. 6, PMID: 24876696.]. PMID- 27508452 TI - Ultrafine Nb2O5 Nanocrystal Coating on Reduced Graphene Oxide as Anode Material for High Performance Sodium Ion Battery. AB - Ultrafine niobium oxide nanocrystals/reduced graphene oxide (Nb2O5 NCs/rGO) was demonstrated as a promising anode material for sodium ion battery with high rate performance and high cycle durability. Nb2O5 NCs/rGO was synthesized by controllable hydrolysis of niobium ethoxide and followed by heat treatment at 450 degrees C in flowing forming gas. Transmission electron microscopy images showed that Nb2O5 NCs with average particle size of 3 nm were uniformly deposited on rGO sheets and voids among Nb2O5 NCs existed. The architecture of ultrafine Nb2O5 NCs anchored on a highly conductive rGO network can not only enhance charge transfer and buffer the volume change during sodiation/desodiation process but also provide more active surface area for sodium ion storage, resulting in superior rate and cycle performance. Ex situ XPS analysis revealed that the sodium ion storage mechanism in Nb2O5 could be accompanied by Nb(5+)/Nb(4+) redox reaction and the ultrafine Nb2O5 NCs provide more surface area to accomplish the redox reaction. PMID- 27508454 TI - American Telemedicine Association Guidelines for TeleICU Operations. PMID- 27508456 TI - Errata: Hypertension and Diabetic Nephropathy. PMID- 27508455 TI - Identification of Genes Involved in Breast Cancer Metastasis by Integrating Protein-Protein Interaction Information with Expression Data. AB - The selection of relevant genes for breast cancer metastasis is critical for the treatment and prognosis of cancer patients. Although much effort has been devoted to the gene selection procedures by use of different statistical analysis methods or computational techniques, the interpretation of the variables in the resulting survival models has been limited so far. This article proposes a new Random Forest (RF)-based algorithm to identify important variables highly related with breast cancer metastasis, which is based on the important scores of two variable selection algorithms, including the mean decrease Gini (MDG) criteria of Random Forest and the GeneRank algorithm with protein-protein interaction (PPI) information. The new gene selection algorithm can be called PPIRF. The improved prediction accuracy fully illustrated the reliability and high interpretability of gene list selected by the PPIRF approach. PMID- 27508457 TI - Bisphenol S Interacts with Catalase and Induces Oxidative Stress in Mouse Liver and Renal Cells. AB - Bisphenol S (BPS) is present in multitudinous consumer products and detected in both food and water. It also has been a main substitute for bisphenol A (BPA) in the food-packaging industry. Yet, the toxicity of BPS is not fully understood. The present study of the toxicity of BPS was divided into two parts. First, oxidative stress, cell viability, apoptosis level, and catalase (CAT) activity in mouse hepatocytes and renal cells were investigated after BPS exposure. After 12 h of incubation with BPS, all of these parameters of hepatocytes and renal cells changed by >15% as the concentration of BPS ranged from 0.1 to 1 mM. Second, the direct interaction between BPS and CAT on the molecule level was investigated by multiple spectral methods and molecular docking investigations. BPS changed the structure and the activity of CAT through binding to the Gly 117 residue on the substrate channel of the enzyme. The main binding forces were hydrogen bond and hydrophobic force. PMID- 27508458 TI - Pressure Profile Calculation with Mesh Ewald Methods. AB - The importance of calculating pressure profiles across liquid interfaces is increasingly gaining recognition, and efficient methods for the calculation of long-range contributions are fundamental in addressing systems with a large number of charges. Here, we show how to compute the local pressure contribution for mesh-based Ewald methods, retaining the typical N log N scaling as a function of the lattice nodes N. This is a considerable improvement on existing methods, which include approximating the electrostatic contribution using a large cutoff and the, much slower, Ewald calculation. As an application, we calculate the contribution to the pressure profile across the water/vapor interface, coming from different molecular layers, both including and removing the effect of thermal capillary waves. We compare the total pressure profile with the one obtained using the cutoff approximation for the calculation of the stresses, showing that the stress distributions obtained using the Harasima and Irving Kirkwood path are quite similar and shifted with respect to each other at most 0.05 nm. PMID- 27508461 TI - Statistical Analysis of the Effectiveness of Seawalls and Coastal Forests in Mitigating Tsunami Impacts in Iwate and Miyagi Prefectures. AB - The Pacific coast of the Tohoku region of Japan experiences repeated tsunamis, with the most recent events having occurred in 1896, 1933, 1960, and 2011. These events have caused large loss of life and damage throughout the coastal region. There is uncertainty about the degree to which seawalls reduce deaths and building damage during tsunamis in Japan. On the one hand they provide physical protection against tsunamis as long as they are not overtopped and do not fail. On the other hand, the presence of a seawall may induce a false sense of security, encouraging additional development behind the seawall and reducing evacuation rates during an event. We analyze municipality-level and sub municipality-level data on the impacts of the 1896, 1933, 1960, and 2011 tsunamis, finding that seawalls larger than 5 m in height generally have served a protective role in these past events, reducing both death rates and the damage rates of residential buildings. However, seawalls smaller than 5 m in height appear to have encouraged development in vulnerable areas and exacerbated damage. We also find that the extent of flooding is a critical factor in estimating both death rates and building damage rates, suggesting that additional measures, such as multiple lines of defense and elevating topography, may have significant benefits in reducing the impacts of tsunamis. Moreover, the area of coastal forests was found to be inversely related to death and destruction rates, indicating that forests either mitigated the impacts of these tsunamis, or displaced development that would otherwise have been damaged. PMID- 27508459 TI - Binding Site Recognition and Docking Dynamics of a Single Electron Transport Protein: Cytochrome c2. AB - Small diffusible redox proteins facilitate electron transfer in respiration and photosynthesis by alternately binding to their redox partners and integral membrane proteins and exchanging electrons. Diffusive search, recognition, binding, and unbinding of these proteins often amount to kinetic bottlenecks in cellular energy conversion, but despite the availability of structures and intense study, the physical mechanisms controlling redox partner interactions remain largely unknown. The present molecular dynamics study provides an all-atom description of the cytochrome c2-docked bc1 complex in Rhodobacter sphaeroides in terms of an ensemble of favorable docking conformations and reveals an intricate series of conformational changes that allow cytochrome c2 to recognize the bc1 complex and bind or unbind in a redox state-dependent manner. In particular, the role of electron transfer in triggering a molecular switch and in altering water mediated interface mobility, thereby strengthening and weakening complex formation, is described. The results resolve long-standing discrepancies between structural and functional data. PMID- 27508462 TI - Comparison of experimental and theoretical quantum-state-selected integral cross sections for the H2O(+) + H2 (D2) reactions in the collision energy range of 0.04 10.00 eV. AB - To understand the dynamics of H3O(+) formation, we report a combined experimental theoretical study of the rovibrationally state-selected ion-molecule reactions H2O(+)(X(2)B1; v1(+)v2(+)v3(+); NKa(+)Kc(+)(+)) + H2 (D2) -> H3O(+) (H2DO(+)) + H (D), where (v1(+)v2(+)v3(+)) = (000), (020), and (100) and NKa(+)Kc(+)(+) = 000, 111, and 211. Both quantum dynamics and quasi-classical trajectory calculations were carried out on an accurate full-dimensional ab initio global potential energy surface, which involves nine degrees of freedom. The theoretical results are in good agreement with experimental measurements of the initial state specific integral cross-sections for the formation of H3O(+) (H2DO(+)) and thus provide valuable insights into the surprising rotational enhancement and vibrational inhibition effects in these prototypical ion-molecule reactions that play a key role in the interstellar generation of OH and H2O species. PMID- 27508463 TI - A Global Synthesis of Jatropha Cultivation: Insights into Land Use Change and Management Practices. AB - Despite setbacks, interest in Jatropha cultivation remains high. This study addressed the question to what extent Jatropha cultivation has replaced specific vegetation and land use types and how the existing areas are managed. Major forms of land use change and management practices were identified based on cluster analysis of data from 106 interviewee's responses to a comprehensive global survey. Of the 1.04 * 10(6) ha cultivated with Jatropha in 2011 40% were established on land that was cleared of vegetation as a result of logging activities unrelated to Jatropha cultivation, 34% was defined as unused, and the remainder was attributable to areas previously used for crops or animal husbandry. With the exception of croplands, these areas were dominated (90-98%) by a few internationally active companies whose cultivation models were almost exclusively based on outgrower schemes. Management practices were largely extensive in nature (low mechanical input and infrequent use of fertilizers, pesticides and herbicides), and also dominated by large projects. Broad surveys, such as this, are useful in identifying general trends in this emerging global industry, but detailed case studies, particularly of large projects, are needed in order to draw more informed conclusions about the site-specific impacts of Jatropha cultivation. PMID- 27508464 TI - Discoveries of Biological Sciences and their implications for nursing practice. PMID- 27508465 TI - Social representations of citizenship by inpatients: implications for hospital care. AB - OBJECTIVE: examine the social representations of citizenship by inpatients receiving hospital care. METHOD: qualitative approach, using the Theory of Social Representations as a framework, with 31 inpatients in the internal medicine sector of a public university hospital. Semi-structured interviews were conducted, whose data were submitted to the Alceste program, with application of lexical analysis. RESULTS: patients understand their rights, and citizenship in the care process is understood based on the right to health, to receive good care from a technical and human standpoint. CONCLUSION: being well treated as a person and the provision of technical-procedural care are rights of patients; the absence of one or the other implies, therefore, lack of respect for their citizenship. PMID- 27508466 TI - Health practices: the view of the black elderly population in a terreiro community. AB - OBJECTIVE: to understand health practices of black, elderly people in a terreiro community (community of followers of traditional African-Brazilian religions). METHOD: qualitative descriptive study under the Black-African paradigm of civilization constituted by the Black-African cultural complex and the structuring elements of the African cosmovision. Semi-structured interviews were carried out from July to September 2013, with six black older people from a terreiro community in Porto Alegre, RS. RESULTS: thematic content analysis resulted in the following categories: Ancestry; Belonging: the way to know and practice health; Health knowledge and practices in terreiro communities; and Complementarity: promoting health in the terreiro and traditional medicine and its respective subcategories. CONCLUSION: the study understood the importance of having a knowledge of the practices of African traditions in both the lifestyle and health of the older black population to help with nursing planning and interventions in response to their needs. PMID- 27508467 TI - Cost of dressings for prevention of sacral pressure ulcers. AB - OBJECTIVE: to identify costs of dressings to prevent sacral pressure ulcers in an adult intensive care unit in Parana, Brazil. METHODS: secondary analysis study with 25 patients admitted between October 2013 and March 2014, using transparent polyurethane film (n=15) or hydrocolloid dressing (n=10) on the sacral region. The cost of each intervention was based on the unit amount used in each type of dressing, and its purchase price (transparent film = R$15.80, hydrocolloid dressing = R$68.00). RESULTS: the mean cost/patient was R$23.17 for use of transparent film and R$190.40 for use of hydrocolloid dressing. The main reason for changing the dressing was detachment. CONCLUSION: the transparent film was the most economically advantageous alternative to prevent sacral pressure ulcers in critical care patients. However, additional studies should be carried out including assessment of the effectiveness of both dressings. PMID- 27508468 TI - Nursing care through the perception of hospitalized children. AB - OBJECTIVE: to describe the perception of hospitalized children of school age, on nursing care and understand what are, from their perspective, the best ways to address it to when performing such care. METHOD: qualitative, descriptive, exploratory research, with concepts of Vygotsky used as theoretical framework. The data collection occurred through interviews mediated by drawings and was performed with ten school children, with the interview later transcribed and submitted to a thematic analysis. RESULTS: showed the importance of playing during hospitalization, of a friendly and caring approach and providing explanations regarding the performed procedures. CONCLUSION: nursing professionals need to consider how the children would like to receive the care being provided, so that their singularities are respected, characterizing nursing actions according to a perspective of the whole human being. PMID- 27508469 TI - Dialogue: network that intertwines the pedagogical relationship into the practical-reflective teaching. AB - OBJECTIVE: to understand how dialogue occurs in the pedagogical relation in the practical reflective teaching in an undergraduate program in nursing. METHOD: qualitative research, case study. Data collection was conducted from May 2013 to September 2014 with eight professors of Nursing, by means of observation and interviews. Data analysis followed the operational proposal constituted by the exploratory stage and the interpretive stage. RESULTS: point the dialogue established within the pedagogical relation as a challenge to be faced in practical-reflective teaching, so professor and student build a relationship that foster thought and action in the theoretical context and in the field of practice. CONCLUSION: in establishing a dialogic-reflective tone in the pedagogical relationship, the professor opens paths to new discoveries, enabling the creation of teaching-learning spaces that stimulate autonomy, abilities, and critical and reflective attitudes of students along their education. PMID- 27508470 TI - Experiences with severe maternal morbidity: a qualitative study on the perception of women. AB - OBJECTIVE: to know and analyze the experiences of women who developed an episode of Severe Maternal Morbidity. METHOD: this is a qualitative study, in which we interviewed 16 women admitted to a tertiary level hospital, as a result of this morbid state. We used content analysis in data processing. RESULTS: two categories were identified: "Understanding maternal morbidity as a negative presence" and "Moving ahead: on constant alert". The interviewees mentioned negative aspects, such as treatment difficulties and hospitalization, feelings of fear, concern for the fetus, frustration with the idealized pregnancy, trauma; and positive aspects, such as learning and the expression of the divine will in the experience of illness. CONCLUSION: effective care during the prenatal period, delivery and postpartum period should provide adequate support for the prevention and assistance in Severe Maternal Morbidity. PMID- 27508471 TI - Analysis of obstetric care provided by the Mobile Emergency Care Service. AB - OBJECTIVE: analyze the pertinence of calls made by obstetric users of the Mobile Emergency Care Service (SAMU 192) of Botucatu-SP. METHOD: retrospective and analytical research. All records of prehospital obstetric care delivered by the SAMU 192 in 2012 were analyzed. To be considered responsive, calls should lead to referral to a reference obstetric hospital or be classified with the colors red, orange and yellow, according to risk criteria defined by the Ministry of Health. RESULTS: considering the two outcomes evaluated: referral to a reference hospital and risk criteria defined by the Ministry of Health, 6.7% and 75.6% of the calls were not pertinent, respectively. There was no matching between outcomes, neither variation between primiparas and multiparas as regards the call pertinence. CONCLUSION: this study ratifies the need for implementing a risk classification protocol in obstetrics, and support managers in the organization, qualification and effective implementation of the Rede Cegonha. PMID- 27508472 TI - Nurses' managerial knowledge in the hospital setting. AB - OBJECTIVE: to analyze nurses' managerial skills in the hospital setting, their perception of their own education and the relevance of training for their professional practice. METHOD: qualitative study based on the dialectical hermeneutics framework. Thirty-two nurses from three hospitals in the Brazilian state of Minas Gerais contributed to the study by taking part in six focus groups. Records were transcribed and three categories emerged from content analysis. RESULTS: results evidenced the following managerial skills: supervision, leadership, decision making, planning and organization, as well as the relevance of education centers for their improvement and the continuing development of the nurses' managerial skills. CONCLUSION: the authors believe this investigation will contribute for the improvement of nurses' necessary managerial skills and also to identify gaps in this area of their education. PMID- 27508473 TI - Analysis of managerial and healthcare indicators after nursing personnel upsizing. AB - OBJECTIVE: analyze healthcare and managerial indicators after nursing personnel upsizing. METHOD: a retrospective, descriptive study was conducted using data from computer systems of a university hospital in southern Brazil. Healthcare and managerial indicators related to the first half of 2013 and 2014 were statistically analyzed. RESULTS: increases of 40.0% in the number of nurses and 16.0% in the number of nursing technicians led to reductions of 12.0% in the number of sickness absences, 21.8% in positive balance for compensatory time off, 92.0% in paid overtime. Reductions of 75.0% in pressure ulcer rates, 10.5% in the number of falls and 50.0% in infections due to indwelling catheter use were also observed. CONCLUSION: nursing staff upsizing caused a positive impact on managerial and healthcare indicators and helped qualify care and improve work conditions for the nursing team. PMID- 27508474 TI - Association of frailty in hospitalized and institutionalized elderly in the community-dwelling. AB - OBJECTIVE: to investigate the association between frailty with hospitalization and institutionalization in a follow-up study of elderly residents. METHOD: the follow-up study was performed in 2008 and 2013 with elderly of both genders, aged 65 years and older who were living in the community-dwelling. The sampling procedure performed was probabilistic, with dual-stage clustering. In 2008, 515 elderly people were interviewed and, in 2013, 262. We used the socioeconomic and demographic data, self-reported morbidity, specific data of hospitalization and institutionalization. Frailty was measured by the Edmonton Frail Scale (EFS), and functional capacity through the Functional Independence Measure. RESULTS: we found the mean gross EFS score was higher among resident elderly who were hospitalized and institutionalized and was statistically significant in both investigated years. CONCLUSION: the confirmation of association between frailty and hospitalization and institutionalization reinforces the importance of the subject, and highlights frailty as an important tool for risk estimates for these adverse events. PMID- 27508475 TI - Factor analysis of an instrument to measure the impact of disease on daily life. AB - OBJECTIVE: to verify the structure of factors of an instrument to measure the Heart Valve Disease Impact on Daily Life (IDCV) when applied to coronary artery disease patients. METHOD: the study included 153 coronary artery disease patients undergoing outpatient follow-up care. The IDCV structure of factors was initially assessed by means of confirmatory factor analysis and, subsequently, by exploratory factor analysis. The Varimax rotation method was used to estimate the main components of analysis, eigenvalues greater than one for extraction of factors, and factor loading greater than 0.40 for selection of items. Internal consistency was estimated using Cronbach's alpha coefficient. RESULTS: confirmatory factor analysis did not confirm the original structure of factors of the IDCV. Exploratory factor analysis showed three dimensions, which together explained 78% of the measurement variance. CONCLUSION: future studies with expansion of case selection are necessary to confirm the IDCV new structure of factors. PMID- 27508476 TI - Validation to Portuguese of the Debriefing Experience Scale. AB - OBJECTIVE: to translate and validate to Portuguese the Debriefing Experience Scale jointly with individuals that used high-fidelity simulation in learning. METHOD: methodological and exploratory study for an instrument translation and validation. For the validation process, the event "III Workshop Brazil - Portugal: Care Delivery to Critical Patients" was created. RESULTS: 103 nurses attended. Validity and reliability of the scale, the correlation pattern among variables, the sampling adequacy test, and the sphericity test showed good results. Since there was no relationship among the groups established in the exploratory factor analysis, the option was to follow the division established by the original version. CONCLUSION: the version of the instrument was called Escala de Experiencia com o Debriefing. The results showed good psychometric properties and a good potential for use. However, further studies will contribute to consolidate the validity of the scale and strengthen its potential use. PMID- 27508477 TI - Fasting of less than eight hours in urgent and emergency surgeries versus complication. AB - OBJECTIVE: to verify the occurrence of intraoperative and postoperative complications in patients undergoing urgent and emergency surgical procedures between January and December 2012, with fasting time of less than 8 hours. METHOD: a quantitative study was conducted, of the retrospective cohort type, through the analysis of medical records. RESULTS: we included 181 records of patients undergoing surgical procedures with average duration of 59.4 minutes. Fractures correction surgeries stood out, totalling 32% of cases. We observed complications in 36 patients (19.9%), vomiting being the most prevalent (47.2%); followed by nausea (16.7%); need for blood transfusion (13.9%); surgical site infection (11.1%); and death (11.1%). The average fasting time was 133.5 minutes. The fasting time showed no statistically significant correlation with the complications investigated. CONCLUSION: intraoperative and postoperative complications were associated with the clinical conditions of the patients and not with the fasting time. PMID- 27508478 TI - Technology-dependent children and the demand for pharmaceutical care. AB - OBJECTIVE: to understand the experience of mothers of technology-dependent children as regards pharmaceutical care. METHOD: this was a qualitative, descriptive-exploratory study developed based on open interviews using a structured characterization tool, and applied during home visits to 12 mothers caring for technology-dependent children. The data was submitted to inductive content analysis. RESULTS: this study is split into two themes: (i) maternal overload during pharmaceutical care, demonstrating the need to administer drugs continuously and the repercussions of this exhaustive care on the caregivers; (ii) the ease or difficulty of access to the medicines required, showing informal strategies and support networks. CONCLUSION: pharmaceutical care is a daily challenge expressed in maternal overload and difficulty accessing the drugs, made worse by failures in the care network and coordinated care. PMID- 27508479 TI - Prevention and monitoring of delirium in older adults: an educational intervention. AB - OBJECTIVE: to conduct an educational intervention with the nursing team members of an intensive care unit (ICU), aiming to increase knowledge and to introduce improvements in their practices regarding prevention and monitoring of delirium in older patients. METHOD: this is an action research, in which workshops were conducted with eleven nurses and a nursing technician from an ICU unit in Salvador, Bahia, Brazil. RESULTS: ten problems regarding nursing practices for prevention and monitoring of delirium were identified. Educational, practical, technical, and managerial actions were planned, involving cross-sector connections for planning ways to solve these problems. The groups reported significant changes in the practices, with the implementation of drug-free measures for preventing and managing the situation. CONCLUSION: the educational intervention contributed to improve the nursing practices in the ICU unit studied, and it also favored the development of critical thinking about the problems mentioned, thus enabling permanent review of offered treatments. PMID- 27508480 TI - Concepts and practices of teaching and exercise of leadership in Nursing. AB - OBJECTIVE: to identify, describe and analyze characteristics of leadership, head nurses and participants in the teaching-learning process of leadership in Nursing, according to nurse professors who performed studies on this theme and taught such content between 1972 and 1994 in nursing schools of the state of Sao Paulo, southeastern Brazil. METHODS: Thematic Oral History was used. A total of four nurse professors were interviewed, whose reports were submitted to content analysis. RESULTS: the following aspects were approached in this study: the context in which students developed leadership, the influence of previous experiences on leadership qualification, its attributes, the importance of leadership, the value of teaching it, the possibilities of emancipation of a head nurse, the repercussions of teaching leadership for one's professional life, the relationships between qualification and job market, the aspects of teaching qualification and students' characteristics. CONCLUSION: although not essential for nursing qualification, leadership had a symbolic capital. PMID- 27508481 TI - Stressors perceived by patients in the immediate postoperative of cardiac surgery. AB - OBJECTIVE: to investigate stressors perceived by patients in the immediate postoperative of cardiac surgery and their association with sociodemographic and clinical characteristics. METHOD: a prospective correlational study conducted in a city in Sao Paulo, between August 2013 and December 2014. A non-probabilistic sample included patients submitted to their first coronary artery bypass graft or mitral valve surgery. The "Environmental Stressor Questionnaire" adapted to Portuguese was used. RESULTS: 105 patients participated in the study. The item "being thirsty" was evaluated as the most stressful and "the nursing staff member does not introduce himself/herself by the name" as the least stressful. Among sociodemographic and clinical variables (gender, age, type and time of surgery, pain, intubation time, use of psychotropic medications and length of stay in the intensive care unit), only pain presented a significant association with the stressors. CONCLUSION: knowing stressors can help implement practices associated with their reduction, favoring patients' recovery. PMID- 27508482 TI - Quality of working life of call-center workers. AB - OBJECTIVE: to analyze the profile and quality of working life (QWL) of call center workers. METHOD: quantitative research, conducted in one call-center of the city of Sao Jose do Rio Preto - SP, using the QVP-35 questionnaire. RESULTS: profile was composed by: 80.2% women; 66.3% were single, with high school diploma and 6 hours of daily working hours; mean age of 28 years; 92.9% had only one job with mean working experience of 3 years. Positive aspects of QWL: intrinsic motivation, working ability, available resources and social support. Negative aspects of QWL: workload and organizational support. CONCLUSION: the data obtained indicate the need for better organization of call-center working processes in the company and suggests other researches in this context. PMID- 27508483 TI - Health care for patients with acute coronary syndrome according to quality indicators. AB - OBJECTIVE: to assess in-hospital care for patients with Acute Coronary Syndrome according to quality indicators. METHOD: a longitudinal quantitative study was performed between November 2012 and March 2013 with 94 patients, including interviews and medical records. RESULTS: a total of 39.4% of patients had unstable angina and 60.6% had myocardial infarction, of which 34% had ST segment elevation. Patients with TIMI and GRACE scores higher than four and 140 (p<0.05) respectively died. Admission to the intensive care unit totaled 2.1%; assessment of left ventricular (LV) ejection fraction, 83.0%; ASA within 24 hours of admission, 77.8%; statins, 72.7%; angiotensin-converting enzyme inhibitor, 62.8%; anti-smoking counseling, 53.3%; and timely reperfusion, 62.5%. Of all participants, 12.0% underwent an invasive strategy in 24h and 50.0% in 72h. Door to-ECG time was 68.3+/-104.3 min and door-to-balloon time, 122+/-54.5 min. CONCLUSIONS: health care protocols are required to standardize practice and improve these indicators. PMID- 27508484 TI - The communication process in Telenursing: integrative review. AB - OBJECTIVE: to identify scientific evidence about the communication process in Telenursing and analyze them. METHOD: integrative review performed in March 2014. The search strategy, structured with the descriptors "telenursing" and "communication", was implemented in the databases Medline, Bireme, Cinahl, Scopus, Web of Science, Scielo, and Cochrane. RESULTS: ten studies were selected after inclusion and exclusion criteria. The main challenges were: the clinical condition of patients, the possibility for inadequate communication to cause misconduct, the absence of visual references in interactions without video, and difficulty understanding nonverbal communication. CONCLUSION: distance imposes communicative barriers in all elements: sender, recipient and message; and in both ways of transmission, verbal and nonverbal. The main difficulty is to understand nonverbal communication. To properly behave in this context, nurses must receive specific training to develop abilities and communication skills. PMID- 27508485 TI - Impact of educational interventions in reducing diabetic complications: a systematic review. AB - OBJECTIVE: To identify in the literature evidence of the effectiveness and efficacy of educational interventions in reducing metabolic and/or vascular complications in adults with diabetes mellitus. METHOD: A systematic review performed in LILACS, IBECS, CUMED, CINAHL and Medline databases and in the online library SciELO with studies published from 2004 to 2014. RESULTS: Eleven studies were included (5 randomized clinical trials and 6 quasi-experimental). We only identified studies that analyzed vascular complications. CONCLUSION: Two clinical trials demonstrated efficacy in reducing cardiovascular complications, of cataract or retinopathy and nephropathy and all the quasi-experimental studies showed effectiveness in reducing feet ulcers, peripheral neuropathy and vasculopathy, and maintenance of kidney function. PMID- 27508486 TI - Nursing diagnoses in patients with cerebral vascular accident: an integrative review. AB - OBJECTIVE: to verify the nursing diagnoses in patients affected by CVAs. METHOD: this is an integrative review of the literature. The search was conducted on LILACS, Scielo, Medline, CINAHL, and Scopus databases between February and March 2015, using the following keywords: "Enfermagem", "Acidente Vascular Cerebral", "Diagnostico de Enfermagem"; and "Nursing", "Stroke", and "Nursing Diagnosis". RESULTS: we found 9 articles published between 2009 and 2015; most of them were Brazilian, cross-sectional, and exploratory, with a level of evidence of 6. The evidence from the publications was classified as: "Evaluation and validation of specific nursing diagnoses for subjects affected by CVAs" and "Application of the nursing process on subjects affected by CVAs". CONCLUSION: we noticed the publications focused on nursing diagnoses related to motor disorders, such as risk of falls and impaired physical mobility. Domains regarding safety/protection (domain 11) and sleep/resting (domain 4) were present in most evaluated publications. PMID- 27508487 TI - Public actions for control of breast cancer in Brazil: integrative review. AB - OBJECTIVE: to analyze the scientific production on "breast cancer" in the period from 2002 to 2013 and determine the public policies for screening and early diagnosis of breast cancer. METHOD: this is an integrative literature review conducted in the databases MEDLINE, LILACS, SciELO and Google Scholar. INCLUSION CRITERIA: year and period of publication; availability of the full article; publication in Brazil; and the cross-check of the keywords Breast Cancer, Primary Health Care, Screening Programs, and Early Detection of Cancer. RESULTS: after analysis, four thematic categories were obtained: breast self-examination, clinical examination of breast, mammography, and factors that hinder the adherence to the screening. CONCLUSION: health professionals have deficits of knowledge on the area, indicating the need for other studies on the subject addressed and greater investment in continuing education of professionals. PMID- 27508488 TI - The Spiritism as therapy in the health care in the epilepsy. AB - OBJECTIVE: to present a brief history of Spiritism, the vision of epilepsy by Spiritism, and the potential of spirituality and religiosity care as complementary and coadjutants treatments in epilepsy. METHOD: this is a brief review about the impact of faith, spirituality, and religiosity, particularly the Spiritism philosophy as complementary treatment to neurological disorders (particularly focusing on epilepsy) and mental health. We conduct a review of published articles (about religion/spirituality and epilepsy) in the Pubmed and SciELO databases. CONCLUSION: the exercise of spirituality and religiosity can be a positive coping strategy to support the traditional therapy of patients with epilepsy and other neurological disorders. However, it is necessary to demystify myths and beliefs about the epilepsy and improve knowledge about this important health dimension among professionals, patients, and caregivers to explore their full treatment and supportive potential. PMID- 27508489 TI - Evaluation of Cardiovascular Risk Factors, Haematological and Biochemical Parameters, and Serum Endocan Levels in Patients with Lichen Planus. AB - BACKGROUND AND OBJECTIVE: The current study aimed to evaluate cardiovascular risk factors, haematological and biochemical parameters, and serum endocan concentrations in lichen planus (LP) patients. METHODS: This study was conducted with 86 cases, including 43 LP patients and 43 healthy controls. Cardiovascular risk factors, haematological and biochemical parameters, and endocan levels were evaluated. RESULTS: The serum endocan concentrations of LP patients were not significantly different from those of the healthy controls (p > 0.05). There were no significant differences in the serum endocan levels according to classification by cardiovascular risk factors and smoking history (p > 0.05). In the LP group, white blood cell count, platelet distribution width and monocyte count/high-density lipoprotein cholesterol ratios were significantly higher when compared to the healthy controls (p < 0.05). The LP group had a lower mean platelet volume than the healthy controls (p < 0.05). CONCLUSIONS: Serum endocan levels did not change significantly in patients with LP, and there were significant differences in haematological and biochemical parameters. PMID- 27508490 TI - Metabolic Syndrome and Associated Factors in a Population-Based Sample of Schoolchildren in Colombia: The FUPRECOL Study. AB - BACKGROUND: In contrast to the definition of metabolic syndrome (MetS) in adults, there is no standard definition of MetS in pediatric populations. We aimed at assessing the differences in the prevalence of MetS in children and adolescents aged 9-17 years using four different operational definitions for these age groups and at examining the associated variables. METHODS: A total of 675 children and 1247 adolescents attending public schools in Bogota (54.4% girls; age range 9 17.9 years) were included. The prevalence of MetS was determined by the definitions provided by the International Diabetes Federation (IDF) and three published studies by Cook et al., de Ferranti et al., and Ford et al. In addition, we further examined the associations between each definition of MetS in the total sample and individual risk factors using binary logistic regression models adjusted for gender, age, pubertal stage, weight status, and inflammation in all participants. RESULTS: The prevalence of MetS was 0.3%, 6.3%, 7.8%, and 11.0% according to the definitions by IDF, Cook et al., Ford et al., and de Ferranti et al., respectively. The most prevalent components were low high density lipoprotein cholesterol and high triglyceride levels, whereas the least prevalent components were higher waist circumference and hyperglycemia. Overall, the prevalence of MetS was higher in obese than in non-obese schoolchildren. CONCLUSIONS: MetS diagnoses in schoolchildren strongly depend on the definition chosen. These findings may be relevant to health promotion efforts for Colombian youth to develop prospective studies and to define which cut-offs are the best indicators of future morbidity. PMID- 27508491 TI - Anti-staphylococcal Activity of Injectable Nano Tigecycline/Chitosan-PRP Composite Hydrogel Using Drosophila melanogaster Model for Infectious Wounds. AB - Compared to the current treatment modalities, the use of an injectable hydrogel system, loaded with antibiotic encapsulated nanoparticles for the purpose of treating Staphylococcus aureus (S. aureus) chronic wound infections have several advantages. These include adhesiveness to infection site, reduced frequency of dressings, sustained drug release, inhibition of bacterial growth, and increased healing. In the present work tigecycline nanoparticles were loaded into chitosan platelet-rich plasma (PRP) hydrogel. The tigecycline nanoparticles (95 +/- 13 nm) were synthesized through ionic cross-linking method using chitosan, tripolyphosphate, and tigecycline and characterized by dynamic light scattering (DLS), scanning electron microscope (SEM), and Fourier transform infrared spectroscopy (FT-IR). The synthesized nanoparticles and activated PRP powder were mixed with chitosan hydrogel to form a homogeneous gel. Rheology studies have confirmed the shear thinning property, thermal stability, and injectability of the prepared gel systems. The gel system was further assessed for its drug release property and found that it was released in a sustained manner. Hemolysis and blood-clotting assays demonstrated that the gel system was neither a hemolysin nor a hamper to the clotting cascade. Cell viability results showed that these nanoparticles were cyto-compatible. The bioactivity of PRP loaded chitosan gel toward fibroblast cell line was studied using cell proliferation and migration assay. In vitro antibacterial studies revealed that the gel system inhibited bacterial growth to a great extent. The antibacterial activity was further analyzed using ex vivo porcine skin assay. In vivo anti-Staphylococcal activity of the prepared hydrogels was studied using a Drosophila melanogaster infection model. The tigecycline and tigecycline nanoparticle incorporated chitosan gel showed a significant antibacterial activity against S. aureus. Thus, the gel system is an effective medium for antibiotic delivery and can be applied on the infection sites to effectively forestall various skin infections caused by S. aureus. PMID- 27508492 TI - Diastereoselective B(C6F5)3-Catalyzed Reductive Carbocyclization of Unsaturated Carbohydrates. AB - A B(C6F5)3-catalyzed method for the selective conversion of unsaturated carbohydrates to cyclopentanes and cyclopropanes is disclosed. Catalyst activation of tertiary silanes generates the ion pair [(C6F5)3B-H][ROSi2] whose components synergistically activate C-O bonds for diastereoselective C-C bond formation. Sila-THF cations are invoked as key intermediates facilitating carbocyclizations. Complex chiral synthons are thereby obtained in a single pot. PMID- 27508493 TI - B-Cyanodicarba-closo-dodecaboranes: Facile Synthesis and Spectroscopic Features. AB - B-Cyanodicarba-closo-dodecaboranes are a poorly explored class of compounds due to their complex synthetic availability. Now, we report a fast, atom-efficient, and high-yielding synthesis. We obtained the cyano derivatives by reacting B iododicarba-closo-dodecaboranes with copper(I) cyanide under both palladium catalysis and microwave irradiation. We successfully applied this method to 9 iodo-o-, 9-iodo-m-, and 2-iodo-p-dicarba-closo-dodecaborane, obtaining the corresponding cyanides up to 89% isolated yield. The facile synthesis and evaluation of their spectroscopic properties reported herein will pave the way to exploring the chemistry and application of B-cyanodicarba-closo-dodecaborane clusters in more detail. PMID- 27508494 TI - Susceptibility to Childhood Pneumonia: A Genome-Wide Analysis. AB - : Previous studies have indicated that in adult smokers, a history of childhood pneumonia is associated with reduced lung function and chronic obstructive pulmonary disease. There have been few previous investigations using genome-wide association studies to investigate genetic predisposition to pneumonia. This study aims to identify the genetic variants associated with the development of pneumonia during childhood and over the course of the lifetime. Study subjects included current and former smokers with and without chronic obstructive pulmonary disease participating in the COPDGene Study. Pneumonia was defined by subject self-report, with childhood pneumonia categorized as having the first episode at <16 years. Genome-wide association studies for childhood pneumonia (843 cases, 9,091 control subjects) and lifetime pneumonia (3,766 cases, 5,659 control subjects) were performed separately in non-Hispanic whites and African Americans. Non-Hispanic white and African American populations were combined in the meta-analysis. Top genetic variants from childhood pneumonia were assessed in network analysis. No single-nucleotide polymorphisms reached genome-wide significance, although we identified potential regions of interest. In the childhood pneumonia analysis, this included variants in NGR1 (P = 6.3 * 10-8), PAK6 (P = 3.3 * 10-7), and near MATN1 (P = 2.8 * 10-7). In the lifetime pneumonia analysis, this included variants in LOC339862 (P = 8.7 * 10-7), RAPGEF2 (P = 8.4 * 10-7), PHACTR1 (P = 6.1 * 10-7), near PRR27 (P = 4.3 * 10-7), and near MCPH1 (P = 2.7 * 10-7). Network analysis of the genes associated with childhood pneumonia included top networks related to development, blood vessel morphogenesis, muscle contraction, WNT signaling, DNA damage, apoptosis, inflammation, and immune response (P <= 0.05). We have identified genes potentially associated with the risk of pneumonia. Further research will be required to confirm these associations and to determine biological mechanisms. CLINICAL TRIAL REGISTRATION: NCT00608764. PMID- 27508495 TI - A let-7-to-miR-125 MicroRNA Switch Regulates Neuronal Integrity and Lifespan in Drosophila. AB - Messenger RNAs (mRNAs) often contain binding sites for multiple, different microRNAs (miRNAs). However, the biological significance of this feature is unclear, since such co-targeting miRNAs could function coordinately, independently, or redundantly with one another. Here, we show that two co transcribed Drosophila miRNAs, let-7 and miR-125, non-redundantly regulate a common target, the transcription factor Chronologically Inappropriate Morphogenesis (Chinmo). We first characterize novel adult phenotypes associated with loss of both let-7 and miR-125, which are derived from a common, polycistronic transcript that also encodes a third miRNA, miR-100. Consistent with the coordinate upregulation of all three miRNAs in aging flies, these phenotypes include brain degeneration and shortened lifespan. However, transgenic rescue analysis reveal separable roles for these miRNAs: adult miR-125 but not let-7 mutant phenotypes are associated with ectopic Chinmo expression in adult brains and are suppressed by chinmo reduction. In contrast, let-7 is predominantly responsible for regulating chinmo during nervous system formation. These results indicate that let-7 and miR-125 function during two distinct stages, development and adulthood, rather than acting at the same time. These different activities are facilitated by an increased rate of processing of let-7 during development and a lower rate of decay of the accumulated miR-125 in the adult nervous system. Thus, this work not only establishes a key role for the highly conserved miR-125 in aging. It also demonstrates that two co-transcribed miRNAs function independently during distinct stages to regulate a common target, raising the possibility that such biphasic control may be a general feature of clustered miRNAs. PMID- 27508496 TI - Interspecific Hybridization in Pilot Whales and Asymmetric Genetic Introgression in Northern Globicephala melas under the Scenario of Global Warming. AB - Pilot whales are two cetacean species (Globicephala melas and G. macrorhynchus) whose distributions are correlated with water temperature and partially overlap in some areas like the North Atlantic Ocean. In the context of global warming, distribution range shifts are expected to occur in species affected by temperature. Consequently, a northward displacement of the tropical pilot whale G. macrorynchus is expected, eventually leading to increased secondary contact areas and opportunities for interspecific hybridization. Here, we describe genetic evidences of recurrent hybridization between pilot whales in northeast Atlantic Ocean. Based on mitochondrial DNA sequences and microsatellite loci, asymmetric introgression of G. macrorhynchus genes into G. melas was observed. For the latter species, a significant correlation was found between historical population growth rate estimates and paleotemperature oscillations. Introgressive hybridization, current temperature increases and lower genetic variation in G. melas suggest that this species could be at risk in its northern range. Under increasing environmental and human-mediated stressors in the North Atlantic Ocean, it seems recommendable to develop a conservation program for G. melas. PMID- 27508498 TI - Short-Term Behavioural Responses of the Great Scallop Pecten maximus Exposed to the Toxic Alga Alexandrium minutum Measured by Accelerometry and Passive Acoustics. AB - Harmful algal blooms produced by toxic dinoflagellates have increased worldwide, impacting human health, the environment, and fisheries. Due to their potential sensitivity (e.g., environmental changes), bivalves through their valve movements can be monitored to detect harmful algal blooms. Methods that measure valve activity require bivalve-attached sensors and usually connected cables to data transfers, leading to stress animals and limit the use to sessile species. As a non-intrusive and continuously deployable tool, passive acoustics could be an effective approach to detecting harmful algal blooms in real time based on animal sound production. This study aimed to detect reaction changes in the valve movements of adult Pecten maximus exposed to the toxic dinoflagellate Alexandrium minutum using both accelerometry and passive acoustic methods. Scallops were experimentally exposed to three ecologically relevant concentrations of A. minutum for 2 hours. The number of each type of valve movement and their sound intensity, opening duration, and valve-opening amplitude were measured. Four behaviours were identified: closures, expulsion, displacement, and swimming. The response of P. maximus to A. minutum occurred rapidly at a high concentration. The valve activity of P. maximus was different when exposed to high concentrations (500 000 cells L-1) of A. minutum compared to the non-toxic dinoflagellate Heterocapsa triquetra; the number of valve movements increased, especially closure and expulsion, which were detected acoustically. Thus, this study demonstrates the potential for acoustics and sound production changes in the detection of harmful algal blooms. However, field trials and longer duration experiments are required to provide further evidence for the use of acoustics as a monitoring tool in the natural environment where several factors may interfere with valve behaviours. PMID- 27508497 TI - Discovery of a Series of Acridinones as Mechanism-Based Tubulin Assembly Inhibitors with Anticancer Activity. AB - Microtubules play critical roles in vital cell processes, including cell growth, division, and migration. Microtubule-targeting small molecules are chemotherapeutic agents that are widely used in the treatment of cancer. Many of these compounds are structurally complex natural products (e.g., paclitaxel, vinblastine, and vincristine) with multiple stereogenic centers. Because of the scarcity of their natural sources and the difficulty of their partial or total synthesis, as well as problems related to their bioavailability, toxicity, and resistance, there is an urgent need for novel microtubule binding agents that are effective for treating cancer but do not have these disadvantages. In the present work, our lead discovery effort toward less structurally complex synthetic compounds led to the discovery of a series of acridinones inspired by the structure of podophyllotoxin, a natural product with important microtubule assembly inhibitory activity, as novel mechanism-based tubulin assembly inhibitors with potent anticancer properties and low toxicity. The compounds were evaluated in vitro by wound healing assays employing the metastatic and triple negative breast cancer cell line MDA-MB-231. Four compounds with IC50 values between 0.294 and 1.7 MUM were identified. These compounds showed selective cytotoxicity against MDA-MB-231 and DU-145 cancer cell lines and promoted cell cycle arrest in G2/M phase and apoptosis. Consistent with molecular modeling results, the acridinones inhibited tubulin assembly in in vitro polymerization assays with IC50 values between 0.9 and 13 MUM. Their binding to the colchicine binding site of tubulin was confirmed through competitive assays. PMID- 27508499 TI - Quality Indicators but Not Admission Volumes of Neonatal Intensive Care Units Are Effective in Reducing Mortality Rates of Preterm Infants. AB - AIM: To investigate how two different strategies to form larger neonatal intensive care units (NICU) impact neonatal mortality rates. METHODS: Cross sectional study modeling admission volumes and mortality rates of 177,086 VLBW infants aggregated into 862 NICUs. Cumulative 3-year data was abstracted from Vermont Oxford Network. The model simulated a reduction in number of NICUs by stepwise exclusion using either admission volume (VOL) or quality (QUAL) cut offs. After randomly redirecting infants of excluded to remaining NICUs resulting system mortality rates were calculated with and without adjusting for effects of experience levels (EL) using published data to reflect effects of different team to-patient exposure. RESULTS: The quality-based strategy is more effective in reducing mortality; while VOL alone was not able to reduce system mortality, QUAL already achieved a 5% improvement after reducing 8% of NICUs and redirecting 6% of infants. Including "EL", a 5% improvement of mortality was achieved by reducing 77% (VOL) vs. 7% (QUAL) of NICUs and redirecting 54% (VOL) vs. 5% (QUAL) of VLBW infants, respectively. CONCLUSION: While a critical number of admissions is needed to maintain skills this study emphasizes the importance of including quality parameters to restructure neonatal care. The findings can be generalized to other medical fields. PMID- 27508500 TI - QTL Mapping in Three Rice Populations Uncovers Major Genomic Regions Associated with African Rice Gall Midge Resistance. AB - African rice gall midge (AfRGM) is one of the most destructive pests of irrigated and lowland African ecologies. This study aimed to identify the quantitative trait loci (QTL) associated with AfRGM pest incidence and resistance in three independent bi-parental rice populations (ITA306xBW348-1, ITA306xTOG7106 and ITA306xTOS14519), and to conduct meta QTL (mQTL) analysis to explore whether any genomic regions are conserved across different genetic backgrounds. Composite interval mapping (CIM) conducted on the three populations independently uncovered a total of 28 QTLs associated with pest incidence (12) and pest severity (16). The number of QTLs per population associated with AfRGM resistance varied from three in the ITA306xBW348-1 population to eight in the ITA306xTOG7106 population. Each QTL individually explained 1.3 to 34.1% of the phenotypic variance. The major genomic region for AfRGM resistance had a LOD score and R2 of 60.0 and 34.1% respectively, and mapped at 111 cM on chromosome 4 (qAfrGM4) in the ITA306xTOS14519 population. The meta-analysis reduced the number of QTLs from 28 to 17 mQTLs, each explaining 1.3 to 24.5% of phenotypic variance, and narrowed the confidence intervals by 2.2 cM. There was only one minor effect mQTL on chromosome 1 that was common in the TOS14519 and TOG7106 genetic backgrounds; all other mQTLs were background specific. We are currently fine-mapping and validating the major effect genomic region on chromosome 4 (qAfRGM4). This is the first report in mapping the genomic regions associated with the AfRGM resistance, and will be highly useful for rice breeders. PMID- 27508501 TI - The Safety, Tolerability and Risks Associated with the Use of Newer Generation Antidepressant Drugs: A Critical Review of the Literature. AB - Newer generation antidepressant drugs (ADs) are widely used as the first line of treatment for major depressive disorders and are considered to be safer than tricyclic agents. In this critical review, we evaluated the literature on adverse events, tolerability and safety of selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, bupropion, mirtazapine, trazodone, agomelatine, vilazodone, levomilnacipran and vortioxetine. Several side effects are transient and may disappear after a few weeks following treatment initiation, but potentially serious adverse events may persist or ensue later. They encompass gastrointestinal symptoms (nausea, diarrhea, gastric bleeding, dyspepsia), hepatotoxicity, weight gain and metabolic abnormalities, cardiovascular disturbances (heart rate, QT interval prolongation, hypertension, orthostatic hypotension), genitourinary symptoms (urinary retention, incontinence), sexual dysfunction, hyponatremia, osteoporosis and risk of fractures, bleeding, central nervous system disturbances (lowering of seizure threshold, extrapyramidal side effects, cognitive disturbances), sweating, sleep disturbances, affective disturbances (apathy, switches, paradoxical effects), ophthalmic manifestations (glaucoma, cataract) and hyperprolactinemia. At times, such adverse events may persist after drug discontinuation, yielding iatrogenic comorbidity. Other areas of concern involve suicidality, safety in overdose, discontinuation syndromes, risks during pregnancy and breast feeding, as well as risk of malignancies. Thus, the rational selection of ADs should consider the potential benefits and risks, likelihood of responsiveness to the treatment option and vulnerability to adverse events. The findings of this review should alert the physician to carefully review the appropriateness of AD prescription on an individual basis and to consider alternative treatments if available. PMID- 27508502 TI - Location Prediction Based on Transition Probability Matrices Constructing from Sequential Rules for Spatial-Temporal K-Anonymity Dataset. AB - Spatial-temporal k-anonymity has become a mainstream approach among techniques for protection of users' privacy in location-based services (LBS) applications, and has been applied to several variants such as LBS snapshot queries and continuous queries. Analyzing large-scale spatial-temporal anonymity sets may benefit several LBS applications. In this paper, we propose two location prediction methods based on transition probability matrices constructing from sequential rules for spatial-temporal k-anonymity dataset. First, we define single-step sequential rules mined from sequential spatial-temporal k-anonymity datasets generated from continuous LBS queries for multiple users. We then construct transition probability matrices from mined single-step sequential rules, and normalize the transition probabilities in the transition matrices. Next, we regard a mobility model for an LBS requester as a stationary stochastic process and compute the n-step transition probability matrices by raising the normalized transition probability matrices to the power n. Furthermore, we propose two location prediction methods: rough prediction and accurate prediction. The former achieves the probabilities of arriving at target locations along simple paths those include only current locations, target locations and transition steps. By iteratively combining the probabilities for simple paths with n steps and the probabilities for detailed paths with n-1 steps, the latter method calculates transition probabilities for detailed paths with n steps from current locations to target locations. Finally, we conduct extensive experiments, and correctness and flexibility of our proposed algorithm have been verified. PMID- 27508503 TI - Age and Sex Ratios in a High-Density Wild Red-Legged Partridge Population. AB - The dynamics of a wild red-legged partridge population were examined over a 14 year period in Spain to identify patterns in age and sex ratios in relation to weather parameters, and to assess the importance of these parameters in population dynamics and management. The results gave age ratios of 1.07 (but 2.13 in July counts), juvenile sex ratios of 1.01 and adult sex ratios of 1.47. Overall, 12% more females were hatched and female juvenile mortality was 7.3% higher than in males. Sex differential mortality explains the 19.2% deficit in adult females, which are more heavily predated than males during the breeding period. Accordingly, age ratios are dependent on sex ratios and both are density dependent. Over time, ratios and density changes appear to be influenced by weather and management. When the habitat is well conserved, partridge population dynamics can be explained by a causal chain: weather operates on net primary production, thereby affecting partridge reproduction and predation and, as a result, age and sex ratios in the October population. A reduction in the impact of predation (i.e. the effects of ground predators on eggs, chicks and breeding females) is the key factor to improve the conservation of partridge populations and associated biological processes. PMID- 27508504 TI - Family factors and health behaviour of thin adolescent boys and girls. AB - AIM: The aim of this study was to examine prevalence of extreme thinness and thinness in adolescent boys and girls and to study associations between family factors, health behaviour and thinness in boys and girls. BACKGROUND: Extreme thinness carries high health risks. The family and health behavioural factors related to adolescent thinness have not been studied previously using a nationally representative data. DESIGN: This is a cross-sectional quantitative study. METHODS: The nationally representative data were obtained from the Finnish School Health Promotion study conducted in 2013. The sample of this study included 12-17 year old adolescents (n = 71,973) who were categorised as extremely thin, thin and normal weight using international age and gender body mass index (BMI) cut-off points for children and adolescents. Associations with family factors and health behaviour were examined separately for boys and girls using cross-tabulations, Chi-square test and multinomial logistic regression. RESULTS: Thinness and extreme thinness were more common in girls than in boys. Health behaviour, such as smoking and exercise, were associated with thinness and extreme thinness in both genders. Regarding family factors; low maternal education, family meal and parental knowledge of adolescents' friends and whereabouts were associated with thinness and, or extreme thinness in both boys and girls. However, there were gender differences in the associations. CONCLUSIONS: It is important for healthcare professionals working with adolescents to be aware of prevalence in thinness and aware of health behaviour and family factors that are associated with thinness and extreme thinness in adolescence. PMID- 27508505 TI - Generation of a Scaffold-Free Three-Dimensional Liver Tissue via a Rapid Cell-to Cell Click Assembly Process. AB - There has been tremendous interest in constructing in vitro liver organ models for a range of fundamental studies of cell signaling, metabolism, and infectious diseases, and as a commercial system to evaluate therapeutic drug discovery prioritization and toxicity. Although there has been progress toward studying two dimensional hepatic function in vitro, there remain challenging obstacles to generate rapid and efficient scaffold-free three-dimensional multiple cell line coculture tissue models of liver. Herein, we develop and employ a strategy to induce specific and stable cell-cell contacts among multiple hepatic cell lines to generate 3D tissues through cell-surface engineering based on liposome delivery and fusion to display bio-orthogonal functional groups from cell membranes. We generate, for the first time, a three cell line coculture 3D liver tissue model by assembling hepatocytes, hepatic endothelial cells, and hepatic stellate cells via a rapid intercell click ligation process. We compare and analyze the function of the superior 3D liver tissue chips with 2D coculture monolayer by assessing mitochondrial metabolic activity and evaluating drug toxicity. PMID- 27508506 TI - VITRECTOMY FOR MACULAR RETINOSCHISIS WITHOUT A DETECTABLE OPTIC DISK PIT. AB - PURPOSE: To evaluate the efficacy of vitrectomy in the treatment of macular retinoschisis without a detectable optic disk pit. METHODS: This retrospective interventional case series included eight patients with acquired, unilateral macular retinoschisis with or without foveal detachment. Patients with an optic disk pit, vitreomacular traction, or high myopia were excluded. Six of the eight patients underwent vitrectomy with internal limiting membrane peeling and fluid air exchange. The surgical outcome was evaluated in terms of the improvement in the macular anatomy and the best-corrected visual acuity. RESULTS: During vitrectomy, all the six eyes were confirmed to have preexisting posterior vitreous detachment. Macular retinoschisis was resolved or reduced in all the six eyes after vitrectomy. The mean central foveal thickness showed significant improvement at the time of the patient's final visit after vitrectomy. The mean best-corrected visual acuity was 20/52 before surgery and 20/31 at the final visit. CONCLUSION: Vitrectomy might be effective for the treatment of macular retinoschisis without an optic disk pit. Although clinically similar to optic pit maculopathy except for the absence of pit, our intraoperative observations of the posterior hyaloid membrane suggest that maculopathy without optic disk pit has a distinct pathogenesis. PMID- 27508507 TI - Anillin controls cleavage furrow formation in the course of asymmetric division during mouse oocyte maturation. AB - Anillin is a scaffold protein that recruits several proteins involved in cleavage furrow formation during cytokinesis. The role of anilllin in symmetric cell divisions in somatic cells has been intensively studied, yet its involvement in cleavage furrow formation is still elusive. In this study, we investigated the role of anillin in mammalian oocyte maturation and cytokinesis. We found that anillin is localized around the nucleus during the oocyte germinal-vesicle stage, and spreads to the cytoplasm after germinal vesicle breakdown. Thereafter, anillin concentrates at the site of the cleavage furrow from anaphase I to metaphase II. Disruption of anillin activity by microinjecting oocytes with specific siRNAs resulted in a failure of polar body extrusion and asymmetric division, and caused abnormal chromosome segregation during anaphase I. Furthermore, pharmacological inhibition of myosin light chain using Y-27632 or ML 7 resulted in decreased anillin expression. Collectively, our data suggest that anillin is an essential intracellular component that maintains the integrity of asymmetric division in mouse oocytes. Mol. Reprod. Dev. 83: 792-801, 2016 (c) 2016 Wiley Periodicals, Inc. PMID- 27508508 TI - Use of Acellular Dermal Matrix versus Latissimus Dorsi Flap for Breast Reconstruction: Clinical and Patient-Reported Outcomes. PMID- 27508509 TI - The Significance of Sessile Serrated Polyps in Inflammatory Bowel Disease. AB - BACKGROUND: The significance of serrated lesions in inflammatory bowel disease (IBD) remains unclear. We aim to characterize synchronous and metachronous lesions in IBD patients with an index serrated polyp and compare them to sporadic subjects with SSP. METHODS: Serrated lesions in patients with IBD were identified from a pathology database and, after review, were reclassified as hyperplastic (HP), sessile serrated (SSPs), or serrated polyps unclassifiable (SPU). RESULTS: One hundred thirty-four IBD patients were found to have 147 serrated polyps at index colonoscopy. SSPs were more likely to be located in the right colon: SSP (76.0%), SPU (41.7%) and HP (27.8%); P = 0.002. Synchronous multifocal visible dysplasia occurred more frequently in the SSP or SPU groups (44.5% and 66%) compared to the HP group (12%); P = 0.031. Among 13 IBD patients with index SSP followed over a median of 6 years, 61.5% developed metachronous visible dysplasia or additional SSPs. Larger index SSP size was associated with higher risk of developing subsequent visible dysplasia with a 10% increase for every 1 mm increase in size (HR = 1.1; P = 0.028), but was not associated with developing subsequent SSP (P = 0.50). The risk of subsequent SSP or visible dysplasia was no different between the IBD and non-IBD groups, but there was a trend suggesting SSP may be a marker of increased early risk of metachronous visible dysplasia in IBD patients. CONCLUSIONS: IBD patients with an index SSP and SPU have a heightened risk of synchronous multifocal visible dysplasia. Additionally, IBD patients with SSP may be at risk of early metachronous visible dysplasia. PMID- 27508511 TI - Hypertrophic Mesenteric Adipose Tissue May Play a Role in Atherogenesis in Inflammatory Bowel Diseases. AB - BACKGROUND: Adipokines released by the adipose tissue are known to play a role in atherogenesis. The hypertrophic mesenteric fat in patients with inflammatory bowel diseases (IBD) also produces adipokines that are considered to play a role in intestinal inflammation. Whether they also contribute to accelerated atherosclerosis in IBD is unknown. The aim of this study was to assess the role of 2 adipokines, resistin and adiponectin, in IBD. METHODS: We previously published data on 3 markers of cardiovascular risk, carotid intima-media thickness, carotid-femoral pulse wave velocity, and lipoprotein-associated phospholipase A2, in 44 patients with IBD and 44 controls matched for established cardiovascular risk factors. In this study, we measured resistin and adiponectin levels, and assessed their correlations with carotid intima-media thickness, pulse wave velocity, and lipoprotein-associated phospholipase A2. RESULTS: Resistin levels were significantly higher in patients with IBD (13.7 versus 10 ng/mL; P = 0.022), but there was no difference in adiponectin levels. Resistin levels were significantly higher in patients with active disease compared with those in remission (18.9 versus 11.3 ng/mL; P = 0.014). Adiponectin levels were significantly lower in Crohn's disease compared with ulcerative colitis (6736.3 +/- 3105 versus 10,476.1 +/- 5575.7 ng/mL; P = 0.026). Adiponectin correlated inversely with pulse wave velocity (rho = -0.434; P < 0.0005) and carotid intima media thickness (rho = -0.255; P = 0.021). CONCLUSIONS: This is the first study to suggest that adipokines produced by the hypertrophic mesenteric fat in IBD may play a role not only in intestinal inflammation but also in atherogenesis. Resistin has mainly pro-inflammatory properties, whereas adiponectin likely exerts an angioprotective effect. PMID- 27508510 TI - Increased Prevalence of Inflammatory Bowel Disease in Patients with Mutations in Genes Encoding the Receptor Subunits for TGFbeta. AB - BACKGROUND: TGFbeta is a multifunctional cytokine that is critical in regulating mucosal immunity. Murine studies have revealed that disruption of canonical TGFbeta signaling leads to systemic inflammation including colitis. Loeys-Dietz syndrome (LDS) results from heterozygous mutations in the genes encoding the subunits of the TGFbeta receptor. METHODS: All patients with confirmed mutations in TGFBR1 or TGFBR2, seen in the Johns Hopkins Connective Tissue Disorders clinic, were asked to participate in the study. Ninety-three consecutive patients were enrolled, including 4 with inflammatory bowel disease (IBD). Using the Illumina Immunochip array, we undertook an exploratory analysis to evaluate the potential genetic risk factors that could predict which patients with LDS would develop IBD. RESULTS: We report an increased prevalence of IBD in patients with LDS types I and II. We describe the course of several patients. In this small sample, the 3 whites with IBD had a genetic risk score in the top 6 highest scores of patients evaluated. CONCLUSION: We report a 10-fold increase in the prevalence of IBD in patients with LDS compared with the general population. Onset of disease in 3 of the 4 patients was at less than 18 years, and the clinical course in 2 of the 4 was severe with a poor response to traditional medications. Further evaluation of the genetic risk score is needed to determine whether it can predict which patients with LDS are most likely to develop IBD. This case series of patients with LDS with IBD suggests that defective TGFbeta signaling may have an influence on IBD risk. PMID- 27508512 TI - A Systematic Review on Infliximab and Adalimumab Drug Monitoring: Levels, Clinical Outcomes and Assays. AB - BACKGROUND: Immunogenicity to therapeutic proteins has been linked to loss of response by a large percentage of patients taking anti-tumor necrosis factor alpha agents. Drug monitoring can be extremely useful, allowing physicians to adjust the therapeutic scheme individually. This article aims to systematically review the published data with respect to cutoff levels of infliximab (IFX) and adalimumab (ADA) and relate them to the methodology adopted for quantification of IFX and ADA levels and clinical outcomes. METHODS: The PubMed database was searched to identify studies focusing on the association between IFX or ADA cutoff levels and clinical outcomes in patients with inflammatory bowel disease. RESULTS: Of the 1654 articles initially selected by queries, 20 were included. A receiver operating characteristic curve analysis was performed to identify cutoff levels of IFX or ADA that correlated with a clinical outcome, but only 6 studies performed the same analysis for antidrug antibody levels. Cutoff levels were different between studies. The methodology chosen for level quantifications, clinical outcomes, and sample size and characteristics were also different. Nevertheless, measurement of drug levels should be performed during maintenance, and with loss of response, with persistent high levels of C-reactive protein, and when mucosal lesions are still present. In these scenarios, drug and antidrug levels were correlated with clinical outcomes. CONCLUSIONS: Concerning drug levels monitoring any methodology is adequate. With respect to antidrug antibody levels, it will be necessary to define a gold standard method or to establish different cutoff levels for different methodologies. PMID- 27508513 TI - Computed Tomography and Magnetic Resonance Enterography in Crohn's Disease: Assessment of Radiologic Criteria and Endpoints for Clinical Practice and Trials. AB - Early recognition of Crohn's disease with initiation of disease-modifying therapy has emerged as a prominent inflammatory bowel disease management strategy. Clinical practice and trials have often focused on patient symptoms, and more recently, serologic tests, stool inflammatory markers, and/or endoscopic inflammatory features for study entry criteria, treatment targets, disease activity monitoring, and to assess therapeutic response. Unfortunately, patient symptoms do not correlate well with biological disease activity, and endoscopy potentially misses or underestimates disease extent and severity in small bowel Crohn's disease. Computed tomography enterography and magnetic resonance enterography (MRE) are potential tools to identify and quantify transmural structural damage and disease activity in the small bowel. In this review, we discuss the role of computed tomography enterography and MRE in disease management algorithms in clinical practice. We also compare the currently developed MRE-based scoring systems, their strengths and pitfalls, as well as the role for MRE in clinical trials for Crohn's disease. PMID- 27508515 TI - Does a Higher Prevalence for Primary Diagnosis of Crohn's Disease Involve the Upper Gastrointestinal Tract? PMID- 27508516 TI - Pediatric Inflammatory Bowel Disease and Hereditary Hemolytic Anemia: A Retrospective Analysis. PMID- 27508514 TI - Emerging Roles for Noncanonical NF-kappaB Signaling in the Modulation of Inflammatory Bowel Disease Pathobiology. AB - Crohn's disease and ulcerative colitis are common and debilitating manifestations of inflammatory bowel disease (IBD). IBD is characterized by a radical imbalance in the activation of proinflammatory and anti-inflammatory signaling pathways in the gut. These pathways are controlled by NF-kappaB, which is a master regulator of gene transcription. In IBD patients, NF-kappaB signaling is often dysregulated resulting in overzealous inflammation. NF-kappaB activation occurs through 2 distinct pathways, defined as either canonical or noncanonical. Canonical NF kappaB pathway activation is well studied in IBD and is associated with the rapid, acute production of diverse proinflammatory mediators, such as COX-2, IL 1beta, and IL-6. In contrast to the canonical pathway, the noncanonical or "alternative" NF-kappaB signaling cascade is tightly regulated and is responsible for the production of highly specific chemokines that tend to be associated with less acute, chronic inflammation. There is a relative paucity of literature regarding all aspects of noncanonical NF-KB signaling. However, it is clear that this alternative signaling pathway plays a considerable role in maintaining immune system homeostasis and likely contributes significantly to the chronic inflammation underlying IBD. Noncanonical NF-kappaB signaling may represent a promising new direction in the search for therapeutic targets and biomarkers associated with IBD. However, significant mechanistic insight is still required to translate the current basic science findings into effective therapeutic strategies. PMID- 27508517 TI - Fortification of condiments with micronutrients in public health: from proof of concept to scaling up. AB - Fortification of condiments or seasonings may be useful for delivering micronutrients if they are consumed consistently by most of the population, as occurs in many countries. The World Health Organization, in collaboration with the Micronutrient Initiative and the Sackler Institute for Nutrition Science at the New York Academy of Sciences, convened a technical consultation on "Fortification of Condiments and Seasonings with Vitamins and Minerals in Public Health: from Proof of Concept to Scaling Up" to review the role of condiments and seasonings in improving micronutrient status, as constituents of regular diets and patterns of production and consumption worldwide. The consultation covered aspects related to implementation, monitoring, evaluation, and legal frameworks of fortification programs, as well as food safety and policy coherence for condiment fortification in the context of other public health strategies. This paper introduces the background and rationale of the technical consultation, synopsizes the presentations, and provides a summary of the main considerations proposed by the working groups. PMID- 27508518 TI - Host-pathogen interactions of nontypeable Haemophilus influenzae: from commensal to pathogen. AB - Nontypeable Haemophilus influenzae (NTHi) is a commensal microbe often isolated from the upper and lower respiratory tract. This bacterial species can cause sinusitis, acute otitis media in preschool children, exacerbations in patients suffering from chronic obstructive pulmonary disease, as well as conjunctivitis and bacteremia. Since the introduction of a vaccine against H. influenzae serotype b in the 1990s, the burden of H. influenzae-related infections has been increasingly dominated by NTHi. Understanding the ability of NTHi to cause infection is currently an expanding area of study. NTHi is able to exert differential binding to the host tissue through the use of a broad range of adhesins. NTHi survival in the host is multifaceted, that is, using virulence factors involved in complement resistance, biofilm, modified immunoglobulin responses, and, finally, formation and utilization of host proteins as a secondary strategy of increasing the adhesive ability. PMID- 27508519 TI - A Graph is Worth a Thousand Words: How Overconfidence and Graphical Disclosure of Numerical Information Influence Financial Analysts Accuracy on Decision Making. AB - Previous researches support that graphs are relevant decision aids to tasks related to the interpretation of numerical information. Moreover, literature shows that different types of graphical information can help or harm the accuracy on decision making of accountants and financial analysts. We conducted a 4*2 mixed-design experiment to examine the effects of numerical information disclosure on financial analysts' accuracy, and investigated the role of overconfidence in decision making. Results show that compared to text, column graph enhanced accuracy on decision making, followed by line graphs. No difference was found between table and textual disclosure. Overconfidence harmed accuracy, and both genders behaved overconfidently. Additionally, the type of disclosure (text, table, line graph and column graph) did not affect the overconfidence of individuals, providing evidence that overconfidence is a personal trait. This study makes three contributions. First, it provides evidence from a larger sample size (295) of financial analysts instead of a smaller sample size of students that graphs are relevant decision aids to tasks related to the interpretation of numerical information. Second, it uses the text as a baseline comparison to test how different ways of information disclosure (line and column graphs, and tables) can enhance understandability of information. Third, it brings an internal factor to this process: overconfidence, a personal trait that harms the decision-making process of individuals. At the end of this paper several research paths are highlighted to further study the effect of internal factors (personal traits) on financial analysts' accuracy on decision making regarding numerical information presented in a graphical form. In addition, we offer suggestions concerning some practical implications for professional accountants, auditors, financial analysts and standard setters. PMID- 27508520 TI - Extracting DNA from 'jaws': high yield and quality from archived tiger shark (Galeocerdo cuvier) skeletal material. AB - Archived specimens are highly valuable sources of DNA for retrospective genetic/genomic analysis. However, often limited effort has been made to evaluate and optimize extraction methods, which may be crucial for downstream applications. Here, we assessed and optimized the usefulness of abundant archived skeletal material from sharks as a source of DNA for temporal genomic studies. Six different methods for DNA extraction, encompassing two different commercial kits and three different protocols, were applied to material, so-called bio swarf, from contemporary and archived jaws and vertebrae of tiger sharks (Galeocerdo cuvier). Protocols were compared for DNA yield and quality using a qPCR approach. For jaw swarf, all methods provided relatively high DNA yield and quality, while large differences in yield between protocols were observed for vertebrae. Similar results were obtained from samples of white shark (Carcharodon carcharias). Application of the optimized methods to 38 museum and private angler trophy specimens dating back to 1912 yielded sufficient DNA for downstream genomic analysis for 68% of the samples. No clear relationships between age of samples, DNA quality and quantity were observed, likely reflecting different preparation and storage methods for the trophies. Trial sequencing of DNA capture genomic libraries using 20 000 baits revealed that a significant proportion of captured sequences were derived from tiger sharks. This study demonstrates that archived shark jaws and vertebrae are potential high-yield sources of DNA for genomic-scale analysis. It also highlights that even for similar tissue types, a careful evaluation of extraction protocols can vastly improve DNA yield. PMID- 27508521 TI - Differential expression of desaturase genes and changes in fatty acid composition of Mortierella sp. AGED in response to environmental factors. AB - BACKGROUND: Some oleaginous fungi can produce large amounts of polyunsaturated fatty acids (PUFAs) which serve many physiological functions. Numerous desaturases are critical for the synthesis of PUFAs. This study aimed to investigate the regulation of lipid production and desaturase gene expression in Mortierella sp. AGED in response to different environmental factors, and the relationships between lipid production and desaturase gene expression. RESULTS: The fatty acid composition and mRNA levels of desaturase genes were significantly changed under low temperatures. With the exception of Delta5-desaturase, the transcript levels of all desaturase genes increased at a temperature of 20 degrees C. Changes in content of lipid and PUFAs responding to low temperature were consistent with desaturase gene expression. Time course studies on gene expression showed that mRNA levels of four desaturase genes increased rapidly after transferring the cells to low temperature. Ethanol (1.5% v/v) increased the transcript levels of Delta9-, Delta6- and Delta5-desaturase genes significantly and of Delta12-desaturase gene slightly. Different metal ions such as Ca2+ , Zn2+ and Fe3+ could stimulate PUFA synthesis and up-regulate desaturase gene transcription, while Cu2+ inhibited desaturase gene expression and lipid accumulation. CONCLUSION: This study should enable us to understand the regulatory mechanism of desaturase gene expression and lipid synthesis. It is helpful to improve PUFA productivity in Mortierella sp. AGED. (c) 2016 Society of Chemical Industry. PMID- 27508523 TI - Nitrous oxide-based versus nitrous oxide-free general anaesthesia and accidental awareness during general anaesthesia in surgical patients. AB - BACKGROUND: Accidental awareness during general anaesthesia (AAGA) is when a patient unintentionally becomes conscious during a procedure performed with general anaesthesia and subsequently has explicit recall of this event. Incidence estimates for AAGA vary, with the most common estimate being one to two cases per 1000 general anaesthetics. Evidence linking nitrous oxide use and an increased risk of AAGA has come from observational studies data but the literature is contradictory, with some studies finding a protective effect of nitrous oxide. OBJECTIVES: To assess the effect of general anaesthesia including nitrous oxide on the risk of AAGA in patients aged five years and over. SEARCH METHODS: We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and trial registers ((www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (www.who.int/ictrp/network/en/) and Current Controlled Trials (www.isrctn.com/)) for eligible studies on December 9 2015. In addition, we conducted forward and backward citation searching using key identified papers. SELECTION CRITERIA: We considered all randomized controlled trials (RCTs), including quasi-randomized studies and cluster randomized studies, of participants aged five years or older receiving general anaesthesia for any type of surgery.We included trials in which participants receiving general anaesthesia that included nitrous oxide for maintenance at a concentration of at least 30% were compared with participants receiving no nitrous oxide during general anaesthesia. The intervention group must have received nitrous oxide in conjunction with an additional anaesthetic. We excluded studies where the depth of anaesthesia differed between the study arms. For inclusion in the review, studies needed to state in their methods that they planned to assess AAGA. We defined this as when a patient becomes conscious during a procedure performed with general anaesthesia and subsequently has explicit recall of this event. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane to identify studies. We extracted data and conducted 'Risk of bias' assessment using the Covidence database. MAIN RESULTS: We included 15 studies. The total number of participants included in the analyses was 3520. Most studies were small with fewer than 120 participants, although two larger studies with 2012 and 671 participants were included. There was considerable variation in many of the study characteristics, including the anaesthetics used. The concentrations of nitrous oxide varied between 50% and 70%, and half of the studies used clinical signs and haemodynamic changes to monitor depth of anaesthesia.As it was not possible to blind the anaesthetist to the anaesthetic used, we rated all studies at high risk of performance bias and we therefore downgraded the quality of evidence by one level for risk of bias using the GRADE approach. Other types of bias were generally low, or were rated unclear due to missing information.No studies were designed to measure AAGA as the primary outcome, and were therefore statistically underpowered to answer this review question. Despite the inclusion of 3520 participants, only three awareness events were reported by two studies. In one study the event was due to technical failure. Due to the rarity of the events, we did not consider it appropriate to pool the data, and we therefore downgraded the quality of evidence by a further level for imprecision using GRADE. AUTHORS' CONCLUSIONS: It is not possible to draw any conclusions from this review. The included studies were mainly small (fewer than 120 participants) and there were limited estimates of effect, with only two studies reporting any events. We cannot therefore determine whether the use of nitrous oxide in general anaesthesia increases, decreases or has no effect on the risk of accidental awareness. PMID- 27508524 TI - Effect of substituents on prediction of TLC retention of tetra-dentate Schiff bases and their Copper(II) and Nickel(II) complexes. AB - The objectives of this study were to gain insights into structure-retention relationships and to propose the model to estimating their retention. Chromatographic investigation of series of 36 Schiff bases and their copper(II) and nickel(II) complexes was performed under both normal- and reverse-phase conditions. Chemical structures of the compounds were characterized by molecular descriptors which are calculated from the structure and related to the chromatographic retention parameters by multiple linear regression analysis. Effects of chelation on retention parameters of investigated compounds, under normal- and reverse-phase chromatographic conditions, were analyzed by principal component analysis, quantitative structure-retention relationship and quantitative structure-activity relationship models were developed on the basis of theoretical molecular descriptors, calculated exclusively from molecular structure, and parameters of retention and lipophilicity. PMID- 27508522 TI - N-terminal fragment of the type-B natriuretic peptide (NT-proBNP) contributes to a simple new frailty score in patients with newly diagnosed multiple myeloma. AB - Multiple myeloma (MM) patient frailty has been delineated primarily by age and ECOG performance score (PS) and recently by the IMWG frailty score based on functional status [Activity of Daily Living (ADL) and Instrumental-ADL scores], comorbidities [Charlson-comorbidity-index (CCI)] and age. It was hypothesized that N-terminal natriuretic peptide type B (NT-proBNP) might be both a more convenient measure of frailty and a predictor of overall survival (OS). Three hundred and fifty-one consecutive symptomatic MM patients who were seen at Mayo Clinic within 30 days of diagnosis and who had blood stored were eligible. Data from the first visit was abstracted and used to calculate an ADL, CCI, and measure the NT-proBNP level. The best cutoff of NT-proBNP predicting OS was 300 ng/L. Variables predictive for OS were ECOG-PS, age, CCI, ADL, ISS, revised-ISS, and NT-proBNP. On multivariate analysis age >=70, PS >=2, and NT-proBNP >=300 were independent predictors of survival. Patients were assigned a score of 1 for each of these variables, creating stages I-IV with scores of 0-3 points, respectively. The median OS from diagnosis was not reached, 58, 28, and 18 months (P < 0.0001), respectively. This frailty risk schema was independent of initial therapy and the revised-ISS. NT-proBNP is a useful predictor of survival independent of age and PS. It is a widely available biomarker that could be added to the panel of laboratory tests of newly diagnosed MM patients and serve as a simple and objective tool of determining frailty in clinical practice. Am. J. Hematol. 91:1129-1134, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27508526 TI - FY17-PDH-EVTest04 GodInput Impact of the Oxygen Defects1 FY17-PDH-EVTest04 Reduction Rates of Stearic AcidFY17-PDH-T04. AB - Test New Article1 GodEarlyview.Publish-on-load testing.The role of the specific physicochemical properties of ZrO2 phases on Ni/ZrO2 has been explored with respect to the reduction of stearic acid. Conversion on pure m?ZrO2 is 1.3 times more active than on t?ZrO2 , whereas Ni/m?ZrO2 is three times more active than Ni/t?ZrO2 . Although the hydrodeoxygenation of stearic acid can be catalyzed solely by Ni, the synergistic interaction between Ni and the ZrO2 support causes the variations in the reaction rates. Adsorption of the carboxylic acid group on an oxygen vacancy of ZrO2 and the abstraction of the ??hydrogen atom with the elimination of the oxygen atom to produce a ketene is the key to enhance the overall rate. The hydrogenated intermediate 1?octadecanol is in turn decarbonylated to heptadecane with identical rates on all catalysts. Decarbonylation of 1?octadecanol is concluded to be limited by the competitive adsorption of reactants and intermediate. The substantially higher adsorption of propionic acid demonstrated by IR spectroscopy and the higher reactivity to O2 exchange reactions with the more active catalyst indicate that the higher concentration of active oxygen defects on m?ZrO2 compared to t?ZrO2 causes the higher activity of Ni/m?ZrO2 . PMID- 27508527 TI - Validation of the Accutrend Plus point-of-care triglyceride analyzer in horses, ponies, and donkeys. AB - OBJECTIVE: To assess the accuracy and reliability of a point-of-care (POC) triglyceride analyzer and to establish reference intervals for blood ([TRIG]POC/WB ) and plasma triglyceride concentrations ([TRIG]POC/PL ) in horses, ponies, and donkeys. DESIGN: Prospective study. SETTING: University teaching hospital. ANIMALS: 120 adult healthy equids (78 horses and ponies, 42 donkeys) and 79 equids suffering from hypertriglyceridemia (73 horses and ponies, 6 donkeys). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: [TRIG]POC/WB and [TRIG]POC/PL were measured using a POC analyzer and plasma triglyceride concentrations were measured using a standard laboratory assay ([TRIG]LAB/PL ). Reference intervals were determined. Test accuracy was assessed by Bland-Altman comparison of POC measurements with standard laboratory measurements and by evaluating linearity of dilutional series. Test reliability was assessed by repeated serial measurements. [TRIG]POC/WB and [TRIG]POC/PL were below the analytic range of the POC assay (<0.8 mmol/L [<70 mg/dL]) in healthy horses and ponies, whereas the reference intervals were 0.82-3.14 mmol/L (73-278 mg/dL) and 0.87-3.02 mmol/L (77-267 mg/dL), respectively, in donkeys. The POC analyzer systematically overestimated triglyceride concentrations when compared to a standard laboratory assay. The difference between [TRIG]POC/WB and [TRIG]POC/PL was small and clinically negligible. The coefficient of variation of repeated measures performed on the POC analyzer was below 10% for [TRIG]POC/WB and [TRIG]POC/PL , both in horses and donkeys and at all concentration ranges. CONCLUSIONS: The POC analyzer allows accurate and reliable measurement of [TRIG]POC/WB and [TRIG]POC/PL in horses, ponies, and donkeys in clinical settings. Assay-specific reference intervals should be determined for diagnosis and clinical monitoring of hypertriglyceridemia in equids. PMID- 27508525 TI - Prognostic significance of day 14 bone marrow evaluation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia. AB - BACKGROUND: The role of day 14 (D14) bone marrow (BM) assessment in detecting increased blasts in patients undergoing induction for acute lymphoblastic leukemia (ALL) is not well defined. METHODS: This study evaluated 389 adolescent and adult patients with previously untreated Philadelphia chromosome-negative ALL who received frontline induction chemotherapy and for whom a D14 BM assessment was performed. RESULTS: A D14 BM blast proportion < 10% (including blast-free aplastic BM) was observed in 319 patients (82%), 10% to 29% was observed in 31 patients (8%), and >=30% was observed in 39 patients (10%). The composite complete remission (CR)/complete remission with inadequate platelet recovery (CRp) rates for these groups were 99.7%, 87%, and 79%, respectively. The median event-free survival (EFS) was 49, 33, and 9 months, respectively (P < .001). The median overall survival (OS) was 88, 37, and 21 months, respectively (P < .001). The D14 BM blast group was the only factor predictive for the achievement of CR/CRp (P < .001). According to a multivariate analysis, the D14 BM blast group was independently prognostic for both EFS (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.12-1.85; P = .004) and OS (HR, 1.45; 95% CI, 1.14 1.85; P = .003). However, when minimal residual disease (MRD) assessment at the time of CR was added to the model, the D14 BM blast group was no longer prognostic for EFS or OS. CONCLUSIONS: An assessment of residual D14 BM blasts in patients with ALL is highly predictive of the achievement of CR with induction chemotherapy and of EFS and OS. However, the D14 BM blast assessment is less prognostic of long-term outcomes when an MRD assessment is also available. Cancer 2016;122:3812-3820. (c) 2016 American Cancer Society. PMID- 27508529 TI - ZODIAC of Diarrhea Management. PMID- 27508528 TI - Ascorbate-dependent impact on cell-derived matrix in modulation of stiffness and rejuvenation of infrapatellar fat derived stem cells toward chondrogenesis. AB - Developing an in vitro microenvironment using cell-derived decellularized extracellular matrix (dECM) is a promising approach to efficiently expand adult stem cells for cartilage engineering and regeneration. Ascorbic acid serves as a critical stimulus for cells to synthesize collagens, which constitute the major component of dECM. In this study, we hypothesized that optimization of ascorbate treatment would maximize the rejuvenation effect of dECM on expanded stem cells from human infrapatellar fat pad in both proliferation and chondrogenic differentiation. In the duration regimen study, we found that dECM without L ascorbic acid phosphate (AA) treatment, exhibiting lower stiffness measured by atomic force microscopy, yielded expanded cells with higher proliferation capacity but lower chondrogenic potential when compared to those with varied durations of AA treatment. dECM with 250 uM of AA treatment for 10 d had better rejuvenation in chondrogenic capacity if the deposited cells were from passage 2 rather than passage 5, despite no significant difference in matrix stiffness. In the dose regimen study, we found that dECMs deposited by varied concentrations of AA yielded expanded cells with higher proliferation capacity despite lower expression levels of stem cell related surface markers. Compared to cells expanded on tissue culture polystyrene, those on dECM exhibited greater chondrogenic potential, particularly for the dECMs with 50 uM and 250 uM of AA treatment. With the supplementation of ethyl-3,4-dihydroxybenzoate (EDHB), an inhibitor targeting procollagen synthesis, the dECM with 50 uM of AA treatment exhibited a dramatic decrease in the rejuvenation effect of expanded cell chondrogenic potential at both mRNA and protein levels despite no significant difference in matrix stiffness. Defined AA treatments during matrix preparation will benefit dECM-mediated stem cell engineering and future treatments for cartilage defects. PMID- 27508530 TI - Ready to Measure Impact? The Introduction of Rotavirus Vaccine in India. PMID- 27508531 TI - Healthcare Interventions and Vaccines. PMID- 27508532 TI - Rotavirus in India: Forty Years of Research. AB - Rotavirus was first identified as a human pathogen just over 40 years ago, and work on this pathogen in India started shortly thereafter. Subsequent studies have confirmed its pre-eminent role in gastroenteritis in children in India. Standardized surveillance has enabled the documentation of the high burden of disease, and has demonstrated that there is considerable geographic and temporal variation in strain circulation. Internationally licensed vaccines, vaccine candidates based on indigenous strains and out-licensed strains have been tested for safety, immunogenicity and efficacy; three vaccines are now licensed in India and are used in the private sector. Public sector vaccination has begun, and it will be path-breaking for Indian vaccinologists to measure impact of vaccine introduction in terms of safety and effectiveness. So far, India has kept pace with international epidemiologic and vaccine research on rotavirus, and these efforts should continue. PMID- 27508533 TI - Expanded Indian National Rotavirus Surveillance Network in the Context of Rotavirus Vaccine Introduction. AB - OBJECTIVE: To extend a nation-wide rotavirus surveillance network in India, and to generate geographically representative data on rotaviral disease burden and prevalent strains. DESIGN: Hospital-based surveillance. SETTING: A comprehensive multicenter, multi-state hospital based surveillance network was established in a phased manner involving 28 hospital sites across 17 states and two union territories in India. PATIENTS: Cases of acute diarrhea among children below 5 years of age admitted in the participating hospitals. RESULTS: During the 28 month study period between September 2012 and December 2014, 11898 children were enrolled and stool samples from 10207 children admitted with acute diarrhea were tested; 39.6% were positive for rotavirus. Highest positivity was seen in Tanda (60.4%) and Bhubaneswar (60.4%) followed by Midnapore (59.5%). Rotavirus infection was seen more among children aged below 2 years with highest (46.7%) positivity in the age group of 12-23 months. Cooler months of September to February accounted for most of the rotavirus associated gastroenteritis, with highest prevalence seen during December to February (56.4%). 64% of rotaviru infected children had severe to very severe disease. G1 P[8] was the predominant rotavirus strain (62.7%) during the surveillance period. CONCLUSION: The surveillance data highlights the high rotaviral disease burden in India. The network will continue to be a platform for monitoring the impact of the vaccine. PMID- 27508534 TI - Rotavirus and other Diarrheal Disease in a Birth Cohort from Southern Indian Community. AB - OBJECTIVE: To describe the incidence, severity and etiology of diarrheal disease in infants and young children residing in an urban slum community in Southern India. SETTING: Three contiguous urban slums in Vellore, Tamil Nadu. PARTICIPANTS: 452 children participating in a birth cohort study on diarrheal disease; 373 completed three years of follow-up. OUTCOME MEASURES: Diarrheal incidence (obtained by twice-weekly home visits) and severity (assessed by the Vesikari scoring system), and etiological agents associated with diarrhea (through examination of stool specimens by bacteriologic culture, rotavirus enzyme immunoassay, PCR for norovirus and microscopy for parasites). RESULTS: A total of 1856 diarrheal episodes were reported in 373 children. The overall incidence rate of diarrhea was 1.66 episodes per child year for three years, with 2.76 episodes per child year in infancy. The incidence peaked during the months of July and August. Severe diarrhea formed 8% of the total episodes. Rotavirus was the most common pathogen detected, being identified in 18% of episodes. Good hygiene status resulted in 33% protection against moderate-to-severe diarrhea. CONCLUSIONS: This study highlights the burden of diarrheal disease and the important etiological agents of childhood diarrhea in Southern India. Promotion of hygienic behavior through health education may help reduce diarrheal incidence in this and similar communities. PMID- 27508535 TI - Rotavirus Infections in Children Vaccinated Against Rotavirus in Pune, Western India. AB - OBJECTIVE: To characterize rotavirus infections detected in rotavirus vaccinated children hospitalized for acute gastroenteritis. DESIGN: Observational, hospital based study. SETTING: Three hospitals in Pune, Western India. PARTICIPANTS: Children aged <5 years hospitalized for acute gastroenteritis during 2013-14. METHODS: Rotavirus capture ELISA was performed on all stool samples that were collected from patients following informed consent from parents. VP7 and VP4 genes of rotavirus strains were genotyped by multiplex RT-PCR. Stool samples from vaccinated children were tested for other enteric viruses. RESULTS: Among the 529 children, 53 were vaccinated with at least one dose of the rotavirus vaccine. There was no difference in the mean (SD) (months) age of vaccinated [14.8 (10.6)] and unvaccinated [14.4 (10.5)] children. Rotavirus positivity was significantly higher (47%) in unvaccinated than in vaccinated (28.3%) children (P=0.01). Mean Vesikari score and severe cases were significantly more in rotavirus positive than in negative children within unvaccinated group (P<0.001), while these did not differ within the vaccinated group. Rotavirus strain G1P[8] was identified as the most prevalent strain in both, vaccinated (60%) and unvaccinated (72.8%) groups. No association was found between mean Vesikari score and viral coinfections. CONCLUSIONS: This study suggests decline in rotavirus positivity in rotavirus-vaccinated children hospitalized for acute gastroenteritis and high prevalence of G1P[8] and non-rotaviral co-infections in Pune, Western India. PMID- 27508536 TI - Racecadotril in the Management of Rotavirus and Non-rotavirus Diarrhea in Under five Children: Two Randomized, Double-blind, Placebo-controlled Trials. AB - OBJECTIVE: To study the effect of racecadotril on reduction in the duration of acute rotavirus and non-rotavirus diarrhea. DESIGN: Two randomized double-blind placebo-controlled trials. SETTING: Community-based trial in an urban area in Vellore, hospital-based trial at a secondary hospital in Vellore. PARTICIPANTS: 199 and 130 3-59 month old children in the community- and hospital-based trials, respectively. METHODS: Racecadotril (1.5 mg/kg/dose, thrice a day for three days) or placebo were given to manage acute diarrhea in both trials. MAIN OUTCOME MEASURE: Median duration of diarrhea. RESULTS: Among 124 children completing the hospital trial, the median duration of diarrhea was 25 h in both arms (P=0.5); median total stool weight was 74 g/kg and 53.5 g/kg in racecadotril group and placebo group, respectively (P=0.4); and average fluid intake per day was 3.6 mL/kg/h and 3mL/kg/h in racecadotril and placebo arms, respectively (P=0.3). Among rotavirus-positive children, median duration of diarrhea was 26.9 h and 30.2 h in racecadotril and placebo arms, respectively (P=0.7). In the community, 196 completed the trial, the median duration of diarrhea was 2 days for both arms (P=0.8) and rotavirus positive children had similar outcomes with median diarrheal duration of 3 d in both arms (P=0.4). CONCLUSIONS: Treatment with racecadotril did not reduce diarrheal duration, stool volume or the requirement for fluid replacement in children with acute gastroenteritis, both with and without rotavirus infection. PMID- 27508537 TI - Rotavirus specific Salivary and Fecal IgA in Indian Children and Adults. AB - OBJECTIVE: To compare serum, salivary and fecal IgA responses in infants and adults following rotavirus vaccination. STUDY DESIGN: Laboratory testing of samples from clinical trials. SETTING: Medical College Hospital. PARTICIPANTS: 13 healthy adult volunteers not given vaccine, 20 healthy adult volunteers given one dose of bovine rotavirus tetravalent vaccine (Shantha Biotechnics), and 88 infants given 3 or 5 doses of Rotarix. OUTCOME MEASURES: Serum, salivary and fecal IgA at one or more time points. METHODS: IgA antibodies were estimated in serum, saliva and fecal samples by enzyme-linked immunosorbent assay, and normalized to total IgA in saliva. RESULTS: In naturally infected adult volunteers, comparing serum and salivary IgA showed significant positive correlation (r=0.759; P=0.003). Of 20 vaccinated adults, complete samples showing change were available for 10; among them there was a significant positive correlation (P<0.05) between pre-vaccination serum and pre-vaccination salivary IgA but not between post-vaccination serum and post-vaccination salivary IgA. Of 88 infants given 3 or 5 doses of vaccine, 13 had more than 4-fold IgA response in serum, saliva and fecal samples, 6 had a 2-4 fold increases in all specimens. There was weak correlation between seroconversion rates measured by serum and salivary antibody responses. Salivary and stool assays were able to detect seroconversion in a few children in whom there was no detectable response in serum. CONCLUSIONS: Evaluation of multiple samples is useful for intensive experimental study designs and may help improve our understanding of the induction and dynamics of immune responses to rotavirus vaccination. PMID- 27508538 TI - Burden of Rotavirus Diarrhea in Under five Indian Children. AB - NEED AND PURPOSE: Rotavirus is the most common cause of severe diarrhea in infants and young children worldwide. The burden of rotavirus diarrhea in Indian children is not well established. The present study reviewed the epidemiology of rotavirus diarrhea in hospitalized children and in the community, molecular serotyping and under-five mortality caused by rotavirus diarrhea. METHODS: Publications, reporting rotavirus diarrhea in Indian children, were retrieved through a systematic search of databases including Medline, PubMed, IndMed, websites of WHO, UNICEF, National Family Health Survey, Ministry of Health and Family Welfare, and Government of India. Human studies in English language were included. Age group selected was 0 month to 5 years. No restrictions were applied in terms of study design and time frame. CONCLUSIONS: Stool sample positivity varied from 4.6% in Kolkata to 89.8% in Manipur, among hospitalized children, and from 4% in Delhi to 33.7% in Manipur in community. Most cases of rotavirus diarrhea in India are caused by G1, G2, and G untypeable strains with distinct regional variations. Rotavirus was identified as an etiological agent in 5.2 to 80.5% cases of nosocomial diarrhea. Data are lacking for rotavirus mortality. PMID- 27508539 TI - Profile and Trends of Rotavirus Gastroenteritis in Under 5 children in India, 2012 - 2014, Preliminary Report of the Indian National Rotavirus Surveillance Network. AB - OBJECTIVE: To estimate the burden of rotavirus-associated gastroenteritis in India. METHODS: Hospital based surveillance network was established, with clinical evaluation and laboratory testing for rotavirus among children aged below 5 years hospitalized with acute gastroenteritis. RESULTS: Between September 2012 and December 2014, stool samples from 10207 children were tested and rotavirus was detected in 39.6% of cases. Infections were more commonly seen among younger children (<2 years). Detection rates were higher during cooler months of September February. Among rotavirus infected children, 64.0% had severe or very severe disease. G1P[8] was the predominant rotavirus genotype (62.7%) observed during the surveillance period. CONCLUSIONS: Surveillance data highlights the high rotavirus disease burden and emphasizes the need for close monitoring to reduce morbidity and mortality associated with rotavirus gastroenteritis in India. PMID- 27508540 TI - Interpretation of Rotavirus positivity Patterns Across India. AB - OBJECTIVE: To analyze variation in rotavirus-positivity using simple alternative statistical measures. METHODS: Hospital-based rotavirus surveillance among children admitted with acute gastroenteritis between 2005 and 2009. Prevalence, adjusted proportions and symmetrized index were calculated. RESULTS: Rotavirus prevalence was 40% (range 37% - 44%). Adjusted proportion analysis revealed higher level of deviation from annual prevalence in seasons (December to February and September to November); age groups (<12 months and 12-23 months) and regions (East and South). Analysis of symmetrized index revealed higher estimates of variation in all years, except in 2006. CONCLUSIONS: Proposed statistical measures are useful as refined measures to study extent of disease spread in surveillance programmes, aiding evaluation of the load and pattern of disease burden in different regions over time. PMID- 27508541 TI - Rotavirus Diarrhea in Children Presenting to an Urban Hospital in Western Uttar Pradesh, India. AB - OBJECTIVE: To determine the proportion and clinical profile of rotavirus associated diarrhea in children aged 6 months to 5 years. METHODS: Clinical details and stool samples were collected from 254 children aged between 6 months to 5 years presenting with acute diarrhea, irrespective of hydration status, to the outpatient department or emergency room of a hospital in Meerut, Uttar Pradesh, India. RESULTS: Rotavirus accounted for 26.3% (51 of 194) of diarrhea cases overall, and 41.2% (14 of 34) in hospitalized children. Rotavirus infection was associated with significantly longer duration [3.3 (1.4) d vs. 2.5 (1.1) d; P=0.004) of diarrhea, and more chances of dehydration (OR 1.85; 95% CI 1.19, 3.57) as compared to non-rotavirus diarrhea. CONCLUSIONS: Rotavirus is a common cause of acute diarrhea in under-five children, and is associated with a longer duration and more chances of dehydration than non-rotavirus diarrhea. PMID- 27508542 TI - Rotavirus Infection in Children with Acute Gastroenteritis in Aurangabad, Central Maharashtra. AB - OBJECTIVE: To determine the prevalence of rotavirus diarrhea and its genotypes in children from Aurangabad, India. METHODS: Stool samples collected during 2012 2013 from 168 children, aged ?3 years, were tested by ELISA to detect rotavirus. Rotavirus strains were genotyped by multiplex reverse-transcription polymerase chain reaction. RESULTS: Stool samples from 20 (11.9%) children tested positive for rotavirus. Rotavirus positivity was higher among the children aged 0-12 months than those in 13-24 and 25-36 months. Severity of disease was moderate in both rotavirus-infected and uninfected children. Genotype G1P[8] combination was detected predominantly in circulation. CONCLUSIONS: Rotavirus diarrhea was caused mainly by G1P[8] strains during 2012-2013 in Aurangabad, Central Maharashtra, India. PMID- 27508543 TI - Leveraging the National Rotavirus Surveillance Network for Monitoring Intussusception. AB - OBJECTIVE: To assess feasibility of monitoring intussusception by hospitals participating in the National Rotavirus Surveillance Network. METHODS: Questionnaire-based survey in 28 hospitals. One hospital with electronic records selected for detailed data analysis. RESULTS: There was 75% response to the questionnaire. Few network hospitals were suitable for monitoring intussusception in addition to ongoing activities, but there was at least one potential sentinel hospital in each region. The hospital selected for detailed data analysis of cases of intussusception reported an incidence rate of 112 per 100,000 child years in infants. Over 90% of intussusceptions were managed without surgery. CONCLUSIONS: Selection of sentinel hospitals for intussusception surveillance is feasible and necessary, but will require training, increased awareness and referral. PMID- 27508544 TI - Direct Medical Costs in Children with Rotavirus and Non-rotavirus Diarrhea Admitted to a Pediatric Intensive Care Unit and High Dependency Unit in Delhi. AB - OBJECTIVE: To estimate direct medical costs of diarrheal hospitalization of children <5 years admitted in pediatric intensive care unit (PICU) or high dependency unit (HDU). METHODS: Analysis of medical records and hospital bills of 84 children during two time frames, 2005-08 and 2012-14. RESULTS: Direct medical costs in PICU increased from INR 17,941 to INR 50,663 per child for rotavirus diarrhea and INR 11,614 to INR 27,106 for non-rotavirus diarrhea, and in HDU from approximately INR 5,800 to INR 10,500 per child for all-cause diarrhea between the two time frames. CONCLUSIONS: Costs of PICU and HDU care are high and should be included in cost-effectiveness analysis of vaccination. PMID- 27508545 TI - Direct and Indirect Costs of Pediatric Gastroenteritis in Vellore, India. AB - OBJECTIVE: To determine costs of pediatric gastroenteritis in out-patient and in patient facilities. METHODS: Cross-sectional survey of children with acute gastroenteritis attending out-patient clinic (n=30) or admitted in the ward (n=30) for management in the Christian Medical College, Vellore, India from July September 2014 to estimate direct (drugs, tests, consultation/hospitalization) and indirect (travel, food, lost wages) costs associated with the episode. RESULTS: Median direct and indirect costs were Rs 590 and Rs 190 for out-patient management and Rs 7258 and Rs. 610 for hospitalization, constituting 1.1% and 11% of median annual household income, respectively. CONCLUSIONS: Escalating healthcare costs need tracking for evaluation of interventions. PMID- 27508546 TI - Time trend Analysis of the Impact of Universal Rotavirus Vaccination in Brazil: Evidence based Medicine Viewpoint. PMID- 27508547 TI - Time trend Analysis of the Impact of Universal Rotavirus Vaccination in Brazil: Immunization Experts Viewpoint. PMID- 27508548 TI - Hospital-based Surveillance of Rotavirus Diarrhea among Under- five Children in Chandigarh. AB - In a prospective hospital-based surveillance of 958 under five children admitted with acute gastroenteritis in Chandigarh (May 2011 to July 2012), 239 stool samples were collected. Rotavirus antigen was detected in 18.8% of samples by reverse transcriptase polymerase chain reaction. Genotypes G1P[8] (53.3%), G12P[6] (15.6%) were prevalent, and G3 not detected. PMID- 27508549 TI - Immunochromatography-based Diagnosis of Rotavirus Infection in Acute Diarrhea. AB - Documentation of rotavirus diarrhea in a rural, resource-poor setting is a difficult task. We analyzed stool samples of 103 children admitted for acute diarrhea in a pediatric hospital in Bijnor, UP, India, using a simple bedside immunochromatography kit. Rotavirus infection was detected in 47 out of total of 103 children (45.6%). PMID- 27508550 TI - Association of Rotavirus Gastroenteritis with Histo-blood Group Antigens. AB - Association of rotavirus gastroenteritis with histo-blood group antigens in children younger than 5 years admitted with diarrhea (n=389) was studied. Distribution of blood groups in rotavirus positive (n=96) and rotavirus negative (n=51) diarrhea gastroenteritis cases did not show any susceptibility to any blood group; blood group O seemed to be protective. PMID- 27508551 TI - Recurrent Intussusception in an Infant. PMID- 27508552 TI - Sudden Death Due to Coronary Blockade by Microfilaremia: An Autopsy Report. AB - Extralymphatic filarial disease has varied clinical manifestations and is largely underestimated worldwide. We report an autopsy case of extralymphatic filarial disease with coronary and pulmonary circulations being involved and causing sudden death. Such an isolated event is, perhaps, rare and has not been reported so far to the best of our knowledge. Microfilaremia on autopsy may be easily missed or overlooked due to unawareness. The present report emphasizes the importance of extensive careful scrutiny of autopsy sections. PMID- 27508859 TI - Type I Interferon-Mediated Induction of Antiviral Genes and Proteins Fails to Protect Cells from the Cytopathic Effects of Sendai Virus Infection. AB - Sendai virus (SeV), a murine paramyxovirus, has been used to study the induction of type I interferon (IFN) subtypes in robust quantities. Few studies have measured whether the IFN that SeV induces actually fulfills its intended purpose of interfering with virus-mediated effects in the cells in which it is produced. We determined the effects of IFN on SeV-mediated cytopathic effects (CPE) and the ability of IFN to protect against virus infection. SeV-induced biologically active IFN resulted in Jak/STAT activation and the production of a number of interferon-stimulated genes (ISGs). However, these responses did not inhibit SeV replication or CPE. This observation was not due to SeV effects on canonical IFN signaling. Furthermore, pretreating cells with type I IFN and establishing an antiviral state before infection did not mediate SeV effects. Therefore, the induction of canonical IFN signaling pathways and ISGs does not always confer protection against the IFN-inducing virus. Because type I IFNs are approved to treat various infections, our findings suggest that typical markers of IFN activity may not be indicative of a protective antiviral response and should not be used alone to determine whether an antiviral state against a particular virus is achieved. PMID- 27508861 TI - Accessory liver lobe attached to the gallbladder wall preoperatively detected by ultrasonography: A case report. AB - INTRODUCTION: An accessory liver lobe is a rare developmental abnormality, which is often not diagnosed preoperatively, and is usually detected incidentally during abdominal surgery. This condition is often asymptomatic; here, we report on a case where the accessory liver lobe was diagnosed preoperatively using ultrasonography. CASE PRESENTATION: A 59-year-old woman presented to our hospital with right upper abdominal pain. An abdominal ultrasonography indicated the presence of gallbladder debris and an accessory liver lobe. She underwent laparoscopic cholecystectomy and resection of the accessory liver lobe without any complications. DISCUSSION: An accessory liver lobe is a rare anomaly of the liver. It is typically asymptomatic and is detected incidentally during surgery or autopsy in most cases. However, we diagnosed the accessory liver lobe using ultrasonography. An accessory liver lobe can occasionally result in complications, such as bleeding, portal vein obstruction, or malignant transformation to hepatocellular carcinoma. CONCLUSION: An accessory liver lobe should be resected to prevent complications and malignant transformation. Ultrasonography is useful for preoperative diagnosis in cases with an accessory liver lobe. PMID- 27508860 TI - The effect of copper from water and food: changes of serum nonceruloplasmin copper and brain's amyloid-beta in mice. AB - Copper is an essential element and also produces adverse health consequences when overloaded. Food and water are the main sources of copper intake, however few studies have been conducted to investigate the difference between the ways of its intake in water and food in animals. In this study, copper was fed to mice with food as well as water (two groups: water and diet) for three months at concentrations of 6, 15 and 30 ppm. The copper concentration in water was adjusted for keeping the same amount during its intake in food. The experimental studies show a slow growth rate, lower hepatic reduced glutathione (GSH)/superoxide dismutase (SOD) activity and higher serum 'free' copper in the water group. The brain's soluble amyloid-beta 1-42 (Abeta42) of the water group was significantly higher than that of the diet group at the levels of 6 and 15 ppm. In conclusion, copper in the water group significantly increased the soluble Abeta42 in the brain and the 'free' copper in the serum, decreased the growth rate and hepatic GSH/SOD activity. The research studies carried out suggest that the copper in water is more 'toxic' than copper in diet and may increase the risk of Alzheimer's disease (AD). PMID- 27508863 TI - Influence of wastewater treatment plant discharges on microplastic concentrations in surface water. AB - The abundance of microplastic particles in the marine environment is well documented, but less is known about microplastics in the freshwater environment. Wastewater treatment plants (WWTPs) may not effectively remove microplastics allowing for their release to the freshwater environment. To investigate concentration of microplastic in fresh water and the impact of WWTP effluent, samples were collected upstream and downstream of four major municipal WWTPs on the Raritan River, NJ. Microplastics were categorized into three quantitative categories (500-2000 MUm, 250-500 MUm, 125-250 MUm), and one semi-quantitative category (63-125 MUm). Then, microplastics were classified as primary (manufactured in small size) or secondary (derived from larger plastics) based on morphology. The concentration of microplastics in the 125-250 and 250-500 MUm size categories significantly increased downstream of WWTP. The smaller size classes, often not quantified in microplastic studies, were in high relative abundance across sampling sites. While primary microplastics significantly increased downstream of WWTP, secondary microplastic was the dominant type in the quantitative size categories (66-88%). A moderate correlation between microplastic and distance downstream was observed. These results have implications for understanding the fate and transport of microplastics in the freshwater environment. PMID- 27508862 TI - Crimean Congo Hemorrhagic Fever Virus and Alkhurma (Alkhumra) Virus in Ticks in Djibouti. AB - Crimean Congo hemorrhagic fever virus and Alkhumra virus, not previously reported in Djibouti, were detected among 141 (infection rate = 15.7 per 100, 95% CI: 13.4 18.1) tick pools from 81 (37%) cattle and 2 (infection rate = 0.2 per 100, 95% CI: 0.0-0.7) tick pools from 2 (1%) cattle, respectively, collected at an abattoir in 2010 and 2011. PMID- 27508864 TI - Cell Metabolism Remembers Cheolho Cheong. PMID- 27508865 TI - How Body Affects Brain. AB - Studies show that physical exercise can affect a range of brain and cognitive functions. However, little is known about the peripheral signals that initiate these central changes. Moon et al. (2016) provide exciting new evidence that a novel myokine, cathepsin B (CTSB), released with exercise is associated with improved memory. PMID- 27508866 TI - Colonic Macrophages "Remote Control" Adipose Tissue Inflammation and Insulin Resistance. AB - The early events linking diet-induced adipose tissue inflammation and insulin resistance remain poorly understood. In this issue of Cell Metabolism, Kawano et al. (2016) show that infiltration of colonic pro-inflammatory macrophages orchestrated by the intestinal CCL2/CCR2 axis kick-starts this process during high-fat-diet feeding. PMID- 27508867 TI - When Hexokinase Gets that NAG-ing Feeling.... AB - Immune cell recognition of bacterial products usually occurs via specific pattern recognition receptors, but new research recently published in Cell by Wolf et al. (2016) demonstrates that the glycolytic enzyme hexokinase can act as an innate immune sensor by binding to bacterial derived N-acetylglucosamine (NAG). PMID- 27508868 TI - Empagliflozin's Fuel Hypothesis: Not so Soon. AB - The EMPA-REG OUTCOME trial (Zinman et al., 2015) established cardioprotective effects of empagliflozin in high-risk diabetic patients, but the underlying mechanisms remain elusive. A recent hypothesis proposed that increased ketone oxidation contributed to the effect, but several caveats indicate that the role of myocardial ketone oxidation is far from clear. PMID- 27508869 TI - Sex and Gender: Critical Variables in Pre-Clinical and Clinical Medical Research. AB - In this Essay, we discuss the critical need to incorporate sex and gender in pre clinical and clinical research to enhance our understanding of the mechanisms by which metabolic processes differ by sex and gender. This knowledge will allow for development of personalized medicine which will optimize therapies specific for individuals. PMID- 27508870 TI - Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): Recommendations for Standardized FDG-PET/CT Experiments in Humans. AB - Human brown adipose tissue (BAT) presence, metabolic activity, and estimated mass are typically measured by imaging [18F]fluorodeoxyglucose (FDG) uptake in response to cold exposure in regions of the body expected to contain BAT, using positron emission tomography combined with X-ray computed tomography (FDG PET/CT). Efforts to describe the epidemiology and biology of human BAT are hampered by diverse experimental practices, making it difficult to directly compare results among laboratories. An expert panel was assembled by the National Institute of Diabetes and Digestive and Kidney Diseases on November 4, 2014 to discuss minimal requirements for conducting FDG-PET/CT experiments of human BAT, data analysis, and publication of results. This resulted in Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0). Since there are no fully validated best practices at this time, panel recommendations are meant to enhance comparability across experiments, but not to constrain experimental design or the questions that can be asked. PMID- 27508871 TI - Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils. AB - The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRbeta-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area. PMID- 27508872 TI - Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents. AB - Human genetics studies have implicated GALNT2, encoding GalNAc-T2, as a regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, but the mechanisms relating GALNT2 to HDL-C remain unclear. We investigated the impact of homozygous GALNT2 deficiency on HDL-C in humans and mammalian models. We identified two humans homozygous for loss-of-function mutations in GALNT2 who demonstrated low HDL-C. We also found that GALNT2 loss of function in mice, rats, and nonhuman primates decreased HDL-C. O-glycoproteomics studies of a human GALNT2-deficient subject validated ANGPTL3 and ApoC-III as GalNAc-T2 targets. Additional glycoproteomics in rodents identified targets influencing HDL-C, including phospholipid transfer protein (PLTP). GALNT2 deficiency reduced plasma PLTP activity in humans and rodents, and in mice this was rescued by reconstitution of hepatic Galnt2. We also found that GALNT2 GWAS SNPs associated with reduced HDL-C also correlate with lower hepatic GALNT2 expression. These results posit GALNT2 as a direct modulator of HDL metabolism across mammals. PMID- 27508873 TI - Human and Mouse Brown Adipose Tissue Mitochondria Have Comparable UCP1 Function. AB - Brown adipose tissue (BAT) plays an important role in mammalian thermoregulation. The component of BAT mitochondria that permits this function is the inner membrane carrier protein uncoupling protein 1 (UCP1). To the best of our knowledge, no studies have directly quantified UCP1 function in human BAT. Further, whether human and rodent BAT have comparable thermogenic function remains unknown. We employed high-resolution respirometry to determine the respiratory capacity, coupling control, and, most importantly, UCP1 function of human supraclavicular BAT and rodent interscapular BAT. Human BAT was sensitive to the purine nucleotide GDP, providing the first direct evidence that human BAT mitochondria have thermogenically functional UCP1. Further, our data demonstrate that human and rodent BAT have similar UCP1 function per mitochondrion. These data indicate that human and rodent BAT are qualitatively similar in terms of UCP1 function. PMID- 27508874 TI - Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle. AB - NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function. PMID- 27508875 TI - Colonic Pro-inflammatory Macrophages Cause Insulin Resistance in an Intestinal Ccl2/Ccr2-Dependent Manner. AB - High-fat diet (HFD) induces low-grade chronic inflammation and insulin resistance. However, little is known about the mechanism underlying HFD-induced chronic inflammation in peripheral insulin-responsive tissues. Here, we show that colonic pro-inflammatory macrophages regulate insulin sensitivity under HFD conditions. To investigate the pathophysiological role of colonic macrophages, we generated macrophage-specific chemokine (C-C Motif) receptor 2 (Ccr2) knockout (M Ccr2KO) and intestinal epithelial cell-specific tamoxifen-inducible Ccl2 knockout (Vil-Ccl2KO) mice. Both strains exhibited similar body weight to control under HFD. However, they exhibited decreased infiltration of colonic pro-inflammatory macrophages, decreased intestinal permeability, and inactivation of the colonic inflammasome. Interestingly, they showed significantly improved glucose tolerance and insulin sensitivity with decreased chronic inflammation of adipose tissue. Therefore, inhibition of pro-inflammatory macrophage infiltration prevents HFD induced insulin resistance and could be a novel therapeutic approach for type 2 diabetes. PMID- 27508876 TI - Acidosis Drives the Reprogramming of Fatty Acid Metabolism in Cancer Cells through Changes in Mitochondrial and Histone Acetylation. AB - Bioenergetic preferences of cancer cells foster tumor acidosis that in turn leads to dramatic reduction in glycolysis and glucose-derived acetyl-coenzyme A (acetyl CoA). Here, we show that the main source of this critical two-carbon intermediate becomes fatty acid (FA) oxidation in acidic pH-adapted cancer cells. FA-derived acetyl-CoA not only fuels the tricarboxylic acid (TCA) cycle and supports tumor cell respiration under acidosis, but also contributes to non-enzymatic mitochondrial protein hyperacetylation, thereby restraining complex I activity and ROS production. Also, while oxidative metabolism of glutamine supports the canonical TCA cycle in acidic conditions, reductive carboxylation of glutamine derived alpha-ketoglutarate sustains FA synthesis. Concomitance of FA oxidation and synthesis is enabled upon sirtuin-mediated histone deacetylation and consecutive downregulation of acetyl-CoA carboxylase ACC2 making mitochondrial fatty acyl-CoA degradation compatible with cytosolic lipogenesis. Perturbations of these regulatory processes lead to tumor growth inhibitory effects further identifying FA metabolism as a critical determinant of tumor cell proliferation under acidosis. PMID- 27508877 TI - Effects of Gut Microbiota Manipulation by Antibiotics on Host Metabolism in Obese Humans: A Randomized Double-Blind Placebo-Controlled Trial. PMID- 27508878 TI - SnapShot: Exercise Metabolism. AB - Exercise represents a major challenge to whole-body homeostasis. To meet this challenge, myriad acute and adaptive responses take place at multiple cellular and systemic levels. The molecular bases of skeletal muscle adaptations to exercise are mediated by an array of signaling events, pre- and post transcriptional processes, regulation of translation, and ultimately the increased abundance and/or maximal activity of key proteins with roles in energy provision. PMID- 27508879 TI - Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis. AB - Tuberculosis (TB) remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide (NO) donors, have been described to exhibit antitubercular activity. Herein, a novel series of hybrid furoxan derivatives (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-c, 8a-c and 14a-c) were designed, synthesized and evaluated in vitro against Mycobacterium tuberculosis (MTB) H37Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC90 values ranging from 1.03 to 62 MUM (H37Rv) and 7.0-50.0 MUM (MDR-TB). For the most active compounds (8c, 14a, 14b and 14c) the selectivity index ranged from 3.78 to 52.74 (MRC-5 cells) and 1.25-34.78 (J774A.1 cells). In addition, it was characterized for those compounds logPo/w values between 2.1 and 2.9. All compounds were able to release NO at levels ranging from 0.16 to 44.23%. Among the series, the phenylsulfonyl furoxan derivatives (compounds 14a-c) were the best NO-donor with the lowest MIC90 values. The most active compound (14c) was also stable at different pHs (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat tuberculosis. PMID- 27508880 TI - Effect of visible laser light on ATP level of anaemic red blood cell. AB - In this work we present influence of visible laser light on ATP level and viability of anaemic red blood cell (RBC). The visible laser lights used in this work are 460nm and 532nm. The responses of ATP level in anaemic and normal RBC before and after laser irradiation at different exposure time (30, 40, 50 and 60s) were observed. Three aliquots were prepared from the ethylenediaminetetraacetic acid (EDTA) blood sample. One served as a control (untreated) and another two were irradiated with 460nm and 560nm lasers. Packed RBC was prepared to study ATP level in the RBC using CellTiter-GloLuminescent cell Viability Assay kit. The assay generates a glow type signal produced by luciferase reaction, which is proportional to the amount of ATP present in RBCs. Paired t-test were done to analyse ATP level before and after laser irradiation. The results revealed laser irradiation improve level of ATP in anaemic RBC. Effect of laser light on anaemic RBCs were significant over different exposure time for both 460nm (p=0.000) and 532nm (p=0.003). The result of ATP level is further used as marker for RBC viability. The influence of ATP level and viability were studied. Optical densities obtained from the data were used to determine cell viability of the samples. Results showed that laser irradiation increased viability of anaemic RBC compared to normal RBC. PMID- 27508881 TI - Pigments from UV-resistant Antarctic bacteria as photosensitizers in Dye Sensitized Solar Cells. AB - Here we report the use of pigments produced by UV-resistant Antarctic bacteria as photosensitizers in Dye Sensitized Solar Cells (DSSCs). Pigments were obtained from red and yellow colored psychrotolerant bacteria isolated from soils of King George Island, Antarctica. Based on metabolic characteristics and 16s DNA sequence, pigmented bacteria were identified as Hymenobacter sp. (red) and Chryseobacterium sp. (yellow). Pigments produced by these microorganisms were extracted and classified as carotenoids based on their spectroscopic and structural characteristics, determined by UV-Vis spectrophotometry and infrared spectroscopy (FTIR), respectively. With the purpose of develop green solar cells based on bacterial pigments, the photostability and capacity of these molecules as light harvesters in DSSCs were determined. Absorbance decay assays determined that bacterial carotenoids present high photostability. In addition, solar cells based on these photosensitizers exhibit an open circuit voltage (VOC) of 435.0 [mV] and a short circuit current density (ISC) of 0.2 [mA.cm(-2)] for the red pigment, and a VOC of 548.8 [mV] and a ISC of 0.13 [mA.cm(-2)] for the yellow pigment. This work constitutes the first approximation of the use of pigments produced by non-photosynthetic bacteria as photosensitizers in DSSCs. Determined photochemical characteristics of bacterial pigments, summed to their easy obtention and low costs, validates its application as photosensitizers in next generation biological solar cells. PMID- 27508882 TI - Toll-like receptor 9 enhances bacterial clearance and limits lung consolidation in murine pneumonia caused by methicillin resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen in pneumonia, associated with severe lung damage. Tissue injury causes release of Damage Associated Molecular Patterns (DAMPs), which may perpetuate inflammation. DNA has been implicated as a DAMP that activates inflammation through Toll-like receptor (TLR)9. The aim of this study was to evaluate the role of TLR9 in MRSA pneumonia. Wild-type (Wt) and TLR9 knockout (tlr9-/-) mice were infected intranasally with MRSA USA300 (BK 11540) (5E7CFU) and euthanized at 6,24,48 or 72 hours for analyses. MRSA pneumonia was associated with profound release of cell free host DNA in the airways, as reflected by increases in nucleosome and DNA levels in bronchoalveolar lavage fluid (BALF), accompanied by transient detection of pathogen DNA in MRSA-free BALF supernatants. In BALF, as compared to Wt -mice tlr9-/- mice showed reduced TNFalpha and IL-6 levels at 6 hours and reduced bacterial clearance at 6 and 24 hours post infection. Furthermore, tlr9-/- mice exhibited a greater influx of neutrophils in BALF and increased lung consolidation at 24 and 48 hours. This study demonstrates the release of host- and pathogen-derived TLR9 ligands (DNA) into the alveolar space after infection with MRSA via the airways and suggests that TLR9 has pro-inflammatory effects during MRSA pneumonia associated with enhanced bacterial clearance and limitation of lung consolidation. PMID- 27508883 TI - The Physiological Profile of a Multiple Tour de France Winning Cyclist. AB - INTRODUCTION: This case study reports a range of physiological characteristics in a two-time Tour de France champion. METHODS: After body composition assessment (dual-energy x-ray absorptiometry), two submaximal cycling step tests were performed in ambient (20 degrees C, 40%) and hot and humid (30 degrees C, 60% [HH]) conditions from which measures of gross efficiency (GE), lactate-power landmarks, and heart rate responses were calculated. In addition, thermoregulatory and sweat responses were collected throughout. VO2peak and peak power output (PPO) were also identified after a separate ramp test to exhaustion. RESULTS: VO2peak and PPO were 5.91 L.min (84 mL.kg.min) and 525 W, respectively, whereas mean GE values were 23.0% and 23.6% for ambient and HH conditions, respectively. In addition to superior GE, power output at 4 mmol.L lactate was higher in HH versus ambient conditions (429.6 vs 419.0 W) supporting anecdotal reports from the participant of good performance in the heat. Peak core and skin temperature, sweat rate, and electrolyte content were higher in HH conditions. Body fat percentage was 9.5%, whereas total fat mass, lean mass, and bone mineral content were 6.7, 61.5, and 2.8 kg, respectively. CONCLUSION: The aerobic physiology and PPO values indentified are among the highest reported for professional road cyclists. Notably, the participant displayed both a high VO2peak and GE, which is uncommon among elite cyclists and may be a contributing factor to their success in elite cycling. In addition, performance in HH conditions was strong, suggesting effective thermoregulatory physiology. In summary, this is the first study to report physiological characteristics of a multiple Tour de France champion in close to peak condition and suggests what may be the prerequisite physiological and thermoregulatory capacities for success at this level. PMID- 27508884 TI - An Amperometric Immunosensor Based on an Ionic Liquid and Single-Walled Carbon Nanotube Composite Electrode for Detection of Tetrodotoxin in Pufferfish. AB - An amperometric immunosensor based on a composite electrode of single-walled carbon nanotubes and ionic liquid n-octylpyridinum afluorophosphate (SWCNT-ILE) was developed for the determination of tetrodotoxin (TTX). Compared with the glassy carbon electrode (GCE), the electrode combined advantages of carbon nanotubes and ionic liquid, which exhibited the excellent antifouling ability of p-nitrophenol (PNP) so that it remarkably improved the stability of the p nitrophenyl phosphate-based sensor. Combining the enzyme-linked immune sorbent assay (ELISA) by alkaline phosphatase (AP) and magnetic particles immobilized with antigens, a real-time assay of tetrodotoxin was developed by amperometric immunosensors. Under the optimium condition, the developed sensor demonstrated a linear range of tetrodotoxin from 2 to 45 ng/mL with a low detection limit of 5 ng/mL. Furthermore, the amperometric immunosensor was applied to determine TTX in real samples and could be used as an effective and sensitive sensor for direct detection of tetrodotoxin within 20 min. PMID- 27508885 TI - [Laser-induced Maculopathy Caused by Strangers]. AB - Background: Laser-induced ocular injuries are of public interest, especially when caused by strangers. Clinical signs and follow-up: Two laser-induced maculopathies were presented which had been caused by strangers. Morphological findings were shown by funduscopy and Spectralis Domain OCT follow-up. Conclusion: Severe retina injuries can be induced by laser pointers of higher classes. PMID- 27508886 TI - [Methotrexate in Atypical Non-Arteritic Ischemic Optic Neuropathy]. AB - Background: Optic nerve disease can occur from a variety of different causes, with vascular, inflammatory or toxic pathologies. In such cases, it is hardly possible to clarify the aetiology. These diseases of the optic nerve are usually accompanied by progressive loss of visual field and visual impairment. Patient: We report a case of a 74-year-old woman complaining of loss of visual acuity, visual and blurred vision in the left eye in 2010. We made the diagnosis of non arteritic ischemic optic neuropathy (NAION). With steroid therapy, there was an improvement in both visual acuity and visual field defects. But if an attempt was made to reduce steroids, her condition progressed. Except for a very small optic disk and arterial hypotension, there were no typical risk factors for NAION. We started treatment with methotrexate (MTX), with a starting dose of 10 mg per week, and observed the patient over two years. Results: Using MTX therapy, the swelling of the optic nerve head and visual field loss were reversible, so we increased the dose of MTX up to 15 mg/week. Steroid therapy could be stopped and the patient's visual acuity and visual field have now been stable for two years. There was no visible pallor in the optic nerve head, as normally occurs after AION, so we considered different underlying pathologies, including autoimmune disease. There were no adverse events with MTX therapy. Conclusion: If the course of the disease is atypical, the pathology may include an autoimmune component. Immunosuppressive MTX therapy may be started in order to avoid long-term steroid use. It may then be possible to maintain a stable visual field and prevent remitting episodes. PMID- 27508887 TI - [Indication and Results of the Anderson Procedure]. AB - The major goal of extraocular muscle surgery for nystagmus is to reduce the abnormal head turn (AHT) which is caused by an eccentric null zone of the nystagmus. Shifting the null zone to the primary gaze position will eliminate the AHT. The Kestenbaum procedure consists of bilateral recession of the yoke muscles opposite to the AHT, combined with bilateral resection or plication of their antagonists. The Anderson procedure is confined to bilateral recession of the yoke muscles and is therefore less invasive. We report on our experience with the Anderson procedure. Patients and Methods: From September 2013 to June 2015, we performed the Anderson procedure in 11 consecutive orthotropic patients with infantile idiopathic or sensory defect nystagmus. Patients responsive to convergence inducing prisms who could benefit from artificial divergence surgery were excluded. Results: Medians and ranges (minimum-maximum) were: Age 7 years (4 30); binocular BCVA 0.5 (0.05-1.0); AHT 30 degrees (20-40); equal recessions on the horizontal yoke muscles opposite to the AHT of 12 mm (10-17), in one case using bovine pericardium grafts. Three (3-6) months post surgery, the AHT was reduced to 7 degrees (0-20). First step success rates, defined by residual AHT <= 10 degrees and <= 15 degrees , were 73 % (95 % CI 39-93 %) and 82 % (95 % CI 48-97 %). No over-correction or other adverse effects were observed. Two patients later received augmenting surgery. One patient with pre-existing exophoria later required strabismus surgery for exotropia. Conclusion: The AHT can be significantly reduced or completely corrected by the Anderson procedure. Recessions of at least 10 mm on both yoke muscles were performed. The success rates equaled success rates of augmented Kestenbaum surgery. Compared to the latter, the Anderson procedure is less invasive. It is followed by a shorter healing process. It is a vessel sparing method - an advantage for potential future surgery. PMID- 27508888 TI - [Visual Snow Syndrome: Symptoms and Ophthalmological Findings]. AB - Background The symptom "visual snow" describes the continuous perception of tiny flickering dots within the whole visual field of both eyes. The diagnosis of a visual snow syndrome requires the appearance of typical additional visual symptoms and the exclusion of ophthalmological or neurological causes, or pharmacological influences. Patients and Methods Three male and four female subjects between 13 and 36 years of age referred with visual snow were investigated and asked about their symptoms. A complete ophthalmological investigation, including binocular fundoscopy, was performed in all patients. Furthermore, best corrected visual acuity, perimetry, binocular functions, colour vision (D15-test), full-field ERG, pattern-reversal VEP and SD-OCT images of macula and optic nerve (RNFL) were analysed. Results Visual acuity of at least 1.0 and normal findings for all further investigations were observed in all patients. The following additional visual symptoms were identified: illusionary palinopsia (n = 6), disturbance of night vision (n = 5), positive light phenomena (n = 7). A history of migraine with aura was reported in five patients. The intake of hallucinogenic drugs or centrally active pharmaceuticals was denied by all patients. The findings of available or initiated neurological investigations were normal. Conclusions The visual snow syndrome has to be regarded as a diagnosis of exclusion. Visual function parameters are not impaired. Apart from eye diseases, a persistent migraine aura as well as neurological diseases or the intake of hallucinogenic drugs must be excluded as possible causes of visual snow and palinopsia. PMID- 27508889 TI - [Comparison of the Results of the Flicker Perimetry (Prototype versus Commercial Perimeter)]. AB - Background: Analysis of the comparison of flicker perimetry with the prototype Pulsar and the new Octopus 600. Methods: Both eyes of 20 patients with primary open-angle glaucoma were studied with 30 degrees visual field flimmer perimetry (dynamic strategy) at the perimeters Pulsar and Octopus 600 (Haag-Streit). The evaluation was based on the mean defect (MD = mean deviation) and the defect depth (square root of lost variance = sLV). Results: In the t test for paired samples, the Pulsar perimetry showed significantly higher values than the Octopus 600 perimetry: right eye MD 4.8 +/- 3.6 src vs. 1.7 +/- 2.9 src, p = 0.005; left eye MD 3.9 +/- 3.6 src v. 1.4 +/- 2.8 src, p = 0.018; both eyes MD 4.35 +/- 3.62 src vs. 1.55 +/- 2.80 src, p = 0.002. The sLV values with the Pulsar perimetry were significantly higher than the values with the Octopus 600 perimetry: right eye sLV 3.6 +/- 1.6 vs. 2.3 +/- 1.3 src, p = 0.006; left eye sLV 3.2 +/- 0.8 vs. 2.0 +/- 0.8 src, p < 0.0001; both eyes sLV 3.37 +/- 1.28 src vs. 2.12 +/- 1.05 src, p < 0.0001. The significances even persisted after the Bonferroni-Holm correction. Conclusion: The investigation results of flicker perimetry are not comparable, because there is a significant difference in MD and sLV. This mainly due to different light intensities, background brightness and varying colour scalings of the perimetric device. PMID- 27508890 TI - ["Eight Days After a Substantial Pleuritic Exudation" - Albrecht von Graefe to William Bowman, the Discovery of Glaucomatous Optic Disc Cupping, and Newly Discovered Graefe Manuscripts]. PMID- 27508891 TI - [Severe Eyeball and Facial Skeletal Injuries Caused by Firefighting Sport]. AB - The aim of this work is to draw attention to possible injuries of the eye and the facial skeleton caused by firefighting sport. There was a group of 9 patients presented who were treated from 2006 to 2015 in the Department of Ophthalmology at the University Hospital in Pilsen and diagnosed with severe eyeball contusion after being hit by a jet of water and/or a water pipe. Three cases are presented in detail. PMID- 27508892 TI - Visualization of NRAS RNA G-Quadruplex Structures in Cells with an Engineered Fluorogenic Hybridization Probe. AB - The RNA G-quadruplex is an important secondary structure formed by guanine-rich RNA sequences. However, its folding studies have mainly been studied in vitro. Accurate identification of RNA G-quadruplex formation within a sequence of interest remains difficult in cells. Herein, and based on the guanine-rich sequence in the 5'-UTR of NRAS mRNA, we designed and synthesized the first G quadruplex-triggered fluorogenic hybridization (GTFH) probe, ISCH-nras1, for the unique visualization of the G-quadruplexes that form in this region. ISCH-nras1 is made up of two parts: The first is a fluorescent light-up moiety specific to G quadruplex structures, and the second is a DNA molecule that can hybridize with a sequence that is adjacent to the guanine-rich sequence in the NRAS mRNA 5'-UTR. Further evaluation studies indicated that ISCH-nras1 could directly and precisely detect the targeted NRAS RNA G-quadruplex structures, both in vitro and in cells. Thus, this GTFH probe was a useful tool for directly investigating the folding of G-quadruplex structures within an RNA of interest and represents a new direction for the design of smart RNA G-quadruplex probes. PMID- 27508894 TI - Prepregnancy Body Mass Index by Maternal Characteristics and State: Data From the Birth Certificate, 2014. AB - Objectives-This report describes prepregnancy body mass index (BMI) among women giving birth in 2014 for the 47-state and District of Columbia reporting areas that implemented the 2003 U.S. Standard Certificate of Live Birth by January 1, 2014. PMID- 27508896 TI - To Invest or Not to Invest, That Is the Question: Analysis of Firm Behavior under Anticipated Shocks. AB - When companies are faced with an upcoming and expected economic shock some of them tend to react better than others. They adapt by initiating investments thus successfully weathering the storm, while others, even though they possess the same information set, fail to adopt the same business strategy and eventually succumb to the crisis. We use a unique setting of the recent financial crisis in Croatia as an exogenous shock that hit the country with a time lag, allowing the domestic firms to adapt. We perform a survival analysis on the entire population of 144,000 firms in Croatia during the period from 2003 to 2015, and test whether investment prior to the anticipated shock makes firms more likely to survive the recession. We find that small and micro firms, which decided to invest, had between 60 and 70% higher survival rates than similar firms that chose not to invest. This claim is supported by both non-parametric and parametric tests in the survival analysis. From a normative perspective this finding could be important in mitigating the negative effects on aggregate demand during strong recessionary periods. PMID- 27508895 TI - Highly Selective Dopamine D3 Receptor (D3R) Antagonists and Partial Agonists Based on Eticlopride and the D3R Crystal Structure: New Leads for Opioid Dependence Treatment. AB - The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D3 receptor (D3R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D3R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D3R crystal structure-guided 4-phenylpiperazines with exceptionally high D3R affinities and/or selectivities with varying efficacies. Lead compound 19 was selected based on its in vitro profile: D3R Ki = 6.84 nM, 1700-fold D3R versus D2R binding selectivity, and its metabolic stability in mouse microsomes. Compound 19 inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with 19 also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D3R as a target for opioid dependence treatment and compound 19 as a new lead molecule for development. PMID- 27508897 TI - Insulin modulates energy and substrate sensing and protein catabolism induced by chronic peritonitis in skeletal muscle of neonatal pigs. AB - BACKGROUND: Acute infection promotes skeletal muscle wasting and insulin resistance, but the effect of insulin on energy and substrate sensing in skeletal muscle of chronically infected neonates has not been studied. METHODS: Eighteen 2 d-old pigs underwent cecal ligation and puncture (CLP) or sham surgery (CON) to induce a chronic infection for 5 d. On d 5, pancreatic-substrate clamps were performed to attain fasting or fed insulin levels but to maintain glucose and amino acids in the fasting range. Total fractional protein synthesis rates (Ks), translational control mechanisms, and energy sensing and degradation signal activation were measured in longissimus dorsi muscle. RESULTS: In fasting conditions, CLP reduced Ks and sirtuin 1 (SIRT1) and increased AMP-activated protein kinase alpha (AMPKalpha) activation and muscle RING-finger protein-1 (MuRF1). Insulin treatment increased Ks and mitochondrial protein synthesis, enhanced translation activation, and reduced SIRT1 in CON. In contrast, in CLP, insulin treatment increased Ks, protein kinase B (PKB) and Forkhead box O1 phosphorylation, antagonized AMPK activation, and decreased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha), MuRF1, and SIRT1. CONCLUSION: Energy and substrate sensing in skeletal muscle by the PKB AMPK-SIRT1-PGC-1alpha axis is impacted by chronic infection in neonatal pigs and can be modulated by insulin. PMID- 27508898 TI - New Insights from Zinc and Copper Isotopic Compositions into the Sources of Atmospheric Particulate Matter from Two Major European Cities. AB - This study reports spatial and temporal variability of Zn and Cu isotopes in atmospheric particulate matter (PM) collected in two major European cities with contrasting atmospheric pollution, Barcelona and London. We demonstrate that nontraditional stable isotopes identify source contributions of Zn and Cu and can play a major role in future air quality studies. In Barcelona, samples of fine PM were collected at street level at sites with variable traffic density. The isotopic signatures ranged between -0.13 +/- 0.09 and -0.51 +/- 0.050/00 for delta(66)ZnIRMM and between +0.04 +/- 0.20 and +0.33 +/- 0.150/00 for delta(65)CuAE633. Copper isotope signatures similar to those of Cu sulfides and Cu/Sb ratios within the range typically found in brake wear suggest that nonexhaust emissions from vehicles are dominant. Negative Zn isotopic signatures characteristic for gaseous emissions from smelting and combustion and large enrichments of Zn and Cd suggest contribution from metallurgical industries. In London, samples of coarse PM collected on the top of a building over 18 months display isotope signatures ranging between +0.03 +/- 0.04 and +0.49 +/- 0.020/00 for delta(66)ZnIRMM and between +0.37 +/- 0.17 and +0.97 +/- 0.210/00 for delta(65)CuAE633. Heavy Cu isotope signatures (up to +0.97 +/- 0.210/00) and higher enrichments and Cu/Sb ratios during winter time indicate important contribution from fossil fuel combustion. The positive delta(66)ZnIRMM signatures are in good agreement with signatures characteristic for ore concentrates used for the production of tires and galvanized materials, suggesting nonexhaust emissions from vehicles as the main source of Zn pollution. PMID- 27508899 TI - Diabetes mellitus and drug abuse during pregnancy and the risk for orofacial clefts and related abnormalities. AB - OBJECTIVE: to assessed the prevalence of diabetes mellitus (DM) and drug abuse in mothers of children with orofacial clefts (OFC). METHODS: 325 women who had children (0-3y) with clefts were interviewed. Data regarding type of diabetes, use of legal/illegal drugs during pregnancy, waist girth and fasting blood sugar at the first prenatal consult were collected. RESULTS: twenty seven percent of the women had DM, out of these, 89% had gestational DM, 5,5% type 1 DM and 5,5% type 2 DM. The prevalence of DM in mothers of children with OFC was 27%, it is significantly higher than the average Brazilian population which is 7.6% (p<0.01) (OR=4.5, 95%CI=3.5-5.8). Regarding drug abuse during pregnancy, 32% of the mothers used drugs and a significant positive correlation was observed between drug abuse and the occurrence of clefts and other craniofacial anomalies (p=0.028) (OR=2.87; 95%CI=1.1-7.4). CONCLUSIONS: DM and drug abuse during pregnancy increases the risk for OFC and related anomalies and early diagnosis of DM and prevention of drug abuse, especially in pregnant women, should be emphasized. PMID- 27508900 TI - Quality of life in the workplace for nursing staff at public healthcare institutions. AB - OBJECTIVE: to determine the quality of life in the workplace for nursing staff at public institutions in Hermosillo, Sonora, Mexico. METHOD: quantitative, correlational, cross-sectional, and comparative. We used a probabilistic sample of 345 nurses with data collected in 2013 using an instrument created by the authors to gather bio-socio-demographic data and the CVT-GOHISALO instrument with a Cronbach's alpha of 0.95. SPSS 15 was used to analyze the data. A Kolmogorov Smirnov test was used to calculate the normality of the data; the medians were compared using the Mann-Whitney U test and Kruskal-Wallis test with the significance level set at 0.05. RESULTS: the average overall quality of life in the workplace for nursing staff was 207.31 (DE 41.74), indicating a moderate level. The quality of life in the workplace was higher for people with permanent contracts (p=0.007) who did not engage in other remunerative activities (p=0.046). Differences in the quality of life in the workplace were observed depending on the institution where the subjects worked (p=0.001). CONCLUSION: the nursing staff perceives itself as having a moderate-level quality of life in the workplace. This level was determined in the statistical analysis based on the type of contract, whether the person performed other remunerated activities, and the institution where the person worked. PMID- 27508901 TI - Second-Generation central venous catheter in the prevention of bloodstream infection: a systematic review. AB - OBJECTIVE: to evaluate the effectiveness and safety in the use of second generation central venous catheters impregnated in clorhexidine and silver sulfadiazine when compared with other catheters, being them impregnated or not, in order to prevent the bloodstream infection prevention. METHOD: systematic review with meta-analysis. Databases searched: MEDLINE, EMBASE, CINAHL, LILACS/SciELO, Cochrane CENTRAL; search in Congress Proceedings and records from Clinical Trials. RESULTS: 1.235 studies were identified, 97 were pre-selected and 4 were included. In catheter-related bloodstream infection, there was no statistical significance between second-generation impregnated catheter compared with the non-impregnated ones, absolute relative risk 1,5% confidence interval 95% (3%-1%), relative risk 0,68 (confidence interval 95%, 0,40-1,15) and number needed to treat 66. In the sensitivity analysis, there was less bloodstream infection in impregnated catheters (relative risk 0,50, confidence interval 95%, 0,26-0,96). Lower colonization, absolute relative risk 9,6% (confidence interval 95%, 10% to 4%), relative risk 0,51 (confidence interval 95% from 0,38-0,85) and number needed to treat 5. CONCLUSION: the use of second-generation catheters was effective in reducing the catheter colonization and infection when a sensitivity analysis is performed. Future clinical trials are suggested to evaluate sepsis rates, mortality and adverse effects. OBJETIVO: evaluar la efectividad y seguridad del uso de cateteres venosos centrales de segunda generacion, impregnados en clorhexidina y sulfadiazina de plata, comparados con otros cateteres impregnados o no impregnados, para prevencion de infeccion de la corriente sanguinea. METODO: revision sistematica con metaanalisis. La busqueda fue realizada en las bases: MEDLINE, EMBASE, CINAHL, LILACS/SciELO, Cochrane CENTRAL; fueron consultados anales de congresos y registros de ensayos clinicos. RESULTADOS: fueron identificados 1.235 estudios, 97 preseleccionados y cuatro incluidos. En la infeccion de la corriente sanguinea, relacionada al cateter, no hubo significacion estadistica entre cateter de segunda generacion impregnado en comparacion a los no impregnados, riesgo relativo absoluto 1,5%, intervalo de confianza 95% (3%-1%), riesgo relativo 0,68 (intervalo de confianza 95%, 0,40 1,15) y numero necesario para tratar 66. En el analisis de sensibilidad, hubo disminucion de la infeccion de la corriente sanguinea en los cateteres impregnados (riesgo relativo 0,50, intervalo de confianza 95%, 0,26-0,96). Reduccion de la colonizacion, riesgo relativo absoluto de 9,6% (intervalo de confianza 95%, 10% a 4%), riesgo relativo 0,51 (intervalo de confianza 95% de 0,38-0,85) y numero necesario para tratar 5. CONCLUSION: el uso de los cateteres de segunda generacion fue efectivo en la reduccion de la colonizacion del cateter y de infeccion cuando realizado analisis de sensibilidad. Se sugirieron ensayos clinicos futuros que evaluen tasas de sepsis, mortalidad y efectos adversos. OBJETIVO: avaliar a efetividade e seguranca do uso de cateteres venosos centrais de segunda geracao, impregnados em clorexidina e sulfadiazina de prata, comparados com outros cateteres impregnados ou nao, na prevencao de infeccao de corrente sanguinea. METODO: revisao sistematica com metanalise. Busca realizada nas bases: MEDLINE, EMBASE, CINAHL, LILACS/SciELO, Cochrane CENTRAL; consulta em anais de congresso e registro de ensaios clinicos. RESULTADOS: foram identificados 1.235 estudos, 97 pre-selecionados e quatro incluidos. Na infeccao de corrente sanguinea, relacionada ao cateter, nao houve significancia estatistica entre cateter de segunda geracao impregnado em comparacao aos nao impregnados risco relativo absoluto 1,5%, intervalo de confianca 95% (3%-1%), risco relativo 0,68 (intervalo de confianca 95%, 0,40-1,15) e numero necessario para tratar 66. Na analise de sensibilidade, houve diminuicao da infeccao de corrente sanguinea nos cateteres impregnados (risco relativo 0,50, intervalo de confianca 95%, 0,26-0,96). Reducao da colonizacao, risco relativo absoluto de 9,6% (intervalo de confianca 95%, 10% a 4%), risco relativo 0,51 (intervalo de confianca 95% de 0,38-0,85) e numero necessario para tratar 5. CONCLUSAO: o uso dos cateteres de segunda geracao foi efetivo na reducao de colonizacao do cateter e de infeccao quando realizada analise de sensibilidade. Sugerem-se ensaios clinicos futuros que avaliem taxas de sepse, mortalidade e efeitos adversos. PMID- 27508902 TI - Care management: agreement between nursing prescriptions and patients' care needs. AB - OBJECTIVES: analyze agreement between nursing prescriptions recorded in medical files and patients' care needs; investigate the correlation between the nurses' professional background and agreement of prescriptions. METHOD: descriptive study with quantitative and documentary approach conducted in the medical clinic, surgical, and specialized units of a university hospital in the interior of Sao Paulo, Brazil. The new validated version of a Patient Classification Instrument was used and 380 nursing prescriptions written at the times of hospital admission and discharge were assessed. RESULTS: 75% of the nursing prescriptions items were compatible with the patients' care needs. Only low correlation between nursing prescription agreement and professional background was found. CONCLUSION: the nursing prescriptions did not fully meet the care needs of patients. The care context and work process should be analyzed to enable more effective prescriptions, while strategies to assess the care needs of patients are recommended. OBJETIVOS: analisar a concordancia entre prescricoes de enfermagem, registradas nos prontuarios, e as necessidades de cuidados dos pacientes; investigar a correlacao entre o perfil profissional dos enfermeiros e a concordancia das prescricoes. METODO: estudo descritivo com abordagem quantitativa e documental, realizado em unidades de clinica medica, cirurgica e especializada de um hospital de ensino, no interior do Estado de Sao Paulo. Foi aplicada a nova versao validada do Instrumento de Classificacao de Pacientes e, posteriormente, investigadas 380 prescricoes de enfermagem no momento da admissao e alta hospitalar. RESULTADOS: foi identificado que 75% dos itens das prescricoes de enfermagem estavam compativeis com as necessidades cuidativas dos pacientes. Encontrou-se baixa correlacao entre a concordancia da prescricao de enfermagem e o perfil profissional. CONCLUSAO: as prescricoes de enfermagem nao estao sendo realizadas, em sua totalidade, em consonancia com as necessidades dos pacientes. Para possibilitar prescricoes mais efetivas, recomenda-se analise do contexto assistencial e processo de trabalho e o uso de estrategias avaliativas das necessida!des de cuidados dos pacientes. OBJETIVOS: analizar la concordancia entre prescripciones de enfermeria, registradas en las fichas medicas, y las necesidades de cuidados de los pacientes; investigar la correlacion entre el perfil profesional de los enfermeros y la concordancia de las prescripciones. METODO: estudio descriptivo con abordaje cuantitativo y documental, realizado en unidades de clinica medica, quirurgica y especializada de un hospital de ensenanza, en el interior del Estado de Sao Paulo. Fue aplicada la nueva version validada del Instrumento de Clasificacion de Pacientes y, posteriormente, investigadas 380 prescripciones de enfermeria en el momento de la admision y alta hospitalaria. RESULTADOS: fue identificado que 75% de los items de las prescripciones de enfermeria eran compatibles con las necesidades de cuidados de los pacientes. Se encontro baja correlacion entre la concordancia de la prescripcion de enfermeria y el perfil profesional. CONCLUSION: las prescripciones de enfermeria no estan siendo realizadas, en su totalidad, en consonancia con las necesidades de los pacientes. Para posibilitar prescripciones mas efectivas, se recomienda analizar el contexto asistencial y el proceso de trabajo y el uso de estrategias de evaluacion de las necesidades de cuidados de los pacientes. PMID- 27508903 TI - Nursing interventions for rehabilitation in Parkinson's disease: cross mapping of terms. AB - OBJECTIVE: to perform a cross-term mapping of nursing language in the patient record with the Nursing Interventions Classification system, in rehabilitation patients with Parkinson's disease. METHOD: a documentary research study to perform cross mapping. A probabilistic, simple random sample composed of 67 records of patients with Parkinson's disease who participated in a rehabilitation program, between March of 2009 and April of 2013. The research was conducted in three stages, in which the nursing terms were mapped to natural language and crossed with the Nursing Interventions Classification. RESULTS: a total of 1,077 standard interventions that, after crossing with the taxonomy and refinement performed by the experts, resulted in 32 interventions equivalent to the Nursing Interventions Classification (NIC) system. The NICs, "Education: The process of the disease.", "Contract with the patient", and "Facilitation of Learning" were present in 100% of the records. For these interventions, 40 activities were described, representing 13 activities by intervention. CONCLUSION: the cross mapping allowed for the identification of corresponding terms with the nursing interventions used every day in rehabilitation nursing, and compared them to the Nursing Interventions Classification. PMID- 27508904 TI - Diagnosis and medical treatment of neuropathic pain in leprosy. AB - OBJECTIVE: to identify the difficulties in diagnosing and treating neuropathic pain caused by leprosy and to understand the main characteristics of this situation. METHODS: 85 patients were treated in outpatient units with reference to leprosy and the accompanying pain. We used a questionnaire known as the Douleur Neuropathic 4 test and we conducted detailed neurological exams. As a result, 42 patients were excluded from the study for not having proved their pain. RESULTS: Out of the 37 patients that experienced pain, 22 (59.5%) had neuropathic pain (or a mixture of this pain and their existing pain) and of these 90.8% considered this pain to be moderate or severe. 81.8% of the sample suffered with this pain for more than 6 months. Only 12 (54.5%) of the patients had been diagnosed with neuropathic pain and in almost half of these cases, this pain had not been diagnosed. With reference to medical treatment (n=12) for neuropathic pain, 5 (41.6%) responded that they became better. For the other 7 (58.4%) there were no changes in relation to the pain or in some cases the pain worsened in comparison to their previous state. Statistical analysis comparing improvements in relation to the pain amongst the patients that were treated (n=12) and those that were not, showed significant differences (value p=0.020). CONCLUSION: we noted difficulties in diagnosing neuropathic pain for leprosy in that almost half of the patients that were studied had not had their pain diagnosed. We attributed this to some factors such as the non-adoption of the appropriate protocols which led to inadequate diagnosis and treatment that overlooked the true picture. PMID- 27508905 TI - Building sustainability indicators in the health dimension for solid waste management. AB - OBJECTIVE: to prepare a list of sustainability indicators in the health dimension, for urban solid waste management. METHODS: a descriptive and exploratory study performed jointly with 52 solid waste specialists, using a three-steps Delphi technique, and a scale measuring the degree of importance for agreement among the researchers in this area. RESULTS: the subjects under study were 92,3% PhD's concentrated in the age group from 30 to 40 years old (32,7%) and 51% were men. At the end of the 3rd step of the Delphi process, the average and standard deviation of all the proposed indicators varied from 4,22 (+/-0,79) to 4,72 (+/-0,64), in a scale of scores for each indicator from 1 to 5 (from "dispensable" to "very important"). Results showed the level of correspondence among the participants ranging from 82% to 94% related to those indicators. CONCLUSION: the proposed indicators may be helpful not only for the identification of data that is updated in this area, but also to enlarge the field of debates of the environmental health policies, directed not only for urban solid waste but for the achievement of better health conditions for the Brazilian context. OBJETIVO: elaborar uma lista de indicadores de sustentabilidade na dimensao da saude para gestao de residuos solidos urbanos. METODO: estudo descritivo e exploratorio, realizado com 52 especialistas na area de residuos solidos, utilizando a tecnica Delphi em tres etapas, com o uso da escala de mensuracao do grau de importancia para obtencao de consenso entre pesquisadores da area da investigacao. RESULTADOS: dos sujeitos estudados , 92,3% eram doutores, com maior concentracao na faixa etaria entre 30 e 40 anos (32,7%) e 51,0% do sexo masculino. Ao final da 3a etapa de aplicacao da tecnica Delphi, a media e o desvio-padrao de todos os indicadores propostos variaram de 4,22 (+/ 0,79) a 4,72 (+/-0,64), em uma escala de pontuacao atribuida para cada indicador de 1 a 5 (Respectivamente, de "dispensavel" a "muito importante"). Os resultados demonstraram nivel de concordancia entre os sujeitos participantes que variou de 82% a 94% em relacao a esses indicadores. CONCLUSAO: os indicadores propostos podem auxiliar, tanto na identificacao de dados atualizados no setor, quanto na ampliacao das discussoes das politicas de saude ambiental, voltadas nao apenas para residuos solidos urbanos, mas objetivando tambem o alcance de melhores condicoes de saude no contexto da atual realidade brasileira. OBJETIVO: elaborar una lista de indicadores de sostenibilidad en la dimension salud para la gestion de residuos solidos urbanos. METODO: estudio descriptivo y exploratorio realizado con 52 especialistas en el area de residuos solidos, utilizando la tecnica Delphi en tres etapas, con uso de escala de medida de grado de importancia para obtencion de consenso entre investigadores de esta area. RESULTADOS: de los sujetos estudiados , 92,3% tenian doctorado con mayor concentracion en el grupo etario entre 30 y 40 anos (32,7%) y 51% del sexo masculino. Al final de la 3a. Etapa de aplicacion de la tecnica Delphi, el promedio y el desvio estandar de todos los indicadores propuestos variaron de 4,22 (+/-0,79) a 4,72 (+/-0,64), en una escala de puntos atribuida a cada indicador de 1 a 5 (Respectivamente de "dispensable" a "muy importante"). Los resultados mostraron un nivel de acuerdo entre los sujetos participantes que vario de 82% a 94% en relacion a estos indicadores. CONCLUSION: los indicadores propuestos pueden ayudar tanto en la identificacion de datos actualizados en este sector, como tambien para ampliar las discusiones de las politicas de salud ambiental, dirigidas no solamente para residuos solidos urbanos pero tambien para alcanzar mejores condiciones de salud en el contexto de la realidad brasilena actual. PMID- 27508906 TI - Lean thinking in health and nursing: an integrative literature review. AB - OBJECTIVES: to demonstrate the scientific knowledge developed on lean thinking in health, highlighting the impact and contributions in health care and nursing. METHOD: an integrative literature review in the PubMed, CINAHL, Scopus, Web of Science, Emerald, LILACS and SciELO electronic library databases, from 2006 to 2014, with syntax keywords for each data base, in which 47 articles were selected for analysis. RESULTS: the categories were developed from the quality triad proposed by Donabedian: structure, process and outcome. Lean thinking is on the rise in health surveys, particularly internationally, especially in the USA and UK, improving the structure, process and outcome of care and management actions. However, it is an emerging theme in nursing. CONCLUSION: this study showed that the use of lean thinking in the context of health has a transforming effect on care and organizational aspects, promoting advantages in terms of quality, safety and efficiency of health care and nursing focused on the patient. PMID- 27508907 TI - Family violence against children and adolescents in context: How the territories of care are imbricated in the picture. AB - OBJECTIVE: to understand the context of care addressed to the families involved in family violence against children and adolescents (IVCA), as produced in the context of the Primary Health Care (PHC), from the vantage point of the practitioners of a municipality in the State of Sao Paulo. METHODS: qualitative research of the social-strategic type, based on the Complexity Paradigm. The participants were 41 health practitioners in five health units of the municipality under study, pertaining to the five districts of the municipality. Data collection was done through 5 focus groups and 10 semi-structured interviews from April 24th 2013 to December 12th 2013. Data analysis was oriented by the comprehension and contextualization mindset and based on the dialogic, recursive and hologramatic principles. RESULTS: two main issues regarding the care provided by the Health of the Family team were identified: the context of this violence (the domestic space) and the power relations that prevail in the territory where this violence surfaces. The community health workers are the targets of specific attention because they experience the live/work dialogic in this same area. CONCLUSION: paying attention to the territory, and considering the complexity of contexts and dimensions is inherently linked to the design of care to families involved in IVCA in the PHC environment. PMID- 27508908 TI - Prevalence of hypoalbuminemia and nutritional issues in hospitalized elders. AB - OBJECTIVE: to estimate the prevalence of hypoalbuminemia in hospitalized elders, related to socio-demographic variables, nutritional status and length of stay. METHODS: crosscutting study with 200 patients hospitalized in a large hospital in the South of Brazil during three months. Evaluations, lab tests and interviews through questionnaires were performed. RESULTS: the average albuminemia was 2,9 +/- 0,5g/dL. Hypoalbuminemia was diagnosed in 173 subjects (87%) and was absent in 27 (13%) that have normal albuminemia (p=0,000). After six days of hospitalization, the prevalence of low levels grew significantly to 90% (p=0,002), average 2,7 +/- 0,5g/dL. Using the Mini Nutritional Assessment, it was observed that 41 patients were malnourished and from those, 40 had hypoalbuminemia. CONCLUSION: the prevalence of hypoalbuminemia proved to be high, in approx. nine in ten elders, and the nutritional status and the length of stay proved to be related to the decrease of serum albumin levels. Thus, it is suggested that monitoring albumin levels should be done to evaluate the risk that the patient has to develop malnutrition and other complications during hospital stays. OBJETIVO: estimar a prevalencia de hipoalbuminemia em idosos hospitalizados, em relacao as variaveis sociodemograficas, estado nutricional e tempo de internacao. METODO: estudo transversal, com 200 pacientes internados em hospital de grande porte do sul do Brasil, durante o periodo de tres meses. Foram realizadas avaliacoes, analise de exames laboratoriais e entrevista atraves de questionario. RESULTADOS: a media de albuminemia foi 2,9 +/- 0,5g/dL. O diagnostico de hipoalbuminemia, foi encontrado em 173 sujeitos (87%), e nao revelado em 27 (13%), que apresentaram albuminemia normal (p=0,000). Constatou-se que apos seis dias de internacao a prevalencia de niveis baixos aumentou significativamente para 90% (p=0,002), com media de 2,7 +/- 0,5g/dL. Utilizando se a Mini Avaliacao Nutricional, observou-se que 41 pacientes estavam desnutridos, e que destes, 40 apresentavam hipoalbuminemia. CONCLUSAO: a prevalencia de hipoalbuminemia mostrou-se elevada, acometendo aproximadamente nove entre dez idosos, sendo que o estado nutricional, da mesma maneira que o tempo de internacao , esta relacionado a diminuicao dos niveis de albumina serica. Assim, sugere-se monitorar os niveis de albuminemia para avaliar o risco que o paciente tem de desenvolver desnutricao e demais complicacoes durante a internacao hospitalar. OBJETIVO: estimar la prevalencia de hipoalbuminemia en ancianos hospitalizados, considerando las variables sociodemograficas, estado nutricional y tiempo de internacion. METODO: estudio transversal, en 200 pacientes internados en hospital de gran porte del sur de Brasil, durante un periodo de tres meses. Fueron realizadas evaluaciones, analisis de examenes de laboratorio y se realizo una entrevista usando un cuestionario. RESULTADOS: el promedio de albuminemia fue 2,9 +/- 0,5g/dL. El diagnostico de hipoalbuminemia, fue encontrado en 173 sujetos (87%), y no revelado en 27 (13%), que presentaron albuminemia normal (p=0,000). Se constato que despues de seis dias de internacion la prevalencia de niveles bajos aumento significativamente para 90% (p=0,002), con promedio de 2,7 +/- 0,5g/dL. Utilizando la Mini Evaluacion Nutricional, se observo que 41 pacientes estaban desnutridos, y que de estos, 40 presentaban hipoalbuminemia. CONCLUSION: la prevalencia de hipoalbuminemia se mostro elevada, afectando aproximadamente nueve entre diez ancianos, siendo que el estado nutricional, de la misma manera que el tiempo de internacion, esta relacionado a la disminucion de los niveles de albumina serica. Asi, se sugiere monitorizar los niveles de albuminemia para evaluar el riesgo que el paciente tiene de desarrollar desnutricion y demas complicaciones durante la internacion hospitalaria. PMID- 27508909 TI - Living arrangements of the elderly and the sociodemographic and health determinants: a longitudinal study. AB - OBJECTIVES: to describe the sociodemographic characteristics and the number of morbidities in the elderly, according to the dynamics of living arrangements and evaluate the sociodemographic and health determinants of the living arrangements. METHODS: this is a household longitudinal survey (2005-2012), carried out with 623 elderly people. Descriptive statistical analysis and multinomial logistic regression were performed (p<0.05). RESULTS: there was predominance of elderly living alone, accompanied and with change in the living arrangements, females, age range between 60? 70 years, 1? 4 years of study and with income between 1?? 3 minimum wages. During the development of this research, it was identified an increase in the incidence of elderly with 1??3 minimum wages. The number of morbidities increased in the three groups throughout the study, with the highest rates observed among the elderly with change in the dynamics of living arrangements. It was found that elderly men showed less chance of living alone (p=0.007) and having change in the living arrangements compared to women (p = 0.005). Incomes less than a minimum wage decreased the chances of change in the living arrangements compared to incomes above three salaries (p=0.034). CONCLUSION: the determining factors of the living arrangements were sex and income, and the variables functional capacity and number of morbidities were not associated with the outcome analyzed. OBJETIVOS: descrever as caracteristicas sociodemograficas e o numero de morbidades de idosos, segundo a dinamica do arranjo domiciliar; e verificar os determinantes sociodemograficos e de saude do arranjo domiciliar. METODOS: trata-se de uma pesquisa domiciliar e longitudinal (2005-2012), conduzida com 623 idosos. Foi realizada analise estatistica descritiva e regressao logistica multinomial (p<0,05). RESULTADOS: predominaram, idosos que moram sozinhos, acompanhados e com mudanca do arranjo domiciliar, do sexo feminino, faixa etaria 60? 70 anos, 1? 4 anos de estudo e com renda entre 1?? 3 salarios minimos. Durante o desenvolvimento dessa pesquisa, identificou-se uma elevacao da distribuicao de idosos com 1??3 salarios minimos. O numero de morbidades aumentou nos tres grupos ao longo do estudo, com maiores taxas entre os idosos que mudaram a dinamica do arranjo domiciliar. Verificou-se que idosos do sexo masculino apresentaram menores chances de morar sozinhos (p=0,007) e mudar o arranjo domiciliar comparados as mulheres (p = 0,005). Ganhar menos de um salario minimo diminuiu as chances de mudanca do arranjo domiciliar em relacao aos que ganham mais de tres salarios (p=0,034). CONCLUSAO: os fatores determinantes do arranjo domiciliar foram o sexo e a renda, sendo que as variaveis capacidade funcional e numero de morbidades nao estiveram associadas ao desfecho analisado. OBJETIVOS: describir las caracteristicas sociodemograficas y el numero de enfermedades concomitantes de ancianos, segun la dinamica de la acomodacion domiciliaria; y verificar los determinantes sociodemograficos y de salud del espacio domiciliario. METODOS: se trata de una investigacion domiciliaria y longitudinal (2005-2012), realiza con 623 ancianos. Fue realizado analisis estadistico descriptivo y regresion logistica multinomial (p<0,05). RESULTADOS: predominaron, ancianos que viven solos, acompanados y con cambio de acomodacion domiciliaria, del sexo femenino, intervalo etario 60? 70 anos, 1? 4 anos de estudio y con ingreso mensual entre 1??3 sueldos minimos. Durante el desarrollo de la investigacion, se identifico una aumento en la distribucion de ancianos de 1??3 sueldos minimos. El numero de enfermedades concomitantes aumento en los tres grupos a lo largo del estudio, con mayores tasas entre los ancianos que cambiaron la dinamica de la acomodacion domiciliaria. Se verifico que ancianos del sexo masculino presentaron menores probabilidades de vivir solos (p=0,007) y de cambiar la acomodacion domiciliaria, comparados a las mujeres (p = 0,005). Ganar menos de un salario minimo disminuye las probabilidades de cambiar la acomodacion domiciliaria en relacion a los que ganan mas de tres sueldos (p=0,034). CONCLUSION: los factores determinantes de la acomodacion domiciliaria fueron el sexo y la ingreso mensual, siendo que las variables capacidad funcional y numero de enfermedades concomitantes, no estuvieron asociadas al resultado analizado. PMID- 27508910 TI - The effects of acupressure on labor pains during child birth: randomized clinical trial. AB - OBJECTIVE: to analyze the effects of acupressure on the sanyinjiao point for pregnant women in labor at public maternity wards. METHOD: single-blind controlled clinical trial, randomly done employing a pragmatic profile. We selected 156 pregnant women in their >= 37 week/s, who had cervical dilations of >= 4 cm and with two or more contractions in 10 minutes. The pregnant women were randomly divided into three groups at a university hospital in the suburbs of Sao Paulo, Brazil, in order to receive either acupressure treatment, a placebo or participate as part of a control group. The acupressure was applied on the sanyinjiao point during the contractions for 20 minutes. Then the intensity of the pain was evaluated using the Visual Analogue Scale (VAS). RESULTS: The averages for the pain measured using the VAS were not different for the three groups that were a part of the study (p-value=0.0929), however they were less in the acupressure groups immediately after receiving the treatment (p value=<0.0001). This was also the case where the treatment lasted for 1 hour (p value=0.0001). This was the case in comparison with placebo and control groups. CONCLUSION: the use of acupressure on the sanyinjiao point is a useful way to alleviate pain in a non-invasive manner. It can improve the quality of care given to pregnant women in labor. Register: RBR-9mhs8r. PMID- 27508911 TI - Translation, adaptation and validation the contents of the Diabetes Medical Management Plan for the Brazilian context. AB - OBJECTIVE: to translate, adapt and validate the contents of the Diabetes Medical Management Plan for the Brazilian context. This protocol was developed by the American Diabetes Association and guides the procedure of educators for the care of children and adolescents with diabetes in schools. METHOD: this methodological study was conducted in four stages: initial translation, synthesis of initial translation, back translation and content validation by an expert committee, composed of 94 specialists (29 applied linguists and 65 health professionals), for evaluation of the translated version through an online questionnaire. The concordance level of the judges was calculated based on the Content Validity Index. Data were exported into the R program for statistical analysis. RESULTS: the evaluation of the instrument showed good concordance between the judges of the Health and Applied Linguistics areas, with a mean content validity index of 0.9 and 0.89, respectively, and slight variability of the index between groups (difference of less than 0.01). The items in the translated version, evaluated as unsatisfactory by the judges, were reformulated based on the considerations of the professionals of each group. CONCLUSION: a Brazilian version of Diabetes Medical Management Plan was constructed, called the Plano de Manejo do Diabetes na Escola. PMID- 27508912 TI - Newborns' temperature submitted to radiant heat and to the Top Maternal device at birth. AB - OBJECTIVE: to compare the axillar temperatures of newborns that are put immediately after birth in skin-to-skin contact under the Top Maternal device, as compared to those in a radiant heat crib. METHODS: comparatives observational study of the case-control type about temperature of 60 babies born at the Obstetric Center and Normal Delivery Center of a public hospital of the municipality of Sao Paulo, being them: 29 receiving assistance in heated crib and 31 in skin-to skin contact, shielded by a cotton tissue placed on mother's thorax, called Top Maternal. RESULTS: the temperature of the babies of the skin to-skin contact group presented higher values in a larger share of the time measures verified, as compared to those that were placed in radiant heat crib, independently from the place of birth. Differences between the two groups were not statistically significant. CONCLUSION: the study contributes to generate new knowledge, supporting the idea of keeping babies with their mothers immediately after birth protected with the Maternal Top, without harming their wellbeing, as it keeps the axillar temperature in recommendable levels. PMID- 27508913 TI - Risk factors for medication errors in the electronic and manual prescription. AB - OBJECTIVE: to compare electronic and manual prescriptions of a public hospital of Brasilia, identifying risk factors for the occurrence of medication errors. METHOD: descriptive-exploratory, comparative and retrospective study. Data collection occurred from July 2012 to January 2013, using an instrument for the review of the information contained in medical records related to the medication process. A total of 190 manual and 199 electronic records composed the sample, with 2027 prescriptions each. RESULTS: compared to the manual prescription, a significant reduction was observed in the risk factors after implantation of the electronic prescription, in items such as "lack of the form of dilution" (71.1% to 22.3%) and "prescription with brand name" (99.5% to 31.5%). Conversely, the risk factors "no check" and "lack of CRM of the prescriber" increased. The lack of the allergy registration and the occurrences related to medication were the same for both groups. CONCLUSION: generally, the use of the electronic prescription system was associated with a significant reduction in risk factors for medication errors, concerning the following aspects: illegibility, prescription with brand name and presence of essential items that provide a safe and effective prescription. PMID- 27508914 TI - The effects of work on the health of nurses who work in clinical surgery departments at university hospitals. AB - OBJECTIVE: to analyze the effects of work on the health of nurses who work in clinical surgery departments at university hospitals in relation to physical, social and psychological suffering and pain. METHODS: a quantitative transversal study was carried out between 2012 and 2013 in four institutions in a state located in the south of Brazil. We studied 65 nurses who responded to questions on their habits. We also obtained sociodemographical information on them as well as conducting an evaluation on work relational damage using an evaluation scale. Associations were checked through the use of the Chi-Sqaure and Fisher's exact test. Correlations were checked using the Spearmann test. RESULTS: we found that physical ailments persisted and that there were connections between social and psychological pain/suffering and variable physical activities as well as connections with accidents in the work place and the option to work shifts. We noted correlations between social and psychological pain/suffering. CONCLUSION: nurses had their health compromised due to their work in clinical surgery departments. PMID- 27508915 TI - Methodological proposal for validation of the disinfecting efficacy of an automated flexible endoscope reprocessor. AB - OBJECTIVE: to elaborate and apply a method to assess the efficacy of automated flexible endoscope reprocessors at a time when there is not an official method or trained laboratories to comply with the requirements described in specific standards for this type of health product in Brazil. METHOD: the present methodological study was developed based on the following theoretical references: International Organization for Standardization (ISO) standard ISO 15883-4/2008 and Brazilian Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria - ANVISA) Collegiate Board Resolution (Resolucao de Diretoria Colegiada - RDC) no. 35/2010 and 15/2012. The proposed method was applied to a commercially available device using a high-level 0.2% peracetic acid-based disinfectant. RESULTS: the proposed method of assessment was found to be robust when the recommendations made in the relevant legislation were incorporated with some adjustments to ensure their feasibility. Application of the proposed method provided evidence of the efficacy of the tested equipment for the high-level disinfection of endoscopes. CONCLUSION: the proposed method may serve as a reference for the assessment of flexible endoscope reprocessors, thereby providing solid ground for the purchase of this category of health products. OBJETIVO: propor e aplicar um metodo para a avaliacao da eficacia de processadoras automaticas de endoscopios flexiveis, em um momento em que ainda nao existe no Brasil um metodo oficial, nem tampouco laboratorios capacitados que contemplem os requisitos das normas especificas aplicaveis a esse tipo de produto para a saude. METODO: caracterizou-se como pesquisa metodologica e foi desenvolvido com base em tres referenciais teoricos: norma tecnica International Organization for Standardization (ISO) - ISO 15883-4/2008, Resolucao de Diretoria Colegiada (RDC) no35/2010 e RDC no15/2012 da Agencia Nacional de Vigilancia Sanitaria (ANVISA). Aplicou-se o metodo proposto em um equipamento especifico, comercialmente disponivel, utilizando desinfetante de alto nivel a base de acido peracetico 0,2%. RESULTADOS: o metodo de avaliacao proposto mostrou-se robusto, a medida que as recomendacoes das legislacoes pertinentes ao equipamento avaliado foram incorporadas, com algumas adaptacoes para sua exequibilidade. A aplicacao do metodo proposto permitiu atestar a eficacia do equipamento utilizado na desinfeccao de alto nivel de endoscopios. CONCLUSAO: o metodo pode servir de referencia para a avaliacao de reprocessadoras de endoscopios flexiveis, subsidiando a aquisicao dessa categoria de produtos para a saude. OBJETIVO: elaborar y aplicar un metodo para evaluar la eficacia de reprocesadores automatizados de endoscopios flexibles en un momento en el que no hay un metodo oficial o laboratorios capacitados para cumplir con los requisitos descritos en las normas especificas para este tipo de producto para la salud en Brasil. METODO: el presente estudio metodologico fue desarrollado en base a las siguientes referencias teoricas: Organizacion Internacional de Normalizacion (International Organization for Standardization - ISO) norma ISO 15883-4/2008 y Agencia Nacional de Vigilancia de la Salud de Brasil (Agencia Nacional de Vigilancia Sanitaria - ANVISA) Resolucion del Directorio Colegiado (Resolucao de Diretoria Colegiada - RDC) No 35/2010 y 15/2012. El metodo propuesto se aplico a un dispositivo comercialmente disponible usando un desinfectante al 0,2% a base de acido peracetico de alto nivel. RESULTADOS: el metodo de evaluacion propuesto se evaluo como fuerte despues de que las recomendaciones formuladas en la legislacion pertinente se incorporaron con algunos ajustes para garantizar su factibilidad. La aplicacion del metodo propuesto proporciona evidencia de la eficacia de los equipos de prueba para la desinfeccion de alto nivel de endoscopios. CONCLUSION: el metodo propuesto puede servir de referencia para la evaluacion de reprocesadores de endoscopios flexibles, proporcionando de este modo bases solidas para la compra de esta categoria de productos de salud. PMID- 27508916 TI - Incidence of phlebitis associated with the use of peripheral IV catheter and following catheter removal. AB - OBJECTIVE: to investigate the incidence of phlebitis and its association with risk factors when using peripheral IV catheters (PIC) and following their removal - (post-infusion phlebitis) in hospitalized adults. METHOD: a cohort study of 171 patients using PIC, totaling 361 punctures. Sociodemographic variables and variables associated with the catheter were collected. Descriptive and analytical statistical analyses were performed. RESULTS: average patient age was 56.96 and 51.5% of the sample population was male. The incidence of phlebitis was 1.25% while using PIC, and 1.38% post-infusion. The incidence of phlebitis while using PIC was associated with the length of time the catheter remained in place, whereas post-infusion phlebitis was associated with puncture in the forearm. Ceftriaxone, Clarithromycin and Oxacillin are associated with post-infusion phlebitis. CONCLUSIONS: this study made it possible to investigate the association between risk factors and phlebitis during catheter use and following its removal. The frequency of post-infusion phlebitis was larger than the incidence of phlebitis with the catheter in place, with Phlebitis Grade III and II being the most frequently found in each of these situations, respectively. Aspects related to post-infusion phlebitis can be explained, given the limited number of studies addressing this theme from this perspective. OBJETIVO: investigar a incidencia de flebites e a associacao de fatores de risco com a sua ocorrencia durante o uso e apos a retirada do cateter intravenoso periferico - CIP (Flebite pos-infusao) em adultos hospitalizados. METODO: estudo de coorte com 171 pacientes com CIP, totalizando 361 puncoes. Foram coletadas variaveis sociodemograficas e relacionadas ao cateter. Analise estatistica descritiva e analitica. RESULTADOS: dos pacientes, 51,5% eram homens e a media de idade foi de 56,96 anos. A incidencia de flebites durante o uso do CIP foi de 1,25% e a pos infusao foi de 1,38%. Associou-se a flebite durante o uso do CIP ao tempo de permanencia do cateter e, com a flebite pos-infusao, a puncao em antebraco. Os medicamentos Ceftriaxona, Claritromicina e Oxacilina foram associados a flebite pos-infusao. CONCLUSOES: este estudo possibilitou investigar a associacao de fatores de risco e a ocorrencia de flebites durante o uso e apos a retirada do cateter. A frequencia da flebite pos-infusao foi maior do que o numero de flebites durante a permanencia do cateter, sendo as de grau III e II, respectivamente, as mais frequentes. Podem ser elucidados aspectos relacionados a flebite pos-infusao, considerando-se poucos estudos abordam o tema sob esta perspectiva. OBJETIVO: investigar la incidencia de flebitis y la asociacion de factores de riesgo con su ocurrencia durante el uso y despues de la retirada del cateter intravenoso periferico (CIP) (flebitis post-infusion) en adultos hospitalizados. METODO: estudio de cohorte con 171 pacientes con CIP, totalizando 361 punciones. Fueron recolectadas variables sociodemograficas y relacionadas al cateter. Analisis estadistico descriptivo y analitico. RESULTADOS: de los pacientes, 51,5% eran hombres y el promedio de edad fue de 56,96 anos. La incidencia de flebitis durante el uso del CIP fue de 1,25% y de post-infusion fue de 1,38%. Se asocio la flebitis durante el uso del CIP al tiempo de permanencia del cateter y con la post-infusion (puncion en el antebrazo). Los medicamentos Ceftriaxona, Claritromicina y Oxacilina fueron asociados a la flebitis post infusion. CONCLUSIONES: este estudio posibilito investigar la asociacion de factores de riesgo y la ocurrencia de flebitis durante el uso y despues de la retirada del cateter. La frecuencia de la flebitis post-infusion fue mayor que el numero de flebitis asociada a la permanencia del cateter, siendo las de grado III y II, respectivamente, las mas frecuentes. Se trato de elucidar aspectos relacionados a la flebitis post-infusion, considerando que existen pocos estudios que abordan el tema bajo esta perspectiva. PMID- 27508917 TI - Effectiveness of personalized face-to-face and telephone nursing counseling interventions for cardiovascular risk factors: a controlled clinical trial. AB - OBJECTIVE: to evaluate the effect and gender differences of an innovative intervention involving in-person and telephone nursing counseling to control cardiovascular risk factors (arterial hypertension, dyslipidemia, and overweight), improve health-related quality of life and strengthen self-efficacy and social support in persons using the municipal health centers' cardiovascular health program. METHOD: a randomized controlled clinical trial involving participants randomized into the intervention group who received traditional consultation plus personalized and telephone nursing counseling for 7 months (n = 53) and the control group (n = 56). The study followed the Consolidated Standards of Reporting Trials Statement. RESULTS: women in the intervention group presented a significant increase in the physical and mental health components compared to the control group, with decreases in weight, abdominal circumference, total cholesterol, low-density lipoprotein cholesterol, and the atherogenic index. The effects attributable to the intervention in the men in the intervention group were increased physical and emotional roles and decreased systolic and diastolic pressure, waist circumference, total cholesterol, low-density lipoprotein cholesterol, atherogenic index, cardiovascular risk factor, and 10-year coronary risk. CONCLUSION: this intervention is an effective strategy for the control of three cardiovascular risk factors and the improvement of health-related quality of life. PMID- 27508918 TI - Factors associated with mortality in patients undergoing coronary artery bypass grafting. AB - OBJECTIVE: to investigate the factors associated with mortality in patients undergoing coronary artery bypass grafting in a cardiovascular referral hospital in Santa Catarina. METHOD: quantitative, exploratory, descriptive and retrospective study. The medical records of 1447 patients, from 2005 to 2013, were analyzed for statistically related variables, these being: profile, hospitalization diagnosis, risk factors for coronary artery disease, complications recorded during the hospitalization, length of hospitalization and cause of death. RESULTS: the mortality rate was 5.3% during the study period. Death was more common in females and those of black skin color, with a mean age of 65 years. Acute myocardial infarction was the most common hospitalization diagnosis. The majority of the complications recorded during hospitalization were characterized by changes in the cardiovascular system, with longer hospitalization periods being directly related to death from septic shock. CONCLUSION: the data provide subsidies for nursing work with preventive measures and early detection of complications associated with coronary artery bypass grafting. This reinforces the importance of using the data as quality indicators, aiming to guarantee care guided by reliable information to guide managers in planning patient care and high complexity health services. PMID- 27508919 TI - Taking a look to promoting health and complications' prevention: differences by context. AB - OBJECTIVES: to acknowledge and compare the health promotion and complications' prevention practices performed by nurses working in hospital and primary health care contexts. METHODS: descriptive, exploratory and crosscutting study, performed with 474 nurses selected by convenience sampling. It was used a form that encompassed two categories of descriptive statements about quality in the professional exercise of nurses. This study had ethical committee approval. RESULTS: the nurses' population was mainly women (87,3%) with an average age of 35,5 years. There was more practices of the hospital's nurses related to the identification of potential problems of the patient (p=0.001) and supervision of the activities that put in place the nursing interventions and the activities that they delegate (p=0.003). CONCLUSION: the nurses perform health promotion and complications' prevention activities, however not in a systematic fashion and professional practices differ by context. This study is relevant as it may promote the critical consciousness of the nurses about the need of stressing quality practices. PMID- 27508920 TI - Social support of adults and elderly with chronic kidney disease on dialysis. AB - OBJECTIVE: to evaluate the instrumental and emotional social support of patients with chronic kidney disease on hemodialysis. METHOD: descriptive cross-sectional study. The sample was sized for convenience and included 103 participants under treatment in a Renal Replacement Therapy Unit. Data were collected through individual interviews, using the Social Support Scale. RESULTS: the mean scores of the emotional and instrumental social support were 3.92 (+/- 0.78) and 3.81 (+/- 0.69) respectively, an indication of good support received. The most frequent sources of instrumental and emotional social support mentioned by participants were partners, spouse, companion or boyfriend and friends. CONCLUSION: patients with chronic kidney disease have high social support, both instrumental and emotional, and the main support comes from the family. PMID- 27508921 TI - Measurement of Family-centered care perception and parental stress in a neonatal unit. AB - OBJECTIVE: to evaluate the effects of the implementation of the Patient and Family-Centered Care Model on parents and healthcare perceptions and parental stress. METHOD: a quasi-experimental study developed in a neonatal unit of a university hospital in the municipality of Sao Paulo, Brazil, with the implementation of this model of care. Data collection were performed by two sample groups, one using non-equivalent groups of parents, and another using equivalent groups of healthcare professionals. The instruments Perceptions of Family-Centered Care-Parent Brazilian Version, Perceptions of Family-Centered Care-Staff Brazilian Version and Parental Stress Scale: Neonatal Intensive Care Unit, were applied to 132 parents of newborns hospitalized and to 57 professionals. RESULTS: there was a statistically significant improvement in the perceptions of the parents in most items assessed (p <=0,05) and for the staff in relation to the family welcome in the neonatal unit (p = 0.041) and to the comprehension of the family's experience with the infant's hospitalization (p = 0,050). There was a reduction in the average scores of parental stress, with a greater decrease in the Alteration in Parental Role from 4,2 to 3,8 (p = 0,048). CONCLUSION: the interventions improved the perceptions of parents and healthcare team related to patient and family-centered care and contributed to reducing parental stress. OBJETIVO: avaliar os efeitos da implementacao do Modelo do Cuidado Centrado no Paciente e Familia na percepcao de pais e profissionais de saude e no estresse parental. METODO: Estudo quase experimental com grupos nao equivalentes para avaliacao dos efeitos da intervencao na percepcao de pais; e com grupos equivalentes para a avaliacao na percepcao de profissionais de saude, desenvolvido na unidade neonatal de um hospital universitario do municipio de Sao Paulo. Os instrumentos, Percepcao do Cuidado Centrado na Familia- Pais versao brasileira, Percepcao do Cuidado Centrado na Familia- Equipe versao brasileira e Parental Stress Scale: Neonatal Intensive Care Unit, foram aplicados com 132 pais de recem-nascidos internados e 57 profissionais da equipe. RESULTADOS: houve melhora estatisticamente significante na percepcao dos pais na maioria dos itens avaliados (p<=0,05) e para os profissionais em relacao ao acolhimento da familia na unidade neonatal (p= 0,041) e a compreensao da vivencia da familia com a hospitalizacao (p=0,050). Houve reducao dos escores medios do estresse parental, com maior queda na Alteracao do Papel de Pais de 4,2 para 3,8 (p=0,048). CONCLUSAO: as intervencoes realizadas melhoraram a percepcao de pais e de profissionais da equipe de saude sobre o Cuidado Centrado no Paciente e Familia e contribuiram para a reducao do estresse parental. OBJETIVO: evaluar los efectos de la implementacion del Modelo del Cuidado Centrado en el Paciente y la Familia en la percepcion de los padres y profesionales de la salud y en lo estres parental. METODO: estudio cuasi-experimental con grupos no equivalentes para evaluar los efectos de la intervencion en la percepcion de los padres; y grupos equivalentes para evaluar la percepcion de los profesionales de la salud, desarrollado en la unidad neonatal de un hospital universitario en el municipio de Sao Paulo. Los instrumentos de Percepcion del Cuidado Centrado en el Paciente y la Familia- Padres version brasilena, Percepcion del Cuidado Centrado en el Paciente y la Familia-Equipo version brasilena y Parental Stress Scale: Neonatal Intensive Care Unit, se aplicaron a 132 padres de los recien nacidos hospitalizados y 57 profesional del equipo. RESULTADOS: se observo una mejoria estadisticamente significativa en la percepcion de los padres en la mayoria de los items evaluados (p = 0,05) y para los profesionales en relacion con el cuidado de la familia en la unidad neonatal (p = 0,041) y la comprension de la experiencia de la familia con la hospitalizacion (p = 0,050). Hubo una reduccion en las puntuaciones medias de estres de los padres, con una mayor disminucion en la Alteracion del Rol Parental 4.2 a 3.8 (p = 0,048). CONCLUSION: las intervenciones mejoran la percepcion de los padres y los profesionales del equipo de salud en el Cuidado Centrado en el Paciente y la Familia y ha contribuido a reducir el estres de los padres. PMID- 27508922 TI - Improvement of nursing students' learning outcomes through scenario-based skills training. AB - OBJECTIVE: this study analyzed the influence of scenario-based skills training on students' learning skills. METHOD: the author evaluated the nursing skills laboratory exam papers of 605 sophomores in nursing programs for seven years. The study determined the common mistakes of students and the laboratory work was designed in a scenario-based format. The effectiveness of this method was evaluated by assessing the number of errors the students committed and their achievement scores in laboratory examinations. This study presents the students' common mistakes in intramuscular and subcutaneous injection and their development of intravenous access skills, included in the nursing skills laboratory examination. RESULTS: an analysis of the students' most common mistakes revealed that the most common was not following the principles of asepsis for all three skills (intramuscular, subcutaneous injection, intravenous access) in the first year of the scenario-based training. The students' exam achievement scores increased gradually, except in the fall semester of the academic year 2009-2010. The study found that the scenario-based skills training reduced students' common mistakes in examinations and enhanced their performance on exams. CONCLUSION: this method received a positive response from both students and instructors. The scenario-based training is available for use in addition to other skills training methods. PMID- 27508923 TI - Advanced practice nursing in Latin America and the Caribbean: regulation, education and practice. AB - OBJECTIVE: to identify the current state of advanced practice nursing regulation, education and practice in Latin America and the Caribbean and the perception of nursing leaders in the region toward an advanced practice nursing role in primary health care to support Universal Access to Health and Universal Health Coverage initiatives. METHOD: a descriptive cross-sectional design utilizing a web-based survey of 173 nursing leaders about their perceptions of the state of nursing practice and potential development of advanced practice nursing in their countries, including definition, work environment, regulation, education, nursing practice, nursing culture, and perceived receptiveness to an expanded role in primary health care. RESULT: the participants were largely familiar with the advanced practice nursing role, but most were unaware of or reported no current existing legislation for the advanced practice nursing role in their countries. Participants reported the need for increased faculty preparation and promotion of curricula reforms to emphasize primary health care programs to train advanced practice nurses. The vast majority of participants believed their countries' populations could benefit from an advanced practice nursing role in primary health care. CONCLUSION: strong legislative support and a solid educational framework are critical to the successful development of advanced practice nursing programs and practitioners to support Universal Access to Health and Universal Health Coverage initiatives. OBJETIVO: identificar o estado atual da regulacao, educacao e pratica do enfermeiro de pratica avancada na America Latina e no Caribe e a percepcao de lideres de enfermagem na regiao quanto ao papel da enfermagem de pratica avancada na atencao primaria a saude em apoio as iniciativas de Acesso Universal a Saude e Cobertura Universal de Saude. METODO: o estudo descritivo transversal utilizou um survey online com 173 lideres de enfermagem questionando suas percepcoes sobre o estado atual da pratica de enfermagem e o potencial desenvolvimento da enfermagem de pratica avancada em seus paises, incluindo a definicao do termo, o ambiente de trabalho, a regulacao, educacao, pratica, cultura de enfermagem e receptividade percebida de um papel mais amplo deste profissional na atencao primaria a saude. RESULTADO: os participantes referiram estar familiarizados com o papel do enfermeiro de pratica avancada, mas a maioria nao sabia ou nao relatou a legislacao vigente para o papel da pratica avancada em seus paises. Os participantes relataram a necessidade de aumentar a preparacao do corpo docente e promover reformas curriculares com enfase na atencao primaria a saude para formar enfermeiros de pratica avancada. A grande maioria dos participantes acredita que as populacoes de seus paises se beneficiara com o papel do enfermeiro de pratica avancada na atencao primaria a saude. CONCLUSAO: forte apoio em termos de legislacao e uma estrutura educacional solida de formacao continua sao fundamentais para o exito do desenvolvimento de programas de enfermagem de pratica avancada em apoio as iniciativas de Acesso Universal a Saude e Cobertura Universal de Saude. OBJETIVO: identificar el estado actual de la regulacion, educacion y practica de la enfermera de practica avanzada en Latinoamerica y el Caribe y la percepcion de los lideres de enfermeria en la region hacia un rol de practica avanzada de enfermeria dentro de la atencion primaria de salud para apoyar las iniciativas de Acceso Universal a la Salud y la Cobertura Universal de Salud. METODO: un diseno transversal descriptivo que utilizo una encuesta basada en la web a 173 lideres de enfermeria acerca de sus percepciones sobre el estado de la enfermeria y el desarrollo potencial de la practica avanzada de enfermeria en sus paises, incluyendo definicion, ambiente laboral, regulacion, educacion, practica de enfermeria, cultura de enfermeria y la receptividad percibida a un papel mas amplio en atencion primaria de salud. RESULTADO: los participantes estaban ampliamente familiarizados con el rol de la enfermera de practica avanzada, pero la mayoria desconocia la legislacion o reportaba no existencia actual de legislacion para el rol de practica avanzada en sus paises. Los participantes reportaron la necesidad de aumentar la preparacion docente y reformas curriculares para apoyar programas de atencion primaria de salud para capacitar las enfermeras de practica avanzada. La gran mayoria de los participantes creian que las poblaciones de sus paises se podrian beneficiar de un rol de practica avanzada de enfermeria en atencion primaria de salud. CONCLUSION: un fuerte apoyo legislativo y un marco educacional solido que continuen informandose entre si, son criticos para el desarrollo exitoso de programas de practica avanzada y de nurse practitioners para apoyar las iniciativas de Acceso Universal a la Salud y Cobertura Universal de Salud. PMID- 27508924 TI - Zero to 50,000 - The 20th Anniversary of the Hospitalist. PMID- 27508925 TI - Nanostructured Aptamer-Functionalized Black Phosphorus Sensing Platform for Label Free Detection of Myoglobin, a Cardiovascular Disease Biomarker. AB - We report the electrochemical detection of the redox active cardiac biomarker myoglobin (Mb) using aptamer-functionalized black phosphorus nanostructured electrodes by measuring direct electron transfer. The as-synthesized few-layer black phosphorus nanosheets have been functionalized with poly-l-lysine (PLL) to facilitate binding with generated anti-Mb DNA aptamers on nanostructured electrodes. This aptasensor platform has a record-low detection limit (~0.524 pg mL(-1)) and sensitivity (36 MUA pg(-1) mL cm(-2)) toward Mb with a dynamic response range from 1 pg mL(-1) to 16 MUg mL(-1) for Mb in serum samples. This strategy opens up avenues to bedside technologies for multiplexed diagnosis of cardiovascular diseases in complex human samples. PMID- 27508926 TI - Synthesis of Cyclic Peptidomimetics via a Pd-Catalyzed Macroamination Reaction. AB - A new method to access cyclic peptidomimetics via a Pd-catalyzed macroamination reaction is presented. Natural amino acid amines are revealed as proficient coupling partners in these transformations. With a commercially available CPhos G3 catalyst system and substrates bearing diverse amino acid and aryl halide backbones, the unique head to side-chain (or side-chain mimic) macrocycles are afforded with ring sizes from 11 to 23 members in yields up to 84%. PMID- 27508927 TI - Predictive Factors for Excellent or Extremely Poor Functional Outcome in Initial Atrial Fibrillation-Related Cardioembolic Stroke. AB - BACKGROUND: We aimed to determine the predictive factors for excellent or extremely poor functional outcome in patients with first-ever atrial fibrillation (AF)-related cardioembolic stroke. METHODS: Retrospective observational study from a database. Patients with AF-related cardioembolic stroke with a premorbid modified Rankin Scale (mRS) score of 0 or 1 and without a previous history of stroke were included. RESULTS: Factors associated with excellent functional outcome (mRS scores of 0 or 1; n = 77; 30.4% of patients) included age >78 years (OR 0.31, 95% CI 0.15-0.61), male sex (OR 2.16, 95% CI 1.04-4.60), absence of hypertension (OR 0.46, 95% CI 0.22-0.94) and initial National Institutes of Health Stroke Scale (NIHSS) score of >9 (OR 0.08, 95% CI 0.03-0.16). Factors associated with extremely poor functional outcome (mRS scores of 5 or 6; n = 63; 24.9%) included age >78 years (OR 3.30, 95% CI 1.54-7.39), initial NIHSS score of >9 (OR 12.38, 95% CI 5.40-32.56), congestive heart failure (OR 4.82, 95% CI 2.00 12.19) and ischemic heart disease (OR 4.02, 95% CI 1.18-14.69). CONCLUSIONS: Predictive factors exist to delineate excellent and extremely poor functional outcomes after a first-time stroke associated with AF. PMID- 27508928 TI - Correction: Effect of Chronic Athletic Activity on Brown Fat in Young Women. AB - [This corrects the article DOI: 10.1371/journal.pone.0156353.]. PMID- 27508929 TI - The Motor Subsystem as a Predictor of Success in Young Football Talents: A Person Oriented Study. AB - Motor tests play a key role in talent selection in football. However, individual motor tests only focus on specific areas of a player's complex performance. To evaluate his or her overall performance during a game, the current study takes a holistic perspective and uses a person-oriented approach. In this approach, several factors are viewed together as a system, whose state is analysed longitudinally. Based on this idea, six motor tests were aggregated to form the Motor Function subsystem. 104 young, top-level, male football talents were tested three times (2011, 2012, 2013; Mage, t2011 = 12.26, SD = 0.29), and their overall level of performance was determined one year later (2014). The data were analysed using the LICUR method, a pattern-analytical procedure for person-oriented approaches. At all three measuring points, four patterns could be identified, which remained stable over time. One of the patterns found at the third measuring point identified more subsequently successful players than random selection would. This pattern is characterised by above-average, but not necessarily the best, performance on the tests. Developmental paths along structurally stable patterns that occur more often than predicted by chance indicate that the Motor Function subsystem is a viable means of forecasting in the age range of 12-15 years. Above-average, though not necessary outstanding, performance both on fitness and technical tests appears to be particularly promising. These findings underscore the view that a holistic perspective may be profitable in talent selection. PMID- 27508931 TI - Overexpression of Hypo-Phosphorylated IkappaBbeta at Ser313 Protects the Heart against Sepsis. AB - IkappaBbetais an inhibitor of nuclear factor kappa B(NF-kappaB) and participates in the cardiac response to sepsis. However, the role of the hypo-phosphorylated form of IkappaBbeta at Ser313, which can be detected during sepsis, is unknown. Here, we examined the effects of IkappaBbeta with a mutation at Ser313->Ala313 on cardiac damage induced by sepsis. Transgenic (Tg) mice were generated to overexpress IkappaBbeta, in which Ser-313 is replaced with alanine ubiquitously, in order to mimic the hypo-phosphorylated form of IkappaBbeta. Survival analysis showed that Tg mice exhibited decreased inflammatory cytokine levels and decreased rates of mortality in comparison to wild type (WT) mice, after sepsis in a cecal-ligation and puncture model (CLP). Compared to WT septic mice, sepsis in Tg mice resulted in improved cardiac functions, lower levels of troponin I and decreased rates of cardiomyocyte apoptosis, compared to WT mice. The increased formation of autophagicvacuoles detected with electron microscopy demonstrated the enhancement of cardiac autophagy. This phenomenon was further confirmed by the differential expression of genes related to autophagy, such as LC3, Atg5, Beclin-1, and p62. The increased expression of Cathepsin L(Ctsl), a specific marker for mitochondrial stress response, may be associated with the beneficial effects of the hypo-phosphorylated form of IkappaBbeta. Our observations suggest that the hypo-phosphorylated form of IkappaBbeta at Ser313 is beneficial to the heart in sepsis through inhibition of apoptosisand enhancement of autophagy in mutated IkappaBbeta transgenic mice. PMID- 27508932 TI - Do Dogs Provide Information Helpfully? AB - Dogs are particularly skilful during communicative interactions with humans. Dogs' abilities to use human communicative cues in cooperative contexts outcompete those of other species, and might be the result of selection pressures during domestication. Dogs also produce signals to direct the attention of humans towards outside entities, a behaviour often referred to as showing behaviour. This showing behaviour in dogs is thought to be something dogs use intentionally and referentially. However, there is currently no evidence that dogs communicate helpfully, i.e. to inform an ignorant human about a target that is of interest to the human but not to the dog. Communicating with a helpful motive is particularly interesting because it might suggest that dogs understand the human's goals and need for information. In study 1, we assessed whether dogs would abandon an object that they find interesting in favour of an object useful for their human partner, a random novel distractor, or an empty container. Results showed that it was mainly self-interest that was driving the dogs' behaviour. The dogs mainly directed their behaviour towards the object they had an interest in, but dogs were more persistent when showing the object relevant to the human, suggesting that to some extent they took the humans interest into account. Another possibility is that dogs' behaviour was driven by an egocentric motivation to interact with novel targets and that the dogs' neophila might have masked their helpful tendencies. Therefore, in study 2 the dogs had initial access to both objects, and were expected to indicate only one (relevant or distractor). The human partner interacted with the dog using vocal communication in half of the trials, and remaining silent in the other half. Dogs from both experimental groups, i.e. indicating the relevant object or indicating the distractor, established joint attention with the human. However, the human's vocal communication and the presence of the object relevant to the human increased the persistency of showing, supporting the hypothesis that the dogs understood the objects' relevance to the human. We propose two non-exclusive explanations. These results might suggest that informative motives could possibly underlie dogs' showing. It is also possible that dogs might have indicated the location of the hidden object because they recognised it as the target of the human's search. This would be consistent with taking into account the objects' relevance, without necessarily implying that the dogs understood the human's state of knowledge. PMID- 27508933 TI - Climate Response of Tree Radial Growth at Different Timescales in the Qinling Mountains. AB - The analysis of the tree radial growth response to climate is crucial for dendroclimatological research. However, the response relationships between tree ring indices and climatic factors at different timescales are not yet clear. In this study, the tree-ring width of Huashan pine (Pinus armandii) from Huashan in the Qinling Mountains, north-central China, was used to explore the response differences of tree growth to climatic factors at daily, pentad (5 days), dekad (10 days) and monthly timescales. Correlation function and linear regression analysis were applied in this paper. The tree-ring width showed a more sensitive response to daily and pentad climatic factors. With the timescale decreasing, the absolute value of the maximum correlation coefficient between the tree-ring data and precipitation increases as well as temperature (mean, minimum and maximum temperature). Compared to the other three timescales, pentad was more suitable for analysing the response of tree growth to climate. Relative to the monthly climate data, the association between the tree-ring data and the pentad climate data was more remarkable and accurate, and the reconstruction function based on the pentad climate was also more reliable and stable. We found that the major climatic factor limiting Huashan pine growth was the precipitation of pentads 20 35 (from April 6 to June 24) rather than the well-known April-June precipitation. The pentad was also proved to be a better timescale for analysing the climate and tree growth in the western and eastern Qinling Mountains. The formation of the earlywood density of Chinese pine (Pinus tabulaeformis) from Shimenshan in western Qinling was mainly affected by the maximum temperature of pentads 28-32 (from May 16 to June 9). The maximum temperature of pentads 28-33 (from May 16 to June 14) was the major factor affecting the ring width of Chinese pine from Shirenshan in eastern Qinling. PMID- 27508930 TI - Lipophosphoglycans from Leishmania amazonensis Strains Display Immunomodulatory Properties via TLR4 and Do Not Affect Sand Fly Infection. AB - The immunomodulatory properties of lipophosphoglycans (LPG) from New World species of Leishmania have been assessed in Leishmania infantum and Leishmania braziliensis, the causative agents of visceral and cutaneous leishmaniasis, respectively. This glycoconjugate is highly polymorphic among species with variation in sugars that branch off the conserved Gal(beta1,4)Man(alpha1)-PO4 backbone of repeat units. Here, the immunomodulatory activity of LPGs from Leishmania amazonensis, the causative agent of diffuse cutaneous leishmaniasis, was evaluated in two strains from Brazil. One strain (PH8) was originally isolated from the sand fly and the other (Josefa) was isolated from a human case. The ability of purified LPGs from both strains was investigated during in vitro interaction with peritoneal murine macrophages and CHO cells and in vivo infection with Lutzomyia migonei. In peritoneal murine macrophages, the LPGs from both strains activated TLR4. Both LPGs equally activate MAPKs and the NF-kappaB inhibitor p-IkappaBalpha, but were not able to translocate NF-kappaB. In vivo experiments with sand flies showed that both stains were able to sustain infection in L. migonei. A preliminary biochemical analysis indicates intraspecies variation in the LPG sugar moieties. However, they did not result in different activation profiles of the innate immune system. Also those polymorphisms did not affect infectivity to the sand fly. PMID- 27508935 TI - Objective assessment of compliance with intra- and extraoral removable appliances. AB - OBJECTIVE: To conduct an objective assessment of the level of compliance in young patients prescribed various types of removable appliances and to determine the influence of device type, treatment duration, and patient age, gender, psychological maturity, and awareness of monitoring on compliance. MATERIALS AND METHODS: A total of 30 patients were fitted with either a class 2 (Frankel or bionator) or a class 3 (face mask) removable appliance, each bearing a compliance indicator chip, and they were instructed to wear them for 13 hours per day. Compliance was monitored by means of the sensor for an average of 8 months. Of the patients, 14 were informed that their appliance was fitted with a monitoring sensor, and 16 were not. The psychological maturity of all patients was assessed on the Nowicki-Strickland Locus of Control Scale, and the effect on compliance of this score as well as the patient- and treatment-related variables considered were determined via statistical analysis Results: The mean compliance recorded by the chips was 8.6 +/- 2.9 hours, far lower than the 13 hours prescribed, and younger patients showed significantly greater compliance than adolescents (P < .01). However, no significant differences in compliance were found between intra- and extraoral appliances, and neither gender, psychological scores, treatment duration, nor awareness of being monitored had any significant effect. CONCLUSIONS: Compliance is generally very poor in young patients, regardless of their gender and psychological maturity. Although awareness of monitoring does not appear to boost compliance, such systems may be a valuable means of providing a dentist with objective information regarding their patients' compliance. PMID- 27508934 TI - Transcriptome Analysis Reveals Regulation of Gene Expression for Lipid Catabolism in Young Broilers by Butyrate Glycerides. AB - BACKGROUND & AIMS: Butyrate has been shown to potently regulate energy expenditure and lipid metabolism in animals, yet the underlying mechanisms remain to be fully understood. The aim of this study was to investigate the molecular mechanisms of butyrate (in the form of butyrate glycerides, BG)-induced lipid metabolism at the level of gene expression in the jejunum and liver of broilers. METHODOLOGY/PRINCIPAL FINDINGS: Two animal experiments were included in this study. In Experiment 1, two hundred and forty male broiler chickens were equally allocated into two groups: 1) basal diet (BD), 2) BG diets (BD + BG). Growth performance was compared between treatments for the 41-day trial. In Experiment 2, forty male broiler chickens were equally allocated into two groups. The general experimental design, group and management were the same as described in Experiment 1 except for reduced bird numbers and 21-day duration of the trial. Growth performance, abdominal fat deposition, serum lipid profiles as well as serum and tissue concentrations of key enzymes involved in lipid metabolism were compared between treatments. RNA-seq was employed to identify both differentially expressed genes (DEGs) and treatment specifically expressed genes (TSEGs). Functional clustering of DEGs and TSEGs and signaling pathways associated with lipid metabolism were identified using Ingenuity Pathways Analysis (IPA) and DAVID Bioinformatics Resources 6.7 (DAVID-BR). Quantitative PCR (qPCR) assays were subsequently conducted to further examine the expression of genes in the peroxisome proliferator-activated receptors (PPAR) signaling pathway identified by DAVID-BR. Dietary BG intervention significantly reduced abdominal fat ratio (abdominal fat weight/final body weight) in broilers. The decreased fat deposition in BG-fed chickens was in accordance with serum lipid profiles as well as the level of lipid metabolism-related enzymes in the serum, abdominal adipose, jejunum and liver. RNA-seq analysis indicated that dietary BG intervention induced 79 and 205 characterized DEGs in the jejunum and liver, respectively. In addition, 255 and 165 TSEGs were detected in the liver and jejunum of BG-fed group, while 162 and 211 TSEGs genes were observed in the liver and jejunum of BD fed birds, respectively. Bioinformatic analysis with both IPA and DAVID-BR further revealed a significant enrichment of DEGs and TSEGs in the biological processes for reducing the synthesis, storage, transportation and secretion of lipids in the jejunum, while those in the liver were for enhancing the oxidation of ingested lipids and fatty acids. In particular, transcriptional regulators of THRSP and EGR-1 as well as several DEGs involved in the PPAR-alpha signaling pathway were significantly induced by dietary BG intervention for lipid catabolism. CONCLUSIONS: Our results demonstrate that BG reduces body fat deposition via regulation of gene expression, which is involved in the biological events relating to the reduction of synthesis, storage, transportation and secretion, and improvement of oxidation of lipids and fatty acids. PMID- 27508936 TI - Different Contributions of Physical Activity on Arterial Stiffness between Diabetics and Non-Diabetics. AB - BACKGROUND: We compared the contribution of physical activity to the change in arterial stiffness between patients with and without diabetes in ischemic heart disease. METHODS: We studied 96 (diabetes) and 109 (without diabetes) patients with ischemic heart disease treated by percutaneous coronary intervention (PCI). Arterial stiffness was assessed by cardio-ankle vascular index (CAVI) at the first diagnosis of significant coronary ischemia and 6 months after PCI and optimal medical therapy. Physical activity was evaluated using the long form of the International Physical Activity Questionnaire (IPAQ). RESULTS: CAVI values increased more for diabetic patients than for non-diabetic. The IPAQ scores did not differ between the two groups. During follow-up, CAVI values did not significantly change in either group. In diabetic patients, the CAVI score for 48 patients did not change (NC-group) and 48 patients improved (Improved-group). Physical activity scores were 937.9 +/- 923.2 and 1524.6 +/- 1166.2 in the NC- and Improved-groups, respectively. IPAQ scores and uric acid levels significantly affect CAVI improvement after adjusting for age, sex, baseline CAVI, total cholesterol, and estimated glomerular filtration rate. CONCLUSION: Determining factors influencing CAVI improvement during follow-up were significantly different between patients with and without diabetes. IPAQ scores and uric acid levels were significantly correlated with CAVI changes. PMID- 27508937 TI - Tailored Therapist-Guided Internet-Based Cognitive Behavioral Treatment for Psoriasis: A Randomized Controlled Trial. AB - OBJECTIVE: Patients with somatic conditions, such as psoriasis, frequently suffer from high burden of their disease in daily life and might benefit from internet based cognitive behavioral therapy (ICBT) tailored to their adjustment problems. The aim of this multicenter randomized controlled trial was to examine the effects of therapist-guided, individually tailored ICBT in a clinical sample of patients with psoriasis. METHODS: A total of 131 patients with psoriasis, who were screened for a psychological risk profile, were randomized to either care as usual (CAU, n = 66) or ICBT in addition to CAU (n = 65). Participants filled out standardized self-report questionnaires assessing physical and psychological functioning and impact on daily activities at baseline, posttreatment assessment, and 6-month follow-up. RESULTS: In covariate-controlled linear mixed-model analyses, significantly larger improvements in ICBT compared to CAU were found in the primary outcomes physical functioning (p = 0.03, d = 0.36) and impact on daily activities (p = 0.04, d = 0.35), but not in psychological functioning (p = 0.32), up to 6 months after treatment compared to baseline. In explorative analyses, the working alliance measured at the beginning of ICBT treatment predicted improved physical (p = 0.02) and psychological (p < 0.001) outcomes. CONCLUSIONS: Results underline the promise of therapist-guided, individually tailored ICBT to improve physical functioning and reduce the impact of psoriasis on daily activities in patients with a psychological risk profile. Establishing a good therapeutic relationship early on may be an important factor that influences treatment outcomes in personalized ICBT interventions. Further research is needed to evaluate ICBT effectiveness in additional samples and to explore its underlying mechanisms. PMID- 27508938 TI - An integrative review of how families are prepared for, and supported during withdrawal of life-sustaining treatment in intensive care. AB - AIM: The aim of this study was to conduct an integrative review on how nurses prepare families for and support families during withdrawal of life-sustaining treatments in intensive care. BACKGROUND: End-of-life care is widely acknowledged as integral to the practice of intensive care. However, little is known about what happens after the decision to withdraw life-sustaining treatments has been made and how families are prepared for death and the dying process. DESIGN: Integrative literature review. DATA SOURCES: MEDLINE, CINAHL Plus, PsychINFO, PUBMED, Scopus, EMBASE and Web of Knowledge were searched for papers published between 2000-May 2015. REVIEW METHODS: A five stage review process, informed by Whittemore and Knafl's methodology was conducted. All papers were reviewed and quality assessment performed. Data were extracted, organized and analysed. Convergent qualitative thematic synthesis was used. RESULTS: From an identified 479 papers, 24 papers were included in this review with a range of research approaches: qualitative (n = 15); quantitative (n = 4); mixed methods (n = 2); case study (n = 2) and discourse analysis (n = 1). Thematic analysis revealed the nurses: equipped families for end of life through information provision and communication; managed the withdrawal of life-sustaining treatments to meet family need; and continued care to build memories. CONCLUSION: Greater understanding is needed of the language that can be used with families to describe death and dying in intensive care. Clearer conceptualization of the relationship between the medically focussed withdrawal of life-sustaining treatments and patient/family-centred end-of-life care is required making the nursing contribution at this time more visible. PMID- 27508939 TI - Baseline characteristics, chromosomal alterations, and treatment affecting prognosis of deletion 17p in newly diagnosed myeloma. AB - Deletion 17p13, del(17p), is associated with poor outcome in myeloma but some patients show long-term survival. With the current study we intended to identify factors impacting outcome of such high risk patients. We analyzed 110 newly diagnosed, symptomatic patients with del(17p) detected by fluorescence in situ hybridization (FISH) in CD138-purified myeloma cells to identify prognostic factors for survival. Age >65 years, ISS III, and elevated LDH negatively impacted survival. Patients with subclonal (10-60% of plasma cells) del(17p) had longer progression-free survival (PFS) than patients with del(17p) in >60% of plasma cells (26 vs. 19 months, P = 0.03). Additional gain of 1q21 was associated with shorter PFS (17 vs. 25 months, P = 0.01). Hyperdiploidy did not ameliorate impact of del(17p), but gain 19q13 predicted longer PFS (30 vs. 18 months, P = 0.01) and overall survival (50 vs. 29 months, P = 0.01). Multivariate analysis in transplant eligible patients (<=65 years) revealed better survival for patients treated with upfront autologous transplantation (hazard ratio, [95% confidence interval]: 0.15 [0.04, 0.58], P = 0.006). Application of maintenance therapy was associated with better survival in transplant-eligible patients (0.30 [0.09, 0.99], P = 0.05). We demonstrate heterogeneous outcome of patients with del(17p) according to baseline characteristics and treatment. 19q13 should be included in routine FISH panel, since gains were associated with better survival. Am. J. Hematol. 91:E473-E477, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27508940 TI - Pneumococcal lipoproteins involved in bacterial fitness, virulence, and immune evasion. AB - Streptococcus pneumoniae (pneumococcus) has evolved sophisticated strategies to survive in several niches within the human body either as a harmless commensal or as a serious pathogen causing a variety of diseases. The dynamic interaction between pneumococci and resident host cells during colonization of the upper respiratory tract and at the site of infection is critical for bacterial survival and the development of disease. Pneumococcal lipoproteins are peripherally anchored membrane proteins and have pivotal roles in bacterial fitness including envelope stability, cell division, nutrient acquisition, signal transduction, transport (as substrate-binding proteins of ABC transporter systems), resistance to oxidative stress and antibiotics, and protein folding. In addition, lipoproteins are directly involved in virulence-associated processes such as adhesion, colonization, and persistence through immune evasion. Conversely, lipoproteins are also targets for the host response both as ligands for toll-like receptors and as targets for acquired antibodies. This review summarizes the multifaceted roles of selected pneumococcal lipoproteins and how this knowledge can be exploited to combat pneumococcal infections. PMID- 27508941 TI - Intrinsic protein disorder could be overlooked in cocrystallization conditions: An SRCD case study. AB - X-ray diffractometry dominates protein studies, as it can provide 3D structures of these diverse macromolecules or their molecular complexes with interacting partners: substrates, inhibitors, and/or cofactors. Here, we show that under cocrystallization conditions the results could reflect induced protein folds instead of the (partially) disordered original structures. The analysis of synchrotron radiation circular dichroism spectra revealed that the Im7 immunity protein stabilizes the native-like solution structure of unfolded NColE7 nuclease mutants via complex formation. This is consistent with the fact that among the several available crystal structures with its inhibitor or substrate, all NColE7 structures are virtually the same. Our results draw attention to the possible structural consequence of protein modifications, which is often hidden by compensational effects of intermolecular interactions. The growing evidence on the importance of protein intrinsic disorder thus, demands more extensive complementary experiments in solution phase with the unligated form of the protein of interest. PMID- 27508942 TI - Ex Vivo and In Vivo Mice Models to Study Blastocystis spp. Adhesion, Colonization and Pathology: Closer to Proving Koch's Postulates. AB - Blastocystis spp. are widely prevalent extra cellular, non-motile anerobic protists that inhabit the gastrointestinal tract. Although Blastocystis spp. have been associated with gastrointestinal symptoms, irritable bowel syndrome and urticaria, their clinical significance has remained controversial. We established an ex vivo mouse explant model to characterize adhesion in the context of tissue architecture and presence of the mucin layer. Using confocal microscopy with tissue whole mounts and two axenic isolates of Blastocystis spp., subtype 7 with notable differences in adhesion to intestinal epithelial cells (IEC), isolate B (ST7-B) and isolate H (more adhesive, ST7-H), we showed that adhesion is both isolate dependent and tissue trophic. The more adhesive isolate, ST7-H was found to bind preferentially to the colon tissue than caecum and terminal ileum. Both isolates were also found to have mucinolytic effects. We then adapted a DSS colitis mouse model as a susceptible model to study colonization and acute infection by intra-caecal inoculation of trophic Blastocystis spp.cells. We found that the more adhesive isolate ST7-H was also a better colonizer with more mice shedding parasites and for a longer duration than ST7-B. Adhesion and colonization was also associated with increased virulence as ST7-H infected mice showed greater tissue damage than ST7-B. Both the ex vivo and in vivo models used in this study showed that Blastocystis spp. remain luminal and predominantly associated with mucin. This was further confirmed using colonic loop experiments. We were also successfully able to re-infect a second batch of mice with ST7-H isolates obtained from fecal cultures and demonstrated similar histopathological findings and tissue damage thereby coming closer to proving Koch's postulates for this parasite. PMID- 27508943 TI - Evaluation of grape pomace from red wine by-product as feed for sheep. AB - BACKGROUND: This work aimed to study the chemical composition and in vitro digestibility of seeds and pulp from grape pomace. In sacco degradability, ruminal fermentation of grape pomace fractions and plasma lipid peroxidation were also studied in sheep fed with or without grape pomace. RESULTS: Seed and pulp fractions of grape pomace had different values for cell walls (523 vs 243 g kg-1 dry matter (DM)), crude protein (CP, 104 vs 138 g kg-1 DM), ether extract (EE, 99.0 vs 31.7 g kg-1 DM), polyunsaturated fatty acids (PUFA, 69.6 vs 53.3%) and extractable polyphenols (55.0 vs 32.1 g kg-1 DM). The in vitro true digestibility, DM in sacco degradability and CP degradability of seeds and pulp were also different (0.51 vs 0.82, 0.30 vs 0.45 and 0.66 vs 0.39 respectively). The ammonia-N concentration and total volatile fatty acids (VFA) in ruminal liquid were significantly lower and plasma lipid peroxidation was also numerically lower in sheep that consumed grape pomace. CONCLUSION: The nutritive value of grape pomace varies depending on the proportion of seeds and pulp. The interest of this by-product in sheep feeding could be related to its polyphenol and PUFA content, which could improve meat and milk quality. (c) 2016 Society of Chemical Industry. PMID- 27508944 TI - Management of Late Seroma in Patients with Breast Implants: The Role of the Radiologists. PMID- 27508945 TI - Determinants of the Intention to Pump Breast Milk on a University Campus. AB - INTRODUCTION: The number of young mothers in the workforce and in schools of higher education has steadily increased. In order to maintain a breastfeeding relationship with their children, these mothers need to pump or express breast milk multiple times a day while at work or school. This study examines the factors associated with the intention to pump breast milk at one university campus. METHODS: Between January and February 2015, an online survey invitation was sent out to all female employees and students at one university. The survey, based on the Theory of Planned Behavior, assessed intentions to pump breast milk on campus. The intention to pump breast milk was examined between employees and students separately. Within these 2 groups, behavioral performers (women who pump or have pumped breast milk while on campus) were compared to nonperformers. Using multiple regression analysis, the most influential predictors of the intention to pump (ie, attitudes, subjective norm, perceived behavioral control, and underlying beliefs) were identified. RESULTS: A total of 218 women participated in the study (62 employees and 156 students, a 71.7% survey completion rate). Among university employees, the most influential factor that predicted pumping intention among performers was attitude toward pumping (beta = 0.36, P = .03). Among student performers, the most influential factor to predict pumping intention was the subjective norm (beta = 0.31, P = .02). For student nonperformers, perceived behavioral control (beta = 0.54, P < .001) was the most influential factor. Important determinants of the intention to pump on campus included relieving discomfort from engorgement, availability of milk storage, experiencing other people's approval of pumping breast milk, and the inconvenience of carrying pump equipment. DISCUSSION: Continued efforts are needed to create a supportive culture for breastfeeding in the campus community as well as to provide pump loan and milk storage options for both employee and student mothers. PMID- 27508946 TI - Population-based study of ruptured abdominal aortic aneurysm. AB - BACKGROUND: The incidence of abdominal aortic aneurysms (AAAs) and their rupture has been reported to be decreasing. The aim was to evaluate trends in ruptured AAA (rAAA) incidence in the hospital district of Helsinki and Uusimaa (HUS) in southern Finland. This was a population-based retrospective review of all patients with rAAA in this well defined geographical area during 2003-2013. METHODS: Data for all patients treated for rAAA at Helsinki University Hospital, the only vascular surgery centre in an area of 1.5 million inhabitants, were collected from local vascular registry. All deaths attributed to rAAA were obtained from the cause of death registry of Statistics Finland. RESULTS: The mean(s.d.) age of the 712 patients with rAAA was 76.5(9.6) years; 76.7 per cent of them were men. Only 330 patients (46.3 per cent of those with rAAA) arrived alive at Helsinki University Hospital. The turn-down rate for surgical treatment was 10.3 per cent. Of the 296 patients operated on, 199 (67.2 per cent) were alive at 30 days. Only 27.9 per cent of all patients were alive 30 days after rupture of the AAA. The incidence of rAAA was 4.3 per 100 000 inhabitants and the mortality rate was 3.2 per 100 000 inhabitants. A decreasing trend was seen in incidence and mortality during the 11-year study interval. CONCLUSION: The incidence of rAAA is decreasing in the HUS district. Mortality from rAAA remains very high, because half of the patients die before reaching the hospital. PMID- 27508947 TI - Distinguishing malignant and benign renal masses with composite models and nomograms: A systematic review and meta-analysis of clinically localized renal masses suspicious for malignancy. AB - Solid renal masses and cystic lesions with solid components are suspicious for renal cell carcinoma. Without an effective screening test, composite models and nomograms rely on patient and tumor characteristics to stratify the risk of benign disease versus malignant disease. To guide decisions about the use of renal mass sampling or excision, a systematic review and meta-analysis of the ability of composite models to predict the likelihood of malignancy on the basis of preoperative clinical variables was performed. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from January 1, 1997, through May 1, 2015, according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Composite models necessarily included imaging results and at least 1 element from the following to be compared with surgical pathology: demographic characteristics, clinical characteristics, and blood or urine tests. Two independent reviewers screened citations and extracted data. Quality Assessment Tool for Diagnostic Accuracy Studies 2 was used to assess the risk of bias. The strength of evidence was graded with the scheme recommended by Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Twenty studies (12,149 patients) were included in this review. The only significant predictors of malignancy in the composite models were tumor size (effect size, 1.33-fold increased risk per centimeter; 95% confidence interval [CI], 1.22-1.43) and male sex (effect size, 2.71; 95% CI, 2.39-3.02). The results were inconclusive or not significant for tumor characteristics, age, body mass index, and incidental presentation. In conclusion, composite models currently have a limited ability to distinguish malignant renal masses from benign renal masses, with increased tumor size and male sex associated with malignancy. Cancer 2016;122:3267-3276. (c) 2016 American Cancer Society. PMID- 27508948 TI - COMPARISON OF THE LAMINA CRIBROSA THICKNESS OF PATIENTS WITH UNILATERAL BRANCH RETINAL VEIN OCCLUSION AND HEALTHY SUBJECTS. AB - PURPOSE: To compare the lamina cribrosa (LC) thickness of healthy subjects and patients with unilateral branch retinal vein occlusion (BRVO), and to determine possible correlations between the LC thickness and the BRVO subtypes. METHODS: This prospective, cross-sectional study included a total of 46 patients with naive, untreated, unilateral BRVO and 31 healthy control subjects. The occlusion site was divided into two BRVO types: arteriovenous crossing BRVO (AV-BRVO) and optic nerve BRVO (ON-BRVO). The optic nerve head was scanned using enhanced-depth imaging with the Spectralis optical coherence tomography system. RESULTS: The mean LC thickness of both eyes in patients with BRVO was thinner than that of eyes (274.0 MUm) of the healthy subjects (both, P < 0.001). Although the LC thickness of the BRVO-affected eyes was slightly thinner than that of the fellow eyes (237.0 MUm vs. 241.4 MUm, respectively), there was no statistically significant difference. In addition, there were no significant differences in the LC thicknesses of both eyes according to the site of occlusion. CONCLUSION: A thinner LC was observed in both eyes of unilateral BRVO patients compared with those of healthy subjects. This finding suggests that thin LC may contribute to the pathogenesis of BRVO as a local mechanical factor in addition to systemic factors. PMID- 27508949 TI - The positive predictive value of "suspicious for high-grade urothelial carcinoma" in urinary tract cytology specimens: A single-institution study of 665 cases. AB - BACKGROUND: "The Paris System" proposes a 7-tier classification system for urine cytology. Establishing the risk of malignancy (ROM) associated with these diagnostic categories is essential to determine the appropriate management of patients. The objective of this study was to determine the ROM associated with the "positive" and "suspicious" categories. METHODS: The authors searched their electronic records for urine cytology specimens that had been diagnosed as "positive" or "suspicious" for high-grade urothelial carcinoma within an 11-year time frame. Then, the ROM was determined for these specimens within a 6-month follow-up interval. The cytologic diagnoses were correlated with surgical biopsy results, follow-up cytology results, and/or fluorescence in situ hybridization (FISH) results. RESULTS: In total, 662 specimens (487 "positive" and 175 "suspicious"), corresponding to 387 patients (295 men and 92 women), were included. The majority of specimens were collected by bladder washing (568 of 662 specimens; 85.4%) and for the indication of surveillance (601 of 662 specimens; 82%). On follow-up, bladder washing specimens were positive more often positive than voided urine specimens (466 of 570 [81.8%] vs 60 of 92 [65.2%]; P = .0005), and surveillance specimens were more often positive than specimens collected for other indications (82% vs 54.1%). The overall positive predictive value was higher for positive specimens than for suspicious specimens (365 of 461 [79.2%] vs 83 of 150 [55.3%]; P < .0001). CONCLUSIONS: Diagnoses of suspicious for high grade urothelial carcinoma, as used at the authors' institution, have an ROM that is high but is lower than that for the "positive" category. Therefore, the authors suggest keeping the 2 categories separate, although management should be aggressive in both groups. Cancer Cytopathol 2016;124:811-9. (c) 2016 American Cancer Society. PMID- 27508950 TI - Prenatally diagnosed fetal tumors of the head and neck: a systematic review with antenatal and postnatal outcomes over the past 20 years. AB - AIM: The aim of this study was to review prenatally diagnosed tumors of the head and neck in the fetus and to report antenatal and postnatal outcomes. METHODS: PubMed/Medline, EMBASE/SCOPUS, Cochrane database and Google Scholar were reviewed over the last 20 years. No language or article type restriction was used. RESULTS: A total of 1940 record were retrieved. Of the 713 records screened, 566 full-text articles were assessed for eligibility. After 445 articles were excluded for specified reasons, 111 studies met the research criteria and were included for qualitative analysis. Overall, 306 cases of fetal tumors of the head and neck were reviewed. Maternal age was an independent factor. The mean maternal age was 28.2 years and gestational age at prenatal diagnosis was 27.1 weeks. Conventional 2D ultrasound was the standard diagnostic procedure in 27.9% of cases and was implemented in 27.3% of cases by 3D ultrasound and fetal magnetic resonance imaging (MRI). Diagnostic evaluation of intracranial spreading and high airway obstructions was greatly enhanced by fetal MRI. The more common type of fetal tumor was hemangioma/lymphangioms (42.1%), followed by teratomas (29.7%), tumors of the gingiva (10.1%) and lymphatic venous malformations (9.1%), respectively. Fetal karyotyping was performed only in 9.8% of cases; within fetuses undergoing karyotype, chromosomal abnormalities accounted for 20% of cases. The most common pregnancy complication was polyhydramnios (26.3%). Ex utero intrapartum treatment (EXIT) procedure was performed in 30.1% of cases while surgical excision was used in 22.9% during postnatal life. The survival rate was 35.35%. CONCLUSION: Fetal tumors of the head and neck are rare congenital malformations. Two-dimensional ultrasound is diagnostic in almost all cases; however, MRI may be an important diagnostic adjunct in targeted cases and help patient selection for immediate intubation at the time of delivery. EXIT procedure and surgical removal of the tumor was associated with good prognosis. PMID- 27508951 TI - Fourfold increase in prevalence of gestational diabetes mellitus after adoption of the new International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. AB - BACKGROUND: The aim was to evaluate the influence of the new International Association of Diabetes and Pregnancy Study Groups (IADPSG) guidelines for screening of gestational diabetes mellitus (GDM) on GDM prevalence in a cohort from a Swiss tertiary hospital. METHODS: This was a retrospective cohort study involving all pregnant women who were screened for GDM between 24 and 28 weeks of gestation. From 2008 until 2010 (period 1), a two-step approach with 1-h 50 g glucose challenge test (GCT) was used, followed by fasting, 1- and 2-h glucose measurements after a 75 g oral glucose tolerance test (OGTT) in case of a positive GCT. From 2010 until 2013 (period 2), all pregnant women were tested with a one-step 75 g OGTT according to new IADPSG guidelines. In both periods, women with risk factors could be screened directly with a 75 g OGTT in early pregnancy. RESULTS: Overall, 647 women were eligible for the study in period 1 and 720 in period 2. The introduction of the IADPSG criteria resulted in an absolute increase of GDM prevalence of 8.5% (3.3% in period 1 to 11.8% in period 2). CONCLUSIONS: The adoption of the IADPSG criteria resulted in a considerable increase in GDM diagnosis in our Swiss cohort. Further studies are needed to investigate if the screening is cost effective and if treatment of our additionally diagnosed GDM mothers might improve short-term as well as long-term outcome. PMID- 27508952 TI - Depressive symptoms, hostility, and hopelessness in inner-city adolescent health clinic patients: factor structure and demographic correlates. AB - BACKGROUND: Depression, hostility, and hopelessness are risk factors for adult cardiovascular disease (CVD). People living in inner-city environments are particularly vulnerable. These associations may begin in adolescence, but research in this area is hampered by inadequate knowledge about how these negative psychological factors are related in teens and how they are affected by demographic characteristics. We hypothesized that depression, hostility, and hopelessness are one construct, and that this construct would be associated with race and gender in attendees at an inner-city adolescent health clinic. METHODS: Two hundred and forty-six 15-18-year-old patients filled out instruments measuring depressive symptoms, hostility, and hopelessness. Confirmatory factor analysis was used to determine whether the negative psychological factors comprised a single construct or three separate ones. General linear modeling (GLM) was used to test the associations between demographic characteristics and the results of the factor analysis. RESULTS: Depressive symptoms, hostility, and hopelessness were best characterized as three separate constructs, not one (root mean square error of approximation (RMSEA)=0.041, 90% confidence interval (CI)=(0.035, 0.047), comparative fit index (CFI)=0.98). There were no significant relationships between demographic variables and depressive symptoms or hostility. Six percent of the variance in hopelessness scores was accounted for by gender, race, and the interaction between the two (F=3.76; p=0.006), with White males, reporting the highest levels of hopelessness. CONCLUSION: In an urban adolescent health clinic population, depressive symptoms, hostility, and hopelessness were best understood as three separate constructs. Hopelessness was significantly higher in White males. Implications for future clinical research on negative psychological factors in teens are discussed. PMID- 27508953 TI - Evaluation of social anxiety, self-esteem, life quality in adolescents with acne vulgaris. AB - BACKGROUND: Acne vulgaris is a visible skin disease commonly seen in adolescence. As it affects the appearance, it is likely to bring stress to the adolescent's life regarding sensitivity about their appearance. OBJECTIVE: The aim of the study was to investigate the social anxiety level, acne-specific life quality, and self-esteem among adolescents with acne vulgaris. In addition, we evaluated the relationship between these parameters, clinical severity, and sociodemographic data. METHODS: One hundred and two adolescents with acne vulgaris, aged 12-17 years without any psychiatric or medical comorbidity were recruited. The control group consisted of 83 adolescents in the same age range, who had neither psychiatric disease nor acne. Sociodemographic form (SDF), Capa Social Phobia Scale for Children and Adolescents (CSPSCA), and Rosenberg Self esteem Scale (RSES) were applied to both groups. Additionally, the severity of acne was determined with Global Acne Grading System (GAGS), and life quality of the patients was evaluated with Acne Quality of Life Scale (AQOL). RESULTS: There was no significant difference in social anxiety levels and self-esteem between the study and control groups. Life quality impairment and high social anxiety levels, as well as low self-esteem, were found to be associated regardless of the clinical severity. CONCLUSION: Clinicians should be aware of the psychiatric comorbidities when treating adolescents with acne vulgaris. Especially, low self esteem and life quality impairment should warn clinicians to predict high social anxiety levels in adolescent acne patients. PMID- 27508954 TI - Immune status of representative infectious diseases among Japanese female university students. AB - OBJECTIVE: To elucidate the immune status of representative infectious diseases among Japanese youth, we retrospectively investigated serum antibody levels in university students, partly comparing these to immunization records and infectious disease histories confirmed by the maternal and child health (MCH) handbooks. MATERIALS AND METHODS: In total, 168 Japanese female university students, aged 20-21 years, were included. Data were collected from examinations of antibody titers against measles, rubella, varicella-zoster (VZ), mumps, and hepatitis B (HB) and C (HC) viruses, and from QuantiFERON(r)-TB Gold tests, between 2011 and 2015. Records of immunization and infectious disease histories were available from MCH handbooks for students who agreed with the use of their data for this study (n=23). RESULTS: All students had positive antibodies, detected by enzyme immunoassay (EIA), against measles, rubella, VZ, and mumps; however, seroprevalences within the range of seroprotective antibody levels were 38.1% (64/168), 67.9% (114/168), 95.9% (141/147), and 89.8% (132/147), respectively. The students had probably not been infected with HB, HC, or tuberculosis at the time of the examinations. DISCUSSION: The study indicated that a two-dose vaccine for measles and rubella (MR) might not be sufficient to produce antibodies at seroprotective levels. Therefore, we propose that health care workers, including students, should receive an additional MR vaccine, even if they have received two doses of MR vaccine or if they have unknown histories of immunizations or infectious diseases. Further investigations in these areas will be needed. PMID- 27508955 TI - From oliguria to urinary incontinence: a case of Munchausen's syndrome in an adolescent boy. AB - Factitious disorders are characterized by physical or psychological symptoms that are intentionally produced or feigned in order to assume the sick role. "Munchausen's syndrome" is one of these disorders and often is under-recognized or only suspected after unnecessary investigations. We report the case of a 15 year-old boy who came to our notice because of reduced urine output and recurrent abdominal pain during the previous 3 months. The patient attended several emergency room visits and he had been hospitalized for 1 month in an adult internal medicine department because of "oliguria". He had undergone several invasive investigations with normal results before the diagnosis of Munchausen's syndrome was made. General pediatricians and practitioners should be aware that suspecting Munchausen's syndrome in the first instance in the management of a patient showing discrepancies between reported urinary symptoms and the detectable clinical signs could avoid unnecessary and invasive exams. PMID- 27508956 TI - Eating habits and presence of cardiovascular risks in children. AB - INTRODUCTION: The changes in the eating habits associated with physical inactivity are directly related to the increase in the prevalence of obesity and associated diseases such as diabetes mellitus (DM), metabolic syndrome and cardiovascular diseases. OBJECTIVE: The aim of this study was to investigate the relationship between the frequency of consumption of some food groups (snacks, fruits, vegetables and candies), physical exercise, nutritional classification and biochemical profile in children. METHODS: After the approval of the Ethics Committee, we studied 882 schoolchildren ranging between 6 and 10 years of age. Biochemical and anthropometric evaluations were performed and questionnaires were used in order to check the eating habits and physical activity. RESULTS: Our results showed that we may relate the consumption of snacks, fruits, vegetables or candies with modifications in the glycemia, triglycerides, total cholesterol, HDL-c, and LDL-c but we did not observe association with the nutritional classification. It is noteworthy to say that almost 50% of the studied children were overweight or obese and many presented alterations in the lipid and glucose levels. CONCLUSION: Our results also show that many children have abnormal levels of lipids and glycemia and a great number of them are classified as overweight or obese. In this context, we can say that urgent approaches are needed to be carried out by a multidisciplinary team in order to improve the diet and reduces the risk factors in this population of children and prevent secondary diseases in adolescence and adulthood. PMID- 27508957 TI - Prevalence and risk factors associated with suicidal ideation among adolescents in Malaysia. AB - BACKGROUND: Suicidal ideation, defined as thoughts, ideas and the desire to commit suicide, is becoming a major public health problem among adolescents. Indeed, suicidal ideation is known as a key predictor of future suicide risk. OBJECTIVE: This study aims to determine the prevalence and risk factors associated with suicidal ideation among adolescents in Malaysia. METHODS: This study used data from the 2013 Malaysian adolescent health risk behavior (MyAHRB) study, a cross-sectional school survey conducted in Peninsular Malaysia among school-going adolescents aged 16-17 years (n=2789). Logistic regression analysis was used to determine the risk factors associated with suicidal ideation among Malaysian adolescents. RESULTS: The overall prevalence of suicidal ideation among the adolescents was 6.2%. The prevalence was significantly higher among females than males (7.6% vs. 4.7%; p=0.002). Multivariate regression analysis revealed that adolescents who were females [odds ratio (OR)=2.02; 95% confidence interval (CI): 1.40-2.92] or of Indian ethnicity (OR=2.32; 95% CI: 1.35-3.98) were more likely to report suicidal ideation. Loneliness (OR=2.54; 95% CI: 1.57-4.11), anxiety or worry (OR=2.70; 95% CI: 1.70-4.31), no close friends (OR=2.71; 95% CI: 1.43-5.14), and lack of supportive peers (OR=1.69; 95% CI: 1.15-2.47) were identified as risk factors for adolescents' suicidal ideation. Adolescents who ever had sexual intercourse (OR=2.70; 95% CI: 1.48-4.92) and had been in a physical fight (OR=2.45; 95% CI: 1.62-3.70) were also reported to have higher risks of suicidal ideation. CONCLUSION: This study provides evidence on risk factors associated with suicidal ideation among Malaysian adolescents. Targeted mental health and health risk behavioral interventions for high-risk adolescents are recommended. PMID- 27508958 TI - Who is teaching the kids to cook? Results from a nationally representative survey of secondary school students in New Zealand. AB - Learning how to cook is an important skill for developing healthy eating behaviors. Moreover, involvement in home cooking may offer young people opportunities for skill building, identity development and social engagement with their families. Recently, there have been concerns that the current generation of young people may not have the opportunities to develop sufficient cooking skills. These concerns have been addressed by the initiation of numerous, localized interventions. Yet, little is known about where the current generation of young people learn cooking skills. The objective of this study was to describe where the current generation of young people report learning to cook, drawing on nationally representative data from New Zealand. Data were collected as part of Youth2012, a nationally representative survey of secondary school students (n=8500) in New Zealand. Almost all students reported learning to cook and from multiple sources. Almost all students reported learning to cook from a family member (mother, father, or other family member), approximately 60% of students reported that they learned to cook from certain media (cookbooks, TV, or the Internet) and half of all students reported learning to cook at school. There were numerous differences in where students learned to cook by socio-demographic characteristics. Findings from the current research highlight the important role that families play in teaching young people to cook and will be useful for those working with young people to develop these skills. PMID- 27508959 TI - Brain-derived neurotrophic factor: a mediator of inflammation-associated neurogenesis in Alzheimer's disease. AB - In early- or late-onset Alzheimer's disease (AD), inflammation, which is triggered by pathologic conditions, influences the progression of neurodegeneration. Brain-derived neurotrophic factor (BDNF) has emerged as a crucial mediator of neurogenesis, because it exhibits a remarkable activity dependent regulation of expression, which suggests that it may link inflammation to neurogenesis. Emerging evidence suggests that acute and chronic inflammation in AD differentially modulates neurotrophin functions, which are related to the roles of inflammation in neuroprotection and neurodegeneration. Recent studies also indicate novel mechanisms of BDNF-mediated neuroprotection, including the modulation of autophagy. Numerous research studies have demonstrated reverse parallel alterations between proinflammatory cytokines and BDNF during neurodegeneration; thus, we hypothesize that one mechanism that underlies the negative impact of chronic inflammation on neurogenesis is the reduction of BDNF production and function by proinflammatory cytokines. PMID- 27508960 TI - Comparison of fluoxetine and 1-methyl-L-tryptophan in treatment of depression like illness in Bacillus Calmette-Guerin-induced inflammatory model of depression in mice. AB - BACKGROUND: The inflammatory response system has been implicated in the pathophysiology of major depression. The pro-inflammatory cytokines like interferon-gamma induce the enzyme indoleamine-2,3-dioxygenase (IDO) of the kynurenine pathway of tryptophan metabolism. The induction of IDO reduces the availability of tryptophan for serotonin synthesis. Furthermore, the metabolites of kynurenine pathway have neurotoxic property, which along with decreased serotonin may account for depression-like illness. METHODS: The aim of this study was to compare the effects of treatment with fluoxetine and 1-methyl-L-tryptophan (1-MT) on Bacillus Calmette-Guerin (BCG)-induced inflammatory model of depression in mice. Behavioral tests included locomotor activity, forced swim test (FST) and tail suspension test (TST). Oxidative stress was assessed by examining the levels of thiobarbituric acid reactive species (TBARS) and non-protein thiols (NP-SH) in homogenized whole brain samples. Comet assays were performed to assess neurotoxicity. RESULTS: The results of this study demonstrate that BCG treatment resulted in an increase in duration of immobility in FST and TST as compared to the saline group. Further, it produced a significant increase in the brain TBARS levels and decrease in the brain NP-SH levels. The hippocampal tissue from BCG group had significantly more comet cells than the saline group. 1-MT and fluoxetine were able to reverse the BCG-induced depression-like behavior and the derangement in oxidative stress parameters. Fluoxetine and 1-MT also reversed the BCG-induced neurotoxicity in such mice. CONCLUSIONS: 1-Methyl-L-tryptophan exhibits antidepressant-like effect comparable to that of fluoxetine in treating BCG-induced depression-like behavior in mice. PMID- 27508961 TI - Anti-acetylcholinesterase activity of essential oils and their major constituents from four Ocimum species. AB - Ocimum is a genus of considerable importance in traditional medicine worldwide. The goal of this study was to examine the anti-acetylcholinesterase activity of Ocimum essential oils and to correlate the activity with their chemical profiles using a metabolome based GC-MS approach coupled to chemometrics. Further, molecular docking was adopted to rationalize the activity of some essential oil isolates. Essential oil prepared from the four species O. basilicum, O. africanum, O. americanum, and O. minimum exhibited significant anti acetylcholinesterase activity with (IC50 0.22, 0.175, 0.57 and 0.152 mg/mL, respectively) comparable to that of physostigmine (IC50 0.27 mg/mL). The phenylpropanoids (i.e. estragole) constituted the most dominant chemical group in O. basilicum (sweet basil) and O. minimum, whereas camphor (a ketone) was the most abundant in O. africanum and O. americanum. Supervised and unsupervised multivariate data analyses clearly separated O. africanum and O. americanum from other accessions, with estragole, camphor and, to less extent, beta-linalool contributing to species segregation. Estragole was found the most active AchE inhibitor (IC50 0.337 uM) followed by cineole (IC50 2.27 uM), camphor (IC50 21.43 uM) and eugenol (IC50 40.32 uM). Molecular docking revealed that these compounds bind to key amino acids in the catalytic domain of AchE, similar to standard drugs. PMID- 27508962 TI - Alpha-synuclein at the intracellular and the extracellular side: functional and dysfunctional implications. AB - Alpha-synuclein (alpha-syn) is an abundant neuronal protein whose physiological function, even if still not completely understood, has been consistently related to synaptic function and vesicle trafficking. A group of disorders known as synucleinopathies, among which Parkinson's disease (PD), is deeply associated with the misfolding and aggregation of alpha-syn, which can give rise to proteinaceous inclusion known as Lewy bodies (LB). Proteostasis stress is a relevant aspect in these diseases and, currently, the presence of oligomeric alpha-syn species rather than insoluble aggregated forms, appeared to be associated with cytotoxicity. Many observations suggest that alpha-syn is responsible for neurodegeneration by interfering with multiple signaling pathways. alpha-syn protein can directly form plasma membrane channels or modify with their activity, thus altering membrane permeability to ions, abnormally associate with mitochondria and cause mitochondrial dysfunction (i.e. mitochondrial depolarization, Ca2+ dys-homeostasis, cytochrome c release) and interfere with autophagy regulation. The picture is further complicated by the fact that single point mutations, duplications and triplication in alpha-syn gene are linked to autosomal dominant forms of PD. In this review we discuss the multi faced aspect of alpha-syn biology and address the main hypothesis at the basis of its involvement in neuronal degeneration. PMID- 27508963 TI - E-beam crosslinked nanogels conjugated with monoclonal antibodies in targeting strategies. AB - Poly(N-vinyl pyrrolidone)-based-nanogels (NGs), produced by e-beam irradiation, are conjugated with monoclonal antibodies (mAb) for active targeting purposes. The uptake of immuno-functionalized nanogels is tested in an endothelial cell line, ECV304, using confocal and epifluorescence microscopy. Intracellular localization studies reveal a faster uptake of the immuno-nanogel conjugate with respect to the 'bare' nanogel. The specific internalization pathway of these immuno-nanogels is clarified by selective endocytosis inhibition experiments, flow cytometry and confocal microscopy. Active targeting ability is also verified by conjugating a monoclonal antibody which recognizes the alphavbeta3 integrin on activated endothelial cells. Epifluorescence images of the 'wound healing assay' on ECV304 cells provide evidence of nanogels localization only in the target cells. Therefore, the immuno-nanogels produced have the potential to recognize specific cell types in heterogeneous systems, which makes them promising candidates for targeted drug delivery applications. PMID- 27508964 TI - Pituitary-bone connection in skeletal regulation. AB - Pituitary hormones have traditionally been thought to exert specific, but limited function on target tissues. More recently, the discovery of these hormones and their receptors in organs such as the skeleton suggests that pituitary hormones have more ubiquitous functions. Here, we discuss the interaction of growth hormone (GH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), prolactin, oxytocin and arginine vasopressin (AVP) with bone. The direct skeletal action of pituitary hormones therefore provides new insights and therapeutic opportunities for metabolic bone diseases, prominently osteoporosis. PMID- 27508966 TI - The self-perception of dyspnoea threshold during the 6-min walk test: a good alternative to estimate the ventilatory threshold in chronic obstructive pulmonary disease. AB - To determine and/or adjust exercise training intensity for patients when the cardiopulmonary exercise test is not accessible, the determination of dyspnoea threshold (defined as the onset of self-perceived breathing discomfort) during the 6-min walk test (6MWT) could be a good alternative. The aim of this study was to evaluate the feasibility and reproducibility of self-perceived dyspnoea threshold and to determine whether a useful equation to estimate ventilatory threshold from self-perceived dyspnoea threshold could be derived. A total of 82 patients were included and performed two 6MWTs, during which they raised a hand to signal self-perceived dyspnoea threshold. The reproducibility in terms of heart rate (HR) was analysed. On a subsample of patients (n=27), a stepwise regression analysis was carried out to obtain a predictive equation of HR at ventilatory threshold measured during a cardiopulmonary exercise test estimated from HR at self-perceived dyspnoea threshold, age and forced expiratory volume in 1 s. Overall, 80% of patients could identify self-perceived dyspnoea threshold during the 6MWT. Self-perceived dyspnoea threshold was reproducibly expressed in HR (coefficient of variation=2.8%). A stepwise regression analysis enabled estimation of HR at ventilatory threshold from HR at self-perceived dyspnoea threshold, age and forced expiratory volume in 1 s (adjusted r=0.79, r=0.63, and relative standard deviation=9.8 bpm). This study shows that a majority of patients with chronic obstructive pulmonary disease can identify a self-perceived dyspnoea threshold during the 6MWT. This HR at the dyspnoea threshold is highly reproducible and enable estimation of the HR at the ventilatory threshold. PMID- 27508967 TI - Interlimb weight adjustments between the lower and upper limbs relate to inaccurate performance during the lateral body weight-shifting task. AB - The lateral body weight-shifting task is commonly used in therapeutic programs for patients with orthopedic complaints or hemiparesis. Although the patients usually support themselves using the upper limbs during the task, it is unclear whether the use of upper limbs affects performance accuracy of lateral body weight shifting. Therefore, the aim of this study was to investigate the effects of support by the upper limbs on performance accuracy, particularly on the central tendency effects (i.e. overshooting for light targets and undershooting for heavy targets). Twenty-three able-bodied, neurologically intact individuals, who were right-handed and right-footed participants performed the lateral body weight-shifting task to shift one-third or two-thirds of their body weight toward the left and right lower limbs using support by the upper limbs. The result of correlation coefficients between interlimb weight adjustment and errors showed that the use of the upper limbs and interlimb weight adjustment related to the enhanced central tendency effects. The use of upper limbs generally contributes toward stabilizing posture, however, this is not the case with performance of the lateral body weight shifting. Moreover, the effects of using the upper limb on performance accuracy differed among leftward and rightward weight shifting. This result might be owing to the dominant side of the hand/foot and hemisphere lateralization. PMID- 27508965 TI - Accumbal MU-Opioid Receptors Modulate Ethanol Intake in Alcohol-Preferring Alko Alcohol Rats. AB - BACKGROUND: The nucleus accumbens shell is a key brain area mediating the reinforcing effects of ethanol (EtOH). Previously, it has been shown that the density of MU-opioid receptors in the nucleus accumbens shell is higher in alcohol-preferring Alko Alcohol (AA) rats than in alcohol-avoiding Alko Non Alcohol rats. In addition, EtOH releases opioid peptides in the nucleus accumbens and opioid receptor antagonists are able to modify EtOH intake, all suggesting an opioidergic mechanism in the control of EtOH consumption. As the exact mechanisms of opioidergic involvement remains to be elucidated, the aim of this study was to clarify the role of accumbal MU- and kappa-opioid receptors in controlling EtOH intake in alcohol-preferring AA rats. METHODS: Microinfusions of the MU-opioid receptor antagonist CTOP (0.3 and 1 MUg/site), MU-opioid receptor agonist DAMGO (0.03 and 0.1 MUg/site), nonselective opioid receptor agonist morphine (30 MUg/site), and kappa-opioid receptor agonist U50488H (0.3 and 1 MUg/site) were administered via bilateral guide cannulas into the nucleus accumbens shell of AA rats that voluntarily consumed 10% EtOH solution in an intermittent, time restricted (90-minute) 2-bottle choice access paradigm. RESULTS: CTOP (1 MUg/site) significantly increased EtOH intake. Conversely, DAMGO resulted in a decreasing trend in EtOH intake. Neither morphine nor U50488H had any effect on EtOH intake in the used paradigm. CONCLUSIONS: The results provide further evidence for the role of accumbens shell MU-opioid receptors but not kappa-opioid receptors in mediating reinforcing effects of EtOH and in regulating EtOH consumption. The results also provide support for views suggesting that the nucleus accumbens shell has a major role in mediating EtOH reward. PMID- 27508968 TI - The use of commercial video games in rehabilitation: a systematic review. AB - The aim of this paper was to investigate the effect of commercial video games (VGs) in physical rehabilitation of motor functions. Several databases were screened (Medline, SAGE Journals Online, and ScienceDirect) using combinations of the following free-text terms: commercial games, video games, exergames, serious gaming, rehabilitation games, PlayStation, Nintendo, Wii, Wii Fit, Xbox, and Kinect. The search was limited to peer-reviewed English journals. The beginning of the search time frame was not restricted and the end of the search time frame was 31 December 2015. Only randomized controlled trial, cohort, and observational studies evaluating the effect of VGs on physical rehabilitation were included in the review. A total of 4728 abstracts were screened, 275 were fully reviewed, and 126 papers were eventually included. The following information was extracted from the selected studies: device type, number and type of patients, intervention, and main outcomes. The integration of VGs into physical rehabilitation has been tested for various pathological conditions, including stroke, cerebral palsy, Parkinson's disease, balance training, weight loss, and aging. There was large variability in the protocols used (e.g. number of sessions, intervention duration, outcome measures, and sample size). The results of this review show that in most cases, the introduction of VG training in physical rehabilitation offered similar results as conventional therapy. Therefore, VGs could be added as an adjunct treatment in rehabilitation for various pathologies to stimulate patient motivation. VGs could also be used at home to maintain rehabilitation benefits. PMID- 27508969 TI - Chitosan crosslinked flat scaffolds for peripheral nerve regeneration. AB - Chitosan (CS) has been widely used in a variety of biomedical applications, including peripheral nerve repair, due to its excellent biocompatibility, biodegradability, readily availability and antibacterial activity. In this study, CS flat membranes, crosslinked with dibasic sodium phosphate (DSP) alone (CS/DSP) or in association with the gamma-glycidoxypropyltrimethoxysilane (CS/GPTMS_DSP), were fabricated with a solvent casting technique. The constituent ratio of crosslinking agents and CS were previously selected to obtain a composite material having both adequate mechanical properties and high biocompatibility. In vitro cytotoxicity tests showed that both CS membranes allowed cell survival and proliferation. Moreover, CS/GPTMS_DSP membranes promoted cell adhesion, induced Schwann cell-like morphology and supported neurite outgrowth from dorsal root ganglia explants. Preliminary in vivo tests carried out on both types of nerve scaffolds (CS/DSP and CS/GPTMS_DSP membranes) demonstrated their potential for: (i) protecting, as a membrane, the site of nerve crush or repair by end-to-end surgery and avoiding post-operative nerve adhesion; (ii) bridging, as a conduit, the two nerve stumps after a severe peripheral nerve lesion with substance loss. A 1 cm gap on rat median nerve was repaired using CS/DSP and CS/GPTMS_DSP conduits to further investigate their ability to induce nerve regeneration in vivo. CS/GPTMS_DSP tubes resulted to be more fragile during suturing and, along a 12 week post-operative lapse of time, they detached from the distal nerve stump. On the contrary CS/DSP conduits promoted nerve fiber regeneration and functional recovery, leading to an outcome comparable to median nerve repaired by autograft. PMID- 27508970 TI - Development and validation of a multiresidue method for the analysis of more than 500 pesticides and drugs in water based on on-line and liquid chromatography coupled to high resolution mass spectrometry. AB - Screening of a large number of emerging pollutants is highly desirable for the control of water quality. In this respect, a novel, fully automated contaminant screening method based on an integrated sample preconcentration and liquid chromatography coupled to high resolution mass spectrometry (SPE-UHPLC-HRMS) has been developed. The optimal chromatographic column and experimental conditions allowing the retention and subsequent elution of the maximum number of analytes were defined. Liquid chromatography and Q-exactive (OrbitrapTM) parameters were optimized to obtain the best separation of molecules of interest, and the lowest detection limits. Due to the large amount of data to compare, a script written in R language was developed to evaluate the quality of the data generated by the comparison of 14 experimental conditions. The developed method enables the simultaneous semi quantitative analysis of 539 compounds (pesticides and drug residues), in 36 min with only 5 mL of water. Method validation was achieved through studies of repeatability, selectivity, linearity and matrix effect. Application to 20 tap water samples collected in and around Paris showed the presence of 34 different compounds all with concentrations below 0.1 MUg/L, the European Union limit for drinking water. Pesticides and transformation products frequently found in water resources such as atrazine and its metabolites, hexazinone, oxadixyl, propazine and simazine were detected. Drug residues such as valsartan and carbamazepine, usually not monitored, were also found. The next step will be to assess the ability of this method to highlight the presence of unexpected contaminants not present in our database. PMID- 27508971 TI - Characterization of the relationship between ceramic pot filter water production and turbidity in source water. AB - Ceramic pot filters represent a common and effective household water treatment technology in developing countries, but factors impacting water production rate are not well-known. Turbidity of source water may be principal indicator in characterizing the filter's lifetime in terms of water production capacity. A flow rate study was conducted by creating four controlled scenarios with different turbidities, and influent and effluent water samples were tested for total suspended solids and particle size distribution. A relationship between average flow rate and turbidity was identified with a negative linear trend of 50 mLh-1/NTU. Also, a positive linear relationship was found between the initial flow rate of the filters and average flow rate calculated over the 23 day life of the experiment. Therefore, it was possible to establish a method to estimate the average flow rate given the initial flow rate and the turbidity in the influent water source, and to back calculate the maximum average turbidity that would need to be maintained in order to achieve a specific average flow rate. However, long term investigations should be conducted to assess how these relationships change over the expected CPF lifetime. CPFs rejected fine suspended particles (below 75 MUm), especially particles with diameters between 0.375 MUm and 10 MUm. The results confirmed that ceramic pot filters are able to effectively reduce turbidity, but pretreatment of influent water should be performed to avoid premature failure. PMID- 27508972 TI - Experimental and theoretical insights into the photochemical decomposition of environmentally persistent perfluorocarboxylic acids. AB - Decomposition of perfluorocarboxylic acids (PFCAs) is of great significance due to their global distribution, persistence and toxicity to organisms. In this study, the photodegradation of a series of PFCAs (~C2C12) in water by a medium pressure mercury lamp was experimentally and theoretically examined. We found that photolysis of PFCAs all follow pseudo-first-order kinetics with the rate constant (kapp) increasing with carbon chain lengths, except for trifluoroacetic acid (TFA) which cannot be degraded by the polychromatic irradiation. Product analysis showed that the PFCAs were mainly decomposed into shorter carbon chain length PFCAs in a stepwise manner, with the accumulation of TFA and fluoride ions as the end products. Moreover, a small amount of perfluoroolefins (CnF2n) was determined as gas-phase products. Wiberg bond order calculations confirmed the cleavage of the CC bond between carboxylic carbon and the adjacent carbon as the first reaction step, and density functional theory-based calculations revealed that kapp value is correlated with some molecular structural parameters. In the case of mixture irradiation, the evolution profiles of individual PFCAs were different from that in single-component systems, due to the dynamic balance between production and degradation. This work reveals the main molecular descriptors controlling the degradation rate of different PFCAs species, and improves the general understanding on the photodegradation mechanisms, which will provide useful information for future researches. PMID- 27508973 TI - Generation of dissolved organic matter and byproducts from activated sludge during contact with sodium hypochlorite and its implications to on-line chemical cleaning in MBR. AB - On-line chemical cleaning of membranes with sodium hypochlorite (NaClO) has been commonly employed for maintaining a constant permeability of membrane bioreactor (MBR) due to its simple and efficient operation. However, activated sludge is inevitably exposed to NaClO during this cleaning process. In spite of the broad applications of on-line chemical cleaning in MBR such as chemical cleaning-in place (CIP) and chemical enhanced backwash (CEB), little information is currently available for the release of emerging dissolved organic matter (DOM) and byproducts from this prevalent practice. Therefore, in this study, activated sludge suspended in a phosphate buffered saline solution was exposed to different doses of NaClO in order to determine the generation of potential DOM and byproducts. The results showed the occurrence of significant DOM release (up to 24.7 mg/L as dissolved organic carbon) after exposure to NaClO for 30 min. The dominant components of the released DOM were characterized to be humic acid-like as well as protein-like substances by using an excitation-emission matrix fluorescence spectrophotometer. Furthermore, after the contact of activated sludge with NaClO, 19 kinds of chlorinated and brominated byproducts were identified by ultra performance liquid chromatography/electrospray ionization triple quadrupole mass spectrometry, eight of which were confirmed and characterized with standard compounds. Many byproducts were found to be halogenated aromatic compounds, including halopyrroles and halo(hydro)benzoquinones, which had been reported to be significantly more toxic than the halogenated aliphatic ones. Consequently, this study offers new insights into the practice of on-line chemical cleaning, and opens up a window to re examine the current operation of MBR by looking into the generation of micropollutants. PMID- 27508974 TI - Thermal hydrolysis for sewage treatment: A critical review. AB - A review concerning the development and applicability of sewage sludge thermal hydrolysis especially prior to anaerobic digestion is presented. Thermal hydrolysis has proven to be a successful approach to making sewage sludge more amenable to anaerobic digestion. Currently there are 75 facilities either in operation or planning, spanning several continents with the first installation in 1995. The reported benefits of thermal hydrolysis relate to: increased digestion loading rate due to altered rheological properties, improved biodegradation of (especially activated) sludge and enhanced dewaterability. In spite of its relative maturity, there has been no attempt to perform a critical review of the pertinent literature relating to the technology. Closer look at the literature reveals complications with comparing both experimental- and full-scale results due to differences in experimental set-up and capability, and also site-specific conditions at full-scale. Furthermore, it appears that understanding of thermodynamic and rheological properties of sludge is key to optimizing the process, however these parameters are largely overlooked by the literature. This paper aims to bridge these complexities in order to elucidate the benefits of thermal hydrolysis for sewage treatment, and makes recommendations for further development and research. PMID- 27508976 TI - MDM2 and CDK4 Immunohistochemistry: Should It Be Used in Problematic Differentiated Lipomatous Tumors?: A New Perspective. AB - Although most cases of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) can be diagnosed solely on the basis of histologic features, those lacking diagnostic histologic features require ancillary studies for accurate classification. Fluorescent in situ hybridization (FISH) for amplification of MDM2 has been considered the gold standard for diagnosis in these situations. Immunostaining for MDM2 and/or CDK4 has been adopted as a surrogate method because of its high concordance rate with FISH and lower cost. However, studies examining the concordance of the 2 methods have been based preferentially on cases in which the diagnosis could be established histologically. No study has explored the concordance between the 2 methods in histologically ambiguous cases or in cases in which the diagnosis of ALT/WDL is not apparent after a review of all slides. To address this, we performed immunostaining for MDM2 and CDK4 on 183 well-differentiated lipomatous tumors that could not be diagnosed on purely histologic grounds and that were, therefore, subjected to FISH analysis. These included ALT/WDLs (n=56), lipomas (n=96), and lipoma variants (n=31). Staining for MDM2 and CDK4 was noted in 25/56 and 23/56 ALT/WDL, respectively, giving a sensitivity of 45% and 41% and a specificity of 98% and 92%. Staining was noted exclusively in the nuclei of atypical cells and not in the nuclei of adipocytes. Staining for MDM2 and CDK4 occurred in 2/125 and 10/117 benign lipomatous lesions, respectively. False-positive staining was equivalent in intensity to ALT/WDL. We conclude that MDM2 and CDK4 staining is a relatively insensitive method for diagnosing ALT/WDL in cases that are histologically ambiguous, as staining is restricted to neoplastic cells with atypia that are underrepresented in these cases. Therefore, in cases like ours that closely simulate clinical practice, FISH is the more reliable and cost-effective option. PMID- 27508975 TI - Undifferentiated Carcinoma With Osteoclastic Giant Cells of the Pancreas: Clinicopathologic Analysis of 38 Cases Highlights a More Protracted Clinical Course Than Currently Appreciated. AB - Undifferentiated carcinomas with osteoclastic giant cells of the pancreas (OGC) are rare tumors. The current impression in the literature is that they are highly aggressive tumors similar in prognosis to ductal adenocarcinomas. In this study, the clinicopathologic characteristics of 38 resected OGCs were investigated and contrasted with 725 resected pancreatic ductal adenocarcinomas without osteoclastic cells (PDCs). The frequency among systematically reviewed pancreatic cancers was 1.4%. OGCs showed a slight female predominance (62.9%, vs. 51.4% in PDCs). The mean age was 57.9 years (vs. 65.0). The mean size of invasive cancer was 5.3 cm (vs. 3.2). They were characterized by nodular, pushing-border growth, and 8 arose in tumoral intraepithelial neoplasms (4 in mucinous cystic neoplasms, 4 in intraductal papillary mucinous neoplasms type lesions), and 23 (61%) also showed prominent intraductal/intracystic growth. Twenty-nine (76%) had an invasive ductal/tubular adenocarcinoma component. Osteoid was seen in 12. Despite their larger size, perineural invasion and nodal metastasis were uncommon (31.6% and 22.6%, vs. 85.5% and 64.0%, respectively). Immunohistochemistry performed on 24 cases revealed that osteoclastic cells expressed the histiocytic marker CD68, and background spindle cells and pleomorphic/giant carcinoma cells often showed p53 and often lacked cytokeratin. Survival of OGCs was significantly better than that of PDCs (5 yr, 59.1% vs. 15.7%, respectively, P=0.0009). In conclusion, pancreatic OGCs present with larger tumor size and in slightly younger patients than PDC, 21% arise in mucinous cystic neoplasms/intraductal papillary mucinous neoplasms, and 61% show intraductal/intracystic polypoid growth. OGCs have a significantly better prognosis than is currently believed in the literature. PMID- 27508977 TI - Abnormal blink reflex recovery cycle in manifesting and nonmanifesting carriers of the DYT1 gene mutation. AB - The aim of this study is to evaluate the brainstem function in DYT1 carriers manifesting clinical dystonia (MDYT1) and those without clinical symptoms (NMDYT1). Motor cortical inhibition and plasticity were found to be abnormal in MDYT1, whereas these were less abnormal in NMDYT1. However, the spinal reciprocal inhibition was abnormal in MDYT1, but normal in NMDYT1. Moreover, protein accumulation and perinuclear inclusion bodies were found in the brainstem, but not in other brain areas, in DYT1 patients. Therefore, we designed this study to investigate the brainstem physiology using the blink reflex (BR) recovery cycle test in MDYT1 and NMDYT1. We recruited eight MDYT1, five NMDYT1, and nine age matched healthy controls. The BR recovery cycle was assessed with paired stimuli that induced the BR in a random order at interstimulus intervals of 250, 500, and 1000 ms. A two-way analysis of variance showed a significant difference between MDYT1, NMDYT1, and the healthy control (P=0.004). Post-hoc analysis showed that this was because of a significantly lower inhibition of R2 in MDYT1 and NMDYT1 compared with the controls (two-way analysis of variance: P=0.003 and 0.021, respectively). There was no difference between MDYT1 and NMDYT1 (P=0.224). The tested brainstem circuits were equally involved in MDYT1 and NMDYT1. The finding is in agreement with the pathological findings in DYT1 carriers. Together with previous findings in the motor cortex and the spinal cord, the brainstem may lie closer to the pathogenesis of dystonia than the motor cortex in DYT1 gene carriers. PMID- 27508978 TI - Genetic effects of XRCC4 and ligase IV genes on human glioma. AB - Ligase IV and XRCC4 genes, important molecules in the nonhomologous end-joining pathway for repairing DNA double-strand breaks, may play crucial roles in carcinogenesis. To detect their effects on the risk of human glioma, their gene expression differences between 110 human glioma tissues and 50 healthy brain tissues were determined using quantitative real-time PCR. Furthermore, two tagging single nucleotide polymorphisms (SNPs) in ligase IV and four SNPs in XRCC4 genes were genotyped in 317 glioma patients and 352 healthy controls. The association of glioma and ligase IV/XRCC4 was evaluated using methods for SNP, haplotype, and gene-gene interaction analysis. Compared with those in normal brain tissues, the relative gene expression levels of ligase IV and XRCC4 were significantly downregulated in glioma tissue (P=0.0017 and 0.0006, respectively). Single SNP analysis indicated that only rs10131 in ligase IV remained significantly associated with glioma (P=0.0036) after 10 000 permutation tests. Haplotype analysis showed that the haplotype profiles of ligase IV and XRCC4 were significantly different between glioma patients and healthy controls (P=0.004 and 3.13E-6, respectively). Finally, the gene-gene interaction analysis suggested that the three-locus model (rs1805388, rs10131, and rs2075685) was the best model for ligase IV and XRCC4 to have interaction effects on the risk of glioma. In conclusion, both ligase IV and XRCC4 may act in concert to modulate the development of glioma. PMID- 27508979 TI - State-dependent alterations in cerebrospinal fluid Abeta42 levels in cognitively intact elderly with late-life major depression. AB - Depression has been linked to Alzheimer's disease as either an increased risk factor for its development or as a prodromal symptom. The neurobiological basis for such an association, however, remains poorly understood. Numerous studies have examined whether changes in amyloid beta (Abeta) metabolism, which are implicated in the pathogenesis of Alzheimer's disease, are also found in depression. In this paper, we investigated the relationship between depressive symptoms and cerebrospinal fluid (CSF) Abeta indices in otherwise healthy, cognitively normal elderly with late-life major depression (LLMD) and controls using a longitudinal approach, which is a novel contribution toward the literature. Significantly lower levels of CSF Abeta42 were observed in the LLMD group at baseline and were associated with more severe depressive symptoms. During longitudinal follow-up, the depressed group remained cognitively unchanged, but was significantly less depressed than at baseline. A greater improvement in depressive symptoms was associated with increases in CSF Abeta42 levels in both groups. Increases in CSF Abeta42 and Abeta40 were also associated with increased CSF total-tau levels. Our results suggest that LLMD may be associated with state-dependent effects of CSF Abeta42 levels. Future studies should determine whether the association reflects state-dependent changes in neuronal activity and/or brain amyloid burden in depression. PMID- 27508980 TI - Human area 5 modulates corticospinal output during movement preparation. AB - Neuroimaging evidence suggests that human Brodmann area 5 (BA5) within the superior parietal lobule contributes to movement planning. However, a causal role for the contribution of BA5 to preparatory processes has yet to be reported. We used paired-pulse transcranial magnetic stimulation to investigate the influence of human BA5 on corticospinal excitability during movement preparation in the context of a GO/NO-GO task. Functional connectivity between BA5 and the ipsilateral primary motor cortex (M1) was investigated by probing corticospinal output to the first dorsal interosseous muscle of the right hand. Results indicate that BA5 influences M1 during movement preparation in a task-specific manner: motor-evoked potentials are suppressed in the context of a NO-GO versus GO task. These findings provide evidence that human BA5 participates in movement preparation and differentiates between whether a movement is withheld or executed. PMID- 27508981 TI - Self-Reported California Hospital Palliative Care Program Composition, Certification, and Staffing Level Are Associated with Lower End-of-Life Medicare Utilization. AB - BACKGROUND: California hospitals report palliative care (PC) program characteristics to the California Office of Statewide Health Planning and Development (OSHPD), but the significance of this information is unknown. OBJECTIVE: Our objective was to determine whether self-reported California hospital PC program characteristics are associated with lower end-of-life (EoL) Medicare utilization. DESIGN: We performed a cross-sectional study of hospitals submitting 2012 data to OSHPD and included in the 2012 Dartmouth Atlas of Healthcare (DAHC) dataset, using statistical hypothesis testing, multivariate regression, and fuzzy set qualitative comparative analysis. SETTING/SUBJECTS: Our analysis included 203 hospitals primarily providing general medical-surgical (GMS) care. MEASUREMENTS: The following measures were available for each hospital: licensed GMS beds; type of control; presence of an inpatient or outpatient PC program; number of physicians, nurses, social workers, and chaplains on the PC team; number of PC-certified staff; percentage of Medicare decedents dying as inpatients; and average total hospital days, ICU days, and physician visits per Medicare decedent in the last six months of life. RESULTS: Investor-owned hospitals have fewer PC programs and higher EoL utilization than do nonprofit hospitals. Among nonprofit hospitals, small size (substantially fewer than 150 medical-surgical beds), or large size and having an inpatient PC program with more than three PC staff per 100 GMS beds, or an interdisciplinary PC-certified team, is associated with significantly lower EoL hospital utilization and percentage of deaths occurring in the inpatient setting. DISCUSSION: Improved program performance associated with higher staffing levels may be mediated by increased access to and earlier PC interventions. CONCLUSION: California hospital-reported PC program characteristics are associated with significantly lower inpatient utilization by Medicare decedents. PMID- 27508983 TI - Canola Implantation Foreign Body Reaction on the Perineum in a Prepubertal Girl. From the ISSVD Case Consultation Committee. PMID- 27508982 TI - Biochemical responses of filamentous algae in different aquatic ecosystems in South East Turkey and associated water quality parameters. AB - To the best of our knowledge, any study about biochemical response of filamentous algae in the complex freshwater ecosystems has not been found in the literature. This study was designed to explore biochemical response of filamentous algae in different water bodies from May 2013 to October 2014, using multivariate approach in the South East of Turkey. Environmental variables were measured in situ: water temperature, oxygen concentration, saturation, conductivity, salinity, pH, redox potential, and total dissolved solid. Chemical variables of aqueous samples and biochemical compounds of filamentous algae were also measured. It was found that geographic position and anthropogenic activities had strong effect on physico chemical variables of water bodies. Variation in environmental conditions caused change in algal biomass composition due to the different response of filamentous species, also indicated by FTIR analysis. Biochemical responses not only changed from species to species, but also varied for the same species at different sampling time and sampling stations. Multivariate analyses showed that heavy metals, nutrients, and water hardness were found as the important variables governing the temporal and spatial succession and biochemical compounds. Nutrients, especially nitrate, could stimulate pigment and total protein production, whereas high metal content had adverse effects. Amount of malondialdehyde (MDA), H2O2, total thiol groups, total phenolic compounds, proline, total carbohydrate, and metal bioaccumulation by filamentous algae could be closely related with heavy metals in the ecosystems. Significant increase in MDA, H2O2, total thiol group, total phenolic compounds, and proline productions by filamentous algae and chlorosis phenomenon seemed to be an important strategy for alleviating environmental factors-induced oxidative stress as biomarkers. PMID- 27508984 TI - Is the DSM-V Leading to the Nondiagnosis of Vulvodynia? PMID- 27508985 TI - Transcriptomic and Proteomic Research To Explore Bruchid-Resistant Genes in Mungbean Isogenic Lines. AB - Mungbean (Vigna radiata (L.) Wilczek) is an important rotation legume crop for human nutrition in Asia. Bruchids (Callosobruchus spp.) currently cause heavy damage as pests of grain legumes during storage. We used omics-related technologies to study the mechanisms of bruchid resistance in seeds of the nearly isogenic lines VC1973A (bruchid-susceptible) and VC6089A (bruchid-resistant). A total of 399 differentially expressed genes (DEGs) were identified between the two lines by transcriptome sequencing. Among these DEGs, 251 exhibited high expression levels and 148 expressed low expression levels in seeds of VC6089A. Forty-five differential proteins (DPs) were identified by isobaric tags for relative and absolute quantification (iTRAQ); 21 DPs had higher abundances in VC6089A, and 24 DPs had higher abundances in VC1973A. According to transcriptome and proteome data, only three DEGs/DPs, including resistant-specific protein (g39185), gag/pol polyprotein (g34458), and aspartic proteinase (g5551), were identified and located on chromosomes 5, 1, and 7, respectively. Both g39185 and g34458 genes encode a protein containing a BURP domain. In previous research on bruchid molecular markers, the g39185 gene located close to the molecular markers of major bruchid-resistant locus may be a bruchid-resistant gene. PMID- 27508986 TI - Fluorogenic Ubiquinone Analogue for Monitoring Chemical and Biological Redox Processes. AB - We report herein the synthesis and characterization of a fluorogenic analogue of ubiquinone designed to reversibly report on redox reactions in biological systems. The analogue, H2B-Q, consists of the redox-active quinone segment found in ubiquinone, 2,3-dimethoxy-1,4-benzoquinone, coupled to a boron-dipyrromethene (BODIPY) fluorophore segment that both imparts lipophilicity in lieu of the isoprenyl tail of ubiquinone, and reports on redox changes at the quinone/quinol segment. Redox sensing is mediated by a photoinduced electron transfer intramolecular switch. In its reduced dihydroquinone form, H2B-QH2 is highly emissive in nonpolar media (quantum yields 55-66%), while once oxidized, the resulting quinone H2B-Q emission is suppressed. Cyclic voltammetry of H2B-Q shows two reversible, 1-electron reduction peaks at -1.05 V and -1.37 V (vs ferrocene) on par with those of ubiquinone. Chemical reduction of H2B-Q by NaBH4 resulted in >200 fold emission enhancement. H2B-QH2 is shown to react with peroxyl radicals, a form of reactive oxygen species (ROS) as well as to cooperatively interact with chromanol (the active segment of alpha-tocopherol). Kinetic analysis further shows the antioxidant reactivity of the nonfluorescent intermediate semiquinone. We anticipate that the H2B-Q/H2B-QH2 off/on reversible couple may serve as a tool to monitor chemical redox processes in real-time and in a noninvasive manner. PMID- 27508987 TI - Chemical composition and acaricidal activity of the essential oils from Vitex agnus-castus L. (Verbenaceae) and selected monoterpenes. AB - Tetranychus urticae is considered one of the main plagues in the world. Its occurrence in Pernambuco was registered for the first time in 1985 and it has caused considerable damage to the farmers, attacking different cultures of agricultural interest. The essential oils from different parts of Vitex agnus castus harvested in the Atlantic forest in the state of Pernambuco, Brazil, were obtained by hydrodistillation and the acaricidal potential was evaluated against Tetranychus urticae using two methods under laboratory conditions. Gas chromatography-mass spectrometry revealed the presence of 47 components accounting for 98.8 +/- 0.0%, 93.0 +/- 0.1% and 97.4 +/- 1.0% of the essential oils from the leaves, fruit and inflorescence, respectively. The compounds 1,8 cineole and beta-(E)-farnesene were the major components of the oils from the leaves (17.6 +/- 0.3% and 13.6 +/- 0.2%, respectively) and fruit (17.5 +/- 0.1% and 15.4 +/- 0.0%, respectively). beta-(E)-farnesene (13.5 +/- 0.1%) and beta caryophyllene (11.7 +/- 0.1%) were the major components of the oils from the flowers. Acaricidal action varied depending on the part of the plant and method employed. Through fumigation, the oil from the leaves (CL50= 0.61 MUL L-1 of air) was approximately six fold more toxic than the oil from the fruit. However, through residual contact, the oil from the fruit (CL50 = 137.11 MULmL-1) was 1.1 fold more toxic than the oil from the leaves. The relationship between the chemical composition of the oils and acaricidal activity is also presented. PMID- 27508988 TI - Physicochemical, Antioxidant and Sensory Quality of Brazilian Blueberry Wine. AB - Currently, Rio Grande do Sul state is the main producer of blueberry in Brazil. Practically all production is commercialized in fresh state and only a small portion is subject to processing. The blueberry wine making process is an alternative to expand the beverage industry and offers to the consumer a value added product as well as a new market for Brazilian blueberry producers. The objectives of this study were to produce wines from blueberries and to evaluate the effect of deacidification (with calcium carbonate) and chaptalization (with glucose syrup or sucrose) on physicochemical characteristics, antioxidant content, and sensory parameters. Samples were analyzed for total soluble solids, pH, total titratable acidity, total sugar content, alcohol content, monomeric and total anthocyanin, total flavonols, total phenolic compounds and antioxidant activity by DPPH and FRAP methods. The use of calcium carbonate caused a reduction in total titratable acidity, while the use of glucose syrup resulted in wines with low alcohol content. The blueberries wine from Climax and Aliceblue cultivars had higher content of anthocyanin when produced with glucose syrup. The use of calcium carbonate and glucose syrup also provided wines more appreciated by tasters in relation to color. With regard to flavor, George and Aliceblue were the cultivars with lower preference under the control treatments (without carbonate and sugar). The presence of phenolic compounds may have provided a positive influence on wine flavor, once the more preferred wines presented the greater phenolic content. PMID- 27508989 TI - Epidemiology of hepatitis B virus in the cities of the northern region of Espirito Santo, Brazil. AB - The World Health Organization (WHO) estimates that approximately 2 billion people worldwide have already had contact with hepatitis B virus (HBV) and 373 million have become chronic carriers. Hepatitis B is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma, leading to a large number of deaths annually. Both viral factors and the host immune response have been implicated in the pathogenesis and clinical result of HBV infection. Many Brazilian cities, including the cities of the northern region of the state of Espirito Santo are located in regions with little health infrastructure. Our study performed an epidemiological analysis of cases of Hepatitis B in Sao Mateus, using methodology of Geographic Information System (GIS), aiming to raise the number of disease cases, establishing preventive measures to control the disease, improving the quality of life of people affected by this pathology. The city of Sao Mateus had the largest number of reported cases of hepatitis B northern region of Espirito Santo. The age group with the highest number of hepatitis B notifications was 20 49 years, mostly females. The major forms of contact with HBV in these cities were dental treatment, use of injectable medications, surgical procedures and multiple sexual partners. PMID- 27508990 TI - The classic episode of biological invasion: Cochliomyia macellaria (Fabricius, 1775) versus Chrysomya megacephala (Fabricius, 1794) (Diptera: Calliphoridae) - evaluation of the biotic potential. AB - The classic episode of biological invasion: Cochliomyia macellaria (Fabricius, 1775) versus Chrysomya megacephala (Fabricius, 1794) (Diptera: Calliphoridae) - evaluation of the biotic potential. The biotic of the native fly Cochliomyia macellaria and the exotic Chrysomya megacephala was compared, through the reproductive capacity and longevity. The experiment took place in a climatized chamber, with four repetitions of 15 grouped couples of each species. The posture, egg mass weight, and death of individuals were observed daily. C. macellaria showed an average of longevity of 27.72 days while in C. megacephala the average was 41.96 days. The egg mass weight average per repetition was 0.58 g and 1.22 g, respectively. These results give a better understanding about the population dynamics of these species in nature. PMID- 27508991 TI - Injuries caused by the venomous catfish pintado and cachara (Pseudoplatystoma genus) in fishermen of the Pantanal region in Brazil. AB - INTRODUCTION: the fishing activity throughout the Upper Paraguay River Basin has huge financial and biological importance. This retrospective study investigated the occurrence of injuries caused by fish of the Pseudoplatystoma genus (spotted catfish or pintado and striped catfish or cachara) in professional fishermen of the Pantanal of Mato Grosso do Sul State. METHODS: we collected information through a questionnaire, showing that fishing is carried out by workers with low level of education, mainly adults or seniors with low financial gains. RESULTS: in Miranda town, 126 of 315 fishermen were interviewed and 38 individuals reported injuries (30.16%). In Corumba town, 355 of 627 fishermen were interviewed, and 111 (56,61%) reported injuries. The lacerated lesions were the most common, associate with edema, erythema, radiating pain to the root of the limb, paresthesias and local necrosis. More rarely, they reported the occurrence of fever, cardiac arrhythmias and cold sweating. These manifestations may be associated with late secondary infections or envenomations caused by the toxins in the stingers of the fish. Many questionable and inappropriate treatments are used, sometimes aggravating the injuries. CONCLUSIONS: the freshwater professional fishermen need guidance on first aid measures and prevention of accidents caused by these venomous fish. PMID- 27508992 TI - What the largest tadpole feeds on? A detailed analysis of the diet composition of Pseudis minuta tadpoles (Hylidae, Dendropsophini). AB - We analyzed the diet of 25 individuals of Pseudis minuta tadpoles which consisted in debris with more than 30%, follow by diatoms, euglenids, green algae, and desmids. With regard to the feeding strategy, P. minuta tadpoles are generalist consumer. The negative correlation between the abundance of items in the digestive tract and the mouth width indicate an effect of metamorphosis on the diet. PMID- 27508993 TI - Phytochemical Screening and Acute Toxicity of Aqueous Extract of Leaves of Conocarpus erectus Linnaeus in Swiss Albino Mice. AB - Mangroves represent areas of high biological productivity and it is a region rich in bioactive substances used in medicine production. Conocarpus erectus (Combretaceae) known as button mangrove is one of the species found in mangroves and it is used in folk medicine in the treatment of anemia, catarrh, conjunctivitis, diabetes, diarrhea, fever, gonorrhea, headache, hemorrhage, orchitis, rash, bumps and syphilis. The present study aimed to investigate the acute toxicity of aqueous extract of leaves of C. erectus in Swiss albino mice. The plant material was collected in Vila Velha mangroves, located in Itamaraca (PE). The material was subjected to a phytochemical screening where extractive protocols to identify majority molecules present in leaves were used. The evaluation of acute toxicity of aqueous extract of C. erectus followed the model of Acute Toxicity Class based on OECD 423 Guideline, 2001. The majority molecules were identified: flavonoids, tannins and saponins. The LD50 was estimated at 2,000 mg/kg bw. Therefore, the aqueous extract showed low acute toxicity classified in category 5. PMID- 27508994 TI - On the presence of the subnarial foramen in Prestosuchus chiniquensis (Pseudosuchia: Loricata) with remarks on its phylogenetic distribution. AB - Many authors have discussed the subnarial foramen in Archosauriformes. Here presence among Archosauriformes, shape, and position of this structure is reported and its phylogenetic importance is investigated. Based on distribution and the phylogenetic tree, it probably arose independently in Erythrosuchus, Herrerasaurus, and Paracrocodylomorpha. In Paracrocodylomorpha the subnarial foramen is oval-shaped, placed in the middle height of the main body of the maxilla, and does not reach the height of ascending process. In basal loricatans from South America (Prestosuchus chiniquensis and Saurosuchus galilei) the subnarial foramen is 'drop-like' shaped, the subnarial foramen is located above the middle height of the main body of the maxilla, reaching the height of ascending process, a condition also present in Herrerasaurus ischigualastensis. These results suggest that this structure might be phylogenetically important and further investigation with a large set of valid taxa is necessary to properly evaluate its importance among Archosauria. PMID- 27508995 TI - Neuroprotective effect of Portulaca oleracea extracts against 6-hydroxydopamine induced lesion of dopaminergic neurons. AB - The Portulaca oleracea L. (Portulacaceae) is a cosmopolitan species with a wide range of biological activities, including antioxidant and neuroprotective actions. We investigated the effects of P. oleracea extracts in a 6 hydroxydopamine rat model of Parkinson's disease, a debilitating disorder without effective treatments. Chemical profiles of aqueous and ethanolic extracts of whole plant were analyzed by thin layer chromatography and the antioxidant activity was assessed by 2,2-diphenyl-1-picrilhidrazila method. Male Wistar rats received intrastriatal 6-hydroxydopamine and were treated with vehicle or extracts (oral, 200 and 400 mg/kg) daily for two weeks. The behavioral open field test was conducted at days 1 and 15. Immunohistochemical analysis was performed 4 weeks after surgery to quantify tyrosine-hydroxylase cell counts in the substantia nigra pars compacta. Extracts presented antioxidant activity in concentrations above 300 ug/kg. The chromatographic analysis revealed the presence of Levodopa, alkaloids, flavonoids, saponins, tannins, terpenoids and polysaccharides. Both extracts improved motor recovery 15 days after lesion and protected from tyrosine-hydroxylase cell loss after 4 weeks, but these effects were more evident for the aqueous extract. Because the dopamine precursor is present, in addition to antioxidant compounds and neuroprotective effects, P. oleracea can be considered as potential strategy for treating Parkinson's disease. PMID- 27508996 TI - Inactivated Parapoxvirus ovis as inducer of immunity in silver catfish (Rhamdia quelen). AB - Molecules with immune modulating activity are ubiquitously distributed in nature and their impact on aquaculture has been exploited in order to increase fish resistance to pathogens. Here, we investigated the effect of inactivated Parapoxvirus ovis (iPPVO) on blood cells and innate and acquired immune response of silver catfish (Rhamdia quelen). iPPVO inoculation had no effect on respiratory burst activity; however, following iPPVO inoculation, we observed a significant decrease on circulating monocytes concomitantly with an increased number of heterophilic granulocytes and thrombocytes, which are the main cells involved in innate immunity and provide connection with acquired immunity. Fish inoculated with a combination of bovine serum albumin (BSA) + iPPVO had significantly higher levels of antibodies to BSA compared to fish inoculated with BSA alone, but lower than fish inoculated with BSA + Freund's incomplete adjuvant (FIA). These findings points to the potential usefulness of iPPVO as immunomodulator in fish and instigate further research to identify its component that interact with immune cells and that could be exploited as adjuvants in fish. PMID- 27508998 TI - Evaluation of Liposome, Heat-Killed Mycobacterium w, and Alum Adjuvants in the Protection Offered by Different Combinations of Recombinant HA, NP proteins, and M2e Against Homologous H5N1 Virus. AB - Continued evolution of highly pathogenic H5N1 viruses causing high mortality in humans obviates need for broadly cross-reactive vaccines. For this, hemagglutinin (HA) inducing specific protective antibodies, highly conserved nucleoprotein (NP), and ectodomain of matrix (M2e) protein, either singly or in combination, were evaluated in BALB/c mice. Recombinant HA and NP (baculovirus system) and M2e (synthetic peptide) and 3 adjuvants, that is, liposomes, Mw (heat killed Mycobacterium w), and alum were utilized for the homologous virus challenge. Additional immunogens included liposome-encapsulated HA/NP proteins and corresponding DNAs. Mice groups received two doses of respective formulations given at 3-week intervals and challenged intranasally with 100LD50 of H5N1 virus strain. Dynamics of weight loss, lung viral load, titres of IgG-anti-HA, NP, and M2e antibodies (ELISA), and IgG-subtype analysis was done. Two doses of all the formulations led to 100% seroconversion against the immunogens evaluated (100% seroconversion after the first dose in majority). Antibody titres against the components were dependent on the adjuvant and combination. HA-driven Th2 response with all the adjuvants, balanced Th1/Th2 response to NP protein, and Th2-bias with alum were noted. Low anti-M2e antibody titres did not allow subtype analysis. On challenge, complete protection was observed with Mw-HA, alum-HA+NP, Lipo-HA+NP+M2e, alum-HA+NP+M2e, and HA-DP formulations with 12-fold, 8-fold, 720 fold, 17-fold, and no reduction, respectively, in lung viral load. In conclusion, the results identify several adjuvant-immunogen combinations conferring 100% protection in mice that need further evaluation in higher animals. PMID- 27508997 TI - Recognition memory and DNA damage in undernourished young rats. AB - This study evaluated the recognition memory and the levels of DNA damage (blood and hippocampus) in undernourished young Wistar rats. The experiment was conducted along 14-week with rodents divided in control group (CG, n=8) and undernourished group (UG, n=12) which was submitted to caloric restriction. Nutritional status for undernutrition was defined by Body Mass Index (BMI) <=0.45g/cm2 and by weighting the organs/tissue (liver, spleen, intestine, peritoneal fat, kidney and encephalon). The Novel Object Recognition Test assessed recognition memory and the Comet Assay evaluated the levels of DNA damage. Student t test, 2-way ANOVA and Pearson's correlation analysis were used and the significance level was of p<0.05. The UG showed lower BMI and organ/tissue weights than CG (p<0.001). In short-term memory, the recognition rate was higher in the UG (p<0.05), only after 4 weeks. In the long-term memory, again recognition rate was higher in the UG than the CG, after 4 weeks (p<0.001) and 14 weeks (p<0.01). The UG showed decreased levels of DNA damage in the blood (p<0.01) and increased levels in the hippocampus (p<0.01). We concluded in this study that the undernutrition by caloric restriction did not cause impairment in recognition memory, however induced DNA damage in the hippocampus. PMID- 27508999 TI - The Ross Procedure in Adults: Long-Term Results of Homografts and Stentless Xenografts for Pulmonary Valve Replacement. AB - Background The Ross procedure is an established method to treat aortic valve disease, offering excellent hemodynamic characteristics, growth potential, low risk of thromboembolism and no need for anticoagulation. Limitation of homograft quality and availability led to the use of different stentless xenografts. Long term outcome and implications are yet to be addressed. Methods Forty five adult patients (mean age 38.8 +/- 9.6 years) with aortic valve stenosis and/or insufficiency, who underwent the Ross procedure between 1995 and 2002 were identified for long-term evaluation. Patients younger than 18 years, with previous heart surgery and endocarditis were excluded. Stentless xenografts were used in 22 cases (Group X) and homografts in 23 cases (Group H). After review of the patients' history, morbidity and mortality were analyzed and risk stratification was performed. Results Between groups, baseline characteristics and operative data did not differ significantly. Total follow-up was 621.0 patient-years and 98.8% complete. Overall freedom from reoperation at 15 years was 68.4 +/- 10.6% in group X and 85. +/- 7.9% in group H (p = 0.09), respectively. Freedom from aortic valve reoperation at 15 years was comparable (83.9 +/- 8.5% in group X and 85.3 +/- 7.9% in group H, p = 0.61), whereas freedom from pulmonary valve reoperation at 15 years was significantly lower in group X (78.9 +/- 9.4% versus 100%, p = 0.02). Long-term survival at 15 years was 79.7 +/- 9.3% in group X and 94.4 +/- 5.4% in group H (p = 0.07), respectively. Conclusions Stentless xenografts used as pulmonary valve substitute in the Ross procedure led to lower freedom from pulmonary valve reoperation compared with homografts. Additionally, there was a trend to inferior long-term survival with xenografts. Therefore, homografts should remain the preferred option for pulmonary valve replacement in the Ross procedure. PMID- 27509000 TI - Individualized Surgical Treatments for Children with Ebstein Anomaly. AB - Objective Ebstein anomaly is a rare type of tricuspid malformation. The present surgical methods to resolve this anomaly include tricuspid valvuloplasty, palliative surgery, and tricuspid valve replacement. The purpose of this study was to evaluate the short- and midterm outcomes of different surgical treatments among children with Ebstein anomaly. Methods This was a retrospective study of 136 Ebstein anomaly patients undergoing surgery at our institution from January, 2006 to August, 2015. This cohort included 118 patients receiving tricuspid valvuloplasty, 14 patients receiving palliative surgery and 4 patients receiving tricuspid valve replacement. Results There were two in-hospital deaths and one delayed death 6 months after bidirectional cavopulmonary shunt during a second stage operation; thus, the mortality rate was 2.2% (3/136). The follow-up variables included echocardiography, chest radiography, oxygen saturation, and cardiac function. After a mean follow-up duration of 35.8 +/- 16.5 months (range: 6-98 months), all survivors had no indications for reoperation; the oxygen saturation following radical surgery and palliative surgery was 95 to 100% and 85 to 95%, respectively. Most of the patients exhibited an improved New York Heart Association (NYHA) functional class from III or IV preoperatively to I or II at follow-up; only two patients who underwent the Fontan procedure continued to exhibit NYHA functional class III. In most patients, tricuspid regurgitation (TR) degree decreased from moderate or severe preoperatively to mild or moderate at follow-up and only six patients continued to exhibit severe TR at follow-up. Conclusions Individualization of surgical methods based on different indications, including age, associated malformations, tricuspid anatomy, cardiac function, and intraoperative status, could effectively improve the outcomes of Ebstein anomaly patients. PMID- 27509001 TI - Data Science Meets the Clinician: Challenges and Future Directions. AB - In the last three decades a profound transformation of the medical profession has taken place. The modern clinician is required to consume vast amounts of information from clinical studies, critically reviewing evidence that may or may not lead to changes in clinical practice. The present article presents some challenges that this era of information poses to clinicians and patients. PMID- 27509002 TI - Modified Transsubxiphoid Thoracoscopic Extended Thymectomy in Patients with Myasthenia Gravis. AB - We developed a new minimally invasive thoracoscopic technique of extended thymectomy for myasthenia gravis by combining a subxiphoid incision with dual costal margin incisions. In our experience of 31 consecutive cases, this procedure provides a good operative view in the neck region and makes verification of the bilateral phrenic nerves easy. All the patients recovered smoothly with less trauma, less bleeding, less complication, and good cosmetic results. This modified transsubxiphoid approach is a satisfactory procedure for performing extended thymectomy in patients with myasthenia gravis. PMID- 27509003 TI - Identifying areas of need relative to liver disease: geographic clustering within a health service district. AB - Background Many people with chronic liver disease (CLD) are not detected until they present to hospital with advanced disease, when opportunities for intervention are reduced and morbidity is high. In order to build capacity and liver expertise in the community, it is important to focus liver healthcare resources in high-prevalence disease areas and specific populations with an identified need. The aim of the present study was to examine the geographic location of people seen in a tertiary hospital hepatology clinic, as well as ethnic and sociodemographic characteristics of these geographic areas. Methods The geographic locations of hepatology out-patients were identified via the out patient scheduling database and grouped into statistical area (SA) regions for demographic analysis using data compiled by the Australian Bureau of Statistics. Results During the 3-month study period, 943 individuals from 71 SA Level 3 regions attended clinic. Nine SA Level 3 regions accounted for 55% of the entire patient cohort. Geographic clustering was seen especially for people living with chronic hepatitis B virus. There was a wide spectrum of socioeconomic advantage and disadvantage in areas with high liver disease prevalence. Conclusions The geographic area from which people living with CLD travel to access liver health care is extensive. However, the greatest demand for tertiary liver disease speciality care is clustered within specific geographic areas. Outreach programs targeted to these areas may enhance liver disease-specific health service resourcing. What is known about the topic? The demand for tertiary hospital clinical services in CLD is rising. However, there is limited knowledge about the geographic areas from which people living with CLD travel to access liver services, or the ethnic, socioeconomic and education characteristics of these areas. What does this paper add? The present study demonstrates that a substantial proportion of people living with CLD and accessing tertiary hospital liver services are clustered within specific geographic areas. The most striking geographic clustering was seen for people living with chronic hepatitis B, in regions with a relatively high proportion of people born in Vietnam and China. In addition to ethnicity, the data show an apparent ecological association between liver disease and both socioeconomic and educational and/or occupational disadvantage. What are the implications for practitioners? Identifying where demand for clinical services arises is an important step for service planning and preparing for potential outreach programs to optimise community-based care. It is likely that outreach programs to engage and enhance primary care services in geographic areas from which the greatest demand for tertiary liver disease speciality care arises would yield greater relative return on investment than non targeted outreach programs. PMID- 27509005 TI - Correction: Enhanced photocatalytic activity of a self-stabilized synthetic flavin anchored on a TiO2 surface. AB - Correction for 'Enhanced photocatalytic activity of a self-stabilized synthetic flavin anchored on a TiO2 surface' by Manjula Pandiri et al., Phys. Chem. Chem. Phys., 2016, 18, 18575-18583. PMID- 27509004 TI - 1,2,3-Triazoles as Amide Bioisosteres: Discovery of a New Class of Potent HIV-1 Vif Antagonists. AB - RN-18 based viral infectivity factor (Vif), Vif antagonists reduce viral infectivity by rescuing APOBEC3G (A3G) expression and enhancing A3G-dependent Vif degradation. Replacement of amide functionality in RN-18 (IC50 = 6 MUM) by isosteric heterocycles resulted in the discovery of a 1,2,3-trizole, 1d (IC50 = 1.2 MUM). We identified several potent HIV-1 inhibitors from a 1d based library including 5ax (IC50 = 0.01 MUM), 5bx (0.2 MUM), 2ey (0.4 MUM), 5ey (0.6 MUM), and 6bx (0.2 MUM). PMID- 27509006 TI - Effects of the Mediterranean Diet on Cardiovascular Outcomes-A Systematic Review and Meta-Analysis. AB - BACKGROUND: A Mediterranean dietary pattern is widely recommended for the prevention of chronic disease. We sought to define the most likely effects of the Mediterranean diet on vascular disease and mortality. METHODS: We searched MEDLINE, EMBASE and the Cochrane Central Register without language restriction for randomized controlled trials comparing Mediterranean to control diets. Data on study design, patient characteristics, interventions, follow-up duration, outcomes and adverse events were sought. Individual study relative risks (RR) were pooled to create summary estimates. RESULTS: Six studies with a total of 10950 participants were included. Effects on major vascular events (n = 477), death (n = 693) and vascular deaths (n = 315) were reported for 3, 5 and 4 studies respectively. For one large study (n = 1000) there were serious concerns about the integrity of the data. When data for all studies were combined there was evidence of protection against major vascular events (RR 0.63, 95% confidence interval 0.53-0.75), coronary events (0.65, 0.50-0.85), stroke (0.65, 0.48-0.88) and heart failure (0.30, 0.17-0.56) but not for all-cause mortality (1.00, 0.86 1.15) or cardiovascular mortality (0.90, 0.72-1.11). After the study of concern was excluded the benefit for vascular events (0.69, 0.55-0.86) and stroke (0.66, 0.48-0.92) persisted but apparently positive findings for coronary events (0.73, 0.51-1.05) and heart failure (0.25, 0.05-1.17) disappeared. CONCLUSION: The Mediterranean diet may protect against vascular disease. However, both the quantity and quality of the available evidence is limited and highly variable. Results must be interpreted with caution. PMID- 27509007 TI - Hospitalists and the Decline of Comprehensive Care. PMID- 27509008 TI - Trends and variation in management and outcomes of very low-birth-weight infants with patent ductus arteriosus. AB - BACKGROUND: We examined recent trends and interhospital variation in use of indomethacin, ibuprofen, and surgical ligation for patent ductus arteriosus (PDA) in very-low-birth-weight (VLBW) infants. METHODS: Included in this retrospective study of the Pediatric Hospital Information System database were 13,853 VLBW infants from 19 US children's hospitals, admitted at age < 3 d between 1 January 2005 and 31 December 2014. PDA management and in-hospital outcomes were examined for trends and variation. RESULTS: PDA was diagnosed in 5,719 (42%) VLBW infants. Cyclooxygenase inhibitors and/or ligation were used in 74% of infants with PDA overall, however studied hospitals varied greatly in PDA management. Odds of any cyclooxygenase inhibitor or surgical treatment for PDA decreased 11% per year during the study period. This was temporally associated with improved survival but also with increasing bronchopulmonary dysplasia, periventricular leukomalacia, retinopathy of prematurity, and acute renal failure in unadjusted analyses. There was no detectable correlation between hospital-specific changes in PDA management and hospital-specific changes in outcomes of preterm birth during the study period. CONCLUSION: Use of cyclooxygenase inhibitors and ligation for PDA in VLBW infants decreased over a 10-y period at the studied hospitals. Further evidence is needed to assess the impact of this change in PDA management. PMID- 27509010 TI - Factors associated with the implementation of programs for drug abuse prevention in schools. AB - OBJECTIVE: To analyze if characteristics of managers, schools, and curriculum are associated with the implementation of programs for drug abuse prevention in elementary and high schools. METHODS: Cross-sectional study, with random sample of 263 school managers. Data were collected between 2012 and 2013 by a program that sends forms via internet. A closed self-filling questionnaire was applied online. Statistical analysis included Chi-square tests and logistic regression models. The outcome variable was the presence of program for drug abuse prevention inserted in the daily life and educational program of the school. The explanatory variables were divided into: demographic data of the manager; characteristics of the school and of the curriculum; health education; and drug use in the school. RESULTS: We found that 42.5% (95%CI 36.1-49.1) of the evaluated schools had programs for drug abuse prevention. With the multiple logistic regression model, we observed that the more time the manager has worked with education, the chance of the school having a program increased at about 4.0%. Experimenting with innovative teaching techniques also increased at about six times the chance of the school developing a program for drug abuse prevention. The difficulties in the implementation of the programs were more present in state and municipal schools, when compared with private schools, due to, for instance: lack of teaching materials, lack of money, and competing demands for teaching other subjects. CONCLUSIONS: The implementation of programs for drug abuse prevention in the city of Sao Paulo is associated with the experience of the manager in education and with the teaching strategies of the school. OBJETIVO: Analisar se caracteristicas dos dirigentes, das escolas e do curriculo escolar estao associadas a implantacao de programas de prevencao ao uso de drogas nas escolas do ciclo fundamental II e medio. METODOS: Estudo transversal, com amostra aleatoria sistematica de 263 dirigentes escolares. Os dados foram coletados nos anos de 2012 e 2013 por meio de um programa de envio de formularios pela internet. Aplicou-se questionario fechado, de autopreenchimento on-line. A analise estatistica incluiu testes Qui-quadrado e modelos de regressao logistica. A variavel desfecho foi a presenca de programa de prevencao ao uso de drogas inserido no cotidiano e no programa pedagogico da escola. As variaveis explicativas foram divididas em: dados demograficos do dirigente; caracteristicas da escola e do curriculo; educacao em saude; e consumo de drogas na escola. RESULTADOS: Constatou-se que 42,5% (IC95% 36,1-49,1) das escolas avaliadas possuiam programa de prevencao ao uso de drogas. Com o modelo de regressao logistica multipla, observou-se que, a cada ano de atuacao do dirigente na educacao, a chance de a escola ter um programa aumentava em aproximadamente 4,0%. O fato de experimentar tecnicas de ensino inovadoras tambem aumentou em cerca de seis vezes a chance de a escola desenvolver um programa de prevencao ao uso de drogas. As dificuldades na implantacao dos programas foram mais presentes nas redes estadual e municipal, quando comparadas a rede privada, destacando-se: a falta de material didatico, a falta de dinheiro e as demandas concorrentes para ensino de outras disciplinas. CONCLUSOES: A implantacao de programas de prevencao ao uso de drogas no municipio de Sao Paulo esta associada a experiencia do dirigente escolar na educacao e nas estrategias de ensino da escola. PMID- 27509009 TI - Postnatal growth restriction augments oxygen-induced pulmonary hypertension in a neonatal rat model of bronchopulmonary dysplasia. AB - BACKGROUND: Prematurity and fetal growth restriction are risk factors for pulmonary hypertension (PH) in infants with bronchopulmonary dysplasia (BPD). Neonatal rats develop PH and vascular remodeling when exposed to hyperoxia. We hypothesize that postnatal growth restriction (PNGR) due to under-nutrition increases the severity of PH induced by hyperoxia in neonatal rats. METHODS: Pups were randomized at birth to litters maintained in room air or 75% oxygen (hyperoxia), together with litters of normal milk intake (10 pups) or PNGR (17 pups). After 14 d, right ventricular hypertrophy (RVH) was assessed by Fulton's index (right ventricular weight/left ventricular plus septal weight) and PH by echocardiography. Lungs were analyzed by immunohistochemistry, morphometrics, western blotting, and metabolomics. RESULTS: Hyperoxia and PNGR each significantly increased pulmonary arterial pressure, RVH and pulmonary arterial medial wall thickness, and significantly decreased pulmonary vessel number. These changes were significantly augmented in pups exposed to both insults. Hyperoxia and PNGR both significantly decreased expression of proteins involved in lung development and vasodilation. CONCLUSION: PNGR induces right ventricular and pulmonary vascular remodeling and augments the effects of oxygen in neonatal rats. This may be a powerful tool to investigate the mechanisms that induce PH in low-birth-weight preterm infants with BPD. PMID- 27509011 TI - Evaluation in health: participatory methodology and involvement of municipal managers. AB - OBJECTIVE: To analyze scopes and limits of the use of participatory methodology of evaluation with municipal health managers and administrators. METHODS: Qualitative research with health policymakers and managers of the Comissao Intergestores Regional (CIR - Regional Interagency Commission) of a health region of the state of Sao Paulo in Brazil. Representatives from seven member cities participated in seven workshops facilitated by the researchers, with the aim of assessing a specific problem of the care line, which would be used as a tracer of the system integrality. The analysis of the collected empirical material was based on the hermeneutic-dialectic methodology and aimed at the evaluation of the applied participatory methodology, according to its capacity of promoting a process of assessment capable to be used as a support for municipal management. RESULTS: With the participatory approach of evaluation, we were able to promote in-depth discussions with the group, especially related to the construction of integral care and to the inclusion of the user's perspective in decision-making, linked to the search for solution to concrete problems of managers. By joint exploration, the possibility of using data from electronic information systems was opened, as well as information coming directly from the users of the services, to enhance discussions and negotiations between partners. The participants were disbelievers of the replication potential of this type of evaluation without the direct monitoring of the academy, given the difficulty of organizing the process in everyday life, already taken by emergency and political issues. CONCLUSIONS: Evaluations of programs and services carried out within the Regional Interagency Commission, starting from the local interest and facilitating the involvement of its members by the use of participatory methodologies, can contribute to the construction of integral care. To the extent that the act of evaluating stay invested with greater significance to the local actors, its involvement with the evaluations at the federal level can also be stimulated. OBJETIVO: Analisar alcances e limites do uso de metodologia participativa de avaliacao junto a gestores e gerentes municipais de saude. METODOS: Pesquisa qualitativa com gestores e gerentes de saude da Comissao Intergestores Regional de uma regiao de saude do estado de Sao Paulo. Representantes de sete municipios membros participaram de sete oficinas facilitadas pelos pesquisadores, com o objetivo de avaliar um problema especifico da linha de cuidados sob a perspectiva da integralidade. A analise do material empirico coletado baseou-se na metodologia hermeneutica-dialetica e visou a avaliacao da metodologia participativa aplicada, segundo sua capacidade de promover um processo de avaliacao passivel de ser utilizado como suporte a gestao municipal. RESULTADOS: Com a abordagem participativa de avaliacao, foi possivel promover debates em profundidade com o grupo, principalmente relacionados a construcao da integralidade da atencao e a inclusao da perspectiva do usuario na tomada de decisao, de forma vinculada a busca de solucao para problemas concretos dos gestores. Mediante a exploracao conjunta, foi aberta a possibilidade de utilizacao de dados advindos dos sistemas eletronicos de informacao, bem como de informacoes advindas diretamente dos usuarios dos servicos, para enriquecer debates e negociacoes entre parceiros. Os participantes se mostraram descrentes do potencial de replicacao deste tipo de avaliacao sem o acompanhamento direto da academia, dada a dificuldade de organizacao do processo no cotidiano, ja tomado por questoes emergenciais e politicas. CONCLUSOES: Avaliacoes de programas e servicos realizadas no ambito da Comissao Intergestores Regional, partindo do interesse local e facilitando o envolvimento de seus membros pelo uso de metodologias participativas, podem contribuir para a construcao da integralidade do cuidado. Na medida em que o ato de avaliar fique investido de maior significado para os atores locais, seu envolvimento com as avaliacoes em nivel federal podera ser tambem estimulado. PMID- 27509012 TI - Community resilience and Chagas disease in a rural region of Mexico. AB - OBJECTIVE: To explore the pillars of community resilience in a region where Chagas disease is endemic, with the aim of promoting participatory processes to deal with this condition from the resilience of the population. METHODS: Qualitative study using ethnographic record and six interviews of focus groups with young people, women and men. The research was carried out in a rural area of the state of Morelos, Mexico, between 2006 and 2007. We carried out educational sessions with the population in general, so that residents could identify the relationship between the vector Triatoma pallidipennis, the parasite (Trypanosoma cruzi), symptoms, and preventive actions for Chagas disease. The ethnographic record and groups were analyzed based on Taylor and Bogdan's modification, and the focus was to understand the socio-cultural meanings that guide the speeches and activities of residents in relation to the pillars of community resilience. RESULTS: The population felt proud of belonging to that location and three pillars of community resilience were clearly identified: collective self-esteem, cultural identity, and social honesty. Having these pillars as bases, we promoted the participation of the population concerning Chagas disease, and a Community Action Group was formed with young people, adult men and women, and social leaders. This Group initiated actions of epidemiological and entomological surveillance in the community to deal with this problem. CONCLUSIONS: It is necessary to create more experiences that deepen the understanding of the pillars of community resilience, and how they contribute to enhance participation in health to deal with Chagas disease. OBJETIVO: Explorar los pilares de la resiliencia comunitaria en una region en la que la enfermedad de Chagas es endemica, con la finalidad de partir de la resiliencia de la poblacion para impulsar procesos participativos para enfrentar este padecimiento. METODOS: Estudio cualitativo que utilizo registro etnografico y seis entrevistas de grupos focales con jovenes, mujeres y hombres adultos. La investigacion se efectuo en una localidad rural del Estado de Morelos, Mexico, entre 2006 y 2007. Se efectuaron sesiones educativas con la poblacion en general, para que los habitantes identificaran la relacion entre el vector Triatoma pallidipennis, el parasito (Trypanosoma cruzi), la sintomatologia y acciones preventivas para la enfermedad de Chagas. El registro etnografico y los grupos fueron analizados con base en una modificacion de Taylor y Bogdan, y el foco fue comprender los significados socioculturales que guian los discursos y actividades de los pobladores en relacion a los pilares de la resiliencia comunitaria. RESULTADOS: La poblacion se sentia orgullosa de pertenecer a esa localidad y se identificaron con claridad tres pilares de la resiliencia comunitaria: autoestima colectiva, identidad cultural y honestidad social. Tomando como base estos pilares, se impulso la participacion de la poblacion en torno a la enfermedad de Chagas, y se formo un Grupo de Accion Comunitaria con jovenes, hombres y mujeres adultos, y lideres sociales. Este Grupo inicio acciones de vigilancia epidemiologica y entomologica en la comunidad para hacer frente a esta problematica. CONCLUSIONES: Es necesario generar mas experiencias que profundicen en la comprension de los pilares de resiliencia comunitaria, y en la manera en que estos contribuyen a potenciar la participacion en salud para enfrentar la enfermedad de Chagas. PMID- 27509013 TI - Linking Oxidative Stress and Magnitude of Compensatory Responses with Life-Stage Specific Differences in Sensitivity of White Sturgeon (Acipenser transmontanus) to Copper or Cadmium. AB - Sensitivity of white sturgeon (Acipenser transmontanus) to copper (Cu) or cadmium (Cd) has been shown to significantly differ as a function of life-stage. This study investigated oxidative stress, metal homeostasis, and associated compensatory responses as potential mechanisms of this sensitivity pattern in three early life-stages. Sturgeon were most sensitive to Cu at 15 days post hatch (dph), which was accompanied by a significant increase in lipid peroxidation (LPO). Genes involved with amelioration of oxidative stress were significantly less inducible at this stage than in older, less sensitive fry. At 48 dph, acute lethality of sturgeon exposed to Cd was greatest and body LPO was significantly induced by 3.5-fold at 5 MUg Cd/L. Moreover, there was a small but significant increase in antioxidative responses. At 139 dph, sturgeon were most tolerant to Cu and Cd and accumulation of these metals was least. Also, expression of metallothionein (MT) and apoptotic genes were greatest while expression of metal transporters was reduced and concentration of LPO was not different from controls. Our results suggest that life-stage specific sensitivity of white sturgeon to metals is complex, encompassing differences in the ability to mount compensatory responses important for metal homeostasis and combating oxidative stress and concomitant damages. PMID- 27509014 TI - Dynamic Interplay between the Transcriptome and Methylome in Response to Oxidative and Alkylating Stress. AB - In recent years, it has been shown that free radicals not only react directly with DNA but also regulate epigenetic processes such as DNA methylation, which may be relevant within the context of, for example, tumorigenesis. However, how these free radicals impact the epigenome remains unclear. We therefore investigated whether methyl and hydroxyl radicals, formed by tert-butyl hydroperoxide (TBH), change temporal DNA methylation patterns and how this interferes with genome-wide gene expression. At three time points, TBH-induced radicals in HepG2 cells were identified by electron spin resonance spectroscopy. Total 5-methylcytosine (5mC) levels were determined by liquid chromatography and tandem mass spectrometry and genome-wide changes in 5mC and gene expression by microarrays. Induced methylome changes rather represent an adaptive response to the oxidative stress-related reactions observed in the transcriptome. More specifically, we found that methyl radicals did not induce DNA methylation directly. An initial oxidative and alkylating stress-related response of the transcriptome during the early phase of TBH treatment was followed by an epigenetic response associated with cell survival signaling. Also, we identified genes of which the expression seems directly regulated by DNA methylation. This work suggests an important role of the methylome in counter-regulating primary oxidative and alkylating stress responses in the transcriptome to restore normal cell function. Altogether, the methylome may play an important role in counter regulating primary oxidative and alkylating stress responses in the transcriptome presumably to restore normal cell function. PMID- 27509015 TI - "Click" Chemistry-Tethered Hyaluronic Acid-Based Contact Lens Coatings Improve Lens Wettability and Lower Protein Adsorption. AB - Improving the wettability of and reducing the protein adsorption to contact lenses may be beneficial for improving wearer comfort. Herein, we describe a simple "click" chemistry approach to surface functionalize poly(2-hydroxyethyl methacrylate) (pHEMA)-based contact lenses with hyaluronic acid (HA), a carbohydrate naturally contributing to the wettability of the native tear film. A two-step preparation technique consisting of laccase/TEMPO-mediated oxidation followed by covalent grafting of hydrazide-functionalized HA via simple immersion resulted in a model lens surface that is significantly more wettable, more water retentive, and less protein binding than unmodified pHEMA while maintaining the favorable transparency, refractive, and mechanical properties of a native lens. The dipping/coating method we developed to covalently tether the HA wetting agent is simple, readily scalable, and a highly efficient route for contact lens modification. PMID- 27509017 TI - Quantitative Analysis of the Cervical Texture by Ultrasound and Correlation with Gestational Age. AB - OBJECTIVES: Quantitative texture analysis has been proposed to extract robust features from the ultrasound image to detect subtle changes in the textures of the images. The aim of this study was to evaluate the feasibility of quantitative cervical texture analysis to assess cervical tissue changes throughout pregnancy. METHODS: This was a cross-sectional study including singleton pregnancies between 20.0 and 41.6 weeks of gestation from women who delivered at term. Cervical length was measured, and a selected region of interest in the cervix was delineated. A model to predict gestational age based on features extracted from cervical images was developed following three steps: data splitting, feature transformation, and regression model computation. RESULTS: Seven hundred images, 30 per gestational week, were included for analysis. There was a strong correlation between the gestational age at which the images were obtained and the estimated gestational age by quantitative analysis of the cervical texture (R = 0.88). DISCUSSION: This study provides evidence that quantitative analysis of cervical texture can extract features from cervical ultrasound images which correlate with gestational age. Further research is needed to evaluate its applicability as a biomarker of the risk of spontaneous preterm birth, as well as its role in cervical assessment in other clinical situations in which cervical evaluation might be relevant. PMID- 27509018 TI - Praying until Death: Apostolicism, Delays and Maternal Mortality in Zimbabwe. AB - Religion affects people's daily lives by solving social problems, although it creates others. Female sexual and reproductive health are among the issues most affected by religion. Apostolic sect members in Zimbabwe have been associated with higher maternal mortality. We explored apostolic beliefs and practices on maternal health using 15 key informant interviews in 5 purposively selected districts of Zimbabwe. Results show that apostolicism promotes high fertility, early marriage, non-use of contraceptives and low or non-use of hospital care. It causes delays in recognizing danger signs, deciding to seek care, reaching and receiving appropriate health care. The existence of a customized spiritual maternal health system demonstrates a huge desire for positive maternal health outcomes among apostolics. We conclude that apostolic beliefs and practices exacerbate delays between onset of maternal complications and receiving help, thus increasing maternal risk. We recommend complementary and adaptive approaches that address the maternal health needs of apostolics in a religiously sensitive manner. PMID- 27509019 TI - A systematic review of the psychometric properties of bronchiolitis assessment tools. AB - AIM: The aim of this study was to assess the psychometric properties of tools developed for the purpose of assessing infants with bronchiolitis. BACKGROUND: Bronchiolitis is the leading cause of hospitalization in infants under the age of 1 year. Several bronchiolitis assessment tools have been developed primarily for use in randomized control trials of medical treatments for infants with bronchiolitis, however, the reliability and validity of many of these tools is not well reported. DESIGN: Systematic review. DATA SOURCES: CINAHL, MEDLINE, EMBASE and PubMed electronic databases were searched between January 1960 December 2015 using the key words 'bronchiolitis' and 'assessment' or 'screen' or 'tool' or 'scale' or 'score'. REVIEW METHODS: A systematic review of the psychometric properties of bronchiolitis assessment tools was undertaken using the COSMIN checklist. RESULTS: Fourteen studies meeting the inclusion criteria were reviewed and the methodological quality of the studies and reported psychometric properties of 11 instruments were assessed. Overall, the reliability and validity of bronchiolitis assessment tools was poorly established. Although several studies reported that their tools had good inter-rater reliability, the methodological quality of these studies was generally poor. Only one study underwent psychometric testing that was assessed as being of excellent quality. The Respiratory Distress Assessment Index was deemed to have undergone the most rigorous psychometric testing but had poor to moderate construct validity and considerable test-retest error. CONCLUSION: Current bronchiolitis assessment tools lack clearly established reliability and validity and may not be sensitive to clinically meaningful outcomes for patients. PMID- 27509020 TI - Extended Evaluation of Virological, Immunological and Pharmacokinetic Endpoints of CELADEN: A Randomized, Placebo-Controlled Trial of Celgosivir in Dengue Fever Patients. AB - CELADEN was a randomized placebo-controlled trial of 50 patients with confirmed dengue fever to evaluate the efficacy and safety of celgosivir (A study registered at ClinicalTrials.gov, number NCT01619969). Celgosivir was given as a 400 mg loading dose and 200 mg bid (twice a day) over 5 days. Replication competent virus was measured by plaque assay and compared to reverse transcription quantitative PCR (qPCR) of viral RNA. Pharmacokinetics (PK) correlations with viremia, immunological profiling, next generation sequence (NGS) analysis and hematological data were evaluated as exploratory endpoints here to identify possible signals of pharmacological activity. Viremia by plaque assay strongly correlated with qPCR during the first four days. Immunological profiling demonstrated a qualitative shift in T helper cell profile during the course of infection. NGS analysis did not reveal any prominent signature that could be associated with drug treatment; however the phylogenetic spread of patients' isolates underlines the importance of strain variability that may potentially confound interpretation of dengue drug trials conducted during different outbreaks and in different countries. Celgosivir rapidly converted to castanospermine (Cast) with mean peak and trough concentrations of 5727 ng/mL (30.2 MUM) and 430 ng/mL (2.3 MUM), respectively and cleared with a half-life of 2.5 (+/- 0.6) hr. Mean viral log reduction between day 2 and 4 (VLR2-4) was significantly greater in secondary dengue than primary dengue (p = 0.002). VLR2-4 did not correlate with drug AUC but showed a trend of greater response with increasing Cmin. PK modeling identified dosing regimens predicted to achieve 2.4 to 4.5 times higher Cmin. than in the CELADEN trial for only 13% to 33% increase in overall dose. A small, non-statistical trend towards better outcome on platelet nadir and difference between maximum and minimum hematocrit was observed in celgosivir-treated patients with secondary dengue infection. Optimization of the dosing regimen and patient stratification may enhance the ability of a clinical trial to demonstrate celgosivir activity in treating dengue fever based on hematological endpoints. A new clinical trial with a revised dosing regimen is slated to start in 2016 (NCT02569827). Furthermore celgosivir's potential value for treatment of other flaviruses such as Zika virus should be investigated urgently. TRIAL REGISTRATION: ClinicalTrials.gov NCT01619969. PMID- 27509021 TI - Human Peripheral Blood Mononuclear Cell Function and Dendritic Cell Differentiation Are Affected by Bisphenol-A Exposure. AB - Environmental pollutants, including endocrine disruptor chemicals (EDCs), interfere on human health, leading to hormonal, immune and metabolic perturbations. Bisphenol-A (BPA), a main component of polycarbonate plastics, has been receiving increased attention due to its worldwide distribution with a large exposure. In humans, BPA, for its estrogenic activity, may have a role in autoimmunity, inflammatory and allergic diseases. To this aim, we assessed the effect of low BPA doses on functionality of human peripheral blood mononuclear cells (PBMCs), and on in vitro differentiation of dendritic cells from monocytes (mDCs). Fresh peripheral blood samples were obtained from 12 healthy adult volunteers. PBMCs were left unstimulated or were activated with the mitogen phytohemagglutinin (PHA) or the anti-CD3 and anti-CD28 antibodies and incubated in presence or absence of BPA at 0.1 and 1nM concentrations. The immune modulatory effect of BPA was assessed by evaluating the cell proliferation and the levels of interferon-gamma (IFN-gamma), interleukin-4 (IL-4), interleukin-10 (IL-10) and interleukin-13 (IL-13) secreted by PBMCs. mDCs were differentiated with IL-4 and GC-CSF with or without BPA and the expression of differentiation/maturation markers (CD11c, CD1a, CD86, HLA-DR) was evaluated by flow cytometry; furthermore, a panel of 27 different cytokines, growth factors and chemokines were assayed in the mDC culture supernatants. PBMCs proliferation significantly increased upon BPA exposure compared to BPA untreated cells. In addition, a significant decrease in IL-10 secretion was observed in PBMCs incubated with BPA, either in unstimulated or mitogen-stimulated cells, and at both 0.1 and 1nM BPA concentrations. Similarly, IL-13 was reduced, mainly in cells activated by antiCD3/CD28. By contrast, no significant changes in IFN-gamma and IL-4 production were found in any condition assayed. Finally, BPA at 1nM increased the density of dendritic cells expressing CD1a and concomitantly decreased the expression of HLA-DR and CD86 activation markers. In conclusion, in humans the exposure to BPA causes on PBMCs a significant modulation of proliferative capacity and cytokine production, and on mDCs alteration in differentiation and phenotype. These immune cell alterations suggest that low dose chronic exposure to BPA could be involved in immune deregulation and possibly in the increased susceptibility to develop inflammatory and autoimmune diseases. PMID- 27509022 TI - Background Colonic 18F-Fluoro-2-Deoxy-D-Glucose Uptake on Positron Emission Tomography Is Associated with the Presence of Colorectal Adenoma. AB - 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan is used to evaluate various kinds of tumors. While most studies on PET findings of the colon focus on the colonic uptake pattern, studies regarding background colonic uptake on PET scan are rare. The purpose of this study was to identify the association between the background colonic uptake and the presence of colorectal adenoma (CRA), which is a frequent precancerous lesion. We retrospectively reviewed the medical records of 241 patients with gynecologic malignancy who had received PET or PET/computed tomography (CT) scan and colonoscopy at the same period as a baseline evaluation. Background colonic 18F FDG uptake was visually graded and the maximal standardized uptake values (SUVmax) of 7 different bowel segments were averaged. In univariate analysis, older age at diagnosis (>= 50 years, p = 0.034), overweight (BMI >= 23 kg/m2, p = 0.010), hypercholesterolemia (>= 200 mg/dL, p = 0.027), and high grade background colonic uptake (p = 0.009) were positively associated with the prevalence of CRA. By multiple logistic regression, high grade background colonic uptake was independently predictive of CRA (odds ratio = 2.25, p = 0.021). The proportion of CRA patients significantly increased as background colonic uptake grade increased from 1 to 4 (trend p = 0.015). Out of the 138 patients who underwent PET/CT, the proportion of CRA patients in the group with high SUVmax (> 2.25) was significantly higher than in the low SUVmax group (27.5% vs. 11.6%, p = 0.031). In conclusion, high grade of background colonic 18F-FDG uptake is significantly associated with the prevalence of CRA. PMID- 27509023 TI - The Small Mammal Sequence from the c. 76 - 72 ka Still Bay Levels at Blombos Cave, South Africa - Taphonomic and Palaeoecological Implications for Human Behaviour. AB - The Still Bay, c. 76-72 ka, a prominent techno-tradition during the Middle Stone Age of southern Africa, has yielded innovative technologies, symbolic material culture, and shows evidence of expansion of hunting techniques and subsistence strategies. In this paper we present the results of the first systematic, taphonomic and palaeoenvironmental study of micromammals from the Still Bay levels at Blombos Cave. Our taphonomic analysis indicates that the micromammals were accumulated by avian predators occupying the cave. Post-depositional processes affecting the micromammal assemblage include organic waste decomposition and conditions associated with a limestone cave environment. The palaeoenvironmental reconstruction shows that Marine Isotope Stage (MIS) 5a at Blombos Cave had diverse micromammal communities occupying a variety of habitats and with rainfall pattern equal to present. The transition from MIS 5a to 4 is indicated by less diverse micromammal assemblages, increase in grassland and scrub vegetation, shifts in seasonal precipitation, and a decline in shrubs associated with fynbos. The onset of the glacial conditions associated with MIS 4 is visible in the micromammal assemblage. However humans occupying Blombos Cave during this c. 5 ka period showed an ability to cope with changing environmental conditions and were able to adapt and utilise a variety of available resources. PMID- 27509024 TI - Exercise Activates p53 and Negatively Regulates IGF-1 Pathway in Epidermis within a Skin Cancer Model. AB - Exercise has been previously reported to lower cancer risk through reducing circulating IGF-1 and IGF-1-dependent signaling in a mouse skin cancer model. This study aims to investigate the underlying mechanisms by which exercise may down-regulate the IGF-1 pathway via p53 and p53-related regulators in the skin epidermis. Female SENCAR mice were pair-fed an AIN-93 diet with or without 10 week treadmill exercise at 20 m/min, 60 min/day and 5 days/week. Animals were topically treated with TPA 2 hours before sacrifice and the target proteins in the epidermis were analyzed by both immunohistochemistry and Western blot. Under TPA or vehicle treatment, MDM2 expression was significantly reduced in exercised mice when compared with sedentary control. Meanwhile, p53 was significantly elevated. In addition, p53-transcriptioned proteins, i.e., p21, IGFBP-3, and PTEN, increased in response to exercise. There was a synergy effect between exercise and TPA on the decreased MDM2 and increased p53, but not p53 transcripted proteins. Taken together, exercise appeared to activate p53, resulting in enhanced expression of p21, IGFBP-3, and PTEN that might induce a negative regulation of IGF-1 pathway and thus contribute to the observed cancer prevention by exercise in this skin cancer model. PMID- 27509025 TI - Retrospective Analysis of the Survival Benefit of Induction Chemotherapy in Stage IVa-b Nasopharyngeal Carcinoma. AB - PURPOSE: The value of adding induction chemotherapy to chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma (LA-NPC) remains controversial, yet high-risk patients with LA-NPC have poor outcomes after chemoradiotherapy. We aimed to assess the survival benefits of induction chemotherapy in stage IVa-b NPC. PATIENTS AND METHODS: A total of 602 patients with stage IVa-b NPC treated with intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy with or without induction chemotherapy were retrospectively analyzed. Overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method, log-rank test and Cox regression analysis. RESULTS: In univariate analysis, 5-year OS was 83.2% for induction chemotherapy plus concurrent chemotherapy and 74.8% for concurrent chemotherapy alone, corresponding to an absolute risk reduction of 8.4% (P = 0.022). Compared to concurrent chemotherapy alone, addition of induction chemotherapy improved 5-year DMFS (83.2% vs. 74.4%, P = 0.018) but not 5-year LRFS (83.7% vs. 83.0%, P = 0.848) or PFS (71.9% vs. 66.0%, P = 0.12). Age, T category, N category, chemotherapy strategy and clinical stage were associated with 5-year OS (P = 0.017, P = 0.031, P = 0.007, P = 0.022, P = 0.001, respectively). In multivariate analysis, induction chemotherapy plus concurrent chemotherapy was an independent favorable prognostic factor for OS (HR, 0.62; 95% CI, 0.43-0.90, P = 0.012) and DMFS (HR, 0.57; 95% CI, 0.38-0.83, P = 0.004). In subgroup analysis, induction chemotherapy significantly improved 5-year DMFS in stage IVa (86.8% vs. 77.3%, P = 0.008), but provided no significant benefit in stage IVb. CONCLUSIONS: In patients with stage IVa-b NPC treated with IMRT, addition of induction chemotherapy to concurrent chemotherapy significantly improved 5-year OS and 5 year DMFS. This study provides a basis for selection of high risk patients in future clinical therapeutic trials. PMID- 27509026 TI - Defining a BMI Cut-Off Point for the Iranian Population: The Shiraz Heart Study. AB - In this study we evaluated and redefined the optimum body mass index (BMI) cut off point for the Iranian population based on metabolic syndrome (MeS) risk factors. We further evaluated BMI cut-off points with and without waist circumference (WC) as a cofactor of risk and compared the differences. This study is part of the largest surveillance programs conducted in Shiraz, Iran, termed the Shiraz Heart study. Our study sample included subjects between the ages of 20 to 65 years old. After excluding pregnant women, those with missing data and those with comorbid disease, a total of 12283 made up the study population. The participants underwent a series of tests and evaluations by trained professionals in accordance with WHO recommendations. Hypertension, abnormal fasting blood sugar (FBS), triglyceride (TG) and high density lipoprotein cholesterol (HDL) (in the context of the definition of metabolic syndrome) were prevalent among 32.4%, 27.6%, 42.1 and 44.2% of our participants, respectively. Women displayed higher rates of overall obesity compared to men (based on the definition by the WHO as higher than 30 kg/m2). Regarding MeS, 38.9% of our population had the all symptoms of MeS which was more prevalent among women (41.5% vs. 36%). When excluding WC in the definition of MeS, results showed that males tend to show a higher rate of metabolic risk factors (19.2% vs. 15.6%). Results of multivariate analysis showed that parallel to an increase in BMI, the odds ratio (OR) for acquiring each component of the metabolic syndrome increased (OR = 1.178; CI: 1.166-1.190). By excluding WC, the previous OR decreased (OR = 1.105; CI: 1.093 1.118). Receiver Operating Characteristic (ROC) curve analysis showed that the optimum BMI cut-off point for predicting metabolic syndrome was 26.1 kg/m2 and 26.2 kg/m2 [Accuracy (Acc) = 69% and 61%, respectively)] for males and females, respectively. The overall BMI cut-off for both sexes was 26.2 kg/m2 (Acc = 65%) with sensitivity and specificity of 69% and 62%, respectively. This cut-off had a positive predictive value of 54% and a negative predictive value of 76%. When we excluded waist circumference, the optimum BMI cut-off for acquiring metabolic risk factors in males decreased to 25.7 kg/m2 (Acc = 67%) and increased for women to 27.05 kg/m2 (Acc = 66%). Iranians are at higher risks of morbidity related to metabolic factors at a lower BMI cut-off and prompt action and preventive health policy are required to prevent and educate Iranians regarding diseases associated with obesity. PMID- 27509027 TI - Well-Being: An Important Concept for Psychotherapy and Psychiatric Neuroscience. PMID- 27509028 TI - Social Interactions Receive Priority to Conscious Perception. AB - Humans are social animals, constantly engaged with other people. The importance of social thought and action is hard to overstate. However, is social information so important that it actually determines which stimuli are promoted to conscious experience and which stimuli are suppressed as invisible? To address this question, we used a binocular rivalry paradigm, in which the two eyes receive different action stimuli. In two experiments we measured the conscious percept of rival actions and found that actions engaged in social interactions are granted preferential access to visual awareness over non-interactive actions. Lastly, an attentional task that presumably engaged the mentalizing system enhanced the priority assigned to social interactions in reaching conscious perception. We also found a positive correlation between human identification of interactive activity and the promotion of socially-relevant information to visual awareness. The present findings suggest that the visual system amplifies socially-relevant sensory information and actively promotes it to consciousness, thereby facilitating inferences about social interactions. PMID- 27509029 TI - Impact of micro-environmental changes on respiratory tract infections with intracellular bacteria. AB - Community-acquired pneumonia is caused by intra- and extracellular bacteria, with some of these bacteria also being linked to the pathogenesis of chronic lung diseases, including asthma and chronic obstructive pulmonary disease. Chlamydia pneumoniae is an obligate intracellular pathogen that is highly sensitive to micro-environmental conditions controlling both pathogen growth and host immune responses. The availability of nutrients, as well as changes in oxygen, pH and interferon-gamma levels, have been shown to directly influence the chlamydial life cycle and clearance. Although the lung has been traditionally regarded as a sterile environment, sequencing approaches have enabled the identification of a large number of bacteria in healthy and diseased lungs. The influence of the lung microbiota on respiratory infections has not been extensively studied so far and data on chlamydial infections are currently unavailable. In the present study, we speculate on how lung microbiota might interfere with acute and chronic infections by focusing exemplarily on the obligate intracellular C. pneumoniae. Furthermore, we consider changes in the gut microbiota as an additional player in the control of lung infections, especially in view the increasing evidence suggesting the involvement of the gut microbiota in various immunological processes throughout the human body. PMID- 27509030 TI - Cross-Linking versus Non-Cross-Linking Aggregation of Gold Nanoparticles Induced by DNA Hybridization: A Comparison of the Rapidity of Solution Color Change. AB - Gold nanoparticles densely modified with single-stranded DNA (ssDNA-AuNPs) form aggregates with cross-linker ssDNAs via duplex formation. Alternatively, the ssDNA-AuNPs are spontaneously aggregated at high ionic strength in a non-cross linking manner when complementary ssDNAs are added to form fully matched duplexes. Both aggregation modes are accompanied by a red-to-purple color change, which has been exploited in various bioassays. The current study compares the rapidity of color change between the cross-linking and non-cross-linking aggregation modes under identical conditions. When a small number of cross linker/complementary DNAs are provided, the cross-linking mode exhibited more rapid color change than the non-cross-linking mode. Conversely, with a large number of the DNAs, the non-cross-linking aggregation occurred more rapidly than the cross-linking counterpart. This finding allows one to select a more appropriate aggregation mode for application of ssDNA-AuNPs to colorimetric assays under given conditions. PMID- 27509032 TI - Angiolipoma of the Breast: Multi-modality Imaging Findings. PMID- 27509031 TI - Characterization of Laminin Binding Integrin Internalization in Prostate Cancer Cells. AB - Laminin binding integrins alpha6 (CD49f) and alpha3 (CD49c) are persistently but differentially expressed in prostate cancer (PCa). Integrin internalization is an important determinant of their cell surface expression and function. Using flow cytometry, and first order kinetic modeling, we quantitated the intrinsic internalization rates of integrin subunits in a single cycle of internalization. In PCa cell line DU145, alpha6 integrin internalized with a rate constant (kactual ) of 3.25 min-1 , threefold faster than alpha3 integrin (1.0 min-1 ), 1.5-fold faster than the vitronectin binding alphav integrin (CD51) (2.2 min-1 ), and significantly slower than the unrelated transferrin receptor (CD71) (15 min-1 ). Silencing of alpha3 integrin protein expression in DU145, PC3, and PC3B1 cells resulted in up to a 1.71-fold increase in kactual for alpha6 integrin. The internalized alpha6 integrin was targeted to early endosomes but not to lamp1 vesicles. Depletion of alpha3 integrin expression resulted in redistribution of alpha6beta4 integrin to an observed cell-cell staining pattern that is consistent with a suprabasal distribution observed in epidermis and early PIN lesions in PCa. Depletion of alpha3 integrin increased cell migration by 1.8-fold, which was dependent on alpha6beta1 integrin. Silencing of alpha6 integrin expression however, had no significant effect on the kactual of alpha3 integrin or its distribution in early endosomes. These results indicate that alpha3 and alpha6 integrins have significantly different internalization kinetics and that coordination exists between them for internalization. J. Cell. Biochem. 118: 1038 1049, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27509033 TI - Mobilization of autologous and allogeneic peripheral blood stem cells for transplantation in haematological malignancies using biosimilar G-CSF. AB - BACKGROUND AND OBJECTIVES: Biosimilars of the granulocyte colony stimulating factor (G-CSF) filgrastim were approved by the European Medicines Agency (EMA) for registered indications of the originator G-CSF, including prevention and treatment of neutropenia, as well as mobilization of peripheral blood stem cells in 2008. Nevertheless, there is still an ongoing debate regarding the quality, efficacy and safety of biosimilar G-CSF. MATERIALS AND METHODS: This article is a meta-analysis of clinical studies on the use of biosimilar G-CSF for mobilization and transplantation of haematopoietic stem cells as available in public databases. All data sets were weighted for the number of patients and parameters and then subjected to statistical meta-analysis employing the Mann-Whitney U-test followed by the Hodges-Lehmann estimator to assess differences between biosimilar and originator G-SCF. RESULTS: A total of 1892 individuals, mostly with haematological malignancies but also including 351 healthy donors have been successfully mobilized for autologous or allogeneic stem cell transplantation using biosimilar G-CSF (Zarzio(TM) : 1239 individuals; Ratiograstim(TM) /Tevagrastim(TM) : 653 individuals). A total of 740 patients with multiple myeloma, 491 with non-Hodgkin's lymphoma (NHL), 150 with Hodgkin's lymphoma (HL) and other diseases are included in this meta-analysis, as well as 161 siblings and 190 volunteer unrelated donors. For biosimilar and originator G-CSF, bioequivalence was observed for the yield of CD34+ stem cells as well as for the engraftment of the transplants. CONCLUSION: Biosimilar G-CSF has equivalent effects and safety as originator G-CSF. PMID- 27509036 TI - Migrant and Refugee Patient Perspectives on Travel and Tuberculosis along the Thailand-Myanmar Border: A Qualitative Study. AB - BACKGROUND: The Thailand-Myanmar border separates two very different health systems. The healthcare system in eastern Myanmar remains underdeveloped as a result of decades of instability. Comparatively, Tak province, Thailand has more healthcare resources. In this Thai border province government hospitals and non governmental organizations provide tuberculosis (TB) treatment to migrants and refugees. OBJECTIVES: Our overall study aimed to explore accessibility of TB treatment, TB surveillance and health system responsiveness specific to migrant and refugee populations in Tak province. In this paper, we focus on the perspectives of migrant and refugee TB patients with respect to travel and treatment in Tak province. METHODS: In 2014 we conducted focus group discussions with 61 TB, Tuberculosis and Human Immunodeficiency Virus co-infection, and multidrug-resistant TB patients in Tak province. We analyzed the data for content and themes and documented individual travel trajectories. RESULTS AND DISCUSSION: Migrants are travelling with active TB within the country and between Thailand and Myanmar. Migrants primarily travelled to obtain treatment but two participants reported travelling home to seek family care in Myanmar before returning to Thailand for treatment. Travel, while expensive and arduous, is an adaptive strategy that migrants use to access healthcare. CONCLUSIONS: Migrant's need for travel points to larger difficulties associated with healthcare access in the border region. Long distance travel with an infectious disease can be seen as an indicator that local healthcare is not available or affordable. These findings suggest that public health officials from both sides of the border should discuss the factors that contribute to travel with active TB and explore potential solutions to mitigate disease transmission in migrant populations. PMID- 27509035 TI - A propensity score matching analysis of dasatinib and nilotinib as a frontline therapy for patients with chronic myeloid leukemia in chronic phase. AB - BACKGROUND: Both dasatinib and nilotinib are approved frontline therapy for chronic myeloid leukemia in chronic phase (CML-CP) based on randomized trials compared with imatinib. However, no head-to-head comparison of dasatinib and nilotinib has been conducted in patients with newly diagnosed CML-CP. METHODS: The authors conducted a propensity score (PS) matched comparison of patients with CML-CP who received frontline therapy with either dasatinib (N = 102) or nilotinib (N = 104) under the respective phase 2 trials conducted in parallel. RESULTS: PS matching resulted in 87 patients from each trial being matched for pretreatment characteristics. The 3-month BCR-ABL1/ABL1 ratio <10% rate was 93% with dasatinib and 94% with nilotinib (P = .25); the rates of major molecular response at 12 months were 77% and 85%, respectively (P = .13); and the rates of molecular response with 4.5-log reduction in the ratio at 36 months were 66% and 64%, respectively (P = .96). All other clinically relevant responses were similar between the 2 treatment cohorts. The 3-year probability of event-free survival was 89% among the patients who received dasatinib and 87% among those who received nilotinib (P = .99), and the corresponding 3-year overall survival probabilities were 99% and 93%, respectively (P = .95). No statistical difference was observed between the dasatinib and nilotinib groups in any of the other survival endpoints. The treatment discontinuation rate also was similar between the 2 cohorts (dasatinib group, 18%; nilotinib group, 19%; P = .82). CONCLUSIONS: In a PS-matched cohort of patients with newly diagnosed CML-CP, dasatinib and nilotinib offer similar response and survival outcomes. Both drugs can be considered reasonable standard-of-care options as first-line therapy for patients with CML-CP. Cancer 2016;122:3336-3343. (c) 2016 American Cancer Society. PMID- 27509038 TI - Surgical Management of Pediatric Developmental Dysplasia of the Hip. AB - In pediatric patients with developmental dysplasia of the hip with late presentation or failure of nonsurgical treatment, surgical management is indicated. The goal of surgery is to obtain a stable reduction to promote development of the femoral head and acetabulum while avoiding osteonecrosis of the femoral head and the need for further surgery. Treatment is related to the age of the patient and the degree of soft-tissue contracture or bony deformity present. As a general rule, in children aged <12 months, closed reduction and spica casting is preferred. Children aged 12 to 18 months may require open reduction, which can be performed safely through a medial or anterior approach. In children aged 18 months to 3 years, residual bony deformity can be corrected with a femoral or pelvic osteotomy in addition to open reduction. In children with complex deformity or in children aged >3 years, both pelvic and femoral osteotomies are commonly required to stabilize an open reduction. PMID- 27509037 TI - Novel Ordered Stepped-Wedge Cluster Trial Designs for Detecting Ebola Vaccine Efficacy Using a Spatially Structured Mathematical Model. AB - BACKGROUND: During the 2014 Ebola virus disease (EVD) outbreak, policy-makers were confronted with difficult decisions on how best to test the efficacy of EVD vaccines. On one hand, many were reluctant to withhold a vaccine that might prevent a fatal disease from study participants randomized to a control arm. On the other, regulatory bodies called for rigorous placebo-controlled trials to permit direct measurement of vaccine efficacy prior to approval of the products. A stepped-wedge cluster study (SWCT) was proposed as an alternative to a more traditional randomized controlled vaccine trial to address these concerns. Here, we propose novel "ordered stepped-wedge cluster trial" (OSWCT) designs to further mitigate tradeoffs between ethical concerns, logistics, and statistical rigor. METHODOLOGY/PRINCIPAL FINDINGS: We constructed a spatially structured mathematical model of the EVD outbreak in Sierra Leone. We used the output of this model to simulate and compare a series of stepped-wedge cluster vaccine studies. Our model reproduced the observed order of first case occurrence within districts of Sierra Leone. Depending on the infection risk within the trial population and the trial start dates, the statistical power to detect a vaccine efficacy of 90% varied from 14% to 32% for standard SWCT, and from 67% to 91% for OSWCTs for an alpha error of 5%. The model's projection of first case occurrence was robust to changes in disease natural history parameters. CONCLUSIONS/SIGNIFICANCE: Ordering clusters in a step-wedge trial based on the cluster's underlying risk of infection as predicted by a spatial model can increase the statistical power of a SWCT. In the event of another hemorrhagic fever outbreak, implementation of our proposed OSWCT designs could improve statistical power when a step-wedge study is desirable based on either ethical concerns or logistical constraints. PMID- 27509039 TI - A Novel Algorithm for Isolated Weber B Ankle Fractures: A Retrospective Review of 51 Nonsurgically Treated Patients. AB - INTRODUCTION: Stability of isolated Weber B ankle fractures can be difficult to determine. Using weight-bearing radiographs, a reliable method to determine the stability of isolated Weber B ankle fractures is described. METHODS: A retrospective review of prospectively gathered data was performed. Weber B ankle fractures were defined as stable when having a medial clear space (MCS) of <7 mm on initial gravity stress radiographs and a normal mortise relationship on weight bearing radiographs. Fifty-one patients meeting these criteria were treated nonsurgically with protected weight bearing and serial radiography for 1 year. RESULTS: Average functional score results were: American Orthopaedic Foot and Ankle Society Hindfoot, 93.2; Foot and Ankle Ability Measure for Activities of Daily Living, 93.2; Olerud-Molander Ankle Score, 91.0; and visual analog scale pain score, 0.57. Despite a mean gravity stress MCS of 4.42 mm, no patient demonstrated subsequent MCS widening. Mean MCS on 1-year follow-up weight-bearing radiographs was 2.64 mm. CONCLUSION: Weight-bearing ankle radiographs are predictive of stability in isolated Weber B ankle fractures. Gravity stress radiographs using traditional measurement criteria may overestimate instability in these injuries. Nonsurgical treatment with protected weight bearing shows good early outcomes. LEVEL OF EVIDENCE: IV. PMID- 27509040 TI - Fetal Heart Rate during in Utero Myelomeningocele Repair: Effect of Anesthesia and Analgesia. PMID- 27509041 TI - MMpI: A WideRange of Available Compounds of Matrix Metalloproteinase Inhibitors. AB - Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the regulation of the extracellular signaling and structural matrix environment of cells and tissues. MMPs are considered as promising targets for the treatment of many diseases. Therefore, creation of database on the inhibitors of MMP would definitely accelerate the research activities in this area due to its implication in above-mentioned diseases and associated limitations in the first and second generation inhibitors. In this communication, we report the development of a new MMpI database which provides resourceful information for all researchers working in this field. It is a web-accessible, unique resource that contains detailed information on the inhibitors of MMP including small molecules, peptides and MMP Drug Leads. The database contains entries of ~3000 inhibitors including ~72 MMP Drug Leads and ~73 peptide based inhibitors. This database provides the detailed molecular and structural details which are necessary for the drug discovery and development. The MMpI database contains physical properties, 2D and 3D structures (mol2 and pdb format files) of inhibitors of MMP. Other data fields are hyperlinked to PubChem, ChEMBL, BindingDB, DrugBank, PDB, MEROPS and PubMed. The database has extensive searching facility with MMpI ID, IUPAC name, chemical structure and with the title of research article. The MMP inhibitors provided in MMpI database are optimized using Python-based Hierarchical Environment for Integrated Xtallography (Phenix) software. MMpI Database is unique and it is the only public database that contains and provides the complete information on the inhibitors of MMP. Database URL: http://clri.res.in/subramanian/databases/mmpi/index.php. PMID- 27509042 TI - DNA Barcoding the Heliothinae (Lepidoptera: Noctuidae) of Australia and Utility of DNA Barcodes for Pest Identification in Helicoverpa and Relatives. AB - Helicoverpa and Heliothis species include some of the world's most significant crop pests, causing billions of dollars of losses globally. As such, a number are regulated quarantine species. For quarantine agencies, the most crucial issue is distinguishing native species from exotics, yet even this task is often not feasible because of poorly known local faunas and the difficulties of identifying closely related species, especially the immature stages. DNA barcoding is a scalable molecular diagnostic method that could provide the solution to this problem, however there has been no large-scale test of the efficacy of DNA barcodes for identifying the Heliothinae of any region of the world to date. This study fills that gap by DNA barcoding the entire heliothine moth fauna of Australia, bar one rare species, and comparing results with existing public domain resources. We find that DNA barcodes provide robust discrimination of all of the major pest species sampled, but poor discrimination of Australian Heliocheilus species, and we discuss ways to improve the use of DNA barcodes for identification of pests. PMID- 27509043 TI - Reinforcer Pathology: The Behavioral Economics of Abuse Liability Testing. AB - Understanding the abuse liability of novel drugs is critical to understanding the risk these new compounds pose to society. Behavioral economics, the integration of psychology and economics, can be used to predict abuse liability of novel substances. Here, we describe the behavioral economic concept of reinforcer pathology and how it may predict the use of novel drugs in existing drug-users and initiation of use in the drug-naive. PMID- 27509044 TI - Creating a More Diverse Midwifery Workforce in the United States: A Historical Reflection. AB - INTRODUCTION: As nurse-midwifery practice expanded beyond areas surrounding early nurse-midwifery education programs, leaders in the profession wanted to establish a strong diverse, inclusive professional organization, a necessary step in creating a diverse workforce (defined here as open to nurse-midwives of all colors, ethnicities, and national origins) that would maintain standards, provide continuing education, and facilitate communication among nurse-midwives. This research presents historical context and organizational factors supporting and limiting development of a workforce reflective of communities served by nurse midwives. METHODS: Searches in the National Library of Medicine Historical Collection, American College of Nurse-Midwives (ACNM) Collections, and the Rockefeller Archives Center, as well as recorded interview data, provided primary sources for analysis. Secondary sources include research and opinions in scholarly publications including journals and books released from 1930 to the present. RESULTS: Nurse-midwifery leaders developed relationships with well respected philanthropists, as well as maternal and child health administrators in state departments of health and the US Children's Bureau, to implement initiatives to recruit and retain midwives of color. Continued interest in the goal of inclusion, work of midwives of color, and commitment to creating a diverse workforce led to the creation of the standing ACNM Midwives of Color Committee in 1990 and the Diversity and Inclusion Task Force, which released its report, "Shifting the Frame: A Report on Diversity and Inclusion in the American College of Nurse-Midwives,"1 in June 2015. DISCUSSION: Over the past 60 years, ACNM leadership and midwives of color have continued to explore new and effective means to create a workforce that reflects the communities in which nurse-midwives practice. PMID- 27509045 TI - Redox-Sensitive and Intrinsically Fluorescent Photoclick Hyaluronic Acid Nanogels for Traceable and Targeted Delivery of Cytochrome c to Breast Tumor in Mice. AB - In spite of their high specificity and potency, few protein therapeutics are applied in clinical cancer therapy owing to a lack of safe and efficacious delivery systems. Here, we report that redox-sensitive and intrinsically fluorescent photoclick hyaluronic acid nanogels (HA-NGs) show highly efficient loading and breast tumor-targeted delivery of cytochrome c (CC). HA-NGs were obtained from hyaluronic acid-graft-oligo(ethylene glycol)-tetrazole (HA-OEG-Tet) via inverse nanoprecipitation and catalyst-free photoclick cross-linking with l cystine dimethacrylamide (MA-Cys-MA). HA-NGs exhibited a superb CC loading content of up to 40.6 wt %, intrinsic fluorescence (lambdaem = 510 nm), and a small size of ca. 170 nm. Notably, CC-loaded nanogels (CC-NGs) showed a fast glutathione-responsive protein release behavior. Importantly, released CC maintained its bioactivity. MTT assays revealed that CC-NGs were highly potent with a low IC50 of 3.07 MUM to CD44+ MCF-7 human breast tumor cells. Confocal microscopy observed efficient and selective internalization of fluorescent HA-NGs into MCF-7 cells. Interestingly, HA-NGs exhibited also effective breast tumor penetration. The therapeutic results demonstrated that CC-NGs effectively inhibited the growth of MCF-7 breast tumor xenografts at a particularly low dose of 80 or 160 nmol CC equiv./kg. Moreover, CC-NGs did not cause any change in mice body weight, corroborating their low systemic side effects. Redox-sensitive and intrinsically fluorescent photoclick hyaluronic acid nanogels have appeared as a "smart" protein delivery nanoplatform enabling safe, efficacious, traceable, and targeted cancer protein therapy in vivo. PMID- 27509046 TI - Differences in Patient Outcomes of Prevalence, Interval, and Screen-Detected Lung Cancers in the CT Arm of the National Lung Screening Trial. AB - Lung cancer screening identifies cancers with heterogeneous behaviors. Some lung cancers will be identified among patients who had prior negative CT screens and upon follow-up scans develop a de novo nodule that was determined to be cancerous. Other lung cancers will be identified among patients who had one or more prior stable positive scans that were not determined to be lung cancer (indeterminate pulmonary nodules), but in follow-up scans was diagnosed with an incidence lung cancer. Using data from the CT arm of the National Lung Screening Trial, this analysis investigated differences in patient characteristics and survival endpoints between prevalence-, interval-, and screen-detected lung cancers, characterized based on sequence of screening results. Lung cancers immediately following a positive baseline (T0), and prior to the T1 screen, formed the prevalence cohort. Interval cancers were diagnosed following a negative screen at any time point prior to the next screening round. Two cohorts of screen-detected lung cancers (SDLC) were identified that had a baseline positive screen that was that was not determined to be lung cancer (i.e., an indeterminate pulmonary nodule), but in follow-up scans was diagnosed with an incidence lung cancer 12 (SDLC1) or 24 (SDLC2) months later. Two other incidence cohorts had screen-detected lung cancers that had baseline negative screen and upon follow-up scans developed a de novo nodule determined to be cancerous at 12 (SDLC3) or 24 (SDLC4) months later. Differences in patient characteristics, progression-free survival (PFS), and overall survival (OS) were assessed. The lung cancer-specific death rate was higher for SDLC3/SDLC4 compared to SDLC1/SDLC2 lung cancers (136.6/1,000 person-years vs. 71.3/1,000 person-years, P < 0.001). Moreover, PFS and OS were significantly lower for SDLC3/SDLC4 compared to SDLC1/SDLC2 (P < 0.004; P < 0.002, respectively). The findings were consistent when stratified by stage and histology. Multivariable Cox proportional models revealed that the SDLC3/SDLC4 case groups were associated with significantly poorer PFS (HR = 1.89; 95% CI 1.31-2.74) and OS (HR = 1.80; 95% CI 1.21-2.67) compared to SDLC1/SDLC2 lung cancers (HR = 1.00). Lung cancer patients who develop a de novo nodule that determined to be cancerous (i.e., at least one negative CT screen prior to cancer diagnosis) had poorer survival outcomes compared to patients who had at least one positive screen prior to cancer diagnosis. As such, the observation that de novo screen-detected are associated with poorer survival could be attributed to faster growing, more aggressive cancers that arose from a lung environment previously lacking focal abnormalities. PMID- 27509047 TI - Curcumin cross-linked collagen aerogels with controlled anti-proteolytic and pro angiogenic efficacy. AB - This paper elucidates the development of a curcumin cross-linked collagen aerogel system with controlled anti-proteolytic activity and pro-angiogenic efficacy. The results of this study showed that in situ cross-linking of curcumin with collagen leads to the development of aerogels with enhanced physical and mechanical properties. The integrity of collagen after cross-linking with curcumin was studied via FTIR spectroscopy. The results confirmed that the cross-linking with curcumin did not induce any structural changes in the collagen. The curcumin cross-linked collagen aerogels exhibited potent anti-proteolytic and anti microbial activity. Scanning electron and atomic force microscopic analysis of curcumin cross-linked collagen aerogels showed a 3D microstructure that enhanced the adhesion and proliferation of cells. The highly organized geometry of collagen-curcumin aerogels enhanced the permeability and water-retaining ability required for the diffusion of nutrients that aid cellular growth. The pro angiogenic properties of collagen-curcumin aerogels were ascribed to the cumulative effect of the nutraceutical and the collagen molecule, which augmented the restoration of damaged tissue. Further, these aerogels exhibited controlled anti-proteolytic activity, which makes them suitable 3D scaffolds for biomedical applications. This study provides scope for the development of biocompatible and bioresorbable collagen aerogel systems that use a nutraceutical as a cross-linker for biomedical applications. PMID- 27509049 TI - Genetic Diversity and Population Structure of Cowpea (Vigna unguiculata L. Walp). AB - The genetic diversity of cowpea was analyzed, and the population structure was estimated in a diverse set of 768 cultivated cowpea genotypes from the USDA GRIN cowpea collection, originally collected from 56 countries. Genotyping by sequencing was used to discover single nucleotide polymorphism (SNP) in cowpea and the identified SNP alleles were used to estimate the level of genetic diversity, population structure, and phylogenetic relationships. The aim of this study was to detect the gene pool structure of cowpea and to determine its relationship between different regions and countries. Based on the model-based ancestry analysis, the phylogenetic tree, and the principal component analysis, three well-differentiated genetic populations were postulated from 768 worldwide cowpea genotypes. According to the phylogenetic analyses between each individual, region, and country, we may trace the accession from off-original, back to the two candidate original areas (West and East of Africa) to predict the migration and domestication history during the cowpea dispersal and development. To our knowledge, this is the first report of the analysis of the genetic variation and relationship between globally cultivated cowpea genotypes. The results will help curators, researchers, and breeders to understand, utilize, conserve, and manage the collection for more efficient contribution to international cowpea research. PMID- 27509048 TI - Elevated Basal Pre-infection CXCL10 in Plasma and in the Small Intestine after Infection Are Associated with More Rapid HIV/SIV Disease Onset. AB - Elevated blood CXCL10/IP-10 levels during primary HIV-1 infection (PHI) were described as an independent marker of rapid disease onset, more robust than peak viremia or CD4 cell nadir. IP-10 enhances the recruitment of CXCR3+ cells, which include major HIV-target cells, raising the question if it promotes the establishment of viral reservoirs. We analyzed data from four cohorts of HIV+ patients, allowing us to study IP-10 levels before infection (Amsterdam cohort), as well as during controlled and uncontrolled viremia (ANRS cohorts). We also addressed IP-10 expression levels with regards to lymphoid tissues (LT) and blood viral reservoirs in patients and non-human primates. Pre-existing elevated IP-10 levels but not sCD63 associated with rapid CD4 T-cell loss upon HIV-1 infection. During PHI, IP-10 levels and to a lesser level IL-18 correlated with cell associated HIV DNA, while 26 other inflammatory soluble markers did not. IP-10 levels tended to differ between HIV controllers with detectable and undetectable viremia. IP-10 was increased in SIV-exposed aviremic macaques with detectable SIV DNA in tissues. IP-10 mRNA was produced at higher levels in the small intestine than in colon or rectum. Jejunal IP-10+ cells corresponded to numerous small and round CD68neg cells as well as to macrophages. Blood IP-10 response negatively correlated with RORC (Th17 marker) gene expression in the small intestine. CXCR3 expression was higher on memory CD4+ T cells than any other immune cells. CD4 T cells from chronically infected animals expressed extremely high levels of intra cellular CXCR3 suggesting internalization after ligand recognition. Elevated systemic IP-10 levels before infection associated with rapid disease progression. Systemic IP-10 during PHI correlated with HIV DNA. IP-10 production was regionalized in the intestine during early SIV infection and CD68+ and CD68neg haematopoietic cells in the small intestine appeared to be the major source of IP 10. PMID- 27509050 TI - The Chronic Effects of Low- and High-Intensity Resistance Training on Muscular Fitness in Adolescents. AB - To compare the effects of high-load, low-repetition maximum (LRM) and low-load, high-repetition maximum (HRM) resistance training regimens on muscular fitness in untrained adolescents. Forty-five untrained adolescents of both sexes (13.7+/-0.8 years; 161.3+/-7.5 cm, 56.8+/-13.4 kg) were randomly assigned into one of three groups: 1) LRM (n = 17): volunteers performed three sets of 4-6-repetition maximum (RM); 2) HRM (n = 16): volunteers performed three sets of 12-15 RM; and 3) control (CON, n = 12). Training was performed two times a week for 9 weeks. After training, there were significant increases in 1 RM chest press (LRM = 14.8% and HRM = 14.2%, p<0.05) and squat (LRM = 26.4% and HRM = 25.7%, p<0.05), with no differences between the LRM and HRM groups (p>0.05). Additionally, muscular endurance increased significantly for the chest press (LRM = 14.5% and HRM = 21.8%, p<0.05) and squat test (LRM = 31.4% and HRM = 32.4%, p<0.05) following resistance training, with no difference between the LRM and HRM groups (p>0.05). These results suggest that both high-load, low-repetition and moderate-load, high repetition resistance training can be prescribed to improve muscular fitness in untrained adolescents. PMID- 27509051 TI - Clostridium difficile Infections in Medical Intensive Care Units of a Medical Center in Southern Taiwan: Variable Seasonality and Disease Severity. AB - Critical patients are susceptible to Clostridium difficile infections (CDIs), which cause significant morbidity and mortality in the hospital. In Taiwan, the epidemiology of CDI in intensive care units (ICUs) is not well understood. This study was aimed to describe the incidence and the characteristics of CDI in the ICUs of a medical center in southern Taiwan. Adult patients with diarrhea but without colostomy/colectomy or laxative use were enrolled. Stool samples were collected with or without 5 ml alcohol and were plated on cycloserine-cefoxitin fructose agar. C. difficile identification was confirmed by polymerase chain reaction. There were 1,551 patients admitted to ICUs, 1,488 screened, and 145 with diarrhea. A total of 75 patients were excluded due either to laxative use, a lack of stool samples, or refusal. Overall, 70 patients were included, and 14 (20%) were diagnosed with CDI, with an incidence of 8.8 cases per 10,000 patient days. The incidence of CDI was found to be highest in March 2013 and lowest in the last quarter of 2013. The cases were categorized as the following: 5 severe, complicated, 5 severe, and 4 mild or moderate diseases. Among the 14 cases of CDI, the median patient age was 74 (range: 47-94) years, and the median time from admission to diarrhea onset was 16.5 (4-53) days. Eight cases received antimicrobial treatment (primarily metronidazole), and the time to diarrheal resolution was 11.5 days. Though 6 cases were left untreated, no patients died of CDI. The in-hospital mortality of CDI cases was 50%, similar to that of patients without CDI (46.4%; P = 1.0). We concluded that the overall incidence of CDI in our medical ICUs was low and there were variable seasonal incidences and disease severities of CDI. PMID- 27509053 TI - Interferon stimulated genes and innate immune activation following infection with hepatitis B and C viruses. AB - Although not directly cytopathic, hepatitis B and C viruses (HBV and HCV) are responsible for millions of deaths per year, and the aging patient population presents a severe public health challenge. Most cases of acute HCV become chronic, but treatment has become increasingly successful following the development of direct acting antiviral agents. Conversely, most cases of acute HBV are cleared in the pre-symptomatic stage and do not become chronic, but treatment options for chronic HBV are limited and rarely result in clearance. Despite these differences, interferon is partially effective against both viruses and has long been used in therapy. Newer treatments have largely moved away from interferon in favor of more targeted approaches, but interferon signaling remains the body's first line of defense against viruses. The recent discovery of type III interferon and IFNL4 has yielded new insights into the mechanism of ISG activation and revealed potential new therapeutic targets. J. Med. Virol. 89:388 396, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27509052 TI - Modelling the Structure and Dynamics of Biological Pathways. AB - There is a need for formalised diagrams that both summarise current biological pathway knowledge and support modelling approaches that explain and predict their behaviour. Here, we present a new, freely available modelling framework that includes a biologist-friendly pathway modelling language (mEPN), a simple but sophisticated method to support model parameterisation using available biological information; a stochastic flow algorithm that simulates the dynamics of pathway activity; and a 3-D visualisation engine that aids understanding of the complexities of a system's dynamics. We present example pathway models that illustrate of the power of approach to depict a diverse range of systems. PMID- 27509054 TI - MALDI imaging reveals NCOA7 as a potential biomarker in oral squamous cell carcinoma arising from oral submucous fibrosis. AB - Oral squamous cell carcinoma (OSCC) ranks among the most common cancer worldwide, and is associated with severe morbidity and high mortality. Oral submucous fibrosis (OSF), characterized by fibrosis of the mucosa of the upper digestive tract, is a pre-malignant lesion, but the molecular mechanisms underlying this malignant transformation remains to be elucidated. In this study, matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS)-based proteomic strategy was employed to profile the differentially expressed peptides/proteins between OSCC tissues and the corresponding adjacent non-cancerous OSF tissues. Sixty-five unique peptide peaks and nine proteins were identified with altered expression levels. Of them, expression of NCOA7 was found to be up-regulated in OSCC tissues by immunohistochemistry staining and western blotting, and correlated with a pan of clinicopathologic parameters, including lesion site, tumor differentiation status and lymph node metastasis. Further, we show that overexpression of NCOA7 promotes OSCC cell proliferation in either in vitro or in vivo models. Mechanistic study demonstrates that NCOA7 induces OSCC cell proliferation probably by activating aryl hydrocarbon receptor (AHR). The present study suggests that NCOA7 is a potential biomarker for early diagnosis of OSF malignant transformation, and leads to a better understanding of the molecular mechanisms responsible for OSCC development. PMID- 27509055 TI - Crosstalk between the mitochondrial fission protein, Drp1, and the cell cycle is identified across various cancer types and can impact survival of epithelial ovarian cancer patients. AB - Mitochondrial metabolic reprogramming is a hallmark of tumorigenesis. Although mitochondrial function can impact cell cycle regulation it has been an understudied area in cancer research. Our study highlights a specific involvement of mitochondria in cell cycle regulation across cancer types. The mitochondrial fission process, which is regulated at the core by Drp1, impacts various cellular functions. Drp1 has been implicated in various cancer types with no common mechanism reported. Our Drp1-directed large-scale analyses of the publically available cancer genomes reveal a robust correlation of Drp1 with cell-cycle genes in 29 of the 31 cancer types examined. Hypothesis driven investigation on epithelial ovarian cancer (EOC) revealed that Drp1 co-expresses specifically with the cell-cycle module responsible for mitotic transition. Repression of Drp1 in EOC cells can specifically attenuate mitotic transition, establishing a potential casual role of Drp1 in mitotic transition. Interestingly, Drp1-Cell-Cycle co expression module is specifically detected in primary epithelial ovarian tumors that robustly responded to chemotherapy, suggesting that Drp1 driven mitosis may underlie chemo-sensitivity of the primary tumors. Analyses of matched primary and relapsed EOC samples revealed a Drp1-based-gene-expression-signature that could identify patients with poor survival probabilities from their primary tumors. Our results imply that around 60% of platinum-sensitive EOC patients undergoing relapse show poor survival, potentially due to further activation of a mitochondria driven cell-cycle regime in their recurrent disease. We speculate that this patient group could possibly benefit from mitochondria directed therapies that are being currently evaluated at various levels, thus enabling targeted or personalized therapy based cancer management. PMID- 27509056 TI - XB130 is overexpressed in prostate cancer and involved in cell growth and invasion. AB - XB130 is a cytosolic adaptor protein involved in various physiological processes and oncogenesis of certain malignancies, but its role in the development of prostate cancer remains unclear. In current study, we examined XB130 expression in prostate cancer tissues and found that XB130 expression was remarkably increased in prostate cancer tissues and significantly correlated with increased prostate specific antigen (PSA), free PSA (f-PSA), prostatic acid phosphatase (PAP) and T classification. Patients with highly expressed XB130 had significantly decreased survival, which suggested XB130 as a possible prognostic indicator for prostate cancer. In vitro experiments showed that reduced XB130 expression restrained tumor growth both in vitro and in vivo. Furthermore, XB130 knockdown hindered transition of G1 to S phase in prostate cancer cell line DU145 and LNCap, which might contribute to the inhibition of cellular proliferation. Results from transwell assay demonstrated that downregulation of XB130 may attenuate invasion and metastasis of prostate cancer. Semiquantitative analysis of Western blot suggested that decreased XB130 expression was accompanied by diminished Akt signaling and EMT process. Thus, above observations suggest that XB130 may be a novel molecular marker and potent therapeutic target for prostate cancer. PMID- 27509058 TI - NLRP3 inflammasome activation is involved in Ang II-induced kidney damage via mitochondrial dysfunction. AB - Growing evidence has shown that NLRP3 inflammasome activation promotes the development of tubularinterstitial inflammation and progression of renal injury. We previously found that mitochondrial dysfunction is a critical determinant for the activation of NLRP3 inflammasome in albumin-overload rats. Angiotensin (Ang) II plays an important role in mitochondrial homeostasis. Here, we investigated the role of Ang II in NLRP3 inflammasome activation and the involvement of mitochondrial dysfunction in this process. In vitro, Ang II triggered NLRP3 inflammasome activation in a dose- and time-dependent manner, and this effect is mediated by AT1 receptor rather than AT2 receptor. MitoTEMPO, a mitochondrial targeted antioxidant, attenuated Ang II induced mitochondrial reactive oxygen species (mROS) production and NLRP3 inflammation activation. Following chronic Ang II infusion for 28 days, we observed remarkable tubular epithelial cells (TECs) injury, mitochondrial damage, and albuminuria in WT mice. However, these abnormalities were significantly attenuated in AT1 receptor KO mice. Then, we examined the role of mitochondria in Ang II-infused mice with or without mitoTEMPO treatment. As expected, Ang II-induced mitochondrial dysfunction and NLRP3 inflammasome activation was markedly inhibited by mitoTEMPO. Notably, NLRP3 deletion signally protected TECs from Ang II-triggered mitochondrial dysfunction and NLRP3 inflammasome activation. Taken together, these data demonstrate that Ang II induces NLRP3 inflammasome activation in TECs which is mediated by mitochondrial dysfunction. PMID- 27509057 TI - Increased Rab35 expression is a potential biomarker and implicated in the pathogenesis of Parkinson's disease. AB - Parkinson's disease (PD) is the second common neurodegenerative disease. Identification of biomarkers for early diagnosis and prediction of disease progression is important. The present comparative proteomic study of serum samples using two-dimensional fluorescence differential gel electrophoresis followed by ELISA confirmation demonstrated that protein expression of Rab35 was increased in PD patients compared with matched control subjects and other parkinsonian disorders, progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). The serum level of Rab35 was significantly correlated with the age at onset of PD. The median age of onset in patients with higher Rab35 serum level was 5 years younger than those with lower Rab35 serum level. There was a positive correlation between the Rab35 level and disease duration of PD. Moreover, the protein expression of Rab35 was increased in the substantia nigra but not in the striatum of mouse models of PD, including MPTP-treated mice, rotenone-treated mice, (R1441C) LRRK2 or (G2019S) LRRK2 transgenic mice. Furthermore, overexpression of Rab35 increased the aggregation and secretion of mutant A53T alpha-synuclein in dopaminergic SH-SY5Y cells. Co-expression of Rab35 with wild type or A53T alpha-synuclein in SH-SY5Y cells deteriorated cell death. Our results suggest that Rab35 is potentially useful in the differential diagnosis of parkinsonian disorders and is implicated in the pathogenesis of PD. PMID- 27509059 TI - Systematic identification of immunodominant CD4+ T cell responses to HpaA in Helicobacter pylori infected individuals. AB - In mice, antigen-specific CD4+ T cell response is indispensible for the protective immunity against Helicobacter pylori (H. pylori). It has been demonstrated that neuraminyllactose-binding hemagglutinin (HpaA) immunization protected mice from H. pylori infection in a CD4+ T cell dependent manner. However, much remains unclear concerning the human CD4+ T cell responses to HpaA. We conducted a systematic study here to explore the immunodominant, HpaA-specific CD4+ T cell responses in H. pylori infected individuals. We found that HpaA specific CD4+ T cell responses varied remarkably in their magnitude and had broad epitope-specificity. Importantly, the main responses focused on two regions: HpaA76-105 and HpaA130-159. The HLA-DRB1*0901 restricted HpaA142-159 specific CD4+ T cell response was the most immunodominant response at a population level. The immunodominant epitope HpaA142-159 was naturally presented and highly conserved. We also demonstrated that it was not the broad peptide specificity, but the strength of HpaA specific CD4+ T cell responses associated with gastric diseases potentially caused by H. pylori infection. Such investigation will aid development of novel vaccines against H. pylori infection. PMID- 27509060 TI - Immortalization of human AE pre-leukemia cells by hTERT allows leukemic transformation. AB - Human CD34+ hematopoietic stem and progenitor cells (HSPC) expressing fusion protein AML1-ETO (AE), generated by the t(8;21)(q22;q22) rearrangement, manifest enhanced self-renewal and dysregulated differentiation without leukemic transformation, representing a pre-leukemia stage. Enabling replicative immortalization via telomerase reactivation is a crucial step in cancer development. However, AE expression alone is not sufficient to maintain high telomerase activity to immortalize human HSPC cells, which may hamper transformation. Here, we investigated the cooperativity of telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, and AE in disease progression. Enforced expression of hTERT immortalized human AE pre-leukemia cells in a telomere-lengthening independent manner, and improved the pre-leukemia stem cell function by enhancing cell proliferation and survival. AE-hTERT cells retained cytokine dependency and multi-lineage differentiation potential similar to parental AE clones. Over the short-term, AE-hTERT cells did not show features of stepwise transformation, with no leukemogenecity evident upon initial injection into immunodeficient mice. Strikingly, after extended culture, we observed full transformation of one AE-hTERT clone, which recapitulated the disease evolution process in patients and emphasizes the importance of acquiring cooperating mutations in t(8;21) AML leukemogenesis. In summary, achieving unlimited proliferative potential via hTERT activation, and thereby allowing for acquisition of additional mutations, is a critical link for transition from pre leukemia to overt disease in human cells. AE-hTERT cells represent a tractable model to study cooperating genetic lesions important for t(8;21) AML disease progression. PMID- 27509061 TI - Weekly versus three weeks chemotherapy for advanced ovarian cancer: a meta analysis. AB - AIM: Three weeks paclitaxel and carboplatin has been considered the standard of care for primary treatment of ovarian cancer (OC). Whether weekly therapy will further improve the clinical outcomes or not is still unclear. We conducted a meta-analysis to compare the two regimens. METHOD: Articles were selected with a systematic approach, using PubMed databases. Trials concerning comparison between carboplatin plus weekly paclitaxel (dose-dense regimen) and carboplatin plus paclitaxel every 3 weeks were considered. Outcomes included overall survival (OS), progression free survival (PFS) and severe acute toxicity. RESULTS: Dose dense regimen was associated with significant improvement of PFS compared with standard schedule, with HR of 0.73 (95% CI 0.61-0.88, p = 0.001). There was no difference in OS between treatment regimens (HR 0.95, 95% CI 0.77-1.16, p=0.06), as well as in term of severe acute toxicity. CONCLUSION: Dose-dense regimen is superior to standard schedule in terms of PFS. Further studies are necessary to firmly confirm this evidence in advanced OC treatment. PMID- 27509062 TI - Interferon gamma peptidomimetic targeted to interstitial myofibroblasts attenuates renal fibrosis after unilateral ureteral obstruction in mice. AB - Renal fibrosis cannot be adequately treated since anti-fibrotic treatment is lacking. Interferon-gamma is a pro-inflammatory cytokine with anti-fibrotic properties. Clinical use of interferon-gamma is hampered due to inflammation mediated systemic side effects. We used an interferon-gamma peptidomimetic (mimgamma) lacking the extracellular IFNgammaReceptor recognition domain, and coupled it to the PDGFbetaR-recognizing peptide BiPPB. Here we tested the efficacy of mimgamma-BiPPB (referred to as "Fibroferon") targeted to PDGFbetaR overexpressing interstitial myofibroblasts to attenuate renal fibrosis without inducing inflammation-mediated side effects in the mouse unilateral ureter obstruction model.Unilateral ureter obstruction induced renal fibrosis characterized by significantly increased alpha-SMA, TGFbeta1, fibronectin, and collagens I and III protein and/or mRNA expression. Fibroferon treatment significantly reduced expression of these fibrotic markers. Compared to full length IFNgamma, anti-fibrotic effects of Fibroferon were more pronounced. Unilateral ureter obstruction-induced lymphangiogenesis was significantly reduced by Fibroferon but not full-length IFNgamma. In contrast to full-length IFNgamma, Fibroferon did not induce IFNgamma-related side-effects as evidenced by preserved low-level brain MHC II expression (similar to vehicle), lowered plasma triglyceride levels, and improved weight gain after unilateral ureter obstruction.In conclusion, compared to full-length IFNgamma, the IFNgamma peptidomimetic Fibroferon targeted to PDGFbetaR-overexpressing myofibroblasts attenuates renal fibrosis in the absence of IFNgamma-mediated adverse effects. PMID- 27509064 TI - Simulation-based Randomized Comparative Assessment of Out-of-Hospital Cardiac Arrest Resuscitation Bundle Completion by Emergency Medical Service Teams Using Standard Life Support or an Experimental Automation-assisted Approach. AB - INTRODUCTION: Effective resuscitation of out-of-hospital cardiac arrest (OHCA) patients is challenging. Alternative resuscitative approaches using electromechanical adjuncts may improve provider performance. Investigators applied simulation to study the effect of an experimental automation-assisted, goal-directed OHCA management protocol on EMS providers' resuscitation performance relative to standard protocols and equipment. METHODS: Two-provider (emergency medical technicians (EMT)-B and EMT-I/C/P) teams were randomized to control or experimental group. Each team engaged in 3 simulations: baseline simulation (standard roles); repeat simulation (standard roles); and abbreviated repeat simulation (reversed roles, i.e., basic life support provider performing ALS tasks). Control teams used standard OHCA protocols and equipment (with high performance cardiopulmonary resuscitation training intervention); for second and third simulations, experimental teams performed chest compression, defibrillation, airway, pulmonary ventilation, vascular access, medication, and transport tasks with goal-directed protocol and resuscitation-automating devices. Videorecorders and simulator logs collected resuscitation data. RESULTS: Ten control and 10 experimental teams comprised 20 EMT-B's; 1 EMT-I, 8 EMT-C's, and 11 EMT-P's; study groups were not fully matched. Both groups suboptimally performed chest compressions and ventilations at baseline. For their second simulations, control teams performed similarly except for reduced on-scene time, and experimental teams improved their chest compressions (P=0.03), pulmonary ventilations (P<0.01), and medication administration (P=0.02); changes in their performance of chest compression, defibrillation, airway, and transport tasks did not attain significance against control teams' changes. Experimental teams maintained performance improvements during reversed-role simulations. CONCLUSION: Simulation-based investigation into OHCA resuscitation revealed considerable variability and improvable deficiencies in small EMS teams. Goal-directed, automation-assisted OHCA management augmented select resuscitation bundle element performance without comprehensive improvement. PMID- 27509065 TI - Psychosomatic Medicine in Germany: More Timely than Ever. PMID- 27509066 TI - A validated, sensitive HPLC-MS/MS method for quantification of cis-para-methyl-4 methylaminorex (cis-4,4'-DMAR) in rat and human plasma: application to pharmacokinetic studies in rats. AB - 4,4'-DMAR is an analogue of the known psychostimulants 4-methylaminorex and aminorex. In the light of reports of deaths associated with its abuse, and the easy access from Internet vendors, the EU Council recently decided on control measures across member states. Here we describe a validated method for measuring plasma levels of cis-4,4'-DMAR, crucial for preclinical studies and analysis in human plasma. Chromatographic separation was done by gradient elution on a Kinetex C18 column with 0.1% formic acid in water and 0.1% formic acid in acetonitrile at 0.2 mL/min. Detection was by positive electrospray ionization (ESI+) in multiple reaction monitoring mode monitoring the quantifier transitions m/z 191.4 -> m/z 148.3 for cis-4,4'-DMAR and m/z 259.3 -> m/z 194.2 for carbamazepine (internal standard). Protein precipitation with 1% of formic acid in acetonitrile was used in cis-4,4'-DMAR extraction from plasma; recovery was high (>93%) with a negligible matrix effect. This method provides an accurate, precise, and sensitive method for cis-4,4'-DMAR quantification in human and rat plasma, following European Medicine Agency guidelines for bioanalytical method validation. Pharmacokinetic studies were conducted in rats. After an intravenous dose of 1 mg/kg, plasma levels declined rapidly (>=80% in 4 h), followed by a slow elimination phase (t1/2 of 5.14 +/- 0.65 h). Absorption was rapid after intraperitoneal injection (tmax = 15 min) with a rapid decline thereafter; Cmax and AUC0-240min showed dose-proportionality over the dose range 1-10 mg/kg. This method was successfully applied to investigate pharmacokinetic properties in rats and could be used to quantify cis-4,4'-DMAR levels in human plasma. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27509063 TI - TIMP-1 is under regulation of the EGF signaling axis and promotes an aggressive phenotype in KRAS-mutated colorectal cancer cells: a potential novel approach to the treatment of metastatic colorectal cancer. AB - It is now widely accepted that therapeutic antibodies targeting epidermal growth factor receptor (EGFR) can have efficacy in KRAS wild-type advanced colorectal cancer (CRC) patients. What remains to be ascertained is whether a subgroup of KRAS-mutated CRC patients might not also derive benefit from EGFR inhibitors. Metalloproteinase inhibitor 1 (TIMP-1) is a pleiotropic factor predictive of survival outcome of CRC patients. Levels of TIMP-1 were measured in pre-treatment plasma samples (n = 426) of metastatic CRC patients randomized to Nordic FLOX (5 fluorouracil and oxaliplatin) +/- cetuximab (NORDIC VII study). Multivariate analysis demonstrated a significant interaction between plasma TIMP-1 protein levels, KRAS status and treatment with patients bearing KRAS mutated tumors and high TIMP-1 plasma level (> 3rd quartile) showing a significantly longer overall survival if treated with cetuximab (HR, 0.48; 95% CI, 0.25 to 0.93). To gain mechanistic insights into this association we analyzed a set of five different CRC cell lines. We show here that EGFR signaling induces TIMP-1 expression in CRC cells, and that TIMP-1 promotes a more aggressive behavior, specifically in KRAS mutated cells. The two sets of data, clinical and in vitro, are complementary and support each other, lending strength to our contention that TIMP- 1 plasma levels can identify a subset of patients with KRAS-mutated metastatic CRC that will have benefit from EGFR-inhibition therapy. PMID- 27509068 TI - Cellular Delivery of RNA Nanoparticles. AB - RNA nanostructures can be programmed to exhibit defined sizes, shapes and stoichiometries from naturally occurring or de novo designed RNA motifs. These constructs can be used as scaffolds to attach functional moieties, such as ligand binding motifs or gene expression regulators, for nanobiology applications. This review is focused on four areas of importance to RNA nanotechnology: the types of RNAs of particular interest for nanobiology, the assembly of RNA nanoconstructs, the challenges of cellular delivery of RNAs in vivo, and the delivery carriers that aid in the matter. The available strategies for the design of nucleic acid nanostructures, as well as for formulation of their carriers, make RNA nanotechnology an important tool in both basic research and applied biomedical science. PMID- 27509069 TI - Stereotactic Radiosurgery for Cystic Vestibular Schwannomas. AB - BACKGROUND: The optimum treatment for cystic vestibular schwannoma (VS) remains controversial. Anecdotally, many treating physicians feel that cystic VSs do not respond to stereotactic radiosurgery (SRS) as well as noncystic tumors. OBJECTIVE: To present outcomes after treatment of predominantly cystic VS with SRS. METHODS: A prospectively maintained clinical database of patients undergoing Gamma Knife (Elekta Instruments, Stockholm, Sweden) radiosurgery (GKRS) for VS at a single tertiary academic referral center was retrospectively reviewed. Patients diagnosed with cystic VS who were treated with GKRS between 1997 and 2014 were analyzed. Size-matched solid tumors treated with GKRS during this period were selected as controls. RESULTS: Twenty patients (12 women; median age at treatment, 56 years; range, 36-85 years) with cystic VS met inclusion criteria. The median radiologic follow-up within the cystic group was 63 months (range, 17 201 months), and the median change in tumor size was -4.9 mm (range, -10.4 to 9.3 mm). Sixteen tumors (80%) shrank, 2 (10%) remained stable, and 2 (10%) enlarged, accounting for a tumor control rate of 90%. The median radiologic follow-up in the noncystic control group was 67 months (range, 6-141 months), and the median change in size was -2.0 mm (range, -10.4 to 2.5 mm). Tumor control in the solid group was 90%. Comparing only those tumors that decreased in size showed that there was a trend toward a greater reduction within the cystic group ( P = .05). CONCLUSION: The present study demonstrates that tumor control after SRS for cystic VS may not differ from that of noncystic VS in selected cases. PMID- 27509067 TI - Mannose 6-Phosphate Receptor Is Reduced in -Synuclein Overexpressing Models of Parkinsons Disease. AB - Increasing evidence points to defects in autophagy as a common denominator in most neurodegenerative conditions. Progressive functional decline in the autophagy-lysosomal pathway (ALP) occurs with age, and the consequent impairment in protein processing capacity has been associated with a higher risk of neurodegeneration. Defects in cathepsin D (CD) processing and alpha-synuclein degradation causing its accumulation in lysosomes are particularly relevant for the development of Parkinson's disease (PD). However, the mechanism by which alterations in CD maturation and alpha-synuclein degradation leads to autophagy defects in PD neurons is still uncertain. Here we demonstrate that MPR300 shuttling between endosomes and the trans Golgi network is altered in alpha synuclein overexpressing neurons. Consequently, CD is not correctly trafficked to lysosomes and cannot be processed to generate its mature active form, leading to a reduced CD-mediated alpha-synuclein degradation and alpha-synuclein accumulation in neurons. MPR300 is downregulated in brain from alpha-synuclein overexpressing animal models and in PD patients with early diagnosis. These data indicate MPR300 as crucial player in the autophagy-lysosomal dysfunctions reported in PD and pinpoint MRP300 as a potential biomarker for PD. PMID- 27509070 TI - Defining Glioblastoma Resectability Through the Wisdom of the Crowd: A Proof-of Principle Study. AB - BACKGROUND: Extent of resection (EOR) correlates with glioblastoma outcomes. Resectability and EOR depend on anatomical, clinical, and surgeon factors. Resectability likely influences outcome in and of itself, but an accurate measurement of resectability remains elusive. An understanding of resectability and the factors that influence it may provide a means to control a confounder in clinical trials and provide reference for decision making. OBJECTIVE: To provide proof of concept of the use of the collective wisdom of experienced brain tumor surgeons in assessing glioblastoma resectability. METHODS: We surveyed 13 academic tumor neurosurgeons nationwide to assess the resectability of newly diagnosed glioblastoma. Participants reviewed 20 cases, including digital imaging and communications in medicine-formatted pre- and postoperative magnetic resonance images and clinical vignettes. The selected cases involved a variety of anatomical locations and a range of EOR. Participants were asked about surgical goal, eg, gross total resection, subtotal resection (STR), or biopsy, and rationale for their decision. We calculated a "resectability index" for each lesion by pooling responses from all 13 surgeons. RESULTS: Neurosurgeons' individual surgical goals varied significantly ( P = .015), but the resectability index calculated from the surgeons' pooled responses was strongly correlated with the percentage of contrast-enhancing residual tumor ( R = 0.817, P < .001). The collective STR goal predicted intraoperative decision of intentional STR documented on operative notes ( P < .01) and nonresectable residual ( P < .01), but not resectable residual. CONCLUSION: In this pilot study, we demonstrate the feasibility of measuring the resectability of glioblastoma through crowdsourcing. This tool could be used to quantify resectability, a potential confounder in neuro-oncology clinical trials. PMID- 27509071 TI - Surgical Management of Carney Complex-Associated Pituitary Pathology. AB - BACKGROUND: Carney complex (CNC) is a familial neoplasia syndrome that is associated with pituitary-associated hypersecretion of growth hormone (GH) (acromegaly). The underlying cause of pituitary GH hypersecretion and its management have been incompletely defined. OBJECTIVE: To provide biological insight into CNC-associated pituitary pathology and improve management, we analyzed findings in CNC patients who underwent transsphenoidal surgery. METHODS: Consecutive CNC patients at the National Institutes of Health with acromegaly and imaging evidence of a pituitary adenoma(s) who underwent transsphenoidal resection of tumor(s) were included. Prospectively acquired magnetic resonance imaging and biochemical, surgical, and histological data were analyzed. RESULTS: Seven acromegalic CNC patients (2 male, 5 female) were included. The mean age at surgery was 29.7 years (range, 18-44 years). The mean follow-up was 4.7 years (range, 0.2-129 months). Magnetic resonance imaging revealed a single pituitary adenoma in 4 patients and multiple pituitary adenomas in 3 patients. Whereas patients with single discrete pituitary adenomas underwent selective adenomectomy, patients with multiple adenomas underwent selective adenomectomy of multiple tumors, as well as partial or total hypophysectomy. All adenomas were either GH and prolactin positive or exclusively prolactin positive. Pituitary tissue surrounding the adenomas in patients with multiple adenomas revealed hyperplastic GH- and prolactin-positive tissue. CONCLUSION: CNC-associated acromegaly results from variable pituitary pathology, including a single GH secreting adenoma or multiple GH-secreting adenomas and/or GH hypersecretion of the pituitary gland surrounding multiple adenomas. Although selective adenomectomy is the preferred treatment for cases of GH-secreting adenomas, multiple adenomas with associated pituitary gland GH hypersecretion may require partial or complete hypophysectomy to achieve biochemical remission. PMID- 27509072 TI - Iodinated X-ray contrast agents: Photoinduced transformation and monitoring in surface water. AB - Conventional wastewater treatment methods have shown to be unsuitable for a complete elimination of iodinated X-ray contrast agents (ICMs), which have thus been found in wastewater treatment plant (WWTP) effluent and in surface water. Once in the surface water, they could be transformed through different processes and form several transformation products that may need to be monitored as well. To this end, we studied the abatement and transformation of ICMs by combining laboratory experiments with in field analyses. We irradiated different aqueous solutions of the selected pollutants in the presence of TiO2 as photocatalyst, aimed to promote ICMs degradation and to generate photoinduced transformation products (TPs) similar to those occurring in the environment and effluent wastewater. This experimental strategy has been applied to the study of three ICMs, namely iopromide, iopamidol and diatrizoate. A total of twenty-four, ten, and ten TPs were detected from iopamidol, diatrizoate and iopromide, respectively. The analyses were performed using a liquid chromatography-LTQ-FT Orbitrap mass spectrometer. The mineralization process and acute toxicity evolution were assessed as well over time and revealed a lack of mineralization for all ICMs and the formation of harmful byproducts. After characterizing these transformation products, WWTP effluent and surface water taken from several branches of the Chicago River were analyzed for ICMs and their TPs. HRMS with MS/MS fragmentation was used as a confirmatory step for proper identification of compounds in water and wastewater samples. All three of ICM were detected in the effluent and surface water samples, while no significant amount of TPs were detected. PMID- 27509073 TI - POPs in the South Latin America: Bioaccumulation of DDT, PCB, HCB, HCH and Mirex in blubber of common dolphin (Delphinus delphis) and Fraser's dolphin (Lagenodelphis hosei) from Argentina. AB - Organic compounds, in particular organochlorines, are highly persistent compounds which accumulate in biotic and abiotic substrates. Marine mammals bioaccumulate and biomagnify persistent organic pollutants (POPs) through diet. ?PCB (26 PCB congeners), ?DDT (pp-DDT, pp-DDD, pp-DDE), ?HCH (alpha-HCH, beta-HCH, gamma-HCH, delta-HCH), HCB and mirex were analyzed from samples of subcutaneous adipose tissue of common dolphins, Delphinus delphis, and Fraser's dolphins, Lagenodelphis hosei, obtained in 1999 and 2012. The aim of this study was to determine the concentrations of POPs to get baseline information on the current state of pollution by these compounds in these two species in South Atlantic. At the same time, to assess concentrations of POPs in relation to age, the total length and sexual maturity in common dolphins. Organochlorine pesticides dominated Fraser's dolphins, DDT being the most abundant, while PCBs were mostly present in common dolphins. In both species, the distributions of isomers or metabolites followed the order: beta-HCH>delta-HCH>gamma-HCH>alpha-HCH and pp DDE>pp-DDD>pp-DDT. As for ?PCB, the largest contribution was given by congeners of high molecular weight, particularly by hexa and hepta - CBs. Common dolphins did not show effects on sexual maturity, age and standard length in the concentration of organochlorines. The mean concentrations found in this study are lower compared to those reported in other studies performed in dolphins elsewhere. This study provides new information regarding levels of organochlorines in common dolphins for the Southwestern Atlantic. PMID- 27509074 TI - Reduction of Cr (VI) into Cr (III) by organelles of Chlorella vulgaris in aqueous solution: An organelle-level attempt. AB - The priority pollutant chromium (Cr) was ubiquitous and great efforts have been made to reduce Cr (VI) into less-toxic Cr (III) by alga for the convenient availability and low expense. However, the functional role of organelle inside the algal cell in Cr (VI) reduction was poorly understood. In this study, organelles in green algae Chlorella vulgaris were extracted and further decorated for Cr (VI) reduction tests. Results showed that the chloroplast exhibited not only adsorption ability of total Cr (21.18% comparing to control) but also reduction potential of Cr (VI) (almost 70% comparing to control), whose most suitable working concentration was at 17MUg/mL. Furtherly, the isolated thylakoid membrane (ITM) showed better Cr (VI) reduction potential with the presence of sodium alginate (SA), even though the Hill reaction activity (HRA) was inhibited. As for photosystem II (PSII), the addition of mesoporous silica SBA-15 enhanced the reduction ability through improving the light-harvesting complex (LHC) II efficiency and electron transport rate. On the whole, the reduction ability order of the three kinds of materials based on chloroplast in C. vulgaris was PSII@SBA 15>Chloroplast>ITM@SA. The attempt made in this study to reduce the Cr (VI) with C. vulgaris organelles might not only offer basement to detect the potential action mechanism of Cr (VI) reduction by C. vulgaris but also provide a new sight for the scavenge of heavy metal with biological materials. PMID- 27509075 TI - Quantitative relationships between the adsorptivity of carbonaceous materials in soil for Pb(II) and soil organic matter content. AB - Strong adsorptivity of manufactured carbonaceous materials (MCMs) mediates the behavior of heavy metals in soil. Laboratory-reported adsorptivity of MCMs often deviates from their actual abilities in soil, because soil organic matter (SOM) can change the adsorptive abilities of MCMs by coating dissolved organic matter (DOM) on the surface of the MCMs. It was considered that the influence of SOM on the adsorptivity of MCMs in soil follows a sequential pathway of SOM releasing DOM in soil solution and subsequent DOM binding onto MCMs, thereby altering MCM surface acidity and hence changing MCM adsorptivity for heavy metals. In this study, we first extracted DOM from ten topsoils collected over a broad region of China with a wide range of SOM. The DOM solutions were then used to load DOM onto four MCMs including activated carbon (AC), multiwalled carbon nanotube (MWCNT), and two biochars (BC400 and BC700), respectively, obtaining a total of 44 MCM-DOM complex samples with known amounts of bound DOM. These MCM-DOM complex samples were then determined for their surface acidities and adsorptive abilities for Pb(II). We found that there were significant correlations between DOM concentration and SOM content, between DOM binding onto MCMs and DOM concentration, between surface acidity of MCM-DOM complexes and DOM binding onto MCMs, as well as between Pb(II) adsorption on MCM-DOM complexes and surface acidity of MCM-DOM complexes. With understanding of these individual linear correlations, linear relationships between the Pb(II) adsorption and SOM content were established by combining individual correlations and by directly plotting the former against the latter. These relationships may be used to accurately predict the adsorptive abilities of MCMs for heavy metals in soils via simply determining SOM. PMID- 27509076 TI - On the origin of the highest ozone episodes in Spain. AB - The 2000-2015 occurrences of the highest ozone (O3) pollution episodes in Spain were evaluated to investigate their origin. To this end, data series available for urban and regional background (UB and RB), traffic (TR) and industrial (IN) sites were analysed separately and intercompared. Results evidenced that during these 16years mean O3 levels in the RB sites did not change significantly, and remained constantly high. However, there is a clear increase at the TR and UB sites. Although sensitivity analysis is needed to interpret the cause of this increasing trend, this might be caused probably by the lower O3 titration intensity due to the preferential abatement of NO vs NO2, as supported from the neutral trend of OX (NO2+O3) at these sites. We found that the exceedances of the hourly information threshold for O3 (>180MUg/m3) are recorded mostly at UB and IN sites located in seven areas of Spain (specific hotspots or at the tail end of large urban plumes), and that these increased during summer heatwaves (i.e. 2003 and 2015). Although the external contribution of regional-to-subcontinental transported O3 might be relevant during the highest O3 episodes in the Western Mediterranean, our results evidenced that in the above specific areas, regional local O3 production decisively contributes to the exceedances of the information threshold. Also that the human protection threshold and the AOT40 are more frequently exceeded in the Central, Southern and Mediterranean sides of the Iberian Peninsula. The design of effective episode abatement measures is quite complex in those conditions, due to both the nonlinearity of the chemical processes of O3 formation and destruction, and to the interplay with the complex meteorological setting, causing frequent recirculation and in situ aging of air masses. However, the combination of meteorological forecasting of the main recirculation processes and sensitivity analysis of NOX/VOC emission abatement measures might be powerful tools to evaluate the effectiveness of potential O3 mitigation strategies. Finally we would like to highlight that the current UB, RB, IN and TR classification (somewhat subjective) is not adequate to interpret the origin of O3 exceedances in complex areas of Southern Europe. Thus, a UB station recording exceedances, and located in a small city in the tail end of an urban plume of a large city, receives not only the contribution from its own UB, but mainly from the specific high O3 RB caused by the urban plume transport. PMID- 27509079 TI - Acne during adolescence did not predict skin rash reaction to cetuximab. AB - Cetuximab, a monoclonal antibody, is a part of the treatment for metastatic colorectal cancer. The most common side effect of cetuximab is skin rash, which has a similar distribution to acne vulgaris and some overlapping pathophysiological mechanisms. The aim of the current study was to determine whether acne vulgaris in adolescence (AinA) is predictive of a cetuximab-related rash to better understand the pathogenesis of this side effect and explore potential preventive actions. From July 2013 to June 2015, patients with metastatic colorectal cancer planned for treatment with cetuximab were enrolled in the study. Before initiating treatment, patients completed a questionnaire evaluating endocrine disorders, other chronic diseases, smoking, chronic medications, allergies, and dermatologic history of AinA and its severity. Patients were followed for 6 months. Data were collected from 32 participants (16 women, 16 men). Twenty-three (69%) patients experienced a cetuximab-associated skin reaction. Nine (28%) patients had a history of AinA. Of these, seven developed a cetuximab-associated skin reaction. Three of the five (60%) patients who used proton pump inhibitors (PPIs) developed severe (grades 3-4) skin toxicity versus 4/27 (15%) patients who were not on PPIs (P=0.057). The degree of skin toxicity correlated to the median time-to-tumor-progression: 2 months for patients with grades 0-1 compared with 5.5 months for grades 2-4 skin toxicity (P=0.047, 95% confidence interval 1.06-4.95). No significant correlation was found between AinA and cetuximab-associated skin reactions. The correlation between PPI treatment and severe skin toxicity related to cetuximab should be examined further. PMID- 27509077 TI - Economic Analysis of the Impact of Overseas and Domestic Treatment and Screening Options for Intestinal Helminth Infection among US-Bound Refugees from Asia. AB - BACKGROUND: Many U.S.-bound refugees travel from countries where intestinal parasites (hookworm, Trichuris trichuria, Ascaris lumbricoides, and Strongyloides stercoralis) are endemic. These infections are rare in the United States and may be underdiagnosed or misdiagnosed, leading to potentially serious consequences. This evaluation examined the costs and benefits of combinations of overseas presumptive treatment of parasitic diseases vs. domestic screening/treating vs. no program. METHODS: An economic decision tree model terminating in Markov processes was developed to estimate the cost and health impacts of four interventions on an annual cohort of 27,700 U.S.-bound Asian refugees: 1) "No Program," 2) U.S. "Domestic Screening and Treatment," 3) "Overseas Albendazole and Ivermectin" presumptive treatment, and 4) "Overseas Albendazole and Domestic Screening for Strongyloides". Markov transition state models were used to estimate long-term effects of parasitic infections. Health outcome measures (four parasites) included outpatient cases, hospitalizations, deaths, life years, and quality-adjusted life years (QALYs). RESULTS: The "No Program" option is the least expensive ($165,923 per cohort) and least effective option (145 outpatient cases, 4.0 hospitalizations, and 0.67 deaths discounted over a 60-year period for a one-year cohort). The "Overseas Albendazole and Ivermectin" option ($418,824) is less expensive than "Domestic Screening and Treatment" ($3,832,572) or "Overseas Albendazole and Domestic Screening for Strongyloides" ($2,182,483). According to the model outcomes, the most effective treatment option is "Overseas Albendazole and Ivermectin," which reduces outpatient cases, deaths and hospitalization by around 80% at an estimated net cost of $458,718 per death averted, or $2,219/$24,036 per QALY/life year gained relative to "No Program". DISCUSSION: Overseas presumptive treatment for U.S.-bound refugees is a cost effective intervention that is less expensive and at least as effective as domestic screening and treatment programs. The addition of ivermectin to albendazole reduces the prevalence of chronic strongyloidiasis and the probability of rare, but potentially fatal, disseminated strongyloidiasis. PMID- 27509078 TI - Neutrophils Directly Recognize Group B Streptococci and Contribute to Interleukin 1beta Production during Infection. AB - Previous studies have shown that the pro-inflammatory cytokine IL-1beta has a crucial role in host defenses against group B streptococcus (GBS), a frequent human pathogen, by recruiting neutrophils to infection sites. We examined here the cell types and mechanisms involved in IL-1beta production during infection. Using a GBS-induced peritonitis model in mice, we first found that a large proportion of exudate cells contain intracellular IL-1beta by immunofluorescence. Of the IL-1beta positive cells, 82 and 7% were neutrophils and macrophages, respectively, suggesting that the former cell type might significantly contribute to IL-1beta production. Accordingly, depletion of neutrophils with anti-Ly6G antibodies resulted in a significant reduction in the levels of IL-1beta, but not of TNF-alpha or IL-6. We next found that neutrophils are capable of releasing mature IL-1beta and TNF-alpha directly in response to in vitro stimulation with GBS. The production of pro-IL-1beta and TNF-alpha in these cells required the Toll-like receptor (TLR) adaptor MyD88 and the chaperone protein UNC93B1, which is involved in mobilization of a subfamily of TLRs to the endosomes. Moreover, pro-IL-1beta processing and IL-1beta release was triggered by GBS hemolysin and required components of the canonical inflammasome, including caspase-1, ASC and NLRP3. Collectively our findings indicate that neutrophils make a significant contribution to IL-1beta production during GBS infection, thereby amplifying their own recruitment. These cells directly recognize GBS by means of endosomal TLRs and cytosolic sensors, leading to activation of the caspase-1 inflammasome. PMID- 27509080 TI - Incorporating peer-to-peer facilitation with a mid-level fidelity student led simulation experience for undergraduate nurses. AB - BACKGROUND: The aim of this study was to evaluate peer-to-peer facilitated student led mid-level fidelity simulation experiences. METHODS: Second and third year nursing students (N = 637) were invited to complete a 16-item 6-point Likert scale questionnaire after the simulation experience. RESULTS: Students reported high self-confidence in their nursing skills (M = 4.14, SD = 0.92) and a high level of satisfaction in the learning they received during the peer-to-peer facilitated student led simulation experience (M = 4.42, SD = 0.93). CONCLUSION: Using peer-to-peer teaching strategies during student led simulation experience is an effective approach for ensuring active engagement of all learners during midlevel fidelity group-based simulations and has the potential for broad applicability. PMID- 27509082 TI - Receipt of vaginal brachytherapy is associated with improved survival in women with stage I endometrioid adenocarcinoma of the uterus: A National Cancer Data Base study. AB - BACKGROUND: Randomized controlled trials have consistently shown that the use of postoperative radiotherapy (RT) for stage I endometrial cancer leads to a reduction in the incidence of pelvic recurrences without a corresponding reduction in overall mortality. It was hypothesized that a reduction in mortality associated with the receipt of RT could be identified in a large data set with greater statistical power. METHODS: Women with surgically staged IA or IB endometrial adenocarcinoma who were treated with total hysterectomy between 2003 and 2011 were identified in the National Cancer Data Base. Chi-square tests and multivariate logistic regression were performed to analyze factors associated with the treatment type. A survival analysis was performed with log-rank testing, Cox proportional hazards regression, and Kaplan-Meier estimates. RESULTS: A total of 44,309 eligible women were identified (33,380 at stage IA and 10,929 at stage IB): 88.4% of the women with stage IA tumors and 51.6% of the women with stage IB tumors received no RT. Older age, comorbid disease, a higher histologic grade, and a larger tumor size were independently associated with an increase in mortality. The receipt of vaginal brachytherapy (VB) was independently associated with a reduction in mortality for both stage IA disease (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.67-0.97) and stage IB disease (HR, 0.62; 95% CI, 0.51-0.74). CONCLUSIONS: Analyses of this large database support the utility of postoperative VB for many women with stage I endometrial cancer. Unfortunately, RT appears to be underused in this population. Greater adherence to consensus guidelines may lead to improved outcomes. Cancer 2016;122:3724-31. (c) 2016 American Cancer Society. PMID- 27509083 TI - Influenza Vaccination Coverage Rates, Knowledge, Attitudes, and Beliefs in Jordan: A Comprehensive Study. AB - Influenza vaccination is the most effective method in preventing influenza and its complications. This study's objectives were to investigate the vaccination coverage and frequency and to assess knowledge, attitudes, and practices toward influenza vaccination in Jordan during the year 2012 and the 5 years preceding it. Additionally, it aimed at identifying the barriers and motivations to receive the vaccine and the factors contributing to its uptake. In May 2012, a self administered cross-sectional survey was distributed to 3,200 adults conveniently selected across Jordan to explore influenza vaccination status, knowledge, attitudes, and practices toward the influenza vaccine. The survey response rate was 98.3%. The overall coverage rate of seasonal influenza vaccination ranged from 9.9% to 27.5%. Results of the univariate analysis revealed that males, participants older than 45 years, business owners, and university students or graduates were more likely to take the vaccine. Healthcare workers (HCW) showed higher rates than non-HCW and those with concomitant chronic diseases were more committed to receive the vaccine. Knowledge about the influenza vaccine is considered high in the Jordanian population. Fear from side effects was the major barrier, while the fear of the virus spread and outbreak was the major reason to receive the vaccine. The coverage rates were low in Jordan compared to other countries. The need for influenza vaccine campaigns and on-going education in Jordan health schools is crucial to increase the rate and remove misconceptions and negative attitudes toward vaccination. PMID- 27509084 TI - A Two-Dimensional Inorganic-Organic Hybrid Solid of Manganese(II) Hydrogenophosphate Showing High Proton Conductivity at Room Temperature. AB - The inorganic-organic hybrid metal hydrogenophosphate with a formula of (C2H10N2)[Mn2(HPO4)3](H2O) (1) shows layered crystal structure. The inorganic anion layer is built from Mn3O13 cluster units, and the interlayer spaces are filled by the charge-compensated ethylenediammonium dications together with the lattice water molecules. The thermogravimetry, variable-temperature powder X-ray diffraction, and the proton conductance under anhydrous and moisture environments were investigated for 1, disclosing that 1 shows high thermal stability and high proton transport nature, and the proton conductivity reaches to 1.64 * 10(-3) S.cm(-1) under 99%RH even at 293 K. The high proton conductivity is related to the formation of denser H-bond networks in the lattice. PMID- 27509085 TI - Changing the chemical and physical properties of high valent heterobimetallic bis (MU-oxido) Cu-Ni complexes by ligand effects. AB - Two new heterobimetallic [LNiO2Cu(RPY2)]+ (RPY2 = N-substituted bis 2 pyridyl(ethylamine) ligands with R = indane, 3a or R = Me, 3b) complexes have been spectroscopically trapped at low temperatures. They were prepared by reacting the mononuclear side-on LNiII superoxo precursor bearing a beta diketiminate ligand (L = [HC-(CMeNC6H3(iPr)2)2]) with the Cu(i) complexes. In contrast to the oxo groups in known high-valent [M2(MU-O)2]n+ (M = Fe, Co, Ni, Cu) cores that display electrophilic reactivities, 3a and 3b display rather nucleophilic oxo cores active in aldehyde deformylation reactions. However, the spectroscopic and reactivity properties of 3a/3b are found to be distinct relative to that of the previously reported [LNiO2Cu(MeAN)]+ complex containing a more basic (nucleophilic) N,N,N',N',N'-pentamethyl-dipropylenetriamine (MeAN) ligand at the copper centre. The geometry and electronic properties of the copper ligands affect the electron density of the oxygen atoms of the heterodinuclear {Ni(MU-O)2} core and 3a/3b undergo slower nucleophilic and faster electrophilic reactions than the previously reported [LNiO2Cu(MeAN)]+ intermediate. The present study therefore demonstrates the tuning of the electrophilicity/nucleophilicity of the oxygen atoms of the heterobimetallic [Ni(MU-O)2Cu]2+ cores by controlling the electron donation from the ancillary ligands, and underlines the significance of subtle electronic changes in the physical and chemical properties of the biologically relevant heterobimetallic metal-dioxygen intermediates. PMID- 27509086 TI - Paired-Pulse TMS and Fine-Wire Recordings Reveal Short-Interval Intracortical Inhibition and Facilitation of Deep Multifidus Muscle Fascicles. AB - OBJECTIVE: Paired-pulse transcranial magnetic stimulation (ppTMS) is used to probe inhibitory and excitatory networks within the primary motor cortex (M1). These mechanisms are identified for limb muscles but it is unclear whether they share properties with trunk muscles. The aim was to determine whether it was possible to test the intracortical inhibition and facilitation of the deep multifidus muscle fascicles (DM) and at which inter-stimulus intervals (ISI). METHODS: In ten pain-free individuals, TMS was applied over M1 and motor evoked potentials (MEP) were recorded using fine-wire electrodes in DM. MEPs were conditioned with subthreshold stimuli at ISIs of 1 to 12 ms to test short interval intracortical inhibition (SICI) and at 15 ms for long-interval intracortical facilitation. Short-interval facilitation (SICF) was tested using 1 ms ISI. RESULTS: SICI of DM was consistently obtained with ISI of 1-, 3-, 4- and 12-ms. Facilitation of DM MEP was only identified using SICF paradigm. CONCLUSIONS: A similar pattern of MEP modulation with ISI changes for deep trunk and limb muscles implies that M1 networks share some functional properties. SIGNIFICANCE: The ppTMS paradigm presents a potential to determine how M1 inhibitory and excitatory mechanisms participate in brain re-organization in back pain that affects control of trunk muscles. PMID- 27509087 TI - Quality of the Exotic Parasitoid Cotesia flavipes (Hymenoptera: Braconidae) Does Not Show Deleterious Effects after Inbreeding for 10 Generations. AB - Although the parasitoid Cotesia flavipes (Cameron) has proven effective in controlling sugarcane borer Diatraea saccharalis (Fabricius) for many years, concern has arisen over the quality of individuals produced at large scales. The parasitoid has been reared in laboratories in Brazil for more than 40 years, with no new introductions of new populations during that period. Since the quality of the parasitoids was not verified at the time of the species' introduction in Brazil, we do not know if there has been any reduction in quality so far. However, it is possible to determine whether the parasitoid could reduce in quality in future generations. Thus, the objective of this research was to assess the quality of these insects over 10 generations and look for evidence of any loss in quality. We used two populations: one from a biofactory that has been maintained in the laboratory for over 40 years, and an inbred laboratory population. Both were bred, and compared for 10 generations. We wanted to determine what happened to the quality of the parasitoid after 10 generations in an extreme inbreeding situation. To assure inbreeding, newly emerged females were forced to mate with a sibling. Individual females were then allowed to parasitize larvae of D. saccharalis. We performed evaluations for each generation until the tenth generation, and recorded the sex ratio, percentage emergence, number of offspring/females, and longevity of both males and females. Results of the measurements of biological characteristics demonstrated random significant differences between populations; best results were obtained intermittently for both the biofactory population and the inbred population. No significant differences across generations for the same population were observed. Thus, rearing of a C. flavipes population subjected to inbreeding for 10 generations was not sufficient to reveal any deleterious effects of inbreeding. PMID- 27509089 TI - Asymmetric Hydrogenation of Unprotected Indoles Catalyzed by eta(6)-Arene/N-Me sulfonyldiamine-Ru(II) Complexes. AB - Protecting-group-free transformation is a challenging and important issue in atom economical organic synthesis. The eta(6)-arene/N-Me-sulfonyldiamine-Ru(II)-BF4 complex-catalyzed asymmetric hydrogenation of 2-substituted unprotected indoles in weakly acidic hexafluoroisopropanol gives optically active indoline compounds with up to >99% ee. Under mild reaction media, halogen atoms and synthetically important protecting groups (e.g., silyl ether, acetal, benzyl ether, and ester) on indoles are maintained, which is advantageous for the synthesis of further complex indoline molecules. PMID- 27509088 TI - Managing Climate Change Refugia for Climate Adaptation. AB - Refugia have long been studied from paleontological and biogeographical perspectives to understand how populations persisted during past periods of unfavorable climate. Recently, researchers have applied the idea to contemporary landscapes to identify climate change refugia, here defined as areas relatively buffered from contemporary climate change over time that enable persistence of valued physical, ecological, and socio-cultural resources. We differentiate historical and contemporary views, and characterize physical and ecological processes that create and maintain climate change refugia. We then delineate how refugia can fit into existing decision support frameworks for climate adaptation and describe seven steps for managing them. Finally, we identify challenges and opportunities for operationalizing the concept of climate change refugia. Managing climate change refugia can be an important option for conservation in the face of ongoing climate change. PMID- 27509091 TI - Rigorous 3-dimensional spectral data activity relationship approach modeling strategy for ToxCast estrogen receptor data classification, validation, and feature extraction. AB - The estrogenic potential (expressed as a score composite of 18 high throughput screening bioassays) of 1528 compounds from the ToxCast database was modeled by a 3-dimensional spectral data activity relationship approach (3D-SDAR). Due to a lack of 17 O nuclear magnetic resonance (NMR) simulation software, the most informative carbon-carbon 3D-SDAR fingerprints were augmented with indicator variables representing oxygen atoms from carbonyl and carboxamide, ester, sulfonyl, nitro, aliphatic hydroxyl, and phenolic hydroxyl groups. To evaluate the true predictive performance of the authors' model the United States Environmental Protection Agency provided them with a blind test set consisting of 2008 compounds. Of these, 543 had available literature data-their binding affinity served to estimate the external classification accuracy of the developed model: predictive accuracy of 0.62, sensitivity of 0.71, and specificity of 0.53 were obtained. Compared with alternative modeling techniques, the authors' model displayed very little reduction in performance between the modeling and the prediction set. A 3D-SDAR mapping technique allowed identification of structural features essential for estrogenicity: 1) the presence of a phenolic OH group or cyclohexenone, 2) a second aromatic or phenolic ring at a distance of 6 A to 8 A from the oxygen of the first phenol ring, 3) the presence of a methyl group approximately 6 A away from the centroid of a phenol ring, and 4) a carbonyl group in close proximity (~4 A measured to the centroid) to 1 of the phenol rings. Environ Toxicol Chem 2017;36:823-830. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 27509090 TI - Dipeptidyl peptidase- IV inhibitor alogliptin improves stress-induced insulin resistance and prothrombotic state in a murine model. AB - BACKGROUND: Stress evokes lipolytic release of free fatty acid (FFA) and low grade inflammation in visceral adipose tissue, mediated by increased adipokine secretion, and contributes to glucose metabolism disorder and prothrombotic state. We tested the hypothesis that alogliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate the biological effects of chronic stress in mice. METHOD AND RESULTS: C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle or alogliptin (dose: 15 or 45mg/kg/day). Plasma levels of lipids, proinflammatory cytokines (monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and interleukin-6), and 8 hydroxydeoxyguanosine were measured with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was examined by CD11b-positive cell count and mRNA expression of CD68 and F4/80 was examined by immunohistochemistry and RT-PCR, respectively. The mRNA levels of the above-mentioned proinflammatory cytokines, NADPH oxidase 4, adiponectin, and coagulation factors (plasminogen activation inhibitor-1 and tissue factor) in WAT were also assessed with RT-PCR. Glucose metabolism was assessed by glucose and insulin tolerance tests, plasma levels of DPP-4 activity, glucagon-like peptide 1, expression of DPP-4, insulin receptor substrate-1 and glucose transporter 4 in WAT and skeletal muscle. Alogliptin administration suppressed stress-induced FFA release, oxidative stress, adipose tissue inflammation, DPP-4 activation, and prothrombotic state in a dose-dependent manner, and improved insulin sensitivity in stressed mice. CONCLUSIONS: The results indicate that alogliptin improves stress-induced prothrombotic state and insulin resistance; suggesting that alogliptin could have beneficial therapeutic effects against cardiovascular complications in diabetic patients under stress. PMID- 27509092 TI - Syntax Score and Major Adverse Cardiac Events in Patients with Suspected Coronary Artery Disease: Results from a Cohort Study in a University-Affiliated Hospital in Southern Brazil. AB - Background:: The importance of coronary anatomy in predicting cardiovascular events is well known. The use of traditional anatomical scores in routine angiography, however, has not been incorporated to clinical practice. SYNTAX score (SXscore) is a scoring system that estimates the anatomical extent of coronary artery disease (CAD). Its ability to predict outcomes based on a baseline diagnostic angiography has not been tested to date. Objective:: To evaluate the performance of the SXscore in predicting major adverse cardiac events (MACE) in patients referred for diagnostic angiography. Methods:: Prospective cohort of 895 patients with suspected CAD referred for elective diagnostic coronary angiography from 2008 to 2011, at a university-affiliated hospital in Brazil. They had their SXscores calculated and were stratified in three categories: no significant CAD (n = 495), SXscoreLOW-INTERMEDIATE: < 23 (n = 346), and SXscoreHIGH: >= 23 (n = 54). Primary outcome was a composite of cardiac death, myocardial infarction, and late revascularization. Secondary endpoints were the components of MACE and death from any cause. Results:: On average, patients were followed up for 1.8 +/- 1.4 years. The primary outcome occurred in 2.2%, 15.3%, and 20.4% in groups with no significant CAD, SXscoreLOW INTERMEDIATE, and SXscoreHIGH, respectively (p < 0.001). All-cause death was significantly higher in the SXscoreHIGH compared with the 'no significant CAD' group, 16.7% and 3.8% (p < 0.001), respectively. After adjustment for confounding factors, all outcomes remained associated with the SXscore. Conclusions:: SXscore independently predicts MACE in patients submitted to diagnostic coronary angiography. Its routine use in this setting could identify patients with worse prognosis. Fundamento:: A importancia da anatomia coronariana na predicao de eventos cardiovasculares e bem conhecida. O uso de escores anatomicos tradicionais na cineangiocoronariografia de rotina, entretanto, nao foi incorporado a pratica clinica. O SYNTAX escore (SXescore) e um sistema de escore que estima a extensao anatomica da doenca arterial coronariana (DAC). Sua capacidade para predizer desfechos com base na cineangiocoronariografia diagnostica de base ainda nao foi testada. Objetivo:: Avaliar o desempenho do SXescore para predizer eventos cardiacos adversos maiores (MACE) em pacientes encaminhados para cineangiocoronariografia diagnostica. Metodos:: Coorte prospectiva de 895 pacientes com suspeita de DAC encaminhados para cineangiocoronariografia diagnostica eletiva de 2008 a 2011, em hospital universitario no Brasil. Os pacientes tiveram seus SXescores calculados e foram estratificados em tres categorias: 'sem DAC significativa' (n = 495); SXescoreBAIXO-INTERMEDIARIO: < 23 (n = 346); e SXescoreALTO: >= 23 (n = 54). O desfecho primario foi composto de morte cardiaca, infarto do miocardio e revascularizacao tardia. Os desfechos secundarios foram MACE e morte por todas as causas. Resultados:: Em media, os pacientes foram acompanhados por 1,8 +/- 1,4 anos. Desfecho primario ocorreu em 2,2%, 15,3% e 20,4% nos grupos 'sem DAC significativa', SXescoreBAIXO-INTERMEDIARIO e SXescoreALTO, respectivamente (p < 0,001). Morte por todas as causas foi significativamente mais frequente no grupo de SXescoreALTO comparado ao grupo 'sem DAC significativa', 16,7% e 3,8% (p < 0,001), respectivamente. Apos ajuste para fatores de confusao, todos os desfechos permaneceram associados com o SXescore. Conclusao:: O SXescore prediz independentemente MACE em pacientes submetidos a cineangiocoronariografia diagnostica. Seu uso rotineiro nesse contexto poderia identificar pacientes de pior prognostico. PMID- 27509093 TI - Relationship Between Neck Circumference and Epicardial Fat Thickness in a Healthy Male Population. AB - Background:: Epicardial fat is an upper body visceral fat depot that may play a significant role in the development of adverse metabolic and cardiovascular risk profiles. There is a significant direct relationship between the amount of epicardial fat and general body adiposity (body mass index, BMI), but data regarding subcutaneous adiposity is limited. Objective:: We conducted a study to determine the association between neck circumference and epicardial fat thickness in healthy young male individuals, and assess their individual correlations with general body adiposity and cardiometabolic risk factors. Methods:: One hundred consecutive male patients aged 18 years or older with no known major medical conditions were included in the study. All participants underwent detailed physical examination including measurement of blood pressure, weight, height, waist/hip ratio, and neck circumference. Blood was collected to determine fasting glucose and lipid parameters. A standard echocardiographic examination was performed with additional epicardial fat thickness determination. Results:: Among 100 study participants, neck circumference correlated significantly with weight, waist circumference, BMI, blood glucose, serum total cholesterol, low-density (LDL)-cholesterol, and triglycerides levels. No significant correlation was found between neck circumference and high-density lipoprotein (HDL)-cholesterol levels. Neck circumference correlated moderately and positively with echocardiographic epicardial fat thickness. Conclusion:: Among patients with low cardiometabolic risk, increased neck circumference was associated with increased epicardial fat thickness. Fundamentos:: A gordura epicardica e um deposito de gordura visceral na parte superior do organismo que pode desempenhar um papel importante no desenvolvimento de perfis cardiovasculares e metabolicos adversos. Ha uma relacao direta significativa entre a quantidade de gordura epicardica e a adiposidade corporal geral (indice de massa corporal, IMC), mas dados sobre a adiposidade subcutanea sao limitados. Objetivos:: Realizamos um estudo para determinar a associacao entre a circunferencia do pescoco e a espessura da gordura epicardica em jovens saudaveis do sexo masculino, alem de avaliar as suas correlacoes individuais com a adiposidade corporal geral e fatores de risco cardiometabolicos. Metodos:: Cem pacientes consecutivos do sexo masculino com idade igual ou superior a 18 anos e sem nenhuma condicao medica importante e conhecida foram incluidos no estudo. Todos os participantes foram submetidos a um exame fisico detalhado que incluiu medida da pressao arterial, peso, altura, razao cintura/quadril e circunferencia do pescoco. Sangue foi coletado para determinacao da glicemia de jejum e parametros lipidicos. Um exame ecocardiografico padrao foi realizado com determinacao adicional da espessura da gordura epicardica. Resultados:: Entre os 100 participantes do estudo, a circunferencia do pescoco mostrou correlacao significativa com o peso, circunferencia de cintura, IMC, glicemia e niveis sericos de colesterol total, lipoproteina de baixa densidade (LDL-colesterol) e triglicerideos. Nao foi observada correlacao significativa entre a circunferencia do pescoco e niveis de colesterol de alta densidade (HDL-colesterol). A circunferencia do pescoco correlacionou moderadamente e positivamente com a espessura da gordura epicardica a ecocardiografia. Conclusao:: Entre pacientes com baixo risco cardiometabolico, o aumento da circunferencia do pescoco foi associado a um aumento da espessura da gordura epicardica. PMID- 27509094 TI - Until Death Do Us Part. PMID- 27509095 TI - New World and Old World Alphaviruses Have Evolved to Exploit Different Components of Stress Granules, FXR and G3BP Proteins, for Assembly of Viral Replication Complexes. AB - The positive-strand RNA viruses initiate their amplification in the cell from a single genome delivered by virion. This single RNA molecule needs to become involved in replication process before it is recognized and degraded by cellular machinery. In this study, we show that distantly related New World and Old World alphaviruses have independently evolved to utilize different cellular stress granule-related proteins for assembly of complexes, which recruit viral genomic RNA and facilitate formation of viral replication complexes (vRCs). Venezuelan equine encephalitis virus (VEEV) utilizes all members of the Fragile X syndrome (FXR) family, while chikungunya and Sindbis viruses exploit both members of the G3BP family. Despite being in different families, these proteins share common characteristics, which determine their role in alphavirus replication, namely, the abilities for RNA-binding and for self-assembly into large structures. Both FXR and G3BP proteins interact with virus-specific, repeating amino acid sequences located in the C-termini of hypervariable, intrinsically disordered domains (HVDs) of viral nonstructural protein nsP3. We demonstrate that these host factors orchestrate assembly of vRCs and play key roles in RNA and virus replication. Only knockout of all of the homologs results in either pronounced or complete inhibition of replication of different alphaviruses. The use of multiple homologous proteins with redundant functions mediates highly efficient recruitment of viral RNA into the replication process. This independently evolved acquisition of different families of cellular proteins by the disordered protein fragment to support alphavirus replication suggests that other RNA viruses may utilize a similar mechanism of host factor recruitment for vRC assembly. The use of different host factors by alphavirus species may be one of the important determinants of their pathogenesis. PMID- 27509096 TI - Domino [Pd]-Catalysis: One-Pot Synthesis of Isobenzofuran-1(3H)-ones. AB - An efficient domino [Pd]-catalysis for the synthesis of isobenzofuran-1(3H)-ones is presented. The strategy shows broad substrate scope and is amenable to o bromobenzyl tertiary/secondary/primary alcohols. Significantly, the method was applied to the synthesis of antiplatelet drug n-butyl phthalide and cytotoxic agonist 3a-[4'-methoxylbenzyl]-5,7-dimethoxyphthalide. PMID- 27509097 TI - The Emergence of the Randomized, Controlled Trial. PMID- 27509098 TI - The DNR Order after 40 Years. PMID- 27509099 TI - Coming Back from the Dead. PMID- 27509101 TI - Fresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome. AB - BACKGROUND: The transfer of fresh embryos is generally preferred over the transfer of frozen embryos for in vitro fertilization (IVF), but some evidence suggests that frozen-embryo transfer may improve the live-birth rate and lower the rates of the ovarian hyperstimulation syndrome and pregnancy complications in women with the polycystic ovary syndrome. METHODS: In this multicenter trial, we randomly assigned 1508 infertile women with the polycystic ovary syndrome who were undergoing their first IVF cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. After 3 days of embryo development, women underwent the transfer of up to two fresh or frozen embryos. The primary outcome was a live birth after the first embryo transfer. RESULTS: Frozen-embryo transfer resulted in a higher frequency of live birth after the first transfer than did fresh-embryo transfer (49.3% vs. 42.0%), for a rate ratio of 1.17 (95% confidence interval [CI], 1.05 to 1.31; P=0.004). Women who underwent frozen-embryo transfer also had a lower frequency of pregnancy loss (22.0% vs. 32.7%), for a rate ratio of 0.67 (95% CI, 0.54 to 0.83; P<0.001), and of the ovarian hyperstimulation syndrome (1.3% vs. 7.1%), for a rate ratio of 0.19 (95% CI, 0.10 to 0.37; P<0.001), but a higher frequency of preeclampsia (4.4% vs. 1.4%), for a rate ratio of 3.12 (95% CI, 1.26 to 7.73; P=0.009). There were no significant between-group differences in rates of other pregnancy and neonatal complications. There were five neonatal deaths in the frozen-embryo group and none in the fresh-embryo group (P=0.06). CONCLUSIONS: Among infertile women with the polycystic ovary syndrome, frozen-embryo transfer was associated with a higher rate of live birth, a lower risk of the ovarian hyperstimulation syndrome, and a higher risk of preeclampsia after the first transfer than was fresh-embryo transfer. (Funded by the National Basic Research Program of China and others; ClinicalTrials.gov number, NCT01841528.). PMID- 27509103 TI - Raynaud's Phenomenon. PMID- 27509102 TI - Treatment of Fabry's Disease with the Pharmacologic Chaperone Migalastat. AB - BACKGROUND: Fabry's disease, an X-linked disorder of lysosomal alpha galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of alpha-galactosidase, increasing enzyme trafficking to lysosomes. METHODS: The initial assay of mutant alpha-galactosidase forms that we used to categorize 67 patients with Fabry's disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant alpha-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (>=50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS: The primary end-point analysis, involving patients with mutant alpha-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant alpha-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30+/-0.66 and -1.51+/ 1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS: Among all randomly assigned patients (with mutant alpha-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].). PMID- 27509104 TI - IMAGES IN CLINICAL MEDICINE. Aortic Calcification and Superior-Mesenteric-Artery Stenosis. PMID- 27509105 TI - CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 24-2016. A 66-Year-Old Man with Malaise, Weakness, and Hypercalcemia. PMID- 27509106 TI - RetroSternal--Looking Back at Thymectomy for Myasthenia Gravis. PMID- 27509100 TI - Randomized Trial of Thymectomy in Myasthenia Gravis. AB - BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3 year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.). PMID- 27509107 TI - "Freeze Only"--An Evolving Standard in Clinical In Vitro Fertilization. PMID- 27509108 TI - After Ebola in West Africa--Unpredictable Risks, Preventable Epidemics. PMID- 27509109 TI - Fusion Surgery for Lumbar Spinal Stenosis. PMID- 27509110 TI - Fusion Surgery for Lumbar Spinal Stenosis. PMID- 27509111 TI - Fusion Surgery for Lumbar Spinal Stenosis. PMID- 27509112 TI - Fusion Surgery for Lumbar Spinal Stenosis. PMID- 27509113 TI - Fusion Surgery for Lumbar Spinal Stenosis. PMID- 27509114 TI - Stenting versus Surgery for Carotid Stenosis. PMID- 27509115 TI - Stenting versus Surgery for Carotid Stenosis. PMID- 27509116 TI - Stenting versus Surgery for Carotid Stenosis. PMID- 27509117 TI - Stenting versus Surgery for Carotid Stenosis. PMID- 27509118 TI - Stenting versus Surgery for Carotid Stenosis. PMID- 27509119 TI - Newborn Bilirubin Screening for Biliary Atresia. PMID- 27509120 TI - Cervical Pessary and Preterm Singleton Birth. PMID- 27509121 TI - Cervical Pessary and Preterm Singleton Birth. PMID- 27509122 TI - IMAGES IN CLINICAL MEDICINE. Enlarged Right Atrium. PMID- 27509123 TI - INTERACTIVE MEDICAL CASE. Tracing the Cause of Abdominal Pain. PMID- 27509124 TI - Assessment of Minimal Residual Disease in Standard-Risk AML. PMID- 27509125 TI - Assessment of Minimal Residual Disease in Standard-Risk AML. PMID- 27509126 TI - Assessment of Minimal Residual Disease in Standard-Risk AML. PMID- 27509127 TI - Assessment of Minimal Residual Disease in Standard-Risk AML. PMID- 27509128 TI - miR-6734 Up-Regulates p21 Gene Expression and Induces Cell Cycle Arrest and Apoptosis in Colon Cancer Cells. AB - Recently, microRNAs have been implicated in the regulation of gene expression in terms of both gene silencing and gene activation. Here, we investigated the effects of miR-6734, which has a sequence homology with a specific region of p21WAF1/CIP1 (p21) promoter, on cancer cell growth and the mechanisms involved in this effect. miR-6734 up-regulated p21 expression at both mRNA and protein levels and chromatin immunoprecipitation analysis using biotin-labeled miR-6734 confirmed the association of miR-6734 with p21 promoter. Moreover, miR-6734 inhibited cancer cell growth and induced cell cycle arrest and apoptosis in HCT 116 cells, which was abolished by knockdown of p21. The phosphorylation of Rb and the cleavage of caspase 3 and PARP were suppressed by miR-6734 transfection in HCT-116 cells and these effects were also reversed by p21 knockdown. In addition, miR-6734 transfection caused prolonged induction of p21 gene and modification of histones in p21 promoter, which are typical aspects of a phenomenon referred to as RNA activation (RNAa). Collectively, our results demonstrated that miR-6734 inhibits the growth of colon cancer cells by up-regulating p21 gene expression and subsequent induction of cell cycle arrest and apoptosis, suggesting its role as an important endogenous regulator of cancer cell proliferation and survival. PMID- 27509129 TI - A Triangle Mesh Standardization Method Based on Particle Swarm Optimization. AB - To enhance the triangle quality of a reconstructed triangle mesh, a novel triangle mesh standardization method based on particle swarm optimization (PSO) is proposed. First, each vertex of the mesh and its first order vertices are fitted to a cubic curve surface by using least square method. Additionally, based on the condition that the local fitted surface is the searching region of PSO and the best average quality of the local triangles is the goal, the vertex position of the mesh is regulated. Finally, the threshold of the normal angle between the original vertex and regulated vertex is used to determine whether the vertex needs to be adjusted to preserve the detailed features of the mesh. Compared with existing methods, experimental results show that the proposed method can effectively improve the triangle quality of the mesh while preserving the geometric features and details of the original mesh. PMID- 27509130 TI - A Causal Role for the Cortical Frontal Eye Fields in Microsaccade Deployment. AB - Microsaccades aid vision by helping to strategically sample visual scenes. Despite the importance of these small eye movements, no cortical area has ever been implicated in their generation. Here, we used unilateral and bilateral reversible inactivation of the frontal eye fields (FEF) to identify a cortical drive for microsaccades. Unexpectedly, FEF inactivation altered microsaccade metrics and kinematics. Such inactivation also impaired microsaccade deployment following peripheral cue onset, regardless of cue side or inactivation configuration. Our results demonstrate that the FEF provides critical top-down drive for microsaccade generation, particularly during the recovery of microsaccades after disruption by sensory transients. Our results constitute the first direct evidence, to our knowledge, for the contribution of any cortical area to microsaccade generation, and they provide a possible substrate for how cognitive processes can influence the strategic deployment of microsaccades. PMID- 27509132 TI - Functional Blood Progenitor Markers in Developing Human Liver Progenitors. AB - In the early fetal liver, hematopoietic progenitors expand and mature together with hepatoblasts, the liver progenitors of hepatocytes and cholangiocytes. Previous analyses of human fetal livers indicated that both progenitors support each other's lineage maturation and curiously share some cell surface markers including CD34 and CD133. Using the human embryonic stem cell (hESC) system, we demonstrate that virtually all hESC-derived hepatoblast-like cells (Hep cells) transition through a progenitor stage expressing CD34 and CD133 as well as GATA2, an additional hematopoietic marker that has not previously been associated with human hepatoblast development. Dynamic expression patterns for CD34, CD133, and GATA2 in hepatoblasts were validated in human fetal livers collected from the first and second trimesters of gestation. Knockdown experiments demonstrate that each gene also functions to regulate hepatic fate mostly in a cell-autonomous fashion, revealing unprecedented roles of fetal hematopoietic progenitor markers in human liver progenitors. PMID- 27509131 TI - A Putative Association of a Single Nucleotide Polymorphism in GPR126 with Aggressive Periodontitis in a Japanese Population. AB - Periodontitis is an inflammatory disease causing loss of tooth-supporting periodontal tissue. Disease susceptibility to the rapidly progressive form of periodontitis, aggressive periodontitis (AgP), appears to be influenced by genetic risk factors. To identify these in a Japanese population, we performed whole exome sequencing of 41 unrelated generalized or localized AgP patients. We found that AgP is putatively associated with single nucleotide polymorphism (SNP) rs536714306 in the G-protein coupled receptor 126 gene, GPR126 [c.3086 G>A (p.Arg1029Gln)]. Since GPR126 activates the cAMP/PKA signaling pathway, we performed cAMP ELISA analysis of cAMP concentrations, and found that rs536714306 impaired the signal transactivation of GPR126. Moreover, transfection of human periodontal ligament (HPDL) cells with wild-type or mutant GPR126 containing rs536714306 showed that wild-type GPR126 significantly increased the mRNA expression of bone sialoprotein, osteopontin, and Runx2 genes, while mutant GPR126 had no effect on the expression of these calcification-related genes. The increase in expression of these genes was through the GPR126-induced increase of bone morphogenic protein-2, inhibitor of DNA binding (ID) 2, and ID4 expression. These data indicate that GPR126 might be important in maintaining the homeostasis of periodontal ligament tissues through regulating the cytodifferentiation of HPDL cells. The GPR126 SNP rs536714306 negatively influences this homeostasis, leading to the development of AgP, suggesting that it is a candidate genetic risk factor for AgP in the Japanese population. PMID- 27509133 TI - Integrin-Associated Focal Adhesion Kinase Protects Human Embryonic Stem Cells from Apoptosis, Detachment, and Differentiation. AB - Human embryonic stem cells (hESCs) can be maintained in a fully defined niche on extracellular matrix substrates, to which they attach through integrin receptors. However, the underlying integrin signaling mechanisms, and their contribution to hESC behavior, are largely unknown. Here, we show that focal adhesion kinase (FAK) transduces integrin activation and supports hESC survival, substrate adhesion, and maintenance of the undifferentiated state. After inhibiting FAK kinase activity we show that hESCs undergo cell detachment-dependent apoptosis or differentiation. We also report deactivation of FAK downstream targets, AKT and MDM2, and upregulation of p53, all key players in hESC regulatory networks. Loss of integrin activity or FAK also induces cell aggregation, revealing a role in the cell-cell interactions of hESCs. This study provides insight into the integrin signaling cascade activated in hESCs and reveals in FAK a key player in the maintenance of hESC survival and undifferentiated state. PMID- 27509134 TI - Embryonic Stem Cell Culture Conditions Support Distinct States Associated with Different Developmental Stages and Potency. AB - Embryonic stem cells (ESCs) are cell lines derived from the mammalian pre implantation embryo. Here we assess the impact of derivation and culture conditions on both functional potency and ESC transcriptional identity. Individual ESCs cultured in either two small-molecule inhibitors (2i) or with knockout serum replacement (KOSR), but not serum, can generate high-level chimeras regardless of how these cells were derived. ESCs cultured in these conditions showed a transcriptional correlation with early pre-implantation embryos (E1.5-E3.5) and contributed to development from the 2-cell stage. Conversely, the transcriptome of serum-cultured ESCs correlated with later stages of development (E4.5), at which point embryonic cells are more restricted in their developmental potential. Thus, ESC culture systems are not equivalent, but support cell types that resemble distinct developmental stages. Cells derived in one condition can be reprogrammed to another developmental state merely by adaptation to another culture condition. PMID- 27509135 TI - MIF Plays a Key Role in Regulating Tissue-Specific Chondro-Osteogenic Differentiation Fate of Human Cartilage Endplate Stem Cells under Hypoxia. AB - Degenerative cartilage endplate (CEP) shows decreased chondrification and increased ossification. Cartilage endplate stem cells (CESCs), with the capacity for chondro-osteogenic differentiation, are responsible for CEP restoration. CEP is avascular and hypoxic, while the physiological hypoxia is disrupted in the degenerated CEP. Hypoxia promoted chondrogenesis but inhibited osteogenesis in CESCs. This tissue-specific differentiation fate of CESCs in response to hypoxia was physiologically significant with regard to CEP maintaining chondrification and refusing ossification. MIF, a downstream target of HIF1A, is involved in cartilage and bone metabolisms, although little is known about its regulatory role in differentiation. In CESCs, MIF was identified as a key point through which HIF1A regulated the chondro-osteogenic differentiation. Unexpectedly, unlike the traditionally recognized mode, increased nuclear-expressed MIF under hypoxia was identified to act as a transcriptional regulator by interacting with the promoter of SOX9 and RUNX2. This mode of HIF1A/MIF function may represent a target for CEP degeneration therapy. PMID- 27509136 TI - Cell-Surface Protein Profiling Identifies Distinctive Markers of Progenitor Cells in Human Skeletal Muscle. AB - Skeletal muscle contains two distinct stem/progenitor populations. One is the satellite cell, which acts as a muscle stem cell, and the other is the mesenchymal progenitor, which contributes to muscle pathogeneses such as fat infiltration and fibrosis. Detailed and accurate characterization of these progenitors in humans remains elusive. Here, we performed comprehensive cell surface protein profiling of the two progenitor populations residing in human skeletal muscle and identified three previously unrecognized markers: CD82 and CD318 for satellite cells and CD201 for mesenchymal progenitors. These markers distinguish myogenic and mesenchymal progenitors, and enable efficient isolation of the two types of progenitors. Functional study revealed that CD82 ensures expansion and preservation of myogenic progenitors by suppressing excessive differentiation, and CD201 signaling favors adipogenesis of mesenchymal progenitors. Thus, cell-surface proteins identified here are not only useful markers but also functionally important molecules, and provide valuable insight into human muscle biology and diseases. PMID- 27509137 TI - The Luteinizing Hormone-Testosterone Pathway Regulates Mouse Spermatogonial Stem Cell Self-Renewal by Suppressing WNT5A Expression in Sertoli Cells. AB - Spermatogenesis originates from self-renewal of spermatogonial stem cells (SSCs). Previous studies have reported conflicting roles of gonadotropic pituitary hormones in SSC self-renewal. Here, we explored the role of hormonal regulation of SSCs using Fshb and Lhcgr knockout (KO) mice. Although follicle-stimulating hormone (FSH) is thought to promote self-renewal by glial cell line-derived neurotrophic factor (GDNF), no abnormalities were found in SSCs and their microenvironment. In contrast, SSCs were enriched in Lhcgr-deficient mice. Moreover, wild-type SSCs transplanted into Lhcgr-deficient mice showed enhanced self-renewal. Microarray analysis revealed that Lhcgr-deficient testes have enhanced WNT5A expression in Sertoli cells, which showed an immature phenotype. Since WNT5A was upregulated by anti-androgen treatment, testosterone produced by luteinizing hormone (LH) is required for Sertoli cell maturation. WNT5A promoted SSC activity both in vitro and in vivo. Therefore, FSH is not responsible for GDNF regulation, while LH negatively regulates SSC self-renewal by suppressing WNT5A via testosterone. PMID- 27509138 TI - A Method to Identify and Isolate Pluripotent Human Stem Cells and Mouse Epiblast Stem Cells Using Lipid Body-Associated Retinyl Ester Fluorescence. PMID- 27509139 TI - Factors affecting adaptation to the role of motherhood in mothers of preterm infants admitted to the neonatal intensive care unit: a qualitative study. AB - AIM: The aim of this study was to explore factors affecting adaptation to the role of motherhood in mothers of preterm infants admitted to the neonatal intensive care unit. BACKGROUND: Transition to motherhood often causes significant issues in terms of adaptation to the role of motherhood. The main factors leading to parental stress, especially in the neonatal intensive care unit, have shown that the greatest source of stress is the loss of women's role as mothers. DESIGN: It was a qualitative study with content analysis approach. METHODS: Semi-structured in-depth interviews were used for data collection. Interviews were conducted with 17 mothers of preterm infants (under 36 weeks) who had been hospitalized for at least one week in the neonatal intensive care unit. Purposive sampling with maximum diversity was used to recruit mothers in Kermanshah province (west of Iran). Data was collected during 2013-2014. Interviews were recorded and transcribed verbatim. Data were analysed using conventional content analysis. FINDINGS: Explanation of the mothers' perspective towards factors affecting adaptation to the role of motherhood led to two main categories of individual factors (emotional distress, self-efficacy, interaction and alienation) and social factors (support, prejudice). CONCLUSION: Adaptation to the role of motherhood can be promoted through supporting mothers of preterm infants, empowering them and increasing their self-efficacy, to eliminate negative factors and emotions. PMID- 27509140 TI - [Not Available]. PMID- 27509141 TI - Postoperative Foot Massage for Patients after Caesarean Delivery. AB - OBJECTIVE: Little evidence is available on complementary therapies for anxiety and pain relief after caesarean delivery. The purpose of this study was to evaluate the effects of foot massage post-operatively in patients after caesarean delivery. MATERIALS AND METHODS: 70 patients were divided to the study or control group after cesarean delivery. Patients in the study group had foot massages for 20 min after surgery. All patients underwent heart rate variability analysis (HRV) and scored their anxiety; pain intensity was evaluated using an 11-point numerical rating scale (NRS). RESULTS: In the study group the HRV, as measured by the low frequency power (LF) value and the LF-to-high frequency power (LF/HF) ratio during Holter assessment, was significantly less after foot massage intervention, but was not changed in the control group. Moreover, the HF value significantly increased and the anxiety score significantly decreased after foot massage intervention, but not in the control group. The pain intensity score obtained 60 min after the massage was significantly lower in the study group than the control group, as were the vital signs (respiratory rate, and systolic and diastolic blood pressure). CONCLUSION: Post-operative massage intervention can reduce anxiety and pain in patients after caesarean delivery. PMID- 27509142 TI - Grape Pomace, an Agricultural Byproduct Reducing Mycotoxin Absorption: In Vivo Assessment in Pig Using Urinary Biomarkers. AB - The efficacy of four agricultural byproducts (ABPs) and two commercial binders (CBs) to reduce the gastrointestinal absorption of a mixture of mycotoxins was tested in piglets using urinary mycotoxin biomarkers as indicator of the absorbed mycotoxins. Twenty-eight piglets were administered a bolus contaminated with the mycotoxin mixture containing or not ABP or CB. Twenty-four hour urine was collected and analyzed for mycotoxin biomarkers by using a multiantibody immunoaffinity-based LC-MS/MS method. Each bolus contained 769 MUg of fumonisin B1 (FB1), 275 MUg of deoxynivalenol (DON), 29 MUg of zearalenone (ZEN), 6.5 MUg of aflatoxin B1 (AFB1) and 6.6 MUg of ochratoxin A (OTA) corresponding to 2.2, 0.8, 0.08, 0.02, and 0.02 MUg/g in the daily diet, respectively. The percentage of ABP in each bolus was 50%, whereas for the two CBs the percentages were 5.2 and 17%, corresponding to 2.8, 0.3, and 0.9% in the daily diet, respectively. The reduction of mycotoxin absorption was up to 69 and 54% for ABPs and CBs, respectively. White grape pomace of Malvasia was the most effective material as it reduced significantly (p < 0.05) urinary mycotoxin biomarker of AFB1 (67%) and ZEN (69%), whereas reductions statistically not significant were observed for FB1 (57%), DON (40%), and OTA (27%). This study demonstrates that grape pomace reduces the gastrointestinal absorption of mycotoxins. This agricultural byproduct can be considered an alternative to commercial products and used in the feed industries as an effective, cheap, and natural binder for multiple mycotoxins. PMID- 27509143 TI - Effectiveness of Phosphodiesterase 5 Inhibitors in the Treatment of Erectile Dysfunction in Patients with Spinal Cord Trauma: Systematic Review and Meta Analysis. AB - OBJECTIVE: To determine the effectiveness of the Phosphodiesterase 5 (PDE5) Inhibitors for the treatment of erectile dysfunction in patients with spinal trauma. METHODS: A systematic review and meta-analysis comparing PDE5 inhibitors versus placebo were carried out for clinical trials conducted between 1980 and 2014 that evaluated male patients older than 18 years, diagnosed with spinal cord trauma and erectile dysfunction. We designed a search strategy for Medline, CENTRAL, EMBASE and other electronic sources. Two investigators independently and blindly screened the studies for inclusion. A random effect meta-analysis was performed. RESULTS: Six studies involving 963 patients were included. Male patients over 18 years with ED attributable or subsequent to traumatic spinal cord injury (SCI) were included from these studies. In 4 of these studies, patients were randomized to the treatment group receiving sildenafil and the comparison group was placebo. Out of the remaining 2 trials, one compared tadalafil against the placebo and the other vardenafil versus placebo. The improvement on SCIs with PDE5 inhibitors was found to be large (standardized mean difference 0.71; 95% CI 0.39-1.03), with a high heterogeneity (I2 = 74.4%). CONCLUSIONS: PDE5 inhibitors are effective for the treatment of erectile dysfunction secondary to SCI. PMID- 27509145 TI - American Thoracic Society and Marron Institute Report. Estimated Excess Morbidity and Mortality Caused by Air Pollution above American Thoracic Society-Recommended Standards, 2011-2013. AB - Estimates of the health impacts of air pollution are needed to make informed air quality management decisions at both the national and local levels. Using design values of ambient pollution concentrations from 2011-2013 as a baseline, the American Thoracic Society (ATS) and the Marron Institute of Urban Management estimated excess morbidity and mortality in the United States attributable to exposure to ambient ozone (O3) and fine particulate matter (PM2.5) at levels above the American Thoracic Society-recommended standards. Within the subset of counties with valid design values for each pollutant, 14% had PM2.5 concentrations greater than the ATS recommendation, whereas 91% had O3 concentrations greater than the ATS recommendation. Approximately 9,320 excess deaths (69% from O3; 31% from PM2.5), 21,400 excess morbidities (74% from O3; 26% from PM2.5), and 19,300,000 adversely impacted days (88% from O3; 12% from PM2.5) in the United States each year are attributable to pollution exceeding the ATS recommended standards. California alone is responsible for 37% of the total estimated health impacts, and the next three states (Pennsylvania, Texas, and Ohio) together contributed to 20% of the total estimates. City-specific health estimates are provided in this report and through an accompanying online tool to help inform air quality management decisions made at the local level. Riverside and Los Angeles, California have the most to gain by attaining the ATS recommendations for O3 and PM2.5. This report will be revised and updated regularly to help cities track their progress. PMID- 27509146 TI - Changing the Climate of Respiratory Clinical Practice. Insights from the 2016 Climate and Health Assessment of the U.S. Global Change Research Program. PMID- 27509144 TI - Lymphoblastoid Cell Lines as a Tool to Study Inter-Individual Differences in the Response to Glucose. AB - BACKGROUND: White blood cells have been shown in animal studies to play a central role in the pathogenesis of diabetic retinopathy. Lymphoblastoid cells are immortalized EBV-transformed primary B-cell leukocytes that have been extensively used as a model for conditions in which white blood cells play a primary role. The purpose of this study was to investigate whether lymphoblastoid cell lines, by retaining many of the key features of primary leukocytes, can be induced with glucose to demonstrate relevant biological responses to those found in diabetic retinopathy. METHODS: Lymphoblastoid cell lines were obtained from twenty-three human subjects. Differences between high and standard glucose conditions were assessed for expression, endothelial adhesion, and reactive oxygen species. RESULTS: Collectively, stimulation of the lymphoblastoid cell lines with high glucose demonstrated corresponding changes on molecular, cellular and functional levels. Lymphoblastoid cell lines up-regulated expression of a panel of genes associated with the leukocyte-mediated inflammation found in diabetic retinopathy that include: a cytokine (IL-1B fold change = 2.11, p-value = 0.02), an enzyme (PKCB fold change = 2.30, p-value = 0.01), transcription factors (NFKB-p50 fold change = 2.05, p-value = 0.01), (NFKB-p65 fold change = 2.82, p-value = 0.003), and an adhesion molecule (CD18 fold change = 2.59, 0.02). Protein expression of CD18 was also increased (p-value = 2.14x10-5). The lymphoblastoid cell lines demonstrated increased adhesiveness to endothelial cells (p = 1.28x10-5). Reactive oxygen species were increased (p = 2.56x10-6). Significant inter individual variation among the lymphoblastoid cell lines in these responses was evident (F = 18.70, p < 0.0001). CONCLUSIONS: Exposure of lymphoblastoid cell lines derived from different human subjects to high glucose demonstrated differential and heterogeneous gene expression, adhesion, and cellular effects that recapitulated features found in the diabetic state. Lymphoblastoid cells may represent a useful tool to guide an individualized understanding of the development and potential treatment of diabetic complications like retinopathy. PMID- 27509147 TI - The Global Emergence of Unregulated Stem Cell Treatments for Respiratory Diseases. Professional Societies Need to Act. PMID- 27509148 TI - Improving Health Literacy. The New American Thoracic Society Guidelines for Patient Education Materials. PMID- 27509149 TI - Acute Chest Syndrome, Asthma, and Lung Function in Sickle Cell Disease. Which Is the Chicken, and Which Is the Egg? PMID- 27509150 TI - The Power and Importance of Accommodation for Communication Impairment in the Intensive Care Unit. PMID- 27509151 TI - Go Big: Measuring and Tackling Psychological Morbidity after Critical Illness. PMID- 27509152 TI - Broken Wings and Resilience after Critical Illness. PMID- 27509153 TI - Incretins and Insulin Resistance in Obstructive Sleep Apnea. Chicken or the Egg? PMID- 27509155 TI - A 62-Year-Old Man with Cough and Dyspnea after Crack Cocaine Inhalation. PMID- 27509154 TI - Sarcoidosis in America. Analysis Based on Health Care Use. AB - RATIONALE: There have been no recent comprehensive studies of the epidemiology of sarcoidosis in the United States. Changes in health care use have made available access to data on large numbers of patients with sarcoidosis. OBJECTIVES: To use a U.S. national health care database to gather data on patients with sarcoidosis identified over a 3-year period who were 18 years of age and older, and to determine health care costs for these patients. METHODS: The Optum health care database was queried for a 3-year period (2010-2013). This database includes approximately 15% of U.S. residents. The incidence rate of sarcoidosis was calculated for new cases identified in each year. Calculation of prevalence was based on any patient with sarcoidosis seen during the year. Incidence and prevalence rates are reported per 100,000 patients. MEASUREMENTS AND MAIN RESULTS: A total of 29,372 adult patients with sarcoidosis were identified. Of these, 14,700 (55%) were over 55 years of age at the time of diagnosis. The incidence and prevalence rates were higher for African Americans (17.8 and 141.4 per 100,000, respectively) than for white individuals (8.1 and 49.8), Hispanics (4.3 and 21.7), or Asians (3.2 and 18.9). Women were two times more likely to have sarcoidosis, with the highest prevalence for sarcoidosis noted in African American women (178.5). Overall, the yearly health care cost reported for patients with sarcoidosis was low, with a median of $18,663 per year. However, the yearly cost for the top 5% was $93,201. CONCLUSIONS: For patients 18 years of age and older enrolled in a U.S. national administrative database, sarcoidosis was more common among African Americans, but it was reported for all four of the major ethnic groups studied. While health care costs were relatively small for most patients, the cost of care for some patients was considerable. PMID- 27509156 TI - Dyspnea and an Arteriovenous Fistula. PMID- 27509157 TI - Nodular Pleural Thickening after Lobectomy for Lung Cancer. Insights on Imaging of the Pleura. PMID- 27509158 TI - Long-Term Effects of Bronchial Thermoplasty on Airway Smooth Muscle and Reticular Basement Membrane Thickness in Severe Asthma. PMID- 27509159 TI - The Real Face of Borderline Pulmonary Hypertension in Connective Tissue Disease. PMID- 27509160 TI - Severe Colitis Associated with Pirfenidone Use in Idiopathic Pulmonary Fibrosis. PMID- 27509161 TI - Reply: Indwelling Tunneled Pleural Catheters for the Management of Hepatic Hydrothorax: A Word of Caution. PMID- 27509162 TI - Indwelling Tunneled Pleural Catheters for the Management of Hepatic Hydrothorax: A Word of Caution. PMID- 27509163 TI - An Official American Thoracic Society Workshop Report 2015. Stem Cells and Cell Therapies in Lung Biology and Diseases. AB - The University of Vermont College of Medicine, in collaboration with the NHLBI, Alpha-1 Foundation, American Thoracic Society, Cystic Fibrosis Foundation, European Respiratory Society, International Society for Cellular Therapy, and the Pulmonary Fibrosis Foundation, convened a workshop, "Stem Cells and Cell Therapies in Lung Biology and Lung Diseases," held July 27 to 30, 2015, at the University of Vermont. The conference objectives were to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy and ex vivo bioengineering approaches for lung diseases. These are all rapidly expanding areas of study that both provide further insight into and challenge traditional views of mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, discuss and debate current controversies, and identify future research directions and opportunities for both basic and translational research in cell based therapies for lung diseases. This 10th anniversary conference was a follow up to five previous biennial conferences held at the University of Vermont in 2005, 2007, 2009, 2011, and 2013. Each of those conferences, also sponsored by the National Institutes of Health, American Thoracic Society, and respiratory disease foundations, has been important in helping guide research and funding priorities. The major conference recommendations are summarized at the end of the report and highlight both the significant progress and major challenges in these rapidly progressing fields. PMID- 27509164 TI - Exploration of Unimolecular Gas-Phase Detoxication Pathways of Sarin and Soman: A Computational Study from the Perspective of Reaction Energetics and Kinetics. AB - A mechanistic investigation has been carried out to explore all possible gas phase unimolecular isomerization as well as decomposition pathways of toxic organophosphorus compounds (OPCs), namely, sarin (GB) and soman (GD), which are better known as nerve agents. We have identified a total of 13 detoxication pathways for sarin, where the alpha-H, beta-H, and gamma-H take part in the H transfer process. However, for soman, due to the presence of omega-H, three additional detoxication pathways are obtained, where the omega-H is involved in the H-transfer process. Among all the pathways, the D3 decomposition pathway, where the phosphorus oxoacid derivative and alkene are generated via the formation of a six-membered ring in the transition state, is identified as the most feasible pathway from the perspective of both activation barrier and reaction enthalpy values. Moreover, we have studied the feasibility of the isomerization and decomposition pathways by performing the reaction kinetics in the temperature range of 300 K-1000 K using the one-dimensional Rice-Ramsperger Kassel-Marcus (RRKM) master equation. From the RRKM calculation also, D3 pathway is confirmed as the most feasible pathway for both OPCs. The rate constant values associated with the D3 pathway within the temperature range of 600 K-700 K imply that the degradation of the OPCs is possible within this temperature range via the D3 pathway, which is in good agreement with the earlier reported experimental result. It is also observed that at higher temperature range (~900 K), the increased rate constant values of other detoxication pathways indicate that along with D3, all other pathways become more or less equally feasible. Therefore, the entire work provides a widespread idea about the kinetic as well as thermodynamic feasibility of the explored detoxication pathways of the titled OPCs. PMID- 27509165 TI - Diabetic patient adherence to pathology request completion in primary care. AB - Objective Little research exists regarding the prevalence of patient non adherence with completing pathology requests for chronic disease monitoring. The aims of the present study were to determine the extent to which this exists in diabetic patients and to identify possible reasons contributing to this behaviour. Methods Patients diagnosed with type 2 diabetes mellitus were recruited from three general practices with different demographics. Data were collected by recording demographic patient information at the time of visit. In addition, information regarding patient pathology request adherence and the reasons provided when this was not achieved were also noted. These reasons were compared with preconceptions by medical staff in each practice. Results General practitioner perceptions of poor patient adherence to pathology requests were confirmed, with rates of non-adherence up to 31% at one practice site. The primary reasons preventing completion of pathology testing included forgetfulness, time poorness, poor health literacy and, in some cases, language barriers. Conclusion A high proportion of patients do not prioritise the monitoring of their diabetes, potentially because of a lack of understanding of the importance such management has on their health. Further research should be conducted to determine the effect of the implementation of point-of-care testing on patient outcomes in such areas of low non-adherence with disease management. What is known about the topic? Little quantitative information exists regarding the adherence rate of patients to pathology request completion. Without up-to date pathology results, a barrier is created, preventing accurate medical treatment of the patient's condition because the doctor cannot ascertain a full picture of the patient's current disease state at the time of consultation. What does this paper add? This paper quantifies the rate of non-adherence among three diabetic patient groups at different practice sites, taking into account patient and site demographics. It also confirms patient non-adherence to timely pathology request completion as a prevalent issue of concern at all practice sites recruited. In addition, it looks at reasons why this issue exists as a means of addressing the problem in the future. What are the implications for practitioners? This research may aid practitioners in addressing such issues at a local level within general practice, because reasons creating barriers to successful completion of pathology requests have been identified and potential solutions suggested. PMID- 27509166 TI - Polymorphism of Metastasis Suppressor Genes MKK4 and NME1 in Kashmiri Patients with Breast Cancer. AB - Genetic polymorphisms in metastatic suppressor genes like MKK4 and NME1 are not well studied in breast cancer. Hence, we analyzed the relationship between MKK4 and NME1 polymorphisms and breast cancer risk in Kashmir, India. The different genotypes of NME1 and MKK4 genes were analyzed by polymerase chain reaction and restriction fragment length polymorphism in 130 breast cancer cases and 200 age- and sex-matched controls. Conditional logistic regression models were used to assess the association of various genotypes with breast cancer. In this study, we found an inverse association between MKK4 promoter polymorphism and breast cancer risk. As compared to TT (wild) genotype, individuals with TG (heterozygous) (OR = 0.32; 95% CI = (0.17-0.58) and GG (mutant) (OR = 0.13; CI = 0.04-0.40) genotypes showed decreased risk of breast cancer. When participants were classified on the basis of lymph node involvement, a strong association between NME1 heterozygous genotype (OR = 3.82; CI = (1.54-9.44) and breast cancer was found. PMID- 27509167 TI - Patient Blood Management in Europe: surveys on top indications for red blood cell use and Patient Blood Management organization and activities in seven European university hospitals. AB - BACKGROUND AND OBJECTIVES: Patient Blood Management (PBM) in Europe is a working group of the European Blood Alliance with the initial objective to identify the starting position of the participating hospitals regarding PBM for benchmarking purposes, and to derive good practices in PBM from the experience and expertise in the participating teams with the further aim of implementing and strengthening these practices in the participating hospitals. METHODS: We conducted two surveys in seven university hospitals in Europe: Survey on top indications for red blood cell use regarding usage of red blood cells during 1 week and Survey on PBM organization and activities. RESULTS: A total of 3320 units of red blood cells were transfused in 1 week at the seven hospitals. Overall, 61% of red cell units were transfused to medical patients and 36% to surgical patients, although there was much variation between hospitals. The organization and activities of PBM in the seven hospitals were variable, but there was a common focus on optimizing the treatment of bleeding patients, monitoring the use of blood components and treatment of preoperative anaemia. CONCLUSION: Although the seven hospitals provide a similar range of clinical services, there was variation in transfusion rates between them. Further, there was variable implementation of PBM activities and monitoring of transfusion practice. These findings provide a baseline to develop joint action plans to further implement and strengthen PBM across a number of hospitals in Europe. PMID- 27509168 TI - Rheopathologic Consequence of Plasmodium vivax Rosette Formation. AB - Malaria parasites dramatically alter the rheological properties of infected red blood cells. In the case of Plasmodium vivax, the parasite rapidly decreases the shear elastic modulus of the invaded RBC, enabling it to avoid splenic clearance. This study highlights correlation between rosette formation and altered membrane deformability of P. vivax-infected erythrocytes, where the rosette-forming infected erythrocytes are significantly more rigid than their non-rosetting counterparts. The adhesion of normocytes to the PvIRBC is strong (mean binding force of 440pN) resulting in stable rosette formation even under high physiological shear flow stress. Rosetting may contribute to the sequestration of PvIRBC schizonts in the host microvasculature or spleen. PMID- 27509169 TI - Differential Analysis of the Nasal Microbiome of Pig Carriers or Non-Carriers of Staphylococcus aureus. AB - Staphylococcus aureus is presently regarded as an emerging zoonotic agent due to the spread of specific methicillin-resistant S. aureus (MRSA) clones in pig farms. Studying the microbiota can be useful for the identification of bacteria that antagonize such opportunistic veterinary and zoonotic pathogen in animal carriers. The aim of this study was to determine whether the nasal microbiome of pig S. aureus carriers differs from that of non-carriers. The V3-V5 region of the 16S rRNA gene was sequenced from nasal swabs of 44 S. aureus carriers and 56 non carriers using the 454 GS FLX titanium system. Carriers and non-carriers were selected on the basis of quantitative longitudinal data on S. aureus carriage in 600 pigs sampled at 20 Danish herds included in two previous studies in Denmark. Raw sequences were analysed with the BION meta package and the resulting abundance matrix was analysed using the DESeq2 package in R to identify operational taxonomic units (OTUs) with differential abundance between S. aureus carriers and non-carriers. Twenty OTUs were significantly associated to non carriers, including species with known probiotic potential and antimicrobial effect such as lactic acid-producing isolates described among Leuconostoc spp. and some members of the Lachnospiraceae family, which is known for butyrate production. Further 5 OTUs were significantly associated to carriage, including known pathogenic bacteria such as Pasteurella multocida and Klebsiella spp. Our results show that the nasal microbiome of pigs that are not colonized with S. aureus harbours several species/taxa that are significantly less abundant in pig carriers, suggesting that the nasal microbiota may play a role in the individual predisposition to S. aureus nasal carriage in pigs. Further research is warranted to isolate these bacteria and assess their possible antagonistic effect on S. aureus for the pursuit of new strategies to control MRSA in pig farming. PMID- 27509170 TI - Language-Appropriate Appointment Reminders: Assessing the Communication Preferences of Women With Limited English Proficiency. AB - INTRODUCTION: The purpose of this study was to assess the communication preferences and the telephone, text, and e-mail usage of women with limited English proficiency who attended an outpatient women's health clinic. METHODS: This study surveyed a convenience sample (N = 220) of Spanish- and Arabic speaking women in an obstetrics and gynecology clinic. The survey instrument was designed to capture the experience of women with limited English proficiency who received automated English-only telephone appointment reminders. We evaluated how these women currently use short message service (SMS) technology and/or access e mail, the costs they incur for these services, and their preferences for and receptiveness to receiving appointment reminders through a variety of modalities including text, e-mail, phone, or direct mail. RESULTS: More than half of women surveyed reported either not receiving an appointment reminder or reported difficulty understanding the reminder they did receive. Of all women surveyed, 91% preferred appointment reminders in their primary language regardless of their ability to read, write, speak, or understand English. Significant variation in preferences was found within and between the 2 language groups. DISCUSSION: The data suggest that the current appointment-reminder system is both inefficient and linguistically inappropriate for female clients with limited English proficiency. This project offers preliminary data on the preferences of Spanish- and Arabic speaking women. Creating language-appropriate appointment reminders in both phone and text formats reflects an institutional commitment to the language preferences of all women, not just those who speak the dominant language, in accordance with accreditation guidelines defined by the Centers for Medicare and Medicaid Services and The Joint Commission. PMID- 27509171 TI - Brilliant Structurally Colored Films with Invariable Stop-Band and Enhanced Mechanical Robustness Inspired by the Cobbled Road. AB - Recently, structural colors have attracted great concentrations because the coloration is free from chemical- or photobleaching. However, the color saturation and mechanical robustness are generally competitive properties in the fabrication of PCs (photonic crystals) films. Besides, the structure of PCs and their derivatives are easy to be invaded by liquids and lead to band gap shifts due to the change of refractive index or periodicity. To solve those problems, we infiltrate polydimethylsiloxane (PDMS) into the intervals between regularly arrayed hollow SiO2 nanospheres, inspired by the cobbled road prepared by embedding stone in the bulk cement matrix. Consequently, the as-prepared PCs films show brilliant colors, invariable stop-bands, and excellent mechanical robustness. Moreover, the water contact angle even reached 166 degrees after a sandpaper abrasion test. The combination of brilliant colors, invariable stop bands, and excellent robustness is significant for potential application in paint and external decoration of architectures. PMID- 27509172 TI - A cohort study of cervical screening using partial HPV typing and cytology triage. AB - HPV testing is more sensitive than cytology for cervical screening. However, to incorporate HPV tests into screening, risk-stratification ("triage") of HPV positive women is needed to avoid excessive colposcopy and overtreatment. We prospectively evaluated combinations of partial HPV typing (Onclarity, BD) and cytology triage, and explored whether management could be simplified, based on grouping combinations yielding similar 3-year or 18-month CIN3+ risks. We typed ~9,000 archived specimens, taken at enrollment (2007-2011) into the NCI-Kaiser Permanente Northern California (KPNC) HPV Persistence and Progression (PaP) cohort. Stratified sampling, with reweighting in the statistical analysis, permitted risk estimation of HPV/cytology combinations for the 700,000+-woman KPNC screening population. Based on 3-year CIN3+ risks, Onclarity results could be combined into five groups (HPV16, else HPV18/45, else HPV31/33/58/52, else HPV51/35/39/68/56/66/68, else HPV negative); cytology results fell into three risk groups ("high-grade," ASC-US/LSIL, NILM). For the resultant 15 HPV group cytology combinations, 3-year CIN3+ risks ranged 1,000-fold from 60.6% to 0.06%. To guide management, we compared the risks to established "benchmark" risk/management thresholds in this same population (e.g., LSIL predicted 3-year CIN3+ risk of 5.8% in the screening population, providing the benchmark for colposcopic referral). By benchmarking to 3-year risk thresholds (supplemented by 18-month estimates), the widely varying risk strata could be condensed into four action bands (very high risk of CIN3+ mandating consideration of cone biopsy if colposcopy did not find precancer; moderate risk justifying colposcopy; low risk managed by intensified follow-up to permit HPV "clearance"; and very low risk permitting routine screening.) Overall, the results support primary HPV testing, with management of HPV-positive women using partial HPV typing and cytology. PMID- 27509173 TI - Implementation and Operational Research: Clinical Impact of the Xpert MTB/RIF Assay in Patients With Multidrug-Resistant Tuberculosis. AB - BACKGROUND: The Xpert MTB/RIF assay has been widely implemented in South Africa for rapid tuberculosis (TB) screening. However, its usefulness in management and improving treatment outcomes in patients with multidrug-resistant TB (MDR-TB) remains undefined. The aim of this study was to evaluate the clinical impact of introduction of the Xpert MTB/RIF assay in patients with MDR-TB. METHODS: We enrolled 921 patients with MDR-TB, who presented to a specialist drug-resistant TB facility in KwaZulu-Natal, South Africa, pre- and post-rollout and implementation of the Xpert MTB/RIF assay. Clinical, laboratory, chest radiograph, and follow-up data from 108 patients with MDR-TB, post-introduction of the Xpert MTB/RIF assay (Xpert group) in November 2010, were analyzed and compared with data from 813 MDR-TB patients from the pre-MTB/RIF assay period (Conventional group), July 2008-2010. Primary impact measure was "treatment success" (World Health Organization definition) at 24 months. Secondary outcomes were time to treatment initiation and disease morbidity. RESULTS: There were no significant differences in treatment success rates between the pre-Xpert MTB/RIF and post-Xpert MTB/RIF groups (54% versus 56.5%, P = 0.681). Median time to treatment initiation was 20 days (interquartile range, 13-31) in the Xpert group versus 92 days (interquartile range, 69-120) in the Conventional group (P < 0.001). CONCLUSIONS: Although use of Xpert MTB/RIF assay significantly reduces the time to initiation of MDR-TB treatment, it had no significant impact on treatment outcomes of patients with MDR-TB. Studies on the impact of the Xpert MTB/RIF assay usage on transmission of MDR-TB are required. PMID- 27509174 TI - Circulating resistin levels and obesity-related cancer risk: A meta-analysis. AB - Resistin levels have been reported to be abnormal in obesity-related cancer patients with epidemiological studies yielding inconsistent results. Therefore, a meta-analysis was performed to assess the association between blood resistin levels and obesity-related cancer risk. A total of 13 studies were included for pooling ORs analysis. High resistin levels were found in cancer patients (OR= 1.20, 95% CI= 1.10-1.30). After excluding one study primarily contributing to between-study heterogeneity, the association between resistin levels and cancer risk was still significant (OR=1.18, 95% CI = 1.09-1.28). Stratification analysis found resistin levels were not associated with cancer risk in prospective studies. Meta-regression analysis identified factors such as geographic area, detection assay, or study design as confounders to between-study variance. The result of 18 studies of pooling measures on SMD analysis was that high resistin levels were associated with increased cancer risk (SMD = 0.94, 95% CI = 0.63 1.25), but not in the pooling SMD analysis of prospective studies. Except for the studies identified as major contributors to heterogeneity by Galbraith plot, resistin levels were still higher in cancer patients (SMD = 0.75, 95% CI = 0.63 0.87) in retrospective studies. Meta-regression analysis found factors, such as geographic area, BMI-match, size, and quality score, could account for 66.7% between-study variance in pooling SMD analysis of retrospective studies. Publication bias was not found in pooling ORs analysis. Our findings indicated high resistin levels were associated with increased obesity-related cancer risk. However, it may not be a predictor. PMID- 27509175 TI - A new predictive model combined of tumor size, lymph nodes count and lymphovascular invasion for survival prognosis in patients with lymph node negative gastric cancer. AB - BACKGROUND: Various factors may affect the clinical prognosis of lymph node negative gastric cancer (GC) patients. This study aimed to provide evaluable prognostic information of combination of tumor size (Ts), lymph nodes count (LNs) and lymphovascular invasion (LVI) in lymph node-negative GC patients. METHODS: A total of 1,019 node-negative GC patients were enrolled in this retrospective study from 2000 to 2010. The cutoff points of Ts and LNs were determined using X tile and patients were randomly categorized into training and validation sets by the sample size ratio 1:1. The clinicopathologic characteristics were analyzed and survival prognostic factors were identified, whereas the survival prediction accuracy was also compared by C-index during the different independent prognostic factors. RESULTS: The cutoff points for Ts were 3cm and 5cm, while 14 was the cutoff point for LNs. Age, T stage, Ts, LNs and LVI were identified as independent prognostic factors in node-negative GC patients, and a new prognostic predictive model, TsNL staging system which was composed of Ts, LNs and LVI, was proposed in this study. Compared with T staging system, significant improvement of predictive accuracy for TsNL system was found. Furthermore, nomogram based on TsNL was more accurate in prognostic prediction than that based on Ts, LNs and LVI, separately. CONCLUSIONS: Age, T stage, Ts, LNs and LVI were independent prognostic factors in lymph node-negative GC patients. The TsNL staging system, composed of Ts, LNs and LVI, which was closely associated with clinicopathologic features, may improve the prognostic prediction accuracy in node-negative GC patients. PMID- 27509177 TI - Smoking, second-hand smoke exposure and smoking cessation in relation to leukocyte telomere length and mortality. AB - OBJECTIVES: To investigate the link between smoking exposure, telomere length and mortality, with emphasis on second-hand smoke (SHS) exposure and the duration of smoking cessation. RESULTS: A total of 1,018 participants died during follow-up (mean: 10.3 years). A 50 base-pair decrease in LTL was shown among cotinine confirmed current versus never smokers. The 90th quantile of LTL decreased with increasing cotinine among never smokers, indicating a role of SHS. Longer telomeres with smoking cessation were indicated but limited to a 3-16 year period of abstaining smoking. When assessing mortality, we observed a lower risk of all cause death for the second quintile compared to the first among never smokers (HR: 0.67, 95% CI: 0.52-0.87), and a higher risk was found among current smokers (HR: 1.89, 1.19-2.92). MATERIALS AND METHODS: We studied 6,456 nationally representative U.S. respondents with mortality follow-up through to 31 December 2011. Smoking status was assessed by interviews and cotinine levels. Relative leukocyte telomere length (LTL) was quantified by polymerase chain reaction (PCR). Multivariable linear regression was performed to examine LTL by smoking exposure, adjusted for age, sex, race/ethnicity, socioeconomic status, education, body mass index, alcohol consumption, and physical activity. We further estimated the association of LTL with cotinine levels using quantile regression, and with smoking cessation dynamics. Cox regression was used to estimate mortality by smoking status and LTL. CONCLUSION: Our findings indicated a complex association between smoking, telomere length, and mortality. LTL alterations with SHS and smoking cessation warrant further investigation for translation to public health measures. PMID- 27509178 TI - Cancer diagnostics: The journey from histomorphology to molecular profiling. AB - Although histomorphology has made significant advances into the understanding of cancer etiology, classification and pathogenesis, it is sometimes complicated by morphologic ambiguities, and other shortcomings that necessitate the development of ancillary tests to complement its diagnostic value. A new approach to cancer patient management consists of targeting specific molecules or gene mutations in the cancer genome by inhibitory therapy. Molecular diagnostic tests and genomic profiling methods are increasingly being developed to identify tumor targeted molecular profile that is the basis of targeted therapy. Novel targeted therapy has revolutionized the treatment of gastrointestinal stromal tumor, renal cell carcinoma and other cancers that were previously difficult to treat with standard chemotherapy. In this review, we discuss the role of histomorphology in cancer diagnosis and management and the rising role of molecular profiling in targeted therapy. Molecular profiling in certain diagnostic and therapeutic difficulties may provide a practical and useful complement to histomorphology and opens new avenues for targeted therapy and alternative methods of cancer patient management. PMID- 27509179 TI - Heritability of Caffeine Metabolism: Environmental Effects Masking Genetic Effects on CYP1A2 Activity but Not on NAT2. AB - Heritability of caffeine pharmacokinetics and cytochrome P450 1A2 (CYP1A2) activity is controversial. Here, we analyzed the pharmacokinetics of caffeine, an in vivo probe drug for CYP1A2 and arylamine N-acetyltransferase 2 (NAT2) activity, in monozygotic (MZ) and dizygotic (DZ) twins. In the entire group, common and unique environmental effects explained most variation in caffeine area under the curve (AUC). Apparently, smoking and hormonal contraceptives masked the genetic effects on CYP1A2 activity. However, when excluding smokers and users of hormonal contraceptives, 89% of caffeine AUC variation was due to genetic effects and, even in the entire group, 8% of caffeine AUC variation could be explained by a CYP1A1/1A2 promotor polymorphism (rs2470893). In contrast, nearly all of the variations (99%) of NAT2 activity were explained by genetic effects. This study illustrates two very different situations in pharmacogenetics from an almost exclusively genetic determination of NAT2 activity with no environmental modulation to only moderate genetic effects on CYP1A2 activity with strong environmental modulation. PMID- 27509180 TI - Biocompatibility, resorption and biofunctionality of a new synthetic biodegradable membrane for guided bone regeneration. AB - Membranes for guided bone regeneration (GBR) were prepared from the synthetic biodegradable polymer poly-D,L-lactic/glycolic acid (PLGA). This GBR membrane has a bi-layered structure with a dense film to prevent gingival fibroblast ingrowth and ensure mechanical function, and a micro-fibrous layer to support colonization by osteogenic cells and promote bone regeneration. Hydrolysis and biodegradation were both studied in vitro through soaking in phosphate buffered saline (PBS) and in vivo by implantation in the subcutis of rats for 4, 8, 16, 26, 48 and 52 weeks. Histology revealed an excellent colonization of the micro-fibrous layer by cells with a minimal inflammatory reaction during resorption. GBR using the synthetic PLGA membrane was evaluated on critical-size calvaria defects in rats for 4 and 8 weeks. Radiographs, micro-computed tomography and histology showed bone regeneration with the PLGA membrane, while the defects covered with a collagen membrane showed a limited amount of mineralized bone, similar to that of the defect left empty. The biofunctionality of the PLGA membranes was also compared to collagen membranes in mandible defects in rabbits, associated or not with beta-tricalcium phosphate granules. This study revealed that the bi-layered synthetic membrane made of PLGA was safer, more biocompatible, and had a greater controlled resorption rate and bone regeneration capacity than collagen membranes. This new PLGA membrane could be used in pre-implantology and peri odontology surgery. PMID- 27509181 TI - Association between Single Nucleotide Polymorphisms in Gamma-Aminobutyric Acid B Receptor, Insulin Receptor Substrate-1, and Hypocretin Neuropeptide Precursor Genes and Susceptibility to Obstructive Sleep Apnea Hypopnea Syndrome in a Chinese Han Population. AB - OBJECTIVE: To investigate genotype-phenotype changes between rs29230 in gamma aminobutyric acid B receptor (GABBR1), rs1801278 in insulin receptor substrate-1 (IRS-1), and rs9902709 in hypocretin neuropeptide precursor (HCRT) and obstructive sleep apnea hypopnea syndrome (OSAHS) in Chinese Han individuals. MATERIALS AND METHODS: A total of 130 patients with OSAHS and 136 age- and gender matched healthy controls were enrolled in this study. A brief description of DNA extraction and genotyping is given. Multivariate unconditional logistic regression analysis adjusted for gender and age was used to estimate the associations of single nucleotide polymorphisms (SNPs) rs29230 (GABBR1), rs1801278 (IRS-1), and rs9902709 (HCRT) with OSAHS risk. Subgroup analysis was performed to evaluate differences in these SNPs among subgroups according to gender, body mass index (BMI), and severity of disease. RESULTS: Genotype and allele frequencies of rs29230 were significantly different between cases and controls (p = 0.0205 and p = 0.0191, respectively; odds ratio = 0.493, 95% confidence interval = 0.271-0.896), especially for male patients (p = 0.0259 and p = 0.0202, respectively). Subgroup analysis according to BMI also revealed a significant allele difference for rs29230 between cases and controls in the overweight subgroup (p = 0.0333). Furthermore, allele and genotype frequencies of rs1801278 showed significant differences between cases and controls (p = 0.0488 and p = 0.0471, respectively). However, no association was observed between rs9902709 and OSAHS risk (p = 0.2762), and no differences were identified in other subgroups. CONCLUSION: In this study, there was an association between variants of rs29230 and rs1801278 and OSAHS risk in the Chinese Han population but not for rs9902709. PMID- 27509182 TI - Facility-Level Factors Influencing Retention of Patients in HIV Care in East Africa. AB - Losses to follow-up (LTFU) remain an important programmatic challenge. While numerous patient-level factors have been associated with LTFU, less is known about facility-level factors. Data from the East African International epidemiologic Databases to Evaluate AIDS (EA-IeDEA) Consortium was used to identify facility-level factors associated with LTFU in Kenya, Tanzania and Uganda. Patients were defined as LTFU if they had no visit within 12 months of the study endpoint for pre-ART patients or 6 months for patients on ART. Adjusting for patient factors, shared frailty proportional hazard models were used to identify the facility-level factors associated with LTFU for the pre- and post-ART periods. Data from 77,362 patients and 29 facilities were analyzed. Median age at enrolment was 36.0 years (Interquartile Range: 30.1, 43.1), 63.9% were women and 58.3% initiated ART. Rates (95% Confidence Interval) of LTFU were 25.1 (24.7-25.6) and 16.7 (16.3-17.2) per 100 person-years in the pre-ART and post-ART periods, respectively. Facility-level factors associated with increased LTFU included secondary-level care, HIV RNA PCR turnaround time >14 days, and no onsite availability of CD4 testing. Increased LTFU was also observed when no nutritional supplements were provided (pre-ART only), when TB patients were treated within the HIV program (pre-ART only), and when the facility was open <=4 mornings per week (ART only). Our findings suggest that facility-based strategies such as point of care laboratory testing and separate clinic spaces for TB patients may improve retention. PMID- 27509183 TI - Older Rural- and Urban-Dwelling Appalachian Adults With Mild Cognitive Impairment. AB - PURPOSE: Mild cognitive impairment (MCI) is a well-recognized risk state for Alzheimer's disease and other dementias. MCI is rapidly increasing among older adults in general and has not yet been examined in older adults within the Appalachian region. Our objective was to compare MCI symptom severity among older rural and urban Appalachian adults with MCI at an initial neuropsychological testing visit. METHODS: A cross-sectional, descriptive study of older Appalachian adults with MCI was conducted using data from the National Alzheimer's Coordinating Center Uniform Data Set. Symptom severity was conceptualized as neuropsychological composite scores across 4 cognitive domains and Clinical Dementia Rating-Sum of Boxes (CDR-SOB) score. For group comparisons, MANCOVA was used for cognitive domains and ANCOVA for CDR-SOB. RESULTS: The sample (N = 289) was about half male (54.3%), predominantly white (91.7%), and living with others (83.5%), with a mean (+/-SD) 74.6 +/- 6.2 years of age and 15.4 +/- 3.0 years of education. Rural and urban groups differed significantly in years since onset of cognitive symptoms (2.98 +/- 1.91 in rural and 3.89 +/- 2.70 in urban adults, t[260] = -2.23, P = .03), but they did not differ across sociodemographic features or comorbid conditions. Rural and urban participants were similar across the 4 cognitive domains and CDR-SOB (P >= .05). DISCUSSION: No differences were found between rural and urban Appalachian residents on MCI symptom severity. However, urban residents reported a longer time lapse from symptom identification to diagnosis than their rural counterparts. Future studies using more representative population samples of Appalachian and non-Appalachian adults will provide an important next step to identifying disparate cognitive health outcomes in this traditionally underserved region. PMID- 27509184 TI - Identification of resveratrol analogs as potent anti-dengue agents using a cell based assay. AB - Dengue virus (DENV) causes a variety of difficult-to-treat diseases that threaten almost half of the world's population. Currently, no effective vaccine or antiviral therapy is available. We have examined a series of synthetic resveratrol analogs to identify potential anti-DENV agents. Here, we demonstrate that two resveratrol analogs, PNR-4-44 and PNR-5-02, possess potent anti-DENV activity with EC50 values in the low nanomolar range. These two resveratrol analogs were shown to mainly target viral RNA translation and viral replication, but PNR-5-02 is also likely to target cellular factors inside host cells. Although the precise molecular mechanism(s) mediating anti-DENV activities have not been elucidated, further structure-guided design might lead to the development of newer improved resveratrol derivatives that might have therapeutic value. J. Med. Virol. 89:397-407, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27509185 TI - From Metaphors to Formalism: A Heuristic Approach to Holistic Assessments of Ecosystem Health. AB - Environmental policies employ metaphoric objectives such as ecosystem health, resilience and sustainable provision of ecosystem services, which influence corresponding sustainability assessments by means of normative settings such as assumptions on system description, indicator selection, aggregation of information and target setting. A heuristic approach is developed for sustainability assessments to avoid ambiguity and applications to the EU Marine Strategy Framework Directive (MSFD) and OSPAR assessments are presented. For MSFD, nineteen different assessment procedures have been proposed, but at present no agreed assessment procedure is available. The heuristic assessment framework is a functional-holistic approach comprising an ex-ante/ex-post assessment framework with specifically defined normative and systemic dimensions (EAEPNS). The outer normative dimension defines the ex-ante/ex-post framework, of which the latter branch delivers one measure of ecosystem health based on indicators and the former allows to account for the multi-dimensional nature of sustainability (social, economic, ecological) in terms of modeling approaches. For MSFD, the ex ante/ex-post framework replaces the current distinction between assessments based on pressure and state descriptors. The ex-ante and the ex-post branch each comprise an inner normative and a systemic dimension. The inner normative dimension in the ex-post branch considers additive utility models and likelihood functions to standardize variables normalized with Bayesian modeling. Likelihood functions allow precautionary target setting. The ex-post systemic dimension considers a posteriori indicator selection by means of analysis of indicator space to avoid redundant indicator information as opposed to a priori indicator selection in deconstructive-structural approaches. Indicator information is expressed in terms of ecosystem variability by means of multivariate analysis procedures. The application to the OSPAR assessment for the southern North Sea showed, that with the selected 36 indicators 48% of ecosystem variability could be explained. Tools for the ex-ante branch are risk and ecosystem models with the capability to analyze trade-offs, generating model output for each of the pressure chains to allow for a phasing-out of human pressures. The Bayesian measure of ecosystem health is sensitive to trends in environmental features, but robust to ecosystem variability in line with state space models. The combination of the ex-ante and ex-post branch is essential to evaluate ecosystem resilience and to adopt adaptive management. Based on requirements of the heuristic approach, three possible developments of this concept can be envisioned, i.e. a governance driven approach built upon participatory processes, a science driven functional-holistic approach requiring extensive monitoring to analyze complete ecosystem variability, and an approach with emphasis on ex-ante modeling and ex post assessment of well-studied subsystems. PMID- 27509186 TI - Structural Insights into the PorK and PorN Components of the Porphyromonas gingivalis Type IX Secretion System. AB - The type IX secretion system (T9SS) has been recently discovered and is specific to Bacteroidetes species. Porphyromonas gingivalis, a keystone pathogen for periodontitis, utilizes the T9SS to transport many proteins including the gingipain virulence factors across the outer membrane and attach them to the cell surface via a sortase-like mechanism. At least 11 proteins have been identified as components of the T9SS including PorK, PorL, PorM, PorN and PorP, however the precise roles of most of these proteins have not been elucidated and the structural organization of these components is unknown. In this study, we purified PorK and PorN complexes from P. gingivalis and using electron microscopy we have shown that PorN and the PorK lipoprotein interact to form a 50 nm diameter ring-shaped structure containing approximately 32-36 subunits of each protein. The formation of these rings was dependent on both PorK and PorN, but was independent of PorL, PorM and PorP. PorL and PorM were found to form a separate stable complex. PorK and PorN were protected from proteinase K cleavage when present in undisrupted cells, but were rapidly degraded when the cells were lysed, which together with bioinformatic analyses suggests that these proteins are exposed in the periplasm and anchored to the outer membrane via the PorK lipid. Chemical cross-linking and mass spectrometry analyses confirmed the interaction between PorK and PorN and further revealed that they interact with the PG0189 outer membrane protein. Furthermore, we established that PorN was required for the stable expression of PorK, PorL and PorM. Collectively, these results suggest that the ring-shaped PorK/N complex may form part of the secretion channel of the T9SS. This is the first report showing the structural organization of any T9SS component. PMID- 27509187 TI - The Effect of High Dose Cholecalciferol on Arterial Stiffness and Peripheral and Central Blood Pressure in Healthy Humans: A Randomized Controlled Trial. AB - BACKGROUND: Low levels of serum 25-hydroxy vitamin D are associated with increased arterial stiffness and hypertension. Supplementation with vitamin D precursors has been proposed as a treatment option for these conditions. We examined the effect of oral cholecalciferol on arterial stiffness and blood pressure in healthy normotensive adults. METHODS: 40 healthy adults were randomised in this double-blinded study to either oral cholecalciferol 3000 IU/day or matching placebo and were followed for 16 weeks to examine any effects on pulse wave velocity (PWV), augmentation index (AIx), peripheral and central blood pressure and 24-hour ambulatory blood pressure. RESULTS: 22 subjects in the cholecalciferol arm and 18 subjects in the placebo arm completed the 16 weeks of follow-up. There was no difference in changes in PWV, AIx corrected for heart rate or central or peripheral blood pressure between the two groups. There was no correlation between serum 25-hydroxy vitamin D and any of these parameters. CONCLUSIONS: Oral cholecalciferol 3000 IU/day does not affect arterial stiffness or blood pressure after 16 weeks of treatment in healthy normotensive adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT00952562. PMID- 27509188 TI - A comparison of hemodynamic metrics and intraluminal thrombus burden in a common iliac artery aneurysm. AB - Aneurysms of the common iliac artery (CIAA) are typically found in association with an abdominal aortic aneurysm (AAA). Isolated CIAAs, in the absence of an AAA, are uncommon. Similar to AAAs, CIAA may develop intraluminal thrombus (ILT). As isolated CIAAs have a contralateral common iliac artery for comparison, they provide an opportunity to study the hemodynamic mechanisms behind ILT formation. In this study, we compared a large isolated CIAA and the contralateral iliac artery using computational fluid dynamics to determine if hemodynamic metrics correlate with the location of ILT. We performed a comprehensive computational fluid dynamics study and investigated the residence time of platelets and monocytes, velocity fields, time-averaged wall shear stress, oscillatory shear index, and endothelial cell activation potential. We then correlated these data to ILT burden determined with computed tomography. We found that high cell residence times, low time-averaged wall shear stress, high oscillatory shear index, and high endothelial cell activation potential all correlate with regions of ILT development. Our results show agreement with previous hypotheses of thrombus formation in AAA and provide insights into the computational hemodynamics of iliac artery aneurysms. PMID- 27509189 TI - Prevalence and Imaging Characteristics of Nonmyelopathic and Myelopathic Spondylotic Cervical Cord Compression. AB - STUDY DESIGN: Cross-sectional population-based observational study. OBJECTIVE: To estimate the prevalence of nonmyelopathic spondylotic cervical cord compression (NMSCCC) and cervical spondylotic myelopathy (CSM) in a population older than 40 years and to evaluate the magnetic resonance imaging (MRI) characteristics of these conditions. SUMMARY OF BACKGROUND DATA: The prevalence of neither NMSCCC nor CSM is known and there exists no commonly accepted quantitative MRI definition of cervical cord compression. METHODS: A group of 183 randomly recruited volunteers, 93 women, median age 66 years, range 40-80 years, underwent MRI examination of the cervical spine and spinal cord on a 1.5 T device using conventional sequences from disc levels C2/C3 to C6/C7. The imaging criterion for cervical cord compression was defined as a change in spinal cord contour at the level of an intervertebral disc on axial or sagittal MRI scan. RESULTS: MRI signs of cervical cord compression were found in 108 individuals (59.0%; 95% CI: 51.5% 66.2%); their numbers increased with age from 31.6% in the fifth decade to 66.8% in the eighth. Clinical signs of symptomatic CSM were found in two cases (1.1%), and 75 cases (41.0%) were without compression. An anteroposterior cervical canal diameter at the level of intervertebral disc (CDdisc) of less than 9.9 mm was associated with the highest probability of NMSCCC-odds ratio (OR) = 32.5, followed by a compression ratio of <=0.5: OR = 11.1. CONCLUSION: The prevalence of NMSCCC in a population older than 40 years is higher than previously reported and increases with age. CDdisc and compression ratio had the highest capacity to discriminate between subjects with and without asymptomatic compression, and their cut-off values could be used to objectify criteria for cervical cord compression. LEVEL OF EVIDENCE: 2. PMID- 27509190 TI - Instrumentation Failure After Posterior Vertebral Column Resection in Adult Spinal Deformity. AB - STUDY DESIGN: Retrospective study of instrumentation failure after posterior vertebral column resection (pVCR) in adult spinal deformity (ASD) patients. OBJECTIVE: The morbidity and related risk factors of the instrumentation failure. SUMMARY OF BACKGROUND DATA: Instrumentation failure is another common complication after pVCR. But no report about it has been published before. The safety of titanium mesh cages (TMCs) for this failure is still unknown so far. METHODS: A total of 35 consecutive ASD patients (18 females and 17 males), who underwent pVCR between May 2005 and December 2014 in our hospital, were retrospectively reviewed. The mean age and follow-up period were 37.8 +/- 12.8 years and 45.5 +/- 27.3 months. Proportion was used to describe the morbidity of instrumentation failure. Potential risk factors were compared between patients with and without instrumentation failures by using Student t test or chi tests (Fisher exact tests). Risk factors related to TMCs were analyzed in TMC group. RESULTS: There were 70 vertebra resected in total, with the mean of 10.3 segments instrumented. The mean correction rates of main curve (n = 25) and segmental kyphosis (n = 35) were 68.8% and 67.9%, respectively. Five patients (14.3%) suffered rod breakage. The failure was noted an average of 6.8 months after surgery. The risk factors included BMI (>27, P = 0.026), comorbidity (Achondroplasia, P = 0.047), and anterior column defect (ACD>20 mm, P = 0.045). TMC subsidence of >=5 mm was the risk factor related to TMC in TMC group (P = 0.041). CONCLUSION: It is safe to reconstruct with a TMC after pVCR in ASD, but the height should be as low as possible to reduce ACD. For those patients with risk factors, autologous bone graft and a satellite rod should be considered. If TMC subsidence >=5 mm, a frequent follow-up should be performed. LEVEL OF EVIDENCE: 4. PMID- 27509191 TI - The Facet Orientation of the Subaxial Cervical Spine and the Implications for Cervical Movements and Clinical Conditions. AB - STUDY DESIGN: Computed tomography study. OBJECTIVE: To obtain detailed information on the facet orientation in the subaxial cervical spine and explore the correlation to the cervical movements and relevant clinical conditions. SUMMARY OF BACKGROUND DATA: Although facet orientation was well studied in the lumbar spine, the literatures on the cervical facet orientation were limited and the descriptions were nonspecific. METHODS: The computed tomography scans of 100 individuals were reconstructed. For each level from C2/C3 to C6/C7, the horizontal plane, the mid-sagittal plane, the coronal plane, and the two facet planes were established. The normal vectors of the five planes were used for the calculation of the facet orientation and the facet tropism. RESULTS: The angle of the facet plane with respect to the horizontal plane at the C6/7 level was the largest (left side: 64.34 degrees +/- 6.60 degrees , right side: 63.37 degrees +/- 6.81 degrees , P >0.05). The angle of the facet plane with respect to the coronal plane decreased from C2/C3 level to C6/C7 level. Regarding the angle of the facet plane with respect to the sagittal plane, for the paired facet joints, three types were found: posteromedially oriented, posterolaterally oriented, and ipsilaterally oriented. All (100%) of the facet joints at the C2/C3 level and 65% at the C3/C4 level were posteromedially oriented. In the lower levels of the cervical spine, the posteromedially oriented facet joints were less common. The facet tropism was common phenomenon in the subaxial cervical spine. CONCLUSION: This study provided detailed information on the facet orientation in the subaxial cervical spine. The cervical facet orientation correlated well with the spinal movements and related clinical conditions. LEVEL OF EVIDENCE: 3. PMID- 27509192 TI - The Influence of Pre- and Postoperative Fear Avoidance Beliefs on Postoperative Pain and Disability in Patients With Lumbar Spinal Stenosis: Analysis of the Lumbar Spinal Outcome Study (LSOS) Data. AB - STUDY DESIGN: Prospective multicenter cohort study. OBJECTIVE: To evaluate the effect of pre- and postoperatively assessed fear avoidance beliefs (FAB) on pain and disability in patients with degenerative lumbar spinal stenosis (LSS) after decompression surgery. SUMMARY OF BACKGROUND DATA: To the present, the influence of pre- and postoperative FAB on the prognosis after surgery for LLS is still unclear. METHODS: Patients of the Swiss Lumbar Stenosis Outcome Study (LSOS) with confirmed LSS undergoing first-time decompression without fusion were enrolled in this study. The main outcome of this study was minimal clinically important difference (MCID) in spinal stenosis measure symptoms (pain) and function (disability) after 12 months. To analyze the influence of pre- and postoperatively assessed FAB on pain and disability we built simple and multiple logistic regression models. RESULTS: In this analysis of 234 patients undergoing decompression surgery for symptomatic degenerative LSS we found baseline FAB measured by the FAB physical activity subscale (FABQ-P) not to be associated with pain (OR 0.95; 95% CI: 0.55-1.67) and disability (OR 1.11; 95% CI: 0.64-1.92) at 12 months' follow-up. In the final multiple logistic regression models patients with high FABQ-P at 6 months (OR 0.46; 95% CI: 0.24-0.91) and high persistent FABQ-P at baseline and 6 months (OR 0.34, 95% CI: 0.16-0.73) were less likely to report a MCID for spinal stenosis measure symptoms at 12 months. Our analysis found a similar trend for disability; however, the results were not statistically significant. CONCLUSION: In elderly patients undergoing decompression surgery for symptomatic degenerative LSS preoperative fear avoidance beliefs were not a prognostic indicator for the outcome. Patients with FAB at 6 months and persistent FAB were less likely to experience clinically relevant improvement in pain at 12 months. Studies should address the importance of persistent postoperative FAB. LEVEL OF EVIDENCE: 3. PMID- 27509193 TI - Soft Tissue and Bone Defect Management in Total Sacrectomy for Primary Sacral Tumors: A Systematic Review With Expert Recommendations. AB - STUDY DESIGN: Systematic review and expert consensus. OBJECTIVE: To address the following two questions: (A) Is there a difference in outcomes after spino-pelvic reconstruction of total sacrectomy defects compared with no reconstruction? (B) What constitutes best surgical technique for soft tissue and bony reconstruction after total sacrectomy? SUMMARY OF BACKGROUND DATA: The management of the soft tissue and bony defect after total sacrectomy for primary sacral tumors remains a challenge due to the complex anatomical relationships and biomechanical requirements. The scarcity of evidence-based literature in this specialized field makes it difficult for the treating surgeon to make an informed choice. METHODS: A systematic literature review was performed (1950-2015), followed by a meeting of an international expert panel. Medline, Embase, and CINAHL databases and Cochrane Libraries were searched. Using the GRADE guidelines, the panel of experts formulated recommendations based on the available evidence. RESULTS: Three hundred fifty-three studies were identified. Of these, 17 studies were included and were case series. Seven were evaluated as high quality of evidence and nine were of low quality. There were a total of 116 participants. Three studies included patients (n = 24) with no spino-pelvic reconstruction. One study included patients (n = 3) with vascularized bone reconstruction. Twelve studies included patients (n = 80) with no soft tissue reconstruction, three studies described patients with a local flap (n = 20), and four studies with patients having regional flap reconstruction (n = 16). Patients with or without spino pelvic reconstruction had similar outcomes with regards to walking; however, most patients in the nonreconstructed group had some ilio-lumbar ligamentous stability preserved. The wound dehiscence and return to theater rates were higher in patients with no soft tissue reconstruction. CONCLUSION: We recommend spino pelvic reconstruction be undertaken with soft tissue reconstruction after total sacrectomy. LEVEL OF EVIDENCE: N/A. PMID- 27509194 TI - Changing the Adverse Event Profile in Metastatic Spine Surgery: An Evidence-Based Approach to Target Wound Complications and Instrumentation Failure. AB - STUDY DESIGN: Systematic review. OBJECTIVE: To identify risk factors and preventive methods for wound complications and instrumentation failure after metastatic spine surgery. SUMMARY OF BACKGROUND DATA: We focused on two postoperative complications of metastatic spine tumor surgery: wound complications and instrumentation failure and preventive measures. METHODS: We performed a systematic review of the literature from 1980 to 2015. The articles were analyzed for the presence of documented infection and/or wound complications and instrumentation failure. RESULTS: Forty articles met our inclusion criteria for wound complications and prevention. There is very low level of evidence that preoperative radiation, preoperative neurological deficit, revision procedures, and posterior approaches can contribute to wound complications (infections, wound dehiscence). There is very low level of evidence that plastic surgery soft tissue reconstruction, intrawound vancomycin powder, and percutaneous pedicle screws may prevent postoperative wound complications. Fourteen articles met our inclusion criteria for instrumentation failure. There is very low level of evidence that constructs greater than six levels, positive sagittal balance, preoperative radiation, and history of chest wall resection can contribute to implant failures. CONCLUSION: * For patients undergoing revision metastatic spine tumor surgery, plastic surgery should perform the soft tissue reconstruction (strong recommendation/very low quality of evidence).* For patients undergoing metastatic spine tumor surgery, plastic surgery may perform immediate soft tissue reconstruction (weak recommendation/very low quality of evidence).* For patients undergoing metastatic spine tumor surgery, intrawound vancomycin can be applied to decrease the risk of postoperative wound infections (weak recommendation/very low quality of evidence).* For patients undergoing metastatic spine tumor surgery, percutaneous pedicle screws can be placed to decrease the risk of postoperative wound complications (weak recommendation/very low quality of evidence).* Instrumentation failure risk factors include constructs greater than six levels, positive sagittal balance, preoperative radiation, and history of chest wall resections (weak recommendation/very low quality of evidence). LEVEL OF EVIDENCE: N/A. PMID- 27509195 TI - Safety and Local Control of Radiation Therapy for Chordoma of the Spine and Sacrum: A Systematic Review. AB - STUDY DESIGN: Systematic literature review. OBJECTIVE: To assess the toxicity, common radiation doses, and local control (LC) rates of radiation therapy for chordoma of the spine and sacrum and identify the difference in LC and toxicity between adjuvant, salvage, and primary therapy using radiation. SUMMARY OF BACKGROUND DATA: Chordoma of the spine is typically a low-grade malignant tumor thought to be relatively radioresistant with a high rate of local recurrence and the potential for metastases. Improved results of modern radiation therapy in the treatment of chordoma support exploration of its role in the management of primary/de novo chordoma or recurrent chordoma. METHODS: We conducted a systematic literature review using PubMed and Embase databases to assess information available regarding the toxicity, LC rates, and overall survival (OS) rates for adjuvant, salvage, and primary radiation therapy for spinal and sacral chordoma. RESULTS: A total of 40 articles were reviewed. Evidence quality was low or very low. The highest rates of LC and OS were with early adjuvant RT for primary/de novo disease. Salvage RT for recurrent disease has very small cohorts and thus strong conclusions were not able be made. CONCLUSION: The use of pre- and/or post-operative photon image-guided radiotherapy (IGRT), proton or carbon ion therapy should be considered for patients undergoing surgery for the treatment of primary and recurrent chordomas in the mobile spine and sacrum, since these RT modalities may improve local control. Preoperative evaluation by the surgeon and radiation oncologist should be used to formulate a cohesive treatment plan.The use of photon IGRT or carbon ion therapy as the primary treatment of chordoma, when currently in its developmental stage, shows promise and requires clear delineation of toxicity profile and long-term local control. LEVEL OF EVIDENCE: 2. PMID- 27509197 TI - Oscillations of Bubble Shape Cause Anomalous Surfactant Diffusion: Experiments, Theory, and Simulations. AB - We investigate, both theoretically and experimentally, the role played by the oscillations of the cell membrane on the capture rate of substances freely diffusing around the cell. To obtain quantitative results, we propose and build up a reproducible and tunable biomimetic experimental model system to simulate the phenomenon of an oscillation-enhanced (or depressed) capture rate (chemoreception) of a diffusant. The main advantage compared to real biological systems is that the different oscillation parameters (type of deformation, frequencies, and amplitudes) can be finely tuned. The model system that we use is an anchored gas drop submitted to a diffusive flow of charged surfactants. When the surfactant meets the surface of the bubble, it is reversibly adsorbed. Bubble oscillations of the order of a few nanometers are selectively excited, and surfactant transport is accurately measured. The surfactant concentration past the oscillating bubbles was detected by conductivity measurements. The results highlight the role of surface oscillations on the diffusant capture rate. Particularly unexpected is the onset of intense overshoots during the adsorption process. The phenomenon is particularly relevant when the bubbles are exposed to intense forced oscillations near resonance. PMID- 27509198 TI - Pyridyl-alanine as a Hydrophilic, Aromatic Element in Peptide Structural Optimization. AB - Glucagon (Gcg) 1 serves a seminal physiological role in buffering against hypoglycemia, but its poor biophysical properties severely complicate its medicinal use. We report a series of novel glucagon analogues of enhanced aqueous solubility and stability at neutral pH, anchored by Gcg[Aib16]. Incorporation of 3- and 4-pyridyl-alanine (3-Pal and 4-Pal) enhanced aqueous solubility of glucagon while maintaining biological properties. Relative to native hormone, analogue 9 (Gcg[3-Pal6,10,13, Aib16]) demonstrated superior biophysical character, better suitability for medicinal purposes, and comparable pharmacology against insulin-induced hypoglycemia in rats and pigs. Our data indicate that Pal is a versatile surrogate to natural aromatic amino acids and can be employed as an alternative or supplement with isoelectric adjustment to refine the biophysical character of peptide drug candidates. PMID- 27509199 TI - Rock Outcrops Redistribute Organic Carbon and Nutrients to Nearby Soil Patches in Three Karst Ecosystems in SW China. AB - Emergent rock outcrops are common in terrestrial ecosystems. However, little research has been conducted regarding their surface function in redistributing organic carbon and nutrient fluxes to soils nearby. Water that fell on and ran off 10 individual rock outcrops was collected in three 100 * 100 m plots within a rock desertification ecosystem, an anthropogenic forest ecosystem, and a secondary forest ecosystem between June 2013 and June 2014 in Shilin, SW China. The concentrations of total organic carbon (TOC), total nitrogen (N), total phosphorus (P), and potassium (K) in the water samples were determined during three seasons, and the total amounts received by and flowing out from the outcrops were calculated. In all three ecosystems, TOC and N, P, and K were found throughout the year in both the water received by and delivered to nearby soil patches. Their concentrations and amounts were generally greater in forested ecosystems than in the rock desertification ecosystem. When rock outcrops constituted a high percentage (>= 30%) of the ground surface, the annual export of rock outcrop runoff contributed a large amount of organic carbon and N, P, and K nutrients to soil patches nearby by comparison to the amount soil patches received via atmospheric deposition. These contributions may increase the spatial heterogeneity of soil fertility within patches, as rock outcrops of different sizes, morphologies, and emergence ratios may surround each soil patch. PMID- 27509200 TI - Structure of polysaccharide moiety of Pseudomonas xanthomarina KMM 1447T lipopolysaccharide. AB - The structural analysis of a polysaccharide moiety of Pseudomonas xanthomarina KMM 1447T lipopolysaccharide (LPS) was carried out. Mild acid degradation of LPS resulted in identification of two polysaccharides. The major one was built of beta-D-GlcpNAcA residues amidated with L-Ala and Gly residues randomly. The minor polysaccharide was composed of branched tetrasaccharide repeating units constituted by two D-Galr, D-GalpNAc and ether of D-Glc with (2R,4R)-2,4 dihydroxypentanoic acid lactone (2R,4R-Dhpl): ->3)-alpha-D-Galr-(1 -> 3)-beta-D Galr-(1 -> 3)-[beta-D-Glcp4(2R,4R-Dhpl)-(1 -> 4)]-beta-D-GalpNAc-(1 -> . PMID- 27509201 TI - Structure of repeating unit of the capsular polysaccharide from Acinetobacter baumannii D78 and assignment of the K4 gene cluster. AB - The structure of the K4 capsular polysaccharide (CPS) from a multiply antibiotic resistant Acinetobacter baumannii isolate D78 was elucidated by chemical and spectroscopical analysis. The K4 repeating unit is composed entirely by aminosugars and the trisaccharide repeating unit of the backbone polysaccharide is branched with a terminal N-acetyl-galactosamine capped with pyruvate as cyclic acetal. Each residue is in the pyranose form, alpha configured at the anomeric center, and has the D absolute configuration. The genes responsible for the synthesis of the K4 repeat unit and its polymerization and export are found in the capsule locus KL4 present in D78. The pyruvate acetal addition to galactosamine is formed by Ptr1, a novel pyruvate transferase, encoded at this locus. PMID- 27509202 TI - The Relationship between the Clinical Progression of Benign Prostatic Hyperplasia and Metabolic Syndrome: A Prospective Study. AB - OBJECTIVE: To investigate whether metabolic syndrome (MetS) may be associated with the clinical progression of benign prostatic hyperplasia (BPH). METHODS: A total of 525 community-dwelling men (aged 45-78) with lower urinary tract symptoms (LUTS) who had complete data at 3-year follow-up were included in this prospective study. International Prostate Symptom Score (IPSS) questionnaire, prostate ultrasonography for prostate volume (PV), maximum urine flow rate (Qmax) and biological parameters were recorded. Participants were divided into a BPH with the MetS group and a BPH without the MetS group, and all received a 3-year follow-up to monitor possible correlations between LUTS/BPH clinical progression and MetS. RESULTS: The results showed that MetS was associated with IPSS, Qmax and PV (p < 0.05) after 3-year follow-up. The mean change of IPSS, PV and Qmax were positively and negatively correlated with time in the BPH with MetS group during the 3-year follow-up. In addition, the BPH clinical progression rate was significantly higher in the BPH with MetS group, compared with the BPH without MetS group (p < 0.05). Diabetes mellitus (DM) and hypertension were related to increased risk of BPH clinical progression. CONCLUSIONS: The present results suggest that MetS, in particular, DM and hypertension, may accelerate the clinical progression of BPH in community-dwelling middle-aged and older men. PMID- 27509204 TI - Quantitation of the DNA Adduct of Semicarbazide in Organs of Semicarbazide Treated Rats by Isotope-Dilution Liquid Chromatography-Tandem Mass Spectrometry: A Comparative Study with the RNA Adduct. AB - Semicarbazide is a widespread food contaminant that is produced by multiple pathways. However, the toxicity of semicarbazide to human health remains unclear. Using a highly accurate and sensitive isotope-dilution liquid chromatography tandem mass spectrometry method, we identified and quantitated in this study for the first time the DNA and RNA adduct of semicarbazide in DNA/RNA isolated from the internal organs of semicarbazide-exposed rats. The analysis revealed a dose dependent formation of the adducts in the internal organs of the semicarbazide dosed rats and with the highest adduct levels identified in the stomach and small intestine. Furthermore, results showed significantly higher levels of the RNA adduct (4.1-7.0 times) than that of the DNA adducts. By analyzing DNA/RNA samples isolated from rat organs in semicarbazide-dosed rats at different time points postdosing, the adduct stability in vivo was also investigated. These findings suggest that semicarbazide could have exerted its toxicity by affecting both the transcription and translation processes of the cell. PMID- 27509203 TI - Relationship of Physical Intimate Partner Violence with Mental Health Diagnoses in the Nationwide Emergency Department Sample. AB - OBJECTIVES: We examined associations of physical intimate partner violence (PIPV) with selected mental health disorders using a nationally representative sample of emergency department (ED) discharges corresponding to men and women (18-64 years) from the 2010 Nationwide Emergency Department Sample. METHODS: PIPV was determined using International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) external cause of injury code E967.3 (battering by spouse or partner). ICD-9-CM clinical classification of discharge diagnoses was used to identify mental health disorders. Multivariable logistic regression models were constructed to estimate adjusted odds ratios (ORadj) and their 95% confidence intervals (CIs). RESULTS: PIPV prevalence was estimated at 0.36 per 1000 ED discharges. The strongest correlates of PIPV were alcohol-related (ORadj = 3.02, 95% CI: 2.62-3.50), adjustment (ORadj = 2.37, 95% CI: 1.56-3.58), intentional self-harm (ORadj = 1.41, 95% CI: 1.05-1.89), anxiety (ORadj = 1.23, 95% CI: 1.07 1.40), drug-related (ORadj = 1.22, 95% CI: 1.01-1.47), and mood (ORadj = 1.16, 95% CI: 1.04-1.31) disorders. PIPV's association with alcohol-related disorders was stronger among women (ORadj = 3.22, 95% CI: 2.79-3.72) versus men (ORadj = 1.98, 95% CI: 1.42-2.77). Similarly, drug-related disorders were stronger correlates of PIPV among women (ORadj = 1.32, 95% CI: 1.09-1.60) versus men (ORadj = 0.59, 95% CI: 0.31-1.16). CONCLUSIONS: In EDs, PIPV was linked to several mental health disorders, with women experiencing comorbid PIPV and substance use more frequently than men. PMID- 27509205 TI - The Characteristics and Prognostic Effect of E-Cadherin Expression in Colorectal Signet Ring Cell Carcinoma. AB - PURPOSE: Signet ring cell carcinoma (SRCC) is rare. The aim of this study is to understand the clinicopathological features and identify the possible prognostic factors in colorectal SRCC. METHODS: Patients with SRCC who underwent primary lesion resection at Fudan University Shanghai Cancer Center from September 2008 to July 2014 were retrospectively analyzed. Patient's gender, age, tumor location, depth of invasion, lymph node metastasis, synchronous distant metastasis, perineural invasion, lymphovascular invasion, and E-cadherin expression were studied with prognosis, and the correlation between E-cadherin expression and clinicopathological features were analyzed. All clinicopathological and molecular factors were put into multivariate analysis using Cox proportional hazards model for detecting independent prognostic factors. RESULTS: 59 patients accounting for 0.89% of total colorectal cancer patients met the criteria and were enrolled in the study. The median survival time is 28.9 months, and the 3-year survival rate is 62.7%. SRCC were seen more common in young male patients. Advanced stage was more common in SRCC, 58 (98.3%) patients had T3/T4 lesions, 52 (88.1%) patients had lymph node metastasis, and 14 (23.7%) patients had distant metastasis. Distant metastases were seen more common in peritoneal cavity. Distant metastasis (HR = 4.194, 95% CI: 1.297-13.567), lymphovascular invasion (HR = 2.888, 95% CI: 1.115-7.483), and E-cadherin expression (HR = 0.272, 95% CI: 0.096-0.768) were independent predictors for survival. CONCLUSIONS: SRCC is a rare subtype of colorectal cancer with poor prognosis. Distant metastasis, lymphovascular invasion, and E-cadherin expression can predict prognosis of colorectal SRCCs independently. More precise therapy and more close surveillance are needed for these patients. PMID- 27509206 TI - A Picea crassifolia Tree-Ring Width-Based Temperature Reconstruction for the Mt. Dongda Region, Northwest China, and Its Relationship to Large-Scale Climate Forcing. AB - The historical May-October mean temperature since 1831 was reconstructed based on tree-ring width of Qinghai spruce (Picea crassifolia Kom.) collected on Mt. Dongda, North of the Hexi Corridor in Northwest China. The regression model explained 46.6% of the variance of the instrumentally observed temperature. The cold periods in the reconstruction were 1831-1889, 1894-1901, 1908-1934 and 1950 1952, and the warm periods were 1890-1893, 1902-1907, 1935-1949 and 1953-2011. During the instrumental period (1951-2011), an obvious warming trend appeared in the last twenty years. The reconstruction displayed similar patterns to a temperature reconstruction from the east-central Tibetan Plateau at the inter decadal timescale, indicating that the temperature reconstruction in this study was a reliable proxy for Northwest China. It was also found that the reconstruction series had good consistency with the Northern Hemisphere temperature at a decadal timescale. Multi-taper method spectral analysis detected some low- and high-frequency cycles (2.3-2.4-year, 2.8-year, 3.4-3.6-year, 5.0 year, 9.9-year and 27.0-year). Combining these cycles, the relationship of the low-frequency change with the Pacific Decadal Oscillation (PDO), North Atlantic Oscillation (NAO) and Southern Oscillation (SO) suggested that the reconstructed temperature variations may be related to large-scale atmospheric-oceanic variations. Major volcanic eruptions were partly reflected in the reconstructed temperatures after high-pass filtering; these events promoted anomalous cooling in this region. The results of this study not only provide new information for assessing the long-term temperature changes in the Hexi Corridor of Northwest China, but also further demonstrate the effects of large-scale atmospheric oceanic circulation on climate change in Northwest China. PMID- 27509207 TI - New Mechanistic Pathways for Criegee-Water Chemistry at the Air/Water Interface. AB - Understanding Criegee chemistry has become one of central topics in atmospheric research recently. The reaction of Criegee intermediates with gas-phase water clusters has been widely viewed as a key Criegee reaction in the troposphere. However, the effect of aerosols or clouds on Criegee chemistry has received little attention. In this work, we have investigated the reaction between the smallest Criegee intermediate, CH2OO, and water clusters in the gas phase, as well as at the air/water surface using ab initio quantum chemical calculations and adaptive buffered force quantum mechanics/molecular mechanics (QM/MM) dynamics simulations. Our simulation results show that the typical time scale for the reaction of CH2OO with water at the air/water interface is on the order of a few picoseconds, 2-3 orders of magnitude shorter than that in the gas phase. Importantly, the adbf-QM/MM dynamics simulations suggest several reaction pathways for the CH2OO + water reaction at the air/water interface, including the loop-structure-mediated mechanism and the stepwise mechanism. Contrary to the conventional gas-phase CH2OO reaction, the loop-structure is not a prerequisite for the stepwise mechanism. For the latter, a water molecule and the CH2OO at the air/water interface, upon their interaction, can result in the formation of (H3O)(+) and (OH)CH2(OO)(-). Thereafter, a hydrogen bond can be formed between (H3O)(+) and the terminal oxygen atom of (OH)CH2(OO)(-), leading to direct proton transfer and the formation of alpha-hydroxy methylperoxide, HOCH2OOH. The mechanistic insights obtained from this simulation study should motivate future experimental studies of the effect of water clouds on Criegee chemistry. PMID- 27509208 TI - Netrin-1 Reduces Monocyte and Macrophage Chemotaxis towards the Complement Component C5a. AB - Netrin-1, acting at its cognate receptor UNC5b, has been previously demonstrated to inhibit CC chemokine-induced immune cell migration. In line with this, we found that netrin-1 was able to inhibit CCL2-induced migration of bone marrow derived macrophages (BMDMs). However, whether netrin-1 is capable of inhibiting chemotaxis to a broader range of chemoattractants remains largely unexplored. As our initial experiments demonstrated that RAW264.7 and BMDMs expressed high levels of C5a receptor 1 (C5aR1) on their surface, we aimed to determine the effect of netrin-1 exposure on monocyte/macrophage cell migration induced by C5a, a complement peptide that plays a major role in multiple inflammatory pathologies. Treatment of RAW264.7 macrophages, BMDMs and human monocytes with netrin-1 inhibited their chemotaxis towards C5a, as measured using two different real-time methods. This inhibitory effect was found to be dependent on netrin-1 receptor signalling, as an UNC5b blocking antibody was able to reverse netrin-1 inhibition of C5a induced BMDM migration. Treatment of BMDMs with netrin-1 had no effect on C5aR1 proximal signalling events, as surface C5aR1 expression, internalisation and intracellular Ca2+ release following C5aR1 ligation remained unaffected after netrin-1 exposure. We next examined receptor distal events that occur following C5aR1 activation, but found that netrin-1 was unable to inhibit C5a induced phosphorylation of ERK1/2, Akt and p38, pathways important for cellular migration. Furthermore, netrin-1 treatment had no effect on BMDM cytoskeletal rearrangement following C5a stimulation as determined by microscopy and real-time electrical impedance sensing. Taken together these data highlight that netrin-1 inhibits monocyte and macrophage cell migration, but that the mechanism behind this effect remains unresolved. Nevertheless, netrin-1 and its cognate receptors warrant further investigation as they may represent a potential avenue for the development of novel anti-inflammatory therapeutics. PMID- 27509210 TI - Gender differences in the effect of grief reactions and burnout on emotional distress among clinical oncologists. AB - BACKGROUND: The current study was conducted to examine gender differences in the effect of grief reactions and burnout on emotional distress among clinical oncologists. METHODS: The participants included a convenience sample of 178 oncologists from Israel (52 of whom were women) and Canada (48 of whom were women). Oncologists completed a questionnaire package that included a sociodemographic survey, the General Health Questionnaire, a burnout measure, and the Adult Oncologists Grief Questionnaire. To examine the effect of grief reactions and burnout on emotional distress while controlling for country and past depression within each gender, 2 hierarchical linear regression analyses were computed. RESULTS: Female oncologists reported significantly more grief responses to patient death (mean, 47.72 [standard deviation (SD), 8.71] and mean, 44.53 [SD, 9.19], respectively), more emotional distress (mean, 12.41 [SD, 4.36] and mean, 10.64 [SD, 3.99], respectively), and more burnout (mean, 2.59 [SD, 1.69] and mean, 1.84 [SD, 1.5], respectively). For both genders, higher levels of grief reactions were associated with greater emotional distress among those who reported high levels of burnout (P<.001). However, for men, the association between grief reactions and emotional distress also was documented at moderate levels of burnout (P<.001). CONCLUSIONS: Patient death is a regular part of clinical oncology. It is essential that oncologists be able to cope effectively with this aspect of their work. The findings of the current study highlight the need to take into account the cumulative stressors that oncologists contend with when designing supportive interventions. Gender differences in burnout, reactions to patient death, and emotional distress need to be addressed to ensure the best quality of life for oncologists and the best quality of care for their patients. Cancer 2016;122:3705-14. (c) 2016 American Cancer Society. PMID- 27509209 TI - The Impact of Cortical Lesions on Thalamo-Cortical Network Dynamics after Acute Ischaemic Stroke: A Combined Experimental and Theoretical Study. AB - The neocortex and thalamus provide a core substrate for perception, cognition, and action, and are interconnected through different direct and indirect pathways that maintain specific dynamics associated with functional states including wakefulness and sleep. It has been shown that a lack of excitation, or enhanced subcortical inhibition, can disrupt this system and drive thalamic nuclei into an attractor state of low-frequency bursting and further entrainment of thalamo cortical circuits, also called thalamo-cortical dysrhythmia (TCD). The question remains however whether similar TCD-like phenomena can arise with a cortical origin. For instance, in stroke, a cortical lesion could disrupt thalamo-cortical interactions through an attenuation of the excitatory drive onto the thalamus, creating an imbalance between excitation and inhibition that can lead to a state of TCD. Here we tested this hypothesis by comparing the resting-state EEG recordings of acute ischaemic stroke patients (N = 21) with those of healthy, age matched control-subjects (N = 17). We observed that these patients displayed the hallmarks of TCD: a characteristic downward shift of dominant alpha-peaks in the EEG power spectra, together with increased power over the lower frequencies (delta and theta-range). Contrary to general observations in TCD, the patients also displayed a broad reduction in beta-band activity. In order to explain the genesis of this stroke-induced TCD, we developed a biologically constrained model of a general thalamo-cortical module, allowing us to identify the specific cellular and network mechanisms involved. Our model showed that a lesion in the cortical component leads to sustained cell membrane hyperpolarization in the corresponding thalamic relay neurons, that in turn leads to the de-inactivation of voltage-gated T-type Ca2+-channels, switching neurons from tonic spiking to a pathological bursting regime. This thalamic bursting synchronises activity on a population level through divergent intrathalamic circuits, and entrains thalamo cortical pathways by means of propagating low-frequency oscillations beyond the restricted region of the lesion. Hence, pathological stroke-induced thalamo cortical dynamics can be the source of diaschisis, and account for the dissociation between lesion location and non-specific symptoms of stroke such as neuropathic pain and hemispatial neglect. PMID- 27509211 TI - Branched Fatty Acid Esters of Hydroxy Fatty Acids Are Preferred Substrates of the MODY8 Protein Carboxyl Ester Lipase. AB - A recently discovered class of endogenous mammalian lipids, branched fatty acid esters of hydroxy fatty acids (FAHFAs), possesses anti-diabetic and anti inflammatory activities. Here, we identified and validated carboxyl ester lipase (CEL), a pancreatic enzyme hydrolyzing cholesteryl esters and other dietary lipids, as a FAHFA hydrolase. Variants of CEL have been linked to maturity-onset diabetes of the young, type 8 (MODY8), and to chronic pancreatitis. We tested the FAHFA hydrolysis activity of the CEL MODY8 variant and found a modest increase in activity as compared with that of the normal enzyme. Together, the data suggest that CEL might break down dietary FAHFAs. PMID- 27509212 TI - Fear of Cancer Recurrence and Its Impacts on Quality of Life in Family Caregivers of Patients With Head and Neck Cancers. AB - BACKGROUND: Fear of cancer recurrence (FCR) is a major concern for family caregivers (FCs) caring for patients with head and neck cancers (HNCs). PURPOSE: This study (a) investigated the FCR experience of HNC FCs, (b) compared the differences in the FCR levels of FCs while taking care of patients with different lengths of time since completing major treatments (posttreatment durations), and (c) examined the correlation between FCR and quality of life (QOL) in these FCs. METHODS: A cross-sectional study was conducted in the radiation outpatient department of a medical center in northern Taiwan. A set of questionnaires, including the Fear of Cancer Recurrence Inventory-Caregiver version and the Medical Outcomes Short-Form Health Survey, and a background information form were employed. One-way analysis of variance was used to examine the differences in the FCR and QOL among groups of FCs taking care of patients with different posttreatment durations (typically concurrent chemoradiotherapy). Pearson's correlation was used to identify the relationship between FCR and QOL. RESULTS: Two hundred fifty FCs were recruited in this study. The FCs used several coping and reassurance strategies to address their FCR experiences. Those FCs who cared for patients with short posttreatment durations (3-6 and 6-12 months) showed significantly higher overall FCR levels and higher FCR severity levels than those who cared for patients with long posttreatment durations (more than 5 years). High FCR was negatively correlated with physical and mental QOL. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The results suggest that FCs caring for patients with a relatively short posttreatment duration experience higher levels of FCR than those caring for patients with a longer posttreatment duration. In clinical settings, healthcare providers should use posttreatment duration as an indicator of risk of FCR in caregivers to address FCR and provide appropriate support. Future research should develop and examine interventions to help HNC FCs cope effectively with their FCR and improve their QOL. PMID- 27509213 TI - Oxytetracycline Delivery in Adult Female Zebrafish by Iron Oxide Nanoparticles. AB - Recently, the indiscriminate use of antibiotics in the aquaculture sector has raised public concern because of possible toxic effects, development of bacterial resistance, and accumulation of residues in individual tissues. Even if several countries have developed regulations about their use, it is clear that long-term growth of the aquaculture industry requires both ecologically sound practices and sustainable resource management. Alternative strategies for better management of antibiotic administration are of primary interest to improve absorption rates and, as a consequence, to reduce their release into the aquatic environment. The present study investigates, for the first time to our knowledge, a new methodology for oxytetracycline (OTC) administration through the use of iron oxide nanoparticles (NPs) (made of maghemite gamma-Fe2O3) in zebrafish (Danio rerio). Fish were divided into 4 experimental groups: control; group A exposed to 4 mg/L OTC (through water); group B exposed to the 100 mg/L SAMNs@OTC complex (equivalent to 4 mg/L OTC), and group C exposed to bare NPs. No detoxification processes or anatomical alterations were observed in fish exposed to bare NPs. Exposure of fish to the SAMNs@OTC complex resulted in a 10 times higher OTC accumulation with respect to using water exposure. This new OTC administration method seems much more efficient with respect to the traditional way of exposure and has the potentiality to reduce antibiotic utilization and possible environmental impacts. However, the dynamics related to OTC release from the SAMNs@OTC complex are still not clear and need further investigations. PMID- 27509214 TI - The use of leucocyte and platelet-rich fibrin in socket management and ridge preservation: a split-mouth, randomized, controlled clinical trial. AB - AIM: To investigate the influence of the use L-PRF as a socket filling material and its ridge preservation properties. MATERIALS AND METHODS: Twenty-two patients in need of single bilateral and closely symmetrical tooth extractions in the maxilla or mandible were included in a split-mouth RCT. Treatments were randomly assigned (L-PRF socket filling versus natural healing). CBCT scans were obtained after tooth extraction and three months. Scans were evaluated by superimposition using the original DICOM data. Mean ridge width differences between timepoints were measured at three levels below the crest on both the buccal and lingual sides (crest -1 mm (primary outcome variable), -3 mm and -5 mm). RESULTS: Mean vertical height changes at the buccal were -1.5 mm (+/-1.3) for control sites and 0.5 mm (+/-2.3) for test sites (p < 0.005). At the buccal side, control sites values were, respectively, -2.1 (+/-2.5), -0.3 mm (+/-0.3) (p < 0.005) and -0.1 mm (+/-0.0), and test sites values were, respectively, -0.6 mm (+/-2.2) (p < 0.005), -0.1 mm (+/-0.3) and 0.0 mm (+/-0.1). Significant differences (p < 0.005) were found for total width reduction between test (-22.84%) and control sites ( 51.92%) at 1 mm below crest level. Significant differences were found for socket fill (visible mineralized bone) between test (94.7%) and control sites (63.3%). CONCLUSION: The use of L-PRF as a socket filling material to achieve preservation of horizontal and vertical ridge dimension at three months after tooth extraction is beneficial. PMID- 27509215 TI - Rotational Dynamics in Ionic Liquids from NMR Relaxation Experiments and Simulations: Benzene and 1-Ethyl-3-Methylimidazolium. AB - Temperature-dependent (2)H longitudinal spin relaxation times (T1) of dilute benzene-d6 in 1-butyl-3-methylimidazolium tetrafluoroborate ([Im41][BF4]) and two deuterated variants of the 1-ethyl-3-methylimidazolium cation (Im21(+)-d1 and Im21(+)-d6) in 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([Im21][Tf2N]), measured at multiple Larmor frequencies, were used to probe rotational dynamics in ionic liquids. Rotational correlation times significantly faster than predicted by slip hydrodynamic calculations were observed for both solutes. Molecular dynamics simulations of these systems enabled extraction of more information about the rotational dynamics from the NMR data than rotation times alone. The multifrequency (2)H T1(T) data could be fit to within uncertainties over a broad region about the T1 minimum using models of the relevant rotational time correlation functions and their viscosity/temperature dependence derived from simulation. Such simulation-guided fitting provided confidence in the semiquantitative accuracy of the simulation models and enabled interpretation of NMR measurements to higher viscosities than previously possible. Simulations of the benzene system were therefore used to explore the nature of solute rotation in ionic liquids and how it might differ from rotation in conventional solvents. Whereas "spinning" about the C6 axis of benzene senses similarly weak solvent friction in both types of solvents, "tumbling" (rotations about in-plane axes) differs significantly in conventional solvents and ionic liquids. In the sluggish environment provided by ionic liquids, orientational caging and the presence of rare but influential large-amplitude (180 degrees ) jumps about in-plane axes lead to rotations being markedly nondiffusive, especially below room temperature. PMID- 27509216 TI - Reproductive phenology of Mauritia flexuosa L. (Arecaceae) in a coastal restinga environment in northeastern Brazil. AB - The buriti, Mauritia flexuosa, is the most common palm in Brazil, where it has considerable ecological and economic importance. However, few data are available on the phenology of the species, mainly in coastal restinga ecosystems. The present study monitored the reproductive phenology of M. flexuosa in the restinga of Barreirinhas, in the Brazilian Northeast, and investigated the relationship between phenophases and climatic variables. The presence/absence of flowers and fruits was recorded monthly in 25 individuals of each sex between August, 2009, and October, 2012. There was no difference in the phenology of male and female specimens, with flowering and fruiting occurring exclusively in the dry season. We believe that the specific abiotic characteristics of the study environment, such as the intense sunlight and availability of water in the soil, contribute to the reproductive success of M. flexuosa in the dry season, with consequent germination and establishment of seedlings occurring during the subsequent rainy season. PMID- 27509217 TI - Physiological response of invasive mussel Limnoperna fortunei (Dunker, 1857) (Bivalvia: Mytilidae) submitted to transport and experimental conditions. AB - Successful animal rearing under laboratory conditions for commercial processes or laboratory experiments is a complex chain that includes several stressors (e.g., sampling and transport) and incurs, as a consequence, the reduction of natural animal conditions, economic losses and inconsistent and unreliable biological results. Since the invasion of the bivalve Limnoperna fortunei (Dunker, 1857) in South America, several studies have been performed to help control and manage this fouling pest in industrial plants that use raw water. Relatively little attention has been given to the laboratory rearing procedure of L. fortunei, its condition when exposed to a stressor or its acclimation into laboratory conditions. Considering this issue, the aims of this study are to (i) investigate L. fortunei physiological responses when submitted to the depuration process and subsequent air transport (without water/dry condition) at two temperatures, based on glycogen concentrations, and (ii) monitor the glycogen concentrations in different groups when maintained for 28 days under laboratory conditions. Based on the obtained results, depuration did not affect either of the groups when they were submitted to approximately eight hours of transport. The variation in glycogen concentration among the specimens that were obtained from the field under depurated and non-depurated conditions was significant only in the first week of laboratory growth for the non-depurated group and in the second week for the depurated group. In addition, the tested temperature did not affect either of the groups that were submitted to transport. The glycogen concentrations were similar to those of the specimens that were obtained from the field in third week, which suggests that the specimens acclimated to laboratory conditions during this period of time. Thus, the results indicate that the air transport and acclimation time can be successfully incorporated into experimental studies of L. fortunei. Finally, the tolerance of L. fortunei specimens to the stressor tested herein can help us understand the invasive capacity of this mussel during the establishment process. PMID- 27509218 TI - Phenolic Compounds of Pomegranate Byproducts (Outer Skin, Mesocarp, Divider Membrane) and Their Antioxidant Activities. AB - Pomegranate peel was separated into outer leathery skin (PS), mesocarp (PM), and divider membrane (PD), and its phenolic compounds were extracted as free (F), esterified (E), and insoluble-bound (B) forms for the first time. The total phenolic content followed the order PD > PM > PS. ABTS(*+), DPPH, and hydroxyl radical scavenging activities and metal chelation were evaluated. In addition, pomegranate peel extracts showed inhibitory effects against alpha-glucosidase activity, lipase activity, and cupric ion-induced LDL-cholesterol oxidation as well as peroxyl and hydroxyl radical-induced DNA scission. Seventy-nine phenolic compounds were identified using HPLC-DAD-ESI-MS(n) mainly in the form of insoluble-bound. Thirty compounds were identified for the first time. Gallic acid was the major phenolic compound in pomegranate peel, whereas kaempferol 3-O glucoside was the major flavonoid. Moreover, ellagic acid and monogalloyl hexoside were the major hydrolyzable tannins, whereas the dominant proanthocyanidin was procyanidin dimers. Proanthocyanidins were detected for the first time. PMID- 27509219 TI - Coronary angiography after successful thrombolysis - Is the recommended time interval of 24h an important issue? AB - INTRODUCTION: Percutaneous coronary intervention (PCI) is currently considered the gold-standard treatment of acute coronary syndromes with ST-segment elevation (STEMI). However, this is not the reality of many European centers, where thrombolysis is performed as primary therapy. AIMS: To determine, in a STEMI population that performed successful fibrinolytic treatment, if the performance of coronary angiography after the first 24h was associated with more hospital complications, including higher mortality, compared with its performance in the recommended time. METHODS: Retrospective study, including 1065 patients with STEMI, who performed successful thrombolysis. The population was divided in three groups: A, patients who didn't undergo coronary angiography after successful thrombolysis (n=278; 26.1%); B, patients who underwent coronary angiography in the first 24h after successful thrombolysis (n=127; 11.9%); and C, patients who underwent angiography after the first 24h (n=660; 62.0%). Groups were compared regarding their characteristics and in-hospital complications. RESULTS: Groups B and C had more male patients and had younger patients than group A. Group A presented higher Killip classes at admission, more severe left ventricle dysfunction and a higher number of complications during hospitalization. Logistic regression revealed that: 1) the non-performance of coronary angiography after thrombolysis was an independent predictor of in-hospital mortality; and 2) the performance of angiography after the recommended time wasn't associated with higher mortality. CONCLUSIONS: Coronary angiography after thrombolysis constitutes an important strategy, whose non-performance carries worse prognosis. The time interval currently recommended of 24h seems clinically acceptable; however, its realization outside the recommended time doesn't seem to lead to higher mortality. PMID- 27509220 TI - Prevalence, determinants, and prognostic significance of delirium in patients with acute heart failure. AB - BACKGROUND: Delirium is a serious syndrome in critically ill patients. However, the prognostic impact of delirium and its determinants in acute heart failure (AHF) patients have not been fully elucidated. METHODS: We examined 611 AHF patients who were admitted to our institution. Delirium was diagnosed based on the Intensive Care Delirium Screening Checklist (ICDSC). RESULTS: Delirium developed in 139 patients (23%) during hospitalization. Patients with delirium had higher incidence of non-cardiovascular death (p=0.046) and worsening heart failure (p<0.001) during hospitalization. Among patients who survived at discharge, the incidence of all-cause death, cardiovascular death and non cardiovascular death after discharge were significantly higher in patients with delirium than those without (log-rank; p<0.001, p=0.001, p<0.001, respectively) during a median follow-up period of 335days. In multivariable model, the development of delirium was an independent determinant of worsening heart failure during hospitalization (OR: 2.44, 95% CI: 1.27-4.63) and all-cause death after discharge (HR: 2.38, 95% CI: 1.30-4.35). Furthermore, multivariate analysis indicated that history of cerebrovascular disease (OR: 2.13, 95% CI: 1.36-3.35), age (OR: 1.43, 95% CI: 1.15-1.80), log BNP (OR: 1.39, 95% CI: 1.09-1.79), serum albumin (OR: 0.84, 95% CI: 0.76-0.93) and blood glucose levels (OR: 1.03, 95% CI: 1.00-1.06) were independent determinants of delirium. CONCLUSION: In patients with AHF, the development of delirium was associated with poor clinical outcomes, suggesting the importance of early screening and careful monitoring of delirium in such patients. PMID- 27509221 TI - Plasma levels of oxidative stress-responsive apoptosis inducing protein (ORAIP) in patients with atrial fibrillation. PMID- 27509222 TI - The association between in-hospital hemoglobin changes, cardiovascular events, and mortality in acute decompensated heart failure: Results from the ESCAPE trial. AB - INTRODUCTION: The effect of acute changes of hemoglobin during index heart failure admission on long-term outcomes remains unknown. METHODS: We examined 433 patients enrolled in the ESCAPE trial. RESULTS: Of the 433 patients, 324 (75%) had baseline and discharge hemoglobin available for analysis. Of those, 64 (20%) had at least 1g/dL drop of hemoglobin by time of discharge. Compared to patients without hemoglobin changes (g/dL), patients with hemoglobin drop were older (59 vs. 55, p=0.011), had lower systolic BP (mmHg) (99 vs. 106, p=0.017), lower sodium (mg/dL) (136 vs. 137 (mg/dL), p=0.025), higher BUN (mg/dL) (37 vs. 26, p<0.001), higher creatinine (mg/dL) (1.6 vs. 1.3, p<0.001) and higher hospital length of stay (10days vs. 6days, p=<0.001). Higher hemoglobin drop was observed in the pulmonary artery catheter (PACs) (vs. clinical care) randomized arm of the trial (2g/dL: 10% versus 3%, p=0.010; 3g/dL: 5% versus 0%, p=0.005). After adjustments, a drop of hemoglobin with at least 1g/dL was associated with increased mortality risk (Adjusted HR 2.38, p=0.003) and higher hemoglobin concentrations by the time of discharge was associated with lower mortality rate (Adjusted HR 0.79, p=0.003). PACs insertion was not associated with adverse clinical outcomes by quartiles of % change of hemoglobin. However, PACs use was an independent predictor of hemoglobin drop during heart failure admission (Adjusted OR: Hb Drop 1g/dL: 1.88, p=0.043; Hb Drop 2g/dL: 3.6 p=0.025). CONCLUSION: In-hospital decrease in hemoglobin is independently associated with increased long-term mortality and hospital length of stay in ADHF. The ideal hemoglobin levels in ADHF patients should be investigated and the insertion of PACs to direct therapy should be weighed against bleeding risks. PMID- 27509223 TI - CXCL13 inhibits microRNA-23a through PI3K/AKT signaling pathway in adipose tissue derived-mesenchymal stem cells. AB - OBJECTIVES: Adipose tissue derived-mesenchymal stem cells (AMSCs) are one of the most widely used MSCs in the cell therapy for regenerative medicine. In the current study, the role of CXCL13 in AMSCs and its potential signaling pathway were investigated. METHODS: AMSCs were isolated from adipose tissue of healthy subjects. After administrating the cells with CXCL13, the expression levels of miR-23a and runt-related transcription factor 2 (Runx2) were assessed by real time PCR and western blot. The alterations of phosphoinositide-3 kinase (PI3K)/Akt, stress-activated protein kinase (SAPK)/c-jun kinase (JNK), and extracellular-signal-regulated kinase (ERK1/2) pathways were also evaluated. RESULTS: CXCL13 down-regulated miR-23a and up-regulated Runx2 expression in AMSCs. The inhibitor specific for PI3K/AKT, but not SAPK/JNK and ERK ERK1/2, reversed the effects of CXCL13 on miR-23a and Runx2 expression. CONCLUSION: CXCL13 inhibits miR-23a expression through modulating PI3K/AKT pathway in AMSCs. PMID- 27509224 TI - Ultrasound Identification of the Guidewire in the Brachiocephalic Vein for the Prevention of Inadvertent Arterial Catheterization During Internal Jugular Central Venous Catheter Placement. AB - BACKGROUND: Imaging the guidewire with ultrasonography in the internal jugular vein during central venous catheterization often is used to verify proper guidewire placement and to aid in prevention of inadvertent arterial catheterization. It is known, however, that inadvertent arterial catheterization can occur despite imaging the guidewire in the internal jugular vein because the guidewire may continue through the far wall of the internal jugular vein and into an adjacent artery. We propose confirmation of the guidewire in the brachiocephalic vein with ultrasonography as a more reliable method of confirming proper guidewire placement. METHODS: A prospective feasibility study of 200 adult cardiothoracic surgery patients undergoing internal jugular vein catheterization was performed to determine whether the guidewire could be imaged with ultrasonography in the brachiocephalic vein. The guidewire was imaged in the internal jugular vein in a short-axis view, and the transducer was then angled caudally under the clavicle, following the guidewire into the brachiocephalic vein. RESULTS: The right internal jugular vein was catheterized in 193 patients and the left internal jugular in 7 patients. The brachiocephalic vein was successfully imaged in all but 2 patients. In 3 patients, the guidewire could not be clearly identified in the brachiocephalic vein because of interference from the leads of a heart rhythm device (pacemaker or defibrillator) or preexisting catheter. In 2 patients, the guidewire was not seen initially in the brachiocephalic vein because of coiling in the internal jugular vein, and in 1 patient because of the guidewire passing into the right subclavian vein, but all 3 were subsequently imaged in the brachiocephalic vein after repositioning. CONCLUSIONS: During internal jugular vein catheterization, the brachiocephalic vein was imaged with ultrasonography in 99% of patients (the lower 1-sided 99% confidence limit is 96%). The guidewire was imaged in the brachiocephalic vein in all cases except when leads from a heart rhythm device caused interference, although in some patients with leads, the guidewire could be imaged without difficulty. The absence of the guidewire from the brachiocephalic vein was indicative of a malpositioned guidewire. PMID- 27509225 TI - The Effect of Combined Spinal-Epidural Versus Epidural Analgesia in Laboring Women on Nonreassuring Fetal Heart Rate Tracings: Systematic Review and Meta analysis. AB - BACKGROUND: Combined spinal-epidural labor analgesia has gained popularity, but it is unclear whether this technique is associated with a higher incidence of nonreassuring fetal heart rate (FHR) tracings compared with epidural analgesia. Our meta-analysis aimed at comparing the incidence of nonreassuring FHR tracings between the 2 neuraxial techniques. METHODS: Databases were searched to identify randomized controlled trials that compared the incidence of nonreassuring FHR tracings, as defined in the individual studies, after combined spinal-epidural versus epidural analgesia in laboring women. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. We performed a subgroup analysis for studies using low-dose epidural bupivacaine concentrations (<=0.125%) for epidural analgesia. RESULTS: Seventeen trials including 3947 parturients were retrieved that compared the 2 neuraxial techniques. All trials used intrathecal opioids in 1 study arm. The pooled effect estimate of low- and high-dose epidural bupivacaine studies together showed a significantly increased risk of nonreassuring FHR tracings with the combined technique (RR 1.31, 95% CI 1.02-1.67, P = .03, I = 18%). A subgroup analysis of 10 trials using low-dose epidural bupivacaine found a RR for nonreassuring FHR tracings between combined spinal-epidural and epidural analgesia of 1.12, 95% CI 0.93-1.34, P = .18. In a sensitivity analysis of those low-dose epidural bupivacaine studies that ensured blinding of the outcome assessor, the RR was 1.41, 95% CI 0.99-2.02, P = .06. CONCLUSIONS: Combined spinal-epidural labor analgesia was associated with a higher risk of nonreassuring FHR tracings than epidural analgesia alone. In the subgroup analysis comparing combined spinal-epidural with low-dose epidural labor analgesia, the 95% CI contains a clinically significant difference between groups; moreover, the 95% CI overlaps with the 95% CI of the comparison of the combined low- and high-dose epidural techniques. Therefore, it cannot be concluded that there was no difference between combined spinal-epidural and low dose epidural techniques. PMID- 27509226 TI - Hermann Dietz. PMID- 27509227 TI - Lanthanoid Template Isolation of the alpha-1,5 Isomer of Dicobalt(II)-Substituted Keggin Type Phosphotungstates: Syntheses, Characterization, and Magnetic Properties. AB - A new series of heterometallic 3d-4f sandwich type phosphotungstates, [Ln{PCo2W10O38(H2O)2}2](11-) (Ln = Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb(III), and Lu(III), denoted 1a-10a, respectively), have been synthesized by a one-pot reaction procedure on reacting the dilacunary K14[P2W19O69(H2O)].24H2O precursor with Ln(NO3)3.nH2O and Co(NO3)2.6H2O in an aqueous potassium chloride solution. All the compounds were isolated as potassium salts and further characterized with different analytical techniques such as single-crystal X-ray diffraction, Fourier transform infrared spectroscopy, high resolution electrospray ionization mass spectrometry, elemental analysis by inductively coupled plasma atomic emission spectroscopy, magnetic measurement, and thermogravimetric analysis. Single-crystal X-ray diffraction analysis of the compounds reveals that all these compounds are isostructural and crystallized in the orthorhombic crystal system in space group Iba2. The polyanions contain the alpha-1,5 isomer of dicobalt-substituted alpha-Keggin phosphotungstate, which sandwiched lanthanoid cation and formed novel heterometallic dimer species. The temperature-dependent magnetic susceptibilities of 1a, 2a, 4a, and 7a-10a indicate the dominant contribution of the ferromagnetic interaction between Co(II) and Co(II) within the cluster, while the antiferromagnetic interaction between Co(II) and Ln(III) dominates for 3a, 5a, and 6a. The isothermal magnetizations of 1a-10a show a gradual increase in magnetization at low fields and do not reach saturation even at 50 kOe. PMID- 27509228 TI - Shape of allied health: an environmental scan of 27 allied health professions in Victoria. AB - Objective In 2015, the Victorian Department of Health and Human Services commissioned the Victorian Allied Health Workforce Research Program to provide data on allied health professions in the Victorian public, private and not-for profit sectors. Herein we present a snapshot of the demographic profiles and distribution of these professions in Victoria and discuss the workforce implications. Methods The program commenced with an environmental scan of 27 allied health professions in Victoria. This substantial scoping exercise identified existing data, resources and contexts for each profession to guide future data collection and research. Each environmental scan reviewed existing data relating to the 27 professions, augmented by an online questionnaire sent to the professional bodies representing each discipline. Results Workforce data were patchy but, based on the evidence available, the allied health professions in Victoria vary greatly in size (ranging from just 17 child life therapists to 6288 psychologists), are predominantly female (83% of professions are more than 50% female) and half the professions report that 30% of their workforce is aged under 30 years. New training programs have increased workforce inflows to many professions, but there is little understanding of attrition rates. Professions reported a lack of senior positions in the public sector and a concomitant lack of senior specialised staff available to support more junior staff. Increasing numbers of allied health graduates are being employed directly in private practice because of a lack of growth in new positions in the public sector and changing funding models. Smaller professions reported that their members are more likely to be professionally isolated within an allied health team or larger organisations. Uneven rural-urban workforce distribution was evident across most professions. Conclusions Workforce planning for allied health is extremely complex because of the lack of data, fragmented funding and regulatory frameworks and diverse employment contexts. What is known about this topic? There is a lack of good-quality workforce data on the allied health professions generally. The allied health workforce is highly feminised and unevenly distributed geographically, but there is little analysis of these issues across professions. What does this paper add? The juxtaposition of the health workforce demographics and distribution of 27 allied health professions in Victoria illustrates some clear trends and identifies several common themes across professions. What are the implications for practitioners? There are opportunities for the allied health professions to collectively address several of the common issues to achieve economies of scale, given the large number of professions and small size of many. PMID- 27509229 TI - Putting pain out of mind with an 'out of body' illusion. AB - BACKGROUND: Chronic pain is a growing societal concern that warrants scientific investigation, especially given the ineffectiveness of many treatments. Given evidence that pain experience relies on multisensory integration, there is interest in using body ownership illusions for reducing acute pain. AIM: In the present study, we investigate whether patients' experience of chronic pain could be reduced by full body illusions (FBIs) that cause participants to dissociate from their own body. METHODS: Participants with chronic pain (including sciatica, osteoarthritis, fibromyalgia, muscular pain, IBS and back pain) viewed their own 'virtual' bodies via a video camera and head-mounted display for two minutes. In the 'back-stroking FBI', their backs were stroked with a stick while they viewed synchronous or asynchronous stroking on the virtual body and in the 'front stroking FBI', they were stroked near their collarbone while viewing the stick approach their field of view in a synchronous or asynchronous fashion. Illusion strength and pain intensity were measured with self-report questionnaires. RESULTS: We found that full body illusions were experienced by patients with chronic pain and further, that pain intensity was reduced by an average of 37% after illusion (synchronous) conditions. CONCLUSION: These findings add support to theories that high-level multisensory body representations can interact with homeostatic regulation and pain perception. SIGNIFICANCE: Pain intensity in chronic pain patients was reduced by 37% by 'out of body' illusions. These data demonstrate the potential of such illusions for the management of chronic pain. PMID- 27509230 TI - Blood transfusion in preterm infants improves intestinal tissue oxygenation without alteration in blood flow. AB - BACKGROUND AND OBJECTIVE: The objective of the study was to investigate the splanchnic blood flow velocity and oximetry response to blood transfusion in preterm infants according to postnatal age. MATERIALS AND METHODS: Preterm infants receiving blood transfusion were recruited to three groups: 1-7 (group 1; n = 20), 8-28 (group 2; n = 21) and >=29 days of life (group 3; n = 18). Superior mesenteric artery (SMA) peak systolic (PSV) and diastolic velocities were measured 30-60 min pre- and post-transfusion using Doppler ultrasound scan. Splanchnic tissue haemoglobin index (sTHI), tissue oxygenation index (sTOI) and fractional tissue oxygen extraction (sFTOE) were measured from 15-20 min before to post-transfusion using near-infrared spectroscopy. RESULTS: The mean pretransfusion Hb in group 1, 2 and 3 was 11, 10 and 9 g/dl, respectively. The mean (SD) pretransfusion SMA PSV in group 1, 2 and 3 was 0.63 (0.32), 0.81 (0.33) and 0.97 (0.40) m/s, respectively, and this did not change significantly following transfusion. The mean (SD) pretransfusion sTOI in group 1, 2 and 3 was 36.7 (19.3), 44.6 (10.4) and 41.3 (10.4)%, respectively. The sTHI and sTOI increased (P < 0.01), and sFTOE decreased (P < 0.01) following transfusion in all groups. On multivariate analysis, changes in SMA PSV and sTOI following blood transfusion were not associated with PDA, feeding, pretransfusion Hb and mean blood pressure. CONCLUSION: Pretransfusion baseline splanchnic tissue oximetry and blood flow velocity varied with postnatal age. Blood transfusion improved intestinal tissue oxygenation without altering mesenteric blood flow velocity irrespective of postnatal ages. PMID- 27509231 TI - Growth, Grazing, and Starvation Survival in Three Heterotrophic Dinoflagellate Species. AB - To assess the effects of fluctuating prey availability on predator population dynamics and grazing impact on phytoplankton, we measured growth and grazing rates of three heterotrophic dinoflagellate species-Oxyrrhis marina, Gyrodinium dominans and Gyrodinium spirale-before and after depriving them of phytoplankton prey. All three dinoflagellate species survived long periods (> 10 d) without algal prey, coincident with decreases in predator abundance and cell size. After 1-3 wks, starvation led to a 17-57% decrease in predator cell volume and some cells became deformed and transparent. When re-exposed to phytoplankton prey, heterotrophs ingested prey within minutes and increased cell volumes by 4-17%. At an equivalent prey concentration, continuously fed predators had ~2-fold higher specific growth rates (0.18 to 0.55 d-1 ) than after starvation (-0.16 to 0.25 d 1 ). Maximum specific predator growth rates would be achievable only after a time lag of at least 3 d. A delay in predator growth poststarvation delays predator induced phytoplankton mortality when prey re-emerges at the onset of a bloom event or in patchy prey distributions. These altered predator-prey population dynamics have implications for the formation of phytoplankton blooms, trophic transfer rates, and potential export of carbon. PMID- 27509232 TI - Ultrasound-guided peripheral venous access for therapeutic apheresis procedures reduces need for central venous catheters. AB - Therapeutic and donor apheresis requires adequate vascular access to achieve inlet flow rates of ~50-100 mL/min. While central dialysis-type venous catheters can usually provide such access, their use includes several associated risks. Some of these risks can be avoided or diminished if adequate peripheral venous access can be established. Some patients have adequate peripheral veins for apheresis that cannot be readily identified visually or by palpation. We hypothesized that ultrasound-guided peripheral venous access would benefit such patients and would lead to placement of fewer central venous catheters. The technique of ultrasound-guided peripheral access for apheresis has been in use at Houston Methodist Hospital since 2012. We performed a prospective review of patients undergoing inpatient and outpatient apheresis at Houston Methodist Hospital from July 1, 2015 to September 30, 2015, to assess its benefit. During this time, we performed 831 procedures on 186 patients, including 787 therapeutic plasma exchanges, three red blood cell exchanges, 41 peripheral stem cell collections. Ultrasound-guided vascular access was used for 68 procedures (8% of all procedures), including 62 therapeutic plasma exchanges, 4 peripheral stem cell collections, and 2 red blood cell changes. Use of ultrasound-guided peripheral access prevented the placement of central venous catheters in 37 (20%) patients, demonstrating its utility in a busy transfusion service. PMID- 27509233 TI - Identification of markers of cancer in urban sewage through the use of a suspect screening approach. AB - The administration of anticancer drugs during chemotherapy treatments has increased considerably in recent years, and based on the growing incidence of cancer worldwide there is a foreseen increase in their use over the coming years. Many anticancer drugs are not removed by conventional wastewater treatment plants (WWTPs) and can therefore reach the aquatic environment and potentially threaten aquatic life. The objective of this work was to apply a suspect screening methodology to detect chemotherapy and radiotherapy drugs and their related compounds such metabolites and/or biomarkers in wastewater. The use of logical pre-determined criteria to refine the suspect list down to a relatively small number of relevant compounds greatly improved the efficiency of the analysis. Mass accuracy, isotopic patterns and predicted retention time were used to tentatively identify the suspects. Successful identification of cancer-related suspects included two antineoplastic hormones, two X-ray contrast agents and a pyrrolizidine alkaloid related to an herbal medicine. This is the first time that a suspect screening paradigm has been successfully applied to the identification of pharmaceuticals and biomarkers related to chemotherapy in wastewater. PMID- 27509235 TI - Thrombotic Microangiopathy in the Setting of HIV Infection: A Case Report and Review of the Differential Diagnosis and Therapy. AB - Before the modern era of HIV/AIDS therapeutics, which enabled a cascade of early recognition of infection, prompt initiation of effective antiretroviral therapies, and close follow-up, severe forms of microvascular clotting disorders known as thrombotic microangiopathies (TMAs) were frequent in the setting of advanced HIV disease. Their incidence was as high as 7% in the period 1984-1999, but fell dramatically, to <0.5%, by 2002. This profound change was predicated on one critical development: availability of new classes of anti-HIV drugs, enabling reduction and maintenance of HIV viral loads to undetectable levels. Another development in the period 1999-2002 related to TMA therapy: with recognition of autoantibodies against the von Willebrand factor cleaving protease ADAMTS13 as the etiology of most cases of one major form of TMA, thrombotic thrombocytopenic purpura, it permitted appropriate use of life-saving interventions based on plasma exchange and immune suppression. A more recent factor in TMA therapeutics was the 2011 approval by the US FDA and European EMA of eculizumab, a humanized monoclonal antibody against complement component C5, for the treatment of atypical hemolytic uremic syndrome, another major form of TMA. Despite these milestones, life- and organ-threatening TMAs still occur in untreated HIV disease and, to a much lesser extent, in those patients with suppressed viral loads. Confusion in terms of the differential diagnosis of these TMAs also impedes use of directed treatments. This report utilizes a case study of a young woman with advanced AIDS who presented with a severe TMA, characterized by coma and renal failure, to highlight the diagnostic and therapeutic challenges raised by complex hematologic conditions occurring in the setting of HIV. PMID- 27509236 TI - Growth of HIV-Infected Children in the Early Stage of Antiretroviral Treatment: A Retrospective Cohort Study in China. AB - Malnutrition and human immunodeficiency virus (HIV)-related complications are commonly seen in HIV-infected children, and these have been shown in high prevalent areas such as Africa. Antiviral therapy (ART) has notably controlled disease progression, whereas it effectively reverses underweight and growth retardation in HIV-infected children. This study was conducted to evaluate the growth status after initiation of ART in HIV-infected children in China. A retrospective cohort study was conducted based on the National Science and Technology Major Project. HIV-infected children who initiated antiretroviral treatment between January 1st, 2012 and December 31st, 2012 were followed up to December 31st, 2014. Z-scores of height and weight were calculated by WHO Anthro (plus). Linear mixed-effects models were used to model trajectories of weight- and height-for-age Z-scores. Seven hundred forty-four participants enrolled in the study, with 585 participants and 712 participants who had WAZ (weight-for-age Z-score) and HAZ (height-for-age Z-score), respectively, before initiation of ART. Among them, 125 (21.4%) were underweight and 301 (42.3%) were stunted. After treatment, among the 125 underweight children, WAZ improved in 69 patients, regained more than -2 on average. Among the 301 stunted children, HAZ improved in 123 patients, regained more than -2 on average. WAZ improved for the first 6 months by 0.052 units each month and then stabilized, whereas HAZ consistently improved by 0.014 units each month over time. Antiretroviral treatment reversed the adverse effects of HIV to some degree. Early diagnosis and treatment, with an effective nutrition program, is necessary to improve malnutrition further. PMID- 27509237 TI - Community-Based HIV and Health Testing for High-Risk Adolescents and Youth. AB - Adolescents account for 40% of new HIV infections, and HIV testing strategies to increase uptake of testing are needed. A community-based adolescent and youth HIV and health testing campaign was conducted in seven slum neighborhoods of Port-au Prince, Haiti, from December 2014 to September 2015. Community health workers provided community sensitization and recruited 10- to 24-year-olds to test for HIV, syphilis, gonorrhea/chlamydia, and to screen for tuberculosis (TB) and pregnancy. HIV-infected individuals were escorted to the GHESKIO HIV clinic for same-day enrollment in care. Among 3425 individuals eligible for testing, 3348 (98%) accepted an HIV test. HIV prevalence was 2.65% (n = 89). Median age was 19 [interquartile range (IQR) 17-20]; 73% were female. HIV prevalence was 0.6-7.4% across slum neighborhoods. All HIV-infected individuals enrolled in care the same day as testing; median CD4 was 529 cells/MUL [IQR 363-761]. Syphilis prevalence was 2.60% (65/2536) and gonorrhea/chlamydia prevalence was 6.25% (96/1536). Among 168 (5%) individuals who reported TB symptoms, 7.7% (13/168) had microbiologically confirmed disease. One hundred twenty-nine females (5% of all females) were pregnant. This community-based testing campaign identified an adolescent and youth population with an HIV prevalence six times higher than the estimated national adolescent HIV prevalence (0.4%) in Haiti, including perinatally infected adolescents. This type of community-based campaign for HIV testing within a package of services can serve as a model for other resource-poor settings to identify high-risk adolescents and youth, and curb the global HIV epidemic among adolescents. PMID- 27509238 TI - Challenges in Recruiting People Who Use Drugs for HIV-Related Biomedical Research: Perspectives from the Field. AB - Recruitment of people who use drugs (PWUD) for HIV-related research has been undertaken since early in the epidemic. In early studies, recruitment was often performed by outreach workers with familiarity with the target population, who distributed risk reduction materials, and administered the surveys being conducted on drug use and risk behaviors. The evolution of effective treatments for HIV has provided opportunities for PWUD to participate in biobehavioral studies testing the efficacy of medical treatment advances and exploring the underlying biomedical basis for prevention and treatment efforts. Recruitment for these studies has led to new challenges for outreach workers and institutions conducting this research. PWUD, particularly those from race/ethnic minority populations, have had lower rates of engagement in HIV care and have been underrepresented in HIV/AIDS medical studies. To address these health disparities, enhanced efforts are needed to increase their participation in biomedical studies. This article examines the challenges identified by experienced outreach workers in recruiting PWUD for HIV-related biomedical studies, including individual (participant)-, institutional-, and recruiter-level challenges, and provides recommendations for addressing them. PMID- 27509240 TI - The brain gets its say: Hepatic encephalopathy and its evolving role in transplant priority. PMID- 27509239 TI - "I Have to Push Him with a Wheelbarrow to the Clinic": Community Health Workers' Roles, Needs, and Strategies to Improve HIV Care in Rural South Africa. AB - With a 19.2% HIV prevalence, South Africa has the largest HIV/AIDS epidemic worldwide. Despite a recent scale-up of public sector HIV resources, including community-based programs to expand HIV care, suboptimal rates of antiretroviral therapy (ART) initiation and adherence persist. As community stakeholders with basic healthcare training, community health workers (CHWs) are uniquely positioned to provide healthcare and insight into potential strategies to improve HIV treatment outcomes. The study goal was to qualitatively explore the self perceived role of the CHW, unmet CHW needs, and strategies to improve HIV care in rural KwaZulu-Natal, South Africa. Focus groups were conducted in May-August 2014, with 21 CHWs working in Msinga subdistrict. Interviews were audio-recorded, transcribed, and translated from Zulu into English. A hybrid deductive and inductive analytical method borrowed from grounded theory was applied to identify emergent themes. CHWs felt they substantially contributed to HIV care provision but were inadequately supported by the healthcare system. CHWs' recommendations included: (1) sufficiently equipping CHWs to provide education, counseling, social support, routine antiretroviral medication, and basic emergency care, (2) modifying clinical practice to provide less stigmatizing, more patient-centered care, (3) collaborating with traditional healers and church leaders to reduce competition with ART and provide more holistic care, and (4) offsetting socioeconomic barriers to HIV care. In conclusion, CHWs can serve as resources when designing and implementing interventions to improve HIV care. As HIV/AIDS policy and practice evolves in South Africa, it will be important to recognize and formally expand CHWs' roles supporting the healthcare system. PMID- 27509241 TI - Electromagnetic Property and Tunable Microwave Absorption of 3D Nets from Nickel Chains at Elevated Temperature. AB - We fabricated the nickel chains by a facile wet chemical method. The morphology of nickel chains were tailored by adjusting the amount of PVP during the synthesis process. Both the complex permittivity and permeability of the three dimensional (3D) nets constructed by nickel chains present strong dependences on temperature in the frequency range of 8.2-12.4 GHz and temperature range of 323 573 K. The peaks in imaginary component of permittivity and permeability mainly derive from interfacial polarizations and resonances, devoting to dielectric and magnetic loss, respectively. The effect from both dielectric and magnetism contribute to enhancing the microwave absorption. The maximum absorption value of the 3D nickel chain nets is approximately -50 dB at 8.8 GHz and 373 K with a thickness of 1.8 mm, and the bandwidth less than -10 dB almost covers the whole investigated frequency band. These are encouraging findings, which provide the potential advantages of magnetic transition metal-based materials for microwave absorption application at elevated temperature. PMID- 27509242 TI - Reduced IL-7R T Cell Expression and Increased Plasma sCD127 in Late Presenting HIV-Infected Individuals. AB - BACKGROUND: Late presentation of HIV infection is associated with reduced chance of optimal immune recovery after initiating combination antiretroviral therapy (cART). Interleukin-7 (IL-7) and the corresponding receptor, IL-7 receptor (IL 7R) made up of CD127 and CD132, are crucial for T cell homeostasis. This study aimed to describe IL-7R and IL-7 before and after initiation of cART in late presenting HIV-infected individuals, and the impact on immune recovery and T cell subset distribution after initiation of cART. METHODS: A total of 100 HIV infected individuals initiating cART were included in a prospective study. Samples were collected at baseline and after 6, 12, and 24 months of cART. Proportion and expression {[median fluorescence intensity (MFI)]} of IL-7R on T cells, and plasma concentrations of soluble CD127 (sCD127) and IL-7 were determined. RESULTS: The IL-7R expression was reduced in late presenters with CD4 cell count <200 cells per microliter compared with nonlate presenters and healthy controls as demonstrated by lower proportion of CD127 + CD132 + T cells and lower CD127 MFI. In contrast, plasma sCD127 was higher. These differences were partly reversed after suppressive cART. Interestingly, the CD127 MFI on CD4 T cells was found to be a predictor of increased thymic output after 24 months of suppressive cART. CONCLUSIONS: Severely altered IL-7R expression was found in late presenters, and associations between IL-7R expression and thymic output after 24 months of suppressive cART indicate an impact of a IL-7 response for the long term de novo production from thymus. PMID- 27509244 TI - Using CD4 Data to Estimate HIV Incidence, Prevalence, and Percent of Undiagnosed Infections in the United States. AB - INTRODUCTION: The incidence and prevalence of HIV infection are important measures of HIV trends; however, they are difficult to estimate because of the long incubation period between infection and symptom development and the relative infrequency of HIV screening. A new method is introduced to estimate HIV incidence, prevalence, and the number of undiagnosed infections in the United States using data from the HIV case surveillance system and CD4 test results. METHODS: Persons with HIV diagnosed during 2006-2013 and their CD4 test results were used to estimate the distribution of diagnosis delay from HIV infection to diagnosis based on a well-characterized CD4 depletion model. This distribution was then used to estimate HIV incidence, prevalence, and the number of undiagnosed infections. RESULTS: Applying this method, we estimated that the annual number of new HIV infections decreased after 2007, from 48,300 (95% confidence interval [CI]: 47,300 to 49,400) to 39,000 (95% CI: 36,600 to 41,400) in 2013. Prevalence increased from 923,200 (95% CI: 914,500 to 931,800) in 2006 to 1,104,600 (95% CI: 1,084,300 to 1,124,900) in 2013, whereas the proportion of undiagnosed infections decreased from 21.0% in 2006 (95% CI: 20.2% to 21.7%) to 16.4% (95% CI: 15.7% to 17.2%) in 2013. CONCLUSIONS: HIV incidence, prevalence, and undiagnosed infections can be estimated using HIV case surveillance data and information on first CD4 test result after diagnosis. Similar to earlier findings, the decreases in incidence and undiagnosed infections are encouraging but intensified efforts for HIV testing and treatment are needed to meet the goals of the National HIV/AIDS Strategy. PMID- 27509243 TI - Chronic HIV-1 Infection Impairs Superantigen-Induced Activation of Peripheral CD4+CXCR5+PD-1+ Cells, With Relative Preservation of Recall Antigen-Specific Responses. AB - Peripheral CD4+CXCR5+PD-1+ T cells are a putative circulating counterpart to germinal center T follicular helper (TFH) cells. They show both phenotypic and functional similarities to TFH cells, which provide necessary help for the differentiation of B cells to antibody-secreting plasmablasts. In this study, we evaluated the frequency, phenotypes, and responses of peripheral TFH-like (pTFH) cells to superantigen and recall antigen stimulation in 10 healthy and 34 chronically infected treatment-naive HIV-1+ individuals. There was no difference in the frequency of pTFH cells between HIV+ and HIV- individuals. Surface expression of ICOS, but not CD40L, was higher on pTFH cells at baseline in HIV+ individuals. Compared with HIV- individuals, pTFH cells from HIV+ individuals had decreased maximal expression of ICOS and CD40L in response to in vitro superantigen stimulation. This decreased response did not correlate with viral control, CD4 T-cell count, duration of infection, or the degree of neutralizing antibody breadth. Despite a decreased maximal response, pTFH responses to HIV Gag and tetanus toxoid recall antigens were preserved. PMID- 27509245 TI - Precursor Forms of Vitamin D Reduce HIV-1 Infection In Vitro. AB - BACKGROUND: Although the anti-HIV-1 effects of vitamin D (VitD) have been reported, mechanisms behind such protection remain largely unexplored. METHODS: The effects of two precursor forms (cholecalciferol/calciol at 0.01, 1 and 100 nM and calcidiol at 100 and 250 nM) on HIV-1 infection, immune activation, and gene expression were analyzed in vitro in cells of Colombian and Italian healthy donors. We quantified levels of released p24 by enzyme-linked immunosorbent assay, of intracellular p24 and cell-surface expression of CD38 and HLA-DR by flow cytometry, and mRNA expression of antiviral and immunoregulatory genes by real-time reverse transcription-polymerase chain reaction. RESULTS: Cholecalciferol decreased the frequency of HIV-1-infected p24CD4 T cells and levels of p24 in supernatants in a dose-dependent manner. Moreover, the CD4CD38HLA-DR and CD4CD38HLA-DR subpopulations were more susceptible to infection but displayed the greatest cholecalciferol-induced decreases in infection rate by an X4-tropic strain. Likewise, cholecalciferol at its highest concentration decreased the frequency of CD38HLA-DR but not of CD38HLA-DR T-cell subsets. Analyzing the effects of calcidiol, the main VitD source for immune cells and an R5-tropic strain as the most frequently transmitted virus, a reduction in HIV-1 productive infection was also observed. In addition, an increase in mRNA expression of APOBEC3G and PI3 and a reduction of TRIM22 and CCR5 expression, this latter positively correlated with p24 levels, was noted. CONCLUSIONS: VitD reduces HIV-1 infection in T cells possibly by inducing antiviral gene expression, reducing the viral co-receptor CCR5 and, at least at the highest cholecalciferol concentration, by promoting an HIV-1-restrictive CD38HLA-DR immunophenotype. PMID- 27509246 TI - Trends in the Marginal Cost of Male Circumcision in Rural Rakai Uganda. AB - INTRODUCTION: Male circumcision (MC) is an effective intervention to reduce HIV acquisition in men in Africa. We conducted a cost analysis using longitudinal data on expenditures on services and community mobilization to estimate the marginal cost of MC over time and understand cost drivers during scale-up. METHODS: We used a time series with monthly records from 2008 to 2013, for a total of 72 monthly observations, from the Rakai MC Program in Uganda. Generalized linear models were used to estimate the marginal cost of an MC procedure. RESULTS: The marginal cost per MC in a mobile camp was $23 (P < 0.01) and in static facilities was $35 (P < 0.1). Major cost drivers included supplies in mobile camps with increasing numbers of surgeries, savings due to task shifting from physicians to clinical officers, and increased efficiency as personnel became more experienced. CONCLUSIONS: As scale-up continues, marginal costs may increase because of mobilization needed for less motivated late adopters, but improved efficiency could contain costs. PMID- 27509247 TI - Performance of the Bio-Rad Geenius HIV1/2 Supplemental Assay in Detecting "Recent" HIV Infection and Calculating Population Incidence. AB - OBJECTIVE: HIV seroconversion biomarkers are being used in cross-sectional studies for HIV incidence estimation. Bio-Rad Geenius HIV-1/2 Supplemental Assay is an immunochromatographic single-use assay that measures antibodies (Ab) against multiple HIV-1/2 antigens. The objective of this study was to determine whether the Geenius assay could additionally be used for recency estimation. DESIGN: This assay was developed for HIV-1/2 confirmation; however, quantitative data acquired give information on increasing concentration and diversity of antibody responses over time during seroconversion. A quantitative threshold of recent HIV infection was proposed to determine "recent" or "nonrecent" HIV infection; performance using this cutoff was evaluated. METHODS: We tested 2500 highly characterized specimens from research subjects in the United States, Brazil, and Africa with well-defined durations of HIV infection. Regression and frequency estimation were used to estimate assay properties relevant to HIV incidence measurement: mean duration of recent infection (MDRI), false-recent rate, and assay reproducibility and robustness. RESULTS: Using the manufacturer's proposed cutoff index of 1.5 to identify "recent" infection, the assay has an estimated false-recent rate of 4.1% (95% CI: 2.2 to 7.0) and MDRI of 179 days (155 to 201) in specimens from treatment-naive subjects, presenting performance challenges similar to other incidence assays. Lower index cutoffs associated with lower MDRI gave a lower rate of false-recent results. CONCLUSIONS: These data suggest that with additional interpretive analysis of the band intensities using an algorithm and cutoff, the Geenius HIV-1/2 Supplemental Assay can be used to identify recent HIV infection in addition to confirming the presence of HIV-1 and HIV-2 antibodies. PMID- 27509250 TI - Marker of Endothelial Dysfunction Asymmetric Dimethylarginine Is Elevated in HIV Infection but Not Associated With Subclinical Atherosclerosis. AB - BACKGROUND: Cardiovascular disease contributes to excess morbidity and mortality in HIV infection, and endothelial dysfunction may contribute to this pattern. We aimed to determine the endothelial function in treated and untreated HIV-infected individuals and investigate potential associations with viral replication, immune activation, coagulation, platelet function, and subclinical atherosclerosis. METHODS: Asymmetric dimethylarginine (ADMA, marker of endothelial dysfunction) and soluble CD14 (sCD14, marker of monocyte activation) were measured in plasma from two previously established cross-sectional cohorts: cohort A including 50 untreated and 50 antiretroviral therapy (ART)-treated HIV-infected individuals with previously assessed coagulation and platelet function and cohort B including 105 HIV-infected individuals on ART and 105 uninfected controls with previously assessed coronary artery calcium score, myocardial perfusion defects, and carotid intima-media thickness. RESULTS: Concentrations of ADMA were higher in HIV infected individuals compared with uninfected controls, and higher ADMA was found in ART-treated compared with untreated HIV-infected individuals. ADMA was associated with viral load, sCD14, D-dimer, and low CD4 T-cell count in untreated HIV infection. Only viral load remained significant in multivariate analyses. In ART-treated HIV-infected individuals, ADMA was not associated with coronary artery calcium score, myocardial perfusion defects, or intima-media thickness. CONCLUSIONS: Evidence of endothelial dysfunction was found in HIV infection and in untreated compared with treated HIV infection. In untreated HIV infection, the main driver of endothelial dysfunction was viral replication. Importantly, in treated HIV infection, ADMA was not associated with subclinical atherosclerosis. Thus, our data question the potential of ADMA as a useful biomarker of early atherosclerosis in treated HIV infection. PMID- 27509251 TI - Evaluation of Sexual Risk Behavior Among Study Participants in the TDF2 PrEP Study Among Heterosexual Adults in Botswana. AB - OBJECTIVE: Among participants of a clinical trial to test the efficacy of tenofovir/emtricitabine in protecting heterosexual men and women living in Botswana from HIV infection, the aim was to determine (1) if sexual risk behavior, specifically condomless sex acts and number of sex partners, changed over time, (2) factors associated with condomless sex acts and number of sex partners, and (3) the effect of participant treatment arm perception on risk behavior to address the possibility of risk compensation. METHODS: A longitudinal modeling of rates of risk behaviors was used to determine if the rate of condomless sex acts (#acts/person) and rate of sex partners (#partners/person) changed over time and which factors were associated with behavior change. RESULTS: One thousand two hundred participants were analyzed over 1 year. There was a 25% decrease in the rate of sex partners among participants sexually active in the last 30 days. The rate of reported condomless sex acts was greater for males [rate ratio (RR) = 1.34; confidence interval (CI): 1.07 to 1.67] and participants whose sexual debut in years was <=15 years of age (RR = 1.65; CI: 1.14 to 2.38) and 16-17 (RR = 1.68; CI: 1.22 to 2.31) compared with those >=20 years. Rate of reported sex partners was greater for males (RR = 3.67; CI: 2.86 to 4.71) and participants whose age at sexual debut in years was <=15 (RR = 2.92; CI: 2.01 to 4.22) and 16-17 (RR = 2.34; CI: 1.69 to 3.24) compared with those >=20. There was no effect of participant treatment arm perception on risk behavior. CONCLUSIONS: Our study of preexposure prophylaxis to prevent HIV infection found no evidence of risk compensation which may have been due to participants' motivations to reduce their risk behaviors and risk-reduction counseling. PMID- 27509254 TI - Brief Report: Sexual Violence Against HIV-Positive Women in the Nyanza Region of Kenya: Is Condom Negotiation an Instigator? AB - For people living with HIV, exposure to sexual violence (SV) is associated with decreased adherence to antiretroviral medication, a primary predictor of their survival. Identification of risk factors for SV is a pressing issue in sub Saharan Africa, where the global majority of HIV-positive women live and the prevalence of SV against women is high. We used qualitative data to examine SV against HIV-positive women enrolled in HIV care in Kenya. Respondents identified husbands as perpetrators of SV in the context of women's efforts to use condoms as directed by HIV care providers. PMID- 27509255 TI - Highly Tunable Complementary Micro/Submicro-Nanopatterned Surfaces Combining Block Copolymer Self-Assembly and Colloidal Lithography. AB - Two kinds of large-area ordered and highly tunable micro/submicro-nanopatterned surfaces in a complementary manner were successfully fabricated by elaborately combining block copolymer self-assembly and colloidal lithography. Employing a monolayer of polystyrene (PS) colloidal spheres assembled on top as etching mask, polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) or polystyrene-block-poly(4 vinylpyridine) (PS-b-P4VP) micelle films were patterned into micro/submicro patches by plasma etching, which could be further transferred into micropatterned metal nanoarrays by subsequent metal precursor loading and a second plasma etching. On the other hand, micro/submicro-nanopatterns in a complementary manner were generated via preloading a metal precursor in initial micelle films before the assembly of PS colloidal spheres on top. Both kinds of micro/submicro nanopatterns showed good fidelity at the micro/submicroscale and nanoscale; meanwhile, they could be flexibly tuned by the sample and processing parameters. Significantly, when the PS colloidal sphere size was reduced to 250 nm, a high resolution submicro-nanostructured surface with 3-5 metal nanoparticles in each patch or a single-nanoparticle interconnected honeycomb network was achieved. Moreover, by applying gold (Au) nanoparticles as anchoring points, micronanopatterned Au arrays can serve as a flexible template to pattern bovine serum albumin (BSA) molecules. This facile and cost-effective approach may provide a novel platform for fabrication of micropatterned nanoarrays with high tunability and controllability, which are promising in the applications of biological and microelectronic fields. PMID- 27509256 TI - Cell autonomous or systemic EGFR blockade alters the immune-environment in squamous cell carcinomas. AB - Targeting mutations and amplifications in the EGFR has been successful precision therapy for cancers of the lung, oral cavity and gastrointestinal track. However, a systemic immune reaction manifested by dose-limiting inflammation in the skin and gut has been a consistent adverse effect. To address the possibility that intra-tumoral immune changes contribute to the anti-cancer activity of EGFR inhibition, squamous cancers were produced by syngeneic orthografts of either EGFR null or wildtype mouse primary keratinocytes transduced with an oncogenic H ras retrovirus. Flow cytometric, RNA and Bioplex immunoassay analyses of the tumor immune milieu were performed. Cancers forming from keratinocytes genetically depleted of EGFR were smaller than wildtype cancers and had fewer infiltrating FoxP3 Treg cells, lower Foxp3 RNA and a lower percentage of CD4 PD1 positive cells indicating a tumor cell autonomous regulation of its microenvironment. Hosts bearing wildtype cancers treated with gefitinib for 1 week showed a trend for smaller tumors. In this short term pharmacological model, there was also a trend to reduced FoxP3 cells and FoxP3 RNA in the tumors of treated mice as well as a substantial increase in the ratio of IL-1A/IL-1RA transcripts. These results suggest that relatively brief systemic inhibition of EGFR signaling alters the immune environment of the targeted cancer. Together these data imply that an EGFR dependent Treg function supports the growth of squamous cancers and is a target for the therapeutic activity of EGFR inhibition. PMID- 27509257 TI - JAN Classic article: Patients' emotional reactions to hospitalization: an exploratory study. PMID- 27509258 TI - On the potential of phase-change adsorbents for CO2 capture by temperature swing adsorption. AB - We investigate the potential of a class of recently discovered metal-organic framework materials for their use in temperature swing adsorption (TSA) processes for CO2 capture; the particularity of the considered materials is their reversible and temperature dependent step-shaped CO2 adsorption isotherm. Specifically, we present a comprehensive modeling study, where the performance of five different materials with step-shaped isotherms [McDonald et al., Nature, 2015, 519, 303] in a four step TSA cycle is assessed. The specific energy requirement of the TSA process operated with these materials is lower than for a commercial 13X zeolite, and a smaller temperature swing is required to reach similar levels of CO2 purity and recovery. The effect of a step in the adsorption isotherm is illustrated and discussed, and design criteria that lead to an optimal and robust operation of the considered TSA cycle are identified. The presented criteria could guide material scientists in designing novel materials whose step position is tailored to specific CO2 separation tasks. PMID- 27509259 TI - Loss of GFAT1 promotes epithelial-to-mesenchymal transition and predicts unfavorable prognosis in gastric cancer. AB - Gastric cancer remains the third leading cause of cancer-related mortality worldwide, and invasion and metastasis of gastric cancer represent the major reason for its poor prognosis. Glutamine: fructose-6-phosphate amidotransferase 1 (GFAT1) is the first and rate-limiting enzyme of hexosamine biosynthesis pathway (HBP). Nevertheless, the role of GFAT1 in gastric cancer is little investigated. In this study, we found that the expression of GFAT1 was decreased in gastric cancer. Low expression of GFAT1 was positively associated with vessel invasion, late T stage, lymph node metastasis, distant metastasis, advanced TNM stage and poor prognosis in patients with gastric cancer. Furthermore, in vitro and in vivo studies revealed that down-regulation of GFAT1 promoted epithelial-to-mesenchymal transition (EMT) and invasive activities in gastric cancer cells through inducing the expression of TGF-beta1. The GFAT1 expression also significantly correlated with EMT-related factors in gastric cancer patients. Together, these findings indicate that GFAT1 functions as a novel suppressor of EMT and tumor metastasis in gastric cancer. PMID- 27509260 TI - Everolimus affects vasculogenic mimicry in renal carcinoma resistant to sunitinib. AB - Angiogenesis is hallmark of clear cell renal cell carcinogenesis. Anti-angiogenic therapies have been successful in improving disease outcome; however, most patients treated with anti-angiogenic agents will eventually progress. In this study we report that clear cell renal cell carcinoma was associated with vasculogenic mimicry in both mice and human with tumor cells expressing endothelial markers in the vicinity of tumor vessels. We show that vasculogenic mimicry was efficiently targeted by sunitinib but eventually associated with tumor resistance and a more aggressive phenotype both in vitro and in vivo. Re challenging these resistant tumors in mice, we showed that second-line treatment with everolimus particularly affected vasculogenic mimicry and tumor cell differentiation compared to sorafenib and axitinib. Finally, our results highlighted the phenotypic and genotypic changes at the tumor cell and microenvironment levels during sunitinib response and progression and the subsequent improvement second-line therapies bring to the current renal cell carcinoma treatment paradigm. PMID- 27509261 TI - Association of peripheral leukocyte telomere length and its variation with pancreatic cancer and colorectal cancer risk in Chinese population. AB - There is increasing evidence supporting the role of telomeres in cancer pathogenesis. However, limited studies have investigated the association between telomere length features and risk of pancreatic cancer and colorectal cancer (CRC), and little was conducted in Asians. To help clarify this issue, We measured relative peripheral leukocytes telomere length (LTL) and telomere length variation (TLV) in a prospective study of 900 pancreatic cancer cases, 300 CRC cases, and 900 controls. Both subjects with longer LTL (quartile 4: adjusted OR=1.51, 95% CI: 1.14-1.99, P=0.004) and shorter LTL (quartile 1: adjusted OR=3.12, 95% CI: 1.89-5.14, P=8.50x10-6) showed increased risk of pancreatic cancer. A linear increased risk was detected For TLV (adjusted OR=1.60, 95% CI: 1.14-2.24, P=0.006). We also identified significant interaction for relative LTL, TLV on pancreatic cancer risk (P interaction =0.009). Significant relationship between shorter RTL and increased CRC risk were also detected. This findings provide insights into telomere dynamics and highlight the complex relationship between relative LTL, TLV and cancer risk. PMID- 27509262 TI - Transporters affecting biochemical test results: Creatinine-drug interactions. AB - Creatinine is eliminated by the kidneys through a combination of glomerular filtration and active transport. Drug-induced increases in serum creatinine (SCr) and/or reduced creatinine renal clearance are used as a marker for acute kidney injury. However, inhibition of active transport of creatinine can result in reversible and, therefore, benign increases in SCr levels. Herein, the transporters involved in creatinine clearance are discussed, in addition to limitations of using creatinine as a biomarker for kidney damage. PMID- 27509263 TI - DNA methylation regulates gabrb2 mRNA expression: developmental variations and disruptions in l-methionine-induced zebrafish with schizophrenia-like symptoms. AB - Single nucleotide polymorphisms (SNPs) in the human type A gamma-aminobutyric acid (GABA) receptor beta2 subunit gene (GABRB2) have been associated with schizophrenia and quantitatively correlated with mRNA expression in the postmortem brain tissue of patients with schizophrenia. l-Methionine (MET) administration has been reported to cause a recrudescence of psychotic symptoms in patients with schizophrenia, and similar symptoms have been generated in MET induced mice. In this study, a zebrafish animal model was used to evaluate the relationship between the gabrb2 mRNA expression and its promoter DNA methylation in developmental and MET-induced schizophrenia-like zebrafish. The results indicated developmental increases in global DNA methylation and decreases in gabrb2 promoter methylation in zebrafish. A significant increase in gabrb2 mRNA levels was observed after GABA was synthesized. Additionally, the MET-triggered schizophrenia-like symptoms in adult zebrafish, involving social withdrawal and cognitive dysfunction analyzed with social interaction and T-maze behavioral tests, were accompanied by significantly increased DNA methylation levels in the global genome and the gabrb2 promoter. Furthermore, the significant correlation between gabrb2 mRNA expression and gabrb2 promoter methylation observed in the developmental stages became non-significant in MET-triggered adult zebrafish. These findings demonstrate that gabrb2 mRNA expression is associated with DNA methylation varies by developmental stage and show that these epigenetic association mechanisms are disrupted in MET-triggered adult zebrafish with schizophrenia-like symptoms. In conclusion, these results provide plausible epigenetic evidence of the GABAA receptor beta2 subunit involvement in the schizophrenia-like behaviors and demonstrate the potential use of zebrafish models in neuropsychiatric research. PMID- 27509264 TI - Glucocorticoid Receptor Gene Variants and Neonatal Outcome in Very-Low-Birth Weight Preterm Infants. AB - BACKGROUND: Induction of lung maturation by prenatal steroid treatment has become the standard of care for pregnant women at risk for preterm birth. In addition to the beneficial effects on lung maturation, prenatal steroids have been shown to reduce the incidence of neonatal death, necrotizing enterocolitis, sepsis, and intraventricular hemorrhage. However, little is known about the role of interindividual differences in corticoid sensitivity arising from polymorphisms in the glucocorticoid receptor (GR) gene. OBJECTIVES: To assess the impact of GR polymorphisms N363S (rs56149945), R23K (rs6190), and BclI (rs41423247) on neonatal outcome. METHODS: The GR polymorphisms N363S, R23K, and BclI were examined in 10,490 very-low-birth-weight (VLBW) preterm infants from 49 German tertiary level neonatal units (German Neonatal Network, GNN) with respect to neonatal outcome. RESULTS: Infants carrying the BclI genotype were at higher risk to develop bronchopulmonary dysplasia (BPD) (OR 1.12 per BclI allele, 95% CI: 1.02-1.23, p = 0.013) in a logistic regression model adjusted for gestational age, mechanical ventilation, and small for gestational age status. A similar relative risk was seen in the children (89.4%) who received antenatal betamethasone treatment (OR 1.16, 95% CI: 1.05-1.27, p = 0.003), whereas no such effect was detectable in infants without antenatal steroids. N363S and R23K did not show any stable association with neonatal outcome parameters. CONCLUSION: Except for a slightly higher risk of BPD in carriers of the GRBclI variant, the GR gene polymorphisms BclI, N363S, and R23K did not affect neonatal outcome parameters in this large multicenter cohort of VLBW preterm infants. PMID- 27509265 TI - Phase transformations, microstructure formation and in vitro osteoblast response in calcium silicate/brushite cement composites. AB - Self-setting simple calcium silicate/brushite (B) biocements with various Ca/P ratios were prepared by mutual mixing of both monocalcium silicate hydrate (CSH) or beta-wollastonite (woll) powders with B and the addition of 2 wt% NaH2PO4 solution as a hardening liquid. The phase composition of the final composites and the texture of the surface calcium phosphate/silica layer were controlled by the starting Ca/P ratio in composites and the pH during setting. It was verified that the presence of continuous bone-like calcium phosphate coating on the surface of the samples was not essential for in vitro osteoblast proliferation. The nanocrystalline calcium deficient hydroxyapatite and amorphous silica were found as the main setting products in composite mixtures with a Ca/P ratio close to the region of the formation of deficient hydroxyapatite-like calcium phosphates. No CSH phase with a lower Ca/Si ratio was identified after transformation. The results confirmed a small effect of the monocalcium silicate addition on the compressive strength (CS) of cements up to 30 wt% (around 20-25 MPa) and a significant rise of the value in 50 woll/B cement (65 MPa). The final setting times of the cement composites varied between 5 and 43 min depending on the P/L ratio and the type of monocalcium silicate phase in the cement mixture. 10CSH/B and 50 woll/B cements with different textures but free of both the needle-like and perpendicularly-oriented hydroxyapatite particles on the surface of the samples had low cytotoxicity. PMID- 27509266 TI - Incidental paranasal sinusitis on routine brain magnetic resonance scans: association with atherosclerosis. AB - BACKGROUND: Incidental paranasal sinusitis (IPS) is common on imaging for non sinusitis disorders, usually without symptoms or obstructive features, and possibly arising from periodontitis (PD). PD associations with atherosclerosis have been widely reported. We test if IPS may also be associated with atherosclerosis. METHODS: IPS was scored retrospectively in a random sample of 180 magnetic resonance (MR) brain scans and compared with chart review for atherosclerosis (all subtypes), rhinosinusitis, and related factors (smoking, asthma, and relevant surgery). IPS was scored out of 30, from all sinuses, with maxillary sinuses weighted double volumetrically. Significant IPS (Sig IPS) was designated as 6 or more out of 30. Bivariate logistic regression was used to test for associations of Sig IPS to the clinical data, with multivariate analysis then testing for potential confounders. RESULTS: A total of 173 subjects were analyzed (7 exclusions). MR indications included suspected acute/prior stroke (22.0%). Sig IPS found in 20 (11.6%). Positive histories for atherosclerosis were cerebral, 57 (32.9%); coronary, 48 (27.7%); and peripheral arterial disease, 14 (8.1%). IPS >=6 was strongly associated with cerebrovascular disease (odds ratio [OR] 6.0, p < 0.001), and less robustly to smoking (OR 2.9, p = 0.07) and rhinosinusitis (OR 2.4, p = 0.09). No associations with coronary or peripheral artery diseases were found. After controlling for smoking and rhinosinusitis, yielding significant subclinical sinusitis, the link of Sig IPS to cerebrovascular disease persisted (modified OR 5.2, p = 0.002). CONCLUSION: Significant incidental sinusitis, which is mostly subclinical sinusitis, is associated with cerebrovascular disease but not other atheroscleroses. This suggests possible common causation of both by PD. PMID- 27509267 TI - Expanding on Successful Concepts, Models, and Organization. PMID- 27509268 TI - Etiology, seasonality, and clinical characteristics of respiratory viruses in children with respiratory tract infections in Eastern India (Bhubaneswar, Odisha). AB - Acute respiratory tract infections (ARTIs) are a leading cause of morbidity and mortality in young children in low and middle income countries. To analyse the overall burden of respiratory viruses responsible for ARTIs in paediatrics population in eastern India, this study was performed. Clinical information, demographic information and nasal/oral swabs were collected from 332 paediatric patients (aged from 1 month to 12 years old) with the symptoms of ARTI, enrolled from the outpatient department from Nov 2012 to Oct 2014. Multiplex PCR was performed to detect eight respiratory viral pathogens. Seasonal, as well as age wise prevalence of respiratory viruses was analysed. Of these 332 cases, 32.53% (108/332) were positive for at least one pathogen. Human rhinovirus (HRV) was the most frequently detected pathogen (24.7%, 82/332) followed by respiratory syncytial virus (RSV) (4.22%, 14/332), PIV (2.11%, 7/332), and hMPV (2.11%, 7/332). Single infection was detected in 92.6% (100/108) of positive cases. Respiratory virus infections showed seasonal variation, with peaks during the rainy season followed by winter season, and were most common in patients under 1 year of age. Phylogenetic analysis of HMPV positive samples confirmed the circulation of A2 subgroup in the study area. The present study is first of its kind and adds to our knowledge of the epidemiological characteristics of these common respiratory viruses among patients with ARTIs in the study area. J. Med. Virol. 89:553-558, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27509270 TI - Influence of Mountaineers' Body Mass Index and Age on the Summiting Success of Mt. Kilimanjaro (5895m) in Tanzania. PMID- 27509271 TI - Effects of 5-O-Ribosylation of Aminoglycosides on Antimicrobial Activity and Selective Perturbation of Bacterial Translation. AB - We studied six pairs of aminoglycosides and their corresponding ribosylated derivatives synthesized by attaching a beta-O-linked ribofuranose to the 5-OH of the deoxystreptamine ring of the parent pseudo-oligosaccharide antibiotic. Ribosylation of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside kanamycin B led to improved selectivity for inhibition of prokaryotic relative to cytosolic eukaryotic in vitro translation. For the pseudodisaccharide aminoglycoside scaffolds neamine and nebramine, ribosylated derivatives were both more potent antimicrobials and more selective to inhibition of prokaryotic translation. On the basis of the results of this study, we suggest that modification of the 5-OH position of the streptamine ring of other natural or semisynthetic pseudodisaccharide aminoglycoside scaffolds containing an equatorial amine at the 2' sugar position with a beta-O-linked ribofuranose is a promising avenue for the development of novel aminoglycoside antibiotics with improved efficacy and reduced toxicity. PMID- 27509273 TI - AJPH Global News. PMID- 27509272 TI - The Real World: Six Strangers Connecting AJPH to the Next Generation. PMID- 27509274 TI - 120 000 Nurses Who Shook Public Health. PMID- 27509275 TI - APHA Voices From the Nurses' Health Study. PMID- 27509276 TI - A Public Health of Consequence: Review of the September 2016 Issue of AJPH. PMID- 27509277 TI - The Nurses' Health Study and the Australian Longitudinal Study on Women's Health: Providing Infrastructure for Public Health Research. PMID- 27509278 TI - Long-Term Cohort Studies in Brazil: On the Tracks of the Nurses' Health Study and Beyond. PMID- 27509279 TI - Large Cohorts: Toward Routine Databases for Public Health Science. PMID- 27509280 TI - How the Nurses' Health Study Helped Americans Take the Trans Fat Out. PMID- 27509281 TI - Preparing Students to Engage in Public Health Research of Consequence. PMID- 27509282 TI - Evaluating Public Health Interventions: 4. The Nurses' Health Study and Methods for Eliminating Bias Attributable to Measurement Error and Misclassification. AB - The Nurses' Health Study and many other large longitudinal cohorts around the world use the food frequency questionnaire to assess dietary intake over time, and to relate diet to health. Controversies concerning this questionnaire's ability to adequately measure diet have led to a flurry of methods for evaluating the magnitude of measurement error and misclassification in exposure assessment, and for correcting the point and interval estimates of effect on the basis of these assessment methods for this error. Nurses' Health Study investigators have been in the forefront of these developments and their applications, although hundreds of other investigators have also used them. This commentary provides an overview of the methods and their uses, and concludes with remarks on their potential applications in the evaluation of public health interventions. PMID- 27509285 TI - Ebola "Ring" Vaccine Trial Was Ethically Innovative. PMID- 27509286 TI - Ploubidis et al. Respond. PMID- 27509287 TI - Do Men Really Benefit More From Marriage Than Women? PMID- 27509288 TI - A Strategic Approach to Eliminating Sexual Orientation-Related Health Disparities. PMID- 27509289 TI - Max et al. Respond. PMID- 27509291 TI - Pre-Implementation Strategies to Adapt and Implement a Veteran Peer Coaching Intervention to Improve Mental Health Treatment Engagement Among Rural Veterans. AB - PURPOSE: Telephone motivational coaching has been shown to increase urban veteran mental health treatment initiation. However, no studies have tested telephone motivational coaching delivered by veteran peers to facilitate mental health treatment initiation and engagement. This study describes pre-implementation strategies with 8 Veterans Affairs (VA) community-based outpatient clinics in the West and Mid-South United States to adapt and implement a multisite pragmatic randomized controlled trial of telephone peer motivational coaching for rural veterans. METHODS: We used 2 pre-implementation strategies, Formative Evaluation (FE) research and Evidence-Based Quality Improvement (EBQI) meetings to adapt the intervention to stakeholders' needs and cultural contexts. FE data were qualitative, semi-structured interviews with rural veterans and VA clinic staff. Results were rapidly analyzed and presented to stakeholders during EBQI meetings to optimize the intervention implementation. FINDINGS: FE research results showed that VA clinic providers felt overwhelmed by veterans' mental health needs and acknowledged limited mental health services at VA clinics. Rural veteran interviews indicated geographical, logistical, and cultural barriers to VA mental health treatment initiation and a preference for self-care to cope with mental health symptoms. EBQI meetings resulted in several intervention adaptations, including veteran study recruitment, peer veteran coach training, and an expanded definition of mental health care outcomes. CONCLUSIONS: As the VA moves to cultivate community partnerships in order to personalize and expand access to care for rural veterans, pre-implementation processes with engaged stakeholders, such as those described here, can help guide other researchers and clinicians to achieve proactive and veteran-centered health care services. PMID- 27509292 TI - Cu-Catalyzed Deoxygenative C2-Sulfonylation Reaction of Quinoline N-Oxides with Sodium Sulfinate. AB - An unexpected Cu-catalyzed deoxygenative C2-sulfonylation reaction of quinoline N oxides in the presence of radical initiator K2S2O8 was developed that used sodium sulfinate as a sulfonyl coupling partner. The mechanism studies indicate that the reaction proceeds via Minisci-like radical coupling step to give sulfonylated quinoline with good chemical yields. PMID- 27509293 TI - Effects of nasal drug delivery device and its orientation on sprayed particle deposition in a realistic human nasal cavity. AB - In this study, the effects of nasal drug delivery device and the spray nozzle orientation on sprayed droplets deposition in a realistic human nasal cavity were numerically studied. Prior to performing the numerical investigation, an in-house designed automated actuation system representing mean adults actuation force was developed to produce realistic spray plume. Then, the spray plume development was filmed by high speed photography system, and spray characteristics such as spray cone angle, break-up length, and average droplet velocity were obtained through off-line image analysis. Continuing studies utilizing those experimental data as boundary conditions were applied in the following numerical spray simulations using a commercially available nasal spray device, which was inserted into a realistic adult nasal passage with external facial features. Through varying the particle releasing direction, the deposition fractions of selected particle sizes on the main nasal passage for targeted drug delivery were compared. The results demonstrated that the middle spray direction showed superior spray efficiency compared with upper or lower directions, and the 10um agents were the most suitable particle size as the majority of sprayed agents can be delivered to the targeted area, the main passage. This study elaborates a comprehensive approach to better understand nasal spray mechanism and evaluate its performance for existing nasal delivery practices. Results of this study can assist the pharmaceutical industry to improve the current design of nasal drug delivery device and ultimately benefit more patients through optimized medications delivery. PMID- 27509294 TI - Meniere's Disease: Molecular Analysis of Aquaporins 2, 3 and Potassium Channel KCNE1 Genes in Brazilian Patients. AB - OBJECTIVES: Meniere's disease (MD) is a complex disease of unknown etiology characterized by a symptomatic tetrad of vertigo, hearing loss, tinnitus, and aural fullness. In addition to factors related to homeostasis of the inner ear, genetic factors have been implicated in its pathophysiology, including genes related to the transport of water and ionic composition maintenance of the endolymph, such as the aquaporin genes AQP2 and AQP3, and the potassium channel gene KCNE1. The aim of this study was to identify polymorphisms of these genes and determine their association with clinical characteristics of patients with MD. DESIGN: A case-control genetic association study was carried out, including 30 patients with definite Meniere's disease and 30 healthy controls. The coding regions of the target genes were amplified from blood samples by polymerase chain reaction (PCR), followed by direct sequencing. The associations of polymorphisms with clinical characteristics were analyzed with logistic regression. RESULTS: Five polymorphisms were identified: rs426496 in AQP2; rs591810 in AQP3; and rs1805127, rs1805128, and rs17173510 in KCNE1. After adjustment, rs426496 was significantly associated with tinnitus during the initial crisis and with altered electronystagmography, and rs1805127 was significantly associated with nephropathy. CONCLUSIONS: The genetic variant rs426496 in AQP2; rs591810 in AQP3 and rs1805127, rs1805128, and rs17173510, in KCNE1 were found in patients with Meniere's disease. The polymorphism rs426496, in AQP2, is associated with tinnitus at the onset of Meniere's disease and altered electronystagmography. In addition, rs1805127, in KCNE1, is associated with the presence of nephropathy. PMID- 27509295 TI - Autonomous Optimization of Targeted Stimulation of Neuronal Networks. AB - Driven by clinical needs and progress in neurotechnology, targeted interaction with neuronal networks is of increasing importance. Yet, the dynamics of interaction between intrinsic ongoing activity in neuronal networks and their response to stimulation is unknown. Nonetheless, electrical stimulation of the brain is increasingly explored as a therapeutic strategy and as a means to artificially inject information into neural circuits. Strategies using regular or event-triggered fixed stimuli discount the influence of ongoing neuronal activity on the stimulation outcome and are therefore not optimal to induce specific responses reliably. Yet, without suitable mechanistic models, it is hardly possible to optimize such interactions, in particular when desired response features are network-dependent and are initially unknown. In this proof-of principle study, we present an experimental paradigm using reinforcement-learning (RL) to optimize stimulus settings autonomously and evaluate the learned control strategy using phenomenological models. We asked how to (1) capture the interaction of ongoing network activity, electrical stimulation and evoked responses in a quantifiable 'state' to formulate a well-posed control problem, (2) find the optimal state for stimulation, and (3) evaluate the quality of the solution found. Electrical stimulation of generic neuronal networks grown from rat cortical tissue in vitro evoked bursts of action potentials (responses). We show that the dynamic interplay of their magnitudes and the probability to be intercepted by spontaneous events defines a trade-off scenario with a network specific unique optimal latency maximizing stimulus efficacy. An RL controller was set to find this optimum autonomously. Across networks, stimulation efficacy increased in 90% of the sessions after learning and learned latencies strongly agreed with those predicted from open-loop experiments. Our results show that autonomous techniques can exploit quantitative relationships underlying activity response interaction in biological neuronal networks to choose optimal actions. Simple phenomenological models can be useful to validate the quality of the resulting controllers. PMID- 27509296 TI - Three-Dimensional Distribution of Phospholipids in Gram Negative Bacteria. AB - Exploration of the molecular structure of the bacterial cell envelope informs our understanding of its role in bacterial growth. This is crucial for research into both inhibiting and promoting bacterial growth as well as fundamental studies of cell cycle control. The spatial arrangement of the lipids in the cell envelope of Gram negative bacteria in particular has attracted considerable research attention in recent years. In this mini-review, we explore advances in understanding the spatial distribution of lipids in the model Gram negative prokaryote Escherichia coli. This includes the distribution of lipids in three dimensions, (a) lateral distribution within a monolayer, (b) asymmetry between bilayers and monolayers, and (c) distribution as a function of progress through membrane division (temporal shifts). We conclude that lipid distribution in E. coli and probably all bacteria is dynamic despite a narrow lipid profile and that the biophysical properties of the membrane are inhomogeneous as a result. Finally, we suggest that further work in this field may indicate how lipid distribution is controlled and what this means for bacterial growth and metabolism and even cell cycle control. PMID- 27509297 TI - Women's Careers in Biomedical Sciences: Implications for the Economy, Scientific Discovery, and Women's Health. AB - While women have been well represented in medical school and biomedical doctoral degree programs, they do not comprise half of academic medicine faculty positions. Furthermore, there is a significant paucity of women in academic medicine leadership positions, as evidenced by the fact that only 16% of dean positions at United States Medical schools are filled by women. In this commentary, the authors review the state of women in academic medicine and argue that increased representation of women in the academic workforce will lead to economic gains, increased scientific discovery, and improvements to women's health. PMID- 27509298 TI - Occlusion of Sulfate-Based Diblock Copolymer Nanoparticles within Calcite: Effect of Varying the Surface Density of Anionic Stabilizer Chains. AB - Polymerization-induced self-assembly (PISA) offers a highly versatile and efficient route to a wide range of organic nanoparticles. In this article, we demonstrate for the first time that poly(ammonium 2-sulfatoethyl methacrylate) poly(benzyl methacrylate) [PSEM-PBzMA] diblock copolymer nanoparticles can be prepared with either a high or low PSEM stabilizer surface density using either RAFT dispersion polymerization in a 2:1 v/v ethanol/water mixture or RAFT aqueous emulsion polymerization, respectively. We then use these model nanoparticles to gain new insight into a key topic in materials chemistry: the occlusion of organic additives into inorganic crystals. Substantial differences are observed for the extent of occlusion of these two types of anionic nanoparticles into calcite (CaCO3), which serves as a suitable model host crystal. A low PSEM stabilizer surface density leads to uniform nanoparticle occlusion within calcite at up to 7.5% w/w (16% v/v), while minimal occlusion occurs when using nanoparticles with a high PSEM stabilizer surface density. This counter-intuitive observation suggests that an optimum anionic surface density is required for efficient occlusion, which provides a hitherto unexpected design rule for the incorporation of nanoparticles within crystals. PMID- 27509299 TI - Salt Taste Enhancing l-Arginyl Dipeptides from Casein and Lysozyme Released by Peptidases of Basidiomycota. AB - Some l-arginyl dipeptides were recently identified as salt taste enhancers, thus opening the possibility to reduce dietary sodium uptake without compromising palatability. A screening of 15 basidiomycete fungi resulted in the identification of 5 species secreting a high peptidolytic activity (>3 kAU/mL; azocasein assay). PFP-LC-MS/MS and HILIC-MS/MS confirmed that l-arginyl dipeptides were liberated when casein or lysozyme served as substrate. Much higher yields of dipeptides (42-75 MUmol/g substrate) were released from lysozyme than from casein. The lysozyme hydrolysate generated by the complex set of peptidases of Trametes versicolor showed the highest l-arginyl dipeptide yields and a significant salt taste enhancing effect in a model cheese matrix and in a curd cheese. With a broad spectrum of novel specific and nonspecific peptidases active in the slightly acidic pH range, T. versicolor might be a suitable enzyme source for low-salt dairy products. PMID- 27509300 TI - Comparative Developmental Toxicity and Stress Protein Responses of Dimethyl Sulfoxide to Rare Minnow and Zebrafish Embryos/Larvae. AB - Dimethyl sulfoxide (DMSO), a widely used carrier solvent, can be toxic to test organisms and has species-specific sensitivity. In this study, the developmental toxicity and stress protein responses of DMSO to rare minnow (Gobiocypris rarus) and zebrafish (Danio rerio) with two tests were compared in the early life stage. In the first test, fertilized eggs were exposed to 0%, 0.0001%, 0.001%, 0.01%, 0.1%, 1.0%, 1.5%, and 2.0% v/v of DMSO until 3 days post hatching. In the second test, larvae from 0 to 8 d were exposed to 2% DMSO until 4 days. Our results showed that DMSO was toxic to rare minnow and zebrafish on multiple indexes, and the no-observed-effect concentrations of DMSO in both species were 1.0% and 0.001% for developmental toxicity analysis and stress protein analysis, respectively. Furthermore, rare minnow larvae were more sensitive than zebrafish to DMSO for spinal malformation. The sensitive period for induction of spinal malformation by DMSO was 0-7 d after hatch (dah) for rare minnow and 0-4 dah for zebrafish. Together, these results will provide support to the use of DMSO in ecotoxicological studies using rare minnow and will contribute to a better understanding of the toxicity of DMSO. PMID- 27509301 TI - Prediction of Estrogenic Bioactivity of Environmental Chemical Metabolites. AB - The US Environmental Protection Agency's (EPA) Endocrine Disruptor Screening Program (EDSP) is using in vitro data generated from ToxCast/Tox21 high throughput screening assays to assess the endocrine activity of environmental chemicals. Considering that in vitro assays may have limited metabolic capacity, inactive chemicals that are biotransformed into metabolites with endocrine bioactivity may be missed for further screening and testing. Therefore, there is a value in developing novel approaches to account for metabolism and endocrine activity of both parent chemicals and their associated metabolites. We used commercially available software to predict metabolites of 50 parent compounds, out of which 38 chemicals are known to have estrogenic metabolites, and 12 compounds and their metabolites are negative for estrogenic activity. Three ER QSAR models were used to determine potential estrogen bioactivity of the parent compounds and predicted metabolites, the outputs of the models were averaged, and the chemicals were then ranked based on the total estrogenicity of the parent chemical and metabolites. The metabolite prediction software correctly identified known estrogenic metabolites for 26 out of 27 parent chemicals with associated metabolite data, and 39 out of 46 estrogenic metabolites were predicted as potential biotransformation products derived from the parent chemical. The QSAR models estimated stronger estrogenic activity for the majority of the known estrogenic metabolites compared to their parent chemicals. Finally, the three models identified a similar set of parent compounds as top ranked chemicals based on the estrogenicity of putative metabolites. This proposed in silico approach is an inexpensive and rapid strategy for the detection of chemicals with estrogenic metabolites and may reduce potential false negative results from in vitro assays. PMID- 27509302 TI - A Unified Picture of S* in Carotenoids. AB - In pi-conjugated chain molecules such as carotenoids, coupling between electronic and vibrational degrees of freedom is of central importance. It governs both dynamic and static properties, such as the time scales of excited state relaxation as well as absorption spectra. In this work, we treat vibronic dynamics in carotenoids on four electronic states (|S0?, |S1?, |S2?, and |Sn?) in a physically rigorous framework. This model explains all features previously associated with the intensely debated S* state. Besides successfully fitting transient absorption data of a zeaxanthin homologue, this model also accounts for previous results from global target analysis and chain length-dependent studies. Additionally, we are able to incorporate findings from pump-deplete-probe experiments, which were incompatible to any pre-existing model. Thus, we present the first comprehensive and unified interpretation of S*-related features, explaining them by vibronic transitions on either S1, S0, or both, depending on the chain length of the investigated carotenoid. PMID- 27509303 TI - Functional engineered human cardiac patches prepared from nature's platform improve heart function after acute myocardial infarction. AB - With the advent of induced pluripotent stem cells and directed differentiation techniques, it is now feasible to derive individual-specific cardiac cells for human heart tissue engineering. Here we report the generation of functional engineered human cardiac patches using human induced pluripotent stem cells derived cardiac cells and decellularized natural heart ECM as scaffolds. The engineered human cardiac patches can be tailored to any desired size and shape and exhibited normal contractile and electrical physiology in vitro. Further, when patching on the infarct area, these patches improved heart function of rats with acute myocardial infarction in vivo. These engineered human cardiac patches can be of great value for normal and disease-specific heart tissue engineering, drug screening, and meet the demands for individual-specific heart tissues for personalized regenerative therapy of myocardial damages in the future. PMID- 27509304 TI - Novel surface-enhanced Raman scattering-based assays for ultra-sensitive detection of human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) are a promising cell source for regenerative medicine, but their derivatives need to be rigorously evaluated for residual stem cells to prevent teratoma formation. Here, we report the development of novel surface-enhanced Raman scattering (SERS)-based assays that can detect trace numbers of undifferentiated hPSCs in mixed cell populations in a highly specific, ultra-sensitive, and time-efficient manner. By targeting stem cell surface markers SSEA-5 and TRA-1-60 individually or simultaneously, these SERS assays were able to identify as few as 1 stem cell in 10(6) cells, a sensitivity (0.0001%) which was ~2000 to 15,000-fold higher than that of flow cytometry assays. Using the SERS assay, we demonstrate that the aggregation of hPSC-based cardiomyocyte differentiation cultures into 3D spheres significantly reduced SSEA 5(+) and TRA-1-60(+) cells compared with parallel 2D cultures. Thus, SERS may provide a powerful new technology for quality control of hPSC-derived products for preclinical and clinical applications. PMID- 27509305 TI - Frequency, predictors, and outcomes of urine drug testing among patients with advanced cancer on chronic opioid therapy at an outpatient supportive care clinic. AB - BACKGROUND: Data are limited on the use and outcomes of urine drug tests (UDTs) among patients with advanced cancer. The main objective of this study was to determine the factors associated with UDT ordering and results in outpatients with advanced cancer. METHODS: A retrospective chart review was conducted of 1058 patients who attended an outpatient supportive care clinic from March 2014 to November 2015. Sixty-one patients who were receiving chronic opioid therapy and underwent UDTs were identified. A control group of 120 patients who did not undergo UDTs was selected for comparison. RESULTS: Sixty-one of 1058 patients (6%) underwent UDTs, and 33 of 61 patients (54%) had abnormal results. Multivariate analysis indicated that the odds ratio for UDT ordering was 3.9 in patients who had positive Cut Down, Annoyed, Guilty, and Eye Opener (CAGE) questionnaire results (P = .002), 4.41 in patients aged < 45 years (P < .001), 5.58 in patients who had moderate-to-severe pain (Edmonton Symptom Assessment Scale pain scores >=4; P < .001), 0.27 in patients with advanced-stage cancer, (P = .008), and 0.25 in patients who had moderate-to-severe fatigue (P = .001). Among 52 abnormal UDT results in 33 patients, the most common opioid findings were prescribed opioids absent in urine (14 of 52 tests; 27%) and unprescribed opioids in urine (13 of 52 tests; 25%). CONCLUSIONS: UDTs were used infrequently among outpatients with advanced cancer who were receiving chronic opioid therapy. Younger age, positive CAGE questionnaire results, early stage cancer or no evidence of disease status, higher pain intensity, and lower fatigue scores were significant predictors of UDT ordering. More than 50% of UDT results were abnormal. More research is necessary to better characterize aberrant opioid use in patients with advanced cancer. Cancer 2016;122:3732-9. (c) 2016 American Cancer Society. PMID- 27509306 TI - Human dental pulp stem cells transplantation combined with treadmill training in rats after traumatic spinal cord injury. AB - Spinal cord injury (SCI) is a disabling condition resulting in deficits of sensory and motor functions, and has no effective treatment. Considering that protocols with stem cell transplantation and treadmill training have shown promising results, the present study evaluated the effectiveness of stem cells from human exfoliated deciduous teeth (SHEDs) transplantation combined with treadmill training in rats with experimental spinal cord injury. Fifty-four Wistar rats were spinalized using NYU impactor. The rats were randomly distributed into 5 groups: Sham (laminectomy with no SCI, n=10); SCI (laminectomy followed by SCI, n=12); SHEDs (SCI treated with SHEDs, n=11); TT (SCI treated with treadmill training, n=11); SHEDs+TT (SCI treated with SHEDs and treadmill training; n=10). Treatment with SHEDs alone or in combination with treadmill training promoted functional recovery, reaching scores of 15 and 14, respectively, in the BBB scale, being different from the SCI group, which reached 11. SHEDs treatment was able to reduce the cystic cavity area and glial scar, increase neurofilament. Treadmill training alone had no functional effectiveness or tissue effects. In a second experiment, the SHEDs transplantation reduced the TNF-alpha levels in the cord tissue measured 6 h after the injury. Contrary to our hypothesis, treadmill training either alone or in combination, caused no functional improvement. However, SHEDs showed to be neuroprotective, by the reduction of TNF-alpha levels, the cystic cavity and the glial scar associated with the improvement of motor function after SCI. These results provide evidence that grafted SHEDs might be an effective therapy to spinal cord lesions, with possible anti-inflammatory action. PMID- 27509307 TI - Galunisertib (LY2157299), a transforming growth factor-beta receptor I kinase inhibitor, attenuates acute pancreatitis in rats. AB - Galunisertib (LY2157299), a selective ATP-mimetic inhibitor of TGF-beta receptor I (TGF-betaRI), is the only known TGF-beta pathway inhibitor. In the present study, we investigated the effect of galunisertib on taurocholate (TAC)-induced acute pancreatitis (AP) in rats, and the role of TGF-beta and NF-kappaB signaling pathways. AP was induced by infusion of TAC into the pancreatic duct of Sprague Dawley male rats (n=30). The rats (220+/-50 g) were administered galunisertib intragastrically [75 mg.kg-1.day-1 for 2 days (0 and 24 h)]. Serum IL-1beta, IL 6, TNF-alpha, amylase (AMY), lipase (LIP), and myeloperoxidase (MPO) levels were measured by ELISA. NF-kappaB activity was detected by electrophoretic mobility shift assay (EMSA); NF-kappaBp65 and TGF-beta1 proteins, as well as TGF-betaRI and p-Smad2/3 proteins, were detected by western blot assay. Cell apoptosis was detected by TUNEL assay. H&E staining was used to evaluate the histopathological alterations of the pancreas. Galunisertib treatment attenuated the severity of AP and decreased the pancreatic histological score. In addition, number of apoptotic cells were significantly increased in the galunisertib-treated group (16.38+/ 2.26) than in the AP group (8.14+/-1.27) and sham-operated group (1.82+/-0.73; P<0.05 and P<0.01, respectively). Galunisertib decreased the expression levels of TGF-betaRI and p-Smad2/3 and inhibited NF-kappaB activation and p65 translocation compared with the sham-operated group. Furthermore, serum IL-1beta, IL-6, TNF alpha, AMY and LIP levels and tissue MPO activity were significantly decreased in the galunisertib-treated group. Our data demonstrate that galunisertib attenuates the severity of TAC-induced experimental AP in rats by inducing apoptosis in the pancreas, inhibiting the activation of TGF-beta signals and NF-kappaB as well as the secretion of pro-inflammatory cytokines. PMID- 27509308 TI - The effect on clinical parameters of periodontal inflammation following non surgical periodontal therapy with ultrasonics and chemotherapeutic cooling solutions: a systematic review. AB - AIM: To establish the added effect of a chemotherapeutic cooling solution in an ultrasonic device on clinical parameters of periodontal inflammation following non-surgical periodontal therapy. METHODS: The MEDLINE-PubMed, Cochrane-CENTRAL, and the EMBASE databases were searched. Probing pocket depth (PPD) and clinical attachment level (CAL) and their changes were selected as outcome variables. Subgroup analyses were performed according to the following active ingredients: essential oils (EO), povidone-iodine (PVP), and chlorhexidine (CHX). RESULTS: Screening of 100 unique papers resulted in 14 eligible publications, including 16 comparisons. The meta-analysis (MA) showed that when the ultrasonic cooling solution had adjuvant chemotherapeutic properties, the difference of means (DiffM) for end value PPD-0.12 (95% CI: -0.42; 0.18) and for CAL the DiffM+-0.13 (95% CI: -0.39; 0.14). None of these were statistically significant, and the findings were supported by the overall descriptive analysis. Subgroup analysis only revealed a small effect for PVP on the difference (DiffM = -0.23, 95% CI: 0.43; -0.02) with respect to CAL (p = 0.03). CONCLUSIONS: The collective evidence indicates that overall, no additional effects were observed. There is a "very weak" recommendation based on the sub-analysis showing that in conjunction with PVP, a very small gain in CAL may be expected. For the use of CHX or EO, the added effect can be considered to be "zero." Therefore, the strength and direction of the recommendation emerging from this review is against their use. PMID- 27509309 TI - Water and solute transport in agricultural soils predicted by volumetric clay and silt contents. AB - Solute transport through the soil matrix is non-uniform and greatly affected by soil texture, soil structure, and macropore networks. Attempts have been made in previous studies to use infiltration experiments to identify the degree of preferential flow, but these attempts have often been based on small datasets or data collected from literature with differing initial and boundary conditions. This study examined the relationship between tracer breakthrough characteristics, soil hydraulic properties, and basic soil properties. From six agricultural fields in Denmark, 193 intact surface soil columns 20cm in height and 20cm in diameter were collected. The soils exhibited a wide range in texture, with clay and organic carbon (OC) contents ranging from 0.03 to 0.41 and 0.01 to 0.08kgkg( 1), respectively. All experiments were carried out under the same initial and boundary conditions using tritium as a conservative tracer. The breakthrough characteristics ranged from being near normally distributed to gradually skewed to the right along with an increase in the content of the mineral fines (particles <=50MUm). The results showed that the mineral fines content was strongly correlated to functional soil structure and the derived tracer breakthrough curves (BTCs), whereas the OC content appeared less important for the shape of the BTC. Organic carbon was believed to support the stability of the soil structure rather than the actual formation of macropores causing preferential flow. The arrival times of 5% and up to 50% of the tracer mass were found to be strongly correlated with volumetric fines content. Predicted tracer concentration breakthrough points as a function of time up to 50% of applied tracer mass could be well fitted to an analytical solution to the classical advection-dispersion equation. Both cumulative tracer mass and concentration as a function of time were well predicted from the simple inputs of bulk density, clay and silt contents, and applied tracer mass. The new concept seems promising as a platform towards more accurate proxy functions for dissolved contaminant transport in intact soil. PMID- 27509310 TI - Alignment of Red Poly[dodecadyin-1,12-diol-bis(4-butoxycarbonyl-methyl-urethane)] in Couette Flow. AB - The flow-induced alignment of red poly[dodecadyin-1,12-diol-bis(4-butoxycarbonyl methyl-urethane)] (poly-4BCMU) in chloroform/toluene solution is reported. Absorption spectra have been measured over a range of shear rates in an optically transparent quartz Couette cell. The measured spectra show that the poly-4BCMU structure stays the same in flow, while the measured absorbance anisotropy is attributed to the flow-induced particle alignment in the red form poly-4BCMU solutions. A limiting orientation at shear rates >50 s(-1) is observed. Numerical simulations show that the spectral changes are consistent with the rodlike poly 4BCMU particle having an aspect ratio of 2.9. The dichroic ratio of 1.9 interpreted from the data indicates that the individual poly-4BCMU chains do not aggregate amorphously in the rodlike conformation, rather they show a preferred orientation along the long axis of the prolate aggregates. PMID- 27509311 TI - Site Redistribution, Partial Frozen-in Defect Chemistry, and Electrical Properties of Ba1-x(Zr,Pr)O3-delta. AB - Changes in nominal composition of the perovskite (ABO3) solid solution Ba1 x(Zr,Pr)O3-delta and adjusted firing conditions at very high temperatures were used to induce structural changes involving site redistribution and frozen-in point defects, as revealed by Raman and photoluminescence spectroscopies. Complementary magnetic measurements allowed quantification of the reduced content of Pr. Weak dependence of oxygen stoichiometry with temperature was obtained by coulometric titration at temperatures below 1000 degrees C, consistent with a somewhat complex partial frozen-in defect chemistry. Electrical conductivity measurements combined with transport number and Seebeck coefficient measurements showed prevailing electronic transport and also indicated trends expected for partial frozen-in conditions. Nominal Ba deficiency and controlled firing at very high temperatures allows adjustment of structure and partial frozen-in defect chemistry, opening the way to engineer relevant properties for high-temperature electrochemical applications. PMID- 27509312 TI - Pharmacological investigations of a yohimbine-impulsivity interaction in rats. AB - Both impulsivity and stress are risk factors for substance abuse, but it is not clear how these two processes interact to alter susceptibility for the disorder. The aim of this project was to examine the pharmacology of a stress-impulsivity interaction in rats. To do so, we tested the effects of yohimbine on impulsive action and then assessed whether behavioural changes could be reduced by antagonists at different receptor subtypes. Male Long-Evans rats were injected with various doses of yohimbine (0-5.0 mg/kg) before testing in the response inhibition task. In subsequent experiments, yohimbine (2.5 mg/kg) was injected following pretreatment with the following receptor antagonists: corticotropin releasing factor receptor 1, antalarmin (0-20 mg/kg); glucocorticoid, mifepristone (0-30 mg/kg); noradrenergic (NA) alpha1, prazosin (0-2 mg/kg); NA alpha2, guanfacine (0-0.5 mg/kg); NA beta2, propranolol (0.5-2.0 mg/kg); dopamine D1/5, SCH 39166 (0-0.0625 mg/kg); MU opioid, naloxone (0-2 mg/kg); or 5-HT2A, M100907 (0.005-0.05 mg/kg). In all experiments, impulsive action was measured as increased premature responding. Yohimbine dose dependently increased impulsive action, but the effect was not reversed by antagonist pretreatment. None of the drugs altered any other behavioural measure. We conclude that stress-impulsivity interactions are likely mediated by a synergy of multiple neurotransmitter systems. PMID- 27509313 TI - Bilobalide alleviates depression-like behavior and cognitive deficit induced by chronic unpredictable mild stress in mice. AB - Bilobalide (BB), a unique constituent of Ginkgo biloba, has powerful neuroprotection and stress-alleviating properties. However, whether BB exerts a positive effect on depression and cognitive deficit induced by chronic stress is not known. The present study was designed to investigate the influence of BB on depression and cognitive impairments induced by chronic unpredictable mild stress (CUMS) in mice. During daily exposure to stressors for 5 consecutive weeks, mice were administered BB at the doses of 0, 3, or 6 mg/kg/day intraperitoneally. We replicated the finding that CUMS induced depression-like behavior and cognitive deficits as the CUMS+vehicle (VEH) group showed a significant increase in immobility in the tail suspension test, a decrease in the discrimination index of the novel object recognition task, and increased latency to platform and decreased number of platform crossings in the Morris water maze compared with the control+VEH group. Chronic administration of BB effectively reversed these alterations. In addition, the CUMS+VEH group showed significantly higher levels of baseline serum corticosterone than those of the control+VEH group and BB dose dependently inhibited this effect. Our results suggest that BB may be useful for inhibition of depression-like behavior and cognitive deficits, and this protective effect was possibly exerted partly through an action on the hypothalamic-pituitary-adrenal axis. PMID- 27509314 TI - Central antinociceptive effect of tapentadol is increased by nitric oxide synthase inhibitors. AB - Nitric oxide synthases (NOSs) have been shown to participate in the mechanism of the antinociceptive action of tapentadol. The results obtained in this study indicate that tapentadol administered intrathecally at a range of doses (30-100 ug) increased nociceptive thresholds in the Randall-Selitto and tail-flick tests in rats; however, this effect was significant only for the higher doses. After intracerebroventricular administration of tapentadol at the same dose range, an antinociceptive effect was observed only in response to mechanical stimuli. In coadministration studies, L-N-nitro arginine (L-NOArg) - a nonselective NOS inhibitor as well as selective inhibitors: 7-Nitroindazole (7-NI), L-N(1 iminoethyl)lysine (L-NIL) or N-(1-iminoethyl)-L-ornithine (L-NIO) for the respective neuronal, inducible, and endothelial NOSs enhanced the antinociceptive activity of intrathecally administered tapentadol in the Randall-Selitto test and to a lesser extent in the tail-flick test. A similar, although less pronounced effect of intracerebroventricular tapentadol was also observed after previous administration of NOS inhibitors in the Randall-Selitto test, but not in the tail flick test. In conclusion, neuronal NOS, inducible NOS, and endothelial NOS influence the antinociceptive action of tapentadol at the spinal level and to a much lesser extent at the supraspinal level. PMID- 27509315 TI - Lack of effect of ethanol on cocaine prime-induced reinstatement of extinguished cocaine self-administration in rhesus monkeys. AB - Cocaine and alcohol are commonly co-abused for reasons that are incompletely understood. Laboratory animal studies have suggested that, although the reinforcing effects of low cocaine doses are increased following chronic ethanol (EtOH) consumption, acute EtOH administration does not consistently alter cocaine self-administration. The present study examined whether EtOH influences another abuse-related effect of cocaine: reinstatement of extinguished responding. Rhesus monkeys that had previously consumed EtOH for 8 weeks (2.0 g/kg over 1 h, 5 days/week) self-administered up to 10 injections per day of 0.1 mg/kg cocaine under a fixed-interval 300-s schedule. After responding had been extinguished by substituting saline for cocaine, a pre-session infusion of saline or EtOH (0.5 or 1.0 g/kg, intravenously over 10 min) was followed by a 'priming' injection of saline or cocaine (intravenously). Responding was increased significantly by priming injections of cocaine, but not saline. EtOH infusions neither reinstated behavior when administered before a saline prime nor altered the priming effect of cocaine. The inability of EtOH to alter the response-reinstating ability of cocaine provides further evidence for a lack of acute behavioral interactions between cocaine and EtOH. PMID- 27509317 TI - Nanotechnology for the diagnosis and treatment of diseases. PMID- 27509316 TI - Punica granatum L. Juice Attenuates Experimental Cerebral Vasospasm in the Rabbit Subarachnoid Hemorrhage Model: A Basilar Artery Morphometric Study and Apoptosis. AB - Background This study investigated the effect of Punica granatum L. (pomegranate) juice on the rabbit basilar artery in an experimental subarachnoid hemorrhage (SAH) model. Methods Eighteen adult male New Zealand white rabbits were randomly divided into three groups: a control group (n = 6), SAH group (n = 6), and SAH + treatment group (n = 6). Basilar artery diameter was measured with magnetic resonance angiography (MRA) in all groups at the beginning of the study. Experimental SAH was created by injecting autologous arterial blood into the cisterna magna. In the treatment group, the subjects were administered a daily dose of 30 ml/kg pomegranate juice via gastric gavage for 4 days after the SAH. The SAH group and SAH + treatment group underwent cerebral MRA after 72 hours. After a neurologic score assessment, all the animals were killed. The wall thickness and lumen area of the basilar artery were measured histometrically in all groups, and the apoptotic cell percentage in the artery was identified. The mean diameter of the basilar artery during MRA was measured. Results Pomegranate improved neurologic functions compared with the SAH group (p < 0.01). The mean basilar artery diameter on MRA in the SAH + treatment group was larger than in the SAH group and smaller than in the control group (p < 0.01 and p < 0.05, respectively). The mean vessel wall thickness value in the SAH + treatment group was lower than in the SAH group (p < 0.01), whereas there was no difference between the control and the SAH + treatment group (p > 0.05). The apoptotic cell rate in the SAH + treatment group was significantly lower than in the SAH group (p < 0.001). Evaluation of the basilar artery luminal area showed no difference between the three groups (p > 0.05). Discussion Pomegranate was shown to have a vasospasm- attenuating effect on the basilar artery in the rabbit SAH model for the first time in our study. PMID- 27509318 TI - Characteristics of gay, bisexual and other men who have sex with men testing and retesting at Australia's first shop-front rapid point-of-care HIV testing service. AB - BACKGROUND: HIV rapid point-of-care (RPOC) testing was approved in Australia in 2012 prompting new testing models. We describe gay, bisexual and other men who have sex with men (GBM) testing in the first year of operations at Australia's first shop-front, community-based RPOC testing service, PRONTO!, and characterise return testers and first-time testers. METHODS: Univariable and multivariable logistic regression using data collected at clients' first test at PRONTO! from 15 August 2013 to 14 August 2014 examined correlates of: 1) return-testing within 6 months of GBMs first test at PRONTO!; and 2) reporting a first ever HIV test at PRONTO!. RESULTS: In the first year, 1226 GBM tested at PRONTO! (median age=30.4 years, 60.2% Australian born). Condomless anal sex with casual or regular partners was reported by 45% and 66% of GBM, respectively. Almost one-quarter (23%) of GBM returned within 6 months of their first test. Return-testing was associated with being born overseas (adjusted odds ratio (AOR)=1.48, 95% confidence interval (CI)=1.10-2.0), reporting a regular check-up as reason to test (AOR=1.53, 95% CI=1.01-2.30) and reporting a HIV test in the 6 months before first testing at PRONTO! (AOR=1.73, 95% CI=1.09-2.73). Reporting first testing at PRONTO! (17.9%) was positively associated with younger age (<30 years; AOR=1.78, 95% CI=1.18-2.71) and negatively associated with reporting a regular check-up as reason to test (AOR=0.45, 95% CI=0.29-0.71) and recent group sex (AOR=0.37, 95% CI=0.23-0.59). CONCLUSION: Despite PRONTO! being designed to reduce barriers to HIV testing, return testing rates in the first year were low and not associated with client risk. Service refinements, including the provision of comprehensive sexually transmissible infection testing, are needed to increase testing frequency and enhance population HIV prevention benefits. PMID- 27509319 TI - MIR196A2 rs11614913 C > T polymorphism correlates with an increased risk of hepatopulmonary syndrome in liver cirrhosis: a case-control study in China. AB - OBJECTIVE: This case-control study is designed to explore the relationship between microRNA-196a2 (MIR196A2) rs11614913 C > T polymorphism and the risk of hepatopulmonary syndrome (HPS) in liver cirrhosis. METHODS: From January 2013 to January 2015, 163 liver cirrhosis patients with HPS (case group), 264 liver cirrhosis patients without HPS (control group), and 195 healthy people (normal group) were selected. A DNA extraction kit was used to extract plasma DNA from peripheral blood. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the allele and genotype frequencies of MIR196A2 C > T polymorphism. Real-time quantitative polymerase chain reaction was adopted to detect the relative expression of MIR196A. RESULTS: The frequencies of C allele in the case group were higher than those in the control and normal groups (all P < 0.05), whereas no significant difference was found between the control and normal groups, which indicated that MIR196A2 C > T polymorphism was closely associated with an increased risk of HPS in patients with liver cirrhosis. Compared with the normal group, the relative expression of MIR196A in the case group was significantly increased (P < 0.05), but there was no significant difference in the control group (P > 0.05). In the case group, compared with patients carrying the TT genotype, the relative expression of MIR196A of patients carrying the C allele (CT + CC) evidently increased (P < 0.05). CONCLUSIONS: The MIR196A2 rs11614913 C > T polymorphism may contribute to an increased risk of HPS in liver cirrhosis patients. PMID- 27509320 TI - Complementary models reveal cellular responses to contact stresses that contribute to post-traumatic osteoarthritis. AB - Two categories of joint overloading cause post-traumatic osteoarthritis (PTOA): single acute traumatic loads/impactions and repetitive overloading due to incongruity/instability. We developed and refined three classes of complementary models to define relationships between joint overloading and progressive cartilage loss across the spectrum of acute injuries and chronic joint abnormalities: explant and whole joint models that allow probing of cellular responses to mechanical injury and contact stresses, animal models that enable study of PTOA pathways in living joints and pre-clinical testing of treatments, and patient-specific computational models that define the overloading that causes OA in humans. We coordinated methodologies across models so that results from each informed the others, maximizing the benefit of this complementary approach. We are incorporating results from these investigations into biomathematical models to provide predictions of PTOA risk and guide treatment. Each approach has limitations, but each provides opportunities to elucidate PTOA pathogenesis. Taken together, they help define levels of joint overloading that cause cartilage destruction, show that both forms of overloading can act through the same biologic pathways, and create a framework for initiating clinical interventions that decrease PTOA risk. Considered collectively, studies extending from explants to humans show that thresholds of joint overloading that cause cartilage loss can be defined, that to at least some extent both forms of joint overloading act through the same biologic pathways, and interventions that interrupt these pathways prevent cartilage damage. These observations suggest that treatments that decrease the risk of all forms of OA progression can be discovered. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:515-523, 2017. PMID- 27509321 TI - Persistent aggregates in apheresis platelet concentrates are commonly collected from donors with a history of aggregate donation. AB - Platelet apheresis sometimes causes persistent aggregates (PA). This study (n = 211) shows that changing the apheresis settings to reach fixed product volumes instead of yields does not influence PA incidence, even though PA products on average contain more platelets than controls. Furthermore, logistic regression was used to model if PA can be predicted on the basis of certain predonation parameters. PA donation history was the only parameter retained, proving a strong determinant of predictability [AUC = 0.735 (SE = 0.022)]. Consequently, donations from a donor with previous PA history are 7.8 times more likely to contain PA than from a donor without preceding history. PMID- 27509322 TI - Kinetic and Theoretical Study of the Nitrate (NO3) Radical Gas Phase Reactions with N-Nitrosodimethylamine and N-Nitrosodiethylamine. AB - The reaction rates of (CH3)2NNO and (CH3CH2)2NNO with NO3 radicals were determined relative to formaldehyde (CH2O) and ethene (CH2CH2) at 298 +/- 2 K and 1013 +/- 10 hPa in purified air by long path FTIR spectroscopy. The reactions are too slow to be of importance at atmospheric conditions: kNO3+(CH3)2NNO = (1.47 +/ 0.23) * 10(-16) and kNO3+(CH3CH2)2NNO = (5.1 +/- 0.4) * 10(-16) cm(3) molecule( 1) s(-1) (1sigma error limits). Theoretical calculations, based on CCSD(T*) F12a/aug-cc-pVTZ//M06-2X/aug-cc-pVTZ results, predict the corresponding imines as the sole primary products in nitrosamine reactions with NO3 and OH radicals. PMID- 27509323 TI - Three rDNA Loci-Based Phylogenies of Tintinnid Ciliates (Ciliophora, Spirotrichea, Choreotrichida). AB - To improve understanding of diversity, phylogeny and evolution in tintinnid ciliates, it is essential to link multiple molecular markers with properly identified and documented morphospecies. Accordingly, 54 tintinnid morphospecies/isolates mainly from the Yellow and East China Seas were collected and analysed. Using single-cell approaches, sequences were obtained for three rDNA loci (18S, ITS1-5.8S-ITS2, D1-D5 region of 28S). Twenty-six tintinnid morphospecies (29 isolates) are documented by micrographs, measurements, morphologically described, and compared with the original species description. Three rDNA loci-based phylogenetic analyses were then performed for these identified isolates. Sequences from 25 unidentified species/isolates were also included in the comparison of the three rDNA loci. Ribosomal DNA genes of the genus Leprotintinnus were analysed for the first time, showing that Leprotintinnus was closely related to Tintinnopsis radix and branched distinctly apart from the family Tintinnidiidae. Four novel clades (VI to IX) of the Tintinnopsis complex emerged in the 18S genealogies. Analyses of the relative variability in the ITS and 28S regions vs. the 18S rDNA showed that the ITS1-5.8S ITS2 and ITS2 regions well co-varied with the 18S rDNA when the variations of the latter were less than 3%, whereas at difference of less than 1%, no correlation was found between the compared loci. These findings highlight the difficulties in using variable locus-based cut-off divergences in circumscribing tintinnid morphospecies. PMID- 27509325 TI - Robotic liver donor right hepatectomy: A pure, minimally invasive approach. AB - Right hepatectomy for a living liver donor via a pure minimally invasive approach is a challenging procedure and only a few cases have been reported. Between May 2013 and August 2015, 13 patients underwent robotic living donor right hepatectomy in our institute, and 54 patients received open surgery. In this series, no conversion was conducted for robotic donor right hepatectomy. The 2 groups shared similar blood loss (169 versus 146 mL), complication rates (7.7% versus 9.3%), and recovery of donor liver function (peak alanine aminotransferase, 269 versus 252 IU/mL). The robotic group needed longer operation time (596 versus 383 minutes) but less postoperative patient-controlled analgesia (0.58 versus 0.84 ng/kg) and a shorter period before returning to work/school (52.9 versus 100.0 days) and sex (100.0 versus 156.0 days). For recipient outcomes regarding the donor procedure, the robotic group shared similar experiences in early allograft dysfunction, complications, and 1-year recipient liver function with the open group. With respect to documented benefits of minimally invasive left-sided liver donor procedure, the development of right donor hepatectomy is slow. In conclusion, with substantial improvements in patient recovery after the minimally invasive approach, the robotic platform would be a big step toward completing pure minimally invasive liver donor surgery. Liver Transplantation 22 1509-1518 2016 AASLD. PMID- 27509326 TI - Carbon-Decorated TiO2 Nanotube Membranes: A Renewable Nanofilter for Charge Selective Enrichment of Proteins. AB - In this work, we design a TiO2 nanomembrane (TiNM) that can be used as a nanofilter platform for selective enrichment of specific proteins. After a first use, the photocatalytic properties of TiO2 allow the decomposition of unwanted remnants on the substrate and thus make the platform reusable. To construct this platform, we fabricate a free-standing TiO2 nanotube array and remove the bottom oxide to form a both-end-open TiNM. By pyrolysis of the natural tube wall contamination, the walls become decorated with graphitic carbon patches (C/TiNM). Owing to the large surface area, the amphiphilic nature and the charge-adjustable character, this C/TiNM can be used to extract and enrich hydrophobic charged biomolecules. Using human serum albumin (HSA) as a model protein as well as protein mixtures, we show that the composite membrane exhibits a highly enhanced loading capacity and protein selectivity and is reusable after a short UV treatment. PMID- 27509327 TI - Osteolysis Complicating Total Knee Arthroplasty. AB - Osteolysis is a process mounted by the host immune system that relies on several variables, including patient-related factors, type of insert material, modes of wear, and implant design. Imaging techniques such as radiography, computed tomography (CT) scans, magnetic resonance imaging (MRI), and tomosynthesis aid in diagnosing osteolysis. Surgical options for the treatment of osteolysis include the insertion of bone grafts, bone cement, and prosthetic augmentation. Although no approved pharmacological therapies for the specific treatment of osteolysis exist, the use of bisphosphonates and statins decreases the risk of osteolysis. PMID- 27509328 TI - Treatment of Osteonecrosis of the Talus. AB - More than 60% of the talar surface area consists of articular cartilage, thereby limiting the possible locations for vascular infiltration and leaving the talus vulnerable to osteonecrosis. Treatment strategies for talar osteonecrosis can be grouped into four categories: nonsurgical, surgical-joint sparing, surgical salvage, and joint-sacrificing treatments. Nonoperative and joint-sparing treatments include restricted weight-bearing, patellar tendon-bearing braces, bone-grafting, extracorporeal shock wave therapy, internal implantation of a bone stimulator, core decompression, and vascularized or non-vascularized autograft, whereas joint-sacrificing or salvage procedures include talar replacement (partial or total) and arthrodesis. In patients with a Ficat and Arlet grade-I through III osteonecrosis, evidence in favor of a specific treatment is poor, although tibiotalar or tibiotalocalcaneal arthrodesis may represent a suitable salvage operation. PMID- 27509329 TI - The Pathogenesis and Treatment of Legg-Calve-Perthes Disease. AB - Legg-Calve-Perthes disease is a childhood hip condition in which the blood supply to the capital femoral epiphysis is interrupted, causing osteonecrosis and chondronecrosis that lead to progressive deformity of the femoral head and secondary degenerative osteoarthritis in later life. The etiology of Legg-Calve Perthes disease remains unclear, with both biological and mechanical factors playing important roles in the pathogenesis of the condition. The treatment of Legg-Calve-Perthes disease remains controversial but is dependent on several salient factors, including the age at clinical onset, the extent of epiphyseal involvement, the stage of the disease, and the degree of femoral head deformity. The literature supports operative containment treatment in the early stage of disease. Such treatment has led to improved femoral head sphericity with better patient outcomes in multicenter prospective cohort studies. The number of hips that need to be treated operatively in order to achieve a modest treatment effect remains high. Multicenter prospective cohort studies have shown that 6 to 7 patients need to be managed to create 1 spherical femoral head that would not have otherwise occurred. PMID- 27509330 TI - Team Approach: Treatment of Diabetic Foot Ulcer. AB - At any point in time, 3% to 4% of the 29.1 million diabetic patients in the United States (9.3% of the population) will have a foot ulcer. Diabetes associated foot ulcers and infection lead to >70,000 lower-extremity amputations yearly in the United States. Between one-third and one-half of diabetic patients undergoing a major lower-extremity amputation will die within 2 years after the amputation. Multidisciplinary population health-management strategies have been developed to decrease the rate and magnitude of this important comorbidity in the diabetic population. The goal of the present review is to provide the reader with a framework for the development of a health-care-system strategy for addressing this complex patient population. PMID- 27509331 TI - Pigmented Villonodular Synovitis: A Comprehensive Review and Proposed Treatment Algorithm. AB - Evidence now exists suggesting a neoplastic origin for pigmented villonodular synovitis, including a thorough description of the translocations involved. Arthroscopic excision for localized pigmented villonodular synovitis allows for both minimal recurrence and morbidity when compared with open excision; however, open excision still plays an important role in treating posterior compartment nodules. The optimal surgical treatment for diffuse pigmented villonodular synovitis is still a matter for debate, with combined anterior arthroscopic and open posterior excision being considered the preferred method. Radiation therapy has re-emerged as an additional treatment method for pigmented villonodular synovitis; however, the potential for serious toxicity makes it a questionable option, especially for such a benign condition. Small molecule and monoclonal antibody targeted therapies are being investigated as novel treatment methods for pigmented villonodular synovitis, with promising results. PMID- 27509332 TI - Biosensing Test-Bed Using Electrochemically Deposited Reduced Graphene Oxide. AB - The development of an efficient test-bed for biosensors requires stable surfaces, capable of interacting with the functional groups present in bioentities. This work demonstrates the formation of highly stable electrochemically reduced graphene oxide (ERGO) thin films reproducibly on indium tin oxide (ITO)-coated glass substrates using a reliable technique through 60 s chronoamperometric reduction of a colloidal suspension maintained at neutral pH containing graphene oxide in deionized water. Structural optimization and biocompatible interactions of the resulting closely packed and uniformly distributed ERGO flakes on ITO surfaces (ERGO/ITO) are characterized using various microscopic and spectroscopic tools. Lipase enzyme is immobilized on the ERGO surface in the presence of ethyl 3-[3-(dimethylamino)propyl]carbodimide and N-hydroxysuccinimide for the detection of triglyceride in a tributyrin (TBN) solution. The ERGO/ITO surfaces prepared using the current technique indicate the noticeable detection of TBN, a source of triglycerides, at a sensitivity of 37 pA mg dL(-1) cm(-2) in the linear range from 50 to 300 mg dL(-1) with a response time of 12 s. The low apparent Michaelies-Menten constant of 0.28 mM suggests high enzyme affinity to TBN. The currently developed fast, simple, highly reproducible, and reliable technique for the formation of an ERGO electrode could be routinely utilized as a test bed for the detection of clinically active bioentities. PMID- 27509333 TI - Molecular differences in the microsatellite stable phenotype between left-sided and right-sided colorectal cancer. AB - Differences in the pathogenesis of microsatellite stable (MSS) sporadic colorectal cancers (CRCs) between left-sided CRC (LC) and right-sided CRC (RC) have not been clarified. To identify pathogenesis-related genomic differences between MSS CRCs within the two locations, we performed a comprehensive molecular analysis using crypt isolation with samples from 92 sporadic CRCs. Microsatellite instability (MSI; high and low/negative) and DNA methylation status (low methylation epigenome; intermediate methylation epigenome [IME] or high methylation epigenome [HME]) were determined using polymerase chain reaction (PCR) microsatellite analysis and PCR-bisulfite pyrosequencing, respectively. Additionally, mutations in the TP53, KRAS, BRAF and PIK3CA genes were examined using PCR-bisulfite pyrosequencing (for KRAS and BRAF mutations) or PCR-single conformation polymorphism (for TP53 and PIK3CA mutations), followed by sequencing of aberrant bands. Finally, a genome-wide study using a copy number alteration (CNA)-targeted single nucleotide polymorphism array was performed. Ninety-two CRCs were classified into 71 MSS and 21 MSI phenotypes. We examined 71 CRCs with the MSS phenotype (LC, 56; RC, 15). Mutations in KRAS were associated with RC with the MSS phenotype, whereas mutations in TP53 were more frequently found in LC with the MSS phenotype. There were significant differences in the frequencies of KRAS and TP53 mutations in the IME between LC and RC with the MSS phenotype. Although CNA gains were associated with LC with the MSS phenotype, CNA losses were not major alterations associated with the MSS phenotype. These findings suggested that the molecular pathogenesis of the MSS phenotype in LC was different from that in RC. PMID- 27509334 TI - Integrative review: nurses' roles and experiences in keeping children safe. AB - AIM: To identify nurses' role and experiences of keeping children safe. BACKGROUND: Approaches to preventing, identifying and responding to child abuse and neglect have moved towards a multidisciplinary approach where all professionals are expected to contribute to the goal of keeping children safe. Frequently in contact with children and families, nurses well positioned to contribute to keeping children safe from abuse and neglect. Much has been published around nurses' experiences of their role in keeping children safe, but this literature has not yet been synthesized to determine the challenges and potential scope of this role. DESIGN: Integrative review following an Integrative Review framework. DATA SOURCES: Studies were identified through a search of the electronic databases CINAHL, Medline, Web of Science, Scopus and Informit to identify literature published between 2005-2015. REVIEW METHODS: All the studies were critically appraised for methodological quality using the Critical Skills Appraisal Programme. Data from each study were extracted and categorized according to the review aims and the study's major findings. RESULTS: Inclusion criteria were met in 60 studies. Three main findings were identified including nurses' insufficient knowledge, need for validation and improved communication and balancing surveillance and support for vulnerable families. CONCLUSIONS: Nurses have many roles and experiences in keeping children safe but often felt they did not have the knowledge, skills and support to take action in this area. Further research is needed to understand why nurses feel inadequate and disempowered to advocate and intervene on the behalf of children at risk of abuse or neglect. PMID- 27509336 TI - [Discussion of values in health care: a crucial test for internal medicine?]. PMID- 27509335 TI - Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates. AB - The onset of Alzheimer disease (AD) is influenced by several risk factors comprising diabetes. Within this context, antidiabetic drugs, including metformin, are investigated for their effect on AD. We report that in the C57B6/J mice, metformin is delivered to the brain where activates AMP-activated kinase (AMPK), its molecular target. This drug affects the levels of beta-secretase (BACE1) and beta-amyloid precursor protein (APP), promoting processing and aggregation of beta-amyloid (Abeta), mainly in the cortex region. Moreover, metformin induces mitochondrial dysfunction and cell death by affecting the level and conformation of Translocase of the Outer Membrane 40 (TOM40), voltage dependent anion-selective channels 1 (VDAC1) and hexokinase I (HKI), proteins involved in mitochondrial transport of molecules, including Abeta. By using biophysical techniques we found that metformin is able to directly interact with Abeta influencing its aggregation kinetics and features. These findings indicate that metformin induces different adverse effects, leading to an overall increase of the risk of AD onset. PMID- 27509337 TI - [Renal artery stenosis: new insights and developments]. PMID- 27509338 TI - [Subclinical hypothyroidism - laboratory finding or disease?]. AB - Subclinical hypothyroidism first of all is a laboratory finding, defined by elevated TSH and normal peripheral thyroxine concentrations. The first steps are to verify the condition and to clarify whether the patient has underlying thyroid disease or other comorbidities. Results of recent studies on subclinical hypothyroidism are reassuring. No consistent association has been demonstrated between mildly elevated TSH levels (5-10 mIU / l) and cardiovascular events, mortality, fracture risk or cognitive impairment. In contrast TSH levels between 5-10 mIU / l may even confer lower mortality in the elderly and may hence be protective. These data strongly suggest that the long-time controversy on definition of normal upper TSH levels should take a more conservative turn. Thus, diagnosis of subclinical hypothyroidism should be handled cautiously. Individualized treatment decision is recommended if TSH levels are only mildly elevated and less than 8-10 mIU / l. In case of autoimmune thyroiditis or previous thyroid therapy (surgery, radioiodine treatment) the risk of progression to overt hypothyroidism has to be considered and there is no doubt that the latter should be avoided. PMID- 27509339 TI - [Sleep Disturbances in the Elderly]. AB - Sleep disturbances are common in the elderly. Endogen regulation mechanisms are often unstable. Light treatment and melatonin are proved chronobiological interventions. Cataract surgery is effective to enhance the sleep-wake rhythm.Mandibular advancement devices are a reliable alternative to continuous positive air pressure (CPAP) in obstructive sleep apnea syndrome (OSAS). PMID- 27509340 TI - [Hemophagocytic lymphohistiocytosis in adults]. AB - Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome with established diagnostic criteria, and well characterized gene mutations in children. In contrast, acquired HLH in adults (aHLH) due to the heterogeneity of trigger diseases (infections, malignancies and autoimmune diseases) is less clear defined. There is both a risk of under- and overtreatment. Due to the lack of validated diagnostic criteria for HLH in adults, diagnostic and therapeutic delay are significant risk factors for patient outcome. This article presents the current status and new developments in epidemiology, pathophysiology, diagnosis and treatment of aHLH. PMID- 27509341 TI - [New aspects on Clostridium difficile infection]. AB - Clostridium difficile infection (CDI) is a frequent and complex disease which is influenced by the repertoire of bacterial virulence factors, by host immunity and by the intestinal microbiome. These complex interaction opens a number of options which may be used for treatment in the future. One example for new treatment options is fecal microbiota transplantation (FMT). Driven by C. difficile related research activities the knowledge of protective microorganism is increasing and it may be assumed that bacteriotherapy by next-generation probiotics may be used very soon also for other diseases. Very often, CDI reflects to the clinician that antibiotic therapy is associated with side effects. Therefore, C. difficile is the guilty conscience which helps to implement targeted and restrictive antibiotic use in the daily practice. PMID- 27509342 TI - [Airway Management In Intensive Care Patients]. AB - Many physicians are working in intensive care and are not additionally anaesthesiological experienced. The situation having to perform an emergency in intubation is often feel anxious. Significant complications, such as severe hypoxemia (25%), life-threatening cardiovascular events (40%) or cardiac arrest (2%) may occur during intubation on ICU. The physician must have a clear strategy in preparation and implemention of emergency intubation. It is equally important to perform an alternative airway management when intubation is difficult.In the last 15 years we became aware of this problem and established clear guidelines and algorithms. Drug innovations, technical innovations and new workflows improve complications and mortality rates and provide security. This article describes the current innovations and study results for intubation of criticall ill patients. PMID- 27509343 TI - [Treatment of ventricular tachyarrhythmias and prevention of sudden cardiac death: commentary on the 2016 ESC guideline]. AB - The 2016 ESC guideline on prevention and therapy of ventricular tachyarrhythmias and sudden cardiac death present an excellent recommendation and summary for all forms of ventricular tachyarrhythmias in patients with and without structural or electrical heart disease. This includes cardiomyopathies as well as conditions such as proarrhythmia, neurologic/psychaitric disorders, or pregnancy. Some aspects are novel; (1) the guideline emphasizes for the first time genetic work up in sudden cardiac death victims; (2) for prevention of sudden cardiac death systematic re-evaluation 6-12 weeks after myocardial infarction is recommended; (3) subcutaneous ICD as well as the wearable cardioverter/defibrillator are for the first time included in the guidelines; (4) automatic external defibrillators are recommended for public places; (5) for patients with recurrent ventricular tachyarrhythmias the role of catheter ablation has been upgraded. PMID- 27509344 TI - [Primary and secondary glomerular diseases]. PMID- 27509345 TI - [Asthma COPD Overlap Syndrome (ACOS): precision medicine or diagnostic dead end?]. AB - Asthma and COPD are two distinct diseases but sometimes patient can show clinical features of asthma and COPD. For this group the term asthma-COPD-overlap syndrome (ACOS) has been created. However, the variability of defining criteria leads to a broad heterogeneity of patients assigned to this syndrome. Therefore, the introduction of the term ACOS is of limited value for a more individualized treatment of patients with obstructive airway disease. PMID- 27509346 TI - [An update on gout: diagnostic approach, treatment and comorbidity]. AB - Muskuloskeletal ultrasound and dual-energy-CT (DECT) findings are increasingly relevant for the establishment of the diagnosis of gout, and are therefore incorporated into the novel ACR / EULAR classification criteria. Canakinumab, a monoclonal antibody directed against interleukin-1beta (IL-1beta) has been approved in 2013 for the treatment of acute gout and for prophylaxis of flares. In patients demonstrating an inadequate response upon treatment with allopurinol or febuxostat, combination therapy with lesinurad might reduce uric acid levels to the target of < 6 mg / dl (< 5 mg / dl in tophaceous gout). Rapid lowering of uric acid levels and effective tophi reduction can be achieved with pegloticase, which can be utilized in selected patients presenting contraindications to xanthine oxidase inhibitors and uricosuric drugs. This article summarizes current scientific aspects of diagnosis, treatment and comorbidities of gout in the context of clinical relevance. PMID- 27509347 TI - [Recent therapeutic options of (severe) gastrointestinal bleedings]. AB - With Idarucizumab, a specific antidote to antagonize the effect of dabigatran, is now available in severe bleeding complications under directly oral anticoagulants (DOAC). In endoscopic treatment of severe gastrointestinal bleeding are alternative treatment options also available with hemostasis sprays and new hemostasis clips. Especially in recurrent ulcer bleedings, the newly developed clips can achieve hemostasis and prevent an operational procedure. In patients with coronary heart disease, a liberal transfusion regimen should be considered. PMID- 27509348 TI - [42-year old man with sudden, progredient dyspnea]. PMID- 27509349 TI - [Acute liver failure after ingestion of ciprofloxacin]. AB - HISTORY AND ADMISSION FINDINGS: A 23-year old female patient is referred to our intensive care unit from another hospital because of progredient neurological deterioration with sopor. One week before, she had experienced non-specific pain in her upper right stomach combined with vomitus and nausea. For two days, she had been treated with ciprofloxacin 2 * 500 mg / d by her primary care physician. Except for appendectomy in childhood, no other diseases were reported. Clinical investigation: Physical examination reveals mild scleral and dermal jaundice. There is tenderness of the upper right abdomen. Initially, no neurological pathological findings are obvious. Laboratory results show an increase of liver aminotransferases, bilirubin, and ammonia. The toxicological screening is negative. TREATMENT AND COURSE: Hepatic encephalopathy due to acute hepatic failure is diagnosed and detoxification of ammonia with lactulose is started. Transiugular liver biopsy confirms lobular hepatitis with cytolysis. Because of progressive deterioration additional treatment to prevent cerebral oedema is initiated. Consecutively serum osmolality decreases, and ammonia and neurological status normalize. CONCLUSION: This report illustrates toxic acute liver failure after treatment with ciprofloxacin. PMID- 27509350 TI - [Constipation in Patients with Incurable Cancer - Recommendations of the German S3 Guideline 'Palliative Medicine']. AB - According to the German S3-guideline 'Palliative Medicine' which has been supported by the German Guideline Program in Oncology, constipation in palliative patients requires a consistent prophylaxis and therapy. Constipation is caused by immobilisation, poor health, exsiccosis, a low-fiber diet or a preexisting functional constipation. Further important causes are substances with constipating side effects, such as opioids or anticholinergic drugs. Pragmatically, constipation should be assessed by subjective parameters such as the feeling of incomplete evacuation, straining, or other complaints. Objective parameters are hard stool or reduced number of bowel movements. For the early detection of constipation the amount of the stool mass and the stool frequency are applicable. If constipation occurs, a standardized escalating protocol applying adequate fluid intake, a high fibre diet, and laxatives is recommended. New prokinetic agents, secretagogues, or opioid antagonists may be used as reserve drugs. PMID- 27509351 TI - Adaptive Design for a Confirmatory Basket Trial in Multiple Tumor Types Based on a Putative Predictive Biomarker. AB - Increasingly, tumors are defined on a molecular basis rather than only on histology, and targeted agents, which address these molecular subtypes, are being approved. This profusion of molecular subtypes creates "rare" diseases as subsets of common cancers, leading to difficulties in enrolling sufficiently large cohorts for confirmatory trials. However, if the molecular subtype is shared across various histologies, these may be pooled into a basket trial. To date, basket trials have been primarily for exploratory early development. In this perspective, we consider qualitative designs for confirmatory basket trials. These confirmatory basket designs will provide patients in niche indications with enhanced access to novel therapies, facilitate development and full approval for niche indications, allow accelerated approval for indications within a basket based on a surrogate endpoint, reduce development cost by combining trials, and enhance the ability of regulatory authorities to evaluate risk and benefit in niche indications. PMID- 27509352 TI - Impulsive choices in mice lacking imprinted Nesp55. AB - Genomic imprinting is the process whereby germline epigenetic events lead to parent-of-origin specific monallelic expression of a number of key mammalian genes. The imprinted gene Nesp is expressed from the maternal allele only and encodes for Nesp55 protein. In the brain, Nesp55 is found predominately in discrete areas of the hypothalamus and midbrain. Previously, we have shown that loss of Nesp55 gives rise to alterations in novelty-related behaviour. Here, we extend these findings and demonstrate, using the Nespm/+ mouse model, that loss of Nesp55 leads to impulsive choices as measured by a delayed-reinforcement task, whereby Nespm/+ mice were less willing to wait for a delayed, larger reward, preferring instead to choose an immediate, smaller reward. These effects were highly specific as performance in another component of impulsive behaviour, the ability to stop a response once started as assayed in the stop-signal reaction time task, was equivalent to controls. We also showed changes in the serotonin system, a key neurotransmitter pathway mediating impulsive behaviour. First, we demonstrated that Nesp55 is co-localized with serotonin and then went on to show that in midbrain regions there were reductions in mRNA expression of the serotonin-specific genes Tph2 and Slc6a4, but not the dopamine-specific gene Th in Nespm/+ mice; suggesting an altered serotonergic system could contribute, in part, to the changes in impulsive behaviour. These data provide a novel mode of action for genomic imprinting in the brain and may have implications for pathological conditions characterized by maladaptive response control. PMID- 27509353 TI - Antimicrobial activity of submicron glass fibres incorporated as a filler to a dental sealer. AB - Two types of antimicrobial glass fibers containing ZnO and CaO, with diameters ranging from tens of nanometers to 1 um, were successfully fabricated by a laser spinning technique. The antimicrobial performance was corroborated according to ISO 20743:2013, by using gram-negative (Escherichia coli) and gram-positive (Streptococcus oralis, Streptococcus mutans and Staphylococcus aureus) bacteria, and yeast (Candida krusei) (more than 3 logs of reduction). The metabolic activity and endosomal system of eukaryotic cells were not altered by using eluents of CaO glass submicrometric fibers and ZnO fibers at 1 : 10 dilution as cellular media (viability rates over 70%). A dental material was functionalized by embedding ZnO nanofibers above the percolation threshold (20% wt), creating a three-dimensional (3D) fiber network that added an antimicrobial profile. This new ZnO glass fiber composite is proved non-cytotoxic and preserved the antimicrobial effect after immersion in human saliva. This is the first time that a fiber-reinforced liner with strong antimicrobial-activity has been created to prevent secondary caries. The potential of developing new fiber-reinforced composites (FRCs) with antimicrobial properties opens up an extensive field of dental applications where most important diseases have an infectious origin. PMID- 27509354 TI - Paranasal sinus opacification-to-pneumatization ratio applied as a rapid and validated clinician assessment. AB - BACKGROUND: The utility of clinician-applied instruments, particularly the Lund Mackay score, in the assessment of paranasal sinus computed tomography (CT) in chronic rhinosinusitis (CRS) remains incompletely defined. The purpose of this study was to determine if a new approach to the evaluation of sinus CT could accurately predict the extent of opacification while remaining simple for clinician use. METHODS: Twenty-four sinus CT scans were measured for the percent of sinus opacification using three-dimensional (3D) volumetric analyses. The same scans were also evaluated using the Lund-Mackay score to measure opacification and the Assessment of Pneumatization of the Paranasal Sinuses (APPS) score to measure total sinus volume (TSV). Correlation analysis was performed for the Lund Mackay to APPS score ratio as a predictor of percent opacification. Validation analysis was also performed to determine the optimal orientation for Lund-Mackay scoring, which has not previously been described. RESULTS: The Lund-Mackay to APPS score ratio was very strongly correlated with the percentage of sinus opacification measured by 3D volumetric analysis (r = 0.862, r2 = 0.743, p < 0.001). Lund-Mackay scoring was not statistically different between axial-only, coronal-only, or triplanar groups for interrater (p = 0.379) and intrarater reliability (p = 0.312). CONCLUSION: The Lund-Mackay score is validated for rater reliability in multiple orientations. Using the APPS score as a measure of TSV, the Lund-Mackay-to-APPS ratio very strongly correlates with the percentage of sinus opacification by 3D volumetric analysis. Further study will be required to determine if this ratio is predictive of symptom severity. PMID- 27509355 TI - Cardiogenic Shock: Failure of Oxygen Delivery and Oxygen Utilization. AB - Cardiogenic shock remains a highly lethal condition. Conventional therapy including revascularization and mechanical circulatory support aims to improve cardiac output and oxygen delivery, but increasing basic and clinical observations indicate wider circulatory and cellular abnormalities, particularly at the advanced stages of shock. Progressive cardiogenic shock is associated with microcirculatory and cellular abnormalities. Cardiogenic shock is initially characterized by a failure to maintain global oxygen delivery; however, progressive cardiogenic shock is associated with the release of pro-inflammatory cytokines, derangement of the regulation of regional blood flow, microcirculatory abnormalities, and cellular dysoxia. These abnormalities are analogous to septic shock and may not be reversed by increase in oxygen delivery, even to supranormal levels. Earlier mechanical circulatory support in cardiogenic shock may limit the development of microcirculatory and cellular abnormalities. PMID- 27509356 TI - Short duration response-guided treatment is effective for most individuals with recent hepatitis C infection: the ATAHC II and DARE-C I studies. PMID- 27509358 TI - alpha-Glucosidase and alpha-Amylase Inhibitors from Arcytophyllum thymifolium. AB - Three new coumarins (1-3), a prenylated flavanone (4), and two iridoids (5 and 6), together with 17 known secondary metabolites, were isolated from the aerial parts of Arcytophyllum thymifolium. The structures of the new compounds were elucidated on the basis of their spectroscopic data. The potential hypoglycemic properties of the new and known compounds were evaluated by measuring their alpha amylase and alpha-glucosidase inhibitory effects. The iridoid asperulosidic acid (15) and the flavonoid rhamnetin (13) showed the highest activities versus alpha amylase (IC50 = 69.4 +/- 3.1 and 73.9 +/- 5.9 MUM, respectively). In turn, the new eriodictyol derivative 4 exhibited the most potent effect as an alpha glucosidase inhibitor, with an IC50 value of 28.1 +/- 2.6 MUM, and was more active than acarbose, used as a positive control. Modeling studies were also performed to suggest the interaction mode of compound 4 in the alpha-glucosidase enzyme active site. PMID- 27509360 TI - Catalyst-Free and Regioconvergent Substitution Reactions of Bromothiophenes with a BH3-Substituted Phosphide Anion. AB - A range of bromothiophenes reacted with lithium boranato(tert butyl)methylphosphide in the absence of transition-metal catalysts under mild conditions to provide the same 2,5-disubstituted and 2-monosubstituted products regardless of the substitution patterns of the starting bromothiophenes. PMID- 27509359 TI - Lung Function in African Infants in the Drakenstein Child Health Study. Impact of Lower Respiratory Tract Illness. AB - RATIONALE: Lower respiratory tract illness is a major cause of childhood morbidity and mortality. It is unknown whether infants are predisposed to illness because of impaired lung function or whether respiratory illness reduces lung function. OBJECTIVES: To investigate the impact of early life exposures, including lower respiratory tract illness, on lung function during infancy. METHODS: Infants enrolled in the Drakenstein child health study had lung function at 6 weeks and 1 year. Testing during quiet natural sleep included tidal breathing, exhaled nitric oxide, and multiple breath washout measures. Risk factors for impaired lung health were collected longitudinally. Lower respiratory tract illness surveillance was performed and any episode investigated. MEASUREMENTS AND MAIN RESULTS: Lung function was tested in 648 children at 1 year. One hundred and fifty (29%) infants had a lower respiratory tract illness during the first year of life. Lower respiratory tract illness was independently associated with increased respiratory rate (4%; 95% confidence interval [CI], 1.01-1.08; P = 0.02). Repeat episodes further increased respiratory rate (3%; 95% CI, 1.01-1.05; P = 0.004), decreased tidal volume (-1.7 ml; 95% CI, -3.3 to -0.2; P = 0.03), and increased the lung clearance index (0.13 turnovers; 95% CI, 0.04 0.22; P = 0.006) compared with infants without illness. Tobacco smoke exposure, lung function at 6 weeks, infant growth, and prematurity were other independent predictors of lung function at 1 year. CONCLUSIONS: Early life lower respiratory tract illness impairs lung function at 1 year, independent of baseline lung function. Preventing early life lower respiratory tract illness is important to optimize lung function and promote respiratory health in childhood. PMID- 27509361 TI - Challenging the One-Dose-Fits-All Model for Insulin in the Acute Treatment of Pediatric Diabetic Ketoacidosis. A Critical Appraisal of "Low-Dose Versus Standard-Dose Insulin in Pediatric Diabetic Ketoacidosis: A Randomized Clinical Trial" by Nallasamy et al (JAMA Pediatrics 2014; 168:999-1005). AB - OBJECTIVE: To review the findings and discuss the implications of the use of low dose insulin infusions in pediatric diabetic ketoacidosis compared with standard dose insulin. DATA SOURCES: A search of the electronic PubMed database was used to perform the clinical query as well as to search for additional relevant literature. STUDY SELECTION AND DATA EXTRACTION: The article by Nallasamy K et al "Low-Dose vs Standard-Dose Insulin in Pediatric Diabetic Ketoacidosis: A Randomized Clinical Trial. JAMA Pediatrics 2014; 17:e477-e480" was selected for critical appraisal and literature review. DATA SYNTHESIS: The authors performed a randomized controlled trial among 50 consecutive patients of 0-12 years old presenting to the emergency department in diabetic ketoacidosis. They found that low-dose (0.05 U/kg/hr) insulin infusion was noninferior to standard-dose (0.1 U/kg/hr) insulin in terms of resolution of hyperglycemia and acidosis with a trend toward lower rates of therapy-related complications in the low-dose group. CONCLUSIONS: Low-dose insulin infusion is noninferior to standard-dose insulin in the treatment of younger pediatric patients with diabetic ketoacidosis and may lead to fewer therapy-related complications. PMID- 27509362 TI - Enteral Nutrition and Acid-Suppressive Therapy in the PICU: Impact on the Risk of Ventilator-Associated Pneumonia. AB - OBJECTIVE: Enteral nutrition has been implicated as a risk factor for ventilator associated pneumonia. We explored the prevalence of ventilator-associated pneumonia and its association with clinical and nutrition-related therapies in mechanically ventilated children. DESIGN: Prospective, multicenter, cohort study. SETTING: Fifty-nine PICU in 15 countries. PATIENTS: Children less than 18 years old, mechanically ventilated for more than 48 hours. INTERVENTIONS: None. Multivariable logistic regression to determine factors associated with ventilator associated pneumonia. MEASUREMENTS AND MAJOR RESULTS: Data are presented as median (interquartile range) or counts (%). We enrolled 1,245 subjects (45% women; 42% surgical), age 20 months (4-84 mo), and duration of mechanical ventilation 7 days (3-13 d). Culture-positive ventilator-associated pneumonia was diagnosed in 80 patients (6.4%); duration of mechanical ventilation for this subgroup was 17 days (8-39 d). Enteral nutrition was delivered in 985 patients (79%), initiated within 48 hours in 592 patients (60%), and via postpyloric route in 354 patients (36%). Acid-suppressive agents were used in 763 patients (61%). The duration of enteral nutrition (p = 0.21), route (gastric vs postpyloric) of delivery (p = 0.94), severity of illness (p = 0.17), and diagnostic category on admission (p = 0.31) were not associated with ventilator-associated pneumonia. After adjusting for enteral nutrition days, illness severity, and site, ventilator-associated pneumonia was significantly associated with mechanical ventilation more than 10 days (odds ratio, 3.7; 95% CI, 2.2-6.5; p < 0.001), PICU length of stay more than 10 days (odds ratio, 1.8; 95% CI, 1.1-3.1; p = 0.029), and the use of acid-suppressive medication (odds ratio, 2.0; 95% CI, 1.2-3.6; p = 0.011). CONCLUSIONS: Ventilator-associated pneumonia was diagnosed in 6.5% of mechanically ventilated children in a heterogeneous multicenter cohort. We did not find a link between enteral nutrition duration or route of delivery and ventilator-associated pneumonia. In addition to duration of mechanical ventilation and length of PICU stay, the use of acid-suppressive therapy independently increased the likelihood of developing ventilator-associated pneumonia in this population. This association must be further explored in clinical trials. PMID- 27509363 TI - Admission PaO2 and Mortality in Critically Ill Children: A Cohort Study and Systematic Review. AB - OBJECTIVE: To describe the relationship between PaO2 at intensive care admission and mortality in critically ill children and to review systematically the literature describing this relationship. DESIGN: Cohort study: A review of consecutive tertiary pediatric intensive care admissions (January 2004 to December 2014) in a single center. The relationship between admission Pao2 and crude and standardized mortality was explored using nonlinear regression. Systematic review: A search of MEDLINE (1950 to January 2015), EMBASE (1980 to January 2015), Cochrane and Database of Abstracts of Reviews of Effects databases was undertaken using the following terms: "hyperoxia," "hypoxia," "critically ill children," "pediatric intensive care," "mortality," and/or "survival." SETTING: Tertiary PICU. PATIENTS: Patients younger than 18 years of age. INTERVENTIONS: The association of hyperoxia (PaO2, > 300 torr [40 kPa]) and hypoxia (PaO2, < 60 torr [8 kPa] or peripheral oxygen saturations, < 90%) to mortality in critically ill children was explored. MEASUREMENTS AND MAIN RESULTS: Cohort study: Of 14,321 admissions, 7,410 children had recorded PaO2 and FIO2 at admission. Crude mortality was 7.4% (555/7,410). This varied with admission PaO2 from 15.4% (204/1,324) in the hypoxia group (< 8 kPa) to 5.3% (287/5,385) with normoxia and 9.1% (64/701) in the hyperoxic group (> 40 kPa). Nonlinear regression displayed a "U-shaped" relationship between PaO2 and crude and case-mix adjusted mortality. Systematic review: Fourteen studies and one conference abstract were eligible for inclusion. Eleven studies (n = 5,280) relate to hypoxia with combined odds ratio for death, of 3.13 (95% CI, 1.79-5.48; p < 0.001) compared to normoxia. Six studies (n = 2,012) relate to hyperoxia and suggest no effect on mortality compared to normoxia (odds ratio, 1.15; 95% CI, 0.42-3.17; p = 0.77). CONCLUSIONS: Hypoxia at admission is associated with increased mortality in critically ill children, whereas the association with hyperoxia is less clear. The cohort study demonstrated a U-shaped association between admission PaO2 and mortality. Further examination is needed to explore the effect of hyperoxia upon mortality prediction accuracy. PMID- 27509364 TI - Stroke in Acquired and Congenital Heart Disease Patients and Its Relationship to Hospital Mortality and Lasting Neurologic Deficits. AB - OBJECTIVE: To describe strokes in patients with acquired or congenital heart disease and investigate risk factors for in-hospital mortality and ongoing neurologic deficits. DESIGN: Single-center, retrospective review of cardiac, neurologic, and radiologic patient databases. SETTING: Tertiary care children's hospital. PATIENTS: All patients with acquired or congenital heart disease admitted from January 2010 to October 2014 identified with stroke. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eighty-four stroke events were identified in 83 patients (median age, 5.9 mo; interquartile range, 0.8-33.4). Thirty-two patients (38%) had single ventricle congenital heart disease. Eight patients (9%) presented with symptoms at home, and the remainder was diagnosed while already admitted to the hospital. Forty patients (48%) presented with clinically evident neurologic deficits (e.g., weakness, seizures). Fifty-eight patients (69%) had arterial ischemic strokes, and 13 (15%) had parenchymal hemorrhages. At diagnosis, 54 patients (64%) were on inotropes. Twenty-nine patients (35%) had greater than or equal to 3 cardiac procedures during their hospitalization before stroke diagnosis. In-hospital mortality occurred in 28 patients (33%). Under multivariate analysis, inotropes, number of cardiac procedures, lack of seizure, and parenchymal hemorrhage were independently associated with in-hospital mortality (p < 0.05). Fifty-four percent of survivors with neurologic follow-up had ongoing neurologic deficits attributable to strokes (median follow-up, 15.3 mo; interquartile range, 7.0-29.9). With multivariate analysis, longer hospital stay (p = 0.02) was independently associated with ongoing deficits. CONCLUSIONS: A majority of patients with acquired or congenital heart disease who suffer stroke present while hospitalized and without focal neurologic findings. In hospital mortality is associated with inotropes, cardiac procedures, lack of seizure, and parenchymal hemorrhage. The majority of survivors have lasting neurologic deficits associated with longer hospital stay. PMID- 27509365 TI - Atrophy and structural covariance of the cholinergic basal forebrain in primary progressive aphasia. AB - Primary progressive aphasia (PPA) is characterized by profound destruction of cortical language areas. Anatomical studies suggest an involvement of cholinergic basal forebrain (BF) in PPA syndromes, particularly in the area of the nucleus subputaminalis (NSP). Here we aimed to determine the pattern of atrophy and structural covariance as a proxy of structural connectivity of BF nuclei in PPA variants. We studied 62 prospectively recruited cases with the clinical diagnosis of PPA and 31 healthy older control participants from the cohort study of the German consortium for frontotemporal lobar degeneration (FTLD). We determined cortical and BF atrophy based on high-resolution magnetic resonance imaging (MRI) scans. Patterns of structural covariance of BF with cortical regions were determined using voxel-based partial least square analysis. We found significant atrophy of total BF and BF subregions in PPA patients compared with controls [F(1, 82) = 20.2, p < .001]. Atrophy was most pronounced in the NSP and the posterior BF, and most severe in the semantic variant and the nonfluent variant of PPA. Structural covariance analysis in healthy controls revealed associations of the BF nuclei, particularly the NSP, with left hemispheric predominant prefrontal, lateral temporal, and parietal cortical areas, including Broca's speech area (p < .001, permutation test). In contrast, the PPA patients showed preserved structural covariance of the BF nuclei mostly with right but not with left hemispheric cortical areas (p < .001, permutation test). Our findings agree with the neuroanatomically proposed involvement of the cholinergic BF, particularly the NSP, in PPA syndromes. We found a shift from a structural covariance of the BF with left hemispheric cortical areas in healthy aging towards right hemispheric cortical areas in PPA, possibly reflecting a consequence of the profound and early destruction of cortical language areas in PPA. PMID- 27509366 TI - Glial ionic excitability: The role for sodium. PMID- 27509367 TI - The VCU Pressure Ulcer Summit: The Search for a Clearer Understanding and More Precise Clinical Definition of the Unavoidable Pressure Injury. AB - This article reports the findings of the Unavoidable Pressure Ulcer Committee (of the VCU Pressure Ulcer Summit) that was tasked with addressing key issues associated with pressure injuries that are unavoidable or unpreventable. Our goals were (1) to clarify nomenclature and descriptions surrounding "terminal ulceration," (2) to describe the medical complications and comorbid conditions that can lead to skin failure and/or terminal ulceration, (3) to describe the variable possible causes of unavoidable pressure injuries, and (4) to present clinical cases to exemplify pressure injuries considered to be unavoidable. PMID- 27509368 TI - Malaria Incidence Rates from Time Series of 2-Wave Panel Surveys. AB - Methodology to estimate malaria incidence rates from a commonly occurring form of interval-censored longitudinal parasitological data-specifically, 2-wave panel data-was first proposed 40 years ago based on the theory of continuous-time homogeneous Markov Chains. Assumptions of the methodology were suitable for settings with high malaria transmission in the absence of control measures, but are violated in areas experiencing fast decline or that have achieved very low transmission. No further developments that can accommodate such violations have been put forth since then. We extend previous work and propose a new methodology to estimate malaria incidence rates from 2-wave panel data, utilizing the class of 2-component mixtures of continuous-time Markov chains, representing two sub populations with distinct behavior/attitude towards malaria prevention and treatment. Model identification, or even partial identification, requires context specific a priori constraints on parameters. The method can be applied to scenarios of any transmission intensity. We provide an application utilizing data from Dar es Salaam, an area that experienced steady decline in malaria over almost five years after a larviciding intervention. We conducted sensitivity analysis to account for possible sampling variation in input data and model assumptions/parameters, and we considered differences in estimates due to submicroscopic infections. Results showed that, assuming defensible a priori constraints on model parameters, most of the uncertainty in the estimated incidence rates was due to sampling variation, not to partial identifiability of the mixture model for the case at hand. Differences between microscopy- and PCR based rates depend on the transmission intensity. Leveraging on a method to estimate incidence rates from 2-wave panel data under any transmission intensity, and from the increasing availability of such data, there is an opportunity to foster further methodological developments, particularly focused on partial identifiability and the diversity of a priori parameter constraints associated with different human-ecosystem interfaces. As a consequence there can be more nuanced planning and evaluation of malaria control programs than heretofore. PMID- 27509369 TI - Diagnostic Ureteroscopy for Upper Tract Urothelial Carcinoma is Independently Associated with Intravesical Recurrence after Radical Nephroureterectomy. AB - PURPOSE: To determine the effect of diagnostic ureteroscopy on intravesical recurrence in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterec!tomy (RNU). MATERIALS AND METHODS: We conducted a retrospective analysis of 664 patients who were treated with RNU for UTUC from June 2000 to December 2011, excluding those who had concomitant/prior bladder tumors. Of the 664 patients, 81 underwent di!agnostic ureteroscopy (URS). We analyzed the impact of diagnostic ureteroscopy on intravesical recurrence (IVR) using the Kaplan Meier method. Univariate and multi!variate analyses were used to determine the independent risk factors. RESULTS: The median follow-up time was 48 months (interquartile range (IQR): 31- 77 months). Patients who underwent ureteroscopy were more likely to have a small (p<0.01), early-staged (p=0.019), multifocality (p=0.035) and ureteral tumor (p<0.001). IVR occurred in 223 patients during follow-up within a median of 17 months (IQR: 7-33). Patients without preoperative ureteroscopy have a statistically significant better 2-year (79.3%+/-0.02 versus 71.4%+/-0.02, p<0.001) and 5-year intravesical recurrence-free survival rates (64.9%+/-0.05 versus 44.3%+/-0.06, p<0.001) than patients who un!derwent ureteroscopy. In multivariate analysis, the diagnostic ureteroscopy (p=0.006), multiple tumors (p=0.001), tumor size <3cm (p=0.008), low-grade (p=0.022) and pN0 stage tumor (p=0.045) were independent predictors of IVR. CONCLUSIONS: Diagnostic ureteroscopy is independently associated with intravesical re!currence after radical nephroureterectomy. PMID- 27509370 TI - Unilateral absence of vas deferens: prevalence among 23.013 men seeking vasectomy. AB - PURPOSE: To determine the prevalence of unilateral absence of vas deferens (UAVD) in men with both testes seeking vasectomy. MATERIALS AND METHODS: Computerized charts of 23.013 patients encountered between January 1994 and December 2013 in one university hospital and two community clinics of Quebec City, Canada, were searched. Pre-vasectomy consultation, operative reports and semen analysis results were reviewed to identify cases of UAVD. Cases were categorized as confirmed (unilateral vasectomy and success confirmed by semen analysis) or possible congenital UAVD further sub-categorized according to whether or not a scrotal anomaly was present. RESULTS: Among 159 men identified as potentially having UAVD, chart review revealed that 47 had only one testicle, 26 had bilateral vasa, and four were misdiagnosed (post-vasectomy semen analysis [PVSA] showing motile sperm after unilateral vasectomy) leaving 82 men deemed cases of UAVD (0.36%, 95% confidence interval 0.28% to 0.43%). These were classified as confirmed (n=48, 0.21%) and possible (n=34, 0.15%; 22 without and 12 with scrotal anomalies) congenital UAVD. The misdiagnosis ratio of UAVD was low when scrotal content was otherwise normal (1:48), but higher if anomalies were present (3:12). CONCLUSIONS: Most surgeons who perform vasectomy will encounter cases of UAVD. In most suspected cases, it is safe and effective to proceed with unilateral vasectomy under local anesthesia while stressing the need for PVSA. Further studies or scrotal exploration may be considered in patient with prior scrotal surgery. PMID- 27509371 TI - Safety and efficacy of intravesical alum for intractable hemorrhagic cystitis: A contemporary evaluation. AB - INTRODUCTION: Hemorrhagic cystitis (HC) represents a challenging clinical entity. While various intravesical agents have been utilized in this setting, limited data exist regard!ing safety or efficacy. Herein, then, we evaluated the effectiveness and complications associated with intravesical alum instillation for HC in a contemporary cohort. MATERIALS AND METHODS: We identified 40 patients treated with intravesical alum for HC between 1997-2014. All patients had failed previous continuous bladder irrigation with normal saline and clot evacuation. Treatment success was defined as requiring no additional therapy beyond normal saline irrigation after alum instillation. RESULTS: Median patient age was 76.5 years (IQR 69, 83). Pelvic radiation was the most common etiology for HC (n=38, 95%). Alum use decreased patient's transfusion requirement, with 82% (32/39) receiving a transfusion within 30 days before alum instillation (median 4 units) versus 59% (23/39) within 30 days after completing alum (median 3 units) (p=0.05). In total, 24 patients (60%) required no additional therapy prior to hospital discharge. Moreover, at a median follow-up of 17 months (IQR 5, 38.5), 13 patients (32.5%) remained without additional treatment for HC. Adverse ef!fects were reported in 15 patients (38%), with bladder spasms representing the most common event (14/40; 35%). No clinical evidence of clinically significant systemic absorption was detected. CONCLUSION: Intravesical alum therapy is well tolerated, with resolution of HC in ap!proximately 60% of patients, and a durable response in approximately one-third. Given its favorable safety/efficacy profile, intravesical alum may be considered as a first-line treatment option for patients with HC. PMID- 27509372 TI - External validation of EORTC risk scores to predict recurrence after transurethral resection of brazilian patients with non -muscle invasive bladder cancer stages Ta and T1. AB - : Validate the EORTC risk tables in Brazilian patients with NMIBC. METHODS: 205 patients were analyzed. The 6 parameters analyzed were: histologic grading, pathologic stage, size and number of tumors, previous recurrence rate and concomitant CIS. The time for first recurrence (TFR), risk score and probability of re!currence were calculated and compared to the probabilities obtained from EORTC risk tables. C-index was calculated and accuracy of EORTC tables was analyzed. RESULTS: pTa was presented in 91 (44.4%) patients and pT1 in 114 (55.6%). Ninety-seven (47.3%) patients had solitary tumor, and 108 (52.7%) multiple tumors. One hundred and three (50.2%) patients had tumors smaller than 3 cm and 102 (40.8%) had bigger than 3 cm. Concomitant CIS was observed in 21 (10.2%) patients. Low grade was presented in 95 (46.3%) patients, and high grade in 110 (53.7%). Intravesical therapy was utilized in 105 (56.1%) patients. Recurrence was observed in 117 (57.1%) patients and the mean TFR was 14,2 +/- 7,3 months. C-index was 0,72 for 1 year and 0,7 for 5 years. The re!currence risk was 28,8% in 1 year and 57,1% in 5 years, independently of the scoring risk. In our population, the EORTC risk tables overestimated the risk of recurrence in 1 year and underestimated in 5 years. CONCLUSION: The validation of the EORTC risk tables in Brazilian patients with NMIBC was satisfactory and should be stimulated to predict recurrence, although these may overestimated the risk of recurrence in 1 year and underestimated in 5 years. PMID- 27509373 TI - Minimally invasive percutaneous nephrolithotomy guided by ultrasonography to treat upper urinary tract calculi complicated with severe spinal deformity. AB - OBJECTIVE: To report our experience of minimally invasive percutaneous nephrolithotomy(MPCNL) in managing upper urinary tract calculi complicated with severe spinal deformity. MATERIALS AND METHODS: Between August 2001 to December 2012, 16 upper urinary calculi in 13 patients with severe spinal deformity were treated by MPCNL. Preoperative investigation of the respiratory function, evaluation of anatomy by intravenous uro!graphy (IVU) and CT scan, and preoperative kidney ultrasonagraphy with simulation of the percutaneous puncture were performed in all patients. The percutaneous puncture was guided by ultrasonography. RESULTS: A total of 19 MPCNL procedures were performed in 16 kidneys, with an ave!rage 1.2 procedures in each kidney. Three kidneys needed two sessions of MPCNL, and 2 kidneys needed combined treatment with retrograde flexible ureterscopic lithotripsy. All procedures were successfully completed with no major complications during or after surgery. The mean (range) operative duration was 67 (20-150) min and the mean postoperative haemoglobin drop was 1.0 (0.2-3.1) g/dL. Complete stone-free status was achieved in 14 kidneys. At a mean follow-up of 48(3-86) months, recurrence of small lower calyx stone was detected in one patient. Recurrent UTI was documented by urine culture in two patients and managed with sensitive antibiotics. CONCLUSION: PCNL for patients with severe spinal deformities is challenging. Ultra!sonography-assisted puncture can allow safe and successfully establishment of PCN tract through a narrow safety margin of puncture and avoid the injury to the adjacent organs. However, the operation should be performed in tertiary centers with significant expertise in managing complex urolithiasis. PMID- 27509374 TI - Sexual Health Matters: Management of Female Sexual Dysfunction. PMID- 27509375 TI - Diminished Phosphorylation of CREB Is a Key Event in the Dysregulation of Gluconeogenesis and Glycogenolysis in PCB126 Hepatotoxicity. AB - The dioxin-like PCB126 elicits toxicity in various target organs. In rat liver, an alteration in the transcript levels of several genes involved in glucose and fatty acid metabolism provides insights into the origin of its hepatotoxicity. To explore the mechanisms, male Sprague-Dawley rats, fed an AIN-93G diet, were injected with PCB126 (1 or 5 MUmol/kg) or corn oil and euthanized after 2 weeks. PCB126 significantly decreased serum glucose levels and the transcript levels of genes of many gluconeogenic and glycogenolytic enzymes under the transcriptional control of a nuclear transcription factor, cAMP response element-binding protein (CREB). As a novel finding, we show that PCB126 significantly decreases CREB phosphorylation, which is important for regulating both gluconeogenesis and fatty acid oxidation in the liver and explains CREB's integrative effects on both carbohydrate and lipid metabolism in PCB126 toxicity. PMID- 27509378 TI - Acute Lymphoblastic Leukemia Presenting With Pancytopenia Followed by a 14-Month Long Period of Transient Remission Possibly Supporting the Adrenal Hypothesis of Leukemogenesis. AB - A small group of children with acute lymphoblastic leukemia (ALL) have a preleukemic phase of pancytopenia followed by a period of spontaneous remission before the diagnosis (pre-ALL). A 6-year-old girl presented with pancytopenia, fever, and myelodysplasia. Following transient remission pre-B ALL was diagnosed 14 months later. Clonal B-lineage blasts at the period of pancytopenia were identified retrospectively. The interval between pre-ALL and ALL-diagnosis was longer than previously reported. The infection was clinically severe and might have induced a significant endogenous corticosteroids production resulting in the long-lasting remission. The case supports the adrenal and the Coley's toxin hypothesis in leukemogenesis. PMID- 27509377 TI - Intensive treatment and survival outcomes in NUT midline carcinoma of the head and neck. AB - BACKGROUND: NUT midline carcinoma is a rare and aggressive genetically characterized subtype of squamous cell carcinoma frequently arising from the head and neck. The characteristics and optimal management of head and neck NUT midline carcinoma (HNNMC) are unclear. METHODS: A retrospective review of all known cases of HNNMC in the International NUT Midline Carcinoma Registry as of December 31, 2014, was performed. Forty-eight consecutive patients were treated from 1993 to 2014, and clinicopathologic variables and outcomes for 40 patients were available for analyses; they composed the largest HNNMC cohort studied to date. Overall survival (OS) and progression-free survival (PFS) according to patient characteristics and treatment were analyzed. RESULTS: This study identified a 5 fold increase in the diagnosis of HNNMC from 2011 to 2014. The median age was 21.9 years (range, 0.1-81.7 years); the male and female proportions were 40% and 60%, respectively; and 86% had bromodomain containing 4-nuclear protein in testis (BRD4-NUT) fusion. The initial treatment was initial surgery with or without adjuvant chemoradiation or adjuvant radiation (56%), initial radiation with or without chemotherapy (15%), or initial chemotherapy with or without surgery or radiation (28%). The median PFS was 6.6 months (range, 4.7-8.4 months). The median OS was 9.7 months (range, 6.6-15.6 months). The 2-year PFS rate was 26% (95% confidence interval [CI], 13%-40%). The 2-year OS rate was 30% (95% CI, 16% 46%). Initial surgery with or without postoperative chemoradiation or radiation (P = .04) and complete resection with negative margins (P = .01) were significant predictors of improved OS even after adjustments for age, tumor size, and neck lymphadenopathy. Initial radiation or chemotherapy and the NUT translocation type were not associated with outcomes. CONCLUSIONS: HNNMC portends a poor prognosis. Aggressive initial surgical resection with or without postoperative chemoradiation or radiation is associated with significantly enhanced survival. Chemotherapy or radiation alone is often inadequate. Cancer 2016;122:3632-40. (c) 2016 American Cancer Society. PMID- 27509379 TI - Transfusion Therapy in Children With Sickle Cell Disease. AB - Hydroxyurea, blood transfusions, and hematopoietic stem cell transplantation represent the 3 disease-modifying therapies in children with sickle cell disease (SCD). Blood transfusions play an increasingly important role in both prevention and management of SCD complications in this age group. This review will focus on the indications of blood transfusion in children with SCD and modalities of its administration. It will also highlight the complications of this life-saving therapy and ways of optimizing transfusion to minimize its associated risks. PMID- 27509380 TI - Progressive Rod-Cone Degeneration (PRCD) Protein Requires N-Terminal S-Acylation and Rhodopsin Binding for Photoreceptor Outer Segment Localization and Maintaining Intracellular Stability. AB - The light-sensing outer segments of photoreceptor cells harbor hundreds of flattened membranous discs containing the visual pigment, rhodopsin, and all the proteins necessary for visual signal transduction. PRCD (progressive rod-cone degeneration) protein is one of a few proteins residing specifically in photoreceptor discs, and the only one with completely unknown function. The importance of PRCD is highlighted by its mutations that cause photoreceptor degeneration and blindness in canine and human patients. Here we report that PRCD is S-acylated at its N-terminal cysteine and anchored to the cytosolic surface of disc membranes. We also showed that mutating the S-acylated cysteine to tyrosine, a common cause of blindness in dogs and a mutation found in affected human families, causes PRCD to be completely mislocalized from the photoreceptor outer segment. We next undertook a proteomic search for PRCD-interacting partners in disc membranes and found that it binds rhodopsin. This interaction was confirmed by reciprocal precipitation and co-chromatography experiments. We further demonstrated this interaction to be critically important for supporting the intracellular stability of PRCD, as the knockout of rhodopsin caused a drastic reduction in the photoreceptor content of PRCD. These data reveal the cause of photoreceptor disease in PRCD mutant dogs and implicate rhodopsin to be involved in PRCD's unknown yet essential function in photoreceptors. PMID- 27509381 TI - Seasonal and Species Variation of the Hepatotoxin Indospicine in Australian Indigofera Legumes As Measured by UPLC-MS/MS. AB - Livestock industries have maintained a keen interest in pasture legumes because of the high protein content and nutritive value. Leguminous Indigofera plant species have been considered as having high feeding values to be utilized as pasture, but the occurrence of the toxic constituent indospicine in some species has restricted this utility. Indospicine has caused both primary and secondary hepatotoxicosis and also reproductive losses, but has only previously been determined in a small number of Indigofera species. This paper validates a high throughput ultraperformance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) method to determine the indospicine content of various Indigofera species found in Australian pasture. Twelve species of Indigofera together with Indigastrum parviflorum plants were collected and analyzed. Of the 84 samples analyzed, *I. spicata (the asterisk indicates a naturalized species) contained the highest indospicine level (1003 +/- 328 mg/kg DM, n = 4) followed by I. linnaei (755 +/- 490 mg/kg DM, n = 51). Indospicine was not detected in 9 of the remaining 11 species and at only low levels (<10 mg/kg DM) in 2 of 8 I. colutea specimens and in 1 of 5 I. linifolia specimens. Indospicine concentrations were below quantitation levels for other Indigofera spp. (I. adesmiifolia, I. georgei, I. hirsuta, I. leucotricha, *I. oblongifolia, I. australis, and I. trita) and Indigastrum parviflorum. One of the more significant findings to emerge from this study is that the indospicine content of I. linnaei is highly variable (from 159 to 2128 mg/kg DM, n = 51) and differs across both regions and seasons. Its first regrowth after spring rain has a higher (p < 0.01) indospicine content than growth following more substantial summer rain. The species collected include the predominant Indigofera in Australia pasture, and of these, only *I. spicata and I. linnaei contain high enough levels of indospicine to pose a potential toxic threat to grazing herbivores. PMID- 27509382 TI - DIETARY SILVER NANOPARTICLES REDUCE FITNESS IN A BENEFICIAL, BUT NOT PEST, INSECT SPECIES. AB - Silver nanoparticles (AgNPs) have antimicrobial and insecticidal properties and they have been considered for their potential use as insecticides. While they do, indeed, kill some insects, two broader issues have not been considered in a critical way. First, reports of insect-lethal AgNPs are often based on simplistic methods that yield nanoparticles of nonuniform shapes and sizes, leaving questions about the precise treatments test insects experienced. Second, we do not know how AgNPs influence beneficial insects. This work addresses these issues. We assessed the influence of AgNPs on life history parameters of two agricultural pest insect species, Heliothis virescens (tobacco budworm) and Trichoplusia ni (cabbage looper) and a beneficial predatory insect species, Podisus maculiventris (spined soldier bug), all of which act in agroecosystems. Rearing the two pest species on standard media amended with AgNPs led to negligible influence on developmental times, pupal weights, and adult emergence, however, they led to retarded development, reductions in adult weight and fecundity, and increased mortality in the predator. These negative effects on the beneficial species, if also true for other beneficial insect species, would have substantial negative implications for continued development of AgNPs for insect pest management programs. PMID- 27509383 TI - Effects of waterborne Cu exposure on intestinal copper transport and lipid metabolism of Synechogobius hasta. AB - The present study was conducted to explore the effects of waterborne Cu exposure on intestinal Cu transport and lipid metabolism of Synechogobius hasta. S. hasta were exposed to 0, 0.4721 and 0.9442MUM Cu, respectively. Sampling occurred on days 0, 21 and 42, respectively. Growth performance, intestinal lipid deposition, Cu content, and activities and mRNA expression of enzymes and genes involved in Cu transport and lipid metabolism were analyzed. Cu exposure decreased WG and SGR on days 21 and 42. Cu exposure increased intestinal Cu and lipid contents. Increased Cu accumulation was attributable to increased enzymatic activities (Cu ATPase and Cu, Zn-SOD) and genes' (CTR1, CTR2, DMT1, ATP7a, ATP7b, MT1 and MT2) expression involved in Cu transport. Waterborne Cu exposure also increased activities of lipogenic enzymes (6PGD and ICDH on both days 21 and 42, ME on day 42), up-regulated mRNA levels of lipogenic genes (G6PD, 6PGD, ME, ICDH, FAS and ACCa), lipolytic genes (ACCb, CPT I and HSLa) and genes involved in intestinal fatty acid uptake (IFABP and FATP4) on both days 21 and 42. The up-regulation of lipolysis may result from the increased metabolic expenditure for detoxification and maintenance of the normal body functions in a response to Cu exposure. Meantime, Cu exposure increased lipogenesis and fatty acid uptake, leading to net lipid accumulation in the intestine despite increased lipolysis. To our knowledge, this is the first report involved in intestinal lipid metabolism in combination with intestinal Cu absorption following waterborne Cu exposure, which provides new insights and evidence into Cu toxicity in fish. PMID- 27509384 TI - Probing the Interstate Coupling near a Conical Intersection by Optical Spectroscopy. AB - Conical intersections are points where adiabatic potential energy surfaces cross. The interstate coupling between the potential energy surfaces plays a crucial role in many processes associated with conical intersections. Still no method exists to measure this coupling driving the chemical reactions between the potential energy surfaces involved. In this Letter, using a generic model for photoisomerization, we propose a novel experimental approach to estimate the coupling that mixes the electronic states near a conical intersection. The approach is based on analyzing the vibrational wavepacket of the reactant in the adiabatic ground and excited electronic states. The nuclear wavepacket dynamics are extracted from linear absorption and two-dimensional electronic spectroscopy. Comparing the frequencies of the coupling mode in the adiabatic ground and excited states from models with and without coupling between the potential energy surfaces suggests an experimental tool to determine the interstate coupling. PMID- 27509386 TI - Targeted Consent for Research on Standard of Care Interventions in the Emergency Setting. AB - OBJECTIVES: There has been significant debate over what consent process, if any, should be used for clinical trials that compare two or more interventions within the standard of care. Some claim that all clinical trials should obtain in-depth research consent because they use subjects to obtain data for the benefit of future patients. Others argue that clinical trials that are limited to interventions within the standard of care do not need to obtain research consent at all. Settling this debate is especially challenging in the emergency setting. The potential for significant morbidity and mortality provides a strong reason to obtain research consent for standard-of-care trials in the emergency setting. Yet, the emergency setting also introduces significant barriers to traditional in depth research consent. The present article considers to what extent a targeted consent process can resolve these tensions. DATA SYNTHESIS: We first identified the ethical goals that are promoted by obtaining consent for standard-of-care research and the barriers to obtaining consent that arise in the emergency setting. We then evaluated whether, despite the barriers, it is possible to develop a targeted consent process that promotes the goals for consent in the context of standard-of-care trials. CONCLUSIONS: Targeted consent offers an ethically appropriate way to obtain consent for many standard-of-care trials in the emergency setting. For studies subject to U.S. regulations, and those subject to other regulations that include similar consent requirements, targeted consent's verbal disclosure and written form provide a way to satisfy research regulations without blocking valuable studies. For trials that qualify for a waiver of the consent requirements, targeted consent's verbal disclosure is preferable to waiving consent, provided a slight delay is consistent with appropriate care, and there is a capacitated patient or surrogate available. PMID- 27509387 TI - Errors, Omissions, and Outliers in Hourly Vital Signs Measurements in Intensive Care. AB - OBJECTIVE: To empirically examine the prevalence of errors, omissions, and outliers in hourly vital signs recorded in the ICU. DESIGN: Retrospective analysis of vital signs measurements from a large-scale clinical data warehouse (Multiparameter Intelligent Monitoring in Intensive Care III). SETTING: Data were collected from the medical, surgical, cardiac, and cardiac surgery ICUs of a tertiary medical center in the United States. PATIENTS: We analyzed data from approximately 48,000 ICU stays including approximately 28 million vital signs measurements. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used the vital sign day as our unit of measurement, defined as all the recordings from a single patient for a specific vital sign over a single 24-hour period. Approximately 30-40% of vital sign days included at least one gap of greater than 70 minutes between measurements. Between 3% and 10% of blood pressure measurements included logical inconsistencies. With the exception of pulse oximetry vital sign days, the readings in most vital sign days were normally distributed. We found that 15-38% of vital sign days contained at least one statistical outlier, of which 6-19% occurred simultaneously with outliers in other vital signs. CONCLUSIONS: We found a significant number of missing, erroneous, and outlying vital signs measurements in a large ICU database. Our results provide empirical evidence of the nonrepresentativeness of hourly vital signs. Additional studies should focus on determining optimal sampling frequencies for recording vital signs in the ICU. PMID- 27509388 TI - Hospital Volume and Outcomes of Noninvasive Ventilation in Patients Hospitalized With an Acute Exacerbation of Chronic Obstructive Pulmonary Disease. AB - OBJECTIVE: To determine the relationship between hospital noninvasive ventilation caseload and outcomes among patients with an acute chronic obstructive pulmonary disease exacerbation. DESIGN: Cross-sectional study of 13,893 patients with chronic obstructive pulmonary disease treated with noninvasive ventilation. SETTING: A total of 243 U.S. hospitals participating in the Premier Inpatient Database. PATIENTS: A total of 13,893 patients admitted between July 2009 and June 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Annual hospital volume of noninvasive ventilation was analyzed as a continuous variable, as well as after grouping it in four categories. The median hospital annual volume of noninvasive ventilation use was 627 and varied from 234 admissions in quartile 1 to 1,529 admissions in quartile 4. Noninvasive ventilation failure occurred in 15.2%, and in-hospital mortality was 6.5%. After adjusting for patient characteristics, relative to low-volume hospitals, high-volume hospitals did not have lower noninvasive ventilation failure (odds ratio quartile 4 vs quartile 1, 1.05; 95% CI, 0.65-1.68) or in-hospital mortality (odds ratio quartile 4 vs quartile 1, 0.88; 95% CI, 0.69-1.12). In a hierarchical multivariable analysis with adjustment for patient characteristics where volume was assessed as a continuous variable, hospital volume was not related to outcomes, including noninvasive ventilation failure (p = 0.87), in-hospital mortality (p = 0.88), 30 day readmission for chronic obstructive pulmonary disease (p = 0.83), or hospital length of stay (p = 0.12). CONCLUSIONS: The results of this large retrospective cohort study suggest that hospitals with higher noninvasive ventilation volume do not achieve better outcomes of patients with chronic obstructive pulmonary disease exacerbation treated with noninvasive ventilation; even hospitals with low noninvasive ventilation volume are able to successfully implement this intervention. PMID- 27509389 TI - The Postcardiac Arrest Consult Team: Impact on Hospital Care Processes for Out-of Hospital Cardiac Arrest Patients. AB - OBJECTIVE: To evaluate whether a Post-Arrest Consult Team improved care and outcomes for patients with out-of-hospital cardiac arrest. DESIGN: Prospective cohort study of Post-Arrest Consult Team implementation at two hospitals, with concurrent controls from 27 others. SETTING: Twenty-nine hospitals within the Strategies for Post-Arrest Care Network of Southern Ontario, Canada. PATIENTS: We included comatose adult nontraumatic out-of-hospital cardiac arrest patients surviving more than or equal to 6 hours after emergency department arrival who had no contraindications to targeted temperature management. INTERVENTION: The Post-Arrest Consult Team was an advisory consult service to improve 1) targeted temperature management, 2) assessment for percutaneous coronary intervention, 3) electrophysiology assessment, and 4) appropriately delayed neuroprognostication. MEASUREMENTS AND MAIN RESULTS: We used generalized linear mixed models to explore the association between Post-Arrest Consult Team implementation and performance of targeted processes. We included 1,006 patients. The Post-Arrest Consult Team was associated with a significant reduction over time in rates of withdrawal of life-sustaining therapy within 72 hours of emergency department arrival on the basis of predictions of poor neurologic prognosis (ratio of odds ratios, 0.13; 95% CI, 0.02-0.98). Post-Arrest Consult Team was not associated with improved successful targeted temperature management (ratio of odds ratios, 0.91; 95% CI, 0.31-2.65), undergoing angiography (ratio of odds ratios, 1.91; 95% CI, 0.17 21.04), receiving electrophysiology consultation (ratio of odds ratios, 0.93; 95% CI, 0.11-8.16), or functional survival (ratio of odds ratios, 0.75; 95% CI, 0.19 2.94). CONCLUSIONS: Implementation of a Post-Arrest Consult Team reduced premature withdrawal of life-sustaining therapy but did not improve rates of successful targeted temperature management, coronary angiography, formal electrophysiology assessments, or functional survival for comatose patients after out-of-hospital cardiac arrest. PMID- 27509391 TI - The Impact of Interventions to Improve Sleep on Delirium in the ICU: A Systematic Review and Research Framework. AB - OBJECTIVE: This study aimed to assess whether interventions targeted at improving sleep in the ICU were associated with reductions in ICU delirium. Secondary outcomes include duration of delirium and ICU length of stay. DATA SOURCES: MEDLINE, CINAHL, Web of Science, Scopus, WorldCat, and International Pharmaceutical Abstracts were searched from inception to January 2016. STUDY SELECTION: Studies investigating any type of sleep intervention (nonpharmacologic or pharmacologic) and assessing the impact on ICU delirium were included. Any type of study design was permitted so long as the delirium assessment was made at least daily with a validated delirium assessment tool. DATA EXTRACTION: The following data were extracted: first author, year of publication, study design, ICU type, components of sleep intervention, use of sleep assessment tool, patient age, sex, severity of illness, sleep measures, delirium assessment tool, incidence of delirium, duration of delirium, and ICU length of stay. The incidence of delirium was used to compare rates of ICU delirium across studies. Methodologic quality of included studies was evaluated using the Effective Public Health Practice Project quality assessment tool. DATA SYNTHESIS: Of 488 citations screened, 10 studies were identified for inclusion in the final review; six of which demonstrated a statistically significant reduction in the incidence of ICU delirium associated with sleep intervention. Four studies assessed duration of delirium; of which, three reported a shorter duration of delirium with sleep intervention. Two studies associated sleep intervention with a reduced ICU length of stay. In regard to quality assessment and risk of bias, only one study was assessed as strong. Multiple identified confounders and the significant qualitative assessment of heterogeneity limit both the conclusions that can be drawn from these findings and the quantitative pooling of data. CONCLUSIONS: Although sleep interventions seem to be a promising approach for improving delirium-related outcomes, studies are limited by bias issues, varying methodologies, and multiple confounders, making the evidence base for this conclusion limited at best. Future studies would benefit from a systematic approach to studying the link between sleep intervention and delirium-related outcomes, which is outlined in the context of reviewing the existing literature. PMID- 27509390 TI - Double-Stranded RNA Interacts With Toll-Like Receptor 3 in Driving the Acute Inflammatory Response Following Lung Contusion. AB - OBJECTIVES: Lung contusion is a major risk factor for the development of acute respiratory distress syndrome. We set to determine the role of toll-like receptor 3 and the binding of double-stranded RNA in the pathogenesis of sterile injury following lung contusion. DESIGN: Toll-like receptor 3 expression was analyzed in postmortem lung samples from patients with lung contusion. Unilateral lung contusion was induced in toll-like receptor 3 (-/-), TIR-domain-containing adapter-inducing interferon-beta (-/-), and wild-type mice. Subsequently, lung injury and inflammation were evaluated. Apoptotic indices, phagocytic activity, and phenotypic characterization of the macrophages were determined. Double stranded RNA in bronchoalveolar lavage and serum samples following lung contusion was measured. A toll-like receptor 3/double-stranded RNA ligand inhibitor was injected into wild-type mice prior to lung contusion. MEASUREMENTS AND MAIN RESULTS: Toll-like receptor 3 expression was higher in patients and wild-type mice with lung contusion. The degree of lung injury, inflammation, and macrophage apoptosis was reduced in toll-like receptor 3 (-/-), TIR-domain-containing adapter-inducing interferon-beta (-/-), and wild-type mice with toll-like receptor 3 antibody neutralization. Alveolar macrophages from toll-like receptor 3 (-/-) mice had a lower early apoptotic index, a predominant M2 phenotype and increased surface translocation of toll-like receptor 3 from the endosome to the surface. When compared with viral activation pathways, lung injury in lung contusion demonstrated increased p38 mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 phosphorylation with inflammasome activation without a corresponding increase in nuclear factor-kappaB or type-1 interferon production. Additionally, pretreatment with toll-like receptor 3/double-stranded RNA ligand inhibitor led to a reduction in injury, inflammation, and macrophage apoptosis. CONCLUSIONS: We conclude that the interaction of double-stranded RNA from injured cells with toll-like receptor 3 drives the acute inflammatory response following lung contusion. PMID- 27509385 TI - Functional Outcome Trajectories After Out-of-Hospital Pediatric Cardiac Arrest. AB - OBJECTIVES: To analyze functional performance measures collected prospectively during the conduct of a clinical trial that enrolled children (up to age 18 yr old), resuscitated after out-of-hospital cardiac arrest, who were at high risk of poor outcomes. DESIGN: Children with Glasgow Motor Scale score less than 5, within 6 hours of resuscitation, were enrolled in a clinical trial that compared two targeted temperature management interventions (THAPCA-OH, NCT00878644). The primary outcome, 12-month survival with Vineland Adaptive Behavior Scale, second edition, score greater or equal to 70, did not differ between groups. SETTING: Thirty-eight North American PICUs. PARTICIPANTS: Two hundred ninety-five children were enrolled; 270 of 295 had baseline Vineland Adaptive Behavior Scale, second edition, scores greater or equal to 70; 87 of 270 survived 1 year. INTERVENTIONS: Targeted temperatures were 33.0 degrees C and 36.8 degrees C for hypothermia and normothermia groups. MEASUREMENTS AND MAIN RESULTS: Baseline measures included Vineland Adaptive Behavior Scale, second edition, Pediatric Cerebral Performance Category, and Pediatric Overall Performance Category. Pediatric Cerebral Performance Category and Pediatric Overall Performance Category were rescored at hospital discharges; all three were scored at 3 and 12 months. In survivors with baseline Vineland Adaptive Behavior Scale, second edition scores greater or equal to 70, we evaluated relationships of hospital discharge Pediatric Cerebral Performance Category with 3- and 12-month scores and between 3- and 12-month Vineland Adaptive Behavior Scale, second edition, scores. Hospital discharge Pediatric Cerebral Performance Category scores strongly predicted 3- and 12-month Pediatric Cerebral Performance Category (r = 0.82 and 0.79; p < 0.0001) and Vineland Adaptive Behavior Scale, second edition, scores (r = -0.81 and -0.77; p < 0.0001). Three-month Vineland Adaptive Behavior Scale, second edition, scores strongly predicted 12-month performance (r = 0.95; p < 0.0001). Hypothermia treatment did not alter these relationships. CONCLUSIONS: In comatose children, with Glasgow Motor Scale score less than 5 in the initial hours after out-of hospital cardiac arrest resuscitation, function scores at hospital discharge and at 3 months predicted 12-month performance well in the majority of survivors. PMID- 27509392 TI - Expression of embryonic stem cell markers in pyogenic granuloma. AB - BACKGROUND: Recent description of hemangioblastic blood islands within pyogenic granuloma (PG) has led us to investigate the expression of embryonic stem cell (ESC) markers in this tumor. METHODS: In this study we examined the expression of ESC markers, OCT4, SOX2, STAT3 and NANOG in PG samples from 11 patients, by immunohistochemical (IHC) staining, NanoString analysis and in situ hybridization (ISH). RESULTS: IHC staining demonstrated the expression of pSTAT3, OCT4, SOX2 and NANOG by the endothelium of the microvessels in PG whilst pSTAT3, SOX2 and NANOG were also expressed by cells in the interstitium, outside of the microvessels. NanoString and ISH analysis showed mRNA expression for STAT3, OCT4 and NANOG in PG. CONCLUSIONS: The expression of the ESC markers, OCT4, SOX2, pSTAT3 and NANOG, suggests the endothelium of PG displays a primitive phenotype. Cells in the interstitium expressing pSTAT3, SOX2 and NANOG may represent a more downstream derivative of the primitive endothelium, or a separate population. The primitive nature of the endothelium and cells in the interstitium reveals novel insights into the biology of PG. To the best of our knowledge, this is the first demonstration of the expression of ESC markers in PG, implying the presence of a hematopoietic stem cell population. PMID- 27509393 TI - Hydrothermal Crystallization of Uranyl Coordination Polymers Involving an Imidazolium Dicarboxylate Ligand: Effect of pH on the Nuclearity of Uranyl Centered Subunits. AB - Four uranyl-bearing coordination polymers (1-4) have been hydrothermally synthesized in the presence of the zwitterionic 1,3-bis(carboxymethyl)imidazolium (= imdc) anion as organic linkers after reaction at 150 degrees C. At low pH (0.8-3.1), the form 1 ((UO2)2(imdc)2(ox).3H2O; ox stands for oxalate group) has been identified. Its crystal structure (XRD analysis) consists of the 8-fold coordinated uranyl centers linked to each other through the imdc ligand together with oxalate species coming from the partial decomposition of the imdc molecule. The resulting structure is based on one-dimensional infinite ribbons intercalated by free water molecules. By adding NaOH solution, a second form 2 is observed for pH 1.9-3.9 but in a mixture with phase 1. The pure phase of 2 is obtained after a hydrothermal treatment at 120 degrees C. It corresponds to a double-layered network (UO2(imdc)2) composed of 7-fold-coordinated uranyl cations linked via the imdc ligands. In the same pH range, a third phase ((UO2)3O2(H2O)(imdc).H2O, 3) is formed: it is composed of hexanuclear units of 7-fold- and 8-fold-coordinated uranyl cations, connected via the imdc molecules in a layered assembly. At higher pH, the chain-like solid (UO2)3O(OH)3(imdc).2H2O (4) is observed and composed of the infinite edge-sharing uranyl-centered pentagonal bipyramidal polyhedra. As a function of pH, uranyl nuclearity increases from discrete 8- or 7-fold uranyl centers (1, 2) to hexanuclear bricks (3) and then infinite chains in 4 (built up from the hexameric fragments found in 3). This observation emphasized the influence of the hydrolysis reaction occurring between uranyl centers. The compounds have been further characterized by thermogravimetric analysis, infrared, and luminescence spectroscopy. PMID- 27509394 TI - Effects of Oxygen Impurities on Glass-Formation Ability in Zr2Cu Alloy. AB - Using ab initio molecular dynamics simulations, we show that oxygen (O) impurities have a noticeable influence on the glass-formation ability (GFA) in Zr2Cu alloy. Cu-centered icosahedral clusters and Zr-centered Kasper polyhedra are the dominate short-range orders in undercooled Zr2Cu liquid which are most likely to be responsible for the glass formation in Zr2Cu systems. When O is introduced, a Zr octahedron is formed around the O impurity. Most of the Zr atoms in the octahedron also serve as the bridging atoms for cross-linked Kasper polyhedral network, resulting in an O-centered medium range order (MRO) structure. Meanwhile, Cu atoms are moved away from the first shell of O-centered octahedral clusters. With 1 at. % O impurities, the fractions of Zr-centered clusters are less affected, while the increase of ideal icosahedral order and decrease of distorted icosahedral order lead to a more stable atomic structure. This result suggests that a low concentration of O impurities would improve the GFA in Zr2Cu alloy. However, when ~5 at. % O impurities are included, the ideal icosahedral clusters and Zr-centered Kasper polyhedra are seriously suppressed by the formation of O-centered MRO, which can lead to deterioration of GFA. Our analyses provide useful insight into glass formation behavior in O-doped metallic alloy systems. PMID- 27509395 TI - The provision of speech-language therapy in services destined to individuals with Autism Spectrum Disorder (ASD). AB - The increased prevalence of autism spectrum disorder (ASD) worldwide has been a major public health concern; therefore, discussion about the services and therapies required has become important. This study aimed to characterize the provision of speech-language therapy services in the metropolitan area of Sao Paulo. To this end, a questionnaire with 23 questions was developed based on the Balanced Scorecard methodology. This questionnaire was applied to 854 individuals assisted in 25 ASD services. The results show that only 64% of the ASD services offer speech-language therapy and that the number of individuals assisted is below the expected. Therefore, there is a necessity for better management in the speech-language therapy services offered to the ASD population. PMID- 27509396 TI - Correlations between vocabulary and phonological acquisition: number of words produced versus acquired consonants. AB - PURPOSE: To verify the probable correlations between the number of word types and the number of consonants in the general phonological system in children with typical language development. METHODS: Study participants were 186 children aged one year and six months to five years, 11 months and 29 days who were monolingual Brazilian Portuguese speakers with typical language development. Data collection involved speech, language and hearing assessments and spontaneous speech recordings. Phonology was assessed with regard to the number of acquired consonants in the general phonological system, in each syllable structure and in Implicational Model of Feature Complexity (IMFC) levels. Vocabulary was assessed with regard to number of word types produced. These data were compared across age groups. After that, correlations between the word types produced and the variables established for the phonological system were analyzed. The significance level adopted was 5%. RESULTS: All phonological aspects evaluated presented gradual growth. Word types produced showed a similar behavior, though with a small regression at the age of five years. Different positive correlations occurred between the spoken word types and the variables analyzed in the phonological system. Only one negative correlation occurred with respect to the production of complex onset in the last age group analyzed. CONCLUSION: The phonology and vocabulary of the study participants present similar behaviors. There are many positive correlations between the word types produced and the different aspects of phonology, except regarding complex onset. PMID- 27509397 TI - Effects of hearing and cognitive impairment in sentence recognition. AB - PURPOSE: To evaluate the effects of hearing and cognitive impairment in sentence recognition in elderly people. METHODS: The study included 30 elderly individuals divided into two groups: GI, with 17 elderly people without hearing loss and GII, with 13 elderly people with mild hearing loss. In order to evaluate their cognition, the Mini Mental State Examination (MMSE) was performed, whereas, for the evaluation of the auditory effects, the Portuguese Sentence List (PSL) was performed, in which the sentence recognition thresholds in silence (SRTS) and the signal-to-noise ratio (S/N) were researched. RESULTS: In MMSE, there was a higher percent of individuals with alteration for GI group when compared with GII group. In both SRTS and S/N, the GI group presented lower thresholds when compared with the GII group for both ears. Regarding the cognitive aspects, no significant statistical difference between normal and altered groups was observed in the MMSE for SRTS and S/N for GI and GII in both ears. CONCLUSION: Mild hearing loss exerted influence on the sentence recognition in silence and in noise. On the other hand, the cognitive aspects did not interfere in speech recognition in both silence and noise. PMID- 27509398 TI - Suppression effect of otoacoustic emissions in term and preterm infants. AB - PURPOSE: This research aims at verifying the occurrence and magnitude of suppression effect of otoacoustic emissions evoked by transient stimulus in term and preterm infants, setting a benchmark for clinical use. METHODS: The study sample consisted of 40 infants, with a rage of age from five days to four months, without any risk indicators for hearing loss and otoacoustic emissions present at birth: the 20 term and 20 preterm infants spent more than five days in the Neonatal Intensive Care Unit. Linear click was presented at 65 dB Sound Pressure Level, in blocks of 15 seconds without noise, and with contralateral noise at 60 dB Sound Pressure Level. The reduced response in the presence of noise indicates positive suppression effect. Mean values of suppression were established and the comparison between the groups was analyzed statistically. RESULTS: Suppression occurred in 100% of the children and did not vary as a function of ear side and between the groups. CONCLUSION: All children presented suppression regardless of the group. The average suppression obtained on the total population was 0.85 dB. The minimum recommended criterion for clinical use was a reduction of 0.20 dB in the overall response. PMID- 27509399 TI - Fluency aspects of oral narrative task in del22q11.2 syndrome. AB - PURPOSE: To investigate the fluency aspects of the oral narrative task in individuals with del22q11.2 syndrome and compare them with those of individuals with typical language development. METHODS: Fifteen individuals diagnosed with del22q11.2 syndrome, both genders, aged 7-17 years participated in this study. They were compared with 15 individuals with typical language development, with similar gender and chronological age profiles. The oral narrative was elicited using the book "Frog, Where Are You?", and the fluency aspects were analyzed according to speech rate and type and frequency of disfluency (typical and stuttering). The number and duration of pauses were also investigated. The data were statistically analyzed. RESULTS: The group with del22q11.2 syndrome showed a higher average when compared with the group without the syndrome for the percentage of typical disfluencies, mainly hesitation and revision. The group presenting the syndrome also showed a higher average for stuttering disfluencies, with pause as the most frequent disfluency. With respect to speech rate, the group with the syndrome presented a lower average for the number of words and syllables per minute. Individuals with del22q11.2 syndrome showed greater difficulties of narration than their peers. CONCLUSION: The fluency aspects of the oral narrative task in subjects with del22q11.2 syndrome were similar to those of individuals with typical language development regarding the presence of hesitation, revision, and pause, but they were different with respect to frequency of disfluency, which was higher in individuals with the syndrome. PMID- 27509400 TI - Executive functions and aging. PMID- 27509401 TI - Is sexual content in new media linked to sexual risk behaviour in young people? A systematic review and meta-analysis. AB - BACKGROUND: Social networking and digital media increasingly have an impact on the lives of young people. We undertook a systematic review and meta-analysis of studies that examined the relationship between exposure to sexually explicit websites (SEWs) and 'sexting' (i.e. sending semi-nude or nude photos from a mobile phone) and the sexual attitudes and practices of young people. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses statement, Medline, EMBASE and PsycINFO were searched for papers that described the statistical association between viewing SEWs or sexting by young people (defined as 10-24 years) and their sexual attitudes and behaviours. RESULTS: Fourteen studies, all cross-sectional in design, met the inclusion criteria. Six studies (10352 participants) examined young people's exposure to SEWs and eight (10429 participants) examined sexting. There was substantial variation across studies in exposure and outcome definitions. Meta-analyses found that SEW exposure was correlated with condomless sexual intercourse (odds ratio (OR) 1.23, 95% confidence interval (CI): 1.08-1.38, two studies); sexting was correlated with ever having had sexual intercourse (OR 5.58, 95% CI: 4.46-6.71, five studies), recent sexual activity (OR 4.79, 95% CI: 3.55-6.04, two studies), alcohol and other drug use before sexual intercourse (OR 2.65, 95% CI: 1.99-3.32, two studies) and multiple recent sexual partners (OR 2.79, 95% CI: 1.95-3.63, two studies). Most studies had limited adjustment for important potential confounders. CONCLUSIONS: Cross-sectional studies show a strong association between self-reported exposure to sexual content in new media and sexual behaviours in young people. Longitudinal studies would provide a greater opportunity to adjust for confounding, and better insight into the causal pathways underlying the observed associations. PMID- 27509402 TI - Human upper airway epithelium produces nitric oxide in response to Staphylococcus epidermidis. AB - BACKGROUND: Nitric oxide (NO) is produced by sinonasal epithelial cells as part of the innate immune response against bacteria. We previously described bitter taste-receptor-dependent and -independent NO responses to product(s) secreted by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. We hypothesized that sinonasal epithelium would be able to detect the gram-positive, coagulase negative bacteria Staphylococcus epidermidis and mount a similar NO response. METHODS: Sinonasal air-liquid interface cultures were treated with conditioned medium (CM) from lab strains and clinical isolates of coagulase-negative staphylococci and S aureus. NO production was quantified by fluorescence imaging. Bitter taste receptor signaling inhibitors were utilized to characterize the pathway responsible for NO production in response to S epidermidis CM. RESULTS: S epidermidis CM contains a low-molecular-weight, heat, and protease-stabile product that induces an NO synthase (NOS)-mediated NO production that is less robust than the response triggered by S aureus CM. The S epidermidis CM stimulated NO response is not inhibited by antagonists of phospholipase C isoform beta-2 nor the transient receptor potential melastatin isoform 5 ion channel, both critical to bitter taste signaling. CONCLUSION: This study identifies an NO mediated innate defense response in sinonasal epithelium elicited by S epidermidis product(s). The active bacterial product is likely a small, nonpeptide molecule that stimulates a pathway independent of bitter taste receptors. Although the NO response to S epidermidis is less vigorous compared with S aureus, the product(s) share similar characteristics. Together, the responses to staphylococci species may help explain the pathophysiology of upper respiratory infections. PMID- 27509404 TI - Association between the MTHFR C677T Polymorphism and Breast Cancer Risk: A Meta Analysis of 23 Case-Control Studies. PMID- 27509403 TI - Occurrence of the Leech, Pontobdella muricata Linnaeus, on Elasmobranch Species in the Northern and Central Adriatic Sea. AB - This study provides a parasitological analysis of the elasmobranch species caught in the northern and central Adriatic Sea. Sixty-two marine leeches were recorded on 747 individuals of Raja clavata Linnaeus, 1758 (thornback ray), Myliobatis aquila Linnaeus, 1758 (common eagle ray), and Torpedo marmorata Risso, 1810 (marbled torpedo ray) caught in 56 hauls over a 5 yr period. All leeches were identified as Pontobdella muricata, which is a typical ectoparasite of benthic elasmobranchs. The prevalence of infection ranged from 7.11% on R. clavata to 12.00% on M. aquila. The intensity of infection, the preferential sites of attachment to the host, and the periodicity of infection were evaluated. PMID- 27509405 TI - A letter from a Syrian refugee camp in Lebanon: Dr. Aldo Morrone. PMID- 27509406 TI - Dopamine as a Novel Electrolyte Additive for High-Voltage Lithium-Ion Batteries. AB - Dopamine, which can be electrochemically oxidized to polydopamine on cathode surface, was introduced as an electrolyte additive for high-voltage lithium-ion batteries (LIBs). The addition of 0.1 wt % dopamine to the electrolyte led to the formation of a polydopamine-containing layer on the cathode, thereby resulting in suppression of the oxidative decomposition of the electrolyte during high-voltage operation (up to 4.5 V) of a LiNi1/3Co1/3Mn1/3O2/artificial graphite cell. The addition of dopamine to the electrolyte improved the capacity retention of the cell from 136 to 147 mAh g(-1) after 100 cycles at a rate of 1 C and a cutoff voltage of 4.5 V, while the cycle performance and rate capability with a cutoff voltage of 4.3 V were comparable to those of the cell without dopamine. Further evidence of the positive impact of dopamine on high-voltage LIBs was the lower DC IRs and AC impedances, as well as the retention of the cathode morphology even after operation at 4.5 V. PMID- 27509407 TI - Growth differentiation factor 11 (GDF11) - a promising anti-ageing factor - is highly concentrated in platelets. AB - Recent research suggests that growth differentiation factor 11 (GDF11) could reverse age-related diseases and that its blood concentration decreases with age. This poses plasma from young donors as a therapeutic GDF11 source to treat age related diseases. In addition, the tissue source of circulating GDF11 remains unknown. We analysed GDF11 levels in paired samples of serum, plasma and platelet lysate (PL) from 23 volunteers. Plasma and PL were collected by plateletpheresis. Here, we show that GDF11 is highly concentrated in platelets and that the circulating levels reported in previous studies could be biased as a result of serum sample manipulation. PMID- 27509408 TI - One-Step and Templateless Electropolymerization Process Using Thienothiophene Derivatives To Develop Arrays of Nanotubes and Tree-like Structures with High Water Adhesion. AB - Here, we report for the first time the possibility to obtain not only arrays of nanotubes but also tree-like structures with high water adhesion using a one-step and templateless electropolymerization process. Using thienothiophene derivatives, particularly thieno[2,3-b]thiophene (Thienothiophene-1) and thieno[3,2-b]thiophene (Thienothiophene-2), we demonstrate this surface fabrication in organic solvent (dichloromethane) and without any surfactants. The formation of nanotubes is due to the stabilization by the polymer of gas bubbles produced in situ during electropolymerization process, and we show that the water content plays an important role in the formation of gas bubbles even if it is not the unique parameter. Using cyclic voltammetry as an electropolymerization method, the amount of released gas is more significant, but at constant potential it is much easier to control the nanotube formation. It is also possible to obtain arrays of tree-like structures when electropolymerizing with high deposition charges, and the resulting surfaces have high thetaw with extremely high water adhesion even if the polymers are intrinsically hydrophilic (theta(Y)w ~ 70 degrees ). This work is extremely important for potential applications in water transportation and harvesting, oil/water separation membranes, energy systems, and biosensing. PMID- 27509409 TI - Interessante Frage: Welche anderen Tumoren werden in der Melanom-Nachsorge mittels PET-CT entdeckt? PMID- 27509410 TI - Primar kutane CD30(+) lymphoproliferative Erkrankungen. AB - Primar kutane CD30(+) lymphoproliferative Erkrankungen zahlen zu der zweit haufigsten Gruppe der kutanen T-Zell-Lymphome (CTCL) und umfassen die Krankheitsbilder der lymphomatoiden Papulose (LyP) und des primar kutanen anaplastischen grobetazelligen Lymphoms (cALCL). Beide Erkrankungen haben klinische, histopathologische und molekulare Gemeinsamkeiten und reprasentieren ein Spektrum von kutanen CD30(+) lymphoproliferativen Erkrankungen. Man kann LyP vom cALCL anhand des Zusammenspiels von klinischen und histopathologischen Befunden unterscheiden. In manchen Patienten konnen LyP und MF gemeinsam auftreten, oder konnen wahrend des Krankheitsverlaufes entstehen. Mycosis fungoides (MF), ist die haufigste Form von CTCL und zahlt nicht zur Gruppe der primar kutanen CD30(+) lymphoproliferativen Erkrankungen. Manche LyP-Patienten konnen jedoch von beiden Krankheitsbildern gemeinsam betroffen sein. Es ist aber auch moglich, dass ein MF-Patient LyP-artige Lasionen entwickelt, die eher eine Manifestation der MF darstellen als zwei unterschiedliche Erkrankungen. Besondere Vorsicht ist jedoch im Zusammenhang mit CD30(+) transformierten MF-Lasionen geboten, da die Gefahr besteht, dass diese falschlicherweise als LyP oder cALCL diagnostiziert werden, was moglicherweise zu einer inadaquaten Behandlung fuhrt. PMID- 27509411 TI - Primary cutaneous CD30(+) lymphoproliferative disorders. AB - Primary cutaneous CD30(+) lymphoproliferative disorders are the second most common group of cutaneous T-cell lymphomas (CTCL) and include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T-cell lymphoma (cALCL). Both disease entities share overlapping clinical, histopathological, and molecular features, thus representing a spectrum of cutaneous CD30(+) lymphoproliferative disorders. LyP may be distinguished from cALCL by clinicopathological correlation. In some patients, both diseases may coexist at initial diagnosis or develop over the course of the disease. Mycosis fungoides (MF), the most common CTCL, is not considered a primary cutaneous CD30(+) lymphoproliferative disorder, but may occur in some LyP patients. In addition, LyP-like lesions may develop in MF patients. However, this is frequently a manifestation of MF rather than a representation of two different disease entities. Caution also has to be taken in the setting of transformed MF with lesions expressing CD30, as they may be mistaken for either LyP or cALCL, resulting in an inadequate therapeutic approach. PMID- 27509412 TI - On the significance of negative-pressure wound therapy with instillation in dermatology. AB - Methods used in the treatment of acute and chronic wounds undergo constant evolution, reevaluation, and innovation. While negative-pressure wound therapy (NPWT) is an established treatment modality, the combination of NPWT and instillation of normal saline as well as solutions with active antiseptic components for topical treatment of the wound bed represents a novel approach. The well-known effects of NPWT may thus be combined with those of local antisepsis. They include a decrease in wound area, induction of granulation tissue, and reduction in bacterial colonization. To date, studies have focused on NPWT with instillation for orthopedic/surgical indications, whereas clinical data in dermatosurgery is limited to case reports or small case series. There are as yet no randomized prospective studies investigating NPWT with instillation in the treatment of skin disorders. The goal of this review is to present the method of NPWT with instillation, to highlight its mode of action as well as possible complications and contraindications, and to review the recent literature. In summary, there is increasing evidence that both simple and complicated wounds may be effectively treated with NPWT with instillation, resulting in markedly accelerated tissue granulation and thus earlier defect closure. PMID- 27509413 TI - Zum Stellenwert der Unterdruck-Instillationstherapie in der Dermatologie. AB - Die Methoden zur Behandlung akuter und chronischer Wunden unterliegen einer steten Weiterentwicklung, Reevaluierung und Anwendung innovativer Therapieformen. Die Vakuumtherapie zur Wundbehandlung gehort zu den etablierten Behandlungsmodalitaten. Ein innovatives Verfahren kombiniert die Vakuumtherapie mit der automatisierten, kontrollierten Zufuhr und Drainage wirkstoffhaltiger Losungen zur topischen Wundbehandlung im Wundbett und auch wirkstofffrei durch Instillation physiologischer Kochsalzlosung (Unterdruck-Instillationstherapie). Hierdurch konnen die Effekte der konventionellen Vakuumtherapie mit denen der lokalen Antisepsis kombiniert werden. Hierdurch kommt es zu einer Reduktion der Wundflache, einer Induktion von Granulationsgewebe sowie einer Reduktion der Keimbesiedelung der Wunden. Bisher publizierte Studien konzentrieren sich auf die Anwendung dieses Therapieverfahrens zur Behandlung orthopadisch-chirurgischer Krankheiten. Die Datenlage bezuglich der Vakuum-Instillationstherapie in der Dermatochirurgie beschrankt sich derzeit auf Fallberichte und Einzelfallerfahrungen. Randomisierte, prospektive Studien zum Vergleich der Vakuum-Instillationstherapie zur Behandlung dermatologischer Krankheitsbilder existieren bislang nicht. Ziele des vorliegenden Artikels sind die Vorstellung der Vakuumtherapie mit Instillation einschliebetalich ihres Wirkprinzips, deren mogliche Komplikationen, die Diskussion erdenklicher Kontraindikationen sowie eine Ubersicht uber die aktuell verfugbare Datenlage. Zusammenfassend scheint sich die Evidenz zu verdichten, dass mittels Unterdruck-Instillationstherapie sowohl einfache als auch komplizierte Wunden effizient behandelt werden konnen, was sich in einer deutlichen Beschleunigung der Wundgranulation mit konsekutiv fruher moglichem Defektverschluss aubetaert. PMID- 27509414 TI - Morphologische Kriterien vesikulobulloser Hauterkrankungen in der konfokalen In vivo-Laserscanmikroskopie. AB - HINTERGRUND UND ZIELVORGABEN: Konfokale Laserscanmikroskopie (Reflectance confocal microscopy; RCM) kann eine nutzliche Methode fur die genaue, schnelle und nicht-invasive Diagnose fur vesikullobullose Hauterkrankungen (VSD) am Krankenbett sein. Das primare Ergebnis dieser Studie war eine deskriptive statistische Analyse von RCM-Merkmalen, die mit einer ausgewahlten Gruppe an VSD einhergehen. PATIENTEN UND METHODEN: Monozentrische Beobachtungsstudie an einer Universitatsklinik fur Dermatologie. Vierzig Hautlasionen bei 24 Patienten mit bullosem Pemphigoid (BP), Infektion mit Varizella Zoster (VZI) oder allergischer Kontaktdermatitis (ACD) wurden ausgewertet. ERGEBNISSE: Patienten mit BP, VZI und ACD wurden auf die Anwesenheit eines grobetaen Spektrums an RCM-Merkmalen hin untersucht, darunter die histopathologische Korrelation von Spongiose, Vesikel/Hautblasen, epidermaler Nekrose, pleomorphen, ballonierte Keratinozyten und entzundlichen Infiltraten. Die drei Erkrankungen zeigten spezifische Muster fur Auftreten dieser RCM-Merkmale. Wir identifizierten mit Hilfe einer multivariaten Regressionsanalyse einen Satz morphologischer Merkmale bei BP (Vesikel/Hautblasen an der dermoepidermalen Junktionszone, entzundliche Infiltrate in Hautblasen und basalen Epidermisschichten, Spongiose in basalen Epidermisschichten), VZI (Akantholyse im Stratum spinosum, epidermale Nekrose, pleomorphe, ballonierte Keratinozyten, multinukleare Riesenzellen) und ACD (Mikrovesikel, Spongiose und auffallige entzundliche Infiltrate im Stratum granulosum/spinosum). SCHLUSSFOLGERUNGEN: RCM scheint ein nutzliches Werkzeug bei der Analyse und der Unterscheidung einer ausgewahlten Gruppe von VSDs zu sein und bietet eine gute Korrelation mit histopathologischen Untersuchungsergebnissen. PMID- 27509415 TI - Morphologic criteria of vesiculobullous skin disorders by in vivo reflectance confocal microscopy. AB - BACKGROUND AND OBJECTIVES: Reflectance confocal microscopy (RCM) may be a useful method for accurate, rapid, and noninvasive bedside diagnosis of vesiculobullous skin diseases (VSD). The main outcome measure of this study was a descriptive statistical analysis of RCM features associated with selected group of VSD. PATIENTS AND METHODS: Single-center, observational study at a university-based dermatology department. Forty skin lesions in 24 patients with bullous pemphigoid (BP), varicella zoster virus infection (VZI), or allergic contact dermatitis (ACD) were assessed. RESULTS: Patients with BP, VZI, and ACD were assessed for the presence of a large spectrum of RCM features, among others including histopathological correlates for spongiosis, vesicles/blisters, epidermal necrosis, pleomorphic ballooned keratinocytes, and inflammatory infiltrate. The three conditions showed distinct patterns of occurrence with respect to these RCM features. Using a multivariate regression model, we identified sets of morphologic features in BP (vesicles/blisters at the dermoepidermal junction, inflammatory infiltrate within blisters and basal epidermal layers, spongiosis in basal epidermal layers), VZI (acantholysis in the stratum spinosum, epidermal necrosis, pleomorphic ballooned keratinocytes, multinucleated giant cells), and ACD (microvesicles, spongiosis, and prominent inflammatory infiltrate in the stratum granulosum/spinosum). CONCLUSIONS: RCM seems to be a useful tool in the evaluation and differentiation of a selected group of VSD, and offers a good correlation with histopathological findings. PMID- 27509416 TI - Retrospective chart analysis of incidental findings detected by (18) F fluorodeoxyglucose-PET/CT in patients with cutaneous malignant melanoma. AB - BACKGROUND AND OBJECTIVES: (18) F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) frequently reveals incidental findings. The present study focused on incidental FDG-PET/CT findings in cutaneous melanoma patients, and verified their relevance with respect to further diagnostic measures and interventions. PATIENTS AND METHODS: Medical records of 181 consecutive melanoma patients were retrospectively evaluated to verify the management of incidental findings, with particular emphasis on histological findings. RESULTS: Thirty-three of 181 (18 %) patients showed 39 relevant incidental findings, located in the colorectal tract (n = 15 patients), thyroid (n = 8), prostate (n = 2), locomotor system (n = 2), lymph nodes (n = 2), parotid gland (n = 1), tonsils (n = 1), kidneys (n = 1), and gallbladder (n = 1). Performed in 25 patients, additional diagnostic procedures revealed a clinical correlate in 21 cases. Sixteen of 21 patients had tumoral involvement, including five malignant lesions (four colorectal and one prostate carcinoma). The malignancies were diagnosed at an early stage, and successfully removed in the majority of cases. CONCLUSIONS: The diagnostic use of FDG-PET/CT is routinely recommended for stage IIC melanoma and higher, and is widely accepted as indication. This study effectively identified otherwise undetected cancers, especially colorectal malignancies. Early interventions were possible in most cases. Incidental findings on FDG-PET/CT should be worked up with appropriate diagnostic measures, considering the patient's condition and wishes. PMID- 27509417 TI - Retrospektive Analyse von Zufallsbefunden, die bei Patienten mit kutanem malignen Malignom durch (18) F-Fluordeoxyglucose-PET/CT erhoben wurden. AB - HINTERGRUND UND ZIELE: Bei der (18) F-Fluordeoxyglucose Positronenemissionstomographie/Computertomographie (FDG-PET/CT) ergeben sich haufig Zufallsbefunde. In der vorliegenden Studie konzentrierten wir uns auf mittels FDG-PET/CT erhaltene Zufallsbefunde bei Patienten mit kutanem Melanom und uberpruften deren Relevanz hinsichtlich weiterer diagnostischer Mabetanahmen und Interventionen. PATIENTEN UND METHODEN: Die Krankenakten von 181 konsekutiven Melanom-Patienten wurden retrospektiv ausgewertet, um das Management von Zufallsbefunden zu dokumentieren. Der Schwerpunkt lag dabei auf den histologischen Befunden. ERGEBNISSE: Bei 33 von 181 (18 %) Patienten lagen 39 relevante Zufallsbefunde vor, und zwar im Kolorektalbereich (n = 15 Patienten), in der Schilddruse (n = 8), der Prostata (n = 2), dem Bewegungsapparat (n = 2), in Lymphknoten (n = 2), der Parotis (n = 1), den Mandeln (n = 1), den Nieren (n = 1) und der Gallenblase (n = 1). Bei 25 Patienten schlossen sich weitere diagnostische Verfahren an, wobei in 21 Fallen ein klinisches Korrelat nachgewiesen wurde. Bei 16 von 21 Patienten ergab sich eine Neoplasie, darunter funf maligne Lasionen (vier Kolonkarzinome und ein Prostatakarzinom). Die Malignome wurden fruhzeitig diagnostiziert und in der Mehrzahl der Falle erfolgreich entfernt. SCHLUSSFOLGERUNGEN: Der Einsatz der FDG-PET/CT als Routine Diagnostik wird in den Leitlinien empfohlen und ist indiziert bei malignem Melanom ab Stadium IIC. In dieser Studie wurden auf effektive Weise ansonsten nicht erkannte Krebserkrankungen, insbesondere Kolonkarzinome, detektiert. In den meisten Fallen war eine fruhe Intervention moglich. Zufallsbefunde durch FDG PET/CT sollten, unter Berucksichtigung des Zustands und der Wunsche des Patienten, mit den geeigneten diagnostischen Mabetanahmen abgeklart werden. PMID- 27509418 TI - Tinea capitis: Erregerspektrum und Epidemiologie im zeitlichen Wandel. AB - HINTERGRUND: Die Tinea capitis ist die haufigste Dermatomykose des Kindesalters. Das Erregerprofil zeigt unterschiedliche geographische Verteilungsmuster und variiert im Laufe der Zeit. PATIENTEN UND METHODIK: Zwischen 1990-2014 an der Wurzburger Universitatsklinik fur Dermatologie erhobene Daten von 150 Patienten mit mykologisch gesicherter Tinea capitis wurden hinsichtlich Alter, Geschlecht und Erregerspektrum analysiert und uber zwei Zeitraume von jeweils 12,5 Jahren miteinander verglichen. ERGEBNISSE: Obwohl eine Tinea capitis am haufigsten bei Kindern der Altersgruppe zwischen 0 und 5 Jahren diagnostiziert wurde, lag der Anteil betroffener Erwachsener mit 16 % hoher als bislang berichtet. Der zoophile Dermatophyt Microsporum canis konnte am haufigsten als Erreger der Tinea capitis identifiziert werden, jedoch war ein Anstieg von Infektionen mit den anthropophilen Pilzen Trichophyton tonsurans und Trichophyton rubrum zu verzeichnen. Tendenziell sank der Anteil zoophiler im Verhaltnis zu den anthropophilen Erregern. Im zeitlichen Verlauf zeigte sich eine zunehmende Heterogenitat des Erregerspektrums: Dermatophyten wie Trichophyton soudanense und Trichophyton violaceum, Trichophyton anamorph von Arthroderma benhamiae sowie Trichophyton schoenleinii und Microsporum audouinii konnten erstmalig bzw. nach langer Zeit wieder erneut isoliert werden. SCHLUSSFOLGERUNGEN: Wenngleich Microsporum-canis-Infektionen noch dominieren, sind zunehmend anthropophile Erreger nachzuweisen. Angesichts des unerwartet hohen Anteils von Erwachsenen sollte eine Tinea capitis in allen Altersgruppen differenzialdiagnostisch in Betracht gezogen werden. PMID- 27509419 TI - Tinea capitis: temporal shift in pathogens and epidemiology. AB - BACKGROUND: Tinea capitis is the most common type of dermatomycosis in children. Its pathogen profile shows geographic variations as well as temporal shifts. PATIENTS AND METHODS: Data from 150 patients with mycologically confirmed tinea capitis treated at the Department of Dermatology, University Hospital Wurzburg, between 1990 and 2014 were analyzed with respect to gender, age, and pathogen spectrum. Two time periods, each 12.5 years long, were compared. RESULTS: Although tinea capitis was most frequently diagnosed in children between the ages of 0 and 5, the percentage of adults (16 %) was higher than previously reported. The zoophilic dermatophyte Microsporum canis was most frequently identified as the causative agent of tinea capitis. However, there was a rise in infections caused by the anthropophilic fungi Trichophyton tonsurans and Trichophyton rubrum, and also a trend towards a lower percentage of zoophilic versus anthropophilic pathogens. Over the course of time, we observed an increase in the diversity of the pathogen spectrum. Dermatophytes such as Trichophyton soudanense, the Trichophyton anamorph of Arthroderma benhamiae, Trichophyton schoenleinii, and Microsporum audouinii were isolated either for the first time or for the first time after a long hiatus. CONCLUSIONS: Although Microsporum canis infections still predominate, there has been an increase in anthropophilic pathogens. Given the unexpectedly high percentage of adults, tinea capitis should be included in the differential diagnostic considerations in all age groups. PMID- 27509420 TI - Generalized morphea with development of bullous lesions at the site of surgical scars. PMID- 27509421 TI - Generalisierte zirkumskripte Sklerodermie (Morphea) mit bullosen Lasionen an Operationsnarben. PMID- 27509422 TI - Infektionsassoziiertes gemeinsames Auftreten von Psoriasis pustulosa, Pemphigus foliaceus und leukozyoklastischer Vaskulitis. PMID- 27509423 TI - Coincidence of annular pustular psoriasis, pemphigus foliaceus, and leukocytoclastic vasculitis associated with chronic cholecystitis. PMID- 27509424 TI - Vulvar and areolar melanosis: a case report and review of the literature. PMID- 27509425 TI - Melanose der Vulva und Areola: Fallbericht und Literaturubersicht. PMID- 27509426 TI - Effektive Behandlung einer durch Leishmania tropica verursachten kutanen Leishmaniose mit topischer, photodynamischer Therapie. PMID- 27509427 TI - Effective treatment of cutaneous leishmaniasis caused by Leishmania tropica with topical photodynamic therapy. PMID- 27509428 TI - Dramatischer Verlauf einer malignen atrophen Papulose (Morbus Kohlmeier-Degos) mit todlichem Ausgang. PMID- 27509429 TI - Generalisierte Herpes-simplex-Virus-Infektion bei Morbus Darier. PMID- 27509430 TI - Generalized herpes simplex virus infection in Darier's disease. PMID- 27509431 TI - Keratotische Papeln und Plaques genitogluteal. PMID- 27509432 TI - Keratotic papules and plaques in the genitogluteal region. PMID- 27509433 TI - Perkutane Ultraschall-gesteuerte Durchstichdrainage therapierefraktarer Serome nach Lymphknotenexzision. PMID- 27509434 TI - Percutaneous ultrasound-guided drainage of needle aspiration-refractory seromas following lymph node excision. PMID- 27509435 TI - S1-Guidelines on UV phototherapy and photochemotherapy. AB - Known in part since antiquity, the salutary effects of sunlight again garnered increasing attention in the second half of the 19(th) century. The development of a device for ultraviolet irradiation of cutaneous tuberculosis by Finnsen at the onset of the twentieth century truly marked the beginning of modern phototherapy. In dermatology, treatment methods almost exclusively use wavelengths below the visible light range (ultraviolet light). Since the early 1970s, increasingly powerful artificial light sources have become available for UVB and UVA therapy as well as the combination of UVA and photosensitizers (photochemotherapy). High structural and procedural quality standards are an essential prerequisite for the implementation of effective as well as safe phototherapy. The following guidelines outline the current consensus of leading experts in the field of phototherapy with respect to indications, contraindications, and side effects of various treatment options available. Particular focus is also on adequate UV doses at the beginning and over the further course of treatment as well as on management of side effects. PMID- 27509438 TI - Forschungspreis der Jorg Wolff-Stiftung - Arnold Rikli-Preis 2016. PMID- 27509437 TI - Osterreichische Gesellschaft fur Dermatologie und Venerologie (OGDV). PMID- 27509440 TI - Kongresskalender 2016. PMID- 27509439 TI - S1-Leitlinie zur UV-Phototherapie und Photochemotherapie. AB - Die heilsame Wirkung des Sonnenlichts war teilweise schon im Altertum bekannt und fand in der zweiten Halfte des 19. Jahrhunderts wieder zunehmend Beachtung. Den Beginn der modernen Phototherapien markiert die Entwicklung einer Apparatur zur ultravioletten Bestrahlung der Hauttuberkulose durch Finnsen zu Beginn des zwanzigsten Jahrhunderts. Zur Therapie von Hauterkrankungen finden beinahe ausschliebetalich die spektralen Bereiche unterhalb des sichtbaren Lichtes (ultraviolett) Anwendung. Seit den 1970er Jahren stehen zunehmend leistungsfahige kunstliche Strahlenquellen bereit fur die Therapie mit UVB, UVA und die Kombination von UVA mit Photosensibilisatoren (Photochemotherapie). Hohe strukturelle und prozedurale Qualitatsstandards sind unabdingbare Voraussetzung fur die Durchfuhrung einer gleichermabetaen wirkungsvollen wie auch sicheren Phototherapie. Die Leitlinie formuliert den aktuellen Konsens fuhrender Experten auf dem Gebiet der Phototherapie in Bezug auf die Indikationen fur die jeweiligen Therapieverfahren, deren Gegenanzeigen und Nebenwirkungen und insbesondere fur die Wahl der korrekten Dosis zu Beginn und im Verlauf einer Therapie sowie das Management von Nebenwirkungen. PMID- 27509441 TI - Cancer incidence in Holocaust male survivors-An Israeli cohort study. AB - Previous studies, often using proxy exposure assessment and not controlling for individual risk factors, suggested higher cancer risk in Holocaust survivors. We have used individual-level data from a male cohort of Israeli civil servants recruited in 1963 to investigate cancer incidence in Holocaust survivors, controlling for potential confounders. The analysis included 4,669 Europe-born subjects; 689 exposed = E (immigrated to Israel after 1939 and reported of being in Nazi camps during World War II); 2,307 potentially exposed = PE (immigrated to Israel after 1939 and reported of not being in Nazi camps); and 1,673 non-exposed = NE (immigrated to Israel prior to 1939). Vital status and cancer incidence in the cohort were determined based on national registries. Socioeconomic level, health behaviors and cancer incidence were compared between the groups and Cox proportional hazards regression models adjusting for potential confounders assessed hazard risk ratios for cancer by exposure status. All-cause mortality was studied as a competing risk. In total, 241, 682, and 522 cancer cases were diagnosed in the E, PE, and NE, respectively. Compared with the NE, all-site cancer incidence was higher in the E (HR = 1.13, 95%CI 0.97-1.32) but not in the PE. All-cause mortality competed with all-site invasive cancer incidence in the E group (HR = 1.18, 95%CI 1.02-1.38). Colorectal and lung cancer seemed to be positively though non-significantly associated with the exposure while prostate cancer was not. Male Holocaust survivors may be at a weakly increased risk for all-site, colorectal and lung cancer. The role of age at exposure and residual confounding should be further investigated. PMID- 27509443 TI - The Reactive-Diffusive Length of OH and Ozone in Model Organic Aerosols. AB - A key step in the heterogeneous oxidation of atmospheric aerosols is the reaction of ozone (O3) and hydroxyl radicals (OH) at the gas-particle interface. The formation of reaction products and free radical intermediates and their spatial distribution inside the particle is a sensitive function of the length over which these oxidants diffuse prior to reaction. The reactive-diffusive length of OH and ozone at organic aerosol interfaces is determined by observing the change in the effective uptake coefficient for size-selected model aerosols comprising a reactive core and a thin nanometer-sized (0-12 nm) organic shell. The core and shell materials are selected so that they are immiscible and adopt an assumed core-shell configuration. The results indicate a reactive-diffusive length of 1.4 nm for hydroxyl (OH) radicals in squalane and 1.0 nm for ozone in squalene. Measurements for a purely diffusive system allow for an estimate for diffusion constant (1.6 * 10(-6) cm(2)/s) of ozone in squalane to be determined. The reactive-diffusive length offers a simple first order estimate of how shielding of aerosols by immiscible layers can alter estimates of oxidative lifetimes of aerosols in the atmosphere. PMID- 27509444 TI - iHEART: a miniaturized near-infrared in-line gas sensor using heart-shaped substrate-integrated hollow waveguides. AB - A novel heart-shaped substrate-integrated hollow waveguide (hiHWG) was integrated with a near-infrared micro-spectrometer (MUNIR) for sensing natural gases, resulting in an ultra-compact near-infrared gas sensing system - iHEART. The iHEART system was evaluated using two different MUNIR spectrometers, and the performance was compared with a laboratory NIR spectrometer for gas analysis based on an acousto-optic tunable filter (AOTF). The spectral data were pre processed using the 1(st) derivative Savitzky-Golay algorithm, and then used for establishing multivariate regression models based on partial least squares (PLS). The root mean square errors of prediction (RMSEPs) obtained for major components of natural gas with both iHEART systems were similar to those associated with the AOTF spectrophotometer combined with a conventional long-path measurement cell. It was demonstrated that the iHEART system has significant potential for the development of compact in-line gas sensing systems, thus facilitating monitoring of (petro)chemically relevant processes and products. However, the flexibility and modularity of the system also allows tailoring iHEART to a wide range of other relevant analytical measurement scenarios requiring short response times and minute gas sample volumes. PMID- 27509445 TI - Does Increased Duodenal Intraepithelial Lymphocytosis Always Equate With Marsh 1 Lesion? PMID- 27509446 TI - Multipolar versus monopolar radiofrequency ablation for hepatocellular carcinoma in the caudate lobe: Results of a propensity score analysis. AB - AIM: This study aimed to compare multipolar radiofrequency ablation (RFA) with monopolar RFA as the major treatment for nodules of hepatocellular carcinoma in the caudate lobe. METHODS: This retrospective study was approved by the institutional review board. Data were reviewed from 101 patients who met the Milan criteria and were treated by multipolar RFA (n = 22) or monopolar RFA (n = 79). After propensity score matching, complications and local tumor progression were compared between the two groups. RESULTS: Before propensity score matching (n = 101), the 2-year relapse-free survival rates for multipolar and monopolar RFA (65.1% vs. 38.8%, respectively; P = 0.064) and the local tumor progression rate (12.5% vs. 14.9%, respectively; P = 0.313) were not significantly different. There were no significant differences between the two RFA techniques by treatment efficacy of transcatheter hepatic arterial embolization, location of tumor, and puncture route. After matching (n = 44), the 2-year relapse-free survival rate for the multipolar and monopolar groups (65.1% vs. 22.7%, respectively; P = 0.004) was significantly different, and the local tumor progression rate (12.5% vs. 22.9%, respectively; P = 0.004) was significantly different. No severe complications occurred in the patients treated by multipolar RFA. CONCLUSION: Multipolar RFA appears to be a safe and effective method for hepatocellular carcinoma nodules in the caudate lobe. PMID- 27509447 TI - The impact of characteristics of nurses' relationships with their supervisor, engagement and trust, on performance behaviours and intent to quit. AB - AIMS: The aim of this study was to investigate the influence of characteristics of nurses' relationship quality with their manager on engagement and trust, onto in-role or discretionary behaviours and intent to quit. BACKGROUND: Nurses having a good relationship with their manager are seen as important, yet the mechanisms of how such relationships are beneficial, or which aspects of the relationship are important, is less clear. Two possible mechanisms are through the nurse being more engaged in work, or through building their trust in their employer. In turn, engagement and trust may impact in-role and discretionary behaviours as well as staff retention. DESIGN: Cross-sectional. METHOD: An online survey in 2013 of 459 nurses across Australia. RESULTS: Structural analyses indicated that the affect dimension of relationship quality was negatively related to engagement, whereas contribution and respect were positively related to engagement. The affect and respect aspects were positively related to trust. Engagement positively related to discretionary and in-role behaviours. Engagement and trust were negatively related to quit intention, as was the loyalty dimension of the nurses' relationship with their supervisor. However, perceptions of variability in their team's relationship quality with their leader was negatively related to trust and positively related to intent to quit. CONCLUSIONS: Nurse managers with a nuanced understanding of social exchange at work are likely to maintain more engaged, well-performing and stable nursing teams. In particular, a willingness by the supervisor to come to their nurses' defence and having a consistent standard of relationship quality across their nurses is likely to improve nurse retention. PMID- 27509449 TI - Decarboxylative Annulation of alpha-Amino Acids with gamma-Nitroaldehydes. AB - Indolizidine and quinolizidine derivatives are readily assembled from proline or pipecolic acid and gamma-nitroaldehydes by means of a decarboxylative annulation process. These reactions are promoted by simple acetic acid and involve azomethine ylides as reactive intermediates. The method was applied to the synthesis of an epiquinamide analog. PMID- 27509450 TI - Evaluation of 126 Consecutive Stereotactic Procedures: Brain Biopsy, Diagnostic Yield, Accuracy, Non-Diagnostic Results, Complications and Follow-up. AB - AIM: A retrospective analysis of 126 consecutive computed tomography (CT)-guided, frame-based stereotactic procedures in 121 patients is presented to evaluate the diagnostic yield, accuracy, complications, management of non-diagnostic cases and followup. MATERIAL AND METHODS: The medical records of the identified patients were investigated retrospectively. Age, sex, surgical procedures, histopathological diagnosis, diagnostic yield, accuracy, complications, management of non-diagnostic cases and follow-up were analyzed in 121 consecutive patients. Stereotactic procedures were performed by the author by using Leksell's stereotactic system, and stereotactic biopsies were conducted under local anesthesia except for those patients who were not able to tolerate this treatment. These patients had control CT scans two hours after the operation. RESULTS: Patient age ranged from 2 to 82 years (mean 48 years). Stereotactic biopsy was performed in 112 patients. Cyst and abscess aspiration, intracystic catheter replacement and tumor resection with stereotactic craniotomy were among the other procedures. The diagnostic yield was 93%, and the histological accuracy was 63% with no mortality. Craniotomy and hematoma evacuation were required in two cases. The patients were followed up from one month to 17 years. CONCLUSION: Frame-based stereotactic biopsy is a safe and efficacious method with acceptable complications. Experience is important, but not sufficient for preventing complications and performing procedures accurately. Necrosis and gliosis are the most common non-diagnostic findings. Empirical treatment with presumptive diagnoses based on clinical and radiological findings and close clinical follow up may not affect patients adversely. The follow-up of patients through examination and imaging is important to allow the revision of treatment when necessary. PMID- 27509451 TI - The Impact of the Stage and Tumor Size on Rare Brain Metastasis of Cervical Cancer. AB - AIM: To investigate the clinical features, prognostic factors and survival times of cervical cancer patients with brain metastasis. MATERIAL AND METHODS: We retrospectively reviewed the medical records of 820 patients with cervical cancer. Data were analyzed using SPSS version 12.0 statistical software (SPSS, Chicago, IL, USA). Overall survival, time interval from diagnosis of cervical cancer to identification of brain metastasis, and median survival time after diagnosis of brain metastasis were calculated using Kaplan-Meier curve analysis. The log-rank test was used to compare differences in survival. Differences were assumed statistically significant when p-values were < 0.05. RESULTS: The incidence of brain metastases from cervical cancer in our institution was 1.82% (15/820) over a ten-year period. The median time interval from diagnosis of cervical cancer to detection of brain metastasis was 12.5 months (range: 2.9-91.9 months). Stage and tumor diameter were found to be significant relating to the interval from diagnosis of cervical cancer to detection of brain metastasis (p=0.001 for both). CONCLUSION: This study provides much information about the prognosis of patients with brain metastases from cervical cancer and highlights the importance of initial stage and tumor diameter when determining the time interval until development of brain metastasis. PMID- 27509452 TI - Gamma Knife Radiosurgery for Arteriovenous Malformations: Clinical Series of 199 Patients. AB - AIM: Cerebral arteriovenous malformations (AVM) are pathological connections between arteries and veins without capillaries. Stereotactic radiosurgery (RS) is a proven and accepted treatment method for cerebral AVMs. Our objective was to analyze the factors influencing the clinical outcome in patients suffering from AVMs. MATERIAL AND METHODS: We retrospectively reviewed 199 patients who were treated with Gamma-Knife RS for intracranial AVMs between 13 October 2005 and 31 October 2010. There were 89 male, 110 female patients with a median age of 32 years (range, 3-74 years). Obliteration was assessed with MRI angiography and DSA imaging. RESULTS: Complete obliteration rate after RS was 71 % (141 out of 199), including second RS treatments. In terms of obliteration rates, there was no significant difference between patients younger and older than 21 years old (p=0.669). After RS, 3 patients died due to intracranial hemorrhage and 1 died of heart disease. Death from AVM was determined as 1.5 %. Intracranial hemorrhage was observed in 7 (3.5 %) patients post-RS. CONCLUSION: Obliteration was found to be associated with Spetzler-Martin Grade, Pollock-Flickinger Grade, AVM volume, RS dose, bleeding history before RS and no previous embolization before RS. Gamma knife RS is an effective treatment method for the treatment of AVMs both for pediatric and adult patients. It provides high obliteration and low mortality rates. PMID- 27509453 TI - Effectiveness of GFAP in Determining Neuronal Damage in Rats with Induced Head Trauma. AB - AIM: To determine whether the serum level of glial fibrillary acidic protein (GFAP), an important indicator of neuron damage, correlates with the extent of tissue damage in the rat with induced head trauma and to obtain data in order to avoid unnecessary cranial computed tomography analyses. MATERIAL AND METHODS: Three-month-old male Sprague-Dawley rats were used. Rats were divided into 5 groups. The experimental head trauma model was examined in five groups (n=8) as follows: The control group had no intervention; Group 1: Head trauma was induced by dropping a 25 mg ball from a height of 20 cm; Group 2: Head trauma was induced by dropping a 50 mg ball from a height of 20 cm; Group 3: Head trauma was induced by dropping a 50 mg ball from a height of 80 cm; Group 4: Head trauma was induced by dropping a 100 mg ball from a height of 80 cm. Thus, according to the Newton's Law, respectively 0.05, 0.1, 0.2 and 0.4 N trauma was created. Serum GFAP levels were analyzed and the damage to cerebral tissues was evaluated in all groups. RESULTS: We determined that number of apoptotic cells and particularly the number of GFAP (+) protoplasmic astrocytes at the perilesional region of the cortex increased in association with the increased serum GFAP level as long as the severity of the trauma increased. CONCLUSION: Serum GFAP concentration can be used as a marker of the severity of head trauma and traumatic brain injury. However, more animal studies are required to reflect this result in clinical practice. PMID- 27509454 TI - Contribution of Neural Elements to Thoracic Stability. AB - AIM: Studies of spinal biomechanics typically do not focus on the contributions to range of motion (ROM) of the primary components of the spinal canal, dura, arachnoid, pia, spinal cord, nerve roots, ligaments, and vessels. We sought to determine the stability offered by these soft tissues in vitro. MATERIAL AND METHODS: Human cadaveric segments were tested intact, after osteoligamentous destabilization, and after transection of T8-9 spinal canal components. Specimens were induced into flexion, extension, axial rotation, and lateral bending using non-constraining, non-destructive pure moment while tracking motion response stereophotogrammetrically. The range of motion (ROM) was compared in each condition after adjusting for soft tissue creep. RESULTS: After spinal canal element transection, ROM increased in all directions (mean 4.7%). This increase was most pronounced during lateral bending (p=0.055). The cumulative ROM from all directions of loading showed a statistically significant mean increase of 3.3% (p=0.040). CONCLUSION: Sectioning of canal elements was found to cause a measurable increase in ROM. Although nonviable tissues were tested, living tissues are also likely to contribute to spinal stability. PMID- 27509455 TI - Optic Nerve Hemangioblastomas?A Review of Visual Outcomes. AB - Supratentorial hemangioblastomas (HBLs) are exceedingly uncommon. They account for less than 5% of all central nervous system HBLs. The commonest location is the cerebral cortex. Rarely, they can involve the visual pathway. Most of the reports have focused on the differential diagnosis, since depending on the location they can often resemble optic nerve gliomas or meningiomas of the optic nerve sheath. In this study, we describe a 67-year-old man with progressive diminution of vision in the left eye with an optic nerve hemangioblastoma. There was no history of von Hippel-Lindau disease. We discuss the diagnostic challenges, and review the visual presentation and visual outcomes in these patients. This report, we believe, may add further clarity in counseling patients with an optic nerve lesion and the factors in surgical decision-making. PMID- 27509456 TI - Does Right-Sided Language Lateralization on BOLD-fMRI Affect Postoperative Language Outcome for AVM Patients? AB - AIM: For cerebral arteriovenous malformations (AVMs) involving language areas, right-sided language lateralization on functional magnetic resonance imaging (fMRI) has been reported, which is regarded as language cortex reorganization. The authors attempted to study if this right-sided language lateralization affects postoperative language outcome. MATERIAL AND METHODS: Clinical and imaging data of 43 right-handed AVM patients who underwent preoperative fMRI were retrospectively reviewed. All lesions involved the language cortex, with the Broca area involved in 13 patients and the Wernicke area involved in 30 patients. Lateralization indices (LI) of BOLD signal activations were calculated to determine language lateralization. All patients underwent craniotomy and total resection. Western aphasia battery (WAB) was used to evaluate language functions preoperatively, 1-2 weeks after surgery and 6-30 months after surgery. RESULTS: On preoperative fMRI, right-sided lateralization was observed in 18 patients (41.9%, R Group), including 3 with rightsided lateralization in the Broca area alone, 14 in the Wernicke area alone, and 1 in both areas. The other 25 patients were non-rightsided lateralized (NR Group). One week after surgery, 7 patients in the R Group (38.9%) and 11 patients in the NR Group (44.0%) had language function deterioration, and no significant difference was found (p=0.983). At long-term follow-up, 3 patients in the R Group (16.7%) and 4 patients in the NR Group (16.0%) still had aphasia, and no significant difference was observed (p=1.000). CONCLUSION: Although right-sided lateralization on fMRI might suggest language cortex reorganization, it is not a factor predicting better postoperative language outcome for AVM patients. PMID- 27509457 TI - Neuroprotective Effects of Chronic Fenofibrate Treatment via Modulating the Immunoreactivity of Cleaved Caspase-3 in Stroke Induced by Transient Middle Cerebral Artery Occlusion Rat Model. AB - AIM: Current stroke therapies include lipid-lowering drugs, which reduce inflammation and serve to stabilize the atherosclerotic plaque to demonstrate better outcome and neuroprotection. Peroxisome proliferator activated receptors (PPAR) ? regulates lipid homeostasis and is a target of fibrates, which have a neuroprotective function by various mechanisms. In this study, we aimed to evaluate the role of the PPAR? agonist, fenofibrate, in the modulation of cleaved caspase-3 immunoreactivity and at the final infarct volume in an experimental ischemia/reperfusion rat model by induced transient proximal middle cerebral artery occlusion. MATERIAL AND METHODS: A total of 65 male Sprague Dawley rats were allocated into 4 groups; sham (n =5), experiment 1 (n=20), experiment 2 (n=20), experiment 3 (n=20). All experiment groups were divided to 3 subgroups in order to evaluate the final infarct volume at 24th hour (n=5) and the immunoreactivity of cleaved caspase -3 at different time periods [at first hour (n=5), at 6th hour (n=5), at 24th hour (n=5)] after transient middle cerebral artery occlusion (MCAo). At the study, the experiment groups (Experiment 1 and Experiment 2) were received the fenofibrate-diet during 14 days before ischemia procedure. All animals were sacrificed at 24th hours after MCAo. Infarction volumes were calculated from 2,3,5,triphenyltetrozolium chloride (TTC)- stained brain sections. RESULTS: We found that fenofibrate-therapy reduced significantly more body weight than the other experiment groups (p < 0.05). At the time intervals, a decrease of immunoreactivity of cleaved caspase-3 was significantly observed with fenofibrate therapy after MCAo (p < 0.05). Chronic fenofibrate treatment before cerebral ischemia significantly reduced the infarction size after MCAo compared with the other groups (respectively; p = 0.011 and p < 0.000). CONCLUSION: Fenofibrate treatment has neuroprotective effects on middle cerebral artery infarcts. PMID- 27509458 TI - A Modified Mini-Pterional (Subfrontal-Suprapterional) Approach to MCA Bifurcation Aneurysms with Minimal Dissection of the Temporal Muscle. AB - There are a number of different surgical approaches in middle cerebral artery (MCA) aneurysm surgery. Evolution from the classical pterional approach towards smaller modified approaches took place over the years. In the present report, we describe a new modified approach in the treatment of MCA aneurysms, which is almost exclusively subfrontal. A modified approach was used on three patients with MCA bifurcation aneurysms. Craniotomy was subfrontal and suprapterional with minimal dissection of the temporal muscle and no drilling of the pterion. In all three cases, after establishing proximal control and dissecting the M1 carefully, retraction of the frontal lobe elevated the sylvian fissure and allowed opening of the fissure. The aneurysm could be identified easily and clips were applied. There was no infection and complete aneurysm clipping was achieved in all 3 patients. The described minimal craniotomy to the MCA through a subfrontal suprapterional approach allows dissection of peripheral MCA bifurcation aneurysms without any problems. PMID- 27509459 TI - Calvarial Reconstruction of Small-Size Skull Defects Performing "8 Cranioplasty" in Children: Surgical Experience, Clinical Results and Treatment Algorithm. AB - AIM: To report our clinical experience, surgical treatment algorithm and technique in the reconstruction of uncomplicated and small-size calvarial defects by performing autologous split-bone grafting technique on anatomical findings and patients" outcome. MATERIAL AND METHODS: We covered the defective calvarial zone without bone (area, 3.8 to 7.5 centimetersquare; median area 4.2 centimetersquare) following the resection of pathological skull region with an inner table of horizontally split adjacent skull site in thirty-six patients (aged between 28 and 125 months; median age, 68.75 months, minimum follow-up 14 months). The donor site, the characteristics of skin incision such as length, shape, location and bone splitting technique were determined based on our treatment algorithm for "8 cranioplasty". Pre- and postoperative clinical outcomes and courses as well as radiological results are documented. RESULTS: Mean follow-up period for all children was 25 months. There was no mortality and 5.55% morbidity (n=2: 1 sterile wound dehiscence and 1 sterile wound discharge). No infected flap was seen and none of the patients required a second surgery. No graft failure, tumor recurrence or residue occurred. CONCLUSION: Almost all of our patients reported good surgical and clinical outcomes with this presented management and surgical algorithm. Autologous split bone grafting technique in small-size skull defects, with its proposed name "8 cranioplasty" is a safe and effective reconstructive procedure due to its short-term surgery, small-size surgical zone, low complication rate, good cosmetic results and cost effectiveness. In addition, our algorithm specified for this procedure is purposive and also saves the surgeon time in the surgical planning stage. PMID- 27509460 TI - Bilateral Thalamic Edema from Coexisting Choroid Plexus Arteriovenous Malformation and Sinus Thrombosis: Case Report. AB - Bilateral thalamic dysfunction secondary to venous congestion may result from either venous sinus thrombosis or high flow arteriovenous malformations or a combination of both. We present a case of bilateral thalamic edema resulting from concomitant choroid plexus arteriovenous malformation (AVM) and straight sinus thrombosis and describe our treatment approach. The patient presented with several weeks of progressive confusion and memory deficits. Magnetic resonance imaging and venography (MRI/ MRV) showed bilateral thalamic T2 hyperintensities and straight sinus thrombosis. Subsequent cerebral angiography revealed a choroid plexus AVM within the right lateral ventricle. The patient underwent surgical resection of the AVM resulting in postoperative resolution of bilateral thalamic edema on MRI and improvement of his confusion and memory deficits. This case demonstrates a rare example of reversible bilateral thalamic edema secondary to venous hypertension from both an AVM and sinus occlusion after appropriate treatment of the AVM. PMID- 27509461 TI - Surgical Strategies and Functional Outcome of Intramedullary Cervicomedullary Ependymoma. AB - AIM: To evaluate the surgical strategies and functional outcomes of intramedullary cervicomedullary ependymoma (ICE). MATERIAL AND METHODS: The authors retrospectively reviewed the clinical and imaging data of 28 ICE patients who underwent surgical resection, including 11 males and 17 females and the average age was 37.9 years (range:11-69 years). The modified McCormick grading system (mMG) was used to evaluate the neurological functions before surgery, at discharge and at long-term follow-up. RESULTS: Gross total resections (GTRs) were performed in 21 patients (75.0%), and subtotal resections (STRs) were achieved in the other 7 patients (25.0%). An ill-defined tumor border was a significant factor leading to STR (p=0.026). At discharge, the mMG improved in 11 patients (39.3%), stabilized in 14 (50.0%), and worsened in 3 (10.7%). The 3 patients with deterioration were all in the STR Group and the neurological deterioration rate was significantly higher in the STR Group than that in the GTR Group (p=0.011). The follow-up period ranged from 9 to 77 months (mean 49.6+/-26.9 months). Two patients (7.1%) had tumor recurrence during this period. The long-term follow-up mMG was improved in 25 patients (89.3%), stabilized in 3 (10.7%), and no one worsened, compared with preoperative mMG. CONCLUSION: GTR of ICE could be achieved in majority of patients, especially for those with well-defined tumor boundaries. GTR lead to a better outcome in the short term after surgery. A favorable functional outcome could be achieved for most ICE patients in the long term. PMID- 27509462 TI - Predictive Role of External Carotid Artery Vasospasm on Cerebral Ischemia After Subarachnoid Hemorrhage: Experimental Study. AB - AIM: Cerebral vasospasm after subarachnoid hemorrhage (SAH) may lead to a devastating neurological outcome by inducing cerebral ischemia. However the role of external carotid artery (ECA) vasospasm has been rarely reported in the literature. The aim of this study was to elucidate the effect of ECA vasospasm on cerebral ischemia related neurodegeneration in the cerebral cortex after SAH. MATERIAL AND METHODS: This study was performed on 23 rabbits, divided into three groups: control (n=5), sham (n=5), and SAH (n=13). Experimental SAH was performed by injecting 0.75 mL auricular arterial homologous blood into the cisterna magna. After three weeks, the animals were decapitated and the common carotid arteries with their external and internal branches and the brains were examined histopathologically. Vasospasm indexes (VSI) of ECAs and internal carotid arteries (ICAs) and degenerated glial cell numbers of temporal cortices (n/mm3) were estimated stereologically and the results were compared statistically. RESULTS: Temporal cortex glial cell density was estimated as 136.950+/-9.257/mm3 in normal rabbits, 131.324+/-7.987/mm3 in sham, 112.320+/-6.112/mm3 in light, and 97.543+/-5.432/mm3 in severe ECA vasospasm. The mean VSI values of ECA of all groups were 1.95+/-0.21, 2.15+/-0.29, 2.95+/-0.65 and 3.12+/-0.276, respectively. Statistical differences between the VSI values of ECA and degenerated neuron densities in temporal cortices were significant (p < 0.005). CONCLUSION: ECA vasospasm was observed to have a more important predictive role on the serious cerebral ischemia and neuronal degeneration after SAH. The mechanism may be related to ischemia of the parasympathetic ganglia of the lower cranial nerves and dorsal root ganglion. PMID- 27509463 TI - Pterional and Unifrontal Approaches for the Microsurgical Resection of Olfactory Groove Meningiomas: Experience with 61 Consecutive Patients. AB - AIM: Olfactory groove meningiomas make up 4 to 13% of meningiomas. The first line treatment of meningiomas is surgery, but the extent and types of approaches advised for olfactory groove meningiomas are diverse, from aggressive skull base approaches to standard or minimally invasive craniotomies and endoscopic approaches. We retrospectively reviewed our series of olfactory groove meningiomas that were operated microsurgically by standard pterional or unifrontal approaches. MATERIAL AND METHODS: Our series of 61 olfactory groove meningioma patients operated through pterional or unifrontal approaches between March 1987 and September 2015 was reviewed and the clinical data, radiological findings, surgical treatment and clinical outcomes of the patients were retrospectively analyzed. RESULTS: Sixty-three craniotomies were performed in total. Pterional and unifrontal approaches were used in 38 (60.3%) and 25 (39.7%) surgical procedures, respectively. Overall, gross total tumor resection was achieved in 59 (93.7%) cases. Complications were seen in 8 cases, and 2 of these patients underwent reoperation. Three of the 4 patients where only subtotal resection could be achieved underwent gamma knife radiosurgery. CONCLUSION: Pterional and unifrontal approaches, which are familiar and standard for neurosurgeons, can accomplish high rates of total resection with acceptable complication and recurrence rates for the treatment of olfactory groove meningiomas. PMID- 27509464 TI - Resveratrol Treatment Prevents Hippocampal Neurodegeneration in a Rodent Model of Traumatic Brain Injury. AB - AIM: Traumatic brain injury (TBI) is a complex process. Increasing evidence has demonstrated that reactive oxygen species contribute to brain injury. Resveratrol (RVT) which exhibits significant antioxidant properties, is neuroprotective against excitotoxicity, ischemia, and hypoxia. The aim of this study was to evaluate the neuroprotective effects of RVT on the hippocampus of a rat model of TBI. MATERIAL AND METHODS: Twenty eight rats were divided into four groups. A moderate degree of head trauma was induced using Feeney"s falling weight technique. Group 1 (control) underwent no intervention or treatment. Head trauma was induced in Group 2 (trauma) and no drug was administered. Head trauma was induced in Group 3 and low-dose RVT (50 mg/kg per day) was injected. In Group 4, high-dose RVT (100 mg/kg per day) was used after head trauma. Brain tissues were extracted immediately after perfusion without damaging the tissues. Histopathological and biochemistry parameters were studied. RESULTS: Brain tissue malondialdehyde (MDA) levels in the trauma group were significantly higher than those in the control, lowdose RVT-treated, and high-dose-RVT-treated groups. The superoxide dismutase (SOD) levels in the control group were significantly higher than those in the trauma, low-dose RVT-treated, and high-dose RVT-treated groups. Glutathione peroxidase (GSH-Px) levels in the control group were significantly higher than those in the trauma and low-dose RVT-treated groups. The level of oxidative deoxyribonucleic acid (DNA) damage (8-OHdG/106 dG) in the trauma group was higher than that in the control group, low-dose RVT-treated, and high-dose RVT-treated groups. CONCLUSION: Resveratrol has a healing effect on neurons after TBI. PMID- 27509465 TI - Does Surgery for Adult Spinal Deformity Affect the Cognitive Abilities in Patients over 50 Years of Age? AB - AIM: To analyze the cognitive abilities of older patients undergoing spinal deformity surgery so as to understand whether adult spinal deformity (ASD) surgery is associated with postoperative cognitive malfunction. MATERIAL AND METHODS: A prospective longitudinal study was performed on surgical patients older than 50 years, enrolled in a prospective multicenter database. Mini-mental state examination (MMSE) was performed to assess cognitive function in addition to the health-related quality of life (HRQOL) tests; (SF-36, ODI and SRS-22) at the pre-operative, post-operative 6 weeks and 6 months points. Demographics, preoperative health status, co-morbidities and surgical characteristics were also analyzed. Descriptive statistics and repeated measures of variance analysis were performed. RESULTS: A total of 90 patients with a mean age of 67.4+/-8.2 years were enrolled in the study; all had MMSE evaluations at 6 weeks follow-up and 58 patients had both 6 weeks and 6 months follow-up. Average (SD) surgical time, estimated blood loss, number of levels fused and hospital stay were 240.1 (111.9) minutes, 1621.2 (1058.7) ml, 11.2 (4.4) levels and 14.2 (11.45) days, respectively. On analysis, a slight increase in mean MMSE score (p > 0.05) between time points was found despite decreases of > 2 points (3 or 4) in 6 patients (6.7%) at both time points. CONCLUSION: Although ASD surgery in older patients is recognized as challenging, this study suggests that it is not necessarily associated with a significant deterioration in the cognitive abilities of patients undergoing surgery. This may be due to the relatively minor influence of ASD itself on the cognitive abilities of the patients involved as well as to the relatively stable hemodynamic conditions obtainable during modern ASD surgery. PMID- 27509466 TI - Endoscopic ultrasound-guided gastrojejunostomy with a Nagi stent for relief of jejunal loop obstruction following hepaticojejunostomy. PMID- 27509467 TI - Unsuspected cervical osteophytes and complex endoscopy: there is cause for concern! PMID- 27509468 TI - Adenomyoma of the common bile duct: a rare lesion diagnosed and treated by ERCP. PMID- 27509469 TI - Endoscopic gastroesophageal mucosal flap valvuloplasty with anti-reflux potential. PMID- 27509470 TI - The use of stand-alone fully covered self-expandable metallic stents for drainage of walled-off necrosis or pseudocyst may lead to poor results. PMID- 27509471 TI - Proximal esophageal cancer missed during esophagogastroduodenoscopy: should the detection of an inlet patch be added to the quality criteria for upper gastrointestinal endoscopy? PMID- 27509472 TI - A new method of polyglycolic acid sheet placement in the stomach after endoscopic submucosal dissection. PMID- 27509473 TI - Endoscopic ultrasound-guided pancreaticogastrostomy using a lumen-apposing metal stent plus a double-pigtail plastic stent. PMID- 27509474 TI - An unforeseeable adverse event during ERCP. PMID- 27509475 TI - Single-operator pancreatoscopy with electrohydraulic lithotripsy of large pancreatic duct stones in post-Whipple anatomy. PMID- 27509476 TI - Fibronectin adsorption on osteoconductive hydroxyapatite and non-osteoconductive alpha-alumina. AB - The osteoconductivity mechanism of hydroxyapatite (HAp) has not been elucidated. It is hypothesized that specific proteins adsorb on HAp, promoting its osteoconductivity. To verify this hypothesis, we compared the adsorption behavior of fibronectin (Fn) on HAp powder and on alpha-alumina (alpha-Al2O3) powder, a material with no osteoconductivity. More Fn adsorbed on alpha-Al2O3 than on HAp, irrespective of the Fn concentration, and there was no significant difference in the secondary structure of Fn adsorbed on HAp and alpha-Al2O3. Further, it is possible that Fn did not adsorb on HAp and alpha-Al2O3 through the Arg-Gry-Asp motif of Fn. The amount of Fn adsorbed on HAp oriented to the a(b)-axis with very little decrease in carbonate and the adsorbed Fn had a smaller alpha-helix structure content. The results suggest that the secondary and/or higher-order structure rather than the amount of adsorbed Fn might affect the osteoconductivity of HAp, which might be electrostatically controlled by the crystal face orientation and/or carbonate content of HAp, although this should be confirmed by a cell culture test in the future. PMID- 27509478 TI - Pharmacogenetics of efavirenz discontinuation for reported central nervous system symptoms appears to differ by race. AB - BACKGROUND: Efavirenz frequently causes central nervous system (CNS) symptoms. We evaluated genetic associations with efavirenz discontinuation for CNS symptoms within 12 months of treatment initiation. METHODS: Patients had initiated efavirenz-containing regimens at an HIV primary care clinic in the Southeastern United States and had at least 12 months of follow-up data. Polymorphisms in CYP2B6 and CYP2A6 defined efavirenz metabolizer categories. Genome-wide genotyping enabled adjustment for population stratification. RESULTS: Among 563 evaluable patients, 99 (17.5%) discontinued efavirenz within 12 months, 29 (5.1%) for CNS symptoms. The hazard ratio (HR) for efavirenz discontinuation for CNS symptoms in slow versus extensive metabolizers was 4.9 [95% confidence interval (CI): 1.9-12.4; P=0.001]. This HR in Whites was 6.5 (95% CI: 2.3-18.8; P=0.001) and 2.6 in Blacks (95% CI: 0.5-14.1; P=0.27). Considering only slow metabolizers, the HR in Whites versus Blacks was 3.1 (95% CI: 0.9-11.0; P=0.081). The positive predictive value of slow metabolizer genotypes for efavirenz discontinuation was 27% in Whites and 11% in Blacks. CONCLUSION: Slow metabolizer genotypes were associated significantly with efavirenz discontinuation for reported CNS symptoms. This association was considerably stronger in Whites than in Blacks. PMID- 27509480 TI - Ionic Liquid-Assisted Electropolymerization for Lithographical Perfluorocarbon Deposition and Hydrophobic Patterning. AB - We developed a novel approach for hydrophobic patterning: combining the photolithography technique with ionic-liquid (IL)-based electropolymerization to fabricate a hydrophobic pattern. Perfluoro-functionalized 3,4 ethylenedioxythiophene (EDOT-F) dispersed in ILs was directly electropolymerized on substrates, which were patterned in advance with positive photoresists. The positive photoresists did not dissolve in ionic liquids during the electropolymerization process, and the poly(EDOT-F) film created hydrophobic domains, which resulted in hydrophobic patterning. This approach provides desired patterns with a lateral resolution consistent with the mask for photolithography. Two kinds of modified indium-tin-oxide-coated glass (ITO-glass) substrates were used to demonstrate the feasibility of process for creating a hydrophobic pattern: ITO-glass substrates coated with nanostructured PEDOT, and the same substrates coated with Au nanoparticles. By confining water droplets on these two patterned substrates to form droplet arrays, we demonstrated two potential applications: multiple droplet-type electrochemical cells and surface-enhanced Raman scattering platforms. In addition, we also applied this approach to create hydrophobic patterning on ITO-coated polyethylene terephthalate (ITO-PET) substrates. The droplet arrays remained well-organized on the ITO-PET substrates even when the substrates were bent. Our work successfully introduced ILs into the photolithography process, implying great potential for these green solvents. PMID- 27509479 TI - Mild leg length discrepancy affects lower limbs, pelvis and trunk biomechanics of individuals with knee osteoarthritis during gait. AB - BACKGROUND: Leg length discrepancy greater than 1cm increases odds of progressive knee osteoarthritis in the shorter limb. METHODS: Biomechanical data of 15 knee osteoarthritis participants were collected while they walked under two conditions: (1) control - wearing thick sandals; (2) short limb - wearing a thin sandal on the osteoarthritic limb and a thick sandal on the contralateral limb. The thick and thin sandals had 1.45cm of thickness difference. The knee osteoarthritis limb was analyzed for both conditions. Ankle, knee, hip, pelvis and trunk kinematics and moments were measured with a motion and force capture system. Principal component analysis and mean hypothesis' tests were used to compare the conditions. FINDINGS: The short limb condition reduced rearfoot plantarflexion in loading response and increased plantarflexion in late stance (p<0.001), increased ankle dorsiflexion moment (p=0.003), increased knee flexion angle in loading response and delayed knee flexion in late stance (p=0.001), increased knee extension moment in loading response and increased knee flexion moment in terminal stance (p=0.023), reduced hip extension moment in early stance and reduced hip flexion moment in late stance (p<0.001), reduced knee adduction moment (p=0.015), reduced hip adduction angle (p=0.001) and moment (p=0.012) and increased pelvic (p=0.023) and trunk (p=0.001) external rotation. INTERPRETATION: Mild leg length discrepancy affects the entire kinetic chain of individuals with knee osteoarthritis during gait, increasing knee sagittal plane loading, which helps to explain why mild leg length discrepancy accelerates knee osteoarthritis progression. Mild leg length discrepancy should not be overlooked in knee osteoarthritis individuals. PMID- 27509481 TI - Risk factors for pancreatitis after posterior spinal fusion in children with cerebral palsy. AB - This study reports on the prevalence and risk factors of acute pancreatitis after posterior spinal fusion for cerebral palsy scoliosis. Pancreatitis diagnosis was based on elevated amylase or lipase above three times the upper normal limit. Perioperative data were compared between patients with and without pancreatitis. We included 300 patients; 55% developed acute pancreatitis. Gastrostomy dependence was more common in the pancreatitis group (P=0.048). Perioperative data were similar between groups. Patients with pancreatitis had longer duration of hospitalization (19 vs. 13 days, P<0.001). Acute pancreatitis is common after cerebral palsy scoliosis surgery. Gastrostomy dependence increases its risk. Although no mortality was reported, hospital stay was longer. PMID- 27509482 TI - Bilateral femoral neck fractures associated with complex pelvic ring injuries in a pediatric patient: a case report. AB - : Femoral neck and pelvic fractures are rarely encountered in the pediatric population secondary to the resilient nature of the immature skeleton. Both fracture types usually result from high-energy blunt trauma including motor vehicle collisions, motor vehicle-pedestrian accidents, and falls from height. Considerable studies have been published on the natural history, management, and complications of pediatric pelvis and femoral neck fractures. However, few case reports have documented both fracture types in the same patient. Management of concomitant injuries presents unique challenges both for operative stabilization and for clinical postoperative care. After appropriate consent was obtained, a thorough review was performed of the patient's hospital records and imaging history. The senior author of the report also provided insight into the management of the patient's initial injuries and subsequent complications. Our case involves a 4-year-old female who was overrun by an all-terrain vehicle. Her orthopedic injuries included a nondisplaced Delbet type 3 fracture of the right femoral neck, a completely displaced Delbet type 3 fracture of the left femoral neck, bilateral sacroiliac fracture-dislocations, severe comminution of her left pubic rami, and a free-floating right pubic rami segment spanning from the triradiate cartilage to the pubic symphysis with severe rotational deformity. Her postoperative recovery was complicated by refracture of her left femoral neck (Delbet type 1), left hip osteomyelitis, and left femoral head avascular necrosis. The salient features of her operative management, subsequent complications, and functional recovery are described in this report. Cases of bilateral femoral neck fractures and multiple pelvic fractures in pediatric patients are sparsely documented in the literature because of their infrequent occurrence. Pediatric pelvic fractures typically do well with conservative treatment secondary to the incredible remodeling ability of the immature pelvis. Femoral neck fractures, in contrast, are highly associated with complications including coxa vara, nonunion, infection, physeal closure, and avascular necrosis. This case report documents two rare fracture types in the same patient and describes the challenges encountered throughout the duration of her recovery. LEVEL OF EVIDENCE: Level V, Case report. PMID- 27509483 TI - Recurrent Bacille Calmette-Guerin osteomyelitis with ankle joint involvement in a toddler: gait analysis and rehabilitation experience. AB - Bacille Calmette-Guerin (BCG) osteomyelitis is a rare complication after vaccination. This article reports on a 1-year-old immunocompetent boy with recurrent BCG osteomyelitis involving the distal tibia who presented with a limping gait from the beginning of toddling. The lesion was located in the metaphysis and crossed the growth plate to the epiphysis, causing concern for ambulation. After surgery, he was initiated on an individualized, intense rehabilitation program and achieved a good functional recovery. Rehabilitation programs with gait analyses provide effective therapeutic and monitoring methods for toddlers recovering from BCG osteomyelitis. PMID- 27509484 TI - Clinical application of back surface topography by means of structured light in the screening of idiopathic scoliosis. AB - We present the results of the clinical validity in the screening of idiopathic scoliosis with a nonharming method of back surface topography by means of structured light projection. A total of 155 patients were evaluated (mean age 13.3 years). They were divided into two groups: pathologic patients (scoliosis) and nonpathologic patients (control and asymmetries). An analytical case-control study was carried out. Our topographic method obtained 92% sensitivity and 74% specificity as a screening test in identifying patients with scoliosis (P=0.05). We could quantify the vertebral deformity of scoliosis in the three spatial planes by means of three topographic variables, Horizontal Plane Deformity Index, Posterior Trunk Symmetry Index and Columnar Profile, and to elaborate a combined screening algorithm with good reliability parameters. PMID- 27509485 TI - Spontaneous healing of fractures and osteotomy within intercalary allograft reconstruction after distal femur osteosarcoma resection in a child. AB - Intercalary biologic reconstructions using allogenic bone grafts remain a useful option in orthopedic oncology; however, these reconstructions are prone to fractures, and treatment is usually required involving surgical interventions. Biologic activity of the implanted allografts remains minimal, but in some cases, spontaneous healing of the graft may occur. We present a report and discussion on two fractures and corrective osteotomy within the implanted allograft that healed with abundant callus without the need for additional surgery. In selected patients, allograft incorporation can be completed to a degree allowing for its biologic activity and spontaneous healing of fractures or osteotomy. PMID- 27509486 TI - Enrichment of enzymatically mineralized gellan gum hydrogels with phlorotannin rich Ecklonia cava extract Seanol((r)) to endow antibacterial properties and promote mineralization. AB - Hydrogels offer several advantages as biomaterials for bone regeneration, including ease of incorporation of soluble substances such as mineralization promoting enzymes and antibacterial agents. Mineralization with calcium phosphate (CaP) increases bioactivity, while antibacterial activity reduces the risk of infection. Here, gellan gum (GG) hydrogels were enriched with alkaline phosphatase (ALP) and/or Seanol((r)), a seaweed extract rich in phlorotannins (brown algae-derived polyphenols), to induce mineralization with CaP and increase antibacterial activity, respectively. The sample groups were unmineralized hydrogels, denoted as GG, GG/ALP, GG/Seanol and GG/Seanol/ALP, and hydrogels incubated in mineralization medium (0.1 M calcium glycerophosphate), denoted as GG/ALP_min, GG/Seanol_min and GG/Seanol/ALP_min. Seanol((r)) enhanced mineralization with CaP and also increased compressive modulus. Seanol((r)) and ALP interacted in a non-covalent manner. Release of Seanol((r)) occurred in a burst phase and was impeded by ALP-mediated mineralization. Groups GG/Seanol and GG/ALP/Seanol exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus. GG/Seanol/ALP_min, but not GG/Seanol_min, retained some antibacterial activity. Eluates taken from groups GG/ALP_min, GG/Seanol_min and GG/ALP/Seanol_min displayed comparable cytotoxicity towards MG-63 osteoblast-like cells. These results suggest that enrichment of hydrogel biomaterials with phlorotannin-rich extracts is a promising strategy to increase mineralizability and antibacterial activity. PMID- 27509487 TI - Residential proximity to environmental pollution sources and risk of rare tumors in children. AB - BACKGROUND: Few epidemiologic studies have explored risk factors for rare tumors in children, and the role of environmental factors needs to be assessed. OBJECTIVES: To ascertain the effect of residential proximity to both industrial and urban areas on childhood cancer risk, taking industrial groups into account. METHODS: We conducted a population-based case-control study of five childhood cancers in Spain (retinoblastoma, hepatic tumors, soft tissue sarcomas, germ cell tumors, and other epithelial neoplasms/melanomas), including 557 incident cases from the Spanish Registry of Childhood Tumors (period 1996-2011), and 3342 controls individually matched by year of birth, sex, and region of residence. Distances were computed from the residences to the 1271 industries and the 30 urban areas with >=75,000 inhabitants located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance to industrial and urban pollution sources were calculated, with adjustment for matching variables and socioeconomic confounders. RESULTS: Children living near industrial and urban areas as a whole showed no excess risk for any of the tumors analyzed. However, isolated statistical associations (OR; 95%CI) were found between retinoblastoma and proximity to industries involved in glass and mineral fibers (2.49; 1.01-6.12 at 3km) and organic chemical industries (2.54; 1.10-5.90 at 2km). Moreover, soft tissue sarcomas registered the lower risks in the environs of industries as a whole (0.59; 0.38-0.93 at 4km). CONCLUSIONS: We have found isolated statistical associations between retinoblastoma and proximity to industries involved in glass and mineral fibers and organic chemical industries. PMID- 27509488 TI - Diversity of Human and Macaque Airway Immune Cells at Baseline and during Tuberculosis Infection. AB - Immune cells of the distal airways serve as "first responders" of host immunity to the airborne pathogen Mycobacterium tuberculosis (Mtb). Mtb infection of cynomolgus macaques recapitulates the range of human outcomes from clinically silent latent tuberculosis infection (LTBI) to active tuberculosis of various degrees of severity. To further advance the application of this model to human studies, we compared profiles of bronchoalveolar lavage (BAL) cells of humans and cynomolgus macaques before and after Mtb infection. A simple gating strategy effectively defined BAL T-cell and phagocyte populations in both species. BAL from Mtb-naive humans and macaques showed similar differential cell counts. BAL T cells of macaques were composed of fewer CD4+cells but more CD8+ and CD4+CD8+ double-positive cells than were BAL T cells of humans. The most common mononuclear phagocyte population in BAL of both species displayed coexpression of HLA-DR, CD206, CD11b, and CD11c; however, multiple phagocyte subsets displaying only some of these markers were observed as well. Macaques with LTBI displayed a marked BAL lymphocytosis that was not observed in humans with LTBI. In macaques, the prevalence of specific mononuclear phagocyte subsets in baseline BAL correlated with ultimate outcomes of Mtb infection (i.e., LTBI versus active disease). Overall, these findings demonstrate the comparability of studies of pulmonary immunity to Mtb in humans and macaques. They also indicate a previously undescribed complexity of airway mononuclear phagocyte populations that suggests further lines of investigation relevant to understanding the mechanisms of both protection from and susceptibility to the development of active tuberculosis within the lung. PMID- 27509489 TI - Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists. AB - Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool), and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl d-Aspartate (NMDA) receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i) a stereoselective cyclocondensation of (S)- or (R)-tryptophanol with appropriate racemic delta oxoesters; (ii) a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson's disease). This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors. PMID- 27509490 TI - Glutamine Synthetase Drugability beyond Its Active Site: Exploring Oligomerization Interfaces and Pockets. AB - BACKGROUND: Glutamine synthetase (GS) is a crucial enzyme to the nitrogen cycle with great commercial and pharmaceutical value. Current inhibitors target the active site, affecting GS activity indiscriminately in all organisms. As the active site is located at the interface between two monomers, the protein-protein interface (PPI) of GSs gains a new role, by providing new targets for enzyme inhibition. Exploring GSs PPI could allow for the development of inhibitors selective for specific organisms. Here we map the PPI of three GSs-human (hsGS), maize (zmGS) and Mycobacterium tuberculosis (mtGS)-and unravel new drugable pockets. METHODS: The PPI binding free energy coming from key residues on three GSs from different organisms were mapped by computational alanine scan mutagenesis, applying a multiple dielectric constant MM-PBSA methodology. The most relevant residues for binding are referred as hot-spots. Drugable pockets on GS were detected with the Fpocket software. RESULTS AND CONCLUSIONS: A total of 23, 19 and 30 hot-spots were identified on hsGS, zmGS and mtGS PPI. Even possessing differences in the hot-spots, hsGS and zmGS PPI are overall very similar. On the other hand, mtGS PPI differs greatly from hsGS and zmGS PPI. A novel drugable pocket was detected on the mtGS PPI. It seems particularly promising for the development of selective anti-tuberculosis drugs given its location on a PPI region that is highly populated with hot-spots and is completely different from the hsGS and zmGS PPIs. Drugs targeting this pockets should be inactive on eukaryotic GS II enzymes. PMID- 27509491 TI - New Sesquiterpenenoids from Ainsliaea yunnanensis. AB - Investigation of the ethanol extract of the whole plant of Ainsliaea yunnanensis led to the isolation of four new dimeric sesquiterpene lactones, ainsliadimer F-I (1-4), together with seven known dimeric sesquiterpene lactones (5-11) and ten sesquiterpenes (12-21). Their structures were elucidated by spectroscopic methods. The relative stereochemistry of ainsliadimer F was further confirmed by single crystal X-ray diffraction analysis. Compounds 1-21 were tested for the inhibition of nuclear factor kappa B (NF-kappaB) in the 293-NF-kappaB-luciferase reporter cell line induced by lipopolysaccharide (LPS), and Compounds 5, 18, 20 and 21 were further tested for the production of TNF-alpha, IL-1beta, IL-6 and IL 10 in RAW 264.7 macrophages induced by LPS. Compounds 5, 18, 20 and 21 exhibited significant activity in anti-inflammatory activity assays. PMID- 27509492 TI - MicroRNA-155 Mediates Augmented CD40 Expression in Bone Marrow Derived Plasmacytoid Dendritic Cells in Symptomatic Lupus-Prone NZB/W F1 Mice. AB - Systemic lupus erythematosus (SLE) is a chronic multi-organ autoimmune disease characterized by hyperactivated immune responses to self-antigens and persistent systemic inflammation. Previously, we reported abnormalities in circulating and bone marrow (BM)-derived plasmacytoid dendritic cells (pDCs) from SLE patients. Here, we aim to seek for potential regulators that mediate functional aberrations of pDCs in SLE. BM-derived pDCs from NZB/W F1 mice before and after the disease onset were compared for toll-like receptor (TLR) induced responses and microRNA profile changes. While pDCs derived from symptomatic mice were phenotypically comparable to pre-symptomatic ones, functionally they exhibited hypersensitivity to TLR7 but not TLR9 stimulation, as represented by the elevated upregulation of CD40, CD86 and MHC class II molecules upon R837 stimulation. Upregulated induction of miR-155 in symptomatic pDCs following TLR7 stimulation was observed. Transfection of miR-155 mimics in pre-symptomatic pDCs induced an augmented expression of Cd40, which is consistent with the increased CD40 expression in symptomatic pDCs. Overall, our results provide evidence for miR-155-mediated regulation in pDC functional abnormalities in SLE. Findings from this study contribute to a better understanding of SLE pathogenesis and ignite future interests in evaluating the molecular regulation in autoimmunity. PMID- 27509493 TI - Zeb1 Is a Potential Regulator of Six2 in the Proliferation, Apoptosis and Migration of Metanephric Mesenchyme Cells. AB - Nephron progenitor cells surround around the ureteric bud tips (UB) and inductively interact with the UB to originate nephrons, the basic units of renal function. This process is determined by the internal balance between self-renewal and consumption of the nephron progenitor cells, which is depending on the complicated regulation networks. It has been reported that Zeb1 regulates the proliferation of mesenchymal cells in mouse embryos. However, the role of Zeb1 in nephrons generation is not clear, especially in metanephric mesenchyme (MM). Here, we detected cell proliferation, apoptosis and migration in MM cells by EdU assay, flow cytometry assay and wound healing assay, respectively. Meanwhile, Western and RT-PCR were used to measure the expression level of Zeb1 and Six2 in MM cells and developing kidney. Besides, the dual-luciferase assay was conducted to study the molecular relationship between Zeb1 and Six2. We found that knock down of Zeb1 decreased cell proliferation, migration and promoted cell apoptosis in MM cells and Zeb1 overexpression leaded to the opposite data. Western-blot and RT-PCR results showed that knock-down of Zeb1 decreased the expression of Six2 in MM cells and Zeb1 overexpression contributed to the opposite results. Similarly, Zeb1 promoted Six2 promoter reporter activity in luciferase assays. However, double knock-down of Zeb1 and Six2 did not enhance the apoptosis of MM cells compared with control cells. Nevertheless, double silence of Zeb1 and Six2 repressed cell proliferation. In addition, we also found that Zeb1 and Six2 had an identical pattern in distinct developing phases of embryonic kidney. These results indicated that there may exist a complicated regulation network between Six2 and Zeb1. Together, we demonstrate Zeb1 promotes proliferation and apoptosis and inhibits the migration of MM cells, in association with Six2. PMID- 27509495 TI - A Wireless Sensor Network with Soft Computing Localization Techniques for Track Cycling Applications. AB - In this paper, we propose two soft computing localization techniques for wireless sensor networks (WSNs). The two techniques, Neural Fuzzy Inference System (ANFIS) and Artificial Neural Network (ANN), focus on a range-based localization method which relies on the measurement of the received signal strength indicator (RSSI) from the three ZigBee anchor nodes distributed throughout the track cycling field. The soft computing techniques aim to estimate the distance between bicycles moving on the cycle track for outdoor and indoor velodromes. In the first approach the ANFIS was considered, whereas in the second approach the ANN was hybridized individually with three optimization algorithms, namely Particle Swarm Optimization (PSO), Gravitational Search Algorithm (GSA), and Backtracking Search Algorithm (BSA). The results revealed that the hybrid GSA-ANN outperforms the other methods adopted in this paper in terms of accuracy localization and distance estimation accuracy. The hybrid GSA-ANN achieves a mean absolute distance estimation error of 0.02 m and 0.2 m for outdoor and indoor velodromes, respectively. PMID- 27509494 TI - beta-Ketoacyl-acyl Carrier Protein Synthase I (KASI) Plays Crucial Roles in the Plant Growth and Fatty Acids Synthesis in Tobacco. AB - Fatty acids serve many functions in plants, but the effects of some key genes involved in fatty acids biosynthesis on plants growth and development are not well understood yet. To understand the functions of 3-ketoacyl-acyl-carrier protein synthase I (KASI) in tobacco, we isolated two KASI homologs, which we have designated NtKASI-1 and NtKASI-2. Expression analysis showed that these two KASI genes were transcribed constitutively in all tissues examined. Over expression of NtKASI-1 in tobacco changed the fatty acid content in leaves, whereas over-expressed lines of NtKASI-2 exhibited distinct phenotypic features such as slightly variegated leaves and reduction of the fatty acid content in leaves, similar to the silencing plants of NtKASI-1 gene. Interestingly, the silencing of NtKASI-2 gene had no discernibly altered phenotypes compared to wild type. The double silencing plants of these two genes enhanced the phenotypic changes during vegetative and reproductive growth compared to wild type. These results uncovered that these two KASI genes had the partially functional redundancy, and that the KASI genes played a key role in regulating fatty acids synthesis and in mediating plant growth and development in tobacco. PMID- 27509496 TI - Novel Low-Cost Sensor for Human Bite Force Measurement. AB - This paper presents the design and development of a low cost and reliable maximal voluntary bite force sensor which can be manufactured in-house by using an acrylic laser cutting machine. The sensor has been designed for ease of fabrication, assembly, calibration, and safe use. The sensor is capable of use within an hour of commencing production, allowing for rapid prototyping/modifications and practical implementation. The measured data shows a good linear relationship between the applied force and the electrical resistance of the sensor. The output signal has low drift, excellent repeatability, and a large measurable range of 0 to 700 N. A high signal-to-noise response to human bite forces was observed, indicating the high potential of the proposed sensor for human bite force measurement. PMID- 27509497 TI - Spatiotemporal Interpolation for Environmental Modelling. AB - A variation of the reduction-based approach to spatiotemporal interpolation (STI), in which time is treated independently from the spatial dimensions, is proposed in this paper. We reviewed and compared three widely-used spatial interpolation techniques: ordinary kriging, inverse distance weighting and the triangular irregular network. We also proposed a new distribution-based distance weighting (DDW) spatial interpolation method. In this study, we utilised one year of Tasmania's South Esk Hydrology model developed by CSIRO. Root mean squared error statistical methods were performed for performance evaluations. Our results show that the proposed reduction approach is superior to the extension approach to STI. However, the proposed DDW provides little benefit compared to the conventional inverse distance weighting (IDW) method. We suggest that the improved IDW technique, with the reduction approach used for the temporal dimension, is the optimal combination for large-scale spatiotemporal interpolation within environmental modelling applications. PMID- 27509498 TI - A Fluidically Tunable Metasurface Absorber for Flexible Large-Scale Wireless Ethanol Sensor Applications. AB - In this paper, a novel flexible tunable metasurface absorber is proposed for large-scale remote ethanol sensor applications. The proposed metasurface absorber consists of periodic split-ring-cross resonators (SRCRs) and microfluidic channels. The SRCR patterns are inkjet-printed on paper using silver nanoparticle inks. The microfluidic channels are laser-etched on polydimethylsiloxane (PDMS) material. The proposed absorber can detect changes in the effective permittivity for different liquids. Therefore, the absorber can be used for a remote chemical sensor by detecting changes in the resonant frequencies. The performance of the proposed absorber is demonstrated with full-wave simulation and measurement results. The experimental results show the resonant frequency increases from 8.9 GHz to 10.04 GHz when the concentration of ethanol is changed from 0% to 100%. In addition, the proposed absorber shows linear frequency shift from 20% to 80% of the different concentrations of ethanol. PMID- 27509499 TI - Stochastic Modeling and Analysis of Multiple Nonlinear Accelerated Degradation Processes through Information Fusion. AB - Accelerated degradation testing (ADT) is an efficient technique for evaluating the lifetime of a highly reliable product whose underlying failure process may be traced by the degradation of the product's performance parameters with time. However, most research on ADT mainly focuses on a single performance parameter. In reality, the performance of a modern product is usually characterized by multiple parameters, and the degradation paths are usually nonlinear. To address such problems, this paper develops a new s-dependent nonlinear ADT model for products with multiple performance parameters using a general Wiener process and copulas. The general Wiener process models the nonlinear ADT data, and the dependency among different degradation measures is analyzed using the copula method. An engineering case study on a tuner's ADT data is conducted to demonstrate the effectiveness of the proposed method. The results illustrate that the proposed method is quite effective in estimating the lifetime of a product with s-dependent performance parameters. PMID- 27509500 TI - Design and Fabrication of Double-Focused Ultrasound Transducers to Achieve Tight Focusing. AB - Beauty treatment for skin requires a high-intensity focused ultrasound (HIFU) transducer to generate coagulative necrosis in a small focal volume (e.g., 1 mm3) placed at a shallow depth (3-4.5 mm from the skin surface). For this, it is desirable to make the F-number as small as possible under the largest possible aperture in order to generate ultrasound energy high enough to induce tissue coagulation in such a small focal volume. However, satisfying both conditions at the same time is demanding. To meet the requirements, this paper, therefore, proposes a double-focusing technique, in which the aperture of an ultrasound transducer is spherically shaped for initial focusing and an acoustic lens is used to finally focus ultrasound on a target depth of treatment; it is possible to achieve the F-number of unity or less while keeping the aperture of a transducer as large as possible. In accordance with the proposed method, we designed and fabricated a 7-MHz double-focused ultrasound transducer. The experimental results demonstrated that the fabricated double-focused transducer had a focal length of 10.2 mm reduced from an initial focal length of 15.2 mm and, thus, the F-number changed from 1.52 to 1.02. Based on the results, we concluded that the proposed double-focusing method is suitable to decrease F number while maintaining a large aperture size. PMID- 27509501 TI - Implementation and Analysis of ISM 2.4 GHz Wireless Sensor Network Systems in Judo Training Venues. AB - In this work, the performance of ISM 2.4 GHz Wireless Sensor Networks (WSNs) deployed in judo training venues is analyzed. Judo is a very popular martial art, which is practiced by thousands of people not only at the competition level, but also as part of physical education programs at different school levels. There is a great variety of judo training venues, and each one has specific morphological aspects, making them unique scenarios in terms of radio propagation due to the presence of furniture, columns, equipment and the presence of human beings, which is a major issue as the person density within this kind of scenarios could be high. Another key aspect is the electromagnetic interference created by other wireless systems, such as WiFi or other WSNs, which make the radio planning a complex task in terms of coexistence. In order to analyze the impact of these features on the radio propagation and the performance of WSNs, an in-house developed 3D ray launching algorithm has been used. The obtained simulation results have been validated with a measurement campaign carried out in the sport facilities of the Public University of Navarre. The analysis is completed with the inclusion of an application designed to monitor biological constants of judokas, aimed to improve their training procedures. The application, that allows the simultaneous monitoring of multiple judokas (collective workouts) minimizing the efforts of the coach and medical supervisor, is based on commercial off-the shelf products. The presented assessment of the presence of interfering wireless systems and the presence of human beings within judo training venues shows that an in-depth radio planning is required as these issues can have a great impact in the overall performance of a ISM 2.4 GHz WSN, affecting negatively the potential applications supported by wireless channel. PMID- 27509502 TI - Comparative Study of Two Different TiO2 Film Sensors on Response to H2 under UV Light and Room Temperature. AB - An anatase TiO2 film sensor was prepared by a facile in-situ method on the interdigitated Au electrode deposited on the alumina substrate. The structure, morphology and the optical properties of the in-situ TiO2 film sensor were characterized by X-ray diffraction, Scanning Electron Microscopy, and UV-vis diffuse reflectance spectra. The photo-assisted gas sensitivities of the prepared film towards H2 gas were evaluated at room temperature in N2 and synthetic air atmospheres. As compared to TiO2 film sensor prepared by drop-coating method, this in-situ TiO2 film sensor exhibited a more compact structure composed of uniform TiO2 microspheres as well as a better gas sensitivity towards H2 under UV irradiation, especially in synthetic air. The photo-electrochemical measurements suggest that these improvements may be associated with the efficient charge transfer in the TiO2 interface induced by the TiO2 microsphere structure. This study might offer a feasible approach to develop photo-assisted gas sensors at ambient temperature. PMID- 27509503 TI - Analysis of the Bias on the Beidou GEO Multipath Combinations. AB - The Beidou navigation satellite system is a very important sensor for positioning in the Asia-Pacific region. The Beidou inclined geosynchronous orbit (IGSO) and medium Earth orbit (MEO) satellites have been analysed in some studies previously conducted by other researchers; this paper seeks to gain more insight regarding the geostationary earth orbit (GEO) satellites. Employing correlation analysis, Fourier transformation and wavelet decomposition, we validate whether there is a systematic bias in their multipath combinations. These biases can be observed clearly in satellites C01, C02 and C04 and have a great correlation with time series instead of elevation, being significantly different from those of the Beidou IGSO and MEO satellites. We propose a correction model to mitigate this bias based on its daily periodicity characteristic. After the model has been applied, the performance of the positioning estimations of the eight stations distributed in the Asia-Pacific region is evaluated and compared. The results show that residuals of multipath series behaves random noise; for the single point positioning (SPP) and precise point positioning (PPP) approaches, the positioning accuracy in the upward direction can be improved by 8 cm and 6 mm, respectively, and by 2 cm and 4 mm, respectively, for the horizontal component. PMID- 27509504 TI - Reversed Three-Dimensional Visible Light Indoor Positioning Utilizing Annular Receivers with Multi-Photodiodes. AB - Exploiting the increasingly wide use of light emitting diodes (LEDs) lighting, in this paper we propose a reversed indoor positioning system (IPS) based on LED visible light communication (VLC) in order to improve indoor positioning accuracy. Unlike other VLC positioning systems, we employ two annular receivers with multi-photodiodes installed on the ceiling to locate the persons who carry LEDs. The basic idea is using multi-photodiodes to calculate the angle while using the received signal strength (RSS) method to calculate the distance. The experiment results show that the effective positioning range of the proposed system is 1.8 m when the distance between two receivers is 1.2 m. Moreover, a positioning error less than 0.2 m can be achieved under the condition that the radius of the PIN circle is between 0.16 m and 0.2 m, and the distance of the transmitter-receiver plane is less than 1.8 m, which will be effective in practice. PMID- 27509505 TI - A Novel Cloud-Based Service Robotics Application to Data Center Environmental Monitoring. AB - This work presents a robotic application aimed at performing environmental monitoring in data centers. Due to the high energy density managed in data centers, environmental monitoring is crucial for controlling air temperature and humidity throughout the whole environment, in order to improve power efficiency, avoid hardware failures and maximize the life cycle of IT devices. State of the art solutions for data center monitoring are nowadays based on environmental sensor networks, which continuously collect temperature and humidity data. These solutions are still expensive and do not scale well in large environments. This paper presents an alternative to environmental sensor networks that relies on autonomous mobile robots equipped with environmental sensors. The robots are controlled by a centralized cloud robotics platform that enables autonomous navigation and provides a remote client user interface for system management. From the user point of view, our solution simulates an environmental sensor network. The system can easily be reconfigured in order to adapt to management requirements and changes in the layout of the data center. For this reason, it is called the virtual sensor network. This paper discusses the implementation choices with regards to the particular requirements of the application and presents and discusses data collected during a long-term experiment in a real scenario. PMID- 27509506 TI - Towards a Real-Time Embedded System for Water Monitoring Installed in a Robotic Sailboat. AB - Problems related to quality (and quantity) of water in natural resources or in artificial reservoirs are frequently arising and are at the center of attention of authorities and governments around the world. Many times the monitoring is not performed in an efficient time frame and a precise manner, whereas the adoption of fast and punctual solutions would undoubtedly improve the water quality and consequently enhance the life of people. To minimize or diminish such kinds of problems, we propose an architecture for sensors installed in a robotic platform, an autonomous sail boat, able to acquire raw data relative to water quality, to process and make them available to people that might be interested in such information. The main contributions are the sensors architecture itself, which uses low cost sensors, with practical experimentation done with a prototype. Results show data collected for points in lakes and rivers in the northeast of Brazil. This embedded system is fixed in the sailboat robot with the intention to facilitate the study of water quality for long endurance missions. This robot can help monitoring water bodies in a more consistent manner. Nonetheless the system can also be used with fixed vases or buoys in strategic points. PMID- 27509507 TI - Accurate Behavioral Simulator of All-Digital Time-Domain Smart Temperature Sensors by Using SIMULINK. AB - This study proposes a new behavioral simulator that uses SIMULINK for all-digital CMOS time-domain smart temperature sensors (TDSTSs) for performing rapid and accurate simulations. Inverter-based TDSTSs offer the benefits of low cost and simple structure for temperature-to-digital conversion and have been developed. Typically, electronic design automation tools, such as HSPICE, are used to simulate TDSTSs for performance evaluations. However, such tools require extremely long simulation time and complex procedures to analyze the results and generate figures. In this paper, we organize simple but accurate equations into a temperature-dependent model (TDM) by which the TDSTSs evaluate temperature behavior. Furthermore, temperature-sensing models of a single CMOS NOT gate were devised using HSPICE simulations. Using the TDM and these temperature-sensing models, a novel simulator in SIMULINK environment was developed to substantially accelerate the simulation and simplify the evaluation procedures. Experiments demonstrated that the simulation results of the proposed simulator have favorable agreement with those obtained from HSPICE simulations, showing that the proposed simulator functions successfully. This is the first behavioral simulator addressing the rapid simulation of TDSTSs. PMID- 27509508 TI - A Study of a Handrim-Activated Power-Assist Wheelchair Based on a Non-Contact Torque Sensor. AB - Demand for wheelchairs is increasing with growing numbers of aged and disabled persons. Manual wheelchairs are the most commonly used assistive device for mobility because they are convenient to transport. Manual wheelchairs have several advantages but are not easy to use for the elderly or those who lack muscular strength. Therefore, handrim-activated power-assist wheelchairs (HAPAW) that can aid driving power with a motor by detecting user driving intentions through the handrim are being researched. This research will be on HAPAW that judge user driving intentions by using non-contact torque sensors. To deliver the desired motion, which is sensed from handrim rotation relative to a fixed controller, a new driving wheel mechanism is designed by applying a non-contact torque sensor, and corresponding torques are simulated. Torques are measured by a driving wheel prototype and compared with simulation results. The HAPAW prototype was developed using the wheels and a driving control algorithm that uses left and right input torques and time differences are used to check if the non-contact torque sensor can distinguish users' driving intentions. Through this procedure, it was confirmed that the proposed sensor can be used effectively in HAPAW. PMID- 27509509 TI - Probing the Kinetic Anabolism of Poly-Beta-Hydroxybutyrate in Cupriavidus necator H16 Using Single-Cell Raman Spectroscopy. AB - Poly-beta-hydroxybutyrate (PHB) can be formed in large amounts in Cupriavidus necator and is important for the industrial production of biodegradable plastics. In this investigation, laser tweezers Raman spectroscopy (LTRS) was used to characterize dynamic changes in PHB content-as well as in the contents of other common biomolecule-in C. necator during batch growth at both the population and single-cell levels. PHB accumulation began in the early stages of bacterial growth, and the maximum PHB production rate occurred in the early and middle exponential phases. The active biosynthesis of DNA, RNA, and proteins occurred in the lag and early exponential phases, whereas the levels of these molecules decreased continuously during the remaining fermentation process until the minimum values were reached. The PHB content inside single cells was relatively homogenous in the middle stage of fermentation; during the late growth stage, the variation in PHB levels between cells increased. In addition, bacterial cells in various growth phases could be clearly discriminated when principle component analysis was performed on the spectral data. These results suggest that LTRS is a valuable single-cell analysis tool that can provide more comprehensive information about the physiological state of a growing microbial population. PMID- 27509510 TI - Thermal Image Sensing Model for Robotic Planning and Search. AB - This work presents a search planning system for a rolling robot to find a source of infra-red (IR) radiation at an unknown location. Heat emissions are observed by a low-cost home-made IR passive visual sensor. The sensor capability for detection of radiation spectra was experimentally characterized. The sensor data were modeled by an exponential model to estimate the distance as a function of the IR image's intensity, and, a polynomial model to estimate temperature as a function of IR intensities. Both theoretical models are combined to deduce a subtle nonlinear exact solution via distance-temperature. A planning system obtains feed back from the IR camera (position, intensity, and temperature) to lead the robot to find the heat source. The planner is a system of nonlinear equations recursively solved by a Newton-based approach to estimate the IR-source in global coordinates. The planning system assists an autonomous navigation control in order to reach the goal and avoid collisions. Trigonometric partial differential equations were established to control the robot's course towards the heat emission. A sine function produces attractive accelerations toward the IR source. A cosine function produces repulsive accelerations against the obstacles observed by an RGB-D sensor. Simulations and real experiments of complex indoor are presented to illustrate the convenience and efficacy of the proposed approach. PMID- 27509511 TI - Shift in HIV/AIDS Epidemic in Southeastern China: A Longitudinal Study from 1987 to 2015. AB - OBJECTIVE: The aim of this study was to investigate the shift in the epidemiological features of HIV/AIDS during the last three decades in Fujian Province, southeastern China, so as to provide evidence for the development of novel HIV/AIDS control strategies. METHODS: Data pertaining to the conventional surveillance, sentinel surveillance and epidemiological survey in Fujian Province during the period from 1987 to 2015 were collected. The epidemiological trends were described, and the subtypes of HIV strain were genotyped. In addition, the response to antiretroviral therapy was evaluated, and HIV genotypic resistance was assayed. RESULTS: There was an increasing trend observed in the reported cases of HIV/AIDS in Fujian Province. From 1987 to the end of 2015, a total of 8651 HIV/AIDS cases were reported across the province, with totally 1557 deaths found. Among the total cases, the ratio of male/female cases was 3.7:1, which appeared to be an increasing trend; 77.1% cases were detected in young and middle aged populations aged 19 to 50 years, however, the new HIV infections recently tended to occur in young people aged 15 to 18 years and in populations aged 50 years and older. Among all infected individuals, 49.3% were married, however, the percentage of unmarried cases increased from 6.67% before 1994 to 40.1% in 2015; 64.8% had junior high school education or lower, however, the proportion of HIV/AIDS cases with junior college education or above gradually increased from 6.5% in 2009 to 21.4% in 2015. The reported HIV/AIDS cases were predominantly found in coastal regions; however, a rapidly increasing trend was seen in the number of HIV/AIDS cases in inland regions, and the geographical variation of the cases gradually reduced. There were multiple routes of HIV transmission found in Fujian Province, and 94.2% infections were sexually transmitted, with a large increase in the percentage of male homosexual transmission. A variety of HIV-1 subtypes were genotyped in the province during the study period, and CRF01-AE and CRF07-BC intersubtype recombinant forms were predominant; however, a declining trend in the proportion of HIV-1 CRF01-AE recombinant virus and a significant rise in the proportion of HIV-1 CRF07-BC recombinant virus were observed. Over 90% HIV inhibition was found in all cases receiving antiretroviral therapy during the period from 2011 to 2015, indicating a low prevalence of HIV drug resistance. CONCLUSIONS: An increasing trend is still observed in the HIV/AIDS epidemics in Fujian Province, southeastern China. However, the epidemiological pattern of HIV/AIDS has recently changed in the province, and effective control interventions targeting the shift in the epidemiological features of HIV/AIDS should therefore be implemented to control the spread of the epidemic. PMID- 27509512 TI - The Covariance between Air Pollution Annoyance and Noise Annoyance, and Its Relationship with Health-Related Quality of Life. AB - Air pollution originating from road traffic is a known risk factor of respiratory and cardiovascular disease (both in terms of chronic and acute effects). While adverse effects on cardiovascular health have also been linked with noise (after controlling for air pollution), noise exposure has been commonly linked to sleep impairment and negative emotional reactions. Health is multi-faceted, both conceptually and operationally; Health-Related Quality of Life (HRQOL) is one of many measures capable of probing health. In this study, we examine pre-collected data from postal surveys probing HRQOL obtained from a variety of urban, suburban, and rural contexts across the North Island of New Zealand. Analyses focus on the covariance between air pollution annoyance and noise annoyances, and their independent and combined effects on HRQOL. Results indicate that the highest ratings of air pollution annoyance and noise annoyances were for residents living close to the motorway, while the lowest were for rural residents. Most of the city samples indicated no significant difference between air pollution- and noise-annoyance ratings, and of all of the correlations between air pollution- and noise-annoyance, the highest were found in the city samples. These findings suggest that annoyance is driven by exposure to environmental factors and not personality characteristics. Analysis of HRQOL indicated that air pollution annoyance predicts greater variability in the physical HRQOL domain while noise annoyance predicts greater variability in the psychological, social and environmental domains. The lack of an interaction effect between air pollution annoyance and noise annoyance suggests that air pollution and noise impact on health independently. These results echo those obtained from objective measures of health and suggest that mitigation of traffic effects should address both air and noise pollution. PMID- 27509513 TI - Increasing HIV Incidence among Men Who Have Sex with Men in Jiangsu Province, China: Results from Five Consecutive Surveys, 2011-2015. AB - Epidemics of HIV among men who have sex with men (MSM) are major public health concerns in most parts of China. This study examined the trends in HIV incidence and associated factors among MSM in Jiangsu Province. Five consecutive cross sectional surveys were conducted among MSM from 2011 to 2015 in eight cities throughout Jiangsu Province. Participants were recruited from MSM venues or via the internet. Demographic and behavioral data were collected through HIV bio behavioral surveys. Blood specimens were collected to test for HIV and syphilis. HIV incidence was estimated by the IgG-capture BED-EIA (BED) method and a chi square trend test was used to compare differences over the years. Multivariate logistic regression analysis was used to identify factors associated with recent infection. A total of 2433, 2678, 2591, 2610 and 2541 participants were enrolled in 2011, 2012, 2013, 2014 and 2015, respectively. HIV incidence increased from 5.10% in 2011 to 6.62% in 2015 (p = 0.025). MSM who had an education level of junior high school or less (aOR = 1.472, p = 0.018), engaged in condomless anal sex in the past 6 months (aOR = 2.389, p < 0.001), did not have an HIV test in the past 12 months (aOR = 3.215, p < 0.001), and were currently infected with syphilis (aOR = 2.025, p = 0.001) were likely to be recently infected with HIV. HIV incidence is increasing among MSM in Jiangsu Province, China. Condom usage and HIV testing promotion should be prioritized when attempting to reduce HIV transmission among MSM in China. PMID- 27509514 TI - Quality of Life and Its Related Factors in Chinese Unemployed People: A Population-Based Cross-Sectional Study. AB - With the global economic crisis and industrial restructuring, the unemployed are suffering from job loss-related stress and loss of income, which is believed to impair their mental and physical health, while coping and self-efficacy could combat the adverse effects of unemployment on health. Thus, this study aims to describe quality of life (QOL) among unemployed Chinese people and explore the associated factors. A cross-sectional study was conducted by convenience sampling, composed of 1825 unemployed people, from January 2011 to September 2011. Questionnaires pertaining to demographic characteristics, the 36-item Short Form Health Survey (SF-36), the abbreviated version of the Cope Inventory (Brief COPE) and self-efficacy scales were used to collect information from unemployed people in the eastern, central, and western regions of China. Hierarchical multiple regression analysis was performed to explore the related factors of QOL. A structural equation model (SEM) was used to test the relations among coping, self-efficacy, and QOL. Mental QOL was significantly lower than physical QOL in Chinese unemployed people. Coping had significant effects on both physical component summary (PCS) and mental component summary (MCS), while self-efficacy played the mediating role in the association between Coping and QOL. Unemployed Chinese people's mental QOL was disrupted more seriously than their physical QOL. An increase in coping could improve QOL by promoting better management of issues brought about by unemployment. In addition, self-efficacy has the ability to reduce the impact of unemployment on QOL, through the mediating path of coping on QOL. This study highlights the need of coping skills training and self-efficacy enhancement for better management of unemployment in order to improve QOL and well-being. PMID- 27509515 TI - The Regularities in Insufficient Leisure-Time Physical Activity in Poland. AB - BACKGROUND: Insufficient physical activity (PA) has become an increasing risk factor of noncommunicable diseases and an important cause of deaths all over the world. The goal of this paper is to provide an in-depth description of insufficient PA in Poland as well as an examination of some of its correlates. METHODS: We take advantage of statistical and econometric (logistic regression) analysis on the basis of a representative survey. Out of 3056 respondents, we analyze the 1260 low-PA ones. RESULTS: The household size is more significant than the household life phase, and only several professions increase the odds of insufficient PA. The influence of socioeconomic status and place of residence is most robust. Gender does not significantly influence insufficient PA. Physical inactivity is concentrated among inhabitants of rural areas and town dwellers, with poor educational profile, and limited labor market opportunities. However, even high socioeconomic status does not completely prevent insufficient activity. CONCLUSIONS: Groups at the highest risk of inactivity should be covered by promotional actions first. Their aim should mainly be raising the leisure-time physical activity (LTPA) awareness. To start with, primary forms of activity would be walking, Nordic walking and jogging. PMID- 27509516 TI - Effects of Long-Term Exposure to 60 GHz Millimeter-Wavelength Radiation on the Genotoxicity and Heat Shock Protein (Hsp) Expression of Cells Derived from Human Eye. AB - Human corneal epithelial (HCE-T) and human lens epithelial (SRA01/04) cells derived from the human eye were exposed to 60 gigahertz (GHz) millimeter wavelength radiation for 24 h. There was no statistically significant increase in the micronucleus (MN) frequency in cells exposed to 60 GHz millimeter-wavelength radiation at 1 mW/cm2 compared with sham-exposed controls and incubator controls. The MN frequency of cells treated with bleomycin for 1 h provided positive controls. The comet assay, used to detect DNA strand breaks, and heat shock protein (Hsp) expression also showed no statistically significant effects of exposure. These results indicate that exposure to millimeter-wavelength radiation has no effect on genotoxicity in human eye cells. PMID- 27509517 TI - Particulate Matter in Second-Hand Smoke Emitted from Different Cigarette Sizes and Types of the Brand Vogue Mainly Smoked by Women. AB - Indoor air pollution with harmful particulate matter (PM) is mainly caused by cigarette smoke. Super-Slim-Size-Cigarettes (SSL) are considered a less harmful alternative to King-Size-Cigarettes (KSC) due to longer filters and relatively low contents. We ask if "Combined Mainstream and Sidestream Smoke" (CMSS) associated PM levels of SSL are lower than of KSC and thus are potentially less harmful. PM concentrations in CMSS (PM10, PM2.5, and PM1) are measured from four cigarette types of the brand Vogue, using an "automatic-environmental-tobacco smoke-emitter" (AETSE) and laser aerosol spectrometry: SSL-BLEUE, -MENTHE, -LILAS and KSC-La Cigarette and -3R4F reference. This analysis shows that SSL MENTHE emitted the highest amount of PM, and KSC-La Cigarette the lowest. 3R4F reference emitted PM in the middle range, exceeding SSL BLEUE and falling slightly below SSL LILAS. It emerged that PM1 constituted the biggest proportion of PM emission. The outcome shows significant type-specific differences for emitted PM concentrations. Our results indicate that SSL are potentially more harmful for passive smokers than the respective KSC. However, this study cannot give precise statements about the general influence of the size of a cigarette on PM. Alarming is that PM1 is responsible for the biggest proportion of PM pollution, since smaller particles cause more harmful effects. PMID- 27509518 TI - Hepatitis E Seroprevalence in Europe: A Meta-Analysis. AB - There have been large numbers of studies on anti-HEV IgG seroprevalence in Europe, however, the results of these studies have produced high variability of seroprevalence rates, making interpretation increasingly problematic. Therefore, the aim of this study was to develop a clearer understanding of anti-HEV IgG seroprevalence in Europe and identify risk groups for HEV exposure by a meta analysis of published studies. METHODS: All European HEV-seroprevalence studies from 2003 to 2015 were reviewed. Data were stratified by assay, geographical location, and patient cohort (general population, patients with HIV, solid-organ transplant recipients, chronic liver disease patients, and individuals in contact with swine/wild animals). Data were pooled using a mixed-effects model. RESULTS: Four hundred thirty-two studies were initially identified, of which 73 studies were included in the analysis. Seroprevalence estimates ranged from 0.6% to 52.5%, increased with age, but were unrelated to gender. General population seroprevalence varied depending on assays: Wantai (WT): 17%, Mikrogen (MG): 10%, MP-diagnostics (MP): 7%, DiaPro: 4%, Abbott 2%. The WT assay reported significantly higher seroprevalence rates across all cohorts (p < 0.001). Individuals in contact with swine/wild animals had significantly higher seroprevalence rates than the general population, irrespective of assay (p < 0.0001). There was no difference between any other cohorts. The highest seroprevalence was observed in France (WT: 32%, MP: 16%) the lowest in Italy (WT: 7.5%, MP 0.9%). Seroprevalence varied between and within countries. The observed heterogeneity was attributed to geographical region (23%), assay employed (23%) and study cohort (7%). CONCLUSION: Seroprevalcence rates primarily depend on the seroassy that is used, followed by the geographical region and study cohort. Seroprevalence is higher in individuals exposed to swine and/or wild animals, and increases with age. PMID- 27509519 TI - Compliance, Palatability and Feasibility of PALEOLITHIC and Australian Guide to Healthy Eating Diets in Healthy Women: A 4-Week Dietary Intervention. AB - (1) BACKGROUND/OBJECTIVES: The Paleolithic diet has been receiving media coverage in Australia and claims to improve overall health. The diet removes grains and dairy, whilst encouraging consumption of fruits, vegetables, meat, eggs and nuts. Our aim was to compare the diet to the Australian Guide to Healthy Eating (AGHE) in terms of compliance, palatability and feasibility; (2) SUBJECTS/METHODS: 39 healthy women (age 47 +/- 13 years, BMI 27 +/- 4 kg/m2) were randomised to an ad libitum Paleolithic (n = 22) or AGHE diet (n = 17) for 4-weeks. A food checklist was completed daily, with mean discretionary consumption (serves/day) calculated to assess compliance. A 12-item questionnaire was administered post intervention to assess palatability and feasibility; (3) RESULTS: The AGHE group reported greater daily consumption of discretionary items (1.0 + 0.6 vs. 0.57 + 0.6 serves/day, p = 0.03). Compared to the AGHE group, the Paleolithic group reported a significantly greater number of events of diarrhoea (23%, 0%, p = 0.046), costs associated with grocery shopping (69%, 6% p < 0.01) and belief that the diet was not healthy (43%, 0% p < 0.01); (4) CONCLUSIONS: Compliance to both diets was high but the potential side effects and increased cost suggest that the Paleolithic diet may not be practical in clinical/public health settings. Further studies are required to assess longer term feasibility. PMID- 27509520 TI - The Effect of the Sodium to Potassium Ratio on Hypertension Prevalence: A Propensity Score Matching Approach. AB - This study investigated the effect of the sodium to potassium ratio on hypertension prevalence and blood pressure. The study population was constructed by pooling the Korean National Health and Nutrition Examination Surveys between 2010 and 2014. The study population was divided into quartiles based on the sodium to potassium ratio, and the effect was inferred by the difference in hypertension prevalence across quartiles by six pairwise comparisons using a propensity score matching technique. The quartiles with the higher sodium to potassium ratio had higher hypertension prevalence rates based on the following pairwise comparisons: the first vs. third quartile, the first vs. fourth quartile, the second vs. third quartile, and the second vs. fourth quartile. The prevalence differences were 2.74% point (p < 0.05), 3.44% point (p < 0.01), 2.47% point (p < 0.05), and 2.95% point (p < 0.01), respectively. In addition, statistically significant higher systolic (p < 0.05) and diastolic blood pressure (p < 0.01) was observed in the second quartiles compared to the first quartiles. Because a strong association was also detected between the sodium to potassium ratio and blood pressure even at a low level of sodium to potassium ratio, a lower sodium to potassium ratio diet than a usual diet is recommended to control high blood pressure in Korea. PMID- 27509521 TI - Effect of Probiotics on Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - It has been reported that gut probiotics play a major role in the bidirectional communication between the gut and the brain. Probiotics may be essential to people with depression, which remains a global health challenge, as depression is a metabolic brain disorder. However, the efficacy of probiotics for depression is controversial. This study aimed to systematically review the existing evidence on the effect of probiotics-based interventions on depression. Randomized, controlled trials, identified through screening multiple databases and grey literature, were included in the meta-analysis. The meta-analysis was performed using Review Manager 5.3 software using a fixed-effects model. The meta-analysis showed that probiotics significantly decreased the depression scale score (MD (depressive disorder) = -0.30, 95% CI (-0.51--0.09), p = 0.005) in the subjects. Probiotics had an effect on both the healthy population (MD = -0.25, 95% CI ( 0.47--0.03), p = 0.03) and patients with major depressive disorder (MDD) (MD = 0.73, 95% CI (-1.37--0.09), p = 0.03). Probiotics had an effect on the population aged under 60 (MD = -0.43, 95% CI (-0.72--0.13), p = 0.005), while it had no effect on people aged over 65 (MD = -0.18, 95% CI (-0.47-0.11), p = 0.22). This is the first systematic review and meta-analysis with the goal of determining the effect of probiotics on depression. We found that probiotics were associated with a significant reduction in depression, underscoring the need for additional research on this potential preventive strategy for depression. PMID- 27509522 TI - Maternal Methyl-Group Donor Intake and Global DNA (Hydroxy)Methylation before and during Pregnancy. AB - It is still unclear to which extent methyl-group intake during pregnancy can affect maternal global DNA (hydroxyl)methylation. Pregnancy methylation profiling and its link with methyl-group intake in a healthy population could enhance our understanding of the development of pregnancy related disorders. One hundred forty-eight women were enrolled in the MANOE (MAternal Nutrition and Offspring's Epigenome) study. Thiry-four women were enrolled before pregnancy and 116 during the first trimester of pregnancy. Global DNA (hydroxy)methylation in blood using LC-MS/MS and dietary methyl-group intake (methionine, folate, betaine, and choline) using a food-frequency questionnaire were estimated pre-pregnancy, during each trimester, and at delivery. Global DNA (hydroxy)methylation levels were highest pre-pregnancy and at weeks 18-22 of pregnancy. We observed a positive relation between folic acid and global DNA methylation (p = 0.04) and hydroxymethylation (p = 0.04). A high intake of methionine pre-pregnancy and in the first trimester showed lower (hydroxy)methylation percentage in weeks 11-13 and weeks 18-22, respectively. Choline and betaine intake in the first weeks was negatively associated with hydroxymethylation. Women with a high intake of these three methyl groups in the second and third trimester showed higher hyrdoxymethylation/methylation levels in the third trimester. To conclude, a time trend in DNA (hydroxy)methylation was found and women with higher methyl-group intake showed higher methylation in the third trimester, and not in earlier phases of pregnancy. PMID- 27509523 TI - Sex-Specific Sociodemographic Correlates of Dietary Patterns in a Large Sample of French Elderly Individuals. AB - This cross-sectional analysis provides up-to-date information about dietary patterns (DP) and their sociodemographic correlates in European elderly individuals. We studied 6686 enrollees aged 65+ (55% women) in the ongoing French population-based NutriNet-Sante e-cohort. Diet was assessed via three 24 h records. The sex-specific correlates of factor analysis derived DP were identified with multivariable linear regression. Using 22 pre-defined food groups, three DP were extracted. The "healthy" DP (fruit, vegetables, grains, nuts, fish) was positively associated with education, living alone, and being a former smoker (women), and negatively associated with being overweight, current smoker (men), age 75+ years, having hypertension, and obesity (women). The "western" DP (meat, appetizers, cheese, alcohol) was positively associated with BMI (men) and being a former/current smoker; it was negatively associated with age 75+ years (women) and living alone. The "traditional" DP (bread, potatoes, milk, vegetables, butter, stock) was positively associated with age and negatively associated with being a former/current smoker, education (men), and residing in an urban/semi-urban area. The findings support the diversity of DP among the elderly, highlighting sex-specific differences. The "healthy" DP explained the largest amount of variance in intake. Future studies could replicate the models in longitudinal and international contexts. PMID- 27509524 TI - A Rapid Assay to Detect Toxigenic Penicillium spp. Contamination in Wine and Musts. AB - Wine and fermenting musts are grape products widely consumed worldwide. Since the presence of mycotoxin-producing fungi may greatly compromise their quality characteristics and safety, there is an increasing need for relatively rapid "user friendly" quantitative assays to detect fungal contamination both in grapes delivered to wineries and in final products. Although other fungi are most frequently involved in grape deterioration, secondary infections by Penicillium spp. are quite common, especially in cool areas with high humidity and in wines obtained by partially dried grapes. In this work, a single-tube nested real-time PCR approach-successfully applied to hazelnut and peanut allergen detection-was tested for the first time to trace Penicillium spp. in musts and wines. The method consisted of two sets of primers specifically designed to target the beta tubulin gene, to be simultaneously applied with the aim of lowering the detection limit of conventional real-time PCR. The assay was able to detect up to 1 fg of Penicillium DNA. As confirmation, patulin content of representative samples was determined. Most of analyzed wines/musts returned contaminated results at >50 ppb and a 76% accordance with molecular assay was observed. Although further large scale trials are needed, these results encourage the use of the newly developed method in the pre-screening of fresh and processed grapes for the presence of Penicillium DNA before the evaluation of related toxins. PMID- 27509525 TI - Ultra Large Gene Families: A Matter of Adaptation or Genomic Parasites? AB - Gene duplication is an important mechanism of molecular evolution. It offers a fast track to modification, diversification, redundancy or rescue of gene function. However, duplication may also be neutral or (slightly) deleterious, and often ends in pseudo-geneisation. Here, we investigate the phylogenetic distribution of ultra large gene families on long and short evolutionary time scales. In particular, we focus on a family of NACHT-domain and leucine-rich repeat-containing (NLR)-genes, which we previously found in large numbers to occupy one chromosome arm of the zebrafish genome. We were interested to see whether such a tight clustering is characteristic for ultra large gene families. Our data reconfirm that most gene family inflations are lineage-specific, but we can only identify very few gene clusters. Based on our observations we hypothesise that, beyond a certain size threshold, ultra large gene families continue to proliferate in a mechanism we term "run-away evolution". This process might ultimately lead to the failure of genomic integrity and drive species to extinction. PMID- 27509526 TI - Clearance of Streptococcus suis in Stomach Contents of Differently Fed Growing Pigs. AB - Streptococcus (S.) suis translocates across the intestinal barrier of piglets after intraintestinal application. Based on these findings, an oro gastrointestinal infection route has been proposed. Thus, the objective of this study was to investigate the survival of S. suis in the porcine stomach. Whereas surviving bacteria of S. suis serotypes 2 and 9 were not detectable after 60 min of incubation in stomach contents with a comparatively high gastric pH of 5 due to feeding of fine pellets, the number of Salmonella Derby bacteria increased under these conditions. Further experiments confirmed the clearance of S. suis serotypes 2 and 9 within 30 min in stomach contents with a pH of 4.7 independently of the bacterial growth phase. Finally, an oral infection experiment was conducted, feeding each of 18 piglets a diet mixed with 10(10) CFU of S. suis serotype 2 or 9. Thorough bacteriological screenings of various mesenteric-intestinal lymph nodes and internal organs after different times of exposure did not lead to any detection of the orally applied challenge strains. In conclusion, the porcine stomach constitutes a very efficient barrier against oro-gastrointenstinal S. suis infections. Conditions leading to the passage of S. suis through the stomach remain to be identified. PMID- 27509528 TI - Permeability-Selectivity Analysis of Microfiltration and Ultrafiltration Membranes: Effect of Pore Size and Shape Distribution and Membrane Stretching. AB - We present a modeling approach to determine the permeability-selectivity tradeoff for microfiltration and ultrafiltration membranes with a distribution of pore sizes and pore shapes. Using the formulated permeability-selectivity model, the effect of pore aspect ratio and pore size distribution on the permeability selectivity tradeoff of the membrane is analyzed. A finite element model is developed to study the effect of membrane stretching on the distribution of pore sizes and shapes in the stretched membrane. The effect of membrane stretching on the permeability-selectivity tradeoff of membranes is also analyzed. The results show that increasing pore aspect ratio improves membrane performance while increasing the width of pore size distribution deteriorates the performance. It was also found that the effect of membrane stretching on the permeability selectivity tradeoff is greatly affected by the uniformity of pore distribution in the membrane. Stretching showed a positive shift in the permeability selectivity tradeoff curve of membranes with well-dispersed pores while in the case of pore clustering, a negative shift in the permeability-selectivity tradeoff curve was observed. PMID- 27509527 TI - Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting. AB - Recent years have seen significant efforts in understanding and modulating the immune response in cancer. In this context, immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), have come under intense investigation for their proposed roles in suppressing tumor specific immune responses and establishing an immunosuppressive tumor microenvironment, thus enabling tumor immune evasion. Additionally, recent evidence indicates that Tregs comprise diverse and heterogeneous subsets; phenotypically and functionally distinct subsets of tumor-infiltrating Tregs could contribute differently to cancer prognosis and clinical outcomes. Understanding Treg biology in the setting of cancer, and specifically the tumor microenvironment, is important for designing effective cancer therapies. In this review, we critically examine the role of Tregs in the tumor microenvironment and in cancer progression focusing on human studies. We also discuss the impact of current therapeutic modalities on Treg biology and the therapeutic opportunities for targeting Tregs to enhance anti-tumor immune responses and clinical benefits. PMID- 27509529 TI - Nanopore-CMOS Interfaces for DNA Sequencing. AB - DNA sequencers based on nanopore sensors present an opportunity for a significant break from the template-based incumbents of the last forty years. Key advantages ushered by nanopore technology include a simplified chemistry and the ability to interface to CMOS technology. The latter opportunity offers substantial promise for improvement in sequencing speed, size and cost. This paper reviews existing and emerging means of interfacing nanopores to CMOS technology with an emphasis on massively-arrayed structures. It presents this in the context of incumbent DNA sequencing techniques, reviews and quantifies nanopore characteristics and models and presents CMOS circuit methods for the amplification of low-current nanopore signals in such interfaces. PMID- 27509530 TI - Effects of Surface Epitope Coverage on the Sensitivity of Displacement Assays that Employ Modified Nanoparticles: Using Bisphenol A as a Model Analyte. AB - With the ever-increasing use of nanoparticles in immunosensors, a fundamental study on the effect of epitope density is presented herein, with a small molecule epitope, on the performance of the displacement assay format in an enzyme-linked immunosorbent assay (ELISA). Thiolated bisphenol A (BPA) functionalized gold nanoparticles (cysBPAv-AuNPs) and specific anti-BPA antibodies are employed for this purpose. It is shown that the displacement of cysBPAv-AuNPs bound to the immobilized antibodies was influenced by both the avidity of bound cysBPAv-AuNPs and the concentration of free BPA to displace it. The importance of surface epitope density was that it changed the number of epitopes in close proximity to the antibody-binding site. This then influenced the avidity of cysBPAv-AuNPs bound to the immobilized antibody. Furthermore, the molar epitope concentration in an assay appears to affect the degree of antibody binding site saturation. Controlling surface epitope density of the functionalized nanoparticles and molar epitope concentration in an assay leads to a decrease of the concentration of free BPA required to displace the bound cysBPAv-AuNP, and hence better assay performance with regards to the D50 value and dynamic range in the displacement assay. PMID- 27509531 TI - DJ-1/Park7 Sensitive Na+ /H+ Exchanger 1 (NHE1) in CD4+ T Cells. AB - DJ-1/Park7 is a redox-sensitive chaperone protein counteracting oxidation and presumably contributing to the control of oxidative stress responses and thus inflammation. DJ-1 gene deletion exacerbates the progression of Parkinson's disease presumably by augmenting oxidative stress. Formation of reactive oxygen species (ROS) is paralleled by activation of the Na+ /H+ exchanger 1 (NHE1). ROS formation in CD4+ T cells plays a decisive role in regulating inflammatory responses. In the present study, we explored whether DJ-1 is expressed in CD4+ T cells, and affects ROS production as well as NHE1 in those cells. To this end, DJ 1 and NHE1 transcript, and protein levels were quantified by qRT-PCR and Western blotting, respectively, intracellular pH (pHi ) utilizing bis-(2-carboxyethyl)-5 (and-6)-carboxyfluorescein (BCECF) fluorescence, NHE activity from realkalinization after an ammonium pulse, and ROS production utilizing 2',7' dichlorofluorescin diacetate (DCFDA) fluorescence. As a result DJ-1 was expressed in CD4+ T cells. ROS formation, NHE1 transcript levels, NHE1 protein, and NHE activity were higher in CD4+ T cells from DJ-1 deficient mice than in CD4+ T cells from wild type mice. Antioxidant N-acetyl-cysteine (NAC) and protein tyrosine kinase (PTK) inhibitor staurosporine decreased the NHE activity in DJ-1 deficient CD4+ T cells, and blunted the difference between DJ-1-/- and DJ-1+/+ CD4+ T cells, an observation pointing to a role of ROS in the up-regulation of NHE1 in DJ-1-/- CD4+ T cells. In conclusion, DJ-1 is a powerful regulator of ROS production as well as NHE1 expression and activity in CD4+ T cells. J. Cell. Physiol. 232: 3050-3059, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27509532 TI - Elevated 1-h post-challenge glucose levels associated with increased arterial stiffness. PMID- 27509534 TI - Graft-to-recipient weight ratio threshold adjusted to the model for end-stage liver disease score for living donor liver transplantation. AB - The graft-to-recipient weight ratio (GRWR) is an important selection criterion for living donor liver transplantation (LDLT). The generally accepted threshold is known to be 0.8%. We believe that this threshold can be reduced under certain conditions. The aim of this study was to evaluate the results of these patients with GRWR < 0.8%. Between 2004 and 2015, 649 patients underwent right lobe LDLT for end-stage liver disease in adult patients. All recipients who had GRWR < 0.8% were identified. The data of these patients were retrospectively analyzed and compared to patients with GRWR >= 0.8%. There were 43 patients with GRWR < 0.8%. Out of these patients, 7 (16%) had GRWR of 0.6%. The median Model for End-Stage Liver Disease (MELD) score was 15, and the median donor age was 30 years. Anterior segment drainage was ensured. Portal inflow modulation was performed by splenic artery ligation according to the portal flow. Postoperative complications were seen in 6 (14%) patients. Of all 43 patients, 3 (7%) died perioperatively within 1 month, and 1 (2%) patient underwent retransplantation due to graft failure. The mean hospital stay was 18 days. The 1-year survival rate was 93%. None of the patients had a laboratory MELD score above 20. The comparison of the results with the patients who had GRWR >= 0.8% has shown no significant difference, except MELD score, body mass index (BMI), and rate of anterior segment drainage. The GRWR can be decreased even to 0.6% if the MELD score is below 20, donor age is below 45 years, and there are no signs for any hepatosteatosis of the donor graft. In these patients, it is essential that the anterior segment drainage is secured and the portal inflow modulation is performed according to the portal flow. Liver Transplantation 22 1643-1648 2016 AASLD. PMID- 27509535 TI - Laparoscopic Common Bile Duct Exploration Versus Open Approach in Cirrhotic Patients with Choledocholithiasis: A Retrospective Study. AB - OBJECTIVE: To evaluate the safety and benefits of laparoscopic common bile duct exploration (LCBDE) compared with open approach (OCBDE) in cirrhotic patients. MATERIALS AND METHODS: Between January 2009 and December 2012, a total of 113 cirrhotic patients with choledocholithiasis underwent common bile duct (CBD) explorations in our department. There were two groups of patients: A:LCBDE (n = 61) and B:OCBDE (n = 52). Patients' demographic characteristics, surgical data, postoperative outcomes, and long-term results were retrospectively collected and analyzed. RESULTS: There were no significant differences between the two groups in the demographic characteristics or preoperative status. The transcystic approach was successfully performed in 52 (46.0%) patients (group A:34, group B:20), whereas choledochotomy was successful in 59 (54.0%) patients (group A:27, group B:32). The differences between group A and group B in terms of surgical time (124.9 +/- 34.2 minutes versus 132.6 +/- 48.6 minutes, P = .323), stone clearance rate (93.4% versus 94.2%, P > .05), short-term complication rate (9.8% versus 13.4%, P = .547), and recurrent stone rate (6.6% versus 5.8%, P > .05) were not statistically significant. However, group A suffered less blood loss [95 (60-200) mL versus 200 (90-450) mL, P < .001] and shorter length of hospital stay (4.7 +/- 2.5 days versus 11.3 +/- 3.1 days, P < .001) than group B. In the LCBDE group, 4 (6.6%) patients were converted due to heavy inflammation and severe adhesions. No mortality, biliary injury, or stricture occurred during follow-up. CONCLUSION: LCBDE can be safely performed in patients with Child-Pugh A or B cirrhosis and choledocholithiasis, with considerable efficiency, minimal short term complications, and acceptable long-term outcomes. LCBDE has the advantages over open CBD exploration of less bleeding and reduced length of hospital stay. PMID- 27509536 TI - Fate of Polycyclic Aromatic Hydrocarbons in Seawater from the Western Pacific to the Southern Ocean (17.5 degrees N to 69.2 degrees S) and Their Inventories on the Antarctic Shelf. AB - Semivolatile organic compounds such as polycyclic aromatic hydrocarbons (PAHs) have the potential to reach pristine environments through long-range transport. To investigate the long-range transport of the PAHs and their fate in Antarctic seawater, dissolved PAHs in the surface waters from the western Pacific to the Southern Ocean (17.5 degrees N to 69.2 degrees S), as well as down to 3500 m PAH profiles in Prydz Bay and the adjacent Southern Ocean, were observed during the 27th Chinese National Antarctic Research Expedition in 2010. The concentrations of Sigma9PAH in the surface seawater ranged from not detected (ND) to 21 ng L( 1), with a mean of 4.3 ng L(-1); and three-ring PAHs were the most abundant compounds. Samples close to the Australian mainland displayed the highest levels across the cruise. PAHs originated mainly from pyrogenic sources, such as grass, wood, and coal combustion. Vertical profiles of PAHs in Prydz Bay showed a maximum at a depth of 50 m and less variance with depth. In general, we inferred that the water masses as well as the phytoplankton were possible influencing factors on PAH surface-enrichment depth-depletion distribution. Inventory estimation highlighted the contribution of intermediate and deep seawater on storing PAHs in seawater from Prydz Bay, and suggested that climate change rarely shows the rapid release of the PAHs currently stored in the major reservoirs (intermediate and deep seawater). PMID- 27509538 TI - Performance of Dynamically Simulated Reference Patterns for Cross-Correlation Electron Backscatter Diffraction. AB - High-resolution (or "cross-correlation") electron backscatter diffraction analysis (HR-EBSD) utilizes cross-correlation techniques to determine relative orientation and distortion of an experimental electron backscatter diffraction pattern with respect to a reference pattern. The integrity of absolute strain and tetragonality measurements of a standard Si/SiGe material have previously been analyzed using reference patterns produced by kinematical simulation. Although the results were promising, the noise levels were significantly higher for kinematically produced patterns, compared with real patterns taken from the Si region of the sample. This paper applies HR-EBSD techniques to analyze lattice distortion in an Si/SiGe sample, using recently developed dynamically simulated patterns. The results are compared with those from experimental and kinematically simulated patterns. Dynamical patterns provide significantly more precision than kinematical patterns. Dynamical patterns also provide better estimates of tetragonality at low levels of distortion relative to the reference pattern; kinematical patterns can perform better at large values of relative tetragonality due to the ability to rapidly generate patterns relating to a distorted lattice. A library of dynamically generated patterns with different lattice parameters might be used to achieve a similar advantage. The convergence of the cross correlation approach is also assessed for the different reference pattern types. PMID- 27509539 TI - Nurse Practitioners have an Opportunity to Shape Health Care and Payment Reform. PMID- 27509540 TI - The four R's of revising and resubmitting a manuscript. PMID- 27509541 TI - Tracer methodology: an appropriate tool for assessing compliance with accreditation standards? AB - OBJECTIVES: Tracer methodology has been used by Accreditation Canada since 2008 to collect evidence on the quality and safety of care and services, and to assess compliance with accreditation standards. Given the importance of this methodology in the accreditation program, the objective of this study is to assess the quality of the methodology and identify its strengths and weaknesses. METHOD: A mixed quantitative and qualitative approach was adopted to evaluate consistency, appropriateness, effectiveness and stakeholder synergy in applying the methodology. An online questionnaire was sent to 468 Accreditation Canada surveyors. RESULTS: According to surveyors' perceptions, tracer methodology is an effective tool for collecting useful, credible and reliable information to assess compliance with Qmentum program standards and priority processes. The results show good coherence between methodology components (appropriateness of the priority processes evaluated, activities to evaluate a tracer, etc.). The main weaknesses are the time constraints faced by surveyors and management's lack of cooperation during the evaluation of tracers. CONCLUSION: The inadequate amount of time allowed for the methodology to be applied properly raises questions about the quality of the information obtained. This study paves the way for a future, more in-depth exploration of the identified weaknesses to help the accreditation organization make more targeted improvements to the methodology. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27509542 TI - Spinal Cord Inflammation: Molecular Imaging after Thoracic Aortic Ischemia Reperfusion Injury. AB - Purpose To evaluate whether noninvasive molecular imaging technologies targeting myeloperoxidase (MPO) can reveal early inflammation associated with spinal cord injury after thoracic aortic ischemia-reperfusion (TAR) in mice. Materials and Methods The study was approved by the institutional animal care and use committee. C57BL6 mice that were 8-10 weeks old underwent TAR (n = 55) or sham (n = 26) surgery. Magnetic resonance (MR) imaging (n = 6) or single photon emission computed tomography (SPECT)/computed tomography (CT) (n = 15) studies targeting MPO activity were performed after intravenous injection of MPO sensors (bis-5 hydroxytryptamide-tetraazacyclododecane [HT]-diethyneletriaminepentaacetic acid [DTPA]-gadolinium or indium 111-bis-5-HT-DTPA, respectively). Immunohistochemistry and flow cytometry were used to identify myeloid cells and neuronal loss. Proinflammatory cytokines, keratinocyte chemoattractant (KC), and interleukin 6 (IL-6) were measured with enzyme-linked immunosorbent assay. Statistical analyses were performed by using nonparametric tests and the Pearson correlation coefficient. P < .05 was considered to indicate a significant difference. Results Myeloid cells infiltrated into the injured cord at 6 and 24 hours after TAR. MR imaging confirmed the presence of ischemic lesions associated with mild MPO-mediated enhancement in the thoracolumbar spine at 24 hours compared with the sham procedure. SPECT/CT imaging of MPO activity showed marked MPO-sensor retention at 6 hours (P = .003) that continued to increase at 24 hours after TAR (P = .0001). The number of motor neurons decreased substantially at 24 hours after TAR (P < .01), which correlated inversely with in vivo inflammatory changes detected at molecular imaging (r = 0.64, P = .0099). MPO was primarily secreted by neutrophils, followed by lymphocyte antigen 6 complexhigh monocytes and/or macrophages. There were corresponding increased levels of proinflammatory cytokines KC (P = .0001) and IL-6 (P = .0001) that mirrored changes in MPO activity. Conclusion MPO is a suitable imaging biomarker for identifying and tracking inflammatory damage in the spinal cord after TAR in a mouse model. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27509543 TI - Application of Modified Spin-Echo-based Sequences for Hepatic MR Elastography: Evaluation, Comparison with the Conventional Gradient-Echo Sequence, and Preliminary Clinical Experience. AB - Purpose To (a) evaluate modified spin-echo (SE) magnetic resonance (MR) elastographic sequences for acquiring MR images with improved signal-to-noise ratio (SNR) in patients in whom the standard gradient-echo (GRE) MR elastographic sequence yields low hepatic signal intensity and (b) compare the stiffness values obtained with these sequences with those obtained with the conventional GRE sequence. Materials and Methods This HIPAA-compliant retrospective study was approved by the institutional review board; the requirement to obtain informed consent was waived. Data obtained with modified SE and SE echo-planar imaging (EPI) MR elastographic pulse sequences with short echo times were compared with those obtained with the conventional GRE MR elastographic sequence in two patient cohorts, one that exhibited adequate liver signal intensity and one that exhibited low liver signal intensity. Shear stiffness values obtained with the three sequences in 130 patients with successful GRE-based examinations were retrospectively tested for statistical equivalence by using a 5% margin. In 47 patients in whom GRE examinations were considered to have failed because of low SNR, the SNR and confidence level with the SE-based sequences were compared with those with the GRE sequence. Results The results of this study helped confirm the equivalence of SE MR elastography and SE-EPI MR elastography to GRE MR elastography (P = .0212 and P = .0001, respectively). The SE and SE-EPI MR elastographic sequences provided substantially improved SNR and stiffness inversion confidence level in 47 patients in whom GRE MR elastography had failed. Conclusion Modified SE-based MR elastographic sequences provide higher SNR MR elastographic data and reliable stiffness measurements; thus, they enable quantification of stiffness in patients in whom the conventional GRE MR elastographic sequence failed owing to low signal intensity. The equivalence of the three sequences indicates that the current diagnostic thresholds are applicable to SE MR elastographic sequences for assessing liver fibrosis. (c) RSNA, 2016. PMID- 27509544 TI - Intravenous Gadoxetate Disodium Administration Reduces Breath-holding Capacity in the Hepatic Arterial Phase: A Multi-Center Randomized Placebo-controlled Trial. AB - Purpose To determine, in a multicenter double-blinded placebo-controlled trial, whether maximal hepatic arterial phase breath-holding duration is affected by gadoxetate disodium administration. Materials and Methods Institutional review board approval was obtained for this prospective multi-institutional HIPAA compliant study; written informed consent was obtained from all subjects. At three sites, a total of 44 volunteers underwent a magnetic resonance (MR) imaging examination in which images were acquired before and dynamically after bolus injection of gadoxetate disodium, normal saline, and gadoterate meglumine, administered in random order in a single session. The technologist and volunteer were blinded to the agent. Arterial phase breath-holding duration was timed after each injection, and volunteers reported subjective symptoms. Heart rate (HR) and oxygen saturation were monitored. Images were independently analyzed for motion artifacts by three radiologists. Arterial phase breath-holding duration and motion artifacts after each agent were compared by using the Mann-Whitney U test and the McNemar test. Factors affecting the above outcomes were assessed by using a univariate, multivariable model. Results Arterial phase breath holds were shorter after gadoxetate disodium (mean, 32 seconds +/- 19) than after saline (mean, 40 seconds +/- 17; P < .001) or gadoterate meglumine (43 seconds +/- 21, P < .001) administration. In 80% (35 of 44) of subjects, arterial phase breath holds were shorter after gadoxetate disodium than after both saline and gadoterate meglumine. Three (7%) of 44 volunteers had severe arterial phase motion artifacts after gadoxetate disodium administration, one (2%; P = .62) had them after gadoterate meglumine administration, and none (P = .25) had them after saline administration. HR and oxygen saturation changes were not significantly associated with contrast agent. Conclusion Maximal hepatic arterial phase breath holding duration is reduced after gadoxetate disodium administration in healthy volunteers, and reduced breath-holding duration is associated with motion artifacts. (c) RSNA, 2016. PMID- 27509545 TI - Service user involvement enhanced the research quality in a study using interpretative phenomenological analysis - the power of multiple perspectives. AB - AIM: The aim of this study was to examine how service user involvement can contribute to the development of interpretative phenomenological analysis methodology and enhance research quality. BACKGROUND: Interpretative phenomenological analysis is a qualitative methodology used in nursing research internationally to understand human experiences that are essential to the participants. Service user involvement is requested in nursing research. DESIGN: We share experiences from 4 years of collaboration (2012-2015) on a mental health promotion project, which involved an advisory team. METHODS: Five research advisors either with a diagnosis or related to a person with severe mental illness constituted the team. They collaborated with the research fellow throughout the entire research process and have co-authored this article. We examined the joint process of analysing the empirical data from interviews. Our analytical discussions were audiotaped, transcribed and subsequently interpreted following the guidelines for good qualitative analysis in interpretative phenomenological analysis studies. RESULTS: The advisory team became 'the researcher's helping hand'. Multiple perspectives influenced the qualitative analysis, which gave more insightful interpretations of nuances, complexity, richness or ambiguity in the interviewed participants' accounts. The outcome of the service user involvement was increased breadth and depth in findings. CONCLUSION: Service user involvement improved the research quality in a nursing research project on mental health promotion. The interpretative element of interpretative phenomenological analysis was enhanced by the emergence of multiple perspectives in the qualitative analysis of the empirical data. We argue that service user involvement and interpretative phenomenological analysis methodology can mutually reinforce each other and strengthen qualitative methodology. PMID- 27509546 TI - [Prospective study on tooth loss in a cohort of dentate elderly]. AB - The aim of this study was to assess factors associated with tooth loss in elderly 60 years or older during a four-year observation period. A representative cohort of dentate elderly from the city of Sao Paulo, Brazil, participated in the study. The outcome was teeth loss incidence from 2006 to 2010. Demographic and socioeconomic characteristics, health services access and use, behavior, reported diseases, cognitive status, functional status, state of dentition, and use of dental prosthesis were recorded as independent variables in 2006 and the outcome was measured in 2010. Negative binomial regression models were used. Participation included 440 dentate elderly. Increased likelihood of tooth loss was associated with use of two removable prostheses (RR = 1.57; 95%CI: 1.02 2.41), fair self-rated oral health (RR = 1.62; 95%CI: 1.11-2.36), bad/very bad self-rated oral health (RR = 1.87; 95%CI: 1.11-3.17), male gender (RR = 1.74; 95%CI: 1.28-2.37), and living alone (RR = 2.03; 95%CI: 1.11-3.72). PMID- 27509547 TI - [Spatial analysis of counting data with excess zeros applied to the study of dengue incidence in Campinas, Sao Paulo State, Brazil]. AB - Dengue incidence occurs predominantly within city limits. Identifying spatial distribution of the disease at the local level helps formulate strategies to control and prevent the disease. Spatial analysis of counting data for small areas commonly violates the assumptions of traditional Poisson models due to the excessive amount of zeros. This study compared the performance of four counting models used in mapping diseases: Poisson, negative binomial, zero-inflated Poisson, and zero-inflated negative binomial. The methods were compared in a simulation study. The models analyzed in the simulation were applied to a spatial ecological study of dengue data aggregated by census tracts in the city of Campinas, Sao Paulo State, Brazil, 2007. Spatial analysis was conducted with Bayesian hierarchical models. The zero-inflated Poisson model showed the best performance for estimating relative risk of dengue incidence in the census tracts. PMID- 27509548 TI - [A Street Clinic in a state capital in Northeast Brazil from the perspective of homeless people]. AB - The objective of this study was to evaluate the Street Clinic strategy in Maceio, Alagoas State, Brazil, from the perspective of its users. This was a qualitative study in coverage areas of the Street Clinic in Maceio. Research subjects were 18 homeless individuals assisted by the clinic (10 men and 8 women), ranging from 20 to 40 years of age. Data were collected from September 2014 to February 2015 using a semi-structured interview. Content analysis was applied to the data and identified two categories: the first, the Street Clinic as such, revealed the strategy's critical points, challenges, and potentialities; the second showed the Street Clinic as social support, affect, and hope for change for the homeless. The strategy was rated positively by users, providing social support on health problems and other daily issues. PMID- 27509549 TI - [Are there differences between paid women workers and housewives in health related quality of life?]. AB - Considering the lack of Brazilian studies on the relationship between participation in the labor market and health-related quality of life (HRQL) in women, the objectives were to verify whether there is an association between paid work versus no paid work and HRQL in women, and whether socioeconomic status modifies this association. This was a population-based cross-sectional study with a sample of 668 women 18 to 64 years of age from the Campinas Health Survey (ISACamp 2008/2009), using SF-36 to assess HRQL. Being a housewife was associated with worse HRQL, especially in mental domains, but this association was modified by socioeconomic status. In the middle and low schooling and family income strata, housewives showed worse HRQL than paid women workers, but there was no difference between the two groups in the high schooling and high income strata. Housewives' worse HRQL emphasizes the importance of public policies to expand opportunities for women's participation in the labor market and access to education. PMID- 27509550 TI - [Use of causal diagrams in Epidemiology: application to a situation with confounding]. AB - Epidemiological research still rarely uses causal diagrams, despite growing recognition of their explanatory potential. One possible reason is that many research programs involve themes in which there is a certain degree of uncertainty as to mechanisms in the processes that generate the data. In this study, the relationship between occupational stress and obesity is used as an example of the application of causal diagrams to questions related to confounding. The article presents the selection stages for variables in statistical adjustment and the derivation of a causal diagram's statistical implications. The main advantage of causal diagrams is that they explicitly reveal the respective model's underlying hypotheses, allowing critical analysis of the implications and thereby facilitating identification of sources of bias and uncertainty in the epidemiological study's results. PMID- 27509551 TI - Causal diagrams: back to the future for Brazilian epidemiology. PMID- 27509552 TI - [Hepatitis C incidence in hemodialysis patients in Brazil from 2000 to 2003]. AB - The study aimed to estimate the incidence of HCV seroconversion in hemodialysis patients in the Brazilian Unified National Health System (SUS). This was a prospective, non-concurrent study using patients' data identified by deterministic and probabilistic record linkage in the SUS information system. The study included 47,079 patients started on hemodialysis between January 1, 2000, and December 31, 2003, followed until seroconversion or conclusion of the study in 2004. Three percent of hemodialysis patients HCV-seroconverted (1.7 per 100 patient-years). Increased risk of HCV seroconversion was associated with age, glomerulonephritis, geographic region, HIV-positivity, and dialysis service. The observed HCV seroconversion rate was similar to that in developed countries, highlighting evidence of transmission among hemodialysis patients. PMID- 27509553 TI - [Dimensional structure of the Brazilian version of the s-EMBU instrument for measuring parental educational practices in adolescents]. AB - The aim of this study was to assess the dimensional structure of the s-EMBU, used to measure parental educational practices in adolescents. The sample included 487 students from Greater Metropolitan Rio de Janeiro, Brazil, in 2013. Mean age was 14 years, and 47% were girls. The original dimensional structure was assessed by confirmatory factor analysis (CFA). The study also applied exploratory structural equation modeling (ESEM). CFA adjustment was unsatisfactory. In light of the ESEM, the most parsimonious solution concerned the three-factor model (RMSEA = 0.03, CFI = 0.97, and TLI = 0.96), but various items in the overprotection dimension showed higher factor loads in the rejection dimension. The items in the rejection and emotional warmth dimensions proved more appropriate. In Brazil, s EMBU partially captures the proposed dimensions for measuring parental educational practices in adolescents. Emotional warmth had its dimensional structure confirmed, but rejection and especially overprotection require further refinement. PMID- 27509554 TI - [Comprehensiveness and healthcare technologies: a narrative on conceptual contributions to the construction of the comprehensiveness principle in the Brazilian Unified National Health System]. AB - Comprehensiveness is the most challenging principle for building health reform in the Brazilian Unified National Health System (SUS). This study aims to identify critical moments in the conceptual debate on comprehensiveness and its contributions to reflection on healthcare technologies in the SUS. The essay addresses some conceptual constructs that approach comprehensiveness as an underlying principle in health programs and actions at various levels and in various dimensions of the healthcare organization - from intersubjective interactions to the organization of regional networks. The study was based on a non-systematic literature review on comprehensiveness and related themes in the Brazilian public health field in the last five decades. The study proposed a chronology/typology spanning the 1960s to the 2010s, divided into four significant periods or categories. The narrative is not intended to be exhaustive, but to build a comprehensive reference base capable of contributing to analyses, assessments, and debates on healthcare organization in the SUS according to the comprehensiveness principle. PMID- 27509555 TI - Predisposing, enabling and need-for-care predictors of adolescents' intention to use sexual health services. AB - BACKGROUND: The study aimed to understand the influence of predisposing, enabling and need-for-care factors on adolescents' intention to use sexual health services, using Andersen's Behavioural Model of Health Service Utilisation to organise and test these factors. METHODS: A sample of predominantly Hispanic teens (n=600) in Los Angeles, California completed a self-report survey about their sexual health knowledge, beliefs, intentions, and behaviours. Hierarchical regression modelling was used to examine the incremental influences on adolescents' intention to use sexual health services of: 1) predisposing sociodemographic factors; 2) predisposing knowledge and beliefs about sexual health; 3) enabling factors regarding perceived access to sexual health services; and 4) a need-for-care factor (sexual experience). RESULTS: Adolescents reported high intentions to use sexual health services (3.25 on a 4-point scale), yet only 42% reported knowing where to access services. Sexual health knowledge and beliefs significantly predicted adolescents' intention to use services beyond the effect of sociodemographics (P<0.001). Enabling factors indicating awareness of and importance attributed to accessibility significantly predicted intention to use services incremental to predisposing factors (P<0.001). However, need for care - that is, sexual experience - was not statistically associated with intention to use services (P=0.402). CONCLUSIONS: Sexual health interventions are needed to provide sexual health information, promote positive beliefs about health care, and ensure adolescents' awareness of and access to sexual health services. PMID- 27509556 TI - President's Message. PMID- 27509557 TI - Medicine Development: What's My Responsibility? PMID- 27509558 TI - Balancing the Risk: Increasing Inpatient Ambulation Without Increasing Falls. PMID- 27509559 TI - Measurement in Intervention Research. PMID- 27509560 TI - Making the Journey from Opioid and Heroin Addiction: One Map for the Clinical Nurse Specialist. PMID- 27509561 TI - Polishing Your Presence Online: Wise Use of Social Media to Enhance Your Reputation. PMID- 27509562 TI - Evaluation of a Regional Australian Nurse-Led Parkinson's Service Using the Context, Input, Process, and Product Evaluation Model. AB - OBJECTIVE: A nurse-led Parkinson's service was introduced at Canberra Hospital and Health Services in 2012 with the primary objective of improving the care and self-management of people with a diagnosis of Parkinson's disease (PD) and related movement disorders. Other objectives of the Service included improving the quality of life of patients with PD and reducing their caregiver burden, improving the knowledge and understanding of PD among healthcare professionals, and reducing unnecessary hospital admissions. This article evaluates the first 2 years of this Service. METHODS: The Context, Input, Process, and Product Evaluation Model was used to evaluate the Parkinson's and Movement Disorder Service. CONTEXT: The context evaluation was conducted through discussions with stakeholders, review of PD guidelines and care pathways, and assessment of service gaps. Input: The input evaluation was carried out by reviewing the resources and strategies used in the development of the Service. PROCESS: The process evaluation was undertaken by reviewing the areas of the implementation that went well and identifying issues and ongoing gaps in service provision. Product: Finally, product evaluation was undertaken by conducting stakeholder interviews and surveying patients in order to assess their knowledge and perception of value, and the patient experience of the Service. Admission data before and after implementation of the Parkinson's and Movement Disorder Service were also compared for any notable trends. RESULTS: CONTEXT: Several gaps in service provision for patients with PD in the Australian Capital Territory were identified, prompting the development of a PD Service to address some of them. Input: Funding for a Parkinson's disease nurse specialist was made available, and existing resources were used to develop clinics, education sessions, and outreach services. PROCESS: Clinics and education sessions were implemented successfully, with positive feedback from patients and healthcare professionals. However, outreach services were limited because of capacity constraints on the Parkinson's disease nurse specialist. Product: The Service has filled an important health need in the local context; 98.3% of patients surveyed reported that the Service met their needs and helped them understand their care plan, achieving the primary objective of improving patient self-management. Interviews with stakeholders provided positive feedback about the value and usefulness of the Service, and healthcare professionals reported improvement in their knowledge about PD management. The evaluation also identified ongoing gaps in service provision and highlighted areas for potential improvement. No discernible trends in admission rates before and after the implementation of the Service were identified. CONCLUSION: The introduction of a nurse-led PD service has had a positive impact on the provision of care for patients with PD and is a valued service. The evaluation highlighted some ongoing gaps in service provision and has generated some recommendations to address these. PMID- 27509563 TI - From Hospital to Ambulatory Care: Realigning the Practice of Clinical Nurse Specialists. AB - PURPOSE/OBJECTIVES: This article describes how a large healthcare organization expanded the practice of clinical nurse specialists from the hospital to the ambulatory setting. BACKGROUND: Clinical nurse specialist practice traditionally focused on actualizing the 3 spheres of influence (patient, nurse, and organization) in the hospital setting. RATIONALE: Changes in the healthcare system shifting patient care to the ambulatory setting created opportunities for clinical nurse specialists to improve patient outcomes in this setting. DESCRIPTION: An innovation framework from the Mayo Clinic Center for Innovation based on inspiration, generation of ideas, experimenting, and diffusion was used to assess and prioritize the work of clinical nurse specialists in the ambulatory setting. OUTCOMES: Clinical nurse specialists became integral members of hospital and ambulatory nursing leadership. In the ambulatory setting, they are partnering to standardize patient care, providing tools for nurses to practice to full scope, and identifying and providing solutions for patient safety issues. CONCLUSION: Aligning clinical nurse specialists in the hospital and ambulatory care settings allows partnership with multidisciplinary teams to ensure that evidence-based practices and standardized care are infused across the continuum of care. IMPLICATIONS: Evidence-based practices and standardized care encourage nurses to practice to full scope and focus on improved patient outcomes. PMID- 27509564 TI - Integrating Retired Registered Nurses Into a New Graduate Orientation Program. AB - PURPOSE: The project goal of was to decrease new graduate nurse (NGN) attrition during the first year of employment by improving communication skills and providing additional mentoring for NGNs employed in a community hospital located in a rural area. DESCRIPTION OF PROJECT: All NGNs participate in the Versant Residency Program. Even with this standardized residency program, exit interviews of NGNs who resigned during their first year of employment revealed 2 major issues: communication problems with patients and staff and perceived lack of support/mentoring from unit staff. A clinical nurse specialist-led nursing team developed an innovative program integrating retired nurses, Volunteer Nurse Ambassadors (VNAs), into the Versant Residency Program to address both of those issues. OUTCOME: All NGNs mentored by a retired nurse remain employed in the hospital (100% retention). Before the VNA program, the retention rate was 37.5%. Both the NGNs and VNAs saw value in their mentor-mentee relationship. There have been no critical incidences or failure to rescue events involving NGNs mentored by a VNA. CONCLUSION: Use of VNAs to support NGNs as they adjust to the staff nurse role can prevent attrition during their first year of nursing practice by providing additional support to the NGN. PMID- 27509565 TI - Two Hours of Teamwork Training Improves Teamwork in Simulated Cardiopulmonary Arrest Events. AB - PURPOSE/AIM: Teamwork during cardiopulmonary arrest events is important for resuscitation. Teamwork improvement programs are usually lengthy. This study assessed the effectiveness of a 2-hour teamwork training program. DESIGN: A prospective, pretest/posttest, quasi-experimental design assessed the teamwork training program targeted to resident physicians, nurses, and respiratory therapists. METHODS: Participants took part in a simulated cardiac arrest. After the simulation, participants and trained observers assessed perceptions of teamwork using the Team Emergency Assessment Measure (TEAM) tool (ratings of 0 [low] to 4 [high]). A debriefing and 45 minutes of teamwork education followed. Participants then took part in a second simulated cardiac arrest scenario. Afterward, participants and observers assessed teamwork. RESULTS: Seventy-three team members participated-resident physicians (25%), registered nurses (32%), and respiratory therapists (41%). The physicians had significantly less experience on code teams (P < .001). Baseline teamwork scores were 2.57 to 2.72. Participants' mean (SD) scores on the TEAM tool for the first and second simulations were 3.2 (0.5) and 3.7 (0.4), respectively (P < .001). Observers' mean (SD) TEAM scores for the first and second simulations were 3.0 (0.5) and 3.7 (0.3), respectively (P < .001). Program evaluations by participants were positive. CONCLUSIONS: A 2 hour simulation-based teamwork educational intervention resulted in improved perceptions of teamwork behaviors. Participants reported interactions with other disciplines, teamwork behavior education, and debriefing sessions were beneficial for enhancing the program. PMID- 27509566 TI - Clinical Nurse Specialist Roles in Conducting Research: Changes Over 3 Years. AB - PURPOSE: The aim of this study is to describe clinical nurse specialists' characteristics, interest, confidence, motivators, and barriers in conducting research. DESIGN: This study was a descriptive, multicohort design. METHODS: Clinical nurse specialists were recruited electronically through national and local organizations to complete anonymous surveys 3 times, over 3 years. Comparative analyses included chi and Kruskal-Wallis tests. RESULTS: Of 2052 responders (initial, n = 629; 18 months, n = 465; and 3 years, n = 958), mean (SD) participant age was 50.3 (9.3) years. Overall, 41.7% of participants were involved as principal or coinvestigators in research. Interest in conducting nursing research (on a 0-100 scale) was 61.1 (38.4) and was lowest among the 18 month time point participant group (score, 39.1 [32.2]) and highest at the 3-year time point (68.3, [30.7]; P < .001). Confidence in conducting research, discussion of statistics, and perceptions of motivators and barriers to conducting research did not differ across time period groups. Access to literature and mentors and research knowledge were the most prevalent barriers to conducting research. CONCLUSIONS: Less than 42% of clinical nurse specialists conducted research and the rate did not change between different time groups. Access and knowledge barriers to conducting research were prominent. Workplace leaders need to consider resources and support of academic educational opportunities to increase research conduct by clinical nurse specialists. PMID- 27509567 TI - Prescriptive Authority and Independent Practice Progress for the Clinical Nurse Specialist-Changes Since 2010. PMID- 27509568 TI - Disruptive Innovation in Graduate Nursing Education: Tipping the Scales for Online Education. PMID- 27509569 TI - Dance 'til the Buffalo Come. PMID- 27509570 TI - "One Flare at a Time": Adaptive and Maladaptive Behaviors of Women Coping With Inflammatory Bowel Disease and Irritable Bowel Syndrome. AB - PURPOSE: The purpose of this investigation is to study the lived experiences of female postsecondary students diagnosed with inflammatory bowel disease and/or irritable bowel syndrome. METHODS: Nine women between the ages of 18 and 26 years were recruited to participate in this study. Participants completed an informed consent form and background questionnaire before completing a semi-structured one on-one interview. This interview explored the lived experiences of these individuals in relation to condition management. RESULTS: Three salient themes that emerged from the data included (1) it can add to my life; (2) why me: my condition runs my life; and (3) I'm doing the best I can with what I have. The salient theme of I'm doing the best I can with what I have, the theme addressed in this article, was subdivided into adaptive and maladaptive coping behaviors. Reasons for the use of these behaviors included to avoid triggers or flare ups/harmful effects, to achieve instant relief/pleasure, to respond to environmental pressures, and to become accustomed to dealing with the everyday hassles of their conditions. CONCLUSION: Community health nurses may become part of the solution to help women with inflammatory bowel disease and irritable bowel syndrome find more adaptive coping behaviors. Other implications are discussed. PMID- 27509571 TI - The Null Effect of Chewing Gum During Hemodialysis on Dry Mouth. AB - AIMS AND OBJECTIVES: The study was conducted to determine the effect of chewing gum during hemodialysis on dry mouth and its symptoms. BACKGROUND: The imposition of fluid restriction and the use of medications that reduce saliva production may lead to dry mouth. DESIGN: This study is a randomized, controlled, single-blind, crossover experimental study. METHODS: The subjects consisted of 61 hemodialysis patients recruited from 4 dialysis centers in southern Turkey. The data were collected using a Patient Identification Form, a Form for Assessing the Symptoms of Dry Mouth, and a Patient Follow-up Form. Saliva samples were obtained for analysis of flow rates. RESULTS: The salivary flow rates of the patients increased during the first hour on the day when gum was chewed, and this increase was statistically significant. However, no significant difference was found between the salivary flow rates at the 0- and 4-hour time points on the day when gum was chewed (P > .05). In addition, the salivary pH values were in the normal range on both days, although the pH values tended to be more acidic on the day when gum was not chewed. CONCLUSIONS: Overall, it was found that chewing gum for 15 minutes each hour during a hemodialysis session did not increase the saliva amount, maintain the pH value of the saliva within a normal range, or control dry mouth symptoms. PMID- 27509572 TI - Making the Journey From Opioid and Heroin Addiction: One Map for the Clinical Nurse Specialist. PMID- 27509573 TI - Gestational Age and the Risk of Maternal Breast Cancer: A Population-Based Case Control Study. AB - There is limited evidence that the gestational age at delivery may influence the risk of maternal breast cancer. While extreme prematurity has been suggested to increase the risk, there seems to be no study available so far that investigates the due effects of a late delivery. This research aimed to identify the impact of both preterm and late deliveries on the risk of maternal breast cancer within a period of 5 years after birth. Our dataset was created by linking data from the Nevada Cancer Registry database (1995-2008) and the birth certificates issued by the Nevada State Health Division (1994-2003). The study cohort consisted of 213,250 women who gave birth from January 1, 1994 to December 31, 2003. We performed a nested population-based case-control study on 126 Nevada mothers with a first lifetime breast cancer diagnosed from January 1, 1995 through December 31, 2003, and 504 Nevada cancer-free mothers. Women with pregnancies who progressed beyond 40 weeks of gestation were at a significantly lower risk of developing breast cancer for the 5-year period following a delivery, when compared to women who delivered at 37-40 weeks of gestation (OR: 0.33, 95% CI: 0.11-0.92) in a multivariate model. Additional pregnancy characteristics did not significantly predict the risk of maternal breast cancer. Pregnancies that extended beyond 40 weeks of gestation were strongly associated with a lower likelihood of premenopausal breast cancer. Biological plausibility for this association may correspond to the fact that as pregnancy develops into more advanced stages, mammary cells have more time to attain complete differentiation and maturation; a process that starts early in the third trimester. PMID- 27509574 TI - A cost utility analysis of the clinical algorithm for nasogastric tube placement confirmation in adult hospital patients. AB - AIM: The aim of this study was to evaluate the effectiveness of pH paper testing of aspirate and chest x-ray for determining nasogastric tube (NGT) placement in terms of cost and patient outcome. BACKGROUND: Nasogastric tubes are frequently used in clinical practice, however during insertion the practitioner is blinded as to the precise final location. Despite robust checking procedures, recognized patient morbidity and mortality associated with this procedure have resulted in national safety alerts prompting the revision of all NGT care clinical guidelines. DESIGN: Cost utility analysis using economic modelling. METHODS: A decision tree was built and populated with effectiveness data gathered from a systematic search of the extant literature. Specificity, pooled sensitivity and event probabilities were calculated using statistical software. Patient outcome was measured in terms of quality of life. Health state utilities were gathered from a sample (n = 23) of adult surgical patients using a recognized instrument. Cost data were gathered using published sources. The study adopted a third party payer perspective in a Scottish context and was completed in June 2013. RESULTS: The results confirm that the current UK algorithm advocated by the National Patient Safety Agency appears to offer the most cost effective approach to NGT confirmation in terms of cost and patient outcome. Sensitivity analyses indicate that these findings may be significantly altered by tube aspiration success and the rates of chest x-ray interpretation errors. CONCLUSION: The results confirm current UK recommendations and have wider policy implications for those areas, whereby chest x-ray is recommended as the first and only acceptable confirmation approach. PMID- 27509575 TI - Mismatch repair system proteins in oral benign and malignant lesions. AB - Different environmental agents may cause DNA mutations by disrupting its double strand structure; however, even normal DNA polymerase function may synthesize mismatch nucleotide bases, occasionally demonstrating failure in its proofreading activity. To overcome this issue, mismatch repair (MMR) system, a group of proteins specialized in finding mispairing bases and small loops of insertion or deletion, works to avoid the occurrence of mutations that could ultimately lead to innumerous human diseases. In the last decades, the role of MMR proteins in oral carcinogenesis and in the development of other oral cavity neoplasms has grown, but their importance in the pathogenesis and their prognostic potential for patients affected by oral malignancies, especially oral squamous cell carcinoma (OSCC), remain unclear. Therefore, in this manuscript we aimed to review and critically discuss the currently available data on MMR proteins expression in oral potentially malignant lesions, in OSCC, and in other oral neoplasms to better understand their relevance in these lesions. PMID- 27509576 TI - Washing of platelets can be fully automated using a closed-system cell processor and BRS-A platelet additive solution. AB - This study evaluated the in vitro properties of platelets (PLTs) washed with BRS A additive solution in the Haemonetics ACP215 automated processing system. Two washing modes, 'manually/automatically adding ACD-A to BRS before/during the washing process', represented the control and test groups, respectively. Outcomes were compared over 7 days of storage (n = 7, for both). PLT recovery following washing processing (26-27 min) was 86.2 +/- 1.7% and 86.0 +/- 2.2% and plasma protein removal was 98.8 +/- 0.3% and 99.0 +/- 0.2% in the control and test groups, respectively (not significant). Both groups exhibited comparable in vitro properties. PMID- 27509577 TI - A rapidly enlarging nodule on the scalp in an infant. PMID- 27509579 TI - Marital quality, marital dissolution, and mortality risk during the later life course. AB - This study examines the relationship between later-life marital quality, marital dissolution, and mortality using discrete-time event history models with data from nine waves (1992-2008) of the Health and Retirement Study (n = 7388). Results show marital status is more important for men's mortality risk than women's, whereas marital quality is more important for women's survival than men's. Being widowed or divorced more than two years raises mortality risk for men, but later-life marital dissolution is not significantly associated with women's mortality risk, regardless of the type of dissolution or length of time since it occurred. Low-quality marital interaction is negatively related to women's odds of death, but none of the marital quality measures are significantly associated with mortality for men. Marital satisfaction moderates the relationship between widowhood and mortality for women, but the relationship between marital dissolution and mortality is similar for men regardless of marital quality prior to divorce/widowhood. Results suggest the importance of accounting for both marital status and marital quality when examining older individuals' mortality risk. PMID- 27509578 TI - Hypogammaglobulinemia and risk of severe infection in kidney transplant recipients. AB - BACKGROUND: Recent data have outlined a link between hypogammaglobulinemia (HGG) and infection risk and suggested that HGG correction may decrease post-transplant infections. METHODS: We analyzed the risk factors of HGG and the relationship between HGG and the risk of severe infection in a cohort of 318 kidney transplant recipients (KTR) who were transplanted between 2003 and 2013. Immunoglobulin (Ig) concentration was measured prospectively at day 15 (D15), month 6 (M6), month 12 (M12), and month 24 (M24) post transplant. RESULTS: The prevalence of IgG HGG was 56% and 36.8% at D15 and M6, respectively. Age was the sole identified risk factors for D15 IgG HGG (odds ratio [OR] 1.02, P = 0.019). Risk factors for M6 IgG HGG were the presence of D15 IgG HGG (OR 6.41, P < 0.001) and treatment of acute rejection (OR 2.63, P = 0.014). Most infections occurred between D15 and M6 post transplant. Only age (hazard ratio 1.03, P < 0.001) was identified as a risk factor of infection between D15 and M6 post transplant. Survival free of infection (overall infections and bacterial or viral infections) did not differ significantly between patients with or without D15 IgG HGG. Only septicemia occurring between M6 and M12 post transplant was more frequently observed in patients with HGG. The low prevalence of severe HGG (<400 mg/dL) did not allow conclusions on the infectious risk associated with this patient subgroup. CONCLUSIONS: This study does not support the existence of a strong link between post-transplant HGG and the risk of severe infections in KTR. Correction of HGG to minimize the risk of severe infections in KTR is thus questionable and needs to be reevaluated in prospective studies. PMID- 27509580 TI - The International Society of Nephrology (ISN). Roles & challenges in Africa and other resource-limited communities. AB - ISN (the International Society of Nephrology) is a global organization with more than 9,000 members in 130 countries. The ISN's mission is to "advance the diagnosis, treatment, and prevention of kidney diseases in the developing and developed world". ISN delivers this mission in low-resource settings through its five education and training programs available exclusively to low- and middle income countries. These programs are designed to enable sustainable growth in capacity in nephrology and related disciplines to provide the basis for the improvement of care for kidney patients worldwide. ISN also directs its efforts towards advocacy for kidney health and kidney care, seeking to increase understanding of kidney disease among the general population, health professionals, and health policy makers. Such advocacy is challenging because of the complexity of kidney health messages; there is a need to emphasize affordable healthcare solutions for prevention and treatment of acute kidney injury (AKI), as well as the prevention and management of chronic kidney disease (CKD), and the provision of renal replacement therapy (both chronic dialysis and kidney transplantation) that is both affordable and ethically acceptable. PMID- 27509581 TI - Kidney disease in disadvantaged populations: An unconquered challenge. PMID- 27509582 TI - Burden of end-stage renal disease (ESRD) in Latin America. AB - INTRODUCTION: End-stage renal disease (ESRD) represents a major challenge for Latin America (LA). Epidemiological information needed to assist in the development of ESRD care in the region. The Latin American Dialysis and Renal Transplant Registry (RLADTR), has published several reports and its continuity has implied a sustained effort of the entire LA Nephrology community. This paper summarizes the results corresponding to year 2012. METHODS: Our methods have been reported previously. Participant countries complete an annual survey collecting data on incident and prevalent patients undergoing renal replacement treatment (RRT) in all modalities. RESULTS: 20 countries participated in the surveys, more than 90% of the Latin America. The prevalence of ESRD under RRT in LA increased from 119 patients Per million population (pmp) in 1991 to 661 pmp in 2012. HD continues to be the treatment of choice in the region (82%). A wide rate variation in incidence is observed: from 472.7 in Jalisco (Mexico) to 14 pmp in Guatemala. Diabetes remained the leading cause of ESRD. The most frequent cause of death was cardiovascular. There is a wide rate variation of nephrologist by country, from 1.8 pmp in Honduras to 45.2 pmp in Cuba. DISCUSSION: The heterogeneity or even absence of registries in some LA countries is congruent with the inequities in access to RRT in such countries, as well as the availability of qualified personnel. The SLANH is currently running training programs as well as cooperation programs between LA countries to help the least developed start ESRD programs. In this spirit, RLADTR is training personnel to carry out dialysis and transplant registries in LA. PMID- 27509583 TI - From man to fish: What can Zebrafish tell us about ApoL1 nephropathy? AB - BACKGROUND: Risk variant Apolipoprotein L1 (G1/G2) are strongly associated with a spectrum of kidney disease in people of recent African descent. The mechanism of ApoL1 nephropathy is unknown. Podocytes and/or endothelial cells are the presumed target kidney cells. Given the close homology in structure and function of zebrafish (ZF) pronephros and human nephron, we studied the effect of podocyte specific or endothelium-specific expression of ApoL1 (G0, G1, or G2) on the structure and function of ZF pronephros. METHODS: Wild type (G0) or risk variant ApoL1 (G1/G2) were expressed in podocyte-specific or endothelium-specific under podocin/Flk promoters, respectively, using Gal4-UAS system. Structural pronephric changes were studied with light and electron microscopy (EM). Proteinuria was assayed by measuring renal excretion of GFP-vitamin D binding protein. Puromycin aminonucleoside (PAN) was used as inducer of podocyte injury. RESULTS: Endothelial-specific transgenic expression of G1/G2 is associated with endothelial injury indicated by endothelial cell swelling, segmental early double contours, and loss of endothelium fenestrae. Podocyte specific expression of G1 is associated with segmental podocyte foot process effacement and irregularities relative to G0. Despite the histological changes, the expression of G1/G2 alone in podocyte or endothelium compartment is not associated with edema, proteinuria, or gross whole fish phenotype. Moreover, PAN produced equal pericardial edema in all transgenic fish as well as nontransgenic controls. CONCLUSIONS: Transgenic expression human ApoL1 (G1/G2) is associated with histologic abnormalities in ZF glomeruli but is insufficient to cause quantifiable renal dysfunction. This finding supports the necessity of a "second hit" in the pathogenesis/progression of ApoL1-associated nephropathy. PMID- 27509584 TI - Fever, thrombocytopenia, and AKI-A profile of malaria, dengue, and leptospirosis with renal failure in a South Indian tertiary-care hospital. AB - INTRODUCTION: In the tropics, the triad of fever, thrombocytopenia, and AKI portends a grim prognosis with high mortality and a severe strain on already stretched resources. Malaria, dengue, and leptospirosis account for most cases. We undertook a review of cases to determine factors accounting for adverse prognosis. METHODS: All patients presenting to the emergency room (ER) with a history of fever, thrombocytopenia, and renal failure were included in the study. Patients were followed until discharge or death, and end points looked at were 1 week and 30-day mortality, and renal function upon discharge. Parameters like liver function test (LFT), renal function, and platelet count upon discharge were also documented. RESULTS: A total of 43 patients was included in the study. Mean age was 42.5 years with 86% males. Mean APACHE and SOFA scores on admission were 23.89 and 15.42, respectively. Mean admission platelet counts were 41,000. Mean serum creatinine was 4.1, and bilirubin was 9.94. A platelet count of < 34,000, serum creatinine of > 4, albumin of > 2.3, SOFA score of > 20, and APACHE score of > 32.2 were significantly predictive of 1 week mortality. Need for mechanical ventilation, oliguria on admission, and need for dialysis all were highly predictive of 30-day mortality. In addition, a serum bicarbonate of < 12, INR of > 1.5, hemoglobin of < 9.5 were highly predictive of higher 30 day mortality. Overall, 1-week mortality was 16.3%, of which 48% was accounted for by patients with leptospirosis. CONCLUSIONS: Factors like low platelet count, oliguria, need for dialysis, high APACHE and SOFA scores on admission, need for mechanical ventilation, and low serum albumin portend a grave prognosis. There is need for randomized control trials (RCT) to further determine adverse prognostic factors in this subsect of patients. PMID- 27509585 TI - Spectrum of kidney diseases in Africa: malaria, schistosomiasis, sickle cell disease, and toxins. AB - Kidney diseases have assumed epidemic proportions in both developed and developing countries, particularly chronic kidney disease (CKD). While treatment modalities are available and accessible in developed economies with improvement in outcomes, survival, and quality of life, they are either unavailable or inaccessible in nations with emerging economies, particularly in sub-Saharan Africa (SSA), with an attendant worsening outcome and survival for CKD patients. The epidemiology of CKD in SSA has revealed that it preferentially affects adults in their economically productive years, usually below the age of 50 years, with consequent drain on the economy. This derives mainly from the major etiologies in the region, which are infection-induced chronic glomerulonephritis and hypertension, compounded by poverty as well as societal and health underdevelopment, poor resource allocation to health, and underdeveloped health infrastructures. This has made preventive nephrology a major goal in the sub region, although those who have already developed CKD must be managed up to tertiary levels. In this review, we assessed the contributions of parasitic diseases (i.e., malaria and schistosomiasis), sickle cell disease and nephrotoxins with the aim of espousing their contributions to the burden of kidney disease, and proposing management options with the goal of ultimately reducing the burden of kidney disease in these disadvantaged populations. PMID- 27509586 TI - Renal histology patterns in a prospective study of nephrology clinics in Lagos, Nigeria. AB - BACKGROUND: The burden of chronic kidney disease (CKD) in Nigeria is quite alarming. The prevalence of CKD ranges from 11 - 23.5%. Hypertension and chronic glomerulonephritis (CGN) remain the two leading causes of CKD in Nigeria. The etiology of CKD in many of these patients remains unknown, as few biopsies are done. In order to demystify the various glomerular diseases that culminate in CGN, performing a kidney biopsy offers a ray of hope. Few studies on renal biopsies have emanated from Nigeria; this study, however, is unique as the histopathological analysis involves light, immunofluorescence, and electron microscopies. METHODS: This study involved two teaching hospitals in Lagos. Patients from these centers, who met the inclusion criteria, underwent real-time renal biopsy; after providing written informed consent. RESULTS: Among the 52 patients analyzed 26, (50%) were males. The mean age was 31.7 +/- 12.8, with age range of 13 - 56 years. The most common indication for kidney biopsy was nephrotic syndrome, accounting for 73%. Focal segmental glomerulosclerosis (FSGS) was the most frequent histopathological diagnosis seen in 25 patients (48.1%). CONCLUSION: The findings from this study highlight the role that renal biopsy plays in making a concrete diagnosis in nephrology practice in a developing country like Nigeria. As almost 80% of the study population was made up of patients with FSGS and lupus nephritis, it remains to be determined by further studies among our patients, the role that Apolipoprotein L1 (APOL 1) gene mutation will play in the etiology of renal diseases in Nigeria. PMID- 27509587 TI - Advances and challenges in renal transplantation in Latin America. AB - Latin America is a region made up of 33 countries that share many characteristics with each other. Since the first kidney transplant in Argentina in 1957, most of the Latin American countries have had a continuous increase in renal transplant activity, accounting for an increase in the total number of kidney transplants over time. In the last years, several advances have been made in the area of renal transplantation in Latin America: There are transplantation activities in almost all countries, the kidney transplantation rate from deceased donors has steadily increased, and almost all the countries have an appropriate legislation for transplantation activity. But much remains to be done to increase the kidney transplantation rate in order to cover the current demand. This could be achieved by ensuring unlimited access to renal transplantation, by improving deceased donor programs to match the increasing burden of chronic diseases, and by incorporating new technology, new tools, and more trained people in transplant programs. PMID- 27509588 TI - Correlation between volume overload, chronic inflammation, and left ventricular dysfunction in chronic kidney disease patients. AB - BACKGROUND: Fluid overload is common in chronic kidney disease (CKD) patients, potentially driving chronic inflammation and left ventricular dysfunction. We investigated the association between volume overload, chronic inflammation, and left ventricular dysfunction across subgroups of CKD patients. METHODS: The study included 160 participants, comprising peritoneal dialysis (PD), hemodialysis (HD), stage-3 CKD patients, and age- and sex-matched controls (40 in each group). Fluid status was assessed using a body composition monitor (BCM); serum endotoxin, lipopolysaccharide binding protein (LBP), C-reactive protein (CRP). and interleukin-6 (IL-6) levels were measured as markers of inflammation. Echocardiography was done to assess left ventricular dimension and function. RESULTS: Endotoxemia and volume overload were common across the spectrum of CKD patients and were aggravated by worsening kidney function. Among HD cohorts, postdialysis endotoxemia was increased among patients with dialysis-induced hemodynamic instability and was also closely related to ultrafiltration volume. Endotoxin, IL-6, CRP, and LBP levels were elevated in patients with volume overload compared to euvolemic patients (p < 0.05). Patients with elevated circulating endotoxemia had higher left ventricular mass index (LVMI) compared to patients with lower endotoxin levels. Fluid overload correlated with endotoxin levels, IL-6, and LVMI; while LVMI correlated weakly with LBP and CRP. CONCLUSION: CKD patients typically presented with significant endotoxemia and overt volume overload, which may contribute significantly to chronic low-grade inflammation and left ventricular dysfunction. An additive contribution from hemodialysis treatment may strongly enhance the severity of endotoxemia in HD patients. PMID- 27509589 TI - The challenges of ESRD care in developing economies: sub-Saharan African opportunities for significant improvement. AB - Chronic kidney disease (CKD) is a significant cause of morbidity and mortality in sub-Saharan Africa. This, along with other noncommunicable diseases like hypertension, diabetes, and heart diseases, poses a double burden on a region that is still struggling to cope with the scourge of communicable diseases like malaria, tuberculosis, HIV, and more recently Ebola. Causes of CKD in the region are predominantly glomerulonephritis and hypertension, although type 2 diabetes is also becoming a significant cause as is the retroviral disease. Patients are generally younger than in the developed world, and there is a significant male preponderance. Most patients are managed by hemodialysis, with peritoneal dialysis and kidney transplantation being available in only few countries in the region. Government funding and support for dialysis is often unavailable, and when available, often with restrictions. There is a dearth of trained manpower to treat the disease, and many countries have a limited number of units, which are often ill-equipped to deal adequately with the number of patients who require end stage renal disease (ESRD) care in the region. Although there has been a significant improvement when compared with the situation, even as recently as 10 years ago, there is also the potential for further improvement, which would significantly improve the outcomes in patients with ESRD in the region. The information in this review was obtained from a combination of renal registry reports (published and unpublished), published articles, responses to a questionnaire sent to nephrologists prior to the World Congress of Nephrology (WCN) in Cape Town, and from nephrologists attending the WCN in Cape Town (March 13 - 17, 2015). PMID- 27509590 TI - Peritoneal dialysis treatment of metformin-associated lactic acidosis in a diabetic nephropathy patient?. AB - We report a case of metformin-associated lactic acidosis (MALA) in a 66-year-old man with end-stage renal disease on peritoneal dialysis (PD). The patient presented with severe lactic acidosis and was treated successfully with automated peritoneal dialysis (APD). During the treatment, PD solution was prepared from hemofiltration substitute fluid. The prescription was 8 cycles of 2,000 mL over 24 hours with the prepared solution, and venoclysis with sodium bicarbonate to improve the acidosis. After 3 days of treatment, his lactic acidosis was corrected. This case demonstrated that PD using hemofiltration substitute fluid is an option for patients with MALA.?. PMID- 27509591 TI - Encapsulated platelets modulate kupffer cell activation and reduce oxidative stress in a model of acute liver failure. AB - Acute liver failure (ALF) is characterized by massive hepatocyte cell death. Kupffer cells (KC) are the first cells to be activated after liver injury. They secrete cytokines and produce reactive oxygen species, leading to apoptosis of hepatocytes. In a previous study, we showed that encapsulated platelets (PLTs) increase survival in a model of ALF. Here, we investigate how PLTs exert their beneficial effect. Wistar rats submitted to 90% hepatectomy were treated with PLTs encapsulated in sodium alginate or empty capsules. Animals were euthanized at 6, 12, 24, 48, and 72 hours after hepatectomy, and livers were collected to assess oxidative stress, caspase activity, and gene expression related to oxidative stress or liver function. The number of KCs in the remnant liver was evaluated. Interaction of encapsulated PLTs and KCs was investigated using a coculture system. PLTs increase superoxide dismutase and catalase activity and reduce lipid peroxidation. In addition, caspase 3 activity was reduced in animals receiving encapsulated PLTs at 48 and 72 hours. Gene expression of endothelial nitric oxide synthase and nuclear factor kappa B were elevated in the PLT group at each time point analyzed. Gene expression of albumin and factor V also increased in the PLT group. The number of KCs in the PLT group returned to normal levels at 12 hours but remained elevated in the control group until 72 hours. Finally, PLTs modulate interleukin (IL) 6 and IL10 expression in KCs after 24 hours of coculture. In conclusion, these results indicate that PLTs interact with KCs in this model and exert their beneficial effect through reduction of oxidative stress that results in healthier hepatocytes and decreased apoptosis. Liver Transplantation 22 1562-1572 2016 AASLD. PMID- 27509592 TI - Insular gliomas and the role of intraoperative assistive technologies: Results from a volumetry-based retrospective cohort. AB - INTRODUCTION: In the field of Glioma surgery, there has been an increasing interest in the use of assistive technologies to overcome the difficulty of preserving brain function while improving surgical radicality. In most reports, tumor localization has seldom been considered a variable and the role of intraoperative adjuncts is yet to be determined for gliomas of the insula. OBJECTIVES: To evaluate the efficacy of fluorescence-guided resection with 5-ALA, intraoperative neurophysiological monitoring (IOM), neuronavigation, and tractography in the Extent of Resection (EOR), functionality scores, overall survival (OS) and progression-free survival (PFS) in a retrospective cohort of insular gliomas. METHODS: We reviewed all cases of insular tumors operated on at the Department of Neurosurgery, University Hospital of Tubingen - Germany, between May 2008 and November 2013. EOR was determined by volumetric analysis. Mann Whitney, Chi-square and Kaplan Meier functions were used for assessment of each technology's effect on primary and secondary outcomes. RESULTS: 28 cases (18 men (64%) and 10 women (36%); median age at diagnosis: 52.5 years, range 12 - 59) were considered eligible for analysis. High grade and low grade gliomas accounted for 20 (71%) and 8 (29%) cases, respectively. The most used technologies were IOM (64%) and Neuronavigation (68%). 5-ALA was the only technique associated with EOR >=90% (p=0.05). Tractography determined improvement in the Karnofsky Performance Scale (50% vs. 5% cases improved, p=0.02). There was a positive association between the use of neuronavigation and overall survival (23 vs. 27.4 months, p=0.03), but the use of 5-ALA was associated with shorter OS (34.8 vs. 21.1 months, p=0.01) and PFS (24.4 vs. 11.8, p=0.01). CONCLUSIONS: We demonstrate for the first time that for insular gliomas 5-ALA plays a role in achieving higher EOR, although this technology was associated with poor OS and PFS; also tractography and neuronavigation can be of great importance in the treatment of insular gliomas as they determined better functionality and OS in this study, respectively. Prospective studies with a more prominent sample and proper multivariate analysis will help determine the real benefit of these adjuncts in the setting of insular gliomas. PMID- 27509593 TI - Free radicals and antioxidant enzymes in older adults after regular senior elastic band exercising: an experimental randomized controlled pilot study. AB - AIM: The aim of this study was to pilot test the effects of regular senior elastic band exercises on the generation of free radicals and antioxidant enzyme activities in older adults. BACKGROUND: Long-term regular exercises have positive health promotion outcomes. On the contrary, high-intensity, high-speed and short term exercises in older adults may increase free radicals and cause chronic disease and ageing effect. DESIGN: A prospective randomized controlled pilot study. METHODS: Data were collected during 2012. Twenty-five older adults were recruited from a community care centre, southern Taiwan and were randomly assigned to either an experimental or control group. Twenty-two participants completed the study: experimental group (n = 10) and control group (n = 12). The experimental group performed 6-month senior elastic band exercises while the control group kept regular daily routines. Both groups received blood tests (thiobarbituric acid-reacting substances and glutathione peroxidase) 30 minutes before the study began and 1 hour after the final intervention treatment. RESULTS: At the end of the 6-month senior elastic band exercises, no statistically significant differences in thiobarbituric acid-reacting substances and glutathione peroxidase values between the experimental and control groups. No significant differences existed in both thiobarbituric acid-reacting substances and glutathione peroxidase values before and after the 6-month senior elastic band exercises either. CONCLUSIONS: Regular senior elastic band exercises did not increase the generation of free radicals and antioxidant enzyme activities. Senior elastic band exercises have the potential to be promoted among older adults in the community as an exercise option without adverse effects on free radicals and have potential for mitigating ageing and increasing disease control. PMID- 27509594 TI - Preclinical acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]fluorocholine in mice. AB - [(18)F]Fluorocholine ([(18)F]FCH) has been proven to be effective in prostate cancer. Since [(18)F]FCH is classified as a new radiopharmaceutical in Brazil, preclinical safety and efficacy data are required to support clinical trials and to obtain its approval. The aim of this work was to perform acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]FCH. The results could support its use in nuclear medicine as an important piece of work for regulatory in Brazil. PMID- 27509595 TI - Retention of barium and europium radionuclides from aqueous solutions on ash based sorbents by application of radiochemical techniques. AB - New materials were synthesized for application in sorption of radionuclides from aqueous solutions. The elaboration was performed by conversion of power plant ash using the hydrothermal method under optimum experimental conditions. Sodalite, Na Y, and analcime were formed from ash precursor during the treatment, exhibiting thermal stability as revealed by the characterization by X-ray diffraction (XRD) and thermogravimetric differential thermal analysis (TG-DTA). The Brunauer-Emmett Teller (BET) surface area and pore volume were determined and they presented higher values than plant ash. The ability of the new products to retain Ba and Eu radionuclides was studied in aqueous solutions using (133)Ba and (152)Eu as tracers and gamma-ray spectroscopy under batch experiments. The experimental data were modeled by the Langmuir and Freundlich equations, whereas sorption kinetics measurements were performed at 293, 308, and 323K and thermodynamic parameters were calculated. The release of the sorbed ions into the environment was also tested by leaching experiments. The results of these tests indicated that the synthesized materials are very efficient in removing the aforementioned metals from aqueous solutions and can be considered as potential low-cost sorbents in nuclear waste management. PMID- 27509596 TI - Palliative Care Congress abstracts. PMID- 27509597 TI - Evaluation of certain veterinary drug residues in food. Eighty-first report of the Joint FAO/WHO Expert Committee on Food Additives. AB - This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of residues of certain veterinary drugs in food and to recommend maximum levels for such residues in food. The first part of the report considers general principles regarding the evaluation of residues of veterinary drugs within the terms of reference of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), including MRLs for generic fish species, acute reference doses (ARfDs) for veterinary drugs, an approach for dietary exposure assessment of compounds used for multiple purposes (i.e veterinary drugs and pesticides), dietary exposure assessment for less-than-lifetime exposure, and the assessment of short-term (90-day and 12-month) studies in dogs. Summaries follow of the Committee's evaluations of toxicological and residue data on a variety of veterinary drugs: two insecticides (diflubenzuron and teflubenzuron), an antiparasitic agent (ivermectin), an ectoparasiticide (sisapronil) and a beta2 adrenoceptor agonist (zilpaterol hydrochloride). In addition, the Committee considered issues raised in concern forms from the Codex Committee on Residues of Veterinary Drugs in Foods on lasalocid sodium, an antiparasitic agent. Annexed to the report is a summary of the Committee's recommendations on these drugs, including acceptable daily intakes (ADIs), ARfDs and proposed MRLs. PMID- 27509598 TI - [Discussion on the impact of acupuncture for the pregnancy of in vitro fertilization-embryo transfer]. AB - The impact of acupuncture for the pregnancy of in vitro fertilization-embryo transfer (IVF-ET) is discussed in the paper. Nowadays there are various conclusions about the impact of acupuncture for IVF-ET, and it may result from the differences in research designs. The effect is closely related to the demographic and clinical characteristics of subjects, such as age, the diagnosis of barrenness, blood flow index of uterine spiral arteries, the cycle of IVF, etc. Besides, the efficacy is influenced by treatment based on syndrome differentiation or not, the frequency and course of acupuncture in both the treating group and the control group, etc. If more reasonable design is achieved in the further study based on them, more reliable evidence will be provided for the effect and mechanism of the pregnancy of IVF-EF by acupuncture. PMID- 27509599 TI - [Acupoints selection based on "disease-symptom-location" combination and acupuncture treatment of pattern/syndrome differentiation]. AB - The pattern/symptom differentiation system in acupuncture treatment is lack of the unique characteristics and advantages in theory and clinical practice and it just rigidly adopts the methods of pattern/symptom differentiation of the other disciplines in TCM. In fact, it is necessary to have the unique and more practical theoretic system to guide acupuncture treatment. According to the characteristics of acupuncture in diagnosis and treatment, the acupoints selection based on "disease-symptom-location" combination becomes the law of acupuncture treatment. The acupoints selection based on "disease-symptom location" combination is the expression to concretize the diagnosis and treatment of disease under the guidance of pattern/syndrome differentiation. Both of them are originated from the general principles of TCM and for the particular disciplines of TCM. The acupoints selection based on "disease-symptom-location" combination benefits the promotion and application of acupuncture. PMID- 27509600 TI - [Acupuncture method of "Huoxue Sanfeng, Shugan Jianpi" for morning blood pressure in patients with cerebral infraction combined with essential hypertension: a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical effects of acupuncture method of "Huoxue Sanfeng, Shugan Jianpi" (activating blood and eliminating wind, soothing liver and strengthening spleen) on morning blood pressure in patients with cerebral infraction combined with essential hypertension. METHODS: Sixty-eight patients were randomly divided into an observation group and a control group, 34 cases in each one. The patients in the two groups were treated with acupuncture method of "Xingnao Kaiqiao" (consciousness-restoring resuscitation) and oral administration of nifedipine. In addition, patients in the observation group were treated with acupuncture method of "Huoxue Sanfeng, Shugan Jianpi" that met the criteria of standard manipulation, in which bilateral Renying (ST 9), Quchi (LI 11), Hegu (LI 4), Zusanli (ST 36) and Taichong (LR 3) were selected. The treatment was given once a day, five times a week, for totally six weeks. The improvement and control rate of morning blood pressure in the two groups were observed. RESULTS: (1) After treatment, the morning blood pressures were decreased significantly in the two groups (all P < 0.05); after 15 treatments, the reduction of systolic pressure and diastolic pressure in the observation group was superior to that in the control group, but the difference was not significant (both P > 0.05); after 30 treatments, the reduction of systolic pressure and diastolic pressure in the observation group was significantly superior to that in the control group (both P < 0.05). (2) After 30 treatments, the control rate of morning blood pressure in the observation group was significantly higher than that in the control group [82.4% (28/34) vs 58.8% (20/34), P < 0.05]. CONCLUSION: Acupuncture method of "Huoxue Sanfeng, Shugan Jianpi", characterized with standard manipulation criteria, can effectively control morning blood pressure in patients with cerebral infraction combined with essential hypertension. PMID- 27509601 TI - [Warming-needle moxibustion for cervical headache: a randomized controlled trial]. AB - OBJECTIVE: To evaluate the clinical efficacy of warming-needle moxibustion on cervical headache. METHODS: Sixty-one patients of cervical headache were randomly divided into a warming-needle moxibustion group (30 cases) and an acupuncture group (31 cases). Tianzhu (BL 10), Fengchi (GB 20), Wangu (GB 12), Tianyou (TE 16), Hegu (LI 4), Taichong (LR 3) and Zulinqi (GB 41) were selected in the two groups. Patients in the acupuncture group were treated with acupuncture; patients in the warming-needle moxibustion group were treated with warming-needle moxibustion at Tianzhu (BL 10), Fengchi (GB 20) and Wangu (GB 12) and acupuncture at the remaining acupoints. The treatment was given once every other day, 3 times a week, and totally 4-week treatment was given. The duration and frequency of headache, numerical rating scale (NRS) of headache and cervical range of motion (ROM) were compared before and after treatment in the two groups; also the efficacy of the two groups was evaluated. RESULTS: After treatment, the duration and frequency of headache, headache NRS.and cervical ROM score were improved in both groups (all P < 0.05), which were more significant in the warming-needle moxibustion group (all P < 0.05). The total effective rate was 84.3% (25/30) in the warming-needle moxibustion group, which was significantly superior to 61.3% (19/31) in the acupuncture group (P < 0.05). CONCLUSION: The warming-needle moxibustion presents significant efficacy on cervical headache, which can obviously improve headache symptoms and cervical ROM. PMID- 27509602 TI - [Clinical efficacy comparison between electroacupuncture and meloxicam in the treatment of knee os- teoarthritis at the early and middle stage: a randomized controlled trial]. AB - OBJECTIVE: To compare the clinical efficacy on knee osteoarthritis (KOA) at the early and middle stage between electroacupuncture (EA) and meloxicam. METHODS: Ninety patients of KOA at the early and middle stage were randomized into an EA group and a meloxicam group, 45 cases in each one. In the EA group, EA was applied to Dubi (ST 35), Neixiyan (EX-LE 4), Liangqiu (ST 34), Heding (EX-LE 2), Xuehai (SP 10), Yan- glingquan (GB 34) and Zusanli (ST 36); the needles were retained for 20 min and EA was applied once every two days. In the meloxicam group, the meloxicam tablets were prescribed for oral administration, 7. 5 mg, once a day. The treatment lasted for 6 weeks in the two groups. The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) score, rectus femoris muscle tension, the 8-foot walking test and 5-time sit-to-stand test were adopted to observe and compare the effects in the two groups. RESULTS: After treatment, every item score in WOMAC was reduced after treatment (all P < 0.05), but the difference was not significant between the two groups (all P > 0.05). In the EA group, the rectus femoris tension after treatment was reduced as compared with that before treatment (P < 0.05) and the reducing result was much more apparent as compared with that in the meloxicam group (P < 0.05). For the 8-foot walking test and 5-time sit-to-stand test, the time was shortened after treatment in the two groups (all P < 0.05) and the result in the EA group was much more obvious than that in the meloxicam group (both P < 0.05). CONCLUSION: Both EA and meloxicam are effective in the treatment of KOA at the early and middle stage. EA improves rectus femoris tension and recovers the internal mechanics balance and the efficacy is better than that of meloxicam. PMID- 27509603 TI - [Clinical efficacy of multi-pattern detumescence after total knee arthroplasty treated with acupoint massage and mild moxibustion]. AB - OBJECTIVE: To discuss the clinical effect on swelling and pain after total knee arthroplasty treated with acupoint massage, mild moxibustion and routine detumescence. METHODS: One hundred and twenty patients of knee osteoarthritis (KOA) after total knee arthroplasty (TKA), were randomized into an observation group and a control group, 60 cases in each one. In the control group, after TKA, the routine detumescence was applied, including elastic bandage compression, the operated limb raising exercise, knee joint braking, local ice compress, intermittent pneumatic compression, active ankle pumping and quadriceps contraction exercise, continuous passive mechanical exercise, using stretch socks, oral administration of rivaroxaban tablets, 10 mg, once a day, continuously for 21 to 24 days. In the observation group, on the basis of the routine detumescence as the control group, 1 h after operation, acupoint massage was done at Zusanli (ST 36) and Sanyinjiao (SP 6) till soreness and distension presented, twice a day; 48 h after operation, mild moxibustion was intervened at Zusanli (ST 36) and Sanyinjiao (SP 6), avoiding burning pain, once a day, continuously till the 7th day after operation. Before and after operation, the limb swelling condition and the scores of visual analogue scale (VAS) and HSS (hospital for special surgery) knee joint function were observed in the patients of the two groups. RESULTS: On the 1st, 3rd, 5th, 7th and 14th days after operation, the swelling incidence in the observation group was apparently lower than that in the control group (P < 0.05, P < 0.01). On the 1st, 3rd, 5th and 7th days after operation, the scores of VAS in the observation group were lower than those in the control group (all P < 0.05). On the 7th and 14th days after operation, the scores of HSS in the observation group were better than those in the control group (all P < 0.05). CONCLUSION: The combined intervention of acupoint massage and mild moxibustion reduces the incidence of lower limb swelling, alleviates pain and promotes knee joint function recovery of TKA and the effects are better than those achieved by the simple routine detumescence therapy. PMID- 27509604 TI - [Case of neck-originated abnormal sensation of throat]. PMID- 27509605 TI - [Effects of acupuncture at stellate ganglion on lower limb atherosclerosis of early diabetes mellitus]. AB - OBJECTIVE: To compare the efficacy between acupuncture at stellate ganglion combined with intravenous administration of alprostadil and simple intravenous administration of alprostadil on lower limb atherosclerosis of early diabetes mellitus. METHODS: Sixty patients of lower limb atherosclerosis of early diabetes mellitus were randomly divided into an observation group and a control group, 30 cases in each one. Patients in the two groups were treated with basic treatment to control blood glucose and lipid. In addition, patients in the control group were treated with intravenous administration of alprostadil (10 ug) and sodium chloride solution (100 mL); based on this, patients in the observation group were treated with acupuncture at stellate ganglion. The treatment was given once a day; the consecutive treatment of two weeks constituted one session, and totally 4 sessions were given. The total syndrome score, glycosylated hemoglobin (HbA1c), blood flow of posterior tibial artery and dorsal artery of foot were observed before and after treatment; the clinical efficacy was compared between the two groups. RESULTS: Compared before treatment, the total syndrome score, HbA1c, blood flow of posterior tibial artery and dorsal artery of foot were significantly improved after treatment (all P < 0.05), which were more obvious in the observation group (all P < 0.05). After treatment, the total effective rate was 93.3% (28/30) in the observation group, which was significantly superior to 86.7% (26/30) in the control group (P < 0.05). CONCLUSION Acupuncture at stellate ganglion combined with intravenous administration of alprostadil achieve better effect than simple intravenous administration of alprostadil for lower limb atherosclerosis of early diabetes mellitus, which improve the clinical symptoms, regulate blood sugar and increase the blood flow of lower limb. PMID- 27509606 TI - [Acupuncture for distal symmetric multiple peripheral neuropathy of diabetes mellitus: a randomized controlled trial]. AB - OBJECTIVE: To compare the clinical efficacy between acupuncture and intravenous administration of lipoic acid and alprostadil for distal symmetric multiple peripheral neuropathy of diabetes mellitus. METHODS: Sixty patients were randomly divided into an acupuncture group (31 cases) and a medication group (29 cases). Patients in the two groups received basic treatment to control blood sugar within a safe range. On this basis, patients in the acupuncture group were treated with acupuncture at Geshu (BL 17), Weiwanxiashu (EX-B 3), Ganshu (BL 18), Pishu (BL 20), Shenshu (BL 23), Zusanli (ST 36), Taixi (KI 3), ashi points, etc. Patients in the medication group were treated with intravenous administration of lipoic acid (0.6 g) and alprostadil (10 mg). The treatment was given once a day, 10 days for a course of treatment; there was an interval of 2 days between courses, and totally 3 courses were given. The score of peripheral neuropathy of diabetes mellitus, the change of nerve conduction: velocity and clinical efficacy before and after treatment in the two groups were observed. RESULTS: After treatment, the score of peripheral neuropathy was significantly reduced in the two groups (both P < 0.05), which was more significant in the acupuncture group (P < 0.05). After treatment, the sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) of median nerve and common peroneal nerve were significantly increased in the two groups (all P < 0.05). Compared between two groups, the SNCV and MNCV of common peroneal nerve in the acupuncture group were significantly superior to those in the medication group (both P < 0.05); the MNCV of median nerve in the acupuncture group was significantly superior to that in the medication group (P < 0.05); the SNCV of median nerve in the acupuncture group was not significantly different from that in the medication group (P > 0.05). The total effective rate was 83.9% (26/31) in the acupuncture group, which was significantly superior to 62.1% (18/29) in the medication group (P < 0.05). CONCLUSION: Acupuncture and conventional medication both have satisfied effects for distal symmetric multiple peripheral neuropathy of diabetes mellitus, and acupuncture is superior to medication on improving clinical signs of sensory disorder, reflection disturbance and muscle weakness, nerve conduction and clinical curative effect. PMID- 27509607 TI - [TEAS for prevention and treatment of orthodontic toothache and oral dysfunction: a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical efficacy of transcutanclus electrical acupoint stimulation (TEAS) on prevention and treatment of orthodontic toothache and oral dysfunction. METHODS: A total of 85 patients of malocclusions in the preliminary diagnosis were randomly divided into a control group (20 cases), a psychological intervention group (22 cases), a medication group (20 cases) and a TEAS group (23 cases). Orthodontics treatment was given in all the groups. Patients in the control group received no further treatment; patients in the psychological intervention group received comprehensive psychological intervention, including cognitive education and music therapy; patients in the medication group received oral administration of ibuprofen; patients in the TEAS group received TEAS at Juliao (ST 3), Jiachengjiang (Extra) and auricular point Ya (LO1). The treatment was given twice a day, one in morning and one at night, for 7 days. The pain scores of orthodontic toothache and changes of oral dysfunction were observed in all groups. RESULTS: (1) At 5 time points from the 12th hour to the 4th day, the scores of spontaneous pain in TEAS group were lower than those in the control group (all P < 0.01); during the time points, the scores in TEAS group were lower than those in the psychological intervention group (P < 0.05, P < 0.01), which were similar to those in the medication group (all P > 0.05). (2) During the peak cycle of spontaneous toothache, the scores of irritation pain in TEAS group were significantly lower than those in the control group (all P < O.01), regardless of time-point statistics or general statistics; the scores of irritation pain in the TEAS group were also significantly lower than those in the psychological intervention group (all P < 0.01), which were similar to those in the medication group (all P > 0. 05). (3) Compared with control group, the grading of talking disorder in the remaining groups did not change significantly (P > 0.05). (4) Compared with control group, the grading of moderate-severe eating disorder in TEAS group was significantly reduced (P < O.05), which was not different from that in the medication group (P > 0.05). The differences of the grading of moderate-severe eating disorder were not significantly different between the psychological intervention group and control group (P > 0.05). (5) There were 3 cases of digestive system adverse reactions in the medication group. CONCLUSION: TEAS can efficiently prevent orthodontic toothache and oral dysfunction, which is superior to psychological intervention and similar to medication. In addition, it can avoid possible side-effect of medication. PMID- 27509608 TI - [Effect of acupuncture for pain threshold among the groups of different constitutions]. AB - OBJECTIVE: To observe the difference in acupuncture for pain threshold at different time points among the groups of 9 TCM constitutions. METHODS: The cross sectional survey was adopted to investigate TCM constitutions among 600 subjects and determine 9 TCM constitution types (neutral constitution, qi-deficiency constitution, yang-deficiency constitution, yin-deficiency constitution, phlegm damp constitution, damp-heat constitution, blood-stagnation constitution, qi stagnation constitution, special diathesis constitution). The same acupuncture manipulation was applied to Zusanli (ST 36) on the left side in the subjects and the needle was retained for 30 min. The tenderness threshold was detected with 2390 type Von Frey apparatus at different time points, named before acupuncture, at the moment after qi arrival, in 10 min of needle retaining, in 30 min of needle retaining and in 15 min after needle withdrawal in the subjects of 9 TCM constitutions. RESULTS: The interactive effect happened between the constitution type and time point (P < 0.05). Among the groups of 9 TCM constitutions, the pain threshold values at the moment after qi arrival (except blood-stagnation constitution, qi-stagnation constitution, special diathesis constitution) in 10 min of needle retaining and in 30 min of needle retaining were increased as compared with those before acupuncture separately (P < 0.01), among which, the value increase was the most significant in 30 min of needle retaining. The differences in the pain thresholds were significant in 15 min after needle withdrawal in the groups of neutral constitution and damp-heat constitution as compared with those before acupuncture (both P < 0.01). In 10 min of needle retaining and in 30 min of needle retaining, as compared with the group of neutral constitution, the changes in pain thresholds of the rest abnormal constitutions were apparently lower (all P < 0.05). CONCLUSION: Acupuncture at Zusanli (ST 36) presents different effects among the groups of different constitution types. The effect maintaining durations are different. PMID- 27509609 TI - [Case of rectal carcinoma postoperative intestinal obstruction]. PMID- 27509610 TI - [Herbal umbilicus therapy plus hot compress with salt packet for 20 cases of malignant ascites]. PMID- 27509612 TI - [Case of macular degeneration]. PMID- 27509611 TI - [Micronucleus in vitro induced by inhalable particulate matters in moxa smoke]. AB - OBJECTIVE: To investigate whether inhalable particulate matters can cause the damage of chromosome or mitotic apparatus to produce micronucleus, and to evaluate genetic toxicology of moxa smoke on chromosome. METHODS: By MTT method, the 24 h half maximal inhibitory concentration (IC50) of moxa smoke condensation (MSC) on Chinese hamster ovary (CHO) cells was 0.087 mg/mL. CHO cells, which were cultured in vitro, were divided into a solvent control group, a positive control group (cyclophosphamide as solvent), a low concentration group, a moderate concentration group and a high concentration group. The low concentration group, moderate concentration group and high concentration group were set approximately 1/8, 1/4, 1/2 of IC50, respectively. Whether micronucleus had dose-effect response induced by the damage of chromosome or mitotic apparatus was observed after CHO cells were contaminated by MSC in the low concentration group, moderate concentration group and high concentration group. RESULTS: The rate of micronucleus induced by MSC in the low concentration group, moderate concentration group and high concentration group was higher than that in the solvent control group (all P < 0.05), which presented dosage-effect response. The experiment was repeated 3 times, indicating it was repeatable with statistical significance. CONCLUSION: High concentration of MSC shows toxicity to induce chromosome damage, which disappears at low concentration. The genetic toxicology is also dependent on concentration, and the concentration of moxa smoke is essential. In clinical treatment, it is noted to control the level of moxa smoke, while the clinical safety standard of moxa smoke concentration is in need of further study. PMID- 27509613 TI - [Effects of electroacupuncture pretreatment on ovarian function and expression of VEGF in rats with ovulation induction]. AB - OBJECTIVE: To explore the protective effect of electroacupuncture (EA) pretreatment on ovarian function in rats with ovulation induction. METHODS: Thirty SD female rats were numbered according to random number table. According to vaginal smear method, rats of estrus were divided into a normal group (10 rats) and cohabitated with male SD rats with the proportion of 1:1. With computer generated random number, the remaining rats were divided into a model group and an EA group, 10 rats in each one. The model of superovulation was established with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (HCG) in the model group and EA group. Before model establishment and cohabitation, rats in the EA group were treated with EA at "Guanyuan (CV 4)" and "Sanyinjiao (SP 6)", once for 15 min, for consecutive 7 days. Rats in the normal group and model group received no further treatment. The third day 23:00 pm after cohabitation, blood samples in three groups were collected to test the level of estradiol (E2) and progesterone (P). After the rats were sacrificed, the HE staining method was applied to observe the morphological changes of ovarian tissue; the immunohistochemical method was applied to measure the expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2; the real-time quantitative PCR technique was applied to measure the gene expression of VEGF and VEGFR-2. RESULTS: The number of ovarian follicle in the EA group was higher than that in the model group and normal group (all P < 0.05); the ratio of corpus luteum size to ovarian size in the EA group was lower than that in the model group (P < 0.01). The ratio of plasma estradiol to progesterone in the EA group tended to be normal group (P < 0.05) and lower than that in the model group (P < 0.01). The protein expression of VEGF and VEGFR-2 in lutein granulosa cell and follicular fluid in the EA group was lower than that in the model group (P < 0.05); gene level of VEGF and VEGFR-2 in ovarian tissue in the EA group was lower than that in the model group (P < 0.05, P < 0.01). CONCLUSION: EA pretreatment has certain protective effect on ovarian function in rats with ovulation induction, which is likely to be related to regulation of VEGF and its receptor. PMID- 27509614 TI - [Mechanism of electroacupuncture on "Zusanli (ST 36)" for chemotherapy-induced peripheral neuropathy]. AB - OBJECTIVE: To observe the effects and duration of electroacupuncture on the mechanical pain threshold induced by paclitaxel and explore its analgesic mechanism. METHODS: Sixty-four C57BL/6J male mice were randomly divided into 4 groups, a normal+sham EA group, a normal+EA group, a medicine+sham EA(Med+ sham EA) group, a medicine + EA (Med + EA) group, 16 cases in each group. The model of chemotherapy-induced peripheral neuropathy was established with paclitaxel intraperitoneal injection on the 1st, 3rd, 5th, 7th day in the Med + sham EA group and the Med + EA group. EA of 30 min was used on bilateral "Zusanli (ST 36)" on the 9th, 11th, 13th, 16th, 18th, 20th, 23rd, 25th, 27th, 30th day in the EA groups, 2 Hz/100 Hz and 1~ 1.5 mA. Acupuncture was applied on the same acupoint at the same times in the sham EA groups. Mechanical pain thresholds were tested by VonFrey before and after model establishment, namely on the 8th, 14th; 21st and, 28th day. The heart blood of 8 mice was drawn quickly to collect serum in every group on the 31st day, and the contents of tumor necrosis factor alpha (TNF-alpha), interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta) in proinflammatory cytokine were examined by ELISA. Mechanical pain thresholds were tested by VonFrey for the rest 8 mice of each group until there was no apparent difference in the two paclitaxel groups once a week,namely on the 35th, 42nd, 49th day. RESULTS: The pain thresholds of each group were not statistically different before model establishment (P > 0.05). After model establishment (on the 8th day), thresholds of the paclitaxel groups were lower than those of the normal groups (all P < 0.05). After EA, the mechanical pain thresholds of the Med + EA group were higher than those of the Med + sham EA group at all the time points, and there was statistical difference on the 14th, 21st and 28th day (all P < 0.05). The analgesic effect was lasting to the 49th day. The contents of TNF alpha, IL-1alpha, IL-1beta of the Med + EA group were decreased than those of the Med+sham EA group in different degree, with statistical significance of IL-1alpha (P < 0.05). CONCLUSION: EA can effectively treat paclitaxel-induced peripheral neuropathy,and the analgesic mechanism is probably related to decreasing the proinflammatory cytokine. PMID- 27509615 TI - [Effects of electrical stimulation at acupoints in the distribution area of auricular vagus nerve combined with sound masking method on auditory brainstem response and neurotransmitters of inferior colliculus in rats of tinnitus]. AB - OBJECTIVE: To explore the effects of electrical stimulation at acupoints in the distribution area of auricular vagus nerve combined with sound masking on auditory brainstem response (ABR) and contents of neurotransmitters of gamma aminobutyric acid (gamma-GABA), 5-hydroxytryptamine (5-HT) and acetyl choline (Ach) in inferior colliculus of tinnitus rats. METHODS: Twenty-four male adult SD rats were randomized into a control group, a model group, a 7-d treatment group and a 15-d treatment group. Except the control group, rats in the remaining groups were treated with intraperitoneal injection of 10% salicylate sodium at a dose of 350 mg/kg to establish tinnitus model. Rats in the control group were treated with injection of 0.9% NaCl. Rats in the 7-d treatment group and 15-d treatment group were treated with electrical stimulation at "Shenmen (TF4)" and "Yidan (CO11)" in the distribution area of auricular vagus nerve combined with sound masking, once a day, for 7 days and 15 days. The SigGenRP software of TDT system was applied to provide voice for single ear and collect the signal, and the voice threshold of ABR was tested. The levels of gamma-GABA, 5-HT and Ach in inferior colliculus of rats were detected by enzyme linked immunosorbent assay (ELISA) and compared. RESULTS: Compared with the model group, the threshold values of ABR in 12 kHz and 16 kHz voice stimulation in the 7-d treatment group were significantly lower all P < 0.05); the threshold values of ABR from 4 kHz to 28 kHz voice stimulation in the 15-d treatment group were signally reduced (P < 0.05, P < 0.01), which was more significant than those in the 7-d treatment group. The level of gamma-GABA in the model group was significantly lower than that in the control group (P < 0.05), and that in the 15-d treatment group was apparently higher than that in the model group (P < 0.05). The level of 5-HT in the model group was markedly higher than that in the control group (P < 0.05), and that in the 7-d treatment group was lower than that in the model group (P < 0.05), while that in the 15-d treatment group was apparently higher than that in the model group (P < 0.05). The level of Ach in the model group was obviously; lower than that in the control group (P < 0.05), and that in the 7-d treatment group was higher than that in the model group (P < 0.05). CONCLUSION: Electrical stimulation at auricular vagus nerve combined with sound masking) could regulate the threshold of ABR, especially in the 15-d treatment group. This may be ascribed to modulating the levels of neurotransmitter of gamma-GABA, 5-HT and Ach in inferior colliculus. PMID- 27509616 TI - [Teaching design of mastering scalp acupuncture fast]. AB - Scalp acupuncture is a method of treating whole-body diseases. The author takes the easy positioning of scalp acupuncture as starting point, covers the positioning of scalp acupuncture and needle insertion points, acupuncture manipulation and the selection of acupoints, so as to introduce the design of teaching the international standardized scalp acupuncture with texts and illustrations. The positions of scalp acupuncture are 4 lines in frontal area, 5 lines in parietal area, 2 lines in temporal area and 3 lines in occipital area. The needle insertion angle is 30 degrees to the skin. Acupoints can be selected crossly and correspondingly in clinic. PMID- 27509617 TI - [Case of enuresis after total hysterectomy]. PMID- 27509618 TI - [Case of Hirschsprung's disease allied disorder in child]. PMID- 27509619 TI - ["Chuan Jia Re" combined with abdominal needle for 23 cases of periarthritis of shoulder with wind cold dampness type]. PMID- 27509620 TI - [Explanation of Evidence-based Guidelines of Clinical Practice with Acupuncture and Moxibustion: Adult Bronchial Asthma]. AB - The development and compilation of Evidence-based Guidelines of Clinical Practice with Acupuncture and Moxibustion: Adult Bronchial Asthma are introduced from three aspects, named the guideline methodology, the guideline structure and the guideline content. Based on the acupuncture-moxibustion practice and clinical research, the evidence-based medicine method is adopted. During the development and compilation of the guideline, the characteristics and advantages of acupuncture and moxibustion are specially considered in the treatment of this disease; the latest optimum evidences at home and abroad, experts' experience and patients' value are closely integrated with each other. Additionally, the worldwide accepted assessments of evidence quality and the recommendation (GRADE system) are combined with the clinical evidences of the ancient and modern famous acupuncture-moxibustion experts, and the clinical research evidences are with the experts' consensus to the large extent. The purpose of the guideline is to provide the maximal guidance to the clinical physicians. PMID- 27509621 TI - [Qijie theory of LAI's Tongyuan acupuncture technique]. AB - Qijie theory is one of the important components of TCM meridian and collateral system. It is the shortcut for the communication from the exterior to the interior and for the transverse connection, strengthens the therapeutic effects of acupuncture and moxibustion on the disorders of internal organs and enlarges the indications of acupoints. Professor LAI Xinsheng originally creats Tongyuan acupuncture technique. It is a kind of acupuncture therapeutic methods, including promoting the circulation of the governor vessel, regulating the mind and conducting qi to the origin. In order to analyze the connection between Tongyuan acupuncture technique and traditional meridian and collateral theory, the connotations of Tongyuan acupuncture technique and qijie, as well as the in terrelationship between them are taken as the basis in the paper. By tracing the literature records, the original concept of qijie is detected. Through proving clinically Tongyuan acupuncture technique, it is revealed that qijie is the arrowhead on the main road of meridian qi circulation and is the essential connotation of the direct path of the body surface connecting with the deep layers of the body as well as the zangfu organs and tissues. It is summarized that the traditional qijie theory provides the powerful theoretic evidence for the treatment with Tongyuan acupuncture technique. PMID- 27509622 TI - [Meaning of exegetics research on acupoint name]. AB - Acupoint name has rich TCM meaning and cultural connotation and its nomenclature originates from ancient Chinese. In order to clearly explore the significance of acupoint name, the exegetics is used in this study. It is found that the study on acupoint name contributed to determining the controversial acupoint locations and revealing the cultural connotation and the basic TCM theory behind the acupoint. Additionally, it helps us to understand the effect mechanisms of acupoints [Tianshu (ST 25) is either for constipation or diarrhea as an example], dig the clinical effects of acupoints, discover and rectify the mistakes in nomenclatures such as pronunciation and glyph. All of these study results benefit the accurate and comprehensive recognition on the acupoints. PMID- 27509623 TI - [Profound meaning of acupuncture taboos in Internal Classic based on the fault of reinforcing and reducing technique by mind conduction of acupuncture therapy]. AB - By analyzing the acupuncture taboos in Neijing (Internal Classic) on clinical application of mind conduction of acupuncture therapy in going against the actual situation, astronomy and others, it is found that the relevant acupuncture taboo implies many subtle mysteries of human body, qi, mind and astronomy, which have not been discovered yet in modern science and are very significant in qi protection. In Neijing, the acupuncture physicians have been highly required in the mind treatment, in which, accurately regulating qi circulation is the target in the treatment. The mind conduction is used for qi circulation to accomplish accurately the reinforcing or reducing in the deficiency or excess condition. All of the taboos are provided to normalize the accuracy of reinforcing and reducing technique of acupuncture therapy and avoid the damage of qi in human body. Hence, those taboos must be obeyed so as to prevent from serious consequence and ensure the safety of this acupuncture therapy. PMID- 27509624 TI - [Case of multiple system atrophy]. PMID- 27509625 TI - [Analysis on intestinal disorders in Jiujing Tu (Illustration of Moxiustion) found from Dunhuang]. AB - Jiujing Tu (Illustration of Moxibustion), excavated from Mo Kao Grotto at Dunhuang, is one of the earliest existing monographs on moxibustion. The medical masters from different schools have focused on this book because it is different from the existing ancient medical works and have not been collected in the medical works of different dynasties. In this study, the literature of Jiujing Tu on five acupoints (Dachangshu, Pangguangshu, Daxiaochangshu, Nieshu and Cigong) relevant with intestinal disorders is collected. It is intended to discuss and analyze the acupoint location, main intestinal disorder, moxibustion characters, recognition on the literature of different dynasties and modern clinical applications. It is believed that the thought of strong moxibustion in the treatment of intestinal disorders advocated in Jiujing Tu has profound impact on the medical development in later generations. It deserves us to have a further digging, collection and promotion of this thought in the modern time. PMID- 27509626 TI - [On the partition of acupuncture academic schools]. AB - Nowadays extensive attention has been paid on the research of acupuncture academic schools, however, a widely accepted method of partition of acupuncture academic schools is still in need. In this paper, the methods of partition of acupuncture academic schools in the history have been arranged, and three typical methods of"partition of five schools" "partition of eighteen schools" and "two stage based partition" are summarized. After adeep analysis on the disadvantages and advantages of these three methods, a new method of partition of acupuncture academic schools that is called "three-stage based partition" is proposed. In this method, after the overall acupuncture academic schools are divided into an ancient stage, a modern stage and a contemporary stage, each schoolis divided into its sub-school category. It is believed that this method of partition can remedy the weaknesses ofcurrent methods, but also explore a new model of inheritance and development under a different aspect through thedifferentiation and interaction of acupuncture academic schools at three stages. PMID- 27509627 TI - [Present situation and development direction of microacupuncture therapy]. AB - There have been many reports of clinical and experimental researches of microacupuncture therapy, the relevant systematic works, teaching materials and national standards in recent decades. It shows that microacupuncture system has been formed and its influence has been promoted. While the rapid development of microacupuncture therapy, there are the problems and contradictions on nomenclature, explanation of theoretical basis, optimal indications, and multiple systems and schools, etc. All the above have blocked the clinical application and development. It is considered that we need to unify the nomenclature, condense the theoretical basis, clear the optimal indications, promote the exchange and blend among different schools and sum up the outcomes by systematic review and data mining technique. PMID- 27509628 TI - [Case of epilepsy after cerebral hemorrhage caused by traumatism]. PMID- 27509629 TI - Overseeing Compliance. AB - Boards can take six practical and simple steps to avoid claims of personal liability. PMID- 27509630 TI - Rural Trustees Take on the World. AB - The dramatic changes underway in health care today have tremendous implications for rural hospitals, and board members must work continuously to understand and react to them. PMID- 27509631 TI - For Rural Boards, an Imperative to Change. AB - Integrated governance, megaboards and "coopetition" are among the op-tions trustees might consider in an increasingly complex health care field Here are seven questions they can ask now. PMID- 27509632 TI - Success Against Sepsis. AB - Sepsis remains one of the most vexing and persistent health care-associated conditions. But hospitals are refusing to back down. Here are strategies they're using to step up the battle. PMID- 27509633 TI - Adaptability in the Face of Uncertainty. PMID- 27509634 TI - Women in Governance: A Savvy Strategy for Advancing Community Health. AB - Women in governance: A savvy strategy for advancing community health. PMID- 27509635 TI - Taming the Roller Coaster. AB - The Rural Health Care Leadership Conference offers the chance for executives and board members to network and gain insights from each other and expert presenters. And there's a bonus: It's in Phoenix in February. PMID- 27509636 TI - The Board Chair's Journey. AB - A real-world rumination on the journey of a hospital board chair and five things that will make it sucessful, from someone who knows. PMID- 27509637 TI - Asking Incisive Questions. AB - Boards must help management chal- lenge their deeply held beliefs about health care by asking incisive questions. PMID- 27509638 TI - The Opioid Crisis and the Physician's Role in Contributing to its Resolution: Step One--Prevention of Overdoses. AB - The escalation of opioid prescriptions, associated misuse, and related mortality continues to pose public health challenges in the United States. Data from the Centers for Disease Control and Prevention (CDC) indicates that opioid overdose death rates remain high, suggesting the need for improved access to, and use of naloxone to save lives. In this context, community-based overdose initiatives have trained laypersons to identify overdose and administer naloxone for reversal. Although there have been efforts to encourage physicians to prescribe naloxone to patients at-risk for opioid overdose, the rate of prescribing remains suboptimal. This article outlines the epidemiology of overdoses, discusses naloxone distribution programs and myths surrounding its use, and reviews relevant legislative developments in Connecticut and proper counseling of patients and families to encourage broader education and prescribing of naloxone. PMID- 27509639 TI - Does Initial Imaging Modality Affect Breast Biopsy Upgrade Rates? A Single Institution Review. AB - INTRODUCTION: Image-guided core needle biopsy (CNB) is the standard for diagnostic breast biopsy. However, the upgrade rate to a higher order lesion defined as identification of malignancy on final pathology from surgical excision remains problematic. MATERIALS AND METHODS: A retrospective chart review of all core needle biopsies from 2008 to 2012 was performed. We identified lesions demonstrating atypia without associated malignancy on core needle biopsy and recorded multiple factors to evaluate predictors of upgrade. RESULTS: Of 151 independent core needle biopsies recorded, 26.5% were upgraded to a higher order lesion. Concurrent mammogram and ultrasound (US) were associated with higher sampling error than any individual imaging modality (P = .021). MRI had a trend toward lower rate of upgrade rate but did not reach statistical significance. DISCUSSION: Although MRI had a lower rate of upgrade rate due to sampling error, this did not reach significance possibly because of our small sample size. PMID- 27509640 TI - Ceramic-on-Ceramic Total Hip Arthroplasty in a Twelve-Year-Old Patient: Case Report with a 27-Year Follow-Up. AB - Total hip arthroplasty in the juvenile patient with a severely diseasedjoint can provide long-term pain relief and improvement in function. We present a patient with juvenile rheumatoid arthritis who underwent a Mittelmeier ceramic-on-ceramic total hip arthroplasty at age 12 in 1986. The implant provided the patient with a functioning hip for 24 years, but subsequently required revision due to femoral component loosening. This case report represents the longest reported clinical follow-up of noncemented, ceramic-on-ceramic total hip arthroplasty in a juvenile patient and depicts an excellent outcome at 27 years. Our case is also unique in that the Mittelmeier ceramic acetabulum was left in place during revision surgery. In this report, we also describe the senior author's choice of the Mittelmeier hip prosthesis within its historical context and provide a brief review of the literature as it relates to total hip arthroplasty in the juvenile patient. PMID- 27509641 TI - Adenovirus Pneumonia Mimicking Legionnaire's Disease with Acute Pancreatitis. PMID- 27509642 TI - Primary Myeloid Sarcoma of the Small Intestine: Case Report and Literature Review. AB - Primary myeloid sarcoma is a rare extramedullary manifestation of acute myeloid leukemia (AML). Typically, myeloid sarcoma presents after a diagnosis of AML or other myeloproliferative disorder. However, primary myeloid sarcoma may present without any preexisting condition, thereby making it extremely difficult to diagnose. We discuss a case of a 22-year-old female who was misdiagnosed initially with acute appendicitis and underwent an appendectomy. Postoperatively, she continued to be symptomatic and eventually developed small bowel obstruction. Diagnostic laparoscopy revealed multiple small bowel masses as well as diffuse abdominal and pelvic lymphadenopathy. After extensive pathological review and additional workup consisting of immunohistochemistry and molecular studies, the correct diagnosis of myeloid sarcoma was made. This review will discuss the presentation, diagnosis, management, and prognosis of primary myeloid sarcoma. PMID- 27509643 TI - Rapidly Fatal Dissemination of Merkel Cell Carcinoma in a Patient Treated with Alemtuzumab for Chronic Lymphocytic Leukemia. AB - Alemtuzumab is FDA-approved for the treatment of chronic lymphocytic leukemia (CLL). Nonetheless, its use for this indication has fallen out of favor due to serious concerns for infectious complications and increased risks of second malignancies from the profound and lasting immunosuppression. We report here in a patient with a rapidly progressive metastatic Merkel cell carcinoma (MCC) who was previously treated with alemtuzumab and fludarabine for CLL. He developed profound lymphopenia and hypogammaglobulinemia. While the risk of MCC is increased in CLL, its rapid dissemination has not been previously reported with fludarabine alone. In light of the rapidly fatal outcome in our patient due to MCC, we advise caution with the use of alemtuzumab. In patients treated with alemtuzumab for nononcologic indications, aggressive surveillance for cutaneous malignancies should be implemented until its safety profile can be further characterized. PMID- 27509644 TI - The Respimat Soft Mist Inhaler, a Novel Inhaled Drug Delivery Device. AB - Summary The Respimat SMI offers a novel delivery mechanism for the management of primarily COPD, but asthma as well. Presently, four different medications, as monotherapy or a combination of two active ingredients, are available using the Respimat SMI technology. Multiple studies have demonstrated safety and efficacy of these drugs when delivered via Respimat SMI. Patients tend to prefer the Respimat SMI over traditional inhaler devices, as it overcomes some of the disadvantages posed by traditional delivery devices. PMID- 27509645 TI - Spiro Writing Awards 2016. PMID- 27509646 TI - The Destruction of Clinical Medicine and What is Needed for its Resurrection. PMID- 27509647 TI - CDC Opioid Guidelines in Today's Drug Culture. PMID- 27509648 TI - Spring Update. PMID- 27509649 TI - Climbing Steep Hills. PMID- 27509650 TI - [ANTITHROMBOTIC MEDICATION IN PREGNANT WOMEN WITH PREVIOUS INTRAUTERINE GROWTH RESTRICTION]. AB - AIM: To analyze pregnancy outcome in patients who were on antithrombotic medication (AM) because of previous pregnancy with fetal intrauterine growth restriction (IUGR). MATERIALS AND METHODS: The studied group (SG) included 21 pregnancies in 15 women with history of previous IUGR. The patients were on low dose aspirin (LDA) and/or low molecular weight heparin (LMWH). Pregnancy outcome was compared to the one in two more groups: 1) primary group (PG) including the previous 15 pregnancies with IUGR of the same women; 2) control group (CG) including 45 pregnancies of women matched for parity with the ones in the SG, with no history of IUGR and without medication. The SG, PG and CG were compared for the following: mean gestational age (g.a.) at birth, mean birth weight (BW), proportion of cases with early preeclampsia (PE), IUGR (total, moderate, and severe), intrauterine fetal death (IUFD), neonatal death (NND), admission to NICU, cesarean section (CS) because of chronic or acute fetal distress (FD) related to IUGR, PE or placental abruption. Student's t-test was applied to assess differences between the groups. P values < 0.05 were considered statistically significant. RESULTS: The differences between the SG and the PG regarding mean g. a. at delivery (33.7 and 29.8 w.g. respectively) and the proportion of babies admitted to NICU (66.7% vs. 71.4%) were not statistically significant. The mean BW in the SG (2114,7 g.) was significantly higher than in the PG (1090.8 g.). In the SG compared with the PG there were significantly less cases of IUFD (14.3% and 53.3% respectively), early PE (9.5% vs. 46.7%) moderate and severe IUGR (10.5% and 36.8% vs. 41.7% and 58.3%). Neonatal mortality in the SG (5.6%) was significantly lower than in the PG (57.1%), The proportion of CS for FD was not significantly different--53.3% in the SG and 57.1% in the PG. On the other hand, comparison between the SG and the CG demonstrated significantly lower g.a. at delivery in the SG (33.7 vs. 38 w.g.) an lower BW (2114 vs. 3094 g). There were significantly more cases with IUGR in the SG compared to the CG- total, moderate and severe (47.4 %, 10.5% and 36.8% in the SG vs. 8.9%, 6.7% and 2.2% in the CG) and NICU admissions (66.7% vs. 4.4%). There were no cases in the control group with severe PE (9.5% in the SG), IUFD (14.3% in the SG), and CS for FD (53.3% in the SG). The proportion of pregnancies without complication in the SG (23.8%) was significantly lower than in the CG (86.7%). CONCLUSIONS: The outcome of pregnancies with AM because of previous fetal IUGR is improved compared to the index ones. However, it is less favorable compared to the outcome in matched cases with no history of IUGR in previous pregnancies. PMID- 27509651 TI - [CLINICAL IMPLEMENTATION OF CELL-FREE DNA ANALYSIS IN MATERNAL BLOOD IN SCREENING FOR ANEUPLOIDIES IN SINGLETON PREGNANCIES]. AB - OBJECTIVE: Clinical implementation of cell free(cf) DNA testing in maternal blood for aneuploidies in singleton pregnancies. METHODS: This is a retrospective study conducted in two centers for fetal medicine in Sofia, Bulgaria, between October 2013 and August 2015. We examined the clinical implementation of cf DNA testing in the routine practice for trisomies 21, 18 and13 after the performance of the first trimester combined test, second trimester biochemical test and/or the combination between first and second trimester integrated test. RESULTS: Cell free DNA testing was performed in 170 singleton pregnancies with a median maternal age of 35 (range 22-46) years. The primary risk assessment for aneuploidies was derived from 95 cases after the first trimester combined screening test, 39 cases after the second trimester biochemical screening test, 16 cases after the integrated screening test and 20 cases there were no screening test performed. The results from the first line screening test were : 8 pregnancies with risk for trisomy 21 > 1: 100; 23 pregnancies with risk for trisomy 21 from 1:100 to 1: 300; 43 pregnancies with risk for trisomy 21 from 1:300 to 1:1000 and 76 pregnancies with risk for trisomy 21 < 1: 1000. No pregnancies with high risk for T13/T18 were identified. The analysis of cf DNA in the maternal blood reported 3 cases with T21 and no cases with T18 or T13. There was only one case of T21 in the group with risk >1:100 identified by the cf DNA analysis which was also identified by the first trimester combined screening test. The positive results were confirmed with invasive testing: CVS in the first trimester (one case) and Amniocentesis in the second trimester (two cases). CONCLUSION: Clinical implementation of cell-free DNA analysis in the contingent policy for screening could improve the detection rate for T21 and could reduce the rate of invasive procedures. PMID- 27509652 TI - [HYPERTENSIVE DISORDERS IN PREGNANT WOMAN WITH EPILEPSY]. AB - PURPOSE: To determine the frequency and the course of hypertensive disorders in pregnant women with epilepsy (PWWE). MATERIALS AND METHODS: The survey is prospective and covers 206 PWWE during the period 1997-2012 year, monitored and treated in Risk Pregnancy Clinic of University Hospital - Pleven. All the patients (PWWE) are with clinically established etiology and prescription of epilepsy, type of seizures and their frequency. EEG records, ultrasound of fetus and cardiotocograph monitoring were conducted. Eleven of PWWE were with Praeeclampsia - Eclampsia (PE-Ecl). RESULTS AND DISCUSSION: The frequency of PE Ecl is 5.33%. Praeeclampsia and Eclampsia were found (monitored) during two consecutive pregnancies in one of the PWWE. Six patients were with severe Praeeclampsia and one of them was with data of HELLP syndrome. There were three cases with Eclampsia. Delivery by surgery was made in 8 cases, (7 patients, but for one of them twice). The other 4 pregnant women with moderate Praeeclampsia got delivery per vias naturales. Epileptic seizures during pregnancy were recorded for 5 of PWWE. One patient was with generalized clonic-tonic seizures and 4 other were with partial seizures. During the period 24 hours after delivery seizures were noted for 4 patients. Six PWWE were without therapy with antiepileptic drugs (AED). Three of them started monotherapy with AED during pregnancy. One other patient with pharmacoresistant symptomatic epilepsy (meningiomas of the brain with two neurosurgical operations) was on polytherapy with 3 AED during the whole pregnancy. The EEG study showed focal activity predominantly occipital, occipito-temporal and parieto-occpital. CONCLUSIONS: The detection of arterial hypertension and proteinuria in PWWE should focus attention on PE-Ecl. The united active clinical monitoring and treatment by a neurologist epileptologist and obstetrician is the most accurate clinical behavior. PMID- 27509653 TI - [HEAD INJURY DURING PREGNANCY]. AB - No matter how severe is head injury during pregnancy, it can threaten both- the maternal and (or) the fetal life. The risk derives from systemic and cerebral consequences of high intracranial pressure, hypotension, anemia or expanding mass lessions in the cranial cavity. The specific hormonal background of the mother may contribute the better outcome after traumatic brain injury (TBI). Pregnancy and trauma push the doctors to create different and specific management than the usual case. Investigating literature data we figure out the initial assessment, management priorities for resuscitation of the head injured pregnant patient, concidering the specific anatomic and physiologic changes during pregnancy. We accept the principal: first save the mother, then the child, if possible, proposing algorithm for severe head injured pregnant patient management. PMID- 27509654 TI - [FREQUENCY AND MEDICAL SOCIAL ASPECTS PREMATURE BIRTH]. AB - Premature birth (PB) remains an unresolved problem, despite progress in prenatal medicine and the introduction of new methods and techniques of prolonged respiratory resuscitation in recent decades. Premature birth is the cause of 70% of neonatal mortality and 50% of long-term neurological complications in newborns, many of whom debilitating. Notwithstanding the significant progress prenatal care in the last twenty years in developed countries is a trend towards a gradual and continuous increase in premature births. PB is not only medical but also social problem. Despite the efforts of the scientific and practical obstetrics and modern tocolytic therapy, the rate of premature births in the last decade reduced. The causes of preterm birth are multifactorial and vary depending on gestational age, genetic factors and environmental factors. The long-term consequences of premature birth bear behind not only economic but also social problems. In many developing countries, premature birth is a major cause of disability. Clinical studies in recent years have been aimed at creating a comprehensive therapeutic algorithm behavior in premature births in order to reduce their frequency, especially for those born weighing less than 1000g. PMID- 27509655 TI - [ZIKA--VIRUS INFECTION]. AB - This review summarizes the knowledge of the scientific community for Zika-virus infection. It became popular because of severe congenital damage causes of CNS in newborns whose mothers are infected during pregnancy, as well as the risk of pandemic distribution. Discusses the peculiarities of the biology and ecology of vectors--blood-sucking mosquitoes Aedes; stages in the spread of infection and practical problems which caused during pregnancy. Attention is paid to the recommendations that allow leading national and international medical organizations to deal with the threat Zika-virus infection. PMID- 27509656 TI - [THE ROLE OF ESTROGENS IN THE CARCINOGENESIS OF LUNG CANCER]. AB - Morbidity and mortality from lung cancer has dramatically increased in women as compared to men over the past few years. Historically, smoking has been considered the major risk factor for lung cancer regardless of gender. Several recent lines of evidence implicate gender differences in the observed differences in prevalence and histologic type which cannot be explained based on the carcinogenic action of nicotine. Several recent studies underscore the importance of reproductive and hormonal factors in the carcinogenesis of lung cancer Lung cancer morbidity and mortality in Bulgaria was 16.2/100000 women and 14.6/ 100000 women, resp. Lung cancer morbidity in Europe was 39/100000 women. Lung cancer is extremely sensitive to estrogens. The latter act directly or as effect modifiers for the relationship between smoking and lung cancer. Further research examining the relationship between serum estrogen levels and the estrogen receptor expression in normal and tumor lung tissue samples can help elucidate the importance of reproductive and hormonal (exogenous and endogenous) factors in the carcinogenesis of lung cancer. PMID- 27509657 TI - [ASSISTED REPRODUCTIVE TECHNOLOGIES AND OVARIAN CANCEROGENESIS]. AB - Development of assisted reproductive technologies (ART) for treatment of infertility poses many questions about potential involvement of the drugs used in ART in the process of ovarian carcinogenesis. The presence of other etiological factors makes the assessment of risks implied by administering these drugs rather difficult. The results obtained in the study are controversial and inconclusive, yet theoretical and epidemiological data suggest that caution is needed in IVF patients, receiving such drug therapy. PMID- 27509658 TI - [DISSEMINATED PERITONEAL LEYOMYOMATOSIS--PRACTICAL APPROACH TO DIAGNOSIS]. AB - Disseminated peritoneal leiomyomatosis (DPL) is a rare condition characterized by the presence of multiple histologically benign smooth muscle nodules on the surface subperitoneal tissue simulating macroscopic peritoneal carcinomatosis. This disease is rare, but in recent years, in connection with the widespread introduction of laparoscopic surgery, the reports of disseminated peritoneal leiomyomatosis occurring after laparoscopic morcellation, were frequent. The knowledge of DPL is necessary to develop methods of prevention, and individualized treatment depending on the pathogenesis and clinical manifestations in each patient. PMID- 27509659 TI - [TORSION OF FALLOPIAN TUBE LEIOMYOMA TREATED BY LAPAROSCOPY]. AB - Leiomyomas of the Fallopian tubes are rare and their correct diagnosis is extremely difficult. Usually they are incidental findings seen at autopsy or unrelated surgical procedures: A 34-year-old woman presented with lower abdominal pain. Transvaginal ultrasound revealed a solid 7 cm extrauterine mass. Both ovaries are normal. Our preoperative diagnosis was torsion of the fallopian tube due intratubal leiomyoma. Laparoscopic surgery was performed and the leiomyoma was found to have originated from the isthmus of the right Fallopian tube. Laparoscopic myomectomy was performed with preservation of the ramus tubarius dextra. The histological examination concluded to a leiomyoma with ischemic changes. We report a case of torsion of a tubal leiomyoma, which was successfully managed laparoscopically. PMID- 27509660 TI - [POLYGYNAX IN THE TREATMENT OF VAGINAL INFECTIONS IN PREGNANT AND NON-PREGNANT WOMEN--CLINICAL EXPERIENCE]. AB - Vaginal infections /VI/ represent some of the most common diseases by infection of FGS. The aim of this study is to analyze clinical and bacteriological efficacy of Polygynax in the treatment of vaginal infections and to take into account the correlation between the results of microbiological controls and reduction of clinical symptoms. The study included 100 patients, including 50 pregnant and non pregnant 50 for a period of 3 months. All of them was diagnosed with vaginitis clinical examination, taken material from vagina for microbiological testing. The studied women was conducted targeted therapy Polygynax 12 capsules, in the form of vaginal capsules for 12 days, after which the sample control microbiology. Behind the subjective complaints of the patient and to reduce them as a result of treatment. The effective implementation of Polygynax 12 capsules is equally good as in non-pregnant and pregnant women. In a summary of the survey data to make relevant analyzes and conclusions from the results. PMID- 27509661 TI - [ENDOMETRIOSIS FERTILITY INDEX]. AB - In women suffering from endometriosis and infertility, the decision as to when and how to perform surgical excision and/or fertility treatment is mainly based on clinical guidelines and expert opinions. However, so far data from randomized controlled trials or meta-analyses to answer the question whether surgical treatment of moderate to severe endometriosis can indeed enhance pregnancy rates compared with expectant management are lacking, as not all studies report fertility outcome or supply sufficiently detailed information. The most frequently used staging system for endometriosis is the revised American Fertility Society (rAFS) score (ASRM, 1997). Unfortunately, this classification system has some serious limitations, including not effectively predicting clinical outcomes of treatment, especially pregnancy rates in infertile patients. For this reason, Adamson and Pasta (2010) developed the endometriosis fertility index (EFI). EFI is a scoring system which includes assessment of historical factors at the time of surgery (age, duration of infertility and pregnancy history), of adnexal function at conclusion of surgery (functional score of Fallopian tubes, fimbriae and ovaries bilaterally), and of the extensiveness of endometriosis (rAFS endometriosis lesion score and total rAFS score). The EFI is intended as a clinical tool to counsel patients on the approach towards fertility after surgery. PMID- 27509662 TI - [POLYHEXAMETHYLENE BIGUANID HYDROCHLORIDE (BIGUANELLE) THERAPY OF BACTERIAL VAGINOSIS]. AB - The aim of our study was to determine the efficacy and tolerability of local therapy with polyhexamethylene biguanid hydrochloride (BIGUANELLE) in women with anaerobic vaginal infection. MATERIAL AND METHODS: We include in our study 23 women (18-50) with established by AMSEL criteria bacterial vaginosis. In all of the women at the beginning and at the end of the survey was performed gynecological examination and microbiological research (AMSEL). The therapeutic scheme at all women is with a single vaginal application of gynecological solution BIGUANELLE. Effectiveness of the treatment was evaluated according to clinical complaints and microbiological research (Amsel criteria: Ph 4.5 >; KOH (+); "clue cells"; specific vaginal fluorine). Tolerability of patients to treatment was assessed by questionnaire. RESULTS: Clinical complaints of patients after the therapy decreased as follows: vaginal fluorine with 73.9%; odor--75%; pruritus--50%; discomfort--90%. Microbiological research and their evaluation by AMSEL, showed the therapeutic efficacy of the therapy in 16 (69.6%) of all (n-23) patients. At 7 (30.4%) women, the treatment remained without effect. At questionnaire answers, 73.9% patients were satisfied with the application of BIGUANELLE, 95.6% of them have implemented it easily, 95.6% of women believe that BIGUANELLE is more convenient to use in comparison with similar products which have a daily application, and none of the patients (100%) have any complaints in applying this gynecological solution. CONCLUSIONS: BIGUANELLE showed good clinical efficacy in the treatment of bacterial vaginosis. It is easily applied and well tolerated by the patients. PMID- 27509663 TI - [FETAL THERAPY: INTRAUTERINE THORACO-AMNIOTIC SHUNTING IN MACROCYSTIC TYPE CYSTIC ADENOMATOID MALFORMATION OF THE LUNG: REVIEW OF THE LITERATURE AND CASE REPORT]. AB - ABSTRACT OBJECTIVE: To present a case of macrocystic type cystic adenomatoid malformation of the lung (CCAM) treated with thoraco-amniotic shunt and to review the published data to evaluate the efficiency of thoraco-amniotic shunts for drainage of (CCAM). MATERIALS AND METHODS: This wass case reported of a fetus with a large thoracic cyst, major mediastinal shift and polyhidramnion treated with thoraco-amniotic shunting. We identified 8 cases diagnosed with CCAM and only one case met the criteria for fetal surgery. Thoracoamniotic shunting was successfully performed under local anesthesia and ultrasound control with operating time of 35 minutes. Medline was searched to identify cases of CCAM treated by thoraco-amniotic shunting. RESULTS: Fetal therapy forlung lesion was successfully performed at 30 weeks of gestation with CCAM volume ratio > 1.6 January, 2015 and amniodrenage after the procedure was carried out. The pregnancy has progressed uneventfully and planned Cesarean section was performed at 38 weeks of gestation. The optimal management of such case was performed for the first time in Bulgaria, which required an experienced interdisciplinary team. The newborn underwent resection of the lesion with no growth or neurodevelopment delay. The literature search identified cases with CCAM treated with thoraco amniotic shunting between 1987 and 2016 and the the survival rate of non-hydropic fetuses that underwent treatment was 88%. CONCLUSIONS: Thoraco-amniotic shunting for macrocystic type CCAM is associated reduced risk of fetal intrauterine death and is also likely to be beneficial for the following major postnatal surgery PMID- 27509664 TI - [COMPLICATION AFTER UNRECOGNIZED ECTOPIC PREGNANCY--A CASE REPORT]. AB - The authors present a clinical case of performing an abortion at patient with unrecognized ectopic pregnancy and subsequent complication- perforation of the uterus and the colon and life-threatening haemoperitoneum. PMID- 27509665 TI - [UTIPRO PLUS CAPSULE, A NEW INNOVATIVE APPROACH FOR THE TREATMENT OF CYSTITIS AND OTHER BACTERIAL URINARY TRACT INFECTIONS]. PMID- 27509666 TI - [FEMINORM OSTEO - A MENOPAUSE AND HEALTHY BONES APPROACH]. PMID- 27509667 TI - [IS THERE A PLACE FOR VIA AND VILI IN OUR PRACTICE]. AB - The aim of this review is to discuss the possibilities and disadvantages of the techniques for visual inspection of the uterine cervix with acetic acid (VIA) and with Lugol's iodine (VILI) for early detection of cervical neoplasia. Efficient cervical screening method, approved in practice, is cytology--PAP smear. The lack of organized screening program in Bulgaria is the reason why a lot of cases of cervical cancer are missed or diagnosed late. This raises the question for searching alternative tests to assess the uterine cervix that do not use special techniques and have a reasonable cost. Published results show that VIA and VILI represent an appropriate alternative for cervical screening. The results of VIA and VILI are immediately available and do not require any laboratory processing. CONCLUSION: Both types of visual inspection of the uterine cervix are easy to accomplish, fast--the result is available at the moment of inspection, they do not require special equipment, the correlation between sensitivity and specificity is good and last but not least--they have low price. VIA and VILI have certain position in our practice. PMID- 27509668 TI - [Paracrine properties of Mesenchymal Stromal Cells]. AB - Mesenchymal stromal cells are multipotent cells found in a large number of adult tissues. Their ability to participate in the repair of these damaged tissues is the origin of the enthusiasm that they elicit in the field of cell therapy. It gradually became apparent that their ability to change a pathological environment is more related to their ability to modulate the behavior of other cell types than their capacity of diferentiation. Recent years have expanded the scope of our knowledge about their way of communication with their environment but also the amount of information that they receive from this environment. In this brief review, we will present some of the mechanisms by which MSCs can communicate remotely with other cell types and how it currently appears possible to direct the secretion pattern of these cells. PMID- 27509669 TI - [Not Available]. AB - In solid organ transplant, immunosuppressive therapy helped to increase graft and patient survival. However, these treatments are associated with toxic risks and infectious or tumor complications. The identification of immunoregulatory properties of regulatory cells and in particular Mesenchymal Stem Cells opens new therapeutic perspectives in the prevention of acute rejection and for the treatment of chronic rejection. In this review we will describe immunoregulatory properties of these cells and their potential use in solid organ transplantation. PMID- 27509670 TI - [Not Available]. PMID- 27509671 TI - [Not Available]. PMID- 27509672 TI - [On the borders of the neurology and the rheumatology]. AB - The links between the rheumatology and the neurology, are ancient and established of one intricacy of pathologies and symptoms. It is not a question here of approaching the inflammatory myositis nor the neurological, essentially central signs, during the inflammatory diseases still called systematic as the lupus or the syndrome of Gougerot-Sjogren, neither compression occurring during rheumatoid arthritis and ankylosing spondylarthritis. It is not either a question of reviewing the compression of osseous origin, as for example the narrow cervical spine, the narrow lumbar spine or the basilaire impression during the bony disease of Paget. Some neurological pathologies can put off the track or mislead the clinician towards symptoms which could impose it for radiculopathy origin occurring in rheumatic conditions In the second place, there are untidy or underestimated neuropathies which deserve a particular attention. PMID- 27509673 TI - [Chronic pain: emotional and cognitive consequences]. AB - Chronic pain which had become a major public health problem, is always accompanied with emotional and cognitive disorders. These comorbidities are circular and auto generated as in low back pain or in somatoform pain as fibromyalgia. Cerebral imagery of pain show the superposition of emotional and cognitive circuits especially in frontal regions from where come the descending control of pain. Therefore common areas regulate the three functions. Consequences on semiology and treatment of chronic pain are discussed. PMID- 27509674 TI - [Chronic pain management: societal impact]. AB - Pain is a real issue of public health, quality and evolution of a system of health test: this is a major social problem. Pain management meets a humanistic, ethical purpose and dignity of man because of the physical and psychological implications. It induces a disability which excludes the patient of society gradually or suddenly. The physical pain and mental suffering to all ages of life make more vulnerable people weakened by disease. Rebel chronic pain are sources of disability, disabilities, disability and major alterations in the quality of life. All of these data shows the impact of pain and its intensity on the professional conditions, on professional activity and productivity, on the use of care systems (very significant increase in medical consultations, hospitalizations), as well as on the mental and physical health. These results confirmed analyses which consider that the unrelieved pain has a major economic impact on care systems and constitutes a public health problem with around two thirds of persons professionally impacted by pain. The progress of medicine has helped the healing of certain serious diseases, but also favoured acute diseases to turn to chronic diseases. The result is an increase in of lifetime sometimes without disease, but this survival may be also accompanied by disease or disability. Progress, pain and suffering, the end of life, ethics will be the core of the basic thoughts of tomorrow. PMID- 27509675 TI - [CONCLUSION]. PMID- 27509676 TI - [Not Available]. PMID- 27509677 TI - [Not Available]. AB - After the second World War, during which medicine was manipulated to serve an ideology, a deep movement arised to protect human beings. In 1964, Helsinki declaration was adapted to protect persons involved in medical research. In 1988, the Seruscalt-Huriet law introduced the obligation of informed consent. In 1994 the bioethics law introduced the notion of care consent. The March 2002 law created the notion of health care system "user". The general philosophy of the law was to give a larger autonomy to the patient. The various heath crises, contaminated blood crisis, mad cow disease, human growth hormone, hospital borne infections, were triggers for the development of patients' associations. The health system appeared fallible. Compagnon report aim is to increase the role of patients' associations in the health system at every level. The "health democracy" term has been coined to place the "political democracy" and "social democracy" concepts face to face. Internet information has transformed the patient into a knowledgeable person. Has it made him an expert? The doctor/patient duality is by essence asymmetric. Public health decisions are constrained by the economical context. The democracy paradox lies in the impossibility to be at the same time a representative anda decision maker. Personal interest collides with common interest. An alliance between representatives of patient's, heath system actors, politics and financers should be knotted to build up a new heath care system. PMID- 27509678 TI - [Not Available]. AB - To date, work on health democracy has never dealt with relationships between patient associations and the pharmaceutical industry. The emergence of a genuine health citizenship depends, however, to a great extent on the quality of such a relationship. This communication, which is based on a survey of 1742 patient associations and 270 French-pharmaceutical companies, conducted by BVA upon request of the Ethics Commitee of the French association of pharmaceutical companies (CODEEM) highlights the significance of the ethical issues. Beyond the financial issue, the relationship between patient associations and pharmaceutical companies raises the issue of associations governance, and reveals the limits of "association expertise" but also a high expectations for effective partnerships. PMID- 27509679 TI - [Patients' associations and clinical research--academic and industrial]. AB - The notion of "health democracy" was introduced as a core principle into the French health law in 2002. Accordingly, stronger individual rights were recognized to patients and, at the same time, patients' representatives have progressively served at all levels of the governance of health system. In clinical research, it is mandatory since 2004 that institutional review board include patient representatives (I). Patient associationsplay a role in clinical research in financing and/or helping to organize clinical trials. In addition, associations play a role in protecting patients from abusive research--as well as from being possibly not solicited as a subject in trials that could open access to medical innovation. There is no question that, with the support of associations, a patient with HIV or myopathy--eligible but who was not solicited- will obtain to participate in a trial of his or her choice (II). If the role of patients' association in health democracy has become both unquestionable and important, it is nevertheless limited. Patients may be disadvantaged if no combative association is committed on their disease. Patients' associations' role is no substitute to that of the State and the law-only able to devote equitable rights to individuals (III). PMID- 27509680 TI - [Not Available]. PMID- 27509681 TI - [Pendred syndrome and nonsyndromic related deafness: a same entity?]. AB - Pendred syndrome is an autosomal recessive familial disorder, defined as a sensorineural deafness coinciding with a goiter related to an iodine organification defect. It constitutes 4 to 10 % of all causes of familial congenital hearing loss. It is now well established that this condition was caused by mutations in the SLC26A4 gene which codes for pendrin, a protein involved in the transport of anions (I-, Cl, HCO3-), particularly in apical iodine efflux in thyroid cells and chloride (Cl-|HCO3-) at the cochlear level. A current issue is to determine factors that distinguish Pendred syndrome from other varieties of isolated deafness also including enlargement of the vestibular aqueduct, but without evidence of thyroid expression. A prospective investigation of these 2 situations, conducted in Lille, leads us to redefine diagnostic criteria and assessment methods, and to discuss genetic or environmental factors contributing to the phenotypes. PMID- 27509682 TI - [Lyme borreliosis and co-infections. Place of Anaplasma phagocytophilum and Bartonella henselae]. AB - Lyme borreliosis (LB) is certainly the most common infection transmitted through the bite of Ixodes in Northern Hemisphere. These ticks are also able to transmit other microorganisms such as the bacteria Anaplasma phagocytophilum (Ap) and Bartonella henselae (Bh), with the latter discovered fairly recently, leading to diferent clinical presentations often close to those of LB. The aim of this study was to evaluate the frequency of co-infection by either of these bacteria in patients with LB, particularly when a treatment with beta-lactam antibiotic was only partially effective. Of these patients, on the basis of serological data, 8.07% were simultaneously contaminated by Bh, 6.83% by Ap and 4.96% were co infected by Bh and Ap. Since the choice of an antibiotic should take into account the specificities of these germs and especially their intracellular proliferation, these results should be considered in selecting treatment. PMID- 27509683 TI - [Not Available]. AB - Evaluation and research of quality factors in surgery necessitates the consideration of 3 types of indicators: indicators of structures, indicators of processes and indicators of outcomes. We used these 3 types of indicators to assess the quality of thyroid surgery and to evaluate quality indicators. These studies allowed us to demonstrate the importance of a permanent monitoring of the outcomes of the thyroid surgery and the presence of human and organizational factors in the mechanisms of the surgical complications. This type of evaluation and research in quality of health care should be extended to all the surgical subspecialties. PMID- 27509684 TI - [New approach for managing microbial risks in food]. AB - The aim of the food legislation is to ensure the protection of human health. Traditionally, the food legislation requires food business operators to apply good hygiene practices and specific procedures to control foodborne pathogens. These regulations allowed reaching a high level of health protection. The improvement of the system will require risk-based approaches. Firstly, risk assessment should allow the identification of high-risk situations where resources should be allocated for a better targeting of risk management. Then, management measures should be adapted to the health objective. In this approach, the appropriate level of protection is converted intofood safety and performance objectives on the food chain, i.e., maximum microbial contamination to fulfil the acceptable risk level. When objectives are defined, the food business operators and competent authorities can identify control options to comply with the objectives and establish microbiological criteria to verify compliance with these objectives. This approach, described for approximately 10 years, operative thanks to the development of quantitative risk assessment techniques, is still difficult to use in practical terms since it requires a commitment of competent authorities to define the acceptable risk and needs also the implementation of sometimes complex risk models. PMID- 27509685 TI - [The Emergence of Ebola virus in humans: a long process not yet fully understood]. AB - Since 1976 Ebola virus regularly has caused small deadly outbreaks in Central Africa, usually controlled in a few months. For the first time, an Ebola epidemic of exceptional magnitude dramatically engulfed several countries in West Africa since December 2013. Major failures of implementing measures to prevent human-to human transmissions are the main cause of this large-scale Ebola outbreak. After about one-week incubation period, the Ebola virus disease is characterized by a sudden onset of high fever leading to multiple hemorrhages and to widespread organ failure. Several bat species constitute the main reservoirs of Ebola viruses. Human contamination would occur either directly from bats, widely consumed by the local populations, or through animal species susceptible to Ebola infection, such as chimpanzees and gorillas. Alongside this "natural cycle", an "epidemic cycle" involving domestic animals living in villages such as dogs or pigs, is seriously suggested. Thus, according to the diversity of concerned animals and their clinical infectionform, modalities of human contamination can be multiple and are still largely unknown. In this context, all efforts that could be made to unravel the mystery of the Ebola virus emergence in humans and clarify modalities of the virus transmission, would allow for predicting or for anticipating the future occurrence of epidemics. This review aims to provide an exhaustive inventory of the Ebola ecology to highlight events governing the virus transmission to humans that still remain unsolved. PMID- 27509686 TI - [NADPH oxidase Nox4, a putative therapeutic target in osteoarthritis]. AB - The NADPH oxidases, Nox, are transmembrane hemoproteins, whose exclusive function is to reduce molecular oxygen to produce superoxide anion O2 degrees - and consequently highly reactive oxidant and toxic oxygen species, ROS. Among the 7 NADPH oxidases expressed in humans, Nox4 is the sole Nox isoform present in human primary chondrocytes. Nox4 was suggested as one of the main actors involved in cartilage degradation in osteoarthritis. The stimulation of chondrocytes, the only cell present in cartilage, by IL-1beta results in the activation of Nox4. This leads to an increase of ROS production which in turn could regulate signaling pathways sensitive to oxidative stress such as gene-encoding matrix metalloproteases MMP1, MMP13 and Adamalysin ADAMTS4. A deep understanding of Nox4 structure/function and mechanisms of regulation could lead both to the identification of new therapeutic targets and to the development of innovative strategies for appropriate osteoarthritis treatment. PMID- 27509687 TI - [Bela Bartok's disease: a hidden leukemia, a defeated leukemia]. AB - The hematological disorder Bela Bartok suffered during his exile in the United States and that led to his death has long remained mysterious, as well as the lung disease that accompanied it. The present historical evocation offers us the opportunity to explain the remarkable biological and therapeutic advances obtained in the field of chronic myelocytic leukemia during the last decades. PMID- 27509688 TI - [Not Available]. PMID- 27509689 TI - New assessment tool ready to help prevent pressure ulcers. PMID- 27509690 TI - Same-day discharge attracts droves of total joint patients. PMID- 27509691 TI - Beyond sponges: Safe practices for avoiding all RSIs. PMID- 27509692 TI - Top 10 Patient Safety Concerns for 2016. PMID- 27509693 TI - Protocols control glycemic levels in diabetic surgical patients. PMID- 27509694 TI - Experts can help ASC leaders solidify building safety. PMID- 27509695 TI - Communications. PMID- 27509696 TI - An Evidence Update from Peer Assistance Program in Nursing (PAPIN). PMID- 27509697 TI - The Imperative: Integrating Evidence-Based Practice into the Clinical Nurse Leader (CNL) Role. PMID- 27509698 TI - Anorectal manometry in dyssynergic defecation: Are we there yet? PMID- 27509699 TI - Renal disease in patients infected with hepatitis B virus. AB - Infection with hepatitis B virus (HBV) can result in hepatic diseases which may include an asymptomatic non-replicative carrier state, immunotolerant phase characterized by high DNA levels without significant hepatic injury, immune reactive phase characterized by occurrence of chronic hepatitis and fibrosis in the liver, or complications like cirrhosis or hepatocellular carcinoma. Extrahepatic manifestations may also accompany HBV infection. These may include serum sickness syndrome, polyarthralgia, polyarthritis, dermatologic manifestations like pitted keratolysis, urticaria, purpura, oral lichen planus or Gianotti-Crosti syndrome-a childhood papular eruption. Renal involvement may occur with HBV infection and usually involves glomerular or vascular injury. Various morphologic forms of renal injury have been reported with HBV infection, the commonest being membranous glomerulonephritis. The manifestations may include swelling over face and body, pedal edema, and urinary abnormalities. Evaluation may detect proteinuria, hematuria and reduction in estimated glomerular filtration rate (GFR). The management options include use of antiviral drugs targeting HBV infection with or without concomitant immunosuppressive medication. With availability of newer drugs like entecavir and tenofovir, these have become the first line agents as they have a high barrier to resistance. Sole use of immunosuppression is not recommended for lack of clear benefit and the possible risk of HBV reactivation or flare. PMID- 27509700 TI - Predictors of outcome after reconstructive hepatico-jejunostomy for post cholecystectomy bile duct injuries. AB - INTRODUCTION: Reconstructive hepatico-jejunostomy is recommended for major bile duct injuries (BDIs) during cholecystectomy. Complications of biliary leak, cholangitis, bleeding, anastomotic strictures and biliary cirrhosis remain a major concern affecting a patient's outcome after surgery. The aim of this study was to analyse the results of surgical repair of major BDIs at our institution and identify predictors for the development of major complications. METHODS: A retrospective study of 57 patients with major BDI after cholecystectomy referred to a tertiary hepato-biliary centre from July 1999 to July 2011 and subsequently managed with reconstructive bilio-enteric anastomosis was performed. RESULTS: Of 57 patents 35 (61.4%) were primary referred. 22 (38.6 %) were secondary referred, of which 17 were for correct reconstructive surgery performed elsewhere and 5 were following attempted endoscopic management. 17 (29.8%) had local and systemic perioperative complications. 13 (22.8%) had major complications (bile leak, bleed, stricture and/or biliary cirrhosis). No association was found between age, type of cholecystectomy, type of injury, vascular injury and occurrence of major complications. Secondarily referred patients after therapeutic interventions (p = 0.010) and reconstructive surgery after repair performed by non-specialists suffered an increased incidence of major complications (p = 0.032). Secondary referral was also an independent predictor of major complications (p = 0.024). CONCLUSION: Early referral of patients with no previous intervention to a tertiary hepato-biliary center and specialist surgical repair is recommended for improved outcome after reconstructive hepatico-jejunostomy for major BDIs during cholecystectomy. PMID- 27509701 TI - Multidetector computed tomography evaluation of post cholecystectomy complications: A tertiary care center experience. AB - OBJECTIVE: To evaluate the role of multidetector computed tomography (CT) and CT angiography (CTA) in post cholecystectomy complications. METHODS: A retrospective analysis of data from December 2012 to August 2014 was performed. Eight hundred sixty consecutive patients with history of cholecystectomy (laparoscopic or open) were evaluated. After exclusion of 645 patients with normal imaging, analysis for post cholecystectomy complications was performed in 215 patients. A contrast enhanced CT/CTA was performed. Mean interval to imaging was 10 months (range 3 days to 15 months). RESULTS: A complication rate of 25% was noted in patients undergoing imaging following cholecystectomy. Gallbladder bed or perihepatic collections were seen in 11.9% cases (n = 103). Intrahepatic biliary radicle dilatation (IHBRD) was seen in 7% patients (n = 60). Isolated right or left ductal dilatation was seen in 9 patients; rest of the patients had bilateral IHBRD. Cholangitic abscesses and mild acute pancreatitis were seen in 11 (1.2%) and 12 (1.3%) patients respectively. These comprised biliary complications. Venous thrombosis involving the portal vein was the most frequently encountered vascular complication (n = 12). Right hepatic artery pseudoaneurysm was seen in two patients. Less common complications were abdominal wall hematoma (n = 2), incisional hernia (n = 6), port site hernia (n = 2), large bowel injury (n = 1), biliocutaneous fistula (n = 1) and enterocutaneous fistula (n = 1). CONCLUSION: CT allows classification of post cholecystectomy complications and guides further management. CTA provides an efficient road map for management of vascular complications. PMID- 27509702 TI - Solitary rectal ulcer syndrome: clinical, endoscopic, histological and anorectal manometry findings in north Indian patients. AB - BACKGROUND: Solitary rectal ulcer syndrome (SRUS) is a chronic, benign defecation disorder often related to excessive straining. SRUS is diagnosed on the basis of clinical symptoms, endoscopic and histological findings. METHODS: All patients diagnosed with SRUS by colonoscopy and confirmed by histopathology from October 2012 to August 2014 in the Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, India, were included in the study. Out of 92 patients, thirty-four patients underwent anorectal manometry. Twenty age-matched healthy volunteers were also studied with anorectal manometry to serve as controls. RESULTS: Mean age of the group was 41 +/- 19 years with age range of 10 82 years; males were 58 (63%) with male to female ratio of 1.7:1. Bleeding per rectum was present in 83%, constipation in 46.7%, abdominal pain in 27.2%, and diarrhea in 25% of the patients. On endoscopy, ulcerative lesions were seen in 83% patients of whom solitary and multiple lesions were present in 44% and 39%, respectively. Polypoidal lesions were reported in 17.4% whilst rectal polyps and erythematous mucosa were found in 5.4% and 2.2%, respectively. Histological examination revealed fibromuscular obliteration in 100% of patients, surface ulceration in 70.6% and crypt distortion in 20.65% of patients. Anal relaxation and balloon expulsion test was significantly abnormal in SRUS patients compared to healthy controls (53% vs. 20%, p < 0.01). CONCLUSION: Rectal bleeding was the most common symptom and ulcerative lesions the most common endoscopic finding. Fecal evaluation disorder was more prevalent inpatients with SRUS. PMID- 27509703 TI - Efficacy of aspiration in amebic liver abscess. AB - BACKGROUND: Amebic liver abscess (ALA) is a common and serious problem in our country. There are only a few controlled trials on the efficacy and advantages of combination therapy with percutaneous needle aspiration and pharmacotherapy, over pharmacotherapy alone for amebic liver abscess. MATERIAL AND METHODS: This study was conducted to compare the efficacy of two different treatment modalities i.e. drug treatment alone vs. drug treatment and aspiration of abscess cavity in patients with small (up to 5 cm) and large (5 cm to 10 cm) size ALA. This is one of the largest single center, prospective, randomized studies comparing the efficacy of aspiration in ALA. RESULTS: (i) Mean body temperature, liver tenderness, total leukocyte count (TLC), serum alanine aminotransferase (ALT) and liver span were significantly decreased in the aspiration group on days 8 and 15 as compared to non-aspiration group especially in large abscess (5 cm to 10 cm). (ii) Abscess cavity maximum diameter decreased significantly in aspiration group on days 8 and 15, and 1 month & 3 months in large abscess (5cm to 10 cm). CONCLUSIONS: (i) Needle aspiration along with metronidazole hastens clinical improvement especially in large (5 cm up to 10 cm) cavities in patients with ALA. (ii) Aspiration is safe and no major complications occurred. (iii) Hence, combination therapy should be the first choice especially in large ALA (5 cm to 10 cm). PMID- 27509704 TI - Validation of Boey's score in predicting morbidity and mortality in peptic perforation peritonitis in Northwestern India. AB - BACKGROUND: The major complications of peptic ulcer are hemorrhage, perforation and gastric outlet obstruction with perforation occurring in about 2-10% of patients. Patients with perforated peptic ulcer still have a high rate of morbidity and mortality and to improve the outcomes it is important to stratify the patients into different categories. AIMS: To evaluate the accuracy of Boey scoring system in predicting postoperative morbidity and mortality in patients operated for peptic perforation. METHODS: It was a prospective observational single centre study conducted at SMS Medical College and Hospital, Jaipur, from October 2011 to October 2012 on 180 patients undergoing open surgery for peptic ulcer perforation. Postoperative outcomes in terms of recovery and complications were studied. For prediction of morbidity and mortality by Boey risk stratification, the odds ratio (OR) and 95% confidence interval (95% CI) of each risk score were compared with the outcomes of "0" risk score. RESULTS: The mortality rate increased progressively with increasing numbers of the Boey score: 1.9%, 7.1%, 31.7% and 40% for 0, 1, 2, and 3 scores, respectively (p < 0.001). The morbidity rates for 0, 1, 2, and 3 Boey scores were 13%, 45.7%, 70.7% and 73.3% respectively (p < 0.001). CONCLUSIONS: Boey score is a useful tool for assessing the prognosis of operated cases of peptic perforation and helps in the assessment of mortality and morbidity of these patients. PMID- 27509705 TI - An unusual case of histiocytic sarcoma. PMID- 27509706 TI - Acute intermittent porphyria: a missed diagnosis in pre-pubertal children with recurrent abdominal pain. PMID- 27509707 TI - Altered sensorium in a chronic alcoholic: pancreatic encephalopathy, Wernicke's encephalopathy or Marchiafava Biganami disease? PMID- 27509708 TI - Chylous ascitis post primary living donor liver transplantation managed by dietary modification. PMID- 27509709 TI - Endoscopic biopsy: a simple guide for beginners. PMID- 27509710 TI - Successful living donor liver transplantation with partial nephrectomy for co existing renal cell carcinoma and cirrhosis. PMID- 27509711 TI - Pancreatic endotherapy in management of pancreatopericardial fistula. PMID- 27509712 TI - Periampullary gastrointestinal stromal tumor presenting with obstructive jaundice. PMID- 27509713 TI - Primary extraskeletal osteosarcoma of gall bladder. PMID- 27509714 TI - Endotipsitis caused by extremely drug-resistant Klebsiella pneumoniae. PMID- 27509715 TI - Giant choledochal cyst in infancy--A rare entity. PMID- 27509716 TI - Incidentally detected ectopic ampulla of vater in the antrum in a patient of colonic tuberculosis. PMID- 27509717 TI - [Histopathological Study of the Relationship between Lymphoid Follicles and Different Endoscopic Types of Nodular Gastritis]. AB - Nodular gastritis is characterized histologically by hyperplasia and enlargement of lymphoid follicles in the lamina propria. With the objective of elucidating the relationship between different endoscopic types of nodular gastritis and lymphoid follicles, distributions of lymphoid follicles in the lamina propria were investigated in young gastric cancer patients with nodular gastritis. For the study, whole-mucosal step sectioning of each resected stomach was performed, the densities of lymphoid follicles of all specimens were measured microscopically, and the horizontal and depth distributions were calculated. For assessment in the horizontal direction, density distribution diagrams of lymphoid follicles were created. For assessment in the depth direction, the different endoscopic types of nodular gastritis were compared in the five different analysis sites. In the assessment of the horizontal distribution, no characteristic distribution tendencies were observed in either the granular type group or the scattered type group; however, it was found that areas with relatively high densities of lymphoid follicles generally coincided with the areas where nodular gastritis was observed endoscopically. These results suggested that hyperplasia and aggregation of lymphoid follicles in the lamina propria are involved at the sites where nodular gastritis is observed endoscopically. In the assessment of the depth distribution, lymphoid follicles tended to be more unevenly distributed in the upper lamina propria in the granular type group than in the scattered type at the three different analysis sites where nodular gastritis was observed endoscopically. These results suggested the possibility of a granular type characteristic. PMID- 27509718 TI - [Evaluation of the Creatine Kinase MB Activity Assay Kit]. AB - CK-MB activity, which is measured by the immunoinhibition method, is an important marker for use in the diagnosis of acute coronary syndromes. In the present study, we evaluated the basal performance of a recently improved CK-MB activity kit, "L-system CK-MB," in which the activity of mitochondrial CK subunits is inhibited. Within-run and between-day precision were in the range of 1.9-2.3% and 3.2-6.0%, respectively. Diluted linearity and limit of detection were determined to be 600 U/L and 0.8 U/L, respectively. The use of L-system CK-MB allowed the inhibition of the activity of 98.1% of sarcomeric mitochondrial CK, 97.7% of ubiquitous mitochondrial CK, and 99.9% of CK-MM. The correlation coefficient (r) between CK-MB activity and CK-MB protein was 0.968. However, we found 4 cases showing CK-MB activity significantly higher than the protein concentration. Increased CK-BB activity was detected by electrophoresis in these cases. In some patients with malignant tumors, the presence of CK-immunoglobulin complex also lead to elevated CK-MB concentrations. Thus, the discrepancy in the CK-MB activity and the protein concentration may be caused by the presence of CK-BB and/or CK-immunoglobulin complex. More attention needs to be focused on samples with high CK-MB protein concentrations, especially when the CK-MB/CK ratio is high. PMID- 27509719 TI - [A Case of Heparin-Induced Thrombocytopenia with Discrepancy in the Results of Anti-Platelet Factor 4/Heparin Antibodies between Latex-Particle-Enhanced Immunoturbidimetric Assay and Enzyme Immunoassay]. AB - A female patient in her seventies with diabetes mellitus, hyper-lipidemia and mitral regurgitation was admitted because of the acute heart failure. She was treated with diuretics and vasodilators, however these were not effective. Therefore the CHDF using heparin was required for the patients. After the introduction of CHDF, the platelet count subsequently decreased to less than 7.0 x 10(4)/MUl. After stopping CHDF, the platelet count recovered. In the second CHDF treatment, the platelet count decreased again. HIT was suspected because of both the usage of heparin and five points of 4T's score in the patient. Heparin was discontinued immediately and then her platelet count improved. The HIT antibody by latex-particle-enhanced immunoturbidimetric assay was performed simultaneously, however it was not detected. After re-using heparin by heparin lock, platelet count had been decreasing. Furthermore the thrombus was observed in the infusion tube. We considered that a clinical course did not accord with the result of HIT antibody. We measured HIT antibody by another method, an enzyme immunoassay (EIA), and the positive antibody was observed. We encountered a rare case with discrepancy in the results of HIT antibody between two methods. When HIT is suspected by the results from the clinical course and 4T's score, even though the negative HIT antibody, heparin should be discontinued and the different assay for HIT antibody such as an EIA in this case should be performed. PMID- 27509720 TI - [Laboratory-Based Clinical Research I am Aiming for]. AB - We have pursued the clinical introduction of assays of lysophospholipids and related proteins. One such example is the multi-functional lysophospholipid mediator lysophosphatidic acid (LPA), which is produced from lysophosphatidylcholine (LPC) through the lysophospholipase D (lysoPLD) activity of autotaxin (ATX) in body fluids. Determination of the LPA concentration in body fluids, especially plasma, is clinically relevant and important for diagnostic purposes, and we have succeeded in the elucidation of disease states in which the levels of LPA/ATX are altered; ATX is promising as a biomarker for several diseases. The department of clinical laboratory in the hospital is a suitable section to perform such research, for which sophisticated assays and sampling techniques are needed. PMID- 27509721 TI - [Emerging Technologies Support the Molecular Basis of the WHO Classification of Hematopoietic Neoplasms]. AB - In the laboratory diagnosis of hematological neoplasms based on the WHO classification, molecular-genetic testing is indispensable. Emerging technologies for such testing have resulted in a shift of the assay platform from the first generation of a single target for detection or quantitation into advanced multiplex analysis, digital image analysis, automation of measurement, and combination with immunophenotypic analysis. The multiplex assay has expanded its platform application to genome-wide analysis, such as array comparative genome hybridization, SNP array, and next-generation sequencers. These have been applied for the diagnosis of hematopoietic neoplasms, enabling whole-genome profiling of diseases. The application of genome-wide analysis, such as target sequencing, is expected to be a practical tool in the laboratory diagnosis of hematopoietic neoplasms. The clinical use of these emerging technologies would provide a molecular basis for the WHO classification of hematological neoplasms and, thus, promote the quality of treatment based on laboratory diagnosis. PMID- 27509722 TI - [Clinical Laboratory Tests for Liver Diseases]. AB - A review lecture at the 60th annual meeting of the Japanese Society of Laboratory Medicine is summarized in this paper, in which novel advancements in acute hepatitis B, interferon therapy for hepatitis C, prediction of the liver fibrosis stage and epidemiology, and diagnosis of hepatocellular carcinoma are presented. Because clinical laboratory tests importantly contribute to progress in the diagnosis and treatment of liver diseases, the lecture focused on the role of such tests. PMID- 27509723 TI - [Mechanism Causing Abnormal Laboratory Data--Significance of Electrophoresis and Information Transmission--Chairmen's Introductory Remarks]. AB - Abnormal laboratory data are observed due to some kinds of modification as well as pathological conditions of patients. Elucidation of the causal mechanism is very important for clinical laboratories. This symposium was planned to highlight the significance of electrophoresis. Electrophoresis is one of the most important tools to provide clinicians with information for medical diagnosis and care. PMID- 27509724 TI - [Electrophoretic Analysis of Abnormal Data on Serum Protein Electrophoresis]. AB - We recently demonstrated glycation of monoclonal IgA and the presence of IgA albumin complexes, but the significance of the complexes was not clear. We describe a non-diabetic patient with IgA type M-protein whose serum fructosamine and glycoalbumin levels were elevated. On electrophoresis of the serum protein of the patient, the albumin band shifted to the cathode side. The abnormal precipitin arc of IgA-albumin complexes was detected by immunoelectrophoresis. To elucidate the mechanism of IgA-albumin complexes, we analyzed their properties using immunoelectrophoresis, Western blotting, and two-dimensional gel electrophoresis. The macromolecularized albumin spots were demonstrated by two dimensional Western blotting with antiserum to human albumin of the patient's serum. Moreover, the IgA-albumin complexes were dissociated on treatment with 2 mercaptoethanol. It can be considered that albumin is bound to the monoclonal IgA molecule by covalent disulfide bonds, and that the albumin binding site is located near the hinge region (311Cys) of the IgA molecule and involves the free SH group, thought to be present in the alpha-chain. PMID- 27509725 TI - [Electrophoretic Analysis of Serum Lipoproteins: Its Usefulness and Problems]. AB - Analysis of serum lipoprotein fractions by electrophoresis (lipoprotein electrophoresis) reveals lipid metabolism disorders, and provides various types of bio-information which lead to an accurate diagnosis and effective treatment for dyslipidemia and related diseases (e.g., coronary artery disease or chronic kidney disease). In particular, lipoprotein electrophoresis enables us to define the phenotypes of dyslipidemia, and to detect abnormal lipoproteins, which are potent biomarkers of atherosclerotic disease. In addition, lipoprotein electrophoresis is an indispensable complement to other assay methods for serum lipid component measurement that have some limitations, such as a homogeneous assay for LDL-C. However, it appears to be underestimated regarding its clinical usefulness. Indeed, the fee for lipoprotein electrophoresis tests is too low. This review specifically discusses the clinical usefulness and problems of lipoprotein electrophoresis, with a special emphasis on cost. PMID- 27509726 TI - [Electrophoretic Analysis of Abnormal Data Discovered by Serum Enzyme Testing]. AB - Lactate dehydrogenase (LD) isozymes are formed by random combinations of two different subunits encoded by LDHA and LDHB. There are a number of reasons for unusual LD electrophoretic isozyme patterns. An abnormal electrophoretic pattern may result from additional LD fractions, altered mobility, an altered molecular structure, or the distortion of one or more normal bands. The distortion of normal bands may be caused by immunoglobulin or other protein binding, genetic variants, or tumor production. The genetic mutations occasionally cause hereditary deficiency of the LD-A subunit or LD-B subunit, yielding specific LD isozyme patterns in serum and erythrocytes. Different LD isozyme patterns in cancer patients possibly originate from changes in expression of LDHA or LDHB due to other regulatory genes or promoter methylation or from deletions, duplications, or changes in gene copy numbers. We encountered a patient with retinoblastoma and a cell line, R51, that showed an LD-1-dominant isozyme pattern. We found that the abnormal isozyme pattern was mainly due to transcriptional silencing by aberrant DNA methylation in the promoter region of the LDHA gene. On the contrary, high LDHA was observed in gastrointestinal cancer, prostate cancer, and breast cancer tissues according to promoter hypermethylation of LDHB. The LD isozyme patterns in cancer patients reflect original tissues or cells regulated by the gene dosage effect or gene expression, which are both genetically and epigenetically controlled (especially aberrant DNA methylation). PMID- 27509727 TI - [Team-Based Clinical Laboratory Testing in Nephrology and Urology--Chairmen's Introductory Remarks]. AB - Recently, the Department of Clinical Examination has been extensively subdivided. When we perform examinations, we often require wide knowledge of other specialized fields. This symposium was planned to consider the procedure for examinations in the kidney urology field. Seven professionals gave lectures on the interpretation and adequacy of examinations involving the kidney urology field. Knowledge of not only specialized fields but also wide, basic, routine fields is required to perform more precise examinations. Therefore, we became aware that cooperation between examination departments is essential to improve our overall judgments. PMID- 27509728 TI - [How Far We can Diagnose by Urine Sediment Tests?]. AB - Morphological examinations for renal disease are mainly renal biopsy and urine sediment tests. Biopsy specimens are now evaluated in detail, and test items are evaluated as highly sensitive and specific compared with urine sediments, which reflect renal changes indirectly and are low in sensitivity and specificity. On the other hand, the standardization of urine sediment tests is now in progress, and some labs can provide sediment results beyond screening for distracted RBC, differential WBC, or atypical cells. The diagnostic importance of sediments is revisited. PMID- 27509729 TI - [Consideration of Physiological Examination and Laboratory Testing: Symposium]. AB - It is very effective to combine physiological examination (resistive index by renal Doppler) and laboratory testing (estimated glomerular filtration rate and albuminuria) when analyzing diabetic nephropathy associated with metabolic syndrome. In particular, the resistive index value is important for increasing diagnostic capabilities. We expect renal blood flow measurement using Sonazoid to increase accuracy. PMID- 27509730 TI - [Overview of Clinical Examination in Nephrology and Urology--Efficacy of Routine Ultrasound in Detection of Chronic Kidney Disease]. AB - PURPOSE: We re-evaluated the usefulness of ultrasound (US) performed in routine examination as a screening procedure for chronic kidney disease. PATIENTS AND METHODS: Of 294 patients screened by US in routine examination, 75 were identified as those with chronic renal damage during a one-month period (March 2013) in our hospital. We examined the patients' clinical background and extracted their characteristics. RESULTS: Thirty-six patients with chronic renal damage were detected out of US in 72 suspected cases, and 39 in 222 unsuspected cases. Among the latter group, US was performed to examine the upper abdomen in 35 cases, and to examine the whole abdomen in 3 cases. Among the latter group, US was performed in a checkup of the liver in 14 cases, as a routine examination for diabetics in 7 cases, and as a screening test for cancer in 4 cases. Among the latter group, US was performed on the request of endocrinologists in 12 cases, surgeons in 6 cases, and cardiovascular teams in 6 cases. CONCLUSION: Many patients with chronic kidney disease were detected by US in unsuspected cases incidentally. In other words, we should note that their physicians often did not intend to look for it at the time of ordering US examination. US may be useful for the detection of chronic kidney disease not only in high-risk cases, but also in low-risk, unsuspected cases. PMID- 27509731 TI - [Management of Personal Information in Clinical Laboratory Medicine:--Chairmen's Introductory Remarks]. AB - The Japanese Society of Laboratory Medicine has been running its own Medical Safety Committee, and holding a symposium on medical safety during the annual meeting. The medical world is filled with a considerable amount of personal information, including genetic information, the ultimate personal information. We, as medical staff, have to manage such personal information not only in times of peace but also during disasters or emergency situations. In Japan, the Act on the Protection of Personal Information is currently being implemented, but a number of problems remain. Human beings have entered the information technology era, including electrical medical record systems, which is useful for research and education besides medical practice. This is why personal information must be more effectively protected from leakage, misconception, and abuse. We should create a sound system to manage personal information, with the spirit of protecting patient information that originated from the Oath of Hippocrates. PMID- 27509732 TI - [Security Management in Clinical Laboratory Departments and Facilities: Current Status and Issues]. AB - We conducted a questionnaire survey regarding the current activities for protecting patients' privacy and the security of information systems (IS) related to the clinical laboratory departments of university hospitals, certified training facilities for clinical laboratories, and general hospitals in Yamaguchi Prefecture. The response rate was 47% from 215 medical institutions, including three commercial clinical laboratory centers. The results showed that there were some differences in management activities among facilities with respect to continuing education, the documentation or regulation of operational management for paper records, electronic information, remaining samples, genetic testing, and laboratory information for secondary use. They were suggested to be caused by differences in functions between university and general hospitals, differences in the scale of hospitals, or whether or not hospitals have received accreditation or ISO 15189. Regarding the IS, although the majority of facilities had sufficiently employed the access control to IS, there was some room for improvement in the management of special cases such as VIPs and patients with HIV infection. Furthermore, there were issues regarding the login method for computers shared by multiple staff, the showing of the names of personnel in charge of reports, and the risks associated with direct connections to systems and the Internet and the use of portable media such as USB memory sticks. These results indicated that further efforts are necessary for each facility to continue self-assessment and make improvements. PMID- 27509733 TI - [Requirements for Dealing with Personal Genetic Information in Clinical Practice]. AB - As clinical genetics evolves, we must deal with a considerable amount of genetic information in clinical practice. In this review, I mention important requirements for dealing with personal genetic information in medical care. Firstly, quality assurance of molecular genetic testing is required for quality assurance of genetic information. As most labs. have developed "home brew" tests without analytical and clinical validity, the standardization or automation of genetic tests should be developed. If not, it is recommended that genetic tests are performed with the "Best Practice Guideline". Secondly, the confidentiality of genetic information is required because genetic information may be highly predictive of the future health of an individual and have important implications for the relatives of the person tested. For the same reasons, genetic counseling is required following genetic tests. Finally, genetic test results have to be interpreted and a report compiled, which must be easy to understand for physicians and clients. The number of genome bioinformaticians is very limited in Japan, and more must be immediately trained. On dealing with personal genetic information in clinical practice, many issues still remain, and each issue should be steadily resolved. PMID- 27509734 TI - [Management System of Personal Data Protection in the Health Care Field]. AB - In Japan, the law on personal data protection was enacted in 2005. Privacy is a human right, including the 1981 right to be let alone. The need for confidentiality in the health care field has been accepted since the ancient Greek era, and privacy in the 19th century was developed in this field. However, the concept of privacy has gradually altered, especially due to the development of information technology. The author suggests that the guideline for the security of heath information systems of the Ministry of Health, Labour, and Welfare is very important and information security management with PDCA cycles is essential for personal data protection in the health care field. In recent years, gathering a large amount of life logging or health-related data and analyzing such data for academic and/or industrial applications has become common. Revising privacy protection legislation has become an urgent political issue in many countries. The Japanese Government published their policy to personal data protection act in Dec. 2013. Balancing public benefit and privacy is a major task of future legislation. The author recommends that health care professionals pay attention to, participate in the discussion of, and make suggestions regarding this act. PMID- 27509735 TI - [Laboratory Medicine and Medical Team Approaches--Opening Remarks from the Chair]. AB - Recently, medical team approaches were pointed out to be important in the field of laboratory medicine. The staff working in laboratory medicine needs to participate in various kinds of medical team such as ICT or NST. With such a background, the working group for medical teams was established in the Japanese Society of Laboratory Medicine in January 2012. Special program II was organized by this group at the 60th annual meeting held in Kobe in 2013. People gathered from representative societies related to laboratory medicine and discussed how we should participate in team approaches. Based on the results of meaningful discussions, we have reached a strong consensus to pursue team approaches in the future. PMID- 27509736 TI - [Nutrition Support as Team Medical Care]. AB - Nutrition support is important to prevent complicating disorders such as infections and decubitus and to improve patient outcomes. The nutrition support team (NST), which is usually composed of a physician, nurse, nutritionist, clinical laboratory technician, pharmacist, and office worker, is effective for preventing complications and reducing costs for hospitalized patients. To screen for malnutrition in an early phase, biochemical markers are useful. Transthyretin (TTR) is a serum protein synthesized mainly by the liver. TTR has a short half life in the bloodstream of 2 days, and is often used as a rapid and sensitive marker of malnutrition. However, TTR also decreases under inflammatory and infectious conditions. We recently established the Kumamoto Index to assess both the inflammatory and nutritional state of patients. PMID- 27509737 TI - [From JSLH (The Japanese Society for Laboratory Hematology): An Active Team Approach to Medicine as Laboratory Technologists, through Showing Bone Marrow and Peripheral Blood Samples Directly to Patients with Hematological Malignancy]. AB - The clinical path for the treatment of acute myeloid leukemia (AML) patients has been in practice in our hospital since 2003. In the clinical path, laboratory technologists take on the role of explaining the microscopic findings in bone marrow and peripheral blood samples to patients (with or without their families) using the view-sharing microscope in our laboratory. From July 2003 to October 2014, 56 patients were enrolled in the AML clinical path and given an explanation of their bone marrow and peripheral blood samples. The patients' median age was 62, and the median time spent for explanation was 40 minutes. We conducted a questionnaire feedback survey involving those who enrolled, and the results showed significant improvement in the recognition of the disease pathophysiology, treatment efficacy, and the importance of precautions against infectious diseases. Based on the feedback, we have made marked efforts to provide patients with an improved environment during the explanatory session. This includes installing a special display for the patients, drawing a schematic illustration that shows how the blood cells differentiate, and putting them into operation in a hematology ward to promote patient privacy and precautions against infectious diseases. Hematological laboratory technologists have played an important role in patient care in our hospital. To perform their role as effectively as possible, hematological laboratory technologists participate in the conferences of the Department of Hematology and Oncology regularly, in which medical staff members can discuss the conditions and clinical courses of patients. We aim to contribute to patient satisfaction by sophisticating specialized knowledge as hematological laboratory technologists and cooperate with other medical staff members. PMID- 27509738 TI - [Laboratory and Team-Based Medicine--From the Standpoint of JSLM]. AB - The Japanese Society of Laboratory Medicine (JSLM) organized a working group to promote team-based medicine 2 years ago. The Japan Society for Clinical Laboratory Automation (JSCLA) formed a committee for team-based medicine and it was active for five years from 2006 to 2011. The author, an officer of the JSCLA, presents previous activities and policies for the future. The three main activities were as follows: Firstly, a seminar with a lecture and practice was held at meetings of the JSCLA. Secondly, Internet services were set up to introduce action programs and promote team-based medicine. Thirdly, the guidebook was edited, written from the point of view of laboratory medicine. The committee worked hard and produced favorable results. It is difficult with the present circumstances to organize a committee for team-based medicine in the JSCLA again. We expect cooperation in seminars and meetings. PMID- 27509739 TI - [Japanese Association of Clinical Laborato Physicians--What We Are Doing Now and How We Should Develop in the Future as Competent Members of Team Medicine]. AB - No clinical laboratory would admit they do not practice team medicine, at least conceptually. However, true team medicine is more than an aspiration--it is an intentional care structure built, led, and delivered by a diverse, multidisciplinary team of physicians, medical technologists, nurses, pharmacists, and dozens of other professionals. We clinical laboratory physicians are able to fulfill an important role as competent members of the team medicine. Because we can look at the results of clinical examinations of patients earlier than anyone else, we can interpret the patient's condition by analyzing that results, and provide useful information to facilitate team medicine. I have conducted a questionnaire survey on team medicine targeting clinical laboratory physicians to clarify the tasks we are performing. In this paper, I describe what clinical laboratory physicians are currently doing, and how should we develop in the future. PMID- 27509740 TI - [Coordination and Role-Sharing between Health Care Professionals]. AB - In recent years, people's demands for medical services are increasing and, simultaneously, the overwork of health professionals has been pointed out. It is important to establish a system with which each medical professional can show higher levels of expertise and work as a team member to provide efficient and safe medical care. For this reason, a list of medical activities which can be performed by not only doctors but also other health professionals was devised by the Director General of the Health Policy Bureau on December 28th, 2007, as the "Promotion of role-sharing between doctors and other medical professionals, clerical staff, etc." In August 2009 the "Committee for the Promotion of Team Approach to Medical Care" was established and it reviewed the situation of collaboration and cooperation with doctors and other medical professionals. In the report "Promotion of Team Approach to Medical Care", which was summarized on March 19th, 2009, "Team Approach to Medical Care" was defined as "appropriate medical care provided by various medical professionals by sharing information and purposes of care while cooperating and complementing each other based on expertise." In May 2010, the "Promotion Council of Team Approach to Medical Care" was established to discuss the scope of practice for nurses and other medical professionals. As a result the council suggested to: 1) Institutionalize a training system for nurses who provide Specified Acts (a part of Assist in Medical Care), 2) Reconsider the scope of practice for radiological technologists, 3) Reconsider the scope of practice for laboratory technicians, and 4) Reconsider the implementation system for dental hygienists. We realized these policies in June 2014. PMID- 27509741 TI - Tracking wild sockeye salmon smolts to the ocean reveals distinct regions of nocturnal movement and high mortality. AB - Few estimates of migration rates or descriptions of behavior or survival exist for wild populations of out-migrating Pacific salmon smolts from natal freshwater rearing areas to the ocean. Using acoustic transmitters and fixed receiver arrays across four years (2010-2013), we tracked the migration of > 1850 wild sockeye salmon (Oncorhynchus nerka) smolts from Chilko Lake, British Columbia, to the coastal Pacific Ocean (> 1000 km distance). Cumulative survival to the ocean ranged 3-10% among years, although this may be slightly underestimated due to technical limitations at the final receiver array. Distinct spatial patterns in both behavior and survival were observed through all years. In small, clear, upper-river reaches, downstream migration largely occurred at night at speeds up to 50 km/d and coincided with poor survival. Among years, only 57-78% of smolts survived the first 80 km. Parallel laboratory experiments revealed excellent short-term survival and unhindered swimming performance of dummy-tagged smolts, suggesting that predators rather than tagging effects were responsible for the initial high mortality of acoustic-tagged smolts. Migration speeds increased in the Fraser River mainstem (~220 km/d in some years), diel movement patterns ceased, and smolt survival generally exceeded 90% in this segment. Marine movement rates and survival were variable across years, with among-year segment specific survival being the most variable and lowest (19-61%) during the final (and longest, 240 km) marine migration segment. Osmoregulatory preparedness was not expected to influence marine survival, as smolts could maintain normal levels of plasma chloride when experimentally exposed to saltwater (30 ppt) immediately upon commencing their migration from Chilko Lake. Transportation of smolts downstream generally increased survival to the farthest marine array. The act of tagging may have affected smolts in the marine environment in some years as dummy tagged fish had poorer survival than control fish when transitioned to saltwater in laboratory-based experiments. Current fisheries models for forecasting the number of adult sockeye returning to spawn have been inaccurate in recent years and generally do not incorporate juvenile or smolt survival information. Our results highlight significant potential for early migration conditions to influence adult recruitment. PMID- 27509742 TI - Assessing reproductive behavior important to fisheries management: a case study with red drum, Sciaenops ocellatus. AB - Spawning site selection and reproductive timing affect stock productivity and structure in marine fishes but are poorly understood. Traditionally, stock assessments measure reproductive potential as spawning stock biomass or egg production and do not include other aspects of reproductive behavior. Red drum make an excellent case study to assess these other aspects, as (1) they are highly fecund, pelagic spawners, like most exploited marine fishes; (2) their life cycle is delineated between nursery (estuarine) and adult (coastal and offshore) habitat; and (3) they are managed at these two spatial scales. This study was conducted from August 2012 to December 2013 and integrates data from multiple methods and spatial scales. Aerial surveys were used for large-scale monitoring of aggregations off two known estuarine nursery areas, Tampa Bay and Charlotte Harbor, Florida, USA. Capture-based sampling in Tampa Bay coastal (n = 2581) and estuarine waters (n = 158) was used to assess reproductive state and to confirm coastal spawning. To assess spatial dynamics, we acoustically tagged two population components in the Tampa Bay system, subadults from the estuary (n = 20) and adults from the coastal spawning site (n = 60). Behavioral plasticity was seen in subadult recruitment to coastal habitat, with some subadults maturing and recruiting before or during the spawning season and others (14 of 20 acoustically tagged fish) recruiting at the end of the 2012 spawning season. Both adults and recruited subadults (n = 29) were consequently detected in the Charlotte Harbor array, 132 km to the south. Spawning-site fidelity to the Tampa Bay spawning site occurred at both the population and individual scales. Aggregations consistently occurred in Tampa Bay coastal waters during the spawning season, and approximately two-thirds of tagged adults returned in the 2013 spawning season. A similar proportion of subadults returned to the Tampa Bay spawning site, exhibiting natal homing. However, these first-time spawners arrived later than repeat spawners and were detected over shorter time periods. This study, and others like it, demonstrates how integrating data from individuals tracked over space and time with more traditional population-based sampling is changing our understanding of ecological processes that affect marine fish productivity and our ability to manage for sustainablity. PMID- 27509743 TI - Cascading effects of fire retardant on plant-microbe interactions, community composition, and invasion. AB - Climate change, historical fire suppression, and a rise in human movements in urban-forest boundaries have resulted in an increased use of long-term fire retardant (LTFR). While LTFR is an effective fire-fighting tool, it contains high concentrations of nitrogen and phosphorus, and little is known about how this nutrient pulse affects terrestrial ecosystems. We used field surveys and greenhouse experiments to quantify effects of LTFR on plant productivity, community composition, and plant interactions with the ubiquitous root symbiont arbuscular mycorrhizal fungi (AMF). In the field, LTFR applications were associated with persistent shifts in plant communities toward exotic annuals with little or no dependency of AMF. Plants exposed to LTFR were less colonized by AMF, both in field surveys and in the greenhouse, and this was most likely due to the substantial and persistent increase in soil available phosphorus. All plants grew bigger with LTFR in the greenhouse, but the invasive annual cheatgrass (Bromus tectorum) benefitted most. While LTFR can control fires, it may cause long-term changes in soil nutrient availabilities, disrupt plant interactions with beneficial soil microbes, and exasperate invasion by some exotic plants. PMID- 27509744 TI - Adaptation services of floodplains and wetlands under transformational climate change. AB - Adaptation services are the ecosystem processes and services that benefit people by increasing their ability to adapt to change. Benefits may accrue from existing but newly used services where ecosystems persist or from novel services supplied following ecosystem transformation. Ecosystem properties that enable persistence or transformation are important adaptation services because they support future options. The adaptation services approach can be applied to decisions on trade offs between currently valued services and benefits from maintaining future options. For example, ecosystem functions and services of floodplains depend on river flows. In those regions of the world where climate change projections are for hotter, drier conditions, floods will be less frequent and floodplains will either persist, though with modified structure and function, or transform to terrestrial (flood-independent) ecosystems. Many currently valued ecosystem services will reduce in supply or become unavailable, but new options are provided by adaptation services. We present a case study from the Murray-Darling Basin, Australia, for operationalizing the adaptation services concept for floodplains and wetlands. We found large changes in flow and flood regimes are likely under a scenario of +1.6 degrees C by 2030, even with additional water restored to rivers under the proposed Murray-Darling Basin Plan. We predict major changes to floodplain ecosystems, including contraction of riparian forests and woodlands and expansion of terrestrial, drought-tolerant vegetation communities. Examples of adaptation services under this scenario include substitution of irrigated agriculture with dryland cropping and floodplain grazing; mitigation of damage from rarer, extreme floods; and increased tourism, recreational, and cultural values derived from fewer, smaller wetlands that can be maintained with environmental flows. Management for adaptation services will require decisions on where intervention can enable ecosystem persistence and where transformation is inevitable. New ways of managing water that include consideration of the increasing importance of adaptation services requires major changes to decision making that better account for landscape heterogeneity and large-scale change rather than attempting to maintain ecosystems in fixed states. PMID- 27509745 TI - Prioritizing land management efforts at a landscape scale: a case study using prescribed fire in Wisconsin. AB - One challenge in the effort to conserve biodiversity is identifying where to prioritize resources for active land management. Cost-benefit analyses have been used successfully as a conservation tool to identify sites that provide the greatest conservation benefit per unit cost. Our goal was to apply cost-benefit analysis to the question of how to prioritize land management efforts, in our case the application of prescribed fire to natural landscapes in Wisconsin, USA. We quantified and mapped frequently burned communities and prioritized management units based on a suite of indices that captured ecological benefits, management effort, and the feasibility of successful long-term management actions. Data for these indices came from LANDFIRE, Wisconsin's Wildlife Action Plan, and a nationwide wildland-urban interface assessment. We found that the majority of frequently burned vegetation types occurred in the southern portion of the state. However, the highest priority areas for applying prescribed fire occurred in the central, northwest, and northeast portion of the state where frequently burned vegetation patches were larger and where identified areas of high biological importance area occurred. Although our focus was on the use of prescribed fire in Wisconsin, our methods can be adapted to prioritize other land management activities. Such prioritization is necessary to achieve the greatest possible benefits from limited funding for land management actions, and our results show that it is feasible at scales that are relevant for land management decisions. PMID- 27509746 TI - A fire history derived from Pinus resinosa Ait. for the Islands of Eastern Lac La Croix, Minnesota, USA. AB - We reconstructed fire occurrence near a fur-trade era canoe travel corridor (used ca. 1780-1802) in the Quetico-Superior region west of Lake Superior to explore the possibility of human influence on pre-fire suppression rates of fire occurrence. Our research objectives were to (1) examine the spatial and temporal patterns of fire in the study area, (2) test fires' strength of association with regional drought, and (3) assess whether reconstructed fire frequencies could be explained by observed rates of lightning fire ignition over the modern period of record. We developed a 420-year fire history for the eastern portion of Lac La Croix in the Boundary Waters Canoe Area Wilderness (BWCAW). Seventy-one fire scarred samples were collected from remnant Pinus resinosa Ait. (red pine) stumps and logs from thirteen distinct island and three mainland forest stands. Collectively these samples contained records of 255 individual fire scars representing 79 fire events from 1636 to 1933 (study area mean fire intervals [MFI] 3.8 yr). Reconstructed fires were spatially and temporally asynchronous and not strongly associated with regional drought (P > 0.05). When compared to the conservative, tree-ring reconstructed estimate of historical fire occurrence and modern lightning-caused fires (1929-2012), a noticeable change in the distribution and frequency of fires within the study area was evident with only two lightning-ignited island fires since 1934 in the study area. Our results suggest a high likelihood that indigenous land use contributed to surface fire ignitions within our study area and highlights the importance of examining the potential effects of past indigenous land use when determining modern approaches to fire and wilderness management in fire-adapted ecosystems. PMID- 27509747 TI - Competitive release and outbreaks of non-target pests associated with transgenic Bt cotton. AB - The adoption of transgenic Bt cotton has, in some cases, led to environmental and economic benefits through reduced insecticide use. However, the distribution of these benefits and associated risks among cotton growers and cotton-growing regions has been uneven due in part to outbreaks of non-target or secondary pests, thereby requiring the continued use of synthetic insecticides. In the southeastern USA, Bt cotton adoption has resulted in increased abundance of and damage from stink bug pests, Euschistus servus and Nezara viridula (Heteroptera: Pentatomidae). While the impact of increased stink bug abundance has been well documented, the causes have remained unclear. We hypothesize that release from competition with Bt-susceptible target pests may drive stink bug outbreaks in Bt cotton. We first examined the evidence for competitive release of stink bugs through meta-analysis of previous studies. We then experimentally tested if herbivory by Bt-susceptible Helicoverpa zea increases stink bug leaving rates and deters oviposition on non-Bt cotton. Consistent with previous studies, we found differences in leaving rates only for E servus, but we found that both species strongly avoided ovipositing on H. zea-damaged plants. Considering all available evidence, competitive release of stink bug populations in Bt cotton likely contributes to outbreaks, though the relative importance of competitive release remains an open question. Ecological risk assessments of Bt crops and other transgenic insecticidal crops would benefit from greater understanding of the ecological mechanisms underlying non-target pest outbreaks and greater attention to indirect ecological effects more broadly. PMID- 27509748 TI - The cost and feasibility of marine coastal restoration. AB - Land-use change in the coastal zone has led to worldwide degradation of marine coastal ecosystems and a loss of the goods and services they provide. Restoration is the process of assisting the recovery of an ecosystem that has been degraded, damaged, or destroyed and is critical for habitats where natural recovery is hindered. Uncertainties about restoration cost and feasibility can impede decisions on whether, what, how, where, and how much to restore. Here, we perform a synthesis of 235 studies with 954 observations from restoration or rehabilitation projects of coral reefs, seagrass, mangroves, salt-marshes, and oyster reefs worldwide, and evaluate cost, survival of restored organisms, project duration, area, and techniques applied. Findings showed that while the median and average reported costs for restoration of one hectare of marine coastal habitat were around US$80000 (2010) and US$1600000 (2010), respectively, the real total costs (median) are likely to be two to four times higher. Coral reefs and seagrass were among the most expensive ecosystems to restore. Mangrove restoration projects were typically the largest and the least expensive per hectare. Most marine coastal restoration projects were conducted in Australia, Europe, and USA, while total restoration costs were significantly (up to 30 times) cheaper in countries with developing economies. Community- or volunteer based marine restoration projects usually have lower costs. Median survival of restored marine and coastal organisms, often assessed only within the first one to two years after restoration, was highest for saltmarshes (64.8%) and coral reefs (64.5%) and lowest for seagrass (38.0%). However, success rates reported in the scientific literature could be biased towards publishing successes rather than failures. The majority of restoration projects were short-lived and seldom reported monitoring costs. Restoration success depended primarily on the ecosystem, site selection, and techniques applied rather than on money spent. We need enhanced investment in both improving restoration practices and large-scale restoration. PMID- 27509749 TI - Prey-mediated behavioral responses of feeding blue whales in controlled sound exposure experiments. AB - Behavioral response studies provide significant insights into the nature, magnitude, and consequences of changes in animal behavior in response to some external stimulus. Controlled exposure experiments (CEEs) to study behavioral response have faced challenges in quantifying the importance of and interaction among individual variability, exposure conditions, and environmental covariates. To investigate these complex parameters relative to blue whale behavior and how it may change as a function of certain sounds, we deployed multi-sensor acoustic tags and conducted CEEs using simulated mid-frequency active sonar (MFAS) and pseudo-random noise (PRN) stimuli, while collecting synoptic, quantitative prey measures. In contrast to previous approaches that lacked such prey data, our integrated approach explained substantially more variance in blue whale dive behavioral responses to mid-frequency sounds (r2 = 0.725 vs. 0.14 previously). Results demonstrate that deep-feeding whales respond more clearly and strongly to CEEs than those in other behavioral states, but this was only evident with the increased explanatory power provided by incorporating prey density and distribution as contextual covariates. Including contextual variables increases the ability to characterize behavioral variability and empirically strengthens previous findings that deep-feeding blue whales respond significantly to mid frequency sound exposure. However, our results are only based on a single behavioral state with a limited sample size, and this analytical framework should be applied broadly across behavioral states. The increased capability to describe and account for individual response variability by including environmental variables, such as prey, that drive foraging behavior underscores the importance of integrating these and other relevant contextual parameters in experimental designs. Our results suggest the need to measure and account for the ecological dynamics of predator-prey interactions when studying the effects of anthropogenic disturbance in feeding animals. PMID- 27509750 TI - Supply-demand equilibria and the size-number trade-off in spatially structured recreational fisheries. AB - Recreational fishing effort varies across complex inland landscapes (e.g., lake districts) and appears influenced by both angler preferences and qualities of the fishery resource, like fish size and abundance. However, fish size and abundance have an ecological trade-off within a population, thereby structuring equal quality isopleths expressing this trade-off across the fishing landscape. Since expressed preferences of recreational anglers (i.e., site-selection of high quality fishing opportunities among many lakes) can be analogous to optimal foraging strategies of natural predators, adopting such concepts can aid in understanding scale-dependence in fish-angler interactions and impacts of fishing across broad landscapes. Here, we assumed a fish supply-angler demand equilibria and adapted a novel bivariate measure of fishing quality based on fish size and catch rates to assess how recreational anglers influence fishing quality among a complex inland landscape. We then applied this metric to evaluate (1) angler preferences for caught and released fish compared to harvested fish, (2) the nonlinear size-numbers trade-off with uncertainty in both traits, and (3) the spatial-scale of the equilibria across 62 lakes and four independent management regions in British Columbia's (BC) rainbow trout Oncorhynchus mykiss fishery. We found anglers had low preference for caught and released fish (~10% of the value compared to harvested fish), which modified anglers' perception of fishing quality. Hence, fishing quality and angler effort was not influenced simply by total fish caught, but largely by harvested fish catch rates. Fishing quality varied from BC's northern regions (larger fish and more abundant) compared to southern regions (smaller fish and less abundant) directly associated with a 2.5 times increase in annual fishing effort in southern regions, suggesting that latent fishing pressure can structure the size-numbers trade-off in rainbow trout populations. The presence of two different equal-quality isopleths suggests at least two effective landscapes support co-occurring ideal free distributions of recreational fishing effort in BC's rainbow fishery. Anglers' expressed preferences among lakes interacted with density dependent growth and survival within lakes to structure a size-numbers trade-off influencing how anglers perceive fishing quality and, ultimately, distribute across complex inland landscapes. PMID- 27509751 TI - Limited carbon and biodiversity co-benefits for tropical forest mammals and birds. AB - The conservation of tropical forest carbon stocks offers the opportunity to curb climate change by reducing greenhouse gas emissions from deforestation and simultaneously conserve biodiversity. However, there has been considerable debate about the extent to which carbon stock conservation will provide benefits to biodiversity in part because whether forests that contain high carbon density in their aboveground biomass also contain high animal diversity is unknown. Here, we empirically examined medium to large bodied ground-dwelling mammal and bird (hereafter "wildlife") diversity and carbon stock levels within the tropics using camera trap and vegetation data from a pantropical network of sites. Specifically, we tested whether tropical forests that stored more carbon contained higher wildlife species richness, taxonomic diversity, and trait diversity. We found that carbon stocks were not a significant predictor for any of these three measures of diversity, which suggests that benefits for wildlife diversity will not be maximized unless wildlife diversity is explicitly taken into account; prioritizing carbon stocks alone will not necessarily meet biodiversity conservation goals. We recommend conservation planning that considers both objectives because there is the potential for more wildlife diversity and carbon stock conservation to be achieved for the same total budget if both objectives are pursued in tandem rather than independently. Tropical forests with low elevation variability and low tree density supported significantly higher wildlife diversity. These tropical forest characteristics may provide more affordable proxies of wildlife diversity for future multi objective conservation planning when fine scale data on wildlife are lacking. PMID- 27509752 TI - Assessing the umbrella value of a range-wide conservation network for jaguars (Panthera onca). AB - Umbrella species are employed as conservation short-cuts for the design of reserves or reserve networks. However, empirical data on the effectiveness of umbrellas is equivocal, which has prevented more widespread application of this conservation strategy. We perform a novel, large-scale evaluation of umbrella species by assessing the potential umbrella value of a jaguar (Panthera onca) conservation network (consisting of viable populations and corridors) that extends from Mexico to Argentina. Using species richness, habitat quality, and fragmentation indices of ~1500 co-occurring mammal species, we show that jaguar populations and corridors overlap a substantial amount and percentage of high quality habitat for co-occurring mammals and that the jaguar network performs better than random networks in protecting high-quality, interior habitat. Significantly, the effectiveness of the jaguar network as an umbrella would not have been noticeable had we focused on species richness as our sole metric of umbrella utility. Substantial inter-order variability existed, indicating the need for complementary conservation strategies for certain groups of mammals. We offer several reasons for the positive result we document, including the large spatial scale of our analysis and our focus on multiple metrics of umbrella effectiveness. Taken together, our results demonstrate that a regional, single species conservation strategy can serve as an effective umbrella for the larger community and should help conserve viable populations and connectivity for a suite of co-occurring mammals. Current and future range-wide planning exercises for other large predators may therefore have important umbrella benefits. PMID- 27509753 TI - Estimating population density and connectivity of American mink using spatial capture-recapture. AB - Estimating the abundance or density of populations is fundamental to the conservation and management of species, and as landscapes become more fragmented, maintaining landscape connectivity has become one of the most important challenges for biodiversity conservation. Yet these two issues have never been formally integrated together in a model that simultaneously models abundance while accounting for connectivity of a landscape. We demonstrate an application of using capture-recapture to develop a model of animal density using a least cost path model for individual encounter probability that accounts for non Euclidean connectivity in a highly structured network. We utilized scat detection dogs (Canis lupus familiaris) as a means of collecting non-invasive genetic samples of American mink (Neovison vison) individuals and used spatial capture recapture models (SCR) to gain inferences about mink population density and connectivity. Density of mink was not constant across the landscape, but rather increased with increasing distance from city, town, or village centers, and mink activity was associated with water. The SCR model allowed us to estimate the density and spatial distribution of individuals across a 388 km2 area. The model was used to investigate patterns of space usage and to evaluate covariate effects on encounter probabilities, including differences between sexes. This study provides an application of capture-recapture models based on ecological distance, allowing us to directly estimate landscape connectivity. This approach should be widely applicable to provide simultaneous direct estimates of density, space usage, and landscape connectivity for many species. PMID- 27509754 TI - A generalizable energetics-based model of avian migration to facilitate continental-scale waterbird conservation. AB - Conserving migratory birds is made especially difficult because of movement among spatially disparate locations across the annual cycle. In light of challenges presented by the scale and ecology of migratory birds, successful conservation requires integrating objectives, management, and monitoring across scales, from local management units to ecoregional and flyway administrative boundaries. We present an integrated approach using a spatially explicit energetic-based mechanistic bird migration model useful to conservation decision-making across disparate scales and locations. This model moves a Mallard-like bird (Anas platyrhynchos), through spring and fall migration as a function of caloric gains and losses across a continental-scale energy landscape. We predicted with this model that fall migration, where birds moved from breeding to wintering habitat, took a mean of 27.5 d of flight with a mean seasonal survivorship of 90.5% (95% Cl = 89.2%, 91.9%), whereas spring migration took a mean of 23.5 d of flight with mean seasonal survivorship of 93.6% (95% CI = 92.5%, 94.7%). Sensitivity analyses suggested that survival during migration was sensitive to flight speed, flight cost, the amount of energy the animal could carry, and the spatial pattern of energy availability, but generally insensitive to total energy availability per se. Nevertheless, continental patterns in the bird-use days occurred principally in relation to wetland cover and agricultural habitat in the fall. Bird-use days were highest in both spring and fall in the Mississippi Alluvial Valley and along the coast and near-shore environments of South Carolina. Spatial sensitivity analyses suggested that locations nearer to migratory endpoints were less important to survivorship; for instance, removing energy from a 1036 km2 stopover site at a time from the Atlantic Flyway suggested coastal areas between New Jersey and North Carolina, including the Chesapeake Bay and the North Carolina piedmont, are essential locations for efficient migration and increasing survivorship during spring migration but not locations in Ontario and Massachusetts. This sort of spatially explicit information may allow decision makers to prioritize their conservation actions toward locations most influential to migratory success. Thus, this mechanistic model of avian migration provides a decision-analytic medium integrating the potential consequences of local actions to flyway-scale phenomena. PMID- 27509755 TI - Addressing potential local adaptation in species distribution models: implications for conservation under climate change. AB - Species distribution models (SDMs) have been criticized for involving assumptions that ignore or categorize many ecologically relevant factors such as dispersal ability and biotic interactions. Another potential source of model error is the assumption that species are ecologically uniform in their climatic tolerances across their range. Typically, SDMs treat a species as a single entity, although populations of many species differ due to local adaptation or other genetic differentiation. Not taking local adaptation into account may lead to incorrect range prediction and therefore misplaced conservation efforts. A constraint is that we often do not know the degree to which populations are locally adapted. Lacking experimental evidence, we still can evaluate niche differentiation within a species' range to promote better conservation decisions. We explore possible conservation implications of making type I or type II errors in this context. For each of two species, we construct three separate Max-Ent models, one considering the species as a single population and two of disjunct populations. Principal component analyses and response curves indicate different climate characteristics in the current environments of the populations. Model projections into future climates indicate minimal overlap between areas predicted to be climatically suitable by the whole species vs. population-based models. We present a workflow for addressing uncertainty surrounding local adaptation in SDM application and illustrate the value of conducting population-based models to compare with whole species models. These comparisons might result in more cautious management actions when alternative range outcomes are considered. PMID- 27509756 TI - Conservation vs. livelihoods: spatial management of non-timber forest product harvests in a two-dimensional model. AB - Areas of high biodiversity often coincide with communities living in extreme poverty. As a livelihood support, these communities often harvest wild products from the environment. But harvest activities can have negative impacts on fragile and globally important ecosystems. This paper examines trade-offs in ecological protection and community welfare from the harvest of wild products. With a novel model and empirical evidence, I show that management of harvest activity does not always resolve these trade-offs. In a model of continuous harvests in a two dimensional landscape, managed harvest activity improves welfare, but is uniformly bad for other ecosystem services that are sensitive to the presence (as opposed to the intensity) of human activity. Empirical results from a unique dataset of mushroom harvesters in Yunnan, China suggest more experienced, poorer, and more vulnerable individuals tend to rely on more distant harvests. Thus, policies that limit the extent of forest travel, such as protected areas, may protect fragile ecosystems but can have a disproportionately negative effect on those most vulnerable. PMID- 27509757 TI - Translocation strategies for multiple species depend on interspecific interaction type. AB - Conservation translocations, anthropogenic movements of species to prevent their extinction, have increased substantially over the last few decades. Although multiple species are frequently moved to the same location, current translocation guidelines consider species in isolation. This practice ignores important interspecific interactions and thereby risks translocation failure. We model three different two-species systems to illustrate the inherent complexity of multispecies translocations and to assess the influence of different interaction types (consumer-resource, mutualism, and competition) on translocation strategies. We focus on how these different interaction types influence the optimal founder population sizes for successful translocations and the order in which the species are moved (simultaneous or sequential). Further, we assess the effect of interaction strength in simultaneous translocations and the time delay between translocations when moving two species sequentially. Our results show that translocation decisions need to reflect the type of interaction. While all translocations of interacting species require a minimum founder population size, which is demarked by an extinction boundary, consumer-resource translocations also have a maximum founder population limit. Above the minimum founder size, increasing the number of translocated individuals leads to a substantial increase in the extinction boundary of competitors and consumers, but not of mutualists. Competitive and consumer-resource systems benefit from sequential translocations, but the order of translocations does not change the outcomes for mutualistic interaction partners noticeably. Interspecific interactions are important processes that shape population dynamics and should therefore be incorporated into the quantitative planning of multispecies translocations. Our findings apply whenever interacting species are moved, for example, in reintroductions, conservation introductions, biological control, or ecosystem restoration. PMID- 27509758 TI - Projecting pest population dynamics under global warming: the combined effect of inter- and intra-annual variations. AB - The typical short generation length of insects makes their population dynamics highly sensitive not only to mean annual temperatures but also to their intra annual variations. To consider the combined effect of both thermal factors under global warming, we propose a modeling framework that links general circulation models (GCMs) with a stochastic weather generator and population dynamics models to predict species population responses to inter- and intra-annual temperature changes. This framework was utilized to explore future changes in populations of Bemisia tabaci, an invasive insect pest-species that affects multiple agricultural systems in the Mediterranean region. We considered three locations representing different pest status and climatic conditions: Montpellier (France), Seville (Spain), and Beit-Jamal (Israel). We produced ensembles of local daily temperature realizations representing current and future (mid-21st century) climatic conditions under two emission scenarios for the three locations. Our simulations predicted a significant increase in the average number of annual generations and in population size, and a significant lengthening of the growing season in all three locations. A negative effect was found only in Seville for the summer season, where future temperatures lead to a reduction in population size. High variability in population size was observed between years with similar annual mean temperatures, suggesting a strong effect of intra-annual temperature variation. Critical periods were from late spring to late summer in Montpellier and from late winter to early summer in Seville and Beit-Jamal. Although our analysis suggested that earlier seasonal activity does not necessarily lead to increased populations load unless an additional generation is produced, it is highly likely that the insect will become a significant pest of open-fields at Mediterranean latitudes above 40 degrees during the next 50 years. Our simulations also implied that current predictions based on mean temperature anomalies are relatively conservative and it is better to apply stochastic tools to resolve complex responses to climate change while taking natural variability into account. In summary, we propose a modeling framework capable of determining distinct intra-annual temperature patterns leading to large or small population sizes, for pest risk assessment and management planning of both natural and agricultural ecosystems. PMID- 27509759 TI - Comparison of solar-induced chlorophyll fluorescence, light-use efficiency, and process-based GPP models in maize. AB - Accurately quantifying cropland gross primary production (GPP) is of great importance to monitor cropland status and carbon budgets. Satellite-based light use efficiency (LUE) models and process-based terrestrial biosphere models (TBMs) have been widely used to quantify cropland GPP at different scales in past decades. However, model estimates of GPP are still subject to large uncertainties, especially for croplands. More recently, space-borne solar-induced chlorophyll fluorescence (SIF) has shown the ability to monitor photosynthesis from space, providing new insights into actual photosynthesis monitoring. In this study, we examined the potential of SIF data to describe maize phenology and evaluated three GPP modeling approaches (space-borne SIF retrievals, a LUE-based vegetation photosynthesis model [VPM], and a process-based soil canopy observation of photochemistry and energy flux [SCOPE] model constrained by SIF) at a maize (Zea mays L.) site in Mead, Nebraska, USA. The result shows that SIF captured the seasonal variations (particularly during the early and late growing season) of tower-derived GPP (GPP_EC) much better than did satellite-based vegetation indices (enhanced vegetation index [EVI] and land surface water index [LSWI]). Consequently, SIF was strongly correlated with GPP_EC than were EVI and LSWI. Evaluation of GPP estimates against GPP_EC during the growing season demonstrated that all three modeling approaches provided reasonable estimates of maize GPP, with Pearson's correlation coefficients (r) of 0.97, 0.94, and 0.93 for the SCOPE, VPM, and SIF models, respectively. The SCOPE model provided the best simulation of maize GPP when SIF observations were incorporated through optimizing the key parameter of maximum carboxylation capacity (Vcmax). Our results illustrate the potential of SIF data to offer an additional way to investigate the seasonality of photosynthetic activity, to constrain process based models for improving GPP estimates, and to reasonably estimate GPP by integrating SIF and GPP_EC data without dependency on climate inputs and satellite-based vegetation indices. PMID- 27509760 TI - Multiscale connectivity and graph theory highlight critical areas for conservation under climate change. AB - Conservation planning and biodiversity management require information on landscape connectivity across a range of spatial scales from individual home ranges to large regions. Reduction in landscape connectivity due changes in land use or development is expected to act synergistically with alterations to habitat mosaic configuration arising from climate change. We illustrate a multiscale connectivity framework to aid habitat conservation prioritization in the context of changing land use and climate. Our approach, which builds upon the strengths of multiple landscape connectivity methods, including graph theory, circuit theory, and least-cost path analysis, is here applied to the conservation planning requirements of the Mohave ground squirrel. The distribution of this threatened Californian species, as for numerous other desert species, overlaps with the proposed placement of several utility-scale renewable energy developments in the American southwest. Our approach uses information derived at three spatial scales to forecast potential changes in habitat connectivity under various scenarios of energy development and climate change. By disentangling the potential effects of habitat loss and fragmentation across multiple scales, we identify priority conservation areas for both core habitat and critical corridor or stepping stone habitats. This approach is a first step toward applying graph theory to analyze habitat connectivity for species with continuously distributed habitat and should be applicable across a broad range of taxa. PMID- 27509761 TI - Invasiveness of plant pathogens depends on the spatial scale of host distribution. AB - Plant diseases often cause serious yield losses in agriculture. A pathogen's invasiveness can be quantified by the basic reproductive number, R0. Since pathogen transmission between host plants depends on the spatial separation between them, R0 is strongly influenced by the spatial scale of the host distribution. We present a proof of principle of a novel approach to estimate the basic reproductivenumber, R0, of plant pathogens as a function of the size of a field planted with crops and its aspect ratio. This general approach is based on a spatially explicit population dynamical model. The basic reproductive number was found to increase with the field size at small field sizes and to saturate to a constant value at large field sizes. It reaches amaximum in square fields and decreases as the field becomes elongated. This pattern appears to be quite general: it holds for dispersal kernels that decrease exponentially or faster, as well as for fat-tailed dispersal kernels that decrease slower than exponential (i.e., power-law kernels). We used this approach to estimate R0 in wheat stripe rust(an important disease caused by Puccinia striiformis), where we inferred both the transmission rates and the dispersal kernels from the measurements of disease gradients. For the two largest datasets, we estimated R0 of P. striiformis in the limit of large fields to be of the order of 30. We found that the spatial extent over which R0 changes strongly is quite fine-scaled (about 30 m of the linear extension of the field). Our results indicate that in order to optimize the spatial scale of deployment of fungicides or host resistances, the adjustments should be made at a fine spatial scale. We also demonstrated how the knowledge of the spatial dependence of R0 can improve recommendations with regard to fungicide treatment. PMID- 27509762 TI - Evolutionary patterns and physicochemical properties explain macroinvertebrate sensitivity to heavy metals. AB - Ecological risk assessment depends strongly on species sensitivity data. Typically, sensitivity data are based on laboratory toxicity bioassays, which for practical constraints cannot be exhaustively performed for all species and chemicals available. Bilinear models integrating phylogenetic information of species and physicochemical properties of compounds allow to predict species sensitivity to chemicals. Combining the molecular information (DNA sequences) of 31 invertebrate species with the physicochemical properties of six bivalent metals, we built bilinear models that explained 70-80% of the variability in species sensitivity to heavy metals. Phylogeny was the most important component of the bilinear models, as it explained the major part of the explained variance (> 40%). Predicted values from bilinear modeling were in agreement with experimental values (> 50%); therefore, this approach is a good starting point to build statistical models which can potentially predict heavy metal toxicity for untested invertebrate species based on empirical values for similar species. Despite their good performance, development of the presented bilinear models would benefit from improved phylogenetic and toxicological datasets. Our analysis is an example for linking evolutionary biology with applied ecotoxicology. Its future applications may encompass other stress factors or traits influencing the survival of aquatic organisms in polluted environments. PMID- 27509763 TI - Rapidly restoring biological soil crusts and ecosystem functions in a severely disturbed desert ecosystem. AB - Restoring biological soil crusts (biocrusts) in degraded drylands can contribute to recovery of ecosystem functions that have global implications, including erosion resistance and nutrient cycling. To examine techniques for restoring biocrusts, we conducted a replicated, factorial experiment on recently abandoned road surfaces by applying biocrust inoculation (salvaged and stored dry for two years), salvaged topsoil, an abiotic soil amendment (wood shavings), and planting of a dominant perennial shrub (Ambrosia dumosa). Eighteen months after treatments, we measured biocrust abundance and species composition, soil chlorophyll a content and fertility, and soil resistance to erosion. Biocrust addition significantly accelerated biocrust recovery on disturbed soils, including increasing lichen and moss cover and cyanobacteria colonization. Compared to undisturbed controls, inoculated plots had similar lichen and moss composition, recovered 43% of total cyanobacteria density, had similar soil chlorophyll content, and exhibited recovery of soil fertility and soil stability. Inoculation was the only treatment that generated lichen and moss cover. Topsoil application resulted in partial recovery of the cyanobacteria community and soil properties. Compared to untreated disturbed plots, topsoil application without inoculum increased cyanobacteria density by 186% and moderately improved soil chlorophyll and ammonium content and soil stability. Topsoil application produced 22% and 51% of the cyanobacteria density g-1 soil compared to undisturbed and inoculated plots, respectively. Plots not treated with either topsoil or inoculum had significantly lower cyanobacteria density, soil chlorophyll and ammonium concentrations, and significantly higher soil nitrate concentration. Wood shavings and Ambrosia had no influence on biocrust lichen and moss species recovery but did affect cyanobacteria composition and soil fertility. Inoculation of severely disturbed soil with native biocrusts rapidly restored biocrust communities and soil stability such that restored areas were similar to undisturbed desert within three years. Using salvaged biocrust as inoculum can be an effective tool in ecological restoration because of its efficacy and simple implementation. Although salvaging biocrust material can be technically difficult and potentially costly, utilizing opportunities to salvage material in planned future disturbance can provide additional land management tools. PMID- 27509764 TI - Ecosystem structure, function, and composition in rangelands are negatively affected by livestock grazing. AB - Reports of positive or neutral effects of grazing on plant species richness have prompted calls for livestock grazing to be used as a tool for managing land for conservation. Grazing effects, however, are likely to vary among different response variables, types, and intensity of grazing, and across abiotic conditions. We aimed to examine how grazing affects ecosystem structure, function, and composition. We compiled a database of 7615 records reporting an effect of grazing by sheep and cattle on 278 biotic and abiotic response variables for published studies across Australia. Using these data, we derived three ecosystem measures based on structure, function, and composition, which were compared against six contrasts of grazing pressure, ranging from low to heavy, two different herbivores (sheep, cattle), and across three different climatic zones. Grazing reduced structure (by 35%), function (24%), and composition (10%). Structure and function (but not composition) declined more when grazed by sheep and cattle together than sheep alone. Grazing reduced plant biomass (40%), animal richness (15%), and plant and animal abundance, and plant and litter cover (25%), but had no effect on plant richness nor soil function. The negative effects of grazing on plant biomass, plant cover, and soil function were more pronounced in drier environments. Grazing effects on plant and animal richness and composition were constant, or even declined, with increasing aridity. Our study represents a comprehensive continental assessment of the implications of grazing for managing Australian rangelands. Grazing effects were largely negative, even at very low levels of grazing. Overall, our results suggest that livestock grazing in Australia is unlikely to produce positive outcomes for ecosystem structure, function, and composition or even as a blanket conservation tool unless reduction in specific response variables is an explicit management objective. PMID- 27509765 TI - KNOWLEDGE AND SKILLS ENHANCEMENT THROUGH PERIOPERATIVE NURSING SIMULATION LAB TRAINING. AB - In Edmonton Zone, the attrition rate among new perioperative nursing staff is an issue of concern and many ORs are facing noticeable staffing challenges. In the Edmonton area there are approximately 79 surgical suites. A series of simulation labs were established in 2015 to provide perioperative nurses in order to increase their comfort on the job and to help build confidence levels. The expectations for this simulation are an overall improvement in perioperative nurses' competency, a reduction in OR orientation and training time, and a decrease in the attrition rates among OR nurses. PMID- 27509766 TI - SPOTLIGHT ON ORNAC MEMBERS. AN INTERVIEW WITH ELIZABETH BECK RN, CPN(C), ORNAC TREASURER. PMID- 27509767 TI - TRADITIONAL CANISTER-BASED OPEN WASTE MANAGEMENT SYSTEM VERSUS CLOSED SYSTEM: HAZARDOUS EXPOSURE PREVENTION AND OPERATING THEATRE STAFF SATISFACTION. AB - INTRODUCTION: Exposure to blood and body fluids is a major concern to health care professionals working in operating rooms (ORs). Thus, it is essential that hospitals use fluid waste management systems that minimise risk to staff, while maximising efficiency. METHOD: The current study compared the utility of a 'closed' system with a traditional canister-based 'open' system in the OR in a private hospital setting. RESULTS: A total of 30 arthroscopy, urology, and orthopaedic cases were observed. The closed system was used in five, four, and six cases, respectively and the open system was used in nine, two, and four cases, respectively. The average number of opportunities for staff to be exposed to hazardous fluids were fewer for the closed system when compared to the open during arthroscopy and urology procedures. The open system required nearly 3.5 times as much staff time for set-up, maintenance during procedures, and post procedure disposal of waste. Theatre staff expressed greater satisfaction with the closed system than with the open. CONCLUSION: In conclusion, compared with the open system, the closed system offers a less hazardous and more efficient method of disposing of fluid waste generated in the OR. PMID- 27509768 TI - Band Gap Engineering with Ultralarge Biaxial Strains in Suspended Monolayer MoS2. AB - We demonstrate the continuous and reversible tuning of the optical band gap of suspended monolayer MoS2 membranes by as much as 500 meV by applying very large biaxial strains. By using chemical vapor deposition (CVD) to grow crystals that are highly impermeable to gas, we are able to apply a pressure difference across suspended membranes to induce biaxial strains. We observe the effect of strain on the energy and intensity of the peaks in the photoluminescence (PL) spectrum and find a linear tuning rate of the optical band gap of 99 meV/%. This method is then used to study the PL spectra of bilayer and trilayer devices under strain and to find the shift rates and Gruneisen parameters of two Raman modes in monolayer MoS2. Finally, we use this result to show that we can apply biaxial strains as large as 5.6% across micron-sized areas and report evidence for the strain tuning of higher level optical transitions. PMID- 27509769 TI - The population cost-effectiveness of delivering universal and indicated school based interventions to prevent the onset of major depression among youth in Australia. AB - AIMS: School-based psychological interventions encompass: universal interventions targeting youth in the general population; and indicated interventions targeting youth with subthreshold depression. This study aimed to: (1) examine the population cost-effectiveness of delivering universal and indicated prevention interventions to youth in the population aged 11-17 years via primary and secondary schools in Australia; and (2) compare the comparative cost effectiveness of delivering these interventions using face-to-face and internet based delivery mechanisms. METHODS: We reviewed literature on the prevention of depression to identify all interventions targeting youth that would be suitable for implementation in Australia and had evidence of efficacy to support analysis. From this, we found evidence of effectiveness for the following intervention types: universal prevention involving group-based psychological interventions delivered to all participating school students; and indicated prevention involving group-based psychological interventions delivered to students with subthreshold depression. We constructed a Markov model to assess the cost effectiveness of delivering universal and indicated interventions in the population relative to a 'no intervention' comparator over a 10-year time horizon. A disease model was used to simulate epidemiological transitions between three health states (i.e., healthy, diseased and dead). Intervention effect sizes were based on meta-analyses of randomised control trial data identified in the aforementioned review; while health benefits were measured as Disability-adjusted Life Years (DALYs) averted attributable to reductions in depression incidence. Net costs of delivering interventions were calculated using relevant Australian data. Uncertainty and sensitivity analyses were conducted to test model assumptions. Incremental cost-effectiveness ratios (ICERs) were measured in 2013 Australian dollars per DALY averted; with costs and benefits discounted at 3%. RESULTS: Universal and indicated psychological interventions delivered through face-to-face modalities had ICERs below a threshold of $50 000 per DALY averted. That is, $7350 per DALY averted (95% uncertainty interval (UI): dominates - 23 070) for universal prevention, and $19 550 per DALY averted (95% UI: 3081-56 713) for indicated prevention. Baseline ICERs were generally robust to changes in model assumptions. We conducted a sensitivity analysis which found that internet delivered prevention interventions were highly cost-effective when assuming intervention effect sizes of 100 and 50% relative to effect sizes observed for face-to-face delivered interventions. These results should, however, be interpreted with caution due to the paucity of data. CONCLUSIONS: School-based psychological interventions appear to be cost-effective. However, realising efficiency gains in the population is ultimately dependent on ensuring successful system-level implementation. PMID- 27509820 TI - A study on the glycemic, lipid and blood pressure control of type 2 diabetes patients of Kerala. AB - AIM: Aim of the study was to detect the level of comprehensive diabetes control among the diabetic patients of Kerala, India. METHOD: Patients (1200) were randomly selected from a diabetes care center. Their blood sugar and other biochemical and anthropometric measurements were done and statistically analyzed. RESULT: Only 28.3% had their A1C at or below 7% and 45% above 9%. 1/3rd of the female and 1/5th of the male patients had CAD. The prevalence of hypertension was almost equal in both sexes. However, there was a statistically significant higher systolic BP (mean 162.12mm Hg vs 147.49mm Hg, p=0.01044) among females. The total Cholesterol was above 200mg/dl in 42.1% of males and 45.61% of females. The triglyceride was >150mg/dl in 38.6% males and 50.88% females. Low HDL cholesterol levels were found in 20.07% of males and 41.12% of females (p=0.0445). The mean LDL was 121.75 (+/-32.29247) DISCUSSION: The mean blood sugar values are found to be high which will lead to a predictable increase in vascular disease, which in turn will affect the quality of health and productivity of the individual and the economic growth of the society as a whole. Studies suggest that therapeutic interventions to improve glycemic control may reduce the risk of CVD and microvascular disease. CONCLUSION: This study shows that the level of diabetes control in Kerala is unsatisfactory. We need more medications, better strategies, and more emphasis on glycemic management than we are currently able to apply. PMID- 27509821 TI - Estimating the carrying capacity of green mussel cultivation by using net nutrient removal model. AB - This study aims to evaluate the nutrient removal potential and carrying capacity of green mussel cultivation by using the mass balance model. The developed model takes into consideration the green mussel growth rate, density and chlorophyll a concentration. The data employed in this study were based on culture conditions at Sriracha Fisheries Research Station, Thailand. Results show that net nutrient removal by green mussel is 3302, 380, and 124mg/year/indv for carbon, nitrogen, and phosphorus respectively. The carrying capacity of green mussel cultivation was found to be 300indv/m2 based on chlorophyll a concentration which will not release phosphorus in the water environment beyond the standard (45MUg-PO4-3 P/L). Higher chlorophyll a concentration results in lowered green mussel carrying capacity. This model can assist farm operators with possible management strategies for a sustainable mussel cultivation and protection of the marine environment. PMID- 27509822 TI - Macondo oil in deep-sea sediments: Part 2 - Distribution and distinction from background and natural oil seeps. AB - Following the Deepwater Horizon oil spill, the spilled Macondo oil was severely weathered during its transport within the deep-sea plume as discrete particles, which were subsequently deposited on the seafloor. The Macondo oil deposited in deep-sea sediments was distinguished from ambient (background) hydrocarbons and naturally-seeped and genetically-similar oils in the Mississippi Canyon region using a forensic method based upon a systematic, multi-year study of 724 deep-sea sediment cores collected in late 2010 and 2011. The method relied upon: (1) chemical fingerprinting of the distinct features of the wax-rich, severely weathered Macondo oil; (2) hydrocarbon concentrations, considering a core's proximity to the Macondo well or to known or apparent natural oil seeps, and also vertically within a core; and (3) results from proximal cores and flocculent material from core supernatants and slurp gun filters. The results presented herein establish the geographic extent of "fingerprintable" Macondo oil recognized on the seafloor in 2010/2011. PMID- 27509823 TI - Loophole-free Bell test using electron spins in diamond: second experiment and additional analysis. AB - The recently reported violation of a Bell inequality using entangled electronic spins in diamonds (Hensen et al., Nature 526, 682-686) provided the first loophole-free evidence against local-realist theories of nature. Here we report on data from a second Bell experiment using the same experimental setup with minor modifications. We find a violation of the CHSH-Bell inequality of 2.35 +/- 0.18, in agreement with the first run, yielding an overall value of S = 2.38 +/- 0.14. We calculate the resulting P-values of the second experiment and of the combined Bell tests. We provide an additional analysis of the distribution of settings choices recorded during the two tests, finding that the observed distributions are consistent with uniform settings for both tests. Finally, we analytically study the effect of particular models of random number generator (RNG) imperfection on our hypothesis test. We find that the winning probability per trial in the CHSH game can be bounded knowing only the mean of the RNG bias. This implies that our experimental result is robust for any model underlying the estimated average RNG bias, for random bits produced up to 690 ns too early by the random number generator. PMID- 27509824 TI - Multidrug-resistant surgical site infections in a humanitarian surgery project. AB - The epidemiology of surgical site infections (SSIs) in surgical programmes in sub Saharan Africa is inadequately described. We reviewed deep and organ-space SSIs occurring within a trauma project that had a high-quality microbiology partnership and active follow-up. Included patients underwent orthopaedic surgery in Teme Hospital (Port Harcourt, Nigeria) for trauma and subsequently developed a SSI requiring debridement and microbiological sampling. Data were collected from structured chart reviews and programmatic databases for 103 patients with suspected SSI [79% male, median age 30 years, interquartile range (IQR) 24-37]. SSIs were commonly detected post-discharge with 58% presenting >28 days after surgery. The most common pathogens were: Staphylococcus aureus (34%), Pseudomonas aeruginosa (16%) and Enterobacter cloacae (11%). Thirty-three (32%) of infections were caused by a multidrug-resistant (MDR) pathogen, including 15 patients with methicillin-resistant S. aureus. Antibiotics were initiated empirically for 43% of patients and after culture and sensitivity report in 32%. The median number of additional surgeries performed in patients with SSI was 5 (IQR 2-6), one patient died (1%), and amputation was performed or recommended in three patients. Our findings suggest the need for active long-term monitoring of SSIs, particularly those associated with MDR organisms, resulting in increased costs for readmission surgery and treatment with late-generation antibiotics. PMID- 27509825 TI - The matricellular ligand Cyr61 contributes to the metastatic spread of tumors by activating integrin VLA-4, independently of thiol redox modulation?. PMID- 27509827 TI - Drug utilization and blood pressure control in ambulatory hypertensive patients: focus on those with compelling indications. AB - OBJECTIVE: Compelling indications require the use of specific antihypertensive drug classes and often two or more antihypertensive medications for blood pressure (BP) control. This study assessed drug utilization patterns among hypertensive patients with compelling indications, conformity with recommended guidelines, and the effect on BP control. MATERIALS AND METHODS: A prospective, cross-sectional study of hypertensive patients attending three subspecialty hospital clinics. Data on demographics, prescriptions, and BP were collected. BP control was defined as BP less than 140/90 mmHg in nondiabetic subjects and less than 130/80 for those with diabetes. Analysis was done with SPSS version 17. RESULTS: Of the 1,926 patients with hypertension, 877 (45.5%) had compelling indications. Patients were aged 59.3 +/- 11.5 years. The most frequently encountered compelling indications were hypertensive heart disease (35.8%), diabetic mellitus (31.9%), and renal diseases (11.5%). The most prescribed drug was angiotensin-converting enzyme inhibitor (ACEIs), which was present in 22.6% of all prescriptions. Only 23.1% of patients had fully controlled BP. Poor BP control significantly correlated with the number of antihypertensive drugs r = 0.205, p < 0.001, but negatively correlated with age and duration of hypertension, r = -0.071, p = 0.038 and r = -0.448, p = 0.042, respectively. CONCLUSION: BP control was very poor in this study, and there was a high prevalence of compelling indications. Poor control was negatively correlated with increasing age and duration of hypertension. The most common compelling indications were hypertensive heart disease, diabetes mellitus, and renal disease. PMID- 27509826 TI - Staphylococcus aureus osteo-articular infection: usefulness of the determination of daptomycin serum concentration to explain a treatment failure. AB - We report two cases of treatment failure in patients with osteoarticular infection associated with Staphylococcus aureus bacteremia and receiving daptomycin. Using a published population-pharmacokinetic model and daptomycin blood level in these patients, area under the curve (AUC) was calculated and compared to the pharmacological target. For the first patient, treated with 6 mg/kg every 48 hours due to acute renal failure and then every 24 hours, the AUC was 820 mg*h*L-1, with a minimal concentration of 23.5 mg/L confirming the right dose adjustment and the absence of underdosing. The methicillin resistant Staphylococcus aureus (MRSA) strain was still susceptible to daptomycin, but it was not sufficient to observe a favorable outcome. For the second patient, treated with 10 mg/kg/d, the steady state residual concentration was 10.4 mg/L, and the calculated AUC value was 550 mg*h*L-1. AUC/MIC values evolved during treatment to be under the cut-off for bactericidal effects (> 800 hours), and the Staphylococcus aureus (SA) strain became daptomycin resistant. This study highlights the inter-individual pharmacokinetic variation leading sometimes to drug underdosing. Drug monitoring should be encouraged in order to avoid treatment failure. PMID- 27509828 TI - Meperidine-induced QTc-interval prolongation: prevalence, risk factors, and correlation to plasma drug and metabolite concentrations?. AB - : A prolongation of the QTc-interval has been described for several opioids, including pethidine (meperidine). OBJECTIVE: To evaluate in the clinical setting the frequency and risk factors associated with the QT-interval prolongation induced by meperidine. RESEARCH DESIGN AND METHODS: We recruited patients requiring meperidine administration and recorded their medical history and comorbidities predisposing to QT-interval prolongation. Ionograms and electrocardiograms (ECGs) were performed at baseline and during treatment; QT was corrected using the Bazzet, Fridericia, Framinghan, and Hogdes formulas. We measured meperidine and normeperidine by gas chromatography. Values are expressed as mean +/- SD (range). RESULTS: 58 patients were studied (43.1% males). All patients received meperidine at a dose of 304 +/- 133 (120 - 480) mg/day. Meperidine and normeperidine concentrations were 369 +/- 60 (265 - 519) and 49 +/ 17 (15 - 78) ng/mL, respectively. Intratreatment control found QTcB 370 +/- 30 (305 - 433), QTcFri 353 +/- 35 (281 - 429), QTcFra 360 +/- 30 (299 - 429), QTcH 359 +/- 27 (304 - 427), DeltaQTcB +9 +/- 42 (-90 to +136), DeltaQTcFri +4 +/- 45 (-86 to +137), DeltaQTcFra +5 +/- 40 (-77 to +129), and DeltaQTcH +7 +/- 40 (-76 to +129) ms. Meperidine concentration correlated with QTc-interval (R > 0.36) and DeltaQTc (R > 0.69) but the correlation was even better for normeperidine concentration, QTc (R > 0.52) and DeltaQTc (R > 0.81). Depending on the QTc correction formula used, 13 - 15 patients (22.41 - 25.86%) presented DeltaQTc values > 30 ms, and 7 - 8 patients (12.07- 13.79%) showed DeltaQTc values > 60 ms. Renal failure was associated with risk for DeltaQTc > 30 ms of 3.74 (IC95% 1.73 - 8.10) and for DeltaQTc > 60 ms of 4.27 (IC 95% 1.26 - 14.48). No patient developed arrhythmias during the study. CONCLUSIONS: Meperidine treatment causes ECG changes (QTc-interval prolongation) in high correlation with normeperidine plasma concentration. Renal failure increases the risk.?. PMID- 27509829 TI - Direct influence of systemic desensitization by resiniferatoxin on the activities of Adelta- and C-fibers in the rat primary bladder mechanosensitive afferent nerves. AB - OBJECTIVES: To examine whether systemic resiniferatoxin treatment can desensitize the single-unit afferent activities of Adelta- and C-fibers in rat primary bladder mechanosensitive afferent nerves. METHODS: Female Sprague-Dawley rats were divided into two groups (resiniferatoxin-treated: n = 9, vehicle-treated: n = 9). Resiniferatoxin (0.3 mg/kg) or its vehicle (10% ethanol) was injected subcutaneously after the first eye-wipe behavior test with capsaicin. The second eye-wipe behavior test was carried out 48 h after the injection under urethane (1.2 g/kg intraperitoneally) anesthesia. The bladder mechanosensitive single-unit afferent activities originating from the left L6 dorsal roots were identified by electrical stimulation of the left pelvic nerve and bladder distension, and classified by conduction velocity as either Adelta-fibers or C-fibers. The single unit afferent activity measurements were carried out with constant bladder filling with saline (0.1 mL/min, <30 cmH2 O). RESULTS: After resiniferatoxin treatment, but not vehicle treatment, eye-wipe behavior with capsaicin was completely abolished. A total of 104 single afferent fibers were isolated (Adelta fibers: n = 41, C-fibers: n = 63). Single-unit afferent activities of both Adelta fibers and C-fibers in response to bladder filling in the resiniferatoxin-treated group were significantly lower than those in the vehicle-treated group. These differences were observed throughout the filling phase in Adelta-fibers and during the initial half of the filling phase in C-fibers. CONCLUSIONS: The present results show the existence of resiniferatoxin desensitization-resistant mechanosensitive Adelta- and C-fibers in rat primary bladder afferent nerves, suggesting that systemic resiniferatoxin treatment might induce non-specific partial desensitization or denervation of mechanosensitive capsaicin-insensitive Adelta- and C-fibers of the rat bladder. PMID- 27509830 TI - Technological aids for improving longitudinal research on substance use disorders. AB - BACKGROUND: There is a broad consensus that addictive behaviors tend to be chronic and relapsing. But for field studies of substance users, successfully tracking, locating, and following up with a representative sample of subjects is a challenge. METHODS: The purpose of this paper is to provide a general overview of how current technological aids can support and improve the quality of longitudinal research on substance use disorders. The review is grouped into four domains: (1) tracking and locating, (2) prompting/engaging, (3) incentivizing, and (4) collecting data. RESULTS & CONCLUSIONS: Although the technologies described in this review will be modified or replaced over time, our findings suggest that incorporating some or all of these currently available approaches may improve research efficiency, follow-up rates, and data quality. PMID- 27509832 TI - Hydrated forms of fluoroacetic acid: a rotational study. AB - The rotational spectra of two conformers of the 1 : 1 adduct of fluoroacetic acid with water have been assigned by pulsed jet Fourier transform microwave spectroscopy. Their shapes differ according to the trans and cis forms of the fluoroacetic acid moiety. This is in contrast to the rotational spectrum of the monomer, for which the cis form has not been observed. Details of the hydrogen bond, structure, dynamics and energetic features of the two species are given. PMID- 27509831 TI - Predicting bee community responses to land-use changes: Effects of geographic and taxonomic biases. AB - Land-use change and intensification threaten bee populations worldwide, imperilling pollination services. Global models are needed to better characterise, project, and mitigate bees' responses to these human impacts. The available data are, however, geographically and taxonomically unrepresentative; most data are from North America and Western Europe, overrepresenting bumblebees and raising concerns that model results may not be generalizable to other regions and taxa. To assess whether the geographic and taxonomic biases of data could undermine effectiveness of models for conservation policy, we have collated from the published literature a global dataset of bee diversity at sites facing land use change and intensification, and assess whether bee responses to these pressures vary across 11 regions (Western, Northern, Eastern and Southern Europe; North, Central and South America; Australia and New Zealand; South East Asia; Middle and Southern Africa) and between bumblebees and other bees. Our analyses highlight strong regionally-based responses of total abundance, species richness and Simpson's diversity to land use, caused by variation in the sensitivity of species and potentially in the nature of threats. These results suggest that global extrapolation of models based on geographically and taxonomically restricted data may underestimate the true uncertainty, increasing the risk of ecological surprises. PMID- 27509833 TI - Small bowel intussusception from renal cell carcinoma metastasis: a case report and review of the literature. AB - BACKGROUND: Renal cell carcinoma is the most frequent malignant neoplasia of the kidney accounting for 90 % of all renal solid tumors. Metastases from renal cell carcinoma are rarely located in the small bowel and generally their clinical presentation includes bleeding and obstruction. Intussusception in adults is an extremely rare pathological condition and only 30 to 35 % of small bowel intussusceptions are derived from malignant lesions. CASE PRESENTATION: We report here a clinical case of a 75-year-old white man hospitalized for anemia and subocclusion. An abdominal ultrasound and computed tomography showed a small bowel intussusception. During a surgical exploration, a polypoid lesion was found to be the lead point of the intussusception. His small intestine was resected and a functional side-to-side anastomosis was performed. The histological features of the surgical specimen confirmed the diagnosis of metastatic renal cell carcinoma. CONCLUSIONS: Small bowel intussusception from renal cell carcinoma metastasis should always be considered in the setting of unexplained intestinal subocclusion in patients with a history of renal cell carcinoma. PMID- 27509834 TI - Bone-density testing interval and transition to osteoporosis in patients with rheumatoid arthritis. AB - : The study aims to evaluate the rate of transition to osteoporosis in 360 RA patients and estimate the rescreening intervals of bone mineral density (BMD) testing. Osteoporosis was newly developed in 24.8 % during mean follow-up of 7.4 years. The estimated time of a BMD testing interval was dependent on the baseline T-score in RA patients. INTRODUCTION: Although BMD testing is routinely performed in RA patients, the interval between BMD tests has not been determined. METHODS: We retrospectively recruited 360 consecutive female patients with RA, who underwent repeated BMD testing, with a mean age of 53.7 +/- 10.2 years and a mean follow-up duration of 7.4 +/- 5.0 years. We stratified the study participants into five groups based on their baseline T-score range. The testing interval was defined as the estimated time for 10 % of patients in each subgroup to transition to osteoporosis. Competing-risk analyses were performed with sensitivity analysis by menopausal status and risk factors for transition to osteoporosis. RESULTS: At baseline, 15 % of screened patients had osteoporosis, and during follow-up, that proportion increased to 24.8 %. The estimated BMD testing interval for 10 % of patients to develop osteoporosis was 9.6 years for those with normal BMD, 7.6 years for those with mild osteopenia, 4.7 years for those with moderate osteopenia, and 2.1 years for those with severe osteopenia. No significant risk factor for transition to osteoporosis was identified in this cohort. CONCLUSIONS: Our data indicate that osteoporosis will develop in less than 10 % of female RA patients during rescreening intervals of approximately 9 years for those with normal bone density at baseline, 7 years for those with mild osteopenia, 4 years for those with moderate osteopenia, and 2 years for those with severe osteopenia at baseline. BMD interval in RA patients could be adjusted according to their baseline BMD T-scores. PMID- 27509835 TI - DNA sequence analysis in 598 individuals with a clinical diagnosis of osteogenesis imperfecta: diagnostic yield and mutation spectrum. AB - : We detected disease-causing mutations in 585 of 598 individuals (98 %) with typical features of osteogenesis imperfecta (OI). In mild OI, only collagen type I encoding genes were involved. In moderate to severe OI, mutations in 12 different genes were found; 11 % of these patients had mutations in recessive genes. INTRODUCTION: OI is usually caused by mutations in COL1A1 or COL1A2, the genes encoding collagen type I alpha chains, but mutations in at least 16 other genes have also been associated with OI. It is presently unknown what proportion of individuals with clinical features of OI has a disease-causing mutation in one of these genes. METHODS: DNA sequence analysis was performed on 598 individuals from 487 families who had a typical OI phenotype. OI type I was diagnosed in 43 % of individuals, and 57 % had moderate to severe OI, defined as OI types other than type I. RESULTS: Disease-causing variants were detected in 97 % of individuals with OI type I and in 99 % of patients with moderate to severe OI. All mutations found in OI type I were dominant and exclusively affected COL1A1 or COL1A2. In moderate to severe OI, dominant mutations were found in COL1A1/COL1A2 (77 %), IFITM5 (9 %), and P4HB (0.6 %). Mutations in one of the recessive OI associated gene were observed in 12 % of individuals with moderate to severe OI. The genes most frequently involved in recessive OI were SERPINF1 (4.0 % of individuals with moderate to severe OI) and CRTAP (2.9 %). CONCLUSIONS: DNA sequence analysis of currently known OI-associated genes identifies disease causing variants in almost all individuals with a typical OI phenotype. About 20 % of individuals with moderate to severe OI had mutations in genes other than COL1A1/COL1A2. PMID- 27509836 TI - MRI-based quantitative susceptibility mapping (QSM) and R2* mapping of liver iron overload: Comparison with SQUID-based biomagnetic liver susceptometry. AB - PURPOSE: We aimed to determine the agreement between quantitative susceptibility mapping (QSM)-based biomagnetic liver susceptometry (BLS) and confounder corrected R2* mapping with superconducting quantum interference device (SQUID) based biomagnetic liver susceptometry in patients with liver iron overload. METHODS: Data were acquired from two healthy controls and 22 patients undergoing MRI and SQUID-BLS as part of routine monitoring for iron overload. Magnetic resonance imaging was performed on a 3T system using a three-dimensional multi echo gradient-echo acquisition. Both magnetic susceptibility and R2* of the liver were estimated from this acquisition. Linear regression was used to compare estimates of QSM-BLS and R2* to SQUID-BLS. RESULTS: Both QSM-BLS and confounder corrected R2* were sensitive to the presence of iron in the liver. Linear regression between QSM-BLS and SQUID-BLS demonstrated the following relationship: QSM-BLS = (-0.22 +/- 0.11) + (0.49 +/- 0.05) . SQUID-BLS with r2 = 0.88. The coefficient of determination between liver R2* and SQUID-BLS was also r2 = 0.88. CONCLUSION: We determined a strong correlation between both QSM-BLS and confounder-corrected R2* to SQUID-BLS. This study demonstrates the feasibility of QSM-BLS and confounder-corrected R2* for assessing liver iron overload, particularly when SQUID systems are not accessible. Magn Reson Med 78:264-270, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27509837 TI - Molecularly Rigid Microporous Polyamine Captures and Stabilizes Conducting Platinum Nanoparticle Networks. AB - A molecularly rigid polyamine based on a polymer of intrinsic microporosity (PIM EA-TB) is shown to capture and stabilize platinum nanoparticles during colloid synthesis in the rigid framework. Stabilization here refers to avoiding aggregation without loss of surface reactivity. In the resulting rigid framework with embedded platinum nanoparticles, the volume ratio of platinum to PIM-EA-TB in starting materials is varied systematically from approximately 1.0 to 0.1 with the resulting platinum nanoparticle diameter varying from approximately 4.2 to 3.1 nm, respectively. Elemental analysis suggests that only a fraction of the polymer is "captured" to give nanocomposites rich in platinum. A transition occurs from electrically conducting and electrochemically active (with shorter average interparticle distance) to nonconducting and only partially electrochemically active (with longer average interparticle distance) polymer platinum composites. The conducting nanoparticle network in the porous rigid macromolecular framework could be beneficial in electrocatalysis and in sensing applications. PMID- 27509838 TI - Microbial Biotechnology-2020. PMID- 27509839 TI - Attachment Dimensions and Post-traumatic Symptoms Following Interpersonal Traumas versus Impersonal Traumas in Young Adults in Taiwan. AB - Greater risk of post-traumatic stress disorder (PTSD) is seen in individuals exposed to interpersonal traumatic events. Based on an attachment perspective, interpersonal trauma exposure may activate one's attachment insecurity system and disrupt affect, behaviour and interpersonal function, which may in turn create more difficulties to cope with interpersonal traumas and exacerbate PTSD symptomatology. The present study examined whether attachment anxiety relative to attachment avoidance would be a stronger predictor of greater PTSD symptoms following interpersonal traumas versus impersonal traumas in a Taiwanese sample. One hundred and sixty-two trauma-exposed Taiwanese young adults completed the measures of symptoms of depression, anxiety and PTSD, and attachment anxiety and attachment avoidance. In this Taiwanese study, higher attachment anxiety was observed in individuals who were exposed to interpersonal traumas. The interpersonal trauma group reported greater PTSD symptoms than did the impersonal trauma group. Specifically, after controlling for age, occurrence of trauma and distress of trauma, attachment anxiety, but not attachment avoidance, predicted more PTSD total severity and avoidance symptoms in the interpersonal trauma group. The findings may be pertinent to attachment anxiety-related hyperactivating strategies, as well as specific cultural values and a forbearance strategy applied to regulate traumatic distress in a collectivist society. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27509840 TI - Effect of Regional Intravenous Limb Perfusate Volume on Synovial Fluid Concentration of Amikacin and Local Venous Blood Pressure in the Horse. AB - OBJECTIVE: To determine the effect of volume of amikacin perfusate for intravenous regional limb perfusion (IVRLP) via the cephalic vein in standing, sedated horses on (1) amikacin concentrations in the synovial fluid of the radiocarpal joint (RCJ) and distal interphalangeal joint (DIPJ) and, (2) amikacin concentration in the systemic circulation, and (3) regional intravenous pressure. STUDY DESIGN: Randomized cross-over design. ANIMALS: Six adult horses. METHODS: Each horse received IVRLP using 4 perfusate volumes (10, 30, 60 & 120 ml) in random order, after a minimum of 1 week washout. After application of a pneumatic tourniquet, IVRLP with 1 g of amikacin in 0.9% NaCl was performed. Synovial fluid from the RCJ and DIPJ, and systemic and regional venous blood were sampled, and regional blood pressure was measured, immediately before perfusion (time 0), and 15 and 30 minutes after perfusion but before tourniquet release. RESULTS: No difference was observed in the mean amikacin concentration of synovial fluid for the 4 perfusate volumes (P>.09). For all volumes, mean amikacin concentration for DIPJ synovial fluid was higher than for RCJ (P<.0001). The mean amikacin concentration in DIPJ synovial fluid was therapeutic for resistant pathogens using the 10, 60, and 120 mL volumes but the mean amikacin concentration for RCJ synovial fluid was not therapeutic for resistant pathogens with any perfusate volume. All volumes resulted in an immediate increase in mean regional intravascular pressure after perfusion (P<.0001) but was not different across the 4 perfusate volumes. CONCLUSION: Cephalic IVRLP of 1 g of amikacin diluted to a volume of 10-120 mL with 0.9% NaCl will achieve amikacin concentrations therapeutic for resistant pathogens in the synovial fluid from the DIPJ. Concentrations below therapeutic levels for resistant pathogens are reached in the synovial fluid from the RCJ. PMID- 27509842 TI - Vitamin D status in Poland. AB - INTRODUCTION Epidemiological data on vitamin D status in the Polish population are limited. OBJECTIVES The aim of the study was to evaluate the vitamin D status in a representative group of adult inhabitants of 22 Polish cities, based on the analysis of serum 25-hydroxyvitamin D [25(OH)D] levels. PATIENTS AND METHODS This cross-sectional study included a total of 5775 adult volunteers (4464 women; 1311 men; mean age, 54.0 +/-15.9 years; range, 15.6-89.8 years), who were enrolled and examined through late winter and spring 2014. Serum concentrations of 25(OH)D were determined using the Liaison XL system (DiaSorin; CLIA method). Demographic and anthropometric data were also analyzed. RESULTS The mean 25(OH)D concentration in the studied population was 18.0 +/-9.6 ng/ml; 65.8% of the patients had 25(OH)D levels of less than 20 ng/ml; 24.1% had suboptimal levels of 20 to 30 ng/ml; and only 9.1% demonstrated the optimal levels of 30 to 50 ng/ml. In 89.9% of the studied population, 25(OH)D levels of less than 30 ng/ml were found. Obesity, defined as body mass index (BMI) over 30 kg/m2, was associated with lower 25(OH)D levels compared with normal weight (15.8 +/-8.5 vs 18.5 +/-9.7 ng/ml; P <0.0001). Lower 25(OH)D levels were observed in men, younger individuals, and individuals with excess body weight and higher BMI. CONCLUSIONS The results of our study, which involved the most representative sample size of Polish adults, support the previously reported data on vitamin D status. The levels of 25(OH)D determined for adults in our study demonstrate that the majority of the Polish population is vitamin D deficient, at least during winter and spring, and that preventive or interventional strategies must be considered to improve the vitamin D status in Poland. PMID- 27509841 TI - Early activation of MyD88-mediated autophagy sustains HSV-1 replication in human monocytic THP-1 cells. AB - Autophagy is a cellular degradation pathway that exerts numerous functions in vital biological processes. Among these, it contributes to both innate and adaptive immunity. On the other hand, pathogens have evolved strategies to manipulate autophagy for their own advantage. By monitoring autophagic markers, we showed that HSV-1 transiently induced autophagosome formation during early times of the infection of monocytic THP-1 cells and human monocytes. Autophagy is induced in THP-1 cells by a mechanism independent of viral gene expression or viral DNA accumulation. We found that the MyD88 signaling pathway is required for HSV-1-mediated autophagy, and it is linked to the toll-like receptor 2 (TLR2). Interestingly, autophagy inhibition by pharmacological modulators or siRNA knockdown impaired viral replication in both THP-1 cells and human monocytes, suggest that the virus exploits the autophagic machinery to its own benefit in these cells. Taken together, these findings indicate that the early autophagic response induced by HSV-1 exerts a proviral role, improving viral production in a semi-permissive model such as THP-1 cells and human monocytes. PMID- 27509843 TI - Stratification of responders towards eculizumab using a structural epitope mapping strategy. AB - The complement component 5 (C5)-binding antibody eculizumab is used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical haemolytic uremic syndrome (aHUS). As recently reported there is a need for a precise classification of eculizumab responsive patients to allow for a safe and cost effective treatment. To allow for such stratification, knowledge of the precise binding site of the drug on its target is crucial. Using a structural epitope mapping strategy based on bacterial surface display, flow cytometric sorting and validation via haemolytic activity testing, we identified six residues essential for binding of eculizumab to C5. This epitope co-localizes with the contact area recently identified by crystallography and includes positions in C5 mutated in non-responders. The identified epitope also includes residue W917, which is unique for human C5 and explains the observed lack of cross-reactivity for eculizumab with other primates. We could demonstrate that Ornithodorus moubata complement inhibitor (OmCI), in contrast to eculizumab, maintained anti haemolytic function for mutations in any of the six epitope residues, thus representing a possible alternative treatment for patients non-responsive to eculizumab. The method for stratification of patients described here allows for precision medicine and should be applicable to several other diseases and therapeutics. PMID- 27509844 TI - A matched comparison study of hepatitis C treatment outcomes in the prison and community setting, and an analysis of the impact of prison release or transfer during therapy. AB - Prisoners are a priority group for hepatitis C (HCV) treatment. Although treatment durations will become shorter using directly acting antivirals (DAAs), nearly half of prison sentences in Scotland are too short to allow completion of DAA therapy prior to release. The purpose of this study was to compare treatment outcomes between prison- and community-based patients and to examine the impact of prison release or transfer during therapy. A national database was used to compare treatment outcomes between prison treatment initiates and a matched community sample. Additional data were collected to investigate the impact of release or transfer on treatment outcomes. Treatment-naive patients infected with genotype 1/2/3/4 and treated between 2009 and 2012 were eligible for inclusion. 291 prison initiates were matched with 1137 community initiates: SVRs were 61% (95% CI 55%-66%) and 63% (95% CI 60%-66%), respectively. Odds of achieving a SVR were not significantly associated with prisoner status (P=.33). SVRs were 74% (95% CI 65%-81%), 59% (95% CI 42%-75%) and 45% (95% CI 29%-62%) among those not released or transferred, transferred during treatment, or released during treatment, respectively. Odds of achieving a SVR were significantly associated with release (P<.01), but not transfer (P=.18). Prison-based HCV treatment achieves similar outcomes to community-based treatment, with those not released or transferred during treatment doing particularly well. Transfer or release during therapy should be avoided whenever possible, using anticipatory planning and medical holds where appropriate. PMID- 27509845 TI - A pilot study of parent education intervention improves early childhood development among toddlers with sickle cell disease. AB - BACKGROUND: Young children with sickle cell disease (SCD) are at risk for cognitive delay. In addition to biologic risk factors associated with SCD, environmental factors contribute to cognitive dysfunction within this cohort. METHODS: We completed a single-arm, prospective cohort study. Children with SCD between the ages of 3 and 36 months and their caregivers were followed between October 2010 and December 2013. The aim was to describe the role of a home visitation model, the home environment, and socioeconomic status in the development of young children with SCD. Primary outcome measures were the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) and the Home Observation for Measurement of the Environment (HOME). We hypothesized that the home visitation model, Parents as Teachers(r) (PAT), would encourage positive parent-child interactions and improve cognitive outcomes. RESULTS: Thirty-five participants had at least two PAT visits and BSID-III assessments. Mean scores within all five subtests of the BSID-III improved between enrollment and exit, with significant changes within cognitive (P = 0.016) and expressive language (EL) domains (P = 0.002). Multivariate modeling found the HOME score associated with the exit results of the cognitive domain. CONCLUSION: We report longitudinal results of the first home visitation program within the early childhood SCD population and show significant improvement in cognitive and EL development. Additionally, home environment was a significant predictor of cognitive development. Randomized controlled trials to test the impact of interventions targeting the home environment are warranted for this vulnerable population. PMID- 27509846 TI - EBP50 interacts with EGFR and regulates EGFR signaling to affect the prognosis of cervical cancer patients. AB - Ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) has a role in the occurrence and progression of multiple types of tumors. However, its role in cervical cancer (CC) remain unknown. EBP50 was reported to interact with epidermal growth factor receptor (EGFR) and regulate EGFR signaling in CC HeLa cells. In this study, the effect of EBP50 expression on CC cell proliferation and prognosis of CC patients by regulating EGFR signaling was investigated. We found that EBP50 expression level was significantly downregulated in CC tissues. EBP50 expression negatively correlated with CC cell proliferation, cell cycle and the activation of EGFR-mediated ERK signaling. EBP50 knockdown abolished its inhibition on EGF-induced ERK activation, suggesting EBP50 regulated EGFR signaling. In order to further explore EBP50 regulated EGFR signaling via interaction, we constructed EBP50_DD mutant which disrupted its interaction with EGFR. EBP50_DD overexpression attenuated the inhibition of EBP50_WT on EGFR mediated ERK signaling, further revealing EBP50 regulated EGFR signaling via its interaction with EGFR. EGFR activation was associated with poor prognosis of CC patients. EBP50 could not predict the prognosis of all CC patients. However, after ruling out patients with egfr/ErbB mutation or copy number variation (CNV) and (chemo)radiation, which caused continuous EGFR activation and affected the prognosis of patients, respectively, EBP50 expression level exhibited the prognosis prediction ability, revealing EBP50 affected prognosis of CC patients via regulating EGFR signaling. In conclusion, EBP50 played an important role in CC cell proliferation and prognosis prediction of CC patients by interacting with EGFR and regulating EGFR signaling. EBP50 might be a potential precise therapeutic target or prognostic marker for CC patients. PMID- 27509848 TI - Facial feedback and autonomic responsiveness reflect impaired emotional processing in Parkinson's Disease. AB - Emotional deficits are part of the non-motor features of Parkinson's disease but few attention has been paid to specific aspects such as subjective emotional experience and autonomic responses. This study aimed to investigate the mechanisms of emotional recognition in Parkinson's Disease (PD) using the following levels: explicit evaluation of emotions (Self-Assessment Manikin) and implicit reactivity (Skin Conductance Response; electromyographic measure of facial feedback of the zygomaticus and corrugator muscles). 20 PD Patients and 34 healthy controls were required to observe and evaluate affective pictures during physiological parameters recording. In PD, the appraisal process on both valence and arousal features of emotional cues were preserved, but we found significant impairment in autonomic responses. Specifically, in comparison to healthy controls, PD patients revealed lower Skin Conductance Response values to negative and high arousing emotional stimuli. In addition, the electromyographic measures showed defective responses exclusively limited to negative and high arousing emotional category: PD did not show increasing of corrugator activity in response to negative emotions as happened in heathy controls. PD subjects inadequately respond to the emotional categories which were considered more "salient": they had preserved appraisal process, but impaired automatic ability to distinguish between different emotional contexts. PMID- 27509849 TI - FGFR3 preferentially colocalizes with IGH in the interphase nucleus of multiple myeloma patient B-cells when FGFR3 is located outside of CT4. AB - Many B-cell malignancies are characterized by chromosomal translocations involving IGH and a proto-oncogene. For translocations to occur, spatial proximity of translocation-prone genes is necessary. Currently, it is not known how such genes are brought into proximity with one another. Although decondensed chromosomes occupy definitive, non-random spaces in the interphase nucleus known as chromosome territories (CTs), chromatin at the edges of CTs can intermingle, and specific genomic regions from some chromosomes have been shown to "loop out" of their respective CTs. This extra-territorial positioning of specific genomic regions may provide a mechanism whereby translocation-prone genes are brought together in the interphase nucleus. FGFR3 and MAF recurrently participate in translocations with IGH at different frequencies. Using 3D, 4-color FISH, and 3D analysis software, we show frequent extra-territorial positioning of FGFR3 and significantly less frequent extra-territorial positioning of MAF. Frequent extra territorial positioning may be characteristic of FGFR3 in B-cells from healthy adult donors and non-malignant B-cells from patients, but not in hematopoietic stem cells from patients with translocations. The frequency of extra-territorial positioning of FGFR3 and MAF in B-cells correlates with the frequency of translocations in the patient population. Most importantly, in patient B-cells, we demonstrate a significant proportion of extra-territorial FGFR3 participating in close loci pairs and/or colocalizing with IGH. This preliminary work suggests that in patient B-cells, extra-territorial positioning of FGFR3 may provide a mechanism for forming close loci pairs and/or colocalization with IGH; indirectly facilitating translocation events involving these two genes. (c) 2016 Wiley Periodicals, Inc. PMID- 27509850 TI - A human neurodevelopmental model for Williams syndrome. AB - Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1-5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain. PMID- 27509851 TI - A progressively wetter climate in southern East Africa over the past 1.3 million years. AB - African climate is generally considered to have evolved towards progressively drier conditions over the past few million years, with increased variability as glacial-interglacial change intensified worldwide. Palaeoclimate records derived mainly from northern Africa exhibit a 100,000-year (eccentricity) cycle overprinted on a pronounced 20,000-year (precession) beat, driven by orbital forcing of summer insolation, global ice volume and long-lived atmospheric greenhouse gases. Here we present a 1.3-million-year-long climate history from the Lake Malawi basin (10 degrees -14 degrees S in eastern Africa), which displays strong 100,000-year (eccentricity) cycles of temperature and rainfall following the Mid-Pleistocene Transition around 900,000 years ago. Interglacial periods were relatively warm and moist, while ice ages were cool and dry. The Malawi record shows limited evidence for precessional variability, which we attribute to the opposing effects of austral summer insolation and the temporal/spatial pattern of sea surface temperature in the Indian Ocean. The temperature history of the Malawi basin, at least for the past 500,000 years, strongly resembles past changes in atmospheric carbon dioxide and terrigenous dust flux in the tropical Pacific Ocean, but not in global ice volume. Climate in this sector of eastern Africa (unlike northern Africa) evolved from a predominantly arid environment with high-frequency variability to generally wetter conditions with more prolonged wet and dry intervals. PMID- 27509852 TI - Postglacial viability and colonization in North America's ice-free corridor. AB - During the Last Glacial Maximum, continental ice sheets isolated Beringia (northeast Siberia and northwest North America) from unglaciated North America. By around 15 to 14 thousand calibrated radiocarbon years before present (cal. kyr bp), glacial retreat opened an approximately 1,500-km-long corridor between the ice sheets. It remains unclear when plants and animals colonized this corridor and it became biologically viable for human migration. We obtained radiocarbon dates, pollen, macrofossils and metagenomic DNA from lake sediment cores in a bottleneck portion of the corridor. We find evidence of steppe vegetation, bison and mammoth by approximately 12.6 cal. kyr bp, followed by open forest, with evidence of moose and elk at about 11.5 cal. kyr bp, and boreal forest approximately 10 cal. kyr bp. Our findings reveal that the first Americans, whether Clovis or earlier groups in unglaciated North America before 12.6 cal. kyr bp, are unlikely to have travelled by this route into the Americas. However, later groups may have used this north-south passageway. PMID- 27509853 TI - Structural biology: Catalytic spliceosome captured. PMID- 27509854 TI - Structure of mammalian respiratory complex I. AB - Complex I (NADH:ubiquinone oxidoreductase), one of the largest membrane-bound enzymes in the cell, powers ATP synthesis in mammalian mitochondria by using the reducing potential of NADH to drive protons across the inner mitochondrial membrane. Mammalian complex I (ref. 1) contains 45 subunits, comprising 14 core subunits that house the catalytic machinery (and are conserved from bacteria to humans) and a mammalian-specific cohort of 31 supernumerary subunits. Knowledge of the structures and functions of the supernumerary subunits is fragmentary. Here we describe a 4.2-A resolution single-particle electron cryomicroscopy structure of complex I from Bos taurus. We have located and modelled all 45 subunits, including the 31 supernumerary subunits, to provide the entire structure of the mammalian complex. Computational sorting of the particles identified different structural classes, related by subtle domain movements, which reveal conformationally dynamic regions and match biochemical descriptions of the 'active-to-de-active' enzyme transition that occurs during hypoxia. Our structures therefore provide a foundation for understanding complex I assembly and the effects of mutations that cause clinically relevant complex I dysfunctions, give insights into the structural and functional roles of the supernumerary subunits and reveal new information on the mechanism and regulation of catalysis. PMID- 27509855 TI - Cell division: Mitotic regulation comes into focus. PMID- 27509856 TI - Natural courtship song variation caused by an intronic retroelement in an ion channel gene. AB - Animal species display enormous variation for innate behaviours, but little is known about how this diversity arose. Here, using an unbiased genetic approach, we map a courtship song difference between wild isolates of Drosophila simulans and Drosophila mauritiana to a 966 base pair region within the slowpoke (slo) locus, which encodes a calcium-activated potassium channel. Using the reciprocal hemizygosity test, we confirm that slo is the causal locus and resolve the causal mutation to the evolutionarily recent insertion of a retroelement in a slo intron within D. simulans. Targeted deletion of this retroelement reverts the song phenotype and alters slo splicing. Like many ion channel genes, slo is expressed widely in the nervous system and influences a variety of behaviours; slo-null males sing little song with severely disrupted features. By contrast, the natural variant of slo alters a specific component of courtship song, illustrating that regulatory evolution of a highly pleiotropic ion channel gene can cause modular changes in behaviour. PMID- 27509857 TI - HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis. AB - During the early stages of infection, the HIV-1 capsid protects viral components from cytosolic sensors and nucleases such as cGAS and TREX, respectively, while allowing access to nucleotides for efficient reverse transcription. Here we show that each capsid hexamer has a size-selective pore bound by a ring of six arginine residues and a 'molecular iris' formed by the amino-terminal beta hairpin. The arginine ring creates a strongly positively charged channel that recruits the four nucleotides with on-rates that approach diffusion limits. Progressive removal of pore arginines results in a dose-dependent and concomitant decrease in nucleotide affinity, reverse transcription and infectivity. This positively charged channel is universally conserved in lentiviral capsids despite the fact that it is strongly destabilizing without nucleotides to counteract charge repulsion. We also describe a channel inhibitor, hexacarboxybenzene, which competes for nucleotide binding and efficiently blocks encapsidated reverse transcription, demonstrating the tractability of the pore as a novel drug target. PMID- 27509858 TI - Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism. The role of the stroma in PDAC biology is complex and it has been shown to play critical roles that differ depending on the biological context. The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment. As such, these tumours must alter how they capture and use nutrients to support their metabolic needs. Here we show that stroma-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non essential amino acids (NEAA). Specifically, we uncover a previously undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel source decreases the tumour's dependence on glucose and serum derived nutrients, which are limited in the pancreatic tumour microenvironment. Moreover, we demonstrate that alanine secretion by PSCs is dependent on PSC autophagy, a process that is stimulated by cancer cells. Thus, our results demonstrate a novel metabolic interaction between PSCs and cancer cells, in which PSC-derived alanine acts as an alternative carbon source. This finding highlights a previously unappreciated metabolic network within pancreatic tumours in which diverse fuel sources are used to promote growth in an austere tumour microenvironment. PMID- 27509859 TI - Compression and ablation of the photo-irradiated molecular cloud the Orion Bar. AB - The Orion Bar is the archetypal edge-on molecular cloud surface illuminated by strong ultraviolet radiation from nearby massive stars. Our relative closeness to the Orion nebula (about 1,350 light years away from Earth) means that we can study the effects of stellar feedback on the parental cloud in detail. Visible light observations of the Orion Bar show that the transition between the hot ionized gas and the warm neutral atomic gas (the ionization front) is spatially well separated from the transition between atomic and molecular gas (the dissociation front), by about 15 arcseconds or 6,200 astronomical units (one astronomical unit is the Earth-Sun distance). Static equilibrium models used to interpret previous far-infrared and radio observations of the neutral gas in the Orion Bar (typically at 10-20 arcsecond resolution) predict an inhomogeneous cloud structure comprised of dense clumps embedded in a lower-density extended gas component. Here we report one-arcsecond-resolution millimetre-wave images that allow us to resolve the molecular cloud surface. In contrast to stationary model predictions, there is no appreciable offset between the peak of the H2 vibrational emission (delineating the H/H2 transition) and the edge of the observed CO and HCO+ emission. This implies that the H/H2 and C+/C/CO transition zones are very close. We find a fragmented ridge of high-density substructures, photoablative gas flows and instabilities at the molecular cloud surface. The results suggest that the cloud edge has been compressed by a high-pressure wave that is moving into the molecular cloud, demonstrating that dynamical and non equilibrium effects are important for the cloud evolution. PMID- 27509860 TI - Ancient DNA: Muddy messages about American migration. PMID- 27509862 TI - Cancer metabolism: Friendly neighbours feed tumour cells. PMID- 27509861 TI - Molecular basis of APC/C regulation by the spindle assembly checkpoint. AB - In the dividing eukaryotic cell, the spindle assembly checkpoint (SAC) ensures that each daughter cell inherits an identical set of chromosomes. The SAC coordinates the correct attachment of sister chromatid kinetochores to the mitotic spindle with activation of the anaphase-promoting complex (APC/C), the E3 ubiquitin ligase responsible for initiating chromosome separation. In response to unattached kinetochores, the SAC generates the mitotic checkpoint complex (MCC), which inhibits the APC/C and delays chromosome segregation. By cryo-electron microscopy, here we determine the near-atomic resolution structure of a human APC/C-MCC complex (APC/C(MCC)). Degron-like sequences of the MCC subunit BubR1 block degron recognition sites on Cdc20, the APC/C coactivator subunit responsible for substrate interactions. BubR1 also obstructs binding of the initiating E2 enzyme UbcH10 to repress APC/C ubiquitination activity. Conformational variability of the complex enables UbcH10 association, and structural analysis shows how the Cdc20 subunit intrinsic to the MCC (Cdc20(MCC)) is ubiquitinated, a process that results in APC/C reactivation when the SAC is silenced. PMID- 27509864 TI - Comprehensive two-dimensional liquid chromatography for polyphenol analysis in foodstuffs. AB - Polyphenols are a class of plant secondary metabolites that are recently drawing a special interest because of their broad spectrum of pharmacological effects. As they are characterized by an enormous structural variability, the identification of these molecules in food samples is a difficult task, and sometimes having only a limited number of commercially available reference materials is not of great help. One-dimensional liquid chromatography is the most widely applied analytical approach for their analysis. In particular, the hyphenation of liquid chromatography to mass spectrometry has come to play an influential role by allowing relatively fast tentative identification and accurate quantification of polyphenolic compounds at trace levels in vegetable media. However, when dealing with very complex real-world food samples, a single separation system often does not provide sufficient resolving power for attaining rewarding results. Comprehensive two-dimensional liquid chromatography is a technique of great analytical impact, since it offers much higher peak capacities than separations in a single dimension. In the present review, we describe applications in the field of comprehensive two-dimensional liquid chromatography for polyphenol analysis in real-world food samples. Comprehensive two-dimensional liquid chromatography applications to nonfood matrices fall outside the scope of the current report and will not be discussed. PMID- 27509863 TI - Capturing a substrate in an activated RING E3/E2-SUMO complex. AB - Post-translational protein modification by ubiquitin (Ub) and ubiquitin-like (Ubl) proteins such as small ubiquitin-like modifier (SUMO) regulates processes including protein homeostasis, the DNA damage response, and the cell cycle. Proliferating cell nuclear antigen (PCNA) is modified by Ub or poly-Ub at lysine (Lys)164 after DNA damage to recruit repair factors. Yeast PCNA is modified by SUMO on Lys164 and Lys127 during S-phase to recruit the anti-recombinogenic helicase Srs2. Lys164 modification requires specialized E2/E3 enzyme pairs for SUMO or Ub conjugation. For SUMO, Lys164 modification is strictly dependent on the E3 ligase Siz1, suggesting the E3 alters E2 specificity to promote Lys164 modification. The structural basis for substrate interactions in activated E3/E2 Ub/Ubl complexes remains unclear. Here we report an engineered E2 protein and cross-linking strategies that trap an E3/E2-Ubl/substrate complex for structure determination, illustrating how an E3 can bypass E2 specificity to force-feed a substrate lysine into the E2 active site. PMID- 27509865 TI - HER2-targeted antibody drug conjugates for ovarian cancer therapy. AB - HER2 targeted delivery of ovarian cancer therapy has been beneficial for some patients, although, its efficacy is yet to be confirmed in large populations. We generated a novel anti-HER2 humanized antibody (Hertuzumab) and conjugated it to a microtubule-disrupting drug monomethyl auristatin E conjugate (MMAE) with a lysosomal protease-cleavable valine-citrulline linker. The average drug to antibody ratio (DAR) of Hertuzumab-vc-MMAE was varied by conjugating Hertuzumab antibodies with increasing linker-drugs (LDs) from D0-D8. The resulting conjugates were tested for kinetic affinity for soluble HER2-ECD, cytotoxicity, and in vivo pharmacokinetics. The kinetic binding constant values (KD) were obtained by the bio-layer interference (BLI) method. The half time (t1/2) and clearance (Cl) results of the pharmacokinetic profile in rats were DAR-dependent. Hertuzumab-vc-MMAE with DAR4 was selected for further evaluation. Both Hertuzumab and Hertuzumab conjugates could bind to HER2 antigen, and exhibited significant cytotoxicity on HER2 positive tumor cells after internalization by receptor mediated endocytosis. Hence, Hertuzumab-vc-MMAE conjugates were significantly selective both in vitro and in vivo as compared to other ovarian cancer clinical therapies that are currently used. Cell signal transduction and cell cycle were also affected, as shown by down regulation of PI3K/AKT pathway and arrested mitosis in the G2/M phase. The pharmacokinetics and pharmacodynamics (PK-PD) of the conjugates in nude mouse xenograft model demonstrated a correlation between efficacy and drug concentration. These results show that Hertuzumab-vc-MMAE is a potential therapeutic agent for HER2 positive ovarian cancer. PMID- 27509866 TI - Neurotensin-based hybrid peptide's anti-inflammatory activity in murine model of a contact sensitivity response. AB - The objective of the study was to investigate the possibility of modulation of skin inflammation by topical treatment with a novel compound: an opioid neurotensin hybrid peptide PK20 encompassing endomorphin-2 analog and modified fragment of neurotensin (8-13). Contact sensitivity response was induced in mice by skin sensitization with dinitrofluorobenzene (DNFB) followed by topical hapten application on ears. Mice were treated locally with PK20 or pure cream 2h after the challenge with DNFB. 2 and 24h after hapten exposure, ear thickness was determined. Ears were collected for histology and homogenization. Supernatants were used for measurement of contents of cytokines and lipid peroxidation products. Treatment with PK20 reduced significantly the late phase of contact sensitivity response, which was revealed by ear thickness diminution and reduction of inflammatory cell infiltration. The average concentrations of IL 1alpha, MCP-1, TNF-alpha and thiobarbituric acid-reactive substances were significantly decreased in the ears treated with the chimera in comparison to the control cream treated ears in DNFB sensitized/DNFB challenged group. We found that PK20 topical treatment alleviates hypersensitivity responses triggered by DNFB challenge and usage of the hybrid peptide may be a novel therapeutic strategy in the treatment of chronic inflammatory diseases. However, the mechanism remains unclear and needs further investigation. PMID- 27509868 TI - Nanoparticles assembled via pH-responsive reversible segregation of cyclodextrins in polyrotaxanes. AB - Supramolecular polymers with monomers bound together by secondary interactions, such as polyrotaxanes (PRXs), consisting of alpha cyclodextrin (alphaCD) threaded onto poly(ethylene glycol) (PEG), have attracted interest as a result of their ability to overcome physical limitations present in conventional, covalently structured polymers. Herein, we describe the formation of pH-responsive supramolecular assemblies from carboxyethylester bearing alphaCD and PEG PRXs. These PRXs were formed using PEG of Mw 20 kDa and a threading degree of 28%. Upon charge neutralisation the threaded alphaCDs co-localise, resulting in aggregation of the PRXs and the formation of a suspension by self-assembly. This process is shown to be reversible and possible via the mobility of CDs along the PEG guest chain. As a result of the inherent properties of PRXs, such as enhanced multivalent interactions and degradation, these responsive supramolecular polymers are expected to be of interest in fields where PRX-based materials have already found application, including paints, self-healing materials, surface coatings, and polymer therapeutics. PMID- 27509867 TI - Impact of statin therapy on plasma leptin concentrations: a systematic review and meta-analysis of randomized placebo-controlled trials. AB - OBJECTIVES: The effects of statins on insulin sensitivity, metabolic homeostasis and adipokines in humans are controversial. Several studies have investigated the impact of statin therapy on plasma leptin concentrations but the results have been inconsistent. The aim of the present study was to conduct a systematic review and meta-analysis of available evidence to calculate the effect size of statin therapy in changing serum leptin concentrations. METHODS: A systematic search in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases was performed to identify randomized placebo-controlled trials investigating the effect of statins on plasma leptin concentrations. A random-effects model and generic inverse variance method were used for meta-analysis. Sensitivity analysis, risk-of-bias evaluation and publication bias assessment were carried out using standard methods. Random-effects meta-regression was used to evaluate the impact of treatment duration on the estimated effect size. RESULTS: Six trials, with a total of 425 subjects, met the eligibility criteria. Overall, statin therapy had no significant effect on leptin levels (weighted mean difference -0.32 ng ml-1 , 95% confidence nterval: -2.94, 2.30, P = 0.813). This effect was robust in the sensitivity analysis and in subgroup analyses of trials with <12 or >=12 weeks' duration. There was no association between the duration of statin therapy and changes in plasma leptin levels. Furthermore, there was no differential effect of hydrophilic and lipophilic statins on plasma leptin concentrations. CONCLUSION: Unless more consistent evidence becomes available in the future, the hypothesis of a relationship between statin use and serum leptin concentrations seem to be unfounded. PMID- 27509869 TI - Measuring policy and related effects of a health impact assessment related to connectivity. AB - Health Impact Assessments are an important tool to help policymakers perceive the potential positive and negative contributions of decisions to public health. While they have been increasingly used in the United States, studies have not examined intermediate effects. Using key stakeholder interviews, this manuscript examines policy outcomes and other related effects of the HIA 21months after completing a Health Impact Assessment Report around connectivity policy. Further, it reflects on the measurement of these effects as part of the monitoring and evaluation stage of the Health Impact Assessment process. PMID- 27509870 TI - The neurobiological and behavioral overlaps of nicotine and food addiction. AB - Both cigarette smoking and obesity are significant public health concerns and are associated with increased risk of early mortality. It is well established that the mesolimbic dopamine pathway is an important component of the reward system within the brain and is implicated in the development of addiction. Indeed, nicotine and highly palatable foods are capable of altering dopamine release within this system, engendering addictive like responses in susceptible individuals. Although additional research is warranted, findings from animal and human literature have elucidated many of neuroadaptions that occur from exposure to nicotine and highly palatable foods, leading to a greater understanding of the underlying mechanisms contributing to these aberrant behaviors. In this review we present the findings taken from preclinical and clinical literature of the known effects of exposure to nicotine and highly palatable foods on the reward related circuitry within the brain. Further, we compare the neurobiological and behavioral overlaps between nicotine, highly palatable foods and obesity. Lastly, we examine the stigma associated with smoking, obesity and food addiction, and the consequences stigma has on the overall health and wellbeing of an individual. PMID- 27509871 TI - Reality-check in physical activity promotion: Self-report-based guidelines vs. measurement-based estimates. PMID- 27509872 TI - Can maternal-fetal hemodynamics influence prenatal development in dogs? AB - The goals of this study were to report embryonic and fetal ultrasound changes and compare blood flow of uteroplacental and umbilical arteries of normal and abnormal conceptus. Accordingly, from the day of mating or artificial insemination, all fetuses in 60 pregnancies were evaluated weekly. According to the ultrasound findings, the gestational age was determined and the conceptuses were divided into normal or abnormal (embryonic and fetal abnormalities). The two dimensional ultrasound assessment consists of measuring and evaluating the echogenicity of conceptus and extra-fetal structures. Doppler velocimetry measured the resistivity index (RI) and pulsatility index (PI) of uteroplacental and umbilical arteries. Two-dimensional and Doppler measurements were expressed as mean and standard deviation. Differences between normal and abnormal groups were subject to Mann-Whitney test (P<0.05). Of 264 fetuses, 15.90% showed embryonic abnormalities (resorption) and 5.68% presented fetal abnormalities (congenital abnormalities, fetal underdevelopment and fetal death). We observed a reduced diameter and abnormalities in the contour of gestational vesicle, lack of viability, increased placental thickness, increased fluid echogenicity and increases in RI and PI of uteroplacental arteries of conceptuses with embryonic resorption between the 2nd and 4th weeks. Fetuses with abnormalities showed changes in the flow of uteroplacental and umbilical arteries prior to visualization of two-dimensional alterations and different vascular behavior according to the classification of the change. Results show that ultrasound is efficient for the detection of embryonic and fetal abnormalities. When combined with Doppler ultrasound, it allows early detection of gestational changes, as well as hemodynamic changes, in conceptuses with abnormalities, which may influence their development. PMID- 27509873 TI - Cryopreservation of bull semen: Evolution from egg yolk based to soybean based extenders. AB - Since the inception of bovine semen cryopreservation, egg yolk and milk based extenders have been used to protect sperm from the detrimental effects of cooling and freezing. In recent years, demand for alternatives to conventional commercial extenders has arisen as the risk of introducing exotic diseases through transporting egg yolk based products has been recognized. Egg yolk can also interfere with sperm evaluation and the presence of particulate material in the extender may reduce fertility. Soybeans contain lecithin, a phospholipid fraction that can substitute for high molecular weight lipoprotein and phospholipids from egg yolk and prevent or ameliorate damage to the sperm plasma membrane that occurs during extension, cooling, and cryopreservation. Soy lecithin based extenders have been evaluated for processing and freezing bovine semen, although extender from soybean milk has not been studied as extensively. Commercially available soy lecithin based extenders are used increasingly but remain under scrutiny and are not universally accepted. With these observations in mind, this review is intended to examine effects of conventional cryopreservation procedures, methods of assessment, and potential for developing soybean extract as an acceptable alternative to traditional egg yolk and milk based extenders for bull sperm cryopreservation. PMID- 27509874 TI - Effect of dietary supplementation with amino acids on boar sperm quality and fertility. AB - The aim of this study was to evaluate the effects of dietary supplementation with amino acids on sperm quality and fertility rates after insemination with boar semen. Twelve Yorkshire boars were paired by age and allocated to one of two dietary treatments composed of total lysine levels of 0.64% (T1) and 0.96% (T2), with the lysine: methionine: threonine: tryptophan: valine ratio in the diets set to 100:27:73:19:69 through the addition of synthetic amino acids. Semen was collected twice weekly (phase 1, 1-12 wk); every other day (phase 2, 13-16 wk); twice weekly (phase 3, 17-26 wk); and daily (phase 4, 27-28 wk). Semen was collected from boars during phase 3 and used to inseminate 64 multiparous sows. Our results showed that sperm concentration and total sperm cells were greater in boars in T2 than in boars in T1 in phases 2 and 4 (P<0.05). Sperm motility parameters, morphologically normal sperm, and acrosome integrity in T2 boars were greater than those in T1 boars (P<0.05) during the experiment. Free amino acid concentrations in seminal plasma increased in T2 boars (P<0.05). Furthermore, sows inseminated with semen collected from T2 boars gave birth to more live piglets than those inseminated with semen collected from T1 boars (P=0.04). In conclusion, supplementation of boar diet with amino acids improves sperm quality, and subsequently increases fertilization capacity and the number of live piglets. PMID- 27509876 TI - Influence of sustained deworming pressure on the anthelmintic resistance status in strongyles of sheep under field conditions. AB - Anthelmintic resistance (AR) status in Madras Red sheep from selected field flocks of a government funded scheme, covered by regular, sustained anthelmintic treatment for more than 10 years was determined. Parameters such as fecal egg count reduction test (FECRT), larval paralysis assay (LPA), and allele-specific PCR (AS-PCR) were used to test the efficacy of fenbendazole, tetramisole, and ivermectin at recommended doses, in two seasons. Sheep belonging to non beneficiary farmers were used as controls. Mean FECRT values of beneficiary group during winter and summer seasons were 77.77 and 76.04, 93.65 and 92.12, and 95.37 and 98.06 %, respectively, for fenbendazole, tetramisole, and ivermectin. In the non-beneficiary groups, the corresponding values were 74.82 and 81.09 %, 96.05 and 97.40 %, and 97.26 and 98.23 %, respectively. The results revealed resistance to fenbendazole, suspect resistance to tetramisole and susceptibility to ivermectin in beneficiary flock. In non-beneficiary flock, while resistance was noticed against fenbendazole, both tetramisole and ivermectin were effective. FECR values were found to be significantly different between beneficiary and non beneficiary groups against tetramisole. The results of LPA confirmed this finding, as 50 % of the Haemonchus contortus larvae were paralyzed at the concentration of 0.0156 MUg/ml in the beneficiary group, while those of non beneficiary groups required lower concentrations of 0.0078 MUg/ml. AS-PCR revealed the predominance of heterozygous susceptible population of H. contortus in the beneficiary group. In this study, resistance to fenbendazole was confirmed in both the beneficiary and non-beneficiary groups and this could be attributed to frequent use of benzimidazoles as seen from the deworming records. Emergence of tetramisole resistance was detected in the beneficiary group, where the drug was used continuously for 4 years. Ivermectin was found to be effective in all the flocks. It is recommended that the practice of routine deworming of three to four times a year should be avoided, as it can lead to emergence of anthelmintic resistance. PMID- 27509875 TI - Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1beta and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer's disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer's disease therapeutics. PMID- 27509877 TI - Seroprevalence and risk factors of bovine viral diarrhoea virus (BVDV) infection in yaks (Bos grunniens) in northwest China. AB - Bovine viral diarrhoea virus (BVDV), a member of the Pestivirus genus, is an important pathogen of cattle worldwide, causing reproductive disorders in adult cattle and mucosal disease in calves. However, limited information about BVDV infection in yaks (Bos grunniens) in China is available, especially in white yaks which is a unique yak breed that only lives in Tianzhu Tibetan Autonomous County (TTAC), Gansu Province, northwest China. Therefore, we conducted a cross sectional study to estimate the seroprevalence and risk factors associated with BVDV infection in 1584 yaks in Gansu province, northwest China, between April 2013 and March 2014 using an indirect ELISA test. The overall seroprevalence of BVDV in yaks was 37.56 % (595/1584), with 45.08 % (275/610) in black yaks and 32.85 % (320/974) in white yaks. Moreover, positive yaks were found in all four regions, varied from 33.22 to 40.31 %. Male yaks had a similar seroprevalence (37.84 %) with that of the female yaks (37.11 %). Season, species and geographical origins of yaks were considered as risk factors analyzed by logistic regression model. To our knowledge, this is the first report of seroprevalence and risk factors associated with BVDV infection in white yaks in China. PMID- 27509878 TI - Urothelium muscarinic activation phosphorylates CBS(Ser227) via cGMP/PKG pathway causing human bladder relaxation through H2S production. AB - The urothelium modulates detrusor activity through releasing factors whose nature has not been clearly defined. Here we have investigated the involvement of H2S as possible mediator released downstream following muscarinic (M) activation, by using human bladder and urothelial T24 cell line. Carbachol stimulation enhances H2S production and in turn cGMP in human urothelium or in T24 cells. This effect is reversed by cysthationine-beta-synthase (CBS) inhibition. The blockade of M1 and M3 receptors reverses the increase in H2S production in human urothelium. In T24 cells, the blockade of M1 receptor significantly reduces carbachol-induced H2S production. In the functional studies, the urothelium removal from human bladder strips leads to an increase in carbachol-induced contraction that is mimicked by CBS inhibition. Instead, the CSE blockade does not significantly affect carbachol-induced contraction. The increase in H2S production and in turn of cGMP is driven by CBS-cGMP/PKG-dependent phosphorylation at Ser(227) following carbachol stimulation. The finding of the presence of this crosstalk between the cGMP/PKG and H2S pathway downstream to the M1/M3 receptor in the human urothelium further implies a key role for H2S in bladder physiopathology. Thus, the modulation of the H2S pathway can represent a feasible therapeutic target to develop drugs for bladder disorders. PMID- 27509879 TI - Isaacs' syndrome and Hodgkin lymphoma: a rare association. PMID- 27509880 TI - Combination of the histone deacetylase inhibitor depsipeptide and 5-fluorouracil upregulates major histocompatibility complex class II and p21 genes and activates caspase-3/7 in human colon cancer HCT-116 cells. AB - Epigenetic anticancer drugs such as histone deacetylase (HDAC) inhibitors have been combined with existing anticancer drugs for synergistic or additive effects. In the present study, we found that a very low concentration of depsipeptide, an HDAC inhibitor, potentiated the antitumor activity of 5-fluorouracil (5-FU) in a human colon cancer cell model using HCT-116, HT29, and SW48 cells via the inhibition of colony formation ability or cellular viability. Exposure to a combination of 5-FU (1.75 uM) and 1 nM depsipeptide for 24 and 48 h resulted in a 3- to 4-fold increase in activated caspase-3/7, while 5-FU alone failed to activate caspase-3/7. Microarray and subsequent gene ontology analyses revealed that compared to 5-FU or depsipeptide alone, the combination treatment of 5-FU and depsipeptide upregulated genes related to cell death and the apoptotic process consistent with the inhibition of colony formation and caspase-3/7 activation. These analyses indicated marked upregulation of antigen processing and presentation of peptide or polysaccharide antigen via major histocompatibility complex (MHC) class (GO:0002504) and MHC protein complex (GO:0042611). Compared with vehicle controls, the cells treated with the combination of 5-FU and depsipeptide showed marked induction (3- to 8.5-fold) of expression of MHC class II genes, but not of MHC class I genes. Furthermore, our global analysis of gene expression, which was focused on genes involved in the molecular regulation of MHC class II genes, showed enhancement of pro-apoptotic PCAF and CIITA after the combination of 5-FU and depsipeptide. These results may indicate a closer relationship between elevation of MHC class II expression and cellular apoptosis induced by the combination of depsipeptide and 5-FU. To the best of our knowledge, this is the first study to report that the combination of 5-FU and depsipeptide induces human colon cancer cell apoptosis in a concerted manner with the induction of MHC class II gene expression. PMID- 27509881 TI - Long-term Outcome of an Organ Preservation Program After Neoadjuvant Treatment for Rectal Cancer. AB - BACKGROUND: The aim of this study was to establish the oncological and functional results of organ preservation with a watch-and-wait approach (W&W) and selective transanal endoscopic microsurgery (TEM) in patients with a clinical complete or near-complete response (cCR) after neoadjuvant chemoradiation for rectal cancer. METHODS: Between 2004 and 2014, organ preservation was offered if response assessment with digital rectal examination, endoscopy, and MRI showed (near) cCR. Watch-and-wait was offered for cCR, and two options were offered for near cCR: TEM or reassessment after three months. Follow-up included endoscopy and MRIs every three months during the first year, and every six months thereafter. Long term outcome was assessed with Kaplan-Meier curves. Functional outcome was assessed with colostomy-free survival and Vaizey incontinence score (0 = perfect continence, 24 = totally incontinent). RESULTS: One hundred patients were included, with median follow-up of 41.1 months. Sixty-one had cCR at initial response assessment. Thirty-nine had near cCR, of whom 24 developed cCR at the second assessment and 15 patients underwent TEM (9 ypT0, 1 ypT1, 5 ypT2). Fifteen patients developed a local regrowth (12 luminal, 3 nodal), all salvageable and within 25 months. Five patients developed metastases, and five patients died. Three-year overall survival was 96.6% (95% confidence interval [CI] = 89.9% to 98.9%), distant metastasis-free survival was 96.8% (95% CI = 90.4% to 99.0%), local regrowth-free survival was 84.6% (95% CI = 75.8% to 90.5%), and disease free survival was 80.6% (95% CI = 70.9% to 87.4%). Colostomy-free survival was 94.8% (95% CI = 88.0% to 97.8%), with a good continence after watch-and-wait (Vaizey = 3.4, SD = 3.9) and moderate after TEM (Vaizey = 9.7, SD = 5.1). CONCLUSIONS: Organ preservation appears oncologically safe for selected rectal cancer patients with a cCR or near cCR after neoadjuvant chemoradiation when applying strict selection criteria and frequent follow-up, including endoscopy and MRI. The low colostomy rate and the good long-term functional outcome warrant discussing this option with the patient as an alternative to major surgery. PMID- 27509882 TI - Contrary microRNA Expression Pattern Between Fetal and Adult Cardiac Remodeling: Therapeutic Value for Heart Failure. AB - microRNAs (miRNAs) belong to a class of non-coding RNAs that regulate post transcriptional gene expression during development and disease. Growing evidence indicates abundant miRNA expression changes and their important role in cardiac hypertrophy and failure. However, the role of miRNAs in fetal cardiac remodeling is little known. Here, we investigated the altered expression of fifteen miRNAs in rat fetal cardiac remodeling compared with adult cardiac remodeling. Among fifteen tested miRNAs, eleven and five miRNAs (miR-199a-5p, miR-214-3p, miR-155 3p, miR-155-5p and miR-499-5p) are significantly differentially expressed in fetal and adult cardiac remodeling, respectively. After comparison of miRNA expression in fetal and adult cardiac remodeling, we find that miRNA expression returns to the fetal level in adult cardiac failure and is activated in advance of the adult level in fetal failure. The current study highlights the contrary expression pattern between fetal and adult cardiac remodeling and that supports a novel potential therapeutic approach to treating heart failure. PMID- 27509883 TI - Simultaneous application of two independent EIT devices for real-time multi-plane imaging. AB - Diagnosis and treatment of many lung diseases like cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD) could benefit from 3D ventilation information. Applying two EIT systems concurrently is a simple approach without specialized hardware that allows monitoring of regional changes of ventilation distribution inside the thorax at different planes with the high temporal resolution much valued in common single plane EIT. Effects of two simultaneously operated EIT devices on one subject were investigated to monitor rapid processes inside the thorax with a multi-plane approach. Results obtained by simulations with a virtual phantom and measurements with a phantom tank reveal that the distance of electrode planes has an important influence on the signal quality. Band-pass filters adapted according to the distance of the planes, can be used to reduce the crosstalk of the concurrent EIT systems. Besides simulations and phantom tank experiments measurements were also taken from a lung healthy volunteer to demonstrate the operation under realistic conditions. Reconstructed images indicate that it is possible to simultaneously visualize regional ventilation at different planes if settings of the EIT devices are chosen appropriately. PMID- 27509884 TI - Identification of distinct genes associated with seawater aspiration-induced acute lung injury by gene expression profile analysis. AB - Seawater aspiration-induced acute lung injury (ALI) is a syndrome associated with a high mortality rate, which is characterized by severe hypoxemia, pulmonary edema and inflammation. The present study is the first, to the best of our knowledge, to analyze gene expression profiles from a rat model of seawater aspiration-induced ALI. Adult male Sprague-Dawley rats were instilled with seawater (4 ml/kg) in the seawater aspiration-induced ALI group (S group) or with distilled water (4 ml/kg) in the distilled water negative control group (D group). In the blank control group (C group) the rats' tracheae were exposed without instillation. Subsequently, lung samples were examined by histopathology; total protein concentration was detected in bronchoalveolar lavage fluid (BALF); lung wet/dry weight ratios were determined; and transcript expression was detected by gene sequencing analysis. The results demonstrated that histopathological alterations, pulmonary edema and total protein concentrations in BALF were increased in the S group compared with in the D group. Analysis of differential gene expression identified up and downregulated genes in the S group compared with in the D and C groups. A gene ontology analysis of the differential gene expression revealed enrichment of genes in the functional pathways associated with neutrophil chemotaxis, immune and defense responses, and cytokine activity. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the cytokine-cytokine receptor interaction pathway was one of the most important pathways involved in seawater aspiration-induced ALI. In conclusion, activation of the cytokine-cytokine receptor interaction pathway may have an essential role in the progression of seawater aspiration-induced ALI, and the downregulation of tumor necrosis factor superfamily member 10 may enhance inflammation. Furthermore, IL-6 may be considered a biomarker in seawater aspiration-induced ALI. PMID- 27509885 TI - Magnetic force-assisted self-locking metallic bead array for fabrication of diverse concave microwell geometries. AB - Spheroid cell culture is very useful for further understanding cellular behavior including motility and biochemical reaction since it mimics three-dimensional (3D) in vivo organ tissue. Among previously proposed various methods for spheroid production, such as hanging drop and spinner flask, microwell is a recently developed method harnessing microtechnology to produce uniform-sized spheroids. Although soft-lithography has been popular for creating microwell arrays, a 3D spherical geometry has been regarded as difficult to fabricate using conventional methods, or often requires complex fabrication processes and expensive equipment. Here, we propose a new method for fabricating concave microwells for cell spheroid production and culture. To demonstrate this method, we fabricated a 30 * 30 microwell array in 3 * 3 cm plates, utilizing metal beads, a through-hole array, and an assembly of small magnets. The spherical metal beads were used as a mold for the microwell, naturally creating the desired 3D concave microwell geometry. One of the key ideas was to place and hold each metal bead in the designated through-hole using the small magnet array. We also performed computational simulation of the magnetostatic force to design and observe the magnetic force field in detail. In addition, to provide a practical demonstration of the proposed system in cell biology, we created and cultured adipose-derived stem cell spheroids for 14 days for chondrogenic differentiation. This method allows further variations in microwell geometry that will enhance the method's applicability as a helpful tool for various studies in cell biology, cancer research, and tissue engineering. PMID- 27509886 TI - Photolabile acetals as profragrances: the effect of structural modifications on the light-induced release of volatile aldehydes on cotton. AB - Because volatile compounds evaporate from surfaces that are usually exposed to daylight, photoresponsive delivery systems are particularly suitable to control their release. In the present study, we investigated 4,4-diphenyl-4H benzo[d][1,3]dioxins as profragrances for the light-induced delivery of aldehydes in functional perfumery. The efficiency of fragrance release was investigated on cotton after direct and indirect surface deposition from a fabric softening formulation as a function of the substitution pattern of the profragrance structure. Dynamic headspace analysis above the cotton surface demonstrated that the structure of the profragrance had a much larger effect on the fragrance release than did the amount of deposition on the target surface. Although some trends observed for the photolysis in solution also applied to the reaction on cotton, it is not generally possible to predict the photochemical behaviour of structurally different precursors on surfaces from their solution properties. The fact that the present system performed on a dry surface makes it an interesting light-triggered delivery vehicle for other classes of bioactive volatile compounds, such as pheromones or agrochemicals. PMID- 27509888 TI - Effective Atom-Molecule Conversions Using Radio Frequency Fields. AB - The present study is inspired by the Wieman group experiment [Phys. Rev. Lett. 2005, 95, 190404], in which they use a slow modulated magnetic field to effectively transfer rubidium atoms into cold molecules near a Feshbach resonance. We develop a time-dependent collision theory based on two channel model potentials to study the atom-molecule population transfer induced by a single-color radio frequency field in an ultracold 87 Rb gas. Wave-packet dynamical simulations allow an investigation of both bound-bound transitions and free-bound transitions. The effects of temperature, detuning and the RF amplitude on the population transfer are discussed in detail. Some of our simulations suggest that oscillatory atom-molecule conversion could originate from the long coherence time of the wave packet. This coherence time is unusually long in ultracold gases because the collision energy is typically quite well-defined. PMID- 27509889 TI - Comparative Study Using 100-300 Versus 300-500 MUm Microspheres for Symptomatic Patients Due to Enlarged-BPH Prostates. AB - PURPOSE: The purpose of the study was to compare safety and efficacy outcomes following prostate artery embolization (PAE) for the treatment of lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) with 100-300 versus 300-500 MUm tris-acryl gelatin microspheres. MATERIALS AND METHODS: Patients were prospectively treated between August 2011 and June 2013 to receive PAE with 100-300 MUm (group A) or 300-500 MUm (group B) tris-acryl gelatin microspheres. Patients were followed for a minimum of 12 months and were assessed for changes in International Prostate Symptom Score (IPSS), quality of life (QoL) index, prostate volume determined by magnetic resonance imaging, serum prostate specific antigen (PSA), and maximum urine flow rate (Qmax), as well as any treatment-related adverse events. RESULTS: Fifteen patients were included in each group, and PAE was technically successful in all cases. Both groups experienced significant improvement in mean IPSS, QoL, prostate volume, PSA, and Qmax (p < 0.05 for all). The differences observed between the two groups included a marginally insignificant more adverse events (p = 0.066) and greater mean serum PSA reduction at 3 months of follow-up (p = 0.056) in group A. CONCLUSIONS: Both 100-300 and 300-500 MUm microspheres are safe and effective embolic agents for PAE to treat LUTS-related to BPH. Although functional and imaging outcomes did not differ significantly following use of the two embolic sizes, the greater incidence of adverse events with 100-300 MUm microspheres suggests that 300-500 MUm embolic materials may be more appropriate. PMID- 27509887 TI - Gastroenterologists' Perceptions Regarding Ulcerative Colitis and Its Management: Results from a Large-Scale Survey. AB - INTRODUCTION: Misperceptions about ulcerative colitis (UC) may influence management strategies and limit opportunities for improving patient outcomes. This study assessed physicians' perceptions of UC, concepts of disease severity and remission, and treatment goals. METHODS: Gastroenterologists who typically treated >=10 adults with UC per month were recruited for a large-scale, web-based survey. Participants were asked about their perceptions of UC (often vs. Crohn's disease [CD]), treatment goals, and medication use. Response data were evaluated via descriptive statistics and univariate and multivariable analyses. RESULTS: Gastroenterologists (N = 500) with a mean of 16.5 years (standard deviation, 8.7 years) in practice participated. In comparison to CD, survey respondents perceived UC as being easier to diagnose, having better treatment outcomes, and being associated with later prescribing of biologics. Treatment goals commonly considered to have the greatest importance included quality of life improvement (31.2% of respondents), maintenance of clinical remission (17.4%), and mucosal healing (17.4%). When respondents evaluated the performance of medication classes in achieving these goals, biologics were rated significantly higher than all other classes (P < 0.05). However, the most common drivers for the initiation of biologic therapy were the development of steroid refractoriness (66.8%) and steroid dependency (65.8%). Medication class use by UC severity was generally consistent with the traditional step-up approach to UC therapy, with biologics being used most commonly for severe UC. CONCLUSION: These results suggest a possible disparity between treatment goals and therapeutic management in UC. An increased awareness of general UC perceptions is an important step toward a better overall understanding of the disease and, ultimately, toward improved management aligned with treatment goals. FUNDING: This study was sponsored by the American Gastroenterological Association (AGA), and the design and conduct of the study as well as article processing charges and the open access fee for this publication were funded by Takeda Pharmaceuticals International, Inc. (TPI). PMID- 27509890 TI - Effects of different training histories upon manufacturing a tool to solve a problem: insight in capuchin monkeys (Sapajus spp.). AB - The emergence of novel behavior is a multilayered phenomenon that comprehends distinct processes. One such process is known as insightful problem solving. "Insight" can be explained as the spontaneous interconnection of previously acquired behavioral repertoires. The objective of this study was to investigate: (1) whether capuchin monkeys (Sapajus spp.) do show the interconnection of repertoires, and (2) whether different performances of problem solving could be produced by different training histories. Two repertoires were independently trained: (a) joining two pieces of a tool to manufacture a new tool and (b) raking food with one tool. In the test situation, food was out of reach, and two joinable pieces of a tool, different from the ones used in training, were presented. To solve the problem, the monkeys had to join the two pieces and rake the food with the new manufactured tool. In Experiment 1, one monkey received symmetric training (equal number of sessions) of both repertoires and solved the task, but not in an insightful manner. In Experiment 2, six monkeys were divided into two groups: one group received symmetric training, and the second group had asymmetrical training of the repertoires (unequal number of sessions). Subjects from the symmetric group performed as the monkey in Experiment 1; subjects from the other group showed a sudden insightful solution of the problem. The different performances in the same problem situation can be explained in terms of the behavioral history provided to each group of subjects. PMID- 27509892 TI - The ConNECT Framework: a model for advancing behavioral medicine science and practice to foster health equity. AB - Health disparities persist despite ongoing efforts. Given the United States' rapidly changing demography and socio-cultural diversity, a paradigm shift in behavioral medicine is needed to advance research and interventions focused on health equity. This paper introduces the ConNECT Framework as a model to link the sciences of behavioral medicine and health equity with the goal of achieving equitable health and outcomes in the twenty-first century. We first evaluate the state of health equity efforts in behavioral medicine science and identify key opportunities to advance the field. We then discuss and present actionable recommendations related to ConNECT's five broad and synergistic principles: (1) Integrating Context; (2) Fostering a Norm of Inclusion; (3) Ensuring Equitable Diffusion of Innovations; (4) Harnessing Communication Technology; and (5) Prioritizing Specialized Training. The framework holds significant promise for furthering health equity and ushering in a new and refreshing era of behavioral medicine science and practice. PMID- 27509893 TI - High-Performance Carbon Aerogel Air Cathodes for Microbial Fuel Cells. AB - Microbial fuel cells (MFCs) can generate electricity from the oxidation of organic substrates using anodic exoelectrogenic bacteria and have great potential for harvesting electric energy from wastewater. Improving oxygen reduction reaction (ORR) performance at a neutral pH is needed for efficient energy production. Here we show a nitrogen doped (~4 wt%) ionothermal carbon aerogel (NDC) with a high surface area, large pore volume, and hierarchical porosity, with good electrocatalytic properties for ORR in MFCs. The MFCs using NDC air cathodes achieved a high maximum power density of 2300 mW m-2 , which was 1.7 times higher than the most commonly used Pt/C air cathodes and also higher than most state-of-the-art ORR catalyst air cathodes. Rotating disk electrode measurements verified the superior electrocatalytic activity of NDC with an efficient four-electron transfer pathway (n=3.9). These findings highlight NDC as a better-performing and cost-efficient catalyst compared with Pt/C, making it highly viable for MFC applications. PMID- 27509894 TI - Sex-based differential regulation of bacterial-induced bone resorption. AB - BACKGROUND AND OBJECTIVE: Periodontal disease pathogenesis is comprised of the complex inflammatory immune response to oral bacterial dysbiosis. Like other inflammatory diseases, there is sexual dimorphism evident in periodontal diseases. During periodontitis, inflammatory chemokines direct neutrophils to migrate to the site of infection to neutralize the pathogen. Interestingly, these same chemokines are also involved in regulating pathogen-induced osteoclast formation. Previous reports show differences in bone turnover and lymphocyte recruitment between sexes. We hypothesize that chemokine expression is differentially regulated by sex and thus results in differential osteoclast formation. MATERIAL AND METHODS: Male and female mice were utilized to isolate neutrophils based on expression of Ly6G-specific, as well as defined osteoclast progenitors. Cells were stimulated with lipopolysaccharide (LPS; 100 ng/mL) then analyzed for neutrophil infiltration and gene expression. Defined osteoclast progenitors were primed: macrophage-colony stimulating factor (25 ng/mL), receptor activator of NF-kappaB ligand (50 ng/mL), then stimulated with LPS. Osteoclasts were enumerated via TRAP stain and mRNA isolated for gene expression analysis via quantitative polymerase chain reaction. RESULTS: In response to LPS, male neutrophils in vitro respond with increased chemokine expression and significantly more osteoclast formed in response to LPS compared to females. CONCLUSIONS: Findings support observations in humans regarding a sexual dimorphism in oral bacterial infections of alveolar bone loss. Males have a strong inflammatory response to bacterial infection, resulting in increased inflammatory microenvironment, reduced pathogenic bacteria clearance and increased osteoclast-driven bone loss in response to differential expression of key chemokines. PMID- 27509895 TI - Synthetic antimicrobial and LPS-neutralising peptides suppress inflammatory and immune responses in skin cells and promote keratinocyte migration. AB - The stagnation in the development of new antibiotics and the concomitant high increase of resistant bacteria emphasize the urgent need for new therapeutic options. Antimicrobial peptides are promising agents for the treatment of bacterial infections and recent studies indicate that Pep19-2.5, a synthetic anti lipopolysaccharide (LPS) peptide (SALP), efficiently neutralises pathogenicity factors of Gram-negative (LPS) and Gram-positive (lipoprotein/-peptide, LP) bacteria and protects against sepsis. Here, we investigated the potential of Pep19-2.5 and the structurally related compound Pep19-4LF for their therapeutic application in bacterial skin infections. SALPs inhibited LP-induced phosphorylation of NF-kappaB p65 and p38 MAPK and reduced cytokine release and gene expression in primary human keratinocytes and dermal fibroblasts. In LPS stimulated human monocyte-derived dendritic cells and Langerhans-like cells, the peptides blocked IL-6 secretion, downregulated expression of maturation markers and inhibited dendritic cell migration. Both SALPs showed a low cytotoxicity in all investigated cell types. Furthermore, SALPs markedly promoted cell migration via EGFR transactivation and ERK1/2 phosphorylation and accelerated artificial wound closure in keratinocytes. Peptide-induced keratinocyte migration was mediated by purinergic receptors and metalloproteases. In contrast, SALPs did not affect proliferation of keratinocytes. Conclusively, our data suggest a novel therapeutic target for the treatment of patients with acute and chronic skin infections. PMID- 27509896 TI - The eardrum bridge of traumatic tympanic membrane perforation. PMID- 27509897 TI - Prognostic significance of extracapsular spread in isolated neck recurrences in head and neck squamous cell carcinoma patients. AB - Few studies have analyzed the appearance of extracapsular spread (ECS) in salvage neck dissections carried out after regional recurrence of the disease. The aim of our study was to evaluate the frequency of ECS in patients with an isolated regional recurrence treated with a salvage neck dissection, and to assess the influence of ECS on prognosis. We conducted a retrospective study of 123 patients treated with a salvage neck dissection. Eighty-two patients (66.7 %) had nodes with ECS. Five-year salvage-specific survival for patients without ECS was 77.2 %, whereas for patients with ECS it was 32.0 % (P = 0.0001). According to the results of a multivariate analysis, the presence of ECS in the salvage neck dissection was the only variable significantly related to the salvage-specific survival. Sixty-six percent of the patients with nodes with ECS had adjuvant treatment with radiotherapy or chemoradiotherapy. Five-year salvage-specific survival for patients with ECS who had not received adjuvant treatment (n = 26) was 15.2 %, whereas for patients treated with adjuvant radiotherapy (n = 39) or chemotherapy (n = 17), 5-year salvage-specific survival was 36.4 and 47.1 %, respectively. Patients with ECS could benefit from adjuvant treatment with radiotherapy or chemoradiotherapy. PMID- 27509898 TI - Articulation Artifacts During Overt Language Production in Event-Related Brain Potentials: Description and Correction. AB - Overt articulation produces strong artifacts in the electroencephalogram and in event-related potentials (ERPs), posing a serious problem for investigating language production with these variables. Here we describe the properties of articulation-related artifacts and propose a novel correction procedure. Experiment 1 co-recorded ERPs and trajectories of the articulators with an electromagnetic articulograph from a single participant. The generalization of the findings from the single participant to standard picture naming was investigated in Experiment 2. Both experiments provided evidence that articulation-induced artifacts may start up to 300 ms or more prior to voice onset or voice key onset-depending on the specific measure; they are highly similar in topography across many different phoneme patterns and differ mainly in their time course and amplitude. ERPs were separated from articulation-related artifacts with residue iteration decomposition (RIDE). After obtaining the artifact-free ERPs, their correlations with the articulatory trajectories dropped near to zero. Artifact removal with independent component analysis was less successful; while correlations with the articulatory movements remained substantial, early components prior to voice onset were attenuated in reconstructed ERPs. These findings offer new insights into the nature of articulation artifacts; together with RIDE as method for artifact removal the present report offers a fresh perspective for ERP studies requiring overt articulation. PMID- 27509899 TI - Combined DTI-fMRI Analysis for a Quantitative Assessment of Connections Between WM Bundles and Their Peripheral Cortical Fields in Verbal Fluency. AB - Diffusion tensor imaging (DTI) tractography and functional magnetic resonance imaging (fMRI) are powerful techniques to elucidate the anatomical and functional aspects of brain connectivity. However, integrating these approaches to describe the precise link between structure and function within specific brain circuits remains challenging. In this study, a novel DTI-fMRI integration method is proposed, to provide the topographical characterization and the volumetric assessment of the functional and anatomical connections within the language circuit. In a group of 21 healthy elderly subjects (mean age 68.5 +/- 5.8 years), the volume of connection between the cortical activity elicited by a verbal fluency task and the cortico-cortical fiber tracts associated with this function are mapped and quantified. An application of the method to a case study in neuro rehabilitation context is also presented. Integrating structural and functional data within the same framework, this approach provides an overall view of white and gray matter when studying specific brain circuits. PMID- 27509900 TI - The Importance of Aging in Gray Matter Changes Within Tinnitus Patients Shown in Cortical Thickness, Surface Area and Volume. AB - Aging and sensorineural hearing loss are known to be involved in the development of chronic tinnitus. This study explores the structural changes of gray matter using surface base methods and focuses more specifically on changes in cortical thickness in 127 tinnitus patients. The linear relationships between cortical thickness and behavioral measures including aging, tinnitus loudness, tinnitus duration, tinnitus distress, and hearing loss were analyzed. Three dimensional T1 weighted MR images were acquired and cortical gray matter volumes were segmented using FreeSurfer on Talairach space. The results showed that cortical thickness and volume are negatively correlated to age in widespread regions of frontal cortices, and positively to bilateral entorhinal cortex and left rostral anterior cingulate cortex. The cortical thickness changes related to hearing loss overlap with those related to normal aging. The gray matter volumes of bilateral amygdalae, hippocampi, nuclei accumbens, and thalami are all significantly negatively correlated to age. Tinnitus-related distress level and subjective loudness were negatively correlated only to the thalamic volume. The results suggest that the primary factor of long-term structural changes in chronic tinnitus patients is age and age related hearing loss, rather than hearing loss per se. Tinnitus related factors such as subjective tinnitus loudness, tinnitus duration, and the level of chronic tinnitus related distress were not correlated to important morphometric changes in this study. PMID- 27509901 TI - Diverse Reactivity of an Electrophilic Phosphasilene towards Anionic Nucleophiles: Substitution or Metal-Amino Exchange. AB - The reaction of MesLi (Mes=2,4,6-trimethylphenyl) with the electrophilic phosphasilene R2 (NMe2 )Si-RSi=PNMe2 (2, R=Tip=2,4,6-triisopropylphenyl) cleanly affords R2 (NMe2 )Si-RSi=PMes and thus provides the first example of a substitution reaction at an unperturbed Si=P bond. In toluene, the reaction of 2 with lithium disilenide, R2 Si=Si(R)Li (1), apparently proceeds via an initial nucleophilic substitution step as well (as suggested by DFT calculations), but affords a saturated bicyclo[1.1.0]butane analogue as the final product, which was further characterized as its Fe(CO)4 complex. In contrast, in 1,2-dimethoxyethane the reaction of 1 with 2 results in an unprecedented metal-amino exchange reaction. PMID- 27509902 TI - Congenital Zika syndrome with arthrogryposis: retrospective case series study. AB - OBJECTIVE: To describe the clinical, radiological, and electromyographic features in a series of children with joint contractures (arthrogryposis) associated with congenital infection presumably caused by Zika virus. DESIGN: Retrospective case series study. SETTING: Association for Assistance of Disabled Children, Pernambuco state, Brazil. PARTICIPANTS: Seven children with arthrogryposis and a diagnosis of congenital infection presumably caused by Zika virus during the Brazilian microcephaly epidemic. MAIN OUTCOME MEASURES: Main clinical, radiological, and electromyographic findings, and likely correlation between clinical and primary neurological abnormalities. RESULTS: The brain images of all seven children were characteristic of congenital infection and arthrogryposis. Two children tested positive for IgM to Zika virus in the cerebrospinal fluid. Arthrogryposis was present in the arms and legs of six children (86%) and the legs of one child (14%). Hip radiographs showed bilateral dislocation in seven children, subluxation of the knee associated with genu valgus in three children (43%), which was bilateral in two (29%). All the children underwent high definition ultrasonography of the joints, and there was no evidence of abnormalities. Moderate signs of remodeling of the motor units and a reduced recruitment pattern were found on needle electromyography (monopolar). Five of the children underwent brain computed tomography (CT) and magnetic resonance imaging (MRI) and the remaining two CT only. All presented malformations of cortical development, calcifications predominantly in the cortex and subcortical white matter (especially in the junction between the cortex and white matter), reduction in brain volume, ventriculomegaly, and hypoplasia of the brainstem and cerebellum. MRI of the spine in four children showed apparent thinning of the cord and reduced ventral roots. CONCLUSIONS: Congenital Zika syndrome should be added to the differential diagnosis of congenital infections and arthrogryposis. The arthrogryposis was unrelated to the abnormalities of the joints themselves, but was possibly of neurogenic origin, with chronic involvement of central and peripheral motor neurones leading to deformities as a result of fixed postures in utero. Based on the neurophysiological observations, we suggest two possible mechanisms: tropism of neurones, with involvement of peripheral and central motor neurones, or a relation with vascular disorders. PMID- 27509903 TI - What Value Can Qualitative Research Add to Quantitative Research Design? An Example From an Adolescent Idiopathic Scoliosis Trial Feasibility Study. AB - Using an example of qualitative research embedded in a non-surgical feasibility trial, we explore the benefits of including qualitative research in trial design and reflect on epistemological challenges. We interviewed 18 trial participants and used methods of Interpretive Phenomenological Analysis. Our findings demonstrate that qualitative research can make a valuable contribution by allowing trial stakeholders to see things from alternative perspectives. Specifically, it can help to make specific recommendations for improved trial design, generate questions which contextualize findings, and also explore disease experience beyond the trial. To make the most out of qualitative research embedded in quantitative design it would be useful to (a) agree specific qualitative study aims that underpin research design, (b) understand the impact of differences in epistemological truth claims, (c) provide clear thematic interpretations for trial researchers to utilize, and (d) include qualitative findings that explore experience beyond the trial setting within the impact plan. PMID- 27509904 TI - The nucleolytic resolution of recombination intermediates in yeast mitotic cells. AB - In mitotic cells, the repair of double-strand breaks by homologous recombination (HR) is important for genome integrity. HR requires the orchestration of a subset of pathways for timely removal of joint-molecule intermediates that would otherwise prevent segregation of chromosomes in mitosis. The use of nucleases to resolve recombination intermediates is important for chromosome segregation, but is hazardous because crossovers can result in loss of heterozygosity or chromosome rearrangements. Unregulated use of the nucleases involved in the resolution of recombination intermediates could also be a risk during replication. The yeast models (Saccharomyces cerevisae and Schizosaccharomyces pombe) have proven effective in determining the major nucleases involved in the processing of such intermediates: Mus81-Mms4 and Yen1. Mus81-Mms4 and Yen1 are regulated by the cell cycle in a gradual activation during G2/M to keep the crossing-over risk low while ensuring proper removal of HJ intermediates. PMID- 27509905 TI - NHS trust may shut emergency department at night because of staffing "crisis". PMID- 27509906 TI - RUNX2 mutation impairs bone remodelling of dental follicle cells and periodontal ligament cells in patients with cleidocranial dysplasia. AB - RUNX2 is an important osteo-specific factor with crucial functions in bone formation and remodelling as well as resorption of teeth. Heterozygous mutation of RUNX2 can cause cleidocranial dysplasia (CCD), a systemic disease with extensive skeletal dysplasia and abnormality of tooth growth. In our study, dental follicle cells (DFCs) and periodontal ligament cells (PDLCs) were isolated, cultured and identified from one patient with CCD and compared with normal controls. This CCD patient was confirmed to have a heterozygous frameshift mutation of RUNX2 (c.514delT, p.Ser172fs) in the previous study. The results showed that the proliferation abilities of DFCs and PDLCs were both disturbed by the RUNX2 mutation in the CCD patient compared with the normal control. A co culture system of these cells with human peripheral blood mononuclear cells was then used to investigate the effect of RUNX2 mutation on osteoclastogenesis. We found that the RUNX2 mutation in CCD reduced the expression of osteoclast-related genes, such as RUNX2, CTR, CTSK, RANKL and OPG The ability of osteoclastogenesis in DFCs and PDLCs detected by tartrate-resistant acid phosphatase staining in the co-culture system was also reduced by the RUNX2 mutation compared with the normal control. These outcomes indicate that the RUNX2 mutation disturbs the modulatory effects of DFCs and PDLCs on the differentiation of osteoclasts and osteoblasts, thereby interfering with bone remodelling. These effects may contribute in part to the pathological manifestations of retention of primary teeth and delayed eruption of permanent teeth in patients with CCD. PMID- 27509907 TI - Hair Cortisol Concentrations in Adolescent Girls with Anorexia Nervosa are Lower Compared to Healthy and Psychiatric Controls. AB - OBJECTIVE: In anorexia nervosa (AN) hypercortisolism has been described using urine, plasma and saliva samples as short-term markers for the hypothalamic pituitary-adrenal (HPA)-axis. Here, for the first time, we analyse hair cortisol concentration (HCC) as a marker for long-term integrated cortisol secretion in female patients with AN compared to female healthy controls (HC) and female psychiatric controls (PC). METHODS: HCC was assessed in 22 female adolescent psychiatric inpatients with AN compared to 20 female HC and to 117 female PC of the same age range. For further analyses we examined the associations of age and body mass index (BMI) with HCC. RESULTS: Log HCC was lower in AN-patients compared to HC (p = 0.030). BMI-standard deviation scores (SDS) but not age correlated with log HCC (BMI-SDS: r = 0.19, bias corrected accelerated 95% confidence interval: [.04, .34], p = 0.015; age: r = 0.10, bias corrected accelerated 95% confidence interval: [-.07, .25], p = 0.213) when combining AN, HC and PC samples. DISCUSSION: We find lower HCC in AN, compared to HC and PC, respectively. Based on the relationship between HCC and BMI-SDS across AN, HC and PC, we argue that HCC might not capture endocrine alterations because of AN pathology-related processes but rather shows consistent relationships with BMI, which extent even to the very low range of BMI values, as present in AN patients. Alternatively, incorporation of cortisol into the hair follicle might have been compromised because of trophic hair follicle disturbances that had been reported in AN patients, previously. Copyright (c) 2016 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 27509908 TI - Evidence That a Subset of Aneurysms Less Than 7 mm Warrant Treatment. PMID- 27509909 TI - Consistency of Hemoglobin A1c Testing and Cardiovascular Outcomes in Medicare Patients With Diabetes. AB - BACKGROUND: Annual hemoglobin A1c testing is recommended for patients with diabetes mellitus. However, it is unknown how consistently patients with diabetes mellitus receive hemoglobin A1c testing over time, or whether testing consistency is associated with adverse cardiovascular outcomes. METHODS AND RESULTS: We identified 1 574 415 Medicare patients (2002-2012) with diabetes mellitus over the age of 65. We followed each patient for a minimum of 3 years to determine their consistency in hemoglobin A1C testing, using 3 categories: low (testing in 0 or 1 of 3 years), medium (testing in 2 of 3 years), and high (testing in all 3 years). In unweighted and inverse propensity-weighted cohorts, we examined associations between testing consistency and major adverse cardiovascular events, defined as death, myocardial infarction, stroke, amputation, or the need for leg revascularization. Overall, 70.2% of patients received high-consistency testing, 17.6% of patients received medium-consistency testing, and 12.2% of patients received low-consistency testing. When compared to high-consistency testing, low consistency testing was associated with a higher risk of adverse cardiovascular events or death in unweighted analyses (hazard ratio [HR]=1.21; 95% CI, 1.20 1.23; P<0.001), inverse propensity-weighted analyses (HR=1.16; 95% CI, 1.15-1.17; P<0.001), and weighted analyses limited to patients who had at least 4 physician visits annually (HR=1.15; 95% CI, 1.15-1.16; P<0.001). Less-consistent testing was associated with worse results for each cardiovascular outcome and in analyses using all years as the exposure. CONCLUSIONS: Consistent annual hemoglobin A1c testing is associated with fewer adverse cardiovascular outcomes in this observational cohort of Medicare patients of diabetes mellitus. PMID- 27509910 TI - For Immunoglobulin Light Chains, It's Time to Fly! PMID- 27509911 TI - Spotting the Cheaters. PMID- 27509912 TI - Erratum: Mitochondrial Hormesis links nutrient restriction to improved metabolism in fat cell. PMID- 27509913 TI - Endocrine disrupting chemicals as potential risk factor for estrogen-dependent cancers. AB - Civilization, industrialization, and urbanization create an environment where humans are continuously exposed to endocrine disrupting chemicals (EDCs). Some of breast cancers and endometrial cancer, which are the most common female malignant neoplasms, are estrogen-dependent tumors. Prolonged exposure to estrogens or substances with estrogenic properties may be a risk factor for their development. This paper aimed to discuss the potential adverse effect of EDCs on human health, including the role of EDCs in hormone-dependent carcinogenesis. A review of literature regarding the sources of environmental exposure to EDCs and molecular mechanisms of their action was performed. We analyzed the possible mechanisms of how these substances alter the function of the endocrine system, resulting in adverse health effects. Hundreds of substances with endocrine disrupting potential have been identified in our environment. There is accumulating evidence linking exposure to EDCs with the development of mammary and endometrial cancer. By interacting with steroid receptors, EDCs can impact the cellular processes potentially leading to carcinogenesis. There are also data showing the effect of EDCs on immune dysfunction. During lifespan, people are usually exposed to a mixture of various EDCs, which complicates the assessment of individual substances or compounds implicated in cancer development. As the prevalence of hormone-dependent tumors among women continues to increase, their successful prevention is of human benefit. Institutions representing medicine, science, industry, and governments should develop joint strategies to decrease exposure to EDC, and thus to reduce the risk of hormonedependent tumors in women. PMID- 27509914 TI - Lycorine protects cartilage through suppressing the expression of matrix metalloprotenases in rat chondrocytes and in a mouse osteoarthritis model. AB - Extracellular matrix (ECM) degrading enzymes, including matrix metalloproteinases (MMPs), are critical for cartilage destruction in the progression of osteoarthritis (OA). Thus, identifying novel drugs, which suppress the synthesis of MMPs may facilitate the treatment of OA. The cytotoxicity of lycorine was determined using a CCK8 assay. The effects of lycorine on IL-1beta-induced upregulation of MMPs and activation of mitogen-activated protein kinase pathways were detected by western blot analysis and reverse transcription-quantitative polymerase chain reaction. Hematoxylin and eosin staining and Safranin O staining were used to evaluate the effect of lycorine in a mouse anterior cruciate ligament transection model. In the present study, it was demonstrated for the first time, to the best of our knowledge, that lycorine (LY) suppressed interleukin-1beta (IL-1beta)-induced synthesis of MMP-3 and MMP-13 in vitro. Molecular analysis revealed that LY abrogated the phosphorylation of c-Jun N terminal kinase (JNK) and the activation of the nuclear factor (NF)-kappaB signaling pathway caused by IL-1beta stimulation. In addition, in vivo experiments in a mouse anterior cruciate ligament transection model confirmed the protective role of LY on cartilage. Taken together, the data obtained in the present study demonstrated that LY suppressed the IL-1beta-induced expression of MMP-3 and MMP-13 through inhibition of the JNK and NF-kappaB pathways, suggesting that LY may be used as a potential drug for the treatment of OA. PMID- 27509915 TI - Effect of Transition From a Unit-Based Team to External Transport Team for a Pediatric Critical Care Unit. AB - OBJECTIVE: Pediatric hospitals must consider staff, training, and direct costs required to maintain a pediatric specialized transport team, balanced with indirect potential benefits of marketing and referral volume. The effect of transitioning a unit-based transport team to an external service on the pediatric intensive care unit (PICU) is unknown, but information is needed as hospital systems focus on population management. We examined the impact on PICU transports after transition to an external transport vendor. METHODS: Single-center retrospective review performed of PICU admissions, referrals, and transfers during baseline, post-, and maintenance period with a total of 9-year follow-up. Transfer volume was analyzed during pre-, post-, and maintenance phase with descriptive statistics and statistical process control charts from 1999 to 2012. RESULTS: Total PICU admissions increased with an annual growth rate of 3.7%, with mean annual 626 admissions prior to implementation to the mean of 890 admissions at the end of period, P < .001. The proportion of transport to total admissions decreased from 27% to 21%, but mean annual transports were unchanged, 175 to 183, P = .6, and mean referrals were similar, 186 to 203, P = .8. Seasonal changes in transport volume remained as a predominant source of variability. Annual transport refusals increased initially in the postimplementation phase, mean 11 versus 33, P < .03, but similar to baseline in the maintenance phase, mean 20/year, P = .07. Patient refusals were due to bed and staffing constraints, with 7% due to the lack of transport vendor availability. CONCLUSION: In a transition to a regional transport service, PICU transport volume was maintained in the long term follow-up and total PICU admissions increased. Further research on the direct and indirect impact of transport regionalization is needed to determine the optimal cost-benefit and quality of care as health-care systems focus on population management. PMID- 27509916 TI - Withdrawing and Withholding Life Support in Patients With Cancer in an ICU Setting: A 5-Year Experience at a European Cancer Center. AB - OBJECTIVE: This was an observational retrospective study aimed to examine the frequency and associated factors of withdrawing or withholding life support (WWLS) in the intensive care unit (ICU) of a comprehensive cancer center. METHODS: Medical records of adult patients with cancer admitted to the ICU between January 2010 and December 2014 were reviewed. Patients who died during that period were classified into 2 groups: full life support and withdrawing and withholding life support. The relative impact of demographic and clinical factors was assessed using logistic regression. RESULTS: A total of 247 patients died in our unit (mortality rate of 16.3%). Their median age was 62 (interquartile range [IQR] 51-73) years, there were 142 (57.5%) male patients, and they had predominantly solid malignancies (62.3%). The median Simplified Acute Physiology Score II and Acute Physiology and Chronic Health Evaluation scores were 67 (IQR 54-80) and 29 (IQR 23-55), respectively. Ninety-six (38.9%) patients died after WWLS with no statistically significant differences in decisions to limit therapy during the study period. Patients with advanced age, solid malignancies, nonneutropenic, and longer duration of mechanical ventilation were more likely to die after WWLS. In multivariate analysis, presenting with neutropenia was independently associated with a lower likelihood of dying after WWLS (odds ratio: 0.34, 95% confidence interval: 0.15-0.80). CONCLUSION: Limitation of therapy has been a common practice in oncologic ICUs over recent years. Neutropenia is an independent predictor of limitation of therapy. PMID- 27509917 TI - Extracorporeal Support for Chronic Obstructive Pulmonary Disease: A Bright Future. AB - In the past the only option for the treatment of respiratory failure due to acute exacerbation of chronic obstructive pulmonary disease (aeCOPD) was invasive mechanical ventilation. In recent decades, the potential for extracorporeal carbon dioxide (CO2) removal has been realized. We review the various types of extracorporeal CO2 removal, outline the optimal use of these therapies for aeCOPD, and make suggestions for future controlled trials. We also describe the advantages and requirements for an ideal long-term ambulatory CO2 removal system for palliation of COPD. PMID- 27509918 TI - Measuring younger onset dementia: A comprehensive literature search of the quantitative psychosocial research. AB - BACKGROUND: Research is beginning to demonstrate the unique psychosocial effects of young onset dementia. Theorising remains at an early stage and there has been little discussion about measurement and methodological issues. Our aim was to conduct a comprehensive literature search of the young onset dementia psychosocial research, and to identify the domains of experience measured with patients and caregivers. METHOD: We conducted a search of five electronic databases (Medline, CINAHL, PsycINFO, Embase, the Cochrane Library) using equivalent database controlled vocabulary terms. We supplemented this search by using free text searches within electronic databases, searching reference sections of salient papers, and using online search engines. We defined psychosocial as referring to patient and caregiver psychological, behavioural, and social functioning in the context of living with young onset dementia. RESULTS: We identified 72 published articles, 49 quantitative and 23 qualitative. The quantitative articles form the focus of the present review. We identified 10 domains of patient experience measured and 14 domains of caregiver experience. The patient domains measured most often were behaviour, cognition, functioning, and severity, and reflected a focus on symptoms and clinical features. Quality of Life (QoL) was the patient domain measured least often. The caregiver domains measured most often were mental health and burden, and reflected a focus on psychological well-being and coping. CONCLUSION: The scope of measurement is broader in caregivers than patients. QoL although under-researched may be a useful domain to measure in future research. Risk factors, measurement and methodological issues are discussed. PMID- 27509919 TI - How do activating interventions fit the personal needs, characteristics and preferences of people with dementia living in the community and their informal caregivers? AB - Psychosocial interventions aim to mitigate the serious consequences of dementia for the daily life of people with dementia and their informal caregivers. To deliver a person-centred approach, it is crucial to take needs, characteristics and preferences of people with dementia and their informal caregivers into account. However, these factors are generally not systematically checked in order to determine which intervention will be most appropriate. Additionally, little is known about which intervention suits which needs, characteristics and preferences. Therefore, this study examined how three multiple-component, activating dyadic interventions fitted needs, characteristics, and preferences of both the people with dementia and their informal caregivers: the Pleasant Events Program, the Exercise and Support Intervention for People with Dementia and Their Caregivers, and Occupational Therapy. Semi-structured interviews were held with participants in either one of the interventions, 34 dyads and 19 professionals. The constant comparative method was used for the analysis. Five factors influenced the dyad's 'fit': timing, need for activity, lifestyle, apart-or together and meaning of (lost) activity. The factors 'timing' and a 'need for activity' were conditional for these activating interventions. Dyads in an early stage of dementia, who were aware of the effects on daily life, were open to a change in routine, and had a need to maintain activities profited from these interventions. Three distinctive factors were important for the fit of one of the three interventions in particular: 'lifestyle', 'apart or together' and 'meaning of (lost) activity'. The Pleasant Events Programme and the Exercise and Support intervention properly addressed the need for activities that afforded daily pastimes or structure. The Exercise and Support Intervention addressed the need for physical activity and emphasized shared activity. Occupational Therapy properly addressed the need for self-sufficiency, maintaining activities and adjustment to physical limitations. These factors can contribute to a more person centred application of the interventions. PMID- 27509920 TI - Postural stability in the cognitively impaired elderly: A systematic review of the literature. AB - INTRODUCTION: The aim of this study was to review the literature and critically analyse publications connecting cognitive impairment with postural stability. METHODS: Four electronic databases were searched. The inclusion criteria comprised the relation between the process of maintaining balance and cognitive impairment. RESULTS: Of the 153 selected articles, 15 met the inclusion criteria. In 83% of publications, cognitive status was determined with the use of the Mini Mental State Examination. In eight publications, postural stability was examined using force plates. Other methods used to test the balance were functional tests, i.e. the Berg Balance Scale or the Balance Evaluation Systems Test. CONCLUSION: As the choice of methodology varies significantly, it is difficult to attempt an objective comparison between different studies. There is a clear need for the normalisation of methods used to assess the degree of dementia and to assess postural stability among this group of people. PMID- 27509921 TI - Increased NEK2 in hepatocellular carcinoma promotes cancer progression and drug resistance by promoting PP1/Akt and Wnt activation. AB - NIMA-related expressed kinase 2 (NEK2) participates in the carcinogenesis and progression of certain types of cancer, however, its expression and roles in the development of hepatocellular carcinoma (HCC) remains unknown. Here, we found that NEK2 expression was significantly upregulated in both human HCC tissues and cell lines, and increased NEK2 expression in HCC was significantly correlated with clinical progression of HCC in patients. Knockdown of NEK2 in HCC cells inhibited HCC progression, as determined by the suppressed cell proliferation, invasion and metastasis. Furthermore, knockdown of NEK2 inhibited drug resistance of HCC cells, as shown by the promoted suppression of cell viability in 5 fluorouracil (5-FU)-treated HCC cells. Mechanistically, protein phosphatase 1 (PP1)/Akt and Wnt signaling activation are significantly inhibited by NEK2 knockdown, which is responsible for the HCC progression and involved in NEK2 induced cancer cell abnormal biological behavior. Thus, enhanced NEK2 expression in HCC promotes HCC progression and drug resistance by promoting PP1/Akt and Wnt pathway activation, which may represent a new therapeutic target for HCC. PMID- 27509923 TI - Observation of a Reactive Rainbow in F + CH3D -> CH2D(v = 0) + HF(v = 3)? AB - Rainbow structures in the scattering angular distribution play an important role in deepening our understanding about the elastic and rotationally inelastic collisions of atoms/molecules. Reported here is the discovery of a rainbow in a chemical reaction. At Ec = 4.3 kcal mol(-1) one of the correlated product pairs in the F + CH3D reaction, (vHF, vCH2D) = (3, 00), displays a distinct bulge in angular distribution. We showed that the bulge originates predominantly from the low-j states of the HF(v = 3) products. Heuristic considerations led us to propose that such a bulge could be regarded as a signature for rainbow scattering. The underlying mechanism for its occurrence in this nearly thermoneutral product pair is ascribed to a delicate interplay of the attractive and repulsive parts of interactions in the vicinity of the transition state. In a sense, the situation bears striking similarity to the more familiar elastic rainbow, thus coined "reactive rainbow". PMID- 27509924 TI - 15d-PGJ2 Induces Apoptosis of MCF-7 and MDA-MB-231 Cells via Increased Intracellular Calcium and Activation of Caspases, Independent of ERalpha and ERbeta. AB - Reports indicate that 15deoxydelta12,14prostaglandinJ2 (15dPGJ2) has anticancer activities, but its mechanisms of action have yet to be fully elucidated. We therefore investigated the effects of 15dPGJ2 on the human breast cancer cell lines, MCF7 (estrogen receptor ERalpha+/ERbeta+) and MDAMB231 (ERalpha/ERbeta+). Cellular proliferation and cytotoxicity were determined using the 3(4,5dimethylthiazol2yl)2,5diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays while apoptosis was determined by fluorescence microscopy and flow cytometry using annexin Vpropidium iodide (PI) staining. ER expression was determined by Western blotting. Intracellular calcium was stained with Fluo4 AM while intracellular caspase activities were detected with CaspaseFLICA(r) and measured by flow cytometry. We showed that 15dPGJ2 caused a significant increase in apoptosis in MCF7 and MDAMB231 cells. ERalpha protein expression was reduced in treated MCF7 cells but preincubation with the ERalpha inhibitor' ICI 182 780' did not affect the percentage of apoptotic cells. The expression of ERbeta was unchanged in both cell lines. In addition, 15dPGJ2 increased intracellular calcium (Ca2+) staining and caspase 8, 9 and3/7 activities. We therefore conclude that 15dPGJ2 induces caspasedependent apoptosis that is associated with an influx of intracellular Ca2+ with no involvement of ER signaling. PMID- 27509922 TI - Investigation of the association between miR-181b, Bcl-2 and LRIG1 in oral verrucous carcinoma. AB - Abnormal expression of microRNAs (miRNAs) is involved in the development of and anti-apoptotic effects in various types of human cancer. However, miRNA-mediated regulation of oral verrucous carcinoma (OVC) remains to be elucidated. The present study aimed to investigate the expression of miR-181b in OVC and oral squamous cell carcinoma (OSCC). The expression levels of miR-181b were determined using reverse transcription-quantitative polymerase chain reaction. The expression levels of B-cell lymphoma 2 (Bcl-2) and leucine rich repeats and immunoglobulin like domains 1 (LRIG1), were evaluated using immunohistochemical staining. The correlation between Bcl-2 and LRIG1 expression was determined using a Pearson correlation analysis. The expression levels of miR-181b and Bcl-2 in OVC were significantly higher compared with normal mucosal tissue (NM); however, lower compared with the OSCC. The key target of miR-181b was LRIG1 and it was significantly lower in OVC tissues compared with NM tissue; however this was higher when compared with OSCC tissue. The expression levels of Bcl-2 were correlated with expression levels of LRIG1 in OVC tissues. Therefore, LRIG1 may be associated with anti-apoptotic function in OVC tissues. PMID- 27509925 TI - Tyrosine Kinase Inhibitors in Ph+ Chronic Myeloid Leukemia Therapy: a Review. AB - Chronic myeloid leukaemia (CML) is a clonal myeloproliferative hematopoietic stem cell disorder. Deregulated BCRABL fusion tyrosine kinase activity is the main cause of CML disease pathogenesis, making BCRABL an ideal target for inhibition. Current tyrosine kinase inhibitors (TKIs) designed to inhibit BCRABL oncoprotein activity, have completely transformed the prognosis of CML. Interruption of TKI treatment leads to minimal residual disease reside (MRD), thought to reside in TKIinsensitive leukaemia stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML either as small molecule master TKIs or phytopharmaceuticals derived from nature to achieve chronic molecular remission. This review outlines the past, present and future therapeutic approaches for CML including coverage of relevant mechanisms, whether ABL dependent or independent, and epigenetic factors responsible for developing resistance against TKIs. Appearance of mutant clones along the course of therapy either preexisting or induced due to therapy is still a challenge for the clinician. A proposed invitro model of generating colony forming units from CML stem cells derived from diagnostic samples seems to be achievable in the era of high throughput technology which can take care of single cell genomic profiling. PMID- 27509926 TI - Breast Cancer in Pakistan a Critical Appraisal of the Situation Regarding Female Health and Where the Nation Stands? AB - Breast cancer (BC) is the most common malignancy of women worldwide. In the past it was considered as disease of older middle aged women, but the incidence of BC in young females is growing in recent years concordant with studies in Pakistan. In this paper, we reviewed the mutant functions of tumor suppressor genes (BRCA1, BRCA2, p53, ATM and PTEN), epigenetic transformation and involvement of estrogen receptors in development of breast cancer. We further reviewed the current situation of BC in Pakistan that depicts a higher incidence in young females. According to SKMCH and RC data, age group 4549 years is more prone to BC with high rate of incidence 45.42%. A few studies explored the high expression of ER, PR and HER2/neu in Pakistani females. Moreover, presence of BRCA1 (c.1961dupA) mutation in Pakistani shows concordance with data in different areas of world. But we are unable to find an authentic study that can explore epigenetic based transformation of breast tumors in Pakistan. This area of research needs more attention to explore the complete picture of BC in Pakistan. PMID- 27509927 TI - Pleiotropic Roles of Metalloproteinases in Hematological Malignancies: an Update. AB - Controlled remodeling of the extracellular matrix (ECM) is essential for cell growth, invasion and metastasis. Matrix metalloproteinases (MMPs) are a family of secreted, zincdependent endopeptidases capable of degradation of ECM components. The expression and activity of MMPs in a variety of human cancers have been intensively studied. They play important roles at different steps of malignant tumor formation and have central significance in embryogenesis, tissue remodeling, inflammation, angiogenesis and metastasis. However, increasing evidence demonstrates that MMPs are involved earlier in tumorigenesis. Recent studies also suggest that MMPs play complex roles in tumor progression. MMPs and membrane type (MT)MMPs are potentially significant therapeutic targets in many cancers, so that designing of specific MMP inhibitors would be helpful for clinical trials. Here, we review the pleiotropic roles of the MMP system in hematological malignancies invitro and invivo models. PMID- 27509928 TI - Gastric Carcinoma: Recent Trends in Diagnostic Biomarkers and Molecular Targeted Therapies. AB - Gastric cancer is generally associated with poor survival rates and accounts for a remarkable proportion of global cancer mortality. The prevalence of gastric carcinoma varies in different regions of world and across teh various ethnic groups. On the basis of pathological assessment, gastric cancer can be categorized as intestinal and diffuse carcinomas. The etiology is diverse, including chemical carcinogen exposure, and high salt intake Helicobacter pylori also plays a vital role in the pathogenesis of certain gastric carcinomas. The development of gastric cancer involves various alterations in mRNAs, genes (GOLPH3, MTA2) and proteins (Coronins). miRNAs, Hsamir135b, MiR21, miR106b, miR17, miR18a, MiR21, miR106b, miR17, miR18a and MiRNA375, miRNA1955p are the latest diagnostic biomarkers which can facilitate the early diagnosis of gastric carcinomas. Recent development in the treatment strategies for gastric carcinoma include the introduction of monoclonal antibodies, TKI inhibitors, inhibitors of PDGFR beta, VEGFR1, VEGFR2, AntiEGFR and antiHER2 agents which can be applied along with conventional therapies. PMID- 27509929 TI - F2 Gel Matrix a Novel Delivery System for Immune and Gene Vaccinations. AB - Exploiting the immune system to abolish cancer growth via vaccination is a promising strategy but that is limited by many clinical issues. For DNA vaccines, viral vectors as a delivery system mediate a strong immune response due to their protein structure, which could afflect the cellular uptake of the genetic vector or even induce cytotoxic immune responses against transfected cells. Recently, synthetic DNA delivery systems have been developed and recommended as much easier and simple approaches for DNA delivery compared with viral vectors. These are based on the attraction of the positively charged cationic transfection reagents to negatively charged DNA molecules, which augments the cellular DNA uptake. In fact, there are three major cellular barriers which hinder successful DNA delivery systems: low uptake across the plasma membrane; inadequate release of DNA molecules with limited stability; and lack of nuclear targeting. Recently, a polysaccharide polymer produced by microalgae has been synthesized in a form of polymeric fiber material polyNacetyl glucosamine (pGlcNAc). Due its unique properties, the F2 gel matrix was suggested as an effective delivery system for immune and gene vaccinations. PMID- 27509930 TI - Tetra Primer ARMS PCR Optimization to Detect Single Nucleotide Polymorphisms of the CYP2E1 Gene. AB - Single nucleotide polymorphism (SNP) detection has been used extensively for genetic association studies of diseases including cancer. For mass, yet accurate and more economic SNP detection we have optimized tetra primer amplification refractory mutation system polymerase chain reaction (ARMS PCR) to detect three SNPs in the cytochrome P450 2E1 (CYP2E1) gene locus; i.e. rs3813865, rs2070672 and rs3813867. The optimization system strategies used were (1) designing inner and outer primers; (2) determining of their optimum primer concentration ratios; and (3) determining of the optimum PCR annealing temperature. The tetra primer ARMS PCR result could be directly observed using agarose gel electrophoresis. The method succesfully determined three SNPs in CYP2E1 locus, the results being consistent with validation using DNA sequencing and restriction fragment length polymorphisms (RFLP). PMID- 27509931 TI - Morin, a Flavonoid from Moraceae, Inhibits Cancer Cell Adhesion to Endothelial Cells and EMT by Downregulating VCAM1 and Ncadherin. AB - Morin, a flavonoid found in figs and other Moraceae species, displays a variety of biological actions, exerting antioxidant, antiinflammatory and anticarcinogenic effects. Here, we investigated the anticancer activity of morin focusing on antiadhesive influence. We performed experiments with MDAMB231 human breast cancer cells. Morin inhibited TNFinduced cancer cell adhesion to human umbilical vein endothelial cells (HUVECs) without showing any toxicity. It further inhibited the expression of VCAM1 on MDAMB231 cells as well as HUVECs. Morin also decreased the expression of Ncadherin on MDAMB231 cells. In addition, there was apparent antimetastatic activity in vivo. In conclusion, this study suggested that morin inhibits cancer cell adhesion to HUVECs by reducing VCAM1, and EMT by targeting Ncadherin, and that it features antimetastatic activity in vivo. Further investigation of possible antimetastatic activity of morin against human breast cancer cells is warranted. PMID- 27509932 TI - AntiTumor and Immunoregulatory Effects of Fermented Papaya Preparation (FPP: SAIDOPS501). AB - Various beneficial effects have been described for fermented papaya preparation (FPP: SAIDOPS501) based on its antioxidative and antiinflammatory functions. The present study was designed to determine the effects of FPP on carcinogenesis in vivo, and immunomodulatory function in vitro. Mice were injected with RL male 1 cells subcutaneously or 3methylcholantherene (MCA) intravenously to induce cancer and orally or intraperitoneally treated with FPP solution. Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers and patients with atopic dermatitis, treated with FPP, and subjected to measurement of cytokine production and changes in Foxp3expressing regulatory T cell (Treg) stimulated with phytohemagglutinin (PHA). Administration of FPP suppressed tumor size and the incidence of malignancy. In vitro, treatment of PBMC with FPP induced IL1?, TNFalpha and IFNgamma production. Moreover, FPP suppressed proliferation of PHAstimulated Foxp3expressing Treg. These results suggest that FPP has chemotherapeutic properties. PMID- 27509933 TI - Evaluation of KRAS Gene Mutations in Metastatic Colorectal Cancer Patients in Kermanshah Province. AB - BACKGROUND: Worldwide, colorectal cancer (CRC) is reported to be the fourth most common cancer in men and the third most common in women. KRAS is a protooncogene located on the short arm of chromosome 12. The aim of this study was to evaluate the KRAS oncogene and its relationship it with clinicopathologic features in 33 Kurdish patients. MATERIALS AND METHODS: Metastatic CRC between 2012 and 2016 that came to Imam Reza hospital, Kermanshah province, Iran, were analysed for KRAS mutations using allele specific PCR primers and pyrosequencing. Correlations between variables was analyzed in PASW SPSS and overall survival curves were plotted in Graph Pad prism 5. RESULTS: The mean age for them at diagnosis was 51.5+/-12.6 years (range, 2276 years). Among the 33 patients that were sequenced, 12 samples in the KRAS gene had a nucleotide change, 11 in codon 12 and 1 in codon 13.There was no significant relationship between the mutation and clinical and pathological aspects of the disease. CONCLUSIONS: Knowledge of the KRAS status can help in decisionmaking to treat metastatic colorectal cancer patients more efficiently and increase survival. However, many Kurdish people due to economic problems are not able to do this valuable genetic test. In addition, we need more careful research of KRAS oncogene at the molecular level in young populations with more patients. PMID- 27509934 TI - Does the Presence of Primary Circulating Prostate Cells Imply the Presence of Agressive Prostate Cancer with Early Biochemical Failure: a Comparison with the Walz Nomogram. AB - BACKGROUND: To determine the utility of primary circulating prostate cells (CPC) for predicting early biochemical failure after radical prostatectomy for prostate cancer and compare the results with the Walz nomogram. MATERIALS AND METHODS: A single centre prospective study of men with prostate cancer treated with radical prostatectomy was conducted between 2004 and 2014. Clinicalpathological details were registered, along with total serum PSA presurgery, Gleason score, extracapsular extension, positive surgical margins, infiltration of lymph nodes, seminal vesicles and pathological stage. Primary circulating prostate cells were obtained using differential gel centrifugation and detected using standard immunocytochemistry with antiPSA. Biochemical failure was defined as a PSA >0.2ng/ml, predictive values were calculated using the Walz nomagram and CPC detection. RESULTS: A total of 285 men participated, of whom 103/285 (36.1%) suffered biochemcial failure; 32/103 (31.1%) within two years of radical prostatectomy. Men with higher Gleason scores, higher pathological stage, infiltration of the surgical margin or prostate capsule and infiltration of seminal vesicles were more likely to undergo biochemical failure. There was a significant increase in the frequency of biochemical failure with increasing number of CPCs detected (p<0.0004 Chi squared for trend) and increasing percent prediction for the Walz nomogram (p<0.0001 Chi squared for trends). The positive predictive value of primary CPC detection, even using a cutoff point of >= 4 cells/sample was very low. CONCLUSIONS: The detection of primary CPCs in men as a prognostic factor pretreatment fails to identify those at high risk of biochemical failure within two years of curative therapy. This is in keeping with their biological significance, that the majority of them will be eliminated by the primary therapy and thus have no influence on the subsequent clinical history of the patient. PMID- 27509935 TI - Quality of Life of Patients with Advanced Cervical Cancer before and after Chemoradiotherapy. AB - BACKGROUND: Cervical cancer is the most frequently diagnosed cancer among women in India. Understanding quality of life (QOL) in women undergoing chemoradiotherapy for cervical cancer will help in introducing interventions for better care and outcomes in these women. This study assessed QOL before and after chemo radiotherapy in cervical cancer patients. MATERIALS AND METHODS: This followup study covered sixtyseven newly diagnosed women with advanced cervical cancer (stages 2b to 4b). Structured questionnaires (the European Organization for Research and Treatment of Cancer, EORTC QLQC30 and EORTC QLQCX24) were used to assess the change in QOL after 6 months of treatment. RESULTS: The mean age of women at the time of detection of cervical cancer was 52.3+/-11.29 years (Range 3075 years). Six months survival was 92.53%. The mean global health score of cervical cancer patients after six months of treatment was 59.52, which was significantly higher than the pretreatment score of 50.15 (p=0.00007). Physical, cognitive and emotional functioning improved significantly (p<0.05) after treatment. Fatigue, pain, insomnia and appetite loss improved but episodes of diarrhea increased after treatment. The mean "symptoms score" using EORTC QLQCX24 post treatment was 20.0 which was significantly lower as compared to the pre treatment score 30.0 (p<0.00001). Sexual enjoyment and sexual functioning decreased significantly after treatment. CONCLUSIONS: QOL of newly diagnosed cervical cancer patients improved significantly following chemoradio therapy. Enhancement was also demonstrated on three of the five functional scales of EORTC QLQC30. To further improve QOL, interventions focusing on social and psychological support and physical rehabilitation may be needed. PMID- 27509936 TI - Prevalence of Abnormal Cervical Cytology in HIVNegative Women Participating in a Cervical Cancer Screening Program in Calmette Hospital, Cambodia. AB - Prevalence of Abnormal Cervical Cytology in HIVNegative Women Participating in a Cervical Cancer Screening Program in Calmette Hospital, Cambodia. PMID- 27509937 TI - Spiritual Needs of Patients with Cancer Referred to Alinasab and Shahid Ghazi Tabatabaie Hospitals of Tabriz, Iran. AB - BACKGROUND: Patients' spiritual needs increase drastically after a diagnosis of cancer because of its threatening nature. It is very important to recognize any spiritual crisis. This study aimed to determine needs among Iranian patients with cancer. MATERIALS AND METHODS: This crosssectional study was undertaken among 200 patients with cancer referred to Alinasab and Shahid Ghazi Tabatabaie hospitals of Tabriz, Iran. The Spiritual Needs Scale was used for data collection. RESULTS: The mean age of participants was 45.9+/-16.4 years. The majority expressed their main spiritual wishes as "think to God", "trust to God", "see others happy", "try for life beside the disease", "to be prayed for by others', and "need for kindness and help others". Regarding the relationship between demographic characteristics, factors related to disease and the total score of spiritual needs, the results of chisquare tests showed a significant statistical correlations with occupation (p=0.01) and number of children (p=0.03). Also the results of Pearson correlation showed that there is a significant statistical correlation between hospitalization frequency and patients' spiritual needs (p<0.01, r=0.24). CONCLUSIONS: Determination of spiritual needs of patients with cancer in this study can help health carers and especially nurses to design appropriate spiritual care programs based on individual preferences. PMID- 27509938 TI - Comparing Recurrence and Complications After Laparoscopy and Laparotomy Surgery among Patients Suffering from Colorectal Cancer, Shiraz, Iran. AB - BACKGROUND: The goal of this study was to compare the rate of recurrence and occurrence of complications in colorectal cancer patients after two kinds of laparoscopy and laparotomy. MATERIALS AND METHODS: A followup study was carried out among 358 patients who suffered from colorectal cancer from 20122014. The data were gathered from colorectal research center in Shiraz, Shahid Faghihi hospital, and analyzed using the chisquare test, logistic regression, and multinomial regression. RESULTS: The average age of these patients was 56.3+/ 14.6, 55.0% being men. Moreover, 57.8% of them underwent laparoscopy surgery and 42.2% of the patients underwent laparotomysurgery and the conversion rate was 58.0% which ultimately was put under the category of laparotomy surgery. After biennial median followup, differences in the occurrence of complications such as bleeding (hemorrhage), fever, intestine blockage and wound infection in these two kinds of surgery werestatistically significant (P<0.05). However, the rate of recurrence and the patients' ultimate status (alive without disease, alive with disease, and death) did not significantly differ between these two surgery groups. CONCLUSIONS: Post operation complications were laparoscopy surgery were less than those in laparotomy. However, the outcomes such as patients' ultimate status and recurrence were similar between the two groups. PMID- 27509939 TI - Quantitative Analyses of Esophageal Cancer Research in Pakistan. AB - BACKGROUND: Healthcare research is a neglected discipline in Pakistan and research related to esophageal cancer (ranks 9th in Pakistani males and 5th in females) is no exception in this regard. Particularly, there are no data available to delineate the overall status of esophageal cancer epidemiological studies in Pakistan. This study describes the first ever effort to make a systematic quantification, in an attempt to provide a roadmap to all stakeholders for designing appropriate epidemiological, diagnostic and therapeutic strategies. MATERIALS AND METHODS: International (PubMed, ISI Web of Knowledge) and local (PakMedinet) scientific databases as well as Google search engine were searched using specified keywords to extract relevant publication. Well defined inclusion criteria were implemented to select publications for final analyses. All data were recorded by at least 3 authors and consensus data were entered into and analyzed for descriptive statistics (such as frequencies, percentages and annual growth rates) using Microsoft Excel and SPSS software. RESULTS: A total of 79 publications fulfilled the inclusion criteria including 20 publications for which full texts were not available. Of the 79 publications, 59 (74.6%) were original/research publications, 5 (6.3%) were case reports, 4 (5.1%) were research communications, 2 (2.5%) were review articles, 1 was (1.2%) correspondence and 8 (10.1%) were un defined categories. Only 13 <20%) cities of Pakistan contributed towards the 79 publications. On average, only 1.9 relevant publications/year were published from 1976 (year of first publication) to the present. Alarmingly, a decline in the annual growth at 4.1% was recorded in the last six years. CONCLUSIONS: Esophageal cancer research is largely unfathomed in Pakistan. Urgent/dramatic steps are required by all concerned to address this common (and under reported) cancer of Pakistan. PMID- 27509940 TI - Surveillance Evaluation of the National Cancer Registry in Sabah, Malaysia. AB - BACKGROUND: Cancer is the fourth leading cause of death in Sabah Malaysia with a reported agestandardized incidence rate was 104.9 per 100,000 in 2007. The incidence rate depends on nonmandatory notification in the registry. Underreporting will provide the false picture of cancer control program effectiveness. The present study was to evaluate the performance of the cancer registry system in terms of representativeness, data quality, simplicity, acceptability and timeliness and provision of recommendations for improvement. MATERIALS AND METHODS: The evaluation was conducted among key informants in the National Cancer Registry (NCR) and reporting facilities from FebMay 2012 and was based on US CDC guidelines. Representativeness was assessed by matching cancer case in the Health Information System (HIS) and state pathology records with those in NCR. Data quality was measured through case finding and reabstracting of medical records by independent auditors. The reabstracting portion comprised 15 data items. Selfadministered questionnaires were used to assess simplicity and acceptability. Timeliness was measured from date of diagnosis to date of notification received and data dissemination. RESULTS: Of 4613 cancer cases reported in HIS, 83.3% were matched with cancer registry. In the state pathology centre, 99.8% was notified to registry. Duplication of notification was 3%. Data completeness calculated for 104 samples was 63.4%. Registrars perceived simplicity in coding diagnosis as moderate. Notification process was moderately acceptable. Median duration of interval 1 was 5.7 months. CONCLUSIONS: The performances of registry's attributes are fairly positive in terms of simplicity, case reporting sensitivity, and predictive value positive. It is moderately acceptable, data completeness and inflexible. The usefulness of registry is the area of concern to achieve registry objectives. Timeliness of reporting is within international standard, whereas timeliness to data dissemination was longer up to 4 years. Integration between existing HIS and national registration department will improve data quality. PMID- 27509941 TI - E1/E2 of Hepatitis C Virus Genotype4 and Apoptosis. AB - Several studies have addressed the possible role of hepatitis C virus genotype4 (HCV GT4) in apoptosis. However, this still not fully understood. In the current study a reconstructed clone of E1/E2 polyprotein region of the HCV GT4 was transfected into the Huh7 cell line and a human apoptotic PCR array of 84 genes was used to investigate its possible significance for apoptosis. Out of the 84 genes, only 35 showed significant differential expression, 12 genes being upregulated and 23 downregulated. The highestup regulated genes were APAF1 (apoptotic peptidaseactivating factor 1), BID (BH3 interacting domain death agonist) and BCL 10 (Bcell CLL/ lymphoma protein 10) with fold regulation of 33.2, 30.1 and 18.9, respectively. The most downregulated were FAS (TNF receptor super family), TNFRSF10B (tumor necrosis factor receptor superfamily member 10b) and FADD (FASassociated death domain) with fold regulation of 30.2, 27.7 and 14.9, respectively. These results suggest that the E1/E2 proteins may be involved in HCVinduced pathogenesis by modulating apoptosis through the induction of the intrinsic apoptosis pathway and disruption of the BCL2 gene family. PMID- 27509942 TI - 35Year Research History of Cytotoxicity and Cancer: a Quantitative and Qualitative Analysis. AB - Cancer is the leading cause of morbidity and mortality worldwide, characterized by irregular cell growth. Cytotoxicity or killing tumor cells that divide rapidly is the basic function of chemotherapeutic drugs. However, these agents can damage normal dividing cells, leading to adverse effects in the body. In view of great advances in cancer therapy, which are increasingly reported each year, we quantitatively and qualitatively evaluated the papers published between 1981 and December 2015, with a closer look at the highly cited papers (HCPs), for a better understanding of literature related to cytotoxicity in cancer therapy. Online documents in the Web of Science (WOS) database were analyzed based on the publication year, the number of times they were cited, research area, source, language, document type, countries, organizationenhanced and funding agencies. A total of 3,473 publications relevant to the target key words were found in the WOS database over 35 years and 86% of them (n=2,993) were published between 20002015. These papers had been cited 54,330 times without self citation from 1981 to 2015. Of the 3,473 publications, 17 (3,557citations) were the most frequently cited ones between 2005 and 2015. The topmost HCP was about generating a comprehensive preclinical database (CCLE) with 825 (23.2%) citations. One third of the remaining HCPs had focused on drug discovery through improving conventional therapeutic agents such as metformin and ginseng. Another 33% of the HCPs concerned engineered nanoparticles (NPs) such as polyamidoamine (PAMAM) dendritic polymers, PTX/SPIOloaded PLGAs and cell derived NPs to increase drug effectiveness and decrease drug toxicity in cancer therapy. The remaining HCPs reported novel factors such as miR205, Nrf2 and p27 suggesting their interference with development of cancer in targeted cancer therapy. In conclusion, analysis of 35year publications and HCPs on cytotoxicity in cancer in the present report provides opportunities for a better understanding the extent of topics published and may help future research in this area. PMID- 27509943 TI - Prevalence and Associated Factors of Abnormal Cervical Cytology and HighRisk HPV DNA among Bangkok Metropolitan Women. AB - BACKGROUND: Many strategies are required for cervical cancer reduction e.g. provision of education cautious sexual behavior, HPV vaccination, and early detection of preinvasive cervical lesions and invasive cancer. Basic health data for cervical cytology/ HPV DNA and associated factors are important to make an appropriate policy to fight against cervical cancer. AIMS: To assess the prevalence of abnormal cervical cytology and/or HPV DNA and associated factors, including sexual behavior, among Bangkok Metropolitan women. MATERIALS AND METHODS: Thai women, aged 25to65 years old, had lived in Bangkok for >=5 years were invited into the study. Liquidbased cervical cytology and HPV DNA tests were performed. Personal data were collected. MAIN OUTCOMES MEASURES: Rates of abnormal cytology and/ or highrisk HPV (HRHPV) and factors associated with abnormal test(s) were studied. RESULTS: Abnormal cytology and positive HRHPV were found in 6.3% (279/4442 women) and 6.7% (295/4428), respectively. The most common abnormal cytology was ASCUS (3.5%) while the most common HRHPV genotype was HPV 16 (1.4%) followed by HPV 52 (1.0%), HPV 58 (0.9%), and HPV 18 and HPV 51 at equal frequency (0.7%). Both tests were abnormal in 1.6% (71/4428 women). Rates of HRHPV detection were directly associated with severity of abnormal cytology: 5.4% among normal cytology and 13.0%, 30.8%, 40.0%, 39.5%, 56.3% and 100.0% among ASCUS, ASCH, AGCNOS, LSIL, HSIL, and SCC, respectively. Some 5% of women who had no HRHPV had abnormal cytology, in which 0.3% had >= HSIL. Factors associated with abnormal cytology or HRHPV were: age <=40 years, education lower than (for cytology) or higher than bachelor for HRHPV), history of sexual intercourse, and sexual partners >=2. CONCLUSIONS: Rates for abnormal cytology and HRHPV detection were 6.3% and 6.7% HRHPV detection was directly associated with severity of abnormal cytology. Significant associated factors were age <=40 years, lower education, history of sexual intercourse, and sexual partners >=2. PMID- 27509944 TI - Incidence and Management of Toxicity Associated with LAsparaginase in the Treatment of ALL and NK/TCell Lymphoma: an Observational Study. AB - BACKGROUND: Lasparaginase (ASNase) is commonly used in the treatment of acute lymphoblastic leukemia (ALL) and natural killer (NK)/Tcell lymphoma. This study was designed to describe the incidence of toxicity associated with ASNase in Asian adults. Secondary objectives were to investigate the management and impact of toxicity on subsequent ASNase use, and to compare the actual management against current recommendations. MATERIALS AND METHODS: In this retrospective, multicenter, observational study, Asian patients >= 18 years old who received >= 1 dose of the native E. coli ASNase from 2008 to 2013 were included. Patients were excluded if they did not receive ASNase. Endpoints of this study were development of specific toxicities, whether ASNase was discontinued or rechallenged, and developmentg of recurrent toxicity. All data analyses were performed using SPSS version 20.0. RESULTS: A total of 56 patients were analyzed. Mean (+/-SD) age was 36.2 (+/-15.2) years old, with 62.5% being males, 55.4% with ALL and 28.6% with NK/Tcell lymphoma. Hypersensitivity (12.5%) was associated with the highest incidence of toxicity (6 out of 7 patients had Grade 3 and 4 toxicity), followed by 10.7% for hepatic transaminitis, 3.6% for nonCNS thrombosis and 1.8% each for hyperbilirubinemia and pancreatitis. Hypersensitivity recurred in the 3 patients who were rechallenged with E. coli ASNase. CONCLUSIONS: ASNase is associated with a wide range of toxicities, with hypersensitivity being the most commonly observed among Asian adult patients. PMID- 27509945 TI - Utilization of Sunitinib for Renal Cell Cancer: an Egyptian University hospital experience. AB - BACKGROUND: Metastatic renal cell carcinoma (mRCC) status as poor prognosis improved with the introduction of tyrosinekinase inhibitors, especially sunitinib. There is sparse data reporting from our region on use of sunitinib in metastatic RCC. Thus the present study explores sunitinib usage at our institute. MATERIALS AND METHODS: An unselected population of patients with metastatic RCC receiving sunitinib was analyzed with respect to patient characteristics, response, toxicity, and outcomes. RESULTS: Fortynine patients with a median age of 50.5 years (range 2171 years) were included. Most were male (61.2%). Twentyone (42.9%) had metastatic disease at presentation. Sunitinib was first line therapy in 45. Conventional clear cell carcinoma was the most common pathology present (39 patients; 79.59 %). The most common site of metastasis was the lung (75.5%). Most patients (30) were started at a dose of 50 mg once a day for 4 weeks and then 2 weeks rest. Clinical benefit rate was 73.5% (n= 36), and 22.5% (n=11) demonstrated progressive disease at first imaging evaluation within the first 36 months. The following objective response performed for patients was 48.9% (n=24) and progression at 24.5 % (n=12). The median followup was 16 months (range, 434 months), the overall estimated median PFS was 9 months and the estimated median OS was 15 months. CONCLUSIONS: This study demonstrated sunitinib is tolerable and effective in advanced/metastatic RCC Egyptian patients and indicates we should further seek second and third lines to increase survival equivalence as reported in the worldwide literature. PMID- 27509946 TI - Prostate Cancer, High Cortisol Levels and Complex Hormonal Interaction. AB - Prostate cancer (PCa) is one of the most common diseases in men. It is important to assess prognostic factors and whether high cortisol levels and complex hormonal interactions could be responsible for PCa development. We evaluated the relationship between cortisol, leptin and estrogens in 141 men, 71 with PCa and the remaining 70 constituting a low risk group (LRG). They were recruited for this study from a total of 2906 middleaged men (ages 4570 years) who completed an evaluation for prostatic diseases at the Urology Division, Hospital de Clinicas "Jose de San Martin", University of Buenos Aires, in May 2009. In this cross sectional study, cortisol, PSA, totaltestosterone, freetestosterone, bioavailable testosterone, LH and estradiol were measured in serum. We observed increased cortisol levels in PCa patients as compared to LRG cases (p=0.004,). Leptin and estradiol levels were also higher in PCa patients (p=0.048; p<0.0001, respectively). Logistic regression analysis indicated that serum cortisol (OR: 1.110 (95% CI 1.0161.213), p=0.022), estradiol (OR: 1.044 (95% CI 1.0081.081), p=0.016) and leptin (OR: 1.248 (95% CI 1.0481.487), p=0.013) explained 27% of the variance of dependent variables, even after adjusting for age, smoking, BMI and waist circumference. We found increased cortisol levels in PCa patients as compared to LRG, as well as an altered circulating hormonal profile. PMID- 27509947 TI - Financial Burden of Cancer Drug Treatment in Lebanon. AB - BACKGROUND: The Ministry of Public Health (MOPH) in Lebanon provides cancer drugs free of charge for uninsured patients who account for more than half the total caseload. Other categories of cancer care are subsidized under more stringent eligibility criteria. MOPH's large database offers an excellent opportunity to analyze the cost of cancer treatment in Lebanon. MATERIALS AND METHODS: Using utilization and spending data accumulated at MOPH during 20082013, the cost to the public budget of cancer drugs was assessed per case and per drug type. RESULTS: The average annual cost of cancer drugs was 6,475$ per patient. Total cancer drug costs were highest for breast cancer, followed by chronic myeloid leukemia (CML), colorectal cancer, lung cancer, and NonHodgkin's lymphoma (NHL), which together represented 74% of total MOPH cancer drug expenditure. The annual average cancer drug cost per case was highest for CML ($31,037), followed by NHL ($11,566). Trastuzumab represented 26% and Imatinib 15% of total MOPH cancer drug expenditure over six years. CONCLUSIONS: Sustained increase in cancer drug cost threatens the sustainability of MOPH coverage, so crucial for socially vulnerable citizens. To enhance the bargaining position with pharmaceutical firms for drug cost containment in a small market like Lebanon, drug price comparisons with neighboring countries which have already obtained lower prices may succeed in lowering drug costs. PMID- 27509948 TI - Pioneering Annual Colorectal Cancer Screening and Treatment Targeting Low Income Communities in Malaysia (20102015). AB - The aim of this study was to assess the rate of uptake of a customised annual Colorectal Cancer Awareness, Screening and Treatment Project (CCASTP) using faecal immunohistochemical test (FIT) kits in low income communities in Malaysia. The immediate objectives were (1) to evaluate the level of adherence of CRC screening among lowincome groups, (2) to assess the knowledge and awareness of the screened population and (3) to assess the accuracy of FIT kits. A total of 1,581 FIT kits were distributed between years 2010 to 2015 to healthy asymptomatic participants of the annual CCASTP organized by Empowered the Cancer Advocacy Society of Malaysia. Data for sociodemographic characteristics, critical health and lifestyle information of the registered subjects were collected. Findings for use of the FIT kits were collected when they were returned for stool analyses. Those testingd positive were invited to undergo a colonoscopy examination. A total of 1,436 (90.8%) of the subjects retuned the FITkits, showing high compliance. Among the 129 subjects with positive FIT results, 92 (71.3%) underwent colonoscopy. Six cases (6.5%) of CRC were found. Based on the data collected, the level of awareness of stool examination and knowledge about CRC was poor amongst the participants. Gender, age group, ethnicity and risk factors (i.e. smoking, lack of exercise and low consumption of fresh fruits) were associated with positive FITkit results. In conclusion, CRC screening can be performed in the community with a single FITkit. Although CRC knowledge and awareness is poor in lowincome communities, the average return rate of the FIT kits and rate of colonoscopy examination were 91.2% and 70.3%, respectively. PMID- 27509949 TI - Applicability of Radioguided Occult Lesion Localization for NonPalpable Benign Breast Lesions, Comparison with Wire Localization, a Clinical Trial. AB - BACKGROUND: This study was designed to compare radioguided versus routine wire localization of non palpable nonmalignant breast lesions in terms of efficacy for complete excision, ease of use, time saving, and cosmetic outcome. MATERIALS AND METHODS: Patients with nonpalpable breast masses and nonmalignant core biopsy results who were candidates for complete surgical lumpectomy were enrolled and randomly assigned to radioguided or wire localization groups. Radiologic, surgical, and pathologic data were collected and analyzed to determine the difficulty and duration of each procedure, ease of use, accuracy, and cosmetic outcomes. RESULTS: This prospective randomized study included 60 patients, randomly divided into wire guided localization (WGL) or radioguided occult lesion localization (ROLL) groups. The mean duration of localization under ultrasound guidance was shorter in the ROLL group (14.4 min) than in the WGL group (16.5 min) (p<0.001). The ROLL method was significantly easier for radiologists (p=0.0001). The mean duration of the surgical procedure was 22.6 min (+/-10.3 min) for ROLL and 23.6 min (+/- 9.6 min) for WGL (p=0.6), a nonsignificant difference. Radiography of the surgical specimens showed 100% lesion excision with clear margins, as proved by pathologic examination, with both techniques. The surgical specimens were slightly heavier in the ROLL group, but the difference was not significant (p=0.06). CONCLUSIONS: The ROLL technique provides effective, fast, and simple localization and excision of nonpalpable nonmalignant breast lesions. PMID- 27509950 TI - High Risk Human Papilloma Virus Genotypes in Kurdistan Region in Patients with Vaginal Discharge. AB - BACKGROUND: The human papilloma virus (HPV) is considered as the major risk factor for the development of cervical cancer. This virus is of different genotypes and generally can be classified into high and low risk types. OBJECTIVE: To determine the rate of high risk HPV genotypes in women with vaginal discharge and lower abdominal pain in Kurdistan region, Iraq. MATERIALS AND METHODS: Cervical swabs were taken from 104 women. DNA was extracted and the polymerase chain reaction (PCR) technique was used to determine the presence of high risk genotypes. RESULTS: It was found that 13/104 (12.5%) of the samples were positive for high risk HPV genotypes. Amongst those who were positive, 4/13 (30.7%) were typed as genotype 16 and 7/13 (53.8%) showed mixed genotyping. On the other hand, genotypes 53 and 56 were found in only one sample each. CONCLUSIONS: High risk HPV genotypes are not uncommon and further community based study is needed to determine the prevalence of HPV and its genotypes and plan for prevention of infection. PMID- 27509951 TI - Skin Cancer: ClinicoPathological Study of 204 Patients in Southern Governorates of Yemen. AB - BACKGROUND: Skin cancer is a group of heterogeneous malignancies, in general classified into nonmelanoma skin cancer (NMSC) and melanoma skin cancer (MSC). Incidences are high in many parts in the world with considerable geographical and racial variation. In the Yemen, there has been scarce information about skin cancer. The aim of this study was to evaluate the demographic characteristics and histological trend of skin cancer in Southern Governorates of Yemen. MATERIALS AND METHODS: This retrospective study covered 204 cases of skin cancer at the Modern Histopathology Laboratory and Aden Cancer Registry and Research Center, Faculty of Medicine and Health Sciences, University of Aden, for the period 20062013. Data were classified regarding different demographic and tumor related variables and analyzed using CanReg4 for cancer registry and SPSS (version 21). RESULTS: The commonest encountered skin cancer was NMSC (93.1%). Generally, skin cancer appears slightly more frequently in females than males with a 1:1.06 male: female ratio, with a mean age of 62.9 years. Slightly higher than onethird (36.3%) were from Aden governorate. The head and neck proved to be the most common site in both males and females (58%). Basal cell carcinoma (BCC) is the most common histological type of skin cancer (50.5%). CONCLUSIONS: Skin cancer is a common cancer in patients living in southern governorates of Yemen. The pattern appears nearly similar to the international figures with a low incidence of MSC. PMID- 27509952 TI - Expression of the p16 and Ki67 in Cervical Squamous Intraepithelial Lesions and Cancer. AB - PURPOSE: To evaluate the expression of p16 and Ki67 in cervical intraepithelial neoplasia (CIN) and cancer. MATERIALS AND METHODS: We performed a immunohistochemical study of p16 and Ki67 in 243 cervical tissues 53 nondysplastic lesions, 106 CIN1, 61 CIN2/3 and 23 squamous cell carcinomas. The expression of p16 and Ki67 was interpreted independently by 2 researchers and the sensitivity and specificity to detect clinically significant lesions (>= CIN2) were determined. RESULTS: The overall agreement results of positive or negative immunostaining of intrainter observer variability were 0.659 for p16 and 0.808 for Ki67. p16 expression was demonstrated in 91.3% of invasive carcinomas, 78.7% of CIN2/3, 10.4% of CIN1 and 9.4% of nondysplasic lesions. The corresponding Ki67 expression was: 100% of all invasive carcinomas, 75.4% of CIN2/3, 22.6% of CIN1, and 11.3% with nondysplasia. The expression was significantly different between CIN2/3 vs CIN1 for both p16 and Ki67 (pvalues <0.001 both), and cancer vs CIN2/3 for Ki67 (pvalue 0.008). The differences were not significant between CIN1 vs nondysplasia (pvalues 1.000 for p16 and 0.130 of Ki67), and cancer vs CIN2/3 for p16 (p value 0.219). The sensitivity and specificity to detect > CIN2 were 84.5% and 90.5% by p16 and 82.1% and 88.6% by Ki67. CONCLUSIONS: The rates for 16 and Ki67 expression were directly associated with the severity of cervical lesions. Significant differences in these markers expression may be useful in cases with equivocal histologic features among cervical intraepithelial lesions, but not between CIN1 and nondysplastic lesions. The two markers had high sensitivity and specificity in determining >CIN2. PMID- 27509953 TI - Prevalent Signs and Symptoms in Patients with Skin Cancer and Nursing Diagnoses. AB - BACKGROUND: Skin cancer has a remarkable importance given the high incidence in the population. In Brazil, it is estimated that there were 98,420 new cases of nonmelanoma skin cancer among men and 83,710 new cases among women in 2014. OBJECTIVES: To verify signs and symptoms present in patients with skin neoplasms according to the literature and relate them to the nursing diagnoses of NANDA International. MATERIALS AND METHODS: Integrative literature review carried out from March to May 2015 in the databases: Cumulative Index to Nursing and Allied Health Literature, SCOPUS, National Library of Medicine and Nattional Institutes of Health, Latin American and Caribbean Sciences of Health and Web of Science. The descriptors used were: 'Signs and Symptoms' and 'Skin Neoplasms'. Sixteen articles were identified as the final sample. After review, the signs and symptoms of skin cancer identified in the literature were related to the defining characteristics present in NANDA International, with the aim to trace possible nursing diagnoses. RESULTS: The most prevalent signs and symptoms were: asymmetric and well circumscribed nodules with irregular borders; speckles with modified color aspect; ulcerations; blisters; pain; itching; and bleeding. The principal nursing diagnoses outlined were: risk for impaired skin integrity; impaired skin integrity; acute pain; risk of shock; and impaired comfort. CONCLUSIONS: The identification of signs and symptoms present in patients with skin cancer and the relationships of these with the nursing diagnoses of NANDA International provide a basis for qualified and systematized nursing care to this clientele. PMID- 27509954 TI - Methyl Donor Status Influences DNMT Expression and Global DNA Methylation in Cervical Cancer Cells. AB - BACKGROUND: Methyl donor status influences DNA stability and DNA methylation although little is known about effects on DNA methyltransferases. The aim of this study was to determine whether methyldonor status influences DNA methyltransferase (Dnmt) gene expression in cervical cancer cells, and if so, whether there are associated effects on global DNA methylation. MATERIALS AND METHODS: The human cervical cancer cell line, C4 II, was grown in complete medium and medium depleted of folate (FM+) and folate and methionine (FM). Growth rate, intracellular folate, intracellular methionine and homocysteine in the extracellular medium were measured to validate the cancer cell model of methyl donor depletion. Dnmt expression was measured by qRT PCR using relative quantification and global DNA methylation was measured using a flow cytometric method. RESULTS: Intracellular folate and methionine concentrations were significantly reduced after growth in depleted media. Growth rate was also reduced in response to methyl donor depletion. Extracellular homocysteine was raised compared with controls, indicating disturbance to the methyl cycle. Combined folate and methionine depletion led to a significant downregulation of Dnmt3a and Dnmt3b; this was associated with an 18% reduction in global DNA methylation compared with controls. Effects of folate and methionine depletion on Dnmt3a and 3b expression were reversed by transferring depleted cells to complete medium. CONCLUSIONS: Methyl donor status can evidently influence expression of Dnmts in cervical cancer cells, which is associated with DNA global hypomethylation. Effects on Dnmt expression are reversible, suggesting reversible modulating effects of dietary methyl donor intake on gene expression, which may be relevant for cancer progression. PMID- 27509955 TI - Bone Mineral Density and Breast Cancer Risk Factors among Premenopausal and Postmenopausal Women A Systematic Review. AB - BACKGROUND: Bone mineral density (BMD) is a lifetime marker of estrogen in a woman's body and has been associated with increased breast cancer risk. Nonetheless the actual association is still debatable. Furthermore, estrogen is very crucial in maintaining human bone density and gradually decreases over age. A systematic search was conducted to assess any association of BMD with breast cancer risk factors among premenopausal and postmenopausal women. MATERIALS AND METHODS: Review identification was performed through databases searching on MEDLINE, CINAHL and SCOPUS and 19 qualified studies were elected. The keywords used were "bone mineral density", "breast cancer", and "breast density". RESULTS: A total of 19 articles showed variation with the majority of the studies focused on postmenopausal and a few focused on premenopausal women. Overall there was no concensus on effects. CONCLUSIONS: An enormous effort is being undertaken by researchers to prove that BMD might be one of the significant risk factors for breast cancer. PMID- 27509956 TI - HealthCare Providers' and Parents' Perspectives on Complementary Alternative Medicine in Children with Cancer in Indonesia. AB - BACKGROUND: Complementary alternative medicine (CAM) use in children with cancer is widespread. Health care providers (HCP) need to acknowledge and address this need. This study explored and compared perspectives on CAM of HCP and parents of young patients with cancer in Indonesia. MATERIALS AND METHODS: We conducted a crosssectional study using semistructured questionnaires in HCP and parents of childhood cancer patients at an Indonesian academic hospital. RESULTS: A total of 351 respondents participated: 175 HCP (response rate 80%) and 176 parents (response rate 80%). Parents were more likely than HCP to think that chemotherapy can cure cancer (80% compared to 69%, P=0.013). Nearly half of all parents (46%) and HCP (45%) doubted whether CAM can cure cancer. Parents were more likely than HCP to think that CAM can be helpful in childhood cancer treatment (54% compared to 35%, P=0.003). The most recommended CAM by HCP was selfprayer (93%). Reasons for recommending CAM were: hope for improvement of the child's condition (48%), patient wants to stop treatment (42%). Most discouraged CAM by HCP was by oldsmart people (70%), the reasons being: lack of evidence for usefulness (77%), lack of CAM knowledge (75%). The proportion thinking that patients were unlikely to raise the CAM topic if they perceived that doctors were skeptical was higher in parents than in HCP (52% versus 1%) (P<0.001). Most HCP (71%) and parents (77%) acknowledged that their knowledge about safety and efficacy of CAM was inadequate (P=ns). The proportion that wanted to learn or read more about CAM was higher among parents than HCP (48% compared to 31%, P=0.002). CONCLUSIONS: HCP and parents have different perspectives on CAM use in children with cancer. HCP should enhance their CAM knowledge and encourage open communication about CAM with parents. If doctors' skepticism is perceived, parents are unlikely to raise CAM as a topic. PMID- 27509957 TI - Survival of Patients with Stomach Cancer and its Determinants in Kurdistan. AB - BACKGROUND: Stomach cancer is the fourth most common cancer and the second leading cause of death from cancer in the world. In Iran, this type of cancer has high rates of incidence and mortality. This study aimed to assess the survival rate of patients with stomach cancer and its determinants in Kurdistan, a province with one of the highest incidence rates of stomach cancer in the country. MATERIALS AND METHODS: We studied a total of 202 patients with stomach cancer who were admitted to Tohid Hospital in Sanandaj from 2009 to 2013. Using KaplanMeier nonparametric methods the survival rate of patients was calculated in terms of different levels of age at diagnosis, gender, education, residential area, occupation, underweight, and clinical variables including tumor histology, site of tumor, disease stage, and type of treatment. In addition, we compared the survival rates using the logrank test. Finally, Cox proportional hazards regression was applied using Stata 12 and R 3.1.0 software. The significance level was set at 0.05. RESULTS: The mean age at diagnosis was 64.7 +/- 12.0 years. The survival rate of patients with stomach cancer was 43.9% and 7% at the first and the fifth year after diagnosis, respectively. The results of logrank test showed significant relationships between survival and age at diagnosis, education, disease stage, type of treatment, and degree of being underweight (P<0.05). Moreover, according to the results of Cox proportional hazards regression model, the variables of education, disease stage, and type of treatment were associated with patient survival (P<0.05). CONCLUSIONS: The survival rate of patients with stomach cancer is low and the prognosis is very poor. Given the poor prognosis of the patients, it is critical to find ways for early diagnosis and facilitating timely access to effective treatment methods. PMID- 27509958 TI - EGFR Mutation Genotype Impact on the Efficacy of Pemetrexed in Patients with Nonsquamous Nonsmall Cell Lung Cancer. AB - BACKGROUND: Pemetrexed monotherapy has come to be recognized as one of the standard secondline therapies for advanced nonsquamous nonsmall cell lung cancer (NSCLC). However, there have been no reports of studies that have evaluated the efficacy of pemetrexed according to type of active EGFR mutation, i.e., an exon 19 deletion or an L858R point mutation. MATERIALS AND METHODS: The records of nonsquamous NSCLC patients harboring an EGFR mutation who received pemetrexed monotherapy as a second or later line of chemotherapy at Kitasato University Hospital between March 2010 and October 2015 were retrospectively reviewed, and the treatment outcomes were evaluated. RESULTS: The overall response rate and progressionfree survival time (PFS) of the 53 patients with nonsquamous NSCLC were 15.1% and 2.3 months, respectively. There were significant differences between the disease control rate (37.5% vs. 76.2%) and PFS time (1.8 months vs. 3.3 months) of the exon 19 deletion group and the L858R point mutation group, and a multivariate analysis identified type of EGFR mutation as well as performance status (PS) as independent predictors of PFS. CONCLUSIONS: The clinical data obtained in this study provided a valuable rationale for considering type of EGFR mutation as well as non squamous histology as predictors of the efficacy of pemetrexed monotherapy. PMID- 27509959 TI - Type 2 Diabetes Mellitus as a Risk Factor for Female Breast Cancer in the Population of Northern Pakistan. AB - BACKGROUND: There has been much research work in the past to ascertain the association between type 2 diabetes mellitus and breast cancer, but definitive evidence has been scanty. The present study was carried out to determine the association of type 2 diabetes mellitus with breast cancer in the female population of Northern Pakistan. MATERIALS AND METHODS: This casecontrol study was carried out in the Oncology Department of NORI Hospital. A total of 400 patients were included. Data were entered into PSPP 0.8.1. Twotailed significance tests were used and a pvalue of 0.05 was considered significant. RESULTS: There were a higher percentage of postmenopausal women in the diabetic breast cancer patients' group as compared to the nondiabetic subset. The odds ratio for the association between diabetes and risk of developing breast cancer was elevated with statistical significance (OR = 2.96; 95 % CI =1.36.3; pvalue=0.004). The results of our study showed that diabetes is associated with a risk of developing breast cancer, especially in postmenopausal women (OR = 4.928; 95 % CI = 2.111.3; pvalue=0.001). The association was particularly marked in obese subjects (OR = 31.49; 95 % CI = 1.8 536; p value=0.01), as compared to nonobese subjects (OR = 0.642; 95 % CI = 0.21.7). CONCLUSIONS: Diabetes is strongly associated with obesity and it tends to increase the risk of breast Cancer, especially in postmenopausal women. A highrisk subset for breast cancer comprised postmenopausal, diabetic and overweight women. PMID- 27509961 TI - Can We Rely on GLOBOCAN and GBD Cancer Estimates? Case Study of Lung Cancer Incidence and Mortality Rates and Trends in Iran. AB - BACKGROUND: Around half of input data in the global burden of disease cancer collaboration (GBDCC) and GLOBOCAN projects come from low quality sources, mainly from developing countries. This may lead to loss of precision in estimates. Our question was: Are the absolute values and trends of the GBDCC and GLOBOCAN estimates for lung cancer (LC) in Iran consistent with available statistics?. MATERIALS AND METHODS: Incidence and mortality statistics were extracted from national reports (N.IRs and N.MRs) and GBDCC (GBDincidence and mortality) and GLOBOCAN databases for 19902013 where available. Trends were analyzed and absolute values and annual percentage changes (APCs) were estimated and compared. Incompleteness of case ascertainment at the Iranian national cancer registry and Iranian national civil registration was assessed for better understanding. RESULTS: Trends of N.IRs were significantly rising for males (APC: 19.4; 95% CI: 12.526.7) and females (23.2; 16.030.8). Trends of GBDincidence were stable for males (0.2; 1.51.1) and females (1.0; 2.30.4). Absolute N.IRs were less than GBDincidence steadily except for 2009. Trend of N.MRs was increasing up to 2004, but stable thereafter. Trends of GBDmortality were also stable. Absolute N.MRs were less than GBDmortality for years up to 2003 and more than GBDmortality since 2005. The estimates of GLOBOCAN were more than N.IRs and N.MRs. CONCLUSIONS: The GBDCC and GLOBOCAN values for LC in Iran are underestimates. Generation of data quality indices to present along with country specific estimates is highly recommended. PMID- 27509960 TI - Suitable Food Textures for Videofluoroscopic Studies of Swallowing in Esophageal Cancer Cases to Prevent Aspiration Pneumonia. AB - AIMS: To determine suitable food textures for videofluoroscopic study of swallowing (VFSS), in order to predict and prevent subsequent aspiration pneumonia in esophageal cancer patients with dysphagia after surgery. MATERIALS AND METHODS: We evaluated 45 hospitalized esophageal cancer patients who underwent surgery between January 2012 and December 2013. The control group consisted of 43 patients treatmed from January 2010 until December 2011 and were not examined by VFSS. Test foods, which were presented in order of increasing thickness, included thin barium sulfate (Ba) liquid (3 or 10 ml), slightly thickened Ba liquid (3 or 10 ml), a spoonful of Ba jelly, and a spoonful of Ba puree. RESULTS: Patients could most safely swallow puree, followed by jelly. The 3mL samples of both the thin and thick liquids put patients at risk for aspiration pneumonia, with incidence rates of 13% and 11%, respectively. While 64.4% of patients could swallow all test foods and liquids safely, 35.6% were at risk for aspiration pneumonia when swallowing liquids. Even though >30% of patients were at risk, only 1 (2.2%) in the VFSS group developed aspiration pneumonia, which occurred at the time of admission. Following VFSS, no incidence of aspiration pneumonia was observed. However, aspiration pneumonia occurred in 4 (9.3%) control patients during hospitalization. CONCLUSIONS: Postoperative esophageal cancer patients were more likely to aspirate any kind of liquid than solid foods, such as jellies. VFSS is very useful in determining suitable food textures for postoperative esophageal cancer patients. PMID- 27509962 TI - Clinical Outcomes of Intracranial Nonvestibular Schwannomas Treated with LinacBased Stereotactic Radiosurgery and Radiotherapy. AB - BACKGROUND: Intracranial nonvestibular schwannomas arising from various cranial nerves excluding CN VIII are uncommon. Recently, stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) have been widely reported as effective treatment modalities for nonvestibular schwannomas. The purpose of this study was to study the long term clinical outcome for nonvestibular schwannomas treated with both XKnife and CyberKnife (CK) radiosurgery at one institution. MATERIALS AND METHODS: From 2004 to 2013, fiftytwo nonvestibular schwannoma patients were included in this study, 33 patients (63%) were treated with CK, and 19 (37%) were treated with XKnife. The majority of the tumors were jugular foramen schwannomas (38%) and trigeminal schwannomas (27%). HSRT was given for 45 patients (86%), whereas CSRT was for 6 (12%) and SRS for 1 (2%). RESULTS: The median pretreatment volume was 9.4 cm3 (range, 0.5752 cm3). With the median follow up time of 36 months (range, 3135), the 3 and 5 year progression free survival was 94 % and 88%, respectively. Tumor size was decreased in 13 (25%), stable in 29 (56%), and increased in 10 (19%). Among the latter, 3 (30%) required additional treatment because of neurologic deterioration. No patient was found to develop any new cranial nerve deficit after SRS/SRT. CONCLUSIONS: These data confirmed that SRS/ SRT provide high tumor control rates with low complications. Large volume tumors and cystic expansion after radiation should be carefully followed up with neurological examination and MRI, because it may frequently cause neurological deterioration requiring further surgery. PMID- 27509963 TI - Oxaliplatin, 5Fluorouracil and Leucovorin (FOLFOX4) as First Line Chemotherapy in Elderly Patients with Advanced Gastric Cancer. AB - BACKGROUND: Gastric cancer is considered the fourth most common cancer and second most common cause of cancerrelated mortalities worldwide. Gastric cancer develops more frequently among elderly. The oxaliplatin/5FU/leucovorin (FOLFOX) regimen has shown a notable activity against gastric cancer. AIM: To evaluate the responses and complications of FOLFOX4 regimen as first line chemotherapy in elderly patients with advanced gastric cancer. MATERIALS AND METHODS: From October 2014 to November 2015, a total of 21 patients with metastatic or local AGC (advanced gastric cancer) were analyzed. All patients were administered a FOLFOX4 regimen consisting of a 2h infusion of oxaliplatin 85 mg/m2 (day 1), continuous infusion of 1000mg/ m2 5Fu in 24h., and leucovorin 200 mg/m2 in 2h infusion as a firstline chemotherapy. RESULTS: A total of 18 patients were assessable for efficacy and toxicity. One of 18 patients achieved a complete response, and 12 had partial responses, giving an overall response rate of 72.6%. Three (16%) patients demonstrated stable disease and 2 (12%) progression. The median progression free survival was 7.3 months, and the median overall survival was 11.9 months. One patient had grade 3 neuropathy. No other grade 3 or 4 NCICTC were seen. CONCLUSIONS: The FOLFOX4 regimen used in our study was both active and acceptable for AGC in elderly patients as neoadjuvant and main therapy. PMID- 27509964 TI - Phytochemicals from Goniothalamus griffithii Induce Human Cancer Cell Apoptosis. AB - Bioactive compounds extracted from leaves and twigs of Goniothalamus griffithii include pinocembrin (PCN) and goniothalamin (GTN). The objectives of this study were to investigate the cytotoxic activities of PCN and GTN and their influence on molecular signaling for cell death in several human cancer cell lines compared to normal murine fibroblast NIH3T3 cells. GTN exhibited the most potent cytotoxicity against MCF7 > HeLa > HepG2 > NIH3T3 cells with IC50 values of 7.33, 14.8, 37.1 and 65.4 MUM, respectively, whereas PCN was cytotoxic only to HepG2 cells with IC50 values of ~80 MUM. Apoptotic cell death was confirmed by staining the cells with annexin VFITC and propidium iodide (PI) employing flow cytometry. Apoptosis was shown by externalization of phosphatidylserine in goniothalamintreated MCF7 cells in a dose response manner. Positive PIstained cells with the typical morphology of apoptotic cells were increased dosedependently. Furthermore, reduction of mitochondrial transmembrane potential was found in goniothalamintreated MCF7, HepG2 and HeLa cells. GTN treatment in MCF7 increased caspase3, 8 and 9 activities while GTNinduced HeLa cells showed an increase of both caspase3 and 9 activities. But an increased caspase8 activity was demonstrated in GTN and PCNtreated MCF7 and HepG2 cells, respectively. Taken together, GTN and PCNinduced human cancer cell apoptosis was through different molecular mechanisms or signaling pathways, which might be due to different machineries in different types of cancer cells, as evidenced by the compoundmodulated caspase activities in both intrinsic and/or extrinsic pathways. PMID- 27509965 TI - Induction of Human Hepatocellular Carcinoma HepG2 Cell Apoptosis by Naringin. AB - Naringin, a bioflavonoid found in Citrus seeds, inhibits proliferation of cancer cells. The objectives of this study were to investigate the mode and mechanism(s) of hepatocellular carcinoma HepG2 cell death induced by naringin. The cytotoxicity of naringin towards HepG2 cells proved dosedependent, measured by MTT assay. Naringintreated HepG2 cells underwent apoptosis also in a concentration related manner, determined by annexin Vfluorescein isothiocyanate (FITC) and propidium iodide (PI) employing flow cytometry. Mitochondrial transmembrane potential (MTP) measured using 3,3'dihexyloxacarbocyanine iodide (DiOC6) and flow cytometer was reduced concentrationdependently, which indicated influence on the mitochondrial signaling pathway. Caspase3, 8 and 9 activities were enhanced as evidenced by colorimetric detection of paranitroaniline tagged with a substrate for each caspase. Thus, the extrinsic and intrinsic pathways were linked in human naringintreated HepG2 cell apoptosis. The expression levels of proapoptotic Bax and Bak proteins were increased whereas that of the antiapoptotic BclxL protein was decreased, confirming the involvement of the mitochondrial pathway by immunoblotting. There was an increased expression of truncated Bid (tBid), which indicated caspase8 proteolysis activity in Bid cleavage as its substrate in the extrinsic pathway. In conclusion, naringin induces human hepatocellular carcinoma HepG2 cell apoptosis via mitochondriamediated activation of caspase9 and caspase8mediated proteolysis of Bid. Naringin anticancer activity warrants further investigation for application in medical treatment. PMID- 27509966 TI - MDM2 Expression in Serous and Mucinous Epithelial Tumours of the Ovary. AB - BACKGROUND: Different types of cancer exhibit abnormalities in cell cycle regulators. The murine double minute2(MDM2) cell cycle regulator is a protooncogene that negatively regulates the P53 tumour suppressor gene. Surface epithelial tumours constitute approximately two thirds of ovarian neoplasms. Each histologic type can be classified as benign, borderline and malignant. This study aimed to examine immunohistochemical expression of the MDM2 protein in ovarian serous and mucinous epithelial tumours (benign, borderline and malignant). MATERIALS AND METHODS: This study included forty five ovarian tumours, subdivided into fifteen cystadenomas (5 serous and 10 mucinous), fifteen borderline tumours (11 serous and 4 mucinous) and fifteen cystadenocarcinomas (9 serous and 6 mucinous). Paraffin sections were stained with haematoxylin and eosin for histopathologic study, and with mouse monoclonal antiMDM2 antibody for immunohistochemistry. RESULTS: MDM2 positivity was detected in 28.9% of the studied ovarian tumours. All benign tumours were negative and positivity was significantly higher in malignant than borderline tumours (P value of chisquare test =0.000). Significantly, all MDM2 positive mucinous tumours were malignant with no positive mucinous borderline tumours. Malignant tumours showed positive MDM2 expression in 83.3% of mucinous type and in 55.6% of serous type. Borderline serous tumours showed negative MDM2 in 72.7% of cases (P value of Z test =0.04). CONCLUSIONS: Alterations in the expression of the cell cycle regulator (MDM2) occur early in the process of tumourigenesis in serous and mucinous ovarian tumours. We suggest that MDM2 may be used in those tumours as a marker for risk stratification and identification of cases with cancer development and progression. We recommend further studies on MDM2 immunohistochemistry, in conjunction with adjuvant methods as DNA ploidy and FISH gene amplification, focusing on the mucinous tumours and differentiating between the three tumour categories, benign, borderline and malignant. PMID- 27509967 TI - Health Beliefs Associated with Cancer Screening Intentions in Korean Workers. AB - BACKGROUND: Cancer is a leading cause of death in Korea. To prevent cancer, it is essential to facilitate and promote appropriate cancer screening behavior in the adult population. The aim of this study was to examine health beliefs related to cancer screening intentions using the Health Belief Model (HBM). MATERIALS AND METHODS: The research participants comprised 275 male health and safety managers at commercial companies in Korea. The selfadministered survey explored demographic characteristics, cancerrelated factors, beliefs about cancer/cancer screening (BCCS) (vulnerability to cancer, severity of cancer, benefits of screening, and barriers to screening), and cancer screening intention. Multivariate logistic regression analyses were used to identify factors associated with an intention to be screened for cancer. RESULTS: Perceived health status and need for cancer prevention education were major factors associated with BCCS. Poorer health status was associated with greater perceived vulnerability, a perception of fewer benefits, and more barriers (p<0.05). A perceived greater need for cancer prevention education was associated with a higher perceived severity of cancer and more perceived barriers to screening (p<0.05). Marital status, cancer screening experience, and perceived vulnerability to cancer were significant influences on the cancer screening intention (p<0.05). Participants who had undergone cancer screening in the past 2 years were more likely to intend to be screened for cancer than were those who had not been screened; this was true across all degrees of intention and all types of cancer (p<0.01). Hesitant people considered themselves less vulnerable to gastric, lung, and liver cancer than did the poeple who intended to undergo cancer screening (p<0.05). CONCLUSIONS: Based on our findings, we recommend that workplace cancer prevention programs attempt to increase awareness about vulnerability to cancer among workers who hesitate to undergo cancer screening. PMID- 27509968 TI - Identification of a Novel Cassette Array in Integronbearing Helicobacter Pylori Strains Isolated from Iranian Patients. AB - Helicobacter pylori as the second most common cause of gastric cancer in the world infects approximately half of the developed countries population and 80% of the population living in developing countries. Integrons as genetic reservoirs play major roles in dissemination of antimicrobial resistance genes. To the best of our knowledge, this is the first study to report carriage of class 1 and 2 integrons and associated gene cassettes in H. pylori isolates from Iran. This crosssectional study was conducted in Tehran among 110 patients with H. pylori infection. Antimicrobial susceptibility testing (AST) for H. pylori strains were assessed by the micro broth dilution method. Class 1 and 2 integrons were detected using PCR. In order to determine gene cassettes, amplified fragments were subjected to DNA sequencing of both amplicon strands. The prevalence of resistance to clarithromycin, metronidazole, clarithromycin, tetracycline, amoxicillin, rifampin, and levofloxacin were 68.2% (n=75), 25.5% (n=28), 24.5% (n=27), 19.1% (n=21), 18.2% (n=20) and 16.4% (n=18), respectively. Frequency of multidrug resistance among H. pylori isolates was 12.7%. Class 2 integron was detected in 50 (45.5%) and class 1 integron in 10 (9.1%) H. pylori isolates. The most predominant gene cassette arrays in class 2 integron bearing H. pylori were included sateraaadA1, dfrA1sat2aadA1, blaoxa2 and, aadB whereas common gene cassette arrays in class 1 integron were aadBaadA1cmlA6, aacA4, blaoxa2, and catB3. The high frequency of class 2 integron and multidrug resistance in the present study should be considered as a warning for clinicians that continuous surveillance is necessary to prevent the further spread of resistant isolates. PMID- 27509969 TI - Comparison of Two Step LEEP and Cold Conisation For Cervical Intraepithelial Lesions to Decrease Positive Surgical Margins. AB - PURPOSE: To assess the success rates of two step loop electrosurgical excision procedure (LEEP) compared with conventional cold conization procedures for decreasing positive surgical margins. MATERIALS AND METHODS: This study was conducted on 70 patients who underwent colposcopic evaluation in Zeynep Kamil Women and Children's Health Training and Research Hospital between 20132015 with indications of CIN 2/3 or persistent CIN 1 for more than 2 years. The study included age matched groups of patients with similar histopathololical lesions who underwent cold conization (n=40) or LEEP (N=30). RESULTS: Comparison of tissue characteristics between the two groups revealed significantly higher deepest depth and lower volume of tissue removed by the two step LEEP. Ectocervical positivity rate was similar between groups (1/39 versus 0/29, P>0.05), while endocervical surgical margin positivity rate was significantly higher in the cold conization group (9/39 versus 0/29, P<0.05). Surgical margin positive cases were significantly older than the cases with negative margins (P<0.05). CONCLUSIONS: Two step LEEP made it easier to reach the squamocolumnar junction in the endocervical region with lower blood loss and applicability in office settings. Our study suggests to use two step approach in cases with high grade and glandular CIN. PMID- 27509970 TI - Androgen Receptor Expression and its Correlation with Other Risk Factors in Triple Negative Breast Cancers: a Report from Western Iran. AB - BACKGROUND: Androgen receptors (ARs) are expressed in more than 70% of breast cancers (BCs) and have been implicated in BC pathogenesis. Some triple negative (TN)BC tumors express AR and may benefit from ARtargeted therapies. The aim of this study was to evaluate survival and the prevalence of AR expression and its correlation with other risk factors in triple negative BCs in women from Western Iran. MATERIALS AND METHODS: In a retrospective study between 20092015, 41 patients with TNBC were referred to the Private Clinic of Oncology, Kermanshah city, Iran. ER, PR and ARpositive expression was defined as >=10% nuclear staining and also HER2 (2+), FISH was performed. Nuclear staining was considered representative for Ki67 and P53. The mean followup for the patients was 25 months. In this time, 5 patients died and 4 lost to followup were censored from survival analysis. RESULTS: The mean age at diagnosis was 46.9 years (range, 2471 years) and all patients were female. The OS rates for ARpositive and ARnegative patients were 90% and 85.1%, respectively, and the mean OS was 26.3 and 23.2 months. Therefore, there was no significant difference between the two groups (Hazard ratio: 0.580, 95% CI: 0.0863.893, P=0.575). CONCLUSIONS: In TNBC patients, evaluation of AR status may provide additional information on prognosis and treatment. The results of studies showed that the prevalence AR expression may differ in the world and probably ethnicity can be an influencing factor. PMID- 27509971 TI - Applicability of Oncoplastic Breast Conserving Surgery in Asian Breast Cancer Patients. AB - BACKGROUND: There are limited studies on oncoplastic breast conserving surgery in Asian women. We aimed to determine the applicability and safety of oncoplastic surgery, highlighting the specific circumstances when it will be most useful and compare our preferred technique with the worldwide practice of oncoplastic approaches. MATERIALS AND METHODS: Breast cancer patients who underwent oncoplastic breast conserving surgery at a single institution from 1st May 201431st March 2015 were included. Data on patient demographics, tumor characteristics and the type of oncoplastic surgery performed were collected. RESULTS: Nineteen breast cancer patients were identified. 42.1% of patients had grade I ptosis. The indications for surgery included a large tumor to breast size ratio (52.6%), multifocal/multicentric lesions (36.8%) and asymmetric breasts (10.6%), averting a mastectomy in 89.4%. Round block was the commonest technique in 63% of patients, in contrast to the inverted T pattern most frequently used in renowned institutions in the West. Mean and median tumor size and weight of specimen were 29.4/25mm (11 75mm) and 77g/64g (10 246g) respectively. Reexcision rate was 10.5%. Complete mastectomy was performed for one patient. One patient developed wound dehiscence which was treated conservatively. Cosmetic outcome was rated as excellent/good by 94.7% of patients. The patients remained clinically well after a median 16 months follow up. CONCLUSIONS: Oncoplastic breast conserving surgery is useful in a specific subgroup of Asian patients with a relatively small breast volume and minimal ptosis. Round block was the commonest technique in our series, in contrast to the worldwide utility of oncoplastic techniques. It is oncologically safe and has good cosmetic outcomes. PMID- 27509972 TI - TALENs Construction: Slowly but Surely. AB - Cancer is thought to be a direct result of transcriptional misregulation. Broad analysis of transcriptional regulatory elements in healthy and cancer cells is needed to understand cancer development. Nucleases regulatory domains are recruited to bind and manipulate a specific genomic locus with high efficacy and specificity. TALENs (transcription activatorlike effector nuclease) fused to endonuclease FokI have been used widely to target specific sequences to edit several genes in healthy and cancer cells. This approach is promising to target specific cancer genes and for this purpose it is needed to pack such TALENs into viral vectors. There are some considerations which control the success of this approach, targeting appropriate sequences with efficient construction of TALENs being crucial factors. We face some obstacles in construction of TALENs; in this study we made a modification to the method of Cermk et al 2011 and added one step to make it easier and increase the availability of constructs. PMID- 27509973 TI - Roles of CYP1A1 and CYP2E1 Gene Polymorphisms in Oral Submucous Fibrosis. AB - BACKGROUND: Oral submucous fibrosis (OSF) is a precancerous condition with a 4 to13% malignant transformation rate. Related to the habit of areca nut chewing it is mainly prevalent in Southeast Asian countries where the habit of betel quid chewing is frequently practised. On chewing, alkaloids and polyphenols are released which undergo nitrosation and give rise to Nnitrosamines which are cytotoxic agents. CYP450 is a microsomal enzyme group which metabolizes various endogenous and exogenous chemicals including those released by areca nut chewing. CYP1A1 plays a central role in metabolic activation of these xenobiotics, whereas CYP2E1 metabolizes nitrosamines and tannins. Polymorphisms in genes that code for these enzymes may alter their expression or function and may therefore affect an individuals susceptibility regarding OSF and oral cancer. The present study was therefore undertaken to investigate the association of polymorphisms in CYP1A1 m2 and CYP2E1 (RsaI/PstI) sites with risk of OSF among areca nut chewers in the Northern India population. A total of 95 histopathologically confirmed cases of OSF with history of areca nut chewing not less than 1 year and 80, age and sex matched controls without any clinical signs and symptoms of OSF with areca nut chewing habit not less than 1 year were enrolled. DNA was extracted from peripheral blood samples and polymorphisms were analyzed by PCRRFLP method. Gene polymorphism of CYP1A1 at NcoI site was observed to be significantly higher (p = 0.016) in cases of OSF when compared to controls. Association of CYP1A1 gene polymorphism at NcoI site and the risk of OSF (Odd's Ratio = 2.275) was also observed to be significant. However, no such association was observed for the CYP2E1 gene polymorphism (Odd's Ratio = 0.815). Our results suggest that the CYP1A1 gene polymorphism at the NcoI site confers an increased risk for OSF. PMID- 27509974 TI - Systematic Review of Smoking Initiation among Asian Adolescents, 20052015: Utilizing the Frameworks of Triadic Influence and Planned Behavior. AB - BACKGROUND: A recent WHO data report on mortality attributable to tobacco use including cigarette smoking indicated a very high burden of deaths in Asia and that people often initiate smoking as early as young adolescents. The objectives of this study were to systematically review peerreviewed articles on cigarette smoking initiation among Asian adolescents and to develop a conceptual model of factors influencing smoking initiation by integrating all relevant factors based on existing data. MATERIALS AND METHODS: Following a PRISMA guideline, a systematic review of articles published between 2005 and June 2015 was conducted using 5 databases on cigarette smoking initiation among adolescents (aged 1019 years) living in Asia. We summarized the main findings of each study according to our research questions and data that emerged during the data extraction process. Analysis and categorization were based on the TTI and TPB models and classification of factors extracted from the study, were as follows: personal factors, social factors, broader environmental factors, mediators, and intention to initiate smoking and smoking behavior. RESULTS: Of 1,227 identified studies, only 20 were included in this review. Our findings found that the mean age of cigarette smoking initiation ranged from 10 to 14 years and those who are more likely to initiate smoking are male, older adolescents, adolescents with low parental SES, individuals with low parental monitoring, low parental education level and having no discussion on smoking at home, those living in public housing and those exhibiting healthrisk behavior. Our study also revealed that the risk of smoking initiation increased when they are exposed to smokers, influenced by peers, exposed to tobacco advertisements, receive pocket money, have lack of knowledge about smoking, have poor school performance, have a family conflict and have psychological problems. The conceptual model developed demonstrated complex networks of factors influencing initiation. CONCLUSIONS: This systematic review presents various factors influencing smoking initiation of the Asian adolescents and provides a conceptual framework to further analyze factors. Future studies should have a standard measure of smoking initiation, should analyze interactions and the intensity of relationships between different factors or variables in the conceptual model. This will in turn consolidate the understanding of the different factors affecting smoking initiation and will help to improve interventions in this area. PMID- 27509975 TI - Ultrasonographic Features of Medullary Thyroid Carcinoma: Do they Correlate with Pre and PostOperative Calcitonin Levels? AB - PURPOSE: To correlate ultrasonographic (US) features of medullary thyroid carcinoma (MTC) with pre operative and postoperative calcitonin levels. MATERIALS AND METHODS: A total of 130 thyroid nodules diagnosed as MTC were evaluated. Two radiologists retrospectively evaluated preoperative US features according to size, shape, margin, echogenicity, type of calcification, and lymph node status. Postoperative clinical and imaging followup (mean duration 31.9 +/- 22.5 months) was performed for detection of tumor recurrence. US features, presence of LN metastasis, and tumor recurrence were compared between MTC nodules with and without elevated preoperative calcitonin (>100 pg/mL). Those with normalized and nonnormalized postoperative calcitonin levels groups were also compared. RESULTS: Common US features of MTCs were solid internal content (90.8%), irregular shape (44.6%), circumscribed margin (46.2%), and hypoechogenicity (56.2%). Comparing MTC nodules with and without elevated preoperative calcitonin levels, the size and shape of MTC nodule and lymph node metastasis showed statistical significance (p<0.05). Postoperative calcitonin normalization correlated with US features of tumor size (p=0.002), margin (p=0.034), shape (p<=0.001), and presence of calcification (p=0.046). Tumor recurrence and LN metastasis were more prevalent in patients without normalization of postoperative calcitonin than in those with normalization (p=0.001). CONCLUSIONS: Serum calcitonin measurement is helpful for early diagnosis and predicting prognosis. Postoperative calcitonin measurement is also important for postoperative US follow up, especially in cases with larger nodule size, presence of calcification, irregular shape, and irregular margin. PMID- 27509976 TI - Correlation of Hormone Receptor and HER2/neu Expression with Clinicopathologic Parameters in Primary Breast Tumors. AB - BACKGROUND: Breast cancer (BC) is a major health issue worldwide as well as in Pakistan. All women belonging to any race, ethnicity or lineage are in danger of developing breast cancer. Significant factors influencing the development of breast malignancies are the genetic background, environmental conditions, reproductive parameters, the consequences of female hormones both intrinsic and extrinsic, alteration of immune status, and biologic determinants. MATERIALS AND METHODS: Overall 150 biopsy proven patients were included in the study. Samples were submitted for histopathology and determination of estrogen and progesterone receptor expression and HER2/neu status. Associations with other characteristics like age, tumor stage, node involvement, histological grade were also studied. RESULTS: Mean age at presentation was 46.7 years. The majority had invasive ductal carcinoma, 100 (84.7%), and were in stage pT3, 54 (45.7%). Important relationships (P<0.05) were found among ER, PR positivity, and Her 2 neu overexpression. However, no noteworthy link was identified amongst ER, PR, Her 2 neu and tumor grade, stage, age, lymph node involvement except for the menopausal status. CONCLUSIONS: In summary, breast cancer patients featured an advanced stage of disease, more lymph node involvement, and moderately high grade tumors and with more estrogen, progesterone receptor and HER2 positive tumors. PMID- 27509977 TI - Combined Genotype Analyses of Precursor miRNA196a2 and 499a Variants with Hepatic and Renal Cancer Susceptibility a Preliminary Study. AB - MicroRNAs, a novel class of small noncoding RNAs, are key players in many cellular processes, including cell proliferation, differentiation, invasion and regeneration. Tissue and circulatory microRNAs could serve as useful clinical biomarkers and deregulated expression levels have been observed in various cancers. Gene variants may alter microRNA processing and maturation. Thus, we aimed to investigate the association of MIR196a2 rs11614913 (C/T), MIR499a rs3746444 (A/G) polymorphisms and their combination with cancer susceptibility in an Egyptian population. Sixty five renal cell carcinoma (RCC) and 60 hepatocellular carcinoma (HCC) patients and 150 controls were enrolled in the study. They were genotyped using realtime polymerase chain reaction technology. Both miR196a2*T and miR499a*G were associated with RCC risk, but only miR196a*T was associated with HCC development. Carriage of the homozygote combinations (MIR196a2*TT + MIR499a*AA) and (MIR196a2*CC + MIR499a*GG) was associated with 25 and 48 fold elevation of likelhood to develop RCC, respectively. The miR196a2 SNP was also linked with larger tumor size in RCC and advanced tumor stage in HCC. miR196a2 and miR499a combined genotypes were associated with RCC and HCC. Further functional analysis of SNPs is required to confirm relationships between genotypes and phenotypes. PMID- 27509978 TI - Clinical Features of Lung Cancer in Japanese Patients Aged Under 50. AB - The proportion of lung cancer patients under 50 years old is small at approximately 510%, but as with patients older than 50, the number is on the rise. Although lung cancer treatment strategies have undergone extensive transformation in recent years based on the presence or absence of oncogenic driver mutations, there are few reports regarding these mutations in the young or the relationship between clinical setting and prognosis. Therefore, we conducted a study of clinical features in 36 patients under the age of 50 who were diagnosed with primary lung cancer from October 2008 to November 2015. The 22 patients in stages I through III A underwent operations, and all 17 whose lung cancer were detected through screening were candidates for surgery. Gene analysis was conducted for 26 (72.2%); 10 (38.5%) were positive for EGFR gene mutations, and ALK gene translocation was present in 4 (15.4%). In stage IV patients, the median progression free survival (PFS) in the ALK translocation positive and negative patients was 518 days and 130 days, respectively, and the median overall survival (OS) was not reached and 280 days, respectively. A trend toward extended PFS (p=0.203) and OS (p=0.056) was observed in patients positive for ALK translocation. We must strive for early detection by increasing screening rates and evaluate oncogenic driver mutations important for prognosis of lung cancer in the young. PMID- 27509979 TI - Tumor Necrosis Factor Alpha 308 G/A Single Nucleotide Polymorphism and Susceptibility to Hepatocellular Carcinoma Via Hepatitis B Infection. AB - BACKGROUND: Hepatitis B virus (HBV) is a key factor for hepatocellular carcinoma (HCC). About 350 million people are affected by chronic infection which is related to the rapid development of liver diseases as well as hepatitis, cirrhosis and hepatocellular carcinoma. Expression of tumor necrosis factor alpha (TNFalpha) in the liver demonstrates a major genetic polymorphism which is involved in resistance or susceptibility to chronic HBV infection. MATERIALS AND METHODS: In this study, two populations were studied by the sequence specific primerpolymerase chain reaction (SSPPCR) method: HBV cases (n=409), who were HBSAg+, and healthy controls (n=483). RESULTS: The results shown that the frequency of TNFalpha 308 G/G genotype in healthy controls (47.2%) was significantly higher than in HBV infected patients (28%) (CI = 1.292.61, OR = 1.83, P = 0.0004). Also TNFalpha 308 A/A and A/G genotype frequencies in the healthy controls were 4.6% and 48.2% and in patient group were 19.5% and 52.5% (CI = 2.237.12, p: 0.0001, OR: 3.94) respectively. CONCLUSIONS: We found that among Iranian people TNFalpha 308A allele not only has the highest genotype frequency but also it has the highest frequency in the world population. In addition, TNFalpha308 G/G polymorphism was associated with HBV resistance, whereas TNFalpha308A (A/A or A/G) polymorphism appeared to associated with chronic HBV infection. These data suggested that among the Iranian population, the 308 G/G polymorphism of TNFalpha gene promoter region has the potential to influence the susceptibility to HBV infection and it may be responsible for viral antigen clearance. PMID- 27509980 TI - Efficacy of Using Sequential Primary Circulating Prostate Cell Detection for Initial Prostate Biopsy in Men Suspected of Prostate Cancer. AB - BACKGROUND: Sequential use of circulating prostate cell (CPC) detection has been reported to potentially decrease the number of unnecessary prostate biopsies in men suspected of prostate cancer. In order to determine the real world effectiveness of the test, we present a prospective study of men referred to two hospitals from primary care physicians, one using CPC detection to determine the necessity of prostate biopsy the other not doing so. MATERIALS AND METHODS: Men with a suspicion of prostate cancer because of elevated PSA >4.0ng/ml or abnormal DRE were referred to Hospitals A or B. In Hospital A all underwent 12 core TRUS biopsy, in Hospital B only men CPC (+), with mononuclear cells obtained by differential gel centrifugation identified using double immunomarking with antiPSA and antiP504S, were recommended to undergo TRUS biopsy. Biopsies were classifed as cancer or nocancer. Diagnostic yields were calculated, including the number of posible biopsies that could be avoided and the number of clinically significant cancers that would be missed. RESULTS: Totals of 649 men attended Hospital A, and 552 men attended Hospital B; there were no significant differences in age or serum PSA levels. In Hospital A, 228 (35.1%) men had prostate cancer detected, CPC detection had a sensitivity of 80.7%, a specificity of 88.6%, and a negative predictive value of 89.5%. Some 39/44 men CPC negative with a positive biopsy had low grade small volume tumors. In Hospital B, 316 (57.2%) underwent biopsy. There were no significant differences between populations in terms of CPC and biopsy results. The reduction in the number of biopsies was 40%. CONCLUSIONS: The use of sequential CPC testing in the real world gives a clear decision structure for patient management and can reduce the number of biopsies considerably. PMID- 27509981 TI - TLR1 Polymorphism Associations with Gastric Mucosa Morphologic Patterns on Magnifying NBI Endoscopy: a Prospective CrossSectional Study. AB - BACKGROUND: Helicobacter pylori is now recognized as a causative factor of chronic gastritis, gastroduodenal ulcers, gastric cancer and mucosaassociated lymphatic tissue lymphoma. Tolllike receptors are important bacterial receptors in gastric epithelial cell signaling transduction and play critical roles in gastric carcinogenesis. MATERIALS AND METHODS: A total of 400 patients undergoing esophagogastroduodenoscopy for investigation of chronic abdominal pain were genotyped for singlenucleotide polymorphisms (SNPs) in TLR1 (rs4833095) using TagMan SNPs genotyping assay by realtime PCR hybridization. Relationships with susceptibility to H. pylori infection and premalignant gastric mucosa morphological patterns, classified by magnifying NBI endoscopy, were investigated. RESULTS: The percentages of TLR1 rs4833095, CC homozygous, CT heterozygous and TT homozygous cases were 34, 46.5 and 19%, respectively. CC showed statistical differences between H. pylori positive and negative cases (P<0.001). CT and TT correlated with type 1 and type 2 gastric mucosal morphological patterns (P<0.01) whereas CC correlated with types 3 and 4 (P<0.01). CONCLUSIONS: This study demonstrated good correlation of TLR1 rs4833095 genotype with severity of inflammation in H. pylori infected gastric mucosa according to gastric mucosal morphologic patterns with magnifying NBI endoscopy. PMID- 27509982 TI - Probiotic Conjugated Linoleic Acid Mediated Apoptosis in Breast Cancer Cells by Downregulation of NFkappaB. AB - Conjugated linoleic acid, a functional lipid, produced from Lactobacillus plantarum (LPCLA), has been demonstrated to possess apoptotic activity. The antiproliferative and apoptotic potential of LPCLA was here evaluated in vitro using the MDAMB231 human breast cancer cell line as a model system. Proliferation of MDA MB231 cells was inhibited with increasing concentrations of LPCLA with altered morphological features like cell detachment, rounding of cells and oligonucleosomal fragmentation of DNA. Flow cytometry confirmed the apoptotic potential of LPCLA by ANNEXIN V/PI double staining. Furthermore, outcome results indicated that the apoptosis was mediated by downregulation of the NF?B pathway which in turn acted through proteasome degradation of I?Balpha, inhibition of p65 nuclear translocation, release of cytochromeC from mitochondria and finally overexpression of Bax protein. Thus, conjugated linoleic acid, a natural product derived from probiotics, could therefore be a possible potential chemotherapeutic agent due to its apoptotic activity against estrogen receptor negative breast cancer cells. PMID- 27509983 TI - Calpeptin Prevents Malignant Pleural Mesothelioma Cell Proliferation via the Angiopoietin1/Tie2 System. AB - Malignant pleural mesothelioma (MPM), an aggressive malignant tumor of mesothelial origin associated with asbestos exposure, shows a limited response to conventional chemotherapy and radiotherapy. Therefore, the overall survival of MPM patients remains very poor. Progress in the development of therapeutic strategies for MPM has been limited. We recently reported that the calpain inhibitor, calpeptin exerted inhibitory effects on pulmonary fibrosis by inhibiting the proliferation of lung fibroblasts. In the present study, we examined the preventive effects of calpeptin on the cell growth of MPM, the origin of which is mesenchymal cells, similar to lung fibroblasts. Calpeptin inhibited the proliferation of MPM cells, but not mesothelial cells. It also prevented 1) the expression of angiopoietin (Ang)1 and Tie2 mRNA in MPM cells, but not mesothelial cells and 2) the Ang1induced proliferation of MPM cells through an NFkB dependent pathway, which may be the mechanism underlying the preventive effects of calpeptin on the growth of MPM cells. These results suggest potential clinical use of calpeptin for the treatment of MPM. PMID- 27509984 TI - Expression of Epstein Barr Virus Encoded EBNA1 and LMP1 Oncoproteins in Nasopharyngeal Carcinomas from Northeast India. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC), a malignancy arising from the epithelial lining of the nasopharynx, is distinct from others cancers in terms of its epidemiologic features. It is rare in most parts of the world except for a few regions with populations of Mongoloid origin. OBJECTIVES: To study the expression pattern of Epstein Barr virus (EBV) encoded oncoproteins EBNA1 and LMP1 in different histological types of NPC and to correlate expression patterns with sex, age and histological types. MATERIALS AND METHODS: A total of 40 formalinfixed, paraffinembedded NPC biopsy samples and tissues from 20 healthy controls were collected to study the expression level of EBNA1 and LMP1 using immunohistochemistry. RESULTS: EBNA1 and LMP1 expression was found in 92.5% and 90% respectively, of the cases and none of the control specimens. The expression patterns of EBNA1 and LMP1 were determined to be statistically significant (p<0.05) when correlated with sex, age and histological distributions. Also immunohistochemistry was found to be a sensitive technique in the detection of EBV. CONCLUSIONS: The study reveals that the potent oncoproteins EBNA1 and LMP1 were over expressed in our population cohort. Our findings are to some extent inconsistent with earlier reports as our population showed a higher expression of both EBNA1 and LMP1 compared to other studies. PMID- 27509985 TI - Clinicopathological Features and Survival Rate of Colorectal Adenocarcinoma Patients with and without a KRAS Mutation: a FiveYear Study in Yazd, Iran. AB - BACKGROUND: By some estimates, colorectal carcinoma is the third most common cancer worldwide. The most appropriate method of treatment, especially of its metastatic form, is determined based on KRAS status. The present study was conducted on patients with colorectal cancer positive or neagtive for a KRAS mutation in terms of survival rate and the response to treatment. MATERIALS AND METHODS: Medical records of all cases with colorectal cancer hospitalized from 2010 to 2015 and with KRAS testing results were studied. Data such as gender, age, tumor (size, grade, location, stage), treatment type, KRAS status and survival were considered as variables. Survival analysis was performed using the KaplanMeier method and Logrank test. Statistical significance level was defined as P value <0.05. RESULTS: Out of 90 patients, 55 (61.2%) were male and 35(38.8%) were female with the age range of 2287 years. The overall disease specific survival was 53+/-3 (Mean +/- SE) months with 95%CI:4760, and there were statistically significant differences between the mean survival rate with tumor stage and the response to treatment (log rank test, PV=0.007 and PV=0.001) respectively. The risk of mortality was 2.02 times higher in patients with mutant KRAS compared to those with the wild type of the gene; however, this difference was not statistically significant (OR=2.016; 95%CI: 0.685.9; PV=0.197). CONCLUSIONS: In our study the overall 5year disease specific survival rate was low as compared to similar studies elsewhere. Significant correlations were found between survival time with treatment type and tumor stage. PMID- 27509986 TI - Cancer Patients Are at High Risk of Mortality if Presenting with Sepsis at an Emergency Department. AB - BACKGROUND: Sepsis is an emergency condition with high mortality and morbidity rate. There are limited data on the association of cancer as a risk factor for mortality in sepsis patients in the emergency department (ED). MATERIALS AND METHODS: This retrospective study was conducted at the ED, Faculty of Medicine, Ramathibodi Hospital, Bangkok, Thailand. The study period was between January 1st and December 31st, 2014. The inclusion criteria were as follows: adult patients over 15 years of age who presented at the ED with suspicion of sepsis, received treatment at the ED, and whose blood culture was found to be positive. Clinical data were recorded from medical records including the Mortality in Emergency Department Sepsis score (MEDS score). The primary outcome of this study was mortality at one month. Multivariate logistic regression analysis was used to identify independent factors associated with death. RESULTS: During the study period, there were 775 eligible patients. The two most common pathogens identified from blood cultures were Staphylococcus aureus (193 patients; 24.9%) and Escherichia coli (158 patients; 20.4%). At one month after presenting at the ED, 110 patients (14.2%) had died. There were four significant factors for death, having cancer, being on an endotracheal tube, initial diagnosis of bacteremia, and high MED scores. Having cancer had an adjusted OR of 2.12 (95% CI of 1.29, 3.47). CONCLUSIONS: Cancer patients have double the risk of mortality if presenting with sepsis at the ED. PMID- 27509987 TI - Severe Manifestations and Grave Prognosis in Young Patients with Gastric Cancer in Thailand. AB - BACKGROUND: Gastric cancer is the second leading cause of cancer death worldwide and occurs most frequently in the age group of 5070 years. Rarely reports have appeared regarding younger age groups. The purpose of this study was to compare clinical characteristics and outcome of treatment between young and elderly patients with gastric cancer in Thailand. MATERIALS AND METHODS: Clinical information, histological features, endoscopic findings and treatment outcome were reviewed and collected from Thammasat University Hospital, Pathumthani and Bangkok Medical Center, Bangkok, Thailand between September 2011March 2015. RESULTS: A total of 154 gastric tumor patients including 101 with benign tumors (22 males and 79 females, mean age= 62.6 years) and 53 with gastric cancers (27 males and 26 females, mean age= 60.6 years) were enrolled in this study. Gastric cancer patients presented with alarm symptoms such as anemia, anorexia and weight loss significantly more frequently than benign gastric tumor patients. In gastric cancer patients, mean duration of symptoms prior to diagnosis was shorter in younger (<40 years) than older patients (age >=40 years) (73.3 days vs 84.8 days). Family history of GI malignancy and diffuse type of gastric cancer were significant greater in younger than older patients (36% vs 5% P=0.01; OR= 11.4, 95%CI = 1.874.7 and 73% vs 14%, P<0.01; OR= 16, 95%CI = 3.378, respectively) and 5year survival rates were 9% in younger age patients and 19% in older age group. CONCLUSIONS: Most young patients with gastric cancer in Thailand feature aggressive manifestations with poorer prognosis than elderly patients. Early detection of gastric cancer in high risk young patients might be important key to improve survival rate and treatment outcome in this particular group. PMID- 27509988 TI - Expression Levels of Tetraspanin KAI1/CD82 in Breast Cancers in North Indian Females. AB - BACKGROUND: Carcinogenesis is a multifaceted intricate cellular mechanism of transformation of the normal functions of a cell into neoplastic alterations. Metastasis may result in failure of conventional treatment and death Hence, research on metastatic suppressors in cancer is a high priority. The metastatic suppressor gene CD82, also known as KAI1, is a member of the transmembrane 4 superfamily which was first identified in carcinoma of prostate. Little work has been done on this gene in breast cancer. Herein, we aimed to determine the gene and protein level expression of CD82/KAI1 in breast cancer and its role as a prognosticator. MATERIALS AND METHODS: In this study, 83 histologically proven cases of breast cancer and a similar number of controls were included. Patient age ranged from 1870 years. Quantitative Real Time Polymerase Chain Reaction (qRT PCR) and immunohistochemistry (IHC) were used to investigate KAI1 expression at gene and protein levels, respectively. Statistical analysis was done to correlate expression of KAI1 and clinicopathological parameters. RESULTS: It was revealed that: (i) KAI1 was remarkably diminished in metastatic vs non metastatic breast cancer both at the gene and the protein levels (P<.05); (ii) KAI1 expression levels were strongly correlated with TNM staging, histological grade and advanced stage (p<0.001) and no association was found with any other studied parameter; (iii) Lastly, a significant correlation was observed between expression of KAI1 and overall median survival of BC patients (P = 0.04). CONCLUSIONS: Our results suggest that lack of expression of the KAI1 might indicate a more aggressive form of breast cancer. Loss of KAI1 may be considered a significant prognostic marker in predicting metastatic manifestation. When evaluated along with the clinical and pathological factors, KAI1 expression may be beneficial to tailor aggressive therapeutic strategies for such patients. PMID- 27509990 TI - Risk Factors for Gallbladder Cancer in Nepal a Case Control Study. AB - BACKGROUND: Gall bladder cancer (GBC) is highly fatal disease with poor prognosis, with a 5 year survival rate of <10%. It is relatively rare cancer worldwide; however it is the sixth cancer and second most common gastrointestinal tract cancer in Nepalese women. The study focused on associations of certain demographic, lifestyle, dietary, and reproductive factors with gall bladder cancer. MATERIALS AND METHODS: We conducted a hospitalbased matched case control study on newly diagnosed cases of primary GBC at BP Koirala Institute of Health Sciences and BP Koirala Memorial Cancer Hospital. Controls were healthy nonGBC relatives of cancer patients, matched for age, sex and marital status (in case of females) with cases at a ratio of 1:2. Data were collected between April 2012April 2013 by semi structured interview from both cases and controls. Analyses were carried out with SPSS. Conditional logistic regression was used to find odds ratios and 95% confidence intervals for bivariate and multivariate analysis. RESULTS: A total of 50 cases and 100 controls were enrolled in this study. On bivariate analysis, factors found to be significantly associated with gallbladder cancer were illiteracy (OR= 3.29, CI= 1.0610.2), history of gallstone disease (OR=27.6, CI=6.57, 115.6), current smoker (OR=2.42, CI=1.005 5.86), early menarche <13 years (OR=2.64, CI=1.096.44), high parity more than 3 (OR=3.12, CI=1.25,7.72), and use of mustard oil (OR=3.63, CI=1.40, 9.40). A significant protective effect was seen with high consumption of fruits at least once a week (OR=0.101, CI=0.030.35). On multivariate analysis, history of gallstone disease, early menarche, current smoker and high consumption of fruits persisted as significant factors. CONCLUSIONS: History of gallstone disease, cigarette smoking and early menarche were associated with increased risk of gallbladder cancer while high consumption of fruits was found to have a protective effect. PMID- 27509989 TI - Roles of MicroRNA21 and MicroRNA29a in Regulating Cell Adhesion Related Genes in Bone Metastasis Secondary to Prostate Cancer. AB - BACKGROUND: There is an increasing concern in the role of microRNA (miRNA) in the pathogenesis of bone metastasis (BM) secondary to prostate cancer (CaP). In this exploratory study, we hypothesized that the expression of vinculin (VCL) and chemokine X3C ligand 1 (CX3CL1) might be downregulated in clinical samples, most likely due to the posttranscriptional modification by microRNAs. Targeted genes would be upregulated upon transfection of the bone metastatic prostate cancer cell line, PC3, with specific microRNA inhibitors. MATERIALS AND METHODS: MicroRNA software predicted that miR21 targets VCL while miR29a targets CX3CL1. Twenty benign prostatic hyperplasia (BPH) and 16 high grade CaP formalinfixed paraffin embedded (FFPE) specimens were analysed. From the bone scan results, high grade CaP samples were further classified into CaP with no BM and CaP with BM. Transient transfection with respective microRNA inhibitors was done in both RWPE1 (normal) and PC3 cell lines. QPCR was performed in all FFPE samples and transfected cell lines to measure VCL and CX3CL1 levels. RESULTS: QPCR confirmed that VCL messenger RNA (mRNA) was significantly down regulated while CX3CL1 was upregulated in all FFPE specimens. Transient transfection with microRNA inhibitors in PC3 cells followed by qPCR of the targeted genes showed that VCL mRNA was significantly up regulated while CX3CL1 mRNA was significantly downregulated compared to the RWPE1 case. CONCLUSIONS: The downregulation of VCL in FFPE specimens is most likely regulated by miR21 based on the in vitro evidence but the exact mechanism of how miR21 can regulate VCL is unclear. Upregulated in CaP, CX3CL1 was found not regulated by miR29a. More microRNA screening is required to understand the regulation of this chemokine in CaP with bone metastasis. Understanding miRNAmRNA interactions may provide additional knowledge for individualized study of cancers. PMID- 27509991 TI - AgeStandardized Incidence Rates and Survival of Osteosarcoma in Northern Thailand. AB - Osteosarcoma is a common primary malignant bone tumor in children and adolescents. Recent worldwide average incidences of osteosarcoma in people aged 0 to 24 years were 4.3 and 3.4 per million, respectively, with a ratio of 1.4:1. However, data on the incidence of osteosarcoma in Thailand are limited. This study analyzed the incidence of osteosarcoma in the upper northern region of Thailand, with a population of 5.85 million people (8.9% of the total Thai population), using data for the years 1998 to 2012, obtained from the Chiang Mai Cancer Registry (CMCR) at Chiang Mai University Hospital and the Lampang Cancer Registry (LCR) at the Lampang Cancer Hospital, a total of 144 cases. The overall annual incidence of osteosarcoma was 1.67 per million with a male:female ratio of 1.36:1. Incidences by age group (male and female) at 0 to 24, 25 to 59 and over 60 years were 3.5 (3.9 and 3.0), 0.8 (0.9 and 0.6), and 0.7 (0.8 and 0.5), respectively. The peak incidence occurred at 15 to 19 years for males and at 10 to 14 years for females. The median survival time was 18 months with a 5year survival rate of 43%. Neither the age group nor the 5year interval period of treatment was significantly correlated with survival during the 15year period studied. PMID- 27509992 TI - Challenges in the Management of Breast Cancer in a Low Resource Setting in South East Asia. AB - BACKGROUND: Breast cancer is the second most common cancer in women in Cambodia, a low income country in SouthEast Asia. The Sihanouk Hospital Centre of Hope (SHCH) is a charity hospital set up by an international nongovernmental organisation, HOPE Worldwide. In 2008, SHCH partnered with AmeriCares, a global health organisation to set up and deliver a breast cancer programme to provide education, diagnosis and treatment for women with breast cancer. The objective of this study is to characterise the presentation, diagnosis, treatment and outcomes of women treated under this program. MATERIALS AND METHODS: A total of 215 women newly diagnosed with breast cancer from 1 March 2008 until 31 March 2011 were studied. Age at diagnosis, tumour size, histological type, tumour grade, ER, lymph node involvement, treatment modalities (surgery, radiotherapy, chemotherapy, hormone therapy) were recorded. Data on mortality at 3 years were obtained whenever possible. RESULTS: The median age was 47 years old. Some 77.8% were diagnosed with stage 3 and 4 lesions, and 78.5% underwent mastectomy, of which 28.4% the intent was palliative. Of those whose ER status were known, only 48.3% were ER positive. Only 6 patients could afford chemotherapy while only 1 patient had radiotherapy. Hormone therapy was provided free for those who were ER positive. The overall survival rate at 3 years was 39.1%. CONCLUSIONS: Breast cancer presents at a late stage, and because treatment is suboptimal, survival is poor in Cambodia. A more aggressive approach to early detection and treatment needs to be developed to improve outcome from this potentially curable disease. PMID- 27509994 TI - Global Sex Differences in Cancer Mortality with Age and Country Specific Characteristics. AB - BACKGROUND: The cancer research literature suggests that women, especially premenopausal women, have lower cancer mortality rates than men. However, it is unclear if that is true for populations at all age levels in all countries and what factors affect such sex differences. This paper attempts to fill that gap. MATERIALS AND METHODS: Sex and countryspecific cancer mortality data were statistically analyzed with particular attention to geographic, social, and economic factors that may affect the sex differences. RESULTS: The sex differences were age and country specific, rather than universal. Premenopausal women actually tend to have a disadvantage compared to men or postmenopausal women. Male cancer mortality appears to be the affecting factor in explaining variations in sex differences. Latitude of residence and literacy rate are the affecting factors in cancer mortality and sex differences. African and Latin American countries tend to have a female disadvantage, while East Asian and Eastern European countries are more likely to have a female advantage. CONCLUSIONS: The findings challenge the cancer mortality literature and indicate that the sex differences and their possible causes are more complicated than the current literature suggests. They also highlight the urgency of adapting age and country specific health systems and policies to better meet the needs of younger women. PMID- 27509993 TI - Significantly Low Effective Dose from 18FDG PET/CT Scans Using Dose Reducing Strategies: "Lesser is Better". AB - BACKGROUND: Fluorodeoxyglucose (18FDG) PET/CT imaging has become an important component of the management paradigm in oncology. However, the significant imparted radiation exposure is a matter of growing concern especially in younger populations who have better odds of survival. The aim of this study was to estimate the effective dose received by patients having whole body 18FFDG PET/CT scanning as per recent dose reducing guidelines at a tertiary care hospital. MATERIALS AND METHODS: This prospective study covered 63 patients with different cancers who were referred for PET/CT study for various indications. Patients were prepared as per departmental protocol and 18FDG was injected at 3 MBq/Kg and a low dose, nonenhanced CT protocol (LD NECT) was used. Diagnostic CT studies of specific regions were subsequently performed if required. Effective dose imparted by 18FDG (internal exposure) was calculated by using multiplying injected dose in MBq with coefficient 1.9?102 mSv/MBq according to ICRP publication 106. Effective dose imparted by CT was calculated by multiplying DLP (mGy.cm) with ICRP conversion coefficient "k" 0.015 [mSv / (mG. cm)]. RESULTS: Mean age of patients was 49 +/-18 years with a male to female ratio of 35:28 (56%:44%). Median dose of 18FDG given was 194 MBq (range: 139293). Median CTDIvol was 3.25 (2.46.2) and median DLP was 334.95 (246.70 576.70). Estimated median effective dose imparted by 18FDG was 3.69 mSv (range: 2.855.57). Similarly the estimated median effective dose by low dose (nondiagnostic) CT examination was 4.93 mSv (range: 2.14 10.49). Median total effective dose by whole body 18FDG PET plus low dose nondiagnostic CT study was 8.85 mSv (range: 5.5613.00). CONCLUSIONS: We conclude that the median effective dose from a whole body 18FDG PET/CT in our patients was significantly low. We suggest adhering to recently published dose reducing strategies, use of ToF scanner with CT dose reducing option to achieve the lower if not the lowest effective dose. This would certainly reduce the risk of second primary malignancy in younger patients with higher odds of cure from first primary cancer. PMID- 27509995 TI - Gene Expression of CYP1A1 and its Possible Clinical Application in Thyroid Cancer Cases. AB - BACKGROUND: Thyroid cancer is the most common endocrine malignancy, and exact causes remain unknown. The role of CYP450 1A1 (CYP1A1) in cancer initiation and progression has been investigated. The aim of this work was to analyze, for the first time, CYP1A1 gene expression and its relationship with several clinicopathological factors in Mexican patients diagnosed with thyroid cancer. MATERIALS AND METHODS: Realtime PCR analysis was conducted on 32 sets of thyroid tumors and benign pathologies. Expression levels were tested for correlations with clinical and pathological data. All statistical analysis were performed using GraphPad Prism version 3.0 software. RESULTS: We found that female gender was associated with thyroid cancer risk (P<0.05). A positive relationship was identified between CYP1A1 mRNA levels and the presence of chronic disease, alcohol use, tumor size, metastasis and an advanced clinical stage (P<0.05). CONCLUSIONS: The results suggest that CYP1A1 gene expression could be used as a marker for thyroid cancer. PMID- 27509996 TI - Reasons and Motivations for Cigarette Smoking and Barriers against Quitting Among a Sample of Young People in Jeddah, Saudi Arabia. AB - BACKGROUND: Cigarette smoking is one of the leading causes of death in the world. Tobacco consumption has grave negative consequences for health so that it is important to understand the reasons and motivations towards cigarette smoking and barriers against quitting smoking among the young generation for developing effective policies to control this widespread problem. MATERIALS AND METHODS: This crosssectional survey was carried out at the Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, Saudi Arabia. A total of 438 young smokers participated from the University and the general population. Data were collected through anonymous, selfadministered questionnaires in the Arabic language that contained questions about the reasons and motivations towards cigarette smoking and barriers against quitting smoking. The questionnaire also contained several questions regarding knowledge and attitude of the participants towards cigarette smoking. The data was analyzed on SPSS16. RESULTS: The mean age of the respondents was 22.9+/-3.48, out of 438 subjects 87 (19.9%) were married, and 351 (80.1%) were unmarried, and 331 (75.6%) belonged to urban areas while 107 (24.5%) were from the rural areas. Responding to a question about a number of cigarettes smoked per day, 31% answered 1120, 29% answered 2130, and 25% answered 110. Questioned about smokers in the family, 34.5% responded more than one, with 19% for brother and 13% for father. About the reasons for not quitting smoking, 26% described lack of willpower, 25% had no reason, 22% said that people around me smoke, and 15.3% responded stress at home/work. The major motivation for smokers was smoker friends (42%), for 33.8% others, for 12% father/brother and 7.8% media. CONCLUSIONS: There are several avoidable and preventable reasons and barriers against quitting smoking. However, knowledge and attitude about smoking were good, and the majority of the smokers were well aware of the associated hazards. Therefore, there is a need to search out ways and means to help them to quit this addiction. PMID- 27509997 TI - SelfSampling Versus Physicians' Sampling for Cervical Cancer Screening Agreement of Cytological Diagnoses. AB - BACKGROUND: A major problem with cervical cancer screening in countries which have no organized national screening program for cervical cancer is suboptimal participation. Implementation of selfsampling method may increase the coverage. OBJECTIVE: We determined the agreement of cytological diagnoses made on samples collected by women themselves (selfsampling) versus samples collected by physicians (Physician sampling). MATERIALS AND METHODS: We invited women volunteers to undergo two procedures; cervical selfsampling using the Evalyn brush and physician sampling using a Cervex brush. The women were shown a video presentation on how to take their own cervical samples before the procedure. The samples taken by physicians were taken as per routine testing (Gold Standard). All samples were subjected to Thin Prep monolayer smears. The diagnoses made were according to the Bethesda classification. The results from these two sampling methods were analysed and compared. RESULTS: A total of 367 women were recruited into the study, ranging from 22 to 65 years age. There was a significant good agreement of the cytological diagnoses made on the samples from the two sampling methods with the Kappa value of 0.568 (p=0.040). Using the cytological smears taken by physicians as the gold standard, the sensitivity of selfsampling was 71.9% (95% CI:70.972.8), the specificity was 86.6% (95% CI:85.7 87.5), the positive predictive value was 74.2% (95% CI:73.375.1) and the negative predictive value was 85.1% (95% CI: 84.286.0). Selfsampling smears (22.9%) allowed detection of microorganisms better than physicians samples (18.5%). CONCLUSIONS: This study shows that samples taken by women themselves (selfsampling) and physicians have good diagnostic agreement. Selfsampling could be the method of choice in countries in which the coverage of women attending clinics for screening for cervical cancer is poor. PMID- 27509998 TI - Maximum Diameter of Intracranial Metastatic Lesions as a Prognostic Factor in Patients Following Whole Brain Radiotherapy. AB - PURPOSE: To evaluate whetehr maximum diameter of intracranial metastatic lesions may be a prognostic factor in intracranial metastatic patients receiving whole brain radiotherapy. MATERIALS AND METHODS: The records of 114 cases who between January 2005 and December 2007 were retrospectively reviewed. There were 85 who met the inclusion criteria. RESULTS: In these 85, the oneyear overall survival rate was 16.5% and the median survival time was 125 days. Median survival in relation to recursive partitioning analysis (RPA) classes I, II and III were 216, 133 and 85 days. Logrank tests of initial prognostic factors were significant for RPA classifications, Karnofsky Performance Status(KPS), maximum diameters of intracranial metastatic lesions and presence of necrotic centers. The median survivals with a maximum diameter of the largest intracranial metastatic lesion <3cm and >=3cm were 162 days and 104 days (p=0.027). Multivariate analysis also showed a statistical significance for maximum diameter of intracranial metastatic lesions and presence of necrotic centers. CONCLUSIONS: Maximum diameters of intracranial metastatic lesions could be used as a prognostic factor in patients receiving whole brain radiotherapy and may help radiation oncologists to make decisions on treatment plans. PMID- 27509999 TI - Lack of an Apparent Association between Mycotoxin Concentrations in Red Chili Peppers and Incidence of Gallbladder Cancer in India : an Ecological Study. AB - Our recent studies conducted in South America have shown that mycotoxin contamination of red chili peppers (RCPs) may be associated with an increased risk of gallbladder cancer (GBC). Whether this relationship exists in India, a country with a high incidence of GBC and high consumption of RCPs, is unclear. We therefore measured concentrations of aflatoxins (AFs) and ochratoxin A (OTA) in RCPs from areas of low, medium, and high incidence of GBC in India, and compared these concentrations with GBC incidence in each area. Twentyone RCP samples were collected from nine cities (eight from a lowincidence area, five from a mediumincidence area, and eight from a highincidence area). Concentrations of AFs and OTA were measured using highperformance liquid chromatography. No significant differences in mean concentrations of AFs and OTA were found in the three areas. AFB1 levels in the lowincidence area (10.81 ?g/kg) and highincidence area (12.00 ?g/kg) were more than 2.2 and 2.4 times higher compared with the maximum permitted level of AFB1 in spices (5.0 ?g/kg) set by the Commission of the European Communities, or that (4.4 ?g/kg) obtained in our previous study in Chile. Our results show that the mean concentrations of mycotoxins in RCPs are similar among the three areas in India with different incidences of GBC. Further studies with human subjects are needed to evaluate any association between AFB1 and GBC. PMID- 27510000 TI - Effects of Application of Social Marketing Theory and the Health Belief Model in Promoting Cervical Cancer Screening among Targeted Women in Sisaket Province, Thailand. AB - Cervical cancer is a major public health problem in Thailand, being ranked second only to breast cancer. Thai women have been reported to have a low rate of cervical cancer screening (27.7% of the 80% goal of WHO). We therefore aimed to apply the social marketing theory and health belief model in promoting cervical cancer screening in Kanthararom District, Sisaket Province. A total of 92 from 974 targeted women aged 3060 years were randomly divided into two groups. The experimental group underwent application of social marketing theory and a health belief model program promoting cervical cancer screening while the control group received normal services. Two research tools were used: (1) application of social marketing theory and health belief model program and (2) questionnaire used to evaluate perceptions of cervical cancer. Descriptive and inferential statistics including paired sample ttest and independent ttest were used to analyze the data. After the program had been used, the mean score of perception of cervical cancer of experimental group was at a higher level (x=4.09; S.D. =0.30), than in the control group (x=3.82; S.D. =0.20) with statistical significance (p<0.001). This research demonstrated an appropriate communication process in behavioral modification to prevent cervical cancer. It can be recommended that this program featuring social marketing and the health belief model be used to promote cervical cancer screening in targeted women and it can be promoted as a guideline for other health services, especially in health promotion and disease prevention. PMID- 27510001 TI - Outcomes of Preoperative Chemoradiotherapy and Combined Chemotherapy with Radiotherapy Without Surgery for Locally Advanced Rectal Cancer. AB - PURPOSE: To evaluate the treatment outcomes of patients with locally advanced rectal cancer treated with preoperative concurrent chemoradiotherapy (CCRT) or combined chemotherapy together with radiotherapy (CMTRT) without surgery. MATERIALS AND METHODS: A total of 84 patients with locally advanced rectal adenocarcinoma (stage II or III) between January 1st, 2003 and December 31st, 2013 were enrolled, 48 treated with preoperative CCRT (Gr.I) and 36 with combined chemotherapy and radiotherapy (CMTRT) without surgery (Gr.II). The chemotherapeutic agents used concurrent with radiotherapy were either 5fluorouracil short infusion plus leucovorin and/or capecitabine or 5fluorouracil infusion alone. All patients received pelvic irradiation. RESULTS: There were 5 patients (10.4%) with a complete pathological response. The 3 yearoverall survival rates were 83.2% in Gr.I and 24.8 % in Gr.II (p<0.01). The respective 5 yearoverall survival rates were 70.3% and 0% (p<0.01). The 5 yearoverall survival rates in Gr.I for patients who received surgery within 56 days after complete CCRT as compared to more than 56 days were 69.5% and 65.1% (p=0.91). Preoperative CCRT used for 12 of 30 patients in Gr.I (40%) with lower rectal cancer demonstrated that in preoperative CCRT a sphincter sparing procedure can be performed. CONCLUSIONS: The results of treatment with preoperative CCRT for locally advanced rectal cancer showed comparable rates of overall survival and sphincter sparing procedures as compared to previous studies. PMID- 27510002 TI - Trends in Survival of Childhood Cancers in a University Hospital, Northeast Thailand, 19932012. AB - BACKGROUND: In Thailand, a national treatment protocol for childhood leukemia and lymphoma (LL) was implemented in 2006. Access to treatment has also improved with the National Health Security system. Since these innovations, survival of childhood LL has not been fully described. MATERIALS AND METHODS: Trends and survival of children under 15 with childhood cancers diagnosed between 1993 and 2012 were investigated using the hospitalbased data from the Khon Kaen Cancer Registry, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand. Childhood cancers were classified into 12 diagnostic groups, according to the ICCC based on the histology of the cancer. Survival rates were described by period, depending on the treatment protocol. For leukemias and lymphomas, survival was assessed for 3 periods (199399, 20005, 200612) while for solid tumors it was for 2 periods (before and after 2000). The impacts of sex, age, use of the national protocol, and catchment area on leukemia and lymphoma were evaluated. Overall survival was calculated using the KaplanMeier method while the Cox proportional hazard model was used for multivariate analysis. Trends were calculated using the R program. RESULTS: A total of 2,343 childhood cancer cases were included. Survival for acute lymphoblastic leukemia (ALL) from 19939, 20005, and 200612 improved significantly (43.7%, 64.6%, and 69.9%). This was to a lesser extent true for acute nonlymphoblastic leukemia (ANLL) (28.1%, 42.0%, and 42.2%). Survival of nonHodgkin lymphoma (NHL) also improved significantly (44%, 65.5%, and 86.8%) but not for Hodgkin disease (HD) (30.1%, 66.1%, and 70.6%). According to multivariate analysis, significant risk factors associated with poor survival in the ALL group were age under 1 and over 10 years, while not using the national protocol had hazard ratios (HR) of 1.6, 1.3, and 2.3 respectively. In NHL, only nonuse of national protocols was a risk factor (HR 3.9). In ANLL and HD, none of the factors influenced survival. Survival of solid tumors (liver tumors, retinoblastomas) were significantly increased compared to after and before 2000 while survival for CNS tumors, neuroblastoma and bone tumors was not changed. CONCLUSIONS: The survival of childhood cancer in Thailand has markedly improved. Since implementation of national protocols, this is particularly the case for ALL and NHL. These results may be generalizable for the whole country. PMID- 27510003 TI - Digital Breast Tomosynthesis in Addition to Conventional 2DMammography Reduces Recall Rates and is CostEffective. AB - Digital breast tomosynthesis (DBT) as a breast cancer screening modality, through generation of three dimensional images during standard mammographic compression, can reduce interference from breast tissue overlap, increasing conspicuity of invasive cancers while concomitantly reducing falsepositive results. We here conducted a systematic review on previous studies to synthesize the evidence of DBT efficacy, eventually 18 articles being included in the analysis. The most commonly emerging topics were advantages of DBT screening tool in terms of recall rates, cancer detection rates and costeffectiveness, preventing unnecessary burdens on women and the healthcare system. Further research is needed to evaluate the potential impact of DBT on longerterm outcomes, such as interval cancer rates and mortality, to better understand the broader clinical and economic implications of its adoption. PMID- 27510004 TI - Lack of Effects of Recombinant Human Bone Morphogenetic Protein2 on Angiogenesis in Oral Squamous Cell Carcinoma Induced in the Syrian hamster Cheek Pouch. AB - Recombinant human bone morphogenetic protein2 (rhBMP2 ), a member of the TGF? family, has been used widely in recent years to regenerate defects of the maxillary and mandible bones. Such defects are sometimes caused by resection of oral squamous cell carcinoma (OSCC) yet the biologic effects of rhBMP2 on these carcinomas are not fully clear. The objective of this study was to determine histologically whether rhBMP2 produces adverse effects on angiogenesis during induction of OSCC, a biologic process critical for tumor formation in an experimental model in the buccal pouch of golden Syrian hamsters. Buccal cavities were exposed to painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks, then biopsies were taken. Division was into 2 groups: a study group of 10 hamsters receiving 0.25?g/ml of rhBMP2 in the 3rd and 6th weeks; and a control group of 10 hamsters which did not receive any additional treatment. VEGF expression and microvessel density were measured but no differences were noted between the two groups. According to this study, rhBMP2 does not stimulate angiogenesis during induction of OCSSs. PMID- 27510005 TI - Smoking Initiation and Continuation A Qualitative Study among Bruneian Male Adolescents. AB - BACKGROUND: Cigarette smoking is one of the leading global causes of premature and preventable death. In Brunei Darussalam, smokingrelated diseases have been a primary cause of mortality for the past three decades. Despite the increasing efforts that have been made in recent years to reduce the consumption of tobacco products in Brunei, the prevalence of adolescent smoking cigarette, however has risen alarmingly, from 8.9% in 2013 to 11.4% in 2014, with a higher prevalence found in males (17.8%) than in females (4.8%). In response to the need for more effective smoking prevention programmes in Brunei, this study sought to explore factors that influence Bruneian male adolescents to start and continue smoking. MATERIALS AND METHODS: A qualitative study using focus group discussions (FGDs) as the data collection method was conducted from October to November 2015. A total of 43 studentss, comprising 31 smokers and 12 nonsmokers, aged 1317 years, from two government secondary schools in Bandar Seri Begawan, participated in six FGDs. Discussions were recorded and translated. Transcripts were entered into NVivo10, before thematic analysis was conducted. RESULTS: We identified three themes under the core construct of 'factors influencing smoking initiation' ('family as teachers', 'overt pressure from peers' and 'perceived smoking has many advantages') and three themes under the core construct of 'factors influencing smoking continuation' ('craving and addiction', 'smoking as a 'social activity' and 'easy accessibility of cigarettes'). CONCLUSIONS: Based on the findings, it is recommended that future prevention activities should be embedded in a comprehensive approach, involving all stakeholders within a community, and should be focused towards bringing a change in smoking and parenting behavior of parents, social norms within the culture towards all population levels, and at strengthening the existing nonsmoking policies in schools and other public places where young people congregate. PMID- 27510006 TI - Comparing Survival of Oral Cancer Patients Before and After Launching of the Universal Coverage Scheme in Thailand. AB - BACKGROUND: As the treatment modalities for oral cancer have been relatively consistent during the last two decades, this study was conducted to compare survivals of oral cancer patients in Khon Kaen Province before and after the universal coverage scheme (UC) was launched in Thailand. MATERIALS AND METHODS: The data were retrieved from the populationbased cancer registry of Khon Kaen for oral cancer patients diagnosed during 19922001 (preUC), and 20042012 (postUC). To compare survival of the two cohorts, Kaplan Meier and log rank tests were employed. RESULTS: Of 1,196 patients, 65% were females and the median age was 65 years. The most common primary sites were lip (31.0%), tongue (29.9%), and buccal mucosa (14.6%). The proportion of early stage cancer increased from 20.4 % in preUC to 41.3% in postUC. The overall 5year survival rate was 36.5% (95% CI =32.640.9) for preUC and 32.4% (95% CI = 28.836.4) for postUC. The declining survival was mainly due to an increasing proportion of tongue cancer. However, no survival improvement was demonstrated on subgroup analysis of the tongue cancer patients. CONCLUSIONS: After the universal coverage scheme had been launched, early diagnosis increased, but no significant gain in survival for oral cancer patients was achieved. PMID- 27510007 TI - Risk Factors for Upper and Lower Urinary Tract Cancer Death in a Japanese Population: Findings from the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). AB - BACKGROUND: The incidence of bladder cancer is lower in Asian than in Western countries. However, the crude incidence and mortality of bladder cancer have recently increased in Japan because of the increased number of senior citizens. We have already reported risk factors for urothelial cancer in a large populationbased cohort study in Japan (JACC study). However, we did not evaluate the cancer risk in the upper and lower urinary tract separately in our previous study. MATERIALS AND METHODS: Here we evaluated the risk of cancer death in the upper and lower urinary tracts, separately, using the database of the JACC study. The analytic cohort included 46,395 males and 64,190 females aged 40 to 79 years old. The Cox proportional hazard model was used to determine hazard ratios and their 95% confidence intervals. RESULTS: Current smoking increased the risk of both upper and lower urinary tract cancer deaths. A history of kidney disease was associated with an increased risk of bladder cancer death, even after controlling for age, sex and smoking status. CONCLUSIONS: The present study confirmed that current smoking increases the risk of both upper and lower urinary tract cancer deaths and indicated the possibility that a history of kidney disease may be a risk factor for bladder cancer death in the Japanese population. PMID- 27510008 TI - Unpolished Thai Rice Prevents Aberrant Crypt Foci Formation through the Invovement of ?catenin and COX2 Expression in AzoxymethaneTreated Rats. AB - Colorectal cancer (CRC) is a major cause of morbidity and mortality throughout the world, with chronic inflammation and diet as major causes in its development. Chemopreventive effects of natural dietary products have been the focus of studies for prevention over the past decade. This study was conducted to determine the effects of unpolished Thai rice during precancerous stage through the involvement of ?catenin, cyclooxygenase2 (COX2) expression and inflammatory cytokines focusing on azoxymethane (AOM)induced aberrant crypt foci (ACF)related to CRC. Male Sprague Dawley rats received two injections of AOM (15 mg/kg body weight) at weeks 4 and 5 while rats were treated with 20% or 70% unpolished Thai rice. The rats were sacrificed at week 38 and the colons removed for aberrant crypt foci (ACF) identification. Histopathologic changes, immunohistochemical analysis of ?catenin and COX2 expression, and cytokine expression of proinflammatory and antiinflammatory markers were determined. The administration of unpolished Thai rice significantly and dose dependently decreased the total number of ACF and the percentages of ACF with highgrade dysplasia. Interestingly, unpolished Thai rice suppressed the expression of betacatenin and COX2. In addition, it also altered proinflammatory (IL6 and IFNgamma) and antiinflammatory (IL 10) markers. The results suggested that unpolished Thai rice may provide a promising dietary intake for prevention during precancerous stage of CRC development, through the involvement of betacatenin and COX2 expression, and also modulate inflammatory cytokinesrelated to CRC. PMID- 27510009 TI - In Vitro Studies on Phytochemical Content, Antioxidant, Anticancer, Immunomodulatory, and Antigenotoxic Activities of Lemon, Grapefruit, and Mandarin Citrus Peels. AB - BACKGROUND: In recent years, there has been considerable research on recycling of agroindustrial waste for production of bioactive compounds. The food processing industry produces large amounts of citrus peels that may be an inexpensive source of useful agents. OBJECTIVE: The present work aimed to explore the phytochemical content, antioxidant, anticancer, antiproliferation, and antigenotxic activities of lemon, grapefruit, and mandarin peels. MATERIALS AND METHODS: Peels were extracted using 98% ethanol and the three crude extracts were assessed for their total polyphenol content (TPC), total flavonoid content (TFC), and antioxidant activity using DPPH (1, 1diphenyl2picrylhydrazyl). Their cytotoxic and mitogenic proliferation activities were also studied in human leukemia HL60 cells and mouse splenocytes by CCK8 assay. In addition, genotoxic/ antigenotoxic activity was explored in mouse splenocytes using chromosomal aberrations (CAs) assay. RESULTS: Lemon peels had the highest of TPC followed by grapefruit and mandarin. In contrast, mandarin peels contained the highest of TFC followed by lemon and grapefruit peels. Among the extracts, lemon peel possessed the strongest antioxidant activity as indicated by the highest DPPH radical scavenging, the lowest effective concentration 50% (EC50= 42.97 ?g extract/ mL), and the highest Trolox equivalent antioxidant capacity (TEAC=0.157). Mandarin peel exhibited moderate cytotoxic activity (IC50 = 77.8 ?g/mL) against HL60 cells, whereas grapefruit and lemon peels were ineffective antileukemia. Further, citrus peels possessed immunostimulation activity via augmentation of proliferation of mouse splenocytes (Tlymphocytes). Citrus extracts exerted noncytotoxic, and antigenotoxic activities through remarkable reduction of CAs induced by cisplatin in mouse splenocytes for 24 h. CONCLUSIONS: The phytochemical constituents of the citrus peels may exert biological activities including anticancer, immunostimulation and antigenotoxic potential. PMID- 27510010 TI - Diagnosis of Hepatocellular Carcinoma Using C11 Choline PET/CT: Comparison with F18 FDG, ContrastEnhanced MRI and MDCT. AB - PURPOSE: The aim of this study was to compare C11 choline and F18 FDG PET/CT, gadoxeticenhanced 3T MRI and contrastenhanced CT for diagnosis of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Twelve chronic hepatitis B patients suspected of having HCC by abdominal ultrasonography received all diagnostic modalities performed within a oneweek timeslot. PET/CT results were analyzed visually by two independent nuclear medicine physicians and quantitatively by tumor to background ratio (T/B). Nine patients then had histopathological confirmation. RESULTS: Six patients had well differentiated HCC, while two and one patient(s) were noted with moderately and poorly differentiated HCC, respectively. All were detected by both CT and MRI with an average tumor size of 5.7+/-3.8 cm. Five patients had positive C11 choline and F18 FDG uptake. Of the remaining four patients, three with well differentiated HCC showed negative FFDG uptake (one of which showed negative results by both tracers) and one patient with moderately differentiated HCC demonstrated no C11 choline uptake despite intense F18 FDG avidity. The overall HCC detection rates with C11 choline and F18 FDG were 78% and 67%, respectively, while the sensitivity of F18 FDG for nonwell differentiated HCC was 100%, compared with 83% of C11 choline. The average T/B of C11 choline in welldifferentiated HCC patients was higher than in moderately and poorly differentiated cases (p=0.5) and vice versa with statistical significance for T/B of F18 FDG (p = 0.02). CONCLUSIONS: Our results suggested better detection rate in C11 choline for well differentiated HCC than F18 FDG PET. However, the overall detection rate of PET/CT with both tracers could not compare with contrastenhanced CT and MRI. PMID- 27510011 TI - Survival Analysis and Prognostic Factors for Colorectal Cancer Patients in Malaysia. AB - BACKGROUND: Cancer survival analysis is an essential indicator for effective early detection and improvements in cancer treatment. This study was undertaken to document colorectal cancer survival and associated prognostic factors in Malaysians. MATERIALS AND METHODS: All data were retrieved from the National Cancer Patient Registry Colorectal Cancer. Only cases with confirmed diagnosis through histology between the year 2008 and 2009 were included. Retrieved data include sociodemographic information, pathological features and treatment received. Survival curves were plotted using the KaplanMeier method. Univariate analysis of all variables was then made using the Logrank test. All significant factors that influenced survival of patients were further analysed in a multivariate analysis using Cox' regression. RESULTS: Total of 1,214 patients were included in the study. The overall 3 and 5year survival rates were 59.1% and 48.7%, respectively. Patients with localized tumours had better prognosis compared to those with advanced stage cancer. In univariate analysis, staging at diagnosis (p<0.001), primary tumour size (p<0.001), involvement of lymph nodes (p<0.001) and treatment modalities (p=0.001) were found to be predictors of survival. None of the sociodemographic characteristics were found to exert any influence. In Cox regression analysis, staging at diagnosis (p<0.001), primary tumour size (p<0.001), involvement of lymph nodes (p<0.001) and treatment modalities (p<0.001) were determined as independent prognostic factors of survival after adjusted for age, gender and ethnicity. CONCLUSIONS: The overall survival rate for colorectal cancer patients in Malaysia is similar to those in other Asian countries, with staging at diagnosis, primary tumor size, involvement of lymph node and treatment modalities having significant effects. More efforts are needed to improve national survival rates in future. PMID- 27510012 TI - Investigating Sexual Function and Affecting Factors in Women with Breast Cancer in Iran. AB - BACKGROUND: Since the breast is strongly relevant to sexual desire, and physical and sexual attractiveness, the high prevalence of breast cancer (BC) in Iran and longterm survival of patients experiencing side effects means that measures to identify associated sexual problems are necessary. Therefore, this study was conducted to assess sexual function and affecting factors in women with BC. MATERIALS AND METHODS: This crosssectional study was performed on 94 women with BC, referred to Imam Reza (AS) Hospital, Mashhad, Iran, in 2014. The data were collected through demographic and clinical questionnaires and also a sexual function questionnaire and analyzed using SPSS version 16. RESULTS: The total score of women's sexual function was about 24.3+/-4.41. Of the total, 63 (71.3%) reported sexual dysfunction, for example reduced satisfaction or more pain. Age was the only significantly related factor. CONCLUSIONS: Breast cancer can adversely affect women's sexual function and decrease quality of life. Thus, taking measures to overcome women's sexual problems are necessary. PMID- 27510013 TI - Risk Factors for Breast Cancer in Postmenopausal Women in Brazil. AB - PURPOSE: To analyze risk factors for postmenopausal breast cancer. METHODS: The present casecontrol study included 600 women treated at a cancer center reference hospital in a municipality in the South of Brazil. RESULTS: Totals of 100 patients and 500 control subjects were evaluated. The mean age of the women was 52.5 +/- 11.9 years; the average was 57.4 +/- 11.8 years, and the average age of the control subjects was 51.5 +/- 11.7 years. The risk factors for breast cancer that were considered included an age >= 40 years, postmenopausal status, a body mass index (BMI) >= 30 kg/m2, and reduced physical activity. Variables like postmenopausal status and an obese BMI were associated with cases of breast cancer. Women who were postmenopausal or obese were 3.80 or 1.80 times more likely to develop breast cancer, respectively, and physically inactive women were 1.72 times more likely to develop breast cancer. CONCLUSIONS: Obesity and postmenopausal status are associated with the occurrence of breast cancer in this population. Being over 40 years of age was also a statistically significant factor for postmenopausal women. PMID- 27510014 TI - Correlation of Preoperative Ki67 and Serum CA15.3 Levels with Outcome in Early Breast Cancers a Multi Institutional Study. AB - BACKGROUND: To investigate the association between preoperative pathological Ki67 labeling index and serum tumor marker cancer antigen 153 (CA 153) with clinicpathological parameters and treatment outcomes in early breast cancer. MATERIALS AND METHODS: A retrospective study at 4 cancer centers in Saudi Arabia and Egypt was performed. Data were collected for female patients diagnosed with unilateral early breast cancer between March 2010 and October 2013. Cases treated with neoadjuvant chemotherapy (NACT) followed by surgery and radiotherapy were included. NACT included 68 cycles of anthracycline and taxane based regimens. Trastuzumab and hormonal treatments were added according to HER2 and hormone receptor status. Baseline serum CA15.3 and pathological Ki67 levels were evaluated and correlated with disease free survival (DFS) and overall survival (OS). RESULTS: A total of 280 pts was included. The median age was 49 years (3866 y) and median overall survival was 35 (2038) months (mo). Estrogen receptors (ER), progesterone receptors (PR) and HER 2 receptors were positive in 233 (83.2%), 198 (70%) and 65 cases (23.2%), respectively. High preoperative Ki67 and CA15.3 were noted in 177 (63.2%) and 131 (46.8%). A total of 45 (16%) patients had distal or local recurrence and 24 (8.6%) died of their disease. Most of the relapsed cases had high preoperative Ki67 (n=41, 91%) and CA15.3 (n=28, 62%) values. All of the patients who died had a high Ki67 but CA15.3 was high in 9 (37%) only. Mean DFS/OS in patients with high preoperative Ki67 was 32 months /32 months as compared to 37 months/35 months in those with normal Ki67 (p<0.001). Correlation of preoperative CA15.3 and survival was statistically not significant. CONCLUSIONS: Preoperative Ki67 can be a predictive and prognostic marker. Higher levels are associated with poor DFS and OS in patients with early BC. PMID- 27510015 TI - Decreased Serum Monocyte Chemoattractant Protein1 in Salivary Gland Tumor Patients. AB - BACKGROUND: The monocyte chemoattractant protein1 (MCP1/CCL2) is a potent chemoattractant for natural killer cells, monocytes, and memory T lymphocytes. However, any role in the genesis of salivary gland tumors (SGT) is unknown. To assess the diagnostic relevance of chemokines in SGT, MCP1 levels in the serum of patients were investigated in association with tumor progression and clinical aggressiveness. MATERIALS AND METHODS: Using an ELISA kit, we assessed and compared the circulating levels of MCP1 in blood serum of 70 SGT patients with 44 healthy control samples. RESULTS: The results of this study showed that the concentration of MCP1 was significantly lower in patients with benign (463.8+/ 158.5pg/ml, P=0.033) and malignant (454.8+/-190.4pg/ ml, P=0.007) SGT than in healthy subjects (645.7+/-338.9). No significant difference in mean serum levels of MCP1 was observed between the benign and malignant group (p=0.9). While MCP1 levels were lower in patients with an advanced clinical stage, advanced tumor size, higher tumor grade, or lymph node involvement, but the mean MCP1 level between groups showed no statistically significant difference (p>0.05). CONCLUSIONS: MCP1 levels in the serum of patients with SGT were decreased, indicating that this might a good marker for discriminating patients with SGT from healthy people. However, no clearcut relationship was detected between MCP1 levels and clinicopathologic factors, and MCP1 is not a good marker for evaluating tumor dissemination. PMID- 27510016 TI - Comparison of Expression Signature of Histone Deacetylases (HDACs) in Mesenchymal Stem Cells from Multiple Myeloma and Normal Donors. AB - BACKGROUND: Histone acetylation in chromatin structures plays a key role in regulation of gene transcription and is strictly controlled by histone acetyltransferase (HAT) and deacetylase (HDAC) activities. HDAC deregulation has been reported in several cancers. MATERIALS AND METHODS: The expression of 10 HDACs (including HDAC class I and II) was studied by quantitative reverse transcriptionPCR (qRTPCR) in a cohort of mesenchymal stem cells (MMMSCs) from 10 multiple myeloma patients with a median age 60y. The results were compared with those obtained for normal donors. Then, a coculture system was performed between MMMSCs and u266 cell line, in the presence or absence of sodium butyrate (NaBT), to understand the effects of HDAC inhibitors (HDACi) in MMMSCs on multiple myeloma cases. Also, the interleukin6 (IL6) and vascular endothelial growth factor (VEGFA) gene expression level and apoptotic effects were investigated in MMMSCs patients and control group following NaBT treatment. RESULTS: The results indicated that upregulated (HDACs) and downregulated (IL6 and VEGFA) genes were differentially expressed in the MMMSCs derived from patients with multiple myeloma and NDMSCs from normal donors. Comparison of the MMMSCs and NDMSCs also showed distinct HDACs expression patterns. For the first time to our knowledge, a significant increase of apoptosis was observed in coculture with MMMSCs treated with NaBT. CONCLUSIONS: The obtained findings elucidate a complex set of actions in MSCs in response to HDAC inhibitors, which may be responsible for anticancer effects. Also, the data support the idea that MSCs are new therapeutic targets as a potential effective strategy for MM. PMID- 27510017 TI - Randomized DoubleBlind PlaceboControlled Trial of Propolis for Oral Mucositis in Patients Receiving Chemotherapy for Head and Neck Cancer. AB - BACKGROUND: Propolis based preparations have a wide range of applications in various specialties of dentistry. The aim of this clinical trial was to test the efficacy of propolis as a mouthwash in the reduction of chemotherapy induced oral mucositis (OM) in a single center. MATERIALS AND METHODS: In this randomised, controlled study patients undergoing chemotherapy were included consecutively and randomised to an experimental group receiving propolis mouthwash (n = 20) and a control group receiving diluted water (n=20). Oral mucositis, erythema and eating and drink ability were assessed at baseline and after 3 and 7 days using the World Health Organization (WHO) scale and the oral mucositis assessment scale (OMAS). RESULTS: There were significant differences in OM, wound and erythema in propolis group compared to placebo, but no significant difference in eating and drink ability. However, it was interesting that 65% of the patients in the propolis group were completely healed at day 7 of the trial. No significant adverse events were reported by the patients. CONCLUSIONS: This study found that oral care with propolis as mouthwash for patients undergoing chemotherapy is an effective intervention to improve oral health. Our findings shouldlencourage health practitioners to apply propolis mouth rinse for the oral care of patients under chemotherapy. PMID- 27510018 TI - Haplotype Analysis of BRCA1 Gene D17S855 and D17S1322 Markers in Iranian Familial Breast Cancer Patients. AB - BACKGROUND: Breast cancer molecular analysis by linkage analysis has the advantage of facilitating early diagnosis in asymptomatic genetic carriers, with a view to the preventive followup of these subjects and genetic counseling. The aim of this study was to evaluate BRCA1 gene D17S855 and D17S1322 markers in breast cancer patients. MATERIALS AND METHODS: A series of 107 BC patients and 93 unrelated healthy women were recruited for haplotype analysis performed using two short tandem repeat markers located within the BRCA1 gene locus. Each marker was amplified with PCR genomic DNA from each individual and fluorescently endlabeled primers. RESULTS: Both D17S855 and D17S1322 markers included 12 kinds of alleles. Results indicate that most of the BC patients shared two common 121150 (11.2%, RR=1.56 and p=0.02) and 121146 (5.6%, RR=1.9 and p=0.02) haplotypes. CONCLUSIONS: Our results should be helpful to understand the haplotype phase in the BRCA1 gene and establish a genetic screening strategy in the Iranian population. PMID- 27510019 TI - Immunohistochemical Expression of B Cell Lymphoma2 with Clinicopathological Correlation in Triple Negative Breast Cancers in Northern Pakistan. AB - BACKGROUND: Triple negative breast cancers (TNBCs) are high grade aggressive tumors generally with a poor prognosis, not responding to hormonal and anti Her2 Neu therapy. Expression of the antiapoptotic B cell lymphoma 2 gene (Bcl2) is associated with low grade, slowly proliferating hormone receptor positive tumors with improved survival. Anti Bcl2 agents can be used as alternative targeted therapy in triple negative cancers. MATERIALS AND METHODS: The objective of this study was to determine the immunohistochemical expression of Bcl2 in triple negative breast cancers and any correlation with clinicopathological variables in Northern Pakistan. RESULTS: All 52 patients were females, aged between 28 and 80 years(average 48.0+/-12.1). 28 cases (53.8%) were positive for Bcl2, this being associated with low grade invasive ductal carcinomas, lymph node metastasis and lymphovascular invasion. CONCLUSIONS: Bcl2 may be an important prognostic factor and its expression might be used for targeted therapy using Anti Bcl2 drugs. PMID- 27510020 TI - Novel Nonsense Variants c.58C>T (p.Q20X) and c.256G>T (p.E85X) in the CHEK2 Gene Identified in Breast Cancer Patients from Balochistan. AB - Breast cancer is very common and the leading cause of cancer deaths among women globally. Hereditary cases account for 510% of the total burden and CHEK2, which plays crucial role in response to DNA damage to promote cell cycle arrest and repair or induce apoptosis, is considered as a moderate penetrance breast cancer risk gene. Our objective in the current study was to analyze mutations in related to breast cancer. A total of 271 individuals including breast cancer patients and normal subjects were enrolled and all 14 exons of CHEK2 were amplified and sequenced. The majority of the patients (>95%) were affected with invasive ductal carcinoma (IDC), 52.1% were diagnosed with grade III tumors and 56.2% and 27.5% with advanced stages III and IV. Two novel nonsense variants i.e. c.58C>T (P.Q20X) and c.256G>T (p.E85X) at exon 1 and 2 in two breast cancer patients were identified, both novel and not reported elsewhere. PMID- 27510021 TI - A Novel Mutation in the DNA Binding Domain of NFKB is Associated with Speckled Leukoplakia. AB - BACKGROUND: Activation and inactivation of nuclear factor of kappa light chain gene enhancer in B cells (NFKB) is tightly regulated to ensure effective onset and cessation of defensive inflammatory signaling. However, mutations within NFKB, or change in activation and inactivation molecules have been reported in a few cancers. Although oral squamous cell carcinoma is one of the most prevalent forms of cancer in India, with a development associated with malignant transformation of precancerous lesions, the genetic status of NFKB and relative rates of change in oral precancerous lesions remain unknown. Hence in the present study we investigated all twenty four exons of NFKB gene in two precancerous lesions, namely oral submucous fibrosis (OSMF) and oral leukoplakia (OL) to understand its occurrence, incidence and assess its possible contribution to malignant transformation. MATERIALS AND METHODS: Chromosomal DNA isolated from twenty five each of OSMF and OL tissue biopsy samples were subjected to PCR amplification with intronic primers flanking twenty four exons of the NFKB gene. The PCR amplicons were subsequently subjected to direct sequencing to elucidate the mutation status. RESULTS: Sequence analysis identified a novel heterozygous mutation, c.419T>A causing substitution of leucine with glutamine at codon 140 (L140Q) in an OL sample. CONCLUSIONS: The identification of a substitution mutation L140Q within the DNA binding domain of NFKB in OL suggests that NFKB mutation may be relatively an early event during transformation. To the best of our knowledge, this study is the first to have identified a missense mutation in NFKB in OL. PMID- 27510022 TI - Breast Lymphoma Treatment Outcomes in a Pakistani Population: 20 Years of Experience at a Single Center. AB - BACKGROUND: Breast lymphomas constitute a rare disease entity. To date, limited relevant data have been reported. We therefore here present a review of breast lymphoma patients treated at a single center over a 20 year period, focusing on histological types, treatment modalities and outcomes. MATERIALS AND METHODS: We identified patients who were diagnosed and treated for breast lymphoma at a single center from January 1995 to January 2014 and extracted data regarding patient demographics and clinical data. RESULTS: Twenty-seven patients with breast lymphoma were identified, of which 3 were males. The median age at diagnosis was 37 years (range: 22-76 years). Chemotherapy was the main stay of treatment and 55.6% patients also received radiation to the affected breast. At our institute, only 3 patients, all with progressive disease, had surgery performed to achieve local palliation. Complete response after chemotherapy was seen in 63% patients and partial response in 7.4%, while 26% patients demonstrated disease progression. The mean follow up was 46.8 months. Seven patients (33.3%) who were alive at last follow up, as well as 1 patient who died, survived more than 5 years after diagnosis. CONCLUSIONS: Patients with breast lymphoma should receive aggressive treatment, with combination of chemotherapy and radiation therapy. Surgery should be limited for diagnosis and palliation of local symptoms in cases of progressive disease. PMID- 27510023 TI - Detection of Human Papillomavirus among Women with Atypical Squamous Cells of Undetermined Significance Referred to Colposcopy: Implications for Clinical Management in Low and MiddleIncome Countries. AB - To determine the prevalence of human papillomavirus (HPV) among women with atypical squamous cells of undetermined significance (ASC-US) referred to colposcopy and the implications for clinical management in low- and middle-income countries (LMIC), the present study was conducted. We included 200 women living in Maringa/Brazil referred to colposcopy service between August 2012 and March 2013 due to an abnormal cytology from ASC-US until high-grade intraepithelial lesion (HSIL). HPV was detected and genotyped by polymerase chain reaction (PCR). The mean age was 36.8+/-10.5 years, and women with and without ASC-US had similar mean ages (37.4+/-11.5 and 36.4+/-9.96 years, respectively). The highest prevalence of ASC-US occurred at 20-24 years (40%). HPV-DNA was positive in 164 (82.0%) women.Of the 57 women with ASC-US, 30 (52.6%) were HPV-DNA-positive and 21 (70%) were high-risk HPV-positive (HR-HPV); the latter was similar to women without ASC-US (76.9%) but with other abnormal cytological findings present. Our data demonstrated that performing tests for HR-HPV can be used for management of women with ASC-US to support the decision of which women should be referred for an immediate or later colposcopy. The same conclusions can be applied to other LMICs for which HPV testing for primary screening has not been adopted. PMID- 27510024 TI - Radiation Therapy for Primary Eyelid Cancers in Tunisia. AB - Management of eyelid cancers is based on surgery and/or radiotherapy (RT). The treatment objective is to control tumors with acceptable functional and esthetic outcomes. The aim of this study was to evaluate the results of radiation therapy in management of epithelial eyelid cancers, reviewing retrospectively the clinical records of patients treated in our institution from January 1989 to December 2013. We focused on clinical and histological features, treatment characteristics, tolerance and disease control. One hundred and eight patients (62 men and 46 women) were enrolled, with a mean age of 61 years [ranges 1587]. The most frequent tumor location was the inner canthus (42.6%). Median tumor size was 21 mm [ranges 470]. Histological type was basal cell carcinoma in 88 cases (81.5%), squamous cell carcinoma in 16 (14.8%) and sebaceous carcinoma in 4 (3.7%). Radiation therapy was exclusive in 67 cases (62%) and postoperative for positive or close margins in the remaining cases. Kilovoltage external beam radiotherapy (KVRT) was used in 63 patients (58.3%) and lowdoserate interstitial brachytherapy in 37 (34.3%). Eight (7.4%) were treated with cobalt or with a combination of KVRTcobalt, KVRTelectron beams, KVRTbrachytherapy or cobaltelectron beams. The total delivered radiation doses were 70 Gy (2 Gy/fraction) in 62 patients (57.4%), 66 Gy (2 Gy/fraction) in 37 (34.3%) and 61.2 Gy (3.4Gy/fraction) in 9 (8.3%). After a median followup of 64 months, we noted 10 cases of local recurrences(9.2%): 7 after exclusive and 3 after postoperative RT. No local recurrence occurred in patients treated with brachytherapy. Actuarial 5year local recurrencefree rate, diseasefree survival and overall survival were respectively 90%, 90% and 97%. Tstage was found to be a significant factor for recurrence (p=0.047). All acute radiationrelated reactions were scored grade I or II. Delayed effects were eye watering in 24 cases (22.2%), eye dryness in 19 (17.6%), unilateral cataract in 7 (6.4%) and ectropion in 4 (3.7%). Radiation therapy and especially brachytherapy is an efficient treatment of eyelid cancers, allowing eye conservation and functional preservation with good local control rates and acceptable toxicity. PMID- 27510025 TI - Colorectal Cancer in the Central Region of Thailand. AB - BACKGROUND: Colorectal cancer is one of the major health problems worldwide. However, limited studies have been reported from ASEAN countries. This study was conducted to evaluate clinical characteristics and survival of colorectal cancer cases aged <65 years and >=65 years in the central region of Thailand. MATERIALS AND METHODS: Clinical information, histological features, endoscopic findings and treatment outcome were collected and reviewed from Thammasat University Hospital, Pathumthani, Thailand between November 2011 and October 2015. RESULTS: A total of 121 colorectal cancer patients, comprising 69 men and 52 women with a mean age of 65.8 years, were included. There were 57 aged <65 years and 64 aged >=65 years. Common presenting symptoms were abdominal pain (37%), weight loss (34%) and anemia (32%). Mean duration of symptoms prior to diagnosis was 173 days. However, longer diagnosis time was demonstrated in patients aged <65 years than age more than >=65 years (119.4 vs 58.4 days, Pvalue=0.30). Colonic fungating mass was the most common endoscopic finding (64.4%) and the location was significantly more commonly left than right side of the colon, both in younger and elderly groups (87.7% vs 12.3%, P=0.02 and 70.3% vs 29.7%, P=0.02, respectively). Adenocarcinoma with moderated differentiated was the most common histology (67.3%). More than half of the patients presented with advanced stage (28.9% with TNM stage 3 and 38.8% TNM stage 4, respectively). Overall 1year and 5year survival rates were 76.9% and 5%. CONCLUSIONS: Most colorectal cancer patients in Thailand have adenocarcinomas and present at advanced stage with poor prognosis. Screening of high risk patients and early detection might be essential factors to improve the treatment outcome and overall survival rate of colon cancer patients in Thailand and other ASEAN countries. PMID- 27510026 TI - Using a GeneticFuzzy Algorithm as a Computer Aided Breast Cancer Diagnostic Tool. AB - Computeraided diagnosis of breast cancer is an important medical approach. In this research paper, we focus on combining two major methodologies, namely fuzzy base systems and the evolutionary genetic algorithms and on applying them to the Saudi Arabian breast cancer diagnosis database, to aid physicians in obtaining an earlycomputerized diagnosis and hence prevent the development of cancer through identification and removal or treatment of premalignant abnormalities; early detection can also improve survival and decrease mortality by detecting cancer at an early stage when treatment is more effective. Our hybrid algorithm, the geneticfuzzy algorithm, has produced optimized systems that attain high classification performance, with simple and readily interpreted rules and with a good degree of confidence. PMID- 27510027 TI - Role of Accredited Social Health Activists in Cancer Screening in India: Brightest 'Ray of Hope'. PMID- 27510028 TI - History of Surgery is an Important Risk Factor for Breast Cancer. PMID- 27510029 TI - Spray-Coated Multiwalled Carbon Nanotube Composite Electrodes for Thermal Energy Scavenging Electrochemical Cells. AB - Spray-coated multiwalled carbon nanotube/poly(vinylidene fluoride) (MWCNT/PVDF) composite electrodes, scCNTs, with varying CNT compositions (2 to 70 wt %) are presented for use in a simple thermal energy-scavenging cell (thermocell) based on the ferro/ferricyanide redox couple. Their utility for direct thermal-to electrical energy conversion is explored at various temperature differentials and cell orientations. Performance is compared to that of buckypaper, a 100% CNT sheet material used as a benchmark electrode in thermocell research. The 30 to 70 wt % scCNT composites give the highest power output by electrode area-seven times greater than buckypaper at DeltaT = 50 degrees C. CNT utilization is drastically enhanced in our electrodes, reaching 1 W gCNT(-1) compared to 0.036 W gCNT(-1) for buckypaper. Superior performance of our spray-coated electrodes is attributed to both wettability with better use of a large portion of electrochemically active CNTs and minimization of ohmic and thermal contact resistances. Even composites with as low as 2 wt % CNTs are still competitive with prior art. The MWCNT/PVDF composites developed herein are inexpensive, scalable, and serve a general need for CNT electrode optimization in next-generation devices. PMID- 27510030 TI - Public stewardship of private for-profit healthcare providers in low- and middle income countries. AB - BACKGROUND: Governments use different approaches to ensure that private for profit healthcare services meet certain quality standards. Such government guidance, referred to as public stewardship, encompasses government policies, regulatory mechanisms, and implementation strategies for ensuring accountability in the delivery of services. However, the effectiveness of these strategies in low- and middle-income countries (LMICs) have not been the subject of a systematic review. OBJECTIVES: To assess the effects of public sector regulation, training, or co-ordination of the private for-profit health sector in low- and middle-income countries. SEARCH METHODS: For related systematic reviews, we searched the Cochrane Database of Systematic Reviews (CDSR) 2015, Issue 4; Database of Abstracts of Reviews of Effectiveness (DARE) 2015, Issue 1; Health Technology Assessment Database (HTA) 2015, Issue 1; all part of The Cochrane Library, and searched 28 April 2015. For primary studies, we searched MEDLINE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, MEDLINE Daily and MEDLINE 1946 to Present, OvidSP (searched 16 June 2016); Science Citation Index and Social Sciences Citation Index 1987 to present, and Emerging Sources Citation Index 2015 to present, ISI Web of Science (searched 3 May 2016 for papers citing included studies); Cochrane Central Register of Controlled Trials (CENTRAL), 2015, Issue 3, part of The Cochrane Library (including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register) (searched 28 April 2015); Embase 1980 to 2015 Week 17, OvidSP (searched 28 April 2015); Global Health 1973 to 2015 Week 16, OvidSP (searched 30 April 2015); WHOLIS, WHO (searched 30 April 2015); Science Citation Index and Social Sciences Citation Index 1975 to present, ISI Web of Science (searched 30 April 2015); Health Management, ProQuest (searched 22 November 2013). In addition, in April 2016, we searched the reference lists of relevant articles, WHO International Clinical Trials Registry Platform, Clinicaltrials.gov, and various electronic databases of grey literature. SELECTION CRITERIA: Randomised trials, non-randomised trials, interrupted time series studies, or controlled before-after studies. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility and extracted data, comparing their results and resolving discrepancies by consensus. We expressed study results as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI), where appropriate, and assessed the certainty of the evidence using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). We did not conduct meta-analysis because of heterogeneity of interventions and study designs. MAIN RESULTS: We identified 20,177 records, 50 of them potentially eligible. We excluded 39 potentially eligible studies because they did not involve a rigorous evaluation of training, regulation, or co ordination of private for-profit healthcare providers in LMICs; five studies identified after the review was submitted are awaiting assessment; and six studies met our inclusion criteria. Two included studies assessed training alone; one assessed regulation alone; three assessed a multifaceted intervention involving training and regulation; and none assessed co-ordination. All six included studies targeted private for-profit pharmacy workers in Africa and Asia.Three studies found that training probably increases sale of oral rehydration solution (one trial in Kenya, 106 pharmacies: RR 3.04, 95% CI 1.37 to 6.75; and one trial in Indonesia, 87 pharmacies: RR 1.41, 95% CI 1.03 to 1.93) and dispensing of anti-malarial drugs (one trial in Kenya, 293 pharmacies: RR 8.76, 95% CI 0.94 to 81.81); moderate-certainty evidence.One study conducted in the Lao People's Democratic Republic shows that regulation of the distribution and sale of registered pharmaceutical products may improve composite pharmacy indicators (one trial, 115 pharmacies: improvements in four of six pharmacy indicators; low-certainty evidence).The outcome in three multifaceted intervention studies was the quality of pharmacy practice; including the ability to ask questions, give advice, and provide appropriate treatment. The trials applied regulation, training, and peer influence in sequence; and the study design does not permit separation of the effects of the different interventions. Two trials conducted among 136 pharmacies in Vietnam found that the multifaceted intervention may improve the quality of pharmacy practice; but the third study, involving 146 pharmacies in Vietnam and Thailand, found that the intervention may have little or no effects on the quality of pharmacy practice (low-certainty evidence).Only two studies (both conducted in Vietnam) reported cost data, with no rigorous assessment of the economic implications of implementing the interventions in resource-constrained settings. No study reported data on equity, mortality, morbidity, adverse effects, satisfaction, or attitudes. AUTHORS' CONCLUSIONS: Training probably improves quality of care (i.e. adherence to recommended practice), regulation may improve quality of care, and we are uncertain about the effects of co-ordination on quality of private for-profit healthcare services in LMICs. The likelihood that further research will find the effect of training to be substantially different from the results of this review is moderate; implying that monitoring of the impact is likely to be needed if training is implemented. The low certainty of the evidence for regulation implies that the likelihood of further research finding the effect of regulation to be substantially different from the results of this review is high. Therefore, an impact evaluation is warranted if government regulation of private for-profit providers is implemented in LMICs. Rigorous evaluations of these interventions should also assess other outcomes such as impacts on equity, cost implications, mortality, morbidity, and adverse effects. PMID- 27510031 TI - Probing Receptor Specificity by Sampling the Conformational Space of the Insulin like Growth Factor II C-domain. AB - Insulin and insulin-like growth factors I and II are closely related protein hormones. Their distinct evolution has resulted in different yet overlapping biological functions with insulin becoming a key regulator of metabolism, whereas insulin-like growth factors (IGF)-I/II are major growth factors. Insulin and IGFs cross-bind with different affinities to closely related insulin receptor isoforms A and B (IR-A and IR-B) and insulin-like growth factor type I receptor (IGF-1R). Identification of structural determinants in IGFs and insulin that trigger their specific signaling pathways is of increasing importance in designing receptor specific analogs with potential therapeutic applications. Here, we developed a straightforward protocol for production of recombinant IGF-II and prepared six IGF-II analogs with IGF-I-like mutations. All modified molecules exhibit significantly reduced affinity toward IR-A, particularly the analogs with a Pro Gln insertion in the C-domain. Moreover, one of the analogs has enhanced binding affinity for IGF-1R due to a synergistic effect of the Pro-Gln insertion and S29N point mutation. Consequently, this analog has almost a 10-fold higher IGF-1R/IR-A binding specificity in comparison with native IGF-II. The established IGF-II purification protocol allowed for cost-effective isotope labeling required for a detailed NMR structural characterization of IGF-II analogs that revealed a link between the altered binding behavior of selected analogs and conformational rearrangement of their C-domains. PMID- 27510032 TI - The Histamine H3 Receptor Differentially Modulates Mitogen-activated Protein Kinase (MAPK) and Akt Signaling in Striatonigral and Striatopallidal Neurons. AB - The basal ganglia have a central role in motor patterning, habits, motivated behaviors, and cognition as well as in numerous neuropsychiatric disorders. Receptors for histamine, especially the H3 receptor (H3R), are highly expressed in the striatum, the primary input nucleus of the basal ganglia, but their effects on this circuitry have been little explored. H3R interacts with dopamine (DA) receptors ex vivo; the nature and functional importance of these interactions in vivo remain obscure. We found H3R activation with the agonist R-( )-alpha-methylhistamine to produce a unique time- and cell type-dependent profile of molecular signaling events in the striatum. H3 agonist treatment did not detectably alter extracellular DA levels or signaling through the cAMP/DARPP-32 signaling pathway in either D1- or D2-expressing striatal medium spiny neurons (MSNs). In D1-MSNs, H3 agonist treatment transiently activated MAPK signaling and phosphorylation of rpS6 and led to phosphorylation of GSK3beta-Ser9, a novel effect. Consequences of H3 activation in D2-MSNs were completely different. MAPK signaling was unchanged, and GSK3beta-Ser9 phosphorylation was reduced. At the behavioral level, two H3 agonists had no significant effect on locomotion or stereotypy, but they dramatically attenuated the locomotor activation produced by the D1 agonist SKF82958. H3 agonist co-administration blocked the activation of MAPK signaling and the phosphorylation of rpS6 produced by D1 activation in D1 MSNs, paralleling behavioral effects. In contrast, GSK3beta-Ser9 phosphorylation was seen only after H3 agonist treatment, with no interactive effects. H3R signaling has been neglected in models of basal ganglia function and has implications for a range of pathophysiologies. PMID- 27510033 TI - HCO3- Transport through Anoctamin/Transmembrane Protein ANO1/TMEM16A in Pancreatic Acinar Cells Regulates Luminal pH. AB - The identification of ANO1/TMEM16A as the likely calcium-dependent chloride channel of exocrine glands has led to a more detailed understanding of its biophysical properties. This includes a calcium-dependent change in channel selectivity and evidence that HCO3 (-) permeability can be significant. Here we use freshly isolated pancreatic acini that preserve the luminal structure to measure intraluminal pH and test the idea that ANO1/TMEM16A contributes to luminal pH balance. Our data show that, under physiologically relevant stimulation with 10 pm cholesystokinin, the luminal acid load that results from the exocytic fusion of zymogen granules is significantly blunted by HCO3 (-) buffer in comparison with HEPES, and that this is blocked by the specific TMEM16A inhibitor T16inh-A01. Furthermore, in a model of acute pancreatitis, we observed substantive luminal acidification and provide evidence that ANO1/TMEM16A acts to attenuate this pH shift. We conclude that ANO1/TMEM16A is a significant pathway in pancreatic acinar cells for HCO3 (-) secretion into the lumen. PMID- 27510034 TI - Phosphatidic Acid Produced by RalA-activated PLD2 Stimulates Caveolae-mediated Endocytosis and Trafficking in Endothelial Cells. AB - Caveolae are the primary route for internalization and transendothelial transport of macromolecules, such as insulin and albumin. Caveolae-mediated endocytosis is activated by Src-dependent caveolin-1 (Cav-1) phosphorylation and subsequent recruitment of dynamin-2 and filamin A (FilA), which facilitate vesicle fission and trafficking, respectively. Here, we tested the role of RalA and phospholipase D (PLD) signaling in the regulation of caveolae-mediated endocytosis and trafficking. The addition of albumin to human lung microvascular endothelial cells induced the activation of RalA within minutes, and siRNA-mediated down regulation of RalA abolished fluorescent BSA uptake. Co-immunoprecipitation studies revealed that albumin induced the association between RalA, Cav-1, and FilA; however, RalA knockdown with siRNA did not affect FilA recruitment to Cav 1, suggesting that RalA was not required for FilA and Cav-1 complex formation. Rather, RalA probably facilitates caveolae-mediated endocytosis by activating downstream effectors. PLD2 was shown to be activated by RalA, and inhibition of PLD2 abolished Alexa-488-BSA uptake, indicating that phosphatidic acid (PA) generated by PLD2 may facilitate caveolae-mediated endocytosis. Furthermore, using a PA biosensor, GFP-PASS, we observed that BSA induced an increase in PA co localization with Cav-1-RFP, which could be blocked by a dominant negative PLD2 mutant. Total internal reflection fluorescence microscopy studies of Cav-1-RFP also showed that fusion of caveolae with the basal plasma membrane was dependent on PLD2 activity. Thus, our results suggest that the small GTPase RalA plays an important role in promoting invagination and trafficking of caveolae, not by potentiating the association between Cav-1 and FilA but by stimulating PLD2 mediated generation of phosphatidic acid. PMID- 27510035 TI - Analyzing N-terminal Arginylation through the Use of Peptide Arrays and Degradation Assays. AB - Nalpha-terminal arginylation (Nt-arginylation) of proteins is mediated by the Ate1 arginyltransferase (R-transferase), a component of the Arg/N-end rule pathway. This proteolytic system recognizes proteins containing N-terminal degradation signals called N-degrons, polyubiquitylates these proteins, and thereby causes their degradation by the proteasome. The definitively identified ("canonical") residues that are Nt-arginylated by R-transferase are N-terminal Asp, Glu, and (oxidized) Cys. Over the last decade, several publications have suggested (i) that Ate1 can also arginylate non-canonical N-terminal residues; (ii) that Ate1 is capable of arginylating not only alpha-amino groups of N terminal residues but also gamma-carboxyl groups of internal (non-N-terminal) Asp and Glu; and (iii) that some isoforms of Ate1 are specific for substrates bearing N-terminal Cys residues. In the present study, we employed arrays of immobilized 11-residue peptides and pulse-chase assays to examine the substrate specificity of mouse R-transferase. We show that amino acid sequences immediately downstream of a substrate's canonical (Nt-arginylatable) N-terminal residue, particularly a residue at position 2, can affect the rate of Nt-arginylation by R-transferase and thereby the rate of degradation of a substrate protein. We also show that the four major isoforms of mouse R-transferase have similar Nt-arginylation specificities in vitro, contrary to the claim about the specificity of some Ate1 isoforms for N-terminal Cys. In addition, we found no evidence for a significant activity of the Ate1 R-transferase toward previously invoked non-canonical N terminal or internal amino acid residues. Together, our results raise technical concerns about earlier studies that invoked non-canonical arginylation specificities of Ate1. PMID- 27510036 TI - Regulation of Neuronal Survival by Nucleophosmin 1 (NPM1) Is Dependent on Its Expression Level, Subcellular Localization, and Oligomerization Status. AB - NPM1 (nucleophosmin 1) is a nucleolar phosphoprotein that regulates many cellular processes, including ribosome biogenesis, proliferation, and genomic integrity. Although its role in proliferating cell types and tissues has been extensively investigated, little is known about its function in neurons and in the brain where it is highly expressed. We report that NPM1 protein expression is increased selectively in the striatum in both the R6/2 transgenic and 3-nitropropionic acid injected mouse models of Huntington's disease. Examination of the effect of ectopic expression on cultured neurons revealed that increasing NPM1 is toxic to otherwise healthy cerebellar granule and cortical neurons. Toxicity is dependent on its cytoplasmic localization and oligomerization status. Forced retention of NPM1 in the nucleus, as well as inhibiting its ability to oligomerize, not only neutralizes NPM1 toxicity but also renders it protective against apoptosis. Although not blocked by pharmacological inhibition of the pro-apoptotic molecules, JNK, glycogen synthase kinase 3 beta, or caspases, toxicity is blocked by compounds targeting cyclin-dependent kinases (CDKs), as well as by dominant negative forms of CDK1 and CDK2 and the pan-CDK inhibitor, p21(Cip1/Waf1) Although induced in in vivo Huntington's disease models, NPM1 protein levels are unchanged in cultured cerebellar granule and cortical neurons induced to die by low potassium or homocysteic acid treatment, respectively. Moreover, and counterintuitively, knockdown of its expression or inhibition of endogenous NPM1 oligomerization in these cultured neurons is toxic. Taken together, our study suggests that although neurons need NPM1 for survival, an increase in its expression beyond physiological levels and its translocation to the cytoplasm leads to death through abortive cell cycle induction. PMID- 27510037 TI - Acidic pH Is a Metabolic Switch for 2-Hydroxyglutarate Generation and Signaling. AB - 2-Hydroxyglutarate (2-HG) is an important epigenetic regulator, with potential roles in cancer and stem cell biology. The d-(R)-enantiomer (d-2-HG) is an oncometabolite generated from alpha-ketoglutarate (alpha-KG) by mutant isocitrate dehydrogenase, whereas l-(S)-2-HG is generated by lactate dehydrogenase and malate dehydrogenase in response to hypoxia. Because acidic pH is a common feature of hypoxia, as well as tumor and stem cell microenvironments, we hypothesized that pH may regulate cellular 2-HG levels. Herein we report that cytosolic acidification under normoxia moderately elevated 2-HG in cells, and boosting endogenous substrate alpha-KG levels further stimulated this elevation. Studies with isolated lactate dehydrogenase-1 and malate dehydrogenase-2 revealed that generation of 2-HG by both enzymes was stimulated severalfold at acidic pH, relative to normal physiologic pH. In addition, acidic pH was found to inhibit the activity of the mitochondrial l-2-HG removal enzyme l-2-HG dehydrogenase and to stimulate the reverse reaction of isocitrate dehydrogenase (carboxylation of alpha-KG to isocitrate). Furthermore, because acidic pH is known to stabilize hypoxia-inducible factor (HIF) and 2-HG is a known inhibitor of HIF prolyl hydroxylases, we hypothesized that 2-HG may be required for acid-induced HIF stabilization. Accordingly, cells stably overexpressing l-2-HG dehydrogenase exhibited a blunted HIF response to acid. Together, these results suggest that acidosis is an important and previously overlooked regulator of 2-HG accumulation and other oncometabolic events, with implications for HIF signaling. PMID- 27510038 TI - Developmental delay and failure to thrive in a 7-month-old baby boy with spontaneous transient Graves' thyrotoxicosis: a case report. AB - BACKGROUND: Thyroid dysfunction can induce developmental delay and failure to thrive in infancy. Congenital hypothyroidism is one of the common causes of these symptoms in infancy. By contrast, hyperthyroidism is a rare cause of these symptoms in infancy. CASE PRESENTATION: A 7-month-old Japanese baby boy was examined for developmental delay and failure to thrive. Blood tests were performed, which showed low levels of thyroid-stimulating hormone (<0.01 MUU/mL) and high levels of free thyroxine (2.14 pg/mL). He was referred to our hospital at 8 months of age. His height was 64 cm (-2.7 standard deviation) and his weight was 6085 g (-2.5 standard deviation). No goiter was detected on examination. His thyrotropin receptor antibody was slightly high (3.9 IU/L), whereas thyroid stimulating antibody, anti-thyroglobulin antibody, and thyroid peroxidase antibody were within normal range. These blood findings indicated hyperthyroidism, most likely Graves' disease. His free thyroxine level decreased in the first month after our examination. No increased vascularity of his thyroid gland was noted. The technetium uptake of his thyroid gland in scintigraphy was relatively increased compared to the intake of his salivary gland. We elected to observe rather than treat with anti-thyroid medications. CONCLUSION: We have to rule out spontaneous transient Graves' thyrotoxicosis when babies have symptoms of developmental delay and fail to thrive. PMID- 27510040 TI - Aortitis as a cause of severe abdominal pain. PMID- 27510039 TI - Q&A: Auxin: the plant molecule that influences almost anything. AB - Auxin is an essential molecule that controls almost every aspect of plant development. Although the core signaling components that control auxin response are well characterized, the precise mechanisms enabling specific responses are not yet fully understood. Considering the significance of auxin in plant growth and its potential applications, deciphering further aspects of its biology is an important and exciting challenge. PMID- 27510041 TI - Recent advances in the biomimicry of structural colours. AB - Nature has mastered the construction of nanostructures with well-defined macroscopic effects and purposes. Structural colouration is a visible consequence of the particular patterning of a reflecting surface with regular structures at submicron length scales. Structural colours usually appear bright, shiny, iridescent or with a metallic look, as a result of physical processes such as diffraction, interference, or scattering with a typically small dissipative loss. These features have recently attracted much research effort in materials science, chemistry, engineering and physics, in order to understand and produce structural colours. In these early stages of photonics, researchers facing an infinite array of possible colour-producing structures are heavily inspired by the elaborate architectures they find in nature. We review here the recent technological strategies employed to artificially mimic the structural colours found in nature, as well as some of their current and potential applications. PMID- 27510042 TI - Solanum tuberosum L. cv Hongyoung extract inhibits 2,4-dinitrochlorobenzene induced atopic dermatitis in NC/Nga mice. AB - Solanum tuberosum L. cv Hongyoung (SH) is a widely consumed anthocyanin-rich food and medicinal plant, which possesses anti-inflammatory and anti-allergic activities. The present study aimed to examine the inhibitory effects of SH extract on atopic dermatitis (AD)-like skin lesions induced by the topical application of 2,4-dinitrochlorobenzene (DNCB) in NC/Nga mice. SH extract was orally administered to the DNCB-treated NC/Nga mice. The anti-AD effects of SH extract were examined by measuring symptom severity; ear thickness; scratching behavior; serum levels of immunoglobulin (Ig)E; T-helper (Th)1, Th2 and Th17 cytokine levels in the spleen; mRNA expression levels of inflammatory cytokines and chemokines; and tissue infiltration of inflammatory cells. The results demonstrated that SH extract inhibited the development of AD-like lesions, and reduced IgE levels and the production of cytokines. Furthermore, SH extract significantly suppressed the expression of AD-associated mRNAs in lesional skin. Histological alterations in the AD-like lesions were visualized using hematoxylin and eosin, and toluidine blue staining in the DNCB-treated group; the alterations were attenuated following SH treatment. In addition, thickening of the epidermis and accumulation of inflammatory cells in the DNCB-treated mice were suppressed by SH treatment. These results suggested that SH extract may suppress the development of AD symptoms through modulation of the Th1 and Th2 responses. PMID- 27510090 TI - Martin Erhard - upper world and underworld. Order and perversion. PMID- 27510093 TI - Phosphine-catalyzed cage carbon functionalization of o-carborane: facile synthesis of alkenylcarboranes. AB - A phosphine-catalyzed alkenylation reaction of o-carborane with electron deficient alkynes at the C-H vertex of the o-carborane cage has been developed, which led to the preparation of a series of 1-alkenyl-o-carboranes in moderate to very good yields with excellent regio- and stereoselectivity. This highly efficient and simple method represents the first example of organophosphine catalyzed C-H functionalization of o-carborane. PMID- 27510092 TI - cDICE method produces giant lipid vesicles under physiological conditions of charged lipids and ionic solutions. AB - Giant unilamellar vesicles are a powerful and common tool employed in biophysical studies of lipid membranes. Here we evaluate a recently introduced method of vesicle formation, "continuous droplet interface crossing encapsulation" (cDICE). This method produces monodisperse giant unilamellar vesicles of controlled sizes and high encapsulation efficiencies, using readily available instrumentation. We find that mixtures of phospholipids within vesicle membranes produced by cDICE undergo phase separation at the same characteristic temperatures as lipids in vesicles formed by a complementary technique. We find that the cDICE method is effective both when vesicles are produced from charged lipids and when the surrounding buffer contains a high concentration of salt. A shortcoming of the technique is that cholesterol is not substantially incorporated into vesicle membranes. PMID- 27510094 TI - MicroRNA-106a regulates phosphatase and tensin homologue expression and promotes the proliferation and invasion of ovarian cancer cells. AB - Ovarian cancer is a leading cause of malignant gynecological tumor-related mortality among women. The treatment of ovarian cancer patients continues to be challenging. MicroRNA-106a (miR-106a) is widely expressed in diverse human tumors. In the present study, we investigated the biological and pathological roles of miR-106a in ovarian cancers. We found that miR-106a expression was significantly increased in primary ovarian cancer tissues and ovarian cancer cells compared with the level in normal tissues. Ectopic expression of an miR 106a inhibitor attenuated ovarian cancer cell proliferation and invasion. miR 106a promoted the growth and invasion of SKOV3 cells by targeting phosphatase and tensin homolog (PTEN). Furthermore, the present study revealed that IL-6 inhibited miR-106a expression by activating STAT3. Tocilizumab, a humanized anti human IL-6R antibody, that competitively inhibits IL-6/IL-6R signaling, did not inhibit the proliferation and invasion of SKOV3 cells. In conclusion, our studies revealed that miR-106a was significantly increased in the ovarian cancer tissues and cell lines. Downregulation of the expression of miR-106a inhibited cell growth and metastasis of ovarian cancer cells. Together, the present study suggests that miR-106a acts as an oncogene in ovarian cancers. PMID- 27510095 TI - Transforming healthcare through regenerative medicine. AB - Regenerative medicine therapies, underpinned by the core principles of rejuvenation, regeneration and replacement, are shifting the paradigm in healthcare from symptomatic treatment in the 20th century to curative treatment in the 21st century. By addressing the reasons behind the rapid expansion of regenerative medicine research and presenting an overview of current clinical trials, we explore the potential of regenerative medicine to reshape modern healthcare. PMID- 27510097 TI - Scaling and automation of a high-throughput single-cell-derived tumor sphere assay chip. AB - Recent research suggests that cancer stem-like cells (CSCs) are the key subpopulation for tumor relapse and metastasis. Due to cancer plasticity in surface antigen and enzymatic activity markers, functional tumorsphere assays are promising alternatives for CSC identification. To reliably quantify rare CSCs (1 5%), thousands of single-cell suspension cultures are required. While microfluidics is a powerful tool in handling single cells, previous works provide limited throughput and lack automatic data analysis capability required for high throughput studies. In this study, we present the scaling and automation of high throughput single-cell-derived tumor sphere assay chips, facilitating the tracking of up to ~10 000 cells on a chip with ~76.5% capture rate. The presented cell capture scheme guarantees sampling a representative population from the bulk cells. To analyze thousands of single-cells with a variety of fluorescent intensities, a highly adaptable analysis program was developed for cell/sphere counting and size measurement. Using a Pluronic(r) F108 (poly(ethylene glycol) block-poly(propylene glycol)-block-poly(ethylene glycol)) coating on polydimethylsiloxane (PDMS), a suspension culture environment was created to test a controversial hypothesis: whether larger or smaller cells are more stem-like defined by the capability to form single-cell-derived spheres. Different cell lines showed different correlations between sphere formation rate and initial cell size, suggesting heterogeneity in pathway regulation among breast cancer cell lines. More interestingly, by monitoring hundreds of spheres, we identified heterogeneity in sphere growth dynamics, indicating the cellular heterogeneity even within CSCs. These preliminary results highlight the power of unprecedented high-throughput and automation in CSC studies. PMID- 27510096 TI - NO* and Pancreatic Cancer: A Complex Interaction with Therapeutic Potential. AB - SIGNIFICANCE: Pancreatic tumors express high level of nitric oxide synthases (NOSs) in particular inducible (iNOS/NOS2) and endothelial (eNOS/NOS3) forms. However, the role of nitric oxide (NO*) in the development and progression of pancreatic cancer is not clearly defined. Delineating the NO*-induced signaling in pancreatic cancer and its potential contribution in disease aggressiveness may provide therapeutic targets to improve survival in this lethal malignancy. Recent Advances: An increased expression of NOS2/iNOS in tumors is associated with poorer survival in early stage resected patients with pancreatic ductal adenocarcinoma (PDAC). Furthermore, genetic deletion of NOS2 enhanced survival in mice with autochthonous PDAC. Additionally, targeting NOS3/eNOS reduced the abundance of precursor lesions in mice, which trended toward improved survival. CRITICAL ISSUES: The extremely poor prognosis in pancreatic cancer is due to the late diagnosis and lack of effective therapy in advanced disease. One of the most critical issues is to decipher the underlying mechanism of disease aggressiveness and therapeutic resistance for identifying potential therapeutic target and effective treatment. Given the evidence of a strong association between inflammation and pancreatic cancer and clinical evidence, which suggests an association between NOS2 and disease aggressiveness, it is critical to define the role of NO* signaling in this lethal malignancy. FUTURE DIRECTIONS: Recent preclinical and clinical evidences indicate a potential therapeutic significance of targeting NO* signaling in pancreatic cancer. With the emergence of new preclinical models, including the patient-derived organoids, further preclinical evaluation using clinically tested NOS inhibitors is needed for designing future clinical investigation. Antioxid. Redox Signal. 26, 1000-1008. PMID- 27510098 TI - Slow Intramolecular Vibrational Relaxation Leads to Long-Lived Excited-State Wavepackets. AB - Broadband optical pump and compressed white light continuum probe were used to measure the transient excited-state absorption, ground-state bleach, and stimulated emission signals of cresyl violet solution in methanol. Amplitude oscillations caused by wavepacket motion in the ground and excited electronic states were analyzed. It was found that vibrational coherences in the excited state persist for more than the experimental waiting time window of 6 ps, and the strongest mode had a dephasing time constant of 2.4 ps. We hypothesize the dephasing of the wavepacket in the excited state is predominantly caused by intramolecular vibrational relaxation (IVR). Slow IVR indicates weak mode-mode coupling and therefore weak anharmonicity of the potential of this vibration. Thus, the initially prepared vibrational wavepacket in the excited state is not significantly perturbed by nonadiabatic coupling to other electronic states, and hence the diabatic and adiabatic representations of the system are essentially identical within the Born-Oppenheimer approximation. The wavepacket therefore evolves with time in an almost harmonic potential, slowly dephased by IVR and the pure vibrational decoherence. The consistency in the position of node (phase change in the wavepacket) in the excited-state absorption and stimulated emission signals without undergoing any frequency shift until the wavepacket is completely dephased conforms to the absence of any reactive internal conversion. PMID- 27510152 TI - Application of ADA1 as a new marker enzyme in sandwich ELISA to study the effect of adenosine on activated monocytes. AB - Enzyme-linked immunosorbent assay (ELISA) is a valuable technique to detect antigens in biological fluids. Horse radish peroxidase (HRP) is one of the most common enzymes used for signal amplification in ELISA. Despite new advances in technology, such as a large-scale production of recombinant enzymes and availability of new detection systems, limited research is devoted to finding alternative enzymes and their substrates to amplify the ELISA signals. Here, HRP avidin was substituted with the human adenosine deaminase (hADA1)-streptavidin complex and adenosine as a detection system in commercial ELISA kits. The hADA1 ELISA was successfully used to demonstrate that adenosine, bound to A1 and A3 adenosine receptors, increases cytokine secretion by LPS activated monocytes. We show that hADA1-based ELISA has the same sensitivity, and also provides identical results, as HRP ELISA. In addition, the sensitivity of hADA1-based ELISA could be easily adjusted by changing the adenosine concentration and the incubation time. Therefore, hADA1 could be used as a detection enzyme with any commercial ELISA kit with a wide range of concentration of antigens. PMID- 27510153 TI - Structural and electronic features of small hybrid organic-inorganic halide perovskite clusters: a theoretical analysis. AB - We herein present the results of a series of calculations performed on some representative cluster models of hybrid organic-inorganic halide perovskites, (MA)jPbkXl (l = 2j + k; MA = methylammonium, +CH3NH3; X = halide). In particular, aimed at finding possible analogies with the bulk, we focused our initial attention on neutral clusters of iodides (X = I) constituted by an increasing number of Pb atoms (k = 1, 2, 8, 12). For the single octahedron (k = 1), we similarly extended our calculations to mixed Br-/I-terminated and fully Br terminated octahedra, finding similar miscibilities for the two dimensionally different systems (i.e., the cluster and bulk). When increasing the size of the models, we found an unequivocally evident relationship between the total dielectric dipole moment of the investigated cluster and the wavefunction spatial distribution of the frontier molecular orbitals. This result rationalizes the structural and electronic properties of such zero-dimensional systems and supports the results previously obtained via linear scaling ab initio methods for very large supercells, i.e., the localization at the nanoscale of the wavefunction of the frontier orbitals as a function of the local fluctuations of the potential, which are mainly associated with the organic cation orientation. PMID- 27510154 TI - Congenital absence of infrarenal inferior vena cava and deep veins of the lower limbs: a case report. AB - BACKGROUND: Congenital anomalies of the venous system are known but congenital absence of infrarenal inferior vena cava with absent deep venous system of the lower limbs is extremely rare. CASE PRESENTATION: We report the case of an 11 year-old Indian girl who presented with large venous collaterals on her anterior abdominal wall and recurrent non-healing venous ulcers on her left leg with complete absence of infrarenal inferior vena cava and absent deep veins of her lower limbs. CONCLUSIONS: Congenital absence of infrarenal inferior vena cava may occur with absence of the deep venous system of the lower limbs. We have reported this case because of its extreme rarity and to enhance awareness of this entity that has no treatment currently. PMID- 27510156 TI - [Longterm risk subtotal splenectomy?] PMID- 27510155 TI - [Complications after thyroid gland operations in Germany : A routine data analysis of 66,902 AOK patients]. AB - BACKGROUND: Routine data from hospitals in the public healthcare system allow the analysis of large patient datasets without generating additional documentation efforts for hospitals. This study reports the frequencies of postoperative complications after thyroid surgery based on routine nationwide data. Moreover, volume-outcome relationships were investigated. MATERIAL AND METHODS: Nationwide routine data from insured patients of the Local Health Insurance Fund (AOK) who underwent thyroid surgery between 2008 and 2010 were analyzed. Complications were determined based on indicators for permanent vocal cord palsy, re-bleeding with re-operations and wound infections with specific treatment. The effect of hospital volumes (volume quintiles) on the indicators was determined by multivariate logistic regression. RESULTS: A total of 66,902 thyroid gland operations were identified. The overall frequency of permanent vocal cord palsy was 1.5 %, re-bleeding 1.8 % and wound infections 0.4 %. In the four lowest case volume categories the risk of permanent vocal cord palsy was significantly higher compared to the highest case volume hospitals (odds ratio 1.5, 1.7, 1.7 and 2.2, respectively). CONCLUSION: This study represents the reality of healthcare for thyroid surgery in Germany. Additionally, it was determined that the risk for permanent vocal cord palsy after thyroid gland operations decreased with increasing case volumes of hospitals. PMID- 27510157 TI - Determinants of patients' needs in asthma treatment: a cross-sectional study. AB - Patients' needs in asthma remain insufficiently understood and met. We therefore aimed to investigate the potential determinants of patients' needs in asthma treatment. Our study was based on survey data on 189 adults with asthma. Needs were measured using the 13-item Needs in Asthma Treatment questionnaire, which yields a total score and subscale-specific scores ('exacerbations', 'patient expertise', 'handling drugs' and 'drug effects'). We considered age, sex, education, years since diagnosis and anxiety/depression (measured by the Patient Health Questionnaire-4) as potential determinants. Associations were estimated by multivariable linear regression. Overall, we observed that younger age, poor mental health and a more recently established asthma diagnosis were independently associated with increased needs. Information on drug effects was an exception to this pattern as the need in that domain was solely determined by sex (being greater in men). In conclusion, our study provides novel evidence on patient characteristics that are associated with needs in asthma treatment. If confirmed by future studies, our observations may assist healthcare professionals to identify asthma patients with potentially elevated information, support and training needs and could contribute to the development of tailored interventions. PMID- 27510158 TI - Inhibitory effects of B-cell translocation gene 2 on skin cancer cells via the Wnt/beta-catenin signaling pathway. AB - B-cell translocation gene 2 (BTG2), a tumor suppressor gene, is downregulated in several types of human cancer cell. However, its function in skin cancer cells has not been fully elucidated. Therefore, the present study investigated the expression and function of BTG2 in skin cancer cells, and investigated the underlying molecular mechanism. The results indicated that BTG2 expression was downregulated in skin cancer cell lines. Overexpression of BTG2 significantly inhibited cell proliferation, cell cycle progression, and the invasion and migration of skin cancer cells. Furthermore, it was determined that overexpression of BTG2 significantly decreased the protein expression levels of beta-catenin, cyclin D1 and v-myc avian myelocytomatosis viral oncogene homolog in skin cancer cells. This suggests that BTG2 may function as a tumor suppressor by interfering with the Wnt/beta-catenin signaling pathway in skin cancer cells. Thus, novel therapeutic strategies and agents targeting BTG2 may be potential treatments for skin cancer. PMID- 27510160 TI - Lead line in rodents: an old sign of lead intoxication turned into a new method for environmental surveillance. AB - The "lead line" was described by Henry Burton in 1840. Rodents are used as sentinels to monitor environmental pollution, but their teeth have not been used to determine lead. To determine whether lead deposits can be observed in the teeth of lead-exposed animals, since the gingival deposits known as "lead line" would likely have a correlate in the calcified tissue to which the gums are opposed during life. Male Wistar rats were exposed to lead in the drinking water (30 mg/L) since birth until 60 days-old. Molars and the incisors of each hemimandible were analyzed by scanning electron microscopy (SEM) on regular and backscattered electrons (BSE) mode. Elements were determined using electron dispersive spectroscopy (EDS). Clean cervical margins were observed on control teeth, as opposed to the findings of extensive deposits on lead-exposed animals, even in hemimandibles that had been exhumed after being buried for 90 days. BSE/EDS indicated that those deposits were an exogenous material compatible with lead sulfite. Presence of calcium, phosphorus, magnesium, carbon, lead, and oxygen is presented. Lead-exposed animals presented marked root resorption. The lead deposits characterized here for the first time show that the "lead line" seen in gums has a calcified tissue counterpart, that is detectable post-mortem even in animals exposed to a low dose of lead. This is likely a good method to detect undue lead exposure and will likely have wide application for pollution surveillance using sentinels. PMID- 27510161 TI - Evaluation of the performances of a biological treatment on tin-enriched bronze. AB - Recently, research gives emphasis to eco-friendly and sustainable approaches for the preservation of cultural heritage that could offer advantages in terms of compatibility, durability and safety. Hence, a biological treatment, based on a specific fungal strain of Beauveria bassiana, is exploited for the stabilization of soluble and/or active bronze corrosion products, converting them into copper oxalates. The chemical stability of the latter represents a real improvement for the long-term preservation of bronze, especially in case of exposure to acid rain. However, the corrosion behaviour of bronze differs from that of pure copper due to the presence of additional alloying elements. In natural environments, the selective dissolution of copper leads to a relative tin-enrichment within the corrosion layers, mostly in unsheltered areas exposed to rainwater runoff. To understand the influence of tin-enrichment on the formation of oxalates, pure tin and artificially tin-enriched bronze coupons were treated with this novel biological system and, in the case of bronze coupons, exposed to accelerated ageing. Tin enrichment and accelerated ageing were performed through runoff tests. Before and after treatment and ageing, the sample surface was characterized through Fourier transform infrared (FTIR) and Raman spectroscopies, scanning electron microscopy coupled to energy dispersive spectroscopy (SEM-EDS). Metals released in the ageing solutions were analysed through atomic absorption spectrometry (AAS). The analytical results allowed to better understand the response of unsheltered areas from outdoor bronze monuments to the biological treatment proposed. PMID- 27510159 TI - Hepatic and serum lipid signatures specific to nonalcoholic steatohepatitis in murine models. AB - Nonalcoholic fatty liver (NAFL) is a precursor of nonalcoholic steatohepatitis (NASH), a condition that may progress to cirrhosis and hepatocellular carcinoma. Markers for diagnosis of NASH are still lacking. We have investigated lipid markers using mouse models that developed NAFL when fed with high fat diet (HFD) or NASH when fed using methionine choline deficient diet (MCDD). We have performed a comprehensive lipidomic analysis on liver tissues as well as on sera from mice fed HFD (n = 5), MCDD (n = 5) or normal diet as controls (n = 10). Machine learning approach based on prediction analysis of microarrays followed by random forests allowed identifying 21 lipids out of 149 in the liver and 14 lipids out of 155 in the serum discriminating mice fed MCDD from HFD or controls. In conclusion, the global approach implemented allowed characterizing lipid signatures specific to NASH in both liver and serum from animal models. This opens new avenue for investigating early and non-invasive lipid markers for diagnosis of NASH in human. PMID- 27510162 TI - Advanced oxidative processes and membrane separation for micropollutant removal from biotreated domestic wastewater. AB - The presence of micropollutants in sewage is already widely known, as well as the effects caused by natural and synthetic hormones. Thus, it is necessary to apply treatments to remove them from water systems, such as advanced oxidation processes (AOPs) and membrane separation processes, which can oxidize and remove high concentrations of organic compounds. This work investigated the removal of 17beta-estradiol (E2), 17alpha-ethinylestradiol (EE2), and estriol (E3) from biotreated sewage. Reverse osmosis processes were conducted at three recoveries (50, 60, and 70 %). For E2 and EE2, the removals were affected by the recovery. The best results for RO were as follows: the E2 compound removal was 89 % for 60 % recovery and the EE2 compound removal was 57 % for 50 % recovery. The RO recovery did not impact the E3 removal. It was concluded that the interaction between the evaluated estrogens, and the membrane was the major factor for the hormone separation. The AOP treatment using H2O2/UV was carried out in two sampling campaigns. First, we evaluated the variation of UV doses (24.48, 73.44, 122.4, and 244.8 kJ m-2) with 18.8 mg L-1 of H2O2 in the reaction. EE2 showed considerable removals (around 70 %). In order to optimize the results, an experimental design was applied. The best result was obtained with higher UV dose (122.4 kJ m-2) and lower H2O2 concentration (4 mg L-1), achieving removal of 91 % for E3 and 100 % for E2 and EE2. PMID- 27510163 TI - Comparison of single extraction procedures and the application of an index for the assessment of heavy metal bioavailability in river sediments. AB - Metals in sediments are present in different chemical forms which affect their ability to transfer. The objective of this body of work was to compare different extraction methods for the bioavailability evaluation of some elements, such as Ba, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Ni, Pb, V and Zn from Serbian river sediments. A bioavailability risk assessment index (BRAI) was used for the quantification of heavy metal bioavailability in the sediments. Actual and potential element availability was assessed by single extractions with mild (CaCl2 and CH3COONH4) and acidic (CH3COOH) extractants and complexing agents (EDTA). Aqua regia extraction was used for the determination of the pseudo-total element content in river sediments. In different single extraction tests, higher extraction of Cd, Cu, Zn and Pb was observed than for the other elements. The results of the single extraction tests revealed that there is a considerable chance of metal leaching from the sediments assessed in this study. When the BRAI was applied, the results showed a high risk of heavy metal bioavailability in Serbian river sediments. PMID- 27510164 TI - Antibiotic resistance, efflux pump genes and virulence determinants in Enterococcus spp. from surface water systems. AB - The aim of this study was to report on antibiotic susceptibility patterns as well as highlight the presence of efflux pump genes and virulence genetic determinants in Enterococcus spp. isolated from South African surface water systems. One hundred and twenty-four Enterococcus isolates consisting of seven species were identified. Antimicrobial susceptibility testing revealed a high percentage of isolates was resistant to beta-lactams and vancomycin. Many were also resistant to other antibiotic groups. These isolates were screened by PCR, for the presence of four efflux pump genes (mefA, tetK, tetL and msrC). Efflux genes mefA and tetK were not detected in any of the Enterococcus spp. However, tetL and msrC were detected in 17 % of the Enterococcus spp. The presence of virulence factors in the Enterococcus spp. harbouring efflux pump genes was determined. Virulence determinants were detected in 86 % of the Enterococcus spp. harbouring efflux pump genes. Four (asa1, cylA, gel and hyl) of the five virulence factors were detected. The findings of this study have demonstrated that Enterococcus from South African surface water systems are resistant to multiple antibiotics, some of which are frequently used for therapy. Furthermore, these isolates harbour efflux pump genes coding for resistance to antibiotics and virulence factors which enhance their pathogenic potential. PMID- 27510165 TI - Efficacy of Bt maize producing the Cry1Ac protein against two important pests of corn in China. AB - Ostrinia furnacalis (Guenee) and Helicoverpa armigera (Hubner) are the most important pests of maize in China. A laboratory study and a 2-year field study on the efficacy of transgenic maize expressing the Cry1Ac protein BT38 against O. furnacalis and H. armigera were performed. We found that the husks, kernels, and silks of BT38 showed significant efficacy against larvae of O. furnacalis and H. armigera. In the field, when neonate larvae of O. furnacalis and H. armigera were on plants at different growth stages and when levels of leaf-damage or number of damaged silks were used to score efficacy, we found that BT38 showed significant insecticidal efficacy against O. furnacalis and H. armigera, but the non-Bt maize did not show significant efficacy against either pest. These results suggest that the insecticidal efficacy of Bt maize expressing the Cry1Ac protein could be useful in the integrated pest management of these key maize pests. PMID- 27510166 TI - Bio- and toxic elements in edible wild mushrooms from two regions of potentially different environmental conditions in eastern Poland. AB - In the present study, the composition of bio-elements (K, Na, Mg, Ca, Fe, Cu, Zn) and toxic elements (Ag, Cd) in seven edible mushrooms from the rural and woodland region of Morag (north-eastern Poland) and the rural and industrial region of the Tarnobrzeska Upland (south-eastern Poland) were investigated using a validated method. The species examined were Boletus edulis, Cantharellus cibarius, Leccinum aurantiacum, Leccinum versipelle, Lycoperdon perlatum, Suillus luteus, and Xerocomus subtomentosus. Final determination was carried out by flame atomic absorption spectroscopy (FAAS) after microwave-assisted decomposition of sample matrices with solutions of concentrated nitric acid in the pressurized polytetrafluoroethylene vessels. The contents of the alkali elements and alkali earth elements were determined in the species surveyed. The alkali elements, earth alkali elements, and transition metals (Ag, Cu, Zn, Fe, and Mn) were at typical concentrations as was determined for the same or similar species elsewhere in Poland and Europe. The results may suggest a lack of local and regional emissions of those metallic elements from industrialization of some sites in the Tarnobrzeska Plain. Cadmium was at elevated concentrations in L. versipelle from the Tarnobrzeska Plain but the reason-pollution or geogenic source-was unknown, while it was at typical concentrations in other species. PMID- 27510167 TI - What can authors do for the papers they published in predatory journals? PMID- 27510168 TI - The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function. AB - Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer's disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer's and age related cognitive impairments may rely on its ability to modulate GR actions. PMID- 27510170 TI - A novel TBX20 loss-of-function mutation contributes to adult-onset dilated cardiomyopathy or congenital atrial septal defect. AB - Dilated cardiomyopathy (DCM) is the most prevalent form of primary cardiomyopathy in humans and is a leading cause of heart failure and sudden cardiac death. Genetic abnormalities have been demonstrated to be a major contributor to the development of DCM. However, DCM is a genetically heterogeneous disease, and the genetic basis underlying DCM in a significant proportion of patients remains unclear. In the current study, the coding exons and splicing junction sites of the T-Box 20 (TBX20) gene, which encodes a T-box transcription factor essential for cardiac morphogenesis and structural remodeling, were sequenced in 115 unrelated patients with idiopathic DCM, and a novel heterozygous mutation, p.E143X, was identified in one patient. Genetic analysis of the mutation carrier's pedigree indicated that the nonsense mutation was present in all the living family members with DCM, and also in a female patient with a congenital atrial septal defect. The mutation, which was predicted to generate a truncated protein with only the N-terminus and a fraction of the T-box domain remaining, was absent in 800 control chromosomes. Functional assays using a dual-luciferase reporter assay system revealed that the truncated TBX20 protein had no transcriptional activity in contrast to its wild-type counterpart. Furthermore, the mutation abolished the synergistic activation between TBX20 and NK2 homeobox 5, or between TBX20 and GATA binding protein 4. The observations of the current study expand the mutation spectrum of TBX20 associated with DCM and congenital heart disease (CHD), which provide novel insight into the molecular mechanisms underlying DCM and CHD, suggesting the potential implications for the effective and personalized treatment of these diseases. PMID- 27510169 TI - Zika virus disease: a current review of the literature. AB - BACKGROUND: The massive pandemic of Zika virus (ZIKV) infection is spreading through South America, Central America, the Caribbean, and possibly the USA. It is the most recent of four surprising appearances of imperative arthropod-borne viral illnesses in the Western Hemisphere over the preceding 20 years. OBJECTIVE: The objective of this narrative review is to summarize the existing knowledge about the epidemiology, transmission, clinical manifestations, complications, replication, pathogenesis, diagnosis, and treatment and prevention of ZIKV infection. METHODS: We used electronic databases to identify relevant published data regarding ZIKV in BOOLEAN and MeSH searches. CONCLUSION: This review concludes that the ZIKV predominantly circulates in arboreal mosquitoes (e.g., Aedes africanus) and wild primates. It rarely causes severe infection in humans, even in extremely enzootic regions. Currently, we do not have any efficacious drugs against ZIKV infection. However, there are virus-specific therapeutic targets, which may lead to the development of targeted anti-ZIKV drugs. PMID- 27510171 TI - Retention in Porous Layer Pillar Array Planar Separation Platforms. AB - This work presents the retention capabilities and surface area enhancement of highly ordered, high-aspect-ratio, open-platform, two-dimensional (2D) pillar arrays when coated with a thin layer of porous silicon oxide (PSO). Photolithographically prepared pillar arrays were coated with 50-250 nm of PSO via plasma-enhanced chemical vapor deposition and then functionalized with either octadecyltrichlorosilane or n-butyldimethylchlorosilane. Theoretical calculations indicate that a 50 nm layer of PSO increases the surface area of a pillar nearly 120-fold. Retention capabilities were tested by observing capillary-action-driven development under various conditions, as well as by running one-dimensional separations on varying thicknesses of PSO. Increasing the thickness of PSO on an array clearly resulted in greater retention of the analyte(s) in question in both experiments. In culmination, a two-dimensional separation of fluorescently derivatized amines was performed to further demonstrate the capabilities of these fabricated platforms. PMID- 27510172 TI - How FSH and AMH reflect probabilities of oocyte numbers in poor prognosis patients with small oocyte yields. AB - In poor prognosis patients undergoing in vitro fertilization, advance determinations of likely oocyte yields are especially important since oocyte numbers to large degree determine in vitro fertilization cycle outcomes. Based on baseline follicle stimulating hormone and anti-mullerian hormone levels at time of initial presentation, we here, therefore, determined at all ages the probabilities of obtaining 1->=5 oocytes in a retrospective analysis of 1554 consecutive patients undergoing in vitro fertilization cycles at an academically affiliated private fertility center. At lowest levels (<=2.5 mIU/mL), Follicle stimulating hormone at all ages was highly predictable for >=1 oocyte (88-96 %). Probabilities declined and diverged between ages with increasing follicle stimulating hormone, though narrowed again at high follicle stimulating hormone. Anti-Mullerian hormone demonstrated at higher levels (2.5->=5 ng/ml) at all ages almost perfect probabilities (99-100 %). With declining anti-Mullerian hormone, age categories, however, increasingly diverged, though to lesser degree than follicle stimulating hormone. In poor prognosis patients, follicle stimulating hormone and anti-Mullerian hormone, thus, offer at different ages very specific probabilities for retrieval of 1->=5 oocytes. Since oocyte numbers are associated with embryo numbers, and numbers of transferable embryos with live birth rates, here presented probability tables should facilitate improved prognostication of poor prognosis patients. Discrepancies in here reported probabilities between follicle stimulating hormone and anti-mullerian hormone also further define follicle stimulating hormone and anti-mullerian hormone in their respective abilities to represent functional ovarian reserve at different ages. PMID- 27510173 TI - Physical exam in asymptomatic people drivers the detection of thyroid nodules undergoing ultrasound guided fine needle aspiration biopsy. AB - Understanding epidemiology and the factors leading to thyroid nodule diagnosis might help alter the course of the thyroid cancer epidemic. Population-based study using the Rochester Epidemiology Project database between 2003 and 2006. Patients with thyroid nodules who underwent ultrasound guided fine needle aspiration biopsy were included. We identified 453 patients with 520 thyroid nodules undergoing ultrasound guided fine needle aspiration. Patients were mostly women (n: 349, 77 %) with a mean age of 52 (standard deviation 17) years. The age adjusted and sex-adjusted incidence of ultrasound guided fine needle aspiration thyroid nodules between 2003 and 2006 was 89 (95 % confidence interval, 80-97) per 100,000 person-years; the incidence in women was 130 (95 % confidence interval, 117-144), and for men 43 (95 % confidence interval, 35-52) per 100,000 person-years. The incidence of ultrasound guided fine needle aspiration-thyroid nodules increased by 42 %, from 68 (95 % confidence interval, 54-82) in 2003 to 97 (95 % confidence interval, 80-113) per 100,000 person-years in 2006. The group with the highest incidence was patients between 70 and 79 years of age, 258 per 100,000 person-years. Most ultrasound guided fine needle aspiration-thyroid nodules were found in asymptomatic patients (n: 371, 82 %) by physical examination (n: 197, 43 %) or on imaging studies performed for non-thyroid issues (n: 108, 24 %). Women were more likely to have nodules detected by palpation (45 %), whereas imaging and physical examination contributed similarly in men (39 and 38 %). There is a large and rapid increase in the ultrasound guided fine needle aspiration-thyroid nodules, particularly among women and elderly patients which mirrors the trends observed in thyroid cancer. Most thyroid nodules were found in asymptomatic patients as a result of routine physical examination or imaging. PMID- 27510174 TI - Lung Microtissue Array to Screen the Fibrogenic Potential of Carbon Nanotubes. AB - Due to their excellent physical and chemical characteristics, multi-wall carbon nanotubes (MWCNT) have the potential to be used in structural composites, conductive materials, sensors, drug delivery and medical imaging. However, because of their small-size and light-weight, the applications of MWCNT also raise health concerns. In vivo animal studies have shown that MWCNT cause biomechanical and genetic alterations in the lung tissue which lead to lung fibrosis. To screen the fibrogenic risk factor of specific types of MWCNT, we developed a human lung microtissue array device that allows real-time and in-situ readout of the biomechanical properties of the engineered lung microtissue upon MWCNT insult. We showed that the higher the MWCNT concentration, the more severe cytotoxicity was observed. More importantly, short type MWCNT at low concentration of 50 ng/ml stimulated microtissue formation and contraction force generation, and caused substantial increase in the fibrogenic marker miR-21 expression, indicating the high fibrogenic potential of this specific carbon nanotube type and concentration. The presented microtissue array system provides a powerful tool for high-throughput examination of the therapeutic and toxicological effects of target compounds in realistic tissue environment. PMID- 27510175 TI - Clinical presentation of CAD and myocardial ischemia in women. AB - Angina is the most frequent initial and subsequent manifestation of ischemic heart disease in women. Women with stable ischemic heart disease have a more diverse symptom presentation than men, with prominent anginal equivalents; symptoms are more often precipitated by emotional or mental stress. Women, especially at younger age, whose acute myocardial infarction presentation is without chest pain have higher mortality rates than men without chest pain. PMID- 27510176 TI - Comparison of the prognostic value of myocardial perfusion imaging using a CZT SPECT camera with a conventional anger camera. AB - BACKGROUND: Recent studies have shown that myocardial perfusion imaging (MPI) in cadmium-zinc-telluride (CZT) cameras allow faster exams with less radiation dose but there are little data comparing its prognosis information with that of dedicated cardiac Na-I SPECT cameras OBJECTIVE: The objective of this study is to compare the prognostic value of MPI using an ultrafast protocol with low radiation dose in a CZT-SPECT and a traditional one. METHODS: Group 1 was submitted to a two-day MIBI protocol in a conventional camera, and group 2 was submitted to a 1-day MIBI protocol in CZT camera. MPI were classified as normal or abnormal, and perfusion scores were calculated. Propensity score matching methods were performed RESULTS: 3554 patients were followed during 33+/-8 months. Groups 1 and 2 had similar distribution of age, gender, body mass index, risk factors, previous revascularization, and use of pharmacological stress. Group 1 had more abnormal scans, higher scores than group 2. Annualized hard events rate was higher in group 1 with normal scans but frequency of revascularization was similar to normal group 2. Patients with abnormal scans had similar event rates in both groups CONCLUSION: New protocol of MPI in CZT-SPECT showed similar prognostic results to those obtained in dedicated cardiac Na-I SPECT camera, with lower prevalence of hard events in patients with normal scan. PMID- 27510177 TI - Effects of molecular chirality on self-assembly and switching in liquid crystals at the cross-over between rod-like and bent shapes. AB - A bent-core compound derived from a 4-cyanoresorcinol core unit with two terephthalate based rod-like wings and carrying chiral 3,7-dimethyloctyloxy side chains has been synthesized in racemic and enantiomerically pure form and characterized by polarizing microscopy, differential scanning calorimetry, X-ray diffraction and electro-optical investigations to study the influence of molecular chirality on the superstructural chirality and polar order in lamellar liquid crystalline phases. Herein we demonstrate that the coupling of molecular chirality with superstructural layer chirality in SmCsPF domain phases (forming energetically distinct diastereomeric pairs) can fix the tilt direction and thus stabilize synpolar order, leading to bistable ferroelectric switching in the SmC* phases of the (S)-enantiomer, whereas tristable modes determine the switching of the racemate. Moreover, the mechanism of electric field induced molecular reorganization changes from a rotation around the molecular long axis in the racemate to a rotation on the tilt-cone for the (S)-enantiomer. At high temperature the enantiomer behaves like a rod-like molecule with a chirality induced ferroelectric SmC* phase and an electroclinic effect in the SmA'* phase. At reduced temperature sterically induced polarization, due to the bent molecular shape, becomes dominating, leading to much higher polarization values, thus providing access to high polarization ferroelectric materials with weakly bent compounds having only "weakly chiral" stereogenic units. Moreover, the field induced alignment of the SmCsPF(()*()) domains gives rise to a special kind of electroclinic effect appearing even in the absence of molecular chirality. Comparison with related compounds indicates that the strongest effects of chirality appear for weakly bent molecules with a relatively short coherence length of polar order, whereas for smectic phases with long range polar order the effects of the interlayer interfaces can override the chirality effects. PMID- 27510178 TI - Identifying the position of the right atrium to align pressure transducer for CVP : Spirit level or 3D electromagnetic positioning? AB - The central venous pressure, CVP, is an important variable in the management of selected perioperative and intensive care cases and in clinical decision support systems, CDSS. In current routine, when measuring CVP the health care provider may use anatomical landmarks and a spirit level, SL, to adjust the pressure transducer to the level of the tricuspid valve, i.e. the phlebostatic axis. The aim of the study was to assess the agreement in the postoperative setting between the SL method and electromagnetic 3D positioning (EM). CVP was measured with patients in positions dictated by nursing routines. The staff members measured CVP using SL to position the transducer at the perceived phlebostatic level. This position was compared to coordinates based on an electromagnetic field with external sensors at anatomical landmarks and an internal sensor in the CV catheter for 3D determination of the phlebostatic axis. An electronic survey took bearing on the accepted error in measurement among colleagues at the department. There was a clinically relevant difference between the CVP measured by the staff members and the CVP based on the 3D EM positioning. The limits of agreement extended in excess of +/-8 mmHg and half of the measurements had deviations outside an accepted error range of +/-2.5 mmHg. There was a large variation in CVP measurements when assessing the agreement with the current method. This may indicate the need for improvement in accuracy, e.g. using the electromagnetic field positioning system, in association with routine monitoring and clinical decision support systems. PMID- 27510179 TI - Selective expansion of regulatory T cells during lenalidomide treatment of myelodysplastic syndrome with isolated deletion 5q. AB - Lenalidomide (LEN) leads to erythroid improvement in the majority of patients with myelodysplastic syndrome and isolated deletion of the long arm of chromosome 5 (MDS-del(5q)). This effect is believed to be exerted via its immunomodulatory properties, although the precise nature is still incompletely understood. We prospectively performed immune profiling in the bone marrow and blood of MDS del(5q) patients undergoing LEN therapy for a median of 6 cycles. Therapy with LEN led to a significant increase in the median absolute lymphocyte count (1.3 fold, p = 0.013) without changes in the distribution of the T helper cells within the entire compartment. In parallel, the frequency of Treg increased significantly during treatment both in the peripheral blood (5.0 vs. 9.6 %, p = 0.001) and bone marrow (3.4 vs. 8.1 %, p = 0.001). Surprisingly, LEN treatment led to a decrease in TGFbeta levels, both in the peripheral blood (4.9 vs. 2.3 ng/ml, p = 0.039) and bone marrow (4.5 vs. 0.8 ng/ml, p = 0.023). These changes were not associated with an increase in pro-inflammatory Th17 cells. Taken together, our results demonstrate that LEN induces a shift in lymphocytic populations towards immunosuppression in MDS-del(5q) patients. PMID- 27510180 TI - Evaluation of neutrophil-lymphocyte ratio in patients with early-stage mycosis fungoides. AB - Neutrophil-lymphocyte ratio (NLR), an indicator of inflammation, has been lately demonstrated as a prognostic factor and an indicator of disease activity in various diseases. However, the effects of NLR have not been investigated in mycosis fungoides (MF) patients yet. The aim of this study is to investigate the relationship between the NLR and treatment demand (systemic PUVA and/or chemotherapy), time to treatment, progression in stage, and time to progression in stage in MF patients. The data of 117 patients, who were followed with the diagnosis of MF at the Department of Dermatology in Istanbul Training and Research Hospital between April 2006 and January 2016, were analyzed retrospectively. The cutoff score for NLR was determined as 2 according to the median NLR level which was 1.96. At the time of diagnosis, the median age of patients was 54 years (range, 21-90) with 62 (53 %) female and 55 (47 %) male. Seventy-seven (65.8 %) patients required treatment during follow-up. Sixty-three (53.8 %) patients showed progression in disease stage. There was no significant difference in treatment demand, time to treatment, progression in stage, and time to progression in stage in patients with a NLR >= 2 and NLR < 2 (p = 0.331, 0.987, 0.065, and 0.119, respectively). It seems that there is no association between the NLR and treatment demand, time to treatment, progression in stage, and time to progression in stage in MF patients. PMID- 27510181 TI - Screening of plasmid-mediated MCR-1 colistin-resistance from bacteremia. PMID- 27510182 TI - Mutant prevention concentration of colistin alone and in combination with rifampicin for multidrug-resistant Acinetobacter baumannii. AB - Colistin-susceptible isolates of Acinetobacter baumannii often contain subpopulations that are resistant to colistin. Monotherapy with colistin can lead to selective growth of these subpopulations and emergence of colistin-resistant strains. Our objectives were to explore the susceptibility pattern of colistin resistant subpopulations and investigate if combining colistin with a second antibiotic could prevent their selective growth. Four colistin-susceptible clinical isolates of A. baumannii and one reference isolate were used. The mutant prevention concentration (MPC) of colistin, i.e. the concentration required to block growth of all single-step-mutant subpopulations, was determined by plating an inoculum of 109 CFU on Mueller Hinton agar (MHA)-plates containing 2-fold dilutions of colistin (0.125-128 mg/L). Susceptibility testing of colistin resistant subpopulations, obtained in the MPC assay, was performed with Etest. The MPC of colistin, in combination with rifampicin, was determined by plating an inoculum of 109 CFU on MHA-plates containing colistin (0.125-128 mg/L) and fixed concentrations of rifampicin (1.1 mg/L or 4.4 mg/L). The colistin-resistant subpopulations demonstrated increased susceptibility to a number of agents compared to their main populations. These subpopulations were even susceptible to agents that normally are inactive against gram-negative bacteria and all had rifampicin MICs of < 0.002 mg/L. The combination of colistin and rifampicin completely inhibited the growth of all colistin-resistant subpopulations and significantly lowered the MPC of colistin for A. baumannii. Combining colistin with rifampicin could be a way to prevent selective growth of colistin-resistant subpopulations of A. baumannii and possibly the emergence of colistin-resistant strains. PMID- 27510183 TI - Increased Mortality in Adult Cystic Fibrosis Patients with Medicaid Insurance Awaiting Lung Transplantation. AB - PURPOSE: Cystic fibrosis (CF) is a progressive disease resulting in end-stage lung disease. Lung transplantation (LTx) is an important consideration in these patients. Studies have suggested greater post-LTx mortality among CF patients with public insurance. We evaluated the influence of insurance status on survival among CF patients during their time on the LTx waitlist. METHODS: Adult LTx candidates diagnosed with CF and listed since the implementation of the lung allocation score, from May 2005 until September 2013, were identified in the United Network for Organ Sharing database. Waitlist mortality was compared across projected primary payment type (private insurance or self-pay; Medicaid; Medicare) using Kaplan-Meier functions and Fine-Gray competing-risks survival analysis, accounting for the competing risk of transplantation. RESULTS: 1770 LTx candidates with CF were included in univariate survival analyses, with Medicaid increasing waitlist mortality hazard relative to private insurance (HR 2.28; 95 % CI 1.62, 3.21; p < 0.001) and relative to Medicare (HR 2.23; 95 % CI 1.43, 3.48; p < 0.001). A multivariable competing-risks model confirmed greater waitlist mortality among Medicaid patients relative to private insurance (HR 2.57; 95 % CI 1.56, 4.23; p < 0.001) or patients with Medicare (HR 4.02; 95 % CI 1.98, 8.17; p < 0.001) after adjusting for potential confounders. No differences in waitlist survival were found between Medicare and private insurance. CONCLUSIONS: CF patients with Medicaid insurance have higher risk of death while awaiting LTx when compared to patients with Medicare or private insurance. The impact of insurance status on survival in this population begins before LTx and compounds the disparities previously observed in post-transplant outcomes. PMID- 27510184 TI - Core-shell Cd0.2Zn0.8S@BiOX (X = Cl, Br and I) microspheres: a family of hetero structured catalysts with adjustable bandgaps, enhanced stability and photocatalytic performance under visible light irradiation. AB - Heterostructures consisting of two semiconductors have merited considerable attention in photocatalytic applications due to synergistic effects in complex redox processes. The incorporation of solid solutions into such architectures can further offer extra variability to control the bandgap. In this study, we report the fabrication of a series of core-shell Cd0.2Zn0.8S@BiOX (X = Cl, Br and I) microspheres via a solvothermal route that lead to enhanced photocatalytic performance under visible light irradiation. By optimizing the synthesis conditions, uniform and porous Cd0.2Zn0.8S@BiOX microspheres were achieved. The products were thoroughly characterized by X-ray diffraction studies, scanning electron microscopy, transmission electron microscopy, photoluminescence studies, absorption measurements and the photodegradation of RhB. Remarkably, the electronic structures of Cd0.2Zn0.8S@BiOX composites can be continuously tuned by varying the composition of BiOX to achieve the best catalytic performance under visible light irradiation. Finally, this greatly enhanced visible-light-driven photocatalytic efficiency was observed in the optimized Cd0.2Zn0.8S@BiOI composites when compared to their single-component counterparts, which may be attributed to increased light absorption and improved electron-hole separation. The photocatalytic mechanism has also been proposed based on the experimental evidences and the theoretical band positions of Cd0.2Zn0.8S@BiOI. PMID- 27510185 TI - Long-term chemotherapy-induced peripheral neuropathy among breast cancer survivors: prevalence, risk factors, and fall risk. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with chemotherapy, but researchers rarely study its risk factors, fall risk, and prevalence in long-term breast cancer survivors. We aimed to determine CIPN prevalence, risk factors, and association with psychological distress and falls among long-term breast cancer survivors. We conducted Cross-sectional analyses among postmenopausal women with a history of stage I-III breast cancer who received taxane-based chemotherapy. Participants reported neuropathic symptoms of tingling/numbness in hands and/or feet on a 0-10 numerical rating scale. We conducted multivariate logistic regression analyses to evaluate risk factors associated with the presence of CIPN and the relationship between CIPN and anxiety, depression, insomnia, and patient-reported falls. Among 296 participants, 173 (58.4 %) reported CIPN symptoms, 91 (30.7 %) rated their symptoms as mild, and 82 (27.7 %) rated them moderate to severe. Compared with women of normal weight, being obese was associated with increased risk of CIPN (adjusted OR 1.94, 95 % CI: 1.03-3.65). Patients with CIPN reported greater insomnia severity, anxiety, and depression than those without (all p < 0.05). Severity of CIPN was associated with higher rates of falls, with 23.8, 31.9, and 41.5 % in the "no CIPN," "mild," and "moderate-to-severe" groups, respectively, experiencing falls (p = 0.028). The majority of long-term breast cancer survivors who received taxane-based chemotherapy reported CIPN symptoms; obesity was a significant risk factor. Those with CIPN also reported increased psychological distress and falls. Interventions need to target CIPN and comorbid psychological symptoms, and incorporate fall prevention strategies for aging breast cancer survivors. PMID- 27510187 TI - Physicists need to make the case for high-energy experiments. PMID- 27510186 TI - Lifetime grain consumption and breast cancer risk. AB - We evaluated individual grain-containing foods and whole and refined grain intake during adolescence, early adulthood, and premenopausal years in relation to breast cancer risk in the Nurses' Health Study II. Grain-containing food intakes were reported on a baseline dietary questionnaire (1991) and every 4 years thereafter. Among 90,516 premenopausal women aged 27-44 years, we prospectively identified 3235 invasive breast cancer cases during follow-up to 2013. 44,263 women reported their diet during high school, and from 1998 to 2013, 1347 breast cancer cases were identified among these women. Cox proportional hazards regression was used to estimate relative risks (RR) and 95 % confidence intervals (95 % CI) of breast cancer for individual, whole and refined grain foods. After adjusting for known breast cancer risk factors, adult intake of whole grain foods was associated with lower premenopausal breast cancer risk (highest vs. lowest quintile: RR 0.82; 95 % CI 0.70-0.97; P trend = 0.03), but not postmenopausal breast cancer. This association was no longer significant after further adjustment for fiber intake. The average of adolescent and early adulthood whole grain food intake was suggestively associated with lower premenopausal breast cancer risk (highest vs lowest quintile: RR 0.74; 95 % CI 0.56-0.99; P trend = 0.09). Total refined grain food intake was not associated with risk of breast cancer. Most individual grain-containing foods were not associated with breast cancer risk. The exceptions were adult brown rice which was associated with lower risk of overall and premenopausal breast cancer (for each 2 servings/week: RR 0.94; 95 % CI 0.89-0.99 and RR 0.91; 95 % CI 0.85-0.99, respectively) and adult white bread intake which was associated with increased overall breast cancer risk (for each 2 servings/week: RR 1.02; 95 % CI 1.01-1.04), as well as breast cancer before and after menopause. Further, pasta intake was inversely associated with overall breast cancer risk. Our results suggest that high whole grain food intake may be associated with lower breast cancer risk before menopause. Fiber in whole grain foods may mediate the association with whole grains. PMID- 27510188 TI - A safe place for nuclear energy? PMID- 27510189 TI - Steer driverless cars towards full automation. PMID- 27510200 TI - Hopes for revolutionary new LHC particle dashed. PMID- 27510201 TI - Glider aims to break world record--and boost climate science. PMID- 27510202 TI - US agency to lift ban on funding human-animal hybrids. PMID- 27510204 TI - Replications, ridicule and a recluse: the controversy over NgAgo gene-editing intensifies. PMID- 27510203 TI - Beyond CRISPR: A guide to the many other ways to edit a genome. PMID- 27510205 TI - Plant and animal DNA suggests first Americans took the coastal route. PMID- 27510206 TI - The bandwidth bottleneck that is throttling the Internet. PMID- 27510207 TI - Biodiversity: The ravages of guns, nets and bulldozers. PMID- 27510210 TI - Education: Reforms set to seep into India's schools. PMID- 27510211 TI - Weather communications: Satellite company clarifies proposal. PMID- 27510212 TI - Funding: Would Mendel have won it? PMID- 27510213 TI - Funding: Spot value in grant proposals. PMID- 27510214 TI - Profiles: Kudos for female Antarctic researchers. PMID- 27510215 TI - Energy science: Fast track for silver. PMID- 27510217 TI - Synergistic, ultrafast mass storage and removal in artificial mixed conductors. AB - Mixed conductors-single phases that conduct electronically and ionically-enable stoichiometric variations in a material and, therefore, mass storage and redistribution, for example, in battery electrodes. We have considered how such properties may be achieved synergistically in solid two-phase systems, forming artificial mixed conductors. Previously investigated composites suffered from poor kinetics and did not allow for a clear determination of such stoichiometric variations. Here we show, using electrochemical and chemical methods, that a melt processed composite of the 'super-ionic' conductor RbAg4I5 and the electronic conductor graphite exhibits both a remarkable silver excess and a silver deficiency, similar to those found in single-phase mixed conductors, even though such behaviour is not possible in the individual phases. Furthermore, the kinetics of silver uptake and release is very fast. Evaluating the upper limit of the relaxation time [corrected] set by interfacial ambipolar diffusion reveals chemical diffusion coefficients that are even higher than those achieved for sodium chloride in bulk liquid water. These results could potentially stimulate systematic research into powerful, even mesoscopic, artificial mixed conductors. PMID- 27510220 TI - Assessing agricultural drought in summer over Oklahoma Mesonet sites using the water-related vegetation index from MODIS. AB - Agricultural drought, a common phenomenon in most parts of the world, is one of the most challenging natural hazards to monitor effectively. Land surface water index (LSWI), calculated as a normalized ratio between near infrared (NIR) and short-wave infrared (SWIR), is sensitive to vegetation and soil water content. This study examined the potential of a LSWI-based, drought-monitoring algorithm to assess summer drought over 113 Oklahoma Mesonet stations comprising various land cover and soil types in Oklahoma. Drought duration in a year was determined by the number of days with LSWI <0 (DNLSWI) during summer months (June-August). Summer rainfall anomalies and LSWI anomalies followed a similar seasonal dynamics and showed strong correlations (r 2 = 0.62-0.73) during drought years (2001, 2006, 2011, and 2012). The DNLSWI tracked the east-west gradient of summer rainfall in Oklahoma. Drought intensity increased with increasing duration of DNLSWI, and the intensity increased rapidly when DNLSWI was more than 48 days. The comparison between LSWI and the US Drought Monitor (USDM) showed a strong linear negative relationship; i.e., higher drought intensity tends to have lower LSWI values and vice versa. However, the agreement between LSWI-based algorithm and USDM indicators varied substantially from 32 % (D 2 class, moderate drought) to 77 % (0 and D 0 class, no drought) for different drought intensity classes and varied from ~30 % (western Oklahoma) to >80 % (eastern Oklahoma) across regions. Our results illustrated that drought intensity thresholds can be established by counting DNLSWI (in days) and used as a simple complementary tool in several drought applications for semi-arid and semi-humid regions of Oklahoma. However, larger discrepancies between USDM and the LSWI-based algorithm in arid regions of western Oklahoma suggest the requirement of further adjustment in the algorithm for its application in arid regions. PMID- 27510221 TI - Impact of the Molecular Environment on Thiol-Ene Coupling For Biofunctionalization and Conjugation. AB - Thiol-ene radical coupling is increasingly used for the biofunctionalization of biomaterials and the formation of 3D hydrogels enabling cell encapsulation. Indeed, thiol-ene chemistry presents interesting features that are particularly attractive for platforms requiring specific reactions of peptides or proteins, in particular, in situ, during cell culture or encapsulation. Despite such interest, little is known about the factors impacting thiol-ene chemistry in situ, under biologically relevant conditions. Here we explore some of the molecular parameters controlling photoinitiated thiol-ene couplings with a series of alkenes and thiols, including peptides, in buffered conditions. (1)H NMR and HPLC were used to quantify the efficiency of couplings and the impact of the pH of the buffer, as well as the molecular structure and local microenvironment close to alkenes and thiols to be coupled. Some of these observations are supported by molecular dynamics and quantum mechanics calculations. An important finding of our work is that the pKa of thiols (and its variation upon changes in molecular structure) have a striking impact on coupling efficiencies. Similarly, positively charged and aromatic amino acids are found to have some impact on thiol-ene couplings. Hence, our study demonstrates that molecular design should be carefully selected in order to achieve high biofunctionalization levels in biomaterials with peptides or promote the efficient formation of peptide-based hydrogels. PMID- 27510219 TI - Mapping B-cell responses to Salmonella enterica serovars Typhimurium and Enteritidis in chickens for the discrimination of infected from vaccinated animals. AB - Serological surveillance and vaccination are important strategies for controlling infectious diseases of food production animals. However, the compatibility of these strategies is limited by a lack of assays capable of differentiating infected from vaccinated animals (DIVA tests) for established killed or attenuated vaccines. Here, we used next generation phage-display (NGPD) and a 2 proportion Z score analysis to identify peptides that were preferentially bound by IgY from chickens infected with Salmonella Typhimurium or S. Enteritidis compared to IgY from vaccinates, for both an attenuated and an inactivated commercial vaccine. Peptides that were highly enriched against IgY from at least 4 out of 10 infected chickens were selected: 18 and 12 peptides for the killed and attenuated vaccines, respectively. The ten most discriminatory peptides for each vaccine were identified in an ELISA using a training set of IgY samples. These peptides were then used in multi-peptide assays that, when analysing a wider set of samples from infected and vaccinated animals, diagnosed infection with 100% sensitivity and specificity. The data describes a method for the development of DIVA assays for conventional attenuated and killed vaccines. PMID- 27510223 TI - Integrative analysis of human omics data using biomolecular networks. AB - High-throughput '-omics' technologies have given rise to an increasing abundance of genome-scale data detailing human biology at the molecular level. Although these datasets have already made substantial contributions to a more comprehensive understanding of human physiology and diseases, their interpretation becomes increasingly cryptic and nontrivial as they continue to expand in size and complexity. Systems biology networks offer a scaffold upon which omics data can be integrated, facilitating the extraction of new and physiologically relevant information from the data. Two of the most prevalent networks that have been used for such integrative analyses of omics data are genome-scale metabolic models (GEMs) and protein-protein interaction (PPI) networks, both of which have demonstrated success among many different omics and sample types. This integrative approach seeks to unite 'top-down' omics data with 'bottom-up' biological networks in a synergistic fashion that draws on the strengths of both strategies. As the volume and resolution of high-throughput omics data continue to grow, integrative network-based analyses are expected to play an increasingly important role in their interpretation. PMID- 27510222 TI - Single and multi-subject clustering of flow cytometry data for cell-type identification and anomaly detection. AB - BACKGROUND: Measurement of various markers of single cells using flow cytometry has several biological applications. These applications include improving our understanding of behavior of cellular systems, identifying rare cell populations and personalized medication. A common critical issue in the existing methods is identification of the number of cellular populations which heavily affects the accuracy of results. Furthermore, anomaly detection is crucial in flow cytometry experiments. In this work, we propose a two-stage clustering technique for cell type identification in single subject flow cytometry data and extend it for anomaly detection among multiple subjects. RESULTS: Our experimentation on 42 flow cytometry datasets indicates high performance and accurate clustering (F measure > 91 %) in identifying main cellular populations. Furthermore, our anomaly detection technique evaluated on Acute Myeloid Leukemia dataset results in only <2 % false positives. PMID- 27510224 TI - Paediatric heart sound signal analysis towards classification using multifractal spectra. AB - Healthy versus unhealthy heart sound computer-aided classification tools are very popular for supporting clinical decisions. In this paper a new method is proposed for the classification of heart sound recordings from a statistical standpoint without detection and localization of fundamental heart sounds (S1, S2). This study analyzes the possibility of detecting healthy heart sound signal from a large set of measurements, corresponding to different pathologies, such as aortic regurgitation, mitral regurgitation, aortic stenosis and ventricular septal defects. The proposed method employs singularity spectra analysis and long-term dependency of irregular structures. Healthy signals are firstly separated from the rest of the recordings. In the second step, the signals with a click syndrome, used here as a reference, are detected in the unhealthy group. Innocent murmurs have not been considered in this paper. Each auscultatory recording is classified into one of the following classes: healthy; click syndrome; and other heart dysfunctions. The results of the proposed method provided high recall and precision values for each of the three classes. Since the presence of additive noise may affect the classification, we also analyzed the possibility of classifying signals in such circumstances. The method was tested, verified and showed high accuracy. PMID- 27510226 TI - Renal replacement therapy during Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective observational study of 238 patients. PMID- 27510225 TI - Dietary and microbiome factors determine longevity in Caenorhabditis elegans. AB - Diet composition affects organismal health. Nutrient uptake depends on the microbiome. Caenorhabditis elegans fed a Bacillus subtilis diet live longer than those fed the standard Escherichia coli diet. Here we report that this longevity difference is primarily caused by dietary coQ, an antioxidant synthesized by E. coli but not by B. subtilis. CoQ-supplemented E. coli fed worms have a lower oxidation state yet live shorter than coQ-less B. subtilis fed worms. We showed that mutations affecting longevity for E. coli fed worms do not always lead to similar effects when worms are fed B. subtilis. We propose that coQ supplementation by the E. coli diet alters the worm cellular REDOX homeostasis, thus decreasing longevity. Our results highlight the importance of microbiome factors in longevity, argue that antioxidant supplementation can be detrimental, and suggest that the C. elegans standard E. coli diet can alter the effect of signaling pathways on longevity. PMID- 27510227 TI - [Preoperative auditory evaluation and postoperative follow-up in cochlear implantees : The role of objective measures]. AB - The primary diagnostic aim prior to cochlear implantation is establishment of a comprehensive and multidisciplinary diagnosis, in order to subsequently begin therapy as early as possible. Audiological evaluation prior to implantation employs a test battery-approach, including subjective and objective procedures. Objective measures show high reliability and therefore play a major role in the diagnosis of difficult-to-test subjects such as infants and young children. During postoperative follow-up, objective measures offer a valid method for analyzing the effects of different stimuli on the auditory system. Particularly in infants, children, and uncooperative patients, the results of these tests enable the speech processor settings to be optimized, the hearing benefit to be assessed, and treatment to be adapted accordingly. Auditory brainstem responses (ABR) offer an excellent test/retest and inter-/intrarater reliability and validity, and are the most commonly used method for objective hearing threshold estimation and evaluation of the functional integrity of the lower auditory pathway. The use of narrow-band stimuli allows frequency-specific threshold estimation; analysis of stationary auditory steady state potentials (ASSR) adds the advantages of automated objective detection. Electrocochleography and electrically evoked ABR give valuable information in special cases. The use of cortical potentials (CAEP) in response to speech stimuli is quite promising, although the high response variability currently limits this method's clinical application. An audiological test-battery approach combining the results of subjective and objective measures leads to significantly increased reliability of preoperative diagnosis and postoperative follow-up in cochlear implantees. PMID- 27510228 TI - [Robot-assisted surgery in the head and neck region]. AB - Robot-assisted surgery (RAS) in the head and neck region is believed to have a large potential for the improvement of patient care. Several systems with a master-slave setup are already in routine clinical use, particularly for oncologic surgery. Although specific patient groups may benefit from RAS, there is a lack of randomized clinical studies validating the advantages of these new technological systems in comparison to the existing standard procedures. On the other hand, RAS in the head and neck region is being constantly developed. Currently, the main limitations are the technical miniaturization of the tools and the loss of haptic feedback, as well as the high costs for acquisition and maintenance without financial reimbursement. In any case, the current generation of head and neck surgeons will face the technical, scientific, and ethical challenges of RAS. PMID- 27510229 TI - Effect of Left Atrial Wall Thickness on Radiofrequency Ablation Success. AB - INTRODUCTION: Radiofrequency (RF) ablation in thicker regions of the left atrium (LA) may require increased ablation energy in order to achieve effective transmural lesions. Consequently, many cases of recurrent atrial fibrillation (AF) postablation may be due to thicker-than-normal atrial tissue. The aim of this study was to test the hypotheses that patients with recurrent AF have thicker tissue overall and that electrical reconnection is more likely in regions of thicker tissue. METHODS AND RESULTS: Retrospective analysis was performed on 86 CT images acquired preoperatively from a cohort of 119 patients who had undergone RF ablation for AF. Of these, 33 patients experienced recurrence of AF within 1 year of initial treatment and 29 returned for a repeat ablation. For each patient, LA wall thickness (LAWT) was measured from the images in 12 anatomical regions using custom software. Patients with recurrent AF had larger LAWT compared to successfully treated patients (1.6 +/- 0.6 mm vs. 1.5 +/- 0.5 mm, P < 0.001) and reconnection was found to be at regions of thicker tissue (1.6 +/- 0.6 mm, P = 0.038) compared to nonreconnected regions (1.5 +/- 0.5 mm). The superior right posterior wall of the LA was significantly related to both recurrence (P = 0.048) and reconnection (P = 0.014). CONCLUSION: Increased LAWT has a small but significant effect on postablation recurrence and reconnection. Measures of LAWT may facilitate appropriate dosing of RF energy, but other factors will be critical in transmural lesion formation and ablation success. PMID- 27510231 TI - Retrospective assessment of childhood ADHD symptoms for diagnosis in adults: validity of a short 8-item version of the Wender-Utah Rating Scale. AB - The Wender-Utah Rating Scale (WURS) is a widely used self-report instrument for retrospective assessment of childhood ADHD. However, many WURS items are not specific to ADHD. Here, we investigated the effect of excluding these items on the performance of the WURS in predicting adult ADHD based on previous diagnosis and current clinically significant symptoms. The study was conducted on a sample of adults (n = 1014; 48 % male) participating in a family-based investigation of ADHD. Participants completed the 61-item WURS questionnaire and the 66-item Conners Adult ADHD Rating Scale. Receiver operating characteristic (ROC) curves were used to compare the performance of the eight-item WURS (WURS-8) and the longer WURS-25 in predicting previous ADHD diagnosis and current clinically significant ADHD symptoms. WURS-8 and WURS-25 have approximately the same power to predict adult ADHD, based on either previous diagnosis or current symptoms (area under the ROC curves >0.8). WURS-8 performs at least as well as the longer WURS-25 in predicting adult ADHD. This 8-item questionnaire is thus a valid instrument and is especially useful for screening for ADHD in large epidemiological samples. PMID- 27510232 TI - Simple and practical measures to reduce tuberculosis transmission in public buildings. PMID- 27510230 TI - Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer diagnosed worldwide. HCC occurs due to chronic liver disease and is often diagnosed at advanced stages. Chemotherapeutic agents such as doxorubicin are currently used as first-line agents for HCC therapy, but these are non-selective cytotoxic molecules with significant side effects. Sorafenib, a multi-targeted tyrosine kinase inhibitor, is the only approved targeted drug for HCC patients. However, due to adverse side effects and limited efficacy, there is a need for the identification of novel pharmacological drugs beyond sorafenib. Several agents that target and inhibit various signaling pathways involved in HCC are currently being assessed for HCC treatment. In the present review article, we summarize the diverse signal transduction pathways responsible for initiation as well as progression of HCC and also the potential anticancer effects of selected targeted therapies that can be employed for HCC therapy. PMID- 27510233 TI - Occupational exposure to tuberculosis in endemic areas: room for improvement. PMID- 27510234 TI - Isolation is not everything. PMID- 27510235 TI - Why patient-centered care matters. PMID- 27510236 TI - Implementing a spirometry program. PMID- 27510237 TI - Gatifloxacin for short, effective treatment of multidrug-resistant tuberculosis. AB - The 9-month regimen for the treatment of multidrug-resistant tuberculosis (MDR TB) piloted in Bangladesh and used, with modifications, in Cameroon and Niger, has achieved treatment success in a very large proportion of patients; gatifloxacin (GFX) is likely to have played a critical role in this success. Two months after the publication of a study reporting that GFX and not moxifloxacin (MFX) was associated with dysglycaemia, the manufacturer announced the withdrawal of GFX from the market. The findings of that study may have less significance for the majority of MDR-TB patients living in high-incidence countries who are much younger, have a lower risk of dysglycaemia and suffer from a highly fatal condition. The problem of dysglycaemia is not limited to GFX use and may occur with other fluoroquinolones; furthermore, GFX-associated dysglycemia was manageable among those MDR-TB patients in Bangladesh and Niger in whom it occurred. GFX has now become unavailable in Bangladesh, Cameroon, Niger and other countries piloting the shorter MDR-TB regimens, depriving resource-poor countries of an efficacious, effective and inexpensive drug with a demonstrated good safety profile for the given indication. There is little reason not to make GFX available for MDR-TB treatment as long as the superiority of non-GFX-based MDR-TB regimens is not demonstrated. PMID- 27510238 TI - Ending tuberculosis by 2030: can we do it? AB - The Sustainable Development Goals aim to end tuberculosis (TB) related deaths, transmission and catastrophic costs by 2030. Multisectorial action to accelerate socio-economic development, a new vaccine and novel diagnostics and medicines for treatment are key advances needed to end TB transmission. Achieving 90-90-90 targets for TB (i.e., 90% of vulnerable populations screened, 90% diagnosed and started on treatment, and at least 90% cured) will help accelerate progress towards reductions in mortality; however, passive case detection strategies, multidrug-resistant TB, human immunodeficiency virus coinfection and outdated pathways to care need to be overcome. Ending the catastrophic costs associated with TB will require expansion of health insurance coverage, comprehensive coverage of TB services, and limited indirect costs by vulnerable and poor populations. PMID- 27510239 TI - Measuring ventilation and modelling M. tuberculosis transmission in indoor congregate settings, rural KwaZulu-Natal. AB - SETTING: Molecular epidemiology suggests that most Mycobacterium tuberculosis transmission in high-burden settings occurs outside the home. OBJECTIVE: To estimate the risk of M. tuberculosis transmission inside public buildings in a high TB burden community in KwaZulu-Natal, South Africa. DESIGN: Carbon dioxide (CO2) sensors were placed inside eight public buildings. Measurements were used with observations of occupancy to estimate infection risk using an adaptation of the Wells-Riley equation. Ventilation modelling using CONTAM was used to examine the impact of low-cost retrofits on transmission in a health clinic. RESULTS: Measurements indicate that infection risk in the church, classroom and clinic waiting room would be high with typical ventilation, occupancy levels and visit durations. For example, we estimated that health care workers in a clinic waiting room had a 16.9-24.5% annual risk of M. tuberculosis infection. Modelling results indicate that the simple addition of two new windows allowing for cross ventilation, at a cost of US$330, would reduce the annual risk to health care workers by 57%. CONCLUSIONS: Results indicate that public buildings in this community have a range of ventilation and occupancy characteristics that may influence transmission risks. Simple retrofits may result in dramatic reductions in M. tuberculosis transmission, and intervention studies should therefore be considered. PMID- 27510240 TI - Occupational exposure and tuberculosis among medical residents in a high-burden setting: an open-cohort study. AB - SETTING: Postgraduate (PG) residency programme of a tertiary care teaching hospital in southern India. OBJECTIVE: To estimate the incidence of tuberculosis (TB) among PG residents, determine the frequency of exposure to infectious TB patients and assess whether particular specialties were associated with higher risk of exposure and incident TB. DESIGN: We assembled an open cohort of PG residents who were on the academic rolls for more than 3 months at any time between December 2011 and January 2013. We collected data both retrospectively and prospectively using two surveys-an entry survey at study initiation or entry into the cohort, and an exit survey at residency completion or study closure. RESULTS: Among 398 PG residents enrolled in the study, we identified five cases of incident TB during a cumulative follow-up period of 10 962 person-months. The incidence rate was 547 per 100 000 person-years, which was 3.1 times the incidence in the general population. Nearly two thirds (n = 257, 65%) of the residents were exposed to at least one infectious patient. Across the three specialty-based risk strata, there was an ordered increase in the median number of exposures (P < 0.001) and evaluation for presumptive TB (P = 0.024), as well as a trend towards higher incident TB. CONCLUSION: TB incidence is significantly higher among PG residents than in the general population. PMID- 27510241 TI - Errors in isolation of patients with infectious tuberculosis at a public teaching hospital in New York. AB - BACKGROUND: Studies report variability in the rates and causes of isolation errors among in-patients with active tuberculosis (TB). We reviewed our experience with delays or premature discontinuation of airborne infection isolation (AII). METHODS: Medical records of patients admitted to the Bellevue Hospital Center, New York City Health & Hospitals, New York, NY, USA, between January 2006 and July 2012 with a positive respiratory culture for Mycobacterium tuberculosis were reviewed. Patients who were out of AII despite being infectious were identified, as the episodes had prompted a contact investigation. RESULTS: Of 246 admissions with positive respiratory cultures, 35 AII errors were identified among 27 patients. Most patients had signs or symptoms of TB on admission. Only four patients had positive sputum smears. In 16 (46%) episodes, the patients had never been isolated, 11 (31%) had delayed isolation, and 8 (23%) were prematurely taken off AII. The most common reasons for patients being off AII while infectious were an incorrect alternative diagnosis (15/35, 43%) or a dual diagnosis (9/35, 26%). CONCLUSIONS: Particularly in smear-negative cases, AII errors due to TB may occur when providers conclude that another diagnosis explains their findings. In many cases, that diagnosis is correct, but TB is also present. This error rate might be a useful quality indicator. PMID- 27510242 TI - Measurement of levels of fractional exhaled nitric oxide in patients with pulmonary tuberculosis. AB - SETTING: The role of fractional exhaled nitric oxide (FeNO) in the diagnosis and treatment of pulmonary tuberculosis (PTB) is uncertain. OBJECTIVE: To examine the value of FeNO as a biomarker for PTB. DESIGN: Baseline FeNO levels were compared in 69 PTB patients and 118 healthy controls. The correlation between baseline FeNO levels and clinical variables of tuberculosis were studied. FeNO levels were checked twice in the PTB group, at diagnosis and after 2 months of anti tuberculosis medication, and factors affecting changes in FeNO levels after treatment were analysed. RESULTS: FeNO levels were not significantly different in the PTB group and controls (mean +/- standard deviation 27.7 +/- 17.6 parts per billion [ppb] vs. 27.0 +/- 10.8 ppb, P = 0.531). In a multivariate regression analysis, no variable was shown to affect FeNO levels at diagnosis. FeNO levels did not significantly change after 2 months of treatment (26.8 +/- 18.3 ppb vs. 24.0 +/- 10.7 ppb, P = 0.257). Only PTB with a high FeNO level (>25 ppb) was related to a decline in FeNO levels after 2 months of treatment. CONCLUSION: FeNO levels do not appear to be affected in PTB patients. PMID- 27510243 TI - Improved tuberculosis outcomes with daily vs. intermittent rifabutin in HIV-TB coinfected patients in India. AB - SETTING: Y R Gaitonde Centre for AIDS Research and Education, Chennai, India. OBJECTIVE: To compare anti-tuberculosis treatment outcomes in individuals with human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection on atazanavir/ritonavir (ATV/r) antiretroviral therapy (ART) plus daily rifabutin (RBT) 150 mg with those on ATV/r plus thrice-weekly RBT 150 mg. DESIGN: A retrospective study was conducted of two HIV-TB co-infected cohorts between 2003 and 2014. Basic demographic and TB outcome data were obtained from an electronic database and patient records. The chi(2) and Fisher's exact test were used to compare daily and intermittent RBT treatment groups. RESULTS: Of 292 individuals on an ATV/r-based ART regimen plus RBT, 118 (40.4%) received thrice-weekly RBT and 174 (59.6%) daily RBT. Patients in the two RBT treatment groups were similar in sex, age, previous history of TB, site of TB and acid-fast bacilli smear status. More individuals in the daily vs. the intermittent RBT group achieved clinical cure (73.0% vs. 44.1%, P < 0.001), with no significant differences in relapse/recurrence or all-cause mortality between groups. CONCLUSION: There were higher rates of clinical TB cure in individuals on a boosted protease inhibitor based ART regimen with daily RBT compared to intermittently dosed RBT. Optimal RBT dosing in this setting requires further investigation. PMID- 27510244 TI - An integrated community TB-HIV adherence model provides an alternative to DOT for tuberculosis patients in Cape Town. AB - SETTING: Cape Town, South Africa. OBJECTIVE: To evaluate anti-tuberculosis treatment outcomes and rate of antiretroviral therapy (ART) initiation using weekly community-based adherence support compared to daily directly observed therapy (DOT). METHODS: This was a retrospective analysis comparing two cohorts treated for tuberculosis (TB) in 70 TB clinics during 6-month periods before and after the introduction of a new adherence model comprising treatment literacy sessions during 2 weeks of DOT, followed by weekly home visits by community care workers to eligible patients managing their own treatment. Odds ratios (ORs) of treatment success and ART initiation were calculated using multivariable random effects logistic regression models. Hazard ratios (HRs) of default and death were calculated using multivariable random effects Cox regression models. RESULTS: The pre-intervention cohort comprised 11 896 patients with TB and the post intervention cohort 11 314. There was no difference in pre- and post-intervention anti-tuberculosis treatment success rates (respectively 82.8% and 82.5%, adjusted OR [aOR] 1.02, 95%CI 0.89-1.17, P = 0.76) nor an increased hazard of death (adjusted HR [aHR] 0.98, 95%CI 0.80-1.21, P = 0.87) or default (aHR 0.97, 95%CI 0.81-1.15, P = 0.69). The ART initiation rate increased from 67% to 74% (aOR 1.43; 95%CI 1.01-1.85, P < 0.01). CONCLUSION: Weekly community-based adherence support was a viable alternative to daily DOT, with no deterioration in anti tuberculosis treatment outcomes and an increase in ART initiation. PMID- 27510245 TI - Trends in tuberculosis case notification and treatment outcomes after interventions in 10 zones of Ethiopia. AB - SETTING: Amhara and Oromia Regions, Ethiopia. OBJECTIVE: To determine trends in case notification rates (CNRs) among new tuberculosis (TB) cases and treatment outcomes of sputum smear-positive (SS+) patients based on geographic setting, sex and age categories. METHODS: We undertook a trend analysis over a 4-year period among new TB cases reported in 10 zones using a trend test, a mean comparison t test and one-way analysis of variance. RESULTS: The average CNR per 100 000 population was 128.9: 126.4 in Amhara and 131.4 in Oromia. The CNR in the project supported zones declined annually by 6.5%, compared with a 14.5% decline in Tigray, the comparator region. TB notification in the intervention zones contributed 26.1% of the national TB case notification, compared to 13.3% before project intervention. The overall male-to-female ratio was 1.2, compared to 0.8 among SS+ children, with a female preponderance. Over 4 years, the cure rate increased from 75% to 88.4%, and treatment success from 89% to 93%. Default, transfer out and mortality rates declined significantly. CONCLUSION: Project supported zones had lower rates of decline in TB case notification than the comparator region; their contribution to national case finding increased, and treatment outcomes improved significantly. High SS+ rates among girls deserve attention. PMID- 27510246 TI - Community knowledge, attitudes and practices in relation to tuberculosis in Cameroon. AB - SETTING: With 15 080 new cases in 2013, Cameroon is a country with high tuberculosis (TB) incidence and prevalence. Understanding the community's knowledge, attitude and practice (KAP) about TB is key to TB control in such endemic settings. OBJECTIVES: To assess TB-related KAP in Cameroon by describing the sociodemographics of respondents, to identify barriers to seeking care and to explore attitudes and experiences of stigma and discrimination related to TB in communities. DESIGN: We conducted a cross-sectional descriptive study using structured questionnaires to assess and compare TB KAP in the entire territory. RESULTS: The results showed that Cameroonians have insufficient understanding of TB, numerous erroneous health assumptions and beliefs concerning TB, and erroneous information about the symptoms and mode of transmission of the disease. CONCLUSION: Negative attitudes and poor practices are obstacles to elimination and control efforts. The National Tuberculosis Control Programme should generate more effective strategies to reach the populations, paying particular attention to rural populations. PMID- 27510247 TI - Multidrug-resistant tuberculosis patients lost to follow-up: self-reported readiness to restart treatment. AB - SETTING: Multidrug-resistant tuberculosis (MDR-TB) patients lost to follow-up (LTFU) from Programmatic Management of Drug-resistant Tuberculosis facilities in the Philippines. OBJECTIVES: To gain insight into patients' readiness to return to treatment. METHODS: MDR-TB patients who initiated treatment and were categorized as LTFU were identified using TB registers, contacted, and asked to consent to an interview and medical record review. At the conclusion of the interview, patients' readiness to restart treatment was assessed and examined in relation to demographic, clinical, and interview data. Odds ratios were calculated. RESULTS: When asked if they would consider restarting MDR-TB treatment, 3% of the 89 participating patients reported that they had already restarted, 34% indicated that they wanted to restart, 33% had not considered restarting, 28% were undecided, and 2% had decided against restarting. Patients who wanted to restart treatment were more likely to report having borrowed money for TB-related expenses (OR 5.97, 95%CI 1.27-28.18), and were less likely to report being self-employed (OR 0.08, 95%CI 0.01-0.67), or perceive themselves at low or no risk for TB relapse (OR 0.30, 95%CI 0.08-0.96) than patients who did not indicate an interest in restarting treatment. CONCLUSIONS: Efforts to re engage LTFU patients in care should consider financial barriers, knowledge gaps, and personal adherence challenges in patients. PMID- 27510248 TI - Higher cost of implementing Xpert((r)) MTB/RIF in Ugandan peripheral settings: implications for cost-effectiveness. AB - SETTING: Initial cost-effectiveness evaluations of Xpert((r)) MTB/RIF for tuberculosis (TB) diagnosis have not fully accounted for the realities of implementation in peripheral settings. OBJECTIVE: To evaluate costs and diagnostic outcomes of Xpert testing implemented at various health care levels in Uganda. DESIGN: We collected empirical cost data from five health centers utilizing Xpert for TB diagnosis, using an ingredients approach. We reviewed laboratory and patient records to assess outcomes at these sites and10 sites without Xpert. We also estimated incremental cost-effectiveness of Xpert testing; our primary outcome was the incremental cost of Xpert testing per newly detected TB case. RESULTS: The mean unit cost of an Xpert test was US$21 based on a mean monthly volume of 54 tests per site, although unit cost varied widely (US$16-58) and was primarily determined by testing volume. Total diagnostic costs were 2.4 fold higher in Xpert clinics than in non-Xpert clinics; however, Xpert only increased diagnoses by 12%. The diagnostic costs of Xpert averaged US$119 per newly detected TB case, but were as high as US$885 at the center with the lowest volume of tests. CONCLUSION: Xpert testing can detect TB cases at reasonable cost, but may double diagnostic budgets for relatively small gains, with cost effectiveness deteriorating with lower testing volumes. PMID- 27510249 TI - Modelling the time to detection of urban tuberculosis in two big cities in Portugal: a spatial survival analysis. AB - SETTING: Portuguese National Tuberculosis Control Programme. OBJECTIVE: To examine delays in tuberculosis (TB) diagnosis using a spatial component in two high-incidence cities, Lisbon and Oporto, in Portugal, a low-incidence country. DESIGN: A retrospective nationwide study was conducted based on official TB data between 2010 and 2013 to analyse diagnostic delays at the lowest administrative level (freguesias) using spatial survival analyses, taking into account individual level covariates. RESULTS: Median diagnostic delays in Lisbon (n = 2706 cases) and Oporto (n = 1883) were respectively 62 (range 1-359, mean 81.01) and 60 days (range 1-3544, mean 79.5). In both cities, case detection rates initially rose until 50 days, then stabilised, but rose again at about 200 days. Diagnostic delay was significantly shorter among males and human immunodeficiency virus positive individuals in both cities, but was significantly longer among migrants in Lisbon. There is evidence of spatial correlation between freguesias; different spatial patterns were observed in diagnostic delays and in likelihood of case detection. CONCLUSION: These results are concordant with existing literature. The two study areas present considerable spatial variations in diagnostic delay, highlighting the fact that large cities should not be treated as homogeneous entities. The potential of spatial survival methods in spatial epidemiology is highlighted. PMID- 27510250 TI - Computer-aided detection of pulmonary tuberculosis on digital chest radiographs: a systematic review. AB - OBJECTIVE: To systematically review the diagnostic accuracy of computer-aided detection (CAD) of pulmonary tuberculosis (PTB) on digital chest radiographs (CXR). DESIGN: We searched four databases for articles published between January 2010 and December 2015 comparing CAD of PTB on CXR to a microbiologic reference standard (smear, culture or polymerase chain reaction). We collected and summarised data on study design, CAD software and diagnostic accuracy (sensitivity, specificity, area under the curve [AUC]). RESULTS: We included 5 of 455 articles identified by searching databases. PTB prevalence ranged from 18% to 60%, and human immunodeficiency virus (HIV) prevalence from 33% to 68%. All articles evaluated CAD4TB, the only commercially available software. AUC ranged from 0.71 to 0.84. Software settings that increased sensitivity resulted in important reductions in specificity, and vice versa. Risk of bias was low in prospective studies (n = 2), and high in retrospective studies (n = 3). CONCLUSION: Evidence assessing CAD's diagnostic accuracy is limited by the small number of studies, most of which have important methodological limitations, the availability and evaluation of only one software programme, and limited generalisability to settings where PTB and HIV are less prevalent. Additional research is required. PMID- 27510251 TI - SLCO1B1 gene polymorphisms do not influence plasma rifampicin concentrations in a South Indian population. AB - OBJECTIVE: To determine the effect of SLCO1B1 gene polymorphisms (rs11045819, rs4149032 and rs4149033) on rifampicin (RMP) concentrations in adult tuberculosis (TB) patients from south India. METHODS: We genotyped adult TB patients for three SLCO1B1 gene polymorphisms-rs11045819, rs4149032 and rs4149033-and compared 2-h post-dosing RMP concentrations of the different genotypes for each of the polymorphisms. Plasma RMP was determined using high-performance liquid chromatography. Genotyping was performed using direct sequencing. RESULTS: Among the 256 study patients, minor allele frequencies were respectively 0.01 (A), 0.46 (C) and 0.07 (A) for rs11045819, rs4149032 and rs4149033 polymorphisms; genotype distributions followed Hardy-Weinberg equilibrium. RMP concentrations did not significantly differ between the different genotypes of the three polymorphisms. CONCLUSION: This is the first study to show that rs11045819, rs4149032 and rs4149033 polymorphisms in the SLCO1B1 gene did not influence RMP concentrations in Indian patients. PMID- 27510252 TI - Pharmacokinetics of thrice-weekly rifampicin, isoniazid and pyrazinamide in adult tuberculosis patients in India. AB - OBJECTIVE: To study the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in adult tuberculosis (TB) patients and examine factors that influence drug pharmacokinetics. METHODS: Adult TB patients (n = 101) receiving thrice-weekly anti-tuberculosis treatment in the Revised National TB Control Programme (RNTCP) were studied. The study was conducted at steady state after directly observed drug administration. RMP, INH and PZA concentrations were estimated using high-performance liquid chromatography and NAT2 genotyping by real-time polymerase chain reaction. RESULTS: RMP peak concentration (Cmax) was sub-therapeutic (<8 MUg/ml) in 88% of the patients. The Cmax of RMP, INH and PZA at 2 h was observed in respectively 83.2%, 97.0% and 92.1% of the patients. The Cmax and area under the curve from 0 to 8 h (AUC0-8) of PZA was lower in TB patients with diabetes mellitus than in non-diabetics. Significant associations were observed between the Cmax and the AUC0-8 of RMP, INH and PZA with drug doses; RMP with category of treatment; INH with smoking, body mass index and N acetyl transferase 2 genotype; and PZA with sex and smoking. CONCLUSIONS: Several risk factors for drug concentration variations were identified. Two-hour post dosing drug concentrations mimicked Cmax. A high proportion of TB patients had RMP Cmax below the expected range, which is a matter of concern. PMID- 27510254 TI - Surveillance provides insight into epidemiology and spectrum of culture-confirmed mycobacterial disease in children. AB - BACKGROUND: Longer-term tuberculosis (TB) drug resistance surveillance among children is rare. We determined the prevalence of drug resistance among children with culture-confirmed TB from 2011 to 2013, compared these results with four previous consecutive 2-year periods and documented other mycobacterial isolates identified. METHOD: Surveillance study of mycobacterial culture in all children aged <13 years conducted from March 2011 to February 2013 at the Tygerberg Children's Hospital, Cape Town, South Africa. Drug susceptibility testing against isoniazid (INH) and rifampicin (RMP) was performed using line-probe assay (GenoType((r)) MTBDRplus). Clinical data were obtained through folder review. RESULTS: Of 381 children, 323 (84.8%; 324 episodes) had Mycobacterium tuberculosis, 46 (12.1%) had M. bovis bacille Calmette-Guerin and 12 (3.1%) had non-tuberculous mycobacteria isolated. Forty-one (12.7%) children had M. tuberculosis resistant to INH and/or RMP; 15 (4.7%) had multidrug-resistant TB (MDR-TB). The prevalence of INH mono- or polyresistance remained stable; however, RMP monoresistance increased (0/313 in 2003-2005 vs. 6/324, 1.9%, in 2011-2013; P = 0.041); MDR-TB prevalence has declined significantly, from 26/292 (8.9%) in 2007-2009 to 15/324 (4.7%) in 2011-2013 (OR 0.50, 95%CI 0.24-0.99). The prevalence of human immunodeficiency virus co-infection has decreased significantly, from a peak of 29% to 15.3%. CONCLUSIONS: There has been a significant reduction in bacteriologically confirmed MDR-TB cases. The increase in RMP monoresistance has important implications for treatment. PMID- 27510253 TI - Genetic polymorphisms of CCL2 associated with susceptibility to latent tuberculous infection in Thailand. AB - BACKGROUND: The extent to which individuals exhibit genetic susceptibility to tuberculosis (TB) is still unclear. Genetic variations in chemokine genes might influence the early clearance of Mycobacterium tuberculosis, affecting TB susceptibility. OBJECTIVES: To study single nucleotide polymorphisms (SNPs) of chemokine genes CCL2, CXCL9, CXCL10 and CXCL11, and their association with TB susceptibility. DESIGN: Of 248 participants enrolled, 49 had active TB, 43 had latent tuberculous infection (LTBI) and 156 were non-infected, including 24 healthy controls with no known TB exposure. These populations were divided into two groups based on TB exposure: susceptible (n = 92) and resistant (early clearance) (n = 132). RESULTS: Only CCL2 SNPs (-2518A/G) were significantly associated with increased TB susceptibility. Based on adjusted multivariate analysis, persons with the GG genotype at this SNP were twice as susceptible to TB as those with the AA genotype (P = 0.018, OR 2.880, 95%CI 1.201-6.903). Risk of LTBI was three times higher among those with GG (P = 0.003, OR 3.358, 95%CI 1.525-7.396 for AA+AG vs. GG and P = 0.012, OR 3.706, 95%CI 1.340-10.254 for AA vs. GG). Persons with the GG genotype produced significantly lower CCL2 levels in response to M. tuberculosis antigen stimulation (AA+AG vs. GG, P = 0.038). CONCLUSION: The CCL2 polymorphism (-2518A/G) was associated with susceptibility to LTBI in a North-East Thai populations. PMID- 27510255 TI - Combined approach to the identification of clinically infrequent non-tuberculous mycobacteria in Argentina. AB - SETTING: Over 150 potentially pathogenic non-tuberculous mycobacteria (NTM) species have been described, posing an onerous challenge for clinical laboratory diagnosis. OBJECTIVE: To evaluate different approaches for the identification of 40 clinically relevant NTM isolates whose species were not reliably identified using our routine diagnostic workflow comprising phenotypic tests and hsp65 polymerase chain reaction restriction analysis. DESIGN: We used 1) sequencing analysis of four conserved gene targets: 16S rRNA, rpoB, hsp65 and sodA; 2) two commercial reverse hybridisation assays; and 3) protein analysis using matrix assisted laser desorption/ionisation time of flight mass spectrometry (MALDI-TOF MS). RESULTS: Combined, but not individual, sequence analysis allowed reliable species identification for 30/40 (75%) isolates, including species previously unknown to be circulating in Argentina. Commercial kits outperformed our routine identification in only 5/35 isolates, and misclassified many more. MALDI-TOF MS accurately identified species in 22/36 (61%) isolates and did not misidentify any. CONCLUSIONS: Commercial kits did not resolve the problem of species of NTM isolates that elude identification. Combined DNA sequence analysis was the approach of choice. MALDI-TOF MS shows promise as a powerful, rapid and accessible tool for the rapid identification of clinically relevant NTM in the diagnostic laboratory, and its accuracy can be maximised by building up a customised NTM spectrum database. PMID- 27510256 TI - Chronic respiratory disease and high altitude are associated with depressive symptoms in four diverse settings. AB - SETTING: Depression is a prevalent comorbidity of chronic respiratory disease (CRD), and may indicate worse clinical outcomes. The relationship between depression and living with chronic hypoxia due to CRD or residence at altitude has received little attention in resource-poor settings. OBJECTIVE: To investigate the association between CRD conditions and depressive symptoms in four settings in Peru. DESIGN: We collected data on CRD and depressive symptoms in adults aged ?35 years. Depressive symptoms were measured according to the Center for Epidemiologic Studies Depression scale. Multivariable ordinal logistic regression was used to assess the adjusted odds of being in a higher category of depressive symptoms as a function of CRD. RESULTS: We analyzed data from 2953 participants (mean age 55.3 years, 49% male). The prevalence of major depressive symptoms was 19%, with significant variation according to setting. Participants with at least one CRD (OR 1.34, 95%CI 1.06-1.69) and those living at altitude (OR 1.64, 95%CI 1.10-2.43) had an increased adjusted odds of being in a higher category of depressive symptoms. CONCLUSION: We found a high prevalence of depressive symptoms, and a positive association between depressive symptoms with CRD and with living at altitude, both of which cause chronic hypoxia. PMID- 27510257 TI - Introduction of spirometry into clinical practice in Georgetown, Guyana: quality and diagnostic outcomes. AB - SETTING: Georgetown Public Hospital Corporation (GPHC), a 600-bed publicly funded referral hospital in Georgetown, Guyana. OBJECTIVE: To assess spirometry quality and diagnostic outcomes 2 years after the introduction of spirometry into routine clinical practice at GPHC. DESIGN: We performed a retrospective review of 476 consecutive spirometry assessments performed from November 2013 to November 2015. We assessed the proportion and trend of spirometry tests meeting acceptability criteria, along with diagnostic interpretations and spirometry laboratory referral patterns. RESULTS: Overall, 80.4% of the 454 initial spirometry measurements on unique patients met the acceptability criteria, with no significant change in the proportion of acceptable spirometry over the study period (P = 0.450). Of the 369 (81.3%) first tests considered interpretable, 139 (30.6%) were normal, 151 (33.3%) were obstructive, 54 (11.9%) were suggestive of a restrictive pattern, 25 (5.5%) were suggestive of a mixed disorder and 119 (26.2%) tests met the definition of reversibility. CONCLUSION: Over a 2-year period, high-quality spirometry was performed in GPHC, a publicly funded hospital in a middle-income country with no pre-existing specialised respiratory service. PMID- 27510258 TI - Isoniazid minimal inhibitory concentrations of tuberculosis strains with katG mutation. PMID- 27510259 TI - Reversion of phenotypic fluoroquinolone resistance in Mycobacterium tuberculosis. PMID- 27510260 TI - Endobronchial valves to treat a recurrent giant emphysematous bulla after bullectomy. PMID- 27510261 TI - Heart failure in elderly patients: differences in clinical characteristics and predictors of 1-year outcome in the Polish ESC-HF Long-Term Registry. AB - INTRODUCTION Heart failure (HF) is the leading cause of hospitalization in elderly patients. OBJECTIVES The aim of the study was to examine the clinical profile and 1-year outcomes of elderly patients (aged >=65 years) compared with younger patients (aged <65 years) hospitalized for HF decompensation, as well as clinical differences among elderly patients aged 65-74 years and those aged >=75 years. PATIENTS AND METHODS The primary endpoint (PE; all-cause death) and the secondary endpoint (SE; all-cause death or rehospitalization for HF worsening) were assessed at 1 year in a group of 765 hospitalized Polish participants of the ESC-HF Long-Term Registry. RESULTS The PE was observed in 9.1% of patients aged <65 years; 18.5% of those aged >=65 years (P = 0.0001); 14.5% of those aged 65-74 years; and 21.6% of those aged >=75 years (P = 0.07). The SE occurred in 28.0% of patients aged <65 years; 36.1% of those aged >=65 years (P = 0.04); 29.2% of those aged 65-74 years; and 41.2% of those aged >=75 years (P = 0.01). Independent predictors of the PE in patients aged >=65 years were as follows: chronic obstructive pulmonary disease (COPD), systolic blood pressure (SBP), New York Heart Association (NYHA) class, beta-blocker use; in patients aged 65-74 years: coronary revascularization, NYHA class, sodium, and creatinine; in patients aged >=75 years: NYHA class and SBP. Independent predictors of the SE in patients aged >=65 years were as follows: COPD, NYHA class, potassium, SBP, and physical activity; in patients aged <65 years: chronic kidney disease (CKD), NYHA, and SBP; in patients aged 65-74 years: NYHA and creatinine; and in patients aged >=75 years, previous HF hospitalization, coronary artery disease, CKD, COPD, alcohol consumption, smoking, NYHA, and SBP. CONCLUSIONS Elderly patients with HF differed from younger patients in terms of long-term outcome and prognostic factors. There were also important differences within the elderly group itself. PMID- 27510262 TI - Therapeutic potential of mesenchymal stem cell based therapy for osteoarthritis. AB - Osteoarthritis (OA) is a chronic degenerative disease affecting articular cartilage in joints, and it is a leading cause of disability in the United States. Current pharmacological treatment strategies are ineffective to prevent the OA progression; however, cellular therapies have the potential to regenerate the lost cartilage, combat cartilage degeneration, provide pain relief, and improve patient mobility. One of the most promising sources of cellular regenerative medicine is from mesenchymal stem cells (MSCs). MSCs can be isolated from adipose tissue, bone marrow, synovial tissue, and other sources. The aim of this review is to compile recent advancement in cellular based therapy more specifically in relation to MSCs in the treatment of osteoarthritis. PMID- 27510263 TI - Does it make sense to target one tumor cell chemotactic factor or its receptor when several chemotactic axes are involved in metastasis of the same cancer? AB - The major problem with cancer progression and anti-cancer therapy is the inherent ability of cancer cells to migrate and establish distant metastases. This ability to metastasize correlates with the presence in a growing tumor of cells with a more malignant phenotype, which express certain cancer stem cell markers. The propensity of malignant cells to migrate and their resistance to radio chemotherapy somewhat mimics the properties of normal developmentally early stem cells that migrate during organogenesis in the developing embryo. In the past, several factors, including cell migration-promoting cytokines, chemokines, growth factors, bioactive lipids, extracellular nucleotides, and even H(+) ions, were found to influence the metastasis of cancer cells. This plethora of pro-migratory factors demonstrates the existence of significant redundancy in the chemoattractants for cancer cells. In spite of this obvious fact, significant research effort has been dedicated to demonstrating the crucial involvement of particular pro-metastatic factor-receptor axes and the development of new drugs targeting one receptor or one chemoattractant. Based on our own experience working with a model of metastatic rhabdomyosarcoma as well as the work of others, in this review we conclude that targeting a single receptor-ligand pro metastatic axis will not effectively prevent metastasis and that we should seek other more effective therapeutic options. PMID- 27510265 TI - Accurate Estimation of the Intrinsic Dimension Using Graph Distances: Unraveling the Geometric Complexity of Datasets. AB - The collective behavior of a large number of degrees of freedom can be often described by a handful of variables. This observation justifies the use of dimensionality reduction approaches to model complex systems and motivates the search for a small set of relevant "collective" variables. Here, we analyze this issue by focusing on the optimal number of variable needed to capture the salient features of a generic dataset and develop a novel estimator for the intrinsic dimension (ID). By approximating geodesics with minimum distance paths on a graph, we analyze the distribution of pairwise distances around the maximum and exploit its dependency on the dimensionality to obtain an ID estimate. We show that the estimator does not depend on the shape of the intrinsic manifold and is highly accurate, even for exceedingly small sample sizes. We apply the method to several relevant datasets from image recognition databases and protein multiple sequence alignments and discuss possible interpretations for the estimated dimension in light of the correlations among input variables and of the information content of the dataset. PMID- 27510268 TI - Electrospun superhydrophobic polystyrene hollow fiber as a probe for liquid liquid microextraction with gas chromatography-mass spectrometry. AB - A superhydrophobic polystyrene hollow fiber was electrospun around a copper spring collector. This approach led to the construction of a hollow fiber membrane, and the copper spring acted as a scaffold. The characteristic properties of the hollow fiber were studied by scanning electron microscopy. The membrane was used as a probe to transfer the extracting solvent from aquatic media to a gas chromatograph. After performing the liquid-liquid microextraction procedure on 10 mL of water sample by octanol, the whole solution was passed through the prepared polystyrene hollow fiber. Propanol, containing 2 mg/L lindane as the internal standard, was used for desorption and an aliquot of 2 MUL of the desorbing solvent was subsequently injected into gas chromatography with mass spectrometry. Effects of different parameters influencing the extraction efficiency were optimized. The limits of detection and quantification were 2 and 6 ng/L, respectively. The relative standard deviations at a concentration level of 100 ng/L were between 2 and 6% (n = 3) while the method linearity ranged from 6 to 200 ng/L. Some real water samples were analyzed by the developed method and relative recoveries were in the range of 76-107%. PMID- 27510264 TI - Clinical significance of T cell metabolic reprogramming in cancer. AB - Conversion of normal cells to cancer is accompanied with changes in their metabolism. During this conversion, cell metabolism undergoes a shift from oxidative phosphorylation to aerobic glycolysis, also known as Warburg effect, which is a hallmark for cancer cell metabolism. In cancer cells, glycolysis functions in parallel with the TCA cycle and other metabolic pathways to enhance biosynthetic processes and thus support proliferation and growth. Similar metabolic features are observed in T cells during activation but, in contrast to cancer, metabolic transitions in T cells are part of a physiological process. Currently, there is intense interest in understanding the cause and effect relationship between metabolic reprogramming and T cell differentiation. After the recent success of cancer immunotherapy, the crosstalk between immune system and cancer has come to the forefront of clinical and basic research. One of the key goals is to delineate how metabolic alterations of cancer influence metabolism-regulated function and differentiation of tumor resident T cells and how such effects might be altered by immunotherapy. Here, we review the unique metabolic features of cancer, the implications of cancer metabolism on T cell metabolic reprogramming during antigen encounters, and the translational prospective of harnessing metabolism in cancer and T cells for cancer therapy. PMID- 27510267 TI - Neuroserpin Attenuates H2O2-Induced Oxidative Stress in Hippocampal Neurons via AKT and BCL-2 Signaling Pathways. AB - Oxidative stress plays a critical role in neuronal injury and is associated with various neurological diseases. Here, we explored the potential protective effect of neuroserpin against oxidative stress in primary cultured hippocampal neurons. Our results show that neuroserpin inhibits H2O2-induced neurotoxicity in hippocampal cultures as measured by WST, LDH release, and TUNEL assays. We found that neuroserpin enhanced the activation of AKT in cultures subjected to oxidative stress and that the AKT inhibitor Ly294002 blocked this neuroprotective effect. Neuroserpin increased the expression of the anti-apoptotic protein BCL-2 and blocked the activation of caspase-3. Neuroserpin did not increase the level of neuroprotection over levels seen in neurons transduced with a BCL-2 expression vector, and an inhibitor of Trk receptors, K252a, did not block neuroserpin's effect. Taken together, our study demonstrates that neuroserpin protects against oxidative stress-induced dysfunction and death of primary cultured hippocampal neurons through the AKT-BCL-2 signaling pathway through a mechanism that does not involve the Trk receptors and leads to inhibition of caspase-3 activation. PMID- 27510269 TI - Metal-free reductive coupling of C[double bond, length as m-dash]O and C[double bond, length as m-dash]N bonds driven by visible light: use of perylene as a simple photoredox catalyst. AB - Perylene, a simple polycyclic aromatic hydrocarbon, was used as a photoredox catalyst to enable the reductive coupling reaction of aromatic aldehydes, ketones, and an imine under visible-light irradiation using a white LED. PMID- 27510266 TI - Efficient liver repopulation of transplanted hepatocyte prevents cirrhosis in a rat model of hereditary tyrosinemia type I. AB - Hereditary tyrosinemia type I (HT1) is caused by a deficiency in the enzyme fumarylacetoacetate hydrolase (Fah). Fah-deficient mice and pigs are phenotypically analogous to human HT1, but do not recapitulate all the chronic features of the human disorder, especially liver fibrosis and cirrhosis. Rats as an important model organism for biomedical research have many advantages over other animal models. Genome engineering in rats is limited till the availability of new gene editing technologies. Using the recently developed CRISPR/Cas9 technique, we generated Fah(-/-) rats. The Fah(-/-) rats faithfully represented major phenotypic and biochemical manifestations of human HT1, including hypertyrosinemia, liver failure, and renal tubular damage. More importantly, the Fah(-/-) rats developed remarkable liver fibrosis and cirrhosis, which have not been observed in Fah mutant mice or pigs. Transplantation of wild-type hepatocytes rescued the Fah(-/-) rats from impending death. Moreover, the highly efficient repopulation of hepatocytes in Fah(-/-) livers prevented the progression of liver fibrosis to cirrhosis and in turn restored liver architecture. These results indicate that Fah(-/-) rats may be used as an animal model of HT1 with liver cirrhosis. Furthermore, Fah(-/-) rats may be used as a tool in studying hepatocyte transplantation and a bioreactor for the expansion of hepatocytes. PMID- 27510271 TI - Magnolol Enhances Hippocampal Neurogenesis and Exerts Antidepressant-Like Effects in Olfactory Bulbectomized Mice. AB - Magnolol is the main constituent of Magnolia bark and has been reported to exhibit antidepressant effects in rodent models. Hippocampal neurogenesis and neurotrophins such as brain-derived neurotrophic factor are integrally involved in the action of conventional antidepressants. Here, we investigated the effects of magnolol on depressive behaviours, impaired hippocampal neurogenesis and neurotrophin-related signal transduction in an olfactory bulbectomy (OBX) mouse model of depression. Mice were submitted to OBX to induce depressive behaviour, which was evaluated in the tail suspension test. Magnolol was administered orally by gavage needle. Neurogenesis was assessed by analysis of cells expressing NeuN, a neuronal marker, and 5-bromo-2'-deoxyuridine (BrdU) uptake. Phosphorylation levels of protein kinase B (Akt), extracellular signal-regulated kinase and cyclic AMP-responsive element-binding protein were evaluated by Western blot. Fourteen day treatment with magnolol (50 or 100 mg/kg/day) significantly improved OBX-induced depressive behaviour in tail suspension test. In agreement, magnolol significantly rescued impairments of hippocampal neurogenesis. Moreover, single treatments with magnolol (50 mg/kg) significantly increased phosphorylation of Akt, extracellular signal-regulated kinase and cyclic AMP-responsive element binding protein after 3 h. The present data indicate that magnolol exerts antidepressant-like effects on behaviours by enhancing hippocampal neurogenesis and neurotrophin-related intracellular signalling in OBX mice. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27510270 TI - The in silico identification and characterization of a bread wheat/Triticum militinae introgression line. AB - The capacity of the bread wheat (Triticum aestivum) genome to tolerate introgression from related genomes can be exploited for wheat improvement. A resistance to powdery mildew expressed by a derivative of the cross-bread wheat cv. Tahti * T. militinae (Tm) is known to be due to the incorporation of a Tm segment into the long arm of chromosome 4A. Here, a newly developed in silico method termed rearrangement identification and characterization (RICh) has been applied to characterize the introgression. A virtual gene order, assembled using the GenomeZipper approach, was obtained for the native copy of chromosome 4A; it incorporated 570 4A DArTseq markers to produce a zipper comprising 2132 loci. A comparison between the native and introgressed forms of the 4AL chromosome arm showed that the introgressed region is located at the distal part of the arm. The Tm segment, derived from chromosome 7G, harbours 131 homoeologs of the 357 genes present on the corresponding region of Chinese Spring 4AL. The estimated number of Tm genes transferred along with the disease resistance gene was 169. Characterizing the introgression's position, gene content and internal gene order should not only facilitate gene isolation, but may also be informative with respect to chromatin structure and behaviour studies. PMID- 27510272 TI - In silico insights into the solvation characteristics of the ionic liquid 1 methyltriethoxy-3-ethylimidazolium acetate for cellulosic biomass. AB - Lignocellulosic biomass is a domestically grown, sustainable, and potentially carbon-neutral feedstock for the production of liquid fuels and other value added chemicals. This underutilized renewable feedstock has the potential to alleviate some of the current socio-economic dependence on foreign petroleum supplies while stimulating rural economies. Unfortunately, the potential of biomass has largely been underdeveloped due to the recalcitrant nature of lignocellulosic materials. Task-specific ionic liquids (ILs) have shown considerable promise as an alternative non-aqueous solvent for solvation and deconstruction of lignocellulose in the presence of metal chloride catalyst or enzymes. Recently it has been hypothesized that adding oxygen atoms to the tail of an imidazolium cation would alleviate some of the negative characteristics of the ILs by increasing mass transport properties, and decreasing IL deactivation of enzymes, while at the same time retaining favorable solvation characteristics for lignocellulose. Reported here are fully atomistic molecular dynamic simulations of 1-methyltriethoxy-3-ethylimidazolium acetate ([Me-(OEt)3-Et-IM(+)] [OAc(-)]) that elucidate promising molecular-level details pertaining to the solvation characteristics of model compounds of cellulose, and IL-induced side-chain and ring puckering conformations. It is found that the anion interactions with the saccharide induce alternate ring puckering conformations from those seen in aqueous environments (i.e.(1)C4), while the cation interactions are found to influence the conformation of the omega dihedral. These perturbations in saccharide structures are discussed in the context of their contribution to the disruption of hydrogen bonding in cellulosic architecture and their role in solvation. PMID- 27510278 TI - A targeted proteomics approach to the quantitative analysis of ERK/Bcl-2-mediated anti-apoptosis and multi-drug resistance in breast cancer. AB - Apoptosis suppression caused by overexpression of anti-apoptotic proteins is a central factor to the acquisition of multi-drug resistance (MDR) in breast cancer. As a highly conserved anti-apoptotic protein, Bcl-2 can initiate an anti apoptosis response via an ERK1/2-mediated pathway. However, the details therein are still far from completely understood and a quantitative description of the associated proteins in the biological context may provide more insights into this process. Following our previous attempts in the quantitative analysis of MDR mechanisms, liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted proteomics was continually employed here to describe ERK/Bcl-2-mediated anti-apoptosis. A targeted proteomics assay was developed and validated first for the simultaneous quantification of ERK1/2 and Bcl-2. In particular, ERK isoforms (i.e., ERK1 and ERK2) and their differential phosphorylated forms including isobaric ones were distinguished. Using this assay, differential protein levels and site-specific phosphorylation stoichiometry were observed in parental drug sensitive MCF-7/WT cancer cells and drug-resistant MCF-7/ADR cancer cells and breast tissue samples from two groups of patients who were either suspected or diagnosed to have drug resistance. In addition, quantitative analysis of the time course of both ERK1/2 and Bcl-2 in doxorubicin (DOX)-treated MCF-7/WT cells confirmed these findings. Overall, we propose that targeted proteomics can be used generally to resolve more complex cellular events. PMID- 27510273 TI - Optimizing identification and management of COPD patients - reviewing the role of the community pharmacist. AB - The aim of this paper was to propose key steps for community pharmacist integration into a patient care pathway for chronic obstructive pulmonary disease (COPD) management. A literature search was conducted to identify publications focusing on the role of the community pharmacist in identification and management of COPD. The literature search highlighted evidence supporting an important role for pharmacists at each of the four key steps in the patient care pathway for COPD management. Step 1 (primary prevention): pharmacists are ideally placed to provide information on disease awareness and risk prevention campaigns, and to encourage lifestyle interventions, including smoking cessation. Step 2 (early detection/case finding): pharmacists are often the first point of contact between the patient and the healthcare system and can therefore play an important role in the early identification of patients with COPD. Step 3 (management and ongoing support): pharmacists can assist patients by providing advice and education on dosage, inhaler technique, treatment expectations and the importance of adherence, and by supporting self-management, including recognition and treatment of COPD exacerbations. Step 4 (review and follow-up): pharmacists can play an important role in monitoring adherence and ongoing inhaler technique in patients with COPD. In summary, pharmacists are ideally positioned to play a vital role in all key stages of an integrated COPD patient care pathway from early disease detection to the support of management plans, including advice and counselling regarding medications, inhaler technique and treatment adherence. Areas requiring additional consideration include pharmacist training, increasing awareness of the pharmacist role, administration and reimbursement, and increasing physician pharmacist collaboration. PMID- 27510279 TI - Time-of-flight secondary ion mass spectrometry to assess spatial distribution of A2E and its oxidized forms within lipofuscin granules isolated from human retinal pigment epithelium. AB - Lipofuscin granules accumulate in the cells of retinal pigment epithelium with age, particularly in patients with hereditary diseases. These granules are heterogeneous, being composed of mixtures of proteins and lipids, including more than 21 different fluorescent compounds. Bisretinoids and their photo-oxidation and photodegradation products represent the main source of lipofuscin fluorescence and exhibit phototoxic properties. This study used time-of-flight secondary ion mass spectrometry (ToF-SIMS) with in-depth probing to assess the depth distribution of N-retinylidene-N-retinylethanolamine (A2E) and its singly and doubly oxidized forms (A2E-ox and A2E-2ox, respectively) within lipofuscin granules and in their surface layer (lipid membrane). ToF-SIMS showed that A2E and its oxidized forms were uniformly distributed throughout lipofuscin granules but were not present at the membrane surface layer. This finding is important for understanding the process involved in the formation of lipofuscin granules and in their toxicity. PMID- 27510280 TI - Chemiluminescence of nitrogen-rich quantum dots in diperiodatoargentate(III) solution and its application in ferulic acid analysis. AB - A novel chemiluminescence (CL) system based on the reaction of fluorescent water soluble nitrogen-rich quantum dots (N-dots) and diperiodatoargentate(III) (DPA) was developed. The prepared N-dots have a small size (<=10 nm) and high percentage of nitrogen (39.9 %), which exceeds the content of carbon in the same N-dots. The N-dots exhibit characteristic blue fluorescence under UV light and up conversion luminescence. The relatively intense CL emission is based on the direct oxidation of N-dots by DPA. The CL emission may be attributed to the high nitrogen content and the special structure of the N-dots. The CL mechanism of N dots and DPA was investigated by using CL, UV-Vis absorption, IR, fluorescence, and radical scavenging experiments. This investigation provides a way to study the optical properties of N-dots. The analytical applicability of the N-dots and DPA CL system in the determination of ferulic acid (FA) was explored. The CL intensity was linearly proportional to the concentration of ferulic acid from 3.0 * 10-7 to 1.0 * 10-5 g mL-1 with a detection limit of 8.0 * 10-8 g mL-1 (3sigma); the relative standard deviation was 2.4 % for 4.0 * 10-7 g mL-1 FA (n = 9). The proposed method was successfully applied to the determination of ferulic acid in Angelica sinensis. The study provides valuable insight into the role of nitrogen rich quantum dots in CL. PMID- 27510281 TI - SALDI-TOF-MS analyses of small molecules (citric acid, dexasone, vitamins E and A) using TiO2 nanocrystals as substrates. AB - Surface-assisted laser desorption/ionisation time-of-flight mass spectrometry (SALDI-TOF-MS) might be the method of choice for the analysis of low mass molecules (less than m/z 500). Titanium dioxide (TiO2) nanocrystals as a substrate for SALDI-TOF-MS improve the reproducibility of the signal intensities and prevent the fragmentation of some molecules upon laser irradiation, as we have previously shown. In addition, variously shaped and sized TiO2 nanocrystals/substrates for SALDI-MS could be used for quantification of small molecules, which are otherwise difficult to detect with the assistance of organic matrices. TiO2-assisted LDI-MS spectra could be acquired with excellent reproducibility and repeatability and with low detection limit. In the current study, we analysed the spectra of dexasone, citric acid, vitamin E and vitamin A acquired with TiO2 nanocrystals of various shapes and dimensions, i.e. the colloidal TiO2 nanoparticles (TiO2 NPs), TiO2 prolate nanospheroids (TiO2 PNSs) and TiO2 nanotubes (TiO2 NTs). Various shapes and dimensions of substrates were used since these factors determine desorption and ionisation processes. The homogeneity on the target plate was compared based on signal-to-noise values of peaks of interest of analysed molecules as well as the within-day and day-to-day repeatability. In summary, the obtained results show that the applicability of individual TiO2 nanocrystals depends on the analyte. Signals which are acquired with the assistance of TiO2 PNSs have the highest sensitivity and reproducibility (the smallest standard deviation), even compared with those in the LDI mode. This implies that TiO2 PNSs could also be suitable for quantitative analyses of small molecules. PMID- 27510282 TI - Further development on DMFC device used for analytical purpose: real applications in the pharmaceutical field and possible in biological fluids. AB - The analytical research devoted to the utilization of the direct methanol fuel cell (DMFC) for analytical purposes has been continued. The research reported in this paper concerns two points, one of which was the possibility of improving the features, from the analytical point of view, of a catalytic fuel cell for methanol and ethanol, by introducing an enzyme, immobilized into a dialysis membrane small bag, in the anodic area of the fuel cell. This objective has been fully achieved, particularly using the enzyme alcohol dehydrogenase, which has increased the sensitivity of the method and reduced dramatically the response time of the cell. The second point concerned the opportunity to determine two particular antibiotics having an alcohol functional group in their molecule, that is, imipenem and chloramphenicol. Also, this goal has been reached, even if the sensitivity of the method is not so high. Graphical abstract Imipenem and Chloramphenicol determination using the DMFC and Ethanol determination using the enzymatic DMFC. PMID- 27510284 TI - The Emergence of Flood Insurance in Canada: Navigating Institutional Uncertainty. AB - Flood insurance has remained unavailable in Canada based on an assessment that it lacks economic viability. In response to Canada's costliest flood event to date in 2013, the Canadian insurance industry has started to develop a framework to expand existing property insurance to cover flood damage. Research on flood insurance has overlooked why and how insurance systems transition to expand insurance coverage without evidence of economic viability. This article will address this gap through a case study on the emergence of flood insurance in Canada, and the approach to its expansion. Between 2013 and 2016, insurance industry officials representing over 60% of premiums collected in Canada were interviewed. These interviews revealed that flood insurance is being expanded in response to institutional pressure, specifically external stakeholder expectations that the insurance industry will adopt a stronger role in managing flood risk through coverage of flood damage. Further evidence of this finding is explored by assessing the emergence of a unique flood insurance model that involves a risk-adjusted and optional product along with an expansion of government policy supporting flood risk mitigation. This approach attempts to balance industry concerns about economic viability with institutional pressure to reduce flood risk through insurance. This analysis builds on existing research by providing the first scholarly analysis of flood insurance in Canada, important "empirical" teeth to existing conceptual analysis on the availability of flood insurance, and the influence of institutional factors on risk analysis within the insurance sector. PMID- 27510283 TI - Spatiotemporal expression of endogenous TLR4 ligands leads to inflammation and bone erosion in mouse collagen-induced arthritis. AB - Increased expression of endogenous Toll-like receptor 4 (TLR4) ligands (e.g., Tenascin-C, S100A8/A9, citrullinated fibrinogen (cFb) immune complexes) has been observed in patients with rheumatoid arthritis (RA). However, their roles in RA pathogenesis are not well understood. Here, we investigated the expression kinetics and role of endogenous TLR4 ligands in the murine model of collagen induced arthritis (CIA). Tenascin-C was upregulated in blood early in CIA, and correlated positively with the clinical score at day 56. Levels of S100A8/A9 increased starting from day 28, peaking at day 42, and correlated positively with joint inflammation. Levels of anti-cFb antibodies increased during the late phase of CIA and correlated positively with both joint inflammation and cartilage damage. Blockade of TLR4 activation at the time of the first TLR4 ligand upregulation prevented clinical and histological signs of arthritis. A TLR4 dependent role was also observed for Tenascin-C and cFb immune complexes in osteoclast differentiation in vitro. Taken together, our data suggests that the pathogenic contribution of TLR4 in promoting joint inflammation and bone erosion during CIA occurs via various TLR4 ligands arising at different stages of disease. The data also suggests that Blockade of TLR4 with monoclonal antibodies is a promising strategy in RA treatment. PMID- 27510285 TI - Fractional carbon dioxide laser versus low-dose UVA-1 phototherapy for treatment of localized scleroderma: a clinical and immunohistochemical randomized controlled study. AB - Morphea is a rare fibrosing skin disorder that occurs as a result of abnormal homogenized collagen synthesis. Fractional ablative laser resurfacing has been used effectively in scar treatment via abnormal collagen degradation and induction of healthy collagen synthesis. Therefore, fractional ablative laser can provide an effective modality in treatment of morphea. The study aimed at evaluating the efficacy of fractional carbon dioxide laser as a new modality for the treatment of localized scleroderma and to compare its results with the well established method of UVA-1 phototherapy. Seventeen patients with plaque and linear morphea were included in this parallel intra-individual comparative randomized controlled clinical trial. Each with two comparable morphea lesions that were randomly assigned to either 30 sessions of low-dose (30 J/cm2) UVA-1 phototherapy (340-400 nm) or 3 sessions of fractional CO2 laser (10,600 nm-power 25 W). The response to therapy was then evaluated clinically and histopathologically via validated scoring systems. Immunohistochemical analysis of TGF-beta1 and MMP1 was done. Patient satisfaction was also assessed. Wilcoxon signed rank test for paired (matched) samples and Spearman rank correlation equation were used as indicated. Comparing the two groups, there was an obvious improvement with fractional CO2 laser that was superior to that of low-dose UVA-1 phototherapy. Statistically, there was a significant difference in the clinical scores (p = 0.001), collagen homogenization scores (p = 0.012), and patient satisfaction scores (p = 0.001). In conclusion, fractional carbon dioxide laser is a promising treatment modality for cases of localized morphea, with proved efficacy of this treatment on clinical and histopathological levels. PMID- 27510287 TI - Connecting Effective Immune Response, Fluorescent Granzyme B-like Peptide, Specific Peptide Binding Patterns, Patients with Cancer and Viral Infection, in Remission, Clinical Significance, and Liquid Biopsy. AB - Functional cytotoxic-T-lymphocytes (CTL) with granzyme B play an important role in an effective immune response to tumor growth and infection progression. Tumor cells and platelets in peripheral whole blood smears of cancer patients have shown the presence of innate binding targets for GP1R, a fluorescent synthetic Granzyme B-like peptide. It is not known if similar GP1R-binding targets and specific binding patterns are detectable in peripheral blood of patients with viral infection. It is also not known if a specific binding pattern may be associated with an effective immune response to indicate a favorable prognosis. We reviewed the GP1R-binding patterns in the peripheral blood smears of 5 patients in remission at the time of sampling (3 with cancer and 2 with flu-like symptoms) and a negative control. We show with fluoroscopic images that there are: 1) fluorescent GP1R-binding targets mostly in the cytoplasmic areas of nucleated cells in patients with breast and lung cancer who have longer survival, 2) intense fluorescent deposits mostly in the nuclear areas of segmented neutrophils in patients recovered from severe to mild flu-like symptoms, 3) discernible fluorescent deposits in the cytoplasmic areas of small lymphocyte like elements and overall intense fluorescent stain in large cells in the patient with advanced pancreatic cancer who had shorter survival, 4) GP1R-binding targets in numerous platelet-like elements in all 5 patients. The control sample did not show similar binding patterns. The potential association between specific GP1R binding patterns in peripheral blood samples and prognostic significance, and its use as liquid biopsy are discussed. PMID- 27510288 TI - The impact of physical function on participation in the first year post-stroke. AB - OBJECTIVES: Studies have investigated predictors of participation and showed that fewer depressive symptoms, physical independence, and age could predict the level of participation after stroke. Association between self-assessed functions and perceived levels of participation over time is not yet known. The aim of this study was to investigate perceptions of participation and how this related to background characteristics and self-assessed rehabilitation outcomes, at 1, 6, and 12 months post-stroke. MATERIALS AND METHODS: To capture experienced functioning and participation, a self-assessment questionnaire, the Stroke Impact Scale (SIS), was used at 1, 6, and 12 months post-stroke. Possible variables with impact on perceived participation were investigated with logistic regression: perceived physical functions, memory and thinking, emotion and communication (SIS), as well as background characteristics. In addition, directions, distributions, and strength of correlations between each independent variable and the participation domain were analyzed using scatterplots. RESULTS: Participation scores were widely distributed during the first year post-stroke. Significant associations were only found between perceived Physical score and participation during the first year post-stroke (1 month, n=92, P<.001; 6 months, n=79, P=.001; 12 months, n=78, P=.002). A moderate-to-high participation score was observed in combination with a high level of perceived emotional health and cognitive skills, at 1, 6, and 12 months. CONCLUSIONS: The findings indicate that to improve participation during the first year post-stroke, physical functioning as well as emotional and cognitive health can be important areas of concern when forming rehabilitation interventions. PMID- 27510286 TI - A Synthetic Supramolecular Receptor for the Hydrosulfide Anion. AB - Hydrogen sulfide (H2 S) has emerged as a crucial biomolecule in physiology and cellular signaling. Key challenges associated with developing new chemical tools for understanding the biological roles of H2 S include developing platforms that enable reversible binding of this important biomolecule. The first synthetic small molecule receptor for the hydrosulfide anion, HS(-) , using only reversible, hydrogen-bonding interactions in a series of bis(ethynylaniline) derivatives, is reported. Binding constants of up to 90 300+/-8700 m(-1) were obtained in MeCN. The fundamental science of reversible sulfide binding, in this case featuring a key CH???S hydrogen bond, will expand the possibility for discovery of sulfide protein targets and molecular recognition agents. PMID- 27510289 TI - [Not Available]. PMID- 27510290 TI - Poor Acceptability of Female Condom by Young Cameroonians: an Unmet Programmatic Agenda for HIV Prevention. AB - BACKGROUND: An important component of the response to the AIDS epidemic is the prevention of HIV infection and other sexually transmitted diseases through the use of condoms. In order to enhance HIV prevention programs and minimize the occurrence of unwanted pregnancies, female condoms have been introduced within the community, with the ultimate goal of reducing vulnerability of women. The success of such a program depends on its acceptance by the target population. METHODS: A survey was conducted among 426 respondents from different regions of Cameroon, to evaluate their perception of HIV/AIDS and their level of acceptance of condom usage in general, and female condom use in particular. RESULTS: Respondents were young adults residing in seven regions of Cameroon (86.4% west, 6.5% Littoral, 3% Centre and 4.1% Adamawa, East, Far-North and North-West). Mean age was 22.6 years; 57% were male, 95% were single, and 77% were university educated. Overall, 76% of participants reported using condoms, though 48% complained of decreased sexual satisfaction. Interestingly, awareness regarding female condoms was 74.5% and 88.5% in men and women respectively, however only 8% and 9.9% respectively reported having ever used them. Respondents generally learnt about sexual education through broadcasting media (~90%). CONCLUSION: In this sexually active Cameroonian population, the rate of acceptance or use of female condom remains very low, even among women. Strategies to increase awareness of female condoms among young women, their benefits and correct use, are needed. PMID- 27510291 TI - [Planning a Health Residence for Prison Security Measures, Tuscany (Italy)]. AB - Health Residences for Prison Security Measures are facilities hosting psychotic persons who have committed crimes and providing them with personalized rehabilitation and treatment plans to promote their reinstatement in society. The aim of this study was to describe the criteria for planning and designing a prison health residence in the Tuscany region (Italy), to be managed by the regional healthcare service, in line with current regulations, with dedicated staff for providing specific treatment plans and programmes. PMID- 27510292 TI - [Definition and variables of complexity of nursing care: a literature review]. AB - Complexity of nursing care represents an important indicator in the planning and management of nursing resources and healthcare management. However, the term is not clearly defined in the literature. The aim of this article is to outline the main concepts associated with complexity of nursing care, trying to shed light on the different variables that constitute it. We conducted a review of the literature and selected 12 articles. The terms associated with the concept of complexity of nursing care include nursing intensity, nursing work, nursing workload, patient acuity and severity of illness. The literature review indicates that complexity of nursing care appears to be one of the variables of care intensity, the latter being defined as a commitment of care delivered to the patient. It is associated with the concepts of nursing work, nursing workload, patient acuity and severity of illness. Understanding and clarifying the concept of complexity of care is fundamental in order to measure and evaluate the real demand for nursing care by individual patients. PMID- 27510293 TI - [A geographical and epidemiological analysis of cancer incidence in the city of Vercelli, Italy, 2002-2009]. AB - The idea of conducting a geographical analysis of cancer incidence in Vercelli, a city with about 46,000 population in the Province of Vercelli (Piedmont, northern Italy), originated from the need to respond to concerns of the population and local administrators regarding the presence of a solid waste incinerator just a few kilometers from the city, and the ongoing intense agricultural activity in the area. The study also aimed to verify the excess risk identified in a similar study on mortality. We obtained census data and mortality data for the years 2002 to 2009, from the Italian Institute of Statistics (ISTAT) and analysed these from both an epidemiological point of view, through standardised mortality rates, and spatial analysis through the use of Bayesian models. Both approaches highlighted an overall increased risk for cancers and increased risks for colorectal and lung cancer, in persons residing south of the capital. They also identified an increased cancer risk in the young adult population of both sexes, which deserves further investigation. PMID- 27510294 TI - [The public health importance of vaccinations in the elderly: an evidence-based guide]. AB - Ageing represents an extremely current issue globally, and involves especially European populations. It is estimated that in Europe by the year 2025, about a third of the population will be over 60 years of age, hence the imperative for "healthy ageing". Vaccinations in seniors, in contrast with paediatric vaccinations, are very often neglected even by health care workers. This article aims to provide an evidence-based guide to establish vaccinations in seniors as one of the pillars of Public Health in the future. PMID- 27510295 TI - The effect of high-dose steroids, and normobaric oxygen therapy, on recent onset non-arteritic anterior ischemic optic neuropathy: a randomized clinical trial. AB - BACKGROUND: To evaluate the effect of high-dose intravenous steroids, as well as normobaric oxygen therapy, in the management of recent onset non-arteritic anterior ischemic optic neuropathy (NAION). METHOD: Ninety eyes of 90 patients diagnosed with NAION within 14 days of onset were included in this single masked randomized clinical trial. Thirty patients were randomized into each set as group 1 (control), group 2 (steroids), and group 3 (oxygen). Controls received placebo; group 2 received methylprednisolone 500 mg twice a day for 3 days followed by 2 weeks of oral prednisolone 1 mg/kg/day; group 3 received 100 % normobaric oxygen with mask, at a flow rate of 5 liters per minute for 1 hour twice a day for two weeks. Functional and structural outcomes were analyzed at 1 and 6 months following treatment. Best corrected visual acuity (BCVA) was the main outcome measure, and mean deviation (MD) of visual field (VF) test and peripaillary retinal nerve fiber layer thickness (PRNFLT) were secondary outcome measures. RESULTS: The mean BCVA at the time of presentation was 1.02 +/- 0.63, 1.05 +/- 0.7, and 0.76 +/- 0.5 LogMAR in groups 1, 2, and 3, respectively (p = 0.293); corresponding values were 0.8 +/- 0.45, 0.84 +/- 0.45, and 0.58 +/- 0.4 at month 1 (p = 0.127, 0.19, and 0.168, respectively). BCVA improved to 0.71 +/- 0.46, 0.73 +/- 0.36, and 0.59 +/- 0.41 LogMAR at the 6-month follow-up point (p = 0.039, 0.048, and 0.195, respectively). The mean deviation (MD) at the time of presentation was 19.26 +/- 7.02, 20.51 +/- 4.68, and 19.3 +/- 7.17 in the control, steroid, and oxygen groups, respectively (p = 0.65). Corresponding values at month 1 were 20.26 +/- 8.52, 19.52 +/- 7.08, and 18.3 +/- 7.45, (p = 0.656); and at month 6 were 18.42 +/- 8.17, 17.66 +/- 6.44 and 16.53 +/- 6.32, respectively (p = 0.635). PRNFLT at presentation was 166 +/- 57, 184 +/- 57, and 193 +/- 65 micrometer in the control, steroid, and oxygen groups, respectively (p = 0.265); which decreased to 73 +/- 11, 87 +/- 26, and 79 +/- 19 at the final foll-w up (all p < 0.001). There were no statistically significant differences between the three groups in terms of final visual function and structure. CONCLUSION: The lack of demonstrable improvement in the structural and functional outcomes of NAION with high-dose IV steroids, or normobaric oxygen, in this randomized controlled trial calls into question the administering of systemic steroid or normobaric oxygen in this condition. PMID- 27510296 TI - Correlation between low tapasin expression and impaired CD8+ T-cell function in patients with chronic hepatitis B. AB - Recent studies have demonstrated that chronic hepatitis B virus (HBV) infection is associated with reduced antigen-presenting capacity and insufficient cytotoxic T lymphocyte (CTL) production. The molecular chaperone tapasin mediates binding of the transporter associated with antigen processing (TAP), and has an important role in endogenous antigen processing and presentation, and the induction of specific CTL responses. The present study aimed to determine whether tapasin is associated with chronic HBV (CHB) infection. The mRNA expression levels of tapasin were detected in peripheral blood mononuclear cells from 27 patients with CHB, 20 patients with acute HBV (AHB) and 26 healthy controls by reverse transcription-quantitative polymerase chain reaction. In addition, CD8+ T immune responses were evaluated in all groups, and the correlation between tapasin expression and CD8+ responses was analyzed. The results demonstrated that the mRNA expression levels of tapasin were significantly downregulated in patients with CHB compared with in healthy controls and patients with AHB. Furthermore, the apoptotic rate of CD8+ T cells was increased in patients with CHB compared with in the other two groups. The percentage of interferon (IFN)-gamma+CD8+ T cells was reduced in patients with CHB compared with in patients with AHB and healthy controls, and serum cytokine levels (IFN-gamma, interleukin-2 and tumor necrosis factor-alpha) were generally low in patients with CHB. Furthermore, the mRNA expression levels of tapasin were positively correlated with IFN-gamma production by CD8+ T cells, and were inversely correlated with the apoptotic ratio of CD8+ T cells. These results indicate that decreased expression of tapasin may be closely associated with CHB, and suggest an important role for tapasin in the pathogenesis of CHB. PMID- 27510297 TI - Membrane bile acid receptor TGR5 predicts good prognosis in ampullary adenocarcinoma patients with hyperbilirubinemia. AB - Bile acids are potential carcinogens in gastrointestinal cancer, and interact with nuclear and membrane receptors to initiate downstream signaling. The effect of TGR5 [also known as G protein-coupled bile acid receptor 1 (GPBAR1)] on cancer progression is dependent on the tissue where it is activated. In this report, the function of TGR5 expression in cancer was studied using a bioinformatic approach. TGR5 expression in ampullary adenocarcinoma and normal duodenum was compared by western blotting, reverse transcription polymerase chain reaction, and immunohistochemistry (IHC). High GPBAR1 gene expression was found to be an indicator of worse prognosis in gastric and breast cancer patients, and an indication of better prognosis in ovarian cancer patients. The level of GPBAR1 gene expression was higher in bile-acid exposed cancer than in other types of cancer, and was increased in well-differentiated ampullary adenocarcinoma. Negative, weak or mild expression of TGR5 was correlated with younger age, higher plasma level of total/direct bilirubin, higher plasma concentration of CA-125, advanced tumor stage and advanced AJCC TNM stage. The disease-specific survival rate was highest in ampullary adenocarcinoma patients with high TGR5 expression and high total bilirubin level. In summary, TGR5 functions as a tumor-suppressor in patients with ampullary adenocarcinoma and preoperative hyperbilirubinemia. Further study of the suppressive mechanism may provide a new therapeutic option for patients with ampullary adenocarcinoma. PMID- 27510298 TI - Underrepresented Minorities in Science: ACNP Strives to Increase Minority Representation and Inclusion. PMID- 27510300 TI - Quantitative fat and R2* mapping in vivo to measure lipid-rich necrotic core and intraplaque hemorrhage in carotid atherosclerosis. AB - PURPOSE: The aim of this work was to quantify the extent of lipid-rich necrotic core (LRNC) and intraplaque hemorrhage (IPH) in atherosclerotic plaques. METHODS: Patients scheduled for carotid endarterectomy underwent four-point Dixon and T1 weighted magnetic resonance imaging (MRI) at 3 Tesla. Fat and R2* maps were generated from the Dixon sequence at the acquired spatial resolution of 0.60 * 0.60 * 0.70 mm voxel size. MRI and three-dimensional (3D) histology volumes of plaques were registered. The registration matrix was applied to segmentations denoting LRNC and IPH in 3D histology to split plaque volumes in regions with and without LRNC and IPH. RESULTS: Five patients were included. Regarding volumes of LRNC identified by 3D histology, the average fat fraction by MRI was significantly higher inside LRNC than outside: 12.64 +/- 0.2737% versus 9.294 +/- 0.1762% (mean +/- standard error of the mean [SEM]; P < 0.001). The same was true for IPH identified by 3D histology, R2* inside versus outside IPH was: 71.81 +/- 1.276 s-1 versus 56.94 +/- 0.9095 s-1 (mean +/- SEM; P < 0.001). There was a strong correlation between the cumulative fat and the volume of LRNC from 3D histology (R2 = 0.92) as well as between cumulative R2* and IPH (R2 = 0.94). CONCLUSION: Quantitative mapping of fat and R2* from Dixon MRI reliably quantifies the extent of LRNC and IPH. Magn Reson Med 78:285-296, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27510301 TI - Vibriosis, not cholera: toxigenic Vibrio cholerae non-O1, non-O139 infections in the United States, 1984-2014. AB - Toxigenic strains of Vibrio cholerae serogroups O1 and O139 have caused cholera epidemics, but other serogroups - such as O75 or O141 - can also produce cholera toxin and cause severe watery diarrhoea similar to cholera. We describe 31 years of surveillance for toxigenic non-O1, non-O139 infections in the United States and map these infections to the state where the exposure probably originated. While serogroups O75 and O141 are closely related pathogens, they differ in how and where they infect people. Oysters were the main vehicle for O75 infection. The vehicles for O141 infection include oysters, clams, and freshwater in lakes and rivers. The patients infected with serogroup O75 who had food traceback information available ate raw oysters from Florida. Patients infected with O141 ate oysters from Florida and clams from New Jersey, and those who only reported being exposed to freshwater were exposed in Arizona, Michigan, Missouri, and Texas. Improving the safety of oysters, specifically, should help prevent future illnesses from these toxigenic strains and similar pathogenic Vibrio species. Post-harvest processing of raw oysters, such as individual quick freezing, heat cool pasteurization, and high hydrostatic pressurization, should be considered. PMID- 27510302 TI - Characterization of two LuxI/R homologs in Pantoea ananatis LMG 2665T. AB - Quorum sensing (QS) plays an important role in the regulation of bacteria-host interactions and ecological fitness in many bacteria. In this study, 2 luxI/R homologs, namely eanI/eanR and rhlI/rhlR, were identified in the genome sequence of Pantoea ananatis LMG 2665T. To determine a role for these luxI/R homologs in pathogenicity and biofilm formation, mutant bacterial strains lacking either eanI/R or rhlI/R and both of these homologs were generated. The results indicated that both the RhlI/R and EanI/R systems are required for pathogenicity and biofilm formation in strain LMG 2665T. This is the first study to characterize the biological significance of the RhlI/R QS system in P. ananatis. PMID- 27510303 TI - Genetic diversity of 21 autosomal STR loci in the Han Chinese population from Hainan Province in South China. PMID- 27510305 TI - Analyzing generalized coherent states for a free particle. AB - Despite the didactic importance of a free particle in quantum mechanics, its coherent state analysis has long been untouched. It is only recently that it has been noticed and studied in the semiclassical domain. While the previously known solutions, reported by Bagrov et al. for a free particle, are described using the linear non-Hermitian invariant operator, we show in this work that the general solution of the Schrodinger equation can also be naturally derived using a simpler method based on an Hermitian linear invariant operator. According to this, an exact Gaussian wave function that corresponds to a coherent state solution is obtained. An interpretation for such general quantum solution designated within the Lewis-Riesenfeld framework is provided and, further, quantum-classical correspondence principle for the system is reexamined. PMID- 27510304 TI - Electrical coupling regulates layer 1 interneuron microcircuit formation in the neocortex. AB - The coexistence of electrical and chemical synapses among interneurons is essential for interneuron function in the neocortex. However, it remains largely unclear whether electrical coupling between interneurons influences chemical synapse formation and microcircuit assembly during development. Here, we show that electrical and GABAergic chemical connections robustly develop between interneurons in neocortical layer 1 over a similar time course. Electrical coupling promotes action potential generation and synchronous firing between layer 1 interneurons. Furthermore, electrically coupled interneurons exhibit strong GABA-A receptor-mediated synchronous synaptic activity. Disruption of electrical coupling leads to a loss of bidirectional, but not unidirectional, GABAergic connections. Moreover, a reduction in electrical coupling induces an increase in excitatory synaptic inputs to layer 1 interneurons. Together, these findings strongly suggest that electrical coupling between neocortical interneurons plays a critical role in regulating chemical synapse development and precise formation of circuits. PMID- 27510306 TI - Dynamic NMR and Quantum-Chemical Study of the Stereochemistry and Stability of the Chiral MoO2(acac)2 Complex in Solution. AB - The stereochemistry and dynamics of MoO2(acac)2 in benzene, chloroform, and toluene were investigated by variable temperature (1)H NMR, density functional theory (SOGGA11-X, B3LYP), and ab initio (MP2) methods. In solution, an equilibrium between two chiral enantiomers with C2 symmetry was identified, Lambda-cis-MoO2(acac)2 and Delta-cis-MoO2(acac)2. The two enantiomers are connected via achiral cis transition states that switch the enantiomeric conformations via a Ray-Dutt, Bailar, and a newly described racemization twisting mechanism. All three mechanisms have similar calculated activation energies. Activation parameters Ea, DeltaH(?), and DeltaS(?) were experimentally determined for the exchange process, with a small, negative DeltaS(?), and a positive DeltaH(?) of 68.1 kJ mol(-1) in benzene, 54.9 kJ mol(-1) in chloroform, and 60.6 kJ mol(-1) in toluene, in reasonable general agreement with the calculations. Trans configurations of MoO2(acac)2 are very much higher in energy than cis and are not relevant in the temperature range experimentally studied, 243-340 K. The enantiomers interconvert within seconds near room temperature and much faster at elevated temperatures. Racemization will thus prevent the use of enantiomerically pure MoO2(acac)2 for chiral catalysis under practical conditions. PMID- 27510307 TI - Differential pre-amplification of STR loci for fragmented forensic DNA profiling. AB - DNA profiling of short tandem repeats (STR) has been successfully used for the identification of individuals in forensic samples, accidents and natural disasters. However, STR profiling of DNA isolated from old crime scenes and damaged biological samples is difficult due to DNA degradation and fragmentation. Here, we show that pre-amplification of STR loci using biotinylated primers for the STR loci is an efficient strategy to obtain STR profiling results from fragmented forensic samples. Analysis of STR loci with longer amplicon sizes is generally hampered, since these relatively long loci are vulnerable to DNA fragmentation. This problem was overcome by using reduced or increased primer concentrations for loci with shorter or longer amplicon sizes, respectively, in our pre-amplification strategy. In addition, pre-amplification of STR loci into two groups of short or long amplicon size increases the efficiency of STR profiling from highly fragmented forensic DNA samples. Therefore, differential pre-amplification of STR loci is an effective way to obtain DNA profiling results from fragmented forensic samples. PMID- 27510308 TI - Ultra-sensitive measurement of peroxy radicals by chemical amplification broadband cavity-enhanced spectroscopy. AB - The PERCA (PEroxy Radical Chemical Amplification) technique, which is based on the catalytic conversion of ambient peroxy radicals (HO2 and RO2, where R stands for any organic chain) to a larger amount of nitrogen dioxide (NO2) amplified by chain reactions by adding high concentrations of NO and CO in the flow reactor, has been widely used for total peroxy radical RO2* (RO2* = HO2 + SigmaRO2) measurements. High-sensitivity and accurate measurement of the NO2 concentration plays a key role in accurate measurement of the RO2* concentration. In this paper, we report on the development of a dual-channel chemical amplification instrument, which combined the PERCA method with the incoherent broadband cavity enhanced absorption spectroscopy (IBBCEAS), for peroxy radical measurements. The IBBCEAS method is capable of simultaneously measuring multiple species with high spectral identification, and can directly measure NO2 concentrations with high sensitivity and high accuracy and without interference from other absorbers. The detection sensitivity of the developed PERCA-IBBCEAS instrument for HO2 radicals was estimated to be about 0.9 pptv (1sigma, 60 s) at a relative humidity (RH) of 10%. Considering the error sources of NO2 detection, CL determination, and the radical partitioning in the air sample, the total uncertainty of RO2* measurements was about 16-20%. PMID- 27510310 TI - Surgical treatment for thoracoabdominal intra-aortic thrombus with multiple infarctions: a case report. AB - BACKGROUND: Mobile intra-aortic thrombus without atherosclerosis, aneurysm, or congenital coagulopathy is very rare, and there are few reports especially in young or middle-aged patients. Furthermore, there are presently no established guidelines or common strategies for the treatment of mobile intra-aortic thrombus. In this case report, we describe the first case of intra-aortic thrombus caused by secondary erythrocytosis and describe the recommended treatment strategy for intra-aortic thrombus. CASE PRESENTATION: We report a case of an independent 40-year-old Asian man with a current history of heavy cigarette smoking who had sudden onset of abdominal and lumbar pain. Contrast-enhanced computed tomography revealed partial renal and splenic infarction, and he was transferred to our hospital. He also had a large mural thrombus in his thoracoabdominal aorta. Blood analysis on admission showed a hemoglobin level of 19.4 g/dL and hematocrit of 54.3 %; his international normalized ratio of prothrombin time, fibrin degradation products, and activated partial thromboplastin time levels were 1.02, 2.8 MUg/ml, and 26.9 seconds respectively. We could find no abnormalities in protein C and protein S activity levels. Lupus anticoagulant and anti-cardiolipin antibody were both negative. He had no past medical history of arrhythmia and we found no signs of an arrhythmic event during admission. We promptly started anticoagulant therapy, but as the thrombus seemed at high risk of causing further critical infarction, we performed emergency aortic thrombectomy using partial extracorporeal circulation. To prevent dissemination of the thrombus during extracorporeal circulation, we first clamped his proximal and distal aorta on either side of the thrombus just before initiating extracorporeal circulation. After the aortotomy we removed a 14-cm length of intra-aortic thrombus without residual lesion. He was discharged from our hospital 20 days after surgery. From the results of his blood analysis, we considered the only cause of this thrombus was secondary erythrocytosis, which was probably induced by his current heavy cigarette smoking. CONCLUSION: We are the first to report such a thrombosis caused by secondary erythrocytosis and conclude that once the diagnosis of intra-aortic thrombus with systemic embolism is clear, emergency surgical removal of such a thrombus must be considered to prevent further embolic complications. PMID- 27510309 TI - Genotype-phenotype correlation of SMN locus genes in spinal muscular atrophy children from Argentina. AB - BACKGROUND/PURPOSE: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, considered one of the leading causes of infant mortality. It is caused by mutations in the SMN1 gene. A highly homologous copy of this gene named SMN2 and other neighbouring genes, SERF1A and NAIP, are considered phenotypic modifiers of the disease. In recent years, notable advances have been made in SMA research regarding evaluation, prognosis, and therapeutic options. Thus, genotype-phenotype studies in SMA are important to stratify patients for motor function tests and for envisaged clinical trials. The aim of this study was to provide clinical and molecular data of a series of Argentinean children with SMA to establish a comprehensive genotype-phenotype correlation. METHODS: 144 Argentinean children with SMA (56 children with type I, 58 with type II, and 30 with type III) were evaluated. The copy number of SMN2, SERF1A, and NAIP genes was established using MLPA (Multiplex Ligation-dependent Probe Amplification) and then correlated with the patients clinical subtypes. To improve clinical characterization we considered the initial symptoms that prompted the consultation, age of acquisition of motor abilities to independent walking and age at loss of gait. We also evaluated clinical and molecular features of sibling pairs in seven families. RESULTS: A strong correlation was observed between the SMN2 copy number and SMA phenotype while SERF1A and NAIP copy number showed a moderate correlation. We observed intra- and inter-family differences among the SMA types. CONCLUSION: This first genotype-phenotype correlation study in Argentinean SMA children provides data to improve patient stratification and define more adequate follow-up parameters. PMID- 27510311 TI - Engineering of Sub-Nanometer SiOx Thickness in Si Photocathodes for Optimized Open Circuit Potential. AB - Silicon is one of the most promising materials to be used for tandem-cell water splitting devices. However, the electrochemical instability of bare Si makes it difficult to be used for stable devices. Besides that, the photovoltage loss in Si, caused by several factors (e.g., metal oxide protection layer and/or SiO2 /Si or catalyst/Si interface), limits its use in these devices. In this work, we present that an optimized open circuit potential (OCP) of Si can be obtained by controlling the SiOx thickness in sub-nanometer range. It can be done by means of a simple and cost-effective way using the combination of a wet chemical etching and the low temperature atomic layer deposition (ALD) of TiO2 . We have found that a certain thickness of the native SiOx is necessary to prevent further oxidation of the Si photocathode during the ALD growth of TiO2 . Moreover, covering the Si photocathode with an ALD TiO2 layer enhances its stability. PMID- 27510312 TI - Local wound healing biomarkers for real-time assessment of periodontal regeneration: pilot study. AB - BACKGROUND AND OBJECTIVES: Within the same surgical procedure, a great variability on achievement of clinical outcomes exists and may be associated to different molecular factors related to tissue healing. The aim of the present study was to assess the distribution of clinical success separately in regenerative therapy (REG) and open flap debridement (OFD) to evaluate if factors related with healing of epithelium, connective tissue and bone may be associated to the clinical outcome within each surgical procedure. MATERIAL AND METHODS: Sixteen patients underwent periodontal REG and nine patients underwent OFD. Periodontal wound fluid was collected at baseline, 3-5, 7, 14 and 21 d after surgery, and expression of wound healing proteins was assessed. Pocket depth and clinical attachment level were taken at baseline and at 6 mo of follow-up. Percentage pocket depth reduction and percentage clinical attachment level gain were computed. Patients were regarded as better or worse responders depending on their percentage pocket depth reduction or percentage clinical attachment level gain. RESULTS: Higher percentage of better responders was observed in the REG group (68.7%) compared to the OFD group (22.2%). At 21 d, no difference in the profile of most of the proteins emerged, with two exceptions, both regarding REG treatment. Bone morphogenetic protein-7 tended to increase in better responders and to decrease in worse responders. Matrix metalloproteinase-1 increased in worse responders and remained substantially unchanged in better responders. CONCLUSION: Local expression of matrix metalloproteinase-1 and bone morphogenetic protein-7 during wound healing is associated with the clinical performance of periodontal regenerative surgery. The use of local biomarkers offers the potential for real-time assessment of the periodontal healing process. PMID- 27510313 TI - Long-term nitrous oxide fluxes in annual and perennial agricultural and unmanaged ecosystems in the upper Midwest USA. AB - Differences in soil nitrous oxide (N2 O) fluxes among ecosystems are often difficult to evaluate and predict due to high spatial and temporal variabilities and few direct experimental comparisons. For 20 years, we measured N2 O fluxes in 11 ecosystems in southwest Michigan USA: four annual grain crops (corn-soybean wheat rotations) managed with conventional, no-till, reduced input, or biologically based/organic inputs; three perennial crops (alfalfa, poplar, and conifers); and four unmanaged ecosystems of different successional age including mature forest. Average N2 O emissions were higher from annual grain and N-fixing cropping systems than from nonleguminous perennial cropping systems and were low across unmanaged ecosystems. Among annual cropping systems full-rotation fluxes were indistinguishable from one another but rotation phase mattered. For example, those systems with cover crops and reduced fertilizer N emitted more N2 O during the corn and soybean phases, but during the wheat phase fluxes were ~40% lower. Likewise, no-till did not differ from conventional tillage over the entire rotation but reduced emissions ~20% in the wheat phase and increased emissions 30 80% in the corn and soybean phases. Greenhouse gas intensity for the annual crops (flux per unit yield) was lowest for soybeans produced under conventional management, while for the 11 other crop * management combinations intensities were similar to one another. Among the fertilized systems, emissions ranged from 0.30 to 1.33 kg N2 O-N ha-1 yr-1 and were best predicted by IPCC Tier 1 and DeltaEF emission factor approaches. Annual cumulative fluxes from perennial systems were best explained by soil NO3- pools (r2 = 0.72) but not so for annual crops, where management differences overrode simple correlations. Daily soil N2 O emissions were poorly predicted by any measured variables. Overall, long-term measurements reveal lower fluxes in nonlegume perennial vegetation and, for conservatively fertilized annual crops, the overriding influence of rotation phase on annual fluxes. PMID- 27510314 TI - 2016 updated MASCC/ESMO consensus recommendations: Anticipatory nausea and vomiting in children and adults receiving chemotherapy. AB - PURPOSE: We aimed to update the 2011 recommendations for the prevention and treatment of anticipatory nausea and vomiting in children and adults receiving chemotherapy. METHODS: The original systematic literature search was updated. Randomized studies were included in the evidence to support this guideline if they as follows: were primary studies published in a journal in full text (i.e., abstracts, letters, book chapters, and dissertations were excluded); published in English; evaluated an intervention for the prevention or treatment of anticipatory nausea and vomiting; reported the proportion of patients experiencing complete control of anticipatory nausea and vomiting consistently and; included at least ten participants per study arm for comparative studies and at least ten participants overall for noncomparative studies. RESULTS: Eighty eight new citations were identified. Of these, nine were brought to full-text screening; none met inclusion criteria. The guideline panel continues to recommend that anticipatory nausea and vomiting are best prevented through optimization of acute and delayed phase chemotherapy-induced nausea and vomiting control. Benzodiazepines and behavioral therapies, in particular progressive muscle relaxation training, systematic desensitization and hypnosis, continue to be recommended for the treatment of anticipatory nausea and vomiting. CONCLUSIONS: No new information regarding interventions aimed at treating or preventing ANV that met criteria for inclusion in this systematic review was identified. The 2015 MASCC recommendations affirm the content of the 2009 MASCC recommendations for the prevention and treatment of anticipatory nausea and vomiting. PMID- 27510315 TI - Lymphedema self-care in patients with head and neck cancer: a qualitative study. AB - PURPOSE: Lymphedema is a frequent side effect from head and neck cancer and/or its treatment. As a chronic and progressive condition, it requires an individual's long-term involvement in self-care for management of lymphedema. This study aimed to report head and neck cancer patients' perceived lymphedema education, self-care practices, and suggestions related to self-care of head and neck lymphedema. METHODS: Twenty head and neck cancer patients who completed lymphedema therapy participated in semi-structured face-to-face interviews. Interviews were audio-recorded and transcribed. Content analysis was used to analyze the interview data. RESULTS: All participants reported that they were educated about self-care activities for lymphedema management by their lymphedema therapists. Although most participants (n = 16, 80 %) expressed positive comments about lymphedema self-care education, some participants (n = 7, 35 %) described issues related to lymphedema self-care education. A majority of the participants (n = 17, 85 %) reported that they were conducting some lymphedema self-care activities; nonetheless, more than half of the participants (n = 11, 55 %) delineated barriers for diminished lymphedema self-care activities over time. Participants further indicated suggestions for improving and ensuring consistency of lymphedema self-care. CONCLUSIONS: Opportunities exist to improve lymphedema self-care in head and neck cancer patients. Healthcare professionals should focus on delivering high quality and targeted information about self-care for management of head and neck lymphedema. Interventional research is warranted to address gaps in long-term self-care of head and neck lymphedema. PMID- 27510316 TI - 2016 updated MASCC/ESMO consensus recommendations: Prevention of nausea and vomiting following moderately emetogenic chemotherapy. AB - PURPOSE: An update of the recommendations for the prophylaxis of acute and delayed emesis induced by moderately emetogenic chemotherapy published after the last MASCC/ESMO antiemetic consensus conference in 2009 has been carried out. METHODS: A systematic literature search using PubMed from January 1, 2009 to January 6, 2015 with a restriction to papers in English was conducted. RESULTS: Overall, two randomized phase II and seven randomized phase III studies plus the results of three subgroup analysis of large phase III trials and those of a pilot study have been included. CONCLUSIONS: In carboplatin-treated patients, a moderate benefit from adding an NK1 receptor antagonist to dexamethasone and a 5 HT3 receptor antagonist has been shown. However, in oxaliplatin-treated patients, contrasting results about the role of NK1 receptor antagonists have been obtained. At present, it is not possible to suggest a specific 5-HT3 receptor antagonist to use for the prevention of acute emesis in these patients. No routine prophylaxis for delayed emesis is recommended but in patients receiving moderately emetogenic chemotherapy with known potential for delayed emesis (e.g., oxaliplatin, doxorubicin, cyclophosphamide) the use of dexamethasone for days 2-3 can be considered. PMID- 27510318 TI - Real-time multi-signal frequency tracking with a bank of notch filters to estimate the respiratory rate from the ECG. AB - Measuring the instantaneous frequency of a signal rapidly and accurately is essential in many applications. However, the instantaneous frequency by definition is a parameter difficult to determine. Fourier-based methods introduce estimation delays as computations are performed in a time-window. Instantaneous methods based on the Hilbert transform lack robustness. State-of-the-art adaptive filters yield accurate estimates, however, with an adaptation delay. In this study we propose an algorithm based on short length-3 FIR notch filters to estimate the instantaneous frequency of a signal at each sample, in a real-time manner and with very low delay. The output powers of a bank of the above mentioned filters are used in a recursive weighting scheme to estimate the dominant frequency of the input. This scheme has been extended to process multiple inputs containing a common frequency by introducing an additional weighting scheme upon the inputs. The algorithm was tested on synthetic data and then evaluated on real biomedical data, i.e. the estimation of the respiratory rate from the electrocardiogram. It was shown that the proposed method provided more accurate estimates with less delay than those of state-of-the-art methods. By virtue of its simplicity and good performance, the proposed method is a worthy candidate to be used in biomedical applications, for example in health monitoring developments based on portable and automatic devices. PMID- 27510317 TI - Transplantation of Human Skin-Derived Mesenchymal Stromal Cells Improves Locomotor Recovery After Spinal Cord Injury in Rats. AB - Spinal cord injury (SCI) is a devastating neurologic disorder with significant impacts on quality of life, life expectancy, and economic burden. Although there are no fully restorative treatments yet available, several animal and small-scale clinical studies have highlighted the therapeutic potential of cellular interventions for SCI. Mesenchymal stem cells (MSCs)-which are conventionally isolated from the bone marrow-recently emerged as promising candidates for treating SCI and have been shown to provide trophic support, ameliorate inflammatory responses, and reduce cell death following the mechanical trauma. Here we evaluated the human skin as an alternative source of adult MSCs suitable for autologous cell transplantation strategies for SCI. We showed that human skin derived MSCs (hSD-MSCs) express a range of neural markers under standard culture conditions and are able to survive and respond to neurogenic stimulation in vitro. In addition, using histological analysis and behavioral assessment, we demonstrated as a proof-of-principle that hSD-MSC transplantation reduces the severity of tissue loss and facilitates locomotor recovery in a rat model of SCI. Altogether, the study provides further characterization of skin-derived MSC cultures and indicates that the human skin may represent an attractive source for cell-based therapies for SCI and other neurological disorders. Further investigation is needed to elucidate the mechanisms by which hSD-MSCs elicit tissue repair and/or locomotor recovery. PMID- 27510319 TI - Integrative approach for inference of gene regulatory networks using lasso-based random featuring and application to psychiatric disorders. AB - BACKGROUND: Inferring gene regulatory networks is one of the most interesting research areas in the systems biology. Many inference methods have been developed by using a variety of computational models and approaches. However, there are two issues to solve. First, depending on the structural or computational model of inference method, the results tend to be inconsistent due to innately different advantages and limitations of the methods. Therefore the combination of dissimilar approaches is demanded as an alternative way in order to overcome the limitations of standalone methods through complementary integration. Second, sparse linear regression that is penalized by the regularization parameter (lasso) and bootstrapping-based sparse linear regression methods were suggested in state of the art methods for network inference but they are not effective for a small sample size data and also a true regulator could be missed if the target gene is strongly affected by an indirect regulator with high correlation or another true regulator. RESULTS: We present two novel network inference methods based on the integration of three different criteria, (i) z-score to measure the variation of gene expression from knockout data, (ii) mutual information for the dependency between two genes, and (iii) linear regression-based feature selection. Based on these criterion, we propose a lasso-based random feature selection algorithm (LARF) to achieve better performance overcoming the limitations of bootstrapping as mentioned above. CONCLUSIONS: In this work, there are three main contributions. First, our z score-based method to measure gene expression variations from knockout data is more effective than similar criteria of related works. Second, we confirmed that the true regulator selection can be effectively improved by LARF. Lastly, we verified that an integrative approach can clearly outperform a single method when two different methods are effectively jointed. In the experiments, our methods were validated by outperforming the state of the art methods on DREAM challenge data, and then LARF was applied to inferences of gene regulatory network associated with psychiatric disorders. PMID- 27510320 TI - Brief Group Intervention Targeting Perfectionism in Adults with Anorexia Nervosa: Empirically Informed Protocol. AB - OBJECTIVE: This study aimed to evaluate the perfectionism group intervention in adults with anorexia nervosa (AN) in an inpatient setting. METHOD: Adults with AN (N = 35) received six weekly sessions of the empirically informed intervention with experiential exercises. Participants' self-reported perfectionism and satisfaction were collected pre-group and post-group intervention. RESULTS: Statistically, significant differences were observed for overall perfectionism, concern over mistakes and personal standard dimensions of perfectionism. Participants found the sessions useful and felt confident in using the skills they had learnt. CONCLUSIONS: The revised perfectionism group with experiential exercises seemed to be a practical and helpful intervention for patients with AN in an inpatient programme. Copyright (c) 2016 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 27510322 TI - Drug-induced photosensitivity: new insights into pathomechanisms and clinical variation through basic and applied science. AB - Drug-induced photosensitivity occurs when a drug is capable of absorbing radiation from the sun (usually ultraviolet A) leading to chemical reactions that cause cellular damage (phototoxicity) or, more rarely, form photoallergens (photoallergy). The manifestation varies considerably in presentation and severity from mild pain to severe blistering. Despite screening strategies and guidelines in place to predict photoreactive drugs during development there are still new drugs coming onto the market that cause photosensitivity. Thus, there is a continuing need for dermatologists to be aware of the different forms of presentation and the culprit drugs. Management usually involves photoprotection and cessation of drug treatment. However, there are always cases where the culprit drug is indispensable. The reason why some patients are susceptible while others remain asymptomatic is not known. A potential mechanism for the phototoxic reactions is the generation of reactive oxygen species (ROS), and there are a number of reasons why some patients might be less able to cope with enhanced levels of ROS. PMID- 27510323 TI - Use of whole-exome sequencing to determine the genetic basis of signs of skin youthfulness in Korean women. PMID- 27510321 TI - Mesenchymal Stem Cells Enhance Nerve Regeneration in a Rat Sciatic Nerve Repair and Hindlimb Transplant Model. AB - This study investigates the efficacy of local and intravenous mesenchymal stem cell (MSC) administration to augment neuroregeneration in both a sciatic nerve cut-and-repair and rat hindlimb transplant model. Bone marrow-derived MSCs were harvested and purified from Brown-Norway (BN) rats. Sciatic nerve transections and repairs were performed in three groups of Lewis (LEW) rats: negative controls (n = 4), local MSCs (epineural) injection (n = 4), and systemic MSCs (intravenous) injection (n = 4). Syngeneic (LEW-LEW) (n = 4) and allogeneic (BN LEW) (n = 4) hindlimb transplants were performed and assessed for neuroregeneration after local or systemic MSC treatment. Rats undergoing sciatic nerve cut-and-repair and treated with either local or systemic injection of MSCs had significant improvement in the speed of recovery of compound muscle action potential amplitudes and axon counts when compared with negative controls. Similarly, rats undergoing allogeneic hindlimb transplants treated with local injection of MSCs exhibited significantly increased axon counts. Similarly, systemic MSC treatment resulted in improved nerve regeneration following allogeneic hindlimb transplants. Systemic administration had a more pronounced effect on electromotor recovery while local injection was more effective at increasing fiber counts, suggesting different targets of action. Local and systemic MSC injections significantly improve the pace and degree of nerve regeneration after nerve injury and hindlimb transplantation. PMID- 27510324 TI - Deviation of sliding drops at a chemical step. AB - The motion of partially wetting liquid drops in contact with a solid surface is strongly affected by contact angle hysteresis and interfacial pinning. However, the majority of models proposed for drops sliding over chemical surface patterns consistently neglect the difference between advancing and receding contact angles. In this article, we present a joint experimental and numerical study of the interaction of gravity-driven drops with a chemical step formed at the junction between a hydrophilic and a hydrophobic region. It demonstrates the strong impact of a contact angle hysteresis contrast on the motion of drops at a linear chemical step. Surprisingly, the smallest driving force required to drag the drop across the step onto the lower hydrophobic surface is not observed at a right angle of incidence. Our model reveals that the non-monotonous response of this passive drop 'filter' is solely due to the higher advancing contact angle on the lower surface, and creates an instance where drop motion is affected by dissipation at the contact line rather than by surface energy. PMID- 27510326 TI - Lumps and Bumps of the Neck in Children-Neuroimaging of Congenital and Acquired Lesions. AB - Neck masses present as palpable lumps and bumps in children with acquired lesions more common than congenital ones. Assessment of the anatomical site of origin, signal, and contrast enhancement characteristics may help define the etiology of the lesions, eg, developmental, inflammatory, vascular, or neoplastic. The age of the patient along with detailed clinical history and physical exam findings are important element to narrow down the differential diagnosis. The correct final diagnosis is essential to guide treatment as well as the urgency of intervention. The objective of this review is to define the characteristic location, classic and differentiating imaging features of the most frequent congenital and acquired cervical lumps and bumps in the pediatric population. PMID- 27510325 TI - Lycopene inhibits the cell proliferation and invasion of human head and neck squamous cell carcinoma. AB - Lycopene has been shown to be associated with anticancer effects in numerous tumor types. However, the underlying mechanisms of lycopene in human head and neck squamous cell carcinoma (HNSCC) remain to be determined. The present study aimed to investigate the involvement of lycopene overload and the cytotoxic effects of lycopene on HNSCC cells, and to determine the possible mechanisms involved. Treatment with lycopene at a dose of >10 uM for >24 h inhibited the growth of FaDu and Cal27 cells in a time- and dose-dependent manner. The clearest increase in growth inhibition was due to the apoptotic population being significantly increased. The invasion abilities decreased with 25 uM lycopene exerting significant inhibitory effects (P<0.01). Mechanistic studies revealed that lycopene induced the upregulation of the pro-apoptotic protein, B-cell lymphoma-associated X protein, and therefore, resulted in the inhibition of the protein kinase B and mitogen-activated protein kinase signaling pathway. These data provided insights into the antitumor activity of lycopene in HNSCC cells. PMID- 27510327 TI - Lipophilic Cationic Cyanines Are Potent Complex I Inhibitors and Specific in Vitro Dopaminergic Toxins with Mechanistic Similarities to Both Rotenone and MPP(.). AB - We have recently reported that simple lipophilic cationic cyanines are specific and potent dopaminergic toxins with a mechanism of toxicity similar to that of the Parkinsonian toxin MPP(+). In the present study, a group of fluorescent lipophilic cyanines have been used to further exploit the structure-activity relationship of the specific dopaminergic toxicity of cyanines. Here, we report that all cyanines tested were highly toxic to dopaminergic MN9D cells with IC50s in the range of 60-100 nM and not toxic to non-neuronal HepG2 cells parallel to that previously reported for 2,2'- and 4,4'-cyanines. All cyanines nonspecifically accumulate in the mitochondria of both MN9D and HepG2 cells at high concentrations, inhibit the mitochondrial complex I with the inhibition potencies similar to the potent complex I inhibitor, rotenone. They increase the reactive oxygen species (ROS) production specifically in dopaminergic cells causing apoptotic cell death. These and other findings suggest that the complex I inhibition, the expression of low levels of antioxidant enzymes, and presence of high levels of oxidatively labile radical propagator, dopamine, could be responsible for the specific increase in ROS production in dopaminergic cells. Thus, the predisposition of dopaminergic cells to produce high levels of ROS in response to mitochondrial toxins together with their inherent greater demand for energy may contribute to their specific vulnerability toward these toxins. The novel findings that cyanines are an unusual class of potent mitochondrial toxins with specific dopaminergic toxicity suggest that their presence in the environment could contribute to the etiology of PD similar to that of MPP(+) and rotenone. PMID- 27510328 TI - A simple but useful way to assess fMRI scan qualities. AB - This short "how to" article describes a plot I find useful for assessing fMRI data quality. I discuss the reasoning behind the plot and how it is constructed. I create the plot in scans from several publicly available datasets to illustrate different kinds of fMRI signal variance, ranging from thermal noise to motion artifacts to respiratory-related signals. I also show how the plot can be used to understand the variance removed during denoising. Code to make the plot is provided with the article, and supplemental movies show plots for hundreds of additional subjects. PMID- 27510329 TI - Feeling the right force: How to contextualize the cell mechanical behavior in physiologic turnover and pathologic evolution of the cardiovascular system. AB - Although traditionally linked to the physiology of tissues in 'motion', the ability of the cells to transduce external forces into coordinated gene expression programs is emerging as an integral component of the fundamental structural organization of multicellular organisms with consequences for cell differentiation even from the beginning of embryonic development. The ability of the cells to 'feel' the surrounding mechanical environment, even in the absence of tissue motion, is then translated into 'positional' or 'social' sensing that instructs, before the organ renewal, the correct patterning of the embryos. In the present review, we will highlight how these basic concepts, emerging from the employment of novel cell engineering tools, can be linked to pathophysiology of the cardiovascular system, and may contribute to understanding the molecular bases of some of the major cardiovascular diseases like heart failure, heart valve stenosis and failure of the venous aorto-coronary bypass. PMID- 27510330 TI - Pericytes for the treatment of orthopedic conditions. AB - Pericytes and other perivascular stem cells are of growing interest in orthopedics and tissue engineering. Long regarded as simple regulators of angiogenesis and blood pressure, pericytes are now recognized to have MSC (mesenchymal stem cell) characteristics, including multipotentiality, self renewal, immunoregulatory functions, and diverse roles in tissue repair. Pericytes are typified by characteristic cell surface marker expression (including alphaSMA, CD146, PDGFRbeta, NG2, RGS5, among others). Although alone no marker is absolutely specific for pericytes, collectively these markers appear to selectively identify an MSC-like pericyte. The purification of pericytes is most well described as a CD146+CD34-CD45- cell population. Pericytes and other perivascular stem cell populations have been applied in diverse orthopedic applications, including both ectopic and orthotopic models. Application of purified cells has sped calvarial repair, induced spine fusion, and prevented fibrous non-union in rodent models. Pericytes induce these effects via both direct and indirect mechanisms. In terms of their paracrine effects, pericytes are known to produce and secrete high levels of a number of growth and differentiation factors both in vitro and after transplantation. The following review will cover existing studies to date regarding pericyte application for bone and cartilage engineering. In addition, further questions in the field will be pondered, including the phenotypic and functional overlap between pericytes and culture-derived MSC, and the concept of pericytes as efficient producers of differentiation factors to speed tissue repair. PMID- 27510331 TI - Factors Leading to Improved Results for Endoscopic Stenting for Metastatic Antropyloric Adenocarcinoma. A Comparison with Gastrojejunostomy. AB - BACKGROUND: Controversies exist about the optimal palliative management for patients with metastatic antropyloric adenocarcinoma. The aim of this study was to analyse the clinical outcome for patients with gastric outlet obstruction syndrome and metastatic antropyloric adenocarcinoma, who underwent endoscopic stenting or open gastrojejunostomy, in a prospective not randomised study. MATERIAL: The clinical course and costs for 70 patients who had endoscopic stenting and for 30 patients who had in the same period a gastrojejunostomy for gastric outlet obstruction syndrome due to metastatic adenocarcinoma of the antropyloric region were prospectively analysed. RESULTS: Hospital stay and time to resume oral feeding was shorter in patients who had endoscopic stenting (p < 0.05). Overall costs for endoscopic stenting were lower than those for gastrojejunostomy (11,000 versus 21,000 euros). Comparing patients who survived more than 6 months, costs between endoscopic stenting and gastrojejunostomy were similar (21,000 versus 22,000 euros). CONCLUSIONS: Endoscopic placement of metallic stents offers an effective therapy in patients with advanced primay adenocarcinoma of the antropyloric region and poor general conditions. In patients with longer life expectancy, surgical gastroenterostomy has still a major role. In contrast to previous reports, costs for endoscopic stenting are similar to those of gastrojejunostomy in patients with longer life expectancy. Laparoscopic gastrojejunostomy has the theoretical advantage to reduce these costs with a less invasive procedure. Results for endoscopic stenting have improved significantly in recent years. PMID- 27510332 TI - Intensity-Modulated Radiation Therapy Is Not Associated with Perioperative or Survival Benefit over 3D-Conformal Radiotherapy for Rectal Cancer. AB - INTRODUCTION: The use of intensity-modulated radiation therapy (IMRT) in rectal cancer has steadily increased over traditional 3D conformal radiotherapy (3D-CRT) due to perceived benefit of delivering higher treatment doses while minimizing exposure to surrounding tissues. However, IMRT is technically challenging and costly, and its effects on rectal cancer outcomes remain unclear. MATERIAL AND METHODS: Adults with clinical stage II and III rectal adenocarcinoma who underwent neoadjuvant chemoradiotherapy with 45-54 Gy of radiation and surgery were included from the 2006-2013 National Cancer Data Base. Patients were grouped based the modality of radiation received: IMRT or 3D-CRT. Multivariable regression modeling adjusting for demographic, clinical, and treatment characteristics was used to examine the impact of IMRT vs. 3D-CRT on pathologic downstaging, resection margin positivity, sphincter loss surgery, 30-day unplanned readmission and mortality after surgery, and overall survival. RESULTS: Among 7386 patients included, 3330 (45 %) received IMRT and 4056 (55 %) received 3D-CRT. While the mean radiation dose delivered was higher with IMRT (4735 vs. 4608 cGy, p < 0.001), it was associated with higher risks of positive margins (adjusted odds ratio (OR) 1.57; p < 0.001) and sphincter loss surgery (OR 1.32; p < 0.001). There were no differences between IMRT and 3D-CRT in the likelihood of pathologic downstaging (OR 0.89, p = 0.051), unplanned readmission (OR 0.79; p = 0.07), or 30-day mortality (OR 0.61; p = 0.31) after surgery. Additionally, there were no differences in overall survival at 8 years (IMRT vs. 3D-CRT: 64 vs. 64 %; adjusted hazard ratio 1.06, p = 0.47). CONCLUSION: IMRT is associated with worse local tumor control without any long-term survival benefit for patients with locally advanced rectal cancer. Given the lack of significant advantage and the higher cost of IMRT, caution should be exercised when using IMRT instead of traditional 3D-CRT for rectal cancer. PMID- 27510333 TI - Practical echocardiographic approach for risk stratification of patients with acute pulmonary embolism. AB - Acute pulmonary embolism remains a common cause of mortality. Early diagnosis and appropriate risk stratification is necessary to individualize treatment strategy. Computed tomography scan of the pulmonary arteries is routinely used to diagnose acute pulmonary embolism and in some cases is useful to assess right ventricular dilation. In patients with acute pulmonary embolism, right ventricular dilation and dysfunction indicates a high-risk situation where immediate administration of thrombolytic agent, catheter-directed thrombolysis, or surgical embolectomy could be considered. A bedside 2D echocardiogram at the time of presentation could provide additional morphological, functional, and hemodynamic parameters including right ventricular dilation, McConnell's sign, reduced tricuspid annular plane systolic excursion (TAPSE), interventricular septal flattening, abnormal right ventricular hemodynamics and in rare cases thrombi in the inferior vena cava, right atrium or ventricle en route to pulmonary arteries may also be visualized. This additional information is useful for selection of appropriate treatment modality. Thus, our objective is to provide a practical echocardiographic approach for risk stratification of patients with acute pulmonary embolism. PMID- 27510335 TI - Cancer control's new STaR. PMID- 27510334 TI - [Hepatic steatosis : Differential diagnostics and current aspects]. AB - The frequency of non-alcoholic fatty liver disease (NAFLD) has continously increased over the last few decades in parallel with the increasing prevalence of metabolic syndrome. With the increasing frequency of obesity and type 2 diabetes an increase in non-alcoholic steatohepatitis (NASH) is also to be expected. The NASH-associated liver cirrhosis and primary hepatocellular carcinoma (HCC) are indications for liver transplantation (LTX), which is gaining importance in Germany. In contrast, liver cirrhosis as a result of alcoholic steatohepatitis (ASH) is already the leading cause for LTX in Germany. A significant number of patients with ASH cirrhosis develop HCC. Less common causes of hepatic steatosis are secondary and include chemotherapy-associated steatohepatitis (CASH). In this article the causes, diagnostics and novel therapeutic approaches for the various forms of steatosis are discussed. PMID- 27510337 TI - Behavioural innovation is key to improving the health of one million Australians living with type 2 diabetes. PMID- 27510338 TI - The Paleo diet and diabetes. PMID- 27510339 TI - Obesity before pregnancy: new evidence and future strategies. PMID- 27510340 TI - Pitting and non-pitting oedema. PMID- 27510341 TI - Homage to my skull. PMID- 27510342 TI - The problem with modern endocrinology. PMID- 27510343 TI - Preventing all the complications of hyperglycaemia: not a straightforward task. PMID- 27510345 TI - Correction. PMID- 27510344 TI - Contemporary type 1 diabetes pregnancy outcomes: impact of obesity and glycaemic control. AB - OBJECTIVE: To compare contemporary pregnancy outcomes in women with and without type 1 diabetes, and to examine the effects of obesity and glycaemic control on these outcomes. DESIGN AND SETTING: Historical cohort study in a specialist diabetes and maternity network in Victoria. PARTICIPANTS: All singleton births (at least 20 weeks' gestation), 2010-2013, were analysed: 107 pregnancies to women with type 1 diabetes and 27 075 pregnancies to women without diabetes. Women with type 2 diabetes or gestational diabetes were excluded. METHODS: Data were extracted from the Birthing Outcomes System database; associations between type 1 diabetes and pregnancy outcomes were analysed by multivariable regression. MAIN OUTCOME MEASURES: Mode of birth; maternal and neonatal outcomes. RESULTS: The mean body mass index was higher for women with type 1 diabetes than for women without diabetes (mean, 27.3 kg/m(2) [SD, 5.0] v 25.7 kg/m(2) [SD, 5.9]; P = 0.01); the median gestation period for their babies was shorter (median, 37.3 weeks [IQR, 34.6-38.1] v 39.4 weeks [IQR, 38.4-40.4]; P < 0.001) and they were more likely to be large for gestational age (LGA) (adjusted odds ratio [aOR], 7.9; 95% CI, 5.3-11.8). Women with type 1 diabetes were more likely to have had labour induced (aOR, 3.0; 95% CI, 2.0-4.5), a caesarean delivery (aOR, 4.6; 95% CI, 3.1-7.0), or a pre-term birth (aOR, 6.7; 95% CI, 4.5-10.0); their babies were more likely to have shoulder dystocia (aOR, 8.2; 95% CI, 3.6-18.7), hypoglycaemia (aOR, 10.3; 95% CI, 6.8-15.6), jaundice (aOR, 5.1; 95% CI, 3.3-7.7), respiratory distress (aOR, 2.5; 95% CI, 1.4-4.4) or to suffer perinatal death (aOR, 4.3; 95% CI, 1.9-9.9). In women with type 1 diabetes, greater obesity was associated with increased odds for an LGA baby or congenital malformation, and increased HbA1c levels were associated with pre-term birth and perinatal death. CONCLUSION: Women with type 1 diabetes, even when managed in a specialist setting, still experience adverse obstetric and neonatal outcomes. Poor glycaemic control is not wholly responsible for adverse outcomes, reinforcing the importance of other risk factors, such as obesity and weight gain. PMID- 27510346 TI - Low HIV testing rates among people with a sexually transmissible infection diagnosis in remote Aboriginal communities. AB - OBJECTIVE: To determine the rates of HIV testing among people who had received positive test results for chlamydia, gonorrhoea and trichomoniasis, or who had been tested for syphilis. DESIGN, SETTING AND PARTICIPANTS: Pathology data for the period January 2010 - December 2014 from 65 remote Aboriginal communities participating in the STRIVE trial of sexually transmissible infection (STI) control were analysed. MAIN OUTCOME MEASURES: Rates of HIV testing within 30 and 90 days of an STI test (for chlamydia, gonorrhoea or trichomoniasis), the result of which was positive, and within 30 days of a test for syphilis; factors independently associated with concurrent HIV testing. RESULTS: 31.8% of 15 260 positive STI test results were linked with an HIV test within 30 days of the test (including 5.6% not on the same day), and 34.8% within 90 days; 44.1% were linked with syphilis testing within 30 days. 53.4% of all those tested for syphilis were also tested for HIV within 30 days. Multivariate analysis found that HIV testing was more likely for men, in geographical regions 3 and 4, in association with positive STI test results during 2012, 2013 or 2014 (v 2010), and in association with positive test results for gonorrhoea or chlamydia. Similar associations with these factors were found for syphilis testing. CONCLUSIONS: A significant challenge in Aboriginal health is avoiding an increase in the number of HIV infections. One critical intervention in this regard is timely and appropriate testing. Adhering to screening recommendations is clearly an aspect of the delivery of sexual health services to remote communities that can be improved in striving to achieve this aim. PMID- 27510347 TI - Evaluation of the performance and outcomes for the first year of a diabetes rapid access clinic. PMID- 27510348 TI - Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy. AB - INTRODUCTION: This article, Part 1 of the Endocrine Society of Australia's position statement on male hypogonadism, focuses on assessment of male hypogonadism, including the indications for testosterone therapy. (Part 2 will deal with treatment and therapeutic considerations.) MAIN RECOMMENDATIONS: Key points and recommendations are:Pathological hypogonadism arises due to diseases of the hypothalamus or pituitary gland (hypogonadotropic hypogonadism) or testes (hypergonadotropic hypogonadism). It is a clinical diagnosis with a pathological basis, confirmed by hormone assays.Hormonal assessment is based on measurement of circulating testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations. Measurement of sex hormone-binding globulin levels can be informative, but use of calculated free testosterone is not recommended for clinical decision making.Testosterone replacement therapy is warranted in men with pathological hypogonadism, regardless of age.Currently, there are limited data from high-quality randomised controlled trials with clinically meaningful outcomes to justify testosterone treatment in older men, usually with chronic disease, who have low circulating testosterone levels but without hypothalamic, pituitary or testicular disease.Obesity, metabolic syndrome and type 2 diabetes are associated with lowering of circulating testosterone level, but without elevation of LH and FSH levels. Whether these are non-specific consequences of non-reproductive disorders or a correctable deficiency state is unknown, but clear evidence for efficacy and safety of testosterone therapy in this setting is lacking.Glucocorticoid and opioid use is associated with possibly reversible reductions in circulating testosterone level, without elevation of LH and FSH levels. Where continuation of glucocorticoid or opioid therapy is necessary, review by an endocrinologist may be warranted.Changes in management as result of the position statement: Men with pathological hypogonadism should be identified and considered for testosterone therapy, while further research is needed to clarify whether there is a role for testosterone in these other settings. PMID- 27510349 TI - Managing thyroid disease in general practice. AB - Serum thyroid-stimulating hormone (TSH) testing is the best screening tool for thyroid dysfunction. When TSH levels are in the reference range, additional tests such as free thyroxine, free triiodothyronine or thyroid antibodies rarely add value, except in patients with pituitary disease, when TSH is unreliable. Overt hypothyroidism and subclinical hypothyroidism with TSH levels > 10 mU/L can be treated without further investigation. The health impact of subclinical hypothyroidism with mildly elevated levels of TSH (4-10 mU/L) remains uncertain, particularly in older people; treatment or observation are reasonable options. Thyroxine remains standard treatment for hypothyroidism, with optimal dosage determined by clinical response and serum TSH. Hyperthyroidism is commonly caused by Graves' disease, thyroiditis or toxic nodular goitre. The cause should be established before offering treatment. Radionuclide scanning is the imaging modality of choice. Positive TSH-receptor antibodies indicate Graves' disease. Thyroid ultrasound is indicated for assessment of palpable goitre and thyroid nodules. It is not part of routine assessment of hyperthyroidism or hypothyroidism. Overzealous use of ultrasound identifies clinically unimportant thyroid nodules and can lead to overdiagnosis of thyroid cancer. For thyroid nodules, the key investigation is ultrasound-guided fine needle aspiration biopsy, depending on size and sonographic appearance. Biopsy should not be performed routinely on small nodules < 1 cm. It remains controversial whether pregnant women should be screened for thyroid disease. Reference intervals for thyroid function tests during pregnancy are not well established, and it is uncertain whether thyroxine treatment for pregnant women with serum TSH levels between 2.5 and 4.0 mU/L is beneficial. Iodine supplementation is recommended during pregnancy. PMID- 27510350 TI - Osteoporosis treatment: a missed opportunity. AB - Osteoporosis affects 1.2 million Australians and, in 2012, fractures due to osteoporosis and osteopenia in Australians aged over 50 years cost $2.75 billion. Even minor minimal trauma fractures are associated with increased morbidity and mortality. Despite increasing therapeutic options for managing osteoporosis, fewer than 20% of patients with a minimal trauma fracture are treated or investigated for osteoporosis, so under-treatment is extremely common. Fracture risk assessment is important for selecting patients who require specific anti osteoporosis therapy. Post-menopausal osteoporosis is frequently due to an imbalance in bone remodelling, with bone resorption exceeding bone formation. Antiresorptive drugs reduce the number, activity and lifespan of osteoclasts, and include bisphosphonates, oestrogen, selective oestrogen receptor-modulating drugs, strontium ranelate, and the human monoclonal antibody denosumab. Teriparatide is the only anabolic agent currently available that stimulates osteoblast recruitment and activity; its antifracture efficacy for non-vertebral fractures increases with the duration of therapy for up to 2 years when it is associated with persisting increases in bone formation rate at the tissue level. Newer anabolic agents are imminent and include an analogue of parathyroid hormone related protein, abaloparatide, and a humanised monoclonal antibody to an inhibitor of bone formation, romosozumab. Selection of anti-osteoporosis therapy should be individualised to patients, and the duration of bisphosphonate therapy has been covered in recent guidelines. The benefits of treatment far outweigh any risks associated with long term treatment. General practitioners need to take up the challenge imposed by osteoporosis and become champions of change to close the evidence-treatment gap. PMID- 27510351 TI - The Burns Registry of Australia and New Zealand: progressing the evidence base for burn care. PMID- 27510352 TI - The Burns Registry of Australia and New Zealand: progressing the evidence base for burn care. PMID- 27510353 TI - Lessons from the bedside: ketoacidosis and SGLT2 inhibitors. PMID- 27510354 TI - A caution regarding high-dose biotin therapy: misdiagnosis of hyperthyroidism in euthyroid patients. PMID- 27510355 TI - Standard redox potentials, pKas, and hydricities of inorganic complexes under electrochemical conditions and implications for CO2 reduction. AB - We use computational chemistry to systematically study the thermodynamic stabilities of protonated and reduced intermediate states for Ru(2,2' bipyridine)3, Ru(1,10-phenanthroline)3, and Ru(phen)2(pyrido[3',4':5,6] pyrazino[2,3-f][1,10]phenanthroline) in aqueous solutions. Following our previous studies of aromatic N-heterocycle molecules, we report pKas, standard redox potentials, and hydricities as well as computationally derived Pourbaix diagrams that show which states would be thermodynamically stable at different conditions of pH and applied potential. Locations of added electrons within ligands and complexes after reductions are also shown with electron density difference plots. As with other aromatic N-heterocycle molecules implicated in CO2 reduction, we find that several of the boundary lines from the Pourbaix diagrams are in close proximity to the thermodynamic redox potentials for CO2 electroreductions, making them thermodynamically appropriate for energetically efficient hydrogen shuttling. PMID- 27510356 TI - Quantitative structure-property relationships of retention indices of some sulfur organic compounds using random forest technique as a variable selection and modeling method. AB - In this work, a noble quantitative structure-property relationship technique is proposed on the basis of the random forest for prediction of the retention indices of some sulfur organic compounds. In order to calculate the retention indices of these compounds, the theoretical descriptors produced using their molecular structures are employed. The influence of the significant parameters affecting the capability of the developed random forest prediction power such as the number of randomly selected variables applied to split each node (m) and the number of trees (nt ) is studied to obtain the best model. After optimizing the nt and m parameters, the random forest model conducted for m = 70 and nt = 460 was found to yield the best results. The artificial neural network and multiple linear regression modeling techniques are also used to predict the retention index values for these compounds for comparison with the results of random forest model. The descriptors selected by the stepwise regression and random forest model are used to build the artificial neural network models. The results achieved showed the superiority of the random forest model over the other models for prediction of the retention indices of the studied compounds. PMID- 27510357 TI - Octahedral Tin Dioxide Nanocrystals Anchored on Vertically Aligned Carbon Aerogels as High Capacity Anode Materials for Lithium-Ion Batteries. AB - A novel binder-free graphene - carbon nanotubes - SnO2 (GCNT-SnO2) aerogel with vertically aligned pores was prepared via a simple and efficient directional freezing method. SnO2 octahedrons exposed of {221} high energy facets were uniformly distributed and tightly anchored on multidimensional graphene/carbon nanotube (GCNT) composites. Vertically aligned pores can effectively prevent the emersion of "closed" pores which cannot load the active SnO2 nanoparticles, further ensure quick immersion of electrolyte throughout the aerogel, and can largely shorten the transport distance between lithium ions and active sites of SnO2. Especially, excellent electrical conductivity of GCNT-SnO2 aerogel was achieved as a result of good interconnected networks of graphene and CNTs. Furthermore, meso- and macroporous structures with large surface area created by the vertically aligned pores can provide great benefit to the favorable transport kinetics for both lithium ion and electrons and afford sufficient space for volume expansion of SnO2. Due to the well-designed architecture of GCNT-SnO2 aerogel, a high specific capacity of 1190 mAh/g with good long-term cycling stability up to 1000 times was achieved. This work provides a promising strategy for preparing free-standing and binder-free active electrode materials with high performance for lithium ion batteries and other energy storage devices. PMID- 27510358 TI - Delays in diagnosis and treatment of childhood cancer in Indonesia. AB - BACKGROUND: Emphasizing timely diagnosis and treatment of cancer are important themes in pediatric cancer management, as delays adversely impact survival. This study explores various delay types among children with cancer and determines factors that influence delays. METHODS: This cross-sectional study was conducted at an Indonesian academic hospital. Parents of newly diagnosed patients were interviewed between October 2013 and September 2014 using semistructured questionnaires. Patient, physician, diagnosis, treatment, healthcare system (HCS), and total delay were analyzed. RESULTS: Parents of 145 children (response rate 89%) with cancer were interviewed. Median total delay was 70 days (range 5 4,055). Patient delay (median 5 days, range 0-189) was significantly shorter than HCS delay (median 49 days, range 4-4,025, P < 0.001). Diagnosis delay (median 58 days, range 3-4,015) was significantly longer than treatment delay (median 3 days, range 1-89, P < 0.001). Older age at diagnosis significantly lengthened patient delay (P = 0.044). Using alternative treatment was associated with significantly longer patient and total delay (P = 0.025, 0.024, respectively). Cancer type significantly influenced physician, diagnosis, treatment, HCS, and total delay (P = 0.001, P = 0.004, P < 0.001, P < 0.001, P < 0.001, respectively). Neurological tumors had the longest delays, whereas hematological tumors had the shortest. Sex, parents' education or income level, disease stage at diagnosis, health insurance status, distance from hospital, and first attended health-facility type did not significantly impact the length of any delay type. CONCLUSIONS: Healthcare providers need training to improve recognition of cancer symptoms and speed up subsequent diagnostic processes. Using alternative treatment increased patient and total delays. Community campaigns to encourage families to seek conventional cancer treatments are recommended. PMID- 27510359 TI - Chiral supramolecular polymers consisting of planar-chiral pillar[5]arene enantiomers. AB - Supramolecular polymers with diverse chiralities were constructed by supramolecular polymerization of planar-chiral host-guest conjugates in pS and pR forms. Hetero-chiral supramolecular polymerization using a racemic mixture of host-guest conjugates with pS and pR forms afforded a supramolecular polymer with a larger hydrodynamic radius than that obtained through homo-chiral supramolecular polymerization of host-guest conjugates with either pS or pR forms alone. PMID- 27510360 TI - Seeking for the links between biochemical markers of remodeling and structural changes in chronic obstructive pulmonary disease: where are we? PMID- 27510361 TI - Dynamic CT myocardial perfusion imaging. AB - Non-invasive cardiac imaging has rapidly evolved during the last decade due to advancements in CT based technologies. Coronary CT angiography has been shown to reliably assess coronary anatomy and detect high risk coronary artery disease. However, this technique is limited to anatomical assessment, thus non-invasive techniques for functional assessment of the heart are necessary. CT myocardial perfusion is a new CT based technique that provides functional assessment of the myocardium and allows for a comprehensive assessment of coronary artery disease with a single modality when combined with CTA. This review aims to discuss dynamic CT myocardial perfusion as a new technique in the assessment of CAD. PMID- 27510362 TI - An Agrobacterium-delivered CRISPR/Cas9 system for high-frequency targeted mutagenesis in maize. AB - CRISPR/Cas9 is a powerful genome editing tool in many organisms, including a number of monocots and dicots. Although the design and application of CRISPR/Cas9 is simpler compared to other nuclease-based genome editing tools, optimization requires the consideration of the DNA delivery and tissue regeneration methods for a particular species to achieve accuracy and efficiency. Here, we describe a public sector system, ISU Maize CRISPR, utilizing Agrobacterium-delivered CRISPR/Cas9 for high-frequency targeted mutagenesis in maize. This system consists of an Escherichia coli cloning vector and an Agrobacterium binary vector. It can be used to clone up to four guide RNAs for single or multiplex gene targeting. We evaluated this system for its mutagenesis frequency and heritability using four maize genes in two duplicated pairs: Argonaute 18 (ZmAgo18a and ZmAgo18b) and dihydroflavonol 4-reductase or anthocyaninless genes (a1 and a4). T0 transgenic events carrying mono- or diallelic mutations of one locus and various combinations of allelic mutations of two loci occurred at rates over 70% mutants per transgenic events in both Hi-II and B104 genotypes. Through genetic segregation, null segregants carrying only the desired mutant alleles without the CRISPR transgene could be generated in T1 progeny. Inheritance of an active CRISPR/Cas9 transgene leads to additional target-specific mutations in subsequent generations. Duplex infection of immature embryos by mixing two individual Agrobacterium strains harbouring different Cas9/gRNA modules can be performed for improved cost efficiency. Together, the findings demonstrate that the ISU Maize CRISPR platform is an effective and robust tool to targeted mutagenesis in maize. PMID- 27510367 TI - Allometric Scaling of Clearance in Paediatric Patients: When Does the Magic of 0.75 Fade? AB - Allometric scaling on the basis of bodyweight raised to the power of 0.75 (AS0.75) is frequently used to scale size-related changes in plasma clearance (CLp) from adults to children. A systematic assessment of its applicability is undertaken for scenarios considering size-related changes with and without maturation processes. A physiologically-based pharmacokinetic (PBPK) simulation workflow was developed in R for 12,620 hypothetical drugs. In scenario one, only size-related changes in liver weight, hepatic blood flow, and glomerular filtration were included in simulations of 'true' paediatric CLp. In a second scenario, maturation in unbound microsomal intrinsic clearance (CLint,mic), plasma protein concentration, and haematocrit were also included in these simulated 'true' paediatric CLp values. For both scenarios, the prediction error (PE) of AS0.75-based paediatric CLp predictions was assessed, while, for the first scenario, an allometric exponent was also estimated based on 'true' CLp. In the first scenario, the PE of AS0.75-based paediatric CLp predictions reached up to 278 % in neonates, and the allometric exponent was estimated to range from 0.50 to 1.20 depending on age and drug properties. In the second scenario, the PE sensitivity to drug properties and maturation was higher in the youngest children, with AS0.75 resulting in accurate CLp predictions above 5 years of age. Using PBPK principles, there is no evidence for one unique allometric exponent in paediatric patients, even in scenarios that only consider size-related changes. As PE is most sensitive to the allometric exponent, drug properties and maturation in younger children, AS0.75 leads to increasingly worse predictions with decreasing age. PMID- 27510368 TI - Overexpression of long non-coding RNA NR_036575.1 contributes to the proliferation and migration of papillary thyroid cancer. AB - Current evidence suggests that the human genome produces a large number of non coding RNAs, including microRNAs and long non-coding RNAs (lncRNAs). Generally, lncRNAs are defined as RNA transcripts longer than 200 nucleotides that are not transcribed into proteins. In recent years, lncRNAs have been reported to play oncogenic roles in tumourigenesis. However, minimal research has been performed on the expression and clinicopathological significance of lncRNAs in papillary thyroid cancer (PTC). In the present study, we investigated not only the expression and clinicopathological significance of a novel lncRNA, NR_036575.1, in PTC tissues and adjacent non-cancerous tissues but also its potential function in TPC1 cells. The expression levels of the lncRNA NR_036575.1 in 83 pairs of PTC tissues and adjacent non-cancerous tissues were detected via quantitative real time polymerase chain reaction. The relationships between the expression levels and clinicopathological characteristics of the lncRNA NR_036575.1 were analysed. In addition, we established two receiver operating characteristic (ROC) curves to assess the diagnostic value of NR_036575.1 expression. Cell Counting Kit-8 and transwell assays were used to assess cell proliferation and migration, respectively. The expression levels of the lncRNA NR_036575.1 were significantly higher in PTC tissues than in adjacent non-cancerous tissues. High NR_036575.1 expression was associated with extrathyroidal extension (ETE) (P = 0.011) and tumour size (P = 0.006). The ROC curves indicated that NR_036575.1 could potentially serve as a biomarker for identifying PTC and related, non-cancerous diseases (sensitivity, 80.7 %; specificity, 88 %), as well as for differentiating between PTC with or without ETE (sensitivity, 57.8 %; specificity, 86.7 %). NR_036575.1 knock-down significantly inhibited the proliferation and migration of TPC1 cells. Our findings are the first to describe lncRNA NR_036575.1 overexpression in PTC. NR_036575.1 expression was associated with both ETE and tumour size. In addition, NR_036575.1 modulation could regulate TPC1 cell proliferation and migration. The results of our study suggest that NR_036575.1 could be applied as a potential biomarker and a novel therapeutic target for PTC patients. PMID- 27510369 TI - Quantum measurement-induced antiferromagnetic order and density modulations in ultracold Fermi gases in optical lattices. AB - Ultracold atomic systems offer a unique tool for understanding behavior of matter in the quantum degenerate regime, promising studies of a vast range of phenomena covering many disciplines from condensed matter to quantum information and particle physics. Coupling these systems to quantized light fields opens further possibilities of observing delicate effects typical of quantum optics in the context of strongly correlated systems. Measurement backaction is one of the most funda- mental manifestations of quantum mechanics and it is at the core of many famous quantum optics experiments. Here we show that quantum backaction of weak measurement can be used for tailoring long-range correlations of ultracold fermions, realizing quantum states with spatial modulations of the density and magnetization, thus overcoming usual requirement for a strong interatomic interactions. We propose detection schemes for implementing antiferromagnetic states and density waves. We demonstrate that such long-range correlations cannot be realized with local addressing, and they are a consequence of the competition between global but spatially structured backaction of weak quantum measurement and unitary dynamics of fermions. PMID- 27510370 TI - Inferential tools in penalized logistic regression for small and sparse data: A comparative study. AB - This paper focuses on inferential tools in the logistic regression model fitted by the Firth penalized likelihood. In this context, the Likelihood Ratio statistic is often reported to be the preferred choice as compared to the 'traditional' Wald statistic. In this work, we consider and discuss a wider range of test statistics, including the robust Wald, the Score, and the recently proposed Gradient statistic. We compare all these asymptotically equivalent statistics in terms of interval estimation and hypothesis testing via simulation experiments and analyses of two real datasets. We find out that the Likelihood Ratio statistic does not appear the best inferential device in the Firth penalized logistic regression. PMID- 27510372 TI - Parsimonious mixtures of multivariate contaminated normal distributions. AB - A mixture of multivariate contaminated normal distributions is developed for model-based clustering. In addition to the parameters of the classical normal mixture, our contaminated mixture has, for each cluster, a parameter controlling the proportion of mild outliers and one specifying the degree of contamination. Crucially, these parameters do not have to be specified a priori, adding a flexibility to our approach. Parsimony is introduced via eigen-decomposition of the component covariance matrices, and sufficient conditions for the identifiability of all the members of the resulting family are provided. An expectation-conditional maximization algorithm is outlined for parameter estimation and various implementation issues are discussed. Using a large-scale simulation study, the behavior of the proposed approach is investigated and comparison with well-established finite mixtures is provided. The performance of this novel family of models is also illustrated on artificial and real data. PMID- 27510371 TI - Mms21 SUMO Ligase Activity Promotes Nucleolar Function in Saccharomyces cerevisiae. AB - The budding yeast E3 SUMO ligase Mms21, also known as Nse2, is a component of the Smc5/6 complex, which regulates sister chromatid cohesion, DNA replication, and repair. Our study shows that the mms21RINGDelta mutant exhibits (1) reduced ribosomal RNA production; (2) nuclear accumulation of ribosomal proteins; (3) elevated Gcn4 translation, indicating translational stress; and (4) upregulation of Gcn4 targets. Genes involved in ribosome biogenesis and translation are downregulated in the mms21RINGDelta mutant. We identified RPL19A as a novel genetic suppressor of the mms21RINGDelta mutant. Deletion of RPL19A partially suppresses growth defects in both smc5-6 and mms21RINGDelta mutants as well as nuclear accumulation of ribosome subunits in the mms21RINGDelta mutant. Deletion of a previously identified strong suppressor, MPH1, rescues both the accumulation of ribosome subunits and translational stress. This study suggests that the Smc5/6 complex supports nucleolar function. PMID- 27510373 TI - Accuracy of teledentistry examinations at predicting actual treatment modality in a pediatric dentistry clinic. AB - Objectives The purpose of this study was to assess the accuracy of predicting dental treatment modalities for children seen initially by means of a live-video teledentistry consultation. Methods A retrospective dental record review was completed of 251 rural pediatric patients from the Finger Lakes region of New York State who had an initial teledentistry appointment with a board-certified pediatric dentist located remotely at the Eastman Institute for Oral Health in Rochester, NY. Proportions of children who were referred for specific treatment modalities and who completed treatment and proportions of children for whom the treatment recommendation was changed were calculated. Fisher's exact test was used to assess statistical significance. Results The initial treatment modality was not changed for 221/251 (88%) children initially seen for a teledentistry consultation. Thirty (12%) children had the initial treatment modality changed, most frequently children who were initially suggested treatment with nitrous oxide. Based on the initial treatment modality, changes to a different treatment modality were statistically significant (Fisher's exact test, p < 0.0001). Conclusions Our data suggest that the use of a live-video teledentistry consultation can be an effective way of predicting the best treatment modality for rural children with significant dental disease. A live-video teledentistry consultation can be an effective intervention to facilitate completion of complex treatment plans for children from a rural area that have extensive dental needs. PMID- 27510374 TI - Margaret McCartney: Game on for Pokemon Go. PMID- 27510375 TI - A Case of Spontaneous Isolated Dissection of Left Gastric Artery. PMID- 27510376 TI - Statement on Publication Ethics for Editors and Publishers. AB - The digitization and related developments in journal editing and publishing necessitate increasing the awareness of all stakeholders of science communication in the emerging global problems and possible solutions. Journal editors and publishers are frequently encountered with the fast-growing problems of authorship, conflicts of interest, peer review, research misconduct, unethical citations, and inappropriate journal impact metrics. While the number of erroneous and unethical research papers and wasteful, or 'predatory', journals is increasing exponentially, responsible editors are urged to 'clean' the literature by correcting or retracting related articles. Indexers are advised to implement measures for accepting truly influential and ethical journals and delisting sources with predatory publishing practices. Updating knowledge and skills of authors, editors and publishers, developing and endorsing recommendations of global editorial associations, and (re)drafting journal instructions can be viewed as potential tools for improving ethics of academic journals. The aim of this Statement is to increase awareness of all stakeholders of science communication of the emerging ethical issues in journal editing and publishing and initiate a campaign of upgrading and enforcing related journal instructions. PMID- 27510378 TI - Affecting Factors of Secondhand Smoke Exposure in Korea: Focused on Different Exposure Locations. AB - Exposure to secondhand smoke (SHS) not only can cause serious illness, but is also an economic and social burden. Contextual and individual factors of non smoker exposure to SHS depend on location. However, studies focusing on this subject are lacking. In this study, we described and compared the factors related to SHS exposure according to location in Korea. Regarding individual factors related to SHS exposure, a common individual variable model and location-specific variable model was used to evaluate SHS exposure at home/work/public locations based on sex. In common individual variables, such as age, and smoking status showed different relationships with SHS exposure in different locations. Among home-related variables, housing type and family with a single father and unmarried children showed the strongest positive relationships with SHS exposure in both males and females. In the workplace, service and sales workers, blue collar workers, and manual laborers showed the strongest positive association with SHS exposure in males and females. For multilevel analysis in public places, only SHS exposure in females was positively related with cancer screening rate. Exposure to SHS in public places showed a positive relationship with drinking rate and single-parent family in males and females. The problem of SHS embodies social policies and interactions between individuals and social contextual factors. Policy makers should consider the contextual factors of specific locations and regional and individual context, along with differences between males and females, to develop effective strategies for reducing SHS exposure. PMID- 27510377 TI - Signal Detection of Adverse Drug Reaction of Amoxicillin Using the Korea Adverse Event Reporting System Database. AB - We conducted pharmacovigilance data mining for a beta-lactam antibiotics, amoxicillin, and compare the adverse events (AEs) with the drug labels of 9 countries including Korea, USA, UK, Japan, Germany, Swiss, Italy, France, and Laos. We used the Korea Adverse Event Reporting System (KAERS) database, a nationwide database of AE reports, between December 1988 and June 2014. Frequentist and Bayesian methods were used to calculate disproportionality distribution of drug-AE pairs. The AE which was detected by all the three indices of proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC) was defined as a signal. The KAERS database contained a total of 807,582 AE reports, among which 1,722 reports were attributed to amoxicillin. Among the 192,510 antibiotics-AE pairs, the number of amoxicillin-AE pairs was 2,913. Among 241 AEs, 52 adverse events were detected as amoxicillin signals. Comparing the drug labels of 9 countries, 12 adverse events including ineffective medicine, bronchitis, rhinitis, sinusitis, dry mouth, gastroesophageal reflux, hypercholesterolemia, gastric carcinoma, abnormal crying, induration, pulmonary carcinoma, and influenza-like symptoms were not listed on any of the labels of nine countries. In conclusion, we detected 12 new signals of amoxicillin which were not listed on the labels of 9 countries. Therefore, it should be followed by signal evaluation including causal association, clinical significance, and preventability. PMID- 27510379 TI - Transplantation of Mesenchymal Stem Cells for Acute Spinal Cord Injury in Rats: Comparative Study between Intralesional Injection and Scaffold Based Transplantation. AB - Experimental stem cell therapy for spinal cord injury (SCI) has been extensively investigated. The selection of effective cell transplantation route is also an important issue. Although various types of scaffold have been widely tried as a carrier of stem cells to the injured spinal cord, there was little comparative study to investigate the efficacy of transplantation comparing with conventional transplantation route. A total of 48 Sprague-Dawley rats were subjected to standardized SCI, followed by transplantation of allogeneic mesenchymal stem cells (MSCs), either via intralesional injection (IL group), or via the poly (lactic-co-glycolic acid) (PLGA) scaffold (IP group) or chitosan scaffold (IC group). Engraftment and differentiation of the transplanted cells, expression of neurotrophic factors in the injured spinal cord, and functional recovery were compared with those of the control group. The mean numbers of engrafted MSCs in the IL, IP, and IC groups were 20.6 +/- 0.7, 25.6 +/- 1.7 and 26.7 +/- 1.8 cells/high power filed (HPF), respectively. Results showed higher success rate of MSCs engraftment in the scaffold groups compared to the IL group. Expression of neuroprotective growth factors in the SCI lesions showed no significant differences between the IL, IP, and IC groups. The mean Basso, Beattie and Bresnahan locomotor scales at 6 weeks post-transplantation in the IL, IP, IC, and control groups were 7.9 +/- 1.1, 7.9 +/- 2.1, 8.7 +/- 2.1, and 2.9 +/- 1.0, respectively. The functional improvement was most excellent in the IC group. The scaffold based MSC transplantation for acute SCI presented the better cell engraftment and neuroprotective effect compared to the intralesional injection transplantation. PMID- 27510381 TI - Detection of MYCN Amplification in Serum DNA Using Conventional Polymerase Chain Reaction. AB - Neuroblastoma (NB) is the most common extra-cranial solid tumor of childhood and is characterized by a wide range of clinical behaviors. Amplification of MYCN is a well-known poor prognostic factor in NB patients. As the MYCN amplification status is usually tested using tumor specimens, lengthy and invasive procedures are unavoidable. To evaluate the possibility of detecting MYCN amplification without invasive procedure, we performed conventional polymerase chain reaction (PCR) analysis to identify MYCN amplification using the preserved serum DNA. PCR of serum DNA was done in 105 NB patients whose MYCN status had been confirmed by fluorescence in situ hybridization. MYCN amplification was evaluated as the ratio of signal intensities between MYCN and NAGK (M/N ratio). When regarding the tissue FISH results as a reference, 10 patients had MYCN-amplified (MNA) NB, and 95 had non-MNA NB. The M/N ratio of the MNA group (median 2.56, range 1.01-3.58) was significantly higher than that of the non-MNA group (median 0.97, range 0.67 5.18) (P < 0.001). In the receiver operating characteristic curve analysis, the area under the curve was 0.957 (95% confidence interval 0.898-1.000; P < 0.001), and it showed 90.9% sensitivity and 97.9% specificity with the selected cut-off value set as 1.6. The detection of MYCN amplification using conventional PCR analysis of serum samples seems to be a simple and promising method to evaluate the MYCN status of NB patients. Further study with a larger set of patients is needed to confirm the accuracy of this result. PMID- 27510382 TI - Complications of Cardiac Perforation and Lead Dislodgement with an MRI Conditional Pacing Lead: a Korean Multi-Center Experience. AB - Medtronic CapSureFix MRI 5086 pacing lead (5086; Medtronic, Inc., Minneapolis, MN, USA) has been reported to be associated with increased cardiac perforation and lead dislodgement. This study aimed to compare the incidence of cardiac perforation and lead dislodgement within 30 days after pacemaker implantation between 5086 MRI lead and previous Medtronic CapSureFix Novus 5076 non-MRI pacing lead. This was a nationwide, multicenter retrospective study in which we compared the incidence of adverse events between 277 patients implanted with 5086 lead and 205 patients implanted with 5076 lead between March 2009 and September 2014. Cardiac perforation within 30 days of pacemaker implantation occurred in 4 patients (1.4%) with the 5086 lead and in no patient with the 5076 lead (P = 0.084). Lead dislodgement occurred in 8 patients (2.9%) with the 5086 lead and in 5 patients (2.4%) with the 5076 lead (P = 0.764). On multivariate logistic regression analysis, age was significantly associated with cardiac perforation. Congestive heart failure and implantation of right atrial (RA) lead at RA free wall or septum were significant factors for the incidence of lead dislodgement and lead revision. The incidence of cardiac perforation and lead dislodgement were not statistically different between the patients with 5086 lead and the patients with 5076 lead. However, careful attention for cardiac perforation may be needed when using the 5086 MRI lead, especially in elderly patients. PMID- 27510380 TI - The Immunogenicity and Safety of a Combined DTaP-IPV//Hib Vaccine Compared with Individual DTaP-IPV and Hib (PRP~T) Vaccines: a Randomized Clinical Trial in South Korean Infants. AB - Recommended infant vaccination in Korea includes DTaP-IPV and Hib vaccines administered as separate injections. In this randomized, open, controlled study we assessed the non-inferiority of immunogenicity of DTaP-IPV//Hib pentavalent combination vaccine (PentaximTM) compared with licensed DTaP-IPV and Hib (PRP~T) vaccines. We enrolled 418 healthy Korean infants to receive either separate DTaP IPV and Hib vaccines (n = 206) or the pentavalent DTaP-IPV//Hib (n = 208) vaccine at 2, 4, 6 months of age. Antibodies to all components were measured before the first vaccination and one month after the third, and safety was assessed after each vaccination including recording of reactions by parents. We confirmed the non-inferiority of DTaP-IPV//Hib compared with DTaP-IPV and Hib vaccines; 100% of both groups achieved seroprotection against D, T, IPV and PRP~T, and 97.5%-99.0% demonstrated seroresponses to pertussis antigens. Antibody levels were similar in both groups, except for those to the Hib component, PRP~T. In separate and combined groups geometric mean concentrations of anti-PRP~T antibodies were 23.9 and 11.0 MUg/mL, respectively, but 98.3% and 97.4% had titers >= 1 MUg/mL, indicative of long-term protection. All vaccines were well tolerated, with no vaccine-related serious adverse event. Both groups had similar safety profiles, but the combined vaccine group had fewer injection site reactions. The immunological non-inferiority and similar safety profile of DTaP-IPV//Hib vaccine to separate DTaP-IPV and Hib vaccines, with the advantage of fewer injections and injection site reactions, supports the licensure and incorporation of DTaP IPV//Hib into the Korean national vaccination schedule (Clinical trial registry, NCT01214889). PMID- 27510384 TI - Association between Growth Differentiation Factor 15 (GDF15) and Cardiovascular Risk in Patients with Newly Diagnosed Type 2 Diabetes Mellitus. AB - We investigated an association between serum Growth Differentiation Factor 15 (GDF15) level and cardiovascular risk in patients with newly diagnosed type 2 diabetes mellitus (T2D). A total of 107 participants were screened for T2D and divided into a T2D group and a control group (without diabetes). We used the Framingham risk score (FRS) and the New Pooled Cohort Equation score to estimate the 10-year risk of atherosclerotic cardiovascular disease. Serum GDF15 levels were measured using an enzyme-linked immunosorbent assay. Correlation analyses were performed to evaluate the associations between GDF15 level and cardiovascular risk scores. The mean serum GDF15 level was elevated in the T2D group compared to the control group (P < 0.001). A positive correlation was evident between serum GDF15 level and age (r = 0.418, P = 0.001), the FRS (r = 0.457, P < 0.001), and the Pooled Cohort Equation score (r = 0.539, P < 0.001). After adjusting for age, LDL-C level, and body mass index (BMI), the serum GDF15 level was positively correlated with the FRS and the New Pooled Cohort Equation score. The serum GDF15 level is independently associated with cardiovascular risk scores of newly diagnosed T2D patients. This suggests that the level of GDF15 may be a useful predictive biomarker of cardiovascular risk in newly diagnosed T2D patients. PMID- 27510383 TI - Renoprotective Effects of a Highly Selective A3 Adenosine Receptor Antagonist in a Mouse Model of Adriamycin-induced Nephropathy. AB - The concentration of adenosine in the normal kidney increases markedly during renal hypoxia, ischemia, and inflammation. A recent study reported that an A3 adenosine receptor (A3AR) antagonist attenuated the progression of renal fibrosis. The adriamycin (ADX)-induced nephropathy model induces podocyte injury, which results in severe proteinuria and progressive glomerulosclerosis. In this study, we investigated the preventive effect of a highly selective A3AR antagonist (LJ1888) in ADX-induced nephropathy. Three groups of six-week-old Balb/c mice were treated with ADX (11 mg/kg) for four weeks and LJ1888 (10 mg/kg) for two weeks as following: 1) control; 2) ADX; and 3) ADX + LJ1888. ADX treatment decreased body weight without a change in water and food intake, but this was ameliorated by LJ1888 treatment. Interestingly, LJ1888 lowered plasma creatinine level, proteinuria, and albuminuria, which had increased during ADX treatment. Furthermore, LJ1888 inhibited urinary nephrin excretion as a podocyte injury marker, and urine 8-isoprostane and kidney lipid peroxide concentration, which are markers of oxidative stress, increased after injection of ADX. ADX also induced the activation of proinflammatory and profibrotic molecules such as TGF beta1, MCP-1, PAI-1, type IV collagen, NF-kappaB, NOX4, TLR4, TNFalpha, IL-1beta, and IFN-gamma, but they were remarkably suppressed after LJ1888 treatment. In conclusion, our results suggest that LJ1888 has a renoprotective effect in ADX induced nephropathy, which might be associated with podocyte injury through oxidative stress. Therefore, LJ1888, a selective A3AR antagonist, could be considered as a potential therapeutic agent in renal glomerular diseases which include podocyte injury and proteinuria. PMID- 27510385 TI - Metformin Reduces Bleomycin-induced Pulmonary Fibrosis in Mice. AB - Metformin has anti-inflammatory and anti-fibrotic effects. We investigated whether metformin has an inhibitory effect on bleomycin (BLM)-induced pulmonary fibrosis in a murine model. A total of 62 mice were divided into 5 groups: control, metformin (100 mg/kg), BLM, and BLM with metformin (50 mg/kg or 100 mg/kg). Metformin was administered to the mice orally once a day from day 1. We sacrificed half of the mice on day 10 and collected the bronchoalveolar lavage fluid (BALF) from their left lungs. The remaining mice were sacrificed and analyzed on day 21. The right lungs were harvested for histological analyses. The messenger RNA (mRNA) levels of epithelial-mesenchymal transition markers were determined via analysis of the harvested lungs on day 21. The mice treated with BLM and metformin (50 mg/kg or 100 mg/kg) showed significantly lower levels of inflammatory cells in the BALF compared with the BLM-only mice on days 10 and 21. The histological examination revealed that the metformin treatment led to a greater reduction in inflammation than the treatment with BLM alone. The mRNA levels of collagen, collagen-1, procollagen, fibronectin, and transforming growth factor-beta in the metformin-treated mice were lower than those in the BLM-only mice on day 21, although statistical significance was observed only in the case of procollagen due to the small number of live mice in the BLM-only group. Additionally, treatment with metformin reduced fibrosis to a greater extent than treatment with BLM alone. Metformin suppresses the inflammatory and fibrotic processes of BLM-induced pulmonary fibrosis in a murine model. PMID- 27510386 TI - Risk Factors of Advanced Adenoma in Small and Diminutive Colorectal Polyp. AB - The aims of this study were to review the clinicopathological characteristics of diminutive (<= 5 mm) and small polyps (> 5 mm but < 10 mm) and to evaluate the risk factors of advanced adenoma for polyps of diameter < 10 mm in the colon. The medical records of 4,711 patients who underwent first colonoscopy at outpatient clinics or health promotion center were reviewed retrospectively. We analyzed the presence and risk factors of advanced adenoma, which was defined as a villous or tubulovillous polyp, high-grade dysplasia or intramucosal carcinoma histologically. Total 5,058 polyps were detected in the 4,711 patients, and 93.0% (4,704/5,058) polyps were < 10 mm in size. Among them, advanced adenoma was noted in 0.6% (28/4,704) with a villous component in 19, high-grade dysplasia in 3, and adenocarcinoma in 6. Advanced and non-advanced adenomas differed significantly in age group, gender, and polyp size. Multivariate analysis showed that an advanced age (> 65 years), a male gender, and a polyp size of > 5 mm were risk factors of advanced adenoma. The incidence of advanced adenoma in polyps of < 10 mm was 0.6%. Polyp size, male gender, and age of > 65 years are independent risk factors of advanced adenoma. PMID- 27510387 TI - Clinical Utility of a New Automated Hepatitis C Virus Core Antigen Assay for Prediction of Treatment Response in Patients with Chronic Hepatitis C. AB - Hepatitis C virus core antigen (HCV Ag) is a recently developed marker of hepatitis C virus (HCV) infection. We investigated the clinical utility of the new HCV Ag assay for prediction of treatment response in HCV infection. We analyzed serum from 92 patients with HCV infection who had been treated with pegylated interferon and ribavirin. HCV Ag levels were determined at baseline in all enrolled patients and at week 4 in 15 patients. Baseline HCV Ag levels showed good correlations with HCV RNA (r = 0.79, P < 0.001). Mean HCV Ag levels at baseline were significantly lower in patients with a sustained virologic response (SVR) than in those with a non SVR (relapse plus non responder) based on HCV RNA analysis (2.8 log10fmol/L vs. 3.27 log10fmol/L, P = 0.023). Monitoring of the viral kinetics by determination of HCV RNA and HCV Ag levels resulted in similarly shaped curves. Patients with undetectable HCV Ag levels at week 4 had a 92.3% probability of achieving SVR based on HCV RNA assay results. The HCV Ag assay may be used as a supplement for predicting treatment response in HCV infection, but not as an alternative to the HCV RNA assay. PMID- 27510388 TI - Development of a Swine Benign Biliary Stricture Model Using Endoscopic Biliary Radiofrequency Ablation. AB - The large animal model with benign biliary stricture (BBS) is essential to undergo experiment on developing new devices and endoscopic treatment. This study conducted to establish a clinically relevant porcine BBS model by means of endobiliary radiofrequency ablation (RFA). Endoscopic retrograde cholangiography (ERC) was performed on 12 swine. The animals were allocated to three groups (60, 80, and 100 W) according to the electrical power level of RFA electrode. Endobiliary RFA was applied to the common bile duct for 60 seconds using an RFA catheter that was endoscopically inserted. ERC was repeated two and four weeks, respectively, after the RFA to identify BBS. After the strictures were identified, histologic evaluations were performed. On the follow-up ERC two weeks after the procedure, a segmental bile duct stricture was observed in all animals. On microscopic examination, severe periductal fibrosis and luminal obliteration with transmural inflammation were demonstrated. Bile duct perforations occurred in two pigs (100 W, n = 1; 80 W, n = 1) but there were no major complications in the 60 W group. The application of endobiliary RFA with 60 W electrical power resulted in a safe and reproducible swine model of BBS. PMID- 27510389 TI - Epidemiologic Study on Kawasaki Disease in Korea, 2007-2014: Based on Health Insurance Review & Assessment Service Claims. AB - The aim of this study is to assess the actual epidemiologic features of Kawasaki disease (KD) in Korea using the data from Health Insurance Review & Assessment Service (HIRA) claims from 2007 to 2014. We investigated HIRA claims of patients who had KD (International Classification of Diseases-10, M30.3) as a major diagnosis and were given intravenous immunoglobulin (IVIG) from 2007 to 2014. A total of 39,082 patients were reported during the period. The male-to-female ratio was 1.42 and the median age was 28 months. The incidence rates were 168.3 per 100,000 population aged 0 to 4 years in 2007, 159.1 in 2008, 167.3 in 2009, 190.4 in 2010, 188.2 in 2011, 190.2 in 2012, 210.4 in 2013 and 217.2 in 2014. These rates were much higher than those in the previous studies in Korea. KD occurred more often in early summer (May, June and July) and winter (December and January). The annual incidence rate of KD had been increasing every year, reaching 217.2 per 100,000 population aged 0 to 4 years in 2014. It is the second highest incidence rate of KD in the world after Japan. PMID- 27510390 TI - Neonatal and Infant Mortality in Korea, Japan, and the U.S.: Effect of Birth Weight Distribution and Birth Weight-Specific Mortality Rates. AB - Difference in crude neonatal and infant mortality rates (NMR and IMR) among different countries is due to the differences in its two determinants: birth weight distribution (BWD) and birth weight-specific mortality rates (BW-SMRs). We aimed to determine impact of BWD and BW-SMRs on differences in crude NMR and IMR among Korea, Japan, and the U.S. Our study used the live birth data of the period 2009 through 2010. Crude NMR/IMR are the lowest in Japan, 1.1/2.1, compared to 1.8/3.2, in Korea, and 4.1/6.2, in the U.S., respectively. Japanese had the best BW-SMRs of all birth weight groups compared to the Koreans and the U.S. The U.S. BWD was unfavorable with very low birth weight (< 1,500 g) rate of 1.4%, compared to 0.6% in Korea, and 0.8% in Japan. If Koreans and Japanese had the same BWD as in the U.S., their crude NMR/IMR would be 3.9/6.1 for the Koreans and 1.5/2.5 for the Japanese. If both Koreans and Japanese had the same BW-SMRs as in the U.S., the crude NMR/IMR would be 2.0/3.8 for the Koreans and 2.7/5.0 for the Japanese. In conclusion, compared to the U.S., lower crude NMR or IMR in Japan is mainly attributable to its better BW-SMRs. Koreans had lower crude NMR and IMR, primarily from its favorable BWD. Comparing crude NMR or IMR among different countries should include further exploration of its two determinants, BW-SMRs reflecting medical care, and BWD reflecting socio-demographic conditions. PMID- 27510391 TI - Ten Triangles around Cavernous Sinus for Surgical Approach, Described by Schematic Diagram and Three Dimensional Models with the Sectioned Images. AB - For the surgical approach to lesions around the cavernous sinus (CS), triangular spaces around CS have been devised. However, educational materials for learning the triangles were insufficient. The purpose of this study is to present educational materials about the triangles, consisting of a schematic diagram and 3-dimensional (3D) models with sectioned images. To achieve the purposes, other studies were analyzed to establish new definitions and names of the triangular spaces. Learning materials including schematic diagrams and 3D models with cadaver's sectioned images were manufactured. Our new definition was attested by observing the sectioned images and 3D models. The triangles and the four representative surgical approaches were stereoscopically indicated on the 3D models. All materials of this study were put into Portable Document Format file and were distributed freely at our homepage (anatomy.dongguk.ac.kr/triangles). By using our schematic diagram and the 3D models with sectioned images, ten triangles and the related structures could be understood and observed accurately. We expect that our data will contribute to anatomy education, surgery training, and radiologic understanding of the triangles and related structures. PMID- 27510392 TI - Impact of Glycemic Control and Metformin Use on the Recurrence and Progression of Non-Muscle Invasive Bladder Cancer in Patients with Diabetes Mellitus. AB - The purpose of the present study was to determine the potential relationships of glycemic control and use of metformin with non-muscle invasive bladder cancer characteristics. We reviewed data from 645 patients with non-muscle invasive bladder cancer between January 2004 and May 2015. We analyzed the association of pre and post-operative glycemic control and use of metformin with clinical characteristics of bladder tumors. We also analyzed the association of glycemic control and use of metformin with recurrence-free and progression-free survivals. Diabetes mellitus patients showed decreased recurrence-free survival (hazard ratio 1.42; 95% confidence interval 1.1-1.9; P = 0.021) and progression-free survival (hazard ratio 1.79; 95% confidence interval 1.1-2.8; P = 0.013). Diabetes mellitus patients with a HbA1c >= 7.0% demonstrated a higher rate of progression (P = 0.026). Kaplan-Meier analysis showed that progression-free survival rate was associated with poor baseline glycemic control (P = 0.026) and post-operative glycemic control (P = 0.025). However, use of metformin had no impact on the recurrence (P = 1.00) and progression (P = 0.282). In conclusion, poor baseline and post-operative glycemic control was related with shorter progression-free survival of patients with non-muscle invasive bladder cancer. Use of metformin had no impact on the recurrence and progression. Therefore, tight glycemic control and close follow-up for bladder tumor may be beneficial in patients with poor glycemic control. PMID- 27510393 TI - Ultrasound Dimensions of the Rotator Cuff and Other Associated Structures in Korean Healthy Adults. AB - In evaluating patients complaining of shoulder pain, ultrasonography is an emerging imaging tool due to convenience, low cost, high sensitivity and specificity. However, normative values of ultrasound dimensions of the shoulder to be compared with pathologic findings in Korean adults are not provided yet. We evaluated the ultrasound dimensions of the rotator cuff, long head of biceps tendon, deltoid muscle and acromioclavicular joint in Korean healthy adults. Shoulder ultrasonography was performed on 200 shoulders from 100 healthy adults. The dimensions of the thickness of rotator cuff (supraspinatus, infraspinatus, subscapularis tendon), deltoid muscle, long head of biceps tendon, subacromial subdeltoid bursa, and acromioclavicular joint interval were measured in a standardized manner. Differences in measurements among sex, age, and dominant arms were compared. The thickness of rotator cuff tendons (supraspinatus, infraspinatus, subscapularis) and deltoid muscle were significantly different between men and women. The thickness of subacromial subdeltoid bursa was significantly different between men and women for non-dominant side. In rotator cuff tendon measurements, the differences between dominant and non-dominant shoulders were not significant, which means the asymptomatic contralateral shoulder can be used to estimate the normal reference values. When stratified by age divided by 10 years, the measurements of supraspinatus, subscapularis and deltoid thickness showed tendency of increase with the age. The acromioclavicular joint interval, on the other hand, revealed decreasing tendency. This report suggests normative values of ultrasound dimensions of healthy Korean population with varying age, and can be useful as reference values in evaluating shoulder pathology, especially in rotator cuff tendon pathology. PMID- 27510394 TI - High Prevalence of Sarcopenia in Korean Patients after Hip Fracture: a Case Control Study. AB - Sarcopenia-related falls and fractures are increasing worldwide due to the aging population. The purpose of this study was to 1) evaluate anthropometric characteristics related to hip fracture in Korean patients, 2) investigate sarcopenia prevalence in hip fracture (HF) and non-hip fracture (NF) groups, and 3) investigate the correlation between sarcopenia and osteoporosis. This case control study examined 359 HF and 1,614 NF normal populations using Korea National Health and Nutrition Examination Survey data. We performed whole-body dual energy X-ray absorptiometry to analyze body composition using the skeletal muscle mass index (SMI: lean mass/height2) and bone mineral density (BMD). In the HF group, using the AWGS definition, the prevalence of sarcopenia in women and men was 44.3% and 68.2%, respectively; in the NF group, it was 7.1% and 16.1%, respectively. Lower appendicular SMI (P < 0.001), leg muscle mass (P < 0.001), and higher prevalence of sarcopenia (P < 0.001) were observed in the HF group after adjustment for age and gender. In multivariate analysis, sarcopenia (OR = 6.52; 95% CI = 4.67-9.09), age (OR = 1.15; 95% CI = 1.13-1.17), and osteoporosis (OR = 1.87; 95% CI = 1.35-2.58) were associated with the occurrence of a hip fracture. This study showed a higher prevalence of sarcopenia in patients with hip fractures compared with a normal population, and higher prevalence of sarcopenia in men. PMID- 27510396 TI - A Randomized Controlled Trial of Compression Rates during Cardiopulmonary Resuscitation. AB - The objective of this study was to compare the efficacy of cardiopulmonary resuscitation (CPR) with 120 compressions per minute (CPM) to CPR with 100 CPM in patients with non-traumatic out-of-hospital cardiac arrest. We randomly assigned patients with non-traumatic out-of-hospital cardiac arrest into two groups upon arrival to the emergency department (ED). The patients received manual CPR either with 100 CPM (CPR-100 group) or 120 CPM (CPR-120 group). The primary outcome measure was sustained restoration of spontaneous circulation (ROSC). The secondary outcome measures were survival discharge from the hospital, one-month survival, and one-month survival with good functional status. Of 470 patients with cardiac arrest, 136 patients in the CPR-100 group and 156 patients in the CPR-120 group were included in the final analysis. A total of 69 patients (50.7%) in the CPR-100 group and 67 patients (42.9%) in the CPR-120 group had ROSC (absolute difference, 7.8% points; 95% confidence interval [CI], -3.7 to 19.2%; P = 0.183). The rates of survival discharge from the hospital, one-month survival, and one-month survival with good functional status were not different between the two groups (16.9% vs. 12.8%, P = 0.325; 12.5% vs. 6.4%, P = 0.073; 5.9% vs. 2.6%, P = 0.154, respectively). We did not find differences in the resuscitation outcomes between those who received CPR with 100 CPM and those with 120 CPM. However, a large trial is warranted, with adequate power to confirm a statistically non-significant trend toward superiority of CPR with 100 CPM. ( CLINICAL TRIAL REGISTRATION INFORMATION: www.cris.nih.go.kr, cris.nih.go.kr number, KCT0000231). PMID- 27510395 TI - Comparison of an Intraoperative Infusion of Dexmedetomidine, Fentanyl, and Remifentanil on Perioperative Hemodynamics, Sedation Quality, and Postoperative Pain Control. AB - We aimed to compare fentanyl, remifentanil and dexmedetomidine with respect to hemodynamic stability, postoperative pain control and achievement of sedation at the postanesthetic care unit (PACU). In this randomized double-blind study, 90 consecutive total laparoscopic hysterectomy patients scheduled for elective surgery were randomly assigned to receive fentanyl (1.0 MUg/kg) over 1 minute followed by a 0.4 MUg/kg/hr infusion (FK group, n = 30), or remifentanil (1.0 MUg/kg) over 1 minute followed by a 0.08 MUg/kg/min infusion (RK group, n = 30), or dexmedetomidine (1 MUg/kg) over 10 minutes followed by a 0.5 MUg/kg/hr infusion (DK group, n = 30) initiating at the end of main procedures of the operation to the time in the PACU. A single dose of intravenous ketorolac (30 mg) was given to all patients at the end of surgery. We respectively evaluated the pain VAS scores, the modified OAA/S scores, the BIS, the vital signs and the perioperative side effects to compare the efficacy of fentanyl, remifentanil and dexmedetomidine. Compared with other groups, the modified OAA/S scores were significantly lower in DK group at 0, 5 and 10 minutes after arrival at the PACU (P < 0.05), whereas the pain VAS and BIS were not significantly different from other groups. The blood pressure and heart rate in the DK group were significantly lower than those of other groups at the PACU (P < 0.05). DK group, at sedative doses, had the better postoperative hemodynamic stability than RK group or FK group and demonstrated a similar effect of pain control as RK group and FK group with patient awareness during sedation in the PACU. (World Health Organization registry, KCT0001524). PMID- 27510397 TI - Delayed Diagnosis of Falciparum Malaria with Acute Kidney Injury. AB - Prompt malaria diagnosis is crucial so antimalarial drugs and supportive care can then be rapidly initiated. A 15-year-old boy who had traveled to Africa (South Africa, Kenya, and Nigeria between January 3 and 25, 2011) presented with fever persisting over 5 days, headache, diarrhea, and dysuria, approximately 17 days after his return from the journey. Urinalysis showed pyuria and hematuria. Blood examination showed hemolytic anemia, thrombocytopenia, disseminated intravascular coagulation, and hyperbilirubinemia. Plasmapheresis and hemodialysis were performed for 19 hospital days. Falciparum malaria was then confirmed by peripheral blood smear, and antimalarial medications were initiated. The patient's condition and laboratory results were quickly normalized. We report a case of severe acute renal failure associated with delayed diagnosis of falciparum malaria, and primary use of supportive treatment rather than antimalarial medicine. The present case suggests that early diagnosis and treatment is important because untreated tropical malaria can be associated with severe acute renal failure and fatality. Physicians must be alert for correct diagnosis and proper management of imported tropical malaria when patients have travel history of endemic areas. PMID- 27510398 TI - Letter to the Editor: Objective Assessment of Surgical Restaging after Concurrent Chemoradiation for Locally Advanced Pancreatic Cancer. PMID- 27510399 TI - The Author's Response: Objective Assessment of Surgical Restaging after Concurrent Chemoradiation for Locally Advanced Pancreatic Cancer. PMID- 27510400 TI - Membranome: a database for proteome-wide analysis of single-pass membrane proteins. AB - The Membranome database was developed to assist analysis and computational modeling of single-pass (bitopic) transmembrane (TM) proteins and their complexes by providing structural information about these proteins on a genomic scale. The database currently collects data on >6000 bitopic proteins from Homo sapiens, Arabidopsis thaliana, Dictyostelium discoideum, Saccharomyces cerevisiae, Escherichia coli and Methanocaldococcus jannaschii It presents the following data: (i) hierarchical classification of bitopic proteins into 15 functional classes, 689 structural superfamilies and 1404 families; (ii) 446 complexes of bitopic proteins with known three-dimensional (3D) structures classified into 129 families; (iii) computationally generated three-dimensional models of TM alpha helices positioned in membranes; (iv) amino acid sequences, domain architecture, functional annotation and available experimental structures of bitopic proteins; (v) TM topology and intracellular localization, (vi) physical interactions between proteins from the database along with links to other resources. The database is freely accessible at http://membranome.org There is a variety of options for browsing, sorting, searching and retrieval of the content, including downloadable coordinate files of TM domains with calculated membrane boundaries. PMID- 27510401 TI - Increased Th2 activity and diminished skin barrier function cooperate in allergic skin inflammation. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease induced by a complex interaction between susceptibility genes encoding skin barrier components and environmental allergen exposure that results in type 2 cytokine production. Although genetic lesions in either component can be risk factors for disease in patients, whether these pathways interact in the development of AD is not clear. To test this, we mated mice with T-cell specific expression of constitutively active Stat6 (Stat6VT) that spontaneously develop allergic skin inflammation with Flaky tail (Ft) mice that have mutations in Flg and Tmem79 genes that each affect skin barrier function. Our results demonstrate that over 90% of the Stat6VT transgenic mice carrying the Ft alleles (Stat6VTxFt-/- ) develop severe atopic dermatitis lesions by 3-5 months of age, compared with only 40% of Stat6VT mice that develop disease by 6-7 months of age. Further, histopathological analysis of skin tissues from Stat6VTxFt-/- mice revealed extensive thickening of the dermis with increased inflammatory infiltrates as compared with Stat6VT mice. Our study suggests that skin barrier defects and altered Th2 responses independently cooperate in the pathogenesis of allergic skin inflammation, similar to effects observed in patients with AD. PMID- 27510402 TI - Association of cardiovascular emerging risk factors with acute coronary syndrome and stroke: A case-control study. AB - In this study, we estimated the risk of acute coronary syndrome and stroke associated with several emerging cardiovascular risk factors. This was a case control study, where an age - and sex-matched acute coronary syndrome group and stroke group were compared with controls. Demographic and clinical data were collected through patient interviews, and blood samples were taken for analysis. In the bivariate analysis, all cardiovascular risk factors analyzed showed as predictors of acute coronary syndrome and stroke, except total cholesterol and smoking. In the multivariate logistic regression model for acute coronary syndrome, hypertension and body mass index, N-terminal section brain natriuretic peptide and pregnancy-associated plasma protein-A were independent predictors. For stroke, the predictors were hypertension, diabetes mellitus, body mass index, and N-terminal section brain natriuretic peptide. Controlling for age, sex, and classical cardiovascular risk factors, N-terminal section brain natriuretic peptide and pregnancy-associated plasma protein-A were independent emerging cardiovascular risk factors for acute coronary syndrome, but pregnancy-associated plasma protein-A was not for stroke. High levels of cardiovascular risk factors in individuals with no episodes of cardiovascular disease requires the implementation of prevention programs, given that at least half of them are modifiable. PMID- 27510403 TI - Lanthanide-Catalyzed Reversible Alkynyl Exchange by Carbon-Carbon Single-Bond Cleavage Assisted by a Secondary Amino Group. AB - Lanthanide-catalyzed alkynyl exchange through C-C single-bond cleavage assisted by a secondary amino group is reported. A lanthanide amido complex is proposed as a key intermediate, which undergoes unprecedented reversible beta-alkynyl elimination followed by alkynyl exchange and imine reinsertion. The in situ homo- and cross-dimerization of the liberated alkyne can serve as an additional driving force to shift the metathesis equilibrium to completion. This reaction is formally complementary to conventional alkyne metathesis and allows the selective transformation of internal propargylamines into those bearing different substituents on the alkyne terminus in moderate to excellent yields under operationally simple reaction conditions. PMID- 27510404 TI - Influence of Lumbricus terrestris and Folsomia candida on N2 O formation pathways in two different soils - with particular focus on N2 emissions. AB - RATIONALE: The gaseous N losses mediated by soil denitrifiers are generally inferred by measuring N2 O fluxes, but should include associated N2 emissions, which may be affected by abiotic soil characteristics and biotic interactions. Soil fauna, particularly anecic earthworms and euedaphic collembola, alter the activity of denitrifiers, creating hotspots for denitrification. These soil fauna are abundant in perennial agroecosystems intended to contribute to more sustainable production of bioenergy. METHODS: Two microcosm experiments were designed to evaluate gaseous N emissions from a silty loam and a sandy soil, both provided with litter from the bioenergy crop Silphium perfoliatum (cup-plant) and inoculated with an anecic earthworm (Lumbricus terrestris), which was added alone or together with an euedaphic collembola (Folsomia candida). In experiment 1, litter-derived N flux was determined by adding 15 N-labelled litter, followed by mass spectrometric analysis of N2 and N2 O isotopologues. In experiment 2, the delta18 O values and 15 N site preference of N2 O were determined by isotope ratio mass spectrometry to reveal underlying N2 O formation pathways. RESULTS: Lumbricus terrestris significantly increased litter-derived N2 emissions in the loamy soil, from 174.5 to 1019.3 MUg N2 -N kg-1 soil, but not in the sandy soil (non-significant change from 944.7 to 1054.7 MUg N2 -N kg-1 soil). Earthworm feeding on plant litter resulted in elevated N2 O emissions in both soils, derived mainly from turnover of the soil mineral N pool during denitrification. Folsomia candida did not affect N losses but showed a tendency to redirect N2 O formation pathways from fungal to bacterial denitrification. The N2 O/(N2 + N2 O) product ratio was predominantly affected by abiotic soil characteristics (loamy soil: 0.14, sandy soil: 0.26). CONCLUSIONS: When feeding on S. perfoliatum litter, the anecic L. terrestris, but not the euedaphic F. candida, has the potential to cause substantial N losses. Biotic interactions between the species are not influential, but abiotic soil characteristics have an effect. The coarse textured sandy soil had lower gaseous N losses attributable to anecic earthworms. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27510405 TI - Does state boredom cause failures of attention? Examining the relations between trait boredom, state boredom, and sustained attention. AB - Boredom is an important personal and social problem, but the phenomena itself remains poorly understood. Recent work has shown that boredom is highly related to attention, and that this relationship may be instrumental in revealing boredom's causes and consequences. In this paper, experimental findings on trait boredom, state boredom, and sustained attention performance are presented. We demonstrate that trait boredom uniquely predicts sustained attention performance, over and above depression and self-report attention problems. We also present exploratory findings consistent with the claim that attention failures may cause boredom and that sustained attention tasks may themselves be boring. Discussion of each of these findings, and potential ramifications for cognitive research as a whole, is included. PMID- 27510406 TI - Retinal Structures and Visual Cortex Activity are Impaired Prior to Clinical Vision Loss in Glaucoma. AB - Glaucoma is the second leading cause of blindness worldwide and its pathogenesis remains unclear. In this study, we measured the structure, metabolism and function of the visual system by optical coherence tomography and multi-modal magnetic resonance imaging in healthy subjects and glaucoma patients with different degrees of vision loss. We found that inner retinal layer thinning, optic nerve cupping and reduced visual cortex activity occurred before patients showed visual field impairment. The primary visual cortex also exhibited more severe functional deficits than higher-order visual brain areas in glaucoma. Within the visual cortex, choline metabolism was perturbed along with increasing disease severity in the eye, optic radiation and visual field. In summary, this study showed evidence that glaucoma deterioration is already present in the eye and the brain before substantial vision loss can be detected clinically using current testing methods. In addition, cortical cholinergic abnormalities are involved during trans-neuronal degeneration and can be detected non-invasively in glaucoma. The current results can be of impact for identifying early glaucoma mechanisms, detecting and monitoring pathophysiological events and eye-brain behavior relationships, and guiding vision preservation strategies in the visual system, which may help reduce the burden of this irreversible but preventable neurodegenerative disease. PMID- 27510408 TI - Sphingomyelin synthase 2 affects CD14-associated induction of NF-kappaB by lipopolysaccharides in acute lung injury in mice. AB - Lipopolysaccharide (LPS) is the predominant component of the outer membrane of Gram-negative bacteria, which can cause severe inflammation in the body. The acute lung injury (ALI) induced by LPS can cause extensive damage to the lung tissue, the severe stage of which is termed acute respiratory distress syndrome, when multiple organ dysfunction syndrome may appear. There are no effective clinical treatment measures at present. The involvement of cluster of differentiation (CD)14 assists LPS in causing inflammatory reactions, and CD14 and sphingomyelin (SM), located in lipid rafts areas, are closely associated. SM synthase (SMS) is a key enzyme in the synthesis of SM, however, the effect of SMS on the inflammatory pathway involving nuclear factor (NF)-kappaB induced by LPS remains to be elucidated. Under the premise of the establishment of an ALI mouse model induced by LPS, the present study established a control group, LPS group and pyrrolidine dithiocarbamate (PDTC; an NF-kappaB pathway inhibitor) group. Hematoxylin-eosin staining, reverse transcription-quantitative polymerase chain reaction analysis, western blot analysis and thin layer chromatography were used to investigate the mechanism of SMS in ALI. Compared with the control group, the mRNA and protein levels of CD14 were significantly increased (P<0.001; n=5 and P<0.05, n=5), and the activity of SMS and expression of SMS2 were significantly upregulated (P<0.001; n=5 and P<0.05, n=5) in the model group. The increases of SMS2 and CD14 in the PDTC group were less marked, compared with those in the model group (P<0.05; n=5). These findings suggested that the degree of lung injury was reduced during the acute inflammatory reaction when NF-kappaB was inhibited, and that the expression of SMS2 may affect the induction of the NF kappaB pathway by LPS through CD14. PMID- 27510407 TI - Impact of language on functional connectivity for audiovisual speech integration. AB - Visual information about lip and facial movements plays a role in audiovisual (AV) speech perception. Although this has been widely confirmed, previous behavioural studies have shown interlanguage differences, that is, native Japanese speakers do not integrate auditory and visual speech as closely as native English speakers. To elucidate the neural basis of such interlanguage differences, 22 native English speakers and 24 native Japanese speakers were examined in behavioural or functional Magnetic Resonance Imaging (fMRI) experiments while mono-syllabic speech was presented under AV, auditory-only, or visual-only conditions for speech identification. Behavioural results indicated that the English speakers identified visual speech more quickly than the Japanese speakers, and that the temporal facilitation effect of congruent visual speech was significant in the English speakers but not in the Japanese speakers. Using fMRI data, we examined the functional connectivity among brain regions important for auditory-visual interplay. The results indicated that the English speakers had significantly stronger connectivity between the visual motion area MT and the Heschl's gyrus compared with the Japanese speakers, which may subserve lower level visual influences on speech perception in English speakers in a multisensory environment. These results suggested that linguistic experience strongly affects neural connectivity involved in AV speech integration. PMID- 27510410 TI - Fine Particulate Matter Pollution and Mortality. PMID- 27510411 TI - Analysis of esophagogastric cancer patients enrolled in the National Cancer Institute Cancer Therapy Evaluation Program sponsored phase 1 trials. AB - BACKGROUND: In phase 1 trials, an important entry criterion is life expectancy predicted to be more than 90 days, which is generally difficult to predict. The Royal Marsden Hospital (RMH) prognostic score that is determined by lactate dehydrogenase level, albumin level, and number of metastatic sites of disease was developed to help project patient outcomes. There have been no systematic analyses to evaluate the utility of the RMH prognostic score for esophagogastric cancer patients. METHODS: All nonpediatric phase 1 oncology trials sponsored by the National Cancer Institute Cancer Therapy Evaluation Program that began between 2001 and 2013 were considered in this review. RESULTS: Of 4722 patients with solid tumors, 115 patients were eligible for our analysis; 54 (47 %) with cancer of the esophagus, 14 (12 %) with cancer of the esopagogastric junction, and 47 (41 %) with stomach cancer. Eighty-six patients (75 %) had a good RMH prognostic score (0 or 1) and 29 patients (25 %) had a poor RMH prognostic score (2 or 3). Disease control rates were significantly different between patients with good and poor RMH prognostic scores (49 % vs 17 %; two-sided Fisher's exact test P = 0.004). The median treatment duration and overall survival for good and poor RMH prognostic score patients were significantly different (median treatment duration 2.1 months vs 1.2 months respectively, P = 0.016; median overall survival 10.9 months vs 2.1 months respectively, P < 0.001). In the multivariate analysis, age (60 years or older), Eastern Cooperative Oncology Group performance status (2 or greater), and the RMH prognostic score (2 or 3) were significant predictors of poor survival. CONCLUSIONS: The RMH prognostic score is a strong tool to predict the prognosis of esophagogastric cancer patients who might participate in a phase 1 trial. PMID- 27510413 TI - Acceleration of convective dissolution by chemical reaction in a Hele-Shaw cell. AB - New laboratory experiments quantify the destabilising effect of a second-order chemical reaction on the fingering instability of a diffusive boundary layer in a Hele-Shaw cell. We show that, for a given chemical system, the dynamics of such a reactive boundary layer is fully determined by two dimensionless groups, Da/Ra(2), which measures the timescale for convection compared to those for reaction and diffusion, and CBo', which reflects the excess of the environmental reactant species relative to the diffusing solute. Results of a systematic study varying CBo' in the range 0-0.1 are presented. It is shown that the chemical reaction increases the growth rate of a perturbation and favours small wavelengths compared to the inert system. A higher concentration of CBo' not only accelerates the onset of convection, but crucially also increases the transport of the solute by up to 150% compared to the inert system. This increase in solute transfer has important practical implications, such as in the storage of carbon dioxide in saline aquifers. PMID- 27510412 TI - How Reliable Is the Pinaya Method for Assessing Cognitive Lateralization with Functional Transcranial Doppler Ultrasound? PMID- 27510414 TI - Impact of hepatitis B on mortality and specific causes of death in adults with and without HIV co-infection in NYC, 2000-2011. AB - High rates of immigration from endemic countries contribute to the high chronic hepatitis B (HBV) prevalence in New York City (NYC) compared to the United States overall, i.e. about 1 million individuals. We describe the impact of HBV infection on mortality and specific causes of death in NYC. We matched surveillance and vital statistics mortality data collected from 2000 to 2011 by the New York City Department of Health and Mental Hygiene (DOHMH) and analysed demographics and premature deaths (i.e. whether death occurred at <65 years) in persons with and without chronic HBV or HIV infection (excluding those with hepatitis C). From 2000 to 2011, a total of 588 346 adults died in NYC. Of all decedents, 568 753 (97%) had no report of HIV or HBV, and 4346 (0.7%) had an HBV report. Of HBV-infected decedents, 1074 (25%) were HIV co-infected. Fifty-five percent of HBV mono-infected and 95% of HBV/HIV co-infected decedents died prematurely. HBV disproportionately impacts two subgroups: Chinese immigrants and HIV-infected individuals. These two subgroups are geographically clustered in different neighbourhoods of NYC. Tailoring prevention and treatment messages to each group is necessary to reduce the overall burden of HBV in NYC. PMID- 27510415 TI - The trophoblast plug during early pregnancy: a deeper insight. AB - During the first trimester of pregnancy, foetal endovascular trophoblasts invade into maternal spiral arteries, accumulate and form plugs in the lumen of the vessels. These plugs only allow blood plasma to seep through. Hence, during the first trimester of pregnancy, a first flow of fluids through the placental intervillous space is established, resulting in a physiological oxygen gradient between mother and foetus. The trophoblast plugs block spiral arteries until the beginning of the second trimester (11-14 weeks). In parallel, uterine glands are invaded and opened by endoglandular trophoblasts towards the intervillous space of the placenta, without showing the formation of plugs (Moser et al. in Hum Reprod 25:1127-1136, 2010, Hum Reprod Oxf Engl 30:2747-2757, 2015). This enables histiotrophic nutrition of the embryo prior to onset of maternal blood flow into the placenta. Failure of these endovascular and endoglandular invasion processes may lead to miscarriage or pregnancy disorders such as intrauterine growth restriction (IUGR). After dissolution of the plugs, the onset of maternal blood flow allows maternal blood cells to enter the intervillous space and oxygen concentrations rise up. In this study, we demonstrate for the first time serial cross sections through a trophoblast plug in a first trimester placental bed specimen. Invaded and plugged arteries as well as invaded uterine glands in week 11 of gestation are visualized with specific immunohistochemical double staining techniques. We show that spiral artery plugs appear throughout the placental invasion zone and illustrate erythrocytes stowed due to trophoblast plugs. In addition, we give evidence of the presence of MMP-1 in plugs of invaded spiral arteries. The results reveal a better understanding and a closer insight into the morphological appearance of trophoblast plugs and the consequences for placental and uterine blood flow. PMID- 27510416 TI - In Focus in HCB. PMID- 27510417 TI - [Predictive PD-L1 immunohistochemistry for non-small cell lung cancer : Current state of the art and experiences of the first German harmonization study]. AB - BACKGROUND: Antibodies against PD-1 and PD-L1 can cause strong and durable anti tumor immune responses in non-small cell lung cancer (NSCLC). Immunohistochemistry for PD-L1 (PD-L1 IHC) was tested as a predictive biomarker. Several IHC assays and interpretation criteria were developed in parallel. AIM: The clinical significance of PD-L1 IHC in NSCLC and the optimum method for staining and interpretation of the results are the subject of ongoing studies. The diagnostic application of immunotherapy in NSCLC necessitates harmonization of PD-L1 IHC to obtain evidence for guidelines; therefore, a consensus opinion on a well-founded diagnostic mode of testing should be defined based on published studies and the results of the first German PD-L1 IHC harmonization study. METHODS: 1. Summary of the current data situation. 2. Evaluation of the first German PD-L1 IHC harmonization study (centralized, staining with PD-L1 IHC analogous to studies, 15 cases of NSCLC, 4 IHC study assays [28-8, 22C3, SP142 and SP263] and scoring by 9 pathologists). RESULTS: The use of PD-L1 IHC in NSCLC is suitable for identification of patients with an increased probability of a clinical benefit from immunotherapy. The various proportional cut-offs used to interpret the staining results can be summarized in a total score, which can be reproducibly assessed. The staining patterns of the four assays investigated were, however, not congruent in all situations. DISCUSSION: In principle, the use of PD-L1 IHC for assessment of the expression in tumor cells is a reliably determinable biomarker. Evaluation algorithms should be based on published clinical trials. For NSCLC approvals with obligatory PD-L1 IHC are to be expected but it remains to be seen to what extent PD-L1 IHC will be implemented in the clinical routine. PMID- 27510418 TI - Room-temperature ferroelectricity in CuInP2S6 ultrathin flakes. AB - Two-dimensional (2D) materials have emerged as promising candidates for various optoelectronic applications based on their diverse electronic properties, ranging from insulating to superconducting. However, cooperative phenomena such as ferroelectricity in the 2D limit have not been well explored. Here, we report room-temperature ferroelectricity in 2D CuInP2S6 (CIPS) with a transition temperature of ~320 K. Switchable polarization is observed in thin CIPS of ~4 nm. To demonstrate the potential of this 2D ferroelectric material, we prepare a van der Waals (vdW) ferroelectric diode formed by CIPS/Si heterostructure, which shows good memory behaviour with on/off ratio of ~100. The addition of ferroelectricity to the 2D family opens up possibilities for numerous novel applications, including sensors, actuators, non-volatile memory devices, and various vdW heterostructures based on 2D ferroelectricity. PMID- 27510419 TI - Quantitative analysis of mucosal oxygenation using ex vivo imaging of healthy and inflamed mammalian colon tissue. AB - Colonic inflammation is associated with decreased tissue oxygenation, significantly affecting gut homeostasis. However, the crosstalk between O2 consumption and supply in the inflamed tissue are not fully understood. Using a murine model of colitis, we analysed O2 in freshly prepared samples of healthy and inflamed colon tissue. We developed protocols for efficient ex vivo staining of mouse distal colon mucosa with a cell-penetrating O2 sensitive probe Pt-Glc and high-resolution imaging of O2 concentration in live tissue by confocal phosphorescence lifetime-imaging microscopy (PLIM). Microscopy analysis revealed that Pt-Glc stained mostly the top 50-60 MUm layer of the mucosa, with high phosphorescence intensity in epithelial cells. Measured O2 values in normal mouse tissue ranged between 5 and 35 MUM (4-28 Torr), tending to decrease in the deeper tissue areas. Four-day treatment with dextran sulphate sodium (DSS) triggered colon inflammation, as evidenced by an increase in local IL6 and mKC mRNA levels, but did not affect the gross architecture of colonic epithelium. We further observed an increase in oxygenation, partial activation of hypoxia inducible factor (HIF) 1 signalling, and negative trends in pyruvate dehydrogenase activity and O2 consumption rate in the colitis mucosa, suggesting a decrease in mitochondrial respiration, which is known to be regulated via HIF-1 signalling and pyruvate oxidation rate. These results along with efficient staining with Pt Glc of rat and human colonic mucosa reveal high potential of PLIM platform as a powerful tool for the high-resolution analysis of the intestinal tissue oxygenation in patients with inflammatory bowel disease and other pathologies, affecting tissue respiration. PMID- 27510420 TI - Liver X receptors: from cholesterol regulation to neuroprotection-a new barrier against neurodegeneration in amyotrophic lateral sclerosis? AB - Cholesterol plays a central role in numerous nervous system functions. Cholesterol is the major constituent of myelin sheaths, is essential for synapse and dendrite formation, axon guidance as well as neurotransmission. Among regulators of cholesterol homeostasis, liver X receptors (LXRs), two members of the nuclear receptor superfamily, play a determinant role. LXRs act as cholesterol sensors and respond to high intracellular cholesterol concentration by decreasing plasmatic and intracellular cholesterol content. Beyond their cholesterol-lowering role, LXRs have been proposed as regulators of immunity and anti-inflammatory factors. Dysregulation of cholesterol metabolism combined to neuroinflammatory context have been described in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). ALS is characterized by the progressive loss of motoneurons in the brain and spinal cord, leading to severe paralytic condition and death of patients in a median time of 3 years. Motoneuron degeneration is accompanied by chronic neuroinflammatory response, involving microglial and astrocytic activation, infiltration of blood-derived immune cells and release of pro-inflammatory factors. We propose to discuss here the role of LXRs as a molecular link between the central nervous system cholesterol metabolism, neuroinflammation, motoneuron survival and their potential as promising therapeutic candidates for ALS therapy. PMID- 27510421 TI - Intracellular localization of DR5 and related regulatory pathways as a mechanism of resistance to TRAIL in cancer. AB - TNF-related apoptosis-inducing ligand (TRAIL) is a prominent cytokine capable of inducing apoptosis. It can bind to five different cognate receptors, through which diverse intracellular pathways can be activated. TRAIL's ability to preferentially kill transformed cells makes it a promising potential weapon for targeted tumor therapy. However, recognition of several resistance mechanisms to TRAIL-induced apoptosis has indicated that a thorough understanding of the details of TRAIL biology is still essential before this weapon can be confidently unleashed. Critical to this aim is revealing the functions and regulation mechanisms of TRAIL's potent death receptor DR5. Although expression and signaling mechanisms of DR5 have been extensively studied, other aspects, such as its subcellular localization, non-signaling functions, and regulation of its membrane transport, have only recently attracted attention. Here, we discuss different aspects of TRAIL/DR5 biology, with a particular emphasis on the factors that seem to influence the cell surface expression pattern of DR5, along with factors that lead to its nuclear localization. Disturbance of this balance apparently affects the sensitivity of cancer cells to TRAIL-mediated apoptosis, thus constituting an eligible target for potential new therapeutic agents. PMID- 27510422 TI - Sleep Health: Reciprocal Regulation of Sleep and Innate Immunity. AB - Sleep disturbances including insomnia independently contribute to risk of inflammatory disorders and major depressive disorder. This review and overview provides an integrated understanding of the reciprocal relationships between sleep and the innate immune system and considers the role of sleep in the nocturnal regulation of the inflammatory biology dynamics; the impact of insomnia complaints, extremes of sleep duration, and experimental sleep deprivation on genomic, cellular, and systemic markers of inflammation; and the influence of sleep complaints and insomnia on inflammaging and molecular processes of cellular aging. Clinical implications of this research include discussion of the contribution of sleep disturbance to depression and especially inflammation related depressive symptoms. Reciprocal action of inflammatory mediators on the homeostatic regulation of sleep continuity and sleep macrostructure, and the potential of interventions that target insomnia to reverse inflammation, are also reviewed. Together, interactions between sleep and inflammatory biology mechanisms underscore the implications of sleep disturbance for inflammatory disease risk, and provide a map to guide the development of treatments that modulate inflammation, improve sleep, and promote sleep health. PMID- 27510424 TI - Thinking Outside the Box: Orbitofrontal Cortex, Imagination, and How We Can Treat Addiction. AB - Addiction involves an inability to control drug-seeking behavior. While this may be thought of as secondary to an overwhelming desire for drugs, it could equally well reflect a failure of the brain mechanisms that allow addicts to learn about and mentally simulate non-drug consequences. Importantly, this process of mental simulation draws upon, but is not normally bound by, our past experiences. Rather we have the ability to think outside the box of our past, integrating knowledge gained from a variety of similar and not-so-similar life experiences to derive estimates or imagine what might happen next. These estimates influence our current behavior directly and also affect future behavior by serving as the background against which outcomes are evaluated to support learning. Here we will review evidence, from our own work using a Pavlovian over-expectation task as well as from other sources, that the orbitofrontal cortex is a critical node in the neural circuit that generates these estimates. Further we will offer the specific hypothesis that degradation of this function secondary to drug-induced changes is a critical and likely addressable part of addiction. PMID- 27510425 TI - Low MU-Opioid Receptor Status in Alcohol Dependence Identified by Combined Positron Emission Tomography and Post-Mortem Brain Analysis. AB - Blockade of the MU-opioid receptor (MOR) by naltrexone reduces relapse risk in a subpopulation of alcohol-dependent patients. Previous positron-emission tomography (PET) studies using the MOR ligand [11C]carfentanil have found increased MOR availability in abstinent alcoholics, which may reflect either increased MOR expression or lower endogenous ligand concentration. To differentiate between both effects, we investigated two cohorts of alcoholic subjects using either post-mortem or clinical PET analysis. Post-mortem brain tissue of alcohol-dependent subjects and controls (N=43/group) was quantitatively analyzed for MOR ([3H]DAMGO)-binding sites and OPRM1 mRNA in striatal regions. [11C]carfentanil PET was performed in detoxified, medication free alcohol dependent patients (N=38), followed by a randomized controlled study of naltrexone versus placebo and follow-up for 1 year (clinical trial number: NCT00317031). Because the functional OPRM1 variant rs1799971:A>G affects the ligand binding, allele carrier status was considered in the analyses. MOR-binding sites were reduced by 23-51% in post-mortem striatal tissue of alcoholics. In the PET study, a significant interaction of OPRM1 genotype, binding potential (BPND) for [11C]carfentanil in the ventral striatum, and relapse risk was found. Particularly in G-allele carriers, lower striatal BPND was associated with a higher relapse risk. Interestingly, this effect was more pronounced in the naltrexone treatment group. Reduced MOR is interpreted as a neuroadaptation to an alcohol-induced release of endogenous ligands in patients with severe alcoholism. Low MOR availability may explain the ineffectiveness of naltrexone treatment in this subpopulation. Finally, low MOR-binding sites are proposed as a molecular marker for a negative disease course. PMID- 27510427 TI - Insignificance of active flow for neural diffusion weighted imaging: A negative result. AB - PURPOSE: To provide a biophysical basis to estimate the effect of cytoplasmic flow in neurons, and assess their contribution to the drop in the Apparent Diffusion Coefficient (ADC) in a nerve tissue following extreme conditions, such as brain injury and epileptic seizures. METHODS: Three mechanisms are treated using the relevant physics of hydrodynamics and electrostatics: cargo induced streaming, electroosmosis, and membrane swelling. RESULTS: We begin by discussing the lack of experimental evidence on the necessary velocities required to influence the Magnetic Resonance (MR) experiments. This is followed by demonstrating that cargo induced streaming, a widely known phenomenon in plant cells, has a minor effect on the ADC in neurons. Subsequently, we suggest and analyze two additional mechanisms that may induce fluid displacement in neurons, and are related to the electrical activity: electroosmosis and membrane swelling. CONCLUSION: Although these mechanisms may induce interesting fluid displacements, these cannot explain the significant drop in the ADC. We conclude by outlining the criteria that any future mechanism should meet to have an influence on standard diffusion-MR measurements. Magn Reson Med 78:746-753, 2017. (c) 2016 International Society for Magnetic Resonance in Medicine. PMID- 27510423 TI - Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond. AB - The study of inflammation in fear- and anxiety-based disorders has gained interest as growing literature indicates that pro-inflammatory markers can directly modulate affective behavior. Indeed, heightened concentrations of inflammatory signals, including cytokines and C-reactive protein, have been described in posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), and phobias (agoraphobia, social phobia, etc.). However, not all reports indicate a positive association between inflammation and fear- and anxiety-based symptoms, suggesting that other factors are important in future assessments of inflammation's role in the maintenance of these disorders (ie, sex, co-morbid conditions, types of trauma exposure, and behavioral sources of inflammation). The most parsimonious explanation of increased inflammation in PTSD, GAD, PD, and phobias is via the activation of the stress response and central and peripheral immune cells to release cytokines. Dysregulation of the stress axis in the face of increased sympathetic tone and decreased parasympathetic activity characteristic of anxiety disorders could further augment inflammation and contribute to increased symptoms by having direct effects on brain regions critical for the regulation of fear and anxiety (such as the prefrontal cortex, insula, amygdala, and hippocampus). Taken together, the available data suggest that targeting inflammation may serve as a potential therapeutic target for treating these fear- and anxiety-based disorders in the future. However, the field must continue to characterize the specific role pro inflammatory signaling in the maintenance of these unique psychiatric conditions. PMID- 27510428 TI - Acid and alkaline phosphatase localization in the digestive tract mucosa of the Hemisorubim platyrhynchos. AB - This cytochemical study investigated the acid and alkaline phosphatase of the digestive tract of Hemisorubim platyrhynchos. Acid phosphatase was detected in the lining epithelium throughout the digestive tract, whereas alkaline phosphatase was only observed in the intestine. In the esophagus, an acid phosphatase reaction occurred in the apical cytoplasm of the epithelial cells and was related to epithelial protection and freeing of superficial cells for sloughing. Similar results were also observed in epithelial cells of gastric epithelium. In the gastric glands, acid phosphatase occurred in lysosomes of the oxynticopeptic cells acting in the macromolecule degradation for use as an energy source, whereas in the vesiculotubular system, its presence could be related to secretion processes. Furthermore, acid phosphatase in the intestine occurred in microvilli and lysosomes of the enterocytes and was correlated to absorption and intracellular digestion. However, no difference was reported among the regions of the intestine. However, alkaline phosphatase reaction revealed a large number of reaction dots in the anterior intestine, with the number decreasing toward the posterior intestine. This enzyme has been related to several functions, highlighting its role in the nutrient absorption primarily in the anterior intestine but also being essential in pH regulation because this is a carnivorous species with many gastric glands with secretions that could damage the intestine. PMID- 27510426 TI - Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders. AB - Both bipolar disorder (BD) and major depressive disorder (MDD) have high morbidity and share a genetic background. Treatment options for these mood disorders are currently suboptimal for many patients; however, specific genetic variables may be involved in both pathophysiology and response to treatment. Agents such as the glutamatergic modulator ketamine are effective in treatment resistant mood disorders, underscoring the potential importance of the glutamatergic system as a target for improved therapeutics. Here we review genetic studies linking the glutamatergic system to the pathophysiology and therapeutics of mood disorders. We screened 763 original genetic studies of BD or MDD that investigated genes encoding targets of the pathway/mediators related to the so-called tripartite glutamate synapse, including pre- and post-synaptic neurons and glial cells; 60 papers were included in this review. The findings suggest the involvement of glutamate-related genes in risk for mood disorders, treatment response, and phenotypic characteristics, although there was no consistent evidence for a specific gene. Target genes of high interest included GRIA3 and GRIK2 (which likely play a role in emergent suicidal ideation after antidepressant treatment), GRIK4 (which may influence treatment response), and GRM7 (which potentially affects risk for mood disorders). There was stronger evidence that glutamate-related genes influence risk for BD compared with MDD. Taken together, the studies show a preliminary relationship between glutamate related genes and risk for mood disorders, suicide, and treatment response, particularly with regard to targets on metabotropic and ionotropic receptors. PMID- 27510429 TI - Changes of trehalose content and expression of relative genes during the bioethanol fermentation by Saccharomyces cerevisiae. AB - Traditionally, trehalose is considered as a protectant to improve the ethanol tolerance of Saccharomyces cerevisiae. In this study, to clarify the changes and roles of trehalose during the bioethanol fermentation, trehalose content and expression of related genes at lag, exponential, and stationary phases (i.e., 2, 8, and 16 h of batch fermentation process) were determined. Although yeast cells at exponential and stationary phase had higher trehalose content than cells at lag phase (P < 0.01), there was no significant difference in trehalose content between exponential and stationary phases (P > 0.05). Moreover, expression of the trehalose degradation-related genes NTH1 and NTH2 decreased at exponential phase in comparison with that at lag phase; compared with cells at lag phase, cells at stationary phase had higher expression of TPS1, ATH1, NTH1, and NTH2 but lower expression of TPS2. During the lag-exponential phase transition, downregulation of NTH1 and NTH2 promoted accumulation of trehalose, and to some extent, trehalose might confer ethanol tolerance to S. cerevisiae before stationary phase. During the exponential-stationary phase transition, upregulation of TPS1 contributed to accumulation of trehalose, and Tps1 protein might be indispensable in yeast cells to withstand ethanol stress at the stationary phase. Moreover, trehalose would be degraded to supply carbon source at stationary phase. PMID- 27510431 TI - Predicting Pt-195 NMR chemical shift using new relativistic all-electron basis set. AB - Predicting NMR properties is a valuable tool to assist the experimentalists in the characterization of molecular structure. For heavy metals, such as Pt-195, only a few computational protocols are available. In the present contribution, all-electron Gaussian basis sets, suitable to calculate the Pt-195 NMR chemical shift, are presented for Pt and all elements commonly found as Pt-ligands. The new basis sets identified as NMR-DKH were partially contracted as a triple-zeta doubly polarized scheme with all coefficients obtained from a Douglas-Kroll-Hess (DKH) second-order scalar relativistic calculation. The Pt-195 chemical shift was predicted through empirical models fitted to reproduce experimental data for a set of 183 Pt(II) complexes which NMR sign ranges from -1000 to -6000 ppm. Furthermore, the models were validated using a new set of 75 Pt(II) complexes, not included in the descriptive set. The models were constructed using non relativistic Hamiltonian at density functional theory (DFT-PBEPBE) level with NMR DKH basis set for all atoms. For the best model, the mean absolute deviation (MAD) and the mean relative deviation (MRD) were 150 ppm and 6%, respectively, for the validation set (75 Pt-complexes) and 168 ppm (MAD) and 5% (MRD) for all 258 Pt(II) complexes. These results were comparable with relativistic DFT calculation, 200 ppm (MAD) and 6% (MRD). (c) 2016 Wiley Periodicals, Inc. PMID- 27510432 TI - A red emitting two-photon fluorescent probe for dynamic imaging of redox balance meditated by a superoxide anion and GSH in living cells and tissues. AB - Cellular self-regulation of reactive oxygen species (ROS) stress via antioxidant repair plays an important role in maintaining the redox balance. The redox balance between reducing and oxidizing species within cells is significant in the regulation of a signal pathway and is achieved by a series of elaborate mechanisms. In this work, we employed our previously reported D-pi-A-structured naphthalene-BODIPY TBET platform to design an efficient two-photon fluorescent probe for dynamic monitoring of superoxide anion oxidative stress and the GSH reducing repair process. The probe displayed high energy transfer efficiency (91.4%), large pseudo-Stokes shifts upon one-photon excitation, and red fluorescence emission (lambdaem = 596 nm), which is highly desirable for bioimaging applications. The probe exhibits reversibility, rapid response, good photostability, high selectivity and sensitivity for the superoxide anion and GSH. More importantly, the probe was successfully applied for visualizing the redox changes in living cells and tissues. PMID- 27510430 TI - TRPV4 regulates calcium homeostasis, cytoskeletal remodeling, conventional outflow and intraocular pressure in the mammalian eye. AB - An intractable challenge in glaucoma treatment has been to identify druggable targets within the conventional aqueous humor outflow pathway, which is thought to be regulated/dysregulated by elusive mechanosensitive protein(s). Here, biochemical and functional analyses localized the putative mechanosensitive cation channel TRPV4 to the plasma membrane of primary and immortalized human TM (hTM) cells, and to human and mouse TM tissue. Selective TRPV4 agonists and substrate stretch evoked TRPV4-dependent cation/Ca(2+) influx, thickening of F actin stress fibers and reinforcement of focal adhesion contacts. TRPV4 inhibition enhanced the outflow facility and lowered perfusate pressure in biomimetic TM scaffolds populated with primary hTM cells. Systemic delivery, intraocular injection or topical application of putative TRPV4 antagonist prodrug analogs lowered IOP in glaucomatous mouse eyes and protected retinal neurons from IOP-induced death. Together, these findings indicate that TRPV4 channels function as a critical component of mechanosensitive, Ca(2+)-signaling machinery within the TM, and that TRPV4-dependent cytoskeletal remodeling regulates TM stiffness and outflow. Thus, TRPV4 is a potential IOP sensor within the conventional outflow pathway and a novel target for treating ocular hypertension. PMID- 27510434 TI - Super non-linear RRAM with ultra-low power for 3D vertical nano-crossbar arrays. AB - Vertical crossbar arrays provide a cost-effective approach for high density three dimensional (3D) integration of resistive random access memory. However, an individual selector device is not allowed to be integrated with the memory cell separately. The development of V-RRAM has impeded the lack of satisfactory self selective cells. In this study, we have developed a high performance bilayer self selective device using HfO2 as the memory switching layer and a mixed ionic and electron conductor as the selective layer. The device exhibits high non-linearity (>10(3)) and ultra-low half-select leakage (<0.1 pA). A four layer vertical crossbar array was successfully demonstrated based on the developed self selective device. High uniformity, ultra-low leakage, sub-nA operation, self compliance, and excellent read/write disturbance immunity were achieved. The robust array level performance shows attractive potential for low power and high density 3D data storage applications. PMID- 27510433 TI - Risk factors for severe clinical events in male and female patients with Fabry disease treated with agalsidase beta enzyme replacement therapy: Data from the Fabry Registry. AB - BACKGROUND: Fabry disease, an X-linked lysosomal storage disorder, causes intracellular accumulation of glycosphingolipids leading to progressive renal, cardiovascular, and cerebrovascular disease, and premature death. METHODS: This longitudinal Fabry Registry study analyzed data from patients with Fabry disease to determine the incidence and type of severe clinical events following initiation of enzyme replacement therapy (ERT) with agalsidase beta, as well as risk factors associated with occurrence of these events. Severe events assessed included chronic dialysis, renal transplantation, cardiac events, stroke, and death. RESULTS: The analyses included 969 male and 442 female Fabry patients. The mean age at first agalsidase beta infusion was 35 and 44, and median treatment follow-up 4.3years and 3.2years, respectively. Among males, cardiac events were the most common on-ERT events, followed by renal, stroke, and non-cardiac death. Among females, cardiac events were also most common followed by stroke and renal events. Patients with on-ERT events had significantly more advanced cardiac and renal disease at baseline as compared with patients without on-ERT events. Severe events were also associated with older age at ERT initiation (males and females), a history of pre-ERT events (females; approaching statistical significance in males), and a higher urinary protein/creatinine ratio (females). Approximately 65% of patients with pre-ERT events did not experience subsequent on-ERT events. Of patients without pre-ERT events, most (84% of males, 92% of females) remained event-free. CONCLUSIONS: Patients with on-ERT severe events had more advanced Fabry organ involvement at baseline than those without such events and patients who initiated ERT at a younger age had less residual risk of on-ERT events. The observed patterns of residual risk may aid clinicians in multidisciplinary monitoring of male and female patients with Fabry disease receiving ERT, and in determining the need for administration of adjunctive therapies. PMID- 27510435 TI - Direct-write liquid phase transformations with a scanning transmission electron microscope. AB - The highly energetic electron beam (e-beam) in a scanning transmission electron microscope (STEM) can induce local changes in the state of matter, ranging from knock-on and atomic movement, to amorphization/crystallization, and to localized chemical/electrochemical reactions. To date, fundamental studies of e-beam induced phenomena and practical applications have been limited by conventional STEM e-beam rastering modes that allow only for uniform e-beam exposures. Here, an automated liquid phase nanolithography method has been developed that enables the direct writing of nanometer scaled features within microfabricated liquid cells. An external e-beam control system, connected to the scan coils of an aberration-corrected STEM, is used to precisely control the position, dwell time, and scan rate of a sub-nanometer STEM probe. Site-specific locations in a sealed liquid cell containing an aqueous solution of H2PdCl4 are irradiated to deposit palladium nanocrystals onto silicon nitride membranes in a highly controlled manner. The threshold electron dose required for the radiolytic deposition of metallic palladium has been determined, the influence of electron dose on the nanolithographically patterned feature size and morphology is explored, and a feedback-controlled monitoring method for active control of the nanofabricated structures through STEM detector signal monitoring is proposed. This approach enables fundamental studies of electron beam induced interactions with matter in liquid cells and opens new pathways to fabricate nanostructures with tailored architectures and chemistries via shape-controlled nanolithographic patterning from liquid-phase precursors. PMID- 27510436 TI - Ionic Liquid Induced Band Shift of Titanium Dioxide. AB - Ionic liquids (ILs) have become an established option for the use as electrolytes in dye-sensitized solar cells. In the present study, the adsorption of a multitude of different ILs on a TiO2 surface is studied systematically, focusing on the energetic modifications of the semiconductor. The cation was found to generally cause an energetic downward shift of the TiO2 band levels by accepting electron density from the surface, and the anions were observed to function in the opposite direction, raising the energy levels by donating electron density. Both effects counterbalance each other, leaving the desired outcome dependent on the choice of the specific IL, i.e., the choice of the cation/anion combination. The correlation of the band levels with the properties of the IL was successfully achieved. The dipole moment of the adsorbed ionic liquid species showed little to no correlation with the semiconductor energetics, but the charge transfer calculated by radical Voronoi tessellation revealed a high correlation. The current findings contribute to a deeper understanding of the role of the electrolyte in dye-sensitized solar cells, and ILs in general, and help with choosing and tuning of the electrolyte solutions in existing applications. PMID- 27510437 TI - Melatonin prevents radiation-induced oxidative stress and periodontal tissue breakdown in irradiated rats with experimental periodontitis. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to analyze the biochemical and histochemical effects of radiation therapy and protective melatonin administration on periodontal tissues in rats with experimental periodontitis. MATERIAL AND METHODS: Sixty male Sprague Dawley rats were divided into six groups, as follows: control; experimental periodontitis (Ped); radiotherapy administration (Rt); experimental periodontitis and exposure to irradiation (Ped Rt); radiotherapy and protective melatonin administration (Rt-Mel); and periodontitis, radiation therapy and protective melatonin administration (Ped-Rt Mel). The rats were killed at the end of the experimental procedure, and the oxidative stress level and periodontal destruction were compared among the groups. RESULTS: The oxidative stress index and the levels of 8-hydroxy-2' deoxyguanosine, malondialdehyde and C-terminal telopeptide of type I collagen were found to be significantly higher in the Ped-Rt group compared with the Ped group (p < 0.05), and the levels were lower in the Ped-Rt-Mel group than in the Ped-Rt group (p < 0.05). Alveolar bone destruction and attachment level were also significantly lower in the Ped-Rt-Mel group than in the Ped-Rt group (p < 0.05). CONCLUSION: It was found that radiotherapy increased oxidative stress, the periodontal attachment level and alveolar bone loss, and protective melatonin administration significantly reduced the oxidative parameters and prevented periodontal damage in irradiated rats with experimental periodontitis. Further research is needed regarding the use of systemic melatonin administration before radiation therapy. PMID- 27510438 TI - Biatrial thrombi resembling myxoma regressed after prolonged anticoagulation in a patient with mitral stenosis: a case report. AB - BACKGROUND: Many cases of cardiac masses have been reported in the literature, but in this case report we described a rare case of biatrial cardiac mass that represented a challenge for diagnosis and therapy. The differentiation between cardiac masses such as thrombi, vegetations, myxomas and other tumors is not always straightforward and an exact diagnosis is important because of its distinct treatment strategy. Transthoracic/esophageal echocardiography and cardiac magnetic resonance play an important role in establishing the diagnosis of cardiac masses. However, no current noninvasive diagnostic tool has the ability to absolutely diagnose cardiac masses; obtaining a pathological specimen by surgical resection of cardiac masses is the only reliable method to diagnose cardiac masses accurately. Our case report is an exception in that the final diagnosis was affirmed by empirical anticoagulation therapy based on clinical judgment and noninvasive characterization of biatrial mass. CASE PRESENTATION: We described a 54-year-old Malay man with severe mitral stenosis and atrial fibrillation who presented with a biatrial mass. Transthoracic/esophageal echocardiography and cardiac magnetic resonance detected a large, homogeneous right atrial mass typical of a thrombus, and a left atrial mass adhering to interatrial septum that mimicked atrial myxoma. The risk factors, morphology, location, and characteristics of the biatrial cardiac mass indicated a diagnosis of thrombi. However, our patient declined surgery. As a result, the nature of his cardiac masses was not specified by histology. Of note, his left atrial mass was completely regressed by long-term warfarin, leaving a residual right atrial mass. Thus, we affirmed the most probable diagnosis of cardiac thrombi. During the course of treatment, he had an episode of non-fatal ischemic stroke most probably because of a thromboembolism. CONCLUSIONS: Noninvasive characterization of cardiac mass is essential in clarifying the diagnosis and directing treatment strategy. Anticoagulation is a feasible treatment when the clinical assessment, risk factors, and imaging findings indicate a diagnosis of thrombi. After prolonged anticoagulation therapy, complete resolution of biatrial thrombi was achievable in our case. PMID- 27510439 TI - Temper Loss and Persistent Irritability in Preschoolers: Implications for Diagnosing Disruptive Mood Dysregulation Disorder in Early Childhood. AB - Disruptive Mood Dysregulation Disorder (DMDD) is a new and controversial child psychiatric disorder characterized by persistent irritability and frequent temper loss. Among the controversies surrounding DMDD is whether the age of onset criterion-that DMDD may not be diagnosed before age 6 years-is justified. This study examined DMDD symptoms and associated patterns of psychiatric comorbidity, behavioral, and family functioning in a sample of 139 preschoolers (ages 4-0 to 5 11 years) admitted to an early childhood psychiatric day treatment program. DMDD symptoms were common in this acute clinical sample, with 63 children (45.3 %) presenting with frequent temper outbursts and chronic irritability. As compared to children who did not present with DMDD symptoms, these children demonstrated more aggression and emotional reactivity and lower receptive language skills, with high rates of comorbidity with the disruptive behavior disorders. Findings contribute to an emerging literature on preschool DMDD, with implications for early childhood psychiatric assessment and clinical interventions. PMID- 27510440 TI - Can't Stand the Pressure: The Association Between Unprotected Standing, Walking, and Wound Healing in People With Diabetes. AB - OBJECTIVE: The objective was to report patterns of physical activity and their relationship to wound healing success in patients with diabetic foot ulcers protected with removable or irremovable offloading devices. METHODS: Forty-nine people with diabetic foot ulcers were randomized to wear either a removable cast walker (RCW) or an irremovable instant total contact cast (iTCC). Primary outcome measures included change in wound size, physical activities including position (ie, sitting, standing, lying) and locomotion (speed, steps, etc). Outcomes parameters were assessed on weekly basis until wound healing or until 12 weeks. RESULTS: A higher proportion of patients healed at 12 weeks in the iTCC group ( P = .038). Significant differences in activity were observed between groups starting at week 4. RCW patients became more active than the iTCC group (75% higher duration of standing, 100% longer duration of walking, and 126% longer unbroken walking bout, P < .05). Overall, there was an inverse association between rate of weekly wound healing and number of steps taken per day ( r < .33, P < .05) for both groups. RCW patients had a significant inverse correlation between duration of daily standing and weekly rate of healing ( r = -.67, P < .05). Standing duration was the only significant predictor of healing at 12 weeks. CONCLUSION: The results from this study suggest significant differences in activity patterns between removable and irremovable offloading devices. These patterns appear to start diverging at week 4, which may indicate a decline in adherence to offloading. Results suggest that while walking may delay wound healing, unprotected standing might be an even more unrealized and sinister culprit. PMID- 27510441 TI - Description of a New Predictive Modeling Approach That Correlates the Risk and Associated Cost of Well-Defined Diabetes-Related Complications With Changes in Glycated Hemoglobin (HbA1c). AB - The modeling approach described here is designed to support the development of spreadsheet-based simple predictive models. It is based on 3 pillars: association of the complications with HbA1c changes, incidence of the complications, and average cost per event of the complication. For each pillar, the goal of the analysis was (1) to find results for a large diversity of populations with a focus on countries/regions, diabetes type, age, diabetes duration, baseline HbA1c value, and gender; (2) to assess the range of incidences and associations previously reported. Unlike simple predictive models, which mostly are based on only 1 source of information for each of the pillars, we conducted a comprehensive, systematic literature review. Each source found was thoroughly reviewed and only sources meeting quality expectations were considered. The approach allows avoidance of unintended use of extreme data. The user can utilize (1) one of the found sources, (2) the found range as validation for the found figures, or (3) the average of all found publications for an expedited estimate. The modeling approach is intended for use in average insulin-treated diabetes populations in which the baseline HbA1c values are within an average range (6.5% to 11.5%); it is not intended for use in individuals or unique diabetes populations (eg, gestational diabetes). Because the modeling approach only considers diabetes-related complications that are positively associated with HbA1c decreases, the costs of negatively associated complications (eg, severe hypoglycemic events) must be calculated separately. PMID- 27510442 TI - Real-World Use of Open Source Artificial Pancreas Systems. PMID- 27510443 TI - SPECTRUM. AB - BACKGROUND: Optimal usage of continuous glucose monitoring (CGM) requires adequate training of the users. Providing patients with a CGM system without such a training usually doesn't lead to the intended improvement in metabolic control. METHODS: In Germany we developed a structured training program ("SPECTRUM") to ensure a high quality standard for the use of CGM systems. RESULTS: This program is suitably for patients of all age groups and is applicable to all CGM systems and all forms of insulin therapy. A curriculum was also developed so that training centers with less experience with CGM could become capable of offering comprehensive CGM training. CONCLUSIONS: We believe that usage of such a program can be an important step forward in achieving more widespread acceptance and use of CGM systems. Translations in other languages and evaluation with a controlled clinical trial are planned. PMID- 27510444 TI - Microvascular hemodynamics in the chick chorioallantoic membrane. AB - OBJECTIVE: The microvasculature of the CAM in the developing chick embryo is characterized by interdigitating arteriolar and venular trees, connected at multiple points along their lengths to a mesh-like capillary plexus. Theoretical modeling techniques were employed to investigate the resulting hemodynamic characteristics of the CAM. METHODS: Based on previously obtained anatomical data, a model was developed in which the capillary plexus was treated as a porous medium. Supply of blood from arterioles and drainage into venules were represented by distributions of flow sources and sinks. Predicted flow velocities were compared with measurements in arterioles and venules obtained via video microscopy. RESULTS: If it was assumed that blood flowed into and out of the capillary plexus only at the ends of terminal arterioles and venules, the predicted velocities increased with decreasing diameter in vessels below 50 MUm in diameter, contrary to the observations. Distributing sources/sinks along arterioles/venules led to velocities consistent with the data. CONCLUSIONS: These results imply that connections to the capillary plexus distributed along the arterioles and venules strongly affect the hemodynamic characteristics of the CAM. The theoretical model provides a basis for quantitative simulations of structural adaptation in CAM networks in response to hemodynamic stimuli. PMID- 27510445 TI - Biomedical event trigger detection by dependency-based word embedding. AB - BACKGROUND: In biomedical research, events revealing complex relations between entities play an important role. Biomedical event trigger identification has become a research hotspot since its important role in biomedical event extraction. Traditional machine learning methods, such as support vector machines (SVM) and maxent classifiers, which aim to manually design powerful features fed to the classifiers, depend on the understanding of the specific task and cannot generalize to the new domain or new examples. METHODS: In this paper, we propose an approach which utilizes neural network model based on dependency-based word embedding to automatically learn significant features from raw input for trigger classification. First, we employ Word2vecf, the modified version of Word2vec, to learn word embedding with rich semantic and functional information based on dependency relation tree. Then neural network architecture is used to learn more significant feature representation based on raw dependency-based word embedding. Meanwhile, we dynamically adjust the embedding while training for adapting to the trigger classification task. Finally, softmax classifier labels the examples by specific trigger class using the features learned by the model. RESULTS: The experimental results show that our approach achieves a micro-averaging F1 score of 78.27 and a macro-averaging F1 score of 76.94 % in significant trigger classes, and performs better than baseline methods. In addition, we can achieve the semantic distributed representation of every trigger word. PMID- 27510446 TI - Accurate and consistent automatic seismocardiogram annotation without concurrent ECG. AB - Seismocardiography (SCG) is the measurement of vibrations in the sternum caused by the beating of the heart. Precise cardiac mechanical timings that are easily obtained from SCG are critically dependent on accurate identification of fiducial points. So far, SCG annotation has relied on concurrent ECG measurements. An algorithm capable of annotating SCG without the use any other concurrent measurement was designed. We subjected 18 participants to graded lower body negative pressure. We collected ECG and SCG, obtained R peaks from the former, and annotated the latter by hand, using these identified peaks. We also annotated the SCG automatically. We compared the isovolumic moment timings obtained by hand to those obtained using our algorithm. Mean +/- confidence interval of the percentage of accurately annotated cardiac cycles were [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text] for levels of negative pressure 0, -20, -30, -40, and -50 mmHg. LF/HF ratios, the relative power of low-frequency variations to high-frequency variations in heart beat intervals, obtained from isovolumic moments were also compared to those obtained from R peaks. The mean differences +/- confidence interval were [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], and [Formula: see text] for increasing levels of negative pressure. The accuracy and consistency of the algorithm enables the use of SCG as a stand-alone heart monitoring tool in healthy individuals at rest, and could serve as a basis for an eventual application in pathological cases. PMID- 27510447 TI - Kicking the tyres of a heart failure trial: physician response to the approval of sacubitril/valsartan in the USA. AB - Angiotensin receptor-neprilysin inhibition has been shown to be superior to target doses of an ACE inhibitor in reducing the risk of cardiovascular death and clinical disease progression in patients with chronic heart failure and a reduced EF. Nevertheless, although sacubitril/valsartan has been available in the USA for a year, uptake of the drug by practitioners has been slow, in part because of misconceptions about the pivotal trial that demonstrated its efficacy in heart failure (PARADIGM-HF). This review addresses questions that have been raised in the USA about the design of the trial as well as the patients who were studied, the replicability and applicability of the results, and the safety of neprilysin inhibition. The totality of evidence indicates that the PARADIGM-HF trial used an appropriate comparator; enrolled patients typical of those seen in the community with mild to moderate symptoms; yielded highly persuasive and replicable results; and demonstrated benefits that are applicable to patients taking subtarget doses of ACE inhibitors and ARBs. Regulatory review in the USA concluded that the established advantages of sacubitril/valsartan on cardiovascular death and disease progression outweighed hypothetical uncertainties about the long-term effects of neprilysin inhibition in patients who might not have survived without the drug. Accordingly, both the new US and European Society of Cardiology heart failure guidelines recommend sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in patients with chronic heart failure who are currently receiving an ACE inhibitor or ARB. PMID- 27510448 TI - CircRNA-protein complexes: IMP3 protein component defines subfamily of circRNPs. AB - Circular RNAs (circRNAs) constitute a new class of noncoding RNAs in higher eukaryotes generated from pre-mRNAs by alternative splicing. Here we investigated in mammalian cells the association of circRNAs with proteins. Using glycerol gradient centrifugation, we characterized in cell lysates circRNA-protein complexes (circRNPs) of distinct sizes. By polysome-gradient fractionation we found no evidence for efficient translation of a set of abundant circRNAs in HeLa cells. To identify circRNPs with a specific protein component, we focused on IMP3 (IGF2BP3, insulin-like growth factor 2 binding protein 3), a known tumor marker and RNA-binding protein. Combining RNA-seq analysis of IMP3-co-immunoprecipitated RNA and filtering for circular-junction reads identified a set of IMP3-associated circRNAs, which were validated and characterized. In sum, our data suggest that specific circRNP families exist defined by a common protein component. In addition, this provides a general approach to identify circRNPs with a given protein component. PMID- 27510449 TI - Increased serum levels of vascular endothelial growth factor in pemphigus foliaceus patients with erythroderma. AB - BACKGROUND: Erythroderma is a clinical skin syndrome shared by patients with cutaneous disorders of distinct aetiologies as a result of the combined actions of chemokines, adhesion molecules, and cytokines, such as vascular endothelial growth factor (VEGF). OBJECTIVE: To evaluate the profile of serum levels of VEGF and soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) in pemphigus foliaceus (PF) patients with erythroderma. METHODS: We conducted a retrospective study, which included (i) a chart review of all PF patients from the Autoimmune Blistering Clinic, University of Sao Paulo, Brazil, from January 1991 to December 2014, together with an evaluation of demographic variables, hospitalization duration and complications and (ii) analysis of the circulating VEGF and sVEGFR-1 levels in PF patients with erythroderma by ELISA. The controls included patients with pemphigus vulgaris or psoriasis. RESULTS: We observed higher serum VEGF levels in PF patients during erythroderma than during the non-erythrodermic phase. PF patients showed increased serum levels of sVEGFR-1 during the erythrodermic phase in comparison to controls. Interestingly, the sVEGFR-1 and antidesmoglein-1 levels were positively correlated during the non-erythrodermic period. CONCLUSION: Erythroderma, which represents one clinical form of PF, implies more severe outcomes. The circulating levels of VEGF, a potent endothelial activator, are increased in PF patients with erythroderma; this result suggests the contribution of the blood vessel endothelium to the pathogenesis of this clinical syndrome. Interestingly, our findings showed a positive correlation between the sVEGFR-1 and antidesmoglein-1 antibody levels, indicating a suppressive response to VEGF augmentation during the erythrodermic phase of PF. PMID- 27510450 TI - Epidermal growth factor receptor expression is associated with poor outcome in cutaneous squamous cell carcinoma. AB - BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans after basal cell carcinoma, and its incidence is dramatically rising. CSCC is rarely problematic, but given its high frequency, the absolute number of complicated cases is also high. It is necessary to identify molecular markers in order to recognize those CSCCs with poor prognosis. There is controversy concerning the role of epidermal growth factor receptor (EGFR) as a marker of prognosis in CSCC. In addition, EGFR-targeted therapies have emerged in recent years and a better understanding of the role of EGFR in CSCC may be of help for some patients in predicting prognosis and guiding curative management. OBJECTIVES: To evaluate the role of EGFR as a prognostic factor in CSCC. METHODS: We evaluated clinical and histopathological features, including events of poor clinical evolution, in a series of 94 cases of CSCC. We also analysed EGFR expression by immunohistochemistry, fluorescent in situ hybridization and quantitative polymerase chain reaction. RESULTS: We detected EGFR in 85 cases (90%), with overexpression in 33 cases (35%), and aberrant EGFR expression in the cytoplasm in 50 cases (53%). EGFR overexpression in the primary tumours was associated with lymph node progression, tumour-nodes-metastasis stage progression and proliferation (Ki-67 staining) in CSCC. EGFR overexpression and poor grade of differentiation were the strongest independent variables defining lymph node metastasis and progression in CSCC in a logistic regression model. CONCLUSIONS: We demonstrate that EGFR overexpression has prognostic implications associated with lymph node metastasis and progression in CSCC. PMID- 27510452 TI - Supportive Care: Time to Change Our Prognostic Tools and Their Use in CKD. AB - In using a patient-centered approach, neither a clinician nor a prognostic score can predict with absolute certainty how well a patient will do or how long he will live; however, validated prognostic scores may improve accuracy of prognostic estimates, thereby enhancing the ability of the clinicians to appreciate the individual burden of disease and the prognosis of their patients and inform them accordingly. They may also facilitate nephrologist's recommendation of dialysis services to those who may benefit and proposal of alternative care pathways that might better respect patients' values and goals to those who are unlikely to benefit. The purpose of this article is to discuss the use as well as the limits and deficiencies of currently available prognostic tools. It will describe new predictors that could be integrated in future scores and the role of patients' priorities in development of new scores. Delivering patient-centered care requires an understanding of patients' priorities that are important and relevant to them. Because of limits of available scores, the contribution of new prognostic tools with specific markers of the trajectories for patients with CKD and patients' health reports should be evaluated in relation to their transportability to different clinical and cultural contexts and their potential for integration into the decision-making processes. The benefit of their use then needs to be quantified in clinical practice by outcome studies including health-related quality of life, patient and caregiver satisfaction, or utility for improving clinical management pathways and tailoring individualized patient-centered strategies of care. Future research also needs to incorporate qualitative methods involving patients and their caregivers to better understand the barriers and facilitators to use of these tools in the clinical setting. Information given to patients should be supported by a more realistic approach to what dialysis is likely to entail for the individual patient in terms of likely quality and quantity of life according to the patient's values and goals and not just the possibility of life prolongation. PMID- 27510453 TI - Supportive Care: Comprehensive Conservative Care in End-Stage Kidney Disease. AB - Comprehensive conservative (nondialytic) kidney care is widely recognized and delivered but until recently, has not been clearly defined. We provide a clear definition of comprehensive conservative care. This includes interventions to delay progression of kidney disease and minimize complications as well as detailed communication, shared decision making, advance care planning, and psychologic and family support. It does not include dialysis. Limited epidemiologic evidence from Australia and Canada indicates that, for every new person diagnosed with ESRD who receives dialysis or transplant, there is one new person who is managed conservatively (either actively or not). For older patients (those >75 or 80 years old) who have higher levels of comorbidity (such as diabetes and heart disease) and poorer functional status, the survival advantage of dialysis may be limited, and comprehensive conservative management may be considered; however, robust comparative evidence remains limited. Considerations of symptoms, quality of life, and hospital-free days are as or sometimes more important for patients and families than survival. There is some evidence that communication about possible conservative management options is generally insufficient, even where comprehensive conservative care pathways are already established. Symptom control and the cost-effectiveness of interventions are addressed in the companion papers within this Moving Points in Nephrology series. There is almost no evidence about which models of care and which interventions might be most beneficial in this population; future research on these areas is much needed. Meanwhile, consistency in definition of comprehensive conservative care and basing interventions on existing evidence about survival, symptoms, quality of life, and experience will maximize patient-centered and holistic care. PMID- 27510454 TI - Supportive Care: Integration of Patient-Centered Kidney Care to Manage Symptoms and Geriatric Syndromes. AB - Dialysis care is often associated with poor outcomes including low quality of life (QOL). To improve patient-reported outcomes, incorporation of the patient's needs and perspective into the medical care they receive is essential. This article provides a framework to help clinicians integrate symptom assessment and other measures such as QOL and frailty scores into a clinical approach to the contemporary supportive care of patients with advanced CKD. This approach involves (1) defining our understanding of kidney supportive care, patient centered dialysis, and palliative dialysis; (2) understanding and recognizing common symptoms associated with advanced CKD; (3) discussing the concepts of physical function, frailty, and QOL and their role in CKD; and (4) identifying the structural and process barriers that may arise when patient-centered dialysis is being introduced into clinical practice. PMID- 27510455 TI - Supportive Care: Economic Considerations in Advanced Kidney Disease. AB - Kidney supportive care describes multiple interventions for patients with advanced CKD that focus on improving the quality of life and addressing what matters most to patients. This includes shared decision making and aligning treatment plans with patient goals through advance care planning and providing relief from pain and other distressing symptoms. Kidney supportive care is an essential component of quality care throughout the illness trajectory. However, in the context of limited health care resources, evidence of its cost effectiveness is required to support decisions regarding appropriate resource allocation. We review the literature and outline the evidence gaps and particular issues associated with measuring the costs, benefits, and cost-effectiveness of kidney supportive care. We find evidence that the dominant evaluative framework of a cost per quality-adjusted life year may not be suitable for evaluations in this context and that relevant outcomes may include broader measures of patient wellbeing, having care aligned with treatment preferences, and family satisfaction with the end of life care experience. To improve the evidence base for the cost-effectiveness of kidney supportive care, large prospective cohort studies are recommended to collect data on both resource use and health outcomes and should include patients who receive conservative kidney management without dialysis. Linkage to administrative datasets, such as Medicare, Hospital Episode Statistics, and the Pharmaceutical Benefits Scheme for prescribed medicines, can provide a detailed estimate of publicly funded resource use and reduce the burden of data collection for patients and families. Longitudinal collection of quality of life and functional status should be added to existing cohort or kidney registry studies. Interventions that improve health outcomes for people with advanced CKD, such as kidney supportive care, not only have the potential to improve quality of life, but also may reduce the high costs associated with unwanted hospitalization and intensive medical treatments. PMID- 27510457 TI - Structural mechanics and helical geometry of thin elastic composites. AB - Helices are ubiquitous in nature, and helical shape transition is often observed in residually stressed bodies, such as composites, wherein materials with different mechanical properties are glued firmly together to form a whole body. Inspired by a variety of biological examples, the basic physical mechanism responsible for the emergence of twisting and bending in such thin composite structures has been extensively studied. Here, we propose a simplified analytical model wherein a slender membrane tube undergoes a helical transition driven by the contraction of an elastic ribbon bound to the membrane surface. We analytically predict the curvature and twist of an emergent helix as functions of differential strains and elastic moduli, which are confirmed by our numerical simulations. Our results may help understand shapes observed in different biological systems, such as spiral bacteria, and could be applied to novel designs of soft machines and robots. PMID- 27510456 TI - Supportive Care: Communication Strategies to Improve Cultural Competence in Shared Decision Making. AB - Historic migration and the ever-increasing current migration into Western countries have greatly changed the ethnic and cultural patterns of patient populations. Because health care beliefs of minority groups may follow their religion and country of origin, inevitable conflict can arise with decision making at the end of life. The principles of truth telling and patient autonomy are embedded in the framework of Anglo-American medical ethics. In contrast, in many parts of the world, the cultural norm is protection of the patient from the truth, decision making by the family, and a tradition of familial piety, where it is dishonorable not to do as much as possible for parents. The challenge for health care professionals is to understand how culture has enormous potential to influence patients' responses to medical issues, such as healing and suffering, as well as the physician-patient relationship. Our paper provides a framework of communication strategies that enhance crosscultural competency within nephrology teams. Shared decision making also enables clinicians to be culturally competent communicators by providing a model where clinicians and patients jointly consider best clinical evidence in light of a patient's specific health characteristics and values when choosing health care. The development of decision aids to include cultural awareness could avoid conflict proactively, more productively address it when it occurs, and enable decision making within the framework of the patient and family cultural beliefs. PMID- 27510458 TI - Visualization of the Intimal Flap in Intracranial Arterial Dissection Using High Resolution 3T MRI. AB - BACKGROUND AND PURPOSE: Presence of an intimal flap is a critical imaging finding in diagnosing intracranial artery dissection (ICAD). Recent reports showed that high-resolution magnetic resonance imaging (MRI) was better at identifying intimal flaps as compared with routine MRI techniques used in clinical settings. However, no current standardized sequence for high-resolution MRI without gadolinium enhancement produces images of satisfactory quality with clinically tolerable scanning times. This study evaluated a nonenhanced high-resolution fast spin echo (HR-FSE) MRI sequence for visualizing intimal flaps in patients with ICAD. SUBJECTS AND METHODS: Three patients with ICAD underwent plain MRI examination using a 2-dimensional T2-weighted FSE imaging sequence optimized for our 3T system (in-plane pixel size, .23 mm * .23 mm; slice thickness 3 mm with no interslice gap), as well as scanning with conventional modalities, including CT angiography, magnetic resonance angiography, and digital subtraction angiography. We assessed whether these imaging methods could visualize an intimal flap and/or double lumen sign in the participants and compared the results between HR-FSE and the other modalities. RESULTS: HR-FSE images clearly showed intimal flaps and double lumen signs in all 3 patients, whereas the conventional modalities identified a double lumen sign in only 2 of the 3 patients. CONCLUSIONS: The present method of optimized HR-FSE imaging with a 3T system improved visualization of intimal flaps and should thus be considered for assessing patients with suspected ICAD that cannot be definitively diagnosed by conventional imaging modalities. PMID- 27510459 TI - Reprogramming A375 cells to induced-resembled neuronal cells by structured overexpression of specific transcription genes. AB - Induced-resembled neuronal cells (irNCs) are generated by reprogramming human melanoma cells through the introduction of key transcription factors, providing novel concepts in the treatment of malignant tumor cells and making it possible to supply neural cells for laboratory use. In the present study, irNCs were derived from A375 cells by inducing the 'forced' overexpression of specific genes, including achaete-scute homolog 1 (Ascl1), neuronal differentiation factor 1 (Neurod1), myelin transcription factor 1 (Myt1), brain protein 2 (Brn2, also termed POU3F2) and human brain-derived neurotrophic factor (h-BDNF). irNCs induced from A375 cells express multiple neuronal markers and fire action potentials, exhibiting properties similar to those of motor neurons. The reprogramming procedure comprised reverse transcription-polymerase chain reaction and immunofluorescence staining; furthermore, electrophysiological profiling demonstrated the characteristics of the induced-resembled neurons. The present study obtained a novel type of human irNC from human melanoma, which secreted BDNF continuously, providing a model for neuron-like cells. Thus, irNCs offer promise in investigating various neural diseases by using neural-like cells derived directly from the patient of interest. PMID- 27510460 TI - Bis(allyl)-ruthenium(iv) complexes with phosphinous acid ligands as catalysts for nitrile hydration reactions. AB - Several mononuclear ruthenium(iv) complexes with phosphinous acid ligands [RuCl2(eta(3):eta(3)-C10H16)(PR2OH)] have been synthesized (78-86% yield) by treatment of the dimeric precursor [{RuCl(MU-Cl)(eta(3):eta(3)-C10H16)}2] (C10H16 = 2,7-dimethylocta-2,6-diene-1,8-diyl) with 2 equivalents of different aromatic, heteroaromatic and aliphatic secondary phosphine oxides R2P([double bond, length as m-dash]O)H. The compounds [RuCl2(eta(3):eta(3)-C10H16)(PR2OH)] could also be prepared, in similar yields, by hydrolysis of the P-Cl bond in the corresponding chlorophosphine-Ru(iv) derivatives [RuCl2(eta(3):eta(3)-C10H16)(PR2Cl)]. In addition to NMR and IR data, the X-ray crystal structures of representative examples are discussed. Moreover, the catalytic behaviour of complexes [RuCl2(eta(3):eta(3)-C10H16)(PR2OH)] has been investigated for the selective hydration of organonitriles in water. The best results were achieved with the complex [RuCl2(eta(3):eta(3)-C10H16)(PMe2OH)], which proved to be active under mild conditions (60 degrees C), with low metal loadings (1 mol%), and showing good functional group tolerance. PMID- 27510461 TI - Silencing KRAS Overexpression in Cadmium-Transformed Prostate Epithelial Cells Mitigates Malignant Phenotype. AB - Cadmium (Cd) is a potential human prostate carcinogen. Chronic Cd exposure malignantly transforms RWPE-1 human prostate epithelial cells into CTPE cells by an unclear mechanism. Previous studies show that RWPE-1 can also be malignantly transformed by arsenic, and KRAS activation is key to causation and maintenance of this phenotype. Although Cd and arsenic can both transform prostate epithelial cells, it is uncertain whether their mechanisms are similar. Thus, here we determined whether KRAS activation is critical in causing and maintaining Cd induced malignant transformation in CTPE cells. Expression of KRAS, miRNAs, and other genes of interest was analyzed by Western blot and RT-PCR. Following stable KRAS knockdown (KD) by RNA interference using shRNAmir, the malignant phenotype was assessed by various physical and genetic parameters. CTPE cells greatly overexpressed KRAS by 20-fold, indicating a likely role in Cd transformation. Thus, we attempted to reverse the malignant phenotype via KRAS KD. Two weeks after shRNAmir transduction, KRAS protein was undetectable in CTPE KD cells, confirming stable KD. KRAS KD reduced stimulated RAS/ERK and PI3K/AKT signaling pathways and markedly mitigated multiple physical and molecular malignant cell characteristics including: hypersecretion of MMP-2, colony formation, cell survival, and expression of cancer-relevant genes (reduced proliferation and cell cycle-related genes; activated tumor suppressor PTEN). However, KRAS KD did not reverse miRNA expression originally down-regulated by Cd transformation. These data strongly suggest KRAS is a key gene in development and maintenance of the Cd induced malignant phenotype, at least in the prostate. It is not, however, the only genetic factor sustaining this phenotype. PMID- 27510462 TI - Validation of RPS13 as a reference gene for absolute quantification of SIV RNA in tissue of rhesus macaques. AB - Persistent HIV reservoirs and the absolute quantification of viral RNA copies in tissues have become a prominent focus of multiple areas ofHIV/SIV research. Absolute quantification of viral RNA via reverse transcription, quantitative PCR (RT-qPCR) necessitates the use of an appropriate RNA reference gene whose expression is unaffected by both experimental and confounding conditions. In this study, we demonstrate the utility of ribosomal protein S13 mRNA (RPS13) as a stable, medium abundance reference gene for RT-qPCR normalization of HIV/SIV RNA copy number. We developed a RPS13 RNA standard assay utilizing an in vitro RNA transcript for normalization of absolute SIV RNA quantities in tissues reservoirs. The RT-qPCR assay showed a high degree of repeatability and reproducibility across RNA levels appropriate for absolute SIV quantification. In assessing the utility of RPS13 as a reference gene, limited variation in the absolute, inter-tissue quantities of RPS13 mRNA was observed within multiple tissue samples obtained from rhesus macaques (average CV=2.86%). We demonstrate rhesus macaque RPS13 mRNA expression is not affected by alcohol administration, SIV infection, or antiviral therapy (PMPA/FTC). Additionally, assay functionality was validated for normalization of SIV copy number using cellular RNA prepared from samples of variable RNA integrity. RPS13 is a suitable reference gene for normalization of absolute SIV RNA quantities in tissues and is most appropriate for intra-tissue or similar tissue type comparisons of SIV copy number. PMID- 27510463 TI - Same-day discharge after craniotomy for supratentorial tumour surgery: a retrospective observational single-centre study. AB - PURPOSE: Enhanced Recovery After Surgery is a multimodal perioperative care pathway designed to achieve early discharge in patients undergoing major surgery. Recent advances in neurosurgery allow for shorter duration of anesthesia and surgery, faster recovery, and earlier discharge from hospital. The purpose of this retrospective observational study was to assess the incidence of early discharge from hospital in patients undergoing craniotomy for supratentorial brain tumours as well as to explore the associated perioperative factors, anesthesia techniques, and complications. METHODS: The medical records of all patients who underwent craniotomy (less than four-hour duration) for supratentorial tumour over a five-year period were retrospectively reviewed. The data analyzed included the postoperative discharge destination, type of anesthesia-i.e., general anesthesia (GA) vs awake craniotomy (AC), and the incidence of adverse events. RESULTS: Data from 329 patients [mean (SD) age 48 (12) yr; 164 male, 165 female] were analyzed, including 198 (AC, n = 157; GA, n = 41) patients who were preoperatively scheduled for same-day discharge. Successful same-day discharge occurred in 175/198 (88.4%) of these patients (AC, n = 139; GA, n = 36). Five (2.9%) of the 175 patients (4 AC, 1 GA) with same-day discharge required readmission to hospital within the first 12 hr after discharge. Six (1.8%) of the 329 total patients had a documented postoperative intracranial bleed, but none occurred after initial discharge from hospital. CONCLUSION: Same day discharge from hospital is possible in carefully selected patients after both GA and AC for supratentorial tumour surgery. PMID- 27510464 TI - Revisiting the consequences of inadequate Canadian physician resource planning: a renewed call to action. PMID- 27510465 TI - Capsule Commentary on Nicolaidis et al., The Development and Evaluation of an Online Healthcare Toolkit for Autistic Adults and their Primary Care Providers. PMID- 27510466 TI - Lipid profiling of cyanobacteria Synechococcus sp. PCC 7002 using two-dimensional liquid chromatography with quadrupole time-of-flight mass spectrometry. AB - Glycerolipid is a main component of membranes in oxygenic photosynthetic organisms. Up to now, the majority of publication in this area has focused on the physiological functions of glycerolipids and lipoprotein complexes in photosynthesis, but the study on the separation and identification of glycerolipids in thylakoid membrane in cyanobacteria is relatively rare. Here we report a new method to separate and identify five photosynthetic glycerolipid classes, including monoglucosyl diacylglycerol, monogalactosyl diacylglycerol, digalactosyl diacylglycerol, sulfoquinovosyl diacylglycerol, and phosphatidylglycerol, in cyanobacteria Synechococcus sp. PCC 7002 by two dimensional (normal- and reversed-phase) liquid chromatography online coupled to quadrupole time-of-flight mass spectrometry. Over twice as many lipid species were detected by our method compared to the previously reported methods. Ten new odd-chain fatty acid glycerolipids were discovered for the first time. Moreover, complete separation of isomers of monogalactosyl diacylglycerol and monoglucosyl diacylglycerol was achieved. According to the tandem mass spectrometry results, we found that the head group of monoglucosyl diacylglycerols was not as stable as that of monogalactosyl diacylglycerols, which might explain why the organism chose monogalactosyl diacylglycerols and digalactosyl diacylglycerols instead of monoglucosyl diacylglycerols as the main content of the photosynthetic membranes in the history of evolution. This work will benefit further research on the physiological function of glycerolipids. PMID- 27510467 TI - Primary female breast sarcoma: clinicopathological features, treatment and prognosis. AB - Primary breast sarcoma (PBS) is a rare and heterogeneous group of malignancies with limited publications. We obtained data from the Surveillance, Epidemiology, and End Results Program and performed analysis to determine clinicopathological characteristics of PBS and estimate their associations with overall survival (OS) and cancer-specific survival (CSS). Median age of PBS was 55-59 years and median OS was 108 months. Age, overlap or entire breast involvement, tumor histology, and tumor spread were associated with poor survival outcomes. In the multivariable analysis, tumor size, lymph node involvement, distant metastasis and histologic grade were correlated with survival outcomes (P < 0.001). In M0 patients, mastectomy was associated with worse survival outcomes compared with breast conservative surgery (BCS) (adjusted hazard ratio [adjHR], 1.80; 95% CI, 1.31-2.47), regardless of tumor size, tumor grade, tumor histology or radiation history. Adjuvant radiation improved survival outcomes in patients with tumor size >5 cm (adjHR, 0.63; 95% CI, 0.43-0.91), but not in patients with tumor size <= 5 cm. Our study demonstrated clinicopathological characteristics of PBS in the US population and supports performing BCS if R0 resection can be achieved, with radiation if tumor size is over 5 cm. PMID- 27510468 TI - [Not Available]. PMID- 27510469 TI - Accelerated hydration reaction of an unsymmetrical tolan evidenced by a Hg(ii) trapped macrocycle and its application as a Hg(ii)-selective indicator. AB - Hg(ii)-mediated hydration reactions of unsymmetrical quinoline type tolans were studied. The observed accelerated reactions of the tolans rely on the additional binding motifs of the tolan, as supported by the X-ray structure of the macrocycle (2b). The analyte-specific reaction allows us to detect Hg(ii) in buffered media. PMID- 27510470 TI - Preoperative Echocardiography Examination of Right Ventricle Function in Patients Scheduled for LVAD Implantation Correlates with Postoperative Hemodynamic Examinations. AB - BACKGROUND Left ventricular assist devices (LVAD) are used to treat heart failure. Preoperative prediction of RV function after LVAD implantation is crucial. Correlations were found between preoperative echo and RV function after LVAD implantation. MATERIAL AND METHODS We retrospectively reviewed 23 male patients (8 ischemic, 15 nonischemic cardiomyopathy) with LVAD implantation (17 HeartWare, 6 HeartMate II) at the Silesian Center for Heart Diseases from 1 January 2013 to 28 October 2014. Preoperative TTE data of RV function included RVFAC (fractional area change), TAPSE (tricuspid annulus plane systolic excursion), RV diameter (RV4), and RV/LV (right/left ventricle) ratio. Postoperative hemodynamic mean pulmonary pressure (mPAP), central venous pressure (CVP), cardiac output (CO), and cardiac index (CI) were measured and recorded every 2 h up to 10 days (1, 2, ...120) and correlated. Study endpoints were mortality, discharge from ICU, and RV dysfunction. RESULTS There were no RV dysfunctions. Correlations of CO and CI with RV4 and RV/LV ratio were significantly positive at many time points, with TAPSE and FAC positive or negative. Correlations mPAP with RV4 were significantly positive: 1, 2, 3, 7, 8, 57, 58, 59. With RV/LV ratio positive: 44, 47, with TAPSE in 36. With FAC positive 11, 13-15, 22 and negative 57. Correlations CVP with RV4 were negative, with positive significance in 1, 52. With RV/LV ratio positively 52, 54, 56 and negative 71, 72, 73. With TAPSE were negative significantly: 30, 68. With FAC positive 11, 12, 13, 14 and negative: 68. CONCLUSIONS RV4 and RV/LV ratio before LVAD implantation are more predictive for postoperative RV function than RVFAC and TAPSE, probably because RVFAC and TAPSE are load-dependent. PMID- 27510471 TI - Utility of thyroid testing in the ED. PMID- 27510472 TI - Subtle presentation of herpes simplex encephalitis. PMID- 27510473 TI - Impact of an emergency medicine pharmacist on time to thrombolysis in acute ischemic stroke. PMID- 27510474 TI - Failed Deglutitive Upper Esophageal Sphincter Relaxation Is a Risk Factor for Aspiration in Stroke Patients with Oropharyngeal Dysphagia. AB - Background/Aims: We attempted to examine the relationship between abnormal findings on high-resolution manometry (HRM) and videofluoroscopic swallowing study (VFSS) of the pharynx and upper esophageal sphincter (UES), and to identify the risk factors for aspiration. Methods: We performed VFSS and HRM on the same day in 36 ischemic stroke patients (mean age, 67.5 years) with dysphagia. Pressure (basal, median intra bolus, and nadir), relaxation time interval of the UES, and mesopharyngeal and hypopharyngeal contractility (as a contractile integral) were examined using HRM. The parameters of VFSS were vallecular residue, pyriform sinus residue, vallecular overflow, penetration, and aspiration. The association between the parameters of VFSS and HRM was analyzed by the Student's t test. Results: Three (8.3%) and 4 (11.1%) stroke patients with dysphagia had pyriform sinus residue and vallecular sinus residue, respectively, and 5 (13.8%) patients showed aspiration. Mesopharyngeal and hypopharyngeal contractile integrals in patients with residue in the pyriform sinus were significantly lower than those in patients without residue in the pyriform sinus (P < 0.05). Relaxation time intervals in patients with aspiration were significantly shorter than those in patients without aspiration (P < 0.05), and multivariate regression analysis revealed a shorter relaxation time interval as the main risk factor for aspiration (OR, 0.03; 95% CI, 0.01-0.65; P < 0.05). Conclusions: Manometric measurements of the pharynx and UES were well correlated with abnormal findings in the VFSS, and a shorter relaxation time interval of the UES during deglutition is an important parameter for the development of aspiration. PMID- 27510475 TI - Advances in the Diagnosis and Treatment of PCOS. AB - While the Rotterdam criteria look simple and easy to follow, in clinical practice diagnosis of PCOS may be problematic because of the use of inaccurate commercial androgen assays. Progresses in ovarian ultrasound and in AMH measurement have modified the way to make the diagnosis of PCOS and an update of Rotterdam criteria may be necessary. In classic severe form of PCOS, ovarian follicle count is a very reliable diagnostic criterion but AMH measurement may also present high diagnostic specificity and sensitivity. This finding is particularly important when no clinical signs of androgen excess are present and only commercial assays for androgen measurement are available. At the contrary, in mild PCOS phenotypes, sensitivity of AMH measurement is too low whileFNPO count maintains a high diagnostic sensitivity. However, at least in ovulatory hyperandrogenic PCOS phenotype, increased AMH values in association with enlarged ovarian size permit the diagnosis of ovulatory PCOS in 85% of these patients. Treatment of PCOS women has to be directed to get fertility or in patients not seeking fertility to solve or attenuate the psychological implications of androgen excess and of irregular menses and the risk of endometrial hyperplasia. The therapeutic protocols that are used in our department are presented. PMID- 27510476 TI - Approaches to Improve Efficiency of Dendritic Cell-based Therapy of High Grade Gliomas. AB - High grade gliomas (HGGs) are the most frequent and highly invasive type of brain tumors, which arise from glial cells. Among HGGs, glioblastoma multiforme (GBM) is the commonest and deadliest tumor type. Standard HGG therapy that involves tumor resection followed by concomitant treatment with radiation exposure and temozolomide (TMZ) cannot prevent recurrent tumor. The median survival of treated patients after surgery does not exceed 1.5 years. Vaccination with autologous dendritic cells (DCs) pulsed with tumor-specific peptides, antigens, or lysates is considered as a promising option to induce a potent anti-tumor immune response and cytotoxicity against GBM cells. However, since the tumor microenvironment is highly immunosuppressive and immunotolerant, specialized approaches should be applied to protect DC transplants against tumor-induced functional impairment and inhibition. So far, many phase I-III clinical trials utilizing DC vaccines for HGG treatment were completed or are underway. In summary, DC vaccination was safe and well tolerated by patients. DC-induced anti-tumor immune responses correlated with prolonged overall and progression- free survival. Combination of DC therapy with other interventional strategies (i.e., radiotherapy, chemotherapy, antibodies, etc.) and multimodal approaches should improve HGG treatment outcomes. In this review, we consider strategies that provide an option to override the immune inhibitory tumor microenvironment and boost DC vaccine-based antitumor immune response. PMID- 27510477 TI - Determinants of Anti-Cancer Effect of Mitochondrial Electron Transport Chain Inhibitors: Bioenergetic Profile and Metabolic Flexibility of Cancer Cells. AB - Recent evidence highlights that energy requirements of cancer cells vary greatly from normal cells and they exhibit different metabolic phenotypes with variable participation of both glycolysis and oxidative phosphorylation (OXPHOS). Interestingly, mitochondrial electron transport chain (ETC) has been identified as an essential component in bioenergetics, biosynthesis and redox control during proliferation and metastasis of cancer cells. This dependence converts ETC of cancer cells in a promising target to design small molecules with anti-cancer actions. Several small molecules have been described as ETC inhibitors with different consequences on mitochondrial bioenergetics, viability and proliferation of cancer cells, when the substrate availability is controlled to favor either the glycolytic or OXPHOS pathway. These ETC inhibitors can be grouped as 1) inhibitors of a respiratory complex (e.g. rotenoids, vanilloids, alkaloids, biguanides and polyphenols), 2) inhibitors of several respiratory complexes (e.g. capsaicin, ME-344 and epigallocatechin-3 gallate) and 3) inhibitors of ETC activity (e.g. elesclomol and VLX600). Although pharmacological ETC inhibition may produce cell death and a decrease of proliferation of cancer cells, factors such as degree of inhibition of ETC activity by small molecules, bioenergetic profile and metabolic flexibility of different cancer types or subpopulations of cells in a particular cancer type, can affect the impact of the anti-cancer actions. Particularly interesting are the adaptive mechanisms induced by ETC inhibition, such as induction of glutamine-dependent reductive carboxylation, which may offer a strategy to sensitize cancer cells to inhibitors of glutamine metabolism. PMID- 27510478 TI - Duration of Dual Antiplatelet Therapy After Coronary Stenting. AB - BACKGROUND: Dual antiplatelet therapy (DAPT) is one of the cornerstones of coronary artery disease (CAD) treatment. Standard DAPT requires one of, P2Y12 receptor inhibitors, clopidogrel, prasugrel or ticagrelor as an adjunct therapy to aspirin administration. The decision over DAPT duration depends on the evaluation of thrombotic risk and the assessment of the probability for major bleeding events. METHODS: The goal of this work was to identify which would be the appropriate combination of antiplatelet agents and the optimal duration of DAPT, based on the patient's medical history and clinical characteristics. A thorough search of PubMed and the Cochrane Database was conducted in order to identify randomized controlled trials, observational studies, current ESC and ACC/AHA guidelines and novel articles on the subject. RESULTS: The decision over DAPT duration is based on a careful approach which requires the evaluation of thrombotic risk and the assessment of the probability for major bleeding events. A series of aspects and special conditions may influence the duration of DAPT after stenting e.g. the type of the implanted stent (DES or BMS) or if the commencement of DAPT is administered in the context of an acute coronary syndrome or in the setting of stable CAD. Current guidelines can assist clinicians in making decisions but treating patients in special groups e.g. with diabetes mellitus or the elderly people can be very demanding. CONCLUSION: Studies which examined optimal DAPT duration, displayed controversial results, mainly observed because of the discrepancy and heterogeneity between different study designs or the decision of a great proportion of investigators to statistically test for non inferiority. A careful, patient-centered approach, which considers thrombotic risk versus the risk for bleeding complications and other individual characteristics and comorbidities, is required when deciding DAPT duration. PMID- 27510479 TI - Carrier Mediated Systemic Delivery of Protein and Peptide Therapeutics. AB - Over the last few decades proteins and peptide therapeutics have occupied an enormous fraction of pharmaceutical industry. Despite their high potential as therapeutics, the big challenge often encountered is the effective administration and bioavailability of protein therapeutics in vivo system. Peptide molecules are well known for their in vivo short half-lives. In addition, due to high molecular weight and susceptibility to enzymatic degradation, often it is not easy to administer peptides and proteins orally or through any other noninvasive routes. Conventional drug management system often demands for frequent and regular interval intravenous/subcutaneous administration, which decreases overall patient compliance and increases chances of side-effects related to dose-fluctuation in systemic circulation. A controlled mode of delivery system could address all these short-comings at a time. Therefore, long-acting sustained release formulations for both invasive and noninvasive routes are under rigorous study currently. Long-acting formulations through invasive routes can address patient compliance and dose-fluctuation issues by less frequent administration. Also, any new route of administration other than invasive routes will address cost effectiveness of the therapeutic by lessening the need to deal with health professional and health care facility. Although a vast number of studies are dealing with novel drug delivery systems, till now only a handful of controlled release formulations for proteins and peptides have been approved by FDA. This study therefore focuses on current and perspective controlled release formulations of existing and novel protein/peptide therapeutics via conventional invasive routes as well as potential novel non-invasive routes of administration, e.g., oral, buccal, sublingual, nasal, ocular, rectal, vaginal and pulmonary. PMID- 27510480 TI - Adrenal Hyperandrogenism and Polycystic Ovary Syndrome. AB - BACKGROUND: The prevalence of adrenal hyperandrogenism (AH), as defined by increased circulating dehydroepiandrosterone-sulfate (DHEAS) levels, ranges from 15 to 45% in women with polycystic ovary syndrome (PCOS). METHODS: The aim of this review is to update the pathogenesis and consequences of AH in PCOS, from molecular genetics to the clinical setting. RESULTS: Mounting evidence derived from animal models suggests that genetically or enviromentally determined prenatal androgen excess, by influencing the hormonal and metabolic phenotype of susceptible female fetuses later in life, may be the capital event for the development of AH in PCOS. Because human placental aromatase activity is likely to prevent any deleterious effect of maternal hyperandrogenemia on the fetus, inheritance of the maternal steroidogenic defect is the more likely culprit, even though other factors such as changes in placental steroidogenesis itself or its nutritional efflux may also be involved in the building a deregulated enzymatic pathway from utero to adult life. Anyhow, the most important issue is whether or not AH influences the cardiometabolic risk of women with PCOS. On the one hand, AH has shown a controversial relationship with carbohydrate metabolism and adiposity, and is also associated with abnormalities in blood pressure regulation in these patients. On the other hand, DHEAS may exert a beneficial effect on the lipid profile of both lean and obese patients. Lastly, available studies in women with PCOS cast doubt upon a protective role of DHEAS levels on subclinical atherosclerosis, despite opposite data from the general population. CONCLUSION: AH is frequent in patients with PCOS yet unraveling its consequences for the management of this disorder requires future longitudinal studies. PMID- 27510481 TI - Hirsutism in Polycystic Ovary Syndrome: Pathophysiology and Management. AB - BACKGROUND: Hirsutism is defined as the presence of terminal hair with male distribution in women, and polycystic ovary syndrome (PCOS) is the most common etiology of hirsutism. METHODS: The aim of this study is to review aspects of hair growth that are relevant for the understanding of hirsutism in PCOS, along with current treatment alternatives. RESULTS: The prevalence of hirsutism in PCOS ranges from 70 to 80%, vs. 4% to 11% in women in the general population. Hirsutism in PCOS is associated with both ovarianderived androgen excess and individual sensitivity of the pilosebaceous unit to androgens. Interventions to decrease hirsutism in PCOS include the suppression of androgen excess by combined oral contraceptives (OCPs). If OCPs are contraindicated, mainly in the presence of insulin-resistance related comorbidities, a second-line option for reducing androgen secretion may be metformin associated with lifestyle changes. Other interventions should be guided by hirsutism severity, determined by the modified Ferriman-Gallwey score, and by the amount of distress hirsutism causes to the patient, and should be maintained for at least 6-12 months. Mild hirsutism is usually treated with a combination of non-pharmacological methods and OCPs, whereas moderate and severe hirsutism may require a combination of antiandrogens and OCPs, or, if OCPs cannot be used, antiandrogens plus a safe contraceptive method. In all cases, strong clinical support is crucial to ensure treatment adherence and success. CONCLUSION: The understanding of the pathophysiology of hirsutism in PCOS, as well as classifying its severity and the distress it causes to each patient is essential to choose the proper treatment. The presence of metabolic comorbidities and menstrual disturbances will also guide the individualized management of hirsutism in women with PCOS. PMID- 27510482 TI - Insulin Resistance and Polycystic Ovary Syndrome. AB - BACKGROUND: Insulin resistance and the associated compensatory hyperinsulinemia are common findings in women with PCOS, and may play a key role in this condition. METHODS: In this article, we focused on the significance of insulin resistance in PCOS, reviewing the available literature on epidemiology, pathogenesis, pathophysiology and treatment of this condition. RESULTS: It has been estimated that approximately 70% of these women are insulin resistant, but this figure is affected by frequent referral bias. In addition, there is metabolic heterogeneity between clinical phenotypes of PCOS. A fundamental issue is the role that hyperinsulinemia plays in androgen overproduction, which is enhanced by bidirectional links between insulin resistance and hyperandrogenism. Available data suggest that women with PCOS may have insulin action alterations of heterogeneous origins, which induce specific abnormalities in these subjects due to the presence of intrinsic defects. Obesity is a common finding in these patients and contributes to the association between PCOS and insulin resistance, combining with the effect of PCOS per se. Insulin sensitization shows several beneficial effects in the treatment of this condition. However, clinical response is heterogeneous. CONCLUSION: Insulin resistance is a common feature of women with PCOS, although it is not universal and differ between clinical phenotypes of PCOS. Insulin resistance and hyperandrogenism appear to be interrelated key factors in the pathogenesis of PCOS. We hypothesize that PCOS might represent a common end-stage clinical phenotype of different processes, in which there are impaired insulin action and hyperandrogenism, probably favoured by specific, intrinsic abnormalities of these women. PMID- 27510483 TI - Current Insights Into Inositol Isoforms, Mediterranean and Ketogenic Diets for Polycystic Ovary Syndrome: From Bench to Bedside. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex syndrome characterized by reproductive and metabolic implications. Lifestyle changes, such as diet and exercise, are considered first-line treatment for women affected by PCOS. Pharmacologic treatments target the hormonal and metabolic dysregulations associated to the disease such as insulin resistance, anovulation, hirsutism and menstrual irregularities. OBJECTIVE: To focus on the role of inositol isoforms, as well as Mediterranean and ketogenic diets, as possible therapeutic strategies in PCOS women. METHOD: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. RESULTS: Accumulating evidence suggests that two inositol isoforms, myo- and D-chiro-, may play a pivotal role in re-addressing both hormonal and metabolic parameters toward homeostasis, counteracting the symptoms and signs typical of this syndrome. In addition, studies focused on Mediterranean and ketogenic diet provided positive results in patients affected by obesity and type 2 diabetes, so these dietetic regimens could represent a fascinating dietetic treatment for the management of PCOS. CONCLUSION: Both the isoforms of inositol are effective in improving ovarian function and metabolism in patients with PCOS. In spite of accumulating evidence, it is currently not possible to draw firm conclusion(s) about the efficacy of these interventions considering the severe bias due to different samples size, dose, and duration of intervention among the published studies on this topic. Furthermore, future longitudinal cohort studies along with prospective interventional trials may contribute to better clarify the role of Mediterranean and ketogenic diets in the treatment of PCOS. PMID- 27510484 TI - Cardiovascular Risk in the Different Phenotypes of Polycystic Ovary Syndrome. AB - BACKGROUND: The polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women of reproductive age and shows substantial phenotypic variability. According to the presence of the three diagnostic criteria of PCOS, i.e. oligo- and/or anovulation, hyperandrogenemia and/or clinical signs of high androgen levels, and polycystic ovaries, four different phenotypes of PCOS are identified. It appears that these phenotypes differ in the prevalence of several established and emerging cardiovascular risk factors. METHODS: We searched the literature for studies that compared the cardiovascular risk profile of patients with the different phenotypes of PCOS. RESULTS: Patients with both anovulation and hyperandrogenemia have more pronounced insulin resistance and higher levels of proinflammatory and prothrombotic mediators than patients with polycystic ovaries and either anovulation or hyperandrogenemia. CONCLUSION: Given that these differences appear to be mainly driven by the more pronounced obesity of the former patients, diet and exercise aiming at weight loss should constitute the cornerstone of management of PCOS and should be particularly emphasized in patients with the higher risk phenotypes of the syndrome. PMID- 27510485 TI - Strategies that Target Tight Junctions for Enhanced Drug Delivery. AB - Ions and molecules move across epithelial barriers by two pathways, the transcellular and the paracellular. The former is taken by lipophilic compounds, or by ions and molecules that move across the plasma membrane through pumps, carriers or exchangers. The second route is regulated by the tight junction (TJ) that through paracellular channels, allows the transport of ions across epithelial barriers. Since, a wide variety of bioactive molecules like peptides, proteins and oligonucleotides cannot use the transcellular route, due to their hydrophilic nature, interest has arisen in devising procedures to open the TJ in a reversible manner for paracellular drug delivery. Here, we describe how different strategies have been devised to enhance the paracellular intestinal absorption of drugs; to open the blood-brain barrier (BBB) to allow the penetration of drugs for the treatment of disorders and tumors of the central nervous system; or to deliver antigens into the subjacent mucosa associated lymphoid tissues, for the development of mucosal vaccines. The strategies described, include the use of peptides, antibodies and miRNAs that target proteins of the apical junctional complex, as well as toxins derived from microorganisms that open the TJ by inducing the contraction of the cortical actomyosin ring. Also, we describe how paracellular absorption, is enhanced by drugs that extract cholesterol from the plasma membrane, surfactants, fatty acids, oligosaccharides, cationic polymers, nitric oxide donors and calcium chelators. Likewise, we explain how the BBB has been opened by employing tumor necrosis factor-alpha, bradykinin, short chain alkylglycerols, hyperosmotic mannitol and focused ultrasound. PMID- 27510486 TI - Structural Aspects of Solid Solutions of Enantiomers. AB - A mixture of two enantiomers can crystallize according to three types of heterogeneous equilibria: a racemic compound (a 1:1 stoichiometric compound), a conglomerate (a physical mixture of particles with opposite chirality) or, more rarely, as a solid solution (a crystalline architecture exhibiting a lack of chiral discrimination with respect to the two enantiomers). Due to the scarce occurrence of solid solutions, only a few examples of such behavior are known, and even fewer systems have been investigated by means of single crystal X-ray diffraction. Yet, preliminary work performed in the 1970s by several research teams revealed that structural investigations of solid solutions could provide valuable insights into chiral discrimination mechanisms at the crystal lattice scale. In the present paper, our aim is to review published cases of enantiomeric solid solutions for which both melting phase diagrams and crystal structures are available in order to analyze the lack of chiral discrimination associated to these phases. Our methodology consists in considering both the molecular and crystallographic aspects of stereoselectivity with the final aim of identifying structural criteria responsible for the occurrence of solid solutions. The experimental conditions allowing access to solid solutions will also be considered in light of these structural criteria. PMID- 27510487 TI - Polyphenol-Related Epigenetic Modifications in Osteoarthritis: Current Therapeutic Perspectives. AB - The hyaline cartilage is an avascular, aneural and alymphatic tissue with a limited ability to repair itself. When the cartilage is exposed to some kind of injury, it usually triggers osteoarthritis (OA), a prevalent and degenerative joint disease closely related to aging. OA is both complex and multifactorial, and is the most common form of arthritis, being positioned as a major cause of pain and dysfunction in the world. In addition, high OA prevalence can greatly affect work capacity, making this disease a significant social problem, therefore, its prevention and treatment becomes a priority. At this time, there are numerous therapeutic strategies available to improve hyaline cartilage repair by using chondrocytes or mesenchymal cells, but neither is effective enough to generate functional and durable tissue reparation over time. In OA, chondrocytes have an aberrant gene expression and phenotype, resulting in a loss of balance between anabolic and catabolic processes. Environmental influences such as radiation, infection, smoking, nutrients, toxins and stress can affect gene expression patterns, which may constitute risk factors for various chronic and degenerative diseases, such as OA. In addition, considerable evidence shows that epigenetic mechanisms play an important role in OA chondrogenesis and pathogenesis. Natural plant-derived products such as polyphenols, which are secondary metabolites considered to have potential activity to block inflammation in several degenerative diseases, can stimulate epigenetic modifications, and may provide new therapeutic targets and cost-effective treatments. This review aims to present various polyphenolbased therapies currently used for the treatment of several progressive diseases, including OA. PMID- 27510488 TI - Development of Novel miRNA-based Vaccines and Antivirals against Enterovirus 71. AB - The Hand, Foot and Mouth Disease (HFMD) is caused by Enterovirus 71 (EV-A71) and Coxsackieviruses. Common HFMD symptoms are high fever (>= 39 degrees C), rashes, and ulcers but complications due to virulent EV-A71 may arise leading to cardiopulmonary failure and death. The lack of vaccines and antiviral drugs against EV-A71 highlights the urgency of developing preventive and treatment agents. Recent studies have reported the emergence of novel antiviral agents and vaccines that utilize microRNAs (miRNAs). They belong to a class of small (19-24 nt) non coding RNA molecules. As miRNAs play a major role in the host regulatory system, there is a huge opportunity for interplay between host miRNAs and EV-A71 expressions. A total of 42 out of 64 miRNAs were up-regulated in EV-A71-infected cells. There was consistent up-regulation of miR-1246 gene expression that targeted the DLG3 gene which contributes to neurological pathogenesis. In contrast, miR-30a that targets calcium channels for membrane transportation was down-regulated. This leads to repression of EV-A71 replication. The impact of host miRNAs on immune activation, shutdown of host protein synthesis, apoptosis, signal transduction and viral replication are discussed. miRNAs have been used in the construction of live attenuated vaccines (LAV) such as the poliovirus LAV that has miRNA binding sites for let-7a or miR-124a. The miRNAbearing vaccine will not replicate in neuronal cells carrying the corresponding miRNA but could still replicate in the gastrointestinal tract and hence remains to act as immunogens. As such, miRNAs are attractive candidates to be developed as vaccines and antivirals. PMID- 27510489 TI - Enkephalin-Fentanyl Multifunctional Opioids as Potential Neuroprotectants for Ischemic Stroke Treatment. AB - BACKGROUND: Ischemic stroke is one of the leading causes of mortality and morbidity in the world and effective neuroprotectants are yet to be developed. Recent studies have demonstrated excellent neuroprotective effects of a bivalent enkephalin opioid agonist, biphalin in multiple stroke models. METHODS: The purpose of this study is to evaluate novel multifunctional enkephalin-fentanyl opioid agonists, LYS436, LYS739 and LYS416 for their neuroprotective potential using in vitro and in vivo ischemic stroke models and to compare the effect to that of biphalin. RESULTS: In general, all non-selective opioid agonists significantly decreased neuronal cell death and levels of reactive oxygen species in primary neurons subjescted to hypoxia-aglycemia/re-oxygenation or NMDA neurotoxicity. Fluorinated enkephalin-fentanyl conjugate, LYS739 showed enhanced neuroprotection in both in vitro models compared to biphalin. Based on further in vitro screening and comparative studies to biphalin, LYS739 was selected as a lead for in vivo experimentation. A mouse middle cerebral artery occlusion (MCAO) stroke model was utilized to study biphalin and the lead analog, LYS739. Both agonists significantly decreased brain infarct and edema ratios compared to saline treated group. Neurological impairment after stroke was statistically significantly improved in terms of neurological score and locomotor activities with LYS739 and biphalin treatment. Importantly, LYS739 and biphalin demonstrated better neuroprotection compared to fentanyl, and this effect was reversed by non selective opioid antagonist naltrexone. CONCLUSION: In summary, the results of this study suggest that the multifunctional fluorinated enkephalin analog, LYS739 can be considered as a potential lead for ischemic stroke research and may provide advantages given the multimeric peptide-opiate structure. PMID- 27510490 TI - Antiepileptic Drugs Based on the alpha-Substituted Amide Group Pharmacophore: From Chemical Crystallography to Molecular Pharmaceutics. AB - The antiepileptic activity of alpha-substituted acetamides, lactams, and cyclic imides has been known for over six decades. We recently proposed an alpha substituted amide group as the minimum pharmacophore responsible for inhibition of neuronal nicotinic acetylcholine receptors by these compounds, with the implication that inhibition of these receptors in the brain might be the unifying mechanism of action for these classes of antiepileptic drugs. In order to realize the pharmacological potential of these orally administered drugs, the relevant aspects of solid-state chemistry and pharmaceutics (including solubility and stability) need to be addressed. A better - more cohesive and generalized - understanding of the solid-state properties of these drugs would pave the road for a rational approach to their development, formulation, and manufacturing. In this paper, Pharmaceutically relevant aspects of the crystal structure and solid state chemistry of antiepileptic drugs containing the alpha-substituted amide bond pharmacophore - alpha-substituted acetamides, lactams, and cyclic imides and the structurally related barbiturates, hydantoins, and acetylureas are reviewed. The applicable experimental and computational approaches are also briefly mentioned. PMID- 27510491 TI - Metabolic Features Across the Female Life Span in Women with PCOS. AB - Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine metabolic disorder and is presently considered a family pathology. It is associated with obesity, insulin resistance and metabolic syndrome. Racial, ethnic and environmental factors may be important in determining the clinical manifestations of this syndrome. Polycystic ovary syndrome is an exclusion diagnosis and, therefore, should be distinguished from the physiological changes typical for the age and from other hyperandrogenic disorders. Early diagnosis is important since this syndrome is associated with reproductive, oncologic and metabolic risks. Interestingly, the clinical features of this disorder may change throughout the lifespan of a PCOS woman, starting from adolescence to postmenopausal age. During the first decades of life the main features are in the reproductive area, while later in life metabolic abnormalities are more evident. While the assessment of insulin resistance is not part of the diagnosis of PCOS, it has been demonstrated that this metabolic component appears early in life and persists over time. Moreover during puberty and pregnancy, insulin resistance is exacerbated. Pregnancy represents an important stage, as the offspring of these patients may be reprogrammed and inherit some of the metabolic and reproductive features of their mothers. In the present review, we will focus on several metabolic aspects of the PCOS condition at different stages of life in a Chilean population. PMID- 27510493 TI - RNAi-Based Therapy in Experimental Ischemia-Reperfusion Injury. The New Targets. AB - BACKGROUND: Ischemia reperfusion injury is an important pathophysiological process in many fields such as transplantation, stroke, atherosclerosis, trauma and myocardial infarction. Recent advances in gene silencing may help to reduce ischemic effects, targeting molecules related to this pathological process. METHODS AND RESULTS: Here, we review the different silencing approaches in ischemic injury, highlighting the role of co-stimulatory molecules in renal transplantation. CONCLUSION: Gene silencing appears as a new strategy to prevent the inflammation and injury associated with ischemia. PMID- 27510492 TI - Neuronutrient Amino-Acid Therapy Protects Against Reward Deficiency Syndrome: Dopaminergic Key to Homeostasis and Neuroplasticity. AB - Willuhn et al., observed that habitual cocaine use was correlated with reductions in D2/D3 receptors linked to decreased cue activation in occipital cortex and cerebellum. Dopamine agonist therapy maintains dopamine function and is a relapse prevention tactic focused on psychoactive drug and behavioral addictions. Medication Assisted Treatment (MAT) with emphasis on glutaminergic medications fails in the long-term treatment of Reward Deficiency Syndrome Behaviors (RDS). While the careful use of "dopamine antagonist-therapy" short-term is supported, the research-based concept of "dopamine agonist therapy" in long-term is proposed. Neurogenetics and epigenetics are important in understanding treatment response and clinical outcomes. The neuro-mechanisms involving "dopamine homeostasis" are key to understanding recovery from drug and non-drug addictive behaviors. For example, patients who carry the DRD2 A1 allele (30-40 less D2 receptors) should consider Neuronutriant-Amino-Acid therapy (KB220 variants) a prevention modality. DRD2 A1 allele carriers show amplified striatal function of L-amino acid decarboxylase, prior to dopamine biosynthesis. Another example is the effect of Acute Tyrosine Phenylalanine Depletion (ATPD) on decision-making and reward found carriers with amino-acid deficiency (ATPD). They experienced attenuated reward and reduced decision-making ability as quantified by Iowa Gambling Task (IGT). Future research should be directed at asking the question; Would "dopamine agonist therapy" using KB220 variants reduce methylation and increase acetyl groups to enhance DRD2 expression especially in DRD2 A1 allele carriers and lead to increased dopamine function and a reduction of drug and non drug seeking behaviors? PMID- 27510494 TI - The role of the dorsolateral prefrontal cortex in early threat processing: a TMS study. AB - Previous studies demonstrated that excitatory (high frequency) offline transcranial magnetic stimulation (TMS) over the left and right dorsolateral prefrontal cortex (DLPFC) modulates attention allocation on threatening stimuli in non-clinical samples. These studies only employed offline TMS protocol that did not allow investigating the effect of the stimulation on the early stage of threat processing. In this study, the role of the right and left dorsolateral prefrontal cortex in early threat processing was investigated in high and low anxious individuals by means of an inhibitory single-pulse online TMS protocol. Our results demonstrated the role of the left DLPFC in an early stage of threat processing and that this effect is modulated by individuals' anxiety level. The inhibitory stimulation of the left DLPFC determined a disengagement bias in high anxious individuals, while the same stimulation determined an attentional avoidance in low anxious individuals. The findings of the present study suggest that right and left DLPFC are differently involved in early threat processing of healthy individuals. PMID- 27510495 TI - Intrinsic functional connectivity underlying successful emotion regulation of angry faces. AB - Most of our social interaction is naturally based on emotional information derived from the perception of faces of other people. Negative facial expressions of a counterpart might trigger negative emotions and initiate emotion regulatory efforts to reduce the impact of the received emotional message in a perceiver. Despite the high adaptive value of emotion regulation in social interaction, the neural underpinnings of it are largely unknown. To remedy this, this study investigated individual differences in emotion regulation effectiveness during the reappraisal of angry faces on the underlying functional activity using functional magnetic resonance imaging (fMRI) as well as the underlying functional connectivity using resting-state fMRI. Greater emotion regulation ability was associated with greater functional activity in the ventromedial prefrontal cortex. Furthermore, greater functional coupling between activity in the ventrolateral prefrontal cortex and the amygdala was associated with emotion regulation success. Our findings provide a first link between prefrontal cognitive control and subcortical emotion processing systems during successful emotion regulation in an explicitly social context. PMID- 27510496 TI - Brain potentials predict learning, transmission and modification of an artificial symbolic system. AB - It has recently been argued that symbolic systems evolve while they are being transmitted across generations of learners, gradually adapting to the relevant brain structures and processes. In the context of this hypothesis, little is known on whether individual differences in neural processing capacity account for aspects of 'variation' observed in symbolic behavior and symbolic systems. We addressed this issue in the domain of auditory processing. We conducted a combined behavioral and EEG study on 2 successive days. On day 1, participants listened to standard and deviant five-tone sequences: as in previous oddball studies, an mismatch negativity (MMN) was elicited by deviant tones. On day 2, participants learned an artificial signaling system from a trained confederate of the experimenters in a coordination game in which five-tone sequences were associated to affective meanings (emotion-laden pictures of human faces). In a subsequent game with identical structure, participants transmitted and occasionally changed the signaling system learned during the first game. The MMN latency from day 1 predicted learning, transmission and structural modification of signaling systems on day 2. Our study introduces neurophysiological methods into research on cultural transmission and evolution, and relates aspects of variation in symbolic systems to individual differences in neural information processing. PMID- 27510497 TI - The role of the orbitofrontal cortex in regulation of interpersonal space: evidence from frontal lesion and frontotemporal dementia patients. AB - Interpersonal distance is central to communication and complex social behaviors but the neural correlates of interpersonal distance preferences are not defined. Previous studies suggest that damage to the orbitofrontal cortex (OFC) is associated with impaired interpersonal behavior. To examine whether the OFC is critical for maintaining appropriate interpersonal distance, we tested two groups of patients with OFC damage: Patients with OFC lesions and patients with behavioral variant frontotemporal dementia. These two groups were compared to healthy controls and to patients with lesions restricted to the dorsolateral prefrontal cortex. Only patients with OFC damage showed abnormal interpersonal distance preferences, which were significantly different from both controls and patients with dorsolateral prefrontal damage. The comfortable distances these patients chose with strangers were significantly closer than the other groups and resembled distances normally used with close others. These results shed light on the role of the OFC in regulating social behavior and may serve as a simple diagnostic tool for dementia or lesion patients. PMID- 27510498 TI - Oxytocin enhances inter-brain synchrony during social coordination in male adults. AB - Recent brain imaging research has revealed oxytocin (OT) effects on an individual's brain activity during social interaction but tells little about whether and how OT modulates the coherence of inter-brain activity related to two individuals' coordination behavior. We developed a new real-time coordination game that required two individuals of a dyad to synchronize with a partner (coordination task) or with a computer (control task) by counting in mind rhythmically. Electroencephalography (EEG) was recorded simultaneously from a dyad to examine OT effects on inter-brain synchrony of neural activity during interpersonal coordination. Experiment 1 found that dyads showed smaller interpersonal time lags of counting and greater inter-brain synchrony of alpha band neural oscillations during the coordination (vs control) task and these effects were reliably observed in female but not male dyads. Moreover, the increased alpha-band inter-brain synchrony predicted better interpersonal behavioral synchrony across all participants. Experiment 2, using a double blind, placebo-controlled between-subjects design, revealed that intranasal OT vs placebo administration in male dyads improved interpersonal behavioral synchrony in both the coordination and control tasks but specifically enhanced alpha-band inter-brain neural oscillations during the coordination task. Our findings provide first evidence that OT enhances inter-brain synchrony in male adults to facilitate social coordination. PMID- 27510500 TI - Highly Boosted Oxygen Reduction Reaction Activity by Tuning the Underwater Wetting State of the Superhydrophobic Electrode. AB - By rationally designing superhydrophobic electrodes with different underwater wetting states, it is revealed that only the underwater Wenzel-Cassie coexistent state shows the clearly enhanced ability in catalyzing the oxygen reduction reaction, a typical underwater gas-consuming reaction at electrode. It is proposed that the maximizing and stabilizing the liquid/gas/solid triphase interface, endowed by the underwater Wenzel-Cassie coexistent state, plays a rather crucial role. PMID- 27510499 TI - Amygdala selectively modulates defensive responses evoked from the superior colliculus in non-human primates. AB - Brain circuitry underlying defensive behaviors includes forebrain modulatory sites, e.g. the amygdala and hypothalamus, and midbrain effector regions, such as the deep/intermediate layers of the superior colliculus (DLSC). When disinhibited, this network biases behavior towards reflexive defense reactions. While well characterized in rodent models, little is known about this system in the primate brain. Employing focal pharmacological manipulations, we have previously shown that activation of the DLSC triggers reflexive defensive responses, including cowering, escape behaviors and defensive vocalizations. Here, we show that activation of the DLSC also disrupts normal dyadic social interactions between familiar pairs of monkeys. When the basolateral complex of the amygdala (BLA) was inhibited concurrent with DLSC activation, cowering behavior was attenuated, whereas escape behaviors and defensive vocalizations were not. Moreover, inhibition of the BLA, previously shown to produce a profound increase in dyadic social interactions, was unable to normalize the decrease in social behavior resulting from DLSC activation. Together these data provide an understanding of forebrain-midbrain interactions in a species and circuit with translational relevance for the psychiatry of anxiety and post-traumatic stress disorders. PMID- 27510501 TI - Design of a Yellow-Emitting Phosphor with Enhanced Red Emission via Valence State control for Warm White LEDs Application. AB - The phosphor-converted warm W-LED have being rapidly developed due to the stringent requirements of general illumination. Here, we utilized a strategy to synergistically enhance the red region and emission intensity of novel Eu activated yellow-emitting LaSiO2N phosphors. This was realized by predicting optimum crystal structure, and governing the concentration of doping ions as well as preparation temperature. By using these straight-forward methods, we were able to vary the valence to enhance the red region and improve the quantum efficiency of LaSiO2N phosphor. The warm W-LED lamp fabricated with this red region enhanced LaSiO2N:Eu phosphor exhibited high CRI (Ra = 86), suitable CCT (5783 K) and CIE chromaticity (0.33, 0.36), indicating this synergistically enhanced strategy could be used for design of yellow-emitting phosphor materials to obtain warm W LEDs. PMID- 27510502 TI - The title and data of Robinson and Madison (2016) are valid. PMID- 27510503 TI - Fosaprepitant Dimeglumine: A Review in the Prevention of Nausea and Vomiting Associated with Chemotherapy. AB - Intravenous fosaprepitant dimeglumine (Emend((r)) for injection, IVEmend((r)); henceforth referred to as fosaprepitant) is a prodrug of and is rapidly converted to the antiemetic aprepitant, and is approved in several countries worldwide (as part of an antiemetic regimen) for the prevention of nausea and vomiting associated with highly and moderately emetogenic chemotherapy (HEC and MEC). This narrative review discusses the pharmacological properties of intravenous fosaprepitant and its clinical efficacy and tolerability in the prevention of nausea and vomiting associated with HEC and MEC. In large, randomized phase III clinical trials, a single intravenous dose of fosaprepitant 150 mg was an effective and generally well tolerated addition to an antiemetic regimen that included dexamethasone and a serotonin 5-HT3 receptor antagonist in adult cancer patients undergoing treatment with HEC or MEC. It was also noninferior to an oral aprepitant-based regimen in adult cancer patients undergoing HEC treatment. The tolerability profile of a fosaprepitant-based regimen was typical of that in patients receiving emetogenic chemotherapy, and adverse events were generally consistent with those observed with an aprepitant-based regimen. Fosaprepitant provides a useful addition to antiemetic therapy regimens. PMID- 27510504 TI - Higher Vulnerability of Menadione-Exposed Cortical Astrocytes of Glutaryl-CoA Dehydrogenase Deficient Mice to Oxidative Stress, Mitochondrial Dysfunction, and Cell Death: Implications for the Neurodegeneration in Glutaric Aciduria Type I. AB - Patients affected by glutaric aciduria type I (GA-I) show progressive cortical leukoencephalopathy whose pathogenesis is poorly known. In the present work, we exposed cortical astrocytes of wild-type (Gcdh +/+ ) and glutaryl-CoA dehydrogenase knockout (Gcdh -/- ) mice to the oxidative stress inducer menadione and measured mitochondrial bioenergetics, redox homeostasis, and cell viability. Mitochondrial function (MTT and JC1-mitochondrial membrane potential assays), redox homeostasis (DCFH oxidation, nitrate and nitrite production, GSH concentrations and activities of the antioxidant enzymes SOD and GPx), and cell death (propidium iodide incorporation) were evaluated in primary cortical astrocyte cultures of Gcdh +/+ and Gcdh -/- mice unstimulated and stimulated by menadione. We also measured the pro-inflammatory response (TNFalpha levels, IL1 beta and NF-kB) in unstimulated astrocytes obtained from these mice. Gcdh -/- mice astrocytes were more vulnerable to menadione-induced oxidative stress (decreased GSH concentrations and altered activities of the antioxidant enzymes), mitochondrial dysfunction (decrease of MTT reduction and JC1 values), and cell death as compared with Gcdh +/+ astrocytes. A higher inflammatory response (TNFalpha, IL1-beta and NF-kB) was also observed in Gcdh -/- mice astrocytes. These data indicate a higher susceptibility of Gcdh -/- cortical astrocytes to oxidative stress and mitochondrial dysfunction, probably leading to cell death. It is presumed that these pathomechanisms may contribute to the cortical leukodystrophy observed in GA-I patients. PMID- 27510506 TI - The Interaction of TXNIP and AFq1 Genes Increases the Susceptibility of Schizophrenia. AB - Although previous studies showed the reduced risk of cancer in patients with schizophrenia, whether patients with schizophrenia possess genetic factors that also contribute to tumor suppressor is still unknown. In the present study, based on our previous microarray data, we focused on the tumor suppressor genes TXNIP and AF1q, which differentially expressed in patients with schizophrenia. A total of 413 patients and 578 healthy controls were recruited. We found no significant differences in genotype, allele, or haplotype frequencies at the selected five single nucleotide polymorphisms (SNPs) (rs2236566 and rs7211 in TXNIP gene; rs10749659, rs2140709, and rs3738481 in AF1q gene) between patients with schizophrenia and controls. However, we found the association between the interaction of TXNIP and AF1q with schizophrenia by using the MDR method followed by traditional statistical analysis. The best gene-gene interaction model identified was a three-locus model TXNIP (rs2236566, rs7211)-AF1q (rs2140709). After traditional statistical analysis, we found the high-risk genotype combination was rs2236566 (GG)-rs7211(CC)-rs2140709(CC) (OR = 1.35 [1.03-1.76]). The low-risk genotype combination was rs2236566 (GT)-rs7211(CC)-rs2140709(CC) (OR = 0.67 [0.49-0.91]). Our finding suggested statistically significant role of interaction of TXNIP and AF1q polymorphisms (TXNIP-rs2236566, TXNIP-rs7211, and AF1q-rs2769605) in schizophrenia susceptibility. PMID- 27510505 TI - The Neurobiology of Depression: an Integrated Overview from Biological Theories to Clinical Evidence. AB - Depressive disorders are heterogeneous diseases, and the complexity of symptoms has led to the formulation of several aethiopathological hypotheses. This heterogeneity may account for the following open issues about antidepressant therapy: (i) antidepressants show a time lag between pharmacological effects, within hours from acute drug administration, and therapeutic effects, within two four weeks of subchronic treatment; (ii) this latency interval is critical for the patient because of the possible further mood worsening that may result in suicide attempts for the seemingly ineffective therapy and for the apparent adverse effects; (iii) and only 60-70 % of treated patients successfully respond to therapy. In this review, the complexity of the biological theories that try to explain the molecular mechanisms of these diseases is considered, encompassing (i) the classic "monoaminergic hypothesis" alongside the updated hypothesis according to which long-term therapeutical action of antidepressants is mediated by intracellular signal transduction pathways and (ii) the hypothalamic-pituitary adrenal axis involvement. Although these models have guided research efforts in the field for decades, they have not generated a compelling and conclusive model either for depression pathophysiology or for antidepressant drugs' action. So, other emerging theories are discussed: (iii) the alterations of neuroplasticity and neurotrophins in selective vulnerable cerebral areas; (iv) the involvement of inflammatory processes; (v) and the alterations in mitochondrial function and neuronal bioenergetics. The focus is put on the molecular and theoretical links between all these hypotheses, which are not mutually exclusive but otherwise tightly correlated, giving an integrated and comprehensive overview of the neurobiology of depressive disorders. PMID- 27510508 TI - Experience of nursing support from the perspective of patients with cancer in mainland China. AB - This study was conducted to understand patients' experiences of nursing support, to identify gaps between patients' expected needs and the nursing support they received, and to explore reasons for such disparity. A qualitative study with a phenomenological approach was used. A purposive sample of 22 patients with different types of cancer was recruited and interviewed using semistructured guidelines. The data were analyzed using phenomenological analytic methods. Several needs regarding nursing support were expressed, including informational, psychological, clinical, care coordination and communication needs, and there were some unmet or partially-met needs. Reasons for the disparities covered both patient- and nurse-related factors, including patients' lack of awareness regarding how to acquire professional assistance and reluctance to express their needs, and nurses' lack of active communication with patients, inability to provide specific support, and limited resources for coordination. The expectations of nursing support did not always correspond with the actual delivery of nursing care. A tailored intervention is warranted to meet patients' expectations, which might contribute to quality-of-care improvements. PMID- 27510507 TI - Advanced Imaging in Osteoarthritis. AB - CONTEXT: Radiography is widely accepted as the gold standard for diagnosing osteoarthritis (OA), but it has limitations when assessing early stage OA and monitoring progression. While there are improvements in the treatment of OA, the challenge is early recognition. EVIDENCE ACQUISITION: MEDLINE and PubMed as well as professional orthopaedic and imaging websites were reviewed from 2006 to 2016. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Magnetic resonance imaging (MRI) can provide the most comprehensive assessment of joint injury and OA with the advantages of being noninvasive and multiplanar with excellent soft tissue contrast. However, MRI is expensive, time consuming, and not widely used for monitoring OA clinically. Computed tomography (CT) and CT arthrography (CTA) can also be used to evaluate OA, but these are also invasive and require radiation exposure. Ultrasound is particularly useful for evaluation of synovitis but not for progression of OA. CONCLUSION: MRI, CT, and CTA are available for the diagnosis and monitoring of OA. Improvement in techniques and decrease in cost can allow some of these modalities to be effective methods of detecting early OA. PMID- 27510509 TI - Mercury Methylation by Cobalt Corrinoids: Relativistic Effects Dictate the Reaction Mechanism. AB - The methylation of Hg(II) (SCH3 )2 by corrinoid-based methyl donors proceeds in a concerted manner through a single transition state by transfer of a methyl radical, in contrast to previously proposed reaction mechanisms. This reaction mechanism is a consequence of relativistic effects that lower the energies of the mercury 6p1/2 and 6p3/2 orbitals, making them energetically accessible for chemical bonding. In the absence of spin-orbit coupling, the predicted reaction mechanism is qualitatively different. This is the first example of relativity being decisive for the nature of an observed enzymatic reaction mechanism. PMID- 27510510 TI - A Comparative Analysis of Sonic Defences in Bombycoidea Caterpillars. AB - Caterpillars have long been used as models for studying animal defence. Their impressive armour, including flamboyant warning colours, poisonous spines, irritating sprays, and mimicry of plant parts, snakes and bird droppings, has been extensively documented. But research has mainly focused on visual and chemical displays. Here we show that some caterpillars also exhibit sonic displays. During simulated attacks, 45% of 38 genera and 33% of 61 species of silk and hawkmoth caterpillars (Bombycoidea) produced sounds. Sonic caterpillars are found in many distantly-related groups of Bombycoidea, and have evolved four distinct sound types- clicks, chirps, whistles and vocalizations. We propose that different sounds convey different messages, with some designed to warn of a chemical defence and others, to startle predators. This research underscores the importance of exploring acoustic communication in juvenile insects, and provides a model system to explore how different signals have evolved to frighten, warn or even trick predators. PMID- 27510512 TI - Cyclization of N-arylcyclopropanecarboxamides into N-arylpyrrolidin-2-ones under electron ionization and in the condensed phase. AB - RATIONALE: Mass spectrometry is known as an excellent method to predict the behavior of organic compounds in solution. The behavior of organic compounds in the gas phase inside the ion source of a mass spectrometer allows their intrinsic properties to be defined, avoiding the influence of intermolecular interactions, counter ions and solvent effects. METHODS: Arylpyrrolidin-2-ones were obtained by condensed-phase synthesis from the corresponding N-arylcyclopropanecarboxamides. Electron ionization (EI) with accurate mass measurements by high-resolution time of-flight mass-spectrometry and quantum chemical calculations were used to understand the behavior of the molecular radical cations of N arylcyclopropanecarboxamides and N-arylpyrrolidin-2-ones in the ion source of a mass spectrometer. The geometries of the molecules, transition states, and intermediates were fully optimized using DFT-PBE calculations. RESULTS: Fragmentation schemes, ion structures, and possible mechanisms of primary isomerisation were proposed for isomeric N-arylcyclopropanecarboxamides and N arylpyrrolidin-2-ones. Based on the fragmentation pattern of the N arylcyclopropanecarboxamides, isomerisation of the original M+* ions into the M+* ions of the N-arylpyrrolidin-2-ones was shown to be only a minor process. In contrast, this cyclization proceeds easily in the condensed phase in the presence of Bronsted acids. CONCLUSIONS: Based on the experimental data and quantum chemical calculations the principal mechanism of decomposition of the molecular ions of N-arylcyclopropanecarboxamides involves their direct fragmentation without any rearrangements. An alternative mechanism is responsible for the isomerisation of a small portion of the higher energy molecular ions into the corresponding N-arylpyrrolidin-2-one ions. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27510513 TI - Engineered T Cells Improve Pancreatic Cancer Outcomes in Mice. PMID- 27510514 TI - "P < 0.05" Might Not Mean What You Think: American Statistical Association Clarifies P Values. PMID- 27510511 TI - Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013. AB - OBJECTIVE: To quantify the dose-response associations between total physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events. DESIGN: Systematic review and Bayesian dose response meta-analysis. DATA SOURCES: PubMed and Embase from 1980 to 27 February 2016, and references from relevant systematic reviews. Data from the Study on Global AGEing and Adult Health conducted in China, Ghana, India, Mexico, Russia, and South Africa from 2007 to 2010 and the US National Health and Nutrition Examination Surveys from 1999 to 2011 were used to map domain specific physical activity (reported in included studies) to total activity. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective cohort studies examining the associations between physical activity (any domain) and at least one of the five diseases studied. RESULTS: 174 articles were identified: 35 for breast cancer, 19 for colon cancer, 55 for diabetes, 43 for ischemic heart disease, and 26 for ischemic stroke (some articles included multiple outcomes). Although higher levels of total physical activity were significantly associated with lower risk for all outcomes, major gains occurred at lower levels of activity (up to 3000-4000 metabolic equivalent (MET) minutes/week). For example, individuals with a total activity level of 600 MET minutes/week (the minimum recommended level) had a 2% lower risk of diabetes compared with those reporting no physical activity. An increase from 600 to 3600 MET minutes/week reduced the risk by an additional 19%. The same amount of increase yielded much smaller returns at higher levels of activity: an increase of total activity from 9000 to 12 000 MET minutes/week reduced the risk of diabetes by only 0.6%. Compared with insufficiently active individuals (total activity <600 MET minutes/week), the risk reduction for those in the highly active category (>=8000 MET minutes/week) was 14% (relative risk 0.863, 95% uncertainty interval 0.829 to 0.900) for breast cancer; 21% (0.789, 0.735 to 0.850) for colon cancer; 28% (0.722, 0.678 to 0.768) for diabetes; 25% (0.754, 0.704 to 0.809) for ischemic heart disease; and 26% (0.736, 0.659 to 0.811) for ischemic stroke. CONCLUSIONS: People who achieve total physical activity levels several times higher than the current recommended minimum level have a significant reduction in the risk of the five diseases studied. More studies with detailed quantification of total physical activity will help to find more precise relative risk estimates for different levels of activity. PMID- 27510515 TI - Physical Activity Associated With Fewer Cancers. PMID- 27510517 TI - Mammaprint Reveals Who Can Skip Chemotherapy for Breast Cancer. PMID- 27510518 TI - Tackling Mesothelioma With Immunotherapies. PMID- 27510520 TI - Accuracy of classification of invasive lobular carcinoma on needle core biopsy of the breast. AB - Although the UK National Institute for Health and Care Excellence guidelines recommend that in patients with biopsy-proven invasive lobular carcinoma (ILC), preoperative MRI scan is considered, the accuracy of diagnosis of ILC in core biopsy of the breast has not been previously investigated. Eleven pathology laboratories from the UK and Ireland submitted data on 1112 cases interpreted as showing features of ILC, or mixed ILC and IDC/no special type (NST)/other tumour type, on needle core biopsy through retrieval of histology reports. Of the total 1112 cases, 844 were shown to be pure ILC on surgical excision, 154 were mixed ILC plus another type (invariably ductal/NST) and 113 were shown to be ductal/NST. Of those lesions categorised as pure ILC on core, 93% had an element of ILC correctly identified in the core biopsy sample and could be considered concordant. Of cores diagnosed as mixed ILC plus another type on core, complete agreement between core and excision was 46%, with 27% cases of pure ILC, whilst 26% non-concordant. These data indicate that there is not a large excess of expensive MRIs being performed as a result of miscategorisation histologically. PMID- 27510521 TI - Voriconazole more likely than posaconazole increases plasma exposure to sublingual buprenorphine causing a risk of a clinically important interaction. AB - PURPOSE: This study aimed to determine possible effects of voriconazole and posaconazole on the pharmacokinetics and pharmacological effects of sublingual buprenorphine. METHODS: We used a randomized, placebo-controlled crossover study design with 12 healthy male volunteers. Subjects were given a dose of 0.4 mg (0.6 mg during placebo phase) sublingual buprenorphine after a 5-day oral pretreatment with either (i) placebo, (ii) voriconazole 400 mg twice daily on the first day and 200 mg twice daily thereafter or (iii) posaconazole 400 mg twice daily. Plasma and urine concentrations of buprenorphine and its primary active metabolite norbuprenorphine were monitored over 18 h and pharmacological effects were measured. RESULTS: Compared to placebo, voriconazole increased the mean area under the plasma concentration-time curve (AUC0-infinity) of buprenorphine 1.80 fold (90 % confidence interval 1.45-2.24; P < 0.001), its peak concentration (Cmax) 1.37-fold (P < 0.013) and half-life (t 1/2 ) 1.37-fold (P < 0.001). Posaconazole increased the AUC00-infinity of buprenorphine 1.25-fold (P < 0.001). Most of the plasma norbuprenorphine concentrations were below the limit of quantification (0.05 ng/ml). Voriconazole, unlike posaconazole, increased the urinary excretion of norbuprenorphine 1.58-fold (90 % confidence interval 1.18 2.12; P < 0.001) but there was no quantifiable parent buprenorphine in urine. Plasma buprenorphine concentrations correlated with the pharmacological effects, but the effects did not differ significantly between the phases. CONCLUSIONS: Voriconazole, and to a minor extent posaconazole, increase plasma exposure to sublingual buprenorphine, probably via inhibition of cytochrome P450 3 A and/or P glycoprotein. Care should be exercised in the combined use of buprenorphine with triazole antimycotics, particularly with voriconazole, because their interaction can be of clinical importance. PMID- 27510522 TI - Traditional Chinese medicine: Pivotal role of the spleen in the metabolism of aristolochic acid I in rats is dependent on oatp2a1. AB - The genotoxicity and cytotoxicity of aristolochic acids is well documented, and the Aristolochiaceae plant family has been widely used in China and India for medical purposes. However, the mechanisms of aristolochic acid I (AAI) in treatment and toxicity remain to be fully elucidated. According to the theory of traditional Chinese medicine (TCM), the spleen is responsible for transportation and transformation, in which a substance is transformed, absorbed and distributed in the body. In the present study, rats were randomized into a blank group without spleen deficiency and a spleen deficiency group to investigate the metabolism of AAI. The results showed that the concentration of AAI was higher in the spleen deficiency group, compared with that of the blank group. To further elucidate this process, the expression of organic anion transporting peptide (oatp)2a1 in the rats of the two groups were examined following oral administration of AAI. It was observed that the mRNA level of oatp2a1 in the small intestine of the blank+AAI 60 min group was downregulated, compared with that in the blank group. Compared with the mRNA level of oatp2a1 in the spleen deficiency group, the expression levels in the lung and liver were downregulated in the spleen deficiency+AAI 5 min group, whereas expression levels in the kidney in the spleen deficiency+AAI 60 min group were upregulated. Based on the above results, it was hypothesized that the expression of oatp2a1 may be one of the mechanisms of AAI metabolism in rats. In TCM, the spleen and certain functions of the small intestine, are important in AAI metabolism, and affect the toxicity of AAI. In addition, the lung, liver and kidney may also be involved in spleen deficiency syndrome in rats. PMID- 27510523 TI - A blueprint for robotic navigation: pre-clinical simulation for transanal total mesorectal excision (taTME). PMID- 27510525 TI - Social networking for patients. PMID- 27510524 TI - Surgical timing after chemoradiotherapy for rectal cancer, analysis of technique (STARRCAT): results of a feasibility multi-centre randomized controlled trial. AB - BACKGROUND: The optimal time of rectal resection after long-course chemoradiotherapy (CRT) remains unclear. A feasibility study was undertaken for a multi-centre randomized controlled trial evaluating the impact of the interval after chemoradiotherapy on the technical complexity of surgery. METHODS: Patients with rectal cancer were randomized to either a 6- or 12-week interval between CRT and surgery between June 2012 and May 2014 (ISRCTN registration number: 88843062). For blinded technical complexity assessment, the Observational Clinical Human Reliability Analysis technique was used to quantify technical errors enacted within video recordings of operations. Other measured outcomes included resection completeness, specimen quality, radiological down-staging, tumour cell density down-staging and surgeon-reported technical complexity. RESULTS: Thirty-one patients were enrolled: 15 were randomized to 6 and 16-12 weeks across 7 centres. Fewer eligible patients were identified than had been predicted. Of 23 patients who underwent resection, mean 12.3 errors were observed per case at 6 weeks vs. 10.7 at 12 weeks (p = 0.401). Other measured outcomes were similar between groups. CONCLUSIONS: The feasibility of measurement of operative performance of rectal cancer surgery as an endpoint was confirmed in this exploratory study. Recruitment of sufficient numbers of patients represented a challenge, and a proportion of patients did not proceed to resection surgery. These results suggest that interval after CRT may not substantially impact upon surgical technical performance. PMID- 27510526 TI - Metabolites of the PAH diol epoxide pathway and other urinary biomarkers of phenanthrene and pyrene in workers with and without exposure to bitumen fumes. AB - PURPOSE: This study investigates the diol epoxide pathway of phenanthrene (PHE) together with phenolic metabolites of PHE and pyrene (PYR) in workers with and without exposure to bitumen fumes. METHODS: The metabolite concentrations were determined in urine samples collected from 91 mastic asphalt workers and 42 construction workers as reference group before and after shift. During shift, vapours and aerosols of bitumen were measured according to a German protocol in the workers' breathing zone. RESULTS: The median concentration of vapours and aerosols of bitumen in mastic asphalt workers was 6.3 mg/m3. Metabolite concentrations were highest in post-shift urines of smokers with bitumen exposure and showed an increase during shift. The Spearman correlations between the creatinine-adjusted concentrations of metabolites and vapours and aerosols of bitumen in non-smokers were weak (e.g. sum of Di-OH-PYR: 0.28) or negligible (e.g. 1,2-PHE-diol: 0.08; PHE-tetrol: 0.12). Metabolites from the diol epoxide pathway of PHE were excreted in higher concentrations than phenolic metabolites (post-shift, non-smoking asphalt workers: 1,2-PHE-diol 2.59 ug/g crea vs. sum of all OH-PHE 1.87 ug/g crea). 1,2-PHE-diol was weakly correlated with PHE-tetrol (Spearman coefficient 0.30), an endpoint of the diol epoxide pathway. By contrast, we found a close correlation between the sum of 1,6-DiOH-PYR and 1,8 DiOH-PYR with 1-OH-PYR (Spearman coefficient 0.76). CONCLUSIONS: Most urinary PAH metabolites were higher after shift in bitumen-exposed workers, although the association with bitumen was weak or negligible likely due to the small PAH content. The additional metabolites of PHE and PYR complete the picture of the complex metabolic pathways. Nevertheless, none of the PAH metabolites can be considered to be a specific biomarker for bitumen exposure. PMID- 27510527 TI - Ministry-Related Burnout and Stress Coping Mechanisms Among Assemblies of God Ordained Clergy in Minnesota. AB - Clergy members suffering from burnout face both personal and professional complications. This study assessed occupational burnout and stress coping mechanisms among ministers affiliated with the Assemblies of God, a denomination that has received little attention in previous burnout-related studies. A cross sectional design was employed using two instruments with acceptable psychometric properties. Approximately 65 % of those surveyed were either suffering from burnout or on the verge of burnout. Statistical differences in coping mechanism use were found between those who were and were not experiencing some level of burnout. The results of this study add to the existing understanding of occupational burnout among clergy members and ways in which burnout may be alleviated. PMID- 27510528 TI - Protective Role of Spirituality from the Perspective of Indian College Students with Suicidal Ideation: "I am here Because God Exists". AB - Spiritual beliefs are found to be having a significant effect during times of struggles and trials in peoples' lives. India being a multi-religious society, it is imperative to establish the relevance of spirituality in the lives of the college students with suicidal ideation. The current study therefore utilized focus group methodology to explore the Indian female college students' perceptions on the protective role of spirituality as a factor contributing to their positive adaptation in times of adversity. Twenty students participated in the discussion. The results interestingly surfaced themes supporting the significance of them on how individuals rely on spiritual beliefs and the possible implications of the need to address it for positive adaptation. Most of the participants analogically stated the themes emerged as "something to stay afloat in the rough sea of life's realities." PMID- 27510529 TI - The role of microRNA-31 and microRNA-21 as regulatory biomarkers in the activation of T lymphocytes of Egyptian lupus patients. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by familial aggregation and genetic predisposition. MicroRNAs (MiRNAs) serve as critical biomarkers in lupus patients because of their aberrant expression in different SLE stages. The study aimed to investigate the correlation of miR-31 and miR-21 with IL-2 in SLE patients as regulatory biomarkers in the activation of T lymphocytes of Egyptian lupus patients. Quantitative RT-PCR is carried out to estimate the expressions of miR-31 and miR-21, and IL-2 levels were determined using ELISA in plasma of 40 patients with SLE, 20 of their first-degree relatives and 20 healthy controls. The study also determined the systemic lupus erythematosus disease activity index (SLEDAI) score and proteinuria in SLE patients. The results revealed that miR-31 was lower expressed, while miR-21 was high expressed in SLE patients compared to their first-degree relatives and controls. MiR-31 was negatively correlated with SLEDAI and proteinuria in lupus patients, while miR-21 showed positive correlation with them. Also we found that there is a significant positive correlation between miR-31 and IL-2 in SLE patients, while miR-21 was negatively correlated with IL-2 level in patients. In conclusion, the study disclosed a significant association between miR-31 and miR 21 expression with IL-2 level in SLE patients. The regulatory biomarkers of miR 31 and miR-21 might have an impact on regulating IL-2 pathway expression and in turn on the activation of T lymphocytes in SLE. PMID- 27510530 TI - Macrophage activation syndrome in children with systemic juvenile idiopathic arthritis and systemic lupus erythematosus. AB - Macrophage activation syndrome (MAS) is a hyper-inflammatory disorder secondary to a rheumatic disease such as systemic juvenile idiopathic arthritis (SJIA) and systemic lupus erythematosus (SLE). We aimed to present the characteristics of our pediatric MAS patients. Clinical features, laboratory parameters, treatment, and outcome of 34 patients (28 SJIA; six SLE; 37 MAS episodes) followed at a tertiary health center between 2009 and 2015 were retrospectively reviewed. The median age at MAS onset was 11 years. More SJIA patients had MAS at disease onset than SLE patients (53.6 vs. 16.7 %). Fever, high C-reactive protein and hyperferritinemia were present in all MAS episodes. Rash was less (p = 0.03), and fatigue was more frequent (p = 0.042) in SLE than SJIA patients. All received corticosteroids. Cyclosporine was given in 74.2 % of SJIA-MAS; 66.7 % of SLE-MAS episodes. Intravenous immunoglobulin, anakinra, or etoposide was administered during 67.7; 41.9; 32.3 % of SJIA-MAS and 33.3; 33.3; 50 % of SLE-MAS episodes, respectively. Plasmapheresis was performed during 41.9 % of SJIA-MAS and 33.3 % of SLE-MAS episodes. The mortality rate was 11.8 % (n = 4;3 SJIA, 1 SLE). Hepatosplenomegaly was more frequent (p = 0.005), and plasmapheresis was performed more frequently (p = 0.021) in the patients who died compared to the cured patients. The median duration between symptom onset and admission to our hospital was longer among the patients who died (16.5 vs. 7 days; p = 0.049). Our patients' characteristics were similar to the reported cases, but our mortality rate is slightly higher probably due to late referral to our center. Early diagnosis and effective treatment are crucial to prevent mortality. PMID- 27510532 TI - The effects of resistance exercise and oral nutritional supplementation during hemodialysis on indicators of nutritional status and quality of life. AB - BACKGROUND: Protein-energy wasting (PEW) is common in patients undergoing hemodialysis (HD). Studies have assessed the positive effect of oral nutritional supplementation (ONS) or resistance exercise (RE) on nutritional status (NS) markers in patients undergoing HD. METHODS: The aim of this study was to assess the effect of ONS and RE on NS and the quality of life (QOL) of 36 patients undergoing HD. In a randomized clinical trial, patients were divided into the following two groups: a control group (ONS) that received a can of ONS during their HD sessions and an intervention group (ONS + RE) that received a can of ONS and underwent a 40-min session of RE during their HD sessions. Both interventions lasted 12 weeks. The patients' anthropometric, biochemical, dietetic and bioelectrical impedance measurements as well as their QOL, evaluated using the Kidney Disease Quality of Life Short Form, were recorded. RESULTS: At baseline, 55.5% of patients presented with PEW according to International Society of Renal Nutrition and Metabolism criteria (20 patients). We found statistically significant changes from baseline in both groups, such as increases in body weight, body mass index, midarm circumference, midarm muscle circumference, triceps skinfold thickness, fat mass percentage, handgrip strength, phase angle and serum albumin. A decrease in the prevalence of PEW was observed in both groups at the end of the intervention. A delta comparison between groups showed no statistically significant differences in the anthropometric and biochemical parameters. No significant improvement was observed in QOL and body composition measured by bioimpedance vector analysis. Dietary energy and protein intake increased significantly during the study period for all patients. CONCLUSION: Oral nutritional supplementation during HD improves NS. The addition of RE during HD does not seem to augment the acute anabolic effects of intradialytic ONS on NS. PMID- 27510531 TI - Intracellular calcium increases in vascular smooth muscle cells with progression of chronic kidney disease in a rat model. AB - Background: Vascular smooth muscle cells (VSMCs) exhibit phenotypic plasticity, promoting vascular calcification and increasing cardiovascular risk. Changes in VSMC intracellular calcium ([Ca 2+ ] i ) are a major determinant of plasticity, but little is known about changes in [Ca 2+ ] i in chronic kidney disease (CKD). We have previously demonstrated such plasticity in aortas from our rat model of CKD and therefore sought to examine changes in [Ca 2+ ] i during CKD progression. Materials and Methods: We examined freshly isolated VSMCs from aortas of normal rats, Cy/+ rats (CKD) with early and advanced CKD, and advanced CKD rats treated without and with 3% calcium gluconate (CKD + Ca 2+ ) to lower parathyroid hormone (PTH) levels. [Ca 2+ ] i was measured with fura-2. Results: Cy/+ rats developed progressive CKD, as assessed by plasma levels of blood urea nitrogen, calcium, phosphorus, parathyroid hormone and fibroblast growth factor 23. VSMCs isolated from rats with CKD demonstrated biphasic alterations in resting [Ca 2+ ] i : VSMCs from rats with early CKD exhibited reduced resting [Ca 2+ ] i , while VSMCs from rats with advanced CKD exhibited elevated resting [Ca 2+ ] i . Caffeine induced sarcoplasmic reticulum (SR) Ca 2+ store release was modestly increased in early CKD and was more drastically increased in advanced CKD. The advanced CKD elevation in SR Ca 2+ store release was associated with a significant increase in the activity of the sarco-endoplasmic reticulum Ca 2+ ATPase (SERCA); however, SERCA2a protein expression was decreased in advanced CKD. Following SR Ca 2+ store release, recovery of [Ca 2+ ] i in the presence of caffeine and extracellular Ca 2+ was attenuated in VSMCs from rats with advanced CKD. This impairment, together with reductions in expression of the Na + /Ca 2+ exchanger, suggest a reduction in Ca 2+ extrusion capability. Finally, store-operated Ca 2+ entry (SOCE) was assessed following SR Ca 2+ store depletion. Ca 2+ entry during recovery from caffeine-induced SR Ca 2+ store release was elevated in advanced CKD, suggesting a role for exacerbated SOCE with progressing CKD. Conclusions: With progressive CKD in the Cy/+ rat there is increased resting [Ca 2+ ] i in VSMCs due, in part, to increased SOCE and impaired calcium extrusion from the cell. Such changes may predispose VSMCs to phenotypic changes that are a prerequisite to calcification. PMID- 27510533 TI - Epicatechin, procyanidins, cocoa, and appetite: a randomized controlled trial. AB - BACKGROUND: In 2 randomized controlled trials, it was reported that dark chocolate acutely decreased appetite in human subjects, but the authors did not assess the types or concentrations of cocoa compounds that are needed. Other studies have suggested that the cocoa compounds epicatechin and procyanidins may be involved. OBJECTIVE: We sought to test the hypotheses that, compared with placebo (an alkalized cocoa mixture containing essentially no epicatechin or procyanidins), the following beverages cause a decrease in appetite: 1) a nonalkalized cocoa mixture; 2) epicatechin plus placebo; and 3) procyanidins plus placebo. We measured the concentrations of cocoa compounds in all beverages. DESIGN: We used a 4-way randomized, crossover, placebo-controlled trial that was balanced for period and carryover effects in 28 healthy, young-adult men. We also conducted a smaller (n = 14), parallel, secondary randomized trial in which we explored the effects of higher doses of epicatechin and procyanidins. Our primary measure of appetite was ad libitum pizza intake 150 min after beverage ingestion. We used a linear mixed-model analysis. RESULTS: Intakes of beverages with the nonalkalized cocoa mixture that contained 0.6 mg epicatechin, 0.2 mg catechin, and 2.9 mg monomer-decamer procyanidins/kg body weight did not decrease pizza intake significantly (P = 0.29) compared with intake of the placebo. In the smaller secondary trial, a combination of epicatechin and the nonalkalized cocoa mixture that contained 1.6 mg epicatechin/kg body weight significantly decreased pizza intake by 18.7% (P = 0.04). CONCLUSIONS: Our nonalkalized cocoa mixture was associated with an acute decrease in food intake only after being supplemented with epicatechin. It is possible that epicatechin at a dose of >1.6 mg/kg body weight, alone or in concert with appropriate catalytic cocoa compounds, may be useful for helping people control their food intakes. This trial was registered at clinicaltrials.gov as NCT02408289. PMID- 27510534 TI - Biofortified beta-carotene rice improves vitamin A intake and reduces the prevalence of inadequacy among women and young children in a simulated analysis in Bangladesh, Indonesia, and the Philippines. AB - BACKGROUND: Vitamin A deficiency continues to be a major public health problem affecting developing countries where people eat mostly rice as a staple food. In Asia, rice provides up to 80% of the total daily energy intake. OBJECTIVE: We used existing data sets from Bangladesh, Indonesia, and the Philippines, where dietary intakes have been quantified at the individual level to 1) determine the rice and vitamin A intake in nonpregnant, nonlactating women of reproductive age and in nonbreastfed children 1-3 y old and 2) simulate the amount of change that could be achieved in the prevalence of inadequate intake of vitamin A if rice biofortified with beta-carotene were consumed instead of the rice consumed at present. DESIGN: We considered a range of 4-20 parts per million (ppm) of beta carotene content and 10-70% substitution levels for the biofortified rice. Software was used to estimate usual rice and vitamin A intake for the simulation analyses. RESULTS: In an analysis by country, the substitution of biofortified rice for white rice in the optimistic scenario (20 ppm and 70% substitution) decreased the prevalence of vitamin A inadequacy from baseline 78% in women and 71% in children in Bangladesh. In Indonesia and the Philippines, the prevalence of inadequacy fell by 55-60% in women and dropped by nearly 30% in children from baseline. CONCLUSIONS: The results of the simulation analysis were striking in that even low substitution levels and modest increases in the beta-carotene of rice produced a meaningful decrease in the prevalence of inadequate intake of vitamin A. Increasing the substitution levels had a greater impact than increasing the beta-carotene content by >12 ppm. PMID- 27510536 TI - Minor degree of hypohydration adversely influences cognition: a mediator analysis. AB - BACKGROUND: Because the assumption that small changes in hydration status are readily compensated by homeostatic mechanisms has been little studied, the influence of hypohydration on cognition was examined. OBJECTIVES: We assessed whether a loss of <1% of body mass due to hypohydration adversely influenced cognition, and examined the possible underlying mechanisms. DESIGN: A total of 101 individuals were subjected to a temperature of 30 degrees C for 4 h and randomly either did or did not consume 300 mL H2O during that period. Changes in body mass, urine osmolality, body temperature, and thirst were monitored. Episodic memory, focused attention, mood, and the perceived difficulty of tasks were measured on 3 occasions. The data were analyzed with the use of a regression based approach whereby we looked for variables that mediated the influence of hypohydration on psychological functioning. RESULTS: Drinking water improved memory and focused attention. In the short-term, thirst was associated with poorer memory. Later, a greater loss of body mass was associated with poorer memory and attention (mean loss: 0.72%). At 90 min, an increase in thirst was associated with a decline in subjective energy and increased anxiety and depression, effects that were reduced by drinking water. At 180 min, subjects found the tests easier if they had consumed water. CONCLUSIONS: Drinking water was shown, for the first time to our knowledge, to benefit cognitive functioning when there was a loss of <1% body mass at levels that may occur during everyday living. Establishing the variables that generate optimal fluid consumption will help to tailor individual advice, particularly in clinical situations. This trial was registered at clinicaltrials.gov as NCT02671149. PMID- 27510535 TI - Predictors of failure of fish-oil therapy for intestinal failure-associated liver disease in children. AB - BACKGROUND: Parenteral fish-oil (FO) therapy is a safe and effective treatment for intestinal failure-associated liver disease (IFALD). Patients whose cholestasis does not resolve with FO may progress to end-stage liver disease. OBJECTIVE: We sought to identify factors associated with the failure of FO therapy in treating IFALD to guide prognostication and referral guidelines. DESIGN: Prospectively collected data for patients treated with FO at Boston Children's Hospital from 2004 to 2014 were retrospectively reviewed. Resolution of cholestasis was defined as sustained direct bilirubin (DB) <2 mg/dL, and treatment failure as liver transplantation or death while DB was >2 mg/dL as of July 2015. Demographics, laboratory values, and medical history at FO therapy initiation were compared between patients who achieved resolution of cholestasis and those who failed therapy. RESULTS: Among 182 patients treated with FO, 86% achieved resolution of cholestasis and 14% failed therapy. Patients who failed therapy had median (IQR) lower birth weight [1020 g (737, 1776 g) compared with 1608 g (815, 2438 g); P = 0.03] and were older at FO initiation [20.4 wk (9.9, 38.6 wk) compared with 11.7 wk (7.3, 21.4 wk); P = 0.02] than patients whose cholestasis resolved. Patients who failed therapy had more advanced liver disease at therapy initiation than patients whose cholestasis resolved, as evidenced by lower median (IQR) gamma-glutamyltransferase [54 U/L (41, 103 U/L) compared with 112 U/L (76, 168 U/L); P < 0.001], higher DB [10.4 mg/dL (7.5, 14.1 mg/dL) compared with 4.4 mg/dL (3.1, 6.6 mg/dL); P < 0.001], and a higher pediatric end stage liver disease (PELD) score [22 (14, 25) compared with 12 (7, 15); P < 0.001]. A PELD score of >=15, history of gastrointestinal bleeding, age at FO initiation >=16 wk, presence of nongastrointestinal comorbidities, and mechanical ventilation at FO initiation were independent predictors of treatment failure. CONCLUSIONS: Most infants with IFALD responded to FO therapy with resolution of cholestasis, and liver transplantation was rarely required. Early FO initiation once biochemical cholestasis is detected in parenteral nutrition-dependent patients is recommended. This trial was registered at clinicaltrials.gov as NCT00910104. PMID- 27510538 TI - Distinct lipid profiles predict improved glycemic control in obese, nondiabetic patients after a low-caloric diet intervention: the Diet, Obesity and Genes randomized trial. AB - BACKGROUND: An aim of weight loss is to reduce the risk of type 2 diabetes (T2D) in obese subjects. However, the relation with long-term glycemic improvement remains unknown. OBJECTIVE: We evaluated the changes in lipid composition during weight loss and their association with long-term glycemic improvement. DESIGN: We investigated the plasma lipidome of 383 obese, nondiabetic patients within a randomized, controlled dietary intervention in 8 European countries at baseline, after an 8-wk low-caloric diet (LCD) (800-1000 kcal/d), and after 6 mo of weight maintenance. RESULTS: After weight loss, a lipid signature identified 2 groups of patients who were comparable at baseline but who differed in their capacities to lose weight and improve glycemic control. Six months after the LCD, one group had significant glycemic improvement [homeostasis model assessment of insulin resistance (HOMA-IR) mean change: -0.92; 95% CI: -1.17, -0.67)]. The other group showed no improvement in glycemic control (HOMA-IR mean change: -0.26; 95% CI: 0.64, 0.13). These differences were sustained for >=1 y after the LCD. The same conclusions were obtained with other endpoints (Matsuda index and fasting insulin and glucose concentrations). Significant differences between the 2 groups were shown in leptin gene expression in adipose tissue biopsies. Significant differences were also observed in weight-related endpoints (body mass index, weight, and fat mass). The lipid signature allowed prediction of which subjects would be considered to be insulin resistant after 6 mo of weight maintenance [validation's receiver operating characteristic (ROC) area under the curve (AUC): 71%; 95% CI: 62%, 81%]. This model outperformed a clinical data-only model (validation's ROC AUC: 61%; 95% CI: 50%, 71%; P = 0.01). CONCLUSIONS: In this study, we report a lipid signature of LCD success (for weight and glycemic outcome) in obese, nondiabetic patients. Lipid changes during an 8-wk LCD allowed us to predict insulin-resistant patients after 6 mo of weight maintenance. The determination of the lipid composition during an LCD enables the identification of nonresponders and may help clinicians manage metabolic outcomes with further intervention, thereby improving the long-term outcome and preventing T2D. This trial was registered at clinicaltrials.gov as NCT00390637. PMID- 27510537 TI - Comparing metabolite profiles of habitual diet in serum and urine. AB - BACKGROUND: Diet plays an important role in chronic disease etiology, but some diet-disease associations remain inconclusive because of methodologic limitations in dietary assessment. Metabolomics is a novel method for identifying objective dietary biomarkers, although it is unclear what dietary information is captured from metabolites found in serum compared with urine. OBJECTIVE: We compared metabolite profiles of habitual diet measured from serum with those measured from urine. DESIGN: We first estimated correlations between consumption of 56 foods, beverages, and supplements assessed by a food-frequency questionnaire, with 676 serum and 848 urine metabolites identified by untargeted liquid chromatography mass spectrometry, ultra-high performance liquid chromatography tandem mass spectrometry, and gas chromatography mass spectrometry in a colon adenoma case control study (n = 125 cases and 128 controls) while adjusting for age, sex, smoking, fasting, case-control status, body mass index, physical activity, education, and caloric intake. We controlled for multiple comparisons with the use of a false discovery rate of <0.1. Next, we created serum and urine multiple metabolite models to predict food intake with the use of 10-fold crossvalidation least absolute shrinkage and selection operator regression for 80% of the data; predicted values were created in the remaining 20%. Finally, we compared predicted values with estimates obtained from self-reported intake for metabolites measured in serum and urine. RESULTS: We identified metabolites associated with 46 of 56 dietary items; 417 urine and 105 serum metabolites were correlated with >=1 food, beverage, or supplement. More metabolites in urine (n = 154) than in serum (n = 39) were associated uniquely with one food. We found previously unreported metabolite associations with leafy green vegetables, sugar sweetened beverages, citrus, added sugar, red meat, shellfish, desserts, and wine. Prediction of dietary intake from multiple-metabolite profiles was similar between biofluids. CONCLUSIONS: Candidate metabolite biomarkers of habitual diet are identifiable in both serum and urine. Urine samples offer a valid alternative or complement to serum for metabolite biomarkers of diet in large-scale clinical or epidemiologic studies. PMID- 27510539 TI - The effect of the apolipoprotein E genotype on response to personalized dietary advice intervention: findings from the Food4Me randomized controlled trial. AB - BACKGROUND: The apolipoprotein E (APOE) risk allele (E4) is associated with higher total cholesterol (TC), amplified response to saturated fatty acid (SFA) reduction, and increased cardiovascular disease. Although knowledge of gene risk may enhance dietary change, it is unclear whether E4 carriers would benefit from gene-based personalized nutrition (PN). OBJECTIVES: The aims of this study were to 1) investigate interactions between APOE genotype and habitual dietary fat intake and modulations of fat intake on metabolic outcomes; 2) determine whether gene-based PN results in greater dietary change than do standard dietary advice (level 0) and nongene-based PN (levels 1-2); and 3) assess the impact of knowledge of APOE risk (risk: E4+, nonrisk: E4-) on dietary change after gene based PN (level 3). DESIGN: Individuals (n = 1466) recruited into the Food4Me pan European PN dietary intervention study were randomly assigned to 4 treatment arms and genotyped for APOE (rs429358 and rs7412). Diet and dried blood spot TC and omega-3 (n-3) index were determined at baseline and after a 6-mo intervention. Data were analyzed with the use of adjusted general linear models. RESULTS: Significantly higher TC concentrations were observed in E4+ participants than in E4- (P < 0.05). Although there were no significant differences in APOE response to gene-based PN (E4+ compared with E4-), both groups had a greater reduction in SFA (percentage of total energy) intake than at level 0 (mean +/- SD: E4+, -0.72% +/- 0.35% compared with -1.95% +/- 0.45%, P = 0.035; E4-, -0.31% +/- 0.20% compared with -1.68% +/- 0.35%, P = 0.029). Gene-based PN was associated with a smaller reduction in SFA intake than in nongene-based PN (level 2) for E4- participants (-1.68% +/- 0.35% compared with -2.56% +/- 0.27%, P = 0.025). CONCLUSIONS: The APOE E4 allele was associated with higher TC. Although gene based PN targeted to APOE was more effective in reducing SFA intake than standard dietary advice, there was no difference between APOE "risk" and "nonrisk" groups. Furthermore, disclosure of APOE nonrisk may have weakened dietary response to PN. This trial was registered at clinicaltrials.gov as NCT01530139. PMID- 27510542 TI - What Defines Us as Professionals in the Field of Risk Analysis? AB - In a recent issue of Risk Analysis, the then-President of the Society for Risk Analysis (SRA), Pamela Williams, has some interesting reflections about the risk analysis field. She states that the ability and desire to tackle difficult problems using a risk analytical approach is what uniquely defines us as professionals in the field of risk analysis. The point of departure for her discussion is interviews with the plenary speakers of the 2014 SRA Annual Meeting, who addressed two divisive topics: hydraulic fracking and marijuana use. She points to several themes that invite contributions from the field of risk analysis, including: Has the full spectrum of potential risks and benefits been identified and weighted, and what are the risk tradeoffs or countervailing risks? Inspired by Williams's reflections, and by analyzing the issues raised in the interviews, this article seeks to clarify what our field is really providing. A main conclusion of the article is that it is essential to acknowledge that professionals in the field of risk analysis merely support the tackling of such problems, and that their genuine competence-that which distinguishes them from other professionals-lies in the risk analytical approach itself. PMID- 27510541 TI - Serum calcium and incident type 2 diabetes: the Atherosclerosis Risk in Communities (ARIC) study. AB - BACKGROUND: Elevated serum calcium has been associated with a variety of metabolic abnormalities and may be associated with a greater risk of diabetes. OBJECTIVE: The purpose of this study was to test the hypothesis that serum calcium concentration is positively and independently associated with the incidence of diabetes and to evaluate the association of calcium-sensing receptor (CaSR) gene single nucleotide polymorphism (SNP) rs1801725 with incident diabetes. DESIGN: Atherosclerosis Risk in Communities study participants free of diabetes at baseline (n = 12,800; mean age: 53.9 y; 22.6% black) were studied for incident diabetes. Serum calcium was measured at baseline and corrected for serum albumin. Diabetes was defined by use of glucose concentrations, self-report, or medication use. Cox proportional hazards regression was used. RESULTS: During a mean 8.8 y of follow-up, 1516 cases of diabetes were reported. Participants in the highest compared with lowest calcium quintile were at greater risk of incident diabetes after adjustment for demographic and lifestyle factors [HR (95% CI): 1.34 (1.14, 1.57); P-trend across quintiles <0.0001] and with further adjustment for waist circumference and body mass index [1.26 (1.07, 1.48); P trend = 0.004]. Additional adjustment for biomarkers on the metabolic pathway (e.g., 25-hydroxyvitamin D, parathyroid hormone, phosphorus) had little impact. The calcium-diabetes association was statistically significant in blacks [1.48 (1.11, 1.98); P-trend = 0.002] but not whites [1.17 (0.96, 1.43); P-trend = 0.17] after adjustment for adiposity. In whites, CaSR gene SNP rs1801725 was associated with serum calcium but not with risk of diabetes. CONCLUSIONS: Consistent with 3 previous cohort studies, elevated serum calcium was found to be associated with a greater risk of type 2 diabetes. Further research is needed to understand the role, if any, that calcium plays in the pathogenesis of diabetes. PMID- 27510543 TI - Are Pediatric Emergency Physicians More Knowledgeable and Confident to Respond to a Pediatric Disaster after an Experiential Learning Experience? AB - OBJECTIVES: Pediatric hospital disaster responders must be well-trained and prepared to manage children in a mass-casualty incident. Simulations of various types have been the traditional way of testing hospital disaster plans and training hospital staff in skills that are used in rare circumstances. The objective of this longitudinal, survey-based, observational study was to assess the effect of disaster response and management-based experiential learning on the knowledge and confidence of advanced learners. METHODS: A simulation-based workshop was created for practicing Pediatric Emergency Medicine (PEM) physicians, senior PEM physicians, and critical care and pediatric surgery residents to learn how to manage a disaster response. Given that this particular group of learners had never been exposed to such a disaster simulation, its educational value was assessed with the goal of improving the quality of the hospital pediatric medical response to a disaster by increasing the responders' knowledge and confidence. Objective and subjective measures were analyzed using both a retrospective, pre-post survey, as well as case-based evaluation grids. RESULTS: The simulation workshop improved the learners' perceived ability to manage patients in a disaster context and identified strengths and areas needing improvement for patient care within the disaster context. CONCLUSION: Advanced learners exposed to an experiential learning activity believed that it improved their ability to manage patients in a disaster situation and felt that it was valuable to their learning. Their confidence was preserved six months later. Bank I , Khalil E . Are pediatric emergency physicians more knowledgeable and confident to respond to a pediatric disaster after an experiential learning experience? Prehosp Disaster Med. 2016;31(5):551-556. PMID- 27510540 TI - Sweet-beverage consumption and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). AB - BACKGROUND: The consumption of sweet beverages has been associated with greater risk of type 2 diabetes and obesity, which may be involved in the development of pancreatic cancer. Therefore, it has been hypothesized that sweet beverages may increase pancreatic cancer risk as well. OBJECTIVE: We examined the association between sweet-beverage consumption (including total, sugar-sweetened, and artificially sweetened soft drink and juice and nectar consumption) and pancreatic cancer risk. DESIGN: The study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort. A total of 477,199 participants (70.2% women) with a mean age of 51 y at baseline were included, and 865 exocrine pancreatic cancers were diagnosed after a median follow-up of 11.60 y (IQR: 10.10-12.60 y). Sweet-beverage consumption was assessed with the use of validated dietary questionnaires at baseline. HRs and 95% CIs were obtained with the use of multivariable Cox regression models that were stratified by age, sex, and center and adjusted for educational level, physical activity, smoking status, and alcohol consumption. Associations with total soft-drink consumption were adjusted for juice and nectar consumption and vice versa. RESULTS: Total soft drink consumption (HR per 100 g/d: 1.03; 95% CI: 0.99, 1.07), sugar-sweetened soft-drink consumption (HR per 100 g/d: 1.02; 95% CI: 0.97, 1.08), and artificially sweetened soft-drink consumption (HR per 100 g/d: 1.04; 95% CI: 0.98, 1.10) were not associated with pancreatic cancer risk. Juice and nectar consumption was inversely associated with pancreatic cancer risk (HR per 100 g/d: 0.91; 95% CI: 0.84, 0.99); this association remained statistically significant after adjustment for body size, type 2 diabetes, and energy intake. CONCLUSIONS: Soft-drink consumption does not seem to be associated with pancreatic cancer risk. Juice and nectar consumption might be associated with a modest decreased pancreatic cancer risk. Additional studies with specific information on juice and nectar subtypes are warranted to clarify these results. PMID- 27510544 TI - U6atac snRNA stem-loop interacts with U12 p65 RNA binding protein and is functionally interchangeable with the U12 apical stem-loop III. AB - Formation of catalytic core of the U12-dependent spliceosome involves U6atac and U12 interaction with the 5' splice site and branch site regions of a U12 dependent intron, respectively. Beyond the formation of intermolecular helix I region between U6atac and U12 snRNAs, several other regions within these RNA molecules are predicted to form stem-loop structures. Our previous work demonstrated that the 3' stem-loop region of U6atac snRNA contains a U12 dependent spliceosome-specific targeting activity. Here, we show a detailed structure-function analysis and requirement of a substructure of U6atac 3' stem loop in U12-dependent in vivo splicing. We show that the C-terminal RNA recognition motif of p65, a U12 snRNA binding protein, also binds to the distal 3' stem-loop of U6atac. By using a binary splice site mutation suppressor assay we demonstrate that p65 protein-binding apical stem-loop of U12 snRNA can be replaced by this U6atac distal 3' stem-loop. Furthermore, we tested the compatibility of the U6atac 3' end from phylogenetically distant species in a human U6atac background, to establish the evolutionary relatedness of these structures and in vivo function. In summary, we demonstrate that RNA-RNA and RNA protein interactions in the minor spliceosome are highly plastic as compared to the major spliceosome. PMID- 27510545 TI - Adaptation to elevated CO2 in different biodiversity contexts. AB - In the absence of migration, species persistence depends on adaption to a changing environment, but whether and how adaptation to global change is altered by community diversity is not understood. Community diversity may prevent, enhance or alter how species adapt to changing conditions by influencing population sizes, genetic diversity and/or the fitness landscape experienced by focal species. We tested the impact of community diversity on adaptation by performing a reciprocal transplant experiment on grasses that evolved for 14 years under ambient and elevated CO2, in communities of low or high species richness. Using biomass as a fitness proxy, we find evidence for local adaptation to elevated CO2, but only for plants assayed in a community of similar diversity to the one experienced during the period of selection. Our results indicate that the biological community shapes the very nature of the fitness landscape within which species evolve in response to elevated CO2. PMID- 27510547 TI - Public health: What's app in emergency cardiovascular care? PMID- 27510546 TI - Calculating protein-ligand binding affinities with MMPBSA: Method and error analysis. AB - Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) methods have become widely adopted in estimating protein-ligand binding affinities due to their efficiency and high correlation with experiment. Here different computational alternatives were investigated to assess their impact to the agreement of MMPBSA calculations with experiment. Seven receptor families with both high-quality crystal structures and binding affinities were selected. First the performance of nonpolar solvation models was studied and it was found that the modern approach that separately models hydrophobic and dispersion interactions dramatically reduces RMSD's of computed relative binding affinities. The numerical setup of the Poisson-Boltzmann methods was analyzed next. The data shows that the impact of grid spacing to the quality of MMPBSA calculations is small: the numerical error at the grid spacing of 0.5 A is already small enough to be negligible. The impact of different atomic radius sets and different molecular surface definitions was further analyzed and weak influences were found on the agreement with experiment. The influence of solute dielectric constant was also analyzed: a higher dielectric constant generally improves the overall agreement with experiment, especially for highly charged binding pockets. The data also showed that the converged simulations caused slight reduction in the agreement with experiment. Finally the direction of estimating absolute binding free energies was briefly explored. Upon correction of the binding-induced rearrangement free energy and the binding entropy lost, the errors in absolute binding affinities were also reduced dramatically when the modern nonpolar solvent model was used, although further developments were apparently necessary to further improve the MMPBSA methods. (c) 2016 Wiley Periodicals, Inc. PMID- 27510548 TI - Diabetes: PCSK9 inhibition is not associated with new-onset diabetes. PMID- 27510549 TI - Anticoagulation therapy: Appropriate dosing of apixaban. PMID- 27510550 TI - Valvular disease: vWF testing for paravalvular regurgitation during TAVI. PMID- 27510551 TI - The transport properties of silicon and carbon nanotubes at the atomic scale: a first-principles study. AB - Nanotubes are one of the most promising functional materials in nanotechnology. Silicon nanotubes (SiNTs) have been experimentally validated; they are unique puckered nanotubular structures unlike carbon nanotubes (CNTs). Although the electronic and optical properties of SiNTs have been previously studied, their structure-related capability for electron transport has not been investigated. Here we report a comparative study of the intrinsic electronic and transport properties of four pairs of SiNTs and CNTs (one armchair nanotubes (3,3) and three zigzag nanotubes (5,0), (6,0) and (7,0)) using density functional theory (DFT) combined with the nonequilibrium Green's function (NEGF) method. All our investigated systems of SiNTs and CNTs are conductors. Both the armchair SiNTs and CNTs possess superior electron transport performance to their zigzag counterparts. Compared with CNTs, SiNTs have more advantages in the high bias voltage region. Especially, Si(3,3) possesses around double the potential charge capacity of C(3,3) under the bias voltage of 2.0 V. In particular, the CNT(6,0) exhibits distinct negative differential resistance (NDR) behavior and the peak valley ratio (PVR) for C(6,0) is about 1.2. PMID- 27510552 TI - Identifying protein aggregation mechanisms and quantifying aggregation rates from combined monomer depletion and continuous scattering. AB - Parallel temperature initial rates (PTIR) from chromatographic separation of aggregating protein solutions are combined with continuous simultaneous multiple sample light scattering (SMSLS) to make quantitative deductions about protein aggregation kinetics and mechanisms. PTIR determines the rates at which initially monomeric proteins are converted to aggregates over a range of temperatures, under initial-rate conditions. Using SMSLS for the same set of conditions provides time courses of the absolute Rayleigh scattering ratio, IR(t), from which a potentially different measure of aggregation rates can be quantified. The present report compares these measures of aggregation rates across a range of solution conditions that result in different aggregation mechanisms for anti streptavidin (AS) immunoglobulin gamma-1 (IgG1). The results illustrate how the two methods provide complementary information when deducing aggregation mechanisms, as well as cases where they provide new mechanistic details that were not possible to deduce in previous work. Criteria are presented for when the two techniques are expected to give equivalent results for quantitative rates, the potential limitations when solution non-idealities are large, as well as a comparison of the temperature dependence of AS-IgG1 aggregation rates with published data for other antibodies. PMID- 27510553 TI - OxLDL receptor chromatography from live human U937 cells identifies SYK(L) that regulates phagocytosis of oxLDL. AB - The binding and activation of macrophages by microscopic aggregates of oxLDL in the intima of the arteries may be an important step towards atherosclerosis leading to heart attack and stroke. Microbeads coated with oxLDL were used to activate, capture and isolate the oxLDL receptor complex from the surface of live cells. Analysis of the resulting tryptic peptides by liquid chromatography and tandem mass spectrometry revealed the Spleen Tyrosine Kinase (SYK), and many of SYK's known interaction network including Fc receptors (FCGR2A, FCER1G and FCGR1A) Toll receptor 4 (TLR4), receptor kinases like EGFRs, as well as RNA binding and metabolism proteins. High-intensity precursor ions (~9*E3 to 2*E5 counts) were correlated to peptides and specific phosphopeptides from long isoform of SYK (SYK-L) by the SEQUEST, OMSSA and X!TANDEM algorithms. Peptides or phosphopeptides from SYK were observed with the oxLDL-microbeads. Pharmacological inhibitors of SYK activity significantly reduced the engulfment of oxLDL microbeads in the presence of serum factors, but had little effect on IgG phagocytosis. Anti SYK siRNA regulated oxLD engulfment in the context of serum factors and or SYK-L siRNA significantly inhibited engulfment of oxLDL microbeads, but not IgG microbeads. PMID- 27510554 TI - The methylome and transcriptome of fetal skin: implications for scarless healing. AB - AIM: Fetal skin is known to heal without scarring. In mice, the phenomenon is observed until the 16-17 day of gestation - the day of transition from scarless to normal healing. The study aims to identify key methylome and transcriptome changes following the transition. MATERIALS & METHODS: Methylome and transcriptome profiles were analyzed in murine dorsal skin using microarray approach. RESULTS & CONCLUSION: The genes associated with inflammatory response and hyaluronate degradation showed increased DNA methylation before the transition, while those involved in embryonic morphogenesis, neuron differentiation and synapse functions did so after. A number of the methylome alterations were retained until adulthood and correlated with gene expression, while the functional associations imply that scarless healing depends on epigenetic regulation. PMID- 27510556 TI - Natural product derivative BIO promotes recovery after myocardial infarction via unique modulation of the cardiac microenvironment. AB - The cardiac microenvironment includes cardiomyocytes, fibroblasts and macrophages, which regulate remodeling after myocardial infarction (MI). Targeting this microenvironment is a novel therapeutic approach for MI. We found that the natural compound derivative, BIO ((2'Z,3'E)-6-Bromoindirubin-3'-oxime) modulated the cardiac microenvironment to exert a therapeutic effect on MI. Using a series of co-culture studies, BIO induced proliferation in cardiomyocytes and inhibited proliferation in cardiac fibroblasts. BIO produced multiple anti fibrotic effects in cardiac fibroblasts. In macrophages, BIO inhibited the expression of pro-inflammatory factors. Significantly, BIO modulated the molecular crosstalk between cardiac fibroblasts and differentiating macrophages to induce polarization to the anti-inflammatory M2 phenotype. In the optically transparent zebrafish-based heart failure model, BIO induced cardiomyocyte proliferation and completely recovered survival rate. BIO is a known glycogen synthase kinase-3beta inhibitor, but these effects could not be recapitulated using the classical inhibitor, lithium chloride; indicating novel therapeutic effects of BIO. We identified the mechanism of BIO as differential modulation of p27 protein expression and potent induction of anti-inflammatory interleukin-10. In a rat MI model, BIO reduced fibrosis and improved cardiac performance. Histological analysis revealed modulation of the cardiac microenvironment by BIO, with increased presence of anti-inflammatory M2 macrophages. Our results demonstrate that BIO produces unique effects in the cardiac microenvironment to promote recovery post-MI. PMID- 27510557 TI - Correlation of nanoscale behaviour of forces and macroscale surface wettability. AB - In this manuscript, we demonstrate a method based on atomic force microscopy which enables local probing of surface wettability. The maximum pull-off force, obtained from force spectroscopy shows a remarkable correlation with the macroscopically observed water contact angle, measured over a wide variety of surfaces starting from hydrophilic, all the way through to hydrophobic ones. This relationship, consequently, facilitates the establishment of a universal behaviour. The adhesion forces scale with the polar component of surface energy. However, no such relation could be established with the dispersive component. Hence, we postulate that the force(s) which enable us to correlate the force spectroscopy data measured on the nanoscale to the macroscopic contact angle are primarily arising from electrostatic-dipole-dipole interactions at the solid liquid interface. London forces play less of a role. This effect in is line with density functional theory (DFT) calculations suggesting a higher degree of hydroxylation of hydrophilic surfaces. This result shows that molecular simulations and measurements on an atomic scale can be extrapolated to macroscopic surface wetting problems. PMID- 27510555 TI - Recent advances in the development and application of nanoelectrodes. AB - Nanoelectrodes have key advantages compared to electrodes of conventional size and are the tool of choice for numerous applications in both fundamental electrochemistry research and bioelectrochemical analysis. This Minireview summarizes recent advances in the development, characterization, and use of nanoelectrodes in nanoscale electroanalytical chemistry. Methods of nanoelectrode preparation include laser-pulled glass-sealed metal nanoelectrodes, mass-produced nanoelectrodes, carbon nanotube based and carbon-filled nanopipettes, and tunneling nanoelectrodes. Several new topics of their recent application are covered, which include the use of nanoelectrodes for electrochemical imaging at ultrahigh spatial resolution, imaging with nanoelectrodes and nanopipettes, electrochemical analysis of single cells, single enzymes, and single nanoparticles, and the use of nanoelectrodes to understand single nanobubbles. PMID- 27510558 TI - Is visual assessment of thyroid attenuation on unenhanced CT of the chest useful for detecting hypothyroidism? AB - AIM: To determine if visual assessment of the attenuation of morphologically normal appearing thyroid glands on unenhanced computed tomography (CT) of the chest is useful for identifying patients with decreased thyroid function. MATERIALS AND METHODS: This was a retrospective study of 765 patients who underwent both unenhanced CT of the chest and thyroid function tests performed within 1 year of the CT examination. Attenuation of the thyroid gland was visually assessed in each patient relative to the attenuation of the surrounding muscles to categorise the gland as "low attenuation" (attenuation similar to surrounding muscles) or "high attenuation" (attenuation greater than surrounding muscles). Thyroid attenuation was quantitatively measured in each case to determine the validity of the visual assessment. Results of thyroid function tests were used to classify thyroid function as hypothyroid, euthyroid, or hyperthyroid. Data were analysed to determine the relationship between visual assessment of thyroid attenuation and status of thyroid function. RESULTS: Thyroid glands of low attenuation were present in 4.2% (32/765) of the patients. Nearly half (47%) of the patients with low-attenuation thyroids had hypofunctioning thyroid glands. Compared to patients with high-attenuation thyroids, patients with low-attenuation thyroids were significantly more likely to have decreased thyroid function (clinical and subclinical hypothyroidism) and significantly less likely to be euthyroid (p<0.0001). Quantitative measurement of thyroid attenuation confirmed the validity of the visual assessment. CONCLUSION: Low attenuation of an otherwise normal-appearing thyroid gland on unenhanced CT of the chest is strongly associated with decreased thyroid function. PMID- 27510559 TI - Thermal ablation for hepatocellular carcinoma: a large-scale analysis of long term outcome and prognostic factors. AB - AIM: To investigate the long-term outcome and prognostic factors when treating hepatocellular carcinoma (HCC) with thermal ablation. MATERIALS AND METHODS: A total of 846 HCC patients, diagnosed histopathologically and/or radiologically, underwent thermal ablation from October 2001 to May 2013. Thermal ablation included both radiofrequency ablation (RFA) and microwave ablation (MWA), and was performed by percutaneous, open, and laparoscopic approaches. Clinical data, especially focused on disease-free survival, were retrospectively analysed by univariate and multivariate analyses. RESULTS: A total of 1,185 thermal ablation treatments were performed, corresponding to 1,240 tumours. The complete ablation rate was 97.1%. The 12-, 24-, 36-, and 60-month disease-free survival rates after thermal ablation were 72.3%, 52.7%, 33.5%, and 16.1%, respectively. Multivariate analysis indicated that the serum alkaline phosphatase levels (ALP) and the number of tumours were independent risk factors affecting disease-free survival. The 12-, 36-, 60-, 84-, and 120-month overall survival rates of all patients were 92.9%, 74.7%, 58.1%, 41.3%, and 15.8%, respectively. Multivariate analysis indicated that age, ALP, number of tumours, and treatment sessions per case were independent risk factors related to overall survival. CONCLUSIONS: Thermal ablation was a relatively safe and effective procedure. Patients with increased serum ALP levels and/or multiple tumours had a higher incidence of recurrence and poorer prognosis, and therefore, should be monitored closely in clinical practice. PMID- 27510560 TI - Prolonged drug-induced myoclonus: is it related to palonosetron? AB - We report a case of drug-induced myoclonus possibly related to palonosetron, a second-generation 5-hydroxytryptamine-3 receptor antagonist which was administered as a prophylaxis for postoperative nausea and vomiting in a 28-year old female. The recurrent episodes of myoclonus jerk involving the head, neck and shoulder persisted for a period of 4 days. The patient also exhibited an episode of severe bradycardia leading to hypotension 7 h after surgery. To our knowledge, this is the first report presenting these adverse events potentially associated with the use of palonosetron. PMID- 27510561 TI - Magnesium-doped Zinc Oxide as Electron Selective Contact Layers for Efficient Perovskite Solar Cells. AB - The electron-selective contact layer (ESL) in organometal halide-based perovskite solar cells (PSCs) determines not only the power conversion efficiency (PCE) but also the thermostability of PSCs. To improve the thermostability of ZnO-based PSCs, we developed Mg-doped ZnO [Zn1-x Mgx O (ZMO)] as a high optical transmittance ESL for the methylammonium lead trihalide perovskite absorber [CH3 NH3 PbI3 ]. We further investigated the optical and electrical properties of the ESL films with Mg contents of 0-30 mol % and the corresponding devices. We achieved a maximum PCE of 16.5 % with improved thermal stability of CH3 NH3 PbI3 on ESL with the optimal ZMO (0.4 m) containing 10 mol % Mg. Moreover, this optimized ZMO PSC exhibited significantly improved durability and photostability owing to the improved chemical/photochemical stability of the wider optical bandgap ZMO. PMID- 27510562 TI - Gene selection for cancer classification with the help of bees. AB - BACKGROUND: Development of biologically relevant models from gene expression data notably, microarray data has become a topic of great interest in the field of bioinformatics and clinical genetics and oncology. Only a small number of gene expression data compared to the total number of genes explored possess a significant correlation with a certain phenotype. Gene selection enables researchers to obtain substantial insight into the genetic nature of the disease and the mechanisms responsible for it. Besides improvement of the performance of cancer classification, it can also cut down the time and cost of medical diagnoses. METHODS: This study presents a modified Artificial Bee Colony Algorithm (ABC) to select minimum number of genes that are deemed to be significant for cancer along with improvement of predictive accuracy. The search equation of ABC is believed to be good at exploration but poor at exploitation. To overcome this limitation we have modified the ABC algorithm by incorporating the concept of pheromones which is one of the major components of Ant Colony Optimization (ACO) algorithm and a new operation in which successive bees communicate to share their findings. RESULTS: The proposed algorithm is evaluated using a suite of ten publicly available datasets after the parameters are tuned scientifically with one of the datasets. Obtained results are compared to other works that used the same datasets. The performance of the proposed method is proved to be superior. CONCLUSION: The method presented in this paper can provide subset of genes leading to more accurate classification results while the number of selected genes is smaller. Additionally, the proposed modified Artificial Bee Colony Algorithm could conceivably be applied to problems in other areas as well. PMID- 27510563 TI - Ectopic expression of MCAM/MUC18 increases in vitro motility and invasiveness, but decreases in vivo tumorigenesis and metastasis of a mouse melanoma K1735-9 subline in a syngeneic mouse model. AB - Ectopic expression of MCAM/MUC18, a cell adhesion molecule in the immunoglobulin like gene superfamily, induces two moMCAM/MUC18-minus, non-metastatic mouse melanoma K1735 sublines, K3 (tumor+/metlow) and K10 (tumor-/metlow), to metastasize to lungs in a syngeneic C3H mouse model. In this report, we extended investigation of effects of moMCAM/MUC18 expression on tumorigenesis and metastasis in another lowly metastatic, however highly tumorigenic moMCAM/MUC18 minus mouse melanoma K1735 subline, K9 (tumor+++/metlow). We transfected this subline with the moMCAM/MUC18 cDNA, selected for G418-resistant clones with different expression levels of moMCAM/MUC18, and used them for testing effects of MCAM/MUC18 expression on in vitro growth rate, motility, and invasiveness, in vivo subcutaneous tumor growth, and pulmonary metastasis in syngeneic C3H brown mice. Similar to K3 and K10 cells, increased expression of MCAM/MUC18 in K9 cells did not significantly affect in vitro growth rate, but increased in vitro motility and invasiveness. Surprisingly, increased expression of MCAM/MUC18 in K9 cells decreased their induction of tumorigenesis and suppressed their establishment of pulmonary nodules in syngeneic C3H brown mice. We concluded that increased MCAM/MUC18 expression in K9 subline increased in vitro epithelial-to mesenchymal transition; however, it suppressed in vivo tumorigenicity and metastasis. Thus MCAM/MUC18 acts as a tumor and metastasis suppressor for the K9 subline, different from its role in other K1735 sublines, K3 and K10. Different intrinsic co-factors in different K1735 sublines, which modulate the functions of MCAM/MUC18 in the cells that interact differently to the tumor microenvironment, may render sublines manifest differently in tumorigenicity and metastasis in vivo. PMID- 27510564 TI - Genomes of Ellobius species provide insight into the evolutionary dynamics of mammalian sex chromosomes. AB - The X and Y sex chromosomes of placental mammals show hallmarks of a tumultuous evolutionary past. The X Chromosome has a rich and conserved gene content, while the Y Chromosome has lost most of its genes. In the Transcaucasian mole vole Ellobius lutescens, the Y Chromosome including Sry has been lost, and both females and males have a 17,X diploid karyotype. Similarly, the closely related Ellobius talpinus, has a 54,XX karyotype in both females and males. Here, we report the sequencing and assembly of the E. lutescens and E. talpinus genomes. The results indicate that the loss of the Y Chromosome in E. lutescens and E. talpinus occurred in two independent events. Four functional homologs of mouse Y Chromosomal genes were detected in both female and male E. lutescens, of which three were also detected in the E. talpinus genome. One of these is Eif2s3y, known as the only Y-derived gene that is crucial for successful male meiosis. Female and male E. lutescens can carry one and the same X Chromosome with a largely conserved gene content, including all genes known to function in X Chromosome inactivation. The availability of the genomes of these mole vole species provides unique models to study the dynamics of sex chromosome evolution. PMID- 27510565 TI - Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles. AB - Alpha satellite is a tandemly organized type of repetitive DNA that comprises 5% of the genome and is found at all human centromeres. A defined number of 171-bp monomers are organized into chromosome-specific higher-order repeats (HORs) that are reiterated thousands of times. At least half of all human chromosomes have two or more distinct HOR alpha satellite arrays within their centromere regions. We previously showed that the two alpha satellite arrays of Homo sapiens Chromosome 17 (HSA17), D17Z1 and D17Z1-B, behave as centromeric epialleles, that is, the centromere, defined by chromatin containing the centromeric histone variant CENPA and recruitment of other centromere proteins, can form at either D17Z1 or D17Z1-B. Some individuals in the human population are functional heterozygotes in that D17Z1 is the active centromere on one homolog and D17Z1-B is active on the other. In this study, we aimed to understand the molecular basis for how centromere location is determined on HSA17. Specifically, we focused on D17Z1 genomic variation as a driver of epiallele formation. We found that D17Z1 arrays that are predominantly composed of HOR size and sequence variants were functionally less competent. They either recruited decreased amounts of the centromere-specific histone variant CENPA and the HSA17 was mitotically unstable, or alternatively, the centromere was assembled at D17Z1-B and the HSA17 was stable. Our study demonstrates that genomic variation within highly repetitive, noncoding DNA of human centromere regions has a pronounced impact on genome stability and basic chromosomal function. PMID- 27510567 TI - Prediction of response to tapentadol in chronic low back pain. AB - BACKGROUND: Many chronic low back pain (cLBP) patients do not satisfactorily respond to treatment. The knowledge of responders and non-responders before initiating treatment would improve decision making and reduce health care costs. The aims of this exploratory prediction study in cLBP patients treated with tapentadol were to identify predictors of treatment outcome based on baseline characteristics, to evaluate quality-of-life and functionality as alternative outcome parameters and to develop nomograms to calculate the individual probability of response. METHODS: In a retrospective analysis of an open-label phase 3b trial, 46 baseline characteristics were included into statistical prediction modelling. One hundred and twenty-one patients were followed up during the titration and treatment period and 67 patients were analysed who discontinued the trial. RESULTS: Demographic data were not relevant for response prediction. Nine baseline co-variables were robust: painDETECT score, intensity of burning and painful attacks, SF36 Health Survey score (MCS, PCS), EuroQol-5, Hospital Anxiety/Depression Scale. Gender had a minor influence. Alternative outcomes (quality-of-life, functionality) were more important for response prediction than conventional pain intensity measures. Neuropathic symptoms (high painDETECT score) had a positive predictive validity. Painful attacks and classical yellow flags (depression, anxiety) negatively influenced the treatment response. High depression scores, female gender and low burning predicted discontinuation during titration. CONCLUSION: In this exploratory study, predictive baseline characteristics have been identified that can be used to calculate the individual probability of tapentadol response in cLBP. The small sample size in relation to the number of initial variables is a limitation of this approach. SIGNIFICANCE: Predictors for treatment response of tapentadol were identified in patients with chronic low back pain based on clinical pre-treatment characteristics that can guide personalized treatment. Quality-of-life and functionality were the most relevant outcomes for response prediction. PMID- 27510566 TI - Pangolin genomes and the evolution of mammalian scales and immunity. AB - Pangolins, unique mammals with scales over most of their body, no teeth, poor vision, and an acute olfactory system, comprise the only placental order (Pholidota) without a whole-genome map. To investigate pangolin biology and evolution, we developed genome assemblies of the Malayan (Manis javanica) and Chinese (M. pentadactyla) pangolins. Strikingly, we found that interferon epsilon (IFNE), exclusively expressed in epithelial cells and important in skin and mucosal immunity, is pseudogenized in all African and Asian pangolin species that we examined, perhaps impacting resistance to infection. We propose that scale development was an innovation that provided protection against injuries or stress and reduced pangolin vulnerability to infection. Further evidence of specialized adaptations was evident from positively selected genes involving immunity-related pathways, inflammation, energy storage and metabolism, muscular and nervous systems, and scale/hair development. Olfactory receptor gene families are significantly expanded in pangolins, reflecting their well-developed olfaction system. This study provides insights into mammalian adaptation and functional diversification, new research tools and questions, and perhaps a new natural IFNE deficient animal model for studying mammalian immunity. PMID- 27510568 TI - Porphyromonas pogonae identification from a soft tissue infection: The first human case. AB - We report a first human case of Porphyromonas pogonae causing soft tissue infection in a patient with open fracture. Strong beta-hemolytic, aerotolerant, and non-pigmented gram-negative coccobacilli which matched Porphyromonas pogonae by PCR for 16S rRNA genes were identified from the pus specimen. The clinical course of the patient improved with repeated surgical drainage and tigecycline administration. PMID- 27510569 TI - First isolation of Clostridium indolis in a patient with chronic osteitis: a case report and literature review of human infections related to Clostridium saccharolyticum group species. AB - Clostridium indolis is an anaerobic spore-forming Gram-positive bacillus belonging to the Clostridium saccharolyticum group. Its clinical significance in human remains poorly known. We describe the first case of osteitis related to C. indolis, identified by MALDI-TOF mass spectrometry and provide a literature review of human infections related to C. saccharolyticum group species. PMID- 27510570 TI - Exposure to light and darkness and its influence on physiological measures of intensive care unit patients-a systematic literature review. AB - Sleep-wake patterns are often significantly disturbed in critically ill patients. This disturbance is closely linked to secondary brain dysfunctions in these patients. Sedation not only impairs sleep quality in ICU patients but also has detrimental effects on short- and long-term outcome. In other contexts, light therapy has been proven to be effective in maintaining and resynchronizing circadian rhythmicity in humans. The objective of this systematic review was to analyse studies that investigated the effect of exposure to light or darkness on physiological measures and clinical outcomes of adult ICU patients. Studies were systematically identified by searching electronic bibliographic databases (The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2002) and MEDLINE via PubMed). The search algorithm identified a total of 156 articles, 10 of which were taken into final review. These 10 selected articles included 3 were monocentric RCTs, five prospective cohort studies, one retrospective cohort study, and one manuscript that included a partial systematic review of the literature. Included trials were published between 2007 and 2015. Five of these studies used multiple intervention approaches while four trials used a single intervention approach. Among all studies, 1,278 patients were analysed (489 prospectively). There was a high heterogeneity among the studies in terms of applied intervention and outcome measures. The most frequent methodological limitations were a lack of precise definitions regarding the illuminance and the light spectrum utilised. The analyses indicate that further studies including clearly defined interventions with objective outcome measures, as these are currently lacking, would add significant knowledge to this new field of research. PMID- 27510571 TI - Structured Instruction With Modified Storybooks to Teach Morphosyntax and Vocabulary to Preschoolers Who are Deaf/Hard of Hearing. AB - Children who are deaf/hard of hearing (D/HH) are at risk for diminished morphosyntactical and vocabulary development. The purpose of this study was to examine the effects of repeated reading combined with structured instruction. Targets were a morphosyntactical form and novel vocabulary words. Participants were 3 preschoolers who are D/HH who were receiving instruction with an oral approach. Data from a multiple baseline design indicated that all children acquired the targeted skills and demonstrated high levels of generalization of these skills to untrained context. Implications for teaching young children who are D/HH using repeated storybook reading are discussed. PMID- 27510572 TI - The BA-HEF trial in Africa: a welcome addition to heart failure history. PMID- 27510573 TI - Chemoprevention of basal cell carcinoma. PMID- 27510574 TI - Punctate palmoplantar keratoderma type 1 with a novel AAGAB frameshift mutation: intrafamilial phenotype variation due to ageing. PMID- 27510575 TI - Long-term Effects of Managed Care. AB - Managed care (MC) plans have been introduced to curb the ever increasing health care costs. Many previous studies on effectiveness lacked a long-term perspective; hence, the sustainability of (possible) savings remains unclear. Moreover, because of their incentives, MC plans are susceptible to under provision of care. Most of these possibly negative effects can only be observed in the long-term. This paper analyzes the long-term effects of MC plans on cost savings, mortality, and the use of service, using administrative data from a large Swiss health insurer. The identification is based on a propensity-score matching approach, where individuals who enter an MC plan are compared over 10 years to individuals who remain in a standard fee-for-service plan. Cost savings are substantial and sustainable, and the mortality rate is lower in MC plans. Cost savings are driven by fewer consultations and fewer days in hospital care, although the probability of visiting a provider at least once per year is similar or even higher for persons in MC plans. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27510576 TI - Taylor line swimming in microchannels and cubic lattices of obstacles. AB - Microorganisms naturally move in microstructured fluids. Using the simulation method of multi-particle collision dynamics, we study in two dimensions an undulatory Taylor line swimming in a microchannel and in a cubic lattice of obstacles, which represent simple forms of a microstructured environment. In the microchannel the Taylor line swims at an acute angle along a channel wall with a clearly enhanced swimming speed due to hydrodynamic interactions with the bounding wall. While in a dilute obstacle lattice swimming speed is also enhanced, a dense obstacle lattice gives rise to geometric swimming. This new type of swimming is characterized by a drastically increased swimming speed. Since the Taylor line has to fit into the free space of the obstacle lattice, the swimming speed is close to the phase velocity of the bending wave traveling along the Taylor line. While adjusting its swimming motion within the lattice, the Taylor line chooses a specific swimming direction, which we classify by a lattice vector. When plotting the swimming velocity versus the magnitude of the lattice vector, all our data collapse on a single master curve. Finally, we also report more complex trajectories within the obstacle lattice. PMID- 27510577 TI - Long-term HIV-1 infection induces an antiviral state in primary macrophages. AB - HIV-1 infection is thought to impair type I interferon (IFN-I) production in macrophages, a cell type that is also relatively resistant to HIV-1 cytotoxic effects. Here, we show that monocyte differentiation into macrophages by M-CSF led to cell proliferation and susceptibility to HIV-1 infection that induced cell cycle arrest and increased cell death. Established HIV-1 infection of monocyte derived macrophages induced the upregulation of the pattern recognition receptors MDA5 and Rig-I that serve as virus sensors; production of interferon-beta, and transcription of interferon-stimulated genes including CXCL10. Infected macrophages showed increased expression of p21 and subsequent inactivation of cyclin-CDK2 activity leading to a hypo-phosphorylated active retinoblastoma protein (pRb) and deactivation of E2F1-dependent transcription and CDK1 downregulation. Additionally, HIV-1 infection limited deoxynucleotide pool by downregulation of the ribonucleotide reductase subunit R2 (RNR2) and reactivation of the HIV-1 restriction factor SAMHD1 together with increased cell death. In conclusion, HIV-1 induced an innate antiviral mechanism associated to IFN-I production, interferon stimulated gene activation, and p21-mediated G2/M arrest leading to elevated levels of cell death in monocyte derived macrophages. Upregulation of MDA5 and Rig-I may serve as targets for the development of antiviral strategies leading to the elimination of HIV-1 infected cells. PMID- 27510578 TI - Electrophilic iodination: a gateway to high iodine compounds and energetic materials. AB - A large number of iodine atoms can be introduced into a single molecule in a one pot reaction using trifluoroperacetic acid-mediated electrophilic iodination methodology. The scope of this reaction was investigated extensively using several pyrazole substrates which resulted in nine polyiodo pyrazole compounds with iodine content as high as 80%. This synthetic methodology was also utilized successfully for iodination of benzimidazoles. Tetraiodobenzimidazole was nitrated with 100% nitric acid to give a high yield of 4,5,6,7-tetranitro-1H benzimidazol-2(3H)-one (14). All of these materials were fully characterized and compounds 5, 9, 10 and 14 were confirmed further with single crystal X-ray analysis. High density, positive oxygen balance, and very good impact sensitivity values characterize 14. For the first time, two 1,2,5-oxadiazole-N-oxide rings were introduced into a benzimidazole ring (11) which remarkably improves the stability of oxadiazole-N-oxide compounds. PMID- 27510579 TI - Retrieval-Based Model Accounts for Striking Profile of Episodic Memory and Generalization. AB - A fundamental theoretical tension exists between the role of the hippocampus in generalizing across a set of related episodes, and in supporting memory for individual episodes. Whilst the former requires an appreciation of the commonalities across episodes, the latter emphasizes the representation of the specifics of individual experiences. We developed a novel version of the hippocampal-dependent paired associate inference (PAI) paradigm, which afforded us the unique opportunity to investigate the relationship between episodic memory and generalization in parallel. Across four experiments, we provide surprising evidence that the overlap between object pairs in the PAI paradigm results in a marked loss of episodic memory. Critically, however, we demonstrate that superior generalization ability was associated with stronger episodic memory. Through computational simulations we show that this striking profile of behavioral findings is best accounted for by a mechanism by which generalization occurs at the point of retrieval, through the recombination of related episodes on the fly. Taken together, our study offers new insights into the intricate relationship between episodic memory and generalization, and constrains theories of the mechanisms by which the hippocampus supports generalization. PMID- 27510580 TI - A Bioorthogonal Near-Infrared Fluorogenic Probe for mRNA Detection. AB - There is significant interest in developing methods that visualize and detect RNA. Bioorthogonal template-driven tetrazine ligations could be a powerful route to visualizing nucleic acids in native cells, yet past work has been limited with respect to the diversity of fluorogens that can be activated via a tetrazine reaction. Herein we report a novel bioorthogonal tetrazine uncaging reaction that harnesses tetrazine reactivity to unmask vinyl ether caged fluorophores spanning the visible spectrum, including a near-infrared (NIR)-emitting cyanine dye. Vinyl ether caged fluorophores and tetrazine partners are conjugated to high-affinity antisense nucleic acid probes, which show highly selective fluorogenic reactivity when annealed to their respective target RNA sequences. A target sequence in the 3' untranslated region of an expressed mRNA was detected in live cells employing appropriate nucleic acid probes bearing a tetrazine-reactive NIR fluorogen. Given the expansion of tetrazine fluorogenic chemistry to NIR dyes, we believe highly selective proximity-induced fluorogenic tetrazine reactions could find broad uses in illuminating endogenous biomolecules in cells and tissues. PMID- 27510582 TI - Original Research: Potential ocular protection and dynamic observation of Polygonatum sibiricum polysaccharide against streptozocin-induced diabetic rats' model. AB - Ocular complications associated with diabetes mellitus are progressive and becoming one of the most important causes of morbidity worldwide. The purpose of the study is to evaluate the protective effect of Polygonatum sibiricum polysaccharide, an important component of Polygonatum sibiricum, on ocular complications in streptozotocin-induced diabetes mellitus rats. Sprague Dawley rats were made diabetic with streptozotocin(60 mg/kg, i.v.) and then the rats were treated with Polygonatum sibiricum polysaccharide 200, 400 and 800 mg/kg.d by gavage for 12 weeks. Biochemical analysis indicated that Polygonatum sibiricum polysaccharide lowered the levels of fasting blood glucose and glycated hemoglobin in blood and elevated the levels of insulin and C-peptide in plasma of diabetes mellitus rats in a dose-dependent manner. Physical measurements revealed that Polygonatum sibiricum polysaccharide improved clinical symptoms of polydipsia, polyphagia, polyuria and weight loss in diabetes mellitus rats. The content of malondialdehyde and activity of superoxide dismutase in plasma were determined, and the data showed Polygonatum sibiricum polysaccharide suppressed oxidative stress reaction. Lens opacification was observed using slit lamp illumination, and the data showed Polygonatum sibiricum polysaccharide delayed cataract progression in a dose-dependent manner. Electroretinogram showed Polygonatum sibiricum polysaccharide treatment reversed the decrease of electroretinogram b and OPs2 waves' amplitudes. Flash-visual evoked potential test indicated that the peak time of P2 wave was prolonged, and the amplitude of N2-P2 was lowered in diabetes mellitus group, and Polygonatum sibiricum polysaccharide suppressed these changes. Fundus fluorescein angiography showed Polygonatum sibiricum polysaccharide alleviated the retinal vasculopathy in a dose-dependent manner. In conclusion, these results suggest that the administration of Polygonatum sibiricum polysaccharide slows the progression of diabetic retinopathy and cataract through alleviating hyperglycemia and reducing oxidative stress in streptozotocin-induced diabetes mellitus rats. PMID- 27510581 TI - Original Research: Effect of various dietary fats on fatty acid profile in duck liver: Efficient conversion of short-chain to long-chain omega-3 fatty acids. AB - Omega-3 fatty acids, especially long-chain omega-3 fatty acids, have been associated with potential health benefits for chronic disease prevention. Our previous studies found that dietary omega-3 fatty acids could accumulate in the meat and eggs in a duck model. This study was to reveal the effects of various dietary fats on fatty acid profile and conversion of omega-3 fatty acids in duck liver. Female Shan Partridge Ducks were randomly assigned to five dietary treatments, each consisting of 6 replicates of 30 birds. The experimental diets substituted the basal diet by 2% of flaxseed oil, rapeseed oil, beef tallow, or fish oil, respectively. In addition, a dose response study was further conducted for flaxseed and fish oil diets at 0.5%, 1%, and 2%, respectively. At the end of the five-week treatment, fatty acids were extracted from the liver samples and analyzed by GC-FID. As expected, the total omega-3 fatty acids and the ratio of total omega-3/omega-6 significantly increased in both flaxseed and fish oil groups when compared with the control diet. No significant change of total saturated fatty acids or omega-3 fatty acids was found in both rapeseed and beef tallow groups. The dose response study further indicated that 59-81% of the short chain omega-3 ALA in flaxseed oil-fed group was efficiently converted to long chain DHA in the duck liver, whereas 1% of dietary flaxseed oil could produce an equivalent level of DHA as 0.5% of dietary fish oil. The more omega-3 fatty acids, the less omega-6 fatty acids in the duck liver. Taken together, this study showed the fatty acid profiling in the duck liver after various dietary fat consumption, provided insight into a dose response change of omega-3 fatty acids, indicated an efficient conversion of short- to long-chain omega-3 fatty acid, and suggested alternative long-chain omega-3 fatty acid-enriched duck products for human health benefits. PMID- 27510583 TI - Toll-like receptor 4 contributes to acute kidney injury after cardiopulmonary resuscitation in mice. AB - Toll-like receptor 4 (TLR4) activation mediates renal injury in regional ischemia and reperfusion (I/R) models generated by clamping renal pedicles. However, it remains unclear whether TLR4 is causal in the kidney injury following global I/R induced by cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). The present study used wild-type (C3H/HeN) and TLR4-mutant (C3H/HeJ) mice to produce the CA/CPR model. CA was induced by injection of cold KCl and left untreated for different time periods. After resuscitation (72 h), the level of blood urea nitrogen (BUN) and serum creatinine (Scr), as well as histological changes in renal tissue were assessed to evaluate the severity of acute kidney injury (AKI). The expression of TLR4, intercellular adhesion molecule-1 (ICAM-1), myeloperoxidase (MPO) and growth-regulated oncogene-beta (GRO-beta) in kidney tissues was detected. The results demonstrated that the levels of Scr and BUN increased significantly in C3H/HeN and C3H/HeJ mice after CPR. CPR also resulted in increased expression of TLR4, ICAM-1, GRO-beta and MPO in a CA-duration dependent manner. However, there was decreased expression of ICAM-1, GRO-beta and MPO in C3H/HeJ mice compared with that in C3H/HeN mice. C3H/HeJ mice were resistant to AKI as demonstrated by the minor changes in renal histology and function following CPR. In conclusion, mice suffered from AKI after successful CPR and severe AKI occurred in mice with prolonged CA duration. TLR4 and its downstream signaling events that promote neutrophil infiltration via ICAM-1 and GRO-beta may be important in mediating inflammatory responses to renal injury after CPR. PMID- 27510584 TI - Determination and pharmacokinetic properties of arsenic speciation in Xiao-Er-Zhi Bao-Wan by high-performance liquid chromatography with inductively coupled plasma mass spectrometry. AB - A method of high performance liquid chromatography with a Hamilton PRP-X100 ion exchange column (250 * 4.1 mm id, 10 MUm) coupled to inductively coupled plasma mass spectrometry was employed to generate a full concentration-time profile of arsenic speciation after oral administration. The results exhibited good linearity and revealed that, in the pills, the average arsenic concentration was 10105.4 +/- 380.7 mg/kg, and in the water extraction solution, the inorganic As(III) and As(V) concentrations were 220.1 +/- 12.6 and 45.5 +/- 2.3 mg/kg, respectively. No trace of monomethyl arsenic acid was detected in any of the plasma samples. We then successfully applied the established methodology to examine the pharmacokinetics of arsenic speciation. The resulting data revealed that, after oral administration in rats, the plasma concentration of each arsenic species reached Cmax shortly after initial dosing, and that the distribution and elimination of As(V) was faster than that of As(III) and dimethyl arsenic acid. Additionally, the t1/2 values of As(V), As(III), and dimethyl arsenic acid were 3.4 +/- 1.6, 14.3 +/- 4.0, and 19.9 +/- 1.6 h, respectively. This study provides references for the determination of arsenic speciation in mineral-containing medicines and could serve as a useful tool in measuring the true toxicity in traditional medicines that contain them. PMID- 27510587 TI - IFSO 2016 21st World Congress. PMID- 27510586 TI - Pouch Reshaping for Significant Weight Regain after Roux-en-Y Gastric Bypass. AB - BACKGROUND: Significant weight regain after Roux-en-Y gastric bypass (RYGB) occurs in around 20 % of patients in the long term. Anatomical reasons include dilatation of the gastric pouch and/or the pouch-jejunal anastomosis, leading to loss of restriction. Pouch reshaping (PR) aims at reestablishing restriction with a subsequent feeling of satiety. This study reports the outcome of PR embedded in a multidisciplinary treatment pathway. METHODS: Twenty-six patients after PR for weight regain >30 % following RYGB in a university hospital between October 2010 and March 2016 were analyzed. Excluded were patients with PR for gastro-gastric fistulae, hypoglycemia, candy cane syndrome, and concomitant alteration of limb lengths. PR consisted in laparoscopic lateral resection of the gastric pouch, the anastomosis and the proximal 5 cm of the alimentary limb over a 32F bougie. RESULTS: Median follow-up after PR was 48 months (range 24-60). Median BMI at PR was 39.1 kg/m2 (32.7-59.1). Median operation time was 85 min (25-190), and median length of stay was 3 days (1-35). Minor complications (grade <= 2) occurred in seven (27 %) patients and major complications (grade >= 3) in four patients (15 %). Nadir BMI and %EBMIL after PR were 32.9 kg/m2 and 43.3 %, reached after a median of 12 months (3-48). Comorbidities were resolved in 81 %. After 48 months, median BMI was 33.8 kg/m2 (20.4-49.2) and %EBMIL was 61.4 (39.1-121.2). CONCLUSIONS: Used selectively in a multidisciplinary treatment pathway, PR leads to prolonged weight stabilization around the previous nadir. However, its associated perioperative morbidity must not be disregarded. PMID- 27510585 TI - Characterization of the Kynurenine Pathway in CD8+ Human Primary Monocyte-Derived Dendritic Cells. AB - The kynurenine (KYN) pathway (KP) is a major degradative pathway of the amino acid, L-tryptophan (TRP), that ultimately leads to the anabolism of the essential pyridine nucleotide, nicotinamide adenine dinucleotide. TRP catabolism results in the production of several important metabolites, including the major immune tolerance-inducing metabolite KYN, and the neurotoxin and excitotoxin quinolinic acid. Dendritic cells (DCs) have been shown to mediate immunoregulatory roles that mediated by TRP catabolism. However, characterization of the KP in human DCs has so far only been partly delineated. It is critical to understand which KP enzymes are expressed and which KP metabolites are produced to be able to understand their regulatory effects on the immune response. In this study, we characterized the KP in human monocyte-derived DCs (MDDCs) in comparison with the human primary macrophages using RT-PCR, high-pressure gas chromatography, mass spectrometry, and immunocytochemistry. Our results show that the KP is entirely expressed in human MDDC. Following activation of the KP using interferon gamma, MDDCs can mediate apoptosis of T h cells in vitro. Understanding the molecular mechanisms regulating KP metabolism in MDDCs may provide renewed insight for the development of novel therapeutics aimed at modulating immunological effects and peripheral tolerance. PMID- 27510588 TI - Primary Inadequate Weight Loss After Roux-en-Y Gastric Bypass Is not Associated with Poor Cardiovascular or Metabolic Outcomes: Experience from a Single Institution. AB - BACKGROUND: It is well accepted that bariatric surgery has cardiovascular and metabolic effects independent of weight loss. METHODS: Weight loss outcomes of patients undergoing Roux-en-Y gastric bypass (RYGB) at a high volume referral center were collected at 1 year postoperatively. Patients with failed primary weight loss were identified. Primary inadequate weight loss was defined as total body weight loss less than 15 %. Changes in hypertension (HTN), dyslipidemia, type 2 diabetes mellitus (T2DM), and metabolic syndrome profiles were investigated using Student's t test. RESULTS: A total of 2500 patients underwent RYGB from the years 2001-2013 at our institution. One hundred five (4.2 %) patients had primary inadequate weight loss. Within this cohort, 81 (77.1 %) patients had hypertension, 67 (63.8 %) had dyslipidemia, 53 (50.5 %) had type 2 diabetes mellitus, and 66 (62.9 %) patients had metabolic syndrome. At 1 year postoperatively, all metabolic parameters were significantly improved. Measures of metabolic disease included high-density lipoprotein (HDL) (46.3 +/- 11.6 versus 54.1 +/- 12.7 mg/dL, p < 0.01), low-density lipoprotein (LDL) (103.6 +/- 35.8 versus 89.2 +/- 30.0 mg/dL, p < 0.01), triglycerides (177.3 +/- 139.1 versus 117.6 +/- 59.3 mg/dL, p < 0.01), mean plasma glucose (128.9 +/- 55.3 versus 102.7 +/- 27.3 mg/dL, p < 0.01), and hemoglobin A1C (7.3 +/- 1.9 versus 6.1 +/- 1.0 %, p < 0.01). HTN was noted to improve in 27 (33.3 %) patients based on a decrease in the number of anti-hypertensives used (1.7 +/- 1.0 versus 1.3 +/- 1.3, p < 0.01), and 21 (31.8 %) patients had resolution of their metabolic syndrome. CONCLUSION: Improvement in cardiometabolic comorbidities still occurs despite suboptimal weight loss following RYGB. PMID- 27510589 TI - Difficult Tracheal Intubation in Obese Gastric Bypass Patients. PMID- 27510590 TI - Beneficial Effects of Bariatric Surgery on Cardiac Structure and Function in Obesity. AB - BACKGROUND: Bariatric surgery is being considered as a therapeutic option for morbidly obese patients. Data are accumulating showing that this surgical intervention may improve in major cardiovascular morbidity and mortality. We evaluated the effects of bariatric surgery on left ventricular (LV) structure and function including LV mechanics in obese patients. METHODS: Thirty-seven patients (age = 36 +/- 10 years; male:female = 11:26) undergoing bariatric surgery were enrolled. Echocardiography was performed before and after at least 1 year of bariatric surgery. Conventional echocardiographic parameters, including tissue Doppler measurements, were measured. LV global longitudinal, circumferential, and radial deformations were assessed utilizing 2D speckle tracking software. RESULTS: Patients decreased body mass index by 11.8 +/- 4.7 over 15.6 +/- 5.5 months. Bariatric surgery led to significant decreases in left ventricular (LV) size and mass (51.0 +/- 3.3 to 49.1 +/- 3.4 mm, p < 0.001 for LV end-diastolic dimension; 192.6 +/- 33.5 to 146.2 +/- 29.1 g, p < 0.001 for LV mass), and increases were noted in the ratio of early-to-late diastolic mitral inflow (E/A), early diastolic tissue Doppler velocity (Em), and LV longitudinal strain (1.42 +/ 0.52 to 1.59 +/- 0.56, p = 0.04 for E/A ratio; 9.7 +/- 2.0 to 11.0 +/- 2.4 cm/s, p < 0.001 for Em; 14.1 +/- 1.9 to 16.2 +/- 1.4 %, p < 0.001 for longitudinal strain). Changes of LV longitudinal strain were related to LV mass reduction (p = 0.04). However, LV ejection fraction, LV circumferential, and radial strains were all comparable at follow-up. CONCLUSION: Significant weight loss by bariatric surgery was associated with improved LV structure and function in obese patients, suggesting potential favorable effects of bariatric surgery to prevent future cardiovascular events. PMID- 27510592 TI - Uniform Li2S precipitation on N,O-codoped porous hollow carbon fibers for high energy-density lithium-sulfur batteries with superior stability. AB - A lithium-polysulfide cell with superior stability is reported with N,O-codoped carbon hollow fiber (NCHF) sheets as a current collector. Due to the highly effective chemisorption and physical adsorption of lithium polysulfides on doped NCHF and a uniform Li2S precipitation during cycling, the Li2S6-impregnated NCHF electrodes exhibit high sulfur utilization and superior cycling stability even with a high areal sulfur loading of 6.2 mg cm(-2). PMID- 27510591 TI - Risk factors for Clostridium difficile infection in hemato-oncological patients: A case control study in 144 patients. AB - Evidence on risk factors for Clostridium difficile infection (CDI) in hemato oncologic patients is conflicting. We studied risk factors for CDI in a large, well-characterized cohort of hemato-oncological patients. 144 hemato-oncological patients were identified in this retrospective, single center study with a microbiologically confirmed CDI-associated diarrhea. Patients were compared with 144 age and sex matched hemato-oncologic patients with CDI negative diarrhea. Risk factors such as prior antimicrobial therapy, type of disease, chemotherapy and survival were evaluated. CDI-positive patients received more frequently any antimicrobial agent and antimicrobial combination therapy than CDI-negative patients (79% vs. 67%; OR = 2.26, p = 0.038 and OR = 2.62, p = 0.003, respectively). CDI positive patients were treated more frequently with antimicrobial agents active against C. difficile than CDI negative ones (25% vs. 13%; OR = 2.2, p = 0.039). The interval between last chemotherapy and onset of diarrhea was significantly shorter in patients without CDI (median, 17 days vs 36 days; p < 0.001). Our study demonstrates that chemotherapy is not a significant risk factor for CDI but for early onset CDI negative diarrhea. The predominant modifiable risk factor for CDI is in hemato-oncological patients antimicrobial treatment. These findings should be taken into account in the daily clinical practice to avoid CDI associated complications and excess health care costs. PMID- 27510593 TI - [Not Available]. PMID- 27510594 TI - A Case of Intraparenchymal Pseudoaneurysms in Kidney Allograft. AB - BACKGROUND Percutaneous needle biopsy is routinely performed for renal allograft management. Vascular complications of the procedure include pseudoaneurysm and arterio-venous fistulae formation. Delayed diagnosis of these complications is due to their mostly asymptomatic and indolent nature. CASE REPORT We present a case of extensive intraparenchymal pseudoaneurysm formation within the inferior pole of the allograft, diagnosed two years following the most recent biopsy procedure. CONCLUSIONS Renal pseudoaneurysms may only be diagnosed years after their formation as they are typically asymptomatic. PMID- 27510595 TI - Safety and efficacy of beclomethasone dipropionate delivered by breath-actuated or metered-dose inhaler for persistent asthma. AB - BACKGROUND: Breath-actuated inhalers (BAI) have been developed to simplify the delivery of inhaled medication. OBJECTIVE: To evaluate the safety and efficacy of beclomethasone dipropionate hydrofluoroalkane BAI and metered-dose inhaler (MDI) versus placebo in patients who previously used a mid- to high-dose inhaled corticosteroid or inhaled corticosteroid/long-acting beta agonist for persistent asthma. METHODS: This phase III study included five treatment groups: placebo, and four beclomethasone dipropionate groups (BAI 320 MUg/day, BAI 640 MUg/day, MDI 320 MUg/day, and MDI 640 MUg/day). Efficacy over 12 weeks was assessed by spirometry, peak flow measurements, and other clinical end points. Safety was assessed by adverse events. RESULTS: Baseline-adjusted trough morning forced expiratory volume in 1 second area under the effect curve from time 0 to 12 weeks (primary end point) was increased in the BAI 320 and BAI 640 MUg/day groups and the MDI 640 MUg/day group versus placebo (not significant). Clinically important improvements were noted in morning and evening peak expiratory flow and decreased rescue medications. More patients who received placebo than patients in active treatment groups withdrew due to meeting the stopping criteria for worsening asthma. Patients in the active treatment groups experienced a greater decrease in asthma symptoms than patients in the placebo group. Quality of life and Asthma Control Test scores improved in the active treatment groups compared with the placebo group (p <= 0.0074). The most common adverse events (>5% in any group) were oral candidiasis and upper respiratory tract infection. CONCLUSION: Clinical benefits for patients who used BAI 320 and 640 MUg/day and MDI 640 MUg/day were demonstrated. The safety profiles of BAI 320 and 640 MUg/day were comparable with that of the MDI. These benefits and the continued need for better symptom control among patients with asthma support the continued development of this controller medication. ClinicalTrials.gov identifier NCT02031640. PMID- 27510596 TI - Antibiotic resistance: a physicist's view. AB - The problem of antibiotic resistance poses challenges across many disciplines. One such challenge is to understand the fundamental science of how antibiotics work, and how resistance to them can emerge. This is an area where physicists can make important contributions. Here, we highlight cases where this is already happening, and suggest directions for further physics involvement in antimicrobial research. PMID- 27510597 TI - Freestanding Boron Nitride Nanosheet Films for Ultrafast Oil/Water Separation. AB - Freestanding boron nitride nanosheet (BNNS) films with designed structures are first fabricated by chemical vapor deposition (CVD) methods. As-prepared freestanding BNNS films exhibit outstanding hydrophobicity and lipophilicity properties. Such brilliant behaviors make them applicable in oil/water separation with very high fluxes up to 1 200 000 L m-2 h-1 bar-1 and excellent separation efficiencies (ppm level in terms of the water content in the filtrate). PMID- 27510598 TI - Gestational diabetes in the United States: temporal changes in prevalence rates between 1979 and 2010. AB - OBJECTIVE: To examine age-period-cohort effects on trends in gestational diabetes mellitus (GDM) prevalence in the US, and to evaluate how these trends have affected the rates of stillbirth and large for gestational age (LGA)/macrosomia. DESIGN: Retrospective cohort study. SETTING: USA, 1979-2010. POPULATION: Over 125 million pregnancies (3 337 284 GDM cases) associated with hospitalisations. METHODS: Trends in GDM prevalence were examined via weighted Poisson models to parse out the extent to which GDM trends can be attributed to maternal age, period of delivery, and maternal birth cohort. Multilevel models were used to assess the contribution of population effects to the rate of GDM. Log-linear Poisson regression models were used to estimate the contributions of the increasing GDM rates to changes in the rates of LGA and stillbirth between 1979 81 and 2008-10. MAIN OUTCOME MEASURES: Rates and rate ratios (RRs). RESULTS: Compared with 1979-1980 (0.3%), the rate of GDM has increased to 5.8% in 2008-10, indicating a strong period effect. Substantial age and modest cohort effects were evident. The period effect is partly explained by period trends in body mass index (BMI), race, and maternal smoking. The increasing prevalence of GDM is associated with a 184% (95% CI 180-188%) decline in the rate of LGA/macrosomia and a 0.75% (95% CI 0.74-0.76) increase in the rate of stillbirths for 2008-10, compared with 1979-81. CONCLUSIONS: The temporal increase in GDM can be attributed to period of pregnancy and age. Increasing BMI appears to partially contribute to the GDM increase in the US. TWEETABLE ABSTRACT: The increasing prevalence of GDM can be attributed to period of delivery and increasing maternal age. PMID- 27510599 TI - Reinstating the Novelty P3. AB - P300 (or P3) is a major positive complex in the human event-related potential, occurring some 300 ms after stimulus onset, and long thought to be the cortical correlate of the Orienting Reflex, our automatic attention-grabbing response to a novel stimulus. The Novelty P3 was the third P3 subcomponent discovered (after P3a and P3b) and appeared promising in its sensitivity to stimulus novelty, the defining characteristic of the Orienting Reflex. But some 15 years later it was claimed to be indistinguishable from the previously-discovered P3a. This led to a decline in interest in the field and confused nomenclature, with some studies using "P3a" and "Novelty P3" interchangeably. However, recent similar studies have again reported three subcomponents of the P3. Further, using single-stimulus habituation paradigms, in addition to P3a and P3b, a later decrementing P3 subcomponent has been reported, and recently labelled "HabP3" to avoid contention. We report three studies to resolve this chaotic situation, arguing for identification of the late subcomponent following the P3a and P3b as the Novelty P3. Reinstatement of the Novelty P3 as the central index of the Orienting Reflex will have widespread impact in a range of theoretical, practical, and clinical areas involving novelty processing and attention. PMID- 27510600 TI - Association between shortened telomere length and systemic lupus erythematosus: a meta-analysis. AB - Objective We aimed to evaluate the relationship between telomere length and systemic lupus erythematosus (SLE). Methods PUBMED and EMBASE databases were searched; meta-analyses were performed comparing telomere length in SLE patients and healthy controls, and on SLE patients in subgroups based on ethnicity, sample type, assay method and data type. Results Eight studies including 472 SLE patients and 365 controls were ultimately selected which showed that telomere length was significantly shorter in the SLE group than in the control group (standardized mean difference (SMD) = -0.835, 95% confidence interval (CI) = 1.291 to -0.380, p = 3.3 * 10-4). Stratification by ethnicity showed significantly shortened telomere length in the SLE group in Caucasian, Asian and mixed populations (SMD = -0.455, 95% CI = -0.763 to -0.147, p = 0.004; SMD = 0.887, 95% CI = -1.261 to -0.513, p = 3.4 * 10-4; SMD = -0.535, 95% CI = -0.923 to -0.147, p = 0.007; respectively). Furthermore, telomere length was significantly shorter in the SLE group than in the control group in whole blood and peripheral blood mononuclear cell groups (SMD = -0.361, 95% CI = -0.553 to 0.169, p = 2.3 * 10-4; SMD = -1.546, 95% CI = -2.583 to -0.510, p = 0.003; respectively); a similar trend was observed in leukocyte groups (SMD = -0.699, 95% CI = -1.511 to -0.114, p = 0.092). Meta-analyses based on assay method or data type revealed similar associations. Conclusions Our meta-analysis demonstrated that telomere length was significantly shorter in patients with SLE, regardless of ethnicity, sample type or assay method evaluated. PMID- 27510601 TI - Association between antiphospholipid antibodies and arterial thrombosis in patients with rheumatoid arthritis. AB - OBJECTIVES: Antiphospholipid antibodies (aPL) are present in a proportion of patients with rheumatoid arthritis but their clinical significance remains unclear. We investigated the association between aPL and thrombotic events in rheumatoid arthritis patients. METHODS: In this cross-sectional study, aPL profiles were evaluated in 376 rheumatoid arthritis patients in accordance with the standard guidelines. Clinical and radiographic data were retrospectively collected. RESULTS: aPL were identified in 39 patients (10.4%). Lupus anticoagulant was the most common subtype (n = 25, 6.6%); anti-cardiolipin antibodies and anti-beta2 glycoprotein I antibodies were detected in six and 12 patients (1.6% and 3.2%), respectively. Compared to the aPL-negative group, aPL positive patients included more male patients (41.0% vs. 15.4%, P < 0.001) and more smokers (41.0% vs. 16.0%, P = 0.001). There was no difference between the two groups in age, disease duration and body mass index, or the frequency of diabetes, hypertension or dyslipidaemia. Of note, arterial thromboses were more common in the aPL-positive than the aPL-negative group (12.8% vs. 2.1%, P = 0.004), whereas the frequency of venous thrombosis did not differ between the two groups (0.0% vs. 0.9%, P = 1.000). On multivariate regression analysis, aPL, age, hypertension, dyslipidaemia and baseline C-reactive protein level were independently associated with arterial thrombotic events (all P values < 0.05). CONCLUSION: aPL was found in a subset of rheumatoid arthritis patients, who were more often smokers, and aPL was independently associated with development of arterial thrombosis. This result suggests that aPL may contribute to an increased risk of arterial thrombosis in rheumatoid arthritis patients. PMID- 27510602 TI - Short-term atorvastatin therapy improves arterial stiffness of middle-aged systemic lupus erythematosus patients with pathological pulse wave velocity. AB - Objectives Statins have been proposed as a potential treatment for systemic lupus erythematosus (SLE) due to their immunomodulatory properties, their role restoring endothelial function and preventing atherosclerosis. We evaluate the effect of a short period treatment with a low dose of atorvastatin and its withdrawal on early stage subclinical atherosclerosis. Methods Thirty-seven SLE females received 20 mg/day atorvastatin during eight weeks. At baseline, at the end of treatment and six months after atorvastatin withdrawal, disease activity, subclinical atherosclerosis -assessed by measuring carotid-femoral pulse wave velocity (PWV) - and quantification of circulating endothelial progenitor cells (EPC) - as a surrogate biological marker of subclinical atherosclerosis - were carried out. Results The group of SLE patients with baseline pathological arterial stiffness showed a significant decrease of PWV after atorvastatin therapy (8.43 +/- 1.45 m/s vs 7.42 +/- 1.06 m/s; p = 0.002) that is maintained six months after treatment finished. Only patients of the middle-aged group showed a nearly significant decrease in the PWV measured along the study (7.16 +/ 1.23 m/s vs 6.76 +/- 0.82 m/s; p = 0.05). Atorvastatin induced a significant decrease in the circulating EPC percentage (0.65 +/- 0.67 vs 0.40 +/- 0.31; p = 0.023) as well as a downward trend of disease activity that it is observed by a decrease in SLE disease activity index simultaneously with an increase in C3 complement and significant decrease in serum concentration of vascular endothelial grow factor (VEGF) and sVCAM-1. Conclusions Short-term atorvastatin therapy reduces arterial stiffness of SLE patients with baseline pathological PWV, who are mainly in the group of middle-aged patients. Further studies are needed to determine whether these patients would benefit from statin therapy in preventing cardiovascular events. PMID- 27510603 TI - Clinical characteristics of children with membranous lupus nephritis: the Childhood Arthritis and Rheumatology Research Alliance Legacy Registry. AB - Objective The objective of this article is to describe and compare clinical features, treatment, and renal outcomes of children with membranous lupus nephritis (MLN), through analysis of a national multicenter registry. Methods Patients with pediatric systemic lupus erythematosus (SLE) and MLN from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry were included. Demographic, disease and medication-related data were collected between 2010 and 2014 from 59 CARRA Legacy Registry sites. Results A total of 132 individuals had MLN, either in isolation or in combination with proliferative LN. Seventy-four patients had pure MLN. The proportion of patients with daily corticosteroid treatment was similar among groups (96%, 91%, and 96%, for class III+V, IV+V, and V, respectively, p = 0.67). Proportion of individuals exposed to any disease-modifying antirheumatic drug (DMARD) or biologic was similar among the three groups (83%, 91%, 95% for class III+V, IV+V, and V, respectively, p = 0.189). Proportion of patients with decreased glomerular filtration rate (less than 90 ml/min/1.73 m2) was significantly different among groups (4%, 38%, and 4%, for class III+V, IV+V, and V, respectively, p < 0.0001). Conclusion This is the largest reported cohort of children with MLN. More research is needed to understand treatment practices for pediatric MLN, particularly decisions related to pharmacologic treatment of pure MLN. More work is also needed to identify prognostic factors and predictors of outcome for pediatric MLN. Future observational studies will be a first step toward understanding and formulating a standardized approach to treatment of pediatric membranous LN and allowing for the initiation of prospective comparative effectiveness studies and interventional trials. PMID- 27510604 TI - Rapidly progressive lupus nephritis associated with golimumab in a patient with systemic lupus erythematosus and rheumatoid arthritis. PMID- 27510605 TI - Evaluation of phosphatidylserine-dependent antiprothrombin antibody testing for the diagnosis of antiphospholipid syndrome: results of an international multicentre study. AB - Objective A task force of scientists at the International Congress on Antiphospholipid Antibodies recognized that phosphatidylserine-dependent antiprothrombin antibodies (aPS/PT) might contribute to a better identification of antiphospholipid syndrome (APS). Accordingly, initial and replication retrospective, cross-sectional multicentre studies were conducted to ascertain the value of aPS/PT for APS diagnosis. Methods In the initial study (eight centres, seven countries), clinical/laboratory data were retrospectively collected. Serum/plasma samples were tested for IgG aPS/PT at Inova Diagnostics (Inova) using two ELISA kits. A replication study (five centres, five countries) was carried out afterwards. Results In the initial study ( n = 247), a moderate agreement between the IgG aPS/PT Inova and MBL ELISA kits was observed ( k = 0.598). IgG aPS/PT were more prevalent in APS patients (51%) than in those without (9%), OR 10.8, 95% CI (4.0-29.3), p < 0.0001. Sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio of IgG aPS/PT for APS diagnosis were 51%, 91%, 5.9 and 0.5, respectively. In the replication study ( n = 214), a moderate/substantial agreement between the IgG aPS/PT results obtained with both ELISA kits was observed ( k = 0.630). IgG aPS/PT were more prevalent in APS patients (47%) than in those without (12%), OR 6.4, 95% CI (2.6-16), p < 0.0001. Sensitivity, specificity, LR + and LR- for APS diagnosis were 47%, 88%, 3.9 and 0.6, respectively. Conclusions IgG aPS/PT detection is an easily performed laboratory parameter that might contribute to a better and more complete identification of patients with APS. PMID- 27510607 TI - Chameleonic electrochemical metallization cells: dual-layer solid electrolyte inducing various switching behaviours. AB - We present 'unusual' resistive switching behaviours in electrochemical metallization (ECM) cells utilizing a dual-layer (SiOx/GeSex: SiOx on GeSex) solid electrolyte (SE). The observed switching behaviour markedly varies with the thickness of the upper SiOx layer and compliance current: (i) monostable switching, (ii) counter-eightwise bipolar switching, and (iii) combination of monostable and eightwise bipolar switching behaviours. Focusing on cases (i) and (iii), electrical and chemical analyses on these chameleonic cells were performed in an attempt to gain clues to the understanding of the observed complexity. The chemical analysis indicated the upper SiOx layer as a chemical potential well for Cu ions-Cu ions were largely confined in the well. This non-uniform distribution of Cu across the SE perhaps hints at the mechanism for the complex behaviour; it may be a 'zero-sum game' between SiOx and GeSex layers, in which the two layers fight over the limited number of Cu atoms/ions. PMID- 27510608 TI - Intrusive Thoughts, Impulses, and Schizoaffective Disorder. PMID- 27510606 TI - A reverse genetic approach identifies an ancestral frameshift mutation in RP1 causing recessive progressive retinal degeneration in European cattle breeds. AB - BACKGROUND: Domestication and artificial selection have resulted in strong genetic drift, relaxation of purifying selection and accumulation of deleterious mutations. As a consequence, bovine breeds experience regular outbreaks of recessive genetic defects which might represent only the tip of the iceberg since their detection depends on the observation of affected animals with distinctive symptoms. Thus, recessive mutations resulting in embryonic mortality or in non specific symptoms are likely to be missed. The increasing availability of whole genome sequences has opened new research avenues such as reverse genetics for their investigation. Our aim was to characterize the genetic load of 15 European breeds using data from the 1000 bull genomes consortium and prove that widespread harmful mutations remain to be detected. RESULTS: We listed 2489 putative deleterious variants (in 1923 genes) segregating at a minimal frequency of 5 % in at least one of the breeds studied. Gene enrichment analysis showed major enrichment for genes related to nervous, visual and auditory systems, and moderate enrichment for genes related to cardiovascular and musculoskeletal systems. For verification purposes, we investigated the phenotypic consequences of a frameshift variant in the retinitis pigmentosa-1 gene segregating in several breeds and at a high frequency (27 %) in Normande cattle. As described in certain human patients, clinical and histological examination revealed that this mutation causes progressive degeneration of photoreceptors leading to complete blindness in homozygotes. We established that the deleterious allele was even more frequent in the Normande breed before 1975 (>40 %) and has been progressively counter selected likely because of its associated negative effect on udder morphology. Finally, using identity-by-descent analysis we demonstrated that this mutation resulted from a unique ancestral event that dates back to ~2800 to 4000 years. CONCLUSIONS: We provide a list of mutations that likely represent a substantial part of the genetic load of domestication in European cattle. We demonstrate that they accumulated non-randomly and that genes related to cognition and sensory functions are particularly affected. Finally, we describe an ancestral deleterious variant segregating in different breeds causing progressive retinal degeneration and irreversible blindness in adult animals. PMID- 27510609 TI - Genetic education, knowledge and experiences between nurses and physicians in primary care in Brazil: A cross-sectional study. AB - Recent advances in genomics and related technologies have the potential to improve health care throughout the world. In this cross-sectional study, we examine genetics education, knowledge, and genetics-related experiences among the nurses and physicians who provide primary care in a Brazilian city. Fifty-four healthcare professionals from family health units participated in the study (response rate: 90%). Data were collected using a structured 36-item questionnaire divided into five axes: sociodemographic data and academic background; genetics education; genetics knowledge; genetics-related experiences in family practice; and knowledge regarding the National Policy for Comprehensive Care in Clinical Genetics in the Unified Health System. Although most participants (85.2%) acknowledged receiving some genetic content during their undergraduate education, the majority (77.8%) advised that they did not feel prepared to deliver genomics-based health care in primary care. The results suggest that nurses and physicians often lack the knowledge to provide genomics based health care in primary care. Therefore, continuing education in genetics/genomics should be provided to primary healthcare professionals in order to enhance family practice and compliance with national policies. PMID- 27510610 TI - Iodinated (Perfluoro)alkyl Quinoxalines by Atom Transfer Radical Addition Using ortho-Diisocyanoarenes as Radical Acceptors. AB - A simple method for the preparation of functionalized quinoxalines is reported. Starting from readily accessible ortho-diisocyanoarenes and (perfluoro)alkyl iodides, the quinoxaline core is constructed during (perfluoro)alkylation by atom transfer radical addition (ATRA), resulting in 2-iodo-3 (perfluoro)alkylquinoxalines. The radical cascades are readily initiated either with visible light or by using alpha,alpha'-azobisisobutyronitrile (AIBN). The heteroarene products are obtained in high yields (up to 94 %), and the method can be readily scaled up. Useful follow-up chemistry documents the value of the novel radical quinoxaline synthesis. PMID- 27510611 TI - Bacteria Delay the Jamming of Particles at Microchannel Bottlenecks. AB - Clogging of channels by complex systems such as mixtures of colloidal and biological particles is commonly encountered in different applications. In this work, we analyze and compare the clogging mechanisms and dynamics by pure and mixture suspensions of polystyrene latex particles and Escherichia coli by coupling fluorescent microscopic observation and dynamic permeability measurements in microfluidic filters. Pure particles filtration leads to arches and deposit formation in the upstream side of the microfilter while pure bacteria form streamers in the downstream zone. When mixing particle and bacteria, an unexpected phenomenon occurs: the clogging dynamics is significantly delayed. This phenomenon is related to apparent "slippery" interactions between the particles and the bacteria. These interactions limit the arches formation at the channels entrances and favour the formation of dendritic structures on the pillars between the channels. When these dendrites are eroded by the flow, fragments of the deposit are dragged towards the channels entrances. However, these bacteria/particles clusters being lubricated by the slippery interactions are deformed and stretched by the shear thus facilitating their passage through the microchannels. PMID- 27510612 TI - Pediatrics in 21st Century and Beyond. AB - Pediatrics is a dynamic discipline and there is awareness and hope for actualizing outstanding achievements in the field of child health in 21st century and beyond. Improved lifestyle and quality of children's health is likely to reduce the burden of adult diseases and enhance longevity because seeds of most adult diseases are sown in childhood. Identification and decoding of human genome is expected to revolutionize the practice of pediatrics. The day is not far off when a patient will walk into doctor's chamber with an electronic or digital health history on a CD or palmtop and a decoded genomic constitution. There will be reduced burden of genetic diseases because of selective abortions of "defective" fetuses and replacement of "bad" genes with "good" ones by genetic engineering. Availability of totipotent stem cells and developments in transplant technology are likely to revolutionize the management of a variety of hematologic cancers and life-threatening genetic disorders. The possibility of producing flawless designer babies by advances in assisted reproductive technologies (ARTs) is likely to be mired by several ethical and legal issues.The availability of newer vaccines by recombinant technology for emerging infective and for non infective lifestyle diseases is likely to improve survival and quality of life. There is going to be a greater focus on the "patient" having the disease rather than "disease" per se by practicing holistic pediatrics by effective utilization of alternative or complementary strategies for health care. Due to advances in technology, pediatrics may get further dehumanized. A true healer cannot simply rely on technology; there must be a spiritual bond between the patient and the physician by exploiting the concept of psycho-neuro-immunology and body-mind interactions. In the years to come, physicians are likely to play "god" but medicine can't achieve immortality because anything born must die in accordance with nature's recycling blueprint. The medical science is likely to improve longevity but our goal should be to improve the quality of life. PMID- 27510613 TI - Editorial: New Horizons in Genetic Diagnosis in Pediatric Practice: The Excitement and Challenges! PMID- 27510614 TI - Morphometric analysis of endometrial cells in liquid-based cervical cytology samples. AB - BACKGROUND: Exfoliated endometrial cells can be seen in cervical smears in association with a wide variety of conditions ranging from normal proliferative endometrium to endometrial malignancies. It is often difficult to differentiate between benign, atypical and malignant endometrial cells using cytomorphology alone. This study was conducted to evaluate if morphometric analysis of endometrial nuclei on liquid-based cervical samples could be of help in differentiating between these endometrial cells. MATERIALS AND METHODS: Three groups of cervical samples with histopathological correlation were selected: Group A: showing benign endometrial cells; Group B: showing atypical endometrial cells and Group C: showing malignant endometrial cells. There were 30 cases each in Group A and B and 39 cases in Group C. Image J, NIH, USA was used for selecting the endometrial nuclei and performing the morphometric measurements. MANOVA was used for statistical analysis. RESULTS: The mean nuclear area and nuclear perimeter were significantly different between the three groups of endometrial cells with a P-value <0.05. However, the mean standard deviation of the nuclear area (SDNA) was not significantly different between atypical and malignant endometrial cells (P = 0.765) and the mean nuclear diameter was not statistically different between benign and atypical cells (P = 0.112). Also, the difference in the mean integrated gray density amongst all three groups was not statistically significant (P = 0.397, 0.844, 0.732). CONCLUSION: We conclude that the morphometric parameters of the nuclear area and nuclear perimeter are helpful in differentiating between benign, atypical and malignant endometrial nuclei even in liquid-based cervical cytology samples. PMID- 27510617 TI - Most patients taking warfarin do not maintain stable INR values. PMID- 27510615 TI - An Algorithm for Neuropathic Pain Management in Older People. AB - Neuropathic pain frequently affects older people, who generally also have several comorbidities. Elderly patients are often poly-medicated, which increases the risk of drug-drug interactions. These patients, especially those with cognitive problems, may also have restricted communication skills, making pain evaluation difficult and pain treatment challenging. Clinicians and other healthcare providers need a decisional algorithm to optimize the recognition and management of neuropathic pain. We present a decisional algorithm developed by a multidisciplinary group of experts, which focuses on pain assessment and therapeutic options for the management of neuropathic pain, particularly in the elderly. The algorithm involves four main steps: (1) detection, (2) evaluation, (3) treatment, and (4) re-evaluation. The detection of neuropathic pain is an essential step in ensuring successful management. The extent of the impact of the neuropathic pain is then assessed, generally with self-report scales, except in patients with communication difficulties who can be assessed using behavioral scales. The management of neuropathic pain frequently requires combination treatments, and recommended treatments should be prescribed with caution in these elderly patients, taking into consideration their comorbidities and potential drug-drug interactions and adverse events. This algorithm can be used in the management of neuropathic pain in the elderly to ensure timely and adequate treatment by a multidisciplinary team. PMID- 27510616 TI - FSH aggravates bone loss in ovariectomised rats with experimental periapical periodontitis. AB - Periapical bone loss is one of the prominent pathological and clinical features of periapical periodontitis. Previous studies have demonstrated that follicle stimulating hormone (FSH) could directly affect skeletal remodelling by stimulating the formation and the function of osteoclasts in vitro and in vivo. However, the effect of FSH on periapical bone loss remained to be fully elucidated. In the current study, a rat model was established in order to verify the effect of FSH in experimental periapical lesions. It was identified that FSH aggravated the bone loss of periapical lesions. In addition, RANKL-, TRAP-, TNF alpha- and IL-1beta-positive cells were increased significantly in FSH-treated groups, which indicated that the function of FSH in bone loss may be mediated through the increasing activity of osteoclasts and the increased secretion of inflammatory cytokines. The results of the current study suggested that FSH, independent of oestrogen, may aggravate periapical bone loss by FSH receptors, which may serve an important role in the immune and inflammatory response of the host to root canal and periradicular infection during menopause. PMID- 27510618 TI - Post-exercise heart-rate recovery correlates to resting heart-rate variability in healthy men. AB - JUSTIFICATIVE: The relationship between post-exercise heart-rate recovery (HRR) and resting cardiac autonomic modulation is an incompletely explored issue. OBJECTIVE: To correlate HRR with resting supine and orthostatic autonomic status. METHOD: HRR at the 1st, 3th, and 5th min following maximal treadmill exercise were correlated with 5-min time-domain (CV, pNN50 and rMSSD) and frequency-domain (TP, LF, HF, LFn, HFn, and LF/HF ratio) indices of heart-rate variability (HRV) in both supine and standing positions in 31 healthy physically active non athletes men. Statistical analysis employed non-parametric tests with two-tailed p value set at 5 %. RESULTS: Absolute HRR and Delta %HRR at each post-exercise time did not correlated with HRV in supine position, as well as at 1st min in standing position. At the 3rd min and 5th min, these measures negatively correlated with pNN50, rMSSD, TP, and HF indices, and only in the 5th min, they showed negative correlation with HFn and positive correlation with LF, LFn, and LF/HF ratio in the standing position. Coefficient of HRR (CHRR) at the 1st min negatively correlated with pNN50 and rMSSD and at 3rd and 5th min showed positive correlation with LFn and LF/HF ratio in supine position. With HRV indices in standing position CHRR from the 1st to 5th min showed the same respective negative and positive correlations as the other measures. CONCLUSION: HRR from the 1st to 5th min post-exercise negatively correlated with parasympathetic modulation in resting orthostatic, but showed no correlation in supine position. At the 3rd and 5th min, a positive correlation with combined sympathetic parasympathetic modulation in both positions was observed. PMID- 27510619 TI - Advancing Risk Analysis for Nanoscale Materials: Report from an International Workshop on the Role of Alternative Testing Strategies for Advancement. AB - The Society for Risk Analysis (SRA) has a history of bringing thought leadership to topics of emerging risk. In September 2014, the SRA Emerging Nanoscale Materials Specialty Group convened an international workshop to examine the use of alternative testing strategies (ATS) for manufactured nanomaterials (NM) from a risk analysis perspective. Experts in NM environmental health and safety, human health, ecotoxicology, regulatory compliance, risk analysis, and ATS evaluated and discussed the state of the science for in vitro and other alternatives to traditional toxicology testing for NM. Based on this review, experts recommended immediate and near-term actions that would advance ATS use in NM risk assessment. Three focal areas-human health, ecological health, and exposure considerations shaped deliberations about information needs, priorities, and the next steps required to increase confidence in and use of ATS in NM risk assessment. The deliberations revealed that ATS are now being used for screening, and that, in the near term, ATS could be developed for use in read-across or categorization decision making within certain regulatory frameworks. Participants recognized that leadership is required from within the scientific community to address basic challenges, including standardizing materials, protocols, techniques and reporting, and designing experiments relevant to real-world conditions, as well as coordination and sharing of large-scale collaborations and data. Experts agreed that it will be critical to include experimental parameters that can support the development of adverse outcome pathways. Numerous other insightful ideas for investment in ATS emerged throughout the discussions and are further highlighted in this article. PMID- 27510620 TI - Seasonal effects on plasma cortisol concentrations in the Bedouin buck: circadian studies and response to ACTH. AB - Our work aims at the exploration of cortisol secretion in the Bedouin goat, native to the Algerian Sahara desert, to understand the mechanisms of adaptation to extreme hot climates. In the present study, diurnal and seasonal variations of cortisol concentrations were measured in basal conditions, as well as the response to ACTH stimulation tests across seasons in bucks. The plasma concentrations of cortisol showed no diurnal cycle but a large variation across seasons. The highest levels occurred in summer and winter when the environmental conditions are at their extreme levels. The rectal temperature showed nychthemeral and seasonal variations, and BW was also different across seasons with highest values in summer and lowest in winter. The results obtained after administration of two doses (2 or 10 MUg/kg BW) of synthetic ACTH to three different age groups (kids, adults and elderly animals) showed a strong increase in plasma cortisol concentrations under all conditions with maximum levels achieved between 15 and 120 min. The analysis of the area under the cortisol curve showed no significant difference between the responses to the two doses of ACTH and between age groups, but showed seasonal variations with the lowest response in autumn than in other seasons. We conclude that season significantly affects secretion of cortisol in both basal state and under ACTH stimulation. However, the variation of adrenal reactivity to ACTH is not sufficient to explain seasonal differences, and in particular the summer peak in basal circulating cortisol concentrations. Further research should focus on the respective contribution of environmental factors (such as day length, temperature, humidity) and the mechanisms involved in cortisol regulation. PMID- 27510621 TI - Commentary: Theoretical and Methodological Dimensions of Convergence and Divergence of Adolescent and Parent Reports about Youth Development and Family Structure and Function-A Relational Developmental Systems Perspective. AB - Using ideas associated with relational developmental systems metatheory, we discuss the links among the operation triad model of adolescent report-parent report convergence, divergence, or compensation and the research reported in this special issue. These contributions highlight the important implications for adolescent adjustment of youth and parent reports about adolescent development and family structure and function. Relational developmental systems metatheory raises both theoretical and methodological issues for research framed by the operation triad model. These issues emphasize the specificity (non-ergodicity) of mutually influential relationships between a youth and his/her parent, that is, the specificity of the adolescent-parent relationship. Relational developmental systems -based ideas may enable the operation triad model to be a means through which the study of adolescent self-reports and parent reports will have a more central place in the construction of key features of the dynamics of adolescent parent relationships. PMID- 27510622 TI - Potassium channels in the Cx43 gap junction perinexus modulate ephaptic coupling: an experimental and modeling study. AB - It was recently demonstrated that cardiac sodium channels (Nav1.5) localized at the perinexus, an intercalated disc (ID) nanodomain associated with gap junctions (GJ), may contribute to electrical coupling between cardiac myocytes via an ephaptic mechanism. Impairment of ephaptic coupling by acute interstitial edema (AIE)-induced swelling of the perinexus was associated with arrhythmogenic, anisotropic conduction slowing. Given that Kir2.1 has also recently been reported to localize at intercalated discs, we hypothesized that Kir2.1 channels may reside within the perinexus and that inhibiting them may mitigate arrhythmogenic conduction slowing observed during AIE. Using gated stimulated emission depletion (gSTED) and stochastic optical reconstruction microscopy (STORM) super-resolution microscopy, we indeed find that a significant proportion of Kir2.1 channels resides within the perinexus. Moreover, whereas Nav1.5 inhibition during AIE exacerbated arrhythmogenic conduction slowing, inhibiting Kir2.1 channels during AIE preferentially increased transverse conduction velocity-decreasing anisotropy and ameliorating arrhythmia risk compared to AIE alone. Comparison of our results with a nanodomain computer model identified enrichment of both Nav1.5 and Kir2.1 at intercalated discs as key factors underlying the experimental observations. We demonstrate that Kir2.1 channels are localized within the perinexus alongside Nav1.5 channels. Further, targeting Kir2.1 modulates intercellular coupling between cardiac myocytes, anisotropy of conduction, and arrhythmia propensity in a manner consistent with a role for ephaptic coupling in cardiac conduction. For over half a century, electrical excitation in the heart has been thought to occur exclusively via gap junction-mediated ionic current flow between cells. Further, excitation was thought to depend almost exclusively on sodium channels with potassium channels being involved mainly in returning the cell to rest. Here, we demonstrate that sodium and potassium channels co-reside within nanoscale domains at cell-to-cell contact sites. Experimental and computer modeling results suggest a role for these channels in electrical coupling between cardiac muscle cells via an ephaptic mechanism working in tandem with gap junctions. This new insight into the mechanism of cardiac electrical excitation could pave the way for novel therapies against cardiac rhythm disturbances. PMID- 27510623 TI - In-vivo monitoring of development of cholangiocarcinoma induced with C. sinensis and N-nitrosodimethylamine in Syrian golen hamsters using ultrasonography and magnetic resonance imaging: a preliminary study. AB - OBJECTIVES: The purpose of this study is to evaluate high-resolution ultrasound and magnetic resonance imaging (MRI) in monitoring of cholangiocarcinoma in the hamsters with C. sinensis infection and N-nitrosodimethylamine (NDMA). MATERIALS AND METHODS: Twenty-four male Syrian golden hamsters of were divided into four groups composed of five hamsters as control, five hamsters receiving 30 metacercariae of C. sinensis per each hamster, five hamsters receiving NDMA in drinking water, and nine hamsters receiving both metacercariae and NDMA. Ultrasound was performed every other week from baseline to the 12th week of infection. MRI and histopathologic examination was done from the 4th week to 12th week. RESULTS: Cholangiocarcinomas appeared as early as the 6th week of infection. There were 12 cholangiocarcinomas, nine and ten of which were demonstrated by ultrasound and MRI, respectively. Ultrasound and MRI findings of cholangiocarcinomas in the hamsters were similar to those of the mass-forming intrahepatic cholangiocarcinomas in humans. Ultrasound and MRI also showed other findings of disease progression such as periductal increased echogenicity or signal intensity, ductal dilatation, complicated cysts, and sludges in the gallbladder. CONCLUSIONS: High-resolution ultrasound and MRI can monitor and detect the occurrence of cholangiocarcinoma in the hamsters non-invasively. KEY POINTS: * High-resolution ultrasound and MRI can monitor occurrence of cholangiocarcinoma in the hamsters. * Cholangiocarcinomas were detected as early as the 6th week after C. sinensis infection. * Axial T2-weighted MRI demonstrated cholangiocarcinomas and various inflammatory findings in the hamsters. PMID- 27510624 TI - Added value of point shear-wave elastography in the diagnosis of acute cholecystitis. AB - OBJECTIVE: To evaluate the added value of point shear-wave elastography (pSWE) in the diagnostic performance of conventional US for diagnosis of acute cholecystitis. METHODS: B-mode and colour Doppler US and pSWE were performed prospectively in 216 patients with clinically suspected acute cholecystitis. The morphology and mural vascularity of the gallbladder and median shear wave velocity (SWV) of the right liver were evaluated. Two observers independently reviewed conventional US images and subsequently reviewed combined conventional US and pSWE images. RESULTS: Mean SWVs of the acute cholecystitis group (n = 91) were significantly higher than those of the control group (n = 85) in the right liver within 2 cm lateral to the gallbladder (1.56 versus 1.03 m/s, 1.39 versus 1.04 m/s, P < 0.0001) with a cut-off value of 1.29 or 1.16 m/s. The area under the receiver operating characteristic curve of both observers in the diagnosis of acute cholecystitis improved significantly from 0.790 and 0.777 to 0.963 and 0.962, respectively, after additional review of pSWE images (P < 0.0001). Diagnostic accuracy, sensitivity, specificity, positive and negative predictive values of combined image sets were higher than those of conventional US images alone. CONCLUSION: Adding pSWE to conventional US improves the diagnosis of acute cholecystitis when compared with conventional US alone. KEY POINTS: * In acute cholecystitis, stiffness of the right liver increases adjacent to the gallbladder. * The cut-off value for diagnosing acute cholecystitis was 1.29 or 1.16 m/s. * Adding pSWE to conventional US improves the diagnosis of acute cholecystitis. PMID- 27510625 TI - Noninvasive evaluation of global and regional left ventricular function using computed tomography and magnetic resonance imaging: a meta-analysis. AB - OBJECTIVES: To compare the diagnostic accuracy of computed tomography (CT) in the assessment of global and regional left ventricular (LV) function with magnetic resonance imaging (MRI). METHODS: MEDLINE, EMBASE and ISI Web of Science were systematically reviewed. Evaluation included: ejection fraction (EF), end diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV) and left ventricular mass (LVM). Differences between modalities were analysed using limits of agreement (LoA). Publication bias was measured by Egger's regression test. Heterogeneity was evaluated using Cochran's Q test and Higgins I2 statistic. In the presence of heterogeneity the DerSimonian-Laird method was used for estimation of heterogeneity variance. RESULTS: Fifty-three studies including 1,814 patients were identified. The mean difference between CT and MRI was -0.56 % (LoA, -11.6-10.5 %) for EF, 2.62 ml (-34.1-39.3 ml) for EDV and 1.61 ml (-22.4 25.7 ml) for ESV, 3.21 ml (-21.8-28.3 ml) for SV and 0.13 g (-28.2-28.4 g) for LVM. CT detected wall motion abnormalities on a per-segment basis with 90 % sensitivity and 97 % specificity. CONCLUSIONS: CT is accurate for assessing global LV function parameters but the limits of agreement versus MRI are moderately wide, while wall motion deficits are detected with high accuracy. KEY POINTS: * CT helps to assess patients with coronary artery disease (CAD). * MRI is the reference standard for evaluation of left ventricular function. * CT provides accurate assessment of global left ventricular function. PMID- 27510626 TI - DNA damage in lymphocytes induced by cardiac CT and comparison with physical exposure parameters. AB - OBJECTIVES: To investigate whether physical exposure parameters such as the dose index (CTDI), dose length product (DLP), and size-specific dose estimate (SSDE) are predictive of DNA damage. METHODS: In vitro, we scanned a phantom containing blood samples from five volunteers at CTDI 50, 100, and 150 mGy. One sample was not scanned. We also scanned samples in three different-size phantoms at CTDI 100 mGy. In vivo, we enrolled 45 patients and obtained blood samples before and after cardiac CT. The gamma-H2AX foci were counted. RESULTS: In vitro, in the control and at CTDI 50, 100, and 150 mGy, the number of gamma-H2AX was 0.94 +/- 0.24 (standard error, SE), 1.28 +/- 0.30, 1.91 +/- 0.47, and 2.16 +/- 0.20. At SSDE 180, 156, and 135 mGy, it was 2.41 +/- 0.20, 1.91 +/- 0.47, and 1.42 +/- 0.20 foci/cell. The gamma-H2AX foci were positively correlated with the radiation dose and negatively correlated with the body size. In vivo, the gamma-H2AX foci were significantly increased after CT (from 1.21 +/- 0.19 to 1.92 +/- 0.22 foci/cell) and correlated with CTDI, DLP, and SSDE. CONCLUSIONS: DNA damage was induced by cardiac CT. There was a correlation between the physical exposure parameters and gamma-H2AX. KEY POINTS: * DNA damage was induced by radiation exposure from cardiac CT. * The gamma-H2AX foci number was correlated with the CT radiation dose. * Physical exposure parameters reflect the DNA damage by CT radiation exposure. PMID- 27510627 TI - Detection of pulmonary fat embolism with dual-energy CT: an experimental study in rabbits. AB - OBJECTIVES: To evaluate the use of dual-energy CT imaging of the lung perfused blood volume (PBV) for the detection of pulmonary fat embolism (PFE). METHODS: Dual-energy CT was performed in 24 rabbits before and 1 hour, 1 day, 4 days and 7 days after artificial induction of PFE via the right ear vein. CT pulmonary angiography (CTPA) and lung PBV images were evaluated by two radiologists, who recorded the presence, number, and location of PFE on a per-lobe basis. Sensitivity, specificity, and accuracy of CTPA and lung PBV for detecting PFE were calculated using histopathological evaluation as the reference standard. RESULTS: A total of 144 lung lobes in 24 rabbits were evaluated and 70 fat emboli were detected on histopathological analysis. The overall sensitivity, specificity and accuracy were 25.4 %, 98.6 %, and 62.5 % for CTPA, and 82.6 %, 76.0 %, and 79.2 % for lung PBV. Higher sensitivity (p < 0.001) and accuracy (p < 0.01), but lower specificity (p < 0.001), were found for lung PBV compared with CTPA. Dual energy CT can detect PFE earlier than CTPA (all p < 0.01). CONCLUSION: Dual energy CT provided higher sensitivity and accuracy in the detection of PFE as well as earlier detection compared with conventional CTPA in this animal model study. KEY POINTS: * Fat embolism occurs commonly in patients with traumatic bone injury. * Dual-energy CT improves diagnostic performance for pulmonary fat embolism detection. * Dual-energy CT can detect pulmonary fat embolism earlier than CTPA. PMID- 27510628 TI - Differentiation of mass-forming focal pancreatitis from pancreatic ductal adenocarcinoma: value of characterizing dynamic enhancement patterns on contrast enhanced MR images by adding signal intensity color mapping. AB - OBJECTIVES: To evaluate the value of dynamic enhancement patterns on contrast enhanced MR images by adding signal intensity colour mapping (SICM) to differentiate mass-forming focal pancreatitis (MFFP) from pancreatic ductal adenocarcinoma (PDAC). METHODS: Forty-one clinicopathologically proven MFFPs and 144 surgically confirmed PDACs were enrolled. Laboratory and MR imaging parameters were used to differentiate MFFP from PDAC. In particular, enhancement patterns on MR images adding SICM were evaluated. By using classification tree analysis (CTA), we determined the predictors for the differentiation of MFFP from PDAC. RESULTS: In the CTA, with all parameters except enhancement pattern on SICM images, ductal obstruction grade and T1 hypointensity grade of the pancreatic lesion were the first and second splitting predictor for differentiation of MFFP from PDAC, in order. By adding an enhancement pattern on the SICM images to CTA, the enhancement pattern was the only splitting predictor to differentiate MFFP from PDAC. The CTA model including enhancement pattern on SICM images has sensitivity of 78.0 %, specificity of 99.3 %, and accuracy of 94.6 % for differentiating MFFP from PDAC. CONCLUSION: The characterization of enhancement pattern for pancreatic lesions on contrast-enhanced MR images adding SICM would be helpful to differentiate MFFP from PDAC. KEY POINTS: * SICM was useful to characterize enhancement pattern. * Enhancement pattern on SICM was the only splitting predictor on CTA. * This model may be useful for differentiating MFFP from PDAC. PMID- 27510629 TI - Arteries of the falciform ligament on C-arm CT hepatic arteriography: The hepatic falciform artery and the Sappey's superior artery. AB - BACKGROUND AND AIM: To investigate the prevalence, anatomy and distribution of the hepatic falciform artery (HFA) and Sappey's superior artery (SSA) using C-arm CT hepatic arteriography (C-arm CTHA). MATERIALS AND METHODS: From January 2011 to December 2012, 220 patients who underwent C-arm CTHA during initial transarterial treatment for hepatocellular carcinoma were included in this retrospective study. The HFAs and SSAs prevalence and origin were evaluated using axial images of C-arm CTHA. A 5-point scale for HFAs and a 4-point scale for SSAs were used to designate the radiologically conspicuous arteries. RESULTS: The prevalences of the total HFAs and SSAs were 95 % (n=209) and 22 % (n=49), while those of radiologically conspicuous HFAs and SSAs were 62 % (n=137) and 10 % (n=22), respectively. Thirty HFAs (22 % of radiologically conspicuous HFAs and 14 % of the total study population) were distributed in the subcutaneous layer of the anterior abdominal wall, while the majority of SSAs ran through the superior part of the falciform ligament in the left-anterior direction and anastomosed with left inferior phrenic artery. CONCLUSION: Our study using C-arm CTHA revealed that the prevalence of the HFA is higher than the existing knowledge and proved the existence of the SSA radiologically for the first time. KEY POINTS: * Prevalence of hepatic falciform artery is 95 %, higher than previously known. * 22 % of conspicious hepatic falciform arteries distributed in subcutaneous tissue around umbilicus. * The existence of Sappey's superior artery was proved with a radiological method. PMID- 27510631 TI - Michael Sharpe: Psychiatry was no "waste of a career". PMID- 27510630 TI - 3D-black-blood 3T-MRI for the diagnosis of thoracic large vessel vasculitis: A feasibility study. AB - OBJECTIVES: To evaluate the feasibility of T1w-3D black-blood turbo spin echo (TSE) sequence with variable flip angles for the diagnosis of thoracic large vessel vasculitis (LVV). METHODS: Thirty-five patients with LVV, diagnosed according to the current standard of reference, and 35 controls were imaged at 3.0T using 1.2 * 1.3 * 2.0 mm3 fat-suppressed, T1w-3D, modified Volumetric Isotropic TSE Acquisition (mVISTA) pre- and post-contrast. Applying a navigator and peripheral pulse unit triggering (PPU), the total scan time was 10-12 min. Thoracic aorta and subclavian and pulmonary arteries were evaluated for image quality (IQ), flow artefact intensity, diagnostic confidence, concentric wall thickening and contrast enhancement (CWT, CCE) using a 4-point scale. RESULTS: IQ was good in all examinations (3.25 +/- 0.72) and good to excellent in 342 of 408 evaluated segments (83.8 %), while 84.1 % showed no or minor flow artefacts. The interobserver reproducibility for the identification of CCE and CWT was 0.969 and 0.971 (p < 0.001) with an average diagnostic confidence of 3.47 +/- 0.64. CCE and CWT were strongly correlated (Cohen's k = 0.87; P < 0.001) and significantly more frequent in the LVV-group (52.8 % vs. 1.0 %; 59.8 % vs. 2.4 %; P < 0.001). CONCLUSIONS: Navigated fat-suppressed T1w-3D black-blood MRI with PPU-triggering allows diagnosis of thoracic LVV. KEY POINTS: * Cross-sectional imaging is frequently applied in the diagnosis of LVV. * Navigated, PPU-triggered, T1w-3D mVISTA pre- and post contrast takes 10-12 min. * In this prospective, single centre study, T1w-3D mVISTA accurately depicted large thoracic vessels. * T1w-3D mVISTA visualized CWT/CCW as correlates of mural inflammation in LVV. * T1w-3D mVISTA might be an alternative diagnostic tool without ionizing radiation. PMID- 27510632 TI - Pretreatment neutrophil-to-lymphocyte ratio and its dynamic changes are associated with the overall survival in advanced cancer patients undergoing palliative care. AB - The objective of this study was to investigate the prognostic value of pretreatment NLR and its dynamic changes responsive to palliative care in advanced cancer patients. The study was retrospectively assessed in 378 consecutive advanced cancer patients receiving palliative care, and in an extended follow-up study of 106 of those patients. The cutoff value of pretreatment NLR was determined to be 3.0. In the 378 advanced cancer patients, 89 had pretreatment NLR <= 3, and 289 had an NLR > 3. Univariate and multivariate analyses showed that tumor stage, palliative care, albumin level, and pretreatment NLR (HR: 1.514, 95% CI: 1.125~2.038, P = 0.006) were independent prognostic indicators of OS. Moreover, in the follow-up cohort of 106 readmitted patients, 43 patients achieved a decreased NLR after palliative care, while the remaining 63 patients showed an increased NLR. Univariate and multivariate analyses showed that an increase in NLR was significantly associated with a poor survival (HR: 2.506, 95% CI: 1.474~4.261, P = 0.001). In conclusion, pretreatment NLR and changes in NLR independently predicted OS in advanced cancer patients undergoing palliative care. Incorporating NLR into clinical practice may better inform the prognosis and therapy decisions of advanced cancer patients in palliative settings. PMID- 27510633 TI - Main competences and skills to perform Essential Public Health Operations, offered by Schools of Public Health in four European countries: a short pilot report. AB - OBJECTIVES: To consider the stage of implementation of main competences and EPHO skills in selected schools of public health in four European countries-France, Poland, Portugal, and the UK. METHODS: By use of visual analogue scales (VAS) ranging 1-5, the leads of three schools of public health (SPH) in each of the four countries, France, Poland, Portugal and the UK, reported the strength of intellectual and practical competences as well as skills to perform essential public health operations (EPHOs), offered by their education and training programmes. RESULTS: The self-reports indicated substantial coverage of the multidimensional public health discipline. Each country representation had its overall characteristic profile, and there was found noteworthy within-country as well as between-country variation. CONCLUSIONS: The schools should meet the challenge of establishing collaborative networks, which will be important for public health strategy making and implementation, for shaping a coherent public health profession, and thus ultimately for population health. This pilot report should be followed up by more systematically penetrating and comprehensive analyses to identify met and unmet needs in public health education and training. PMID- 27510634 TI - Projected increase in amyotrophic lateral sclerosis from 2015 to 2040. AB - Although amyotrophic lateral sclerosis (ALS) is relatively rare, the socioeconomic significance of the disease is extensive. It is therefore vital to project the epidemiologic trend of ALS. To date, there have been few published studies attempting to estimate the number and distribution of ALS cases in the upcoming years. Here we show that the number of ALS cases across the globe will increase from 222,801 in 2015 to 376,674 in 2040, representing an increase of 69%. This increase is predominantly due to ageing of the population, particularly among developing nations. This projection is likely an underestimate due to improving healthcare and economic conditions. The results should be used to inform healthcare policy to more efficiently allocate healthcare resources. PMID- 27510635 TI - Population PK Modeling and Target Attainment Simulations to Support Dosing of Ceftaroline Fosamil in Pediatric Patients With Acute Bacterial Skin and Skin Structure Infections and Community-Acquired Bacterial Pneumonia. AB - Ceftaroline, the active form of the prodrug ceftaroline fosamil, is approved for use in adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI) in the United States and for similar indications in Europe. Pharmacokinetic (PK) data from 5 pediatric (birth to <18 years) studies of ceftaroline fosamil were combined with PK data from adults to update a population PK model for ceftaroline and ceftaroline fosamil. This model, based on a data set including 305 children, was used to conduct simulations to estimate ceftaroline exposures and percentage of time that free drug concentrations were above the minimum inhibitory concentration (%fT>MIC) for pediatric dose regimens. With dose regimens of 8 mg/kg every 8 hours (q8h) in children aged 2 months to <2 years and 12 mg/kg (up to a maximum of 400 mg) q8h in children aged 2 years to <18 years or 600 mg q12h in children aged 12 to <18 years, >90% of children were predicted to achieve a target of 36% fT>MIC at an MIC of 2 mg/L, and >97% were predicted to achieve 44% fT>MIC at an MIC of 1 mg/L. Thus, high PK/pharmacodynamic target attainment would be maintained in children for targets associated with 1-log kill of Staphylococcus aureus and Streptococcus pneumoniae. The predicted ceftaroline exposures for these dose regimens were similar to those in adults given 600 mg q12h ceftaroline fosamil. This work contributed to the approval of dose regimens for children aged 2 months to <18 years by the FDA and EMA, which are presented. PMID- 27510636 TI - Description of excited states in [Re(Imidazole)(CO)3 (Phen)](+) including solvent and spin-orbit coupling effects: Density functional theory versus multiconfigurational wavefunction approach. AB - The low-lying electronic excited states of [Re(imidazole)(CO)3 (phen)](+) (phen = 1,10-phenanthroline) ranging between 420 nm and 330 nm have been calculated by means of relativistic spin-orbit time-dependent density functional theory (TD DFT) and wavefunction approaches (state-average-CASSCF/CASPT2). A direct comparison between the theoretical absorption spectra obtained with different methods including SOC and solvent corrections for water points to the difficulties at describing on the same footing the bands generated by metal-to ligand charge transfer (MLCT), intraligand (IL) transition, and ligand-to-Ligand- charge transfer (LLCT). While TD-DFT and three-roots-state-average CASSCF (10,10) reproduce rather well the lowest broad MLCT band observed in the experimental spectrum between 420 nm and 330 nm, more flexible wavefunctions enlarged either by the number of roots or by the number of active orbitals and electrons destabilize the MLCT states by introducing IL and LLCT character in the lowest part of the absorption spectrum. (c) 2016 Wiley Periodicals, Inc. PMID- 27510637 TI - Polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder. PMID- 27510638 TI - Mechanical response of all-MoS2 single-layer heterostructures: a ReaxFF investigation. AB - Molybdenum disulfide (MoS2) is a highly attractive 2D material due to its interesting electronic properties. Recent experimental advances confirm the possibility of further tuning the electronic properties of MoS2 through the fabrication of single-layer heterostructures consisting of semiconducting (2H) and metallic (1T) MoS2 phases. Nonetheless, despite significant technological and scientific interest, there is currently limited information concerning the mechanical properties of these heterostructure systems. This investigation aims at extending our understanding of the mechanical properties of all-MoS2 single layer structures at room temperature. This goal was achieved by performing extensive classical molecular dynamics simulations using a recently developed ReaxFF force field. We first studied the direction dependent mechanical properties of defect-free 2H and 1T phases. Our modelling results for pristine 2H MoS2 were found to be in good agreement with the experimental tests and first principles theoretical predictions. We also discuss the mechanical response of 2H/1T single layer heterostructures. Our reactive molecular dynamics results suggest all-MoS2 heterostructures as suitable candidates for providing a strong and flexible material with tuneable electronic properties. PMID- 27510639 TI - CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation. AB - Ferroptosis is a form of non-apoptotic cell death originally identified in cancer cells. However, the key regulator of ferroptosis in mitochondria remains unknown. Here, we show that CDGSH iron sulfur domain 1 (CISD1, also termed mitoNEET), an iron-containing outer mitochondrial membrane protein, negatively regulates ferroptotic cancer cell death. The classical ferroptosis inducer erastin promotes CISD1 expression in an iron-dependent manner in human hepatocellular carcinoma cells (e.g., HepG2 and Hep3B). Genetic inhibition of CISD1 increased iron mediated intramitochondrial lipid peroxidation, which contributes to erastin induced ferroptosis. In contrast, stabilization of the iron sulfur cluster of CISD1 by pioglitazone inhibits mitochondrial iron uptake, lipid peroxidation, and subsequent ferroptosis. These findings indicate a novel role of CISD1 in protecting against mitochondrial injury in ferroptosis. PMID- 27510640 TI - The GPI anchor pathway: a promising antifungal target? PMID- 27510641 TI - Clustered marginalization of minorities during social transitions induced by co evolution of behaviour and network structure. AB - Large-scale transitions in societies are associated with both individual behavioural change and restructuring of the social network. These two factors have often been considered independently, yet recent advances in social network research challenge this view. Here we show that common features of societal marginalization and clustering emerge naturally during transitions in a co evolutionary adaptive network model. This is achieved by explicitly considering the interplay between individual interaction and a dynamic network structure in behavioural selection. We exemplify this mechanism by simulating how smoking behaviour and the network structure get reconfigured by changing social norms. Our results are consistent with empirical findings: The prevalence of smoking was reduced, remaining smokers were preferentially connected among each other and formed increasingly marginalized clusters. We propose that self-amplifying feedbacks between individual behaviour and dynamic restructuring of the network are main drivers of the transition. This generative mechanism for co-evolution of individual behaviour and social network structure may apply to a wide range of examples beyond smoking. PMID- 27510642 TI - Corrigendum. PMID- 27510643 TI - RETRACTED: Investigation of the GeneXpert(r) CT/NG assay for use with male pharyngeal and rectal swabs. PMID- 27510644 TI - Stroke in a young patient with neurosyphilis and HIV. AB - Syphilis has long been known as the great imitator. Its heterogeneity can manifest in the form of meningitis, space occupying gummas, vasculitis, strokes, cranial neuropathies, myelopathy, dementia, and seizures. The incidence has been rising with each year, mainly in men who have sex with men accounting for 83% of cases. With the coexistence of immunocompromised states, especially HIV (human immunodeficiency virus), the usually chronic and insidious course of tertiary neurosyphilis can be accelerated. Stroke can occur as a result of neurosyphilis in its meningovascular form, and the likelihood of this increases with HIV co infection, especially in high-risk groups such as intravenous drug users and men who have sex with men. Here, we discuss a case of a young man who presented with an ischemic stroke found to have neurosyphilis and HIV and consider the management of these co-morbid conditions. PMID- 27510645 TI - Low levels of neurocognitive impairment detected in screening HIV-infected men who have sex with men: The MSM Neurocog Study. AB - This study aimed to determine the prevalence of HIV neurocognitive impairment in HIV-infected men who have sex with men aged 18-50 years, using a simple battery of screening tests in routine clinical appointments. Those with suspected abnormalities were referred on for further assessment. The cohort was also followed up over time to look at evolving changes. HIV-infected participants were recruited at three clinical sites in London during from routine clinical visits. They could be clinician or self-referred and did not need to be symptomatic. They completed questionnaires on anxiety, depression, and memory. They were then screened using the Brief Neurocognitive Screen (BNCS) and International HIV Dementia Scale (IHDS). Two hundred and five HIV-infected subjects were recruited. Of these, 59 patients were excluded as having a mood disorder and two patients were excluded due to insufficient data, leaving 144 patients for analysis. One hundred and twenty-four (86.1%) had a normal composite z score (within 1 SD of mean) calculated for their scores on the three component tests of the BNCS. Twenty (13.9%) had an abnormal z score, of which seven (35%) were symptomatic and 13 (65%) asymptomatic. Current employment and previous educational level were significantly associated with BNCS scores. Of those referred onwards for diagnostic testing, only one participant was found to have impairment likely related to HIV infection. We were able to easily screen for mood disorders and cognitive impairment in routine clinical practice. We identified a high level of depression and anxiety in our cohort. Using simple screening tests in clinic and an onward referral process for further testing, we were not able to identify neurocognitive impairment in this cohort at levels consistent with published data. PMID- 27510646 TI - Perforating domed plasmonic films for broadband and omnidirectional antireflection. AB - Domed Ag nano-hole/disk array films exhibit a reflectivity of less than 0.7% over a wide spectral range (400-1000 nm) and even lower values down to 0.05% with an oblique incidence angle; this unique optical response is attributed to three key factors: diffractive scattering loss on nanostructures, localized plasmonic absorption and curved surface (domed units). PMID- 27510647 TI - Specific patterns of laryngeal electromyography during wakefulness are associated to sleep disordered breathing and nocturnal stridor in multiple system atrophy. AB - BACKGROUND: Nocturnal stridor and respiratory abnormalities are important features of multiple system atrophy (MSA) with relevance to patient survival, and they are detected and evaluated mainly through video-polysomnography (video-PSG). Diurnal laryngoscopy seems to yield abnormal findings only in the presence of significant vocal cord (VC) dysfunction. AIM: To assess whether specific electrophysiological patterns of diurnal EMG of VC muscles may indicate nocturnal stridor or respiratory dysfunctions in MSA patients. MATERIALS AND METHODS: Seventeen patients with probable MSA were examined. A full-night video-PSG to collect standard breathing parameters (apnea/hypopnea index, mean HbSAO2, oxygen desaturation index, total sleep time with HbSaO2 below 90%) was performed in all the patients. Laryngoscopy and EMG investigation of adductor (thyroarytenoid-TA) and abductor (posterior cricoarytenoid-PCA) muscles of the VCs were also performed. RESULTS: Both the laryngeal EMG abnormalities (based on MUAP analysis and kinesiologic EMG investigation of VC muscles) and the laryngoscopic alterations correlated with video-PSG respiratory abnormalities. Specific patterns of EMG findings were consistently found in MSA subjects with nocturnal stridor detected at PSG. In particular, the following EMG findings were related to the severity of breathing abnormalities and the presence of stridor on video PSG: neurogenic pattern on MUAP analysis of the PCA, paradoxical activation of the TA during inspiration and tonic EMG activity of the TA during quiet breathing. CONCLUSIONS: Electromyographic/kinesiologic investigation of VC muscles during wakefulness provides additional information on the pathophysiology of the respiratory abnormalities in MSA patients that could be useful for guiding the choice of the best appropriate treatment and care. PMID- 27510648 TI - Timing of Breeding Determines Growth and Development in a Long-Distance Migratory Bird. AB - The timing of breeding can have significant consequences for adult and offspring fitness, yet our current hypotheses of seasonal timing focus on the parent perspective. When offspring survival is affected by timing of breeding, we expect to see offspring mechanisms to detect and respond to cues of seasonal timing. Avian embryos respond to photoperiod and seasonal cues during development and in this study we evaluate the influence of photoperiod and season on posthatching growth and development in Franklin's gull (Leucophaeus pipixcan). Early- and late season chicks exposed to short and long photoperiods during development were reared under common garden conditions. Photoperiod had no effect on posthatching growth and development, but seasonal effects present in the egg (maternal egg effects or genetic) did influence posthatching growth and development. Late season chicks grew body mass and primary flight feathers at faster rates than early-season chicks, which we hypothesize facilitates independence and readiness for migration. Growth rates are complex phenotypes and we propose a general growth model that incorporates delays in negative feedback systems regulating growth. We show that the timing of breeding programs intrinsic growth rates in offspring, which suggests that many of the metrics used to describe seasonal patterns of reproductive success may be biased. PMID- 27510649 TI - Erratum to: Donor age and long-term culture do not negatively influence the stem potential of limbal fibroblast-like stem cells. PMID- 27510650 TI - Letter to the editor: Progressive neurology in a young woman with a known Currarino's triad. PMID- 27510651 TI - Identifying enriched drug fragments as possible candidates for metabolic engineering. AB - BACKGROUND: Fragment-based approaches have now become an important component of the drug discovery process. At the same time, pharmaceutical chemists are more often turning to the natural world and its extremely large and diverse collection of natural compounds to discover new leads that can potentially be turned into drugs. In this study we introduce and discuss a computational pipeline to automatically extract statistically overrepresented chemical fragments in therapeutic classes, and search for similar fragments in a large database of natural products. By systematically identifying enriched fragments in therapeutic groups, we are able to extract and focus on few fragments that are likely to be active or structurally important. RESULTS: We show that several therapeutic classes (including antibacterial, antineoplastic, and drugs active on the cardiovascular system, among others) have enriched fragments that are also found in many natural compounds. Further, our method is able to detect fragments shared by a drug and a natural product even when the global similarity between the two molecules is generally low. CONCLUSIONS: A further development of this computational pipeline is to help predict putative therapeutic activities of natural compounds, and to help identify novel leads for drug discovery. PMID- 27510652 TI - Interleukin-1beta effect on the endogenous ADP-ribosylation and phosphorylation of eukaryotic elongation factor 2. AB - Eukaryotic elongation factor 2 (eEF2) plays an important role in eukaryotic polypeptide chain elongation. Adenosine diphosphate (ADP)-ribosylation is a post translational modification reaction that catalyzes the transfer of ADP-ribose group to eEF2 and this causes the inhibition of protein synthesis. Indeed, in the absence of diptheria toxin, endogenous ADP-ribosylation can occur. eEF2 is phosphorylated by eEF2 kinase which prevents binding to ribosomes thus inhibiting its activity. Increase in endogenous ADP-ribosylation level approximately 70-75 % was observed in IL-1beta treated HUVECs. Moreover, a 70 % rise of phosphorylation of eEF2 was measured. Alteration of endogenous ADP-ribosylation of eEF2 activity was related with cellular mono-ADP-ribosyltransferases (ADPrT). Increment of endogenous ADP-ribosylation on eEF2 did not seem to occur as a direct effect of IL-1beta; it arises from the activation of ADPrT. This 2.5 fold increase was abolished by ADPrT inhibitors. Due to these post-translational modifications, global protein synthesis is inhibited. After dephosphorylation of phospho-eEF2, around 20 % increase in protein synthesis was observed. In conclusion, systemic IL-1beta has an important role in the regulation of global protein synthesis. PMID- 27510653 TI - Effects of free amino acids on cytokine secretion and proliferative activity of feline T cells in an in vitro study using the cell line MYA-1. AB - In vitro studies might be an interesting screening method for targeted in vivo studies in the field of immunonutrition and help to reduce and refine animal studies. As the role of amino acids for immune function of cats has not been evaluated in detail so far, the present study aimed at investigating the effects of eight different amino acids (arginine, leucine, isoleucine, valine, glutamine, lysine, threonine and tryptophan) in six concentrations each (0, 0.25, 0.5, 1, 2 and 8x the cat blood level) on cytokine secretion and proliferative activity of feline T cells (MYA-1) in vitro. The results demonstrated that high doses of arginine increased IL-4, IL-10 and TNF-alpha secretion of T cells, while increasing concentrations of lysine increased IL-10 secretion and proliferative activity of the T cells. High doses of leucine enhanced GM-CSF and IL-10 secretion, while concentrations of threonine in the cell culture media greater than blood concentration also increased GM-CSF and additionally TNF-alpha secretion of the cells. The effects of glutamine and isoleucine on T cell function were only small. In conclusion, the present in vitro study could evaluate the immunomodulating potential of specific amino acids for feline T cell function. High doses of arginine, lysine, leucine and threonine had a significant impact on cytokine secretion and proliferative activity of the T cells. Targeted in vivo studies should investigate the clinical relevance of dietary supplementation of those amino acids in healthy and diseased cats as a next step. PMID- 27510654 TI - Weight Change in Midlife and Risk of Mortality From Dementia up to 35 Years Later. AB - Background: The relationship between body mass index (BMI) and dementia is complex and controversial. This study investigates the association of weight change during midlife and later dementia-related mortality. Methods: Two BMI measurements (average of 9.0 years apart) were available for 43,721 participants in the Norwegian Counties Study (NCS), with mean age 42 years at first BMI measurement and 51 at the final measurement. NCS was linked with the Cause of Death Registry until year 2015 (mean follow-up time 25.9 years). Cox regression with a conditional growth model was used. Results: Our study comprised 1,205 dementia-related deaths. Weight loss was associated with increased dementia related mortality, irrespectively of baseline BMI and confounders; those with 10% or more loss had hazard ratio (HR) = 1.52 (95% confidence interval [CI]: 1.09, 2.12) compared to those being stable (0%-2.5% BMI gain), and those with 5%-10% loss had HR = 1.38 (95% CI: 1.08, 1.76). Gaining weigh was associated with reduced dementia-related mortality. Associations with BMI change did not vary by baseline BMI. Conclusions: Weight loss during midlife was associated with increased dementia-related mortality risk more than 3 decades later, while weight gain was associated with reduced risk. These associations held both for low and high baseline BMI. Weight loss was an independent risk factor for dementia related mortality and more strongly related with dementia-related mortality than stable BMI (stable high or low). Overweight and obesity were associated with an increased risk for nondementia-related mortality, which was far more common than dementia-related mortality. PMID- 27510656 TI - From Editor's desk. PMID- 27510657 TI - Combination of laboratory diagnostic tests for cutaneous tuberculosis. PMID- 27510655 TI - Systemic availability and metabolism of colonic-derived short-chain fatty acids in healthy subjects: a stable isotope study. AB - KEY POINTS: The short-chain fatty acids (SCFAs) are bacterial metabolites produced during the colonic fermentation of undigested carbohydrates, such as dietary fibre and prebiotics, and can mediate the interaction between the diet, the microbiota and the host. We quantified the fraction of colonic administered SCFAs that could be recovered in the systemic circulation, the fraction that was excreted via the breath and urine, and the fraction that was used as a precursor for glucose, cholesterol and fatty acids. This information is essential for understanding the molecular mechanisms by which SCFAs beneficially affect physiological functions such as glucose and lipid metabolism and immune function. ABSTRACT: The short-chain fatty acids (SCFAs), acetate, propionate and butyrate, are bacterial metabolites that mediate the interaction between the diet, the microbiota and the host. In the present study, the systemic availability of SCFAs and their incorporation into biologically relevant molecules was quantified. Known amounts of 13 C-labelled acetate, propionate and butyrate were introduced in the colon of 12 healthy subjects using colon delivery capsules and plasma levels of 13 C-SCFAs 13 C-glucose, 13 C-cholesterol and 13 C-fatty acids were measured. The butyrate-producing capacity of the intestinal microbiota was also quantified. Systemic availability of colonic-administered acetate, propionate and butyrate was 36%, 9% and 2%, respectively. Conversion of acetate into butyrate (24%) was the most prevalent interconversion by the colonic microbiota and was not related to the butyrate-producing capacity in the faecal samples. Less than 1% of administered acetate was incorporated into cholesterol and <15% in fatty acids. On average, 6% of colonic propionate was incorporated into glucose. The SCFAs were mainly excreted via the lungs after oxidation to 13 CO2 , whereas less than 0.05% of the SCFAs were excreted into urine. These results will allow future evaluation and quantification of SCFA production from 13 C-labelled fibres in the human colon by measurement of 13 C-labelled SCFA concentrations in blood. PMID- 27510658 TI - Salivary gland anlage tumor in a neonate. PMID- 27510659 TI - Evaluation of laboratory diagnosis for cutaneous tuberculosis. AB - BACKGROUND AND AIM: Cutaneous tuberculosis (CTB) is still difficult to diagnose due to its varied clinical presentation and limitations of diagnostic methods. The aim of this study was to evaluate the results of diagnostic laboratory tests available for CTB. MATERIALS AND METHODS: Twenty-six skin biopsy specimens belonging to clinically suspected cases of CTB were studied retrospectively. The specimens were divided into two portions, one part processed for histopathological evaluation and the other was used for microscopy and inoculation for the isolation of mycobacteria. Polymerase chain reaction (PCR) technique was applied to 14 of 26 specimens to detect Mycobacterium tuberculosis complex (MTBC) DNA. RESULTS: Of the 26 biopsy specimens, 11 were confirmed as CTB by identification of MTBC in culture and/or histopathologic affirmation. Of these, four were lupus vulgaris, four were TB verrucosa cutis, one was scrofuloderma, one was primary inoculation TB, and one was periorifical CTB. Culture for mycobacteria was positive for five (45.45%) specimens, while histopathologic affirmation was obtained in ten (90.90%) specimens. Acid-fast Bacilli were not demonstrated in any of the specimens on microscopic examination. The PCR was found to be applied to six of the 11 specimens diagnosed as CTB and was positive in two specimens (33.3%), which were positive for growth in culture and histopathological correlation. CONCLUSION: The recovery rate of MTBC from biopsy specimens was found to be satisfactory for CTB with histopathological correlation, but the combination of culture with a rapid method, PCR, may improve the diagnostic rate. PMID- 27510660 TI - Pathology of thyroid in acquired immunodeficiency syndrome. AB - BACKGROUND: The course of human immunodeficiency virus infection and the acquired immunodeficiency syndrome can be complicated by a variety of endocrine abnormalities, including abnormalities of thyroid gland. MATERIALS AND METHODS: This study was designed to understand the spectrum of pathology of thyroid in Indian patients with AIDS. The present study describes the findings of retrospective autopsy findings of 158 patients with AIDS which revealed infectious diseases from a time period before the use of highly active antiretroviral regimen. RESULTS: A wide range of bacterial, fungal, and viral infections were observed. Tuberculosis was recorded in 14 (09%) patients, Cryptococcus neoformans in 11 (7%) patients and cytomegalovirus in 3 (2%) patients. Hashimoto's thyroiditis and lymphocytic thyroiditis were seen in 02 (01%) patients each. One patient had dual infection comprising of tuberculosis and cytomegalovirus infection. The other microscopic findings observed were goiter (2 patients), interstitial fibrosis in thyroid (7 patients), and calcification in thyroid (8 patients). CONCLUSIONS: Abnormalities of thyroid are uncommon findings in patients with HIV infection however several case reports of thyroid involvement by infectious agents and neoplasm are described in these patients; hence patients with HIV infection should be closely followed up for development of goiter or abnormalities of thyroid functions. PMID- 27510661 TI - Apoptosis in oral epithelial dysplastic lesions and oral squamous cell carcinoma: A prognostic marker. AB - BACKGROUND: Apoptotic index (AI) using light microscopy as an indirect measure to assess the significance of apoptosis as a proliferative marker in dysplastic lesions and malignant epithelial lesions of the oral cavity. AIMS: (1) To quantify the apoptotic bodies/cells in oral epithelial dysplastic (OED) lesions and oral squamous cell carcinoma (OSCC). (2) To measure AI in OED and OSCC. (3) To compare AI in OED and OSCC. SETTINGS AND DESIGN: The proposed laboratory-based retrospective study involved the use of hematoxylin and eosin (H and E)-stained slides of previously diagnosed OED lesions and OSCC from institutional archives. MATERIALS AND METHODS: This study constituted 50 cases, each of H and E-stained slides of previously diagnosed cases of OED and OSCC. AI was calculated as the number of apoptotic bodies/cells expressed as a percentage of the total number of nonapoptotic tumor/dysplastic cells counted in each case. STATISTICAL ANALYSIS USED: Nonparametric tests such as Kruskal-Wallis test and Mann-Whitney test were used. RESULTS: There was a statistically significant increase in AI from OED to OSCC (P = 0.000). CONCLUSIONS: Further studies need to be undertaken to detect and understand the apoptotic mechanisms in the progression from OED to OSCC. PMID- 27510662 TI - Do phosphatase of regenerating liver-3, matrix metalloproteinases-2, matrix metalloproteinases-9, and epidermal growth factor receptor-1 predict response to therapy and survival in glioblastoma multiforme? AB - CONTEXT: Poor survival of the glioblastoma multiforme (GBM) has been attributed in part to the invasive nature of the lesion making complete surgical removal near impossible. Phosphatase of regenerating liver-3 (PRL-3), matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9), and epidermal growth factor receptor (EGFR-1) play a role in invasive nature of tumor cells. AIMS: This study was conducted to evaluate PRL-3, MMP-2, MMP-9, and EGFR-1 (markers) expression in cases to GBM and to correlate their expression with therapy response and survival. SETTINGS AND DESIGN: GBM cases (n = 62) underwent surgery followed by radiation (n = 34) and chemoradiation (n = 28). Using WHO Response Evaluation Criteria in Solid Tumors criteria response to therapy was assessed at 3 months and cases followed up for survival. SUBJECTS AND METHODS: Expression of markers was assessed by immunohistochemistry as a percentage of positive tumor cells in hot spots. STATISTICAL ANALYSIS USED: Kaplan-Meier, ANOVA, Chi-square test, univariate, and multivariate Cox-regression analysis was done. RESULTS: Response to therapy was evident in 54.8% cases of responders with the mean survival of 494.03 +/- 201.13 days and 45.2% cases of non responders (278.32 +/- 121.66 days) with P = 0.001. Mean survival for the patient's opted chemoradiation was 457.43 +/- 222.48 days which was approximately 3 months greater than those who opted radiation alone (P = 0.029). We found PRL-3 overexpression was an independent, significant, poor prognostic factor for survival by multivariate analysis (P = 0.044). Cases negative for MMP's and EGFR showed increased survival, but the difference was insignificant. CONCLUSION: PRL-3 expression appears to be related to an adverse disease outcome. PMID- 27510663 TI - A tissue microarray study of toll-like receptor 4, decoy receptor 3, and external signal regulated kinase 1/2 expressions in astrocytoma. AB - INTRODUCTION: Decoy receptor 3 (DcR3) functions as a death decoy inhibiting apoptosis mediated by the tumor necrosis factor receptor family. It is highly expressed in many tumors and its expression can be regulated by the MAPK/ERK signaling pathway and ERK is a vital member of this pathway. Toll-like receptor 4 (TLR4) is expressed on immune cells. Increased TLR4 expression has been associated with various types of cancers. MATERIAL AND METHODS: The study was conducted to investigate the expression of DcR3, ERK1/2, and TLR4 in astrocytomas and evaluate if they are validating markers for discriminating glioblastoma from anaplastic astrocytoma in limited surgical specimen. Expression of DcR3, ERK1/2, and TLR4 was determined by immunohistochemical staining of tissue microarray from 48 paraffin-embedded tissues. A binary logistic regression method was used to generate functions that discriminate between anaplastic astrocytomas and glioblastomas. RESULTS: The expression of TLR4 and DcR3 was significantly higher in glioblastomas than in anaplastic astrocytomas. DcR3 could discriminate anaplastic astrocytomas from glioblastomas with high sensitivity (93.8%), specificity (90%), and accuracy (92.3%). CONCLUSION: Our results suggest that DcR3 may be a useful marker for discriminating anaplastic astrocytomas from glioblastomas. PMID- 27510664 TI - The evaluation of the caveolin-1 and AT-rich interactive domain 1 alpha expressions in uterine smooth muscle tumors. AB - OBJECTIVES: This retrospective study was designed to evaluate the importance of tissue expressions of caveolin-1 (Cav-1) and AT-rich interactive domain 1 alpha (ARID-1A) which are known as signal regulator and tumor suppressor in differential diagnosis of uterine smooth muscle tumors (SMTs). MATERIALS AND METHODS: Thirty patients recently diagnosed as uterine SMTs at the Tepecik Training and Research Hospital were identified using pathology databases. Immunohistochemical stains for Cav-1 and ARID-1A were performed. RESULTS: In this series, there were 10 leiomyosarcomas (LMSs), 10 uterine smooth muscle tumors of uncertain malignant potentials (STUMPs), and 10 leiomyomas (LMs). Cav-1 expression located cytoplasmic or perivascular area. Cytoplasmic Cav-1 expression was determined in 5 LMSs and 2 STUMPs while perivascular Cav-1 expression was determined in 9 LMSs and 2 STUMPs. Statistically, it was determined that if the tumor becomes malignant and more invasive, it gains the perivascular Cav-1 expression (P = 0.029). On the other hand, the mean nuclear staining rate for ARID-1A in LMSs (63 +/- 23.4%) was higher than both STUMPs (60 +/- 18.5%) and LMs (34.5 +/- 16.5%). Statistically, it was determined that the expression of ARID-1A was significantly downregulated in LMs when compared with STUMPs and LMSs (P = 0.004). CONCLUSIONS: Our findings were demonstrated that perivascular Cav-1 expression was seen to be a marker for malignancy of uterine SMTs. Similarly, we found to link of ARID-1A expression and the aggressiveness of SMTs. Therefore, it may be suggested that Cav-1 and ARID-1A may act as predictive biomarkers in uterine SMTs. PMID- 27510665 TI - Comparative evaluation of immunoperoxidase versus immunofluorescent techniques in interpretation of kidney biopsies. AB - BACKGROUND: Immunofluorescence (IF) on frozen sections has been considered to be the gold standard for evaluation of kidney biopsy specimens. Immunohistochemistry (IHC) method can also be used for this purpose with advantages of being applicable on paraffin embedded tissue, providing permanent sections, and not requiring a specialized microscope for interpretation. Our aim was to evaluate IHC as an alternative to IF in the diagnostic assessment of kidney biopsy specimens. METHODS: One hundred kidney biopsy specimens were subjected to both IF and IHC staining for immunoglobulins (Ig), IgG, IgA, IgM and complement components c3 and c1q. IF staining was done on frozen sections. IHC staining was performed on paraffin-embedded tissue following proteolytic antigen retrieval. The sections were evaluated, and the results of IHC were compared with IF. RESULTS: Concordant observations were 98%, 87%, 89%, 83%, and 89% for IgA, IgM, IgG, C3 and C1q, respectively. The sensitivity of IHC method for Igs was found to be high (92%, 86.5%, and 95.1%, respectively for IgA, IgM, and IgG). 91% cases showed concordance of the intensity of the deposits while 100% cases showed a concordance of the pattern. Statistically, there was no significant difference in outcomes between IF and IHC for IgA, IgM, and IgG. However, statistically significant difference was found in the results for complement proteins. CONCLUSION: In this study, it is documented that IHC is, with few exceptions, equal to IF for the detection of Igs. Standardized immunoperoxidase method on the paraffin embedded, formalin fixed needle kidney biopsies could successfully replace the IF method in the diagnosis of glomerulonephritis. PMID- 27510666 TI - Expression of CD71 by flow cytometry in acute leukemias: More often seen in acute myeloid leukemia. AB - BACKGROUND: CD71 is a marker that has been usually used for identifying dysplasia in the erythroid series. We have tried to evaluate the expression of CD71 in various types of acute leukemias. MATERIALS AND METHODS: We studied 48 patients of acute leukemia, of which 25 were acute myeloid leukemia (AML), 13 were precursor B-acute lymphoblastic leukemia (B-ALL), 8 were T-ALL, and 2 were mixed phenotype acute leukemia (T/myeloid) as per the WHO classification. RESULTS: We found that the expression of CD71 was most prevalent in AMLs (84%), followed by T ALL (50%) and least in B-ALL (30%). CONCLUSION: This finding clearly shows the higher expression of CD71 in AMLs compared to other common type of leukemias, such as B- and T-ALL. We suggest that the high expression of CD71 in AMLs could be used as a diagnostic marker and may also be used for minimal residual disease analysis after further studies in posttreatment scenario. This study is the first of its kind in the South Asian population. PMID- 27510667 TI - Comparative analysis of phenotypic and genotypic detection of methicillin resistance among Staphylococcus aureus. AB - AIMS: Staphylococcus aureus is a common pathogen causing a wide range of infections ranging from mild skin and soft tissue infections to severe, life threatening infections. Accuracy in the detection of methicillin resistance is important to avoid treatment failures. The aim of this study was to compare the results of phenotypic and genotypic test methods to detect methicillin resistance and also to determine the antimicrobial susceptibilities. MATERIALS AND METHODS: Two hundred and forty-two S. aureus strains isolated from skin and soft tissue samples were analyzed for methicillin resistance using oxacillin and cefoxitin disk diffusion (DD), oxacillin screen agar test, cefoxitin E-test, and mecA gene polymerase chain reaction (PCR). RESULTS: 77 of 242 S. aureus isolates were mecA positive. Oxacillin, cefoxitin DD, oxacillin screen agar test and cefoxitin E test exhibited sensitivities as 98.7%, 98.7%, 100%, 100%, and specificities as 96.9%, 97.5%, 96.9%, 97.5%, respectively. CONCLUSION: Results of oxacillin screen agar and cefoxitin DD test were in concordance with mecA gene PCR. Thus, it is determined that especially cefoxitin test can be an alternative to PCR in routine. PMID- 27510669 TI - Distribution of plasmid-mediated quinolone resistance in Gram-negative bacteria from a tertiary hospital in Nigeria. AB - BACKGROUND: Until recently, mechanisms of resistance to quinolones in Gram negative bacteria were believed to be only chromosome encoded. However, emergence of plasmid-mediated quinolone resistance (PMQR) has been reported worldwide. AIM: This study investigated distribution of PMQR in Gram-negative bacteria from a tertiary hospital in eastern part of Nigeria. MATERIALS AND METHODS: Seventy-one nonduplicate Gram-negative bacterial isolates of eight species were analyzed for antimicrobial susceptibility, genotypic detection of various PMQRs, typed by random amplified polymorphic DNA (RAPD) and analysis of plasmids present, including replicon typing. RESULTS: The minimum inhibitory concentrations showed MIC90values as high as 256 MUg/ml for fluoroquinolones. Carriage of PMQR was found to be 35.2%. Twenty (28.2%) isolates carried various qnr genes, of which seven (9.9%) qnrA1; four (5.6%) qnrB1; eight (11.3%) qnrS1 while one (1.4%) encoded qnrD1. Eighteen (25.4%) isolates were positive for aac(6')-Ib-cr while carriage of multiple genes exists in some strains. Similarly, 13 isolates (18.7%) were found to carry PMQR efflux pump gene, qepA. Conjugation experiments revealed that the plasmids once transferred coded for fluoroquinolone resistance. The transconjugant strains carried a common plasmid estimated to be 65 kb. These plasmids were untypable for replicon/incompatibility. Typing revealed high diversity among all species tested with no identical RAPD pattern seen. CONCLUSION: This study further confirms high level resistance to many antimicrobials in different species of Gram-negative bacteria including fluoroquinolones and spread of PMQR genes in Southern Nigeria. PMID- 27510668 TI - Role of type-specific herpes simplex virus-1 and 2 serology as a diagnostic modality in patients with clinically suspected genital herpes: A comparative study in Indian population from a tertiary care hospital. AB - INTRODUCTION: Type-specific serology (TSS) test for herpes simplex virus (HSV) have been used as a research tool in seroepidemiological studies for some years. However, TSS as a diagnostic modality for diagnosis of current episode of genital herpes is not well documented. AIMS AND OBJECTIVES: To measure the seroprevalence of type-specific HSV Type 1 (HSV-1) and Type 2 (HSV-2) IgG antibodies in cases provisionally diagnosed as primary and recurrent genital herpes and to evaluate the role of TSS as a diagnostic modality for diagnosis of genital herpes versus polymerase chain reaction (PCR). MATERIALS AND METHODS: A cross-sectional study was performed over a period of 10 months in which 44 adult patients with clinically suspected genital herpes were recruited. An in-house glycoprotein G gene base PCR was performed directly from the genital lesion specimen for simultaneous detection and typing of HSV. TSS was performed to detect IgG antibody against HSV-1 and 2 in all patients using commercially available kits, and the results were compared. RESULTS: Seroprevalence of HSV-1 IgG was 43% among primary and 65% among recurrent genital herpes cases (P = 0.22). Whereas that of HSV-2 IgG was found to be 14% and 83% in respective patient group (P = 0.0001). When compared to PCR results HSV-1 IgG detection in both primary and recurrent genital herpes diagnosis had poor specificity, positive predictive value, and sensitivity. Whereas, HSV-2 serology had a sensitivity of 13.33% and 73.33% in primary and recurrent genital herpes and specificity of 83.33% and 85.71%, respectively. CONCLUSION: HSV-2 IgG detection helps in strengthening the diagnosis of recurrent HSV-2 disease, whereas the absence of HSV-2 IgG antibody helps in excluding genital herpes as a likely cause of recurrent genital ulceration. However, detection of HSV-1 IgG antibody may not be useful for diagnosis in patients of genital ulcer disease. PMID- 27510671 TI - Comparison of multiplex RT-PCR and real-time HybProbe assay for serotyping of dengue virus using reference strains and clinical samples from India. AB - BACKGROUND: Dengue virus serotyping is crucial from clinical management and epidemiological point of view. AIMS: To compare efficacy of two molecular detection and typing methods, namely, multiplex reverse transcription polymerase chain reaction (RT-PCR) and real-time Hybprobe assay using a panel of known dilution of four reference Dengue virus strains and a panel of sera collected from clinically suspected dengue patients. SETTINGS: This study was conducted at a tertiary-care teaching hospital in Delhi, India. MATERIALS AND METHODS: Dengue serotype specific virus strains were used as prototypes for serotyping assays. Viral load was quantified by quantitative real time reverse transcription polymerase chain reaction (qRT-PCR). Acute phase serum samples were collected from 79 patients with clinically suspected Dengue fever on their first day of presentation during September-October 2012. Viral RNA from serum and cell culture supernatant was extracted. Reverse transcription was carried out. Quantitative detection of DENV RNA from reference strain culture supernatants and each of the 79 patient samples by real-time PCR was performed using light cycler Taqman master mix kit. Serotyping was done by multiplex RT-PCR assay and Hybprobe assay. RESULTS: The multiplex RT-PCR assay, though found to be 100% specific, couldn't serotype either patient or reference strains with viral load less than 1000 RNA copies/ml. The Hybprobe assay was found to have 100% specificity and had a lower limit of serotype detection of merely 3.54 RNA copies/ml. CONCLUSIONS: HybProbe assay has an important role especially in situations where serotyping is to be performed in clinical samples with low viral load. PMID- 27510670 TI - Emerging enteric fever due to switching biotype of Salmonella (paratyphi A) in Eastern Odisha. AB - BACKGROUND: Typhoid fever is classically caused by Salmonella enterica serotype typhi.Recently the frequency of isolation of S. paratyphi A (SPA) has been increased in comparison to S. typhi in Indian scenario. AIM: To observe the rate of isolation and antimicrobial susceptibility pattern of SPA from suspected enteric fever cases attending tertiary care centres of Eastern Orissa. SETTINGS AND DESIGN: Retrospective study Materials and Methods: 1488 blood samples were collected during different duration of fever and cultured in BACTEC blood culture system and bottles showing signal for growth were subcultured and identified as Salmonella spp. by standard procedure and mini API (Biomeriux) and antimicrobial susceptibility by disc diffusion method. STATISTICAL ANALYSIS: Chi square test. RESULTS: 167 Salmonella spp. were isolated including 83.8% Salmonella paratyphi A and 16.6% S. typhi. Among them 102 were males and 65 were females with mean age of 22.7 yrs. S. paratyphi A was the predominant spp. each year but during 2008 - 2011, there was a dramatic rise (significant P value- 0.034). Multidrug resistance was noticed in 10.2% of the isolates. 98% of S. paratyphi A were resistant to nalidixic acid and 41% to ciprofloxacin, but the MIC of ciprofloxacin was raised between 1-2 MUgm/dl showing the relation between nalidixic acid resistance and raised MIC of ciprofloxacin. CONCLUSION: Nalidixic acid should be tested along with ciprofloxacin disc while testing for susceptibility and MIC of ciprofloxacin is mandatory before advocating therapy to prevent treatment failure. PMID- 27510672 TI - A novel PTCH1 gene mutation in a pediatric patient associated multiple keratocystic odontogenic tumors of the jaws and Gorlin-Goltz syndrome. AB - Gorlin-Goltz syndrome (GGS) is an uncommon autosomal dominant inherited disorder which comprises the triad of basal cell carcinomas (BCCs), odontogenic keratocysts, and musculoskeletal malformations. Besides this triad, neurological, ophthalmic, endocrine, and genital manifestations are known to be variable. It is occasionally associated with aggressive BCC and internal malignancies. This report documents a case of GGS with a novel mutation in the PTCH1 gene in an 11 year-old child. The clinical, radiographic, histopathologic and molecular findings of this condition, and treatment are described, and a review of GGS was carried out. PMID- 27510673 TI - Severe liver dysfunction in an infant with cystic fibrosis masquerading as metabolic liver disease. AB - We present a rare presentation of cystic fibrosis with neonatal cholestasis. Histological features of mucoviscidosis were present in liver involving the biliary tract, intestinal mucosa, pancreas, and lung. Besides, there was a rare association with autosomal dominant type of polycystic renal disease. PMID- 27510674 TI - Solid pseudopapillary neoplasm of the ovary with metastases to the omentum and regional lymph nodes. AB - Extrapancreatic solid pseudopapillary neoplasms (SPNs) are rare tumors, which bear morphological, immunohistochemical, and molecular features similar to those of pancreatic counterparts. SPN occurs primarily in adolescent girls and young women. It is considered to be a malignant neoplasm with low-grade biology. Ovarian SPNs are uncommon, have benign morphology, usually limited to the ovary and local surgical excision is curative. We report an unusual case of SPN of right ovary with extraovarian spread and metastases to lymph nodes. To the best of our knowledge, this is the second documented case of extragonadal spread of ovarian SPN. PMID- 27510675 TI - Primary thymic mediastinal seminoma with florid granulomatous reaction. AB - Primary mediastinal seminomas are rare tumors. Morphologically, they can be associated with secondary changes in the form of thymic remnants, cystic change, epithelioid granulomas, abundant fibrosis, and syncytiotrophoblast like cells. Ours was an interesting case where a 17-year-old adolescent male presented with anterior mediastinal mass. Fine needle aspiration and trucut biopsy of the mass favored tuberculosis; however, he did not respond to antituberculosis treatment regime. He was subjected to video-assisted thoracoscopic surgery and the histopathological examination along with supportive immunohistochemistry of the mass revealed scattered seminoma cells which were being masked by extensive granulomatous reaction. The aim of this article is to report a case of primary mediastinal thymic seminoma in a young male associated with extensive granulomatous reaction masking the neoplastic population of cells leading to erroneous diagnosis on small biopsy. PMID- 27510676 TI - Lipoleiomyoma of the left broad ligament with dermoid cyst in ipsilateral ovary and synchronous multiple benign lesions of female genital tract: An unusual association. AB - Lipoleiomyoma of the uterus is a rare variant of leiomyoma, and lipoleiomyoma of the broad ligament is still rarer, with only a handful of cases being reported. The present case was a perimenopausal woman who presented with a huge lower abdominal mass. Ultrasonography and computed tomography showed a heterogeneous solid mass in the left adnexa. The histopathological findings confirmed the nature of the lesions as a benign lipoleiomyoma with dermoid cyst of the left ovary and its other associated benign lesions, were the interesting features seen in this case which were not suspected clinically and radiologically. PMID- 27510677 TI - Combined presence of multiple gastrointestinal stromal tumors along with duodenal submucosal somatostatinoma in a patient with neurofibromatosis type 1. AB - Neurofibromatosis type-1 (NF-1) is an autosomal dominant disorder, with increased risk of developing benign and malignant tumors of the gastrointestinal tract (GIT). However, the synchronous presence of multiple GIT stromal tumors and duodenal submucosal somatostatinoma, like in this 50-year-old female NF-1 patient, is very rare. She presented with hematemesis, malena, along with multiple neurofibromas all over the body. Thorough radiological and peroperative work-up revealed multiple ulcerated submucosal and serosal nodules in the proximal small intestine. Histological work-up revealed diagnosis of a duodenal submucosal somatostatinoma with multifocal serosal gastrointestinal stromal tumors. This case is being reported to highlight the rare coincidence of multiple GIT tumors in an NF-1 patient. PMID- 27510678 TI - An unusual presentation of chondroid syringoma. AB - Chondroid syringoma (CS) is a rare benign tumor of the sweat gland. It generally presents as a painless, slowly growing, subcutaneous swelling, typically located on the head and neck region. The majority of the cases develop in middle aged and elderly males. We present a case of CS located over the right thumb of a 25-year old male. The diagnosis was made initially by cytological evaluation and later confirmed by histopathological examination. There was no recurrence on two year follow up after the complete surgical excision of the tumor. PMID- 27510679 TI - Isolated ileal ganglioneuromatosis in an 11-year-old boy: Case report and review of literature. AB - Ganglioneuromatous proliferation in the gastrointestinal tract is a rare occurrence and is usually associated with specific syndrome complexes such as multiple endocrine neoplasia Type 2B or von Recklinghausen's disease. We report here a case of diffuse intestinal ganglioneuromatosis, presenting as intestinal obstruction and chronic constipation in an 11-year-old boy. Sporadic cases of intestinal ganglioneuromatosis in the absence of any systemic manifestations are a very rare cause of enteric motility disorders in childhood, and we discuss the pathological and clinical significance of this finding. Histopathological identification of this uncommon cause of a common pediatric problem is important since the condition is amenable to surgical treatment. PMID- 27510680 TI - Cytomorphological findings and histological correlation of papillary cystadenocarcinoma of the parotid: Not always a low-grade tumor. AB - Papillary cystadenocarcinoma (PCAC) is a rare salivary gland tumor characterized by a predominantly cystic growth that often exhibits intraluminal papillary growth without specific histologic features of other cystic salivary gland tumors. The preoperative cytological diagnosis can pose a diagnostic challenge as it has to be differentiated from other cystic papillary tumors such as mucoepidermoid carcinoma, papillary cystic variant of acinic cell carcinoma, and low-grade cribriform CAC. It is considered to be a low-grade malignant salivary gland tumor with an indolent biological behavior. We report a case of PCAC of the parotid in a 55-year-old male diagnosed on fine needle aspiration cytology. Although it showed mild atypia cytologically, on excision tumor showed vascular and perineural invasion with regional node metastasis indicating a wider morphologic spectrum than what is described. This prompted us to write a case report describing the cytological and histological features of this rare tumor and also discuss the diagnostic challenges. PMID- 27510681 TI - Sertoli cell tumor arising in a cryptorchid testis presenting as a content of inguinal hernial sac. AB - Sertoli cell tumors (SCTs) are rare tumors accounting for <1% of all testicular tumors. Here, we report a rare case of SCT in a 60-year-old man presenting as a painless swelling in the right groin since childhood. Clinically, he presented with right-sided inguinal hernia with absence of the right testis. He had normal left testis and had no gynecomastia or infertility. The specimen of hernial sac showed testis with a 1.6 cm * 1.5 cm nodular mass having gray tan-cut surface. Histopathologically, the testis showed atrophy and the nodular portion showed tumor cells arranged in tubular and microcystic pattern, with no solid pattern or necrosis. The diagnosis of SCT was confirmed with immunohistochemical staining for inhibin which showed fine granular cytoplasmic positivity. Cryptorchid testis having SCT and presenting as a content of inguinal hernia is a rare occurrence. PMID- 27510682 TI - Pseudoangiomatous variant of spindle cell lipoma: Report of a rare case. AB - Pseudoangiomatous spindle cell lipoma is a rare variant of spindle cell lipoma. It exhibits irregular and branching spaces with villiform connective tissue projections, leading to formation of a characteristic angiomatoid pattern in addition to benign spindle cells and mature adipocytes. Recent studies have shown that these branching spaces are lined by endothelial cells and express markers. Therefore, the term "angiomatous variant" instead of "pseudoangiomatous" has been proposed for these lesions. We describe one of such lesions in the thumb of a young female. To the best of our knowledge, this is the first reported case of pseudoangiomatous variant of spindle cell lipoma from India. PMID- 27510683 TI - Pleomorphic rhabdomyosarcoma of the left atrium mimicking myxoma. AB - Primary rhabdomyosarcoma (RMS) of the heart is a rare malignant tumor which has poor prognosis and survival despite surgery and adjuvant chemotherapy. The preoperative diagnosis is often difficult in view of nonspecific clinicoradiological findings. This report describes a case of a 60-year-old woman who was clinically diagnosed as left atrial myxoma. A diagnosis of pleomorphic RMS was made on histopathology after excision. Our case discusses the clinicopathological features and treatment options of cardiac RMS emphasizing the fact that histopathology and immunohistochemistry are essential to confirm the diagnosis of such an aggressive malignant tumor. PMID- 27510684 TI - A rare case of multifocal pseudomyogenic hemangioendothelioma, involving soft tissues and bone, misdiagnosed as a rhabdomyosarcoma: Diagnostic and treatment implications. AB - Pseudomyogenic hemangioendothelioma (PHE) is an uncommon, but distinctive soft tissue tumor, characterized by multifocality. A 17-year-old male referred to us with progressively increasing multiple subcutaneous nodular lesions over his left leg and foot, reported elsewhere as a spindle cell rhabdomyosarcoma. On review, microscopy showed a cellular tumor comprising plump spindle cells arranged in loose fascicles with interspersed inflammatory cells. Tumor cells exhibited mild nuclear variation. Immunohistochemically, tumor cells expressed AE1/AE3, CD31, Fli-1, and smooth muscle actin (SMA), confirming diagnosis of PHE. Whole-body positron emission tomography-computed tomography (PET-CT) scan revealed multiple, metabolically active, subcutaneous nodular lesions over the left lower leg and in the distal tibia. Subsequently, resection specimens from the various lesions and bone curettage also revealed features of PHE. Three months later, the patient developed multiple lesions over his fourth toe and left foot, for which he underwent tumor resections. At present, he is disease-free. PHE is a locally aggressive soft tissue tumor characterized by multifocality, rarely bony involvement and can be misdiagnosed as a high-grade sarcoma. PMID- 27510686 TI - Vulvar granular cell tumor. AB - Granular cell tumors (GCTs) are rare and approximately half of the all lesions arise from head and neck, especially from the tongue. However, they are rarely seen in the vulva. They can occur in patients of any age, but peak age incidence is in the fourth to sixth decades. They generally occur as small, slow growing, and skin-colored nodule. GCTs are usually benign, but malignant cases were reported. Recurrence can be seen in benign tumors with clear margins, but rates increase with positive margins. The treatment is complete surgical excision. We report a case of benign GCT of the vulva. A 41-year-old patient presented with vulvar mass, and biopsy was consisted with GCT. PMID- 27510685 TI - Primary intraosseous atypical inflammatory meningioma presenting as a lytic skull lesion: Case report with review of literature. AB - Primary extradural meningiomas of the skull comprise 1% of all meningiomas, and lytic skull meningiomas are still rarer and are said to be more aggressive. We present a case of 38-year-old male with an extradural tumor which on histopathological examination showed features of inflammatory atypical meningioma (WHO Grade II). The intense inflammatory nature of osteolytic primary intraosseous meningioma has not been reported before. This entity deserves special mention because of the need for adjuvant therapy and proper follow-up. PMID- 27510687 TI - Recurrent multifocal cutaneous Kaposiform hemangioendothelioma: A rare vascular tumor of infancy and childhood. AB - Kaposiform hemangioendothelioma (KHE) is a locally aggressive vascular tumor of childhood although cases occurring in adulthood are also described. The features overlap with juvenile capillary hemangioma and Kaposi sarcoma. We report a rare case of recurrent, multifocal (nose and chin) cutaneous KHE initially occurring in a 3-year-old female child, uncomplicated by Kasabach-Merritt syndrome. Recurrences occurred over the next 6 years and resulted in complete distortion of the nose, requiring plastic repair. PMID- 27510688 TI - Unusual ganglioglioma with extensive calcification and ossification. AB - Ganglioglioma is a slow-growing relatively low-grade mixed glioneuronal tumor with most cases corresponding to the WHO Grade I category. It frequently presents with seizures. The temporal lobe is the most common location followed by frontal, parietal, and occipital lobes. These generally behave in a benign fashion and have a favorable prognosis. We describe a case of a 24-year-old male presenting with convulsions and a calcified parieto-occipital mass. This mass removed from the parietal lobe showed neoplastic glial and dysplastic neuronal tissue amidst extensive areas of calcification and foci of ossification. On immunohistochemistry, the glial component expressed glial fibrillary acidic protein whereas the dysplastic neuronal component expressed synaptophysin and CD34. Epithelial membrane antigen was negative and Ki-67 showed a low proliferative index. After the surgery, the patient is free of neurological symptoms. Widespread calcification and ossification are very unusual in ganglioglioma, which prompted us to report this case. PMID- 27510689 TI - Pulmonary hemangioendothelioma with osteoclast-like giant cells: A rare observation. AB - Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular neoplasm, predominantly encountered in women, more often in the age group of 40 years and below. It is a tumor of borderline malignant potential with a clinical course intermediate between hemangioma and angiosarcoma. The tumor has variable prognosis, and treatment options include surgical excision in operable cases and chemotherapy in disseminated ones. The present report describes complete clinical, radiological, and histopathological features of PEH with osteoclast like giant cells and metaplastic ossification in a 20-year-old boy who presented with dyspnea and episodes of hemoptysis with review of literature. PMID- 27510690 TI - Fine-needle aspiration cytology of isolated skull nodule: Unfolding the clinical spectrum. AB - Follicular thyroid carcinoma (FTC) has been classified as either minimally invasive or widely invasive carcinoma and shows a propensity for blood-borne metastasis. Most common sites of metastasis are lung and bone followed by brain, liver, and skin. Minimally invasive FTC (MIFTC) is characterized by limited capsular and/or vascular invasion with good long-term outcomes, some cases of which show a poor prognosis because of severe distant metastasis. Skull metastasis in adults commonly arises from the lung, breast, and prostate and uncommonly from the thyroid. In our case, fine-needle aspiration cytology of isolated skull nodule was a reliable tool in the diagnosis of metastasis and suggesting the primary in thyroid thereby prompting early workup of a patient. The case is unique since it represents the rare disseminated metastasis from MIFTC with incomplete capsular penetration alone without angioinvasion that can behave as aggressively as a widely invasive FTC. PMID- 27510691 TI - Adenocarcinoma of the anal canal: A report of two cases with review of literature. AB - Adenocarcinoma of the anal canal accounts for about 20% of all anal canal cancers. It is subclassified into two types. (1) Colorectal type, which arises from the mucosa above dentate line and (2) extramucosal type, which includes adenocarcinoma arising in anorectal fistulae and adenocarcinoma arising from anal glands. Anal gland adenocarcinomas are extremely rare. In this article, we present two cases of anal adenocarcinoma, one colorectal type, and other anal gland carcinoma along with review of literature. PMID- 27510692 TI - 'Childhood systemic mastocytosis associated with t (8; 21) (q22; q22) acute myeloid leukemia'. AB - Systemic mastocytosis (SM) with associated clonal nonmast cell lineage disease is seen in up to 20% cases of SM. SM is uncommon in the pediatric population. T (8; 21) (q22; q22) is a good prognostic factor in acute myeloid leukemia (AML). However, the presence of SM confers poor prognosis in t (8; 21) (q22; q22) associated AML. We report the case of a child with t (8; 21) (q22; q22) associated AML with SM and her minimal residual disease status over the course of her treatment. In our case, the abnormal mast cells, showing co-expression of CD25 and CD2, persisted even after the marrow showed no evidence of residual AML. PMID- 27510693 TI - Lymphoblastic leukemia with surface light chain restriction: A diagnostic dilemma. AB - Surface light chain expression is a feature of mature B-cell neoplasms. Light chain restriction in precursor B acute lymphoblastic leukemia is infrequently seen. We report a case of a 28-year-old female with non-FAB L3 morphology blasts and immunophenotypic features showing overlap between a precursor and mature B cell neoplasm. PMID- 27510694 TI - Early cirrhosis in a young female with protein C deficiency: An extremely unusual case report with review. AB - Protein C deficiency is a well recognized risk factor for development of venous thromboembolism but has never been reported to be associated with development of liver cirrhosis .We report a case of a 26 years old female who presented with multiple thrombosis involving superior mesenteric vein ,main portal vein and multiple cerebral veins. Liver biopsy done was reported as cirrhosis possibly due to Wilson's disease. However no improvement was seen with D penicillamine and patient's condition detiorated. Further, work up of patient revealed absence of Protein C levels in the plasma. So finally the case was diagnosed as Cirrhosis liver with Protein C deficiency as the likely etiology. We conclude that Protein C deficiency should be investigated in patients with cirrhosis with thrombotic lesions of unknown etiology. PMID- 27510695 TI - Neurological melioidosis presenting as intracranial abscess. AB - Melioidosis is an emerging disease in our country caused by the bacteria Burkholderia pseudomallei. Melioidosis can virtually affect any organ. It has varying clinical presentations ranging from pneumonia to fatal sepsis. Central nervous system (CNS) involvement in melioidosis is rare. We present a case of CNS melioidosis from South India. As the incidence of diabetes is increasing in our country varying manifestations of melioidosis will be seen in routine clinical practice. Melioidosis should be considered in the differential diagnosis of intracranial abscess and meningoencephalitis, especially in diabetics. PMID- 27510696 TI - Extended spectrum beta-lactamase producing Shigella flexneri serotype-2 causing bacteremia in a patient with uncontrolled diabetes mellitus. AB - We report a case of Shigella flexneri serotype-2 causing bacteremia in an elderly gentleman with uncontrolled diabetes mellitus, who had no other apparent risk factors. Antibiotic susceptibility testing revealed that the organism was a multidrug resistant extended spectrum beta-lactamase producing straian, which was confirmed by molecular characterization. This rare case alerts both the clinician and microbiologist to a previously unaddressed risk factor of Shigella spp. causing bacteremia, as well as emerging resistant strains that are on the rise in immunocompromised patients. PMID- 27510697 TI - Maculopapular rash presentation of febrile illness in an adult with Varicella zoster virus infection. AB - Varicella zoster usually manifests as maculopapular rash (MPR), which later progresses to vesicle. It can also manifest as MPR without progression to the vesicle stage. This atypical manifestation is more common in adults and immunocompromised patients. A 30-year-old female presented with high-grade fever and rash over face and body for 5 days. She was diagnosed to have Varicella zoster virus (VZV) infection by positive VZV immunoglobulin M enzyme-linked immunosorbent assay and polymerase chain reaction. We present this case to increase awareness among clinicians on the atypical manifestations of VZV and prevent complications by early diagnosis. PMID- 27510698 TI - Clear cell metaplasia of the prostatic urethra. PMID- 27510699 TI - Concomitant occurrence of multiple myeloma with diffuse large B-cell lymphoma. PMID- 27510700 TI - Comparison of carbapenem breakpoints in Clinical Laboratory Standard Institute and European Committee on Antimicrobial Susceptibility Testing guidelines on antibiotic susceptibility test reporting of Acinetobacter baumannii. PMID- 27510701 TI - Undergraduate medical students' perspectives on objective structured practical examination in Pathology. PMID- 27510702 TI - Salivary gland anlage tumor. PMID- 27510703 TI - Issue Cover (September 2016). AB - Cover legend: Macrophages phagocytosing RFP-labeled E.coli. GFP-APPL2 labels the phagosomal membrane. Image produced by N. Condon. See Yeo et al. Traffic 2016; 17(9):1014-1026. Read the full article on doi:10.1111/tra.12415. PMID- 27510704 TI - Atrial natriuretic peptide induces peroxisome proliferator activated receptor gamma during cardiac ischemia-reperfusion in swine heart. AB - OBJECTIVES: Atrial natriuretic peptide is a cardiac atrium-derived hormone and its cardioprotective effects have recently been confirmed, but the actual mechanism underlying these effects has not been well elucidated. In this study, we proposed that atrial natriuretic peptide achieves its effects in part via peroxisome proliferator activated receptor gamma, a nuclear receptor. METHODS: Hemodynamic data in swine heart ischemia-reperfusion model were measured under the conditions of no medication for control (Group N, n = 8) or that of carperitide (synthetic human atrial natriuretic peptide) systemic administration (Group A, n = 8). After 30 min of left anterior descending artery total occlusion and 4 h of reperfusion, peroxisome proliferator activated receptor gamma mRNA and protein expressions in cardiac muscle were examined. The mRNA expression of Liver X receptor alpha, the downstream agent of peroxisome proliferator activated receptor gamma, was also evaluated. Creatine kinase-myocardial band and Troponin T elevations after reperfusion were evaluated as markers of cardiac damage. RESULTS: The dP/dT decrease during reperfusion was ameliorated in Group A. Peroxisome proliferator activated receptor gamma mRNA expression in Group A was significantly higher in ischemic area than that in Group N, although the difference was not significant in the marginal and non-ischemic areas. The peroxisome proliferator activated receptor gamma protein expression in ischemic area was also significantly dominant in Group A. CONCLUSIONS: Atrial natriuretic peptide may achieve its cardioprotective effects in part via the activation of the peroxisome proliferator activated receptor gamma pathway, particularly in central areas of ischemic lesions. PMID- 27510705 TI - Thoracoscopic pulmonary wedge resection without post-operative chest drain: an observational study. AB - OBJECTIVE: Chest drains are used routinely after wedge resection by video assisted thoracoscopic surgery (VATS), although this practice is based largely on tradition rather than evidence. Chest drains may furthermore cause pain, infections, and prolonged length of stay. The aim of this prospective observational study was to assess the feasibility of avoiding chest drains following VATS wedge resection for pulmonary nodules. METHODS: Between 1 February and 25 August 2015 166 consecutive patients planned for VATS wedge resection of pulmonary nodules were screened for inclusion using the following criteria: Forced expiratory volume in 1 s (FEV1) >=60 % of expected, FEV1/forced vital capacity >=70 %, tumour diameter <=2 cm, distance from tumour to visceral pleura <=3 cm, <=2 separate wedges, no air leak on an intraoperative air leakage test and absence of severe adhesions, bullous/emphysematous disease, pleural effusion and coagulopathy. Chest X-rays were done twice on the day of surgery. 30-day complications were compiled from patient records. RESULTS: 49 patients underwent 51 unilateral VATS wedge resections without using a post-operative chest drain. No patient required reinsertion of a chest drain. 30 (59 %) patients had a pneumothorax of mean size 12 +/- 12 mm on supine 8-h post-operative X-ray for which the majority resolved spontaneously within 2-week control. There were no complications on 30-day follow-up. Median length of stay was 1 day. CONCLUSIONS: The results support that VATS wedge resection for pulmonary nodules without a post-operative chest drain may be safe in a selected group of patients. PMID- 27510706 TI - Frequency of colonic adenomatous polyps in a tertiary hospital in Mumbai. AB - INTRODUCTION: Incidence of colorectal carcinoma is increasing all over world. There is limited data on colorectal polyps from India. We evaluated the histomorphological features of colorectal polyps and determined risk stratification in adenomatous polyps. METHODS: In 4970 consecutive colonoscopies, colorectal polyps were detected in 515 cases (10.3 %). Polyps were classified using standard histological criteria. Each polyp was evaluated for presence of dysplasia. Adenomatous polyps were classified as low-risk adenomas (1-2 tubular adenomas <10 mm) and high-risk adenomas characterized by villous histology, high grade dysplasia, size >=10 mm, or >=3 adenomas. RESULTS: Of 515 colorectal polyps, 270 (52.4 %) were adenomatous, followed by 78 (15.1 %) inflammatory, 78 (15.1 %) hyperplastic, 32 (6.2 %) hamartomatous polyps, 25 (4.8 %) benign epithelial polyps, 5 (0.9 %) cap polyps, 5 (0.9 %) lipomatous polyps, 3 (0.5 %) angiomatous polyps, 4 (0.7 %) lymphoid, and 15 (2.9 %) cases with adenocarcinoma masquerading as polyps. Mean (SD) age with colorectal polyps was 54.8 (33.0) years while for adenomatous polyps, 59.5 (14.8) years with male to female ratio of 2:1. Majority of adenomatous polyps 124 (45.9 %) were tubular adenomas present in rectosigmoid. High-grade dysplasia was found in 38 (14 %) adenomas. One hundred and fifty-five (57.4 %) were high risk of which majority were villous adenomas and nine (7.2 %) tubular adenomas. CONCLUSION: The most common colorectal polyps found during routine colonoscopy were 270 adenomatous (52.4 %) cases. Of these, 155 (57.4 %) adenomatous polyps were high-risk category. Population prevalence data of colonic polyps in general population beyond the age of 50 years needs to be obtained. PMID- 27510707 TI - Multivariable predictors of substantial blood loss in children undergoing craniosynostosis repair: implications for risk stratification. AB - BACKGROUND: Operative treatment of craniosynostosis is associated with substantial blood loss, often requiring transfusion of packed red blood cells (PRBC) and coagulation products. AIMS: The aim of this prospective study was to analyze thromboelastographic (TEG) parameters and platelet fibrinogen product to determine predictors of substantial blood loss, and the need for PRBC transfusion and coagulation products. METHODS: With IRB approval, we enrolled 120 children undergoing craniosynostosis repair with a standardized anesthetic, fluid management, and TEG measurements at predefined times. Outcomes of interest were intraoperative blood loss, and need for PRBC transfusion and coagulation products. Multivariable logistic regression and receiver operating characteristic (ROC) curve analysis was applied to determine independent predictors of substantial blood loss and need for coagulation products. RESULTS: One hundred and eighteen children were included in the analysis. Forty-four required PRBC transfusion (median 26 ml.kg(-1) ; IQR: 22-42) with median blood loss of 56 ml.kg(-1) (IQR: 43-83). Factors associated with the PRBC transfusion included type of surgery, duration of surgery, and three TEG parameters, alpha-angle, MA, and K-time (all P < 0.001). A predictive algorithm was developed by subgroup analysis of cranial vault reconstruction (CVR) patients for substantial intraoperative blood loss (defined as >=60 ml.kg(-1) ) and need for coagulation products with ROC-derived cut-off values: platelet fibrinogen product, <343; alpha-angle, <62 degrees ; MA, <55 mm; K-time, >2.1 min. The best prognostic combination included at least two of these four predictors (sensitivity 89%, specificity 90%). Multivariable regression identified MA as the only independent predictor of coagulation product administration (P < 0.001) and ROC analysis identified MA <46 mm as the optimal cut-off (sensitivity 86%, specificity 94%). CONCLUSIONS: Risk for substantial intraoperative blood loss can be assessed using TEG parameters and platelet fibrinogen product, whereas the need for coagulation products is strongly related to low MA. Patients susceptible to substantial blood loss can be risk stratified based on their TEG/platelet fibrinogen product profile. PMID- 27510708 TI - A war psychiatry approach to warfare in the Middle Byzantine period. AB - Combat stress cases were traced in historical texts and military manuals on warfare from the Middle Byzantine period; they were mainly labelled as cowardice. Soldiers suffered from nostalgia or exhaustion; officers looked stunned, or could not speak during the battle. Cruel punishments were often enforced. Suicide and alcohol abuse were rarely mentioned. The Byzantines' evacuation system for battle casualties was well organized. Psychological operations were conducted and prisoners-of-war were usually part of them. The Byzantine army had 'parakletores', officers assigned to encourage soldiers before combat. The leaders dealt with combat stress by using their rhetoric skills and emphasizing religious faith in eternal life. The treatment of the 'cowards' was rather similar to modern war psychiatry principles of treatment. No description of PTSD was found. PMID- 27510709 TI - Erratum to: Practical impacts of genomic data "cleaning" on biological discovery using surrogate variable analysis. PMID- 27510711 TI - Role of let-7b/Fzd4 axis in mitochondrial biogenesis through wnt signaling: In neonatal and adult megakaryocytes. AB - BACKGROUND: Megakaryocytes (MKs), a rare population of bone marrow cells, are responsible for the production of platelets. Sick neonates are predisposed to developing thrombocytopenia (platelet count <150*109/L) and neonates are affected by several megakaryocyte disorders as compared to adults. HYPOTHESIS: MicroRNAs (miRNAs) have been shown to crucially involve in the regulation of stem-cell differentiation in normal as well as malignant hematopoiesis, but their role in regulation of biological differences between adult and neonatal megakaryopoiesis is unknown. METHODS: To study this, we cultured human cord blood (CB) and peripheral blood (PB) derived CD34+ cells in the presence of thrombopoietin for 14days and collected cultures expressing>90% CD41+ by flow cytometry and studied 88 miRNAs involved in stem cell development and differentiation. miRNA validation studies were performed in Dami cell line. RESULTS: Out of 88 miRNAs involved in stem cell development, let-7b was the only miRNA down regulated (~10-fold) in neonates compared to adult-MKs. Let-7b has not been previously described in MKs, however reduced expression of let-7b was found in several human cancers, suggesting that it functions as a tumor suppressor. Our results showed the inhibitory effect of let-7b on wnt signaling pathway by regulating Fzd4 (frizzled family receptor 4) and thereby regulating proliferation as well as differentiation. Let-7b down regulation induced mitochondrial biogenesis and its markers PGC-1alpha and NRF1 during megakaryocyte development. CONCLUSIONS: Our findings for the first time unveil the novel role of let-7b/Fzd4 axis through wnt signaling by regulating mitochondrial biogenesis during megakaryocyte development. PMID- 27510710 TI - Evaluation of artificial selection in Standard Poodles using whole-genome sequencing. AB - Identifying regions of artificial selection within dog breeds may provide insights into genetic variation that underlies breed-specific traits or diseases particularly if these traits or disease predispositions are fixed within a breed. In this study, we searched for runs of homozygosity (ROH) and calculated the d i statistic (which is based upon F ST) to identify regions of artificial selection in Standard Poodles using high-coverage, whole-genome sequencing data of 15 Standard Poodles and 49 dogs across seven other breeds. We identified consensus ROH regions >=1 Mb in length and common to at least ten Standard Poodles covering 0.6 % of the genome, and d i regions that most distinguish Standard Poodles from other breeds covering 3.7 % of the genome. Within these regions, we identified enriched gene pathways related to olfaction, digestion, and taste, as well as pathways related to adrenal hormone biosynthesis, T cell function, and protein ubiquitination that could contribute to the pathogenesis of some Poodle-prevalent autoimmune diseases. We also validated variants related to hair coat and skull morphology that have previously been identified as being under selective pressure in Poodles, and flagged additional polymorphisms in genes such as ITGA2B, CBX4, and TNXB that may represent strong candidates for other common Poodle disorders. PMID- 27510714 TI - Not "just" a shoulder dislocation. PMID- 27510712 TI - Apoptotic signaling pathways induced by acute administration of branched-chain amino acids in an animal model of maple syrup urine disease. AB - Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex activity. This blockage leads to accumulation of the branched-chain amino acids leucine, isoleucine and valine, as well as their corresponding alpha-keto acids and alpha hydroxy acids. The affected patients present severe neurological symptoms, such as coma and seizures, as well as edema and cerebral atrophy. Considering that the mechanisms of the neurological symptoms presented by MSUD patients are still poorly understood, in this study, protein levels of apoptotic factors are measured, such as Bcl-2, Bcl-xL, Bax, caspase-3 and -8 in hippocampus and cerebral cortex of rats submitted to acute administration of branched-chain amino acids during their development. The results in this study demonstrated that BCAA acute exposure during the early postnatal period did not significantly change Bcl 2, Bcl-xL, Bax and caspase-8 protein levels. However, the Bax/Bcl-2 ratio and procaspase-3 protein levels were decreased in hippocampus. On the other hand, acute administration of BCAA in 30-day-old rats increase in Bax/Bcl-2 ratio followed by an increased caspase-3 activity in cerebral cortex, whereas BCAA induces apoptosis in hippocampus through activation and cleavage of caspase-3 and -8 without changing the Bax/Bcl-2 ratio. In conclusion, the results suggest that apoptosis could be of pivotal importance in the developmental neurotoxic effects of BCAA. In addition, the current studies also suggest that multiple mechanisms may be involved in BCAA-induced apoptosis in the cerebral cortex and hippocampus. PMID- 27510713 TI - Behavioral effects of Citrus limon and Punica granatum combinations in rats. AB - Dietary supplements are becoming more influential as viable treatment for common chronic diseases and to promote normal development and functions of all system including brain. Disorders like anxiety and depression may be managed through healthier variations is dietary pattern, since there are indications that diet rich in antioxidants and vitamins diminish anxiety and depression. Hence this investigation was planned to assess the behavioral effects of Citrus limon and Punica granatum in two combination doses i.e. 0.4 + 5 ml/kg and 0.2 + 8 ml/kg C. limon and P. granatum respectively in rats. Antidepressant and anxiolytic effects were explicitly judged twice during 15 days using forced swimming and open field tests and elevated plus maze. In open field test C. limon and P. granatum showed increase in distance travelled, number of central entries and number of rearing's at 0.4 + 5 ml/kg combination, in the elevated plus maze, number of open arm entries were found to be augmented and in forced swimming test, there was decline in duration of immobility and rise in duration of climbing at both combinations i.e. 0.4 + 5 ml/kg and 0.2 + 8 ml/kg C. limon and P. granatum. These results suggest that C. limon and P. granatum at 0.4 + 5 ml/kg combination have anxiolytic and antidepressant effect. PMID- 27510715 TI - Algorithmic Approach With Clinical Pathology Consultation Improves Access to Specialty Care for Patients With Systemic Lupus Erythematosus. AB - OBJECTIVES: Harris Health System (HHS) is a safety net system providing health care to the underserved of Harris County, Texas. There was a 6-month waiting period for a rheumatologist consult for patients with suspected systemic lupus erythematosus (SLE). The objective of the intervention was to improve access to specialty care. METHODS: An algorithmic approach to testing for SLE was implemented initially through the HHS referral center. The algorithm was further offered as a "one-click" order for physicians, with automated reflex testing, interpretation, and case triaging by clinical pathology. RESULTS: Data review revealed that prior to the intervention, 80% of patients did not have complete laboratory workups available at the first rheumatology visit. Implementation of algorithmic testing and triaging of referrals by pathologists resulted in decreasing the waiting time for a rheumatologist by 50%. CONCLUSIONS: Clinical pathology intervention and case triaging can improve access to care in a county health care system. PMID- 27510716 TI - An Assessment of the State of Current Practice in Coagulation Laboratories. AB - OBJECTIVES: To assess the state of current practice in coagulation laboratories regarding three pressing issues: staffing, handling Ebola specimens, and testing/billing for tests that measure direct oral anticoagulants (DOAC). METHODS: A survey and analysis of specialized coagulation laboratories in North America was conducted. RESULTS: Approximately 4,000 special coagulation tests-per technologist-per-year was rated as either a "good" staffing level or "adequate but-ideally-need-more" employees. Requiring technologists to perform more than that was rated as an "inadequate" staffing level. For Ebola patients, coagulation testing is mostly performed by point-of-care. Only 26.1% would perform coagulation tests for Ebola specimens within their laboratory (rather than at the bed side or a separate designated space outside the laboratory). Coagulation tests offered for Ebola patients were limited: prothrombin time (63.0% of laboratories), activated partial thromboplastin time (37.0%), D-dimer (13.0%), and fibrinogen (8.7%); 26.1% of laboratories did not offer any coagulation tests for Ebola patients. Approximately 35% of special coagulation laboratories bill for at least one laboratory test for DOACs: 33% bill for an anti-Xa calibrated with rivaroxaban, 17% bill for an anti-Xa calibrated with apixaban, and 27% bill for at least one of several tests for dabigatran. Approximately 48% do not offer any tests for DOACs. CONCLUSIONS: These results may help laboratories negotiate for additional technologists if needed, prepare for Ebola specimens, and manage the demand for laboratory tests for new DOAC anticoagulants. PMID- 27510717 TI - Opportunities for Improvement in Pathology Reporting of Childhood Nonrhabdomyosarcoma Soft Tissue Sarcomas: A Report From Children's Oncology Group (COG) Study ARST0332. AB - OBJECTIVES: Treatment of soft tissue tumors in young patients relies on the diagnostic information conveyed in the pathology report. We examined pathology reports from Children's Oncology Group ARST0332 for inclusion of data elements required in published guidelines. METHODS: Pathology reports for 551 eligible patients were examined for required data elements defined by the College of American Pathologists, including tissue type, procedure, tumor site, tumor maximum diameter, macroscopic extent of tumor, histologic type, mitotic rate, extent of necrosis, tumor grade, margin status, use of ancillary studies, and pathologic stage. RESULTS: Only 65 (12%) of 551 reports included all required data elements. Of reports containing synoptic templates, 57% were complete. CONCLUSIONS: This study reveals significant opportunity to improve the quality of pathology reports in young patients with soft tissue tumors. Use of templates or checklists improves completeness of reports. PMID- 27510718 TI - Massive Transfusion Protocol: Communication Ordering Practice Survey (MTP COPS). AB - OBJECTIVES: We sought to assess ordering practices and quality of communication during massive transfusion at US level I trauma centers. METHODS: An anonymous, web-based survey was distributed to blood banks supporting US level I trauma centers. Information gathered in the survey included demographics, utilization of and perceived level of support for computerized physician order entry (CPOE), frequency of order confusion, and nonprotocol ordering. Responses were analyzed using descriptive statistics. RESULTS: Responses were received from 43 of 121 centers (35.5% response rate), with the majority completed by blood bank physicians (67.4%) and blood bank supervisors (25.6%). Allowable pathways for massive transfusion protocol (MTP) ordering included CPOE (48.8%), verbal/telephone (86.1%), and written (44.2%). The preferred method of MTP activation was verbal/telephone (86.1%). Initial activation of MTP was well communicated (97.6% agreement), but confusion associated with ongoing needs was reported to occur at least sometimes by 32.6%. CONCLUSIONS: Although CPOE-based MTP ordering is offered by nearly half of US level I trauma centers, verbal/telephone ordering is by far the preferred mechanism. Our survey identifies confusion surrounding blood component needs during MTP resuscitation as an opportunity for practice improvement. PMID- 27510719 TI - The Faith of Sacrifice: Leadership Trade-Offs in an Afro-Brazilian Religion. AB - Despite secular trends in some countries, prestige-based authority in the form of religious leadership remains hugely influential in the everyday lives of millions of people around the world. Here, the costs and benefits of religious leadership are explored in an urban setting in northeastern Brazil. An economic game, within group cooperation questionnaires, and social network analyses were carried out among adherents of an Afro-Brazilian religion. Results reveal that leaders display high levels of religious commitment and disproportionally provide cooperative services to group members. On the other hand, initiates cooperate less than leaders but do not differ in levels of received cooperation or social cohesion measures. This may indicate some level of exploitation or free-riding. Demographic and group variables also appear to play an important role in the degree of social cohesion a group achieves. These findings are discussed in the context of non-Western urban settings where religious leadership may represent both an alternative to social advancement and a crucial source of material aid, social support, and a strong sense of community. PMID- 27510720 TI - Size Effects on the Interaction of QDs with the Mitochondrial Membrane In Vitro. AB - The mitochondrial toxicity induced by GSH-CdTe Quantum dots (QDs) of different sizes was investigated. The decreases in absorbance and transmission electron microscopy images show that QDs induce the swelling of mitochondria. Results of flow cytometry indicate that QDs cause a reduction of mitochondrial membrane potential (MMP). A remarkable increase in fluidity of protein regions of mitochondrial membrane is observed, whereas the lipid regions are not obviously affected. Cyclosporin A (CsA) effectively prevents the QD-induced mitochondrial swelling. On the basis of these results, it is proposed that QDs induce mitochondrial permeability transition (MPT). Moreover, with increasing QDs size, a pronounced MPT is observed. The difference between the membrane fluidity induced by QDs and Cadmium ion and the ineffective protective effects of EDTA suggests that the mitochondrial toxicity of QDs cannot be only attributed to the release of metal ion. The protective effects of HSA indicate that the interaction of QDs with pore-forming protein gives rise to the increase in membrane fluidity. This hypothesis is demonstrated by the interaction of QDs with model membranes and proteins using differential scanning calorimetry and isothermal titration microcalorimetry. In conclusion, as the size of QDs increases, the binding affinity of QDs with membrane protein increases, and therefore causes a pronounced mitochondrial damage. PMID- 27510722 TI - Website aims to help people understand health research. PMID- 27510721 TI - Cost Effectiveness of Pneumococcal Vaccination in Children in Low- and Middle Income Countries: A Systematic Review. AB - BACKGROUND: Although pneumococcal conjugate vaccines (PCVs) have been available for prevention of invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae (S. pneumoniae) for over a decade, their adoption into national immunization programmes in low- and middle-income countries (LMICs) is still limited. Economic evaluations (EEs) play a crucial role in support of evidence informed decisions. OBJECTIVE: This systematic review aims to provide a critical summary of EEs of PCVs and identify key drivers of EE findings in LMICs. METHODS: We searched Scopus, ISI Web of Science, PubMed, Embase and Cochrane Central from their inception to 30 September 2015 and limited the search to LMICs. The search was undertaken using the search strings 'pneumococc* AND conjugat* AND (vaccin* OR immun*)' AND 'economic OR cost-effectiveness OR cost-benefit OR cost-utility OR cost-effectiveness OR cost-benefit OR cost-utility' in the abstract, title or keyword fields. To be included, each study had to be a full EE of a PCV and conducted for an LMIC. Studies were extracted and reviewed by two authors. The review involved standard extraction of the study overview or the characteristics of the study, key drivers or parameters of the EE, assumptions behind the analyses and major areas of uncertainty. RESULTS: Out of 134 records identified, 22 articles were included. Seven studies used a Markov model for analysis, while 15 studies used a decision-tree analytic model. Eighteen studies performed a cost utility analysis (CUA), with disability-adjusted life-years, quality-adjusted life-years or life-years gained as a measure of health outcome, while four studies focused only on cost-effectiveness analysis (CEA). Both CEA and CUA findings were provided by eight studies. Herd effects and serotype replacement were considered in 10 and 13 studies, respectively. The current evidence shows that both the 10-valent and 13-valent PCVs are probably cost effective in comparison with the 7-valent PCV or no vaccination. The most influential parameters were vaccine efficacy and coverage (in 16 of 22 studies), vaccine price (in 13 of 22 studies), disease incidence (in 11 of 22 studies), mortality from IPD and pneumonia (in 8 of 22 studies) and herd effects (in 4 of 22 studies). The findings were found to be supportive of the products owned by the manufacturers. CONCLUSION: Our review demonstrated that an infant PCV programme was a cost-effective intervention in most LMICs (in 20 of 22 studies included). The results were sensitive to vaccine efficacy, price, burden of disease and sponsorship. Decision makers should consider EE findings and affordability before adoption of PCVs. PMID- 27510723 TI - Signaling pathways coordinating the alkaline pH response confer resistance to the hevein-type plant antimicrobial peptide Pn-AMP1 in Saccharomyces cerevisiae. AB - MAIN CONCLUSION: Genome-wide screening of Saccharomyces cerevisiae revealed that signaling pathways related to the alkaline pH stress contribute to resistance to plant antimicrobial peptide, Pn-AMP1. Plant antimicrobial peptides (AMPs) are considered to be promising candidates for controlling phytopathogens. Pn-AMP1 is a hevein-type plant AMP that shows potent and broad-spectrum antifungal activity. Genome-wide chemogenomic screening was performed using heterozygous and homozygous diploid deletion pools of Saccharomyces cerevisiae as a chemogenetic model system to identify genes whose deletion conferred enhanced sensitivity to Pn-AMP1. This assay identified 44 deletion strains with fitness defects in the presence of Pn-AMP1. Strong fitness defects were observed in strains with deletions of genes encoding components of several pathways and complex known to participate in the adaptive response to alkaline pH stress, including the cell wall integrity (CWI), calcineurin/Crz1, Rim101, SNF1 pathways and endosomal sorting complex required for transport (ESCRT complex). Gene ontology (GO) enrichment analysis of these genes revealed that the most highly overrepresented GO term was "cellular response to alkaline pH". We found that 32 of the 44 deletion strains tested (72 %) showed significant growth defects compared with their wild type at alkaline pH. Furthermore, 9 deletion strains (20 %) exhibited enhanced sensitivity to Pn-AMP1 at ambient pH compared to acidic pH. Although several hundred plant AMPs have been reported, their modes of action remain largely uncharacterized. This study demonstrates that the signaling pathways that coordinate the adaptive response to alkaline pH also confer resistance to a hevein-type plant AMP in S. cerevisiae. Our findings have broad implications for the design of novel and potent antifungal agents. PMID- 27510724 TI - Two-Dimensional Infrared Study of Vibrational Coupling between Azide and Nitrile Reporters in a RNA Nucleoside. AB - The vibrations in the azide, N3, asymmetric stretching region and nitrile, CN, symmetric stretching region of 2'-azido-5-cyano-2'-deoxyuridine (N3CNdU) are examined by two-dimensional infrared (2D IR) spectroscopy. At earlier waiting times, the 2D IR spectrum shows the presence of both vibrational transitions along the diagonal and off-diagonal cross peaks indicating vibrational coupling. The coupling strength is determined from the off-diagonal anharmonicity to be 66 cm(-1) for the intramolecular distance of ~7.9 A, based on a structural map generated for this model system. In addition, the frequency-frequency correlation decay is detected, monitoring the solvent dynamics around each individual probe position. Overall, these vibrational reporters can be utilized in tandem to simultaneously track global structural information and fast structural fluctuations. PMID- 27510725 TI - Effect of Three Statins on Glucose Uptake of Cardiomyocytes and its Mechanism. AB - BACKGROUND The aim of this study was to investigate the effects of different statins on glucose uptake and to confirm its mechanism in primary cultured rat cardiomyocytes after administration of atorvastatin, pravastatin, and rosuvastatin. MATERIAL AND METHODS Primary cultured rat cardiomyocytes were randomly assigned to 5 groups: normal control group (OB), insulin group (S1), statin 1-MUM (S2), 5-MUM (S3), and 10-MUM (S4) groups for 3 different statins. The 2-[3H]-DG uptake of each group was determined and the mRNA and protein expression levels of glucose transporter type 4 (GLUT4), insulin receptor substrate (IRs), and RhoA were assessed. RESULTS After treatment with different concentrations of statins and insulin, the 2-[3H]-DG uptake showed a significant negative correlation with the concentration of atorvastatin (P<0.05), and no significant correlation with pravastatin and rosuvastatin. The mRNA and protein expression levels of GLUT4 and IRs-1 in primary cultured cardiomyocytes were both significantly reduced by atorvastatin treatment (P<0.05). Pravastatin and rosuvastatin showed no significant effects on GLUT4 and IRs-1 expression. The mRNA and protein expression levels of RhoA both showed no significant difference when treated with the 3 statins. CONCLUSIONS These results confirm that atorvastatin can inhibit insulin-induced glucose uptake in primary cultured rat cardiomyocytes by regulating the PI3K/Akt insulin signal transduction pathway. PMID- 27510726 TI - Phase II trial of pegylated interferon alfa-2b in young patients with neurofibromatosis type 1 and unresectable plexiform neurofibromas. AB - Background: There is no proven medical therapy for plexiform neurofibromas (PNs). We undertook a phase II trial of pegylated interferon (PI) to evaluate response and time to progression (TTP). Methods: PI was administered as a subcutaneous injection to patients with neurofibromatosis type 1-related PN, stratified by the presence of symptoms (asymptomatic: stratum 1, symptomatic: stratum 2) or documented imaging progression (stratum 3). Patients in strata 1 and 2 received PI for up to one year if stable, 2 years for those with clinical (stratum 2) or imaging response (>=20% decrease in volume). Patients on stratum 3 continued PI until progression. PI was considered active in stratum 3 if TTP doubled compared with the placebo arm of a previous randomized trial using tipifarnib. Results: Enrolled were 82 evaluable patients (median age 10 y; range 1.6 to 21.4). Fatigue and/or worsening of behavioral issues were the most common toxicities requiring dose modification. Across all strata, imaging responses were seen in 4 patients (5%). Three of 26 symptomatic patients on stratum 2 met the criteria for clinical response without corresponding imaging changes. In stratum 3, median TTP was 29.4 months versus 11.8 for the placebo arm of the previous trial (P=.031). The slope of tumor growth on PI slowed significantly compared with the slope before starting PI (P=.044). Conclusions: In patients with active PN, PI results in more than doubling of the TTP compared with placebo. Imaging changes in symptomatic patients were not associated with changes in clinical status. PMID- 27510727 TI - A Novel Nitrobenzoate Microtubule Inhibitor that Overcomes Multidrug Resistance Exhibits Antitumor Activity. AB - Multidrug resistance is a major limitation for microtubule-binding agents in cancer treatment. Here we report a novel microtubule inhibitor (2-morpholin-4-yl 5-nitro-benzoic acid 4-methylsulfanyl-benzyl ester, IMB5046), its cytotoxicity against multidrug-resistant cell lines and its antitumor efficacy in animal models. IMB5046 disrupted microtubule structures in cells and inhibited purified tubulin polymerization in vitro. It bound to the colchicine pocket of tubulin. IMB5046 displayed potent cytotoxicity against multiple tumor cell lines with an IC50 range of 0.037-0.426 MUM. Notably, several multidrug-resistant cell lines which were resistant to colchicine, vincristine and paclitaxel remained sensitive to IMB5046. IMB5046 was not a P-glycoprotein substrate. IMB5046 blocked cell cycle at G2/M phase and induced cell apoptosis. Microarray assay indicated that the differentially expressed genes after IMB5046 treatment were highly related to immune system, cell death and cancer. In a mouse xenograft model IMB5046 inhibited the growth of human lung tumor xenograft by 83% at a well-tolerated dose. It is concluded that IMB5046 is a tubulin polymerization inhibitor with novel chemical structure and can overcome multidrug resistance. It is a promising lead compound for cancer chemotherapy, especially for treatment of multidrug resistant tumors. PMID- 27510729 TI - Structural entropy of glassy systems from graph isomorphism. AB - Configurational entropy plays a central role in thermodynamic scenarios of the glass transition. As a measure of the number of basins in the potential energy landscape, configurational entropy for a glass-forming liquid can be evaluated by explicitly counting distinct inherent structures. In this work, we propose a graph-theory based method to examine local structure and obtain the corresponding entropy of hard-particle systems. Voronoi diagrams of associated clusters are classified using a graph isomorphism algorithm. The statistics of these clusters reveal structural motifs such as icosahedron-like order, and also allow us to calculate the structural entropy SG. We find the structural entropy of an n particle subsystem grows linearly with n. Thus the structural entropy per particle can be obtained from the slope dSG/dn. Our results are consistent with previous values for configurational entropy obtained via thermodynamic integration. Structural entropies per particle are measured for hard-disk and hard-sphere polydisperse systems, and extrapolated for monodisperse hard disks, all of which are nonzero at the dynamic glass transition. PMID- 27510728 TI - Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendleridine Derivatives. AB - We report the first total syntheses of (+)-haplocidine and its N1-amide congener (+)-haplocine. Our concise synthesis of these alkaloids required the development of a late-stage and highly selective C-H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide-directed ortho-acetoxylation of indoline amides enabled our implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions. An electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provided access to hexacyclic C19-hemiaminal ether alkaloids (+) fendleridine, (+)-acetylaspidoalbidine, and (+)-propionylaspidoalbidine. A highly effective enzymatic resolution of a non-beta-branched primary alcohol (E = 22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. Our synthetic strategy provides succinct access to hexacyclic aspidosperma derivatives, including the antiproliferative alkaloid (+)-haplocidine. PMID- 27510730 TI - Stabilisation of metastable polymorphs: the case of paracetamol form III. AB - The design of a melt synthesis of the first air-stable formulation of the metastable form III of paracetamol is derived from thermo-spectroscopic and thermo-diffraction experiments. Melt crystallisation in the presence of beta-1,4 saccharides produces form III selectively and the excipients appear to act as stabilising 'active' templates of the metastable polymorph. PMID- 27510732 TI - Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials. AB - A detailed, high-spatiotemporal-resolution characterization of neuronal responses to local electrical fields and the capability of precise extracellular microstimulation of selected neurons are pivotal for studying and manipulating neuronal activity and circuits in networks and for developing neural prosthetics. Here, we studied cultured neocortical neurons by using high-density microelectrode arrays and optical imaging, complemented by the patch-clamp technique, and with the aim to correlate morphological and electrical features of neuronal compartments with their responsiveness to extracellular stimulation. We developed strategies to electrically identify any neuron in the network, while subcellular spatial resolution recording of extracellular action potential (AP) traces enabled their assignment to the axon initial segment (AIS), axonal arbor and proximal somatodendritic compartments. Stimulation at the AIS required low voltages and provided immediate, selective and reliable neuronal activation, whereas stimulation at the soma required high voltages and produced delayed and unreliable responses. Subthreshold stimulation at the soma depolarized the somatic membrane potential without eliciting APs. PMID- 27510731 TI - A community-based prospective cohort study of dengue viral infection in Malaysia: the study protocol. AB - BACKGROUND: Globally, dengue infections constitute a significant public health burden. In recent decades, Malaysia has become a dengue hyper-endemic country with the co-circulation of the four dengue virus serotypes. The cyclical dominance of sub-types contributes to a pattern of major outbreaks. The consequences can be observed in the rising incidence of reported dengue cases and dengue related deaths. Understanding the complex interaction of the dengue virus, its human hosts and the mosquito vectors at the community level may help develop strategies for addressing the problem. METHODS: A prospective cohort study will be conducted in Segamat district of Johor State in Peninsular Malaysia. Researchers received approval from the Malaysian Medical Research Ethics Committee and Monash University Human Research Ethics Committee. The study will be conducted at a Malaysian based health and demographic surveillance site over a 1 year period in three different settings (urban, semi-urban and rural). The study will recruit healthy adults (male and female) aged 18 years and over, from three ethnic groups (Malay, Chinese and Indian). The sample size calculated using the Fleiss method with continuity correction is 333. Sero-surveillance of participants will be undertaken to identify asymptomatic, otherwise healthy cases; cases with dengue fever who are managed as out-patients; and cases with dengue fever admitted to a hospital. A genetic analysis of the participants will be undertaken to determine whether there is a relationship between genetic predisposition and disease severity. A detailed medical history, past history of dengue infection, vaccination history against other flaviviruses such as Japanese encephalitis and Yellow fever, and the family history of dengue infection will also be collected. In addition, a mosquito surveillance will be carried out simultaneously in recruitment areas to determine the molecular taxonomy of circulating vectors. DISCUSSION: The research findings will estimate the burden of asymptomatic and symptomatic dengue at the community level. It will also examine the relationship between virus serotypes and host genotypes, and the association of the clinical manifestation of the early phase with the entire course of illness. PMID- 27510734 TI - What Factors Do People with Joint Pain Feel are Important in Designing and Developing Community Information-Based Self-Management Approaches? A Patient and Public Engagement Report. PMID- 27510735 TI - Spiny hyperkeratosis (trichodysplasia spinulosa-like eruption): a cutaneous adverse effect of Hedgehog pathway inhibitors involving expression of p16. PMID- 27510733 TI - A Panel of TrpB Biocatalysts Derived from Tryptophan Synthase through the Transfer of Mutations that Mimic Allosteric Activation. AB - Naturally occurring enzyme homologues often display highly divergent activity with non-natural substrates. Exploiting this diversity with enzymes engineered for new or altered function, however, is laborious because the engineering must be replicated for each homologue. A small set of mutations of the tryptophan synthase beta-subunit (TrpB) from Pyrococcus furiosus, which mimics the activation afforded by binding of the alpha-subunit, was demonstrated to have a similar activating effect in different TrpB homologues with as little as 57 % sequence identity. Kinetic and spectroscopic analyses indicate that the mutations function through the same mechanism: mimicry of alpha-subunit binding. From these enzymes, we identified a new TrpB catalyst that displays a remarkably broad activity profile in the synthesis of 5-substituted tryptophans. This demonstrates that allosteric activation can be recapitulated throughout a protein family to explore natural sequence diversity for desirable biocatalytic transformations. PMID- 27510736 TI - Presenting changes in acoustic features synchronously to respiration alters the affective evaluation of sound. AB - Synchronization of respiration to cyclic auditory stimuli is a well-observed phenomenon and known to have an effect on affective evaluation of the presented sound. However, no studies have separated the effect of the change in respiratory movement itself and that when there is synchrony between respiration and sound. In this study, we used a system that can change the acoustic features synchronously with the respiration phase and directly investigated the effect the synchrony has on affective ratings without changing respiratory movements. An acoustic stimulation was presented where the sound intensity (SI) or fundamental frequency (F0) was modulated in response to the participant's respiration phase. Affective evaluations of the acoustic stimuli were made by using the Self Assessment Manikin (SAM). The experiments compared synchronous and asynchronous conditions. In the synchronous condition, SI (or F0) was increased with inhalation (decreased with exhalation) or decreased with inhalation (increased with exhalation). In the asynchronous condition, a sound identical to that presented in the synchronous condition was replayed. The participants evaluated sounds that were acoustically the same but where the temporal relationship differed between respiration and the acoustic features. In our results, significantly higher arousal ratings were observed when the change in SI and respiration (inhalation or exhalation) was synchronous and when the increase in F0 and inhalation was synchronous. This suggests that the synchronous phenomenon between respiration and auditory stimuli can play a critical role in affective evaluation. PMID- 27510737 TI - Development and validation of an ultra-performance convergence chromatography method for the quality control of Angelica gigas Nakai. AB - Ultra-performance convergence chromatography, which integrates the advantages of supercritical fluid chromatography and ultra high performance liquid chromatography technologies, is an environmentally friendly analytical method that uses dramatically reduced amounts of organic solvents. An ultra-performance convergence chromatography method was developed and validated for the quantification of decursinol angelate and decursin in Angelica gigas using a CSH Fluoro-Phenyl column (2.1 mm * 150 mm, 1.7 MUm) with a run time of 4 min. The method had an improved resolution and a shorter analysis time in comparison to the conventional high-performance liquid chromatography method. This method was validated in terms of linearity, precision, and accuracy. The limits of detection were 0.005 and 0.004 MUg/mL for decursinol angelate and decursin, respectively, while the limits of quantitation were 0.014 and 0.012 MUg/mL, respectively. The two components showed good regression (correlation coefficient (r2 ) > 0.999), excellent precision (RSD < 2.28%), and acceptable recoveries (99.75-102.62%). The proposed method can be used to efficiently separate, characterize, and quantify decursinol angelate and decursin in Angelica gigas and its related medicinal materials or preparations, with the advantages of a shorter analysis time, greater sensitivity, and better environmental compatibility. PMID- 27510739 TI - XL1st Sir Peter Freyer Memorial Lecture and Surgical Symposium Arts Millennium Building, National University of Ireland Galway, 2nd & 3rd September 2016. PMID- 27510738 TI - Reply to the article: Gleeson M et al. (2013) An audit of generic prescribing in a general surgical department. Ir J Med Sci 182:403-408. PMID- 27510740 TI - Physician Recommendations Trump Patient Preferences in Prostate Cancer Treatment Decisions. AB - OBJECTIVE: To assess the influence of patient preferences and urologist recommendations in treatment decisions for clinically localized prostate cancer. METHODS: We enrolled 257 men with clinically localized prostate cancer (prostate specific antigen <20; Gleason score 6 or 7) seen by urologists (primarily residents and fellows) in 4 Veterans Affairs medical centers. We measured patients' baseline preferences prior to their urology appointments, including initial treatment preference, cancer-related anxiety, and interest in sex. In longitudinal follow-up, we determined which treatment patients received. We used hierarchical logistic regression to determine the factors that predicted treatment received (active treatment v. active surveillance) and urologist recommendations. We also conducted a directed content analysis of recorded clinical encounters to determine if urologists discussed patients' interest in sex. RESULTS: Patients' initial treatment preferences did not predict receipt of active treatment versus surveillance, Deltachi2(4) = 3.67, P = 0.45. Instead, receipt of active treatment was predicted primarily by urologists' recommendations, Deltachi2(2) = 32.81, P < 0.001. Urologists' recommendations, in turn, were influenced heavily by medical factors (age and Gleason score) but were unrelated to patient preferences, Deltachi2(6) = 0, P = 1. Urologists rarely discussed patients' interest in sex (<15% of appointments). CONCLUSIONS: Patients' treatment decisions were based largely on urologists' recommendations, which, in turn, were based on medical factors (age and Gleason score) and not on patients' personal views of the relative pros and cons of treatment alternatives. PMID- 27510742 TI - Corrigendum to CSF-1 receptor signalling is governed by pre-requisite EHD1 mediated receptor display on the macrophage cell surface [Cell Signalling 2016 Sep.; 28(9): 1325-35]. PMID- 27510741 TI - A Randomized Trial of Expanding Choice Sets to Motivate Advance Directive Completion. AB - BACKGROUND: Evidence suggests that advance directives may improve end-of-life care among seriously ill patients, but improving completion rates remains a challenge. OBJECTIVE: This study tested the influence of increasing the number of options for completing an advance directive among seriously ill patients. METHODOLOGY: Outpatients ( N = 316) receiving hemodialysis across 15 dialysis centers in the Philadelphia region between July 2014 and July 2015 were randomized to receive either the option to complete a brief advance directive form or expanded options including a brief, expanded, or comprehensive form. Patients in both groups could decline to complete an advance directive or take their selected version home. The primary outcome was a returned, completed advance directive. Secondary outcomes included whether patients wanted to complete an advance directive, decision satisfaction, quality of life at 3 months, and patient factors associated with advance directive completion. RESULTS: Although offering more advance directive options was not significantly associated with increased rates of completion (13.1% in the standard group v. 12.2% in the expanded group, P = 0.80), it did significantly increase the proportion of patients who wanted to complete an advance directive and took one home (71.9% in standard v. 85.3% in expanded, P = 0.004). There was no difference in satisfaction ( P = 0.65) or change in quality of life between groups ( P = 0.63). A higher baseline quality of life was independently associated with advance directive completion ( P = 0.006). CONCLUSIONS AND RELEVANCE: These results suggest that although an expanded choice set may initially nudge patients toward completing advance directives without restricting choice, increasing actual completion requires additional interventions that overcome downstream barriers. PMID- 27510744 TI - A Stated Preference Approach to Assess whether Health Status Impacts on Marginal Utility of Consumption. AB - A sample of Danish citizens (n = 2000) was asked to participate in a hypothetical experiment in which they could self-insure against a certain loss in income across two periods of time (one in which the person is in good health and one in which the person is in poorer health). Our results suggest that reduced health impacts on the marginal utility of consumption, but not in a linear fashion. Amongst a majority of respondents inferior, health increases the marginal utility of consumption for intermediate health states, whereas this is not the case for less and more severe health states. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27510743 TI - Joint level-set and spatio-temporal motion detection for cell segmentation. AB - BACKGROUND: Cell segmentation is a critical step for quantification and monitoring of cell cycle progression, cell migration, and growth control to investigate cellular immune response, embryonic development, tumorigenesis, and drug effects on live cells in time-lapse microscopy images. METHODS: In this study, we propose a joint spatio-temporal diffusion and region-based level-set optimization approach for moving cell segmentation. Moving regions are initially detected in each set of three consecutive sequence images by numerically solving a system of coupled spatio-temporal partial differential equations. In order to standardize intensities of each frame, we apply a histogram transformation approach to match the pixel intensities of each processed frame with an intensity distribution model learned from all frames of the sequence during the training stage. After the spatio-temporal diffusion stage is completed, we compute the edge map by nonparametric density estimation using Parzen kernels. This process is followed by watershed-based segmentation and moving cell detection. We use this result as an initial level-set function to evolve the cell boundaries, refine the delineation, and optimize the final segmentation result. RESULTS: We applied this method to several datasets of fluorescence microscopy images with varying levels of difficulty with respect to cell density, resolution, contrast, and signal-to-noise ratio. We compared the results with those produced by Chan and Vese segmentation, a temporally linked level-set technique, and nonlinear diffusion-based segmentation. We validated all segmentation techniques against reference masks provided by the international Cell Tracking Challenge consortium. The proposed approach delineated cells with an average Dice similarity coefficient of 89 % over a variety of simulated and real fluorescent image sequences. It yielded average improvements of 11 % in segmentation accuracy compared to both strictly spatial and temporally linked Chan-Vese techniques, and 4 % compared to the nonlinear spatio-temporal diffusion method. CONCLUSIONS: Despite the wide variation in cell shape, density, mitotic events, and image quality among the datasets, our proposed method produced promising segmentation results. These results indicate the efficiency and robustness of this method especially for mitotic events and low SNR imaging, enabling the application of subsequent quantification tasks. PMID- 27510746 TI - Synthesis of organic photosensitizers containing dithienogermole and thiadiazolo[3,4-c]pyridine units for dye-sensitized solar cells. AB - Dithienogermole (DTG) is a germanium-bridged bithiophene system that has been applied as a building unit of conjugated materials for organic electronic devices, including organic photovoltaics and organic light emitting diodes. However, DTG has not been used as a component of sensitizers for dye-sensitized solar cells (DSSCs). In this work, we have synthesized three D-pi-A-pi-A type sensitizers containing DTG and thiadiazolo[3,4-c]pyridine (PTz). We expected that combining DTG and a strong acceptor PTz would give rise to a strong absorption in the visible region. In addition, we introduced bulky 2-ethylhexyl groups on the germanium atom to prevent dye aggregation on TiO2 films. Three DTG-containing dyes with different anchor units were synthesized and their optical/electrochemical properties were investigated. The DTG-containing dyes exhibited broad and strong absorption bands around 600 nm on TiO2. We fabricated DSSCs based on the DTG-containing dyes. The onsets of incident photon to current conversion efficiency (IPCE) spectra reached 900 nm and a maximal power conversion efficiency of 2.76% was achieved. PMID- 27510747 TI - Studying genetic resilience to improve human health. PMID- 27510745 TI - N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes. AB - Influenza virus PA endonuclease has recently emerged as an attractive target for the development of novel antiviral therapeutics. This is an enzyme with divalent metal ion(s) (Mg(2+) or Mn(2+)) in its catalytic site: chelation of these metal cofactors is an attractive strategy to inhibit enzymatic activity. Here we report the activity of a series of N-acylhydrazones in an enzymatic assay with PA-Nter endonuclease, as well as in cell-based influenza vRNP reconstitution and virus yield assays. Several N-acylhydrazones were found to have promising anti influenza activity in the low micromolar concentration range and good selectivity. Computational docking studies are carried on to investigate the key features that determine inhibition of the endonuclease enzyme by N acylhydrazones. Moreover, we here describe the crystal structure of PA-Nter in complex with one of the most active inhibitors, revealing its interactions within the protein's active site. PMID- 27510748 TI - Overexpression of transport proteins improves the production of 5-aminovalerate from l-lysine in Escherichia coli. AB - Bacterial transporters mediate the exchanges between intracellular and extracellular environments. Modification of transport route could be applied to speed up the metabolic reactions and promote the production of aimed compounds. Herein, lysine 2-monooxygenase (DavB) and delta-aminovaleramidase (DavA) were co expressed in Escherichia coli BL21(DE3) to produce nylon-5 monomer 5 aminovalerate from l-lysine. Then, PP2911 (4-aminobutyrate transporter in Pseudomonas putida) and LysP (the lysine specific permease in E. coli) were overexpressed to promote 5-aminovalerate production using whole cells of recombinant E. coli. The constructed E. coli strain overexpressing transport proteins exhibited good 5-aminovalerate production performance and might serve as a promising biocatalyst for 5-aminovalerate production from l-lysine. This strategy not only shows an efficient process for the production of nylon monomers but also might be used in production of other chemicals. PMID- 27510749 TI - Anhydrobiosis in yeast: cell wall mannoproteins are important for yeast Saccharomyces cerevisiae resistance to dehydration. AB - The state of anhydrobiosis is linked with the reversible delay of metabolism as a result of strong dehydration of cells, and is widely distributed in nature. A number of factors responsible for the maintenance of organisms' viability in these conditions have been revealed. This study was directed to understanding how changes in cell wall structure may influence the resistance of yeasts to dehydration-rehydration. Mutants lacking various cell wall mannoproteins were tested to address this issue. It was revealed that mutants lacking proteins belonging to two structurally and functionally unrelated groups (proteins non covalently attached to the cell wall, and Pir proteins) possessed significantly lower cell resistance to dehydration-rehydration than the mother wild-type strain. At the same time, the absence of the GPI-anchored cell wall protein Ccw12 unexpectedly resulted in an increase of cell resistance to this treatment; this phenomenon is explained by the compensatory synthesis of chitin. The results clearly indicate that the cell wall structure/composition relates to parameters strongly influencing yeast viability during the processes of dehydration rehydration, and that damage to cell wall proteins during yeast desiccation can be an important factor leading to cell death. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27510750 TI - Sonic hedgehog protein regulates fibroblast growth factor 8 expression in metanephric explant culture from BALB/c mice: Possible mechanisms associated with renal morphogenesis. AB - The sonic hedgehog (SHH) morphogen regulates cell differentiation and controls a number of genes during renal morphogenesis. To date, the effects of SHH on fibroblast growth factors (Fgfs) in embryonic kidney development remain unclear. In the present study, explants of BALB/c mouse embryonic kidney tissues were used to investigate the role of exogenous SHH on Fgf8 and Fgf10 expression levels ex vivo. Ureteric bud branches and epithelial metanephric derivatives were used to determine the renal morphogenesis with Dolichos biflorus agglutinin or hematoxylin-eosin staining. mRNA expression levels were determined using reverse transcription-quantitative polymerase chain reaction, while the protein expression levels were examined using immunohistochemistry and western blot analysis. During the initial stages of metanephric development, low levels of SHH, Fgf8, and Fgf10 expression were observed, which were found to increase significantly during more advanced stages of metanephric development. In addition, exogenous SHH protein treatment increased the number of ureteric bud branches and enhanced the formation of nephrons. Exogenous SHH reduced the Fgf8 mRNA and protein expression levels, whereas cyclopamine (an SHH-smoothened receptor inhibitor) interfered with SHH-mediated downregulation of Fgf8 expression. By contrast, exogenous SHH protein was not found to modulate Fgf10 mRNA and protein expression levels. In conclusion, these results indicate that the modulatory effects of SHH on BALB/c mouse metanephric explant cultures may involve the regulation of Fgf8 expression but not Fgf10 expression, which provides evidence for the functional role of Fgf proteins in renal morphogenesis. PMID- 27510751 TI - Prevalence and Predictors of Gastroesophageal Reflux Complications in Community Subjects. AB - BACKGROUND: Predictors of erosive esophagitis (EE) and Barrett's esophagus (BE) and the influence of number of risk factors in the community are not well defined. METHODS: Rates of BE and EE among community residents identified in a randomized screening trial were defined. The risk of EE and BE associated with single and multiple risk factors (gender, age, GERD, Caucasian ethnicity, ever tobacco use, excess alcohol use, family history of BE or EAC, and central obesity) was analyzed. RESULTS: Sixty-eight (33 %) of 205 subjects had EE and/or BE. BE prevalence was 7.8 % with dysplasia present in 1.5 %. Rates were comparable between subjects with and without GERD. Male sex and central obesity were independent risk factors. The odds of EE or BE were 3.7 times higher in subjects with three or four risk factors and 5.7 times higher in subjects with five or more risk factors compared with those with two or less factors. CONCLUSIONS: EE and BE are prevalent in the community regardless of the presence of GERD. Risk appeared to be additive, increasing substantially with three or more risk factors. PMID- 27510752 TI - Frequency of and Factors Associated with Receipt of Liver-Related Specialty Care Among Patients with Hepatitis C in the Chronic Hepatitis Cohort Study. AB - BACKGROUND: Linking persons with hepatitis C virus (HCV) to care and treatment is critical to reduction in disease burden; typically, this entailed referral to a specialist. However, data regarding the frequency and factors associated with referral among patients in healthcare organizations (HCOs) are lacking. METHODS: Among persons in four US HCOs with newly diagnosed HCV during 2006-2011, we determined the frequency of liver-related specialist care after diagnosis. We also identified sociodemographic and clinical characteristics associated with such care by multivariate analysis, adjusted for all variables. RESULTS: Among 3592 patients with newly diagnosed HCV, 57 % (range among sites 45-90 %) received specialist care; of these, 57 % received care within 90 days of diagnosis. Patient characteristics associated with receipt of specialist care included: affiliation with one of the study sites [adjusted odds ratio (aOR) 4.8 vs. the referent site); having Medicare plus private insurance (aOR 1.6 vs. Medicaid); and having elevated alanine aminotransferase (ALT) (aOR 1.6 vs. normal ALT) or lower platelet values (aOR 1.4 vs. normal platelet level). Specialist care within 90 days of diagnosis was associated with private insurance (aOR 1.5 vs. Medicaid), elevated ALT levels (aOR 1.3-2.3 vs. normal), and having >=2 comorbid conditions (aOR 1.4 vs. no comorbid conditions). Compared to patients not referred, those referred were more likely to be treated (aOR 3.5). CONCLUSIONS: Receipt of specialist care among persons with newly diagnosed HCV varied among HCOs. Clinical evidence of liver disease and having private insurance were associated with prompt receipt of specialist care and HCV treatment. PMID- 27510753 TI - Gastrointestinal Bleeding During the Index Hospitalization for Mechanical Circulatory Support Devices Implantation, a Nationwide Perspective. AB - BACKGROUND: Gastrointestinal bleeding (GIB) is a common adverse event after mechanical circulatory support device implantation. However, the majority of the reported data were obtained from small single-center studies. Our aim was to study the prevalence and predictors of GIB during the index hospitalization of mechanical circulatory support devices implantation using a nationwide database. METHODS: Nationwide inpatient sample (2009-2011) was used to perform a retrospective cross-sectional study. Adult patients with discharge diagnosis codes of congestive heart failure and procedure codes of left-ventricular assist device (LVAD) or intra-aortic balloon pump (IABP) implantation or orthotopic heart transplant (OHT, reference group) were identified. Our outcome was GIB during the index hospitalization when the device was implanted. Predictors that achieved statistical significance on the univariate analysis were included in a multivariable logistic-regression analysis. RESULTS: A total of 87,462 patients were included, 87 % of the patients received an IABP, 6 % received LVAD, and 5 % underwent OHT. Prevalence of GIB was 8, 5, and 3 % among those who had LVAD, IABP implantation, and OHT recipients, respectively (p < 0.001). Patients who underwent LVAD implantation had twofold increase in the prevalence of GIB (OR 2.1, 1.7-2.5, p < 0.001) when using IABP or OHT groups as a reference. This increase in the prevalence was not demonstrated among IABP recipients on a multivariate level. CONCLUSION: Prevalence of GIB was higher among LVAD compared to OHT and IABP recipients and could occur as early as the index admission of the device implantation. PMID- 27510754 TI - Correction: A pH-driven, reconfigurable DNA nanotriangle. AB - Correction for 'A pH-driven, reconfigurable DNA nanotriangle' by Wenxing Wang et al., Chem. Commun., 2009, 824-826. PMID- 27510755 TI - Toward Reducing Ageism: PEACE (Positive Education about Aging and Contact Experiences) Model. AB - The population of older adults is growing worldwide. Negative ageism (negative attitudes and behavior toward older adults) is a serious international concern that negatively influences not only older adults but also individuals across the age continuum. This article proposes and examines the application of an integrative theoretical model across empirical evidence in the literature on ageism in psychology, medicine, social work, and sociology. The proposed Positive Education about Aging and Contact Experiences (PEACE) model focuses on 2 key contributing factors expected to reduce negative ageism: (a) education about aging including facts on aging along with positive older role models that dispel negative and inaccurate images of older adulthood; and (b) positive contact experiences with older adults that are individualized, provide or promote equal status, are cooperative, involve sharing of personal information, and are sanctioned within the setting. These 2 key contributing factors have the potential to be interconnected and work together to reduce negative stereotypes, aging anxiety, prejudice, and discrimination associated with older adults and aging. This model has implications for policies and programs that can improve the health and well-being of individuals, as well as expand the residential, educational, and career options of individuals across the age continuum. PMID- 27510756 TI - The protective role of p72 in doxorubicin-induced cardiomyocytes injury in vitro. AB - p72 (probable ATP-dependent RNA helicase DDX17) belongs to the DEAD-box RNA helicase family. p72 is important in RNA processing. Thus, the role of p72 in doxorubicin (DOX)-induced cardiomyocyte injury was investigated in the present study. The changes in p72 expression levels were studied in cultured neonatal cardiomyocytes and p72 overexpression was induced using adenovirus vectors. To investigate the production of reactive oxygen species (ROS), dihydroethidium staining was conducted. TUNEL and Hoechst staining were used to indicate cell apoptosis. Microarrays were used to determine the altered expression of microRNAs. In DOX-induced cardiomyocyte injury, the protein expression level of p72 was reduced. Overexpression of p72 protected cardiomyocytes from DOX-induced ROS production and cell apoptosis. p72 reduced the activation of estrogen receptor alpha (ERalpha), thereby reducing DOX-induced cell apoptosis. The present study indicated that p72 exerts a protective effect against DOX-induced cell apoptosis via inhibition of ERalpha activation, indicating this may be a potential target of therapy for cardiac injury. PMID- 27510757 TI - Protective Effect of Metformin against Acute Inflammation and Oxidative Stress in Rat. AB - Preclinical Research The antidiabetic drug, metformin, can inhibit the release of inflammatory mediators in several disease conditions. The present study was carried out to evaluate the efficacy of metformin in ameliorating edema formation, oxidative stress, mediator release and vascular changes associated with acute inflammation in the rat carrageenan model. Metformin dose-dependently inhibited paw swelling induced by carrageenan and normalized the tissue levels of the inflammatory markers myeloperoxidase and nitrite. It also maintained oxidative homeostasis as indicated by near normal levels of the oxidative stress markers glutathione, thiobarbituric acid reactive substances, catalase and superoxide dismutase. The histopathology of the paw tissue in metformin-treated animals was similar to that in normal paw and had similar effects to diclofenac. In a rat peritonitis model, metformin reduced vascular permeability and cellular infiltration. In conclusion, this study shows that metformin has a potential for use in treating various inflammatory conditions. PMID- 27510758 TI - Niacin for phosphate control: A case of David versus Goliath. PMID- 27510759 TI - Tinea capitis: a retrospective epidemiological comparative study. AB - BACKGROUND: Currently, a wide spectrum of retrospective studies regarding the incidence of TC among children and adults are available in the world literature, but none of them are comparative, aiming to distinguish etiological diversity depending on the different geographic areas. OBJECTIVE: This study aimed to investigate the epidemiology of TC in Plovdiv, Bulgaria and Thessaloniki, and Greece, and to compare the results and predominant etiological agents using retrospective comparative analysis for an 11-year time period. MATERIALS AND METHODS: The subjects included were selected from archives of the Mycological Laboratory of the University Dermatologic Clinic, University Hospital "St. George" Plovdiv, Bulgaria, and the Mycological Laboratory of the First Dermatology Department of Aristotle University Thessaloniki, Greece, by retrospective analysis of data from an 11-year time period (2004-2014). A total count of 374 children aged 0-18, with confirmed diagnosis of TC via direct mycological examination and culture were included (128 children from Plovdiv, Bulgaria, and 246 children from Thessaloniki, Greece). Samples were plated on Sabouraud agar, followed by species identification of the isolated colonies. RESULTS: Our results demonstrate that the incidence of TC in the region of Bulgaria and Thessaloniki for the investigated period was lower than for the previously reported period. In Plovdiv, Bulgaria, it was 1.20 +/- 0.09 % (n = 172 from a total count of 14,278 cases of mycoses), as the disease accounts for 23.10 +/- 1.79 % of all mycological infections among the pediatric population and 0.36 +/- 0.05 % (n = 49 from a total count of 13,724) among the adults patients in Plovdiv, Bulgaria. The incidence of the disease during the period 2004-2014 in Thessaloniki was 2.49 +/- 0.15 % (n = 253 cases of TC from a total count of 10,168 mycoses), as it accounts for approximately 27.06 +/- 1.47 % of mycological infections among the pediatric population in Thessaloniki, Greece, and 0.08 +/- 0.03 % (n = 7 from a total count of 9259) of the population of adult patients with mycoses. Our study confirmed the presumption that M. canis is the leader among the causative agents in TC in children in both of the included countries, but its presence in the etiology of disease in adult patients was very low and nonsignificant. We categorically identified dominance of the female gender among the children with TC in Plovdiv, Bulgaria; while in Thessaloniki, Greece, the gender distribution had an almost equal ratio of males to females. CONCLUSION: Our results suggest that the gender predisposition depends also on the investigated geographic region and the time of the study, rather than only on the causative pathogen and age. PMID- 27510760 TI - Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain. AB - Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 +/- 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs. PMID- 27510761 TI - Challenging the wisdom of puncture at the calyceal fornix in percutaneous nephrolithotripsy: feasibility and safety study with 137 patients operated via a non-calyceal percutaneous track. AB - OBJECTIVES: To present our experience with a central, non-calyceal puncture protocol for percutaneous nephrolithotripsy (PCNL) in an attempt to challenge the opinion of worldwide adopted calyceal puncture as the less traumatic site of percutaneous entrance into the collecting system. PATIENTS AND METHODS: During 2012, a total of 137 consecutive, unselected patients were subjected to PCNL in our department. Non-calyceal punctures were performed to all cases and followed by subsequent track dilations up to 30 Fr. Perioperative and postoperative data were prospectively collected and analyzed. RESULTS: Mean operative time (from skin puncture to nephrostomy tube placement) was 48 min. Patients with single, multiple and staghorn stones had primary stone-free rates of 89.2, 80.4 and 66.7 % after PCNL, respectively. The overall complication rate was 10.2 %, while bleeding complications were minimal. Only 4 patients (2.9 %) required blood transfusion. Five patients (3.6 %) had Clavien Grade IIIa complications requiring an intervention for their management and none Grade IV or V. CONCLUSIONS: Despite the absence of evidence that non-calyceal percutaneous tracts could be a risk factor for complications, the concept of calyceal puncture has been worldwide adopted by PCNL surgeons as the sole safe percutaneous entrance into the collective system. Based on our experience, other pathways than the worldwide recognized rule, calyceal puncture, are possible and probably not as dangerous as has been previously stated. PMID- 27510762 TI - Performance of PI-RADS version 1 versus version 2 regarding the relation with histopathological results. AB - PURPOSE: Aim of this study was to compare the diagnostic performance of PI-RADS version 1 (v1) and version 2 (v2) in the detection of prostate cancer (PCa). METHODS: Multiparametric MRIs (mpMRI) of 50 consecutive patients with biopsy proven PCa, which had originally been evaluated according to PIRADS v1, were now retrospectively re-evaluated, comparing PI-RADS v1 and v2. MpMRI data were evaluated in comparison with histopathological whole-mount step-section slides. MRI examinations included T2-weighted, diffusion-weighted, and dynamic contrast enhanced MRI. RESULTS: Overall PI-RADS v1 showed a significantly larger discriminative ability of tumor detection: PI-RADS v1 AUC 0.96 (95 % CI 0.94 0.98) and v2 AUC 0.90 (95 % CI 0.86-0.94). For peripheral zone lesions, PI-RADS v1 showed a significantly larger ability of PCa discrimination: v1 AUC 0.97 (95 % CI 0.95-0.99) and v2 AUC 0.92 (95 % CI 0.88-0.96). For transition zone lesions, PI-RADS v1 showed more discrimination: v1 AUC 0.96 (95 % CI 0.92-1.00) and v2 0.90 (95 % CI 0.83-0.97), but the difference was not significant. PI-RADS v2 resulted in significantly more false negative results (3 % in v1, 14 % in v2) and a comparable number of true positive results (82 % in v1, 80 % in v2). CONCLUSION: PI-RADS v2 uses a simplified approach, but shows a lower diagnostic accuracy. This could lead to a higher rate of false negative results with the risk of missing tumors within low PI-RADS score levels. Therefore, its use cannot be recommended unconditionally, and further improvement should be considered. PMID- 27510763 TI - Laterally Confined Microfluidic Patterning of Cells for Engineering Spatially Defined Vascularization. AB - A biofabrication strategy for creating planar multiscale protein, hydrogel, and cellular patterns, and simultaneously generating microscale topographical features is developed that laterally confines the patterned cells and direct their growth in cell permissive hydrogels. PMID- 27510764 TI - Vitamin E is the major contributor to the antioxidant capacity in lambs fed whole dried citrus pulp. AB - The aim of this study was to investigate the effect of dietary whole dried citrus pulp (DCP) on the antioxidant status of lamb tissues. In total, 17 lambs were divided into two groups and fed for 56 days: a barley-based concentrate diet (CON - eight animals), or a concentrate-based diet including 35% DCP to partially replace barley (CIT - nine animals). The CIT diet contained a double concentration of phenolic compounds than the CON diet (7.9 v. 4.0 g/kg dry matter (DM), respectively), but had no effect (P>0.05) on the overall antioxidant capacity of the hydrophilic fraction of blood plasma, liver and muscle. The CIT diet contained clearly more alpha-tocopherol than the CON diet (45.7 v. 10.3 mg/kg DM), which could explain the higher concentration of alpha-tocopherol in liver, plasma and muscle (P<0.05). The dietary treatment had no effect on the extent of lipid peroxidation, measured as thiobarbituric acid and reactive substances assay (TBARS values) in the faeces, small intestine, liver, plasma and muscle. Nevertheless, when muscle homogenates were incubated in the presence of Fe3+/ascorbate to induce lipid peroxidation, the muscle from lambs fed DCP displayed lower TBARS values (P<0.01), which negatively correlated with the concentration of alpha-tocopherol in muscle. These results showed that feeding whole DCP to ruminants increases the antioxidant status of muscle through an increase in the deposition of alpha-tocopherol. PMID- 27510765 TI - Number of accelerometer monitoring days needed for stable group-level estimates of activity. AB - To determine the number and distribution of days required to produce stable group level estimates of a 7 d mean for common accelerometer-derived activity measures. Data from the 2003-2006 NHANES were used in this analysis. The sample included 986 youth (6-19 year) and 2532 adults (?20 year) with 7 d of ?10 h of wear. Accelerometer measures included minutes of inactive, light physical activity, moderate-to-vigorous physical activity (MVPA); and total activity counts/d. Twenty-five alternative protocols were bootstrapped with 50 000 samples drawn for each protocol. Alternative protocols included: 1-6 random days, Saturday plus 1-5 random weekdays (WD), Sunday plus 1-5 random WD, 1 random weekend day (WE) plus 1 5 WD, and both WE plus 1-4 random WD. Relative difference was calculated between the 7 d mean and alternative protocol mean (((alternative protocol mean - 7 d mean)/7 d mean) (*) 100). Adult MVPA is used as an example; however, similar trends were observed across age groups and variables except adult inactive time, which was stable across protocols. The 7 d mean for adult MVPA was 44.1(0.9) min d(-1). The mean bias for any 1-6 random days ranged from -0.0(0.3) to 0.0(0.2) min d(-1) with a relative difference of -0.1 to 0.0%. For protocols with non random components, bias ranged from -1.4(0.2) to 0.6(0.1) min d(-1) with relative difference ranging from -7.2 to 3.1%. Simulation data suggest that stable estimates of group-level means can be obtained from as few as one randomly selected monitoring day from a sampled week. On the other hand, estimates using non-random selection of weekend days may be significantly biased. Purposeful sampling that disproportionally forces inclusion of weekend data in analyses should be discouraged. PMID- 27510766 TI - Proteomic analysis of an engineered isolate of Lactobacillus plantarum with enhanced raffinose metabolic capacity. AB - Lactic acid bacteria that can produce alpha-galactosidase are a promising solution for improving the nutritional value of soy-derived products. For their commercial use in the manufacturing process, it is essential to understand the catabolic mechanisms that facilitate their growth and performance. In this study, we used comparative proteomic analysis to compare catabolism in an engineered isolate of Lactobacillus plantarum P-8 with enhanced raffinose metabolic capacity, with the parent (or wild-type) isolate from which it was derived. When growing on semi-defined medium with raffinose, a total of one hundred and twenty five proteins were significantly up-regulated (>1.5 fold, P < 0.05) in the engineered isolate, whilst and one hundred and six proteins were significantly down-regulated (<-1.5 fold, P < 0.05). During the late stages of growth, the engineered isolate was able to utilise alternative carbohydrates such as sorbitol instead of raffinose to sustain cell division. To avoid acid damage the cell layer of the engineered isolate altered through a combination of de novo fatty acid biosynthesis and modification of existing lipid membrane phospholipid acyl chains. Interestingly, aspartate and glutamate metabolism was associated with this acid response. Higher intracellular aspartate and glutamate levels in the engineered isolate compared with the parent isolate were confirmed by further chemical analysis. Our study will underpin the future use of this engineered isolate in the manufacture of soymilk products. PMID- 27510767 TI - True ferroelectric switching in thin films of trialkylbenzene-1,3,5 tricarboxamide (BTA). AB - We have investigated the ferroelectric polarization switching properties of trialkylbenzene-1,3,5-tricarboxamide (BTA), which is a model system for a large class of novel organic ferroelectric materials. In the solid state BTAs form a liquid crystalline columnar hexagonal phase that provides long range order that was previously shown to give rise to hysteretic dipolar switching. In this work the nature of the polar switching process is investigated by a combination of dielectric relaxation spectroscopy, depth-resolved pyroelectric response measurements, and classical frequency- and time-dependent electrical switching. We show that BTAs, when brought in a homeotropically aligned hexagonal liquid crystalline phase, are truly ferroelectric. Analysis of the transient switching behavior suggests that the ferroelectric switching is limited by a highly dispersive nucleation process, giving rise to a wide distribution of switching times. PMID- 27510768 TI - Real-time PCR detection and phylogenetic relationships of Neorickettsia spp. in digeneans from Egypt, Philippines, Thailand, Vietnam and the United States. AB - Neorickettsia (Rickettsiales, Anaplasmataceae) is a genus of obligate intracellular bacterial endosymbionts of digeneans (Platyhelminthes, Digenea). Some Neorickettsia are able to invade cells of the digenean's vertebrate host and are known to cause diseases of domestic animals, wildlife, and humans. In this study we report the results of screening digenean samples for Neorickettsia collected from bats in Egypt and Mindoro Island, Philippines, snails and fishes from Thailand, and fishes from Vietnam and the USA. Neorickettsia were detected using a real-time PCR protocol targeting a 152bp fragment of the heat shock protein coding gene, GroEL, and verified with nested PCR and sequencing of a 1853bp long region of the GroESL operon and a 1371bp long region of 16S rRNA. Eight unique genotypes of Neorickettsia were obtained from digenean samples. Neorickettsia sp. 8 obtained from Lecithodendrium sp. from Egypt; Neorickettsia sp. 9 and 10 obtained from two species of Paralecithodendrium from Mindoro, Philippines; Neorickettsia sp. 11 from Lecithodendrium sp. and Neorickettsia sp. 4 (previously identified from Saccocoelioides lizae, from China) from Thailand; Neorickettsia sp. 12 from Dicrogaster sp. Florida, USA; Neorickettsia sp. 13 and SF agent from Vietnam. Sequence comparison and phylogenetic analysis demonstrated that the forms, provisionally named Neorickettsia sp. 8-13, represent new genotypes. We have for the first time detected Neorickettsia in a digenean from Egypt (and the African continent as a whole), the Philippines, Thailand and Vietnam based on PCR and sequencing evidence. Our findings suggest that further surveys from the African continent, SE Asia, and island countries are likely to reveal new Neorickettsia lineages as well as new digenean host associations. PMID- 27510770 TI - Erratum to: eSTGt: a programming and simulation environment for population dynamics. PMID- 27510771 TI - [The standardized development of breast pathology in recent years of China]. PMID- 27510772 TI - [Granulomatous lobular mastitis: clinical pathological diagnosis and differential diagnosis]. PMID- 27510769 TI - cPKCgamma-Modulated Autophagy in Neurons Alleviates Ischemic Injury in Brain of Mice with Ischemic Stroke Through Akt-mTOR Pathway. AB - We have reported that neuron-specific conventional protein kinase C (cPKC)gamma is involved in the development of cerebral hypoxic preconditioning (HPC) and the neuroprotection against ischemic injuries, but its molecular mechanism is unclear. In this study, the adult and postnatal 24 h C57BL/6J wild-type (cPKCgamma+/+) and cPKCgamma knockout (cPKCgamma-/-) mice were respectively used to establish the models of middle cerebral artery occlusion (MCAO)-induced ischemic stroke in vivo and oxygen-glucose deprivation (OGD)-treated primarily cultured cortical neurons as cell ischemia in vitro. The results showed that cPKCgamma knockout could increase the infarct volume and neuronal cell loss in the peri-infarct region, and enhance the neurological deficits, the impaired coordination, and the reduced muscle strength of mice following 1 h MCAO/1-7 days reperfusion. Meanwhile, cPKCgamma knockout significantly increased the conversion of LC3-I to LC3-II and beclin-1 protein expression, and resulted in more reductions in P-Akt, P-mTOR, and P-S6 phosphorylation levels in the peri-infarct region of mice with ischemic stroke. The autophagy inhibitor BafA1 could enhance or reduce neuronal cell loss in the peri-infarct region of cPKCgamma+/+ and cPKCgamma-/- mice after ischemic stroke. In addition, cPKCgamma knockout and restoration could aggravate or alleviate OGD-induced neuronal ischemic injury in vitro through Akt-mTOR pathway-mediated autophagy. These results suggested that cPKCgamma-modulated neuron-specific autophagy improves the neurological outcome of mice following ischemic stroke through the Akt-mTOR pathway, providing a potential therapeutic target for ischemic stroke. PMID- 27510773 TI - [2016 World Health Organization classification of tumors of the prostate: an update]. PMID- 27510774 TI - [2016 World Health Organization classification of tumors of the testis and the penis: an update]. PMID- 27510775 TI - [Standardization for diagnostic tumor pathology]. PMID- 27510776 TI - [Standardization for diagnostic tumor pathology (breast cancer)]. PMID- 27510777 TI - [Guidelines for HER2 detection in gastric cancer(2016)]. PMID- 27510778 TI - [Association of single nucleotide polymorphisms in PAI-1 with breast cancer susceptibility and prognosis]. AB - OBJECTIVE: To study the effects of single nucleotide polymorphisms (SNP) in Plasminogen activator inhibitor 1(PAI-1) on breast cancer susceptibility and patients' prognosis among a Chinese Han women population. METHODS: Six tag SNP (tSNP) of PAI-1 were selected according to HapMap CHB population, and TaqMan realtime PCR method was used to genotype the 6 tSNP in 1 160 breast cancer cases and 1 318 age-matched controls among Chinese Han women. Haplotypes and diplotypes were inferred according to genotyping data and linkage disequilibrium. Finally, the associations of tSNP, haplotypes and dipltypes with breast cancer susceptibility and patients' prognosis were analyzed. RESULTS: Regarding to breast cancer susceptibility, for rs6090 (G>A), AA genotype carriers had 3.79 times higher risk of developing breast cancer (OR=4.79, 95%CI=1.01-22.64, P=0.048 0) than GG or GA genotype carriers. For rs2227672 (G>T), TT genotype carriers had 1.52 times higher breast cancer risk than GG or GT genotype carriers (OR=2.52, 95%CI=1.26-5.01, P=0.008 6). Regarding to breast cancer prognosis, women who carried rs2227692 (C>T) CT genotype had 46% lower risk of developing recurrence, metastasis or death than CC genotype carriers (HR=0.54, 95%CI=0.30-0.97, P=0.040 4). Using stratified association analysis, among BMI<23 patients, those women who carried AA genotype of rs2227631 (G>A) had 3.99 times higher risk of developing the events (recurrence, metastasis or death) than GG or GA genotype carriers (HR=4.99, 95%CI=1.66-15.02, P=0.004 2). Among HER2 positive patients, those women who carried AA genotype of rs2227667 (G>A) had 2.98 times higher risk of developing the events (recurrence, metastasis or death) than GG or GA genotype carriers (HR=3.98, 95%CI=1.47-10.80, P=0.006 7). Among patients with tumors>2 cm, those women who carried rs2227692 (C>T) CT or TT genotype had 51% lower risk of developing the events (recurrence, metastasis or death) than CC genotype carriers (HR=0.49, 95%CI=0.27-0.88, P=0.017 0). CONCLUSIONS: The study indicates that single nucleotide polymorphisms in PAI-1 may affect breast cancer susceptibility and survival in Chinese Han women. The study may contribute to individualized evaluation of breast cancer risk and patients' prognosis if these data are validated in some other Chinese Han populations. PMID- 27510779 TI - [CD8 and FOXP3 expression in stromal tumor-infiltrating lymphocytes of triple negative breast carcinomas: a clinicopathologic study]. AB - OBJECTIVE: To investigate the relationship between stromal tumor-infiltrating lymphocytes (TIL) and CD8 or FOXP3 positive lymphocytes in triple-negative breast carcinoma. METHODS: A total of 160 triple-negative breast carcinomas were collected from the First Affiliated Hospital of Nanjing Medical University during 2012 to 2014. All were surgical excision or biopsy specimens from patients without prior chemotherapy and radiotherapy. Histopathologic analysis of stromal TIL was performed on hematoxylin and eosin-stained sections, and MaxVision immunohistochemical method was used for detection of CD8 and FOXP3 protein expression. RESULTS: Stromal TILs were positively correlated with Ki-67 labeling index (P=0.002). The density of CD8(+) cytotoxic T-lymphocyte (CTL) was negatively correlated with tumor size (P=0.009), and positively correlated with Ki-67 index (P=0.021). The density of FOXP3(+) regulatory T-lymphocyte (Treg) was inversely correlated with the patient age (P=0.030), and positively correlated with histological grade (P=0.026). Stromal TILs were positively correlated with the density of CD8(+) CTL (P=0.014). CONCLUSIONS: The percentage of stromal TILs and density of CD8(+) CTL are associated with tumor cell proliferation of triple negative breast cancers. The density of FOXP3(+) Treg is significantly associated with poor prognosis. Stromal TIL is positively correlated with the density of CD8(+) CTL. Stromal TIL may provide a potential marker for pathological diagnosis and a target for guiding adjuvant therapy in patients with triple-negative breast cancers. PMID- 27510780 TI - [Impact of 2013 American Society of Clinical Oncology/College of American Pathologist guidelines on borderline immunostaining results for HER2: a retrospective study on HER2 FISH results in 1 780 cases of invasive breast cancers]. AB - OBJECTIVE: To analyze the impact of the revised 2013 American Society of Clinical Oncology/College of American Pathologist(ASCO/CAP)HER2 testing guidelines on the status of HER2 and its clinical significance in invasive breast cancers by fluorescent in situ hybridization(FISH). METHODS: One thousand seven hundred and eighty invasive breast cancer cases with equivocal 2+ immunostaining detected by FISH were retrospectively selected from 2010 to 2014, and the HER2/CEP17 dual probe results were evaluated according to both the 2007 and 2013 ASCO/CAP guidelines for comparative analysis. RESULTS: Among the 1 780 IHC HER2 (2+ ) invasive breast cancers, the number of HER2 positive, equivocal and negative case were 310(17.41%), 66(3.71%)and 1 404(78.88%) respectively, basing on the 2007 guidelines; whereas basing on the 2013 ASCO/CAP HER2 guidelines, the number of HER2 positive, equivocal and negative case was 360 (20.22%), 182 (10.23%)and 1 238 (69.55%) respectively. Compared with the 2007 guidelines, the proportion of positive and equivocal cases were higher in the 2013 guidelines (17.41% versus 20.22%, 3.71% versus 10.23% respectively), while the proportion of negative cases was lower(78.88% versus 69.55%). CONCLUSIONS: Using the 2013 ASCO/CAP guidelines could lead to an increase in positive and equivocal cases, and a decrease in negative cases. The increase can probably be attributable to the inclusion of HER2 copy number besides HER2/CEP17 ratio as positive criteria, and it improves the accuracy and may be of important value for screening more population who benefit from HER2 targeting treatment; however the benefits for HER2 positive with low HER2 copy number and the clinical significance of the equivocal cases need to be further investigated. PMID- 27510781 TI - [Expression and clinical significance of moesin and E-cadherin in invasive carcinoma of breast, no specific type]. AB - OBJECTIVE: To investigate the correlation of moesin and E-cadherin with biological behavior of breast cancer and its mechanism by comparing expression of moesin and E-cadherin in breast invasive carcinoma of no specific type(BIC-NST), breast ductal carcinoma in situ(BDCIS) and normal breast tissues adjacent to carcinoma. METHODS: Breast cancer cases of the Huizhou Municipal Center People Hospital were collected between Jan 2008 and Dec 2010, expression of moesin and E cadherin in 104 cases of BIC-NST, 84 cases of BDCIS and 53 cases of normal breast tissues adjacent to carcinoma were detected by tissue-microarray and SP immunohistochemical staining. Western blot was used to detect moesin expression of 16 BIC-NST fresh tissues. RESULTS: Expression rate of moesin in BIC-NST and BDCIS were significantly higher than normal tissues(P<0.01), but the expression rate of E-cadherin in BIC-NST and BDCIS were significantly lower than those of normal tissues(P<0.01). Expression rate of moesin in BIC-NST grade III group was significantly higher than that of the grade I group.There was a significantly positive correlation between histological grade and moesin expression(P<0.05). However, E-cadherin expression rate in BIC-NST grade III group was significantly lower than that in grade I group , and there was a significantly negative correlation between histological grade and E-cadherin expression(P<0.05). Moreover, no significant correlation was observed between moesin and E-cadherin expression in BDCIS tissues. Expression of moesin in clinical stage II + III BIC NST was significantly higher than that in stage I(P<0.01) . Expression of moesin was significantly associated with lymph node metastasis (P<0.01). But no significant correlation was observed between moesin expression and age, tumor size and vascular invasion . However, expression of E-cadherin in clinical stage II+ III BIC-NST was significantly lower than that in stage I(P<0.01). Expression of E-cadherin was significantly associated with lymph node metastasis and vascular invasion (P<0.01). But no significant correlation was observed between E cadherin expression, age and tumor size. There was a negative correlation between expression of moesin and E-cadherin in BIC-NST(P=0.021)and BDCIS(P=0.032). CONCLUSION: Higher moesin and lower E-cadherin signal transduction is closely related to the recurrence and development of breast carcinoma, therefore moesin and E-cadherin might provide new targets for gene therapy in breast carcinoma. PMID- 27510782 TI - [Clinicopathologic analysis of extranodal Rosai-Dorfman disease of breast: a report of 12 cases]. AB - OBJECTIVE: To investigate the clinicopathologic features, diagnosis and differential diagnosis of extranodal Rosai-Dorfman disease(RDD)of the breast. METHODS: Twelve cases of extranodal RDD of the breast were analyzed using hematoxylin-eosin stain and immunohistochemical staining.The morphological features and immunophenotype were observed by light microscopy, accompanied with a review of the literature. RESULTS: Twelve cases of extranodal RDD of the breast are presented. The patients were women and their ages ranged from 15 to 55 years (mean =37 years). Except one patient with involvement of the right breast and ipsilateral axillary lymph nodes, other eleven patients' disease confined to the breast. Seven cases located in the right breast, the other five cases in the left breast. Microscopically, it showed a typical morphology, characterized by diffuse infiltration of large histiocytes, lymphocytes and plasmocytes that formed irregular nodular structure with light and dark appearance under microscope. Spindling of histiocytosis often arranged in a vague storiform with prominent fibrosis, accumulation of foamy histiocytes and scattered atypical nuclei. The characteristic histocytes and emperipolesis could not be seen obviously in extranodal RDD of the breast.Immunohistochemical staining showed histocytes were strongly positive for S-100 protein, CD68 and CD163, while negative for CD1a. CONCLUSIONS: Extranodal RDD of the breast is very rare. Because of unconspicuous emperipolesis and lack of specificity in clinic and images, extranodal RDD of the breast is easy to be misdiagnosed as other histiocytosis. The microscopic differential diagnosis includes idiopathic granulomatous mastitis, infective granulomas, langerhans cell histiocytosis, IgG4 related sclerosing disease, Erdheim-Chester disease, benign fibrous histiocytoma, malignant fibrous histiocytoma and Hodgkin Lymphoma. Light and dark appearance under microscope is the important clue in diagnosis of extranodal RDD in breast. Immunohistochemistry is also helpful. PMID- 27510783 TI - [Expression of long non-coding RNA MALAT1 in osteosarcoma and its effect on invasiveness and metastatic potential of osteosarcoma cells]. AB - OBJECTIVE: To investigate the significance of long non-coding RNA MALAT1 expression in osteosarcoma, and the potential mechanism by which MALAT1 promotes tumor metastasis. METHODS: Twenty cases of osteosarcoma in the First Affiliated Hospital of Xinxiang Medical University and Ping Ding Shan First People's Hospital were collected from January 2014 to December 2015. The expression of MALAT1 in osteosarcoma tissue and paired adjacent noncancerous tissue were analyzed by qRT-PCR. Correlation of MALAT1 expression in osteosarcoma with clinical pathologic features was performed by the Mann-Whitney U test. U-2OS cells were transfected with lenti-virus carrying MALAT1-shRNA and nonspecific shRNA (LV-vector). The expression of MALAT1 was detected by qRT-PCR. The cell activity was evaluated by MTT asssy. The impact of MALAT1-shRNA on invasion in U 2OS cells were determined by transwell migration assay. The expression of Wnt/beta-catenin signal pathway related proteins were detected by Immunofluorescence stain and Western blot. RESULTS: The expression level of MALAT1 in osteosarcoma tissue was higher than that in paired adjacent noncancerous tissue and correlated significantly with nodal and pulmonary metastasis(P<0.01). MTT assay showed that knockdown of MALAT1 with lenti virus MALAT1 shRNA inhibited the growth of U-2OS cells, along with marked decrease of invasive ability of U-2OS cells in the transwell migration assay. By immunofluorescence stain and Western blot assay, MALAT1 significantly reduced the expression of beta-catenin, MMP7, and c-MYC in U-2OS cells. CONCLUSIONS: The expression of MALAT1 is high in osteosarcoma and correlates with tumor metastasis. MALAT1 promotes invasion and metastasis of osteosarcoma cells likely thought the Wnt/beta-catenin signal pathway. PMID- 27510784 TI - [Application of BRAF V600E mutation-specific immunohistochemistry in diagnosis of gastrointestinal stromal tumors]. AB - OBJECTIVE: To evaluate the utility of BRAF V600E allele-specific antibody in the diagnosis of gastrointestinal stromal tumors (GISTs). METHODS: BRAF V600E mutation-specific immunohistochemistry and BRAF sequencing were performed in 24 consecutive GISTs, including 14 cases of KIT or PDGFRA mutations and 10 cases of KIT/PDGFRA wild GISTs. RESULTS: GISTs of 11 men and 13 women with a mean age 54 years(range 29-75 years) were included with tumors arising from stomach (16 cases), small bowel (7 cases), and peritoneal cavity (1 case). Strong and diffuse cytoplasmic BRAF staining was noted in 4 of 24 cases (17%), while 1 of 24 cases (4%) showed weak staining, and 19 of 24 cases (79%) had no staining. The four cases with strong BRAF immunostain were confirmed to have BRAF mutations, including 3 cases in the stomach and 1 case in the small intestine. All tumors showed spindle cell morphology. Only one case had progressive disease. No BRAF mutations were detected in cases with weak or negative BRAF immunostain. CONCLUSION: BRAF V600E mutation-specific immunohistochemistry is a highly sensitive and specific marker for detecting BRAF-mutated GISTs. PMID- 27510786 TI - [Clinicopathologic study of chordoid glioma of third ventricle: a report of 5 cases]. PMID- 27510785 TI - [ARID1A expression of SWI/SNF remodeling complex in pancreatic neuroendocrine tumor]. AB - OBJECTIVE: To study ARID1A expression and its role in pancreatic neuroendocrine tumors. METHODS: 51 cases of pancreatic neuroendocrine tumors were collected from July 2003 to May 2012 from Peking Union Medical College Hospital.Eighteen normal pancreatic tissues were used as positive control. HE staining method was used to observe general clinicopathological features. ARID1A expression was detected immunohistochemically by EnVision method. The relationship between ARID1A expression and tumor grade and stage was analyzed. RESULTS: The level of ARID1A expression was not associated with patients' gender, age, TNM stage, and tumor size (P>0.05); but showed significantly negative correlation with tumor grade (P<0.05). CONCLUSIONS: Low ARID1A expression was significantly related to the high grade level of pancreatic neuroendocrine tumors. It has a certain effect on the clinical classification of pancreatic neuroendocring tumors. ARID1A may play a role as a tumor suppressor gene. PMID- 27510788 TI - [Secretory carcinoma of breast in adult patient with sentinel lymph node metastasis]. PMID- 27510787 TI - [Hyalinizing clear cell carcinoma of salivary gland: a clinicopathologic study]. PMID- 27510789 TI - [Encapsulated papillary carcinoma of breast in male patient: report of a case]. PMID- 27510790 TI - [Primary gastric aggressive fibromatosis: report of a case]. PMID- 27510791 TI - [Research progress on breast intraductal carcinoma infiltration]. PMID- 27510792 TI - [Research progress of ECRG4 genes and molecular mechanism of tumor suppressor]. PMID- 27510793 TI - [Recent progress on estrogen sulfotransferase]. PMID- 27510794 TI - Polycystic ovary syndrome. PMID- 27510795 TI - Object Pragmatics and Language Development. AB - The purpose of this contribution is to investigate the advent of language in the light of the appropriation of the cultural uses of the material objects related to material culture and the constitution of their public and shared meanings linked to their uses. First, we suggest that the Object Pragmatics paradigm offers a framework which allows us to take into account the uses of objects in daily life as a site of social conventions, communication and public and shared meanings. Second, we would like to underline the key role of the adult's mediations in the child's ability to evolve towards linguistic development. This contribution will discuss the notion of scenario involving primarily the object, as a possible semiotic tool to support the child's transition to language. We will finally illustrate that it is possible to take into consideration the mastery of conventional uses of the object in the child's ability to engage in a scenario and then to move towards communication and speech development. These issues will be addressed in the context of a research project which focuses on the observation of children interacting with an adult at 16, 20 and 24 months. These longitudinal data were collected by video in a semi-experimental triadic interaction design. The triadic interaction is considered as a relevant unit for the observation and analysis of the role of material culture in speech development, suggesting the existence of new mechanisms to be taken into account in addition to the interactive conditions largely mentioned in literature. PMID- 27510796 TI - Zone of Proximal Development (ZPD) as an Emergent System: A Dynamic Systems Theory Perspective. AB - This paper sets out to present a novel construal of one of the notions of Vygotskian cultural-historical theory viz., zone of proximal development (ZPD) drawing upon dynamic systems theory. The principal thesis maintains that ZDP is an emergent and dynamic system which is engendered by a dialectical concatenation of psychogenesic and sociogenesic facets of human development over time. It is reasoned that Vygotskian cultural-historical theory of human development, by invoking dialectical logic, has transcended Cartesian substance dualism and in turn has proffered a monistic and process-anchored ontology for emerging becoming of human consciousness. Likewise, it is contended that dynamic systems theory, having assumed fluent flux of reality with a capital R as its ontological axiom, entails a consilience of cognitive and contextual conceptual schemes to describe, explain, and optimize human development. The paper concludes by drawing some interpretive conclusions in regard to ZPD from dynamic systems theory perspective. PMID- 27510797 TI - Chemical modification of extracellular matrix by cold atmospheric plasma generated reactive species affects chondrogenesis and bone formation. AB - The goal of this study was to investigate whether cold plasma generated by dielectric barrier discharge (DBD) modifies extracellular matrices (ECM) to influence chondrogenesis and endochondral ossification. Replacement of cartilage by bone during endochondral ossification is essential in fetal skeletal development, bone growth and fracture healing. Regulation of this process by the ECM occurs through matrix remodelling, involving a variety of cell attachment molecules and growth factors, which influence cell morphology and protein expression. The commercially available ECM, Matrigel, was treated with microsecond or nanosecond pulsed (MUsp or nsp, respectively) DBD frequencies conditions at the equivalent frequencies (1 kHz) or power (~1 W). Recombinant human bone morphogenetic protein-2 was added and the mixture subcutaneously injected into mice to simulate ectopic endochondral ossification. Two weeks later, the masses were extracted and analysed by microcomputed tomography. A significant increase in bone formation was observed in Matrigel treated with MUsp DBD compared with control, while a significant decrease in bone formation was observed for both nsp treatments. Histological and immunohistochemical analysis showed Matrigel treated with MUsp plasma increased the number of invading cells, the amount of vascular endothelial growth factor and chondrogenesis while the opposite was true for Matrigel treated with nsp plasma. In support of the in vivo Matrigel study, 10 T1/2 cells cultured in vitro on MUsp DBD-treated type I collagen showed increased expression of adhesion proteins and activation of survival pathways, which decreased with nsp plasma treatments. These results indicate DBD modification of ECM can influence cellular behaviours to accelerate or inhibit chondrogenesis and endochondral ossification. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27510799 TI - Alkali Metal Salts with Designable Aryltrifluoroborate Anions. AB - Aryltrifluoroborate ([ArBF3](-)) has a designable basic anion structure. Various [ArBF3](-)-based anions were synthesized to create novel alkali metal salts using a simple and safe process. Nearly 40 novel alkali metal salts were successfully obtained, and their physicochemical characteristics, particularly their thermal properties, were elucidated. These salts have lower melting points than those of simple inorganic alkali halide salts, such as KCl and LiCl, because of the weaker interactions between the alkali metal cations and the [ArBF3](-) anions and the anions' larger entropy. Moreover, interestingly, potassium cations were electrochemically reduced in the potassium (meta-ethoxyphenyl)trifluoroborate (K[m-OEtC6H4BF3]) molten salt at 433 K. These findings contribute substantially to furthering molten salt chemistry, ionic liquid chemistry, and electrochemistry. PMID- 27510798 TI - Identification of extracellular miRNA in archived serum samples by next generation sequencing from RNA extracted using multiple methods. AB - miRNAs act as important regulators of gene expression by promoting mRNA degradation or by attenuating protein translation. Since miRNAs are stably expressed in bodily fluids, there is growing interest in profiling these miRNAs, as it is minimally invasive and cost-effective as a diagnostic matrix. A technical hurdle in studying miRNA dynamics is the ability to reliably extract miRNA as small sample volumes and low RNA abundance create challenges for extraction and downstream applications. The purpose of this study was to develop a pipeline for the recovery of miRNA using small volumes of archived serum samples. The RNA was extracted employing several widely utilized RNA isolation kits/methods with and without addition of a carrier. The small RNA library preparation was carried out using Illumina TruSeq small RNA kit and sequencing was carried out using Illumina platform. A fraction of five microliters of total RNA was used for library preparation as quantification is below the detection limit. We were able to profile miRNA levels in serum from all the methods tested. We found out that addition of nucleic acid based carrier molecules had higher numbers of processed reads but it did not enhance the mapping of any miRBase annotated sequences. However, some of the extraction procedures offer certain advantages: RNA extracted by TRIzol seemed to align to the miRBase best; extractions using TRIzol with carrier yielded higher miRNA-to-small RNA ratios. Nuclease free glycogen can be carrier of choice for miRNA sequencing. Our findings illustrate that miRNA extraction and quantification is influenced by the choice of methodologies. Addition of nucleic acid- based carrier molecules during extraction procedure is not a good choice when assaying miRNA using sequencing. The careful selection of an extraction method permits the archived serum samples to become valuable resources for high-throughput applications. PMID- 27510800 TI - Metabolic disturbances in Chinese children with urolithiasis: a single center report. AB - Urinary stones and urine composition are the first steps in the process of recurrence prevention, but data concerning the association between the two compositions are scarce in Chinese children with urolithiasis. We retrospectively analyzed the records of children (age range 0-18 years) with urolithiasis in our center between March 2004 and December 2013. Stone analysis was carried out in 382 children and 24-hour urine analysis in 80 children. Analysis of both stone and 24-hour urine composition was completed in 56 children. Stone samples were analyzed by Fourier transform-infrared spectrometry. The major stone constituents were calcium oxalate (78.8 %). Of 80 children with 24 h urine analysis, only 2.5 % were without urinary metabolic abnormalities. Hypocitraturia was recorded in 97.5 %, high sodium excretion in 50.0 %, cystinuria in 48.7 %, hypercalciuria in 18.8 %, small urine volumes in 12.5 %, hyperoxaluria in 5.0 % and hyperuricosuria in 1.3 %. Interestingly, higher urine volumes were recorded in girls than in boys (73.2 +/- 58.5 vs 51.3 +/- 45.3 mL/kg, p = 0.036). Urine sodium (p = 0.002) and oxalate (p = 0.004) were significantly higher in children >9 year old. Moreover, compared with calcium oxalate stone formers, the urine volume (p = 0.040), citrate (p = 0.007) and cystine (p = 0.004) were higher in patients with cystine stones. Hypocitraturia was the common abnormality among Chinese children with urolithiasis. The surprisingly high incidence of cystinuria is of note. PMID- 27510802 TI - Meaningless METS: studying the link between physical activity and health. PMID- 27510801 TI - Structure-5-HT/D2 Receptor Affinity Relationship in a New Group of 1 Arylpiperazynylalkyl Derivatives of 8-Dialkylamino-3,7-dimethyl-1H-purine 2,6(3H,7H)-dione. AB - In our previous papers, we have reported that some 8-amino-1,3-dimethyl-1H-purine 2,6(3H,7H)-dione derivatives possessed high affinity and displayed agonistic, partial agonistic, or antagonistic activity for serotonin 5-HT1A and dopamine D2 receptors. In order to examine further the influence of the substituent in the position 8 of the purine moiety and the influence of the xanthine core on the affinity for serotonin 5-HT1A , 5-HT2A , 5-HT6 , 5-HT7 , and dopamine D2 receptors, two series of 1-arylpiperazynylalkyl derivatives of 8-amino-3,7 dimethyl-1H-purine-2,6(3H,7H)-dione were synthesized. All the final compounds were investigated in in vitro competition binding experiments for the serotonin 5 HT1A , 5-HT2A , 5-HT6 , 5-HT7 , and dopamine D2 receptors. The structure-affinity relationships for this group of compounds were discussed. For selected compounds, the functional assays for the 5-HT1A and D2 receptors were carried out. The results of the assays indicated that these groups of derivatives possessed antagonistic activity for 5-HT1A receptors and agonistic, partial agonistic, or antagonistic activity for D2 receptors. In total, 26 new compounds were synthesized, 20 of which were tested in in vitro binding experiments and 5 were tested in in vitro functional assays. PMID- 27510803 TI - Identification of Siglec-1 null individuals infected with HIV-1. AB - Siglec-1/CD169 is a myeloid-cell surface receptor critical for HIV-1 capture and infection of bystander target cells. To dissect the role of SIGLEC1 in natura, we scan a large population genetic database and identify a loss-of-function variant (Glu88Ter) that is found in ~1% of healthy people. Exome analysis and direct genotyping of 4,233 HIV-1-infected individuals reveals two Glu88Ter homozygous and 97 heterozygous subjects, allowing the analysis of ex vivo and in vivo consequences of SIGLEC1 loss-of-function. Cells from these individuals are functionally null or haploinsufficient for Siglec-1 activity in HIV-1 capture and trans-infection ex vivo. However, Siglec-1 protein truncation does not have a measurable impact on HIV-1 acquisition or AIDS outcomes in vivo. This result contrasts with the known in vitro functional role of Siglec-1 in HIV-1 trans infection. Thus, it provides evidence that the classical HIV-1 infectious routes may compensate for the lack of Siglec-1 in fuelling HIV-1 dissemination within infected individuals. PMID- 27510804 TI - Delivery of an Adeno-Associated Virus Vector into Cerebrospinal Fluid Attenuates Central Nervous System Disease in Mucopolysaccharidosis Type II Mice. AB - Mucopolysaccharidosis type II (MPS II) is a rare X-linked genetic disorder caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), leading to impaired catabolism of ubiquitous polysaccharides and abnormal accumulation of these undegraded substrates in the lysosome. Like many lysosomal storage diseases, MPS II is characterized by both somatic and central nervous system (CNS) involvement. Intravenous enzyme replacement therapy can improve somatic manifestations of MPS II, but systemic IDS does not cross the blood-brain barrier and therefore cannot address CNS disease. In this study, an adeno-associated virus serotype 9 vector carrying the IDS gene was injected into the cerebrospinal fluid (CSF) of IDS deficient mice, a model of MPS II. Treated mice exhibited dose dependent IDS expression and resolution of brain storage lesions, as well as improvement in long-term memory in a novel object recognition test. These findings suggest that delivery of adeno-associated virus vectors into CSF could serve as a platform for efficient, long-term enzyme delivery to the CNS, potentially addressing this critical unmet need for patients with MPS II and many related lysosomal enzyme deficiencies. PMID- 27510805 TI - Pickering emulsions stabilized by charged nanoparticles. AB - The stabilization of o/w Pickering emulsions in cases of weak adsorption of solid particles at the surface of oil droplets is addressed. Though the adsorption is usually very strong and irreversible when partial wetting conditions are fulfilled, electrostatic repulsions between charged solid particles act against the adsorption. The regime of weak adsorption was reached using charged silica nanoparticles at high pH and low ionic strength. O/w Pickering emulsions of the diisopropyl adipate oil were stabilized by colloidal nanoparticles of Ludox(r) AS40 consisting of non-aggregated particles of bare silica (hydrophilic). The combination of stability assessment, droplet size and electrokinetic potential measurements at various pH values, adsorption isotherms and cryo-SEM observations of the adsorbed layers disclosed the specificities of the stabilization of Pickering emulsions by adsorption of solid nanoparticles against strong electrostatic repulsions. Not only the long-term stability of emulsions was poor under strong electrostatic repulsions at high pH, but emulsification failed since full dispersion of oil could not be achieved. Emulsion stability was ensured by decreasing electrostatic repulsions by lowering the pH from 9 to 3. Stable emulsions were stabilized by a monolayer of silica particles at 54% coverage of the oil droplet surface at low silica content and an adsorption regime as multilayers was reached at higher concentrations of silica although there was no aggregation of silica in the bulk aqueous phase. PMID- 27510806 TI - Total Synthesis of (-)-Spinosyn A via Carbonylative Macrolactonization. AB - Spinosyn A (1), a complex natural product featuring a unique 5,6,5,12-fused tetracyclic core structure, is the major component of spinosad, an organic insecticide and an FDA-approved agent used worldwide. Herein, we report an efficient total synthesis of (-)-spinosyn A with 15 steps in the longest linear sequence and 23 steps total from readily available compounds 14 and 23. The synthetic approach features several important catalytic transformations including a chiral amine-catalyzed intramolecular Diels-Alder reaction to afford 22 in excellent diastereoselectivity, a one-step gold-catalyzed propargylic acetate rearrangement to convert 28 to alpha-iodoenone 31, an unprecedented palladium catalyzed carbonylative Heck macrolactonization to form the 5,12-fused macrolactone in one step, and a gold-catalyzed Yu glycosylation to install the challenging beta-forosamine. This total synthesis is highly convergent and modular, thus offering opportunities to synthesize spinosyn analogues in order to address the emerging cross-resistance problems. PMID- 27510807 TI - Improving the productivity of S-adenosyl-l-methionine by metabolic engineering in an industrial Saccharomyces cerevisiae strain. AB - S-Adenosyl-l-methionine (SAM) is an important metabolite having prominent roles in treating various diseases. In order to improve the production of SAM, the regulation of three metabolic pathways involved in SAM biosynthesis were investigated in an industrial yeast strain ZJU001. GLC3 encoded glycogen branching enzyme (GBE), SPE2 encoded SAM decarboxylase, as well as ERG4 and ERG6 encoded key enzymes in ergosterol biosynthesis, were knocked out in ZJU001 accordingly. The results indicated that blocking of either glycogen pathway or SAM decarboxylation pathway could improve the SAM accumulation significantly in ZJU001, while single disruption of either ERG4 or ERG6 gene had no obvious effect on SAM production. Moreover, the double mutant ZJU001-GS with deletion of both GLC3 and SPE2 genes was also constructed, which showed further improvement of SAM accumulation. Finally, SAM2 was overexpressed in ZJU001-GS to give the best SAM producing recombinant strain ZJU001-GS-SAM2, in which 12.47g/L SAM was produced by following our developed pseudo-exponential fed-batch cultivation strategy, about 81.0% increase comparing to its parent strain ZJU001. The present work laid a solid base for large-scale SAM production with the industrial Saccharomyces cerevisiae strain. PMID- 27510808 TI - Engineered Upconversion Nanoparticles for Resolving Protein Interactions inside Living Cells. AB - Upconversion nanoparticles (UCNPs) convert near-infrared into visible light at much lower excitation densities than those used in classic two-photon absorption microscopy. Here, we engineered <50 nm UCNPs for application as efficient lanthanide resonance energy transfer (LRET) donors inside living cells. By optimizing the dopant concentrations and the core-shell structure for higher excitation densities, we observed enhanced UCNP emission as well as strongly increased sensitized acceptor fluorescence. For the application of these UCNPs in complex biological environments, we developed a biocompatible surface coating functionalized with a nanobody recognizing green fluorescent protein (GFP). Thus, rapid and specific targeting to GFP-tagged fusion proteins in the mitochondrial outer membrane and detection of protein interactions by LRET in living cells was achieved. PMID- 27510810 TI - One-year Survey of human enteroviruses from sewage and the factors affecting virus adsorption to the suspended solids. AB - This study described the results of environmental enterovirus surveillance conducted in Shandong Province of China in 2013. Altogether 39 sewage samples were collected and 873 enterovirus isolates (including 334 polioviruses) belonging to 22 serotypes were obtained. Echovirus (E) -7, coxsackievirus (CV) B5, E-11, E-6, and E-3 were the most commonly detected non-polio enterovirus serotypes, and phylogeny of E-7 and CV-B5 was described. The numbers of isolates of different serotypes from sewage supernatant were compared with those from the solids. Interestingly, dramatic divergence was observed between the supernatant and solids origin for the serotypes of E-3 and E-6, which were prone to the solids and supernatant, respectively. A following adsorption test with E-3 and E 6 added sewage specimens confirmed the different preference. Furthermore, the adsorption of Sabin poliovirus type 1 to the solids under different conditions was investigated, and the results showed that acid medium, cold temperature, and high solids concentration facilitated the viral adsorption to the solids, whereas change of virus titer did not influence the proportion of adsorption. These results highlighted the importance of combining the enterovirus isolates from the supernatant and solids together in environmental surveillance so as to better understand the local circulation of different serotypes. PMID- 27510812 TI - Renal failure in dogs kept by a man with severe psoriasis. PMID- 27510813 TI - Experiences of Prenatal Genetic Screening and Diagnostic Testing Among Pregnant Korean Women of Advanced Maternal Age. AB - PURPOSE: This study explored the experiences of Korean women of advanced maternal age undergoing prenatal genetic screening and diagnostic testing. DESIGN: A descriptive, qualitative design was used to guide the study. METHOD: Ten participants were purposely recruited from a large metropolitan Korean hospital for clinical observations and individual, semistructured interviews. The content analysis method was used to analyze field notes and interview transcripts. FINDINGS: Three themes emerged: reacting to an unfavorable screening result, dealing with the anticipated consequences of diagnostic testing, and realistically embracing the unborn child. CONCLUSIONS: The findings of this study inform the development of tailored interventions aimed at reducing the heavy emotional burdens placed on pregnant women and the stigma of bearing children with genetic conditions. Clear reciprocal communication and shared decision making should be promoted in the day-to-day practice of delivering health care for pregnant Korean women. PMID- 27510811 TI - Ca2+ transport and signalling in enamel cells. AB - Dental enamel is one of the most remarkable examples of matrix-mediated biomineralization. Enamel crystals form de novo in a rich extracellular environment in a stage-dependent manner producing complex microstructural patterns that are visually stunning. This process is orchestrated by specialized epithelial cells known as ameloblasts which themselves undergo striking morphological changes, switching function from a secretory role to a cell primarily engaged in ionic transport. Ameloblasts are supported by a host of cell types which combined represent the enamel organ. Fully mineralized enamel is the hardest tissue found in vertebrates owing its properties partly to the unique mixture of ionic species represented and their highly organized assembly in the crystal lattice. Among the main elements found in enamel, Ca2+ is the most abundant ion, yet how ameloblasts modulate Ca2+ dynamics remains poorly known. This review describes previously proposed models for passive and active Ca2+ transport, the intracellular Ca2+ buffering systems expressed in ameloblasts and provides an up-dated view of current models concerning Ca2+ influx and extrusion mechanisms, where most of the recent advances have been made. We also advance a new model for Ca2+ transport by the enamel organ. PMID- 27510814 TI - Parenting African American Children With Autism: The Influence of Respect and Faith in Mother, Father, Single-, and Two-Parent Care. AB - PURPOSE: Parents are the most significant contributor to care of children with autism spectrum disorder (ASD), and as such research on African American parenting in ASD is conspicuously absent. Findings relevant to parenting are discussed from a study with urban African American families caring for children with ASD. DESIGN: An ethnonursing study was conducted with 24 African American family members of children with ASD and 28 professionals. Data were analyzed and reported as themes. FINDINGS: Two universal themes of were found of respect and faith in God and family that influenced parental care. Two diverse themes of mother's watchful care and father's protective care, along with differences in feelings of isolation and dependence on supports were found among single- and two parent families. DISCUSSION AND PRACTICE IMPLICATIONS: When health care professionals increase their knowledge and understanding of cultural practices in the parental care of children with ASD, they provide health care that is culturally congruent. PMID- 27510815 TI - Asymmetrical reproductive interference between two sibling species of tea looper: Ectropis grisescens and Ectropis obliqua. AB - Ectropis grisescens Warren and Ectropis obliqua (Prout) are two morphologically similar sibling species with overlapping ranges. In this study, manipulative laboratory experiments were conducted to examine the possibility of reproductive interference in sympatric populations of E. grisescens and E. obliqua and the potential consequences of the mating interaction. Our results showed that the presence of males or females of different species could incur mating interference and significant reduction of F 1 offspring. The reduction was not significant relevant to the initial relative abundance of E. grisescens and E. obliqua. Detailed observations of mating opportunity showed that female mating frequencies of both species were not significantly affected by the absolute species density, but the mating success of E. obliqua females with conspecific males depended on species ratio. In addition, adding males to the other species resulted in lower number of offspring suggesting that the males' behaviour might be linked with mating interference. Males of both E. grisescens and E. obliqua could interfere the intraspecific mating of the other species, but the impact of the mating interference differed. These combined data indicated that asymmetric reproductive interference existed in E. grisescens and E. obliqua under laboratory conditions, and the offspring of the mixed species were significantly reduced. The long term outcome of this effect is yet to be determined since additional reproductive factors such as oviposition rate and progeny survival to adulthood may reduce the probability of demographic displacement of one species by the other in overlapping niches. PMID- 27510816 TI - Safety and efficacy of rush allergen-specific immunotherapy in Chinese allergic rhinitis patients. AB - The purpose of this prospective, open-IV clinical trial was to assess the safety and efficacy differences between Rush immunotherapy (RIT) and conventional immunotherapy in Chinese allergic rhinitis (AR) patients. The trial involved 174 patients with AR. They were divided into two groups according to their preference of therapy: RIT or conventional immunotherapy. A total of 162 patients completed a 1-year treatment course. For safety and effectiveness evaluation, the local and systemic adverse reactions were recorded throughout the initial phase of both groups. Weeks 0, 2, 5, and 17 were set as observation time points for immunoglobulin G (IgG) and IgG4. Besides that, another observation time point (Week 11) was added in for a visual analog scale (VAS) and a weekly drug dosage scale. In the RIT group, systemic adverse events of AR were similar to those of the conventional therapy group. LTB4 was descended. The VAS of the RIT group did not show a downward trend clearly, instead Week 5 was higher compared with Week 0. The weekly drug dosage scale did not indicate a significant decline, but there was a clear rise in IgG4 in the RIT group. The safety and efficacy of RIT for AR is positive, but further study is needed for improvement. PMID- 27510817 TI - Kruppel-like factor 6 suppresses growth and invasion of hepatocellular carcinoma cells in vitro and in vivo. AB - Kruppel-like factor 6 (KLF6) as a novel tumor suppressive gene participates in multiple biological behaviors and plays an important role in regulating tumor cell growth and invasion. However, the functions of KLF6 in hepatocellular carcinoma (HCC) remain poorly understood. The expression level of KLF6 was examined by immunohistochemical assay in human HCC tissues, and KLF6 overexpressed HCC cells (SMCC-7721 and HepG2) were used for evaluating cell proliferation and invasion by MTT and Transwell assays. A subcutaneous HCC tumor model was established for assessing tumor growth in vivo. Our results showed that the expression of KLF6 was significantly downregulated in HCC tissues compared with the adjacent non-cancerous tissues (50.0% vs. 72.0%, P = 0.034) and negatively associated with the lymph-vascular space invasion (LVSI) in HCC patients (P = 0.003). Furthermore, overexpression of KLF6 reduced cell proliferation and weakened the cell invasive potential followed with the decreased expression of PCNA and MMP-9 in HCC cells. The in vivo experiment indicated that KLF6 overexpression suppressed the xenograft tumor growth. Therefore, our findings show that KLF6 suppresses growth and invasion of HCC cells in vitro and in vivo, suggesting a tumor suppressive function in HCC and provides the potential therapeutic target for the treatment of HCC. PMID- 27510818 TI - The effect of HDL-bound and free PON1 on copper-induced LDL oxidation. AB - Oxidative modification of LDL plays an important role in the development of atherosclerosis. High-density lipoprotein (HDL) confers protection against atherosclerosis and the antioxidative properties of paraoxonase 1 (PON1) has been suggested to contribute to this effect of HDL. The PON1 exist in two major polymorphic forms (Q and R), which regulate the concentration and activity of the enzyme and alter its ability to prevent lipid oxidation. However, the association of Q192R polymorphism with PON1's capacity to protect against LDL lipoperoxidation is controversial. The aim of this study was to evaluate the effects of the purified PON1 Q192R and the partially purified HDL-bound PON1 Q192R isoenzymes (HDL-PON1 Q192R) on LDL oxidation, with respect to their arylesterase/homocysteine thiolactonase (HTLase) activities. Cupric ion-induced LDL oxidation was reduced up to 48% by purified PON1 Q192, but only 33% by an equivalent activity of PON1 R192. HDL-PON1 Q192 isoenzyme caused a 65% reduction, whereas HDL-PON1 R192 isoenzyme caused only 46% reduction in copper ion-induced LDL oxidation. These findings reflect the fact that PON1 Q and PON1 R allozymes may have different protective characteristics against LDL oxidation. The protection against LDL oxidation provided by HDL-PON1 Q192R isoenzymes is more prominent than the purified soluble enzymes. Inhibition of the Ca(+2)-dependent PON1 Q192R arylesterase/HTLase by the metal chelator EDTA, did not alter PON1's ability to inhibit LDL oxidation. These studies indicate that the active site involvement of the purified enzyme is not similar to the HDL-bound one, in terms of both PON1 arylesterase/HTLase activity and the protection of LDL from copper ion-induced oxidation. Moreover, PON1's ability to protect LDL from oxidation does not seem to require calcium. PMID- 27510819 TI - Efficient Room-Temperature Activation of Methane by TaN(+) under C-N Coupling. AB - The thermal reaction of diatomic tantalum nitride cation [TaN](+) with methane has been explored using FT-ICR mass spectrometry complemented by high-level quantum chemical calculation; based on this combined experimental/computational approach, mechanistic aspects of this novel, highly efficient C-N coupling process have been uncovered. In distinct contrast to [TaN](+) , its lighter congeners [VN](+) and [NbN](+) are inert towards methane under ambient conditions, and the origins of the remarkably variable efficiencies of the three metal nitrides are uncovered by CCSD(T) calculations. PMID- 27510820 TI - Predictors of stereoacuity outcome in visually mature subjects with exotropia. PMID- 27510821 TI - Conflicts over host manipulation between different parasites and pathogens: Investigating the ecological and medical consequences. AB - When parasites have different interests in regard to how their host should behave this can result in a conflict over host manipulation, i.e. parasite induced changes in host behaviour that enhance parasite fitness. Such a conflict can result in the alteration, or even complete suppression, of one parasite's host manipulation. Many parasites, and probably also symbionts and commensals, have the ability to manipulate the behaviour of their host. Non-manipulating parasites should also have an interest in host behaviour. Given the frequency of multiple parasite infections in nature, potential conflicts of interest over host behaviour and manipulation may be common. This review summarizes the evidence on how parasites can alter other parasite's host manipulation. Host manipulation can have important ecological and medical consequences. I speculate on how a conflict over host manipulation could alter these consequences and potentially offer a new avenue of research to ameliorate harmful consequences of host manipulation. PMID- 27510822 TI - DL-ADR: a novel deep learning model for classifying genomic variants into adverse drug reactions. AB - BACKGROUND: Genomic variations are associated with the metabolism and the occurrence of adverse reactions of many therapeutic agents. The polymorphisms on over 2000 locations of cytochrome P450 enzymes (CYP) due to many factors such as ethnicity, mutations, and inheritance attribute to the diversity of response and side effects of various drugs. The associations of the single nucleotide polymorphisms (SNPs), the internal pharmacokinetic patterns and the vulnerability of specific adverse reactions become one of the research interests of pharmacogenomics. The conventional genomewide association studies (GWAS) mainly focuses on the relation of single or multiple SNPs to a specific risk factors which are a one-to-many relation. However, there are no robust methods to establish a many-to-many network which can combine the direct and indirect associations between multiple SNPs and a serial of events (e.g. adverse reactions, metabolic patterns, prognostic factors etc.). In this paper, we present a novel deep learning model based on generative stochastic networks and hidden Markov chain to classify the observed samples with SNPs on five loci of two genes (CYP2D6 and CYP1A2) respectively to the vulnerable population of 14 types of adverse reactions. METHODS: A supervised deep learning model is proposed in this study. The revised generative stochastic networks (GSN) model with transited by the hidden Markov chain is used. The data of the training set are collected from clinical observation. The training set is composed of 83 observations of blood samples with the genotypes respectively on CYP2D6*2, *10, *14 and CYP1A2*1C, *1 F. The samples are genotyped by the polymerase chain reaction (PCR) method. A hidden Markov chain is used as the transition operator to simulate the probabilistic distribution. The model can perform learning at lower cost compared to the conventional maximal likelihood method because the transition distribution is conditional on the previous state of the hidden Markov chain. A least square loss (LASSO) algorithm and a k-Nearest Neighbors (kNN) algorithm are used as the baselines for comparison and to evaluate the performance of our proposed deep learning model. RESULTS: There are 53 adverse reactions reported during the observation. They are assigned to 14 categories. In the comparison of classification accuracy, the deep learning model shows superiority over the LASSO and kNN model with a rate over 80 %. In the comparison of reliability, the deep learning model shows the best stability among the three models. CONCLUSIONS: Machine learning provides a new method to explore the complex associations among genomic variations and multiple events in pharmacogenomics studies. The new deep learning algorithm is capable of classifying various SNPs to the corresponding adverse reactions. We expect that as more genomic variations are added as features and more observations are made, the deep learning model can improve its performance and can act as a black-box but reliable verifier for other GWAS studies. PMID- 27510823 TI - Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update. AB - Children with constitutional trisomy 21 (Down syndrome (DS)) have a unique predisposition to develop myeloid leukaemia of Down syndrome (ML-DS). This disorder is preceded by a transient neonatal preleukaemic syndrome, transient abnormal myelopoiesis (TAM). TAM and ML-DS are caused by co-operation between trisomy 21, which itself perturbs fetal haematopoiesis and acquired mutations in the key haematopoietic transcription factor gene GATA1. These mutations are found in almost one third of DS neonates and are frequently clinically and haematologcially 'silent'. While the majority of cases of TAM undergo spontaneous remission, ~10 % will progress to ML-DS by acquiring transforming mutations in additional oncogenes. Recent advances in the unique biological, cytogenetic and molecular characteristics of TAM and ML-DS are reviewed here. PMID- 27510824 TI - Spontaneous ovarian hyperstimulation syndrome in a young female subject with a lingual thyroid and primary hypothyroidism. PMID- 27510825 TI - Safety and efficacy of polyetheretherketone (PEEK) cages in combination with posterior pedicel screw fixation in pyogenic spinal infection. AB - BACKGROUND: To date, there is growing consensus that PEEK material may be used for interbody fusion in spinal infections. Data supporting that claim are however restricted to a few very small clinical series. The aim of this study is to evaluate the outcome of surgical treatment of pyogenic spinal infections with PEEK cages in combination with posterior pedicel screw fixation. METHODS: Between 2006 and 2013, a total of 211 patients suffering from spondylodiscitis underwent surgical debridement and instrumentation. There were 52 cases where PEEK cages were used. Laboratory and physical examinations were assessed at a 3-month follow up. Last follow-up was performed with at a minimum of 12 months after surgery via a telephone interview. RESULTS: Mean age at presentation was 67 years, with 19 (37 %) male patients and 33 (63 %) female. Distribution of the infection was lumbar in 29 (56 %%), thoracic in 3 (6 %) and cervical in 11 (21 %) cases. Nine patients (17 %) had concomitant non-contiguous spondylodiscitis. Epidural abscess was found in 17 patients (33 %); 48 (92 %%) had pain; neurological deficits were found in 20 patients (38 %). All patients in this series underwent surgical debridement with instrumentation of the spine. Postoperative intravenous antibiotics were administered for 15.4 +/- 6.8 days followed by 2.9 +/- 0.5 months of oral antibiotics. Complete resolution of the infection was achieved in all cases. Of the 28 patients with neurological deficits, 6 had full recovery and 10 had improved incompletely after surgery. One patient suffered from a pulmonary embolism postoperatively. There were no mortalities. CONCLUSIONS: Use of PEEK cages for interbody fusion is feasible and safe in patients suffering from a pyogenic spinal infection. PMID- 27510826 TI - Cystic meningioma: radiological, histological, and surgical particularities in 43 patients. AB - BACKGROUND: The presence of cysts is a rare occurrence for intracranial meningiomas in adults. We report our experience in a large consecutive series of cystic meningiomas. METHOD: We prospectively collected data for a dedicated database of cystic meningioma cases between January 2004 and December 2011 in two tertiary neurosurgical centers. Studied data included preoperative imaging, surgical records, and pathology reports. RESULTS: Among 1214 surgeries for intracranial meningioma, we identified 43 cases of cystic meningioma, corresponding to an incidence of 3.5 %. The most common localization was the hemispheric convexity (17/43 cases). Twenty-eight patients had intratumoral cysts, nine peritumoral, and five mixed intra and extratumoral. In 29 patients with available diffusion imaging, ADC coefficients were significantly lower in grade II-III tumors compared to grade I (p = 0.01). Complete resection of the cystic components was possible in 27/43 patients (63 %); partial resection in 4/43 (9 %); in 6/43 (14 %) cyst resection was not possible but multiple biopsies were performed from the cystic walls; in another 6/43 (14 %) the cystic wall was not identified during surgery. Cells with neoplastic features were identified within the cyst walls at pathology in 26/43 cases (60 %). All patients were followed-up for 24 months; long-term follow-up was available only in 32 patients for an average period of 49 months (range, 36-96 months). No recurrence requiring surgery was observed. CONCLUSIONS: Cystic meningiomas are rare. Cells with neoplastic features are often identified within the cyst walls. Complete cyst resection is recommendable when considered technically feasible and safe. PMID- 27510827 TI - Comparison of Mechanical Disruption Techniques for Rapid Inactivation of Mycobacterium and Nocardia Species before Identification Using Matrix-Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) Mass Spectrometry. PMID- 27510828 TI - Next-Generation Sequencing: a Diagnostic One-Stop Shop for Hepatitis C? AB - Before starting chronic hepatitis C treatment, the viral genotype/subtype has to be accurately determined and potentially coupled with drug resistance testing. Due to the high genetic variability of the hepatitis C virus, this can be a demanding task that can potentially be streamlined by viral whole-genome sequencing using next-generation sequencing as demonstrated by an article in this issue of the Journal of Clinical Microbiology by E. Thomson, C. L. C. Ip, A. Badhan, M. T. Christiansen, W. Adamson, et al. (J Clin Microbiol. 54:2455-2469, 2016, http://dx.doi.org/10.1128/JCM.00330-16). PMID- 27510829 TI - Evaluation of Hologic Aptima HIV-1 Quant Dx Assay on the Panther System on HIV Subtypes. AB - Quantitation of the HIV-1 viral load in plasma is the current standard of care for clinical monitoring of HIV-infected individuals undergoing antiretroviral therapy. This study evaluated the analytical and clinical performances of the Aptima HIV-1 Quant Dx assay (Hologic, San Diego, CA) for monitoring viral load by using 277 well-characterized subtype samples, including 171 cultured virus isolates and 106 plasma samples from 35 countries, representing all major HIV subtypes, recombinants, and circulating recombinant forms (CRFs) currently in circulation worldwide. Linearity of the Aptima assay was tested on each of 6 major HIV-1 subtypes (A, B, C, D, CRF01_AE, and CRF02_AG) and demonstrated an R(2) value of >=0.996. The performance of the Aptima assay was also compared to those of the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 v.2 (CAP/CTM) and Abbott m2000 RealTime HIV-1 (RealTime) assays on all subtype samples. The Aptima assay values averaged 0.21 log higher than the CAP/CTM values and 0.30 log higher than the RealTime values, and the values were >0.4 log higher than CAP/CTM values for subtypes F and G and than RealTime values for subtypes C, F, and G and CRF02_AG. Two samples demonstrated results with >1-log differences from RealTime results. When the data were adjusted by the average difference, 94.9% and 87.0% of Aptima results fell within 0.5 log of the CAP/CTM and RealTime results, respectively. The linearity and accuracy of the Aptima assay in correctly quantitating all major HIV-1 subtypes, coupled with the completely automated format and high throughput of the Panther system, make this system well suited for reliable measurement of viral load in the clinical laboratory. PMID- 27510830 TI - Malnutrition Is Associated with Protection from Rotavirus Diarrhea: Evidence from a Longitudinal Birth Cohort Study in Bangladesh. AB - Rotavirus is a leading cause of dehydrating diarrhea and death among infants and children globally, particularly in communities of the developing world. While numerous studies have described the complex relationships among infectious diarrhea, growth faltering, and poverty, the impact of nutritional status on susceptibility to rotavirus diarrhea is not well understood. In a longitudinal study conducted over the first 3 years of life among 626 slum-dwelling infants enrolled at birth in Dhaka, Bangladesh, we observed that common measures of healthy growth and development were positively associated with a risk of symptomatic rotavirus infection. This finding runs counter to the idea that improving childhood nutrition will implicitly decrease the incidence of symptomatic infection by enteric pathogens. As childhood nutrition improves worldwide, rotavirus infection may remain a public health challenge, making universal vaccination of even greater importance. PMID- 27510831 TI - Assuring the Quality of Next-Generation Sequencing in Clinical Microbiology and Public Health Laboratories. AB - Clinical microbiology and public health laboratories are beginning to utilize next-generation sequencing (NGS) for a range of applications. This technology has the potential to transform the field by providing approaches that will complement, or even replace, many conventional laboratory tests. While the benefits of NGS are significant, the complexities of these assays require an evolving set of standards to ensure testing quality. Regulatory and accreditation requirements, professional guidelines, and best practices that help ensure the quality of NGS-based tests are emerging. This review highlights currently available standards and guidelines for the implementation of NGS in the clinical and public health laboratory setting, and it includes considerations for NGS test validation, quality control procedures, proficiency testing, and reference materials. PMID- 27510833 TI - Automatic Digital Plate Reading for Surveillance Cultures. AB - The automation of specimen processing and culture workup has rapidly emerged in clinical microbiology laboratories throughout the world and more recently in the United States. While many U.S. laboratories have implemented some form of automated specimen processing and some have begun performing digital plate reading, automated colony analysis is just beginning to be utilized clinically. In this issue of the Journal of Clinical Microbiology, M. L. Faron et al. (J Clin Microbiol 54:2470-2475, 2016, http://dx.doi.org/10.1128/JCM.01040-16) report the results of their evaluation of the performance of the WASPLab Chromogenic Detection Module (CDM) for categorizing chromogenic agar plates as negative or "nonnegative" for vancomycin-resistant enterococci (VRE). Their major finding was 100% sensitivity for detection of "nonnegative" specimens using CDM compared to manual methods for specimens plated on two different types of VRE chromogenic agar plates. Additionally, utilization of digital plate reading in conjunction with automated colony analysis was predicted to result in significant savings based on greatly reduced labor costs. PMID- 27510834 TI - A review of anesthetic techniques and outcomes following minimally invasive repair of pectus excavatum (Nuss procedure). AB - BACKGROUND: Pectus excavatum (PE) is the most common congenital chest wall deformity, occurring in 1 : 1000 children with a male to female ratio of 4 : 1. Several procedures have been described to manage this deformity, including cartilage resection with sternal osteotomy (the Ravitch procedure) and a minimally invasive repair technique (the Nuss procedure). While initially described as a nonthoracoscopic technique, the current surgical approach of the Royal Childrens Hospital involves thoracoscopic assistance. Postoperative pain is significant in patients undergoing the pectus repair and multiple analgesic regimens have been advocated with continuous thoracic epidural infusions and opioid infusions the most common. Some authors have advocated patient-controlled analgesia (PCA), paravertebral nerve blocks (PVNB), and wound infusion catheters as alternatives. AIMS: The primary aim of this study was to assess our experience with postoperative pain and analgesia requirements associated with the minimally invasive repair of pectus excavatum in children. METHODS: This is a retrospective cohort study with a contemporaneous comparison group examining patients treated between January 2005 and December 2015 for minimally invasive repair of pectus excavatum by the Nuss procedure. RESULTS: Two hundred and seventeen patients [mean age 14.9 (sd 1.9) years] with pectus excavatum treated at the Royal Childrens Hospital between 2005 and 2015 were identified. All patients were managed with thoracic epidural analgesia and intravenous morphine infusions. The epidural was effective in the postanesthesia care unit in 97.3% (failure to place an epidural rate was 4 (1.9%); no block on awakening 0.9%). A further 4 (1.8%) were removed within 24 h. The mean morphine equivalent dose in the first 24 h was 0.8 mg.kg-1 .day-1 . PCA was continued for a mean of 3.8 days and the total mean morphine equivalent dose was 2.2 mg.kg-1 .day-1 . Minor complications occurred in 67 (30.9%) with postoperative nausea and vomiting in 36 patients (16.6%) and urinary retention requiring an indwelling catheter in 40 patients (18.4%). CONCLUSION: An epidural-based analgesic regime is associated with low pain scores and few acute complications. The continuation of morphine analgesia after the first postoperative day is common but associated with an increased incidence of urinary retention and nausea and vomiting. PMID- 27510832 TI - KlebSeq, a Diagnostic Tool for Surveillance, Detection, and Monitoring of Klebsiella pneumoniae. AB - Health care-acquired infections (HAIs) kill tens of thousands of people each year and add significantly to health care costs. Multidrug-resistant and epidemic strains are a large proportion of HAI agents, and multidrug-resistant strains of Klebsiella pneumoniae, a leading HAI agent, have caused an urgent public health crisis. In the health care environment, patient colonization by K. pneumoniae precedes infection, and transmission via colonization leads to outbreaks. Periodic patient screening for K. pneumoniae colonization has the potential to curb the number of HAIs. In this report, we describe the design and validation of KlebSeq, a highly informative screening tool that detects Klebsiella species and identifies clinically important strains and characteristics by using highly multiplexed amplicon sequencing without a live-culturing step. We demonstrate the utility of this tool on several complex specimen types, including urine, wound swabs and tissue, and several types of respiratory and fecal specimens, showing K. pneumoniae species and clonal group identification and antimicrobial resistance and virulence profiling, including capsule typing. Use of this amplicon sequencing tool to screen patients for Klebsiella carriage could inform health care staff of the risk of infection and outbreak potential. KlebSeq also serves as a model for next-generation molecular tools for public health and health care, as expansion of this tool can be used for several other HAI agents or applications. PMID- 27510835 TI - Achieving value for money in health: a comparative analysis of OECD countries and regional countries. AB - OBJECTIVE: To measure efficiency gains in health sector over the years 1995 to 2013 in OECD, EU, non-member European countries. METHODS: An output-oriented DEA model with variable return to scale, and residuals estimated by regression equations were used to estimate efficiencies of health systems. Slacks for health care outputs and inputs were calculated by using DEA multistage method of estimating country efficiency scores. RESULTS: Better health outcomes of countries were related with higher efficiency. Japan, France, or Sweden were found to be peer-efficient countries when compared to other developed countries like Germany and United States. Increasing life expectancy beyond a certain high level becomes very difficult to achieve. Despite declining marginal productivity of inputs on health outcomes, some developed countries and developing countries were found to have lowered their inefficiencies in the use of health inputs. Although there was no systematic relationship between political system of countries and health system efficiency, the objectives of countries on social and health policy and the way of achieving these objectives might be a factor increasing the efficiency of health systems. CONCLUSIONS: Economic and political stability might be as important as health expenditure in improving health system goals. A better understanding of the value created by health expenditures, especially in developed countries, will require analysis of specific health interventions that can increase value for money in health. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27510836 TI - Curcumin attenuates cyclosporine A-induced renal fibrosis by inhibiting hypermethylation of the klotho promoter. AB - Chronic kidney disease is increasingly considered to be a worldwide public health problem and usually leads to renal fibrosis. In the present study, curcumin, a polyphenol pigment extracted from turmeric, was demonstrated to exert protective effects on renal fibrosis via the suppression of transforming growth factor-beta (TGF-beta) downstream signaling, such as plasminogen activator inhibitor-1 (PAI 1), alpha-smooth muscle actin (alpha-SMA) and collagen I (Col I) downregulation. The present findings demonstrate that curcumin exerted a protective effect on cyclosporine A-induced renal fibrosis via a klotho (KL)-dependent mechanism, which inhibits the TGF-beta signaling pathway. Further research indicated that curcumin induced KL expression in HK-2 tubular epithelial cells by inhibiting CpG hypermethylation in the KL promoter, which mediates the loss of expression in cells. Methylation-specific polymerase chain reaction (PCR) combined with bisulfite sequencing identified numerous key CpG sites, such as 249, 240 and 236, whose methylation statuses are important for KL expression. A PCR reporter assay was utilized to further confirm these findings. In addition, the effects of curcumin on the regulation of DNA methyltransferase 1 (Dnmt1) expression were evaluated, and the data suggest that curcumin inhibits Dnmt1 expression and restricts CpG hypermethylation. Thus, the current study reveals that curcumin attenuated renal fibrosis by suppressing CpG methylation in the KL promoter, thus inducing KL expression, which inhibited TGF-beta signaling, which may provide a novel therapeutic approach for the treatment of renal fibrosis. PMID- 27510837 TI - Detecting default mode networks in utero by integrated 4D fMRI reconstruction and analysis. AB - Recently, there has been considerable interest, especially for in utero imaging, in the detection of functional connectivity in subjects whose motion cannot be controlled while in the MRI scanner. These cases require two advances over current studies: (1) multiecho acquisitions and (2) post processing and reconstruction that can deal with significant between slice motion during multislice protocols to allow for the ability to detect temporal correlations introduced by spatial scattering of slices into account. This article focuses on the estimation of a spatially and temporally regular time series from motion scattered slices of multiecho fMRI datasets using a full four-dimensional (4D) iterative image reconstruction framework. The framework which includes quantitative MRI methods for artifact correction is evaluated using adult studies with and without motion to both refine parameter settings and evaluate the analysis pipeline. ICA analysis is then applied to the 4D image reconstruction of both adult and in utero fetal studies where resting state activity is perturbed by motion. Results indicate quantitative improvements in reconstruction quality when compared to the conventional 3D reconstruction approach (using simulated adult data) and demonstrate the ability to detect the default mode network in moving adults and fetuses with single-subject and group analysis. Hum Brain Mapp 37:4158-4178, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27510838 TI - Molecular mechanisms underlying progesterone-enhanced breast cancer cell migration. AB - Progesterone (P4) was demonstrated to inhibit migration in vascular smooth muscle cells (VSMCs), but to enhance migration in T47D breast cancer cells. To investigate the mechanism responsible for this switch in P4 action, we examined the signaling pathway responsible for the P4-induced migration enhancement in breast cancer cell lines, T47D and MCF-7. Here, we demonstrated that P4 activated the cSrc/AKT signaling pathway, subsequently inducing RSK1 activation, which in turn increased phosphorylation of p27 at T198 and formation of the p27pT198-RhoA complex in the cytosol, thereby preventing RhoA degradation, and eventually enhanced migration in T47D cells. These findings were confirmed in the P4-treated MCF-7. Comparing the P4-induced molecular events in between breast cancer cells and VSMCs, we found that P4 increased p27 phosphorylation at T198 in breast cancer cells through RSK1 activation, while P4 increased p27 phosphorlation at Ser10 in VSMCs through KIS activation. P27pT198 formed the complex with RhoA and prevented RhoA degradation in T47D cells, whereas p-p27Ser10 formed the complex with RhoA and caused RhoA degradation in VSMCs. The results of this study highlight the molecular mechanism underlying P4-enhanced breast cancer cell migration, and suggest that RSK1 activation is responsible for the P4-induced migration enhancement in breast cancer cells. PMID- 27510839 TI - Hypolipidemic effects of HVC1 in a high cholesterol diet-induced rat model of hyperlipidemia. AB - HVC1, a novel formation containing four herbs, was developed and its hypolipidemic effects in rats with high cholesterol diet (HCD)-induced hyperlipidemia were investigated. The rats were given a HCD for 8 weeks. The HVC1 treated groups were orally administered HVC1 at doses of 10, 50 or 250 mg/kg, respectively, and the simvastatin group was treated at a dose of 10 mg/kg. The normal diet and HCD control groups were administered with physiological saline. Oral administration of HVC1 (10, 50 or 250 mg/kg) significantly reduced the body weight of rats with hyperlipidemia and regulated the total cholesterol, low density lipoprotein cholesterol and high-density lipoprotein cholesterol levels in the serum. In addition, tissue analysis revealed that lipid accumulation in the liver and aorta was reduced by HVC1 administration. Furthermore, HVC1 significantly reduced the mRNA expression of peroxisome proliferator-activated receptor-gamma, 3-hydroxy-3-methylglutaryl-CoA reductase and low-density lipoprotein receptor, as well as the protein level of 5' adenosine monophosphate activated protein kinase in the liver. The results clearly demonstrate that HVC1 has a potent hypolipidemic effect, and suggest that HVC1 should be evaluated as a potential treatment for hyperlipidemia. PMID- 27510840 TI - Copy number variation of genes involved in the hepatitis C virus-human interactome. AB - Copy number variation (CNV) is a newly discovered form of intra-species genetic polymorphism that is defined as deletions or duplications of genome segments ranging from 1 kbp to several Mbp. CNV accounts for the majority of the genetic variation observed in humans (CNV regions cover more than 10% of the human genome); therefore, it may significantly influence both the phenotype and susceptibility to various diseases. Unfortunately, the impact of CNV on a number of diseases, including hepatitis C virus (HCV) infection, remains largely unexplored. Here, we analyzed 421 human genes encoding proteins that have been shown to interact with HCV proteins or genomic RNA (proteins from the HCV-human interactome). We found that 19 of the 421 candidate genes are located in putative CNV regions. For all of these genes, copy numbers were determined for European, Asiatic and African populations using the multiplex ligation-dependent amplification (MLPA) method. As a result, we identified 4 genes, IGLL1, MLLT4, PDPK1, PPP1R13L, for which the CN-genotype ranged from 1 to 6. All of these genes are involved in host-virus interaction; thus, their polymorphism has a potential impact on the development of HCV infection and/or therapy outcome. PMID- 27510841 TI - Comparison of distribution and toxicity of different types of zinc-based nanoparticles. AB - Zinc-based nanoparticles (Zn-NPs), mainly zinc oxide (ZnO) NPs, have promising application in a wide area, but their potential harmful effects on environment and human health have been continuously raised together with their high dissolution rate. In this study, we coated the surface of ZnO NPs with phosphate (ZnP NPs) and sulfide (ZnS NPs) which have very low solubility in water, administered orally (0.5 and 1 mg/kg) to mice for 28 days, and then compared their biodistribution and toxicity. As expected, ZnO NPs were rapidly ionized in an artificial gastric fluid. On the other hand, ZnO NPs were more particlized in an artificial intestinal fluid than ZnP and ZnS NPs. After repeated dosing, all three types of Zn-NPs the most distributed in the spleen and thymus and altered the level of redox reaction-related metal ions in the tissues. We also found that three types of Zn-NPs clearly disturb tissue ion homeostasis and influence immune regulation function. However, there were no remarkable difference in distribution and toxicity following repeated exposure of three types of Zn-NPs, although Na+ and K+ level in the spleen and thymus were notably higher in mice exposed to ZnO NPs compared to ZnP and ZnS NPs. Taken together, we suggest that all three types of Zn-NPs may influence human health by disrupting homeostasis of trace elements and ions in the tissues. In addition, the surface transformation of ZnO NPs with phosphate and sulfide may not attenuate toxicity due to the higher particlization rate of ZnO NPs in the intestine, at least in part. (c) 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1363-1374, 2017. PMID- 27510843 TI - "Adjuvant" Hyperthermic Intraperitoneal Chemotherapy: A Call to Action. PMID- 27510842 TI - Tooth agenesis in osteogenesis imperfecta related to mutations in the collagen type I genes. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous group of disorders of connective tissue, mainly caused by mutations in the collagen type I genes (COL1A1 and COL1A2). Tooth agenesis is a common feature of OI. We investigated the association between tooth agenesis and collagen type I mutations in individuals with OI. SUBJECTS AND METHODS: In this cohort study, 128 unrelated individuals with OI were included. Panoramic radiographs were analyzed regarding dentinogenesis imperfecta (DGI) and congenitally missing teeth. The collagen I genes were sequenced in all individuals, and in 25, multiplex ligation-dependent probe amplification was performed. RESULTS: Mutations in the COL1A1 and COL1A2 genes were found in 104 of 128 individuals. Tooth agenesis was diagnosed in 17% (hypodontia 11%, oligodontia 6%) and was more frequent in those with DGI (P = 0.016), and in those with OI type III, 47%, compared to those with OI types I, 12% (P = 0.003), and IV, 13% (P = 0.017). Seventy-five percent of the individuals with oligodontia (>=6 missing teeth) had qualitative mutations, but there was no association with OI type, gender, or presence of DGI. CONCLUSION: The prevalence of tooth agenesis is high (17%) in individuals with OI, and OI caused by a qualitative collagen I mutation is associated with oligodontia. PMID- 27510844 TI - Comparison of Single-Incision and Conventional Multi-Port Laparoscopic Distal Gastrectomy with D2 Lymph Node Dissection for Gastric Cancer: A Propensity Score Matched Analysis. AB - BACKGROUND: Single-incision laparoscopic surgery maximizes the advantages of laparoscopic surgery by reducing abdominal trauma; however, few comparative studies have addressed its role in gastric cancer. PURPOSE: This study sought to demonstrate the safety and feasibility of single-incision laparoscopic distal gastrectomy (SLDG) with radical D2 lymphadenectomy by comparing its short- and long-term outcomes with those of conventional multi-port laparoscopic surgery (MLDG). METHODS: From October 2007 to December 2011, we identified 175 patients with clinical stage I-III gastric cancer who underwent SLDG with D2 lymphadenectomy (n = 90) and MLDG (n = 85) according to a review of our prospective gastric cancer database in our institute. One-to-one propensity score matching was performed to compare short-term outcomes and long-term survival between the two groups. RESULTS: Mean operative time was similar between the two groups, while blood loss was significantly lower in the SLDG group than in the MLDG group. Postoperative recovery was faster in the SLDG group in terms of earlier initiation of oral intake, less use of analgesics, and shorter hospital stay. Serum C-reactive protein levels were significantly lower in the SLDG group than in the MLDG group on postoperative days 1, 3, and 7, and the 5-year overall survival rate was not significantly different between the two groups (93.7 vs. 87.6 %; p = 0.689). CONCLUSIONS: This study shows that SLDG with D2 lymphadenectomy is safe and feasible for gastric cancer, with better short-term outcomes than MLDG and acceptable oncologic outcomes. Thus, SLDG may be an attractive surgical alternative in minimally invasive surgery. PMID- 27510845 TI - Evolving Trends Towards Minimally Invasive Surgery for Solid-Pseudopapillary Neoplasms. AB - BACKGROUND: Solid-pseudopapillary neoplasms are rare pancreatic neoplasms with low malignant potential that predominantly arise in young women. We sought to characterize this population and the evolving trend at our institution towards laparoscopic management. METHODS: We identified all patients at our institution that were surgically treated for solid-pseudopapillary neoplasm from 2008-2015. Demographic and clinical information were queried from the medical record, and descriptive statistics were performed. Student's t test and chi-square analysis were used for comparison where appropriate. RESULTS: We identified 11 women and 1 man (average age 26 years; range 14-48 years) who were surgically treated for solid-pseudopapillary neoplasms; 5 with distal pancreatectomy (4 open, 1 laparoscopic), 6 with pancreaticoduodenectomy (3 open, 3 laparoscopic), and 1 open enucleation. From 2008 to 2013, seven of eight (87 %) procedures were performed open. Since 2014, three of four (75 %) procedures have successfully been completed laparoscopically (see video clips). Length of stay was similar for patients who had open versus laparoscopic procedures (8 vs. 9 days, p = 0.61). Two-thirds of patients (5/8) who had open procedures experienced postoperative complications compared with half (2/4) of patients who had laparoscopic procedures (p = 0.28). There have been no recurrences. CONCLUSIONS: Minimally invasive surgical management of solid-pseudopapillary neoplasms is becoming more popular, can be performed safely, and appears to have comparable outcomes to an open approach. Quality of life is an important metric for this relatively young population and may be improved with a laparoscopic approach, which warrants further investigation. PMID- 27510846 TI - Fast Targeting and Cancer Cell Uptake of Luminescent Antibody-Nanozeolite Bioconjugates. AB - Understanding the targeted cellular uptake of nanomaterials is an essential step to engineer and program functional and effective biomedical devices. In this respect, the targeting and ultrafast uptake of zeolite nanocrystals functionalized with Cetuximab antibodies (Ctxb) by cells overexpressing the epidermal growth factor receptor are described here. Biochemical assays show that the cellular uptake of the bioconjugate in the targeted cancer cells already begins 15 min after incubation, at a rate around tenfold faster than that observed in the negative control cells. These findings further show the role of Ctxb exposed at the surfaces of the zeolite nanocrystals in mediating the targeted and rapid cellular uptake. By using temperature and pharmacological inhibitors as modulators of the internalization pathways, the results univocally suggest a dissipative uptake mechanism of these nanomaterials, which seems to occur using different internalization pathways, according to the targeting properties of these nanocrystals. Owing to the ultrafast uptake process, harmless for the cell viability, these results further pave the way for the design of novel theranostic tools based on nanozeolites. PMID- 27510847 TI - Competitive coordination aggregation for V-shaped [Co3] and disc-like [Co7] complexes: synthesis, magnetic properties and catechol oxidase activity. AB - Unique dependence on the nature of metal salt and reaction conditions for coordination assembly reactions of varying architecture and nuclearity have been identified in V-shaped [Co3L4] and planar disc-like [Co7L6] compounds: [CoL2(MU L)2(MU-OH2)2(CF3CO2)2] (1) and [Co(MU-L)6(MU-OMe)6]Cl2 (2) (HL = 2-{(3 ethoxypropylimino)methyl}-6-methoxyphenol). At room temperature varying reaction conditions, cobalt-ligand ratios and use of different bases allowed unique types of coordination self-assembly. The synthetic marvel lies in the nature of aggregation with respect to the two unrelated cores in 1 and 2. Complex 1 assumes a V-shaped arrangement bound to L(-), water and a trifluoroacetate anion, while 2 grows around a central Co(II) ion surrounded by a {Co} hexagon bound to methoxide and L(-). Magnetic measurements revealed that the intermetallic interactions are antiferromagnetic in nature in the case of complex 1 and ferromagnetic in the case of 2 involving high spin cobalt(ii) ions with stabilization of the high-spin ground state in the latter case. In MeCN solutions complexes 1 and 2 showed catalytic oxidation of 3,5-di-tert-butylcatechol (3,5-DTBCH2) to 3,5-di-tert butylbenzoquinone (3,5-DTBQ) in air. The kinetic study in MeCN revealed that with respect to the catalytic turnover number (kcat) 2 is more effective than 1 for oxidation of 3,5-DTBCH2. PMID- 27510848 TI - Terrestrial carbohydrates support freshwater zooplankton during phytoplankton deficiency. AB - Freshwater food webs can be partly supported by terrestrial primary production, often deriving from plant litter of surrounding catchment vegetation. Although consisting mainly of poorly bioavailable lignin, with low protein and lipid content, the carbohydrates from fallen tree leaves and shoreline vegetation may be utilized by aquatic consumers. Here we show that during phytoplankton deficiency, zooplankton (Daphnia magna) can benefit from terrestrial particulate organic matter by using terrestrial-origin carbohydrates for energy and sparing essential fatty acids and amino acids for somatic growth and reproduction. Assimilated terrestrial-origin fatty acids from shoreline reed particles exceeded available diet, indicating that Daphnia may convert a part of their dietary carbohydrates to saturated fatty acids. This conversion was not observed with birch leaf diets, which had lower carbohydrate content. Subsequent analysis of 21 boreal and subarctic lakes showed that diet of herbivorous zooplankton is mainly based on high-quality phytoplankton rich in essential polyunsaturated fatty acids. The proportion of low-quality diets (bacteria and terrestrial particulate organic matter) was <28% of the assimilated carbon. Taken collectively, the incorporation of terrestrial carbon into zooplankton was not directly related to the concentration of terrestrial organic matter in experiments or lakes, but rather to the low availability of phytoplankton. PMID- 27510849 TI - Tumor-associated macrophages in human breast cancer parenchyma negatively correlate with lymphatic metastasis after neoadjuvant chemotherapy. AB - Breast cancer is the leading cause of cancer death in women worldwide with high morbidity and mortality. Tumor-associated macrophages (TAM) are major innate immune cells in the tumor microenvironment controlling primary tumor growth and metastasis. Neoadjuvant chemotherapy (NACT) is a conventional pre-operative treatment for breast cancer. In the present study we examined the distribution of TAM in five distinct intratumoral morphological compartments of human breast cancer and their correlation with clinical parameters after NACT. Our data indicated that CD68+ but not stabilin-1+ TAM in areas with parenchymal elements negatively correlate with lymphatic metastasis after NACT. However, in cases where lymphatic metastases were detected (28 out of 50 analyzed samples) both amount of CD68+ and stabilin-1+ macrophages in the areas with coarse fibrous stroma directly correlated with the number of positive lymph nodes. In patients with complete response to the preoperative NACT the average score of CD68 expression in the areas with coarse fibrous stroma was lower compared with cases of a partial response and stable disease. We concluded that function of TAM after NACT depends on their intratumoral localization and local tumor microenvironment which plays an important role in polarization of macrophages towards tumor suppressive or tumor-supportive types. PMID- 27510850 TI - [Not Available]. PMID- 27510851 TI - Bayesian inference of genetic parameters for ultrasound scanning traits of Kivircik lambs. AB - Ultrasound scanning traits have been adapted in selection programs in many countries to improve carcass traits for lean meat production. As the genetic parameters of the traits interested are important for breeding programs, the estimation of these parameters was aimed at the present investigation. The estimated parameters were direct and maternal heritability as well as genetic correlations between the studied traits. The traits were backfat thickness (BFT), skin+backfat thickness (SBFT), eye muscle depth (MD) and live weights at the day of scanning (LW). The breed investigated was Kivircik, which has a high quality of meat. Six different multi-trait animal models were fitted to determine the most suitable model for the data using Bayesian approach. Based on deviance information criterion, a model that includes direct additive genetic effects, maternal additive genetic effects, direct maternal genetic covariance and maternal permanent environmental effects revealed to be the most appropriate for the data, and therefore, inferences were built on the results of that model. The direct heritability estimates for BFT, SBFT, MD and LW were 0.26, 0.26, 0.23 and 0.09, whereas the maternal heritability estimates were 0.27, 0.27, 0.24 and 0.20, respectively. Negative genetic correlations were obtained between direct and maternal effects for BFT, SBFT and MD. Both direct and maternal genetic correlations between traits were favorable, whereas BFT-MD and SBFT-MD had negligible direct genetic correlation. The highest direct and maternal genetic correlations were between BFT and SBFT (0.39) and between MD and LW (0.48), respectively. Our results, in general, indicated that maternal effects should be accounted for in estimation of genetic parameters of ultrasound scanning traits in Kivircik lambs, and SBFT can be used as a selection criterion to improve BFT. PMID- 27510852 TI - Rapid compensatory evolution promotes the survival of conjugative plasmids. AB - Conjugative plasmids play a vital role in bacterial adaptation through horizontal gene transfer. Explaining how plasmids persist in host populations however is difficult, given the high costs often associated with plasmid carriage. Compensatory evolution to ameliorate this cost can rescue plasmids from extinction. In a recently published study we showed that compensatory evolution repeatedly targeted the same bacterial regulatory system, GacA/GacS, in populations of plasmid-carrying bacteria evolving across a range of selective environments. Mutations in these genes arose rapidly and completely eliminated the cost of plasmid carriage. Here we extend our analysis using an individual based model to explore the dynamics of compensatory evolution in this system. We show that mutations which ameliorate the cost of plasmid carriage can prevent both the loss of plasmids from the population and the fixation of accessory traits on the bacterial chromosome. We discuss how dependent the outcome of compensatory evolution is on the strength and availability of such mutations and the rate at which beneficial accessory traits integrate on the host chromosome. PMID- 27510853 TI - New strategies in myelofibrosis: the evolving paradigm of disease pathogenesis, prognostication and treatment. AB - Myelofibrosis (MF) is the most severe among the classical Philadelphia-negative myeloproliferative neoplasms that also include essential thrombocytemia and polycythemia vera. Myelofibrosis is characterized by numerous genetic lesions, often variously associated with each other, and by an aggressive clinical phenotype leading to severely reduced survival. Also, the inflammatory microenvironment plays a key role in disease initiation and progression. Because of the complexity of its pathogenesis and the variability of clinical features, MF is a disease that requires a personalized approach and remains orphan of curative treatments besides allogeneic transplantation. JAK2 inhibitors have marked a remarkable progress, because they alleviate systemic symptoms and reduce splenomegaly but have a limited effect on survival, on mutation load, and on marrow fibrosis. Here, we review the main contributing factors to MF pathogenesis and prognosis, focusing on how these factors relate to therapeutic choices. We discuss results from ongoing studies of JAK2 inhibitors and report on new therapeutic strategies that proved effective in early preclinical and clinical trials, including combination treatments, antifibrotic agents, and telomerase inhibitors. PMID- 27510854 TI - T-wave morphology can distinguish healthy controls from LQTS patients. AB - Long QT syndrome (LQTS) is an inherited disorder associated with prolongation of the QT/QTc interval on the surface electrocardiogram (ECG) and a markedly increased risk of sudden cardiac death due to cardiac arrhythmias. Up to 25% of genotype-positive LQTS patients have QT/QTc intervals in the normal range. These patients are, however, still at increased risk of life-threatening events compared to their genotype-negative siblings. Previous studies have shown that analysis of T-wave morphology may enhance discrimination between control and LQTS patients. In this study we tested the hypothesis that automated analysis of T wave morphology from Holter ECG recordings could distinguish between control and LQTS patients with QTc values in the range 400-450 ms. Holter ECGs were obtained from the Telemetric and Holter ECG Warehouse (THEW) database. Frequency binned averaged ECG waveforms were obtained and extracted T-waves were fitted with a combination of 3 sigmoid functions (upslope, downslope and switch) or two 9th order polynomial functions (upslope and downslope). Neural network classifiers, based on parameters obtained from the sigmoid or polynomial fits to the 1 Hz and 1.3 Hz ECG waveforms, were able to achieve up to 92% discrimination between control and LQTS patients and 88% discrimination between LQTS1 and LQTS2 patients. When we analysed a subgroup of subjects with normal QT intervals (400 450 ms, 67 controls and 61 LQTS), T-wave morphology based parameters enabled 90% discrimination between control and LQTS patients, compared to only 71% when the groups were classified based on QTc alone. In summary, our Holter ECG analysis algorithms demonstrate the feasibility of using automated analysis of T-wave morphology to distinguish LQTS patients, even those with normal QTc, from healthy controls. PMID- 27510855 TI - Implications for the thalamic reticular nucleus in impaired attention and sleep in schizophrenia. AB - The thalamic reticular nucleus (TRN) is an inhibitory shell positioned between the thalamus and the cortex. It is uniquely situated to modulate the flow of sensory information from the surroundings to the cortex as well as influencing ongoing cortical activity by modulating cortico-thalamo-cortical transmission. Although the thinness, architecture and location of the TRN deep in the brain has previously made this a difficult structure to study, novel optical and genetic tools have allowed for more precise targeting of this area. Recent research has implicated a role for the TRN in attention and sleep. Interestingly, impairments in attention and sleep resulting from TRN perturbation are strikingly similar to the clinical deficits observed in schizophrenia. This review aims to discuss recent evidence for the role of TRN in attention and sleep born from optogenetic work and connect these findings with those clinically observed in schizophrenia. PMID- 27510856 TI - Colicins U and Y inhibit growth of Escherichia coli strains via recognition of conserved OmpA extracellular loop 1. AB - Interactions of colicins U and Y with the OmpA (Outer membrane protein A) receptor molecule were studied using site-directed mutagenesis and colicin binding assay. A systematic mutagenesis of the colicin-susceptible OmpA sequence from Escherichia coli (OmpAEC) to the colicin-resistant OmpA sequence from Serratia marcescens (OmpASM) was performed in regions corresponding to extracellular OmpA loops 1-4. Susceptibility to colicins U and Y was significantly affected by the OmpA mutation in loop 1. As with functional analysis, a decrease in binding capacity of His-tagged colicin U was found for recombinant OmpA with a mutated segment in loop 1 compared to control OmpAEC. To verify the importance of the identified amino acid residues in OmpA loop 1, we introduced loop 1 from OmpAEC into OmpASM, which resulted in the substantial increase of susceptibility to colicins U and Y. In addition, colicins U and Y were tested against a panel of 118 bacteriocin non-producing strains of four Escherichia species, including E. coli (39 strains), E. fergusonii (10 strains), E. hermannii (42 strains), and E. vulneris (27 strains). A majority (82%) of E. coli strains was susceptible to colicins U and Y. Interestingly, colicins U and Y also inhibited all of the 30 tested multidrug-resistant E. coli O25b-ST131 isolates. These findings, together with the fact that OmpA loop 1 is important for bacterial virulence and is evolutionary conserved, offer the potential of using colicins U and Y as specific anti-OmpA loop 1 directed antibacterial proteins. PMID- 27510857 TI - Controllably Alloyed, Low Density, Free-standing Ni-Co and Ni-Graphene Sponges for Electrocatalytic Water Splitting. AB - Synthesis of low cost, durable and efficient electrocatalysts that support oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) are the bottlenecks in water electrolysis. Here we propose a strategy for the development of controllably alloyed, porous, and low density nickel (Ni) and cobalt (Co) based alloys - whose electrocatalytic properties can be tuned to make them multifunctional. Ni and Co based alloy with the chemical structure of Ni1Co2 is identified as an efficient OER catalyst among other stoichiometric structures in terms of over potential @ 10 mAcm(-2) (1.629 V), stability, low tafel slope (87.3 mV/dec), and high Faradaic efficiency (92%), and its OER performance is also found to be on par with the benchmarked IrO2. Tunability in the porous metal synthesis strategy allowed the incorporation of graphene during the Ni sponge formation, and the Ni- incorporated nitrogen doped graphene sponge (Ni-NG) is found to have very high HER activity. A water electrolysis cell fabricated and demonstrated with these freestanding electrodes is found to have high stability (>10 hours) and large current density (10 mAcm(-2) @ 1.6 V), opening new avenues in the design and development of cost effective and light weight energy devices. PMID- 27510858 TI - Ozone/graphene oxide catalytic oxidation: a novel method to degrade emerging organic contaminant N, N-diethyl-m-toluamide (DEET). AB - N, N-diethyl-m-toluamide (DEET) is one of the important emerging contaminants that are being increasingly detected in reclaimed water as well as in drinking water sources. However, DEET is refractory to conventional biological treatment and pure ozone which is absent of hydroxyl radical. Current researches on the efficient removal of DEET are still quite limited. This study utilizes a novel method, namely ozone/graphene oxide (O3/GO), to investigate the effects on DEET removal in aqueous systems, especially in reclaimed water. The results indicate that the DEET degradation rate was significantly accelerated through the combined effect of GO and ozonation which can yield abundant hydroxyl radical, compared to pure ozone condition. According to hydroxyl radical scavenging experiments, hydroxyl radical was found to play a dominant role in synergistic removal of DEET. These findings can offer sound suggestions for future research on the removal of emerging organic contaminants. The information could also be beneficial to reclaimed water safety and sustainable management. PMID- 27510859 TI - The peculiar behavior of the molecular dynamics of a glass-forming liquid confined in native porous materials - the role of negative pressure. AB - In this paper, we combine Broadband Dielectric Spectroscopy (BDS) at ambient and high pressure, and positron annihilation lifetime spectroscopy (PALS) data of 2 ethylhexanol in the bulk state and when infiltrated in native silica nanopores to elucidate the relative role of surface effects on the Debye and structural relaxation processes under 2D spatial constraints. We show that the two processes have different sensitivities to (i) the changes in density as quantified by the EV/Hp ratio and (ii) the degree of confinement. Significant enhancement of the dynamics of the confined molecules at low temperatures is related to the vitrification of the interfacial molecules (Tg,int) affecting the packing density of the core molecules. This is corroborated by the PALS measurements, which demonstrated that the effective volume for the confined samples is slightly higher and seems to be temperature invariant below Tg,int. Consequently, negative pressure systematically develops with lowering temperature reaching values of 100 and -110 MPa (depending on the pore size) at the glass transition temperature. This result offers a better understanding of the counterbalance between surface and finite size effects as well as the role of negative pressure in controlling the dynamics and the glass transition of liquids under 2D spatial restrictions. PMID- 27510860 TI - Acute ammonia toxicity in crucian carp Carassius auratus and effects of taurine on hyperammonemia. AB - The four experimental groups were carried out to test the response of crucian carp Carassius auratus to ammonia toxicity and taurine: group 1 was injected with NaCl, group 2 was injected with ammonium acetate, group 3 was injected with ammonium acetate and taurine, and group 4 was injected with taurine. Fish in group 2 had the highest ammonia and glutamine contents, and the lowest glutamate content in liver and brain. Serum superoxide dismutase (SOD), glutathione (GSH) activities, red cell count (RBC), white cell count (WBC), lysozyme (LYZ) activity, complement C3 content of fish in group 2 reflected the lowest, but malondialdehyde content was the highest. Importantly, serum SOD and GSH activites, RBC, WBC, and LYZ activity, C3, C4 and total immunoglobulin contents of fish in group 3 were significantly higher than those of fish in group 2. This study indicates that ammonia exerts its toxic effects by interfering with amino acid transport, inducing ROS generation, leading to malondialdehyde accumulation and immunosuppression of crucian carp. The exogenous taurine could mitigate the adverse effect of high ammonia level on fish physiological disorder. PMID- 27510861 TI - A bit of a mouthful. AB - This month's Genome Watch explores recent advances in the identification of species-level and strain-level diversity in microbiome studies, and highlights how these have provided insights into the tropism and persistence of Neisseria spp. in the human oral cavity. PMID- 27510862 TI - The physiology of growth arrest: uniting molecular and environmental microbiology. AB - Most bacteria spend the majority of their time in prolonged states of very low metabolic activity and little or no growth, in which electron donors, electron acceptors and/or nutrients are limited, but cells are poised to undergo rapid division cycles when resources become available. These non-growing states are far less studied than other growth states, which leaves many questions regarding basic bacterial physiology unanswered. In this Review, we discuss findings from a small but diverse set of systems that have been used to investigate how growth arrested bacteria adjust metabolism, regulate transcription and translation, and maintain their chromosomes. We highlight major questions that remain to be addressed, and suggest that progress in answering them will be aided by recent methodological advances and by dialectic between environmental and molecular microbiology perspectives. PMID- 27510863 TI - Biofilms: an emergent form of bacterial life. AB - Bacterial biofilms are formed by communities that are embedded in a self-produced matrix of extracellular polymeric substances (EPS). Importantly, bacteria in biofilms exhibit a set of 'emergent properties' that differ substantially from free-living bacterial cells. In this Review, we consider the fundamental role of the biofilm matrix in establishing the emergent properties of biofilms, describing how the characteristic features of biofilms - such as social cooperation, resource capture and enhanced survival of exposure to antimicrobials - all rely on the structural and functional properties of the matrix. Finally, we highlight the value of an ecological perspective in the study of the emergent properties of biofilms, which enables an appreciation of the ecological success of biofilms as habitat formers and, more generally, as a bacterial lifestyle. PMID- 27510865 TI - [Attach importance to diseases associated with severe Epstein-Barr virus infection in children]. PMID- 27510864 TI - Quorum sensing signal-response systems in Gram-negative bacteria. AB - Bacteria use quorum sensing to orchestrate gene expression programmes that underlie collective behaviours. Quorum sensing relies on the production, release, detection and group-level response to extracellular signalling molecules, which are called autoinducers. Recent work has discovered new autoinducers in Gram negative bacteria, shown how these molecules are recognized by cognate receptors, revealed new regulatory components that are embedded in canonical signalling circuits and identified novel regulatory network designs. In this Review we examine how, together, these features of quorum sensing signal-response systems combine to control collective behaviours in Gram-negative bacteria and we discuss the implications for host-microbial associations and antibacterial therapy. PMID- 27510866 TI - [Principle suggestions for diagnosis and treatment of main nontumorous Epstein Barr virus-associated diseases in children]. PMID- 27510867 TI - [Consensus statement on diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency]. PMID- 27510868 TI - [An analysis of 181 cases with blood stream infection caused by Streptococcus agalactiae in children from 2011 to 2015: a multi-center retrospective study]. AB - OBJECTIVE: To analyze the clinical characteristics of blood stream infection caused by Streptococcus agalactiae in children and the drug-resistance of the isolates. METHOD: All cases with Streptococcus agalactiae growth in blood or cerebrospinal fluid cultures from January 1, 2011 to December 31, 2015 were enrolled by checking the laboratory information system (LIS) from 7 Class 3 Grade A hospitals (4 in Zhejiang, 2 in Shanghai and 1 in Chongqing). Clinical data were collected for analysis. chi(2) test, t test and non parametric test were used in the study. RESULT: One hundred and eighty-one pediatric cases of blood stream infection caused by Streptococcus agalactiae were included in current study. Eighty-six cases (47.5%) were male, and with age range from one day to 9 years (media 13 days). Thirty cases (16.6%) were premature infants and 127 cases (70.2%) were born via vaginal delivery. Seventy-one cases (39.2%) had early onset (<7 d) infections, and 106 cases (58.6%) had late onset (7-89 d) infections. Seventy-eight cases (43.1%) were complicated with purulent meningitis. Incidences of vaginal delivery(81.7%(58/71) vs. 62.3%(66/106)), shortness of breath moaning (43.7%(31/71) vs. 15.1%(16/106)) and preterm premature rupture of membranes (25.4%(18/71) vs. 3.8%(4/106)) were higher in the early onset infection group compared with the late onset group(P all<0.05). However, the number of cases who had fever(25.4%(18/71)vs.85.8%(91/106)) and complicated with purulent meningitis (29.6%(21/71) vs. 53.8%(57/106)) in early onset infections group was less than that in the late onset group(P both<0.05). The blood cultures of most patients (87.8%) were performed before the use of antibiotics. Drug-resistant tests showed that the sensitive rates to penicillin G, ceftriaxone and cefotaxime were 98.9%, 99.0% and 99.0% respectively. All strains were sensitive to vancomucine. The rates of resistance to clindamycin and erythromycin were 68.0% and 34.0%, respectively. Only 39 cases (22.0%) were treated with single antibiotics of either penicillins or cephalosporins, 80 cases (45.2%) were treated with antibiotics containing beta lactamase inhibitor, 61 cases (34.5%) were treated with either meropenem or cefoperazone-sulbactam. One hundred and fifty-four cases were cured, while 19 died (including 13 complicated with purulent meningitis) and 8 lost to follow up after giving up of treatment. CONCLUSION: The incidence and mortality of blood stream infection caused by Streptococcus agalactiae complicated with purulent meningitis are high in children. Penicillin is the first choice in treatment. Antibiotics should be selected accorrding to the drug resistance test. PMID- 27510869 TI - [Prevalence characteristics of influenza viruses in children in Beijing during 2014-2015 and 2015-2016 influenza seasons]. AB - OBJECTIVE: To compare the prevalence characteristics of influenza viruses in children in Beijing during 2014-2015 and 2015-2016 influenza seasons. METHOD: Throat swabs were collected weekly from children with influenza-like illnesses who visited in Children's Hospital affiliated to Capital Institute of Pediatrics during the period from September 2014 to May 2016.Influenza viruses A and B viruses were detected by real-time RT-PCR, followed by identification of H3N2, H1N1pdm, B/Victoria-like and B/Yamagata-like.The prevalence characteristics of influenza viruses was estimated by means of descriptive statistics.The t test and chi-square test were used to compare median age and gender ratio of infected children among different types of influenza viruses. RESULT: Out of 1 821 throat swabs collected, 139 (7.6%) were positive for H3N2 and 43 (2.4%) for H1N1pdm and 204 (11.2%) for influenza B virus, including 108 for B/Victoria-like and 96 for B/Yamagata-like.The median age of H1N1pdm infected children ((3.3+/-2.2) years) was significantly younger than that of H3N2 ((4.7+/-3.2) years) and influenza B virus((4.9+/-2.8) years) (H1N1pdm vs. H3N2: t=2.848, P=0.002; H1N1pdm vs. influenza B, t=3.682, P=0.000). Two epidemic peaks were presented in 2014-2015 influenza season, dominated definitely by H3N2 and B/Yamagata-like, respectively, while one delayed peak started at the 51(st) week, 2015, co-circulated with H3N2, H1N1pdm and influenza B viruses, among which B/Victoria-like virus was predominant during the 2015-2016 season. CONCLUSION: Prevalence characteristics of influenza viruses are different between 2014-2015 and 2015-2016 influenza seasonal epidemics in children in Beijing. It is important to monitor the genetic variations of influenza viruses and to keep close attention to influenza B virus as well as influenza A virus. PMID- 27510870 TI - [A retrospective study on the liver pathological characteristics and the effect of antiviral treatment for 1 to 7 years old children with heptitis B e antigen negative chronic hepatitis B]. AB - OBJECTIVE: To investigate the liver pathological characteristics and the clearance rate of hepatitis B surface antigen (HBsAg) with antiviral treatment for 1 to 7 years old children with heptitis B e antigen(HBeAg)-negative chronic hepatitis B. METHOD: A total of 49 cases with HBeAg-negative chronic hepatitis B were treated with interferon (IFN) or IFN treatment for 6 months added with lamivudine, and were followed up for at least 6 months.Retrospective analysis was performed on the liver pathological characteristics, the efficacy of antivirus treatment and its influencing factors of the HBsAg clearance rate in the cases from June 2006 to December 2013 in the 302 Hospital of People's Liberation Army.The chi(2) test was used to compare the rates. RESULT: (1)The median age of cases was 3 years old(1-7 years old), 38 children were male(78%). Cases in the age group 1-2, >2 -3, >3 -4, >4-5, >5-6 and >6-7 were 7, 8, 14, 6, 6 and 8 respectively. HBsAg was 100% positive in mother of the cases. (2)There were 7 children whose pre-treatment alanine aminotransferase (ALT) were <=80 U/L and pre treatment ALT>200 U/L in 25 children. There were 24 children whose pre-treatment HBVDNA >=1*10(7) U/ml. Genetype analysis was detected in 43 children, 3 children were B genotype, 38 were C genotype, 2 were B and C genotype. (3)Liver biopsy was performed in all children. The degree of liver inflammation >=2 was seen in 48 (98%) children.Severe liver fibrosis and cirrhosis were found in 21(43%) children. (4)In the age group 1-2, >2-3, >3-4, >4-5, >5-6 and >6-7 years old , the clearance of HBsAg was 5, 6, 2, 1, 0 and 0 respectively. The HBsAg clearance rate between 1-3 years old group and 3-7 years old group has significant difference ((73%(11/15) vs. 9%(3/34), chi(2)=18.180, P=0.000). (5)The clearance of HBsAg in male group was 11, but 3 in female group.It showed no significant difference between two groups (chi(2)=0.073, P=0.787). (6) The clearance rate of HBsAg were 0, 24%(4/17) and 40%(10/25) in the groups of pre-treatment ALT <=80 U/L, 80200 U/L, respectively. There were no significant difference between the groups of ALT<=200 U/L and ALT > 200 U/L(chi(2)=2.223, P=0.136). In the groups with pre-treatment HBV DNA <1*10(7)U/ml and HBV DNA>=1*10(7)U/ml, the clearance rate of HBsAg was 28%(7/25) and 29%(7/24). There were no significant elifference between two groups(chi(2)=0.008, P=0.928). (7)The clearance rate of HBsAg was 33%(7/21) in children with severe liver fibrosis and cirrhosis, while 25%(7/28) in children who had no severe liver fibrosis and cirrhosis.There were no significant difference between two groups(chi(2)=0.408, P=0.523). CONCLUSION: There are obvious liver injuries and severe liver fibrosis in 1-7 years old children with HBeAg-negative chronic hepatitis B. The HBsAg clearance rate in the children with antiviral treatment correlated with age, among those who received antiviral treatment before 3 years old, the HBsAg clearance rate is relatively higher. PMID- 27510871 TI - [Clinical and genetic characteristics and detection of urinary pipecolic acid in pyridoxine dependent epilepsy]. AB - OBJECTIVE: To analyze the clinical and genetic characteristics of patients with pyridoxine dependent epilepsy (PDE), and build a method to detect and analyze the concentration of urinary pipecolic acid in PDE patients receiving pyridoxine treatment. METHOD: Twelve patients (8 were male, 4 were female) were diagnosed as PDE in Peking University First Hospital between April 2012 and September 2015. The clinical manifestations, diagnosis and treatment process, video electroencephalogram, magnetic resonance imaging were retrospectively analyzed. ALDH7A1 gene was detected using Sanger sequencing or targeted next-generation sequencing. The concentration of urinary pipecolic acid in PDE patients was detected with gas chromatography-mass spectrometry (GC-MS), as well as in some non-PDE children served as normal control. All controls, 58 cases totally, were neonates born in our hospital or children came to our hospital for reasons such as syncope (without disturbing pipecolic acid metabolism) from November 2015 to January 2016. Of them, 25 were <=6 months old(14 were male, 11 were female), 33 were >6 months old(14 were male, 19 were female). The Student's t-test or Mann Whitney U test was used for comparing the pipecolic acid between the two groups. Correlation analysis was conducted using Pearson or Spearman test. RESULT: Of the 12 patients, seven of them were abnormal at birth. The age of epilepsy onset was from 5 h to 5 months, within 10 d in 8 patients. After a diagnostic delay time of 15 d to 20 months, seizures in all patients were controlled by pyridoxine monotherapy, at a dose of higher than 10.0 mg/(kg.d) in 10 patients, and 8.5 and 2.5 mg/(kg.d) in the other 2 patients respectively. The range of maintenance dose was 2.5-20.0 mg/(kg.d) during the follow up. Interictal electroencephalogram showed nonspecific abnormality in 10, normal in 2. Brain magnetic resonance imaging showed nonspecific abnormality in 7, normal in 5. ALDH7A1 mutations were found in all patients, including 15 different mutation sites, four of which were never reported before. Splicing mutation IVS11+ 1G>A was carried in 6 patients, with a frequency of 25% (6/24). At the last follow-up, eleven patients were in various degree of psychomotor development delay, including the 4 patients with severe delay in whom birth abnormalities presented, and no significant delay was found in one patient. The concentration of urinary pipecolic acid in control: age <=6 months, median 8.47 (0.46-35.33) mmol/mol creatinine; age >6 months, median 0.66 (0.12-3.52) mmol/mol creatinine. The concentration of urinary pipecolic acid was different between two groups of control (Z=-5.464, P<0.01). Twelve patients were all older than 6 months when they were tested, and the concentration was only mildly elevated in one patient, the range of 12 patients was 0.14-4.08 mmol/mol creatinine. The concentration was not significantly different between the control with age >6 months and our PDE patients (Z=-0.655, P>0.05). There were no significant correlations between the concentration of urinary pipecolic acid and the initial dose or maintenance dose at last follow-up of pyridoxine (r=0.418 and 0.166, P=0.176 and 0.607). CONCLUSION: Seizures start in early infancy in most PDE patients. The splicing mutation IVS11+ 1G>A is supposed to be a probable"hotspot"mutation with a high frequency in Chinese PDE patients. Most patients have different levels of psychomotor development delay after seizures are controlled, and the patients with birth abnormalities may have worse outcomes. No relationships between the diagnostic delay time and the development outcome are found. The concentration of urinary pipecolic acid can return to normal during treatment with pyridoxine. PMID- 27510872 TI - [Evaluation of an automatic image-based screening technique for neonatal hyperbilirubinemia]. AB - OBJECTIVE: To verify the accuracy of a smart phone software application, which is an automated image-based bilirubin (AIB) testing technique for testing peripheral blood total bilirubin (TB) in term and late preterm neonates. METHOD: During July 2015 to January 2016, jaundiced neonates were enrolled from department of neonatology in Tongji Hospital, Children's Hospital of Zhejiang University School of Medicine and Shenzhen Bao'an Maternal and Child Health Hospital. The enrolling criteria included gestational age (GA)>=34 weeks and peripheral blood total bilirubin test is required. Near-simultaneous TB, transcutaneous bilirubin (TcB), and AIB were determined. AIB consists of a cloud based off-line learning module and an on-line prediction module. Skin image, by smart phone is uploaded to a specific cloud server that includes learning based software to provide an individualized and immediate predicted bilirubin index. The t-test was used to determine if AIB and peripheral blood TB are significantly different. Agreement of AIB and TcB were compared with peripheral blood TB by Bland-Altman analysis. Linear regression was adopted to model the relationship of AIB and peripheral blood TB. The ROC curve of AIB was also plotted. RESULT: Two hundred and fifteen neonates were enrolled, gestational age 37 weeks+ 5 d, postnatal age (11+/-4) d, weight (2.9+/-0.7) kg, 116 male and 99 female. One hundred and forty-eight term neonates (GA>=37 weeks) and 67 preterm neonates (GA 34-<37 weeks) were enrolled in this study. There was no significant difference between AIB (197+/-51)MUmol/L and peripheral blood TB(191+/-65)MUmol/L (t=1.611, P=0.109). There was strong relevance between peripheral blood TB and AIB as shown by Bland-Altman analysis (96% (207/215) samples lay within the 95% limits of agreement). The regression analysis showed that the r(2) was 0.593 in the whole population, while the r(2) was 0.628 in the term neonates. The ROC of AIB yielded a 0.743 AUC, and with 82% sensitivity and 60% specificity based on Youden index criterion. CONCLUSION: Based on AIB's agreement with peripheral blood TB, the sensitivity and specificity, AIB can be used as a new technique to provide results for objective follow-up for progression and regression of jaundice. PMID- 27510873 TI - [Complications of critically ill children supported by venoarterial extracorporeal membrane oxygenation]. AB - OBJECTIVE: To study the complications occurred in the process of venoarterial extracorporeal membrane oxygenation (VA-EMCO) in critically ill children. METHOD: To analyze retrospectively 25 children who were admitted to PICU of Children's Hospital of Fudan University from December 2011 to December 2015. They were all treated with VA-ECMO with incision and catheterization in right internal carotid artery and jugular vein. Complications were recorded during ECMO process. RESULT: The duration of ECMO treatment was 14 to 567 h (153 (112, 204) h). Seventeen cases (68%) withdrew from ECMO successfully and 15 cases (60%) survived to discharge. Thirty-three complications occurred during ECMO treatment. Of which, mechanical complications occurred 9 times, including oxygenator leakage (n=3), hemolysis (n=2), water tank failure (n=2), pump head rupture (n=1) and piping thrombosis (n=1). Somatic complications appeared 24 times, including neurological complications (n=8) which included cerebral infarction (n=2), convulsions (n=2), intracranial hemorrhage (n=2), thrombosis after ligation of internal jugular vein (n=1) and cerebral atrophy (n=1); bleeding complications (n=8) which included bleeding at puncture sites (n=4), ECMO canalized site bleeding (n=3), and spontaneous (n=1), intracranial hemorrhage or hematoma cases(n=2) in mechanical complications; acute kidney injury (n=5) and microcirculation thrombosis (n=3). CONCLUSION: ECMO technique may cause complications, which mainly include neurological, mechanical and clotting complications. Advanced equipments and materials and well-managed teamwork are helpful in decreasing complications. PMID- 27510874 TI - [Application of the computer-based respiratory sound analysis system based on Mel frequency cepstral coefficient and dynamic time warping in healthy children]. AB - OBJECTIVE: We designed a computer-based respiratory sound analysis system to identify pediatric normal lung sound. To verify the validity of the computer based respiratory sound analysis system. METHOD: First we downloaded the standard lung sounds from the network database (website: http: //www.easyauscultation.com/lung-sounds-reference-guide) and recorded 3 samples of abnormal loud sound (rhonchi, wheeze and crackles) from three patients of The Department of Pediatrics, the First Affiliated Hospital of Xiamen University. We regarded such lung sounds as"reference lung sounds". The"test lung sounds"were recorded from 29 children form Kindergarten of Xiamen University. we recorded lung sound by portable electronic stethoscope and valid lung sounds were selected by manual identification. We introduced Mel-frequency cepstral coefficient (MFCC) to extract lung sound features and dynamic time warping (DTW) for signal classification. RESULT: We had 39 standard lung sounds, recorded 58 test lung sounds. This computer-based respiratory sound analysis system was carried out in 58 lung sound recognition, correct identification of 52 times, error identification 6 times. Accuracy was 89.7%. CONCLUSION: Based on MFCC and DTW, our computer-based respiratory sound analysis system can effectively identify healthy lung sounds of children (accuracy can reach 89.7%), fully embodies the reliability of the lung sounds analysis system. PMID- 27510875 TI - [Clinical and pathological analysis of IgA nephropathy with acute kidney injury]. AB - OBJECTIVE: To investigate the incidence, etiology, clinico- pathological characteristics and prognosis in primary IgA nephropathy (IgAN) children with acute kidney injury (AKI). METHOD: Retrospective analysis of the clinical and pathological manifestations and follow-up results of 19 Chlidren, who were associated with AKI in 196 cases of children with IgA nephropathy treated in our department from January, 1996 to Jun, 2012 was performed. RESULT: (1) The 19 cases associated with AKI accounted for 9.7% of all 196 Chlidren with IgAN. Within the 19 cases, there were gross hematuria in 17 cases, massive proteinuria in 16 cases, hypoalbuminemia in 10 cases, edema in 10 cases and hypertension in one case. The peak serum creatinine was from 94.5 MUmol/ L to 282 MUmol/L. (2) Histological changes: with the formation of crescent in 10 cases, diffuse endocapillary proliferation in 5 cases, 15 cases had renal tubular injury, 10 cases had red blood cell and protein cast, 1 case with acute interstitial nephritis. (3) The cause of IgA nephropathy with AKI: 13 patients had severe glomerular damage, including crescentic glomerulonephritis and diffuse endocapillary proliferation; 1 case was complicated with acute interstitial nephritis after being treated with antibiotics, 2 patients had decreased glomerular filtration rate because of taking benazepril or oral indomethacin, 1 case with renal tubular injury induced by gross hematuria, and the other two cases the reason was not clear. (4) Multivariate Logistic regression analysis showed that massive proteinuria was independent risk factor of IgAN in children with AKI (OR=27.370, 95% confidence interval was 3.151-237.740, P<0.01). (5) None of the patients were on dialysis, steroid therapy was used in 13 cases (including 7 cases of methylprednisolone pulse therapy), 6 cases were treated with combined cyclophosphamide treatment. Except 1 cases no significant improvement, the renal functiones of all patients recovered or improved within 1-2 months after treatment. Follow-up period was from 1 month to 7 years, 3 cases had renal function improved, but 2 cases were lost to follow-up for 3 years and then entered the chronic renal failure, 1 case had renal function loss after 32 months and repeated renal biopsy showed glomerular sclerosis of 32% during the follow-up period. CONCLUSION: In children with IgAN, AKI accounted for about 10%, except glomerular severe lesion, the onset of AKI is also relevant to clinical medication and repeated gross hematuria, and the heavy proteinuria is an independent risk factor. Based on clinical observation, the short-term prognosis of IgAN children with AKI is optimistic. PMID- 27510876 TI - [A major histocompatibility complex class II deficiency case report and literature review]. AB - OBJECTIVE: To summarize and report the clinical characteristics and laboratory results of a case and those reported in literature with MHC class II deficiency. METHOD: The clinical features, laboratory results and gene mutation analysis of an infant with MHC class II deficiency, who was diagnosed and treated in Peking Union Medical College Hospital since December 2013, were retrospectively analyzed."Major histocompatibility complex class II deficiency"or"bare lymphocyte syndrome"were used as keywords in order to retrieve reports from CNKI (from its establishment to October 2015) and Wanfang Database (from its establishment to October 2015), PubMed Database (from its establishment to October 2015) was searched. The characteristics, diagnosis, treatment and prognosis were summarized by reviewing related articles. RESULT: The patient was a 8-month-old boy. Since the fourth month of life, he started to have repeated fever, susceptible to a variety of pathogens, immune hemolytic anemia, severe malnutrition, and finally diagnosed as MHC class II deficiency disease when he was 20-month-old.No related reports were retrieved from CNKI and Wanfang database, there were 20 articles and 179 patients were reported worldwide in the past 10 years. Patients exhibit an extreme vulnerability to infections(resptratory infection(82%, 146/178), inpection of gastroin testinal(76%, 135/178)). The common laboratory examinations showed hypogammaglobulinemia, CD4(+) lymphopenia(93%, 107/115) etc. Diagnosis relies on the flow-cytometric analysis and genetic analysis. CONCLUSION: It is considered necessary for patients with young onset age, manifestation of clinically opportunistic infection as immune deficient disease, including the MHC class II deficiency disease, especially long-term diarrhea, poor development and cryptosporidium infection. This disease could coexist with autoimmune disorders. PMID- 27510877 TI - [Clinical and genetic analysis of an infant with isolated 17, 20-lyase deficiency]. AB - OBJECTIVE: To explore the clinical and genetic characteristics of an infant with isolated 17, 20-lyase deficiency. METHOD: The clinical, biochemical and genetic characteristics were analyzed in an 8-month-old infant with 46, XY gonadal dysgenesis who presented predominantly the female external genitalia. RESULT: The infant was referred because of"masses in bilateral inguinal region and 46, XY gonadal dysgenesis". He was normotensive. Laboratory tests revealed elevated levels of progesterone and 17-hydroxyprogesterone. The detailed parameters are as follows: progesterone 29.35(reference range 0.09-1.0)nmol/L, 17 hydroxyprogesterone 10.9(reference range 0.6-2.6)nmol/L, testosterone 0.7(reference range 0.1-3.1)nmol/L, dehydroepiandrosterone sulfate <0.15(reference range 0.80-5.6)mg/L, androstenedione <0.3 (reference range 0.6 3.1) MUg/L, luteinizing hormone 6.6(reference range 0.6-1.7)U/L, follicle stimulating hormone 1.8 (reference range 0.5-3.7)U/L, estradiol 37.66(reference range 73.4-146.8)pmol/L. The patient had normal levels of serum sodium, potassium, corticosteroid and plasma adrenocorticotropic hormone. Genomic DNA was extracted from the leukocytes of peripheral blood of the patient and subjected to next generation sequencing (NGS) for testing more than 200 sexual development related genes. Sanger sequencing was used to confirm the results of NGS. Genetic analysis revealed that the patient harbored compound heterozygous mutations of c. 1226C>G (p.Pro409Arg, P409R) and c. 707T>G (p.Val236Gly, V236G) in CYP17A1 gene derived from paternal and maternal allele. V236G was a novel mutation predicted to be pathogenic. The infant was diagnosed as isolated 17, 20-lyase deficiency combined with clinical and molecular characteristics of CYP17A1 gene. CONCLUSION: We have identified the compound heterozygous mutations of P409R and V236G in the CYP17A1 gene in one infant with isolated 17, 20-lyase deficiency. He presented with 46, XY gonadal dysgenesis, normal blood pressure and elevated concentration of progesterone and 17-hydroxyprogesterone. PMID- 27510878 TI - [Vein of Galen malformations in two neonates]. PMID- 27510879 TI - [Zika virus: research progress, diagnosis and control]. PMID- 27510881 TI - [The effect of human cytomegalovirus microRNA on virus latent infection]. PMID- 27510880 TI - [Immunotherapy for Epstein-Barr virus-associated disorders]. PMID- 27510882 TI - [Therapeutic progress in spinal muscular atrophy]. PMID- 27510883 TI - [Sleep-disordered breathing in the Pierre-Robin syndrome children]. PMID- 27510884 TI - In vitro comparison of intracranial stent visibility using various concentrations of gadolinium contrast agent under 1.5 T and 3 T MR angiography. AB - BACKGROUND AND PURPOSE: MR angiography (MRA) is an increasingly used evaluation method following intracranial stenting. However, the various artifacts created by the stent limit this technique. The purpose of this study was to investigate the effects of various concentrations of gadolinium contrast agent on the visibility and signal characteristics of two stents using the a contrast enhanced MRA technique. MATERIAL AND METHOD: Two intracranial stents (Enterprise and Helistent) were placed in polyvinyl chloride tubes as vascular phantoms. They were filled with six different doses of gadolinium contrast agent (1.0, 2.0, 4.0, 6.0, 8.0, and 10.0 mmol/L dimeglumine gadopentetate, respectively) and imaged using 3 T and 1.5 T MR systems. Relative in-stent signal (RIS) was calculated and artificial luminal narrowing (ALN) was obtained using pixel by pixel analysis. RESULT: The Enterprise stent, performed in both 1.5 T and 3 T MR systems, showed mean RIS values much less than those for the Helistent for all different doses of gadolinium solution. Increased gadolinium concentration resulted in a gradual reduction in RIS values in the Enterprise group. Also, ALN in the Enterprise group showed no or little change with various gadolinium doses. CONCLUSIONS: The Enterprise stent demonstrated good luminal visibility regardless of gadolinium concentration. The relative in-stent signals were more predictable in the Enterprise stent with various doses of gadolinium. Therefore, the Enterprise stent has been shown to provide better in-stent visibility compared with the Helistent using various gadolinium doses. PMID- 27510885 TI - Fistulous-type vein of Galen malformation phantom model for endovascular training and research. AB - INTRODUCTION: Vein of Galen malformation (VGM), a high-flow intracranial arteriovenous shunt, is among the most severe neurovascular diseases in childhood. In many cases untreated children die or survive only severely disabled. Endovascular embolization is the preferred treatment. OBJECTIVE: To develop a simple fistulous-type VGM phantom model for teaching and training of different endovascular treatment methods and to investigate new treatment options and devices. METHODS: An experimental in vitro pulsatile phantom model was developed imitating a high-flow fistulous-type VGM, which is typical, especially in the neonatal phase. Pressure measurements at different arterial sites were performed before and after closure of the VGM. Closure of the VGM was achieved by coiling using a combined microcatheter-based transvenous and transarterial approach called 'kissing microcatheter technique'. RESULTS: The behaviour of the phantom model in vitro under fluoroscopy and under angiographic runs was extremely similar to that in in vivo conditions in children. The results showed that intra-arterial pressures changed and increased statistically significantly at all measurement sites after embolization, as in human arteriovenous malformation. We also demonstrated different and complementary visualizations of hemodynamics and angioarchitecture by antegrade and retrograde microcatheter injections. CONCLUSIONS: Our phantom model behaves like a typical fistulous-type VGM and can be used in vitro for teaching and training and for further research. It offers a new and better understanding of hemodynamics and angioarchitecture in the endovascular management of VGM. PMID- 27510886 TI - The law and medicine - One family's view. PMID- 27510887 TI - Res ipsa loquitor: No sui generis application to aesthetic surgery. AB - The doctrine of res ipsa loquitor can allow a plaintiff to raise an inference of negligence which a defendant is then compelled to refute. However, the doctrine has rarely been applied in clinical negligence contexts because courts have been reluctant to require doctors to refute an inference of responsibility for pathophysiological outcomes. But does that imperative apply equally to aesthetic surgery? A recent case shows that it does. PMID- 27510888 TI - When Your N >1: Drawing Meaningful Conclusions from Registry Studies. PMID- 27510889 TI - Etoposide damages female germ cells in the developing ovary. AB - BACKGROUND: As with many anti-cancer drugs, the topoisomerase II inhibitor etoposide is considered safe for administration to women in the second and third trimesters of pregnancy, but assessment of effects on the developing fetus have been limited. The purpose of this research was to examine the effect of etoposide on germ cells in the developing ovary. Mouse ovary tissue culture was used as the experimental model, thus allowing us to examine effects of etoposide on all stages of germ cell development in the same way, in vitro. RESULTS: Fetal ovaries from embryonic day 13.5 CD1 mice or neonatal ovaries from postnatal day 0 CD1 mice were cultured with 50-150 ng ml(-1) or 50-200 ng ml(-1) etoposide respectively, concentrations that are low relative to that in patient serum. When fetal ovaries were treated prior to follicle formation, etoposide resulted in dose-dependent damage, with 150 ng ml(-1) inducing a near-complete absence of healthy follicles. In contrast, treatment of neonatal ovaries, after follicle formation, had no effect on follicle numbers and only a minor effect on follicle health, even at 200 ng ml(-1). The sensitivity of female germ cells to etoposide coincided with topoisomerase IIalpha expression: in the developing ovary of both mouse and human, topoisomerase IIalpha was expressed in germ cells only prior to follicle formation. CONCLUSIONS: Exposure of pre-follicular ovaries, in which topoisomerase IIalpha expression was germ cell-specific, resulted in a near complete elimination of germ cells prior to follicle formation, with the remaining germ cells going on to form unhealthy follicles by the end of culture. In contrast, exposure to follicle-enclosed oocytes, which no longer expressed topoisomerase IIalpha in the germ cells, had no effect on total follicle numbers or health, the only effect seen specific to transitional follicles. Results indicate the potential for adverse effects on fetal ovarian development if etoposide is administered to pregnant women when germ cells are not yet enclosed within ovarian follicles, a process that starts at approximately 17 weeks gestation and is only complete towards the end of pregnancy. PMID- 27510890 TI - Predicting the outcomes of using longer-acting prophylactic factor VIII to treat people with severe hemophilia A: a hypothetical decision analysis. AB - Essentials No randomized trials have compared long-acting factor VIII (FVIII) with currently used products. A comparison was undertaken using a decision model to predict FVIII use and number of bleeds. In the base case, longer acting FVIII reduced factor use by 17% while resulting in similar bleeds. The value of longer acting FVIII will be largely determined by existing regimens and unit price. Click to hear Prof. Makris's presentation on new treatments in hemophilia SUMMARY: Background Recently, factor VIII (FVIII) products with longer half lives, such as recombinant FVIII Fc fusion protein (rFVIIIFc), have become available. Use of longer-acting FVIII products will largely depend on effectiveness and cost; no direct evaluations have compared these parameters between conventional and longer-acting FVIII therapies. Objectives To present a hypothetical decision analysis, combining evidence from multiple sources to estimate bleeding frequency, resource use and cost of longer-acting prophylactic products, such as rFVIIIFc, vs. conventional recombinant FVIII (rFVIII). Patients/Methods The decision model used published pharmacokinetic parameters, bleeding frequency vs. time information below a 1-IU dL-1 FVIII trough level, and adherence. Prophylactic treatment scenarios were modelled for a hypothetical patient with severe hemophilia A (<1 IU/dL) receiving rFVIIIFc or rFVIII. Results Infusing twice weekly with rFVIIIFc 42.7 IU kg-1 per dose required less clotting factor than infusing every 56 h with rFVIII 33.75 IU kg-1 per dose; annual bleeding rates were similar. Base case analysis suggested that total FVIII costs were equated when rFVIIIFc cost 1.18 times more per IU than rFVIII, assuming similar adherence. Other modelled scenarios produced similar results, although differences in FVIII consumption were particularly sensitive to assumptions regarding frequency and dose of the rFVIII and rFVIIIFc regimens. For example, decreasing rFVIII from 33.75 IU kg-1 to 30 IU kg-1 per dose decreased the price factor to 1.05. Conclusions Longer-acting FVIII products may reduce FVIII consumption and infusion frequency without compromising hemostatic effect; this should be considered along with other factors (e.g. adherence and underlying FVIII regimen) when evaluating a suitable price for these agents. PMID- 27510891 TI - A New Advanced Backcross Tomato Population Enables High Resolution Leaf QTL Mapping and Gene Identification. AB - Quantitative Trait Loci (QTL) mapping is a powerful technique for dissecting the genetic basis of traits and species differences. Established tomato mapping populations between domesticated tomato (Solanum lycopersicum) and its more distant interfertile relatives typically follow a near isogenic line (NIL) design, such as the S. pennellii Introgression Line (IL) population, with a single wild introgression per line in an otherwise domesticated genetic background. Here, we report on a new advanced backcross QTL mapping resource for tomato, derived from a cross between the M82 tomato cultivar and S. pennellii This so-called Backcrossed Inbred Line (BIL) population is comprised of a mix of BC2 and BC3 lines, with domesticated tomato as the recurrent parent. The BIL population is complementary to the existing S. pennellii IL population, with which it shares parents. Using the BILs, we mapped traits for leaf complexity, leaflet shape, and flowering time. We demonstrate the utility of the BILs for fine-mapping QTL, particularly QTL initially mapped in the ILs, by fine-mapping several QTL to single or few candidate genes. Moreover, we confirm the value of a backcrossed population with multiple introgressions per line, such as the BILs, for epistatic QTL mapping. Our work was further enabled by the development of our own statistical inference and visualization tools, namely a heterogeneous hidden Markov model for genotyping the lines, and by using state-of-the-art sparse regression techniques for QTL mapping. PMID- 27510892 TI - Correlation between vitiligo occurrence and clinical benefit in advanced melanoma patients treated with nivolumab: A multi-institutional retrospective study. AB - Vitiligo is occasionally seen in melanoma patients. Although several studies indicate a correlation between vitiligo occurrence and clinical response in melanoma patients receiving immunotherapy, most studies have included heterogeneous patient and treatment settings. The aim of this study is to investigate the correlation between the occurrence of vitiligo and clinical benefit of nivolumab treatment in advanced melanoma patients. We retrospectively reviewed unresectable stage III or IV melanoma patients treated with nivolumab. Of 35 melanoma patients treated with nivolumab, 25.7% (9/35) developed vitiligo during treatment. The time from the start of nivolumab treatment to occurrence of vitiligo ranged 2-9 months (mean, 5.2). Of nine patients who developed vitiligo, two (22.2%) had a complete response to nivolumab and two (22.2%) had a partial response. The objective response rate was significantly higher in patients with vitiligo than in patients without vitiligo (4/9 [44.4%] vs 2/26 [7.7%]; P = 0.027). The mean time to vitiligo occurrence in patients achieving an objective response was significantly less than that in patients who showed no response (3.1 vs 6.8 months, P = 0.004). Vitiligo occurrence was significantly associated with prolonged progression-free and overall survival (hazard ratio, 0.24 and 0.16; 95% confidence interval, 0.11-0.55 and 0.03-0.79; P = 0.005, and 0.047, respectively). At the 20-week landmark analysis, however, vitiligo was not associated with a statistically significant overall survival benefit (P = 0.28). The occurrence of vitiligo during nivolumab treatment may be correlated with favorable clinical outcome. PMID- 27510893 TI - Analysis of the influence of 111In on 90Y-bremsstrahlung SPECT based on Monte Carlo simulation. AB - OBJECTIVE: 90Y-ibritumomab tiuxetan (Zevalin) which is used for the treatment of malignant lymphomas can be used for SPECT imaging based on bremsstrahlung from 90Y beta particles. However, gamma rays emitted by 111In, which is administered to evaluate the indication for the treatment, contaminate the 90Y bremsstrahlung images. Our objective is to investigate the influence of 111In on the 90Y SPECT images using Monte Carlo simulation. METHODS: We used an in-house developed simulation code for the Monte Carlo simulation of electrons and photons (MCEP). Two hot spheres with diameters of 40 mm were put in an elliptical phantom. Both spheres ("sphere 1" and "sphere 2") were filled with 90Y and 111In mixed solutions. The activities of 90Y in sphere 1 and sphere 2 were 241 and 394 kBq/mL, respectively, and the ones of 111In were 8.14 and 13.3 kBq/mL, respectively. The background activity of 90Y was 38.6 kBq/mL, whereas that of 111In was 1.30 kBq/mL; moreover, the acquisition time was 30 min. Two energy windows were used: one is 90-190 keV included the 111In photopeak; the other is 90-160 keV. To evaluate the quality of the SPECT images, the contrast recovery coefficient (CRC) and the constant noise ratio (CNR) of the SPECT images were derived. RESULTS: For the energy window between 90 and 160 keV, the 111In count was 74 % of the total. In that case, the CRC values were 30.1 and 30.7 % for "sphere 1" and "sphere 2", respectively, whereas the CNR values were 6.8 and 12.1, respectively. For the energy window between 90 and 190 keV, the 111In count reached 85 % of the total count. The CRC and CNR values were 38.6 and 40.0 % and 10.6 and 19.4, respectively. CONCLUSIONS: Our simulation study revealed that the cross talk between 111In and 90Y in SPECT imaging is rather serious. Even for the energy window excluding the 111In photopeak, the count ratio of 90Y was less than 30 % of the total. However, the influence of 111In on 90Y-SPECT imaging cannot be ignored, and the count ratio because of 111In is important to estimate the density of 90Y. PMID- 27510894 TI - An Unusual Case of White Piedra Due to Trichosporon inkin Mimicking Trichobacteriosis. AB - White piedra is a superficial mycosis characterized by soft, white-to-tan, irregular nodules attached to the hair shafts. A 36-year-old man presented with small lumps in his pubic hair, without any other symptoms. The clinical features were suggestive of trichobacteriosis. Pathology analysis of the infected hair revealed that the concretions surrounding the hair shaft were full of fungal elements, parts of which had invaded into the cuticle. Culture on Sabouraud dextrose agar grew creamy, yellow-white colonies identified as Trichosporon inkin by the sequence of the nuclear ribosomal intergenic spacer region. The condition was treated by shaving the pubic hair and administering antifungal therapy (oral itraconazole and topical ketoconazole). PMID- 27510896 TI - Transient spontaneous remission in congenital MLL-AF10 rearranged acute myeloid leukemia presenting with cardiorespiratory failure and meconium ileus. AB - BACKGROUND: Neonatal leukemia is a rare disease with an estimated prevalence of about one to five in a million neonates. The majority being acute myeloid leukemia (AML), neonatal leukemia can present with a variety of symptoms including hyperleucocytosis, cytopenia, hepatosplenomegaly, and skin infiltrates. Chromosomal rearrangements including mixed lineage leukemia (MLL) translocations are common in neonatal AML. CASE PRESENTATION: A female neonate born at 34 weeks gestation presented with cardiorespiratory failure, hepatosplenomegaly, pancytopenia, and coagulopathy. She required intensive care treatment including mechanical ventilation, high-dose catecholamine therapy, and multiple transfusions. Small intestinal biopsy obtained during laparotomy for meconium ileus revealed an infiltrate by an undifferentiated monoblastic, MLL-rearranged leukemia. No other manifestations of leukemia could be detected. After spontaneous clinical remission, lasting 5 months without any specific treatment, the patient presented with leukemia cutis and full-blown monoblastic leukemia. MLL-AF10-rearranged AML could be re-diagnosed and successfully treated with chemotherapy and hematopoietic stem cell transplantation. CONCLUSIONS: Our patient exhibited a unique manifestation of neonatal MLL-AF10 rearranged AML with cardiorespiratory failure and intestinal infiltration. It highlights the importance of leukemia in the differential diagnosis of neonatal distress, congenital hematological abnormalities, and skin lesions. PMID- 27510897 TI - Early origins of asthma (and allergy). AB - Asthma is the most common chronic disease starting in childhood and persisting into adulthood in many cases. During childhood, different forms of asthma and wheezing disorders exist that can be discriminated by the mechanisms they are caused by. Specific genetic constellations and exposure against environmental factors during early childhood and in utero play a decisive role in the early development of the disease. Epigenetic mechanisms which are master regulators of gene transcription and thus govern the accessibility and use of genome information, have recently been identified as a "third power" determining many features in the early development of asthma and allergy. PMID- 27510895 TI - Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice. AB - Developmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319. PMID- 27510898 TI - Rita Redberg: an unwavering campaigner against the harms of too much medicine. PMID- 27510899 TI - A physician-scientist's wish list for the 2016 U.S. presidential candidates. PMID- 27510900 TI - Erratum for the Research Article: "Maternal HIV infection influences the microbiome of HIV-uninfected infants" by J. M. Bender, F. Li, S. Martelly, E. Byrt, V. Rouzier, M. Leo, N. Tobin, P. S. Pannaraj, H. Adisetiyo, A. Rollie, C. Santiskulvong, S. Wang, C. Autran, L. Bode, D. Fitzgerald, L. Kuhn, G. M. Aldrovandi. PMID- 27510901 TI - Hematopoietic stem cell transplantation in immunocompetent hosts without radiation or chemotherapy. AB - Hematopoietic stem cell (HSC) transplantation can cure diverse diseases of the blood system, including hematologic malignancies, anemias, and autoimmune disorders. However, patients must undergo toxic conditioning regimens that use chemotherapy and/or radiation to eliminate host HSCs and enable donor HSC engraftment. Previous studies have shown that anti-c-Kit monoclonal antibodies deplete HSCs from bone marrow niches, allowing donor HSC engraftment in immunodeficient mice. We show that host HSC clearance is dependent on Fc-mediated antibody effector functions, and enhancing effector activity through blockade of CD47, a myeloid-specific immune checkpoint, extends anti-c-Kit conditioning to fully immunocompetent mice. The combined treatment leads to elimination of >99% of host HSCs and robust multilineage blood reconstitution after HSC transplantation. This targeted conditioning regimen that uses only biologic agents has the potential to transform the practice of HSC transplantation and enable its use in a wider spectrum of patients. PMID- 27510902 TI - Insights into neuroepigenetics through human histone deacetylase PET imaging. AB - Epigenetic dysfunction is implicated in many neurological and psychiatric diseases, including Alzheimer's disease and schizophrenia. Consequently, histone deacetylases (HDACs) are being aggressively pursued as therapeutic targets. However, a fundamental knowledge gap exists regarding the expression and distribution of HDACs in healthy individuals for comparison to disease states. Here, we report the first-in-human evaluation of neuroepigenetic regulation in vivo. Using positron emission tomography with [(11)C]Martinostat, an imaging probe selective for class I HDACs (isoforms 1, 2, and 3), we found that HDAC expression is higher in cortical gray matter than in white matter, with conserved regional distribution patterns within and between healthy individuals. Among gray matter regions, HDAC expression was lowest in the hippocampus and amygdala. Through biochemical profiling of postmortem human brain tissue, we confirmed that [(11)C]Martinostat selectively binds HDAC isoforms 1, 2, and 3, the HDAC subtypes most implicated in regulating neuroplasticity and cognitive function. In human stem cell-derived neural progenitor cells, pharmacologic-level doses of Martinostat induced changes in genes closely associated with synaptic plasticity, including BDNF (brain-derived neurotrophic factor) and SYP (synaptophysin), as well as genes implicated in neurodegeneration, including GRN (progranulin), at the transcript level, in concert with increased acetylation at both histone H3 lysine 9 and histone H4 lysine 12. This study quantifies HDAC expression in the living human brain and provides the foundation for gaining unprecedented in vivo epigenetic information in health and disease. PMID- 27510904 TI - Vacuolar H+-ATPase in the nuclear membranes regulates nucleo-cytosolic proton gradients. AB - The regulation of the luminal pH of each organelle is crucial for its function and must be controlled tightly. Nevertheless, it has been assumed that the nuclear pH is regulated by the cytoplasmic proton transporters via the diffusion of H+ across the nuclear pores because of their large diameter. However, it has been demonstrated that ion gradients exist between cytosol and nucleus, suggesting that the permeability of ions across the nuclear pores is restricted. Vacuolar H+-ATPase (V-H+-ATPase) is responsible for the creation and maintenance of trans-membrane electrochemical gradient. We hypothesize that V-H+-ATPase located in the nuclear membranes functions as the primary mechanism to regulate nuclear pH and generate H+ gradients across the nuclear envelope. We studied the subcellular heterogeneity of H+ concentration in the nucleus and cytosol using ratio imaging microscopy and SNARF-1, a pH indicator, in prostate cells. Our results indicate that there are proton gradients across the nuclear membranes that are generated by V-H+-ATPase located in the outer and inner nuclear membranes. We demonstrated that these gradients are mostly dissipated by inhibiting V-H+-ATPase. Immunoblots and V-H+-ATPase activity corroborated the existence of V-H+-ATPase in the nuclear membranes. This study demonstrates that V H+-ATPase is functionally expressed in nuclear membranes and is responsible for nuclear H+ gradients that may promote not only the coupled transport of substrates, but also most electrochemically driven events across the nuclear membranes. This study represents a paradigm shift that the nucleus can regulate its own pH microenvironment, providing new insights into nuclear ion homeostasis and signaling. PMID- 27510905 TI - The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation. AB - Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. In this review, we have collated the enzymes in the UPS whose roles in muscle wasting have been confirmed through loss-of-function studies. We have integrated information on their mechanisms of action to create a model of how they work together to produce muscle atrophy. These enzymes are involved in promoting myofibrillar disassembly and degradation, activation of autophagy, inhibition of myogenesis as well as in modulating the signaling pathways that control these processes. Many anabolic and catabolic signaling pathways are involved in regulating these UPS genes, but none appear to coordinately regulate a large number of these genes. A number of catabolic signaling pathways appear to instead function by inhibition of the insulin/IGF-I/protein kinase B anabolic pathway. This pathway is a critical determinant of muscle mass, since it can suppress key ubiquitin ligases and autophagy, activate protein synthesis, and promote myogenesis through its downstream mediators such as forkhead box O, mammalian target of rapamycin, and GSK3beta, respectively. Although much progress has been made, a more complete inventory of the UPS genes involved in mediating muscle atrophy, their mechanisms of action, and their regulation will be useful for identifying novel therapeutic approaches to this important clinical problem. PMID- 27510903 TI - Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema. AB - Chronic obstructive pulmonary disease and pulmonary fibrosis have been hypothesized to represent premature aging phenotypes. At times, they cluster in families, but the genetic basis is not understood. We identified rare, frameshift mutations in the gene for nuclear assembly factor 1, NAF1, a box H/ACA RNA biogenesis factor, in pulmonary fibrosis-emphysema patients. The mutations segregated with short telomere length, low telomerase RNA levels, and extrapulmonary manifestations including myelodysplastic syndrome and liver disease. A truncated NAF1 was detected in cells derived from patients, and, in cells in which the frameshift mutation was introduced by genome editing, telomerase RNA levels were reduced. The mutant NAF1 lacked a conserved carboxyl terminal motif, which we show is required for nuclear localization. To understand the disease mechanism, we used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein-9 nuclease) to generate Naf1(+/-) mice and found that they had half the levels of telomerase RNA. Other box H/ACA RNA levels were also decreased, but rRNA pseudouridylation, which is guided by snoRNAs, was intact. Moreover, first-generation Naf1(+/-) mice showed no evidence of ribosomal pathology. Our data indicate that disease in NAF1 mutation carriers is telomere-mediated; they show that NAF1 haploinsufficiency selectively disturbs telomere length homeostasis by decreasing the levels of telomerase RNA while sparing rRNA pseudouridylation. PMID- 27510906 TI - Angiotensin II counteracts the effects of cAMP/PKA on NHE3 activity and phosphorylation in proximal tubule cells. AB - Binding of angiotensin II (ANG II) to the AT1 receptor (AT1R) in the proximal tubule stimulates Na+/H+ exchanger isoform 3 (NHE3) activity through multiple signaling pathways. However, the effects of ANG II/AT1R-induced inihibitory G protein (Gi) activation and subsequent decrease in cAMP accumulation on NHE3 regulation are not well established. We therefore tested the hypothesis that ANG II reduces cAMP/PKA-mediated phosphorylation of NHE3 on serine 552 and, in doing so, stimulates NHE3 activity. Under basal conditions, ANG II stimulated NHE3 activity but did not affect PKA-mediated NHE3 phosphorylation at serine 552 in opossum kidney (OKP) cells. However, in the presence of the cAMP-elevating agent forskolin (FSK), ANG II blocked FSK-induced NHE3 inhibition, reduced intracellular cAMP concentrations, lowered PKA activity, and prevented the FSK mediated increase in NHE3 serine 552 phosphorylation. All effects of ANG II were blocked by pretreating OKP cells with the AT1R antagonist losartan, highlighting the contribution of the AT1R/Gi pathway in ANG II-mediated NHE3 upregulation under cAMP-elevating conditions. Accordingly, Gi inhibition by pertussis toxin treatment decreased NHE3 activity both in vitro and in vivo and, more importantly, prevented the stimulatory effect of ANG II on NHE3 activity in rat proximal tubules. Collectively, our results suggest that ANG II counteracts the effects of cAMP/PKA on NHE3 phosphorylation and inhibition by activating the AT1R/Gi pathway. Moreover, these findings support the notion that NHE3 dephosphorylation at serine 552 may represent a key event in the regulation of renal proximal tubule sodium handling by ANG II in the presence of natriuretic hormones that promote cAMP accumulation and transporter phosphorylation. PMID- 27510907 TI - NK Cell Regulatory Property is Involved in the Protective Role of MSC-Derived Extracellular Vesicles in Renal Ischemic Reperfusion Injury. AB - Immunomodulation has been regarded as an important therapeutic aspect of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) in renal ischemic reperfusion injury (IRI), and the specific mechanism still unclear. Here, we attempt to test the function of human MSC-EVs on renal IRI by targeting the natural killer (NK) cells and to investigate the possible mechanism. Data indicated that EVs decreased NK cells in spleen and ischemic kidney. Both the EVs and antibody-dependent depletion of NK cells displayed a protective role in IRI rats. Moreover, the splenectomy model was established to evaluate the role of spleen in this process. It showed that the NK cell regulatory ability and renal protective effects by EVs still exist without spleen, which is unlike MSC properties published previously. Further, the down-regulation of chemokines in injured kidney and the delivery of RNAs through EVs in vitro were also observed. Through the microRNA array test, various inflammation-related microRNAs highly expressed in MSC-EVs compared with fibroblast EVs were tested. Thus, these results indicated that MSC-EVs could ameliorate renal ischemic reperfusion injury by decreasing NK cells and the spleen is not necessary in this process. The regulation of chemokines in injured kidney was the other factor, and the transfer of various microRNAs in the MSC-EVs may be involved. This provides direction for future clinical applications. PMID- 27510908 TI - Visual analytics of geo-social interaction patterns for epidemic control. AB - BACKGROUND: Human interaction and population mobility determine the spatio temporal course of the spread of an airborne disease. This research views such spreads as geo-social interaction problems, because population mobility connects different groups of people over geographical locations via which the viruses transmit. Previous research argued that geo-social interaction patterns identified from population movement data can provide great potential in designing effective pandemic mitigation. However, little work has been done to examine the effectiveness of designing control strategies taking into account geo-social interaction patterns. METHODS: To address this gap, this research proposes a new framework for effective disease control; specifically this framework proposes that disease control strategies should start from identifying geo-social interaction patterns, designing effective control measures accordingly, and evaluating the efficacy of different control measures. This framework is used to structure design of a new visual analytic tool that consists of three components: a reorderable matrix for geo-social mixing patterns, agent-based epidemic models, and combined visualization methods. RESULTS: With real world human interaction data in a French primary school as a proof of concept, this research compares the efficacy of vaccination strategies between the spatial-social interaction patterns and the whole areas. The simulation results show that locally targeted vaccination has the potential to keep infection to a small number and prevent spread to other regions. At some small probability, the local control strategies will fail; in these cases other control strategies will be needed. This research further explores the impact of varying spatial-social scales on the success of local vaccination strategies. The results show that a proper spatial-social scale can help achieve the best control efficacy with a limited number of vaccines. CONCLUSIONS: The case study shows how GS-EpiViz does support the design and testing of advanced control scenarios in airborne disease (e.g., influenza). The geo-social patterns identified through exploring human interaction data can help target critical individuals, locations, and clusters of locations for disease control purposes. The varying spatial-social scales can help geographically and socially prioritize limited resources (e.g., vaccines). PMID- 27510909 TI - HIV Testing Services in Africa: Are They Sustainable? AB - HIV testing services (HTS) are an essential component of a national response to the HIV epidemic, and in lower and middle income countries, at least 150 million persons are tested annually. HIV testing is necessary to identify persons in need of antiretroviral treatment, which has been documented to be highly effective not only for treatment but also for prevention of HIV transmission to both adults and children. An assessment of the recent literature on sustainability of health and HIV services suggests that organizational performance, flexibility, and integration with other health interventions contribute to sustainability of HIV services and programs. This article describes the experiences of two HIV testing service providers in Uganda and Zambia as well as the track record of services to prevent mother-to-child HIV transmission to illustrate the factors of performance, flexibility, adaptability, and integration which are key to the sustainability of HIV testing services. PMID- 27510910 TI - MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice. AB - AIMS/HYPOTHESIS: Diabetic cardiomyopathy (DCM) is associated with suppressed autophagy and augmented apoptosis in the heart although the interplay between the two remains elusive. The ability of mammalian sterile 20-like kinase 1 to regulate both autophagy and apoptosis prompted us to investigate it as a possible candidate in the progression of DCM. METHODS: Wild-type, Mst1 (also known as Stk4) transgenic and Mst1-knockout mice were challenged with streptozotocin to induce experimental diabetes. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe mechanisms. RESULTS: Mst1 knockout alleviated while Mst1 overexpression aggravated cardiac dysfunction in diabetes. Diabetic Mst1 transgenic mice exhibited decreased LC3 expression and enhanced protein aggregation. In contrast, typical autophagosomes were observed in diabetic Mst1-knockout mice with increased LC3 expression and reduced protein aggregation. Mst1 downregulation promoted autophagic flux as demonstrated by increased LC3-II and decreased p62 expression in the presence of bafilomycin A1. Furthermore, Mst1 overexpression increased, while Mst1 knockout decreased, cardiomyocyte apoptosis both in vivo and in vitro. Co-immunoprecipitation assays showed that Mst1 overexpression promoted Beclin1 binding to B cell lymphoma 2 (Bcl-2) and induced dissociation of Bcl-2 from Bax in diabetic mice. Conversely, Mst1 knockout disrupted the Beclin1-Bcl-2 complex and enhanced the interaction between Bcl-2 and Bax. CONCLUSIONS/INTERPRETATION: Mst1 knockout restores autophagy and protects against apoptosis in cardiomyocytes, en route to the rescue against DCM. PMID- 27510911 TI - Maternal gestational diabetes and childhood obesity at age 9-11: results of a multinational study. AB - AIMS/HYPOTHESIS: The aim of this study was to examine the association between maternal gestational diabetes mellitus (GDM) and childhood obesity at age 9-11 years in 12 countries around the world. METHODS: A multinational cross-sectional study of 4740 children aged 9-11 years was conducted. Maternal GDM was diagnosed according to the ADA or WHO criteria. Height and waist circumference were measured using standardised methods. Weight and body fat were measured using a portable Tanita SC-240 Body Composition Analyzer. Multilevel modelling was used to account for the nested nature of the data. RESULTS: The prevalence of reported maternal GDM was 4.3%. The overall prevalence of childhood obesity, central obesity and high body fat were 12.3%, 9.9% and 8.1%, respectively. The multivariable-adjusted (maternal age at delivery, education, infant feeding mode, gestational age, number of younger siblings, child unhealthy diet pattern scores, moderate-to-vigorous physical activity, sleeping time, sedentary time, sex and birthweight) odds ratios among children of GDM mothers compared with children of non-GDM mothers were 1.53 (95% CI 1.03, 2.27) for obesity, 1.73 (95% CI 1.14, 2.62) for central obesity and 1.42 (95% CI 0.90, 2.26) for high body fat. The positive association was still statistically significant for central obesity after additional adjustment for current maternal BMI but was no longer significant for obesity and high body fat. CONCLUSIONS/INTERPRETATION: Maternal GDM was associated with increased odds of childhood obesity at 9-11 years old but this association was not fully independent of maternal BMI. PMID- 27510912 TI - Transfer characteristics of subretinal visual implants: corneally recorded implant responses. AB - PURPOSE: The subretinal Alpha IMS visual implant is a CE-approved medical device for restoration of visual functions in blind patients with end-stage outer retina degeneration. We present a method to test the function of the implant objectively in vivo using standard electroretinographic equipment and to assess the devices' parameter range for an optimal perception. METHODS: Subretinal implant Alpha IMS (Retina Implant AG, Reutlingen, Germany) consists of 1500 photodiode-amplifier electrode units and is implanted surgically into the subretinal space in blind retinitis pigmentosa patients. The voltages that regulate the amplifiers' sensitivity (V gl) and gain (V bias), related to the perception of contrast and brightness, respectively, are adjusted manually on a handheld power supply device. Corneally recorded implant responses (CRIR) to full-field illumination with long duration flashes in various implant settings for brightness gain (V bias) and amplifiers' sensitivity (V gl) are measured using electroretinographic setup with a Ganzfeld bowl in a protocol of increasing stimulus luminances up to 1000 cd/m2. RESULTS: CRIRs are a meaningful tool for assessing the transfer characteristic curves of the electronic implant in vivo monitoring the implants' voltage output as a function of log luminance in a sigmoidal shape. Changing the amplifiers' sensitivity (V gl) shifts the curve left or right along the log luminance axis. Adjustment of the gain (V bias) changes the maximal output. Contrast perception is only possible within the luminance range of the increasing slope of the function. CONCLUSIONS: The technical function of subretinal visual implants can be measured objectively using a standard electroretinographic setup. CRIRs help the patient to optimise the perception by adjusting the gain and luminance range of the device and are a useful tool for clinicians to objectively assess the function of subretinal visual implants in vivo. PMID- 27510913 TI - 3D nanostructured inkjet printed graphene via UV-pulsed laser irradiation enables paper-based electronics and electrochemical devices. AB - Emerging research on printed and flexible graphene-based electronics is beginning to show tremendous promise for a wide variety of fields including wearable sensors and thin film transistors. However, post-print annealing/reduction processes that are necessary to increase the electrical conductivity of the printed graphene degrade sensitive substrates (e.g., paper) and are whole substrate processes that are unable to selectively anneal/reduce only the printed graphene-leaving sensitive device components exposed to damaging heat or chemicals. Herein a pulsed laser process is introduced that can selectively irradiate inkjet printed reduced graphene oxide (RGO) and subsequently improve the electrical conductivity (Rsheet~0.7 kOmega?(-1)) of printed graphene above previously published reports. Furthermore, the laser process is capable of developing 3D petal-like graphene nanostructures from 2D planar printed graphene. These visible morphological changes display favorable electrochemical sensing characteristics-ferricyanide cyclic voltammetry with a redox peak separation (DeltaEp) ~ 0.7 V as well as hydrogen peroxide (H2O2) amperometry with a sensitivity of 3.32 MUA mM(-1) and a response time of <5 s. Thus this work paves the way for not only paper-based electronics with graphene circuits, it enables the creation of low-cost and disposable graphene-based electrochemical electrodes for myriad applications including sensors, biosensors, fuel cells, and theranostic devices. PMID- 27510914 TI - RIFM fragrance ingredient safety assessment, benzyl butyrate, CAS Registry Number 103-37-7. AB - The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data from the suitable read across analog benzyl acetate (CAS # 140-11-4) show that this material is not genotoxic nor does it have skin sensitization potential and also provided a MOE > 100 for the repeated dose, developmental and reproductive, and local respiratory toxicity endpoints. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra. The environmental endpoint was completed as described in the RIFM Framework. PMID- 27510916 TI - Role of Pulse Pressure and Geometry of Primary Entry Tear in Acute Type B Dissection Propagation. AB - The hemodynamic and geometric factors leading to propagation of acute Type B dissections are poorly understood. The objective is to elucidate whether geometric and hemodynamic parameters increase the predilection for aortic dissection propagation. A pulse duplicator set-up was used on porcine aorta with a single entry tear. Mean pressures of 100 and 180 mmHg were used, with pulse pressures ranging from 40 to 200 mmHg. The propagation for varying geometric conditions (%circumference of the entry tear: 15-65%, axial length: 0.5-3.2 cm) were tested for two flap thicknesses (1/3rd and 2/3rd of the thickness of vessel wall, respectively). To assess the effect of pulse and mean pressure on flap dynamics, the %true lumen (TL) cross-sectional area of the entry tear were compared. The % circumference for propagation of thin flap (47 +/- 1%) was not significantly different (p = 0.14) from thick flap (44 +/- 2%). On the contrary, the axial length of propagation for thin flap (2.57 +/- 0.15 cm) was significantly different (p < 0.05) from the thick flap (1.56 +/- 0.10 cm). TL compression was observed during systolic phase. For a fixed geometry of entry tear (%circumference = 39 +/- 2%; axial length = 1.43 +/- 0.13 cm), mean pressure did not have significant (p = 0.84) effect on flap movement. Increase in pulse pressure resulted in a significant change (p = 0.02) in %TL area (52 +/- 4%). The energy acting on the false lumen immediately before propagation was calculated as 75 +/- 9 J/m2 and was fairly uniform across different specimens. Pulse pressure had a significant effect on the flap movement in contrast to mean pressure. Hence, mitigation of pulse pressure and restriction of flap movement may be beneficial in patients with type B acute dissections. PMID- 27510917 TI - Tissue-Engineered Tubular Heart Valves Combining a Novel Precontraction Phase with the Self-Assembly Method. AB - Recently, the tubular shape has been suggested as an effective geometry for tissue-engineered heart valves, allowing easy fabrication, fast implantation, and a minimal crimped footprint from a transcatheter delivery perspective. This simple design is well suited for the self-assembly method, with which the only support for the cells is the extracellular matrix they produce, allowing the tissue to be completely free from exogenous materials during its entire fabrication process. Tubular constructs were produced by rolling self-assembled human fibroblast sheets on plastic mandrels. After maturation, the tubes were transferred onto smaller diameter mandrels and allowed to contract freely. This precontraction phase thickened the tissue and prevented further contraction, while improving fusion between the self-assembled layers and aligning the cells circumferentially. When mounted in a pulsed-flow bioreactor, the valves showed good functionality with large leaflets coaptation and opening area. Although physiological aortic flow conditions were not reached, the leaflets could withstand a 1 Hz pulsed flow with a 300 mL/s peak flow rate and a 70 mmHg peak transvalvular pressure. This study shows that the self-assembly method, which has already proven its potential for the production of small diameter vascular grafts, could also be used to achieve functional tubular heart valves. PMID- 27510918 TI - Distribution of coniferin in freeze-fixed stem of Ginkgo biloba L. by cryo-TOF SIMS/SEM. AB - To clarify the role of coniferin in planta, semi-quantitative cellular distribution of coniferin in quick-frozen Ginkgo biloba L. (ginkgo) was visualized by cryo time-of-flight secondary ion mass spectrometry and scanning electron microscopy (cryo-TOF-SIMS/SEM) analysis. The amount and rough distribution of coniferin were confirmed through quantitative chromatography measurement using serial tangential sections of the freeze-fixed ginkgo stem. The lignification stage of the sample was estimated using microscopic observations. Coniferin distribution visualized at the transverse and radial surfaces of freeze fixed ginkgo stem suggested that coniferin is stored in the vacuoles, and showed good agreement with the assimilation timing of coniferin to lignin in differentiating xylem. Consequently, it is suggested that coniferin is stored in the tracheid cells of differentiating xylem and is a lignin precursor. PMID- 27510919 TI - How and why transient testing may better reveal peripheral chemoreceptor function in humans. PMID- 27510920 TI - Non-vitamin K antagonist oral anticoagulation usage according to age among patients with atrial fibrillation: Temporal trends 2011-2015 in Denmark. AB - Among atrial fibrillation (AF) patients, Danish nationwide registries (2011-2015) were used to examine temporal trends of initiation patterns of oral anticoagulation (OAC) treatment according to age. Overall, 43,299 AF patients initiating vitamin K antagonists (VKA) (42%), dabigatran (29%), rivaroxaban (13%), or apixaban (16%) were included with mean age (SD) 72.1 (11.3), 71.5 (11.0), 74.3 (11.1), and 75.3 (11.1) years, respectively. Patients aged >=85 years comprised 15%. Trend tests showed increase in patients >=85 years initiating OAC (p < 0.0001). VKA usage decreased from 92% to 24% (p < 0.0001). This decrease was independent of age. Dabigatran was the most common non-VKA OAC (NOAC) (40% users), but usage decreased from 2014 until study end (6%) (p < 0.0001). Apixaban was the most used OAC at study end (41%), in particular among those >=85 years (44%). Compared with patients aged <65 years, the odds ratios associated with initiating VKA, dabigatran, rivaroxaban, or apixaban for patients aged >=85 years were 0.81 (95% CI 0.75-0.86), 0.65 (95% CI 0.60-0.70), 1.52 (95% CI 1.38-1.67), and 2.09 (95% CI 1.89-2.30), respectively. In conclusion, substantial increase in NOAC usage has occurred. Increasing age was associated with upstart of rivaroxaban or apixaban with reference to age <65 within the specific agent. PMID- 27510921 TI - Two-Dimensional Supramolecular Polymers Embodying Large Unilamellar Vesicles in Water. AB - We hereby describe a strategy for obtaining novel topological nanostructures consisting of dual-cavity basket 1, forming a curved monolayer of large unilamellar vesicles in water (CAC < 0.25 MUM), and bivalent guests 4/5 populating the cavities of such bolaamphiphilic hosts. On the basis of the results of (1)H NMR spectroscopy, electron microscopy, and dynamic light scattering measurements, we postulated that divalent guest molecules 4/5 cover the curved vesicular surface in a lateral fashion to satisfy the complexation [2 + 2] valency and thereby give stable two-dimensional supramolecular polymers [1?4]n and [1?5]n. The results of experimental studies are also supported with coarse-grained molecular dynamics simulations and molecular mechanics. Our discovery about the assembly of novel vesicular structures could be of interest for stabilization/functionalization of liposomal surfaces as well as detection of polyvalent molecules and removal of targeted substances from aqueous environments. PMID- 27510923 TI - Cancer stem cells and epithelial-mesenchymal transition: Novel therapeutic targets for cancer. AB - Despite the development of various therapeutic approaches, recurrence and metastasis remain major problems for patients with advanced cancer. Recent studies have shown that cancer stem cells (CSCs) play an important role in cancer aggressiveness. In cancer tissues, a small number of CSCs are able to self-renew and differentiate into heterogeneous cancer cells. CSCs usually remain in the resting phase of the cell cycle and possess efficient drug efflux pathways. Thus, they are resistant to chemoradiotherapy and surviving CSCs contribute to recurrence. During cancer metastasis, CSCs undergo epithelial-mesenchymal transition (EMT), thereby acquiring mesenchymal features, migrating to adjacent stromal tissues, and invading blood or lymph vessels. Recent studies showed that EMT-inducible factors also enhance or induce CSC-like features in cancer cells. These findings suggest that EMT is closely correlated with cancer recurrence and metastasis. Inhibition of nestin, a CSC marker, reduces the aggressiveness of several types of cancer. Suppression of the mesenchymal variant of fibroblast growth factor (FGFR)-2, FGFR-2 IIIc, and regulation of the EMT using epithelial splicing regulatory protein 1 (ESRP1) are effective in the treatment of immunodeficient mice with pancreatic cancer. The roles of CSCs and EMT in cancer and possible therapies are discussed in this review. PMID- 27510922 TI - Autophagy initiation by ULK complex assembly on ER tubulovesicular regions marked by ATG9 vesicles. AB - Autophagosome formation requires sequential translocation of autophagy-specific proteins to membranes enriched in PI3P and connected to the ER. Preceding this, the earliest autophagy-specific structure forming de novo is a small punctum of the ULK1 complex. The provenance of this structure and its mode of formation are unknown. We show that the ULK1 structure emerges from regions, where ATG9 vesicles align with the ER and its formation requires ER exit and coatomer function. Super-resolution microscopy reveals that the ULK1 compartment consists of regularly assembled punctate elements that cluster in progressively larger spherical structures and associates uniquely with the early autophagy machinery. Correlative electron microscopy after live imaging shows tubulovesicular membranes present at the locus of this structure. We propose that the nucleation of autophagosomes occurs in regions, where the ULK1 complex coalesces with ER and the ATG9 compartment. PMID- 27510924 TI - Development and validation of a multiplex methylation specific PCR-coupled liquid bead array for liquid biopsy analysis. AB - BACKGROUND: Liquid biopsy is based on minimally invasive blood tests and has the potential to characterize the evolution of a solid tumor in real time, by extracting molecular information from circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Epigenetic silencing of tumor and metastasis suppressor genes plays a key role in survival and metastatic potential of cancer cells. Our group was the first to show the presence of epigenetic alterations in CTCs. METHODS: We present the development and analytical validation of a highly specific and sensitive Multiplex Methylation Specific PCR-coupled liquid bead array (MMSPA) for the simultaneous detection of the methylation status of three tumor and metastasis suppressor genes (CST6, SOX17 and BRMS1) in liquid biopsy material (CTCs, corresponding ctDNA) and paired primary breast tumors. RESULTS: In the EpCAM-positive CTCs fraction we observed methylation of: a) CST6, in 11/30(37%) and 11/30(37%), b) BRMS1 in 8/30(27%) and 11/30(37%) c) SOX17 in 8/30(27%) and 13/30(43%) early breast cancer patients and patients with verified metastasis respectively. In ctDNA we observed methylation of: a) CST6, in 5/30(17%) and 10/31(32%), b) BRMS1 in 8/30 (27%) and 8/31 (26%) c) SOX17 in 5/30(17%) and 13/31(42%) early breast cancer patients and patients with verified metastasis respectively. CONCLUSIONS: Our results indicate a high cancerous load at the epigenetic level in EpCAM-positive CTCs fractions and corresponding ctDNA in breast cancer. The main principle of the developed methodology has the potential to be extended in a large number of gene-targets and be applied in many types of cancer. PMID- 27510925 TI - Disappearing the asylum: Modernizing psychiatry and generating manpower in India. AB - In recent years, the Movement for Global Mental Health (MGMH) and the World Health Organization have worked closely with governments across the global South to redress major treatment gaps to improve access to mental health services. In India, recent reforms include transforming public psychiatric institutions from sites of treatment to research and training institutes, known as "Centres of Excellence," to combat acute manpower shortages and modernize psychiatry. Drawing on ethnographic fieldwork at a public psychiatric hospital in Srinagar, Kashmir, one of the institutions selected to be a future "Centre of Excellence," this article focuses on how these reforms have affected psychiatric institutions themselves. Efforts at modernizing and increasing access to mental health care that is, emphasizing shortened stays, increasing outpatient treatment, and providing care in the "community"-depend on quarantining stigmatized, chronically ill, long-term patients who reside in custodial conditions with fewer resources and limited attention from providers. Psychiatrists have a radically different vision for redressing manpower shortages than the MGMH and Indian state, revealing contradictions in the reform process. This paper demonstrates how modernizing mental health care splits mental institutions spatially, ontologically, temporally, and epistemologically, so that the process of modernizing the institution is neither seamless nor complete. PMID- 27510926 TI - Does culture impact on notions of criminal responsibility and action? The case of spirit possession. AB - Multicultural societies such as the United Kingdom are host to people with diverse belief systems and behavioral norms. Whilst a country requires that all members of society conform to standardized legal requirements, cases arise that involve certain complexities related to the cultural or religious context in which a certain action was committed. This paper addresses the impact of culture on notions of criminal responsibility and action. Through a case study of a recent event in the United Kingdom, we explore whether a cultural defense is relevant for contextualizing incidents in which an individual commits a criminal action during an alleged period of spirit possession From this analysis, we suggest that using a cultural defense can aid understanding of an individual's relationship to the society that he or she identifies with and facilitate the practice of justice in a multicultural society. PMID- 27510927 TI - The relationship between chronic conditions and absenteeism and associated costs in Canada. AB - OBJECTIVES: This study aimed to measure and compare the relationship between chronic diseases and the number of absent workdays due to health problems and the associated costs among working Canadians. METHODS: The study sample included respondents to the 2010 Canadian Community Health Survey between aged 15-75 years who reported employment in the past three months. Respondents reported their number of absent workdays due to health problems and chronic conditions. A negative binomial regression was used to estimate the incremental absent workdays associated with having a particular chronic condition (of 16 conditions), conditional on other chronic conditions and confounders. For each condition, we calculated the incremental number of absent workdays, the incremental productivity loss attributed to absenteeism per employee, and the overall productivity loss in the population. RESULTS: The final sample consisted of 28 678 respondents representing 15 468 788 employed Canadians. The average number of absent workdays due to health problems was 1.35 days over a 3-month period. The three conditions with the greatest association with absent workdays were mood disorders, heart disease, and bowel disorders. They were associated with 1.17, 0.81, and 0.80 additional absent workdays, respectively, compared to workers without this condition, holding other conditions and confounders at their means. At the national working population level, back problems (CAD$621 million), mood disorders (CAD$299 million) and migraine (CAD$245 million) accounted for the largest incremental productivity loss. CONCLUSIONS: Chronic conditions, especially mood disorders and back problems, are associated with substantial work productivity loss. The study findings can help policy-makers and employers prioritize their programs and resources aimed at reducing absenteeism among the working population with chronic conditions. PMID- 27510928 TI - Endogenous non-retroviral RNA virus elements evidence a novel type of antiviral immunity. AB - Vertebrate genomes contain many virus-related sequences derived from both retroviruses and non-retroviral RNA and DNA viruses. Such non-retroviral RNA sequences are possibly produced by reverse-transcription and integration of viral mRNAs of ancient RNA viruses using retrotransposon machineries. We refer to this process as transcript reversion. During an ancient bornavirus infection, transcript reversion may have left bornavirus-related sequences, known as endogenous bornavirus-like nucleoproteins (EBLNs), in the genome. We have recently demonstrated that all Homo sapiens EBLNs are expressed in at least one tissue. Because species with EBLNs appear relatively protected against infection by a current bornavirus, Borna disease virus, it is speculated that EBLNs play some roles in antiviral immunity, as seen with some endogenous retroviruses. EBLNs can function as dominant negative forms of viral proteins, small RNAs targeting viral sequences, or DNA or RNA elements modulating the gene expression. Growing evidence reveals that various RNA viruses are reverse-transcribed and integrated into the genome of infected cells, suggesting transcript reversion generally occurs during ongoing infection. Considering this, transcript reversion mediated interference with related viruses may be a novel type of antiviral immunity in vertebrates. Understanding the biological significance of transcript reversion will provide novel insights into host defenses against viral infections. PMID- 27510929 TI - Much Ado about Something: Cuban Biotech. AB - Cuban advances in biotech have made headlines, particularly since the US-Cuba rapprochement and signing of the historic memorandum of understanding between the US Department of Health and Human Services and Cuba's Ministry of Public Health in June. Some 34 Cuban institutions with 22,000 employees are the backbone of a biotech industry that dates to the early 1980s, obtaining novel products that have sparked interest among potential global partners. While a number of these Cuban products are registered in various countries, their testing in the USA remains ensnared in the red tape of embargo laws that tend to make investors skittish and thus delay, if not curtail, joint research and clinical trial applications to the FDA. PMID- 27510930 TI - Charting the Course to Universal Health in the Americas: Cristian Morales PhD, PAHO/WHO Representative in Cuba. AB - After leaving Chile during the Pinochet era, Dr Morales studied economics, health administration and international health at the University of Montreal. But his baptism in the field came in Haiti, where he was first PAHO advisor to the health ministry, and then for five years was responsible for human resources and health economics in the PAHO offices in the capital of Port-au-Prince. He was at his post during the flooding in Gonaives, five hurricanes, the 2010 earthquake and the ensuing cholera epidemic-doubtless the most dramatic and complex times for the country's health in recent history. Before becoming the PAHO/WHO Representative in Cuba in 2015, he was Regional Advisor in Financing and Health Economics based in Washington, DC. In that role, he plunged into the often thorny debates about just how far governments of the Americas were willing to go towards achieving universal health-universal coverage plus universal access. The result was a historic resolution passed in late 2014 by PAHO's Directing Council (CD53.R14 Strategy for Universal Access to Health and Universal Health Coverage). Dr Morales talks about the process, the outcomes... and the road ahead. PMID- 27510931 TI - The ABCs of Clinical Trials in Cuba. AB - In 1981, Cuba's biotechnology sector was born when Cuban scientists, trained by Finnish colleagues, successfully isolated large quantities of human leukocyte interferon alpha. Within a decade and following a $1-billion dollar investment by the Cuban government, 52 scientific research institutions were established in and around Havana to develop vaccines, therapies and other medical applications to meet demands of the national health system. PMID- 27510932 TI - Epidemiology of Suicide in Cuba, 1987-2014. AB - INTRODUCTION Suicide is a health problem influenced by biological, genetic, psychological, social and economic factors. It is responsible for 50% of violent deaths in the male population, worldwide, and 71% in the female. In the Americas, 65,000 deaths by suicide occur every year. It is the ninth most frequent cause of death in Cuba, and third among people aged 10-19. OBJECTIVE Characterize the epidemiology of suicide in Cuba from 1987 to 2014. METHODS A retrospective descriptive study was conducted. The information comprised all records of death by suicide from January 1, 1987 to December 31, 2014, in the Cuban Ministry of Public Health's National Statistics Division database. The variables were sex, age, skin color, employment status/occupation, marital status, and method of suicide. Crude and age-standardized mortality rates and age-sex specific mortality rates were calculated, all per 100,000 population, as well as the sex ratio. Relative change over the series was calculated as a percentage. Distribution of suicides by variable was calculated and proportions expressed as percentages. RESULTS A total of 51,113 deaths by suicide were reported (annual average 1825), of which 34,671 (67.8%) were among men. The sex ratio was 2.1:1 for the entire study period, and 3.9:1 for 2011-2014. Over the course of the period studied, age-standardized suicide rates decreased from 23.9 to 10.8 per 100,000 population (54.8% reduction). The group aged >=60 years had the highest average age-standardized rate, 44.6 per 100,000 population. The highest suicide burden by age was in the group aged 20-59 years (60.5%). By skin color, the highest burden was in those recorded as white, 68.9%. By marital status, the highest burden was in persons with a stable partner (46.7%), and by employment status/occupation, in retired (25.9%). The most commonly used method was hanging (59.4%). CONCLUSIONS Over the course of about three decades, suicide mortality rates have declined by almost half and they are still slightly higher than overall rates in the Americas. The most commonly used method is hanging. The sex ratio is greater than two and has increased over time. The highest rates occur in the group aged >=60 years, but finer stratification is needed to identify an age related risk trend. In view of Cuba's aging population, these results are of interest for epidemiology and public health. KEYWORDS Suicide, suicide attempt, death, mental health, Cuba. PMID- 27510933 TI - Improving Disability Care in Countries of the Bolivarian Alliance for the Peoples of Our America. AB - Persons with disabilities constitute one of the most vulnerable groups in every society; their identification, assessment and care present a major challenge. In 2001-2003, Cuba conducted the first comprehensive national study of persons with disabilities in the Americas. In 2007-2010, the study was replicated in Bolivia, Ecuador, Nicaragua, Saint Vincent and the Grenadines, and Venezuela, at their governments' request. Study results have enabled implementation of strategies with substancial impact on human health in these countries. In response to it, more than a million medical consultations were provided by professionals whose specialties are lacking in the participating countries, including 139,772 clinical genetic consultations. Once each country's needs were identified, Cuba provided technical assistance with equipment supplied by Venezuela. The study led to development of public policies and programs for disability prevention and care of disabled persons in Bolivia, Ecuador, Nicaragua and Venezuela, and the opening of the National Medical Genetics Center and orthotic and prosthetic laboratories in Venezuela, and rehabilitation centers in Bolivia. KEYWORDS Disability, epidemiology, health services research, needs assessment, human resources, workforce, Bolivia, Cuba, Ecuador, Nicaragua, Saint Vincent and the Grenadines, Venezuela. PMID- 27510934 TI - An Intersectoral Intervention to Prevent Early Alcohol Use in Cuban Adolescents. AB - To encourage development of negative attitudes toward alcohol use and thus prevent early onset of alcohol use, an intersectoral intervention was conducted from 2014 to 2015 among Cuban adolescents in 14 schools in Havana. The intervention included 312 students (189 girls and 123 boys) aged 14 to 15 years in 10th grade of high school or vocational school. Workshops were conducted using participatory techniques and group dynamics. Qualitative methods were applied, including narrative, desiderative and projective techniques. Indicators included attitudes, motivation, interests and perception of risk. Following the intervention, 82.7% (258/312) of participants reported healthy cultural and recreational interests and 61.9% (193/312) reinforced negative attitudes toward drinking. Such interventions can help prevent early onset of alcohol use in school settings. Given the positive results, the intervention is slated to be reproduced in other Cuban provinces. KEYWORDS Adolescents, prevention, alcoholism, attitudes, Cuba. PMID- 27510935 TI - Alcohol Control in Cuba: Preventing Countervailing Cultural and Mass Media Influences. AB - Harmful use of alcohol-the prime gateway drug to other addictions-is also a problem in Cuba, even though the National Program for Prevention of Harmful Use of Alcohol includes the most effective measures used in analogous programs around the world. As a participant in the program's committee and empirical observer of its accomplishments and unaccomplished goals, I draw attention to the community's attitude of tolerance toward intoxication manifested by the lack of proportional consequences, and I insist on the need to broaden the community's understanding of the risks of non-social drinking, which in Latin America is practically limited to alcoholism and its complications. This undervalues the damage wreaked by unpredictable and dangerous behavior under the influence, as well as the suffering of codependents and other "passive drinkers," and the adverse effects of even social drinking. KEYWORDS Alcohol abuse/prevention and control, alcohol consumption, alcohol drinking/culture, alcoholism, drinking behavior, behavior and behavior mechanisms, social determinants of health, social reinforcement, mass media, communication, Cuba. PMID- 27510936 TI - Saharan Dust Effects on Human Health: A Challenge for Cuba's Researchers. AB - WHO considers the effects of air pollution one of the most pressing global health priorities. Several years ago, scientists began noting a link between Saharan dust (a meteorological phenomenon that diminishes air quality as it spreads over the globe) and some diseases, but the few studies to date have been inconsistent. Cuba has the human and material resources to study the association between Saharan dust and health. It is important to encourage creation of multidisciplinary research teams to do so. KEYWORDS Health, airborne particulate matter, dust, air pollutants, environmental health, climate, Cuba. PMID- 27510937 TI - Controversies in Screening and Diagnosis of Gestational Diabetes: Cuba's Position. AB - Gestational diabetes is the most common endocrine disorder affecting pregnant women and its prevalence is on the rise. Prevalence in Cuba is about 5.8%, and global prevalence ranges from 2% to 18% depending on the criteria applied. Gestational diabetes can lead to adverse gestational outcomes, such as fetal death, preterm delivery, dystocia, perinatal asphyxia and neonatal complications. Prompt, accurate diagnosis allowing early treatment can benefit both mother and child. The disease is asymptomatic, so clinical laboratory testing plays a key role in its screening and diagnosis. Cuba's approach to diabetes screening and diagnosis differs from some international practices. All pregnant women in Cuba are screened with a fasting plasma glucose test and diagnosed using modified WHO criteria. Some international recommendations are to skip the screening step and instead follow the diagnostic criteria of the Hyperglycemia and Adverse Pregnancy Outcomes study. In Cuba, gestational outcomes for women with diabetes (including gestational diabetes) are satisfactory (preeclampsia 5%; preterm delivery 12%; neonatal macrosomia 7.5%; congenital abnormalities 4.3% and perinatal deaths 4.8%). These data do not indicate a need to change established screening and diagnostic criteria. KEYWORDS Gestational diabetes, screening, diagnosis, early detection, early diagnosis, Cuba. PMID- 27510938 TI - Havana: A Bike-Friendly City? AB - The abrupt breakup of the USSR and socialist bloc in the early 1990s dealt a devastating blow to the island's economy. Almost overnight, beneficial aid and trade provided by the Council for Mutual Economic Assistance ground to a halt, including 80% of foreign trade previously conducted as barter and sales of 13 million tons of oil per year at preferential prices. When the Cuban economy bottomed out in 1993, oil imports had dropped from 13 to 4 million tons annually. At the time, Cuba depended almost entirely on imported oil and the dramatic decline in imports created massive blackouts, leaving most Cuban homes without electricity 12 hours a day. PMID- 27510939 TI - Immediate and delayed signal of slab breakoff in Oligo/Miocene Molasse deposits from the European Alps. AB - High-resolution 32-20 Ma-old stratigraphic records from the Molasse foreland basin situated north of the Alps, and Gonfolite Lombarda conglomerates deposited on the southern Alpine margin, document two consecutive sedimentary responses - an immediate and delayed response - to slab breakoff beneath the central Alps c. 32-30 Ma ago. The first signal, which occurred due to rebound and surface uplift in the Alps, was a regional and simultaneous switch from basin underfill to overfill at 30 Ma paired with shifts to coarse-grained depositional environments in the foreland basin. The second signal, however, arrived several million years after slab breakoff and was marked by larger contributions of crystalline clasts in the conglomerates, larger clast sizes, larger sediment fluxes and shifts to more proximal facies. We propose that this secondary pulse reflects a delayed whiplash-type erosional response to surface uplift, where erosion and sediment flux became amplified through positive feedbacks once larger erosional thresholds of crystalline bedrock were exceeded. PMID- 27510940 TI - Single scrotal incision orchiopexy versus the inguinal approach in children with palpable undescended testis: a systematic review and meta-analysis. AB - PURPOSE: We performed a systematic review and meta-analysis to compare the efficacy and safety between single-incision, transscrotal orchidopexy, and the traditional inguinal orchidopexy in children. METHODS: A systematic search of the electronic databases was conducted to identify studies compared the transscrotal orchidopexy (SO) and inguinal orchidopexy (IO) for children. Parameters, such as operative time, the incidence of patent processus vaginalis, and postoperative complications, including wound infection, testicular atrophy, testicular reascent, hernia, or hydrocele, were pooled and compared by meta-analysis. RESULTS: Among the 1376 children with palpable undescended testes (UDTs) included in the eight studies, 697 had received SO and 679 IO. There were shorter operative times with the SO approach compared with IO. However, no significant difference was found between SO and IO in the incidence of patent processus vaginalis and postoperative complications, including wound infection, testicular atrophy, testicular reascent, and hernia. CONCLUSION: SO is a safe and effective surgical approach alternative to IO for pediatric UDTs. Compared with IO, SO has the advantage of shorter operative times. Besides, the incidence of postoperative wound infection may be slightly lower in SO. We suggest that SO should be considered as an acceptable option for children with UDTs. PMID- 27510941 TI - AIEgens-Functionalized Inorganic-Organic Hybrid Materials: Fabrications and Applications. AB - Inorganic materials functionalized with organic fluorescent molecules combine advantages of them both, showing potential applications in biomedicine, chemosensors, light-emitting, and so on. However, when more traditional organic dyes are doped into the inorganic materials, the emission of resulting hybrid materials may be quenched, which is not conducive to the efficiency and sensitivity of detection. In contrast to the aggregation-caused quenching (ACQ) system, the aggregation-induced emission luminogens (AIEgens) with high solid quantum efficiency, offer new potential for developing highly efficient inorganic organic hybrid luminescent materials. So far, many AIEgens have been incorporated into inorganic materials through either physical doping caused by aggregation induced emission (AIE) or chemical bonding (e.g., covalent bonding, ionic bonding, and coordination bonding) caused by bonding induced emission (BIE) strategy. The hybrid materials exhibit excellent photoactive properties due to the intramolecular motion of AIEgens is restricted by inorganic matrix. Recent advances in the fabrication of AIEgens-functionalized inorganic-organic hybrid materials and their applications in biomedicine, chemical sensing, and solid state light emitting are presented. PMID- 27510942 TI - Managing Migraine. PMID- 27510943 TI - Exacerbation of Hailey-Hailey disease by topiramate. PMID- 27510944 TI - Functional dissociation between anterior temporal lobe and inferior frontal gyrus in the processing of dynamic body expressions: Insights from behavioral variant frontotemporal dementia. AB - Several brain regions are involved in the processing of emotional stimuli, however, the contribution of specific regions to emotion perception is still under debate. To investigate this issue, we combined behavioral testing, structural and resting state imaging in patients diagnosed with behavioral variant frontotemporal dementia (bvFTD) and age matched controls, with task-based functional imaging in young, healthy volunteers. As expected, bvFTD patients were impaired in emotion detection as well as emotion categorization tasks, testing dynamic emotional body expressions as stimuli. Interestingly, their performance in the two tasks correlated with gray matter volume in two distinct brain regions, the left anterior temporal lobe for emotion detection and the left inferior frontal gyrus (IFG) for emotion categorization. Confirming this observation, multivoxel pattern analysis in healthy volunteers demonstrated that both ROIs contained information for emotion detection, but that emotion categorization was only possible from the pattern in the IFG. Furthermore, functional connectivity analysis showed reduced connectivity between the two regions in bvFTD patients. Our results illustrate that the mentalizing network and the action observation network perform distinct tasks during emotion processing. In bvFTD, communication between the networks is reduced, indicating one possible cause underlying the behavioral symptoms. Hum Brain Mapp 37:4472 4486, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27510945 TI - Evidence-Based Continence Care: An Integrative Review. AB - PURPOSE: The purpose of this integrative review is to identify the best nurse managed continence care strategies among rehabilitation patients from the current body of evidence. DESIGN: The newly designed 2015 Competency Model for Professional Rehabilitation Nursing serves as a conceptual framework to categorize evidence-based recommendations for continence care into the four domains of the model. METHODS: A search of the evidence was completed in December 2015. Literature reviewed was limited to articles published from 2005-2015 in the English language. Search priority was given to systematic reviews and randomized controlled trials. FINDINGS: Nurse-led interventions include evidence-based clinical assessments with use of validated instruments following step-wise algorithms derived from clinical practice guidelines. The interprofessional team emphasizes role-based continence interventions with shared work to reach goals. Leadership recommendations call for administrative support and allocation of resources for continence care and also empower select bedside nurses to become continence champions. Finally, nurse-patient education and caregiver training target the promotion of successful living. System-based continence recommendations are identified to include rehab-oriented electronic documentation systems, written continence policies and procedures, and ongoing nursing education emphasizing accountability to high performance standards. CONCLUSIONS: Rehabilitation nurses are the team leaders in promoting continence in the rehabilitation setting. They are the cultivators of hope and foster resilience among patients to move forward despite acute or chronic illness and disability. This article is intended to support rehabilitation nurses in their review of clinical evidence in effort to move toward a more uniform approach to bowel and bladder management. CLINICAL RELEVANCE: This review equips rehabilitation nurses who seek to improve their practice by identifying the best evidence-based approaches to continence care. PMID- 27510946 TI - Rapid pacing using the left ventricular guidewire: Reviving an old technique to simplify BAV and TAVI procedures. AB - OBJECTIVES: We sought to demonstrate the safety and efficacy of rapid left ventricular (LV) pacing through the guidewire during balloon aortic valvuloplasty (BAV) and Transaortic valve implantation (TAVI). BACKGROUND: Right ventricular temporary pacing during TAVI and BAV is time-consuming and associated with vascular and pericardial complications. METHODS: Rapid left ventricular pacing was provided via the back-up 0.035" guidewire. The cathode of an external pacemaker was placed on the tip of the 0.035" wire and the anode on a needle inserted into the groin. Insulation was ensured by the balloon or TAVI catheter. RESULTS: 38 BAV and 87 TAVI procedures were performed in 113 consecutive patients in three centers with one for one pacing (160-200 bpm) in all patients. A significant reduction in blood pressure was achieved with a mean systolic pressure of 44 mm Hg during stimulation. Mean procedural time was 49.7 +/- 31 min for BAV and 68.7 +/- 30.9 for TAVI. A temporary venous pacemaker was required in 12 patients; only 12% of TAVI patients had a femoral central venous catheter. Femoral venous puncture was not performed in BAV patients. No venous vascular complications were observed. One case of successfully treated tamponade (0.8%) occurred 8 hr post procedure. In-hospital mortality rates were 4.6% and 2.6% in the TAVI and BAV groups, respectively. CONCLUSIONS: Use of the LV guidewire for rapid pacing during BAV and TAVI was shown to be simple, reproducible, and prevented complications associated with RV temporary leads thus potentially simplifying TAVI and enhancing its safety. (c) 2016 Wiley Periodicals, Inc. PMID- 27510947 TI - Design-corrected variation by centre in mortality reduction in the ERSPC randomised prostate cancer screening trial. AB - Objectives To calculate design-corrected estimates of the effect of screening on prostate cancer mortality by centre in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Setting The ERSPC has shown a 21% reduction in prostate cancer mortality in men invited to screening with follow-up truncated at 13 years. Centres either used pre-consent randomisation (effectiveness design) or post-consent randomisation (efficacy design). Methods In six centres (three effectiveness design, three efficacy design) with follow-up until the end of 2010, or maximum 13 years, the effect of screening was estimated as both effectiveness (mortality reduction in the target population) and efficacy (reduction in those actually screened). Results The overall crude prostate cancer mortality risk ratio in the intervention arm vs control arm for the six centres was 0.79 ranging from a 14% increase to a 38% reduction. The risk ratio was 0.85 in centres with effectiveness design and 0.73 in those with efficacy design. After correcting for design, overall efficacy was 27%, 24% in pre-consent and 29% in post-consent centres, ranging between a 12% increase and a 52% reduction. Conclusion The estimated overall effect of screening in attenders (efficacy) was a 27% reduction in prostate cancer mortality at 13 years' follow-up. The variation in efficacy between centres was greater than the range in risk ratio without correction for design. The centre-specific variation in the mortality reduction could not be accounted for by the randomisation method. PMID- 27510949 TI - A model of tissue contraction during thermal ablation. AB - A model of a globular protein is used to describe the contraction of tissue exposed to elevated temperatures. This will be useful in predicting the contraction of tissue that is observed during thermal ablation of tumours, which is a problem when trying to determine the ablation zone in post-operative images. The transitions between the states of the protein can be related to a change in the length of the molecule, which can be directly observed as a change in the length of the tissue. A three state model of a globular protein is used to describe the contraction of tissue exposed to elevated temperatures. A nonlinear fitting algorithm is considered here to fit available experimental data and thus to obtain the values of the model parameters. A sensitivity analysis of the proposed mathematical model is performed to determine the most important parameters in the model. The model parameters were obtained from experimental data of isothermal free shrinkage experiments. The predictions of the complete model show similar agreement with the data, well within the experimental error of 10%. The overall activation energy and frequency factor were found to be 201 kJ mol(-1) and [Formula: see text] s(-1) respectively. The results show that the experimental data were well described by the three state model considered here. Furthermore, it was possible to determine the most sensitive parameters in the model. The model presented here will allow predictions of thermal ablation to be corrected for tissue shrinkage, thus improving mathematical simulations for treatment planning, although clinical translation will require adapting the model from experimentally obtained tendon data to soft tissue data. PMID- 27510948 TI - Cellular model of neuronal atrophy induced by DYNC1I1 deficiency reveals protective roles of RAS-RAF-MEK signaling. AB - Neuronal atrophy is a common pathological feature occurred in aging and neurodegenerative diseases. A variety of abnormalities including motor protein malfunction and mitochondrial dysfunction contribute to the loss of neuronal architecture; however, less is known about the intracellular signaling pathways that can protect against or delay this pathogenic process. Here, we show that the DYNC1I1 deficiency, a neuron-specific dynein intermediate chain, causes neuronal atrophy in primary hippocampal neurons. With this cellular model, we are able to find that activation of RAS-RAF-MEK signaling protects against neuronal atrophy induced by DYNC1I1 deficiency, which relies on MEK-dependent autophagy in neuron. Moreover, we further reveal that BRAF also protects against neuronal atrophy induced by mitochondrial impairment. These findings demonstrate protective roles of the RAS-RAF-MEK axis against neuronal atrophy, and imply a new therapeutic target for clinical intervention. PMID- 27510950 TI - Update on the Toriello-Carey syndrome. AB - Toriello and Carey described a provisionally-unique syndrome comprised of agenesis of the corpus callosum, Pierre Robin anomaly, and a characteristic facial phenotype. Because the condition affected siblings, this entity was postulated to be an autosomal recessive multiple anomaly syndrome. Several patients were subsequently reported, and over time, it became apparent that the Toriello-Carey syndrome was etiologically heterogeneous. Based on previous reports, it is estimated that at least 20% of patients with a clinical diagnosis of Toriello-Carey syndrome have a chromosomal anomaly as the basis of the phenotype. However, no basis for the non-chromosomal cases has been found. This review summarizes the literature to date and provides speculation regarding the possible explanations for failing to find the cause of Toriello-Carey syndrome. (c) 2016 Wiley Periodicals, Inc. PMID- 27510951 TI - Carotid sinus denervation ameliorates renovascular hypertension in adult Wistar rats. AB - KEY POINTS: Peripheral chemoreflex sensitization is a feature of renovascular hypertension. Carotid sinus nerve denervation (CSD) has recently been shown to relieve hypertension and reduce sympathetic activity in other rat models of hypertension. We show that CSD in renovascular hypertension halts further increases in blood pressure. Possible mechanisms include improvements in baroreceptor reflex sensitivity and renal function, restoration of cardiac calcium signalling towards control levels, and reduced neural inflammation. Our data suggest that the peripheral chemoreflex may be a viable therapeutic target for renovascular hypertension. ABSTRACT: The peripheral chemoreflex is known to be hyper-responsive in both spontaneously hypertensive (SHR) and Goldblatt hypertensive (two kidney one clip; 2K1C) rats. We have previously shown that carotid sinus nerve denervation (CSD) reduces arterial blood pressure (ABP) in SHR. In the present study, we show that CSD ameliorates 2K1C hypertension and reveal the potential underlying mechanisms. Adult Wistar rats were instrumented to record ABP via telemetry, and then underwent CSD (n = 9) or sham CSD (n = 9) 5 weeks after renal artery clipping, in comparison with normal Wistar rats (n = 5). After 21 days, renal function was assessed, and tissue was collected to assess sympathetic postganglionic intracellular calcium transients ([Ca2+ ]i ) and immune cell infiltrates. Hypertensive 2K1C rats showed a profound elevation in ABP (Wistar: 98 +/- 4 mmHg vs. 2K1C: 147 +/- 8 mmHg; P < 0.001), coupled with impairments in renal function and baroreflex sensitivity, increased neuroinflammatory markers and enhanced [Ca2+ ]I in stellate neurons (P < 0.05). CSD reduced ABP in 2K1C+CSD rats and prevented the further progressive increase in ABP seen in 2K1C+sham CSD rats, with a between-group difference of 14 +/- 2 mmHg by week 3 (P < 0.01), which was accompanied by improvements in both baroreflex control and spectral indicators of cardiac sympatho-vagal balance. Furthermore, CSD improved protein and albuminuria, decreased [Ca2+ ]i evoked responses from stellate neurons, and also reduced indicators of brainstem inflammation. In summary, CSD in 2K1C rats reduces the hypertensive burden and improves renal function. This may be mediated by improvements in autonomic balance, functional remodelling of post-ganglionic neurons and reduced inflammation. Our results suggest that the peripheral chemoreflex may be considered as a potential therapeutic target for controlling renovascular hypertension. PMID- 27510952 TI - Inhibition of STAT3 enhances the radiosensitizing effect of temozolomide in glioblastoma cells in vitro and in vivo. AB - Even with aggressive treatment involving radiation therapy plus temozolomide (TMZ), the prognosis for glioblastoma remains poor. We investigated the potential for targeting signal transducer and activator of transcription-3 (STAT3) to improve the therapeutic outcome in glioblastoma. We evaluated the preclinical potential of a STAT3 inhibitor, Cpd188, combined with temozolomide and radiation using in vitro assays with two established glioblastoma cell lines (U251 and U87) and two patient-derived glioblastoma cell lines (GBL12 and GBL28) as well as in vivo studies with nude mice bearing intracranial U251 xenografts. Cpd188 potentiated the radiosensitizing effect of TMZ in U251 cells, which have high p STAT3 expression levels. The enhanced radiosensitizing effects of TMZ were associated with impaired DNA damage repair, apoptosis and reversion of the epithelial-mesenchymal transition (EMT). Cpd188 delayed in vivo tumor growth alone and in combination with radiation and TMZ. We also confirmed the radiosensitizing effect of Cpd188 in GBL28 cells, which were originated from a patient with a high level of STAT3 expression and unmethylated MGMT. Targeting STAT3 using Cpd188 could be a viable therapeutic approach for improving the outcome of current standard therapy in glioblastoma patients with high p-STAT3 expression. PMID- 27510953 TI - Migrating glioma cells express stem cell markers and give rise to new tumors upon xenografting. AB - Glioblastoma (GBM) is the most frequent and malignant brain tumor with an overall survival of only 14.6 months. Although these tumors are treated with surgery, radiation and chemotherapy, recurrence is inevitable. A critical population of tumor cells in terms of therapy, the so-called cancer stem cells (CSCs), has been identified in gliomas and many other cancers. These tumor cells have a stem cell like phenotype and are suggested to be responsible for tumor growth, chemo- and radio-resistance as well as recurrence. However, functional evidence for migrating glioma cells having a stem cell-like phenotype is currently lacking. In the present study, the aim was to characterize the phenotype of migrating tumor cells using a novel migration assay based on serum-free stem cell medium and patient-derived spheroid cultures. The results showed pronounced migration of five different GBM spheroid cultures, but not of the commercial cell line U87MG. An in vitro limiting dilution assay showed preserved but reduced spheroid formation capacity of migrating cells. Orthotopic xenografting in mice showed preserved but reduced tumorigenic capacity. Profiling of mRNAs revealed no significant deregulation of 16 predefined CSC-related genes and the HOX-gene list in migrating cells compared to spheroids. Determination of GBM molecular subtypes revealed that subtypes of spheroids and migrating cells were identical. In conclusion, migrating tumor cells preserve expression of stem cell markers and functional CSC characteristics. Since CSCs are reported to be highly resistant to therapy, these results emphasize that the CSC phenotype should be taken into consideration in future treatment of GBMs. PMID- 27510954 TI - Detection and molecular characterization of Torque Teno Virus (TTV) in Uruguay. AB - Torque Teno Virus (TTV), member of Anelloviridae family, is considered a worldwide distributed emergent virus and is currently classified into seven genogroups. Interestingly, the pathogenicity of TTV remains unclear. However, it has been constantly associated to hepatitis cases of unknown etiology (HUE) as well as extensively studied in concurrent infections with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) and Human Immunodeficiency Virus type 1 (HIV-1). In South America, TTV epidemiological data is scant, involving some studies from Brazil, Venezuela, Colombia and Bolivia. The aim of this work was to investigate for the first time in Uruguay the presence of TTV by a nested-PCR system in 85 human serum samples infected with HBV and/or HCV and/or HIV-1 and in HUE cases. Overall, our results reported a TTV infection rate of 79% (67/85). Furthermore, the molecular characterization of Uruguayan strains revealed that one of them clustered in genogroup 1, while the remaining ones formed separate clusters closely related to genogroup 3, which should be confirmed by complete genome sequencing. Further investigation about TTV circulation in Uruguayan population is needed in order to provide additional information about the genetic variability and TTV epidemiology in South America. PMID- 27510955 TI - Barriers to HIV Medication Adherence as a Function of Regimen Simplification. AB - BACKGROUND: Barriers to HIV medication adherence may differ by levels of dosing schedules. PURPOSE: The current study examined adherence barriers associated with medication regimen complexity and simplification. METHODS: A total of 755 people living with HIV currently taking anti-retroviral therapy were recruited from community services in Atlanta, Georgia. Participants completed audio-computer assisted self-interviews that assessed demographic and behavioral characteristics, provided their HIV viral load obtained from their health care provider, and completed unannounced phone-based pill counts to monitor medication adherence over 1 month. RESULTS: Participants taking a single-tablet regimen (STR) were more likely to be adherent than those taking multi-tablets in a single dose regimen (single-dose MTR) and those taking multi-tablets in a multi-dose regimen (multi-dose MTR), with no difference between the latter two. Regarding barriers to adherence, individuals taking STR were least likely to report scheduling issues and confusion as reasons for missing doses, but they were equally likely to report multiple lifestyle and logistical barriers to adherence. CONCLUSIONS: Adherence interventions may need tailoring to address barriers that are specific to dosing regimens. PMID- 27510956 TI - Single-Session Behavioral Interventions for Sexual Risk Reduction: A Meta Analysis. AB - BACKGROUND: Evidence-based, single-session STI/HIV interventions to reduce sexual risk taking are potentially effective options for implementation in resource limited settings and may solve problems associated with poor participant retention. PURPOSE: The purpose of the study is to estimate the efficacy of single-session, behavioral interventions in reducing unprotected sex or increasing condom use. METHODS: Data sources were searched through April 2013 producing 67 single-session interventions (52 unique reports; N = 20,039) that included outcomes on condom use and/or unprotected sex. RESULTS: Overall, participants in single-session interventions reduced sexual risk taking relative to control groups (d + = 0.19, 95 % CI = 0.11, 0.27). Within-group effects of the interventions were larger than the between-groups effects when compared to controls. CONCLUSIONS: Brief, targeted single-session sexual risk reduction interventions demonstrate a small but significant effect and should be prioritized. PMID- 27510957 TI - Effectiveness of temporary implants in teenage patients: a prospective clinical trial. AB - AIMS: The objective of this study was to assess prospectively the outcomes of extra-narrow diameter implants (XNDI) placed in teenage patients as a temporary restorative option. MATERIAL AND METHODS: Twenty consecutive young patients presenting one or several missing teeth received XNDI that were immediately restored with composite, Polymethylmethacrylate (Acrylic) or ceramic crown. Clinical and radiographical outcomes were assessed for a minimum follow-up period of 1 year. Additionally, each patient completed retrospectively a satisfaction questionnaire using Visual Analog Scale (VAS). RESULTS: A total of 30 implants were placed and followed for a period of 1-7.4 years (mean: 3.59 years). One implant failed after 3 weeks and was replaced successfully. No further biological complications occurred during the follow-up period, leading to an implant survival rate of 96.6%. The patient satisfaction evaluations displayed high levels of comfort and function. CONCLUSION: Immediately restored XNDI to replace missing teeth on teenager patients seems to be an effective temporary restorative option to replace missing teeth in young patients. Composite or ceramic crowns should be preferred. Clinical trials with long-term follow-ups and the assessment of passive egression are needed. PMID- 27510958 TI - The role of DNA methylation in ST6Gal1 expression in gliomas. AB - The mechanism of transcriptional silencing of ST6Gal1 in gliomas has not yet been elucidated. Multiple independent promoters govern the expression of the ST6Gal I gene. Here, we investigated whether epigenetic abnormalities involving DNA methylation affect ST6Gal1 expression. Transcript-specific qRT-PCR following exposure of glioma cell lines to 5-aza-2'-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, resulted in the re-expression of the normally quiescent ST6Gal1 mRNA driven exclusively by the P3 promoter sequence. The P3 promoter-specific transcription start site (TSS) was delineated by primer extension and core promoter sequences and associated functional transcription elements identified by deletion analysis utilizing chloramphenicol acetyltransferase reporter constructs. Minimal promoter activity was found to reside within the first 100 bp of the TSS and maximal activity was controlled by functional AP2 binding sites residing between 400 and 500 bp upstream of the initiation site. As altered AP2 binding was not directly associated with AP2 availability, these analyses demonstrate that ST6Gal1 transcription is regulated by DNA methylation within core promoter regions, ultimately by determining critical transcription factor accessibility within these regions. Transcriptional reactivation of ST6Gal1 expression by 5-aza-dC resulted in increased cell surface alpha2,6 sialoglycoconjugate expression, increased alpha2,6 sialylation of beta1 integrin, and decreased adhesion to fibronectin substrate: functional correlates of decreased invasivity. The effects of global hypomethylation are not glycome wide. Focused glycotranscriptomic analyses of three invasive glioma cell lines following 5-aza-dC treatment demonstrated the modulation of select glycogene transcripts. Taken together, these results demonstrate that epigenetic modulation of ST6Gal1 expression plays a key role in the glioma phenotype in vitro and that that therapeutic approaches targeting elements of the epigenetic machinery for the treatment of human glioblastoma are warranted. PMID- 27510959 TI - A Retrospective Study of thrombolysis with 0.6 mg/kg Recombinant Tissue Plasminogen Activator (rt-PA) in Mild Stroke. AB - We sought to assess the safety, effectiveness and cost of 0.6 mg/kg rt-PA treatment for patients with acute mild stroke and to compare that with 0.9 mg/kg. We retrospectively analyzed consecutive acute ischemic stroke patients who had a NIHSS score <=5 at admission and who were treated with rt-PA within 4.5 hours of symptom onset. The demographic data, clinical outcomes and hospitalization cost were analyzed. A total of 108 patients were included. Forty six patients (42.6%) received a 0.6 mg/kg dosage of rt-PA. The baseline characteristics of the two groups were well matched (p > 0.05). Regarding the safety and effectiveness, the 0.6 mg/kg dosage group had a comparable proportion of symptomatic intracranial hemorrhage (sICH) (0.6 mg/kg, 4.3% vs 0.9 mg/kg, 4.8%; p > 0.05), early neurological deterioration (END) (19.6% vs 17.7%; p > 0.05), in-hospital mortality (4.3% vs 1.6%; p > 0.05), and a similar rate of favorable functional outcome (mRS score 0-1) at 3 months (73.9% vs 71.0%; p > 0.05) to those who received the standard dosage. However, the hospital cost was markedly lower in the 0.6 mg/kg group (0.6 mg/kg, 3,401.7 USD vs 0.9 mg/kg, 4,157.4 USD; p < 0.01). Our study suggest that 0.6 mg/kg rt-PA shared similar effectiveness and safety profile compared with that of 0.9 mg/kg in treating mild stroke, but cost less. PMID- 27510960 TI - Effects of series elastic compliance on muscle force summation and the rate of force rise. AB - Compliant tendons permit mechanically unfavourable fascicle dynamics during fixed end contractions. The purpose of this study was to reduce the effective compliance of tendon and investigate how small reductions in active shortening affect twitch kinetics and contractile performance in response to a second stimulus. The series elastic element (SEE) of the human triceps surae (N=15) was effectively stiffened by applying a 55 ms rotation to the ankle, through a range of 5 deg, at the onset of twitch and doublet [interstimulus interval (ISI) of 80 ms] stimulation. Ultrasonography was employed to quantify lateral gastrocnemius and soleus fascicle lengths. Rotation increased twitch torque (40-75%), rate of torque development (RTD; 124-154%) and torque-time integral (TTI; 70-110%) relative to constant-length contractions at the initial and final joint positions, yet caused only modest reductions in shortening amplitude and velocity. The torque contribution of the second pulse increased when stimulation was preceded by rotation, a finding unable to be explained on the basis of fascicle length or SEE stiffness during contraction post-rotation. A further increase in torque contribution was not demonstrated, nor was an increase in doublet TTI, when the second pulse was delivered during rotation and shortly after the initial pulse (ISI of 10 ms). The depressant effect of active shortening on subsequent torque generation suggests that compliant tendons, by affording large length changes, may limit torque summation. Our findings indicate that changes in tendon compliance shown to occur in response to resistance training or unloading are likely sufficient to considerably alter contractile performance, particularly maximal RTD. PMID- 27510961 TI - Echolocation behavior in big brown bats is not impaired after intense broadband noise exposures. AB - Echolocating bats emit trains of intense ultrasonic biosonar pulses and listen to weaker echoes returning from objects in their environment. Identification and categorization of echoes are crucial for orientation and prey capture. Bats are social animals and often fly in groups in which they are exposed to their own emissions and to those from other bats, as well as to echoes from multiple surrounding objects. Sound pressure levels in these noisy conditions can exceed 110 dB, with no obvious deleterious effects on echolocation performance. Psychophysical experiments show that big brown bats (Eptesicus fuscus) do not experience temporary threshold shifts after exposure to intense broadband ultrasonic noise, but it is not known if they make fine-scale adjustments in their pulse emissions to compensate for any effects of the noise. We investigated whether big brown bats adapt the number, temporal patterning or relative amplitude of their emitted pulses while flying through an acoustically cluttered corridor after exposure to intense broadband noise (frequency range 10-100 kHz; sound exposure level 152 dB). Under these conditions, four bats made no significant changes in navigation errors or in pulse number, timing and amplitude 20 min, 24 h or 48 h after noise exposure. These data suggest that big brown bats remain able to perform difficult echolocation tasks after exposure to ecologically realistic levels of broadband noise. PMID- 27510962 TI - Introducing a novel mechanism to control heart rate in the ancestral Pacific hagfish. AB - Although neural modulation of heart rate is well established among chordate animals, the Pacific hagfish (Eptatretus stoutii) lacks any cardiac innervation, yet it can increase its heart rate from the steady, depressed heart rate seen in prolonged anoxia to almost double its normal normoxic heart rate, an almost fourfold overall change during the 1-h recovery from anoxia. The present study sought mechanistic explanations for these regulatory changes in heart rate. We provide evidence for a bicarbonate-activated, soluble adenylyl cyclase (sAC) dependent mechanism to control heart rate, a mechanism never previously implicated in chordate cardiac control. PMID- 27510963 TI - A Description of Vibrational Modes in Hexaphyrins: Understanding the Aromaticity Reversal in the Lowest Triplet State. AB - Aromaticity reversal in the lowest triplet state, or Baird's rule, has been postulated for the past few decades. Despite numerous theoretical works on aromaticity reversal, experimental study is still at a rudimentary stage. Herein, we investigate the aromaticity reversal in the lowest excited triplet state using a comparable set of [26]- and [28]hexaphyrins by femtosecond time-resolved infrared (IR) spectroscopy. Compared to the relatively simple IR spectra of [26]bis(rhodium) hexaphyrin (R26H), those of [28]bis(rhodium) hexaphyrin (R28H) show complex IR spectra the region for the stretching modes of conjugated rings. Whereas time-resolved IR spectra of R26H in the excited triplet state are dominated by excited state IR absorption peaks, while those of R28H largely show ground state IR bleaching peaks, reflecting the aromaticity reversal in the lowest triplet state. These contrasting IR spectral features serve as new experimental aromaticity indices for Baird's rule. PMID- 27510964 TI - Bedside pleuroscopy in Taiwan : a great vision for critically-ill patients and intensivists. AB - Bedside pleuroscopy can be used in daily practice by medical pulmonologists if a patient cannot tolerate either general anesthesia or being moved to an operating or endoscopy room due to their critical condition. It is a simple and safe technique that rarely has complications. The aim of this review is to summarize recent literatures about bedside pleuroscopy and share our experiences with using it in Taiwan. PMID- 27510965 TI - Quercetin suppresses cellular migration and invasion in human head and neck squamous cell carcinoma (HNSCC). AB - Head and neck squamous cell carcinoma (HNSCC) with aberrant epidermal growth factor receptor (EGFR) signaling is often associated with a poor prognosis and a low survival rate. Hence, efficient inhibition of the EGFR signaling-mediated malignancy would improve survival rate. In a previous study, we demonstrated that quercetin appears to be a potent anti-tumorigenic agent through its inhibition of the EGFR/Akt pathway in oral cancer, but its anti-metastatic potential in HNSCC remains unclear [1]. Here, we have hypothesized that quercetin might be effective in metastatic inhibition in EGFR-overexpressing HNSCC cells. Quercetin treatment with 10 MUM (half concentration of IC50) suppressed cell migration and invasion in EGFR-overexpressing HSC-3 and FaDu HNSCC cells. Quercetin also inhibited the colony growth of HSC-3 cells embedded in a Matrigel matrix. Among matrix metalloproteinases (MMPs), the secreted gelatinases MMP-2 and MMP-9 are responsible for the degradation of gelatin in the extracellular matrix and type IV collagen in the basement membrane; and this degradation event is crucial for the migration from the origin and the invasion into the bone in HNSCC. Quercetin (10 MUM) treatment also suppressed the expression and proteolytic activity of MMP 2 and MMP-9. Taken together, our data indicate that quercetin is an effective anti-cancer agent against MMP-2- and MMP-9-mediated metastasis in EGFR overexpressing HNSCC. PMID- 27510966 TI - Prevalence, awareness, treatment, control of type 2 diabetes mellitus and risk factors in Chinese rural population: the RuralDiab study. AB - The study aimed to investigate prevalence, awareness, treatment and control of type 2 diabetes mellitus (T2DM), and to explore potential risk factors in rural areas of China. A total of 16413 individuals aged 18-74 years in rural districts were recruited from the Rural Diabetes, Obesity and Lifestyle (RuralDiab) study for the epidemiological research. Meanwhile, a meta-analysis including 7 published studies was conducted to validate the result of the cross-sectional study. The rates of crude and age-standardized prevalence, awareness, treatment and control of T2DM were 12.19%, 67.00%, 62.35%, 22.20% and 6.98%, 60.11%, 54.85%, 18.77%, respectively. The prevalence, awareness, treatment and control of T2DM displayed increased trends with age (Ptrend < 0.01) and were strongly associated with education, drinking, more vegetable and fruit intake, physical activity, family history of diabetes, body mass index (BMI). The results of this meta-analysis showed that the pooled prevalence, awareness, treatment and control of T2DM in China countryside were 7.3% (5.3-9.4%), 57.3% (36.9-77.6%), 48.4% (32.4-64.5%) and 21.0% (9.9-32.1%), respectively. The prevalence of T2DM was high with inadequate awareness, treatment and control of T2DM in China rural areas. Healthy lifestyles should be advocated to reduce prevalence and improve awareness, treatment, and control of T2DM in Chinese rural residents. PMID- 27510967 TI - Seed abscission and fruit dehiscence required for seed dispersal rely on similar genetic networks. AB - Seed dispersal is an essential trait that enables colonization of new favorable habitats, ensuring species survival. In plants with dehiscent fruits, such as Arabidopsis, seed dispersal depends on two processes: the separation of the fruit valves that protect the seeds (fruit dehiscence) and the detachment of the seeds from the funiculus connecting them to the mother plant (seed abscission). The key factors required to establish a proper lignin pattern for fruit dehiscence are SHATTERPROOF 1 and 2 (SHP1 and SHP2). Here, we demonstrate that the SHP-related gene SEEDSTICK (STK) is a key factor required to establish the proper lignin pattern in the seed abscission zone but in an opposite way. We show that STK acts as a repressor of lignin deposition in the seed abscission zone through the direct repression of HECATE3, whereas the SHP proteins promote lignin deposition in the valve margins by activating INDEHISCENT. The interaction of STK with the SEUSS co-repressor determines the difference in the way STK and SHP proteins control the lignification patterns. Despite this difference in the molecular control of lignification during seed abscission and fruit dehiscence, we show that the genetic networks regulating these two developmental pathways are highly conserved. PMID- 27510968 TI - Epb41l5 competes with Delta as a substrate for Mib1 to coordinate specification and differentiation of neurons. AB - We identified Erythrocyte membrane protein band 4.1-like 5 (Epb41l5) as a substrate for the E3 ubiquitin ligase Mind bomb 1 (Mib1), which is essential for activation of Notch signaling. Although loss of Epb41l5 does not significantly alter the pattern of neural progenitor cells (NPCs) specified as neurons at the neural plate stage, it delays their delamination and differentiation after neurulation when NPCs normally acquire organized apical junctional complexes (AJCs) in the zebrafish hindbrain. Delays in differentiation are reduced by knocking down N-cadherin, a manipulation expected to help destabilize adherens junctions (AJs). This suggested that delays in neuronal differentiation in epb41l5-deficient embryos are related to a previously described role for Epb41l5 in facilitating disassembly of cadherin-dependent AJCs. Mib1 ubiquitylates Epb41l5 to promote its degradation. DeltaD can compete with Epb41l5 to reduce Mib1-dependent Epb41l5 degradation. In this context, increasing the number of NPCs specified to become neurons, i.e. cells expressing high levels of DeltaD, stabilizes Epb41l5 in the embryo. Together, these observations suggest that relatively high levels of Delta stabilize Epb41l5 in NPCs specified as neurons. This, we suggest, helps coordinate NPC specification with Epb41l5-dependent delamination and differentiation as neurons. PMID- 27510969 TI - The Ets protein Pointed prevents both premature differentiation and dedifferentiation of Drosophila intermediate neural progenitors. AB - Intermediate neural progenitors (INPs) need to avoid both dedifferentiation and differentiation during neurogenesis, but the underlying mechanisms are not well understood. In Drosophila, the Ets protein Pointed P1 (PntP1) is required to generate INPs from type II neuroblasts. Here, we investigated how PntP1 promotes INP generation. By generating pntP1-specific mutants and using RNAi knockdown, we show that the loss of PntP1 leads to both an increase in type II neuroblast number and the elimination of INPs. The elimination of INPs results from the premature differentiation of INPs due to ectopic Prospero expression in newly generated immature INPs (imINPs), whereas the increase in type II neuroblasts results from the dedifferentiation of imINPs due to loss of Earmuff at later stages of imINP development. Furthermore, reducing Buttonhead enhances the loss of INPs in pntP1 mutants, suggesting that PntP1 and Buttonhead act cooperatively to prevent premature INP differentiation. Our results demonstrate that PntP1 prevents both the premature differentiation and the dedifferentiation of INPs by regulating the expression of distinct target genes at different stages of imINP development. PMID- 27510970 TI - Modeling halotropism: a key role for root tip architecture and reflux loop remodeling in redistributing auxin. AB - A key characteristic of plant development is its plasticity in response to various and dynamically changing environmental conditions. Tropisms contribute to this flexibility by allowing plant organs to grow from or towards environmental cues. Halotropism is a recently described tropism in which plant roots bend away from salt. During halotropism, as in most other tropisms, directional growth is generated through an asymmetric auxin distribution that generates differences in growth rate and hence induces bending. Here, we develop a detailed model of auxin transport in the Arabidopsis root tip and combine this with experiments to investigate the processes generating auxin asymmetry during halotropism. Our model points to the key role of root tip architecture in allowing the decrease in PIN2 at the salt-exposed side of the root to result in a re-routing of auxin to the opposite side. In addition, our model demonstrates how feedback of auxin on the auxin transporter AUX1 amplifies this auxin asymmetry, while a salt-induced transient increase in PIN1 levels increases the speed at which this occurs. Using AUX1-GFP imaging and pin1 mutants, we experimentally confirmed these model predictions, thus expanding our knowledge of the cellular basis of halotropism. PMID- 27510971 TI - Quiescent center initiation in the Arabidopsis lateral root primordia is dependent on the SCARECROW transcription factor. AB - Lateral root formation is an important determinant of root system architecture. In Arabidopsis, lateral roots originate from pericycle cells, which undergo a program of morphogenesis to generate a new lateral root meristem. Despite its importance for root meristem organization, the onset of quiescent center (QC) formation during lateral root morphogenesis remains unclear. Here, we used live 3D confocal imaging to monitor cell organization and identity acquisition during lateral root development. Our dynamic observations revealed an early morphogenesis phase and a late meristem formation phase as proposed in the bi phasic growth model. Establishment of lateral root QCs coincided with this developmental phase transition. QC precursor cells originated from the outer layer of stage II lateral root primordia, within which the SCARECROW (SCR) transcription factor was specifically expressed. Disrupting SCR function abolished periclinal divisions in this lateral root primordia cell layer and perturbed the formation of QC precursor cells. We conclude that de novo QC establishment in lateral root primordia operates via SCR-mediated formative cell division and coincides with the developmental phase transition. PMID- 27510973 TI - Control of germline stem cell differentiation by Polycomb and Trithorax group genes in the niche microenvironment. AB - Polycomb and Trithorax group (PcG and TrxG) genes function to regulate gene transcription by maintaining a repressive or active chromatin state, respectively. This antagonistic activity is important for body patterning during embryonic development, but whether this function module has a role in adult tissues is unclear. Here, we report that in the Drosophila ovary, disruption of the Polycomb repressive complex 1 (PRC1), specifically in the supporting escort cells, causes blockage of cystoblast differentiation and germline stem cell-like tumor formation. Tumors are caused by derepression of decapentaplegic (dpp), which prevents cystoblast differentiation. Interestingly, activation of dpp in escort cells requires the function of the TrxG gene brahma (brm), suggesting that loss of PRC1 in escort cells causes Brm-dependent dpp expression. Our study suggests a requirement for balanced activity between PcG and TrxG in an adult stem cell niche, and disruption of this balance could lead to the loss of tissue homeostasis and tumorigenesis. PMID- 27510972 TI - A novel small molecule that disrupts a key event during the oocyte-to-embryo transition in C. elegans. AB - The complex cellular events that occur in response to fertilization are essential for mediating the oocyte-to-embryo transition. Here, we describe a comprehensive small-molecule screen focused on identifying compounds that affect early embryonic events in Caenorhabditis elegans We identify a single novel compound that disrupts early embryogenesis with remarkable stage and species specificity. The compound, named C22, primarily impairs eggshell integrity, leading to osmotic sensitivity and embryonic lethality. The C22-induced phenotype is dependent upon the upregulation of the LET-607/CREBH transcription factor and its candidate target genes, which primarily encode factors involved in diverse aspects of protein trafficking. Together, our data suggest that in the presence of C22, one or more key components of the eggshell are inappropriately processed, leading to permeable, inviable embryos. The remarkable specificity and reversibility of this compound will facilitate further investigation into the role and regulation of protein trafficking in the early embryo, as well as serve as a tool for manipulating the life cycle for other studies such as those involving aging. PMID- 27510974 TI - Plastid osmotic stress influences cell differentiation at the plant shoot apex. AB - The balance between proliferation and differentiation in the plant shoot apical meristem is controlled by regulatory loops involving the phytohormone cytokinin and stem cell identity genes. Concurrently, cellular differentiation in the developing shoot is coordinated with the environmental and developmental status of plastids within those cells. Here, we employ an Arabidopsis thaliana mutant exhibiting constitutive plastid osmotic stress to investigate the molecular and genetic pathways connecting plastid osmotic stress with cell differentiation at the shoot apex. msl2 msl3 mutants exhibit dramatically enlarged and deformed plastids in the shoot apical meristem, and develop a mass of callus tissue at the shoot apex. Callus production in this mutant requires the cytokinin receptor AHK2 and is characterized by increased cytokinin levels, downregulation of cytokinin signaling inhibitors ARR7 and ARR15, and induction of the stem cell identity gene WUSCHEL Furthermore, plastid stress-induced apical callus production requires elevated plastidic reactive oxygen species, ABA biosynthesis, the retrograde signaling protein GUN1, and ABI4. These results are consistent with a model wherein the cytokinin/WUS pathway and retrograde signaling control cell differentiation at the shoot apex. PMID- 27510975 TI - Minibrain drives the Dacapo-dependent cell cycle exit of neurons in the Drosophila brain by promoting asense and prospero expression. AB - A key aim of neurodevelopmental research is to understand how precursor cells decide to stop dividing and commence their terminal differentiation at the correct time and place. Here, we show that minibrain (mnb), the Drosophila ortholog of the Down syndrome candidate gene DYRK1A, is transiently expressed in newborn neuronal precursors known as ganglion cells (GCs). Mnb promotes the cell cycle exit of GCs through a dual mechanism that regulates the expression of the cyclin-dependent kinase inhibitor Dacapo, the homolog of vertebrate p27(Kip1) (Cdkn1b). Mnb upregulates the expression of the proneural transcription factor (TF) Asense, which promotes Dacapo expression. Mnb also induces the expression of Prospero, a homeodomain TF that in turn inhibits the expression of Deadpan, a pan neural TF that represses dacapo In addition to its effects on Asense and Prospero, Mnb also promotes the expression of the neuronal-specific RNA regulator Elav, strongly suggesting that Mnb facilitates neuronal differentiation. These actions of Mnb ensure the precise timing of neuronal birth, coupling the mechanisms that regulate neurogenesis, cell cycle control and terminal differentiation of neurons. PMID- 27510976 TI - A role for post-transcriptional control of endoplasmic reticulum dynamics and function in C. elegans germline stem cell maintenance. AB - Membrane-bound receptors, which are crucial for mediating several key developmental signals, are synthesized on endoplasmic reticulum (ER). The functional integrity of ER must therefore be important for the regulation of at least some developmental programs. However, the developmental control of ER function is not well understood. Here, we identify the C. elegans protein FARL 11, an ortholog of the mammalian STRIPAK complex component STRIP1/2 (FAM40A/B), as an ER protein. In the C. elegans embryo, we find that FARL-11 is essential for the cell cycle-dependent morphological changes of ER and for embryonic viability. In the germline, FARL-11 is required for normal ER morphology and for membrane localization of the GLP-1/Notch receptor involved in germline stem cell (GSC) maintenance. Furthermore, we provide evidence that PUF-8, a key translational regulator in the germline, promotes the translation of farl-11 mRNA. These findings reveal that ER form and function in the C. elegans germline are post transcriptionally regulated and essential for the niche-GSC signaling mediated by GLP-1. PMID- 27510977 TI - Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling. AB - Brg1, a core subunit of the SWI/SNF chromatin remodeling complex, is essential for development and homeostasis of various organs. However, the functional role of Brg1 in intestinal development and homeostasis, and the underlying molecular mechanism, remain unknown. We found that deletion of Brg1 in the mouse intestine resulted in growth impairment and early death associated with abnormal crypt villous formation, skewed differentiation into secretory lineage cells, markedly increased apoptosis, and stem cell loss in the duodenum. Furthermore, we found that the Notch signaling pathway was dramatically downregulated in Brg1-deficient duodenum. Remarkably, overexpression of the Notch1 intercellular domain (ICD) partially reversed the prognosis of intestinal Brg1 mutant mice. Notch1 ICD overexpression rescued morphogenesis, prevented over-differentiation into secretory lineage cells, and restored apoptosis to normal levels in Brg1 deficient duodenum, although stem cell loss was not rescued. Our data demonstrate that Brg1 plays an essential role in development and homeostasis, including morphogenesis, stem cell differentiation and cell survival in the duodenum. Mechanistically, the rescue of the intestinal Brg1 mutant phenotype by overexpression of the Notch1 ICD indicates that Notch signaling is a key downstream target that mediates the effects of Brg1. PMID- 27510978 TI - Eye development and photoreceptor differentiation in the cephalopod Doryteuthis pealeii. AB - Photoreception is a ubiquitous sensory ability found across the Metazoa, and photoreceptive organs are intricate and diverse in their structure. Although the morphology of the compound eye in Drosophila and the single-chambered eye in vertebrates have elaborated independently, the amount of conservation within the 'eye' gene regulatory network remains controversial, with few taxa studied. To better understand the evolution of photoreceptive organs, we established the cephalopod Doryteuthis pealeii as a lophotrochozoan model for eye development. Utilizing histological, transcriptomic and molecular assays, we characterize eye formation in Doryteuthis pealeii Through lineage tracing and gene expression analyses, we demonstrate that cells expressing Pax and Six genes incorporate into the lens, cornea and iris, and the eye placode is the sole source of retinal tissue. Functional assays demonstrate that Notch signaling is required for photoreceptor cell differentiation and retinal organization. This comparative approach places the canon of eye research in traditional models into perspective, highlighting complexity as a result of both conserved and convergent mechanisms. PMID- 27510979 TI - Identification and characterization of thermostable glucose dehydrogenases from thermophilic filamentous fungi. AB - FAD-dependent glucose dehydrogenase (FAD-GDH), which contains FAD as a cofactor, catalyzes the oxidation of D-glucose to D-glucono-1,5-lactone, and plays an important role in biosensors measuring blood glucose levels. In order to obtain a novel FAD-GDH gene homolog, we performed degenerate PCR screening of genomic DNAs from 17 species of thermophilic filamentous fungi. Two FAD-GDH gene homologs were identified and cloned from Talaromyces emersonii NBRC 31232 and Thermoascus crustaceus NBRC 9129. We then prepared the recombinant enzymes produced by Escherichia coli and Pichia pastoris. Absorption spectra and enzymatic assays revealed that the resulting enzymes contained oxidized FAD as a cofactor and exhibited glucose dehydrogenase activity. The transition midpoint temperatures (T m) were 66.4 and 62.5 degrees C for glycosylated FAD-GDHs of T. emersonii and T. crustaceus prepared by using P. pastoris as a host, respectively. Therefore, both FAD-GDHs exhibited high thermostability. In conclusion, we propose that these thermostable FAD-GDHs could be ideal enzymes for use as thermotolerant glucose sensors with high accuracy. PMID- 27510980 TI - Effect of air-blast drying and the presence of protectants on the viability of yeast entrapped in calcium alginate beads with an aim to improve the survival rate. AB - Five yeast strains, Saccharomyces cerevisiae D8, M12, and S13; Hanseniaspora uvarum S6; and Issatchenkia orientalis KMBL5774, isolated from Korean grapes, were entrapped in Ca-alginate beads, which are non-toxic, simple to use, and economical. Ca-alginate beads containing yeast cells were soaked in protective solutions, such as skim milk, saccharides, polyols, and nitrogen compounds, before air-blast drying to improve the yeast survival rate and storage ability. The results showed that both entrapment in Ca-alginate beads and soaking in protective agents favorably affected the survival of all strains. The microenvironment formed by the beads and protective agents can protect the yeast cells from harsh environmental conditions, such as low water (below 10 %). All the yeast strains entrapped in Ca-alginate beads showed greater than 80 % survival and less than 11 % water content after air-blast drying at 37 degrees C for 5 h. In addition, air-blast dried cells of S. cerevisiae D8, M12, S13; H. uvarum S6; and I. orientalis KMBL5774 entrapped in 2 % Ca-alginate beads and soaked in protective agents (10 % skim milk containing 10 % sucrose, 10 % raffinose, 10 % trehalose, 10 % trehalose, and 10 % glucose, respectively) after air-blast drying at 37 degrees C for 5 h showed 90, 87, 92, 90, and 87 % viability, respectively. All dried entrapped yeast cells showed survival rates of at least 51 % after storage at 4 degrees C for 3 months. PMID- 27510981 TI - SOS gene induction and possible mutagenic effects of freeze-drying in Escherichia coli and Salmonella typhimurium. AB - We report the results of a study of the potential negative effects of the freeze drying process, normally considered a benign means for long-term conservation of living cells and the golden standard in bacterial preservation. By monitoring gene induction using a whole-cell Escherichia coli bioreporter panel, in which diverse stress-responsive gene promoters are fused to luminescent or fluorescent reporting systems, we have demonstrated that DNA repair genes belonging to the SOS operon (recA, sulA, uvrA, umuD, and lexA) were induced upon resuscitation from the freeze-dried state, whereas other stress-responsive promoters such as grpE, katG, phoA, soxS, and sodA were not affected. This observation was confirmed by the UMU-chromotest (activation of the umuD gene promoter) in Salmonella typhimurium, as well as by real-time PCR analyses of selected E. coli SOS genes. We further show that a functional SOS operon is important in viability maintenance following resuscitation, but that at the same time, this repair system may introduce significantly higher mutation rates, comparable to those induced by high concentrations of a known mutagen. Our results also indicate that the entire freeze-drying process, rather than either freezing or drying separately, is instrumental in the induction of DNA damage. PMID- 27510983 TI - WOMEN'S EMPOWERMENT, HOUSEHOLD STATUS AND CONTRACEPTION USE IN GHANA. AB - Gender inequality is often cited as a barrier to improving women's sexual and reproductive health outcomes, including contraceptive use, in low- and middle income countries such as those in sub-Saharan Africa. To date there is limited, recent, evidence available regarding women's empowerment, household status and contraceptive use in Ghana. The objective of this study was to investigate whether women's empowerment and status in the household were associated with contraceptive use and unmet need for contraception using the 2014 Ghana Demographic and Health Survey. The study sample consisted of 1828 women aged 15 49. Women's empowerment was measured based on two composite indexes created by the DHS: attitudes towards intimate partner violence and decision-making. Women's status in the home was measured using indicators of work status, relationship to household head, control over monetary earnings and land ownership. Decision making was found to be positively associated with contraceptive use and not having unmet need for contraception. Women who justified wife beating in one or more instances were less likely to use contraception, and more likely to have unmet need for contraception. Current or past employment and higher levels of male partner education were associated with contraceptive use. This study indicates that women's empowerment and household status are influential for contraceptive indicators. Future interventions aimed at improving contraceptive uptake and use should promote women's empowerment, i.e. decision-making, self worth and education. PMID- 27510982 TI - Impact of quercetin-induced changes in drug-metabolizing enzyme and transporter expression on the pharmacokinetics of cyclosporine in rats. AB - The aim of the present study was to evaluate whether quercetin (Que) modulates the mRNA and protein expression levels of drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in the small intestine and liver, and thus modifies the pharmacokinetic profile of cyclosporine (CsA) in rats. This two-part study evaluated the pharmacokinetic profiles of CsA in the presence or absence of Que (experiment I) and the involvement of DMEs and DTs (experiment II). In experiment I, 24 rats received single-dose CsA (10 mg/kg) on day 1, single-dose Que (25, 50 and 100 mg/kg/day; eight rats in each group) on days 3-8, and concomitant CsA/Que on day 9. In experiment II, the mRNA and protein expression levels of cytochrome P (CYP)3A1, CYP3A2, UDP glucuronosyltransferase family 1 member A complex locus, organic anion-transporting polypeptide (OATP)2B1, OATP1B2, P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 2 in the small intestine and liver of rats were analyzed following oral administration of Que at 25, 50 and 100 mg/kg in the presence or absence of CsA (10 mg/kg) for seven consecutive days. Co-administration of Que (25,50 and 100 mg/kg) decreased the maximum serum concentration of CsA by 46, 50 and 47% in a dose-independent manner. In addition, the area under the curve to the last measurable concentration and area under the curve to infinite time were decreased, by 21 and 16%, 30 and 33%, and 33 and 34% (P<0.01), respectively. However, the mRNA and protein expression levels of the above-mentioned DMEs and DTs were inhibited by Que in a dose-dependent manner (P<0.01) to a similar extent in the small intestine and liver. It was demonstrated that Que was able to reduce the bioavailability of CsA following multiple concomitant doses in rats. Overlapping modulation of intestinal and hepatic DMEs and DTs, as well as the DME-DT interplay are potential explanations for these observations. PMID- 27510984 TI - Bimetallic salen aluminum complexes: cooperation between reactive centers in the ring-opening polymerization of lactides and epoxides. AB - Three dinuclear aluminum alkyl complexes of the general formula LAl2Me4, where L are salen ligands with an alkyl backbone of different lengths between the nitrogen atoms (1,3-propylene (1), 1,5-pentylene (2) and 1,12-dodecaylene (3)), have been prepared through alkane elimination reactions between each ligand and two equivalents of AlMe3. The related hemi-salen aluminum complex 4 was prepared by an analogous reaction between a phenoxy-imine ligand and a single equivalent of AlMe3. The activities of these aluminum complexes in the ring-opening polymerization (ROP) of rac-lactide and of several epoxides have been investigated and compared. The dinuclear complex 1, bearing the salen ligand with the shortest alkyl bridge, was the most active in the ROP of LA producing isotactic enriched PLA. Otherwise, the other complexes (2 and 3), in which the metal centers are remote, produced atactic PLA with inferior activity. Analogous differences in terms of activity emerged in the ROP of epoxides. The comparison of the catalytic behavior of the dinuclear complexes as well as their mononuclear counterparts suggests the cooperation between the two aluminum metal centers of the dinuclear species in which these are close enough. PMID- 27510985 TI - Effect of hesperidin on the pharmacokinetics of CPT-11 and its active metabolite SN-38 by regulating hepatic Mrp2 in rats. AB - The usage of irinotecan hydrochloride (CPT-11) chemotherapy is hindered by its dose-limiting diarrhea which appears to be associated with the intestinal exposure to SN-38, the active metabolite of CPT-11. Hesperidin, a safe and natural food ingredient flavonoid, exhibits various biological properties. Accumulated evidence showed that the regulatory effect of hesperidin on the expression of Mrp2 in the liver may be one of the critical factors controlling the biliary excretion of SN-38. This study examined the effect of hesperidin on the pharmacokinetics of CPT-11 and SN-38 as well as the regulatory effect on the hepatic expression of Mrp2. Compared with the control group, the AUC5-t was increased to 115% of CPT-11 and 122% of SN-38; the CL was decreased to 87% for CPT-11; the tissue concentration was increased in the liver, kidney and colon; and the accumulated biliary excretion was significantly decreased to 77% for CPT 11 and 76% for SN-38 in hesperidin-treated rats. Furthermore, the expression of Mrp2 in the liver was significantly decreased to 37% in the hesperidin-treated rats compared with that of the control group. These results indicate that oral administration of hesperidin significantly increased the AUC5-t and reduced the clearance of CPT-11 and SN-38, possibly by decreasing the hepatic expression of Mrp2, and thus inhibiting the biliary excretion of CPT-11 and SN-38. The results from this present study suggest that hesperidin may reduce the exposure of CPT-11 and SN-38 in the intestine by reducing the amount of biliary excretion of CPT-11 and SN-38. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27510986 TI - Assessment of the spatial variability in tall wheatgrass forage using LANDSAT 8 satellite imagery to delineate potential management zones. AB - Little information is available on the degree of within-field variability of potential production of Tall wheatgrass (Thinopyrum ponticum) forage under unirrigated conditions. The aim of this study was to characterize the spatial variability of the accumulated biomass (AB) without nutritional limitations through vegetation indexes, and then use this information to determine potential management zones. A 27-*-27-m grid cell size was chosen and 84 biomass sampling areas (BSA), each 2 m(2) in size, were georeferenced. Nitrogen and phosphorus fertilizers were applied after an initial cut at 3 cm height. At 500 degrees C day, the AB from each sampling area, was collected and evaluated. The spatial variability of AB was estimated more accurately using the Normalized Difference Vegetation Index (NDVI), calculated from LANDSAT 8 images obtained on 24 November 2014 (NDVInov) and 10 December 2014 (NDVIdec) because the potential AB was highly associated with NDVInov and NDVIdec (r (2) = 0.85 and 0.83, respectively). These models between the potential AB data and NDVI were evaluated by root mean squared error (RMSE) and relative root mean squared error (RRMSE). This last coefficient was 12 and 15 % for NDVInov and NDVIdec, respectively. Potential AB and NDVI spatial correlation were quantified with semivariograms. The spatial dependence of AB was low. Six classes of NDVI were analyzed for comparison, and two management zones (MZ) were established with them. In order to evaluate if the NDVI method allows us to delimit MZ with different attainable yields, the AB estimated for these MZ were compared through an ANOVA test. The potential AB had significant differences among MZ. Based on these findings, it can be concluded that NDVI obtained from LANDSAT 8 images can be reliably used for creating MZ in soils under permanent pastures dominated by Tall wheatgrass. PMID- 27510987 TI - Microthymoma in elderly-onset myasthenia gravis detected preoperatively. AB - A 77-year-old woman with a 3-month history of muscle weakness was diagnosed with elderly-onset generalized myasthenia gravis (Myasthenia Gravis Foundation of America classification IIa) based on a high serum acetylcholine receptor antibody level (25.4 nmol.L-1) and neurological findings. Computed tomography detected a small nodule (diameter 15 mm) in the anterior mediastinum, which was suspected to be a thymoma. An extended thymectomy was performed. The pathological examination revealed a 6-mm-diameter thymoma, termed a microthymoma, accompanied with a unilocular thymic cyst without capsule formation (type B2 according to the World Health Organization classification). Some fat tissue was also found within the tumor. PMID- 27510988 TI - Stand up for the NHS: Margaret McCartney joins Phil Hammond on stage in Edinburgh. PMID- 27510989 TI - Local environment of metal ions in phthalocyanines: K-edge X-ray absorption spectra. AB - We report a detailed study of the K-edge X-ray absorption spectra of four transition metal phthalocyanines (MPc, M = Fe, Co, Cu and Zn). We identify the important single and multiple scattering contributions to the spectra in the extended energy range and provide a robust treatment of thermal damping; thus, a generally applicable model for the interpretation of X-ray absorption fine structure spectra is proposed. Consistent variations of bond lengths and Debye Waller factors are found as a function of atomic number of the metal ion, indicating a variation of the metal-ligand bond strength which correlates with the spatial arrangement and occupation of molecular orbitals. We also provide an interpretation of the near edge spectral features in the framework of a full potential real space multiple scattering approach and provide a connection to the local electronic structure. PMID- 27510990 TI - Impaired Ca(2+) release contributes to muscle weakness in a rat model of critical illness myopathy. AB - BACKGROUND: Critical illness myopathy is an acquired skeletal muscle disorder with severe myosin loss and muscle weakness frequently seen in intensive care unit (ICU) patients. It is unknown if impaired excitation-contraction coupling contributes to the muscle weakness. METHODS: We used a unique ICU model where rats were deeply sedated, post-synaptically pharmacologically paralyzed, mechanically ventilated and closely monitored for up to ten days. Single intact fibers from the flexor digitorum brevis muscle were isolated and used to measure force and free myoplasmic [Ca(2+)] ([Ca(2+)]i) during tetanic contractions. RESULTS: Fibers from ICU rats had 80 % lower tetanic [Ca(2+)]i and produced only 15 % of the force seen in fibers from sham-operated (SHAM) rats. In the presence of 5 mM caffeine, tetanic [Ca(2+)]i was similar in fibers from ICU and SHAM rats but force was 50 % lower in fibers from ICU rats than SHAM rats. Confocal imaging showed disrupted tetanic [Ca(2+)]i transients in fibers from ICU rats compared to SHAM rats. Western blots showed similar levels of Na(+) channel and dihydropyridine receptor (DHPR) protein expression, whereas ryanodine receptor (RyR) and sarco-endoplasmic reticulum Ca(2+) ATPase 1 (SERCA1) expression was markedly lower in muscle of ICU rats than in SHAM rats. Immunohistochemical analysis showed that distribution of Na(+) channel and DHPR protein on the sarcolemma was disrupted in fibers from ICU rats compared with SHAM rats. CONCLUSIONS: These results suggest that impaired SR Ca(2+) release contributes to the muscle weakness seen in patients in ICU. PMID- 27510991 TI - Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation. AB - Post-traumatic stress disorder patients experience chronic systemic inflammation. However, the molecular pathways involved and mechanisms regulating the expression of genes involved in inflammatory pathways in PTSD are reported inadequately. Through RNA sequencing and miRNA microarray, we identified 326 genes and 190 miRNAs that were significantly different in their expression levels in the PBMCs of PTSD patients. Expression pairing of the differentially expressed genes and miRNAs indicated an inverse relationship in their expression. Functional analysis of the differentially expressed genes indicated their involvement in the canonical pathways specific to immune system biology. DNA methylation analysis of differentially expressed genes also showed a gradual trend towards differences between control and PTSD patients, again indicating a possible role of this epigenetic mechanism in PTSD inflammation. Overall, combining data from the three techniques provided a holistic view of several pathways in which the differentially expressed genes were impacted through epigenetic mechanisms, in PTSD. Thus, analysis combining data from RNA-Seq, miRNA array and DNA methylation, can provide key evidence about dysregulated pathways and the controlling mechanism in PTSD. Most importantly, the present study provides further evidence that inflammation in PTSD could be epigenetically regulated. PMID- 27510992 TI - Reduction of Hexavalent Chromium by Green Tea Polyphenols and Green Tea Nano Zero Valent Iron (GT-nZVI). AB - This study reports on the direct reduction of hexavalent chromium [Cr(VI)] by green tea polyphenols, including a green tea solution and pure epigallocatechin gallate (EGCG) solution. A linear trend was observed between the amount of reduced Cr(VI) and the amount of added polyphenols. The green tea solution showed a continued decrease in the observed stoichiometry with increasing pH, from a maximum of 1.4 mol per gallic acid equivalent (GAE) of green tea at pH 2.5, to 0.2 mol/GAE at pH 8.8. The EGCG solution exhibited different behavior, with a maximum stoichiometry of 2 at pH 7 and minimum of 1.6 at pH 4.4 and 8.9. When green tea was used to first react with Fe3+ and form GT-nZVI, the amount of Cr(VI) reduced by a certain volume of GT-nZVI was double compared to green tea, and 6 times as high considering that GT-nZVI only contains 33 % green tea. PMID- 27510993 TI - A Review of Organophosphate Esters in the Environment from Biological Effects to Distribution and Fate. AB - Organophosphate esters (OPEs) are synthetic phosphoric acid derivatives used in a wide variety of applications including as flame retardants and plasticizers. Their production and usage has increased in recent years, due to the phase-out of other flame retardant formulations (e.g., polybrominated diphenyl ethers). As such, there has been a recent push to understand the global distribution of OPEs and their behaviour in biota. Multiple studies have been published over the last few years pertaining to OPE concentrations in biotic and abiotic environmental compartments, as well as the metabolism of OPEs in biota. This paper aims to provide a brief review of the occurrence and levels of OPEs in the environment, as well as recent developments concerning the elucidation of OPE metabolism in biota. PMID- 27510994 TI - Assessing the Effects of Amoxicillin on Antioxidant Enzyme Activities, Lipid Peroxidation and Protein Carbonyl Content in the Clam Ruditapes philippinarum and the Mussel Mytilus galloprovincialis. AB - In this study, we evaluated the capability of amoxicillin (AMX)-one of the most widely used antibiotics worldwide-to induce oxidative stress in both gills and digestive gland from two bivalve species, the clam Ruditapes philippinarum and the mussel Mytilus galloprovincialis. Superoxide dismutase (SOD) and catalase (CAT) activities, as well as the lipid peroxidation levels (LPO) and protein carbonyl content (PCC), were measured in bivalves exposed to 100, 200 and 400 ug AMX/L for 1, 3 and 7 days. The results obtained demonstrated that AMX affected slightly biomarker responses of molluscs. PMID- 27510995 TI - The Road to Resilience: Insights on Training Community Coalitions in the Los Angeles County Community Disaster Resilience Project. AB - OBJECTIVE: Local health departments (LHDs) have little guidance for operationalizing community resilience (CR). We explored how community coalitions responded to 4 CR levers (education, engagement, partnerships, and community self sufficiency) during the first planning year of the Los Angeles County Community Disaster Resilience (LACCDR) Project. METHODS: Sixteen communities were selected and randomly assigned to the experimental CR group or the control preparedness group. Eight CR coalitions met monthly to plan CR-building activities or to receive CR training from a public health nurse. Trained observers documented the coalitions' understanding and application of CR at each meeting. Qualitative content analysis was used to analyze structured observation reports around the 4 levers. RESULTS: Analysis of 41 reports suggested that coalitions underwent a process of learning about and applying CR concepts in the planning year. Groups resonated with ideas of education, community self-sufficiency, and engagement, but increasing partnerships was challenging. CONCLUSIONS: LHDs can support coalitions by anticipating the time necessary to understand CR and by facilitating engagement. Understanding the issues that emerge in the early phases of planning and implementing CR-building activities is critical. LHDs can use the experience of the LACCDR Project's planning year as a guide to navigate challenges and issues that emerge as they operationalize the CR model. (Disaster Med Public Health Preparedness. 2016;10:812-821). PMID- 27510996 TI - [Autologous stem cell transplantation in systemic sclerosis]. AB - Autologous hematopoietic stem cell transplantation (HSCT) is a very effective treatment option for patients with severe systemic sclerosis (SSc). In addition to various case series two randomized controlled trials could prove its superiority over intense cyclophosphamide pulse therapy. Nevertheless, HSCT is associated with a treatment-related mortality of approximately 10 %; therefore, further studies should be carried out to reduce the toxicity of HSCT by adaptation of the therapy regimen and the option of HSCT should be made available earlier to patients with a high risk of mortality. The mechanism of action of HSCT is still poorly understood. While profibrotic cytokines or even autoantibodies hardly appear to be influenced by the treatment, alterations to regulatory T-cells may play a role. Further improvement of transplantation regimens as well as a better understanding of the underlying pathogenetic principles and mechanisms of action should be the aim of further studies on HSCT. PMID- 27510998 TI - Nocardia lasii sp. nov., a novel actinomycete isolated from the cuticle of an ant (Lasius fuliginosus L). AB - A novel actinomycete, designated strain 3C-HV12T, was isolated from the cuticle of an ant (Lasius fuliginosus L) and characterised using a polyphasic approach. 16S rRNA gene sequence similarity studies showed that strain 3C-HV12T belongs to the genus Nocardia with high sequence similarities to Nocardia soli DSM 44488T (99.2 %) and Nocardia cummidelens R89T (99.2 %), and phylogenetically clustered with these two species and Nocardia ignorata DSM 44496T (98.8 %), Nocardia salmonicida JCM 4826T (98.8 %), Nocardia fluminea S1T (98.8 %), Nocardia coubleae OFN N12T (98 %) and Nocardia camponoti 1H-HV4T (97.4 %). The morphological and chemotaxonomic properties of the strain are also consistent with those of members of the genus Nocardia. The strain was observed to form extensively branched substrate hyphae which fragmented into rod-shaped and non-motile elements. The cell wall was found to contain meso-diaminopimelic acid and the whole cell sugars were identified as arabinose and galactose. The predominant menaquinone was identified as MK-8(H4, omega-cycl). The phospholipid profile was found to consist of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside. The major fatty acids were identified as C18:0 10 methyl, C16:0 and C16:1omega7c. Mycolic acids were found to be present. A combination of DNA-DNA hybridisation experiments and phenotypic tests were carried out between strain 3C-HV12T and its phylogenetically closely related strains, which further clarified their relatedness and demonstrated that 3C-HV12T could be distinguished from these strains. Therefore, the strain is concluded to represent a novel species of the genus Nocardia, for which the name Nocardia lasii sp. nov. is proposed. The type strain is 3C-HV12T (=DSM 100525T = CGMCC 4.7279T). PMID- 27510997 TI - Transglutaminase 2 in cartilage homoeostasis: novel links with inflammatory osteoarthritis. AB - Transglutaminase 2 (TG2) is highly expressed during chondrocyte maturation and contributes to the formation of a mineralised scaffold by introducing crosslinks between extracellular matrix (ECM) proteins. In healthy cartilage, TG2 stabilises integrity of ECM and likely influences cartilage stiffness and mechanistic properties. At the same time, the abnormal accumulation of TG2 in the ECM promotes chondrocyte hypertrophy and cartilage calcification, which might be an important aspect of osteoarthritis (OA) initiation. Although excessive joint loading and injuries are one of the main causes leading to OA development, it is now being recognised that the presence of inflammatory mediators accelerates OA progression. Inflammatory signalling is known to stimulate the extracellular TG2 activity in cartilage and promote TG2-catalysed crosslinking of molecules that promote chondrocyte osteoarthritic differentiation. It is, however, unclear whether TG2 activity aims to resolve or aggravate damages within the arthritic joint. Better understanding of the complex signalling pathways linking inflammation with TG2 activities is needed to identify the role of TG2 in OA and to define possible avenues for therapeutic interventions. PMID- 27510999 TI - Establishment and gene expression analysis of disease-derived induced pluripotent stem cells of scleroderma. AB - BACKGROUND: We recently generated induced pluripotent stem cells (iPSCs) from cultured dermal fibroblasts of systemic sclerosis (SSc-iPSC) to study the disease mechanisms. OBJECTIVE: In the present study, we have performed gene expression analysis using cultured SSc dermal fibroblasts, SSc-iPSC, and fibroblasts re differentiated from SSc-iPSC (SSc-iPSC-FB). METHODS: mRNA and protein levels of collagen and integrins were analyzed using PCR array, PCR, immunoblotting, and immunofluorescence. RESULTS: We compared expression pattern of TGF-beta-related genes between normal iPSC (NS-iPSC) and SSc-iPSC by PCR array, and found constitutive and significant down-regulation of S100A8, Smad6, and TGF-beta2 in SSc-iPSC. The expression of these genes was not altered in cultured SSc fibroblasts or SSc-iPSC-FB compared to NS fibroblasts or NS-iPSC-FB, respectively. On the other hand, the expression of collagen, integrin alpha and beta was up-regulated in SSc fibroblasts, while SSc-iPSC-FB showed normalized levels of collagen and integrin beta. CONCLUSIONS: So far, there have been no reports investigating disease-derived iPSCs of SSc. Our results suggest that S100A8, Smad6, and TGF-beta2 may be the key molecules of this disease. On the other hand, the normalization of collagen and integrins by iPSC reprogramming suggests that epigenetic modifications of genes may play a role in the mechanism of collagen accumulation seen in SSc fibroblasts, and that gene reprogramming may become novel therapeutic approach. As the limitation of this study, we established only one iPSC line from each patient, which may not be enough to discuss disease-specific phenotypes. Larger studies including increased number of iPSC lines are needed in the future. PMID- 27511000 TI - Cancer symptom scale preferences: does one size fit all? AB - OBJECTIVES: Patients with advanced cancer do not report all symptoms, so assessment is best done systematically. However, for such patients, completion rates of some symptom instruments are <50%. Symptoms can be quantified by various scales including the Categorical Response Scale (CRS), Numerical Rating Scale (NRS) and Visual Analogue Scale (VAS). Patient preferences for CRS, NRS and VAS in symptom assessment and their clinical utility in 3 cancer symptoms: pain, tiredness and appetite loss were determined. METHODS: A prospective survey was conducted involving cancer admissions to a 36-bed palliative care unit. RESULTS: 100 inpatients were recruited, aged 38-93 years (x =71 years; SD=11.6), with median Eastern Cooperative Oncology Group (ECOG) scores of 2 (range 0-4). VAS was the least preferred measure. 52% of patients choose the same scale for all 3 symptoms and 44% for 2, with 4% choosing a different individual scale per symptom. There was moderate agreement between participant scale preference and observer determined ease of scale completion (loss of appetite: kappa=0.36; pain: kappa=0.49; tiredness: kappa=0.45). Participants preferred CRS for appetite loss (48%) and tiredness (40%) and NRS for pain (44%). CONCLUSIONS: VAS was the least favoured scale and should be used cautiously in this population. Most participants had a scale preference with high intrapatient consistency between scales. CRS was preferred for appetite loss and tiredness and NRS for pain. Consideration should be given to individualised cancer symptom assessment according to patient scale preference. PMID- 27511001 TI - Evaluating the experiences and support needs of people living with chronic cancer: development and initial validation of the Chronic Cancer Experiences Questionnaire (CCEQ). AB - BACKGROUND: Many advanced cancers are managed as chronic diseases, yet there are currently no international guidelines for the support of patients living with chronic cancer. It is important to understand whether care and service arrangements meet the needs of this rapidly growing patient group. This study aimed to develop and validate a questionnaire to capture patients' experiences of living with chronic cancer and their views of clinical and support services. METHODS: The research was carried out between 1 July 2010 and 21 February 2013. A conceptual framework and initial item bank were derived from prior interviews with 56 patients with chronic cancer. Items were reviewed by 4 oncologists and 1 clinical nurse specialist and during 2 focus groups with 9 patients. Pilot questionnaires were completed by 416 patients across 5 cancer units. Item selection and scale reliability was explored using descriptive data, exploratory factor analysis, internal consistency analyses, multitrait scaling analyses and known-groups comparisons. RESULTS: The final Chronic Cancer Experiences Questionnaire (CCEQ) includes 75 items. 62 items contribute to 14 subscales with internal consistency between alpha 0.68-0.88 and minimal scaling errors. Known groups comparisons confirmed subscale utility in distinguishing between patient groups. Subscales were labelled: managing appointments, coordination of care, general practitioner involvement, clinical trials, information and questions, making treatment decisions, symptom non-reporting, key worker, limitations, sustaining normality, financial advice, worries and anxieties, sharing feelings with others, and accessing support. 13 items assessing symptom experiences were retained as single items. CONCLUSIONS: The CCEQ has the potential to be used as a clinical instrument to assess patient experiences of chronic cancer or to screen for patient needs. It may also be used as an outcome measure for evaluating programmes and models of care and may identify areas for service development that could ultimately improve the care and support received by patients with chronic cancer. PMID- 27511002 TI - Specialized Networks for Social Cognition: A Defining Role for the Oxytocin Receptor. PMID- 27511003 TI - Distributed Representation of "What" and "Where" Information in the Parahippocampal Region. PMID- 27511004 TI - GABAB Receptors Tune Cortical Feedback to the Olfactory Bulb. AB - Sensory perception emerges from the confluence of sensory inputs that encode the composition of external environment and top-down feedback that conveys information from higher brain centers. In olfaction, sensory input activity is initially processed in the olfactory bulb (OB), serving as the first central relay before being transferred to the olfactory cortex. In addition, the OB receives dense connectivity from feedback projections, so the OB has the capacity to implement a wide array of sensory neuronal computation. However, little is known about the impact and the regulation of this cortical feedback. Here, we describe a novel mechanism to gate glutamatergic feedback selectively from the anterior olfactory cortex (AOC) to the OB. Combining in vitro and in vivo electrophysiological recordings, optogenetics, and fiber-photometry-based calcium imaging applied to wild-type and conditional transgenic mice, we explore the functional consequences of circuit-specific GABA type-B receptor (GABABR) manipulation. We found that activation of presynaptic GABABRs specifically depresses synaptic transmission from the AOC to OB inhibitory interneurons, but spares direct excitation to principal neurons. As a consequence, feedforward inhibition of spontaneous and odor-evoked activity of principal neurons is diminished. We also show that tunable cortico-bulbar feedback is critical for generating beta, but not gamma, OB oscillations. Together, these results show that GABABRs on cortico-bulbar afferents gate excitatory transmission in a target specific manner and thus shape how the OB integrates sensory inputs and top-down information. SIGNIFICANCE STATEMENT: The olfactory bulb (OB) receives top-down inputs from the olfactory cortex that produce direct excitation and feedforward inhibition onto mitral and tufted cells, the principal neurons. The functional role of this feedback and the mechanisms regulating the balance of feedback excitation and inhibition remain unknown. We found that GABAB receptors are expressed in cortico-bulbar axons that synapse on granule cells and receptor activation reduces the feedforward inhibition of spontaneous and odor-driven mitral and tufted cells' firing activity. In contrast, direct excitatory inputs to these principal neurons remain unchanged. This study demonstrates that activation of GABAB receptors biases the excitation/inhibition balance provided by cortical inputs to the OB, leading to profound effects on early stages of sensory information processing. PMID- 27511005 TI - Silent Expectations: Dynamic Causal Modeling of Cortical Prediction and Attention to Sounds That Weren't. AB - There is increasing evidence that human perception is realized by a hierarchy of neural processes in which predictions sent backward from higher levels result in prediction errors that are fed forward from lower levels, to update the current model of the environment. Moreover, the precision of prediction errors is thought to be modulated by attention. Much of this evidence comes from paradigms in which a stimulus differs from that predicted by the recent history of other stimuli (generating a so-called "mismatch response"). There is less evidence from situations where a prediction is not fulfilled by any sensory input (an "omission" response). This situation arguably provides a more direct measure of "top-down" predictions in the absence of confounding "bottom-up" input. We applied Dynamic Causal Modeling of evoked electromagnetic responses recorded by EEG and MEG to an auditory paradigm in which we factorially crossed the presence versus absence of "bottom-up" stimuli with the presence versus absence of "top down" attention. Model comparison revealed that both mismatch and omission responses were mediated by increased forward and backward connections, differing primarily in the driving input. In both responses, modeling results suggested that the presence of attention selectively modulated backward "prediction" connections. Our results provide new model-driven evidence of the pure top-down prediction signal posited in theories of hierarchical perception, and highlight the role of attentional precision in strengthening this prediction. SIGNIFICANCE STATEMENT: Human auditory perception is thought to be realized by a network of neurons that maintain a model of and predict future stimuli. Much of the evidence for this comes from experiments where a stimulus unexpectedly differs from previous ones, which generates a well-known "mismatch response." But what happens when a stimulus is unexpectedly omitted altogether? By measuring the brain's electromagnetic activity, we show that it also generates an "omission response" that is contingent on the presence of attention. We model these responses computationally, revealing that mismatch and omission responses only differ in the location of inputs into the same underlying neuronal network. In both cases, we show that attention selectively strengthens the brain's prediction of the future. PMID- 27511006 TI - Compartment-Dependent Degradation of Mutant Huntingtin Accounts for Its Preferential Accumulation in Neuronal Processes. AB - In neurodegenerative diseases caused by misfolded proteins, including Huntington's disease (HD), the neuronal processes and terminals are particularly prone to the accumulation of misfolded proteins, leading to axonal and synaptic dysfunction. This compartment-dependent accumulation can result from either the altered transport of misfolded proteins or impaired protein degradation. Mutant huntingtin (mHtt), the HD protein, is known to affect intracellular transport and can be degraded by the proteasome and autophagy, but how mHtt accumulates in the neuronal processes, an early pathological event in the brains of HD patients, still remains unclear. Using an "optical pulse-chase" assay that can quantify protein degradation in specific subcellular regions, we found that neuronal mHtt is removed faster in the cell body than in neurites. Furthermore, mHtt is cleared more rapidly in astrocytes than in neurons. The ubiquitin-proteasome system plays a much bigger role than autophagy in degrading soluble mHtt via K48 ubiquitination in both the cytoplasm and processes of neurons and astrocytes. By injecting adenoviral vectors expressing mHtt into the mouse brain, we confirmed that mHtt is removed more slowly in neurites than in the cytoplasm of the cell body of neurons. Our findings provide evidence for the cell type- and compartment dependent degradation of mHtt and explain why mHtt preferentially accumulates and aggregates in the neuropils of vulnerable neurons. In addition, our findings suggest that enhancing proteasomal activity could be an effective way to reduce the preferential accumulation of soluble mHtt in neuronal processes. SIGNIFICANCE STATEMENT: The clearance of misfolded proteins is key to preventing neurodegeneration in Huntington's disease, but how mutant huntingtin (mHtt) accumulates differentially in different cell types and subcellular regions remains unclear. We found mHtt is cleared slowly in neuronal processes compared with the cytoplasm and is cleared more efficiently in astrocytes than in neurons. Moreover, this compartment-dependent degradation of soluble mHtt is mediated primarily by the ubiquitin-proteasome system rather than autophagy. Our findings imply that enhancing proteasome activity could be an efficient way to clear soluble misfolded proteins in the neuronal processes. PMID- 27511007 TI - Synchronous Spike Patterns in Macaque Motor Cortex during an Instructed-Delay Reach-to-Grasp Task. AB - The computational role of spike time synchronization at millisecond precision among neurons in the cerebral cortex is hotly debated. Studies performed on data of limited size provided experimental evidence that low-order correlations occur in relation to behavior. Advances in electrophysiological technology to record from hundreds of neurons simultaneously provide the opportunity to observe coordinated spiking activity of larger populations of cells. We recently published a method that combines data mining and statistical evaluation to search for significant patterns of synchronous spikes in massively parallel spike trains (Torre et al., 2013). The method solves the computational and multiple testing problems raised by the high dimensionality of the data. In the current study, we used our method on simultaneous recordings from two macaque monkeys engaged in an instructed-delay reach-to-grasp task to determine the emergence of spike synchronization in relation to behavior. We found a multitude of synchronous spike patterns aligned in both monkeys along a preferential mediolateral orientation in brain space. The occurrence of the patterns is highly specific to behavior, indicating that different behaviors are associated with the synchronization of different groups of neurons ("cell assemblies"). However, pooled patterns that overlap in neuronal composition exhibit no specificity, suggesting that exclusive cell assemblies become active during different behaviors, but can recruit partly identical neurons. These findings are consistent across multiple recording sessions analyzed across the two monkeys. SIGNIFICANCE STATEMENT: Neurons in the brain communicate via electrical impulses called spikes. How spikes are coordinated to process information is still largely unknown. Synchronous spikes are effective in triggering a spike emission in receiving neurons and have been shown to occur in relation to behavior in a number of studies on simultaneous recordings of few neurons. We recently published a method to extend this type of investigation to larger data. Here, we apply it to simultaneous recordings of hundreds of neurons from the motor cortex of macaque monkeys performing a motor task. Our analysis reveals groups of neurons selectively synchronizing their activity in relation to behavior, which sheds new light on the role of synchrony in information processing in the cerebral cortex. PMID- 27511008 TI - Teaching Adult Rats Spinalized as Neonates to Walk Using Trunk Robotic Rehabilitation: Elements of Success, Failure, and Dependence. AB - Robot therapy promotes functional recovery after spinal cord injury (SCI) in animal and clinical studies. Trunk actions are important in adult rats spinalized as neonates (NTX rats) that walk autonomously. Quadrupedal robot rehabilitation was tested using an implanted orthosis at the pelvis. Trunk cortical reorganization follows such rehabilitation. Here, we test the functional outcomes of such training. Robot impedance control at the pelvis allowed hindlimb, trunk, and forelimb mechanical interactions. Rats gradually increased weight support. Rats showed significant improvement in hindlimb stepping ability, quadrupedal weight support, and all measures examined. Function in NTX rats both before and after training showed bimodal distributions, with "poor" and "high weight support" groupings. A total of 35% of rats initially classified as "poor" were able to increase their weight-supported step measures to a level considered "high weight support" after robot training, thus moving between weight support groups. Recovered function in these rats persisted on treadmill with the robot both actuated and nonactuated, but returned to pretraining levels if they were completely disconnected from the robot. Locomotor recovery in robot rehabilitation of NTX rats thus likely included context dependence and/or incorporation of models of robot mechanics that became essential parts of their learned strategy. Such learned dependence is likely a hurdle to autonomy to be overcome for many robot locomotor therapies. Notwithstanding these limitations, trunk-based quadrupedal robot rehabilitation helped the rats to visit mechanical states they would never have achieved alone, to learn novel coordinations, and to achieve major improvements in locomotor function. SIGNIFICANCE STATEMENT: Neonatal spinal transected rats without any weight support can be taught weight support as adults by using robot rehabilitation at trunk. No adult control rats with neonatal spinal transections spontaneously achieve similar changes. The robot rehabilitation system can be inactivated and the skills that were learned persist. Responding rats cannot be detached from the robot altogether, a dependence develops in the skill learned. From data and analysis here, the likelihood of such rats to respond to the robot therapy can also now be predicted. These results are all novel. Understanding trunk roles in voluntary and spinal reflex integration after spinal cord injury and in recovery of function are broadly significant for basic and clinical understanding of motor function. PMID- 27511009 TI - Amyloid Precursor Protein Protects Neuronal Network Function after Hypoxia via Control of Voltage-Gated Calcium Channels. AB - Acute cerebral ischemia and chronic neurovascular diseases share various common mechanisms with neurodegenerative diseases, such as disturbed cellular calcium and energy homeostasis and accumulation of toxic metabolites. A link between these conditions may be constituted by amyloid precursor protein (APP), which plays a pivotal role in the pathogenesis of Alzheimer's disease, but has also been associated with the response to acute hypoxia and regulation of calcium homeostasis. We therefore studied hypoxia-induced loss of function and recovery upon reoxygenation in hippocampal slices of mice lacking APP (APP(-/-)) or selectively expressing its soluble extracellular domain (APPsalpha-KI). Transient hypoxia disrupted electrical activity at the network and cellular level. In mice lacking APP, these impairments were significantly more severe, showing increased rise of intracellular calcium, faster loss of function, and higher incidence of spreading depression. Likewise, functional recovery upon reoxygenation was much slower and less complete than in controls. Most of these deficits were rescued by selective expression of the soluble extracellular fragment APPsalpha, or by pharmacological block of L-type calcium channels. We conclude that APP supports neuronal resistance toward acute hypoxia. This effect is mediated by the secreted APPsalpha-domain and involves L-type calcium channels. SIGNIFICANCE STATEMENT: Amyloid precursor protein (APP) is involved in the pathophysiology of Alzheimer's disease, but its normal function in the brain remains elusive. Here, we describe a neuroprotective role of the protein in acute hypoxia. Functional recovery of mouse hippocampal networks after transient reduction of oxygen supply was strongly impaired in animals lacking APP. Most protective effects are mediated by the soluble extracellular fragment APPsalpha and involve L-type calcium channels. Thus, APP contributes to calcium homeostasis in situations of metabolic stress. This finding may shed light on the physiological function of APP and may be important for understanding mechanisms of neurodegenerative diseases. PMID- 27511010 TI - Ventral Midline Thalamus Is Critical for Hippocampal-Prefrontal Synchrony and Spatial Working Memory. AB - Maintaining behaviorally relevant information in spatial working memory (SWM) requires functional synchrony between the dorsal hippocampus and medial prefrontal cortex (mPFC). However, the mechanism that regulates synchrony between these structures remains unknown. Here, we used a unique dual-task approach to compare hippocampal-prefrontal synchrony while rats switched between an SWM dependent task and an SWM-independent task within a single behavioral session. We show that task-specific representations in mPFC neuronal populations are accompanied by SWM-specific oscillatory synchrony and directionality between the dorsal hippocampus and mPFC. We then demonstrate that transient inactivation of the reuniens and rhomboid (Re/Rh) nuclei of the ventral midline thalamus abolished only the SWM-specific activity patterns that were seen during dual-task sessions within the hippocampal-prefrontal circuit. These findings demonstrate that Re/Rh facilitate bidirectional communication between the dorsal hippocampus and mPFC during SWM, providing evidence for a causal role of Re/Rh in regulating hippocampal-prefrontal synchrony and SWM-directed behavior. SIGNIFICANCE STATEMENT: Hippocampal-prefrontal synchrony has long been thought to be critical for spatial working memory (SWM) and the ventral midline thalamic reuniens and rhomboid nuclei (Re/Rh) have long been considered a potential site for synchronizing the hippocampus and medial prefrontal cortex. However, the hypothesis that Re/Rh are critical for hippocampal-prefrontal synchrony and SWM has not been tested. We first used a dual-task approach to identify SWM-specific patterns of hippocampal-prefrontal synchrony. We then demonstrated that Re/Rh inactivation concurrently disrupted SWM-specific behavior and the SWM-specific patterns of hippocampal-prefrontal synchrony seen during dual-task performance. These results provide the first direct evidence that Re/Rh contribute to SWM by modulating hippocampal-prefrontal synchrony. PMID- 27511011 TI - BDNF Val66Met Polymorphism Interacts with Sleep Consolidation to Predict Ability to Create New Declarative Memories. AB - It is hypothesized that a fundamental function of sleep is to restore an individual's day-to-day ability to learn and to constantly adapt to a changing environment through brain plasticity. Brain-derived neurotrophic factor (BDNF) is among the key regulators that shape brain plasticity. However, advancing age and carrying the BDNF Met allele were both identified as factors that potentially reduce BDNF secretion, brain plasticity, and memory. Here, we investigated the moderating role of BDNF polymorphism on sleep and next-morning learning ability in 107 nondemented individuals who were between 55 and 84 years of age. All subjects were tested with 1 night of in-laboratory polysomnography followed by a cognitive evaluation the next morning. We found that in subjects carrying the BDNF Val66Val polymorphism, consolidated sleep was associated with significantly better performance on hippocampus-dependent episodic memory tasks the next morning (beta-values from 0.290 to 0.434, p <= 0.01). In subjects carrying at least one copy of the BDNF Met allele, a more consolidated sleep was not associated with better memory performance in most memory tests (beta-values from 0.309 to -0.392, p values from 0.06 to 0.15). Strikingly, increased sleep consolidation was associated with poorer performance in learning a short story presented verbally in Met allele carriers (beta = -0.585, p = 0.005). This study provides new evidence regarding the interacting roles of consolidated sleep and BDNF polymorphism in the ability to learn and stresses the importance of considering BDNF polymorphism when studying how sleep affects cognition. SIGNIFICANCE STATEMENT: Individuals with the BDNF Val/Val (valine allele) polymorphism showed better memory performance after a night of consolidated sleep. However, we observed that middle-aged and older individuals who are carriers of the BDNF Met allele displayed no positive association between sleep quality and their ability to learn the next morning. This interaction between sleep and BDNF polymorphism was more salient for hippocampus-dependent tasks than for other cognitive tasks. Our results support the hypothesis that reduced activity-dependent secretion of BDNF impairs the benefits of sleep on synaptic plasticity and next-day memory. Our work advances the field by revealing new evidence of a clear genetic heterogeneity in how sleep consolidation contributes to the ability to learn. PMID- 27511012 TI - 3D Visual Response Properties of MSTd Emerge from an Efficient, Sparse Population Code. AB - Neurons in the dorsal subregion of the medial superior temporal (MSTd) area of the macaque respond to large, complex patterns of retinal flow, implying a role in the analysis of self-motion. Some neurons are selective for the expanding radial motion that occurs as an observer moves through the environment ("heading"), and computational models can account for this finding. However, ample evidence suggests that MSTd neurons exhibit a continuum of visual response selectivity to large-field motion stimuli. Furthermore, the underlying computational principles by which these response properties are derived remain poorly understood. Here we describe a computational model of macaque MSTd based on the hypothesis that neurons in MSTd efficiently encode the continuum of large field retinal flow patterns on the basis of inputs received from neurons in MT with receptive fields that resemble basis vectors recovered with non-negative matrix factorization. These assumptions are sufficient to quantitatively simulate neurophysiological response properties of MSTd cells, such as 3D translation and rotation selectivity, suggesting that these properties might simply be a byproduct of MSTd neurons performing dimensionality reduction on their inputs. At the population level, model MSTd accurately predicts eye velocity and heading using a sparse distributed code, consistent with the idea that biological MSTd might be well equipped to efficiently encode various self-motion variables. The present work aims to add some structure to the often contradictory findings about macaque MSTd, and offers a biologically plausible account of a wide range of visual response properties ranging from single-unit selectivity to population statistics. SIGNIFICANCE STATEMENT: Using a dimensionality reduction technique known as non-negative matrix factorization, we found that a variety of medial superior temporal (MSTd) neural response properties could be derived from MT-like input features. The responses that emerge from this technique, such as 3D translation and rotation selectivity, spiral tuning, and heading selectivity, can account for a number of empirical results. These findings (1) provide a further step toward a scientific understanding of the often nonintuitive response properties of MSTd neurons; (2) suggest that response properties, such as complex motion tuning and heading selectivity, might simply be a byproduct of MSTd neurons performing dimensionality reduction on their inputs; and (3) imply that motion perception in the cortex is consistent with ideas from the efficient coding and free-energy principles. PMID- 27511013 TI - Medial Orbitofrontal Neurons Preferentially Signal Cues Predicting Changes in Reward during Unblocking. AB - The orbitofrontal cortex (OFC) has been broadly implicated in the ability to use the current value of expected outcomes to guide behavior. Although value correlates have been prominently reported in lateral OFC, they are more often associated with more medial areas. Further, recent studies in primates have suggested a dissociation in which the lateral OFC is involved in credit assignment and representation of reward identity and more medial areas are critical to representing value. Previously, we used unblocking to test more specifically what information about outcomes is represented by OFC neurons in rats; consistent with the proposed dichotomy between the lateral and medial OFC, we found relatively little linear value coding in the lateral OFC (Lopatina et al., 2015). Here we have repeated this experiment, recording in the medial OFC, to test whether such value signals might be found there. Neurons were recorded in an unblocking task as rats learned about cues that signaled either more, less, or the same amount of reward. We found that medial OFC neurons acquired responses to these cues; however, these responses did not signal different reward values across cues. Surprisingly, we found that cells developed responses to cues predicting a change, particularly a decrease, in reward value. This is consistent with a special role for medial OFC in representing current value to support devaluation/revaluation sensitive changes in behavior. SIGNIFICANCE STATEMENT: This study uniquely examines encoding in rodent mOFC at the single-unit level in response to cues that predict more, less, or no change in reward in rats during training in a Pavlovian unblocking task, finding more cells responding to change predictive cues and stronger activity in response to cues predictive of less reward. PMID- 27511014 TI - The Face-Processing Network Is Resilient to Focal Resection of Human Visual Cortex. AB - Human face perception requires a network of brain regions distributed throughout the occipital and temporal lobes with a right hemisphere advantage. Present theories consider this network as either a processing hierarchy beginning with the inferior occipital gyrus (occipital face area; IOG-faces/OFA) or a multiple route network with nonhierarchical components. The former predicts that removing IOG-faces/OFA will detrimentally affect downstream stages, whereas the latter does not. We tested this prediction in a human patient (Patient S.P.) requiring removal of the right inferior occipital cortex, including IOG-faces/OFA. We acquired multiple fMRI measurements in Patient S.P. before and after a preplanned surgery and multiple measurements in typical controls, enabling both within subject/across-session comparisons (Patient S.P. before resection vs Patient S.P. after resection) and between-subject/across-session comparisons (Patient S.P. vs controls). We found that the spatial topology and selectivity of downstream ipsilateral face-selective regions were stable 1 and 8 month(s) after surgery. Additionally, the reliability of distributed patterns of face selectivity in Patient S.P. before versus after resection was not different from across-session reliability in controls. Nevertheless, postoperatively, representations of visual space were typical in dorsal face-selective regions but atypical in ventral face selective regions and V1 of the resected hemisphere. Diffusion weighted imaging in Patient S.P. and controls identifies white matter tracts connecting retinotopic areas to downstream face-selective regions, which may contribute to the stable and plastic features of the face network in Patient S.P. after surgery. Together, our results support a multiple-route network of face processing with nonhierarchical components and shed light on stable and plastic features of high-level visual cortex following focal brain damage. SIGNIFICANCE STATEMENT: Brain networks consist of interconnected functional regions commonly organized in processing hierarchies. Prevailing theories predict that damage to the input of the hierarchy will detrimentally affect later stages. We tested this prediction with multiple brain measurements in a rare human patient requiring surgical removal of the putative input to a network processing faces. Surprisingly, the spatial topology and selectivity of downstream face-selective regions are stable after surgery. Nevertheless, representations of visual space were typical in dorsal face-selective regions but atypical in ventral face selective regions and V1. White matter connections from outside the face network may support these stable and plastic features. As processing hierarchies are ubiquitous in biological and nonbiological systems, our results have pervasive implications for understanding the construction of resilient networks. PMID- 27511015 TI - SIRT1 Mediates Depression-Like Behaviors in the Nucleus Accumbens. AB - Depression is a recurring and life-threatening illness that affects up to 120 million people worldwide. In the present study, we show that chronic social defeat stress, an ethologically validated model of depression in mice, increases SIRT1 levels in the nucleus accumbens (NAc), a key brain reward region. Increases in SIRT1, a well characterized class III histone deacetylase, after chronic social defeat suggest a role for this enzyme in mediating depression-like behaviors. When resveratrol, a pharmacological activator of SIRT1, was directly infused bilaterally into the NAc, we observed an increase in depression- and anxiety-like behaviors. Conversely, intra-NAc infusions of EX-527, a SIRT1 antagonist, reduced these behaviors; EX-527 also reduced acute stress responses in stress-naive mice. Next, we increased SIRT1 levels directly in NAc by use of viral-mediated gene transfer and observed an increase in depressive- and anxiety like behaviors when mice were assessed in the open-field, elevated-plus-maze, and forced swim tests. Using a Cre-inducible viral vector system to overexpress SIRT1 selectively in dopamine D1 or D2 subpopulations of medium spiny neurons (MSNs) in the NAc, we found that SIRT1 promotes depressive-like behaviors only when overexpressed in D1 MSNs, with no effect seen in D2 MSNs. Conversely, selective ablation of SIRT1 in the NAc using viral-Cre in floxed Sirt1 mice resulted in decreased depression- and anxiety-like behaviors. Together, these results demonstrate that SIRT1 plays an essential role in the NAc in regulating mood related behavioral abnormalities and identifies a novel signaling pathway for the development of innovative antidepressants to treat major depressive disorders. SIGNIFICANCE STATEMENT: In this study, we demonstrate a pivotal role for SIRT1 in anxiety- and depression-like behaviors in the nucleus accumbens (NAc), a key brain reward region. We show that stress stably induces SIRT1 expression in this brain region and that altering SIRT1 activity using a pharmacological or genetic approach regulates anxiety- and depression-like behaviors. These results suggest that SIRT1 plays an essential role in regulating mood-related behaviors and introduces a novel signaling pathway for the development of innovative antidepressants to treat depression and other stress-related disorders. A recent groundbreaking publication by the CONVERGE Consortium (2015) identified a reproducible association of the SIRT1 locus with major depression in humans. Therefore, our results are timely and have significant translational relevance. PMID- 27511016 TI - Transient Modulations of Neural Responses to Heartbeats Covary with Bodily Self Consciousness. AB - Recent research has investigated self-consciousness associated with the multisensory processing of bodily signals (e.g., somatosensory, visual, vestibular signals), a notion referred to as bodily self-consciousness, and these studies have shown that the manipulation of bodily inputs induces changes in bodily self-consciousness such as self-identification. Another line of research has highlighted the importance of signals from the inside of the body (e.g., visceral signals) and proposed that neural representations of internal bodily signals underlie self-consciousness, which to date has been based on philosophical inquiry, clinical case studies, and behavioral studies. Here, we investigated the relationship of bodily self-consciousness with the neural processing of internal bodily signals. By combining electrical neuroimaging, analysis of peripheral physiological signals, and virtual reality technology in humans, we show that transient modulations of neural responses to heartbeats in the posterior cingulate cortex covary with changes in bodily self-consciousness induced by the full-body illusion. Additional analyses excluded that measured basic cardiorespiratory parameters or interoceptive sensitivity traits could account for this finding. These neurophysiological data link experimentally the cortical mapping of the internal body to self-consciousness. SIGNIFICANCE STATEMENT: What are the brain mechanisms of self-consciousness? Prominent views propose that the neural processing associated with signals from the internal organs (such as the heart and the lung) plays a critical role in self consciousness. Although this hypothesis dates back to influential views in philosophy and psychology (e.g., William James), definitive experimental evidence supporting this idea is lacking despite its recent impact in neuroscience. In the present study, we show that posterior cingulate activities responding to heartbeat signals covary with changes in participants' conscious self identification with a body that were manipulated experimentally using virtual reality technology. Our finding provides important neural evidence about the long standing proposal that self-consciousness is linked to the cortical processing of internal bodily signals. PMID- 27511017 TI - Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala. AB - Stress and glucocorticoids stimulate the rapid mobilization of endocannabinoids in the basolateral amygdala (BLA). Cannabinoid receptors in the BLA contribute to anxiogenesis and fear-memory formation. We tested for rapid glucocorticoid induced endocannabinoid regulation of synaptic inhibition in the rat BLA. Glucocorticoid application to amygdala slices elicited a rapid, nonreversible suppression of spontaneous, but not evoked, GABAergic synaptic currents in BLA principal neurons; the effect was also seen with a membrane-impermeant glucocorticoid, but not with intracellular glucocorticoid application, implicating a membrane-associated glucocorticoid receptor. The glucocorticoid suppression of GABA currents was not blocked by antagonists of nuclear corticosteroid receptors, or by inhibitors of gene transcription or protein synthesis, but was blocked by inhibiting postsynaptic G-protein activity, suggesting a postsynaptic nongenomic steroid signaling mechanism that stimulates the release of a retrograde messenger. The rapid glucocorticoid-induced suppression of inhibition was prevented by blocking CB1 receptors and 2 arachidonoylglycerol (2-AG) synthesis, and it was mimicked and occluded by CB1 receptor agonists, indicating it was mediated by the retrograde release of the endocannabinoid 2-AG. The rapid glucocorticoid effect in BLA neurons in vitro was occluded by prior in vivo acute stress-induced, or prior in vitro glucocorticoid induced, release of endocannabinoid. Acute stress also caused an increase in anxiety-like behavior that was attenuated by blocking CB1 receptor activation and inhibiting 2-AG synthesis in the BLA. Together, these findings suggest that acute stress causes a long-lasting suppression of synaptic inhibition in BLA neurons via a membrane glucocorticoid receptor-induced release of 2-AG at GABA synapses, which contributes to stress-induced anxiogenesis. SIGNIFICANCE STATEMENT: We provide a cellular mechanism in the basolateral amygdala (BLA) for the rapid stress regulation of anxiogenesis in rats. We demonstrate a nongenomic glucocorticoid induction of long-lasting suppression of synaptic inhibition that is mediated by retrograde endocannabinoid release at GABA synapses. The rapid glucocorticoid-induced endocannabinoid suppression of synaptic inhibition is initiated by a membrane-associated glucocorticoid receptor in BLA principal neurons. We show that acute stress increases anxiety-like behavior via an endocannabinoid-dependent mechanism centered in the BLA. The stress-induced endocannabinoid modulation of synaptic transmission in the BLA contributes, therefore, to the stress regulation of anxiety, and may play a role in anxiety disorders of the amygdala. PMID- 27511018 TI - APP Regulates Microglial Phenotype in a Mouse Model of Alzheimer's Disease. AB - Prior work suggests that amyloid precursor protein (APP) can function as a proinflammatory receptor on immune cells, such as monocytes and microglia. Therefore, we hypothesized that APP serves this function in microglia during Alzheimer's disease. Although fibrillar amyloid beta (Abeta)-stimulated cytokine secretion from both wild-type and APP knock-out (mAPP(-/-)) microglial cultures, oligomeric Abeta was unable to stimulate increased secretion from mAPP(-/-) cells. This was consistent with an ability of oligomeric Abeta to bind APP. Similarly, intracerebroventricular infusions of oligomeric Abeta produced less microgliosis in mAPP(-/-) mice compared with wild-type mice. The mAPP(-/-) mice crossed to an APP/PS1 transgenic mouse line demonstrated reduced microgliosis and cytokine levels and improved memory compared with wild-type mice despite robust fibrillar Abeta plaque deposition. These data define a novel function for microglial APP in regulating their ability to acquire a proinflammatory phenotype during disease. SIGNIFICANCE STATEMENT: A hallmark of Alzheimer's disease (AD) brains is the accumulation of amyloid beta (Abeta) peptide within plaques robustly invested with reactive microglia. This supports the notion that Abeta stimulation of microglial activation is one source of brain inflammatory changes during disease. Abeta is a cleavage product of the ubiquitously expressed amyloid precursor protein (APP) and is able to self-associate into a wide variety of differently sized and structurally distinct multimers. In this study, we demonstrate both in vitro and in vivo that nonfibrillar, oligomeric forms of Abeta are able to interact with the parent APP protein to stimulate microglial activation. This provides a mechanism by which metabolism of APP results in possible autocrine or paracrine Abeta production to drive the microgliosis associated with AD brains. PMID- 27511019 TI - Cell-Specific Cholinergic Modulation of Excitability of Layer 5B Principal Neurons in Mouse Auditory Cortex. AB - The neuromodulator acetylcholine (ACh) is crucial for several cognitive functions, such as perception, attention, and learning and memory. Whereas, in most cases, the cellular circuits or the specific neurons via which ACh exerts its cognitive effects remain unknown, it is known that auditory cortex (AC) neurons projecting from layer 5B (L5B) to the inferior colliculus, corticocollicular neurons, are required for cholinergic-mediated relearning of sound localization after occlusion of one ear. Therefore, elucidation of the effects of ACh on the excitability of corticocollicular neurons will bridge the cell-specific and cognitive properties of ACh. Because AC L5B contains another class of neurons that project to the contralateral cortex, corticocallosal neurons, to identify the cell-specific mechanisms that enable corticocollicular neurons to participate in sound localization relearning, we investigated the effects of ACh release on both L5B corticocallosal and corticocollicular neurons. Using in vitro electrophysiology and optogenetics in mouse brain slices, we found that ACh generated nicotinic ACh receptor (nAChR)-mediated depolarizing potentials and muscarinic ACh receptor (mAChR)-mediated hyperpolarizing potentials in AC L5B corticocallosal neurons. In corticocollicular neurons, ACh release also generated nAChR-mediated depolarizing potentials. However, in contrast to the mAChR-mediated hyperpolarizing potentials in corticocallosal neurons, ACh generated prolonged mAChR-mediated depolarizing potentials in corticocollicular neurons. These prolonged depolarizing potentials generated persistent firing in corticocollicular neurons, whereas corticocallosal neurons lacking mAChR-mediated depolarizing potentials did not show persistent firing. We propose that ACh-mediated persistent firing in corticocollicular neurons may represent a critical mechanism required for learning-induced plasticity in AC. SIGNIFICANCE STATEMENT: Acetylcholine (ACh) is crucial for cognitive functions. Whereas in most cases the cellular circuits or the specific neurons via which ACh exerts its cognitive effects remain unknown, it is known that auditory cortex (AC) corticocollicular neurons projecting from layer 5B to the inferior colliculus are required for cholinergic-mediated relearning of sound localization after occlusion of one ear. Therefore, elucidation of the effects of ACh on the excitability of corticocollicular neurons will bridge the cell-specific and cognitive properties of ACh. Our results suggest that cell-specific ACh-mediated persistent firing in corticocollicular neurons may represent a critical mechanism required for learning-induced plasticity in AC. Moreover, our results provide synaptic mechanisms via which ACh may mediate its effects on AC receptive fields. PMID- 27511020 TI - Tonotopic Optimization for Temporal Processing in the Cochlear Nucleus. AB - In the auditory system, sounds are processed in parallel frequency-tuned circuits, beginning in the cochlea. Auditory nerve fibers reflect this tonotopy and encode temporal properties of acoustic stimuli by "locking" discharges to a particular stimulus phase. However, physiological constraints on phase-locking depend on stimulus frequency. Interestingly, low characteristic frequency (LCF) neurons in the cochlear nucleus improve phase-locking precision relative to their auditory nerve inputs. This is proposed to arise through synaptic integration, but the postsynaptic membrane's selectivity for varying levels of synaptic convergence is poorly understood. The chick cochlear nucleus, nucleus magnocellularis (NM), exhibits tonotopic distribution of both input and membrane properties. LCF neurons receive many small inputs and have low input thresholds, whereas high characteristic frequency (HCF) neurons receive few, large synapses and require larger currents to spike. NM therefore presents an opportunity to study how small membrane variations interact with a systematic topographic gradient of synaptic inputs. We investigated membrane input selectivity and observed that HCF neurons preferentially select faster input than their LCF counterparts, and that this preference is tolerant of changes to membrane voltage. We then used computational models to probe which properties are crucial to phase-locking. The model predicted that the optimal arrangement of synaptic and membrane properties for phase-locking is specific to stimulus frequency and that the tonotopic distribution of input number and membrane excitability in NM closely tracks a stimulus-defined optimum. These findings were then confirmed physiologically with dynamic-clamp simulations of inputs to NM neurons. SIGNIFICANCE STATEMENT: One way that neurons represent temporal information is by phase-locking, which is discharging in response to a particular phase of the stimulus waveform. In the auditory system, central neurons are optimized to retain or improve phase-locking precision compared with input from the auditory nerve. However, the difficulty of this computation varies systematically with stimulus frequency. We examined properties that contribute to temporal processing both physiologically and in a computational model. Neurons processing low frequency input benefit from integration of many weak inputs, whereas those processing higher frequencies progressively lose precision by integration of multiple inputs. Here, we reveal general features of input-output optimization that apply to all neurons that process time varying input. PMID- 27511021 TI - miR-155 Deletion in Mice Overcomes Neuron-Intrinsic and Neuron-Extrinsic Barriers to Spinal Cord Repair. AB - Axon regeneration after spinal cord injury (SCI) fails due to neuron-intrinsic mechanisms and extracellular barriers including inflammation. microRNA (miR)-155 5p is a small, noncoding RNA that negatively regulates mRNA translation. In macrophages, miR-155-5p is induced by inflammatory stimuli and elicits a response that could be toxic after SCI. miR-155 may also independently alter expression of genes that regulate axon growth in neurons. Here, we hypothesized that miR-155 deletion would simultaneously improve axon growth and reduce neuroinflammation after SCI by acting on both neurons and macrophages. New data show that miR-155 deletion attenuates inflammatory signaling in macrophages, reduces macrophage mediated neuron toxicity, and increases macrophage-elicited axon growth by ~40% relative to control conditions. In addition, miR-155 deletion increases spontaneous axon growth from neurons; adult miR-155 KO dorsal root ganglion (DRG) neurons extend 44% longer neurites than WT neurons. In vivo, miR-155 deletion augments conditioning lesion-induced intraneuronal expression of SPRR1A, a regeneration-associated gene; ~50% more injured KO DRG neurons expressed SPRR1A versus WT neurons. After dorsal column SCI, miR-155 KO mouse spinal cord has reduced neuroinflammation and increased peripheral conditioning-lesion-enhanced axon regeneration beyond the epicenter. Finally, in a model of spinal contusion injury, miR-155 deletion improves locomotor function at postinjury times corresponding with the arrival and maximal appearance of activated intraspinal macrophages. In miR-155 KO mice, improved locomotor function is associated with smaller contusion lesions and decreased accumulation of inflammatory macrophages. Collectively, these data indicate that miR-155 is a novel therapeutic target capable of simultaneously overcoming neuron-intrinsic and neuron-extrinsic barriers to repair after SCI. SIGNIFICANCE STATEMENT: Axon regeneration after spinal cord injury (SCI) fails due to neuron-intrinsic mechanisms and extracellular barriers, including inflammation. Here, new data show that deleting microRNA-155 (miR-155) affects both mechanisms and improves repair and functional recovery after SCI. Macrophages lacking miR-155 have altered inflammatory capacity, which enhances neuron survival and axon growth of cocultured neurons. In addition, independent of macrophages, adult miR-155 KO neurons show enhanced spontaneous axon growth. Using either spinal cord dorsal column crush or contusion injury models, miR-155 deletion improves indices of repair and recovery. Therefore, miR-155 has a dual role in regulating spinal cord repair and may be a novel therapeutic target for SCI and other CNS pathologies. PMID- 27511022 TI - The development of modified human Hsp70 (HSPA1A) and its production in the milk of transgenic mice. AB - The production of major human heat shock protein Hsp70 (HSPA1A) in a eukaryotic expression system is needed for testing and possible medical applications. In this study, transgenic mice were produced containing wild-type human Hsp70 allele in the vector providing expression in the milk. The results indicated that human Hsp70 was readily expressed in the transgenic animals but did not apparently preserve its intact structure and, hence, it was not possible to purify the protein using conventional isolation techniques. It was suggested that the protein underwent glycosylation in the process of expression, and this quite common modification for proteins expressed in the milk complicated its isolation. To check this possibility, we mutated all presumptive sites of glycosylation and tested the properties of the resulting modified Hsp70 expressed in E. coli. The investigation demonstrated that the modified protein exhibited all beneficial properties of the wild-type Hsp70 and was even superior to the latter for a few parameters. Based on these results, a transgenic mouse strain was obtained which expressed the modified Hsp70 in milk and which was easy to isolate using ATP columns. Therefore, the developed construct can be explored in various bioreactors for reliable manufacture of high quality, uniform, and reproducible human Hsp70 for possible medical applications including neurodegenerative diseases and cancer. PMID- 27511023 TI - The expression of thioredoxin-1 in acute epinephrine stressed mice. AB - Stress, a state of perceived threat to homeostasis, regulates a panel of important physiological functions. The human mind and body respond to stress by activating the sympathetic nervous system and secreting the catecholamines epinephrine and norepinephrine in the "fight-or-flight" response. However, the protective mechanism of acute stress is still unknown. In the present study, an acute stress mouse model was constructed by intraperitoneal injection of epinephrine (0.2 mg kg(-1)) for 4 h. Epinephrine treatment induced heat shock 70(Hsp70) expression in the stress responsive tissues, such as the cortex, hippocampus, thymus, and kidney. Further, the expression of thioredoxin-1(Trx-1), a cytoprotective protein, was also upregulated in these stress responsive tissues. In addition, the phosphorylation of cAMP-response element binding protein (CREB), a transcription factor of Trx-1, was increased after treatment with epinephrine. The block of CREB activation by H89 inhibited the acute epinephrine stress-induced Trx-1 and Hsp70 expression. Taken together, our data suggest that acute stimuli of epinephrine induced Trx-1 expression through activating CREB and may represent a protective role against stress. PMID- 27511025 TI - Selective High-Resolution Detection of Membrane Protein-Ligand Interaction in Native Membranes Using Trityl-Nitroxide PELDOR. AB - The orchestrated interaction of transmembrane proteins with other molecules mediates several crucial biological processes. Detergent solubilization may significantly alter or even abolish such hetero-oligomeric interactions, which makes observing them at high resolution in their native environment technically challenging. Dipolar electron paramagnetic resonance (EPR) techniques such as pulsed electro-electron double resonance (PELDOR) can provide very precise distances within biomolecules. To concurrently determine the inter-subunit interaction and the intra-subunit conformational changes in hetero-oligomeric complexes, a combination of different spin labels is required. Orthogonal spin labeling using a triarylmethyl (TAM) label in combination with a nitroxide label is used to detect protein-ligand interactions in native lipid bilayers. This approach provides a higher sensitivity and total selectivity and will greatly facilitate the investigation of multimeric transmembrane complexes employing different spin labels in the native lipid environment. PMID- 27511024 TI - Hsp72 and Hsp90alpha mRNA transcription is characterised by large, sustained changes in core temperature during heat acclimation. AB - Increased intracellular heat shock protein-72 (Hsp72) and heat shock protein 90alpha (Hsp90alpha) have been implicated as important components of acquired thermotolerance, providing cytoprotection during stress. This experiment determined the physiological responses characterising increases in Hsp72 and Hsp90alpha mRNA on the first and tenth day of 90-min heat acclimation (in 40.2 degrees C, 41.0 % relative humidity (RH)) or equivalent normothermic training (in 20 degrees C, 29 % RH). Pearson's product-moment correlation and stepwise multiple regression were performed to determine relationships between physiological [e.g. (Trec, sweat rate (SR) and heart rate (HR)] and training variables (exercise duration, exercise intensity, work done), and the leukocyte Hsp72 and Hsp90alpha mRNA responses via reverse transcription quantitative polymerase chain reaction (RT-QPCR) (n = 15). Significant (p < 0.05) correlations existed between increased Hsp72 and Hsp90alpha mRNA (r = 0.879). Increased core temperature was the most important criteria for gene transcription with DeltaTrec (r = 0.714), SR (r = 0.709), Trecfinal45 (r = 0.682), area under the curve where Trec >= 38.5 degrees C (AUC38.5 degrees C; r = 0.678), peak Trec (r = 0.661), duration Trec >= 38.5 degrees C (r = 0.650) and DeltaHR (r = 0.511) each demonstrating a significant (p < 0.05) correlation with the increase in Hsp72 mRNA. The Trec AUC38.5 degrees C (r = 0.729), DeltaTrec (r = 0.691), peak Trec (r = 0.680), Trecfinal45 (r = 0.678), SR (r = 0.660), duration Trec >= 38.5 degrees C (r = 0.629), the rate of change in Trec (r = 0.600) and DeltaHR (r = 0.531) were the strongest correlate with the increase in Hsp90alpha mRNA. Multiple regression improved the model for Hsp90alpha mRNA only, when Trec AUC38.5 degrees C and SR were combined. Training variables showed insignificant (p > 0.05) weak (r < 0.300) relationships with Hsp72 and Hsp90alpha mRNA. Hsp72 and Hsp90alpha mRNA correlates were comparable on the first and tenth day. When transcription of the related Hsp72 and Hsp90alpha mRNA is important, protocols should rapidly induce large, prolonged changes in core temperature. PMID- 27511026 TI - BES1 regulates the localization of the brassinosteroid receptor BRL3 within the provascular tissue of the Arabidopsis primary root. AB - Brassinosteroid (BR) hormones are important regulators of plant growth and development. Recent studies revealed the cell-specific role of BRs in vascular and stem cell development by the action of cell-specific BR receptor complexes and downstream signaling components in Arabidopsis thaliana Despite the importance of spatiotemporal regulation of hormone signaling in the control of plant vascular development, the mechanisms that confer cellular specificity to BR receptors within the vascular cells are not yet understood. The present work shows that BRI1-like receptor genes 1 and 3 (BRL1 and BRL3) are differently regulated by BRs. By using promoter deletion constructs of BRL1 and BRL3 fused to GFP/GUS (green fluorescent protein/beta-glucuronidase) reporters in Arabidopsis, analysis of their cell-specific expression and regulation by BRs in the root apex has been carried out. We found that BRL3 expression is finely modulated by BRs in different root cell types, whereas the location of BRL1 appears to be independent of this hormone. Physiological and genetic analysis show a BR-dependent expression of BRL3 in the root meristem. In particular, BRL3 expression requires active BES1, a central transcriptional effector within the BRI1 pathway. ChIP analysis showed that BES1 directly binds to the BRRE present in the BRL3 promoter region, modulating its transcription in different subsets of cells of the root apex. Overall our study reveals the existence of a cell-specific negative feedback loop from BRI1-mediated BES1 transcription factor to BRL3 in phloem cells, while contributing to a general understanding of the spatial control of steroid signaling in plant development. PMID- 27511027 TI - MRI signal intensity of anterior cruciate ligament graft after transtibial versus anteromedial portal technique (TRANSIG): design of a randomized controlled clinical trial. AB - BACKGROUND: There are two primary surgical techniques to reconstruct the anterior cruciate ligament (ACL), transtibial (TT) technique and anteromedial portal (AMP) technique. Currently, there is no consensus which surgical technique elicits the best clinical and functional outcomes. MRI-derived measures of the signal intensity (SI) of the ACL graft have been described as an independent predictor of graft properties. The purpose of this study is to compare the MRI derived SI measurements of the ACL graft one year after ACL reconstruction, in order to compare the outcomes of both the AMP and TT ACL reconstruction technique. METHODS/DESIGN: Thirty-six patients will be included in a randomized controlled trial. Patients who are admitted for primary unilateral ACL reconstruction will be included in the study. Exclusion criteria are a history of previous surgery on the ipsilateral knee, re-rupture of the ipsilateral ACL graft, associated ligamentous injuries or meniscal tear of the ipsilateral knee, unhealthy contralateral knee, contra-indications for MRI and a preference for one of the two surgical techniques and/or orthopaedic surgeon. Primary outcome is MRI Signal intensity ratio (SIR) of the ACL graft. Secondary outcome measures are the International Knee Documentation Committee (IKDC) Knee Examination Form,the Knee injury and Osteoarthritis Outcome Scores (KOOS) and the Anterior Cruciate Ligament OsteoArthritis Score (ACLOAS). Differences between MRI SIR assessment with the current MRI protocol (proton density weighted imaging protocol) and the additional T2*-weighted gradient-echo protocol will be assessed. DISCUSSION: There is no consensus regarding the TT or AMP ACL reconstruction technique. SI measurements with MRI have been used in other clinical studies for evaluation of the ACL graft and maturation after ACL reconstruction compared to clinical and functional outcomes. This randomized controlled trial has been designed to compare the TT technique with the AMP technique with the use of MRI SI of the graft after ACL reconstruction. TRIAL REGISTRATION: Netherlands Trial Registry NTR5410 (registered on August 24, 2015). PMID- 27511029 TI - Australasian Musculoskeletal Imaging Group (AMSIG) annual scientific meeting (ASM). PMID- 27511028 TI - Emodin-Loaded PLGA-TPGS Nanoparticles Combined with Heparin Sodium-Loaded PLGA TPGS Nanoparticles to Enhance Chemotherapeutic Efficacy Against Liver Cancer. AB - PURPOSE: Heparin sodium (HS)-loaded polylactic-co-glycolic acid-D-alpha tocopheryl polyethylene glycol 1000 succinate (PLGA-TPGS) nanoparticles (HPTNs) were prepared as a sustained and targeting delivery carrier and combined with emodin (EMO)-loaded PLGA-TPGS nanoparticles (EPTNs), which were investigated previously to form a combination therapy system for the treatment of liver cancer. METHODS: To assess cellular uptake and evaluate the liver-targeting capacity by analyzing the drug concentrations and frozen slices, HS/eosin-loaded PLGA-TPGS nanoparticles, HS/fluorescein- loaded PLGA-TPGS nanoparticles and EMO/C6-loaded PLGA-TPGS nanoparticles, which contained eosin, fluorescein and C6 as fluorescent probes, respectively, were also prepared. All of these nanoparticles were characterized in terms of their size, size distribution, surface charge, drug loading, encapsulation efficiency, in vitro release profile and cellular uptake. The apoptosis of HepG2 cells induced by EPTNs in combination with HPTNs was determined by Annexin V-FITC staining and PI labelling. RESULTS: Transmission electron microscopy indicated that these nanoparticles were stably dispersed spheres with sizes ranging from 100 to 200 nm. The results demonstrated that fluorescent nanoparticles were internalized into HepG2 and HCa-F cells efficiently and had improved liver-targeting properties. The combination of EPTNs and HPTNs effectively inhibited cell growth in vitro and had a remarkable synergistic anticancer effect in vivo. EPTNs combined with HPTNs induced HepG2 cell apoptosis with synergistic effects. The liver H&E slice images of a hepatocarcinogenic mouse model indicated that EPTNs in combination with HPTNs significantly suppressed tumour growth in vivo. CONCLUSIONS: The research suggests that the combination therapy system of EPTNs and HPTNs could be a new direction for liver cancer therapy. PMID- 27511030 TI - MR imaging and ultrasonography findings of early myositis ossificans: a case report. AB - Myositis ossificans (MO) is a benign soft tissue lesion with non-neoplastic heterotopic bone formation. MO in the intermediate and mature stages can be easily diagnosed if characteristic imaging findings such as a peripheral zonal pattern of ossification with variable thickness is observed. However, it is difficult to correctly diagnose early MO because it can mimic malignancy clinically, radiologically, and histopathologically. We report a case of early pseudosarcomatous phase of non-traumatic MO with atypical imaging findings. A 59 year-old woman presented with pain followed by a mass in the left thigh within a week. MR imaging and ultrasonography showed an intramuscular lesion with preserved muscle fascicles in the vastus lateralis muscle. Intralesional ossification or calcification was not seen on ultrasonography. A diagnosis of myositis ossificans was made by ultrasonographically guided biopsy. PMID- 27511031 TI - [Formulation of guidelines for microscopic endodontics suitable for the situation of China]. AB - In order to promote the use of dental operating microscope in endodontics, Society of Cariology and Endodontology of Chinese Stomatological Association formulated these guidelines, after extensive consultation with related authorities and careful reference to the available published materials and literatures. It is hoped that these guidelines will be useful for dental practitioners embarking on microscopic endodontics. PMID- 27511032 TI - [An analysis of key points for root canal therapy technique]. AB - The success rate of root canal therapy(RCT)have been improved continuously along with the advancement in RCT techniques in the past several decades. If standard procedures of modern RCT techniques are strictly followed, the success rate of RCT may exceed 90%. The success of RCT is mainly affected by such factors as clear concept of the anatomy of root canals, proper mechanical and chemical preparation and perfect filling of root canal system. If these factors are sufficiently noted, a success is easy to achieve. Even though the primary RCT fails, retreatment can further be conducted to save the diseased teeth. PMID- 27511033 TI - [Analysis of the key points in the micro-endodontic treatment]. AB - Micro-endodontic treatment refers to the microscope-assisted endodontic treatment techniques. The microscope offers a stereoscopic, enlarged image under great magnification and illumination at a comfortable working position. It will greatly promote the precision and improve the outcomes of endodontic treatment through enhancing the ability to detect the complexity of the root canal system of teeth that probably cannot be seen by the naked eyes, remove the infectious substances in root canal more efficiently, provide a tight root canal obturation and carry out effective retreatment procedures. The requirements of micro-endodontic treatment are different from the conventional root canal therapy carried out without microscope due to the complicated structure of the microscope. In order to make the use of microscope easier, it is of great importance to learn how to adjust the position of the operator and the patient, preset the angle of objective lens and the eyepiece, select the proper magnification and instruments, practice eye-hand cooperation under the microscope, etc. The purpose of this article was to analyze the key points in the applications of the microscope in endodontic treatment by reviewing the literature together with the author's clinical experience. PMID- 27511034 TI - [Theory and practice of minimally invasive endodontics]. AB - The primary goal of modern endodontic therapy is to achieve the long-term retention of a functional tooth by preventing or treating pulpitis or apical periodontitis is. The long-term retention of endodontically treated tooth is correlated with the remaining amount of tooth tissue and the quality of the restoration after root canal filling. In recent years, there has been rapid progress and development in the basic research of endodontic biology, instrument and applied materials, making treatment procedures safer, more accurate, and more efficient. Thus, minimally invasive endodontics(MIE)has received increasing attention at present. MIE aims to preserve the maximum of tooth structure during root canal therapy, and the concept covers the whole process of diagnosis and treatment of teeth. This review article focuses on describing the minimally invasive concepts and operating essentials in endodontics, from diagnosis and treatment planning to the access opening, pulp cavity finishing, root canal cleaning and shaping, 3-dimensional root canal filling and restoration after root canal treatment. PMID- 27511035 TI - [Guidelines for the use of microscopes in endodontics]. PMID- 27511036 TI - [Diagnosis and treatment of a maxillary premolar with vertical root fracture: a case report]. PMID- 27511037 TI - [The application of laser in endodontics]. AB - Since laser was introduced in the field of medicine in 1970's, its application range has continuously expanded. The application of laser in endodontics also increased due to its safety and effectiveness in dental treatments. The majority of the laser application researches in dentistry focused on dentin hypersensitivity, removal of carious tissues, tooth preparations, pulp capping or pulpotomy, and root canal treatment. In this article, we reviewed literature on the effects of laser in the treatments of dental and pulp diseases. PMID- 27511038 TI - [Accuracy and reliability of three-dimensional craniofacial cone-beam CT superimposition method based on voxel registration]. AB - OBJECTIVE: To set up a three-dimensional(3D)craniofacial cone-beam CT(CBCT)superimposition method based on voxel registration, and evaluate the accuracy and reliability of different reference superimposition areas. METHODS: CBCT scans were taken on a dry skull for three times with a time-interval of two weeks, and CBCT scans were taken on ten adult volunteers twice with a time interval of one month. The 3D superimposition based on voxel registration was set up by means of Analyze 12.0. The bilateral-zygomatic bone and anterior cranial base were selected as different reference areas for voxel overlapping. The 3D overlapping images were output into Geomagic Qualify 2013, and the surface distances on different craniofacial regions were measured. Three operators repeated three times of these superimposition and measurement. SPSS 19.0 were used to analyze the accuracy and reliability. RESULTS: When bilateral-zygomatic bone used as superimposition reference, the mean surface distance range of dry skull were from 0.035 to 0.064 mm, and volunteers from 0.099 to 0.182 mm. When the anterior cranial base used as superimposition reference, the mean surface distance range of dry skull were from 0.038 to 0.071 mm, and volunteers from 0.127 to 0.218 mm. All these mean values were less than the CBCT voxel size 0.25 mm(P<0.05), and got sub-pixel precision. No significant difference was found between the different operators at different times(P>0.05). CONCLUSIONS: This study showed the high accuracy and reliability of 3D CBCT superimposition based on voxel registration, either the anterior cranial base or the bilateral zygomatic bone as reference. This method could be used for evaluating 3D craniofacial treatment effects. PMID- 27511039 TI - [Biomechanics analysis of the impact of maxillofacial injury on skull base damage]. AB - OBJECTIVE: To analyze the impact of maxillofacial injury on skull base. METHODS: A three-dimensional(3D)finite-element model of cranio-maxillofacial bone was established by CT scan data. A lead cylinder in base diameter of 3 cm was designed as an impactor. There regions(upper right maxilla, left infraorbital margin and left zygomatic body)subjected to an impact at the speed of 8.6 m/s(about 30 km/h)was simulated. Thirteen landmarks at the skull base were selected. The values of stress at the end of 0.5, 1.0, 1.5, 2.0 ms were obtained, and the results were analyzed. RESULTS: The dynamic process of the fracture of the jaw and the stress distribution and conduction of the skull base were successfully simulated in three parts of the face. When the impact was on the right maxillary bone region, the stress values of the three points(medial foramen rotundum, medial foramen rotundum, anterior clivus reached the peak at each time point, 26.2, 22.4, 21.5 MPa(t=0.5 ms)and 70.0, 55.0, 45.0 MPa(t=1.0 ms)and 38.0, 26.5, 39.5 MPa(t=1.5 ms)and 26.0, 19.0, 23.0 MPa(t=2.0 ms), respectively. When the impact was on the left margo infraorbitalis orbitaeta region, the stress values of the two points(medial left foramen rotundum, posterior clivus)reached the peak at each time point, 8.8, 16.0 MPa(t=0.5 ms)and 10.0, 18.0 MPa(t=1.0 ms)and 5.5, 6.0 MPa(t=1.5 ms)and 11.5, 12.5 MPa(t=2.0 ms), respectively. When the impact was on the body of left zygomatic bone, the stress values of posterior clivus were 45.0 MPa(t=0.5 ms), 40.0 MPa(t=1.0 ms), 12.0 MPa(t=1.5 ms), 42.5 MPa(t= 2.0 ms), respectively. CONCLUSIONS: According to the difference of stress distribution and conduction of maxillofacial and skull base bone, the speed and the path of force transfer to the skull base were different. Finite-element dynamic simulation can be used for the biomechanics research on maxillofacial trauma. PMID- 27511040 TI - [Effect of zinc ion on the expression of osteoblastic proteins in MC3T3-E1 cells in inflammatory environment]. AB - OBJECTIVE: To investigate the effect of zinc ion on the expression of osteoblastic proteins. METHODS: Mice osteoblasts MC3T3-E1 cells were subcultured. Inflammatory environment model was established by tumor necrosis factor alpha(TNF alpha)at a concentration of 10 mg/L. According to different concentration of Zn(2+), the cells were divided into TNF-alpha group, control group, group A(TNF alpha+10(-4) mol/L Zn(2+)), group B(TNF-alpha+10(-5) mol/L Zn(2+)), group C(TNF alpha+10(-6) mol/L Zn(2+)). After 24, 48, and 72 h of culture, cell counting kit 8(CCK-8)assay was used to analyze the proliferation of the cells. ALP activity was examined. Bone morphogenetic protein-2(BMP-2), Runt-related transcription factor 2(RUNX2), Osterix and receptor activator of NF-kappaB ligand(RANKL)protein levels were determined by Western blotting after 72 h of culture. RESULTS: The cells grew by adherence after 24 h. After 72 h, the cells grew dense, and the cells showed long spindle shape or irregular shape. The proliferation of osteoblasts in TNF-alpha group, group B and group C became lower than that in the control group(P<0.05), and was not significantly different between group A and the control group(P >0.05). ALP activity examination demonstrated that the groups cultured for 72 h revealed the highest ALP activity and the most prominent differentation compared with 24 h and 48 h groups. ALP activity was significantly decreased in TNF-alpha group, group B and group C compared with control group(P<0.05), but was not significantly different between group A and control group(P>0.05). The protein levels of BMP-2, RUNX2 and Osterix were significantly decreased in TNF-alpha group, group B and group C compared with control group(P<0.05), while showed no significant difference between group A and the control group. Protein level of RANKL was significantly increased in TNF-alpha group, grope B and group C compared with control group(P<0.05), while showed no significant difference between group A and control group. CONCLUSIONS: The concentration of 10(-4) mol/L Zn(2+) can significantly increase the expression of osteoblastic proteins such as ALP, BMP-2, RUNX2, Osterix and decrease the expression of RANKL in mice osteoblasts in TNF-alpha inflammatory environment. PMID- 27511041 TI - [Effect of modification of titanium surfaces to graft poly(ethylene glycol)methacrylate-arginine-glycine-aspartic polymer brushes on bacterial adhesion and osteoblast cell attachment]. AB - OBJECTIVE: To study the effect of poly(ethylene glycol)methacrylate(PEG)-arginine glycine-aspartic(RGD)polymer brushes graft on bacterial adhesion and MC3T3 osteoblast cell attachment on titanium, and to investigate if the modification of titanium will enable the implant to be anti-fouling and promot osteointegration. METHODS: PEG was tethered on titanium surface modified with 2-bromoisobutyryl bromide(denoted as Ti-Br)to form Ti-PEG brushes. Functionalization of the Ti-PEG surface with RGD was performed to form Ti-PEG-RGD brushes. The chemical composition of modified titanium surfaces was characterized by X-ray photoelectron spectroscopy(XPS). Changes in surface hydrophilicity and hydrophobicity were characterized by static water contact angle measurements. Streptococcus mutans(Sm), Actinomyces naeslundii(An)and osteoblast cell were cultured on pure titanium(Ti), Ti-PEG, Ti-PEG-RGD surfaces respectively. There were ten samples in each group. The bacterial adhesion ability and cell attachment were confirmed by fluorescence microscopy and scanning electron microscopy(SEM). RESULTS: The static water contact angle of Ti, Ti-Br, Ti-PEG, Ti PEG-RGD was less than 10 degrees , 80 degrees , 45 degrees , 55 degrees respectively. XPS confirmed that PEG-RGD brushes were successfully tethered on titanium surfaces. Anti-bacterial test showed that on the pure-Ti, there were large amount of bacteria from both groups, however, in the Ti-PEG, Ti-PEG-RGD surfaces, both kind of bacteria were rare and distributed diffusely. Cell culture test showed that on the Ti-PEG-RGD surfaces, the number of cells was significantly more than that on the Ti and the Ti-PEG surfaces. CONCLUSIONS: PEG can inhibit both kind of bacteria adhesion and osteoblast cell attachment, and PEG-RGD brushes can not only inhibit bacterial adhesion but also promote osteoblast cell attachment. PMID- 27511042 TI - [Effect of three surface modification techniques of pure titanium on bacteria adhesion and ultrasonic cleaning efficacy]. AB - OBJECTIVE: To evaluate the bacteria adhesion behavior and ultrasonic cleaning efficacy on pure titanium modified with 3 different techiques. METHODS: Pure titanium disks with mechanically polished surfaces(MP), titania nanotube surfaces(TNT)and sandblast-large grit and acid-etched surfaces(SLA)were used as substrates. The surface characteristics of the 3 types of specimens were detected. The disks of all groups were co-cultured with Porphyromonas gingivalis(Pg)and microcosm for 1 day and 5 days respectively. The cell viabilities of bacteria attached to the 3 types of surfaces were tested. The remaining bacteria on different surfaces after ultrasonic treatment were observed through live/dead bacteria staining. RESULTS: MP and SLA surfaces demonstrated a micro-scale structure, while TNT surfaces showed a nano-scale structure. The surface roughness of SLA specimen was the highest([1.62 +/- 0.13]MUm), and that of MP([0.81 +/- 0.10]MUm)and TNT specimen([0.792 +/- 0.080]MUm)were relatively lower and showed no statistical difference(P >0.05). At 1 and 5 d, the cell viability and the biomass of Pg attached to MP surfaces were as low as 1 829+/ 210 and 13 811+/-3 110 and A570 value were 0.80+/-0.35 and 1.56+/-0.30 respectively. At 1 d, the cell viability of microcosm adhered on MP and TNT surfaces were lower(63 943+/-6 990 and 69 860+/-5 555)than that on the SLA surface, and the biomass of microcosm adhered on MP surfaces demonstrated the lowest value(A570 value 5.84+/-0.60). At 5 d, both the cell viability and biomass of micorcosm adhered on the three surfaces were of no statistical difference(P<0.05). The remaining bacteria on TNT surfaces were the least in the three groups and distributed sporadically after ultrasonic treatment. The remaining bacteria on all surfaces increased with culture time. CONCLUSIONS: Both surface topography and roughness affect early bacteria adhesion. However, this effect can be weakened as the biofilm getting mature. The surface topography can significantly affect the mechanical cleaning efficacy of the biofilm. TNT surface reveals a lower adhesion of microcosm and a higher efficacy of ultrasonic cleaning compared to MP and SLA surfaces. PMID- 27511043 TI - [Evaluating the accuracy of three-dimensional reconstruction of the intercuspal position for dentition casts aided by a mechanical appliance]. AB - OBJECTIVE: To develop a aided mechanical appliance for rapid reconstruction of three-dimensional(3D)relationship of dentition model after scanning and evaluation of its accuracy. METHODS: The appliance was designed by forward engineering software and fabricated by a high precision computer numerical control(CNC)system. It contained upper and lower body, magnetic pedestal and three pillars. Nine 3 mm diameter hemispheres were distributed equally on the axial surface of each pedestal. Faro Edge 1.8m was used to directly obtain center of each hemisphere(contact method), defined as known center. A pair of die-stone standard dentition model were fixed in intercuspal position and then fixed on the magnetic pedestals with low expansion ratio plaster. Activity 880 dental scanner was used to scan casts after the plaster was completely set. In Geomagic 2012, the centers of each hemisphere were fitted and defined as scanning centers. Scanning centers were aligned to known centers by reference point system to finish the 3D reconstruction of the intercuspal occlusion for the dentition casts. An observation coordinate system was interactively established. The straight-line distances in the X(coronal), Y(saggital), and Z(vertical)between the remaining 6 pairs of center points derived from contact method and fitting method were measured respectively and analyzed using a paired t-test. RESULTS: The differences of the straight-line distances of the remaining 6 pairs of center points between the two methods were X:(-0.05+/-0.10)mm, Y:(0.02+/-0.06)mm, and Z:(0.01 +/- 0.05)mm. The results of paired t-test showed no significant differences(P>0.05). CONCLUSIONS: The mechanical appliance can help to reconstruct 3D jaw relation by scanning single upper and lower dentition model with usual commercial available dental cast scanning system. PMID- 27511044 TI - [The reliability of electrochemical enzyme-linked immunosorbent assay for detection of dentin sialophosphoprotein in gingival crevicular fluid]. AB - OBJECTIVE: To investigate the reliability of electrochemical enzyme-linked immunosorbent assay(ELISA)for the detection of dentin sialophosphoprotein(DSPP)in gingival crevicular fluid(GCF)of orthodontic patients. METHODS: GCF were collected from the orthodontic patients, and then the amount of DSPP in GCF were detected by electrochemical ELISA and spectroscopic ELISA respectively. The difference between the results of two methods were analyzed. RESULTS: In electrochemical ELISA, the second order derivative linear sweep voltammetric peak current was linear with DSPP concentration in the range from 0.25-800.00 ng/L. It was found that the detection limit of the electrochemical method(0.25 ng/L)was much lower than that of the spectroscopic method. The paired-samples rank sum test showed no significant difference between the DSPP concentrations in human GCF samples measured by spectroscopic ELISA procedure and those measured by electrochemical ELISA procedure(P=0.063). CONCLUSIONS: Electrochemical ELISA is a viable way of detecting DSPP in GCF with higher sensitivity than spectroscopic ELISA. PMID- 27511045 TI - [The historical materials of stomatology in the All Things, Prescriptions of Fifty-two Diseases and Yinshu]. AB - All Things, Prescriptions of Fifty-two Diseases and Yinshu were three bamboo and silk medical manuscripts which form-time was no later than the late Warring States period. From the visible bamboo and silk, the ancient Chinese knew the relationships between some drugs and the volume of saliva and used compound drugs to treat dental caries. Some oral and maxillofacial diseases, such as inflammation and pain of oromaxillo-facial region, temporomandibular dislocation and the methods of treatment were descriped in these books. Mouth-rinsing and tooth-picking were the more often used methods for maintaining oral hygiene. Kouchi(clicking the tooth)was also used for prevention and/or treatment of caries. Most of these knowledge were the first documents in ancient China. PMID- 27511046 TI - Intervention not always necessary in post-appendectomy abscesses in children; clinical experience in a tertiary surgical centre and an overview of the literature. AB - This study aims to provide an overview of both our own experience and the available literature on the treatment of post-appendectomy abscess (PAA) in children. We performed a historical cohort study encompassing all children aged 0 17 years old treated for a radiologically confirmed PAA between 2007 and 2013. Their medical charts were reviewed and descriptive analyses were performed. A literature search on the treatment of PAA in children was performed. In our cohort, 25 out of 372 (7 %) children developed a PAA. Thirteen were treated with a noninvasive strategy and 12 with an invasive strategy (percutaneous or surgical drainage). The immediate success rate was 9/13 (69 %) and 8/12 (67 %) for the noninvasive and invasive strategy, respectively. In both groups, four children (31 and 33 % resp.) required delayed interventions after their initial treatment. In the literature review, six studies were included which reported a median (range) frequency of persistent or recurrent abscess of 9 % (0-30 %), 50 % (0-100 %) and 24 % (0-33 %) for the antibiotic (noninvasive), percutaneous drainage (invasive) and surgical drainage strategies, respectively. CONCLUSION: Although confounding by indication cannot be excluded, we recommend noninvasive treatment as a safe strategy for PAA in children with stable condition. WHAT IS KNOWN: * Post-appendectomy abscess is a well-known and feared complication, occurring in up to 24 % of the children treated surgically for appendicitis. * Several strategies are available to treat this condition, all with advantages and disadvantages. What is new: * Noninvasive strategy is a safe strategy for children with a PAA in a stable condition. * An overview of the literature (the first to our knowledge) supports the above-mentioned statement. PMID- 27511047 TI - Predicting Motor Sequence Learning in Individuals With Chronic Stroke. AB - BACKGROUND: Conventionally, change in motor performance is quantified with discrete measures of behavior taken pre- and postpractice. As a high degree of movement variability exists in motor performance after stroke, pre- and posttesting of motor skill may lack sensitivity to predict potential for motor recovery. OBJECTIVE: Evaluate the use of predictive models of motor learning based on individual performance curves and clinical characteristics of motor function in individuals with stroke. METHODS: Ten healthy and fourteen individuals with chronic stroke performed a continuous joystick-based tracking task over 6 days, and at a 24-hour delayed retention test, to assess implicit motor sequence learning. RESULTS: Individuals with chronic stroke demonstrated significantly slower rates of improvements in implicit sequence-specific motor performance compared with a healthy control (HC) group when root mean squared error performance data were fit to an exponential function. The HC group showed a positive relationship between a faster rate of change in implicit sequence specific motor performance during practice and superior performance at the delayed retention test. The same relationship was shown for individuals with stroke only after accounting for overall motor function by including Wolf Motor Function Test rate in our model. CONCLUSION: Nonlinear information extracted from multiple time points across practice, specifically the rate of motor skill acquisition during practice, relates strongly with changes in motor behavior at the retention test following practice and could be used to predict optimal doses of practice on an individual basis. PMID- 27511048 TI - Small-World Characteristics of Cortical Connectivity Changes in Acute Stroke. AB - Background After cerebral ischemia, disruption and subsequent reorganization of functional connections occur both locally and remote to the lesion. Recently, complexity of brain connectivity has been described using graph theory, a mathematical approach that depicts important properties of complex systems by quantifying topologies of network representations. Functional and dynamic changes of brain connectivity can be reliably analyzed via electroencephalography (EEG) recordings even when they are not yet reflected in structural changes of connections. Objective We tested whether and how ischemic stroke in the acute stage may determine changes in small-worldness of cortical networks as measured by cortical sources of EEG. Methods Graph characteristics of EEG of 30 consecutive stroke patients in acute stage (no more than 5 days after the event) were examined. Connectivity analysis was performed using eLORETA in both hemispheres. Results Network rearrangements were mainly detected in delta, theta, and alpha bands when patients were compared with healthy subjects. In delta and alpha bands similar findings were observed in both hemispheres regardless of the side of ischemic lesion: bilaterally decreased small-worldness in the delta band and bilaterally increased small-worldness in the alpha2 band. In the theta band, bilaterally decreased small-worldness was observed only in patients with stroke in the left hemisphere. Conclusions After an acute stroke, brain cortex rearranges its network connections diffusely, in a frequency-dependent modality probably in order to face the new anatomical and functional frame. PMID- 27511049 TI - Saline versus balanced solutions: are clinical trials comparing two crystalloid solutions really needed? PMID- 27511050 TI - The study on mechanism of the modified Chinese herbal compound, jianpijiedu, on a mouse model of hepatic carcinoma cachexia. AB - Various studies have investigated hepatic carcinoma cachexia, however, there is little published information regarding the effect of Chinese Medicine carcinoma cachexia. The present study was performed to investigate the effect of modified Chinese herbal compound jianpijiedu (MJPJD) on a mouse model of ascites-induced hepatic carcinoma cachexia. C57BL/6 mice were randomized to five groups: Control (Group A); xenograft tumor (Group B); low concentration of MJPJD (Group C); high concentration of MJPJD (Group D) and medroxyprogesterone (MPA) combined with indometacin (IND; Group E). The mouse model of ascites-induced hepatic carcinoma cachexia was established by abdominal injection of H22 hepatic carcinoma cells. Subsequently, the body weight, food intake and gastrocnemius weight were recorded, and the levels of interleukin (IL)-lalpha, IL-6, tumor necrosis factor alpha (TNF-alpha) in ascites were detected by enzyme-linked immunosorbent assay. The protein expression levels of muscle RING-finger protein-1 (MU-RF1) and atrogin 1 were detected by western blotting and immunohistochemistry, and the mRNA levels in gastrocnemius were detected by reverse transcription-quantitative polymerase chain reaction. Compared with the xenograft tumor group, the administration of MJPJD inhibited the increase in body weight and the volume of ascites, the consumption of gastrocnemius was reduced, the net weight of ascites was maintained, the food intake was enhanced and the levels of the cytokines IL lalpha, IL-6, TNF-alpha in ascites and the levels of MU-RF1 and atrogin 1 proteins were reduced. These results indicated that MJPJD delays the pathological process of ascites-induced hepatic carcinoma cachexia, and the mechanism of action may be correlated with a reduction in the levels of IL-lalpha, IL-6, TNF alpha and inhibiting the activation of the ubiquitin proteosome pathway. PMID- 27511051 TI - Integrating gross pathology into teaching of undergraduate medical science students using human cadavers. AB - Human cadavers offer a great opportunity for histopathology students for the learning and teaching of tissue pathology. In this study, we aimed to implement an integrated learning approach by using cadavers to enhance students' knowledge and to develop their skills in gross tissue identification, handling and dissection techniques. A total of 35 students enrolled in the undergraduate medical science program participated in this study. A 3-hour laboratory session was conducted that included an active exploration of cadaveric specimens to identify normal and pathological tissues as well as tissue dissection. The majority of the students strongly agreed that the integration of normal and morbid anatomy improved their understanding of tissue pathology. All the students either agreed or strongly agreed that this laboratory session was useful to improve their tissue dissection and instrument handling skills. Furthermore, students from both cohorts rated the session as very relevant to their learning and recommended that this approach be added to the existing histopathology curriculum. To conclude, an integrated cadaver-based practical session can be used effectively to enhance the learning experience of histopathology science students, as well as improving their manual skills of tissue treatment, instrument handling and dissection. PMID- 27511052 TI - Hormesis, mithridatism and Paracelsus: A little oxidative stress goes a long way. PMID- 27511053 TI - Adherence to the Mediterranean diet is associated with reduced risk of incident chronic kidney diseases among Tehranian adults. AB - Greater adherence to the Mediterranean diet has beneficial effects on the prevention of chronic diseases. In the current study, we investigated the association between the Mediterranean diet score (MDS) and the 6-year incidence of chronic kidney disease (CKD), conducted in the framework of the Tehran Lipid and Glucose Study with 1212 adults, aged 30-71 years. Dietary intake was assessed using a valid and reliable food-frequency questionnaire, and all subjects received scores between 0 and 8 points based on the traditional MDS. The components of the MDS were fruits and nuts, vegetables, legumes, cereals, fish, meat, dairy products and the monounsaturated to saturated fatty acid ratio. The odds ratio (OR) for the occurrence of CKD according to the quartiles of the MDS was assessed by multivariable logistic regression. The mean (s.d.) age of participants (51% male) at baseline was 43.5 (9.4) years. The median (25-75 interquartile range) of MDS for all subjects was 4 (3-5).The incidence of CKD was 19%. After adjustment for all potential confounding variables, individuals in the highest quartile of the MDS were 51% less likely to have CKD than those in the lowest quartile (OR=0.49; 95% confidence interval (CI): 0.30-0.82). Additionally, after further adjustment for baseline estimated glomerular filtration rate (GFR), the inverse association between the MDS and the 6-year incidence of CKD remained significant (OR=0.53; 95% CI: 0.31-0.91). Our findings demonstrate a significant inverse association between the MDS and the risk of incident CKD, indicating that adherence to the Mediterranean diet has favorable effects on the prevention of kidney dysfunction. PMID- 27511054 TI - Increased cardiovascular risk of treated white coat and masked hypertension in patients with diabetes and chronic kidney disease: the HONEST Study. AB - The prognostic implications of treated white coat hypertension (WCH) and masked hypertension (MH) in patients with diabetes mellitus (DM) or chronic kidney disease (CKD) are not well documented. Using data from the HONEST study (n=21 591), we investigated the relationships between morning home systolic blood pressure (MHSBP) or clinic systolic blood pressure (CSBP) and cardiovascular (CV) risk in hypertensive patients with and without DM or CKD receiving olmesartan based antihypertensive therapy. The study included 4426 DM patients and 4346 CKD patients at baseline who had 101 and 87 major CV events, respectively, during the follow-up. Compared with well-controlled non-DM patients (MHSBP <135 mm Hg; CSBP <140 mm Hg), DM patients with WCH (MHSBP <135 mm Hg; CSBP ?140 mm Hg), MH (MHSBP ?135 mm Hg; CSBP <140 mm Hg) or poorly controlled hypertension (PCH) (MHSBP ?135 mm Hg; CSBP ?140 mm Hg) had significantly higher CV risk (hazard ratio (HR), 2.73, 2.77 and 2.81, respectively). CV risk was also significantly increased in CKD patients with WCH, MH and PCH (HR, 2.14, 1.70 and 2.20, respectively) compared with well-controlled non-CKD patients. Furthermore, DM patients had significantly higher incidence rate than non-DM patients of MHSBP ?125 to <135 mm Hg (HR, 1.98) and ?135 to <145 mm Hg (HR, 2.41). In conclusion, both WCH and MH are associated with increased CV risk, and thus control of both MHSBP and CSBP is important to reduce CV risk in DM or CKD patients. The results also suggest that even lower MHSBP (<125 mm Hg) may be beneficial for DM patients, although this conclusion is limited by the small number of patients. PMID- 27511055 TI - Mesenchymal-to-epithelial transition in the placental tissues of patients with preeclampsia. AB - During early pregnancy in humans, mesenchymal-to-epithelial transition (MET) contributes to decidualization of endometrial stromal cells in the uterus. Defects in decidualization can interfere with placental formation and can lead to pregnancy complications, including preeclampsia. However, MET markers in preeclamptic placental tissues have not been characterized. To investigate the association between changes in MET and preeclampsia, we evaluated MET markers in preeclamptic placental tissues relative to normal placentas. Placentas were collected from 20 preeclamptic and 20 normotensive healthy women. Protein and mRNA levels of MET-related markers, including E-cadherin, N-cadherin (neural cadherin), vimentin, ZO-1 (zona occludens 1) and SLUG, were analyzed via western blot and quantitative real-time PCR (Q-PCR), respectively. E- and N-cadherin were localized in the placentas through immunohistochemistry. The mRNA and protein expressions of GLI1 and GLI2 were detected by Q-PCR and western blot. In preeclamptic placentas, the mRNA and protein levels of E-cadherin and ZO-1 were elevated relative to the controls, whereas the levels of N-cadherin, SLUG and vimentin were lower. The staining intensities of E- and N-cadherin were consistent with their protein levels detected by western blot. The mRNA and protein levels of GLI1 and GLI2 were significantly lower in preeclamptic placentas compared with that in control placentas. We conclude that MET in the placenta may be associated with the progression of preeclampsia. PMID- 27511056 TI - Treatment of Inappropriate Sexual Behavior in Dementia. AB - OPINION STATEMENT: Inappropriate sexual behavior (ISB) is a relatively common and potentially disruptive form of behavior in people with dementia. It can cause considerable distress and put placements and people at risk. Yet it is poorly researched and understood. In addition to non-pharmacological approaches to management, a wide range of classes of medication has been used in ISB, and the results have been reported as single cases or short series, though none has been the subject of a randomized clinical trial, in part because of the lack of a well defined method of observing and measuring ISB, as well as the significant ethical considerations. Pharmacological treatments for which there is low-level evidence of efficacy in the literature include antidepressants, antipsychotics, anticonvulsants, cholinesterase inhibitors, hormonal agents, and beta-blockers. None of the drugs discussed here is licensed for use in ISB, and elderly people, particularly those with dementia, are at high risk of adverse effects. Caution is advised before using medication in this group of people. It is important to consider alternative non-pharmacological treatments, as well as discussing issues of ethics and consent with those involved, before initiating treatment. It is helpful to identify and monitor target symptoms. Pharmacological treatments should be started at low dose and titrated up slowly and carefully. Nevertheless, in some situations, medication may provide a useful part of a management plan for ISB. PMID- 27511057 TI - Three cases of tubulointerstitial nephritis and uveitis syndrome with different clinical manifestations. AB - We here describe three different clinical manifestations of tubulointerstitial nephritis and uveitis (TINU) syndrome. We examined and diagnosed the following 3 patients: a 15-year-old boy with bilateral anterior uveitis (Case 1), a 14-year old girl with bilateral papilledema (Case 2), and a 49-year-old woman with panuveitis (Case 3). The findings are presented herein. Case 1: The patient had bilateral anterior uveitis. Urinalysis revealed markedly increased beta2 microglobulin and N-acetyl-beta-D-glucosaminidase levels. As the patient was pathologically diagnosed with tubulointerstitial nephritis (TIN), we diagnosed TINU based on the presence of both uveitis and TIN. He was treated with oral corticosteroids. Case 2: This patient showed anterior uveitis and papilledema in both eyes. On initial examination, the urine test results did not show any abnormality. Three months later, high beta2-microglobulin and N-acetyl-beta-D glucosaminidase levels were detected. As the patient was clinically diagnosed with TIN, we subsequently diagnosed TINU. Both the ocular and renal findings improved without treatment. Case 3: The patient developed bilateral panuveitis, retinal vasculitis, and macular edema, which were initially suspected to be sarcoidosis. However, she was pathologically diagnosed with TIN 12 months before the onset of uveitis; therefore, she was finally diagnosed with TINU. She recovered with local corticosteroid administration only. TINU may present with fundal features in addition to anterior uveitis. Detailed history taking and urinalysis are important to determine the presence of tubular disorders in similar patients. PMID- 27511058 TI - Modulation of postprandial lipaemia by a single meal containing a commonly consumed interesterified palmitic acid-rich fat blend compared to a non interesterified equivalent. AB - PURPOSE: Interesterification of palm stearin and palm kernal (PSt/PK) is widely used by the food industry to create fats with desirable functional characteristics for applications in spreads and bakery products, negating the need for trans fatty acids. Previous studies have reported reduced postprandial lipaemia, an independent risk factor for CVD, following interesterified (IE) palmitic and stearic acid-rich fats that are not currently widely used by the food industry. The current study investigates the effect of the most commonly consumed PSt/PK IE blend on postprandial lipaemia. METHODS: A randomised, controlled, crossover (1 week washout) double-blind design study (n = 12 healthy males, 18-45 years), compared the postprandial (0-4 h) effects of meals containing 50 g fat [PSt/PK (80:20); IE vs. non-IE] on changes in plasma triacylglycerol (TAG), glucose, glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY), insulin, gastric emptying (paracetamol concentrations) and satiety (visual analogue scales). RESULTS: The postprandial increase in plasma TAG was higher following the IE PSt/PK versus the non-IE PSt/PK, with a 51 % greater incremental area under the curve [mean difference with 95 % CI 41 (23, 58) mmol/L min P = 0.001]. The pattern of lipaemia was different between meals; at 4-h plasma TAG concentrations declined following the IE fat but continued to rise following the non-IE fat. Insulin, glucose, paracetamol, PYY and GIP concentrations increased significantly after the test meals (time effect; P < 0.001 for all), but did not differ between test meals. Feelings of fullness were higher following the non-IE PSt/PK meal (diet effect; P = 0.034). No other significant differences were noted. CONCLUSIONS: Interesterification of PSt/PK increases early phase postprandial lipaemia (0-4 h); however, further investigation during the late postprandial phase (4-8 h) is warranted to determine the rate of return to baseline values. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov as NCT02365987. PMID- 27511060 TI - High performance flexible double-sided micro-supercapacitors with an organic gel electrolyte containing a redox-active additive. AB - In this study, we report the fabrication of a high performance flexible micro supercapacitor (MSC) with an organic gel electrolyte containing a redox-active additive, referred to as poly(methyl methacrylate)-propylene carbonate-lithium perchlorate-hydroquinone (PMMA-PC-LiClO4-HQ). Hexagonal MSCs fabricated on thin polyethylene terephthalate (PET) films had interdigitated electrodes made of spray-coated multi-walled carbon nanotubes (MWNTs) on Au. The addition of HQ as a redox-active additive enhanced not only the specific capacitance but also the energy density of the MSCs dramatically, which is approximately 35 times higher than that of MSCs without the HQ additive. In addition, both areal capacitance and areal energy density could be doubled by fabrication of double-sided MSCs, where two MSCs are connected in parallel. The double-sided MSCs exhibited stable electrochemical performance during repeated deformation by bending. By dry transferring the double-sided MSCs based on PMMA-PC-LiClO4-HQ on a deformable polymer substrate, we fabricated a stretchable MSC array, which also retained its electrochemical performance during a uniaxial strain of 40%. Furthermore, a wearable energy storage bracelet made of such an MSC array could operate a MU-LED on the wrist. PMID- 27511059 TI - New pregnane and phenolic glycosides from Solenostemma argel. AB - From the aerial parts, pericarps and roots of Solenostemma argel, three new pregnane glycosides (1-3) with two known ones and a new phenolic glycoside (4) have been isolated. Their structures were established by extensive 1D - and 2D NMR and mass spectroscopic analysis. The cytotoxicity of all compounds was evaluated against two human tumor cell lines (SW 480, MCF-7), but none of them was active in the concentration range 0.9-59.0MUM. Compounds 2 and the known argeloside F at non toxic concentrations for the PBMCs (27.3MUM and 27.6MUM, respectively) significantly decreased the Il-1beta production by LPS-stimulated PBMCs. All isolated compounds showed a significant antioxidant potential with ORAC values in the concentration range 3481-9617MUmoleq. Trolox/100g. PMID- 27511061 TI - Impact of leptin on memory function and hippocampal structure in mild cognitive impairment. AB - Metabolic changes have been suggested to contribute to dementia and its precursor mild cognitive impairment (MCI), yet previous results particularly for the "satiety hormone" leptin are mixed. Therefore, we aimed to determine if MCI patients show systematic differences in leptin, independent of sex, adipose mass, age, and glucose and lipid metabolism, and whether leptin levels correlated with memory performance and hippocampal integrity. Forty MCI patients (20 females, aged 67 years +/- 7 SD) were compared to 40 healthy controls (HC) that were pair wise matched for sex, age, and body fat. Memory performance was assessed using the auditory verbal learning test. Volume and microstructure of the hippocampus were determined using 3T-neuroimaging. Fasting serum markers of leptin, glucose and lipid metabolism, and other confounding factors were assayed. MCI patients, compared with HC, showed lower serum leptin, independent of sex, age, and body fat (P < 0.001). Glucose and lipid markers did not attenuate these results. Moreover, MCI patients exhibited poorer memory and lower volume and microstructural integrity within hippocampal subfields. While leptin and memory were not significantly correlated, mediation analyses indicated that lower leptin contributed to poorer memory through its negative effect on right hippocampus volume and left hippocampus microstructure. We demonstrated that MCI is associated with lower serum leptin independent of sex, age, body fat, glucose, and lipid metabolism. Our data further suggest that inefficient leptin signaling could partly contribute to decreases in memory performance through changes in hippocampus structure, a hypothesis that should now be verified in longitudinal studies. Hum Brain Mapp 37:4539-4549, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27511062 TI - The master female triathlete. AB - The world of triathlon has expanded to include all ages and both sexes. One of the largest growing age groups is the master female athlete. It is important for the physical therapist to understand the special needs of this population in order to adequately care for master female athletes so they can participate at a high level and injury-free. Biology of aging, injury prevention and a suggested training program are presented in this Masterclass article. PMID- 27511063 TI - Generalized optimal design for two-arm, randomized phase II clinical trials with endpoints from the exponential dispersion family. AB - For two-arm randomized phase II clinical trials, previous literature proposed an optimal design that minimizes the total sample sizes subject to multiple constraints on the standard errors of the estimated event rates and their difference. The original design is limited to trials with dichotomous endpoints. This paper extends the original approach to be applicable to phase II clinical trials with endpoints from the exponential dispersion family distributions. The proposed optimal design minimizes the total sample sizes needed to provide estimates of population means of both arms and their difference with pre specified precision. Its applications on data from specific distribution families are discussed under multiple design considerations. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27511065 TI - The cellular mechanisms that maintain neuronal polarity. AB - As polarized cells, neurons maintain different sets of resident plasma membrane proteins in their axons and dendrites, which is consistent with the different roles that these neurites have in electrochemical signalling. Axonal and dendritic proteins are synthesized together within the somatodendritic domain; this raises a fundamental question: what is the nature of the intracellular trafficking machinery that ensures that these proteins reach the correct domain? Recent studies have advanced our understanding of the processes underlying the selective sorting and selective transport of axonal and dendritic proteins and have created potential avenues for future progress. PMID- 27511066 TI - Bile acid receptor TGR5, NADPH Oxidase NOX5-S and CREB Mediate Bile Acid-Induced DNA Damage In Barrett's Esophageal Adenocarcinoma Cells. AB - The mechanisms whereby bile acid reflux may accelerate the progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not fully understood. In this study we found that bile acid taurodeoxycholic acid (TDCA) significantly increased the tail moment (TM) and histone H2AX phosphorylation in FLO-1 EA cells, an increase which was significantly decreased by knockdown of TGR5. Overexpression of TGR5 significantly increased TDCA-induced TM increase and H2AX phosphorylation. In addition, NADPH oxidase inhibitor diphenylene iodonium significantly inhibited the TDCA-induced increase in TM and H2AX phosphorylation. TDCA-induced increase in TM and H2AX phosphorylation was significantly decreased by knockdown of NOX5-S and overexpression of NOX5-S significantly increased TDCA induced increase in the tail moment and H2AX phosphorylation. Furthermore, TDCA significantly increased cAMP response element binding protein (CREB) phosphorylation in FLO-1 cells. Knockdown of CREB significantly decreased TDCA induced increase in NOX5-S mRNA and the tail moment. Conversely, overexpression of CREB significantly increased TDCA-induced TM increase. We conclude that TDCA induced DNA damage may depend on the activation of TGR5, CREB and NOX5-S. It is possible that in Barrett's patients bile acids may activate NOX5-S and increase reactive oxygen species (ROS) production via activation of TGR5 and CREB. NOX5-S derived ROS may cause DNA damage, thereby contributing to the progression from BE to EA. PMID- 27511103 TI - Synchronizing Watches: The Challenge of Aligning Implementation Science and Public Systems. AB - This special issue of Administration and Policy in Mental Health explores the complexities of the outer system context in implementation science research. In this commentary, we highlight areas of asynchrony between implementation science research and policy realities of public systems. Timing is a critical factor for many aspects of system-level implementation including when and how evidence-based practice initiatives are launched, short and inconsistent timeframes for funding and support, need for early indicators of success and demonstrating return on investment. Greater consideration for the timing that drives change in public systems will strengthen efforts to implement and sustain EBPs in community settings. PMID- 27511067 TI - Blood pressure variability and cardiovascular disease: systematic review and meta analysis. AB - OBJECTIVE: To systematically review studies quantifying the associations of long term (clinic), mid-term (home), and short term (ambulatory) variability in blood pressure, independent of mean blood pressure, with cardiovascular disease events and mortality. DATA SOURCES: Medline, Embase, Cinahl, and Web of Science, searched to 15 February 2016 for full text articles in English. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Prospective cohort studies or clinical trials in adults, except those in patients receiving haemodialysis, where the condition may directly impact blood pressure variability. Standardised hazard ratios were extracted and, if there was little risk of confounding, combined using random effects meta-analysis in main analyses. Outcomes included all cause and cardiovascular disease mortality and cardiovascular disease events. Measures of variability included standard deviation, coefficient of variation, variation independent of mean, and average real variability, but not night dipping or day night variation. RESULTS: 41 papers representing 19 observational cohort studies and 17 clinical trial cohorts, comprising 46 separate analyses were identified. Long term variability in blood pressure was studied in 24 papers, mid-term in four, and short-term in 15 (two studied both long term and short term variability). Results from 23 analyses were excluded from main analyses owing to high risks of confounding. Increased long term variability in systolic blood pressure was associated with risk of all cause mortality (hazard ratio 1.15, 95% confidence interval 1.09 to 1.22), cardiovascular disease mortality (1.18, 1.09 to 1.28), cardiovascular disease events (1.18, 1.07 to 1.30), coronary heart disease (1.10, 1.04 to 1.16), and stroke (1.15, 1.04 to 1.27). Increased mid-term and short term variability in daytime systolic blood pressure were also associated with all cause mortality (1.15, 1.06 to 1.26 and 1.10, 1.04 to 1.16, respectively). CONCLUSIONS: Long term variability in blood pressure is associated with cardiovascular and mortality outcomes, over and above the effect of mean blood pressure. Associations are similar in magnitude to those of cholesterol measures with cardiovascular disease. Limited data for mid-term and short term variability showed similar associations. Future work should focus on the clinical implications of assessment of variability in blood pressure and avoid the common confounding pitfalls observed to date. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014015695. PMID- 27511104 TI - [Not Available]. PMID- 27511106 TI - Case of severe acneiform eruptions associated with the BRAF inhibitor vemurafenib. PMID- 27511105 TI - Administration of prostacyclin modulates cutaneous blood flow but not sweating in young and older males: roles for nitric oxide and calcium-activated potassium channels. AB - KEY POINTS: In young adults, cyclooxygenase (COX) contributes to the heat loss responses of cutaneous vasodilatation and sweating, and this may be mediated by prostacyclin-induced activation of nitric oxide synthase (NOS) and calcium activated potassium (KCa) channels. This prostacyclin-induced response may be diminished in older relative to young adults because ageing is known to attenuate COX-dependent heat loss responses. We observed that, although prostacyclin does not mediate sweating in young and older males, it does modulate cutaneous vasodilatation, although the magnitude of increase is similar between groups. We also found that, although NOS and KCa channels contribute to prostacyclin-induced cutaneous vasodilatation in young males, these contributions are diminished in older males. Our findings provide new insight into the mechanisms governing heat loss responses and suggest that the age-related diminished COX-dependent heat loss responses reported in previous studies may be a result of the reduced COX derived production of prostanoids (e.g., prostacyclin) rather than the decreased sensitivity of prostanoid receptors. ABSTRACT: Cyclooxygenase (COX) contributes to the regulation of cutaneous vasodilatation and sweating; however, the mechanism(s) underpinning this response remain unresolved. We hypothesized that prostacyclin (a COX-derived product) may directly mediate cutaneous vasodilatation and sweating through nitric oxide synthase (NOS) and calcium activated potassium (KCa) channels in young adults. However, these responses would be diminished in older adults because ageing attenuates COX-dependent cutaneous vasodilatation and sweating. In young (25 +/- 4 years) and older (60 +/ 6 years) males (nine per group), cutaneous vascular conductance (CVC) and sweat rate were evaluated at four intradermal forearm skin sites: (i) control; (ii) 10 mm NG -nitro-l-arginine (l-NNA), a non-specific NOS inhibitor; (iii) 50 mm tetraethylammonium (TEA), a non-specific KCa channel blocker; and (iv) 10 mm l NNA + 50 mm TEA. All four sites were coadministered with prostacyclin in an incremental manner (0.04, 0.4, 4, 40 and 400 MUm each for 25 min). Prostacyclin induced increases in CVC were similar between groups (all concentrations, P > 0.05). l-NNA and TEA, as well as their combination, lowered CVC in young males at all prostacyclin concentrations (P <= 0.05), with the exception of l-NNA at 0.04 MUm (P > 0.05). In older males, CVC during prostacyclin administration was not influenced by l-NNA (all concentrations), TEA (4-400 MUm) or their combination (400 MUm) (P > 0.05). No effect on sweat rate was observed in either group (all concentrations, P > 0.05). We conclude that, although prostacyclin does not mediate sweating, it modulates cutaneous vasodilatation to a similar extent in young and older males. Furthermore, although NOS and KCa channels contribute to the prostacyclin-induced cutaneous vasodilatation in young males, these contributions are diminished in older males. PMID- 27511107 TI - Salt secretion is linked to acid-base regulation of ionocytes in seawater acclimated medaka: new insights into the salt-secreting mechanism. AB - Ionocytes in the skin and gills of seawater (SW) teleosts are responsible for both salt and acid secretion. However, the mechanism through which ionocytes secrete acid is still unclear. Here, we hypothesized that apical Na(+)/H(+) exchangers (NHE2/3), carbonic anhydrase (CA2-like), and basolateral HCO3(-)/Cl(-) exchanger (AE1) are involved in acid secretion. In addition, the hypothesized involvement of basolateral AE1 suggested that acid secretion may be linked to Cl( ) secretion by ionocytes. The scanning ion-selective electrode technique (SIET) was used to measure H(+) and Cl(-) secretion by ionocytes in the skin of medaka larvae acclimated to SW. Treatment with inhibitors of NHE, CA, and AE suppressed both H(+) and Cl(-) secretion by ionocytes. Short-term exposure to hypercapnic SW stimulated both H(+) and Cl(-) secretion. mRNA of CA2-like and AE1 were localized to ionocytes in the skin. Branchial mRNA levels of NKCC1a, CA2-like, and AE1a increased together with the salinity to which fish were acclimated. In addition, both AE1a and AE1b mRNA increased in fish acclimated to acidified (pH 7) SW; NKCC1a mRNA increased in fish acclimated to pH 9 SW. This study reveals the mechanism of H(+) secretion by ionocytes, and refines our understanding of the well-established mechanism of Cl(-) secretion by ionocytes of SW fish. PMID- 27511108 TI - Leucine Zipper-bearing Kinase promotes axon growth in mammalian central nervous system neurons. AB - Leucine Zipper-bearing Kinase (LZK/MAP3K13) is a member of the mixed lineage kinase family with high sequence identity to Dual Leucine Zipper Kinase (DLK/MAP3K12). While DLK is established as a key regulator of axonal responses to injury, the role of LZK in mammalian neurons is poorly understood. By gain- and loss-of-function analyses in neuronal cultures, we identify LZK as a novel positive regulator of axon growth. LZK signals specifically through MKK4 and JNKs among MAP2Ks and MAPKs respectively in neuronal cells, with JNK activity positively regulating LZK protein levels. Neuronal maturation or activity deprivation activates the LZK-MKK4-JNK pathway. LZK and DLK share commonalities in signaling, regulation, and effects on axon extension. Furthermore, LZK dependent regulation of DLK protein expression and the lack of additive effects on axon growth upon co-manipulation suggest complex functional interaction and cross-regulation between these two kinases. Together, our data support the possibility for two structurally related MAP3Ks to work in concert to mediate axonal responses to external insult or injury in mammalian CNS neurons. PMID- 27511109 TI - Postpartum psychiatric emergency visits: a nested case-control study. AB - Mental health conditions are one of the most common reasons for postpartum emergency department (ED) visits. Characteristics of women using the ED and their mental health service use before presentation are unknown. We characterized all women in Ontario, Canada (2006-2012), who delivered a live born infant and had a psychiatric ED visit within 1 year postpartum (n = 8728). We compared those whose ED visit was the first physician mental health contact since delivery to those who had accessed mental health services on specific indicators of marginalization hypothesized to be associated with lower likelihood of mental health contact prior to the ED visit. For 60.4 % of women, this was the first physician mental health contact since delivery. The majority were presenting with a mood or anxiety disorder, and only 13.6 % required hospital admission. These women were more likely to have material deprivation and residential instability than women with contact (Q5 vs. Q1 aORs 1.30, 95 % CI 1.12-1.50; 1.17, 95 % CI 1.01-1.36), to live in rural vs. urban areas (aOR 1.58, 95 % CI 1.38-1.80), and to be low vs. high income quintile (aOR 1.18, 95 % CI 1.01-1.38). The frequent use of ED services as the first point of contact for mental health concerns suggests that interventions to improve timely and equitable access to effective outpatient postpartum mental health care are needed. Marginalized women are at particularly high risk of not having accessed outpatient services prior to an ED visit, and therefore, future research and interventions will specifically need to consider the needs of this group. PMID- 27511110 TI - Risk of false positive results to SARM S-4 in case of therapeutic use of antineoplastic/antiandrogen drug containing flutamide: a case study. PMID- 27511111 TI - Study of the Transformations of Micro/Nano-crystalline Acetaminophen Polymorphs in Drug-Polymer Binary Mixtures. AB - This study elucidates the physical properties of sono-crystallised micro/nano sized acetaminophen/paracetamol (PMOL) and monitors its possible transformation from polymorphic form I (monoclinic) to form II (orthorhombic). Hydrophilic Plasdone(r) S630 copovidone (S630), N-vinyl-2-pyrrolidone and vinyl acetate copolymer, and methacrylate-based cationic copolymer, Eudragit(r) EPO (EPO), were used as polymeric carriers to prepare drug/polymer binary mixtures. Commercially available PMOL was crystallised under ultra sound sonication to produce micro/nano-sized (0.2-10 microns) crystals in monoclinic form. Homogeneous binary blends of drug-polymer mixtures at various drug concentrations were obtained via a thorough mixing. The analysis conducted via the single X-ray crystallography determined the detailed structure of the crystallised PMOL in its monoclinic form. The solid state and the morphology analyses of the PMOL in the binary blends evaluated via differential scanning calorimetry (DSC), modulated temperature DSC (MTDSC), scanning electron microscopy (SEM) and hot stage microscopy (HSM) revealed the crystalline existence of the drug within the amorphous polymeric matrices. The application of temperature controlled X-ray diffraction (VTXRPD) to study the polymorphism of PMOL showed that the most stable form I (monoclinic) was altered to its less stable form II (orthorhombic) at high temperature (>112 degrees C) in the binary blends regardless of the drug amount. Thus, VTXRD was used as a useful tool to monitor polymorphic transformations of crystalline drug (e.g. PMOL) to assess their thermal stability in terms of pharmaceutical product development and research. PMID- 27511112 TI - Formulation and In Vitro Characterization of Thiolated Buccoadhesive Film of Fluconazole. AB - The present work is focused on the development of thiolated film for fluconazole buccal delivery. To this end, unmodified polymers chitosan and sodium carboxymethylcellulose (NaCMC) backbone was covalently modified by thioglycolic acid (TGA) and cysteine, respectively. The thiolated buccoadhesive film was evaluated in terms of thickness, weight uniformity, water-uptake capacity, drug content, and release patterns. Moreover, mucoadhesion profile was investigated on buccal mucosa. The resulting chitosan-TGA and NaCMC-cysteine conjugates displayed 171 +/- 13 and 380 +/- 19 MUmol thiol groups per gram of polymer (mean +/- SD; n = 3), respectively. The water binding capacity of the thiolated film was significantly ~2-fold higher (p < 0.05) as compared to unmodified film. The obtained thiolated film displayed 5.8-fold higher mucoadhesive properties compared with corresponding film. Controlled release of drugs from film was observed over 8 h. The transport of fluconazole across excised buccal mucosa was enhanced up to 17-fold in comparison with fluconazole applied in buffer. Based on these findings, thiolated film seems to be promising for fluconazole buccal delivery. PMID- 27511113 TI - Nanocomposites of 2D-MoS2 nanosheets with the metal-organic framework, ZIF-8. AB - The nanocomposites of MoS2 nanosheets with the metal-organic framework, ZIF-8, have been synthesized starting with the layers of 1T-MoS2 generated by Li intercalation of bulk MoS2, followed by exfoliation. The nanocomposites contain the Zn-S bond and exhibit reasonably high surface areas. They exhibit CO2 uptake higher than ZIF-8. Heating the nanocomposites to 900 degrees C under a N2 atmosphere yields MoS2-ZnS nanocomposites which show good activity for the visible-light induced hydrogen evolution reaction. PMID- 27511114 TI - TERT promoter mutations and chromosome 8p loss are characteristic of nonalcoholic fatty liver disease-related hepatocellular carcinoma. AB - The number of patients with nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) is increasing. To understand the molecular features of the tumor phenotype, we aimed to clarify the overall landscape of genetic aberrations accumulated in NAFLD-related HCC. Of 247 HCC patients who underwent hepatectomy during 2010 to 2014 at a single center in Japan, 10 were diagnosed with NAFLD-HCC based on strict clinical and pathologic criteria. We analyzed the genetic aberrations of 11 NAFLD-HCC tumor samples from these 10 patients by whole-exome sequencing, targeted sequencing of the selected genes, and copy number variation studies. Whole-exome sequencing revealed a mean somatic mutation rate of 1.86 per megabase, and 12 genes were recurrently mutated in NAFLD-HCCs. Targeted sequencing of the 26 selected genes (12 recurrently mutated genes in whole-exome sequencing and 14 representative HCC-associated genes) revealed that TERT promoter mutations occurred in 9 of 11 HCCs (82%), followed by CTNNB1 (45%) and TP53 (36%) mutations. Array-based copy number variation studies identified recurrent gains at 1q and 8q, and recurrent losses at 1p, 4q, 6q, 8p, 13q, 16p, 17p, and 18q. Notably, chromosome 8p loss occurred in all of the NAFLD HCC samples. The current study provided the characteristics of genetic aberrations in NAFLD-HCC and suggested that TERT promoter mutations and chromosome 8p loss mainly contribute to NAFLD-related liver carcinogenesis. PMID- 27511115 TI - Does cryotherapy improve skin circulation compared with compression and elevation in preventing venous leg ulcers? AB - This trial compared skin blood flow, temperature and incidence of venous leg ulcers in patients with chronic venous disease using compression wraps and elevation pillows. Patients with CEAP C4 skin damage and C5 history of ulcers were randomly assigned to a cryotherapy intervention (n = 138) or placebo cuff control (n = 138) applied to the lower legs over 9 months. The time the ulcers healed prior to enrollment in the study for the cryotherapy group ranged from 1 to 2218 days (n = 8, median = 32 days); for the control group, the range was 24 to 489 days (n = 6, median = 390 days). There were no statistically significant blood flow changes measured in perfusion units with a laser Doppler flowmetre within or between the groups; mean difference between the groups was 0.62, P = 0.619. No differences were noted in skin temperature measured with an infrared thermometer within and between the groups; mean difference between the groups was -0.17 degrees C, P = 0.540. Cryotherapy did not improve skin blood flow or temperature and did not show efficacy in preventing ulcers. However, at least 30% of intervention and 50% of control participants were anticipated to develop an ulcer during the study; only ~7% occurred. These findings suggest that strict adherence to standard of care decreases the incidence of leg ulcers and remains a best practice for leg ulcer prevention. PMID- 27511116 TI - Overall survival of cancer patients with serum lactate dehydrogenase greater than 1000 IU/L. AB - High level of serum lactate dehydrogenase (LDH) is a well-known poor prognostic factor in patients with malignancies. However, there was no data on overall survival (OS) in cancer patients with serum LDH level > 1000 IU/L, and the prognostic value of the changes in LDH over time for OS had not been reported. Clinical data of 311 cancer patients with metastatic disease with serum LDH >1000 IU/L (four times upper limit of normal) admitted consecutively to a single center were reviewed in this retrospective study. LDH level ranged from 1002 to 8235 U/L with a mean of 1689 U/L. The median OS was 1.7 months (95 % CI: 1.4-2.0). About half of patients (n = 163, 52 %) died within 2 months with the median OS of 0.5 months (95 % CI: 0.3-0.7). Only 173 patients were indicated for salvage treatment. Fifty-one patients' serum LDH level decreased to normal at 2 months following chemotherapy; OS was significantly longer in these patients (22.6 months, 95 % CI: 10.9-34.3, p < 0.001) compared to those with persistently abnormal serum LDH at 2 months (4.0 months, 95 % CI: 3.4-4.6). The independent factors that increased the death risk were ECOG performance status 3-4 (HR: 2.05, 95 % CI: 1.42-2.97, p < 0.001), supportive care only (HR: 2.91, 95 % CI: 2.06 4.10, p < 0.001), and persistently abnormal serum LDH at 2 months (HR: 2.72, 95 % CI: 1.67-4.42, p < 0.001). In conclusion, serum LDH level > 1000 IU/L predicted a terminal stage in metastatic cancer patients. OS was significantly prolonged in patients indicated for effective palliative treatment and LDH level decreased to normal at 2 months. PMID- 27511117 TI - Experimental verification of a predicted novel microRNA located in human PIK3CA gene with a potential oncogenic function in colorectal cancer. AB - PI3K/AKT signaling is involved in cell survival, proliferation, and migration. In this pathway, PI3Kalpha enzyme is composed of a regulatory protein encoded by p85 gene and a catalytic protein encoded by PIK3CA gene. Human PIK3CA locus is amplified in several cancers including lung and colorectal cancer (CRC). Therefore, microRNAs (miRNAs) that are encoded within the PIK3CA gene might have a role in cancer development. Here, we report a novel microRNA named PIK3CA-miR1 (EBI accession no. LN626315), which is located within PIK3CA gene. A DNA segment corresponding to PIK3CA-premir1 sequence was transfected in human cell lines that resulted in generation of mature exogenous PIK3CA-miR1. Following the overexpression of PIK3CA-miR1, its predicted target genes (APPL1 and TrkC) were significantly downregulated in the CRC-originated HCT116 and SW480 cell lines, detected by qRT-PCR. Then, dual luciferase assay supported the interaction of PIK3CA-miR1 with APPL1 and TrkC transcripts. Endogenous PIK3CA-miR1 expression was also detected in several cell lines (highly in HCT116 and SW480) and highly in CRC specimens. Consistently, overexpression of PIK3CA-premir1 in HCT116 and SW480 cells resulted in significant reduction of the sub-G1 cell distribution and apoptotic cell rate, as detected by flowcytometry, and resulted in increased cell proliferation, as detected by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. PIK3CA-miR1 overexpression also resulted in Wnt signaling upregulation detected by Top/Fop assay. Overall, accumulative evidences indicated the presence of a bona fide novel onco-miRNA encoded within the PIK3CA oncogene, which is highly expressed in colorectal cancer and has a survival effect in CRC-originated cells. PMID- 27511118 TI - Molecular genetic analysis and phenotypic characteristics of a consanguineous family with glycogen storage disease type Ia. AB - Glycogen storage disease type-Ia (GSD-Ia) is a rare autosomal recessive disease caused by a mutation in the gene encoding glucose-6-phosphate-alpha (G6PC). The present study reported the case of a 3-month-old female Chinese patient with GSD Ia born to consanguineous parents. The aim of the present study was to identify the precise mutation of the G6PC gene associated with this family and to describe the phenotypic characteristics of the patient. A comprehensive examination was performed on the patient, including physical examination, vein blood gas analysis, abdominal sonography and biochemical analyses. In addition, gene sequencing was performed on the coding region of the G6PC gene to identify the mutation. The patient was diagnosed with GSD-Ia and a G6PC missense mutation of c.518T>C (p.L173P) located in a highly conserved area was identified. The mutation is in a non-helical region of the protein, which previous studies have suggested should result in a lesser effect on G6PC enzymatic activity and milder phenotypic characteristics compared with mutations located in helical regions. However, the severity of the disease phenotype in the subject of the present study was inconsistent with that predicted from her genotype. The patient suffered from serious hypoglycemia, lactic acidosis, increased triglycerides, hepatic dysfunction, clear hepatomegaly and nephromegaly. The incidence of the p.L173P mutation may be relatively high in the Chinese population. Knowledge of the various phenotypic presentations of the p.L173P mutation may beneficial for future investigations. PMID- 27511119 TI - Rise of the tendon research. PMID- 27511120 TI - Safety and efficacy of coil embolization of the septal perforator for septal ablation in patients with hypertrophic obstructive cardiomyopathy. AB - OBJECTIVE: The objective of this study was to evaluate safety, efficacy, and durability of coil embolization of the major septal perforator of the left anterior descending coronary artery in patients with hypertrophic obstructive cardiomyopathy (HOCM). BACKGROUND: The long-term effect of coil embolization therapy in HOCM patients is not well defined. METHODS: We evaluated 24 symptomatic HOCM patients in a single center who underwent coil embolization of the septal perforator artery(ies). RESULTS: Twenty-four patients on optimal medical therapy presented with NYHA functional class III (75%) or IV (25%) underwent the procedure. The procedure was successful in 22 patients, with significant reduction in left ventricular outflow tract (LVOT) gradient. The functional class significantly improved to class I (54.2%) or II (41.7%) (P < = 0.01). The LVOT gradient was significantly lower during follow up echocardiography (21.3 +/- 19 vs. 81.3 +/- 41 mm Hg; P < = 0.01). Interventricular septal thickness decreased over time (16.3 +/- 3 vs. 18.5 +/- 2 mm, P< = 0.01). The procedure was aborted in one of the patients after the third coil prolapsed from the septal perforator in to the left anterior descending artery. The coil was effectively snared out. Three patients required additional coil placement in the second major septal perforator. New permanent pacemaker placement was required in one patient. However, three patients underwent ICD implantation at follow up due to ventricular arrhythmias. CONCLUSIONS: The results of this study suggest that the use of coil embolization for septal ablation is safe, effective, and durable in patients with symptomatic HOCM. (c) 2016 Wiley Periodicals, Inc. PMID- 27511121 TI - SIBLING- AND FAMILY-LEVEL CLUSTERING OF UNDERWEIGHT CHILDREN IN NORTHERN INDIA. AB - Child undernutrition remains a major child health and developmental issue in low- and middle-income countries. The concentration (clustering) of underweight children among siblings at the family level is known to exist in India. This study examined the extent and covariates of clustering of underweight children at the sibling and family level in Uttar Pradesh, the largest state of northern India. Clustering of underweight (low weight-for-age) children was assessed using data on 7533 under-five children from the National Family Health Survey (NFHS) conducted in 2005-06, analysed using binary logistic and binomial regression models. Related bio-demographic, socioeconomic and health care variables were used as covariates in the models. The odds of being underweight for the index child were about two times higher (OR=2.34, p<0.001) if any of the siblings within the household was malnourished or underweight. A longer birth interval increased the odds of a child being underweight. The odds of underweight were significantly lower (OR=0.69, p<0.001) for children born to normal-weight mothers compared with those born to underweight mothers. Similarly, the odds of underweight were significantly lower (OR=0.49, p=0.01) for children born to educated mothers (high school and above) compared with those born to illiterate mothers. The results of the binomial regression model suggested that the deviations between observed and expected number of children were positive (3.09, 3.78 and 2.71) for 1, 2 and 2+ underweight children within the households of underweight women, indicating the concentration of underweight children among underweight/malnourished mothers. Underweight children were found to be clustered among underweight mothers with multiple underweight siblings. The findings suggest that policy interventions need to focus on underweight mothers with multiple underweight children. PMID- 27511123 TI - Sex hormone effects on autonomic and endothelial function. AB - A video slideshow Introduction to the Symposium by symposium organiser Nina S. Stachenfeld can be found here. PMID- 27511122 TI - Transposable elements and miRNA: Regulation of genomic stability and plasticity. AB - Transposable elements, the class of mobile DNA sequences that change their copies or positions within the genome have an ever increasing role in shaping the genetic and evolutionary landscape. Approximately half of the mammalian genome is composed of repetitive elements, including LINE-1 (L1) elements. Because of their ability to "copy and paste" into other regions of the genome, their activation represent an opportunity as well as a threat, as L1-induced mutations results in genomic instability and plasticity. On one hand L1 retrotransposition and integration fosters genomic diversity and on the other, de-repressed L1 functions as a driver of diseases such as cancer. The regulation of L1 is an area of intense research and novel epigenetic mechanisms have recently been discovered to now include DNA methylation, histone modifications, and miR-induced L1 silencing. During development, reprogramming and in transformed cells, specific classes of repetitive elements are upregulated, presumably due to the loss of epigenetic regulation in this process, increasing the risk of L1-induced mutations. Here we discuss how miR regulation of L1 activation fits into the complex picture of L1 repression in somatic cells and touch on some of the possible implications. PMID- 27511124 TI - Enzyme overexpression - an exercise toward understanding regulation of heparan sulfate biosynthesis. AB - Biosynthesis of heparan sulfate (HS) involves conversion of D-glucuronic acid (GlcA) to L-iduronic acid (IdoA) units catalyzed by glucuronyl C5-epimerase (Hsepi). IdoA units are the favored substrate for 2-O-sulfotransferase (2OST). We used HEK293 cells as a model to investigate the effects of overexpression of these enzymes on HS structure. Overexpression of Hsepi alone resulted in an unexpected increase in HS chain length. A Hsepi point-mutant (Y168A), devoid of catalytic activity, failed to affect chain length. Moreover, the effect of Hsepi overexpression on HS chain length was abolished by simultaneous overexpression of 2OST. These findings raise novel aspects on regulation of HS biosynthesis. We propose a hypothetical enzyme-binding protein (EBP) with distinct, specific and partly overlapping binding sites, the interactions of which will determine levels of enzymes available to the biosynthetic process. PMID- 27511125 TI - Neuroprotective effects of sodium hydrosulfide against beta-amyloid-induced neurotoxicity. AB - Alzheimer's disease (AD) is known to be caused by the accumulation of amyloid beta peptide (Abeta). The accumulation of Abeta has been shown to cause learning and memory impairment in rats, and it has been shown that hydrogen sulfide donors, such as sodium hydrosulfide (NaHS) can attenuate these effects. However, the underlying mechanisms have not yet been fully eludicated. This study was designed to investigate whether NaHS attenuates the inflammation and apoptosis induced by Abeta. We demonstrated that NaHS attenuated Abeta25-35-induced neuronal reduction and apoptosis, and inhibited the activation of pro-caspase-3. It also decreased the protein expresion of phosphodiesterase 5 (PDE5) in the hippocampus of the rats. In addition, NaHS upregulated the expression of peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma, but it did not affect the expression of PPAR-beta. Moreover, the Abeta25-35-exposed rats exhibited a decrease in IkappaB-alpha degradation and an increase in nuclear factor-kappaB (NF-kappaB) p65 phosphorylation levels, whereas these effects were attenuated by NaHS. Our data suggest that NaHS prevents Abeta-induced neurotoxicity via the upregulation of PPAR-alpha and PPAR-gamma and the inhibition of PDE5. Hence NaHS may prove to be beneficial in the treatment of AD. PMID- 27511126 TI - Yemen's Unprecedented Humanitarian Crisis: Implications for International Humanitarian Law, the Geneva Convention, and the Future of Global Health Security. AB - The current humanitarian crisis in Yemen is unprecedented in many ways. The Yemeni War tragedy is symptomatic of gross failures to recognize, by combatants, existing humanitarian law and the Geneva Convention that have become the new norm in unconventional armed conflicts and are increasingly replicated in Africa, Afghanistan, and other areas of the Middle East with dire consequences on aid workers and the noncombatant population. The health and humanitarian professions must take collective responsibility in calling for all belligerent parties to cease the massacre and commit to guaranteed medical assistance, humanitarian aid, and the free flow of information and respect for the humanitarian principles that protect the neutrality and impartiality of the humanitarian workforce. (Disaster Med Public Health Preparedness. 2016;page 1 of 3). PMID- 27511127 TI - Age, sex and arterial pressure: the kidney is essential. PMID- 27511128 TI - The Leicester cerebral haemodynamics database: normative values and the influence of age and sex. AB - Normative values of physiological parameters hold significance in modern day clinical decision-making. Lack of such normative values has been a major hurdle in the translation of research into clinical practice. A large database containing uniform recordings was constructed to allow more robust estimates of normative ranges and also assess the influence of age and sex. Doppler recordings were performed on healthy volunteers in the same laboratory, using similar protocols and equipment. Beat-to-beat blood pressure, heart-rate, electrocardiogram, and end-tidal CO2 were measured continuously. Bilateral insonation of the middle cerebral arteries (MCAs) was performed using TCD following a 15 min stabilisation, and a 5 min baseline recording. Good quality Doppler recordings for both MCAs were obtained in 129 participants (57 female) with a median age of 57 years (range 20-82). Age was found to influence baseline haemodynamic and transfer function analysis parameters. Cerebral blood flow velocity and critical closing pressure were the only sex-related differences found, which was significantly higher in females than males. Normative values for cerebral haemodynamic parameters have been defined in a large, healthy population. Such age/sex-defined normal values can be used to reduce the burden of collecting additional control data in future studies, as well as to identify disease-associated changes. PMID- 27511129 TI - Successful treatment of angiokeratoma circumscriptum naeviforme with long pulse alexandrite laser. PMID- 27511130 TI - Microscopic Charge Transport and Recombination Processes behind the Photoelectric Hysteresis in Perovskite Solar Cells. AB - The microscopic charge transport and recombination processes behind the widely concerned photoelectric hysteresis in the perovskite solar cell have been investigated with both in situ transient photovoltage/photocurrent measurements and the semiconductor device simulation. Time-dependent behaviors of intensity and direction of the photocurrent and photovoltage are observed under the steady state bias voltages and open-circuit conditions. These charge processes reveal the electric properties of the cell, demonstrating evolutions of both strength and direction of the internal electric field during the hysteresis. Further calculation indicates that this behavior is mainly attributed to both the interfacial doping and defect effects induced by the ion accumulation, which may be the origins for the general hysteresis in this cell. PMID- 27511132 TI - Bis(4-nitraminofurazanyl-3-azoxy)azofurazan and Derivatives: 1,2,5-Oxadiazole Structures and High-Performance Energetic Materials. AB - Bis(4-nitraminofurazanyl-3-azoxy)azofurazan (1) and ten of its energetic salts were prepared and fully characterized. Computational analysis based on isochemical shielding surface and trigger bond dissociation enthalpy provide a better understanding of the thermal stabilities for nitramine-furazans. These energetic compounds exhibit good densities, high heats of formation, and excellent detonation velocity and pressure. Some representative compounds, for example, 1 (vD : 9541 m s(-1) ; P: 40.5 GPa), and 4 (vD : 9256 m s(-1) ; P: 38.0 GPa) exhibit excellent detonation performances, which are comparable with current high explosives such as RDX (vD : 8724 m s(-1) ; P: 35.2 GPa) and HMX (vD : 9059 m s(-1) ; P: 39.2 GPa). PMID- 27511131 TI - Insulin-like growth factor 1 rescues R28 retinal neurons from apoptotic death through ERK-mediated BimEL phosphorylation independent of Akt. AB - Insulin-like growth factor 1 (IGF-1) can provide long-term neurotrophic support by activation of Akt, inhibition of FoxO nuclear localization and suppression of Bim gene transcription in multiple neuronal systems. However, MEK/ERK activation can also promote neuron survival through phosphorylation of BimEL. We explored the contribution of the PI3K/Akt/FoxO and MEK/ERK/BimEL pathways in IGF-1 stimulated survival after serum deprivation (SD) of R28 cells differentiated to model retinal neurons. IGF-1 caused rapid activation of Akt leading to FoxO1/3 T32/T24 phosphorylation, and prevented FoxO1/3 nuclear translocation and Bim mRNA upregulation in response to SD. IGF-1 also caused MAPK/MEK pathway activation as indicated by ERK1/2-T202/Y204 and Bim-S65 phosphorylation. Overexpression of FoxO1 increased Bim mRNA expression and amplified the apoptotic response to SD without shifting the serum response curve. Inhibition of Akt activation with LY294002 or by Rictor knockdown did not block the protective effect of IGF-1, while inhibition of MEK activity with PD98059 prevented Bim phosphorylation and blocked IGF-1 protection. In addition, knockdown of Bim expression was protective during SD, while co-silencing of FoxO1 and Fox03 expression had little effect. Thus, the PI3K/Akt/FoxO pathway was not essential for protection from SD-induced apoptosis by IGF-1 in R28 cells. Instead, IGF-1 protection was dependent on activation of the MEK/ERK pathway leading to BimEL phosphorylation, which is known to prevent Bax/Bak oligomerization and activation of the intrinsic mitochondrial apoptosis pathway. These studies demonstrate the requirement of the MEK/ERK pathway in a model of retinal neuron cell survival and highlight the cell specificity for IGF-1 signaling in this response. PMID- 27511133 TI - Selective recognition and stabilization of new ligands targeting the potassium form of the human telomeric G-quadruplex DNA. AB - The development of a ligand that is capable of distinguishing among the wide variety of G-quadruplex structures and targeting telomeres to treat cancer is particularly challenging. In this study, the ability of two anthraquinone telomerase inhibitors (NSC749235 and NSC764638) to target telomeric G-quadruplex DNA was probed. We found that these ligands specifically target the potassium form of telomeric G-quadruplex DNA over the DNA counterpart. The characteristic interaction with the telomeric G-quadruplex DNA and the anticancer activities of these ligands were also explored. The results of this present work emphasize our understanding of the binding selectivity of anthraquinone derivatives to G quadruplex DNA and assists in future drug development for G-quadruplex-specific ligands. PMID- 27511134 TI - Editorial: non-invasive assessment of hepatic fibrosis in alpha-1 antitrypsin deficiency using magnetic resonance elastography. PMID- 27511135 TI - Editorial: non-invasive assessment of hepatic fibrosis in alpha-1 antitrypsin deficiency using magnetic resonance elastography - authors' reply. PMID- 27511136 TI - Letter: investigating the intestinal mucosa-associated microbiota - relevance and potential pitfalls. PMID- 27511137 TI - Letter: investigating the intestinal mucosa-associated microbiota - relevance and potential pitfalls. Authors' reply. PMID- 27511138 TI - Letter: cure of chronic hepatitis B and D after 12 years of treatment with low dose standard interferon alfa-2b. PMID- 27511139 TI - Letter: hepatitis B surface seroclearance does reduce the risk of hepatocellular carcinoma - authors' reply. PMID- 27511140 TI - Shaping of Metal-Organic Frameworks: From Fluid to Shaped Bodies and Robust Foams. AB - The applications of metal-organic frameworks (MOFs) toward industrial separation, catalysis, sensing, and some sophisticated devices are drastically affected by their intrinsic fragility and poor processability. Unlike organic polymers, MOF crystals are insoluble in any solvents and are usually not thermoplastic, which means traditional solvent- or melting-based processing techniques are not applicable for MOFs. Herein, a continuous phase transformation processing strategy is proposed for fabricating and shaping MOFs into processable fluids, shaped bodies, and even MOF foams that are capable of reversible transformation among these states. Based on this strategy, a cup-shaped Cu-MOF composite and hierarchically porous MOF foam were developed for highly efficient catalytic C-H oxidation (conv. 76% and sele. 93% for cup-shaped Cu-MOF composite and conv. 92% and sele. 97% for porous foam) with ease of recycling and dramatically improved kinetics. Furthermore, various MOF-based foams with low densities (<0.1 g cm(-3)) and high MOF loadings (up to 80 wt %) were obtained via this protocol. Imparted with hierarchically porous structures and fully accessible MOFs uniformly distributed, these foams presented low energy penalty (pressure drop <20 Pa, at 500 mL min(-1)) and showed potential applications as efficient membrane reactors. PMID- 27511141 TI - Modifying the 5'-Cap for Click Reactions of Eukaryotic mRNA and To Tune Translation Efficiency in Living Cells. AB - The 5'-cap is a hallmark of eukaryotic mRNAs and plays fundamental roles in RNA metabolism, ranging from quality control to export and translation. Modifying the 5'-cap may thus enable modulation of the underlying processes and investigation or tuning of several biological functions. A straightforward approach is presented for the efficient production of a range of N7-modified caps based on the highly promiscuous methyltransferase Ecm1. We show that these, as well as N(2) -modified 5'-caps, can be used to tune translation of the respective mRNAs both in vitro and in cells. Appropriate modifications allow subsequent bioorthogonal chemistry, as demonstrated by intracellular live-cell labeling of a target mRNA. The efficient and versatile N7 manipulation of the mRNA cap makes mRNAs amenable to both modulation of their biological function and intracellular labeling, and represents a valuable addition to the chemical biology toolbox. PMID- 27511143 TI - Tribotronic control of friction in oil-based lubricants with ionic liquid additives. AB - Atomic force microscopy (AFM) reveals that tribotronic control of friction using an external potential applied to a gold surface is possible for ionic liquid (IL) concentrations as low as 5 mol% in hexadecane. The IL used is trihexyl(tetradecyl)phosphonium bis(2,4,4-trimethylpentyl)phosphinate, in which both the cation and anion have surfactant-like structures, and is miscible with hexadecane in all proportions. For IL concentrations less than 5 mol% friction does not vary with applied potential, but for 5 mol% and above changing the potential changes the composition of the IL boundary layer from cation-enriched (negative potentials) to anion-enriched (positive potentials). As the lubricities of the cation-rich and anion-rich boundary layers differ, this enables active control of friction in oil-based lubricants. PMID- 27511142 TI - Hyperphosphorylation amplifies UPF1 activity to resolve stalls in nonsense mediated mRNA decay. AB - Many gene expression factors contain repetitive phosphorylation sites for single kinases, but the functional significance is poorly understood. Here we present evidence for hyperphosphorylation as a mechanism allowing UPF1, the central factor in nonsense-mediated decay (NMD), to increasingly attract downstream machinery with time of residence on target mRNAs. Indeed, slowing NMD by inhibiting late-acting factors triggers UPF1 hyperphosphorylation, which in turn enhances affinity for factors linking UPF1 to decay machinery. Mutational analyses reveal multiple phosphorylation sites contributing to different extents to UPF1 activity with no single site being essential. Moreover, the ability of UPF1 to undergo hyperphosphorylation becomes increasingly important for NMD when downstream factors are depleted. This hyperphosphorylation-dependent feedback mechanism may serve as a molecular clock ensuring timely degradation of target mRNAs while preventing degradation of non-targets, which, given the prevalence of repetitive phosphorylation among central gene regulatory factors, may represent an important general principle in gene expression. PMID- 27511144 TI - Shooting for the moon, and the stars? PMID- 27511145 TI - The case for informative phase 2 trials in osteosarcoma. PMID- 27511146 TI - When cancer gets gnarly. PMID- 27511147 TI - The C Word. PMID- 27511148 TI - Timing of androgen-deprivation therapy for prostate cancer: still a long way to go - Authors' reply. PMID- 27511149 TI - Timing of androgen-deprivation therapy for prostate cancer: still a long way to go. PMID- 27511150 TI - Salvage radiotherapy for patients with rising PSA. PMID- 27511151 TI - Quality of life after video-assisted surgery for lung cancer. PMID- 27511152 TI - Salvage radiotherapy for patients with rising PSA - Authors' reply. PMID- 27511153 TI - Quality of life after video-assisted surgery for lung cancer. PMID- 27511154 TI - Quality of life after video-assisted surgery for lung cancer. PMID- 27511155 TI - Quality of life after video-assisted surgery for lung cancer. PMID- 27511156 TI - Quality of life after video-assisted surgery for lung cancer - Author's reply. PMID- 27511157 TI - Venetoclax in cancer therapy and potential effects on bone. PMID- 27511158 TI - International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. AB - Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments. PMID- 27511159 TI - Novel therapeutic targets on the horizon for lung cancer. AB - Lung cancer is a leading cause of cancer-related mortality worldwide, and is classically divided into two major histological subtypes: non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although NSCLC and SCLC are considered distinct entities with different genomic landscapes, emerging evidence highlights a convergence in therapeutically relevant targets for both histologies. In adenocarcinomas with defined alterations such as EGFR mutations and ALK translocations, targeted therapies are now first-line standard of care. By contrast, many experimental and targeted agents remain largely unsuccessful for SCLC. Intense preclinical research and clinical trials are underway to exploit unique traits of lung cancer, such as oncogene dependency, DNA damage response, angiogenesis, and cellular plasticity arising from presence of cancer stem cell lineages. In addition, the promising clinical activity observed in NSCLC in response to immune checkpoint blockade has spurred great interest in the field of immunooncology, with the scope to develop a diverse repertoire of synergistic and personalised immunotherapeutics. In this Review, we discuss novel therapeutic agents for lung cancer that are in early-stage development, and how prospective clinical trials and drug development may be shaped by a deeper understanding of this heterogeneous disease. PMID- 27511160 TI - Brazilian health-care policy for targeted oncology therapies and companion diagnostic testing. AB - A growing understanding of the molecular pathology of tumours combined with a surge of new drugs and associated diagnostic technologies (ie, precision medicine) has translated into substantial improvements in survival for patients with cancer. However, to achieve the promise that precision medicine has to offer will require overcoming hurdles within a national health-care system in which it is to be implemented. Brazil is one such nation, an emerging middle-income country with a very complex health-care system. To address the challenges associated with implementing precision medicine into a country such as Brazil, a group of experts convened (Nov 16-18, 2015, Miami) to discuss challenges related to precision medicine within an oncology setting. Complex regulatory hurdles, a shortage of human and technical resources, and the complexities of a two-tiered health-care delivery system were all identified as the main shortcomings to effectively implementing this new field of medicine. A path forward was proposed that relies on active collaboration between clinicians, private organisations, and government. It seems entirely possible that, despite many intrinsic economic and political problems, Brazil can readily emerge as a model for other countries in Latin America for the potential benefits of precision medicine and companion diagnostics. PMID- 27511161 TI - Hirschsprung disease as a yet undescribed phenotype in a patient with ARID1B mutation. AB - Mutations in the BAF complex (mammalian SWI/SNF complex) are responsible for Coffin-Siris syndrome, which is characterized by developmental delay, distinctive facial features, hirsutism, and hypoplasia/aplasia of the fifth finger/fingernails. Hirschsprung disease is characterized by defective stem cells in the enteric neural system, and the involvement of multiple signaling cascades has been implicated. So far, the roles of the BAF complex in the genesis of Hirschsprung disease have remained unknown. Here, we document a patient with coarse facial features, postnatal growth failure, developmental delay, epilepsy, and hypoplasia of the corpus callosum and cerebellum but without a hypoplastic fifth finger/fingernail. In addition, he had Hirschsprung disease. Exome sequencing with a gene set representing a total of 4,813 genes with known relationships to human diseases revealed a heterozygous frameshift mutation in ARID1B (c.5789delC p.Pro1930Leufs*44). The presence of a congenital cataract and Hirschsprung disease in the presently reported patient further expands the phenotypic spectrum of patients with ARID1B mutations and may suggest the potential role of the BAF complex in the pathogenesis of the enteric neural system. The present observation is in agreement with a recent study of Drosophila neuroblasts showing that the dysregulated BAF complex leads to an abnormal lineage progression of neural stem cell lineages and that Hirschsprung disease is caused by abnormal stem cell lineages in the peripheral neural tissues. (c) 2016 Wiley Periodicals, Inc. PMID- 27511162 TI - C-Banding of Plant Chromosomes. AB - C-banding is used to differentially stain metaphase chromosomes in organisms having appreciable amounts of constitutive heterochromatin. Its primary benefits are that it is an inexpensive and a relatively fast method of identifying individual chromosomes and morphological or karyotypic variation, including large chromosomal rearrangements and aneuploidies. We currently employ this technique with considerable effect in genome analysis of oat (Avena sativa) and related grass species, though it has been most extensively used for chromosome analysis of wheat (Triticum aestivum) and its relatives of the Triticeae. PMID- 27511163 TI - Chromosome Painting by GISH and Multicolor FISH. AB - Fluorescent in situ hybridization (FISH) is a powerful cytogenetic technique for identifying chromosomes and mapping specific genes and DNA sequences on individual chromosomes. Genomic in situ hybridization (GISH) and multicolor FISH (mc-FISH) represent two special types of FISH techniques. Both GISH and mc-FISH experiments have general steps and features of FISH, including chromosome preparation, probe labeling, blocking DNA preparation, target-probe DNA hybridization, post-hybridization washes, and hybridization signal detection. Specifically, GISH uses total genomic DNA from two species as probe and blocking DNA, respectively, and it can differentiate chromosomes from different genomes. The mc-FISH takes advantage of simultaneous hybridization of several DNA probes labeled by different fluorochromes to different targets on the same chromosome sample. Hybridization signals from different probes are detected using different fluorescence filter sets. Multicolor FISH can provide more structural details for target chromosomes than single-color FISH. In this chapter, we present the general experimental procedures for these two techniques with specific details in the critical steps we have modified in our laboratories. PMID- 27511164 TI - Fluorescent In Situ Hybridization on Extended Chromatin Fibers for High Resolution Analysis of Plant Chromosomes. AB - Fiber FISH is a high-resolution cytogenetic method and a powerful tool of genome analysis to study the localization and the physical organization of markers, genes, and repetitive sequences on a molecular level. Measurement of physical distances between sequences can be performed along extended chromatin fibers with the resolution of up to 1 kb and is applicable to all plant species. PMID- 27511165 TI - Tyramide Signal Amplification: Fluorescence In Situ Hybridization for Identifying Homoeologous Chromosomes. AB - Tyramide signal amplification (TSA) fluorescence in situ hybridization (FISH) has been shown as a valuable molecular tool for visualizing specific amplified DNA sequences in chromosome preparations. This chapter describes how to perform TSA FISH, paying special interest to its two critical steps: probe generation and metaphase plate generation. The potential of physically mapping 12S-globulin sequences by TSA-FISH as a means of identifying homeology among chromosome regions of Avena species was tested and is discussed. PMID- 27511166 TI - Localization of Low-Copy DNA Sequences on Mitotic Chromosomes by FISH. AB - Fluorescence in situ hybridization (FISH) is a widely used method to localize DNA sequences on mitotic and meiotic chromosomes and interphase nuclei. It was developed in early 1980s and since then it has contributed to numerous studies and important discoveries. Over the decades, the protocol was modified for ease of use, allowing for localizing multiple probes simultaneously and increasing its sensitivity and specificity. Despite the continuous improvements, the ability to detect short single-copy sequences of only a few kilobases or less, such as genes, remains limited. Here, we provide a detailed protocol for detection of short, single- or low-copy sequences on plant mitotic metaphase chromosomes. PMID- 27511167 TI - Immunolabeling and In Situ Labeling of Isolated Plant Interphase Nuclei. AB - Specific labeling of proteins and nucleic acids by immunofluorescence or in situ techniques is an important adjunct to microscopical analysis for cell biology. Labeling of nuclear structures in intact complex tissues is often hampered by problems of penetration of the macromolecular labeling reagents needed. Here we describe a method of labeling isolated plant nuclei that we have found to be a useful approach that can help to overcome these problems. PMID- 27511168 TI - Manipulation of Homologous and Homoeologous Chromosome Recombination in Wheat. AB - Given the sizes of the three genomes in wheat (A, B, and D) and a limited number of chiasmata formed in meiosis, recombination by crossing-over is a very rare event. It is also restricted to very similar homologues; the pairing homoeologous (Ph) system of wheat prevents differentiated chromosomes from pairing and crossing-over. This chapter presents an overview and describes several systems by which the frequency or density of crossing-over can be increased, both in homologues and homoeologues. It also presents the standard system of E.R. Sears for engineering alien chromosome transfers into wheat. PMID- 27511169 TI - Dissecting Plant Chromosomes by the Use of Ionizing Radiation. AB - Radiation treatment of genomes is used to generate chromosome breaks for numerous applications. This protocol describes the preparation of seeds and the determination of the optimal level of irradiation dosage for the creation of a radiation hybrid (RH) population. These RH lines can be used to generate high resolution physical maps for the assembly of sequenced genomes as well as the fine mapping of genes. This procedure can also be used for mutation breeding and forward/reverse genetics. PMID- 27511171 TI - Flow Sorting Plant Chromosomes. AB - Nuclear genomes of many important plant species are tremendously complicated to map and sequence. The ability to isolate single chromosomes, which represent small units of nuclear genome, is priceless in many areas of plant research including cytogenetics, genomics, and proteomics. Flow cytometry is the only technique which can provide large quantities of pure chromosome fractions suitable for downstream applications including physical mapping, preparation of chromosome-specific BAC libraries, sequencing, and optical mapping. Here, we describe step-by-step procedure of preparation of liquid suspensions of intact mitotic metaphase chromosomes and their flow cytometric analysis and sorting. PMID- 27511170 TI - Optical Nano-mapping and Analysis of Plant Genomes. AB - Application of optical mapping based on BioNano Genomics Irys((r)) technology ( http://www.bionanogenomics.com/ ) is growing rapidly since its debut in November 2012. The technology can be used to facilitate genome sequence assembly and analysis of genome structural variations. We describe here the detailed protocol that we used to generate a whole genome BioNano map for Aegilops tauschii, the D genome progenitor of hexaploid wheat (Triticum aestivum). We are using the whole genome BioNano map to validate sequence assembly based on the next-generation sequencing, order sequence scaffolds, and ultimately build pseudomolecules for the genome. PMID- 27511172 TI - Construction of BAC Libraries from Flow-Sorted Chromosomes. AB - Cloned DNA libraries in bacterial artificial chromosome (BAC) are the most widely used form of large-insert DNA libraries. BAC libraries are typically represented by ordered clones derived from genomic DNA of a particular organism. In the case of large eukaryotic genomes, whole-genome libraries consist of a hundred thousand to a million clones, which make their handling and screening a daunting task. The labor and cost of working with whole-genome libraries can be greatly reduced by constructing a library derived from a smaller part of the genome. Here we describe construction of BAC libraries from mitotic chromosomes purified by flow cytometric sorting. Chromosome-specific BAC libraries facilitate positional gene cloning, physical mapping, and sequencing in complex plant genomes. PMID- 27511173 TI - The Chromosome Microdissection and Microcloning Technique. AB - Chromosome microdissection followed by microcloning is an efficient tool combining cytogenetics and molecular genetics that can be used for the construction of the high density molecular marker linkage map and fine physical map, the generation of probes for chromosome painting, and the localization and cloning of important genes. Here, we describe a modified technique to microdissect a single chromosome, paint individual chromosomes, and construct single-chromosome DNA libraries. PMID- 27511174 TI - Immunolocalization on Whole Anther Chromosome Spreads for Male Meiosis. AB - Immunolocalization of cells undergoing meiosis has proven to be one of the most important tools to decipher chromatin-associated protein dynamics and causal relationships. Here, we describe a protocol established for maize which is easily adaptable to other plants, for example, with minor modifications to Arabidopsis as stated here. In contrast to many other protocols, the following protocol is based on fixation by a 3:1 mixture of ethanol and acetic acid. Spreading of cells is followed by freeze-shattering, protein antigenicity retrieval by a hot citrate buffer bath, antibody incubations and washes, and DNA staining. PMID- 27511175 TI - Mapping Recombination Initiation Sites Using Chromatin Immunoprecipitation. AB - Genome-wide maps of recombination sites provide valuable information not only on the recombination pathway itself but also facilitate the understanding of genome dynamics and evolution. Here, we describe a chromatin immunoprecipitation (ChIP) protocol to map the sites of recombination initiation in plants with maize used as an example. ChIP is a method that allows identification of chromosomal sites occupied by specific proteins. Our protocol utilizes RAD51, a protein involved in repair of double-strand breaks (DSBs) that initiate meiotic recombination, to identify DSB formation hotspots. Chromatin is extracted from meiotic flowers, sheared and enriched in fragments bound to RAD51. Genomic location of the protein is then identified by next-generation sequencing. This protocol can also be used in other species of plants, animals, and fungi. PMID- 27511176 TI - Chromatin Immunoprecipitation to Study The Plant Epigenome. AB - Chromatin immunoprecipitation (ChIP) has been widely used for studying in vivo protein-DNA interactions for decades. ChIP is a powerful tool that is adaptable for studying epigenetic modifications at certain genomic loci or the genomic level. Given its utility in studying the epigenome and the many technical challenges, we present a detailed in-lab ChIP protocol primarily used for studying histone modifications in plants, but can be easily adapted for other chromatin targets in other species. PMID- 27511177 TI - Erratum to: development and psychometric testing of a new instrument to measure factors influencing women's breast cancer prevention behaviors (ASSISTS). PMID- 27511178 TI - Comparative Transcriptome Analysis Identifies Candidate Genes Related to Skin Color Differentiation in Red Tilapia. AB - Red tilapia is becoming more popular for aquaculture production in China in recent years. However, the pigmentation differentiation in genetic breeding is the main problem limiting its development of commercial red tilapia culture and the genetic basis of skin color variation is still unknown. In this study, we conducted Illumina sequencing of transcriptome on three color variety red tilapia. A total of 224,895,758 reads were generated, resulting in 160,762 assembled contigs that were used as reference contigs. The contigs of red tilapia transcriptome had hits in the range of 53.4% to 86.7% of the unique proteins of zebrafish, fugu, medaka, three-spined stickleback and tilapia. And 44,723 contigs containing 77,423 simple sequence repeats (SSRs) were identified, with 16,646 contigs containing more than one SSR. Three skin transcriptomes were compared pairwise and the results revealed that there were 148 common significantly differentially expressed unigenes and several key genes related to pigment synthesis, i.e. tyr, tyrp1, silv, sox10, slc24a5, cbs and slc7a11, were included. The results will facilitate understanding the molecular mechanisms of skin pigmentation differentiation in red tilapia and accelerate the molecular selection of the specific strain with consistent skin colors. PMID- 27511179 TI - Cardiac involvement in hereditary myopathy with early respiratory failure: A cohort study. AB - OBJECTIVE: To assess whether hereditary myopathy with early respiratory failure (HMERF) due to the c.951434T>C; (p.Cys31712Arg) TTN missense mutation also includes a cardiac phenotype. METHOD: Clinical cohort study of our HMERF cohort using ECG, 2D echocardiogram, and cross-sectional cardiac imaging with MRI or CT. RESULTS: We studied 22 participants with the c.951434T>C; (p.Cys31712Arg) TTN missense mutation. Three were deceased. Cardiac conduction abnormalities were identified in 7/22 (32%): sustained atrioventricular tachycardia (n = 2), atrial fibrillation (n = 2), nonsustained atrial tachycardia (n = 1), premature supraventricular complexes (n = 1), and unexplained sinus bradycardia (n = 1). In addition, 4/22 (18%) had imaging evidence of otherwise unexplained cardiomyopathy. These findings are supported by histopathologic correlation suggestive of myocardial cytoskeletal remodeling. CONCLUSIONS: Coexisting cardiac and skeletal muscle involvement is not uncommon in patients with HMERF arising due to the c.951434T>C; (p.Cys31712Arg) TTN mutation. All patients with pathogenic or putative pathogenic TTN mutations should be offered periodic cardiac surveillance. PMID- 27511180 TI - Twelve-month recovery of medical decision-making capacity following traumatic brain injury. AB - OBJECTIVE: To investigate recovery of medical decision-making capacity (MDC) over the first year following traumatic brain injury (TBI). METHODS: A total of 177 participants (111 persons with TBI and 66 healthy controls) were recruited from an inpatient/outpatient TBI rehabilitation unit and outpatient neurology department. Participants with TBI were classified by injury severity into subgroups: mild TBI (mTBI; n = 28), complicated mild TBI (cmTBI; n = 23), and moderate/severe TBI (msevTBI; n = 60). Control and TBI groups were compared at 1 month (t1), 6 months (t2), and 12 months (t3) postinjury using the Capacity to Consent to Treatment Instrument (CCTI), which evaluates MDC using 5 consent standards: expressing choice, reasonable choice, appreciation, reasoning, and understanding. RESULTS: Relative to controls, no TBI group displayed impairment on CCTI expressing choice or reasonable choice at any timepoint. Those with mTBI had reduced appreciation and understanding at t1, which resolved by t2. The cmTBI and msevTBI groups were impaired on all 3 complex consent standards at t1. While patients with cmTBI improved to a level similar to controls by t3, those with msevTBI remained impaired on reasoning and understanding. Across all TBI groups, notable MDC improvement only occurred over the first 6 months postinjury. CONCLUSIONS: Over 1 year, most individuals with mTBI or cmTBI regain MDC, while many individuals with msevTBI have lingering deficits in reasoning and comprehension of treatment information. Clinical recovery of MDC occurs primarily during the first 6 months post-TBI regardless of injury severity. Clinicians can therefore identify MDC outcomes in TBI at 6 months postinjury. PMID- 27511181 TI - Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial. AB - OBJECTIVE: To investigate whether mammalian target of rapamycin complex 1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous sclerosis complex (TSC). METHODS: Due to slow inclusion rate, target inclusion of 30 children was not reached. Twenty-three children with TSC and intractable epilepsy (age 1.8-10.9 years) were randomly assigned (1:1) to open-label, add-on sirolimus treatment immediately or after 6 months. Sirolimus was titrated to trough levels of 5-10 ng/mL. Primary endpoint was seizure frequency change during the sixth month of sirolimus treatment. RESULTS: Intention-to-treat analysis showed sirolimus treatment resulted in 41% seizure frequency decrease (95% confidence interval [CI] -69% to +14%; p = 0.11) compared to the standard-care period. Per protocol analysis of 14 children who reached sirolimus target trough levels in the sixth sirolimus month showed a seizure frequency decrease of 61% (95% CI -86% to +6%; p = 0.06). Cognitive development did not change. All children had adverse events. Five children discontinued sirolimus prematurely. CONCLUSIONS: We describe a randomized controlled trial for a non-antiepileptic drug that directly targets a presumed causal mechanism of epileptogenesis in a genetic disorder. Although seizure frequency decreased, especially in children reaching target trough levels, we could not show a significant benefit. Larger trials or meta-analyses are needed to investigate if patients with TSC with seizures benefit from mTORC1 inhibition. This trial was registered at trialregister.nl (NTR3178) and supported by the Dutch Epilepsy Foundation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that sirolimus does not significantly reduce seizure frequency in children with TSC and intractable epilepsy. The study lacked the precision to exclude a benefit from sirolimus. PMID- 27511184 TI - mTORC1 inhibition for epilepsy in TSC: Feasibility in question. PMID- 27511183 TI - Evolution of clinical features in possible DLB depending on FP-CIT SPECT result. AB - OBJECTIVE: To test the hypothesis that core and suggestive features in possible dementia with Lewy bodies (DLB) would vary in their ability to predict an abnormal dopamine transporter scan and therefore a follow-up diagnosis of probable DLB. A further objective was to assess the evolution of core and suggestive features in patients with possible DLB over time depending on the (123)I-FP-CIT SPECT scan result. METHODS: A total of 187 patients with possible DLB (dementia plus one core or one suggestive feature) were randomized to have dopamine transporter imaging or to follow-up without scan. DLB features were compared at baseline and at 6-month follow-up according to imaging results and follow-up diagnosis. RESULTS: For the whole cohort, the baseline frequency of parkinsonism was 30%, fluctuations 29%, visual hallucinations 24%, and REM sleep behavior disorder 17%. Clinician-rated presence of parkinsonism at baseline was significantly (p = 0.001) more frequent and Unified Parkinson's Disease Rating Scale (UPDRS) score at baseline was significantly higher (p = 0.02) in patients with abnormal imaging. There was a significant increase in UPDRS score in the abnormal scan group over time (p < 0.01). There was relatively little evolution of the rest of the DLB features regardless of the imaging result. CONCLUSIONS: In patients with possible DLB, apart from UPDRS score, there was no difference in the evolution of DLB clinical features over 6 months between cases with normal and abnormal imaging. Only parkinsonism and dopamine transporter imaging helped to differentiate DLB from non-DLB dementia. PMID- 27511185 TI - Does early (treatment in) BENEFIT lead to late MS benefit? PMID- 27511186 TI - Retinal microvasculature and white matter microstructure: The Rotterdam Study. AB - OBJECTIVE: To investigate whether retinal microvascular damage is related to normal-appearing white matter microstructure on diffusion tensor MRI. METHODS: We included 2,436 participants (age >=45 years) from the population-based Rotterdam Study (2005-2009) who had gradable retinal images and brain MRI scans. Retinal arteriolar and venular calibers were measured semiautomatically on fundus photographs. White matter microstructure was assessed using diffusion tensor MRI. We used linear regression models to investigate the associations of retinal vascular calibers with markers of normal-appearing white matter microstructure, adjusting for age, sex, the fellow vascular caliber, and additionally for structural MRI markers and cardiovascular risk factors. RESULTS: Narrower arterioles and wider venules were associated with poor white matter microstructure: adjusted difference in fractional anisotropy per SD decrease in arteriolar caliber -0.061 (95% confidence interval -0.106 to -0.016), increase in venular caliber -0.054 (-0.096 to -0.011), adjusted difference in mean diffusivity per SD decrease in arteriolar caliber 0.048 (0.007-0.088), and increase in venular caliber 0.047 (0.008-0.085). The associations for venules were more prominent in women. CONCLUSIONS: Retinal vascular calibers are related to normal-appearing white matter microstructure. This suggests that microvascular damage in the white matter is more widespread than visually detectable as white matter lesions. PMID- 27511182 TI - The 11-year long-term follow-up study from the randomized BENEFIT CIS trial. AB - OBJECTIVE: To assess outcomes for patients treated with interferon beta-1b immediately after clinically isolated syndrome (CIS) or after a short delay. METHODS: Participants in BENEFIT (Betaferon/Betaseron in Newly Emerging MS for Initial Treatment) were randomly assigned to receive interferon beta-1b (early treatment) or placebo (delayed treatment). After conversion to clinically definite multiple sclerosis (CDMS) or 2 years, patients on placebo could switch to interferon beta-1b or another treatment. Eleven years after randomization, patients were reassessed. RESULTS: Two hundred seventy-eight (59.4%) of the original 468 patients (71.3% of those eligible at participating sites) were enrolled (early: 167 [57.2%]; delayed: 111 [63.1%]). After 11 years, risk of CDMS remained lower in the early-treatment arm compared with the delayed-treatment arm (p = 0.0012), with longer time to first relapse (median [Q1, Q3] days: 1,888 [540, not reached] vs 931 [253, 3,296]; p = 0.0005) and lower overall annualized relapse rate (0.21 vs 0.26; p = 0.0018). Only 25 patients (5.9%, overall; early, 4.5%; delayed, 8.3%) converted to secondary progressive multiple sclerosis. Expanded Disability Status Scale scores remained low and stable, with no difference between treatment arms (median [Q1, Q3]: 2.0 [1.0, 3.0]). The early treatment group had better Paced Auditory Serial Addition Task-3 total scores (p = 0.0070). Employment rates remained high, and health resource utilization tended to be low in both groups. MRI metrics did not differ between groups. CONCLUSIONS: Although the delay in treatment was relatively short, several clinical outcomes favored earlier treatment. Along with low rates of disability and disease progression in both groups, this supports the value of treatment at CIS. CLINICALTRIALSGOV IDENTIFIER: NCT01795872. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that early compared to delayed treatment prolongs time to CDMS in CIS after 11 years. PMID- 27511187 TI - How reliable is 18FDG PET for predicting the onset of Huntington's disease? PMID- 27511189 TI - Paraneoplastic syndrome demonstrated on 99mTc-HMDP bone scan. AB - A 23-year-old man, with no relevant medical history, presented with inflammatory peripheral and axial polyarthritis, wrist pain, and persistent low-grade fever for the past 4 months. A bone scintigraphy showed intense periosteal early and delayed uptake in long bones, with normal uptake in the spine, pelvis, and rib cage, and no clear focus of hypermetabolism. CT scan revealed a mediastinal mass. A biopsy of the mass demonstrated Hodgkin lymphoma with bulky disease. This paraneoplastic syndrome as the first sign of intrathoracic Hodgkin's disease is rare. PMID- 27511188 TI - The value of 18F-FDG PET before and after induction chemotherapy for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy in oesophageal adenocarcinoma. AB - PURPOSE: The purpose of our study was to determine the value of 18F-FDG PET before and after induction chemotherapy in patients with oesophageal adenocarcinoma for the early prediction of a poor pathologic response to subsequent preoperative chemoradiotherapy (CRT). METHODS: In 70 consecutive patients receiving a three-step treatment strategy of induction chemotherapy and preoperative chemoradiotherapy for oesophageal adenocarcinoma, 18F-FDG PET scans were performed before and after induction chemotherapy (before preoperative CRT). SUVmax, SUVmean, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were determined at these two time points. The predictive potential of (the change in) these parameters for a poor pathologic response, progression-free survival (PFS) and overall survival (OS) was assessed. RESULTS: A poor pathologic response after induction chemotherapy and preoperative CRT was found in 27 patients (39 %). Patients with a poor pathologic response experienced less of a reduction in TLG after induction chemotherapy (p < 0.01). The change in TLG was predictive for a poor pathologic response at a threshold of -26 % (sensitivity 67 %, specificity 84 %, accuracy 77 %, PPV 72 %, NPV 80 %), yielding an area-under-the-curve of 0.74 in ROC analysis. Also, patients with a decrease in TLG lower than 26 % had a significantly worse PFS (p = 0.02), but not OS (p = 0.18). CONCLUSIONS: 18F-FDG PET appears useful to predict a poor pathologic response as well as PFS early after induction chemotherapy in patients with oesophageal adenocarcinoma undergoing a three-step treatment strategy. As such, the early 18F-FDG PET response after induction chemotherapy could aid in individualizing treatment by modification or withdrawal of subsequent preoperative CRT in poor responders. PMID- 27511190 TI - Genomic Methods Take the Plunge: Recent Advances in High-Throughput Sequencing of Marine Mammals. AB - The dramatic increase in the application of genomic techniques to non-model organisms (NMOs) over the past decade has yielded numerous valuable contributions to evolutionary biology and ecology, many of which would not have been possible with traditional genetic markers. We review this recent progression with a particular focus on genomic studies of marine mammals, a group of taxa that represent key macroevolutionary transitions from terrestrial to marine environments and for which available genomic resources have recently undergone notable rapid growth. Genomic studies of NMOs utilize an expanding range of approaches, including whole genome sequencing, restriction site-associated DNA sequencing, array-based sequencing of single nucleotide polymorphisms and target sequence probes (e.g., exomes), and transcriptome sequencing. These approaches generate different types and quantities of data, and many can be applied with limited or no prior genomic resources, thus overcoming one traditional limitation of research on NMOs. Within marine mammals, such studies have thus far yielded significant contributions to the fields of phylogenomics and comparative genomics, as well as enabled investigations of fitness, demography, and population structure. Here we review the primary options for generating genomic data, introduce several emerging techniques, and discuss the suitability of each approach for different applications in the study of NMOs. PMID- 27511191 TI - Nitrogen assimilation system in maize is regulated by developmental and tissue specific mechanisms. AB - KEY MESSAGE: We found metabolites, enzyme activities and enzyme transcript abundances vary significantly across the maize lifecycle, but weak correlation exists between the three groups. We identified putative genes regulating nitrate assimilation. Progress in improving nitrogen (N) use efficiency (NUE) of crop plants has been hampered by the complexity of the N uptake and utilisation systems. To understand this complexity we measured the activities of seven enzymes and ten metabolites related to N metabolism in the leaf and root tissues of Gaspe Flint maize plants grown in 0.5 or 2.5 mM NO3 (-) throughout the lifecycle. The amino acids had remarkably similar profiles across the lifecycle except for transient responses, which only appeared in the leaves for aspartate or in the roots for asparagine, serine and glycine. The activities of the enzymes for N assimilation were also coordinated to a certain degree, most noticeably with a peak in root activity late in the lifecycle, but with wide variation in the activity levels over the course of development. We analysed the transcriptional data for gene sets encoding the measured enzymes and found that, unlike the enzyme activities, transcript levels of the corresponding genes did not exhibit the same coordination across the lifecycle and were only weakly correlated with the levels of various amino acids or individual enzyme activities. We identified gene sets which were correlated with the enzyme activity profiles, including seven genes located within previously known quantitative trait loci for enzyme activities and hypothesise that these genes are important for the regulation of enzyme activities. This work provides insights into the complexity of the N assimilation system throughout development and identifies candidate regulatory genes, which warrant further investigation in efforts to improve NUE in crop plants. PMID- 27511192 TI - De novo transcriptome analysis reveals insights into dynamic homeostasis regulation of somatic embryogenesis in upland cotton (G. hirsutum L.). AB - Plant regeneration via somatic embryogenesis (SE) is the key step for genetic improvement of cotton (Gossypium hirsutum L.) through genetic engineering mediated by Agrobacteria, but the molecular mechanisms underlying SE in cotton is still unclear. Here, RNA-Sequencing was used to analyze the genes expressed during SE and their expression dynamics using RNAs isolated from non-embryogenic callus (NEC), embryogenic callus (EC) and somatic embryos (SEs). A total of 101, 670 unigenes were de novo assembled. The genes differentially expressed (DEGs) amongst NEC, EC and SEs were identified, annotated and classified. More DEGs were found between SEs and EC than between EC and NEC. A significant number of DEGs were related to hormone homeostasis, stress and ROS responses, and metabolism of polyamines. To confirm the expression dynamics of selected DEGs involved in various pathways, experiments were set up to investigate the effects of hormones (Indole-3-butytric acid, IBA; Kinetin, KT), polyamines, H2O2 and stresses on SE. Our results showed that exogenous application of IBA and KT positively regulated the development of EC and SEs, and that polyamines and H2O2 promoted the conversion of EC into SEs. Furthermore, we found that low and moderate stress is beneficial for proliferation of EC and SEs formation. Together, our global analysis of transcriptomic dynamics reveals that hormone homeostasis, polyamines, and stress response synergistically regulating SE in cotton. PMID- 27511194 TI - Maternal Exposure to Occupational Asthmagens During Pregnancy and Autism Spectrum Disorder in the Study to Explore Early Development. AB - Maternal immune activity has been linked to children with autism spectrum disorder (ASD). We examined maternal occupational exposure to asthma-causing agents during pregnancy in relation to ASD risk. Our sample included 463 ASD cases and 710 general population controls from the Study to Explore Early Development whose mothers reported at least one job during pregnancy. Asthmagen exposure was estimated from a published job-exposure matrix. The adjusted odds ratio for ASD comparing asthmagen-exposed to unexposed was 1.39 (95 % CI 0.96 2.02). Maternal workplace asthmagen exposure was not associated with ASD risk in this study, but this result does not exclude some involvement of maternal exposure to asthma-causing agents in ASD. PMID- 27511195 TI - Relationship Between Subtypes of Restricted and Repetitive Behaviors and Sleep Disturbance in Autism Spectrum Disorder. AB - We examined the association of two types of restricted and repetitive behaviors, repetitive sensory motor (RSM) and insistence on sameness (IS), with sleep problems in children with autism spectrum disorder (ASD). Participants included 532 children (aged 2-17) who participated in the Autism Speaks Autism Treatment Network research registry. Confirmatory factor analysis of the Autism Diagnostic Interview-Revised detected the presence of RSM and IS. RSM behaviors were positively associated with parent-reported sleep problems, and this relationship remained significant after controlling for anxiety symptoms. IS was not significantly associated with sleep problems. Better understanding of the relationship between specific types of repetitive behaviors and sleep problems may allow providers to tailor interventions to the individual presentations of their patients with ASD. PMID- 27511193 TI - An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. AB - BACKGROUND: Epigenetic biomarkers of aging (the "epigenetic clock") have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors. RESULTS: We analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue. CONCLUSIONS: Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women. PMID- 27511196 TI - Reverse polyaxial less invasive stabilization systems for treatment of femoral intertrochanteric fractures of the distal femur. AB - INTRODUCTION: The reverse less invasive stabilization system (LISS) for the distal femur remains generally regarded as a safe and satisfactory option for the treatment of unstable proximal femoral fractures. The polyaxial LISS provides a reverse plating technique that leverages the advantages of proximal screws by allowing the adjustable locking screw to be better positioned and providing more reliable fixation on the proximal femur compared with the standard axial LISS. To assess this fixation method, a detailed evaluation of institutional outcomes of femoral intertrochanteric fractures treated with reverse polyaxial LISS was performed. MATERIALS AND METHODS: A total of 29 patients presenting with femoral intertrochanteric fractures were treated with the reverse polyaxial LISS system between January 2010 and March 2011. Patients were classified into stable and unstable fracture groups according to the Orthopaedic Trauma Association's (OTA) classification. Clinical data, including operative time, blood loss, radiological records and complications, Harris Hip scores and Parker scores, were collected and analyzed. RESULTS: There were no significant between-group differences in age, sex, or American Society of Anesthesiologists score. Operative time and blood loss were significantly higher in the unstable fracture group compared with the stable fracture group. Four cases of fixation failure, consisting of one case of A2.3, one case of A3.2 and two cases of A3.3, occurred 4-7 m postoperatively. CONCLUSIONS: Treatment of femoral intertrochanteric fractures with unstable pattern using polyaxial reverse LISS results in high failure rates; therefore, it should not be recommended as a routine alternative method for the treatment of femoral intertrochanteric fractures with unstable pattern. PMID- 27511197 TI - Efficacy and safety of sofosbuvir plus simeprevir therapy in Egyptian patients with chronic hepatitis C: a real-world experience. AB - BACKGROUND: Simeprevir plus sofosbuvir (SIM/SOF) regimen was recommended by professional guidelines for certain patients with HCV genotype 1 infection and there is lack of data about this regimen in patients with genotype 4 infection. AIM: To evaluate the efficacy and safety of this regimen in Egyptian patients with chronic HCV genotype 4 infection in the real world. METHODS: Multicentre observational study included 583 patients with HCV genotype 4 infection who began 12 weeks of treatment with SIM plus SOF. Demographic, clinical and virological data as well as adverse outcomes were collected. Treatment naive patients were 342 (59%) of all included patients, 45% of patients had severe fibrosis (F3 and F4) while 55% had mild fibrosis (F1 and F2) and the primary outcome was sustained virological response (SVR). RESULTS: The overall SVR rate was 95.7% (558 out of 583 patients). In total, SVR12 in naive patients with mild fibrosis score (F1 and F2) was achieved in 98.9% (94/95) for F1 and 98.1% (105/107) for F2, while naive patients with severe fibrosis (F3 and F4) achieved SVR of 97.7% (86/88) for F3 and (42/52) 80.8% for F4. SVR in patients with previous interferon treatment achieved in 100% (45/45) for patients with F1 and 98.7% (74/75) for F2. While 94.7% (72/76) in experienced patients with F3; and 88.9% (40/45) for F4 achieved SVR12. Notable side effects included rash in 21 patients, photosensitivity in 18 patients, pruritus in 44 patients and hyperbilirubinemia in 42 patients. CONCLUSIONS: A 12-week regimen of simeprevir/sofosbuvir was efficacious and well tolerated by treatment-naive and treatment-experienced patients with chronic HCV genotype 4. PMID- 27511198 TI - Assessment of faecal microbial transfer in irritable bowel syndrome with severe bloating. PMID- 27511200 TI - CORR Insights(r): High Risk of Surgical Glove Perforation From Surgical Rotatory Instruments. PMID- 27511199 TI - RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis. AB - OBJECTIVE: The gross majority of colorectal cancer cases results from aberrant Wnt/beta-catenin signalling through adenomatous polyposis coli (APC) or CTNNB1 mutations. However, a subset of human colon tumours harbour, mutually exclusive with APC and CTNNB1 mutations, gene fusions in RSPO2 or RSPO3, leading to enhanced expression of these R-spondin genes. This suggested that RSPO activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in RSPO3-fusion-positive xenograft models. The current study determines the extent into which solely a gain in RSPO3 actually functions as a driver of intestinal cancer in a direct, causal fashion, and addresses the in vivo activities of RSPO3 in parallel. DESIGN: We generated a conditional Rspo3 transgenic mouse model in which the Rspo3 transgene is expressed upon Cre activity. Cre is provided by cross-breeding with Lgr5-GFP-CreERT2 mice. RESULTS: Upon in vivo Rspo3 expression, mice rapidly developed extensive hyperplastic, adenomatous and adenocarcinomatous lesions throughout the intestine. RSPO3 induced the expansion of Lgr5+ stem cells, Paneth cells, non-Paneth cell label-retaining cells and Lgr4+ cells, thus promoting both intestinal stem cell and niche compartments. Wnt/beta-catenin signalling was modestly increased upon Rspo3 expression and mutant Kras synergised with Rspo3 in hyperplastic growth. CONCLUSIONS: We provide in vivo evidence that RSPO3 stimulates the crypt stem cell and niche compartments and drives rapid intestinal tumorigenesis. This establishes RSPO3 as a potent driver of intestinal cancer and proposes RSPO3 as a candidate target for therapy in patients with colorectal cancer harbouring RSPO3 fusions. PMID- 27511201 TI - One-stage Revision With Catheter Infusion of Intraarticular Antibiotics Successfully Treats Infected THA. AB - BACKGROUND: Two-stage revision surgery for infected total hip arthroplasty (THA) is commonly advocated, but substantial morbidity and expense are associated with this technique. In certain cases of infected THA, treatment with one-stage revision surgery and intraarticular infusion of antibiotics may offer a reasonable alternative with the distinct advantage of providing a means of delivering the drug in high concentrations. QUESTIONS/PURPOSES: We describe a protocol for intraarticular delivery of antibiotics to the hip through an indwelling catheter combined with one-stage revision surgery and examine (1) the success as judged by eradication of infection at 1 year when treating chronically infected cemented stems; (2) success in treating late-onset acute infections in well-ingrown cementless stems; and (3) what complications were associated with this approach in a small case series. METHODS: Between January 2002 and July 2013, 30 patients (30 hips) presented to the senior author for treatment of infected THA. Of those, 21 patients (21 hips) with infected cemented THAs underwent debridement and single-stage revision to cementless total hip implants followed by catheter infusion of intraarticular antibiotics. Nine patients (nine hips) with late-onset acute infections in cementless THA had bone-ingrown implants. These patients were all more than 2 years from their original surgery and had acute symptoms of infection for 4 to 9 days. Seven had their original THA elsewhere, and two were the author's patients. All were symptom-free until the onset of their infection, and none had postoperative wound complications, fever, or prolonged pain suggestive of a more chronic process. They were treated with debridement and head and liner exchange, again followed by catheter infusion of intraarticular antibiotics. During this time period, this represented all infected THAs treated by the senior author, and all were treated with this protocol; no patient underwent two-stage exchange during this time, and no patients were lost to followup. At the time of the surgery, two Hickman catheters were placed in each hip to begin intraarticular delivery of antibiotics in the early postoperative period. Antibiotics were infused daily into the hip for 6 weeks with the tubes used for infusion only. Eleven of the single-stage revisions and four of the hips treated with debridement had methicillin-resistant Staphylococcus aureus. Patients were considered free of infection if they had no clinical signs of infection and had a normal C-reactive protein and erythrocyte sedimentation rate at 1 year. Complications were ascertained by chart review. RESULTS: Twenty of 21 (95%) infections in patients who had single-stage revision for chronically infected cemented THA were apparently free from infection and remained so at a mean followup of 63 months (range, 25-157 months). One case grew Candida albicans in the operative cultures and remained free of signs of infection after rerevision followed by infusion of fluconazole. The nine cementless THAs treated with debridement and head/liner exchange all remained free of signs of infection at a mean followup of 74 months (range, 62-121 months). Few complications were associated with the technique. Four patients had elevated serum levels of vancomycin without renal function changes and two patients had transient blood urea nitrogen/creatinine elevations with normal vancomycin levels that resolved with dosage adjustments. No patient had evidence of permanent renal damage. None of the patients in this study developed a chronic fistula or had significant drainage from the catheter site. CONCLUSIONS: Single stage revision for chronically infected cemented THA and debridement of bone ingrown cementless THA with late-onset acute infection followed with indwelling catheter antibiotic infusion can result in infection eradication even when resistant organisms are involved. Larger study groups would better assess this technique and prospective comparisons to more traditional one- and two-stage revision techniques for infected THA will likely require multi-institutional approaches. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 27511202 TI - Are Recently Trained Tumor Fellows Performing Less Tumor Surgery? An Analysis of 10 Years of the ABOS Part II Database. AB - BACKGROUND: The majority of orthopaedic trainees pursue additional subspecialty training at the conclusion of residency. Although national trends indicate that fellowship-trained surgeons are more frequently performing cases in their defined subspecialties, this may not be the case for recently trained tumor fellows. Prior work has established that low tumor case volume is a significant stressor for recently trained tumor fellows. Given the relative rarity of musculoskeletal tumors, it is important for prospective trainees to have clear expectations for the proportion of specialty-specific procedures early during their careers. In addition, knowledge of anticipated specialty case volume is important to optimize fellowship training and to provide guidance for meeting the public health requirements for orthopaedic oncology. QUESTIONS/PURPOSES: We wished to determine (1) the number of examinees who self-reported tumor fellowship training during the last decade; (2) how many tumor fellowship-educated surgeons did an additional fellowship(s) in other subspecialties; (3) the number and proportion of tumor, trauma, adult reconstruction, and other procedures performed by tumor trained fellows; and (4) changes in the proportion of procedures performed by tumor-trained fellows during the 10-year period of the study. METHODS: The American Board of Orthopaedic Surgery Part II database was used to identify examinees who reported tumor fellowship training between 2004 and 2013. All submitted procedures were broadly categorized as "tumor," "trauma," "adult reconstruction," or "other." Annual procedure volumes were calculated and univariate analysis allowed comparison of categorized procedures during the duration of the study. RESULTS: The median annual number of candidates reporting tumor fellowship training was 12.5 (range, 7-16). There were 28 of 118 (24%) candidates who reported additional fellowship training. A total of 14,718 procedures were performed by all candidates with tumor fellowship training during the 10-year period of the study, 42% of which were categorized as tumor procedures. Overall, only 36% of candidates reported tumor procedures making up greater than 50% of their case volume. Between 2004 to 2005 and 2012 to 2013, the proportion of tumor procedures decreased (45% versus 36%; p < 0.001), whereas the number of adult reconstruction procedures increased (9% versus 19%; p < 0.001). CONCLUSIONS: Between 2004 and 2013, only one-third of recently trained tumor fellows had practices with tumor procedures accounting for greater than 50% of their total case volume. Furthermore, the proportion of tumor cases performed by recently trained tumor fellows decreased during the same time. The proportion of specialty-specific procedures is lower in orthopaedic oncology than other orthopaedic subspecialties, which is important information for current trainees interested in orthopaedic oncology fellowship training and for orthopaedic oncology educators. The findings in this study should serve as an initial platform for further discussion regarding the optimal number of fellowship trained orthopaedic oncologists required to meet regional and national needs for an accessible and proficient work force. PMID- 27511203 TI - Can Surgeons Adequately Capture Adverse Events Using the Spinal Adverse Events Severity System (SAVES) and OrthoSAVES? AB - BACKGROUND: Physicians have consistently shown poor adverse-event reporting practices in the literature and yet they have the clinical acumen to properly stratify and appraise these events. The Spine Adverse Events Severity System (SAVES) and Orthopaedic Surgical Adverse Events Severity System (OrthoSAVES) are standardized assessment tools designed to record adverse events in orthopaedic patients. These tools provide a list of prespecified adverse events for users to choose from-an aid that may improve adverse-event reporting by physicians. QUESTIONS/PURPOSES: The primary objective was to compare surgeons' adverse-event reporting with reporting by independent clinical reviewers using SAVES Version 2 (SAVES V2) and OrthoSAVES in elective orthopaedic procedures. METHOD: This was a 10-week prospective study where SAVES V2 and OrthoSAVES were used by six orthopaedic surgeons and two independent, non-MD clinical reviewers to record adverse events after all elective procedures to the point of patient discharge. Neither surgeons nor reviewers received specific training on adverse-event reporting. Surgeons were aware of the ongoing study, and reported adverse events based on their clinical interactions with the patients. Reviewers recorded adverse events by reviewing clinical notes by surgeons and other healthcare professionals (such as nurses and physiotherapists). Adverse events were graded using the severity-grading system included in SAVES V2 and OrthoSAVES. At discharge, adverse events recorded by surgeons and reviewers were recorded in our database. RESULTS: Adverse-event data for 164 patients were collected (48 patients who had spine surgery, 51 who had hip surgery, 34 who had knee surgery, and 31 who had shoulder surgery). Overall, 99 adverse events were captured by the reviewers, compared with 14 captured by the surgeons (p < 0.001). Surgeons adequately captured major adverse events, but failed to record minor events that were captured by the reviewers. A total of 93 of 99 (94%) adverse events reported by reviewers required only simple or minor treatment and had no long-term adverse effect. Three patients experienced adverse events that resulted in use of invasive or complex treatment that had a temporary adverse effect on outcome. CONCLUSION: Using SAVES V2 and OrthoSAVES, independent reviewers reported more minor adverse events compared with surgeons. The value of third-party reviewers requires further investigation in a detailed cost-benefit analysis. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 27511205 TI - Correction to: Cytochrome P450 and Non-Cytochrome P450 Oxidative Metabolism: Contributions to the Pharmacokinetics, Safety, and Efficacy of Xenobiotics. PMID- 27511204 TI - Revascularization of acute basilar artery occlusion using the Tigertriever adjustable clot retriever. PMID- 27511206 TI - Gender-Specificity in Viewing Time Among Heterosexual Women. AB - Measures of sexual interest tend to be more gender-specific in heterosexual men than in heterosexual women. Cognitive measures, such as viewing time to attractive stimuli, may also show similar patterns of gender-specificity or nonspecificity among men and women and thus serve as useful adjuncts to more direct measures of sexual interest. The objectives of the present research were to determine the extent of gender-specificity in women's viewing times for female pictures (varying in their perceived physical attractiveness) and explore the influence of social comparison of physical appearance on these patterns of responses. In Study 1, we recorded only women's viewing times for pictures of both genders, measured self-reported menstrual cycle phase, and manipulated the waist-to-hip ratio of the women in the female pictures. In Study 2, we recorded women's and men's viewing times, self-reported sexual attraction to pictures of males and females, and physical appearance social comparison. Study 1 found that heterosexual women's viewing time toward female pictures was not associated with manipulation of the perceived attractiveness of those pictures. Study 2 found that heterosexual men were more gender-specific than heterosexual women in their viewing time patterns. We also found that reported sexual attraction and physical appearance social comparison were associated with heterosexual women's viewing times for female pictures, while heterosexual men's viewing times were associated with sexual attraction only. Our results are discussed in relation to the utility of viewing time as an indicator of visual attention toward attractive or sexually appealing visual stimuli. PMID- 27511209 TI - Sexual Perfectionism in Women: Not as Simple as Adaptive or Maladaptive. AB - According to research and theory, the construct of perfectionism may apply to specific life domains, including being a perfect sexual partner. We extended the research on sexual perfectionism (SP) by examining the relationships between its various dimensions (i.e., self-directed, partner-directed, socially prescribed, partner-prescribed) and communication about sex, sexual functioning, and appearance self-consciousness during sex. Women (N = 208) of ages 19-50 were recruited online to respond to the Multidimensional Sexual Perfectionism Questionnaire and measures of communication about sex, sexual functioning, and physical appearance self-consciousness during sex. Dimensions of SP demonstrated a mixed pattern of relationships with measures of adaptive functioning. Partner prescribed SP was related to greater appearance self-consciousness during sex, indicating an unfavorable role of this dimension of SP. An indirect effect of socially prescribed and partner-prescribed SP on sexual functioning through poor dyadic communication about sex and greater appearance self-consciousness was also found. Self-directed SP was less clearly problematic and uniquely related to better dyadic communication, whereas partner-directed SP was uniquely related to fewer concerns about the body appearance during sex. In conclusion, with respect to personal functioning, higher standards directed towards sexual partners may be less problematic but perceptions that romantic partners expect one to be a perfect sexual partner may have deleterious effects. Overall, SP may relate to sexual experiences of women beyond the college-age group with some aspects of SP being more problematic than others. PMID- 27511207 TI - Pubertal Stress and Nutrition and their Association with Sexual Orientation and Height in the Add Health Data. AB - A number of studies have indicated that gay men tend to be shorter, on average, than heterosexual men. Less evidence exists that lesbian women are taller, on average, than heterosexual women. The most popular explanation of the association between sexual orientation and height involves prenatal factors, such that, for example, gay men may have been exposed to lower than typical androgens during fetal development, which impacts their height and sexual orientation as adults. An alternative explanation involves stress, given that stress has been associated with sexual minority identification and with lower height. Another alternative explanation involves nutrition, although its relationship is less clear with sexual minority identification. Using the Add Health data, which is a large, nationally representative and longitudinal sample of American adolescents (n = 14,786), we tested a mediation model, such that sexual orientation -> pubertal stress/nutrition -> height. Within men, we found that gay men (n = 126) were shorter, on average, than heterosexual men (n = 6412). None of the 24 pubertal stress-related and 15 pubertal nutrition-related variables assessed in the Add Health data mediated the relationship between sexual orientation and height in men. Within women, lesbians (n = 75) did not differ significantly in stature compared to heterosexual women (n = 6267). Thus, prenatal mechanisms (e.g., hormones, maternal immune response) are likely better candidates for explaining the height difference between gay men and heterosexual men. PMID- 27511208 TI - Decisions About Testing for HIV While in a Relationship: Perspectives From an Urban, Convenience Sample of HIV-Negative Male Couples Who Have a Sexual Agreement. AB - Many HIV-negative male couples establish a sexual agreement to help manage their HIV risk; however, less is known about their decisions about testing in this context. The present study examined whether male couples discussed HIV testing and explored their decisions about testing in the context of their sexual agreement at the individual- and couple-levels. Qualitative dyadic interview data were collected from 29 HIV-negative male couples with a sexual agreement who resided in Atlanta or Detroit; the sample was stratified by agreement type. Content analysis revealed male couples' decisions about HIV testing as routine, self-assurance, reliance and assumption on partner, beginning of relationship testers, and/or trust; decisions varied between partners and by agreement type. Findings suggest prevention efforts should help male couples integrate HIV testing into their sexual agreement that matches their agreement type and associated HIV-related risk behavior, and help shift their one-sided decisions about testing to a couple's mutually shared decision. PMID- 27511210 TI - miR-483-5p promotes growth, invasion and self-renewal of gastric cancer stem cells by Wnt/beta-catenin signaling. AB - Gastric carcinoma (GC) ranks as the second most common cause of cancer-associated mortality worldwide. Emerging evidence has suggested a potential novel therapeutic strategy based on the ability of cancer stem cells (CSCs) to trigger tumorigenesis. MicroRNAs (miRNAs) have previously been implicated in CSC formation and regulation of their functional characteristics. In the current study, a significant upregulation of miR-483-5p levels was demonstrated in spheroid body-forming cells (P<0.01) by reverse transcription-quantitative polymerase chain reaction, which were isolated from the MKN-45 gastric cancer cell line and possessed gastric CSC (GCSC) properties. An MTT assay demonstrated that overexpression of miR-483-5p by transfection with miR-483-5p mimics significantly increased cell proliferation and Annexin V-propidium iodide staining indicated the suppression of cell apoptosis, suggesting that miR-483-5p has an important function in GCSC growth. Notably, Transwell and sphere formation assays demonstrated that miR-483-5p elevation promoted GCSC invasion and cell self-renewal ability, respectively. Further western blotting assays demonstrated that miR-483-5p upregulation induced an increase in the protein expression levels of beta-catenin and its downstream target molecules, including cyclin D1, Bcl-2 and matrix metalloproteinase 2, indicating that miR-483-5p activates Wnt/beta catenin signaling. Inhibition of this pathway by beta-catenin small interfering RNA transfection attenuated the miR-483-5p-induced effects on cell growth, invasion and self-renewal. These results demonstrate that miR-483-5p may act as an oncogene to promote the development of GC by regulating GCSC growth, invasion and self-renewal via the Wnt/beta-catenin signaling pathway. Thus, the present study suggests that miR-483-5p may be a promising therapeutic target against GC. PMID- 27511211 TI - Changes in testicular function proteins and sperm acrosome status in rats treated with valproic acid. AB - Valproic acid (VPA), an anti-epileptic drug, reduces testosterone levels and sperm quality. However, the degree to which testosterone levels and sperm quality are decreased under VPA treatment needs to be clarified. The aim of the present study was to investigate the testicular proteins involved in testosterone synthesis and spermatogenesis, histopathology and sperm acrosome status in VPA treated rats. Adult rats were divided into control and experimental groups (n=8 in each). Rats in the experimental group were treated with 500mg kg-1, i.p., VPA for 10 consecutive days. Expression of Ki-67, tyrosine phosphorylated proteins and testicular steroidogenic proteins was examined. As expected, VPA-treated rats exhibited adverse changes in almost all reproductive parameters, particularly an increase in precocious acrosome reactions, compared with the control group. In addition, fibrosis of the tunica albuginea and tubule basement membrane was observed in testes from VPA-treated rats. Moreover, the expression of testicular Ki-67, cholesterol side-chain cleavage enzyme (P450scc) and phosphorylated proteins (41, 51 and 83 kDa) was decreased significantly in VPA-treated rats compared with control. In contrast, the expression of steroidogenic acute regulatory proteins in the VPA-treated group was significantly higher than in the control group. In conclusion, VPA treatment changes the expression of testicular proteins responsible for spermatogenesis and testosterone production, resulting in male infertility. PMID- 27511212 TI - Risk factors for morbidities and mortality in children following pneumonectomy. AB - BACKGROUND AND OBJECTIVE: Pneumonectomy (PNE) is a procedure infrequently performed in children. A high morbidity/mortality rate associated with PNE has been described. Few series have been published in the last 15 years. Risk factors associated with morbidity/mortality after PNE were evaluated. Indications, course, survival and complications of PNE in children were also analized. METHODS: In a case series of 51 children who underwent PNE, death within 30 days of surgery, pneumonia, empyema, sepsis, adult respiratory distress syndrome, bronchopleural fistula, bleeding, pneumothorax and post-PNE syndrome were considered major morbidities. Scoliosis, wound infection and atelectasis were considered minor morbidities. RESULTS: Median age at PNE was 7.4 years; 45% were males. Indications of pneumonectomy were postinfectious bronchiectasis (61%), tumours (17%), pulmonary malformations (17%), aspiration syndrome (14%), cystic fibrosis (6%), immunodeficiency (4%) and trauma (2%). Mortality rate was 4% at 1 month. Major and minor morbidities were present in 23% and 27% of patients, respectively. Risk factors for development of morbidities after PNE were age <= 3 years (OR: 16.7; 95% CI: 2.4-117) and the need for mechanical ventilation for at least 4 days (OR: 8; 95% CI: 1.5-43.6). CONCLUSION: Children are at high risk of death, major and minor morbidities following PNE. Caution is recommended for this group of patients. PMID- 27511213 TI - Malpractice claims related to tooth extractions. AB - OBJECTIVE: The aim of this study was to analyze malpractice claims related to tooth extractions in order to identify areas requiring emphasis and eventually to reduce the number of complications. MATERIAL AND METHODS: We compiled a file of all malpractice claims related to tooth extractions (EBA code) between 1997 and 2010 from the Finnish Patient Insurance Centre. We then examined the data with respect to date, tooth, surgery, injury diagnosis, and the authority's decision on the case. RESULTS: The material consisted of 852 completed patient cases. Most of the teeth were third molars (66 %), followed by first molars (8 %), and second molars (7 %). The majority of claims were related to operative extraction (71 %) followed by ordinary extraction (17 %) and apicoectomy of a single-rooted tooth (7 %) or multi-rooted tooth (2 %). The most common diagnosis was injury of the lingual or inferior alveolar nerve. According to the authority's decision, the patient received compensation more often in cases involving a third molar than other teeth (56 vs. 46 %, P < 0.05). CONCLUSION: The removal of a mandibular third molar was the basis for the majority of malpractice claims. CLINICAL RELEVANCE: To reduce the numbers of lingual and inferior alveolar nerve injuries, the removal of mandibular third molars necessitates recent and high-quality panoramic radiograph, preoperative assessment of the difficulty of removal, and consciousness of the variable anatomical course of the lingual nerve. PMID- 27511214 TI - Prevalence of otologic signs and symptoms in adult patients with temporomandibular disorders: a systematic review and meta-analysis. AB - OBJECTIVE: This study aims to estimate the prevalence of otologic signs and symptoms in adult patients with temporomandibular disorders (TMD). MATERIAL AND METHODS: Search strategies were developed for each of the following databases: PubMed, LILACS, Scopus, Web of Science, Proquest, LIVIVO, and Google Scholar and OpenGrey was used to assess the grey literature. It was included in this review only observational studies using either research diagnostic criteria (RDC)/TMD or DC/TMD indexes were selected. The Critical Appraisal Checklist for Studies Reporting Prevalence Data from the Joanna Briggs Institute was used to assess the risk of bias of the included studies. A proportion random effects meta-analysis was conducted within the eight included studies. RESULTS: Eight studies met the eligibility criteria and were selected. All of the included studies used the RDC/TMD and report associated otologic signs and symptoms. The studies were clustered into groups based on prevalence for each individual sign or symptom. The most prevalent otologic symptom associated with TMD was ear fullness (74.8 % standard deviation (SD), 43.02 to 96.25 %; n = 50), followed by otalgia (55.1 % SD, 31.78 to 77.30; n = 386), tinnitus (52.1 % SD, 38.43 to 65.74; n = 1293), vertigo (40.8 % SD, 11.29 to 74.72; n = 374), and hearing loss (38.9 % SD, 2.83 to 85.46; n = 744). CONCLUSION: The prevalence of otologic signs and symptoms in adult patients with TMD is high. The most prevalent otologic symptom in patient adults with TMD is ear fullness. CLINICAL RELEVANCE: This study intends to provide understanding over the prevalence of otologic signs and symptoms in TMD cases in adults. PMID- 27511215 TI - Sustained clinico-radiologic response to anti-cytotoxic T lymphocyte antigen 4 antibody therapy in metastatic myxoid liposarcoma. AB - Rarity and heterogeneity of sarcomas pose significant challenges in terms of developing new therapies. Therefore, efforts towards studying immunotherapy in sarcomas may provide hope for effective control of this group of devastating cancers. A sustained clinico-radiologic response to the anti-cytotoxic T lymphocyte antigen 4 antibody ipilimumab in a patient with metastatic myxoid liposarcoma is reported. Although the patient was treated with this agent for metastatic melanoma, both his metastatic cancers - melanoma and sarcoma - meaningfully responded to this agent. Consideration of enrolling patients in immunotherapy trials using various immune checkpoint inhibitors, where available, is of paramount importance, especially when facing advanced and/or refractory sarcoma situation. PMID- 27511216 TI - Potential drug-drug interactions in hospitalised haematological patients. AB - Background Frequently, haematological patients undergo highly complex and intensive treatment protocols, so a high risk of drug-drug interactions could be expected. Objectives To determine prevalence of clinically relevant drug-drug interactions, to identify the most frequent drug-drug interactions and associated risk factors. Methods A prospective, observational and descriptive study was carried out from November 2012 to February 2013. Twice a week, every patient's treatment sheet was collected. Each medication list was screened through two databases: Thomson MicromedexTM and Drug Interaction FactsTM. All identified potential drug-drug interactions with a moderate or higher severity rating were recorded. Summary statistics were used to describe patient and disease characteristics, most often prescribed drugs, and frequency, types and classification of drug-drug interactions. Multiple logistic regression models were used to identify risk factors associated with drug-drug interactions. Results A total of 2061 drug-drug interactions were detected in 317 treatment sheets from 58 patients. The prevalence of treatment sheets with drug-drug interactions by Micromedex and Drug Interaction Facts databases were 74.1% and 56.8%, respectively. Azole antifungals, immunosuppressive drugs, antiemetics, antidepressants, acid suppressants and corticosteroids were the most frequent involved drugs. In multivariate analysis, the main risk factor associated with increased odds for drug-drug interactions was a higher number of non antineoplastic drugs. Conclusions The prevalence of drug-drug interactions was common, with immunosuppressant and azole antifungal agents being the most commonly involved drugs. The factor having the greatest influence on drug-drug interactions was a higher number of non-antineoplastic drugs. PMID- 27511217 TI - Comparison of patellofemoral outcomes after TKA using two prostheses with different patellofemoral design features. AB - PURPOSE: The purpose of the present study was to compare the clinical and radiographic results after TKA using two prostheses with different sagittal patellofemoral design features, including outcomes related to compatibility of the patellofemoral joint. METHODS: The clinical and radiographic results of 81 patients (100 knees) who underwent TKA using the specific prosthesis (group A) were compared with those in a control group who underwent TKA using the other prosthesis (group B). The presence of anterior knee joint pain, patellar crepitation, and patellar clunk syndrome was also checked. RESULTS: The function score and maximum flexion angle at the last follow-up were slightly better in group A than those in group B (92.0 +/- 2.3 vs. 90.6 +/- 4.2) (133.6 degrees +/- 8.4 degrees vs. 129.6 degrees +/- 11.4 degrees ). Anterior knee pain was observed in 6 knees and patellar crepitation in four knees in group A. In group B, these symptoms were observed in 22 knees and 18 knees, respectively. There was no patellar clunk syndrome in either group. The alignment was corrected with satisfactory positioning of components. The patellar height remained unchanged after TKA in the two groups. The differences between preoperative and postoperative patellar tilt angle and patellar translation were small. CONCLUSION: When comparing the clinical and radiographic results after TKA using two prostheses with different sagittal patellofemoral design features, TKA using the specific prosthesis provided satisfactory results with less clinical symptoms related to the patellofemoral kinematics with TKA using the other prosthesis. LEVEL OF EVIDENCE: III. PMID- 27511218 TI - In vivo kinematic analysis of the glenohumeral joint during dynamic full axial rotation and scapular plane full abduction in healthy shoulders. AB - PURPOSE: The purpose of this study was to evaluate the kinematics of healthy shoulders during dynamic full axial rotation and scapular plane full abduction using three-dimensional (3D)-to-two-dimensional (2D) model-to-image registration techniques. METHODS: Dynamic glenohumeral kinematics during axial rotation and scapular plane abduction were analysed in 10 healthy participants. Continuous radiographic images of axial rotation and scapular plane abduction were taken using a flat panel radiographic detector. The participants received a computed tomography scan to generate virtual digitally reconstructed radiographs. The density-based digitally reconstructed radiographs were then compared with the serial radiographic images acquired using image correlations. These 3D-to-2D model-to-image registration techniques determined the 3D positions and orientations of the humerus and scapula during dynamic full axial rotation and scapular plane full abduction. RESULTS: The humeral head centre translated an average of 2.5 +/- 3.1 mm posteriorly, and 1.4 +/- 1.0 mm superiorly in the early phase, then an average of 2.0 +/- 0.8 mm inferiorly in the late phase during external rotation motion. The glenohumeral external rotation angle had a significant effect on the anterior/posterior (A/P) and superior/inferior (S/I) translation of the humeral head centre (both p < 0.05). 33.6 +/- 15.6 degrees of glenohumeral external rotation occurred during scapular plane abduction. The humeral head centre translated an average of 0.6 +/- 0.9 mm superiorly in the early phase, then 1.7 +/- 2.6 mm inferiorly in the late phase, and translated an average of 0.4 +/- 0.5 mm medially in the early phase, then 1.6 +/- 1.0 mm laterally in the late phase during scapular plane abduction. The humeral abduction angle had a significant effect on the S/I and lateral/medial (L/M) translation of the humeral head centre (both p < 0.05). CONCLUSION: This study investigated 3D translations of the humerus relative to the scapula: during scapular plane full abduction, the humerus rotated 33.6 degrees externally relative to the scapula, and during external rotation motion in the adducted position, the humeral head centre translated an average of 2.5 mm posteriorly. Kinematic data will provide important insights into evaluating the kinematics of pathological shoulders. For clinical relevance, quantitative assessment of dynamic healthy shoulder kinematics might be a physiological indicator for the assessment of pathological shoulders. PMID- 27511219 TI - Variations in EGFR ctDNA Correlates to the Clinical Efficacy of Afatinib in Non Small Cell Lung Cancer with Acquired Resistance. AB - Monitoring of non small cell lung cancer (NSCLC) patients on afatinib after acquired resistance to 1st generation tyrosine kinase inhibitors is important. Circulating tumor DNA (ctDNA) offers an attractive means other than conventional tissue biopsy to characterize real time dynamic changes of the disease. In our study, we aim to ascertain the clinical value for ctDNA monitoring of NSCLC patients with acquired resistance for afatinib treatment. 200 patients positive for the activating epithermal growth factor receptor (EGFR) mutations were recruited for the study. Baseline molecular profiling for L858R, Exon 19 deletion and T790M were performed. Thereafter, serial blood samples were taken and patients were assessed by overall survival (OS) to determine the usefulness of ctDNA monitoring. At baseline, matched tumor biopsy and ctDNA analysis had a concordance agreement of 93.5% for L858R and exon 19 deletion. We also determined that a large proportion of patients had the drug resistance mutation T790M prior to starting afatinib and these patients were linked to a worse survival outcome. For patients that registered a drop in ctDNA levels after afatinib was administered, we observed that their survival outcome was more favorable (hazard ratio 1.56, (95% CI 1.04 to 2.43). ctDNA levels were mostly elevated after the 3rd sampling cycle. Our results suggest that ctDNA can be used to predict the clinical benefits of afatinib treatment. Pre and post blood sampling aids to identify patient groups that may benefit most from the treatment and ctDNA is relatively sensitive to address the dynamic changes of the disease at the molecular level. PMID- 27511220 TI - Sixty seconds on . . . the NHS "reset". PMID- 27511221 TI - Epigenetics: New insights into site-specific variations in RA and OA. PMID- 27511270 TI - Critical features of acute stress-induced cross-sensitization identified through the hypothalamic-pituitary-adrenal axis output. AB - Stress-induced sensitization represents a process whereby prior exposure to severe stressors leaves animals or humans in a hyper-responsive state to further stressors. Indeed, this phenomenon is assumed to be the basis of certain stress associated pathologies, including post-traumatic stress disorder and psychosis. One biological system particularly prone to sensitization is the hypothalamic pituitary-adrenal (HPA) axis, the prototypic stress system. It is well established that under certain conditions, prior exposure of animals to acute and chronic (triggering) stressors enhances HPA responses to novel (heterotypic) stressors on subsequent days (e.g. raised plasma ACTH and corticosterone levels). However, such changes remain somewhat controversial and thus, the present study aimed to identify the critical characteristics of the triggering and challenging stressors that affect acute stress-induced HPA cross-sensitization in adult rats. We found that HPA cross-sensitization is markedly influenced by the intensity of the triggering stressor, whereas the length of exposure mainly affects its persistence. Importantly, HPA sensitization is more evident with mild than strong challenging stressors, and it may remain unnoticed if exposure to the challenging stressor is prolonged beyond 15 min. We speculate that heterotypic HPA sensitization might have developed to optimize biologically adaptive responses to further brief stressors. PMID- 27511269 TI - Association between IRF6 and 8q24 polymorphisms and nonsyndromic cleft lip with or without cleft palate: Systematic review and meta-analysis. AB - BACKGROUND: We conducted a systematic review and meta-analysis of interferon regulatory factor 6 and 8q24 polymorphisms with nonsyndromic cleft lip with/without cleft palate (NSCL/P). METHODS: Data extraction was independently performed by two reviewers. Genotypic effects of four polymorphisms from 31 studies were pooled separately by ethnicity using a mixed-effect logit model with accounting for heterogeneity. RESULTS: For rs2235371, AA and GA carried, respectively, 51% (95% confidence interval [CI], 37%-61%) and 42% (95% CI, 32% 50%) lower risks of NSCL/P than GG genotypes in Asians, but these genotypes were not significant in Caucasians. For rs2013162, only AA was significant, that is, carried 0.65 (95% CI, 0.52-0.82) times lower odds than CC in Caucasians but not for Asians. For rs642961, AA and GA genotypes, respectively, carried 2.47 (95% CI, 1.41-4.35) and 1.40 (95% CI, 1.12-1.75) times higher odds in Asian, and 2.03 (95% CI, 1.52-2.71) and 1.58 (95% CI, 1.37-1.82) times higher odds in Caucasians compare with GG genotypes. For rs987525, AA and CA genotypes carried 2.27 (95% CI, 1.43-3.60) and 1.34 (95% CI, 1.02-1.77) times higher odds in Asian, and 5.25 (95% CI, 3.98-6.91) and 2.13 (95% CI-1.82, 2.49) times higher odds in Caucasians, and 1.42 (95% CI, 1.10-1.82) and 1.28 (95% CI, 1.09-1.50) times higher odds in mixed ethnicities compared with CC genotypes. These variant effects remained significant based on applying Bonferroni corrected-thresholds, except in the mixed ethnicity. CONCLUSION: We show robust variant effects in NSCL/P. Considering them with other genes and risk factors might be useful to improve prediction of NSCL/P occurrence. Birth Defects Research (Part A) 106:773-788, 2016. (c) 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc. PMID- 27511271 TI - Elastic Carbon Aerogels Reconstructed from Electrospun Nanofibers and Graphene as Three-Dimensional Networked Matrix for Efficient Energy Storage/Conversion. AB - Three-dimensional (3D) all-carbon nanofibrous aerogels with good structural stability and elasticity are highly desirable in flexible energy storage/conversion devices. Hence, an efficient surface-induced co-assembly strategy is reported for the novel design and reconstruction of electrospun nanofibers into graphene/carbon nanofiber (CNF) composite aerogels (GCA) with hierarchical structures utilizing graphene flakes as cross-linkers. The as obtained GCA monoliths possess interconnected macropores and integrated conductive networks, which exhibit high elasticity and great structural robustness. Benefitting from the largely increased surface area and charge transfer efficiency derived from the multi-form firm interconnections (including pillaring, bridging and jointing) between graphene flakes and CNF ribs, GCA not only reveals prominent capacitive performance as supercapacitor electrode, but also shows excellent hydrogen evolution reaction activity in both acidic and alkaline solutions as a 3D template for decoration of few-layered MoSe2 nanosheets, holding great potentials for energy-related applications. PMID- 27511272 TI - Frequent Surfing on Social Health Networks is Associated With Increased Knowledge and Patient Health Activation. AB - BACKGROUND: The advent of the Internet has driven a technological revolution that has changed our lives. As part of this phenomenon, social networks have attained a prominent role in health care. A variety of medical services is provided over the Internet, including home monitoring, interactive communications between the patient and service providers, and social support, among others. This study emphasizes some of the practical implications of Web-based health social networks for patients and for health care systems. OBJECTIVE: The objective of this study was to assess how participation in a social network among individuals with a chronic condition contributed to patient activation, based on the Patient Activation Measure (PAM). METHODS: A prospective, cross-sectional survey with a retrospective component was conducted. Data were collected from Camoni, a Hebrew language Web-based social health network, participants in the diabetes mellitus, pain, hypertension, and depression/anxiety forums, during November 2012 to 2013. Experienced users (enrolled at least 6 months) and newly enrolled received similar versions of the same questionnaire including sociodemographics and PAM. RESULTS: Among 686 participants, 154 of 337 experienced and 123 of 349 newly enrolled completed the questionnaire. Positive correlations (P<.05) were found between frequency and duration of site visits and patient activation, social relationships, and chronic disease knowledge. Men surfed longer than women (chi23=10.104, P<.05). Experienced users with diabetes surfed more than those with other illnesses and had significantly higher PAM scores (mean, M=69.3, standard deviation, SD=19.1, PAM level 4; Z=-4.197, P<.001) than new users (M=62.8, SD=18.7, PAM level 3). Disease knowledge directly predicted PAM for all users (beta=.26 and .21, respectively). Frequency and duration of social health network use were correlated with increased knowledge about a chronic disease. Experienced surfers had higher PAM than newly enrolled, suggesting that continued site use may contribute to increased activation. CONCLUSIONS: Web-based social health networks offer an opportunity to expand patient knowledge and increase involvement in personal health, thereby increasing patient activation. Further studies are needed to examine these changes on other aspects of chronic illnesses such as quality of life and costs. PMID- 27511273 TI - Bullous eosinophilic annular erythema. PMID- 27511274 TI - Improving Long-Term Care Facility Disaster Preparedness and Response: A Literature Review. AB - Long-term care facilities (LTCFs) and their residents are especially susceptible to disruptions associated with natural disasters and often have limited experience and resources for disaster planning and response. Previous reports have offered disaster planning and response recommendations. We could not find a comprehensive review of studied interventions or facility attributes that affect disaster outcomes in LTCFs and their residents. We reviewed articles published from 1974 through September 30, 2015, that studied disaster characteristics, facility characteristics, patient characteristics, or an intervention that affected outcomes for LTCFs experiencing or preparing for a disaster. Twenty-one articles were included in the review. All of the articles fell into 1 of the following categories: facility or disaster characteristics that predicted preparedness or response, interventions to improve preparedness, and health effects of disaster response, most often related to facility evacuation. All of the articles described observational studies that were heterogeneous in design and metrics. We believe that the evidence-based literature supports 6 specific recommendations for facilities, governmental agencies, health care communities and academia. These include integrated and coordinated disaster planning, staff training, careful consideration before governments order mandatory evacuations, anticipation of the increased medical needs of LTCF residents following a disaster, and the need for more outcomes research. (Disaster Med Public Health Preparedness. 2017;11:140-149). PMID- 27511276 TI - Major contribution of central pulmonary reservoir discharge to increased pulmonary arterial diastolic blood flow after birth in near-term lambs. AB - Recent fetal lamb data have suggested that the pulmonary trunk (PT) region displays a reservoir function and that a pharmacologically induced fall in pulmonary vascular resistance (PVR) increases and redistributes diastolic discharge from this central pulmonary reservoir toward the lungs, thereby producing a positive diastolic offset in the pulmonary arterial (PA) blood flow profile. As a similar offset in PA flow characteristically occurs after birth, this study tested the hypotheses that 1) central pulmonary reservoir discharge is both redistributed toward the lungs and increased in magnitude during the birth transition and 2) discharge from this reservoir constitutes a major component of increased PA diastolic blood flow after birth. Six anesthetized near-term fetal lambs were instrumented with PT, ductal and left PA transit-time flow probes, and aortic, PT and left atrial catheters. Hemodynamic data were recorded in fetuses and at regular intervals during 2-h mechanical ventilation following cesarean section delivery. Diastolic PA blood flow rose from near zero in fetuses to 468 +/- 188 ml/min by 15 min (P < 0.001). Central pulmonary reservoir discharge in fetuses (99 +/- 44 ml/min) passed primarily right-to-left across the ductus. However, this reservoir discharge redistributed entirely to the lungs by 1 min after birth, and then doubled to a peak of 214 +/- 167 ml/min at 15 min (P < 0.001). Reservoir discharge subsequently stabilized at 151 +/- 60 ml/min at 30 120 min, which comprised ~50% of diastolic and ~20% of mean PA blood flow. These findings suggest that enhanced diastolic central pulmonary reservoir discharge plays a major role in supporting an increased pulmonary perfusion after birth. PMID- 27511275 TI - Associations between microRNA binding site SNPs in FGFs and FGFRs and the risk of non-syndromic orofacial cleft. AB - We hypothesized that microRNA binding site single nucleotide polymorphisms (SNPs) in fibroblast growth factors (FGFs) and their receptor genes (FGFRs) may affect microRNA and mRNA interactions and are thereby associated with susceptibility of non-syndromic orofacial cleft (NSOC). Ten SNPs among the FGF and FGFR genes were selected and their associations with NSOC susceptibility were investigated in a case-control study of 602 patients with NSOC and 605 healthy controls. FGF2/rs1048201, FGF5/rs3733336 and FGF9/rs546782 showed suggestive association with NSOC susceptibility. In the combination analysis, the observed odds ratios (ORs) decreased with the number of protective alleles (rs1048201-T, rs3733336-G and rs546782-T) but were not statistically significant beyond the first comparison. Hsa-miRNA-496, hsa-miRNA-145 and hsa-miRNA-187 were predicted to be miRNAs with binding sites within/near these SNPs and were expressed in lip tissues. Decreased FGF2, FGF5 and FGF9 expression was observed in three cell lines transfected with the corresponding miRNAs. Moreover, the three SNPs could contribute to differential binding efficacy between hsa-miRNA-496 and FGF2, hsa miRNA-145 and FGF5, hsa-miRNA-187 and FGF9 in luciferase assay. The results suggest that FGF2/rs1048201, FGF5/rs3733336 and FGF9/rs546782 are associated with the risk of NSOC and that these miRNA-FGF interactions may affect NSOC development. PMID- 27511278 TI - Sustained increases in blood pressure elicited by prolonged face cooling in humans. AB - We tested the hypothesis that increases in blood pressure are sustained throughout 15 min of face cooling. Two independent trials were carried out. In the Face-Cooling Trial, 10 healthy adults underwent 15 min of face cooling where a 2.5-liter bag of ice water (0 +/- 0 degrees C) was placed over their cheeks, eyes, and forehead. The Sham Trial was identical except that the temperature of the water was 34 +/- 1 degrees C. Primary dependent variables were forehead temperature, mean arterial pressure, and forearm vascular resistance. The square root of the mean of successive differences in R-R interval (RMSSD) provided an index of cardiac parasympathetic activity. In the Face Cooling Trial, forehead temperature fell from 34.1 +/- 0.9 degrees C at baseline to 12.9 +/- 3.3 degrees C at the end of face cooling (P < 0.01). Mean arterial pressure increased from 83 +/- 9 mmHg at baseline to 106 +/- 13 mmHg at the end of face cooling (P < 0.01). RMSSD increased from 61 +/- 40 ms at baseline to 165 +/- 97 ms during the first 2 min of face cooling (P <= 0.05), but returned to baseline levels thereafter (65 +/- 49 ms, P >= 0.46). Forearm vascular resistance increased from 18.3 +/- 4.4 mmHg.ml-1.100 g tissue-1.min at baseline to 26.6 +/- 4.0 mmHg.ml-1.100 g tissue 1.min at the end of face cooling (P < 0.01). There were no changes in the Sham Trial. These data indicate that increases in blood pressure are sustained throughout 15 min of face cooling, and face cooling elicits differential time dependent parasympathetic and likely sympathetic activation. PMID- 27511277 TI - Post-oral sugar detection rapidly and chemospecifically modulates taste-guided behavior. AB - Several recent studies have shown that post-oral sugar sensing rapidly stimulates ingestion. Here, we explored the specificity with which early-phase post-oral sugar sensing influenced ingestive motivation. In experiment 1, rats were trained to associate the consumption of 0.3 M sucrose with injections of LiCl (3.0 meq/kg ip, conditioned taste aversion) or given equivalent exposures to the stimuli, but in an unpaired fashion. Then, all rats were subjected to two brief-access tests to assess appetitive and consummatory responses to the taste properties of sucrose (0.01-1.0 M), 0.12 M NaCl, and dH2O (in 10-s trials in randomized blocks). Intraduodenal infusions of either 0.3 M sucrose or equiosmolar 0.15 M NaCl (3.0 ml) were administered, beginning just before each test. For unpaired rats, intraduodenal sucrose specifically enhanced licking for 0.03-1.0 M sucrose, with no effect on trial initiation, relative to intraduodenal NaCl. Rats with an aversion to sucrose suppressed licking responses to sucrose in a concentration dependent manner, as expected, but the intraduodenal sucrose preload did not appear to further influence licking responses; instead, intraduodenal sucrose attenuated trial initiation. Using a serial taste reactivity (TR) paradigm, however, experiment 2 demonstrated that intraduodenal sucrose preloads suppressed ingestive oromotor responses to intraorally delivered sucrose in rats with a sucrose aversion. Finally, experiment 3 showed that intraduodenal sucrose preloads enhanced preferential licking to some representative tastants tested (sucrose, Polycose, and Intralipid), but not others (NaCl, quinine). Together, the results suggest that the early phase-reinforcing efficacy of post-oral sugar is dependent on the sensory and motivational properties of the ingesta. PMID- 27511279 TI - Heart rate variability during high heat stress: a comparison between young and older adults with and without Type 2 diabetes. AB - We examined whether older individuals with and without Type 2 diabetes (T2D) experience differences in heart rate variability (HRV) during a 3-h exposure to high heat stress compared with young adults. Young (Young; n = 22; 23 +/- 3 yr) and older individuals with (T2D; n = 11; 59 +/- 9 yr) and without (Older; n = 25; 63 +/- 5 yr) T2D were exposed to heat stress (44 degrees C, 30% relative humidity) for 3 h. Fifty-five HRV measures were assessed for 15 min at baseline and at minutes 82.5-97.5 (Mid) and minutes 165-180 (End) during heat stress. When compared with Young, a similar number of HRV indices were significantly different (P < 0.05) in Older (Baseline: 35; Mid: 29; End: 32) and T2D (Baseline: 31; Mid: 30; End: 27). In contrast, the number of HRV indices significantly different (P < 0.05) between Older and T2D were far fewer (Baseline: 13, Mid: 1, End: 3). Within group analyses demonstrated a greater change in the Young group's HRV during heat stress compared with Older and T2D; the number of significantly different (P < 0.05) HRV indices between baseline and End were 42, 29, and 20, for Young, Older, and T2D, respectively. Analysis of specific HRV domains suggest that the Young group experienced greater sympathetic activity during heat stress compared with Older and T2D. In conclusion, when compared with young, older individuals with and without T2D demonstrate low HRV at baseline and less change in HRV (including an attenuated sympathetic response) during 3 h high heat stress, potentially contributing to impaired thermoregulatory function. PMID- 27511280 TI - Sex differences in obesity-induced hypertension and vascular dysfunction: a protective role for estrogen in adipose tissue inflammation? AB - Obesity is a potent predictor of cardiovascular disease and associated risk factors, including hypertension. Systemic inflammation has been suggested by a number of studies to be an important link between excess adiposity and hypertension, yet the majority of the studies have been conducted exclusively in males. This is problematic since women represent ~53% of hypertensive cases and are more likely than men to be obese. There is a growing body of literature supporting a central role for immune cell activation in numerous experimental models of hypertension, and both the sex of the subject and the sex of the T cell have been shown to impact blood pressure (BP) responses to hypertensive stimuli. Moreover, sex steroid hormones play an important role in energy homeostasis, as well as in the regulation of immune responses; estrogen, in particular, has a well-known impact on both cardiovascular and metabolic disorders. Therefore, the purpose of this review is to examine whether sex or sex hormones regulate the role of the immune system in the development of hypertension and related vascular dysfunction in response to metabolic changes and stimuli, including a high-fat diet. PMID- 27511281 TI - alpha4-Containing nicotinic receptors contribute to the effects of perinatal nicotine on ventilatory and metabolic responses of neonatal mice to ambient cooling. AB - Among numerous studies, perinatal nicotine exposure (PN) has had variable effects on respiratory control in the neonatal period. The effects of acute nicotine exposure on breathing are largely mediated by alpha4-containing nicotine acetylcholine receptors (nAChRs). These receptors are also involved in thermoregulatory responses induced by both acetylcholine and nicotine. We therefore hypothesized that alpha4-containing nAChRs would mediate the effects of PN on the metabolic and ventilatory responses of neonates to modest cold exposure. Wild-type (WT) and alpha4 knockout (KO) mice were exposed to 6 mg.kg 1.day-1 nicotine or vehicle from embryonic day 14 At postnatal day (P) 7 mice were cooled from an ambient temperature (TA) of 32 to 20 degrees C. Body temperature (TB), rate of O2 consumption (Vo2), ventilation (Ve), respiratory frequency (FB), and tidal volume (VT) were continually monitored. An absence of alpha4 had no effect on the metabolic response to ambient cooling. Surprisingly, PN selectively increased the metabolic response of KO pups to cooling. Regardless, KO pups became hypothermic to the same degree as WT pups, and for both genotypes the drop in TB was exacerbated by PN. PN led to hyperventilation in WT pups caused by an increase in VT, an effect that was absent in alpha4 KO littermates. We show that PN interacts with alpha4-containing nAChRs in unique ways to modulate the control of breathing and thermoregulation in the early postnatal period. PMID- 27511282 TI - Oxytocin redux. PMID- 27511283 TI - Effects of estrogen replacement on stress-induced cardiovascular responses via renin-angiotensin system in ovariectomized rats. AB - The purpose of this study was to determine whether chronic estrogen replacement in ovariectomized rats inhibits the pressor response to psychological stress by attenuating the activation of the renin-angiotensin system. Female Wistar rats aged 9 wk were ovariectomized. After 4 wk, the rats were randomly assigned to be implanted subcutaneously with pellets containing either 17beta-estradiol (E2) or placebo (Pla). After 4 wk of treatment, the rats underwent cage-switch stress and, in a separate experiment, a subset received an infusion of angiotensin II. The cage-switch stress rapidly elevated blood pressure (BP) and heart rate (HR) as measured by radiotelemetry in both groups. However, the BP and HR responses to the stress were significantly attenuated in the E2 group compared with the Pla group. An angiotensin II type 1 receptor blocker, losartan, given in drinking water, abolished the difference in the pressor response to stress between the two groups. Moreover, the stress-induced elevation in plasma renin activity and angiotensin II concentration was significant in the Pla group, but not in the E2 group. In addition, the expression of renin mRNA in the kidney was lower in the E2 group relative to the Pla group. Finally, we found that intravenous angiotensin II infusion increased BP and decreased HR to a similar degree in both groups. These results suggest that the inhibitory effects of estrogen on psychological stress-induced activation of the renin-angiotensin system could be at least partially responsible for the suppression of the pressor responses to psychological stress seen in estrogen-replaced ovariectomized rats. PMID- 27511285 TI - Comparison of neoadjuvant versus a surgery first approach for gastric and esophagogastric cancer. AB - Gastric cancer remains a significant worldwide health concern. While surgery is required for cure, all but the earliest of cancers will require multimodality therapy. Chemotherapy and chemoradiation in the neoadjuvant and adjuvant settings have shown to improve overall survival, but the sequencing of treatment is controversial. As healthcare expenses surge, it is increasingly important to impart value to these treatments. This review will look at the intersection of effective treatment and costs for gastric cancer. J. Surg. Oncol. 2016;114:296 303. (c) 2016 Wiley Periodicals, Inc. PMID- 27511284 TI - A qualitative investigation of recovery after femoral fracture in Rett syndrome. AB - BACKGROUND: Children with severe disability often develop osteoporosis and have an increased risk of fracture. In Rett syndrome, the prevalence of fracture is four times greater than in the general population, and the femur is commonly affected. This study used qualitative methods to investigate the regaining of mobility within 12 months following femoral fracture in Rett syndrome and parent caregiver experiences. METHODS: Caregivers (n = 14) of cases registered with the Australian Rett Syndrome Database with a daughter with Rett syndrome were recruited if their daughter sustained a femoral fracture between 2009 and 2014. Median (interquartile range) age at fracture was 11 years and 4 months (8 years and 8 months to 22 years and 3 months). Qualitative methods were used to investigate parent/caregiver experiences and their daughter's recovery following fracture. Themes in the interview data were identified with thematic analysis. RESULTS: Operative management was chosen for those walking independently and non operative management for most of the remaining. All who walked independently and one of the four who required assistance recovered pre-operative walking skills within 6 months. Themes identified by caregivers related to the complexities of pain recognition, the caregiver emotional journey and later rebuilding of relationships with service providers. CONCLUSIONS: Those who walked with assistance were vulnerable to loss of this skill. Difficulties in pain recognition increased time to diagnose fracture, and the acute episode was associated with heightened caregiver stress. Service providers can use family centred practice models to support the strengthening of family functioning following this acute event that is surprisingly common in those with severe disability. PMID- 27511286 TI - Terazulene Isomers: Polarity Change of OFETs through Molecular Orbital Distribution Contrast. AB - Intermolecular orbital coupling is fundamentally important to organic semiconductor performance. Recently, we reported that 2,6':2',6"-terazulene (TAz1) exhibited excellent performance as an n-type organic field-effect transistor (OFET) via molecular orbital distribution control. To validate and develop this concept, here we present three other terazulene regioisomers, which have three azulene molecules connected at the 2- or 6-position along the long axis of the azulene, thus constructing a linear expanded pi-conjugation system: 2,2':6',2"-terazulene (TAz2), 2,2':6',6"-terazulene (TAz3), and 6,2':6',6" terazulene (TAz4). TAz2 and TAz3 exhibit ambipolar characteristics; TAz4 exhibits clear n-type transistor behavior as an OFET. The lowest unoccupied molecular orbitals (LUMOs) of all terazulenes are fully delocalized over the entire molecule. In contrast, the highest occupied molecular orbitals (HOMOs) of TAz2 and TAz3 are delocalized over the 2,2'-biazulene units; the HOMOs of TAz4 are localized at one end of the azulene unit. These findings confirm that terazulene isomers which are simple hydrocarbon compounds are versatile materials with a tunable-polarity FET characteristic that depends on the direction of the azulene unit and the related contrast of the molecular orbital distribution in the terazulene backbone. PMID- 27511287 TI - Aligning Spinoza with Descartes: An informed Cartesian account of the truth bias. AB - There is a bias towards believing information is true rather than false. The Spinozan account claims there is an early, automatic bias towards believing. Only afterwards can people engage in an effortful re-evaluation and disbelieve the information. Supporting this account, there is a greater bias towards believing information is true when under cognitive load. However, developing on the Adaptive Lie Detector (ALIED) theory, the informed Cartesian can equally explain this data. The account claims the bias under load is not evidence of automatic belief; rather, people are undecided, but if forced to guess they can rely on context information to make an informed judgement. The account predicts, and we found, that if people can explicitly indicate their uncertainty, there should be no bias towards believing because they are no longer required to guess. Thus, we conclude that belief formation can be better explained by an informed Cartesian account - an attempt to make an informed judgment under uncertainty. PMID- 27511288 TI - Observation of intrinsic emission in beta-BiNbO4 available for excitation of both UV light and high energy irradiation. AB - beta-BiNbO4 with a high temperature triclinic form was prepared via a high temperature solid-state reaction ceramic method. Structural refinement and surface characteristic studies were performed. The optical absorption, and electronic calculation of the band structures and density of states were also studied. beta-BiNbO4 ceramic has an indirect transition with a band energy of 3.05 eV. The valence band is dominated by O-2p states whereas the conduction band has predominantly Nb 4d and Bi 6s character. The intrinsic luminescence properties of beta-BiNbO4 were reported, and present a blue emission band peak at 435 nm under the excitation of UV light. The beta-BiNbO4 ceramic presents scintillation properties under high energy irradiation. The luminescence was studied via the combinations of the color centers, band calculation and energy transfer from NbO6 to Bi(3+) in the lattices. The thermal quenching and activation energy for the luminescence were reported. beta-BiNbO4 has potential applications in photoluminescence and scintillation materials. PMID- 27511290 TI - Self-assembled vesicles of urea-tethered foldamers as hydrophobic drug carriers. AB - Molecular self-assembly of nonamphiphilic alpha,beta-hybrid foldamers based on urea-tethered anthranilic acid-proline (Ant-Pro) foldamers is reported. These self-assembled hollow vesicular architectures can take up and release the anticancer hydrophobic drug curcumin. PMID- 27511289 TI - Evaluation of Substituted 1,2,3-Dithiazoles as Inhibitors of the Feline Immunodeficiency Virus (FIV) Nucleocapsid Protein via a Proposed Zinc Ejection Mechanism. AB - A diverse library of 5-thieno-, 5-oxo-, and 5-imino-1,2,3-dithiazole derivatives was synthesized and evaluated for efficacy against the feline immunodeficiency virus (FIV) as a model for HIV in cells. Several diverse compounds from this series displayed nanomolar activity and low toxicity, representing a potential new class of compounds for the treatment of FIV and HIV. PMID- 27511291 TI - TE-domestication and horizontal transfer in a putative Nef-AP1mu mimic of HLA-A cytoplasmic domain re-trafficking. AB - Genes of the major histocompatibility complex (MHC; also called HLA in human) are polymorphic elements in the genomes of sharks to humans. Class-I and class-II MHC loci appear responsible for much of the genetic linkage to myriad disease states via the capacity to bind short (~8-15 a.a.) peptides of a given pathogen's proteome, or in some cases, the altered proteomes of cancerous cells, and even (in autoimmunity) certain nominal 'self' peptides (Janeway, 2004).(1) Unfortunately, little is known about how the canonical structure of the MHC-I/-II peptide-presenting gene evolved, particularly since beyond ~500 Mya (sharks) no paralogs exist.(2,3) We previously reported that HLA-A isotype alleles with the alpha1-helix, R65 motif, are wide-spread in phylogeny, but that the alpha 2 helix, H151R motif, has apparently segregated out of most species. Surprisingly, an uncharacterized orf in T. syrichta (Loc-103275158) encoded R151, but within a truncated A-23 like gene containing 5'- and 3'- footprints of the transposon (TE), tigger-1; the extant tarsier A-23 allele is totally missing exon-3 and part of exon-4; together, suggesting TE-mediated inactivation of an intact/ancestral A 23 allele (Murray, 2015a).(4) The unique Loc-103275158 orf encodes a putative 15 exon transcript with no apparent paralogs throughout phylogeny. However, an HLA A11 like gene in M. leucophaeus with a shortened C-terminal domain, and an HLA-A like orf in C. atys with two linked alpha1/alpha2/alpha3 domains, both contain a second transmembrane segment, which is conserved in Loc-103275158. Thus, we could model the putative protein with its Nef-like tail domain docked to its MHC-I like alpha3 domain (i.e., on the same side of a membrane). This modeled tertiary structure is strikingly similar to the solved structure of the Nef:MHC-I CD:AP1mu transporter (Jia, 2012).(5) Nef:AP1mu binds the CD of MHC-I in trafficking MHC-I away from the trans-golgi and into the endocytic pathway in HIV-1 infected cells. The CD loop of the Loc-103275158 provisional protein conserved the nominal MHC-I CD tyrosine phosphorylation site, and it has an N-terminal SH3 domain that we docked in one conformation to its internal Nef-like domain. Here, we suggest that phosphorylation of the protein's CD-loop signals an exchange between the internal Nef-like domain and a lentiviral-Nef for binding the N-terminal SH3 domain - freeing the Nef-like domain to bind MHC-I CD. Since the 5'-tigger sequence encodes part of the pseudo alpha1/alpha2 MHC-I domain, and the 3'-tigger part of the Nef-like domain, we speculate that transposition proceeded phylogenetically disparate horizontal transfers, involving adjacent 5'- and 3'- parasitic footprints, which we also found in the Loc-103275158 orf. PMID- 27511292 TI - Cognitive Biases for Social Alcohol-Related Pictures and Alcohol Use in Specific Social Settings: An Event-Level Study. AB - BACKGROUND: Alcohol use occurs mainly among friends, in social contexts, and for social reasons. Moreover, cognitive biases, such as attentional and approach biases, have repeatedly been associated with alcohol use. This study aimed to test whether nondependent drinkers display cognitive biases for social alcohol related (SA) pictures and whether these biases are associated with alcohol use in social drinking contexts. METHODS: The visual dot probe task and stimulus response compatibility tasks were used to measure attentional and approach biases for alcohol-related pictures at baseline. Event-level alcohol use was measured using Ecological Momentary Assessments via personal smartphones. One hundred and ninety-two young adults (51.6% men; Mage = 20.73) completed the study, resulting in 11,257 assessments conducted on Thursday, Friday, and Saturday evenings for 5 consecutive weeks. RESULTS: While no overall attentional bias for alcohol-related pictures was found, young adults showed an approach bias for both social and nonsocial alcohol-related pictures. Multilevel models revealed no direct association between cognitive biases for alcohol-related pictures and alcohol use. However, higher levels of attentional bias for SA pictures were associated with more drinking when individuals were surrounded by a greater number of friends of opposite gender. Higher levels of an approach bias for SA pictures were associated with more drinking in women surrounded by a greater number of friends of the same gender. CONCLUSIONS: In a nondependent sample, cognitive biases for SA pictures could not be associated with drinking directly. However, a cognitive bias for SA pictures moderated the association between alcohol use and number of friends present. As most observed effects were gender and situation specific, replication of these effects is warranted. PMID- 27511293 TI - Click-Chemistry Based Allergen Arrays Generated by Polymer Pen Lithography for Mast Cell Activation Studies. AB - The profiling of allergic responses is a powerful tool in biomedical research and in judging therapeutic outcome in patients suffering from allergy. Novel insights into the signaling cascades and easier readouts can be achieved by shifting activation studies of bulk immune cells to the single cell level on patterned surfaces. The functionality of dinitrophenol (DNP) as a hapten in the induction of allergic reactions has allowed the activation process of single mast cells seeded on patterned surfaces to be studied following treatment with allergen specific Immunoglobulin E antibodies. Here, a click-chemistry approach is applied in combination with polymer pen lithography (PPL) to pattern DNP-azide on alkyne terminated surfaces to generate arrays of allergen. The large area functionalization offered by PPL allows an easy incorporation of such arrays into microfluidic chips. In such a setup, easy handling of cell suspension, incubation process, and read-out by fluorescence microscopy will allow immune cell activation screening to be easily adapted for diagnostics and biomedical research. PMID- 27511295 TI - Odor-induced recall of emotional memories in PTSD-Review and new paradigm for research. AB - It is clinically well known that olfactory intrusions in PTSD can be a disabling phenomena due to the involuntary recall of odor memories. Odorants can trigger involuntary recall of emotional memories as well have the potential to help diminishing emotional arousal as grounding stimuli. Despite major advances in our understanding of the function of olfactory system, the study of the relation of olfaction and emotional memory is still relatively scarce. Odor memory is long thought to be different than other types of memories such as verbal or visual memories, being more strongly engraved and more closely related to strong emotions. Brain areas mediating smell memory including orbitofrontal cortex and other parts of medial prefrontal cortex, hippocampus and amygdala, have been implicated in learning and memory and are part of a neural circuitry that is involved in PTSD. The olfactory cortex itself also plays an important role in emotional processing. Clinical observations support the notion that odor-evoked memories can play a role in the symptomatology of PTSD. This paper reviews a re emerging body of science linking odor processing to emotional processing in PTSD using the calming and grounding effect of odors as well as the use of odors in augmented exposure therapy. This results in converging evidence that olfaction is an excellent model for studying many questions germane to the field of human emotional memory processing. PMID- 27511296 TI - The novel model peptide, alphaAL14, regulates angiogenesis by inhibiting VEGFR 2 mediated signaling in HUVECs. AB - Inhibition of angiogenesis has been focused on as a strategy for treating several diseases including cancer. In this study, a novel model peptide alphaAL14 was synthesized and used to identify its inhibitory effects on angiogenesis. The anti angiogenic effects of alphaAL14 were investigated using vascular endothelial cells, HUVECs. alphaAL14 inhibited critical angiogenic processes including tubule formation, cell migration and cell invasion with no influence on cell proliferation in HUVECs. Activity of VEGFR2 was inhibited by alphaAL14 treatment in HUVECs. Additionally, activities of major subsequent downstream factors of VEGFR2 such as ERK, FAK and Akt were decreased. alphaAL14 affected expression of Rac1, Cdc42, Arp2 and WAVE2 which are involved in formation of lamellipodia. Moreover, alphaAL14 reduced NF-kappaB that can promote expression of several genes relating to cell invasion such as MMP2 and MMP9. Therefore, the results suggest that alphaAL14 has a potential to be developed as anti-angiogenic drug for treating diseases driven by abnormal angiogenesis. PMID- 27511297 TI - Multimodal MRI reveals structural connectivity differences in 22q11 deletion syndrome related to impaired spatial working memory. AB - INTRODUCTION: Impaired spatial working memory is a core cognitive deficit observed in people with 22q11 Deletion syndrome (22q11DS) and has been suggested as a candidate endophenotype for schizophrenia. However, to date, the neuroanatomical mechanisms describing its structural and functional underpinnings in 22q11DS remain unclear. We quantitatively investigate the cognitive processes and associated neuroanatomy of spatial working memory in people with 22q11DS compared to matched controls. We examine whether there are significant between group differences in spatial working memory using task related fMRI, Voxel based morphometry and white matter fiber tractography. MATERIALS AND METHODS: Multimodal magnetic resonance imaging employing functional, diffusion and volumetric techniques were used to quantitatively assess the cognitive and neuroanatomical features of spatial working memory processes in 22q11DS. Twenty six participants with genetically confirmed 22q11DS aged between 9 and 52 years and 26 controls aged between 8 and 46 years, matched for age, gender, and handedness were recruited. RESULTS: People with 22q11DS have significant differences in spatial working memory functioning accompanied by a gray matter volume reduction in the right precuneus. Gray matter volume was significantly correlated with task performance scores in these areas. Tractography revealed extensive differences along fibers between task-related cortical activations with pronounced differences localized to interhemispheric commissural fibers within the parietal section of the corpus callosum. CONCLUSIONS: Abnormal spatial working memory in 22q11DS is associated with aberrant functional activity in conjunction with gray and white matter structural abnormalities. These anomalies in discrete brain regions may increase susceptibility to the development of psychiatric disorders such as schizophrenia. Hum Brain Mapp 37:4689-4705, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27511294 TI - The need for calcium imaging in nonhuman primates: New motor neuroscience and brain-machine interfaces. AB - A central goal of neuroscience is to understand how populations of neurons coordinate and cooperate in order to give rise to perception, cognition, and action. Nonhuman primates (NHPs) are an attractive model with which to understand these mechanisms in humans, primarily due to the strong homology of their brains and the cognitively sophisticated behaviors they can be trained to perform. Using electrode recordings, the activity of one to a few hundred individual neurons may be measured electrically, which has enabled many scientific findings and the development of brain-machine interfaces. Despite these successes, electrophysiology samples sparsely from neural populations and provides little information about the genetic identity and spatial micro-organization of recorded neurons. These limitations have spurred the development of all-optical methods for neural circuit interrogation. Fluorescent calcium signals serve as a reporter of neuronal responses, and when combined with post-mortem optical clearing techniques such as CLARITY, provide dense recordings of neuronal populations, spatially organized and annotated with genetic and anatomical information. Here, we advocate that this methodology, which has been of tremendous utility in smaller animal models, can and should be developed for use with NHPs. We review here several of the key opportunities and challenges for calcium-based optical imaging in NHPs. We focus on motor neuroscience and brain-machine interface design as representative domains of opportunity within the larger field of NHP neuroscience. PMID- 27511298 TI - Glycerol metabolism in hypersaline environments. AB - Glycerol is a key compound for the understanding of the microbiology of hypersaline environments. At the highest salt concentrations the main or even sole primary producer is the green unicellular alga Dunaliella, which uses photosynthetically produced glycerol as osmotic stabilizer and compatible solute. Glycerol can be expected to be a major carbon source available to the heterotrophic communities of Archaea and Bacteria in hypersaline ecosystems. Use of Dunaliella has even been explored for the commercial production of glycerol. This article reviews our current understanding of glycerol metabolism in Dunaliella and of the ways glycerol can be degraded by heterotrophic prokaryote communities under aerobic and under anaerobic conditions. Dunaliella-derived glycerol may also be the key toward long-term survival of heterotrophic prokaryotes in fluid inclusions within salt crystals. PMID- 27511299 TI - Cardiac signal estimation based on the arterial and venous pressure signals of a hemodialysis machine. AB - Continuous cardiac monitoring is usually not performed during hemodialysis treatment, although a majority of patients with kidney failure suffer from cardiovascular disease. In the present paper, a method is proposed for estimating a cardiac pressure signal by combining the arterial and the venous pressure sensor signals of the hemodialysis machine. The estimation is complicated by the periodic pressure disturbance caused by the peristaltic blood pump, with an amplitude much larger than that of the cardiac pressure signal. Using different techniques for combining the arterial and venous pressure signals, the performance is evaluated and compared to that of an earlier method which made use of the venous pressure only. The heart rate and the heartbeat occurrence times, determined from the estimated cardiac pressure signal, are compared to the corresponding quantities determined from a photoplethysmographic reference signal. Signals from 9 complete hemodialysis treatments were analyzed. For a heartbeat amplitude of 0.5 mmHg, the median absolute deviation between estimated and reference heart rate was 1.3 bpm when using the venous pressure signal only, but dropped to 0.6 bpm when combining the pressure signals. The results show that the proposed method offers superior estimation at low heartbeat amplitudes. Consequently, more patients can be successfully monitored during treatment without the need of extra sensors. The results are preliminary, and need to be verified on a separate dataset. PMID- 27511300 TI - Pinch-off of microfluidic droplets with oscillatory velocity of inner phase flow. AB - When one liquid is introduced into another immiscible one, it ultimately fragments due to hydrodynamic instability. In contrast to neck pinch-off without external actuation, the viscous two-fluid system subjected to an oscillatory flow demonstrates higher efficiency in breaking fluid threads. However, the underlying dynamics of this process is less well understood. Here we show that the neck thinning rate is accelerated by the amplitude of oscillation. By simply evaluating the momentum transfer from external actuation, we derive a dimensionless pre-factor to quantify the accelerated pinch-off. Our data ascribes the acceleration to the non-negligible inner fluid inertia, which neutralizes the inner phase viscous stress that retards the pinch-off. Moreover, we characterize an equivalent neck-thinning behavior between an actuated system and its unactuated counterpart with decreased viscosity ratio. Finally, we demonstrate that oscillation is capable of modulating satellite droplet formation by shifting the pinch-off location. Our study would be useful for manipulating fluids at microscale by external forcing. PMID- 27511301 TI - Monodisperse Cylindrical Micelles of Controlled Length with a Liquid-Crystalline Perfluorinated Core by 1D "Self-Seeding". AB - Precise control over the morphology and dimensions of block copolymer (BCP) micelles has attracted interest due to the potential of this approach to generate functional nanostructures. Incorporation of liquid crystalline (LC) block can provide additional ways to vary micellar morphologies, but the formation of uniform micelles with controllable dimensions from LC BCPs has not yet been realized. Herein, we report the preparation of monodisperse cylindrical micelles with a LC poly(2-(perfluorooctyl)ethyl methacrylate (PFMA) core via a fragmentation-thermal annealing (F-TA) process, resembling the "self-seeding" process of crystalline BCP micelles. The average length of the cylinders increases with annealing temperature, with a narrow length distribution (Lw /Ln <1.1). We also demonstrate the potential application of the cylinders with LC cores as a cargo-carrier by the successful incorporation of a hydrophobic fluorescent dye tagged with a fluorooctyl group. PMID- 27511302 TI - Geometrical modified nesbit corporoplasty to correct different types of penile curvature: description of the surgical procedure based on geometrical principles and long-term results. AB - We present the use of a modified corporoplasty, based on geometrical principles, to determine the exact site for the incision in the tunica or plaque and the exact amount of albuginea for overlaying to correct with extreme precision the different types of congenital or acquired penile curvature due to Peyronie's disease. To describe our experience with a new surgical procedure for the enhancement of penile curvature avoiding any overcorrection or undercorrection. Between March 2004 and April 2013, a total of 74 patients underwent the geometrical modified corporoplasty. All patients had congenital curvature until 90 degrees or acquired stable penile curvature 'less' than 60 degrees , that made sexual intercourse very difficult or impossible, normal erectile function, absence of hourglass or hinge effect. Preoperative testing included a physical examination, 3 photographs (frontal, dorsal and lateral) of penis during erection, a 10 mcg PGE1-induced erection and Doppler ultrasound, administration of the International Index of Erectile Function (IIEF-15) questionnaire. A follow up with postoperative evaluation at 12 weeks, 12 and 24 months, included the same preoperative testing. Satisfaction rates were better assessed with the use of validated questionnaire such as the International Erectile Dysfunction Inventory of the Treatment Satisfaction (EDITS). Statistical analysis with Student's t-test was performed using commercially available, personal computer software. A total of 25 patients had congenital penile curvature with a mean deviation of 46.8 degrees (range 40-90), another 49 patients had Peyronie's disease with a mean deviation of 58.4 (range 45-60). No major complications were reported. Postoperative correction of the curvature was achieved in all patients (100%). Neither undercorrection nor overcorrection were recorded. No significant relapse (curvature>15 degrees ) occurred in our patients. Shortening of the penis was reported by 74% but did not influence the high overall satisfaction of 92% (patients completely satisfied with their sexual life). The erectile function was analyzed in both groups, Student's t-test showed a significant improvement in erectile function, preoperative average IIEF-15 scores were 17.43+/-4.67, whereas postoperatively it was 22.57+/-4.83 (P=0.001). This geometrical modified Nesbit corporoplasty is a valid therapy which allows penile straightening. The geometric principles make the technique reproducible in multicentre studies. PMID- 27511304 TI - A crystalline anionic complex of scandium nitride endometallofullerene: experimental observation of single-bonded (Sc3N@Ih-C80(-))2 dimers. AB - Reduction of scandium nitride clusterfullerene, Sc3N@Ih-C80, by sodium fluorenone ketyl in the presence of cryptand[2,2,2] allows the crystallization of the {cryptand[2,2,2](Na(+))}2(Sc3N@Ih-C80(-))2.2.5C6H4Cl2 (1) salt. The Sc3N@Ih-C80( ) radical anions are dimerized to form single-bonded (Sc3N@Ih-C80(-))2 dimers. PMID- 27511303 TI - Molecular immunology profiles of monkeys following xenografting with the islets and heart of alpha-1,3-galactosyltransferase knockout pigs. AB - Effective immunosuppression strategies and genetically modified animals have been used to prevent hyperacute and acute xenograft rejection; however, the underlying mechanisms remain unknown. In this study, we evaluated the expression of a comprehensive set of immune system-related genes (89 genes, including five housekeeping genes) in the blood of cynomolgus monkeys (~5 yr old) used as graft recipients, before and after the xenografting of the islets and heart from single and double alpha-1,3-galactosyltransferase (GalT) knockout (KO) pigs (<6 weeks old). The immunosuppressive regimen included administration of cobra venom factor, anti-thymocyte globulin, rituximab, and anti-CD154 monoclonal antibodies to recipients before and after grafting. Islets were xenografted into the portal vein in type 1 diabetic monkeys, and the heart was xenografted by heterotopic abdominal heart transplantation. Genes from recipient blood were analyzed using RT(2) profiler PCR arrays and the web-based RT(2) profiler PCR array software v.3.5. Recipients treated with immunosuppressive agents without grafting showed significant downregulation of CCL5, CCR4, CCR6, CD4, CD40LG, CXCR3, FASLG, CXCR3, FOXP3, GATA3, IGNG, L10, IL23A, TRAF6, MAPK8, MIF, STAT4, TBX21, TLR3, TLR7, and TYK2 and upregulation of IFNGR1; thus, genes involved in protection against viral and bacterial infection were downregulated, confirming the risk of infection. Notably, C3-level control resulted in xenograft failure within 2 days because of a 7- to 11-fold increase in all xenotransplanted models. Islet grafting using single GalT-KO pigs resulted in upregulation of CXCL10 and MX1, early inflammation, and acute rejection-associated signals at 2 days after xenografting. We observed at least 5-fold upregulation in recipients transplanted with islets grafts from single (MX1) or double (C3, CCR8, IL6, IL13, IRF6, CXCL10, and MX1) GalT-KO pigs after 77 days; single GalT-KO incurred early losses owing to immune attacks. Our results suggest that this novel, simple, non invasive, and time-efficient procedure (requiring only 1.5 ml blood) for evaluating graft success, minimizing immune rejection, and blocking infection. PMID- 27511305 TI - Triboluminescence and crystal structure of the complex [Eu(NO3 )3 (HMPA)3 ]: role of cleavage planes. AB - The atomic structure of crystals of the [Eu(NO3 )3 (HMPA)3 ] [hexamethylphosphotriamide (HMPA)] complex characterized by an intensive luminescence and triboluminescence was determined using X-ray structural analysis. Noncentrosymmetric crystals have a monoclinic syngony: a = 16.0686 (3), b = 11.0853 (2), c = 20.9655 A (4), beta = 93.232 degrees (1), space group P21 , Z = 4, rhocalc = 1.560 g/cm3. The crystal structure is represented by individual S18 N54 EuN12 O12 P3 complexes linked through van der Waals interactions with clearly expressed cleavage planes. The Eu(III) atom coordination polyhedron reflected the state of a distorted square antiprism. Structural aspects of the suggested model, including formation of triboluminescence properties, were considered and the role of the cleavage planes was discussed. PMID- 27511306 TI - THE ENIGMA OF ETHIOPIAN SEX RATIOS AT BIRTH. AB - This study analysed sex ratios at birth (defined as the number of male births per 100 female births) using data on children ever-born from three censuses conducted in Ethiopia in 1984, 1994 and 2007. The results showed very high values by any standard, with an average of 108.4 for a sample of some 8.2 million births, with somewhat lower values in urban areas. Analysis of socioeconomic correlates revealed that the sex ratio varied very much by household wealth, from about 110 for very poor women to about 102 for wealthier women. The high value of the sex ratio at birth in Ethiopia could be explained by poverty, used as a proxy for poor nutritional status. In multivariate analysis, the effects of living in urban areas and of maternal education were less important than household wealth. Among the many ethno-linguistic groups, the Nilotic family had higher sex ratios than other groups. The results were confirmed using data from DHS surveys conducted in the country, and by the analysis of children still living at time of census. PMID- 27511307 TI - The effect of counteranions on the molecular structures of phosphanegold(i) cluster cations formed by polyoxometalate (POM)-mediated clusterization. AB - The effect of counteranions on the molecular structures of phosphanegold(i) cluster cations formed by polyoxometalate (POM)-mediated clusterization was investigated. A novel intercluster compound, [{(AuLCl)2(MU-OH)}2]3[alpha PMo12O40]2.3EtOH (1-PMo12), was obtained as orange-yellow plate crystals in 12.0% yield from a 6 : 1 molar ratio reaction of the monomeric phosphanegold(i) carboxylato complex [Au(RS-pyrrld)(LCl)] (RS-Hpyrrld = RS-2-pyrrolidone-5 carboxylic acid; LCl = tris(4-chlorophenyl)phosphane) in CH2Cl2 with the free acid-form of Keggin polyoxometalate (POM), H3[alpha-PMo12O40].14H2O. An EtOH/H2O (5 : 1, v/v) solvent mixture was used. The dimeric cation [{(AuLCl)2(MU OH)}2](2+) in 1-PMo12 was in a parallel-edge arrangement that was formed by self assembly through the inter-cationic aurophilic interactions of the MU-OH-bridged dinuclear phosphanegold(i) cation. The POM anion in 1-PMo12 was successfully exchanged with a smaller PF6(-) anion by the use of an anion-exchange resin. POM free, colorless block crystals of [{(AuLCl)3(MU3-O)}2](PF6)2.4CH2Cl2 (2-PF6) were obtained by vapor diffusion in 14.1% yield. During the synthesis of 2-PF6, a compound with mixed counteranions (one POM and one PF6(-) anion), i.e. [{(AuLCl)4(MU4-O)}]2[alpha-PMo12O40]PF6 (3-PMo12PF6), was obtained in 66.4% yield. Both products were characterized by elemental analysis, TG/DTA, FT-IR, (31)P{(1)H} NMR, (1)H NMR, and X-ray crystallography. X-ray crystallography revealed that the countercation in 2-PF6 was the dimeric cation of the MU3-O bridged tris{phosphanegold(i)} species, whereas that in 3-PMo12PF6 consisted of an unusual MU4-O-bridged tetragonal-pyramidal tetrakis{phosphanegold(i)} cation. Therefore, we concluded that the POM anion significantly contributed to the stabilization of these countercations (parallel-edged arrangement in 1-PMo12 and MU4-O-bridged tetragonal-pyramid in 3-PMo12PF6). Moreover, the previously reported yellow crystals of [{(AuLF)2(MU-OH)}2]3[PMo12O40]2.3EtOH (4-PMo12: LF = tris(4-fluoro phenyl)phosphane) were successfully converted to the POM-free crystalline OTf(-) salt [{(AuLF)2(MU-OH)}2](OTf)2.0.5Et2O (4-OTf) by the use of an anion-exchange resin. X-ray crystallography also revealed that the parallel edge arrangement of the dimeric cation in 4-PMo12 was converted to the crossed edge arrangement of that in 4-OTf. These results illustrate that the AuOPOM and hydrogen-bonding (C-HOPOM and O-HOPOM) interactions between the phosphanegold(i) cluster cation and the Keggin POM anion in the solid state significantly contribute to the structure, composition, and stability of the phosphane gold(i) cluster cations in 4-PMo12. PMID- 27511308 TI - Hoxa-10 and Cyclin D3 Overexpression in the Decidual Reaction in a Superovulation Protocol in Young Adult C57BL/6J Mice. AB - Following the performance of a superovulation protocol, multiple nodules were observed bilaterally in the uterine horns of 31 of 276 (11.2%) C57BL/6 J female mice aged 8.5 +/- 0.6 (mean and standard error of mean) weeks. These lesions prevented embryo collection, and the uterine decidual reaction was suspected. Samples of pathological uteri (n = 20) and the normal genital tracts of donors treated with a similar superovulation protocol (control group, n = 10) were collected. Immunohistochemistry was performed to evaluate pancytokeratin, desmin, vimentin, progesterone receptor (PR), estrogen receptor alpha (ERalpha), Ki-67, cyclin D3 and c-Myc expression, as well as quantitative polymerase chain reaction to assess cyclin D3, Hoxa-10 and heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA expression. The uterine decidual reaction presented a high degree of structural organization and specifically affected the antimesometrial region of the endometrium. The abnormal decidual cells were large polygonal cells that were frequently polyploid or binucleated and strongly positive for desmin. Immunohistochemistry showed higher Ki-67 proliferation index and higher expression of PR and cyclin D3 in decidual cells in the antimesometrial aspect of the endometrium, compared to nondecidualized endometrial stromal cells in the mesometrial aspect of affected uteri, and compared to endometrial stromal cells in healthy uteri. High expression of cyclin D3 and Hoxa-10 mRNA was also observed in uteri affected by the decidual reaction. These results suggest that PR overexpression in endometrial stromal cells, likely due to high progesterone levels, triggers cyclin D3 and Hoxa-10 overexpression, which may be involved in the pathological mechanisms of the mouse uterine decidual reaction. PMID- 27511309 TI - Amyloid-Producing Odontogenic Tumors of the Facial Skin in Three Cats. AB - Amyloid-producing odontogenic tumors (APOTs) of the facial skin were diagnosed in 3 domestic cats. The neoplasms had the histopathological characteristics of the odontogenic tumor. The neoplastic cells were present in irregular islands, strands, and sheets. The peripheral neoplastic cells of the islands and strands were arranged in a palisading fashion, while the central cells were polyhedral to stellate and randomly arranged. Multiple spherules of homogeneous eosinophilic material were closely apposed to the neoplastic epithelial cells. The spherules stained with Congo red and produced an apple green birefringence under polarization microscopy, indicative of amyloid. Immunohistochemically, amyloid materials of the neoplasms reacted with polyclonal antibodies for ameloblastin, amelogenin, and sheathlin antibodies. Neoplastic epithelial cells also reacted with antiameloblastin, amelogenin, and sheathlin antibodies, with varied intensity. The histopathological and immunohistochemical characteristics of dermal neoplasms of the 3 cats were analogous to those of APOTs reported in the dog and the cat. PMID- 27511310 TI - Pathogenesis of Enterococcal Spondylitis Caused by Enterococcus cecorum in Broiler Chickens. AB - Enterococcal spondylitis (ES) is a disease of commercial broiler chickens, with a worldwide distribution. Symmetrical hind limb paralysis typical of ES results from infection of the free thoracic vertebra (FTV) by pathogenic strains of Enterococcus cecorum . To determine the pathogenesis of ES, birds with natural and experimental ES were studied over time. In natural disease, case birds (n = 150) from an affected farm and control birds (n = 100) from an unaffected farm were evaluated at weeks 1-6. In control birds, intestinal colonization by E. cecorum began at week 3. In case birds, E. cecorum was detected in intestine and spleen at week 1, followed by infection of the FTV beginning at week 3. E. cecorum isolates recovered from intestine, spleen, and FTV of case birds had matching genotypes, confirming that intestinal colonization with pathogenic strains precedes bacteremia and infection of the FTV. Clinical intestinal disease was not required for E. cecorum bacteremia. In 1- to 3-week-old case birds, pathogenic E. cecorum was observed within osteochondrosis dissecans (OCD) lesions in the FTV. To determine whether OCD of the FTV was a risk factor for ES, 214 birds were orally infected with E. cecorum, and the FTV was evaluated histologically at weeks 1-7. Birds without cartilage clefts of OCD in the FTV did not develop ES; while birds with OCD scores >=3 were susceptible to lesion development. These findings suggest that intestinal colonization, bacteremia, and OCD of the FTV in early life are crucial to the pathogenesis of ES. PMID- 27511311 TI - Wooden Breast Myodegeneration of Pectoralis Major Muscle Over the Growth Period in Broilers. AB - Wooden breast (WB) myopathy of broiler chickens is a myodegenerative disease of an unknown etiology and is macroscopically characterized by a hardened consistency of the pectoralis major muscle. Our aim was to describe the development and morphology of WB over the growth period in broilers. Additionally, the effect of restricted dietary selenium on the occurrence of WB was examined by allocating the birds in 2 dietary groups: restricted and conventional level of selenium. The experiment included 240 male broilers that were euthanized at ages of 10, 18, 24, 35, 38, or 42 days and evaluated for WB based on abnormal hardness of the pectoralis major muscle. The severity and the distribution of the lesion and presence of white striping were recorded. The first WB cases were seen at 18 days; 13/47 birds (28%) were affected and the majority exhibited a mild focal lesion. In subsequent age groups the WB prevalence varied between 48% and 73% and the lesion was usually diffuse and markedly firm. White striping often coexisted with WB. Histological evaluation performed on 111 cases revealed a significant association of myodegeneration and lymphocytic vasculitis with WB. Vasculitis and perivascular cell infiltration were restricted to the veins. Restricted dietary selenium did not affect the occurrence of WB ( P = .44). Our results indicate that WB starts focally and spreads to form a diffuse and more severe lesion. PMID- 27511312 TI - Syncytial Hepatitis of Tilapia ( Oreochromis niloticus L.) is Associated With Orthomyxovirus-Like Virions in Hepatocytes. AB - Using transmission electron microscopy (TEM), the presented work expands on the ultrastructural findings of an earlier report on "syncytial hepatitis," a novel disease of tilapia (SHT). Briefly, TEM confirmed the presence of an orthomyxovirus-like virus within the diseased hepatocytes but not within the endothelium. This was supported by observing extracellular and intracellular (mostly intraendosomal), 60-100 nm round virions with a trilaminar capsid containing up to 7 electron-dense aggregates. Other patterns noted included enveloped or filamentous virions and virion-containing cytoplasmic membrane folds, suggestive of endocytosis. Patterns atypical for orthymyxovirus included the formation of syncytia and the presence of virions within the perinuclear cisternae (suspected to be the Golgi apparatus). The ultrastructural morphology of SHT-associated virions is similar to that previously reported for tilapia lake virus (TiLV). A genetic homology was investigated using the available reverse transcriptase polymerase chain reaction (RT-PCR) probes for TiLV and comparing clinically sick with clinically normal fish and negative controls. By RT-PCR analysis, viral nucleic acid was detected only in diseased fish. Taken together, these findings strongly suggest that a virus is causally associated with SHT, that this virus shares ultrastructural features with orthomyxoviruses, and it presents with partial genetic homology with TiLV (190 nucleotides). PMID- 27511313 TI - Canine Nervous System Lymphoma Subtypes Display Characteristic Neuroanatomical Patterns. AB - Primary and secondary nervous system involvement occurs in 4% and 5%-12%, respectively, of all canine non-Hodgkin lymphomas. The recent new classification of canine malignant lymphomas, based on the human World Health Organization classification, has been endorsed with international acceptance. This histological and immunocytochemical classification provides a unique opportunity to study the histologic anatomic distribution patterns in the central and peripheral nervous system of these defined lymphoma subtypes. In this study, we studied a cohort of 37 dogs with lymphoma, which at necropsy had either primary (n = 1, 2.7%) or secondary (n = 36; 97.3%) neural involvement. These T- (n = 16; 43.2%) or B-cell (n = 21; 56.8%) lymphomas were further classified into 12 lymphoma subtypes, with predominant subtypes including peripheral T-cell lymphoma (PTCL) or diffuse large B-cell lymphoma (DLBCL), respectively. This systematic study identified 6 different anatomically based histologically defined patterns of lymphoma infiltration in the nervous system of dogs. Different and distinct combinations of anatomical patterns correlated with specific lymphoma subtypes. Lymphoma infiltration within the meningeal, perivascular, and periventricular compartments were characteristic of DLBCL, whereas peripheral nerve involvement was a frequent feature of PTCL. Similarly cell counts above 64 cells/MUL in cerebrospinal samples correlated best with marked meningeal and periventricular lymphoma infiltration histologically. Prospective studies are needed in order to confirm the hypothesis that these combinations of histological neuroanatomic patterns reflect targeting of receptors specific for the lymphoma subtypes at these various sites. PMID- 27511314 TI - Attitudes toward carrier screening and prenatal diagnosis for recessive hereditary deafness among the educated population in urban China. AB - Approximately 80% of hereditary deafness is recessive, in which case most mutation carriers were unaware of their carrier status. Though parental attitudes toward genetic testing and prenatal diagnosis are overall positive in those with deaf children, there is little information about that in the general population. To this end, we designed a self-completed questionnaire and distributed it in two colleges in Shanghai, China. A total of 975 completed surveys were returned in print or online forms. Our results showed that 98.7% of the respondents without family history of early onset deafness did not know or underestimated their likelihood to carry a recessive mutation in common deafness genes. After brief written information was given using GJB2, the most common recessive deafness gene as the example, 67.7% of the respondents expressed interest in knowing if they are carriers of GJB2 mutations through genetic testing. In hypothetical circumstance of carrying a recessive GJB2 mutation, 86.9% would suggest their partners to also take the test. In case that both were carriers, 88.7% would consider prenatal diagnosis and 80.7% would consider terminating an affected pregnancy. On the basis of these results, it was concluded that despite the poor awareness to the risk of recessive hereditary deafness, the majority of the educated population in urban China likely hold a positive view toward carrier screening and prenatal diagnosis of recessive deafness genes. (c) 2016 Wiley Periodicals, Inc. PMID- 27511315 TI - A universal explanation of tunneling conductance in exotic superconductors. AB - A longstanding mystery in understanding cuprate superconductors is the inconsistency between the experimental data measured by scanning tunneling spectroscopy (STS) and angle-resolved photoemission spectroscopy (ARPES). In particular, the gap between prominent side peaks observed in STS is much bigger than the superconducting gap observed by ARPES measurements. Here, we reconcile the two experimental techniques by generalising a theory which was previously applied to zero-dimensional mesoscopic Kondo systems to strongly correlated two dimensional (2D) exotic superconductors. We show that the side peaks observed in tunneling conductance measurements in all these materials have a universal origin: They are formed by coherence-mediated tunneling under bias and do not directly reflect the underlying density of states (DOS) of the sample. We obtain theoretical predictions of the tunneling conductance and the density of states of the sample simultaneously and show that for cuprate and pnictide superconductors, the extracted sample DOS is consistent with the superconducting gap measured by ARPES. PMID- 27511316 TI - Donor liver steatosis: A risk factor for early new-onset diabetes after liver transplantation. AB - AIMS/INTRODUCTION: To investigate whether donor liver steatosis increases the incidence of new-onset diabetes after transplantation (NODAT) in liver transplant recipients. MATERIALS AND METHODS: We retrospectively analyzed liver transplant recipients at Zhongshan Hospital, Shanghai, China, from April 2001 to December 2014. The final analysis involved 763 patients. The cumulative incidence of NODAT at 1, 3, 5 and 10 years after liver transplantation was investigated. Furthermore, according to the findings of donor liver biopsy before transplantation, patients were divided into steatotic and non-steatotic donor liver groups, and NODAT incidence was compared between these groups. Multivariate Cox regression was used to explore the risk factors for NODAT in the patients. RESULTS: Of the 763 donors, 309 (40.5%) had liver steatosis. At the end of follow up, 130 (42.1%) patients in the steatotic donor liver group developed NODAT, an incidence that exceeded that in the non-steatotic donor liver group (P = 0.001). The cumulative incidence of NODAT among all patients at 1, 3, 5, and 10 years after transplantation was 33, 43, 50 and 56%, respectively. The cumulative incidences of NODAT at 1, 3, 5 and 10 years in the steatotic donor liver group were significantly higher than those in the non-steatotic donor liver group (P = 0.003). Multivariate Cox regression analyses showed that donor liver steatosis was an independent risk factor for NODAT among liver transplant recipients, after other potential risk factors were adjusted for (hazard ratio 1.774, 95% confidence interval: 1.025-3.073; P = 0.041). CONCLUSIONS: Donor liver steatosis increases NODAT incidence among liver transplant recipients. PMID- 27511318 TI - Effective implementation of a patient blood management programme for platelets. AB - OBJECTIVES: To implement a patient blood management (PBM) programme in platelet transfusion. AIMS: To improve the appropriate use of blood components, reduce wastage and generate savings. BACKGROUND: PBM is a multidisciplinary, evidence based approach to optimising the care of patients who need blood transfusion and to use blood products appropriately. Strategies for PBM ensure that patients receive the best possible treatment with the transfusion of components when indicated, at the same time avoiding or reducing unnecessary transfusions. Typically, PBM initiatives have addressed the use of red cells. PBM initiatives in platelets (PBM-P) are an important aspect of Transfusion Medicine. METHODS: We present data from an initiative for PBM-platelets (PBM-P) comprising a service improvement programme through the role of a 'platelet co-ordinator' (PBM-Pc) to optimise the use of platelets in a large complex tertiary care hospital in a National Health Service (NHS) setting. RESULTS: Analysis at 18 months of the role showed sustained improvement in compliance with quality standards defined by British Committee for Standards in Haematology (BCSH) guidelines and significant financial savings due to improved use and reduced wastage. The appropriate use of platelets increased by 17, 23 and 18% in the prophylactic, pre-procedure and peri procedure categories, respectively. Importantly, despite concurrent increases of patient activity, platelet issues and cost reduced by 21% over the period of analysis. CONCLUSIONS: Our model has been efficacious in delivering the effective stewardship of platelets and can be successfully implemented in NHS. PMID- 27511319 TI - Bullous pemphigoid developed in a patient with prurigo nodularis. PMID- 27511317 TI - Potential fluid biomarkers for pathological brain changes in Alzheimer's disease: Implication for the screening of cognitive frailty. AB - Cognitive frailty (CF) overlaps with early neuropathological alterations associated with aging-related major neurocognitive disorders, including Alzheimer's disease (AD). Fluid biomarkers for these pathological brain alterations allow for early diagnosis in the preclinical stages of AD, and for objective prognostic assessments in clinical intervention trials. These biomarkers may also be helpful in the screening of CF. The present study reviewed the literature and identified systematic reviews of cohort studies and other authoritative reports. The selection criteria for potentially suitable fluid biomarkers included: i) Frequent use in studies of fluid-derived markers and ii) evidence of novel measurement techniques for fluid-derived markers. The present study focused on studies that assessed these biomarkers in AD, mild cognitive impairment and non-AD demented subjects. At present, widely used fluid biomarkers include cerebrospinal fluid (CSF), total tau, phosphorylated tau and amyloid-beta levels. With the development of novel measurement techniques and improvements in understanding regarding the mechanisms underlying aging-related major neurocognitive disorders, numerous novel biomarkers associated with various aspects of AD neuropathology are being explored. These include specific measurements of Abeta oligomer or monomer forms, tau proteins in the peripheral plasma and CSF, and novel markers of synaptic dysfunction, neuronal damage and apoptosis, neuronal activity alteration, neuroinflammation, blood brain barrier dysfunction, oxidative stress, metabolites, mitochondrial function and aberrant lipid metabolism. The proposed panels of fluid biomarkers may be useful in the early diagnosis of AD, prediction of the progression of AD from preclinical stages to the dementia stage, and the differentiation of AD from non-AD dementia. In combination with physical frailty, the present study surmised that these biomarkers may also be used as biomarkers for CF, thus contribute to discovering causes and informing interventions for cognitive impairment in individuals with CF. PMID- 27511320 TI - The impact of cognitive reserve in the outcome of first-episode psychoses: 2-year follow-up study. AB - The concept of cognitive reserve (CR) suggests that the premorbid intelligence quotient (IQ), years of education and leisure activities provide more efficient cognitive networks and therefore allow a better management of some conditions associated to cognitive impairment. Fifty-two DSM-IV diagnosed FEP subjects were matched with 41 healthy controls by age, gender and parental socio-economic status. All subjects were assessed clinically, neuropsychologically and functionally at baseline and after a two-year follow-up. To assess CR at baseline, three proxies have been integrated: premorbid IQ, years of education occupation and leisure activities. Higher CR was associated with better cognitive, functional and clinical outcomes at baseline. The CR proxy was able to predict working memory, attention, executive functioning, verbal memory and global composite cognitive score accounting for 48.9%, 19.1%, 16.9%, 10.8% and 14.9% respectively of the variance at two-year follow-up. CR was also significantly predictive of PANSS negative scale score (12.5%), FAST global score (13.4%) and GAF (13%) at two-year follow-up. In addition, CR behaved as a mediator of working memory (B=4.123) and executive function (B=3.298) at baseline and of working memory (B=5.034) at 2-year follow-up. An additional analysis was performed, in order to test whether this mediation could be attributed mainly to the premorbid IQ. We obtained that this measure was not enough by itself to explain this mediation. CR may contribute to neuropsychological and functional outcome. Specific programs addressed to improve cognition and functioning conducted at the early stages of the illness may be helpful in order to prevent cognitive and functional decline. PMID- 27511321 TI - It's only a matter of time: the altered role of subsidies in a warming world. AB - Clockwise from left: an experimental stream reach from the study, highlighting the fences used to contain fish as the apex predator; a cutthroat trout from the experiment, the only fish species in the study streams; stomach contents from a fish, highlighting the major role of the terrestrial subsidy (mealworms) in the diet. In Focus: Sato, T., El-Sabaawi, R.W., Campbell, K., Ohta, T. & Richardson, J.S. (2016) A test of the effects of timing of a pulsed resource subsidy on stream ecosystems. Journal of Animal Ecology, 85, 1136-1146. Cross-ecosystem subsidies play a critical role in maintaining the structure and functioning of natural communities, especially if they are asynchronous with resource production in the recipient ecosystem. Sato et al. () use a large-scale field experiment to show that changes in the timing of a pulsed terrestrial subsidy can alter stream dynamics from the individual to the ecosystem level. With increasing evidence that global warming will alter the timing, magnitude and frequency of allochthonous inputs, these findings make an important contribution to our understanding of how such changes will reverberate throughout ecosystems that depend on subsidies. PMID- 27511322 TI - Erratum. PMID- 27511324 TI - Two-Dimensional Skyrmion Lattice Formation in a Nematic Liquid Crystal Consisting of Highly Bent Banana Molecules. AB - We synthesized a novel banana-shaped molecule based on a 1,7-naphthalene central core that exhibits a distinct mesomorphism of the nematic-to-nematic phase transition. Both the X-ray profile and direct imaging of atomic force microscopy (AFM) investigations clearly indicates the formation of an anomalous nematic phase possessing a two-dimensional (2D) tetragonal lattice with a large edge (ca. 59 A) directed perpendicular to the director in the low-temperature nematic phase. One plausible model is proposed by an analogy of skyrmion lattice in which two types of cylinders formed from left- and right-handed twist-bend helices stack into a 2D tetragonal lattice, diminishing the inversion domain wall. PMID- 27511325 TI - Simvastatin's effects on survival and outcome in traumatic braininjury patients: a comparative study. AB - BACKGROUND/AIM: Mortality and morbidity still remain high in patients with traumatic brain injuries. Understanding the role of new treatments in these patients is critical. The aim of this study was to determine the effect of simvastatin on survival and outcome in traumatic brain injury patients. MATERIALS AND METHODS: Forty-four patients were assigned to receive either simvastatin or a placebo. The serum interleukin-6 and C-reactive protein levels were measured at the first 24 h and 48 h after trauma. All data, including the Glasgow Coma Scale score, survival at discharge, length of intensive care unit stay, and duration of mechanical ventilation, were collected. The effect of simvastatin on the collected data was then investigated. RESULTS: The Glasgow Coma Scale level at discharge was significantly higher in the simvastatin group. The overall mortality rate, duration of mechanical ventilation, and length of intensive care unit stay were similar between the 2 groups. The C-reactive protein concentration 48 h after trauma was significantly lower in the simvastatin group, but there was no significant difference according to the interleukin-6 level 48 h after trauma between the 2 groups. CONCLUSION: Simvastatin could be suggested as an adjunctive therapy in traumatic brain injury patients. PMID- 27511326 TI - CRP, HbA1c, lipid, and biochemical parameters and their relation with maternal visceral adipose tissue and subcutaneous fat tissue thickness. AB - BACKGROUND/AIM: The aim of this study was to find whether maternal visceral tissue (VAT) or subcutaneous fat tissue (SCFT) thicknesses are associated with CRP, HbA1c, lipid, and biochemical parameters in the first trimester of pregnancy. MATERIALS AND METHODS: Ninety pregnant women were enrolled. Body mass index (BMI), VAT, and SCFT were measured. The best cut-off points for grouping subjects were found to be 4 cm for VAT and 2 cm for SCFT. Venous blood samples were collected. RESULTS: VAT was higher than 4 cm in all cases with high BMIs. High CRP and HbA1c were found in 45.5% and 18.2% of cases with VAT over 4 cm, respectively. CONCLUSION: Besides overall obesity, VAT thickness is the most important parameter. Decreasing obesity may prevent pathologies caused by inflammation during pregnancy as well as decrease the risk for future metabolic and cardiovascular disorders. PMID- 27511327 TI - The relation between serum cathepsin D level and carotid intima-media thickness in nondiabetic hypertensive patients. AB - BACKGROUND/AIM: We aimed to investigate the relation between carotid intima-media thickness (CIMT) and serum cathepsin D level in hypertensive patients. MATERIALS AND METHODS: This was a cross-sectional study of 74 hypertensive patients (22 males and 52 females, with a mean age of 51.86 +/- 11.75 years). Serum levels of cathepsin D were measured with an enzyme-linked immunosorbent assay. CIMT measurements were taken from 3 different points: right and left common carotid arteries, bifurcation, and the first 2 cm of the internal carotid artery. Mean CIMT was calculated by averaging the measurements taken 3 times from each carotid artery. RESULTS: Mean CIMT value was 0.76 +/- 0.15 mm, and median cathepsin D level was 190.3 (12.8-2681.3) ng/mL. A marked positive correlation was found between cathepsin D levels and CIMT (r = 0.331, P = 0.04). In multivariate linear regression analysis, cathepsin D, albumin levels, and the duration of hypertension were significant predictors of CIMT (P = 0.017, P = 0.008, and P = 0.043, respectively). CONCLUSIONS: Increased serum cathepsin D level was found to be associated with CIMT in nondiabetic hypertensive patients. PMID- 27511328 TI - Genotypes and virulence factors of Candida species isolated from oralcavities of patients with type 2 diabetes mellitus. AB - BACKGROUND/AIM: This study compared the genotypes and virulence factors of Candida species isolated from oral cavities of healthy individuals and patients with diabetes mellitus (DM). MATERIALS AND METHODS: A total of 142 healthy individuals and 73 diabetic patients participated in this study. Study populations were classified into 4 groups as follows: Group I - Healthy, without caries; Group II - Healthy, with caries; Group III - DM, with caries; Group IV - DM, without caries. Diabetic patients' blood glucose and hemoglobin A1c concentrations were determined. Identification of Candida species was performed with conventional methods. Biofilm production, proteinase, phospholipase, and esterase were analyzed. The genetic diversity of Candida species was established using rep-PCR. RESULTS: The most isolated species was Candida albicans. There were statistical differences in terms of isolated Candida frequency between healthy subjects and diabetic patients. There was no statistical difference between the virulence factors of groups. Twelve genotypes were determined. While there were statistical differences in aerobe biofilm production, proteinase, and phospholipase activity between genotypes, there were no statistical differences in anaerobe biofilm production and esterase activity between genotypes. CONCLUSION: Diabetes has no effect on the activities of virulence factors of Candida species. Different genotypes of Candida albicans exhibited different virulence activities. PMID- 27511329 TI - Host immune responses and peritumoral stromal reactions in different basal cell carcinoma subtypes: histopathological comparison of basosquamous carcinoma and high-risk and low-risk basal cell carcinoma subtypes. AB - BACKGROUND/AIM: The literature does not include sufficient data on the associations between host immune responses and stromal reactions in different basal cell carcinoma (BCC) subtypes. The aim of the study was to compare host immune responses and stromal reactions between basosquamous carcinoma (BSC) and high-risk (HR) and low-risk (LR) BCC subtypes. MATERIALS AND METHODS: The study included 35 BSC, 40 HR-BCC, and 40 LR-BCC patients. Age, sex, lesion location, density of peritumoral/adjacent perivascular inflammation, presence of lymphoid follicle formation, and stromal reaction type were compared between groups. RESULTS: In all 3 groups, age, sex distribution, and lesion location were similar. Overall, 70% of lesions in the LR-BCC group exhibited mild peritumoral inflammation, whereas in the BSC and HR-BCC groups dense inflammation was observed in 50% and 57.5% of lesions, respectively (P < 0.001). All lesions (100%) in the LR-BCC group had fibromyxoid stroma, whereas 61.8% and 80% of lesions in the BSC and HR-BCC groups, respectively, had desmoplastic stroma (P < 0.001). CONCLUSION: The BSC and HR-BCC groups were similar in terms of host immune responses and stromal reactions. Furthermore, BSC and HR-BCC were associated with dense peritumoral inflammation, adjacent perivascular inflammation, and desmoplastic stroma. PMID- 27511330 TI - Analysis of the hip fracture records of a central training and research hospital by selected characteristics. AB - BACKGROUND/AIM: Despite the importance of hip fractures, very few studies have assessed their epidemiological characteristics in Turkey. The aim of this study was to evaluate the frequency and demography of hip fractures from the recent data of a central training and research hospital. MATERIALS AND METHODS: In this descriptive study, we identified hip fracture cases between 2009 and 2013. The age, sex, region, injury pattern, and calendar year for all patients were evaluated. RESULTS: Among the 687 patients (488 women, 199 men) described in our clinic's records, 122, 131, 144, 138, and 154 patients applied with hip fractures from the years 2009 to 2013, respectively. The mean ages of the women and men were 74.8 and 68.5 years, respectively. There were 220 patients who had femoral neck fracture (32%), 419 who had intertrochanteric fracture (61%), and 48 who had subtrochanteric fracture (7%). CONCLUSION: The female geriatric population may have an increasing and distinct hip fracture risk, mainly in the trochanteric region. Furthermore, recent studies that show variations in the frequency and demography of hip fractures highlight the importance of meticulous recording of patients' information. A nationwide survey of different categories of hospitals and various geographic regions of Turkey is also needed to inform effective prevention strategies. PMID- 27511332 TI - A persistently low HBV DNA level is a predictor of spontaneous HBsAg clearance in patients with chronic hepatitis B. AB - BACKGROUND/AIM: The incidence and predictors of spontaneous hepatitis B surface antigen (HBsAg) seroclearance in patients with chronic hepatitis B virus (HBV) were evaluated. MATERIALS AND METHODS: A total of 1427 patients with chronic HBV infection, who were followed between 1994 and 2013, were investigated in this retrospective study. All data were extracted from patient files. RESULTS: Spontaneous HBsAg seroclearance occurred in 84 patients during 8798 person-years of follow-up. The patients were categorized into 3 groups at follow-up based on HBV DNA features as continuously <100 copies/mL (Group A), 0-10,000 copies/mL (Group B), and 0 to >10,000 copies/mL (Group C). Alanine aminotransferase features in the 2 groups were categorized as continuously normal (<40 U/L) and 0 to >40 U/L. Spontaneous HBsAg seroclearance was seen primarily in patients with Group A HBV DNA features, and continuously low HBV DNA values were the main predictor of HBsAg seroclearance (P < 0.001). CONCLUSION: These results suggest that a continuously low viral load is the most important factor affecting spontaneous HBsAg seroclearance. PMID- 27511331 TI - Clinical features of infants treated for severe retinopathy of prematurity: 8 yearstudy from a large tertiary neonatal intensive care unit in Turkey. AB - BACKGROUND/AIM: The aim of this study was to report the gestational age (GA) and birth weight (BW) distribution of premature babies who needed treatment for retinopathy of prematurity (ROP) and to assess the timing of the treatment. MATERIALS AND METHODS: The records of 9008 infants who were screened for ROP were examined and 556 infants who underwent laser therapy for ROP were reviewed. Sex, GA, BW, postnatal age, and postmenstrual (PM) age at the time of laser therapy were recorded. The babies were classified as in-born (Group 1) and out-born infants (Group 2). RESULTS: The mean GA was 27.3 weeks (range: 22-33 weeks) and the mean BW was 991.1 g (range: 520-2160 g). Of the treated infants, 7.0% were born later than 32 weeks and 8.3% were born over 1500 g. The mean postnatal age was 9.48 weeks (range: 5-22 weeks) and the mean PM age was 36.72 weeks (range: 29 48 weeks) at the time of treatment. Mean BWs and GAs were significantly higher and the mean postnatal age at the time of laser therapy was significantly earlier in Group 2. CONCLUSION: Infants with severe ROP had a wider range of BWs and GAs compared to those from developed countries and earlier treatment was needed for out-born infants. PMID- 27511333 TI - Evaluation of intraabdominal hypertension and genitofemoral nerve motor conduction. AB - BACKGROUND/AIM: The aim of this study was to electrophysiologically evaluate the effect of increased intraabdominal pressure (IAP) on genitofemoral nerve (GFN) motor conduction. MATERIALS AND METHODS: Seven Wistar albino rats were included. After anesthetization, latency and duration of GFN conduction was recorded with a needle-probe at rest. IAP was increased to 15 mmHg by insufflating atmospheric air with a percutaneous intraperitoneal needle. At 30 min of IAP, GFN motor conduction was recorded. Abdominal pressure was then increased to 20 mmHg. At 60 min, GFN motor conduction was recorded again. The consecutive recordings of latency and duration of GFN conduction (rest, 30 min, 60 min) were evaluated statistically. RESULTS: There was a significant difference between latencies at rest (1.90 +/- 0.22 ms), at 30 min (2.3 +/- 0.36 ms), and at 60 min (2.74 +/- 0.57 ms) (Friedman test, P = 0.001). The latency was significantly increased at 60 min compared to rest (post hoc Tukey test, P = 0.003). No similar difference was detected between the recordings at 30 and 60 min. The duration of GFN motor conduction showed no difference between consecutive recordings (P = 0.067). CONCLUSION: Both increased and prolonged IAP causes prolonged latency of GFN conduction, probably due to a compression effect on GFN. Neuropraxial consequences of increased IAP are thought to be related to the compression effect of peripheral nerves. PMID- 27511334 TI - Mucormycosis: a 10-year experience at a tertiary care center in Turkey. AB - BACKGROUND/AIM: Mucormycosis is a rare invasive fungal infection most commonly encountered in the immunocompromised host. We analyzed 51 adult patients treated for mucormycosis between 2003 and 2013 and recorded at a tertiary university hospital in Turkey. MATERIALS AND METHODS: We examined the following data for all patients: age, sex, predisposing disease, symptoms, treatment, surgical procedure, concomitant infections, intensive care requirement, and outcomes. RESULTS: During the study period 51 cases of mucormycosis were documented; 54.9% of the patients were female. The mean age was 44.2 +/- 18.2 years. Rhinocerebral presentation was reported in 94.1% of patients. Almost all patients (88.2%) had at least one risk factor. The common predisposing factors were hematologic malignancies (52.9%), diabetes mellitus (25.5%), and solid malignancies (5.8%). The most common initial symptoms were fever, cellulitis, and facial pain. The primary medication used was liposomal amphotericin B or conventional amphotericin B. Surgery was performed in 94.1% of patients. Mortality was 52.9%. CONCLUSION: Our study revealed that mucormycosis continues to be a mortal disease in about half of the cases. Our findings indicate that treatment with L-AMB is associated with a favorable response. Also, in the case of facial pain, the low mortality rate may indicate the importance of early diagnosis. PMID- 27511335 TI - Minor salivary gland evaluation: Sjogren's syndrome. AB - BACKGROUND/AIM: We aimed to analyze the value of 3 serial sections, spaced 200 um apart, for quantification of lymphocyte and plasma cell foci in minor salivary gland biopsy (MSGB). MATERIALS AND METHODS: Labial MSGBs from 69 patients with Sjogren's syndrome (SS) and scleroderma were used for this study. Each sample was prepared as 3 serial sections spaced 200 um apart. Lymphocytic and plasma cell focus score (LFS, PFS) were determined for each section, and the diagnostic results were compared to those obtained from a single section. RESULTS: For 22 of the 69 patients, all 3 sections were scored at <1 and interpreted as inconclusive for the presence of SS. For 20 cases, all 3 sections were scored at >=1 and interpreted as diagnostic for SS. In the remaining 27 cases, the score was found to vary between sections. Plasma cell foci were observed in 11 cases, with 5 cases exhibiting a PFS of >=1. Of those 5 cases, 4 also had a LFS of >=1. CONCLUSION: Assessment of 3 serial sections in MSGB has the potential to improve accuracy of SS diagnosis by detecting specific features that may not have been detected in a single section. We concluded that data about the PFS require further evaluation. PMID- 27511336 TI - Distribution of hepatitis C virus genotypes among intravenous drug users in the Cukurova region of Turkey. AB - BACKGROUND/AIM: The most common hepatitis C virus (HCV) genotype in Turkey is genotype 1. However, there has not been a study about the distribution of HCV genotypes among intravenous drug users (IVDUs) in the Cukurova region of Turkey. This study was planned to understand if there is a difference between IVDUs and the normal population. MATERIALS AND METHODS: Between May 2010 and May 2014, anti HCV positive IVDUs who applied to the 6 hospitals in the Cukurova region of Turkey were included in this study. Their HCV genotypes were studied. RESULTS: Ninety-seven anti-HCV positive IVDUs were screened in terms of HCV RNA and genotype. Ten were excluded from the study because their HCV RNA results were negative. Fifty-one of the 87 patients (58.6%) had genotype 3. Genotype 2 was detected in 26 (29.9%) and genotype 1 was detected in 10 (11.5%) patients. CONCLUSION: HCV genotypes seem to be different between the normal population and IVDUs according to studies worldwide. Among IVDUs, we detected a dominance of genotype 3 and genotype 2, which is apparently different from the normal population. The reason for this difference can be simply explained by infection through shared needles. However, there may still be a different immunological response in IVDUs, the investigation of which may lead to further studies. PMID- 27511337 TI - Seasonal vitamin D status and endothelial function in healthcare workers. AB - BACKGROUND/AIM: Healthcare workers have long working hours indoors and are at risk of vitamin D deficiency. The aim of this study was to determine seasonal vitamin D status and its relationship with early atherosclerotic markers, endothelial function, and carotid intima-media thickness (CIMT) in healthcare workers of Marmara University Hospital, Istanbul. MATERIALS AND METHODS: One hundred and ninety healthy volunteer healthcare workers and 66 nonmedical volunteers of Marmara University Hospital were included in the study and 25 hydroxyvitamin D (25(OH)D), calcium, intact parathyroid hormone (PTH), endothelial function, and CIMT were measured twice during winter and summer seasons. RESULTS: Mean vitamin D levels were 20 ng/mL in summer and 16.4 ng/mL in winter. Out of the healthcare workers, 48.9% were vitamin D deficient at the end of summer and 71.5% in winter. Flow-mediated dilation (FMD) values were similar in both groups in both seasons; however, FMD values of 64 healthcare workers in summer were significantly higher than in winter. Serum 25(OH)D was positively associated with FMD (r = 0.1797, P = 0.0441) and negatively correlated with serum PTH (r = -0.2459, P < 0.0001). A negative correlation between FMD and serum PTH (r = -0.1757, P = 0.0473) was observed. CONCLUSION: Vitamin D levels of healthcare workers are very low, even in summer time. Healthcare workers must be considered a group at major risk for vitamin D deficiency. PMID- 27511338 TI - Recurrent dilatation in resistant benign esophageal strictures: timing is significant. AB - BACKGROUND/AIM: Benign esophageal strictures are frequently encountered pathologies occurring due to various reasons. Repeated dilatations may be needed, particularly in resistant strictures. This study aimed to evaluate patients who underwent repeated dilatations in our clinic due to resistant esophageal strictures. MATERIALS AND METHODS: Sixteen patients who underwent multiple dilatations in our clinic with the diagnosis of resistant benign esophageal stricture between 2007 and 2014 were studied for age, sex, etiology, symptoms, complications, number of dilatations, and intervals between dilatations. Under general anesthesia, all patients underwent dilatation with Savary-Gilliard bougie dilators with the help of rigid esophagoscopy. RESULTS: In 10 of the patients, stenosis was cervical, and in others it was in the thoracic esophagus. The mean dilatation performance was 4.4 (range: 3-12). In 9 patients, dilatations were performed when the patients presented with the complaint of dysphagia. Following the initial dilatation performed for dysphagia, 7 patients underwent endoscopy and dilatation 3-5 times with 1-week intervals without waiting for the development of dysphagia symptoms. These patients developed no complications, and no stenting was needed. In 5 patients, restenosis developed despite multiple dilatations, and esophageal stent placement was performed. CONCLUSION: Dilatations performed at frequent intervals without waiting for the symptoms of dysphagia can contribute to safer and more effective results in resistant benign esophageal strictures. PMID- 27511339 TI - Diagnostic accuracy of noninvasive end-tidal carbon dioxide measurement in emergency department patients with suspected pulmonary embolism84-90. AB - BACKGROUND/AIM: Pulmonary embolism (PE) is a frequent health problem representing a diagnostic challenge with high mortality and morbidity rates. The aim of this study was to investigate the value of end-tidal carbon dioxide (ETCO2) and alveolar dead space fraction (ADSF) in the diagnosis of PE. MATERIALS AND METHODS: ETCO2 levels of patients with suspected PE were measured with a noninvasive mainstream sensor. ADSF of patients was calculated and PaCO2 levels were also obtained. ROC curve analysis was used to determine diagnostic values of ETCO2 and ADSF for PE. RESULTS: The study included 159 patients. The mean values for ETCO2 and ADSF were 16.27 (95% CI, 14.52-18.03) and 0.48 (95% CI, 0.43-0.539) in the PE group and 21.57 (95% CI, 20.52-22.639) and 0.35 (95% CI, 0.32-0.38) in the non-PE group. The area under the curve (AUC) and the cut-off point for ETCO2 were found as 0.751 and <=19, with 83.8% sensitivity and 61.5% specificity. AUC and cut-off point for ADSF were found as 0.738 and >0.443, with 67.57% sensitivity and 73.77% specificity. CONCLUSION: The diagnostic value of calculated ADSF and noninvasive bedside ETCO2 for PE was found to be low. PMID- 27511340 TI - An experimental comparative study on classic tube thoracostomy and thoracostomy with a newly designed thorax drainage catheter. AB - BACKGROUND/AIM: The collection of fluids, blood, pus, or air in the pleural cavity is a pathological condition requiring pleural drainage. A newly designed thorax drainage catheter in the prototype phase was used in this experimental study to test its efficacy. MATERIALS AND METHODS: A hemopneumothorax was first caused by a penetrating injury on the frontal axis of the sixth intercostal space on the right hemithorax with a scalpel on 6 female Sus domesticus swine subjects. After resting for 5 min, a tube or catheter was inserted. The same procedure with a tube thoracostomy or thorax drainage catheter was repeated on the left hemithorax. The time periods were recorded. After all procedures were completed, the thoracic organs were assessed for iatrogenic injuries. RESULTS: In terms of time elapsed for procedure, statistically significant differences between the tube thoracostomy and thorax drainage catheter applications were identified (P < 0.05). Additional iatrogenic injuries were nonexistent for both groups. During the thorax drainage catheter application, a surgical set or the use of sutures was not required. CONCLUSION: This study showed promising results regarding the efficacy of the thorax drainage catheter for convenient use in prehospital and hospital settings by physicians with little experience with tube thoracostomy. PMID- 27511341 TI - Frequency of twelve carcinogenic human papilloma virus types among women from the South Backa region, Vojvodina, Serbia. AB - BACKGROUND/AIM: The aim of this study was to determine the presence and age distribution of different oncogenic human papilloma virus (HPV) types in women in the South Backa region and its relationship to Pap results. MATERIALS AND METHODS: In a group of 1087 women with normal and abnormal cytology, the commercial HR HPV Real-TM kit (Sacace Biotechnologies, Italy) was used. RESULTS: Overall, 50.5% of the women were HPV positive. The presence of HPV types 18, 31, 51, and 58 was significantly influenced by age, while the presence of HPV types 16 and 45 was significantly influenced by cervical cytology. Results of the LSD test show a wide spectrum of high risk HPV among women with normal cytology and women with a low grade cervical lesion rate (atypical squamous cell of undetermined significance (ASCUS) and low grade squamous intraepithelial lesions (LSIL). The most prevalent HPV types found were 16, 31, 51, 18, and 52. In the HSIL group the most prevalent HPV types were 16 and 45. CONCLUSION: The reported results provide new data on the circulation of oncogenic HPV genotypes and frequency of multiple infections among women in Vojvodina and suggest that a prophylactic vaccine against HPV 16 and 18 has the potential to prevent approximately half of the high-grade lesions. PMID- 27511342 TI - The effect of transtheoretical model-based individual counseling, training, and a 6-month follow-up on smoking cessation in adult women: a randomized controlled trial. AB - BACKGROUND/AIM: This study was conducted to determine the effect of transtheoretical model (TTM)-based individual counseling, training, and a 6-month follow-up on smoking cessation in adult women. MATERIALS AND METHODS: We carried out this randomized controlled trial in Konya, Turkey. Female subjects were randomly assigned into groups in a 1:1 ratio using block randomization, block size 3 * 3, divided by stages (precontemplation, contemplation, and preparation) and age (20-29, 30-39, and 40-49 years). The study was completed with 77 women (an intervention group containing 38 participants and a control group of 39 participants). The intervention group was interviewed 5 times (baseline and 1, 1.5, 2, and 6 months). Counseling and training were given to the intervention group at the first 3 interviews. The TTM scales were assessed for both groups at baseline and at 2 and 6 months. RESULTS: In the 6-month follow-up, the rate of smoking cessation and the rate of progress were higher in the intervention group than in the control group. All the TTM variables had differences except the cognitive processes in the intervention group over time. Analysis of variance related to time * groups indicated that all variables had significantly changed except the cognitive processes and the pros of change. CONCLUSION: Results suggest that the TTM may be useful in understanding the stages individuals are at and in deciding on the appropriate treatment for smoking cessation. PMID- 27511343 TI - The utility of EBUS-TBNA in mediastinal or hilar lymph node evaluation in extrapulmonary malignancy. AB - BACKGROUND/AIM: The aim of this study was to determine the diagnostic performance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of mediastinal and hilar lymph nodes (LNs) in patients with known extrapulmonary malignancy. MATERIALS AND METHODS: Between March 2011 and August 2013, 378 EBUS-TBNA procedures were performed. Sixty-three (16.6%) of these were performed on known extrapulmonary malignancy patients. RESULTS: There were 28 male and 35 female patients, with median ages of 65 years (min-max: 53 87) and 57 years (min-max: 39-76), respectively. From the 63 cases, 138 lymph nodes (LNs) were sampled with EBUS-TBNA (median: 2 LNs/patient; min-max: 1-4). Results of EBUS-TBNA revealed malignancy in 18 (28.5%) and nonmalignancy in 45 (71.5%). In the nonmalignant group, there were false negatives in 5 (7.9%), anthracosis in 13 (20.6%), reactive adenitis in 16 (25.3%), sarcoidosis in 7 (11.1%), and tuberculosis in 2 (3.1%), and 2 were not evaluated (lost to follow up) (3.1%). The diagnostic sensitivity, accuracy, and negative predictive value of EBUS-TBNA per patient were 78.2%, 91.8%, and 88.3%, respectively. CONCLUSION: EBUS-TBNA is a safe, minimally invasive, and effective method and can be considered as the initial test for the histopathological diagnosis of mediastinal and hilar lymphadenopathy in patients with extrapulmonary malignancy. PMID- 27511344 TI - Liporotein-associated phospholipase-A2 can be a diagnostic marker inthe early stage diagnosis of acute mesenteric ischemia. AB - BACKGROUND/AIM: The purpose of this experimental study was to investigate the role of lipoprotein-associated phospholipase-A2 (Lp-PLA2) in the diagnosis of acute mesenteric ischemia (AMI) in the early stage. MATERIALS AND METHODS: Twenty seven New Zealand rabbits were randomly divided into 3 groups in this study. Blood specimens were obtained from the groups at hours 0, 1, 3, and 6. Using the blood samples drawn from all groups, Lp-PLA2 and C-reactive protein (CRP) parameters were investigated. RESULTS: There was a significant rise in the levels of both Lp-PLA2 and CRP starting at hour 1 (P < 0.05) (hour 1; Lp-PLA2, P = 0.003) in the ischemia group. In the sham group, the levels of Lp-PLA2 and CRP started to rise at hour 3 (P < 0.05) (hour 3; Lp-PLA2, P = 0.011). At hour 6 of ischemia, the area under the ROC curve was 100%, and the cut-off value of 63.91 ng/mL revealed a sensitivity of 88% and a specificity of 100% for Lp-PLA2. CONCLUSION: These findings showed the role of serum Lp-PLA2 and CRP levels in the early diagnosis of AMI. Thus, further studies are needed to describe the role of Lp-PLA2 in the early diagnosis of AMI. PMID- 27511345 TI - Investigation of ischemia-modified albumin levels and some atherosclerosis related serum parameters in patients with diabetic foot. AB - BACKGROUND/AIM: To investigate serum ischemia-modified albumin (IMA), oxidized low-density lipoprotein (ox-LDL) levels, and paraoxonase 1 (PON1) activity in patients with diabetic foot. MATERIALS AND METHODS: Thirty patients with diabetes mellitus (DM), 30 patients with diabetic foot (29 and 27 of these patients had type 2 DM, respectively), and 30 healthy volunteers as the control group were included in the study. The patients with diabetic foot were divided into 2 groups, as those who had or had not undergone lower extremity amputation. Serum PON1 activity, ox-LDL, and IMA levels were measured. RESULTS: Serum PON1 activity was lower (P < 0.05) and ox-LDL levels were higher (P < 0.05) in the diabetic foot group than in the control and diabetes groups. Albumin-adjusted IMA values were higher (P < 0.001) in the diabetic foot group compared to the diabetes group. The postamputation levels of IMA were decreased compared to the preamputation condition (P < 0.05). CONCLUSION: The low activity of PON1 and the high levels of ox-LDL and IMA may play an important role in the pathogenesis of diabetic foot. The use of these parameters in the follow-up of patients with DM may prevent the development of diabetic foot. In order to reach a definitive judgment, further studies with a larger number of subjects are necessary. PMID- 27511346 TI - Impact of antimicrobial drug restrictions on doctors' behaviors. AB - BACKGROUND/AIM: Broad-spectrum antibiotics have become available for use only with the approval of infectious disease specialists (IDSs) since 2003 in Turkey. This study aimed to analyze the tendencies of doctors who are not disease specialists (non-IDSs) towards the restriction of antibiotics. MATERIALS AND METHODS: A questionnaire form was prepared, which included a total of 22 questions about the impact of antibiotic restriction (AR) policy, the role of IDSs in the restriction, and the perception of this change in antibiotic consumption. The questionnaire was completed by each participating physician. RESULTS: A total of 1906 specialists from 20 cities in Turkey participated in the study. Of those who participated, 1271 (67.5%) had <=5 years of occupational experience (junior specialists = JSs) and 942 (49.4%) of them were physicians. Specialists having >5 years of occupational experience in their branch expressed that they followed the antibiotic guidelines more strictly than the JSs (P < 0.05) and 755 of physicians (88%) and 720 of surgeons (84.6%) thought that the AR policy was necessary and useful (P < 0.05). CONCLUSION: This study indicated that the AR policy was supported by most of the specialists. Physicians supported this restriction policy more so than surgeons did. PMID- 27511347 TI - Ophthalmic pathologies in female subjects with bilateralcongenital sensorineural hearing loss. AB - BACKGROUND/AIM: The high prevalence of ophthalmologic pathologies in hearing disabled subjects necessitates early screening of other sensory deficits, especially visual function. The aim of this study is to determine the frequency and clinical characteristics of ophthalmic pathologies in patients with congenital bilateral sensorineural hearing loss (SNHL). MATERIALS AND METHODS: This descriptive study is a prospective analysis of 78 young female SNHL subjects who were examined at a tertiary care university hospital with a detailed ophthalmic examination, including electroretinography (ERG) and visual field tests as needed. RESULTS: The mean age was 19.00 +/- 1.69 years (range: 15 to 24 years). A total of 39 cases (50%) had at least one ocular pathology. Refractive errors were the leading problem, found in 35 patients (44.9%). Anterior segment examination revealed heterochromia iridis or Waardenburg syndrome in 2 cases (2.56%). Dilated fundus examination revealed retinal pathologies in 15 cases (19.23%), including retinitis pigmentosa or Usher's syndrome in 8 cases (10.25%). Most of the Usher's syndrome cases (87.5%) had consanguinity. CONCLUSION: Screening for congenital SNHL in the early years of life and routine yearly follow-ups are essential for maximizing the rehabilitation of this disabled group. The high rate of visually debilitating syndromic ocular pathologies associated with high frequency of consanguinity doubles the importance. PMID- 27511348 TI - Effects of immunosuppressive drugs on oral mucosa in patients with Behcet's disease: cytomorphological and cytopathological assessment. AB - BACKGROUND/AIM: The aim of this study was to investigate cytomorphological and cytopathological changes in oral exfoliated smears collected from immunosuppressed patients with Behcet's disease (BD) using stereological methods. MATERIALS AND METHODS: For cytomorphometric analysis, mucosal cell smears were obtained from the buccal mucosa and the floor of the mouths of BD patients treated with immunosuppressive drugs and from healthy volunteers. All mucosal smears from the patients and the healthy volunteers were stained using the Papanicolaou method and examined cytopathologically under light microscopy and cytomorphologically via the stereological nucleator method. RESULTS: The cytomorphological analysis revealed 3 types of mucosal cells, with numbers of particularly pink cells lower in the aphthous areas of the patients with BD compared to the healthy controls (P < 0.05). The nuclear volumes (NVs) and cytoplasmic volume (CVs) were significantly higher in the BD patients (P < 0.05), but the NV/CV ratio was higher only in the drug-use patient groups (P > 0.05). There was lower apoptotic activity in the nondrug-use patients with BD and in the immunosuppressive-taking BD patients. CONCLUSION: The findings suggest that quantifiably morphological and morphometric changes in oral mucosa can be detected by stereological techniques. Changes in these parameters may indicate malignant transformation in the oral mucosa. PMID- 27511349 TI - Cost-effectiveness analysis of pemetrexed and gemcitabine treatment for advanced nonsmall cell lung cancer in Turkey. AB - BACKGROUND/AIM: The purpose of the study is to determine the cost-effectiveness of the chemotherapy medications that contain gemcitabine and pemetrexed, which are used in the treatment of advanced nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: The study evaluated the effectiveness and cost of platinum based pemetrexed and gemcitabine treatments as the first-line treatment of advanced NSCLC with the use of the Markov model, and from the perspective of the Social Security Institution. NSCLC costs calculated on the basis of experts' opinions and the effectiveness values calculated by administering the EQ-5D questionnaire to the patients were analyzed. All direct medical costs were included in the model. RESULTS: While the life-long cost of gemcitabine/cisplatin treatment was determined to be 10,347.45 Turkish lira per patient, it was determined as 17,783.34 for pemetrexed/cisplatin treatment. The incremental cost of pemetrexed/cisplatin treatment is 220,754 per quality-adjusted life year. CONCLUSION: Although there is no official threshold value in Turkey, due to the fact that the incremental cost effectiveness ratio exceeds the threshold value calculated on the basis of GDP per capita, it is understood that pemetrexed/cisplatin is not cost-effective in the first-line treatment of advanced NSCLC. PMID- 27511350 TI - Significance of using a nonlinear analysis technique, the Lyapunov exponent, on the understanding of the dynamics of the cardiorespiratory system in rats. AB - BACKGROUND/AIM: Pneumocardiography (PNCG) is the recording method of cardiac induced tracheal air flow and pressure pulsations in the respiratory airways. PNCG signals reflect both the lung and heart actions and could be accurately recorded in spontaneously breathing anesthetized rats. Nonlinear analysis methods, including the Lyapunov exponent, can be used to explain the biological dynamics of systems such as the cardiorespiratory system. MATERIALS AND METHODS: In this study, we recorded tracheal air flow signals, including PNCG signals, from 3 representative anesthetized rats and analyzed the nonlinear behavior of these complex signals using Lyapunov exponents. RESULTS: Lyapunov exponents may also be used to determine the normal and pathological structure of biological systems. If the signals have at least one positive Lyapunov exponent, the signals reflect chaotic activity, as seen in PNCG signals in rats; the largest Lyapunov exponents of the signals of the healthy rats were greater than zero in this study. CONCLUSION: A method was proposed to determine the diagnostic and prognostic values of the cardiorespiratory system of rats using the arrangement of the PNCG and Lyapunov exponents, which may be monitored as vitality indicators. PMID- 27511351 TI - Effects and mechanisms of curcumin on the hemodynamic variablesof isolated perfused rat hearts. AB - BACKGROUND/AIM: There is no information on the dose-response relationship of curcumin on the hemodynamic variables of the heart at the organ level in isolated perfused rat hearts. We aimed to investigate the effects and mechanisms of curcumin on the hemodynamic variables of isolated perfused rat hearts. MATERIALS AND METHODS: Rats were randomly divided into 9 groups. The isolated rat heart was retrogradely perfused with modified Krebs-Henseleit solution. After the stabilization period, each group was administered one of the following treatments for 25 min: saline, dimethyl sulfoxide, and curcumin (0.2 uM, 1 uM, and 5 uM); atropine (1 uM); atropine (1 uM) + curcumin (1 uM); L-NAME (100 uM); or L-NAME (100 uM) + curcumin (1 uM). Hemodynamic variables of the heart were measured. RESULTS: Curcumin at dose of 1 uM decreased the heart rate (from 271 +/- 11.1 to 200.4 +/- 14.3 beats/min, P = 0.011) but increased end-diastolic pressure (from 7.0 +/- 0.4 to 54.6 +/- 7.9 mmHg, P = 0.0008). A dose of 5 uM curcumin caused a decrease in the developed pressure (from 87.58 +/- 9.0 to 65.40 +/- 7.0 mmHg, P = 0.047) but an increase in the end-diastolic pressure (from 6.8 +/- 0.6 to 48.9 +/ 7.7 mmHg, P = 0.005). Atropine (1 uM) reversed the effects of curcumin on the heart. CONCLUSION: Our results suggest that curcumin produces dose-dependent negative chronotropic and inotropic effects in isolated perfused rat hearts. PMID- 27511352 TI - Intrabone marrow injection enhances placental mesenchymal stem cellmediated support of hematopoiesis in mice. AB - BACKGROUND/AIM: In order to determine the synergistic effects of human placental mesenchymal stem cells (PMSCs) on hematopoiesis in vivo, we compared the intrabone marrow injection (IBMI) with the conventional intravenous injection (IVI). MATERIALS AND METHODS: C57BL/6 recipient mice conditioned with lethal doses of irradiation were transplanted with bone marrow mononuclear cells (MNCs) and bone marrow-derived mesenchymal stem cells (BMSCs) from BALB/c mice by IBMI or IVI. NOD/SCID recipient mice conditioned with sublethal doses of irradiation were transplanted with human umbilical cord blood MNCs (UCB-MNCs) and PMSCs by IBMI or IVI. RESULTS: The number of hematopoietic cells was significantly higher in mice transplanted with BMSCs by IBMI than in those transplanted by IVI in a murine transplantation model (BALB/c->C57BL/6). Moreover, the percentage of human hematopoietic cells in the tibiae of the NOD/SCID mice that were transplanted with PMSCs plus UCB-MNCs was higher than that in mice transplanted with UCB-MNCs alone. In addition, in mice that were transplanted with PMSCs, PMSCs injected by IBMI were more efficient than those injected by IVI. CONCLUSION: Our results not only elucidated the role of PMSCs in promoting hematopoiesis, but also revealed the therapeutic potential of the combination of PMSCs and IBMI in transplantation. PMID- 27511353 TI - The effect of proanthocyanidin on formaldehyde-induced toxicity in rat testes. AB - BACKGROUND/AIM: This study investigated the effect of proanthocyanidin (PA) against formaldehyde (FA)-induced lipid peroxidation damage and morphological changes in rat testes. MATERIALS AND METHODS: Twenty-one Wistar albino rats were randomized into 3 groups: control, FA, and FA + PA groups. Plasma and tissue malondialdehyde (MDA) and total sialic acid (TSA) levels were measured. Testes tissues were observed by light and electron microscopy. RESULTS: TSA (plasma and tissue) levels decreased and MDA (plasma) significantly increased (P < 0.05) in rats treated with FA compared to the controls. Tissue MDA levels were not significantly different. Several necrotic changes were observed in testes tissues by light and electron microscopy. Disordering in epithelia of seminiferous tubules, vacuolization between germinal epithelium cells, and separated basement membranes were observed by light microscope. Immunopositivity in Leydig cells decreased in the FA group (P < 0.05). In the FA + PA group there were more immune Leydig cells reacting immune-positively than in the FA group (P < 0.05). Ultrastructurally, FA also caused disorganization and loss of mitochondrial cristae, and dilatation in endoplasmic reticulum in testes. CONCLUSION: The results suggest that PA has a protective effect on FA toxicity in testes. PMID- 27511354 TI - Apitherapy products enhance the recovery of CCL4-induced hepatic damages in rats. AB - BACKGROUND/AIM: Our objective was to identify the antioxidant properties of honeybee products from Turkey, chestnut honey, pollen, propolis, and royal jelly, and their hepatoprotective activity against CCl4-induced hepatic damage in rats. MATERIALS AND METHODS: Animals were fed with honeybee products for 7 days following CCl4 injection. Development of liver damage and oxidative stress were monitored by measuring the activities of the enzymes alanine transaminase, aspartate transaminase, malondialdehyde, superoxide dismutase, and catalase. Antioxidant capacities of the bee products were identified using FRAP and DPPH assays, as well as by measuring total phenolic and flavonoid contents. RESULTS: The antioxidant activities of the honeybee products were highest in propolis, followed, in order, by pollen, honey, and royal jelly. Despite their different levels of antioxidant capacity, their roles in the prevention of liver damage induced by CCl4 were very similar, which can be explained through their bioavailability to the treated animals. CONCLUSIONS: Our results suggest that honey, propolis, pollen, and royal jelly significantly enhanced the healing of CCl4-induced liver damage, partially due to their antioxidant properties and bioavailability. PMID- 27511355 TI - Comparison of a real-time polymerase chain reaction-based system and Erlich-Ziehl Neelsen method with culture in the identification of Mycobacterium tuberculosis. AB - BASCKGROUND/AIM: Mycobacterium tuberculosis is still a major health problem throughout the world, especially in developing countries. Disease control heavily depends on the establishment of early diagnosis. The aim of this study is to compare the efficacy of culture, GeneXpert MTB/RIF device, and Erlich-Ziehl Neelsen direct microscopic method. MATERIALS AND METHODS: A total of 927 samples (243 respiratory and 684 nonrespiratory), which were sent to Ondokuz Mayis University Medical Faculty Tuberculosis Laboratory on suspicion of M. tuberculosis, were included in the study. RESULTS: When compared to standard culture, sensitivity, specificity, and positive and negative predictive values of the GeneXpert system for respiratory samples were 100%, 98.7%, 87%, and 100%, respectively; these values for nonrespiratory samples were 71%, 98.6%, 71%, and 98.6%, respectively. CONCLUSION: New, reliable, rapid, and easy-to-use methods that display high specificity and sensitivity are required for an effective struggle against tuberculosis. According to these results, we suggest that GeneXpert MTB/RIF is a rapid and reliable system, and when used in company with conventional tests, it would make significant contributions to the diagnosis of tuberculosis. PMID- 27511356 TI - Evaluation of new multiplex PCR primers for the identification ofPlasmodium species found in Sabah, Malaysia. AB - BACKGROUND/AIM: Malaria is a major public health problem, especially in the Southeast Asia region, caused by 5 species of Plasmodium (P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi). The aim of this study was to compare parasite species identification methods using the new multiplex polymerase chain reaction (PCR) against nested PCR and microscopy. MATERIALS AND METHODS: Blood samples on filter papers were subject to conventional PCR methods using primers designed by us in multiplex PCR and previously designed primers of nested PCR. Both sets of results were compared with microscopic identification. RESULTS: Of the 129 samples identified as malaria-positive by microscopy, 15 samples were positive for P. falciparum, 14 for P. vivax, 6 for P. knowlesi, 72 for P. malariae, and 2 for mixed infection of P. falciparum/P. malariae. Both multiplex and nested PCR identified 12 P. falciparum single infections. For P. vivax, 9 were identified by multiplex and 12 by nested PCR. For 72 P. malariae cases, multiplex PCR identified 58 as P. knowlesi and 10 as P. malariae compared to nested PCR, which identified 59 as P. knowlesi and 7 as P. malariae. CONCLUSION: Multiplex PCR could be used as alternative molecular diagnosis for the identification of all Plasmodium species as it requires a shorter time to screen a large number of samples. PMID- 27511357 TI - Quantitative comparison of immunohistochemical and PCR analysis of midkine expression in breast cancer types and serum midkine level. AB - BACKGROUND/AIM: Midkine (MK), a heparin-binding growth factor, has an important role in cancer progression. The aim of this study was to determine MK expression in breast tissue and the preoperative and postoperative serum levels of patients with breast cancer. MATERIALS AND METHODS: Sixty-one patients with breast cancer participated in our study. The MK serum levels were measured pre- and postoperatively for these patients. We also analyzed breast tissues of the 61 patients immunohistochemically. We examined serum midkine levels in 49 healthy volunteers. RESULTS: MK expression was observed in 44 (72.1%) of 61 breast cancer patients. In breast cancer patients the serum MK levels (3.68 +/- 2.13 ng/mL (mean +/- SD)) were significantly higher than in the control group (1.77 +/- 0.38 ng/mL) before tumor removal (P = 0.000). After tumor removal, serum MK levels (2.47 +/- 1.00 ng/mL) were significantly (P = 0.000) decreased according to preoperative levels. Increased serum levels of MK were related with tumor stages when clinical parameters were analyzed. CONCLUSION: We found that increased serum MK levels and protein expressions were associated with the carcinogenesis of breast cancer. MK levels decreased after tumor removal. According to our findings, MK might be a useful tumor marker for patients with breast cancer. PMID- 27511358 TI - Promoter methylation profile of GSTP1 and RASSF1A in prostate cancerand benign hyperplasia in Vietnamese men. AB - BACKGROUND/AIM: The GSTP1 and RASSF1A methylations that were considered as prostate cancer-specific molecular biomarkers have been extensively reported in Western/American patients with prostate cancer but are rarely reported in Southeast Asian patients. In the present study, the methylation status of the GSTP1 and RASSF1A promoters was evaluated in prostate cancer (PCa) and benign prostate hyperplasia (BPH) tissues from Vietnamese men. MATERIALS AND METHODS: The accuracy of methylation-specific polymerase chain reaction (MSP) was validated to analyze the methylation pattern of GSTP1 and RASSF1A in 59 PCa and 37 BPH patients, respectively. The methylation status was confirmed by the sequencing of cloned MSP products. The association between methylation status and the clinical and pathological parameters of tumors was statistically analyzed. RESULTS: The methylation of GSTP1 and RASSF1A was detected in 39/59 and 19/59 PCa patients and in 4/37 and 10/37 BPH patients, respectively. The methylation frequency of GSTP1 was significantly associated with PCa (P < 0.01). The RASSF1A methylation frequency (32.2%) observed in the study was lower relative to that detected in other populations. CONCLUSIONS: GSTP1 and RASSF1A methylation was accurately detected using the validated MSP method and can be used as a biomarker to diagnose prostate cancer. PMID- 27511359 TI - Intraarticular Ankaferd blood stopper application increases cartilagedegeneration: an experimental study. AB - BACKGROUND/AIM: Ankaferd blood stopper (ABS) is a mixture of certain ratios of 5 different plant roots (Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica). The aim of this study is to evaluate the histopathological effects of ABS on articular cartilage in vitro. MATERIALS AND METHODS: Twenty-one albino Sprague Dawley rats were randomly allocated to 3 groups: 0.1 mL of saline was injected in the first group, 0.1 mL of ABS was injected in the second group, and 0.1 mL of blood and 0.1 mL of ABS were injected in the third group. One month later all rats were sacrificed. Specimens were obtained for histopathological evaluation. RESULTS: Significant results were detected in the groups with respect to International Cartilage Repair Society and synovial proliferation scores (P < 0.05 and P < 0.01). According to inflammatory cell infiltration and fibrin formation scores, there was no significant difference between group 1 and group 2 (P < 0.01), although there was significant difference between group 3 and the other groups (P > 0.05). CONCLUSION: ABS and hemarthrosis had toxic effects on knee cartilage. The side effects were increased with the combination of hemarthrosis and ABS. As a result, ABS had unexpected effects on experimental hemarthrosis. PMID- 27511360 TI - Clarifying aspects of noninvasive mechanical ventilation in acute exacerbations of chronic obstructive pulmonary disease. PMID- 27511361 TI - Nomenclature for factors of the HLA system, update May 2016. PMID- 27511362 TI - A novel secondary structure based on fused five-membered rings motif. AB - An analysis of protein structures indicates the existence of a novel, fused five membered rings motif, comprising of two residues (i and i + 1), stabilized by interresidue Ni+1-H???Ni and intraresidue Ni+1-H???O=Ci+1 hydrogen bonds. Fused rings geometry is the common thread running through many commonly occurring motifs, such as beta-turn, beta-bulge, Asx-turn, Ser/Thr-turn, Schellman motif, and points to its structural robustness. A location close to the beginning of a beta-strand is rather common for the motif. Devoid of side chain, Gly seems to be a key player in this motif, occurring at i, for which the backbone torsion angles cluster at ~(-90 degrees , -10 degrees ) and (70 degrees , 20 degrees ). The fused-rings structures, distant from each other in sequence, can hydrogen bond with each other, and the two segments aligned to each other in a parallel fashion, give rise to a novel secondary structure, topi, which is quite common in proteins, distinct from two major secondary structures, alpha-helix and beta sheet. Majority of the peptide segments making topi are identified as aggregation prone and the residues tend to be conserved among homologous proteins. PMID- 27511363 TI - Erratum to: Physicians' responses to computerized drug interaction alerts with password overrides. PMID- 27511364 TI - Newly discovered myokines in chronic kidney disease. PMID- 27511365 TI - Correlation of hepatic fractional extracellular space using gadolinium enhanced MRI with liver stiffness using magnetic resonance elastography. AB - PURPOSE: To compare MR hepatic fractional extracellular space (fECS) to liver stiffness (LS) with magnetic resonance elastography (MRE) for evaluation of liver fibrosis. METHODS AND MATERIALS: 71 consecutive patients with suspected chronic liver disease underwent standard liver MRI with MR elastography and additional delayed Gd-DTPA-enhanced sequences at 5 and 10 min in order to calculate hepatic fECS (%) and LS (kilopascals, kPa). Two radiologists blinded to clinical history examined MR images and calculated fECS and LS in identical locations for every patient. Interobserver agreement was calculated using the intraclass correlation coefficient. Pearson's correlation was calculated for LS and fECS measures, as was the area under the receiver operatic curve (AUROC), sensitivity and specificity of fECS to predict liver stiffness >=2.93 and >=5 kPa. The sensitivity of fECS for detecting fibrosis was separately analyzed in the subgroup of patients without anatomic findings of cirrhosis. RESULTS: Substantial to excellent interobserver agreement for both LS and fECS measurements was seen with intraclass correlation of 0.88 (95% CI 0.81-0.92) for LS, 0.77 (95% CI 0.66 0.85) for fECS5 and 0.76 (95% CI 0.64-0.84) for fECS10. A significant correlation was found between MRE and fECS5 (r = 0.47, p < 0.0001) and fECS10 (r = 0.44, p < 0.0001). The performance of fECS improved for detection of advanced fibrosis (>=5 kPa) with AUROC, sensitivity and specificity of 0.72, 38%, and 94% for fECS5 and 0.72, 67%, and 66% for fECS10. CONCLUSION: fECS correlates modestly with MRE determined LS. fECS at MRI is a simple calculation to perform and may represent a practical way to suggest the presence of fibrosis during routine liver evaluation. PMID- 27511366 TI - MRI for appendicitis in pregnancy: is seeing believing? clinical outcomes in cases of appendix nonvisualization. AB - PURPOSE: The primary objective of this study was to determine the clinical outcomes in cases of appendix nonvisualization with MRI in pregnant patients with suspected appendicitis and the implications of appendix nonvisualization for excluding appendicitis. METHODS: Fifty-eight pregnant patients with suspected appendicitis evaluated with MRI at three centers from a single institution were retrospectively reviewed by three radiologists with varying levels of abdominal imaging experience. All scans were performed on a 1.5-Tesla Siemens unit. Cases were evaluated for diagnostic quality, visualization of the appendix, presence of appendicitis, and alternate diagnoses. Clinical outcomes were gathered from the electronic medical record. RESULTS: Of the 58 patients who underwent MRI for suspected appendicitis, 50 cases were considered adequate diagnostic quality by all three radiologists. The rate of appendix visualization among the three radiologists ranged from 60 to 76% (p = 0.44). The appendix was nonvisualized by at least one of the three radiologists in 25 cases (50%). Of these, none had a final diagnosis of appendicitis including one patient who underwent appendectomy. MRI suggested an alternate diagnosis in 6 (24%) patients with appendix nonvisualization. For the three reviewers, the agreement level on whether or not the appendix was visualized on the MRI had a Light's kappa value of 0.526, indicating a "moderate" level of agreement (p value < 0.01). CONCLUSION: Despite only moderate level of interobserver agreement for appendix visualization, appendix nonvisualization on MRI in pregnant patients with suspected appendicitis confers a significant reduction in the risk of appendicitis compared to all comers as long as the study is adequate diagnostic quality and there are no secondary signs of appendicitis present. PMID- 27511367 TI - Morphology and molecular characterization hold hands: clarifying the taxonomy of Hysterothylacium (Nematoda: Anisakidae) larval forms. AB - During the last decade, many morphotypes of larval forms of Hysterothylacium have been proposed; however, their boundaries are taxonomically unclear. We compare newly collected material with data available for Hysterothylacium larvae, based on genetics and morphology, in order to evaluate their relationships and simplify their classification. The previously described Hysterothylacium larval type IV, type V, and type X were found in several marine fishes from Brazil. A new Hysterothylacium larval type XV, parasitic in Elops saurus from State of Sergipe, north-eastern Brazil, was proposed based on its genetic singularity and the presence of numerous spines throughout the body. Based upon phylogenetic reconstruction using the ribosomal DNA (rDNA) ITS2 sequences along with morphological traits, the following third stage larvae were considered valid (synonyms are inside parenthesis) type III (= types VII and VIII), type V (= types VI, XII, and XIII), and type X (= type XIV). Despite the lack of molecular data, Hysterothylacium larval type II is considered as synonym of type I because of their identical morphology. The morphometry of Hysterothylacium third stage larvae proved to be weak as a diagnostic tool due to its high rates of variation. Phylogenetic reconstruction using the concatenated sequences of rDNA ITS1-5.8S ITS2 and the mitochondrion DNA (mtDNA) cox2 revealed that the sampled Hysterothylacium larval types V may represent three different species and H. deardorffovestreetorum may represent two different taxa. Furthermore, H. deardorffovestreetorum is considered species inquirenda due to its problematic description and diagnosis which are based only on larvae. A key to Hysterothylacium larvae from marine fishes is provided. PMID- 27511368 TI - Toll-like receptors in the brain of mice following infection with Acanthamoeba spp. AB - The Toll-like receptors (TLRs) of the innate immune system play an important role in the recognition of pathogens such as bacteria, viruses, fungi, and parasites. In this study, we examined the changes in the level of expression of TLR2 and TLR4 mRNA and protein in the brains of mice infected with Acanthamoeba spp. The Acanthamoeba strains were isolated from a patient with Acanthamoeba keratitis (AK) (Ac55) and Malta Lake (Ac43). In the brain isolated from mice at 2 days post infection (dpi) with Acanthamoeba strains Ac55 and Ac43, mRNAs for TLR2 and TLR4 were significantly more strongly expressed in comparison with the uninfected mice. In Acanthamoeba-infected mice, TLR2 and TLR4 expression was detected in neurons, glial cells, and endothelial cells within the neocortex. These receptors showed more intense expression in ependymocytes of the choroid plexus of infected mice at 2 dpi. Increased levels of TLR2 and TLR4 mRNA expression in infected mice suggest the involvement of these TLRs in the recognition of Acanthamoeba spp. pathogen-associated molecular patterns (PAMPs). PMID- 27511369 TI - Emergence of Aedes koreicus (Diptera: Culicidae) in an urban area, Hungary, 2016. AB - In June 2016, three adult females of Aedes koreicus mosquitoes were trapped in the urban area of Pecs, Southwest Hungary. The introduction of this invasive mosquito species in this region, along with the recent detection in Germany, may indicate the capability of the species to spread across Europe. Along with Aedes albopictus and Aedes japonicus mosquitoes, this is the third invasive mosquito species occurred in Hungary. PMID- 27511370 TI - Discovery of DNA dyes Hoechst 34580 and 33342 as good candidates for inhibiting amyloid beta formation: in silico and in vitro study. AB - Combining Lipinski's rule with the docking and steered molecular dynamics simulations and using the PubChem data base of about 1.4 million compounds, we have obtained DNA dyes Hoechst 34580 and Hoechst 33342 as top-leads for the Alzheimer's disease. The binding properties of these ligands to amyloid beta (Abeta) fibril were thoroughly studied by in silico and in vitro experiments. Hoechst 34580 and Hoechst 33342 prefer to locate near hydrophobic regions with binding affinity mainly governed by the van der Waals interaction. By the Thioflavin T assay, it was found that the inhibition constant IC50 ~ 0.86 and 0.68 MUM for Hoechst 34580 and Hoechst 33342, respectively. This result qualitatively agrees with the binding free energy estimated using the molecular mechanic-Poisson Boltzmann surface area method and all-atom simulations with the AMBER-f99SB-ILDN force field and water model TIP3P. In addition, DNA dyes have the high capability to cross the blood brain barrier. Thus, both in silico and in vitro experiments have shown that Hoechst 34580 and 33342 are good candidates for treating the Alzheimer's disease by inhibiting Abeta formation. PMID- 27511372 TI - Mild heat treatments induce long-term changes in metabolites associated with energy metabolism in Drosophila melanogaster. AB - Heat-induced hormesis, the beneficial effect of mild heat-induced stress, increases the average lifespan of many organisms. Yet little is known about the mechanisms underlying this effect. We used nuclear magnetic resonance spectroscopy to investigate the long-term effects of repeated mild heat treatments on the metabolome of male Drosophila melanogaster. 10 days after the heat treatment, metabolic aging appears to be slowed down, and a treatment response with 40 % higher levels of alanine and lactate and lower levels of aspartate and glutamate were measured. All treatment effects had disappeared 16 days later. Metabolic reprogramming has been associated with the life extending effects of dietary restriction. The metabolite changes induced by the hormetic treatment suggest that the positive effects might not be limited to the repair pathways induced, but that there also is a change in energy metabolism. A possible direct link between changes in energy metabolism and heat induced increase in Hsp70 expression is discussed. PMID- 27511371 TI - Correlation of Cadmium and Magnesium in the Blood and Serum Samples of Smokers and Non-Smokers Chronic Leukemia Patients. AB - It was studied that cancer-causing processes are related with the disproportions of essential and toxic elements in body tissues and fluid. The purpose of the current study was to evaluate the levels of magnesium (Mg) and cadmium (Cd) in serum and blood samples of smokers and nonsmokers who have chronic myeloid (CML) and lymphocytic (CLL) leukemia, age ranged 31-50 years. For comparative study, age-matched smokers and nonsmoker males were chosen as controls/referents. The levels of elements in patient were analyzed before any treatment by atomic absorption spectrophotometer, after microwave assisted acid digestion. The validation of the method was done by using certified reference materials of serum and blood samples. The resulted data indicated that the adult male smokers and nonsmokers have two- to fourfold higher levels of Cd in the blood and sera samples as compared to the referents (p < 0.01), whereas two- to threefold lower levels of Mg was found in blood and serum samples of both types of leukemia patients as related to referent values. The resulted data indicates significant negative correlation among Mg and Cd in leukemia patients and smoker referents. Further studies are needed to clarify the role of these elements in pathogenesis of chronic leukemia. PMID- 27511373 TI - Comparative RNA-sequencing profiling reveals novel Delta-class glutathione S transferases relative genes expression patterns in Tribolium castaneum. AB - Glutathione S-transferases (GSTs) are a large group of enzymes having both detoxification roles conferring insecticide resistance and specialist metabolic functions. Tribolium castaneum GST Delta 1 (TcGSTd1) has been found playing crucial role in insecticide resistance and biological processes in insect species. However, the regulatory system of TcGSTd1 has still rarely been known. Comparing the transcriptome profile of RNAi treated larvae (ds-TcGSTd1) and control larvae of T. canstaneum by using RNA-sequencing, we obtained 14,284,085 sequence reads aligned with 13,275 genes. And 512 differentially expressed genes (DEGs) were identified from ds-TcGSTd1 treated group. Est/CCE, CYP, MRPs were significantly down-regulated in ds-TcGSTd1 group when compared with control group, which illustrated that they cooperated with TcGSTd1 to reduce the activity of cellular metabolism system. While, SNO was up-regulated in ds-TcGSTd1 insects suggested it may also involve in detoxifying alkaloid of insect metabolism system. These results established that TcGSTd1 not only acts as a vital gene for phase II cellular detoxification but also participates in phase 0, I, and III cellular detoxification by cooperating with CSPs, OBPs, CYP9, ESTB1, CCE6, MRPs and other detoxification genes. Knockdown of TcGSTd1 also suppressed several genes encoding antioxidant enzymes, e.g. CuZnSOD, Duox, Prx, HPX, CPO, and MCORP. Suggested that they may modulate the function of TcGSTd1 on lifespan, immune, development and reproduction. All these results shed the new insights into the regulatory mechanism of TcGSTd1 involved in insect physiology and could further facilitate the research of suitable and sustainable managements for the pest control. PMID- 27511374 TI - LncRNAs expression in adjuvant-induced arthritis rats reveals the potential role of LncRNAs contributing to rheumatoid arthritis pathogenesis. AB - BACKGROUND: Long non-coding RNAs (LncRNAs) are an important class of widespread molecules involved in diverse biological functions, which are exceptionally expressed in numerous types of diseases. Currently, limited study on LncRNA in rheumatoid arthritis (RA) is available. In this study, we aimed to identify the specifically expressed LncRNA that are relevant to adjuvant-induced arthritis (AA) in rats, and to explore the possible molecular mechanisms of RA pathogenesis. METHODS: To identify LncRNAs specifically expressed in rheumatoid arthritis, the expression of LncRNAs in synoviums of rats from the model group (n=3) was compared with that in the control group (n=3) using Arraystar Rat LncRNA/mRNA microarray and real-time polymerase chain reaction (RT-PCR). RESULTS: Up to 260 LncRNAs were found to be differentially expressed (>=1.5-fold-change) in the synoviums between AA model and the normal rats (170 up-regulated and 90 down-regulated LncRNAs in AA rats compared with normal rats). Coding-non-coding gene co-expression networks (CNC network) were drawn based on the correlation analysis between the differentially expressed LncRNAs and mRNAs. Six LncRNAs, XR_008357, U75927, MRAK046251, XR_006457, DQ266363 and MRAK003448, were selected to analyze the relationship between LncRNAs and RA via the CNC network and GO analysis. Real-time PCR result confirmed that the six LncRNAs were specifically expressed in the AA rats. CONCLUSIONS: These results revealed that clusters of LncRNAs were uniquely expressed in AA rats compared with controls, which manifests that these differentially expressed LncRNAs in AA rats might play a vital role in RA development. Up-regulation or down-regulation of the six LncRNAs might contribute to the molecular mechanism underlying RA. To sum up, our study provides potential targets for treatment of RA and novel profound understanding of the pathogenesis of RA. PMID- 27511375 TI - Elevated expression of steroidogenesis pathway genes; CYP17, GATA6 and StAR in prenatally androgenized rats. AB - It is believed that excess androgen exposure of the fetus, via altered gene expression, causes hyperandrogenism a key feature of polycystic ovary syndrome (PCOS). The aim of this study was to evaluate expression of Cytochrome P450-17 (CYP17), GATA-binding protein (GAGT6) and Steroidogenic acute regulatory protein (StAR), genes of adult female rats prenatally exposed to androgen excess, closely reflect endocrine and ovarian disturbances of PCOS in women, by comparing them during different phases of estrus cycle with those of non-treated rats. Both the adult prenatally testosterone exposed and control rats (n=23, each) were divided into four groups based on their observed vaginal smear (proestrus, estrus, metestrus and diestrus) and the relative expression of CYP17, GATA6 and StAR genes was measured in ovarian theca cells using Cyber-green Real-Time PCR. Serum sex steroid hormones and gonadotropins levels were measured using the ELISA method; a comparison of these two groups showed that there was an overall increase in the studied genes (CYP17; 2.39 fold change, 95% CI: 1.23-3.55; P<0.05, GATA6; 2.08 fold change, 95% CI: 1.62-2.55; P<0.0001, and StAR; 1.4 fold change, 95% CI: 1.02-1.78; P<0.05), despite variations in different phases with maximum elevation for all genes in diestrus. The changes observed may impair the normal development of ovaries that mediate the programming of adult PCOS. PMID- 27511376 TI - Nursing home staff should ensure that advance treatment decisions are discussed with residents and relatives. PMID- 27511377 TI - Acute gastrointestinal manifestation of situs inversus abdominus. AB - PURPOSE: Whilst situs inversus is associated with intestinal malrotation and volvulus particularly in infants, this is the first known report of acute intestinal obstruction in an adult patient with a situs anomaly specifically due to a congenital transmesenteric hernia. CASE: A 54-year-old woman presented with a 12-h history of progressive abdominal pain. Contrast-enhanced computed tomography scan of the abdomen revealed an incidental finding of situs inversus abdominus, ischemic small bowel obstruction and a potential occlusive thrombus of the superior mesenteric artery. At operation, the cause of intestinal obstruction was found to be secondary to herniation of the intestine through a congenital mesenteric defect. The hernia was reduced and a strong pulse was subsequently felt in the distal superior mesenteric artery. The patient required resection of a segment of compromised small bowel, and was later anastomosed at a planned second laparotomy. Her laparostomy was closed using an absorbable BioA mesh. CONCLUSION: A high index of suspicion and low threshold for exploratory surgery should be maintained in patients with major congenital abdominal anomalies presenting with an acute abdomen. PMID- 27511378 TI - Aggressive angiomyxoma presenting as massive irreducible vaginal prolapse. PMID- 27511379 TI - Knowledge of pelvic floor problems: a study of third trimester, primiparous women. AB - INTRODUCTION AND HYPOTHESIS: Pelvic floor problems in women (urinary incontinence, faecal incontinence, uterovaginal prolapse) are common, and have an adverse effect on quality of life. We hypothesized that there is low knowledge of these problems amongst primiparous women in their third trimester of pregnancy. METHODS: We conducted a cross-sectional study in antenatal clinics of three hospitals in London, UK, from 2011 to 2013. Primiparous women aged >=18 years and in the third trimester of pregnancy answered questions on pelvic floor problems. Knowledge scores were calculated based on the proportion of questions answered correctly. RESULTS: A total of 249 women completed the question set. The average knowledge score across all domains was low at 45 %. Scores were lowest for the less common problems of faecal incontinence (35 %) and prolapse (36 %). The score for urinary incontinence was higher at 63 %, but low when questions explored more detailed levels of knowledge (41 %). Knowledge scores were positively associated with both education to tertiary level and the use of books as the information source on pregnancy and delivery. Only 35 % of women cited antenatal classes as a source. CONCLUSIONS: Knowledge of pelvic floor problems is low amongst third trimester, primiparous women in this London-based population. Adequate knowledge of these problems is important for women to be able to make informed choices about their antenatal care and to seek help if problems arise. The data suggest scope for health-care professionals to raise these issues early during pregnancy, and to help women access accurate sources of information. PMID- 27511380 TI - Human tonsil-derived mesenchymal stromal cells enhanced myelopoiesis in a mouse model of allogeneic bone marrow transplantation. AB - Mesenchymal stromal cells (MSCs) have therapeutic potential for repairing tissue damage and are involved in immune regulation. MSCs are predominantly isolated from bone marrow (BM), adipose tissue or placental tissue. Further to these well known sources, the isolation of MSCs from human tonsils was previously reported. The aim of the present study was to investigate a potential role for tonsil derived MSCs (T-MSCs) in BM reconstitution and application towards supplementing hematopoiesis in a mouse model of BM transplantation (BMT). Eight-week-old BALB/c female mice received 80 mg/kg busulfan (Bu)/200 mg/kg cyclophosphamide (Cy) conditioning chemotherapy for BM ablation. Subsequently, human T-MSCs were injected into the Bu/Cy-treated mice with or without BM cells (BMCs) obtained from allogeneic C57BL/6 male mice. After 3 weeks, peripheral blood and BM was collected for analysis. The red blood cell count in the group that received BMCs had almost returned to normal, whereas mononuclear cell counts and BM cellularity were most improved in the T-MSCs + BMCs group. These results indicate that the T MSCs enhanced myelopoiesis in the allogeneic BMT mouse model, as evidenced by the restoration of BM with hematopoietic cells, as well as increased myeloid colony formation in vitro. Therefore, T-MSCs may provide a source of MSCs to facilitate myelopoiesis and megakaryocytosis following BMT. PMID- 27511381 TI - Effects of High-cholesterol Diet on Pravastatin Disposition in the Perfused Rat Liver. AB - BACKGROUND AND OBJECTIVES: Various nutrients modulate the expression of transporters; however, the effect of a high-cholesterol (HC) diet on the expression and function of hepatic transporters remains unclear. Here, we examined the effects of an HC diet on drug disposition via hepatic transporters, including organic anion-transporting polypeptide (Oatp), multidrug resistance associated protein (Mrp), and bile salt export pump (Bsep). METHODS: In situ perfused rat liver system was performed. The levels of pravastatin, which is taken up into hepatocytes by Oatp and excreted into bile by Mrp2, in the perfusate and in bile were measured using high-performance liquid chromatography. RESULTS: Pravastatin was rapidly eliminated in control and HC rats; however, the cumulative amounts of excreted in bile were significantly higher in HC rats than in controls possibly because of the enhanced bile flow in HC rats (0.93 +/- 0.05 MUL/min in control, and 1.22 +/- 0.18 MUL/min in HC). Real-time reverse transcriptase polymerase chain reaction (PCR) and western blot assessment of the mRNA and protein levels of hepatic transporters showed a significant downregulation of the Oatp1a1 and Bsep proteins in HC rats, whereas no differences in Mrp2 and Mrp3 levels were observed between HC and control rats. The analysis of the localization of Mrp2 on the canalicular membrane by immunofluorescence showed no changes in HC rats, although Mrp2 was readily internalized from the canalicular membrane under specific conditions. CONCLUSIONS: The findings of the present study indicate that the HC diet affected the biliary excretion of pravastatin concomitant with increased bile flow, despite minimal effects on the expression of hepatic transporters. The HC diet could promote the biliary excretion of other drugs and metabolites that are substrates of Mrp2 and Bsep. PMID- 27511382 TI - Gestational diabetes mellitus: an evaluation of gynecologists' knowledge of guidelines and counseling behavior. AB - PURPOSE: Knowledge of risks, adequate pre- and post-partum care, and counseling is essential to reduce short- and long-term consequences for women with gestational diabetes mellitus (GDM) and their offspring. Our study explored the current GDM guideline knowledge and practiced patient counseling of private gynecologists in Germany. METHODS: A survey assessing the GDM guidelines and patient counseling was mailed to 775 practicing gynecologists. We evaluated the knowledge of maternal and offspring disease risks, counseling practice, and guideline awareness. Descriptive statistics were used to analyze the responses and Chi-Square or Fisher exact test to explore differences between groups. RESULTS: Of the 418 private gynecologists (54.1 % response rate) who responded, the majority was aware of obesity and GDM in the previous pregnancy as risk factors for GDM. To a lesser extent, risk factors like recurrent miscarriages and stillbirth were recalled. Eighty percent stated that GDM was associated with a higher risk for the development for hypertension and 96 % with type 2 diabetes in the mother. Respondents with knowledge of the current GDM guidelines were more often aware of the development of chronic diseases, counseled patients more frequently, and performed post-partum glucose screenings more regularly compared with private gynecologists with no knowledge of the guidelines. CONCLUSIONS: The majority of participants incorporated recent recommendations into their practice patterns for GDM. Providing private gynecologists with additional training may further improve care for women with GDM-affected pregnancies. PMID- 27511384 TI - Junior doctors will have whistleblowing protection added to contracts. PMID- 27511432 TI - Case of a neutrophilic dermatosis involving lung abscess after influenza vaccination. PMID- 27511383 TI - Gaze data reveal distinct choice processes underlying model-based and model-free reinforcement learning. AB - Organisms appear to learn and make decisions using different strategies known as model-free and model-based learning; the former is mere reinforcement of previously rewarded actions and the latter is a forward-looking strategy that involves evaluation of action-state transition probabilities. Prior work has used neural data to argue that both model-based and model-free learners implement a value comparison process at trial onset, but model-based learners assign more weight to forward-looking computations. Here using eye-tracking, we report evidence for a different interpretation of prior results: model-based subjects make their choices prior to trial onset. In contrast, model-free subjects tend to ignore model-based aspects of the task and instead seem to treat the decision problem as a simple comparison process between two differentially valued items, consistent with previous work on sequential-sampling models of decision making. These findings illustrate a problem with assuming that experimental subjects make their decisions at the same prescribed time. PMID- 27511433 TI - An Assessment of Coherence Between Early Warning and Response Systems and Serious Cross-Border Health Threats in the European Union and Turkey. AB - Disease outbreaks have attracted the attention of the public health community to early warning and response systems (EWRS) for communicable diseases and other cross-border threats to health. The European Union (EU) and the World Health Organization (WHO) have published regulations in this area. Decision 1082/2013/EU brought a new approach the management of public health threats in EU member states. Decision 1082/2013/EU brought several innovations, which included establishing a Health Security Committee; preparedness and response planning; joint procurement of medical countermeasures; ad hoc monitoring for biological, chemical, and environmental threats; EWRS; and recognition of an emergency situation and interoperability between various sectors. Turkey, as an acceding country to the EU and a member of the WHO, has been improving its national public health system to meet EU legislations and WHO standards. This article first explains EWRS as defined in Decision 1082/2013/EU and Turkey's obligations to align its public health laws to the EU acquis. EWRS in Turkey are addressed, particularly their coherence with EU policies regarding preparedness and response, alert notification, and interoperability between health and other sectors. Finally, the challenges and limitations of the current Turkish system are discussed and further improvements are suggested. (Disaster Med Public Health Preparedness. 2016;10:883-892). PMID- 27511434 TI - Porous V2O5/RGO/CNT hierarchical architecture as a cathode material: Emphasis on the contribution of surface lithium storage. AB - A three dimensional vanadium pentoxide/reduced graphene oxide/carbon nanotube (3D V2O5/RGO/CNT) composite is synthesized by microwave-assisted hydrothermal method. The combination of 2D RGO and 1D CNT establishes continuous 3D conductive network, and most notably, the 1D CNT is designed to form hierarchically porous structure by penetrating into V2O5 microsphere assembly constituted of numerous V2O5 nanoparticles. The highly porous V2O5 microsphere enhances electrolyte contact and shortens Li(+) diffusion path as a consequence of its developed surface area and mesoporosity. The successive phase transformations of 3D V2O5/RGO/CNT from alpha-phase to epsilon-, delta-, gamma-, and omega-phase and its structural reversibility upon Li(+) intercalation/de-intercalation are investigated by in situ XRD analysis, and the electronic and local structure reversibility around vanadium atom in 3D V2O5/RGO/CNT is observed by in situ XANES analysis. The 3D V2O5/RGO/CNT achieves a high capacity of 220 mAh g(-1) at 1 C after 80 cycles and an excellent rate capability of 100 mAh g(-1) even at a considerably high rate of 20 C. The porous 3D V2O5/RGO/CNT structure not only provides facile Li(+) diffusion into bulk but contributes to surface Li(+) storage as well, which enables the design of 3D V2O5/RGO/CNT composite to become a promising cathode architecture for high performance LIBs. PMID- 27511435 TI - Supersonic shearwave elastography in the assessment of liver fibrosis for postoperative patients with biliary atresia. AB - To explore an effective noninvasive tool for monitoring liver fibrosis of children with biliary atresia (BA) is important but evidences are limited. This study is to investigate the predictive accuracy of supersonic shearwave elastography (SSWE) in liver fibrosis for postoperative patients with BA and to compare it with aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 (FIB-4). 24 patients with BA received SSWE and laboratory tests before scheduled for liver biopsy. Spearman rank coefficient and receiver operating characteristic (ROC) were used to analyze data. Metavir scores were F0 in 3, F1 in 2, F2 in 4, F3 in 7 and F4 in 8 patients. FIB-4 failed to correlate with fibrosis stage. The areas under the ROC curves of SSWE, APRI and their combination were 0.79, 0.65 and 0.78 for significant fibrosis, 0.81, 0.64 and 0.76 for advanced fibrosis, 0.82, 0.56 and 0.84 for cirrhosis. SSWE values at biopsy was correlated with platelet count (r = -0.426, P = 0.038), serum albumin (r = -0.670, P < 0.001), total bilirubin (r = 0.419, P = 0.041) and direct bilirubin levels (r = 0.518, P = 0.010) measured at 6 months after liver biopsy. Our results indicate that SSWE is a more promising tool to assess liver fibrosis than APRI and FIB-4 in children with BA. PMID- 27511436 TI - Small bowel neuroendocrine tumors: A critical analysis of diagnostic work-up and operative approach. AB - BACKGROUND: Small bowel neuroendocrine tumors (SB-NETs) are often small, multifocal, difficult to localize preoperatively, and can be overlooked during operative exploration. The optimal work-up and operative approach is unknown. METHODS: Patients who underwent resection of SB-NETs at a single-institution from 2000 to 2014 were included. Primary aim was to describe the diagnostic work-up and compare minimally invasive (MIS) to open resection. RESULTS: Ninety-three patients underwent resection for SB-NETs. About 71% were symptomatic and on average underwent three diagnostic tests: 45% had octreoscans (85% diagnostic yield); 11% had SB-enteroscopy (10% yield); 19% had capsule endoscopy (83% yield, but identified the correct tumor number in only 21%). About 27 pts underwent MIS versus 66 open. MIS pts were younger (56 vs. 61 yrs; P = 0.035), and less likely to have obstruction (4% vs. 24%; P = 0.019) and metastases (19% vs. 44%; P = 0.038). Compared to open, MIS had smaller (1.7 vs. 2.4 cm; P = 0.03) and fewer tumors resected (2 vs. 5; P = 0.049), but similar LN yield (13 vs. 12; P = 0.7). In non-metastatic, curative-intent resections, MIS still resected fewer tumors compared to open (1.5 vs. 4; P = 0.034). CONCLUSION: Capsule endoscopy may be better than small bowel enteroscopy at identifying occult SB-NETs, but may underestimate tumor burden. While MIS may be appropriate in select patients, recognizing the limitations of preoperative evaluation is critical for these tumors, as heightened operative vigilance is often required. J. Surg. Oncol. 2016;114:671-676. (c) 2016 Wiley Periodicals, Inc. PMID- 27511438 TI - Why are sec-alkylperoxyl bimolecular self-reactions orders of magnitude faster than the analogous reactions of tert-alkylperoxyls? The unanticipated role of CH hydrogen bond donation. AB - High-level ab initio calculations are used to identify the mechanism of secondary (and primary) alkylperoxyl radical termination and explain why their reactions are much faster than their tertiary counterparts. Contrary to existing literature, the decomposition of both tertiary and non-tertiary tetroxides follows the same asymmetric two-step bond cleavage pathway to form a caged intermediate of overall singlet multiplicity comprising triplet oxygen and two alkoxyl radicals. The alpha hydrogen atoms of non-tertiary species facilitate this process by forming unexpected CHO hydrogen bonds to the evolving O2. For non tertiary peroxyls, subsequent alpha hydrogen atom transfer then yields the experimentally observed non-radical products, ketone, alcohol and O2, whereas for tertiary species, this reaction is precluded and cage escape of the (unpaired) alkoxyl radicals is a likely outcome with important consequences for autoxidation. PMID- 27511437 TI - Spanish-Language Consumer Health Information Technology Interventions: A Systematic Review. AB - BACKGROUND: As consumer health information technology (IT) becomes more thoroughly integrated into patient care, it is critical that these tools are appropriate for the diverse patient populations whom they are intended to serve. Cultural differences associated with ethnicity are one aspect of diversity that may play a role in user-technology interactions. OBJECTIVE: Our aim was to evaluate the current scope of consumer health IT interventions targeted to the US Spanish-speaking Latino population and to characterize these interventions in terms of technological attributes, health domains, cultural tailoring, and evaluation metrics. METHODS: A narrative synthesis was conducted of existing Spanish-language consumer health IT interventions indexed within health and computer science databases. Database searches were limited to English-language articles published between January 1990 and September 2015. Studies were included if they detailed an assessment of a patient-centered electronic technology intervention targeting health within the US Spanish-speaking Latino population. Included studies were required to have a majority Latino population sample. The following were extracted from articles: first author's last name, publication year, population characteristics, journal domain, health domain, technology platform and functionality, available languages of intervention, US region, cultural tailoring, intervention delivery location, study design, and evaluation metrics. RESULTS: We included 42 studies in the review. Most of the studies were published between 2009 and 2015 and had a majority percentage of female study participants. The mean age of participants ranged from 15 to 68. Interventions most commonly focused on urban population centers and within the western region of the United States. Of articles specifying a technology domain, computer was found to be most common; however, a fairly even distribution across all technologies was noted. Cancer, diabetes, and child, infant, or maternal health were the most common health domains targeted by consumer health IT interventions. More than half of the interventions were culturally tailored. The most frequently used evaluation metric was behavior/attitude change, followed by usability and knowledge retention. CONCLUSIONS: This study characterizes the existing body of research exploring consumer health IT interventions for the US Spanish-speaking Latino population. In doing so, it reveals three primary needs within the field. First, while the increase in studies targeting the Latino population in the last decade is a promising advancement, future research is needed that focuses on Latino subpopulations previously overlooked. Second, preliminary steps have been taken to culturally tailor consumer health IT interventions for the US Spanish speaking Latino population; however, focus must expand beyond intervention content. Finally, the field should work to promote long-term evaluation of technology efficacy, moving beyond intermediary measures toward measures of health outcomes. PMID- 27511439 TI - Cadmium-induced immune abnormality is a key pathogenic event in human and rat models of preeclampsia. AB - With increased industrial development, cadmium is an increasingly important environmental pollutant. Studies have identified various adverse effects of cadmium on human beings. However, the relationships between cadmium pollution and the pathogenesis of preeclampsia remain elusive. The objective of this study is to explore the effects of cadmium on immune system among preeclamptic patients and rats. The results showed that the cadmium levels in the peripheral blood of preeclamptic patients were significantly higher than those observed in normal pregnancy. Based on it, a novel rat model of preeclampsia was established by the intraperitoneal administration of cadmium chloride (CdCl2) (0.125 mg of Cd/kg body weight) on gestational days 9-14. Key features of preeclampsia, including hypertension, proteinuria, placental abnormalities and small foetal size, appeared in pregnant rats after the administration of low-dose of CdCl2. Cadmium increased immunoglobulin production, mainly angiotensin II type 1-receptor agonistic autoantibodies (AT1-AA), by increasing the expression of activation induced cytosine deaminase (AID) in B cells. AID is critical for the maturation of antibody and autoantibody responses. In addition, angiotensin II type 1 receptor-agonistic autoantibody, which emerged recently as a potential pathogenic contributor to PE, was responsible for the deposition of complement component 5 (C5) in kidneys of pregnant rats via angiotensin II type 1 receptor (AT1R) activation. C5a is a fragment of C5 that is released during C5 activation. Selectively interfering with C5a signalling by a complement C5a receptor-specific antagonist significantly attenuated hypertension and proteinuria in Cd-injected pregnant rats. Our results suggest that cadmium induces immune abnormalities that may be a key pathogenic contributor to preeclampsia and provide new insights into treatment strategies of preeclampsia. PMID- 27511440 TI - Comparisons of discrete and integrative sampling accuracy in estimating pulsed aquatic exposures. AB - Most current-use pesticides have short half-lives in the water column and thus the most relevant exposure scenarios for many aquatic organisms are pulsed exposures. Quantifying exposure using discrete water samples may not be accurate as few studies are able to sample frequently enough to accurately determine time weighted average (TWA) concentrations of short aquatic exposures. Integrative sampling methods that continuously sample freely dissolved contaminants over time intervals (such as integrative passive samplers) have been demonstrated to be a promising measurement technique. We conducted several modeling scenarios to test the assumption that integrative methods may require many less samples for accurate estimation of peak 96-h TWA concentrations. We compared the accuracies of discrete point samples and integrative samples while varying sampling frequencies and a range of contaminant water half-lives (t50 = 0.5, 2, and 8 d). Differences the predictive accuracy of discrete point samples and integrative samples were greatest at low sampling frequencies. For example, when the half life was 0.5 d, discrete point samples required 7 sampling events to ensure median values > 50% and no sampling events reporting highly inaccurate results (defined as < 10% of the true 96-h TWA). Across all water half-lives investigated, integrative sampling only required two samples to prevent highly inaccurate results and measurements resulting in median values > 50% of the true concentration. Regardless, the need for integrative sampling diminished as water half-life increased. For an 8-d water half-life, two discrete samples produced accurate estimates and median values greater than those obtained for two integrative samples. Overall, integrative methods are the more accurate method for monitoring contaminants with short water half-lives due to reduced frequency of extreme values, especially with uncertainties around the timing of pulsed events. However, the acceptability of discrete sampling methods for providing accurate concentration measurements increases with increasing aquatic half-lives. PMID- 27511441 TI - A Novel Trihybrid Material Based on Renewables: An Efficient Recyclable Heterogeneous Catalyst for C-C Coupling and Reduction Reactions. AB - The generation of organic-inorganic hybrid materials from renewable resources and their utilization in basic and applied areas has been at the forefront of research in recent years for sustainable development. Herein, a novel organic inorganic trihybrid material was synthesized by in situ generation of palladium nanoparticles (PdNPs) in a hybrid gel matrix based on renewable chemicals. Constituents of the hybrid gel included a pentacyclic triterpenoid arjunolic acid extractable from Terminalia arjuna and the leaf extract of Chrysophyllum cainito rich in flavonoids. We took advantage of the presence of flavonoid molecules in this hybrid gel to generate an advanced trihybrid gel through in situ reduction of doped Pd(II) salts to stable PdNPs. The xerogel of this trihybrid material was used as a recyclable heterogeneous catalyst for C-C coupling and reduction reactions in aqueous media. We also demonstrated that the in situ generated PdNPs containing trihybrid material was a more efficient catalyst than the trihybrid material generated with presynthesized PdNPs. PMID- 27511442 TI - Unravelling Li-Ion Transport from Picoseconds to Seconds: Bulk versus Interfaces in an Argyrodite Li6PS5Cl-Li2S All-Solid-State Li-Ion Battery. AB - One of the main challenges of all-solid-state Li-ion batteries is the restricted power density due to the poor Li-ion transport between the electrodes via the electrolyte. However, to establish what diffusional process is the bottleneck for Li-ion transport requires the ability to distinguish the various processes. The present work investigates the Li-ion diffusion in argyrodite Li6PS5Cl, a promising electrolyte based on its high Li-ion conductivity, using a combination of (7)Li NMR experiments and DFT based molecular dynamics simulations. This allows us to distinguish the local Li-ion mobility from the long-range Li-ion motional process, quantifying both and giving a coherent and consistent picture of the bulk diffusion in Li6PS5Cl. NMR exchange experiments are used to unambiguously characterize Li-ion transport over the solid electrolyte-electrode interface for the electrolyte-electrode combination Li6PS5Cl-Li2S, giving unprecedented and direct quantitative insight into the impact of the interface on Li-ion charge transport in all-solid-state batteries. The limited Li-ion transport over the Li6PS5Cl-Li2S interface, orders of magnitude smaller compared with that in the bulk Li6PS5Cl, appears to be the bottleneck for the performance of the Li6PS5Cl-Li2S battery, quantifying one of the major challenges toward improved performance of all-solid-state batteries. PMID- 27511443 TI - NSAID-induced symptomatic hypophosphataemia. PMID- 27511444 TI - Radiofrequency ablation compared with laparoscopic adrenalectomy for aldosterone producing adenoma. AB - BACKGROUND: Radiofrequency ablation (RFA) is an emerging treatment for primary aldosteronism owing to aldosterone-producing adenoma. Whether RFA could be an alternative treatment to laparoscopic adrenalectomy is unknown. METHODS: This was a retrospective comparative study in patients with aldosterone-producing adenoma undergoing either laparoscopic adrenalectomy or CT-guided percutaneous RFA between 2004 and 2012. Short-term outcomes and long-term resolution rates of primary aldosteronism (normalized aldosterone to renin ratio), hypokalaemia and hypertension (BP lower than 140/90 mmHg without antihypertensive medical therapy) were evaluated. RESULTS: Some 63 patients were included, 27 in the laparoscopic adrenalectomy group and 36 in the RFA group. RFA was associated with shorter duration of operation (median 12 versus 124 min; P < 0.001), shorter hospital stay (2 versus 4 days; P < 0.001), lower analgesic requirements (13 of 36 versus 23 of 27 patients; P < 0.001) and earlier resumption of work (median 4 versus 14 days; P = 0.006). Morbidity rates were similar in the two groups. With median follow-up of 5.7 (range 1.9-10.6) years, resolution of primary aldosteronism was seen in 33 of 36 patients treated with RFA and all 27 patients who had laparoscopic adrenalectomy (P = 0.180). Hypertension was resolved less frequently after treatment with RFA compared with laparoscopic adrenalectomy (13 of 36 versus 19 of 27 patients; P = 0.007). Hypokalaemia was resolved in all patients. CONCLUSION: For patients with aldosterone-producing adenoma the efficacy of resolution of primary aldosteronism and hypertension was inferior after treatment with RFA compared with laparoscopic adrenalectomy. PMID- 27511446 TI - Five-year clinical performance of a biodegradable polymer-coated biolimus-eluting stent in unselected patients. AB - OBJECTIVE: To evaluate the long-term follow-up of the unrestricted use of a biodegradable polymer-coated drug-eluting stent in patients undergoing percutaneous coronary intervention (PCI). METHODS: The Nobori 2 study was a prospective, multicentre, observational registry evaluating the safety and the efficacy of the biodegradable polymer biolimus-eluting stent (BP-BES) among 3067 patients recruited at 125 international sites. The primary combined endpoint was a composite of cardiac death, myocardial infarction and target-lesion revascularisation (TLR). RESULTS: Five-year follow-up was available in 2738 (89.3%) patients. The combined endpoint occurred in 268 patients (10%, 95% CIs 8.9% to 11.3%) at 5 years, with 3.9% of events during the first year and 6.2% during years 1-5 of follow-up. Cumulative rates of TLR and definite/probable stent thrombosis were 5.3% (95% CI 4.5% to 6.3%) and 1.1% (95% CI 0.8% to 1.6%), respectively. Between 1 and 5 years, TLR and very late stent thrombosis rates were 3.5% (95% CI 2.8% to 4.4%) and 0.6% (95% CI 0.3% to 1.1%), respectively. Previous PCI (HR, 2.05, 95% CI 1.68 to 2.50), moderate-to-severe renal disease (HR, 1.89, 95% CI 1.30 to 2.74) and peripheral vascular disease (HR, 1.86, 95% CI 1.38 to 2.52) were the three most powerful independent predictors of the combined endpoint at 5 years. CONCLUSIONS: The final 5-year follow-up of the Nobori 2 registry demonstrates the safety and effectiveness of the BP-BES in an unselected, broadly inclusive cohort of PCI patients, highlighting the excellent performance of this coronary stent technology after polymer biodegradation. TRIAL REGISTRATION NUMBER: ISRCTN81649913; Results. PMID- 27511445 TI - Gene expression of muscular and neuronal pathways is cooperatively dysregulated in patients with idiopathic achalasia. AB - Idiopathic achalasia is characterized by the absence of peristalsis secondary to loss of neurons in the myenteric plexus that hampers proper relaxation of the lower esophageal sphincter. Achalasia can be considered a multifactorial disorder as it occurs in related individuals and is associated with HLA class II genes, thereby suggesting genetic influence. We used microarray technology and advanced in-silico functional analyses to perform the first genome-wide expression profiling of mRNA in tissue samples from 12 achalasia and 5 control patients. It revealed 1,728 differentially expressed genes, of these, 837 (48.4%) were up regulated in cases. In particular, genes participating to the smooth muscle contraction biological function were mostly up-regulated. Functional analysis revealed a significant enrichment of neuronal/muscular and neuronal/immunity processes. Upstream regulatory analysis of 180 genes involved in these processes suggested TLR4 and IL18 as critical key-players. Two functional gene networks were significantly over-represented: one involved in organ morphology, skeletal muscle system development and function, and neurological diseases, and the other participating in cell morphology, humoral immune response and cellular movement. These results highlight on pivotal genes that may play critical roles in neuronal/muscular and neuronal/immunity processes, and that may contribute to the onset and development of achalasia. PMID- 27511447 TI - Pregnancy outcomes in patients with pulmonary arterial hypertension associated with congenital heart disease. AB - OBJECTIVE: There is growing evidence that maternal mortality in pregnant women with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is lower than that in available data. In order to evaluate this hypothesis, we collected data of pregnancies in women with PAH-CHD. METHODS: Women with PAH-CHD followed in seven French referral centres were retrospectively included from 1997 to 2015. All pregnancies were recorded. We collected data on maternal, obstetrical and neonatal outcomes. RESULTS: 28 pregnancies in 20 women (26+/-6 years old) with PAH-CHD were managed during this period. There were 18 complete pregnancies (>=20 weeks' gestation (WG)), 8 abortions and 2 miscarriages. Six (33%, 95% CI (11.9 to 54.3)) patients experienced severe cardiac events. The concerned women had lower resting oxygen saturation (79.6+/ 4.1% vs 89.3+/-3.8%, p<0.01). The most common cardiac complications during the complete pregnancies were heart failure (n=4) and severe hypoxaemia (n=5). Heart failure was overall severe, requiring inotropic treatment in three patients, mechanical circulatory support in one and led to one maternal death (mortality=5.0% 95% CI (0.1 to 24.9)). Obstetrical complications occurred in 25% of pregnancies. Small for gestational age was diagnosed in 39% (7/18) of fetuses. 12/18 (67%) pregnancies were delivered by caesarean section, of which 10 in emergency for obstetrical reason. Prematurity was frequent (78%), but no neonatal death occurred. CONCLUSIONS: Outcome of pregnancy in women with PAH-CHD is better than previously reported, with only 5% maternal mortality in our cohort. However, because of the severity of heart failure and the high rate of neonatal complications, patients should still be advised against pregnancy. PMID- 27511449 TI - Corrigendum. AB - [This corrects the article DOI: 10.1111/rcr2.151.]. PMID- 27511448 TI - Posttraumatic stress disorder under ongoing threat: a review of neurobiological and neuroendocrine findings. AB - BACKGROUND: Although numerous studies have investigated the neurobiology and neuroendocrinology of posttraumatic stress disorder (PTSD) after single finished trauma, studies on PTSD under ongoing threat are scarce and it is still unclear whether these individuals present similar abnormalities. OBJECTIVE: The purpose of this review is to present the neurobiological and neuroendocrine findings on PTSD under ongoing threat. Ongoing threat considerably affects PTSD severity and treatment response and thus disentangling its neurobiological and neuroendocrine differences from PTSD after finished trauma could provide useful information for treatment. METHOD: Eighteen studies that examined brain functioning and cortisol levels in relation to PTSD in individuals exposed to intimate partner violence, police officers, and fire fighters were included. RESULTS: Hippocampal volume was decreased in PTSD under ongoing threat, although not consistently associated with symptom severity. The neuroimaging studies revealed that PTSD under ongoing threat was not characterized by reduced volume of amygdala or parahippocampal gyrus. The neurocircuitry model of PTSD after finished trauma with hyperactivation of amygdala and hypoactivation of prefrontal cortex and hippocampus was also confirmed in PTSD under ongoing threat. The neuroendocrine findings were inconsistent, revealing increased, decreased, or no association between cortisol levels and PTSD under ongoing threat. CONCLUSIONS: Although PTSD under ongoing threat is characterized by abnormal neurocircuitry patterns similar to those previously found in PTSD after finished trauma, this is less so for other neurobiological and in particular neuroendocrine findings. Direct comparisons between samples with ongoing versus finished trauma are needed in future research to draw more solid conclusions before administering cortisol to patients with PTSD under ongoing threat who may already exhibit increased endogenous cortisol levels. PMID- 27511450 TI - Clinical-pathologic correlations in voltage-gated Kv1 potassium channel complex subtyped autoimmune painful polyneuropathy. AB - INTRODUCTION: Voltage-gated Kv1 potassium channel complex (VGKC) autoantibodies subtyped for leucine-rich glioma-inactivated 1 (LGI1), contactin-associated proteinlike 2 (CASPR2), and Kv IgGs have a spectrum of neurological presentations. Painful polyneuropathy is seen in some patients, but nerve pathology descriptions are lacking. METHODS: Clinicopathologic features were studied in subtyped VGKC-autoantibody-seropositive patients who had undergone nerve biopsies. RESULTS: Five patients were identified, 1 LGI1 IgG positive and 1 CASPR2 IgG positive, but all negative for Kv1.1-, 1.2-, 1.6-subtyped IgG autoantibodies. Median symptom duration was 17 months. Pain was the predominant symptom; 3 had mild sensory loss and/or weakness. Histopathological abnormalities were limited to axonal loss in 3. None had mononuclear cellular infiltrates. Electron micrographs revealed no interstitial abnormalities. Three patients reported marked improvement in pain with immunotherapy. CONCLUSIONS: The nerve biopsy histopathology of patients subtyped for LGI1 and CASPR2 IgGs within the VGKC-complex spectrum disorders shows either normal density or axonal fiber loss without inflammatory infiltrates. A reversible neural hyperexcitable mechanism is considered to be the cause of this painful polyneuropathy. Muscle Nerve 55: 520 525, 2017. PMID- 27511452 TI - Effects of exogenous testosterone and mating context on men's preferences for female facial femininity. AB - Correlational research suggests that men show greater attraction to feminine female faces when their testosterone (T) levels are high. Men's preferences for feminine faces also seem to vary as a function of relationship context (short versus long-term). However, the relationship between T and preferences for female facial femininity has yet to be tested experimentally. In the current paper, we report the results of two experiments examining the causal role of T in modulating preferences for facial femininity across both short and long-term mating contexts. Results of Experiment 1 (within-subject design, n=24) showed that participants significantly preferred feminized versus masculinized versions of women's faces. Further, participants showed a stronger preference for feminine faces in the short versus the long-term context after they received T, but not after they received placebo. Post-hoc analyses suggested that this effect was driven by a lower preference for feminine faces in the long-term context when on T relative to placebo, and this effect was found exclusively for men who received placebo on the first day of testing, and T on the second day of testing (i.e., Order x Drug x Mating context interaction). In Experiment 2 (between-subject design, n=93), men demonstrated a significant preference for feminized female faces in the short versus the long-term context after T, but not after placebo administration. Collectively, these findings provide the first causal evidence that T modulates men's preferences for facial femininity as a function of mating context. PMID- 27511451 TI - NIR Light Propulsive Janus-like Nanohybrids for Enhanced Photothermal Tumor Therapy. AB - Au-BP7@SP nanohybrids with active motion under NIR laser irradiation can effectively enhance the temperature of tumor potentially by converting the kinetic energy to thermal energy, enhancing the killing efficiency of the tumor cells compared with Au@SP. The study provides an insight of nanohybrids' effect on photothermal treatment and opens a new avenue to cancer treatment by using self-propulsion Janus nanohybrids. PMID- 27511453 TI - Identification of proteomic and metabolic signatures associated with chemoresistance of human epithelial ovarian cancer. AB - Emerging drug resistance in epithelial ovarian cancer (EOC) thwarted progress in platinum-based chemotherapy, resulting in increased mortality, morbidity and healthcare costs. The aim of this study was to detect the responses induced by chemotherapy at protein and metabolite levels, and to search for new plasma markers that can predict resistance to platinum-based chemotherapy in EOC patients, leading to improved clinical response rates. Serum samples were collected and subjected to proteomic relative quantitation analysis and metabolomic analysis. Differentially expressed proteins and metabolites were subjected to bioinformatics and statistical analysis. Proteins that played a key role in platinum resistance were validated by western blotting and enzyme-linked immunosorbent assay (ELISA). Metabolites that were the main contributors to the groups and closely with clinical characteristics were identified based on the database using nuclear magnetic resonance (NMR). In total, 248 proteins from two independent experiments were identified using isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic approach. Among them, FN1, SERPINA1, GPX3 and ORM1 were chosen for western blotting and ELISA validation. Platinum resistance likely associated with differentially expressed proteins and FN1, SERPINA1 and ORM1 may play a positive role in chemotherapy. HPLC-MS analysis of four groups revealed a total of 25,800 metabolic features, of which six compounds were chosen for candidate biomarkers and identified based on the database using NMR. The metabolic signatures of normal control (NC), platinum sensitive (PTS) and platinum-resistant (PTR) groups were clearly separated from each other. Those findings may provide theoretical clues for the prediction of chemotherapeutic response and reverse of drug resistance, even lead to novel targets for therapeutic intervention. PMID- 27511454 TI - Implementation errors in the GingerALE Software: Description and recommendations. AB - Neuroscience imaging is a burgeoning, highly sophisticated field the growth of which has been fostered by grant-funded, freely distributed software libraries that perform voxel-wise analyses in anatomically standardized three-dimensional space on multi-subject, whole-brain, primary datasets. Despite the ongoing advances made using these non-commercial computational tools, the replicability of individual studies is an acknowledged limitation. Coordinate-based meta analysis offers a practical solution to this limitation and, consequently, plays an important role in filtering and consolidating the enormous corpus of functional and structural neuroimaging results reported in the peer-reviewed literature. In both primary data and meta-analytic neuroimaging analyses, correction for multiple comparisons is a complex but critical step for ensuring statistical rigor. Reports of errors in multiple-comparison corrections in primary-data analyses have recently appeared. Here, we report two such errors in GingerALE, a widely used, US National Institutes of Health (NIH)-funded, freely distributed software package for coordinate-based meta-analysis. These errors have given rise to published reports with more liberal statistical inferences than were specified by the authors. The intent of this technical report is threefold. First, we inform authors who used GingerALE of these errors so that they can take appropriate actions including re-analyses and corrective publications. Second, we seek to exemplify and promote an open approach to error management. Third, we discuss the implications of these and similar errors in a scientific environment dependent on third-party software. Hum Brain Mapp 38:7-11, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27511455 TI - Linking microbial diversity and functionality of arctic glacial surface habitats. AB - Distinct microbial habitats on glacial surfaces are dominated by snow and ice algae, which are the critical players and the dominant primary colonisers and net producers during the melt season. Here for the first time we have evaluated the role of these algae in association with the full microbial community composition (i.e., algae, bacteria, archaea) in distinct surface habitats and on 12 glaciers and permanent snow fields in Svalbard and Arctic Sweden. We cross-correlated these data with the analyses of specific metabolites such as fatty acids and pigments, and a full suite of potential critical physico-chemical parameters including major and minor nutrients, and trace metals. It has been shown that correlations between single algal species, metabolites, and specific geochemical parameters can be used to unravel mixed metabolic signals in complex communities, further assign them to single species and infer their functionality. The data also clearly show that the production of metabolites in snow and ice algae is driven mainly by nitrogen and less so by phosphorus limitation. This is especially important for the synthesis of secondary carotenoids, which cause a darkening of glacial surfaces leading to a decrease in surface albedo and eventually higher melting rates. PMID- 27511456 TI - Quantification of intact plasma AGT consisting of oxidized and reduced conformations using a modified ELISA. AB - The pleiotropic actions of the renin-angiotensin system (RAS) depend on the availability of angiotensinogen (AGT) which generates angiotensin I (ANG I) when cleaved by renin. Thus, quantification of the intact AGT (iAGT) concentrations is important to evaluate the actual renin substrate available. The iAGT conformation exists as oxidized AGT (oxi-AGT) and reduced AGT (red-AGT) in a disulfide bond, and oxi-AGT has a higher affinity for renin, which may exacerbate RAS-associated diseases. Accordingly, we determined iAGT, oxi-AGT, and red-AGT levels in plasma from rats and mice. Blood samples were obtained by cardiac puncture and then immediately mixed with an inhibitor solution containing a renin inhibitor. Total AGT (tAGT) levels were measured by tAGT ELISA which detects both cleaved and iAGT. iAGT levels were determined by iAGT ELISA which was found to only detect red-AGT. Thus, it was necessary to treat samples with dithiothreitol, a reducing agent, to quantify total iAGT concentration. tAGT levels in rat and mouse plasma were 1,839 +/- 139 and 1,082 +/- 77 ng/ml, respectively. iAGT levels were 53% of tAGT in rat plasma but only 22% in mouse plasma, probably reflecting the greater plasma renin activity in mice. The ratios of oxi-AGT and red-AGT were ~4:1 (rat) and 16:1 (mouse). Plasma iAGT consists of oxi-AGT and red-AGT, suggesting that oxidative stress can influence ANG I generation by the AGT conformation switch. Furthermore, the lower availability of plasma iAGT in mice suggests that it may serve as a limiting factor in ANG I formation in this species. PMID- 27511458 TI - WUWHS 2016: What Promises for the Future? PMID- 27511457 TI - An additive effect of anti-PAI-1 antibody to ACE inhibitor on slowing the progression of diabetic kidney disease. AB - While angiotensin II blockade slows the progression of diabetic nephropathy, current data suggest that it alone cannot stop the disease process. New therapies or drug combinations will be required to further slow or halt disease progression. Inhibition of plasminogen activator inhibitor type 1 (PAI-1) aimed at enhancing ECM degradation has shown therapeutic potential in diabetic nephropathy. Here, using a mouse model of type diabetes, the maximally therapeutic dose of the PAI-1-neutralizing mouse monoclonal antibody (MEDI-579) was determined and compared with the maximally effective dose of enalapril. We then examined whether addition of MEDI-579 to enalapril would enhance the efficacy in slowing the progression of diabetic nephropathy. Untreated uninephrectomized diabetic db/db mice developed progressive albuminuria and glomerulosclerosis associated with increased expression of transforming growth factor (TGF)-beta1, PAI-1, type IV collagen, and fibronectin from weeks 18 to 22, which were reduced by MEDI-579 at 3 mg/kg body wt, similar to enalapril given alone from weeks 12 to 22 Adding MEDI-579 to enalapril from weeks 18 to 22 resulted in further reduction in albuminuria and markers of renal fibrosis. Renal plasmin generation was dramatically reduced by 57% in diabetic mice, a decrease that was partially reversed by MEDI-579 or enalapril given alone but was further restored by these two treatments given in combination. Our results suggest that MEDI-579 is effective in slowing the progression of diabetic nephropathy in db/db mice and that the effect is additive to ACEI. While enalapril is renal protective, the add-on PAI-1 antibody may offer additional renoprotection in progressive diabetic nephropathy via enhancing ECM turnover. PMID- 27511460 TI - Endothelial Transcytosis of Insulin: Does It Contribute to Insulin Resistance? AB - Most research on insulin resistance has focused on impaired signaling at the level of target tissues like skeletal muscle. Insulin delivery is also important and includes recruitment and perfusion of capillaries bearing insulin, but also the transit of insulin across the capillary endothelium. The mechanisms of this second stage (insulin transcytosis) and whether it contributes to insulin resistance remain uncertain. PMID- 27511459 TI - Gut Microbiota: Modulation of Host Physiology in Obesity. AB - Many factors are involved in weight gain and metabolic disturbances associated with obesity. The gut microbiota has been of particular interest in recent years, since both human and animal studies have increased our understanding of the delicate symbiosis between the trillions of microbes that reside in the GI tract and the host. It has been suggested that disruption of this mutual tolerance may play a significant role in modulating host physiology during obesity. Environmental influences such as diet, exercise, and early life exposures can significantly impact the composition of the microbiota, and this dysbiosis can in turn lead to increased host adiposity via a number of different mechanisms. The ability of the microbiota to regulate host fat deposition, metabolism, and immune function makes it an attractive target for achieving sustained weight loss. PMID- 27511461 TI - Regulatory Roles of Fluctuation-Driven Mechanotransduction in Cell Function. AB - Cells in the body are exposed to irregular mechanical stimuli. Here, we review the so-called fluctuation-driven mechanotransduction in which stresses stretching cells vary on a cycle-by-cycle basis. We argue that such mechanotransduction is an emergent network phenomenon and offer several potential mechanisms of how it regulates cell function. Several examples from the vasculature, the lung, and tissue engineering are discussed. We conclude with a list of important open questions. PMID- 27511463 TI - Negative News: Cl- and HCO3- in the Vascular Wall. AB - Cl(-) and HCO3 (-) are the most prevalent membrane-permeable anions in the intra- and extracellular spaces of the vascular wall. Outwardly directed electrochemical gradients for Cl(-) and HCO3 (-) permit anion channel opening to depolarize vascular smooth muscle and endothelial cells. Transporters and channels for Cl(-) and HCO3 (-) also modify vascular contractility and structure independently of membrane potential. Transport of HCO3 (-) regulates intracellular pH and thereby modifies the activity of enzymes, ion channels, and receptors. There is also evidence that Cl(-) and HCO3 (-) transport proteins affect gene expression and protein trafficking. Considering the extensive implications of Cl(-) and HCO3 (-) in the vascular wall, it is critical to understand how these ions are transported under physiological conditions and how disturbances in their transport can contribute to disease development. Recently, sensing mechanisms for Cl(-) and HCO3 (-) have been identified in the vascular wall where they modify ion transport and vasomotor function, for instance, during metabolic disturbances. This review discusses current evidence that transport (e.g., via NKCC1, NBCn1, Ca(2+)-activated Cl(-) channels, volume-regulated anion channels, and CFTR) and sensing (e.g., via WNK and RPTPgamma) of Cl(-) and HCO3 (-) influence cardiovascular health and disease. PMID- 27511462 TI - Ion Channels in Endothelial Responses to Fluid Shear Stress. AB - Fluid shear stress is an important environmental cue that governs vascular physiology and pathology, but the molecular mechanisms that mediate endothelial responses to flow are only partially understood. Gating of ion channels by flow is one mechanism that may underlie many of the known responses. Here, we review the literature on endothelial ion channels whose activity is modulated by flow with an eye toward identifying important questions for future research. PMID- 27511464 TI - Clinical validation of a precision electromagnetic tremor measurement system in participants receiving deep brain stimulation for essential tremor. AB - Tremor is characterized commonly through subjective clinical rating scales. Accelerometer-based techniques for objective tremor measurement have been developed in the past, yet these measures are usually presented as an unintuitive dimensionless index without measurement units. Here we have developed a tool (TREMBAL) to provide quantifiable and objective measures of tremor severity using electromagnetic motion tracking. We aimed to compare TREMBAL's objective measures with clinical tremor ratings and determine the test-retest reliability of our technique. Eight participants with ET receiving deep brain stimulation (DBS) therapy were consented. Tremor was simultaneously recorded using TREMBAL and video during DBS adjustment. After each adjustment, participants performed a hands-outstretched task (for postural tremor) and a finger-nose task (for kinetic tremor). Video recordings were de-identified, randomized, and shown to a panel of movement disorder specialists to obtain their ratings. Regression analysis and Pearson's correlations were used to determine agreement between datasets. Subsets of the trial were repeated to assess test-retest reliability. Tremor amplitude and velocity measures were in close agreement with mean clinical ratings (r > 0.90) for both postural and kinetic tremors. Test-retest reliability for both translational and rotational components of tremor showed intra-class correlations >0.80. TREMBAL assessments showed that tremor gradually improved with increasing DBS therapy-this was also supported by clinical observation. TREMBAL measurements are a sensitive, objective and reliable assessment of tremor severity. This tool may have application in clinical trials and in aiding automated optimization of deep brain stimulation. PMID- 27511465 TI - Divergent habitat filtering of root and soil fungal communities in temperate beech forests. AB - Distance decay, the general reduction in similarity of community composition with increasing geographical distance, is known as predictor of spatial variation and distribution patterns of organisms. However, changes in fungal communities along environmental gradients are little known. Here we show that distance decays of soil-inhabiting and root-associated fungal assemblages differ, and identify explanatory environmental variables. High-throughput sequencing analysis of fungal communities of beech-dominated forests at three study sites across Germany shows that root-associated fungi are recruited from the soil fungal community. However, distance decay is substantially weaker in the root-associated than in the soil community. Variance partitioning of factors contributing to the observed distance decay patterns support the hypothesis that host trees stabilize the composition of root-associated fungi communities, relative to soil communities. Thus, they not only have selective impacts on associated communities, but also buffer effects of changes in microclimatic and environmental variables that directly influence fungal community composition. PMID- 27511466 TI - Assessment of the mean time in the therapeutic INR range and the SAME-TT2R2 score in patients with atrial fibrillation and cognitive impairment. AB - INTRODUCTION Most patients with atrial fibrillation (AF) are elderly and may have an increased risk of cognitive disorders. Low mean values of the therapeutic international normalized ratio (INR) range (TTR) (<=60%) are associated with increased risk of stroke, vascular events, and bleeding complications. OBJECTIVES The aim of the study was to evaluate the efficacy of long-term anticoagulant therapy in patients treated with vitamin K antagonists (VKAs), depending on their cognitive functions. In addition, we used the SAMe-TT2R2 risk score to predict the risk of ineffective anticoagulation. PATIENTS AND METHODS The analysis comprised 154 patients (68 men and 86 women; mean age, 76 +/-10 years) with AF and indications for long-term therapy with VKA (CHA2DS2-VASc score >=1, HAS-BLED score <3). Cognitive functions were evaluated using the Mini-Mental State Examination (MMSE) score. The efficacy of VKA therapy was determined by the TTR values from the preceding 6 months of treatment. We used the SAMe-TT2R2 score to identify patients who were likely to have poor INR control. RESULTS Depending on the number of MMSE points, patients treated with VKAs were divided into 2 groups: patients with normal cognitive functions (MMSE score >=27; n = 62) and those with cognitive impairment (MMSE score <27; n = 42). Despite the fact that all patients had indications for anticoagulant therapy, 50 patients (32%) received no VKAs on admission. The mean TTR value exceeded 60% in 61% of patients with an MMSE score of 27 points or higher, whereas mean TTR value was 28% in patients with an MMSE score of less than 27 (P <0.0001). Patients with a SAMe TT2R2 score of 0 to 1 had higher TTR values than those with a SAMe-TT2R2 score of 2 or higher (r = -0.24; P <0.05 ). The cognitive status was significantly more impaired in patients with persistent and permanent AF compared with patients with paroxysmal AF (MMSE score, 25.8 +/-3.7 vs 28.6 +/-2; P <0.0001). CONCLUSIONS Cognitive disorders in patients with AF significantly reduce the efficacy of VKA therapy. The decision to administer VKA treatment should be based not only on the CHA2DS2-VASc and HAS-BLED scores, but also on the SAMe-TT2R2 score and the evaluation of the patient's cognitive functions. PMID- 27511467 TI - Extra-articular tenodesis combined with an anterior cruciate ligament reconstruction in acute anterior cruciate ligament tear in elite female football players. AB - PURPOSE: The growing popularity of elite soccer among female participants has led to increased incidents of anterior cruciate ligament (ACL) ruptures. Many authors underline a positive glide after ACL reconstruction (ACLR), especially in women. In fact, an isolated intra-articular ACLR may be inadequate to control rotational instability after a combined injury of the ACL and the peripheral structures of the knee. Extra-articular procedures are sometimes used in primary cases displaying excessive antero-lateral rotatory instability. The purpose of this case series was to report subjective and objective outcomes after combined ACL and lateral extra-articular tenodesis (LET) with a minimum 4-year follow-up in a selected high-risk population of elite female football players. METHODS: Between January 2007 and December 2010, 16 elite Italian female football players were included in the study. All patients underwent the same surgical technique: anatomical ACLR with autogenous semitendinosus and gracilis tendons. After the intra-articular reconstruction was performed, an additional extra-articular MacIntosh modified Coker-Arnold procedure was carried out. Patients were assessed pre- and post-operatively with the subjective and objective International Knee Documentation Committee (IKDC) evaluation form, Tegner activity scale (TAS) and Lysholm score. Joint laxity was assessed with KT-1000 by measuring the side-to side (S/S) differences in displacement at manual maximum (mm) testing. RESULTS: At a mean follow-up of 72.6 +/- 8.1 months, two independent examiners reviewed all players. All of the patients had a fully recovered range of motion. Lachman test was negative in all patients (100 %). The evaluation of joint laxity and clinical evaluation showed a statistically significant improvement. No patients experienced complication or a re-rupture. DISCUSSION: The rationale of combining extra-articular procedures with ACLR is to restrict the internal rotation of the reconstructed knee, taking advantage of its long lever arm and thus providing more stability in the rotational axis and preventing the ACL graft from undergoing further excessive strain. CONCLUSIONS: The combination of an LET with ACLR in elite female football players demonstrated excellent results in terms of subjective scales, post-operative residual laxity and re-rupture rate with no complication, and a complete return to sport activity. PMID- 27511468 TI - Persistent non-union of the humeral shaft treated by plating and autologous bone grafting. AB - INTRODUCTION: Surgical treatment of persistent non-union of the humeral shaft is a complex situation because of the risk of failure and surgery-related complications. The primary objective of this study was to evaluate clinical and radiological results of a continuous series of persistent non-union treated with plating and bone grafting. The secondary objective was to expose factors contributing to the failure of prior bone union attempts. MATERIAL AND METHODS: Sixteen patients (average age of 52 years) were treated for persistent non-union of the humeral shaft in our department; six of these patients had predisposing comorbidities or addictions. The persistent non-union was treated by plating with autologous bone graft from the iliac crest in a single-stage procedure in 12 cases and a two-stage procedure in three cases; one case was treated with plating and vascularized fibula graft. RESULTS: At a minimum follow-up of 12 months (average 78 months), four (25 %) failed to heal. The 12 other patients had bone union after an average of eight months. The average QuickDASH score was 48 points (18-72). A retrospective analysis of the prior attempts to treat the non-union revealed three cases of unstable fixation, four cases with no osteogenic supply and seven cases of positive microbiological cultures at the non-union site. CONCLUSION: Plating and autologous bone grafting resulted in union in only 75 % of persistent non-union of the humeral shaft. The persistent nature of the humeral shaft non-union could be attributed to deviating from validated rules for surgical treatment and/or the presence of a surgical site infection. PMID- 27511469 TI - Variations in the obturator artery around the obturator foramen assessed by three dimensional computed tomographic angiography and prevention of vascular-related complications in rotational acetabular osteotomy. AB - PURPOSE: The aims of this study were (1) to evaluate the anatomical variations and locations of the obturator artery at the obturator foramen using computed tomographic (CT) angiography images and (2) to evaluate the pubic osteotomy site in rotational acetabular osteotomy using postoperative CT images in order to assess the relationship between the obturator artery and the pubic osteotomy site. METHODS: We examined a total of 196 hips in 98 consecutive Japanese patients for aim (1), and 38 consecutive patients who underwent rotational acetabular osteotomy for aim (2). RESULTS: The prevalence of arterial anastomosis of the obturator artery (corona mortis) was 14.3 %, with the obturator artery being located closer to the superior pubic ramus and the osteotomy site in these subjects. CONCLUSIONS: Extensive care should be taken during rotational acetabular osteotomy in patients showing variations of the obturator artery with corona mortis. PMID- 27511470 TI - Comparison of open reduction and internal fixation and primary total hip replacement for osteoporotic acetabular fractures: a retrospective clinical study. AB - PURPOSE: Treating acetabular fractures with open reduction and internal fixation (ORIF) may lead to poorer outcomes in older patients. As data for osteoporotic acetabular fractures are limited, we compared primary total hip replacement (THR) with ORIF for treating osteoporotic acetabular fractures, including those with posterior column instability. METHODS: All patients with osteoporotic acetabular fractures, treated with ORIF or primary THR from 2005 to 2015, were assessed retrospectively for clinical and radiologic outcomes. Indication criteria for selecting primary THR were evaluated. RESULTS: Twenty-three patients were treated with ORIF and nine with primary THR (performed with an anti-protrusion cage). If the posterior column was unstable, THR was combined with posterior column bridge plating. Indications for THR were the presence of a comminuted fracture pattern, approach-related risk factors for ORIF, and mobilization issues. Biomechanical reconstruction was acceptable with THR. Acetabular component loosening was observed only once. Secondary THR was indicated in 45 % of the ORIF cases. DISCUSSION: ORIF for acetabular fracture in older patients is unsatisfactory and may be even worse for osteoporotic fractures. Immobilization for long-term restricted weight bearing after ORIF is hazardous. Primary THR may enable early post-operative full weight-bearing. Various techniques, affording fixation of the unstable acetabular columns, are described. In THR with an anti-protrusion cage, only dorsal column instability needs to be addressed. CONCLUSION: The described technique achieved sufficient acetabular component stability. Primary THR with an anti-protrusion cage is an advantageous option to ORIF and should be strongly considered for osteoporotic acetabular fractures. PMID- 27511472 TI - Automated lesion annotation during pulmonary vein isolation: influence on acute isolation rates and lesion characteristics. AB - PURPOSE: Recovery of pulmonary vein (PV) conduction is a common mechanism of atrial fibrillation recurrence after PV isolation (PVI), underscoring the need for durable lesion formation. We aimed to evaluate the utility of an automated lesion annotation algorithm (ALAA) on acute isolation rates and resulting lesion characteristics. METHODS: Fifty patients underwent PVI using a contact force (CF) sensing catheter and ALAA. Single antral circles around ipsilateral PVs were performed with ALAA-1 settings including catheter stability (range of motion <=2 mm, duration >10 s). Target CF was 10-20 g but not part of ALAA-1 settings. If PV conduction persisted after circle completion, force over time was added to automated settings (ALAA-2). Emerging gaps were subsequently ablated, followed by re-assessment for PVI. RESULTS: ALAA-1 isolated 70 % of the left and 78 % of the right PVs using 756.3 +/- 212.3 s (left) and 737.1 +/- 145.9 s (right) of energy delivery. ALAA-2 settings identified 29 gaps in previously unisolated PVs, closure significantly increased isolation rates to 88 % of the left and 96 % of the right PVs with additional 325.4 +/- 354.1 s (left) and 266.8 +/- 279.5 s (right) of energy delivery (p = 0.001). Lesion characteristics significantly differed between ALAA-1 (n = 3521 lesions) and ALAA-2 (n = 3037 lesions) settings, and between isolated and non-isolated PV segments, particularly with respect to CF. Interlesion distances with ALAA-2 were significantly longer in the left superior, left superior-anterior, and right superior-posterior segments when compared to ALAA-1. CONCLUSIONS: Settings of an ALAA affect lesion characteristics reveal areas of insufficient lesion formation and influence acute effectiveness of PVI. Combination of CF and stability shows superior performance over stability alone. PMID- 27511471 TI - Oral sensory nerve damage: Causes and consequences. AB - Oral sensations (i.e., taste, oral somatosensation, retronasal olfaction) are integrated into a composite sense of flavor, which guides dietary choices with long-term health impact. The nerves carrying this input are vulnerable to peripheral damage from multiple sources (e.g., otitis media, tonsillectomy, head injury), and this regional damage can boost sensations elsewhere in the mouth because of central interactions among nerve targets. Mutual inhibition governs this compensatory process, but individual differences lead to variation in whole mouth outcomes: some individuals are unaffected, others experience severe loss, and some encounter sensory increases that may (if experienced early in life) elevate sweet-fat palatability and body mass. Phantom taste, touch, or pain sensations (e.g., burning mouth syndrome) may also occur, particularly in those expressing the most taste buds. To identify and treat these conditions effectively, emerging clinical tests measure regional vs. whole-mouth sensation, stimulated vs. phantom cues, and oral anatomy. Scaling methods allowing valid group comparisons have strongly aided these efforts. Overall, advances in measuring oral sensory function in health and disease show promise for understanding the varied clinical consequences of nerve damage. PMID- 27511473 TI - Fraction of exhaled nitric oxide as a predictor in juvenile idiopathic arthritis progression. AB - In this study, the relation between the nitric oxide (NO) levels in the serum and fraction of exhaled nitric oxide (FENO) in children with juvenile idiopathic arthritis (JIA) and the activation criteria of the disease has been investigated. The study group consisted of 35 JIA-diagnosed patients and 18 healthy children. According to the clinical and laboratory findings, the patients with JIA were divided into two groups, active (group I) and in remission (group II). The healthy children were classified as group III. The activation criteria of the disease were determined for each patient. The serum NO level and FENO level were measured in all the patients. In the group with JIA, correlation was detected between FENO level and number of involved joints and number of joints with limited motion. In addition, correlation was determined between the FENO level and number of involved joints in group I and the serum NO level and activity score in group II. However, it was seen that there is no statistical difference in the serum NO level and FENO level of the patients with JIA and the control group and groups I and II. This study demonstrated the correlation between FENO level and number of involved joints and number of joints with limited motion in patients with JIA. Our results matter in terms of FENO being a noninvasive laboratory marker in following the progression of the disease. PMID- 27511474 TI - Intramolecular Radical Aziridination of Allylic Sulfamoyl Azides by Cobalt(II) Based Metalloradical Catalysis: Effective Construction of Strained Heterobicyclic Structures. AB - Cobalt(II)-based metalloradical catalysis (MRC) has been successfully applied for effective construction of the highly strained 2-sulfonyl-1,3 diazabicyclo[3.1.0]hexane structures in high yields through intramolecular radical aziridination of allylic sulfamoyl azides. The resulting [3.1.0] bicyclic aziridines prove to be versatile synthons for the preparation of a diverse range of 1,2- and 1,3-diamine derivatives by selective ring-opening reactions. As a demonstration of its application for target synthesis, the metalloradical intramolecular aziridination reaction has been incorporated as a key step for efficient synthesis of a potent neurokinin 1 (NK1 ) antagonist in 60 % overall yield. PMID- 27511475 TI - Dietary sodium and nocturnal blood pressure dipping in normotensive men and women. AB - Impaired nocturnal blood pressure (BP) dipping (i.e., <10% decline in nocturnal BP) is associated with an increased risk of cerebrovascular and cardiovascular diseases. Excess sodium has been shown to impair BP regulation and increase cardiovascular disease risk, yet few studies have assessed the influence of dietary sodium on nocturnal dipping in normotensive adults. The purpose of this study was to determine the effects of dietary sodium on BP dipping in normotensive men and women. Eighty healthy normotensive adults participated in a controlled feeding study (men: n=39, 34+/-2 years; women: n=41, 41+/-2 years). Participants consumed a standardized run-in 100 mmol sodium per day diet for 7 days, followed by 7 days of low-sodium (LS; 20 mmol per day) and high-sodium (HS; 300 mmol per day) diets in random order. On the final day of each diet, subjects wore a 24 h ambulatory BP monitor, collected a 24 h urine sample and provided a blood sample. During the run-in diet, 24 h urinary sodium excretion was 79.4+/ 5.1 mmol per 24 h in men and 85.3+/-5.5 mmol per 24 h in women (P>0.05). Systolic BP dipping was not different between men (11.4+/-1.0%) and women (11.2+/-0.9%); (P>0.05). During the HS diet, 24 h urinary sodium excretion increased compared with the LS diet in men (LS=31.7+/-4.6 mmol per 24 h vs HS=235.0+/-13.9 mmol per 24 h, P<0.01) and women (LS=25.8+/-2.2 mmol per 24 h vs HS=234.7+/-13.8 mmol per 24 h, P<0.01). Despite this large increase in sodium intake and excretion, systolic BP dipping was not blunted in men (LS=8.9+/-1.0% vs HS=9.4+/-1.2%, P>0.05) or women (LS=10.3+/-0.8% vs HS=10.5+/-0.8%, P>0.05). Among normotensive men and women, HS does not blunt nocturnal BP dipping. PMID- 27511476 TI - Blood pressure-lowering effects of nifedipine/candesartan combinations in high risk individuals: subgroup analysis of the DISTINCT randomised trial. AB - The DISTINCT study (reDefining Intervention with Studies Testing Innovative Nifedipine GITS-Candesartan Therapy) investigated the efficacy and safety of nifedipine GITS/candesartan cilexetil combinations vs respective monotherapies and placebo in patients with hypertension. This descriptive sub-analysis examined blood pressure (BP)-lowering effects in high-risk participants, including those with renal impairment (estimated glomerular filtration rate<90 ml min-1, n=422), type 2 diabetes mellitus (n=202), hypercholesterolaemia (n=206) and cardiovascular (CV) risk factors (n=971), as well as the impact of gender, age and body mass index (BMI). Participants with grade I/II hypertension were randomised to treatment with nifedipine GITS (N) 20, 30, 60 mg and/or candesartan cilexetil (C) 4, 8, 16, 32 mg or placebo for 8 weeks. Mean systolic BP and diastolic BP reductions after treatment in high-risk participants were greater, overall, with N/C combinations vs respective monotherapies or placebo, with indicators of a dose-response effect. Highest rates of BP control (ESH/ESC 2013 guideline criteria) were also achieved with highest doses of N/C combinations in each high-risk subgroup. The benefits of combination therapy vs monotherapy were additionally observed in patient subgroups categorised by gender, age or BMI. All high-risk participants reported fewer vasodilatory adverse events in the pooled N/C combination therapy than the N monotherapy group. In conclusion, consistent with the DISTINCT main study outcomes, high-risk participants showed greater reductions in BP and higher control rates with N/C combinations compared with respective monotherapies and lesser vasodilatory side-effects compared with N monotherapy. PMID- 27511477 TI - Association between sleep disorders and hypertension in Taiwan: a nationwide population-based retrospective cohort study. AB - There is insufficient evidence to assess the risk for hypertension in patients with sleep disorders (SDs) in a large population-based cohort study. The aim of this study was to examine the risk of hypertension in groups both with and without SDs. Taiwan's National Health Insurance Research Database (NHIRD) data from 2005 to 2010 were used in a retrospective cohort study. A Cox proportional hazard regression analysis was used to evaluate the effects of SDs on hypertension risk. The overall incidence of hypertension was 120.7 per 1000 person-years for patients with SDs, which was significantly higher than that of the non-SD comparison cohort (76.4 per 1000 person-years). Overall, patients with SDs had a higher risk of hypertension compared with comparison cohort (adjusted hazard ratio (HR)=1.58, 95% confidence interval (CI)=1.26-1.79). Among patients aged <40 years, patients with SDs had a higher risk for hypertension than the comparison cohort (adjusted HR, 2.90 (95% CI, 2.46-3.14)). Compared with the cohort without insomnia, patients with insomnia had a 21% higher risk for hypertension (adjusted HR, 1.21 (95% CI, 1.01-1.76)). Compared with non-SD comparison cohort, patients with SDs had a higher risk for developing hypertension, particularly pronounced among those who were younger adults (age ?40 years) and who had insomnia. We suggest that possible persisting exposure to sleep problems was correlated with a greater risk of hypertension. PMID- 27511479 TI - Initial experience with delivery of palliative care toterminal cancer patients. AB - BACKGROUND/AIM: We investigated the symptoms and needs of terminal cancer patients in a region where formal palliative care is limited. Here we present the demographic features and symptoms of end-stage cancer patients living in a city in northern Turkey. MATERIALS AND METHODS: The study was conducted at Gaziosmanpasa University (Tokat, Turkey), in 2011 and 2012. End-stage cancer patients admitted or referred by various departments to our outpatient pain unit were included. Demographic data, treatment histories, primary tumor sites, patient complaints, and symptom intensities measured using the Edmonton Symptom Assessment System Scale were prospectively entered into a database. RESULTS: A total of 107 patients (36 female and 71 male) were included. Gastrointestinal cancer was the most common form of cancer (43%), followed by genitourinary (25.3%) and lung cancer (15%). The most common symptom was fatigue (98.1%). The other symptoms (in decreasing order) were pain (92.5%), insomnia (92.5%), loss of appetite (76.6%), constipation (71%), dyspnea (63.6%), nausea (60.7%), cough (57.9%), and vomiting (48.6%). Eighty-six percent of the patients (n = 92) had metastases. Most lived in the city (59.8%) and 84 (78.5%) lived with their spouses. CONCLUSION: Patients were referred at the late stages of disease with pain as the principal presenting symptom. Family members were the principal caregivers. PMID- 27511480 TI - Depression, anxiety, and their relation with clinical parametersand androgen levels in hirsute women. AB - BACKGROUND/AIM: The purpose of this study was to assess the prevalence of anxiety and depression among patients with hirsutism and to evaluate the relationships of anxiety and depression with clinical parameters and androgen levels. MATERIALS AND METHODS: One hundred and seven women with hirsutism were enrolled in the study. All participants completed standardized questionnaires to assess depression (Beck Depression Inventory (BDI)) and anxiety (Beck Anxiety Inventory (BAI)). The Ferriman-Gallwey (FG) scores, body mass indexes (BMIs), homeostatic model assessments of insulin resistance (HOMA-IR), and serum androgen levels of all patients were obtained. RESULTS: Seventy-four of the 107 patients (69.15%) had BDI scores indicating depression, and 47 of the 107 patients (43.9%) had BAI scores indicating anxiety disorders. No difference was found between high BAI and normal BAI patients related to BMI, age, FG scores, testosterone levels, and HOMA IR levels (P > 0.05), and no difference was found between high BDI and normal BDI patients related to BMI, age, FG scores, free testosterone levels, and HOMA-IR levels. There was a positive correlation between BDI scores and dehydroepiandrosterone sulphate (DHEA-S) levels (P < 0.01). CONCLUSION: We found considerable amounts of depression, anxiety, and the coexistence of depression and anxiety in patients with hirsutism. Depression and the severity of depressive symptoms were positively correlated with DHEA-S levels. PMID- 27511478 TI - High-dose calcium channel blocker (CCB) monotherapy vs combination therapy of standard-dose CCBs and angiotensin receptor blockers for hypertension: a meta analysis. AB - In this study, we evaluated the efficacy and safety of high-dose calcium channel blocker (CCB) monotherapy and standard-dose CCBs combined with angiotensin receptor blockers (ARBs) for patients with hypertension. A comprehensive search of PubMed, Embase and the Cochrane Central Register of Controlled Trials was performed in December 2015. Randomized controlled trials designed to identify the above goal were included. Thirteen trials including 2371 patients were identified. The standard-dose CCB/ARB combination resulted in a greater reduction of systolic blood pressure (WMD -2.52, 95% confidence interval (CI): -3.76 to 1.28) and diastolic blood pressure (weighted mean difference (WMD) -2.07, 95% CI: -3.73 to -0.42) compared to high-dose CCB monotherapy. The overall hypertension control rate for the CCB/ARB combination was higher than that for CCB monotherapy (relative risk (RR): 1.17, 95% CI: 1.08-1.26). Furthermore, the CCB/ARB combination treatment yielded significantly fewer overall adverse events (RR: 0.84, 95% CI: 0.74-0.95), oedema (RR: 0.31; 95% CI: 0.18-0.52) and rash (RR: 0.27, 95% CI: 0.08-0.96, P=0.04) than did CCB monotherapy. The standard-dose CCB/ARB combination is superior to high-dose CCB monotherapy for lowering blood pressure and reducing adverse events in hypertensive patients. Future research should focus on the cost-effectiveness and long-term effects of these two treatment strategies for patients with hypertension. PMID- 27511481 TI - The relationship of mean platelet volume with microalbuminuriain type 2 diabetic patients. AB - BACKGROUND/AIM: Activation and size of platelets have been suggested to be involved in the pathogenesis of vascular complications in diabetes mellitus. The purpose of the present study was to investigate the association of mean platelet volume with microalbuminuria in type 2 diabetic patients. MATERIALS AND METHODS: Mean platelet volume levels were investigated in healthy participants and type 2 diabetic patients with and without microalbuminuria. After their mean platelet volume values were compared, correlation of mean platelet volume with sex, duration of diabetes, microalbuminuria, fasting blood glucose, hemoglobin A1c, creatinine clearance, and body mass index was examined. RESULTS: Mean platelet volume levels were higher in all diabetic patients than those in controls. Mean platelet volume levels were highest in diabetics with microalbuminuria. The mean platelet volume levels had a positive correlation with microalbuminuria. CONCLUSION: Mean platelet volume values of diabetic patients were higher than those of nondiabetics, the highest levels being in diabetics with microalbuminuria. Our results suggest that microalbuminuria might be related with mean platelet volume in diabetic patients. PMID- 27511482 TI - Total white blood cell count, liver enzymes, and metabolic syndrome in schizophrenia. AB - BACKGROUND/AIM: Metabolic syndrome (MetS) is an important clinical issue in patients with schizophrenia, but its associated factors are still ambiguous. The aim of the present study was to test whether there are any associations between MetS and white blood cell (WBC) levels, liver enzymes, or sociodemographic variables. MATERIALS AND METHODS: The study included 91 patients with a diagnosis of schizophrenia. We used the National Cholesterol Education Program's Third Adult Treatment Protocol criteria to evaluate MetS in patients. Schizophrenia patients with MetS were compared with those without MetS on the basis of demographic and clinical characteristics and total WBC counts. We conducted Spearman's correlation and binary logistic regression analyses to achieve the best prediction of MetS in schizophrenia. RESULTS: Compared with schizophrenia patients without MetS, those with MetS were older, less educated, and more likely to be smokers. They were also more likely to have a longer duration of the illness, a longer untreated period, and higher alanine aminotransferase (ALT) and WBC levels. MetS was correlated with age, duration of illness, income, ALT, gamma glutamyl transpeptidase, WBC, and hemoglobin values. Age and WBC levels were found to be the best predictors of MetS. CONCLUSION: Hemograms and liver tests should be conducted to test for MetS in schizophrenia. PMID- 27511483 TI - The effect of hip and knee exercises on pain, function, and strength in patientswith patellofemoral pain syndrome: a randomized controlled trial. AB - BACKGROUND/AIM: The role of hip muscles in the rehabilitation of patellofemoral pain syndrome has recently received interest. The aim of this study was to compare the efficiencies of hip exercises alongside knee exercises versus only knee exercises on pain, function, and isokinetic muscle strength in patients with this syndrome. MATERIALS AND METHODS: Fifty-five young female patients (mean age: 34.1 +/- 6.2 years; mean BMI: 25.9 +/- 3.9 kg/m2) with patellofemoral pain syndrome were included. The patients were randomized into groups of hip-and-knee exercises and knee-only exercise programs for 6 weeks with a total of 30 sessions at the clinic. Both groups were evaluated before therapy, after 6 weeks of a supervised exercise program, and after 6 weeks of an at-home exercise program. The outcome measures were muscle strength, pain, and both subjective and objective function. RESULTS: The improvements of the patients in the hip-and-knee exercise group were better than in patients of the knee-only exercise group in terms of scores of pain relief (P < 0.001) and functional gain (P = 0.002) after 12 weeks. CONCLUSION: We suggest additional hip-strengthening exercises to patients with patellofemoral pain syndrome in order to decrease pain and increase functional status. PMID- 27511484 TI - Sensitization to food and inhalant allergens in healthy children in Van, East Turkey. AB - BACKGROUND/AIM: The purpose of this study was to determine the most frequent food and inhalant allergens leading to allergic sensitization in children in Van Province of Turkey. MATERIALS AND METHODS: The study included 1052 serum samples with no diagnosis of allergy. The sera were tested with the Euroline Pediatric IgE test kit (EUROIMMUN, Germany). By using the EUROLineScan digital evaluation system, the intensity of bands was calculated with enzyme allergosorbent test classification. RESULTS: Out of the 1052 tested sera, 143 were found to be cross reactive carbohydrate determinant-positive and were discarded from the study. Of the remaining 909 sera, 513 (56%) were from males and 296 (44%) were from females. Among the food allergens, specific IgE was most frequently found against codfish, potato, cow's milk, egg yolk, egg white, and rice, and among the inhalant allergens against cats, dogs, grass mix, Dermatophagoides pteronyssinus, and Aspergillus fumigatus, respectively. CONCLUSION: The finding of codfish being the most frequent allergen was related to the high consumption of trout in the region and endemicity of pearl mullet in Lake Van. The results obtained could contribute to determining the etiology of allergic diseases. Additionally, regular analysis of changes in allergen sensitization is important for prevention of allergic disease. PMID- 27511485 TI - How to close open choledochotomy: primary closure, primary closurewith T-tube drainage, or choledochoduodenostomy? AB - BACKGROUND/AIM: Although common bile duct stones are generally treated endoscopically, surgery is required if endoscopic removal is impossible. The aim of this study was to compare the surgical options in such patients. MATERIALS AND METHODS: A total of 282 patients with common bile duct stones underwent open choledochotomy; primary closure was applied in 48 (17.0%), primary closure with T tube drainage in 81 (28.7%), and choledochoduodenostomy in 153 (54.3%) patients. RESULTS: Postoperative complications were seen in 8 (16.7%) patients in the primary closure, 33 (40.7%) patients in the primary closure with T-drainage, and 37 (24.2%) patients in the choledochoduodenostomy group. No significant differences were observed among the groups (P > 0.05). The mean postoperative hospital stays in the primary closure, primary closure with T-tube drainage, and choledochoduodenostomy groups were 5.5, 13.5, and 8.9 days, respectively. The mean postoperative hospitalization was significantly shorter in the primary closure group than in the other groups (P < 0.05). CONCLUSION: Primary closure is a safe and feasible method in selected patients. PMID- 27511486 TI - Comparison of nasal senses following open and closed rhinoplasty. AB - BACKGROUND/AIM: The objective of this study was to compare the postoperative changes taking place in the nasal senses of patients who underwent a rhinoplasty through the open or closed incision method. MATERIALS AND METHODS: In a prospective study, 15 patients had a closed rhinoplasty surgery and 15 others had an open one. By pinpointing 9 spots in the nose, a sensory assessment was made by means of Semmes-Weinstein monofilaments prior to the surgery and 1 week and 1, 3, and 6 months after the surgery. RESULTS: In the open and closed groups, there was hypoesthesia 1 week after the surgery compared with the preoperative period (P = 0.01 and P = 0.016). In the first week a sense reduction in the upper columella was observed in the open group when compared with the closed one (P = 0.035). There were no other significant differences between the groups in the nasal regions at other times. CONCLUSION: It was ascertained that there was reduced sensation in the upper columella in the open incision group in the first postoperative week. The sensation was reduced in both groups in the first postoperative week. The nasal sensation recovered after the first month. PMID- 27511487 TI - Is the Nexfin finger cuff method for cardiac output measurement reliableduring coronary artery bypass grafting? A prospective comparison with the echocardiography and FloTrac/Vigileo methods. AB - BACKGROUND/AIM: The aim of the current study was to assess the accuracy of cardiac output (CO) measurements obtained by the Nexfin finger cuff method as compared with the FloTrac/Vigileo and echocardiography methods in coronary artery bypass grafting (CABG) patients. MATERIALS AND METHODS: First-time elective CABG patients were prospectively enrolled in this study and divided into three groups according to CO measurement method. CO measurements were performed simultaneously by three different contributors and were collected by the fourth one 24 h postoperative in the intensive care unit (ICU). Data were statistically analyzed. RESULTS: Seventeen female and 13 male patients between 42 and 78 years of age (with a mean of 56 +/- 4) were the subjects of this study. The mean CO measurements were 5.9 +/- 1.4 L/min, 5.8 +/- 1.1 L/min, and 6.0 +/- 1.1 L/min for the Nexfin, FloTrac/Vigileo, and echocardiography methods, respectively (P > 0.05). The correlation values between Nexfin and FloTrac/Vigileo, Nexfin and echocardiography, and FloTrac/Vigileo and echocardiography were r = 0.445, r = 0.377, and r = 0.384, respectively (P < 0.05). CONCLUSION: Nexfin yielded results comparable to those obtained with FloTrac/Vigileo and echocardiography for the postoperative CO assessment of CABG patients. Nexfin may be used in uncomplicated, hemodynamically stable patients in ICU as a reliable and totally noninvasive method of CO measurement. PMID- 27511488 TI - Effect of exposure to violence on the development of burnoutsyndrome in ambulance staff. AB - BACKGROUND/AIM: The aim of this study is to determine the condition of ambulance staff (AS) who have been exposed to any kind of violence and to predict risk of development of burnout syndrome. MATERIALS AND METHODS: Our study was performed with 120 AS working for the Kirikkale Ambulance Services. During the research, questionnaires collecting descriptive information and the extent of violence to which the AS were exposed were administered; participants were asked to fill out the questionnaire themselves. RESULTS: It was found that 81 (67.5%) participants had been subjected to at least one type of violence (verbal or physical). Sixty two percent were exposed to verbal abuse and 55.8% to verbal threats. Rates of physical threats and attacks were higher among male staff (P = 0.036, P = 0.022), while the rate of personal accomplishment was determined to be significantly lower in males (P = 0.006). Emotional exhaustion and depersonalization scores were determined to be significantly higher in those who perceived less support from administrators (P = 0.014, P = 0.032). CONCLUSION: All kinds of negative situations exhaust an individual physically and mentally and lead to the development of burnout syndrome. AS are more prone to these kinds of situations. PMID- 27511489 TI - Prevalence and related factors of psoriasis and seborrheic dermatitis: a community-based study. AB - BACKGROUND/AIM: We aimed to determine the prevalence of psoriasis (PS) and seborrheic dermatitis (SD) (erythematous-squamous diseases) in our region and reveal the frequently encountered associated factors to aid in planning appropriate healthcare. MATERIALS AND METHODS: A community-based study was conducted with 85 sample groups that reflected the population rate and demography of Tokat Province in northern Anatolia. RESULTS: In this community, the prevalence of PS in people older than 20 years of age was 1.2% and the prevalence of SD was 5.2%. SD rates were higher in patients who used tobacco and especially alcohol. SD prevalence was also higher in patients treated for depression and epilepsy. Furthermore, as education levels increased, SD prevalence increased proportionally. CONCLUSION: In general, PS prevalence in this region was higher than in Asia and Africa but lower than in Europe and the United States. Whereas SD prevalence varies between 2% and 12% throughout the world, the average SD prevalence was 5.2% in this study. PMID- 27511490 TI - The role of human papilloma virus and herpes viruses in the etiology of nasal polyposis. AB - BACKGROUND/AIM: The aim of this study was to investigate the etiological role of human papilloma virus (HPV), herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpes virus-6 (HHV-6) and -7 (HHV-7) in the occurrence of nasal polyposis. MATERIALS AND METHODS: Nasal polyp samples from 30 patients with nasal polyposis and normal nasal mucosa from 10 patients without nasal polyps were obtained. DNA was extracted from tissues. Real-time polymerase chain reaction was performed for all runs. RESULTS: No HSV-1, HSV-2, or VZV was detected in the samples. Among the patient samples, EBV and HHV-7 DNA were detected in 18 (60%), HHV-6 was detected in 20 (66.7%), and HPV was detected in 4 (13.3%) samples. Among the controls, CMV DNA was positive in one (10%). EBV was positive in 5 (50%), HHV-6 and HHV-7 were positive in 7 (70%), and HPV was positive in 2 (20%) samples. No significant difference was found among the groups with any test in terms of positivity. CONCLUSION: The association of Herpesviridae and HPV with the pathogenesis of nasal polyps was investigated in this study and no relationship was found. Thus, these viruses do not play a significant role in the formation of nasal polyps. PMID- 27511491 TI - Retinopathy of prematurity: incidence, risk factors, and evaluation of screening criteria. AB - BACKGROUND/AIM: The goal of this study was to investigate the incidence of retinopathy of prematurity (ROP) and the relationship between risk factors and disease in premature newborns in our neonatal intensive care unit. MATERIALS AND METHODS: A total of 219 premature subjects were retrospectively evaluated for retinopathy. Demographic information, clinical data, and risk factors were reviewed. RESULTS: The gestational ages of the infants included in the study ranged between 25 and 36 weeks, and the birth weights ranged between 670 and 4460 g. In this study, the incidence of ROP was 20.1% (44) in preterm infants: 16 had stage 1 (36.4%), 15 had stage 2 (34.1%), 11 had stage 3 (25%), 1 had stage 4 (2.3%), 1 had stage 5 (2.3%), and 6 had plus (+) disease (7.2%). The risk factors associated with the development of ROP included low birth weight, ventilation treatment, bronchopulmonary dysplasia, and maternal preeclampsia. The risk factors were analyzed with logistic regression analysis. The odds ratios were 5.952 (95% confidence interval [CI]: 2.030-17.447), 20.070 (95% CI: 4.213 95.600), 5.879 (1.916-18.037), and 3.200 (95% CI: 1.002-11.535), respectively. CONCLUSION: In this study, birth weight, ventilation treatment, bronchopulmonary dysplasia, and maternal preeclampsia were the most important risk factors for the development of ROP. PMID- 27511492 TI - Intraoperative application of 5-fluorouracil and mitomycin C aschemoadjuvants in primary pterygium surgery. AB - BACKGROUND/AIM: To compare the effectiveness of intraoperative 5 fluorouracil (5 FU) and mitomycin C (MMC) application in preventing recurrence following primary pterygium excision. MATERIALS AND METHODS: This was a prospective clinical trial that included 93 patients with primary pterygia assigned to three treatment groups in which 29 patients received an intraoperative application of 25 mg/mL 5 FU for 5 min, 32 patients received an intraoperative application of 0.02% MMC for 5 min, and 32 patients underwent only surgical excision (the control group). Follow-up visits were done on postoperative days 1, 3, 7, 15, and 30, and then every month. RESULTS: After a mean follow-up of 14 months, the surgical excision recurrence rates in the 5-FU, MMC, and control groups were 27.6%, 12.5%, and 43.75%, respectively. There was a statistically significant difference in the 5 FU and MMC groups when compared with the control group (chi-square; P = 0.04); however, the difference between the 5-FU and MMC groups was not significant. No serious complications were seen in the 5-FU and MMC groups. CONCLUSION: Intraoperative application of MMC and 5-FU is effective and safe for the prevention of recurrence. Our findings suggest that MMC is more potent for the prevention of recurrence and it causes less complaints than 5-FU. PMID- 27511493 TI - Does the course of laboratory parameters help us to predict the outcome of CCHF? AB - BACKGROUND/AIM: This study was performed to identify the characteristics distinguishing fatal and nonfatal cases of patients diagnosed with Crimean-Congo hemorrhagic fever (CCHF). MATERIALS AND METHODS: A total of 92 patients with confirmed diagnosis of CCHF in 2009-2013 were included in the study. RESULTS: A high level of urea and aPTT on the third day of hospital stay, diarrhea, somnolence, and the interval from the beginning of the symptoms to hospital admission were independently associated with fatality. Each 10-unit increase in aPTT and urea levels increased the fatality rate by 3.379-fold and 1.236-fold, respectively. Delay in hospital admission increased the fatality rate 1.453-fold for each day of delay. When comparing first and third admission-day laboratory values, the increase in leukocyte counts and the decrease in CPK, urea, creatinine, aPTT, PT, INR, and hemoglobin levels were significant in nonfatal cases. CONCLUSION: This study showed that the course of these laboratory tests helps us to predict the outcome of the disease. In a few days of hospitalization, persistence or progress of the abnormal laboratory parameters may warn us about poor prognosis. PMID- 27511494 TI - Comparison of galactomannan, beta-D-glucan, and Aspergillus DNA in sera of high risk adult patients with hematological malignancies for the diagnosis of invasive aspergillosis. AB - BACKGROUND/AIM: Invasive aspergillosis (IA) is a fatal infection that is difficult to diagnose in immunocompromised patients. In this study, Aspergillus specific DNA was searched using real-time PCR (RT-PCR) in serum samples. Galactomannan (GM) and/or beta-D-glucan (BDG) tests were previously performed on these samples for 70 neutropenic patients with hematological malignancy. MATERIALS AND METHODS: The patients were categorized according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG). Among the patient serum samples, the first positive GM or BDG test sample and the median sample of GM or BDG test for negative patients were used to detect DNA levels by RT-PCR method (Light Cycler 480, Roche Molecular Biochemicals, Meylan, France) using a commercial kit (Way2Gene Fungi; Genmar, Izmir, Turkey). RESULTS: When the proven and probable IA group were considered as real patients, sensitivity of Aspergillus-specific DNA test was 90%, specificity was 73.3%, positive predictive value was 81.8%, and negative predictive value was 84.6%. CONCLUSION: This study found that searching for specific DNA by RT-PCR method has a sensitivity as high as the GM test. Although specificity was rather low, it was concluded that it can be used jointly with GM and BDG tests after decreasing contamination by severe laboratory applications. PMID- 27511495 TI - Fully automated morphological analysis of patients with obstructive sleep apnea. AB - BACKGROUND/AIM: Obstructive sleep apnea syndrome (OSAS) is a disease characterized by episodic hypoxia. We aimed to use the Freesurfer program for global evaluation of morphological changes in OSAS patients. MATERIALS AND METHODS: Three-dimensional T1-weighted images were obtained, and intracranial morphology was assessed in 18 patients with OSAS and 20 controls. Results of the volume and the cortical thickness analyses of both groups were compared statistically. RESULTS: The total cortical, left-right hemispheres gray matter (GM), corpus callosum, and total GM volumes were lower in OSAS patients when compared with the control group (P < 0.001). The average cortical thickness was lower in OSAS patients bilaterally in pars orbitalis, paracentral, rostral middle frontal, middle frontal, orbital, and superior frontal gyri when compared with the control group (P < 0.05). Furthermore, the volume and average cortical thickness of multiple anatomic regions, apart from the brain parts mentioned above, were decreased unilaterally (e.g., hippocampus, cingulum, putamen, thalamus) in OSAS patients (P < 0.05). CONCLUSION: Multiple morphologic changes occur in the cerebral structures of OSAS patients due to intermittent ischemia episodes. Detection of those areas with Freesurfer is easier. New studies with large series would be needed for these subjects. PMID- 27511497 TI - Association analysis of five SNP variants with gout in the Minnan population in China. AB - BACKGROUND/AIM: There is a very high prevalence of gout in the Minnan population in China. We aimed to explore the genetic characteristics and genetic mechanisms of gout in the Minnan population by studying the association of 5 single nucleotide polymorphisms (SNPs) with gout. MATERIALS AND METHODS: A total of 163 gout patients and 187 normal controls from Minnan were enrolled in this case control study. SNPs (rs1165205, rs3733591, rs6855911, rs2231142, rs333049) were genotyped by allele-specific polymerase chain reaction (PCR) and analyzed with SPSS 16.0. RESULTS: Significant association with gout was found for rs2231142 (P < 0.001), consistent with our prior studies. An association between rs1333049 and gout was also found (P = 0.03) in the Minnan population. No association of SNPs rs6855911, rs3733591, and rs1165205 was found with gout in the Minnan population. CONCLUSION: Rs1333049 is associated with gout in the Minnan population, although rs2231142 shows an even stronger association with gout. The C allele of rs1333049 and the A allele of rs2231142 might be crucial risk factors for gout. PMID- 27511496 TI - The role of FDG PET/CT in detection of distant metastasis in theinitial staging of breast cancer. AB - BACKGROUND/AIM: We aimed to evaluate the role of FDG PET/CT in the detection of extraaxillary regional nodal/distant metastasis in breast cancer patients and to assess the value of FDG PET/CT for detecting distant metastases in patient subgroups. MATERIALS AND METHODS: A total of 254 patients with breast cancer (248 female, 6 male) who underwent PET/CT for initial staging were enrolled. Patients were divided into four groups: Group 1 consisted of 154 patients diagnosed by tru cut/core/FNAB, Group 2 comprised 32 patients diagnosed by excisional biopsy, Group 3 included 62 patients who had mastectomy-axillary lymph node dissection, and Group 4 consisted of 6 patients who had axillary lymph node metastasis diagnosed by excisional biopsy. RESULTS: PET/CT detected distant metastasis in 76 of the 254 patients. Of these patients, 21.7% had bone/bone marrow metastasis, 7.1% had lung metastasis, 13% had mediastinal lymph node metastasis, 4.8% had liver metastasis, 9.8% had other organ/system metastasis, and 6% had other lymphadenopathies. According to T staging, the percentages of distant metastasis were as follows: 13.6% of the 66 T1 stage patients, 35.7% of the 129 T2 stage patients, 40% of the 20 T3 stage patients, and 33.3% of the 39 T4 stage patients. CONCLUSION: FDG-PET/CT led to a change in the stage of disease and the treatment approach in newly diagnosed breast cancer patients due to its superiority in detecting extraaxillary regional lymph node metastases and distant metastases. PMID- 27511498 TI - Serological prevalence of human parvovirus B19 in diseases or disordersrelated to different human body systems. AB - BACKGROUND/AIM: Human parvovirus B19 is a pathogen that affects different parts of the body. We planned this study because of the lack of data on B19 seroprevalence based on different body-system diseases. MATERIALS AND METHODS: The prevalence of parvovirus B19 antibodies was investigated retrospectively in 1239 patients by review of medical records from 2009-2012, according to their diseases classified under general titles in compliance with the International Classification of Diseases (ICD-10). Parvovirus B19-specific antibodies were detected by quantitative enzyme immunoassays. RESULTS: The positivity rate was 27.8% for only IgG, 8.5% for only IgM, and 2.6% for both IgG and IgM. The highest positivity for IgG alone was found in musculoskeletal system and connective tissue diseases (55.9%), while the highest positivity for IgM was found in neoplasms (16.4%). The highest positivity for IgG was seen in rheumatoid arthritis (72.2%) and pregnancy (52.6%), and the highest positivity for total IgM was found in upper respiratory tract disease (21.0%) and hepatic failure (17.1%). CONCLUSION: Parvovirus B19 seroprevalence was relatively low in northeastern Anatolia compared to most serological studies conducted in other regions. We think that this study has provided the first wide-ranging information on the seroprevalence of B19 in diseases and disorders of the major human body systems. PMID- 27511499 TI - Distribution of LDL subgroups in patients with hyperlipidemia. AB - BACKGROUND/AIM: Low-density lipoproteins (LDLs) have been shown to be a major risk factor for coronary artery disease. Multiple distinct subspecies have been identified among LDL particles on the basis of differences in size, density, and chemical composition. Particles with a diameter of <25.5 nm are defined as small dense LDL (sdLDL) and have been shown to be associated with increased risk of coronary disease. Subjects with predominance of sdLDL (pattern B) tend to have higher levels of triglyceride (TG) and lower levels of high-density lipoprotein cholesterol (HDL-C). In this study, we investigated the distribution of LDL subgroups in subjects with different types of hyperlipidemia, such as hypertriglyceridemia (hyperTG), hypercholesterolemia (hyperCHO), and combined hyperlipidemia (HL). MATERIALS AND METHODS: We used gradient gel electrophoresis and a precipitation method with heparin-magnesium reagent to determine LDL subgroups. RESULTS: It was found that there was a significant (P < 0.02) association between the lipid panel and LDL subgroups. The percentage of sdLDL in all HL groups was higher than in controls, and the ratio of sdLDL was highest in patients with hyperTG. CONCLUSION: The predominance of sdLDL is closely related to hyperTG and low HDL-C levels. PMID- 27511500 TI - Determination of regional screening criteria for retinopathy ofprematurity in the Eastern Black Sea region of Turkey. AB - BACKGROUND/AIM: To establish a regional screening protocol for retinopathy of prematurity (ROP). MATERIALS AND METHODS: Data were analyzed from the hospital records of 1241 infants with gestational age (GA) at birth <=36 weeks and birth weight (BW) of <=3600 g. RESULTS: The mean GA of the infants was 32.05 +/- 2.7 weeks and the mean BW was 1780.5 +/- 576 g. ROP at any stage was detected in 703 of the 1241 infants (555 female). Eleven infants with type 1 ROP were treated with 810 nm diode laser photocoagulation. No treatment was needed in infants born after 33 weeks of gestation and weighing over 1760 g. Logistic regression analysis showed a significant relationship between the development of ROP and GA, BW, number of deliveries, respiratory distress syndrome, and treatment with oxygen or mechanical ventilation. Receiver operating characteristic curve analysis showed that a GA of 33 weeks or a BW of 1770 g appears to be an appropriate criterion for identifying infants who may require ROP treatment. CONCLUSION: GA <= 33 weeks and BW <= 1770 g can be used as screening criteria in terms of ROP in infants for the Eastern Black Sea region. PMID- 27511501 TI - The effect of enteral immunonutrition in upper gastrointestinalsurgery for cancer: a prospective study. AB - BACKGROUND/AIM: Enteral feeding and immunonutrition (ImN) have been shown to be associated with a number of favorable effects in patients undergoing cancer surgery. In this prospective study, we aimed to assess the perioperative use of enteral immunonutrition in patients undergoing radical gastrointestinal surgery for malignancy. MATERIALS AND METHODS: Forty-one patients with malignancy were included in this study and were randomized into one of the two following nutritional strategies: enteral only (EN) or enteral with enteral immunonutrition (ENIN). These regimens were followed for 7 days perioperatively by all patients. Nutritional parameters and postoperative morbidity, mortality, and length of hospital stay (LHS) were assessed. RESULTS: Serum prealbumin levels increased significantly in the ENIN group (P = 0.033). Moreover, patients in the ENIN group showed a more marked decrease in the rate of postoperative infections (P = 0.021) and anastomotic leakage (P = 0.018) than patients fed with EN. In the EN group, LHS was significantly longer than that in the ENIN group (18 vs. 12 days) (P = 0.032). Rates of overall morbidity and mortality were similar in the two groups (P > 0.05). CONCLUSION: ENIN was found to have a favorable effect on the outcome of radical gastrointestinal surgery for malignancy. Meticulous preoperative assessment of malnutrition and at least a 7-day perioperative enteral use can increase the effectiveness of immunonutrition. PMID- 27511502 TI - Management of hyperbilirubinemia in preterm infants in Turkey. AB - BACKGROUND/AIM: Prematurity is a significant risk factor for developing unconjugated hyperbilirubinemia. This study investigated the current approach to managing hyperbilirubinemia in preterm newborns in Turkey. MATERIALS AND METHODS: A study-specific questionnaire on the management of jaundice in preterm infants was sent to 100 level III neonatal intensive care units in Turkey. RESULTS: Responses were obtained from 84 centers from all regions of Turkey. Of the centers, 75.3% used the Turkish Neonatology Society guidelines for deciding to start phototherapy, and 24.7% used different guidelines. The monitoring of bilirubin varied among the participants. Of the participants, 53.6% believed that prophylactic phototherapy was necessary if the infant's birth weight was below 1000 g. The participants reported 6 cases of kernicterus in preterm infants in recent years. CONCLUSION: There is no single standard approach for managing neonatal hyperbilirubinemia in preterm infants in Turkey. Prophylactic phototherapy for extremely low birth-weight infants might be added to the guidelines for Turkey. PMID- 27511503 TI - Evaluation and identification of IDUA gene mutations in Turkishpatients with mucopolysaccharidosis type I. AB - BACKGROUND/AIM: This study aimed to identify IDUA gene mutations in Turkish patients morphologically (phenotypic) diagnosed with MPS type I. It also sought to discuss the possible effects of detected mutations on alpha-L-iduronidase enzyme function based on current knowledge. MATERIALS AND METHODS: Genetic analysis was carried out in 15 patients using direct DNA sequencing. Moreover, segregation analysis was performed among family members to predict the pathogenic effect of novel mutations, and computational programs were used to predict their functional impact. RESULTS: Nine different mutations (c.494-1G>A, c.793-6C>G, c.793-5C>A, p.M1L, p.Y64X, p.A327P, p.W402X, p.P533L, and p.R628X) were identified. Computational analysis results supported the pathogenicity of novel mutations, suggesting improper splicing. Seven already-known polymorphisms were detected in the screened cohort as well. CONCLUSION: Our results revealed heterogeneity in the mutation spectrum of Turkish patients. Six of the mutations, including the novel ones, have never before been reported in the Turkish population. Moreover, 5 patients who were phenotypically diagnosed with MPS type I could not be confirmed by genetic analysis, indicating the importance of the molecular characterization of MPS subtypes. PMID- 27511504 TI - The role of baseline Ga-68 DOTATATE positron emission tomography/computed tomography in the prediction of response to fixed-dose peptide receptor radionuclide therapy with Lu-177 DOTATATE. AB - BACKGROUND/AIM: To describe the role of baseline gallium (Ga)-68 DOTATATE positron emission tomography (PET)/computed tomography (CT) in the prediction of the response to peptide receptor radionuclide therapy (PRRT) using lutetium (Lu) 177 DOTATATE. MATERIALS AND METHODS: Analysis was made of baseline Ga-68 DOTATATE PET/CT images of 29 patients (17 females and 12 males; mean age: 50.7 +/- 14.6 years) with metastatic neuroendocrine tumors who received PRRT with Lu-177 DOTATATE. Maximum standardized uptake values (SUVmax) of reference lesions and their ratios to physiological uptake organs were calculated. The relationship between these values and the radiological response was analyzed. RESULTS: Partial response was observed in 8 (28%) patients, stable disease in 18 (62%) patients, and progressive disease in 3 (10%) patients. Mean SUVmax of reference lesions was calculated as 23.8 +/- 20.5 (min-max: 5.1-87.3). There was no significant correlation between radiological responses and SUVmax of reference lesions and their ratios to other organs. CONCLUSION: Baseline Ga-68 DOTATATE PET/CT helps to show somatostatin receptor expression status and disease stage in patients who are candidates for PRRT. However, SUVs do not have a role in the prediction of treatment response. PMID- 27511505 TI - Genetic association of the COL1A1 gene promoter -1997 G/T (rs1107946) andSp1 +1245 G/T (rs1800012) polymorphisms and keloid scars in a Jeddah population. AB - BACKGROUND/AIM: Scars develop at the end of the natural wound-healing process and are characterized by excessive collagen deposition, particularly types I and III collagen. This study aimed to investigate the genetic association of COL1A1 -1997 G/T (rs1107946) and COL1A1 Sp1 +1245 G/T (rs1800012) polymorphisms with the incidence of scars. MATERIALS AND METHODS: A case-control association study was conducted with 84 volunteers from Jeddah, Saudi Arabia (47 patients and 37 controls). The allele frequency distribution and nucleotide genotypes of -1997 G/T, +1245 G/T were ascertained by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: Our results indicated that the distribution of COL1A1 (rs1107946) genotypes was significantly different between patients and controls (P = 0.00). The incidence of COL1A1 (rs1107946) genotype GG was significantly associated with a risk of scars. The distribution of the (rs1107946) genotype was drastically higher in women with scars (P= 0.00). One haplotype block in COL1A1 was documented by the pair-wise linkage disequilibrium between the single nucleotide polymorphisms (SNPs). The frequency of the GG haplotype constructed by the two SNPs was robustly high and associated with risk of scars. CONCLUSION: Our results strengthen the evidence for the association between polymorphisms of -1997 G/T, +1245 G/T of the COL1A1 gene in the genetic etiology of keloid scars. PMID- 27511506 TI - Posterior laminoforaminotomy in the treatment of lateralcervical herniated disc and foraminal stenosis. AB - BACKGROUND/AIM: Posterior cervical laminoforaminotomy is an effective surgical treatment in selected cases of cervical radiculopathy caused by posterolateral herniated discs or foraminal stenosis. The aim of the present study was to evaluate the surgical techniques, rates of complications, long-term outcomes, advantages, and disadvantages of keyhole foraminotomy retrospectively. MATERIALS AND METHODS: Keyhole foraminotomy was performed in 83 patients. In 51 patients (61.5%) soft disc herniation was removed, and in 32 of them (38.5%) osteophytes were evident. The clinical data were evaluated according to Odom's criteria, and the mean follow-up time was 6 months. RESULTS: Postoperative results were classed as excellent in 66 patients (79.5%), good in 13 patients (15.7%), fair in 3 patients (3.6%), and poor in only 1 patient (1.2%). Radiculopathy symptoms regressed in 79 patients (95%). Among the 83 patients, surgical complications (dural injury and level error) were noted in 2 patients (2.4%). CONCLUSION: Posterior laminoforaminotomy is applied to selected patients with a low complication rate. The advantages of this surgery are suitable visualization of the nerve root, preserved motion of the operated segment, avoidance of cervical instability, and a decrease in the length of hospital stay. PMID- 27511507 TI - Common variable immunodeficiency in adults requires reserved protocols for long term follow-up. AB - BACKGROUND/AIM: The aim of this study is to establish follow-up protocols for adult patients with common variable immunodeficiency (CVID) in a recently founded adult immunology clinic in the Central Anatolia Region of Turkey, where a clinical immunology center for adults was not available previously. MATERIALS AND METHODS: A total of 25 patients with CVID aged 18 years and older were included in this study. The file format consisted of 13 pages and was developed for the purpose of the study. Separate sections were designated for identity information, medical history, disease course, previous and current laboratory and imaging studies, follow-up plans, detection and management of complications/comorbidities, and treatment results. RESULTS: The mean age of the patients was 36.6 +/- 13.4 years. The delay in diagnosis was 107 +/- 95.6 months. In 92% of patients, initial symptoms resulting in admission to healthcare facilities were infections. Seventeen of 25 patients (68%) had bronchiectasis at the beginning of follow-up. CONCLUSION: Early identification of complications and comorbidities in patients with CVID will significantly improve quality of life and survival. Close observation and standardized protocols for follow-up are essential components of management. PMID- 27511508 TI - Is silicone stent insertion a clinically useful option for tracheobronchomalacia? AB - BACKGROUND/AIM: Tracheobronchomalacia (TBM) leads to the obstruction of expiratory airflow and interference with secretion clearance. Stabilization of the airway wall using a silicon stent or laser coagulation of the posterior wall may be treatment options. This study aimed to retrospectively analyze which interventional bronchoscopic method could be used to provide airway stabilization and gain control of symptoms and for whom this method could be used. MATERIALS AND METHODS: Fifteen patients who had received treatment in our interventional pulmonology unit were analyzed. We analyzed the techniques used, stent duration, complications, and long-term treatment success retrospectively. RESULTS: Stents were used in 10 patients: 4 patients had silicon Y-stents and 4 patients had silicon tracheal stents. Stents were removed due to early migration in 3 patients. In 5 of the 7 cases, the stent was removed due to frequent obstructions of the stent due to recurrent severe mucostasis. A suitable stent was not found for one patient who had an extremely enlarged trachea. Good clinical results were achieved in just two cases. The frequency of admissions to the emergency room and hospitalizations were diminished during the follow-up time in these two patients. CONCLUSION: Silicon stents may be a good treatment option in selected patients with TBM and dynamic collapse. However, our patients were high-risk; thus, the criteria for candidates for bronchoscopic treatment should be carefully defined. PMID- 27511509 TI - Physical activity and physical fitness in obese, overweight, and normal-weight children. AB - BACKGROUND/AIM: The aim was to assess the differences between physical activity and physical fitness in obese, overweight, and normal-weight children. MATERIALS AND METHODS: The cross-sectional study was accomplished using cluster sampling method at 3 Lithuanian schools. An analysis of anthropometric data for 532 Lithuanian children was performed. Height, weight, waist and hip circumferences, and skinfold thickness were measured. Body mass index, waist-to-hip ratio, and body fat percentage were calculated. The Youth Physical Activity Questionnaire and a 6-min walk test (6MWT) were administered to evaluate physical activity and physical fitness. Maximal oxygen consumption was calculated to assess the children's aerobic capacity. Correlations among anthropometric data, 6MWT-walked distance, and moderate-vigorous physical activity duration were analyzed. RESULTS: The study showed that 20.1% of the studied children were obese or overweight. They engaged in moderate-to-vigorous physical activity 22.4 min less per day and walked 50.9 m less on average during a 6-min test than normal-weight children. Physical fitness parameters correlated with daily moderate-vigorous physical activity duration and with most of the children's anthropometric parameters. CONCLUSION: Obese and overweight children were less physically active and had lower physical fitness than normal-weight children. The findings underline the need for interventions to increase physical activity and improve fitness in obese and overweight children. PMID- 27511510 TI - The prevalence of tularemia in occupational groups that have contact with animals. AB - BACKGROUND/AIM: The aim of the current study was to investigate the presence of antibodies against Francisella tularensis in individuals in different occupations that have contact with animals in the Kars region of northeastern Turkey. MATERIALS AND METHODS: A total of 201 blood samples specifically including 103 farmers, 45 clinical veterinarians, 42 butchers, and 11 hunters were analyzed. The results of the study were reported in relation to some sociodemographic features (age, sex, occupation, and experience) of the volunteers. The presence of antibodies was determined by a microagglutination (MA) test. In addition, positive sera were confirmed using an ELISA kit. RESULTS: Fifteen (7.46%) individuals, including fourteen farmers and one clinical veterinarian, were found to be positive for F. tularensis by both MA and ELISA with a titer range of 1/10 to 1/160. The highest seroprevalence rate was observed in farmers (13.59%), followed by clinical veterinarians (2.22%). The occurrence of tularemia was found to increase with age. CONCLUSION: Though the main route of tularemia outbreaks is water-borne in Turkey, it was determined that people whose occupations bring them into contact with animals are at risk. Similar studies are recommended in order to further clarify the epidemiology of the disease in the northeast of Turkey. PMID- 27511511 TI - Amniotic membrane transplantation in bacterial and herpetic stromal keratitis. AB - BACKGROUND/AIM: The aim of this study was to describe the results of amniotic membrane transplantation (AMT) in patients with bacterial and herpetic stromal keratitis. MATERIALS AND METHODS: This was a retrospective chart review study including 42 patients with herpetic keratitis (group 1) and 42 patients with bacterial keratitis (group 2). AMT was performed in addition to antimicrobial therapy. Topical steroids were administered after surgery. The outcome parameters evaluated were epithelialization time, decrease of stromal inflammation, and uncorrected visual acuity (UCVA). RESULTS: The average age of our patients was 55.85 +/- 19.07 years, and average follow-up was 14.70 +/- 11.75 months. The period of epithelialization was 19.23 +/- 7.32 days in the herpetic group and 19.31 +/- 6.30 days in the bacterial group. Descemetocele developed in 2 patients of the herpetic group. Other patients in both groups completed epithelialization after AMT procedures with varying amounts of corneal scarring. The bacterial group showed an improvement in UCVA, but the herpetic group showed no improvement in UCVA. CONCLUSION: AMT is a convenient approach for the treatment of corneal keratitis resistant to conventional treatment and allows the use of early topical steroid application. It provides patients with corneal scarring an opportunity for subsequent keratoplasty by arresting the inflammatory response. PMID- 27511513 TI - Growth of biometric components and development of refractive errors in premature infants with or without retinopathy of prematurity. AB - BACKGROUND/AIM: To investigate the biometric components and refractive errors in premature infants with or without retinopathy of prematurity (ROP). MATERIALS AND METHODS: Anterior chamber depth, lens thickness, vitreous length, and axial length were measured with an ultrasound biometer. Cycloplegic refraction was performed by streak skiascopy. Infants with or without ROP were grouped according to postmenstrual age at the time of ocular examination: Group 1, <=33 weeks; Group 2, 34-37 weeks; Group 3, 38-41 weeks; Group 4, 42-45 weeks; Group 5, >=46 weeks. RESULTS: The mean postnatal age of 894 infants (451 females and 443 males) was 8.7 +/- 4.5 weeks, gestational age was 30.9 +/- 2.8 weeks, and birth weight was 1506 +/- 484 g. In Group 2, the mean vitreous length and axial length of infants with ROP were significantly lower than those of infants without ROP (P = 0.011, P = 0.001). The mean anterior chamber depth, lens thickness, spherical equivalent, and astigmatism in all groups did not differ significantly among the infants with or without ROP (P > 0.05). CONCLUSION: The anterior chamber depth, lens thickness, vitreous length, and axial length showed a linear growth throughout the follow-up period. The maximum elongation was observed in vitreous length and axial length. PMID- 27511512 TI - Review of 306 evisceration surgeries performed between 2005 and 2013. AB - BACKGROUND/AIM: The purpose of the present study was to evaluate the reasons for eye evisceration surgeries performed from 2005 to 2013 in our clinic. MATERIALS AND METHODS: The medical records of patients who underwent evisceration surgery over the past 9 years were retrospectively evaluated. Detailed data were reviewed, with a focus on the first precipitating factor for evisceration. RESULTS: Of the 306 patients who underwent evisceration surgery in the studied period, 111 (36.27%) were female (with a mean age of 41.56 +/- 21.38 years) and 195 (63.73%) were male (with a mean age of 37.76 +/- 21.92 years). The most common cause of evisceration was ocular trauma (184 patients; 60.1%). Male patients experienced significantly more trauma, while glaucoma was more common in female patients. CONCLUSIONS: Eye removal is devastating for both patients and their relatives, and its most important and preventable cause is ocular trauma. PMID- 27511514 TI - The role of 18F-FDG PET-CT in the detection of unknown primary malignancy: a retrospective study. AB - BACKGROUND/AIM: This study aimed to retrospectively evaluate the role of 18F-FDG PET/CT imaging in the detection of unknown primary tumor sites in patients with a suspicious malignancy. MATERIALS AND METHODS: We retrospectively examined the 18F FDG PET/CT images of 50 unknown primary malignancy patients. The malignancy of the lesions with increased 18F-FDG uptake on PET images was defined by interpreting the nondiagnostic CT images that were obtained with the PET study. The primary tumor site was decided according to the combined PET/CT findings, and the results were subsequently confirmed with a histopathological examination. RESULTS: Fifty patients (29 M; 21 F) aged 18-85 years were included in the study. The sample included 32 malignant and 18 benign lesions according to the histopathological evaluation. 18F-FDG PET/CT study accurately identified malignant lesions in 28 (average SUVmax +/- SD: 8.27 +/- 7.22) and benign lesions in 12 (average SUVmax +/- SD: 3.63 +/- 3.07) patients; these findings were histopathologically confirmed. PET/CT correctly detected the primary tumor site in 16 (50%) of 32 patients. CONCLUSION: 18F-FDG-PET/CT identified the primary tumor site well in 50% of our cases. We propose that 18F-FDG PET/CT imaging may help to accurately detect malignant lesions in patients with unknown primary tumors. PMID- 27511515 TI - Glycemic index values of monofloral Turkish honeys and the effect oftheir consumption on glucose metabolism. AB - BACKGROUND/AIM: Clinical trials have shown that low glycemic index (GI) nutrition reduces mean blood glucose concentrations and insulin secretions. The aim of the present study was to determine the GI values of various monofloral (citrus, milk vetch, chestnut, thyme, lime, pine) honeys of Turkey, and the effect of their consumption on glucose metabolism. MATERIALS AND METHODS: Processing data from 20 healthy volunteers, GI values were determined from the glycemia values by using the incremental area method. Serum insulin and C-peptide levels were also measured before and 120 min after the test. RESULTS: The GI values of citrus, thyme, lime, chestnut, pine, and milk-vetch honeys were found to be 44.9, 52.6, 55.3, 55.5, 58.8, and 69, respectively. Serum insulin and C-peptide values after honey consumption were relatively lower than those after reference food (glucose) consumption. By the end of the 120 min, serum insulin levels were significantly higher, while a significant decrease was observed after the consumption of chestnut honey (P < 0.05). CONCLUSION: Citrus and thyme honeys were determined to have low GI, while serum insulin levels were significantly lower after the consumption of chestnut honey. Long-term research is needed to compare the effects of honey consumption on healthy and diabetic individuals. PMID- 27511517 TI - Nail changes in patients with inflammatory bowel diseases. AB - BACKGROUND/AIM: Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine. To our knowledge, no studies to date pertain to the profile of nail changes in IBD, except for onychomycosis. We aimed to study the frequency and pattern of nail changes among patients with IBD and evaluate their potential relationships with several parameters in IBD. MATERIALS AND METHODS: The study included 73 patients with IBD and 51 healthy control subjects. Nails of both groups were examined for changes with regard to color, striations, texture, curvature of nail plates, dystrophy of nail plates, and pigmentation. Mycological examinations were performed when onychomycosis was suspected. RESULTS: Nail changes were statistically higher in patients with IBD than in the control group (P = 0.001). The presence of onychomycosis was significantly more common in patients with IBD (P = 0.041). Subungual hyperkeratosis and brownish discoloration of the nail were the most common findings in patients with IBD. CONCLUSION: Our study is the first report showing all nail changes in IBD. Further studies with more subjects are needed to reveal more detailed information about nail changes in IBD. PMID- 27511516 TI - Evaluation of maternal serum folate, vitamin B12, and homocysteine levels andfactor V Leiden, factor II g.20210G>A, and MTHFR variations in prenatallydiagnosed neural tube defects. AB - BACKGROUND/AIM: Neural tube defects (NTDs) are common congenital malformations that develop as a result of interactions between several genes and environmental factors. Many factors have been investigated in order to understand the etiology of NTDs, and many studies have identified folate intake as a common contributing factor. The exact etiology of the disease is still unknown. MATERIALS AND METHODS: In this study, we compared serum folate, vitamin B12, and homocysteine levels, along with common thrombophilia-related genetic variations, including factor V Leiden, factor II g.20210G>A, MTHFR c.677C>T, and MTHFR c.1298A>C, in 35 pregnant women with fetal NTDs and 38 pregnant women with healthy fetuses. RESULTS: A significant difference in serum vitamin B12 level and factor V Leiden frequency was detected between the two groups. On the other hand, serum folate, homocysteine levels, and factor II g.20210G>A, MTHFR c.677C>T, and MTHFR c.1298A>C were not significantly different in the NTD group compared to the controls. CONCLUSION: These results indicate that vitamin B12 supplementation along with folate may help in lowering NTD frequency. In addition, this is the first study that provides evidence for a possible relationship between increased NTD risk and factor V Leiden. PMID- 27511518 TI - Traditional practices of Konya women during pregnancy, birth, the postpartumperiod, and newborn care. AB - BACKGROUND/AIM: The purpose of the present study was to identify traditional practices and the extent to which they are practiced by mothers during pregnancy, birth, the postpartum period, and newborn care. MATERIALS AND METHODS: This study was conducted in the city center of Konya (Turkey). Data were collected through questionnaires completed by volunteers. The research sample comprised 450 mothers, all of whom had given birth to at least one live baby. The forms were completed during face-to-face interviews. RESULTS: Some traditional pregnancy practices were followed by 70.7% of the participants. Of the women who performed these practices, 57.4% consciously chose foods they craved, tried not to take nutrients believed to be unsuitable in pregnancy, and took nutrients believed to influence the sex of the baby; 85.6% reported breastfeeding their babies in the first 4 h after birth and 9.7% waited for the first call to prayer (azan) to start breastfeeding. Additionally, 72.2% of the mothers reported performing kirklama (making the forties), a ceremony performed to celebrate the 40th day after a baby's birth. CONCLUSION: Most of the women who participated in the study still followed some traditional practices and rituals during pregnancy and the postpartum period. Therefore, health care professionals should provide health education that accounts for the women's cultural and social environment. PMID- 27511519 TI - Free radical-induced nephrotoxicity following repeated oral exposureto chlorpyrifos alone and in conjunction with fluoride in rats. AB - BACKGROUND/AIM: Chronic renal disorder is becoming a major health problem worldwide. The purpose of the present study was to investigate alterations in the renal antioxidant system in rats induced by repeated exposure to chlorpyrifos (CPF) alone and in conjunction with fluoride. MATERIALS AND METHODS: Wistar rats were randomly allocated to seven groups, each consisting of six rats, and were subjected to different treatment regiments for 28 days. RESULTS: Significant increases (P < 0.05) in plasma protein, blood urea nitrogen, and creatinine levels indicated alterations in renal functions on repeated exposure to CPF or fluoride; moreover, these changes were more pronounced in animals exposed to both toxicants concurrently. A significant increase (P < 0.05) in malondialdehyde levels and decreases in superoxide dismutase, catalase, and glutathione peroxidase activities in renal tissue were noted, indicating renal damage on exposure to CPF, fluoride, or the combination of those. CONCLUSION: Our observations suggested that the concurrent exposure to CPF and fluoride increased the extent of renal damage. These findings indicate that this damage is due to increased free radical formation and a reduced function of the antioxidant system in renal tissue. Thus, the application of CPF as an insecticide should be reduced in areas where the fluoride levels in ground waters are high in order to minimize renal damage in exposed populations. PMID- 27511520 TI - Combination immunotherapy with extract of heated 4T1 and naloxone in mouse model of breast cancer. AB - BACKGROUND/AIM: This study was designed to investigate the efficacy of a new vaccine against breast cancer, which was made by mixing the extract of heated 4T1 cells and naloxone, as an adjuvant. MATERIALS AND METHODS: Female BALB/c mice of 6-8 weeks old were challenged subcutaneously in the right flanks with 4T1 cells. When all animals developed a palpable tumor, immunotherapy was initiated. Mice in the experimental groups received, twice with a 1-week interval, either the extract of heated 4T1 alone or in combination with naloxone, and mice in the negative control group received phosphate-buffered saline. One week after the last immunotherapy, half of the mice were euthanized in order to determine the immune response profile. The remaining animals were kept until the time when death occurred spontaneously. RESULTS: The combined-treated mice with mammary tumors showed a more favorable survival curve and slower rate of tumor development compared to the mice with tumors that received only heated 4T1 and/or negative control mice. Moreover, the combined immunization significantly amplified the respiratory burst potential and the secretion of IFN-gamma, and, conversely, diminished the secretion of IL-4, IL-10, and TGF-beta in the splenocyte population compared to splenocytes from other groups. CONCLUSION: The combined naloxone and heated 4T1 cells promote beneficial outcomes in the mouse model of breast cancer. PMID- 27511521 TI - Comparison between the protective effects of vitamin K and vitamin A on the modulation of hypervitaminosis D3 short-term toxicity in adult albino rats. AB - BACKGROUND/AIM: Vitamin D3 has increased risk of toxicity due to its common use in multivitamin preparations. Vitamin K and vitamin A play an important role in vitamin D action. The goal of the current study was to compare the protective effects of vitamin K and vitamin A on the modulation of hypervitaminosis D3 toxicity in rats by assessing serum calcium, renal function tests, cardiac enzymes, and related histopathological changes. MATERIALS AND METHODS: Eighty adult albino rats were divided into four groups; each group consisted of 20 rats. The first group received water; the second received a toxic dose of vitamin D3; the third received a toxic dose of vitamin D3 with vitamin A; and the fourth received a toxic dose of vitamin D3 with vitamin K. RESULTS: Vitamin D3 toxicity led to significant abnormalities of cardiac enzymes, renal function tests, and serum calcium associated with histopathological changes in the kidney, heart, lung, adrenal gland, and aorta. Individual administration of vitamin A or vitamin K with a toxic dose of vitamin D improved the biochemical and histopathological abnormalities of hypervitaminosis D3. CONCLUSION: Vitamins A and K showed the same protective effects in the modulation of hypervitaminosis D3 short-term toxicity. PMID- 27511522 TI - Evaluation of the effectiveness of biodegradable electrospun caprolactoneand poly(lactic acid-epsilon-caprolactone) nerve conduits for peripheral nerveregenerations in a rat sciatic nerve defect model. AB - BACKGROUND/AIM: The aim of this study was to compare electrospun caprolactone (EC) and poly(lactic acid-epsilon-caprolactone) (PLCL) nerve conduits with nerve graft in a rat sciatic nerve defect model. MATERIALS AND METHODS: A total of 32 male Wistar albino rats were divided into 4 groups, with 8 rats in each group. A nerve defect of 1 cm was constructed in the left sciatic nerve of the rats. These defects were left denuded in the sham group, and reconstructed with nerve grafts, PLCL, and EC nerve conduits in the other groups. After 3 months, nerve regenerations were evaluated macroscopically, microscopically, and electrophysiologically. The numbers of myelinated axons in the cross-sections of the nerves were compared between the groups. RESULTS: Macroscopically, all nerve coaptations were intact and biodegradation was detected in nerve conduits. Electromyographic assessment and count of myelinated axons in the cross-sections of the nerves displayed the best regeneration in the nerve graft group (P < 0.001) and similar results were obtained in the PLCL and EC nerve conduit groups (P = 0.79). Light and electron microscopy studies demonstrated nerve regeneration in both nerve conduit groups. CONCLUSION: EC nerve conduits and PLCL nerve conduits yielded similar results and may be alternatives to nerve grafts as they biodegrade. PMID- 27511523 TI - Ameliorating effects of curcumin on nicotine-induced mice testes. AB - BACKGROUND/AIM: The aim of this study was to determine the antioxidative effect of curcumin on nicotine-induced mice testis. MATERIALS AND METHODS: Sixty Swiss albino male mice were divided into five groups, each containing 12 mice. The first group was used as a control. To induce toxicity in the second and third group, nicotine (0.4 mg/kg/day) was injected intraperitoneally into mice for 14 and 28 days, respectively. The mice in the fourth and fifth group were injected with nicotine (0.4 mg/kg/day) and orally treated with curcumin (200 mg/kg) for 14 and 28 days, respectively. Testosterone levels were measured from blood samples and testis tissues were examined under light and electron microscopes. RESULTS: Light and electron microscopic examinations of the nicotine-induced groups showed evident degenerations in spermatogenic cells, Sertoli cells, and Leydig cells. The groups treated with curcumin had less testicular alterations. The mice that were sacrificed after 28 days in the groups treated with curcumin showed minor degenerations. Furthermore, the median levels of testosterone significantly decreased in the nicotine-induced groups in comparison with those in the control group. CONCLUSION: The results indicated that curcumin might be a potential therapeutic agent for testicular injury caused by nicotine addiction. PMID- 27511524 TI - The protective effect of Capparis ovata in acute hepatotoxicity induced by paracetamol. AB - BACKGROUND/AIM: To investigate the efficiency of Capparis ovata as a protective agent against acute paracetamol toxicity of the liver. MATERIALS AND METHODS: A total of 36 Wistar albino rats were divided into 4 groups: 1) paracetamol, 2) Capparis ovata + paracetamol, 3) Capparis ovata, and 4) control. Groups 2 and 3 were given Capparis ovata and Groups 1 and 4 distilled water for 8 days. On day 8, 3000 mg kg-1 paracetamol was administered orally to Groups 1 and 2. Samples were taken on day 9. AST, ALT, total bilirubin, direct bilirubin, GGT, and ALP levels were assessed. Lipid peroxidation markers and thiobarbituric acid-reactive substance (TBARS) levels were measured in the blood and liver. Liver tissues were evaluated histologically. RESULTS: AST, ALT, and total bilirubin levels were lower in Group 2 than in Group 1 (P < 0.05). TBARS levels were lower in Groups 2 (P = 0.000), 3 (P = 0.001), and 4 (P = 0.001) than in Group 1. Degenerative findings were lower in the Capparis ovata + paracetamol group than in the paracetamol group (P < 0.05). CONCLUSION: It can be concluded that Capparis ovata has a protective effect on the liver, both histopathologically and biochemically, against paracetamol-induced liver injury. PMID- 27511525 TI - Efficacy of pegylated liposomal etoposide nanoparticles on breast cancer cell lines. AB - BACKGROUND/AIM: This study aimed to investigate the efficacy of pegylated liposomal etoposide nanoparticles (NPs) against T-47D and MCF-7 breast cancer cell lines. MATERIALS AND METHODS: Pegylated liposomal etoposide NPs were prepared by reverse phase evaporation method. The size, size distribution, and zeta potential of the NPs was measured by a Zetasizer instrument. The cytotoxicity of NPs was inspected by methyl thiazol tetrazolium assay. The release pattern of the drug from the vesicles was studied by the dialysis method. Drug loading and encapsulation efficiency (EE) were also measured. RESULTS: The mean size, size distribution, and zeta potential of pegylated liposomal etoposide NPs were 491 +/- 15.5 nm, 0.504 +/- 0.14, and -35.8 +/- 2.5 mV, respectively. Drug loading and EE were 10.3 +/- 1.6% and 99.1 +/- 2.8%, respectively. The etoposide release in the formulation was estimated at about 3.48% after 48 h. The cytotoxicity effect of etoposide NPs on T-47D and MCF-7 cell lines of breast cancer showed higher antitumor activity as compared with those of the free drug. CONCLUSION: Liposome-based NPs may hold great potential as a drug delivery system. PMID- 27511526 TI - Role of FLT3 in the proliferation and aggressiveness of hepatocellular carcinoma. AB - BACKGROUND/AIM: Previously we showed that Fms-like tyrosine kinase (FLT3) changes its cellular localization upon partial hepatectomy, suggesting a role in liver regeneration. FLT3 was also shown to play an important function in cellular proliferation and activation of PI3K and Ras. Thus, we aimed to investigate the role of FLT3 in hepatocellular tumorigenesis utilizing in vitro and in vivo models. MATERIALS AND METHODS: We used Snu398 cells that express FLT3. We investigated these cells' in vitro proliferation and invasion abilities by treatment with the FLT3 inhibitor K-252a or by knocking-down with FLT3 shRNA,. Furthermore, the effect of blocking FLT3 activity and expression during in vivo tumorigenesis was assessed with xenograft models. RESULTS: After K-252a treatment or stable knock-down, these cells' proliferation and migration abilities were highly diminished in vitro. In addition, significant diminution in tumorigenicity of Snu398 cells was also obtained in vivo. When FLT3 knocked-down Snu398 cells were injected into nude mice, we did not detect alphaSMA expression in these tumors, suggesting a role for FLT3 in in vivo invasiveness. CONCLUSION: Our data provided evidence that FLT3 has a crucial role both in hepatocarcinogenesis and its invasiveness. Therefore, targeting FLT3 and/or its activity may be a promising tool for combating hepatocellular carcinomas. PMID- 27511527 TI - Aqueous synthesis of highly stable CdTe/ZnS Core/Shell quantum dots for bioimaging. AB - In this work, we report the synthesis, characterization and biological application of highly stable CdTe/ZnS (cadmium tellurite/zinc sulphide) Core/Shell (CS) quantum dots (QDs) capped with mercaptosuccinic acid (MSA). The CS QDs were synthesized using a simple one-pot aqueous method. The synthesized CdTe/ZnS CS QDs were found to exhibit excellent stability even 100 days after preparation and also showed better photoluminescence quantum yield (PLQY) of about 50% compared with that of only CdTe QDs which was nearly 12%. The formation of the CdTe/ZnS CS was confirmed by high-resolution transmission electron microscopy (HR-TEM), and Fourier transform infra-red (FTIR) and X-ray diffraction (XRD) analyses. Further, on extending our study towards bioimaging of E. coli cells using the QDs samples, we found that CdTe/ZnS CS QDs showed better results compared with CdTe QDs. PMID- 27511528 TI - Nickel-catalyzed transfer hydrogenation of ketones using ethanol as a solvent and a hydrogen donor. AB - We report a nickel(0)-catalyzed direct transfer hydrogenation (TH) of a variety of alkyl-aryl, diaryl, and aliphatic ketones with ethanol. This protocol implies a reaction in which a primary alcohol serves as a hydrogen atom source and solvent in a one-pot reaction without any added base. The catalytic activity of the nickel complex [(dcype)Ni(COD)] (e) (dcype: 1,2-bis(dicyclohexyl phosphine)ethane, COD: 1,5-cyclooctadiene), towards transfer hydrogenation (TH) of carbonyl compounds using ethanol as the hydrogen donor was assessed using a broad scope of ketones, giving excellent results (up to 99% yield) compared to other homogeneous phosphine-nickel catalysts. Control experiments and a mercury poisoning experiment support a homogeneous catalytic system; the yield of the secondary alcohols formed in the TH reaction was monitored by gas chromatography (GC) and NMR spectroscopy. PMID- 27511529 TI - Photodetectors: Broad Detection Range Rhenium Diselenide Photodetector Enhanced by (3-Aminopropyl)Triethoxysilane and Triphenylphosphine Treatment (Adv. Mater. 31/2016). AB - The effects of triphenylphosphine (PPh3 ) and (3-amino-propyl)triethoxysilane (APTES) on a rhenium diselenide (ReSe2 ) photodetector are systematically studied by J.-H. Park and co-workers on page 6711 in comparison with a conventional MoS2 device. A very high performance ReSe2 photodetector is demonstrated, which has a broad photodetection range, high photoresponsivity (1.18 * 10(6) A W(-1) ), and fast photoswitching speed (rising/decaying time: 58/263 ms). PMID- 27511531 TI - Wearable Strain Sensors: Carbonized Silk Fabric for Ultrastretchable, Highly Sensitive, and Wearable Strain Sensors (Adv. Mater. 31/2016). AB - A novel carbonized plain-weave silk-fabric-based wearable strain sensor is proposed by Y. Y. Zhang and co-workers on page 6640. The sensor can be stretched up to 500% with high sensitivity in a wide strain range and can be assembled into wearable devices for the detection of both large and subtle human activities, showing great potential in human-motion detection and robotics. PMID- 27511532 TI - Flexible Batteries: Hierarchical Assemblies of Carbon Nanotubes for Ultraflexible Li-Ion Batteries (Adv. Mater. 31/2016). AB - An advanced battery architecture composed of 3D carbon nanotube (CNT) current collectors is used to mitigate stresses in flexible batteries. On Page 6705, C. George, M. De Volder, and co-workers describe the fabrication process and characteristics of this new generation of ultraflexible batteries, which show high rate and cyclablility. These batteries may find applications in the powering of flexible displays and logics. PMID- 27511533 TI - Perovskite Solar Cells: High Efficiency Pb-In Binary Metal Perovskite Solar Cells (Adv. Mater. 31/2016). AB - On page 6695, X. Y. Gao, L.-S. Liao, and co-workers describe the fabrication of mixed Pb-In perovskite solar cells, using indium (III) chloride and lead (II) chloride with methylammonium iodide. A maximum power conversion efficiency as high as 17.55% is achieved owing to the high quality of the perovskites with multiple ordered crystal orientations. This work demonstrates the possibility of substituting the Pb (II) by using In (III), which opens a broad route to fabricating alloy perovskite solar cells with mitigated ecological impact. PMID- 27511534 TI - High-Resolution Electronics: Spontaneous Patterning of High-Resolution Electronics via Parallel Vacuum Ultraviolet (Adv. Mater. 31/2016). AB - On page 6568, T. Minari and co-workers describe spontaneous patterning based on the parallel vacuum ultraviolet (PVUV) technique, enabling the homogeneous integration of complex, high-resolution electronic circuits, even on large-scale, flexible, transparent substrates. Irradiation of PVUV to the hydrophobic polymer surface precisely renders the selected surface into highly wettable regions with sharply defined boundaries, which spontaneously guides a metal nanoparticle ink into a series of circuit lines and gaps with the widths down to a resolution of 1 MUm. PMID- 27511589 TI - An investigation on the interaction modes of a single-strand DNA aptamer and RBP4 protein: a molecular dynamic simulations approach. AB - Type two diabetes is one of the primary health issues threatening public well being worldwide. One of the pre-diagnosis biomarkers of this disease, retinol binding protein 4 (RBP4), has been demonstrated to be detected with a 76-mer ssDNA aptamer instead of conventional antibodies. However, there is no structural information on the RBP4 binding aptamer (RBA) and the mechanism of its binding to RBP4 still remains unexplored. The objective of the present study is to achieve a better understanding of specific binding interactions of the target protein (RBP4) and RBA, employing Molecular Dynamics simulations (MDs) to provide detailed information on fluctuations, conformational changes, critical bases and effective forces to develop regulated aptamers to be employed in designing new aptamers for many useful recognition applications. RBA was designed according to its reported base pair sequence and secondary structure. The HADDOCK on line docking program was used to predict a suitable RBP4-RBA mode of interaction to start MDs with. MDs methodology was used to analyze the final complex stability and detect interacting residues. Eventually, we conclude that single strand located bases are the key components that conduct the intercalation phenomenon with big targets rather than those involving loops and folded motifs, to encompass targets and probably inhibit their activity. Also, UV-visible, circular dichroism and fluorescence spectroscopy measurements confirmed the interactions between RBA and RBP4 and RBP4-RBA complex formation. PMID- 27511536 TI - Effects of T592 phosphomimetic mutations on tetramer stability and dNTPase activity of SAMHD1 can not explain the retroviral restriction defect. AB - SAMHD1, a dNTP triphosphohydrolase, contributes to interferon signaling and restriction of retroviral replication. SAMHD1-mediated retroviral restriction is thought to result from the depletion of cellular dNTP pools, but it remains controversial whether the dNTPase activity of SAMHD1 is sufficient for restriction. The restriction ability of SAMHD1 is regulated in cells by phosphorylation on T592. Phosphomimetic mutations of T592 are not restriction competent, but appear intact in their ability to deplete cellular dNTPs. Here we use analytical ultracentrifugation, fluorescence polarization and NMR-based enzymatic assays to investigate the impact of phosphomimetic mutations on SAMHD1 tetramerization and dNTPase activity in vitro. We find that phosphomimetic mutations affect kinetics of tetramer assembly and disassembly, but their effects on tetramerization equilibrium and dNTPase activity are insignificant. In contrast, the Y146S/Y154S dimerization-defective mutant displays a severe dNTPase defect in vitro, but is indistinguishable from WT in its ability to deplete cellular dNTP pools and to restrict HIV replication. Our data suggest that the effect of T592 phosphorylation on SAMHD1 tetramerization is not likely to explain the retroviral restriction defect, and we hypothesize that enzymatic activity of SAMHD1 is subject to additional cellular regulatory mechanisms that have not yet been recapitulated in vitro. PMID- 27511590 TI - Hematinic deficiencies and anemia statuses in antigastric parietal cell antibody positive erosive oral lichen planus patients with desquamative gingivitis. AB - BACKGROUND/PURPOSE: Erosive oral lichen planus (EOLP) patients with desquamative gingivitis (DG) are sometimes encountered in our oral mucosal disease clinic. This study assessed hematinic deficiencies and anemia statuses in antigastric parietal cell antibody (GPCA)-positive EOLP patients with DG (GPCA+/DG+/EOLP patients). METHODS: The blood hemoglobin, iron, vitamin B12, folic acid, and homocysteine concentrations and serum GPCA levels in 92 GPCA+/DG+/EOLP patients and 184 age- and sex-matched healthy controls were measured and compared between the two groups. RESULTS: We found that 27 (29.3%), 16 (17.4%), and 27 (29.3%) of 92 GPCA+/DG+/EOLP patients had hemoglobin (men < 13 g/dL and women < 12 g/dL), iron (< 60 MUg/dL), and vitamin B12 (< 200 pg/mL) deficiencies, respectively. Moreover, 37 (40.2%) of 92 GPCA+/DG+/EOLP patients had an abnormally high blood homocysteine level (> 12.1MUM). GPCA+/DG+/EOLP patients had a significantly higher frequency of hemoglobin, iron, or vitamin B12 deficiency and an abnormally high blood homocysteine level than healthy control individuals (all p < 0.001). Of 27 anemic GPCA+/DG+/EOLP patients, 13 (48.2%) had pernicious anemia, five (18.5%) had iron deficiency anemia, one (3.7%) had thalassemia trait, and the remaining eight (29.6%) had normocytic anemia. Moreover, of the 92 GPCA+/DG+/EOLP patients, 24 had macrocytosis, and only 13 (54.2%) of these 24 patients had pernicious anemia. CONCLUSION: We conclude that GPCA+/DG+/EOLP patients may have vitamin B12 deficiency, iron deficiency, and an abnormally high blood homocysteine level. In addition to pernicious anemia, GPCA+/DG+/EOLP patients may sometimes have normocytic anemia or iron deficiency anemia. PMID- 27511591 TI - Healthcare-Associated Infections in Pediatric and Neonatal Intensive Care Units: Impact of Underlying Risk Factors and Antimicrobial Resistance on 30-Day Case Fatality in Italy and Brazil. AB - OBJECTIVES To describe trends in the epidemiology of healthcare-associated Infections (HAIs) in pediatric/neonatal intensive care units (ICUs) and to evaluate risk factors and impact of multidrug resistance in children admitted to ICUs. DESIGN Multicenter, retrospective, cohort study with a nested case-control study conducted from January 1, 2010, through December 31, 2014. SETTING Three tertiary care pediatric hospitals in Italy and Brazil with a total of 103 ICU beds. PATIENTS Inclusion criteria were admission to ICU during the study period, age at onset less than 18 years, and microbiologically confirmed HAI. RESULTS A total of 538 HAIs in 454 children were included; 93.3% of patients had comorbidities. Bloodstream infections were the leading pattern (45.4%). The cumulative incidence of HAI was 3.6/100 ICU admissions and the crude 30-day fatality rate was 5.7/1,000 admissions. The most frequently isolated pathogens were Enterobacteriaceae, followed by Pseudomonas aeruginosa and Staphylococcus aureus. Forty-four percent of isolates were multidrug-resistant (MDR). Two multivariate logistic regressions were performed. Factors independently associated with an MDR-HAI were country, previous antibiotics, transplantation, major surgery, and colonization by an MDR strain. Factors independently associated with 30-day case fatality were country, previous transplantation, fungal infection, bloodstream infection, lower respiratory tract infection, and infection caused by MDR strains. CONCLUSIONS Infection control and prevention can limit the spread of MDR strains and improve outcomes. Targeted surveillance programs collecting neonatal and pediatric HAI/bloodstream infection data and outcomes would allow global benchmarking. The next step is to identify methods to monitor key HAIs and integrate these into affordable intervention programs. Infect Control Hosp Epidemiol 2016;1-8. PMID- 27511592 TI - Efficacy of fluralaner in 17 dogs with sarcoptic mange. AB - BACKGROUND: There are few licensed options for the treatment of canine sarcoptic mange. OBJECTIVE: To evaluate the efficacy of fluralaner in dogs with sarcoptic mange infestation. ANIMALS: Seventeen dogs with a diagnosis of Sarcoptes scabiei based on positive skin scrapings. METHODS: A single dose of oral fluralaner was administered according to the manufacturer's instructions. Assessments of pruritus and lesions were performed every 7 days for 1 month. RESULTS: By Day 14 post-treatment, skin scrapings from all dogs were negative for mites. At the beginning of the study there was a negative correlation between body weight of the subject and pruritus [Pearson correlation coefficient (PCC) = -0.396, P = 0.007] and a positive correlation between pruritus and lesion severity (PCC 0.755, P = 0.0001). Significant decreases in lesion size and pruritus were observed within the first 14-21 days, respectively, and improvement in these parameters continued until the end of the study at Day 28. CONCLUSION: Fluralaner was effective in eliminating scabies mites within 14 days and significantly resolved the clinical signs associated with sarcoptic mange within 21 days after a single dose. PMID- 27511593 TI - Human antibody recognition of xenogeneic antigens (NeuGc and Gal) on porcine heart valves: could genetically modified pig heart valves reduce structural valve deterioration? AB - BACKGROUND: Glutaraldehyde-fixed bioprosthetic heart valves (GBHVs) derived from wild-type (WT, genetically unmodified) pigs are widely used clinically for heart valve replacement. There is evidence that their failure is related to an immune response. The use of valves from genetically engineered pigs that do not express specific pig antigens may prolong GBHV survival. Our aims were to determine (i) expression of Gal and NeuGc on heart (aortic and pulmonary) valves and pericardium of WT, alpha1,3-galactosyltransferase gene knockout (GTKO) and GTKO/N glycolylneuraminic acid gene-knockout (GTKO/NeuGcKO) pigs in comparison with three different commercially available GBHVs and (ii) to determine human antibody binding to these tissues. METHODS: Wild-type, GTKO/CD46, and GTKO/CD46/NeuGcKO pig valves and pericardium were tested (i) fresh and (ii) after fixation with glutaraldehyde (0.02%, 0.2%, 2%). Sections of GBHVs, fresh and fixed valves, and pericardium were stained for Gal and NeuGc expression, and for human IgM and IgG antibody binding. RESULTS: Gal and NeuGc expression was high on all GBHVs and WT pig valves/pericardium, but was absent after antigen-specific-knockout. There was no difference in antigen expression or antibody binding among WT aortic, pulmonary valves, and pericardium as well as GBHVs. Glutaraldehyde fixation did not alter expression of Gal or NeuGc. After incubation with human serum, human IgM and IgG bound to all GBHVs and WT pig valves/pericardium. Valves from GTKO/CD46 pigs and, particularly, GTKO/CD46/NeuGcKO pigs (with/without glutaraldehyde fixation) showed less IgM and IgG binding. CONCLUSION: Compared to WT pigs, GTKO/CD46/NeuGcKO pigs would be preferable sources of GBHVs, because the absence of Gal/NeuGc expression reduces human antibody binding. PMID- 27511594 TI - Comparison and Evaluation of the Effectiveness of Two Approaches of Diffusible Iodine-Based Contrast-Enhanced Computed Tomography (diceCT) for Avian Cephalic Material. AB - Diffusible iodine-based contrast-enhanced computed tomography presents a comparatively new tool kit for imaging fine-scale three-dimensional phenotypes that is rapidly becoming standard anatomical practice. However, relatively few studies have attempted to look at subtle differences in staining protocols or attempted to model tissue reactions to gain insight into staining mechanisms. Here, two iodine-based contrast agents, iodine-ethanol (I2 E) and iodine potassium iodide (I2 KI) in neutral buffered formalin , were applied to avian cephalic specimens to investigate their effectiveness. We found that the two solutions had markedly different results for staining of mineralized skeletal tissues (i.e., bone). Other tissues, including muscles, epithelia, and common connective tissues (e.g., lamina propria) were assessed individually and show minor differences in the sorption of iodine. Numerical simulations suggest that different results from I2 E and I2 KI-formaldehyde staining are due to different partition coefficients and retardation factors of tissues, fixation effects, as well as distinct iodine diffusion and sorption patterns. We found a clear positive relationship between glycogen concentration and grayscale values measured within muscle, epithelia, nervous tissues, and glands. We also found the use of ethanol for tissue fixation and following I2 E staining outperforms I2 KI formaldehyde by providing higher efficiency for acquiring greater contrast both between different soft tissues and between mineralized and nonmineralized tissues. PMID- 27511595 TI - Effects of perfluorinated alkyl acids on cellular responses of MCF-10A mammary epithelial cells in monolayers and on acini formation in vitro. AB - Perfluorinated alkyl acids (PFAAs) are stable chemicals detected in tissue and serum from various species, including humans, and have been linked to adverse health outcomes. Experimental PFAA exposure in rodents has been associated with changes in mammary gland development. The estrogen receptor (ER)-negative human breast epithelial cell line, MCF-10A, can be grown as monolayer, but also has the ability to form three-dimensional acini in vitro, reflecting aspects of mammary glandular morphogenesis. Cells were exposed to five different PFAAs, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), both in monolayer and acini cultures. In monolayer cultures only the higher concentrations of PFOS, PFNA and PFDA (400 500MUM) caused a significant increase in cell death, whereas PFOA and PFUnDA had no effect. Normal acini maturation was negatively impacted by PFOS, PFNA and PFDA already at the lowest concentration tested (0.6MUM). Observed effects included loss of organization of the cell clusters and absence of a hollow lumen. Overall, this study demonstrated that PFAAs can interfere with cellular events related to normal development of glandular breast tissue through ER-independent mechanisms. PMID- 27511596 TI - Arthroscopic irrigation of the bovine stifle joint increases cartilage surface friction and decreases superficial zone lubricin. AB - The purpose of this study was to determine the effects of arthroscopic irrigation on cartilage superficial zone lubricin and surface friction. Arthroscopic partial meniscectomy is one of the most commonly performed orthopedic surgeries in the United States, but rates of osteoarthritis progression following this procedure are high. The effect of arthroscopic irrigation on articular surface lubrication has not been previously considered as a contributing factor in outcomes after arthroscopy. Fourteen bovine stifle joints were randomized to receive arthroscopic irrigation (n=7) or no treatment (n=7). Full-thickness osteochondral explants from these joints underwent friction testing to measure static and dynamic coefficients of friction. Following mechanical testing, samples were fixed and stained for lubricin. Percent integrated density, a measure of the amount of lubricin in the superficial zone (0-100um depth), was determined. Static and dynamic coefficients of friction were found to be significantly greater in arthroscopy specimens compared to controls (p=0.02 and p<0.001, respectively). Percent integrated density of lubricin in the superficial zone was significantly lower in arthroscopy specimens compared to controls (p<0.001). PMID- 27511597 TI - Mechanisms influencing retrograde flow in the atrioventricular canal during early embryonic cardiogenesis. AB - Normal development of the heart is regulated, in part, by mechanical influences associated with blood flow during early stages of embryogenesis. Specifically, the potential for retrograde flow at the atrioventricular canal (AVC) is particularly important in valve development. However, the mechanisms causing this retrograde flow have received little attention. In this study, a numerical analysis was performed on images of the embryonic zebrafish heart between 48 and 55hpf. During these stages, normal retrograde flow is prevalent. To manipulate this flow, zebrafish were placed in a centrifuge and subjected to a hypergravity environment to alter the cardiac preload at various six-hour intervals between 24 and 48hpf. Parameters of the pumping mechanics were then analyzed through a spatiotemporal analysis of processed image sequences. We find that the loss of retrograde flow in experimentally manipulated embryos occurs in part because of a greater resistance in the form of atrial and AVC contractile closure. Additionally, during retrograde flow, these embryos exhibit significantly greater pressure difference across the AVC based on calculations of expansive and contractile rates of the atrium and ventricle. These results elucidated that the developing heart is highly sensitive to small changes in pumping mechanics as it strives to maintain normal hemodynamic conditions necessary for later cardiac development. PMID- 27511598 TI - Review of bioanalytical assays for the quantitation of various HDAC inhibitors such as vorinostat, belinostat, panobinostat, romidepsin and chidamine. AB - Histone deacetylase inhibitors (HDAC inhibitors) are used to treat malignancies such as cutaneous T cell lymphoma and peripheral T cell lymphoma. Only four drugs are approved by the US Food and Drug Administration, namely vorinostat, romidepsin, panobinostat and belinostat, while chidamide has been approved in China. There are a number of bioanalytical methods reported for the measurement of HDAC inhibitors in clinical (human plasma and serum) and preclinical (mouse plasma, rat plasma, urine and tissue homogenates, etc.) studies. This review covers various HDAC inhibitors such as vorinostat, romidepsin, panobinostat, belinostat and chidamide. In addition to providing a comprehensive review of the available methods for the above mentioned HDAC inhibitors, it also provides case studies with perspectives for chosen drugs. Based on the review, it is concluded that the published methodologies using either HPLC or LC-MS/MS are well suited for the quantification of HDAC inhibitors in various biological fluids to delineate pharmacokinetic data. PMID- 27511599 TI - Natural Products at Work: Structural Insights into Inhibition of the Bacterial Membrane Protein MraY. AB - Natural(ly) fit: The X-ray crystal structure of the bacterial membrane protein MraY in complex with its natural product inhibitor muraymycin D2 is discussed. MraY catalyzes one of the membrane-associated steps in peptidoglycan biosynthesis and, therefore, represents a promising target for novel antibiotics. Structural insights derived from the protein-inhibitor complex might now pave the way for the development of new antimicrobial drugs. PMID- 27511600 TI - The Associations of HLA-A*02:01 and DRB1*11:01 with Hepatitis C Virus Spontaneous Clearance Are Independent of IL28B in the Chinese Population. AB - Spontaneous clearance of hepatitis C virus (HCV) occurs in 10-40% of the infections. Specific human leukocyte antigen (HLA) alleles have been identified in associating with HCV clearance. However, data on the association of HLA with the spontaneous clearance of HCV are scarce in the Chinese population. In the current study we studied the HLA class I and class II genes in 231 Chinese voluntary blood donors who had cleared HCV infection spontaneously compared to 429 subjects with chronic HCV infections. We also studied their IL28B SNP (rs8099917) genotype, since a number of investigators have found a strong association of IL28B with spontaneous or treatment induced HCV clearance. We found that HLA-A*02:01 and DQB1*05:02 distributed differently between the two groups after Bonferroni correction (odds ratio [OR] = 1.839, Pc = 0.024 and OR = 0.547, Pc = 0.016, respectively). Multivariate logistic regression analysis suggested that A*02:01 and DRB1*11:01 (OR = 1.798, P = 0.008 and OR = 1.921, P = 0.005, respectively) were associated with HCV spontaneous clearance, independent of age, gender and IL28B polymorphism. We concluded that in the Chinese population, HLA-A*02:01 and DRB1*11:01 might be associated with the host capacity to clear HCV independent of IL28B, which suggesting that the innate and adaptive immune responses both play an important role in the control of HCV. PMID- 27511602 TI - Blue-sky bifurcation of ion energies and the limits of neutral-gas sympathetic cooling of trapped ions. AB - Sympathetic cooling of trapped ions through collisions with neutral buffer gases is critical to a variety of modern scientific fields, including fundamental chemistry, mass spectrometry, nuclear and particle physics, and atomic and molecular physics. Despite its widespread use over four decades, there remain open questions regarding its fundamental limitations. To probe these limits, here we examine the steady-state evolution of up to 10 barium ions immersed in a gas of three-million laser-cooled calcium atoms. We observe and explain the emergence of nonequilibrium behaviour as evidenced by bifurcations in the ion steady-state temperature, parameterized by ion number. We show that this behaviour leads to the limitations in creating and maintaining translationally cold samples of trapped ions using neutral-gas sympathetic cooling. These results may provide a route to studying non-equilibrium thermodynamics at the atomic level. PMID- 27511601 TI - Age-dependent increase in the expression of antioxidant-like protein-1 in the gerbil hippocampus. AB - Antioxidant-like protein-1 (AOP-1) reduces the intracellular level of reactive oxygen species. In the present study, the age-related change in AOP-1 expression in the hippocampus among young, adult and aged gerbils was compared using western blot analysis and immunohistochemistry. The results demonstrated that the protein expression of AOP-1 was gradually and significantly increased in the hippocampus during the normal aging process. In addition, the age-dependent increase in AOP-1 immunoreactivity was also observed in pyramidal neurons of the hippocampus proper; however, in the dentate gyrus, AOP-1 immunoreactivity was not altered during the normal aging process. These results indicated that the expression of AOP-1 is significantly increased in the hippocampus proper, but not in the dentate gyrus, during the normal aging process. PMID- 27511604 TI - Reply. PMID- 27511603 TI - PRDM16 is associated with evasion of apoptosis by prostatic cancer cells according to RNA interference screening. AB - Histone methylation, which is regulated by histone methyltransferases (HMTs) and histone demethylases (HDMs), has been indicated to be involved in a variety of diseases, particularly in cancer, including androgen-independent prostate cancer (PCa). However, the functions of HMTs and HDTs in cancer have largely remained elusive. The present study, utilized an RNA interference screening using a lentiviral small hairpin (sh)RNA library to systematically elucidate the function of HMTs and HDTs in PCa cell growth and viability. Nine HMTs and HDTs, namely FBXO11, PRDM10, JMJD8, MLL, SETD4, JMJD7, PRMT2, MEN1 and PRDM16, were identified to affect DU145 cell viability, as indicated by an MTS assay subsequent to knockdown of the specific genes using shRNA pools. Furthermore, flow cytometric analysis and western blot analysis of apoptosis-associated proteins indicated that PRDM16 has an anti-apoptotic role in PCa cells. In addition, the spliced form, sPRDM16/MEL1S, was detected to be overexpressed in PCa cell lines. In conclusion, the present study indicated an important oncogenic role of sPRDM16/MEL1S in PCa and suggested that PRDM16 may represent a novel therapeutic target. PMID- 27511605 TI - Nomenclature for factors of the HLA system, update April 2016. PMID- 27511606 TI - Temporal and spectral properties of esophageal mucosal blood perfusion: a comparison between normal subjects and nutcracker esophagus patients. AB - BACKGROUND: The mechanism of esophageal pain in patients with nutcracker esophagus (NE) and other esophageal motor disorders is not known. Our recent study shows that baseline esophageal mucosal perfusion, measured by laser Doppler perfusion monitoring, is lower in NE patients compared to controls. The goal of our current study was to perform a more detailed analysis of esophageal mucosal blood perfusion (EMBP) waveform of NE patients and controls to determine the optimal EMBP biomarkers that combined with suitable statistical learning models produce robust discrimination between the two groups. METHODS: Laser Doppler recordings of 10 normal subjects (mean age 43 +/- 15 years, 8 males) and 10 patients (mean age 47 +/- 5.5 years., 8 males) with NE were analyzed. Time and frequency domain features were extracted from the first twenty-minute recordings of the EMBP waveforms, statistically ranked according to four independent evaluation criterions, and analyzed using two statistical learning models, namely, logistic regression (LR) and support vector machines (SVM). KEY RESULTS: The top three ranked predictors between the two groups were the 0.5 and 0.75 perfusion quantile values followed by the surface of the EMBP power spectrum in the frequency domain. ROC curve ranking produced a cross-validated AUC (area under the curve) of 0.93 for SVM and 0.90 for LR. CONCLUSIONS & INFERENCES: We show that as a group NE patients have lower perfusion values compared to controls, however, there is an overlap between the two groups, suggesting that not all NE patients suffer from low mucosal perfusion levels. PMID- 27511607 TI - Improving Team Performance for Public Health Preparedness. AB - OBJECTIVE: Between May 2010 and September 2011, the University of Minnesota School of Public Health partnered with the Minnesota Department of Health (MDH) to assess the effect of exercises on team performance during public health emergency response. METHODS: Participants were divided into 3 research teams exposed to various levels of intervention. Groups consisted of a control group that was given standard MDH training exercises, a didactic group exposed to team dynamics and communication training, and a treatment group that received the didactic training in addition to a post-exercise facilitated debriefing. To assess differences in team performance, teams engaged in 15 functional exercises. RESULTS: Differences in team performance across the 3 groups were identified, although there was no trend in team performance over time for any of the groups. Groups demonstrated fluctuation in team performance during the study period. Attitudinal surveys demonstrated an increase in workplace satisfaction and confidence in training among all groups throughout the study period. CONCLUSIONS: Findings from this research support that a critical link exists between training type and team performance during public health emergency response. This research supports that intentional teamwork training for emergency response workers is essential for effective public health emergency response. (Disaster Med Public Health Preparedness. 2017;11:7-10). PMID- 27511608 TI - Metabolic syndrome and psoriasis severity in South-East Asian patients: An investigation of potential association using current and chronological assessments. AB - Although studies regarding prevalence of metabolic syndrome (MS) in Asian psoriatic patients are limited and show varying results, a previous report describes a significant increase in prevalence of MS in Thai psoriatic patients, as compared with rates in the general population. However, no significant association between MS and psoriasis severity using the Psoriasis Area and Severity Index (PASI) was found, which differs from the findings of Korean and Japanese studies. This study aimed at re-evaluating the association between MS and psoriasis severity in Thai patients using current assessment (PASI) and chronological assessment (historical course and interventions). A total of 273 psoriatic patients were recruited. After controlling for age and sex, 96 patients were assigned to the MS group and 96 patients to the non-MS group. Similar to the previous study, no significant differences were identified between metabolic and non-metabolic patients regarding PASI, age of onset, disease duration and family history of psoriasis. However, the numbers of hospitalizations (P = 0.018) and interventions (P = 0.028) were significantly higher in metabolic patients than in non-metabolic patients. Further, a greater number of metabolic components was significantly associated with a higher number of hospitalizations (P = 0.012), pustular or erythrodermic psoriasis episodes (P = 0.049), and interventions (P = 0.005). Body mass index of 23 kg/m2 or more, abdominal obesity and high blood pressure were associated with an increased risk of treatment failure. Using chronological assessment, our study supported that MS negatively affects psoriasis severity and treatment outcomes. Screening for MS is highly recommended for psoriatic patients. PMID- 27511609 TI - Emotional Modulation of Conflict Processing in the Affective Domain: Evidence from Event-related Potentials and Event-related Spectral Perturbation Analysis. AB - Previous studies have revealed the impact of emotion on conflict processing. The present study was conducted to investigate whether cognitive control in the affective domain is also affected by emotion. Emotional face-word and body-word Stroop tasks were explored and contrasted, and both behavioural and electrophysiological measures were recorded. Behavioural results showed that both tasks replicated previous robust interference effects. At the physiological level, the two tasks showed dissociable neural activity in the early attention and perception stages. It was also found that the face-word task evoked more pronounced N1 and P2 amplitudes than the body-word task. However, the two tasks evoked comparable N450 amplitudes. At later processing stages, positive slow potentials were modulated by target emotion and congruency. In addition, time frequency analyses also revealed that the face-word task induced enhanced theta activity compared to the body-word task at both early and later stages of processing. The present findings provide support for the dual competition framework and suggest the dynamic modulation of emotion on cognitive control in the affective domain. PMID- 27511610 TI - RAMPred: identifying the N(1)-methyladenosine sites in eukaryotic transcriptomes. AB - N(1)-methyladenosine (m(1)A) is a prominent RNA modification involved in many biological processes. Accurate identification of m(1)A site is invaluable for better understanding the biological functions of m(1)A. However, limitations in experimental methods preclude the progress towards the identification of m(1)A site. As an excellent complement of experimental methods, a support vector machine based-method called RAMPred is proposed to identify m(1)A sites in H. sapiens, M. musculus and S. cerevisiae genomes for the first time. In this method, RNA sequences are encoded by using nucleotide chemical property and nucleotide compositions. RAMPred achieves promising performances in jackknife tests, cross cell line tests and cross species tests, indicating that RAMPred holds very high potential to become a useful tool for identifying m(1)A sites. For the convenience of experimental scientists, a web-server based on the proposed model was constructed and could be freely accessible at http://lin.uestc.edu.cn/server/RAMPred. PMID- 27511611 TI - A comparison of questionnaires for assessing physical function in patients with lower extremity bone metastases. AB - OBJECTIVES: To assess, (i) the degree to which the: PROMIS Physical Function Cancer, PROMIS Neuro-QoL Mobility, Toronto Extremity Salvage Score (TESS), Lower Extremity Function Score (LEFS), and Musculoskeletal Tumor Society score (MSTS), measure physical function; (ii) differences in coverage and reliability; and (iii) difference in completion time. METHODS: One hundred of 115 (87%) patients with lower extremity metastases participated in this prospective study. We used exploratory factor analysis-correlating questionnaires with an underlying trait to assess if questionnaires measure the same. Coverage was assessed by floor and ceiling effect and reliability by the standard error of measurement (SEM). Completion time was compared using the Friedman test. RESULTS: All questionnaires measured the same concept; demonstrated by high correlations (>0.7). Floor effect was absent, while ceiling effect was present in all, but highest for the PROMIS Neuro-QoL Mobility (7%). The SEM was below the threshold-indicating reliability over a wide range of ability levels for the PROMIS-Physical Function, TESS, and LEFS. Completion time differed between questionnaires (P < 0.001) and was shortest for the PROMIS questionnaires. CONCLUSIONS: The PROMIS Physical Function is the most useful questionnaire. This is due to its reliability over a wide range of ability levels, validity, brevity, and good coverage. J. Surg. Oncol. 2016;114:691-696. (c) 2016 Wiley Periodicals, Inc. PMID- 27511613 TI - Blood pressure variability and cardiovascular risk. PMID- 27511612 TI - Taking mHealth Forward: Examining the Core Characteristics. AB - The emergence of mobile health (mHealth) offers unique and varied opportunities to address some of the most difficult problems of health. Some of the most promising and active efforts of mHealth involve the engagement of mobile phone technology. As this technology has spread and as this technology is still evolving, we begin a conversation about the core characteristics of mHealth relevant to any mobile phone platform. We assert that the relevance of these characteristics to mHealth will endure as the technology advances, so an understanding of these characteristics is essential to the design, implementation, and adoption of mHealth-based solutions. The core characteristics we discuss are (1) the penetration or adoption into populations, (2) the availability and form of apps, (3) the availability and form of wireless broadband access to the Internet, and (4) the tethering of the device to individuals. These collectively act to both enable and constrain the provision of population health in general, as well as personalized and precision individual health in particular. PMID- 27511614 TI - The light-matter interaction of a single semiconducting AlGaN nanowire and noble metal Au nanoparticles in the sub-diffraction limit. AB - Near field scanning optical microscopy (NSOM) is not only a tool for imaging of sub-diffraction limited objects but also a prominent characteristic tool for understanding the intrinsic properties of nanostructures. In order to understand light-matter interactions in the near field regime using a NSOM technique with an excitation of 532 nm (2.33 eV), we selected an isolated single semiconducting AlGaN nanowire (NW) of diameter ~120 nm grown via a vapor liquid solid (VLS) mechanism along with a metallic Au nanoparticle (NP) catalyst. The role of electronic transitions from different native defect related energy states of AlGaN is discussed in understanding the NSOM images for the semiconducting NW. The effect of strong surface plasmon resonance absorption of an excitation laser on the NSOM images for Au NPs, involved in the VLS growth mechanism of NWs, is also observed. PMID- 27511615 TI - Congenital abnormalities in newborns of women with pregestational diabetes: A time-trend analysis, 1994 to 2009. AB - BACKGROUND: The main objective of the current study is to examine the trend of congenital abnormalities among children born by women with and without diabetes, and to explore the impact of food fortification by folic acid on the rate of birth defects among these two groups of mothers. METHODS: All children born alive in Ontario, Canada, during 1994 to 2009 and their mothers were included in study. Diagnosis of pregestational diabetes among mothers was identified using Diabetes registry, and diagnosis of birth defects among children were identified using hospital records. RESULTS: The prevalence of births among diabetic mothers increased by almost 200% during the study period. Among children born to mothers with diabetes, the prevalence for all anomalies combined was approximately 47% higher and for various cardiac and central nervous system anomalies up to a three to fivefold higher than those born to nondiabetic mothers. While the rate of birth defects in both groups observed a considerable decline after food fortification in 1999, but the gap between two groups remained unchanged over time. CONCLUSION: While the prevalence of birth defects among diabetic pregnancies is still considerably higher that nondiabetic pregnancies, results of the current study indicate a declining trend in the prevalence of some congenital abnormalities among babies born to both diabetic and nondiabetic mothers after 1999. We need to be more aggressive in implementing preventive measures, including a national diabetes plan or the proposed universal policy of supra dietary folic acid supplementation for women with diabetes who are of reproductive age. Birth Defects Research (Part A) 106:831-839, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27511616 TI - The effect of environmental contamination on the community structure and fructification of ectomycorrhizal fungi. AB - Ectomycorrhizal fungi are an essential component of forest ecosystems, most of which can form edible and medical fruiting bodies. Although many studies have focused on the fructification of ectomycorrhizal fungi in phenology, the impact of environmental contamination, especially living garbage, on the formation of fruiting body is still unknown. A field investigation, combined with a high throughput sequencing method, was used to study the effect of living garbage pollution on the fructification and hypogeous community structure of ectomycorrhizal fungi symbiosing with cedar (Cedrus deodara (Roxb.) G. Don). The results showed that garbage significantly altered soil abiotic and biotic properties, increasing soil urease activity, decreasing the soil exchangeable metal content and phosphatase activity, and ultimately inhibiting the formation of fruiting bodies. The pollution of garbage also changed the community structure of hypogeous ectomycorrhizal fungi where ectomycorrhizal ascomycetes dominated. In unpolluted sites, the relative abundance of ectomycorrhizal ascomycetes and basidiomycetes were almost equal. Although no fruiting bodies were observed in that soil polluted by living garbage, the sequencing result showed that various ectomycorrhizal fungi were present underground, suggesting that these taxonomic fungi had the potential to cope with adverse conditions. This study not only provided a deeper understanding of the relationship between ectomycorrhizal fungal communities and prevailing environmental conditions, but provided a new pathway for the excavation and utilization of the resource of antistress ectomycorrhizal fungi. PMID- 27511617 TI - Barriers and facilitators to health screening in men: A systematic review. AB - RATIONALE: Men have poorer health status and are less likely to attend health screening compared to women. OBJECTIVE: This systematic review presents current evidence on the barriers and facilitators to engaging men in health screening. METHODS: We included qualitative, quantitative and mixed-method studies identified through five electronic databases, contact with experts and reference mining. Two researchers selected and appraised the studies independently. Data extraction and synthesis were conducted using the 'best fit' framework synthesis method. RESULTS: 53 qualitative, 44 quantitative and 6 mixed-method studies were included. Factors influencing health screening uptake in men can be categorized into five domains: individual, social, health system, healthcare professional and screening procedure. The most commonly reported barriers are fear of getting the disease and low risk perception; for facilitators, they are perceived risk and benefits of screening. Male-dominant barriers include heterosexual -self presentation, avoidance of femininity and lack of time. The partner's role is the most common male-dominant facilitator to screening. CONCLUSIONS: This systematic review provides a comprehensive overview of barriers and facilitators to health screening in men including the male-dominant factors. The findings are particularly useful for clinicians, researchers and policy makers who are developing interventions and policies to increase screening uptake in men. PMID- 27511618 TI - Tailoring Size and Coverage Density of Silver Nanoparticles on Monodispersed Polymer Spheres as Highly Sensitive SERS Substrates. AB - Silver nanoparticles (AgNPs) were deposited onto the monodispersed carboxylic polystyrene (CPS) spheres by an improved in situ reduction method. The size and coverage density of the AgNPs on the surface of CPS spheres could be easily tailored by tuning the concentrations of carboxylic functional groups and silver precursor. The morphologies and structures of the resulting CPS/Ag hybrid particles were studied by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), UV-Vis-NIR spectrometer and X ray photoelectron spectroscopy (XPS), etc. The surface enhanced Raman scattering (SERS) performances of the resulting uniform CPS/Ag hybrid particles were investigated using 4-aminobenzenethiol (4-ABT) as the probe molecule. The optimized CPS/Ag hybrid particles show high enhancement factor (EF) of 2.71*10(7) , low limit of detection (LOD) of 10(-10) m and good reproducibility with relative standard deviation (RSD) of 9.64 %. The good SERS improvement properties demonstrate these hybrid particles could be employed as simple and effective substrates in the SERS spectroscopy. PMID- 27511619 TI - Systematic review of the methodological and reporting quality of case series in surgery. AB - BACKGROUND: Case series are an important and common study type. No guideline exists for reporting case series and there is evidence of key data being missed from such reports. The first step in the process of developing a methodologically sound reporting guideline is a systematic review of literature relevant to the reporting deficiencies of case series. METHODS: A systematic review of methodological and reporting quality in surgical case series was performed. The electronic search strategy was developed by an information specialist and included MEDLINE, Embase, Cochrane Methods Register, Science Citation Index and Conference Proceedings Citation index, from the start of indexing to 5 November 2014. Independent screening, eligibility assessments and data extraction were performed. Included articles were then analysed for five areas of deficiency: failure to use standardized definitions, missing or selective data (including the omission of whole cases or important variables), transparency or incomplete reporting, whether alternative study designs were considered, and other issues. RESULTS: Database searching identified 2205 records. Through the process of screening and eligibility assessments, 92 articles met inclusion criteria. Frequencies of methodological and reporting issues identified were: failure to use standardized definitions (57 per cent), missing or selective data (66 per cent), transparency or incomplete reporting (70 per cent), whether alternative study designs were considered (11 per cent) and other issues (52 per cent). CONCLUSION: The methodological and reporting quality of surgical case series needs improvement. The data indicate that evidence-based guidelines for the conduct and reporting of case series may be useful. PMID- 27511621 TI - A dialdehyde-diboronate-functionalized AIE luminogen: design, synthesis and application in the detection of hydrogen peroxide. AB - A dialdehyde-diboronate-functionalized tetraphenylethene (TPE-DABF) was reported as a H2O2-specific AIE luminogen. TPE-DABF, bearing multiple reductive units (aldehyde, boronate and fructose) in one molecule, afforded an excellent H2O2 selectivity over other ROS in biological buffer, and can be used for sensitive detection of glucose under neutral conditions. PMID- 27511620 TI - Value of corneal epithelial and Bowman's layer vertical thickness profiles generated by UHR-OCT for sub-clinical keratoconus diagnosis. AB - Ultra-high resolution optical coherence tomography (UHR-OCT) can image the corneal epithelium and Bowman's layer and measurement the thicknesses. The purpose of this study was to validate the diagnostic power of vertical thickness profiles of the corneal epithelium and Bowman's layer imaged by UHR-OCT in the diagnosis of sub-clinical keratoconus (KC). Each eye of 37 KC patients, asymptomatic fellow eyes of 32 KC patients, and each eye of 81 normal subjects were enrolled. Vertical thickness profiles of the corneal epithelium and Bowman's layer were measured by UHR-OCT. Diagnostic indices were calculated from vertical thickness profiles of each layer and output values of discriminant functions based on individual indices. Receiver operating characteristic curves were determined, and the accuracy of the diagnostic indices were assessed as the area under the curves (AUC). Among all of the individual indices, the maximum ectasia index for epithelium had the highest ability to discriminate sub-clinical KC from normal corneas (AUC = 0.939). The discriminant function containing maximum ectasia indices of epithelium and Bowman's layer further increased the AUC value (AUC = 0.970) for sub-clinical KC diagnosis. UHR-OCT-derived thickness indices from the entire vertical thickness profiles of the corneal epithelium and Bowman's layer can provide valuable diagnostic references to detect sub-clinical KC. PMID- 27511622 TI - Laterality of motor cortical function measured by transcranial magnetic stimulation threshold tracking. AB - INTRODUCTION: Threshold tracking paired-pulse transcranial magnetic stimulation (TTTMS) examines cortical function and is useful for diagnosis of motor neuron disorders. Differences in cortical function have been identified between dominant and non-dominant limbs using constant stimulus methods, but they remain unclear, potentially due to methodological differences. In this study we aimed to clarify differences in cortical function between dominant and non-dominant limbs using TTTMS. METHODS: Single-pulse TMS, TTTMS, and nerve conduction studies were performed in 25 healthy, right-handed participants by recording from the abductor pollicis brevis muscle. RESULTS: There were no side-to-side differences observed in resting motor threshold, motor evoked potential (MEP) amplitude, MEP latency, central motor conduction time, cortical silent period, short-interval intracortical inhibition and facilitation, compound muscle action potential (CMAP) amplitude, CMAP latency, F-wave latency, or neurophysiological index. CONCLUSIONS: These findings suggest that, when using TTTMS, there are no differences in cortical function between dominant and non-dominant hemispheres. Muscle Nerve 55: 424-427, 2017. PMID- 27511623 TI - Bio-Inspired Design and Fabrication of Micro/Nano-Brush Dual Structural Surfaces for Switchable Oil Adhesion and Antifouling. AB - The underwater superoleophobic surfaces play a significant role in anti-oil contamination, marine antifouling, etc. Inspired by the Gecko's feet and its self cleaning property, a hierarchical structure composed of poly (acrylic acid) gel micro-brushes is designed by the liquid-infused method. This surface exhibits underwater superoleophobicity with very low oil adhesion. It is then modified with stimuli-responsive polymer nano-brushes via surface-initiated atom transfer radical polymerization from the embedded initiator. The micro/nano-brush dual structural surfaces can switch the underwater oil adhesion between low and high while keeping the superoleophobicity. The antifouling properties against algae attachment under different mediums are also investigated to show a strong link between oleophobicity and antibiofouling property. The model surface will be very useful in directing the design of marine self-cleaning coatings to both living and non-living species. PMID- 27511625 TI - Concordance of poor child feeding and preventive behavior and its predictors in southwest rural Ethiopia. AB - BACKGROUND: Inappropriate child feeding and caring practices are a major cause of malnutrition. To date, no studies have examined concordance and discordance of child feeding and preventive behavior and their predictors in developing countries. METHODS: We used baseline data generated from A 2-year-longitudinal agriculture-nutrition panel survey conducted from February 9 to April 9, 2014, in nine districts encompassing 20 randomly selected counties in Oromiya Region and Southern Nation, Nationality and Peoples Region in Ethiopia. Households were recruited using the Expanded Program on Immunization sampling method. A total of 623 children under the age of 5 years and their respective caregivers were included in the analyses. Generalized estimating equations were used to account for clustered observations. RESULTS: Concordance of poor child feeding and preventive behavior was observed in 45.1% of the children, while 45.5% of the children were suffering from discordance of poor child feeding and preventive behavior. Concordance and discordance of poor child feeding and preventive behavior had almost different predictors. Concordance of poor child feeding and preventive behavior was significantly associated with the age of the caretaker of >=40 years (odds ratio (OR)=2.14; 95% confidence interval (CI): 1.04, 4.41), low household dietary diversity (OR=3.69; 95% CI: 1.93, 7.04), medium household dietary diversity (OR=2.17; 95% CI: 1.17, 4.00), severe household food insecurity (OR=1.72; 95% CI: 1.01, 2.93), and increase with increasing child age. CONCLUSION: A substantial number of children in the southwest of rural Ethiopia are exposed to both poor child feeding and preventive behavior. Low household dietary diversity and extreme food insecurity household were predictors of concordance of poor child feeding and poor preventive behavior and provide useful entry points for comprehensive interventions to address child feeding and caring in the area. PMID- 27511624 TI - Ribonucleotides and Transcription-Associated Mutagenesis in Yeast. AB - High levels of transcription stimulate mutation rates in microorganisms, and this occurs primarily through an enhanced accumulation of DNA damage. The major source of transcription-associated damage in yeast is Topoisomerase I (Top1), an enzyme that removes torsional stress that accumulates when DNA strands are separated. Top1 relieves torsional stress by nicking and resealing one DNA strand, and some Top1-dependent mutations are due to trapping and processing of the covalent cleavage intermediate. Most, however, reflect enzyme incision at ribonucleotides, which are the most abundant noncanonical component of DNA. In either case, Top1 generates a distinctive mutation signature composed of short deletions in tandem repeats; in the specific case of ribonucleotide-initiated events, mutations reflect sequential cleavage by the enzyme. Top1-dependent mutations do not require highly activated transcription, but their levels are greatly increased by transcription, which partially reflects an interaction of Top1 with RNA polymerase. Recent studies have demonstrated that Top1-dependent mutations exhibit a strand bias, with the nature of the bias differing depending on the transcriptional status of the underlying DNA. Under low-transcription conditions, most Top1-dependent mutations arise in the context of replication and reflect incision at ribonucleotides incorporated during leading-strand synthesis. Under high-transcription conditions, most Top1-dependent events arise when the enzyme cleaves the non-transcribed strand of DNA. In addition to increasing genetic instability in growing cells, Top1 activity in transcriptionally active regions may be a source of mutations in quiescent cells. PMID- 27511626 TI - Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-alpha-TNFR1-NF-kappaB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis. AB - To study the role of TNF-alpha in tongue cancer metastasis, we made highly metastatic cells from a human oral squamous cell carcinoma cell line (SAS) by repeating the passage in which the cells were injected into a nude mouse tongue and harvested from metastasized cervical lymph nodes. Cancer cells after 5 passages (GSAS/N5) increased invasive activity 7-fold in a TNF-alpha receptor 1 (TNFR1)-dependent manner and enhanced mRNA expression of TNF-alpha and TNFR1. In the highly metastatic cells, NF-kappaB activation was upregulated via elevated phosphorylation of Akt and Ikkalpha/beta in the signaling pathway and secretion of TNF-alpha, active MMP-2 and MMP-9 increased. Suppression of increase of TNF alpha mRNA expression and MMP secretion by NF-kappaB inhibitor NBD peptide suggested a positive feedback loop in GSAS/N5 cells; TNF-alpha activates NF kappaB and activated NF-kappaB induces further TNF-alpha secretion, leading to increase of active MMP release and promotion of invasion and metastasis of the cells. GSAS/N5 cells that had been injected into the nude mouse tongue and harvested from metastasized lungs multiplied angiopoietin-like 4 (angptl4) expression with enhanced migration activity, which indicated a possible involvement of angptl4 in lung metastasis of the cells. These results suggest that TNF-alpha and angptl4 promote metastasis of the oral cancer cells, thus, these molecules may be therapeutic targets for patients with tongue cancer. PMID- 27511628 TI - Unexpected functions of automatically annotated genes: a lesson learnt from Bacillus subtilis. PMID- 27511627 TI - Age-related differences in autism: The case of white matter microstructure. AB - Autism spectrum disorder (ASD) is typified as a brain connectivity disorder in which white matter abnormalities are already present early on in life. However, it is unknown if and to which extent these abnormalities are hard-wired in (older) adults with ASD and how this interacts with age-related white matter changes as observed in typical aging. The aim of this first cross-sectional study in mid- and late-aged adults with ASD was to characterize white matter microstructure and its relationship with age. We utilized diffusion tensor imaging with head motion control in 48 adults with ASD and 48 age-matched controls (30-74 years), who also completed a Flanker task. Intra-individual variability of reaction times (IIVRT) measures based on performance on the Flanker interference task were used to assess IIVRT-white matter microstructure associations. We observed primarily higher mean and radial diffusivity in white matter microstructure in ASD, particularly in long-range fibers, which persisted after taking head motion into account. Importantly, group-by-age interactions revealed higher age-related mean and radial diffusivity in ASD, in projection and association fiber tracts. Subtle dissociations were observed in IIVRT-white matter microstructure relations between groups, with the IIVRT-white matter association pattern in ASD resembling observations in cognitive aging. The observed white matter microstructure differences are lending support to the structural underconnectivity hypothesis in ASD. These reductions seem to have behavioral percussions given the atypical relationship with IIVRT. Taken together, the current results may indicate different age-related patterns of white matter microstructure in adults with ASD. Hum Brain Mapp 38:82-96, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27511629 TI - The Bindex((r)) ultrasound device: reliability of cortical bone thickness measures and their relationship to regional bone mineral density. AB - The Bindex((r)) quantitative ultrasound (QUS) device is currently available and this study analyzed (I) its relative and absolute intra- and inter-session reliability and (II) the relationship between the data provided by Bindex((r)) QUS and the bone mineral density (BMD) measured by dual-energy x-ray absorptiometry at corresponding skeletal sites in young and healthy subjects (age: 25.0 +/- 3.6 years). Bindex((r))-QUS calculates a density index on the basis of the thickness of cortical bone measured at the distal radius and the distal plus proximal tibia. The data show a very good relative and absolute intra (ICC = 0.977, CV = 1.5%) and inter-session reliability (ICC = 0.978, CV = 1.4%) for the density index. The highest positive correlations were found between cortical thickness and BMD for the distal radius and distal tibia (r ? 0.71, p < 0.001). The data indicate that the Bindex((r))-QUS parameters are repeatable within and between measurement sessions. Furthermore, the measurements reflect the BMD at specific skeletal sites. Bindex((r))-QUS might be a useful tool for the measurement of skeletal adaptations. PMID- 27511631 TI - Sweat chloride testing: controversies and issues. PMID- 27511632 TI - Data security in the brave new world of eHealth. PMID- 27511630 TI - Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis. AB - Rheumatoid arthritis is characterised by synovial inflammation and proliferation of fibroblast-like synoviocytes. The induction of apoptosis has long been proposed as a target for proliferative autoimmune diseases, and has further been shown to act as a successful treatment of experimental models of arthritis, such as collagen-induced arthritis. Here we examined the effects of specific oral small-molecule inhibitors of the transcription regulating cyclin-dependent kinase 9 on the development and progression of collagen-induced arthritis. DBA/1 mice were immunised with bovine collagen type II and treated orally with specific CDK9 inhibitors. The effects of CDK9 inhibition on RNA levels and protein expression, apoptosis induction, caspase activation and lymphocyte phenotype were further analysed. Mice showed a significant delay in disease onset and a reduction in disease severity following treatment with CDK9 inhibitors. Inhibiting CDK9 activity in peripheral blood mononuclear cells resulted in the loss of Mcl-1 expression at both the protein and RNA levels, along with a subsequent increase in apoptosis. CDK9 specific inhibitors may be a potential alternative treatment not only of cancer, but also for autoimmune- and inflammatory diseases. Taken together, these results show that transient inhibition of CDK9 induces apoptosis in leukocyte subsets and modulates the immune response. PMID- 27511633 TI - Medicine and Me: a breath of fresh air for IPF. PMID- 27511634 TI - Corrections. PMID- 27511635 TI - Amyloid Aggregates Arise from Amino Acid Condensations under Prebiotic Conditions. AB - Current theories on the origin of life reveal significant gaps in our understanding of the mechanisms that allowed simple chemical precursors to coalesce into the complex polymers that are needed to sustain life. The volcanic gas carbonyl sulfide (COS) is known to catalyze the condensation of amino acids under aqueous conditions, but the reported di-, tri-, and tetra-peptides are too short to support a regular tertiary structure. Here, we demonstrate that alanine and valine, two of the proteinogenic amino acids believed to have been among the most abundant on a prebiotic earth, can polymerize into peptides and subsequently assemble into ordered amyloid fibers comprising a cross-beta-sheet quaternary structure following COS-activated continuous polymerization of as little as 1 mm amino acid. Furthermore, this spontaneous assembly is not limited to pure amino acids, since mixtures of glycine, alanine, aspartate, and valine yield similar structures. PMID- 27511637 TI - Parental Self-Control and the Development of Male Aggression in Early Childhood: A Longitudinal Test of Self-Control Theory. AB - A number of studies have evaluated associations between parenting practices, adolescent self-control, and adolescent antisocial behavior. Yet, few studies have examined associations between these constructs in early childhood or examined the extent to which both maternal and paternal self-control shapes them. To address these gaps, the current study utilizes longitudinal data collected on a sample of 117 Dutch boys and their parents to investigate the across time interrelationships between parental self-control, ineffective parenting, child self-control, and child aggression. The results provide evidence of an indirect association between maternal self-control and early childhood self-control through maternal ineffective parenting, an indirect association between maternal ineffective parenting and early childhood aggression through early childhood self control, and an indirect association between maternal self-control and early childhood aggression through both maternal ineffective parenting and early childhood self-control. In contrast, paternal self-control and paternal ineffective parenting were unrelated to child self-control and child aggression. The implications and limitations of the study are discussed. PMID- 27511636 TI - Distribution Characteristics and Combined Effect of Polymorphisms Affecting Alcohol Consumption Behaviour in the Hungarian General and Roma Populations. AB - AIMS: Harmful alcohol drinking habits, even among Roma children and adolescents, are more common than in the majority population. The aim of the study was to evaluate the genetic susceptibility of Roma to hazardous alcohol consumption compared to the Hungarian general population. METHODS: A total of 1273 samples from the population of segregated Hungarian Roma colonies and 2967 samples from the Hungarian general population were genotyped for 25 polymorphisms. Differences in genotype and allele distributions were investigated. Genetic risk scores (GRS) were generated to estimate the joint effect of individual single-nucleotide polymorphisms (SNPs). After unweighted and weighted GRS were calculated the distribution of scores in study populations was compared. RESULTS: The allele frequencies differed significantly between the study populations for 17 SNPs (P < 0.002), but the genetic alterations that predispose to or protect against harmful alcohol consumption were not overrepresented in the Roma population. The distribution of unweighted GRS in Roma population was left shifted compared to general population (P = 0.0013). The median weighted genetic risk score was lower among the subjects of Roma population compared to the subjects of general population (0.53 vs 0.65, P = 3.33 * 10-27) even after adjustment for confounding factors. CONCLUSIONS: Differences in alcohol consumption habits between the Hungarian Roma and Hungarian general populations do not appear to be linked to genetic constitution, this behaviour may occur as a result of different cultural values and environmental exposures. Population-based measures to tackle the fundamental drivers of consumption, which take account of cultural acceptability, are needed to reduce harmful alcohol consumption in the Roma population. PMID- 27511638 TI - Resonant and non-resonant energy transfer from Ce3+ -> X (X = Tb3+ , Eu3+ or Dy3+ ) in NaMgSO4 F material. AB - An inorganic NaMgSO4 F fluoride material was prepared by the wet chemical method and studied for its photoluminescence (PL) and resonant-non-resonant energy transfer (RET and NORET) capabilities between Ce3+ -> Tb3+ , Ce3+ -> Eu3+ and Ce3+ -> Dy3+ rare earth ions. The Tb3+ emission for Ce3+ -> Tb3+ transfers under ultraviolet (UV) wavelengths peaked at 491, 547, and 586 nm, for excitation at 308 nm due to 5 D4 -> 7 FJ (J = 4, 5, 6) transitions. Eu emission spectra were observed at 440 nm (Eu2+ ), 593 nm and 616 nm (Eu3+ ) recorded for different concentrations of materials, whereas Dy3+ emission from Ce3+ -> Dy3+ transfer under UV wavelengths peaked at 485 nm and 577 nm due to 4 F9/2 -> 6 H15/2 and 6 H13/2 transitions. The purpose of the present study is to understand the RET and NORET effects of Tb3+ , Eu3+ and Dy3+ co-doping in a NaMgSO4 F:Ce3+ luminescent material, which could be used as a green-emitting material for lamp phosphors. PMID- 27511639 TI - Serum levels of 12 renal function and injury markers in patients with glomerulonephritis. AB - INTRODUCTION Glomerulonephritis (GN) is a complex disease that affects the function of the whole nephron. There are few data on the serum levels of the most common biomarkers of kidney function and injury in GN, or the studies provide ambiguous results. OBJECTIVES The aim of the study was to evaluate the levels of known kidney-specific and nonspecific markers of renal function or injury in the serum of patients with diagnosed primary or secondary GN, with or without the presence of nephrotic syndrome (NS) and arterial hypertension (AH). PATIENTS AND METHODS The study included 58 patients with diagnosed GN and 6 patients with congenital defects (CD) of the kidney and AH (CD+AH). The serum levels of beta2 microglobulin (beta2M), neutrophil-gelatinase associated lipocalin (NGAL), osteopontin, trefoil factor 3 (TFF-3), calbindin, glutathione-S-transferase- pi (GST-pi), interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), and monocyte chemoattractant protein 1 (MCP-1) were measured with Kidney Toxicity Panels 1 and 2 using the Bio-Plex method. Renalase levels were measured using an enzyme-linked immunosorbent assay. RESULTS In the whole group and in the subgroups (GN, GN+AH, GN+NS, CD+AH), NGAL, KIM-1, TFF-3, IL-18, beta2M, and calbindin levels correlated with estimated glomerular filtration rate (eGFR). In patients with NS, this correlation for calbindin was reversed. Renalase, MCP-1, GST-pi, and osteopontin levels were independent of eGFR. Increase in IL-18 levels in the group with GN was assiociated with lower odds of the kidney disease. When this group was divided according to eGFR into subgroups G1-G5, TFF-3, NGAL, and beta2M levels increased with the stage of the disease. CONCLUSIONS In patients with NS, renalase and MCP-1 might regulate each other's levels. Further studies are needed to investigate associations between renalase, MCP-1, and osteopontin as factors unrelated to eGFR in GN. NS may contribute to the loss of calbindin from serum. NGAL, KIM-1, TFF-3, IL-18, beta2M, and calbindin are good indicators of kidney function loss in patients with GN. PMID- 27511640 TI - New insights into the infection of the American cockroach Periplaneta americana nymphs with Metarhizium anisopliae s.l. (Ascomycota: Hypocreales). AB - AIMS: To study the marked resistance of Periplaneta americana to entomopathogenic Metarhizium anisopliae. METHODS AND RESULTS: The low susceptibility of 4th instar nymphs applied topically with conidia seemed to be related to an active removal of conidia by the cockroach and to a disabled or retarded germination and subsequent development of conidia on the cuticle (up to 80% germination in the next 7 days after application). Inhibitions or delays of germination were related to the composition of the epicuticular fatty acids (30.1% w/w oleic, 28.3% w/w linoleic, 24.5% w/w palmitic and 11.7% w/w stearic acid) reported here. Propagules invading the nymphs through the cuticle took at least 3 days to reach the haemocoel, and no propagules were found after day 8 post-treatment. Strain IP 46 infected >50% of nymphs treated with doses >=2 * 104 hyphal bodies (HB) nymph 1 and reduced the survival of nymphs <=50%. Most nymphs (>70%) survived after injection of 6 * 103 and 2 * 103 HB nymph-1 . CONCLUSIONS: Findings emphasize a distinct resistance of nymphs of the American cockroach to infections by M. anisopliae. SIGNIFICANCE AND IMPACT OF THE STUDY: Our findings provide support for the development of biological control of this synanthropic cockroach pest. PMID- 27511641 TI - beta-Secretase (BACE1) inhibitory and neuroprotective effects of p-terphenyls from Polyozellus multiplex. AB - Alzheimer's disease (AD), a major neurodegenerative disorder, is associated with the enzymatic reaction of beta-secretase (BACE1) on the amyloid precursor protein (APP) for the generation of neurotoxic amyloid-beta (Abeta). Therefore, Abeta accumulation and oxidative stress-induced neuronal cell death are the pathogenic hallmarks of AD. In this study, we tried to identify BACE1 inhibitors and neuroprotectants from natural products, in particular, from the Korean mushroom Polyozellus multiplex. Four p-terphenyls were identified from the ethanolic extract of P. multiplex; polyozellin (1), thelephoric acid (2), polyozellic acid (3), and kynapcin-12 (4). Compounds 1-4 effectively inhibited BACE1 activity with a half-maximal inhibitory concentration (IC50) of 3.08, 3.50, 4.78, and 15.79 MUM, respectively. Compounds 1-3 reduced the production of neurotoxic Abeta1-42 production in APPswe-N2a cells in a concentration-dependent manner. When HT22 cells were stressed with 5 mM glutamate, compounds 2 and 3 significantly recovered cell viability. It was correlated with their inhibitory properties against glutamate-mediated Ca(2+) influx, intracellular reactive oxygen species (ROS) generation, lipid peroxidation, reduction in Bcl-2 and Bid levels, and enhanced phosphorylation of mitogen-activated protein kinase (MAPK). Thus, P. multiplex and the isolated p-terphenyls might be useful in the development of lead compounds for the prevention of neurodegenerative diseases, especially AD. PMID- 27511643 TI - Biocompatible Red Fluorescent Organic Nanoparticles with Tunable Size and Aggregation-Induced Emission for Evaluation of Blood-Brain Barrier Damage. AB - Detection of damage to the blood-brain barrier (BBB) is important for the diagnosis of brain diseases and therapeutic drug evaluation. The widely used probe, Evans blue, suffers from low specificity and high toxicity in vivo. It is shown that organic nanoparticles with tuneable size, good biocompatibility, and aggregation-induced emission characteristics offer high detection specificity to detect BBB damage via a photothrombotic ischemia rat model. PMID- 27511644 TI - Physiological and pathological clinical conditions and light scattering in brain. AB - MRI of preterm infants at term commonly reveals subtle brain lesions such as diffuse white matter injury, which are linked with later cognitive impairments. The timing and mechanism of such injury remains unclear. The reduced scattering coefficient of near-infrared light (MUs') has been shown to correlate linearly with gestational age in neonates. To identify clinical variables associated with brain MUs', 60 preterm and full-term infants were studied within 7 days of birth. Dependence of MUs' obtained from the frontal head on clinical variables was assessed. In the univariate analysis, smaller MUs' was associated with antenatal glucocorticoid, emergency Caesarean section, requirement for mechanical ventilation, smaller gestational age, smaller body sizes, low 1- and 5-minute Apgar scores, higher cord blood pH and PO2, and higher blood HCO3(-) at the time of study. Multivariate analysis revealed that smaller gestational age, requirement for mechanical ventilation, and higher HCO3(-) at the time of study were correlated with smaller MUs'. Brain MUs' depended on variables associated with physiological maturation and pathological conditions of the brain. Further longitudinal studies may help identify pathological events and clinical conditions responsible for subtle brain injury and subsequent cognitive impairments following preterm birth. PMID- 27511703 TI - Natural product inspired design and synthesis of beta-carboline and gamma-lactone based molecular hybrids. AB - beta-Carboline and gamma-lactone moieties have been selected by nature as privileged scaffolds and display a wide range of pharmacological properties. Following nature, we envisaged the preparation of new beta-carboline and gamma lactone based molecular hybrids incorporating both the pharmacophores. In this regard, a water-assisted In-mediated environmentally benign and easy to execute single-step tandem Barbier type allylation-lactonisation process has been devised in order to afford the targeted molecular architectures. It is anticipated that aqueous medium plays the key role in allylation as well as in the subsequent lactonisation process for the diastereo-selective synthesis of these conjugates. It is believed that water drives the reaction pathway through dual activation, it increases the electrophilic character of formyl and ester functionalities and simultaneously enhances the nucleophilic potential of the hydroxyl group to facilitate the in situ intramolecular condensation. Importantly, during this synthetic strategy no column chromatographic purification was required at any stage. PMID- 27511704 TI - Examining the role of socioeconomic deprivation in ethnic differences in sexually transmitted infection diagnosis rates in England: evidence from surveillance data. AB - Differences by ethnic group in STI diagnosis rates have long been recognized in England. We investigated whether these may be explained by ethnic disparities in socioeconomic deprivation (SED). Data on all diagnoses made in sexual health clinics in England in 2013 were obtained from the mandatory STI surveillance system. Poisson regression was used to calculate incidence rate ratios (IRRs) of STIs, by ethnicity, with and without adjustment for index of multiple deprivation (IMD) a measure of area-level deprivation. Unadjusted IRRs (95% confidence intervals) were highest for gonorrhoea [8.18 (7.77-8.61) and 5.76 (5.28-6.29)] and genital herpes [4.24 (3.99-4.51) and 3.58 (3.23-3.98)] for people of black Caribbean and non-Caribbean/non-African black ethnicity and IRRs were highest for syphilis [8.76 (7.97-9.63)] and genital warts [2.23 (2.17-2.29)] for people of non-British/non-Irish white ethnicity compared to white British ethnicity. After adjustment for IMD, IRRs for gonorrhoea [5.76 (5.47-6.07)] and genital herpes [3.73 (3.50-3.97)] declined but remained highest for black Caribbeans and IRRs for syphilis [7.35 (6.68-8.09)] and genital warts [2.10 (2.04-2.16)] declined but remained highest for non-British/non-Irish white compared to white British. In England, ethnic disparities in STI diagnosis rates are partially explained by SED, but behavioural and contextual factors likely contribute. Clinic and community-based interventions should involve social peer networks to ensure they are targeted and culturally sensitive. PMID- 27511705 TI - Baseline metabolic disturbances and the twenty-five years risk of incident cancer in a Mediterranean population. AB - BACKGROUND AND AIMS: Obesity is predictive of metabolic syndrome (metS), type 2 diabetes, cardiovascular (CV) disease and cancer. The aim of the study is to assess the risk of incident cancer connected to obesity and metS in a Mediterranean population characterized by a high prevalence of obesity. METHODS AND RESULTS: As many as 1133 subjects were enrolled in two phases and followed for 25 years (859 subjects) or 11 years (274 subjects) and incident cancer was registered in the follow-up period. Anthropometric measures and biochemical parameters were filed at baseline and evaluated as predictors of incident cancer by measuring hazards ratios (HR) using multivariate Cox parametric hazards models. Best predictive threshold for metabolic parameters and metS criteria were recalculated by ROC analysis. Fasting Blood Glucose >5.19 mmol/L [HR = 1.58 (1.0 2.4)] and the TG/HDL ratio (log10) (Males > 0.225, Females > 0.272) [HR = 2.44 (1.3-4.4)] resulted independent predictors of survival free of cancer with a clear additive effect together with age classes [45-65 years, HR = 2.47 (1.3 4.4), 65-75 years HR = 3.80 (2.0-7.1)] and male gender [HR = 2.07 (2.3-3.1)]. CONCLUSIONS: Metabolic disturbances are predictive of cancer in a 25 years follow up of a Mediterranean population following a traditional Mediterranean diet. The high prevalence of obesity and metS and the observed underlying condition of insulin resistance expose this population to an increased risk of cardiovascular disease and cancer despite the healthy nutritional habits. PMID- 27511706 TI - Comments on "Association of consumption of dairy products and meat with retinal vessel calibers in subjects at increased cardiovascular risk". PMID- 27511708 TI - Pilot study on the correlation between skin auto-fluorescence and serum antioxidant enzyme: skin auto-fluorescence is negatively associated with levels of malondialdehyde. AB - BACKGROUND/PURPOSE: Various methods have been used to objectively record skin changes. However, estimating the intrinsic and extrinsic aging of skin remains a challenge. Our objective was to study intrinsic skin aging with respect to patient age and extrinsic photo-aging of human dorsal (photo-exposed) and volar (photo-protected) forearm in vivo through skin auto-fluorescence (AF). We also examined the correlations between serum antioxidant enzyme, malondialdehyde(MDA), and skin AF. METHODS: 37 healthy volunteers were enrolled. We measured skin AF and its heterogeneity on the dorsal and volar forearms. We also examined serum concentration of catalase, superoxide dismutase, vitamin E, and MDA levels in every participant. RESULTS: In photo-protected areas, skin AF intensity in the 40 years or older group was significantly higher compared to the group less than 40 years-old. On the other hand, heterogeneity value was significantly higher in the less than 40 years-old group in photo-protected area. With respect to serum antioxidant enzyme and MDA level, only MDA level showed a negative correlation with skin AF intensity in photo-exposed area. CONCLUSION: We determined that skin AF intensity of the photo-protected area reflects intrinsic skin aging. In addition, degree of photo-aging could be indirectly inferred by skin AF of photo exposed area and serum MDA level. PMID- 27511707 TI - Synthesis and cardiovascular protective effects of quercetin 7-O-sialic acid. AB - Oxidative stress and inflammation play important roles in the pathogenesis of cardiovascular disease (CVD). Oxidative stress-induced desialylation is considered to be a primary step in atherogenic modification, and therefore, the attenuation of oxidative stress and/or inflammatory reactions may ameliorate CVD. In this study, quercetin 7-O-sialic acid (QA) was synthesized aiming to put together the cardiovascular protective effect of quercetin and the recently reported anti-oxidant and anti-atherosclerosis functions of N-acetylneuraminic acid. The biological efficacy of QA was evaluated in vitro in various cellular models. The results demonstrated that 50 MUM QA could effectively protect human umbilical vein endothelial cells (HUVEC, EA.hy926) against hydrogen peroxide- or oxidized low-density lipoprotein-induced oxidative damage by reducing the production of reactive oxygen species. QA attenuated hydrogen peroxide-induced desialylation of HUVEC and lipoproteins. QA decreased lipopolysaccharide-induced secretion of tumour necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1), and it significantly reduced the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, TNF-alpha and MCP-1. Furthermore, QA effectively promoted cholesterol efflux from Raw 264.7 macrophages to apolipoprotein A-1 and high-density lipoprotein by up-regulating ATP-binding cassette transporter A1 and G1, respectively. Results indicated that the novel compound QA exhibited a better capacity than quercetin for anti oxidation, anti-inflammation, cholesterol efflux promotion and biomolecule protection against desialylation and therefore could be a candidate compound for the prevention or treatment of CVD. PMID- 27511709 TI - The use of chemometrics to study multifunctional indole alkaloids from Psychotria nemorosa (Palicourea comb. nov.). Part II: Indication of peaks related to the inhibition of butyrylcholinesterase and monoamine oxidase-A. AB - Psychotria nemorosa is chemically characterized by indole alkaloids and displays significant inhibitory activity on butyrylcholinesterase (BChE) and monoamine oxidase-A (MAO-A), both enzymes related to neurodegenerative disorders. In the present study, 43 samples of P. nemorosa leaves were extracted and fractionated in accordance to previously optimized methods (see Part I). These fractions were analyzed by means of UPLC-DAD and assayed for their BChE and MAO-A inhibitory potencies. The chromatographic fingerprint data was first aligned using correlation optimized warping and Principal Component Analysis to explore the data structure was performed. Multivariate calibration techniques, namely Partial Least Squares (PLS1), PLS2 and Orthogonal Projections to Latent Structure (O PLS1), were evaluated for modelling the activities as a function of the fingerprints. Since the best results were obtained with O-PLS1 model (RMSECV=9.3 and 3.3 for BChE and MAO-A, respectively), the regression coefficients of the model were analyzed and plotted relative to the original fingerprints. Four peaks were indicated as multifunctional compounds, with the capacity to impair both BChE and MAO-A activities. In order to confirm these results, a semi-prep HPLC technique was used and a fraction containing the four peaks was purified and evaluated in vitro. It was observed that the fraction exhibited an IC50 of 2.12MUgmL(-1) for BChE and 1.07MUgmL(-1) for MAO-A. These results reinforce the prediction obtained by O-PLS1 modelling. PMID- 27511710 TI - Design of smart GE11-PLGA/PEG-PLGA blend nanoparticulate platforms for parenteral administration of hydrophilic macromolecular drugs: synthesis, preparation and in vitro/ex vivo characterization. AB - Active drug targeting and controlled release of hydrophilic macromolecular drugs represent crucial points in designing efficient polymeric drug delivery nanoplatforms. In the present work EGFR-targeted polylactide-co-glycolide (PLGA) nanoparticles were made by a blend of two different PLGA-based polymers. The first, GE11-PLGA, in which PLGA was functionalized with GE11, a small peptide and EGFR allosteric ligand, able to give nanoparticles selective targeting features. The second polymer was a PEGylated PLGA (PEG-PLGA) aimed at improving nanoparticles hydrophilicity and stealth features. GE11 and GE11-PLGA were custom synthetized through a simple and inexpensive method. The nanoprecipitation technique was exploited for the preparation of polymeric nanoparticles composed by a 1:1weight ratio between GE11-PLGA and PEG-PLGA, obtaining smart nanoplatforms with proper size for parenteral administration (143.9+/-5.0nm). In vitro cellular uptake in EGFR-overexpressing cell line (A549) demonstrated an active internalization of GE11-functionalized nanoparticles. GE11-PLGA/PEG-PLGA blend nanoparticles were loaded with Myoglobin, a model hydrophilic macromolecule, reaching a good loading (2.42% respect to the theoretical 4.00% w/w) and a prolonged release over 60days. GE11-PLGA/PEG-PLGA blend nanoparticles showed good in vitro stability for 30days in physiological saline solution at 4 degrees C and for 24h in pH 7.4 or pH 5.0 buffer at 37 degrees C respectively, giving indications about potential storage and administration conditions. Furthermore ex vivo stability study in human plasma using fluorescence Single Particle Tracking (fSPT) assessed good GE11-PLGA/PEG-PLGA nanoparticles dimensional stability after 1 and 4h. Thanks to the versatility in polymeric composition and relative tunable nanoparticles features in terms of drug incorporation and release, GE11-PLGA/PEG-PLGA blend NPs can be considered highly promising as smart nanoparticulate platforms for the treatment of diseases characterized by EGFR overexpression by parenteral administration . PMID- 27511711 TI - Valuable Metals-Recovery Processes, Current Trends, and Recycling Strategies. AB - This Review provides an overview of valuable metals, the supply of which has been classified as critical for Europe. Starting with a description of the current state of the art, novel approaches for their recovery from primary resources are presented as well as recycling processes. The focus lies on developments since 2005. Chemistry strategies which are used in metal recovery are summarized on the basis of the individual types of deposit and mineral. In addition, the economic importance as well as utilization of the metals is outlined. PMID- 27511712 TI - Application of Cookson-type reagents for biomedical HPLC and LC/MS analyses: a brief overview. AB - High-performance liquid chromatography (HPLC), LC/mass spectrometry (MS) and LC/tandem mass spectrometry (MS/MS) have been widely used for biomedical analyses, in which chemical derivatization is one of the most important methods to increase the sensitivity and selectivity. A Cookson-type reagent [4 substituted-1,2,4-triazoline-3,5-dione (4-substituted-TAD)] reacts with the compound bearing a conjugated diene, such as the vitamin D compound, to quantitatively form the stable Diels-Alder adduct. The reagent with a chromophore or fluorophore at the 4-position of TAD yields a highly responsive adduct for the UV or fluorescence detection, respectively. The Diels-Alder adduct with a Cookson type reagent having a permanently charged, proton-affinitive or electron affinitive moiety is sensitively detected by a specific MS analyzer. This paper is a brief overview of the applications of the reagents for biomedical analyses mainly using HPLC or LC/MS(/MS). PMID- 27511713 TI - Evidence of salt accumulation in beach intertidal zone due to evaporation. AB - In coastal environments, evaporation is an important driver of subsurface salinity gradients in marsh systems. However, it has not been addressed in the intertidal zone of sandy beaches. Here, we used field data on an estuarine beach foreshore with numerical simulations to show that evaporation causes upper intertidal zone pore-water salinity to be double that of seawater. We found the increase in pore-water salinity mainly depends on air temperature and relative humidity, and tide and wave actions dilute a fraction of the high salinity plume, resulting in a complex process. This is in contrast to previous studies that consider seawater as the most saline source to a coastal aquifer system, thereby concluding that seawater infiltration always increases pore-water salinity by seawater-groundwater mixing dynamics. Our results demonstrate the combined effects of evaporation and tide and waves on subsurface salinity distribution on a beach face. We anticipate our quantitative investigation will shed light on the studies of salt-affected biological activities in the intertidal zone. It also impacts our understanding of the impact of global warming; in particular, the increase in temperature does not only shift the saltwater landward, but creates a different salinity distribution that would have implications on intertidal biological zonation. PMID- 27511714 TI - Lymphoedema is a potential sequela of Kaposiform haemangioendothelioma: reply from the authors. PMID- 27511715 TI - Stereotactic Radiosurgery for Treatment of Brain Metastases. AB - Brain metastases are the most common intracranial malignancy. Incidence of brain metastases has risen as systemic therapies have improved and patients with metastatic disease live longer. Whole-brain radiation therapy, for many years, has been the standard treatment approach. Stereotactic radiosurgery has become an increasingly popular option because of its relatively short, convenient, and noninvasive treatment course. Although recently published data have renewed interest in use of whole-brain radiation therapy or systemic therapies for control of micrometastatic disease, stereotactic radiosurgery continues to be an important modality, capable of delivering ablative doses of radiation for long term control of macroscopic disease. The purpose of this review is to explore the different paradigms for incorporation of stereotactic radiosurgery into management of brain metastases. Current uses for stereotactic radiosurgery include delivery as a boost with whole-brain radiation therapy; alone for patients with a limited number of brain metastases; in pre- or postoperative settings; and in combination with systemic, targeted, and immune-based therapies. Mature prospective data on use of stereotactic radiosurgery in combination with whole-brain radiation therapy is available; however, prospective, randomized data on stereotactic radiosurgery for patients with a greater number of brain metastases, its use in pre- and postoperative settings, and its use in combination with systemic therapies are limited. Data from ongoing and future studies are needed to define the appropriate use of stereotactic radiosurgery in these settings. PMID- 27511716 TI - Searching for Synergy: Combining Drugs and Stereotactic Radiosurgery for the Treatment of Brain Metastases. PMID- 27511717 TI - Stereotactic Radiosurgery for Brain Metastases: More Work to Be Done. PMID- 27511718 TI - Multidisciplinary Care of Laryngeal Cancer. AB - Treatment of larynx cancer has changed dramatically over the past several years. Novel modalities of treatment have been introduced as organ preservation has been developed. In addition, new targeted therapies have appeared, and improvements in radiotherapeutic and surgical techniques have been introduced. Thus, a large variety of treatment options is increasing local control rates and overall survival; however, selecting the most appropriate treatment remains a challenging decision. This article focuses on the multidisciplinary care of early-stage and locally advanced larynx cancer and attempts to sum up different approaches. Moreover, it reviews state-of-the-art treatment in larynx preservation, which has been consolidated in recent years. PMID- 27511719 TI - A Multidisciplinary Approach to Larynx Cancer: One Size Does Not Fit All. PMID- 27511720 TI - Functional Organ Preservation in Larynx Cancer: A Continuing Debate. PMID- 27511721 TI - Acute, Unilateral Breast Toxicity From Gemcitabine in the Setting of Thoracic Inlet Obstruction. PMID- 27511722 TI - Environmental change makes robust ecological networks fragile. AB - Complex ecological networks appear robust to primary extinctions, possibly due to consumers' tendency to specialize on dependable (available and persistent) resources. However, modifications to the conditions under which the network has evolved might alter resource dependability. Here, we ask whether adaptation to historical conditions can increase community robustness, and whether such robustness can protect communities from collapse when conditions change. Using artificial life simulations, we first evolved digital consumer-resource networks that we subsequently subjected to rapid environmental change. We then investigated how empirical host-parasite networks would respond to historical, random and expected extinction sequences. In both the cases, networks were far more robust to historical conditions than new ones, suggesting that new environmental challenges, as expected under global change, might collapse otherwise robust natural ecosystems. PMID- 27511723 TI - Identification of microRNA profiles associated with refractory primary biliary cirrhosis. AB - MicroRNAs (miRNAs) are small, endogenous, non-coding RNAs that control the target gene translation by RNA interference; miRNAs are associated with cellular processes, including proliferation, differentiation, apoptosis, and cell survival. Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology. One third of patients with PBC demonstrate suboptimal responses, which result in worse outcomes. It has been previously reported that miRNAs are involved in drug resistance, however, the association between miRNA expression levels and refractory PBC remains to be fully elucidated. In the present study, among the 20 patients with PBC treated with ursodeoxycholic acid or bezafibrate, 15 patients were classed as treatment-effective, and 5 were classed as being treatment-resistant. Using the miRNA array technique, miRNA profiles were identified for each group. A total of 35 miRNAs were significantly upregulated, and 23 were significantly downregulated in the treatment-resistant group compared with the treatment-effective group. In order to examine the association between the highly altered miRNAs and clinical features of the two groups, numerous parameters were analyzed. Elevated levels of direct bilirubin, aspartate transaminase (AST), and alanine transaminase (ALT) were identified to be associated with miRNA-122 upregulation. AST, ALT, and gamma guanosine triphosphate were additionally associated with miRNA-378f upregulation. However, the reduction of miRNA-4311 was associated with reduced levels of AST and ALT. miRNA-4714-3p was also negatively correlated with total bilirubin and lactate dehydrogenase. Therefore, identifying the miRNA profile was demonstrated to be a useful approach in the characterization of PBC development. It is suggested that highly altered miRNAs may be potential biomarkers for use in the development of treatment of patients with refractory PBC. PMID- 27511724 TI - A novel missense mutation of the GRK1 gene in Oguchi disease. AB - Oguchi disease is a rare form of congenital stationary night blindness with an autosomal recessive inheritance pattern. The presence of S-antigen (SAG) and G protein-dependent receptor kinase 1 (GRK1) mutations were investigated in the family members with Oguchi disease. All exons of the SAG and GRK1 genes were amplified by polymerase chain reaction and sequenced. The patients were shown to have characteristic clinical features of Oguchi disease. Gene analysis determined a novel GRK1 mutation c.923T>C, which caused Oguchi disease in all siblings. This mutation, was demonstrated by amino acid alignment analysis to be in a phylogenetically conserved region and resulted in an amino acid change from leucine to proline at position 308. Thus, the present study reports a novel missense mutation of GRK1 in the affected members of a consanguineous Turkish family. Homozygosity at position 308, which resides in the catalytic domain of the GRK1 gene, is the cause of Oguchi disease in this Turkish family. PMID- 27511725 TI - Gene set analysis for interpreting genetic studies. AB - Interpretation of genome-wide association study (GWAS) results is lacking behind the discovery of new genetic associations. Consequently, there is an urgent need for data-driven methods for interpreting genetic association studies. Gene set analysis (GSA) can identify aetiologic pathways and functional annotations and may hence point towards novel biological insights. However, despite the growing availability of GSA tools, the sizeable amount of variants identified for a vast number of complex traits, and many irrefutably trait-associated gene sets, the gap between discovery and interpretation remains. More efficient interpretation requires more complete and consistent gene set representations of biological pathways, phenotypes and functional annotations. In this review, I examine different types of gene sets, discuss how inconsistencies in gene set definitions impact GSA, describe how GSA has helped to elucidate biology and outline potential future directions. PMID- 27511726 TI - HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies of 10 918 Koreans from bone marrow donor registry in Korea. AB - The human leucocyte antigen (HLA) system is the most polymorphic genetic system in humans, and HLA matching is crucial in organ transplantation, especially in hematopoietic stem cell transplantation. We investigated HLA-A, HLA-B and HLA DRB1 allele and haplotype frequencies at allelic level in 10 918 Koreans from bone marrow donor registry in Korea. Intermediate resolution HLA typing was performed using Luminex technology (Wakunaga, Japan), and additional allelic level typing was performed using PCR-single-strand conformation polymorphism method and/or sequence-based typing (Abbott Molecular, USA). Allele and haplotype frequencies were calculated by direct counting and maximum likelihood methods, respectively. A total of 39 HLA-A, 66 HLA-B and 47 HLA-DRB1 alleles were identified. High-frequency alleles found at a frequency of >=5% were 6 HLA-A (A*02:01, *02:06, *11:01, *24:02, *31:01 and *33:03), 6 HLA-B (B*15:01, *35:01, *44:03, *51:01, 54:01 and *58:01) and 8 HLA-DRB1 (DRB1*01:01, *04:05, *04:06, *07:01, *08:03, *09:01, *13:02 and *15:01) alleles. At each locus, A*02, B*15 and DRB1*14 generic groups were most diverse at allelic level, consisting of 9, 12 and 11 different alleles, respectively. A total of 366, 197 and 21 different HLA A-B-DRB1 haplotypes were estimated with frequencies of >=0.05%, >=0.1% and >=0.5%, respectively. The five most common haplotypes with frequencies of >=2.0% were A*33:03-B*44:03-DRB1*13:02 (4.97%), A*33:03-B*58:01-DRB1*13:02, A*33:03 B*44:03-DRB1*07:01, A*24:02-B*07:02-DRB1*01:01 and A*24:02-B*52:01-DRB1*15:02. Among 34 serologic HLA-A-B-DR haplotypes with frequencies of >=0.5%, 17 haplotypes revealed allele-level diversity and majority of the allelic variation was arising from A2, A26, B61, B62, DR4 and DR14 specificities. Haplotype diversity obtained in this study is the most comprehensive data thus far reported in Koreans, and the information will be useful for unrelated stem cell transplantation as well as for disease association studies. PMID- 27511727 TI - Knowledge of and Preparedness for Use of Environmental Assessments in Shelters During Disasters: Results of the 2013 State and Territorial Use of Shelter Assessments Survey. AB - OBJECTIVE: Environmental health assessments of disaster shelters are critical for monitoring the living conditions of the occupants. However, knowledge and levels of utilization of these assessments have never been estimated in the United States or its territories. We aimed to conduct a cross-sectional survey to ascertain knowledge and Utilization of environmental health disaster shelter assessments. METHODS: The State and Territorial Use of Shelter Assessments Survey (STUSA) of environmental health department directors (N=56) was carried out in 2013. RESULTS: Survey responses were received from 55 of 56 targeted jurisdictions. Of those respondents, 92% of state jurisdictions and 100% of territories reported having knowledge about shelter assessments. However, only 40% of states and 60% of territories reported receiving formal training, and 53% of states and 50% of territories reported having operational procedures for shelter assessments. High levels of knowledge and familiarity and low levels of training and processes for operationalizing assessments were assessed. CONCLUSIONS: Because environmental health assessments may provide useful information in disaster settings, we need to understand the barriers to their implementation. The results of these assessments may also help to validate their usefulness in protecting shelter occupants during disasters. (Disaster Med Public Health Preparedness. 2017;11:11-14). PMID- 27511729 TI - Unsupervised HLA Peptidome Deconvolution Improves Ligand Prediction Accuracy and Predicts Cooperative Effects in Peptide-HLA Interactions. AB - Ag presentation on HLA molecules plays a central role in infectious diseases and tumor immunology. To date, large-scale identification of (neo-)Ags from DNA sequencing data has mainly relied on predictions. In parallel, mass spectrometry analysis of HLA peptidome is increasingly performed to directly detect peptides presented on HLA molecules. In this study, we use a novel unsupervised approach to assign mass spectrometry-based HLA peptidomics data to their cognate HLA molecules. We show that incorporation of deconvoluted HLA peptidomics data in ligand prediction algorithms can improve their accuracy for HLA alleles with few ligands in existing databases. The results of our computational analysis of large datasets of naturally processed HLA peptides, together with experimental validation and protein structure analysis, further reveal how HLA-binding motifs change with peptide length and predict new cooperative effects between distant residues in HLA-B07:02 ligands. PMID- 27511728 TI - Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia. AB - Leukemia can promote T cell dysfunction and exhaustion that contributes to increased susceptibility to infection and mortality. The treatment-independent mechanisms that mediate leukemia-associated T cell impairments are poorly understood, but metabolism tightly regulates T cell function and may contribute. In this study, we show that B cell leukemia causes T cells to become activated and hyporesponsive with increased PD-1 and TIM3 expression similar to exhausted T cells and that T cells from leukemic hosts become metabolically impaired. Metabolic defects included reduced Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, decreased expression of the glucose transporter Glut1 and hexokinase 2, and reduced glucose uptake. These metabolic changes correlated with increased regulatory T cell frequency and expression of PD-L1 and Gal-9 on both leukemic and stromal cells in the leukemic microenvironment. PD-1, however, was not sufficient to drive T cell impairment, as in vivo and in vitro anti-PD-1 blockade on its own only modestly improved T cell function. Importantly, impaired T cell metabolism directly contributed to dysfunction, as a rescue of T cell metabolism by genetically increasing Akt/mTORC1 signaling or expression of Glut1 partially restored T cell function. Enforced Akt/mTORC1 signaling also decreased expression of inhibitory receptors TIM3 and PD-1, as well as partially improved antileukemia immunity. Similar findings were obtained in T cells from patients with acute or chronic B cell leukemia, which were also metabolically exhausted and had defective Akt/mTORC1 signaling, reduced expression of Glut1 and hexokinase 2, and decreased glucose metabolism. Thus, B cell leukemia-induced inhibition of T cell Akt/mTORC1 signaling and glucose metabolism drives T cell dysfunction. PMID- 27511730 TI - Loss of Trex1 in Dendritic Cells Is Sufficient To Trigger Systemic Autoimmunity. AB - Defects of the intracellular enzyme 3' repair exonuclease 1 (Trex1) cause the rare autoimmune condition Aicardi-Goutieres syndrome and are associated with systemic lupus erythematosus. Trex1(-/-) mice develop type I IFN-driven autoimmunity, resulting from activation of the cytoplasmic DNA sensor cyclic GMP AMP synthase by a nucleic acid substrate of Trex1 that remains unknown. To identify cell types responsible for initiation of autoimmunity, we generated conditional Trex1 knockout mice. Loss of Trex1 in dendritic cells was sufficient to cause IFN release and autoimmunity, whereas Trex1-deficient keratinocytes and microglia produced IFN but did not induce inflammation. In contrast, B cells, cardiomyocytes, neurons, and astrocytes did not show any detectable response to the inactivation of Trex1. Thus, individual cell types differentially respond to the loss of Trex1, and Trex1 expression in dendritic cells is essential to prevent breakdown of self-tolerance ensuing from aberrant detection of endogenous DNA. PMID- 27511731 TI - A Histone Methyltransferase ESET Is Critical for T Cell Development. AB - ESET/SETDB1, one of the major histone methyltransferases, catalyzes histone 3 lysine 9 (H3K9) trimethylation. ESET is critical for suppressing expression of retroviral elements in embryonic stem cells; however, its role in the immune system is not known. We found that thymocyte-specific deletion of ESET caused impaired T cell development, with CD8 lineage cells being most severely affected. Increased apoptosis of CD8 single-positive cells was observed, and TCR-induced ERK activation was severely inhibited in ESET(-/-) thymocytes. Genome-wide comprehensive analysis of mRNA expression and H3K9 trimethylation revealed that ESET regulates expression of numerous genes in thymocytes. Among them, FcgammaRIIB, whose signaling can inhibit ERK activation, was strongly and ectopically expressed in ESET(-/-) thymocytes. Indeed, genetic depletion of FcgammaRIIB in ESET(-/-) thymocytes rescued impaired ERK activation and partially restored defective positive selection in ESET(-/-) mice. Therefore, impaired T cell development in ESET(-/-) mice is partly due to the aberrant expression of FcgammaRIIB. Collectively, to our knowledge, we identify ESET as the first trimethylated H3K9 histone methyltransferase playing a crucial role in T cell development. PMID- 27511732 TI - Diversified Anchoring Features the Peptide Presentation of DLA-88*50801: First Structural Insight into Domestic Dog MHC Class I. AB - Canines represent a crucial animal model for studying human diseases and organ transplantation, as well as the evolution of domestic animals. MHCs, with a central role in cellular immunity, are commonly used in the study of dog population genetics and genome evolution. However, the molecular basis for the peptide presentation of dog MHC remains largely unknown. In this study, peptide presentation by canine MHC class I DLA-88*50801 was structurally determined, revealing diversified anchoring modes of the binding peptides. Flexible and large pockets composed of both hydrophobic and hydrophilic residues can accommodate pathogen-derived peptides with diverse anchor residues, as confirmed by thermostability measurements. Furthermore, DLA-88*50801 contains an unusual alpha2 helix with a large coil in the TCR contact region. These results further our understanding of canine T cell immunity through peptide presentation of MHC class I and shed light on the molecular basis for vaccine development for canine infectious diseases, for example, canine distemper virus. PMID- 27511733 TI - Systems Analysis of the Complement-Induced Priming Phase of Liver Regeneration. AB - Liver regeneration is a well-orchestrated process in the liver that allows mature hepatocytes to reenter the cell cycle to proliferate and replace lost or damaged cells. This process is often impaired in fatty or diseased livers, leading to cirrhosis and other deleterious phenotypes. Prior research has established the role of the complement system and its effector proteins in the progression of liver regeneration; however, a detailed mechanistic understanding of the involvement of complement in regeneration is yet to be established. In this study, we have examined the role of the complement system during the priming phase of liver regeneration through a systems level analysis using a combination of transcriptomic and metabolomic measurements. More specifically, we have performed partial hepatectomy on mice with genetic deficiency in C3, the major component of the complement cascade, and collected their livers at various time points. Based on our analysis, we show that the C3 cascade activates c-fos and promotes the TNF-alpha signaling pathway, which then activates acute-phase genes such as serum amyloid proteins and orosomucoids. The complement activation also regulates the efflux and the metabolism of cholesterol, an important metabolite for cell cycle and proliferation. Based on our systems level analysis, we provide an integrated model for the complement-induced priming phase of liver regeneration. PMID- 27511734 TI - Regulatory T Cell Numbers in Inflamed Skin Are Controlled by Local Inflammatory Cues That Upregulate CD25 and Facilitate Antigen-Driven Local Proliferation. AB - CD4(+)Foxp3(+) regulatory T cells (Tregs) are key immune suppressors that regulate immunity in diverse tissues. The tissue and/or inflammatory signals that influence the magnitude of the Treg response remain unclear. To define signals that promote Treg accumulation, we developed a simple system of skin inflammation using defined Ags and adjuvants that induce distinct cytokine milieus: OVA protein in CFA, aluminum salts (Alum), and Schistosoma mansoni eggs (Sm Egg). Polyclonal and Ag-specific Treg accumulation in the skin differed significantly between adjuvants. CFA and Alum led to robust Treg accumulation, with >50% of all skin CD4(+) T cells being Foxp3(+) In contrast, Tregs accumulated poorly in the Sm Egg-inflamed skin. Surprisingly, we found no evidence of inflammation-specific changes to the Treg gene program between adjuvant-inflamed skin types, suggesting a lack of selective recruitment or adaptation to the inflammatory milieu. Instead, Treg accumulation patterns were linked to differences in CD80/CD86 expression by APC and the regulation of CD25 expression, specifically in the inflamed skin. Inflammatory cues alone, without cognate Ag, differentially supported CD25 upregulation (CFA and Alum > Sm Egg). Only in inflammatory milieus that upregulated CD25 did the provision of Ag enhance local Treg proliferation. Reduced IL-33 in the Sm Egg-inflamed environment was shown to contribute to the failure to upregulate CD25. Thus, the magnitude of the Treg response in inflamed tissues is controlled at two interdependent levels: inflammatory signals that support the upregulation of the important Treg survival factor CD25 and Ag signals that drive local expansion. PMID- 27511735 TI - Expansion and Protection by a Virus-Specific NK Cell Subset Lacking Expression of the Inhibitory NKR-P1B Receptor during Murine Cytomegalovirus Infection. AB - NK cells play a major role in immune defense against human and murine CMV (MCMV) infection. Although the MCMV genome encodes for MHC class I-homologous decoy ligands for inhibitory NK cell receptors to evade detection, some mouse strains have evolved activating receptors, such as Ly49H, to recognize these ligands and initiate an immune response. In this study, we demonstrate that approximately half of the Ly49H-expressing (Ly49H(+)) NK cells in the spleen and liver of C57BL/6 mice also express the inhibitory NKR-P1B receptor. During MCMV infection, the NKR-P1B(-)Ly49H(+) NK cell subset proliferates to constitute the bulk of the NK cell population. This NK cell subset also confers better protection against MCMV infection compared with the NKR-P1B(+)Ly49H(+) subset. The two populations are composed of cells that differ in their surface expression of receptors such as Ly49C/I and NKG2A/C/E, as well as developmental markers, CD27 and CD11b, and the high-affinity IL-2R (CD25) following infection. Although the NKR-P1B(+) NK cells can produce effector molecules such as IFNs and granzymes, their proliferation is inhibited during infection. A similar phenotype in MCMV-infected Clr-b-deficient mice, which lack the ligand for NKR-P1B, suggests the involvement of ligands other than the host Clr-b. Most interestingly, genetic deficiency of the NKR-P1B, but not Clr-b, results in accelerated virus clearance and recovery from MCMV infection. This study is particularly significant because the mouse NKR P1B:Clr-b receptor:ligand system represents the closest homolog of the human NKR P1A:LLT1 system and may have a direct relevance to human CMV infection. PMID- 27511737 TI - Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis. AB - The etiopathogenesis of autoimmune hepatitis (AIH) remains poorly understood. In this study, we sought to develop an animal model of human AIH to gain insight into the immunological mechanisms driving this condition. C57BL/6 mice were i.v. injected with adeno-associated viral vectors encoding murine IL-12 or luciferase under the control of a liver-specific promoter. Organ histology, response to immunosuppressive therapy, and biochemical and immunological parameters, including Ag-specific humoral and cellular response, were analyzed. Mechanistic studies were carried out using genetically modified mice and depletion of lymphocyte subpopulations. Adeno-associated virus IL-12-treated mice developed histological, biochemical, and immunological changes resembling type 1 AIH, including marked and persistent liver mononuclear cell infiltration, hepatic fibrosis, hypergammaglobulinemia, anti-nuclear and anti-smooth muscle actin Abs, and disease remission with immunosuppressive drugs. Interestingly, transgenic IL 12 was short-lived, but endogenous IL-12 expression was induced, and both IL-12 and IFN-gamma remained elevated during the entire study period. IFN-gamma was identified as an essential mediator of liver damage, and CD4 and CD8 T cells but not NK, NKT, or B cells were essential executors of hepatic injury. Furthermore, both MHC class I and MHC class II expression was upregulated at the hepatocellular membrane, and induction of autoreactive liver-specific T cells was detected. Remarkably, although immunoregulatory mechanisms were activated, they only partially mitigated liver damage. Thus, low and transient expression of transgenic IL-12 in hepatocytes causes loss of tolerance to hepatocellular Ags, leading to chronic hepatitis resembling human AIH type 1. This model provides a practical tool to explore AIH pathogenesis and novel therapies. PMID- 27511736 TI - Herpesvirus-Associated Lymphadenitis Distorts Fibroblastic Reticular Cell Microarchitecture and Attenuates CD8 T Cell Responses to Neurotropic Infection in Mice Lacking the STING-IFNalpha/beta Defense Pathways. AB - Type I IFN (IFN-alpha/beta)-driven immune responses to acute viral infection are critical to counter replication and prevent dissemination. However, the mechanisms underlying host resistance to HSV type 1 (HSV-1) are incompletely understood. In this study, we show that mice with deficiencies in IFN-alpha/beta signaling or stimulator of IFN genes (STING) exhibit exacerbated neurovirulence and atypical lymphotropic dissemination of HSV-1 following ocular infection. Synergy between IFN-alpha/beta signaling and efficacy of early adaptive immune responses to HSV-1 were dissected using bone marrow chimeras and adoptive cell transfer approaches to profile clonal expansion, effector function, and recruitment of HSV-specific CD8(+) T cells. Lymphotropic viral dissemination was commensurate with abrogated CD8(+) T cell responses and pathological alterations of fibroblastic reticular cell networks in the draining lymph nodes. Our results show that resistance to HSV-1 in the trigeminal ganglia during acute infection is conferred in part by STING and IFN-alpha/beta signaling in both bone marrow derived and -resident cells, which coalesce to support a robust HSV-1-specific CD8(+) T cell response. PMID- 27511740 TI - SolCos model-based individual reminiscence for older adults with mild to moderate dementia in nursing homes: a randomized controlled intervention study. AB - : WHAT IS KNOWN ON THE SUBJECT?: To stimulate reminiscence of older adults with dementia performed individually or through group sessions is a well-known practice in nursing homes resulting in effects on behaviour and well-being as an alternative for medication. Robust scientific proof of the effectiveness of individual reminiscence therapy performed in nursing homes is sparse. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: We have provided individual standardized reminiscence therapy to residents with dementia. The therapy was developed and tested in a previous study and performed in this study by trained nursing home volunteers. In comparison with a control group who received usual care, residents who received the reminiscence therapy showed significant less depressive symptoms. Moreover, residents were, in general, attentive, open and collaborative during the sessions and volunteers experienced the sessions as useful and pleasant. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Individual reminiscence therapy can be learned and used by nursing home volunteers to improve care in nursing homes. ABSTRACT: Aim To investigate the effect of a standardized individualized intervention based on the SolCos transformational reminiscence model on depressive symptoms (primary outcome), cognition and behaviour (secondary outcomes) for older people with mild to moderate dementia, performed by trained nursing home volunteers as facilitators. Background Because of limited pharmacological treatment options for older adults with dementia relevant physical, sensory, psychological or social interventions offer alternative opportunities. Method Randomized controlled trial (ISRCTN74355073) was set up in two nursing homes with 29 and 31 residents in the intervention and the control groups respectively. Eighteen nursing home volunteers were trained to perform the reminiscence therapy. Various assessment scales were measured pre- and post sessions. Results Linear regression analysis showed an impact on depressive symptoms. However, no impact was identified on cognition and behaviour. Facilitators experienced the sessions as useful and pleasant, and study participants were, in general, attentive, open and collaborative. Discussion Study results showed that organizing standardized individual reminiscence therapy with nursing home volunteers was feasible and study participants' attention and participation were overall good. Further study initiatives to explore the potential of individual reminiscence therapy within a person-centred framework are recommended in order to improve care in nursing homes. PMID- 27511738 TI - Involvement of NK Cells and NKp30 Pathway in Antisynthetase Syndrome. AB - Antisynthetase syndrome (aSS) is characterized by the association of interstitial lung disease and myositis with anti-tRNA synthetase autoantibodies. Immune mechanisms leading to aSS could be initiated in the lungs, but the role of NK cells has not yet been studied. Both extensive NK cell phenotype and functions were compared between 33 patients and 26 controls. Direct and redirected polyfunctionality assays (degranulation and intracellular production of TNF-alpha and IFN-gamma) were performed spontaneously or after IL-12 plus IL-18 stimulation in the presence of K562 or P815 target cells, respectively. NK cells from inactive patients showed normal phenotype, whereas active aSS revealed a differentiated NK cell profile, as indicated by increased CD57 and Ig-like transcript 2 and an inability to produce IFN-gamma (p = 0.002) compared with controls. Importantly, active aSS was more specifically associated with a significant NKp30 decrease (p = 0.009), although levels of mRNA and intracellular protein were similar in aSS and healthy controls. This NKp30 decrease was strongly correlated with reduced NK cell polyfunctionality in both direct and redirected killing assays with anti-NKp30 Abs (p = 0.009 and p = 0.03, respectively), confirming its important impact in aSS. Histological studies revealed massive infiltrations of NK cells inside the lungs of aSS patients (148 versus 11/mm(2)). Taken together, these data suggest that NK cells and NKp30 could play a role in aSS pathogenesis. PMID- 27511739 TI - Characterization of the Filum terminale as a neural progenitor cell niche in both rats and humans. AB - Neural stem cells (NSCs) reside in a unique microenvironment within the central nervous system (CNS) called the NSC niche. Although they are relatively rare, niches have been previously characterized in both the brain and spinal cord of adult animals. Recently, another potential NSC niche has been identified in the filum terminale (FT), which is a thin band of tissue at the caudal end of the spinal cord. While previous studies have demonstrated that NSCs can be isolated from the FT, the in vivo architecture of this tissue and its relation to other NSC niches in the CNS has not yet been established. In this article we report a histological analysis of the FT NSC niche in postnatal rats and humans. Immunohistochemical characterization reveals that the FT is mitotically active and its cells express similar markers to those in other CNS niches. In addition, the organization of the FT most closely resembles that of the adult spinal cord niche. J. Comp. Neurol. 525:661-675, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27511741 TI - Ungual aspergillosis successfully treated with topical efinaconazole. PMID- 27511742 TI - A double-blind, randomised, placebo-controlled trial of Ganoderma lucidum for the treatment of cardiovascular risk factors of metabolic syndrome. AB - This study aimed to evaluate the efficacy and safety of Ganoderma lucidum for the treatment of hyperglycaemia and other cardiovascular risk components of metabolic syndrome using a prospective, double-blind, randomised, placebo-controlled trial. Eighty-four participants with type 2 diabetes mellitus and metabolic syndrome were randomised to one of three intervention groups: Ganoderma lucidum, Ganoderma lucidum with Cordyceps sinensis, or placebo. The dosage was 3 g/day of Ganoderma lucidum, with or without Cordyceps sinensis, for 16 weeks. The primary outcome measure was blood glucose (glycosylated haemoglobin [HbA1c] and fasting plasma glucose [FPG]); a number of secondary outcome measures were also tested. Data from the two intervention groups were combined. The combined intervention had no effect on any of the primary (baseline-adjusted difference in means: HbA1c = 0.13%, 95% CI [-0.35, 0.60], p = 0.60; FPG = 0.03 mmol/L, 95% CI [-0.90, 0.96], p = 0.95) or secondary outcome measures over the course of the 16-week trial, and no overall increased risk of adverse events with either active treatment. Evidence from this randomised clinical trial does not support the use of Ganoderma lucidum for treatment of cardiovascular risk factors in people with diabetes mellitus or metabolic syndrome. This Clinical Trial was registered with the Australian New Zealand Clinical Trials Registry on November 23, 2006. Trial ID: ACTRN12606000485538 and can be accessed here: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=81705. PMID- 27511743 TI - VHLdb: A database of von Hippel-Lindau protein interactors and mutations. AB - Mutations in von Hippel-Lindau tumor suppressor protein (pVHL) predispose to develop tumors affecting specific target organs, such as the retina, epididymis, adrenal glands, pancreas and kidneys. Currently, more than 400 pVHL interacting proteins are either described in the literature or predicted in public databases. This data is scattered among several different sources, slowing down the comprehension of pVHL's biological role. Here we present VHLdb, a novel database collecting available interaction and mutation data on pVHL to provide novel integrated annotations. In VHLdb, pVHL interactors are organized according to two annotation levels, manual and automatic. Mutation data are easily accessible and a novel visualization tool has been implemented. A user-friendly feedback function to improve database content through community-driven curation is also provided. VHLdb presently contains 478 interactors, of which 117 have been manually curated, and 1,074 mutations. This makes it the largest available database for pVHL-related information. VHLdb is available from URL: http://vhldb.bio.unipd.it/. PMID- 27511744 TI - Recursive partition analysis of peritoneal and systemic recurrence in patients with gastric cancer who underwent D2 gastrectomy: Implications for neoadjuvant therapy consideration. AB - BACKGROUND AND OBJECTIVES: To classify patients with nonmetastatic advanced gastric cancer who underwent D2-gastrectomy into prognostic groups based on peritoneal and systemic recurrence risks. METHODS: Between 2004 and 2007, 1,090 patients with T3-4 or N+ gastric cancer were identified from our registry. Recurrence rates were estimated using a competing-risk analysis. Different prognostic groups were defined using recursive partitioning analysis (RPA). RESULTS: Median follow-up was 7 years. In the RPA-model for peritoneal recurrence risk, the initial node was split by T stage, indicating that differences between patients with T1-3 and T4 cancer were the greatest. The 5-year peritoneal recurrence rates for patients with T4 (n = 627) and T1-3 (n = 463) disease were 34.3% and 9.1%, respectively. N stage and neural invasion had an additive impact on high-risk patients. The RPA model for systemic relapse incorporated N stage alone and gave two terminal nodes: N0-2 (n = 721) and N3 (n = 369). The 5-year cumulative incidences were 7.7% and 24.5%, respectively. CONCLUSIONS: We proposed risk stratification models of peritoneal and systemic recurrence in patients undergoing D2-gastrectomy. This classification could be used for stratification protocols in future studies evaluating adjuvant therapies such as preoperative chemoradiotherapy. J. Surg. Oncol. 2016;114:859-864. (c) 2016 2016 Wiley Periodicals, Inc. PMID- 27511745 TI - Birth defects and neonatal morbidity caused by teratogen exposure after the embryonic period. AB - BACKGROUND: Pharmaceutical pregnancy exposure registries seek to evaluate temporal associations between drug exposures and adverse outcomes, particularly congenital anomalies. These registries record observed associations that may or may not be causally-related to the exposure. Most major congenital malformations (i.e., structural birth defects) result from abnormal development during embryogenesis. A standardized catalog of defects of concern (colloquially the "BPA Codes") is used both in public health surveillance programs and pregnancy exposure registries. There are, however, some anomalies that cause significant morbidity and mortality for which isolated second or third trimester exposures may be pathogenically significant. There currently exists no standardized list of defects for which exposure limited to the fetal period may be problematic. METHODS: The six-digit-code list was used to determine anomalies that might result from medication exposures limited to the fetal period. RESULTS: Defects with documented first trimester pathogenesis (e.g., anencephaly, heterotaxy) were eliminated from consideration, as were chromosomal and single gene disorders (e.g., trisomy 21, achondroplasia). The remaining defects include the following: (1) those that are known to or could reasonably originate or manifest after the embryonic period (e.g., porencephaly, cataracts); (2) those for which pathogenesis is unclear or variable enough that exposure at any gestational age might be considered relevant (e.g., club foot, microcephaly); and (3) those that include some component of abnormal growth (e.g., hemihyperplasia). "Unspecified" defects (e.g., "abnormality of the leg") were included by default because there is insufficient information to assume first trimester embryogenesis. CONCLUSION: The final result is a list of major and minor anomalies in 11 organ system categories that may be caused by teratogen exposure during the fetal period. Birth Defects Research (Part A) 106:935-939, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27511746 TI - Social exclusion modulates priorities of attention allocation in cognitive control. AB - Many studies have investigated how exclusion affects cognitive control and have reported inconsistent results. However, these studies usually treated cognitive control as a unitary concept, whereas it actually involved two main sub processes: conflict detection and response implementation. Furthermore, existing studies have focused primarily on exclusion's effects on conscious cognitive control, while recent studies have shown the existence of unconscious cognitive control. Therefore, the present study investigated whether and how exclusion affects the sub-processes underlying conscious and unconscious cognitive control differently. The Cyberball game was used to manipulate social exclusion and participants subsequently performed a masked Go/No-Go task during which event related potentials were measured. For conscious cognitive control, excluded participants showed a larger N2 but smaller P3 effects than included participants, suggesting that excluded people invest more attention in conscious conflict detection, but less in conscious inhibition of impulsive responses. However, for unconscious cognitive control, excluded participants showed a smaller N2 but larger P3 effects than included participants, suggesting that excluded people invest less attention in unconscious conflict detection, but more in unconscious inhibition of impulsive responses. Together, these results suggest that exclusion causes people to rebalance attention allocation priorities for cognitive control according to a more flexible and adaptive strategy. PMID- 27511747 TI - Analysis of protein profiling studies of beta-thalassemia/Hb E disease. AB - A number of studies have used global protein profiling technologies on a range of patient samples to detect proteins that are differentially expressed in beta thalassemia/Hb E as an aid for understanding the physiopathology of this disease. Seven studies have identified a total of 111 unique, differentially expressed proteins. Seven proteins (prothrombin, alpha-1-antichymotrypsin, fibrinogen beta chain, hemoglobin beta, selenium-binding protein, microtubule-actin cross-linking factor and adenomatous polyposis coli protein 2) have been identified in two independent studies, whereas two proteins (carbonic anhydrase 1 and peroxiredoxin 2) have been identified in three independent studies. Both of these latter two proteins were consistently upregulated in the studies that identified them. Ontological analysis of all differentially regulated proteins identified "response to inorganic substances" as the most significant functional annotation cluster, which is consistent with iron overload being a major pathological consequence of this disease. Despite the range of samples investigated and the relatively small number of studies undertaken, a coherent picture of the mediators of the pathological consequences of beta-thalassemia/Hb E disease is starting to emerge. PMID- 27511748 TI - Predicting Negative Emotions Based on Mobile Phone Usage Patterns: An Exploratory Study. AB - BACKGROUND: Prompt recognition and intervention of negative emotions is crucial for patients with depression. Mobile phones and mobile apps are suitable technologies that can be used to recognize negative emotions and intervene if necessary. OBJECTIVE: Mobile phone usage patterns can be associated with concurrent emotional states. The objective of this study is to adapt machine learning methods to analyze such patterns for the prediction of negative emotion. METHODS: We developed an Android-based app to capture emotional states and mobile phone usage patterns, which included call logs (and use of apps). Visual analog scales (VASs) were used to report negative emotions in dimensions of depression, anxiety, and stress. In the system-training phase, participants were requested to tag their emotions for 14 consecutive days. Five feature-selection methods were used to determine individual usage patterns and four machine-learning methods were tested. Finally, rank product scoring was used to select the best combination to construct the prediction model. In the system evaluation phase, participants were then requested to verify the predicted negative emotions for at least 5 days. RESULTS: Out of 40 enrolled healthy participants, we analyzed data from 28 participants, including 30% (9/28) women with a mean (SD) age of 29.2 (5.1) years with sufficient emotion tags. The combination of time slots of 2 hours, greedy forward selection, and Naive Bayes method was chosen for the prediction model. We further validated the personalized models in 18 participants who performed at least 5 days of model evaluation. Overall, the predictive accuracy for negative emotions was 86.17%. CONCLUSION: We developed a system capable of predicting negative emotions based on mobile phone usage patterns. This system has potential for ecological momentary intervention (EMI) for depressive disorders by automatically recognizing negative emotions and providing people with preventive treatments before it escalates to clinical depression. PMID- 27511750 TI - Puffy feet in a female neonate. PMID- 27511749 TI - Case of CML lymphoid blast crisis presenting as bilateral breast masses. AB - A woman aged 42 years with a 1-month history of rapidly expanding bilateral breast masses presented with severe leucocytosis, anaemia, blurry vision, headaches and shortness of breath. Evaluation revealed chronic myeloid leukaemia in lymphoid blast crisis with extramedullary leukaemia involving her breasts. PMID- 27511751 TI - What is inside the hernia sac? AB - Most ovarian inguinal hernias occur in children and are frequently associated with congenital genitalia defects. The authors present the case of a multiparous 89-year-old woman, without any genitalia defect, who was brought to the emergency department with an irreducible inguinal hernia. The patient was proposed for emergency surgery during which we encountered an ovary and a fallopian tube inside the hernial sac. An oophorosalpingectomy and a Lichtenstein procedure were carried out and the postoperative period was uneventful. This case shows that, even though it is rare, a hernial sac may contain almost any intra-abdominal organ, including those least frequent such as the appendix, an ovary or the fallopian tubes. PMID- 27511752 TI - Haemophilia-A-related haematoma: management in resource constraint settings. PMID- 27511753 TI - Peduncular psychosis. AB - Psychotic symptoms are rarely documented in association with cortex-sparing central nervous system (CNS) lesions limited to the midbrain. We present the case of a 15-year-old boy with hereditary and environmental risk factors for psychiatric illness, as well as a history of midbrain pilocytic astrocytoma treated with chemotherapy and focused radiation, who presented with non-epileptic seizures, hyper-religiosity and frank psychosis. The space-occupying midbrain lesion has been radiographically stable while the patient has decompensated psychiatrically. Differential aetiology for the patient's psychiatric decompensation is discussed, including psychosis secondary to a lesion of the midbrain. Literature linking midbrain lesions to psychotic features, such as in peduncular hallucinosis, is briefly reviewed. This case suggests that a midbrain lesion in a susceptible patient may contribute to psychosis. PMID- 27511754 TI - Rapid recovery from catastrophic paraneoplastic anti-NMDAR encephalitis secondary to an ovarian teratoma following ovarian cystectomy. AB - This report is aimed to describe a life-threatening case of anti-N-methyl-d aspartate receptor (NMDAR) encephalitis secondary to ovarian teratoma with rapid recovery in 1 day after the removal of the tumour. A 23-year-old woman presented with sudden headache, personality changes and seizure. After neurological assessment, limbic or herpes encephalitis was provisionally diagnosed and treated with intravenous immunoglobulin, acyclovir and steroids. The patient had progressive severe neurological symptoms, requiring prolonged intubation and mechanical ventilation. An anti-NMDAR antibody test revealed positive in serum and cerebrospinal fluid at 3 weeks of admission. Pelvic ultrasound examination and CT scan revealed bilateral small ovarian teratomas. Bilateral ovarian cystectomy was performed by open surgery. The patient showed rapid improvement and no longer needed intubation 2 days after the operation. In conclusion, we described a catastrophic case of ovarian teratoma-associated encephalitis with delayed diagnosis but rapid recovery after ovarian cystectomy. This information can probably be helpful to neurologists and gynaecologists. PMID- 27511755 TI - Single benign metastasising leiomyoma of an inguinal lymph node. AB - Benign metastasising leiomyoma (BML) is a rare benign disease associated with uterine leiomyoma and history of uterine surgery. It most frequently occurs in premenopausal woman, with a pulmonary localisation, and consisting of multiple nodules. We present an uncommon case of a 69-year-old woman with a single BML of an inguinal lymph node. CT scans of thorax and abdomen excluded other metastasis localisation. The patient was cured with surgical excision of the mass. Lymph node involvement has been reported incidentally in BML literature. Lymphangitic spread can be considered a possible mechanism of BML metastasis. PMID- 27511756 TI - Spontaneous transvaginal small bowel evisceration 40 years post-abdominal hysterectomy. PMID- 27511758 TI - Russell body gastritis in an Hp-negative patient. PMID- 27511759 TI - Gastric siderosis as a cause of dyspepsia. PMID- 27511757 TI - Progressive outer retinal necrosis-like retinitis in immunocompetent hosts. AB - We describe two young immunocompetent women presenting with bilateral retinitis with outer retinal necrosis involving posterior pole with centrifugal spread and multifocal lesions simulating progressive outer retinal necrosis (PORN) like retinitis. Serology was negative for HIV and CD4 counts were normal; however, both women were on oral steroids at presentation for suspected autoimmune chorioretinitis. The retinitis in both eyes responded well to oral valaciclovir therapy. However, the eye with the more fulminant involvement developed retinal detachment with a loss of vision. Retinal atrophy was seen in the less involved eye with preservation of vision. Through these cases, we aim to describe a unique evolution of PORN-like retinitis in immunocompetent women, which was probably aggravated by a short-term immunosuppression secondary to oral steroids. PMID- 27511761 TI - Maternal mortality rates rise in US, study finds. PMID- 27511760 TI - Interactions among Drosophila larvae before and during collision. AB - In populations of Drosophila larvae, both, an aggregation and a dispersal behavior can be observed. However, the mechanisms coordinating larval locomotion in respect to other animals, especially in close proximity and during/after physical contacts are currently only little understood. Here we test whether relevant information is perceived before or during larva-larva contacts, analyze its influence on behavior and ask whether larvae avoid or pursue collisions. Employing frustrated total internal reflection-based imaging (FIM) we first found that larvae visually detect other moving larvae in a narrow perceptive field and respond with characteristic escape reactions. To decipher larval locomotion not only before but also during the collision we utilized a two color FIM approach (FIM(2c)), which allowed to faithfully extract the posture and motion of colliding animals. We show that during collision, larval locomotion freezes and sensory information is sampled during a KISS phase (german: Kollisions Induziertes Stopp Syndrom or english: collision induced stop syndrome). Interestingly, larvae react differently to living, dead or artificial larvae, discriminate other Drosophila species and have an increased bending probability for a short period after the collision terminates. Thus, Drosophila larvae evolved means to specify behaviors in response to other larvae. PMID- 27511762 TI - When Co-Authors Are Missing in Action. PMID- 27511763 TI - Midwest Nursing Research Society News. PMID- 27511764 TI - Development of a robust DNA quality and quantity assessment qPCR assay for targeted next-generation sequencing library preparation. AB - Next-generation sequencing (NGS) is becoming a standard for genetic analyses of clinical samples. DNAs retrieved from formalin-fixed, paraffin-embedded (FFPE) tissue specimens are commonly degraded, and specimens such as core biopsies are sometimes too small to obtain enough DNA for NGS applications. Thus, it is important to measure both the DNA quantity and quality accurately from clinical samples. However, there is no standard method for DNA quantity and quality analyses for NGS library preparation. We tested four different methods (PicoGreen, Qubit(r) fluorometry, TaqMan and SYBR-Green-based qPCR assay) and compared each to RNase P TaqMan as a reference control. We found that SYBR-Green based qPCR assay provides a consistent and accurate DNA quantification while keeping its cost relatively low and the throughput high. We designed a dual-probe SYBR-Green qPCR assay for DNA quantity and quality assessment for targeted NGS library preparation. This assay provides a Dscore (degradation score) of the interrogated DNA by analyzing two different sizes of amplicons. We show an example of a clinical sample with a very high Dscore (high degradation). With a regular DNA quantification, without considering the degradation status, no correct NGS libraries were obtained. However, after optimizing the library condition by considering its poor DNA quality, a reasonably good library and sequencing results were obtained. In summary, we developed and presented a new DNA quantity and quality analysis qPCR assay for the targeted NGS library preparation. This assay may be mostly efficient for the clinical samples with high degradation and poor DNA quality. PMID- 27511765 TI - A novel HLA-A*24 allele, HLA-A*24:325, identified in a Chinese individual. AB - HLA-A*24:325 differs from A*24:02:01:01 by two nucleotide substitutions at position 411 and 412. PMID- 27511766 TI - Relationship of retinal vascular caliber variation with intracranial arterial stenosis. AB - BACKGROUND & PURPOSE: To investigate the associations of retinal vessel parameters with intracranial arterial stenosis (ICAS) assessed by Transcranial Doppler ultrasonography. METHOD: Data on transcranial Doppler ultrasonography and quantitative retinal vessel parameters from 627 participants in a health screening program were included in this study. ICAS was defined as >50% intracranial arterial stenosis (ICAS) based on criteria modified from the stroke outcomes and neuroimaging of intracranial atherosclerosis (SONIA) trial assessed by transcranial Doppler (TCD) ultrasonography. A semi-automated computer-assisted program (Singapore I Vessel Assessment) was used to measure the retinal vascular parameters from the photographs. Multivariate analysis was performed to identify which retinal vessel parameters were associated with increased risk of ICAS. RESULTS: Among 627 participants, 24 (3.8%) had ICAS diagnosed by TCD. Subjects with ICAS had eyes with wider mean central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) in comparison to subjects without ICAS. Men (odds ratio [OR]:13.1, 95% confidence interval: 3.13-33.33) and a large standard deviation of mean arterial width (STDWa) were associated with ICAS (first vs. third tertile: OR ratio: 14.04, 95% confidence interval: 1.71-115.32; first vs. third tertile: OR ratio: 22.1, 95% confidence interval: 2.56-190.97) after adjusting for possible confounders. CONCLUSION: A large variation in retinal arteriolar diameter is associated with ICAS. This study suggests the possible relationship between retina vessel and early changes within the cerebrovascular network. PMID- 27511767 TI - Lung cancer: despite advances, prevention is still best. PMID- 27511768 TI - Argentina acts on violence against women and girls. PMID- 27511769 TI - Reassessing blood donation by men who have sex with men. PMID- 27511770 TI - The unfinished race: 30 years of gender verification in sport. PMID- 27511772 TI - Unresolved issues in Canada's law on physician-assisted dying. PMID- 27511771 TI - Finding a balance: Canada's law on medical assistance in dying. PMID- 27511773 TI - Reducing research waste with implementation laboratories. PMID- 27511776 TI - Clinical examination nowadays. PMID- 27511774 TI - Drug scandals in France: have the lessons been learnt? PMID- 27511777 TI - The first recorded use of microscopy in medicine: Pope Innocent XII's autopsy report. PMID- 27511778 TI - Risk factors for neonatal disorders and the Global Burden of Disease. PMID- 27511779 TI - Mental illness: the forgotten burden on diabetes populations? PMID- 27511780 TI - Freedom of expression and health: is the association causal? PMID- 27511781 TI - Increasing value and reducing waste in biomedical research. PMID- 27511782 TI - Foot print of a paper: accountability in academic publishing. PMID- 27511783 TI - Academic apartheid in Italy. PMID- 27511784 TI - The benefits of screening--and its harms. PMID- 27511785 TI - The CHAMPION trial outcomes were not adequately prespecified. PMID- 27511786 TI - Department of Error. PMID- 27511787 TI - Renal apnoea: extreme disturbance of homoeostasis in a child with Bartter syndrome type IV. PMID- 27511788 TI - The importance of being rare. PMID- 27511789 TI - Cardiac Risk and Disordered Eating: Decreased R Wave Amplitude in Women with Bulimia Nervosa and Women with Subclinical Binge/Purge Symptoms. AB - The purpose of the present study was threefold. First, we examined whether women with bulimia nervosa (n = 12) and women with subthreshold binge/purge symptoms (n = 20) showed decreased mean R wave amplitude, an indicator of cardiac risk, on electrocardiograph compared to asymptomatic women (n = 20). Second, we examined whether this marker was pervasive across experimental paradigms, including before and after sympathetic challenge tasks. Third, we investigated behavioural predictors of this marker, including binge frequency and purge frequency assessed by subtype (dietary restriction, excessive exercise, self-induced vomiting, and laxative abuse). Results of a 3 (ED symptom status) * 5 (experimental condition) mixed factorial ANCOVA (covariates: body mass index, age) indicated women with bulimia nervosa and women with subclinical binge/purge symptoms demonstrated significantly reduced mean R wave amplitude compared to asymptomatic women; this effect was pervasive across experimental conditions. Multiple regression analyses showed binge and purge behaviours, most notably laxative abuse as a purge method, predicted decreased R wave amplitude across all experimental conditions. Copyright (c) 2016 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 27511790 TI - Modeling functional decline over time in sporadic inclusion body myositis. AB - INTRODUCTION: The ability to individualize recommendations or expectations of disease progression based on a patient's unique characteristics has merit for use in sporadic inclusion body myositis (sIBM). METHODS: Fifty-five subjects with sIBM completed a battery of strength and functional outcomes at 2 study visits. These were used to develop mathematical models of disease progression in patients with sIBM for use in clinical and research settings. RESULTS: The 6-minute walk test (6MWT) distance declined by an average of 27.5 meters (12%) per year. Significant factors that predict 6MWT were knee extension and plantarflexion strength and body weight, whereas the ability to stand from a chair was impacted by elbow extension strength. Stepping up on a curb was influenced by the patient's age at diagnosis and by knee extension. Statistical models to predict functional decline in sIBM were developed. CONCLUSION: Statistical models help explain the complex factors that influence decreased walking ability and other functional activities in sIBM. Muscle Nerve 55: 526-531, 2017. PMID- 27511791 TI - The initial break-up of Pangaea elicited by Late Palaeozoic deglaciation. AB - The break-up of Pangaea was principally facilitated by tensional plate stress acting on pre-existing suture zones. The rifting of Pangaea began during the Early Permian along the southern Tethys margin and produced the lenticular-shaped continent known as Cimmeria. A mantle-plume model is ascribed to explain the rift related volcanism but the NW-SE oriented Cimmerian rifts do not correlate well with pre-existing suture zones or 'structural heterogeneities' but appear to have a pertinent spatial and temporal association with Late Palaeozoic glacial interglacial cycles. Mantle potential temperature estimates of Cimmerian rift related basalts (1410 degrees C +/- 50 degrees C) are similar to ambient mantle conditions rather than an active mantle-plume rift as previously suggested. Moreover, we find that the distribution of glacial deposits shows significant temporal and spatial concurrence between the glacial retreat margins and rifting sites. We conclude that the location and timing of Cimmerian rifting resulted from the exploitation of structural heterogeneities within the crust that formed due to repeated glacial-interglacial cycles during the Late Palaeozoic. Such effects of continental deglaciation helped to create the lenticular shape of Cimmeria and Neotethys Ocean suggesting that, in some instances, climate change may directly influence the location of rifting. PMID- 27511792 TI - Increasing Lower Extremity Injury Rates Across the 2009-2010 to 2014-2015 Seasons of National Collegiate Athletic Association Football: An Unintended Consequence of the "Targeting" Rule Used to Prevent Concussions? AB - BACKGROUND: Sports-related concussions (SRCs) have gained increased societal interest in the past decade. The National Collegiate Athletic Association (NCAA) has implemented legislation and rule changes to decrease the incidence and risk of head injury impacts. The "targeting" rule forbids initiating contact with the crown of a helmet and targeting defenseless players in the head and neck area; however, there are concerns that this rule change has unintentionally led to an increased incidence of lower extremity injuries. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate the change in lower extremity injury rates in NCAA football during the 2009-2010 to 2014-2015 seasons. We hypothesized that the lower extremity injury rate has increased across the time period. STUDY DESIGN: Descriptive epidemiology study. METHODS: Sixty-eight NCAA football programs provided 153 team-seasons of data to the NCAA Injury Surveillance Program. Lower extremity injuries (ie, hip/groin, upper leg/thigh, knee, lower leg/Achilles, foot/toes) and SRCs sustained during NCAA football games were examined. We calculated injury rates per 1000 athlete-exposures (AEs) for lower extremity injuries and SRCs. Rate ratios (RRs) compared injury rates between the 2009-2010 to 2011-2012 and 2012-2013 to 2014-2015 seasons. RESULTS: Overall, 2400 lower extremity injuries were reported during the 2009-2010 to 2014-2015 seasons; most were to the knee (33.6%) and ankle (28.5%) and caused by player contact (59.2%). The lower extremity injury rate increased in 2012-2013 to 2014-2015 compared with 2009-2010 to 2011-2012 (23.55 vs 20.45/1000 AEs, respectively; RR, 1.15; 95% CI, 1.06-1.25). This finding was retained when restricted to injuries due to player contact (RR, 1.19; 95% CI, 1.07-1.32) but not for injuries due to noncontact/overuse (RR, 0.96; 95% CI, 0.80-1.14). When examining player contact injury rates by anatomic site, only ankle injuries had an increase (RR, 1.36; 95% CI, 1.13-1.64). The SRC rate also increased in 2012-2013 to 2014-2015 compared with 2009-2010 to 2011-2012 (3.52 vs 2.63/1000 AEs, respectively; RR, 1.34; 95% CI, 1.08-1.66). CONCLUSION: The lower extremity injury rate has increased in NCAA football athletes. Similarly, SRC rates have increased, although this may be caused by concurrent policies related to better education, identification, and management. Targeting rule changes may be contributing to increased rates of player contact-related ankle injuries. Alongside continued surveillance research to examine longitudinal time trends, more in-depth individual-level examinations of how targeting rule changes influence coaching and player behaviors are warranted. PMID- 27511793 TI - Anterior Cruciate Ligament Injuries Alter the Kinematics of Knees With or Without Meniscal Deficiency. AB - BACKGROUND: Numerous studies have investigated kinematic alterations in patients with an isolated anterior cruciate ligament (ACL) injury. However, a substantial proportion of patients with injured ACLs also have concomitant meniscal tears. PURPOSE: To evaluate the in vivo alteration of knee kinematics after an ACL tear, with or without a combined medial or lateral meniscal tear, during level walking activity. STUDY DESIGN: Controlled laboratory study. METHODS: Fifty-six patients with unilateral ACL-deficient (ACLD) knees were studied. Among these patients, 15 had isolated ACL injuries (group 1), 15 had combined ACL and medial meniscal injuries (group 2), 15 had combined ACL and lateral meniscal injuries (group 3), and 11 had combined ACL and medial/lateral meniscal injuries (group 4). The kinematics of each knee was determined using an optical tracking system during treadmill gait. Range of motion (ROM) and kinematic alterations were compared between the contralateral ACL-intact (ACLI) and ACLD knees. RESULTS: All ACLD knees, with or without meniscal deficiency, had significantly less flexion than the ACLI knees (~3 degrees -8 degrees ; P < .05). In groups 1, 3, and 4, the injured knees exhibited more femoral external rotation by approximately 1 degrees to 2 degrees (P < .05). Group 4 showed posterior femoral translation (anterior tibial translation) in the swing phase (~13 mm), while groups 2 and 3 showed increased anterior femoral translation (~2-3 mm). During medial-lateral translation, patients in group 2 had a more medial femoral shift (~4 mm) relative to the tibia initially, while those in group 4 exhibited a lateral femoral shift. CONCLUSION: The results indicate that meniscal injuries alter the kinematics of the ACLD knee when compared with knees with an isolated ACL injury. The location of the meniscal tear also affects knee kinematics. CLINICAL RELEVANCE: Considering the varying effects of meniscal injuries on knee joint kinematics, these data provide insight into the pathological function of the ACL-injured knee joint during walking. PMID- 27511794 TI - tRNA Shifts the G-quadruplex-Hairpin Conformational Equilibrium in RNA towards the Hairpin Conformer. AB - Non-coding RNAs play important roles in cellular homeostasis and are involved in many human diseases including cancer. Intermolecular RNA-RNA interactions are the basis for the diverse functions of many non-coding RNAs. Herein, we show how the presence of tRNA influences the equilibrium between hairpin and G-quadruplex conformations in the 5' untranslated regions of oncogenes and model sequences. Kinetic and equilibrium analyses of the hairpin to G-quadruplex conformational transition of purified RNA as well as during co-transcriptional folding indicate that tRNA significantly shifts the equilibrium toward the hairpin conformer. The enhancement of relative translation efficiency in a reporter gene assay is shown to be due to the tRNA-mediated shift in hairpin-G-quadruplex equilibrium of oncogenic mRNAs. Our findings suggest that tRNA is a possible therapeutic target in diseases in which RNA conformational equilibria is dysregulated. PMID- 27511795 TI - Cross-validated stable-isotope dilution GC-MS and LC-MS/MS assays for monoacylglycerol lipase (MAGL) activity by measuring arachidonic acid released from the endocannabinoid 2-arachidonoyl glycerol. AB - 2-Arachidonoyl glycerol (2AG) is an endocannabinoid that activates cannabinoid (CB) receptors CB1 and CB2. Monoacylglycerol lipase (MAGL) inactivates 2AG through hydrolysis to arachidonic acid (AA) and glycerol, thus modulating the activity at CB receptors. In the brain, AA released from 2AG by the action of MAGL serves as a substrate for cyclooxygenases which produce pro-inflammatory prostaglandins. Here we report stable-isotope GC-MS and LC-MS/MS assays for the reliable measurement of MAGL activity. The assays utilize deuterium-labeled 2AG (d8-2AG; 10MUM) as the MAGL substrate and measure deuterium-labeled AA (d8-AA; range 0-1MUM) as the MAGL product. Unlabelled AA (d0-AA, 1MUM) serves as the internal standard. d8-AA and d0-AA are extracted from the aqueous buffered incubation mixtures by ethyl acetate. Upon solvent evaporation the residue is reconstituted in the mobile phase prior to LC-MS/MS analysis or in anhydrous acetonitrile for GC-MS analysis. LC-MS/MS analysis is performed in the negative electrospray ionization mode by selected-reaction monitoring the mass transitions [M-H]-->[M-H - CO2]-, i.e., m/z 311->m/z 267 for d8-AA and m/z 303->m/z 259 for d0-AA. Prior to GC-MS analysis d8-AA and d0-AA were converted to their pentafluorobenzyl (PFB) esters by means of PFB-Br. GC-MS analysis is performed in the electron-capture negative-ion chemical ionization mode by selected-ion monitoring the ions [M-PFB]-, i.e., m/z 311 for d8-AA and m/z 303 for d0-AA. The GC-MS and LC-MS/MS assays were cross-validated. Linear regression analysis between the concentration (range, 0-1MUM) of d8-AA measured by LC-MS/MS (y) and that by GC-MS (x) revealed a straight line (r2=0.9848) with the regression equation y=0.003+0.898x, indicating a good agreement. In dog liver, we detected MAGL activity that was inhibitable by the MAGL inhibitor JZL-184. Exogenous eicosatetraynoic acid is suitable as internal standard for the quantitative determination of d8-AA produced from d8-2AG by hepatic MAGL activity. The formation of d8-prostaglandin E2 by the consecutive catalytic action of recombinant MAGL on d8-2AG and recombinant cyclooxygenase-2 (COX) on d8-AA was demonstrated by GC-MS/MS. PMID- 27511796 TI - Hypertension and risk of prostate cancer: a systematic review and meta-analysis. AB - The previously reported association between hypertension and prostate cancer risk was controversial. We performed this systematic review and meta-analysis of all available studies to summarize evidence on this association. Studies were identified by searching PubMed, Web of Science and Chinese National Knowledge Infrastructure (CNKI) databases through January 2016. Pooled relative risks (RRs) with their corresponding 95% confidence intervals (CIs) were calculated using a random-effects model. A total of 21 published studies were included in this meta analysis. A significant increase in the risk of prostate cancer (RR 1.08, 95% CI 1.02-1.15, P = 0.014) was observed among individuals with hypertension. There was statistically significant heterogeneity among included studies (P < 0.001 for heterogeneity, I(2) = 72.1%). No obvious evidence of significant publication bias was detected by either Begg's test (P = 0.174) or Egger's test (P = 0.277). In conclusion, this meta-analysis indicates that hypertension may be associated with an increased risk of prostate cancer. Considering the substantial heterogeneity and residual confounding among included studies, further large-scale, well designed prospective cohorts, as well as mechanistic studies, are urgently needed to confirm our preliminary findings. PMID- 27511797 TI - Comparative study of skin autofluorescence expression in atopic dermatitis and psoriasis: A prospective in vivo study. AB - BACKGROUND/PURPOSE: Treatment of atopic dermatitis (AD) and psoriasis requires their differentiation from other eczematoid dermatitis and a determination of disease severity. However, both can be clinically difficult and the findings subjectively interpreted. We investigated the utility of in vivo autofluorescence (AF) measurements for diagnosis of both diseases, and determination of severity. MATERIALS AND METHODS: Thirty patients with AD and 30 with psoriasis were recruited, together with sex- and age-matched patients with healthy skin. AF intensity was measured using the EcoSkin(r) fluorescence video dermatoscope. In AD and psoriasis patients, AF in non-sun-exposed lesional and non-lesional skin was measured. To identify the locations that reflect characteristics of AD, AF was also measured at the other sites in the patients with AD. RESULTS: AD was associated with lower AF and psoriasis with higher AF intensity peaking around 620 nm. In addition, skin AF intensity of each disease was associated with severity of lesion. CONCLUSIONS: Non-invasive measurement of skin AF in vivo can aid in diagnosis of AD and psoriasis as well as in treatment monitoring. PMID- 27511798 TI - Characterization of polymeric pigments and pyranoanthocyanins formed in microfermentations of non-Saccharomyces yeasts. AB - AIMS: To assess the influence of non-Saccharomyces yeasts on the pyranoanthocyanins and polymeric pigments formation after the addition of (+) catechin and procyanidin B2 to fresh red grape must. METHODS AND RESULTS: The fermentation of red grape musts was done with non-Saccharomyces yeasts either alone or in sequential fermentations with the Saccharomyces cerevisiae species. The characterization of both pyranoanthocyanin and polymeric pigments has been carried out with liquid chromatography coupled to mass spectroscopy (HPLC-DAD ESI/MS). Red wines were also characterized by infrared spectroscopy (FTIR), gas chromatography (GC-FID) and spectrophotometry (UV-Vis). It has been observed that fermentation with the species Schizosaccharomyces pombe led to higher concentrations of pigments of all types: anthocyanins, polymeric pigments and pyranoanthocyanins, particularly vitisin A. CONCLUSIONS: The use of non Saccharomyces yeasts improve the formation of stable pigments in red wines thanks to the differences in the microbial metabolism from among the yeasts studied. SIGNIFICANCE AND IMPACT OF THE STUDY: Colour stability as one of the main organoleptic properties in red wines, may be improved by the controlled use of selected non-Saccharomyces yeasts during red must fermentation. PMID- 27511799 TI - Heroin overdose. AB - BACKGROUND AND AIMS: This narrative review aims to provide a brief history of the development of the heroin overdose field by discussing a selection of major 'classics' from the latter part of the 20th century. METHODS: Papers considered landmarks were selected from 1972, 1977, 1983, 1984 and 1999. RESULTS: Findings of earlier works suggest much of what later research was to demonstrate. These include arguing that overdoses occurred primarily among tolerant older users, that most 'overdose' deaths involved low morphine concentrations, that most overdoses involve polypharmacy, that drug purity has only a moderate influence on overdose rates and that instant death following heroin administration is rare. CONCLUSIONS: Landmark studies of heroin overdose from the 1970s, 1980s and 1990s laid the foundations for subsequent overdose research, mainly by identifying the major demographic characteristics of overdose cases, risk factors, survival times and behaviours at overdose events. PMID- 27511801 TI - Solubility-driven toxicity of CuO nanoparticles to Caco2 cells and Escherichia coli: Effect of sonication energy and test environment. AB - Due to small size and high surface energy nanoparticles (NPs) tend to agglomerate and precipitate. To avoid/diminish that, sonication of NPs stock suspensions prior toxicity testing is often applied. Currently, there is no standardized particle sonication protocol available leading to inconsistent toxicity data, especially if toxicity is driven by NPs' dissolution that may be enhanced by sonication. In this study we addressed the effect of sonication on hydrodynamic size (Dh), dissolution and toxicity of copper oxide (CuO) NPs to mammalian cell line Caco-2 in vitro and bacteria Escherichia coli in the respective test environments (cell culture MEM medium, bacterial LB medium and deionised (DI) water). NPs were suspended using no sonication, water bath and probe sonication with different energy intensities. Increased sonication energy (i) decreased the Dh of CuO NPs in all three test environments; (ii) increased dissolution of NPs in MEM medium and their toxicity to Caco-2; (iii) increased dissolution of NPs in LB medium and their bioavailability to E. coli; and (iv) had no effect on dissolution and antibacterial effects of NPs in DI water. Thus, to reduce variations in dissolution and toxicity, we recommend sonication of NPs in DI water following the dilution into suitable test media. PMID- 27511800 TI - The presence of macrophages and inflammatory responses in an in vitro testicular co-culture model of male reproductive development enhance relevance to in vivo conditions. AB - Our 3-dimensional testis co-culture system (3D-TCS) represents a promising model of male reproductive toxicity which captures sensitive processes of male reproductive development and contains the main testes cell types (germ, Leydig and Sertoli cells). Macrophages are another cell type important for testicular function and help to modulate immuno-endocrine processes during testes development. Chemicals such as phthalate esters (PE's) affect macrophage function and testosterone production in the testes in vivo. The aim of this study was to determine whether macrophages were present in the 3D-TCS and investigate responses in our model that may be related to immuno-endocrine functions. We observed consistent expression of the resident macrophage marker ED2 as well as increases in inflammatory cytokines produced by macrophages and testes cells (IL 6, TNF-alpha and KC/GRO) after exposure to toxic PE's. Pathway analysis of gene expression changes after exposure to PE's showed that IL-6 and TNF-alpha signaling pathways were enriched after treatment with reproductively toxic, but not non-reproductively toxic phthalates. These results indicate that macrophages and inflammatory processes are captured in the 3D-TCS and that these processes are impacted by exposure to reproductive toxicants. These processes represent a major mode of action for in vivo testis toxicity for a variety of compounds and our novel in vitro model is able to capture toxicant perturbation of immune function. PMID- 27511802 TI - Pd-catalyzed cascade allylic alkylation and dearomatization reactions of indoles with vinyloxirane. AB - We have developed Pd-catalyzed intermolecular Friedel-Crafts-type allylic alkylation and allylic dearomatization reactions of substituted indoles bearing a nucleophilic group with vinyloxirane, providing an efficient method to synthesize structurally diverse tetrahydrocarboline and spiroindolenine derivatives under mild conditions. PMID- 27511803 TI - Radical-scavenging activity of penicillin G, ampicillin, oxacillin, and dicloxacillin. AB - The aim of this study was to characterize the antioxidant activity of penicillin G (PG), ampicillin (AMP), oxacillin (OX) and dicloxacillin (DOX) through their reactivity towards reactive oxygen species (superoxide anion radical, O2*; hydroxyl radical, HO* ; peroxyl radical, ROO* ; hydrogen peroxide, H2 O2 ; DPPH* ) using various in vitro antioxidant assays with chemiluminescence (CL) and spectrophotometry as measurement techniques. In hydroxyl radical assays , PG, OX and AMP were found to inhibit the CL signal arising from the Fenton-like reaction in a dose-dependent manner with IC50 = 0.480 +/- 0.020 mM, IC50 = 0.569 +/- 0.021 mM, and IC50 = 0.630 +/- 0.019 mM, respectively. The highest reactivity of PG among the tested penicillins towards the HO radical was confirmed in the deoxyribose degradation assay. In the ABAP-derived ROO radical assay, the radical scavenging ability of the test penicillins was in the following order: AMP > PG > DOX > OX. The number of reduced DPPH radicals by the drugs tested was <1 being the biggest for PG. The weak antioxidant capacity of the test penicillins was confirmed in the trolox antioxidant capacity assay (0.075 +/- 0.004; 0.093 +/- 0.006; 0.123 +/- 0.005; 0.126 +/- 0.004) for OX, AMP, DOX, PG, respectively. Use of luminol as a CL probe for estimation of penicillin reactivity towards H2 O2 showed that only AMP was able to quench light emission; the remaining antibiotics demonstrated a strong enhancing effect. All the examined compounds showed a weak antioxidant potential when estimated using the ferric-ferrozine assay. This study is the first to report the evaluation of test penicillins as antioxidants under the same reaction conditions. PMID- 27511804 TI - Contact Resistance Effects in Highly Doped Organic Electrochemical Transistors. AB - Injection at the source contact critically determines the behavior of depletion type organic electrochemical transistors (OETs). The contact resistance of OETs increases exponentially with the gate voltage and strongly influences the modulation of the drain current by the gate voltage over a wide voltage range. A modified standard model accounting contact resistance can explain the particular shape of the transconductance. PMID- 27511806 TI - Macromolecular structure phasing by neutron anomalous diffraction. AB - In this report we show for the first time that neutron anomalous dispersion can be used in a practical manner to determine experimental phases of a protein crystal structure, providing a new tool for structural biologists. The approach is demonstrated through the use of a state-of-the-art monochromatic neutron diffractometer at the Institut Laue-Langevin (ILL) in combination with crystals of perdeuterated protein that minimise the level of hydrogen incoherent scattering and enhance the visibility of the anomalous signal. The protein used was rubredoxin in which cadmium replaced the iron at the iron-sulphur site. While this study was carried out using a steady-state neutron beam source, the results will be of major interest for capabilities at existing and emerging spallation neutron sources where time-of-flight instruments provide inherent energy discrimination. In particular this capability may be expected to offer unique opportunities to a rapidly developing structural biology community where there is increasing interest in the identification of protonation states, protein/water interactions and protein-ligand interactions - all of which are of central importance to a wide range of fundamental and applied areas in the biosciences. PMID- 27511807 TI - Experimental realization of stimulated Raman shortcut-to-adiabatic passage with cold atoms. AB - Accurate control of a quantum system is a fundamental requirement in many areas of modern science ranging from quantum information processing to high-precision measurements. A significantly important goal in quantum control is preparing a desired state as fast as possible, with sufficiently high fidelity allowed by available resources and experimental constraints. Stimulated Raman adiabatic passage (STIRAP) is a robust way to realize high-fidelity state transfer but it requires a sufficiently long operation time to satisfy the adiabatic criteria. Here we theoretically propose and then experimentally demonstrate a shortcut-to adiabatic protocol to speed-up the STIRAP. By modifying the shapes of the Raman pulses, we experimentally realize a fast and high-fidelity stimulated Raman shortcut-to-adiabatic passage that is robust against control parameter variations. The all-optical, robust and fast protocol demonstrated here provides an efficient and practical way to control quantum systems. PMID- 27511808 TI - Correlation between antimicrobial consumption and antimicrobial resistance of Pseudomonas aeruginosa in a hospital setting: a 10-year study. AB - WHAT IS KNOWN AND OBJECTIVE: Antimicrobial resistance is one of the greatest threats to human health. One of the most important factors leading to the emergence of resistant bacteria is overuse of antibiotics. The purpose of this study was to investigate the correlation between antimicrobial usage and bacterial resistance of Pseudomonas aeruginosa (P. aeruginosa) over a 10-year period in the Clinical Center Nis, one of the biggest tertiary care hospitals in Serbia. We focused on possible relationships between the consumption of carbapenems and beta-lactam antibiotics and the rates of resistance of P. aeruginosa to carbapenems. METHODS: We recorded utilization of antibiotics expressed as defined daily doses per 100 bed days (DBD). Bacterial resistance was reported as the percentage of resistant isolates (percentage of all resistant and intermediate resistant strains) among all tested isolates. RESULTS AND DISCUSSION: A significant increasing trend in resistance was seen in imipenem (P < 0.05, Spearman rho = 0.758) and meropenem (P < 0.05, rho = 0.745). We found a significant correlation between aminoglycoside consumption and resistance to amikacin (P < 0.01, Pearson r = 0.837) and gentamicin (P < 0.01, Pearson r = 0.827). The correlation between the consumption of carbapenems and resistance to imipenem in P. aeruginosa shows significance (P < 0.01, Pearson r = 0.795), whereas resistance to meropenem showed a trend towards significance (P > 0.05, Pearson r = 0.607). We found a very good correlation between the use of all beta lactam and P. aeruginosa resistance to carbapenems (P < 0.01, Pearson r = 0.847 for imipenem and P < 0.05, Pearson r = 0.668 for meropenem). WHAT IS NEW AND CONCLUSION: Our data demonstrated a significant increase in antimicrobial resistance to carbapenems, significant correlations between the consumption of antibiotics, especially carbapenems and beta-lactams, and rates of antimicrobial resistance of P. aeruginosa to imipenem and meropenem. PMID- 27511810 TI - Single, community-based blood glucose readings may be a viable alternative for community surveillance of HbA1c and poor glycaemic control in people with known diabetes in resource-poor settings. AB - BACKGROUND: The term HbA1c (glycated haemoglobin) is commonly used in relation to diabetes mellitus. The measure gives an indication of the average blood sugar levels over a period of weeks or months prior to testing. For most low- and middle-income countries HbA1c measurement in community surveillance is prohibitively expensive. A question arises about the possibility of using a single blood glucose measure for estimating HbA1c and therefore identifying poor glycaemic control in resource-poor settings. DESIGN: Using data from the 2011 2012 US National Health and Nutrition Examination Surveys, we examined the relationship between HbA1c and a single fasting measure of blood glucose in a non clinical population of people with known diabetes (n=333). A linear equation for estimating HbA1c from blood glucose was developed. Appropriate blood glucose cut off values were set for poor glycaemic control (HbA1c>=69.4 mmol/mol). RESULTS: The HbA1c and blood glucose measures were well correlated (r=0.7). Three blood glucose cut-off values were considered for classifying poor glycaemic control: 8.0, 8.9, and 11.4 mmol/L. A blood glucose of 11.4 had a specificity of 1, but poor sensitivity (0.37); 8.9 had high specificity (0.94) and moderate sensitivity (0.7); 8.0 was associated with good specificity (0.81) and sensitivity (0.75). CONCLUSIONS: Where HbA1c measurement is too expensive for community surveillance, a single blood glucose measure may be a reasonable alternative. Generalising the specific results from these US data to low resource settings may not be appropriate, but the general approach is worthy of further investigation. PMID- 27511809 TI - The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. AB - BACKGROUND: Here we describe the consensus guideline methodology, summarise the evidence-based recommendations we provided to the World Health Organisation (WHO) for their consideration in the development of global guidance and present a narrative review on the management of anovulatory infertility in women with polycystic ovary syndrome (PCOS). OBJECTIVE AND RATIONALE: The aim of this paper was to present an evidence base for the management of anovulatory PCOS. SEARCH METHODS: The evidence to support providing recommendations involved a collaborative process for: (i) identification of priority questions and critical outcomes, (ii) retrieval of up-to-date evidence and exiting guidelines, (iii) assessment and synthesis of the evidence and (iv) the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation, the methodologist evaluated the quality of the supporting evidence that was then graded as very low, low, moderate or high for consideration during consensus. OUTCOMES: Evidence was synthesized and we made recommendations across the definition of PCOS including hyperandrogenism, menstrual cycle regulation and ovarian assessment. Metabolic features and the impact of ethnicity were covered. Management includes lifestyle changes, bariatric surgery, pharmacotherapy (including clomiphene citrate (CC), aromatase inhibitors, metformin and gonadotropins), as well as laparoscopic surgery. In-vitro fertilization (IVF) was considered as were the risks of ovulation induction and of pregnancy in PCOS. Approximately 80% of women who suffer from anovulatory infertility have PCOS. Lifestyle intervention is recommended first in women who are obese largely on the basis of general health benefits. Bariatric surgery can be considered where the body mass index (BMI) is >=35 kg/m2 and lifestyle therapy has failed. Carefully conducted and monitored pharmacological ovulation induction can achieve good cumulative pregnancy rates and multiple pregnancy rates can be minimized with adherence to recommended protocols. CC should be first-line pharmacotherapy for ovulation induction and letrozole can also be used as first-line therapy. Metformin alone has limited benefits in improving live birth rates. Gonadotropins and laparoscopic surgery can be used as second-line treatment. There is no clear evidence for efficacy of acupuncture or herbal mixtures in women with PCOS. For women with PCOS who fail lifestyle and ovulation induction therapy or have additional infertility factors, IVF can be used with the safer gonadotropin releasing hormone (GnRH) antagonist protocol. If a GnRH-agonist protocol is used, metformin as an adjunct may reduce the risk of ovarian hyperstimulation syndrome. Patients should be informed of the potential side effects of ovulation induction agents and of IVF on the foetus, and of the risks of multiple pregnancy. Increased risks for the mother during pregnancy and for the child, including the exacerbating impact of obesity on adverse outcomes, should also be discussed. WIDER IMPLICATIONS: This guidance generation and evidence-synthesis analysis has been conducted in a manner to be considered for global applicability for the safe administration of ovulation induction for anovulatory women with PCOS. PMID- 27511812 TI - A giant anguilliform leptocephalus Thalassenchelys foliaceus Castle & Raju is a junior synonym of Congriscus maldivensis (Norman 1939). AB - A single specimen of giant leptocephalus Thalassenchelys foliaceus Castle & Raju 1975 was caught in subtropical waters of the western North Pacific Ocean. Mitochondrial coI gene sequence divergence between T. foliaceus and Congriscus maldivensis (Norman 1939) was 0.64 +/- 0.27% (mean +/- s.e.), and the myomere and vertebral counts of these species were similar, indicating T. foliaceus is a junior synonym of C. maldivensis. PMID- 27511811 TI - The impact of a livelihood program on depressive symptoms among people living with HIV in Cambodia. AB - BACKGROUND: Psychological and social problems are major concerns in this era of successful antiretroviral therapy. Although livelihood programs have been implemented extensively to improve the daily living conditions of people living with HIV in Cambodia, no studies have yet investigated the impacts of these programs on the mental health of this vulnerable population. Therefore, we examined the impact of a livelihood program on depressive symptoms and associated factors among people living with HIV in Cambodia. DESIGN: A quasi-experimental, nonequivalent comparison group study was conducted in six provinces of Cambodia in 2014. Data were collected from an intervention group comprising 357 people living with HIV who had participated in the livelihood program and a comparison group comprising 328 people living with HIV who had not participated in this program. Multiple logistic regression analysis was carried out to examine the association between livelihood-program participation and depressive symptoms as measured by the depressive symptoms subscale of the 25-item Cambodian version of the Hopkins Symptom Checklist. A propensity score matching was used to examine the effect of the livelihood program on depressive symptoms while controlling for selection bias. RESULTS: Overall, 56.0% and 62.7% of the participants in the intervention and comparison groups, respectively, met the Hopkins Symptom Checklist threshold for depressive symptoms. The multiple logistic regression analysis showed that the participants in the intervention group had significantly lower odds of having depressive symptoms (adjusted odds ratio 0.68, 95% confidence interval 0.52-0.88). The analysis from propensity score matching indicated that the livelihood program helped mitigate depressive symptoms among the participants in the intervention group (T=-1.99). CONCLUSIONS: The livelihood program appeared to help mitigate the burden of depressive symptoms among people living with HIV in Cambodia. Thus, this program should be scaled up and modified to better improve participants' mental health. PMID- 27511813 TI - Association Between Train-of-Four Values and Gas Exchange Indices in Moderate to Severe Acute Respiratory Distress Syndrome. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is associated with a mortality rate of approximately 40%. Neuromuscular blockade is associated with an improvement in oxygenation and a reduction in mortality in ARDS. OBJECTIVE: The goal of this evaluation was to determine if the depth of paralysis, determined by train-of-four (TOF) monitoring, correlates with gas exchange in moderate to severe ARDS. METHODS: This was a retrospective review of moderate to severe ARDS patients who were prescribed >12 hours of continuous infusion cisatracurium between January 1, 2013, and December 31, 2014, with a PaO2:FiO2 ratio <150 and documented TOF and arterial blood gases. Patients were evaluated for inclusion at 12, 24, and 48 hours after initiation of neuromuscular blockade. RESULTS: A total of 378 patients were screened for inclusion, with 107 evaluable patients meeting criteria at baseline. Poor correlation existed between TOF and oxygenation index (OI) at 12 (tau = 0.03), 24 (tau = 0.15) and 48 hours (tau = 0.08). When controlling for proning and baseline OI, the depth of paralysis did not have a significant effect on OI at 12, 24, or 48 hours. CONCLUSIONS: This evaluation demonstrates that the use of TOF monitoring for neuromuscular blockade does not correlate with gas exchange markers in moderate to severe ARDS. PMID- 27511814 TI - Methotrexate Elimination When Coadministered With Levetiracetam. AB - BACKGROUND: Delayed elimination of methotrexate was previously reported in 2 patients receiving concomitant levetiracetam. OBJECTIVE: To explore the potential interaction between methotrexate and levetiracetam in patients receiving high dose methotrexate. METHODS: This retrospective study reviewed the records of 81 adults receiving 280 cycles of methotrexate to determine the effects of levetiracetam on methotrexate elimination. Institutional review board approval was obtained. RESULTS: Levetiracetam was administered in 33 (12%) cycles of methotrexate. Patients receiving levetiracetam had significantly lower 24-hour methotrexate concentrations compared with those not receiving levetiracetam (2.91 vs 7.37 umol/L, P = 0.005). Despite this difference, concentrations at 48 and 72 hours were similar between groups. Times to nontoxic methotrexate concentration (<0.1 umol/L) were the same regardless of the presence of levetiracetam. The frequency of delayed elimination at 24, 48, and 72 hours was similar in both groups as was the frequency of delayed elimination at any time point. Cox regression demonstrated that levetiracetam was not a significant predictor of time to nontoxic methotrexate concentration (P = 0.796; HR = 1.058; 95% CI = 0.692-1.617), and logistic regression demonstrated that levetiracetam was not a significant predictor of delayed elimination at any time point. Levetiracetam use was similar between groups when comparing patients experiencing delayed elimination at any time point with those without delayed elimination (13% vs 10%, respectively, P = 0.527). CONCLUSION: This study does not support the previous reports of a significant interaction between levetiracetam and methotrexate. A clinically significant interaction is unlikely in those without additional risk factors for delayed elimination. PMID- 27511815 TI - EAN guidelines on central neurostimulation therapy in chronic pain conditions. AB - BACKGROUND AND PURPOSE: Our aim was to update previous European Federation of Neurological Societies guidelines on neurostimulation for neuropathic pain, expanding the search to new techniques and to chronic pain conditions other than neuropathic pain, and assessing the evidence with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. METHODS: A systematic review and meta-analysis of trials published between 2006 and December 2014 was conducted. Pain conditions included neuropathic pain, fibromyalgia, complex regional pain syndrome (CRPS) type I and post-surgical chronic back and leg pain (CBLP). Spinal cord stimulation (SCS), deep brain stimulation (DBS), epidural motor cortex stimulation (MCS), repetitive transcranial magnetic stimulation (rTMS) and transcranial direct electrical stimulation (tDCS) of the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) were assessed. The GRADE system was used to assess quality of evidence and propose recommendations. RESULTS: The following recommendations were reached: 'weak' for SCS added to conventional medical management in diabetic painful neuropathy, CBLP and CRPS, for SCS versus reoperation in CBLP, for MCS in neuropathic pain, for rTMS of M1 in neuropathic pain and fibromyalgia and for tDCS of M1 in neuropathic pain; 'inconclusive' for DBS in neuropathic pain, rTMS and tDCS of the DLPFC, and for motor cortex tDCS in fibromyalgia and spinal cord injury pain. CONCLUSIONS: Given the poor to moderate quality of evidence identified by this review, future large scale multicentre studies of non-invasive and invasive neurostimulation are encouraged. The collection of higher quality evidence of the predictive factors for the efficacy of these techniques, such as the duration, quality and severity of pain, is also recommended. PMID- 27511816 TI - The insidious appearance of the dissecting aneurysm: Imaging findings and related pathophysiology. A report of two cases. AB - Intracranial dissecting aneurysms have been frequently reported to present with fairly challenging and time-variable imaging findings that can be mostly explained by the pathological mechanisms that underline the dissection. We present two cases of spontaneous dissecting aneurysm of the supraclinoid ICA, both clinically presenting with SAH, but characterized by different progression of clinical symptoms and imaging. However, in both cases an outpouch and a mild fusiform dilation of the supraclinoid ICA was present in the initial CTA performed after the occurrence of symptoms. These findings were well depicted by the MPR reformats performed retrospectively. We postulate that this finding may represent the point of initial transmural dissection and we recommend that careful analysis of the CTA MRP reformatted images should be performed in order to detect this finding promptly. PMID- 27511818 TI - Early angiographic changes of intra-aneurysmal flow after flow-diverter stent treatment are not predictive of therapeutic success. AB - BACKGROUND AND PURPOSE: Flow-diverter stents (FDS) are new devices for the endovascular treatment of intracranial aneurysms (IAs) promoting progressive aneurysmal thrombosis. To date, the delay of aneurysmal exclusion remains unclear. We evaluated the correlation between angiographic changes in the first 24 hours and 12-month occlusion in aneurysms treated with FDS. METHODS: We retrospectively analyzed the intra-aneurysmal flow by evaluating the in-flow and out-flow delays on preoperative, immediate postoperative, 24-hour and 12-month follow-up angiography. Dichotomy of in-flow and out-flow within the aneurysm was considered as the time of contrast filling and time of contrast washing relatively to the parent artery. The delay times were compared and correlated with the therapeutic success of FDS at 12 months of follow-up. RESULTS: Out of 14 treated IAs, in 13 consecutive patients, n = 10 (71%) aneurysms showed complete occlusion at 12 months. Between immediate postoperative and 24-hour control, 10 aneurysms (71%) demonstrated in-flow modification, with eight increasing, two decreasing and four having no change. There were no statistical differences in therapeutic success in relation to the different flow-related profiles of intra aneurysmal flux.Out-flow modifications were found in 11 aneurysms (79%) between immediate postoperative and 24-hour control, with five increasing, six decreasing and three having no change. Similar to the in-flow changes, there were no statistical differences in therapeutic success relative to the flow-related profiles. CONCLUSIONS: Early angiographic changes after FDS placement are very frequent, but are not correlated with the 12-month technical success of flow diversion techniques. PMID- 27511819 TI - Significant Improvement of Antithrombotic Responses to Clopidogrel by Use of a Novel Conjugate as Revealed in an Arterial Model of Thrombosis. AB - Clopidogrel is a prodrug that requires bioactivation by cytochrome P450 (P450) enzymes to a pharmacologically active metabolite for antiplatelet action. The clinical limitations of clopidogrel are in large part due to its poor pharmacokinetics resulting from inefficient bioactivation by P450s. In this study, we determined the pharmacokinetics and pharmacodynamics of a novel conjugate of clopidogrel, referred to as ClopNPT, in animal models and we evaluated its potential to overcome the limitations of clopidogrel. Results from pharmacokinetic (PK) studies showed that ClopNPT released the active metabolite with a time to maximal plasma concentration of <5 minutes in C57BL/6 mice after either oral or intravenous administration, and plasma concentrations of the active metabolite reached Cmax values of 1242 and 1100 ng/ml after a 10-mg/kg oral dose and a 5-mg/kg intravenous dose, respectively. Furthermore, ClopNPT was highly effective in preventing arterial thrombosis in rabbits and mice after vascular injuries. Formation of occlusive thrombi was prevented by ClopNPT at the 1-mg/kg dose with no significant increase in tongue bleeding time, whereas clopidogrel was ineffective at the same dose. These results suggest that ClopNPT has favorable PK/pharmacodynamic properties that can potentially overcome the attenuated PK properties of clopidogrel and thus significantly improve the efficacy of antiplatelet therapy. PMID- 27511817 TI - Neurovascular manifestations of connective-tissue diseases: A review. AB - Patients with connective tissue diseases are thought to be at a higher risk for a number of cerebrovascular diseases such as intracranial aneurysms, dissections, and acute ischemic strokes. In this report, we aim to understand the prevalence and occurrences of such neurovascular manifestations in four heritable connective tissue disorders: Marfan syndrome, Ehlers-Danlos syndrome, Neurofibromatosis Type 1, and Loeys-Dietz syndrome. We discuss the fact that although there are various case studies reporting neurovascular findings in these connective tissue diseases, there is a general lack of case-control and prospective studies investigating the true prevalence of these findings in these patient populations. Furthermore, the differences observed in the manifestations and histology of such disease pathologies encourages future multi-center registries and studies in better characterizing the pathophysiology, prevalence, and ideal treatment options of neurovascular lesions in patents with connective tissue diseases. PMID- 27511821 TI - Case of immunoglobulin G4-related disease with unusual cutaneous manifestation. PMID- 27511822 TI - Dislocation network with pair-coupling structure in {111} gamma/gamma' interface of Ni-based single crystal superalloy. AB - The gamma/gamma' interface dislocation network is reported to improve the high temperature creep resistance of single crystal superalloys and is usually found to deposit in {001} interface. In this work, a new type of dislocation network was found in {111} gamma/gamma' interface at a single crystal model superalloy crept at 1100 degrees C/100 MPa. The dislocations in the network are screw with Burgers vectors of 1/2 a<110> and most interestingly, they exhibit a pair coupling structure. Further investigation indicates that the formation of {111} interface dislocation network occurs when the gamma' raft structure begins to degrade by the dislocations cutting into the rafted gamma' through the interface. In this condition, the pair-coupling structure is established by the dislocations gliding in a single {111} plane of gamma', in order to remove the anti-phase boundary in gamma'; these dislocations also act as diffusion channels for dissolving of the gamma' particle that is unstable under the interfacial stress from lattice misfit, which leads to the formation of {111}-type zigzag interface. The formation of this network arises as a consequence of more negative misfit, low-alloying gamma' particle and proper test conditions of temperature and stress. PMID- 27511823 TI - The role of FDG-PET in localization of recurrent lesions of differentiated thyroid cancer (DTC) in patients with asymptomatic hyperthyroglobulinemia in a real clinical practice. AB - INTRODUCTION: Available methods, including serum thyroglobulin (Tg) measurement and whole-body scan (WBS) performed after radioiodine administration, allow for a precise diagnostics in differentiated thyroid cancer (DTC). However, some asymptomatic patients demonstrate negative WBS despite a high Tg serum concentration. In these subjects, fluorodeoxyglucose-positron emission tomography (FDG-PET) should be considered. The primary aim of our study was to evaluate a diagnostic value of FDG-PET in asymptomatic hyperthyroglobulinemia. The secondary one was to determine a prognostic value of a negative FDG-PET result in DTC patients with elevated Tg level. MATERIAL: One hundred and ten FDG-PET/CT scans were retrospectively analyzed, 85 scans were done under TSH stimulation and 25 on LT4 suppressive therapy. Follow-up ranged between 4 and 9 years. RESULTS: The first FDG-PET/CT detected cancer foci in 49 subjects with a global sensitivity of 45%. When the sensitivity was evaluated with reference to TSH stimulation and suppression, its values were 50 and 28% respectively. In 42 patients, FDG-PET failed to diagnose the reason for elevated Tg level. During further follow-up, in 17 of them, DTC recurrence was detected by other methods (CT, MRI, US). Fourteen subjects with asymptomatic hyperthyroglobulinemia were free of DTC progression for at least 4 years. CONCLUSIONS: FDG-PET in DTC patients with asymptomatic hyperthyroglobulinemia constitutes a valuable diagnostic tool. Negative FDG-PET demonstrated a limited prognostic significance, as only every third patient did not show DTC progression. Moreover, negative FDG-PET does not justify less strict DTC monitoring, because it is related to 40% risk of relapse during the 5-year follow-up. PMID- 27511820 TI - Target Organ Metabolism, Toxicity, and Mechanisms of Trichloroethylene and Perchloroethylene: Key Similarities, Differences, and Data Gaps. AB - Trichloroethylene (TCE) and perchloroethylene or tetrachloroethylene (PCE) are high-production volume chemicals with numerous industrial applications. As a consequence of their widespread use, these chemicals are ubiquitous environmental contaminants to which the general population is commonly exposed. It is widely assumed that TCE and PCE are toxicologically similar; both are simple olefins with three (TCE) or four (PCE) chlorines. Nonetheless, despite decades of research on the adverse health effects of TCE or PCE, few studies have directly compared these two toxicants. Although the metabolic pathways are qualitatively similar, quantitative differences in the flux and yield of metabolites exist. Recent human health assessments have uncovered some overlap in target organs that are affected by exposure to TCE or PCE, and divergent species- and sex specificity with regard to cancer and noncancer hazards. The objective of this minireview is to highlight key similarities, differences, and data gaps in target organ metabolism and mechanism of toxicity. The main anticipated outcome of this review is to encourage research to 1) directly compare the responses to TCE and PCE using more sensitive biochemical techniques and robust statistical comparisons; 2) more closely examine interindividual variability in the relationship between toxicokinetics and toxicodynamics for TCE and PCE; 3) elucidate the effect of coexposure to these two toxicants; and 4) explore new mechanisms for target organ toxicity associated with TCE and/or PCE exposure. PMID- 27511824 TI - Hypothyroidism incidence in and around pregnancy: a Danish nationwide study. AB - OBJECTIVE: Immunological changes in and after a pregnancy may influence the onset of autoimmune diseases. An increased incidence of hyperthyroidism has been observed both in early pregnancy and postpartum, but it remains to be studied if the incidence of hypothyroidism varies in a similar way. DESIGN: Population-based cohort study using Danish nationwide registers. METHOD: All women who gave birth to a singleton live-born child in Denmark from 1999 to 2008 (n = 403 958) were identified, and data on hospital diagnosis of hypothyroidism and redeemed prescriptions of thyroid hormone were extracted. The overall incidence rate (IR) of hypothyroidism during 1997-2010 and the IR in three-month intervals before, during and after the woman's first pregnancy in the study period were calculated and compared with the IR of hyperthyroidism. RESULTS: Altogether 5220 women were identified with onset of hypothyroidism from 1997 to 2010 (overall IR 92.3/100 000/year) and 1572 women developed hypothyroidism in the period from 2 years before to 2 years after birth of the first child in the study period. The incidence of hypothyroidism decreased during the pregnancy (incidence rate ratio (IRR) vs overall IR in the rest of the study period: first trimester: 0.89 (95% CI: 0.66-1.19), second trimester: 0.71 (0.52-0.97), third trimester: 0.29 (0.19 0.45)) and increased after birth with the highest level at 4-6 months postpartum (IRR 3.62 (2.85-4.60)). CONCLUSION: These are the first population-based data on the incidence of hypothyroidism in and around pregnancy. The incidence declined during pregnancy followed by a sharp increase postpartum. Notably, hypothyroidism as opposed to hyperthyroidism showed no early pregnancy increase. PMID- 27511826 TI - Congenital hypothyroidism with delayed TSH elevation in low-birth-weight infants: incidence, diagnosis and management. AB - OBJECTIVE: To evaluate the incidence of congenital hypothyroidism (CH) with delayed TSH elevation among low-birth-weight (LBW) newborns in North-Eastern Italy and to verify if they need a second or third screening. DESIGN: Analysis of clinical and biochemical data of newborns affected by CH with delayed TSH elevation identified by neonatal screening. METHODS: Data of all newborns with birth weight (BW) <2500 g and evidence of delayed TSH elevation at newborn screening were collected between 2011 and 2014. Confirmatory tests were based on serum TSH and FT4 levels. All their clinical signs at diagnosis were reported. RESULTS: 57.5% of LBW newborns with delayed TSH increase at neonatal screening presented a CH with delayed TSH elevation and began a treatment with l-thyroxine. The incidence of this condition in North-Eastern Italy is therefore 1:908. The remaining infants presented a subclinical hypothyroidism (21.25%) or a complete normal serum thyroid function (21.25%). These data could be drawn only from a retesting strategy of neonatal screening. CONCLUSIONS: Our report describes the incidence of CH with delayed TSH rise in North-Eastern Italy and differentiates this clinical condition from other thyroid dysfunctions of preterm or LBW newborns. The second-screening strategy for CH in neonates with BW < 2500 g proved useful in detecting newborns who otherwise would not be identified at the first screening. PMID- 27511825 TI - The link between metabolic features and TSH levels in polycystic ovary syndrome is modulated by the body weight: an euglycaemic-hyperinsulinaemic clamp study. AB - OBJECTIVE: To evaluate the link among thyroid function, glucose/insulin metabolism and steroid hormones in women with polycystic ovary syndrome (PCOS), and to verify if the body mass index (BMI) might influence the interplay between PCOS features and subclinical hypothyroidism (SCH). STUDY DESIGN: Case-control study conducted from January to December 2014. METHODS: One-hundred fifty-four young women with PCOS, according to Rotterdam criteria, and 88 controls were enrolled in an academic research environment. Anthropometric evaluation, hormonal and lipid assays, oral glucose tolerance test (OGTT) and euglycaemic hyperinsulinaemic clamp were performed. Hirsutism was assessed with the Ferriman Gallwey (FG) score. MAIN RESULTS: SCH was found in 14% of PCOS subjects and in 1% of controls (P < 0.01). In PCOS women, TSH levels were directly correlated with fasting glycaemia, but not with other hormonal and metabolic parameters. When PCOS patients were classified on the basis of BMI, TSH levels significantly correlated with insulin secretion, insulin resistance, DHEAS and cortisol levels in obese PCOS women. Inverse correlations were found between TSH and both oestradiol and SHBG in the same group. In nonobese PCOS patients, only waist-to hip ratio values were correlated with TSH. The prevalence of SCH was not different between nonobese and obese PCOS groups (14 and 15% respectively). However, SCH was associated with higher levels of insulin, DHEAS, cortisol and FG score only in the obese subgroup. CONCLUSIONS: Our data confirm that the prevalence of SCH is increased in PCOS women. The presence of SCH is associated with endocrine and metabolic imbalances of PCOS, and the excessive body weight seems to promote this interplay. PMID- 27511827 TI - Performance comparison of MOF and other sorbent materials in removing key odorants emitted from pigpen slurry. AB - A batch-type dynamic headspace (HS) system was used to generate vapor-phase volatile organic compounds (VOCs) from a pigpen slurry sample. Sorptive removal capability of MOF-199 and other sorbents (zeolite (ZL) and activated carbon (AC)) was assessed against a total of 13 slurry-borne odorants ((methyl ethyl ketone (MEK), isobutyl alcohol (i-BuAl), benzene (B), toluene (T), p-xylene (p-X), m xylene (m-X), o-xylene (o-X), styrene (S), o-cresol (o-C), phenol (PhAl), p cresol (p-C), indole (ID), and skatole (SK)). Adsorption capacity of MOF-199 and two sorbents, when assessed for the 13 odorants at a 10% breakthrough volume (BTV), was 22.6 +/- 42.3, 0.70 +/- 1.08, and 11.0 +/- 18.3 MUg g(-1), respectively. The adsorption capacity (MUg g(-1)) assessed at 10% BTV showed the superiority of MOF-199 towards phenolic and indolic compounds (such as o-C (0.31 +/- 0.04), PhAl (61.6 +/- 4.98), p-C (140 +/- 7.95), ID (27.8 +/- 2.23), and SK (63.9 +/- 1.55)), demonstrating the feasibility of MOF as sorption media for treating certain nuisance components. PMID- 27511828 TI - Sustainability assessment of electrokinetic bioremediation compared with alternative remediation options for a petroleum release site. AB - Sustainable management practices can be applied to the remediation of contaminated land to maximise the economic, environmental and social benefits of the process. The Sustainable Remediation Forum UK (SuRF-UK) have developed a framework to support the implementation of sustainable practices within contaminated land management and decision making. This study applies the framework, including qualitative (Tier 1) and semi-quantitative (Tier 2) sustainability assessments, to a complex site where the principal contaminant source is unleaded gasoline, giving rise to a dissolved phase BTEX and MTBE plume. The pathway is groundwater migration through a chalk aquifer and the receptor is a water supply borehole. A hydraulic containment system (HCS) has been installed to manage the MTBE plume migration. The options considered to remediate the MTBE source include monitored natural attenuation (MNA), air sparging/soil vapour extraction (AS/SVE), pump and treat (PT) and electrokinetic enhanced bioremediation (EK-BIO). A sustainability indictor set from the SuRF-UK framework, including priority indicator categories selected during a stakeholder engagement workshop, was used to frame the assessments. At Tier 1 the options are ranked based on qualitative supporting information, whereas in Tier 2 a multi criteria analysis is applied. Furthermore, the multi-criteria analysis was refined for scenarios where photovoltaics (PVs) are included and amendments are excluded from the EK-BIO option. Overall, the analysis identified AS/SVE and EK BIO as more sustainable remediation options at this site than either PT or MNA. The wider implications of this study include: (1) an appraisal of the management decision from each Tier of the assessment with the aim to highlight areas for time and cost savings for similar assessments in the future; (2) the observation that EK-BIO performed well against key indicator categories compared to the other intensive treatments; and (3) introducing methods to improve the sustainability of the EK-BIO treatment design (such as PVs) did not have a significant effect in this instance. PMID- 27511829 TI - The Effectiveness Of Social Media (Facebook) Compared With More Traditional Advertising Methods for Recruiting Eligible Participants To Health Research Studies: A Randomized, Controlled Clinical Trial. AB - BACKGROUND: Recruiting participants for research studies can be difficult and costly. The popularity of social media platforms (eg, Facebook) has seen corresponding growth in the number of researchers turning to social networking sites and their embedded advertising frameworks to locate eligible participants for studies. Compared with traditional recruitment strategies such as print media, social media advertising has been shown to be favorable in terms of its reach (especially with hard-to-reach populations), cost effectiveness, and usability. However, to date, no studies have examined how participants recruited via social media progress through a study compared with those recruited using more traditional recruitment strategies. OBJECTIVES: (1) Examine whether visiting the study website prior to being contacted by researchers creates self-screened participants who are more likely to progress through all study phases (eligible, enrolled, completed); (2) compare conversion percentages and cost effectiveness of each recruitment method at each study phase; and, (3) compare demographic and smoking characteristics of participants recruited through each strategy to determine if they attract similar samples. METHODS: Participants recruited to a smoking cessation clinical trial were grouped by how they had become aware of the study: via social media (Facebook) or traditional media (eg, newspaper, flyers, radio, word of mouth). Groups were compared based on throughput data (conversion percentages and cost) as well as demographic and smoking characteristics. RESULTS: Visiting the study website did not result in individuals who were more likely to be eligible for (P=.24), enroll in (P=.20), or complete (P=.25) the study. While using social media was more cost effective than traditional methods when we examined earlier endpoints of the recruitment process (cost to obtain a screened respondent: AUD $22.73 vs $29.35; cost to obtain an eligible respondent: $37.56 vs $44.77), it was less cost effective in later endpoints (cost per enrolled participant: $56.34 vs $52.33; cost per completed participant: $103.66 vs $80.43). Participants recruited via social media were more likely to be younger (P=.001) and less confident in their quit attempts (P=.004) compared to those recruited via traditional methods. CONCLUSIONS: Our study suggests that while social media advertising may be effective in generating interest from potential participants, this strategy's ability to attract conscientious recruits is more questionable. Researchers considering using online resources (eg, social media advertising, matrix codes) should consider including prescreening questions to promote conversion percentages. Ultimately, researchers seeking to maximize their recruitment budget should consider using a combination of advertising strategies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN 12614000329662; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365947l (Archived by WebCite at http://www.webcitation.org/6jc6zXWZI). PMID- 27511830 TI - Healthcare Professionals' Preferences and Perceived Barriers for Routine Assessment of Patient-Reported Outcomes in Pediatric Oncology Practice: Moving Toward International Processes of Change. AB - BACKGROUND: Using patient-reported outcomes (PROs) in clinical practice has been shown to enhance detection of health-related quality of life problems and satisfaction with care in children with cancer. This study seeks to identify which PRO information healthcare professionals (HCPs) find useful and what the perceived barriers for routinely assessing PROs are. PROCEDURE: A total of 352 pediatric HCPs (43% male) from 52 countries completed a semistructured online 28 item questionnaire. Descriptive statistics (percentages) were used to identify highly important PRO information and perceived barriers. HCPs' perceived barriers were compared according to gender, years of work experience, and country using a Fishers exact test. RESULTS: The five highest ranked PRO topics relevant in routine assessment by HCPs were as follows: pain (98%), feeling sad or depressed (96%), overall physical symptoms (95%), problems with therapy adherence (94%), and overall emotional issues (93%). Five lowest ranked topics were as follows: difficulties praying (50%), other spiritual concerns (55, 56, and 60%), and feeling bored (60%). Barriers for assessing PROs included: time (58%), insufficient staff (49%), logistics (32%), and financial resources (26%). Providers from developing countries more often reported barriers concerning insufficient staff, logistics, and financial resources. CONCLUSIONS: HCPs strongly value the use of physical and psychosocial PROs within pediatric oncology practice, but mainly perceive organizational barriers for routine assessment. To successfully integrate PROs, efforts should be made to address HCP perceived barriers, such that patient-reported problems can be detected and timely referrals made. PMID- 27511831 TI - Fibroproliferative response to urothelial failure obliterates the ureter lumen in a mouse model of prenatal congenital obstructive nephropathy. AB - Congenital obstructive nephropathy (CON) is the most prevalent cause of pediatric chronic kidney disease and end-stage renal disease. The ureteropelvic junction (UPJ) region, where the renal pelvis transitions to the ureter, is the most commonly obstructed site in CON. The underlying causes of congenital UPJ obstructions remain poorly understood, especially when they occur in utero, in part due to the lack of genetic animal models. We previously showed that conditional inactivation of Sec10, a central subunit of the exocyst complex, in the epithelial cells of the ureter and renal collecting system resulted in late gestational bilateral UPJ obstructions with neonatal anuria and death. In this study, we show that without Sec10, the urothelial progenitor cells that line the ureter fail to differentiate into superficial cells, which are responsible for producing uroplakin plaques on the luminal surface. These Sec10-knockout urothelial cells undergo cell death by E17.5 and the urothelial barrier becomes leaky to luminal fluid. Also at E17.5, we measured increased expression of TGFbeta1 and genes associated with myofibroblast activation, with evidence of stromal remodeling. Our findings support the model that a defective urothelial barrier allows urine to induce a fibrotic wound healing mechanism, which may contribute to human prenatal UPJ obstructions. PMID- 27511832 TI - The protein inventory of Clostridium difficile grown in complex and minimal medium. AB - The intestinal pathogen Clostridium difficile is causing an increasing number of infections often characterized by severity and high relapse rates. Profound knowledge of the physiology of the pathogen could help to develop new treatment strategies. Proteomics, a valuable tool to study bacterial physiology, was used in this work to establish a benchmark proteome of reference strain C. difficile 630Deltaerm with MS-based details on all identified proteins. Our elaborate annotation and visualization of C. difficile 630Deltaerm 3764 ORFs will serve as a valuable base for researchers having to evaluate global expression studies. To exemplify expression variability, protein expression of late exponentially growing cells in complex brain-heart infusion medium and C. difficile minimal medium was compared. Noteworthy results of this comparison are as follows: (i) the higher expression of enzymes for the biosynthesis of some vitamins and purine and (ii) downregulation of proteins involved in butanoate fermentation in C. difficile minimal medium. However, the abundance of proteins involved in DNA metabolism, protein synthesis, and the cell envelope showed no variation between the two growth media. PMID- 27511833 TI - Prognostic implications of 2005 Gleason grade modification. Population-based study of biochemical recurrence following radical prostatectomy. AB - OBJECTIVE: To assess the impact of the 2005 modification of the Gleason classification on risk of biochemical recurrence (BCR) after radical prostatectomy (RP). PATIENTS AND METHODS: In the Prostate Cancer data Base Sweden (PCBaSe), 2,574 men assessed with the original Gleason classification and 1,890 men assessed with the modified Gleason classification, diagnosed between 2003 and 2007, underwent primary RP. Histopathology was reported according to the Gleason Grading Groups (GGG): GGG1 = Gleason score (GS) 6, GGG2 = GS 7(3 + 4), GGG3 = GS 7(4 + 3), GGG4 = GS 8 and GGG5 = GS 9-10. Cumulative incidence and multivariable Cox proportional hazards regression models were used to assess difference in BCR. RESULTS: The cumulative incidence of BCR was lower using the modified compared to the original classification: GGG2 (16% vs. 23%), GGG3 (21% vs. 35%) and GGG4 (18% vs. 34%), respectively. Risk of BCR was lower for modified versus original classification, GGG2 Hazard ratio (HR) 0.66, (95%CI 0.49-0.88), GGG3 HR 0.57 (95%CI 0.38-0.88) and GGG4 HR 0.53 (95%CI 0.29-0.94). CONCLUSION: Due to grade migration following the 2005 Gleason modification, outcome after RP are more favourable. Consequently, outcomes from historical studies cannot directly be applied to a contemporary setting. J. Surg. Oncol. 2016;114:664-670. (c) 2016 Wiley Periodicals, Inc. PMID- 27511834 TI - Transgenic overexpression of VEGF-C induces weight gain and insulin resistance in mice. AB - Obesity comprises great risks for human health, contributing to the development of other diseases such as metabolic syndrome, type 2 diabetes and cardiovascular disease. Previously, obese patients were found to have elevated serum levels of VEGF-C, which correlated with worsening of lipid parameters. We recently identified that neutralization of VEGF-C and -D in the subcutaneous adipose tissue during the development of obesity improves metabolic parameters and insulin sensitivity in mice. To test the hypothesis that VEGF-C plays a role in the promotion of the metabolic disease, we used K14-VEGF-C mice that overexpress human VEGF-C under control of the keratin-14 promoter in the skin and monitored metabolic parameters over time. K14-VEGF-C mice had high levels of VEGF-C in the subcutaneous adipose tissue and gained more weight than wildtype littermates, became insulin resistant and had increased ectopic lipid accumulation at 20 weeks of age on regular mouse chow. The metabolic differences persisted under high-fat diet induced obesity. These results indicate that elevated VEGF-C levels contribute to metabolic deterioration and the development of insulin resistance, and that blockade of VEGF-C in obesity represents a suitable approach to alleviate the development of insulin resistance. PMID- 27511835 TI - Do pharmacist-led medication reviews in hospitals help reduce hospital readmissions? A systematic review and meta-analysis. AB - AIMS: The aim of this meta-analysis is to examine the impact of in-hospital pharmacist-led medication reviews in paediatric and adult patients. METHODS: Relevant studies were identified from the Medline and Cochrane Library databases. Studies were included if they met the following criteria (without any language or date restrictions): design: randomized controlled trial; intervention: in hospital pharmacist-led medication review (experimental group) vs. usual care (control group); participants: paediatric or adult population. The primary outcome was all-cause readmissions and/or emergency department (ED) visits at different time points. The secondary outcomes were all-cause readmissions, all cause ED visits, drug-related readmissions, mortality, length of hospital stay, adherence and quality of life. We calculated the relative risk (RR) or mean differences (MD) with 95% confidence intervals (CIs) for each study. We used fixed and/or random effects models. Heterogeneity was assessed using the I2 statistic. RESULTS: We systematically reviewed 19 randomized controlled trials (4805 participants). The readmission rates did not differ between the experimental group and the control group (RR = 0.97, 95% CI 0.89; 1.05, p = 0.470). The secondary outcomes did not differ between the two groups, except for in drug-related readmissions, which were lower in the experimental group (RR = 0.25, 95% CI 0.14; 0.45, p < 0.001), and all-cause ED visits (RR = 0.70, 95% CI 0.59; 0.85 p = 0.001). CONCLUSION: The low-quality evidence in this analysis suggests an impact of pharmacist-led medication reviews on drug-related readmissions and all-cause ED visits. Few studies reported on adherence and quality of life. More high-quality randomized clinical trials are needed to assess the impact of pharmacist-led medication reviews on patient-relevant outcomes, including adherence and quality of life. PMID- 27511836 TI - Population Pharmacokinetic and Pharmacodynamic Modeling Analysis of GCC-4401C, a Novel Direct Factor Xa Inhibitor, in Healthy Volunteers. AB - GCC-4401C, an orally active direct factor Xa inhibitor that is similar to rivaroxaban, is currently under development for venous thromboembolic disease (VTE). The purpose of this study was to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of GCC-4401C by population modeling analysis and to predict proper dosage regimens compared to rivaroxaban using data from two phase I clinical studies. Plasma GCC-4401C concentrations over time were best described by a two-compartment linear model and body weight was associated with central volume of distribution. Relevant PD markers generally changed in a dose-dependent manner and were described well with sigmoid, simple maximum effect, or linear models. GCC-4401C was absorbed more rapidly than rivaroxaban. Comparisons based on simulations of PD marker changes over time suggest that 20 mg and 40 mg of GCC 4401C administered under fasted status are comparable to 10 mg and 20 mg of rivaroxaban under fed status. PMID- 27511837 TI - Control of sensory neuron excitability by serotonin involves 5HT2C receptors and Ca(2+)-activated chloride channels. AB - Serotonin (5HT) is a constituent of the so-called "inflammatory soup" that sensitizes nociceptors during inflammation. Nevertheless, receptors and signaling mechanisms that mediate an excitation of dorsal root ganglion (DRG) neurons by 5HT remained controversial. Therefore, capsaicin-sensitive nociceptive neurons dissociated from rat DRGs were used to investigate effects of 5HT on membrane excitability and currents through ligand- as well as voltage-gated ion channels. In 58% of the neurons tested, 5HT increased action potential firing, an effect that was abolished by the 5HT2 receptor antagonist ritanserin, but not by the 5HT3 antagonist tropisetron. Unlike other algogenic mediators, such as PGE2 and bradykinin, 5HT did not affect currents through TTX-resistant Na(+) channels or Kv7 K(+) channels. In all neurons investigated, 5HT potentiated capsaicin-evoked currents through TRPV1 channels, an effect that was attenuated by antagonists at 5HT2A (4 F 4 PP), 5HT2B (SB 204741), as well as 5HT2C (RS 102221) receptors. 5HT triggered slowly arising inward Cl(-) currents in 53% of the neurons. This effect was antagonized by the 5HT2C receptor blocker only, and the current was prevented by an inhibitor of Ca(2+)-activated chloride channels (CaCC). The 5HT-induced increase in action potential firing was also abolished by this CaCC blocker and by the TRPV1 inhibitor capsazepine. Amongst the subtype selective 5HT2 antagonists, only RS 102221 (5HT2C-selectively) counteracted the rise in action potential firing elicited by 5HT. These results show that 5HT excites DRG neurons mainly via 5HT2C receptors which concomitantly mediate a sensitization of TRPV1 channels and an opening of CaCCs. PMID- 27511839 TI - Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation. AB - Pancreatic insulin-secreting beta-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired glucose tolerance. Pharmacological blockade of alpha2A-adrenergic receptors prevented DAMGO-induced glucose intolerance and gluconeogenesis. Accordingly, DAMGO failed to inhibit GSIS and to impair glucose tolerance in alpha2A-adrenoceptor knockout mice, indicating that the effects of central MOR activation on beta-cells are mediated via sympathetic innervation. Our results show for the first time a new role of the central opioid system, specifically the MOR, in the regulation of insulin secretion and glucose metabolism. PMID- 27511840 TI - Progress in Vulvar and Endometrial Cancers: Exploiting Anatomy and Biology and Improving Systemic Therapy. PMID- 27511838 TI - The kynurenine pathway and the brain: Challenges, controversies and promises. AB - Research on the neurobiology of the kynurenine pathway has suffered years of relative obscurity because tryptophan degradation, and its involvement in both physiology and major brain diseases, was viewed almost exclusively through the lens of the well-established metabolite serotonin. With increasing recognition that kynurenine and its metabolites can affect and even control a variety of classic neurotransmitter systems directly and indirectly, interest is expanding rapidly. Moreover, kynurenine pathway metabolism itself is modulated in conditions such as infection and stress, which are known to induce major changes in well-being and behaviour, so that kynurenines may be instrumental in the etiology of psychiatric and neurological disorders. It is therefore likely that the near future will not only witness the discovery of additional physiological and pathological roles for brain kynurenines, but also ever-increasing interest in drug development based on these roles. In particular, targeting the kynurenine pathway with new specific agents may make it possible to prevent disease by appropriate pharmacological or genetic manipulations. The following overview focuses on areas of kynurenine research which are either controversial, of major potential therapeutic interest, or just beginning to receive the degree of attention which will clarify their relevance to neurobiology and medicine. It also highlights technical issues so that investigators entering the field, and new research initiatives, are not misdirected by inappropriate experimental approaches or incorrect interpretations at this time of skyrocketing interest in the subject matter. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'. PMID- 27511841 TI - Mathematical Optimization of Treatment Schedules. PMID- 27511843 TI - The Challenges of Treatment Adaptation and De-intensification in Human Papillomavirus-Positive Oropharyngeal Cancer: The Difficult Journey Back. PMID- 27511842 TI - Strategy of Using Intratreatment Hypoxia Imaging to Selectively and Safely Guide Radiation Dose De-escalation Concurrent With Chemotherapy for Locoregionally Advanced Human Papillomavirus-Related Oropharyngeal Carcinoma. AB - PURPOSE: To report a small substudy of an ongoing large, multi-arm study using functional imaging to assess pre-/intratreatment hypoxia for all head and neck cancer, in which we hypothesized that pre- and early-treatment hypoxia assessment using functional positron emission tomography (PET) imaging may help select which human papillomavirus (HPV)-positive (HPV(+)) oropharyngeal cancer (OPC) patients can safely receive radiation de-escalation without jeopardizing treatment outcomes. METHODS AND MATERIALS: Patients with HPV(+) oropharyngeal carcinoma were enrolled on an institutional review board-approved prospective study of which de-escalation based on imaging response was done for node(s) only. Pretreatment (18)F-fluorodeoxyglucose and dynamic (18)F-FMISO (fluoromisonidazole) positron emission tomography (PET) scans were performed. For patients with pretreatment hypoxia on(18)F-FMISO PET (defined as a >1.2 tumor to muscle standard uptake value ratio), a repeat scan was done 1 week after chemoradiation. Patients without pretreatment hypoxia or with resolution of hypoxia on repeat scan received a 10-Gy dose reduction to metastatic lymph node(s). The 2-year local, regional, distant metastasis-free, and overall survival rates were estimated using the Kaplan-Meier product-limit method. A subset of patients had biopsy of a hypoxic node done under image guidance. RESULTS: Thirty-three HPV(+) OPC patients were enrolled in this pilot study. One hundred percent showed pretreatment hypoxia (at primary site and/or node[s]), and among these, 48% resolved (at primary site and/or node[s]); 30% met criteria and received 10-Gy reduction to the lymph node(s). At the median follow-up of 32 months (range, 21-61 months), the 2-year locoregional control rate was 100%. One patient failed distantly with persistence of hypoxia on (18)F-FMISO PET. The 2 year distant metastasis-free rate was 97%. The 2-year OS rate was 100%. Hypoxia on imaging was confirmed pathologically. CONCLUSIONS: Hypoxia is present in HPV(+) tumors but resolves within 1 week of treatment in 48% of cases either at the primary site and/or lymph node(s). Our 100% locoregional control rate suggests that intratreatment functional imaging used to selectively de-escalate node(s) to 60 Gy was confirmed safe using our stringent imaging criteria. Intratreatment functional imaging warrants further study to determine its ultimate role in de-escalation treatment strategies. PMID- 27511844 TI - Final Results of a Randomized Phase 2 Trial Investigating the Addition of Cetuximab to Induction Chemotherapy and Accelerated or Hyperfractionated Chemoradiation for Locoregionally Advanced Head and Neck Cancer. AB - PURPOSE: The role of cetuximab in the treatment of locoregionally advanced head and neck squamous cell cancer (LA-HNSCC) remains poorly defined. In this phase 2 randomized study, we investigated the addition of cetuximab to both induction chemotherapy (IC) and hyperfractionated or accelerated chemoradiation. METHODS AND MATERIALS: Patients with LA-HNSCC were randomized to receive 2 cycles of weekly IC (cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (concurrent cetuximab, 5-fluorouracil, hydroxyurea, and 1.5 Gy twice-daily radiation therapy every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated radiation therapy with delayed concomitant boost to 72 Gy in 42 fractions). The primary endpoint was progression-free survival (PFS), with superiority compared with historical control achieved if either arm had 2-year PFS >=70%. RESULTS: 110 patients were randomly assigned to either Cetux-FHX (n=57) or Cetux-PX (n=53). The overall response rate to IC was 91%. Severe toxicity on IC was limited to rash (23% grade >=3) and myelosuppression (38% grade >=3 neutropenia). The 2-year rates of PFS for both Cetux-FHX (82.5%) and Cetux-PX (84.9%) were significantly higher than for historical control (P<.001). The 2-year overall survival (OS) was 91.2% for Cetux-FHX and 94.3% for Cetux-PX. With a median follow-up time of 72 months, there were no significant differences in PFS (P=.35) or OS (P=.15) between the treatment arms. The late outcomes for the entire cohort included 5 year PFS, OS, locoregional failure, and distant metastasis rates of 74.1%, 80.3%, 15.7%, and 7.4%, respectively. The 5-year PFS and OS were 84.4% and 91.3%, respectively, among human papillomavirus (HPV)-positive patients and 65.9% and 72.5%, respectively, among HPV-negative patients. CONCLUSIONS: The addition of cetuximab to IC and chemoradiation was tolerable and produced long-term control of LA-HNSCC, particularly among poor-prognosis HPV-negative patients. Further investigation of cetuximab may be warranted in the neoadjuvant setting and with non-platinum-based chemoradiation. PMID- 27511845 TI - Free Thyroid Transfer: A Novel Procedure to Prevent Radiation-induced Hypothyroidism. AB - PURPOSE: The incidence of hypothyroidism after radiation therapy for head and neck cancer (HNC) has been found to be <=53%. Medical treatment of hypothyroidism can be costly and difficult to titrate. The aim of the present study was to assess the feasibility of free thyroid transfer as a strategy for the prevention of radiation-induced damage to the thyroid gland during radiation therapy for HNC. METHODS AND MATERIALS: A prospective feasibility study was performed involving 10 patients with a new diagnosis of advanced HNC undergoing ablative surgery, radial forearm free-tissue transfer reconstruction, and postoperative adjuvant radiation therapy. During the neck dissection, hemithyroid dissection was completed with preservation of the thyroid arterial and venous supply for implantation into the donor forearm site. All patients underwent a diagnostic thyroid technetium scan 6 weeks and 12 months postoperatively to examine the functional integrity of the transferred thyroid tissue. RESULTS: Free thyroid transfer was executed in 9 of the 10 recruited patients with advanced HNC. The postoperative technetium scans demonstrated strong uptake of technetium at the forearm donor site at 6 weeks and 12 months for all 9 of the transplanted patients. CONCLUSIONS: The thyroid gland can be transferred as a microvascular free transfer with maintenance of function. This technique could represent a novel strategy for maintenance of thyroid function after head and neck irradiation. PMID- 27511846 TI - A Novel Form of Breast Intraoperative Radiation Therapy With CT-Guided High-Dose Rate Brachytherapy: Results of a Prospective Phase 1 Clinical Trial. AB - PURPOSE: Existing intraoperative radiation therapy (IORT) techniques are criticized for the lack of image guided treatment planning and energy deposition with, at times, poor resultant dosimetry and low radiation dose. We pioneered a novel method of IORT that incorporates customized, computed tomography (CT)-based treatment planning and high-dose-rate (HDR) brachytherapy to overcome these drawbacks: CT-HDR-IORT. METHODS AND MATERIALS: A phase 1 study was conducted to demonstrate the feasibility and safety of CT-HDR-IORT. Eligibility criteria included age >=50 years, invasive or in situ breast cancer, tumor size <3 cm, and N0 disease. Patients were eligible before or within 30 days of breast-conserving surgery (BCS). BCS was performed, and a multilumen balloon catheter was placed. CT images were obtained, a customized HDR brachytherapy plan was created, and a dose of 12.5 Gy was delivered to 1-cm depth from the balloon surface. The catheter was removed, and the skin was closed. The primary endpoints were feasibility and acute toxicity. Feasibility was defined as IORT treatment interval (time from CT acquisition until IORT completion) <=90 minutes. The secondary endpoints included dosimetry, cosmetic outcome, quality of life, and late toxicity. RESULTS: Twenty-eight patients were enrolled. The 6-month follow up assessments were completed by 93% of enrollees. The median IORT treatment interval was 67.2 minutes (range, 50-108 minutes). The treatment met feasibility criteria in 26 women (93%). The dosimetric goals were met in 22 patients (79%). There were no Radiation Therapy Oncology Group grade 3+ toxicities; 6 patients (21%) experienced grade 2 events. Most patients (93%) had good/excellent cosmetic outcomes at the last follow-up visit. CONCLUSIONS: CT-HDR-IORT is feasible and safe. This promising approach for a conformal, image-based, higher-dose breast IORT is being evaluated in a phase 2 trial. PMID- 27511847 TI - Cosmesis and Breast-Related Quality of Life Outcomes After Intraoperative Radiation Therapy for Early Breast Cancer: A Substudy of the TARGIT-A Trial. AB - PURPOSE: To report the first comprehensive investigation of patient-reported cosmesis and breast-related quality of life (QOL) outcomes comparing patients randomized to risk-adapted single-dose intraoperative radiation therapy (TARGIT IORT) versus external beam radiation therapy (EBRT) on the TARGIT-A trial. METHODS AND MATERIALS: Longitudinal cosmesis and QOL data were collected from a subset of TARGIT-A participants who received TARGIT-IORT as a separate procedure (postpathology). Patients completed a cosmetic assessment before radiation therapy and annually thereafter for at least 5 years. Patients also completed the combined European Organization for Research and Treatment of Cancer (EORTC) core questionnaire and Breast-Specific Module in addition to the Body Image after Breast Cancer Questionnaire at baseline and annually thereafter. The combined EORTC questionnaires were also collected 3, 6, and 9 months after wide local excision. RESULTS: An Excellent-Good cosmetic result was scored more often than a Fair-Poor result for both treatment groups across all time points. The TARGIT IORT patients reported better breast-related QOL than EBRT patients. Statistically and clinically significant differences were seen at month 6 and year 1, with EBRT patients having moderately worse breast symptoms (a statistically significant difference of more than 10 in a 100-point scale) than TARGIT-IORT patients at these time points. CONCLUSION: Patients treated with TARGIT-IORT on the TARGIT-A trial have similar self-reported cosmetic outcome but better breast-related QOL outcomes than patients treated with EBRT. This important evidence can facilitate the treatment decision-making process for patients who have early breast cancer suitable for breast-conserving surgery and inform their clinicians. PMID- 27511850 TI - Quantitative Analysis of (18)F-Fluorodeoxyglucose Positron Emission Tomography Identifies Novel Prognostic Imaging Biomarkers in Locally Advanced Pancreatic Cancer Patients Treated With Stereotactic Body Radiation Therapy. AB - PURPOSE: To identify prognostic biomarkers in pancreatic cancer using high throughput quantitative image analysis. METHODS AND MATERIALS: In this institutional review board-approved study, we retrospectively analyzed images and outcomes for 139 locally advanced pancreatic cancer patients treated with stereotactic body radiation therapy (SBRT). The overall population was split into a training cohort (n=90) and a validation cohort (n=49) according to the time of treatment. We extracted quantitative imaging characteristics from pre-SBRT (18)F fluorodeoxyglucose positron emission tomography, including statistical, morphologic, and texture features. A Cox proportional hazard regression model was built to predict overall survival (OS) in the training cohort using 162 robust image features. To avoid over-fitting, we applied the elastic net to obtain a sparse set of image features, whose linear combination constitutes a prognostic imaging signature. Univariate and multivariate Cox regression analyses were used to evaluate the association with OS, and concordance index (CI) was used to evaluate the survival prediction accuracy. RESULTS: The prognostic imaging signature included 7 features characterizing different tumor phenotypes, including shape, intensity, and texture. On the validation cohort, univariate analysis showed that this prognostic signature was significantly associated with OS (P=.002, hazard ratio 2.74), which improved upon conventional imaging predictors including tumor volume, maximum standardized uptake value, and total legion glycolysis (P=.018-.028, hazard ratio 1.51-1.57). On multivariate analysis, the proposed signature was the only significant prognostic index (P=.037, hazard ratio 3.72) when adjusted for conventional imaging and clinical factors (P=.123-.870, hazard ratio 0.53-1.30). In terms of CI, the proposed signature scored 0.66 and was significantly better than competing prognostic indices (CI 0.48-0.64, Wilcoxon rank sum test P<1e-6). CONCLUSION: Quantitative analysis identified novel (18)F-fluorodeoxyglucose positron emission tomography image features that showed improved prognostic value over conventional imaging metrics. If validated in large, prospective cohorts, the new prognostic signature might be used to identify patients for individualized risk-adaptive therapy. PMID- 27511848 TI - Association of Locoregional Control With High Body Mass Index in Women Undergoing Breast Conservation Therapy for Early-Stage Breast Cancer. AB - PURPOSE: Obesity, as measured by the body mass index (BMI), is a risk factor for distant recurrence and decreased survival in breast cancer. We sought to determine whether the BMI correlated with local recurrence and reduced survival in a cohort of predominantly obese women treated with breast conservation therapy. METHODS AND MATERIALS: From 1998 to 2010, 154 women with early-stage invasive breast cancer and 39 patients with ductal carcinoma in situ underwent prone whole breast irradiation. Cox proportional hazards regression, Kaplan-Meier methods with the log-rank test, and multivariate analysis were used to explore the association of the outcomes with the BMI. RESULTS: The median patient age was 60 years, and the median follow-up duration was 73 months. The median BMI was 33.2 kg/m(2); 91% of the patients were overweight (BMI >=25 kg/m(2)) and 69% of the patients were clinically obese (BMI >=30 kg/m(2)). The BMI was significantly associated with the locoregional recurrence-free interval for patients with invasive cancer and ductal carcinoma in situ (hazard ratio [HR], 1.09; P=.047). Also, a trend was seen for increased locoregional recurrence with a higher BMI (P=.09) for patients with invasive disease, which was significant when examining the outcomes with a BMI stratified by the median value of 33.2 kg/m(2) (P=.008). A greater BMI was also significantly associated with decreased distant recurrence free interval (HR, 1.09; P=.011) and overall survival (HR, 1.09; P=.004); this association remained on multivariate analysis (distant recurrence-free interval, P=.034; overall survival, P=.0007). CONCLUSIONS: These data suggest that the BMI might affect the rate of locoregional recurrence in breast cancer patients. A higher BMI predicted a worse distant recurrence-free interval and overall survival. The present investigation adds to the increasing evidence that BMI is an important prognostic factor in early-stage breast cancer treated with breast conservation therapy. PMID- 27511849 TI - Development and Validation of Consensus Contouring Guidelines for Adjuvant Radiation Therapy for Bladder Cancer After Radical Cystectomy. AB - PURPOSE: To develop multi-institutional consensus clinical target volumes (CTVs) and organs at risk (OARs) for male and female bladder cancer patients undergoing adjuvant radiation therapy (RT) in clinical trials. METHODS AND MATERIALS: We convened a multidisciplinary group of bladder cancer specialists from 15 centers and 5 countries. Six radiation oncologists and 7 urologists participated in the development of the initial contours. The group proposed initial language for the CTVs and OARs, and each radiation oncologist contoured them on computed tomography scans of a male and female cystectomy patient with input from >=1 urologist. On the basis of the initial contouring, the group updated its CTV and OAR descriptions. The cystectomy bed, the area of greatest controversy, was contoured by another 6 radiation oncologists, and the cystectomy bed contouring language was again updated. To determine whether the revised language produced consistent contours, CTVs and OARs were redrawn by 6 additional radiation oncologists. We evaluated their contours for level of agreement using the Landis Koch interpretation of the kappa statistic. RESULTS: The group proposed that patients at elevated risk for local-regional failure with negative margins should be treated to the pelvic nodes alone (internal/external iliac, distal common iliac, obturator, and presacral), whereas patients with positive margins should be treated to the pelvic nodes and cystectomy bed. Proposed OARs included the rectum, bowel space, bone marrow, and urinary diversion. Consensus language describing the CTVs and OARs was developed and externally validated. The revised instructions were found to produce consistent contours. CONCLUSIONS: Consensus descriptions of CTVs and OARs were successfully developed and can be used in clinical trials of adjuvant radiation therapy for bladder cancer. PMID- 27511851 TI - A Voxel-Based Approach to Explore Local Dose Differences Associated With Radiation-Induced Lung Damage. AB - PURPOSE: To apply a voxel-based (VB) approach aimed at exploring local dose differences associated with late radiation-induced lung damage (RILD). METHODS AND MATERIALS: An interinstitutional database of 98 patients who were Hodgkin lymphoma (HL) survivors treated with postchemotherapy supradiaphragmatic radiation therapy was analyzed in the study. Eighteen patients experienced late RILD, classified according to the Radiation Therapy Oncology Group scoring system. Each patient's computed tomographic (CT) scan was normalized to a single reference case anatomy (common coordinate system, CCS) through a log diffeomorphic approach. The obtained deformation fields were used to map the dose of each patient into the CCS. The coregistration robustness and the dose mapping accuracy were evaluated by geometric and dose scores. Two different statistical mapping schemes for nonparametric multiple permutation inference on dose maps were applied, and the corresponding P<.05 significance lung subregions were generated. A receiver operating characteristic (ROC)-based test was performed on the mean dose extracted from each subregion. RESULTS: The coregistration process resulted in a geometrically robust and accurate dose warping. A significantly higher dose was consistently delivered to RILD patients in voxel clusters near the peripheral medial-basal portion of the lungs. The area under the ROC curves (AUC) from the mean dose of the voxel clusters was higher than the corresponding AUC derived from the total lung mean dose. CONCLUSIONS: We implemented a framework including a robust registration process and a VB approach accounting for the multiple comparison problem in dose-response modeling, and applied it to a cohort of HL survivors to explore a local dose-RILD relationship in the lungs. Patients with RILD received a significantly greater dose in parenchymal regions where low doses (~6 Gy) were delivered. Interestingly, the relation between differences in the high-dose range and RILD seems to lack a clear spatial signature. PMID- 27511853 TI - Pulsed Radiation Therapy With Concurrent Cisplatin Results in Superior Tumor Growth Delay in a Head and Neck Squamous Cell Carcinoma Murine Model. AB - PURPOSE: To assess the efficacy of 3-week schedules of low-dose pulsed radiation treatment (PRT) and standard radiation therapy (SRT), with concurrent cisplatin (CDDP) in a head and neck squamous cell carcinoma xenograft model. METHODS AND MATERIALS: Subcutaneous UT-SCC-14 tumors were established in athymic NIH III HO female mice. A total of 30 Gy was administered as 2 Gy/d, 5 d/wk for 3 weeks, either by PRT (10 * 0.2 Gy/d, with a 3-minute break between each 0.2-Gy dose) or SRT (2 Gy/d, uninterrupted delivery) in combination with concurrent 2 mg/kg CDDP 3 times per week in the final 2 weeks of radiation therapy. Treatment-induced growth delays were defined from twice-weekly tumor volume measurements. Tumor hypoxia was assessed by (18)F-fluoromisonidazole positron emission tomography imaging, and calculated maximum standardized uptake values compared with tumor histology. Tumor vessel density and hypoxia were measured by quantitative immunohistochemistry. Normal tissues effects were evaluated in gut and skin. RESULTS: Untreated tumors grew to 1000 mm(3) in 25.4 days (+/-1.2), compared with delays of 62.3 days (+/-3.5) for SRT + CDDP and 80.2 days (+/-5.0) for PRT + CDDP. Time to reach 2* pretreatment volume ranged from 8.2 days (+/-1.8) for untreated tumors to 67.1 days (+/-4.7) after PRT + CDDP. Significant differences in tumor growth delay were observed for SRT versus SRT + CDDP (P=.04), PRT versus PRT + CDDP (P=.035), and SRT + CDDP versus PRT + CDDP (P=.033), and for survival between PRT versus PRT + CDDP (P=.017) and SRT + CDDP versus PRT + CDDP (P=.008). Differences in tumor hypoxia were evident by (18)F-fluoromisonidazole positron emission tomography imaging between SRT and PRT (P=.025), although not with concurrent CDDP. Tumor vessel density differed between SRT + CDDP and PRT + CDDP (P=.011). No differences in normal tissue parameters were seen. CONCLUSIONS: Concurrent CDDP was more effective in combination PRT than SRT at restricting tumor growth. Significant differences in tumor vascular density were evident between PRT and SRT, suggesting a preservation of vascular network with PRT. PMID- 27511852 TI - Monitoring Tumor Response to Carbogen Breathing by Oxygen-Sensitive Magnetic Resonance Parameters to Predict the Outcome of Radiation Therapy: A Preclinical Study. AB - PURPOSE: In an effort to develop noninvasive in vivo methods for mapping tumor oxygenation, magnetic resonance (MR)-derived parameters are being considered, including global R1, water R1, lipids R1, and R2*. R1 is sensitive to dissolved molecular oxygen, whereas R2* is sensitive to blood oxygenation, detecting changes in dHb. This work compares global R1, water R1, lipids R1, and R2* with pO2 assessed by electron paramagnetic resonance (EPR) oximetry, as potential markers of the outcome of radiation therapy (RT). METHODS AND MATERIALS: R1, R2*, and EPR were performed on rhabdomyosarcoma and 9L-glioma tumor models, under air and carbogen breathing conditions (95% O2, 5% CO2). Because the models demonstrated different radiosensitivity properties toward carbogen, a growth delay (GD) assay was performed on the rhabdomyosarcoma model and a tumor control dose 50% (TCD50) was performed on the 9L-glioma model. RESULTS: Magnetic resonance imaging oxygen-sensitive parameters detected the positive changes in oxygenation induced by carbogen within tumors. No consistent correlation was seen throughout the study between MR parameters and pO2. Global and lipids R1 were found to be correlated to pO2 in the rhabdomyosarcoma model, whereas R2* was found to be inversely correlated to pO2 in the 9L-glioma model (P=.05 and .03). Carbogen increased the TCD50 of 9L-glioma but did not increase the GD of rhabdomyosarcoma. Only R2* was predictive (P<.05) for the curability of 9L-glioma at 40 Gy, a dose that showed a difference in response to RT between carbogen and air-breathing groups. (18)F-FAZA positron emission tomography imaging has been shown to be a predictive marker under the same conditions. CONCLUSION: This work illustrates the sensitivity of oxygen-sensitive R1 and R2* parameters to changes in tumor oxygenation. However, R1 parameters showed limitations in terms of predicting the outcome of RT in the tumor models studied, whereas R2* was found to be correlated with the outcome in the responsive model. PMID- 27511854 TI - Effect of Irradiation on Tumor Microenvironment and Bone Marrow Cell Migration in a Preclinical Tumor Model. AB - PURPOSE: To characterize the tumor microenvironment after standard radiation therapy (SRT) and pulsed radiation therapy (PRT) in Lewis lung carcinoma (LLC) allografts. METHODS AND MATERIALS: Subcutaneous LLC tumors were established in C57BL/6 mice. Standard RT or PRT was given at 2 Gy/d for a total dose of 20 Gy using a 5 days on, 2 days off schedule to mimic clinical delivery. Radiation induced tumor microenvironment changes were examined after treatment using flow cytometry and antibody-specific histopathology. Normal tissue effects were measured using noninvasive (18)F-fluorodeoxyglucose positron emission tomography/computed tomography after naive animals were given whole-lung irradiation to 40 Gy in 4 weeks using the same 2-Gy/d regimens. RESULTS: Over the 2 weeks of therapy, PRT was more effective than SRT at reducing tumor growth rate (0.31 +/- 0.02 mm(3)/d and 0.55 +/- 0.04 mm(3)/d, respectively; P<.007). Histopathology showed a significant comparative reduction in the levels of Ki-67 (14.5% +/- 3%), hypoxia (10% +/- 3.5%), vascular endothelial growth factor (2.3% +/- 1%), and stromal-derived factor-1alpha (2.5% +/- 1.4%), as well as a concomitant decrease in CD45(+) bone marrow-derived cell (BMDC) migration (7.8% +/- 2.2%) after PRT. The addition of AMD3100 also decreased CD45(+) BMDC migration in treated tumors (0.6% +/- 0.1%). Higher vessel density was observed in treated tumors. No differences were observed in normal lung tissue after PRT or SRT. CONCLUSIONS: Pulsed RT-treated tumors exhibited slower growth and reduced hypoxia. Pulsed RT eliminated initiation of supportive mechanisms utilized by tumors in low oxygen microenvironments, including angiogenesis and recruitment of BMDCs. PMID- 27511855 TI - Computational Modeling of Micrometastatic Breast Cancer Radiation Dose Response. AB - PURPOSE: Prophylactic cranial irradiation (PCI) involves giving radiation to the entire brain with the goals of reducing the incidence of brain metastasis and improving overall survival. Experimentally, we have demonstrated that PCI prevents brain metastases in a breast cancer mouse model. We developed a computational model to expand on and aid in the interpretation of our experimental results. METHODS AND MATERIALS: MATLAB was used to develop a computational model of brain metastasis and PCI in mice. Model input parameters were optimized such that the model output would match the experimental number of metastases per mouse from the unirradiated group. An independent in vivo-limiting dilution experiment was performed to validate the model. The effect of whole brain irradiation at different measurement points after tumor cells were injected was evaluated in terms of the incidence, number of metastases, and tumor burden and was then compared with the corresponding experimental data. RESULTS: In the optimized model, the correlation between the number of metastases per mouse and the experimental fits was >95. Our attempt to validate the model with a limiting dilution assay produced 99.9% correlation with respect to the incidence of metastases. The model accurately predicted the effect of whole-brain irradiation given 3 weeks after cell injection but substantially underestimated its effect when delivered 5 days after cell injection. The model further demonstrated that delaying whole-brain irradiation until the development of gross disease introduces a dose threshold that must be reached before a reduction in incidence can be realized. CONCLUSIONS: Our computational model of mouse brain metastasis and PCI correlated strongly with our experiments with unirradiated mice. The results further suggest that early treatment of subclinical disease is more effective than irradiating established disease. PMID- 27511857 TI - The Use of Cone Beam Computed Tomography for Image Guided Gamma Knife Stereotactic Radiosurgery: Initial Clinical Evaluation. AB - PURPOSE: The present study used cone beam computed tomography (CBCT) to measure the inter- and intrafraction uncertainties for intracranial stereotactic radiosurgery (SRS) using the Leksell Gamma Knife (GK). METHODS AND MATERIALS: Using a novel CBCT system adapted to the GK radiosurgery treatment unit, CBCT images were acquired immediately before and after treatment for each treatment session within the context of a research ethics board-approved prospective clinical trial. Patients were immobilized in the Leksell coordinate frame (LCF) for both volumetric CBCT imaging and GK-SRS delivery. The relative displacement of the patient's skull to the stereotactic reference (interfraction motion) was measured for each CBCT scan. Differences between the pre- and post-treatment CBCT scans were used to determine the intrafraction motion. RESULTS: We analyzed 20 pre- and 17 post-treatment CBCT scans in 20 LCF patients treated with SRS. The mean translational pretreatment setup error +/- standard deviation in the left right, anteroposterior, and craniocaudal directions was -0.19 +/- 0.32, 0.06 +/- 0.27, and -0.23 +/- 0.2 mm, with a maximum of -0.74, -0.53, and -0.68 mm, respectively. After an average time between the pre- and post-treatment CBCT scans of 82 minutes (range 27-170), the mean intrafraction error +/- standard deviation for the LCF was -0.03 +/- 0.05, -0.03 +/- 0.18, and -0.03 +/- 0.12 mm in the left-right, anteroposterior, and craniocaudual direction, respectively. CONCLUSIONS: Using CBCT on a prototype image guided GK Perfexion unit, we were able to measure the inter- and intrafraction positional changes for GK-SRS using the invasive frame. In the era of image guided radiation therapy, the use of CBCT image guidance for both frame- and non-frame-based immobilization systems could serve as a useful quality assurance tool. Our preliminary measurements can guide the application of achievable thresholds for inter- and intrafraction discrepancy when moving to a frameless approach. PMID- 27511858 TI - Time-Lapse Monitoring of DNA Damage Colocalized With Particle Tracks in Single Living Cells. AB - PURPOSE: Understanding the DNA damage and repair induced by hadron therapy (HT) beams is crucial for developing novel strategies to maximize the use of HT beams to treat cancer patients. However, spatiotemporal studies of DNA damage and repair for beam energies relevant to HT have been challenging. We report a technique that enables spatiotemporal measurement of radiation-induced damage in live cells and colocalization of this damage with charged particle tracks over a broad range of clinically relevant beam energies. The technique uses novel fluorescence nuclear track detectors with fluorescence confocal laser scanning microscopy in the beam line to visualize particle track traversals within the subcellular compartments of live cells within seconds after injury. METHODS AND MATERIALS: We designed and built a portable fluorescence confocal laser scanning microscope for use in the beam path, coated fluorescence nuclear track detectors with fluorescent-tagged live cells (HT1080 expressing enhanced green fluorescent protein tagged to XRCC1, a single-strand break repair protein), placed the entire assembly into a proton therapy beam line, and irradiated the cells with a fluence of ~1 * 10(6) protons/cm(2). RESULTS: We successfully obtained confocal images of proton tracks and foci of DNA single-strand breaks immediately after irradiation. CONCLUSIONS: This technique represents an innovative method for analyzing biological responses in any HT beam line at energies and dose rates relevant to therapy. It allows precise determination of the number of tracks traversing a subcellular compartment and monitoring the cellular damage therein, and has the potential to measure the linear energy transfer of each track from therapeutic beams. PMID- 27511859 TI - In Regard to Kjems et al. PMID- 27511856 TI - Image Guided Planning for Prostate Carcinomas With Incorporation of Anti-3 [18F]FACBC (Fluciclovine) Positron Emission Tomography: Workflow and Initial Findings From a Randomized Trial. AB - PURPOSE: (18)F-Fluciclovine (anti-1-amino-3-[(18)F]fluorocyclobutane-1-carboxylic acid) is a novel positron emission tomography (PET)/computed tomography (CT) radiotracer that has demonstrated utility for detection of prostate cancer. Our goal is to report the initial results from a randomized controlled trial of the integration of (18)F-fluciclovine PET-CT into treatment planning for defining prostate bed and lymph node target volumes. METHODS AND MATERIALS: We report our initial findings from a cohort of 41 patients, of the first enrolled on a randomized controlled trial, who were randomized to the (18)F-fluciclovine arm. All patients underwent (18)F-fluciclovine PET-CT for the detection of metabolic abnormalities and high-resolution CT for treatment planning. The 2 datasets were registered first by use of a rigid registration. If soft tissue displacement was observable, the rigid registration was improved with a deformable registration. Each (18)F-fluciclovine abnormality was segmented as a percentage of the maximum standard uptake value (SUV) within a small region of interest around the lesion. The percentage best describing the SUV falloff was integrated in planning by expanding standard target volumes with the PET abnormality. RESULTS: In 21 of 55 abnormalities, a deformable registration was needed to map the (18)F-fluciclovine activity into the simulation CT. The most selected percentage was 50% of maximum SUV, although values ranging from 15% to 70% were used for specific patients, illustrating the need for a per-patient selection of a threshold SUV value. The inclusion of (18)F-fluciclovine changed the planning volumes for 46 abnormalities (83%) of the total 55, with 28 (51%) located in the lymph nodes, 11 (20%) in the prostate bed, 10 (18%) in the prostate, and 6 (11%) in the seminal vesicles. Only 9 PET abnormalities were fully contained in the standard target volumes based on the CT-based segmentations and did not necessitate expansion. CONCLUSIONS: The use of (18)F-fluciclovine in postprostatectomy radiation therapy planning was feasible and led to augmentation of the target volumes in the majority (30 of 41) of the patients studied. PMID- 27511860 TI - In Reply to Gunn and Garden. PMID- 27511861 TI - In Regard to Habl et al. PMID- 27511862 TI - Erratum. PMID- 27511864 TI - Avoiding unconscious bias. PMID- 27511863 TI - Serum levels of enclomiphene and zuclomiphene in men with hypogonadism on long term clomiphene citrate treatment. AB - OBJECTIVES: To determine the relative concentrations of enclomiphene (ENC) and zuclomiphene (ZUC) isomers in men with hypogonadism on long-term clomiphene citrate (CC) therapy, and to determine whether patient age, body mass index (BMI) or duration of therapy were predictive of relative concentrations of ENC and ZUC. PATIENTS AND METHODS: Men already receiving CC 25 mg daily therapy for secondary hypogonadism for a minimum of 6 weeks were recruited to have their ENC and ZUC levels assessed. Total testosterone, free testosterone, oestradiol, follicle stimulating hormone (FSH), and luteinizing hormone (LH) before initiation of and while on CC therapy were recorded for all patients. Patient demographics including age, BMI and medical comorbidites were recorded. Serum samples were obtained at the time of enrolment to determine ENC and ZUC concentrations. RESULTS: A total of 15 men were enrolled in the period from June 2015 to August 2015. The median (range) patient age was 36 (22-70) years, BMI 32.0 (21.1-40.3) kg/m2 and duration of treatment 25.9 (1.7-86.6) months. Baseline median total testosterone, oestradiol and LH levels were 205.0 ng/dL, 17.0 pg/mL and 4.0 mlU/mL, respectively. The post-treatment median total testosterone, oestradiol and LH level increased to 488.0 ng/dL, 34.0 pg/mL and 6.1 mIU/mL, respectively (all P<0.001). The median ENC and ZUC concentrations were 2.2 and 44.0 ng/mL, respectively. After at least 6 weeks of CC therapy, the median ZUC: ENC serum concentration ratio was 20:1. On linear regression analysis. patient age, BMI, duration of treatment and serum testosterone levels were not predictive of ENC or ZUC concentrations. CONCLUSIONS: Long-term CC therapy resulted in a significant alteration of ENC and ZUC concentrations, with ZUC as the predominant isomer. Given the vastly different biochemical and toxicological properties of ENC and ZUC, this study supports the need for the development of a pure selective oestrogen receptor antagonist for the treatment of men with hypogonadism. PMID- 27511865 TI - What's in a Self-report? A Comparison of Pregnant Women with Self-reported and Hospital Diagnosed Eating Disorder. AB - The aim of this study was to examine how similar pregnant women with self reported lifetime eating disorder (ED) were to pregnant women with a hospital diagnosis of ED. A total of 83 731 pregnant women enrolled in the Danish National Birth Cohort reported on ED, and by linkage to the Danish health registers, hospital diagnoses of ED were obtained. Characteristics of women with self reported ED, hospital diagnosed ED and without ED were compared using chi-square tests, t-test and logistic regression models with robust standard errors. In total, 4.8% women reported ED, and 0.5% had a hospital diagnosis of ED recorded in the health registers. Women with self-reported ED were comparable with women with hospital diagnosed ED on most reproductive and health characteristics, while they differed from women without ED concerning all characteristics studied. Our findings highlight that women with self-reported ED have impaired function and adverse health outcomes, consistent with diagnosable ED. Copyright (c) 2016 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 27511866 TI - New strategy for improving the diagnostic sensitivity of repetitive nerve stimulation in myasthenia gravis. AB - INTRODUCTION: The diagnostic sensitivity of repetitive nerve stimulation (RNS) in patients with myasthenia gravis (MG) varies as a function of the number of muscles or the choice of muscles studied. METHODS: By exploring 12 muscles bilaterally, we evaluated the global sensitivity of RNS at rest, the sensitivity in different clinical forms, and the sensitivity of different combinations of muscles studied. RESULTS: The global sensitivity of RNS was 82%, and specificity was 100%. The sensitivity in the MG subgroups was as follows: ocular (O) = 67%; oculobulbar (OB) = 86%; and generalized (G) = 89%. The most sensitive muscles were the anconeus in group O, orbicularis oculi (OO) or nasalis in group OB, and the trapezius in group G. Maximum sensitivity was obtained by exploring OO, trapezius, and anconeus bilaterally. CONCLUSIONS: We recommend bilateral exploration of at least 3 muscles, a facial muscle, trapezius, and anconeus. Muscle Nerve 55: 532-538, 2017. PMID- 27511867 TI - Preparation and evaluation of 3 m open tubular capillary columns with a zwitterionic polymeric porous layer for liquid chromatography. AB - A 3 m zwitterionic polymeric porous layer open tubular column (3 m * 25 MUm id * 375 MUm od) with a polymeric porous layer thickness of 4 MUm was fabricated by the copolymerization of [2-(methacryloyloxy)ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide and N,N'-methylenebis(acrylamide). The effects of the diameter of the capillary, reaction temperature, and polymerization time on the preparation of the open tubular column were investigated. Characterized by scanning electron microscopy, the zwitterionic layer was observed to be rough and throughout the fused-silica capillary homogenously, which increased the phase ratio. The separation of neutral, basic, and acidic compounds demonstrates the strong hydrophilicity of the poly[2-(methacryloyloxy)ethyl] dimethyl-(3 sulfopropyl) ammonium hydroxide coating. In addition, the poly[2 (methacryloyloxy) ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide porous layer open tubular column was applied for the analysis of flavonoids from the rootstalk of licorice, revealing the potential in separating complex samples. The relative standard deviation of retention time for run-to-run (n = 5), day-to-day (n = 3), and column-to-column (n = 3) of toluene, N,N-dimethylformamide, formamide, and thiourea were below 1.2%, exhibiting good repeatability. PMID- 27511868 TI - Palladium-Catalyzed Defluorinative Coupling of 1-Aryl-2,2-Difluoroalkenes and Boronic Acids: Stereoselective Synthesis of Monofluorostilbenes. AB - The palladium-catalyzed defluorinative coupling of 1-aryl-2,2-difluoroalkenes with boronic acids is described. Broad functional-group tolerance arises from a redox-neutral process by a palladium(II) active species which is proposed to undergo a beta-fluoride elimination to afford the products. The monofluorostilbene products were formed with excellent diastereoselectivity (>=50:1) in all cases, and it is critical, as traditional chromatographic techniques often fail to separate monofluoroalkene isomers. As a demonstration of this method's unique combination of reactivity and functional-group tolerance, a Gleevec(r) analogue, using a monofluorostilbene as an amide isostere, was synthesized. PMID- 27511869 TI - Improved methods for evaluating pre-clinical and histological effects of subcutaneous fat reduction using high-intensity focused ultrasound in a porcine model. AB - BACKGROUND: Non-invasive body sculpting procedures are becoming increasingly popular. High-intensity focused ultrasound (HIFU) treatment is a non-surgical fat reduction procedure that permanently destroys unwanted abdominal fat. Despite its increasing popularity, evaluation methods for the procedure have not yet been fully developed. AIMS: The objective of this study was to develop evaluation methods for HIFU for non-surgical, permanent fat reduction in the anterior abdomen using a porcine model. METHODS: The abdomens of female pigs (Sus scrofa, n = 7) were treated with a HIFU device (SCIZERTM , Classys Inc, Seoul, Korea). We examined treatment effects using photography, ultrasound, gross and microscopic pathology, and serum lipid and liver function level analysis, carbon tracer test, and histological examination in order to determine the mechanism of action, efficacy, and safety of the procedure. RESULTS: HIFU treatment effectively reduced abdominal fat in a porcine model; it accurately treated the target subcutaneous fat layer and the subcutaneous fat was reduced effectively via ultrasonic measurement after HIFU treatment. On histological staining (H&E, toluidine blue, oil red O and immunohistochemistry), we found that subcutaneous fat reduction occurred effectively via accurate treatment of the targeted subcutaneous fat layer. On hematological assay, there were changes within normal range, and values remained stable after 48 h. Via carbon tracer test, the migration of activated macrophages was identified within the axillary lymph node (LN). PPAR-delta, a protein defined by immunohistochemistry staining, was overexpressed in the early stage on days 1 and 7, but a gradual decreasing pattern was confirmed. CONCLUSION: We successfully used a HIFU device for body contouring and fat reduction in a pre-clinical study. These results provide that the essential clues toward the effective evaluation, guiding selection of the appropriate diagnostic investigations. PMID- 27511870 TI - Near infrared photoimmunotherapy of B-cell lymphoma. AB - Near infrared photoimmunotherapy (NIR-PIT) is a new, highly-selective cancer theranostics that employs an antibody-photo absorber conjugate (APC). NIR-PIT has successfully treated preclinical tumor models with APCs and is now in the first in-human phase 1 clinical trial for head and neck cancer patients against EGFR. CD20 is highly expressed in many B-cell lymphomas and is emerging as a molecular target for this disease. Here, we describe the use of the anti-CD20 monoclonal antibody (mAb), rituximab-IR700 APC for NIR-PIT of B-cell lymphoma in two CD20 expressing lymphoma mouse models. CD20 expressing B-cell lymphoma cell lines (Daudi and Ramos) were used in this study. Rituximab-IR700, rituximab conjugated with IRDye700DX, showed specific binding, and cell-specific killing only after exposure of NIR light to both cells in vitro. To evaluate effects of NIR-PIT in vivo, tumor-bearing mice were separated into 4 groups: (1) control; (2) APC i.v. only; (3) NIR light exposure only; (4) APC and NIR light (NIR-PIT). These were performed every week for up to 3 weeks. Rituximab-IR700 showed high tumor accumulation and high target-to-background ratio in vivo. Tumor growth was significantly inhibited by NIR-PIT in comparison with the other groups (p < 0.001 for both tumors), and survival was significantly prolonged in both tumors (p < 0.001 for Daudi tumors and p < 0.0001 for Ramos tumors vs other groups). More than half of tumors were cured with this single regimen of NIR-PIT. In conclusion, anti-CD20 rituximab-IR700 works as a highly effective APC for NIR-PIT against B-cell lymphoma. PMID- 27511872 TI - Self-regulatory speech during planning and problem-solving in children with SLI and their typically developing peers. AB - BACKGROUND: Past research with children with specific language impairment (SLI) has shown them to have poorer planning and problem-solving ability, and delayed self-regulatory speech (SRS) relative to their typically developing (TD) peers. However, the studies are few in number and are restricted in terms of the number and age range of participants, which limits our understanding of the nature and extent of any delays. Moreover, no study has examined the performance of a significant subset of children with SLI, those who have hyperactive and inattentive behaviours. AIMS: This cross-sectional study aimed to compare the performance of young children with SLI (aged 4-7 years) with that of their TD peers on a planning and problem-solving task and to examine the use of SRS while performing the task. Within each language group, the performance of children with and without hyperactive and inattentive behaviours was further examined. METHODS & PROCEDURES: Children with SLI (n = 91) and TD children (n = 81), with and without hyperactive and inattentive behaviours across the three earliest school years (Kindergarten, Preprimary and Year 1) were video-taped while they completed the Tower of London (TOL), a planning and problem-solving task. Their recorded speech was coded and analysed to look at differences in SRS and its relation to TOL performance across the groups. MAIN CONTRIBUTION: Children with SLI scored lower on the TOL than TD children. Additionally, children with hyperactive and inattentive behaviours performed worse than those without hyperactive and inattentive behaviours, but only in the SLI group. This suggests that children with SLI with hyperactive and inattentive behaviours experience a double deficit. Children with SLI produced less inaudible muttering than TD children, and showed no reduction in social speech across the first three years of school. Finally, for children with SLI, a higher percentage performed better on the TOL when they used SRS than when they did not. CONCLUSIONS & IMPLICATIONS: The results point towards a significant delay in the development and internalization of SRS in the SLI group, which should be taken into account when considering the planning and problem-solving of young children with SLI. PMID- 27511871 TI - A ribonucleotide reductase inhibitor with deoxyribonucleoside-reversible cytotoxicity. AB - Ribonucleotide Reductase (RNR) is the sole enzyme that catalyzes the reduction of ribonucleotides into deoxyribonucleotides. Even though RNR is a recognized target for antiproliferative molecules, and the main target of the approved drug hydroxyurea, few new leads targeted to this enzyme have been developed. We have evaluated a recently identified set of RNR inhibitors with respect to inhibition of the human enzyme and cellular toxicity. One compound, NSC73735, is particularly interesting; it is specific for leukemia cells and is the first identified compound that hinders oligomerization of the mammalian large RNR subunit. Similar to hydroxyurea, it caused a disruption of the cell cycle distribution of cultured HL-60 cells. In contrast to hydroxyurea, the disruption was reversible, indicating higher specificity. NSC73735 thus defines a potential lead candidate for RNR-targeted anticancer drugs, as well as a chemical probe with better selectivity for RNR inhibition than hydroxyurea. PMID- 27511874 TI - Natural exposure to domoic acid causes behavioral perseveration in Wild Sea lions: Neural underpinnings and diagnostic application. AB - Domoic acid is a naturally occurring algal toxin that causes neurological symptoms and mortality in exposed marine life. California sea lions (Zalophus californianus) are the most visible victims, and suffer epilepsy and progressive hippocampal atrophy. Despite its reliable neurological effects, little is known about how exposure to domoic acid alters behavior, which is critical for understanding the impact of toxic exposure on long-term survival in sea lions and other exposed animals, including humans. Better understanding of the behavioral effects may also inform veterinary diagnosis and treatment. Anecdotally, exposed sea lions have been reported to show enhanced perseverative behavior. To assess the neurobehavioral effects of domoic acid, we compared veterinary diagnoses, measures of hippocampal volume from in vivo MRI, and behavioral measures of habituation and dishabituation in 27 wild sea lions undergoing rehabilitation. The sample was divided post-hoc between subjects with clear veterinary diagnoses of chronic domoic acid toxicosis and those with no evidence of the disease. In the behavioral task, subjects were exposed repeatedly to sounds from two source locations, and, following a short delay, exposed again. Veterinary diagnosis of domoic acid toxicosis was associated with extent of hippocampal damage, predicted delayed habituation in phase 1, and enhanced dishabituation in phase 2. Receiver operating characteristic analysis indicated that delayed habituation in phase 1 was diagnostically predictive. Enhanced dishabituation in phase 2 was correlated with reduced right ventral hippocampal volume. Together, delayed habituation and enhanced dishabituation following domoic acid exposure indicate a clinically relevant and potentially maladaptive behavioral pattern of perseveration. PMID- 27511873 TI - A point mutation in AgrC determines cytotoxic or colonizing properties associated with phenotypic variants of ST22 MRSA strains. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of skin and soft tissue infections. One of the highly successful and rapidly disseminating clones is MRSA ST22 commonly associated with skin tropism. Here we show that a naturally occurring single amino acid substitution (tyrosine to cysteine) at position 223 of AgrC determines starkly different ST22 S. aureus virulence phenotypes, e.g. cytotoxic or colonizing, as evident in both in vitro and in vivo skin infections. Y223C amino acid substitution destabilizes AgrC-AgrA interaction leading to a colonizing phenotype characterized by upregulation of bacterial surface proteins. The colonizing phenotype strains cause less severe skin tissue damage, show decreased susceptibility towards the antimicrobial LL-37 and induce autophagy. In contrast, cytotoxic strains with tyrosine at position 223 of AgrC cause infections characterized by inflammasome activation and severe skin tissue pathology. Taken together, the study demonstrates how a single amino acid substitution in the histidine kinase receptor AgrC of ST22 strains determines virulence properties and infection outcome. PMID- 27511875 TI - Surface roughness and adaptation of different materials to secure implant attachment housings. AB - STATEMENT OF PROBLEM: Various materials are available to secure implant attachment housings in overdentures. Surface roughness and the adaptation of these materials to the denture base and the housings may increase the microcracks and bacterial adhesion at the interfaces in the long term. The surface characteristics of the interface between the denture base orientation material and the attachment housing have not been extensively studied. PURPOSE: The purpose of this in vitro study was to evaluate the surface roughness and the adaptation of 5 different housing orientation materials to the housings and the denture base. MATERIAL AND METHODS: Fifty-five poly(methyl methacrylate) (PMMA) specimens (15 mm in diameter and 4 mm in height) were prepared with a clearance inside to allow the insertion of overdenture housings. Five different materials were used for housing orientation (Quick Up, Ufi Gel Hard, Tokuyama Rebase II Fast, Meliodent, and Paladent). The specimens were thermocycled 5000 times between 5 degrees C and 55 degrees C. The surface roughness (Ra values) of the specimens was measured with a noncontact profilometer. Scanning electron images were made in order to inspect the PMMA-orientation material-housing interfaces. The Kruskal-Wallis test was used to investigate the differences between the surface roughness values of the orientation materials, and the Iman-Conover test was used for pairwise comparisons (alpha=.05). RESULTS: The surface roughness values significantly differed between Quick up and Ufi Gel orientation materials only, and Quick up had smaller surface roughness values than Ufi Gel (P=.009). Microcracks were observed among the groups only at the junction of the orientation material and the housing after thermocycling. CONCLUSIONS: Ufi Gel Hard showed the roughest surfaces around the overdenture attachment housings. The adaptation between the orientation material and the housing may deteriorate, and increased surface roughness and microcrack formation may be seen around the housings. PMID- 27511876 TI - Complete mouth rehabilitation and gastroesophageal reflux disease: Conventional and contemporary treatment approaches. AB - This report describes the diagnosis and prosthodontic management of 2 patients with a history of chronic gastroesophageal reflux disease and worn dentition. Different treatment approaches were used for oral rehabilitation. Use of conventional and contemporary restorative materials resulted in functional and esthetic prosthodontic rehabilitation with a favorable prognosis. PMID- 27511877 TI - Masticatory efficiency and muscular activity in removable partial dental prostheses with different cusp angles. AB - STATEMENT OF PROBLEM: The loss of posterior teeth has a negative effect on the masticatory efficiency and activity of mastication muscles. How these muscles are affected by partial removable dental prostheses (PRDPs) with different cusp angles is unknown. PURPOSE: The purpose of this clinical study was to evaluate the influence of different cusp angles, with anatomic (33 degrees), semianatomic (20 degrees), and nonanatomic teeth (0 degree), on the masticatory efficiency and muscular activity of participants receiving mandibular bilateral distal PRDPs. MATERIAL AND METHODS: Fifteen participants consented to the evaluation of masticatory efficiency and electromyographic (EMG) activity with a PRDP with a unified bilateral design. The cusp angles of the artificial teeth were randomly changed from anatomic (33 degrees), semianatomic (20 degrees), and nonanatomic teeth (0 degree). Masticatory efficiency was evaluated by recording 5 parameters, including number of strokes, and time of mastication while the EMG activities of the masseter and temporalis muscles, measured using surface electromyography. The data were analyzed with 1-way ANOVA and the Tukey multiple post hoc test with statistical software (alpha=.05). RESULTS: With regard to masticatory efficiency, PRDPs with anatomic and semianatomic teeth exhibited higher masticatory efficiency than those with nonanatomic teeth, whereas no significant differences were found between PRDPs with anatomic and semianatomic teeth. With respect to EMG activity, the least EMG activity was observed in PRDPs with anatomic teeth, whereas the highest activity was observed with nonanatomic teeth. No significant differences were found between the effect of PRDPs with anatomic and semianatomic teeth on masseter activity. CONCLUSIONS: Changing the cusp angle from 33 to 20 degrees in PRDPs did not influence the masticatory efficiency or the EMG activity of the masseters. However, it did lead to increased EMG activities of the temporalis muscle. PRDPs with nonanatomic teeth were associated with a significant decrease in masticatory efficiency accompanied by a significant increase in EMG activity. PMID- 27511878 TI - In vitro effects of acid challenge on incisal/occlusal cupping/cratering. AB - STATEMENT OF PROBLEM: The cause of occlusal/incisal cupping/cratering (depressed dentin surrounded by elevated rims of enamel) has been postulated to be primarily the effect of acid on exposed dentin. It is hypothesized that abrasion, bruxism, attrition, and stress-corrosion may play a secondary role in lesion formation. The primary cause and sequence of occlusal/incisal cupping/cratering remain scientifically controversial. PURPOSE: The purpose of this in vitro study was to determine the effects of acid on human enamel, mantle dentin, and peritubular dentin in the creation of incisal/occlusal cupping/cratering. This study was designed to visually illustrate the role of acid in the formation of cupping/cratering. MATERIAL AND METHODS: A soft compact toothbrush was tested using both high relative dentin abrasivity (RDA)- and low-RDA dentifrices and water only (nonabrasive) on extracted human teeth. Seventeen specimens of 4 teeth each (68 teeth) were subjected to horizontal brushing with a 1:1 dentifrice-to water slurry or water only. Twelve of these 17 specimens, a total of 48 teeth, were subjected to acid challenge. Each of these 12 specimens were brushed for 500 strokes after each acid challenge for a total of 150000 strokes and 300 acid immersions. Half the specimens were acid challenged for 5 minutes and the other half for 10 minutes between brushings. RESULTS: No visible loss of tooth structure was noted in the control specimens brushed in water only. The control specimens brushed in a 1:1 slurry of toothpaste/water demonstrated incisal/occlusal cupping/cratering. The acid-challenged specimens brushed in water only demonstrated enamel and peritubular dentin loss with elevated rims and/or plateaus of mantle dentin, the opposite of occlusal/incisal cupping/cratering. All specimens brushed with the higher abrasive dentifrice demonstrated visible wear of enamel, mantle, and peritubular dentin, culminating in occlusal/incisal cupping/cratering. Surprisingly, those acid-challenged specimens brushed with the lower abrasive toothpaste demonstrated visible wear of the enamel and peritubular dentin, resulting in elevated rims and/or plateaus of mantle dentin. CONCLUSIONS: Acid affects both the enamel and the mineralized component of dentin. This study demonstrated that incisal/occlusal cupping/cratering occurring in worn dentition can be caused by the use of dentifrice alone. Acid challenge affects the inorganic components of tooth structure but not the organic components and so does not cause the dentinal cupping/cratering of the incisal/occlusal surfaces of the human dentition. PMID- 27511879 TI - Numeric simulation of occlusal interferences in molars restored with ultrathin occlusal veneers. AB - STATEMENT OF PROBLEM: Selecting material for a minimally invasive occlusal veneer reconstruction concept requires an understanding of how stresses are distributed during functional and parafunctional forces. PURPOSE: The purpose of this in vitro study was to investigate stress distribution in a maxillary molar restored with ultrathin occlusal veneers and subjected by an antagonistic mandibular molar to clenching and working and nonworking movements. MATERIAL AND METHODS: A maxillary first molar was modeled from microcomputed tomography (micro-CT) data, using medical image processing software, stereolithography editing/optimizing software, and finite element software. Simulated ultrathin occlusal veneer materials were used. The mandibular molar antagonist was a solid nondeformable geometric entity. Loads simulated clenching, working, and nonworking movements with loading of 500 N. The values of the maximum principal stress were recorded. RESULTS: In the clenching load situation, maximum tensile stresses were located at the occlusal veneer (52 MPa for composite resin versus 47 MPa for ceramic). In the working movement, significant additional tensile stresses were found on the palatal root (87 MPa for composite resin and 85 MPa for ceramic). In the nonworking movement, tensile stress on the ultrathin occlusal veneer increased to 118 MPa for composite resin and 143 MPa for ceramic veneers. Tensile stress peaks shifted to the mesiobuccal root (75 MPa for composite resin and 74 MPa for ceramic). CONCLUSIONS: The topography of stresses generated by the various occlusal interferences were clearly identified. Significant tensile stress concentrations were found within the restoration's occlusal topography and root, with the nonworking interference being the most harmful and also the most revealing of the difference between the composite resin and ceramic ultrathin occlusal veneers. PMID- 27511880 TI - Effects of Obesity and Hypertension on Pulse Wave Velocity in Children. AB - Pulse wave velocity (PWV) is a biomarker of arterial stiffness. Findings from prior studies are conflicting regarding the impact of obesity on PWV in children. The authors measured carotid-femoral PWV in 159 children aged 4 to 18 years, of whom 95 were healthy, 25 were obese, 15 had hypertension (HTN), and 24 were both obese and hypertensive. Mean PWV increased with age but did not differ by race or sex. In adjusted analyses in children 10 years and older (n=102), PWV was significantly higher in children with hypertension (PWV+/-standard deviation, 4.9+/-0.7 m/s), obesity (5.0+/-0.9 m/s), and combined obesity-hypertension (5.2+/ 0.6 m/s) vs healthy children (4.3+/-0.7 m/s) (each group, P<.001 vs control). In our study, obesity and HTN both significantly and independently increased PWV, while African American children did not have a higher PWV than Caucasian children. PMID- 27511881 TI - 3D Cross-Point Plasmonic Nanoarchitectures Containing Dense and Regular Hot Spots for Surface-Enhanced Raman Spectroscopy Analysis. AB - 3D stacking of plasmonic nanostructures is achieved using a solvent-assisted nanotransfer printing (S-nTP) technique to provide extremely dense and regular hot spot arrays for highly sensitive surface-enhanced Raman spectroscopy (SERS) analysis. Moreover, hybrid plasmonic nanostructures obtained by printing the nanowires on a continuous metal film or graphene surface show significantly intensified SERS signals due to vertical plasmonic coupling. PMID- 27511882 TI - Comparison of microbubble presence in the right heart during mechanochemical and radiofrequency ablation for varicose veins. AB - Objective Mechanochemical ablation is a novel technique for ablation of varicose veins utilising a rotating catheter and liquid sclerosant. Mechanochemical ablation and radiofrequency ablation have no reported neurological side-effect but the rotating mechanism of mechanochemical ablation may produce microbubbles. Air emboli have been implicated as a cause of cerebrovascular events during ultrasound-guided foam sclerotherapy and microbubbles in the heart during ultrasound-guided foam sclerotherapy have been demonstrated. This study investigated the presence of microbubbles in the right heart during varicose vein ablation by mechanochemical abaltion and radiofrequency abaltion. Methods Patients undergoing great saphenous vein ablation by mechanochemical abaltion or radiofrequency ablation were recruited. During the ablative procedure, the presence of microbubbles was assessed using transthoracic echocardiogram. Offline blinded image quantification was performed using International Consensus Criteria grading guidelines. Results From 32 recruited patients, 28 data sets were analysed. Eleven underwent mechanochemical abaltion and 17 underwent radiofrequency abaltion. There were no neurological complications. In total, 39% (11/28) of patients had grade 1 or 2 microbubbles detected. Thirty-six percent (4/11) of mechanochemical abaltion patients and 29% (5/17) of radiofrequency ablation patients had microbubbles with no significant difference between the groups ( p=0.8065). Conclusion A comparable prevalence of microbubbles between mechanochemical abaltion and radiofrequency ablation both of which are lower than that previously reported for ultrasound-guided foam sclerotherapy suggests that mechanochemical abaltion may not confer the same risk of neurological events as ultrasound-guided foam sclerotherapy for treatment of varicose veins. PMID- 27511883 TI - Parkes Weber syndrome-Diagnostic and management paradigms: A systematic review. AB - Objectives Parkes Weber syndrome is a congenital vascular malformation which consists of capillary malformation, venous malformation, lymphatic malformation, and arteriovenous malformation. Although Parkes Weber syndrome is a clinically distinctive entity with serious complications, it is still frequently misdiagnosed as Klippel-Trenaunay syndrome that consists of the triad capillary malformation, venous malformation, and lymphatic malformation. Methods We performed a systematic review investigating clinical, diagnostic, and treatment modalities of Parkes Weber syndrome (PubMed/MEDLINE, Embase, and Cochrane databases). Thirty-six publications (48 patients) fulfilled the eligibility criteria. Results The median age of patients was 23 years (IQR, 8-32), and 24 (50.0%) were males. Lower extremity was affected in 42 (87.5%) and upper extremity in 6 (12.5%) patients; 15 (31.3%) patients developed high-output heart failure; 12 (25.0%) patients had chronic venous ulcerations, whereas 4 (8.3%) manifested distal arterial ischemia. The spinal arteriovenous malformations were reported in six (12.5%) patients and coexistence of aneurysmatic disease in five (10.4%) patients. The most frequently utilized invasive treatments were embotherapy followed by amputation and surgical arteriovenous malformation resection, and occasionally stent-graft implantation. All modalities showed clinical improvement. However, long follow-up and outcome remained unclear. Conclusion A diagnosis of Parkes Weber syndrome should be made on the presence of capillary malformation, venous malformation, lymphatic malformation, and arteriovenous malformation (as main defect) in overgrowth extremity. Arteriovenous malformation presents the criterion for distinguishing Parkes Weber syndrome from Klippel-Trenaunay syndrome, which is substantial for treatment strategy. The primary management goal should be patient's quality of life improvement and complication reduction. Embolization alone/combined with surgical resection targeting occlusion or removal of arteriovenous malformation "nidus" reliably leads to clinical improvement. PMID- 27511884 TI - CD14/TLR4 priming potentially recalibrates and exerts anti-tumor efficacy in tumor associated macrophages in a mouse model of pancreatic carcinoma. AB - Pancreatic cancer is the fourth major cause of cancer related deaths in the world and 5 year survival is below 5%. Among various tumor directed therapies, stimulation of Toll-like receptors (TLR) has shown promising effects in various tumor models. However, pancreatic cancer cells frequently express these receptors themselves and their stimulation (TLR 2 and/or 4 particularly) within tumor microenvironment is known to potentially enhance tumor cell proliferation and cancer progression. Consistent stimulation of tumor associated macrophages (TAMs), in particular with tumor derived TLR ligand within the tumor microenvironment promotes cancer related inflammation, which is sterile, non immunogenic and carcinogenic in nature. In view of this, recalibrating of TAM has the potential to induce immunogenic inflammation. Consistent with this, we provide experimental evidence for the first time in this study that priming of TAMs with TLR4 ligend (LPS) alone or in combination with IFN-gamma not only recalibrates pancreatic tumor cells induced M2 polarization, but also confers anti-tumor potential in TAMs. Most interestingly, reduced tumor growth in macrophage depleted animals suggests that macrophage directed approaches are important for the management of pancreatic tumors. PMID- 27511886 TI - Associations of the CYP3A5*3 and CYP3A4*1G polymorphisms with the pharmacokinetics of oral midazolam and the urinary 6beta-hydroxycortisol/cortisol ratio as markers of CYP3A activity in healthy male Chinese. AB - WHAT IS KNOWN AND OBJECTIVE: The oral plasma clearance of midazolam and the ratio of 6beta-hydroxycortisol (6beta-OHF) to cortisol (F) in urine are two potential markers for evaluating CYP3A activity in vivo. We assessed the influence of two common CYP3A polymorphisms on the pharmacokinetics of oral midazolam and urinary ratio of 6beta-OHF/F in healthy Chinese. METHODS: Single oral 15 mg doses of midazolam were given to 20 healthy male Chinese subjects who were genotyped for the CYP3A5*3 and CYP3A4*1G polymorphisms. The plasma concentrations of midazolam were determined by LC/MS/MS. Morning urine samples were collected after overnight fasting, and urine F and 6beta-OHF concentrations were measured using UPLC. RESULTS AND DISCUSSION: There were no significant correlations between the pharmacokinetic parameters of midazolam and urinary ratios of 6beta-OHF/F. The CYP3A polymorphisms examined had no significant associations with the urinary ratios of 6beta-OHF/F or the pharmacokinetics of midazolam. However, diplotype analysis suggested that CYP3A5 expressers with the CYP3A4*1/*1G genotype (n = 3) had significantly lower midazolam AUC0-infinity values (210.0 +/- 33.5 vs. 313.9 +/- 204.6 h?ng/mL, P = 0.044) and higher CL/F values (1.16 +/- 0.16 vs. 0.88 +/- 0.48 L/h/kg, P = 0.005) compared to subjects with the CYP3A4*1/*1 genotype (n = 4), which is consistent with some previous studies with tacrolimus. WHAT IS NEW AND CONCLUSION: There were no significant associations between midazolam pharmacokinetic parameters and urinary ratios of 6beta-OHF/F and the two CYP3A polymorphisms were not associated with the urinary ratios of 6beta-OHF/F or midazolam pharmacokinetic parameters. The possible association of CYP3A5*3 and CYP3A4*1G polymorphisms on CYP3A activity and their potential interaction require confirmation in a larger study. PMID- 27511887 TI - Clinical effects of internal fixation for ulnar styloid fractures associated with distal radius fractures: A matched case-control study. AB - BACKGROUND: Ulnar styloid fractures are often associated with distal radius fractures. However, controversy exists regarding whether to treat ulnar styloid fractures. This study aimed to evaluate clinical effects of internal fixation for ulnar styloid fractures after distal radius fractures were treated with the volar locking plate system. METHODS: We used prospectively collected data of distal radius fractures. 111 patients were enrolled in this study. A matched case control study design was used. We selected patients who underwent fixation for ulnar styloid fractures (case group). Three control patients for each patient of the case group were matched on the basis of age, sex, and fracture type of distal radius fractures from among patients who did not undergo fixation for ulnar styloid fractures (control group). The case group included 16 patients (7 men, 9 women; mean age: 52.6 years; classification of ulnar styloid fractures: center, 3; base, 11; and proximal, 2). The control group included 48 patients (15 men, 33 women; mean age: 61.1 years; classification of ulnar styloid fractures: center, 10; base, 31; and proximal, 7). For radiographic examination, the volar tilt angle, radial inclination angle, and ulnar variance length were measured, and the union of ulnar styloid fractures was judged. For clinical examination, the range of motions, grip strength, Hand20 score, and Numeric Rating Scale score were evaluated. RESULTS: There was little correction loss for each radiological parameter of fracture reduction, and these parameters were not significantly different between the groups. The bone-healing rate of ulnar styloid fractures was significantly higher in the case group than in the control group, but the clinical results were not significantly different. CONCLUSIONS: We revealed that there was no need to fix ulnar styloid fractures when distal radius fractures were treated via open reduction and internal fixation with a volar locking plate system. PMID- 27511888 TI - MnO2-induced synthesis of fluorescent polydopamine nanoparticles for reduced glutathione sensing in human whole blood. AB - Polydopamine (PDA) nanoparticles, as a kind of popular polymer material, have attracted a great deal of attention from various areas including materials science, biomedicine, energy, environmental science and so on owing to their striking physicochemical properties. Herein, we reported for the first time the synthesis of intrinsic fluorescent PDA nanoparticles using MnO2 as an oxidant. In the presence of MnO2, dopamine was quickly oxidized into its quinone derivative, and autopolymerized into fluorescent PDA nanoparticles. Using fluorescent PDA nanoparticles as a fluorescence signal indicator, we further established a cost effective sensor for rapid, sensitive and selective sensing of reduced glutathione (GSH) based on the redox reaction between MnO2 and GSH, and the key role of MnO2 in the formation of fluorescent PDA nanoparticles. GSH has the capability of reducing MnO2 into Mn(2+), which inhibited the formation of the fluorescent PDA nanoparticles. Thus, the concentration of GSH was directly related to the decreased fluorescence signal intensity of the PDA nanoparticles. The sensor showed good sensing performance for GSH detection with high sensitivity and desirable selectivity over other potential interfering species. Additionally, the sensor exhibited excellent practical applications for GSH detection in human whole blood samples, which presents potential applications in biological detection and clinical diagnosis. PMID- 27511885 TI - Regulation of energy homeostasis by the ubiquitin-independent REGgamma proteasome. AB - Maintenance of energy homeostasis is essential for cell survival. Here, we report that the ATP- and ubiquitin-independent REGgamma-proteasome system plays a role in maintaining energy homeostasis and cell survival during energy starvation via repressing rDNA transcription, a major intracellular energy-consuming process. Mechanistically, REGgamma-proteasome limits cellular rDNA transcription and energy consumption by targeting the rDNA transcription activator SirT7 for ubiquitin-independent degradation under normal conditions. Moreover, energy starvation induces an AMPK-directed SirT7 phosphorylation and subsequent REGgamma dependent SirT7 subcellular redistribution and degradation, thereby further reducing rDNA transcription to save energy to overcome cell death. Energy starvation is a promising strategy for cancer therapy. Our report also shows that REGgamma knockdown markedly improves the anti-tumour activity of energy metabolism inhibitors in mice. Our results underscore a control mechanism for an ubiquitin-independent process in maintaining energy homeostasis and cell viability under starvation conditions, suggesting that REGgamma-proteasome inhibition has a potential to provide tumour-starving benefits. PMID- 27511889 TI - Analysis of an astounding aggregation of Ranzania laevis (Molidae: Actinopterygii) in the tropical south-western Atlantic. AB - Unusual catches of more than 4200 kg of the slender sunfish Ranzania laevis are described from the south-western Atlantic, corresponding to the largest aggregation records for the species. These unexpected records were associated with unusually warm currents in the area. Males and females were physiologically able to spawn at the moment of capture, suggesting the occurrence of reproductive aggregation in this species. PMID- 27511890 TI - Recombinant porcine sequence factor VIII (rpFVIII) for acquired haemophilia A: practical clinical experience of its use in seven patients. AB - INTRODUCTION: A recombinant porcine factor VIII B-domain-deleted product (rpFVIII; OBIZUR, Baxalta Incorporated, Deerfield, IL 60015, USA) was recently approved for treatment of bleeding episodes in adults with acquired haemophilia A (AHA) in the United States. To date, no clinical experience outside the registration study has been reported. AIM: To describe early clinical experience using rpFVIII for AHA. METHODS: A retrospective chart review of seven patients with AHA treated with rpFVIII at four institutions from November 2014 to October 2015. RESULTS: The time to diagnosis of AHA ranged from 5 days to 6 weeks. Six major and one other bleed were treated with rpFVIII following unsatisfactory bypassing agent (BPA) therapy. Good haemostatic efficacy was seen in five of seven cases. rpFVIII loading doses of 100 (n = 6) or 200 U kg-1 (n = 1) increased FVIII activity from <1 to 9% at baseline to 109-650% within 0.25-7 h in six of seven cases. Subsequent median doses ranged from 30 to 100 U kg-1 for 3-26 days. No rpFVIII-related adverse events were reported. Three patients survived with inhibitor eradication, one with persistent inhibitor, two died with inhibitors present and one was discharged and later died from unrelated causes. CONCLUSIONS: rpFVIII showed good haemostatic efficacy with no recurrences in most cases, with consumption substantially less than in the registration study. Treatment decisions were based on FVIII activity levels and clinical assessment. The ability to titrate rpFVIII dose using FVIII activity was considered advantageous compared with BPA therapy. Notable delays in diagnosis were observed. PMID- 27511891 TI - Synovial fluid pretreatment with hyaluronidase facilitates isolation of CD44+ extracellular vesicles. AB - Extracellular vesicles (EVs) in synovial fluid (SF) are gaining increased recognition as important factors in joint homeostasis, joint regeneration, and as biomarkers of joint disease. A limited number of studies have investigated EVs in SF samples of patients with joint disease, but knowledge on the role of EVs in healthy joints is lacking. In addition, no standardized protocol is available for isolation of EVs from SF. Based on the high viscosity of SF caused by high concentrations of hyaluronic acid (HA) - a prominent extracellular matrix component - it was hypothesized that EV recovery could be optimized by pretreatment with hyaluronidase (HYase). Therefore, the efficiency of EV isolation from healthy equine SF samples was tested by performing sequential ultracentrifugation steps (10,000g, 100,000g and 200,000g) in the presence or absence of HYase. Quantitative EV analysis using high-resolution flow cytometry showed an efficient recovery of EVs after 100,000g ultracentrifugation, with an increased yield of CD44+ EVs when SF samples were pretreated with HYase. Morphological analysis of SF-derived EVs with cryo-transmission-electron microscopy did not indicate damage by high-speed ultracentrifugation and revealed that most EVs are spherical with a diameter of 20-200 nm. Further protein characterization by Western blotting revealed that healthy SF-derived EVs contain CD9, Annexin-1, and CD90/Thy1.1. Taken together, these data suggest that EV isolation protocols for body fluids that contain relatively high amounts of HA, such as SF, could benefit from treatment of the fluid with HYase prior to ultracentrifugation. This method facilitates recovery and detection of CD44+ EVs within the HA-rich extracellular matrix. Furthermore, based on the findings presented here, it is recommended to sediment SF-derived EVs with at least 100,000g for optimal EV recovery. PMID- 27511892 TI - Coexistence of acquired hemophilia A and epidermolysis bullosa acquisita: Two case reports and published work review. AB - Epidermolysis bullosa acquisita (EBA) is a rare chronic subepidermal bullous autoimmune disease. The occurrence of acquired hemophilia A (AHA) is low and so the coexistence of EBA and AHA is extremely rare. We herein described a case of EBA coexisting with AHA and a case of EBA coexisting with AHA and hepatitis B. These EBA may be related to the pathogenesis of AHA. In this study, we analyzed the clinical features in the two Chinese cases of EBA coexisting with AHA, and found esophageal hemorrhage and hematemesis were the main symptoms of both patients. Cyclosporin, prednisone and lamivudine effectively control EBA with AHA and hepatitis B. The dose of cyclosporin should be more than 4 mg/kg per day and the period of treatment should be longer than 5 months to reduce the risk of EBA co-occurring with AHA. PMID- 27511893 TI - Rearing environment differentially modulates cocaine self-administration after opioid pretreatment: A behavioral economic analysis. AB - BACKGROUND: Research has shown that previous experiences during development, especially if stressful, can alter an organism's response to opioids later in life. Given the previous literature on opioid modulation of cocaine self administration, the current study raised rats in either an enriched condition (EC) or isolated condition (IC) and employed behavioral economics to study the effects of naltrexone and morphine on cocaine self-administration. METHODS: EC and IC rats were trained to lever press for cocaine using a within-session demand procedure. This procedure measured cocaine consumption under changing cocaine price by decreasing the dose of cocaine earned throughout a session. Rats were able to self-administer cocaine on a FR1; every 10min the cocaine dose was systematically decreased (0.75-0.003mg/kg/infusion cocaine). After reaching stability on this procedure, rats were randomly pretreated with 0, 0.3, 1, or 3mg/kg naltrexone once every 3days, followed by random pretreatments of 0, 0.3, 1, or 3mg/kg morphine once every 3days. Economic demand functions were fit to each rat's cocaine consumption from each pretreatment, and appropriate mathematical parameters were extracted and analyzed. RESULTS: Naltrexone decreased the essential value of cocaine in IC rats only. However, morphine decreased the essential value of cocaine and the consumption of cocaine at zero price in both EC and IC rats. CONCLUSION: These results indicate that environmental experiences during development should be considered when determining the efficacy of opioid drugs, especially for the treatment of substance abuse. PMID- 27511894 TI - Alisporivir Has Limited Antiviral Effects Against Ebola Virus Strains Makona and Mayinga. AB - Antiviral therapeutics with existing clinical safety profiles would be highly desirable in an outbreak situation, such as the 2013-2016 emergence of Ebola virus (EBOV) in West Africa. Although, the World Health Organization declared the end of the outbreak early 2016, sporadic cases of EBOV infection have since been reported. Alisporivir is the most clinically advanced broad-spectrum antiviral that functions by targeting a host protein, cyclophilin A (CypA). A modest antiviral effect of alisporivir against contemporary (Makona) but not historical (Mayinga) EBOV strains was observed in tissue culture. However, this effect was not comparable to observations for an alisporivir-susceptible virus, the flavivirus tick-borne encephalitis virus. Thus, EBOV does not depend on (CypA) for replication, in contrast to many other viruses pathogenic to humans. PMID- 27511895 TI - FAM134B, the Selective Autophagy Receptor for Endoplasmic Reticulum Turnover, Inhibits Replication of Ebola Virus Strains Makona and Mayinga. AB - Selective autophagy of the endoplasmic reticulum (termed ER-phagy) is controlled by members of the FAM134 reticulon protein family. Here we used mouse embryonic fibroblasts from mice deficient in FAM134B to examine the role of the ER in replication of historic (Mayinga) or contemporary (Makona GCO7) strains of Ebola virus (EBOV). Loss of FAM134B resulted in 1-2 log10 higher production of infectious EBOV, which was associated with increased production of viral proteins GP and VP40 and greater accumulation of nucleocaspid lattices. In addition, only 10% of wild-type cells contained detectable nucleoprotein, whereas knockout of FAM134B resulted in 80% of cells positive for nucleoprotein. Together, these data suggest that FAM134B-dependent ER-phagy is an important limiting event in EBOV replication in mouse cells and may have implications for further development of antiviral therapeutics and murine models of infection. PMID- 27511896 TI - Quadrivalent Human Papillomavirus (HPV) Vaccine Induces HPV-Specific Antibodies in the Oral Cavity: Results From the Mid-Adult Male Vaccine Trial. AB - BACKGROUND: Human papillomavirus virus type 16 (HPV-16) and HPV-18 cause a large proportion of oropharyngeal cancers, which are increasing in incidence among males, and vaccine efficacy against oral HPV infections in men has not been previously evaluated. METHODS: Sera and saliva collected in mouthwash and Merocel sponges at day 1 and month 7 were obtained from 150 men aged 27-45 years from Tampa, Florida, and Cuernavaca, Mexico, who received Gardasil at day 1 and months 2 and 6. Specimens were tested for anti-HPV-16 and anti-HPV-18 immunoglobulin G (IgG) levels by an L1 virus-like particle-based enzyme-linked immunosorbent assay. RESULTS: All participants developed detectable serum anti-HPV-16 and anti HPV-18 antibodies, and most had detectable antibodies in both oral specimen types at month 7 (HPV-16 was detected in 93.2% of mouthwash specimens and 95.7% of sponge specimens; HPV-18 was detected in 72.1% and 65.5%, respectively). Antibody concentrations in saliva were approximately 3 logs lower than in serum. HPV-16- and HPV-18-specific antibody levels, normalized to total IgG levels, in both oral specimen types at month 7 were significantly correlated with serum levels (for HPV-16, rho was 0.90 for mouthwash specimens and 0.92 for sponge specimens; for HPV-18, rho was 0.89 and 0.86, respectively). CONCLUSIONS: This is the first study demonstrating that vaccination of males with Gardasil induces HPV antibody levels at the oral cavity that correlate with circulating levels. PMID- 27511897 TI - High-Resolution Molecular Typing of Trypanosoma cruzi in 2 Large Outbreaks of Acute Chagas Disease in Colombia. AB - Oral transmission of Trypanosoma cruzi has gained relevance because of its association with high morbidity and lethality rates. This transmission route is responsible for maintaining the infection of the parasite in sylvatic cycles, and human cases have been associated mainly with the consumption of food contaminated with triatomine feces or didelphid secretions. Several ecological changes allow the intrusion of sylvatic reservoirs and triatomines to the domestic environments with subsequent food contamination. Here, high-resolution molecular tools were used to detect and genotype T. cruzi across humans, reservoirs, and insect vectors in 2 acute outbreaks of presumptive oral transmission in eastern Colombia. PMID- 27511898 TI - Identification of Giardia lamblia Assemblage E in Humans Points to a New Anthropozoonotic Cycle. AB - Giardia lamblia is a pathogen transmitted by water and food that causes infection worldwide. Giardia genotypes are classified into 8 assemblages (A-H). Assemblages A and B are detected in humans, but they are potentially zoonotic because they infect other mammalian hosts. Giardia in samples from 44 children was genotyped. Conserved fragments of the genes encoding beta-giardin and glutamate dehydrogenase were sequenced and their alignment were carried out with sequences deposited in GenBank. As expected for Rio de Janeiro, the majority of samples were related to assemblage A. Surprisingly, assemblage E was detected in 15 samples. Detection of assemblage E in humans suggests a new zoonotic route of Giardia transmission. PMID- 27511900 TI - Unprecedented Catalytic Wet Oxidation of Glucose to Succinic Acid Induced by the Addition of n-Butylamine to a Ru(III) Catalyst. AB - A new pathway for the catalytic wet oxidation (CWO) of glucose is described. Employing a cationic Ru@MNP catalyst, succinic acid is obtained in unprecedently high yield (87.5 %) for a >99.9 % conversion of glucose, most probably through a free radical mechanism combined with catalytic didehydroxylation of vicinal diols and hydrogenation of the resulted unsaturated intermediate. PMID- 27511899 TI - miR-155 expression and correlation with clinical outcome in pediatric AML: A report from Children's Oncology Group. AB - BACKGROUND: Aberrant expression of microRNA-155 (miR-155) has been implicated in acute myeloid leukemia (AML) and associated with clinical outcome. PROCEDURE: We evaluated miR-155 expression in 198 children with normal karyotype AML (NK-AML) enrolled in Children's Oncology Group (COG) AML trial AAML0531 and correlated miR 155 expression levels with disease characteristics and clinical outcome. Patients were divided into quartiles (Q1-Q4) based on miR-155 expression level, and disease characteristics were then evaluated and correlated with miR-155 expression. RESULTS: MiR-155 expression varied over 4-log10-fold range relative to its expression in normal marrow with a median expression level of 0.825 (range 0.043-25.630) for the entire study cohort. Increasing miR-155 expression was highly associated with the presence of FLT3/ITD mutations (P < 0.001) and high risk disease (P < 0.001) and inversely associated with standard-risk (P = 0.008) and low-risk disease (P = 0.041). Patients with highest miR-155 expression had a complete remission (CR) rate of 46% compared with 82% in low expressers (P < 0.001) with a correspondingly lower event-free (EFS) and overall survival (OS) (P < 0.001 and P = 0.002, respectively). In a multivariate model that included molecular risk factors, high miR-155 expression remained a significant independent predictor of OS (P = 0.022) and EFS (0.019). CONCLUSIONS: High miR 155 expression is an adverse prognostic factor in pediatric NK-AML patients. Specifically, high miR-155 expression not only correlates with FLT3/ITD mutation status and high-risk disease but it is also an independent predictor of worse EFS and OS. PMID- 27511901 TI - The prevalence of Chlamydia trachomatis and Mycoplasma genitalium tubal infections and their effects on the expression of IL-6 and leukaemia inhibitory factor in Fallopian tubes with and without an ectopic pregnancy. AB - This was a prospective case-control study that measured the prevalence of Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Mycoplasma genitalium (MG) by an IVD CE multiplex PCR kit in fresh Fallopian tubes (FT) obtained from 96 ectopic pregnancies (EP) and 61 controls in the midluteal phase of the cycle. We later measured the expression profile of IL-6, leukaemia inhibitory factor (LIF) and their signalling molecules, in respect to the type and number of infections, by immunohistochemistry, ELISA and quantitative RT-PCR. The frequencies of CT, and MG mono- and co-infections were significantly higher in EP. IL-6, LIF, their receptors and intracellular mediators were significantly up regulated at the gene and protein levels in positive compared with negative FTs within each group (P < 0.05). EP tubal samples with co-infections showed the highest significant expression of the candidate cytokines by all techniques (P < 0.05). CT and MG are frequent in EP and up-regulate the tubal expression of IL-6, LIF and their signalling molecules. Both cytokines could be involved in the tubal immune response against bacterial infections, as well as the pathogenesis of EP. Further studies are needed to explore the roles of IL-6 family in infection induced tubal inflammation and EP. PMID- 27511902 TI - Predictive global trends in the incidence and mortality of pancreatic cancer based on geographic location, socio-economic status, and demographic shift. AB - BACKGROUND AND OBJECTIVES: Pancreatic Cancer (PC) is a lethal malignancy that accounts for about 4% of cancer-related deaths worldwide. The aim of this study is to describe the influence of geography (based on WHO regions), socio-economic development (based on Human Development Index [HDI]) and demographic shift on the temporal trends in global incidence and mortality of PC. METHODS: Data (2012 2030) relating to the incidence, mortality of PC and demographic shifts based on WHO regions and HDI areas were extracted from GLOBOCAN 2012. Linear regression was used to evaluate trends in total incidence and mortality. RESULTS: We noted a definite association between PC and higher socio-economic status. Advanced age (age >=65) contributed to the rising burden in all socio-economic regions of the world except in the Low Human Development (LHD) countries where the disease predominantly affected population <65 years of age. CONCLUSIONS: The global burden of PC is expected to rise significantly over the next few decades regardless of geographic location, socio-economic development, age and gender. Advance knowledge of this data can help formulate strategies to specifically target countries and populations that promote public health policy to tackle this lethal disease on the global stage. J. Surg. Oncol. 2016;114:736-742. (c) 2016 Wiley Periodicals, Inc. PMID- 27511903 TI - Golgi membrane-associated degradation pathway in yeast and mammals. AB - Autophagy is a cellular process that degrades subcellular constituents, and is conserved from yeast to mammals. Although autophagy is believed to be essential for living cells, cells lacking Atg5 or Atg7 are healthy, suggesting that a non canonical degradation pathway exists to compensate for the lack of autophagy. In this study, we show that the budding yeast Saccharomyces cerevisiae, which lacks Atg5, undergoes bulk protein degradation using Golgi-mediated structures to compensate for autophagy when treated with amphotericin B1, a polyene antifungal drug. We named this mechanism Golgi membrane-associated degradation (GOMED) pathway. This process is driven by the disruption of PI(4)P-dependent anterograde trafficking from the Golgi, and it also exists in Atg5-deficient mammalian cells. Biologically, when an Atg5-deficient beta-cell line and Atg7-deficient beta-cells were cultured in glucose-deprived medium, a disruption in the secretion of insulin granules from the Golgi occurred, and GOMED was induced to digest these (pro)insulin granules. In conclusion, GOMED is activated by the disruption of PI(4)P-dependent anterograde trafficking in autophagy-deficient yeast and mammalian cells. PMID- 27511904 TI - Decision Aids Can Support Cancer Clinical Trials Decisions: Results of a Randomized Trial. AB - BACKGROUND: Cancer patients often do not make informed decisions regarding clinical trial participation. This study evaluated whether a web-based decision aid (DA) could support trial decisions compared with our cancer center's website. METHODS: Adults diagnosed with cancer in the past 6 months who had not previously participated in a cancer clinical trial were eligible. Participants were randomized to view the DA or our cancer center's website (enhanced usual care [UC]). Controlling for whether participants had heard of cancer clinical trials and educational attainment, multivariable linear regression examined group on knowledge, self-efficacy for finding trial information, decisional conflict (values clarity and uncertainty), intent to participate, decision readiness, and trial perceptions. RESULTS: Two hundred patients (86%) consented between May 2014 and April 2015. One hundred were randomized to each group. Surveys were completed by 87 in the DA group and 90 in the UC group. DA group participants reported clearer values regarding trial participation than UC group participants reported (least squares [LS] mean = 15.8 vs. 32, p < .0001) and less uncertainty (LS mean = 24.3 vs. 36.4, p = .025). The DA group had higher objective knowledge than the UC group's (LS mean = 69.8 vs. 55.8, p < .0001). There were no differences between groups in intent to participate. CONCLUSIONS: Improvements on key decision outcomes including knowledge, self-efficacy, certainty about choice, and values clarity among participants who viewed the DA suggest web-based DAs can support informed decisions about trial participation among cancer patients facing this preference-sensitive choice. Although better informing patients before trial participation could improve retention, more work is needed to examine DA impact on enrollment and retention. IMPLICATIONS FOR PRACTICE: This paper describes evidence regarding a decision tool to support patients' decisions about trial participation. By improving knowledge, helping patients clarify preferences for participation, and facilitating conversations about trials, decision aids could lead to decisions about participation that better match patients' preferences, promoting patient-centered care and the ethical conduct of clinical research. PMID- 27511905 TI - Characterization and Management of Hedgehog Pathway Inhibitor-Related Adverse Events in Patients With Advanced Basal Cell Carcinoma. AB - : Abnormal activation of hedgehog pathway signaling is a key driver in the pathogenesis of basal cell carcinoma (BCC). Vismodegib, a first-in-class small molecule inhibitor of hedgehog pathway signaling, is approved by regulatory authorities for the treatment of adults who have metastatic BCC or locally advanced BCC that has recurred after surgery, or who are not candidates for surgery and who are not candidates for radiation. A second inhibitor, sonidegib, was also recently approved for the same patient group with locally advanced BCC. Adverse events (AEs) commonly observed in hedgehog pathway inhibitor (HPI) treated patients include muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and asthenia (fatigue). These AEs are thought to be mechanistically related to inhibition of the hedgehog pathway in normal tissue. Although the severity of the majority of AEs associated with HPIs is grade 1-2, the long-term nature of these AEs can lead to decreased quality of life, treatment interruption, and in some cases discontinuation, all of which might affect clinical outcome. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to HPIs in advanced BCC are described. These observations represent the first step toward the development of mechanism-based preventive and management strategies. Knowledge of these AEs will allow health care professionals to provide appropriate counseling and supportive care interventions, all of which will contribute to improved quality of life and optimal benefit from therapy. IMPLICATIONS FOR PRACTICE: The hedgehog pathway inhibitors (HPIs) vismodegib and sonidegib represent a therapeutic breakthrough for patients with advanced basal cell carcinoma. However, the nature of the low-grade adverse events (AEs) commonly observed in HPI-treated patients, including muscle spasms, ageusia/dysgeusia, alopecia, weight loss, and fatigue, can impact clinical outcomes as a result of decreased quality of life and treatment discontinuation. The incidence, clinical presentation, putative mechanisms, and management strategies for AEs related to administration of HPIs are described, with the goal of enabling health care professionals to provide appropriate counseling and supportive care interventions to their patients. PMID- 27511906 TI - Acupuncture for Chemoradiation Therapy-Related Dysphagia in Head and Neck Cancer: A Pilot Randomized Sham-Controlled Trial. AB - INTRODUCTION: Dysphagia is common in head and neck cancer patients after concurrent chemoradiation therapy (CRT). This study evaluated the feasibility of conducting a randomized sham-controlled trial and collected preliminary data on safety and efficacy of acupuncture. PATIENTS AND METHODS: Head and neck cancer (HNC) patients with stage III-IV squamous cell carcinoma were randomized to 12 sessions of either active acupuncture (AA) or sham acupuncture (SA) during and following CRT. Patients were blinded to treatment assignment. Swallowing-related quality of life (QOL) was assessed using the MD Anderson Dysphagia Inventory (MDADI) total and subscale scores. RESULTS: Multiple aspects of trial feasibility were confirmed. Forty-two of 196 patients screened (21%) were enrolled and randomized to receive AA (n = 21) or SA (n = 21); 79% completed at least 10 of 12 planned acupuncture sessions; 81% completed the study follow-ups. The majority of patients reported uncertainty regarding their treatment assignment, with no difference between the AA and SA groups. Audits confirmed both AA and SA treatments were delivered with high fidelity. No serious acupuncture-related side effects were observed. MDADI total scores significantly improved from baseline to 12 months post-CRT in both groups (AA: +7.9; SA +13.9; p = .044, p < .001). Similar patterns were observed for the MDADI global subscale (AA: +25.0; SA +22.7; p = .001, p = .002). Intent-to-treat analyses suggested no difference between the treatment groups (p = .17, p = .76 for MDADI total and global scores, respectively). CONCLUSION: A sham-controlled randomized trial evaluating acupuncture in dysphagia-related QOL in HNC found the procedure to be feasible and safe. Further investigation is required to evaluate efficacy. IMPLICATIONS FOR PRACTICE: Dysphagia or swallowing difficulty is an important and common condition after concurrent chemoradiation therapy in head and neck cancer patients. In addition to current available supportive care, acupuncture may offer potential for treating dysphagia. This study demonstrated that both active acupuncture and sham acupuncture are safe and were associated with improved dysphagia-related quality of life from baseline to 12 months after concurrent chemoradiation therapy. This study was not designed to inform underlying specific versus nonspecific effects. Future larger-scale pragmatic clinical trials evaluating the effectiveness of acupuncture versus standard of care are warranted, and further mechanistic research is needed to understand how active versus purportedly sham acupuncture procedures affect dysphagia-related symptoms. PMID- 27511908 TI - Increased Risk of Autism Development in Children Whose Mothers Experienced Birth Complications or Received Labor and Delivery Drugs. AB - Autism spectrum disorder (ASD) is a perplexing and pervasive developmental disorder characterized by social difficulties, communicative deficits, and repetitive behavior. The increased rate of ASD diagnosis has raised questions concerning the genetic and environmental factors contributing to the development of this disorder; meanwhile, the cause of ASD remains unknown. This study surveyed mothers of ASD and non-ASD children to determine possible effects of labor and delivery (L&D) drugs on the development of ASD. The survey was administered to mothers; however, the results were analyzed by child, as the study focused on the development of autism. Furthermore, an independent ASD dataset from the Southwest Autism Research and Resource Center was analyzed and compared. Indeed, L&D drugs are associated with ASD (p = .039). Moreover, the Southwest Autism Research and Resource Center dataset shows that the labor induction drug, Pitocin, is significantly associated with ASD (p = .004). We also observed a synergistic effect between administrations of L&D drugs and experiencing a birth complication, in which both obstetrics factors occurring together increased the likelihood of the fetus developing ASD later in life (p = .0003). The present study shows the possible effects of L&D drugs, such as Pitocin labor-inducing and analgesic drugs, on children and ASD. PMID- 27511907 TI - Repairing the Brain by SCF+G-CSF Treatment at 6 Months Postexperimental Stroke: Mechanistic Determination of the Causal Link Between Neurovascular Regeneration and Motor Functional Recovery. AB - Stroke, a leading cause of adult disability in the world, is a severe medical condition with limited treatment. Physical therapy, the only treatment available for stroke rehabilitation, appears to be effective within 6 months post-stroke. Here, we have mechanistically determined the efficacy of combined two hematopoietic growth factors, stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF; SCF + G-CSF), in brain repair 6 months after cortical infarct induction in the transgenic mice carrying yellow fluorescent protein in Layer V pyramidal neurons (Thy1-YFP-H). Using a combination of live brain imaging, whole brain imaging, molecular manipulation, synaptic and vascular assessments, and motor function examination, we found that SCF + G-CSF promoted mushroom spine formation, enlarged postsynaptic membrane size, and increased postsynaptic density-95 accumulation and blood vessel density in the peri-infarct cavity cortex; and that SCF + G-CSF treatment improved motor functional recovery. The SCF + G-CSF-enhanced motor functional recovery was dependent on the synaptic and vascular regeneration in the peri-infarct cavity cortex. These data suggest that a stroke-damaged brain is repairable by SCF + G-CSF even 6 months after the lesion occurs. This study provides novel insights into the development of new restorative strategies for stroke recovery. PMID- 27511910 TI - Extramammary Paget disease of the perianal region: the potential role of imiquimod in achieving disease control. AB - Extramammary Paget disease (EMPD) is a rare perineal neoplasia associated with a high rate of local recurrence. Surgical excision is the standard treatment; however, this has high rates of post-operative morbidity in combination with potentially mutilating results. Previous literature has demonstrated good response with imiquimod 5% cream in patients with vulval EMPD, yet its effectiveness in primary perianal disease is unknown.We describe the case of a 40 year-old woman presenting with EMPD of the perianal region, providing detailed histological and pictoral evidence of its response to topical imiquimod 5% cream over a 16-week period, which initially resulted in remission prior to metastatic lymph node recurrence. This case demonstrates the potential for topical imiquimod cream to avoid major surgery and its associated complications in patients presenting with EMPD of the perianal region. We discuss the current evidence for treating this rare condition with medical therapy, how this case adds to current literature and possible future directions. PMID- 27511909 TI - Diffusible Factors Secreted by Glioblastoma and Medulloblastoma Cells Induce Oxidative Stress in Bystander Neural Stem Progenitors. AB - Harmful effects that alter the homeostasis of neural stem or progenitor cells (NSPs) can affect regenerative processes in the central nervous system. We investigated the effect of soluble factors secreted by control or (137)Cs-gamma irradiated glioblastoma or medulloblastoma cells on redox-modulated endpoints in recipient human NSPs. Growth medium harvested from the nonirradiated brain tumor cells, following 24 h of growth, induced prominent oxidative stress in recipient NSPs as judged by overall increases in mitochondrial superoxide radical levels (p < .001), activation of c-jun N-terminal kinase, and decrease in the active form of FoxO3a. The induced oxidative stress was associated with phosphorylation of p53 on serine 15, a marker of DNA damage, induction of the cyclin-cyclin dependent kinase inhibitors p21(Waf1) and p27(Kip1), and perturbations in cell cycle progression (p < .001). These changes were also associated with increased apoptosis as determined by enhanced annexin V staining (p < .001) and caspase 8 activation (p < .05) and altered expression of critical regulators of self renewal, proliferation, and differentiation. Exposure of the tumor cells to radiation only slightly altered the induced oxidative changes in the bystander NSPs, except for medium from irradiated medulloblastoma cells that was more potent at inducing apoptosis in the NSPs than medium from nonirradiated cells (p < .001). The elucidation of such stressful bystander effects provides avenues to understand the biochemical events underlying the development or exacerbation of degenerative outcomes associated with brain cancers. It is also relevant to tissue culture protocols whereby growth medium conditioned by tumor cells is often used to support the growth of stem cells. PMID- 27511911 TI - 21st century twist on Cullen's sign: new generation anticoagulants and splenic traum. AB - New anticoagulants such as Rivaroxaban have become a popular choice for patients needing anticoagulation for atrial fibrillation or venous thromboembolism, chiefly because anticoagulation is maintained without the need for monitoring. This can be problematic in cases of trauma, and in this article, we discuss the management and outcome of managing an elderly patient with a shattered spleen while on Rivaroxaban. PMID- 27511912 TI - Peribiliary hepatic cysts presenting as hilar cholangiocarcinoma in a patient with end-stage liver disease. AB - Peribiliary cysts are cystic dilatations of peribiliary glands in the liver. They are present in ~50% of cirrhotic patients, but are underrecognized because they are usually asymptomatic and rarely present as obstructive jaundice. A 63-year old male with hepatitis C cirrhosis, awaiting liver transplantation, had a new finding of intrahepatic dilatation on magnetic resonance imaging. This was initially concerning for cholangiocarcinoma, but was ultimately diagnosed as peribiliary cysts. Peribiliary cysts can imitate cholangiocarcinoma on imaging. Therefore, awareness of this condition is essential because misdiagnosis may lead to inappropriate delay or denial for liver transplantation. The ideal imaging modalities to identify peribiliary cysts are magnetic resonance cholangiography and drip infusion cholangiographic computed tomography, though hepatic dysfunction may limit the usefulness of the latter. Peribiliary cysts should be considered in cirrhotic patients with cholestasis, biliary dilatations and negative biopsy of the biliary system for malignancy. PMID- 27511913 TI - Hepatocyte-protective effect of nectandrin B, a nutmeg lignan, against oxidative stress: Role of Nrf2 activation through ERK phosphorylation and AMPK-dependent inhibition of GSK-3beta. AB - Oxidative stress can contribute to the development and progression of liver diseases, such as drug-induced or alcoholic liver injury, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis. Nectandrin B is a bioactive lignan isolated from nutmeg extract. To date, little information is available about its pharmacological activities in the liver. This study investigated the hepatocyte-protective effect of nectandrin B against tert-butylhydroperoxide induced oxidative injury and the underlying molecular mechanism. The cell viability assay revealed that nectandrin B prevents apoptosis stimulated by tert butylhydroperoxide in both HepG2 cells and primary mouse hepatocytes. Nectandrin B also attenuated ROS production and restored the depleted glutathione level. Real-time PCR and immunoblot analyses showed that the expression of glutamate cysteine ligase, an enzyme responsible for the glutathione biosynthesis, was induced by nectandrin B, indicating its indirect antioxidative effect. The NF-E2 related factor-2 (Nrf2) regulates gene expression of an array of antioxidant enzymes in hepatocytes. Nectandrin B stimulated Nrf2 activation as evidenced by its enhanced nuclear accumulation and increased antioxidant response element (ARE)-luciferase activity. Intriguingly, the hepatocyte-protective effect of nectandrin B against oxidative damage was completely abrogated by Nrf2 knockdown using Nrf2 specific siRNA. Nectandrin B promoted ERK activation, but inactivated GSK-3beta through the AMPK-mediated inhibitory phosphorylation. The enforced overexpression of dominant-negative mutant of MEK1 or AMPKalpha, or wild-type GSK 3beta inhibited the increase in the NQO1-ARE-luciferase activity stimulated by nectandrin B, suggesting that both ERK and AMPK-GSK-3beta signalings are involved in the activation of Nrf2/ARE pathway by nectandrin B. Consistent with this, cytoprotection and restoration of glutathione level by nectandrin B was also blocked by the overexpression of dominant-negative MEK1 or wild-type GSK-3beta. Finally, our data demonstrate that nectandrin B has the ability to protect hepatocytes against oxidative injury through the activation of Nrf2/ARE pathway mediated by ERK phosphorylation and AMPK-dependent inactivation of GSK-3beta. PMID- 27511914 TI - A computer-aided system for automatic extraction of femur neck trabecular bone architecture using isotropic volume construction from clinical hip computed tomography images. AB - Hip fractures due to osteoporosis are increasing progressively across the globe. It is also difficult for those fractured patients to undergo dual-energy X-ray absorptiometry scans due to its complicated protocol and its associated cost. The utilisation of computed tomography for the fracture treatment has become common in the clinical practice. It would be helpful for orthopaedic clinicians, if they could get some additional information related to bone strength for better treatment planning. The aim of our study was to develop an automated system to segment the femoral neck region, extract the cortical and trabecular bone parameters, and assess the bone strength using an isotropic volume construction from clinical computed tomography images. The right hip computed tomography and right femur dual-energy X-ray absorptiometry measurements were taken from 50 south-Indian females aged 30-80 years. Each computed tomography image volume was re-constructed to form isotropic volumes. An automated system by incorporating active contour models was used to segment the neck region. A minimum distance boundary method was applied to isolate the cortical and trabecular bone components. The trabecular bone was enhanced and segmented using trabecular enrichment approach. The cortical and trabecular bone features were extracted and statistically compared with dual-energy X-ray absorptiometry measured femur neck bone mineral density. The extracted bone measures demonstrated a significant correlation with neck bone mineral density (r > 0.7, p < 0.001). The inclusion of cortical measures, along with the trabecular measures extracted after isotropic volume construction and trabecular enrichment approach procedures, resulted in better estimation of bone strength. The findings suggest that the proposed system using the clinical computed tomography images scanned with low dose could eventually be helpful in osteoporosis diagnosis and its treatment planning. PMID- 27511915 TI - Royal London space analysis: plaster versus digital model assessment. AB - Aim: With the advent of digital study models, the importance of being able to evaluate space requirements becomes valuable to treatment planning and the justification for any required extraction pattern. This study was undertaken to compare the validity and reliability of the Royal London space analysis (RLSA) undertaken on plaster as compared with digital models. Materials and methods: A pilot study (n = 5) was undertaken on plaster and digital models to evaluate the feasibility of digital space planning. This also helped to determine the sample size calculation and as a result, 30 sets of study models with specified inclusion criteria were selected. All five components of the RLSA, namely: crowding; depth of occlusal curve; arch expansion/contraction; incisor antero posterior advancement and inclination (assessed from the pre-treatment lateral cephalogram) were accounted for in relation to both model types. The plaster models served as the gold standard. Intra-operator measurement error (reliability) was evaluated along with a direct comparison of the measured digital values (validity) with the plaster models. Results: The measurement error or coefficient of repeatability was comparable for plaster and digital space analyses and ranged from 0.66 to 0.95mm. No difference was found between the space analysis performed in either the upper or lower dental arch. Hence, the null hypothesis was accepted. The digital model measurements were consistently larger, albeit by a relatively small amount, than the plaster models (0.35mm upper arch and 0.32mm lower arch). Conclusion: No difference was detected in the RLSA when performed using either plaster or digital models. Thus, digital space analysis provides a valid and reproducible alternative method in the new era of digital records. PMID- 27511917 TI - Science and Culture: Modern "cathedral" offers artistic inspiration. PMID- 27511918 TI - Inner Workings: Spotting gravitational waves using pulsar ticks. PMID- 27511920 TI - Atomic structure of a rhinovirus C, a virus species linked to severe childhood asthma. AB - Isolates of rhinovirus C (RV-C), a recently identified Enterovirus (EV) species, are the causative agents of severe respiratory infections among children and are linked to childhood asthma exacerbations. The RV-C have been refractory to structure determination because they are difficult to propagate in vitro. Here, we report the cryo-EM atomic structures of the full virion and native empty particle (NEP) of RV-C15a. The virus has 60 "fingers" on the virus outer surface that probably function as dominant immunogens. Because the NEPs also display these fingers, they may have utility as vaccine candidates. A sequence-conserved surface depression adjacent to each finger forms a likely binding site for the sialic acid on its receptor. The RV-C, unlike other EVs, are resistant to capsid binding antiviral compounds because the hydrophobic pocket in VP1 is filled with multiple bulky residues. These results define potential molecular determinants for designing antiviral therapeutics and vaccines. PMID- 27511921 TI - A Secondary Analysis of Sleep Quality Changes in Older Adults From a Randomized Trial of an MBSR Program. AB - This secondary analysis examined changes in sleep quality associated with participation in a Mindfulness-Based Stress Reduction (MBSR) program among healthy older adults. Data were collected at baseline, 8-weeks post-treatment, and a 6-month follow-up from adults aged >= 65 ( N = 200), randomly assigned to MBSR or a waitlist control. Group differences were examined using mixed analysis of covariance with repeated measures on the total Pittsburgh Sleep Quality Index (PSQI) score. A small-sized, significant effect was found on overall sleep among MBSR participants with baseline PSQI scores > 5, indicative of a sleep disturbance, F(2, 80) = 4.32, p = .02, etap2 = .05. A medium-sized, significant effect was found for MBSR participants with baseline PSQI scores >= 10, F(2, 28) = 3.13, p = .04, etap2 = .10. These findings indicate that improved sleep quality for older adults who have higher levels of sleep disturbance may be associated with participation in MBSR. PMID- 27511922 TI - Enhancing and Maintaining Memory in Older Adulthood. PMID- 27511923 TI - The Efficiency of Sensory Integration Interventions in Preterm Infants. AB - This study aimed to explore the effects of individualized sensory integration interventions on the sensory processing functions of preterm infants. Thirty-four preterm infants (intervention group) at a corrected age of seven months and 34 term infants (control group) were included. The preterm infants underwent an eight-week sensory integration intervention. Before and after the intervention, the preterm infants' sensory processing functions were evaluated using the Test of Sensory Functions in Infants and compared with those of term infants. Preterm infants had significantly poorer sensory processing function preintervention when compared with term infants. There was a significant improvement in preterm infants' sensory processing functions after the sensory integration intervention. In conclusion, preterm infants should be evaluated for sensory processing disorders and individualized sensory integration interventions should be implemented. PMID- 27511924 TI - Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers. AB - Germline BRCA2 mutations are the first known cause of inherited (familial) pancreatic ductal adenocarcinoma (PDAC). This tumor is the third most frequent cancer in carriers of germline BRCA2 mutations, as it occurs in around 10% of BRCA2 families. PDAC is known as one of the most highly lethal cancers, mainly because of its chemoresistance and frequently late diagnosis. Based on recent developments in molecular biology, a subgroup of BRCA2-associated PDAC has been created, allowing screening, early surgical treatment and personalized systemic treatment. BRCA2 germline mutation carriers who have >=1 first-degree relative, or >=2 blood relatives with PDAC, should undergo screening and regular follow-up based on magnetic resonance imaging and endoscopic ultrasound. The goal of screening is to detect early invasive PDAC and advanced precancerous lesions suitable for a stepwise surgical complete (R0) resection. Increasing evidence on the molecular role of the BRCA2 protein in the homologous recombination of DNA damages suggest that BRCA2-related PDAC are sensitive to agents causing DNA cross linking damage, such as platinum salts, and treatments targeting rescue DNA repair pathways, such as poly(ADP-ribose) polymerase inhibitors that are currently under investigation. PMID- 27511925 TI - Shifts in Rumen Fermentation and Microbiota Are Associated with Dissolved Ruminal Hydrogen Concentrations in Lactating Dairy Cows Fed Different Types of Carbohydrates. AB - BACKGROUND: Different carbohydrates ingested greatly influence rumen fermentation and microbiota and gaseous methane emissions. Dissolved hydrogen concentration is related to rumen fermentation and methane production. OBJECTIVES: We tested the hypothesis that carbohydrates ingested greatly alter the rumen environment in dairy cows, and that dissolved hydrogen concentration is associated with these changes in rumen fermentation and microbiota. METHODS: Twenty-eight lactating Chinese Holstein dairy cows [aged 4-5 y, body weight 480 +/- 37 kg (mean +/- SD)] were used in a randomized complete block design to investigate effects of 4 diets differing in forage content (45% compared with 35%) and source (rice straw compared with a mixture of rice straw and corn silage) on feed intake, rumen fermentation, and microbial populations. RESULTS: Feed intake (10.7-12.6 kg/d) and fiber degradation (0.584-0.692) greatly differed (P <= 0.05) between cows fed the 4 diets, leading to large differences (P <= 0.05) in gaseous methane yield (27.2-37.3 g/kg organic matter digested), dissolved hydrogen (0.258-1.64 MUmol/L), rumen fermentation products, and microbiota. Ruminal dissolved hydrogen was negatively correlated (r < -0.40; P < 0.05) with molar proportion of acetate, numbers of fungi, abundance of Fibrobacter succinogenes, and methane yield, but positively correlated (r > 0.40; P < 0.05) with molar proportions of propionate and n-butyrate, numbers of methanogens, and abundance of Selenomonas ruminantium and Prevotella spp. Ruminal dissolved hydrogen was positively correlated (r = 0.93; P < 0.001) with Gibbs free energy changes of reactions producing greater acetate and hydrogen, but not correlated with those reactions producing more propionate without hydrogen. CONCLUSIONS: Changes in fermentation pathways from acetate toward propionate production and in microbiota from fibrolytic toward amylolytic species were closely associated with ruminal dissolved hydrogen in lactating dairy cows. An unresolved paradox was that greater dissolved hydrogen was associated with greater numbers of methanogens but with lower gaseous methane emissions. PMID- 27511926 TI - Plasma Concentrations of Ferritin in Early Pregnancy Are Associated with Risk of Gestational Diabetes Mellitus in Women in the Danish National Birth Cohort. AB - BACKGROUND: Evidence from experimental studies has demonstrated that higher than normal iron concentrations can lead to pancreatic beta cell dysfunction and impaired glucose metabolism. Studies on body iron stores in early pregnancy and subsequent gestational diabetes mellitus (GDM) risk are sparse. OBJECTIVE: Our objective was to determine whether biomarkers of body iron stores measured in early pregnancy are associated with GDM risk. METHODS: A case-control study of 350 GDM cases and 349 non-GDM controls was conducted in participants from the Danish National Birth Cohort. Blood was collected at a mean +/- SD gestational age of 9.4 +/- 3.2 wk. Plasma biomarkers of iron stores, including ferritin and soluble transferrin receptor (sTfR), were measured. Logistic regression was used to estimate the OR of GDM associated with quintiles of plasma biomarkers of body iron stores, controlling for maternal age, family history of diabetes, exercise in pregnancy, parity, and prepregnancy body mass index (BMI). RESULTS: Cases were older (mean +/- SD age: 32.2 +/- 4.3 compared with 29.9 +/- 4.2 y) and had a higher BMI (in kg/m(2); mean +/- SD: 28.7 +/- 6.0 compared with 24.1 +/- 4.6) than controls. Plasma concentrations of both ferritin and sTfR in early pregnancy were significantly higher in GDM cases than in controls [means +/- SDs: 80.6 +/- 56.0 compared with 71.8 +/- 50.1 MUg/L (P = 0.03) and 1.5 +/- 0.7 compared with 1.4 +/- 0.6 mg/L (P = 0.002) for ferritin and sTfR, respectively]. Ferritin was positively and significantly associated with GDM risk even after adjustment for major risk factors of GDM, including prepregnancy BMI. ORs across increasing quintiles of ferritin were 1.00 (reference), 1.25 (95% CI: 0.70, 2.22), 1.89 (95% CI: 1.06, 3.37), 0.82 (95% CI: 0.46, 1.48), and 2.34 (95% CI: 1.30, 4.21) (P linear trend = 0.02). CONCLUSION: These findings suggest that plasma ferritin measured in early pregnancy is significantly and positively associated with GDM risk. PMID- 27511927 TI - Among 4 Diet Quality Indexes, Only the Alternate Mediterranean Diet Score Is Associated with Better Colorectal Cancer Survival and Only in African American Women in the Multiethnic Cohort. AB - BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States, with a 5-y survival rate of ~65%. Therefore, the identification of modifiable health factors to improve CRC survival is crucial. OBJECTIVE: We investigated the association of 4 prediagnostic a priori diet quality indexes with CRC-specific and all-cause mortality in the Multiethnic Cohort (MEC). METHODS: The MEC included >215,000 African-American, Native Hawaiian, Japanese-American, Latino, and white adults living in Hawaii and California who completed a validated quantitative food-frequency questionnaire in 1993-1996. CRC cases and deaths were identified through linkages to cancer registries and to state and national vital registries. Sex-specific HRs and 95% CIs were estimated for the Healthy Eating Index (HEI) 2010, the Alternative HEI (AHEI) 2010, the alternate Mediterranean Diet (aMED) score, and the Dietary Approaches to Stop Hypertension (DASH) index with CRC-specific and overall mortality as the primary outcomes. Ethnicity-specific analyses were the secondary outcomes. RESULTS: Among 4204 MEC participants diagnosed with invasive CRC through 2010, 1976 all-cause and 1095 CRC-specific deaths were identified. A higher aMED score was associated with lower CRC-specific mortality in women [HR continuous pattern score divided by its respective SD (HR1SD): 0.86; 95% CI: 0.77, 0.96] but not in men (HR1SD: 1.01; 95% CI: 0.92, 1.11). A higher aMED score was also associated with lower all-cause mortality in women (HR1SD: 0.88; 95% CI: 0.81, 0.96) but not in men (HR1SD: 1.00; 95% CI: 0.93, 1.07). The HEI-2010, AHEI 2010, and DASH index were not significantly associated with CRC-specific or with all-cause mortality. The inverse relation for the aMED score was limited to African Americans and to colon (compared with rectal) cancer. CONCLUSIONS: The aMED score was related to lower mortality only in African-American women (1 of 5 ethnic groups studied). The results should be interpreted with caution due to the small numbers of cases within ethnic groups and the issue of multiple testing. PMID- 27511928 TI - Discretionary Foods Have a High Contribution and Fruit, Vegetables, and Legumes Have a Low Contribution to the Total Energy Intake of the Mexican Population. AB - BACKGROUND: Overweight and obesity prevalences in Mexico are among the highest in the world, with dietary factors being the third-leading category of risk contributing to the burden of disease. Consequently, studying the compliance of the Mexican population to food-based dietary recommendations is essential for informing nutritional policies. OBJECTIVES: We described the energy contribution of food groups to total dietary energy intake of the Mexican population and by sociodemographic subgroups and compared these results with Mexican dietary recommendations. METHODS: Twenty-four-hour dietary recalls for participants aged >=5 y (n = 7983) from the 2012 Mexican National Health and Nutrition Survey were used. Foods and beverages were classified into 8 groups (the first 6 were called "basic foods" and the last 2 "discretionary foods"), as follows: 1) cereals, 2) legumes, 3) milk and dairy, 4) meat and animal products, 5) fruit and vegetables, 6) fats and oils, 7) sugar-sweetened beverages (SSBs), and 8) products high in saturated fat and/or added sugar (HSFAS). Recommendations were based on the Mexican Dietary Guidelines (MDG). Energy contributions from the food groups by age, sex, region, residence (rural or urban), and socioeconomic status (SES) were estimated. RESULTS: The highest contribution to total energy intake came from cereals (33%) followed by HSFAS (16%), meat and animal products (14%), and SSBs (9.8%). Fruit and vegetables (5.7%) and legumes (3.8%) had the lowest contribution. Energy contribution of several food groups differed significantly between population subgroups. Overall, discretionary foods contributed more than one-quarter of total energy intake (26%) and were 13 percentage points above the maximum allowed by the recommendations, whereas the intakes of legumes and fruit and vegetables were much lower than recommended. CONCLUSIONS: Our results show the need to generate a food environment conducive to a healthier diet in the Mexican population. PMID- 27511930 TI - The Mexican Dietary and Physical Activity Guidelines: Moving Public Nutrition Forward in a Globalized World. AB - The objective of this article is to explain the process of the development of and to assess the Mexican food-based dietary and physical activity guidelines (FBDGs). The FBDGs were developed by an intersectoral and interdisciplinary committee of 11 national experts with input from 11 external advisors. The sectors represented were research and academic institutions, the Ministry of Health, and a nongovernmental organization. The evidence-based process included the following: literature reviews of local, national, and international evidence; review of dietary patterns of the Mexican population; key national and international recommendations; and review of FBDGs and visual icons from other countries. The guidelines' report follows the life-course socioecological model rooted in a deep understanding of the epidemiology and underlying causes of malnutrition in Mexico. The guidelines are summarized in 10 pretested main recommendations that include, and go beyond, simply promoting the consumption of a healthy and varied diet that includes fresh fruits, vegetables, legumes, and whole grains and staying within caloric needs and staying active. The guidelines strongly emphasize healthy cooking habits, enjoyable meals with family and friends, drinking water, and avoiding the consumption of sweetened beverages, grain-based desserts, and highly processed foods. Detailed guidelines specific to different groups (on the basis of age and physiologic status) are also included. An innovative aspect of the Mexican FBDGs is the inclusion of dietary guidance of children <2 y of age. Future editions of these guidelines should consider removing their emphasis on dietary cholesterol and total dietary fat and placing more attention on the substitution of saturated and trans fats with healthy oils. The process of national agenda setting, policy articulation, and implementation of the Mexican FBDGs in the context of addressing the national obesity epidemic deserves to be initiated and formally assessed through the lens of evidence based, public nutrition complex adaptive systems. PMID- 27511931 TI - Sugar-Sweetened Beverages Are the Main Sources of Added Sugar Intake in the Mexican Population. AB - BACKGROUND: Sugar intake has been associated with an increased prevalence of obesity, other noncommunicable diseases, and dental caries. The WHO recommends that free sugars should be <10% of total energy intake (TEI) and that additional health benefits could be obtained with a reduction below 5% of TEI. OBJECTIVE: The objective of this study was to estimate the total, intrinsic, and added sugar intake in the Mexican diet and to identify the food groups that are the main sources of these sugars. METHODS: We used data from a national probabilistic survey [ENSANUT (National Health and Nutrition Survey) 2012], which represents 3 geographic regions and urban and rural areas. Dietary information was obtained by administering a 24-h recall questionnaire to 10,096 participants. Total sugar intake was estimated by using the National Institute of Public Health (INSP) food composition table and an established method to estimate added sugars. RESULTS: The mean intakes of total, intrinsic, and added sugars were 365, 127, and 238 kcal/d, respectively. Added sugars contributed 13% of TEI. Sugar-sweetened beverages (SSBs) were the main source of sugars, contributing 69% of added sugars. Food products high in saturated fat and/or added sugar (HSFAS) were the second main sources of added sugars, contributing 25% of added sugars. CONCLUSIONS: The average intake of added sugars in the Mexican diet is higher than WHO recommendations, which may partly explain the high prevalence of obesity and diabetes in Mexico. Because SSBs and HSFAS contribute >94% of total added sugars, strategies to reduce their intake should be strengthened. This includes stronger food labels to warn the consumer about the content of added sugars in foods and beverages. PMID- 27511932 TI - Usual Intake of Added Sugars and Saturated Fats Is High while Dietary Fiber Is Low in the Mexican Population. AB - BACKGROUND: The Mexican National Health and Nutrition Survey (ENSANUT) was carried out in 2012. Information from the survey is used to design and evaluate food and nutrition policies in Mexico. OBJECTIVE: The objective of this study was to estimate the usual intake of energy and macronutrients in the Mexican population by using the ENSANUT 2012. METHODS: Twenty-four-hour recall interviews were administered to a nationally representative subsample of 10,096 individuals aged >=1 y from the ENSANUT 2012. Usual intake distributions and the prevalence of inadequate intakes were estimated by using the Iowa State University method. Student's t tests and tests on the equality of proportions were used to compare usual intakes and prevalence of inadequacy across socioeconomic status, area (rural or urban), and region of residence (North, Center, or South). RESULTS: Energy and macronutrient intakes and indicators of dietary adequacy are presented for children (ages 1-4 y and 5-11 y), adolescents (12-19 y), and adults (>=20 y). At the national level, the estimated mean fiber intake was below the Adequate Intake for all population subgroups, suggesting inadequacies. The estimated proportion with a usual added sugars intake of >10% of total energy intake was >64% in all age groups. The proportion with a usual saturated fat intake of >10% of total energy intake was estimated to be >78% in children, >66% in adolescents, and >50% in adults. Overall, fiber intake was lower and intakes of saturated fat and added sugars were higher in urban compared with rural areas, in the North compared with South regions, and among those with high compared with low socioeconomic status (P < 0.05). CONCLUSIONS: Fiber intake is lower and added sugar and saturated fat intakes are higher than recommended for >50% of the Mexican population aged >=1 y. These results highlight the importance of improving the diets of the overall population to reduce the risk of noncommunicable chronic diseases. PMID- 27511934 TI - Intakes of Energy and Discretionary Food in Mexico Are Associated with the Context of Eating: Mealtime, Activity, and Place. AB - BACKGROUND: The prevalence of obesity and the intake of discretionary foods [high saturated fat and/or added sugar (HSFAS) products and sugar-sweetened beverages (SSBs)] are high in Mexico. It is important to understand whether the intakes of HSFAS products and SSBs are associated with the context in which they are consumed. OBJECTIVE: Our aim was to estimate the associations between total energy and discretionary food (HSFAS products and SSBs) intakes and the context of eating (mealtime, activity, and place). METHODS: We used data from 10,087 participants aged >=1 y from the Mexican National Health and Nutrition Survey 2012. Dietary intake was estimated through a 24-h dietary recall that included questions on mealtime, activity, and place in which each food item was consumed. The associations between energy and discretionary food intakes and the context of eating were estimated by using multiple linear regression stratified by age group and adjusted for sociodemographic variables. RESULTS: Compared with breakfast, the percentage of energy that HSFAS products contributed was 16-29 (range in all age groups) percentage points higher during midafternoon snacks and 16-23 percentage points lower at lunch and almuerzo (Mexican brunch); the percentage of energy from SSBs was 3.4-7.6 percentage points higher during midmorning snacks (P < 0.05). In many age groups and mealtimes, we found that compared with eating only while seated, the percentage of energy as HSFAS was 5.3-14 percentage points higher when watching television (P < 0.05). Compared with eating at home, the percentage of energy from HSFAS was 12-26 percentage points higher on the street and the percentage of energy from SSBs was 3.4-6.0 percentage points higher at school and 2.9-15 percentage points higher at work (P < 0.05). CONCLUSIONS: These results highlight the need to promote healthier food selection among the Mexican population when snacking and watching television and healthier food environments at work, school, and on the street. PMID- 27511933 TI - Vitamin A Supplementation Increases the Uptake of Chylomicron Retinyl Esters into the Brain of Neonatal Rats Raised under Vitamin A-Marginal Conditions. AB - BACKGROUND: The most rapid phase of brain development occurs during the neonatal period. Vitamin A (VA; retinol) is critical for many aspects of this process, including neurogenesis, synaptic plasticity, learning, and memory formation. However, the metabolism of retinol in the neonatal brain has not been extensively explored. OBJECTIVE: We examined the uptake of VA into the brain in neonatal rats raised under VA-marginal conditions (control group) and assessed the effect of VA supplementation on the uptake of VA into the brain. METHODS: Sprague-Dawley neonatal rats (n = 104) nursed by mothers fed a VA-marginal diet were randomly assigned and treated on postnatal day 4 with an oral dose of either VA (6 MUg retinyl palmitate/g body weight) or canola oil as the control, both of which contained 1.8 MUCi [(3)H]retinol. Pups (n = 4/group at a time) were killed at 13 sampling times from 30 min to 24 d after dosing. The uptake of total retinol, chylomicron-associated retinyl esters (REs), and retinol bound to retinol-binding protein (RBP) was estimated with the use of WinSAAM version 3.0.8. RESULTS: Total retinol mass in the brain was closely dependent on its mass in plasma over time (r = 0.91; P < 0.001). The uptake of retinol into the brain involved both postprandial chylomicrons and RBP, with RBP delivering most of the retinol in the control group [0.27 nmol/d (RBP) compared with 0.01 nmol/d (chylomicrons)]. VA supplementation increased the fractional uptake of chylomicron REs from 0.3% to 1.2% of plasma pool/d, decreased that of RBP retinol from 0.5% to 0.2% of plasma pool/d, and increased the transfer rate of chylomicron REs from nearly zero to 0.7 nmol/d, causing a day-long elevation in the brain mass of total retinol. CONCLUSION: Postprandial chylomicrons may be a primary mechanism for delivering a recently ingested large dose of VA to the brain of neonatal rats raised under VA marginal conditions. PMID- 27511929 TI - Biomarkers of Nutrition for Development (BOND)-Vitamin A Review. AB - The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-informed advice to anyone with an interest in the role of nutrition in health. The BOND program provides information with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect, which will be especially useful for readers who want to assess nutrient status. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutritional status at the individual and population levels. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, folate, zinc, iron, vitamin A, and vitamin B-12. This review of vitamin A is the current article in this series. Although the vitamin was discovered >100 y ago, vitamin A status assessment is not trivial. Serum retinol concentrations are under homeostatic control due in part to vitamin A's use in the body for growth and cellular differentiation and because of its toxic properties at high concentrations. Furthermore, serum retinol concentrations are depressed during infection and inflammation because retinol-binding protein (RBP) is a negative acute-phase reactant, which makes status assessment challenging. Thus, this review describes the clinical and functional indicators related to eye health and biochemical biomarkers of vitamin A status (i.e., serum retinol, RBP, breast-milk retinol, dose-response tests, isotope dilution methodology, and serum retinyl esters). These biomarkers are then related to liver vitamin A concentrations, which are usually considered the gold standard for vitamin A status. With regard to biomarkers, future research questions and gaps in our current understanding as well as limitations of the methods are described. PMID- 27511935 TI - High Prevalence of Inadequate Calcium and Iron Intakes by Mexican Population Groups as Assessed by 24-Hour Recalls. AB - BACKGROUND: A National Health and Nutrition Survey (ENSANUT) conducted in Mexico in 1999 identified a high prevalence of inadequate mineral intakes in the population by using 24-h recall questionnaires. However, the 1999 survey did not adjust for within-person variance. The 2012 ENSANUT implemented a more up-to-date 24-h recall methodology to estimate usual intake distributions and prevalence of inadequate intakes. OBJECTIVE: We examined the distribution of usual intakes and prevalences of inadequate intakes of calcium, iron, magnesium, and zinc in the Mexican population in groups defined according to sex, rural or urban area, geographic region of residence, and socioeconomic status (SES). METHODS: We used dietary intake data obtained through the 24-h recall automated multiple-pass method for 10,886 subjects as part of ENSANUT 2012. A second measurement on a nonconsecutive day was obtained for 9% of the sample. Distributions of usual intakes of the 4 minerals were obtained by using the Iowa State University method, and the prevalence of inadequacy was estimated by using the Institute of Medicine's Estimated Average Requirement cutoff. RESULTS: Calcium inadequacy was 25.6% in children aged 1-4 y and 54.5-88.1% in subjects >5 y old. More than 45% of subjects >5 y old had an inadequate intake of iron. Less than 5% of children aged <12 y and 25-35% of subjects aged >12 y had inadequate intakes of magnesium, whereas zinc inadequacy ranged from <10% in children aged <12 y to 21.6% in men aged >=20 y. Few differences were found between rural and urban areas, regions, and tertiles of SES. CONCLUSIONS: Intakes of calcium, iron, magnesium, and zinc are inadequate in the Mexican population, especially among adolescents and adults. These results suggest a public health concern that must be addressed. PMID- 27511936 TI - Usual Vitamin Intakes by Mexican Populations. AB - BACKGROUND: In the past several years, the consumption of high-energy, nutrient poor foods has increased globally. Dietary intake data collected by the National Health and Nutrition Survey (ENSANUT) 2012 provide information to assess the quality of the Mexican diet and to guide food and nutrition policy. OBJECTIVE: The aim was to describe the usual intake and the prevalence of inadequate intakes of vitamins for the overall Mexican population and by subgroups defined by sex, age, region, urban or rural areas, and socioeconomic status (SES). METHODS: ENSANUT 2012 is a cross-sectional probabilistic survey representative of the Mexican population. Dietary information was collected by using the 24-h recall automated multiple-pass method (n = 10,096) with a repeated measurement on a subsample (n = 889) to permit adjustment for intraindividual variability with the use of the Iowa State University method. Mean usual intakes and the prevalence of inadequate intakes of thiamin, riboflavin, niacin, folate, and vitamins A, D, E, C, B-6, and B-12 were calculated for children aged 1-4 y (CH1-4y), children aged 5-11 y (CH5-11y), adolescents aged 12-19 y, and adults aged >=20 y. RESULTS: In all of the age groups, prevalences of inadequate intakes of vitamins D and E were the highest (77-99% of adults and adolescents and 53-95% of CH5-11y and CH1-4y) and those of folate and vitamin A were intermediate (47-70% of adults and adolescents, 15-23% of CH5-11y and 8-13% of CH1-4y), whereas those of thiamin, riboflavin, niacin, and vitamins B-6, B-12, and C were the lowest (0-37% of adults, 1-27% of adolescents, and 0-2.4% of CH5-11y and CH1-4y). With few exceptions, the highest prevalences of inadequate intakes for vitamins were observed in the poorest populations (rural South region and the lowest tertile of SES). CONCLUSIONS: The intake of vitamins among Mexicans is inadequate overall. Information collected by ENSANUT can help target food assistance programs and develop strategies to prevent vitamin deficiencies. PMID- 27511937 TI - A Retinol Isotope Dilution Equation Predicts Both Group and Individual Total Body Vitamin A Stores in Adults Based on Data from an Early Postdosing Blood Sample. AB - BACKGROUND: Retinol isotope dilution (RID) is used to determine vitamin A total body stores (TBS) after an oral dose of a vitamin A stable isotope. The generally accepted prediction equation proposed by Olson's group in 1989 (Furr et al. Am J Clin Nutr 1989;49:713-6) includes factors related to dose absorption and retention, isotope equilibration in plasma compared with stores, catabolism during the mixing period, and the optimal time for measuring plasma isotope enrichment. OBJECTIVES: The objectives were 1) to develop a modified RID equation and identify an earlier sampling time for predicting TBS and 2) to improve prediction in individuals as well as groups. METHODS: To develop a modified RID equation, we used results of model-based compartmental analysis [the Simulation, Analysis and Modeling software (WinSAAM version 3.0.8; http://www.WinSAAM.org)] of plasma [13C10]retinol kinetic data from 32 previously studied, healthy young adults of European ancestry who had moderate vitamin A intakes and who ingested 2.95 MUmol [13C10]retinyl acetate. RESULTS: We examined the time dependence of factors in the prediction equation related to absorption/retention (Fa) and isotope equilibration (S) and determined that 4 or 5 d postdosing was the optimal sampling time. TBS calculated by the equation TBS = Fa x S x (1/SAp), where SAp is plasma retinol specific activity (fraction of dose/MUmol), were highly correlated with model-predicted TBS (r = 0.95 and 0.96 for 4 and 5 d, respectively; P < 0.001); predictions for individuals were also highly correlated (Rs = 0.94 and 0.94; P < 0.001). CONCLUSION: The equation TBS ~ 0.5 * (1/SAp) accurately predicted vitamin A TBS in this group of 32 healthy young adults and its individual members with the use of data from 1 blood sample taken 4 d after isotope administration. PMID- 27511938 TI - Mexican Children under 2 Years of Age Consume Food Groups High in Energy and Low in Micronutrients. AB - BACKGROUND: Mexico faces malnutrition problems in the child population. Analysis of food consumption in small children allows us to identify and propose strategies focused on feeding to improve their nutritional status. OBJECTIVE: We described the consumption of beverages and food groups in Mexican children <24 mo of age. METHODS: A cross-sectional study was carried out in 926 children aged <24 mo participating in the 2012 ENSANUT (National Health and Nutrition Study). Dietary information was obtained through 24-h recalls. The foods and beverages consumed were divided into 17 groups. Consumption was estimated in grams or milliliters, kilocalories per day, and percentage of energy (PE) per day. The percentage of consumers was calculated for each food group and stratified by age (<6, 6-11, and 12-23 mo) and by breastfeeding status (breastfed or not breastfed). Differences in the consumption of food groups were analyzed by breastfeeding status, area of residence (urban or rural), and socioeconomic status (SES) by using linear regression adjusted for age, breastfeeding status, and survey design. RESULTS: Only 35% of the children consumed breast milk. Infant formula was consumed by 48% in children aged <6 mo and by 33% in children 6-11 mo old. More than 35% of the children aged 6-11 and 12-23 mo and 12% of children <6 mo old consumed nondairy sugar-sweetened beverages. Legumes and seeds and maize based preparations contributed a higher PE in rural areas (3.4% and 1.9%, respectively) than in urban areas (11.1% and 6.4%, respectively) (P < 0.05). Children from the lowest SES category consumed less PE from cereals other than maize (2.4%) and more from maize-based preparations (10.2%) than did the middle (4.9% from other cereals and 8.0% from maize) and high (6.0% from other cereals and 4.5% from maize) SES categories (P < 0.05). CONCLUSION: Mexican children <24 mo of age do not consume a diet that meets recommendations, which is consistent with the high prevalence of malnutrition in Mexico. PMID- 27511939 TI - Overview of the Dietary Intakes of the Mexican Population: Results from the National Health and Nutrition Survey 2012. AB - BACKGROUND: Mexico is facing the double burden of malnutrition: stunting and micronutrient deficiencies in young children, iron deficiency in pregnant women, and widespread obesity across age groups. OBJECTIVE: The aim was to summarize and discuss findings published in this supplement on dietary intakes and the eating habits of the Mexican population. METHODS: A 24-h recall questionnaire that used the multiple-pass method with a repeated measure in a fraction of the sample was applied in a nationally representative sample. We estimated mean intakes and percentages of inadequacy for macronutrients and micronutrients; mean intakes and percentages of the population who adhere to dietary recommendations for food groups; sources of added sugars; intakes of discretionary foods by mealtime, place, and activity; and mean dietary intakes in children <2 y old. RESULTS: Infant formula was consumed by almost half of infants aged <6 mo and sugar sweetened beverages were consumed by two-thirds of children aged 12-23 mo. In the different age groups, a high proportion of the population had excessive intakes of added sugars (58-85%) and saturated fats (54-92%), whereas a high prevalence of insufficient intakes was found for fiber (65-87%), vitamin A (8-70%), folates (13-69%), calcium (26-88%), and iron (46-89%). Discretionary foods (nonbasic foods high in saturated fats and/or added sugars) contributed 26% of the population's total energy intake, whereas only 1-23% met recommendations for legumes, seafood, fruit, vegetables, and dairy foods. CONCLUSIONS: High proportions of Mexicans consume diets that do not meet recommendations. Breastfeeding and complementary feeding diverged from recommendations, intakes of discretionary foods were high, and the prevalence of nutrient inadequacies and age groups not meeting intake recommendations of basic food groups were also high. The results are consistent with the high prevalence of the double burden of malnutrition and are useful to design food and nutrition policies. PMID- 27511940 TI - Adherence to Dietary Recommendations for Food Group Intakes Is Low in the Mexican Population. AB - BACKGROUND: Given the high prevalence of obesity and noncommunicable diseases in Mexico and the key role of dietary quality in these conditions, it is important to determine Mexicans' adherence to dietary recommendations. OBJECTIVE: Our aim was to estimate the percentage of the Mexican population who adhere to dietary recommendations for key food groups. METHODS: We analyzed 7983 participants aged >=5 y from the nationally representative Mexican National Health and Nutrition Survey 2012. Dietary intake data were collected by using one 24-h recall and a repeated 24-h recall in 9% of the sample. We used the National Cancer Institute method for episodically consumed foods, which uses a 2-part (probability and amount) mixed regression model to estimate the usual intake distribution and its association with sociodemographic variables. RESULTS: For the food groups that are encouraged, only 1-4% of the population (range across sex and age groups) reached the recommended intake of legumes, 4-8% for seafood, 7-16% for fruit and vegetables, and 9-23% for dairy. For food groups that are discouraged, only 10 22% did not exceed the recommended upper limit for sugar-sweetened beverages, 14 42% for high saturated fat and/or added sugar (HSFAS) products, and 9-50% for processed meats, whereas the majority (77-93%) did not exceed the limit for red meat. A lower proportion of adolescents than children and adults adhered to recommendations for several food groups. Participants with higher socioeconomic status (SES) and living in urban areas consumed more (probability of consuming and/or amount consumed) fruit and vegetables, dairy, and HSFAS products, but they consumed fewer legumes than those of lower SES and living in rural areas. CONCLUSIONS: These results reveal the poor dietary quality of the Mexican population and the urgent need to shift these habits. If current intakes continue, the burden of disease due to obesity and noncommunicable chronic diseases will likely remain elevated in the Mexican population. PMID- 27511941 TI - Plasma Retinol Kinetics and beta-Carotene Bioefficacy Are Quantified by Model Based Compartmental Analysis in Healthy Young Adults with Low Vitamin A Stores. AB - BACKGROUND: Model-based compartmental analysis of data on plasma retinol kinetics after administration of labeled retinol provides unique information about whole body vitamin A metabolism. If labeled beta-carotene is coadministered, its bioefficacy relative to the retinol reference dose can also be estimated. OBJECTIVES: The objectives were to model plasma retinol kinetics after administration of labeled preformed vitamin A and provitamin A beta-carotene and to determine relative beta-carotene bioefficacy. METHODS: We used the Simulation, Analysis and Modeling software (WinSAAM version 3.0.8; http://www.WinSAAM.org) to analyze previously collected data on plasma [13C10]- and [13C5]retinol kinetics for 14 d after oral administration of 1 mg [13C10]retinyl acetate and 2 mg [13C10]beta-carotene in oil to 30 healthy young adults of European ancestry [13 men, 17 women; mean +/- SD age: 24.5 +/- 4.2 y; mean +/- SD body weight: 65.2 +/- 10 kg; mean +/- SD body mass index (in kg/m2): 22.5 +/- 1.9] with moderate vitamin A intakes. RESULTS: A 6-component model provided the best fit to the data, including compartments for initial metabolism of vitamin A, plasma retinol, and extravascular vitamin A storage. The disposal rate was 6.7 +/- 3.1 MUmol/d, fractional catabolic rate was 6.0% +/- 2.3%/d, and vitamin A stores were 123 +/- 71 MUmol. Relative beta-carotene bioefficacy, based on the ratio of the areas under the fraction of dose curves calculated by WinSAAM, averaged 13.5% +/- 6.02% (retinol activity equivalents = 7.7:1.0 MUg). Interindividual variation in relative beta-carotene bioefficacy was high (CV: 44%). CONCLUSIONS: Vitamin A kinetics in these young adults were best described by essentially the same model that had been previously developed by using data for older adults with higher vitamin A stores; differences in parameter values reflected differences in vitamin A status. Estimated beta-carotene bioefficacy was relatively low but similar to previously reported estimates obtained by graphical methods. This trial was registered at the UK Clinical Research Network as UKCRN 7413. PMID- 27511942 TI - From the Cover: Ethylmercury-Induced Oxidative and Endoplasmic Reticulum Stress Mediated Autophagic Cell Death: Involvement of Autophagosome-Lysosome Fusion Arrest. AB - Ethylmercury (EtHg) is derived from the degradation of thimerosal, the most widely used organomercury compound. In this study, EtHg-induced toxicity and autophagy in the mouse kidney was observed and then the mechanism of toxicity was explored in vitro in HK-2 cells. Low doses of EtHg induced autophagy without causing any histopathological changes in mouse kidneys. However, mice treated with high doses of EtHg exhibited severe focal tubular cell necrosis of the proximal tubules with autophagy. EtHg dose-dependently increased the production of reactive oxygen species, reduced the mitochondrial membrane potential, activated the unfolded protein response, and increased cytosolic Ca2+ levels in HK-2 cells. Cell death induced by EtHg exposure was caused by autophagy and necrosis. N-acetyl cysteine and 4-phenylbutyric acid attenuated EtHg-induced stress and ameliorated the autophagic response in HK-2 cells. Furthermore, EtHg blocked autophagosome fusion with lysosomes, which was demonstrated via treatment with wortmannin and chloroquine. Low doses of EtHg and rapamycin, which resulted in minimal cytotoxicity, increased the levels of the autophagic SNARE complex STX17 (syntaxin 17)-VAMP8-SNAP29 without altering mRNA levels, but high dose of EtHg was cytotoxic. Inhibition of autophagic flux by chloroquin increased autophagosome formation and necrotic cell death in HK-2 cells. Collectively, our results show that EtHg induces autophagy via oxidative and ER stress and blockade of autophagic flux. Autophagy might play a dual role in EtHg-induced renal toxicity, being both protective following treatment with low doses of EtHg and detrimental following treatment with high doses. PMID- 27511943 TI - Effects of Capillary Microsampling on Toxicological Endpoints in Juvenile Rats. AB - Blood sampling during juvenile rat toxicology studies is required to determine the toxicokinetic (TK) profile of compounds. Juvenile rats are too small to undergo repeated blood sampling using conventional methods, which collect 200-300 MUl blood at each time point. Recently, capillary microsampling (CMS) gained interest because sample sizes are almost 10 times smaller enabling multi-sample collection from 1 rat. Here, we evaluated the use of CMS in juvenile rats in support of reduced animal usage. Juvenile rats at postnatal day (PND) 4, 10, and 17 underwent CMS via the submandibular, tail, and jugular veins. The CMS methods for pups at different ages were evaluated based on sample quality and technical practicality as well as on acute and chronic changes of toxicological parameters. The best location for CMS was the submandibular vein for PND 4 and 10 pups and the tail vein for PND 17 pups. No effects were found on clinical signs, body and organ weights and biochemistry parameters when 2 * 32 MUl of blood was withdrawn from PND 4 pups or when 3 * 32 MUl was taken from PND 10 and 17 pups within 24 h. Significant changes in several hematology parameters were observed 24 h after CMS due to a decrease of red blood cells and renewed production. These values had recovered to normal 7 days after CMS. CMS is feasible in juvenile rats for TK assessment. Utilizing this method could decrease the number of additional animals by 75%. PMID- 27511944 TI - Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease. AB - Efficient intercellular transfer of RNAs, proteins, and lipids as protected exosomal cargo has been demonstrated in the CNS, but distinct physiologic and pathologic roles have not been well defined for this pathway. The capacity to isolate immunochemically human plasma neuron-derived exosomes (NDEs), containing neuron-specific cargo, has permitted characterization of CNS-derived exosomes in living humans. Constituents of the amyloid beta-peptide (Abeta)42-generating system now are examined in 2 distinct sets of human neural cells by quantification in astrocyte-derived exosomes (ADEs) and NDEs, enriched separately from plasmas of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD) and matched cognitively normal controls. ADE levels of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1), gamma-secretase, soluble Abeta42, soluble amyloid precursor protein (sAPP)beta, sAPPalpha, glial-derived neurotrophic factor (GDNF), P-T181-tau, and P-S396-tau were significantly (3- to 20-fold) higher than levels in NDEs for patients and controls. BACE-1 levels also were a mean of 7-fold higher in ADEs than in NDEs from cultured rat type-specific neural cells. Levels of BACE-1 and sAPPbeta were significantly higher and of GDNF significantly lower in ADEs of patients with AD than in those of controls, but not significantly different in patients with FTD than in controls. Abundant proteins of the Abeta42 peptide-generating system in ADEs may sustain levels in neurons. ADE cargo proteins may be useful for studies of mechanisms of cellular interactions and effects of BACE-1 inhibitors in AD.-Goetzl, E. J., Mustapic, M., Kapogiannis, D., Eitan, E., Lobach, I. V., Goetzl, L., Schwartz, J. B., Miller, B. L. Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease. PMID- 27511946 TI - Inferior vena cava thrombosis as a cause of haemolysis in a patient on ECMO. AB - Haemolysis, thrombosis and haemorrhage are well-documented complications of extracorporeal membrane oxygenation. This case report outlines an unusual case of haemolysis, thought secondary to a large mobile thrombus in the inferior vena cava. PMID- 27511947 TI - Children's Experiences of Epilepsy: A Systematic Review of Qualitative Studies. AB - CONTEXT: Epilepsy is a common and severe neurologic disease associated with increased mortality, seizure-related injury, and adverse psychological and quality-of-life outcomes. OBJECTIVE: To describe the perspectives of children and adolescents with epilepsy. DATA SOURCES: Medline, Embase, PsycINFO, and CINAHL from inception to August 2015. STUDY SELECTION: Qualitative studies on children's experiences of epilepsy. DATA EXTRACTION: Results from primary studies. We used thematic synthesis to analyze the findings. RESULTS: Forty-three articles involving 951 participants aged 3 to 21 years across 21 countries were included. We identified 6 themes: loss of bodily control (being overtaken, susceptibility to physical harm, fragility of the brain, alertness to mortality, incapacitating fatigue), loss of privacy (declarative disease, humiliating involuntary function, unwanted special attention, social embarrassment of medicine-taking), inescapable inferiority and discrimination (vulnerability to prejudice, inability to achieve academically, consciousness of abnormality, parental shame, limiting social freedom), therapeutic burden and futility (unattainable closure, financial burden, overwhelming life disruption, exhaustion from trialing therapies, insurmountable side effects, awaiting a fabled remission), navigating health care (empowerment through information, valuing empathetic and responsive care, unexpected necessity of transition, fragmented and inconsistent care), and recontextualizing to regain normality (distinguishing disease from identity, taking ownership, gaining perspective and maturity, social and spiritual connectedness). LIMITATIONS: Non-English articles were excluded. CONCLUSIONS: Children with epilepsy experience vulnerability, disempowerment, and discrimination. Repeated treatment failure can raise doubt about the attainment of remission. Addressing stigma, future independence, and fear of death may improve the overall well-being of children with epilepsy. PMID- 27511945 TI - Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism. AB - As many as 10% of bone fractures heal poorly, and large bone defects resulting from trauma, tumor, or infection may not heal without surgical intervention. Activation of adenosine A2A receptors (A2ARs) stimulates bone formation. Ticagrelor and dipyridamole inhibit platelet function by inhibiting P2Y12 receptors and platelet phosphodiesterase, respectively, but share the capacity to inhibit cellular uptake of adenosine and thereby increase extracellular adenosine levels. Because dipyridamole promotes bone regeneration by an A2AR-mediated mechanism we determined whether ticagrelor could regulate the cells involved in bone homeostasis and regeneration in a murine model and whether inhibition of P2Y12 or indirect A2AR activation via adenosine was involved. Ticagrelor, dipyridamole and the active metabolite of clopidogrel (CAM), an alternative P2Y12 antagonist, inhibited osteoclast differentiation and promoted osteoblast differentiation in vitro. A2AR blockade abrogated the effects of ticagrelor and dipyridamole on osteoclast and osteoblast differentiation whereas A2BR blockade abrogated the effects of CAM. Ticagrelor and CAM, when applied to a 3-dimentional printed resorbable calcium-triphosphate/hydroxyapatite scaffold implanted in a calvarial bone defect, promoted significantly more bone regeneration than the scaffold alone and as much bone regeneration as BMP-2, a growth factor currently used to promote bone regeneration. These results suggest novel approaches to targeting adenosine receptors in the promotion of bone regeneration.-Mediero, A., Wilder, T., Reddy, V. S. R., Cheng, Q., Tovar, N., Coelho, P. G., Witek, L., Whatling, C., Cronstein, B. N. Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism. PMID- 27511952 TI - Human Neuron Cultures: Micropatterning Facilitates the Long-Term Growth and Analysis of iPSC-Derived Individual Human Neurons and Neuronal Networks (Adv. Healthcare Mater. 15/2016). AB - Dimitri Krainc, Milan Mrksich, and co-workers demonstrate the utility of microcontact printing technology for culturing of human neurons in defined patterns over extended periods of time on page 1894. This approach facilitates studies of neuronal development, cellular trafficking, and related mechanisms that require assessment of individual neurons and neuronal networks. PMID- 27511948 TI - Medicaid Expenditures for Children Remaining at Home After a First Finding of Child Maltreatment. AB - BACKGROUND: Child maltreatment is associated with physical and mental health problems. The objective of this study was to compare Medicaid expenditures based on a first-time finding of child maltreatment by Child Protective Services (CPS). METHODS: This retrospective cohort study included children aged 0 to 14 years enrolled in Utah Medicaid between January 2007 and December 2009. The exposed group included children enrolled in Medicaid during the month of a first-time CPS finding of maltreatment not resulting in out-of-home placement. The unexposed group included children enrolled in Medicaid in the same months without CPS involvement. Quantile regression was used to describe differences in average nonpharmacy Medicaid expenditures per child-year associated with a first-time CPS finding of maltreatment. RESULTS: A total of 6593 exposed children and 39 181 unexposed children contributed 20 670 and 105 982 child-years to this analysis, respectively. In adjusted quantile regression, exposed children at the 50th percentile of health care spending had annual expenditures $78 (95% confidence interval [CI], 65 to 90) higher than unexposed children. This difference increased to $336 (95% CI, 283 to 389) and $1038 (95% CI, 812 to 1264) at the 75th and 90th percentiles of health care spending. Differences were higher among older children, children with mental health diagnoses, and children with repeated episodes of CPS involvement; differences were lower among children with severe chronic health conditions. CONCLUSIONS: Maltreatment is associated with increased health care expenditures, but these costs are not evenly distributed. Better understanding of the reasons for and outcomes associated with differences in health care costs for children with a history of maltreatment is needed. PMID- 27511953 TI - Photothermal Gene Delivery: Stimuli-Regulated Enzymatically Degradable Smart Graphene-Oxide-Polymer Nanocarrier Facilitating Photothermal Gene Delivery (Adv. Healthcare Mater. 15/2016). AB - On page 1918, Won Jong Kim and co-workers use disulfide bonding for the rational design of graphene oxide (GO) based nanocarriers. In the lower left side, photothermally triggered gene release is illustrated in cancer cell. Polymer detached GOis exocytosed, and subsequently gets into the macrophage (middle right). In the macrophage, peroxidase binds to GO, thus degrades it to small fragments which are fluorescent. PMID- 27511954 TI - Designed Stem Cell Aggregates: Enhanced Biological Functions of Human Mesenchymal Stem-Cell Aggregates Incorporating E-Cadherin-Modified PLGA Microparticles (Adv. Healthcare Mater. 15/2016). AB - E-cadherin-modified poly(lactic-co-glycolic acid) (hE-cad-PLGA) microparticles were fabricated and then mediated the 3D cell aggregates of human mesenchymal stem cells (MSCs) on page 1949 by Jun Yang and co-workers. The hE-cad-Fc matrix and the PLGA microparticles synergistically regulate the proliferation and bioactive factors secretions of MSCs by activating EGFR, AKT and ERK1/2 signaling pathways. The hE-cad-PLGA microparticles offer a novel route to expand multipotent stem cell-based clinical applications. PMID- 27511956 TI - Factors That Influence Self-Reported Health Changes With Caregiving. AB - OBJECTIVE: This study examined factors associated with the self-reported change in health status as a result of caregiving. METHOD: Multinomial logistic regression were performed to examine the sociodemographic characteristics, care recipients' characteristics, and caregiving experiences that affect caregivers' perceptions of health affected by caregiving using data from 1,087 caregiver respondents in the Caregiving in the U.S. 2015 data set. Data were collected through an online or telephone survey of randomly selected adults in 50 states. RESULTS: Worsened self-reported health with caregiving occurred for caregivers aged 50 to 64, racial/ethnic minorities, those who lived within 20 min of the care recipient's home, the presence of cognitive deficits, prolonged caregiving, and limited availability of accessible and affordable care services. Importantly, the feeling of choice in taking on care responsibilities was associated with an over fourfold increase in the odds ratio (OR) of better health in response to caregiving (OR = 4.21; confidence interval [CI] = [1.95, 9.08]; p < .001). DISCUSSION: Results suggest that improving accessibility of social service resources to assist caregivers in being better supported and having more choice in caregiving responsibilities may foster a positive change in health status with caregiving. PMID- 27511957 TI - A Novel Exercise Initiative for Seniors to Improve Balance and Physical Function. AB - OBJECTIVE: To investigate the feasibility, effectiveness, and short-term effects of an exercise intervention using a novel exercise park in improving seniors' balance, physical function, and quality of life. METHOD: Randomized controlled trial with pre- and post-intervention design (baseline and 18-week intervention) was used. Outcome measures included measures of balance, strength, and function, as well as quality of life and fear of falling. MANCOVA was used to assess differences between groups (control and exercise intervention) over time. RESULTS: Intervention group showed significant improvement on single leg stance ( p = .02, 95% confidence interval [CI] = [-8.35, -0.549]), knee strength ( p < .01, 95% CI = [-29.14, -5.86]), 2-min walk ( p = 0.02, 95% CI = [-19.13, 0.859]), and timed sit to stand ( p = .03, 95% CI = [-2.26, -0.143]) tests. DISCUSSION: The exercise park program improved physical function and had high adherence and participation rate. Such intervention has been shown to be safe and therefore might enhance participation in exercise programs for older adults. PMID- 27511958 TI - One-Pot Synthesis of Highly Anisotropic Five-Fold-Twinned PtCu Nanoframes Used as a Bifunctional Electrocatalyst for Oxygen Reduction and Methanol Oxidation. AB - Five-fold-twinned PtCu nanoframes (NFs) with nanothorns protruding from their edges are synthesized by a facile one-pot method. Compared to commercial Pt/C catalyst, the obtained highly anisotropic five-fold-twinned PtCu NFs show enhanced electrocatalytic performance toward the oxygen reduction reaction and methanol oxidation reaction under alkaline conditions. PMID- 27511959 TI - Eha, a regulator of Edwardsiella tarda, required for resistance to oxidative stress in macrophages. AB - Edwardsiella tarda is distributed widely in a variety of hosts. Eha has recently been found to be its virulence regulator. In order to explore the mechanism of its regulation, we investigated the survival rates of wild type strain ET13, and its eha mutant and complemented strains in RAW264.7 macrophages under light microscopic observation as well as by counting bacterial CFUs on the plates. All of the different strains could live within the macrophages; however, the intracellular numbers of the wild type were significantly higher than the mutant when the incubation time extended 4 h or 6 h (P < 0.05). Furthermore, more ROS were produced by the mutant-infected cells, indicating that Eha may enhance ET13's capacity to detoxify ROS. In agreement with this, we found that the mutant exhibited more sensitivity by H2O2 disk inhibitory assay and less survival ability with H2O2 treatment. We further demonstrated that the bacterial antioxidant enzymes SodC and KatG were regulated by Eha with qRT-PCR and beta galactosidase assay. Collectively, our data show Eha is required for E. tarda to resist the oxidative stress from the macrophages. PMID- 27511960 TI - Fast and Robust Nanocellulose Width Estimation Using Turbidimetry. AB - The dimensions of nanocelluloses are important factors in controlling their material properties. The present study reports a fast and robust method for estimating the widths of individual nanocellulose particles based on the turbidities of their water dispersions. Seven types of nanocellulose, including short and rigid cellulose nanocrystals and long and flexible cellulose nanofibers, are prepared via different processes. Their widths are calculated from the respective turbidity plots of their water dispersions, based on the theory of light scattering by thin and long particles. The turbidity-derived widths of the seven nanocelluloses range from 2 to 10 nm, and show good correlations with the thicknesses of nanocellulose particles spread on flat mica surfaces determined using atomic force microscopy. PMID- 27511961 TI - A review of the ecosystem functions in oil palm plantations, using forests as a reference system. AB - Oil palm plantations have expanded rapidly in recent decades. This large-scale land-use change has had great ecological, economic, and social impacts on both the areas converted to oil palm and their surroundings. However, research on the impacts of oil palm cultivation is scattered and patchy, and no clear overview exists. We address this gap through a systematic and comprehensive literature review of all ecosystem functions in oil palm plantations, including several (genetic, medicinal and ornamental resources, information functions) not included in previous systematic reviews. We compare ecosystem functions in oil palm plantations to those in forests, as the conversion of forest to oil palm is prevalent in the tropics. We find that oil palm plantations generally have reduced ecosystem functioning compared to forests: 11 out of 14 ecosystem functions show a net decrease in level of function. Some functions show decreases with potentially irreversible global impacts (e.g. reductions in gas and climate regulation, habitat and nursery functions, genetic resources, medicinal resources, and information functions). The most serious impacts occur when forest is cleared to establish new plantations, and immediately afterwards, especially on peat soils. To variable degrees, specific plantation management measures can prevent or reduce losses of some ecosystem functions (e.g. avoid illegal land clearing via fire, avoid draining of peat, use of integrated pest management, use of cover crops, mulch, and compost) and we highlight synergistic mitigation measures that can improve multiple ecosystem functions simultaneously. The only ecosystem function which increases in oil palm plantations is, unsurprisingly, the production of marketable goods. Our review highlights numerous research gaps. In particular, there are significant gaps with respect to socio-cultural information functions. Further, there is a need for more empirical data on the importance of spatial and temporal scales, such as differences among plantations in different environments, of different sizes, and of different ages, as our review has identified examples where ecosystem functions vary spatially and temporally. Finally, more research is needed on developing management practices that can offset the losses of ecosystem functions. Our findings should stimulate research to address the identified gaps, and provide a foundation for more systematic research and discussion on ways to minimize the negative impacts and maximize the positive impacts of oil palm cultivation. PMID- 27511962 TI - Optimizing electrical impedance myography of the tongue in amyotrophic lateral sclerosis. AB - INTRODUCTION: Electrical impedance myography (EIM) can quantify muscle health at a range of frequencies, including that most commonly employed, 50 kHz. However, disease-related changes in EIM data suggest the distinction between normal and patient EIM values could be more apparent at frequencies of >50 kHz. We investigated at what other selected frequencies tongue EIM may differentiate healthy individuals and amyotrophic lateral sclerosis (ALS) patients, remain reliable, and correlate with a standard metric of bulbar function. METHODS: Tongue EIM phase data from 30 volunteers and 11 ALS patients were analyzed at 6 discrete frequencies from 50 to 500 kHz. RESULTS: Of the frequencies assessed, EIM demonstrated maximal separation and reliability at 100 kHz, where phase value was also significantly correlated with the bulbar subscore on the revised version of the ALS Functional Rating Scale. CONCLUSIONS: One hundred kilohertz could serve as an optimal frequency at which to measure EIM phase values of the tongue in ALS. Muscle Nerve 55: 539-543, 2017. PMID- 27511963 TI - Establishing estrogen-responsive mouse mammary organoids from single Lgr5+ cells. AB - Recent evidence suggests that mammary cells expressing R-spondin receptor and Wnt pathway regulator Lgr5, regarded as a stem cell marker in multiple tissues, might represent mammary stem cells (MaSCs). Whether L gr5 marks a multipotent subpopulation of Lin-CD24low/medCD49fhigh MaSCs remains controversial. To some extent the differing results reflect different assays used to assess properties of stemness, including lineage tracing in vivo, mammosphere culture, and mammary fat pad transplantation assays. To address this issue directly, we isolated Lgr5+ cells from mammary glands of Lgr5-lacZ mice and established organoids based on principles adapted from studies of Wnt-driven Lgr5+ cell populations in other organs. Mammary organoids were grown from single Lgr5+ mammary cells in Matrigel, the substratum of choice for intestinal organoids, and in a growth factor cocktail containing EGF, Wnt3a and R-spondin, designed to optimally activate the endogenous Wnt signaling program of stem cells. Colonies derived from single Lgr5+ cells manifest at least four distinct cell populations: Lgr5+ and Lgr5- basal cells and c-Kit+ and c-Kit- luminal cells that spontaneously organize into a ductal structure with basal cells around the periphery and luminal cells lining an interior cavity, reminiscent of normal mammary duct structure. Lgr5+ cell derived organoids were sustainable during prolonged passaging. In contrast, although Lgr5- cells expand into primary colonies, colony-forming efficiency immediately dissipated upon passaging. Furthermore, reproductive hormones induce epithelial cell proliferation resulting in marked increases in lumen diameter accompanied by squamous transdifferentiation. We propose this estrogen responsive, self-organizing duct-like structure derived from single murine Lgr5+ mammary cells represents a "mini-breast" organoid. PMID- 27511964 TI - Respiratory and oral vaccination improves protection conferred by the live vaccine strain against pneumonic tularemia in the rabbit model. AB - Tularemia is a severe, zoonotic disease caused by a gram-negative bacterium, Francisella tularensis We have previously shown that rabbits are a good model of human pneumonic tularemia when exposed to aerosols containing a virulent, type A strain, SCHU S4. We further demonstrated that the live vaccine strain (LVS), an attenuated type B strain, extended time to death when given by scarification. Oral or aerosol vaccination has been previously shown in humans to offer superior protection to parenteral vaccination against respiratory tularemia challenge. Both oral and aerosol vaccination with LVS were well tolerated in the rabbit with only minimal fever and no weight loss after inoculation. Plasma antibody titers against F. tularensis were higher in rabbits that were vaccinated by either oral or aerosol routes compared to scarification. Thirty days after vaccination, all rabbits were challenged with aerosolized SCHU S4. LVS given by scarification extended time to death compared to mock-vaccinated controls. One orally vaccinated rabbit did survive aerosol challenge, however, only aerosol vaccination extended time to death significantly compared to scarification. These results further demonstrate the utility of the rabbit model of pneumonic tularemia in replicating what has been reported in humans and macaques as well as demonstrating the utility of vaccination by oral and respiratory routes against an aerosol tularemia challenge. PMID- 27511966 TI - Relation Between Lack of Forgiveness and Depression: The Moderating Effect of Self-Compassion. AB - Although an association between lack of forgiveness and poor mental health is known, prior studies have reported mixed findings of the relationship between lack of forgiveness and depressive symptoms. In an attempt to explain the strength differences between lack of forgiveness and depressive symptoms, this study examined the moderating effect of self-compassion. A total of 311 Korean teachers (89 men, 222 women; M age = 39.3 year, SD = 9.1) were asked to complete self-report questionnaires, including the Korean versions of the Trait Forgivingness Scale, the Self-Compassion Scale, and the Center for Epidemiologic Studies Depression Scale. Moderated multiple regression was used for analysis, and a buffering interaction of self-compassion was discovered. Specifically, self compassion moderated the relationship between lack of forgiveness and depression; the relationship was stronger for those low on self-compassion. PMID- 27511965 TI - The Risk of Atrial Fibrillation With Ivabradine Treatment: A Meta-analysis With Trial Sequential Analysis of More Than 40000 Patients. AB - Recent trials reported that risk of atrial fibrillation (AF) is increased in patients using ivabradine compared with controls. We performed this meta-analysis to investigate the risk of AF association with ivabradine treatment on the basis of data obtained from randomized controlled trials (RCTs). We searched PubMed, EMBASE, Scopus, and the Cochrane Library for RCTs that comprised >100 patients. The incidence of AF was assessed. We obtained data from European Medicines Agency (EMA) scientific reports for the RCTs in which the incidence of AF was not reported. We used trial sequential analysis (TSA) to provide information on when we had reached firm evidence of new AF based on a 15% relative risk increase (RRI) in ivabradine treatment. Three RCTs and 1 EMA overall oral safety set (OOSS) pooled analysis (included 5 RCTs) were included in the meta-analysis (N = 40 437). The incidence of AF was 5.34% in patients using ivabradine and 4.56% in placebo. There was significantly higher incidence of AF (24% RRI) in the ivabradine group when compared with placebo before (RR: 1.24, 95% confidence interval: 1.08-1.42, P = 0.003, I 1980 = 53%) and after excluding OOSS (RR: 1.24, 95% confidence interval: 1.06-1.44, P = 0.008). In the TSA, the cumulative z curve crossed both the traditional boundary (P = 0.05) and the trial sequential monitoring boundary, indicating firm evidence for >=15% increase in ivabradine treatment when compared with placebo. Study results indicate that AF is more common in the ivabradine group (24% RRI) than in controls. PMID- 27511967 TI - Relationships Between Refraining From Catastrophic Thinking, Repetitive Negative Thinking, and Psychological Distress. AB - Skills to refrain from catastrophic thinking were negatively related to worry and a wide range of psychological distress. Repetitive negative thinking (including worry) is proposed as a common etiological factor for a wide range of psychological distress. Therefore, reduced repetitive negative thinking would mediate the negative relation between refraining from catastrophic thinking and psychological distress (depression, social anxiety, phobia, generalized anxiety, and obsessions and compulsions). As an overlap between five indices of psychological distress was expected, we first computed latent factors underlying them, which were then predicted by refraining from catastrophic thinking and repetitive negative thinking. Cross-sectional questionnaire data from 125 nonclinical voluntarily participating students (M age = 19.0 years, SD = 3.6; 54% women) supported the predictions: refraining from catastrophic thinking was negatively correlated with depression, social anxiety, phobia, generalized anxiety, and obsession and compulsion. Repetitive negative thinking mediated the negative relationship between refraining from catastrophic thinking and latent factors underlying psychological distress (Fear and Distress). Refraining from catastrophic thinking may be negatively correlated with psychological distress due to its negative relation to repetitive negative thinking. PMID- 27511968 TI - Psychological insulin resistance: scope of the problem. PMID- 27511969 TI - Babesiosis acquired from a pet dog: a second reported case in Hong Kong. PMID- 27511970 TI - Intracoronary thrombus in an 18-year-old teenager. Why? PMID- 27511971 TI - Neurocysticercosis in a young Indian male. PMID- 27511972 TI - Crowned dens syndrome: an uncommon cause of cord compression. PMID- 27511973 TI - Myocardial Contrast Stress Echo Versus Fractional Flow Reserve: A Fair Fight Among Ischemic Tests? PMID- 27511974 TI - Cardiac Magnetic Resonance-Measured Left Atrial Volume and Function and Incident Atrial Fibrillation: Results From MESA (Multi-Ethnic Study of Atherosclerosis). AB - BACKGROUND: Early detection of structural changes in left atrium (LA) before atrial fibrillation (AF) development could be helpful in identification of those at higher risk for AF. Using cardiac magnetic resonance imaging, we examined the association of LA volume and function, and incident AF in a multiethnic population free of clinical cardiovascular diseases. METHODS AND RESULTS: In a case-cohort study embedded in MESA (Multi-Ethnic Study of Atherosclerosis), baseline LA size and function assessed by cardiac magnetic resonance feature tracking were compared between 197 participants with incident AF and 322 participants randomly selected from the whole MESA cohort. Participants were followed up for 8 years. Incident AF cases had a larger LA volume and decreased passive, active, and total LA emptying fractions and peak global LA longitudinal strain (peak LA strain) at baseline. In multivariable analysis, elevated LA maximum volume index (hazard ratio, 1.38 per SD; 95% confidence interval, 1.01 1.89) and decreased peak LA strain (hazard ratio, 0.68 per SD; 95% confidence interval, 0.48-0.96), and passive and total LA emptying fractions (hazard ratio for passive LA emptying fractions, 0.55 per SD; 95% confidence interval, 0.40 0.75 and hazard ratio for active LA emptying fractions, 0.70 per SD; 95% confidence interval, 0.52-0.95), but not active LA emptying fraction, were associated with incident AF. CONCLUSIONS: Elevated LA volumes and decreased passive and total LA emptying fractions were independently associated with incident AF in an asymptomatic multiethnic population. Including LA functional variables along with other risk factors of AF may help to better risk stratify individuals at risk of AF development. PMID- 27511975 TI - Sex Differences in Nonculprit Coronary Plaque Microstructures on Frequency-Domain Optical Coherence Tomography in Acute Coronary Syndromes and Stable Coronary Artery Disease. AB - BACKGROUND: Numerous reports suggest sex-related differences in atherosclerosis. Frequency-domain optical coherence tomography has enabled visualization of plaque microstructures associated with disease instability. The prevalence of plaque microstructures between sexes has not been characterized. We investigated sex differences in plaque features in patients with coronary artery disease. METHODS AND RESULTS: Nonculprit plaques on frequency-domain optical coherence tomography imaging were compared between men and women with either stable coronary artery disease (n=320) or acute coronary syndromes (n=115). A greater prevalence of cardiovascular risk factors was observed in women. Nonculprit plaques in women with stable coronary artery disease were more likely to exhibit plaque erosion (8.6% versus 0.3%; P=0.03) and a smaller lipid arc (163.1+/-71.4 degrees versus 211.2+/-71.2 degrees ; P=0.03), and less likely to harbor cholesterol crystals (17.2% versus 27.5%; P=0.01) and calcification (15.4% versus 34.4%; P=0.008), whereas fibrous cap thickness (105.2+/-62.1 versus 96.1+/-40.4 um; P=0.57), the prevalence of thin-cap fibroatheroma (26.5% versus 25.2%; P=0.85), and microchannels (19.2% versus 20.5%; P=0.95) were comparable. In women with acute coronary syndrome, a smaller lipid arc (171.6+/-53.2 degrees versus 235.8+/-86.4 degrees ; P=0.03), a higher frequency of plaque erosion (11.4% versus 0.6%; P=0.04), and a lower prevalence of cholesterol crystal (28.6% versus 38.2%; P=0.03) and calcification (10.0% versus 23.7%; P=0.01) were observed. These differences persisted after adjusting clinical demographics. Although thin-cap fibroatheromas in men clustered within proximal arterial segments, thin-cap fibroatheromas were evenly distributed in women. CONCLUSIONS: Despite more comorbid risk factors in women, their nonculprit plaques exhibited more plaque erosion, and less cholesterol and calcium content. This distinct phenotype suggests sex-related differences in the pathophysiology of atherosclerosis. PMID- 27511976 TI - Understanding the Risk to Develop Atrial Fibrillation: And What Cardiac Magnetic Resonance Can Add. PMID- 27511977 TI - Insights Into Coronary Plaque Microstructure Differences Between Women and Men. PMID- 27511978 TI - Comparison of Fractional Flow Reserve Assessment With Demand Stress Myocardial Contrast Echocardiography in Angiographically Intermediate Coronary Stenoses. AB - BACKGROUND: Real-time myocardial contrast echocardiography (RTMCE) directly measures capillary flow (CBF), which in turn is a major regulator of coronary flow and resistance during demand or hyperemic stress. Although fractional flow reserve (FFR) was developed to assess the physiological relevance of an epicardial stenosis, it assumes maximal microvascular vasodilation and minimal resistance during vasodilator stress. Therefore, we sought to determine the relationship between CBF assessed with RTMCE during stress echocardiography and FFR in intermediate coronary lesions. METHODS AND RESULTS: Sixty-seven vessels with 50% to 80% diameter stenoses by quantitative coronary angiography in 58 consecutive patients were examined with FFR and RTMCE (mean age, 60+/-13 years). RTMCE was performed using an incremental dobutamine (n=32) or exercise (n=26) stress protocol, and myocardial perfusion was assessed using a continuous infusion of ultrasound contrast. The presence or absence of inducible perfusion defects and wall motion abnormalities were correlated with FFR. Mean percent diameter stenosis was 60+/-9%. Eighteen stenoses (27%) had an FFR <= 0.8. Although 17 of the 18 stenoses that were FFR+ had abnormal CBF during RTMCE, 28 of the 49 stenoses (57%) that were FFR had abnormal CBF, and 24 (49%) had abnormal wall motion in the corresponding coronary artery territory during stress echocardiography. CONCLUSIONS: In a significant percentage of intermediate stenoses with normal FFR values, CBF during demand stress is reduced, resulting in myocardial ischemia. PMID- 27511980 TI - Prognostic Significance of Occult Transthyretin Cardiac Amyloidosis in Patients With Severe Aortic Stenosis Undergoing Surgical Aortic Valve Replacement: An Unrecognized Disease Modifier. PMID- 27511979 TI - Occult Transthyretin Cardiac Amyloid in Severe Calcific Aortic Stenosis: Prevalence and Prognosis in Patients Undergoing Surgical Aortic Valve Replacement. AB - BACKGROUND: Calcific aortic stenosis (cAS) affects 3% of individuals aged >75 years, leading to heart failure and death unless the valve is replaced. Wild-type transthyretin cardiac amyloid is also a disorder of ageing individuals. Prevalence and clinical significance of dual pathology are unknown. This study explored the prevalence of wild-type transthyretin amyloid in cAS by myocardial biopsy, its imaging phenotype and prognostic significance. METHODS AND RESULTS: A total of 146 patients with severe AS requiring surgical valve replacement underwent cardiovascular magnetic resonance and intraoperative biopsies; 112 had cAS (75+/-6 years; 57% men). Amyloid was sought histologically using Congo red staining and then typed using immunohistochemistry and mass spectrometry; patients with amyloid underwent clinical evaluation including genotyping and (99m)TC-3,3-diphosphono-1,2-propanodicarboxylic-acid (DPD) bone scintigraphy. Amyloid was identified in 6 of 146 patients, all with cAS and >65 years (prevalence 5.6% in cAS >65). All 6 patients had wild-type transthyretin amyloid (mean age 75 years; range, 69-85; 4 men), not suspected on echocardiography. Cardiovascular magnetic resonance findings were of definite cardiac amyloidosis in 2, but could be explained solely by AS in the other 4. Postoperative DPD scans demonstrated cardiac localization in all 4 patients who had this investigation (2 died prior). At follow-up (median, 2.3 years), 50% with amyloid had died (versus 7.5% in cAS; 6.9% in age >65 years). In univariable analyses, the presence of transthyretin amyloidosis amyloid had the highest hazard ratio for death (9.5 [95% confidence interval, 2.5-35.8]; P=0.001). CONCLUSIONS: Occult wild-type transthyretin cardiac amyloid had a prevalence of 6% among patients with AS aged >65 years undergoing surgical aortic valve replacement and was associated with a poor outcome. PMID- 27511981 TI - Bone cement with a modified polyphosphate network structure stimulates hard tissue regeneration. AB - In this study, a calcium polyphosphate cement (CpPC) consisting of basic components was investigated to assess its potential for hard tissue regeneration. The added basic components for improving the structural stability, which controlled the setting time, where the setting reaction resulted in the formation of amorphous structure with a re-constructed polyphosphate. Moreover, the characteristics were controlled by the composition, which determined the polyphosphate structure. CpPC exhibited outstanding dissolution rate compared with the common biodegradable cement, brushite cement (2.5 times). Despite high amounts of dissolution products, no significant cytotoxicity ensued. Induction of calcification in MG-63 cells treated with CpPC, the level of calcification increased with increasing CpPC dissolution rate. Induced calcification was observed also in CpPC-treated ST2 cells, in contrast with MG-63 and ST2 treated with brushite cement, for which no calcification was observed. In vivo tests using a rat calvarial defect model showed that resorbed CpPC resulted in favorable host responses and promoted bone formation. Additionally, there was a significant increase in defect closure, and new bone formation progressed from CpPC mid-sites as well as defect margins. From these results, CpPC exhibits significant potential as biodegradable bone substitute for bone regeneration. PMID- 27511982 TI - Elution profiles of tobramycin and vancomycin from high-purity calcium sulphate beads incubated in a range of simulated body fluids. AB - The aim of this study was to characterise the elution profiles of antibiotics in combination with pharmaceutical grade calcium sulphate beads in phosphate buffered saline and other physiological solutions which more closely mimic the in vivo environment. Synthetic recrystallised calcium sulphate was combined with vancomycin hydrochloride powder and tobramycin sulphate solution and the paste was formed into 3 mm diameter hemispherical beads. Then 2 g of beads were immersed in 2 ml of either phosphate buffered saline, Dulbecco's Modified Eagle Medium or Hartmann's solution and incubated at 37C for up to 21 days. At a range of time points, eluent was removed for analysis by liquid chromatography-mass spectrometry (LC-MS). Tobramycin sulphate and vancomycin hydrochloride release was successfully quantified against standard curves from solutions eluted in all three physiological media (phosphate buffered saline, Dulbecco's Modified Eagle Medium and Hartmann's solution) during incubation with calcium sulphate beads. One hour eluate concentrations were high, up to 2602 ug/ml for tobramycin in phosphate buffered saline and 7417 ug/ml for vancomycin, whereas in DMEM, the levels of tobramycin were 2458 ug/ml and 4401 ug/ml for vancomycin. The levels in HRT were 2354 ug/ml for tobramycin and 5948 ug/ml for vancomycin. The results show highest levels of antibiotic elution over the first 24 h, which gradually diminish over the following 21 days. PMID- 27511983 TI - Extrapancreatic effects of incretin hormones: evidence for weight-independent changes in morphological aspects and oxidative status in insulin-sensitive organs of the obese nondiabetic Zucker rat (ZFR). AB - Incretin-based therapies are widely used to treat type 2 diabetes. Although hypoglycemic actions of incretins are mostly due to their insulinotropic/glucagonostatic effects, they may also influence extrapancreatic metabolism. We administered exendin-4 (Ex-4), a long-acting glucagon-like peptide receptor agonist, at low dose (0.1 nmol/kg/day) for a short period (10 days), in obese nondiabetic fa/fa Zucker rats (ZFRs). Ex-4-treated ZFRs were compared to vehicle (saline)-treated ZFRs and vehicle- and Ex-4-treated lean rats (LRs). Blood glucose levels were measured at days 0, 9, and 10. Ingested food and animal weight were recorded daily. On the day of sacrifice (d10), blood was sampled along with liver, epididymal, subcutaneous, brown adipose, and skeletal muscle tissues from animals fasted for 24 h. Plasma insulin and blood glucose levels, food intake, and body and epididymal fat weight were unchanged, but gross morphological changes were observed in insulin-sensitive tissues. The average size of hepatocytes was significantly lower in Ex-4-treated ZFRs, associated with decreased number and size of lipid droplets and 4-hydroxy-2-nonenal (HNE) staining, a marker of oxidative stress (OS). Myocytes, which were smaller in ZFRs than in LRs, were significantly enlarged and depleted of lipid droplets in Ex-4 treated ZFRs. Weak HNE staining was increased by Ex-4. A similar observation was made in brown adipose tissue, whereas the elevated HNE staining observed in epididymal adipocytes of ZFRs, suggestive of strong OS, was decreased by Ex-4. These results suggest that incretins by acting on OS in insulin-sensitive tissues may contribute to weight-independent improvement in insulin sensitivity. PMID- 27511984 TI - Mitochondrial function assessed by 31P MRS and BOLD MRI in non-obese type 2 diabetic rats. AB - The study aims to characterize age-associated changes in skeletal muscle bioenergetics by evaluating the response to ischemia-reperfusion in the skeletal muscle of the Goto-Kakizaki (GK) rats, a rat model of non-obese type 2 diabetes (T2D). (31)P magnetic resonance spectroscopy (MRS) and blood oxygen level dependent (BOLD) MRI was performed on the hindlimb of young (12 weeks) and adult (20 weeks) GK and Wistar (control) rats. (31)P-MRS and BOLD-MRI data were acquired continuously during an ischemia and reperfusion protocol to quantify changes in phosphate metabolites and muscle oxygenation. The time constant of phosphocreatine recovery, an index of mitochondrial oxidative capacity, was not statistically different between GK rats (60.8 +/- 13.9 sec in young group, 83.7 +/- 13.0 sec in adult group) and their age-matched controls (62.4 +/- 11.6 sec in young group, 77.5 +/- 7.1 sec in adult group). During ischemia, baseline normalized BOLD-MRI signal was significantly lower in GK rats than in their age matched controls. These results suggest that insulin resistance leads to alterations in tissue metabolism without impaired mitochondrial oxidative capacity in GK rats. PMID- 27511985 TI - The response of muscle protein synthesis following whole-body resistance exercise is greater following 40 g than 20 g of ingested whey protein. AB - The currently accepted amount of protein required to achieve maximal stimulation of myofibrillar protein synthesis (MPS) following resistance exercise is 20-25 g. However, the influence of lean body mass (LBM) on the response of MPS to protein ingestion is unclear. Our aim was to assess the influence of LBM, both total and the amount activated during exercise, on the maximal response of MPS to ingestion of 20 or 40 g of whey protein following a bout of whole-body resistance exercise. Resistance-trained males were assigned to a group with lower LBM (<=65 kg; LLBM n = 15) or higher LBM (>=70 kg; HLBM n = 15) and participated in two trials in random order. MPS was measured with the infusion of (13)C6-phenylalanine tracer and collection of muscle biopsies following ingestion of either 20 or 40 g protein during recovery from a single bout of whole-body resistance exercise. A similar response of MPS during exercise recovery was observed between LBM groups following protein ingestion (20 g - LLBM: 0.048 +/- 0.018%.h(-1); HLBM: 0.051 +/- 0.014%.h(-1); 40 g - LLBM: 0.059 +/- 0.021%.h(-1); HLBM: 0.059 +/- 0.012%.h(-1)). Overall (groups combined), MPS was stimulated to a greater extent following ingestion of 40 g (0.059 +/- 0.020%.h(-1)) compared with 20 g (0.049 +/- 0.020%.h(-1); P = 0.005) of protein. Our data indicate that ingestion of 40 g whey protein following whole-body resistance exercise stimulates a greater MPS response than 20 g in young resistance-trained men. However, with the current doses, the total amount of LBM does not seem to influence the response. PMID- 27511986 TI - Clinical predictors for high-grade bladder cancer before first-time transurethral resection of the bladder tumor: a retrospective cohort study. AB - The aim of this study was to identify the clinical predictors related to the risk of high-grade bladder cancer before first-time transurethral resection of the bladder tumor (TUR-Bt) and to externally validate the accuracy of Shapur's nomogram predicting the risk of high-grade bladder cancer in Japanese patients. As a result, episode of gross hematuria (odds ratio: 2.68, P = 0.02), larger tumor size (odds ratio: 1.89, P < 0.01) and positive urinary cytology (odds ratio: 8.34, P < 0.01) were found to be significant predictors for high-grade bladder cancer. Furthermore, the nomogram showed a high predictive accuracy in our Japanese population (area under the curve: 0.79). Clinicians will be able to predict high-grade bladder cancer using the common factors in Shapur's study and ours, such as tumor size and urinary cytology, and gross hematuria as the additional factor first identified here to decide priorities for the treatment of patients diagnosed with bladder cancer. PMID- 27511988 TI - Dosimetric comparison between proton beam therapy and photon radiation therapy for locally advanced non-small cell lung cancer. AB - OBJECTIVE: To assess the feasibility of proton beam therapy for the patients with locally advanced non-small lung cancer. METHODS: The dosimetry was analyzed retrospectively to calculate the doses to organs at risk, such as the lung, heart, esophagus and spinal cord. A dosimetric comparison between proton beam therapy and dummy photon radiotherapy (three-dimensional conformal radiotherapy) plans was performed. Dummy intensity-modulated radiotherapy plans were also generated for the patients for whom curative three-dimensional conformal radiotherapy plans could not be generated. RESULTS: Overall, 33 patients with stage III non-small cell lung cancer were treated with proton beam therapy between December 2011 and August 2014. The median age of the eligible patients was 67 years (range: 44-87 years). All the patients were treated with chemotherapy consisting of cisplatin/vinorelbine or carboplatin. The median prescribed dose was 60 GyE (range: 60-66 GyE). The mean normal lung V20 GyE was 23.6% (range: 14.9-32%), and the mean normal lung dose was 11.9 GyE (range: 6.0 19 GyE). The mean esophageal V50 GyE was 25.5% (range: 0.01-63.6%), the mean heart V40 GyE was 13.4% (range: 1.4-29.3%) and the mean maximum spinal cord dose was 40.7 GyE (range: 22.9-48 GyE). Based on dummy three-dimensional conformal radiotherapy planning, 12 patients were regarded as not being suitable for radical thoracic three-dimensional conformal radiotherapy. All the dose parameters of proton beam therapy, except for the esophageal dose, were lower than those for the dummy three-dimensional conformal radiotherapy plans. In comparison to the intensity-modulated radiotherapy plan, proton beam therapy also achieved dose reduction in the normal lung. None of the patients experienced grade 4 or worse non-hematological toxicities. CONCLUSIONS: Proton beam therapy for patients with stage III non-small cell lung cancer was feasible and was superior to three-dimensional conformal radiotherapy for several dosimetric parameters. PMID- 27511987 TI - Secondhand smoke exposure and risk of lung cancer in Japan: a systematic review and meta-analysis of epidemiologic studies. AB - OBJECTIVE: Systematic evaluation of the association between secondhand smoke exposure and lung cancer in Japan has yet to be conducted. Here, we performed a systematic review and meta-analysis of the relationship between secondhand smoke and lung cancer in Japanese non-smokers. METHODS: Relevant studies were collected from the MEDLINE and Ichushi Web databases using a combination of search terms and Medical Subject Headings. Eligible studies were identified, and relative risks or odds ratios were extracted to calculate pooled risk estimates. This procedure was performed independently by at least two authors. Stratified analyses were carried out according to study design, publication year, and whether or not potential confounding variables were accounted for. The presence of publication bias was assessed via funnel plots. RESULTS: We identified four cohort studies and five case-control studies. Quantitative synthesis was conducted only for secondhand smoke exposure in the home during adulthood. Of the 12 populations included in meta-analysis, positive secondhand smoke exposure-lung cancer associations were observed in 11, whereas an inverse association was found in the remaining 1. The pooled relative risk of lung cancer associated with secondhand smoke exposure was 1.28 (95% confidence interval: 1.10-1.48). We found no evidence of publication bias, and a significant association remained even when potentially missing studies were included (pooled relative risk: 1.26; 95% confidence interval: 1.09-1.46). The results were stable across different subgroup analyses, including by study design, publication year, and when adjusting for confounding variables. CONCLUSIONS: Secondhand smoke exposure in the home during adulthood results in a statistically significant increase in the risk of lung cancer. PMID- 27511989 TI - Patterns of failure after postoperative intensity-modulated radiotherapy for locally advanced and recurrent head and neck cancer. AB - OBJECTIVE: To evaluate the feasibility of postoperative intensity-modulated radiotherapy for head and neck cancer by investigating the patterns of failure after this therapy. METHODS: A retrospective chart review was performed. RESULTS: Between March 2006 and December 2013, 122 consecutive patients with head and neck squamous cell carcinoma were treated by surgery followed by postoperative intensity-modulated radiotherapy. In regard to the site of the primary tumor, 59 (48%) patients had cancer of the oral cavity, 31 (26%) patients had cancer of the hypopharynx, 14 (11%) patients had cancer of the oropharynx, 10 (8%) patients had cancer of the larynx and 8 (7%) patients had cancer of unknown primary. The median follow-up period of the surviving patients was 54 months (range, 25-115). Concurrent chemotherapy was administered in 76 patients (62%). The median prescribed radiation dose was 66 Gy. The 3-year overall survival, progression free survival, distant metastasis free survival and loco-regional control rates were 59%, 48%, 52.4% and 71%, respectively. Of the 122 patients, 32 developed loco-regional recurrence as the initial recurrence, including in-field recurrence in 26 patients, marginal recurrence in five patients and out-field recurrence in seven patients. Of the five patients with marginal recurrence, four have had two or more surgeries before the intensity-modulated radiotherapy and three had oral cavity cancer. Severe adverse events were not frequent, occurring at a frequency of <5%, except for mucositis. No severe toxicities associated with the flap reconstruction were observed either. CONCLUSION: Postoperative intensity modulated radiotherapy appears to be effective and feasible for patients with head and neck squamous cell carcinoma. PMID- 27511990 TI - Relationship of tumor PD-L1 expression with EGFR wild-type status and poor prognosis in lung adenocarcinoma. AB - BACKGROUND: Programmed death-ligand 1 is an immune modulator that promotes immunosuppression by binding to programmed death-1 of T-lymphocytes. Whereas programmed death-ligand 1 expression has been shown to be associated with the clinical response to anti-programmed death-ligand 1 antibody, the association of tumor programmed death-ligand 1 expression with clinicopathological/molecular features and with prognosis remains inconclusive in lung adenocarcinoma. We therefore examined the association of programmed death-ligand 1 expression with the clinicopathological/molecular features and prognosis of lung adenocarcinoma. METHODS: Using tissue microarrays of 268 consecutive cases of lung adenocarcinoma, we evaluated programmed death-ligand 1 expression by immunohistochemistry. We examined the association of programmed death-ligand 1 expression with clinicopathological and molecular features. We also examined the prognostic association of programmed death-ligand 1 expression, using the log rank test as well as Cox proportional hazards regression models to compute the mortality hazard ratio (HR). RESULTS: Programmed death-ligand 1 immunoreactivity (at least 5% of the tumor cells) was observed in 43 (16%) of 268 cases of lung adenocarcinoma. Programmed death-ligand 1 positivity was associated with less tumor differentiation (P < 0.0001) and EGFR wild-type status (P = 0.0008). In a multivariable logistic regression analysis, less tumor differentiation was independently associated with programmed death-ligand 1 positivity (multivariable odds ratio, 6.54; 95% confidence interval [CI], 2.37-23.3; P = 0.0001). Programmed death-ligand 1 positivity was associated with a poor prognosis for lung cancer-specific survival (log-rank, P = 0.019; HR, 1.73; 95% CI, 1.06-2.72; P = 0.030) and overall survival (log-rank, P = 0.0014; HR, 1.88; 95% CI, 1.25 2.74). CONCLUSION: Our study demonstrated that programmed death-ligand 1 positivity in lung adenocarcinoma was associated with less tumor differentiation and EGFR wild-type status, as well as a poor prognosis. PMID- 27511991 TI - A simple home-based self-monitoring tool for early detection of hand-foot syndrome in cancer patients. AB - OBJECTIVE: Development of hand-foot syndrome symptoms, which is a common adverse effect of several cancer chemotherapy agents, can result in patient withdrawal from treatment. Its early identification allows appropriate modification of chemotherapy regimens and can avert treatment withdrawal by minimizing the impact on quality of life and duration of discontinued therapy. We sought to develop a simple home-based self-monitoring tool to facilitate reliable early identification of hand-foot syndrome, based on the self-administered quality of life questionnaire hand-foot syndrome-14. METHODS: We modified the hand-foot syndrome-14 to create a simple tool with binary responses ('yes' or 'no') for patients to self-evaluate subjective hand-foot syndrome symptoms daily. We evaluated this tool with 187 consecutive, consenting, eligible adult patients attending four centers and treated with capecitabine, sorafenib or sunitinib for various cancers. Univariate and multivariate logistic regression analyses were used to select the items with the greatest discrimination for detecting Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or 3 reactions, which indicate the need to modify the treatment regimen. RESULTS: There were four items that were most strongly associated with Common Terminology Criteria for Adverse Events grade 2 or higher symptoms. 'Pain associated with hand-foot syndrome' was the most strongly associated with moderate hand-foot syndrome. For detecting moderate hand-foot syndrome symptoms, the sensitivity was 100.0%, specificity was 94.6%, positive predictive value was 82.6% and area under the curve was 0.98 by a sum of the scores of four-item self-monitoring tool with cut-off value. CONCLUSIONS: We present a simple self-monitoring tool that can be used at home with high sensitivity and specificity for identifying grade 2 hand-foot syndrome. In addition, this tool might facilitate self-care. PMID- 27511992 TI - Comparison of visual assessment and image analysis in the evaluation of Ki-67 expression and their prognostic significance in immunohistochemically defined luminal breast carcinoma. AB - OBJECTIVES: To compare the Ki-67 labeling index value obtained through immunohistochemistry analysis by human examiners to that obtained from computer assisted image analysis, and to establish a cut-off value for Ki-67 labeling index for each method in luminal B breast carcinoma. METHODS: Immunohistochemistry analysis for Ki-67 was performed on the formalin-fixed, paraffin-embedded tissue samples from 403 patients with primary luminal breast cancers. Whole slide images were obtained using the NanoZoomer (Hamamatsu Photonics, Hamamatsu, Japan) and thoroughly analyzed using the Definiens Tissue Studio version 1.1 (Definiens AG, Munich, Germany) to detect the percentage of positively-stained nuclei of carcinoma cells. RESULTS: Although a significant correlation was found between the Ki-67 labeling index obtained by manual assessment and computer-assisted image analysis (Spearman rank correlation coefficient, P < 0.01), the Ki-67 labeling index value obtained by manual assessment was significantly higher than that obtained by computer-assisted image analysis (Wilcoxon signed rank test, P < 0.0001). Disease-free survival was significantly lower in 403 patients with tumors having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P < 0.00001) and visual counting (cut-off value: 28.5%; P < 0.00001). Disease-free survival was also significantly lower in 288 patients who received adjuvant endocrine therapy alone having high Ki-67 labeling index values determined by automated analysis (cut-off value: 11.5%; P < 0.0001) and visual counting (cut-off value: 19.7%, P < 0. 0001). CONCLUSIONS: The Ki-67 labeling index values determined by automated analysis and visual counting could equally predict disease-free survival in patients with luminal B breast carcinoma, including those who received endocrine therapy. PMID- 27511993 TI - Analysis of Gait Disturbance in Glut 1 Deficiency Syndrome. AB - Anticipating potential therapies for Glut 1 deficiency syndrome (Glut1DS) emphasizes the need for effective clinical outcome measures. The 6-minute walk test is a well-established outcome measure that evaluates walking ability in neurological diseases. Twenty-one children with Glut 1 deficiency syndrome and 21 controls performed the 6-minute walk test. Fatigue was determined by comparing distance walked in the first and sixth minutes. Gait was analyzed by stride length, velocity, cadence, base of support, and percentage time in double support. Independent sample t-tests examined differences between group. Repeated measures analysis of variance evaluated gait parameters over time. Glut 1 deficiency syndrome patients walked less (P < .05), had slower velocities (P < .0001), had shorter stride lengths (P < .0001), spent more time in double support (P < .001), and had increasing variability in base of support (P = .009). Glut 1 deficiency syndrome patients have impaired motor performance, walk more slowly, and have poor balance. The 6-minute walk test with gait analysis may serve as a useful outcome measure in clinical trials in Glut 1 deficiency syndrome. PMID- 27511994 TI - Role of glutathione metabolism and glutathione-related antioxidant defense systems in hypertension. AB - The risk of developing chronic hypertension increases with age. Among others factors, increased oxidative stress is a well-recognized etiological factor for the development of hypertension. The co-occurrence of oxidative stress and hypertension may occur as a consequence of a decrease in antioxidant defense system activity or elevated reactive oxygen species generation. Glutathione is a major intracellular thiol-disulfide redox buffer that serves as a cofactor for many antioxidant enzymes. Glutathione-related parameters are altered in hypertension, suggesting that there is an association between the glutathione related redox system and hypertension. In this review, we provide mechanistic explanations for how glutathione maintains blood pressure. More specifically, we discuss glutathione's role in combating oxidative stress and maintaining nitric oxide bioavailability via the formation of nitrosothiols and nitrosohemoglobin. Although impaired vasodilator responses are observed in S-nitrosothiol-deficient red blood cells, this potential hypertensive mechanism is currently overlooked in the literature. Here we fill in this gap by discussing the role of glutathione in nitric oxide metabolism and controlling blood pressure. We conclude that disturbances in glutathione metabolism might explain age-dependent increases in blood pressure. PMID- 27511995 TI - Effect of ethanol and acetaldehyde at clinically relevant concentrations on atrial inward rectifier potassium current IK1: separate and combined effect. AB - Atrial fibrillation is the most common arrhythmia at alcohol consumption. Its pathogenesis is complex, at least partly related to changes of cardiac inward rectifier potassium currents including IK1. Both ethanol and acetaldehyde have been demonstrated to considerably modify IK1 in rat ventricular myocytes. However, analogical data on the atrial IK1 are lacking. The present study aimed to analyse IK1 changes induced by ethanol and acetyldehyde in atrial myocytes. The experiments were performed by the whole cell patch-clamp technique at 23 +/- 1 degrees C on enzymatically isolated rat and guinea-pig atrial myocytes as well as on expressed human Kir2.3 channels. Ethanol (8 - 80 mM) caused a dual effect on the atrial IK1 showing the steady-state activation in some cells but inhibition in others in agreement with the ventricular data; on average, the activation was observed (at 20 mM by 4.3 and 4.5% in rat and guinea-pig atrial myocytes, respectively). The effect slightly increased with depolarization above 60 mV. In contrast, the current through human Kir2.3 channels (prevailing atrial IK1 subunit) was inhibited in all measured cells. Unlike ethanol, acetaldehyde (3 MUM) markedly inhibited the rat atrial IK1 (by 15.1%) in a voltage-independent manner, comparably to the rat ventricular IK1. The concurrent application of ethanol (20 mM) and acetaldehyde (3 MUM) resulted in the steady-state IK1 activation by 2.1% on average. We conclude that ethanol and even more acetaldehyde affected IK1 at clinically relevant concentrations if applied separately. Their combined effect did not significantly differ from the effect of ethanol alone. PMID- 27511996 TI - The expression profile of angiogenic genes in critical limb ischemia popliteal arteries. AB - Critical limb ischemia (CLI) represents the most severe form of peripheral arterial disease (PAD) and is the leading cause of non-traumatic amputations in western populations. In recent years, therapeutic angiogenesis has been considered to be a potential treatment option for CLI patients, however the molecular mechanism of ischemia-induced vascularization is still not fully understood. The identification of genetic factors underlying vascular responses to ischemia will improve our understanding of the biological causes of the disease and enhance personalized therapies in the future. In this work, we determined, for the first time, the expression profile of angiogenesis-related genes utilizing unique human material: the popliteal arteries retrieved during lower limb amputation from patients with CLI. Using custom-designed TaqMan Low Density Array (TLDA) cards we investigated the mRNA level of 90 genes on CLI samples compared to healthy donors. We identified three significantly up regulated genes in CLI group: matrix metalloproteinase 9 (MMP-9), VE-cadherin (CDH5) and integrin alpha 4 (ITGA4). However, among all investigated genes, only lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) was significantly reduced. In order to verify whether hypoxic conditions occur in popliteal arteries of CLI patients, we validated the transcription level of selected proangiogenic genes by real-time PCR on a larger number of samples. These results showed that the expression of key genes involved in angiogenesis, such as MMP9, HGF, HIF1A, VEGF-A and FLT1 were elevated in patients with CLI. Moreover, the study revealed that the expression of VEGF-A and FLT1 was associated with activation of HIF1A transcription. In conclusion, our data revealed the alteration in the mRNA level of genes involved in matrix remodelling, cell-cell adhesion as well as endothelial cell migration and proliferation in human popliteal arteries. PMID- 27511997 TI - Stereoselectivity of tradinterol's inhibition on proliferation of airway smooth muscle cells induced by acetylcholine through suppressing Ca(2+) signalling. AB - The objective of this study is to investigate whether the inhibition of tradinterol (SPFF) against acetylcholine (ACh)-induced proliferation is mediated by Ca(2+) signaling in airway smooth muscle cells (ASMCs), and whether stereoselectivity of the drug exists. Guinea pig ASMCs were primarily prepared with the method described and treated with ACh combined to SPFF isomers for 24 or 48 hours, respectively. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to determine the proliferation of the guinea pig ASMCs. Ca(2+) fluorescent intensity in the guinea pig ASMCs, expressed with percentage increase in fluorescence when the intensity was determined with varioskan flash or shown with percentage increase in Geo Mean (GM) measured with flow cytometry, was recorded. Images of the intensity were obtained with fluorescent microscope. 2-APB, an (inositol 1,4,5-trisphosphate receptor) IP3R blocker, and NiCl2, a store-operated channel (SOC) inhibitor, were used to investigate the mechanism of SPFF isomers regulating intracellular Ca(2+) via IP3R on sarcoplasmic reticulum (SR) and/or SOC on plasma membrane. (-)SPFF and (+/-)SPFF, treated for 48 hours, showed significant inhibition against ACh induced proliferation. The Ca(2+) elevation induced by ACh was concentration dependently suppressed by SPFF isomers. (-)SPFF is the most effective but the potency of (+/-)SPFF is less than that of the former and stronger than that of (+)SPFF based on the half maximal inhibitory concentration (IC50) value. No significant additive effect was observed when (-)SPFF/(+/-)SPFF was used alone and combined with NiCl2/2-APB. As far as (+)SPFF is concerned, no similar phenomenon was observed. (-)SPFF and (+/-)SPFF but (+)SPFF showed significant inhibition against the percentage increase in fluorescence induced by CaCl2. It is likely that the influence of IP2RSOC-mediated Ca(2+) signaling in ASMCs helps (-)SPFF and (+/-)SPFF contribute to the suppression of ASMCs proliferation. Stereoselectivity of SPFF isomers may lead to different levels of suppression of ACh-induced intracellular Ca(2+) and ASMCs proliferation. Moreover, cell cycle analysis with flow cytometry was applied to the evaluation of the action in human ASMCs in order to further confirm the anti-proliferative effect of the drugs. It was found that (-)SPFF, (+/-)SPFF but (+)SPFF suppressed the elevated rate of cell population in Phase S over all the cells stimulated with ACh, when SPFF and its isomers were individually exposed to the cells for 72 hours. These results that demonstrate the different stereoselective activities of SPFF are in consistent with those obtained from the guinea pig ASMCs. PMID- 27511998 TI - 11-dehydro thromboxane B2 levels after percutaneous transluminal angioplasty in patients with peripheral arterial occlusive disease during a one year follow-up period. AB - The aim of our study was to determine if the generation of thromboxane is altered in patients with peripheral arterial occlusive disease following percutaneous transluminal angioplasty (PTA) during a one year follow-up period. In this study, 175 patients diagnosed with peripheral arterial occlusive disease (PAOD) and demonstrating short-distance claudication or ischemic rest pain, requiring PTA in either the iliac, femoral, or popliteal arteries, were enrolled. The excretion of 11-dehydro thromboxane B2 (TXB2) was measured in urine samples by high performance liquid chromatography-mass spectrometry and recalculated based on the creatinine concentration. The urine samples were collected the morning prior to PTA, immediately following PTA and the day after PTA. All of the study subjects were then observed for a period of 12 months. Urine samples were also collected during the follow-up visits, and the levels of 11-dehydro TXB2 were measured at 1 month (1458.1 pg/mg creatinine +/- 1240.8), 3 months (1623.3 pg/mg creatinine +/- 1362.2), 6 months (1314.8 pg/mg creatinine +/- 1378.7) and 12 months (1473.2 pg/mg creatinine +/- 1455.2) after the PTA procedure. All of the patients were taking 75 mg of aspirin per day throughout the course of the study, as well as 75 mg of clopidogrel for six weeks following PTA. Overall, the mean TXB2 values immediately after PTA were significantly higher than either before the procedure (1524.4 pg/mg creatinine +/- 1411.1 vs. 2098.1 pg/mg creatinine +/- 1661.8; P = 0.00002), the day after PTA, or at any other point during the study. Moreover, preoperative TXB2 levels correlated well with the composite endpoints of death, myocardial infarction and stroke during the follow-up period (OR 7.42 [CI 95% = 1.2-48.8]; P = 0.02). Our findings suggest that clinicians should consider the use of TXA2 synthase inhibitors and receptor antagonists in combination with peripheral percutaneous transluminal angioplasty in patients with peripheral arterial occlusive disease. PMID- 27511999 TI - Factors influencing quality of anticoagulation control and warfarin dosage in patients after aortic valve replacement within the 3 months of follow up. AB - Warfarin dosage estimation using the pharmacogenetic algorithms has been shown to improve the quality of anticoagulation control in patients with atrial fibrillation. We sought to assess the genetic, demographic and clinical factors that determine the quality of anticoagulation in patients following aortic valve replacement (AVR). We studied 200 consecutive patients (130 men) aged 63 +/- 12.3 years, undergoing AVR, in whom warfarin dose was established using a pharmacogenetic algorithm. The quality of anticoagulation within the first 3 months since surgery was expressed as the time of international normalized ratio (INR) in the therapeutic range (TTR). The median TTR in the entire cohort was 59.6% (interquartile range, 38.7 - 82.7). Ninety-nine (49.5%) patients with TTR >= 60% did not differ from those with poor anticoagulation control (TTR < 60%) with regard to demographic and cardiovascular risk factors. Coronary artery disease (n = 84, 42%) and previous stroke (n = 5, 2.5%) predicted higher TTR, while possession of CYP2C9*2 variant allele (n = 49, 25%) was associated with lower TTR (P = 0.01). In turn, VKORC1 c.-1639A, CYP2C9*2 and *3 variants were independently associated with actual warfarin dose (P < 0.0001). In AVR patients better anticoagulation control is observed in patients with coronary artery disease and history of stroke, which might result in part from previous lifestyle modification and therapy. Possession of CYP2C9*2 and/or CYP2C9*3 allele variants is associated with lower TTR values and warfarin dose variations in AVR patients, the latter affected also by VKORC1 c.-1693G>A polymorphism. PMID- 27512000 TI - Association of the immunohistochemical detection of gamma-glutamyl transferase expression with clinicopathological findings in postmenopausal women with endometrioid adenocarcinoma of the uterus. AB - Gamma-glutamyl transferase (GGT) is a membrane enzyme present not only in the liver but also in healthy endometrial epithelium. Its overexpression has been demonstrated in numerous malignancies, where it exerts an anti-apoptotic effect and causes drug resistance in response to oxidation stress. Aim of the study was investigation of GGT expression in postmenopausal patients with endometrioid adenocarcinoma of the uterus (EAC). The material comprised 98 paraffin-embedded post-operative tumour samples of EAC from postmenopausal patients and a control group of 60 normal human postmenopausal endometrium samples. For immunohistochemical specimen staining, polyclonal IgG anti-GGT was used; for GGT expression measurement, a semi-quantitative method was applied. In EAC patients, 16 (16.33%) were diagnosed as stage IA, 46 (46.93%) as stage IB, 14 (14.29%) as stage II, and 22 (22.45%) as stage IIIA-C, according to the International Federation of Gynaecology and Obstetrics (FIGO) classification. Fifty-six (57.14%) patients were diagnosed with low- or moderate-grade (G1-2) disease, and 42 (42.86%) were diagnosed with high-grade (G3) disease. Cytoplasmic GGT staining was confirmed in all samples, while apical membrane GGT staining was observed only in G1-2 EAC specimens and the control group. In G3 EAC specimens, GGT cytoplasmic staining and high nuclear polymorphism areas were predominantly shown. Comparable high GGT median apical expression was confirmed in healthy endometrium (2.0, S.E.M. = 0.28) and in G1-2 EAC (2.0, S.E.M. = 0.27); however, in G3 tumours, GGT expression was significantly lower (0.0, S.E.M. = 0.07) than in healthy endometrium (P < 0.001 and P < 0.001, respectively). After stratification of the cancer cases according to FIGO staging, the lowest median apical GGT expression levels were in II EAC (0.0, S.E.M. = 0.64) tumours compared with IA (4.0, S.E.M. = 0.47) tumours, specimen and normal endometrium (2.0, S.E.M. = 2.8) (P < 0001). Stage IB EAC and IIIA-C EAC (1.0, S.E.M. = 0.16) cases showed only moderate median apical expression of GGT (1.0, S.E.M. = 0.24). We concluded that impaired GGT expression has the potential to become a valuable tool for stratifying EEC patients' prognosis and treatment planning. PMID- 27512001 TI - The role of apelin in the modulation of gastric and pancreatic enzymes activity in adult rats. AB - Apelin is considered as important gut regulatory peptide ligand of APJ receptor with a potential physiological role in gastrointestinal cytoprotection, regulation of food intake and drinking behavior. Circulating apelin inhibits secretion of pancreatic juice through vagal- cholecystokinin-dependent mechanism and reduces local blood flow. Our study was aimed to determine the effect of fundectomy and intraperitoneal or intragastric administration of apelin-13 on pancreatic and gastric enzymes activities in adult rats. Fundectomy is a surgical removal of stomach fundus - maine site apelin synthesis. Three independent experiments were carried out on Wistar rats. In the first and second experiment apelin-13 was given by intragastric or intraperitoneal way twice a day for 10 days (100 nmol/kg b.w.). Control groups received the physiological saline respectively. In the third experiment the group of rats after fundectomy were used. Fundectomized rats did not receive apelin and the rats from control group were 'sham operated'. At the end of experiment rats were sacrificed and blood from rats was withdrawn for apelin and CCK (cholecystokinin) radioimmunoassay analysis and pancreas and stomach tissues were collected for enzyme activity analyses. Intragastric and intraperitoneal administrations of apelin-13 increased basal plasma CCK level and stimulated gastric and pancreatic enzymes activity in rats. In animals after fundectomy decreased activity of studied enzymes was observed, as well as basal plasma apelin and CCK levels. In conclusion, apelin can effects on CCK release and stimulates some gastric and pancreatic enzymes activity in adult rats while fudectomy suppresses those processes. Changes in the level of pancreatic lipase activity point out that apelin may occurs as a regulator of lipase secretion. PMID- 27512002 TI - Melatonin metabolite, N(1)-acetyl-N(1)-formyl-5-methoxykynuramine (AFMK), attenuates acute pancreatitis in the rat: in vivo and in vitro studies. AB - Melatonin protects the pancreas from inflammation and free radical damage but the effect of the melatonin metabolite: N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) on acute pancreatitis is unknown. This study assessed the effects of AFMK on acute pancreatitis (AP) in the rats in vivo and on pancreatic cell line AR42J in vitro. AFMK (5, 10 or 20 mg/kg) was given intraperitoneally to the rats 30 min prior to the induction of AP by subcutaneous caerulein infusion (25 MUg/kg). Lipid peroxidation products (MDA + 4-HNE) and the activity of an antioxidant enzyme glutathione peroxidase (GPx) were measured in pancreatic tissue. Blood samples were taken for evaluation of amylase activity and TNF-alpha concentration. GPx, TNF-alpha, proapoptotic Bax protein, antiapoptotic Bcl-2 protein and the executor of apoptosis, caspase-3, were determined by Western blot in AR42J cells subjected to AFMK or to melatonin (both used at 10(-12), 10(-10), or 10(-8)M), without or with addition of caerulein (10(-8)M). AP was confirmed by histological examination and by serum increases of amylase and TNF-alpha (by 800% and 300%, respectively). In AP rats, pancreatic MDA + 4-HNE levels were increased by 300%, whereas GPx was reduced by 50%. AFMK significantly diminished histological manifestations of AP, decreased serum amylase activity and TNF-alpha concentrations, reduced MDA + 4-HNE levels and augmented GPx in the pancreas of AP rats. In AR42J cells, AFMK combined with caerulein markedly increased protein signals for GPx, Bax, caspase-3 and reduced these for TNF-alpha and Bcl-2. In conclusion, AFMK significantly attenuated acute pancreatitis in the rat. This may relate to the antioxidative and anti-inflammatory effects of this molecule and possibly to the stimulation of proapoptotic signal transduction pathway. PMID- 27512003 TI - Pituitary galaninergic system activity in female rats: the regulatory role of gonadal steroids. AB - The well-recognized sensitivity of the galanin gene in the anterior pituitary gland to estrogen suggests that estrogen receptor activity may influence the galaninergic system through modulation of galanin receptor (GALR) gene expression. Here, we evaluated the following: (i) the effects of estrogen on GALR mRNA expression; (ii) the estrogen receptor subtype that is specifically involved in this activity; and (iii) the effects of progesterone in the absence or presence of estrogen on galanin concentration in anterior pituitary gland. In the first experiment, ovariectomized 4-month-old rats were pre-treated subcutaneously with 17beta-estradiol (3 x 20 MUg), the ESR1 (ERalpha) agonist propyl pyrazole triol (PPT) (3 x 5 mg), and the ESR2 (ERbeta) agonist diarylpropionitrile (DPN) (3 x 0.5 mg). In the second experiment, 4-month-old ovariectomized females received daily subcutaneous injections of 17beta-estradiol (3 x 20 MUg), progesterone (2 x 5 mg), or combined estradiol (3 x 20 MUg) and progesterone (2 x 5 mg). Anterior pituitaries were excised the day after the final 17beta-estradiol injection (experiment I) and 1 hour after receiving the second progesterone dose. Relative GALR1, GALR2, and GALR3 mRNA expression was evaluated using quantitative real-time PCR, and pituitary galanin concentration was determined using a specific radioimmunoassay. The results revealed that estrogen predominantly induced a 5-fold increase in GALR3 gene transcription. To a lesser extent, 17beta estradiol also increased GALR1 mRNA expression, but had no effect on GALR2 mRNA levels. The estrogen-induced increase in GALR3 gene expression occurred exclusively through ESR1 activation. The increase in GALR1 gene expression occurred through activation of both estrogen receptor subtypes, but the ESR2 subtype was predominantly involved. Furthermore, the results revealed that progesterone regulates the activity of the pituitary galaninergic system by facilitating estradiol-induced galanin synthesis in the female rat anterior pituitary gland. PMID- 27512004 TI - Changes in gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor gene expression after an increase in carbon monoxide concentration in the cavernous sinus of male wild boar and pig crossbread. AB - Previous studies indicate that there are at least a few regulatory systems involved in photoperiodic synchronisation of reproductive activity, which starts with the retina and ends at the gonadotropin-releasing hormone (GnRH) pulse generator. Recently we have shown indicated that the amount of carbon monoxide (CO) released from the eye into the ophthalmic venous blood depends on the intensity of sunlight. The aim of this study was to test whether changes in the concentration of carbon monoxide in the ophthalmic venous blood may modulate reproductive activity, as measured by changes in GnRH and GnRH receptor gene expression. The animal model used was mature male swine crossbred from wild boars and domestic sows (n = 48). We conducted in vivo experiments to determine the effect of increased CO concentrations in the cavernous sinus of the mammalian perihypophyseal vascular complex on gene expression of GnRH and GnRH receptors as well as serum luteinizing hormone (LH) levels. The experiments were performed during long photoperiod days near the summer solstice (second half of June) and short photoperiod days near the winter solstice (second half of December). These crossbred swine demonstrated a seasonally-dependent marked variation in GnRH and GnRH receptor gene expression and systemic LH levels in response to changes in CO concentration in ophthalmic venous blood. These results seem to confirm the hypothesis of humoral phototransduction as a mechanism for some of bright light's effects in animal chronobiology and the effect of CO on GnRH and GnRH receptor gene expression. PMID- 27512005 TI - Effect of adiponectin on the steroidogenic acute regulatory protein, P450 side chain cleavage enzyme and 3beta-hydroxysteroid dehydrogenase gene expression, progesterone and androstenedione production by the porcine uterus during early pregnancy. AB - Adiponectin and its receptors are expressed in the human and porcine uterus and this endocrine system has important role in the regulation of reproductive processes. The expression of steroidogenic acute regulatory protein (StAR) and 3beta-hydroxysteroid dehydrogenase (HSD3B1) were observed in the human and porcine uterus during the oestrous cycle and pregnancy. The de novo synthesis of steroids in the uterus might be a crucial factor for effective implantation and maintenance of pregnancy. We hypothesized that adiponectin modulates the expression of key enzymes in the synthesis of the steroids: StAR, P450 side chain cleavage enzyme (CYP11A1) and HSD3B1, as well as progesterone (P4) and androstenedione (A4) secretion by the porcine uterus. Endometrial and myometrial explants harvested from gilts (n = 5) on days 10 to 11, 12 to 13, 15 to 16 and 27 to 28 of pregnancy and on days 10 to 11 of the oestrous cycle were cultured in vitro in the presence of adiponectin (1, 10 MUg/ml), adiponectin with insulin (10 ng/ml) and insulin alone (10 ng/ml). Gene expression was examined by real-time PCR, and the secretion of the steroids was determined by radioimmunoassay. The content of StAR, CYP11A1 and HSD3B1 mRNAs and the secretion of P4 and A4 was modulated by adiponectin in endometrial and myometrial tissue explants during early pregnancy and the oestrous cycle. In this action adiponectin interacted with insulin. Insulin itself also regulated the steroidogenic activity of the porcine uterus. ere we reported, for the first time, the expression of CYP11A1 genes in the porcine endometrium and myometrium. Our novel findings indicate that adiponectin affects basal and insulin-stimulated expression of key steroidogenic genes and production of steroid hormones by the porcine uterus during maternal recognition of pregnancy and implantation. PMID- 27512006 TI - The inhibitory effect of combination treatment with leptin and cannabinoid CB1 receptor agonist on food intake and body weight gain is mediated by serotonin 1B and 2C receptors. AB - Previous studies reported that the co-injection of leptin and cannabinoid CB1 receptor antagonists reduces food intake and body weight in rats, and this effect is more profound than that induced by these compounds individually. Additionally, serotonin mediates the effects of numerous anorectic drugs. To investigate whether serotonin interacts with leptin and endocannabinoids to affect food intake and body weight, we administered 5-hydroxytryptamine(HT)1B and 5 hydroxytryptamine(HT)2C serotonin receptor antagonists (3 mg/kg GR 127935 and 0.5 mg/kg SB 242084, respectively) to male Wistar rats treated simultaneously with leptin (100 MUg/kg) and the CB1 receptor inverse agonist AM 251 (1 mg/kg) for 3 days. In accordance with previous findings, the co-injection of leptin and AM 251, but not the individual injection of each drug, resulted in a significant decrease in food intake and body weight gain. Blockade of the 5-HT1B and 5-HT2C receptors completely abolished the leptin- and AM 251-induced anorectic and body weight-reducing effects. These results suggest that serotonin mediates the leptin and AM 251-dependent regulation of feeding behavior in rats via the 5-HT1B and 5 HT2C receptors. PMID- 27512007 TI - The effect of pregabalin - codeine combination on partial sciatic nerve ligation induced peripheral mononeuropathy in rats. AB - The present study investigates the effects of pregabalin (PGB) and codeine (COD) combination on neuropathic hyperalgesia in an animal model of peripheral nerve injury represented by partial sciatic nerve ligation. Hot plate and analgesimeter tests were performed to evaluate the influence of PGB, COD and their combination on thermal and mechanical hyperalgesia in the hind paw with partial sciatic nerve ligation. Reactivity was evaluated by measuring the latency to withdrawal of the operated hind paw from the noxious heat and pressure stimulation. Nociceptive thresholds were evaluated before (baseline) and in the 1(st), 3(rd), 5(th) and 7(th) day after surgical procedure. The investigation demonstrates that the treatment with PGB attenuated partial sciatic nerve ligation development of thermal and mechanical hyperalgesia in rats operated hind paw. The oral administration, during 14 consecutive days of PGB-COD combination significantly reduced the degree of both thermal and mechanical hyperalgesia in the hind paw with partial sciatic nerve ligation. These results suggest that the association of PGB with COD exerted ameliorative effect on partial sciatic nerve ligation induced neuropathic pain in rats. PMID- 27512008 TI - The antidepressant- and anxiolytic-like effects following co-treatment with escitalopram and risperidone in rats. AB - Several clinical reports have documented a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants, in particular selective serotonin reuptake inhibitors (SSRI), in the treatment of drug-resistant depression and treatment-resistant anxiety disorders. In the present study, we investigated the effect of treatment with the antidepressant escitalopram (SSRI) given separately or jointly with a low dose of risperidone (an atypical antipsychotic) in the forced swim test and in the elevated plus-maze test in rats. The obtained results showed that escitalopram at doses of 2.5 or 5 mg/kg evoked antidepressant-like effect in the forced swim test. Moreover, risperidone at low doses (0.05 or 0.1 mg/kg) enhanced the antidepressant-like activity of escitalopram (1 mg/kg) in this test by increasing the swimming time and decreasing the immobility time in those animals. WAY 100635 (a serotonin 5 HT1A receptor antagonist) at a dose of 0.1 mg/kg abolished the antidepressant like effect induced by co-administration of escitalopram and risperidone. The active behavior in that test did not reflect an increase in general activity, since the combined treatment with escitalopram and risperidone failed to enhance the exploratory activity of rats. In the following experiment, we showed that escitalopram (5 mg/kg) and mirtazapine (5 or 10 mg/kg) or risperidone (0.1 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze test, and the combined treatment with an ineffective dose of risperidone (0.05 mg/kg) enhanced the anxiolytic-like effects of escitalopram (2.5 mg/kg) or mirtazapine (1 and 2.5 mg/kg) in this test. The obtained results suggest that risperidone applied at a low dose enhances the antidepressant-like activity of escitalopram in the forced swim test, and that 5-HT1A receptors may play some role in these effects. Moreover, a low dose of risperidone may also enhance the anxiolytic-like action of the studied antidepressants. PMID- 27512009 TI - The Inositol Trisphosphate/Calcium Signaling Pathway in Health and Disease. AB - Many cellular functions are regulated by calcium (Ca(2+)) signals that are generated by different signaling pathways. One of these is the inositol 1,4,5 trisphosphate/calcium (InsP3/Ca(2+)) signaling pathway that operates through either primary or modulatory mechanisms. In its primary role, it generates the Ca(2+) that acts directly to control processes such as metabolism, secretion, fertilization, proliferation, and smooth muscle contraction. Its modulatory role occurs in excitable cells where it modulates the primary Ca(2+) signal generated by the entry of Ca(2+) through voltage-operated channels that releases Ca(2+) from ryanodine receptors (RYRs) on the internal stores. In carrying out this modulatory role, the InsP3/Ca(2+) signaling pathway induces subtle changes in the generation and function of the voltage-dependent primary Ca(2+) signal. Changes in the nature of both the primary and modulatory roles of InsP3/Ca(2+) signaling are a contributory factor responsible for the onset of a large number human diseases. PMID- 27512010 TI - CXCL3 positively regulates adipogenic differentiation. AB - Chemokines are a family of cytokines inducing cell migration and inflammation. Recent reports have implicated the roles of chemokines in cell differentiation. However, little is known about the functional roles of chemokines in adipocytes. Here, we explored gene expression levels of chemokines and chemokine receptors during adipogenic differentiation. We have found that two chemokines, chemokine (C-X-C motif) ligand 3 (CXCL3) and CXCL13, as well as CXC chemokine receptor 2 (CXCR2), a CXCL3 receptor, are highly expressed in mature adipocytes. When 3T3-L1 cells and ST2 cells were induced to differentiate, both the number of lipid droplets and the expression levels of adipogenic markers were significantly promoted by the addition of CXCL3, but not CXCL13. Conversely, gene knockdown of either CXCL3 or CXCR2 by specific siRNA effectively inhibited the course of adipogenic differentiation. CXCL3 treatment of 3T3-L1 cells significantly induced the phosphorylation of ERK and c-jun N-terminal kinase (JNK). Furthermore, CXCL3 induced CCAAT-enhancer binding protein (C/EBP)beta and delta expression was suppressed by both ERK and JNK-specific inhibitors. Furthermore, chromatin immunoprecipitation assay revealed functional binding of PPARgamma2 within the cxcl3 promoter region. Taken together, these results have indicated that CXCL3 is a novel adipokine that facilitates adipogenesis in an autocrine and/or a paracrine manner through induction of c/ebpb and c/ebpd. PMID- 27512011 TI - Elite Distance Runners and Breastfeeding. AB - BACKGROUND: Elite female distance runners lack guidelines regarding breastfeeding while training at a high intensity. OBJECTIVES: The purpose of this research was to understand how elite female distance runners manage breastfeeding. METHODS: Semistructured interviews were conducted with 14 women who had had at least one pregnancy within the past 5 years and had achieved a minimum of the USA Track and Field 2012 Olympic Trials "B" entry standard for running for the marathon or equivalent performance for 1,500 m or longer. RESULTS: Using thematic analysis, we identified the following themes: breastfeeding as a barrier to training and competition, limited access to relevant breastfeeding information, and concerns for the baby's health. Our findings show that despite the considerable barriers with which these women contend, they breastfed at higher rates and for longer duration than members of the general public. CONCLUSION: Based on our findings, we argue that elite female distance runners' experiences of breastfeeding would be enhanced if more research were conducted on breastfeeding practices while training and competing at an elite level. PMID- 27512012 TI - Are We There Yet? Reliably Estimating the Completeness of Plant Genome Sequences. AB - Genome sequencing is becoming cheaper and faster thanks to the introduction of next-generation sequencing techniques. Dozens of new plant genome sequences have been released in recent years, ranging from small to gigantic repeat-rich or polyploid genomes. Most genome projects have a dual purpose: delivering a contiguous, complete genome assembly and creating a full catalog of correctly predicted genes. Frequently, the completeness of a species' gene catalog is measured using a set of marker genes that are expected to be present. This expectation can be defined along an evolutionary gradient, ranging from highly conserved genes to species-specific genes. Large-scale population resequencing studies have revealed that gene space is fairly variable even between closely related individuals, which limits the definition of the expected gene space, and, consequently, the accuracy of estimates used to assess genome and gene space completeness. We argue that, based on the desired applications of a genome sequencing project, different completeness scores for the genome assembly and/or gene space should be determined. Using examples from several dicot and monocot genomes, we outline some pitfalls and recommendations regarding methods to estimate completeness during different steps of genome assembly and annotation. PMID- 27512013 TI - Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies. AB - BACKGROUND: A constellation of neurodegenerative disorders exists (Gordon Holmes syndrome, 4H leucodystrophy, Boucher-Neuhauser syndrome) in which patients suffer from both neurological disease (typically manifested by ataxia) and reproductive failure (idiopathic hypogonadotropic hypogonadism (IHH)). POLR3B, which encodes the second largest subunit of RNA polymerase III (pol III), and POLR3A, which forms the pol III catalytic centre, are associated with 4H leucodystrophy. METHODS: Whole exome sequencing was performed on a large cohort of subjects with IHH (n=565). Detailed neuroendocrine studies were performed in some individuals within this cohort. RESULTS: Four individuals (two of them siblings) were identified with two rare nucleotide variants in POLR3B. On initial evaluation, all subjects were free of neurological disease. One patient underwent treatment with exogenous pulsatile gonadotropin-releasing hormone for 8 weeks which failed to result in normalisation of his sex steroid milieu due to pituitary resistance. CONCLUSIONS: These findings suggest that the spectrum of phenotypes resulting from POLR3B mutations is wider than previously believed and that POLR3B can be associated exclusively with disorders characterised by abnormal gonadotropin secretion. PMID- 27512014 TI - Quantitative measurement of hydrophilicity/hydrophobicity of the plasma polymerized naphthalene film (Super Support Film) and other support films and grids in electron microscopy. AB - Hydrophilicity/hydrophobicity of the surfaces of plasma-polymerized naphthalene film (Super Support Film, Nisshin EM Co. Ltd., Tokyo), carbon and formvar support films, and copper and nickel grids were quantitatively estimated by contact angles measured from diameters and heights of water droplets placed on various specimens. With treatment of glow discharge, the surfaces of plasma-polymerized naphthalene and carbon support films became fully hydrophilic in 20 s. They remained hydrophilic for 6 h. The surfaces of copper and nickel grids became fully hydrophilic with 60 s of glow discharge treatment. They remained hydrophilic for only 1 h. This information is useful for negative staining, ultrathin sectioning and rapid freezing of biological specimens using the sandwich method. PMID- 27512015 TI - Constituent elements and their distribution in the radioactive Cs-bearing silicate glass microparticles released from Fukushima nuclear plant. AB - Microparticles of radioactive cesium (Cs)-bearing silicate glass emitted from the Fukushima Daiichi nuclear power plant were investigated mainly using state-of-the art energy-dispersive X-ray spectroscopy in scanning transmission electron microscopes. Precise elemental maps of the particles were obtained using double silicon drift detectors with a large collection angle of X-rays, and qualitative elemental analysis was performed using high-resolution X-ray spectroscopy with a microcalorimetry detector. Beside the substantial elements (O, Si, Cl, K, Fe, Zn, Rb, Sn and Cs) as previously reported, Mn and Ba were also common, though their amounts were small. The atomic ratios of the substantial elements were not the same but varied among individual particles. Fe and Zn were relatively homogeneously distributed, whereas the concentration of alkali ions varied radially. Generally, Cs was rich and K and Rb were poor outward of the particles but the degree of such radial dependence was considerably different among the particles. A concentration of Sn on the particle surface was observed. High resolution imaging indicated the formation of SnO2 (cassiterite) nanocrystals on the surface. Synthesis of the bulk glass with a similar composition to the microparticles was attempted by quenching the silicate melt from ~1600 degrees C. However, homogeneous silicate glass like that of the microparticles could not be obtained due to the segregation of nano-spherules rich in Fe and Zn, suggesting that the microparticles were formed in a very specific condition in the nuclear reactor. PMID- 27512016 TI - Proline Coordination with Fatty Acid Synthesis and Redox Metabolism of Chloroplast and Mitochondria. AB - Proline (Pro) accumulation is one of the most prominent changes in plant metabolism during drought and low water potential; however, the regulation and function of Pro metabolism remain unclear. We used a combination of forward genetic screening based on a Proline Dehydrogenase1 (PDH1) promoter-luciferase reporter (PDH1pro:LUC2) and RNA sequencing of the Pro synthesis mutant p5cs1-4 to identify multiple loci affecting Pro accumulation in Arabidopsis (Arabidopsis thaliana). Two mutants having high PDH1pro:LUC2 expression and increased Pro accumulation at low water potential were found to be alleles of Cytochrome P450, Family 86, Subfamily A, Polypeptide2 (CYP86A2) and Long Chain Acyl Synthetase2 (LACS2), which catalyze two successive steps in very-long-chain fatty acid (VLCFA) synthesis. Reverse genetic experiments found additional VLCFA and lipid metabolism-related mutants with increased Pro accumulation. Altered cellular redox status is a key factor in the coordination of Pro and VLCFA metabolism. The NADPH oxidase inhibitor diphenyleneiodonium (DPI) induced high levels of Pro accumulation and strongly repressed PDH1pro:LUC2 expression. cyp86a2 and lacs2 mutants were hypersensitive to diphenyleneiodonium but could be reverted to wild type Pro and PDH1pro:LUC2 expression by reactive oxygen species scavengers. The coordination of Pro and redox metabolism also was indicated by the altered expression of chloroplast and mitochondria electron transport genes in p5cs1-4 These results show that Pro metabolism is both influenced by and influences cellular redox status via previously unknown coordination with several metabolic pathways. In particular, Pro and VLCFA synthesis share dual roles to help buffer cellular redox status while producing products useful for stress resistance, namely the compatible solute Pro and cuticle lipids. PMID- 27512017 TI - The Exonuclease Homolog OsRAD1 Promotes Accurate Meiotic Double-Strand Break Repair by Suppressing Nonhomologous End Joining. AB - During meiosis, programmed double-strand breaks (DSBs) are generated to initiate homologous recombination, which is crucial for faithful chromosome segregation. In yeast, Radiation sensitive1 (RAD1) acts together with Radiation sensitive9 (RAD9) and Hydroxyurea sensitive1 (HUS1) to facilitate meiotic recombination via cell-cycle checkpoint control. However, little is known about the meiotic functions of these proteins in higher eukaryotes. Here, we characterized a RAD1 homolog in rice (Oryza sativa) and obtained evidence that O. sativa RAD1 (OsRAD1) is important for meiotic DSB repair. Loss of OsRAD1 led to abnormal chromosome association and fragmentation upon completion of homologous pairing and synapsis. These aberrant chromosome associations were independent of OsDMC1. We found that classical nonhomologous end-joining mediated by Ku70 accounted for most of the ectopic associations in Osrad1 In addition, OsRAD1 interacts directly with OsHUS1 and OsRAD9, suggesting that these proteins act as a complex to promote DSB repair during rice meiosis. Together, these findings suggest that the 9-1-1 complex facilitates accurate meiotic recombination by suppressing nonhomologous end joining during meiosis in rice. PMID- 27512018 TI - Responses of cerebellar Purkinje cells during fictive optomotor behavior in larval zebrafish. AB - Although most studies of the cerebellum have been conducted in mammals, cerebellar circuitry is highly conserved across vertebrates, suggesting that studies of simpler systems may be useful for understanding cerebellar function. The larval zebrafish is particularly promising in this regard because of its accessibility to optical monitoring and manipulations of neural activity. Although several studies suggest that the cerebellum plays a role in behavior at larval stages, little is known about the signals conveyed by particular classes of cerebellar neurons. Here we use electrophysiological recordings to characterize subthreshold, simple spike, and climbing fiber responses in larval zebrafish Purkinje cells in the context of the fictive optomotor response (OMR)-a paradigm in which fish adjust motor output to stabilize their virtual position relative to a visual stimulus. Although visual responses were prominent in Purkinje cells, they lacked the direction or velocity sensitivity that would be expected for controlling the OMR. On the other hand, Purkinje cells exhibited strong responses during fictive swim bouts. Temporal characteristics of these responses are suggestive of a general role for the larval zebrafish cerebellum in controlling swimming. Climbing fibers encoded both visual and motor signals but did not appear to encode signals that could be used to adjust OMR gain, such as retinal slip. Finally, the observation of diverse relationships between simple spikes and climbing fiber responses in individual Purkinje cells highlights the importance of distinguishing between these two types of activity in calcium imaging experiments. PMID- 27512019 TI - White matter and cognition: making the connection. AB - Whereas the cerebral cortex has long been regarded by neuroscientists as the major locus of cognitive function, the white matter of the brain is increasingly recognized as equally critical for cognition. White matter comprises half of the brain, has expanded more than gray matter in evolution, and forms an indispensable component of distributed neural networks that subserve neurobehavioral operations. White matter tracts mediate the essential connectivity by which human behavior is organized, working in concert with gray matter to enable the extraordinary repertoire of human cognitive capacities. In this review, we present evidence from behavioral neurology that white matter lesions regularly disturb cognition, consider the role of white matter in the physiology of distributed neural networks, develop the hypothesis that white matter dysfunction is relevant to neurodegenerative disorders, including Alzheimer's disease and the newly described entity chronic traumatic encephalopathy, and discuss emerging concepts regarding the prevention and treatment of cognitive dysfunction associated with white matter disorders. Investigation of the role of white matter in cognition has yielded many valuable insights and promises to expand understanding of normal brain structure and function, improve the treatment of many neurobehavioral disorders, and disclose new opportunities for research on many challenging problems facing medicine and society. PMID- 27512020 TI - The destination defines the journey: an examination of the kinematics of hand-to mouth movements. AB - Long-train electrical stimulation of the motor and premotor cortices of nonhuman primates can produce either hand-to-mouth or grasp-to-inspect movements, depending on the precise location of stimulation. Furthermore, single-neuron recording studies identify discrete neuronal populations in the inferior parietal and ventral premotor cortices that respond uniquely to either grasp-to-eat or grasp-to-place movements, despite their identical mechanistic requirements. These studies demonstrate that the macaque motor cortex is organized around producing functional, goal-oriented movements, rather than simply fulfilling muscular prerequisites of action. In humans, right-handed hand-to-mouth movements have a unique kinematic signature; smaller maximum grip apertures are produced when grasping to eat than when grasping to place identical targets. This is evidence that the motor cortex in humans is also organized around producing functional movements. However, in both macaques and humans, grasp-to-eat/hand-to-mouth movements have always been elicited using edible targets and have (necessarily) been paired with mouth movement. It is therefore unknown whether the kinematic distinction is a natural result of grasping food and/or is simply attributable to concurrent opening of the mouth while grasping. In experiment 1, we used goal differentiated grasping tasks, directed toward edible and inedible targets, to show that the unique kinematic signature is present even with inedible targets. In experiment 2, we used the same goal-differentiated grasping tasks, either coupled with or divorced from an open-mouth movement, to show that the signature is not attributable merely to a planned opening of the mouth during the grasp. These results are discussed in relation to the role of hand-to-mouth movements in human development, independently of grasp-to-eat behavior. PMID- 27512021 TI - Contextual processing in unpredictable auditory environments: the limited resource model of auditory refractoriness in the rhesus. AB - Auditory refractoriness refers to the finding of smaller electroencephalographic (EEG) responses to tones preceded by shorter periods of silence. To date, its physiological mechanisms remain unclear, limiting the insights gained from findings of abnormal refractoriness in individuals with schizophrenia. To resolve this roadblock, we studied auditory refractoriness in the rhesus, one of the most important animal models of auditory function, using grids of up to 32 chronically implanted cranial EEG electrodes. Four macaques passively listened to sounds whose identity and timing was random, thus preventing animals from forming valid predictions about upcoming sounds. Stimulus onset asynchrony ranged between 0.2 and 12.8 s, thus encompassing the clinically relevant timescale of refractoriness. Our results show refractoriness in all 8 previously identified middle- and long-latency components that peaked between 14 and 170 ms after tone onset. Refractoriness may reflect the formation and gradual decay of a basic sensory memory trace that may be mirrored by the expenditure and gradual recovery of a limited physiological resource that determines generator excitability. For all 8 components, results were consistent with the assumption that processing of each tone expends ~65% of the available resource. Differences between components are caused by how quickly the resource recovers. Recovery time constants of different components ranged between 0.5 and 2 s. This work provides a solid conceptual, methodological, and computational foundation to dissect the physiological mechanisms of auditory refractoriness in the rhesus. Such knowledge may, in turn, help develop novel pharmacological, mechanism-targeted interventions. PMID- 27512022 TI - Nonreciprocal mechanisms in up- and downregulation of spinal motoneuron excitability by modulators of KCNQ/Kv7 channels. AB - KCNQ/Kv7 channels form a slow noninactivating K+ current, also known as the M current. They activate in the subthreshold range of membrane potentials and regulate different aspects of excitability in neurons of the central nervous system. In spinal motoneurons (MNs), KCNQ/Kv7 channels have been identified in the somata, axonal initial segment, and nodes of Ranvier, where they generate a slow, noninactivating, K+ current sensitive to both muscarinic receptor-mediated inhibition and KCNQ/Kv7 channel blockers. In this study, we thoroughly reevaluated the function of up- and downregulation of KCNQ/Kv7 channels in mouse immature spinal MNs. Using electrophysiological techniques together with specific pharmacological modulators of the activity of KCNQ/Kv7 channels, we show that enhancement of the activity of these channels decreases the excitability of spinal MNs in mouse neonates. This action on MNs results from a combination of hyperpolarization of the resting membrane potential, a decrease in the input resistance, and depolarization of the voltage threshold. On the other hand, the effect of inhibition of KCNQ/Kv7 channels suggested that these channels play a limited role in regulating basal excitability. Computer simulations confirmed that pharmacological enhancement of KCNQ/Kv7 channel activity decreases excitability and also suggested that the effects of inhibition of KCNQ/Kv7 channels on the excitability of spinal MNs do not depend on a direct effect in these neurons but likely on spinal cord synaptic partners. These results indicate that KCNQ/Kv7 channels have a fundamental role in the modulation of the excitability of spinal MNs acting both in these neurons and in their local presynaptic partners. PMID- 27512029 TI - Newsletter. PMID- 27512023 TI - Sciatic nerve stimulation activates the retrotrapezoid nucleus in anesthetized rats. AB - Retrotrapezoid nucleus (RTN) neurons sustain breathing automaticity. These neurons have chemoreceptor properties, but their firing is also regulated by multiple synaptic inputs of uncertain function. Here we test whether RTN neurons, like neighboring presympathetic neurons, are excited by somatic afferent stimulation. Experiments were performed in Inactin-anesthetized, bilaterally vagotomized, paralyzed, mechanically ventilated Sprague-Dawley rats. End expiratory CO2 (eeCO2) was varied between 4% and 10% to modify rate and amplitude of phrenic nerve discharge (PND). RTN and presympathetic neurons were recorded extracellularly below the facial motor nucleus with established criteria. Sciatic nerve stimulation (SNstim, 1 ms, 0.5 Hz) slightly increased blood pressure (6.6 +/- 1.6 mmHg) and heart rate and, at low eeCO2 (<5.5%), entrained PND. Ipsi- and contralateral SNstim produced the known biphasic activation of presympathetic neurons. SNstim evoked a similar but weaker biphasic response in up to 67% of RTN neurons and monophasic excitation in the rest. At low eeCO2, RTN neurons were silent and responded more weakly to SNstim than at high eeCO2 RTN neuron firing was respiratory modulated to various degrees. The phasic activation of RTN neurons elicited by SNstim was virtually unchanged at high eeCO2 when PND entrainment to the stimulus was disrupted. Thus RTN neuron response to SNstim did not result from entrainment to the central pattern generator. Overall, SNstim shifted the relationship between RTN firing and eeCO2 upward. In conclusion, somatic afferent stimulation increases RTN neuron firing probability without altering their response to CO2. This pathway may contribute to the hyperpnea triggered by nociception, exercise (muscle metabotropic reflex), or hyperthermia. PMID- 27512032 TI - Reply to Willis: Powerful predictions of biodiversity from ecological models and scaling laws. PMID- 27512033 TI - Extrapolating abundance curves has no predictive power for estimating microbial biodiversity. PMID- 27512034 TI - Microtubule-microtubule sliding by kinesin-1 is essential for normal cytoplasmic streaming in Drosophila oocytes. AB - Cytoplasmic streaming in Drosophila oocytes is a microtubule-based bulk cytoplasmic movement. Streaming efficiently circulates and localizes mRNAs and proteins deposited by the nurse cells across the oocyte. This movement is driven by kinesin-1, a major microtubule motor. Recently, we have shown that kinesin-1 heavy chain (KHC) can transport one microtubule on another microtubule, thus driving microtubule-microtubule sliding in multiple cell types. To study the role of microtubule sliding in oocyte cytoplasmic streaming, we used a Khc mutant that is deficient in microtubule sliding but able to transport a majority of cargoes. We demonstrated that streaming is reduced by genomic replacement of wild-type Khc with this sliding-deficient mutant. Streaming can be fully rescued by wild-type KHC and partially rescued by a chimeric motor that cannot move organelles but is active in microtubule sliding. Consistent with these data, we identified two populations of microtubules in fast-streaming oocytes: a network of stable microtubules anchored to the actin cortex and free cytoplasmic microtubules that moved in the ooplasm. We further demonstrated that the reduced streaming in sliding-deficient oocytes resulted in posterior determination defects. Together, we propose that kinesin-1 slides free cytoplasmic microtubules against cortically immobilized microtubules, generating forces that contribute to cytoplasmic streaming and are essential for the refinement of posterior determinants. PMID- 27512035 TI - Cracking the allosteric code of NMR chemical shifts. PMID- 27512036 TI - The heart in sickle cell disease, a model for heart failure with preserved ejection fraction. PMID- 27512037 TI - Critically jammed. PMID- 27512038 TI - Critically evaluating the theory and performance of Bayesian analysis of macroevolutionary mixtures. AB - Bayesian analysis of macroevolutionary mixtures (BAMM) has recently taken the study of lineage diversification by storm. BAMM estimates the diversification rate parameters (speciation and extinction) for every branch of a study phylogeny and infers the number and location of diversification-rate shifts across branches of a tree. Our evaluation of BAMM reveals two major theoretical errors: (i) the likelihood function (which estimates the model parameters from the data) is incorrect, and (ii) the compound Poisson process prior model (which describes the prior distribution of diversification-rate shifts across branches) is incoherent. Using simulation, we demonstrate that these theoretical issues cause statistical pathologies; posterior estimates of the number of diversification-rate shifts are strongly influenced by the assumed prior, and estimates of diversification-rate parameters are unreliable. Moreover, the inability to correctly compute the likelihood or to correctly specify the prior for rate-variable trees precludes the use of Bayesian approaches for testing hypotheses regarding the number and location of diversification-rate shifts using BAMM. PMID- 27512039 TI - miR-322/-503 cluster is expressed in the earliest cardiac progenitor cells and drives cardiomyocyte specification. AB - Understanding the mechanisms of early cardiac fate determination may lead to better approaches in promoting heart regeneration. We used a mesoderm posterior 1 (Mesp1)-Cre/Rosa26-EYFP reporter system to identify microRNAs (miRNAs) enriched in early cardiac progenitor cells. Most of these miRNA genes bear MESP1-binding sites and active histone signatures. In a calcium transient-based screening assay, we identified miRNAs that may promote the cardiomyocyte program. An X chromosome miRNA cluster, miR-322/-503, is the most enriched in the Mesp1 lineage and is the most potent in the screening assay. It is specifically expressed in the looping heart. Ectopic miR-322/-503 mimicking the endogenous temporal patterns specifically drives a cardiomyocyte program while inhibiting neural lineages, likely by targeting the RNA-binding protein CUG-binding protein Elav like family member 1 (Celf1). Thus, early miRNAs in lineage-committed cells may play powerful roles in cell-fate determination by cross-suppressing other lineages. miRNAs identified in this study, especially miR-322/-503, are potent regulators of early cardiac fate. PMID- 27512040 TI - Spontaneous eyelid closures link vigilance fluctuation with fMRI dynamic connectivity states. AB - Fluctuations in resting-state functional connectivity occur but their behavioral significance remains unclear, largely because correlating behavioral state with dynamic functional connectivity states (DCS) engages probes that disrupt the very behavioral state we seek to observe. Observing spontaneous eyelid closures following sleep deprivation permits nonintrusive arousal monitoring. During periods of low arousal dominated by eyelid closures, sliding-window correlation analysis uncovered a DCS associated with reduced within-network functional connectivity of default mode and dorsal/ventral attention networks, as well as reduced anticorrelation between these networks. Conversely, during periods when participants' eyelids were wide open, a second DCS was associated with less decoupling between the visual network and higher-order cognitive networks that included dorsal/ventral attention and default mode networks. In subcortical structures, eyelid closures were associated with increased connectivity between the striatum and thalamus with the ventral attention network, and greater anticorrelation with the dorsal attention network. When applied to task-based fMRI data, these two DCS predicted interindividual differences in frequency of behavioral lapsing and intraindividual temporal fluctuations in response speed. These findings with participants who underwent a night of total sleep deprivation were replicated in an independent dataset involving partially sleep-deprived participants. Fluctuations in functional connectivity thus appear to be clearly associated with changes in arousal. PMID- 27512041 TI - Scaling ansatz for the jamming transition. AB - We propose a Widom-like scaling ansatz for the critical jamming transition. Our ansatz for the elastic energy shows that the scaling of the energy, compressive strain, shear strain, system size, pressure, shear stress, bulk modulus, and shear modulus are all related to each other via scaling relations, with only three independent scaling exponents. We extract the values of these exponents from already known numerical or theoretical results, and we numerically verify the resulting predictions of the scaling theory for the energy and residual shear stress. We also derive a scaling relation between pressure and residual shear stress that yields insight into why the shear and bulk moduli scale differently. Our theory shows that the jamming transition exhibits an emergent scale invariance, setting the stage for the potential development of a renormalization group theory for jamming. PMID- 27512042 TI - Hydrodynamic theory of thermoelectric transport and negative magnetoresistance in Weyl semimetals. AB - We present a theory of thermoelectric transport in weakly disordered Weyl semimetals where the electron-electron scattering time is faster than the electron-impurity scattering time. Our hydrodynamic theory consists of relativistic fluids at each Weyl node, coupled together by perturbatively small intervalley scattering, and long-range Coulomb interactions. The conductivity matrix of our theory is Onsager reciprocal and positive semidefinite. In addition to the usual axial anomaly, we account for the effects of a distinct, axial gravitational anomaly expected to be present in Weyl semimetals. Negative thermal magnetoresistance is a sharp, experimentally accessible signature of this axial gravitational anomaly, even beyond the hydrodynamic limit. PMID- 27512043 TI - Coiled-coil destabilizing residues in the group A Streptococcus M1 protein are required for functional interaction. AB - The sequences of M proteins, the major surface-associated virulence factors of the widespread bacterial pathogen group A Streptococcus, are antigenically variable but have in common a strong propensity to form coiled coils. Paradoxically, these sequences are also replete with coiled-coil destabilizing residues. These features are evident in the irregular coiled-coil structure and thermal instability of M proteins. We present an explanation for this paradox through studies of the B repeats of the medically important M1 protein. The B repeats are required for interaction of M1 with fibrinogen (Fg) and consequent proinflammatory activation. The B repeats sample multiple conformations, including intrinsically disordered, dissociated, as well as two alternate coiled coil conformations: a Fg-nonbinding register 1 and a Fg-binding register 2. Stabilization of M1 in the Fg-nonbinding register 1 resulted in attenuation of Fg binding as expected, but counterintuitively, so did stabilization in the Fg binding register 2. Strikingly, these register-stabilized M1 proteins gained the ability to bind Fg when they were destabilized by a chaotrope. These results indicate that M1 stability is antithetical to Fg interaction and that M1 conformational dynamics, as specified by destabilizing residues, are essential for interaction. A "capture-and-collapse" model of association accounts for these observations, in which M1 captures Fg through a dynamic conformation and then collapses into a register 2-coiled coil as a result of stabilization provided by binding energy. Our results support the general conclusion that destabilizing residues are evolutionarily conserved in M proteins to enable functional interactions necessary for pathogenesis. PMID- 27512044 TI - Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer-dimer interface. AB - Approaches to improving the biological properties of natural products typically strive to modify their structures to identify the essential pharmacophore, or make functional group changes to improve biological target affinity or functional activity, change physical properties, enhance stability, or introduce conformational constraints. Aside from accessible semisynthetic modifications of existing functional groups, rarely does one consider using chemical synthesis to add molecular complexity to the natural product. In part, this may be attributed to the added challenge intrinsic in the synthesis of an even more complex compound. Herein, we report synthetically derived, structurally more complex vinblastines inaccessible from the natural product itself that are a stunning 100 fold more active (IC50 values, 50-75 pM vs. 7 nM; HCT116), and that are now accessible because of advances in the total synthesis of the natural product. The newly discovered ultrapotent vinblastines, which may look highly unusual upon first inspection, bind tubulin with much higher affinity and likely further disrupt the tubulin head-to-tail alpha/beta dimer-dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid, and extended C20' urea along the adjacent continuing protein-protein interface. In this case, the added molecular complexity was used to markedly enhance target binding and functional biological activity (100-fold), and likely represents a general approach to improving the properties of other natural products targeting a protein-protein interaction. PMID- 27512045 TI - Profile of Nancy C. Andrews. PMID- 27512046 TI - Role of kinesin-1-based microtubule sliding in Drosophila nervous system development. AB - The plus-end microtubule (MT) motor kinesin-1 is essential for normal development, with key roles in the nervous system. Kinesin-1 drives axonal transport of membrane cargoes to fulfill the metabolic needs of neurons and maintain synapses. We have previously demonstrated that kinesin-1, in addition to its well-established role in organelle transport, can drive MT-MT sliding by transporting "cargo" MTs along "track" MTs, resulting in dramatic cell shape changes. The mechanism and physiological relevance of this MT sliding are unclear. In addition to its motor domain, kinesin-1 contains a second MT-binding site, located at the C terminus of the heavy chain. Here, we mutated this C terminal MT-binding site such that the ability of kinesin-1 to slide MTs is significantly compromised, whereas cargo transport is unaffected. We introduced this mutation into the genomic locus of kinesin-1 heavy chain (KHC), generating the Khc(mutA) allele. Khc(mutA) neurons displayed significant MT sliding defects while maintaining normal transport of many cargoes. Using this mutant, we demonstrated that MT sliding is required for axon and dendrite outgrowth in vivo. Consistent with these results, Khc(mutA) flies displayed severe locomotion and viability defects. To test the role of MT sliding further, we engineered a chimeric motor that actively slides MTs but cannot transport organelles. Activation of MT sliding in Khc(mutA) neurons using this chimeric motor rescued axon outgrowth in cultured neurons and in vivo, firmly establishing the role of sliding in axon outgrowth. These results demonstrate that MT sliding by kinesin-1 is an essential biological phenomenon required for neuronal morphogenesis and normal nervous system development. PMID- 27512048 TI - Reply to Inbar: Contextual sensitivity helps explain the reproducibility gap between social and cognitive psychology. PMID- 27512047 TI - Cellular normoxic biophysical markers of hydroxyurea treatment in sickle cell disease. AB - Hydroxyurea (HU) has been used clinically to reduce the frequency of painful crisis and the need for blood transfusion in sickle cell disease (SCD) patients. However, the mechanisms underlying such beneficial effects of HU treatment are still not fully understood. Studies have indicated a weak correlation between clinical outcome and molecular markers, and the scientific quest to develop companion biophysical markers have mostly targeted studies of blood properties under hypoxia. Using a common-path interferometric technique, we measure biomechanical and morphological properties of individual red blood cells in SCD patients as a function of cell density, and investigate the correlation of these biophysical properties with drug intake as well as other clinically measured parameters. Our results show that patient-specific HU effects on the cellular biophysical properties are detectable at normoxia, and that these properties are strongly correlated with the clinically measured mean cellular volume rather than fetal hemoglobin level. PMID- 27512049 TI - Association between contextual dependence and replicability in psychology may be spurious. PMID- 27512050 TI - Cognitive impairment among patients with multiple sclerosis: associations with employment and quality of life. AB - OBJECTIVES: To explore the relationship between cognitive impairment and conventional measures of disability in multiple sclerosis (MS), quality of life (QOL) and employment status using the brief international cognitive assessment for multiple sclerosis (BICAMS) in the routine outpatient clinic. METHODS: 62 patients with MS were assessed on the BICAMS test battery for cognitive impairment. Data were obtained on employment status and a number of questionnaires completed including fatigue severity score, multiple sclerosis neuropsychological questionnaire, hospital anxiety and depression scale, the functional assessment of multiple sclerosis (FAMS) as well as on the EuroQOL five dimension questionnaire (EQ-5D). Other assessments include the patient activation measure and unidimensional self-efficacy scale for multiple sclerosis. RESULTS: Cognitive assessment revealed 44 subjects (65%) had evidence of cognitive impairment on formal testing. In comparison with patients without evidence of cognitive impairment, cognitively impaired patients exhibited significantly higher rates of unemployment (p=0.009). The symbol digits modalities test was the most significant predictor of unemployment. Cognitive impairment was associated with lower QOL scores on the FAMS (p=0.001) and EQ-5D (p<0.001). CONCLUSIONS: BICAMS provides a sensitive and easy to administer screening test for cognitive impairment within the outpatient setting. Cognitive impairment is common in our cohort of patients with MS attending outpatients and appears to be associated with increased rates of unemployment and lower measures of QOL. PMID- 27512051 TI - Patterns, predictors and effects of texting intervention on physical activity in CHD - insights from the TEXT ME randomized clinical trial. AB - BACKGROUND: Mobile phone text message interventions are used to support behaviour change including physical activity, but we have less insight into how these interventions work and what factors predict response. AIMS: To study the effect of TEXT ME (Tobacco EXercise and dieT Messages) text message intervention on physical activity domains, consistency of effects across sub-groups and its additive value in patients that received traditional cardiac rehabilitation programme. METHODS: This is a secondary analysis of the TEXT ME, a randomized clinical trial of lifestyle-focused text message intervention compared with usual care in patients with coronary heart disease. A quarter of the messages were designed specifically to encourage physical activity. Sedentary time and physical activity were assessed using the Global Physical Activity Questionnaire. RESULTS: At baseline, 85% of the 710 participants reported low physical activity levels. At six months, compared with controls, the intervention arm reported higher recreational physical activity (471 vs. 307 metabolic equivalent-min/week, p = 0.001) and travel physical activity (230 vs. 128 MET-min/week, p = 0.002), similar work-related physical activity and lower sedentary times (494 vs. 587 min, p < 0.001). Male gender, high baseline physical activity, cardiac rehabilitation participation and text message intervention predicted physically active status at six months. Subjects that received both cardiac rehabilitation and text messaging intervention were more likely to achieve target physical activity levels compared with cardiac rehabilitation alone (odds ratio 7.07 vs. 1.80, p < 0.001). CONCLUSIONS: The TEXT ME intervention improved recreational and travel physical activity, reduced sedentary times but had no effects on work related physical activity. It had incremental benefits at achieving target physical activity levels even in patients participating in the traditional cardiac rehabilitation programme. PMID- 27512052 TI - The blood pressure-lowering effect of a single bout of resistance exercise: A systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: Current exercise guidelines recommend aerobic types of exercises on most days of the week, supplemented with dynamic resistance exercise twice weekly. Whereas the blood pressure (BP)-lowering effects of a single session of aerobic exercise have been well studied, less is known about the hypotensive effect of a single bout of resistance exercise. OBJECTIVES: To evaluate the transient effect of resistance exercise on BP by means of meta-analytic techniques. METHODS: A systematic electronic search in Medline, Scientific Electronic Library Online (SciELO), Latin American and Caribbean Health Sciences Literature (LILACS), Elton B Stephens Company (EBSCO), EMBASE and SPORTDiscus was completed in March 2015 identifying randomised controlled trials investigating the effect of a single bout of resistance exercise on resting or ambulatory BP in healthy adults. A subsequent meta-analysis was performed. RESULTS: The meta analysis involved 30 studies, 81 interventions and 646 participants (normotensive (n = 505) or hypertensive (n = 141)). A single bout of resistance exercise elicited small-to-moderate reductions in office systolic BP at 60 minutes postexercise [-3.3 (-4.0 to -2.6)/-2.7 (-3.2 to -2.1) mmHg (CI 95%)], 90 minutes postexercise [-5.3 (-8.5 to -2.1)/-4.7 (-6.9 to -2.4) mmHg (CI 95%)] and in 24 hour ambulatory BP [-1.7 (-2.8 to -0.67)/-1.2 (-2.4 to -0.022) mmHg (CI 95%)] compared to a control session. The reduction in office BP was more pronounced in hypertensive compared to normotensive individuals (p < 0.01), when using larger muscle groups (p < 0.05) and when participants were recovering in the supine position (p < 0.01). CONCLUSION: A single bout of resistance exercise can have a BP-lowering effect that last for up to 24 hours. Supine recovery and the use of larger muscle groups resulted in greater BP reductions after resistance exercise. PMID- 27512053 TI - Refined interpretation of exercise ECG testing: Opportunities for a comeback in the era of expanding advanced cardiac imaging technologies? PMID- 27512054 TI - The calcium-dependent protein kinase RcCDPK2 phosphorylates sucrose synthase at Ser11 in developing castor oil seeds. AB - Imported sucrose is cleaved by sucrose synthase (SUS) as a critical initial reaction in the biosynthesis of storage end-products by developing seeds. Although SUS is phosphorylated at a conserved seryl residue by an apparent CDPK (Ca2+-dependent protein kinase) in diverse plant tissues, the functions and mechanistic details of this process remain obscure. Thus, the native CDPK that phosphorylates RcSUS1 (Ricinus communis SUS1) at Ser11 in developing COS (castor oil seeds) was highly purified and identified as RcCDPK2 by MS/MS. Purified RcSUS1-K (-kinase) and heterologously expressed RcCDPK2 catalyzed Ca2+-dependent Ser11 phosphorylation of RcSUS1 and its corresponding dephosphopeptide, while exhibiting a high affinity for free Ca2+ ions [K0.5(Ca2+) < 0.4 uM]. RcSUS1-K activity, RcCDPK2 expression, and RcSUS1 Ser11 phosphorylation peaked during early COS development and then declined in parallel. The elimination of sucrose import via fruit excision triggered RcSUS1 dephosphorylation but did not alter RcSUS1-K activity, suggesting a link between sucrose signaling and posttranslational RcCDPK2 control. Both RcCDPK2-mCherry and RcSUS1-EYFP co localized throughout the cytosol when transiently co-expressed in tobacco suspension cells, although RcCDPK2-mCherry was also partially localized to the nucleus. Subcellular fractionation revealed that ~20% of RcSUS1-K activity associates with microsomal membranes in developing COS, as does RcSUS1. In contrast with RcCDPK1, which catalyzes inhibitory phosphorylation of COS bacterial-type phosphoenolpyruvate carboxylase at Ser451, RcCDPK2 exhibited broad substrate specificity, a wide pH-activity profile centered at pH 8.5, and insensitivity to metabolite effectors or thiol redox status. Our combined results indicate a possible link between cytosolic Ca2+-signaling and the control of photosynthate partitioning during COS development. PMID- 27512055 TI - Antigenic Fingerprinting of Antibody Response in Humans following Exposure to Highly Pathogenic H7N7 Avian Influenza Virus: Evidence for Anti-PA-X Antibodies. AB - Infections with H7 highly pathogenic avian influenza (HPAI) viruses remain a major public health concern. Adaptation of low-pathogenic H7N7 to highly pathogenic H7N7 in Europe in 2015 raised further alarm for a potential pandemic. An in-depth understanding of antibody responses to HPAI H7 virus following infection in humans could provide important insight into virus gene expression as well as define key protective and serodiagnostic targets. Here we used whole genome gene fragment phage display libraries (GFPDLs) expressing peptides of 15 to 350 amino acids across the complete genome of the HPAI H7N7 A/Netherlands/33/03 virus. The hemagglutinin (HA) antibody epitope repertoires of 15 H7N7-exposed humans identified clear differences between individuals with no hemagglutination inhibition (HI) titers (<1:10) and those with HI titers of >1:40. Several potentially protective H7N7 epitopes close to the HA receptor binding domain (RBD) and neuraminidase (NA) catalytic site were identified. Surface plasmon resonance (SPR) analysis identified a strong correlation between HA1 (but not HA2) binding antibodies and H7N7 HI titers. A proportion of HA1 binding in plasma was contributed by IgA antibodies. Antibodies against the N7 neuraminidase were less frequent but targeted sites close to the sialic acid binding site. Importantly, we identified strong antibody reactivity against PA-X, a putative virulence factor, in most H7N7-exposed individuals, providing the first evidence for in vivo expression of PA-X and its recognition by the immune system during human influenza A virus infection. This knowledge can help inform the development and selection of the most effective countermeasures for prophylactic as well as therapeutic treatments of HPAI H7N7 avian influenza virus. IMPORTANCE: An outbreak of pathogenic H7N7 virus occurred in poultry farms in The Netherlands in 2003. Severe outcome included conjunctivitis, influenza like illness, and one lethal infection. In this study, we investigated convalescent-phase sera from H7N7-exposed individuals by using a whole-genome phage display library (H7N7-GFPDL) to explore the complete repertoire of post H7N7-exposure antibodies. PA-X is a recently identified influenza virus virulence protein generated by ribosomal frameshifting in segment 3 of influenza virus coding for PA. However, PA-X expression during influenza virus infection in humans is unknown. We identified strong antibody reactivity against PA-X in most H7N7-exposed individuals (but not in unexposed adults), providing the first evidence for in vivo expression of PA-X and its recognition by the immune system during human infection with pathogenic H7N7 avian influenza virus. PMID- 27512056 TI - Influenza A Virus Infection in Pigs Attracts Multifunctional and Cross-Reactive T Cells to the Lung. AB - Pigs are natural hosts for influenza A viruses and play a critical role in influenza epidemiology. However, little is known about their influenza-evoked T cell response. We performed a thorough analysis of both the local and systemic T cell response in influenza virus-infected pigs, addressing kinetics and phenotype as well as multifunctionality (gamma interferon [IFN-gamma], tumor necrosis factor alpha [TNF-alpha], and interleukin-2 [IL-2]) and cross-reactivity. A total of 31 pigs were intratracheally infected with an H1N2 swine influenza A virus (FLUAVsw) and consecutively euthanized. Lungs, tracheobronchial lymph nodes, and blood were sampled during the first 15 days postinfection (p.i.) and at 6 weeks p.i. Ex vivo flow cytometry of lung lymphocytes revealed an increase in proliferating (Ki-67(+)) CD8(+) T cells with an early effector phenotype (perforin(+) CD27(+)) at day 6 p.i. Low frequencies of influenza virus-specific IFN-gamma-producing CD4(+) and CD8(+) T cells could be detected in the lung as early as 4 days p.i. On consecutive days, influenza virus-specific CD4(+) and CD8(+) T cells produced mainly IFN-gamma and/or TNF-alpha, reaching peak frequencies around day 9 p.i., which were up to 30-fold higher in the lung than in tracheobronchial lymph nodes or blood. At 6 weeks p.i., CD4(+) and CD8(+) memory T cells had accumulated in lung tissue. These cells showed diverse cytokine profiles and in vitro reactivity against heterologous influenza virus strains, all of which supports their potential to combat heterologous influenza virus infections in pigs. IMPORTANCE: Pigs not only are a suitable large-animal model for human influenza virus infection and vaccine development but also play a central role in the emergence of new pandemic strains. Although promising candidate universal vaccines are tested in pigs and local T cells are the major correlate of heterologous control, detailed and targeted analyses of T-cell responses at the site of infection are scarce. With the present study, we provide the first detailed characterization of magnitude, kinetics, and phenotype of specific T cells recruited to the lungs of influenza virus-infected pigs, and we could demonstrate multifunctionality, cross-reactivity, and memory formation of these cells. This, and ensuing work in the pig, will strengthen the position of this species as a large-animal model for human influenza virus infection and will immediately benefit vaccine development for improved control of influenza virus infections in pigs. PMID- 27512058 TI - Graf1 Controls the Growth of Human Parainfluenza Virus Type 2 through Inactivation of RhoA Signaling. AB - Rho GTPases are involved in a variety of cellular activities and are regulated by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). We found that the activation of Rho GTPases by lysophosphatidic acid promotes the growth of human parainfluenza virus type 2 (hPIV-2). Furthermore, hPIV-2 infection causes activation of RhoA, a Rho GTPase. We hypothesized that Graf1 (also known as ARHGAP26), a GAP, regulates hPIV-2 growth by controlling RhoA signaling. Immunofluorescence analysis showed that hPIV-2 infection altered Graf1 localization from a homogenous distribution within the cytoplasm to granules. Graf1 colocalized with hPIV-2 P, NP, and L proteins. Graf1 interacts with P and V proteins via their N-terminal common region, and the C-terminal Src homology 3 domain-containing region of Graf1 is important for these interactions. In HEK293 cells constitutively expressing Graf1, hPIV-2 growth was inhibited, and RhoA activation was not observed during hPIV-2 infection. In contrast, Graf1 knockdown restored hPIV-2 growth and RhoA activation. Overexpression of hPIV-2 P and V proteins enhanced hPIV-2-induced RhoA activation. These results collectively suggested that hPIV-2 P and V proteins enhanced hPIV-2 growth by binding to Graf1 and that Graf1 inhibits hPIV-2 growth through RhoA inactivation. IMPORTANCE: Robust growth of hPIV-2 requires Rho activation. hPIV-2 infection causes RhoA activation, which is suppressed by Graf1. Graf1 colocalizes with viral RNP (vRNP) in hPIV-2-infected cells. We found that Graf1 interacts with hPIV-2 P and V proteins. We also identified regions in these proteins which are important for this interaction. hPIV-2 P and V proteins enhanced the hPIV-2 growth via binding to Graf1, while Graf1 inhibited hPIV-2 growth through RhoA inactivation. PMID- 27512057 TI - Japanese Macaque Rhadinovirus Encodes a Viral MicroRNA Mimic of the miR-17 Family. AB - Japanese macaque (JM) rhadinovirus (JMRV) is a novel, gamma-2 herpesvirus that was recently isolated from JM with inflammatory demyelinating encephalomyelitis (JME). JME is a spontaneous and chronic disease with clinical characteristics and immunohistopathology comparable to those of multiple sclerosis in humans. Little is known about the molecular biology of JMRV. Here, we sought to identify and characterize the small RNAs expressed during lytic JMRV infection using deep sequencing. Fifteen novel viral microRNAs (miRNAs) were identified in JMRV infected fibroblasts, all of which were readily detectable by 24 h postinfection and accumulated to high levels by 72 h. Sequence comparisons to human Kaposi's sarcoma-associated herpesvirus (KSHV) miRNAs revealed several viral miRNA homologs. To functionally characterize JMRV miRNAs, we screened for their effects on nuclear factor kappa B (NF-kappaB) signaling in the presence of two proinflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta). Multiple JMRV miRNAs suppressed cytokine-induced NF kappaB activation. One of these miRNAs, miR-J8, has seed sequence homology to members of the cellular miR-17/20/106 and miR-373 families, which are key players in cell cycle regulation as well as inflammation. Using reporters, we show that miR-J8 can target 3' untranslated regions (UTRs) with miR-17-5p or miR-20a cognate sites. Our studies implicate JMRV miRNAs in the suppression of innate antiviral immune responses, which is an emerging feature of many viral miRNAs. IMPORTANCE: Gammaherpesviruses are associated with multiple diseases linked to immunosuppression and inflammation, including AIDS-related cancers and autoimmune diseases. JMRV is a recently identified herpesvirus that has been linked to JME, an inflammatory demyelinating disease in Japanese macaques that mimics multiple sclerosis. There are few large-animal models for gammaherpesvirus-associated pathogenesis. Here, we provide the first experimental evidence of JMRV miRNAs in vitro and demonstrate that one of these viral miRNAs can mimic the activity of the cellular miR-17/20/106 family. Our work provides unique insight into the roles of viral miRNAs during rhadinovirus infection and provides an important step toward understanding viral miRNA function in a nonhuman primate model system. PMID- 27512059 TI - Benign Rabbit Caliciviruses Exhibit Evolutionary Dynamics Similar to Those of Their Virulent Relatives. AB - Two closely related caliciviruses cocirculate in Australia: rabbit hemorrhagic disease virus (RHDV) and rabbit calicivirus Australia 1 (RCV-A1). RCV-A1 causes benign enteric infections in the European rabbit (Oryctolagus cuniculus) in Australia and New Zealand, while its close relative RHDV causes a highly pathogenic infection of the liver in the same host. The comparison of these viruses provides important information on the nature and trajectory of virulence evolution, particularly as highly virulent strains of RHDV may have evolved from nonpathogenic ancestors such as RCV-A1. To determine the evolution of RCV-A1 we sequenced the full-length genomes of 44 RCV-A1 samples isolated from healthy rabbits and compared key evolutionary parameters to those of its virulent relative, RHDV. Despite their marked differences in pathogenicity and tissue tropism, RCV-A1 and RHDV have evolved in a very similar manner. Both viruses have evolved at broadly similar rates, suggesting that their dynamics are largely shaped by high background mutation rates, and both exhibit occasional recombination and an evolutionary environment dominated by purifying selection. In addition, our comparative analysis revealed that there have been multiple changes in both virulence and tissue tropism in the evolutionary history of these and related viruses. Finally, these new genomic data suggest that either RCV-A1 was introduced into Australia after the introduction of myxoma virus as a biocontrol agent in 1950 or there was drastic reduction of the rabbit population, and hence of RCV-A1 genetic diversity, perhaps coincident with the emergence of myxoma virus. IMPORTANCE: The comparison of closely related viruses that differ profoundly in propensity to cause disease in their hosts offers a powerful opportunity to reveal the causes of changes in virulence and to study how such changes alter the evolutionary dynamics of these pathogens. Here we describe such a novel comparison involving two closely related RNA viruses that cocirculate in Australia, the highly virulent rabbit hemorrhagic disease virus (RHDV) and the nonpathogenic rabbit calicivirus Australia 1 (RCV-A1). Both viruses infect the European rabbit, but they differ in virulence, tissue tropism, and mechanisms of transmission. Surprisingly, and despite these fundamental differences, RCV-A1 and RHDV have evolved at very similar (high) rates and with strong purifying selection. Furthermore, candidate key mutations were identified that may play a role in virulence and/or tissue tropism and therefore warrant further investigation. PMID- 27512060 TI - RIG-I-Mediated STING Upregulation Restricts Herpes Simplex Virus 1 Infection. AB - STING has emerged in recent years as a key player in orchestrating innate immune responses to cytosolic DNA and RNA derived from pathogens. However, the regulation of STING still remains poorly defined. In the present study, we investigated the mechanism of the regulation of STING expression in relation to the RIG-I pathway. Our data show that signaling through RIG-I induces STING expression at both the transcriptional and protein levels in various cell types. STING induction by the RIG-I agonist 5'triphosphorylated RNA (5'pppRNA) was recognized to be a delayed event resulting from an autocrine/paracrine mechanism. Indeed, cotreatment with tumor necrosis factor alpha and type I/II interferon was found to have a synergistic effect on the regulation of STING expression and could be potently decreased by impairing NF-kappaB and/or STAT1/2 signaling. STING induction significantly contributed to sustainment of the immune signaling cascade following 5'pppRNA treatment. Physiologically, this cross talk between the RNA- and DNA-sensing pathways allowed 5'pppRNA to efficiently block infection by herpes simplex virus 1 (HSV-1) both in vitro and in vivo in a STING-dependent fashion. These observations demonstrate that STING induction by RIG-I signaling through the NF-kappaB and STAT1/2 cascades is essential for RIG-I agonist mediated HSV-1 restriction. IMPORTANCE: The innate immune system represents the first line of defense against invading pathogens. The dysregulation of this system can result in failure to combat pathogens, inflammation, and autoimmune diseases. Thus, precise regulation at each level of the innate immune system is crucial. Recently, a number of studies have established STING to be a central molecule in the innate immune response to cytosolic DNA and RNA derived from pathogens. Here, we describe the regulation of STING via RIG-I-mediated innate immune sensing. We found that STING is synergistically induced via proinflammatory and antiviral cytokine cascades. In addition, we show that in vivo protection against herpes simplex virus 1 (HSV-1) by a RIG-I agonist required STING. Our study provides new insights into the cross talk between DNA and RNA pathogen-sensing systems via the control of STING. PMID- 27512061 TI - In Vivo Conditions Enable IFNAR-Independent Type I Interferon Production by Peritoneal CD11b+ Cells upon Thogoto Virus Infection. AB - Type I interferons (IFNs) crucially contribute to host survival upon viral infections. Robust expression of type I IFNs (IFN-alpha/beta) and induction of an antiviral state critically depend on amplification of the IFN signal via the type I IFN receptor (IFNAR). A small amount of type I IFN produced early upon virus infection binds the IFNAR and activates a self-enhancing positive feedback loop, resulting in induction of large, protective amounts of IFN-alpha. Unexpectedly, we found robust, systemic IFN-alpha expression upon infection of IFNAR knockout mice with the orthomyxovirus Thogoto virus (THOV). The IFNAR-independent IFN alpha production required in vivo conditions and was not achieved during in vitro infection. Using replication-incompetent THOV-derived virus-like particles, we demonstrate that IFNAR-independent type I IFN induction depends on viral polymerase activity but is largely independent of viral replication. To discover the cell type responsible for this effect, we used type I IFN reporter mice and identified CD11b(+) F4/80(+) myeloid cells within the peritoneal cavity of infected animals as the main source of IFNAR-independent type I IFN, corresponding to the particular tropism of THOV for this cell type. IMPORTANCE: Type I IFNs are crucial for the survival of a host upon most viral infections, and, moreover, they shape subsequent adaptive immune responses. Production of protective amounts of type I IFN critically depends on the positive feedback amplification via the IFNAR. Unexpectedly, we observed robust IFNAR-independent type I IFN expression upon THOV infection and unraveled molecular mechanisms and determined the tissue and cell type involved. Our data indicate that the host can effectively use alternative pathways to induce type I IFN responses if the classical feedback amplification is not available. Understanding how type I IFN can be produced in large amounts independently of IFNAR-dependent enhancement will identify mechanisms which might contribute to novel therapeutic strategies to fight viral pathogens. PMID- 27512062 TI - NF-kappaB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon Stimulated Response Elements in Its 5' Long Terminal Repeat. AB - Thousands of endogenous retroviruses (ERV), viral fossils of ancient germ line infections, reside within the human genome. Evidence of ERV activity has been observed widely in both health and disease. While this is most often cited as a bystander effect of cell culture or disease states, it is unclear which signals control ERV transcription. Bioinformatic analysis suggests that the viral promoter of endogenous retrovirus K (ERVK) is responsive to inflammatory transcription factors. Here we show that one reason for ERVK upregulation in amyotrophic lateral sclerosis (ALS) is the presence of functional interferon stimulated response elements (ISREs) in the viral promoter. Transcription factor overexpression assays revealed independent and synergistic upregulation of ERVK by interferon regulatory factor 1 (IRF1) and NF-kappaB isoforms. Tumor necrosis factor alpha (TNF-alpha) and LIGHT cytokine treatments of human astrocytes and neurons enhanced ERVK transcription and protein levels through IRF1 and NF-kappaB binding to the ISREs. We further show that in ALS brain tissue, neuronal ERVK reactivation is associated with the nuclear translocation of IRF1 and NF-kappaB isoforms p50 and p65. ERVK overexpression can cause motor neuron pathology in murine models. Our results implicate neuroinflammation as a key trigger of ERVK provirus reactivation in ALS. These molecular mechanisms may also extend to the pathobiology of other ERVK-associated inflammatory diseases, such as cancers, HIV infection, rheumatoid arthritis, and schizophrenia. IMPORTANCE: It has been well established that inflammatory signaling pathways in ALS converge at NF-kappaB to promote neuronal damage. Our findings suggest that inflammation-driven IRF1 and NF-kappaB activity promotes ERVK reactivation in neurons of the motor cortex in ALS. Thus, quenching ERVK activity through antiretroviral or immunomodulatory regimens may hinder virus-mediated neuropathology and improve the symptoms of ALS or other ERVK-associated diseases. PMID- 27512063 TI - B Virus (Macacine Herpesvirus 1) Divergence: Variations in Glycoprotein D from Clinical and Laboratory Isolates Diversify Virus Entry Strategies. AB - B virus (Macacine herpesvirus 1) can cause deadly zoonotic disease in humans. Molecular mechanisms of B virus cell entry are poorly understood for both macaques and humans. Here we investigated the abilities of clinical B virus isolates to use entry receptors of herpes simplex viruses (HSV). We showed that resistant B78H1 cells became susceptible to B virus clinical strains upon expression of either human nectin-2 or nectin-1. Antibody against glycoprotein D (gD) protected these nectin-bearing cells from B virus infection, and a gD negative recombinant B virus failed to enter these cells, indicating that the nectin-mediated B virus entry depends on gD. We observed that the infectivity of B virus isolates with a single amino acid substitution (D122N) in the IgV-core of the gD ectodomain was impaired on nectin-1-bearing cells. Computational homology based modeling of the B virus gD-nectin-1 complex revealed conformational differences between the structures of the gD-122N and gD-122D variants that affected the gD-nectin-1 protein-protein interface and binding affinity. Unlike HSV, B virus clinical strains were unable to use herpesvirus entry mediator (HVEM) as a receptor, regardless of conservation of the gD amino acid residues essential for HSV-1 entry via HVEM. Based on the model of the B virus gD-HVEM interface, we predict that residues R7, R11, and G15 are largely responsible for the inability of B virus to utilize HVEM for entry. The ability of B virus to enter cells of a human host by using a combination of receptors distinct from those for HSV-1 or HSV-2 suggests a possible mechanism of enhanced neuropathogenicity associated with zoonotic infections. IMPORTANCE: B virus causes brainstem destruction in infected humans in the absence of timely diagnosis and intervention. Nectins are cell adhesion molecules that are widely expressed in human tissues, including neurons and neuronal synapses. Here we report that human nectin-2 is a target receptor for B virus entry, in addition to the reported receptor human nectin-1. Similar to a B virus lab strain, B virus clinical strains can effectively use both nectin-1 and nectin-2 as cellular receptors for entry into human cells, but unlike HSV-1 and HSV-2, none of the clinical strains uses an HVEM-mediated entry pathway. Ultimately, these differences between B virus and HSV-1 and -2 may provide insight into the neuropathogenicity of B virus during zoonotic infections. PMID- 27512064 TI - Epitope-Independent Purification of Native-Like Envelope Trimers from Diverse HIV 1 Isolates. AB - Soluble forms of trimeric HIV-1 envelope glycoprotein (Env) have long been sought as immunogens and as reagents for analysis of Env structure and function. Isolation of trimers that mimic native Env, derived from diverse viruses, however, represents a major challenge. Thus far, the most promising native-like (NL) structures have been obtained by engineering trimer-stabilizing mutations, termed SOSIP, into truncated Env sequences. However, the abundances of NL trimeric conformers vary among Envs, necessitating purification by monoclonal antibodies (MAbs) like PGT145, which target specific epitopes. To surmount this inherent limitation, we developed an approach that uses lectin affinity chromatography, ion-exchange chromatography, hydrophobic-interaction chromatography (HIC), and size exclusion chromatography (SEC) to isolate NL trimers from nonnative Env species. We validated this method with SOSIP trimers from HIV-1 clades A and B. Analyses by SEC, blue native PAGE, SDS-PAGE, and dynamic light scattering indicated that the resulting material was homogeneous (>95% pure), fully cleaved, and of the appropriate molecular weight and size for SOSIP trimers. Negative-stain electron microscopy further demonstrated that our preparations were composed of NL trimeric structures. By hydrogen/deuterium exchange mass spectrometry, these HIC-pure trimers exhibited structural organization consistent with NL trimers and inconsistent with profiles seen in nonnative Envs. Screened for antigenicity, some Envs, like BS208.b1 and KNH1144 T162A, did not present the glycan/quaternary structure-dependent epitope for PGT145 binding, suggesting that these SOSIPs would be challenging to isolate by existing MAb affinity methods. By selecting based on biochemical rather than antigenic properties, our method offers an epitope-independent alternative to MAbs for isolation of NL Env trimers. IMPORTANCE: The production and purification of diverse soluble Env trimers that maintain native-like (NL) structure present technical challenges that must be overcome in order to advance vaccine development and provide reagents for HIV research. Low levels of NL trimer expression amid heterogeneous Env conformers, even with the addition of stabilizing mutations, have presented a major challenge. In addition, it has been difficult to separate the NL trimers from these heterogeneous mixtures. While MAbs with specificity for quaternary NL trimer epitopes have provided one approach to purifying the desirable species, such methods are dependent on the Env displaying the proper epitope. In addition, MAb affinity chromatography can be expensive, the necessary MAb may be in limited supply, and large-scale purification may not be feasible. Our method based on biochemical separation techniques offers an epitope-independent approach to purification of NL trimers with general application to diverse Envs. PMID- 27512065 TI - Avian Leukosis Virus Activation of an Antisense RNA Upstream of TERT in B-Cell Lymphomas. AB - Avian leukosis virus (ALV) induces tumors by integrating its proviral DNA into the chicken genome and altering the expression of nearby genes via strong promoter and enhancer elements. Viral integration sites that contribute to oncogenesis are selected in tumor cells. Deep-sequencing analysis of B-cell lymphoma DNA confirmed that the telomerase reverse transcriptase (TERT) gene promoter is a common ALV integration target. Twenty-six unique proviral integration sites were mapped between 46 and 3,552 nucleotides (nt) upstream of the TERT transcription start site, predominantly in the opposite transcriptional orientation to TERT Transcriptome-sequencing (RNA-seq) analysis of normal bursa revealed a transcribed region upstream of TERT in the opposite orientation, suggesting the TERT promoter is bidirectional. This transcript appears to be an uncharacterized antisense RNA. We have previously shown that TERT expression is upregulated in tumors with integrations in the TERT promoter region. We now report that the viral promoter drives the expression of a chimeric transcript containing viral sequences spliced to exons 4 through 7 of this antisense RNA. Clonal expansion of cells with ALV integrations driving overexpression of the TERT antisense RNA suggest it may have a role in tumorigenesis. IMPORTANCE: The data suggest that ALV integrations in the TERT promoter region drive the overexpression of a novel antisense RNA and contribute to the development of lymphomas. PMID- 27512066 TI - Inhibition of the Membrane Attack Complex by Dengue Virus NS1 through Interaction with Vitronectin and Terminal Complement Proteins. AB - : Dengue virus (DENV) infects millions of people worldwide and is a major public health problem. DENV nonstructural protein 1 (NS1) is a conserved glycoprotein that associates with membranes and is also secreted into the plasma in DENV infected patients. The present study describes a novel mechanism by which NS1 inhibits the terminal complement pathway. We first identified the terminal complement regulator vitronectin (VN) as a novel DENV2 NS1 binding partner by using a yeast two-hybrid system. This interaction was further assessed by enzyme linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) assay. The NS1-VN complex was also detected in plasmas from DENV-infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the DENV2 NS1 protein, either by itself or by interacting with VN, hinders the formation of the membrane attack complex (MAC) and C9 polymerization. Finally, we showed that DENV2, West Nile virus (WNV), and Zika virus (ZIKV) NS1 proteins produced in mammalian cells inhibited C9 polymerization. Taken together, our results points to a role for NS1 as a terminal pathway inhibitor of the complement system. IMPORTANCE: Dengue is the most important arthropod-borne viral disease nowadays and is caused by dengue virus (DENV). The flavivirus NS1 glycoprotein has been characterized functionally as a complement evasion protein that can attenuate the activation of the classical, lectin, and alternative pathways. The present study describes a novel mechanism by which DENV NS1 inhibits the terminal complement pathway. We identified the terminal complement regulator vitronectin (VN) as a novel DENV NS1 binding partner, and the NS1-VN complex was detected in plasmas from DENV infected patients, suggesting that this interaction occurs during DENV infection. We also demonstrated that the NS1-VN complex inhibited membrane attack complex (MAC) formation, thus interfering with the complement terminal pathway. Interestingly, NS1 itself also inhibited MAC activity, suggesting a direct role of this protein in the inhibition process. Our findings imply a role for NS1 as a terminal pathway inhibitor of the complement system. PMID- 27512067 TI - Activation of the Chicken Anemia Virus Apoptin Protein by Chk1/2 Phosphorylation Is Required for Apoptotic Activity and Efficient Viral Replication. AB - Chicken anemia virus (CAV) is a single-stranded circular DNA virus that carries 3 genes, the most studied of which is the gene encoding VP3, also known as apoptin. This protein has been demonstrated to specifically kill transformed cells while leaving normal cells unharmed in a manner that is independent of p53 status. Although the mechanistic basis for this differential activity is unclear, it is evident that the subcellular localization of the protein is important for the difference. In normal cells, apoptin exists in filamentous networks in the cytoplasm, whereas in transformed cells, apoptin is present in the nucleus and appears as distinct foci. We have previously demonstrated that DNA damage signaling through the ataxia telangiectasia mutated (ATM) pathway induces the translocation of apoptin from the cytoplasm to the nucleus, where it induces apoptosis. We found that apoptin contains four checkpoint kinase consensus sites and that mutation of either threonine 56 or 61 to alanine restricts apoptin to the cytoplasm. Furthermore, treatment of tumor cells expressing apoptin with inhibitors of checkpoint kinase 1 (Chk1) and Chk2 causes apoptin to localize to the cytoplasm. Importantly, silencing of Chk2 rescues cancer cells from the cytotoxic effects of apoptin. Finally, treatment of virus-producing cells with Chk inhibitor protects them from virus-mediated toxicity and reduces the titer of progeny virus. Taken together, our results indicate that apoptin is a sensor of DNA damage signaling through the ATM-Chk2 pathway, which induces it to migrate to the nucleus during viral replication. IMPORTANCE: The chicken anemia virus (CAV) protein apoptin is known to induce tumor cell-specific death when expressed. Therefore, understanding its regulation and mechanism of action could provide new insights into tumor cell biology. We have determined that checkpoint kinase 1 and 2 signaling is important for apoptin regulation and is a likely feature of both tumor cells and host cells producing virus progeny. Inhibition of checkpoint signaling prevents apoptin toxicity in tumor cells and attenuates CAV replication, suggesting it may be a future target for antiviral therapy. PMID- 27512068 TI - Human IFIT1 Inhibits mRNA Translation of Rubulaviruses but Not Other Members of the Paramyxoviridae Family. AB - We have previously shown that IFIT1 is primarily responsible for the antiviral action of interferon (IFN) alpha/beta against parainfluenza virus type 5 (PIV5), selectively inhibiting the translation of PIV5 mRNAs. Here we report that while PIV2, PIV5, and mumps virus (MuV) are sensitive to IFIT1, nonrubulavirus members of the paramyxoviridae such as PIV3, Sendai virus (SeV), and canine distemper virus (CDV) are resistant. The IFIT1 sensitivity of PIV5 was not rescued by coinfection with an IFIT1-resistant virus (PIV3), demonstrating that PIV3 does not specifically inhibit the antiviral activity of IFIT1 and that the inhibition of PIV5 mRNAs is regulated by cis-acting elements. We developed an in vitro translation system using purified human IFIT1 to further investigate the mechanism of action of IFIT1. While the translations of PIV2, PIV5, and MuV mRNAs were directly inhibited by IFIT1, the translations of PIV3, SeV, and CDV mRNAs were not. Using purified human mRNA-capping enzymes, we show biochemically that efficient inhibition by IFIT1 is dependent upon a 5' guanosine nucleoside cap (which need not be N7 methylated) and that this sensitivity is partly abrogated by 2'O methylation of the cap 1 ribose. Intriguingly, PIV5 M mRNA, in contrast to NP mRNA, remained sensitive to inhibition by IFIT1 following in vitro 2'O methylation, suggesting that other structural features of mRNAs may influence their sensitivity to IFIT1. Thus, surprisingly, the viral polymerases (which have 2'-O-methyltransferase activity) of rubulaviruses do not protect these viruses from inhibition by IFIT1. Possible biological consequences of this are discussed. IMPORTANCE: Paramyxoviruses cause a wide variety of diseases, and yet most of their genes encode structural proteins and proteins involved in their replication cycle. Thus, the amount of genetic information that determines the type of disease that paramyxoviruses cause is relatively small. One factor that will influence disease outcomes is how they interact with innate host cell defenses, including the interferon (IFN) system. Here we show that different paramyxoviruses interact in distinct ways with cells in a preexisting IFN-induced antiviral state. Strikingly, all the rubulaviruses tested were sensitive to the antiviral action of ISG56/IFIT1, while all the other paramyxoviruses tested were resistant. We developed novel in vitro biochemical assays to investigate the mechanism of action of IFIT1, demonstrating that the mRNAs of rubulaviruses can be directly inhibited by IFIT1 and that this is at least partially because their mRNAs are not correctly methylated. PMID- 27512069 TI - Long and Short Isoforms of the Human Cytomegalovirus UL138 Protein Silence IE Transcription and Promote Latency. AB - The UL133-138 locus present in clinical strains of human cytomegalovirus (HCMV) encodes proteins required for latency and reactivation in CD34(+) hematopoietic progenitor cells and virion maturation in endothelial cells. The encoded proteins form multiple homo- and hetero-interactions and localize within secretory membranes. One of these genes, UL136 gene, is expressed as at least five different protein isoforms with overlapping and unique functions. Here we show that another gene from this locus, the UL138 gene, also generates more than one protein isoform. A long form of UL138 (pUL138-L) initiates translation from codon 1, possesses an amino-terminal signal sequence, and is a type one integral membrane protein. Here we identify a short protein isoform (pUL138-S) initiating from codon 16 that displays a subcellular localization similar to that of pUL138 L. Reporter, short-term transcription, and long-term virus production assays revealed that both pUL138-L and pUL138-S are able to suppress major immediate early (IE) gene transcription and the generation of infectious virions in cells in which HCMV latency is studied. The long form appears to be more potent at silencing IE transcription shortly after infection, while the short form seems more potent at restricting progeny virion production at later times, indicating that both isoforms of UL138 likely cooperate to promote HCMV latency. IMPORTANCE: Latency allows herpesviruses to persist for the lives of their hosts in the face of effective immune control measures for productively infected cells. Controlling latent reservoirs is an attractive antiviral approach complicated by knowledge deficits for how latently infected cells are established, maintained, and reactivated. This is especially true for betaherpesviruses. The functional consequences of HCMV UL138 protein expression during latency include repression of viral IE1 transcription and suppression of virus replication. Here we show that short and long isoforms of UL138 exist and can themselves support latency but may do so in temporally distinct manners. Understanding the complexity of gene expression and its impact on latency is important for considering potential antivirals targeting latent reservoirs. PMID- 27512071 TI - In Vitro Studies Show that Sequence Variability Contributes to Marked Variation in Hepatitis B Virus Replication, Protein Expression, and Function Observed across Genotypes. AB - : The hepatitis B virus (HBV) exists as 9 major genotypes (A to I), one minor strain (designated J) and multiple subtypes. Marked differences in HBV natural history, disease progression and treatment response are exhibited by many of these genotypes and subtypes. For example, HBV genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion and high rates of liver cancer compared to other HBV genotypes, whereas genotype A2 is rarely associated with HBeAg-negative disease or liver cancer. The reasons for these and other differences in HBV natural history are yet to be determined but could in part be due to sequence differences in the HBV genome that alter replicative capacity and/or gene expression. Direct comparative studies on HBV replication and protein expression have been limited to date due largely to the absence of infectious HBV cDNA clones for each of the HBV genotypes present in the same genetic arrangement. We have produced replication-competent infectious cDNA clones of the most common subtypes of genotypes A to D, namely, A2, B2, C2, D3, and the minor strain J, and compared their HBV replication phenotype using transient transfection models. We identified striking differences in HBV replicative capacity as well as HBeAg and surface (HBsAg) protein expression across genotypes, which may in part be due to sequence variability in regulatory regions of the HBV genome. Functional analysis showed that sequence differences in the major upstream regulatory region across genotypes impacted promoter activity. IMPORTANCE: There have been very few studies directly comparing the replication phenotype of different HBV genotypes, for which there are marked differences in natural history and disease progression worldwide. We have generated replication competent 1.3-mer cDNA clones of the major genotypes A2, B2, C2, and D3, as well as a recently identified strain J, and identified striking differences in replicative capacity and protein expression that may contribute to some of the observed differences in HBV natural history observed globally. PMID- 27512070 TI - Heat Shock Protein 70 Family Members Interact with Crimean-Congo Hemorrhagic Fever Virus and Hazara Virus Nucleocapsid Proteins and Perform a Functional Role in the Nairovirus Replication Cycle. AB - The Nairovirus genus of the Bunyaviridae family contains serious human and animal pathogens classified within multiple serogroups and species. Of these serogroups, the Crimean-Congo hemorrhagic fever virus (CCHFV) serogroup comprises sole members CCHFV and Hazara virus (HAZV). CCHFV is an emerging zoonotic virus that causes often-fatal hemorrhagic fever in infected humans for which preventative or therapeutic strategies are not available. In contrast, HAZV is nonpathogenic to humans and thus represents an excellent model to study aspects of CCHFV biology under conditions of more-accessible biological containment. The three RNA segments that form the nairovirus genome are encapsidated by the viral nucleocapsid protein (N) to form ribonucleoprotein (RNP) complexes that are substrates for RNA synthesis and packaging into virus particles. We used quantitative proteomics to identify cellular interaction partners of CCHFV N and identified robust interactions with cellular chaperones. These interactions were validated using immunological methods, and the specific interaction between native CCHFV N and cellular chaperones of the HSP70 family was confirmed during live CCHFV infection. Using infectious HAZV, we showed for the first time that the nairovirus N-HSP70 association was maintained within both infected cells and virus particles, where N is assembled as RNPs. Reduction of active HSP70 levels in cells by the use of small-molecule inhibitors significantly reduced HAZV titers, and a model for chaperone function in the context of high genetic variability is proposed. These results suggest that chaperones of the HSP70 family are required for nairovirus replication and thus represent a genetically stable cellular therapeutic target for preventing nairovirus-mediated disease. IMPORTANCE: Nairoviruses compose a group of human and animal viruses that are transmitted by ticks and associated with serious or fatal disease. One member is Crimean-Congo hemorrhagic fever virus (CCHFV), which is responsible for fatal human disease and is recognized as an emerging threat within Europe in response to climate change. No preventative or therapeutic strategies against nairovirus mediated disease are currently available. Here we show that the N protein of CCHFV and the related Hazara virus interact with a cellular protein, HSP70, during both the intracellular and extracellular stages of the virus life cycle. The use of inhibitors that block HSP70 function reduces virus titers by up to 1,000-fold, suggesting that this interaction is important within the context of the nairovirus life cycle and may represent a potent target for antinairovirus therapies against which the virus cannot easily develop resistance. PMID- 27512072 TI - Interrelationship of Primary Virus Replication, Level of Latency, and Time to Reactivation in the Trigeminal Ganglia of Latently Infected Mice. AB - We sought to determine the possibility of an interrelationship between primary virus replication in the eye, the level of viral DNA in the trigeminal ganglia (TG) during latency, and the amount of virus reactivation following ocular herpes simplex virus type 1 (HSV-1) infection. Mice were infected with virulent (McKrae) or avirulent (KOS and RE) strains of HSV-1, and virus titers in the eyes and TG during primary infection, level of viral gB DNA in TG on day 28 postinfection (p.i.), and virus reactivation on day 28 p.i. as measured by explant reactivation were calculated. Our results suggest that the avirulent strains of HSV-1, even after corneal scarification, had lower virus titers in the eye, had less latency in the TG, and took a longer time to reactivate than virulent strains of HSV-1. The time to explant reactivation of avirulent strains of HSV-1 was similar to that of the virulent LAT((-)) McKrae-derived mutant. The viral dose with the McKrae strain of HSV-1 affected the level of viral DNA and time to explant reactivation. Overall, our results suggest that there is no absolute correlation between primary virus titer in the eye and TG and the level of viral DNA in latent TG and time to reactivation. IMPORTANCE: Very little is known regarding the interrelationship between primary virus replication in the eye, the level of latency in TG, and the time to reactivate in the mouse model. This study was designed to answer these questions. Our results point to the absence of any correlation between the level of primary virus replication and the level of viral DNA during latency, and neither was an indicator of how rapidly the virus reactivated following explant TG-induced reactivation. PMID- 27512073 TI - Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis. AB - : Human adenoviruses (HAdVs) contain seven species (HAdV-A to -G), each associated with specific disease conditions. Among these, HAdV-D includes those viruses associated with epidemic keratoconjunctivitis (EKC), a severe ocular surface infection. The reasons for corneal tropism for some but not all HAdV-Ds are not known. The fiber protein is a major capsid protein; its C-terminal "knob" mediates binding with host cell receptors to facilitate subsequent viral entry. In a comprehensive phylogenetic analysis of HAdV-D capsid genes, fiber knob gene sequences of HAdV-D types associated with EKC formed a unique clade. By proteotyping analysis, EKC virus-associated fiber knobs were uniquely shared. Comparative structural modeling showed no distinct variations in fiber knobs of EKC types but did show variation among HAdV-Ds in a region overlapping with the known CD46 binding site in HAdV-B. We also found signature amino acid positions that distinguish EKC from non-EKC types, and by in vitro studies we showed that corneal epithelial cell tropism can be predicted by the presence of a lysine or alanine at residue 240. This same amino acid residue in EKC viruses shows evidence for positive selection, suggesting that evolutionary pressure enhances fitness in corneal infection, and may be a molecular determinant in EKC pathogenesis. IMPORTANCE: Viruses adapt various survival strategies to gain entry into target host cells. Human adenovirus (HAdV) types are associated with distinct disease conditions, yet evidence for connections between genotype and cellular tropism is generally lacking. Here, we provide a structural and evolutionary basis for the association between specific genotypes within HAdV species D and epidemic keratoconjunctivitis, a severe ocular surface infection. We find that HAdV-D fiber genes of major EKC pathogens, specifically the fiber knob gene region, share a distinct phylogenetic clade. Deeper analysis of the fiber gene revealed that evolutionary pressure at crucial amino acid sites has a significant impact on its structural conformation, which is likely important in host cell binding and entry. Specific amino acids in hot spot residues provide a link to ocular cell tropism and possibly to corneal pathogenesis. PMID- 27512074 TI - Novel Acylguanidine-Based Inhibitor of HIV-1. AB - The emergence of transmissible HIV-1 strains with resistance to antiretroviral drugs highlights a continual need for new therapies. Here we describe a novel acylguanidine-containing compound, 1-(2-(azepan-1-yl)nicotinoyl)guanidine (or SM111), that inhibits in vitro replication of HIV-1, including strains resistant to licensed protease, reverse transcriptase, and integrase inhibitors, without major cellular toxicity. At inhibitory concentrations, intracellular p24(Gag) production was unaffected, but virion release (measured as extracellular p24(Gag)) was reduced and virion infectivity was substantially impaired, suggesting that SM111 acts at a late stage of viral replication. SM111-mediated inhibition of HIV-1 was partially overcome by a Vpu I17R mutation alone or a Vpu W22* truncation in combination with Env N136Y. These mutations enhanced virion infectivity and Env expression on the surface of infected cells in the absence and presence of SM111 but also impaired Vpu's ability to downregulate CD4 and BST2/tetherin. Taken together, our results support acylguanidines as a class of HIV-1 inhibitors with a distinct mechanism of action compared to that of licensed antiretrovirals. Further research on SM111 and similar compounds may help to elucidate knowledge gaps related to Vpu's role in promoting viral egress and infectivity. IMPORTANCE: New inhibitors of HIV-1 replication may be useful as therapeutics to counteract drug resistance and as reagents to perform more detailed studies of viral pathogenesis. SM111 is a small molecule that blocks the replication of wild-type and drug-resistant HIV-1 strains by impairing viral release and substantially reducing virion infectivity, most likely through its ability to prevent Env expression at the infected cell surface. Partial resistance to SM111 is mediated by mutations in Vpu and/or Env, suggesting that the compound affects host/viral protein interactions that are important during viral egress. Further characterization of SM111 and similar compounds may allow more detailed pharmacological studies of HIV-1 egress and provide opportunities to develop new treatments for HIV-1. PMID- 27512075 TI - Identification of Residues That Affect Oligomerization and/or Enzymatic Activity of Influenza Virus H5N1 Neuraminidase Proteins. AB - Influenza A virus (IAV) attachment to and release from sialoside receptors is determined by the balance between hemagglutinin (HA) and neuraminidase (NA). The molecular determinants that mediate the specificity and activity of NA are still poorly understood. In this study, we aimed to design the optimal recombinant soluble NA protein to identify residues that affect NA enzymatic activity. To this end, recombinant soluble versions of four different NA proteins from H5N1 viruses were compared with their full-length counterparts. The soluble NA ectodomains were fused to three commonly used tetramerization domains. Our results indicate that the particular oligomerization domain used does not affect the Km value but may affect the specific enzymatic activity. This particularly holds true when the stalk domain is included and for NA ectodomains that display a low intrinsic ability to oligomerize. NA ectodomains extended with a Tetrabrachion domain, which forms a nearly parallel four-helix bundle, better mimicked the enzymatic properties of full-length proteins than when other coiled coil tetramerization domains were used, which probably distort the stalk domain. Comparison of different NA proteins and mutagenic analysis of recombinant soluble versions thereof resulted in the identification of several residues that affected oligomerization of the NA head domain (position 95) and therefore the specific activity or sialic acid binding affinity (Km value; positions 252 and 347). This study demonstrates the potential of using recombinant soluble NA proteins to reveal determinants of NA assembly and enzymatic activity. IMPORTANCE: The IAV HA and NA glycoproteins are important determinants of host tropism and pathogenicity. However, NA is relatively understudied compared to HA. Analysis of soluble versions of these glycoproteins is an attractive way to study their activities, as they are easily purified from cell culture media and applied in downstream assays. In the present study, we analyzed the enzymatic activity of different NA ectodomains with three commonly used tetramerization domains and compared them with full-length NA proteins. By performing a mutagenic analysis, we identified several residues that affected NA assembly, activity, and/or substrate binding. In addition, our results indicate that the design of the recombinant soluble NA protein, including the particular tetramerization domain, is an important determinant for maintaining the enzymatic properties within the head domain. NA ectodomains extended with a Tetrabrachion domain better mimicked the full-length proteins than when the other tetramerization domains were used. PMID- 27512076 TI - Effects of Membrane Charge and Order on Membrane Binding of the Retroviral Structural Protein Gag. AB - The retroviral structural protein Gag binds to the inner leaflet of the plasma membrane (PM), and many cellular proteins do so as well. We used Rous sarcoma virus (RSV) Gag together with membrane sensors to study the principles governing peripheral protein membrane binding, including electrostatics, specific recognition of phospholipid headgroups, sensitivity to phospholipid acyl chain compositions, preference for membrane order, and protein multimerization. We used an in vitro liposome-pelleting assay to test protein membrane binding properties of Gag, the well-characterized MARCKS peptide, a series of fluorescent electrostatic sensor proteins (mNG-KRn), and the specific phosphatidylserine (PS) binding protein Evectin2. RSV Gag and mNG-KRn bound well to membranes with saturated and unsaturated acyl chains, whereas the MARCKS peptide and Evectin2 preferentially bound to membranes with unsaturated acyl chains. To further discriminate whether the primary driving force for Gag membrane binding is electrostatic interactions or preference for membrane order, we measured protein binding to giant unilamellar vesicles (GUVs) containing the same PS concentration in both disordered (Ld) and ordered (Lo) phases. RSV Gag and mNG-KRn membrane association followed membrane charge, independent of membrane order. Consistent with pelleting data, the MARCKS peptide showed preference for the Ld domain. Surprisingly, the PS sensor Evectin2 bound to the PS-rich Ld domain with 10-fold greater affinity than to the PS-rich Lo domain. In summary, we found that RSV Gag shows no preference for membrane order, while proteins with reported membrane penetrating domains show preference for disordered membranes. IMPORTANCE: Retroviral particles assemble on the PM and bud from infected cells. Our understanding of how Gag interacts with the PM and how different membrane properties contribute to overall Gag assembly is incomplete. This study examined how membrane charge and membrane order influence Gag membrane association. Consistent with previous work on RSV Gag, we report here that electrostatic interactions provide the primary driving force for RSV Gag membrane association. Using phase-separated GUVs with known lipid composition of the Ld and Lo phases, we demonstrate for the first time that RSV Gag is sensitive to membrane charge but not membrane order. In contrast, the cellular protein domain MARCKS and the PS sensor Evectin2 show preference for disordered membranes. We also demonstrate how to define GUV phase composition, which could serve as a tool in future studies of protein membrane interactions. PMID- 27512077 TI - ARID3B: a Novel Regulator of the Kaposi's Sarcoma-Associated Herpesvirus Lytic Cycle. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of commonly fatal malignancies of immunocompromised individuals, including primary effusion lymphoma (PEL) and Kaposi's sarcoma (KS). A hallmark of all herpesviruses is their biphasic life cycle-viral latency and the productive lytic cycle-and it is well established that reactivation of the KSHV lytic cycle is associated with KS pathogenesis. Therefore, a thorough appreciation of the mechanisms that govern reactivation is required to better understand disease progression. The viral protein replication and transcription activator (RTA) is the KSHV lytic switch protein due to its ability to drive the expression of various lytic genes, leading to reactivation of the entire lytic cycle. While the mechanisms for activating lytic gene expression have received much attention, how RTA impacts cellular function is less well understood. To address this, we developed a cell line with doxycycline-inducible RTA expression and applied stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative proteomics. Using this methodology, we have identified a novel cellular protein (AT-rich interacting domain containing 3B [ARID3B]) whose expression was enhanced by RTA and that relocalized to replication compartments upon lytic reactivation. We also show that small interfering RNA (siRNA) knockdown or overexpression of ARID3B led to an enhancement or inhibition of lytic reactivation, respectively. Furthermore, DNA affinity and chromatin immunoprecipitation assays demonstrated that ARID3B specifically interacts with A/T-rich elements in the KSHV origin of lytic replication (oriLyt), and this was dependent on lytic cycle reactivation. Therefore, we have identified a novel cellular protein whose expression is enhanced by KSHV RTA with the ability to inhibit KSHV reactivation. IMPORTANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of fatal malignancies of immunocompromised individuals, including Kaposi's sarcoma (KS). Herpesviruses are able to establish a latent infection, in which they escape immune detection by restricting viral gene expression. Importantly, however, reactivation of productive viral replication (the lytic cycle) is necessary for the pathogenesis of KS. Therefore, it is important that we comprehensively understand the mechanisms that govern lytic reactivation, to better understand disease progression. In this study, we have identified a novel cellular protein (AT-rich interacting domain protein 3B [ARID3B]) that we show is able to temper lytic reactivation. We showed that the master lytic switch protein, RTA, enhanced ARID3B levels, which then interacted with viral DNA in a lytic cycle-dependent manner. Therefore, we have added a new factor to the list of cellular proteins that regulate the KSHV lytic cycle, which has implications for our understanding of KSHV biology. PMID- 27512078 TI - Baculovirus FP25K Localization: Role of the Coiled-Coil Domain. AB - : Two types of viruses are produced during the baculovirus life cycle: budded virus (BV) and occlusion-derived virus (ODV). A particular baculovirus protein, FP25K, is involved in the switch from BV to ODV production. Previously, FP25K from the model alphabaculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) was shown to traffic ODV envelope proteins. However, FP25K localization and the domains involved are inconclusive. Here we used a quantitative approach to study FP25K subcellular localization during infection using an AcMNPV bacmid virus that produces a functional AcMNPV FP25K green fluorescent protein (GFP) fusion protein. During cell infection, FP25K-GFP localized primarily to the cytoplasm, particularly amorphous structures, with a small fraction being localized in the nucleus. To investigate the sequences involved in FP25K localization, an alignment of baculovirus FP25K sequences revealed that the N-terminal putative coiled-coil domain is present in all alphabaculoviruses but absent in betabaculoviruses. Structural prediction indicated a strong relatedness of AcMNPV FP25K to long interspersed element 1 (LINE-1) open reading frame 1 protein (ORF1p), which contains an N-terminal coiled-coil domain responsible for cytoplasmic retention. Point mutations and deletions of this domain lead to a change in AcMNPV FP25K localization from cytoplasmic to nuclear. The coiled-coil and C-terminal deletion viruses increased BV production. Furthermore, a betabaculovirus FP25K protein lacking this N terminal coiled-coil domain localized predominantly to the nucleus and exhibited increased BV production. These data suggest that the acquisition of this N terminal coiled-coil domain in FP25K is important for the evolution of alphabaculoviruses. Moreover, with the divergence of preocclusion nuclear membrane breakdown in betabaculoviruses and membrane integrity in alphabaculoviruses, this domain represents an alphabaculovirus adaptation for nuclear trafficking of occlusion-associated proteins. IMPORTANCE: Baculovirus infection produces two forms of viruses: BV and ODV. Manufacturing of ODV involves trafficking of envelope proteins to the inner nuclear membrane, mediated partly through the FP25K protein. Since FP25K is present in alpha-, beta-, and gammabaculoviruses, it is uncertain if this trafficking function is conserved. In this study, we looked at alpha- and betabaculovirus FP25K trafficking by its localization. Alphabaculovirus FP25K localized primarily to the cytoplasm, whereas betabaculovirus FP25K localized to the nucleus. We found that an N terminal coiled-coil domain present in all alphabaculovirus FP25K proteins, but absent in betabaculovirus FP25K, was critical for alphabaculovirus FP25K cytoplasmic localization. We believe that this represents an evolutionary process that partly led to the gain of function of this N-terminal coiled-coil domain in alphabaculovirus FP25K to aid in nuclear trafficking of occlusion-associated proteins. Due to betabaculovirus breakdown of the nuclear membrane before occlusion, this function is not needed, and the domain was lost or never acquired. PMID- 27512080 TI - Combination Use of Clopidogrel and Proton Pump Inhibitors Increases Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease: A Meta-Analysis. AB - BACKGROUND: Published data indicated that combination use of clopidogrel and proton pump inhibitors (PPIs) may increase the incidence of major adverse cardiovascular events (MACEs). This has been a highly controversial topic for years. DESIGN: The present study was performed to evaluate whether combination therapy of clopidogrel and PPIs is associated with increased risk of MACEs than with clopidogrel alone in patients with coronary artery disease. METHODS: A systematic search of MEDLINE, EMBASE, and the Cochrane Library was conducted for studies recording the occurrence of MACEs in patients with exposure to concomitant use of clopidogrel and PPIs up to February 2015. Odds ratios (ORs) were combined using a random-effects model. RESULTS: Patients receiving combination therapy with PPIs and clopidogrel were at significantly increased risk of MACEs (OR: 1.42; 95% confidence interval [CI]: 1.30-1.55). Adding a PPI to clopidogrel treatment was associated with a higher rate of MACE occurrence in rapid metabolizers (RMs, *1/*1) of CYP2C19 (OR: 1.42; 95% CI: 1.12-1.81), but there was no obviously increased rate (OR: 1.43; 95% CI: 0.89-2.28) in decreased metabolizers (with 1 or 2 loss-of-function allele). The increased risk of MACEs was similar in 4 classes of PPIs (omeprazole, lansoprazole, esomeprazole, and pantoprazole), but rabeprazole (OR: 1.03; 95% CI: 0.55-1.95) wasn't. CONCLUSION: The combination use of clopidogrel and certain types of PPIs (omeprazole, lansoprazole, esomeprazole, pantoprazole) increases the risk of MACE in patients with coronary artery disease. Only in the RMs of CYP2C19, PPIs were associated with significantly increased MACE in patients coadministered with clopidogrel. PMID- 27512079 TI - Quantitative Non-canonical Amino Acid Tagging (QuaNCAT) Proteomics Identifies Distinct Patterns of Protein Synthesis Rapidly Induced by Hypertrophic Agents in Cardiomyocytes, Revealing New Aspects of Metabolic Remodeling. AB - Cardiomyocytes undergo growth and remodeling in response to specific pathological or physiological conditions. In the former, myocardial growth is a risk factor for cardiac failure and faster protein synthesis is a major factor driving cardiomyocyte growth. Our goal was to quantify the rapid effects of different pro hypertrophic stimuli on the synthesis of specific proteins in ARVC and to determine whether such effects are caused by alterations on mRNA abundance or the translation of specific mRNAs. Cardiomyocytes have very low rates of protein synthesis, posing a challenging problem in terms of studying changes in the synthesis of specific proteins, which also applies to other nondividing primary cells. To study the rates of accumulation of specific proteins in these cells, we developed an optimized version of the Quantitative Noncanonical Amino acid Tagging LC/MS proteomic method to label and selectively enrich newly synthesized proteins in these primary cells while eliminating the suppressive effects of pre existing and highly abundant nonisotope-tagged polypeptides. Our data revealed that a classical pathologic (phenylephrine; PE) and the recently identified insulin stimulus that also contributes to the development of pathological cardiac hypertrophy (insulin), both increased the synthesis of proteins involved in, e.g. glycolysis, the Krebs cycle and beta-oxidation, and sarcomeric components. However, insulin increased synthesis of many metabolic enzymes to a greater extent than PE. Using a novel validation method, we confirmed that synthesis of selected candidates is indeed up-regulated by PE and insulin. Synthesis of all proteins studied was up-regulated by signaling through mammalian target of rapamycin complex 1 without changes in their mRNA levels, showing the key importance of translational control in the rapid effects of hypertrophic stimuli. Expression of PKM2 was up-regulated in rat hearts following TAC. This isoform possesses specific regulatory properties, so this finding indicates it may be involved in metabolic remodeling and also serve as a novel candidate biomarker. Levels of translation factor eEF1 also increased during TAC, likely contributing to faster cell mass accumulation. Interestingly those two candidates were not up regulated in pregnancy or exercise induced CH, indicating PKM2 and eEF1 were pathological CH specific markers. We anticipate that the methodologies described here will be valuable for other researchers studying protein synthesis in primary cells. PMID- 27512081 TI - Cholesteryl Ester Transfer Protein Inhibitors: Trials and Tribulations. AB - The cholesteryl ester transfer protein (CETP) is a plasma protein that plays an important role in the transfer of lipids between plasma lipoproteins. The CETP inhibitors have been widely studied as a pharmacologic therapy to target plasma cholesterol in order to reduce the risk of atherosclerotic cardiovascular disease . Using CETP inhibitors as cholesterol modifiers was based on the genetic research that found correlations between CETP activity and cholesterol levels. Although CETP inhibitors are successful at altering targeted cholesterol markers, recent phase 3 outcome trials have shown limited benefit on cardiovascular outcomes when combined with the current standard of care. We discuss the science of CETP inhibition, compare the CETP inhibitors developed (torcetrapib, evacetrapib, dalcetrapib, and anacetrapib), the findings from the CETP inhibitor trials, and the future outlook for CETP inhibitors in cholesterol modification. PMID- 27512082 TI - Early and long-term outcome of infants born extremely preterm. AB - There is no question that birth at extremely low gestational ages presents a significant threat to an infant's survival, health and development. Growing evidence suggests that gestational age may be conceptualised as a continuum in which births before 28 weeks of gestation (extremely preterm: EP) represent the severe end of a spectrum of health and developmental adversity. Although comprising just 1%-2% of all births, EP deliveries pose the greatest challenge to neonatal medicine and to health, education and social services for the provision of ongoing support for survivors with additional needs. Studying the outcomes of these infants remains critical for evaluating and enhancing clinical care, planning long-term support and for advancing our understanding of the life-course consequences of immaturity at birth. Here we review literature relating to early and long-term neurodevelopmental, cognitive, behavioural and educational outcomes following EP birth focusing on key themes and considering implications for intervention. PMID- 27512083 TI - On-tissue Direct Monitoring of Global Hydrogen/Deuterium Exchange by MALDI Mass Spectrometry: Tissue Deuterium Exchange Mass Spectrometry (TDXMS). AB - Hydrogen/deuterium exchange mass spectrometric (H/DXMS) methods for protein structural analysis are conventionally performed in solution. We present Tissue Deuterium Exchange Mass Spectrometry (TDXMS), a method to directly monitor deuterium uptake on tissue, as a means to better approximate the deuterium exchange behavior of proteins in their native microenvironment. Using this method, a difference in deuterium uptake behavior was observed when the same proteins were monitored in solution and on tissue. The higher maximum deuterium uptake at equilibrium for all proteins analyzed in solution suggests a more open conformation in the absence of interacting partners normally observed on tissue. We also demonstrate a difference in the deuterium uptake behavior of a few proteins across different morphological regions of the same tissue section. Modifications of the total number of hydrogens exchanged, as well as the kinetics of exchange, were both observed. These results provide information on the implication of protein interactions with partners as well as on the conformational changes related to these interactions, and illustrate the importance of examining protein deuterium exchange behavior in the presence of its specific microenvironment directly at the level of tissues. PMID- 27512084 TI - Living with asthma and chronic obstructive airways disease: Using technology to support self-management - An overview. AB - Long-term respiratory conditions such as asthma and chronic obstructive pulmonary disease (COPD) are common, and cause high levels of morbidity and mortality. Supporting self-management is advocated for both asthma and increasingly so for COPD, and there is growing interest in the potential role of a range of new technologies, such as smartphone apps, the web or telehealth to facilitate and promote self-management in these conditions. Treatment goals for both asthma and COPD include aiming to control symptoms, maintain activities, achieve the best possible quality of life and minimize risks of exacerbation. To do this, health professionals should be (a) helping patients to recognize deteriorating symptoms and act appropriately; (b) promoting adherence to maintenance therapy; (c) promoting a regular review where triggers can be established, and strategies for managing such triggers discussed; and (d) promoting healthy lifestyles and positive self-management of symptoms. In particular, low uptake of asthma action plans is a modifiable contributor to morbidity and possibly also to mortality in those with asthma and should be addressed as a priority. Using technology to support self-management is an evolving strategy that shows promise. This review provides an overview of self-management support and discusses how newer technologies may help patients and health professionals to meet key treatment goals. PMID- 27512085 TI - Mother-Daughter-Granddaughter Double GuideLiner Technique for Delivering Stents Past Multiple Extreme Angulations. PMID- 27512086 TI - Of Stents and Scaffolds: Trial Data and the Real World. PMID- 27512088 TI - Intraindividual Comparison of Everolimus-Eluting Bioresorbable Vascular Scaffolds Versus Drug-Eluting Metallic Stents. AB - BACKGROUND: The performance of everolimus-eluting bioresorbable vascular scaffold (BVS) versus drug-eluting metallic stent (DES) in the same individual receiving multilesion percutaneous coronary intervention (PCI) remains poorly studied. This report investigates the intraindividual performance of BVS and DES in patients receiving multilesion PCI and follow-up angiography. METHODS AND RESULTS: Data of patients undergoing BVS implantation for de novo lesions from 2012 to 2014 at 2 centers in Munich, Germany, were prospectively collected. Individuals receiving multilesion PCI with BVS and DES and follow-up angiography at 6 to 8 months were studied. Primary end point was in-device late lumen loss. Secondary end points were binary restenosis, target lesion revascularization, and definite stent/scaffold thrombosis. A total of 90 PCI patients with 239 lesions received BVS (n=112) and DES (n=127). Follow-up angiography after a median of 6.6 months (5.8-7.1) showed a higher degree of late lumen loss in lesions treated with BVS versus DES (0.30+/-0.59 versus 0.22+/-0.48 mm; P=0.035). However, the adjustment for baseline angiographic imbalances discarded an influence of stent type on late lumen loss (P=0.82). At the same time point, binary restenosis was comparable between BVS and DES (7.8% versus 8.9%; P=0.90). After a median of 13.2 months (9.2-17.6), target lesion revascularization (9.8% versus 10.2%; P=0.97) and definite stent/scaffold thrombosis (2.7% versus 1.6%; P=0.48) did not differ between BVS and DES. CONCLUSIONS: In patients receiving multilesion PCI, BVS displays acceptable intraindividual performance compared with DES. Larger trials, extended follow-up, and continuous device iteration remain essential to improve BVS technology. PMID- 27512087 TI - Very Long-Term (10 to 14 Year) Outcomes After Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Multivessel Coronary Artery Disease in the Bare-Metal Stent Era. AB - BACKGROUND: Many of the previous randomized trials comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) in patients with multivessel coronary artery disease reported equivalent or better survival with CABG as compared with PCI at 5-year follow-up. However, 5-year follow-up might be too short to evaluate the true differences in long-term clinical outcomes between PCI and CABG. METHODS AND RESULTS: Among 8934 patients enrolled in the extended 10- to 14-year follow-up study of the CREDO-Kyoto registry cohort-1 (Coronary Revascularization Demonstrating Outcome study in Kyoto) conducted in the bare-metal stent era, 5152 (PCI: n=3490 and CABG: n=1662) patients had multivessel coronary artery disease without left main disease. Median follow-up duration was 11.2 (interquartile range: 10.2-12.2) years. The cumulative 10-year incidence of all-cause death was not significantly different between PCI and CABG (32.2% versus 31.7%; log-rank P=0.93). After adjusting for confounders, however, the mortality risk of PCI was significantly higher than that of CABG (hazard ratio, 1.19 [95% confidence interval, 1.02-1.39]; P=0.03). Within 5 years after the index procedure, the risk for all-cause death was significantly higher after PCI than after CABG (hazard ratio, 1.41; 95% CI, 1.12 1.79; P=0.004). By a landmark analysis at 5 years, however, the cumulative 10 year incidence of and adjusted risk for all-cause death beyond 5 years were not significantly different between PCI and CABG (19.3% versus 20.0%; log-rank P=0.22 and hazard ratio, 1.02, 95% confidence interval, 0.83-1.26; P=0.82). CONCLUSIONS: CABG as compared with PCI was associated with better 10-year survival in patients with multivessel coronary artery disease. However, the benefit of CABG compared with PCI on late mortality beyond 5 years was not observed in this study. PMID- 27512089 TI - Routine Endovascular Treatment With a Stent Graft for Access-Site and Access Related Vascular Injury in Transfemoral Transcatheter Aortic Valve Implantation. AB - BACKGROUND: Access-site and access-related vascular injury (ASARVI) is still a major limiting factor in transcatheter aortic valve implantation and affects the outcome of patients. Management strategies for ASARVI include manual compression, stent grafts, and vascular surgery. We hypothesized that the standard use of a self-expanding stent graft for the management of ASARVI is feasible and safe. METHODS AND RESULTS: Of 407 patients treated by transfemoral transcatheter aortic valve implantation, 110 experienced ASARVI (27.0%). Of these, 96 (87.3%) were managed by the implantation of a self-expanding nitinol stent graft. In the majority of patients, minor vascular complications triggered the implantation of a stent graft (86.5%), mainly because of bleeding (90.6%) and dissection (5.2%) of the common femoral artery with high rates of primary treatment success (97.9%). Patients receiving stent grafts were more often female (62.2 versus 45.6%, P<0.01), had higher body mass indices (27.8+/-6.7 versus 25.7+/-4.7, P=0.01), and suffered more often from diabetes mellitus (34.4 versus 24.5%, P=0.04). Angiographic assessment after a median follow-up of 345 days (interquartile range, 23-745 days) revealed only one patient with moderate, asymptomatic instent-stenosis (1.0%). Compared with a propensity score-matched cohort of patients without ASARVI, stented patients had comparable long-term mortality, despite the occurrence of a vascular complication (1-year mortality: 17.7% versus 26.6%; stent versus matched cohort, respectively; P=0.1). CONCLUSIONS: Routine use of a self-expanding nitinol stent graft in selected patients experiencing ASARVI after transcatheter aortic valve implantation is feasible, safe, and associated with favorable short- and midterm clinical outcome. PMID- 27512090 TI - Absorb Bioresorbable Vascular Scaffold in Complex Coronary Bifurcation Interventions: Insights From an In Vivo Multimodality Imaging Study. AB - BACKGROUND: Although bioresorbable scaffolds offer potential advantages compared with metallic drug-eluting stents in the treatment of complex coronary bifurcation lesions, there are concerns that the polymeric scaffold integrity may be compromised. This in vivo study sought to provide insights about the feasibility of performing complex bifurcation stenting with Absorb bioresorbable vascular scaffolds (Abbott Vascular, Santa Clara, CA). METHODS AND RESULTS: Twenty New Zealand white rabbits underwent stenting of the nondiseased aortoiliac bifurcation with bioresorbable vascular scaffolds using provisional (PS, n=5), culotte (n=5), modified-T (n=5), or T-and protrusion (n=5) stenting techniques. Angiography, optical coherence tomography, and microcomputed tomography were performed. Angiographic results were excellent without evidence of dissection or side branch (SB) compromise. PS optimally opened the SB ostium without deforming the main vessel (MV) bioresorbable vascular scaffolds, avoiding malapposition, and revealing a single connector fracture in 1 of 5 cases on microcomputed tomography. Culotte stenting resulted in complete bifurcation coverage with extensive segments of double-layered struts and inappropriately apposed struts at the bifurcation level in 3 of 5 cases. On microcomputed tomography, there was MV and SB scaffold distortion at the bifurcation with single strut fractures in 4 of 5 and double fractures in 1 of 5. Modified-T and T-and protrusion resulted in complete bifurcation coverage and in minimal double-strut layers at the neocarina. On microcomputed tomography, no strut fractures were present after modified-T, whereas in 3 of 5 T-and protrusion procedures single strut fractures were noted. CONCLUSIONS: Bifurcation stenting using bioresorbable vascular scaffolds is feasible with excellent angiographic results. PS with additional T and protrusion whenever needed seems a reasonable approach. Whenever a 2-stent technique is planned, modified T-stenting appears the most promising. PMID- 27512091 TI - Antihypertensive Effects of a Central Arteriovenous Anastomosis Are Mediated Through Profound Reduction in Systemic Vascular Resistance. PMID- 27512092 TI - Towards a structure of feeling: abjection and allegories of disease in science fiction 'mutation' films. AB - This article considers differences between the representation of mutation in science fiction films from the 1950s and the present, and identifies distinctive changes over this time period, both in relation to the narrative causes of genetic disruption and in the aesthetics of its visual display. Discerning an increasingly abject quality to science fiction mutations from the 1970s onwards as a progressive tendency to view the physically opened body, one that has a seemingly fluid interior-exterior reversal, or one that is almost beyond recognition as humanoid-the article connects a propensity for disgust to the corresponding socio-cultural and political zeitgeist. Specifically, it suggests that such imagery is tied to a more expansive 'structure of feeling', proposed by Raymond Williams and emergent since the 1970s, but gathering momentum in later decades, that reflects an 'opening up' of society in all its visual, socio cultural and political configurations. Expressly, it parallels a change from a repressive, patriarchal society that constructed medicine as infallible and male doctors as omnipotent to one that is generally more liberated, transparent and equitable. Engaging theoretically with the concept of a 'structure of feeling', and critically with scientific, cinematic and cultural discourses, two post 1970s' 'mutation' films, The Fly (1986) and District 9 (2009), are considered in relation to their pre-1970s' predecessors, and their aesthetics related to the perceptions and articulations of the medical profession at their respective historic moments, locating such instances within a broader medico-political canvas. PMID- 27512094 TI - Numerical investigation of the haemodynamics in the human fetal umbilical vein/ductus venosus based on the experimental data. AB - Abortion of the fetus due to a disease, in an early stage of pregnancy, has been dramatically increased in the last decades. There is a still lack of knowledge on the various types of diseases which lead fetus to a vulnerable circumstance. The transport of oxygenated blood from the placenta to the human fetus has been an important clinical feature in Doppler velocimetry studies, especially the ductus venosus (DV). The DV connects intra-abdominal portion of the umbilical vein and the inferior vena cava (IVC) at the inlet of the right atrium and is, therefore, important when examining the fetus state of health. An abnormal flow in the DV can indicate a fetal disease such as, chromosomal abnormalities, cardiac defect, hypoxaemia and intrauterine growth restriction (IUGR). The blood flow in the fetal circulation has not been investigated much in detail. The blood flow in the fetal circulation provides necessary information for physician to make a suitable decision on abortion or alternative medical practice before or even after birth. The present study performed a comparative study to quantify the blood velocity in DV by a combination approach based on 3D computational simulation and Doppler measurement. The results showed that the velocity value in DV is significant and can be considered as an indicator of any kind of disease in fetal. The nodal displacement of the model was also analysed. It shows that DV tolerates a higher level of displacement compared with the other regions of the model, whereas the nodal pressure shows different results as the lowest values are located in DV. PMID- 27512093 TI - Role of the prostaglandin E2 receptor agonists in TGF-beta1-induced mesangial cell damage. AB - PGE2 exerts its biological effect through binding to various EP receptors that result inactivation of various signal transduction pathways. It also plays an important role in mice glomerular mesangial cells (MCs) damage induced by transforming growth factor-beta1 (TGF-beta1); however, the molecular mechanisms remain unknown. In the present study, we tested the efficacy of four selective agonists of PGE2 receptor, EP1A (17-phenyl trinor prostaglandin E2 ethyl amid), EP2A (butaprost), EP3A (sulprostone) and EP4A (cay10580), on mice MCs. Compared with the cAMP produced by TGF-beta1, additional pretreatment of EP3A decreased the cAMP level. MCs treated with EP1A and EP3A augmented PGE2, cyclooxygenase-2 (COX-2), membrane-bound PGE synthase 1 (mPGES1), laminin (LN), connective tissue growth factor (CTGF) and cyclin D1 expression stimulated by TGFbeta1. EP1A and EP3A increased the number of cells in S+G2/M phase and reduced cells in G0/G1 phase. EP1 and EP3 agonists also strengthened TGFbeta1-induced mitogen-activated protein kinase (p38MAPK) and extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Whereas MCs treated with EP2A and EP4A weakened PGE2, COX-2, mPGES1, LN, CTGF and cyclin D1 expression stimulated by TGFbeta1. EP2A and EP4A decreased the number of cells in S+G2/M phase and increased cells in G0/G1 phase. EP2 and EP4 agonists weakened TGFbeta1-induced p38MAPK and ERK1/2 phosphorylation. These findings suggest that PGE2 has an important role in the progression of kidney disease via the EP1/EP3 receptor, whereas EP2 and EP4 receptors are equally important in preserving the progression of chronic kidney failure. Thus, agonists of EP2 and EP4 receptors may provide a basis for treating kidney damage induced by TGF-beta1. PMID- 27512095 TI - IL-1beta/HMGB1 signalling promotes the inflammatory cytokines release via TLR signalling in human intervertebral disc cells. AB - Inflammation and cytokines have been recognized to correlate with intervertebral disc (IVD) degeneration (IDD), via mediating the development of clinical signs and symptoms. However, the regulation mechanism remains unclear. We aimed at investigating the regulatory role of interleukin (IL)beta and high mobility group box 1 (HMGB1) in the inflammatory response in human IVD cells, and then explored the signalling pathways mediating such regulatory effect. Firstly, the promotion to inflammatory cytokines in IVD cells was examined with ELISA method. And then western blot and real time quantitative PCR were performed to analyse the expression of toll-like receptors (TLRs), receptors for advanced glycation endproducts (RAGE) and NF-kappaB signalling markers in the IL-1beta- or (and) HMGB1-treated IVD cells. Results demonstrated that either IL-1beta or HMGB1 promoted the release of the inflammatory cytokines such as prostaglandin E2 (PGE2), TNF-alpha, IL-6 and IL-8 in human IVD cells. And the expression of matrix metalloproteinases (MMPs) such as MMP-1, -3 and -9 was also additively up regulated by IL-1beta and HMGB1. We also found such additive promotion to the expression of TLR-2, TLR-4 and RAGE, and the NF-kappaB signalling in intervertebral disc cells. In summary, our study demonstrated that IL-1beta and HMGB1 additively promotes the release of inflammatory cytokines and the expression of MMPs in human IVD cells. The TLRs and RAGE and the NF-kappaB signalling were also additively promoted by IL-1beta and HMGB1. Our study implied that the additive promotion by IL-1beta and HMGB1 to inflammatory cytokines and MMPs might aggravate the progression of IDD. PMID- 27512096 TI - Mechanisms for the inhibition of amyloid aggregation by small ligands. AB - The formation of amyloid aggregates is the hallmark of systemic and neurodegenerative disorders, also known as amyloidoses. Many proteins have been found to aggregate into amyloid-like fibrils and this process is recognized as a general tendency of polypeptides. Lysozyme, an antibacterial protein, is a well studied model since it is associated in human with systemic amyloidosis and that is widely available from chicken eggs (HEWL, hen egg white lysozyme). In the present study we investigated the mechanism of interaction of aggregating HEWL with rosmarinic acid and resveratrol, that we verified to be effective and ineffective, respectively, in inhibiting aggregate formation. We used a multidisciplinary strategy to characterize such effects, combining biochemical and biophysical methods with molecular dynamics (MD) simulations on the HEWL peptide 49-64 to gain insights into the mechanisms and energy variations associated to amyloid formation and inhibition. MD revealed that neither resveratrol nor rosmarinic acid were able to compete with the initial formation of the beta-sheet structure. We then tested the association of two beta-sheets, representing the model of an amyloid core structure. MD showed that rosmarinic acid displayed an interaction energy and a contact map comparable to that of sheet pairings. On the contrary, resveratrol association energy was found to be much lower and its contact map largely different than that of sheet pairings. The overall characterization elucidated a possible mechanism explaining why, in this model, resveratrol is inactive in blocking fibril formation, whereas rosmarinic acid is instead a powerful inhibitor. PMID- 27512097 TI - Adipose-specific inactivation of JNK alleviates atherosclerosis in apoE-deficient mice. AB - Both atherosclerosis and obesity, an independent atherosclerotic risk factor, are associated with enhanced systemic inflammation. Obesity is also characterized by increased adipose tissue inflammation. However, the molecular mechanism underlying the accelerated atherosclerosis in obesity remains unclear. In obesity, activation of c-Jun N-terminal kinase (JNK) contributes to adipose tissue inflammation. The present study investigated whether the suppression of fat inflammation through adipose-specific JNK inactivation could protect against atherosclerosis in mice. ApoE-/- mice were cross-bred with transgenic mice with adipose-specific expression of a dominant negative form of JNK (dnJNK) to generate apoE-/-/dnJNK (ADJ) mice. ADJ mice treated with a high-fat-high cholesterol diet exhibited significant attenuations of visceral fat and systemic inflammation without changes in lipid or glucose metabolism, and were protected against atherosclerosis, when compared with apoE-/- mice. Lean apoE-/- mice that received transplantation of visceral fat from obese wild-type donor mice for 4 weeks showed exacerbated systemic inflammation and atherosclerotic plaque formation. Conversely, apoE-/- recipients carrying a visceral fat graft from obese dnJNK donors were protected against enhanced systemic inflammation and atherogenesis. The beneficial effects of adipose-specific JNK inactivation on atherogenesis in apoE-/- recipients were significantly compromised by continuous infusion of recombinant adipocyte-fatty acid-binding protein (A-FABP), previously shown to interact with JNK via a positive feedback loop to modulate inflammatory responses. Together these data suggested that enhanced atherosclerosis in obesity can be attributed, at least in part, to a distant cross-talk between visceral fat and the vasculature, mediated by the release of proinflammatory cytokines, such as A-FABP, from the inflamed visceral adipose tissue with JNK activation. PMID- 27512098 TI - Effectiveness and safety of Chinese massage therapy (Tui Na) on post-stroke spasticity: a prospective multicenter randomized controlled trial. AB - OBJECTIVE: To evaluate the effectiveness and safety of Chinese massage therapy (Tui Na) for patients with post-stroke spasticity. DESIGN: A prospective, multicenter, blinded, randomized, placebo-controlled intervention trial. SUBJECT: A total of 90 patients with post-stroke spasticity were randomly assigned to the experimental (Tui Na therapy) group ( n = 45) or control (placebo Tui Na therapy) group ( n = 45). INTERVENTION: Participants in the experimental group received Tui Na therapy, while those in the control group received placebo-Tai Na (gentle rubbing) for 20-25 minutes per limb, once per day, five days per week for a total of four weeks. All participants in both groups received conventional rehabilitation. MAIN MEASURE: The Modified Ashworth Scale, the Fugl-Meyer Assessment and the Modified Barthel Index were used to assess the severity of spasticity, motor function of limbs and activities of daily living, respectively. Assessments were performed at baseline, at four weeks and at three months. RESULTS: Tui Na group had a significantly greater reduction in Modified Ashworth Scale in only four muscle groups than the control did (elbow flexors, P = 0.026; wrist flexors, P = 0.005; knee flexors, P = 0.023; knee extensors, P = 0.017). Improvements were sustained at three months follow-up. There was no significant difference between the two groups in Fugl-Meyer Assessment ( P = 0.503) and Modified Barthel Index ( P = 0.544). No adverse reaction was recorded in any of the cases mentioned at all study sites. CONCLUSIONS: Tui Na might be a safe and effective treatment to reduce post-stroke spasticity of several muscle groups. PMID- 27512099 TI - Water-based vs. non-water-based physiotherapy for rehabilitation of postural deformities in Parkinson's disease: a randomized controlled pilot study. AB - OBJECTIVE: To compare the efficacy of two physiotherapy protocols (water-based vs. non-water-based) on postural deformities of patients with Parkinson's disease. DESIGN: A single blind, randomized controlled pilot study. SETTING: Inpatient (Rehabilitative Department). PARTICIPANTS: A total of 30 patients with idiopathic Parkinson's disease. INTERVENTIONS: Participants were randomly assigned to one of two eight-week treatment groups: Water-based ( n = 15) or non water-based physiotherapy exercises ( n = 15). OUTCOME MEASURES: Changes in the degree of cervical and dorsal flexion and in the angle of lateral inclination of the trunk (evaluated by means of a posturographic system) were used as primary outcomes. Unified Parkinson Disease Rating Scale section III, Time Up and Go Test, Berg Balance Scale, Activities-specific Balance Confidence, Falls Efficacy Scale and the Parkinson's disease quality of life questionnaire (39 items) were the secondary outcomes. All outcomes were assessed at baseline, at the end of training and eight weeks after treatment. Patients were always tested at the time of their optimal antiparkinsonian medication ('on' phase). RESULTS: After the treatment, only Parkinson's disease subjects randomized to water-based treatment showed a significant improvement of trunk posture with a significant reduction of cervical flexion (water-based group: -65.2 degrees ; non-water-based group: +1.7 degrees ) and dorsal flexion (water-based group: -22.5 degrees ; non-water-based group: -6.5 degrees ) and lateral inclination of the trunk (water-based group: 2.3 degrees ; non-water-based group: +0.3 degrees ). Both groups presented significant improvements in the secondary clinical outcomes without between-group differences. CONCLUSION: Our results show that water-based physiotherapy was effective for improving postural deformities in patients with Parkinson's disease. PMID- 27512101 TI - Correction for Chakroun et al., Bacterial Vegetative Insecticidal Proteins (Vip) from Entomopathogenic Bacteria. PMID- 27512100 TI - Lipoproteins of Gram-Positive Bacteria: Key Players in the Immune Response and Virulence. AB - Since the discovery in 1973 of the first of the bacterial lipoproteins (Lpp) in Escherichia coli, Braun's lipoprotein, the ever-increasing number of publications indicates the importance of these proteins. Bacterial Lpp belong to the class of lipid-anchored proteins that in Gram-negative bacteria are anchored in both the cytoplasmic and outer membranes and in Gram-positive bacteria are anchored only in the cytoplasmic membrane. In contrast to the case for Gram-negative bacteria, in Gram-positive bacteria lipoprotein maturation and processing are not vital. Physiologically, Lpp play an important role in nutrient and ion acquisition, allowing particularly pathogenic species to better survive in the host. Bacterial Lpp are recognized by Toll-like receptor 2 (TLR2) of the innate immune system. The important role of Lpp in Gram-positive bacteria, particularly in the phylum Firmicutes, as key players in the immune response and pathogenicity has emerged only in recent years. In this review, we address the role of Lpp in signaling and modulating the immune response, in inflammation, and in pathogenicity. We also address the potential of Lpp as promising vaccine candidates. PMID- 27512102 TI - Implementation and de-implementation: two sides of the same coin? AB - Avoiding low value care received increasing attention in many countries, as with the Choosing Wisely campaign and other initiatives to abandon care that wastes resources or delivers no benefit to patients. While an extensive literature characterises approaches to implementing evidence-based care, we have limited understanding of the process of de-implementation, such as abandoning existing low value practices. To learn more about the differences between implementation and de-implementation, we explored the literature and analysed data from two published studies (one implementation and one de-implementation) by the same orthopaedic surgeons. We defined 'leaders' as those orthopaedic surgeons who implemented, or de-implemented, the target processes of care and laggards as those who did not. Our findings suggest that leaders in implementation share some characteristics with leaders in de-implementation when comparing them with laggards, such as more open to new evidence, younger and less time in clinical practice. However, leaders in de-implementation and implementation differed in some other characteristics and were not the same persons. Thus, leading in implementation or de-implementation may depend to some degree on the type of intervention rather than entirely reflecting personal characteristics. De implementation seemed to be hampered by motivational factors such as department priorities, and economic and political factors such as cost-benefit considerations in care delivery, whereas organisational factors were associated only with implementation. The only barrier or facilitator common to both implementation and de-implementation consisted of outcome expectancy (ie, the perceived net benefit to patients). Future studies need to test the hypotheses generated from this study and improve our understanding of differences between the processes of implementation and de-implementation in the people who are most likely to lead (or resist) these efforts. PMID- 27512103 TI - Differential Response to Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Reduced or Preserved Ejection Fraction: Results From the ROSE AHF Trial (Renal Optimization Strategies Evaluation in Acute Heart Failure). AB - BACKGROUND: The ROSE AHF trial (Renal Optimization Strategies Evaluation in Acute Heart Failure) found that when compared with placebo, neither low-dose dopamine (2 ug/kg per minute) nor low-dose nesiritide (0.005 MUg/kg per minute without bolus) enhanced decongestion or preserved renal function in AHF patients with renal dysfunction. However, there may be differential responses to vasoactive agents in AHF patients with reduced versus preserved ejection fraction (EF). This post hoc analysis examined potential interaction between treatment effect and EF (EF <=40% versus >40%) on the ROSE AHF end points. METHODS AND RESULTS: ROSE AHF enrolled AHF patients (n=360; any EF) with renal dysfunction. The coprimary end points were cumulative urine volume and the change in serum cystatin-C in 72 hours. The effect of dopamine (interaction P=0.001) and nesiritide (interaction P=0.039) on urine volume varied by EF group. In heart failure with reduced EF, urine volume was higher with active treatment versus placebo, whereas in heart failure with preserved EF, urine volume was lower with active treatment. The effect of dopamine and nesiritide on weight change, sodium excretion, and incidence of AHF treatment failure also varied by EF group (interaction P<0.05 for all). There was no interaction between vasoactive treatment's effect and EF on change in cystatin-C. Compared with placebo, dopamine was associated with improved clinical outcomes in heart failure with reduced EF and worse clinical outcomes in heart failure with preserved EF. With nesiritide, there were no differences in clinical outcomes when compared with placebo in both heart failure with reduced EF and heart failure with preserved EF. CONCLUSIONS: In this post hoc analysis of ROSE AHF, the response to vasoactive therapies differed in patients with heart failure with reduced EF and heart failure with preserved EF. Investigations of AHF therapies should assess the potential for differential responses in AHF with preserved versus reduced EF. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01132846. PMID- 27512105 TI - BREXIT and science, where do we go from here. PMID- 27512104 TI - Association of Weight and Body Composition on Cardiac Structure and Function in the ARIC Study (Atherosclerosis Risk in Communities). AB - BACKGROUND: Obesity increases cardiovascular risk. However, the extent to which various measures of body composition are associated with abnormalities in cardiac structure and function, independent of comorbidities commonly affecting obese individuals, is not clear. This study sought to examine the relationship between body mass index, waist circumference, and percent body fat with conventional and advanced measures of cardiac structure and function. METHODS AND RESULTS: We studied 4343 participants of the ARIC study (Atherosclerosis Risk in Communities) who were aged 69 to 82 years, free of coronary heart disease and heart failure, and underwent comprehensive echocardiography. Increasing body mass index, waist circumference, and body fat were associated with greater left ventricular (LV) mass and left atrial volume indexed to height(2.7) in both men and women (P<0.001). In women, all 3 measures were associated with abnormal LV geometry, and increasing waist circumference and body fat were associated with worse global longitudinal strain, a measure of LV systolic function. In both sexes, increasing body mass index was associated with greater right ventricular end-diastolic area and worse right ventricular fractional area change (P<=0.001). We observed similar associations for both waist circumference and percent body fat. CONCLUSIONS: In a large, biracial cohort of older adults free of clinically overt coronary heart disease or heart failure, obesity was associated with subclinical abnormalities in cardiac structure in both men and women and with adverse LV remodeling and impaired LV systolic function in women. These data highlight the association of obesity and subclinical abnormalities of cardiac structure and function, particularly in women. PMID- 27512106 TI - Precision medicine in idiopathic pulmonary fibrosis. PMID- 27512107 TI - Spectrum and outcome of acute infectious encephalitis/encephalopathy in an intensive care unit from India. AB - Purpose: To evaluate the spectrum of acute infectious encephalitis/encephalopathy syndrome (AIES) in intensive care unit (ICU) and the predictors of mechanical ventilation (MV) and outcome of these patients. Methods: AIES patients diagnosed on the basis of fever, altered sensorium, seizure and cerebrospinal fluid pleocytosis admitted to the neurology ICU were prospectively included. The demographic and clinical details, hematological, biochemical, MRI and etiological findings of the patients were noted. Need of MV, death in hospital and 3-month functional outcome were analyzed. Results: One hundred sixty-four out of 258 (64%) AIES patients needed ICU admission. Their median age was 35 (2-85) years and 71 (43%) were females. The etiology was viral in 44 (herpes and Japanese encephalitis in 12 each, dengue in 17, mumps, measles and varicella in 1 patient each), non-viral in 64 (scrub typhus in 48, falciparum malaria in 6, leptospira in 3 and bacterial in 7) and undetermined etiology in 56 (34%) patients. Sixty nine (42%) patients needed MV. On multivariate analysis, Glasgow Coma Scale (GCS) score, Sequential Organ Failure Assessment (SOFA) score and raised intracranial pressure were independent predictors of MV. Forty-three (26%) patients died, and all were in the MV group. Higher SOFA score and untreatable etiology were independent predictors of mortality. At 3-month follow-up, 14% had poor and 86% had good outcome. Low GCS score, focal weakness and status epilepticus independently predicted poor outcome. Conclusion: Twenty-six percent patients with AIES died in ICU, and 86% had good recovery at 3 months. Admission SOFA scores and untreatable etiology predicted mortality. PMID- 27512109 TI - Trajectories of Risk Factors and Risk of New-Onset Atrial Fibrillation in the Framingham Heart Study. AB - The associations of long-term patterns of risk factors and the risk of incident atrial fibrillation (AF) are incompletely characterized. Among 4351 Framingham Study participants (mean age 50+/-11 years at baseline examination, 57% women) from the original and offspring cohorts, we defined longitudinal patterns, referred to as trajectories, of AF risk factors and a composite AF risk score using ~16 years of data. We used Cox proportional hazards models to examine the association of trajectories to 15-year risk of AF. During follow-up, 719 participants developed AF. Five distinct trajectory groups were identified for systolic blood pressure (BP): groups 1 and 2 (normotensive throughout), group 3 (prehypertensive), group 4 (hypertensive initially with decreasing BP), and group 5 (hypertensive and increasing BP). In multivariable-adjusted analyses, compared with group 1, groups 4 (hazard ratio 2.05; 95% confidence interval 1.24-3.37) and 5 (hazard ratio 1.95; 95% confidence interval 1.08-3.49) were associated with incident AF. Three trajectory groups were identified for antihypertensive treatment. Compared with the group with no treatment throughout, the other 2 groups were associated with increased risk of incident AF. Distinct trajectories for diastolic BP, smoking, diabetes mellitus, and the composite risk score were not associated with increased 15-year risk of AF. Longitudinal trajectories may distinguish how exposures related to AF contribute toward prospective AF risk. Distinct trajectory groups with persistently elevated systolic BP and longer antihypertensive treatment are associated with increased risk of incident AF. PMID- 27512110 TI - Establishing an injury indicator for severe paediatric injury. AB - BACKGROUND: Routinely gathered injury data, such as hospitalisations, may be subject to variation from sources other than injury incidence. There is a need for an indicator that defines severe injury, which may be less vulnerable to fluctuations due to changes in care policies. The purpose of this study was to identify International Classification of Diseases-10 codes associated with severe paediatric injuries and to specify and validate a severe paediatric injury indicator. METHODS: Two data sets that included the ISS and the survival risk ratio were used to produce a list of diagnoses to define severe paediatric injury. The list was sent to trauma surgeons who classified each code as severe enough or not severe enough to require care in a trauma centre. The indicator was fully specified, then validated by using a different data set to validate the codes in a real-world situation. RESULTS: Sixty diagnoses were identified as representing severe paediatric injury. Following specification, the indicator was applied to an existing comprehensive data set of paediatric injuries. The decline in hospitalisation of paediatric injuries was significantly steeper for severe than non-severe injuries, suggesting that factors related to the decline in this trauma subset are unlikely to be related to changes in access or other components of trauma care delivery. CONCLUSIONS: This indicator can be used for the evaluation of trends in severe paediatric trauma and will help identify populations at risk. This research may inform policies and procedures for referrals of severe childhood injury to appropriate levels of care. PMID- 27512111 TI - Unusual Diversity of Myoglobin Genes in the Lungfish. AB - Myoglobin is a respiratory protein that serves as a model system in a variety of biological fields. Its main function is to deliver and store O2 in the heart and skeletal muscles, but myoglobin is also instrumental in homeostasis of nitric oxide (NO) and detoxification of reactive oxygen species (ROS). Almost every vertebrate harbors a single myoglobin gene; only some cyprinid fishes have two recently duplicated myoglobin genes. Here we show that the West African lungfish Protopterus annectens has at least seven distinct myoglobin genes (PanMb1-7), which diverged early in the evolution of lungfish and showed an enhanced evolutionary rate. These myoglobins are lungfish specific, and no other globin gene was found amplified. The myoglobins are differentially expressed in various lungfish tissues, and the brain is the main site of myoglobin expression. The typical myoglobin-containing tissues, the skeletal muscle and the heart, have much lower myoglobin mRNA levels. Muscle and heart express distinct myoglobins (PanMb1 and PanMb3, respectively). In cell culture, lungfish myoglobins improved cellular survival under hypoxia albeit with different efficiencies and reduced the production of reactive oxygen species. Only Mb2 and Mb6 enhanced the energy status of the cells. The unexpected diversity of myoglobin hints to a functional diversification of this gene: some myoglobins may have adapted to the O2 requirements of the specific tissue and help the lungfish to survive hypoxic periods; other myoglobins may have taken over the roles of neuroglobin and cytoglobin, which appear to be missing in the West African lungfish. PMID- 27512112 TI - Positive Selection Drives Evolution at the Host-Filovirus Interaction Surface. AB - Filovirus infection is mediated by engagement of the surface-exposed glycoprotein (GP) by its cellular receptor, NPC1 (Niemann-Pick C1). Two loops in the C domain of NPC1 (NPC1-C) bind filovirus GP. Herein, we show that filovirus GP and NPC1-C evolve under mutual selective pressure. Analysis of a large mammalian phylogeny indicated that strong functional/structural constraints limit the NPC1 sequence space available for adaptive change and most sites at the contact interface with GP are under negative selection. These constraints notwithstanding, we detected positive selection at NPC1-C in all mammalian orders, from Primates to Xenarthra. Different codons evolved adaptively in distinct mammals, and most selected sites are located within the two NPC1-C loops that engage GP, or at their anchor points. In Homininae, NPC1-C was a preferential selection target, and the T419I variant possibly represents a human-specific adaptation to filovirus infection. On the other side of the arms-race, GP evolved adaptively during filovirus speciation. One of the selected sites (S142Q) establishes several atom-to-atom contacts with NPC1-C. Additional selected sites are located within epitopes recognized by neutralizing antibodies, including the 14G7 epitope, where sites selected during the recent EBOV epidemic also map. Finally, pairs of co-evolving sites in Marburgviruses and Ebolaviruses were found to involve antigenic determinants. These findings suggest that the host humoral immune response was a major selective pressure during filovirus speciation. The S142Q variant may contribute to determine Ebolavirus host range in the wild. If this were the case, EBOV/BDBV (S142) and SUDV (Q142) may not share the same reservoir(s). PMID- 27512113 TI - A Phylogenomic Framework to Study the Diversity and Evolution of Stramenopiles (=Heterokonts). AB - Stramenopiles or heterokonts constitute one of the most speciose and diverse clades of protists. It includes ecologically important algae (such as diatoms or large multicellular brown seaweeds), as well as heterotrophic (e.g., bicosoecids, MAST groups) and parasitic (e.g., Blastocystis, oomycetes) species. Despite their evolutionary and ecological relevance, deep phylogenetic relationships among stramenopile groups, inferred mostly from small-subunit rDNA phylogenies, remain unresolved, especially for the heterotrophic taxa. Taking advantage of recently released stramenopile transcriptome and genome sequences, as well as data from the genomic assembly of the MAST-3 species Incisomonas marina generated in our laboratory, we have carried out the first extensive phylogenomic analysis of stramenopiles, including representatives of most major lineages. Our analyses, based on a large data set of 339 widely distributed proteins, strongly support a root of stramenopiles lying between two clades, Bigyra and Gyrista (Pseudofungi plus Ochrophyta). Additionally, our analyses challenge the Phaeista-Khakista dichotomy of photosynthetic stramenopiles (ochrophytes) as two groups previously considered to be part of the Phaeista (Pelagophyceae and Dictyochophyceae), branch with strong support with the Khakista (Bolidophyceae and Diatomeae). We propose a new classification of ochrophytes within the two groups Chrysista and Diatomista to reflect the new phylogenomic results. Our stramenopile phylogeny provides a robust phylogenetic framework to investigate the evolution and diversification of this group of ecologically relevant protists. PMID- 27512114 TI - Recombination Rate Variation, Hitchhiking, and Demographic History Shape Deleterious Load in Poplar. AB - Deleterious alleles are expected to be purged by purifying selection or maintained at low frequency. However, many additional evolutionary forces may shape the pattern of deleterious mutations across the genome and among populations, including selection, hitchhiking, recombination, and demographic history. We used exome capture data to estimate the genome-wide distribution of deleterious alleles across natural populations of the model tree black cottonwood (Populus trichocarpa). Although deleterious alleles were on average present at low frequency suggesting purifying selection, they were preferentially enriched both within genomic regions of low-recombination and in regions showing evidence of positive selection. The demographic history of this species also appeared to play a role in the distribution of deleterious alleles among populations, with peripheral populations having higher rates of deleterious homozygosity. This be due to less efficient selection arising from smaller effective population sizes at the edges of the range, and possibly also due to recent bottlenecks associated with postglacial recolonization. Finally, correlations between deleterious homozygosity and plant growth suggest a significant effect of deleterious load on fitness. Our results show that both genomic context and historical demography play a role in shaping the distribution of deleterious alleles across the genome and range of P. trichocarpa. PMID- 27512115 TI - Extensively Parameterized Mutation-Selection Models Reliably Capture Site Specific Selective Constraint. AB - The mutation-selection model of coding sequence evolution has received renewed attention for its use in estimating site-specific amino acid propensities and selection coefficient distributions. Two computationally tractable mutation selection inference frameworks have been introduced: One framework employs a fixed-effects, highly parameterized maximum likelihood approach, whereas the other employs a random-effects Bayesian Dirichlet Process approach. While both implementations follow the same model, they appear to make distinct predictions about the distribution of selection coefficients. The fixed-effects framework estimates a large proportion of highly deleterious substitutions, whereas the random-effects framework estimates that all substitutions are either nearly neutral or weakly deleterious. It remains unknown, however, how accurately each method infers evolutionary constraints at individual sites. Indeed, selection coefficient distributions pool all site-specific inferences, thereby obscuring a precise assessment of site-specific estimates. Therefore, in this study, we use a simulation-based strategy to determine how accurately each approach recapitulates the selective constraint at individual sites. We find that the fixed-effects approach, despite its extensive parameterization, consistently and accurately estimates site-specific evolutionary constraint. By contrast, the random-effects Bayesian approach systematically underestimates the strength of natural selection, particularly for slowly evolving sites. We also find that, despite the strong differences between their inferred selection coefficient distributions, the fixed- and random-effects approaches yield surprisingly similar inferences of site-specific selective constraint. We conclude that the fixed-effects mutation selection framework provides the more reliable software platform for model application and future development. PMID- 27512116 TI - The Diversification of Plant NBS-LRR Defense Genes Directs the Evolution of MicroRNAs That Target Them. AB - High expression of plant nucleotide binding site leucine-rich repeat (NBS-LRR) defense genes is often lethal to plant cells, a phenotype perhaps associated with fitness costs. Plants implement several mechanisms to control the transcript level of NBS-LRR defense genes. As negative transcriptional regulators, diverse miRNAs target NBS-LRRs in eudicots and gymnosperms. To understand the evolutionary benefits of this miRNA-NBS-LRR regulatory system, we investigated the NBS-LRRs of 70 land plants, coupling this analysis with extensive small RNA data. A tight association between the diversity of NBS-LRRs and miRNAs was found. The miRNAs typically target highly duplicated NBS-LRRs In comparison, families of heterogeneous NBS-LRRs were rarely targeted by miRNAs in Poaceae and Brassicaceae genomes. We observed that duplicated NBS-LRRs from different gene families periodically gave birth to new miRNAs. Most of these newly emerged miRNAs target the same conserved, encoded protein motif of NBS-LRRs, consistent with a model of convergent evolution for these miRNAs. By assessing the interactions between miRNAs and NBS-LRRs, we found nucleotide diversity in the wobble position of the codons in the target site drives the diversification of miRNAs. Taken together, we propose a co-evolutionary model of plant NBS-LRRs and miRNAs hypothesizing how plants balance the benefits and costs of NBS-LRR defense genes. PMID- 27512117 TI - BPR1J373, an Oral Multiple Tyrosine Kinase Inhibitor, Targets c-KIT for the Treatment of c-KIT-Driven Myeloid Leukemia. AB - Acute myelogenous leukemia (AML) carrying t(8;21)(q22;q22) or inv(16)/t(16;16)(p13;q22) is classified as core binding factor (CBF)-AML and accounts for approximately 15% of AML. c-KIT mutation can be detected in 17%~46% of CBF-AML and is associated with poor prognosis. c-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22;q22) to cause overt AML. Tyrosine kinase inhibitors (TKI) targeting c-KIT, such as imatinib, has been used successfully to treat c-KIT driven gastrointestinal stromal tumors. However, the effect of TKI on c-KIT-driven leukemia, including CBF-AML and systemic mastocytosis (SM), has not been satisfactory. BPR1J373 is a 5-phenylthiazol-2 ylamine-pyriminide derivative targeting multiple tyrosine kinases. It was shown to inhibit cell proliferation and induce apoptosis in AML cells with constitutively activated c-KIT via inhibiting c-KIT phosphorylation and its downstream signals. The compound induced apoptosis by the mitochondrial intrinsic pathway through upregulation of proapoptotic proteins Bax and Bak and caspase 8 and 9 activation in c-KIT mutant Kasumi-1 cells. Furthermore, it induced cell cycle arrest via targeting aurora kinase B in c-KIT wild-type KG-1 cells. The antitumor response of BPR1J373 was also shown in subcutaneously grafted SCID mice. BPR1J373 was shown to effectively suppress c-KIT phosphorylation of D816V mutation by treating c-KIT-null COS-1 cells transfected with c-KIT D816V mutant plasmid. In conclusion, BPR1J373 inhibits cell proliferation of c-KIT-driven AML cells via induction of apoptosis and cell-cycle arrest. It is also effective for multiple drug-resistant c-KIT D816V mutation. BPR1J373 deserves further development for clinical use in c-KIT-driven myeloid leukemia. Mol Cancer Ther; 15(10); 2323-33. (c)2016 AACR. PMID- 27512118 TI - Trabectedin Is Active against Malignant Pleural Mesothelioma Cell and Xenograft Models and Synergizes with Chemotherapy and Bcl-2 Inhibition In Vitro. AB - Malignant pleural mesothelioma (MPM) is characterized by widespread resistance to systemic therapy. Trabectedin is an antineoplastic agent targeting both the malignant cells and the tumor microenvironment that has been approved for the treatment of advanced soft tissue sarcoma and ovarian cancer. In this preclinical study, we evaluated the antineoplastic potential of trabectedin as a single agent and in drug combination approaches in human MPM. Therefore, we utilized an extended panel of MPM cell lines (n = 6) and primary cell cultures from surgical MPM specimens (n = 13), as well as nonmalignant pleural tissue samples (n = 2). Trabectedin exerted a dose-dependent cytotoxic effect in all MPM cell cultures in vitro when growing as adherent monolayers or nonadherent spheroids with IC50 values <= 2.6 nmol/L. Nonmalignant mesothelial cells were significantly less responsive. The strong antimesothelioma activity was based on cell-cycle perturbation and apoptosis induction. The activity of trabectedin against MPM cells was synergistically enhanced by coadministration of cisplatin, a drug routinely used for systemic MPM treatment. Comparison of gene expression signatures indicated an inverse correlation between trabectedin response and bcl 2 expression. Accordingly, bcl-2 inhibitors (Obatoclax, ABT-199) markedly synergized with trabectedin paralleled by deregulated expression of the bcl-2 family members bcl-2, bim, bax, Mcl-1, and bcl-xL as a consequence of trabectedin exposure. In addition, trabectedin exerted significant antitumor activity against an intraperitoneal MPM xenograft model. Together, these data suggest that trabectedin exerts strong activity in MPM and synergizes with chemotherapy and experimental bcl-2 inhibitors in vitro Thus, it represents a promising new therapeutic option for MPM. Mol Cancer Ther; 15(10); 2357-69. (c)2016 AACR. PMID- 27512119 TI - CXC Chemokine Receptor 3 Alternative Splice Variants Selectively Activate Different Signaling Pathways. AB - The G protein-coupled receptor (GPCR) C-X-C chemokine receptor 3 (CXCR3) is a potential drug target that mediates signaling involved in cancer metastasis and inflammatory diseases. The CXCR3 primary transcript has three potential alternative splice variants and cell-type specific expression results in receptor variants that are believed to have different functional characteristics. However, the molecular pharmacology of ligand binding to CXCR3 alternative splice variants and their downstream signaling pathways remain poorly explored. To better understand the role of the functional consequences of alternative splicing of CXCR3, we measured signaling in response to four different chemokine ligands (CXCL4, CXCL9, CXCL10, and CXCL11) with agonist activity at CXCR3. Both CXCL10 and CXCL11 activated splice variant CXCR3A. Whereas CXCL10 displayed full agonistic activity for Galphai activation and extracellular signal regulated kinase (ERK) 1/2 phosphorylation and partial agonist activity for beta-arrestin recruitment, CXCL9 triggered only modest ERK1/2 phosphorylation. CXCL11 induced CXCR3B-mediated beta-arrestin recruitment and little ERK phosphorylation. CXCR3Alt signaling was limited to modest ligand-induced receptor internalization and ERK1/2 phosphorylation in response to chemokines CXCL11, CXCL10, and CXCL9. These results show that CXCR3 splice variants activate different signaling pathways and that CXCR3 variant function is not redundant, suggesting a mechanism for tissue specific biased agonism. Our data show an additional layer of complexity for chemokine receptor signaling that might be exploited to target specific CXCR3 splice variants. PMID- 27512120 TI - Human granulosa-luteal cells initiate an innate immune response to pathogen associated molecules. AB - The microenvironment of the ovarian follicle is key to the developmental success of the oocyte. Minor changes within the follicular microenvironment can significantly disrupt oocyte development, compromising the formation of competent embryos and reducing fertility. Previously described as a sterile environment, the ovarian follicle of women has been shown to contain colonizing bacterial strains, whereas in domestic species, pathogen-associated molecules are concentrated in the follicular fluid of animals with uterine infection. The aim of this study is to determine whether human granulosa-luteal cells mount an innate immune response to pathogen-associated molecules, potentially disrupting the microenvironment of the ovarian follicle. Human granulosa-luteal cells were collected from patients undergoing assisted reproduction. Cells were cultured in the presence of pathogen-associated molecules (LPS, FSL-1 and Pam3CSK4) for 24h. Supernatants and total RNA were collected for assessment by PCR and ELISA. Granulosa-luteal cells were shown to express the molecular machinery required to respond to a range of pathogen-associated molecules. Expression of TLR4 varied up to 15-fold between individual patients. Granulosa-luteal cells increased the expression of the inflammatory mediators IL1B, IL6 and CXCL8 in the presence of the TLR4 agonist E. coli LPS. Similarly, the TLR2/6 ligand, FSL-1, increased the expression of IL6 and CXCL8. Although no detectable changes in CYP19A1 or STAR expression were observed in granulosa-luteal cells following challenge, a significant reduction in progesterone secretion was measured after treatment with FSL-1. These findings demonstrate the ability of human granulosa-luteal cells to respond to pathogen-associated molecules and generate an innate immune response. PMID- 27512121 TI - Only a small population of adult Sertoli cells actively proliferates in culture. AB - Adult mammalian Sertoli cells (SCs) have been considered to be quiescent terminal differentiated cells for many years, but recently, proliferation of adult SCs was demonstrated in vitro and in vivo We further examined mouse SC behavior in culture and found that there are two populations of adult SCs. The first population is SCs from seminiferous tubules that hardly proliferate in vitro The second population is small and consists of SCs with atypical nuclear morphology from the terminal segments of seminiferous tubules, a transitional zone (TZ). TZ SCs multiply in culture and form colonies, display mixture of mature and immature SC characteristics, and generate cord-like structures in a collagen matrix. The specific features of TZ SCs are ACTA2 expression in vitro and DMRT1 low levels in vivo and in vitro Although the in vivo function of TZ SCs still remains unclear, this finding has significant implications for our understanding of SC differentiation and functioning in adult mammals. PMID- 27512122 TI - Elucidating human male germ cell development by studying germ cell cancer. AB - Human germ cell development is regulated in a spatio-temporal manner by complex regulatory networks. Here, we summarize results obtained in germ cell tumors and respective cell lines and try to pinpoint similarities to normal germ cell development. This comparison allows speculating about the critical and error prone mechanisms, which when disturbed, lead to the development of germ cell tumors. Short after specification, primordial germ cells express markers of pluripotency, which, in humans, persists up to the stage of fetal/infantile spermatogonia. Aside from the rare spermatocytic tumors, virtually all seminomas and embryonal carcinomas express markers of pluripotency and show signs of pluripotency or totipotency. Therefore, it appears that proper handling of the pluripotency program appears to be the most critical step in germ cell development in terms of tumor biology. Furthermore, data from mice reveal that germline cells display an epigenetic signature, which is highly similar to pluripotent cells. This signature (poised histone code, DNA hypomethylation) is required for the rapid induction of toti- and pluripotency upon fertilization. We propose that adult spermatogonial cells, when exposed to endocrine disruptors or epigenetic active substances, are prone to reinitiate the pluripotency program, giving rise to a germ cell tumor. The fact that pluripotent cells can be derived from adult murine and human testicular cells further corroborates this idea. PMID- 27512123 TI - Oviductal response to gametes and early embryos in mammals. AB - The oviduct is a complex and organized thin tubular structure connecting the ovary with the uterus. It is the site of final sperm capacitation, oocyte fertilization and, in most species, the first 3-4days of early embryo development. The oviductal epithelium is made up of ciliary and secretory cells responsible for the secretion of proteins and other factors which contribute to the formation of the oviductal fluid. Despite significant research, most of the pathways and oviductal factors implicated in the crosstalk between gametes/early embryo and the oviduct remain unknown. Therefore, studying the oviductal environment is crucial to improve our understanding of the regulatory mechanisms controlling fertilization and embryo development. In vitro systems are a valuable tool to study in vivo pathways and mechanisms, particularly those in the oviducts which in livestock species are challenging to access. In studies of gamete and embryo interaction with the reproductive tract, oviductal epithelial cells, oviductal fluid and microvesicles co-cultured with gametes/embryos represent the most appropriate in vitro models to mimic the physiological conditions in vivo. PMID- 27512124 TI - 3'READS+, a sensitive and accurate method for 3' end sequencing of polyadenylated RNA. AB - Sequencing of the 3' end of poly(A)(+) RNA identifies cleavage and polyadenylation sites (pAs) and measures transcript expression. We previously developed a method, 3' region extraction and deep sequencing (3'READS), to address mispriming issues that often plague 3' end sequencing. Here we report a new version, named 3'READS+, which has vastly improved accuracy and sensitivity. Using a special locked nucleic acid oligo to capture poly(A)(+) RNA and to remove the bulk of the poly(A) tail, 3'READS+ generates RNA fragments with an optimal number of terminal A's that balance data quality and detection of genuine pAs. With improved RNA ligation steps for efficiency, the method shows much higher sensitivity (over two orders of magnitude) compared to the previous version. Using 3'READS+, we have uncovered a sizable fraction of previously overlooked pAs located next to or within a stretch of adenylate residues in human genes and more accurately assessed the frequency of alternative cleavage and polyadenylation (APA) in HeLa cells (~50%). 3'READS+ will be a useful tool to accurately study APA and to analyze gene expression by 3' end counting, especially when the amount of input total RNA is limited. PMID- 27512125 TI - Monitoring maternal and newborn health outcomes in Bauchi State, Nigeria: an evaluation of a standards-based quality improvement intervention. AB - OBJECTIVE: This study assessed the correlation between compliance with set performance standards and maternal and neonatal deaths in health facilities. DESIGN: Baseline and three annual follow-up assessments were conducted, and each was followed by a quality improvement initiative using the Standards Based Management and Recognition (SBM-R) approach. SETTING: Twenty-three secondary health facilities of Bauchi state, Nigeria. PARTICIPANTS: Health care workers and maternity unit patients. MAIN OUTCOME MEASURES: We examined trends in: (i) achievement of SBM-R set performance standards based on annual assessment data, (ii) the use of maternal and newborn health (MNH) service delivery practices based on data from health facility registers and supportive supervision and (iii) MNH outcomes based on routine service statistics. RESULTS: At the baseline assessment in 2010, the facilities achieved 4% of SBM-R standards for MNH, on average, and this increased to 86% in 2013. Over the same time period, the study measured an increase in the administration of uterotonic for active management of third stage of labor from 10% to 95% and a decline in the incidence of postpartum hemorrhage from 3.3% to 1.9%. Institutional neonatal mortality rate decreased from 9 to 2 deaths per 1000 live births, while the institutional maternal mortality ratio dropped from 4113 to 1317 deaths per 100 000 live births. CONCLUSION: Scaling up SBM-R for quality improvement has the potential to prevent maternal and neonatal deaths in Nigeria and similar settings. PMID- 27512126 TI - Assessing the impact of general practitioner team service on perceived quality of care among patients with non-communicable diseases in China: a natural experimental study. AB - OBJECTIVE: China issued the national primary care policy of promoting general practitioner (GP) team service in 2011. We conducted this study to assess the impact of the GP team service on quality of primary care as perceived by patients with non-communicable diseases (NCDs). DESIGN: Natural experimental study. SETTING: This study was conducted in Shanghai, where the policy was effectively implemented, and Kunming, where the policy was not implemented. PARTICIPANTS: In both cities, NCD patients were interviewed with primary care assessment tool (PCAT) after their clinical consultations in their community health centers. INTERVENTION: The implementation of GP team service policy. MAIN OUTCOME MEASURES: Multiple linear regressions were employed to compare PCAT scores between the two rounds of the surveys in each city. Difference-in-difference (DID) analysis was used to identify the changes between two cities over time. RESULTS: A total of 663 and 587 patients in Shanghai, and 400 and 441 patients in Kunming were surveyed in 2011 and 2013, respectively. The DID analysis showed that the total primary care quality scores improved in Shanghai compared with Kunming between 2011 and 2013 (beta = 1.30, 95% CI: 0.74, 1.87). In Shanghai, care quality in 2013 improved significantly for the total score and the six components when compared with those in 2011. No significant changes were observed in Kunming in the same period. CONCLUSION: Primary care policies that promote long-term provider-patient relationships, coordinated service with hospitals and capitation payment for the GP team may contribute to the improvement of care quality in Shanghai. PMID- 27512127 TI - Guidance on how to achieve comprehensible patient information leaflets in four steps. AB - Comprehensible information leaflets can improve a patient's knowledge. However, in clinical studies leaflets are often introduced without meticulously verifying their comprehensibility. In an attempt to provide a feasible guidance on how to design comprehensible leaflets we complied and evaluated an easy-to-use development procedure. In January 2015, a literature search was performed to identify evidence for readily available quality assurance strategies as a starting point for a standardized strategy to develop and validate written patient information. The suggested development strategy is a consecutive four step procedure that comprised already validated distinct quality assessments: (i) an initial requirement analysis specifying the needs and constraints of the target population and evidence-based preparation of the leaflets, (ii) a readability assessment, (iii) the Suitability Assessment of Materials instrument and (iv) iterative consumer test in the target population. The consecutive combination of pertinent and previously validated quality assessments provides an easy-to-use guidance on how to create comprehensibly written patient information, particularly for small-scale research projects with time and money constraints. PMID- 27512128 TI - Impact of general practitioner on perceived quality of care and monitoring maternal-newborn health outcomes in developing countries. PMID- 27512129 TI - Implementing electronic handover: interventions to improve efficiency, safety and sustainability. AB - PROBLEM: Effective handovers are critical for patient care and safety. Electronic handover tools are increasingly used today to provide an effective and standardized platform for information exchange. The implementation of an electronic handover system in tertiary hospitals can be a major challenge. Previous efforts in implementing an electronic handover tool failed due to poor compliance and buy-in from end-users. A new electronic handover tool was developed and incorporated into the existing electronic medical records (EMRs) for medical patients in Singapore General Hospital (SGH). INITIAL ASSESSMENT: There was poor compliance by on-call doctors in acknowledging electronic handovers, and lack of adherence to safety rules, raising concerns about the safety and efficiency of the electronic handover tool. Urgent measures were needed to ensure its safe and sustained use. SOLUTION: A quality improvement group comprising stakeholders, including end-users, developed multi-faceted interventions using rapid PDSA (P-Plan, D-Do, S-Study, A-Act ) cycles to address these issues. IMPLEMENTATION: Innovative solutions using media and online software provided cost-efficient measures to improve compliance. EVALUATION: The percentage of unacknowledged handovers per day was used as the main outcome measure throughout all PDSA cycles. Doctors were also assessed for improvement in their knowledge of safety rules and their perception of the electronic handover tool. LESSONS LEARNT: An electronic handover tool complementing daily clinical practice can be successfully implemented using solutions devised through close collaboration with end-users supported by the senior leadership. A combined 'bottom-up' and 'top-down' approach with regular process evaluations is crucial for its long-term sustainability. PMID- 27512130 TI - Improving inpatient environments to support patient sleep. AB - PURPOSE: Although sleep is important for healing, sleep deprivation is a major concern for patients in hospitals. The purpose of this review is to consolidate the observational and interventional studies that have been done to understand exogenous, non-pharmacological strategies for improving sleep in hospitals. DATA SOURCES: We searched Medline, CINAHL, PsycINFO and the Web of Science databases for peer-reviewed articles published between 1970 and 2015 in English. STUDY SELECTION: A title review of 13,113 articles from four databases resulted in 783 articles that were further culled to 277 based on a review of the abstracts. The net result after reading the articles and a hand search was 42 articles. DATA EXTRACTION: From each article we recorded the independent variables, methods used for measuring sleep and specific sleep outcomes reported. RESULTS OF DATA SYNTHESIS: Noise is a modifiable cause of some sleep disruptions in hospitals, and when reduced can lead to more sleep. Earplugs and eye masks may help, but changing the sound and light environment is more effective. Calming music in the evening has been shown to be effective as well as daytime bright light exposure. Nursing care activities cause sleep disruption, but efforts at limiting interventions have not been demonstrated to improve sleep conditions. CONCLUSION: The research is hard to consolidate due to the multitude of independent variables and outcome metrics, but overall points to the potential for making meaningful improvements in the quality of patient sleep. PMID- 27512131 TI - Evidence for ship noise impacts on humpback whale foraging behaviour. AB - Noise from shipping activity in North Atlantic coastal waters has been steadily increasing and is an area of growing conservation concern, as it has the potential to disrupt the behaviour of marine organisms. This study examines the impacts of ship noise on bottom foraging humpback whales (Megaptera novaeangliae) in the western North Atlantic. Data were collected from 10 foraging whales using non-invasive archival tags that simultaneously recorded underwater movements and the acoustic environment at the whale. Using mixed models, we assess the effects of ship noise on seven parameters of their feeding behaviours. Independent variables included the presence or absence of ship noise and the received level of ship noise at the whale. We found significant effects on foraging, including slower descent rates and fewer side-roll feeding events per dive with increasing ship noise. During 5 of 18 ship passages, dives without side-rolls were observed. These findings indicate that humpback whales on Stellwagen Bank, an area with chronically elevated levels of shipping traffic, significantly change foraging activity when exposed to high levels of ship noise. This measureable reduction in within-dive foraging effort of individual whales could potentially lead to population-level impacts of shipping noise on baleen whale foraging success. PMID- 27512132 TI - Seascape and life-history traits do not predict self-recruitment in a coral reef fish. AB - The persistence and resilience of many coral reef species are dependent on rates of connectivity among sub-populations. However, despite increasing research efforts, the spatial scale of larval dispersal remains unpredictable for most marine metapopulations. Here, we assess patterns of larval dispersal in the angelfish Centropyge bicolor in Kimbe Bay, Papua New Guinea, using parentage and sibling reconstruction analyses based on 23 microsatellite DNA loci. We found that, contrary to previous findings in this system, self-recruitment (SR) was virtually absent at both the reef (0.4-0.5% at 0.15 km(2)) and the lagoon scale (0.6-0.8% at approx. 700 km(2)). While approximately 25% of the collected juveniles were identified as potential siblings, the majority of sibling pairs were sampled from separate reefs. Integrating our findings with earlier research from the same system suggests that geographical setting and life-history traits alone are not suitable predictors of SR and that high levels of localized recruitment are not universal in coral reef fishes. PMID- 27512133 TI - Inferring node dates from tip dates in fossil Canidae: the importance of tree priors. AB - Tip-dating methods are becoming popular alternatives to traditional node calibration approaches for building time-scaled phylogenetic trees, but questions remain about their application to empirical datasets. We compared the performance of the most popular methods against a dated tree of fossil Canidae derived from previously published monographs. Using a canid morphology dataset, we performed tip-dating using BEAST v. 2.1.3 and MrBayes v. 3.2.5. We find that for key nodes (Canis, approx. 3.2 Ma, Caninae approx. 11.7 Ma) a non-mechanistic model using a uniform tree prior produces estimates that are unrealistically old (27.5, 38.9 Ma). Mechanistic models (incorporating lineage birth, death and sampling rates) estimate ages that are closely in line with prior research. We provide a discussion of these two families of models (mechanistic versus non-mechanistic) and their applicability to fossil datasets. PMID- 27512134 TI - Spider silk felting-functional morphology of the ovipositor tip of Clistopyga sp. (Ichneumonidae) reveals a novel use of the hymenopteran ovipositor. AB - Apical serrations of the hymenopteran ovipositor have been widely postulated to originally constitute adaptations for cutting through hard substrates. Simplifications of the ovipositor tip have occurred in several ichneumonid wasp genera associated with spiders. Despite such reduction in Clistopyga (Hymenoptera, Ichneumonidae), the ovipositor still possesses some apical serrations. Through the first detailed study, we believe, on the behaviour of an ovipositing Clistopyga species, we show that it can alter its ovipositor for different purposes and that the primary function of the apical serrations is clinging to its spider host as the spider attempts to escape. Intriguingly, we also discover a hitherto undocumented adaptation for the hymenopteran ovipositor. The female wasp seals openings in the silken spider nest by using its ovipositor on the silk in a highly sophisticated way that is comparable to how humans entangle wool by needle felting. By studying the ovipositor morphology through a scanning electron microscope, we elucidate how this works, and we hypothesize that by closing the nest the female wasp protects its developing kin. PMID- 27512135 TI - Intruder colour and light environment jointly determine how nesting male stickleback respond to simulated territorial intrusions. AB - Variation in male nuptial colour signals might be maintained by negative frequency-dependent selection. This can occur if males are more aggressive towards rivals with locally common colour phenotypes. To test this hypothesis, we introduced red or melanic three-dimensional printed-model males into the territories of nesting male stickleback from two optically distinct lakes with different coloured residents. Red-throated models were attacked more in the population with red males, while melanic models were attacked more in the melanic male lake. Aggression against red versus melanic models also varied across a depth gradient within each lake, implying that the local light environment also modulated the strength of negative frequency dependence acting on male nuptial colour. PMID- 27512136 TI - Maternal condition and previous reproduction interact to affect offspring sex in a wild mammal. AB - Trivers and Willard proposed that offspring sex ratio should vary with maternal condition when condition, meant as maternal capacity to care, has different fitness consequences for sons and daughters. In polygynous and dimorphic species, mothers in good condition should preferentially produce sons, whereas mothers in poor condition should produce more daughters. Despite its logical appeal, support for this hypothesis has been inconsistent. Sex-ratio variation may be influenced by additional factors, such as environmental conditions and previous reproduction, which are often ignored in empirical studies. We analysed 39 years of data on bighorn sheep (Ovis canadensis) that fit all the assumptions of the Trivers-Willard hypothesis. Production of sons increased with maternal condition only for mothers that weaned a son the previous year. This relationship likely reflects a mother's ability to bear the higher reproductive costs of sons. The interaction between maternal condition and previous weaning success on the probability of producing a son was independent of the positive effect of paternal reproductive success. Maternal and paternal effects accounted for similar proportions of the variance in offspring sex. Maternal reproductive history should be considered in addition to current condition in studies of sex allocation. PMID- 27512137 TI - Sampling methods for exploring between-subject variability in cardiac electrophysiology experiments. AB - Between-subject and within-subject variability is ubiquitous in biology and physiology, and understanding and dealing with this is one of the biggest challenges in medicine. At the same time, it is difficult to investigate this variability by experiments alone. A recent modelling and simulation approach, known as population of models (POM), allows this exploration to take place by building a mathematical model consisting of multiple parameter sets calibrated against experimental data. However, finding such sets within a high-dimensional parameter space of complex electrophysiological models is computationally challenging. By placing the POM approach within a statistical framework, we develop a novel and efficient algorithm based on sequential Monte Carlo (SMC). We compare the SMC approach with Latin hypercube sampling (LHS), a method commonly adopted in the literature for obtaining the POM, in terms of efficiency and output variability in the presence of a drug block through an in-depth investigation via the Beeler-Reuter cardiac electrophysiological model. We show improved efficiency for SMC that produces similar responses to LHS when making out-of-sample predictions in the presence of a simulated drug block. Finally, we show the performance of our approach on a complex atrial electrophysiological model, namely the Courtemanche-Ramirez-Nattel model. PMID- 27512138 TI - Controlled cobalt doping in the spinel structure of magnetosome magnetite: new evidences from element- and site-specific X-ray magnetic circular dichroism analyses. AB - The biomineralization of magnetite nanocrystals (called magnetosomes) by magnetotactic bacteria (MTB) has attracted intense interest in biology, geology and materials science due to the precise morphology of the particles, the chain like assembly and their unique magnetic properties. Great efforts have been recently made in producing transition metal-doped magnetosomes with modified magnetic properties for a range of applications. Despite some successful outcomes, the coordination chemistry and magnetism of such metal-doped magnetosomes still remain largely unknown. Here, we present new evidences from X ray magnetic circular dichroism (XMCD) for element- and site-specific magnetic analyses that cobalt is incorporated in the spinel structure of the magnetosomes within Magnetospirillum magneticum AMB-1 through the replacement of Fe(2+) ions by Co(2+) ions in octahedral (Oh) sites of magnetite. Both XMCD at Fe and Co L2,3 edges, and energy-dispersive X-ray spectroscopy on transmission electron microscopy analyses reveal a heterogeneous distribution of cobalt occurring either in different particles or inside individual particles. Compared with non doped one, cobalt-doped magnetosome sample has lower Verwey transition temperature and larger magnetic coercivity, related to the amount of doped cobalt. This study also demonstrates that the addition of trace cobalt in the growth medium can significantly improve both the cell growth and the magnetosome formation within M. magneticum AMB-1. Together with the cobalt occupancy within the spinel structure of magnetosomes, this study indicates that MTB may provide a promising biomimetic system for producing chains of metal-doped single-domain magnetite with an appropriate tuning of the magnetic properties for technological and biomedical applications. PMID- 27512139 TI - Splendid coloration of the peacock spider Maratus splendens. AB - Jumping spiders are well known for their acute vision and often bright colours. The male peacock spider Maratus splendens is richly coloured by scales that cover the body. The colours of the white, cream and red scales, which have an elaborate shape with numerous spines, are pigmentary. Blue scales are unpigmented and have a structural colour, created by an intricate photonic system consisting of two chitinous layers with ridges, separated by an air gap, with on the inner sides of the chitin layers an array of filaments. We have characterized the optical properties of the scales by microspectrophotometry, imaging scatterometry and light and scanning electron microscopy. Optical modelling revealed that the filament array constitutes a novel structural coloration system, which subtly fine tunes the scale reflectance to the observed blue coloration. PMID- 27512140 TI - The telomeric protein AKTIP interacts with A- and B-type lamins and is involved in regulation of cellular senescence. AB - AKTIP is a shelterin-interacting protein required for replication of telomeric DNA. Here, we show that AKTIP biochemically interacts with A- and B-type lamins and affects lamin A, but not lamin C or B, expression. In interphase cells, AKTIP localizes at the nuclear rim and in discrete regions of the nucleoplasm just like lamins. Double immunostaining revealed that AKTIP partially co-localizes with lamin B1 and lamin A/C in interphase cells, and that proper AKTIP localization requires functional lamin A. In mitotic cells, AKTIP is enriched at the spindle poles and at the midbody of late telophase cells similar to lamin B1. AKTIP depleted cells show senescence-associated markers and recapitulate several aspects of the progeroid phenotype. Collectively, our results indicate that AKTIP is a new player in lamin-related processes, including those that govern nuclear architecture, telomere homeostasis and cellular senescence. PMID- 27512141 TI - Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers. AB - Cell fate in response to an aberrant mitosis is governed by two competing networks: the spindle assembly checkpoint (SAC) and the intrinsic apoptosis pathway. The mechanistic interplay between these two networks is obscured by functional redundancy and the ability of cells to die either in mitosis or in the subsequent interphase. By coupling time-lapse microscopy with selective pharmacological agents, we systematically probe pro-survival Bcl-xL in response to various mitotic perturbations. Concentration matrices show that BH3-mimetic mediated inhibition of Bcl-xL synergises with perturbations that induce an SAC mediated mitotic block, including drugs that dampen microtubule dynamics, and inhibitors targeting kinesins and kinases required for spindle assembly. By contrast, Bcl-xL inhibition does not synergize with drugs which drive cells through an aberrant mitosis by overriding the SAC. This differential effect, which is explained by compensatory Mcl-1 function, provides opportunities for patient stratification and combination treatments in the context of cancer chemotherapy. PMID- 27512142 TI - A drug-compatible and temperature-controlled microfluidic device for live-cell imaging. AB - Monitoring cellular responses to changes in growth conditions and perturbation of targeted pathways is integral to the investigation of biological processes. However, manipulating cells and their environment during live-cell-imaging experiments still represents a major challenge. While the coupling of microfluidics with microscopy has emerged as a powerful solution to this problem, this approach remains severely underexploited. Indeed, most microdevices rely on the polymer polydimethylsiloxane (PDMS), which strongly absorbs a variety of molecules commonly used in cell biology. This effect of the microsystems on the cellular environment hampers our capacity to accurately modulate the composition of the medium and the concentration of specific compounds within the microchips, with implications for the reliability of these experiments. To overcome this critical issue, we developed new PDMS-free microdevices dedicated to live-cell imaging that show no interference with small molecules. They also integrate a module for maintaining precise sample temperature both above and below ambient as well as for rapid temperature shifts. Importantly, changes in medium composition and temperature can be efficiently achieved within the chips while recording cell behaviour by microscopy. Compatible with different model systems, our platforms provide a versatile solution for the dynamic regulation of the cellular environment during live-cell imaging. PMID- 27512143 TI - Autophagy protects cardiomyocytes from the myocardial ischaemia-reperfusion injury through the clearance of CLP36. AB - Cardiovascular disease (CVD) is the leading cause of the death worldwide. An increasing number of studies have found that autophagy is involved in the progression or prevention of CVD. However, the precise mechanism of autophagy in CVD, especially the myocardial ischaemia-reperfusion injury (MI/R injury), is unclear and controversial. Here, we show that the cardiomyocyte-specific disruption of autophagy by conditional knockout of Atg7 leads to severe contractile dysfunction, myofibrillar disarray and vacuolar cardiomyocytes. A negative cytoskeleton organization regulator, CLP36, was found to be accumulated in Atg7-deficient cardiomyocytes. The cardiomyocyte-specific knockout of Atg7 aggravates the MI/R injury with cardiac hypertrophy, contractile dysfunction, myofibrillar disarray and severe cardiac fibrosis, most probably due to CLP36 accumulation in cardiomyocytes. Altogether, this work reveals autophagy may protect cardiomyocytes from the MI/R injury through the clearance of CLP36, and these findings define a novel relationship between autophagy and the regulation of stress fibre in heart. PMID- 27512144 TI - Continental cichlid radiations: functional diversity reveals the role of changing ecological opportunity in the Neotropics. AB - Adaptive radiations have been hypothesized to contribute broadly to the diversity of organisms. Models of adaptive radiation predict that ecological opportunity and ecological release, the availability of empty ecological niches and the response by adapting lineages to occupy them, respectively, drive patterns of phenotypic and lineage diversification. Adaptive radiations driven by 'ecological opportunity' are well established in island systems; it is less clear if ecological opportunity influences continent-wide diversification. We use Neotropical cichlid fishes to test if variation in rates of functional evolution is consistent with changing ecological opportunity. Across a functional morphological axis associated with ram-suction feeding traits, evolutionary rates declined through time as lineages diversified in South America. Evolutionary rates of ram-suction functional morphology also appear to have accelerated as cichlids colonized Central America and encountered renewed opportunity. Our results suggest that ecological opportunity may play an important role in shaping patterns of morphological diversity of even broadly distributed lineages like Neotropical cichlids. PMID- 27512145 TI - Parasites contribute to ecologically dependent postmating isolation in the adaptive radiation of three-spined stickleback. AB - Spatial variation in parasitic infections is common, and has the potential to drive population divergence and the reproductive isolation of hosts. However, despite support from theory and model laboratory systems, little strong evidence has been forthcoming from the wild. Here, we show that parasites are likely to cause reproductive isolation in the adaptive radiation of three-spined stickleback. Adjacent wild populations on the Scottish island of North Uist differ greatly and consistently in the occurrence of different parasites that have substantial effects on fitness. Laboratory-reared fish are more resistant to experimental infection by parasite species from their own population. Furthermore, hybrid backcrosses between the host populations are more resistant to parasites from the parental population to which they are more closely related. These patterns provide strong evidence that parasites can cause ecological speciation, by contributing to selection against migrants and ecologically dependent postmating isolation. PMID- 27512146 TI - Evidence for water-mediated mechanisms in coral-algal interactions. AB - Although many coral reefs have shifted from coral-to-algal dominance, the consequence of such a transition for coral-algal interactions and their underlying mechanisms remain poorly understood. At the microscale, it is unclear how diffusive boundary layers (DBLs) and surface oxygen concentrations at the coral-algal interface vary with algal competitors and competitiveness. Using field observations and microsensor measurements in a flow chamber, we show that coral (massive Porites) interfaces with thick turf algae, macroalgae, and cyanobacteria, which are successful competitors against coral in the field, are characterized by a thick DBL and hypoxia at night. In contrast, coral interfaces with crustose coralline algae, conspecifics, and thin turf algae, which are poorer competitors, have a thin DBL and low hypoxia at night. Furthermore, DBL thickness and hypoxia at the interface with turf decreased with increasing flow speed, but not when thick turf was upstream. Our results support the importance of water-mediated transport mechanisms in coral-algal interactions. Shifts towards algal dominance, particularly dense assemblages, may lead to thicker DBLs, higher hypoxia, and higher concentrations of harmful metabolites and pathogens along coral borders, which in turn may facilitate algal overgrowth of live corals. These effects may be mediated by flow speed and orientation. PMID- 27512147 TI - Host stress hormones alter vector feeding preferences, success, and productivity. AB - Stress hormones might represent a key link between individual-level infection outcome, population-level parasite transmission, and zoonotic disease risk. Although the effects of stress on immunity are well known, stress hormones could also affect host-vector interactions via modification of host behaviours or vector-feeding patterns and subsequent reproductive success. Here, we experimentally manipulated songbird stress hormones and examined subsequent feeding preferences, feeding success, and productivity of mosquito vectors in addition to defensive behaviours of hosts. Despite being more defensive, birds with elevated stress hormone concentrations were approximately twice as likely to be fed on by mosquitoes compared to control birds. Moreover, stress hormones altered the relationship between the timing of laying and clutch size in blood fed mosquitoes. Our results suggest that host stress could affect the transmission dynamics of vector-borne parasites via multiple pathways. PMID- 27512148 TI - Dead ant walking: a myrmecophilous beetle predator uses parasitoid host location cues to selectively prey on parasitized ants. AB - Myrmecophiles (i.e. organisms that associate with ants) use a variety of ecological niches and employ different strategies to survive encounters with ants. Because ants are typically excellent defenders, myrmecophiles may choose moments of weakness to take advantage of their ant associates. This hypothesis was studied in the rove beetle, Myrmedonota xipe, which associates with Azteca sericeasur ants in the presence of parasitoid flies. A combination of laboratory and field experiments show that M. xipe beetles selectively locate and prey upon parasitized ants. These parasitized ants are less aggressive towards beetles than healthy ants, allowing beetles to eat the parasitized ants alive without interruption. Moreover, behavioural assays and chemical analysis reveal that M. xipe are attracted to the ant's alarm pheromone, the same secretion used by the phorid fly parasitoids in host location. This strategy allows beetles access to an abundant but otherwise inaccessible resource, as A. sericeasur ants are typically highly aggressive. These results are the first, to our knowledge, to demonstrate a predator sharing cues with a parasitoid to gain access to an otherwise unavailable prey item. Furthermore, this work highlights the importance of studying ant-myrmecophile interactions beyond just their pairwise context. PMID- 27512149 TI - Uterotonic Neuromedin U Receptor 2 and Its Ligands Are Upregulated by Inflammation in Mice and Humans, and Elicit Preterm Birth. AB - Uterine labor requires the conversion of a quiescent (propregnancy) uterus into an activated (prolabor) uterus, with increased sensitivity to endogenous uterotonic molecules. This activation is induced by stressors, particularly inflammation in term and preterm labor. Neuromedin U (NmU) is a neuropeptide known for its uterocontractile effects in rodents. The objective of the study was to assess the expression and function of neuromedin U receptor 2 (NmU-R2) and its ligands NmU and the more potent neuromedin S (NmS) in gestational tissues, and the possible implication of inflammatory stressors in triggering this system. Our data show that NmU and NmS are uterotonic ex vivo in murine tissue, and they dose dependently trigger labor by acting specifically via NmU-R2. Expression of NmU R2, NmU, and NmS is detected in murine and human gestational tissues by immunoblot, and the expression of NmS in placenta and of NmU-R2 in uterus increases considerably with gestation age and labor, which is associated with amplified NmU-induced uterocontractile response in mice. NmU- and NmS-induced contraction is associated with increased NmU-R2-coupled Ca++ transients, and Akt and Erk activation in murine primary myometrial smooth muscle cells (mSMCs), which are potentiated with gestational age. NmU-R2 is upregulated in vitro in mSMCs and in vivo in uterus in response to proinflammatory interleukin 1beta (IL1beta), which is associated with increased NmU-induced uterocontractile response and Ca++ transients in murine and human mSMCs; additionally, placental NmS is markedly upregulated in vivo in response to IL1beta. In human placenta at term, immunohistological analysis revealed NmS expression primarily in cytotrophoblasts; furthermore, stimulation with lipopolysaccharide (LPS; Gram negative endotoxin) markedly upregulates NmS expression in primary human cytotrophoblasts isolated from term placentas. Correspondingly, decidua of women with clinical signs of infection who delivered preterm display significantly higher expression of NmS compared with those without infection. Importantly, in vivo knockdown of NmU-R2 prevents LPS-triggered preterm birth in mice and the associated neonatal mortality. Altogether, our data suggest a critical role for NmU-R2 and its ligands NmU and NmS in preterm labor triggered by infection. We hereby identify NmU-R2 as a relevant target for preterm birth. PMID- 27512150 TI - EPHB4 Regulates Human Trophoblast Cell Line HTR-8/SVneo Function: Implications for the Role of EPHB4 in Preeclampsia. AB - Successful pregnancy depends on well-regulated extravillous trophoblast (EVT) invasion into the uterine decidua and moderate uterine spiral artery remodeling. Ephrin receptor B4 (EPHB4) is a membrane-anchored receptor tyrosine kinase that plays an important role in various cellular functions in human normal tissue and tumors. Reportedly, EPHB4 plays important roles during placentation. Still, there is no investigation of EPHB4 modulating trophoblast function. In our study, term placentas of preeclamptic pregnancies showed a significantly increased EPHB4 expression compared to those of uncomplicated pregnancies (n = 15). Exogenous up regulation of EPHB4 in HTR-8/SVneo cells was performed to investigate the effects of EPHB4 on cell biological behavior. The results showed that EPHB4 enhancement reduced cell proliferation and promoted trophoblast apoptosis; and inhibited cell migration, invasion, and endothelial replacement. Associated factors, such as matrix metalloproteinases, vascular endothelial growth factor, placental growth factor, and soluble Fms-like tyrosine kinase 1 were examined at transcriptional level. Furthermore, cell functional results were confirmed in a placenta-decidua coculture system, showing poor vascular remodeling. Additionally, we detected possible down-stream PI3K-Akt signal pathway involved in EPHB4-mediated function of HTR-8/SVneo cells. Our study demonstrates that EPHB4 overexpression may contribute to trophoblasts dysfunction and impair maternal artery remodeling, as is associated with the pathogenesis of preeclampsia. PMID- 27512151 TI - Involvement of Protein Acyltransferase ZDHHC3 in Maintaining Oocyte Meiotic Arrest in Xenopus laevis. AB - Fully grown oocytes of most vertebrates are arrested at prophase I of meiosis (G2 arrest). Upon exposure to steroid hormones, oocytes resume meiotic process, also called G2/M transition. The G protein-signaling pathway has been shown to play essential roles in the meiotic arrest at G2 phase. Previously, we showed that long chain fatty acyl-coenzyme A synthetase acsl1b was required for maintaining the meiotic arrest in Xenopus Acsl1b presumably synthesizes palmitoyl-coenzyme A that can be utilized by acyltransferases to modify proteins essential for the G2 arrest. In the present study, we report that protein acyltransferase ZDHHC3 functions downstream of acsl1b to maintain oocyte meiotic arrest. Depletion of maternal ZDHHC3 RNA in oocytes reduces the progesterone threshold to promote G2/M transition from 2 to 0.01 MUM. As expected, Gs alpha palmitoylation level is greatly decreased in ZDHHC3-depleted oocytes. Furthermore, we mapped ZDHHC3 palmitoylation sites in Gs alpha and showed that palmitoylation-deficient Gs alpha failed to arrest oocytes at G2. We also identified a critical residue in ZDHHC3 critically required for its palmitoylation activity toward Gs alpha. Taken together, ZDHHC3 is a key acyltransferase to palmitoylate proteins in order to maintain G2 arrest in Xenopus oocytes. PMID- 27512152 TI - Uterine Histotroph and Conceptus Development. II. Arginine and Secreted Phosphoprotein 1 Cooperatively Stimulate Migration and Adhesion of Ovine Trophectoderm Cells via Focal Adhesion-MTORC2 Mediated Cytoskeleton Reorganization. AB - In all mammalian species, critical events, including uterine receptivity and development of the conceptus (embryo/fetus and its associated extraembryonic membranes), must be intricately orchestrated and carefully timed during the window of implantation. Otherwise, failure of conceptuses to implant is inevitable, which accounts for 50%-75% of failures to establish pregnancy. Unlike human and rodent blastocysts, the blastocysts of pigs and ruminants undergo rapid transitions from spherical to tubular and filamentous conceptuses in response to histotroph during the peri-implantation period of pregnancy. Both arginine and secreted phosphoprotein 1 (SPP1; also known as osteopontin) are multifunctional molecules that increase significantly in ovine uterine histotroph during early pregnancy; however, little is known about their relationship and synergistic effects on conceptus development. Therefore, we conducted in vitro experiments using our established ovine trophectoderm cell line (oTr1) isolated from Day 15 ovine conceptuses to determine their migratory and adhesive responses to individual and combined effects of arginine and recombinant SPP1 (rSPP1) that contains an Arg-Gly-Asp (RGD) binding sequence. Migration and adhesion of oTr1 cells were significantly stimulated by rSPP1, whereas arginine alone only induced a significant increase in cell migration. However, the combination of arginine and rSPP1 had an additive effect on migration, and a synergistic effect on adhesion of oTr1 cells. Those cooperative effects of arginine and SPP1 were mediated by focal adhesion assembly-MTORC2-cytoskeletal reorganization and MAPK pathways. Collectively, results suggest that arginine and SPP1 in histotroph affect cellular events required for rapid elongation of ovine conceptuses during the peri-implantation period of pregnancy. PMID- 27512153 TI - Estrogenic Compounds Impair Primordial Follicle Formation by Inhibiting the Expression of Proapoptotic Hrk in Neonatal Rat Ovary. AB - Exposure to endocrine-disrupting chemicals (EDCs) during fetal and neonatal periods can have toxic effects that are irreversible and last a lifetime. However, the mechanism underlying this phenomenon is still unknown. Here, we show the effect of 17alpha-ethynyl estradiol (EE) on the development of the primordial follicle during early ovarian development in female rats. Microarray analysis revealed the down-regulation of Hrk, an activator of apoptosis, in neonatal ovaries exposed to EE. Real-time PCR analysis also showed a decrease of Hrk mRNA expression in ovaries treated with EE both in vitro and in neonatal rats. An immunostaining assay showed that HRK protein and cleaved caspase 3 colocalize in the oocytes at Postnatal Day 1 (PND1). The EE-exposed ovaries had a reduced number of oocytes positive for TUNEL staining compared to control ovaries at PND1. Abnormal follicle formation of EE-exposed ovaries was observed at PND7 and PND21. A TUNEL staining assay revealed that Hrk depletion reduced the number of apoptotic oocytes. In addition, down-regulation of Hrk mRNA expression was observed in ovaries treated with other estrogenic chemicals. We propose a model in which EE inhibits oocyte apoptosis in the neonatal ovary by suppressing the expression of Hrk, thereby disrupting follicle formation and ovary function. PMID- 27512154 TI - Changes in Myeloid Lineage Cells in the Uterus and Peripheral Blood of Dairy Heifers During Early Pregnancy. AB - Establishment of pregnancy requires interaction between the developing conceptus and the uterine mucosal immune system. Myeloid lineage cells (macrophages and dendritic cells) are key mediators of pregnancy in rodents and humans but relatively little is known regarding their role and distribution during early pregnancy in ruminants. We tested the hypothesis that myeloid lineage cell number, distribution, and function are altered during early pregnancy in dairy heifers. Dairy heifers were inseminated using sperm from a single bull (Day 0), and uteri and blood were collected at slaughter on Days 17 and 20 of pregnancy to investigate the response of myeloid lineage cells to the presence of a conceptus. Responses were compared to noninseminated heifers on Day 17 of the estrous cycle. Peripheral blood and uterine-derived immune cells were isolated magnetically and examined using flow cytometry. Immunohistochemical analysis was used to evaluate the spatial distribution of myeloid lineage cells in the endometrium and quantitative polymerase chain reaction was conducted to quantify abundance of mRNA transcripts associated with myeloid lineage cell function. Transcripts for major histocompatibility complex (MHC) II, cluster of differentiation (CD) 80, CD86, CD163, and indoleamine 2,3-dioxygenase (IDO) 1 were greater in endometrium of pregnant compared to cyclic heifers. Immunofluorescence analysis revealed increased labeling for MHCII and SIRPA in pregnant compared to cyclic heifers. There were approximately 50% more CD14+CD11c+ cells in the peripheral circulation of pregnant compared to cyclic heifers. A greater number of myeloid lineage cells were observed during early pregnancy, and this increase was most pronounced in and around the shallow glands. Furthermore, expression of molecules associated with a tolerogenic or alternatively activated phenotype of these cells also increased in pregnant heifers. The results support the hypothesis that myeloid lineage cells with a tolerogenic phenotype are involved in establishment of pregnancy in dairy heifers. PMID- 27512155 TI - Transplacental transfer of essential thrombocythemia in monozygotic twins. PMID- 27512156 TI - Total Radiosynthesis: Thinking outside "the box". AB - The logic of total synthesis transformed a stagnant state of medicinal and synthetic organic chemistry when there was a paucity of methods and reagents to synthesize drug molecules and/or natural products. Molecular imaging by positron emission tomography (PET) is now experiencing a renaissance in the way radiopharmaceuticals for molecular imaging are synthesized, however, a paradigm shift is desperately needed in the discovery pipeline to accelerate in vivo imaging studies. A significant challenge in radiochemistry is the limited choice of labeled reagents (or building blocks) available for the synthesis of novel radiopharmaceuticals with the most commonly used short-lived radionuclides carbon 11 (11C; half-life ~20 minutes) and fluorine-18 (18F; half-life ~2 hours). In fact, most drugs cannot be labeled with 11C or 18F due to a lack of efficient and diverse radiosynthetic methods. In general, routine radiopharmaceutical production relies on the incorporation of the isotope at the last or penultimate step of synthesis, ideally within one half-life of the radionuclide, to maximize radiochemical yields and specific activities thereby reducing losses due to radioactive decay. Reliance on radiochemistry conducted within the constraints of an automated synthesis unit ("box") has stifled the exploration of multi-step reactions with short-lived radionuclides. Radiopharmaceutical synthesis can be transformed by considering logic of total synthesis to develop novel approaches for 11C- and 18F-radiolabeling complex molecules via retrosynthetic analysis and multi-step reactions. As a result of such exploration, new methods, reagents and radiopharmaceuticals for in vivo imaging studies are discovered. A new avenue to develop radiotracers that were previously unattainable due to the lack of efficient radiosynthetic methods is necessary to work towards our ultimate, albeit impossible goal - the concept we term total radiosynthesis - to radiolabel virtually any molecule. As with the vast majority of drugs, most radiotracers also fail, therefore expeditious evaluation of tracers in preclinical models prior to optimization or derivatization of the lead molecules/drugs is necessary. Furthermore the exact position of the 11C and 18F radionuclide in tracers is often critical for metabolic considerations, and flexible methodologies to introduce the radiolabel are needed. Using the principles of total synthesis our laboratory and others have shown that multi-step radiochemical reactions are indeed suitable for preclinical and even clinical use. As the goal of total synthesis is to be concise, we have also simplified the syntheses of radiopharmaceuticals. We are presently developing new strategies via [11C]CO2 fixation which has enabled library radiosynthesis as well as labeling non activated arenes using [18F]fluoride via iodonium ylides. Both of which have proven to be suitable for human PET imaging. We concurrently utilize state-of-the art automation technologies including microfluidic flow chemistry and rapid purification strategies for radiopharmaceutical production. In this account we highlight how total radiosynthesis has impacted our radiochemistry program, with prominent examples from others, focusing on its impact towards preclinical and clinical research studies. PMID- 27512157 TI - Comparison of the Multiple Reaction Monitoring and Enhanced Product Ion Scan Modes for Confirmation of Stilbenes in Bovine Urine Samples Using LC-MS/MS QTRAP(r) System. AB - In accordance with Commission Decision 2002/657/EC, confirmatory methods for the detection of prohibited substances should comply with specific requirements, including the criteria for confirmation. Two strategies: multiple reaction monitoring (MRM) and enhanced product ion (EPI) scanning functions were compared for confirming the anabolic compounds from synthetic stilbenes group in bovine urine samples. In the research, twenty samples fortified at the Recommended Concentration (RC) of 1 ug L-1 with diethylstilbestrol, dienestrol and hexestrol were analyzed by liquid chromatography-tandem mass spectrometry on a QTRAP 5500 instrument. The analytical procedure, validated in accordance with the Commission Decision 2002/657/EC, used in the official control of hormones in Poland was applied. The validation parameters were in agreement with 2002/657/EC performance criteria. The effectiveness of MRM and EPI scanning modes for confirmation purposes was evaluated based on the percentage of the results confirmed. In all urine samples recorded in the MRM mode, the confirmation criteria (retention time, relative intensities between transitions) have been fulfilled. The presence of stilbenes in all urine samples using EPI scan mode was confirmed too as evidenced by a good matching of stilbenes spectra in the samples to the reference spectra with critical match factor above 0.7. The results of the research show that EPI scanning function provides the same effectiveness for confirmation of banned compounds as the mostly used MRM scan mode and can be an additional tool to confirm the doubtful case results in the analysis of hormones residues, even at such low concentration levels. PMID- 27512158 TI - Transporting critically Ill patients: Look before you leap! PMID- 27512160 TI - Comparative assessment of ProSealTM laryngeal mask airway intervention versus standard technique of endotracheal extubation for attenuation of pressor response in controlled hypertensive patients. AB - BACKGROUND AND AIMS: Swapping of the endotracheal tube with laryngeal mask airway (LMA) before emergence from anaesthesia is one of the methods employed for attenuation of pressor response at extubation. We decided to compare the placement of ProSealTM LMA (PLMA) before endotracheal extubation versus conventional endotracheal extubation in controlled hypertensive patients scheduled for elective surgeries under general anaesthesia. METHODS: Sixty consenting adult patients were randomly allocated to two groups of thirty each; Group E in whom extubation was performed using standard technique and Group P in whom PLMA was inserted before endotracheal extubation (Bailey manoeuvre). The primary outcome parameter was heart rate (HR). The secondary outcomes were systolic, diastolic and mean blood pressure (MBP), electrocardiogram, oxygen saturation and end-tidal carbon dioxide. Two-tailed paired Student's t-test was used for comparison between the two study groups. The value of P < 0.05 was considered as statistically significant. RESULTS: The patient characteristics, demographic data and surgical procedures were comparable in the two groups. A statistically significant decrease was observed in HR in Group P as compared to Group E. Secondary outcomes such as systolic, diastolic and MBP depicted a statistically insignificant difference. CONCLUSION: Bailey manoeuvre was not effective method to be completely relied upon during extubation when compared to standard extubation. PMID- 27512159 TI - Inter-hospital and intra-hospital patient transfer: Recent concepts. AB - The intra- and inter-hospital patient transfer is an important aspect of patient care which is often undertaken to improve upon the existing management of the patient. It may involve transfer of patient within the same facility for any diagnostic procedure or transfer to another facility with more advanced care. The main aim in all such transfers is maintaining the continuity of medical care. As the transfer of sick patient may induce various physiological alterations which may adversely affect the prognosis of the patient, it should be initiated systematically and according to the evidence-based guidelines. The key elements of safe transfer involve decision to transfer and communication, pre-transfer stabilisation and preparation, choosing the appropriate mode of transfer, i.e., land transport or air transport, personnel accompanying the patient, equipment and monitoring required during the transfer, and finally, the documentation and handover of the patient at the receiving facility. These key elements should be followed in each transfer to prevent any adverse events which may severely affect the patient prognosis. The existing international guidelines are evidence based from various professional bodies in developed countries. However, in developing countries like India, with limited infrastructure, these guidelines can be modified accordingly. The most important aspect is implementation of these guidelines in Indian scenario with periodical quality assessments to improve the standard of care. PMID- 27512161 TI - Post-operative hypertension, a surrogate marker of the graft function and predictor of survival in living donor liver transplant recipients: A retrospective study. AB - BACKGROUND AND AIMS: De novo hypertension (HTN) in liver transplantation recipients is a known entity. We investigated haemodynamic behaviour after a liver transplant to see if it can predict survival to discharge from the hospital. METHODS: electronic records of Haemodynamic parameters and laboratory investigations of 95 patients of living donor liver transplant (LDLT) were retrospectively analysed. RESULTS: Twenty-three patients were operated for acute liver failure (ALF) and 72 patients for chronic liver disease (CLD). Eight patients of CLD and four of ALF did not survive. CLD patients had statistically significant rise in systolic blood pressure from the post-operative day (POD) 1 to POD 4 and diastolic blood pressure (DBP) from POD 3 to POD 6. Heart rate (HR) significantly decreased from POD 3 to POD 5. Haemodynamic parameters returned to baseline values within 20 days. Diastolic HTN had a positive predictive value of 100% for survival with 100% sensitivity and specificity. Systolic HTN had a positive predictive value of 100% for survival (sensitivity-89%, specificity 100%). ALF patients had a significant decrease in HR from POD 2 to POD 10. Bradycardia (HR <=60/min) had a positive predictive value of 100% for survival with a sensitivity of 45% and 58% in CLD and ALF, respectively, with a specificity of 100% in both the groups. Non-survivors had no significant change in haemodynamics. In CLD group, International Normalised Ratio had statistically significant, strong negative correlation with DBP. CONCLUSION: Haemodynamic pattern of recovery may be used for predicting survival to discharge after LDLT. PMID- 27512162 TI - A comparative study of two techniques (electrocardiogram- and landmark-guided) for correct depth of the central venous catheter placement in paediatric patients undergoing elective cardiovascular surgery. AB - BACKGROUND AND AIMS: The complications of central venous catheterisation can be minimized by ensuring catheter tip placement just above the superior vena cava right atrium junction. We aimed to compare two methods, using an electrocardiogram (ECG) or landmark as guides, for assessing correct depth of central venous catheter (CVC) placement. METHODS: In a prospective randomised study of sixty patients of <12 years of age, thirty patients each were allotted randomly to two groups (ECG and landmark). After induction, central venous catheterisation was performed by either of the two techniques and position of CVC tip was compared in post-operative chest X-ray with respect to carina. Unpaired t test was used for quantitative data and Chi-square test was used for qualitative data. RESULTS: In ECG group, positions of CVC tip were above carina in 12, at carina in 9 and below carina in 9 patients. In landmark group, the positions of CVC tips were above carina in 10, at carina in 4 and below carina in 16 patients. Mean distance of CVC tip in ECG group was 0.34 +/- 0.23 cm and 0.66 +/- 0.35 cm in landmark group (P = 0.0001). Complications occurred in one patient in ECG group and in nine patients in landmark group (P = 0.0056). CONCLUSION: Overall, landmark-guided technique was comparable with ECG technique. ECG-guided technique was more precise for CVC tip placement closer to carina. The incidence of complications was more in the landmark group. PMID- 27512163 TI - Anaesthesia and intensive care for simultaneous liver-kidney transplantation: A single-centre experience with 12 recipients. AB - BACKGROUND AND AIMS: The perioperative management of patients presenting for simultaneous liver and kidney transplantation (SLKT) is a complex process. We analysed SLKTs performed in our institution to identify preoperative, intraoperative and post-operative challenges encountered in the management. METHODS: We retrospectively studied the case records of 12 patients who underwent SLKT between 2009 and 2014 and analysed details of pre-operative evaluation and optimisation, intraoperative anaesthetic management and the implications of use of perioperative continuous renal replacement therapy (CRRT) and the post operative course of these patients. RESULTS: Of the total 12 cases, 4 were under 16 years of age. The indications for SLKT were primary hyperoxaluria (5), congenital hepatic fibrosis with polycystic kidney disease (2), ethanol-related end-stage liver disease (ESLD) with hepatorenal syndrome type 1 (1). Four patients had ESLD with end-stage renal disease due to other causes. Six recipients received live donor grafts and 6 patients received cadaveric grafts. Seven patients received intraoperative CRRT. Mean duration of surgery was 12.5 h. Cardiac output monitors used were trans-oesophageal echocardiogram (2), pulmonary artery catheter (1) and pulse contour cardiac output monitor (3). There was 1 sepsis-related mortality on 7(th) post-operative day. CONCLUSION: A thorough pre operative evaluation and optimisation, knowledge and anticipation of potential problems, and meticulous intraoperative fluid management guided by appropriate monitoring and use of CRRT when needed can help in achieving successful outcomes. PMID- 27512164 TI - Ultrasound-guided femoro-sciatic nerve block for post-operative analgesia after below knee orthopaedic surgeries under subarachnoid block: Comparison between clonidine and dexmedetomidine as adjuvants to levobupivacaine. AB - BACKGROUND AND AIMS: The advent of ultrasonographic-guided techniques has led to increased interest in femoro-sciatic nerve block (FSNB) for lower limb surgeries. alpha2-agonists have been used recently as adjuvants to local anaesthetics in nerve blocks. We aimed to compare equal doses of clonidine or dexmedetomidine as an adjuvant to levobupivacaine in FSNB for post-operative analgesia. METHODS: Ninety patients scheduled to undergo below knee orthopaedic surgeries under subarachnoid block were divided into three groups: Group LL (n = 30) patients received 38 mL of 0.125% levobupivacaine with 2 mL normal saline, Group LD (n = 30) patients received 38 mL of 0.125% levobupivacaine with 0.5 MUg/kg dexmedetomidine and Group LC (n = 30) received 38 mL of 0.125% levobupivacaine with 0.5 MUg/kg clonidine in saline to make total drug volume of 40 mL. The primary and secondary outcome variables were duration of analgesia and rescue analgesic requirement, verbal rating score respectively. Continuous variables were analysed with analysis of variance or the Kruskal-Wallis test on the basis of data distribution. Categorical variables were analysed with the contingency table analysis and the Fisher's exact test. RESULTS: Duration of analgesia was prolonged with dexmedetomidine (10.17 +/- 2.40 h) and clonidine (7.31 +/- 1.76 h) as compared to control (4.16 +/- 1.04 h, P = 0.00). Significantly lower pain scores were observed in dexmedetomidine group as compared to clonidine up to 8 h post-operatively. CONCLUSION: Equal doses of clonidine or dexmedetomidine added to levobupivacaine prolonged the duration of analgesia, decreased requirement of rescue analgesia. Dexmedetomidine delays the requirement of rescue analgesics with better pain scores as compared to clonidine. PMID- 27512166 TI - A comparative study of landmark-based topographic method versus the formula method for estimating depth of insertion of right subclavian central venous catheters. AB - BACKGROUND AND AIMS: Subclavian central venous catheterisation (CVC) is employed in critically ill patients requiring long-term central venous access. There is no gold standard for estimating their depth of insertion. In this study, we compared the landmark topographic method with the formula technique for estimating depth of insertion of right subclavian CVCs. METHODS: Two hundred and sixty patients admitted to Intensive Care Unit requiring subclavian CVC were randomly assigned to either topographic method or formula method (130 in each group). Catheter tip position in relation to the carina was measured on a post-procedure chest X-ray. The primary endpoint was the need for catheter repositioning. Mann-Whitney test and Chi-square test was performed for statistical analysis using SPSS for windows version 18.0 (Armonk, NY: IBM Corp). RESULTS: Nearly, half the catheters positioned by both the methods were situated >1 cm below the carina and required repositioning. CONCLUSION: Both the techniques were not effective in estimating the approximate depth of insertion of right subclavian CVCs. PMID- 27512165 TI - Efficacy of magnesium as an adjuvant to bupivacaine in 3-in-1 nerve block for arthroscopic anterior cruciate ligament repair. AB - BACKGROUND AND AIMS: Three-in-one and femoral nerve blocks are proven modalities for postoperative analgesia following anterior cruciate ligament (ACL) reconstruction. The aim of this study was to evaluate the efficacy of magnesium (Mg) as an adjuvant to bupivacaine in 3-in-1 block for ACL reconstruction. METHODS: Sixty patients undergoing arthroscopic ACL reconstruction were randomly allocated to Group I (3-in-1 block with 30 ml of 0.25% bupivacaine preceded by 1.5 ml of intravenous [IV] saline), Group II (3-in-1 block with 30 ml of 0.25% bupivacaine preceded by 1.5 ml of solution containing 150 mg Mg IV) or Group III (3-in-1 block with 30 ml containing 0.25% bupivacaine and 150 mg of Mg as adjuvant preceded by 1.5 ml of IV saline). Post-operatively, patients received morphine when visual analogue scale (VAS) score was >=4. Quantitative parameters were compared using one-way ANOVA and Kruskal-Wallis test and qualitative data were analysed using Chi-square test. RESULTS: Demographics, haemodynamic parameters, intra-operative fentanyl requirement, post-operative VAS scores and total morphine requirement were comparable between groups. Time to first analgesic requirement was significantly prolonged in Group III (789 +/- 436) min compared to Group I (466 +/- 290 min) and Group II (519 +/- 274 min), (P = 0.02 and 0.05). Significantly less number of patients in Group III (1/20) received morphine in the first 6 h post-operatively, compared to Group I (8/20) and Group II (6/20) (P = 0.008 and 0.03). No side effects were observed. CONCLUSION: Mg as an adjuvant to bupivacaine in 3-in-1 block for ACL reconstruction significantly prolongs the time to first analgesic requirement and reduces the number of patients requiring morphine in the immediate post-operative period. PMID- 27512167 TI - The comparative evaluation of safety and efficacy of unilateral paravertebral block with conventional spinal anaesthesia for inguinal hernia repair. AB - BACKGROUND AND AIMS: Unilateral paravertebral block (PVB) as a sole anaesthetic technique is underutilised even in experienced hands. Hence, this study was undertaken regarding the efficacy and safety of PVB and compared with subarachnoid block (SAB) for inguinal hernia repair procedures. METHODS: Sixty three consenting adult male patients scheduled for unilateral inguinal hernia repair were randomly assigned to receive either PVB or SAB (Group P: PVBs at T10 L2 levels, 5 mL of 0.5% bupivacaine at each segment; Group S: SAB at L3-L4 level with 12.5 mg 0.5% of hyperbaric bupivacaine). Primary objective was to compare duration of post-operative analgesia and time to reach discharge criteria (modified Aldrete scores and modified post-anaesthetic discharge scoring [PADS] scores). Secondary objectives were to compare the block characteristics (time required for performing the block, time to surgical anaesthesia, time to ambulation, time to the first analgesic, total rescue analgesic consumption) and adverse effects. Independent Student's t-test was used for continuous data and Pearson Chi-square test for categorical data. P <0.05 was considered as statistically significant. RESULTS: The duration of post-operative analgesia (min) was 384.57 +/- 38.67 in Group P and 194.27 +/- 20.30 in Group S (P < 0.05). Modified PADS scores were significantly higher at 4 h and 6 h (P < 0.0001) in Group P. Time to reach the discharge criteria was early in Group P than Group S. CONCLUSION: PVB provides excellent post-operative analgesic conditions with lesser adverse effects and shorter time to reach the discharge criteria compared to SAB. PMID- 27512168 TI - Failed fibreoptic intubation: 70 degrees rigid nasendoscope and Frova introducer to the rescue. AB - Endotracheal intubation was successfully accomplished with 70 degrees rigid nasendoscope under video guidance in two patients in whom repeated attempts to secure airway with flexible fibreoptic bronchoscope were unsuccessful. Both patients had compromised airway (laryngeal papillomatosis and a huge thyroid swelling) and were uncooperative. Frova intubating introducer was used along with 70 degrees rigid nasendoscope to accomplish tracheal intubation under video guidance. PMID- 27512169 TI - A novel method of airway management in a case of penetrating neck injury. AB - Direct injury to airway is a rare event and also a challenge to anaesthesiologist and surgeon. We present a case report of open tracheal injury with right pneumothorax in a young male following assault with a sharp weapon. In spite of a chest tube in situ, the patient came with collapse of one lung and tachypnoea which required surgical exploration. Lower airway was evaluated by fibre-optic bronchoscopy through the open tracheal wound while he was awake and tracheal tube was passed over the bronchoscope. There was no vascular or oesophageal injury detected. Although there was a pleural tear, there were no signs of injury to lung parenchyma. After evaluation, end to end anastomosis of the trachea was planned, for which orotracheal tube was passed with surgical assistance. Patient was shifted to post-operative high dependency unit and was electively ventilated for 7 days and was later successfully extubated under fibre-optic bronchoscope guidance. PMID- 27512170 TI - A low cost, customised anaesthesia information management system: An evolving process. PMID- 27512171 TI - Intraoperative hyperthermia: Can surgery itself be a cause? PMID- 27512172 TI - Anaesthetic concerns of a pregnant patient with Pott's spine for spine surgery in prone position. PMID- 27512173 TI - Intra-hospital transfer: Human error and safety concerns with improper setting up of a cylinder-based oxygen delivery system. PMID- 27512174 TI - A novel technique for securing supra-glottic airway device to prevent mal positioning. PMID- 27512175 TI - Intraoperative air embolism during hepatectomy. PMID- 27512176 TI - Difficult epidural in a patient with undiagnosed alkaptonuria. PMID- 27512177 TI - Spinal needle with prefilled syringe to prevent medication error: A proposal. PMID- 27512178 TI - Post-operative pneumothorax with subcutaneous emphysema in a pre-eclamptic patient. PMID- 27512179 TI - Erratum: Effect of addition of dexmedetomidine to ropivacaine 0.2% for femoral nerve block in patients undergoing unilateral total knee replacement: A randomised double blind study. AB - [This corrects the article on p. 403 in vol. 60, PMID: 27330202.]. PMID- 27512180 TI - Indian Journal of Dermatology (IJD((r))) gets into the Science Citation Index Expanded (SCIe). PMID- 27512183 TI - Biostatistics Series Module 4: Comparing Groups - Categorical Variables. AB - Categorical variables are commonly represented as counts or frequencies. For analysis, such data are conveniently arranged in contingency tables. Conventionally, such tables are designated as r * c tables, with r denoting number of rows and c denoting number of columns. The Chi-square (chi(2)) probability distribution is particularly useful in analyzing categorical variables. A number of tests yield test statistics that fit, at least approximately, a chi(2) distribution and hence are referred to as chi(2) tests. Examples include Pearson's chi(2) test (or simply the chi(2) test), McNemar's chi(2) test, Mantel-Haenszel chi(2) test and others. The Pearson's chi(2) test is the most commonly used test for assessing difference in distribution of a categorical variable between two or more independent groups. If the groups are ordered in some manner, the chi(2) test for trend should be used. The Fisher's exact probability test is a test of the independence between two dichotomous categorical variables. It provides a better alternative to the chi(2) statistic to assess the difference between two independent proportions when numbers are small, but cannot be applied to a contingency table larger than a two-dimensional one. The McNemar's chi(2) test assesses the difference between paired proportions. It is used when the frequencies in a 2 * 2 table represent paired samples or observations. The Cochran's Q test is a generalization of the McNemar's test that compares more than two related proportions. The P value from the chi(2) test or its counterparts does not indicate the strength of the difference or association between the categorical variables involved. This information can be obtained from the relative risk or the odds ratio statistic which is measures of dichotomous association obtained from 2 * 2 tables. PMID- 27512184 TI - Methodology Series Module 4: Clinical Trials. AB - In a clinical trial, study participants are (usually) divided into two groups. One group is then given the intervention and the other group is not given the intervention (or may be given some existing standard of care). We compare the outcomes in these groups and assess the role of intervention. Some of the trial designs are (1) parallel study design, (2) cross-over design, (3) factorial design, and (4) withdrawal group design. The trials can also be classified according to the stage of the trial (Phase I, II, III, and IV) or the nature of the trial (efficacy vs. effectiveness trials, superiority vs. equivalence trials). Randomization is one of the procedures by which we allocate different interventions to the groups. It ensures that all the included participants have a specified probability of being allocated to either of the groups in the intervention study. If participants and the investigator know about the allocation of the intervention, then it is called an "open trial." However, many of the trials are not open - they are blinded. Blinding is useful to minimize bias in clinical trials. The researcher should familiarize themselves with the CONSORT statement and the appropriate Clinical Trials Registry of India. PMID- 27512182 TI - Pityriasis Rosea: An Update on Etiopathogenesis and Management of Difficult Aspects. AB - Pityriasis rosea (PR) is a benign papulosquamous disorder seen commonly in clinical practice. Despite its prevalence and benign nature, there are still times when this common disorder presents in an uncommon way or course posing diagnostic or management problems for the treating physician. The etiopathogenesis of PR has always been a dilemma, and extensive research is going on to elicit the exact cause. This review focuses mainly on the difficult aspects of this benign common disorder such as etiopathogenesis, atypical manifestations, recurrent cases, differential diagnosis, therapy and pregnancy considerations. Although we could not find a black and white solution to all these problems, we have tried to compile the related literature to draw out some conclusions. PMID- 27512181 TI - Approach to Cutaneous Lymphoid Infiltrates: When to Consider Lymphoma? AB - Cutaneous lymphoid infiltrates (CLIs) are common in routine dermatopathology. However, differentiating a reactive CLI from a malignant lymphocytic infiltrate is often a significant challenge since many inflammatory dermatoses can clinically and/or histopathologically mimic cutaneous lymphomas, coined pseudolymphomas. We conducted a literature review from 1966 to July 1, 2015, at PubMed.gov using the search terms: Cutaneous lymphoma, cutaneous pseudolymphoma, cutaneous lymphoid hyperplasia, simulants/mimics/imitators of cutaneous lymphomas, and cutaneous lymphoid infiltrates. The diagnostic approach to CLIs and the most common differential imitators of lymphoma is discussed herein based on six predominant morphologic and immunophenotypic, histopathologic patterns: (1) Superficial dermal T-cell infiltrates (2) superficial and deep dermal perivascular and/or nodular natural killer/T-cell infiltrates (3) pan-dermal diffuse T-cell infiltrates (4) panniculitic T-cell infiltrates (5) small cell predominant B-cell infiltrates, and (6) large-cell predominant B-cell infiltrates. Since no single histopathological feature is sufficient to discern between a benign and a malignant CLI, the overall balance of clinical, histopathological, immunophenotypic, and molecular features should be considered carefully to establish a diagnosis. Despite advances in ancillary studies such as immunohistochemistry and molecular clonality, these studies often display specificity and sensitivity limitations. Therefore, proper clinicopathological correlation still remains the gold standard for the precise diagnosis of CLIs. PMID- 27512185 TI - Etiopathogenesis and Therapeutic Approach to Adult Onset Acne. AB - Acne vulgaris is usually considered as a skin disorder that primarily affects adolescents reaching a peak at the age of 14-17 years in females and 16-19 years in males. However, recent epidemiologic studies have shown that a significant number of female patients aged >25 years experience acne. As it is regarded as a disease of teenagers, adults are more apprehensive and experience social anxiety. Hence, adult onset acne has become a matter of concern. PMID- 27512186 TI - Heat Shock Protein-70 Expression in Vitiligo and its Relation to the Disease Activity. AB - BACKGROUND: Vitiligo is a progressive depigmenting disorder characterized by the loss of functional melanocytes from the epidermis. The etiopathogenesis of vitiligo is still unclear. Heat shock proteins (HSPs) are prime candidates to connect stress to the skin. HSPs were found to be implicated in autoimmune diseases such as rheumatoid arthritis and other skin disorders as psoriasis. AIM AND OBJECTIVES: The aim of this study was to map the level of HSP-70 in vitiligo lesions to declare its role in the pathogenesis and activity of vitiligo. MATERIALS AND METHODS: The study included thirty patients with vitiligo and 30 age- and sex-matched healthy controls. Vitiligo patients were divided as regards to the disease activity into highly active, moderately active, and inactive vitiligo groups. Skin biopsies were taken from the lesional and nonlesional skin of patients and from the normal skin of the controls. HSP-70 messenger RNA (mRNA) expression was estimated using quantitative real-time polymerase chain reaction. RESULTS: Our analysis revealed a significantly higher expression of HSP-70 mRNA in lesional skin biopsies from vitiligo patients compared to nonlesional skin biopsies from vitiligo patients (P < 0.001) and compared to skin biopsies from healthy controls (P < 0.001). The level of HSP-70 was not found to be correlated with age, sex, or disease duration. The expression of HSP-70 was correlated with the disease activity and patients with active vitiligo showed higher mean HSP-70 level compared to those with inactive disease. CONCLUSIONS: HSP-70 plays a role in the pathogenesis of vitiligo and may enhance the immune response in active disease. PMID- 27512187 TI - A Comparative Study of Two Modalities, 4% Hydroquinone Versus 30% Salicylic Acid in Periorbital Hyperpigmentation and Assessment of Quality of Life Before and After Treatment. AB - BACKGROUND: Periorbital hyperpigmentation (POH) is a common hyperpigmentary problem of the face, which can be psychologically distressing and it can influence an individual's quality of life. However, this condition has received less attention in literature. AIMS AND OBJECTIVES: To study the clinico etiological features and the effect of two therapeutic modalities on the quality of life in patients of POH before and after treatment. MATERIALS AND METHODS: Fifty patients attending the outpatient clinic of Dermatology Department, with clinically evident POH were included. All patients were divided randomly into two groups of 25 each and one group was treated with 4% hydroquinone and another group with 30% salicylic acid for 12 weeks. Assessment with visual analog scale (VAS) was done at 4, 6, and 12 weeks, and outcome of the patients was analyzed statistically. RESULTS: Majority of the cases, i.e. 26 (52%) were in the age group of 20-30 years. Females comprised 74% of the study population. On VAS, most of the patients showed mild improvement (10-30%) at 12 weeks of treatment in both the groups. Separately, both the treatments significantly improved the dermatological life quality index of the patients although there was no significant difference found between the two groups. CONCLUSION: POH is less responsive to standard treatments due to its multifactorial etiology and deposition of melanin in both dermis and epidermis. However, even the mild to moderate improvement in appearance can cause an improvement in the quality of life of the patients. PMID- 27512188 TI - A Comparative Effectiveness Research of Azathioprine and Cyclophosphamide on the Clinical and Serological Response in Pemphigus Vulgaris. AB - CONTEXT: A prospective study was carried out to examine the efficacy of cyclophosphamide and azathioprine in pemphigus vulgaris. AIMS: To compare the clinical and serological effect of azathioprine and cyclophosphamide in pemphigus patients. MATERIALS AND METHODS: Prospective, institutional based study was conducted twenty-one patients of pemphigus vulgaris were initiated on either azathioprine (n = 9) or cyclophosphamide (n = 7) in addition to prednisolone and were evaluated clinically (mucosal and cutaneous severity) and serologically enzyme-linked immunosorbent assay (ELISA) at 0, 3 and 6 months. RESULTS: Azathioprine had a slower onset of action with a statistically significant improvement seen by 6 months (P = 0.016). Cyclophosphamide had a faster onset of action (3 months) though there was no statistical difference in the efficacy between the two at the end of 6 months. The (RonT) was 33.3-44.4% for azathioprine and 28.8-42.9% for cyclophosphamide at 6 months. Though ELISA had a high sensitivity and specificity for diagnosis, as a tool for assessing therapeutic response a significant decrease was seen only till 3 months. This was restricted to Dsg1 for the azathioprine group and both Dsg3 and Dsg1 levels for the cyclophosphamide group. There were two deaths, both in the cyclophosphamide group. CONCLUSIONS: Azathiorpine and cyclophosphamide are equally effective for mucosal and cutaneous disease in pemphigus after 6 months of therapy. Dsg ELISA is useful for diagnosis of pemphigus but is not a useful tool for monitoring response to therapy. PMID- 27512189 TI - Long-lasting Localized Pemphigus Vulgaris without Detectable Serum Autoantibodies Against Desmoglein 3 and Desmoglein 1. AB - Pemphigus vulgaris (PV) is an autoimmune blistering disease elicited by anti desmoglein (DsG) 3 antibody. Although skin lesions tend to be distributed over the entire body, in some patients, they are confined to a restricted area. We report two patients who presented with long-lasting localized PV without detectable anti-DsG antibodies after suffering antibody-positive systemic PV. Initial treatment with prednisolone (PSL) was successful in both patients, but a local relapse occurred on the cheek or lower lip after a reduction in the PSL dose. Biopsy of the localized lesions showed suprabasal acantholysis; no serum DsG antibodies were found. Local immunosuppression therapy was effective in both patients. Based on our findings, we suggest that localized PV without detectable antibodies can develop after systemic PV. PMID- 27512190 TI - Malignant Eccrine Poroma of the Vulva: An Intriguing Case of a Rare Tumor at an Unusual Site. AB - Malignant eccrine poroma is a rare malignancy of the eccrine sweat glands, occurring most frequently on the lower extremities. It affects both sexes equally usually in the 6(th) to 7(th) decade of life. Metastasis to regional lymph nodes may occur in 20% that may be fatal in 60% cases. Its aggressive nature, rarity of occurrence, and unusual presentations make it very important to be evaluated properly by the clinician. We hereby report a case of a 75-year-old female presenting with two exophytic tumors over her vulva with local extension. On histopathological examination, it was diagnosed as malignant eccrine poroma. On magnetic resonance imaging of the pelvic region, metastatic extension in regional lymph nodes was found. She was treated by radical vulvectomy with bilateral inguinal and femoral lymph node dissection followed by radiotherapy. PMID- 27512191 TI - A Report of 10 Individuals with Weathering Nodules and Review of the Literature. AB - Weathering nodules are a benign skin condition that usually present as papules on the helices of patients with significant prior sun exposure. They are easily recognized clinically and blanch upon application of pressure to the adjacent helical rim: a positive blanch sign. We describe the clinical presentation of weathering nodules in 10 patients, nine men and one woman, aging from 38 to 70 (median 59), and their associated risk factors. Eight patients had a history of actinic keratosis, three had a history of nonmelanoma skin cancer, and all patients had increased Sun exposure through outdoor activities. Weathering nodules are rarely mentioned in the literature and may be confused with other cutaneous disorders. Therefore, it is paramount for clinicians to become familiar with weathering nodules and include them in the differential diagnosis of ear nodules. Appropriate diagnosis will help avoid unnecessary biopsies while reassuring the patient that the lesions are benign. PMID- 27512192 TI - Chronic Eosinophilic Leukemia Presenting Predominantly with Cutaneous Manifestations. AB - A 37-year-old male presented with severe oral and genital mucosal ulcers, lichenoid eruption and twenty-nail dystrophy. Systemic examination was normal, except for anemia. On investigations, he was found to have persistently elevated peripheral eosinophilia, absolute eosinophil count >5000/mm(3), bone marrow showing increased eosinophilic precursors, and infiltration by atypical cells. The serum vitamin B12 levels were grossly elevated, and Philadelphia chromosome study was negative. Thus, a diagnosis of chronic eosinophilic leukemia was made. The patient showed excellent response to imatinib mesylate. We are reporting a rare type of leukemia presenting with predominantly cutaneous manifestations. PMID- 27512193 TI - Curious Case of Photo-distributed Verrucae in a Renal Transplant Patient: Report of Three Cases. AB - Viral warts are a common lesion found in patients who have undergone a renal transplant. The occurrence of verrucae also depends on the choice of immunosuppressant and posttransplant time interval. The presence of viral warts only on sun-exposed parts of the body is extremely uncommon and rarely reported. It might also influence the choice of treatment since these warts are often resistant to treatment. PMID- 27512194 TI - Nodulocystic Basal Cell Carcinoma Arising Directly from a Seborrheic Keratosis: A Rare Case Report. AB - Seborrheic keratoses (SKs) are common epidermal tumors composed of benign keratinocytes. Malignant skin tumors including basal cell carcinoma (BCC) rarely arise within SKs. We report a rare case of an 82-year-old man with nodulocystic BCC that appeared at the center of a scaly hyperpigmented SK that had been presented for more than 10 years. It was histologically confirmed that CK19 positive BCC arose directly from the wall of the pseudohorn cyst, a part of the SK. Nodular and/or cystic BCC also rarely arise within SKs while the most common histologic type of BCC within SKs is the superficial type. Careful observation of SKs is important even though it is rarely a background condition for malignant transformation. PMID- 27512195 TI - Drug-induced CD30+ Skin Lesions: Complex Interplay Between Infectious Agents, Human Leukocyte Antigen System and Mast Cells/T Cells. PMID- 27512196 TI - Author's Reply. PMID- 27512197 TI - Late Onset Progressive Symmetric Erythrokeratoderma with Pseudo Ainhum. PMID- 27512198 TI - Dermatosis Neglecta: An Increasingly Recognized Entity with Review of Literature. PMID- 27512199 TI - Clues to Facial Demodicidosis: A Case Illustration. PMID- 27512200 TI - Red and Black Pseudochromhidrosis. PMID- 27512201 TI - Superficial Acral Fibromyxoma. PMID- 27512202 TI - Monomorphic Papillae on Inner Labia and Vulvar Vestibule. PMID- 27512203 TI - Erratum: Interstitial Granulomatous Drug Reaction After Intranasal Desmopressin Administration. AB - [This corrects the article on p. 125 in vol. 61.]. PMID- 27512204 TI - Treatment of Chronic Spontaneous Urticaria with a Single Dose of Omalizumab: A Study of Four Cases. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) has a detrimental effect on patients' emotional and physical quality of life. Omalizumab, an anti immunoglobulin E humanized monoclonal antibody, has been shown to be very effective in the treatment of refractory chronic urticaria patients but may not be an economically viable option for all CSU patients. However, we present a case series where a single dose of omalizumab gave sustained relief of symptoms in patients with CSU, which may be an economical option. AIMS: The aim of this study is to assess the efficacy of a single dose of omalizumab in the treatment of CSU. MATERIALS AND METHODS: Four patients of CSU whose disease was not controlled with four times the licensed dose of tablet fexofenadine 180 mg were exhibited one subcutaneous injection of omalizumab and were followed up at 4 weekly intervals for 24 weeks for Weekly Urticaria Activity Score 7 (UAS7) and Dermatology Life Quality Index (DLQI). RESULTS: A sharp decline in UAS7 and DLQI was documented in 7-10 days. The decline was maintained up to 16 weeks in one case and 20 weeks in the other three cases. Both the scores at the end of the follow-up period of 24 weeks were better than the pre-omalizumab scores. CONCLUSION: The results of this case series indicate the efficacy of a single-dose omalizumab in treating moderate to severe refractory CSU. Further studies are required to identify the minimum frequency of administering omalizumab to effectively control CSU. This would greatly reduce the cost of this novel therapy. PMID- 27512205 TI - Folliculotropic Mycosis Fungoides in an Adolescent: A Rare Case. AB - Folliculotropic mycosis fungoides (FMF) is an uncommon and aggressive form of mycoses fungoides with preferential involvement of head and neck region. Lesions of FMF present as erythematous plaques or papules with follicular prominences, acneiform lesions, cysts, nodules, patches of scarring alopecia, and prurigo-like lesions. The mean age of diagnosis is at 60 years and it is extremely rare in childhood and adolescence. We report a case of a 16-year-old male patient who presented with a 2-month history of an asymptomatic erythematous infiltrated plaque over the forehead. Histological examination was consistent with diagnosis of FMF. He was successfully treated with local electron beam therapy. PMID- 27512206 TI - Co-occurrence of Erythrosis Pigmentosa Mediofacialis and Erythromelanosis Follicularis Faciei et Colli Associated with Keratosis Pilaris in an Adolescent Female. AB - Erythromelanosis follicularis faciei et colli (EFFC) is a rare disease characterized by a triad of reddish-brown pigmentation, erythema and follicular papules localized on face and neck and is usually described in males. Erythrosis pigmentosa mediofacialis (also known as Brocq or erythrosis pigmentosa peribuccalis) is a similar disorder of the mediofacial area but with female predominance. We report a case of simultaneous occurrence of erythrosis pigmentosa peribuccalis and EFFC associated with keratosis pilaris in an adolescent female. PMID- 27512207 TI - Primary Cutaneous Histoplasmosis in an Immunocompetent Host from a Nonendemic Area. AB - A 32-year-old male presented to Dermatology outpatient Department with complaints of a single nonhealing ulcer on his right thigh. This lesion was there for the last 1? months. It had begun as a small nodule and increased up to the present size of 3 cm with an oozing and ulcerated surface and thickened everted margins. The systemic investigations were normal which included hemogram, biochemistry, including liver and renal function tests, chest X-ray, ultrasonography of abdomen, computed tomography of the thorax, and abdomen. Skin biopsy revealed multiple rounds to oval spores with surrounding halo intracellularly as well as extracellularly. A diagnosis of deep fungal infection as histoplasmosis was made and confirmed on culture. PMID- 27512208 TI - Congenital Erythropoietic Porphyria with Undescended Testis. AB - Hereditary porphyrias are a group of metabolic disorders of heme biosynthesis pathway that are characterized by acute neurovisceral symptoms, skin lesions, or both. Congenital erythropoietic porphyria (CEP) is an extremely rare disease with a mutation in the gene that codes for uroporphyrinogen III synthase leading to accumulation of porphyrin in different tissues and marked cutaneous photosensitivity. We report a case of CEP with infancy onset blistering, photosensitivity, red colored urine, and teeth along with scarring. Examination revealed an undescended testis of the left side. Mutation analysis revealed mutation in the uroporphyrinogen III synthase gene (UROS) resulting in c. 56 A > G (Tyr19Cys). The presence of undescended testis with a rare mutation in a case of CEP which itself is an extremely rare condition make the case interesting. PMID- 27512209 TI - Adult Onset of Xanthelasmoid Mastocytosis: Report of a Rare Entity. AB - Xanthelasmoid or pseudoxanthomatous mastocytosis is an extremely rare variant of diffuse cutaneous mastocytosis. Herein, we describe an adult male with cutaneous mastocytosis showing multiple widespread yellowish ovoid papules like eruptive xanthoma. A 60-year-old male visited our outpatient clinic with a 1-year history of generalized yellowish, ovoid, and skin color papular eruption located on the trunk, groin, extremities, with the modest pruritus. Vital signs were stable, and Darier's sign was negative. No other subjective and objective signs were detected during the examination. No abnormality was detected in his diagnostic laboratory tests. Skin biopsy was taken, and histopathologic examination revealed proliferation of mast cells with ovoid and spindle nuclei with distinct cytoplasm borders around the capillaries, which was compatible with mastocytosis. Antihistamine was prescribed for pruritus control which was successful, but eruptions were persistent, and even 1-year phototherapy was not useful. PMID- 27512210 TI - Distant Skin Metastases from Carcinoma Buccal Mucosa: A Rare Presentation. AB - Cancer of the oral cavity makes up approximately 30% of all head and neck region tumors. Skin metastasis is rare with an incidence ranging between 0.7% and 2.4%. Skin metastasis usually occurs in the neck, scalp, and over the skin near the primary site. We report a patient with carcinoma left buccal mucosa who presented with distant skin metastases to the right side chest wall. PMID- 27512211 TI - Dermatopathia Pigmentosa Reticularis: Report of a New Cases and Literature Review. AB - Dermatopathia pigmentosa reticularis (DPR) is a very rare autosomal dominant ectodermal dysplasia caused by mutations in keratin 14 and characterized by the triad of generalized reticulate hyperpigmentation, nonscarring alopecia, and onychodystrophy. We report two Saudi brothers with DPR that had normal hair shafts, as assessed by scanning and transmission electron microscopy. PMID- 27512212 TI - Kindler's Syndrome: A Tale of Two Siblings. AB - Kindler's syndrome (KS) is a rare inherited skin disease characterized by acral blistering, photosensitivity, progressive poikiloderma, and cutaneous atrophy along with different types of mucosal involvement. We hereby report KS in two siblings. The case is being reported for its rarity and for emphasizing the importance of considering this condition in the differential diagnosis of disorders that may cause blistering, cutaneous atrophy, and/or poikilodermatous skin changes. Besides, the presentation of the disease in two of the members of the same family makes the case even more interesting. PMID- 27512213 TI - Current state of orthopedic education in India. PMID- 27512214 TI - Nonvascularized fibular grafting in nonunion of femoral neck fracture: A systematic review. AB - Nonunion of femoral neck fractures following primary fixation and neglected femoral neck fracture in young adults is a challenging task. Every effort should be directed toward hip joint salvage in these patients. Among different available options of hip salvage, nonvascularized fibular graft (NVFG) osteosynthesis is simple, easy to perform, and a successful technique. In this review, the available literature on NVFG in neglected and nonunion femoral neck fractures has been analyzed. After review of 15 articles on NVFG, the average nonunion rate was estimated to be 7.86% (range 0-31%). Six articles that evaluated the preoperative and postoperative osteonecrosis reported improvement in 50% patients. The clinical and/or functional outcome was good to excellent in 56-96% patients following fibular osteosynthesis. Few complications such as coxa vara deformity, limb shortening, and intraarticular penetration of the graft or hardware have been reported. However, there are minimal donor site morbidities such as mild ankle pain, transient loss of toe flexors and extensors and transient lateral popliteal nerve palsy. PMID- 27512215 TI - Total enbloc spondylectomy for metastatic high grade spinal tumors: Early results. AB - BACKGROUND: High grade metastatic spinal tumors are most common and are invasive. These patients can succumb to disease progression if not treated timely. Although considered as invasive and morbid, total enbloc spondylectomy (TES) in selected cases has better survival rates. The authors describe the results of TES for high grade metastatic spinal tumors. MATERIALS AND METHODS: Five patients (four females and one male) underwent TES for solitary metastatic vertebral lesion between November 2012 and January 2014. These patients presented to us with spinal instability, unrelenting severe spinal pain and/or with severe progressive radiculopathy. Average age was 46.2 years (range 39-62 years). After complete investigations, computed tomography scan, magnetic resonance imaging scan and positron emission tomography (PET) scan, it was confirmed that these patients had high grade solitary vertebral metastatic tumor. RESULTS: Average duration of followup was 18 months (range 16-20 months). The average preoperative visual analog scale score of 9.4 (range 9-10) improved to 2 (range 1-4) at last followup. Average blood loss was 1440 mL (range 1000-2000 mL). Average duration of surgery was 198 min (range 180-240 min). Significant pain relief was noticed in each patient in the immediate postoperative period and during followups. These patients attained complete functional activities of daily living with in a month. The imaging showed implants in situ, no recurrence of tumor, and no activity on PET scan at the final followup. CONCLUSION: The present series shows favorable short term results of TES for solitary, metastatic, high grade vertebral body tumors by a team approach. PMID- 27512216 TI - Management of osteonecrosis of the femoral head: A novel technique. AB - BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a debilitating disease in orthopedics, frequently progressing to femoral head collapse and osteoarthritis. It is thought to be a multifactorial disease. ONFH ultimately results in femoral head collapse in 75-85% of untreated patients. Total hip arthroplasty (THA) yields satisfactory results in the treatment of the end stage of the disease. However, disease typically affects males between the ages of 20 and 40 years and joint replacement is not the ideal option for younger patients. Recently, mesenchymal stem cells and platelet rich plasma (PRP) have been used as an adjunct to core decompression to improve clinical success in the treatment of precollapse hips. MATERIALS AND METHODS: A prospective study of 40 hips in 30 patients was done. There were 19 males and 11 females with a mean age 36.7 +/- 6.93 years. The indication for the operation was restricted primarily to modified Ficat stages IIb and III. 16 hips (40%) had stage IIb and 24 hips (60%) had stage III ONFH. The period of follow up ranged between 36-50 months with a mean 41.4 +/ 3.53 months. All patients were assessed clinically during pre- and post operative period according to the Harris Hip Score (HHS), Visual Analog Score (VAS) and radiologically by X-rays. Magnetic resonance imaging (MRI) was done preoperatively to confirm the diagnosis and every 6 months postoperatively for assessment of healing. The operative procedure include removal of necrotic area with drilling then the cavity was filled with a composite of bone graft mixed with PRP. RESULTS: The mean HHS improved from 46.0 +/- 7.8 preoperatively to 90.28 +/- 19 at the end of followup (P < 0.0001). The mean values of VAS were 78 +/- 21 and 35 +/- 19 at preoperatively period and final followup, respectively, with an average reduction of 43 points. CONCLUSION: We found that the use of PRP with collagen sheet can increase the reparable capacity after drilling of necrotic segment in stage IIb and III ONFH. PMID- 27512217 TI - Osteosynthesis of ununited femoral neck fracture by internal fixation combined with iliac crest bone chips and muscle pedicle bone grafting. AB - BACKGROUND: Ununited femoral neck fracture is seen commonly in developing countries due to delayed presentation or failure of primary internal fixation. Such fractures, commonly present with partial or total absorption of femoral neck, osteonecrosis of femoral head in 8-30% cases with upward migration of trochanter posing problem for osteosynthesis, especially in younger individuals. Several techniques for treatment of such conditions are described like osteotomies or nonvascularied cortical or cancellous bone grafting provided varying degrees of success in terms of fracture union but unsatisfactory long term results occurred due to varying incidence of avascular necrosis (AVN) of femoral head. Moreover, in presence of AVN of femoral head neither free fibular graft nor cancellous bone graft is satisfactory. The vascularied bone grafting by deep circumflex iliac artery based on iliac crest bone grafting, free vascularied fibular grafting and muscle pedicle periosteal grafting showed high incidence of success rate. Osteosynthesis is the preferred treatment of choice in ununited femoral neck fracture in younger individuals. MATERIALS AND METHODS: Of the 293 patients operated during the period from June 1977 to June 2009, 42 were lost to followup. Seven patients with gluteus medius muscle pedicle bone grafting (MPBG) were excluded. Thus, out of 244 patients, 208 (85.3%) untreated nonunion and 36 (14.7%) following failure of primary internal fixation were available for studies. Time interval between the date of injury and operation in untreated nonunion cases was mean 6.5 months and in failed internal fixation cases was mean 11.2 months. Ages of the patients varied from 16 to 55 years. Seventy patients had partial and 174 had subtotal absorption of the femoral neck. Evidence of avascular necrosis (AVN) femoral head was found histologically in 135 (54.3%) and radiologically in 48 (19.7%) patients. The patients were operated by open reduction of fracture, cannulated hip screw fixation, iliac crest bone chips and quadratus femoris MPBG. RESULTS: The mean followup is 12.5 years (range 3-35). The union of fractures occurred in 202 (82.8%), delayed union in 18 (7.3%), and established nonunion in 24 (9.8%) patients. Full weight bearing was permitted at 16-22 weeks after union of fractures. Mean Harris hip score at the longest followup was 85.5. Among the complications, superficial wound infection occurred in 20 (8.2%), deep infection in seven (2.9%), and coxa vara in 39 (16%) patients. Preoperative radiodensity of femoral head disappeared mostly after the union of fracture whereas fresh radiodensity of femoral head appeared in 20 (8%) patients; nine (45%) of them developed segmental collapse. CONCLUSION: Ununited femoral neck fractureis characterized by absorption of femoral neck, posterior cortical defect, smoothening and overriding of fracture surfaces with intervening fibrous tissues associated with or without AVN of femoral head. The above method of osteosynthesis rectified the above pathology and provided satisfactory results with union of fractures in 90.1% patients at long term followup. PMID- 27512218 TI - Reverse distal femoral locking compression plate a salvage option in nonunion of proximal femoral fractures. AB - BACKGROUND: When primary fixation of proximal femoral fractures with implants fails, revision osteosynthesis may be challenging. Tracts of previous implants and remaining insufficient bone stock in the proximal femur pose unique problems for the treatment. Intramedullary implants like proximal femoral nail (PFN) or surface implants like Dynamic Condylar Screw (DCS) are few of the described implants for revision surgery. There is no evidence in the literature to choose one implant over the other. We used the reverse distal femur locking compression plate (LCP) of the contralateral side in such cases undergoing revision surgery. This implant has multiple options of fixation in proximal femur and its curvature along the length matches the anterior bow of the femur. We aimed to evaluate the efficacy of this implant in salvage situations. MATERIALS AND METHODS: Twenty patients of failed primary proximal femoral fractures who underwent revision surgery with reverse distal femoral locking plate from February 2009 to November 2012 were included in this retrospective study. There were 18 subtrochanteric fractures and two ipsilateral femoral neck and shaft fractures, which exhibited delayed union or nonunion. The study included 14 males and six females. The mean patient age was 43.6 years (range 22-65 years) and mean followup period was 52.1 months (range 27-72 months). Delayed union was considered when clinical and radiological signs of union failed to progress at the end of four months from initial surgery. RESULTS: All fractures exhibited union without any complications. Union was assessed clinically and radiologically. One case of ipsilateral femoral neck and shaft fracture required bone grafting at the second stage for delayed union of the femoral shaft fracture. CONCLUSIONS: Reverse distal femoral LCP of the contralateral side can be used as a salvage option for failed fixation of proximal femoral fractures exhibiting nonunion. PMID- 27512219 TI - Arthroscopic resection of the distal clavicle in osteoarthritis of the acromioclavicular joint. AB - BACKGROUND: Symptomatic acromioclavicular joint (ACJ) lesions are a common cause of shoulder complaints that can be treated successfully with both conservative and surgical methods. There are several operative techniques, including both open and arthroscopic surgery, for excising the distal end of the clavicle. Here, we present a new modified arthroscopic technique for painful osteoarthritis of the ACJ and evaluate its clinical outcomes. Our hypothesis was that 4- to 7-mm resection of the distal clavicle in an en bloc fashion would have several advantages, including no bony remnants, maintenance of stability of the ACJ, and reduced prevalence of heterotopic ossification, in addition to elimination of the pathologic portion of the distal clavicle. MATERIALS AND METHODS: 20 shoulders of 20 consecutive patients with painful and isolated osteoarthritis of the ACJ who were treated by arthroscopic en bloc resection of the distal clavicle were included in the study. There were 10 males and 10 females with an average age of 56 years (range 42-70 years). The mean duration of followup was 6 years and 2 months (range 4-8 years 10 months). The results were evaluated using the University of California Los Angeles (UCLA) shoulder rating score. RESULTS: The overall UCLA score was 13.7 preoperatively, which improved to 33.4 postoperatively. All subscores were improved significantly (P < 0.001). There were no specific complications at the latest followup. CONCLUSION: It is critical in this procedure to resect the distal clavicle evenly from superior to inferior in an en bloc fashion without any small bony remnants and to preserve the capsule and acromioclavicular ligament superoposteriorly. This arthroscopic procedure is a reliable and reproducible technique for painful osteoarthritis of the ACJ lesions in active patients engaged in overhead throwing sports and heavy labor. PMID- 27512220 TI - Assessment of survival rates compared according to the Tamai and Yamano classifications in fingertip replantations. AB - BACKGROUND: The fingertip is the most frequently injured and amputated segment of the hand. There are controversies about defining clear indications for microsurgical replantation. Many classification systems have been proposed to solve this problem. No previous study has simultaneously correlated different classification systems with replant survival rate. The aim of the study is to compare the outcomes of fingertip replantations according to Tamai and Yamano classifications. MATERIALS AND METHODS: 34 consecutive patients who underwent fingertip replantation between 2007 and 2014 were retrospectively reviewed with respect to the Tamai and Yamano classifications. The medical charts from record room were reviewed. The mean age of the patients was 36.2 years. There were 30 men and 4 women. All the injuries were complete amputations. Of the 34 fingertip amputations, 19 were in Tamai zone 2 and 15 were in Tamai zone 1. When all the amputations were grouped in reference to the Yamano classification, 6 were type 1 guillotine, 8 were type 2 crush and 20 were type 3 crush avulsions. RESULTS: Of the 34 fingertips, 26 (76.4%) survived. Ten (66.6%) of 15 digits replanted in Tamai zone 1 and 16 (84.2%) of 19 digits replanted in Tamai zone 2 survived. There were no replantation failures in Yamano type 1 injuries (100%) and only two failed in Yamano type 2 (75%). Replantation was successful in 14 of 20 Yamano type 3 injuries, but six failed (70%). The percentage of success rates was the least in the hybridized groups of Tamai zone 1-Yamano type 2 and Tamai zone 1 Yamano type 3. Although clinically distinct, the survival rates between the groups were not statistically significantly different. CONCLUSIONS: The level and mechanism of injury play a decisive role in the success of fingertip replantation. Success rate increases in proximal fingertip amputations without crush injury. PMID- 27512221 TI - Anterior cervical discectomy and fusion for noncontiguous cervical spondylotic myelopathy. AB - BACKGROUND: Noncontiguous cervical spondylotic myelopathy (CSM) is a special degenerative disease because of the intermediate normal level or levels between supra and infraabnormal levels. Some controversy exists over the optimal procedure for two noncontiguous levels of CSM. The study was to evaluate the outcomes of the anterior cervical discectomy and fusion (ACDF) with zero-profile devices for two noncontiguous levels of CSM. MATERIALS AND METHODS: 17 consecutive patients with two noncontiguous levels of CSM operated between December 2009 and August 2012 were included in the study. There were 12 men and 5 women with a mean age of 60.7 years (range 45-75 years). Involved disc levels were C3/4 and C5/6 in 11 patients and C4/5 and C6/7 in six patients. Preoperative plain radiographs, computed tomography (CT) with 3-D reconstruction and magnetic resonance imaging (MRI) of the cervical spine were taken in all patients. All radiographs were independently evaluated by 2 spine surgeons and 1 radiologist. The outcomes were assessed by the average operative time, blood loss, Japanese Orthopedic Association (JOA) score, improvement rate, neck dysfunction index (NDI), swallowing quality of life (SWAL-QOL) score, the cervical lordosis and complications. RESULTS: The mean followup was 48.59 months (range 24-56 months). The average operative time and blood loss was 105.29 min and 136.47 ml, respectively. The preoperative JOA score was 8.35, which significantly increased to 13.7 at the final followup (P < 0.01). The NDI score was significantly decreased from preoperative 13.06 to postoperative 3.35 (P < 0.01). The operation also provided a significant increase in the cervical lordosis (P < 0.01) from preoperative 10.17 degrees to postoperative 17.06 degrees . The fusion rate was 94.1% at 6 months postoperatively, and 100% at 12 months after surgery. The mean SWAL-QOL score decreased from preoperative 68.06 to immediate postoperatively 65.65 and then increased to 67.65 at final followup. There was a statistically significant difference between preoperative and immediate postoperatively values (P < 0.05), but none between preoperative and at final followup (P > 0.05). Cerebrospinal fluid leak, dysphagia and radiological adjacent segment degeneration occurred in one patient, respectively. CONCLUSION: The ACDF with zero-profile devices is generally effective and safe in treating two noncontiguous levels of CSM. PMID- 27512222 TI - Limb lengthening in achondroplasia. AB - BACKGROUND: Stature lengthening in skeletal dysplasia is a contentious issue. Specific guidelines regarding the age and sequence of surgery, methods and extent of lengthening at each stage are not uniform around the world. Despite the need for multiple surgeries, with their attendant complications, parents demanding stature lengthening are not rare, due to the social bias and psychological effects experienced by these patients. This study describes the outcome and complications of extensive stature lengthening performed at our center. MATERIALS AND METHODS: Eight achondroplasic and one hypochondroplasic patient underwent bilateral transverse lengthening for tibiae, humeri and femora. Tibia lengthening was carried out using a ring fixator and bifocal corticotomy, while a monolateral pediatric limb reconstruction system with unifocal corticotomy was used for the femur and humerus. Lengthening of each bone segment, height gain, healing index and complications were assessed. Subgroup analysis was carried out to assess the effect of age and bone segment on the healing index. RESULTS: Nine patients aged five to 25 years (mean age 10.2 years) underwent limb lengthening procedures for 18 tibiae, 10 femora and 8 humeri. Four patients underwent bilateral lengthening of all three segments. The mean length gain for the tibia, femur and humerus was 15.4 cm (100.7%), 9.9 cm (52.8%) and 9.6 cm (77.9%), respectively. Healing index was 25.7, 25.6 and 20.6 days/cm, respectively, for the tibia, femur and humerus. An average of 33.3% height gain was attained. Lengthening of both tibia and femur added to projected height achieved as the 3(rd) percentile of standard height in three out of four patients. In all, 33 complications were encountered (0.9 complications per segment). Healing index was not affected by age or bone segment. CONCLUSION: Extensive limb lengthening (more than 50% over initial length) carries significant risk and should be undertaken only after due consideration. PMID- 27512223 TI - Relation between the development of osteoporosis and osteonecrosis following glucocorticoid in a rabbit model. AB - BACKGROUND: There has been a recent increase in the number of patients suffering from bone and joint diseases, as a consequence of corticosteroids administration. There are more patients treated with low dose of GCs under long-term conditions in clinical, such as effect of GCs on Rheumatoid arthritis, Crohn's disease and Asthma patients. Hence, it was difficult for doctor to determine which problem occur first - OP or ON; however, there was no clinical report previously in the literature, and there was no effective animal model of OP and ON about low dose GCs. This study was conducted to develop rabbit models of glucocorticoid (GC) induced femoral head ON and OP and to investigate the temporal relationship between the occurrence of the two events following administration of glucocorticoids. MATERIALS AND METHODS: Fifty six, 6 months old female rabbits were randomly divided into the GC group and control group (C). Rabbits received gluteal injections of methylprednisolone sodium succinate once a day for 4 weeks, while normal saline solution in the control group. Rabbits were sacrificed at 0, 2, 4, and 8 weeks. Hip magnetic resonance imaging was performed before the rabbits were sacrificed. Serum calcium (Ca), phosphorus (P), total cholesterol, and triglyceride levels were also measured. The bone mineral density (BMD) of femoral head and the femoral shaft were measured by dual-energy X-ray absorptiometry. The trabecular parameters of the femur and the 4(th) lumbar vertebrae (L4) were measured with a micro-computed tomography (MU-CT). Also, the femoral head was stained with hematoxylin-eosin staining. RESULTS: At 4 weeks in the GC group, the BMD of the femur reduced 33% and 22% in the femoral head and shaft; there was irregular intermediate to high T2-weighted images signals; MU-CT showed microfractures and cystic changes in the femoral head and L4 at 4 weeks. At 8 weeks in the GC group, the classical "line-like sign" indicating ON of the femoral head was observed in 64.3% of the rabbits. CONCLUSION: A rabbit model of GC-induced OP and ON was developed by repetitive injection with small doses of GCs in the gluteal region. OP was observed at 4 weeks while ON developed at 8 weeks and followed a clear temporal pattern. PMID- 27512224 TI - Effect of insulin-like growth factor-1 and hyaluronic acid in experimentally produced osteochondral defects in rats. AB - BACKGROUND: The common purpose of almost all methods used to treat the osteochondral injuries is to produce a normal cartilage matrix. However current methods are not sufficient to provide a normal cartilage matrix. For that reason, researchers have studied to increase the effectiveness of this methods using chondrogenic and chondroprotective molecules in recent experimental studies. Insulin-like growth factor-1 (IGF-1) and hyaluronic acid (HA) are two important agents used in this field. This study compared the effects of IGF-1 and HA in an experimental osteochondral defect in rat femora. MATERIALS AND METHODS: The rats were divided into three groups (n = 15 per group) as follows: The IGF-1 group, HA group, and control group. An osteochondral defect of a diameter of 1.5 mm and a depth of 2 mm was created on the patellar joint side of femoral condyles. The IGF 1 group received an absorbable gelatin sponge soaked with 15 MUg/15 MUl of IGF-1, and the HA group received an absorbable gelatin sponge soaked with 80 MUg HA. The control group received only an absorbable gelatin sponge. Rats were sacrificed at the 6(th) week, and the femur condyles were evaluated histologically. RESULTS: According to the total Mankin scale, there was a statistically significant difference between IGF-1 and HA groups and between IGF-1 and control groups. There was also a significant statistical difference between HA and control groups. CONCLUSION: It was shown histopathologically that IGF-1 is an effective molecule for osteochondral lesions. Although it is weaker than IGF-1, HA also strengthened the repair tissue. PMID- 27512225 TI - N-terminal telopeptides of type I collagen and bone mineral density for early diagnosis of nonunion: An experimental study in rabbits. AB - BACKGROUND: The diagnosis and treatment of bone nonunion have been studied extensively. Diagnosis and treatment of nonunion are mainly performed based on the interpretation of clinico-radiographic findings, which depend on the clinician's experience and the degree of bone callus formation during the fracture-healing process. However, resolution may be compromised when the bone mineral content is <25%. A feasible method of monitoring bone-healing is therefore needed. We monitored a rabbit model of bone nonunion by regular radiographic examinations, QCT detection, and biomarker concentrations. MATERIALS AND METHODS: Twenty purebred New Zealand rabbits (10 male and 10 female, 5-6 months of age, 2.5-3.0 kg) were divided into bone defect Group (I) that 10 left radius bones underwent resection of 1.5 cm of mid-radius bone and bone fracture Group (II) that another 10 left radius bones underwent only mid-radius fracture. Quantitative computed tomography detection of bone mineral density (BMD) and serum markers of bone formation (osteocalcin [OC], bone-specific alkaline phosphatase) and bone resorption (C- and N-terminal telopeptides of type I collagen (NTX) and tartrate-resistant acid phosphatase 5b) were assayed. There are twenty rabbits (10 male and 10 females). The age was 5-6 months weighing 2.5 3.0 kg). The defect was created in middle 1/3 radius in 10 rabbits and fracture was created in middle 1/3 radius of 10 rabbits. RESULTS: BMD and NTX concentrations were significantly lower at 5 weeks postoperatively compared to the preoperative values and were significantly different between the two groups. OC showed no significant difference before and after surgery. CONCLUSIONS: BMD and NTX concentrations may be useful for early detection of bone nonunion in rabbits. PMID- 27512226 TI - Decalcified allograft in repair of lytic lesions of bone: A study to evolve bone bank in developing countries. AB - BACKGROUND: The quest for ideal bone graft substitutes still haunts orthopedic researchers. The impetus for this search of newer bone substitutes is provided by mismatch between the demand and supply of autogenous bone grafts. Bone banking facilities such as deep frozen and freeze-dried allografts are not so widely available in most of the developing countries. To overcome the problem, we have used partially decalcified, ethanol preserved, and domestic refrigerator stored allografts which are economical and needs simple technology for procurement, preparation, and preservation. The aim of the study was to assess the radiological and functional outcome of the partially decalcified allograft (by weak hydrochloric acid) in patients of benign lytic lesions of bone. Through this study, we have also tried to evolve, establish, and disseminate the concept of the bone bank. MATERIALS AND METHODS: 42 cases of lytic lesions of bone who were treated by decalcified (by weak hydrochloric acid), ethanol preserved, allografts were included in this prospective study. The allograft was obtained from freshly amputated limbs or excised femoral heads during hip arthroplasties under strict aseptic conditions. The causes of lytic lesions were unicameral bone cyst (n = 3), aneurysmal bone cyst (n = 3), giant cell tumor (n = 9), fibrous dysplasia (n = 12), chondromyxoid fibroma, chondroma, nonossifying fibroma (n = 1 each), tubercular osteomyelitis (n = 7), and chronic pyogenic osteomyelitis (n = 5). The cavity of the lesion was thoroughly curetted and compactly filled with matchstick sized allografts. RESULTS: Quantitative assessment based on the criteria of Sethi et al. (1993) was done. There was complete assimilation in 27 cases, partial healing in 12 cases, and failure in 3 cases. Functional assessment was also done according to which there were 29 excellent results, 6 good, and 7 cases of failure (infection, recurrence, and nonunion of pathological fracture). We observed that after biological incorporation, the graft participates in bone physiology and morphology. We did not observe any adverse host graft antigenic reaction. CONCLUSIONS: We conclude that decalcified allograft is suitable alloimplant for use in benign lesions of bone, is easy to prepare and store, and is thus well suited for use in developing countries. PMID- 27512227 TI - Caveats of bisphosphonate abuse. AB - BACKGROUND: Bisphosphonates (BPs) are the common drugs used for the treatment of postmenopausal osteoporosis. Short term benefits of the BPs are well known. However, there are concerns regarding their long term use. The aim of the study was to analyze the association between atypical femoral fractures and BP misuse/abuse as well as study the outcome of management of these fractures. MATERIALS AND METHODS: A retrospective study of a prospectively studied patients who presented with atypical femoral fractures between January 2010 and August 2012 and were followed up upto June 2014. The cohort consisted of nine female patients (12 fractures) with an average age of 71 years (range 58-85 years). Analysis was done for the indications, duration of BP use, configuration of associated fractures and method of treatment. RESULTS: The mean duration of BP use was 6.6 years (range 4-10 years). BP treatment was initiated without sufficient indication and continued without proper review and followup in most cases. Most patients did not followup and continued to consume BPs without any review by the doctors. All patients had prodromal thigh pain of various duration, which was inadequately investigated and managed before the presentation. Two cases with an incomplete fracture and no thigh pain were managed successfully with conservative treatment. The rest were treated by surgery with intramedullary nailing. The average union time was longer and two fractures went into nonunion which required further surgical intervention. CONCLUSION: Atypical femoral fractures appear to be strongly related to abuse of BPs. Great care is to be exercised at initiation as well as the continuation of BP therapy, and regular review is required. There is a need for improved awareness among physicians about the possibility of such fractures, and interpretation of thigh pain and radiological findings, especially if the patient has been on BPs therapy. Internal fixation for complete fractures and for incomplete fractures with thigh pain is needed. Delayed union is common. PMID- 27512228 TI - Lumbar epidural varices: An unusual cause of lumbar claudication. AB - Lumbar epidural varices can also present with radiculopathy similar to acute intervertebral disc prolapse (IVDP). However as the magnetic resonance imaging (MRI) in these patients are usually normal without significant compressive lesions of the nerve roots, the diagnosis is commonly missed or delayed leading to persistent symptoms. We present a rare case of acute severe unilateral claudication with a normal MRI unresponsive to conservative management who was treated surgically. The nerve root on the symptomatic side was found to be compressed by large anterior epidural varices secondary to an abnormal cranial attachment of ligamentum flavum. Decompression of the root and coagulation of the varices resulted in complete pain relief. To conclude, lumbar epidural varices should be considered in the differential diagnosis of acute onset radiculopathy and claudication in the absence of significant MRI findings. PMID- 27512229 TI - Complete dorsal dislocation of the carpal scaphoid with perilunate dorsal dislocation. AB - Complete dorsal dislocation of the carpal scaphoid combined with dorsal perilunate dislocation is an extremely rare carpal injury. We describe the case of a 23-year-old man who presented with a complete dorsal dislocation of the carpal scaphoid, combined with a perilunate dislocation. Surgical treatment was performed with open reduction and interosseus ligament repair. At 4 years follow up, the patient's wrist pain had completely resolved without limitations of wrist joint motion and without evidence of avascular necrosis of the carpal scaphoid. PMID- 27512230 TI - Early results of displaced supracondylar fractures of humerus in children treated by closed reduction and percutaneous pinning. PMID- 27512231 TI - Author's reply. PMID- 27512232 TI - Erratum: Surgical hip dislocation for treatment of cam femoroacetabular impingement. AB - [This corrects the article on p. 496 in vol. 49, PMID: 26538754.]. PMID- 27512233 TI - Synthesis of 18F-Arenes from Spirocyclic Iodonium(III) Ylides via Continuous-Flow Microfluidics. AB - Spirocyclic hypervalent iodine(III) ylides have proven to be synthetically versatile precursors for efficient radiolabelling of a diverse range of non activated (hetero)arenes, highly functionalised small molecules, building blocks and radiopharmaceuticals from [18F]fluoride ion. Herein, we report the implementation of these reactions onto a continuous-flow microfluidic platform, thereby offering an alterative and automated synthetic procedure of a radiopharmaceutical, 3-[18F]fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile ([18F]FPEB) and a routinely used building block for click-radiochemistry, 4 [18F]fluorobenzyl azide. This new protocol was applied to the synthesis of [18F]FPEB (radiochemical conversion (RCC) = 68 +/- 5%) and 4-[18F]fluorobenzyl azide (RCC=68 +/- 5%; isolated radiochemical yield = 24+/-0%). We anticipate that the high throughput microfluidic platform will accelerate the discovery and applications of 18F-labelled building blocks and labelled compounds prepared by iodonium ylide precursors as well as the production of radiotracers for preclinical imaging studies. PMID- 27512234 TI - Identifying the physical features of marina infrastructure associated with the presence of non-native species in the UK. AB - Marine invasive non-native species (NNS) are one of the greatest threats to global marine biodiversity, causing significant economic and social impacts. Marinas are increasingly recognised as key reservoirs for invasive NNS. They provide submersed artificial habitat that unintentionally supports the establishment of NNS introduced from visiting recreational vessels. While ballast water and shipping vectors have been well documented, the role of recreational vessels in spreading NNS has been relatively poorly studied. Identification of the main physical features found within marinas, which relate to the presence of NNS, is important to inform the development of effective biosecurity measures and prevent further spread. Towards this aim, physical features that could influence the presence of NNS were assessed for marinas throughout the UK in July 2013. Thirty-three marine and brackish NNS have been recorded in UK marinas, and of the 88 marinas studied in detail, 83 contained between 1 and 13 NNS. Significant differences in freshwater input, marina entrance width and seawall length were associated with the presence of NNS. Additionally, questionnaires were distributed to marina managers and recreational vessel owners to understand current biosecurity practices and attitudes to recreational vessel biosecurity. The main barriers to biosecurity compliance were cited as cost and time. Further work identifying easily distinguished features of marinas could be used as a proxy to assess risk of invasion. PMID- 27512235 TI - Computational Simulation of Equivalence Class Formation Using the go/no-go Procedure with Compound Stimuli. AB - Research about equivalence has commonly utilized human participants as experimental subjects. More recently, computational models have been capable of reproducing performances observed in experiments with humans. The computational model often utilized is called RELNET, and it simulates training and testing trials of conditional relations using the matching-to-sample procedure (MTS). The differentiation between sample stimulus and comparison stimuli, indispensable in MTS, implies operational difficulties for simulations. For this reason, new studies seek to utilize alternative procedures to MTS, which do not differentiate the functions of the antecedent stimuli. This work evaluated the possibility of developing a new computational model to simulate equivalence class formation using the go/no-go procedure with compound stimuli. In Experiment 1, artificial neural networks were utilized to simulate training of the AB and BC relations as well as the testing of the AC relation. The results showed that four out of six runs demonstrated equivalence class formation. Experiment 2 evaluated whether the additional class training performed in Experiment 1, which was analogous to the simulation of pre-experimental experience of human participants, would be essential for simulating the establishment of equivalence classes. It was found that it was not possible to simulate equivalence class formation without the additional class training. Altogether, the experiments show that it is possible to simulate equivalence class formation using the go/no-go procedure with compound stimuli and that it is necessary to conduct additional class training. The model developed is, therefore, an alternative to RELNET for the study of equivalence relations using computational simulations. PMID- 27512236 TI - The Inappropriate Symmetries of Multivariate Statistical Analysis in Geometric Morphometrics. AB - In today's geometric morphometrics the commonest multivariate statistical procedures, such as principal component analysis or regressions of Procrustes shape coordinates on Centroid Size, embody a tacit roster of symmetries-axioms concerning the homogeneity of the multiple spatial domains or descriptor vectors involved-that do not correspond to actual biological fact. These techniques are hence inappropriate for any application regarding which we have a-priori biological knowledge to the contrary (e.g., genetic/morphogenetic processes common to multiple landmarks, the range of normal in anatomy atlases, the consequences of growth or function for form). But nearly every morphometric investigation is motivated by prior insights of this sort. We therefore need new tools that explicitly incorporate these elements of knowledge, should they be quantitative, to break the symmetries of the classic morphometric approaches. Some of these are already available in our literature but deserve to be known more widely: deflated (spatially adaptive) reference distributions of Procrustes coordinates, Sewall Wright's century-old variant of factor analysis, the geometric algebra of importing explicit biomechanical formulas into Procrustes space. Other methods, not yet fully formulated, might involve parameterized models for strain in idealized forms under load, principled approaches to the separation of functional from Brownian aspects of shape variation over time, and, in general, a better understanding of how the formalism of landmarks interacts with the many other approaches to quantification of anatomy. To more powerfully organize inferences from the high-dimensional measurements that characterize so much of today's organismal biology, tomorrow's toolkit must rely neither on principal component analysis nor on the Procrustes distance formula, but instead on sound prior biological knowledge as expressed in formulas whose coefficients are not all the same. I describe the problems of the standard techniques, discuss several examples of the alternatives, and draw some conclusions. PMID- 27512238 TI - Response of Development and Body Mass to Daily Temperature Fluctuations: a Study on Tribolium castaneum. AB - Differences in thermal regimes are of paramount importance in insect development. However, experiments that examine trait development under constant temperature conditions may yield less evolutionarily relevant results than those that take naturally occurring temperature fluctuations into account. We investigated the effect of different temperature regimes (constant 30 degrees C, constant 35 degrees C, fluctuating with a daily mean of 30 degrees C, or fluctuating with a daily mean of 35 degrees C) on sex-specific development time and body mass in Tribolium castaneum. Using a half-sib breeding design, we also examined whether there is any evidence for genotype-by-environment interactions (GEI) for the studied traits. In response to fluctuating temperature regimes, beetles demonstrated reaction norm patterns in which thermal fluctuations influenced traits negatively above the species' thermal optimum but had little to no effect close to the thermal optimum. Estimated heritabilities of development time were in general low and non-significant. In case of body mass of pupae and adults, despite significant genetic variance, we did not find any GEI due to crossing of reaction norms, both between temperatures and between variability treatments. We have observed a weak tendency towards higher heritabilities of adult and pupa body mass in optimal fluctuating thermal conditions. Thus, we have not found any biasing effect of stable thermal conditions as compared to fluctuating temperatures on the breeding values of heritable body-size traits. Contrary to this we have observed a strong population-wide effect of thermal fluctuations, indicated by the significant temperature-fluctuations interaction in both adult and pupa mass. PMID- 27512237 TI - Phenotypic Novelty in EvoDevo: The Distinction Between Continuous and Discontinuous Variation and Its Importance in Evolutionary Theory. AB - The introduction of novel phenotypic structures is one of the most significant aspects of organismal evolution. Yet the concept of evolutionary novelty is used with drastically different connotations in various fields of research, and debate exists about whether novelties represent features that are distinct from standard forms of phenotypic variation. This article contrasts four separate uses for novelty in genetics, population genetics, morphology, and behavioral science, before establishing how novelties are used in evolutionary developmental biology (EvoDevo). In particular, it is detailed how an EvoDevo-specific research approach to novelty produces insight distinct from other fields, gives the concept explanatory power with predictive capacities, and brings new consequences to evolutionary theory. This includes the outlining of research strategies that draw attention to productive areas of inquiry, such as threshold dynamics in development. It is argued that an EvoDevo-based approach to novelty is inherently mechanistic, treats the phenotype as an agent with generative potential, and prompts a distinction between continuous and discontinuous variation in evolutionary theory. PMID- 27512239 TI - Interagency Collaborative Team Model for Capacity Building to Scale-Up Evidence Based Practice. AB - BACKGROUND: System-wide scale up of evidence-based practice (EBP) is a complex process. Yet, few strategic approaches exist to support EBP implementation and sustainment across a service system. Building on the Exploration, Preparation, Implementation, and Sustainment (EPIS) implementation framework, we developed and are testing the Interagency Collaborative Team (ICT) process model to implement an evidence-based child neglect intervention (i.e., SafeCare(r)) within a large children's service system. The ICT model emphasizes the role of local agency collaborations in creating structural supports for successful implementation. METHODS: We describe the ICT model and present preliminary qualitative results from use of the implementation model in one large scale EBP implementation. Qualitative interviews were conducted to assess challenges in building system, organization, and home visitor collaboration and capacity to implement the EBP. Data collection and analysis centered on EBP implementation issues, as well as the experiences of home visitors under the ICT model. RESULTS: Six notable issues relating to implementation process emerged from participant interviews, including: (a) initial commitment and collaboration among stakeholders, (b) leadership, (c) communication, (d) practice fit with local context, (e) ongoing negotiation and problem solving, and (f) early successes. These issues highlight strengths and areas for development in the ICT model. CONCLUSIONS: Use of the ICT model led to sustained and widespread use of SafeCare in one large county. Although some aspects of the implementation model may benefit from enhancement, qualitative findings suggest that the ICT process generates strong structural supports for implementation and creates conditions in which tensions between EBP structure and local contextual variations can be resolved in ways that support the expansion and maintenance of an EBP while preserving potential for public health benefit. PMID- 27512240 TI - Cryptotephras: the revolution in correlation and precision dating. AB - From its Icelandic origins in the study of visible tephra horizons, tephrochronology took a remarkable step in the late 1980 s with the discovery of a ca. 4300-year-old microscopic ash layer in a Scottish peat bog. Since then, the search for these cryptotephra deposits in distal areas has gone from strength to strength. Indeed, a recent discovery demonstrates how a few fine-grained glass shards from an Alaskan eruption have been dispersed more than 7000 km to northern Europe. Instantaneous deposition of geochemically distinct volcanic ash over such large geographical areas gives rise to a powerful correlation tool with considerable potential for addressing a range of scientific questions. A prerequisite of this work is the establishment of regional tephrochronological frameworks that include well-constrained age estimates and robust geochemical signatures for each deposit. With distal sites revealing a complex record of previously unknown volcanic events, frameworks are regularly revised, and it has become apparent that some closely timed eruptions have similar geochemical signatures. The search for unique and robust geochemical fingerprints thus hinges on rigorous analysis by electron microprobe and laser ablation-inductively coupled plasma-mass spectrometry. Historical developments and significant breakthroughs are presented to chart the revolution in correlation and precision dating over the last 50 years using tephrochronology and cryptotephrochronology. PMID- 27512241 TI - Chronic exposure to a neonicotinoid pesticide alters the interactions between bumblebees and wild plants. AB - Insect pollinators are essential for both the production of a large proportion of world crops and the health of natural ecosystems. As important pollinators, bumblebees must learn to forage on flowers to feed both themselves and provision their colonies.Increased use of pesticides has caused concern over sublethal effects on bees, such as impacts on reproduction or learning ability. However, little is known about how sublethal exposure to field-realistic levels of pesticide might affect the ability of bees to visit and manipulate flowers.We observed the behaviour of individual bumblebees from colonies chronically exposed to a neonicotinoid pesticide (10 ppb thiamethoxam) or control solutions foraging for the first time on an array of morphologically complex wildflowers (Lotus corniculatus and Trifolium repens) in an outdoor flight arena.We found that more bees released from pesticide-treated colonies became foragers, and that they visited more L. corniculatus flowers than controls. Interestingly, bees exposed to pesticide collected pollen more often than controls, but control bees learnt to handle flowers efficiently after fewer learning visits than bees exposed to pesticide. There were also different initial floral preferences of our treatment groups; control bees visited a higher proportion of T. repens flowers, and bees exposed to pesticide were more likely to choose L. corniculatus on their first visit.Our results suggest that the foraging behaviour of bumblebees on real flowers can be altered by sublethal exposure to field-realistic levels of pesticide. This has implications for the foraging success and persistence of bumblebee colonies, but perhaps more importantly for the interactions between wild plants and flower-visiting insects and ability of bees to deliver the crucial pollination services to plants necessary for ecosystem functioning. PMID- 27512242 TI - A clinical comparative study of anatomic parameters before and after total hip replacement on congenital dysplasia. AB - [Purpose] To study preoperative and postoperative hip circumference data of various types of congenital dysplasia of the hip treated with total hip replacement, including the femoral offset, femoral neck length, height, and hip abductor arm parameters. [Subjects and Methods] This study included seventy-eight cases of congenital dysplasia of the hip (I-III type). Furthermore, four parameters were measured, including the preoperative and postoperative femoral offset. Statistical data analysis was performed using the SPSS 13.0 software. [Results] The femoral offset was 33.3 +/- 8.4 mm (preoperative) and 39.1 +/- 7.1 mm (postoperative). The femoral head height was 59.5 +/- 8.7 mm (preoperative) and 68.8 +/- 11.0 mm (postoperative). The femoral neck length was 50.8 +/- 10.8 mm (preoperative) and 61.5 +/- 10.4 mm (postoperative). The hip abductor arm was 54.3 +/- 9.6 mm (preoperative) 64.7 +/- 10.1 mm (postoperative). The preoperative and postoperative parameters showed statistical differences. Furthermore, no significant differences were evidenced when comparing the postoperative hip parameters with the normal data parameters. [Conclusion] Total hip replacement on congenital dysplasia of the hip could lead to the rebuilt of an almost normal physiological anatomy for each hip case (type I-III). PMID- 27512243 TI - The effect of exercise intervention on frail elderly in need of care: half-day program in a senior day-care service facility specializing in functional training. AB - [Purpose] This study investigated the long-term effect of a half-day exercise intervention program on health-related quality of life, life function, and physical function in frail elderly in need of care. The program was conducted at a senior day-care facility specializing in functional training. [Subjects and Methods] Subjects included 41 elderly in need of care who had visited the service facility for at least 1 year. Physical function and life function were evaluated at baseline, 6 months, and 12 months. Quality of life was evaluated with the Short Form-36 at baseline and 12 months. [Results] Improvements in balance, walking speed and endurance, complex performance abilities, self-efficacy during the activities, and the level and sphere of activity were observed at 6 months and maintained up to 12 months. Moreover, improvements in agility, activities of daily living, life function, and quality of life were also observed at 12 months. Improvements in muscle strength, walking ability, self-efficacy over an action, and activities of daily living were related to the improvement in quality of life. [Conclusion] The use of individualized exercise programs developed by physiotherapists led to improvements in activities of daily living and quality of life among elderly in need of care. PMID- 27512244 TI - Effect of chronic knee osteoarthritis on flexion-relaxation phenomenon of the erector spinae in elderly females. AB - [Purpose] This study investigated the flexion-relaxation phenomenon of the erector spinae in elderly women with chronic knee osteoarthritis and determined whether the flexion-relaxation phenomenon can be used as a pain evaluation tool in such cases. [Subjects and Methods] Seventeen elderly females with chronic knee osteoarthritis and 13 healthy young females voluntarily participated in this study. They performed three postural positions in 15 s: trunk flexion, complete trunk flexion, and trunk extension, each for 5 s. While these positions were held, muscle activation of the thoracic and lumbar erector spinae were measured using surface electromyography. The flexion-relaxation rate was determined by dividing the values for trunk extension by those of complete trunk flexion and by dividing the values for trunk flexion by those of complete trunk flexion. [Results] According to our results, the flexion-relaxation phenomenon was different between healthy young and elderly females with chronic knee osteoarthritis. Specifically, there was a difference in the left thoracic erector spinae muscle, but not in the left and right lumbar erector spinae or right thoracic spinae muscle. [Conclusion] Our study demonstrated that the erector spinae muscle flexion-relaxation phenomenon can be used as a pain evaluation tool in elderly females with chronic knee osteoarthritis. PMID- 27512245 TI - Raster-stereographic evaluation of the effects of biomechanical foot orthoses in patients with scoliosis. AB - [Purpose] Little is known about the effects of biomechanical foot orthoses in scoliosis, as determined by raster stereography. The objective of this study was to investigate the effect of individually manufactured biomechanical foot orthoses on scoliosis angle, trunk imbalance, and pelvic obliquity by comparing them with general insoles by using DIERS formetric 4 dimensional in patients with scoliosis. [Subjects and Methods] Twenty-six patients with scoliosis were recruited at Yeungnam University Hospital and allocated equally to one of two groups, the biomechanical foot orthoses group or the control group. Parameters, such as, trunk rotation, imbalance, and scoliosis angle, were obtained using a DIERS formetric 4D. [Results] Scoliosis angle, pelvic obliquity, and trunk imbalance were significantly different between the two groups and improved in the biomechanical foot orthoses group with time, but no significant improvement in any parameter was observed in the control group. [Conclusion] Biomechanical foot orthoses could be effective in patients with scoliosis, and DIERS formetric 4D provides a useful method for evaluating scoliosis parameters. PMID- 27512246 TI - Design, development, and clinical validation of therapeutic toys for autistic children. AB - [Purpose] One of the characteristics of autistic children is social interaction difficulties. Although therapeutic toys can promote social interaction, however its related research remains insufficient. The aim of the present study was to build a set of cooperative play toys that are suitable for autistic children. [Subjects and Methods] This study used an innovative product design and development approach as the basis for the creation of cooperative play toys. [Results] The present study has successfully developed cooperative play toys. Compared to the traditional game therapy for autism, cooperative play toy therapy can significantly improve the interactions between autistic children and their peers. [Conclusion] The most critical design theme of cooperative play toys focuses on captivating the interest of autistic children. Based on the needs of the individual cases, the design of the therapeutic toy set was specifically tailored, i.e., by reinforcing the sound and light effects to improve the attractiveness of the toys. In the future, different play modes can be combined with this toy set to further enhance the degree of interaction of autistic children and improve their quality of life and social skills. PMID- 27512247 TI - Effect of sequential pneumatic compression therapy on venous blood velocity, refilling time, pain and quality of life in women with varicose veins: a randomized control study. AB - [Purpose] The aim of this study was to investigate the effects of sequential pneumatic compression therapy on venous blood flow, refilling time, pain level, and quality of life in women with varicose veins. [Subjects and Methods] Twenty eight females with varicose veins were selected and randomly allocated to a control group, and experimental group. Maximum and mean venous blood velocities, the refilling time, pain by visual analog scale and quality of life by Aberdeen Varicose Veins Questionnaire were measured in all patients before and after six weeks of treatment. Both groups received lower extremity exercises; in addition, patients in the experimental group received sequential pneumatic compression therapy for 30 minutes daily, five days a week for six weeks. [Results] All measured parameters improved significantly in both groups, comparison of post treatment measurements between groups showed that the maximum and mean blood flow velocity, the pain level, and quality of life were significantly higher in the experimental group compared with the control group. On the other hand there was no significant difference between groups for refilling time. [Conclusion] Sequential pneumatic compression therapy with the applied parameters was an effective modality for increasing venous blood flow, reducing pain, and improving quality of women life with varicose veins. PMID- 27512248 TI - The effects of short-term use of compression stockings on health related quality of life in patients with chronic venous insufficiency. AB - [Purpose] This study was aimed to analyse the effects of short-term use of compression stockings (CS) on symptoms and QoL in patients with Chronic Venous Insufficiency (CVI). [Subjects and Methods] Based on the CEAP classification C2 and C3, 117 patients with CVI were enrolled in this study. The participants were divided into two groups. The control group refused to use CS, however, was advised to do exercises and take skin care whereas the CS group used CS and performed exercise. The data were collected by using Nottingham Health Profile (NHP), Venous Insufficiency Epidemiological and Economic Study (VEINES-QoL/Sym) and Beck Depression Inventory (BDI) at baseline and after four weeks of treatment and compared within and in between groups. [Results] The comparison of pre- and post-treatment differences between groups was statistically significant for all parameters. In the study group, pre- and post-treatment scores for each parameter were significantly different. However, elevated scores in the control group suggested worsening of the illness. [Conclusion] This study established that short-term use of CS in patients with CVI significantly improved disease specific and general QoL by reducing venous symptoms. Further studies with larger sample size are necessary to confirm these findings. PMID- 27512249 TI - Comparison of the efficacy of physical therapy and corticosteroid injection in the treatment of pes anserine tendino-bursitis. AB - [Purpose] The aims of this study were twofold. The first was to compare the functional capacity and pain of patients with knee osteoarthritis (KOA), with or without pes anserine tendino-bursitis (PATB). The second is to compare the efficacy of two treatment methods (physical therapy and corticosteroid injection) for patients with PATB. [Subjects and Methods] Sixty patient with KOA and PATB (Group 1) and 57 patients with KOA but without PATB (Group 2) were enrolled in the study. The patients' visual analog scale (VAS), Western Ontario and McMaster Universities osteoarthritis index (WOMAC) scores and three-meter timed-up and go scores were measured. The PATB group was randomly divided into two groups (Group A and B). Physical therapy (PT) modalities were applied to the first group (Group A), and the second group (Group B) received corticosteroid injections to the pes anserine area. Eight weeks later, patients' parameters were measured again. [Results] Initial WOMAC scores and timed up-and-go times were significantly higher in Group 1 than in Group 2. Both treatments resulted in significant improvements in all measured parameters, but no significant difference was detected between Group A and B. [Conclusion] Patients with PATB tend to have more severe pain, more altered functionality, and greater disability than those with KOA but without PATB. Both corticosteroid injection and PT are effective methods of treatment for PATB. Injection therapy can be considered an effective, inexpensive and fast therapeutic method. PMID- 27512251 TI - Effect of high-frequency repetitive transcranial magnetic stimulation on motor cortical excitability and sensory nerve conduction velocity in subacute-stage incomplete spinal cord injury patients. AB - [Purpose] The aim of the present study was to determine whether repetitive transcranial magnetic stimulation can improve sensory recovery of the lower extremities in subacute-stage spinal cord injury patients. [Subjects and Methods] This study was conducted on 20 subjects with diagnosed paraplegia due to spinal cord injury. These 20 subjects were allocated to an experimental group of 10 subjects that underwent active repetitive transcranial magnetic stimulation or to a control group of 10 subjects that underwent sham repetitive transcranial magnetic stimulation. The SCI patients in the experimental group underwent active repetitive transcranial magnetic stimulation and conventional rehabilitation therapy, whereas the spinal cord injury patients in the control group underwent sham repetitive transcranial magnetic stimulation and conventional rehabilitation therapy. Participants in both groups received therapy five days per week for six weeks. Latency, amplitude, and sensory nerve conduction velocity were assessed before and after the six week therapy period. [Results] A significant intergroup difference was observed for posttreatment velocity gains, but no significant intergroup difference was observed for amplitude or latency. [Conclusion] repetitive transcranial magnetic stimulation may be improve sensory recovery of the lower extremities in subacute-stage spinal cord injury patients. PMID- 27512250 TI - Comparison of upper extremity function, pain, and tactile sense between the uneffected side of hemiparetic patients and healthy subjects. AB - [Purpose] The aim of this study was to compare the unaffected upper extremity of patients with hemiparesis with that of healthy subjects in terms of function, pain, and tactile sense. [Subjects and Methods] Upper extremity evaluation parameters of 20 patients with hemiparesis were compared with an age-matched control group of 20 healthy subjects. A shorter version of the Disability of Arm and Shoulder Questionnaire, Upper Extremity Functional Index, and Simple Shoulder Test were used to evaluate the upper extremity functionality. The Visual Analog Scale was used to measure pain severity at rest, at night, and during activity. Tactile sensation levels were assessed by Semmes-Weinstein monofilaments at four palmar areas. [Results] A statistically significant difference was found in the upper extremity functionality between the groups. Pain severity at rest was significantly higher in the hemiparetic group. There was no significant difference in night and activity pain severities or tactile sensation levels between the groups. [Conclusion] According to our results, the unaffected side of patients with hemiparesis differs in functionality and pain at rest compared with that of healthy persons. Studies with larger sample size and various evaluation tests are needed to further investigate the unaffected side of patients with hemiparesis. PMID- 27512252 TI - Functional limitations due to foot involvement in spondyloarthritis. AB - [Purpose] Spondyloarthritis is a major inflammatory disease followed-up in the rheumatology clinics, foot involvement in spodyloarthritis is common. The functional states of patients with spondyloarthritis are usually evaluated globally. The aim of this study was to assess the foot involvement-related functional limitations in patients with spondyloarthritis. [Subjects and Methods] Patients with ankylosing spondylitis and psoriatic arthritis with foot pain more than 4 weeks who underwent anteroposterior and lateral feet radiography were enrolled into the study. A "clinical findings score" was calculated by assigning 1 point for every finding of swelling, redness, and tenderness. C-reactive protein and erythrocyte sedimentation rate were used as serum markers for disease activity. Foot radiograms were evaluated using the spondyloarthropathy tarsal radiographic index and the foot-related functional state of patients was determined by the Turkish version of the Foot and Ankle Outcome Score. [Results] There were no relationships between Foot and Ankle Outcome Score subscales and clinical findings score, serum markers, or radiologic score. Pain and symptoms subscale scores were result positively correlated with activity of daily living, sport and recreation, and quality of life subscale scores. [Conclusion] Pain and symptoms are the main determinants of foot-related functional limitations in spondyloarthritis. PMID- 27512253 TI - Clinical effectiveness of a Pilates treatment for forward head posture. AB - [Purpose] This study compared the effects of pilates and an exercise program on the craniovertebral angle, cervical range of motion, pain, and muscle fatigue in subjects with a forward head posture (FHP). [Subjects and Methods] A total of 28 sedentary females (age 20 to 39 years) with FHP were randomly assigned to pilates (n=14) and combined (n=14) exercise groups. The study was a randomized, controlled, double-blind study with the two groups performing exercise 50 min/day, 3 days/week, with an intensity of 11-15 rating of perceived exertion (RPE) for ten weeks. The main outcome measures were craniovertebral angle, cervical range of motion (ROM), pain levels assessed by visual analog scale (VAS), and neck disability index (NDI). Surface electromyography was also used to measure muscle fatigue. [Results] There were significant increases in craniovertebral angle and cervical ROM in the pilates group, but none in the control group. The only significant differences in muscle activity were recorded in the sternocleidomastoid muscle in the pilates group. Both exercise programs had positive effects on pain measures, as VAS and NDI were significantly decreased. [Conclusion] The results suggest that pilates could be recommended as an appropriate exercise for treatment of FHP in sedentary individuals. PMID- 27512254 TI - Effects of trunk stability exercise using proprioceptive neuromuscular facilitation with changes in chair height on the gait of patients who had a stroke. AB - [Purpose] The purpose of this study was to identify the effects of trunk stability exercise using proprioceptive neuromuscular facilitation with changes in chair heights on the gait of stroke patients. [Subjects and Methods] The subjects of this study were 11 stroke patients. The intervention method was trunk stability exercise using proprioceptive neuromuscular facilitation with different chair heights (50, 60, and 70 cm). These exercises were performed 5 times per week for 6 weeks. Gait velocity, cadence, stride length, gait cycle, and stance phase duration were used to measure gait function. [Results] Significant changes in gait velocity, cadence, and stride length were observed on the affected side. However, no significant changes in gait cycle and stance phase were observed on the affected side. [Conclusion] These results indicate that trunk stability exercise using proprioceptive neuromuscular facilitation with change in chair heights were effective in improving gait velocity, cadence, and stride length on the affected side. However, in this study, no significant changes were observed in gait cycle and stance phase on the affected side. Therefore, various interventions for stroke patients should be investigated in further studies. PMID- 27512255 TI - Canoe game-based virtual reality training to improve trunk postural stability, balance, and upper limb motor function in subacute stroke patients: a randomized controlled pilot study. AB - [Purpose] This study was aimed at investigating the preliminary therapeutic efficacy and usefulness of canoe game-based virtual reality training for stroke patients. [Subjects and Methods] Ten stroke patients were randomly assigned to an experimental group (EG; n=5) or a control group (CG; n=5). Patients in both groups participated in a conventional rehabilitation program, but those in the EG additionally participated in a 30-min canoe game-based virtual reality training program 3 days a week for 4 weeks. Therapeutic efficacy was assessed based on trunk postural stability, balance, and upper limb motor function. In addition, the usefulness of canoe game-based virtual reality training was assessed in the EG and therapist group (TG; n=20), which consisted of physical and occupational therapists, by using the System Usability Scale (SUS). [Results] Improvements in trunk postural stability, balance, and upper limb motor function were observed in the EG and CG, but were greater in the EG. The mean SUS scores in the EG and TG were 71 +/- 5.2 and 74.2 +/- 4.8, respectively. [Conclusion] Canoe game-based virtual reality training is an acceptable and effective intervention for improving trunk postural stability, balance, and upper limb motor function in stroke patients. PMID- 27512256 TI - The effects of gait time and trunk acceleration ratio during stair climbing in old-old adult females. AB - [Purpose] This study investigated the effects of gait time and trunk acceleration ratio in old-old adult females during stair climbing. [Subjects and Methods] Twenty-five older adult females who were able to walk independently volunteered for this study and were categorized into two age groups (older adults or old-old adults). Gait time and trunk acceleration ratio were measured using an accelerometer during stair climbing. [Results] Gait time and trunk acceleration ratio when climbing stairs were significantly higher in the old-old age group than in the older adults group. [Conclusions] These findings suggest that old-old females have decreased upper trunk control. In addition, gait time and the trunk acceleration ratio during stair climbing are useful clinical markers for predicting function and balance control ability in old-old elderly populations. PMID- 27512257 TI - Zhoubo plus uncaria tincture in the treatment of cerebral concussion sequelae. AB - [Purpose] This study investigated the clinical efficacy of the compound gouteng tincture combined with Zhoubo (GT-ZB) in treating the sequelae of cerebral concussion (CC) in children. [Subjects and Methods] Sixty children with CC sequelae were randomily divided into a treatment group and a control group, with 30 cases in each group. The treatment group was treated using GT-ZB, and the control group was treated using the standard method of venoruton, dibazol, and Vitamin B6. The efficacies of the two treatments were compared. [Results] Compared with the control group, the clinical symptoms and signs in the treatment group were significantly mitigated. [Conclusion] GT-ZB demonstrated efficacy in treating the sequelae of CC in children, and it is worthy of further studies and possible clinical recommendations. PMID- 27512258 TI - The immediate intervention effects of robotic training in patients after anterior cruciate ligament reconstruction. AB - [Purpose] The purpose of this study was to examine the immediate effects of robot assisted therapy on functional activity level after anterior cruciate ligament reconstruction. [Subjects and Methods] Participants included 10 patients (8 males and 2 females) following anterior cruciate ligament reconstruction. The subjects participated in robot-assisted therapy and treadmill exercise on different days. The Timed Up-and-Go test, Functional Reach Test, surface electromyography of the vastus lateralis and vastus medialis, and maximal extensor strength of isokinetic movement of the knee joint were evaluated in both groups before and after the experiment. [Results] The results for the Timed Up-and-Go Test and the 10-Meter Walk Test improved in the robot-assisted rehabilitation group. Surface electromyography of the vastus medialis muscle showed significant increases in maximum and average discharge after the intervention. [Conclusion] The results suggest that walking ability and muscle strength can be improved by robotic training. PMID- 27512259 TI - Short-term effects of kinesio tape on joint position sense, isokinetic measurements, and clinical parameters in patellofemoral pain syndrome. AB - [Purpose] To evaluate the short-term effects of kinesio tape on joint position sense, isokinetic measurements, kinesiophobia, symptoms, and functional limitations in patients with patellofemoral pain syndrome. [Subjects and Methods] A total of 90 patients (112 knees) with patellofemoral pain syndrome were randomized into a kinesio tape group (n=45) or placebo kinesio tape group (n=45). Baseline isokinetic quadriceps muscle tests and measurements of joint position sense were performed in both groups. Pain was measured with a Visual Analog Scale, kinesiophobia with the Tampa kinesiophobia scale, and symptoms and functional limitations with the Kujala pain scale. Measurements were repeated 2 days after kinesio tape application. [Results] No differences were found between baseline isokinetic muscle measurements and those taken 2 days after application. However, significant improvements were observed in the kinesio tape group, with regard to joint position sense, pain, kinesiophobia, symptoms, and functional limitations after treatment. Examination of the differences between pre- and post treatment values in both groups revealed that the kinesio tape group demonstrated greater improvements compared to the placebo kinesio tape group. [Conclusion] Although short-term kinesio tape application did not increase hamstring muscle strength, it may have improved joint position sense, pain, kinesiophobia, symptoms, and daily limitations. PMID- 27512260 TI - Effects of mental practice on normal adult balance ability. AB - [Purpose] This study aimed to examine the effects of mental practice on the balance abilities of normal individuals. [Subjects and Methods] Thirty subjects were randomly assigned to an experimental or control group (n=15 each). Participants in both groups performed balance training in a seated position on a gym ball for 20 minutes per session, five sessions per week, for 4 weeks. Members of the experimental group also performed mental practice for 10 minutes before the balance training. After the intervention, balance measuring equipment (Good Balance, Metitur, Finland) was used to quantitatively measure balance ability. [Results] Significant post-training gains were observed in the mediolateral, index of balance function, and time variables of participants of the experimental group. [Conclusion] The application of mental practice with balance training positively affected balance ability. PMID- 27512261 TI - Effect of aquatic dual-task training on balance and gait in stroke patients. AB - [Purpose] The purpose of this study was to determine the effect of aquatic dual task training on balance and gait in stroke patients. [Subjects and Methods] Twenty stroke patients were divided into the experimental (n=10) and control (n=10) groups. Both groups underwent neurodevelopmental treatment. The experimental group additionally underwent aquatic dual-task training for 30 minutes a day, 5 days a week, for 6 weeks. Balance was measured using the Berg balance scale, Five Times Sit-to Stand Test, and Functional Reach Test. Gait was measured using the 10-Meter Walk Test, Timed Up and Go Test, and Functional Gait Assessment. [Results] For intragroup comparison, the experimental group showed a significant change after the experiment in all balance and gait assessment tests. For intergroup comparison, the experimental group showed relatively more significant change after the experiment in all balance and gait assessment tests. [Conclusion] Our results showed that aquatic dual-task training has a positive effect on balance and gait in stroke patients. PMID- 27512263 TI - The effect of virtual reality-based eccentric training on lower extremity muscle activation and balance in stroke patients. AB - [Purpose] The purpose of this study was to examine the effect of virtual reality based eccentric training on lower extremity muscle activity and balance in stroke patients. [Subjects and Methods] Thirty stroke patients participated, with 15 patients allotted to each of two eccentric training groups: one using a slow velocity (group I) and one using a fast velocity (group II). The virtual reality based eccentric training was performed by the patients for 30 minutes once a day, 5 days a week, for 8 weeks using an Eccentron system. Surface electromyography was used to measure the lower extremity muscle activity, while a BioRescue was used to measure balancing ability. [Results] A significant difference in lower extremity muscle activation and balance ability was observed in group I compared with group II. [Conclusion] This study showed that virtual reality-based eccentric training using a slow velocity is effective for improving lower extremity muscle activity and balance in stroke patients. PMID- 27512262 TI - The impact of physical therapy in patients with severe traumatic brain injury during acute and post-acute rehabilitation according to coma duration. AB - [Purpose] The aim of study was to evaluate the impact of physical therapy on the recovery of motor and mental status in patients who sustained a severe traumatic brain injury, according to coma duration in acute and post-acute rehabilitation. [Subjects and Methods] The study population comprised patients with levels of consciousness ranging from 3 to 8 according to Glasgow Coma Scale score. The patients were divided into 2 groups based on coma duration as follows: group 1, those who were in a coma up to 1 week, and group 2, those who were in a coma for more than 2 weeks. The recovery of the patients' motor function was evaluated according to the Motor Assessment Scale and the recovery of mental status according to the Mini-Mental State Examination. [Results] The evaluation of motor and mental status recovery revealed that the patients who were in a coma up to 1 week recovered significantly better after physical therapy during the acute rehabilitation than those who were in a coma for longer than 2 weeks. [Conclusion] The recovery of motor and mental status of the patients in acute rehabilitation was significantly better for those in a coma for a shorter period. PMID- 27512264 TI - Influence of load and carrying method on gait, specifically pelvic movement. AB - [Purpose] The purpose of this study was to examine how carrying methods and load affects pelvic movement while walking. [Subjects and Methods] Sixteen healthy subjects (age 20.68 +/- 1.95 years, height 167.56 +/- 8.46 cm, weight 60.25 +/- 9.37 kg) volunteered. The items carried included a hand bag, shoulder bag, cross bag, and a back pack. The load weights were 0%, 5%, 10% and 15% of body weight. G Walk was used to record and analyze pelvic movement while the participants walked with different loads. [Results] In the case of hand bags and shoulder bags, pelvic tilt increased along with weight. In particular, when compared with the 0%, 5% and 10% load conditions, the 15% load of a hand bag induced a significant increase. Pelvic rotation showed a tendency to decrease as the weight increased. [Conclusion] Lateral pelvic tilt is thought to increase when the weight exceeds 15% of body weight, thereby resulting in decreased efficiency of gait. The pelvic rotation is thought to decrease as the weight increases, causing restricted upper limb movements. PMID- 27512265 TI - Autonomic cardiovascular control recovery in quadriplegics after handcycle training. AB - The aim of this study was to investigate the cardiovascular autonomic acute response, during recovery after handcycle training, in quadriplegics with spinal cord injury (SCI). [Subjects and Methods] Seven quadriplegics (SCIG -level C6-C7, male, age 28.00 +/- 6.97 years) and eight healthy subjects (CG -male, age 25.00 +/- 7.38 years) were studied. Their heart rate variability (HRV) was assessed before and after one handcycle training. [Results] After the training, the SCIG showed significantly reduced: intervals between R waves of the electrocardiogram (RR), standard deviation of the NN intervals (SDNN), square root of the mean squares differences of sucessive NN intervals (rMSSD), low frequency power (LF), high frequency power (HF), and Poincare plot (standard deviation of short-term HRV -SD1 and standard deviation of long-term HRV -SD2). The SDNN, LF, and SD2 remained decreased during the recovery time. The CG showed significantly reduced: RR, rMSSD, number of pairs of adjacent NN intervals differing by more than 50 ms (pNN50), LF, HF, SD1, and sample entropy (SampEn). Among these parameters, only RR remained decreased during recovery time. Comparisons of the means of HRV parameters evaluated between the CG and SCIG showed that the SCIG had significantly lower pNN50, LF, HF, and SampEn before training, while immediately after training, the SCIG had significantly lower SDNN, LF, HF, and SD2. The rMSSD30s of the SCIG significantly reduced in the windows 180 and 330 seconds and between the windows 300 seconds in the CG. [Conclusion] There was a reduction of sympathetic and parasympathetic activity in the recovery period after the training in both groups; however, the CG showed a higher HRV. The parasympathetic activity also gradually increased after training, and in the SCIG, this activity remained reduced even at three minutes after the end of training, which suggests a deficiency in parasympathetic reactivation in quadriplegics after SCI. PMID- 27512266 TI - Effect of the Masako maneuver and neuromuscular electrical stimulation on the improvement of swallowing function in patients with dysphagia caused by stroke. AB - [Purpose] The aim of this study was to compare improvements in swallowing function by the intervention of the Masako maneuver and neuromuscular electrical stimulation in patients with dysphagia caused by stroke. [Subjects and Methods] The Masako maneuver (n=23) and neuromuscular electrical stimulation (n=24) were conducted in 47 patients with dysphagia caused by stroke over a period of 4 weeks. Swallowing recovery was recorded using the functional dysphagia scale based on videofluoroscopic studies. [Results] Mean functional dysphagia scale values for the Masako maneuver and neuromuscular electrical stimulation groups decreased after the treatments. However, the pre-post functional dysphagia scale values showed no statistically significant differences between the groups. [Conclusion] The Masako maneuver and neuromuscular electrical stimulation each showed significant effects on the improvement of swallowing function for the patients with dysphagia caused by stroke, but no significant difference was observed between the two treatment methods. PMID- 27512267 TI - Prior swimming exercise favors muscle recovery in adult female rats after joint immobilization. AB - [Purpose] To evaluate the efficacy of pre-exercise on immobilization and subsequent recovery of white gastrocnemius (WG) and soleus (SOL) muscles of female rats. [Subjects and Methods] Thirty, 8-month-old, female Wistar rats were randomly and evenly allocated to six groups: sedentary (S); immobilized sedentary (IS); immobilized/rehabilitated sedentary (IRS); trained (T); immobilized trained (IT); and immobilized/rehabilitated trained (IRT). For four months, T, IT and IRT group animals performed swimming exercise (three sessions per week, 60 minutes per session), while S, IS and IRS groups animals remained housed in cages. After this period, the left hindlimb of the animals from the IS, IRS, IT and IRT groups was immobilized for five days, with the ankle at 90 degrees . After removal of the orthosis, animals from the IRS and IRT groups followed a rehabilitation program based on swimming (five sessions per week, 60 minutes per session) for two weeks. [Results] Immobilization significantly reduced the cross-sectional area of the white gastrocnemius muscle; no changes were observed in the soleus muscles of the trained animals. Transforming growth factor-beta1 protein levels were similar among the trained groups. [Conclusion] Prior swimming prevents hypotrophy of the soleus muscle after immobilization, and protein levels reflected the adaptive capacity of the skeletal muscle. PMID- 27512268 TI - Treatment of trochanteric bursitis: our experience. AB - [Purpose] Trochanteric bursitis is a disease for which there are no effective standardized therapy protocols. Very often pain persists in spite of applying all therapeutic treatments. The purpose of this study was to determine whether treatment of trochanteric bursitis with a local injection of bicomponent corticosteroid and 2% lidocaine would improve patients' conditions and relieve pain symptoms in the trochanteric area. [Subjects and Methods] A retrospective observational study was conducted of 2,217 patients in a 6 year follow-up period at the Special Hospital "Agens", Mataruska Banja, Serbia. [Results] Of 2,217 examined patients, 58 (2.6%) patients were found to suffer from trochanteritis associated with low back pain, and 157 (7%) were found to suffer from trochanteric pains without low back pains. Local corticosteroid therapy followed by physical therapy was effective in 77 (49%) of these patients, and only corticosteroid injection in 61 (39%) patients. A single injection was given to 47 (29.9%) of the patients. Two injections were given to 9 (5.7%) patients, and from 3 to 5 injections were given repeatedly every 4-6 weeks to 7 (4.5%) patients. [Conclusion] For most patients, local injections of corticosteroids with lidocaine alone or followed by physical therapy gave satisfactory results. PMID- 27512269 TI - Intra-rater reliability when using a tympanic thermometer under different self measurement conditions. AB - [Purpose] This study investigated intra-rater reliability when using a tympanic thermometer under different self-measurement conditions. [Subjects and Methods] Ten males participated. Intra-rater reliability was assessed by comparing the values under three conditions of measurement using a tympanic thermometer. Intraclass correlation coefficients were used to assess intra-rater reliability. [Results] According to the intraclass correlation coefficient analysis, reliability could be ranked according to the conditions of measurement. [Conclusion] The results showed that self-measurement of body temperature is more precise when combined with common sense and basic education about the anatomy of the eardrum. PMID- 27512270 TI - Immediate effects of neuromuscular joint facilitation intervention after anterior cruciate ligament reconstruction. AB - [Purpose] The aim of this study was to examine the immediate effects of neuromuscular joint facilitation (NJF) on the functional activity level after rehabilitation of anterior cruciate ligament (ACL) reconstruction. [Subjects and Methods] Ten young subjects (8 males and 2 females) who underwent ACL reconstruction were included in the study. The subjects were divided into two groups, namely, knee joint extension muscle strength training (MST) group and knee joint extension outside rotation pattern of NJF group. Extension strength was measured in both groups before and after the experiment. Surface electromyography (sEMG) of the vastus medialis and vastus lateralis muscles and joint position error (JPE) test of the knee joint were also conducted. [Results] JPE test results and extension strength measurements in the NJF group were improved compared with those in the MST group. Moreover, the average discharge of the vastus medialis and vastus lateralis muscles on sEMG in the NJF group was significantly increased after MST and NJF treatments. [Conclusion] The obtained results suggest that NJF training in patients with ACL reconstruction can improve knee proprioception ability and muscle strength. PMID- 27512271 TI - Effects of 12 weeks combined aerobic and resistance exercise on heart rate variability in type 2 diabetes mellitus patients. AB - [Purpose] This study evaluated the effects of 12 weeks combined aerobic and resistance exercise on heart rate variability in patients with Type 2 diabetes mellitus. [Subjects and Methods] The subjects were 16 female patients with Type 2 diabetes mellitus selected among the participants of a chronic disease management exercise class at C Region Public Health Center in South Korea. Subjects were randomly assigned to the exercise group (n=8; age, 55.97 +/- 7.37) or the control group (n=8; age, 57.53 +/- 4.63) The exercise group performed aerobic and resistance exercises for 60 minutes per day, 3 times per week for 12 weeks. Anthropometric measurements, biochemical markers, physical fitness, and heart rate variability were examined. [Results] After 12 weeks of exercise, weight, body fat percentage, waist circumference, blood glucose, insulin resistance, glycated hemoglobin level, systolic blood pressure, and diastolic blood pressure significantly decreased and cardiorespiratory fitness and muscular strength significantly increased in the exercise group. Although heart rate variability measures showed favorable changes with the exercise program, none were significant. [Conclusion] Although the exercise program did not show notable changes in heart rate variability in patients with Type 2 diabetes within the timeframe of the study, exercise may contribute to the prevention and control of cardiovascular autonomic neuropathy. PMID- 27512272 TI - Differences in performance on the functional movement screen between chronic low back pain patients and healthy control subjects. AB - [Purpose] Differences in scores on the Functional Movement Screen between patients with chronic lower back pain and healthy control subjects were investigated. [Subjects and Methods] In all, 20 chronic lower back pain patients and 20 healthy control subjects were recruited. Chronic lower back pain patients and healthy controls performed the Functional Movement Screen (deep squat, hurdle step, inline lunge, shoulder mobility, active straight leg raise, trunk stability pushup, and rotary stability). The Mann-Whitney test was used to analyze differences in Functional Movement Screen scores between the two groups. [Results] Chronic lower back pain patients scored lower on the Functional Movement Screen total composite compared with healthy control subjects. Chronic lower back pain patients scored lower on Functional Movement Screen subtests including the deep squat, hurdle step, active straight leg raise, and rotary stability tests. [Conclusion] The deep squat, hurdle step, active straight leg raise, and rotary stability tasks of the Functional Movement Screen can be recommended as a functional assessment tools to identify functional deficits in chronic lower back pain patients. PMID- 27512273 TI - Effect of respiratory warm-up on anaerobic power. AB - [Purpose] The aim of the present study was to examine the effects of respiratory muscle warm-up on anaerobic power. [Subjects and Methods] Thirty male field hockey players (age, 20.5 +/- 2.0 years) each participated in a control (CAN) trial and an experimental (EAN) trial. The EAN trial involved respiratory muscle warm-up, while the CAN trial did not. Anaerobic power was measured using the Wingate protocol. Paired sample t-tests were used to compare the EAN and CAN trials. [Results] There were significant increases in peak power and relative peak power, and decreases in the time to peak after the EAN trial by 8.9%, 9.6%, and 28.8% respectively. [Conclusion] Respiratory muscle warm-up may positively affect anaerobic power due to faster attainment of peak power. PMID- 27512274 TI - The immediate effects of keyboard-based music therapy on probe reaction time. AB - [Purpose] This study examined the immediate effects of keyboard-based music therapy on Probe Reaction Time. [Subjects and Methods] Probe Reaction Time was determined in 10 subjects by self-evaluation before and after music therapy intervention. The Probe Reaction Time was separately measured 4 times. [Results] After completion of music therapy intervention, the Probe Reaction Time in the 10 subjects was significantly decreased. [Conclusion] The results suggest that keyboard-based music therapy is an effective and novel treatment, and should be applied in clinical practice. PMID- 27512275 TI - The effects of exercising on an unstable surface on the gait and balance ability of normal adults. AB - [Purpose] This study aimed to examine that therapeutic efficacy of an unstable surface on balance and gait ability in normal individuals. [Subjects and Methods] Forty subjects participated in the experiment and were randomly assigned to an experimental group of 20 subjects and a control group of 20 subjects. The experimental group performed balance exercise on an Aero-Step device (Aero-Step XL, TOGU, Prien-Bachham, Germany). The control group performed balance exercise on rigid ground. All subjects performed balance training 30 minutes a day, 5 days a week, for 4 weeks. After the intervention, balance measuring equipment (Good Balance, Metitur, Jyvaskyla, Finland) was used to quantitatively measure balance ability. [Results] Significant differences in post-training gains in the variables of static balance, dynamic balance, and velocity were observed between the experimental group and the control group. [Conclusion] Unstable surface training aimed at improving balance ability is considered to have a positive effect. PMID- 27512276 TI - Relationship of body composition, knee extensor strength, and standing balance to lumbar bone mineral density in postmenopausal females. AB - [Purpose] This study aimed to investigate correlations between lumbar bone mineral density (BMD) and general characteristics of postmenopausal females, including body composition, knee extensor strength, standing balance, and femur BMD. [Subjects and Methods] A total of 40 postmenopausal females (55.6 +/- 4.6 years) who were caregivers or guardians of patients in the K hospital were included in the study. The weight, height, body composition, left and right knee extensor strength, standing balance, femur BMD, and lumbar BMD measurements of the subjects were obtained. [Results] The effect of measurement variables on lumbar BMD was examined. Increases in age and menopausal duration were observed to significantly increase lumbar BMD, whereas an increase in height was found to significantly decrease lumbar BMD. An increase in soft lean mass, skeletal muscle mass, fat-free mass, and femur BMD was also associated with significantly decreased lumbar BMD. [Conclusion] Age, menopausal duration, soft lean mass, skeletal muscle mass, and fat-free mass were factors that decreased lumbar BMD in menopausal females. This study is expected to provide basic knowledge for osteoporosis prevention and treatment programs for postmenopausal females. PMID- 27512277 TI - Cut-off point for the trail making test to predict unsafe driving after stroke. AB - [Purpose] This study examined the cut-off point of the Trail Making Test in predicting the risk of unsafe driving in stroke patients. [Subjects and Methods] A total of 81 stroke patients with a driver's license participated in this study. The DriveABLE Cognitive Assessment Tool, Trail Making Test-A, and Trail Making Test-B evaluations were conducted in all participants. All participants were classified into the safety or risk groups based on the DriveABLE Cognitive Assessment Tool evaluation results. The Trail Making Test results underwent a receiver operating characteristic analysis in each group. [Results] The results of the receiver operating characteristic curve analysis showed that the cut-off point for Trail Making Test-A was 32 seconds and the cut-off point for Trail Making Test-B was 79 seconds. The positive predictive values of the Trail Making Test-A and Trail Making Test-B were 98.3% and 98.3%, respectively, and the negative predictive values of the Trail Making Test-A and Trail Making Test-B were 81.0% and 73.9%, respectively. [Conclusion] The Trail Making Test is a useful tool for predicting the risk of unsafe driving in stroke patients. This tool is expected to be used more actively for screening stroke drivers with respect to their cognitive function. PMID- 27512278 TI - EMG activity of the serratus anterior and trapezius muscles during the different phases of the push-up plus exercise on different support surfaces and different hand positions. AB - [Purpose] The appropriate exercise prescription is crucial for achieving scapular stability and providing successful rehabilitation, and the Push-up Plus (PuP) exercise has an important role in shoulder rehabilitation. Consequently, this study examined the effect of support surface stability, hand positioning, and phase of exercise, on the trapezius and serratus anterior muscle contractions as well as on the EMG ratio of the upper/lower trapezius. [Subjects and Methods] Thirteen healthy male volunteers participated in this study. The subjects performed the PuP exercise on stable and unstable supporting surfaces with three different hand orientations. During the PuP exercise, the muscle activities of the upper (UT) and lower (LT) trapezius, as well as the serratus anterior (SA) were measured and expressed as percentages of maximum voluntary isometric contraction (%MVIC). [Results] The EMG activities of UT and LT were statistically greater during the push-up phase compared to the plus phase of the exercise. The contrary was recorded for the activity of the SA. SA was affected by the support surface as well as by the hand positioning. [Conclusion] The results suggest that different phases of the PuP exercise require different muscle stability actions with corresponding activations of appropriate muscle fibers. A detailed prescription of the required phase of the exercise can more effectively activate the scapula-thoracic musculature. PMID- 27512279 TI - The effect of co-stabilizer muscle activation on knee joint position sense: a single group pre-post test. AB - [Purpose] The purpose of this study was to investigate the effect of co stabilizer muscle activation on knee joint position sense. [Subjects and Methods] This study was a pre-post, single-blinded randomly controlled trial (angle sequence randomly selected) design. Seven healthy adults with no orthopaedic or neurological problems participated in this study. Knee joint position sense was measured by a target matching test at target angles of 30 degrees , 45 degrees and 80 degrees of knee flexion a using digital inclinometer under two conditions: erect sitting, which is known to highly activate co-stabilizer muscle and slump sitting, which is known to little activate the co-stabilizer muscle. [Results] A significant difference in joint position matching error at the knee flexion angle of 45 degrees was founded between two conditions erect sitting: (3.83 +/- 1.47) and slump sitting: (1.00 +/- 0.63). There were no significant differences in joint position matching error at the other target angles. [Conclusion] Knee joint position sense at 45 degrees is likely to be affected by activation of co-stabilizer muscle, and this value is suitable for facilitation of joint position sense with skilled movement. PMID- 27512280 TI - Validity and reliability of isometric muscle strength measurements of hip abduction and abduction with external hip rotation in a bent-hip position using a handheld dynamometer with a belt. AB - [Purpose] This study aimed to investigate the relatedness, reliability, and validity of isometric muscle strength measurements of hip abduction and abduction with an external hip rotation in a bent-hip position using a handheld dynamometer with a belt. [Subjects and Methods] Twenty healthy young adults, with a mean age of 21.5 +/- 0.6 years were included. Isometric hip muscle strength in the subjects' right legs was measured under two posture positions using two devices: a handheld dynamometer with a belt and an isokinetic dynamometer. Reliability was evaluated using an intra-class correlation coefficient (ICC); relatedness and validity were evaluated using Pearson's product moment correlation coefficient. Differences in measurements of devices were assessed by two-way ANOVA. [Results] ICC (1, 1) was >=0.9; significant positive correlations in measurements were found between the two devices under both conditions. No main effect was found between the measurement values. [Conclusion] Our findings revealed that there was relatedness, reliability, and validity of this method for isometric muscle strength measurements using a handheld dynamometer with a belt. PMID- 27512281 TI - Effects of concentric and eccentric control exercise on gross motor function and balance ability of paretic leg in children with spastic hemiplegia. AB - [Purpose] This study examines the effect of concentric and eccentric control training of the paretic leg on balance and gross motor function in children with spastic hemiplegia. [Subjects and Methods] Thirty children with spastic hemiplegia were randomly divided into experimental and control groups. In the experimental group, 20 min of neurodevelopmental therapy and 20 min of concentric and eccentric control exercise were applied to the paretic leg. In the control group, 40 min of neurodevelopmental therapy was applied. The Pediatric Balance Scale test and standing and gait items of the Gross Motor Function Measure were evaluated before and after intervention. [Results] In the experimental group, Gross Motor Function Measure and Pediatric Balance Scale scores statistically significantly increased after the intervention. The control group showed no statistically significant difference in either score after the intervention. [Conclusion] Concentric and eccentric control exercise therapy in children with spastic hemiplegia can be effective in improving gross motor function and balance ability, and can be used to solve functional problems in a paretic leg. PMID- 27512282 TI - A study of the development of the Korean version of PedsQL(TM) 3.0 cerebral palsy module and reliability and validity. AB - [Purpose] The purpose of this study was to develop the Korean version of the PedsQL(TM) 3.0 Cerebral Palsy Module to evaluate the health-related quality of life of children with cerebral palsy and to test the reliability and validity. [Subjects and Methods] The study included 108 caregivers of children with cerebral palsy aged 2 to 4 years and 72 caregivers of children aged 5 to 7 years, who visited multiple sites between February and August 2015. The Translation Commission performed the first translation with the approval of the Mapi Research Trust Company to create a Korean-version of the PedsQL(TM). Afterwards, back translation was performed by one translator specializing in health and medical treatment who was a native English-speaker fluent in Korean, and one native Korean-speaker fluent in English. The consistency of each question was confirmed and a translation-integrated version was created. Test components were explained to caregivers during a one-on-one interview; caregivers then completed the PedsQL(TM) questionnaire and a Pediatric Evaluation Disability Inventory (PEDI) questionnaire. Subjects contributing to test-retest measures were asked to repeat the PedsQL questionnaire one week later and return it by mail. To assess data quality for the survey question results, non-response rate, ceiling effect, and floor effect were analyzed. Test-retest reliability and internal consistency reliability were assessed. For test-retest reliability, an intraclass correlation coefficient (ICC) was calculated, and for internal consistency reliability, Cronbach's alpha was used. To test criterion-related validity, Pearson's correlation coefficient was used. [Results] The content validity of the PedsQL 3.0 Cerebral Palsy Module was high for both age groups, and demonstrated significant internal consistency (>0.7) in all areas. For test-retest reliability, both groups demonstrated a significant ICC (>0.61). Correlation with the PEDI was statistically significant in all areas except pain and hurt. [Conclusion] The Korean version of the PedsQL(TM) 3.0 Cerebral Palsy Module was found to be reliable and valid, and is expected to contribute greatly to the evaluation of the quality of life of children with cerebral palsy. PMID- 27512283 TI - Clinical usefulness of the clock drawing test applying rasch analysis in predicting of cognitive impairment. AB - [Purpose] This study examined the clinical usefulness of the clock drawing test applying Rasch analysis for predicting the level of cognitive impairment. [Subjects and Methods] A total of 187 stroke patients with cognitive impairment were enrolled in this study. The 187 patients were evaluated by the clock drawing test developed through Rasch analysis along with the mini-mental state examination of cognitive evaluation tool. An analysis of the variance was performed to examine the significance of the mini-mental state examination and the clock drawing test according to the general characteristics of the subjects. Receiver operating characteristic analysis was performed to determine the cutoff point for cognitive impairment and to calculate the sensitivity and specificity values. [Results] The results of comparison of the clock drawing test with the mini-mental state showed significant differences in according to gender, age, education, and affected side. A total CDT of 10.5, which was selected as the cutoff point to identify cognitive impairement, showed a sensitivity, specificity, Youden index, positive predictive, and negative predicive values of 86.4%, 91.5%, 0.8, 95%, and 88.2%. [Conclusion] The clock drawing test is believed to be useful in assessments and interventions based on its excellent ability to identify cognitive disorders. PMID- 27512284 TI - The effects of trunk stabilization exercise using a Swiss ball in the absence of visual stimulus on balance in the elderly. AB - [Purpose] This study was undertaken to investigate the effects of the balance exercises with a Swiss ball on static and dynamic balance abilities in elderly (>=65 years) subjects. [Subjects and Methods] Twenty elderly subjects with no relevant orthopedic history of a back condition were selected for trunk stabilization exercises with a Swiss ball (Thera-Band, USA). The subjects performed these trunk stabilization exercises for 20 minutes, five times per week for 4 weeks. The experimental group (n=10) was blindfolded during these balance exercises, while the control group control group (n=10) was not. [Results] The experimental group showed significant improvements in velocity in the evaluation of static balance and in time, total distance, and left/right movement distance in the evaluation of dynamic balance after the intervention, whereas the control group showed significant improvements in time in the evaluation of dynamic balance. A significant intergroup difference was observed after the intervention for velocity gain. [Conclusion] Exercising with a blindfold stimulates other senses by blocking visual information, and hence it enhances improvements in balance ability. PMID- 27512285 TI - Comparison of spatiotemporal gait parameters with a spinal orthosis and without a spinal orthosis on level ground and stairs. AB - [Purpose] This study attempted to examine the impact on the pattern of walking on both level ground and stairs after restricting the movement of the spine and the trunk of the body by using a spinal orthosis. [Subjects and Methods] Forty healthy males in their 20s were selected as the sample, which was randomly and evenly divided into two groups: (1) the WT group (with a thoracolumbosacral orthosis group) and (2) the WOT group (Without a thoracolumbosacral orthosis group). The spinal orthosis used in this study was a thoracolumbosacral orthosis called a plastic body jacket. [Results] In walking on level ground, step width showed a significant difference, but no statistically significant difference was found between the WT group and the WOT group with respect to the other variables. In walking on stairs, the double stance phase showed a statistically significant difference during stair descent in the WT group compared with the WOT group. [Conclusion] It was proven that wearing a TLSO increased walking stability in the case of walking on level ground and stairs. Hence, it is believed that proper use of a spinal orthosis can play an ancillary role in daily life and therapeutic interventions. PMID- 27512286 TI - Effects of shoulder reaching exercise on the balance of patients with hemiplegia after stroke. AB - [Purpose] This study investigated whether a shoulder reaching exercise was beneficial for restoring the standing balance of patients with hemiplegia after stroke. [Subjects and Methods] There were 13 subjects in the experimental group (EG) and 14 subjects in the control group (CG), all with hemiplegia following stroke. The shoulder reaching exercise intervention was performed by the EG and conventional physical therapy was administered to the CG for 30 minutes, 3 times a week for 4 weeks. Virtual reality (RM, BioRescue -AP 1153, France) was used as an assessment tool. All data were analyzed using SPSS version 18 (Statistical Package for the Social Science). [Results] After the intervention, the EG showed significant differences in the distances moved in the anteroposterior and mediolateral directions. The length and velocity were reduced after the intervention in both the EG and the CG. There were significant differences in the distances moved in the north, south and west directions between the groups. The sway path lengths of the subjects in the Romberg test were reduced under both the eyes open and closed conditions in the EG. There was no significant variation in sway velocity in the EG and the CG. [Conclusion] The shoulder reaching exercise had beneficial effects on the distances moved in the anteroposterior and mediolateral directions. PMID- 27512287 TI - Effects of neurofeedback and computer-assisted cognitive rehabilitation on relative brain wave ratios and activities of daily living of stroke patients: a randomized control trial. AB - [Purpose] This study investigated the effects of neurofeedback (NFB) and computer assisted cognitive rehabilitation (CACR) on the relative brain wave ratios and activities of daily living (ADL) of stroke patients. [Subjects and Methods] Forty four participants were randomly allocated to the NFB (n=14), CACR (n=14), or control (CON) (n=16) groups. Two expert therapists provided the NFB, CACR, and CON groups with traditional rehabilitation therapy in 30-minute sessions, 5 times a week, for 6 weeks. NFB training was provided only to the NFB group and CACR training was provided only to the CACR group. The CON group received traditional rehabilitation therapy only. Before and after 6 weeks of intervention, brain wave and ADL evaluations were performed, and the results were analyzed. [Results] The relative ratio of beta waves, only showed a significant increase in the frontal and parietal areas of the NFB group. Significant changes in ADL were shown by all three groups after the intervention. However, there were no significant differences between the NFB and CACR groups and the CON group. [Conclusion] Our results suggest that CACR and NFB are effective at improving cognitive function and ADL of stroke patients. PMID- 27512288 TI - The association of vitamin D with inflammatory cytokines in diabetic peripheral neuropathy. AB - [Purpose] The effects of vitamin D on the circulating levels of IL-17 and IL-13 were investigated in patients with diabetic peripheral neuropathy, patients with diabetes mellitus type 2 without neuropathy, and healthy controls. [Subjects and Methods] A single-blind controlled clinical study was performed, including70 type 2 diabetic patients with or without diabetic peripheral neuropathy and 33 healthy volunteer controls. The 25(OH)D levels were evaluated using ultra-performance liquid chromatography, and IL-17 and IL-13 levels were assessed using enzyme linked immunosorbent assays. [Results] The 25(OH) vitamin D concentration was lower in diabetic peripheral neuropathy patients than in diabetes mellitus patients without neuropathy and healthy controls. Similarly, 25(OH)D levels were lower in diabetes mellitus patients than healthy controls. IL-17 and IL-13 levels were higher in diabetes mellitus patients than in controls. Additionally, IL-13 levels were higher in diabetic peripheral neuropathy patients than in diabetes mellitus patients without neuropathy. These differences were statistically significant. There was a significant positive correlation between 25(OH)D and IL 13,and a negative correlation between 25(OH)D andIL-17 in the diabetic and diabetic neuropathy groups. [Conclusion] Vitamin D is a potential modifiable risk factor for diabetic peripheral neuropathy and may regulate inflammatory mediators, e.g., IL-17 and IL-13. PMID- 27512289 TI - A systematic review of sleep disorders in patients with chronic kidney disease undergoing hemodialysis. AB - The purpose of this study was to conduct a systematic review of the available evidence on sleep disorders in patients with end stage renal disease (ESRD) undergoing hemodialysis (HD). [Subjects and Methods] Two independent reviewers performed a computer-assisted search of the MEDLINE, SciELO, LILACS, and BIREME Virtual Health Library medical databases from their inception to November 2015. [Results] One thousand one hundred twenty-six articles were found that met the inclusion criteria. Articles were excluded if they were not in English, the patients did not undergo HD, or the studies were not cross-sectional or clinical trials. After reading the full text, a further 300 studies were excluded because they did not use polysomnography. The remaining 18 studies with ESRD patients undergoing HD comprised 8 clinical trials and 10 cross-sectional studies. This systematic review followed the criteria outlined by the PRISMA declaration. [Conclusion] In this systematic review, a high prevalence of sleep disorders was observed in ESRD, including sleep-disordered breathing. This knowledge may enable health professionals to devise new strategies for the diagnosis and treatment of these patients, in order to reduce morbidity and mortality and improve their quality of life. PMID- 27512290 TI - Effects of yoga on chronic neck pain: a systematic review of randomized controlled trials. AB - [Purpose] The aim of this study was to investigate the effectiveness of yoga in the management of chronic neck pain. [Subjects and Methods] Five electronic databases were searched to identify randomized controlled trials (RCTs) of yoga intervention on chronic neck pain. The trials were published in the English language between January 1966 and December 2015. The Cochrane Risk of Bias Tool was used to assess the quality of the trials. [Results] Three trials were identified and included in this review. A critical appraisal was performed on the trials, and the result indicated a high risk of bias. A narrative description was processed because of the small number of RCTs. Neck pain intensity and functional disability were significantly lower in the yoga groups than in the control groups. [Conclusion] Evidence from the 3 randomly controlled trials shows that yoga may be beneficial for chronic neck pain. The low-quality result of the critical appraisal and the small number of trials suggest that high-quality RCTs are required to examine further the effects of yoga intervention on chronic neck pain relief. PMID- 27512291 TI - Effect of pain scrambler therapy on shoulder joint pain and range of motion in patients who had undergone arthroscopic rotator cuff repair for the first time. AB - [Purpose] This study aimed to determine the effect of pain scrambler therapy on shoulder joint pain and range of motion in patients who had undergone arthroscopic rotator cuff repair for the first time. [Subjects and Methods] Pain scrambler therapy was administered once a day every 40 minutes for 10 days to patients that had undergone arthroscopic rotator cuff repair for the first time. The visual analog scale was used to measure pain, and a goniometer was used to measure shoulder range of motion. [Results] After 10 sessions of pain scrambler therapy, pain was significantly reduced from that before the treatment. In addition, shoulder range of motion was increased after 10 treatment sessions. [Conclusion] Thus, pain scrambler therapy greatly reduced pain and increased should range of motion in the patients who had undergone arthroscopic rotator cuff repair for the first time. PMID- 27512292 TI - Integer programming models and branch-and-cut approaches to generalized {0,1,2} survivable network design problems. AB - In this article, we introduce the Generalized [Formula: see text]-Survivable Network Design Problem ([Formula: see text]-GSNDP) which has applications in the design of backbone networks. Different mixed integer linear programming formulations are derived by combining previous results obtained for the related [Formula: see text]-GSNDP and Generalized Network Design Problems. An extensive computational study comparing the correspondingly developed branch-and-cut approaches shows clear advantages for two particular variants. Additional insights into individual advantages and disadvantages of the developed algorithms for different instance characteristics are given. PMID- 27512294 TI - Effect of low dose nicotinic acid on hyperphosphatemia in patients with end stage renal disease. AB - Hyperphosphatemia is a risk factor for ectopic calcification and coronary artery diseases in end stage renal diseases (ESRD). The aim of this study was to assess the effect of low-dose nicotinic acid on hyperphosphatemia in patients with ESRD. This randomized, double-blind clinical trial was done on 70 ESRD patients with serum phosphoure >=5.5 mg/dl. Patients were randomly divided into two equal groups (n = 35) and the intervention group received niacin 25 mg/day as the initial dose. After 4 weeks, in patients who did not respond to treatment, niacin dose was increased up to 50 mg/dl. At the end of week 8, in case there was no treatment effect, the dose was raised to 100 mg/day. The appropriate response to treatment was defined as serum phosphorous level reductions <5.5 mg/dl. The age was 50.5 +/- 14.3 years and duration of dialysis 5.1 +/- 5.3 months. In the niacin group, mean phosphorus level decreased from 6.7 +/- 0.84 mg/dl at the end of the 1(st) month to 5.8 +/- 1.0 mg/dl at the end of the 2(nd) month and to 4.4 +/- 1.4 mg/dl at the end of the 3(rd) month (P = 0.004). In the placebo group, mean phosphorus level increased from 6.5 +/- 1.2 mg/dl to 7.2 +/- 0.91 mg/dl at the end of the 3(rd) month (P = 0.006). In the niacin group, high density lipoprotein (HDL) increased significantly from 45.00 +/- 14.9 to 47.2 +/- 11.6 (P = 0.009). We conclude that niacin (100 mg/day) decreased phosphorus serum level and increased HDL serum level in patients on dialysis. PMID- 27512293 TI - Negative pressure wound therapy induces early wound healing by increased and accelerated expression of vascular endothelial growth factor receptors. AB - BACKGROUND: Negative pressure wound therapy (NPWT) is commonly used to accelerate wound healing, especially following thoracic surgery; however, the mechanism remains elusive. Given the important role of vasculogenesis in wound healing, we evaluated whether NPWT might accelerate vasculogenesis in the wound area. Toward this end, we investigated the temporal expression of vascular endothelial growth factor receptors (VEGFRs) in an NPWT-wound healing rabbit model. METHODS: Rabbits were divided into an NPWT group and a non-NPWT control group, and tissue samples were collected around wounds made in the skin of each rabbit at five time points: 0, 7, 14, 21, and 28 days after wound creation. Cryopreserved samples were then immunostained and subject to image analysis to evaluate the temporal changes in VEGFR1, VEGFR2, and VEGFR3 expression in the wound-healing process. RESULTS: Results of histological analysis of the temporal changes in VEGFR expression throughout the healing process showed that compared to the control group, VEGFR2 and VEGFR3 were abundantly and rapidly expressed in the NPWT group, and were expressed earlier than VEGFR1. CONCLUSIONS: NPWT promotes the expression of VEGFR2 and VEGFR3, which provides insight into the mechanism by which NPWT accelerates wound healing. Level of Evidence: Not ratable. PMID- 27512295 TI - Pegylated interferon monotherapy for hepatitis C virus infection in patients on hemodialysis: A single center study. AB - There is no published study from India on hepatitis C virus (HCV) treatment in dialysis patients. Patients on dialysis with HCV infection treated with pegylated interferon (Peg-INF) monotherapy were studied. All patients were subjected to HCV polymerase chain reaction, viral load, genotype, and liver biopsy. Quantitative HCV-RNA was performed monthly. Patients with genotype 1 and 4 were given 12 month therapy while those with genotypes 2 and 3 were given 6 months therapy. Response was classified as per standard criteria of rapid virological response (RVR), early virological response (EVR), end of treatment response (ETR), and sustained virological response (SVR). A total of 85 patients were treated. Mean age was 35.2 +/- 10.5 (range 15-67) years, and 77.6% were males. HCV genotypes were 1 in 40.9%, 2 in 12%, 3 in 36.1%, 4 in 3.6%, and others in 7.2%. Mean viral load was 10(6) copies/mL. Mean liver biopsy grade was 4 +/- 1.7 and stage 0.8 +/- 0.8. Mean time from diagnosis of HCV infection and the treatment start was 10.7 +/- 14.3 months. One patient died of unrelated illness, one was lost to follow-up, and three could not sustain treatment due to cost. Forty-three of the 80 (54%) patients had RVR while 49 (61%) patients had EVR and ETR. There was no difference in term of RVR related to genotype. Fifty -four percentage had SVR. Mild flu-like symptoms were seen in all patients. Sixty-four (80%) patients required increase in erythropoietin doses. Twenty-eight (35%) patients developed leukopenia (three treatment-limiting) and 16 (20%) developed thrombocytopenia (one treatment limiting). Five patients developed tuberculosis, five bacterial pneumonia, and one bacterial knee monoarthritis. None of the patients developed depression. Our study concludes that Peg-INF monotherapy resulted in 54% RVR and SVR in dialysis patients with HCV infection. Therapy was well-tolerated with minimal side effects. There was no effect of viral genotype on response to therapy. PMID- 27512296 TI - Clinical spectrum and outcomes of crescentic glomerulonephritis: A single center experience. AB - There is limited data on the etiology, clinical and histopathological spectrum and outcomes of crescentic glomerulonephritis (CrGN) in adult Indian population. This prospective study was done to evaluate the etiology, clinicohistological patterns and predictors of outcome of CrGN in South Indian population. All the patients received standard protocol based immunosuppression in addition to supportive care. Immune-complex glomerulonephritis (ICGN) was the most common etiology (n = 31; 77.5%) followed by pauci-immune glomerulonephritis (PauciGN; n = 8; 20%) and anti-glomerular basement membrane disease (n = 1; 2.5%). The most common etiology of ICGN was IgA nephropathy (n = 11; 27.5%) followed by lupus nephritis (n = 7; 17.5%) and post-infectious glomerulonephritis (PIGN) (n = 7; 17.5%). The patients with PauciGN were significantly older compared to those with ICGN (44.5 +/- 15 years vs. 31.8 +/- 11 years; P = 0.01). The patients with PauciGN presented with significantly higher serum creatinine (9.7 +/- 4.4 vs. 6.6 +/- 3.3 mg/dl; P = 0.03). The histopathologic parameters of ICGN and PauciGN were comparable except for a higher proportion of sclerosed glomeruli in ICGN. At the end of 3 months follow-up, only two patients went into complete remission (5.4%). Majority of the patients had end-stage renal failure (48.6%) and were dialysis dependent and seven patients (18.9%) expired. There was no signifi difference in the renal survival (10.9 +/- 1.9 vs. 9.6 +/- 3.3 months) or patient survival (17.5 +/- 2.1 vs. 17.3 +/- 4.3 months). The parameters associated with adverse outcomes at 3 months were hypertension (odds ratio [OR]: 0.58; confidence interval [CI]: 0.36-0.94), need for renal replacement therapy (OR: 0.19; CI: 0.04 0.9), serum creatinine at admission (P = 0.019), estimated glomerular filtration rate (P = 0.022) and percentage of fibrocellular crescents (P = 0.022). PMID- 27512297 TI - Prevalence of serum anti M-type phospholipase A2 receptor antibody in primary membranous nephropathy: A single center experience. AB - We conducted a prospective study to assess utility of detection of antibodies to phospholipase A2receptor (PLA2R) in the serum of patients with membranous nephropathy. Seventy five patients with biopsy proven membranous nephropathy admitted between January 2011 and September 2014 were studied. Serum anti- PLA2R was tested by indirect immunofluorescence. The test was positive in 45 out of 60 patients with primary membranous nephropathy (PMN) and in none of the 15 patients with secondary membranous nephropathy, with a sensitivity of 75% and specificity of 100% for PMN. Anti PLA2R positivity also showed a significant correlation with quantum of proteinuria and negative correlation with serum albumin. This study has validated detection of serum anti PLA2R in PMN as a non invasive diagnostic tool in Indian patients. PMID- 27512298 TI - Changing picture of acute kidney injury in pregnancy: Study of 259 cases over a period of 33 years. AB - The incidence of acute kidney injury (AKI) in pregnancy is declining in developing countries but still remains a major cause of maternal and fetal morbidity and mortality. The aim of the study was to analyze the changing trends in pregnancy related AKI (PR-AKI) over a period of thirty-three years. Clinical characteristics of PR-AKI with respect to incidence, etiology and fetal and maternal outcomes were compared in three study periods, namely 1982-1991,1992 2002 and 2003-2014. The incidence of PR-AKI decreased to 10.4% in 1992-2002, from 15.2% in 1982-1991, with declining trend continuing in 2003-2014 (4.68%).Postabortal AKI decreased to 1.49% in 2003-2014 from 9.4% in 1982-1991of total AKI cases. The AKI related to puerperal sepsis increased to 1.56% of all AKI cases in 2003-2014 from 1.4% in 1982-1991. Preeclampsia/eclampsia associated AKI decreased from 3.5% of total AKI cases in 1982-1991 to 0.54% in 2003-2014. Pregnancy associated - thrombotic microangiopathy and acute fatty liver of pregnancy were uncommon causes of AKI. Hyperemesis gravidarum associated AKI was not observed in our study. Incidence of renal cortical necrosis (RCN) decreased to 1.4% in 2003-2014 from 17% in 1982-1991.Maternal mortality reduced to 5.79% from initial high value 20% in 1982-1991. The progression of PR-AKI to ESRD decreased to1.4% in 2003-2014 from 6.15% in 1982-1991. The incidence of PR-AKI has decreased over last three decades, mainly due to decrease in incidence of postabortal AKI. Puerperal sepsis and obstetric hemorrhage were the major causes of PR-AKI followed by preeclampsia in late pregnancy. Maternal mortality and incidence and severity of RCN have significantly decreased in PR-AKI. The progression to CKD and ESRD has decreased in women with AKI in pregnancy in recent decade. However, the perinatal mortality did not change throughout study period. PMID- 27512299 TI - Comparison of outcomes between surgically placed and percutaneously placed peritoneal dialysis catheters: A retrospective study. AB - There is lack of adequate data on comparison of outcomes between percutaneously placed peritoneal dialysis (PD) catheters inserted by nephrologists and PD catheters placed by surgeons. The aim of this study is to retrospectively analyze the outcomes of PD catheters inserted by surgeons (by open surgical or laparoscopic technique) and compare them with those inserted by nephrologists among ESRD patients who underwent elective PD catheter insertions between January 2009 and December 2012. The primary outcome measure was the proportion of catheters removed because of primary nonfunction. The secondary outcome measures were catheter survival, patient survival, and incidence of complications of catheter insertion. A total of 143 PD catheter insertions (88 by surgeons and 55 by nephrologists) performed in 132 patients were considered for the analysis. The primary nonfunction rate of PD catheter insertions in both groups was comparable (18.2% and 7.3%, P = 0.08). Break-in period was shorter in Group N (p = <0.001). No differences were noted in patient or catheter survival. Percutaneously placed PD catheters performed by nephrologists have comparable outcomes with surgically placed PD catheters among selected cases and have the advantage of lower costs, avoidance of operation theater scheduling issues, smaller incision length, and shorter break-in period. Therefore, more nephrologists should acquire the expertise on percutaneous PD catheter placement as it leads to lesser waiting times and better utilization of PD. PMID- 27512300 TI - Association of chemokine receptor CX3CR1 V249I and T280M polymorphisms with chronic kidney disease. AB - The chemokine fractalkine (CX3CL1) and its receptor CX3CR1 are involved in the activation of leukocytes. Two common single-nucleotide polymorphisms of the CX3CR1 gene, V249I and T280M, have been associated with reduced fractalkine signaling, leading to decreased adhesive function and leukocyte chemotaxis. We hypothesized that variation in the CX3CR1 gene could be associated with chronic kidney disease (CKD), a disease of inflammatory activation. We studied the association between CX3CR1 V249I and T280M polymorphisms, and fractalkine and highly sensitive C-reactive protein (hs-CRP) levels in 123 patients with CKD and 100 healthy controls (HCs). Genotype analysis was done by polymerase chain reaction-restriction fragment length polymorphism, and fractalkine and hs-CRP levels were analyzed by enzyme-linked immunosorbent assay. MM genotype of T280M was absent in CKD patients, while in controls it was seen in 1% of the individuals. The allele frequencies in both the groups were similar (P = 0.059). Compared to HC, M280M + T280M genotype was more frequent in CKD (P = 0.041). The frequency of II genotype of V249I was 0.8% in CKD, whereas in HC, it was 2%. I249I + V249I genotype was more frequent in CKD as compared to HC (P = 0.034). No difference in allelic frequency of V249I was noted between the two groups (P = 0.061, odds ratios = 1.74, 95% confidence intervals = 0.96-3.12). Plasma fractalkine and serum hs-CRP levels were higher in CKD subjects (P = 0.004 and P < 0.0001). No association of either genotype was found with fractalkine and hs CRP levels. Polymorphisms at I249 and M280 genotype in CX3CR1 gene are associated with CKD; however, there was no association of fractalkine or inflammatory marker with these genotypes. PMID- 27512301 TI - Epstein-Barr virus-positive multiple myeloma following an ABO incompatible second renal transplantation. AB - ABO incompatible kidney transplant recipients receive higher dose of immunosuppression. Previous data indicate that the incidence of malignancy is not higher in these patients. Compared to the general population, renal transplant recipients are at 4.4-fold higher risk of developing myeloma. We describe a case of posttransplant multiple myeloma in an ABO incompatible renal transplant recipient of a second graft. PMID- 27512302 TI - Lupus podocytopathy: An important differential diagnosis of nephrotic syndrome in systemic lupus erythematosus. AB - Some patients with systemic lupus erythematosus (SLE) present with sudden onset of nephrotic syndrome and biopsy findings may be of minimal change disease or focal segmental glomerulosclerosis with diffuse foot process effacement on electron microscopy but without significant immune deposits. This entity is termed lupus podocytopathy. Clinicians and renal pathologists need to be aware of this condition. Though steroid sensitive, it needs follow-up to recognize flare and class change, thereby optimizing therapy. PMID- 27512303 TI - Recurrent truncating mutations in alanine-glyoxylate aminotransferase gene in two South Indian families with primary hyperoxaluria type 1 causing later onset end stage kidney disease. AB - Primary hyperoxaluria type 1 is an autosomal recessive inborn error of metabolism due to liver-specific peroxisomal enzyme alanine-glyoxylate transaminase deficiency. Here, we describe two unrelated patients who were diagnosed to have primary hyperoxaluria. Homozygous c.445_452delGTGCTGCT (p.L151Nfs*14) (Transcript ID: ENST00000307503; human genome assembly GRCh38.p2) (HGMD ID CD073567) mutation was detected in both the patients and the parents were found to be heterozygous carriers. Our patients developed end-stage renal disease at 23 years and 35 years of age. However, in the largest series published from OxalEurope cohort, the median age of end-stage renal disease for null mutations carriers was 9.9 years, which is much earlier than our cases. Our patients had slower progressions as compared to three unrelated patients from North India and Pakistan, who had homozygous c.302T>C (p.L101P) (HGMD ID CM093792) mutation in exon 2. Further, patients need to be studied to find out if c.445_452delGTGCTGCT mutation represents a founder mutation in Southern India. PMID- 27512304 TI - Collapsing glomerulopathy associated with hepatitis B infection: A case report. AB - Collapsing glomerulopathy has been classified as a variant of focal segmental glomerulosclerosis. It is associated with infections, inflammations, and certain medications. While its association with human immunodeficiency virus has been well established its occurrence with hepatitis B has not been reported. We present here a case of collapsing glomerulopathy in a child with hepatitis B infection. PMID- 27512305 TI - Karyomegalic interstitial nephropathy following ifosfamide therapy. AB - Ifosfamide (IFO), an alkylating agent used for the management of solid organ tumors, can cause reversible Fanconi's syndrome and acute kidney injury. Karyomegalic interstitial nephropathy (KIN) is a rare form of chronic tubulointerstitial nephritis, initially described as a familial nephropathy in adults. So far, four cases of KIN have been reported in pediatric and adolescent population following treatment with IFO. We report a 22-year-old man who developed renal dysfunction following IFO therapy for relapsed Hodgkin's lymphoma. Renal biopsy revealed chronic tubulointerstitial nephritis with atypical tubular epithelial cells showing nuclear enlargement and hyperchromasia, consistent with a diagnosis of KIN. The renal function improved following a short course of corticosteroids. PMID- 27512306 TI - Lymphoblastic lymphoma presenting as bilateral renal enlargement diagnosed by percutaneous kidney biopsy: Report of three cases. AB - Renal involvement by lymphoma can be a diagnostic challenge. Acute kidney injury (AKI) is an unusual manifestation of lymphomatous infiltration in the kidneys. We report three cases of lymphoblastic lymphoma, a very rare form of lymphoma, presenting with AKI and bilateral enlargement of kidneys, diagnosed by percutaneous kidney biopsy. Lymphomatous infiltration should be suspected with such clinical presentation. Kidney biopsy is a valuable diagnostic tool, to establish the correct diagnosis and subtype of lymphoma for timely initiation of therapy for these aggressive hematological malignancies. PMID- 27512307 TI - Microfilaria associated macroscopic hematuria and nephrotic range proteinuria. PMID- 27512308 TI - Acquired perforating dermatosis in a diabetic patient on hemodialysis. PMID- 27512309 TI - Spontaneous reno-colic fistula in an elderly patient. PMID- 27512310 TI - Collapsing focal segmental glomerulosclerosis in a patient with systemic lupus erythematosus. PMID- 27512311 TI - An unusual cause of lower limb ulcer in renal allograft recipient. PMID- 27512312 TI - Bilateral renal cortical necrosis in a patient undergoing in vitro fertilization. PMID- 27512313 TI - Membranous glomerulonephritis overlapping with scabies. PMID- 27512314 TI - Secret in the eyes - fish eye disease. PMID- 27512315 TI - piRNAs and Their Functions in the Brain. AB - Piwi-interacting RNAs (piRNAs) are the non-coding RNAs with 24-32 nucleotides (nt). They exhibit stark differences in length, expression pattern, abundance, and genomic organization when compared to micro-RNAs (miRNAs). There are hundreds of thousands unique piRNA sequences in each species. Numerous piRNAs have been identified and deposited in public databases. Since the piRNAs were originally discovered and well-studied in the germline, a few other studies have reported the presence of piRNAs in somatic cells including neurons. This paper reviewed the common features, biogenesis, functions, and distributions of piRNAs and summarized their specific functions in the brain. This review may provide new insights and research direction for brain disorders. PMID- 27512316 TI - From Yama to Samyama. PMID- 27512317 TI - Yoga and heart rate variability: A comprehensive review of the literature. AB - Heart rate variability (HRV) has been used as a proxy for health and fitness and indicator of autonomic regulation and therefore, appears well placed to assess the changes occurring with mind.-body practices that facilitate autonomic balance. While many studies suggest that yoga influences HRV, such studies have not been systematically reviewed. We aimed to systematically review all published papers that report on yoga practices and HRV. A comprehensive search of multiple databases was conducted and all studies that reported a measure of HRV associated with any yoga practice were included. Studies were categorized by the study design and type of yoga practice. A total of 59 studies were reviewed involving a total of 2358 participants. Most studies were performed in India on relatively small numbers of healthy male yoga practitioners during a single laboratory session. Of the reviewed studies, 15 were randomized controlled trials with 6 having a Jadad score of 3. The reviewed studies suggest that yoga can affect cardiac autonomic regulation with increased HRV and vagal dominance during yoga practices. Regular yoga practitioners were also found to have increased vagal tone at rest compared to non-yoga practitioners. It is premature to draw any firm conclusions about yoga and HRV as most studies were of poor quality, with small sample sizes and insufficient reporting of study design and statistical methods. Rigorous studies with detailed reporting of yoga practices and any corresponding changes in respiration are required to determine the effect of yoga on HRV. PMID- 27512318 TI - Yoga-teaching protocol adapted for children with visual impairment. AB - CONTEXT: Childhood visual deficiency impairs children's neuro-psychomotor development, considerably affecting physical, mental, social, and emotional health. Yoga's multifaceted approach may help children with visual impairment (VI) to cope with their challenges. AIM: This study aimed to develop a special protocol for teaching yoga to children with VI, and to evaluate their preferred method of learning. METHODS: The study was carried out at Ramana Maharishi Academy for the Blind, Bengaluru, South India. Forty-one students volunteered to learn yoga practices, and classes were held weekly 5 days, 1 hr per session for 16 weeks. The study introduced a new method using a sequence of five teaching steps: verbal instructions, tactile modeling, step-by-step teaching, learning in a group, and physical guidance. A questionnaire concerning the preferred steps of learning was then given to each student, and verbal answers were obtained. RESULTS: A total of 33 (out of 41), aged 11.97 +/- 1.94, 15 girls and 18 boys responded. Twenty-six (78.79%) chose physical guidance as their most favored learning mode. CONCLUSIONS: Specially designed protocol may pave the way to impart yoga in an exciting and comfortable way to children with VI. More studies are needed to further investigate the effectiveness of this new yoga protocol in similar settings. PMID- 27512319 TI - Elements of yogic practice: Perceptions of students in healthcare programs. AB - BACKGROUND: The practice of yoga has a long history as an integrated lifestyle science. Those who have practiced yoga in its full form (including all eight traditional aspects) find that it touches almost every aspect of their inter- and intra-personal lives. Despite this rich history, the West has adopted limited aspects of yoga practice. When understood narrowly as a physical fitness practice, healthful benefits of yoga may be lost, possibly promoting body consciousness and injury instead. AIM: To understand whether students in healthcare programs view yoga from a physical fitness versus holistic perspective, we explored perceptions of what constitute yoga's essential practices. METHODS: We assessed endorsement of the eight limbs of yoga via the acceptability of yoga survey. The sample (n = 498) was recruited from programs in 10 healthcare professions at a Northwestern university. Participants were categorized as nonyogis, contemplators, yogis, and superyogis. RESULTS: Across all groups, findings confirmed a narrow definition of yoga as portrayed in popular media and gym-based yoga classes. Breathing and posture practices were the most commonly endorsed practices, even among the sample's most seasoned yoga practitioners. Ethical practices and daily commitments of introspection, disciplined practice, or living with purity were least commonly associated with yoga despite their foundational nature in yoga philosophy. Concentration and meditation practices were only moderately endorsed as essential practices. Super yogis endorsed a wider variety of limbs than nonyogis, contemplators, and yogis. CONCLUSIONS: We offer a rationale for these findings along with recommendations that may help augment the definition of yoga and hence maximize its benefits. PMID- 27512320 TI - Impact of individualized yoga therapy on perceived quality of life performance on cognitive tasks and depression among Type II diabetic patients. AB - CONTEXT: An individualized approach of providing yoga support can address many of the disease-related concerns indicated in the management of diabetes, specifically the impact on other life activities and long-term functional wellbeing. AIM: To analyze the role of regular yoga practice as a self-management approach to achieve glycemic control and psychological wellbeing in Type II diabetic patients. METHODS: Ninety-one subjects of both sexes responded to the announcement and consented to participate in the study. This was a single group, before and after yoga evaluation without control comparison. The fasting and postprandial blood sugar, glycosylated hemoglobin (HBA1c), cognitive tasks, depression, cognitive failure, and diabetic-related quality of life (QOL) were measured as pretest. The subjects underwent one-to-one individualized yoga therapy sessions, which included 12 supervised sessions spread over a 3-month period. The posttest data were analyzed using paired t-test and Wilcoxon paired rank test. RESULTS: Showed significant reduction in fasting blood sugar. QOL of the diabetic patients had improved significantly. There was a significant reduction in the frequency (mean difference of 7.58, P > 0.01) of depressive symptoms and intensity of depression (mean difference 1.66, P > 0.05). Concentration and attention span improved significantly and mean discrepancy score reduced (mean difference 3.42, P > 0.01). There were no marked changes in the postprandial blood sugar and HBA1c. CONCLUSION: Yoga practice enhances the subjective wellbeing, QOL, improves mood and concentration, and facilitates achievement of adequate glycemic control among Type II diabetic patients. PMID- 27512321 TI - A randomized controlled study on assessment of health status, depression, and anxiety in coal miners with chronic obstructive pulmonary disease following yoga training. AB - CONTEXT: Psychological comorbidities are prevalent in coal miners with chronic obstructive pulmonary disease (COPD) and contribute to the severity of the disease reducing their health status. Yoga has been shown to alleviate depression and anxiety associated with other chronic diseases but in COPD not been fully investigated. AIM: This study aimed to evaluate the role of yoga on health status, depression, and anxiety in coal miners with COPD. MATERIALS AND METHODS: This was a randomized trial with two study arms (yoga and control), which enrolled 81 coal miners, ranging from 36 to 60 years with stage II and III stable COPD. Both groups were either on conventional treatment or combination of conventional care with yoga program for 12 weeks. RESULTS: Data were collected through standardized questionnaires; COPD Assessment Test, Beck Depression Inventory and State and Trait Anxiety Inventory at the beginning and the end of the intervention. The yoga group showed statistically significant (P < 0.001) improvements on all scales within the group, all significantly different (P < 0.001) from changes observed in the controls. No significant prepost changes were observed in the control group (P > 0.05). CONCLUSION: Yoga program led to greater improvement in physical and mental health status than did conventional care. Yoga seems to be a safe, feasible, and effective treatment for patients with COPD. There is a need to conduct more comprehensive, high-quality, evidence-based studies to shed light on the current understanding of the efficacy of yoga in these chronic conditions and identify unanswered questions. PMID- 27512322 TI - Yoga protocol for treatment of breast cancer-related lymphedema. AB - INTRODUCTION: Vaqas and Ryan (2003) advocated yoga and breathing exercises for lymphedema. Narahari et al. (2007) developed an integrative medicine protocol for lower-limb lymphedema using yoga. Studies have hypothesized that yoga plays a similar role as that of central manual lymph drainage of Foldi's technique. This study explains how we have used yoga and breathing as a self-care intervention for breast cancer-related lymphedema (BCRL). METHODS: The study outcome was to create a yoga protocol for BCRL. Selection of yoga was based on the actions of muscles on joints, anatomical areas associated with different groups of lymph nodes, stretching of skin, and method of breathing in each yoga. The protocol was piloted in eight BCRL patients, observed its difficulties by interacting with patients. A literature search was conducted in PubMed and Cochrane library to identify the yoga protocols for BCRL. RESULTS: Twenty yoga and 5 breathing exercises were adopted. They have slow, methodical joint movements which helped patients to tolerate pain. Breathing was long and diaphragmatic. Flexion of joints was coordinated with exhalation and extension with inhalation. Alternate yoga was introduced to facilitate patients to perform complex movements. Yoga's joint movements, initial positions, and mode of breathing were compared to two other protocols. The volume reduced from 2.4 to 1.2 L in eight patients after continuous practice of yoga and compression at home for 3 months. There was improvement in the range of movement and intensity of pain. DISCUSSION: Yoga exercises were selected on the basis of their role in chest expansion, maximizing range of movements: flexion of large muscles, maximum stretch of skin, and thus part-by-part lymph drainage from center and periphery. This protocol addressed functional, volume, and movement issues of BCRL and was found to be superior to other BCRL yoga protocols. However, this protocol needs to be tested in centers routinely managing BCRL. PMID- 27512323 TI - The effects of yoga practice in school physical education on children's motor abilities and social behavior. AB - BACKGROUND: In recent years, yoga programs in childhood have been implemented in schools, to promote the development for children. AIM: To investigate the effects of yoga program in physical education classes on the motor abilities and social behavior parameters of 6-8-year-old children. METHODS: The study included 16 children from the 1(st) grade of a public elementary school in the South of Brazil. The children participated in a 12-week intervention, twice weekly, with 45 min each session. To assess children's performance, we used the Bruininks Oseretsky Test of Motor Proficiency - Second Edition, the flexibility test (sit and reach - Eurofit, 1988), the Pictorial Scale of Perceived Competence and Social Acceptance for Young Children and semi-structured interviews with children, parents, and classroom' teacher. Data were analyzed with Wilcoxon test and level of significance was 5%. RESULTS: The yoga program was well accepted by children, children also demonstrated significant and positive changes in overall motor abilities scores (balance, strength, and flexibility). In addition, the interviews reported changing in social behavior and the use of the knowledge learned in the program in contexts outside of school. CONCLUSION: These findings suggest that the implementation of yoga practice in physical education lessons contributed to children's development. PMID- 27512324 TI - Kapalabhati pranayama: An answer to modern day polycystic ovarian syndrome and coexisting metabolic syndrome? AB - Breath, the vital force of life, is controlled positively by pranayama to ensure homeostasis and wellbeing in humans. Kapalabhati is the rapid breathing technique of pranayama, which is considered as a cure for various ailments. The possible use of this technique to combat metabolic syndrome (MS) and polycystic ovarian syndrome (PCOS) has been discussed in this article. Various published literature from PubMed, Scopus, and theses were reviewed to reinforce the hypothesis that this technique is the answer to ailments due to modernization. It was worthwhile to note that Kapalabhati does combat various features of MS, but its efficacy against PCOS is yet to be proven. However, since both syndromes arise due to a common factor hyperinsulinemia primarily induced by stress in this modern world, it is hypothesized that Kapalabhati holds good against PCOS too. Hence, in conclusion, it can be said that it would be beneficial to conduct a study on PCOS women to ascertain the efficacy of Kapalabhati in their population. PMID- 27512325 TI - Mindfulness-based cognitive therapy in patients with late-life depression: A case series. AB - Depression is the most common mental illness in the elderly, and cost-effective treatments are required. Therefore, this study is aimed at evaluating the effectiveness of a mindfulness-based cognitive therapy (MBCT) on depressive symptoms, mindfulness skills, acceptance, and quality of life across four domains in patients with late-onset depression. A single case design with pre- and post assessment was adopted. Five patients meeting the specified inclusion and exclusion criteria were recruited for the study and assessed on the behavioral analysis pro forma, geriatric depression scale, Hamilton depression rating scale, Kentucky inventory of mindfulness skills, Acceptance and Action Questionnaire II, The World Health Organization quality of life Assessment Brief version (WHOQO-L BREF). The therapeutic program consisted of education regarding the nature of depression, training in formal and informal mindfulness meditation, and cognitive restructuring. A total of 8 sessions over 8 weeks were conducted for each patient. The results of this study indicate clinically significant improvement in the severity of depression, mindfulness skills, acceptance, and overall quality of life in all 5 patients. Eight-week MBCT program has led to reduction in depression and increased mindfulness skills, acceptance, and overall quality of life in patients with late-life depression. PMID- 27512326 TI - A rare case of branch retinal vein occlusion following Sirsasana. AB - Sirsasana is a type of headstand postural yoga in which the body is completely inverted. It is performed with or without wall support. In this position, the body is held upright supported by the forearms, while the crown of the head rests lightly on the floor. This is an advanced pose and should be attempted under the supervision of a qualified yoga instructor. The practice of Sirsasana is postulated to increase blood flow to the brain, improving memory, and other intellectual functions. It is also known to cause causes raised intraocular pressure, decompression retinopathy, glaucomatous visual field defects, central retinal vein occlusion, progression of glaucoma, optic neuropathy, and conjunctival varix thrombosis. We report a case of branch retinal vein occlusion following Sirsasana in a patient with systemic hypertension. PMID- 27512327 TI - Yoga as an adjunct modality for promotion of healthy use of information technology. PMID- 27512328 TI - What's new in emergencies, trauma, and shock: Intentional or accidental hypothermia in Intensive Care Unit patients: Time to strike the colors? PMID- 27512329 TI - In the blink of an eye: Instant countertransference and its application in modern healthcare. PMID- 27512330 TI - Hypothermia as a predictor for mortality in trauma patients at admittance to the Intensive Care Unit. AB - AIMS: To study the impact of hypothermia upon admission to the Intensive Care Unit (ICU) on early and late mortality and to develop a prediction model for late mortality in severely injured trauma patients. MATERIALS AND METHODS: A multicenter retrospective cohort study was performed in adult trauma patients admitted to the ICU of two Level-1 trauma centers between 2007 and 2012. Hypothermia was defined as a core body temperature of <=35 degrees Celsius. Logistic regression analyses were performed to quantify the effect of hypothermia on 24-hour and 28-day mortality and to develop a prediction model. RESULTS: A total of 953 patients were included, of which 354 patients had hypothermia (37%) upon ICU admission. Patients were divided into a normothermic or hypothermic group. Hypothermia was associated with a significantly increased mortality at 24 hours and 28 days (OR 2.72 (1.18-6.29 and OR 2.82 (1.83-4.35) resp.). The variables included in the final prediction model were hypothermia, age, APACHE II score (corrected for temperature), INR, platelet count, traumatic brain injury and Injury Severity Score. The final prediction model discriminated between survivors and non-survivors with high accuracy (AUC = 0.871, 95% CI 0.844-0.898). CONCLUSIONS: Hypothermia, defined as a temperature <=35 degrees Celsius, is common in critically ill trauma patients and is one of the most important physiological predictors for early and late mortality in trauma patients. Trauma patients admitted to the ICU may be at high risk for late mortality if the patient is hypothermic, coagulopathic, severely injured and has traumatic brain injury or an advanced age. PMID- 27512331 TI - Extremes of shock index predicts death in trauma patients. AB - CONTEXT: We noted a bimodal relationship between mortality and shock index (SI), the ratio of heart rate to systolic blood pressure. AIMS: To determine if extremes of SI can predict mortality in trauma patients. SETTINGS AND DESIGNS: Retrospective evaluation of adult trauma patients at a tertiary care center from 2000 to 2012 in the United States. MATERIALS AND METHODS: We examined the SI in trauma patients and determined the adjusted mortality for patients with and without head injuries. STATISTICAL ANALYSIS USED: Descriptive statistics and multivariable logistic regression. RESULTS: SI values demonstrated a U-shaped relationship with mortality. Compared with patients with a SI between 0.5 and 0.7, patients with a SI of <0.3 had an odds ratio for death of 2.2 (95% confidence interval [CI] 21.2-4.1) after adjustment for age, Glasgow Coma score, and injury severity score while patients with SI >1.3 had an odds ratio of death of 3.1. (95% CI 1.6-5.9). Elevated SI is associated with increased mortality in patients with isolated torso injuries, and is associated with death at both low and high values in patients with head injury. CONCLUSION: Our data indicate a bimodal relationship between SI and mortality in head injured patients that persists after correction for various co-factors. The distribution of mortality is different between head injured patients and patients without head injuries. Elevated SI predicts death in all trauma patients, but low SI values only predict death in head injured patients. PMID- 27512332 TI - Mortality in trauma patients with active arterial bleeding managed by embolization or surgical packing: An observational cohort study of 66 patients. AB - OBJECTIVE: Exsanguination due to coagulopathy and vascular injury is a common cause of death among trauma patients. Arterial injury can be treated either by angiography and embolization or by explorative laparotomy and surgical packing. The purpose of this study was to compare 30-day mortality and blood product consumption in trauma patients with active arterial haemorrhage in the abdominal and/or pelvic region treated with either angiography and embolization or explorative laparotomy and surgical packing. MATERIAL AND METHODS: From January 1(st) 2006 to December 31(st) 2011 2,173 patients with an ISS of >9 were admitted to the Trauma Centre of Copenhagen University Hospital, Rigshospitalet, Denmark. Of these, 66 patients met the inclusion criteria: age above 15 years and active arterial haemorrhage from the abdominal and/or pelvic region verified by a CT scan at admission. Gender, age, initial oxygen saturation, pulse rate and respiratory rate, mechanism of injury, ISS, Probability of Survival, treatment modality, 30-day mortality and number and type of blood products applied were retrieved from the TARN database, patient records and the Danish Civil Registration System. RESULTS: Thirty-one patients received angiography and embolization, and 35 patients underwent exploratory laparotomy and surgical packing. Gender, age, initial oxygen saturation, pulse rate and respiratory rate, ISS and Probability of Survival were comparable in the two groups. CONCLUSION: A significant increased risk of 30-day mortality (P = 0.04) was found in patients with active bleeding treated with explorative laparotomy and surgical packing compared to angiography and embolization when data was adjusted for age and ISS. No statistical significant difference (P > 0.05) was found in number of transfused blood products applied in the two groups of patients. PMID- 27512333 TI - Assessment of cardiopulmonary resuscitation practices in emergency departments for out-of-hospital cardiac arrest victims in Lebanon. AB - BACKGROUND: The survival rate of out-of-hospital cardiac arrest (OHCA) victims in Lebanon is low. A national policy on resuscitation practice is lacking. This survey explored the practices of emergency physicians related to the resuscitation of OHCA victims in Lebanon. METHODS: A sample of 705 physicians working in emergency departments (EDs) was recruited and surveyed using the LimeSurvey software (Carsten Schmitz, Germany). Seventy-five participants responded, yielding 10.64% response rate. RESULTS: The most important factors in the participants' decision to initiate or continue resuscitation were presence of pulse on arrival (93.2%), underlying cardiac rhythm (93.1%), the physician's ethical duty to resuscitate (93.2%), transport time to the ED (89%), and down time (84.9%). The participants were optimistic regarding the survival of OHCA victims (58.1% reporting > 10% survival) and reported frequent resuscitation attempts in medically futile situations. The most frequently reported challenges during resuscitation decisions were related to pressure or presence of victim's family (38.8%) and lack of policy (30%). CONCLUSION: In our setting, physicians often rely on well-established criteria for initiating/continuing resuscitation; however, their decisions are also influenced by cultural factors such as victim's family wishes. The findings support the need for a national policy on resuscitation of OHCA victims. PMID- 27512334 TI - Medical demographics in sub-Saharan Africa: Does the proportion of elderly patients in accident and emergency units mirror life expectancy trends? PMID- 27512335 TI - Delayed diagnosis of a thoracolumbar flexion-distraction injury. PMID- 27512336 TI - The Need for Psychosocial Interventions to Facilitate the Transition to Extended Release Naltrexone (XR-NTX) Treatment for Opioid Dependence: A Concise Review of the Literature. AB - Given the increase of opioid dependence and opioid-related morbidity and mortality, improving treatment options for individuals with opioid dependence warrants increased attention. This article provides a concise review of work in this area. Remission from opioid dependence can be very difficult to sustain, particularly in the absence of opioid replacement or opioid antagonist therapy. For those who wish to transition from opioid use or opioid replacement therapy to opioid antagonist therapy, a significant challenge can be the period of withdrawal symptoms that must be endured prior to the initiation of opioid antagonist therapy. Studies that have incorporated psychosocial interventions into detoxification protocols have found that they can result in improved treatment outcomes. Interventions based on Acceptance and Commitment Therapy have shown promise in the treatment of clinical disorders that present with symptoms similar to those of opioid withdrawal and have been found to positively impact outcomes among those tapering from methadone. However, the use of an Acceptance and Commitment Therapy-based intervention has yet to be studied among opioid dependent patients transitioning to XR-NTX, and its value to those transitioning to XR-NTX is currently unknown. PMID- 27512337 TI - Interactions Between Internalizing Symptoms and Urgency in the Prediction of Alcohol Use and Expectancies Among Low-Income, Minority Early Adolescents. AB - This study examined whether urgency, a disposition to rash action under conditions of strong emotion, moderates associations between internalizing symptoms and alcohol use and related expectancies. Data from the Camden Youth Development Study, a longitudinal, community-based study of early adolescents (N = 144, mean age at intake = 11.9 years; 65% Hispanic, 30% African-American; 50% male), were used. Self-report questionnaire measures of depressive symptoms, social and generalized anxiety symptoms, urgency, alcohol use, and alcohol expectancies were used. Mixed models were used to examine the effects of internalizing symptoms, urgency, and their interaction on alcohol use and expectancy trajectories over time. Depressive symptoms interacted with urgency such that youth with high levels of both tended to have elevated levels of global positive alcohol expectancies. Social anxiety symptoms interacted with urgency to be associated with increasing levels of social behavior alcohol expectancies such that youth with high levels of both tended to experience particular increases in these expectancies over time. Generalized anxiety was not found to be associated with alcohol-related constructs. Therefore, high levels of urgency combine with depressive and social anxiety symptoms to be associated with particularly increased risk for alcohol expectancies that are associated with later alcohol use and problems, indicating particular risk for youth with these combinations of personality traits and psychopathology symptoms. PMID- 27512338 TI - Molecular Properties of Red Wine Compounds and Cardiometabolic Benefits. AB - Wine has been used since the dawn of human civilization. Despite many health benefits, there is still a lot of discussion about the real properties of its components and its actions on cells and molecular interactions. A large part of these issues permeate the fine line between the amount of alcohol that causes problems to organic systems and the amount that could be beneficial for the health. However, even after the process of fermentation, wine conserves different organic compounds from grapes, such as polysaccharides, acids, and phenolic compounds, such as flavonoids and nonflavonoids. These substances have known anti inflammatory and antioxidant capacities, and are considered as regulatory agents in cardiometabolic process. In this study, the main chemical components present in the wine, its interaction with molecules and biological mechanisms, and their interference with intra- and extracellular signaling are reviewed. Finally, the properties of wine that may benefit cardiovascular system are also revised. PMID- 27512340 TI - Resetting Human Naive Pluripotency. AB - The rodent naive pluripotent state is believed to represent the preimplantation inner cell mass state of the developing blastocyst and can derive self-renewing pluripotent embryonic stem cells (ESCs) in vitro. Nevertheless, human ESCs exhibit epigenetic, metabolic, and transcriptomic characteristics more akin to primed pluripotent stem cells (PSCs) derived from the postimplantation epiblast. Understanding the genetic and epigenetic mechanisms that constrain human ESCs in the primed state is crucial for the human naive pluripotent state resetting and numerous applications in regenerative medicine. In this review, we begin by defining the naive and primed states in the murine model and compare the epigenetic characteristics of those states to the human PSCs. We also examine the various reprogramming schemes to derive the human naive pluripotent state. Finally, we discuss future perspectives of studying and deriving the human naive PSCs in the context of cellular engineering and regenerative medicine. PMID- 27512339 TI - The Evolution of Epigenetics: From Prokaryotes to Humans and Its Biological Consequences. AB - The evolution process includes genetic alterations that started with prokaryotes and now continues in humans. A distinct difference between prokaryotic chromosomes and eukaryotic chromosomes involves histones. As evolution progressed, genetic alterations accumulated and a mechanism for gene selection developed. It was as if nature was experimenting to optimally utilize the gene pool without changing individual gene sequences. This mechanism is called epigenetics, as it is above the genome. Curiously, the mechanism of epigenetic regulation in prokaryotes is strikingly different from that in eukaryotes, mainly higher eukaryotes, like mammals. In fact, epigenetics plays a significant role in the conserved process of embryogenesis and human development. Malfunction of epigenetic regulation results in many types of undesirable effects, including cardiovascular disease, metabolic disorders, autoimmune diseases, and cancer. This review provides a comparative analysis and new insights into these aspects. PMID- 27512341 TI - Concomitant Classic Hodgkin Lymphoma of Lymph Node and cMYC-Positive Burkitt Leukemia/Lymphoma of the Bone Marrow Presented Concurrently at the Time of Presentation: A Rare Combination of Discordant Lymphomas. AB - Discordant lymphoma is rare condition in which different types of malignant lymphomas occurring in different anatomic sites. The two diseases may present clinically as concurrent or sequential disease (10). Herein we are reporting a Pakistani female in her 60s, a carrier of hepatitis B virus with multiple comorbidities presented with cervical lymphadenopathy, diagnosed as Hodgkin's lymphoma, mixed cellularity. During the staging workup, the patient was discovered to have extensive bone marrow (BM) involvement by Burkitt leukaemia/lymphoma (BL). Cytogenetic analysis revealed positivity for t(8;14)(q24;q32) confirmed by Fluorescence In Situ Hybridization (FISH) for IGH/MYC. Epstein-Barr virus (EBV) was demonstrated heavily in our case, with (EBV) DNA of 24,295,560 copies/ml by PCR at time of presentation, in addition, the neoplastic cells in both diagnostic tissues (cervical lymph node and BM) demonstrated positivity for EBV. A diagnosis of concomitant EBV related discordant lymphoma (classical Hodgkin lymphoma (cHL) and Burkitt lymphoma (BL) in leukemic phase was made. Among all reported cases, this case is highly exceptional because it is the first case of discordant/composite lymphoma, with this combination and concomitant presentation. Since we are dealing with a case with an exceptionally rare combination, we found it significant to elaborate more on its clinical features, contributing factors including EBV role, response to treatment, complications, and prognosis. PMID- 27512342 TI - Cytokines and Prognostic Factors in Epithelial Ovarian Cancer. AB - INTRODUCTION: Ovarian cancer has a high mortality and delayed diagnosis. Inflammation is a risk factor for ovarian cancer, and the inflammatory response is involved in almost all stages of tumor development. Immunohistochemical staining in stroma and epithelium of a panel of cytokines in benign and malignant ovarian neoplasm was evaluated. In addition, immunostaining was related to prognostic factors in malignant tumors. METHOD: The study group comprised 28 ovarian benign neoplasias and 28 ovarian malignant neoplasms. A panel of cytokines was evaluated by immunohistochemistry (Th1: IL-2 and IL-8; Th2: IL-5, IL-6, and IL-10; and TNFR1). Chi-square test with Yates' correction was used, which was considered significant if less than 0.05. RESULTS: TNFR1, IL-5, and IL 10 had more frequent immunostaining 2/3 in benign neoplasms compared with malignant tumors. Malignant tumors had more frequent immunostaining 2/3 for IL-2 in relation to benign tumors. The immunostaining 0/1 of IL 8 was more frequent in the stroma of benign neoplasms compared with malignant neoplasms. Evaluation of the ovarian cancer stroma showed that histological grade 3 was significantly correlated with staining 2/3 for IL-2 (P = 0.004). Women whose disease-free survival was less than 2.5 years had TNFR1 stromal staining 2/3 (P = 0.03) more frequently. CONCLUSION: IL-2 and TNFR1 stromal immunostaining are related prognostic factors in ovarian cancer and can be the target of new therapeutic strategies. PMID- 27512343 TI - An evidence-based laparoscopic simulation curriculum shortens the clinical learning curve and reduces surgical adverse events. AB - BACKGROUND: Surgical simulation is becoming increasingly important in surgical education. However, the method of simulation to be incorporated into a surgical curriculum is unclear. We compared the effectiveness of a proficiency-based preclinical simulation training in laparoscopy with conventional surgical training and conventional surgical training interspersed with standard simulation sessions. MATERIALS AND METHODS: In this prospective single-blinded trial, 30 final-year medical students were randomized into three groups, which differed in the way they were exposed to laparoscopic simulation training. The control group received only clinical training during residency, whereas the interval group received clinical training in combination with simulation training. The Center for Surgical Technologies Preclinical Training Program (CST PTP) group received a proficiency-based preclinical simulation course during the final year of medical school but was not exposed to any extra simulation training during surgical residency. After 6 months of surgical residency, the influence on the learning curve while performing five consecutive human laparoscopic cholecystectomies was evaluated with motion tracking, time, Global Operative Assessment of Laparoscopic Skills, and number of adverse events (perforation of gall bladder, bleeding, and damage to liver tissue). RESULTS: The odds of adverse events were 4.5 (95% confidence interval 1.3-15.3) and 3.9 (95% confidence interval 1.5-9.7) times lower for the CST PTP group compared with the control and interval groups. For raw time, corrected time, movements, path length, and Global Operative Assessment of Laparoscopic Skills, the CST PTP trainees nearly always started at a better level and were never outperformed by the other trainees. CONCLUSION: Proficiency based preclinical training has a positive impact on the learning curve of a laparoscopic cholecystectomy and diminishes adverse events. PMID- 27512344 TI - A non-autonomous optimal control model of renewable energy production under the aspect of fluctuating supply and learning by doing. AB - Given the constantly raising world-wide energy demand and the accompanying increase in greenhouse gas emissions that pushes the progression of climate change, the possibly most important task in future is to find a carbon-low energy supply that finds the right balance between sustainability and energy security. For renewable energy generation, however, especially the second aspect turns out to be difficult as the supply of renewable sources underlies strong volatility. Further on, investment costs for new technologies are so high that competitiveness with conventional energy forms is hard to achieve. To address this issue, we analyze in this paper a non-autonomous optimal control model considering the optimal composition of a portfolio that consists of fossil and renewable energy and which is used to cover the energy demand of a small country. While fossil energy is assumed to be constantly available, the supply of the renewable resource fluctuates seasonally. We further on include learning effects for the renewable energy technology, which will underline the importance of considering the whole life span of such a technology for long-term energy planning decisions. PMID- 27512345 TI - Role of CaCO3 degrees Neutral Pair in Calcium Carbonate Crystallization. AB - The molecular structure of the units that get incorporated into the nuclei of the crystalline phase and sustain their growth is a fundamental issue in the pathway from a supersaturated solution to the formation of crystals. Using a fluorescent dye we have recorded the variation of the pH value in time along a gel where CaCl2 and NaHCO3 counter-diffuse to crystallize CaCO3. The same pH-space-time distribution maps were also computationally obtained using a chemical speciation code (phreeqc). Using data arising from this model we investigated the space-time evolution of the activity of the single species (ions and ion pairs) involved in the crystallization process. Our combined results suggest that, whatever the pathway from solution to crystals, the neutral pair CaCO3 degrees is a key species in the CaCO3 precipitation system. PMID- 27512346 TI - Internet-Based Interventions for Women's Sexual Dysfunction. AB - The present paper gives an overview of the methodology and results of the first decade of research into Internet-based interventions for women's sexual dysfunction. The interventions, retrieved in a literature search, were mostly well grounded on common theoretical models of sexual dysfunction and psychological disorders, and most ingredients of the interventions were theory informed. Most interventions offered Web-based therapeutic content within a more or less preprogrammed structure. Most of these also offered prescheduled and/or participant-initiated contact with a sexual health care professional. Comparative effect studies showed improvements in sexual functioning as well as relational functioning at the point of termination of the intervention period. Improvements at posttreatment were generally maintained for several months after termination of the active intervention period. The results of this review seem to warrant further development of Internet-based interventions for women's sexual dysfunctions. PMID- 27512347 TI - Fibrocytes in the Pathogenesis of Chronic Fibrotic Lung Disease. AB - Fibrocytes were initially described in 1999 and since that time there has been a growing body of literature to suggest their importance in a number of chronic lung diseases. It is now well established that fibrocytes derive from the bone marrow and circulate within the peripheral blood. However, when injury occurs, fibrocytes can travel to the site of damage via chemokine-mediated recruitment. Recent studies suggest that fibrocyte numbers increase within the lung or circulation during numerous disease processes. Although fibrocytes readily differentiate into fibroblasts in vitro, whether they do so in vivo is still unknown. The variety of pro-fibrotic mediators that are secreted by fibrocytes makes it likely that they act via paracrine functions to influence the behavior of resident lung cells. This review summarizes recent insights regarding fibrocytes in asthma, scleroderma and IPF. PMID- 27512348 TI - MiRNA in atopic dermatitis. AB - MicroRNAs are relatively new molecules that have been widely studied in recent years as to determine their exact function in the human body. It is suggested that microRNAs control approx. 30% of all genes, making them one of the largest groups that control the expression of proteins. Various functions of miRNAs have already been described. In skin diseases, there are more and more studies describing an altered expression of microRNAs in the skin or serum. Relatively little is known about the function of these molecules in atopic dermatitis, which prompted us to gather current reports on this subject. PMID- 27512349 TI - In vivo studies of substances used in the cosmetic industry. AB - Cosmetic producers are obliged to guarantee the safety and stability of their products. The current legal regulations are based on the European Union Directive (1223/2009) of 30 November 2009. The main aim of the directive is to formulate criteria of safety of a cosmetic product and requirements that it must meet to be placed on the market. A new cosmetic product is subjected to thorough investigation prior to its introduction on the market. It should be studied not only with respect to its safety, but also with respect to its effectiveness declared by the producer. The studies are performed in vivo, by the contact or epidermal patch tests on the human skin. PMID- 27512350 TI - Medium dose ultraviolet A1 phototherapy and mRNA expression of interleukin 8, interferon gamma, and chemokine receptor 4 in acute skin lesions in atopic dermatitis. AB - INTRODUCTION: Mechanisms responsible for UVA1 efficacy in atopic dermatitis (AD) are not fully elucidated. AIM: To investigate IL-8, CCR-4, and IFN-gamma mRNA expression in AD before and after UVA1, to identify correlations among them, and to determine whether and to what degree mRNA expression is influenced by UVA1. MATERIAL AND METHODS: Twenty-five patients with AD underwent medium dose UVA1 phototherapy at daily dosages of 10, 20, 30, 45, and then continuing 45 J/cm(2) up to 20 days, from Monday to Friday for 4 weeks. Before and after UVA1, biopsies from acute skin lesions were studied using reverse-transcription and RT-PCR. RESULTS: The levels of CCR-4 mRNA correlated with those of IFN-gamma, both before and after UVA1 phototherapy (p < 0.05). A significant correlation was found after UVA1 between mRNA levels of IL-8 and IFN-gamma (p < 0.05). After UVA1 an increase in IL-8 mRNA expression in comparison to the baseline assessment (p = 0.02) was found, while no significant difference was revealed in the expression of CCR-4 and IFN-gamma mRNA. UVA1 improved both SCORAD and severity of AD (p < 0.001). SCORAD and the severity of AD did not correlate with the degree of expression of measured cytokine mRNA, neither before nor after UVA1. CONCLUSIONS: CCR-4 is expressed in parallel with IFN-gamma in acute skin lesions of patients with AD both before and after UVA1 phototherapy. UVA1 significantly improves SCORAD index, lessens the severity of AD and increases the expression of IL-8, with no direct effects on other studied molecules. PMID- 27512351 TI - Prevalence of skin disorders in primary and secondary school age children in Canakkale, Turkey: a community-based survey. AB - INTRODUCTION: Skin lesions may be of dermatological importance, affect appearance, and cause problems communicating with peers and may be especially more significant in childhood. AIM: Information on the prevalence of pediatric dermatoses in Western Turkey. This study was aimed to define the existing data. MATERIAL AND METHODS: A cross-sectional study was conducted in Canakkale, Turkey, in September-December 2013. It involved 1,957 students from five randomly selected primary and secondary schools. Each student was interviewed for age, gender, and family history, and a dermatologic examination was performed by a dermatologist. Data were coded and analyzed. RESULTS: Of the students, 79.9% revealed at least one dermatosis. The most common disease was benign neoplasms (76%), followed by pigmentary disorders (26.8%), and xerosis (5.8%). In primary schools, the acquired melanocytic nevus, hypopigmented macule, and xerosis; in secondary school the acne was statistically significantly more common. Acne and xerosis was more common in girls, and pityriasis alba was statistically more common in boys. Students who had at least one dermatosis were positively correlated with monthly income. CONCLUSIONS: In Turkish school age children, the prevalence of dermatosis is 79.9%. It may be due to not using preventive means for adequate protection from the sun and other environmental factors. Infectious dermatosis and atopic dermatitis are rare and it may depend on the adequacy of public health work. PMID- 27512352 TI - Can mean platelet volume be used as a biomarker for asthma? AB - INTRODUCTION: Platelets play important roles in airway inflammation and are activated in inflammatory lung diseases, including asthma. AIM: We evaluated the mean platelet volume (MPV), used as a marker of platelet activation, in asthmatic patients during asymptomatic periods and exacerbations compared to healthy controls to determine whether MPV can be used as an indicator of inflammation. MATERIAL AND METHODS: Our patient group consisted of 95 children with exacerbation of asthma who were admitted to our allergy clinic. The control group consisted of 100 healthy children matched for age, gender, and ethnicity. Mean platelet volume values of the patient group obtained during exacerbation of asthma were compared to those of the same group during the asymptomatic period and with the control group. We investigated factors that can affect the MPV values of asthma patients, including infection, atopy, immunotherapy treatment, and severity of asthma exacerbation. RESULTS: The patient group consisted of 50 (52.6%) boys and 45 (47.4%) girls with a mean age of 125 +/-38 months old. Mean MPV values in the exacerbation period, the healthy period, and in the control group were 8.1 +/-0.8 fl, 8.1 +/-1.06 fl, and 8.2 +/-0.9 fl, respectively; there were no significant differences between groups (p > 0.05). The severity of asthma, severity of asthma exacerbation, immunotherapy, coinfection, eosinophil count, and IgE level also had no effect on MPV (p > 0.05). CONCLUSIONS: Although platelets play a role in the pathophysiology of asthma, MPV measurement is insufficient to detect inflammation through platelets. PMID- 27512353 TI - Assessment of systemic inflammation with neutrophil-lymphocyte ratio in lichen planus. AB - INTRODUCTION: Lichen planus (LP) is a papulosquamous eruption of the skin and mucous membranes. Although the exact pathogenesis of the disease remains unclear, it is believed that LP represents an inflammatory disorder. Neutrophil-lymphocyte (N/L) ratio is considered a systemic inflammatory marker that correlated with severity of the diseases. AIM: To investigate whether N/L ratio increases in LP and may be an independent severity marker for LP lesions. MATERIAL AND METHODS: White blood cell (WBC), neutrophil and lymphocyte counts, N/L ratio, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were statistically compared between the patient (n = 55) and the control group (n = 48). The relationship of N/L ratio and the body surface area (BSA) was assessed. RESULTS: Erythrocyte sedimentation rate and CRP were statistically higher in patients with LP than in controls (p < 0.0001). Our analysis revealed a significantly higher level of N/L ratio in patients with LP compared with controls, respectively (2.5 +/-1.1 (1.2 7.3) vs. 1.4 +/-0.4 (0.8-2.7), p < 0.0001). Body surface area (p = 0.001), CRP (p = 0.006), and ESR (p = 0.003) were identified as possible predictors of N/L ratio, but only BSA (p = 0.002) and ESR (p = 0.003) were found as significant independent predictors in a multiple linear regression model. CONCLUSIONS: The inflammatory process in LP was supported by our results. N/L ratio may have an impact to show the inflammatory status in patients with LP as an inexpensive, simple and effective predictor. It may be used for the severity and treatment option of LP. But, N/L ratio and LP relationship could be confirmed by other large prospective studies. PMID- 27512354 TI - Thermographic assessment of skin prick tests in comparison with the routine evaluation methods. AB - INTRODUCTION: The skin prick test is still the first and basic procedure in the diagnosis of allergic diseases. The possibility of using a sensitive thermographic method supported by the mathematical model for the assessment of skin test results will be highlighted in the studies. AIM: To compare the proposed approach with routine planimetric and thermographic methods. MATERIAL AND METHODS: A mathematical model of allergic reaction was developed. Simplifying assumptions of the IgE-mediated skin reaction is the essence of the model. Investigations were performed in a group of 40 patients. RESULTS: Using the spatio-temporal evolution of temperature distributions, the ratios of the histamine released from mast cells to the control histamine were determined. The obtained values very well correlate with the standard evaluation of skin prick tests (correlation coefficient = 0.98). CONCLUSIONS: The proposed method of skin test evaluation presents several advantages. The continuous acquisition of data provides the monitoring of time course of the allergic response. The transport of mediator and its concentration were distinctly discriminated, which may be diagnostically useful, especially for abnormal cases. The high sensitivity of the method enables studying patients regardless of age and skin sensitivity. PMID- 27512355 TI - Comparison of efficacy of chemical peeling with 25% trichloroacetic acid and 0.1% retinoic acid for facial rejuvenation. AB - INTRODUCTION: Skin aging is a problem which negatively affects the psyche of the person, social relations, as well as work life and health and which compels the patients to find appropriate treatment methods. Numerous treatment methods have been developed in order to delay aging and to reduce the aging effects in addition to having a younger, healthier and more beautiful facial appearance. AIM: To compare the efficiency, cosmetic results and possible adverse effects of the peeling treatment with 25% trichloroacetic acid (TCA) and 0.1% retinoic acid for facial rejuvenation in patients presenting with skin aging. MATERIAL AND METHODS: Fifty female patients in total presenting with medium and advanced degree skin aging were subject to this study. Two separate treatment groups were formed; the first group underwent chemical skin treatment with 25% TCA while the other group was applied with 0.1% retinoic acid treatment. Following the 4 months' treatment the patients were controlled three times in total for post lesional hypopigmentation, hyperpigmentation, scars, skin irritation and other possible changes per month. The pretreatment and first follow-up visit, and final control images were comparatively evaluated by three observers via specific software. RESULTS: The healing rates of the group subject to retinoic acid were statistically higher (p < 0.05) compared to patients in the TCA group in the final follow-up visit following the treatment according to the first and second observers. On the other hand, according to the third observer, patients applied with retinoic acid presented with higher healing rates compared to those treated with TCA, however; this rate was not statistically significant (p > 0.05). The frequency of TCA- and retinoic acid-associated adverse effects was similar in both groups (p > 0.05). As a result of both treatments, a reduction in the quality of life scores as well as a pronounced recovery (p = 0.001) in the quality of life of those patients with skin aging was observed. CONCLUSIONS: The photo aging treatment option with 0.1% retinoic acid is cheaper and more feasible for patients compared to 25% TCA, and it is also as reliable and effective as TCA. PMID- 27512356 TI - The correlation between anti phospholipase A2 specific IgE and clinical symptoms after a bee sting in beekeepers. AB - INTRODUCTION: Beekeepers are a group of people with high exposure to honeybee stings and with a very high risk of allergy to bee venom. Therefore, they are a proper population to study the correlations between clinical symptoms and results of diagnostic tests. AIM: The primary aim of our study was to assess the correlations between total IgE, venom- and phospholipase A2-specific IgE and clinical symptoms after a bee sting in beekeepers. The secondary aim was to compare the results of diagnostic tests in beekeepers and in individuals with standard exposure to bees. MATERIAL AND METHODS: Fifty-four individuals were divided into two groups: beekeepers and control group. The levels of total IgE (tIgE), venom-specific IgE (venom sIgE), and phospholipase A2-specific IgE (phospholipase A2 sIgE) were analyzed. RESULTS: Our study showed no statistically significant correlation between the clinical symptoms after a sting and tIgE in the entire analyzed group. There was also no correlation between venom sIgE level and clinical symptoms either in beekeepers or in the group with standard exposure to bees. We observed a statistically significant correlation between phospholipase A2 sIgE level and clinical signs after a sting in the group of beekeepers, whereas no such correlation was detected in the control group. Significantly higher venom-specific IgE levels in the beekeepers, as compared to control individuals were shown. CONCLUSIONS: In beekeepers, the severity of clinical symptoms after a bee sting correlated better with phospholipase A2 sIgE than with venom sIgE levels. PMID- 27512357 TI - Selected immunological parameters in clinical evaluation of patients with atopic dermatitis. AB - INTRODUCTION: It has been suggested that soluble immune receptors (SIRs) such as sCD25 and sCD30 may serve as potential biomarkers in evaluation of atopic dermatitis (AD). Previous studies clearly indicated that serum levels of interleukin (IL)-13 and total IgE (tIgE) might be potentially useful in the evaluation of patents with AD. AIM: To evaluate whether serum levels of sCD25 and sCD30 are suitable biomarkers of AD. Moreover, we have decided to estimate the usefulness of tIgE and IL-13 serum level determination in the evaluated population. MATERIAL AND METHODS: A group of 102 AD patients was investigated. Serum concentrations of sCD30, sCD25, IL-13 and tIgE were measured. The clinical phenotype of AD was classified as extrinsic (ADe) or intrinsic (ADi) based on the presence of IgE. Statistical analysis was performed to estimate correlations between obtained results and clinical features of the population such as AD phenotype, age, disease extent and severity. RESULTS: Extrinsic AD was diagnosed in 71% of patients, while ADi phenotype was observed in 29% of the investigated population. A negative correlation between serum levels of sCD25 and sCD30 and disease severity as well patients' age was established. Serum levels of IL-13 did not reach the cut-off point set by the manufacturer. A positive correlation between serum levels of total IgE and disease severity and patients' age was observed. CONCLUSIONS: This paper shows that serum levels of sCD25 and sCD30 as well as tIgE are age dependent. Determination of serum levels of sCD25, sCD30 and IL-13 is not useful in everyday practice. PMID- 27512358 TI - The relationship between body mass index, waist circumference and psoriatic arthritis in the Turkish population. AB - INTRODUCTION: Psoriasis is a chronic, immune-mediated inflammatory disease predominantly affecting the skin, with a complex aetiology. Recently it has been suggested that the chronic inflammation of psoriasis may cause metabolic and vascular disorders. The relationship between obesity and psoriatic arthritis (PsA) is not clear, and there are insufficient prospective studies addressing this subject. AIM: To investigate the relationship between psoriatic arthritis, severity of psoriasis and obesity in the Turkish population. MATERIAL AND METHODS: Patient data from psoriasis outpatient clinics from February 2007 to July 2013 were reviewed retrospectively using the Psoriasis-Turkey (PSR-TR) registration system. Patients' age, onset age, body mass index (BMI), waist circumference, psoriasis area and severity index (PASI), and arthritis information were reviewed. In the outpatient clinics, patients who had joint pain consulted rheumatology clinics. The CASPAR criteria were used for the diagnosis of arthritis. RESULTS: A total of 443 males and 495 females enrolled in this study. The mean age of females was 43.9 years (18-93 years) and the mean age of males was 44.6 years (18-89 years). A total of 231 (25%) patients had psoriatic arthritis. Investigation of the relationship between PASI, BMI, waist circumference (WC) and arthritis revealed a statistically significant relationship between each variable. CONCLUSIONS: In this study we observed a relationship between PsA and high BMI, high WC and high PASI. Psoriatic arthritis is a chronic inflammatory disorder and a chronic inflammatory state induced by adiposity may lead to PsA. PMID- 27512359 TI - The effect of an emollient with benfothiamine and Biolin prebiotic on the improvement of epidermal skin function. AB - INTRODUCTION: Complications of diabetes can damage internal organs and the skin. Diabetic skin, irritated and dry, is susceptible to skin infections. However little is known about influence of emollients on biophysical changes in skin during diabetes. AIM: To evaluate clinical skin changes after application of emollients with benfothiamine and Biolin prebiotic and to assess changes in biophysical parameters of the skin before and 4 weeks after daily application of an emollient. MATERIAL AND METHODS: We recruited 50 patients with diabetes mellitus type 1 (DM1) or type 2 (DM2). All participants applied emollients on their left forearms and left shins for 4 weeks. The biophysical properties: pH, transepidermal water loss (TEWL), hydration of the stratum corneum and sebum content were measured and compared to those before enrollment to the study, after 1 h, 1 week and 4 weeks after application of an emollient. RESULTS: After 4 weeks of treatment, there was an increase in skin hydration (40.61 +/-19.03 vs. 48.83 +/-15.51), pH (5.11 +/-0.56 to 5.27 +/-0.48) and sebum content (22.16 +/-8.67 to 63.99 +/-25.41) and a decrease in TEWL (12.54 +/-5.6 vs. 9.85 +/-5.69 g/m(2)/h) on forearms (p < 0.05 for all comparisons). On lower legs, significant changes in skin hydration (37.21 +/-14.01 vs. 43.95 +/-12.67), pH (5.04 +/-0.57 to 5.31 +/ 0.49), sebum content (25.82 +/-10.46 to 72.63 +/-31.23) and TEWL (8.87 +/-4.05 vs. 7.39 +/-3.22 g/m(2)/h) were observed (p < 0.05 for all comparisons). CONCLUSIONS: Our study provides an insight into changes in diabetic skin after application of an emollient. To our knowledge, this is the first report on the emollient containing benfothiamine and Biolin prebiotic and its influence on biophysical parameters of epidermis. PMID- 27512360 TI - Thyroid abnormalities in paediatric patients with vitiligo: retrospective study. AB - INTRODUCTION: The association between vitiligo and thyroid disease is not fully investigated especially in paediatric patients. AIM: To determine the incidence of vitiligo and thyroid disorders in children. This is the first report from middle Anatolia and the second report from Turkey. MATERIAL AND METHODS: A retrospective chart review was performed to examine the presence of thyroid abnormalities in paediatric patients who had been admitted to the dermatology department with vitiligo. RESULTS: A total of 155 paediatric patients, including 80 (52%) male and 75 (48%) female patients were included. The mean age was 8.6 years. Non segmental vitiligo was the most common type of the disease in 140 (90%) reviewed patients, while segmental vitiligo appeared only in 15 (10%) patients. The mean onset of vitiligo was 5.6 +/-0.9 years. A family history of vitiligo was found in 14 (9%) children. Thirty-four (22%) patients had thyroid function tests and/or thyroid autoantibody abnormality. All of these patients had non segmental vitiligo. It was statistically significant (p < 0.05) in types of vitiligo and thyroid disease parameters. CONCLUSIONS: Our results show that it may be useful to screen thyroid in children with non segmental vitiligo. PMID- 27512361 TI - Extensive, neglected basal cell carcinoma of the half of the face-surgical treatment and reconstruction with an anterolateral microvascular thigh flap. PMID- 27512362 TI - Photosensitive pityriasis rubra pilaris. PMID- 27512363 TI - Could aluminum be a new hidden allergen in type 1 hypersensitivity reactions when used as a drug additive? PMID- 27512364 TI - Target Speaker Detection with Concealed EEG Around the Ear. AB - Target speaker identification is essential for speech enhancement algorithms in assistive devices aimed toward helping the hearing impaired. Several recent studies have reported that target speaker identification is possible through electroencephalography (EEG) recordings. If the EEG system could be reduced to acceptable size while retaining the signal quality, hearing aids could benefit from the integration with concealed EEG. To compare the performance of a multichannel around-the-ear EEG system with high-density cap EEG recordings an envelope tracking algorithm was applied in a competitive speaker paradigm. The data from 20 normal hearing listeners were concurrently collected from the traditional state-of-the-art laboratory wired EEG system and a wireless mobile EEG system with two bilaterally-placed around-the-ear electrode arrays (cEEGrids). The results show that the cEEGrid ear-EEG technology captured neural signals that allowed the identification of the attended speaker above chance level, with 69.3% accuracy, while cap-EEG signals resulted in the accuracy of 84.8%. Further analyses investigated the influence of ear-EEG signal quality and revealed that the envelope tracking procedure was unaffected by variability in channel impedances. We conclude that the quality of concealed ear-EEG recordings as acquired with the cEEGrid array has potential to be used in the brain-computer interface steering of hearing aids. PMID- 27512365 TI - Synthesis and Biological Evaluation of Thiophene-Based Cannabinoid Receptor Type 2 Radiotracers for PET Imaging. AB - Over the past two decades, our understanding of the endocannabinoid system has greatly improved due to the wealth of results obtained from exploratory studies. Currently, two cannabinoid receptor subtypes have been well-characterized. The cannabinoid receptor type 1 (CB1) is widely expressed in the central nervous system, while the levels of the cannabinoid receptor type 2 (CB2) in the brain and spinal cord of healthy individuals are relatively low. However, recent studies demonstrated a CB2 upregulation on activated microglia upon neuroinflammation, an indicator of neurodegeneration. Our research group aims to develop a suitable positron emission tomography (PET) tracer to visualize the CB2 receptor in patients suffering from neurodegenerative diseases. Herein we report two novel thiophene-based (11)C-labeled PET ligands designated [(11)C]AAT-015 and [(11)C]AAT-778. The reference compounds were synthesized using Gewald reaction conditions to obtain the aminothiophene intermediates, followed by amide formation. Saponification of the esters provided their corresponding precursors. Binding affinity studies revealed Ki-values of 3.3 +/- 0.5 nM (CB2) and 1.0 +/- 0.2 MUM (CB1) for AAT-015. AAT-778 showed similar Ki-values of 4.3 +/- 0.7 nM (CB2) and 1.1 +/- 0.1 MUM (CB1). Radiosynthesis was carried out under basic conditions using [(11)C]iodomethane as methylating agent. After semi-preparative HPLC purification both radiolabeled compounds were obtained in 99% radiochemical purity and the radiochemical yields ranged from 12 to 37%. Specific activity was between 96 and 449 GBq/MUmol for both tracers. In order to demonstrate CB2 specificity of [(11)C]AAT-015 and [(11)C]AAT-778, we carried out autoradiography studies using CB2-positive mouse/rat spleen tissues. The obtained results revealed unspecific binding in spleen tissue that was not blocked by an excess of CB2-specific ligand GW402833. For in vivo analysis, [(11)C]AAT-015 was administered to healthy rats via tail-vein injection. Evaluation of the CB2 positive spleen, however, showed no accumulation of the radiotracer. Despite the promising in vitro binding affinities, specific binding of [(11)C]AAT-015, and [(11)C]AAT-778 could not be demonstrated. PMID- 27512366 TI - Corrigendum: Perceptual factors contribute more than acoustical factors to sound localization abilities with virtual sources. AB - [This corrects the article on p. 451 in vol. 8, PMID: 25688182.]. PMID- 27512367 TI - Non-Invasive Brain Stimulation to Enhance Post-Stroke Recovery. AB - Brain plasticity after stroke remains poorly understood. Patients may improve spontaneously within the first 3 months and then more slowly in the coming year. The first day, decreased edema and reperfusion of the ischemic penumbra may possibly account for these phenomena, but the improvement during the next weeks suggests plasticity phenomena and cortical reorganization of the brain ischemic areas and of more remote areas. Indeed, the injured ischemic motor cortex has a reduced cortical excitability at the acute phase and a suspension of the topographic representation of affected muscles, whereas the contralateral motor cortex has an increased excitability and an enlarged somatomotor representation; furthermore, contralateral cortex exerts a transcallosal interhemispheric inhibition on the ischemic cortex. This results from the imbalance of the physiological reciprocal interhemispheric inhibition of each hemisphere on the other, contributing to worsening of neurological deficit. Cortical excitability is measurable through transcranial magnetic stimulation (TMS) and prognosis has been established according to the presence of motor evoked potentials (MEP) at the acute phase of stroke, which is predictive of better recovery. Conversely, the lack of response to early stimulation is associated with a poor functional outcome. Non-invasive stimulation techniques such as repetitive TMS (rTMS) or transcranial direct current stimulation (tDCS) have the potential to modulate brain cortical excitability with long lasting effects. In the setting of cerebrovascular disease, around 1000 stroke subjects have been included in placebo-controlled trials so far, most often with an objective of promoting motor recovery of the upper limb. High frequency repetitive stimulation (>3 Hz) rTMS, aiming to increase excitability of the ischemic cortex, or low frequency repetitive stimulation (<=1 Hz), aiming to reduce excitability of the contralateral homonymous cortex, or combined therapies, have shown various effects on the functional disability score and neurological scales of treated patients and on the duration of the treatment. We review here the patients' characteristics and parameters of stimulation that could predict a good response, as well as safety issues. At last, we review what we have learnt from experimental studies and discuss potential directions to conduct future studies. PMID- 27512368 TI - Non-invasive Brain Stimulation, a Tool to Revert Maladaptive Plasticity in Neuropathic Pain. AB - Neuromodulatory effects of non-invasive brain stimulation (NIBS) have been extensively studied in chronic pain. A hypothetic mechanism of action would be to prevent or revert the ongoing maladaptive plasticity within the pain matrix. In this review, the authors discuss the mechanisms underlying the development of maladaptive plasticity in patients with chronic pain and the putative mechanisms of NIBS in modulating synaptic plasticity in neuropathic pain conditions. PMID- 27512369 TI - Interoception and Positive Symptoms in Schizophrenia. AB - The present study focuses on the multifaceted concept of self-disturbance in schizophrenia, adding knowledge about a not yet investigated aspect, which is the interoceptive accuracy. Starting from the assumption that interoceptive accuracy requires an intact sense of self, which otherwise was proved to be altered in schizophrenia, the aim of the present study was to explore interoceptive accuracy in a group of schizophrenia patients, compared to healthy controls. Furthermore, the possible association between interoceptive accuracy and patients' positive and negative symptomatology was assessed. To pursue these goals, a group of 23 schizophrenia patients and a group of 23 healthy controls performed a heartbeat perception task. Patients' symptomatology was assessed by means of the Positive and Negative Syndrome Scale (PANSS). Results demonstrated significantly lower interoceptive accuracy in schizophrenia patients compared to healthy controls. This difference was not accounted for participants' age, BMI, anxiety levels, and heart rate. Furthermore, patients' illness severity, attention and pharmacological treatment did not influence their interoceptive accuracy levels. Interestingly, a strong positive relation between interoceptive accuracy and positive symptoms severity, especially Grandiosity, was found. The present results demonstrate for the first time that interoceptive accuracy is altered in schizophrenia. Furthermore, they prove a specific association between interoceptive accuracy and positive symptomatology, suggesting that the symptom Grandiosity might be protective against an altered basic sense of self in patients characterized by higher sensibility to their inner bodily sensations. PMID- 27512370 TI - Anterior Cingulate Cortico-Hippocampal Dysconnectivity in Unaffected Relatives of Schizophrenia Patients: A Stochastic Dynamic Causal Modeling Study. AB - Familial risk plays a significant role in the etiology of schizophrenia (SZ). Many studies using neuroimaging have demonstrated structural and functional alterations in relatives of SZ patients, with significant results found in diverse brain regions involving the anterior cingulate cortex (ACC), caudate, dorsolateral prefrontal cortex (DLPFC), and hippocampus. This study investigated whether unaffected relatives of first episode SZ differ from healthy controls (HCs) in effective connectivity measures among these regions. Forty-six unaffected first-degree relatives of first episode SZ patients-according to the DSM-IV-were studied. Fifty HCs were included for comparison. All subjects underwent resting state functional magnetic resonance imaging (fMRI). We used stochastic dynamic causal modeling (sDCM) to estimate the directed connections between the left ACC, right ACC, left caudate, right caudate, left DLPFC, left hippocampus, and right hippocampus. We used Bayesian parameter averaging (BPA) to characterize the differences. The BPA results showed hyperconnectivity from the left ACC to right hippocampus and hypoconnectivity from the right ACC to right hippocampus in SZ relatives compared to HCs. The pattern of anterior cingulate cortico-hippocampal connectivity in SZ relatives may be a familial feature of SZ risk, appearing to reflect familial susceptibility for SZ. PMID- 27512371 TI - Cortical Gamma Oscillations: Details of Their Genesis Preclude a Role in Cognition. PMID- 27512372 TI - volBrain: An Online MRI Brain Volumetry System. AB - The amount of medical image data produced in clinical and research settings is rapidly growing resulting in vast amount of data to analyze. Automatic and reliable quantitative analysis tools, including segmentation, allow to analyze brain development and to understand specific patterns of many neurological diseases. This field has recently experienced many advances with successful techniques based on non-linear warping and label fusion. In this work we present a novel and fully automatic pipeline for volumetric brain analysis based on multi atlas label fusion technology that is able to provide accurate volumetric information at different levels of detail in a short time. This method is available through the volBrain online web interface (http://volbrain.upv.es), which is publically and freely accessible to the scientific community. Our new framework has been compared with current state-of-the-art methods showing very competitive results. PMID- 27512373 TI - Gabor frame sets of invariance: a Hamiltonian approach to Gabor frame deformations. AB - In this work we study families of pairs of window functions and lattices which lead to Gabor frames which all possess the same frame bounds. To be more precise, for every generalized Gaussian g, we will construct an uncountable family of lattices [Formula: see text] such that each pairing of g with some [Formula: see text] yields a Gabor frame, and all pairings yield the same frame bounds. On the other hand, for each lattice we will find a countable family of generalized Gaussians [Formula: see text] such that each pairing leaves the frame bounds invariant. Therefore, we are tempted to speak about Gabor Frame Sets of Invariance. PMID- 27512374 TI - Sub-toxic Ethanol Exposure Modulates Gene Expression and Enzyme Activity of Antioxidant Systems to Provide Neuroprotection in Hippocampal HT22 Cells. AB - Ethanol is known to cause severe systemic damage often explained as secondary to oxidative stress. Brain is particularly vulnerable to ethanol-induced reactive oxygen species (ROS) because the high amounts of lipids, and because nerve cell membranes contain high amounts of peroxidable fatty acids. Usually these effects of ethanol are associated to high and/or chronic exposure to ethanol. However, as we show in this manuscript, a low and acute dose of ethanol trigger a completely different response in hippocampal cells. Thus, we have observed that 0.1% ethanol exposure to HT22 cells, a murine hippocampal-derived cell line, increases the transcriptional expression of different genes belonging to the classical, glutathione/glutaredoxin and thioredoxin/peroxiredoxin antioxidant systems, these including Sod1, Sod2, Gpx1, Gclc, and Txnrd1. Paralleling these changes, enzyme activities of total superoxide dismutase (tSOD), catalase, total glutathione peroxidase (tGPx), glutathione-S-reductase (GSR), and total thioredoxin reductase (tTXNRD), were all increased, while the generation of thiobarbituric acid reactive substances (TBARS), as indicators of lipid peroxidation, and glutathione levels remained unaltered. Ethanol exposure did not affect cell viability or cell growing as assessed by real-time cell culture monitoring, indicating that low ethanol doses are not deleterious for hippocampal cells, but rather prevented glutamate-induced excitotoxicity. In summary, we conclude that sub-toxic exposure to ethanol may well be neuroprotective against oxidative insults in hippocampal cells. PMID- 27512375 TI - Doxorubicin Induces Inflammatory Modulation and Metabolic Dysregulation in Diabetic Skeletal Muscle. AB - Anti-cancer agent doxorubicin (DOX) has been demonstrated to worsen insulin signaling, engender muscle atrophy, trigger pro-inflammation, and induce a shift to anaerobic glycolytic metabolism in skeletal muscle. The myotoxicity of DOX in diabetic skeletal muscle remains largely unclear. This study examined the effects of DOX on insulin signaling, muscle atrophy, pro-/anti-inflammatory microenvironment, and glycolysis metabolic regulation in skeletal muscle of db/db diabetic and db/+ non-diabetic mice. Non-diabetic db/+ mice and diabetic db/db mice were randomly assigned to the following groups: db/+CON, db/+DOX, db/dbCON, and db/dbDOX. Mice in db/+DOX and db/dbDOX groups were intraperitoneally injected with DOX at a dose of 15 mg per kg body weight whereas mice in db/+CON and db/dbCON groups were injected with the same volume of saline instead of DOX. Gastrocnemius was immediately harvested, weighed, washed with cold phosphate buffered saline, frozen in liquid nitrogen, and stored at -80 degrees C for later analysis. The effects of DOX on diabetic muscle were neither seen in insulin signaling markers (Glut4, pIRS1Ser(636/639), and pAktSer(473)) nor muscle atrophy markers (muscle mass, MuRF1 and MAFbx). However, DOX exposure resulted in enhancement of pro-inflammatory favoring microenvironment (as indicated by TNF alpha, HIFalpha and pNFkappaBp65) accompanied by diminution of anti-inflammatory favoring microenvironment (as indicated by IL15, PGC1alpha and pAMPKbeta1Ser108). Metabolism of diabetic muscle was shifted to anaerobic glycolysis after DOX exposure as demonstrated by our analyses of PDK4, LDH and pACCSer(79). Our results demonstrated that there might be a link between inflammatory modulation and the dysregulation of aerobic glycolytic metabolism in DOX-injured diabetic skeletal muscle. These findings help to understand the pathogenesis of DOX induced myotoxicity in diabetic muscle. PMID- 27512376 TI - New Imaging Methods for Non-invasive Assessment of Mechanical, Structural, and Biochemical Properties of Human Achilles Tendon: A Mini Review. AB - The mechanical properties of tendon play a fundamental role to passively transmit forces from muscle to bone, withstand sudden stretches, and act as a mechanical buffer allowing the muscle to work more efficiently. The use of non-invasive imaging methods for the assessment of human tendon's mechanical, structural, and biochemical properties in vivo is relatively young in sports medicine, clinical practice, and basic science. Non-invasive assessment of the tendon properties may enhance the diagnosis of tendon injury and the characterization of recovery treatments. While ultrasonographic imaging is the most popular tool to assess the tendon's structural and indirectly, mechanical properties, ultrasonographic elastography, and ultra-high field magnetic resonance imaging (UHF MRI) have recently emerged as potentially powerful techniques to explore tendon tissues. This paper highlights some methodological cautions associated with conventional ultrasonography and perspectives for in vivo human Achilles tendon assessment using ultrasonographic elastography and UHF MRI. PMID- 27512377 TI - System, Subsystem, Hive: Boundary Problems in Computational Theories of Consciousness. AB - A computational theory of consciousness should include a quantitative measure of consciousness, or MoC, that (i) would reveal to what extent a given system is conscious, (ii) would make it possible to compare not only different systems, but also the same system at different times, and (iii) would be graded, because so is consciousness. However, unless its design is properly constrained, such an MoC gives rise to what we call the boundary problem: an MoC that labels a system as conscious will do so for some-perhaps most-of its subsystems, as well as for irrelevantly extended systems (e.g., the original system augmented with physical appendages that contribute nothing to the properties supposedly supporting consciousness), and for aggregates of individually conscious systems (e.g., groups of people). This problem suggests that the properties that are being measured are epiphenomenal to consciousness, or else it implies a bizarre proliferation of minds. We propose that a solution to the boundary problem can be found by identifying properties that are intrinsic or systemic: properties that clearly differentiate between systems whose existence is a matter of fact, as opposed to those whose existence is a matter of interpretation (in the eye of the beholder). We argue that if a putative MoC can be shown to be systemic, this ipso facto resolves any associated boundary issues. As test cases, we analyze two recent theories of consciousness in light of our definitions: the Integrated Information Theory and the Geometric Theory of consciousness. PMID- 27512378 TI - Holistic Patterns as an Instrument for Predicting the Performance of Promising Young Soccer Players - A 3-Years Longitudinal Study. AB - Multidimensional and dynamic talent models represent the current state of the art, but these demands have hardly ever been implemented so far. One reason for this could be the methodological problems associated with these requirements. This paper will present a proposal for dealing with this, namely for examining the development of young soccer players holistically. The patterns formed by the constructs net hope, motor abilities, technical skills and biological maturity were examined, as well as the way in which these holistic patterns are related to subsequent sporting success. 119 young elite soccer players were questioned and tested three times at intervals of 1 year, beginning at the age of 12. At the age of 15, the level of performance reached by the players was determined. At all three measuring points, four patterns were identified, which displayed partial structural and high individual stability. The highly skilled players, scoring above average on all factors - but not necessarily those having the highest overall scores - were significantly more likely to advance to the highest level of performance. Failure-fearing fit players, i.e., physically strong, early developed players but with some technical weaknesses, have good chances of reaching the middle performance level. In contrast, none of the achievement oriented, highly skilled, late-matured or late-matured, low skilled players reached the highest performance level. The results indicate the importance of holistic approaches for predicting performance among promising soccer talents in the medium-term and thus provide valuable clues for their selection and promotion. PMID- 27512379 TI - The Role of Metarepresentation in the Production and Resolution of Referring Expressions. AB - In this paper we consider the potential role of metarepresentation-the representation of another representation, or as commonly considered within cognitive science, the mental representation of another individual's knowledge and beliefs-in mediating definite reference and common ground in conversation. Using dialogues from a referential communication study in which speakers conversed in succession with two different addressees, we highlight ways in which interlocutors work together to successfully refer to objects, and achieve shared conceptualizations. We briefly review accounts of how such shared conceptualizations could be represented in memory, from simple associations between label and referent, to "triple co-presence" representations that track interlocutors in an episode of referring, to more elaborate metarepresentations that invoke theory of mind, mutual knowledge, or a model of a conversational partner. We consider how some forms of metarepresentation, once created and activated, could account for definite reference in conversation by appealing to ordinary processes in memory. We conclude that any representations that capture information about others' perspectives are likely to be relatively simple and subject to the same kinds of constraints on attention and memory that influence other kinds of cognitive representations. PMID- 27512380 TI - Editorial: From Meaning of Working to Meaningful Lives: The Challenges of Expanding Decent Work. PMID- 27512381 TI - Orthographic Activation in L2 Spoken Word Recognition Depends on Proficiency: Evidence from Eye-Tracking. AB - The use of orthographic and phonological information in spoken word recognition was studied in a visual world task where L1 Finnish learners of L2 French (n = 64) and L1 French native speakers (n = 24) were asked to match spoken word forms with printed words while their eye movements were recorded. In Experiment 1, French target words were contrasted with competitors having a longer ( vs. ) or a shorter word initial phonological overlap ( vs. ) and an identical orthographic overlap. In Experiment 2, target words were contrasted with competitors of either longer ( vs. ) or shorter word initial orthographic overlap ( vs. ) and of an identical phonological overlap. A general phonological effect was observed in the L2 listener group but not in the L1 control group. No general orthographic effects were observed in the L2 or L1 groups, but a significant effect of proficiency was observed for orthographic overlap over time: higher proficiency L2 listeners used also orthographic information in the matching task in a time-window from 400 to 700 ms, whereas no such effect was observed for lower proficiency listeners. These results suggest that the activation of orthographic information in L2 spoken word recognition depends on proficiency in L2. PMID- 27512382 TI - Macrocognition through the Multiscale Enaction Model (MEM) Lens: Identification of a Blind Spot of Macrocognition Research. PMID- 27512383 TI - Obesity, Cardiovascular Fitness, and Inhibition Function: An Electrophysiological Study. AB - The purpose of the present study was to examine how obesity and cardiovascular fitness are associated with the inhibition aspect of executive function from behavioral and electrophysiological perspectives. One hundred college students, aged 18-25 years, were categorized into four groups of equal size on the basis of body mass index and cardiovascular fitness: a normal-weight and high-fitness (NH) group, an obese-weight and high-fitness (OH) group, a normal-weight and low fitness (NL) group, and an obese-weight and low-fitness (OL) group. Behavioral measures of response time and number of errors, as well as event-related potential measures of P3 and N1, were assessed during the Stroop Task. The results revealed that, in general, the NH group exhibited shorter response times and larger P3 amplitudes relative to the NL and OL groups, wherein the OL group exhibited the longest response time in the incongruent condition. No group differences in N1 indices were also revealed. These findings suggest that the status of being both normal weight and having high cardiovascular fitness is associated with better behavioral and later stages of electrophysiological indices of cognitive function. PMID- 27512384 TI - Links between the Brain and Retina: The Effects of Cigarette Smoking-Induced Age Related Changes in Alzheimer's Disease and Macular Degeneration. PMID- 27512385 TI - Mechanisms of Progranulin Action and Regulation in Genitourinary Cancers. AB - The growth factor progranulin has emerged in recent years as a critical regulator of transformation in several cancer models, including breast cancer, glioblastomas, leukemias, and hepatocellular carcinomas. Several laboratories, including ours, have also demonstrated an important role of progranulin in several genitourinary cancers, including ovarian, endometrial, cervical, prostate, and bladder tumors, where progranulin acts as an autocrine growth factor thereby modulating motility and invasion of transformed cells. In this review, we will focus on the mechanisms of action and regulation of progranulin signaling in genitourinary cancers with a special emphasis on prostate and bladder tumors. PMID- 27512386 TI - Changes in Skeletal Integrity and Marrow Adiposity during High-Fat Diet and after Weight Loss. AB - The prevalence of obesity has continued to rise over the past three decades leading to significant increases in obesity-related medical care costs from metabolic and non-metabolic sequelae. It is now clear that expansion of body fat leads to an increase in inflammation with systemic effects on metabolism. In mouse models of diet-induced obesity, there is also an expansion of bone marrow adipocytes. However, the persistence of these changes after weight loss has not been well described. The objective of this study was to investigate the impact of high-fat diet (HFD) and subsequent weight loss on skeletal parameters in C57Bl6/J mice. Male mice were given a normal chow diet (ND) or 60% HFD at 6 weeks of age for 12, 16, or 20 weeks. A third group of mice was put on HFD for 12 weeks and then on ND for 8 weeks to mimic weight loss. After these dietary challenges, the tibia and femur were removed and analyzed by micro computed-tomography for bone morphology. Decalcification followed by osmium staining was used to assess bone marrow adiposity, and mechanical testing was performed to assess bone strength. After 12, 16, or 20 weeks of HFD, mice had significant weight gain relative to controls. Body mass returned to normal after weight loss. Marrow adipose tissue (MAT) volume in the tibia increased after 16 weeks of HFD and persisted in the 20 week HFD group. Weight loss prevented HFD-induced MAT expansion. Trabecular bone volume fraction, mineral content, and number were decreased after 12, 16, or 20 weeks of HFD, relative to ND controls, with only partial recovery after weight loss. Mechanical testing demonstrated decreased fracture resistance after 20 weeks of HFD. Loss of mechanical integrity did not recover after weight loss. Our study demonstrates that HFD causes long-term, persistent changes in bone quality, despite prevention of marrow adipose tissue accumulation, as demonstrated through changes in bone morphology and mechanical strength in a mouse model of diet induced obesity and weight loss. PMID- 27512387 TI - The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia. AB - Somatic GNAS point mutations, commonly known as gsp mutations, are involved in the pathogenesis of McCune-Albright syndrome (MAS) and have also been described in autonomous hormone-producing tumors, such as somatotropinoma, corticotrophoma, thyroid cancer, ovarian and testicular Leydig cell tumors, and primary macronodular adrenocortical hyperplasia (PMAH) (1-3). The involvement of gsp mutations in adrenal tumors was first described by Lyons et al. Since then, several studies have detected the presence of gsp mutations in adrenal tumors, but none of them could explain its presence along or the mechanism that leads to tumor formation and hormone hypersecretion. As a result, the molecular pathogenesis of the majority of sporadic adrenocortical tumors remains unclear (3). PMAH has also been reported with gsp somatic mutations in a few cases. Fragoso et al. identified two distinct gsp somatic mutations affecting arginine residues on codon 201 of GNAS in a few patients with PMAH who lacked any features or manifestations of MAS. Followed by this discovery, other studies have continued looking for gsp mutations based on strong prior evidence demonstrating that increased cAMP signaling is sufficient for cell proliferation and cortisol production (2, 4). With consideration for the previously reported findings, we conjecture that although somatic activating mutations in GNAS are a rare molecular event, these mutations could probably be sufficient to induce the development of macronodule hyperplasia and variable cortisol secretion. In this manuscript, we revised the presence of gsp mutations associated with adrenal cortical tumors and hyperplasia. PMID- 27512388 TI - An Enantiomer of an Oral Small-Molecule TSH Receptor Agonist Exhibits Improved Pharmacologic Properties. AB - We are developing an orally available small-molecule, allosteric TSH receptor (TSHR) agonist for follow-up diagnostics of patients with thyroid cancer. The agonist C2 (NCGC00161870) that we have studied so far is a racemic mixture containing equal amounts of two enantiomers, E1 and E2. As enantiomers of many drugs exhibit different pharmacologic properties, we assessed the properties of E1 and E2. We separated the two enantiomers by chiral chromatography and determined E2 as the (S)-(+) isomer via crystal structure analysis. E1 and E2 were shown to bind differently to a homology model of the transmembrane domain of TSHR in which E2 was calculated to exhibit lower binding energy than E1 and was, therefore, predicted to be more potent than E1. In HEK293 cells expressing human TSHRs, C2, E1, and E2 were equally efficacious in stimulating cAMP production, but their potencies were different. E2 was more potent (EC50 = 18 nM) than C2 (EC50 = 46 nM), which was more potent than E1 (EC50 = 217 nM). In primary cultures of human thyrocytes, C2, E1, and E2 stimulated increases in thyroperoxidase mRNA of 92-, 55-, and 137-fold and in sodium-iodide symporter mRNA of 20-, 4-, and 121-fold above basal levels, respectively. In mice, C2 stimulated an increase in radioactive iodine uptake of 1.5-fold and E2 of 2.8 fold above basal level, whereas E1 did not have an effect. C2 stimulated an increase in serum T4 of 2.4-fold, E1 of 1.9-fold, and E2 of 5.6-fold above basal levels, and a 5-day oral dosing regimen of E2 increased serum T4 levels comparable to recombinant human TSH (rhTSH, Thyrogen((r))). Thus, E2 is more effective than either C2 or E1 in stimulating thyroid function and as efficacious as rhTSH in vivo. E2 represents the next step toward developing an oral drug for patients with thyroid cancer. PMID- 27512389 TI - Genomic and Transcriptomic Resolution of Organic Matter Utilization Among Deep Sea Bacteria in Guaymas Basin Hydrothermal Plumes. AB - Microbial chemosynthesis within deep-sea hydrothermal vent plumes is a regionally important source of organic carbon to the deep ocean. Although chemolithoautotrophs within hydrothermal plumes have attracted much attention, a gap remains in understanding the fate of organic carbon produced via chemosynthesis. In the present study, we conducted shotgun metagenomic and metatranscriptomic sequencing on samples from deep-sea hydrothermal vent plumes and surrounding background seawaters at Guaymas Basin (GB) in the Gulf of California. De novo assembly of metagenomic reads and binning by tetranucleotide signatures using emergent self-organizing maps (ESOM) revealed 66 partial and nearly complete bacterial genomes. These bacterial genomes belong to 10 different phyla: Actinobacteria, Bacteroidetes, Chloroflexi, Deferribacteres, Firmicutes, Gemmatimonadetes, Nitrospirae, Planctomycetes, Proteobacteria, Verrucomicrobia. Although several major transcriptionally active bacterial groups (Methylococcaceae, Methylomicrobium, SUP05, and SAR324) displayed methanotrophic and chemolithoautotrophic metabolisms, most other bacterial groups contain genes encoding extracellular peptidases and carbohydrate metabolizing enzymes with significantly higher transcripts in the plume than in background, indicating they are involved in degrading organic carbon derived from hydrothermal chemosynthesis. Among the most abundant and active heterotrophic bacteria in deep sea hydrothermal plumes are Planctomycetes, which accounted for seven genomes with distinct functional and transcriptional activities. The Gemmatimonadetes and Verrucomicrobia also had abundant transcripts involved in organic carbon utilization. These results extend our knowledge of heterotrophic metabolism of bacterial communities in deep-sea hydrothermal plumes. PMID- 27512390 TI - Characterization of Chemosynthetic Microbial Mats Associated with Intertidal Hydrothermal Sulfur Vents in White Point, San Pedro, CA, USA. AB - The shallow-sea hydrothermal vents at White Point (WP) in Palos Verdes on the southern California coast support microbial mats and provide easily accessed settings in which to study chemolithoautotrophic sulfur cycling. Previous studies have cultured sulfur-oxidizing bacteria from the WP mats; however, almost nothing is known about the in situ diversity and activity of the microorganisms in these habitats. We studied the diversity, micron-scale spatial associations and metabolic activity of the mat community via sequence analysis of 16S rRNA and aprA genes, fluorescence in situ hybridization (FISH) microscopy and sulfate reduction rate (SRR) measurements. Sequence analysis revealed a diverse group of bacteria, dominated by sulfur cycling gamma-, epsilon-, and deltaproteobacterial lineages such as Marithrix, Sulfurovum, and Desulfuromusa. FISH microscopy suggests a close physical association between sulfur-oxidizing and sulfur reducing genotypes, while radiotracer studies showed low, but detectable, SRR. Comparative 16S rRNA gene sequence analyses indicate the WP sulfur vent microbial mat community is similar, but distinct from other hydrothermal vent communities representing a range of biotopes and lithologic settings. These findings suggest a complete biological sulfur cycle is operating in the WP mat ecosystem mediated by diverse bacterial lineages, with some similarity with deep-sea hydrothermal vent communities. PMID- 27512391 TI - Diet Diversity Is Associated with Beta but not Alpha Diversity of Pika Gut Microbiota. AB - Wild mammals often consume different food sources as they become geographical available. This change in diet composition is likely to influence the gut microbial community, yet it remains unclear what the relationship looks like particularly in small herbivores-under natural conditions. We used DNA sequencing approaches to characterize the diet composition and gut microbial community of wild plateau pikas (Ochotona curzoniae) collected from three altitudes. We tested if diet and gut microbiota composition changes across altitudes, and the relationship between diet diversity and gut microbiota diversity. Our results showed that altitude significantly influences the composition of diet and gut microbial communities. Notably, the alpha diversity (Shannon diversity and observed OTUs) of individual diet was not significantly correlated with that of gut microbiota, whereas the beta diversity (Jaccard and Bray-Curtis dissimilarity) of diet was positively correlated with that of gut microbiota. Our study is the first time to highlight the relationship between diet and gut microbiota composition in wild pikas on the Qinghai-Tibet Plateau. It suggests that the species richness within individual gut microbiota does not linearly increase with diet diversity, whereas those individuals that are more similar in diet composition harbor more similar gut microbiota. PMID- 27512393 TI - Corrigendum: Food Allergy and Helicobacter pylori Infection: A Systematic Review. AB - [This corrects the article on p. 368 in vol. 7, PMID: 27047479.]. PMID- 27512392 TI - Cystic Fibrosis Isolates of Pseudomonas aeruginosa Retain Iron-Regulated Antimicrobial Activity against Staphylococcus aureus through the Action of Multiple Alkylquinolones. AB - Cystic fibrosis (CF) is a hereditary disease that predisposes individuals to pulmonary dysfunction and chronic infections. Early infection of the CF lung with Staphylococcus aureus is common, while Pseudomonas aeruginosa becomes dominant as disease progresses. Emergence of P. aeruginosa likely depends on the action of multiple 2-alkyl-4-(1H)-quinolones (AQ) secreted by this organism. We recently showed that antimicrobial activity against S. aureus is enhanced by iron depletion and is dependent upon multiple AQ metabolites. Two of these AQs, the Pseudomonas quinolone signal [PQS; 2-heptyl-3-hydroxy-4(1H)-quinolone] and 2 heptyl-4-hydroxyquinoline (HHQ), are quorum sensing molecules that activate the expression of multiple microbicidal factors. Here we show for the first time that HHQ also exhibits innate antimicrobial activity against S. aureus. We further show that iron depletion potentiates the antistaphylococcal activity of HHQ, as well as 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO), another AQ that functions as a cytochrome B inhibitor. Notably, we found that deletion of the genes for the terminal biosynthetic steps for either PQS or HQNO results in overproduction of the HHQ intermediate, likely maintaining the ability of these mutants to mediate antimicrobial activity. Compensatory increases in HHQ were also observed in PQS deficient CF isolates, which also retained the ability to mediate iron-regulated antimicrobial activity against S. aureus. These studies demonstrate that iron regulated antimicrobial activity of P. aeruginosa against S. aureus is due to the cumulative effects of multiple AQ metabolites, both the production and activity of which are modulated by environmental iron levels. PMID- 27512394 TI - Editorial: Role of HLA and KIR in Viral Infections. PMID- 27512395 TI - Genome-Wide Association Study Identifies Candidate Genes for Starch Content Regulation in Maize Kernels. AB - Kernel starch content is an important trait in maize (Zea mays L.) as it accounts for 65-75% of the dry kernel weight and positively correlates with seed yield. A number of starch synthesis-related genes have been identified in maize in recent years. However, many loci underlying variation in starch content among maize inbred lines still remain to be identified. The current study is a genome-wide association study that used a set of 263 maize inbred lines. In this panel, the average kernel starch content was 66.99%, ranging from 60.60 to 71.58% over the three study years. These inbred lines were genotyped with the SNP50 BeadChip maize array, which is comprised of 56,110 evenly spaced, random SNPs. Population structure was controlled by a mixed linear model (MLM) as implemented in the software package TASSEL. After the statistical analyses, four SNPs were identified as significantly associated with starch content (P <= 0.0001), among which one each are located on chromosomes 1 and 5 and two are on chromosome 2. Furthermore, 77 candidate genes associated with starch synthesis were found within the 100-kb intervals containing these four QTLs, and four highly associated genes were within 20-kb intervals of the associated SNPs. Among the four genes, Glucose-1-phosphate adenylyltransferase (APS1; Gene ID GRMZM2G163437) is known as an important regulator of kernel starch content. The identified SNPs, QTLs, and candidate genes may not only be readily used for germplasm improvement by marker-assisted selection in breeding, but can also elucidate the genetic basis of starch content. Further studies on these identified candidate genes may help determine the molecular mechanisms regulating kernel starch content in maize and other important cereal crops. PMID- 27512396 TI - Genome-Wide Association Study Provides Insight into the Genetic Control of Plant Height in Rapeseed (Brassica napus L.). AB - Plant height is a key morphological trait of rapeseed. In this study, we measured plant height of a rapeseed population across six environments. This population contains 476 inbred lines representing the major Chinese rapeseed genepool and 44 lines from other countries. The 60K Brassica Infinium(r) SNP array was utilized to genotype the association panel. A genome-wide association study (GWAS) was performed via three methods, including a robust, novel, nonparametric Anderson Darling (A-D) test. Consequently, 68 loci were identified as significantly associated with plant height (P < 5.22 * 10(-5)), and more than 70% of the loci (48) overlapped the confidence intervals of reported QTLs from nine mapping populations. Moreover, 24 GWAS loci were detected with selective sweep signals, which reflected the signatures of historical semi-dwarf breeding. In the linkage disequilibrium (LD) decay range up-and downstream of 65 loci (r (2) > 0.1), we found plausible candidates orthologous to the documented Arabidopsis genes involved in height regulation. One significant association found by GWAS colocalized with the established height locus BnRGA in rapeseed. Our results provide insights into the genetic basis of plant height in rapeseed and may facilitate marker-based breeding. PMID- 27512397 TI - Plant-Herbivore Interaction: Dissection of the Cellular Pattern of Tetranychus urticae Feeding on the Host Plant. AB - The two-spotted spider mite, Tetranychus urticae Koch (Acari: Tetranychidae), is one of the most polyphagous herbivores feeding on cell contents of over 1100 plant species including more than 150 crops. It is being established as a model for chelicerate herbivores with tools that enable tracking of reciprocal responses in plant-spider mite interactions. However, despite their important pest status and a growing understanding of the molecular basis of interactions with plant hosts, knowledge of the way mites interface with the plant while feeding and the plant damage directly inflicted by mites is lacking. Here, utilizing histology and microscopy methods, we uncovered several key features of T. urticae feeding. By following the stylet path within the plant tissue, we determined that the stylet penetrates the leaf either in between epidermal pavement cells or through a stomatal opening, without damaging the epidermal cellular layer. Our recordings of mite feeding established that duration of the feeding event ranges from several minutes to more than half an hour, during which time mites consume a single mesophyll cell in a pattern that is common to both bean and Arabidopsis plant hosts. In addition, this study determined that leaf chlorotic spots, a common symptom of mite herbivory, do not form as an immediate consequence of mite feeding. Our results establish a cellular context for the plant-spider mite interaction that will support our understanding of the molecular mechanisms and cell signaling associated with spider mite feeding. PMID- 27512398 TI - Shallow Whole Genome Sequencing for the Assembly of Complete Chloroplast Genome Sequence of Arachis hypogaea L. PMID- 27512399 TI - Analysis of Drought-Induced Proteomic and Metabolomic Changes in Barley (Hordeum vulgare L.) Leaves and Roots Unravels Some Aspects of Biochemical Mechanisms Involved in Drought Tolerance. AB - In this study, proteomic and metabolomic changes in leaves and roots of two barley (Hordeum vulgare L.) genotypes, with contrasting drought tolerance, subjected to water deficit were investigated. Our two-dimensional electrophoresis (2D-PAGE) combined with matrix-assisted laser desorption time of flight mass spectrometry (MALDI-TOF and MALDI-TOF/TOF) analyses revealed 121 drought responsive proteins in leaves and 182 in roots of both genotypes. Many of the identified drought-responsive proteins were associated with processes that are typically severely affected during water deficit, including photosynthesis and carbon metabolism. However, the highest number of identified leaf and root proteins represented general defense mechanisms. In addition, changes in the accumulation of proteins that represent processes formerly unassociated with drought response, e.g., phenylpropanoid metabolism, were also identified. Our tandem gas chromatography - time of flight mass spectrometry (GC/MS TOF) analyses revealed approximately 100 drought-affected low molecular weight compounds representing various metabolite types with amino acids being the most affected metabolite class. We compared the results from proteomic and metabolomic analyses to search for existing relationship between these two levels of molecular organization. We also uncovered organ specificity of the observed changes and revealed differences in the response to water deficit of drought susceptible and tolerant barley lines. Particularly, our results indicated that several of identified proteins and metabolites whose accumulation levels were increased with drought in the analyzed susceptible barley variety revealed elevated constitutive accumulation levels in the drought-resistant line. This may suggest that constitutive biochemical predisposition represents a better drought tolerance mechanism than inducible responses. PMID- 27512400 TI - Circadian Oscillation of the Lettuce Transcriptome under Constant Light and Light Dark Conditions. AB - Although, the circadian clock is a universal biological system in plants and it orchestrates important role of plant production such as photosynthesis, floral induction and growth, there are few such studies on cultivated species. Lettuce is one major cultivated species for both open culture and plant factories and there is little information concerning its circadian clock system. In addition, most of the relevant genes have not been identified. In this study, we detected circadian oscillation in the lettuce transcriptome using time-course RNA sequencing (RNA-Seq) data. Constant light (LL) and light-dark (LD) conditions were used to detect circadian oscillation because the circadian clock has some basic properties: one is self-sustaining oscillation under constant light and another is entrainment to environmental cycles such as light and temperature. In the results, 215 contigs were detected as common oscillating contigs under both LL and LD conditions. The 215 common oscillating contigs included clock gene-like contigs CCA1 (CIRCADIAN CLOCK ASSOCIATED 1)-like, TOC1 (TIMING OF CAB EXPRESSION 1)-like and LHY (LATE ELONGATED HYPOCOTYL)-like, and their expression patterns were similar to those of Arabidopsis. Functional enrichment analysis by GO (gene ontology) Slim and GO Fat showed that the GO terms of response to light stimulus, response to stress, photosynthesis and circadian rhythms were enriched in the 215 common oscillating contigs and these terms were actually regulated by circadian clocks in plants. The 215 common oscillating contigs can be used to evaluate whether the gene expression pattern related to photosynthesis and optical response performs normally in lettuce. PMID- 27512401 TI - Role of Silicon Counteracting Cadmium Toxicity in Alfalfa (Medicago sativa L.). AB - Cadmium (Cd) is one of the most phytotoxic elements causing an agricultural problem and human health hazards. This work investigates whether and how silicon (Si) ameliorates Cd toxicity in Alfalfa. The addition of Si in Cd-stressed plants caused significant improvement in morpho-physiological features as well as total protein and membrane stability, indicating that Si does have critical roles in Cd detoxification in Alfalfa. Furthermore, Si supplementation in Cd-stressed plants showed a significant decrease in Cd and Fe concentrations in both roots and shoots compared with Cd-stressed plants, revealing that Si-mediated tolerance to Cd stress is associated with Cd inhibition in Alfalfa. Results also showed no significant changes in the expression of two metal chelators [MsPCS1 (phytochelatin synthase) and MsMT2 (metallothionein)] and PC (phytochelatin) accumulation, indicating that there may be no metal sequestration or change in metal sequestration following Si application under Cd stress in Alfalfa. We further performed a targeted study on the effect of Si on Fe uptake mechanisms. We observed the consistent reduction in Fe reductase activity, expression of Fe related genes [MsIRT1 (Fe transporter), MsNramp1 (metal transporter) and OsFRO1 (ferric chelate reductase] and Fe chelators (citrate and malate) by Si application to Cd stress in roots of Alfalfa. These results support that limiting Fe uptake through the down-regulation of Fe acquisition mechanisms confers Si mediated alleviation of Cd toxicity in Alfalfa. Finally, an increase of catalase, ascorbate peroxidase, and superoxide dismutase activities along with elevated methionine and proline subjected to Si application might play roles, at least in part, to reduce H2O2 and to provide antioxidant defense against Cd stress in Alfalfa. The study shows evidence of the effect of Si on alleviating Cd toxicity in Alfalfa and can be further extended for phytoremediation of Cd toxicity in plants. PMID- 27512402 TI - Physiological Degradation of Pectin in Papaya Cell Walls: Release of Long Chains Galacturonans Derived from Insoluble Fractions during Postharvest Fruit Ripening. AB - Papaya (Carica papaya L.) is a fleshy fruit that presents a rapid pulp softening during ripening. However, the timeline on how papaya pectinases act in polysaccharide solubilization and the consequent modification of the cell wall fractions during ripening is still not clear. In this work, the gene expression correlations between, on one hand, 16 enzymes potentially acting during papaya cell wall disassembling and, on the other hand, the monosaccharide composition of cell wall fractions during papaya ripening were evaluated. In order to explain differences in the ripening of papaya samplings, the molecular mass distribution of polysaccharides from water-soluble and oxalate-soluble fractions (WSF and OSF, respectively), as well as the oligosaccharide profiling from the WSF fraction, were evaluated by high performance size exclusion chromatography coupled to a refractive index detector and high performance anion-exchange chromatography coupled to pulse amperometric detection analyses, respectively. Results showed that up-regulated polygalacturonase and beta-galactosidase genes were positively correlated with some monosaccharide profiles. In addition, an overall increase in the retention time of high molecular weight (HMW) and low molecular weight (LMW) polysaccharides in WSF and OSF was shown. The apparent disappearance of one HMW peak of the OSF may result from the conversion of pectin that were crosslinked with calcium into more soluble forms through the action of PGs, which would increase the solubilization of polysaccharides by lowering their molecular weight. Thus, the results allowed us to propose a detailed process of papaya cell wall disassembling that would affect sensorial properties and post-harvesting losses of this commercially important fruit. PMID- 27512403 TI - Plant Abiotic Stress Challenges from the Changing Environment. PMID- 27512404 TI - Fundamental Issues of Melatonin-Mediated Stress Signaling in Plants. AB - As a widely known hormone in animals, melatonin (N-acetyl-5-methoxytryptamine) has been more and more popular research topic in various aspects of plants. To summarize the these recent advances, this review focuses on the regulatory effects of melatonin in plant response to multiple abiotic stresses including salt, drought, cold, heat and oxidative stresses and biotic stress such as pathogen infection. We highlight the changes of endogenous melatonin levels under stress conditions, and the extensive metabolome, transcriptome, and proteome reprogramming by exogenous melatonin application. Moreover, melatonin-mediated stress signaling and underlying mechanism in plants are extensively discussed. Much more is needed to further study in detail the mechanisms of melatonin mediated stress signaling in plants. PMID- 27512405 TI - Cellular Recycling of Proteins in Seed Dormancy Alleviation and Germination. AB - Each step of the seed-to-seed cycle of plant development including seed germination is characterized by a specific set of proteins. The continual renewal and/or replacement of these biomolecules are crucial for optimal plant adaptation. As proteins are the main effectors inside the cells, their levels need to be tightly regulated. This is partially achieved by specific proteolytic pathways via multicatalytic protease complexes defined as 20S and 26S proteasomes. In plants, the 20S proteasome is responsible for degradation of carbonylated proteins, while the 26S being a part of ubiquitin-proteasome pathway is known to be involved in proteolysis of phytohormone signaling regulators. On the other hand, the role of translational control of plant development is also well-documented, especially in the context of pollen tube growth and light signaling. Despite the current progress that has been made in seed biology, the sequence of cellular events that determine if the seed can germinate or not are still far from complete understanding. The role and mechanisms of regulation of proteome composition during processes occurring in the plant's photosynthetic tissues have been well-characterized since many years, but in non-photosynthetic seeds it has emerged as a tempting research task only since the last decade. This review discusses the recent discoveries providing insights into the role of protein turnover in seed dormancy alleviation, and germination, with a focus on the control of translation and proteasomal proteolysis. The presented novel data of translatome profiling in seeds highlighted that post-transcriptional regulation of germination results from a timely regulated initiation of translation. In addition, the importance of 26S proteasome in the degradation of regulatory elements of cellular signaling and that of the 20S complex in proteolysis of specific carbonylated proteins in hormonal- and light-dependent processes occurring in seeds is discussed. Based on the current knowledge the model of cellular recycling of proteins in germinating seeds is also proposed. PMID- 27512406 TI - Limitation of Grassland Productivity by Low Temperature and Seasonality of Growth. AB - The productivity of temperate grassland is limited by the response of plants to low temperature, affecting winter persistence and seasonal growth rates. During the winter, the growth of perennial grasses is restricted by a combination of low temperature and the lack of available light, but during early spring low ground temperature is the main limiting factor. Once temperature increases, growth is stimulated, resulting in a peak in growth in spring before growth rates decline later in the season. Growth is not primarily limited by the ability to photosynthesize, but controlled by active regulatory processes that, e.g., enable plants to restrict growth and conserve resources for cold acclimation and winter survival. An insufficient ability to cold acclimate can affect winter persistence, thereby also reducing grassland productivity. While some mechanistic knowledge is available that explains how low temperature limits plant growth, the seasonal mechanisms that promote growth in response to increasing spring temperatures but restrict growth later in the season are only partially understood. Here, we assess the available knowledge of the physiological and signaling processes that determine growth, including hormonal effects, on cellular growth and on carbohydrate metabolism. Using data for grass growth in Ireland, we identify environmental factors that limit growth at different times of the year. Ideas are proposed how developmental factors, e.g., epigenetic changes, can lead to seasonality of the growth response to temperature. We also discuss perspectives for modeling grass growth and breeding to improve grassland productivity in a changing climate. PMID- 27512407 TI - High-fat but not sucrose intake is essential for induction of dyslipidemia and non-alcoholic steatohepatitis in guinea pigs. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and dyslipidemia are closely related. Diet plays an important role in the progression of these diseases, but the role of specific dietary components is not completely understood. Therefore, we investigated the role of dietary sucrose and fat/cholesterol on the development of dyslipidemia and NAFLD. METHODS: Seventy female guinea pigs were block-randomized (based on weight) into five groups and fed a normal chow diet (control: 4 % fat), a very high-sucrose diet (vHS: 4 % fat, 25 % sucrose), a high-fat diet (HF: 20 % fat, 0.35 % cholesterol), a high fat/high-sucrose diet (HFHS: 20 % fat, 15 % sucrose, 0.35 % cholesterol) or a high-fat/very high-sucrose diet (HFvHS: 20 % fat, 25 % sucrose, 0.35 % cholesterol) for 16 and 25 weeks. RESULTS: All three high-fat diets induced dyslipidemia with increased concentrations of plasma cholesterol (p < 0.0001), LDL-C (p < 0.0001) and VLDL-C (p < 0.05) compared to control and vHS. Contrary to this, plasma triglycerides were increased in control and vHS compared to high-fat fed animals (p < 0.01), while circulating levels of free fatty acids were even between groups. Histological evaluation of liver sections revealed non-alcoholic steatohepatitis (NASH) with progressive inflammation and bridging fibrosis in high-fat fed animals. Accordingly, hepatic triglycerides (p < 0.05) and cholesterol (p < 0.0001) was increased alongside elevated levels of alanine and aspartate aminotransferase (p < 0.01) compared to control and vHS. CONCLUSION: Collectively, our results suggest that intake of fat and cholesterol, but not sucrose, are the main factors driving the development and progression of dyslipidemia and NAFLD/NASH. PMID- 27512408 TI - Understanding Counterfactuality: A Review of Experimental Evidence for the Dual Meaning of Counterfactuals. AB - Cognitive and linguistic theories of counterfactual language comprehension assume that counterfactuals convey a dual meaning. Subjunctive-counterfactual conditionals (e.g., 'If Tom had studied hard, he would have passed the test') express a supposition while implying the factual state of affairs (Tom has not studied hard and failed). The question of how counterfactual dual meaning plays out during language processing is currently gaining interest in psycholinguistics. Whereas numerous studies using offline measures of language processing consistently support counterfactual dual meaning, evidence coming from online studies is less conclusive. Here, we review the available studies that examine online counterfactual language comprehension through behavioural measurement (self-paced reading times, eye-tracking) and neuroimaging (electroencephalography, functional magnetic resonance imaging). While we argue that these studies do not offer direct evidence for the online computation of counterfactual dual meaning, they provide valuable information about the way counterfactual meaning unfolds in time and influences successive information processing. Further advances in research on counterfactual comprehension require more specific predictions about how counterfactual dual meaning impacts incremental sentence processing. PMID- 27512410 TI - Editorial resolutions. PMID- 27512409 TI - A review of the infection-associated cancers in North African countries. AB - Cancer is typically classified as a leading non-communicable disease; however, infectious agents, such as Helicobacter pylori (H. pylori), hepatitis B virus (HBV), hepatitis C virus (HCV) and human papilloma virus (HPV), contribute significantly to the pathogenesis of various cancers. Less developed countries, including countries of the North African (NA) region, endure the highest burden of infection-related cancers. The five most common infection-associated cancers in NA in order of incidence are bladder cancer, cervical cancer, liver cancer, stomach cancer, and nasopharyngeal carcinoma. This review aims to outline the epidemiologic pattern of infection-associated cancers in five NA countries (namely: Morocco, Algeria, Tunisia, Libya and Egypt) highlighting the similarities and differences across the region. The present study employed an initial literature review of peer-reviewed articles selected from PubMed, ScienceDirect and World Health Organization (WHO) databases based on key word searches without restriction on publication dates. Original research articles and reports written in French, as well as data from institutional reports and regional meeting abstracts were also included in this extensive review. Egypt, Libya, Tunisia, Algeria and Morocco were selected to be the focus of this review. PMID- 27512411 TI - Update on vitamin D: More than just a nutrient. AB - An increasing number of pregnancy complications have been ascribed or at least associated with vitamin D deficiency. Vitamin D has undergone a metamorphosis from nutrient to hormone and more recently has been recognised to have broader biological relevance. This includes potential immunogenic, oncogenic and metabolic actions. This review outlines the roles of vitamin D, the problems in accurate measurement and determining normal ranges and how this is important in an understanding of vitamin D in normal and abnormal pregnancy. PMID- 27512413 TI - Amniotic fluid embolism: the known and not known. AB - Amniotic fluid embolism was first recognized in 1926, in a Brazilian journal case report, on the basis of large amounts of fetal material in the maternal pulmonary vasculature at autopsy. The first English language description appeared in 1941 and consisted of eight parturients dying suddenly in which, once again, fetal material was seen in the pulmonary vasculature. A control group of 34 pregnant women dying of other recognized causes did not have fetal material in their lungs. The incidence of recognized, serious illness is on the order of two to eight per 100,000, with a mortality rate ranging from 13% to 35%. The diagnosis rests largely on one or more of four clinical signs: circulatory collapse, respiratory distress, coagulopathy, and seizures/ coma. The only confirmatory laboratory test remains autopsy findings although serum tests for fetal antigen, insulin-like growth factor binding protein-1, and complement are currently being investigated. One of the paradoxes of diagnosis is that fetal material in the pulmonary circulation at autopsy is specific for amniotic fluid embolism, while the same finding in the living is not. The mechanism of disease remains uncertain although the best available evidence suggests that complement activation might have a role. In contrast, mast cell degranulation probably is not a mechanism, so amniotic fluid embolism is not an anaphylaxis or anaphylactoid reaction as has been occasionally suggested. Perhaps the greatest unknown is not why 1 in 50,000 pregnant women develop what appears to be an immune response to their fetus, but rather why the other 49,999 do not? PMID- 27512415 TI - Response to fifty grams oral glucose challenge test and pattern of preceding fasting plasma glucose in normal pregnant Nigerians. AB - BACKGROUND: Diabetes mellitus in pregnancy has profound implications for the baby and mother and thus active screening for this is desirable. METHOD: Fifty grams oral glucose challenge test was administered after obtaining consent to 222 women in good health with singleton pregnancies without diabetes mellitus at 24 to 28 weeks gestation after an overnight fast. Venous blood sample was obtained before and 1 hour after the glucose load. A diagnostic 3-hour 100 g oral glucose tolerance test was subsequently performed in all. RESULTS: Two hundred and ten women had a normal response to oral glucose tolerance test i.e. venous plasma glucose below these cut-off levels: fasting 95 mg/dl (5.3 mmol/l), 1 hour 180 mg/dl (10.0 mmol/l), 2 hours 155 mg/dl (8.6 mmol/l) and 3 hours 140 mg/dl (7.8 mmol/l), while 12 were found to have gestational diabetes mellitus and were subsequently excluded from the study. They were appropriately managed. The mean maternal age was 30.9 +/- 4.1 years (range 19 to 45 years) and the mean parity was 1.2 +/- 1.1 (range 0 to 5). The mean fasting plasma glucose was 74.5 +/- 11.5 mg/dl (range 42 to 117 mg/dl), while the mean plasma glucose 1 hour after 50 g glucose challenge test was 115.3 +/- 19.1 mg/dl (range 56 to 180 mg/dl). CONCLUSIONS: The mean fasting plasma glucose in normal pregnant Nigerians was 74.5 +/- 11.5 mg/dl (range 42 to 117 mg/dl). There is a need to re-appraise and possibly review downwards the World Health Organization fasting plasma glucose diagnostic criteria in pregnant Nigerians for better detection of gestational diabetes mellitus. Pregnant women with venous plasma glucose greater than 153.5 mg/dl (8.5 mmol/l) 1 hour after 50 g glucose challenge test are strongly recommended for diagnostic test of gestational diabetes mellitus. PMID- 27512414 TI - The importance of visceral fat mass in obese pregnant women and relation with pregnancy outcomes. AB - BACKGROUND: Maternal obesity is a well established risk factor for gestational diabetes but it is not known if the pattern of maternal fat distribution predicts adverse pregnancy outcomes. METHODS: Body composition was assessed by bioimpedance using Inbody 720(r) in 302 consecutive obese pregnant women attending a weight management clinic. The relation of visceral fat mass and total percentage body fat with the development of gestational diabetes and perinatal outcomes was evaluated. RESULTS: Women developing gestational diabetes (Group 1; n = 72) were older, had higher body mass indices and greater central obesity (waist:hip ratio, visceral fat mass) compared with those remaining normoglycaemic. Visceral fat mass, but not percentage body fat, correlated with fasting glucose in all patients (r = 0.2, p < 0.001) and particularly those in Group 1 (r = 0.35, p = 0.002). Visceral fat mass, but not percentage body fat, also correlated strongly with glycaemia, particularly in Group 1 (r = 0.47, p < 0.0001). Visceral fat mass also showed a weak but significant correlation with baby weight (r = 0.17, p = 0.01). DISCUSSION: Central obesity, as assessed by early pregnancy waist:hip ratio and particularly by visceral fat mass, is a predictor of gestational diabetes in addition to classical risk factors and may help identify those obese patients at increased risk of complications. PMID- 27512412 TI - Timing of delivery in women with diabetes in pregnancy. AB - The incidence of both gestational and pre-gestational diabetes is increasing worldwide. The main cause of this increase is likely the concomitant increase in the incidence of global obesity, but in the case of gestational diabetes, changes in the diagnostic criteria are also a contributing factor. The adverse outcomes associated with pre-gestational diabetes are well known and have led clinicians to implement various strategies that include increased fetal surveillance and induction of labour at various gestational ages. In many cases these same strategies have been applied in clinical practice also to women with gestational diabetes despite there being differences in the type and magnitude of perinatal complications associated with this diagnosis. Despite the widespread application of these clinical practices, there is a paucity of quality data in the medical literature to guide the clinician in choosing a strategy for fetal surveillance and timing of delivery in both gestational diabetes and pre-gestational diabetes pregnancies. In the following review, we will discuss the rationale and consequences of planned delivery in gestational diabetes and pre-gestational diabetes, the evidence supporting different strategies for delivery and finally highlight future targets for research in this area. PMID- 27512416 TI - Pregnancy outcome and follow-up cardiac outcome in women with aortic valve replacement. AB - OBJECTIVES: To compare the maternal, fetal and cardiac outcomes in women who have undergone aortic valve replacement. METHOD: Retrospective observational study of all women with aortic valve replacement, who underwent a pregnancy (1998-2012). Maternal-, fetal- and valve-related cardiac outcomes were assessed. RESULTS: Thirty-two pregnancies in 16 women with aortic valve replacement (nine bioprosthetic, six Ross and 17 mechanical) were evaluated. There were no adverse maternal events in the bioprosthetic and Ross groups but three in the mechanical group. Fetal loss rate was highest in the mechanical valve pregnancies (53%). One woman in the bioprosthetic group needed valve re-operation, and one woman in the mechanical valve group died. There was no difference in the change of Vmax over the follow-up between the valves (p = 0.25). CONCLUSIONS: There was no difference in deterioration between aortic valve replacements during and after pregnancy. The highest risk of maternal and fetal complications occurred in the mechanical valve group. PMID- 27512417 TI - Amniotic fluid embolism: Then and now. AB - BACKGROUND: The first case report to describe amniotic fluid embolism that appeared in 1926 in Basil-Medico is translated from Portuguese to English. CASE: A patient with a dead fetus for several weeks, presented in labor and died suddenly with fetal squames evident in the maternal pulmonary vasculature at autopsy. CONCLUSION: As can be seen from the translation, this case report is remarkably similar in many of its features to some of the eight patients described 15 years later in the first English language discussion of the disease by Steiner and Luschbaugh in JAMA. An enigma presented by this first case remains today: fetal material in the maternal pulmonary vasculature appears specific for amniotic fluid embolism at autopsy but not in living patients. PMID- 27512418 TI - Idiopathic granulomatous mastitis with erythema nodosum simulating breast abscess in pregnancy: A case report. AB - Granulomatous mastitis is a rare benign inflammatory condition of the breast and is known to be associated with pregnancy. A 25-year-old Hispanic G2P1 at 17 weeks gestation presented to the emergency department with findings consistent of a breast abscess. The abscess failed to resolve with incision and drainage followed by multiple courses of antibiotic therapy. A biopsy was then obtained and yielded a diagnosis of granulomatous lobulitis. The patient was treated with steroids and her symptoms resolved. Granulomatous lobulitis may present with characteristics of various clinical entities including neoplasm or, as in this case, abscess. Clinicians should consider a diagnosis of granulomatous mastitis in cases of recalcitrant breast abscess. PMID- 27512419 TI - Pregnancy outcomes in patients with severe pulmonary hypertension and Eisenmenger syndrome treated with sildenafil monotherapy. AB - Pregnancy outcomes in patients with pulmonary arterial hypertension have not been documented in our local setting. In our institution, access to therapies like nitric oxide, inhaled prostacyclin and iloprost is limited. We describe two such women given sildenafil monotherapy between April and May 2011. Both had an atrial septal defect complicated by Eisenmenger syndrome. Both survived - one after elective Caesarean section for malpresentation (breech) under general anaesthesia, the other after an assisted vaginal delivery. In addition to oral sildenafil, both received oxygen supplementation. To date, there have been three reported cases of pulmonary arterial hypertension in pregnancy treated with sildenafil in combination with another drug. Our two cases demonstrate that treatment for pulmonary arterial hypertension using sildenafil as monotherapy may allow stabilization of the maternal condition and improve clinical outcomes for both mother and baby. However, pregnancy is still discouraged in women with pulmonary arterial hypertension. PMID- 27512420 TI - A stormy and rare presentation: Eclampsia at 18 weeks of gestation. AB - Eclampsia is an Obstetric emergency. It is uncommon in early second trimester and an early diagnosis will aid in preventing complications. We report an unusual case of eclampsia at an 18 weeks gestation with a good maternal outcome. PMID- 27512421 TI - Adrenal cortical carcinoma mimicking early severe preeclampsia. AB - Preeclampsia is a common disorder in pregnancy and may affect multiple maternal and foetal organ systems. Less common disorders with similar features may imitate preeclampsia though require different management strategies and with different prognostic implications for mother and baby. We present a case of a pregnant woman who developed severe hypertension and proteinuria in pregnancy. The early onset of these changes prompted investigation for causes other than preeclampsia, leading to a diagnosis of Cushing's syndrome due to stage III adrenocortical cancer. The changes in management strategy, the importance of a multidisciplinary approach to care, and the prognostic implications for the mother are discussed. PMID- 27512422 TI - Fluid management: Not just a problem in preeclampsia. PMID- 27512423 TI - Multidisciplinary meeting of minds. PMID- 27512425 TI - Techniques to measure free-living energy expenditure during pregnancy - A guide for clinicians and researchers. AB - As maternal overweight and obesity increase in prevalence, the need to optimise gestational weight gain has entered the forefront due to the well-documented poor fetal and maternal outcomes associated with excess adipose tissue. Measurements of changes in energy expenditure form crucial components of effective weight management programmes, and they are also important for clarifying the energy requirements of pregnancy. This review evaluates the primary techniques for measuring free-living energy expenditure for use in pregnancy, with special consideration of the dynamic physiological changes that occur in this state. The methods that will be discussed include the doubly labelled water method, activity recall and activity logs, heart rate monitors and motion sensors. This article may be useful for clinicians seeking to implement active gestational weight management by enabling advice on increases in caloric intake linked to measured changes in energy expenditure, and for researchers studying energy metabolism in pregnancy. PMID- 27512424 TI - Factors determining insulin requirements in women with type 1 diabetes mellitus during pregnancy: a review. AB - Most women with type 1 diabetes mellitus (T1DM) have increased insulin requirements during pregnancy. However, a minority of women have a fall in insulin requirements. When this occurs in late gestation, it often provokes concern regarding possible compromise of the feto-placental unit. In some centres, this is considered as an indication for delivery, including premature delivery. There are, however, many other factors that affect insulin requirements in pregnancy in women with type 1 diabetes mellitus and the decline in insulin requirements may represent a variant of normal pregnancy. If there is no underlying pathological process, expedited delivery in these women is not warranted and confers increased risks to the newborn. We will explore the factors affecting insulin requirements in gestation in this review. We will also discuss some novel concepts regarding beta-cell function in pregnancy. PMID- 27512426 TI - A mother-baby psychiatric day hospital: History, rationale, and why perinatal mental health is important for obstetric medicine. AB - BACKGROUND: Women frequently experience depression, anxiety, or other mental health concerns during pregnancy and postpartum, impacting her and her infant's health. Patients who require management of medical conditions during the perinatal period are even more likely to experience depression and anxiety compared to those without comorbid medical issues. Despite the availability of effective treatments, perinatal mental health utilization rates are strikingly low. METHODS: To address common treatment barriers, we developed a specialized mother-baby day hospital for women with psychiatric distress during the peripartum. In this report, we summarize findings from 800 patient satisfaction surveys collected from women treated at the program between 2007 and 2012. RESULTS: Findings suggest that women are highly satisfied with the treatment received, often noting that the inclusion of the baby in their treatment is a highly valued feature of care. CONCLUSION: The relevance of perinatal mental health services for patients who are followed by obstetrical medicine specialists is discussed. PMID- 27512427 TI - Magnesium sulfate for eclampsia prevention: Quality of care evaluation in a tertiary centre in Quebec, Canada. AB - BACKGROUND: The current Canadian guidelines endorse the use of MgSO4 for treatment of eclampsia and for prophylaxis in severe preeclampsia. Our study aimed to audit our institution's compliance regarding these guidelines. METHODS: We conducted a retrospective study to evaluate MgSO4 use in: all our cases of eclampsia since 2002, 50 cases of severe preeclampsia, and 50 cases of non-severe preeclampsia. RESULTS: Sixty-five cases of preeclampsia were analyzed after initial chart review. A high rate of preeclampsia severity misdiagnosis was observed (35%, 23/65). Only 69% (25/36) of the patients correctly diagnosed with severe preeclampsia received MgSO4; after diagnosis correction, 42% (25/59) of the patients with severe preeclampsia received the medication. Of our eight cases of eclampsia, none of the patients received MgSO4 before the seizure (although three had clear indications). CONCLUSION: Given the importance of prophylactic MgSO4 use in preventing eclampsia, we have implemented informative measures aimed at rapidly achieving complete compliance with the national guidelines. PMID- 27512428 TI - Haemorrhagic complications of peripartum anticoagulation: A retrospective chart review. AB - BACKGROUND: Women with venous thromboembolism (VTE), thrombophilias or mechanical heart valves may require anticoagulation during pregnancy and postpartum. The incidence of postpartum hemorrhage (PPH) in the literature is 2.9-6%, but the rate while on anticoagulation is not well documented. AIMS: To determine the incidence of haemorrhagic complications associated with the use of peripartum anticoagulation, and the types and risk factors for haemorrhagic complications. METHODS: A retrospective chart review was conducted on women who delivered at an academic teaching hospital and received peripartum anticoagulation between January 2000 and August 2009. Women with known bleeding disorders were excluded. RESULTS: In total, 195 cases were identified with mean age 31.3 years and gestational age of 37.7 weeks. Of these, 49% had a history of VTE, 21% had active VTE in the index pregnancy, and 63% had vaginal delivery. Types of anticoagulation used antepartum were unfractionated heparin (UFH) (43%) and low molecular weight heparin (LMWH) (36%), with 26% receiving therapeutic doses. The rate of haemorrhagic complications was 12.8%, with majority being PPH (80%). Sixty percent of the PPH occurred before reintroduction of anticoagulation postpartum. Use of therapeutic UFH antepartum was associated with increased risk of haemorrhagic complications compared to LMWH (OR 3.08, 95% CI 0.663 - 15.03, p = 0.183). CONCLUSION: The rate of haemorrhagic complications is higher in women on peripartum anticoagulation compared with published incidence in unselected obstetric populations; however, this rate is similar to our institution's reported rates. Our findings inform clinicians about competing risks of thrombotic and haemorrhagic complications in this population. PMID- 27512429 TI - The effect of pregnancy on venous valve repair to the sapheno-femoral junction for varicose veins. AB - OBJECTIVES: Pregnancy represents a special situation where both the mechanical and hormonal instigating factors of varicose veins are reversible with the venous valve cusps preserved. Exostent venous valve repairs are a physiological alternative which minimises stimulus to collateral growth (recurrence). The study purpose was to assess the effect of pregnancy on the durability of valve repairs. METHODS: In a prospective study of 36 limbs, 20 young females (30 +/- 4.7 years) had an exostent implanted to the terminal valve of the saphenofemoral junction for varicose veins. At routine long-term follow up (9.7 +/- 3.8 years), 38 pregnancies were completed (mean: 1.8, range: 1-4). The controls were a non pregnant group of limbs (n = 386). RESULTS: At 9.7 years, the internal diameter of the greater saphenous vein (GSV) changed from 7.8 +/- 2.8 mm preoperatively to 4.5 +/- 1.4 mm post-operatively. Recurrence was associated with reflux, preoperative deep system and ovarian vein involvement. Pregnancy induced 33.3% recurrences compared with non-pregnant controls (4.7%) similarly treated or 22.8% compared with non-pregnant ablative controls. At 9.7 years, symptomatic improvement continued with significantly better CEAP status (described later) (31CSEAP preoperative to 6CSEAP) with no further truncal ablation (strip, laser) required. CONCLUSIONS: Venous valve repairs can withstand the special stresses of pregnancy. There is no need to ablate the GSV. This approach is contrary to the traditional dictum; the treatment of varicose veins should be delayed until the family is completed. PMID- 27512430 TI - Who develops carpal tunnel syndrome during pregnancy: An analysis of obesity, gestational weight gain, and parity. AB - PURPOSE: To examine the prevalence, onset, and risk factors of carpal tunnel syndrome during pregnancy. METHODS: Maternal electronic medical records were linked to birth certificate records using social security number. The outcome of carpal tunnel syndrome during pregnancy was defined as ICD9 code 354.0 given at a prenatal visit. Chi-square, t-test, and adjusted logistic regression were performed. RESULTS: We analyzed 17,623 prenatal visits from the Hospital of the University of Pennsylvania from 1/2003-12/2007. Mean maternal age was 26.4 (6.5) years, with 21% white, 69% black, and 46% overweight or obese. Ninety-one (2.8%) mothers participated in 765 prenatal visits given a carpal tunnel syndrome diagnosis code. Compared to mothers without carpal tunnel syndrome, mothers with carpal tunnel syndrome were older (29.72 (5.42) versus 26.04 (6.37) years, p = 0.005), gained more weight during pregnancy (40.65 (10.13) pounds versus 34.2 (9.41) pounds, p = 0.04), and more likely to have college education (69.9% versus 44.5%, p = 0.03). Average onset (SD) of carpal tunnel syndrome was 18.1 (8.4) weeks' gestation. CONCLUSION: Mothers with carpal tunnel syndrome had high rates of overweight, obesity, and excessive gestational weight gain. Diagnosis of carpal tunnel syndrome was rare but often occurred in the first and second trimesters, earlier than the frequently reported third trimester onset seen in literature. When looking at predictors of carpal tunnel syndrome, obese prepregnancy body mass index (BMI >= 30 kg/m(2)) and excessive gestational weight gain, greater than two previous live births, higher level of maternal education and more prenatal care (>10 visits) were associated with increased risk of carpal tunnel syndrome. Higher maternal age was not associated with carpal tunnel syndrome diagnosis after adjusting for weight and parity, suggesting mediation by these covariates. PMID- 27512431 TI - Editorial. PMID- 27512432 TI - Post partum infections: A review for the non-OBGYN. AB - The epidemiology of infections in the puerperium (post partum period) is not well understood and remains underestimated because surveillance systems are often limited to the acute care setting. The most common source of persistent fever after delivery is genital tract infection for which diagnosis remains mostly clinical and antibiotic treatment empiric. This review will emphasize surgical site infections (SSIs) and endometritis. Septic thrombo-phlebitis, mastitis, urinary tract infections and rare infections will be covered in less detail. Puerperal sepsis will not be reviewed. PMID- 27512433 TI - Renal stones in pregnancy. AB - Diagnosis and treatment of renal stones during pregnancy is a complex problem. Risks to the fetus from ionising radiation and interventional procedures need to be balanced with optimising clinical care for the mother. Management of such patients requires a clear understanding of available options, with a multidisciplinary team approach. In this review, we discuss the role of different diagnostic tests including ultrasound, magnetic resonance urography, and computerized tomography. We also provide an update on recent developments in the treatment of renal stones during pregnancy. Expectant management remains first line treatment. Where definitive treatment of the stone is required, new evidence suggests that ureteroscopic stone removal may be equally safe, and possibly better than traditional temporising procedures. PMID- 27512434 TI - Screening, diagnosis and management of gestational diabetes mellitus: A national survey. AB - BACKGROUND AND METHODS: We conducted a National survey between February and June 2012 to evaluate the practices concerning screening, diagnosis and management of Gestational Diabetes (GDM) in England. RESULTS: A total of 102/126 (80%) maternity units responded. The National Institute of Health and Clinical Excellence (NICE) recommended screening criteria were used by 83% of units. All the units performed 2 h 75 g oral glucose tolerance test (OGTT) between 24 and 28 weeks. There was a wide variation in the diagnostic blood glucose values used by different units. About 86% of units used a 2 h blood glucose value of >=7.8 mmol/l and 45% of units used fasting value >=6.1 mmol/l to diagnose GDM. Only 26% of units advised self-monitoring of blood glucose pre meal and 1 h post-meal, whereas 64% of units advised monitoring 2 h after the meal. Metformin was started when women did not respond to dietary measures in 101 units (99%). Regular growth scans every four weeks from 28 weeks onwards were performed by 99 units (97%). Women on metformin with no complications were offered induction of labour at 38 completed weeks in 97 units (95%). 84 maternity units (82.3%) offered OGTT six weeks postnatally. CONCLUSION: Our survey has shown consistency in screening using the NICE criteria, use of 2 h 75 g OGTT at 24-28 weeks, in providing dietary support, use of metformin and ultrasound for fetal growth. But there is wide variation in the criteria used to diagnose GDM, self-monitoring of blood glucose, induction of labour and six weeks postnatal testing. PMID- 27512435 TI - Clinical predictors for diabetes screening in the first year postpartum after gestational diabetes. AB - BACKGROUND: Postpartum screening for diabetes in women with gestational diabetes (GDM) improves with use of reminder systems. Our primary objective was to identify predictors of diabetes screening in the first year after delivery. METHODS: A retrospective study was performed of 556 women with GDM who received outpatient prenatal care between 2007 and 2009. A mailed reminder system was utilized at two sites. Rates of postpartum glucose testing at 6 and 12 months postpartum were measured. RESULTS: Site of care and non-smoking status were identified as the only predictors of postpartum diabetes screening (p<0.001 and p = 0.02, respectively). Rates of OGTT completion at one year (38% vs. 19% p<0.001) were higher in women who attended clinics with postpartum reminders. CONCLUSIONS: The site of diabetes care in pregnancy is a major predictor of adherence to diabetes screening postpartum. Health care delivery should be considered in the development of strategies to increase screening rates. PMID- 27512436 TI - A woman with familial partial lipodystrophy and the complications of her four pregnancies. AB - We discuss a case of a woman ultimately diagnosed with familial partial lipodystrophy following her fourth pregnancy. In her previous pregnancies she had numerous complications thought to be related to diabetes including recurrent macrosomia and polyhydramnios. In her second pregnancy she underwent emergency caesarean section for fetal tachycardia at 34 weeks' gestation. Her baby was diagnosed with unexplained cerebral ischaemic injury and limb ischaemia requiring amputation. Postnatally she was diagnosed with type 2 diabetes mellitus with subsequent poor control. Very high insulin demands in this fourth pregnancy and an unusual phenotypic appearance in the patient and her mother raised suspicion of an underlying condition. Genetic studies confirmed the clinical diagnosis of familial partial lipodystrophy. PMID- 27512437 TI - Pregnancy in multiple endocrine neoplasia type 1 equals multiple complications. AB - Multiple endocrine neoplasia type 1 (MEN 1) is a rare inherited disorder caused by mutations in the tumour suppressor gene MEN 1. It is characterised by a predisposition towards the development of parathyroid, anterior pituitary and entero-pancreatic tumours. Clinically, MEN 1 is defined following development of two out of these three tumours. There have been no published cases of the management of MEN 1 in pregnancy. We report the first case of a 31-year-old primigravida with a confirmed diagnosis of MEN 1 prior to conception. Due to the rare nature of MEN 1, there are no guidelines on how such women should be managed. The main issues were to assess and manage potential complications, such as hypercalcaemia, diabetes mellitus and the symptoms from a pituitary tumour as well the issues around a gastrinoma and monitor fetal well-being. A Caesarean section was performed at 35 weeks gestation for a growth-restricted fetus with raised umbilical artery Dopplers. The neonate was treated with intravenous calcium secondary to hypocalcaemia. The patient and neonate recovered well. We have demonstrated successful management of a woman with MEN 1 who completed her pregnancy with few complications and a healthy neonate. It is vital for such women to be managed in the context of a multidisciplinary team setting to optimise maternal and fetal outcomes. PMID- 27512438 TI - Successful pregnancy outcome in a woman with Turner's syndrome. AB - Women with Turner's syndrome have a high incidence of cardiovascular complications, endocrine and hypertensive disorders. Those with the 45X chromosome complement require oocyte donation and in vitro fertilisation to conceive. Pregnancies in such women are challenging to manage due to the high risk of pregnancy-related hypertensive disorders, impaired glucose tolerance, fetal growth restriction and preterm birth. Women also need to be aware of the significant risk of aortic dilatation, dissection or rupture in pregnancy, which may be fatal. Despite these risks, favourable obstetric outcomes are achievable with careful pre-pregnancy counselling and cardiovascular assessment, intensive multidisciplinary antenatal monitoring and individualised delivery planning. We report the case of a 33-year-old woman with Turner's syndrome, pre-existing hypertension, insulin-dependent diabetes and primary hypoparathyroidism who had a successful pregnancy with good maternal and fetal outcomes despite the complexity of her medical conditions. PMID- 27512439 TI - First reported case of ganglioneuroblastoma in pregnancy and a review of the literature. AB - Ganglioneuroblastoma is a variant of neuroblastoma tumours with mature ganglion cell differentiation which occurs commonly in cervical, mediastinal and retroperitoneal locations. Approximately 90% of ganglioneuroblastomas are seen in children younger than five years old. There are 50 adult cases of ganglioneuroblastomas reported to date. Our patient is the 51st case and she is the first to be diagnosed in pregnancy. Our patient's tumour site was the thoraco abdominal retroperitoneal space adjacent to her kidney. This tumour is generally diagnosed incidentally or by compression presentations, i.e. pain or neurological symptoms. Our patient's ultrasound scan appearances triggered suspicion of an atypical mass after presenting with loin pain. Caesarean section with tumour removal in the same session is preferred if tumour is small and localized. However in this case, there was uncertainty regarding the extent of the tumour. Therefore, the patient underwent thoracotomy after delivery to excise the thoraco abdominal tumour, which extended from the level of the T9 to L2 vertebrae. PMID- 27512440 TI - The investigation and management of broad complex tachycardia and ventricular standstill presenting in pregnancy: A case report. AB - A 23 year old pregnant lady at 35 weeks gestation presented to accident and emergency with worsening dyspnoea, palpitations and dizziness. Twelve lead electrocardiogram, routine bloods and echocardiography were normal. Ambulatory monitoring previously had shown an episode of monomorphic broad complex tachycardia (BCT) and a short episode of ventricular standstill. She was admitted for cardiac monitoring until delivery. Several episodes of ventricular standstill and self-terminating BCT were recorded, which were not associated with symptoms. The patient's symptoms either corresponded with sinus rhythm or supraventricular tachycardia. She underwent elective caesarean section at 37 weeks with no complications. The patient's symptoms reduced considerably post delivery, and she was discharged three days later. Unfortunately she then had a presyncopal episode whilst holding her baby. Due to concern regarding the safety of her baby she had a permanent pacemaker implanted to allow safe beta-blockade. She remains asymptomatic six months later. PMID- 27512441 TI - Defining competencies for training in obstetric medicine. PMID- 27512442 TI - Congenital cytomegalovirus infection: Clinical presentation, epidemiology, diagnosis and prevention. AB - Cytomegalovirus is the most common congenital infection causing serious disease in infants. It is the leading infectious cause of sensorineural hearing loss and neurodevelopmental disability in developed countries. Despite the clinical importance of congenital cytomegalovirus, surveys show there is limited awareness and knowledge in the medical and general community about congenital cytomegalovirus infection. This article reviews the clinical features, global epidemiology, transmission and risk factors for cytomegalovirus infections. It also highlights several major advances made in recent years in the diagnosis and prevention of cytomegalovirus infection during pregnancy. Although research is ongoing, no therapy is currently proven to prevent or treat maternal, fetal or neonatal cytomegalovirus infection. Education of women regarding hygiene measures can help prevent cytomegalovirus infection and are currently the best strategy to prevent congenital cytomegalovirus disease. PMID- 27512444 TI - A longitudinal study of skin barrier function in pregnancy and the postnatal period. AB - BACKGROUND: It is unknown whether skin's barrier function changes in pregnancy. Trans Epidermal Water Loss (TEWL) refers to the total amount of water loss through the skin and TEWL can be measured non-invasively as an index of skin barrier function. We measured TEWL during and after pregnancy to evaluate pregnancy-related skin barrier function. METHODS: This was a prospective, longitudinal cohort study of 52 low-risk, first-time pregnant women nested within the Screening for Pregnancy Endpoints (SCOPE) Ireland study. TEWL (gwater/m2/h) was measured three times during pregnancy: 19-21 weeks, 27-32 weeks and 36 weeks; and three times postnatally: 2-4 days, 2 months and 6 months post-delivery. Data were analysed using SPSS 18.0 and P > 0.05 was considered statistically significant. RESULTS: A rise in TEWL was seen between each visit with the highest readings, exceeding the normal range of 0-20 gwater/m(2)/h, recorded at two months post-delivery. Forty women attended at two months post-delivery of whom 22 women had an average reading between 0 and 20 gwater/m(2)/h; 10 women had an average reading between 21 and 40 gwater/m(2)/h and 8 women had an average reading between 41 and 75 gwater/m(2)/h. Readings had returned to an average of 0 20 gwater/m(2)/h at six months postnatally. CONCLUSION: TEWL increases slightly in pregnancy and the postnatal period. The clinical significance of this is unclear and requires further investigation. PMID- 27512443 TI - Pregnancy and cystic fibrosis: Approach to contemporary management. AB - Over the previous 50 years survival of patients with cystic fibrosis has progressively increased. As a result of improvements in health care, increasing numbers of patients with cystic fibrosis are now considering starting families of their own. For the health care professionals who look after these patients, the assessment of the potential risks, and the process of guiding prospective parents through pregnancy and beyond can be both challenging and rewarding. To facilitate appropriate discussions about pregnancy, health care workers must have a detailed understanding of the various important issues that will ultimately need to be considered for any patient with cystic fibrosis considering parenthood. This review will address these issues. In particular, it will outline pregnancy outcomes for mothers with cystic fibrosis, issues that need to be taken into account when planning a pregnancy and the management of pregnancy for mothers with cystic fibrosis or mothers who have undergone organ transplantation as a result of cystic fibrosis. PMID- 27512445 TI - Trends in maternal deaths from epilepsy in the United Kingdom: a 30-year retrospective review. AB - OBJECTIVE: Neurological diseases remain the second most common cause of maternal mortality from indirect causes, according to the last United Kingdom confidential enquiry into maternal death. The maternal mortality rate from epilepsy is reported as 0.61 per 100,000 maternities. The aim of this study was to analyse the trends and causes of maternal death from epilepsy in the UK over the last 30 years. Information on sub-standard care associated with fatalities was also consolidated to inform guidance and clinical care by obstetricians and physicians caring for pregnant women with epilepsy. STUDY DESIGN: A retrospective review of 10 triennial confidential enquiry into maternal death reports (1979-2008) was performed, encompassing 21,514,457 maternities. Late and coincidental deaths were not included in the analyses. RESULTS: Between 1979 and 2008, there were 92 maternal deaths from epilepsy. The proportion of total maternal deaths from epilepsy over 30 years is 3.7% (95% CI 3.0-4.5), which showed an increasing trend. Sudden unexpected death in epilepsy remains the single greatest cause of maternal death from epilepsy followed by aspiration of gastric contents during seizures and drowning during bathing. CONCLUSION: All women with epilepsy should be looked after by specialist combined obstetric and medical or neurological teams in pregnancy to improve maternal and fetal outcomes. PMID- 27512446 TI - Missed opportunities: Peripartum hepatic failure in a Chinese immigrant. AB - Hepatitis B surface antigen (HBsAg) positivity presents unique management challenges in pregnancy. We present the case of a 26-year-old HBsAg-positive woman who presented at 35 weeks gestational age with nausea, vomiting, and abdominal pain with markedly elevated liver enzymes. An elevated alpha feto protein on antenatal screening had been misconstrued as fetal in origin. Magnetic resonance imaging and liver biopsy confirmed hepatocellular carcinoma. She died of fulminant hepatic failure two weeks after emergent delivery. This case highlights the importance of adequate evaluation and management of pregnant patients testing positive for HBsAg on routine antenatal testing. PMID- 27512447 TI - Pregnancy in women after coronary revascularization. AB - Pregnancy after coronary revascularization presents unique challenges to the management of antiplatelet therapy, anesthesia and mode of delivery. We present two cases where women of reproductive age required coronary revascularization with drug eluting stents after a myocardial infarction, and discuss key aspects of pregnancy and labor management. PMID- 27512448 TI - Managing severe peripartum hyponatraemia: A case report. AB - We present a case of severe peripartum hyponatraemia that occurred following a major obstetric haemorrhage causing both an ischaemic stroke and Sheehan's syndrome and outline the investigations and management strategy required. PMID- 27512449 TI - A case of euglyacemic diabetic ketoacidosis in a patient with gestational diabetes mellitus. AB - A 30-year old woman at 30 weeks gestation with insulin-controlled gestational diabetes was admitted with nausea and vomiting. Plasma glucose was 3.3 mmol/l with pH 7.23 and raised capillary ketones at 6.1 mmol/l. She was diagnosed with euglycaemic diabetic ketoacidosis. Cardiotocography showed good fetal movement and accelerations. She was given intramuscular betamethasone and started on intravenous dextrose, insulin and 0.9% saline with potassium chloride with resolution of ketosis. Euglycaemic diabetic ketoacidosis has been reported during pregnancy in patients with type 1 and type 2 diabetes. We believe that this is a report of such an occurrence in a patient with gestational diabetes. PMID- 27512450 TI - Acidosis: A potential explanation for adverse fetal outcome in intrahepatic cholestasis of pregnancy. A case report. AB - BACKGROUND: Intrahepatic cholestasis of pregnancy is a cholestatic disorder with an increased risk for adverse perinatal outcome. The mechanism underlying intrauterine demise is poorly understood. CASE: A nulliparous woman with gestational age of 36 plus 6 weeks presented with suspected intrahepatic cholestasis. Continuous CTG monitoring evolved from a normal pattern towards a non-reassuring pattern. A male neonate was delivered by caesarean section. Apgar scores 0, 1 and 4 at 1, 5 and 10 min. Fetal cord gas analysis showed pH 6.98, base deficit -15 mmol/L. Blood results showed maternal serum bile acid concentration of 220 umol/L. CONCLUSION: Our case suggests gradual evolution towards hypoxia and acidosis. It is unknown whether certain components in the bile acid concentrations might contribute to a fetal metabolic component of the acidosis. PMID- 27512451 TI - The UK maternal death report. PMID- 27512452 TI - Prevention of mother-to-child transmission in South Africa: an ever-changing landscape. AB - Almost 30% of pregnant women attending public health clinics in South Africa are HIV positive; which represents approximately 280,000 women each year. South Africa has the largest antiretroviral therapy programme in the world, with over 2.7 million people on treatment in 2013. Since its belated and controversial beginning, the Prevention of Mother-to-Child Transmission programme has achieved a substantial reduction in vertical transmission. South Africa is justifiably proud of this success. However, the history of Prevention of Mother-to-Child Transmission (PMTCT) and antiretroviral therapy programmes in South Africa has been fraught with delays and political intervention. South Africa could have started both PMTCT and antiretroviral therapy programmes in 2000. Instead, the AIDS denialist views of the government allowed the HIV epidemic to spiral out of control. Roll-out of a national PMTCT programme began in 2002, but only after the government was forced to do so by a Constitutional Court ruling. Now, a decade later, HIV treatment and prevention programmes have been completely transformed. This article will discuss the evolution of the HIV epidemic in South Africa, and give a historical overview of the struggle to establish a national PMTCT, and the impact of delaying PMTCT and treatment programmes on infant and maternal health. PMID- 27512453 TI - Care of the HIV-infected pregnant woman in the developed world. AB - The reduction of human immunodeficiency virus (HIV) transmission from mother to child is one of the success stories of modern medicine and public health. In the developed world, with universal HIV counseling and testing, antiretroviral prophylaxis, scheduled Caesarean delivery if indicated, and avoidance of breastfeeding, HIV transmission from mother to infant can be <2%. Despite this, transmissions continue to occur, often due to lack of knowledge of HIV status. Missed opportunities for prevention and prevention challenges include late prenatal care, lack of HIV testing in pregnancy, lack of preconception counseling, unintended pregnancy, and substance abuse. We review preconception counseling including options for serodiscordant couples, and antepartum, peripartum and postpartum care of the HIV-infected woman in the developed world, and advocate for a comprehensive, collaborative, multidisciplinary approach. PMID- 27512454 TI - Pregnancy in women with congenital heart disease. AB - Due to advances in paediatric congenital heart surgery, there are a growing number of women with congenital heart disease (CHD) reaching childbearing age. Pregnancy, however, is associated with haemodynamic stresses which can result in cardiac decompensation in women with CHD. Many women with CHD are aware of their cardiac condition prior to pregnancy, and preconception counselling is an important aspect of their care. Preconception counselling allows women to make informed pregnancy decisions, provides an opportunity for modifications of teratogenic medications and, when necessary, repair of cardiac lesions prior to pregnancy. Less commonly, the haemodynamic changes of pregnancy unmask a previously unrecognised heart lesion. In general, pregnancy outcomes are favourable for women with CHD, but there are some cardiac lesions that carry high risk for both the mother and the baby, and this group of women require care by an experienced multidisciplinary team. This review discusses preconception counselling including contraception, an approach to risk stratification and management recommendations in women with some common CHDs. PMID- 27512455 TI - Letter regarding: Managing severe peripartum hyponatraemia: A case report, Obstetric Medicine: The Medicine of Pregnancy. PMID- 27512456 TI - Authors' response to letter by Adam Morton regarding: "Managing severe peripartum hyponatraemia: A case report". PMID- 27512457 TI - Clinical practice guidelines in obstetric medicine. PMID- 27512458 TI - Pregnancy in women with inherited metabolic disease. AB - An increasing number of women with rare inherited disorders of metabolism are becoming pregnant. Whilst, in general, outcomes for women and their children are good, there are issues that need to be considered. Due to the rarity of many conditions, there is limited specific guidance available on best management. Prepregnancy counselling with information on inheritance, options for reproduction, teratogenicity risk, potential impact on maternal health and long term health of children should be offered. With appropriate specialist management, the teratogenic risk of conditions such as maternal phenylketonuria (PKU) can be eliminated, and the risk of metabolic decompensation in other disorders of intoxication or energy metabolism significantly reduced. Newer therapies, such as enzyme replacement therapy, appear to be safe in pregnancy, but specific advice should be sought. Multidisciplinary management, and close liaison between obstetricians and other specialists is required for women in whom there is cardiac, renal, respiratory, joint or other organ involvement. PMID- 27512459 TI - Prevention of gestational diabetes in pregnant women with risk factors for gestational diabetes: a systematic review and meta-analysis of randomised trials. AB - BACKGROUND: Gestational diabetes mellitus can be defined as 'glucose intolerance or hyperglycaemia with onset or first recognition during pregnancy.' OBJECTIVE: The objective of our systematic review was to see if there was any intervention that could be used for primary prevention of gestational diabetes mellitus in women with risk factors for gestational diabetes mellitus. SEARCH STRATEGY: Major databases were searched from 1966 to Aug 2012 without language restriction. SELECTION CRITERIA: Randomised trials comparing intervention with standard care in women with risk factors for gestational diabetes were included. Meta-analysis was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. The primary outcome assessed was the incidence of gestational diabetes. DATA COLLECTION AND ANALYSIS: Data from included trials were extracted independently by two authors and analysed using Rev-Man 5. MAIN RESULTS: A total of 2422 women from 14 randomised trials were included; which compared diet (four randomised trials), exercise (three randomised trials), lifestyle changes (five randomised trials) and metformin (two randomised trials) with standard care in women with risk factors for gestational diabetes mellitus. Dietary intervention was associated with a statistically significantly lower incidence of gestational diabetes (Odds ratio 0.33, 95% CI 0.14 to 0.76) and gestational hypertension (Odds ratio 0.28, 95% CI 0.09, 0.86) compared to standard care. There was no statistically significant difference in the incidence of gestational diabetes mellitus or in the secondary outcomes with exercise, lifestyle changes or metformin use compared to standard care. CONCLUSIONS: The use of dietary intervention has shown a statistically significantly lower incidence of gestational diabetes mellitus and gestational hypertension compared to standard care in women with risk factors for gestational diabetes mellitus. PMID- 27512460 TI - Maternal mortality and its relationship to emergency obstetric care (EmOC) in a tertiary care hospital in South India. AB - OBJECTIVE: To determine the trends in maternal mortality ratio over 5 years at JIPMER Hospital and to find out the proportion of maternal deaths in relation to emergency admissions. METHODS: A retrospective analysis of maternal deaths from 2008 to 2012 with respect to type of admission, referral and ICU care and cause of death according to WHO classification of maternal deaths. RESULTS: Of the 104 maternal deaths 90% were emergency admissions and 59% of them were referrals. Thirty two percent of them died within 24 hours of admission. Forty four percent could be admitted to ICU and few patients could not get ICU bed. The trend in cause of death was increasing proportion of indirect causes from 2008 to 2012. CONCLUSION: The trend in MMR was increasing proportion of indirect deaths. Ninety percent of maternal deaths were emergency admissions with complications requiring ICU care. Hence comprehensive EmOC facilities should incorporate Obstetric ICU care. PMID- 27512461 TI - Chronic kidney disease in pregnancy: Maternal and fetal outcomes and progression of kidney disease. AB - BACKGROUND: There is a paucity of Australian data regarding renal disease in pregnancy. We undertook a retrospective cohort study at a tertiary institution to examine the impact of renal disease on pregnancy outcomes and the effect of pregnancy on disease progression. METHODS: A total of 55 pregnancies of patients with renal disease admitted from 2003 to 2010 to the Royal Brisbane and Women's Hospital were analysed. Pre-conception variables, fetal/delivery and maternal outcomes were analysed in this group and in a control group of women with normal kidney function pre-pregnancy. RESULTS: Of the 55 pregnancies, 71% experienced pre-term delivery, 38% had intra-uterine growth restriction and 62% required caesarean section. Of all, 60% of neonates required neonatal intensive care unit (NICU) admission and six perinatal deaths occurred. Of all, 67% of women suffered preeclampsia, 47% anaemia and 3 patients required dialysis in pregnancy. Postpartum deterioration of renal function occurred in patients with pre conception chronic kidney disease stage 3-5. CONCLUSIONS: Chronic kidney disease of all stages is a risk factor for adverse pregnancy outcomes. In a tertiary institution however, there is a high rate of successful pregnancy (84%). PMID- 27512462 TI - Pregnancy outcomes in cystic fibrosis: a 10-year experience from a UK centre. AB - BACKGROUND: Cystic fibrosis manifests as a multisystem disease, despite this female fertility is relatively preserved with levels approaching that of the non cystic fibrosis population. We reviewed pregnancies in cystic fibrosis patients over a 10-year period from a UK adult cystic fibrosis centre by considering maternal and fetal outcomes. METHODS: We conducted a retrospective case-note review of pregnancies during 2003-2013 using respiratory and obstetric records. RESULTS: We observed moderate falls in lung function immediately after delivery, which persisted at 12 months postpartum. We found that a decline in lung function at delivery was a marker for further decline in function during the subsequent postpartum period. We found baseline lung function was predictive of gestational age at delivery. We observed a high incidence of haemoptysis. CONCLUSION: Consistent with current guidance we found pregnancy is feasible and well tolerated in the majority of patients with cystic fibrosis. There was a high incidence of haemoptysis, which warrants further study. PMID- 27512463 TI - Infective endocarditis in pregnancy: Case report and review of the literature. AB - Infective endocarditis in pregnancy is associated with high maternal and fetal morbidity and mortality and is estimated to complicate approximately 1 in 100,000 pregnancies. We report the case of a 33-year-old patient who presented at 30 weeks and 3 days gestation in her third pregnancy. The patient described a 3 week history of feeling generally unwell, an episode of temporary speech disturbance, right shoulder tip pain, left subscapular pain on inspiration and chest discomfort. Investigations included an echocardiogram, which revealed a large mobile mass on the aortic coronary cusp and a small mass on the non-coronary cusp. There was significant aortic regurgitation. Blood cultures were positive for staphylococcus lugdunensis. A diagnosis of infective endocarditis was made. The patient deteriorated, with worsening cardiac function, and proceeded to have a caesarean section on day 7 of admission. Her baby had multiple limb abnormalities, subsequently diagnosed as arthrogryposis multiplex congenita. Aortic valve replacement with a mechanical valve was then performed on day 3 post partum. The patient recovered well post operatively and was discharged home with her baby on day 45 post partum. The commonest complications of IE are congestive cardiac failure, perivalvular extension and systemic embolization. The management of infective endocarditis in pregnancy is similar to that of the non-pregnant however there is high foetal mortality associated with cardiopulmonary by-pass for cardiac surgery. The patient described here developed staphylococcus lugdunensis infective endocarditis, which is a rare but aggressive causative organism in infective endocarditis. Infective endocarditis in pregnancy is a rare but serious condition with significant fetal and maternal morbidity and mortality. Early diagnosis with a multidisciplinary team approach is essential to improve outcomes. PMID- 27512464 TI - Putting the world to rights. PMID- 27512465 TI - Monogenic diabetes and pregnancy. AB - Monogenic diabetes is frequently mistakenly diagnosed as either type 1 or type 2 diabetes, yet accounts for approximately 1-2% of diabetes. Identifying monogenic forms of diabetes has practical implications for specific therapy, screening of family members and genetic counselling. The most common forms of monogenic diabetes are due to glucokinase (GCK), hepatocyte nuclear factor (HNF)-1A and HNF 4A, HNF-1B, m.3243A>G gene defects. Practical aspects of their recognition, diagnosis and management are outlined, particularly as they relate to pregnancy. This knowledge is important for all physicians managing diabetes in pregnancy, given this is a time when previously unrecognised monogenic diabetes may be uncovered with careful attention to atypical features of diabetes misclassified as type 1, type 2, or gestational diabetes. PMID- 27512466 TI - Restless leg syndrome in pregnancy. AB - Restless leg syndrome, more recently renamed Willis-Ekbom disease, is a condition that disrupts sleep and occurs more frequently in the pregnant population. We present a 39-year-old woman with restless legs syndrome in the third trimester and discuss the epidemiology, pathophysiology and therapeutic options in the pregnant population while highlighting the challenges posed by the lack of safety data of approved drugs. PMID- 27512467 TI - Acute respiratory failure in pregnancy. AB - Respiratory failure affects up to 0.2% of pregnancies, more commonly in the postpartum period. Altered maternal respiratory physiology affects the assessment and management of these patients. Respiratory failure may result from pregnancy specific conditions such as preeclampsia, amniotic fluid embolism or peripartum cardiomyopathy. Pregnancy may increase the risk or severity of other conditions, including thromboembolism, asthma, viral pneumonitis, and gastric acid aspiration. Management during pregnancy is similar to the nonpregnant patient. Endotracheal intubation in pregnancy carries an increased risk, due to airway edema and rapid oxygen desaturation following apnea. Few data are available to direct prolonged mechanical ventilation in pregnancy. Chest wall compliance is reduced, perhaps permitting slightly higher airway pressures. Optimizing oxygenation is important, but data on the use of permissive hypercapnia are limited. Delivery of the fetus does not always improve maternal respiratory function, but should be considered if benefit to the fetus is anticipated. PMID- 27512468 TI - Gestational weight gain and medical outcomes of pregnancy. AB - This narrative review discusses gestational weight gain (GWG) and medical outcomes of pregnancy, including metabolic, cardiovascular, respiratory, musculoskeletal and psychiatric systems. Taken as a whole, the available evidence shows that excessive GWG increases the risk of all medical complications of pregnancy, and negatively impacts the long-term health and weight of both mothers and their offspring. Briefly, interventions to encourage appropriate GWG are discussed and readers are directed to resources to facilitate discussion of pregnancy weight. PMID- 27512469 TI - Global obstetric medicine: Collaborating towards global progress in maternal health. AB - Globally, the nature of maternal mortality and morbidity is shifting from direct obstetric causes to an increasing proportion of indirect causes due to chronic conditions and ageing of the maternal population. Obstetric medicine can address an important gap in the care of women by broadening its scope to include colleagues, communities and countries that do not yet have established obstetric medicine training, education and resources. We present the concept of global obstetric medicine by highlighting three low- and middle-income country experiences as well as an example of successful collaboration. The article also discusses ideas and initiatives to build future partnerships within the global obstetric medicine community. PMID- 27512470 TI - Acute pancreatitis with eclampsia-preeclampsia syndrome and poor maternal outcome: two case reports and review of literature. AB - Acute pancreatitis in pregnancy is a rare entity and has been reported to be associated with preeclampsia in the literature. Fulminant pancreatitis may have a guarded prognosis despite intensive multidisciplinary management. Two cases of maternal mortality in women with acute pancreatitis noted in the setting of preeclampsia-eclampsia syndrome are reported here. PMID- 27512471 TI - All that wheezes is not asthma: A cautionary case study of shortness of breath in pregnancy. AB - BACKGROUND: Shortness of breath is a common physiological pregnancy presentation, secondary to both hormonal and mechanical effects. Its pathological causes are common (asthma exacerbation or infection); new-onset cardiac pathology is rarely considered. CASE: JC, a 39-year old G4P2T1, presented at 34 weeks' gestation with shortness of breath unrelieved by salbutamol. History included asthma, poly-drug abuse and smoking. Initial presentation was consistent with asthma exacerbation and she was treated as such. There was deterioration of symptoms and on re examination raised jugular venous pressure was noted with bibasal lung crepitations and cardiac systolic murmur. Echocardiogram showed severe cardiomyopathy (left ventricular ejection fraction 20%). JC was commenced on diuretics, digoxin and fluid restricted. Labour was induced at 35 weeks' gestation, with birth of a healthy female infant (BW 2475 g) by elective assisted vaginal delivery. Cardiac function improved in subsequent weeks, confirming peripartum cardiomyopathy. CONCLUSION: Peripartum cardiomyopathy affects 1 in 2500-4000 live births. Over 90% of women regain normal cardiac function postpartum with optimal medical management. Peripartum cardiomyopathy presents a diagnostic conundrum as its primary symptoms mimic not only those of normal pregnancy but also a number of other, more common conditions. It is important to consider cardiac causes of shortness of breath initially, and vital to revisit an initial non-cardiac shortness of breath diagnosis if there is no sustained improvement with treatment. In this case, asthma history and initial wheeze on examination impeded correct diagnosis; however, the situation was re-evaluated and correct diagnosis made when the patient's shortness of breath deteriorated. Subsequent multidisciplinary management and birth in an appropriate setting facilitated the best outcome for both mother and baby. PMID- 27512472 TI - Coronary artery disease secondary to familial hypercholesterolaemia: An infrequent cause of increasingly common pregnancy co-morbidity. AB - BACKGROUND: Cardiovascular disease affects 0.2-4% of pregnancies. Coupled with the physiological stress of pregnancy, cardiovascular disease may present significant management challenges including appropriate risk:benefit analysis of medical and surgical management options. CASE: A 33-year-old gravida 4 para 1 miscarriage 2 presented at 18 weeks' gestation to the high-risk pregnancy service with a history of coronary artery disease and homozygous familial hypercholesterolaemia. Pre-pregnancy echocardiogram showed probable aortic xanthoma and preserved cardiac function. Prior to planned interventional cardiology assessment for her coronary artery disease she became pregnant, taking aspirin and multivitamins only. She had exertional angina responsive to metoprolol, agreed to recommencing statin therapy when serum cholesterol worsened, but declined angiography during pregnancy. At 36 weeks' gestation, she had further angina symptoms but no acute coronary syndrome. Induction in the High Dependency Unit with elective assisted vaginal delivery of a healthy female infant (birthweight 2460 g) occurred at 37 weeks. She underwent triple-vessel coronary artery bypass postpartum, recovering well. CONCLUSION: Whilst this specific condition is rare, the increase in cardiovascular disease and cardiovascular risks in the obstetric population emphasises the need for clear, multidisciplinary management from the outset of pregnancy for these women. PMID- 27512473 TI - Editorial. PMID- 27512474 TI - Severe gestational hypertriglyceridemia: A practical approach for clinicians. AB - Severe gestational hypertriglyceridemia is a potentially life threatening and complex condition to manage, requiring attention to a delicate balance between maternal and fetal needs. During pregnancy, significant alterations to lipid homeostasis occur to ensure transfer of nutrients to the fetus. In women with an underlying genetic predisposition or a secondary exacerbating factor, severe gestational hypertriglyceridemia can arise, leading to devastating complications, including acute pancreatitis. Multidisciplinary care, implementation of a low-fat diet with nutritional support, and institution of a hierarchical therapeutic approach are all crucial to reduce maternal and fetal morbidity. To avoid maternal pancreatitis, close surveillance of triglycerides throughout pregnancy with elective hospitalization for refractory cases is recommended. Careful dietary planning is required to prevent neural and retinal complications from fetal essential fatty acid deficiency. Questions remain about the safety of fibrates and plasmapheresis in pregnancy as well as the optimal timing for induction and delivery of these women. PMID- 27512475 TI - Insomnia and sleep deficiency in pregnancy. AB - Insomnia and sleep deficiency in pregnancy are very common with most women reporting sleep disturbances during pregnancy. Insomnia and sleep deficiency are also more prevalent as pregnancy progresses, possibly related to pregnancy related physical symptoms or discomfort. There is increasing evidence indicating that these sleep problems may be associated with adverse maternal and fetal outcomes such as depressive symptoms, increased pain during labor, more Caesarean sections, preterm birth, and low birth weight. Treatment of insomnia remains challenging as some of the more commonly used sleep inducing medications such as benzodiazepines and hypnotic benzodiazepine receptor agonists may be associated with adverse neonatal outcomes. Nonpharmacological treatments such as cognitive behavioral therapy are available but the data in pregnancy is often lacking. PMID- 27512476 TI - Antenatal steroids for fetal lung maturity: Time to target more frequent doses to fewer women? AB - Antenatal corticosteroids for fetal lung maturation have become mainstay treatment in women thought to be at high-risk of premature birth. To ensure treatment efficacy before delivery, the current practice is to administer steroids early to a woman considered at risk; however, neonatal benefit is lost after the seven-day treatment-to-delivery window. Over half of women who deliver before 34 weeks' gestation do not receive antenatal corticosteroids within this timeframe, but many still deliver prematurely; however, clinicians are reluctant to administer repeated courses of steroids due to concerns, among others, of impaired fetal growth. However, evidence is mounting regarding the optimal timing for steroids, including substantive benefits close to delivery, and the benefits of repeated courses if delivery has not occurred. Better targeted treatment is required to allow for maximum benefit; reducing unnecessary treatment in low-risk women, while targeting therapy in the high-risk cohort and offering repeat courses if the seven-day window is exceeded. Novel tools to aid prediction may help implement this strategy. PMID- 27512477 TI - Pituitary apoplexy in pregnancy: A case series and literature review. AB - BACKGROUND: Severe headache during pregnancy is a challenging condition that may rarely imply endocrine disturbances. Rapid recognition of pituitary apoplexy is needed to improve pregnancy outcome. OBJECTIVE: To review and compare maternal and fetal outcomes after pituitary apoplexy. METHODS: Four cases of pituitary apoplexy during pregnancy in our centre are reported and literature review covering the past 54 years was performed. RESULTS: In the four cases presented and the 33 reported in the literature, most women presented with severe headaches and systemic symptoms. Overall, 42% were treated surgically, 31% received bromocriptine or cabergoline and 61% were given hormone replacement. No major obstetrical complication was reported and all babies were healthy. CONCLUSION: Pituitary apoplexy is a rare cause of sudden and severe headache during pregnancy. Rapid identification of this condition with potentially associated endocrine disturbances is important to ensure maternal and fetal well-being. A multidisciplinary team approach seems to reduce morbidity and mortality. PMID- 27512479 TI - Drug-induced fulminant hepatic failure in pregnancy. AB - Liver disease in pregnancy can be classified as predating, co-incidental or unique to pregnancy. Medications are often overlooked as a significant cause of liver disease. We present the case of a 39-year-old patient who presented at 20 weeks with jaundice, elevated liver enzymes, and abnormal liver function progressing eventually to fulminant hepatic failure. The patient was on methyldopa and labetalol from 12 weeks' gestational age. Liver biopsy was consistent with drug-induced liver injury. Both methyldopa and labetalol have been associated with hepatotoxicity including liver failure. This case highlights the importance of including medications as a cause of liver failure in pregnant patients. PMID- 27512478 TI - Antenatal haemoglobinopathy screening: Patterns within a large obstetric service. Working towards a standard of care. AB - BACKGROUND: Antenatal screening can predict clinically significant haemoglobinopathies, however in Australia, practices are not standardised and are evolving as the population becomes more ethnically diverse. This study describes antenatal screening practices in a large Australian laboratory/antenatal service. METHODS: Data were collected retrospectively on consecutive antenatal haemoglobin electrophoresis over 16 months and correlated with obstetric data, obtained from the local obstetric database. RESULTS: 462 patients were included, with an average gestation of 25.8 weeks. 'Pregnancy' was the most common stated indication, with absent indication/clinical information in 8%. Gestational age was documented in 54%. In 15%, no contact details of the referrer were documented and partner screening was traceable in only 25 cases (5.4%). In 82% of cases, no abnormalities were detected. Beta thalassemia trait was the most common positive result. Only 52% of patients had recent iron studies. The mean haemoglobin was 111.6 g/L and mean cell volume was 80.5 fl at the time of testing. Ethnicity was documented on the request form in 3%. After Australasia, the most common ethnicity of patients was South East Asia and the Middle East. CONCLUSION: Referral patterns in our health service are diverse and reflect our changing population and care practices. Detailed guidelines are required and we propose a comprehensive algorithm for general use where selective screening is practiced within an Australasian population or one with similar demographics. PMID- 27512480 TI - Rare problems with RhD immunoglobulin for postnatal prophylaxis after large fetomaternal haemorrhage. AB - We report a case of unusually large fetomaternal haemorrhage in a RhD- patient; of symptomatic non-sustained haemolysis of fetal red cells in the maternal circulation with infusion of intravenous high-dose RhD immunoglobulin; and of a failure to prevent RhD alloimmunisation. The haemolytic reaction is not previously reported in this patient group and we suggest would be limited to patients where the number of fetal red cells in the circulation is high. We advocate caution in treatment and spaced dosing of RhD immunoglobulin where the required dose is high, and refer readers to the WinRhoSDFTM RhD immunoglobulin product information for their updated dosing recommendations. There is a need for better understanding of pathophysiology and RhD immunoglobulin effects, to further reduce alloimmunisation rates, and we support the reporting of prophylaxis failures to haemovigilance programmes as is in place in the United Kingdom. PMID- 27512481 TI - Percutaneous mitral commisurotomy during pregnancy - A report of two cases performed in a United Kingdom tertiary centre and a review of the literature. AB - We report two cases of severe mitral stenosis where percutaneous mitral commisurotomy was performed within pregnancy. The first case involves an emergency procedure for a new diagnosis of severe mitral stenosis in a woman presenting with pulmonary oedema at 27 weeks' gestation. The second case is of a woman known to have mitral stenosis who underwent a semi-elective procedure for deterioration in symptoms. This procedure is not commonly performed in the United Kingdom because of low incidence of rheumatic heart disease. In addition, percutaneous mitral commisurotomy during pregnancy is rarely performed in the United Kingdom because of the improved healthcare system where majority of the women with moderate to severe mitral stenosis (even asymptomatic) will undergo planned interventions (percutaneous mitral commisurotomy or mitral valve surgery) before contemplating pregnancy. These cases highlight both the acute and chronic presentations of mitral stenosis and the impact pregnancy has on this condition. In addition, these cases show the importance of retaining skills in performing percutaneous mitral commisurotomy within our United Kingdom cardiologists. PMID- 27512482 TI - Presentation and management of acute hypertriglyceridemic pancreatitis in pregnancy: A case report. AB - Pancreatitis related to hypertriglyceridemia can occasionally occur during pregnancy, particularly if there are underlying genetic abnormalities in lipid metabolism. We report the case of a 27-year-old female with hypertriglyceridemic pancreatitis in pregnancy that was treated initially with lipid lowering medications, followed by plasma exchange for persistently elevated triglyceride levels. Despite multiple interventions, she developed recurrent pancreatitis and simultaneously had a preterm birth. In this case report, we highlight the various therapies and the use of plasmapharesis in secondary prevention of hypertriglyceridemic pancreatitis in pregnancy. PMID- 27512483 TI - Prescribing in pregnancy. PMID- 27512484 TI - Preconception counselling for women with acromegaly: More questions than answers. AB - BACKGROUND AND AIMS: Approximately 174 pregnancies in acromegaly have been reported. Our objectives were to identify the key challenges of preconception counselling in this population. METHODS: Case series of three acromegalic women with desire for pregnancy. Issues were identified from chart review and discussion with attending physicians. Literature review of acromegaly and pregnancy was conducted. RESULTS: Important issues identified included: impact of acromegaly on fertility, management of acromegaly in the peripartum period, screening for associated conditions, risk of progression of acromegaly/tumour growth during pregnancy, impact of acromegaly on pregnancy outcomes, surveillance during pregnancy, method of delivery and impact on neonatal outcomes and breastfeeding. CONCLUSIONS: Pregnancy can be safely achieved in patients with acromegaly. There is little evidence to guide recommendations around conception and pregnancy surveillance. Patients can be reassured that in most situations, pregnancy proceeds without complication and that medical treatment can be used during pregnancy if necessary. PMID- 27512485 TI - Thrombocytopenic syndromes in pregnancy. AB - The physiological changes in pregnancy result in platelet counts that are lower than in nonpregnant women. Consequently, thrombocytopenia is a common finding occurring in 7-12% of pregnant women. Gestational thrombocytopenia, the most common cause of low platelet counts, tends to be mild in most women and does not affect maternal, fetal or neonatal outcomes. Gestational thrombocytopenia needs to be distinguished from other less common causes of isolated thrombocytopenia, such as immune thrombocytopenia, which affects approximately 3% of thrombocytopenic pregnant women and can lead to neonatal thrombocytopenia. Hypertensive disorders of pregnancy and thrombotic microangiopathies are both associated with thrombocytopenia. They share a considerable number of similar characteristics and are associated with significant maternal and neonatal morbidity and rarely mortality. Accurate identification of the aetiology of thrombocytopenia and appropriate management are integral to optimizing the pregnancy, delivery and neonatal outcomes of this population. Clinical cases are described to illustrate the various aetiologies of thrombocytopenia in pregnancy and their treatment. PMID- 27512486 TI - Frequency and type of medications and vaccines used during pregnancy. AB - Providing safe pharmacotherapy for pregnant women is challenging. Nearly all pregnant women are prescribed or inadvertently receive medication during their pregnancy. We reviewed the scientific literature to identify the specific medications and vaccines that are most often used during pregnancy and described them by category and indication. Our interest was to update the research before the implementation of the recently released FDA labeling rule for pregnancy and lactation that eliminates the use of pregnancy categories in product labels. Our results confirm that most products taken during pregnancy are over-the-counter or in the former FDA pregnancy categories A or B. However, medications taken prior to pregnancy recognition (inadvertent exposures) and those prescribed for chronic illness such as allergies, depression, and pain are of concern. A better understanding of medication and vaccine utilization during pregnancy may help clinicians reduce inadvertent first trimester exposures and improve the safe and effective treatment of pregnant women. PMID- 27512487 TI - Ondansetron and pregnancy: Understanding the data. AB - Nausea and vomiting of pregnancy (NVP) is a common condition affecting 75% of pregnant women. NVP generally commences early in the first trimester, peaking in severity between 7 and 12 weeks and in over 90% symptoms will have abated by week 20. Thus, the time when women are most likely to have NVP and require treatment coincides with the embryonic period when there is maximum susceptibility to any teratogenic risk. Following the thalidomide tragedy of 55 years ago there is a particular awareness and sensitivity about these potential risks, especially in relation to any medication used to treat NVP. Despite several studies showing no clear benefits of ondansetron over other NVP treatments such as doxylamine, and the paucity of safety data, the off-label prescribing and use of ondansetron to treat NVP has increased significantly worldwide. Albeit based on limited human pregnancy data, ondansetron has not been associated with a significantly increased risk of birth defects or other adverse pregnancy outcomes. This review attempts to highlight some of the difficulties in interpreting the available data and the need to follow practical guidelines regarding treatment of NVP. PMID- 27512488 TI - The influence of obesity on perinatal outcomes in pregnancies achieved with assisted reproductive technology: A population-based retrospective cohort study. AB - OBJECTIVE: To determine the influence of obesity on neonatal outcomes of pregnancies resulting from assisted reproductive technology. METHODS: Population based retrospective cohort study of all non-anomalous, live births in Ohio from 2007 to 2011, comparing differences in the frequency of adverse neonatal outcomes of women who conceived with assisted reproductive technology versus spontaneously conceived pregnancies and stratified by obesity status. Primary outcome was a composite of neonatal morbidities defined as >=1 of the following: neonatal death, Apgar score of <7 at 5 min, assisted ventilation, neonatal intensive care unit admission, or transport to a tertiary care facility. RESULTS: Rates of adverse neonatal outcomes were significantly higher for assisted reproductive technology pregnancies than spontaneously conceived neonates; non-obese 25% versus 8% and obese 27% versus 10%, p < 0.001. Assisted reproductive technology was associated with a similar increased risk for adverse outcomes in both obese (adjusted odds ratio (aOR): 1.33, 95% confidence interval (CI): 1.11-1.59) and non-obese women (aOR: 1.34, 95% CI: 1.18-1.51) even after adjustment for coexisting risk factors. This increased risk was driven by higher preterm births in assisted reproductive technology pregnancies; obese (aOR: 1.06, 95% CI: 0.86 1.31) and non-obese (aOR: 1.15, 95% CI: 1.00-1.32). DISCUSSION: Assisted reproductive technology is associated with a higher risk of adverse neonatal outcomes. Obesity does not appear to adversely modify perinatal risks associated with assisted reproductive technology. PMID- 27512489 TI - Unplanned pregnancy on a direct oral anticoagulant (Rivaroxaban): A warning. AB - Direct oral anticoagulants (DOACs or NOACs -non-vitamin K oral anticoagulants), as the name suggests, are oral anticoagulants with a direct inhibitory action either against factor X or factor II (thrombin). Pregnant women were excluded from participating in all the large trials of the DOACs and they are considered contra-indicated in pregnancy and breast feeding. We present a case of inadvertent exposure to rivaroxaban in a woman who presented at 25 weeks' gestation. The management of her pregnancy and delivery is described, and the previous published case reports are reviewed with a discussion about the use of DOACs in woman of childbearing age. PMID- 27512490 TI - Adrenal Cushing's syndrome in pregnancy: Clinical and molecular characterisation of a case. AB - BACKGROUND: Cushing's syndrome is rare during pregnancy and more commonly due to adrenal pathology, in contrast to the non-pregnant population. Increased levels of cortisol-binding globulin and placental production of corticotropin-releasing hormone and adrenocorticotropic hormone complicate the diagnostic strategies usually employed. CASE: A 32-year-old G1P0 at 15/40 gestation presented with severe peripheral oedema and excessive weight gain. Examination revealed pitting oedema to the abdominal wall, wide violaceous striae, moon facies and acne. Cortisol excess was confirmed with elevated 24 h urinary free cortisol, raised midnight salivary cortisol and lack of diurnal variation. Adrenocorticotropic hormone ranged between 22 and 36 pg/ml (5-8 pmol/L). Fetal ultrasound confirmed a single live intrauterine gestation with an incidental finding of a maternal left adrenal mass. Magnetic resonance imaging confirmed an adrenal mass measuring 3.0 * 4.4 * 4.1 cm. She underwent a laparoscopic left adrenalectomy at 18 weeks' gestation without complication. Her postoperative cortisol level was undetectable. Hydrocortisone replacement was commenced with slow weaning as an outpatient. Histology was consistent with an adrenal adenoma. Immunohistochemistry revealed strong staining for the luteinising hormone/choriogonadotropin receptor, and expression of the luteinising hormone/choriogonadotropin receptor gene was in the range seen in normal ovary. DNA analysis revealed a mutation in GNAS encoding the Galpha subunit in the cyclic adenosine monophosphate pathway. CONCLUSION: Cushing's syndrome may present in pregnancy as a result of betahCG acting on the luteinising hormone/choriogonadotropin receptor over-expression by the adenoma amplifying the aberrant cyclic adenosine monophosphate signaling implicated in the development of cortisol-secreting adenomas. PMID- 27512491 TI - Life-threatening ketoacidosis in a pregnant woman with psychotic disorder. AB - Pregnancy is an insulin resistant state. Hyperglycaemia and gestational diabetes mellitus are well-recognised complications even in women without existing metabolic syndrome or obesity. Pregnant women also appear to be more vulnerable to ketoacidosis, particularly after short periods of reduced oral intake in the third trimester, and may present with very severe starvation ketoacidosis, prompting emergent delivery. We present a case of a woman with a background of depression and psychotic episodes. Olanzapine had been commenced after a psychotic episode at 20 weeks' gestation. Gestational diabetes mellitus was diagnosed at 28 weeks, and she was then admitted at 31 weeks with severe euglycaemic ketoacidosis following a short period of vomiting. She underwent caesarean section when the metabolic disturbances did not resolve with medical treatment. We believe atypical antipsychotic therapy contributed to the profound insulin resistance seen here, and that obstetricians, physicians and psychiatrists must be aware of the risks conferred by these agents in pregnancy. PMID- 27512492 TI - Ebola and pregnancy. PMID- 27512493 TI - Zika infection: From obscurity to public health emergency. PMID- 27512494 TI - Two case reports of generalized pustular psoriasis of pregnancy: Different outcomes. AB - Generalized pustular psoriasis of pregnancy is a rare dermatosis with potential serious consequences for both the mother and fetus. Treatment is difficult and historically steroids were the mainstay of treatment. Cyclosporin has been used for a few cases resistant to steroids. We report our own experience of two cases of generalized pustular psoriasis of pregnancy. Cases of generalized pustular psoriasis of pregnancy need review by a dermatologist with experience of skin disorders in pregnancy. Both the fetus and mother need to be monitored closely when systemic illness occurs, as there is a risk of stillbirth. Maternal sepsis is a known complication of generalized pustular psoriasis of pregnancy. Cyclosporin, when used appropriately is effective and relatively safe. PMID- 27512495 TI - Pregnancy and ketoacidosis: Is pancreatitis a missing link? AB - Non-diabetic ketoacidosis is increasingly recognised in pregnancy, particularly during the third trimester, and is usually associated with vomiting. In many cases, the cause of the vomiting is not identified and resolves rapidly, alongside the metabolic abnormalities, following delivery. Here, we report three cases in which pancreatitis was identified as an underlying cause of the gastrointestinal symptoms. To our knowledge, these are the first reports of pancreatitis precipitating non-diabetic ketoacidosis in pregnancy. This case series highlights the importance of searching for a precipitant for non-diabetic ketoacidosis in pregnancy, rather than focusing solely on management of the resulting metabolic abnormalities. PMID- 27512496 TI - Update on inherited disorders of haemostasis and pregnancy. AB - Inherited bleeding disorders have the potential to cause bleeding complications during pregnancy, childbirth and the postpartum period as well as effect fetal outcomes. There is an evolving understanding of the need for specialised and individualised care for affected women during these times. The aim for each patient is to estimate the risk to mother, fetus and neonate; to implement measures to minimise these risks; and to anticipate complications and develop contingencies for these scenarios. This includes accurate diagnosis, preconceptual care, prenatal diagnostic options, antenatal care, delivery and postpartum care as well as care of an affected neonate. An understanding of the physiologic haemostatic changes associated with pregnancy as well as the scope of defects, inheritance and management of inherited bleeding disorders is paramount when caring for these women. Collaborative and prospective management in conjunction with haematology services underpins the approach advocated. This review draws on the available literature, and outlines the principles of care for women with inherited bleeding disorders before, during and after pregnancy, as well as their babies, based on both available data and collective clinical experience. PMID- 27512497 TI - Momentary stress, cortisol, and gestational length among pregnant victims of childhood maltreatment: a pilot study. AB - BACKGROUND: Pregnant victims of childhood maltreatment are more likely to deliver preterm. The mechanisms explaining this relationship are unclear. The goal of the current pilot study was to investigate whether momentary stress and cortisol serve as mechanisms linking maltreatment history to gestational length. METHODS: Seventeen women enrolled in the study (35% maltreated). Women completed two study sessions at 27 and 34 weeks gestation. Following each session, at four times/day over two days, women reported their momentary stress levels by text message and provided corresponding salivary cortisol samples. Gestational length was determined by medical chart review. RESULTS: Higher reports of momentary stress were associated with shortened gestational length. High stress predicted lower cortisol concentrations for women with maltreatment histories but higher concentrations among women without maltreatment. CONCLUSION: Results from this pilot study provide preliminary evidence for understanding mechanisms explaining increased risk for preterm birth among childhood maltreatment victims. PMID- 27512498 TI - Perinatal determinants of D-dimer levels in a cross-sectional study of low risk pregnant women. AB - BACKGROUND: To examine perinatal determinants of the antenatal levels of D dimers. METHODS: Cross-sectional study of 760 low risk pregnant women recruited into five gestational groups. Variables examined in antenatal groups included maternal age, body mass index, parity, smoking, family history venous thromboembolism (VTE) and previous use of the oral contraceptive pill (OCP). Onset of labour and mode of delivery were also examined in the post-natal group. RESULTS: D-dimer levels in group 4 (38-40 + 6) were significantly lower in the women with a history of taking the OCP when compared to those that had not taken it in the past (P = 0.027). In the day 2 post-natal group, the median level of D dimer was significantly higher in primparous when compared to multiparous women (P = 0.015). The median D-dimer levels were significantly lower in the elective Caesarean section group in comparison to spontaneous onset (P = 0.003) and induction of labour (P = 0.016). When the mode of delivery was examined, the median D-dimer levels were significantly lower in those that had an elective Caesarean section when compared to normal vaginal delivery (P = 0.008) and instrumental vaginal delivery (P = 0.007). Women post elective Caesarean section had a significantly lower D-dimer than those after emergency Caesarean section (P = 0.008). DISCUSSION: There are some significant differences in D-dimer levels when certain perinatal determinants are examined. This work is potentially beneficial to the future diagnosis of VTE in pregnancy as it supports previously published recommended D-dimer levels for the diagnosis of VTE in pregnancy. PMID- 27512499 TI - Pregnancy outcomes of antiphospholipid syndrome: In a low resource South Asian setting. AB - PROBLEM: Antiphospholipid syndrome is associated with recurrent pregnancy loss, and specific treatment improves pregnancy outcome. Laboratory diagnosis is limited in South Asia. We assessed management outcomes of definite/probable antiphospholipid syndrome treated at a tertiary centre in Sri Lanka. METHOD: Descriptive cross-sectional study of pregnancy outcomes with heparin and aspirin therapy. OUTCOME MEASURES: miscarriage, intrauterine death and live birth when compared to previous untreated pregnancies. RESULTS: Of 646 gestations in 145 women, 146 (22.6%) received specific treatment. In the preceding pregnancies without specific treatment, the rates of miscarriage, late fetal loss, stillbirth and live birth were 60%, 26%, 8% and 7%, respectively. Following specific treatment with low-dose aspirin +/- low-molecular weight heparin in 146 pregnancies (145 women), the rates of miscarriage, late fetal loss, stillbirth and live birth were 14%, 10%, 3% and 74%, respectively. Mean birth weight was 2.54 +/- 0.62 kg, preterm births complicated 32 (29.6%) with a mean gestational age at delivery 33.7 +/- 2.6 weeks, with three neonatal deaths. Maternal complications were: pre-eclampsia 16 (10.9%), gestational diabetes 28 (19.2%), antepartum haemorrhage in 1 patient. Only 73/145 (50.3%) women had laboratory confirmation of antiphospholipid syndrome, while others were treated empirically. Live births in diagnosed vs. empiric treatment - 80.8% vs. 67.1%. CONCLUSION: Pregnant women with clinical antiphospholipid syndrome when treated with low-dose aspirin and heparin, the live birth rate of 7% in the previous pregnancy resulted in live births of 74% in a resource limited South Asian setting. PMID- 27512500 TI - Adrenal infarction in a healthy pregnant woman. AB - Adrenal infarction is a very rare event but occasionally seen in hypercoagulable states. We present a case of a 31-year-old woman at 38 weeks of gestation who developed a severe upper abdominal pain and unilateral adrenal infarction due to thrombosis of the adrenal vein. The only thrombogenic factor found was pregnancy. The case highlights that adrenal infarction may complicate a normal pregnancy and should be included in the differential diagnosis of the acute abdomen in pregnancy. PMID- 27512501 TI - Management of venous thromboembolism secondary to ovarian hyperstimulation syndrome: A case report documenting the first use of a superior vena caval filter for upper limb venous thromboembolism in pregnancy, and the difficulties and complications relating to anticoagulation in antenatal and peri-partum periods. AB - The management of venous thromboembolism and subsequent pulmonary embolism in pregnancy remains hugely challenging. In this case, we report the first use of a superior vena caval filter in pregnancy as an adjunct to pharmacological anticoagulation. This is the first reported use of a superior vena caval filter in pregnancy. We discuss the complexities of managing thromboembolism in pregnancy and the peri-partum period. PMID- 27512502 TI - Supraventricular tachycardia presenting in labour: A case report achieving vaginal birth and review of the literature. AB - Arrhythmias are one of the most common forms of cardiac disease presenting in pregnancy. Women with underlying arrhythmias may only present to health care professionals when they are pregnant. The most common type of sustained arrhythmia presenting in pregnancy is a supraventricular tachycardia (SVT). This can be difficult to diagnose, as symptoms such as palpitations, dizziness and shortness of breath are also common symptoms of pregnancy. We present the management of a woman who developed intrapartum SVT. Her case highlights the importance of considering the diagnosis in the antenatal period, the use of antiarrhythmic drugs, as well as the fact that achieving vaginal delivery is possible in correctly selected cases while the mother and baby remain stable. PMID- 27512503 TI - The micromorphology of Trichoderma reesei analyzed in cultivations on lactose and solid lignocellulosic substrate, and its relationship with cellulase production. AB - BACKGROUND: Trichoderma reesei is the principal producer of cellulolytic enzymes. Because of the strong influence on the enzyme production, the morphology of the filamentous fungi is a key parameter for process optimization. For cost-effective production of cellulolytic enzymes, the cultivation of T. reesei is performed on lignocellulosic waste streams. These insoluble substrates prevent the application of the conventional light microscopy for the analysis of fungal morphology. Here, we present a novel method for the micromorphological analysis based on confocal laser-scanning microscopy (CLSM) and the computer-aided image analysis. This method enabled the quantification of the dimensions of the single cell (intercalary length and cell width) and the degree of branching in cultivations on the industrially relevant substrates wheat straw and lactose. The micromorphology of two T. reesei strains, QM9414 and a carbon catabolite derepressed cre1 knockout mutant (Deltacre1), was analyzed in dependence of substrate, inoculation method, and agitation velocity. RESULTS: Trichoderma reesei strain Deltacre1 formed shorter cells (10.09 um) on average and developed more ramified mycelia (0.36 branches/cell) than strain QM9414 (12.03 um, 0.22 branches/cell). Cultivated on wheat straw, the average cell length of QM9414 (10.87 um) and Deltacre1 (9.74 um) was 10 and 21 % shorter as compared to reference cultivations on lactose. When inoculation was done with spores as compared to hyphal biomass, cell lengths of QM9414 (10.97 um) and Deltacre1 (9.10 um) were on average about 20 % shorter. Strain performance was evaluated in protein concentration and total cellulase activity, which varied between 0.69 and 2.31 FPU/mL for Deltacre1 and between 0.84 and 1.64 FPU/mL for QM9414. The cell length exhibited slightly negative correlation with the protein (regression coefficient -0.04 g/(L um), R (2) 0.33) and the cellulase (-0.30 FPU/(mL um), R (2) 0.53) production. CONCLUSIONS: The dimensions of the single cell of T. reesei were dependent on strain background, substrate used and process conditions applied. Micromorphological changes were correlated semi-quantitatively with the efficiency of enzyme production. In providing a process analytical tool for enzyme production by T. reesei on lignocellulosic substrate, this study has relevance for the characterization and optimization of a critical step in the overall saccharification process. PMID- 27512504 TI - High-flow nasal oxygen versus noninvasive ventilation for hypoxemic respiratory failure: Do we know enough? PMID- 27512505 TI - Rapid shallow breathing index. AB - Predicting successful liberation of patients from mechanical ventilation has been a focus of interest to clinicians practicing in intensive care. Various weaning indices have been investigated to identify an optimal weaning window. Among them, the rapid shallow breathing index (RSBI) has gained wide use due to its simple technique and avoidance of calculation of complex pulmonary mechanics. Since its first description, several modifications have been suggested, such as the serial measurements and the rate of change of RSBI, to further improve its predictive value. The objective of this paper is to review the utility of RSBI in predicting weaning success. In addition, the use of RSBI in specific patient populations and the reported modifications of RSBI technique that attempt to improve the utility of RSBI are also reviewed. PMID- 27512506 TI - Medical thoracoscopy: Analysis on diagnostic yield through 30 years of experience. AB - BACKGROUND: Medical thoracoscopy (MT) or pleuroscopy is a procedure performed to diagnose and treat malignant and benign pleural diseases. Totally 2752 pleuroscopies executed in 1984-2013 in our center were considered in this study. METHODS: A retrospective observational study was performed. Observational time was divided into six series of 5 years. We calculated MT diagnostic yield and analyzed trends of main diseases diagnosed along the time. RESULTS: Along the 30 years population became progressively older. Number of pleuroscopies firstly increased, then stabilized and decreased in the last 5 years. The overall diagnostic yield of MT was 71%, increasing from 57% to 79%. The diagnostic yield was significantly higher in the presence of monolateral pleural effusion. Cancer represented more than half of diagnosis; tuberculosis was the most common nonneoplastic disease. The frequency of all cancers, mesothelioma, and lung cancer increased through the time; tuberculosis first decreased and then increased. All specimens resulted appropriate during the last 25 years. CONCLUSION: MT has a great diagnostic yield that can be improved by practice, permitting to achieve a specific histological diagnosis in about 80% of patients. Our experience demonstrates that the accurate selection of the patients undergoing to MT is very important to reach these results. PMID- 27512507 TI - Smoking among Lebanese medical students: Prevalence and attitudes. AB - INTRODUCTION: The tobacco epidemic is a major public health threat facing the world. Tobacco dependence is recognized as the greatest preventable cause of disease and death. Medical students are in key position influencing future tobacco cessation programs. OBJECTIVES: The primary objective of this study is to evaluate the prevalence of smoking among medical students across Lebanon and their smoking attitudes. It also investigates their attitude toward smoking, showing where they really stand on this major public health issue. This study helps better tackle anti-smoking campaigns among both physicians and patients. METHODS: This cross-sectional study was conducted by sending a questionnaire to currently enrolled medical students at all seven medical schools in Lebanon. The 32-item questionnaire was used, comprised three sections assessing sociodemographic characteristics, smoking habits, and attitudes toward smoking among Lebanese medical students. The questionnaire was launched online on Limesurvey to retain anonymity. The data were then transferred to Statistical Package for Social Sciences for analysis. Data were expressed as percentages for discrete variables and as mean +/- standard deviation for continuous variables. RESULTS: One hundred sixty-three complete responses remained of the 182 obtained responses. Forty-two of the total 163 students identified themselves as either daily or occasional smokers yielding a prevalence of 25.8%. Smokers were less likely to ask patients about their smoking habit and to counsel them about smoking cessation. Almost one-third of smokers felt that they had no obligations toward the society. CONCLUSION: Approximately 1 in 4 Lebanese medical students is a smoker. Students who smoke are less likely to ask patients about their smoking habits and to counsel them on smoking cessation. This is a major drawback in the fight against tobacco. This calls for better education of our future doctors on smoking cessation to decrease the smoking burden on our Lebanese society and worldwide. PMID- 27512508 TI - A 10-year retrospective review of pediatric lung abscesses from a single center. AB - INTRODUCTION: Pediatric lung abscesses can be primary or secondary, and there is limited data regarding response to treatments and patient outcomes. OBJECTIVES: To assess the clinical and microbiologic profile of pediatric patients with lung abscess and assess the differences in outcomes for patients treated with medical therapy or medical plus surgical therapy. METHODS: A retrospective review of all pediatric patients <= 18 years of age that were treated as an inpatient for lung abscess between the dates of August 2004 and August 2014 was conducted. Patients were divided into two subgroups based on the need for surgical intervention. RESULTS: A total of 39 patients with lung abscess (30 treated with medical therapy alone, 9 also required surgical interventions) were included. Fever, cough, and emesis were the most common presenting symptoms, and most of the patients had underlying respiratory (31%) or neurologic disorders (15%). Staphylococcus aureus was the most common organism in those that had culture results available, and ceftriaxone with clindamycin was the most common combination of antibiotics used for treatment. Comparison of medical and surgical subgroups identified the duration of fever and abscess size as risk factors for surgical intervention. CONCLUSIONS: Pediatric lung abscesses can be managed with medical therapy alone in most cases. Presence of prolonged duration of fever and larger abscess size may be predictive of the need for surgical intervention. Good clinical response to prolonged therapy with ceftriaxone and clindamycin was noted. PMID- 27512509 TI - Comparison of QuantiFERON-TB gold in tube test versus tuberculin skin test for screening of latent tuberculosis infection in Saudi Arabia: A population-based study. AB - OBJECTIVES: To compare QuantiFERON-TB gold in tube (QFT-GIT) test with tuberculin skin test (TST) in detecting latent tuberculosis infection (LTBI) among a general population in Saudi Arabia. METHODS: A population-based cross-sectional study was conducted between July 2010 and March 2013 among individuals randomly selected from the list of those receiving care at primary healthcare centers in three provinces of Saudi Arabia; Central, Western, and Eastern provinces. Those younger than 5 years, immunocompromised, had a current or previous history of active TB, LTBI, or who were receiving anti-TB medications were excluded. Informed consent was obtained before the study questionnaire was completed. Participants were then evaluated for LTBI using QFT-GIT test followed immediately by TST. RESULTS: Of the 1369 subjects included in the final analysis, QFT-GIT was positive in 124 (9.1%) and TST was positive in 127 (9.3%). Positive concordance was observed in 49 (3.6%) subjects while negative concordance was observed in 1167 (85.2%) subjects. The overall agreement between the two tests was 88.8% with a significant kappa (kappa) test (kappa = 0.332, P < 0.001). Concordance was significantly higher in younger age, female gender, single status, students, primary education, living in middle-sized families, and never smoked. CONCLUSIONS: The overall agreement of TST and QFT-GIT for the detection of LTBI among a Saudi general population was 88.8%. QFT-GIT is probably comparable to TST for detecting LTBI in an intermediate TB burden country with high at birth bacille calmette guerin vaccination coverage. Further prospective studies are needed to compare the ability of both tests to predict TB disease. PMID- 27512510 TI - A systematic review on prevalence and risk factors associated with treatment- emergent central sleep apnea. AB - INTRODUCTION: Treatment-emergent central sleep apnea (TECSA) is the appearance of central apneas and hypopneas after significant resolution of the obstructive events has been attained using positive airway pressure (PAP) therapy. The aim of the study was to determine the prevalence of TECSA and to understand what factors are associated with its development. METHODS: PubMed, MEDLINE, Scopus, Web of Science and Cochran Library databases were searched with Mesh headings to locate studies linking TECSA and obstructive sleep apnea (OSA). RESULTS: Nine studies were identified that reported the prevalence of TECSA ranging from 5.0% to 20.3%. Prevalence of TECSA for studies using only full night titration was between 5.0% and 12.1% where as it was between 6.5% and 20.3% for studies using split-night polysomnogram. The mean effective continuous PAP (CPAP) setting varied between 7.5 cm and 15.2 cm of water for patients in TECSA group and between 7.4 cm and 13.6 cm of water for the group without TECSA. CONCLUSIONS: The aggregate point prevalence of TECSA is about 8% with the estimated range varying from 5% to 20% in patients with untreated OSA. The prevalence tends to be higher for split-night studies compared to full night titration studies. TECSA can occur at any CPAP setting although extremely high CPAP settings could increase the likelihood. Male gender, higher baseline apnea-hypopnea index, and central apnea index at the time of diagnostic study could be associated with the development of TECSA at a subsequent titration study. PMID- 27512511 TI - Association of human leukocyte antigen class II alleles with severe Middle East respiratory syndrome-coronavirus infection. AB - BACKGROUND: Middle East Respiratory Syndrome (MERS) is a disease of the lower respiratory tract and is characterized by high mortality. It is caused by a beta coronavirus (CoV) referred to as MERS-CoV. Majority of MERS-CoV cases have been reported from Saudi Arabia. AIM: We investigated the human leukocyte antigen (HLA) Class II alleles in patients with severe MERS who were admitted in our Intensive Care Unit. METHODS: A total of 23 Saudi patients with severe MERS-CoV infection were typed for HLA class II, results were compared with those of 161 healthy controls. RESULTS: Two HLA class II alleles were associated with the disease; HLA-DRB1*11:01 and DQB1*02:02, but not with the disease outcome. CONCLUSIONS: Our results suggest that the HLA-DRB1*11:01 and DQB1*02:02 may be associated with susceptibility to MERS. PMID- 27512512 TI - Nuss procedure: Technical modifications to ease bending of the support bar and lateral stabilizer placement. AB - BACKGROUND: Modifications defined to ease bending of the support bar and lateral stabilizer placement during minimal invasive repair of pectus excavatum (MIRPE) have not been reported. We herein report our experience with MIRPE including several technical modifications. METHODS: A total of 87 patients who underwent MIRPE were evaluated retrospectively. Technical modifications are (1) a template drawn preoperatively according to the anthropometric measurements, (2) more laterally placed thoracal incisions, (3) single existing incision for multiple support bars, (4) to secure lateral stabilizers to support bar in inverted position. RESULTS: The mean patient age was 11.2 +/- 3.8 years. The mean operating time was 63.7 +/- 18.7 min. The mean Haller index was 5.4 +/- 2.1. Eight patients necessitated two support bars. The support bars were removed in 69 patients after the completion of treatment. Support bars were left in place 26.8 +/- 4.3 months. Final chest contours of the 56 patients were evaluated as 12 months passed after support bar removal and excellent repair results were determined in 84.2%. CONCLUSION: Preoperative bending of the support bar according to anthropometric measurements and fixation of the lateral stabilizers to the support bar in inverted position facilitates bar shaping and lateral stabilizer placement. PMID- 27512513 TI - Information technology to improve patient safety: A round table discussion from the 5(th) International Patient Safety Forum, Riyadh, Saudi Arabia, April 14-16, 2015. PMID- 27512514 TI - Pulmonary eosinophilia associated to treatment with natalizumab. AB - Natalizumab (Tysabri((r))) is a leukocytes chemotaxis inhibitor that decreases the leukocytes passage through the hematoencephalic barrier and it is currently used in relapsing-remitting forms of multiple sclerosis (MS). We present a patient with allergic rhinoconjunctivitis diagnosed with MS who started treatment with natalizumab. She began to show mild asthmatic symptoms until she needed admission to the hospital due to respiratory insufficiency. Blood tests showed peripheral eosinophilia and the thoracic computed tomography scan demonstrated pulmonary infiltrates. The bronchoscopy with the bronchoalveolar lavage resulted in eosinophilic alveolitis. No evidence of bacterial, fungal and parasitic infection, connective tissue disease, or vasculitis were observed. After discontinuation of natalizumab, the patient improved without other treatments. As MS is a prevalent disease and the use of natalizumab is increasing, we consider important to point out that this drug can be associated with pulmonary eosinophilia, especially in patients with allergic rhinoconjunctivitis or asthma. PMID- 27512515 TI - Adenosine triphosphate-binding cassette member A3 gene mutation in children from one family from Saudi Arabia. AB - Mutation in ABCA3, which is adenosine triphosphate-binding cassette member A3, a member of protein transporter family for phospholipids into the lamellar bodies during synthesis of surfactant, can cause lung disease related to surfactant dysfunction with autosomal recessive pattern. We reported three cases from same family with ABCA3 mutation, their gene, clinical course, and outcomes mentioning that one patient had successful lung transplantation, one started the process of the lung transplantation while the third one died during infancy. We concluded that the patients with ABCA3 gene mutations are increasing in numbers may be due to the availability of the genetic testing and high index of suspicion among physicians. Lung transplantation is the definitive treatment, but availability is limited in our region. PMID- 27512516 TI - Sarcoidosis presenting with acute respiratory distress syndrome. PMID- 27512517 TI - Decortication of empyema. PMID- 27512518 TI - External RNA Controls Consortium Beta Version Update. AB - Spike-in RNAs are valuable controls for a variety of gene expression measurements. The External RNA Controls Consortium developed test sets that were used in a number of published reports. Here we provide an authoritative table that summarizes, updates, and corrects errors in the test version that ultimately resulted in the certified Standard Reference Material 2374. We have noted existence of anti-sense RNA controls in the material, corrected sub-pool memberships, and commented on control RNAs that displayed inconsistent behavior. PMID- 27512519 TI - Draft Genome Sequence of Carotenoid Producing Yellow Pigmented Planococcus maritimus MKU009. AB - Planococcus maritimus MKU009 is a Gram positive cocci and a moderate halophilic bacterium isolated from marine water of Pichavaram, South East Coast of India. Here we report the draft genome of Planococcus maritimus MKU009 with a total size of 3,251,644 bp with N50 value of 1681571 bp. The overall G+C content of the genome was 47.27%. The carotenoid producing crtN, crtB, crtP and crtI genes were located within the first contig of the genome assembly. This genome source will provide insights into functional genomics of carotenoid production and metabolic engineering. PMID- 27512520 TI - Pseudomonas lini Strain ZBG1 Revealed Carboxylic Acid Utilization and Copper Resistance Features Required for Adaptation to Vineyard Soil Environment: A Draft Genome Analysis. AB - Pseudomonas lini strain ZBG1 was isolated from the soil of vineyard in Zellenberg, France and the draft genome was reported in this study. Bioinformatics analyses of the genome revealed presence of genes encoding tartaric and malic acid utilization as well as copper resistance that correspond to the adaptation this strain in vineyard soil environment. PMID- 27512521 TI - Gorman revisited: nonparametric conditions for exact linear aggregation. AB - In the tradition of Afriat (Int Econ Rev 8:67-77, 1967), Diewert (Rev Econ Stud 40:419-425, 1973) and Varian (Econometrica 50:945-972, 1982), we provide a revealed preference characterisation of exact linear aggregation. This guarantees that aggregate demand can be written as a function of prices and aggregate income alone, while abstracting from income-distributional aspects. We also establish nonparametric conditions for individual consumption to be representable in terms of Gorman Polar Form preferences. Our results are simple and complement those of Gorman (1953, 1961). We illustrate the practical usefulness of our results by means of an empirical application to a Spanish balanced microdata panel. We find strong evidence against the existence of a limited set of representative agents, which in turn seems to empirically support the need for (macroeconomic) models using a continuum of heterogeneous agents. PMID- 27512522 TI - Leading indicators of mosquito-borne disease elimination. AB - Mosquito-borne diseases contribute significantly to the global disease burden. High-profile elimination campaigns are currently underway for many parasites, e.g., Plasmodium spp., the causal agent of malaria. Sustaining momentum near the end of elimination programs is often difficult to achieve and consequently quantitative tools that enable monitoring the effectiveness of elimination activities after the initial reduction of cases has occurred are needed. Documenting progress in vector-borne disease elimination is a potentially important application for the theory of critical transitions. Non-parametric approaches that are independent of model-fitting would advance infectious disease forecasting significantly. In this paper, we consider compartmental Ross-McDonald models that are slowly forced through a critical transition through gradually deployed control measures. We derive expressions for the behavior of candidate indicators, including the autocorrelation coefficient, variance, and coefficient of variation in the number of human cases during the approach to elimination. We conducted a simulation study to test the performance of each summary statistic as an early warning system of mosquito-borne disease elimination. Variance and coefficient of variation were highly predictive of elimination but autocorrelation performed poorly as an indicator in some control contexts. Our results suggest that tipping points (bifurcations) in mosquito-borne infectious disease systems may be foreshadowed by characteristic temporal patterns of disease prevalence. PMID- 27512523 TI - The probabilistic no miracles argument. AB - This paper develops a probabilistic reconstruction of the No Miracles Argument (NMA) in the debate between scientific realists and anti-realists. The goal of the paper is to clarify and to sharpen the NMA by means of a probabilistic formalization. In particular, I demonstrate that the persuasive force of the NMA depends on the particular disciplinary context where it is applied, and the stability of theories in that discipline. Assessments and critiques of "the" NMA, without reference to a particular context, are misleading and should be relinquished. This result has repercussions for recent anti-realist arguments, such as the claim that the NMA commits the base rate fallacy (Howson (2000), Magnus and Callender (Philosophy of Science, 71:320-338, 2004)). It also helps to explain the persistent disagreement between realists and anti-realists. PMID- 27512525 TI - Developmental Changes in Mental Rotation: A Dissociation Between Object-Based and Egocentric Transformations. AB - The present study was conducted to investigate developmental changes of mental rotation performance. We compared children, adults, and older adults regarding their performance in object-based and egocentric transformations. Both children and older adults showed higher overall reaction times compared to adults. Results were interpreted against the background of impaired working memory capacity in both children and older adults. Since mental changes in working memory are mediated by age differences in cognitive processing speed, cognitive speed is supposed to be the underlying factor. Regarding both types of transformations, an advantage of egocentric over object-based human figures was only found in adults which led us to tentatively propose that children and older adults show deficits in perspective taking compared to adults. PMID- 27512526 TI - The Effects of the Amount of Information on Episodic Memory Binding. AB - The effects of increasing the number of items to be remembered on associative recognition and cued recall were examined. Thirty participants were asked during encoding to determine whether two- and three-item stimuli contained natural objects, artificial objects, or both. In an associative recognition task, the participants indicated whether the stimuli were identical to those presented during encoding, were rearranged by exchanging one of the two-item stimuli for one of the three-item stimuli, or represented a new stimulus. The correctly identified rearranged item pairs and triads were included in a subsequent cued recall task in which participants verbally reported the missing item. As the number of items increased, the discrimination of rearranged stimuli diminished, but that of identical trials remained the same. Furthermore, the ability to retrieve the missing item was unaffected. It was concluded that the effect of the amount of information on binding depends on how the information must be retrieved. PMID- 27512527 TI - Do Rare Stimuli Evoke Large P3s by Being Unexpected? A Comparison of Oddball Effects Between Standard-Oddball and Prediction-Oddball Tasks. AB - The P3 component of event-related potentials increases when stimuli are rarely presented. It has been assumed that this oddball effect (rare-frequent difference) reflects the unexpectedness of rare stimuli. The assumption of unexpectedness and its link to P3 amplitude were tested here. A standard- oddball task requiring alternative key-press responses to frequent and rare stimuli was compared with an oddball-prediction task where stimuli had to be first predicted and then confirmed by key-pressing. Oddball effects in the prediction task depended on whether the frequent or the rare stimulus had been predicted. Oddball effects on P3 amplitudes and error rates in the standard oddball task closely resembled effects after frequent predictions. This corroborates the notion that these effects occur because frequent stimuli are expected and rare stimuli are unexpected. However, a closer look at the prediction task put this notion into doubt because the modifications of oddball effects on P3 by expectancies were entirely due to effects on frequent stimuli, whereas the large P3 amplitudes evoked by rare stimuli were insensitive to predictions (unlike response times and error rates). Therefore, rare stimuli cannot be said to evoke large P3 amplitudes because they are unexpected. We discuss these diverging effects of frequency and expectancy, as well as general differences between tasks, with respect to concepts and hypotheses about P3b's function and conclude that each discussed concept or hypothesis encounters some problems, with a conception in terms of subjective relevance assigned to stimuli offering the most consistent account of these basic effects. PMID- 27512528 TI - Phenomenological Characteristics of Autobiographical Memories: Responsiveness to an Induced Negative Mood State in Those With and Without a Previous History of Depression. AB - In this study we investigated the relative accessibility of phenomenological characteristics in autobiographical memories of 104 students with and without a previous history of a depression. Participants recalled personal events that were elicited with cue words and then asked to rate these personal events for a number of phenomenological characteristics. The characteristics were typicality, rumination, valence, importance of others, expectancy, desirability, and personal importance. The effects of previous history of depression (without history or with previous history of depression) and self-reported mood (pre- and post negative mood induction) on autobiographical recall was examined by employing a mixed factor design. Self-reported mood was measured as a manipulation check, before and after Mood Induction Procedure. Typicality, rumination and personal importance showed significant interaction effects in those with a history of depression. Ordinal regression supported the finding that those with a history of depression had a higher chance of typicality and personal importance than those without a history of depression. The results indicate that recall of autobiographical characteristics is in part dependent on induced negative mood state and on previous history of depression. The findings may prompt future research into targeted interventions that reduce individual tendencies for heightened cognitive reactivity in negative mood states for those with a history of depression. PMID- 27512529 TI - Interplay Between the Object and Its Symbol: The Size-Congruency Effect. AB - Grounded cognition suggests that conceptual processing shares cognitive resources with perceptual processing. Hence, conceptual processing should be affected by perceptual processing, and vice versa. The current study explored the relationship between conceptual and perceptual processing of size. Within a pair of words, we manipulated the font size of each word, which was either congruent or incongruent with the actual size of the referred object. In Experiment 1a, participants compared object sizes that were referred to by word pairs. Higher accuracy was observed in the congruent condition (e.g., word pairs referring to larger objects in larger font sizes) than in the incongruent condition. This is known as the size-congruency effect. In Experiments 1b and 2, participants compared the font sizes of these word pairs. The size-congruency effect was not observed. In Experiments 3a and 3b, participants compared object and font sizes of word pairs depending on a task cue. Results showed that perceptual processing affected conceptual processing, and vice versa. This suggested that the association between conceptual and perceptual processes may be bidirectional but further modulated by semantic processing. Specifically, conceptual processing might only affect perceptual processing when semantic information is activated. The current study. PMID- 27512530 TI - Three-Dimensional Printing Based Hybrid Manufacturing of Microfluidic Devices. AB - Microfluidic platforms offer revolutionary and practical solutions to challenging problems in biology and medicine. Even though traditional micro/nanofabrication technologies expedited the emergence of the microfluidics field, recent advances in advanced additive manufacturing hold significant potential for single-step, stand-alone microfluidic device fabrication. One such technology, which holds a significant promise for next generation microsystem fabrication is three dimensional (3D) printing. Presently, building 3D printed stand-alone microfluidic devices with fully embedded microchannels for applications in biology and medicine has the following challenges: (i) limitations in achievable design complexity, (ii) need for a wider variety of transparent materials, (iii) limited z-resolution, (iv) absence of extremely smooth surface finish, and (v) limitations in precision fabrication of hollow and void sections with extremely high surface area to volume ratio. We developed a new way to fabricate stand alone microfluidic devices with integrated manifolds and embedded microchannels by utilizing a 3D printing and laser micromachined lamination based hybrid manufacturing approach. In this new fabrication method, we exploit the minimized fabrication steps enabled by 3D printing, and reduced assembly complexities facilitated by laser micromachined lamination method. The new hybrid fabrication method enables key features for advanced microfluidic system architecture: (i) increased design complexity in 3D, (ii) improved control over microflow behavior in all three directions and in multiple layers, (iii) transverse multilayer flow and precisely integrated flow distribution, and (iv) enhanced transparency for high resolution imaging and analysis. Hybrid manufacturing approaches hold great potential in advancing microfluidic device fabrication in terms of standardization, fast production, and user-independent manufacturing. PMID- 27512531 TI - Benchmarking matching color in composite restorations. AB - The purpose of this study was to investigate the color samples (A2, A3 and B1) of three different brands of resin composites using dentine masses. 135 discs were prepared (5 plates for each thickness, color and brand of composite material). A colorimetric evaluation, using white and black background, was performed just after preparation. The color was measured corresponding to "Vita" scale and DeltaL, Deltaa, Deltab and DeltaE values were calculated using a spectrophotometer. The results showed that Value, Chroma and Hue often differ even if the same commercial color and same thickness is used. In conclusion, this study showed that the perfect aesthetics restoration is possible combining individual abilities, experience and correct techniques. PMID- 27512532 TI - Utilizations and Perceptions of Emergency Medical Services by Patients with ST Segments Elevation Acute Myocardial Infarction in Abu Dhabi: A Multicenter Study. AB - BACKGROUND: Data on the use of emergency medical services (EMS) by patients with cardiac conditions in the Gulf region are scarce, and prior studies have suggested underutilization. Patient perception and knowledge of EMS care is critical to proper utilization of such services. OBJECTIVES: To estimate utilization, knowledge, and perceptions of EMS among patients with ST-elevation myocardial infarction (STEMI) in the Emirate of Abu Dhabi. METHODS: We conducted a multicenter prospective study of consecutive patients admitted with STEMI in four government-operated hospitals in Abu Dhabi. Semi-structured interviews were conducted with patients to assess the rationale for choosing their prehospital mode of transport and their knowledge of EMS services. RESULTS: Of 587 patients with STEMI (age 51 +/- 11 years, male 95%), only 15% presented through EMS, and the remainder came via private transport. Over half of the participants (55%) stated that they did not know the telephone number for EMS. The most common reasons stated for not using EMS were that private transport was quicker (40%) or easier (11%). A small percentage of participants (7%) did not use EMS because they did not think their symptoms were cardiac-related or warranted an EMS call. Stated reasons for not using EMS did not significantly differ by age, gender, or primary language of the patients. CONCLUSIONS: EMS care for STEMI is grossly underutilized in Abu Dhabi. Patient knowledge and perceptions may contribute to underutilization, and public education efforts are needed to raise their perception and knowledge of EMS. PMID- 27512533 TI - One Year Survival in Nigerians with Peripartum Cardiomyopathy. AB - BACKGROUND: Peripartum cardiomyopathy (PPCM) is common in North-Western Nigeria. This study aimed to describe the 1-year survival and left ventricular reverse remodeling (LVRR) in a group of patients with PPCM from three referral hospitals in Kano, Nigeria. METHODS: PPCM was defined according to recommendations of the Heart Failure (HF) Association of the European Society of Cardiology Working Group on PPCM. LVRR was defined as absolute increase in left ventricular ejection fraction (LVEF) by >=10.0% and decrease in left ventricular (LV) end-diastolic dimension indexed to body surface area <=33.0 mm/m(2), while recovered LV systolic function as LVEF >=55%, at 12 months follow-up. RESULTS: A total of 54 newly diagnosed PPCM patients with mean age of 26.6 +/- 6.7 years, presented with classical features of predominantly left-sided HF and 33 of them qualified for follow-up. Of the 17 survivors at 12 months, 8 patients (47.1%) satisfied the criteria for LVRR, of whom 5 (29.4%) had recovered LV systolic function (LVEF >=55%), but LVRR was not predicted by any variable in the regression models. The prevalence of normal LV diastolic function increased from 11.1% at baseline to 35.3% at 12 months (P = 0.02). At 1-year follow-up, 41.4% of patients had died (two-thirds of them within the first 6 months), but mortality was not predicted by any variable including LVRR. CONCLUSIONS: In Kano, PPCM patients had modest LVRR but high mortality at 1-year. Further studies should be carried out to identify reasons for the high mortality and how to curb it. PMID- 27512534 TI - Pulmonary Embolism in Young Natives of High Altitude. AB - Thrombotic events are relatively common in high altitude areas and known to occur in young soldiers working at high altitude without usual risk factors associated with thrombosis at sea-level. However, till now, cases with thrombotic events were reported only in lowlanders staying at high altitude. These two cases of pulmonary embolism demonstrate that thrombotic events can occur in highlanders after a prolonged stay at the extreme altitude. PMID- 27512535 TI - Large Saphenous Venous Graft Aneurysm with Right Atrial Fistulous Communication: Case Report and Review of Literature. AB - We report a case of a 56-year-old Caucasian man who presented with acute onset of substernal chest pain at rest with electrocardiogram showing diffuse ST segment depression. He had coronary artery bypass graft surgery 16 years ago with a left internal mammary artery graft to the left anterior descending artery and saphenous vein grafts to the right coronary artery (RCA) and left circumflex artery. He underwent coronary angiography, which showed two large aneurysms in the saphenous venous graft (SVG) to the RCA and a venous leak from the aneurysm. The venous leak was later confirmed with computer tomographic scan to be a fistulous communication between the SVG and the right atrium. We discuss in detail about the treatment options of SVG aneurysm. PMID- 27512536 TI - Endovascular Treatment of Renal Artery Stenosis due to Fibromuscular Dysplasia - Is Stent Implantation Underused in this Circumstance? AB - Fibromuscular dysplasia (FMD) is a nonatherosclerotic and noninflammatory arterial disease that commonly affects the renal and carotid arteries. The primary target in treating patients with renal artery FMD is the control of blood pressure in order to prevent end-organ damage, which can be caused by poorly controlled hypertension. Invasive endovascular treatment should be taken into consideration both when hypertension cannot be controlled with medication. According to current opinion, hypertension attributed to renal artery FMD is often successfully treated solely with percutaneous renal balloon angioplasty (PRBA), with no requirement for stent implantation under most circumstances. However, an FMD recurrence after PRBA occurs frequently in these patients. PMID- 27512537 TI - Takotsubo Cardiomyopathy Associated with Severe Hypothyroidism in an Elderly Female. AB - Takotsubo cardiomyopathy, also known as stress cardiomyopathy, is a syndrome that affects predominantly postmenopausal women. Despite multiple described mechanisms, intense, neuroadrenergic myocardial stimulation appears to be the main trigger. Hyperthyroidism, but rarely hypothyroidism, has been described in association with Takotsubo cardiomyopathy. Herein, we present a case of stress cardiomyopathy in the setting of symptomatic hypothyroidism. PMID- 27512538 TI - Transradial Percutaneous Closure of Coronary Artery-Pulmonary Artery Fistula. PMID- 27512539 TI - Can incorporating art into medical education help medical students become better doctors? PMID- 27512540 TI - Framingham Contribution to Cardiovascular Disease. PMID- 27512541 TI - Female Urethral Duplication: Rare Anomaly with Unusual Presentation. AB - Urethral duplication (UD) in females is a rare congenital anomaly and requires a high degree of clinical suspicion for diagnosis. The preoperative evaluation requires thorough investigations to delineate anatomy which is imperative for surgical reconstruction to provide excellent functional and cosmetic outcome. We describe the successful management of a 6-year-old girl with UD (presented as ambiguous genitalia and urinary incontinence) along with a review of pertinent literature. PMID- 27512542 TI - Persistent Mullerian Duct Syndrome with Transverse Testicular Ectopia. AB - Persistent Mullerian duct syndrome (PMDS) is a rare form of male pseudohermaphroditism characterized by the presence of Mullerian duct structures in a normal male with 46, XY karyotype. Transverse testicular ectopia (TTE) is rare form of testicular ectopia in which two testes are located on one inguinal side. The opposite scrotum is empty. PMDS with TTE is rare. We report a case of PMDS with TTE discovered during surgery for a right inguinal hernia in a 25-year old male. PMID- 27512543 TI - Single Visit Feeding Appliance for 1-day-old Neonate with Cleft Palate Using Safe Dental Putty-Gauze Hybrid Impression Technique for Maxillary Impression. AB - Cleft lip and palate is one of the most common craniofacial anomalies of humans. Intraoral impression making is the first clinical step in the fabrication of feeding appliance for infants with oro-nasal communication. It is difficult to control the flow of the impression material in the cleft area and undercuts in a child patient. This clinical report presents a simple and safe impression technique for maxillary impression making in neonates and infants with cleft palate. A gauze piece was used to confine the impression material during functional movements of sucking while impression making in an awake child to avoid the risk of aspiration or swallowing. PMID- 27512545 TI - Female Urethral Anomalies in Pediatric Age Group: Uncovered. AB - Female urethral anomalies such as epispadias and hypospadias have been rarely reported in the literature. Clinical diagnosis of female urethral anomalies is significant for management. Diagnosis may be missed leading to mismanagement of the clinical condition. Herein, we report a case of female epispadias and hypospadias managed by us at Tertiary Care Center. PMID- 27512544 TI - A Rare Cause of Postprandial Abdominal Pain. AB - A 49-year-old woman with medical history of polymyalgia rheumatica presented with 3 weeks history of epigastric pain worse after meal. Gallstones, peptic ulcer, bowel ischemia, bowel obstruction, gastroesophageal reflux disease, chest pathology, etc., were excluded from the study. Computerized tomography showed a short stenotic segment at coeliac trunk with poststenotic dilatation of 8 mm. Ultrasound scan showed peak velocity of 326 cm/s at the coeliac artery. Diagnosis of median arcuate ligament syndrome was made. PMID- 27512546 TI - Malignant Transformation of Vagal Nerve Schwannoma in to Angiosarcoma: A Rare Event. AB - Schwannomas are benign, rare peripheral nerve sheath tumors that occur in the head and neck region. Some physicians opt to closely observe cases of schwannoma of the neck on an outpatient basis rather than to perform radical surgery. However, there is a possibility, albeit rare, of malignant transformation of a benign schwannoma. Here, we are reporting the first case from the Indian subcontinent which was transformed into the angiosarcoma from benign vagal schwannoma over a long period. A 47-year-old male patient complaining of left sided neck swelling since last 12 years, swelling was insidious in onset, gradually progressive very slowly. In last 2 months, the size of the swelling was suddenly increased. On examination, there was an approximately 6 cm * 6 cm of size, firm, nodular, well-defined, nontender swelling in the left lateral part of the neck. Fine-needle aspiration cytology (FNAC) revealed paraganglioma and magnetic resonance imaging demonstrated very clearly a tumor, its morphology, and its relation to the surrounding structures, the tumor was thought to be a vagal schwannoma. Surgery was done, and the whole of the tumor was removed in toto. On final histopathological diagnosis, the tumor was proved to be angiosarcoma developed from vagal schwannoma. Postoperative chemotherapy was given but due to distant metastasis, the patient died. Long standing neck masses can convert into malignancy as in our case, therefore, work up of the patient should be done properly. Multiple FNAC should be done because single FNAC can give the false negative result as in our case. This was our diagnostic drawback not to do multiple computed tomography guided FNAC. PMID- 27512547 TI - Intraoperative Development of Tension Pneumocephalus in a Patient Undergoing Repair of a Cranial-Dural Defect Under Nitrous Oxide Anesthesia. AB - Rapid buildup of gas within the cranial vault can result in a life-threatening condition known as "tension pneumocephalus," necessitating immediate surgical intervention. Nitrous oxide (N2O), a commonly used inhaled anesthetic, is associated with the development of tension pneumocephalus and its role in neurosurgical procedures has been debated in the literature. We present a case of tension pneumocephalus with preexisting pneumocephalus secondary to the usage of N2O as an inhaled anesthetic. Included is a literature review of studies discussing the role of N2O in the development of tension pneumocephalus. N2O is associated with tension pneumocephalus especially in the setting of preexisting pneumocephalus. Tension pneumocephalus can manifest as Cushing response and immediate decompression is life-saving. Nitrous oxide should be used cautiously in neurosurgical procedures, especially with preexisting pneumocephalus. PMID- 27512548 TI - Propeller Flap for Complex Distal Leg Reconstruction: A Versatile Alternative when Reverse Sural Artery Flap is Not Feasible. AB - Reverse sural artery fasciocutaneous flap has become a workhorse for the reconstruction of distal leg soft tissue defects. When its use is not feasible, perforator-based propeller flap offers a better, easier, faster, and cheaper alternative to free flap. We present our experience with two men both aged 34 years who sustained Gustilo 3B injuries from gunshot. The donor area for reversed sural artery flap was involved in the injuries. They had early debridement, external fixation, and wound coverage with perforator-based propeller flaps. The donor sites were covered with skin graft. All flaps survived. There were minor wound edge ulcers due to the pressure of positioning that did not affect flap survival and the ulcers healed with conservative management. Perforator-based propeller flap is a versatile armamentarium for reconstruction of soft tissue defects of the distal leg in resource-constrained settings, especially when the donor area for a reverse flow sural flap artery is involved in the injury. PMID- 27512549 TI - Reduction and Fixation of Unstable Fractures of the Zygomatic Arch: Report of a Series of Cases. AB - BACKGROUND: This study evaluated a series of cases of fracture in the zygomatic arch with displacement of the fractured segment. MATERIALS AND METHODS: This prospective cohort study was conducted between May 2008 and February 2009. The study sample which consist of 10 patients of both genders with fractures in the zygomatic arch. The collection instrument included a specific sheet with data concerning the patient's age, cause, side of the fracture, type of treatment performed, recurrence and presence of lesions in the facial nerve. The radiographic indices of Waters and Hirtz were used. The data were presented by means of descriptive statistics (absolute and percentage distributions). RESULTS: Most of the patients were male (90.0%), the most frequent etiology was a motorcycle accident (70.0%) and the left side was more affected (60.0%). There was no recurrence in any of the patients examined; however, 1 patient had a lesion in the facial nerve. The treatment performed for all patients was reduction and fixation with titanium miniplates. CONCLUSION: Fractures in the zygomatic arch are more frequent in young male individuals and the most common cause is a motorcycle accident, with the use of miniplates constituting an effective treatment without recurrence. PMID- 27512550 TI - Acute Physiological and Chronic Health Evaluation II Score and its Correlation with Three Surgical Strategies for Management of Ileal Perforations. AB - INTRODUCTION: Ileal perforation peritonitis is a common surgical emergency in the Indian subcontinent and in tropical countries. It is reported to constitute the fifth common cause of abdominal emergencies due to high incidence of enteric fever and tuberculosis in these management based on Acute Physiological and Chronic Health Evaluation II (APACHE II) score. METHODS: The following study was conducted in the Department of General Surgery, Government Medical College, Patiala. A total of 57 patients were studied and divided in to Group I, II, and III. APACHE II score accessed and score between 10 and 19 were blindly randomized into three procedures primary closure, resection-anastomosis, and ileostomy. The outcome was compared. RESULTS: Ileal perforations were most commonly observed in the third and fourth decade of life with male dominance. APACHE II score was accessed and out of total 57 patients, 6 patients had APACHE II score of 0-9, 48 patients had APACHE II score of 10-19, and 3 patients had APACHE II score of >=20. In APACHE II score 10-19, 15 patients underwent primary closure, 16 patients underwent resection-anastomosis, and 17 patients underwent ileostomy. DISCUSSION AND CONCLUSION: Primary closure of perforation is advocated in patients with single, small perforation (<1 cm) with APACHE II score 10-19 irrespective of duration of perforation. Ileostomy is advocated in APACHE II score 10-19, where the terminal ileum is grossly inflamed with multiple perforations, large perforations (>1 cm), fecal peritonitis, matted bowel loops, intraoperative evidence of caseating lymph nodes, strictures, and an unhealthy gut due to edema. PMID- 27512551 TI - Elective Bowel Surgery with or without Prophylactic Nasogastric Decompression: A Prospective, Randomized Trial. AB - INTRODUCTION: Routinely postoperative nasogastric decompression was done until the nasogastric drainage is minimal, reoccurrence of bowel sounds and passing flatus. But prolonged nasogastric intubation is associated with complications like basal atelectasis due to poor cough reflux, loss of electrolytes and increased patient morbidity. AIMS AND OBJECTIVES: To study the need for routine use of nasogastric tube post operatively in bowel surgeries with reference to (1) Return of bowel movements (2) Compare the incidence of complications (3) Duration of hospital stay. METHODOLOGY: 100 patients who underwent elective bowel surgery were randomized into two groups: Study group (50): Nasogastric tube was removed immediately after operation or in the recovery room. Control group (50): Underwent nasogastric tube removal postoperatively after the patient passed flatus and audible bowel sounds on auscultation. RESULTS: Incidence of complications were less in the study group i.e., only three patients had vomiting, and two patients had abdominal distension which lead to postponement of oral feeds. Most of our control group patients complained of discomfort and difficulty in coughing and in bringing out sputum, which was the probable cause for high incidence of pulmonary complications. CONCLUSION: Routine use of the nasogastric tube adjunct to patient care following bowel surgery may be safely eliminated. PMID- 27512552 TI - Anterior Palatal Island Advancement Flap for Bone Graft Coverage: Technical Note. AB - BACKGROUND: The most important step in bone graft management is soft tissue coverage. Dehiscence of the wound leads to graft exposure and subsequent problems. PURPOSE: This study introduces an axial pattern flap for bone graft coverage in anterior maxilla. PATIENTS AND METHODS: Use of Anterior Palatal Island Advancement Flap is presented by the authors. It is a mucoperiosteal flap with axial pattern blood supply, based on nasopalatine artery. It is easy to raise and predictable. RESULTS: Anterior Palatal Island Advancement Flap was effective in bone graft coverage in premaxillary edentulous area. CONCLUSION: It can be used as an aid for bone graft coverage of premaxillary edentulous ridge, where the need for mucosa is small in width but long in length. PMID- 27512553 TI - Primary Squamous Cell Carcinoma of Stomach: A Rare Entity - Case Report and Brief Review of Literature. AB - Very few case reports of pure squamous cell carcinoma (SCC) of stomach are available in the world literature. The exact pathology of this uncommon carcinoma in stomach remains unknown. This is an additional case report of SCC in an elderly female arising in the gastric antrum. She underwent distal gastrectomy, gastrojejunostomy and jejunojejunostomy. The histopathology was reported as SCC of stomach without any adenocarcinomatous component. She had no other source of extra gastric primary SCC. After surgery, the patient was advised adjuvant chemotherapy. This is an additional case of primary SCC of stomach. PMID- 27512554 TI - Echinococcal Cyst of the Pancreas with Cystopancreatic Duct Fistula Successfully Treated by Partial Cystectomy and Cystogastrostomy. AB - The primary pancreatic hydatid (echinococcal) cyst is extremely rare with a reported incidence of <1%. Owing to its rareness and a considerable overlap of imaging features, a preoperative diagnosis is usually difficult. The dilemma in confirming this benign diagnosis has often questioned the extent of radical pancreatic resection. The involvement of pancreatic duct (cystopancreatic duct fistula) further complicates the management of such cystic lesions. In this report, we present a case of isolated hydatid cyst of the pancreatic body and tail communicating with the pancreatic duct. Cystogastrostomy preceded by partial cystectomy in the same setting has never been reported to date. The patient had an uneventful postoperative course and follow-up showed no evidence of cyst recurrence or dissemination. We consider this a safe surgical option in longstanding large cysts, especially if a cystopancreatic fistula is detected beforehand. The success of such a procedure however may rely on the size and thickness of the cyst wall to support this anastomosis. PMID- 27512555 TI - Negative Response of Phytoestrogens of Pomegranate Flower Extract against Cisplatin-induced Nephrotoxicity in Female Rats. PMID- 27512556 TI - Intake of Dietary Supplements and Malnutrition in Patients in Intensive Care Unit. AB - BACKGROUND: Malnutrition is prevalent among patients hospitalized in Intensive Care Units (ICUs) and causes various complications. Dietary supplementation to provide appropriate nutritional support may reduce the malnutrition and complications through improvement in nutritional status. This study was carried out to assess the association between dietary supplementation and malnutrition among patients in ICUs. METHODS: A case-control study was conducted on 180 male patients aged 20-60 years in the ICUs of the hospitals in Ahvaz, Iran in 2013. Data of two groups including 83 patients (cases) who had consumed regular hospital meals and dietary supplements and 97 patients (controls) who had received regular hospital meals were compared. Anthropometric measurements, laboratory values, and dietary intakes were extracted from medical records, and Maastricht index (MI) was calculated. Data were analyzed using the IBM SPSS Statistics 21. T-test and paired-sample t-test were used to determine the difference between groups. RESULTS: Taking supplements increased daily energy intake, carbohydrate, and protein in case group (n = 83) significantly (P < 0.05). MI changed to 3.1 +/- 3.8 and 4.3 +/- 4.2 in case (n = 83) and control (n = 97) groups, respectively. Although the MI fell in both groups, it showed a greater reduction in case group (from 6.3 +/- 5.3 to 3.1 +/- 3.8). CONCLUSIONS: Since consuming dietary supplements besides the regular hospital meals increased intake of energy and macronutrients and reduced the MI significantly, it was concluded that it helped supply nutritional requirements more effectively and improved the malnutrition in ICU. PMID- 27512557 TI - Effect of a Trampoline Exercise on the Anthropometric Measures and Motor Performance of Adolescent Students. AB - BACKGROUND: Physical exercises can influence some anthropometric and fitness components differently. The aim of present study was to evaluate how a relatively long-term training program in 11-14-year-old male Iranian students affects their anthropometric and motor performance measures. METHODS: Measurements were conducted on the anthropometric and fitness components of participants (n = 28) prior to and following the program. They trained 20 weeks, 1.5 h/session with 10 min rest, in 4 times trampoline training programs per week. Motor performance of all participants was assessed using standing long jump and vertical jump based on Eurofit Test Battery. RESULTS: The analysis of variance (ANOVA) repeated measurement test showed a statistically significant main effect of time in calf girth P = 0.001, fat% P = 0.01, vertical jump P = 0.001, and long jump P = 0.001. The ANOVA repeated measurement test revealed a statistically significant main effect of group in fat% P = 0.001. Post hoc paired t-tests indicated statistical significant differences in trampoline group between the two measurements about calf girth (t = -4.35, P = 0.001), fat% (t = 5.87, P = 0.001), vertical jump (t = -5.53, P = 0.001), and long jump (t = -10.00, P = 0.001). CONCLUSIONS: We can conclude that 20-week trampoline training with four physical activity sessions/week in 11-14-year-old students seems to have a significant effect on body fat% reduction and effective results in terms of anaerobic physical fitness. Therefore, it is suggested that different training model approach such as trampoline exercises can help students to promote the level of health and motor performance. PMID- 27512558 TI - A Proposed Strategy for Research Misconduct Policy: A Review on Misconduct Management in Health Research System. AB - BACKGROUND: Today, with the rapid growth of scientific production, research misconduct has become a worldwide problem. This article is intended to introduce the successful experience on the management of research paper misconducts in the field of health research. METHODS: Our aim was to design and develop the strategy for research misconduct policy. Focusing on the national regulatory system, we developed a hierarchical model for paper misconduct policy in all the medical sciences universities and their affiliated research units. RESULTS: Through our regulatory policy for paper misconduct management, specific protocol was followed in the field of health research publications through which the capabilities of covering the four main elements of prevention, investigation, punishment, and correction have come together. CONCLUSIONS: Considering the proposed strategy, regarding the strengths and weaknesses, utilization of evaluation tool can be one of the best strategies to achieving the prospective of health research papers by 2025. PMID- 27512559 TI - Terminal investment induced by a bacteriophage in a rhizosphere bacterium. AB - Despite knowledge about microbial responses to abiotic stress, few studies have investigated stress responses to antagonistic species, such as competitors, predators and pathogens. While it is often assumed that interacting populations of bacteria and phage will coevolve resistance and exploitation strategies, an alternative is that individual bacteria tolerate or evade phage predation through inducible responses to phage presence. Using the microbial model Pseudomonas fluorescens SBW25 and its lytic DNA phage SBW25Phi2, we demonstrate the existence of an inducible response in the form of a transient increase in population growth rate, and found that the response was induced by phage binding. This response was accompanied by a decrease in bacterial cell size, which we propose to be an associated cost. We discuss these results in the context of bacterial ecology and phage-bacteria co-evolution. PMID- 27512560 TI - Endoscopic bronchial occlusion with silicone spigots under virtual bronchoscopic navigation. AB - A 68-year-old woman with interstitial lung disease related to dermatomyositis and systemic scleroderma was admitted to our hospital with fever and dyspnoea. Although the fever was reduced after antibiotic therapy, a left pneumothorax suddenly occurred on day 27 after admission. A continuous air leak persisted despite chest drainage with three tubes and repeated pleurodesis. Chest computed tomography (CT) images showed a cavitary lesion with a pinhole in the left upper division, which was suspected to be the affected lesion with the air leak. Virtual bronchoscopic navigation images were constructed from CT data. Bronchial occlusion with Endobronchial Watanabe Spigots (EWSs) was performed on day 52. Two medium-sized EWSs were inserted into the left B1 + 2a and B1 + 2b, and the air leak stopped immediately. No procedure-related adverse events occurred. All three chest tubes were successfully removed by day 60. This case demonstrates that virtual bronchoscopic navigation can improve bronchial occlusion procedures using EWSs. PMID- 27512561 TI - Herpetic tracheitis in association with rituximab therapy. AB - A 58-year old lady under active follow-up with the respiratory services at our institution for bronchiectasis secondary to hypogammaglobulinaemia presented with hoarseness and haemoptysis. She was also receiving rituximab maintenance therapy for follicular lymphoma. Bronchoscopy demonstrated vesicular lesions on her vocal cords and trachea, confirmed as herpes simplex virus (HSV) on cytological analysis of brushings. She responded well to intravenous valacyclovir. Rituximab is increasingly utilised in the treatment of haematological and auto-immune disorders. This case highlights the potential of this drug to potentiate susceptibility to infection in an already immunocompromised individual. PMID- 27512562 TI - Role of granulocyte-macrophage colony-stimulating factor in pulmonary fibrosis following pulmonary alveolar proteinosis. AB - Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease characterized by accumulation of lipoproteinacious material in alveoli, with distinct features on high resolution computed tomography and biopsy. Its association with pulmonary fibrosis is infrequently encountered, and a clear understanding of the underlying pathogenesis is yet to be established. We report the case of a 48-year-old woman with known autoimmune PAP (aPAP) first diagnosed 20 years ago, who presented with worsening hypoxemia and radiological features consistent with pulmonary fibrosis, after many years of stable disease. We present a review of previously considered mechanisms of causation behind such changes, and in particular, postulate the role of granulocyte-macrophage colony-stimulating factor deficiency in pulmonary fibrosis seen in aPAP. PMID- 27512563 TI - Boerhaave's syndrome - tension hydropneumothorax and rapidly developing hydropneumothorax: two radiographic clues in one case. AB - Boerhaave's syndrome is a rare and severe condition with high mortality partly because of its atypical presentation resulting in delayed diagnosis and management. Diagnostic clues play an important role in the approach to this syndrome. Here, we report a 48 year-old male patient hospitalized with fever and left chest pain radiating into the interscapular area. Two chest radiographs undertaken 22 h apart showed a rapidly developing tension hydropneumothorax. The amylase level in the pleural fluid was high. The fluid in the chest tube turned bluish after the patient drank methylene blue. The diagnosis of Boerhaave's syndrome was suspected based on the aforementioned clinical clues and confirmed at the operation. The patient recovered completely with the use of antibiotics and surgical treatment. In this case, we describe key findings on chest radiographs that are useful in diagnosing Boerhaave's syndrome. PMID- 27512564 TI - Exercise-induced endobronchial hemorrhage: a rare clinical presentation. AB - The phenomenon of exercise-induced hemoptysis is still relatively underrecognised in humans. We report a case of recurrent hemoptysis brought on by vigorous exercise. A 33-year-old male presented with several episodes of intermittent fresh small-volume hemoptysis reproducible on vigorous exercise. There was no other significant medical history other than a past history of testicular tumor, treated with orchidectomy and adjuvant Bleomycin-based chemotherapy 1 year prior to onset of symptoms. Computed tomography scan showed no major abnormalities other than few small bilateral non-specific nodules. Computed tomography aortogram and pulmonary angiogram, ventilation/perfusion scan, and echocardiography yielded no significant abnormalities. Infectious, autoimmune disease, coagulopathy, vasculitis, and malignant causes were excluded. Bronchoscopy showed possible endobronchial bleeding. This phenomenon is thought to be due to vulnerability of pulmonary capillaries to stress or mechanical failure during strenuous exercise at high cardiorespiratory workload. PMID- 27512565 TI - Appendicitis complicated by appendiceal metastasis via peritoneal dissemination from lung cancer. AB - Peritoneal disseminations from lung cancer are difficult to detect during the patient's clinical course. Therefore, complications of this condition are unclear. We report a case in which peritoneal dissemination from lung cancer complicated appendicitis. A 74-year-old man with lung cancer who was receiving maintenance therapy presented at our hospital because of abdominal pain. It was the seventh day after the 14th cycle of maintenance therapy with bevacizumab. He was diagnosed with acute appendicitis. The resected appendix showed acute appendicitis complicated by appendiceal metastasis from lung cancer. Adenocarcinoma was observed predominantly in the serous membrane from the neck to the tail of the appendix. The distribution of the adenocarcinoma was diffuse. Peritoneal dissemination was considered the route of metastasis. He was admitted to the palliative care unit 10 months after appendectomy. Appendiceal metastasis via peritoneal dissemination from lung cancer complicated appendicitis in our patient who had been receiving bevacizumab. PMID- 27512566 TI - Descending necrotizing mediastinitis complicating hyperimmunoglobulin E syndrome. AB - Descending necrotizing mediastinitis (DNM) is a potentially lethal disease that originates from a deep neck infection (DNI); it is often associated with an immunocompromised state. Hyperimmunoglobulin E syndrome (HIES) is an extremely rare complex immune deficiency characterized by recurrent abscesses of staphylococcal etiology. A rare case of a 34-year-old woman wherein HIES putatively promoted the development of DNI into DNM is described. She presented with cervical purulent lymphadenitis and retropharyngeal abscess. Despite immediate cervical drainage and use of broad-spectrum antibiotics, she developed DNI and subsequently DNM. Mediastinal drainage with thoracotomy and subsequent deep neck drainage were performed. Bacterial culture of the abscess isolated methicillin-resistant Staphylococcus aureus (MRSA). Although a postoperative recurrent deep neck abscess required a second surgery, we succeeded in conservative remission of recurrent mediastinal abscess with long-term use of anti-MRSA drugs. Sufficient drainage under thoracotomy and robust administration of postoperative antibiotics resulted in successful management of HIES-associated DNM. PMID- 27512567 TI - Disseminated cryptococcosis presenting as mediastinal and hilar lymphadenopathy in an immunocompetent patient. AB - We herein report a rare case of disseminated cryptococcosis presenting as mediastinal and hilar lymphadenopathy in a young immunocompetent man. A previously healthy 26-year-old man presented with persistent headache and nonproductive cough. Chest computed tomography indicated mediastinal and hilar lymphadenopathy. Cryptococcal lymphadenitis and meningitis was confirmed by endobronchial ultrasound-guided transbronchial needle aspiration and central spinal fluid examination, respectively. He received liposomal amphotericin B and flucytosine followed by fluconazole and finally improved. PMID- 27512568 TI - Multicentric Castleman's disease developing during follow-up of sarcoidosis. AB - Pulmonary sarcoidosis is reported to have complication of lymphoproliferative disease such as malignant lymphoma, but the complication of multicentric Castleman's disease (MCD) is rarely reported. In our case of a 60-year-old woman, bilateral hilar lymphadenopathy was noted in her chest X-ray. We performed a transbronchial lung biopsy. She was diagnosed as having pulmonary sarcoidosis (Stage II). The shadow on chest X-ray disappeared without treatment. However, after 8 years, swelling of the mediastinal and abdominal lymph node, thickened bronchovascular bundle, and multiple nodular shadows were identified, and a thoracoscopic lung biopsy was performed. Based on the histopathological findings and elevated serum interleukin-6 level (75.7 pg/mL), she was diagnosed with pulmonary sarcoidosis complicated by MCD. When a change in chest X-ray findings are found during monitoring of pulmonary sarcoidosis, it is important to proceed with a thoracoscopic lung biopsy, because of the possibility of the rare complication of MCD. PMID- 27512569 TI - The effect of X-ray beam distortion on the Edwards Sapien XT(TM) trans-catheter aortic valve replacement prosthesis. AB - INTRODUCTION: Profiling the Aortic root perpendicular to the fluoroscopic image plane will achieve a more successful implant position for trans-catheter aortic valve replacement (TAVR). This study aimed to investigate whether the divergent nature of the X-ray beam from the C-arm altered the appearance of the TAVR device. METHODS: Under bench-top testing, a 23, 26 and 29 mm Edwards Sapien XT valve was positioned coaxially at the bottom of a fluoroscopic image utilising 22 and 32 cm fields of view (FOV). The table was then moved so that the valve was positioned at the top of the image. The valve's appearance was scored using a previously published three tier classification tool (excellent, satisfactory and poor) and quantified with measurements. The number of degrees of C-arm rotation that were required to bring the valve back to a coaxial appearance was recorded. RESULTS: When using the 32 cm FOV, the valve's appearance changes from excellent to satisfactory. When a 22 cm FOV was used, the change is less marked. More C-arm rotation is required to bring the appearance back to coaxial with the 32 cm FOV. CONCLUSION: Not maintaining the valve in the centre of the image can distort the valves appearance. This has the potential to affect the final implantation depth. PMID- 27512570 TI - A benchmarking and comparative analysis of emotional intelligence in student and qualified radiographers: an international study. AB - INTRODUCTION: Emotional intelligence (EI) has been identified as an important trait for healthcare students and healthcare professionals alike and is a predictor of improved work performance and patient satisfaction. In this paper, we benchmark an international cohort of radiography students and compare their scores to those of known qualified practitioner and normative data. METHODS: EI scores were at commencement from radiography degree programmes at four universities in Australia, Hong Kong, Republic of Ireland and the United Kingdom using the short form of the trait EI questionnaire (TEIQue-SF), which yields a Global score and four sub-factors. In total 293 students chose to participate. RESULTS: For the Australian combined Irish and UK groups, there were significant differences in Global EI and three of the four sub-factors between students and qualified radiographers (Australia: students = 5.01, qualified = 5.27; P <= 0.01) (Irish/UK students = 5.04, qualified = 5.28; P <= 0.01). When compared to the UK normative data, there was a significant difference for Global EI between the UK students and the UK norm data set (students = 4.71, normative = 4.99; P <= 0.01). CONCLUSION: This study provides benchmarking data for an international radiography student group. The clear differences of higher EI scores for qualified practicing radiographers when compared to student score opens discussion of the impact of academic and clinical practicum as a contributing factor in EI skills development. PMID- 27512571 TI - Practice patterns of radiation therapy technology in Australia: results of a national audit. AB - INTRODUCTION: This article presents the results of a single-day census of radiation therapy (RT) treatment and technology use in Australia. The primary aim of the study was to ascertain patterns of RT practice and technology in use across Australia. These data were primarily collated to inform curriculum development of academic programs, thereby ensuring that training is matched to workforce patterns of practice. METHODS: The study design was a census method with all 59 RT centres in Australia being invited to provide quantitative summary data relating to patient case mix and technology use on a randomly selected but common date. Anonymous and demographic-free data were analysed using descriptive statistics. RESULTS: Overall data were provided across all six Australian States by 29 centres of a possible 59, yielding a response rate of 49% and representing a total of 2743 patients. Findings from this study indicate the increasing use of emerging intensity-modulated radiotherapy (IMRT), image fusion and image-guided radiation therapy (IGRT) technology in Australian RT planning and delivery phases. IMRT in particular was used for 37% of patients, indicating a high uptake of the technology in Australia when compared to other published data. The results also highlight the resource-intensive nature of benign tumour radiotherapy. CONCLUSIONS: In the absence of routine national data collection, the single-day census method offers a relatively convenient means of measuring and tracking RT resource utilisation. Wider use of this tool has the potential to not only track trends in technology implementation but also inform evidence-based guidelines for referral and resource planning. PMID- 27512572 TI - Transperineal implantation of gold fiducial markers (gold seeds) for prostate image-guided radiation therapy: a feasible technique associated with a low risk of complications. AB - INTRODUCTION: The purpose is to describe the method, safety and efficacy of transperineal gold seed placement for image-guided radiation therapy. METHODS: An ethics committee approved database was used to review records of consecutive patients from October 2008 through December 2013, who underwent transperineal implantation of three gold markers into the prostate using staged local anaesthesia and transrectal ultrasound. Seeds were counted on radiographs from CT simulation, first treatment and last treatment. Retention and use of at least three markers for kV/kV matching was considered a successful implant. A visual analogue scale (VAS) pain assessment was performed. SAS was used for data analysis. RESULTS: Fiducial marker placement was successful for kV/kV matching in 556/581 patients (95.7%). The procedure was aborted due to pain in two patients. Additional sedation during the procedure was required in two patients. Complications include urinary infections (2 patients, <0.5%) and transient haematuria (2 patients, <0.5%). There were no recorded calls requesting additional pain medication or delays in radiation due to complications. The number of seeds identified at simulation: 4 (2 patients), 3 (554 patients), 2 (21 patients), 1 (1 patient), 0 (1 patient). One patient with three seeds and two patients with <2 seeds had cone beam CT instead of kV/kV imaging for image guidance. No seeds were lost after simulation. The mean visual analogue pain score associated with transperineal gold seed insertion met patients' expectations (respectively 4.1 vs. 4.4 P = 0.19). CONCLUSION: Outpatient transperineal insertion of fiducials avoids the rectum, is effective, convenient, well tolerated and has few side effects. PMID- 27512573 TI - The provision of enteral nutritional support during definitive chemoradiotherapy in head and neck cancer patients. AB - Combination chemoradiation is the gold standard of management for locally advanced squamous cell carcinomas of the head and neck. One of the most significant advantages of this approach to treatment is organ preservation which may not be possible with radical surgery. Unfortunately, few treatments are without side-effects and the toxicity associated with combined modality treatment causes meaningful morbidity. Patients with head and neck cancer (HNC) may have difficulties meeting their nutritional requirements as a consequence of tumour location or size or because of the acute toxicity associated with treatment. In particular, severe mucositis, xerostomia, dysgeusia and nausea and vomiting limit intake. In addition to this, dysphagia is often present at diagnosis, with many patients experiencing silent aspiration. As such, many patients will require enteral nutrition in order to complete chemoradiotherapy (CRT). Feeding occurs via catheters placed transnasally (nasogastric tubes) or directly into the stomach through the anterior abdominal wall (percutaneous gastrostomy tubes). In the absence of clear evidence concerning the superiority of one method over another, the choice of feeding tube tends to be dependent on clinician and patient preference. This review examines key issues associated with the provision of enteral nutritional support during definitive CRT in HNC patients, including feeding methods, patient outcomes and timing of tube insertion and use. PMID- 27512574 TI - Adaptive radiation therapy for bladder cancer: a review of adaptive techniques used in clinical practice. AB - Significant changes in the shape, size and position of the bladder during radiotherapy (RT) treatment for bladder cancer have been correlated with high local failure rates; typically due to geographical misses. To account for this, large margins are added around the target volumes in conventional RT; however, this increases the volume of healthy tissue irradiation. The availability of cone beam computed tomography (CBCT) has not only allowed in-room volumetric imaging of the bladder, but also the development of adaptive radiotherapy (ART) for modification of plans to patient-specific changes. The aim of this review is to: (1) identify and explain the different ART techniques being used in clinical practice and (2) compare and contrast these different ART techniques to conventional RT in terms of target coverage and dose to healthy tissue: A literature search was conducted using EMBASE, MEDLINE and Scopus with the key words 'bladder, adaptive, radiotherapy/radiation therapy'. 11 studies were obtained that compared different adaptive RT techniques to conventional RT in terms of target volume coverage and healthy tissue sparing. All studies showed superior target volume coverage and/or healthy tissue sparing in adaptive RT compared to conventional RT. Cross-study comparison between different adaptive techniques could not be made due to the difference in protocols used in different studies. However, one study found daily re-optimisation of plans to be superior to plan of the day technique. The use of adaptive RT for bladder cancer is promising. Further study is required to assess adaptive RT versus conventional RT in terms of local control and long-term toxicity. PMID- 27512575 TI - Synchronous prostate and rectal adenocarcinomas irradiation utilising volumetric modulated arc therapy. AB - Cases of synchronous prostate and colorectal adenocarcinomas have been sporadically reported. There are case reports on patients with synchronous prostate and rectal cancers treated with external beam radiotherapy alone or combined with high-dose rate brachytherapy boost to the prostate. Here, we illustrate a patient with synchronous prostate and rectal cancers treated using the volumetric arc therapy (VMAT) technique. The patient was treated with radical radiotherapy to 50.4 Gy in 28 fractions to the pelvis, incorporating the involved internal iliac node and the prostate. A boost of 24 Gy in 12 fractions was delivered to the prostate only, using VMAT. Treatment-related toxicities and follow-up prostate-specific antigen and carcinoembryonic antigen were collected for data analysis. At 12 months, the patient achieved complete response for both rectal and prostate cancers without significant treatment-related toxicities. PMID- 27512576 TI - Letter in response to 'The role of research for advanced practitioners'. AB - This letter to the Editor is in response to the paper 'Conceptualisation of the characteristics advanced practitioners in the medical radiation professions' by Smith et al. and the subsequent letter from Jenny Sim. The writers agree that research should be explicitly listed in the conceptual model of advanced practice, and provide some evidence and viewpoints from over a decade of advanced practice work in Canada. PMID- 27512577 TI - Letter in response to correspondence on 'Conceptualisation of the characteristics of advanced practitioners in the medical radiation professions'. AB - There is ongoing debate on the position of research as an attribute of advanced practice. This letter highlights some issues to be considered in light of recent correspondence published in the JMRS. PMID- 27512579 TI - Acknowledging the peer reviewers of Journal of Medical Radiation Sciences October 2014-September 2015. PMID- 27512578 TI - Letter in response to 'The conceptual model of advanced practice does include research'. AB - This letter refutes the suggestion made the authors of other letters to the Editor that the proposed model of the characteristics of advanced practitioners excludes research. PMID- 27512581 TI - Patients or prisoners? Time to reconsider the voting rights of mentally disordered offenders. AB - Although the Representation of the People Act 2000 permits most psychiatric in patients to register on the electoral register, transferred prisoners and those admitted to hospital under hospital orders remain disenfranchised by law. This article clarifies the voting rights of individuals receiving in-patient psychiatric care and contends that the selective disenfranchisement of some mentally disordered offenders is problematic, discriminatory and may breach international human rights law. There are therefore strong arguments for the UK government to address this long-standing inequality before the next general election. PMID- 27512580 TI - A pilot study about infertile men's awareness of their reprotoxic exposures and the intervention of occupational medicine to assess them. AB - BACKGROUND: Male infertility related to professional reprotoxic exposure has been assessed in several studies. Collaboration between occupational physicians and patients can yield information about the preventive measures that can be taken to avoid such exposure. The use of preventive measures is determined by the collaboration between reproductive medicine and occupational medicine and also by the patient's awareness of reprotoxic occupational exposures. Our andrology laboratory developed a systematic environmental interview that an occupational physician administers before semen analysis to assess patients' occupational reprotoxic chemical and physical exposures. This observational prospective study evaluated patients' feelings regarding this interview. The main outcome measure was the participants' score to determine their general reprotoxicant knowledge. The study also evaluated the patients' satisfaction about the interview with occupational physician and their attitude about reproductive toxicants. RESULTS: The mean score for general knowledge of reprotoxicants was 9.6 +/- 2.7/16. The most frequently underestimated reprotoxic factor was excessive heat (34.7 % correct responses). In cases of semen parameter abnormalities AND recognized occupational reprotoxic exposure, 63.2 % of the patients said they would use individual protective devices, and 55.1 % said they would temporarily adapt their workstation. Regarding the interview with the laboratory's occupational physician, 80.7 % considered it moderately or very useful. Of the interviewed patients, 46.2 % reported having changed their living habits 2 months after the interview, and 88.5 % were satisfied or very satisfied with the care they received. All of the respondents said it would be useful to extend the interview to include their wives. CONCLUSIONS: The data suggest that patients' knowledge about reprotoxic exposures can be improved, particularly knowledge related to physical exposure. The vast majority of patients were satisfied with the introduction of this new collaboration between reproductive and occupational medicine. PMID- 27512582 TI - Suicide under crisis resolution home treatment - a key setting for patient safety. AB - Recent years have seen a substantial increase in the use of crisis resolution home treatment (CRHT) teams as an alternative to psychiatric in-patient admission. We discuss the functions of these services and their effectiveness. Our research suggests high rates of suicide in patients under CRHT. Specific strategies need to be developed to improve patient safety in this setting. PMID- 27512583 TI - Opening the 'black box': liaison psychiatry services and what they actually do. AB - Aims and method To develop a simple, pragmatic typology to characterise the nature of liaison interventions delivered by a liaison service in a National Health Service setting. We carried out a retrospective electronic case-note review of referrals to a ward-based liaison psychiatry service. Results Three hundred and forty-four patients were referred to the service over a 12-month period. Ten different types of liaison interventions were identified, with the most common interventions being diagnosis (112 patients, 32.6%), medication management (57 patients, 16.6%), risk assessment and treatment (56 patients, 16.3% each). Mental Health Act work accounted for the greatest number of contacts per patient (median 7). Clinical implications There are inherent limitations in any single-site observational study, as site-specific results cannot be generalised to other liaison services. The intervention categories we developed, however, are easy to use and will provide a way of comparing and benchmarking the range of interventions delivered by different liaison psychiatry services. PMID- 27512584 TI - Colleague and patient appraisal of consultant psychiatrists and the effects of patient detention on appraisal scores. AB - Aims and method This paper aims to review colleague and patient feedback from the 10-year period of the operation of the Royal College of Psychiatrists' 360-degree appraisal system, specifically: (1) examine the overall distribution of ratings; (2) examine the effect of working primarily with detained patients on patient feedback, represented by forensic psychiatrists; and (3) look for a relationship between colleague and patient ratings. Results Data were analysed for 977 participating psychiatrists. Both colleagues and patients rated psychiatrists overall with high scores. Less than 1% were identified as low scorers, although there was no relationship between those identified by colleagues or patients. Colleague and patient feedback scores varied little between subspecialties including forensic consultants. Clinical implications Psychiatrists in all subspecialties obtained high scores from colleagues and staff. Working with detained patients appeared to have little effect on patient ratings. PMID- 27512585 TI - Service and treatment engagement of people with very late-onset schizophrenia like psychosis. AB - Aims and method Electronic patient records were used to investigate the level of engagement and treatment that patients with very late-onset schizophrenia-like psychosis (VLOSLP) had with mental health services. Results Of 131 patients assessed and diagnosed, 63 (48%) were taking antipsychotic treatment at 3 months, 46 (35%) at 6 months and 36 (27%) at 12 months. At discharge from mental health services, 54% of patients had failed to engage with services or became lost to follow-up, 18% had engaged with services but were not taking antipsychotic medication and only 28% were taking treatment. Clinical implications Results showed that less than half of the patients with VLOSLP were commenced on antipsychotic treatment and less than a third remained on treatment at 1 year or at point of discharge. This highlights the need for services to consider being more assertive in taking potentially effective treatment to this patient group. PMID- 27512586 TI - Talking therapy groups on acute psychiatric wards: patients' experience of two structured group formats. AB - Aims and method We report the results of a clinical audit of patients' reactions to two types of talking therapy groups facilitated by assistant psychologists and psychology graduates on three acute wards. Patients' experiences of problem solving and interpersonal group formats were explored via focus groups and structured interviews with 29 group participants. Results Both group formats generated high satisfaction ratings, with benefits related mostly to generic factors. Clinical implications Adequately trained and supported assistant psychologists and psychology graduates can provide supportive talking groups that patients find helpful. PMID- 27512587 TI - A multidimensional Framework for Routine Outcome Measurement in Liaison Psychiatry (FROM-LP). AB - In the field of liaison psychiatry, as in all areas of healthcare, there is an essential need for well-organised and consistent collection of information on outcomes, from a range of perspectives. This special article introduces, and describes the development of, the multidimensional Framework for Routine Outcome Measurement in Liaison Psychiatry (FROM-LP). This was challenging owing to the variety of service settings and types of intervention which characterise liaison psychiatry. Similar challenges may be faced by other specialties and this, along with the direct relevance of much of the eventual content of the framework, will broaden the interest of this article. PMID- 27512588 TI - Intelligent outcome measures in liaison psychiatry: essential even if not desirable: Commentary on ... a multidimensional Framework for Routine Outcome Measurement in Liaison Psychiatry (FROM-LP). AB - Service development is guided by outcome measures that inform service commissioners and providers. Those in liaison psychiatry should be encouraged to develop a positive approach that integrates the collection of outcome measures into everyday clinical practice. The Framework for Routine Outcome Measurement in Liaison Psychiatry (FROM-LP) is a very useful tool to measure service quality and clinical effectiveness, using a combination of clinician-rated and patient-rated outcome measures and patient-rated experience measures. However, it does not include measures of cost-effectiveness or training activities. The FROM-LP is a significant step towards developing nationally unified outcome measures. PMID- 27512589 TI - A history of liaison psychiatry in the UK. AB - Aims and method To record the development of liaison psychiatry in the UK and to summarise the current levels of activity. We also highlight the challenges the specialty may face if it is to develop further. History since the 1970s is reviewed by early pioneers and those involved in the present day, with a focus on the key role played by members of the Royal College of Psychiatrists. Results We describe the development of training guidelines, the publication of joint documents with other Royal Colleges, establishing international collaborations and defining service specifications. We emphasise the importance of collaboration with other medical organisations, and describe successes and pitfalls. Clinical implications Much has been achieved but challenges remain. Liaison psychiatry has a potentially important role in improving patient care. It needs to adapt to the requirements of the current National Health Service, marshal evidence for cost effectiveness and persuade healthcare commissioners to fund services that are appropriate for the psychological needs of general hospital patients. PMID- 27512590 TI - It is time to bring borderline intellectual functioning back into the main fold of classification systems. AB - Borderline intellectual functioning is an important and frequently unrecognised comorbid condition relevant to the diagnosis and treatment of any and all psychiatric disorders. In the DSM-IV-TR, it is defined by IQ in the 71-84 range. In DSM-5, IQ boundaries are no longer part of the classification, leaving the concept without a clear definition. This modification is one of the least highlighted changes in DSM-5. In this article we describe the history of the classification of borderline intellectual functioning. We provide information about it and on the importance of placing it in the right context and in the right place in future DSM editions and other classification systems such as the International Classification of Diseases. PMID- 27512591 TI - Lessons to be learned from the oldest community psychiatric service in the world: Geel in Belgium. AB - This article reviews the family foster care model practised in the small Belgian town of Geel. A historical introduction is followed by a description of a family foster care project in its current form. Issues are raised as to whether the current culture of care pathways, managed care, payment by results and an emphasis on 'cure' are conducive to recovery as promoted by the recovery model. Finally, the lessons from Geel are summarised and it is argued that there is much that can be learned from this way of working to support the recovery movement. PMID- 27512592 TI - Psychiatrists' understanding and use of psychological formulation: a qualitative exploration. AB - Aims and method To establish an initial conceptualisation of how psychiatrists understand and use formulation within adult psychiatry practice. Twelve psychiatrists took part in semi-structured interviews. Transcripts were analysed using a constructivist grounded theory methodology. Results Formulation was conceptualised as an addition to diagnosis, triggered by risk, complexity and a need for an enhanced understanding. Participants valued collaborative formulation with psychologists. Multiple contextual factors were perceived to either facilitate or inhibit the process. Barriers to formulation led to a disjointed way of working. Clinical implications Findings contribute to an understanding of formulation within psychiatry training and practice. PMID- 27512593 TI - Psychiatrists' use of formulation: Commentary on ... Psychiatrists' understanding and use of psychological formulation. AB - Both psychologists and psychiatrists are trained to write formulations of their patients' illnesses, with some differences in how they do this. Psychologists focus on psychological understanding, while psychiatrists' formulation brings together aetiology, functioning and a management plan. Mohtashemi et al's study records how some psychiatrists understand formulation and its usefulness. Time pressure was an important barrier to making a full formulation, and some believed the medical role of the psychiatrist was a priority. The study illustrates some of the challenges facing psychiatrists working in the NHS in terms of maintaining high clinical standards and a holistic approach to patient care. PMID- 27512594 TI - Vulnerable patients going to court: a psychiatrist's guide to special measures. AB - There have been significant changes to how vulnerable people are treated in the court system, including the introduction of special measures to support people both as witness and as accused. This paper summarises the use of special measures and their application to people with mental health diagnoses or cognitive impairment. PMID- 27512595 TI - The expansion of the Foundation Programme in psychiatry. AB - The Broadening the Foundation Programme report has led to an expansion in the number of psychiatry foundation placements. This change will have far-reaching benefits for foundation doctors doing psychiatry, no matter what their future career intentions. Doctors will develop a better understanding of mental illness, they will improve their communication skills and they will gain experience of working within multidisciplinary teams. Recruitment into psychiatry is also likely to improve. The Royal College of Psychiatrists is putting in place a number of measures to ensure that placements are of a high quality so that foundation doctors have a good experience of psychiatry. PMID- 27512597 TI - Julia Bland interviews a group of anonymous (and frank) core trainees in psychiatry. PMID- 27512596 TI - Profile: Professor Ian Jones. PMID- 27512598 TI - Female genital mutilation and mental health: how can research help the victims? PMID- 27512599 TI - Mental Health Officer status and recruitment in psychiatry. PMID- 27512600 TI - Authors' reply: psychiatrists' use of formulation. PMID- 27512602 TI - Preparation, loading, and cytotoxicity analysis of polymer nanotubes from an ethylene glycol dimethacrylate homopolymer in comparison to multi-walled carbon nanotubes. AB - Despite concerns over toxicity, carbon nanotubes have been extensively investigated for potential applications in nanomedicine because of their small size, unique properties, and ability to carry cargo such as small molecules and nucleic acids. Herein, we show that polymer nanotubes can be synthesized quickly and easily from a homopolymer of ethylene glycol dimethacrylate (EGDMA). The nanotubes formed via photo-initiated polymerization of the highly functional prepolymer, inside an anodized aluminium oxide template, have a regular structure and large internal pore and can be loaded with a fluorescent dye within minutes representing a simple alternative to multi-walled carbon nanotubes for biomedical applications. PMID- 27512601 TI - Cognitive neuroepigenetics: the next evolution in our understanding of the molecular mechanisms underlying learning and memory? AB - A complete understanding of the fundamental mechanisms of learning and memory continues to elude neuroscientists. Although many important discoveries have been made, the question of how memories are encoded and maintained at the molecular level remains. To date, this issue has been framed within the context of one of the most dominant concepts in molecular biology, the central dogma, and the result has been a protein-centric view of memory. Here we discuss the evidence supporting a role for neuroepigenetic mechanisms, which constitute dynamic and reversible, state-dependent modifications at all levels of control over cellular function, and their role in learning and memory. This neuroepigenetic view suggests that DNA, RNA and protein each influence one another to produce a holistic cellular state that contributes to the formation and maintenance of memory, and predicts a parallel and distributed system for the consolidation, storage and retrieval of the engram. PMID- 27512603 TI - Crystal structure of Clostridium difficile toxin A. AB - Clostridium difficile infection is the leading cause of hospital-acquired diarrhoea and pseudomembranous colitis. Disease is mediated by the actions of two toxins, TcdA and TcdB, which cause the diarrhoea, as well as inflammation and necrosis within the colon1,2. The toxins are large (308 and 270 kDa, respectively), homologous (47% amino acid identity) glucosyltransferases that target small GTPases within the host3,4. The multidomain toxins enter cells by receptor-mediated endocytosis and, upon exposure to the low pH of the endosome, insert into and deliver two enzymatic domains across the membrane. Eukaryotic inositol-hexakisphosphate (InsP6) binds an autoprocessing domain to activate a proteolysis event that releases the N-terminal glucosyltransferase domain into the cytosol. Here, we report the crystal structure of a 1,832-amino-acid fragment of TcdA (TcdA1832), which reveals a requirement for zinc in the mechanism of toxin autoprocessing and an extended delivery domain that serves as a scaffold for the hydrophobic alpha-helices involved in pH-dependent pore formation. A surface loop of the delivery domain whose sequence is strictly conserved among all large clostridial toxins is shown to be functionally important, and is highlighted for future efforts in the development of vaccines and novel therapeutics. PMID- 27512604 TI - Activation of nuclear factor kappa B pathway and reduction of hypothalamic oxytocin following hypothalamic lesions. AB - BACKGROUND: Hypothalamic obesity (HO) occurs in patients with tumors and lesions in the medial hypothalamic region. In this study, a hyperphagic rat model of combined medial hypothalamic lesions (CMHL) was used to test which specific inflammatory molecules are involved. METHODS: In order to target specific homeostatic medial hypothalamic nuclei (arcuate, ventromedial, and dorsomedial nuclei), male Sprague-Dawley rats (age of 8 weeks, ~250 g body weight) received four electrolytic lesions or sham surgery. Post-surgery food intake and weight changes were tracked and hypothalamic gene expression for inflammatory molecules as well as anorexigenic peptide oxytocin 7 days and 7 months post-surgery were tested. RESULTS: Seven days post-surgery, average food intake increased by 23%, and body weight gain had increased by 68%. Toll-like 4 receptor/nuclear factor kappaB (TLR4/NF-kappaB)-pathway was specifically activated in the mediobasal hypothalamus (MBH), resulting in 3-fold higher tumor necrosis factor (TNF)-alpha, 10-fold higher interleukin (IL) 1-beta mRNA levels, and higher expression of suppression of cytokine signaling (SOCS) 3, while oxytocin mRNA levels were significantly reduced in CMHL rats versus sham surgery rats 7 days post-surgery. At 7 months, inflammation was less stimulated in MBH of CMHL rats compared to 7 days post-surgery and SOCS 3 as well as oxytocin mRNA levels were comparable between the two groups. CONCLUSION: Medial hypothalamic lesions are associated with strong post-surgery hyperphagia and activation of TLR4/NF-kappaB-pathway as well as reduced expression of oxytocin in the hypothalamus. PMID- 27512605 TI - Sarcoid reaction: a rare occurrence associated to colon adenocarcinoma (case report and literature review). AB - Granulomatous reactions are related to infectious and non infectious diseases, but more rarely, granulomas may occur in association to malignancies. The presence of sarcoid-like granulomas in lymph nodes draining malignant tumors is an uncommon but well known occurrence. However, their presence in the stroma of malignant tumors is much rarer. We have only found two previous cases reported in the Japanese and English literature. In this study we report a well differentiated adenocarcinoma of the right colon associated to a stromal granulomatous sarcoid-like reaction. Lymph nodes were not involved. The patient had a clinical history of tuberculosis treated 15 years ago, but there was no clinical, histomorphological, immunohistochemical or molecular evidence of disease at the moment of these findings. We have reviewed the literature to find the keys and the diagnostic challenges posed by granulomatous sarcoid-like reaction occurring in lymph nodes draining malignant neoplasms, peritumoral stroma and in other organs far from the primary tumor. The diagnosis of granulomatous sarcoid-like reactions associated to malignancies can be challenging and it can only be made after ruling out specific infectious and non infectious causes of granulomatous inflammation. The mechanisms involved in granuloma formation, their relationship with demographic and histopathological features, their possible association with autoimmune disorders, their cytokine profile and, more importantly, their prognostic significance in each type of tumor are still unclear and require studies with larger number of patients. PMID- 27512606 TI - Breast metastasis from recurrent gallbladder adenocarcinoma: a case report with review of the literature. AB - Gallbladder adenocarcinoma has a poor prognostic. The leading modes of dissemination in gallbladder cancer (GBC) are lymphatic, vascular, neural, intraperitoneal, and intraductal. The most common site of dissemination is liver. Breast metastasis in GBC is an unusual site of dissemination. Only few cases have been reported in the literature. We report a rare case of solitary breast metastasis from recurrent gallbladder carcinoma in light of existing literature. PMID- 27512607 TI - Aneurysmal subarachnoid hemorrhage prognostic decision-making algorithm using classification and regression tree analysis. AB - BACKGROUND: Classification and regression tree analysis involves the creation of a decision tree by recursive partitioning of a dataset into more homogeneous subgroups. Thus far, there is scarce literature on using this technique to create clinical prediction tools for aneurysmal subarachnoid hemorrhage (SAH). METHODS: The classification and regression tree analysis technique was applied to the multicenter Tirilazad database (3551 patients) in order to create the decision making algorithm. In order to elucidate prognostic subgroups in aneurysmal SAH, neurologic, systemic, and demographic factors were taken into account. The dependent variable used for analysis was the dichotomized Glasgow Outcome Score at 3 months. RESULTS: Classification and regression tree analysis revealed seven prognostic subgroups. Neurological grade, occurrence of post-admission stroke, occurrence of post-admission fever, and age represented the explanatory nodes of this decision tree. Split sample validation revealed classification accuracy of 79% for the training dataset and 77% for the testing dataset. In addition, the occurrence of fever at 1-week post-aneurysmal SAH is associated with increased odds of post-admission stroke (odds ratio: 1.83, 95% confidence interval: 1.56 2.45, P < 0.01). CONCLUSIONS: A clinically useful classification tree was generated, which serves as a prediction tool to guide bedside prognostication and clinical treatment decision making. This prognostic decision-making algorithm also shed light on the complex interactions between a number of risk factors in determining outcome after aneurysmal SAH. PMID- 27512608 TI - Intramedullary cyst formation after removal of multiple intradural spinal arachnoid cysts: A case report. AB - BACKGROUND: A rare cause of spinal cord compression is spinal arachnoid cysts. Symptoms are caused by spinal cord compression, however, asymptomatic patients have been also reported. Treatment options depend upon symptom severity and clinical course. CASE DESCRIPTION: We report the case of a 47-year-old patient who developed an intramedullary arachnoid cyst after removal of an intradural extramedullary cyst. CONCLUSION: Surgery should be considered early in a symptomatic disease course. Longstanding medullary compression may reduce the possibility of neurological recovery as well as secondary complications such as intramedullary cyst formation. PMID- 27512610 TI - Adult medulloblastoma: A rare case report and literature review. AB - BACKGROUND: Medulloblastoma is a highly malignant embryonal tumor which commonly arises in the cerebellum. It is relatively rare and accounts for less than 2% of all primary brain tumors. The tumor primarily occurs in childhood; however, rarely, it may be found in adult population. In addition, medulloblastoma in adult population shows features which are quite distinct from the pediatric group. CASE DESCRIPTION: We report the case of a 33-year-old man who presented to our institution with a history of blurred vision of both eyes for 5 months preceded by intermittent headache since the previous year. Preoperative investigation suggested a posterior fossa mass and we suspected an ependymoma. The patient underwent ventriculoperitoneal shunt and craniotomy tumor removal, followed by radiotherapy. Histopathological and immunohistochemical examination were performed, and the results showed a diagnosis of medulloblastoma. CONCLUSION: This case is exceptional because adult medulloblastoma occurrence in our center is extremely rare, and the diagnosis can only be established through histopathological and immunohistochemical studies. PMID- 27512609 TI - mTORC1 signaling in primary central nervous system lymphoma. AB - BACKGROUND: Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) acts as a downstream effector of phosphatidyl-inositol-3 kinase, which is frequently hyperactivated in glioblastoma multiforme and links to cell signaling in cellular proliferation, differentiation, metabolism, and survival. Although many studies have suggested the importance of mTORC1 in tumorigenesis, its role remains unclear in brain tumors other than glioblastoma. METHODS: In the present study, we evaluated the activation of mTORC1 in 24 cases of primary central nervous system lymphoma (PCNSL). RESULTS: Immunohistochemical analysis showed overexpression of Rheb, which is immediately upstream of mTORC1, in 20 cases of PCNSL. Immunohistochemical analysis also showed overexpression of phospho-4E-BP1 (Thr37/46) and phospho-S6 (Ser235/236), which are increased after mTORC1 activation as mTORC1 downstream effectors in 17 and 21 cases, respectively. CONCLUSION: Our data suggest that abnormal activation of the mTORC1 signaling pathway may cause tumor growth in patients with PCNSL. PMID- 27512611 TI - Glioblastoma multiforme of the optic chiasm: A rare case of common pathology. AB - BACKGROUND: Malignant optic and chiasmatic gliomas are extremely rare, and are classified pathologically as anaplastic astrocytoma or glioblastoma multiforme (GBM). Approximately 40 cases of optic GBM in adults have been reported in the literature, and only five of them were described to originate from the optic chiasm. CASE DESCRIPTION: An 82-year-old male patient with a past medical history of diabetes mellitus type 2, melanoma, and bladder cancer presented with gradual vision loss of the left eye in a period of 1 month. After neuro-ophthalmological examination, the decision of thither magnetic resonance imaging (MRI) studies was made. It showed a contrast enhancing mass in the region of the optic chiasm. In this case, imaging study was not enough to establish an accurate diagnosis and a left pterional craniotomy for biopsy and resection of the optic chiasmal mass was performed. After histological evaluation of the mass tissue, the diagnosis of GBM was made. Taking into account the patient's poor condition and unfavorable prognosis he was moved to inpatient hospice. The patient deceased within 2 months after surgery. CONCLUSION: Chiasmal GBM is an extremely rare condition where a biopsy is necessary for accurate diagnosis and optimal treatment. Differential diagnosis for such lesions can be very difficult and include demyelinating optic neuritis and non-demyelinating inflammatory optic neuropathy (e.g., sarcoid), vascular lesions (e.g., cavernoma), compressive lesions of the optic apparatus, metastatic malignancy, and primary tumors of the anterior optic pathway. The role of chemotherapy and radiotherapy including novel stereotaxic radiosurgery methods is still unclear and will need to be evaluated. PMID- 27512612 TI - Metastatic brain tumor from urothelial carcinoma of the prostatic urethra. AB - BACKGROUND: Urothelial carcinoma occurs in the bladder, upper urinary tract, and lower urinary tract, including prostatic urethra. A majority of the reported cases of intracranial metastasis from urothelial carcinoma originates from the bladder and upper urinary tract. Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. CASE DESCRIPTION: A 72-year-old male presented with a metastatic brain tumor and a 3 year history of urothelial carcinoma of the prostatic urethra treated with cystourethrectomy and chemotherapy with gemcitabine-cisplatin. Pathological diagnosis for tumor removal was compatible with metastatic brain tumor from urothelial carcinoma. CONCLUSION: Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. It is an extremely rare case, however, we should be careful of brain metastasis during follow-up for urothelial carcinoma in the lower urinary tract. PMID- 27512613 TI - Multicentric spinal cord and brain glioblastoma without previous craniotomy. AB - BACKGROUND: Glioblastoma multiforme (GBS) is a highly malignant glioma that rarely presents as an infratentorial tumor. Multicentric gliomas lesions are widely separated in site and/or time and its incidence has been reported between 0.15 and 10%. Multicentric gliomas involving supratentorial and infratentorial region are even more rare. In most cases, infratentorial disease is seen after surgical manipulation or radiation therapy and is usually located in the cerebellum or cervical region. CASE REPORT: We present a rare case of symptomatic multicentric glioma in the brain, fourth ventricle, cervical as well as lumbar glioblastoma in an adult without previous therapeutic intervention. We also review the literature of this rare presentation. CONCLUSIONS: This report suggests that GBM is a diffuse disease; the more extended the disease, the worse prognosis it has. The management still remains controversial and further studies are required to understand the prognosis factors of dissemination. PMID- 27512614 TI - Genomic and expression analysis of transition proteins in Drosophila. AB - The current study was aimed at analyzing putative protein sequences of the transition protein-like proteins in 12 Drosophila species based on the reference sequences of transition protein-like protein (Tpl (94D) ) expressed in Drosophila melanogaster sperm nuclei. Transition proteins aid in transforming chromatin from a histone-based nucleosome structure to a protamine-based structure during spermiogenesis - the post-meiotic stage of spermatogenesis. Sequences were obtained from NCBI Ref-Seq database using NCBI ORF-Finder (PSI-BLAST). Sequence alignments and analysis of the amino acid content indicate that orthologs for Tpl (94D) are present in the melanogaster species subgroup (D. simulans, D. sechellia, D. erecta, and D. yakuba), D. ananassae, and D. pseudoobscura, but absent in D. persmilis, D. willistoni, D. mojavensis, D. virilis, and D. grimshawi. Transcriptome next generation sequence (RNA-Seq) data for testes and ovaries was used to conduct differential gene expression analysis for Tpl (94D) in D. melanogaster, D. simulans, D. yakuba, D. ananassae, and D. pseudoobscura. The identified Tpl (94D) orthologs show high expression in the testes as compared to the ovaries. Additionally, 2 isoforms of Tpl (94D) were detected in D. melanogaster with isoform A being much more highly expressed than isoform B. Functional analyses of the conserved region revealed that the same high mobility group (HMG) box/DNA binding region is conserved for both Drosophila Tpl (94D) and Drosophila protamine-like proteins (MST35Ba and MST35Bb). Based on the rigorous bioinformatic approach and the conservation of the HMG box reported in this work, we suggest that the Drosophila Tpl (94D) orthologs should be classified as their own transition protein group. PMID- 27512615 TI - Principles and Clinical Application of Dual-energy Computed Tomography in the Evaluation of Cerebrovascular Disease. AB - Dual-energy computed tomography (DECT) simultaneously acquires images at two X ray energy levels, at both high- and low-peak voltages (kVp). The material attenuation difference obtained from the two X-ray energies can be processed by software to analyze material decomposition and to create additional image datasets, namely, virtual noncontrast, virtual contrast also known as iodine overlay, and bone/calcium subtraction images. DECT has a vast array of clinical applications in imaging cerebrovascular diseases, which includes: (1) Identification of active extravasation of iodinated contrast in various types of intracranial hemorrhage; (2) differentiation between hemorrhagic transformation and iodine staining in acute ischemic stroke following diagnostic and/or therapeutic catheter angiography; (3) identification of culprit lesions in intra axial hemorrhage; (4) calcium subtraction from atheromatous plaque for the assessment of plaque morphology and improved quantification of luminal stenosis; (5) bone subtraction to improve the depiction of vascular anatomy with more clarity, especially at the skull base; (6) metal artifact reduction utilizing virtual monoenergetic reconstructions for improved luminal assessment postaneurysm coiling or clipping. We discuss the physical principles of DECT and review the clinical applications of DECT for the evaluation of cerebrovascular diseases. PMID- 27512616 TI - Erratum: Percutaneous CT Guided Ablation in the Hepatic Dome: Artificially Induced Pneumothorax for Safe Transpleural Access. AB - [This corrects the article on p. 63 in vol. 5, PMID: 26713179.]. PMID- 27512618 TI - The past and present Earth-Moon system: the speed of light stays steady as tides evolve. AB - Tides induce a semimajor axis rate of +38.08 +/- 0.19 mm/yr, corresponding to an acceleration of the Moon's orbital mean longitude of -25.82 +/- 0.13 "/cent2, as determined by the analysis of 43 yr of Lunar Laser Ranging (LLR) data. The LLR result is consistent with analyses made with different data spans, different analysis techniques, analysis of optical observations, and independent knowledge of tides. Plate motions change ocean shapes, and geological evidence and model calculations indicate lower rates of tidal evolution for extended past intervals. Earth rotation has long-term slowing due to tidal dissipation, but it also experiences variations for times up to about 105 yr due to changes in the moment of inertia. An analysis of LLR data also tests for any rate of change in either the speed of light c or apparent mean distance. The result is (-2.8 +/- 3.4)*10 12 /yr for either scale rate or -(dc/dt)/c, or equivalently -1.0 +/- 1.3 mm/yr for apparent distance rate. The lunar range does not reveal any change in the speed of light. PMID- 27512617 TI - Constitutive IFNalpha/beta signaling maintains expression of signaling intermediaries for efficient cytokine responses. AB - Interferons (IFNs) are a family of immunoregulatory cytokines with important roles in anti-viral and anti-tumor responses. Type I and II IFNs bind distinct receptors and are associated with different stages of the immune response. There is however, considerable crosstalk between these two cytokines with enhancement of IFNgamma responses following IFNalpha/beta priming and loss of IFNalpha/beta receptor (IFNAR) resulting in diminished IFNgamma responses. In this study, we sought to define the mechanism of crosstalk between the type I and II IFNs. Our previous reports demonstrated reduced expression of the canonically activated transcription factor signal transducer and activator of transcription (STAT)1, in cells lacking the IFNAR alpha chain (IFNAR1). Therefore, we used microarray analysis to determine whether reconstitution of STAT1 in IFNAR1-deficient cells was sufficient to restore IFNgamma responses. We identified several biological pathways, including the MHC class I antigen presentation pathway, in which STAT1 reconstitution was able to significantly rescue IFNgamma-mediated gene regulation in Ifnar1 (-/-) cells. Notably, we also found that in addition to low basal expression of STAT1, cells lacking the IFNAR1 also had aberrant expression of multiple other transcription factors and signaling intermediaries. The studies described herein demonstrate that basal and regulated expression of signaling intermediaries is a mechanism for crosstalk between cytokines including type I and II IFNs. PMID- 27512619 TI - Cassini/VIMS observes rough surfaces on Titan's Punga Mare in specular reflection. AB - Cassini/VIMS high-phase specular observations of Titan's north pole during the T85 flyby show evidence for isolated patches of rough liquid surface within the boundaries of the sea Punga Mare. The roughness shows typical slopes of 6 degrees +/-1 degrees . These rough areas could be either wet mudflats or a wavy sea. Because of their large areal extent, patchy geographic distribution, and uniform appearance at low phase, we prefer a waves interpretation. Applying theoretical wave calculations based on Titan conditions our slope determination allows us to infer winds of 0.76+/-0.09 m/s and significant wave heights of [Formula: see text] cm at the time and locations of the observation. If correct, these would represent the first waves seen on Titan's seas, and also the first extraterrestrial sea-surface waves in general. PMID- 27512620 TI - Determination of plasma and leukocyte vitamin C concentrations in a randomized, double-blind, placebo-controlled trial with Ester-C((r)). AB - BACKGROUND: Rapid uptake of vitamin C into blood and retention in tissues are important indicators of the efficacy of vitamin C supplementation and its immune supporting role. The objective of this study was to evaluate the bioavailability of vitamin C in plasma (reflective of recent intake) and leukocytes (reflective of tissue stores and influences on immune function) from a novel vitamin C formulation, Ester-C((r)). METHODS: The study was a double-blind, placebo controlled, crossover trial. Thirty-six subjects, 18-60 years of age, were randomized to receive placebo (PL, 0 mg vitamin C), ascorbic acid (AA, 1000 mg vitamin C), and Ester-C((r)) (EC, 1000 mg vitamin C). Plasma and leukocyte vitamin C were measured baseline and at 2, 4, 8 and 24 h postdose. RESULTS: The concentration and percent change from baseline in plasma were significantly higher with EC at all time points when compared to PL. No significant differences between EC and AA were observed in plasma concentration. Maximum plasma concentration was higher for EC compared to AA (P = 0.039) and PL (P < 0.001). Plasma area under the curve (AUC0-24h) was higher for EC (P < 0.001) compared to PL. The concentration change from baseline in leukocyte vitamin C was increased with EC at 24 h post-dose (P = 0.036) while no significant within-group changes were observed in AA or PL at any time point. The percent change in leukocyte vitamin C concentration was higher for EC at 8 and 24 h compared to AA (P = 0.028 and P = 0.034, respectively) and PL (P = 0.042 and P = 0.036, respectively). CONCLUSIONS: A single dose of EC resulted in favorable percent change in leukocyte vitamin C concentration compared to AA and PL, indicating EC is retained longer within leukocytes. Trial registration ClinicalTrials.gov Identifier NCT01852903. PMID- 27512621 TI - Weighted K-means support vector machine for cancer prediction. AB - To date, the support vector machine (SVM) has been widely applied to diverse bio medical fields to address disease subtype identification and pathogenicity of genetic variants. In this paper, I propose the weighted K-means support vector machine (wKM-SVM) and weighted support vector machine (wSVM), for which I allow the SVM to impose weights to the loss term. Besides, I demonstrate the numerical relations between the objective function of the SVM and weights. Motivated by general ensemble techniques, which are known to improve accuracy, I directly adopt the boosting algorithm to the newly proposed weighted KM-SVM (and wSVM). For predictive performance, a range of simulation studies demonstrate that the weighted KM-SVM (and wSVM) with boosting outperforms the standard KM-SVM (and SVM) including but not limited to many popular classification rules. I applied the proposed methods to simulated data and two large-scale real applications in the TCGA pan-cancer methylation data of breast and kidney cancer. In conclusion, the weighted KM-SVM (and wSVM) increases accuracy of the classification model, and will facilitate disease diagnosis and clinical treatment decisions to benefit patients. A software package (wSVM) is publicly available at the R-project webpage (https://www.r-project.org). PMID- 27512622 TI - Cardiovascular magnetic resonance evaluation of left ventricular peak filling rate using steady-state free precession and phase contrast sequences. AB - BACKGROUND: We investigated a practical method to measure peak filling rate (PFR) as an indicator of diastolic function of the left ventricle. Ten adult volunteers underwent cine MR imaging using steady-state free precession (SSFP) and phase contrast (PC) sequences to measure PFR. Two PC image sets were acquired at the mitral valve orifice, and PFR was determined from the set with high true temporal resolution (temporal PC method) or with high spatial resolution (spatial PC method). SSFP images covering the left ventricle were acquired, and a time-volume curve was generated around the peak filling phase. PFR was determined using parabolic curve fitting on the first-derivative curve of the LV time-volume curve. FINDINGS: PFR values estimated by the PC methods correlated well with those estimated by the SSFP method, despite apparent underestimation. The underestimation was smaller for the temporal PC method (12 %) than for the spatial PC method (28 %). Intra- and inter-observer repeatabilities were better for the PC methods than for the SSFP method. CONCLUSIONS: PFR measurement by PC imaging with high true temporal resolution is convenient and offers excellent repeatability and acceptable accuracy, indicating suitability for clinical use. PMID- 27512623 TI - A comparison of the clinical effect of two fixation methods on Hoffa fractures. AB - INTRODUCTION: Hoffa fractures are rare and difficult to treat for orthopaedic surgeons. The mechanism of injury of Hoffa fracture is still unknown and the operation approch and fixation method are still controversial. The aim of this study is to compare the clinical effect between two fixation methods on Hoffa fractures. CASE DESCRIPTION: From April 2004 to July 2013, we treated eleven patients (new method group) with Hoffa fracture using the new fixation method (fixed with intercondylar screw and crossed screws) and sixteen patients (traditional method group) using the traditional fixation method (fixed with anteroposteriorly placed screws). All documents from their admission until the last followup in December 2015 were reviewed, data regarding complications collected and results were evaluated using the Knee Society Score. DISCUSSION AND EVALUATION: After an average follow-up period of 27.1 months (range 24-32 months), all fractures had healed. The average healing time of the new method group was 11.36 weeks (range 9-14 weeks) and the average healing time of the traditional method group was 11.88 weeks (range 9-14 weeks). According to the Knee Society Score, the average score of the new method group was 176.36 points (range 125-199 points), and the average score of the traditional method group was 171.19 points (range 148-197 points). Statistical analysis (t test, t = 0.76, P > 0.05) showed that the difference of both the healing time (t test, t = 0.94, P > 0.05) and the score between these two groups was not significant. CONCLUSIONS: These results indicate that the new fixation method for Hoffa fracture is as effective as the traditional method and may provide a new way to treat Hoffa fractures. PMID- 27512624 TI - Clinicopathological and prognostic significance of heat shock protein 27 (HSP27) expression in non-small cell lung cancer: a systematic review and meta-analysis. AB - Numbers of clinical and experimental investigations have provided increasing evidences to demonstrate that heat shock protein 27 (HSP27) is a qualified predictor for many cancers. However, no consensus has been reached on its clinicopathological and prognostic significance in patients with non-small cell lung cancer (NSCLC). Therefore, we performed this systematic meta-analysis to help addressing this issue. PubMed, EMBASE, the Web of Science and China National Knowledge Infrastructure were searched for full-text literatures met out eligibility criteria. We determined the odds ratio (OR) and hazard ratio (HR) as the appropriate summarized statistics for assessments of clinicopathological and prognostic roles of HSP27, respectively. Q-test and I(2)-statistic were used to evaluate the level of heterogeneity. Sensitivity analysis was conducted to examine the stability of overall estimates. Potential publication bias was detected by Begg's test and Egger's test. Finally, ten articles were identified to be included into our meta-analysis. The pooled analyses suggested that HSP27 expression was significantly associated with the unfavorable conditions for differentiation degree, lymphatic metastasis, clinical stage, squamous cell carcinoma and tumor size. However, HSP27 expression had no significant relationship to gender, age and smoking status. Meanwhile, pooled HRs indicated that HSP27 expression could be a predictor for a lower 5-year overall survival (OS) rate (HR: 1.832; 95 % CI 1.322-2.538; P < 0.001) but not for 1-year OS of NSCLC (HR: 0.885; 95 % CI 0.140-5.599; P = 0.896). In conclusion, our meta analysis demonstrates that HSP27 expression may be a strong biomarker to predict both the poor clinicopathological and prognostic characteristics in patients with NSCLC. PMID- 27512625 TI - Modelling and simulation of wood chip combustion in a hot air generator system. AB - This study focuses on modelling and simulation of horizontal moving bed/grate wood chip combustor. A standalone finite volume based 2-D steady state Euler Euler Computational Fluid Dynamics (CFD) model was developed for packed bed combustion. Packed bed combustion of a medium scale biomass combustor, which was retrofitted from wood log to wood chip feeding for Tea drying in Sri Lanka, was evaluated by a CFD simulation study. The model was validated by the experimental results of an industrial biomass combustor for a hot air generation system in tea industry. Open-source CFD tool; OpenFOAM was used to generate CFD model source code for the packed bed combustion and simulated along with an available solver for free board region modelling in the CFD tool. Height of the packed bed is about 20 cm and biomass particles are assumed to be spherical shape with constant surface area to volume ratio. Temperature measurements of the combustor are well agreed with simulation results while gas phase compositions have discrepancies. Combustion efficiency of the validated hot air generator is around 52.2 %. PMID- 27512626 TI - A retrospective evaluation of preoperative anemia in patients undergoing radical cystectomy for muscle-invasive urothelial urinary bladder cancer, with or without neoadjuvant chemotherapy. AB - BACKGROUND AND OBJECTIVE: Neoadjuvant chemotherapy (NAC) can be associated with anemia, which can lead to more perioperative blood transfusions (PBT). Usage of PBT is associated with worse oncological outcomes. We evaluated the prevalence of preoperative anemia (PA) and the effect on hemoglobin levels depending on surgery timing after NAC. METHODS: A retrospective single-center study with 240 consecutive patients undergoing radical cystectomy (RC) between 2001 and 2014 for muscle-invasive urothelial carcinoma (MIBC). Anemia was defined according to the WHO classification (male <= 130 g/L, female <= 120 g/L). Multivariable logistical regression was used to identify factors associated with PA and Pearson correlation for evaluating the change in hemoglobin levels depending on surgery timing. RESULTS: Overall, 128 (53.3 %) patients were anemic pre-RC and 87 (36.3 %) patients received NAC. In a multivariable analysis, age, receipt of NAC, female gender, and low BMI were independent predictors of PA. In patients receiving NAC, the time to surgery from the last NAC cycle was correlated with the change in hemoglobin levels between the initiation of NAC and surgery. CONCLUSIONS: PA was common in patients undergoing RC for MIBC. Receipt of NAC was found to be a strong predictor of PA. CLINICAL MESSAGE: The emerging treatment of cisplatin based neoadjuvant chemotherapy for muscle-invasive bladder cancer, confers an increased risk for preoperative anemia. In the management of this malignancy, preoperative anemia renders further attention and focus. PMID- 27512627 TI - Experimental study of thermal comfort on stab resistant body armor. AB - PURPOSE: This research aims to investigate the impacts of exercise intensity and sequence on human physiology parameters and subjective thermal sensation when wearing stab resistant body armor under daily working conditions in China [26 and 31 degrees C, 45-50 % relative humidity (RH)], and to investigate on the relationship between subjective judgments and objective parameters. METHODS: Eight male volunteers were recruited to complete 3 terms of exercises with different velocity set on treadmill for 90 min at 26 degrees C and 31 degrees C, 45-50 % RH. In Exercise 1 volunteers were seated during the test. In Exercise 2, volunteers walked with the velocity of 3 km/h in the first 45 min and 6 km/h in the left 45 min. In Exercise 3, volunteers walked with the velocity of 6 km/h in the first 45 min and 3 km/h in the left 45 min. The body core temperature, skin temperature and subjective judgments were recorded during the whole process. Analysis of variance was performed among all the tests. RESULTS: Individual discrepancy of Exercise 1 is larger than that of Exercise 2 and 3. On the premise of the same walking distance and environmental conditions, core temperature in Exercise 3 is about 0.2 degrees C lower than that in Exercise 2 in the end; and with the velocity decrease from 6 km/h to 3 km/h in the end, thermal tolerance of Exercise 3 is about 1 degree lower than that in Exercise 2. Skin temperatures of human trunk were at least 1 degrees C higher than that of limbs. CONCLUSIONS: Activity narrows the individual discrepancy on core temperature. Within experimental conditions, decreasing of intensity at last stage makes the core temperature lower and the whole process much tolerable. The core temperature is more sensitive to the external disturbance on the balance of the whole body, and it can reflect the subjective thermal sensation and physical exertion. PMID- 27512628 TI - Spectrophotometric determination of Cu(II) in soil and vegetable samples collected from Abraha Atsbeha, Tigray, Ethiopia using heterocyclic thiosemicarbazone. AB - Two selective and sensitive reagents, 2-acetylpyridine thiosemicarbazone (2-APT) and 3-acetylpyridine thiosemicarbazone (3-APT) were used for the spectrophotometric determination of Cu(II). Both reagents gave yellowish Cu(II) complex at a pH range of 8.0-10.0. Beer's law was obeyed for Cu(II)-2-APT and Cu(II)-3-APT in the concentration range of 0.16-1.3 and 0.44-1.05 ug/mL, respectively. The molar absorptivity and of Cu(II)-2-APT and Cu(II)-3-APT were 2.14 * 10(4) at 370 nm, and 6.7 * 10(3) L/mol cm at 350 nm, respectively, while the Sandell's sensitivity were 0.009 and 0.029 ug/cm(2) in that order. The correlation coefficient of the standard curves of Cu(II)-2-APT and Cu(II)-3-APT were 0.999 and 0.998, respectively. The detection limit of the Cu(II)-2-APT and Cu(II)-3-APT methods were 0.053 and 0.147 ug/mL, respectively. The results demonstrated that the procedure is precise (relative standard deviation <2 %, n = 10). The method was tested for Cu(II) determination in soil and vegetable samples. Comparisons of the results with those obtained using a flame atomic absorption spectrophotometer for Cu(II) determination also tested the validity of the method using paired sample t test at the 0.05 level showing a good agreement between them. PMID- 27512629 TI - A new point of view for mosaicplasty in the treatment of focal cartilage defects of knee joint: honeycomb pattern. AB - BACKGROUND: A focal full thickness cartilage lesion of knee joint is one of the commonly seen intraarticular pathologies among the joint cartilage problems. Osteochondral autograft transfer mosaicplasty is a method which has satisfactory outcomes among the treatment preferences of cartilage defects. In spite of the favorable clinical results there are some pitfalls of mosaicplasty treatment especially in cases of large defects. One of the major problems of the classical OAT mosaicplasty is the gap spaces between the plugs. The objective of the present study is to report the early clinical and radiological outcomes and to evaluate the clinical application of a new hexagonal osteochondral graft system (HOGS) with the hypothesis of improvement of the OAT mosaicplasty method with the use of hexagonally shaped plugs. The study has intended to answer two questions. (1) Does mosaicplasty with the new HOGS has favorable early clinical outcomes? (2) Is it possible to arrange the osteochondral autografts without leaving gap spaces by using hexagonal pattern in OAT mosaicplasty? PATIENTS AND METHODS: We designed a retrospective study to report analysis of early outcomes of the initial case series of OAT mosaicplasty by using a new HOGS. Six male individuals with the diagnosis of osteochondral defect and treated with HOGS and reached sixth month follow-up formed the basis of the study. The clinical status of the patients were evaluated with IKDC score. The radiological evaluations were carried out with direct X-rays and magnetic resonance imaging (MRI) studies. The mosaicplasty procedures were carried out via standard surgical method of classical OAT mosaicplasty by using the HOGS following a diagnostic arthroscopy in the same session. The inclusion criteria was a full thickness osteochondral lesion of femoral condyle between 1.5 and 6 cm(2) and completion of 6 month follow-ups. The patients having deformities around the knee or major ligament lesions were excluded. MOCART scoring system was used for the evaluation of follow-up MRI findings. The clinical status of the patients were evaluated with IKDC scores. RESULTS: The mean age of the patients was 40.8 (+/-5.2) years and the mean duration of the symptoms on presentation was 16 (+/-4.3) months. On the initial MRI studies mean defect area was measured 3.7 cm(2) (+/-0.9) which was compatible with arthroscopic findings. During the surgical procedures it was possible to fill the defect area completely. The mean number of plugs in this series was 4.8 (+/-1.1). We did not faced with insufficient donor reserve problem in any of the cases. On the sixth month follow-up physical examination there was no limitation of the knee joint range of motion in the cases. All patients were able to bear weight on to their operated extremities without pain. The mean postoperative IKDC score improvement was 70.2 (+/-3.5) which shows significant improvement compared to preoperative scores. On the control MRI studies the bone integration of the hexagonal plugs were complete the cartilage continuity of the articular surfaces were intact and the grafts were well incorporated in all cases. The mean MOCART score on the 6th month MRI studies was 65.8 (+/-4.1). CONCLUSION: The early outcomes of OAT mosaicplasty with HOGS are comparable to studies on the classical mosaicplasty. According to our observations in this study we can say that the gap space left between the cylindrical plugs can be solved by using hexagonal prism shaped plugs. PMID- 27512630 TI - Characterizing and explaining spatio-temporal variation of water quality in a highly disturbed river by multi-statistical techniques. AB - Assessing the spatio-temporal variations of surface water quality is important for water environment management. In this study, surface water samples are collected from 2008 to 2015 at 17 stations in the Ying River basin in China. The two pollutants i.e. chemical oxygen demand (COD) and ammonia nitrogen (NH3-N) are analyzed to characterize the river water quality. Cluster analysis and the seasonal Kendall test are used to detect the seasonal and inter-annual variations in the dataset, while the Moran's index is utilized to understand the spatial autocorrelation of the variables. The influence of natural factors such as hydrological regime, water temperature and etc., and anthropogenic activities with respect to land use and pollutant load are considered as driving factors to understand the water quality evolution. The results of cluster analysis present three groups according to the similarity in seasonal pattern of water quality. The trend analysis indicates an improvement in water quality during the dry seasons at most of the stations. Further, the spatial autocorrelation of water quality shows great difference between the dry and wet seasons due to sluices and dams regulation and local nonpoint source pollution. The seasonal variation in water quality is found associated with the climatic factors (hydrological and biochemical processes) and flow regulation. The analysis of land use indicates a good explanation for spatial distribution and seasonality of COD at the sub catchment scale. Our results suggest that an integrated water quality measures including city sewage treatment, agricultural diffuse pollution control as well as joint scientific operations of river projects is needed for an effective water quality management in the Ying River basin. PMID- 27512631 TI - KRAS, GNAS, and RNF43 mutations in intraductal papillary mucinous neoplasm of the pancreas: a meta-analysis. AB - BACKGROUND: The prevalence and clinical significances of KRAS, GNAS, and RNF43 mutations in patients with pancreatic intraductal papillary mucinous neoplasm (IPMN) remain elusive. To evaluate the incidence of the gene mutations and clinicopathologic differences between KRAS and GNAS mutations in pancreatic cystic lesions, we performed a meta-analysis of published 33 KRAS, 11 GNAS, and 4 RNF43 studies including 1253, 835, and 143 cases, respectively. METHODS: We pooled the results of relevant studies identified using the PubMed and EMBASE databases. The effect sizes of outcome parameters were computed by the prevalence rate, weighted mean difference, or odds ratio (OR) using a random-effects model. RESULTS: The pooled prevalence of KRAS, GNAS, and RNF43 mutations in IPMN was 61, 56, and 23 %, respectively. The KRAS (OR 7.4 and 71.2) and GNAS (OR 30.2 and 15.3) mutations were more frequently found in IPMNs than in mucinous cystic neoplasms and in serous cystadenomas, respectively. Of the microscopic subtypes of IPMN, KRAS and GNAS were frequently mutated in gastric type (OR 2.7, P < 0.001) and intestinal type (OR 3.0, P < 0.001), respectively. KRAS mutation was infrequently found in high-grade dysplasia lesions of IPMN (OR 0.6, P = 0.032). GNAS mutation was associated with male (OR 1.9, P = 0.012). CONCLUSIONS: This meta-analysis supports that KRAS and GNAS mutations could be diagnostic markers for IPMN. In addition, the frequencies of KRAS and GNAS mutations in IPMNs are highly variable according to the microscopic duct subtypes, reflecting their independent roles in the IPMN-adenocarcinoma sequence. PMID- 27512632 TI - Vegetation greenness modelling in response to interannual precipitation and temperature changes between 2001 and 2012 in Liao River Basin in Jilin Province, China. AB - BACKGROUND: Liao River basin in Jilin Province is the place of origin of the Dongliao River. This study gives a comprehensive analysis of the vegetation coverage in the region and provides a potential theoretical basis for ecological restoration. METHODS: The seasonal variation of vegetation greenness and dynamics based on the Normalized Difference Vegetation Index (NDVI) in major land cover types in the region was studied. Analyzing the relationship NDVI, temperature and rainfall, we derived a set of predictor variables from 2001 to 2012 using the MODIS Terra level 1 Product (MOD02QKM). RESULTS: The results showed a general increasing trend in NDVI value in the region, while 34.63 % of the region showed degradation. NDVI values begin to rise from April when plants are regreening and they drop in September when temperature are decreasing and the leaves are falling in the study area and temperature was found decreasing during the period of 2001 2012 while rainfall showed an increasing trend. This model could be used to observe the change in vegetation greenness and the dynamic effects of temperature and rainfall. CONCLUSION: This study provided important data for the environmental protection of the basin area. And we hope to provide scientific analysis for controlling water and soil erosion, maintaining the sustainable productivity of land resources, enhancing the treatment of water pollution and stimulating the virtuous cycle of the ecological system. PMID- 27512633 TI - Viewing biodiversity through the lens of science...and art! AB - With global environmental sustainability at the crossroads, approaches are needed to build an ecologically literate culture for collective societal navigation through the intricacies of swift environmental change. This paper demonstrates a transdisciplinary approach, grounded at the intersection between the arts and sciences, to increase awareness and understanding of the current biodiversity crisis. It focuses on one aspect of biodiversity, beta diversity, which examines how sets of animal and plant species differ between habitats. Theory and real examples of beta diversity of aquatic animal and plant species from dried-out ponds in Mediterranean Spain are presented in pixelized visuals. These visuals are artistic expression of and build the prior knowledge about beta diversity, which is scrutinized subsequently with statistical analyses to support the artistic approach with an objectively identified and numerically underpinned presentation of structure in the visuals. The choice to examine beta diversity in theory and reality first through art and then through science is deliberate. Combined, these aspects examine biodiversity through an eco-centric, rather than a species- and habitat centric view, incorporate elements of surprise (how can aquatic species in dry ecosystems survive), and reduce uncertainty (by providing a common numerical yardstick for interpreting the visuals). Together they can optimize a goal-directed learning process in the viewers necessary for making judgments, inducing affective reactions, and facilitating memory and decision making. The approach presented here provides an integral qualitative and quantitative model useful for a broader inductive-deductive education process towards finding sustainable solutions as our planet moves swiftly to a future without historical analogue. Combined art-sciences approaches, as the one presented here, are useful to facilitate citizens' comprehension of the scientific and potential policy dimensions of environmental change, including biodiversity problems, especially because it is the general public that bears the costs of transformation and adaptation measures. PMID- 27512634 TI - Intelligent decision support algorithm for distribution system restoration. AB - Distribution system is the means of revenue for electric utility. It needs to be restored at the earliest if any feeder or complete system is tripped out due to fault or any other cause. Further, uncertainty of the loads, result in variations in the distribution network's parameters. Thus, an intelligent algorithm incorporating hybrid fuzzy-grey relation, which can take into account the uncertainties and compare the sequences is discussed to analyse and restore the distribution system. The simulation studies are carried out to show the utility of the method by ranking the restoration plans for a typical distribution system. This algorithm also meets the smart grid requirements in terms of an automated restoration plan for the partial/full blackout of network. PMID- 27512635 TI - Covariance and crossover matrix guided differential evolution for global numerical optimization. AB - Differential evolution (DE) is an efficient and robust evolutionary algorithm and has wide application in various science and engineering fields. DE is sensitive to the selection of mutation and crossover strategies and their associated control parameters. However, the structure and implementation of DEs are becoming more complex because of the diverse mutation and crossover strategies that use distinct parameter settings during the different stages of the evolution. A novel strategy is used in this study to improve the crossover and mutation operations. The crossover matrix, instead of a crossover operator and its control parameter CR, is proposed to implement the function of the crossover operation. Meanwhile, Gaussian distribution centers the best individuals found in each generation based on the proposed covariance matrix, which is generated between the best individual and several better individuals. Improved mutation operator based on the crossover matrix is randomly selected to generate the trial population. This operator is used to generate high-quality solutions to improve the capability of exploitation and enhance the preference of exploration. In addition, the memory population is randomly chosen from previous generation and used to control the search direction in the novel mutation strategy. Accordingly, the diversity of the population is improved. Thus, CCDE, which is a novel efficient and simple DE variant, is presented in this paper. CCDE has been tested on 30 benchmarks and 5 real-world optimization problems from the IEEE Congress on Evolutionary Computation (CEC) 2014 and CEC 2011, respectively. Experimental and statistical results demonstrate the effectiveness of CCDE for global numerical and engineering optimization. CCDE can solve the test benchmark functions and engineering problems more successfully than the other DE variants and algorithms from CEC 2014. PMID- 27512636 TI - Non-stationary component extraction in noisy multicomponent signal using polynomial chirping Fourier transform. AB - Inspired by track-before-detection technology in radar, a novel time-frequency transform, namely polynomial chirping Fourier transform (PCFT), is exploited to extract components from noisy multicomponent signal. The PCFT combines advantages of Fourier transform and polynomial chirplet transform to accumulate component energy along a polynomial chirping curve in the time-frequency plane. The particle swarm optimization algorithm is employed to search optimal polynomial parameters with which the PCFT will achieve a most concentrated energy ridge in the time-frequency plane for the target component. The component can be well separated in the polynomial chirping Fourier domain with a narrow-band filter and then reconstructed by inverse PCFT. Furthermore, an iterative procedure, involving parameter estimation, PCFT, filtering and recovery, is introduced to extract components from a noisy multicomponent signal successively. The Simulations and experiments show that the proposed method has better performance in component extraction from noisy multicomponent signal as well as provides more time-frequency details about the analyzed signal than conventional methods. PMID- 27512637 TI - Sufficient conditions for oscillation of a nonlinear fractional nabla difference system. AB - In this paper, we study the oscillation of nonlinear fractional nabla difference equations of the form [Formula: see text]where c and alpha are constants, [Formula: see text] is the Riemann-Liouville fractional nabla difference operator of order [Formula: see text] is a real number, and [Formula: see text]. Some sufficient conditions for oscillation are established. PMID- 27512638 TI - Crowd behavior representation: an attribute-based approach. AB - In crowd behavior studies, a model of crowd behavior needs to be trained using the information extracted from video sequences. Most of the previous methods are based on low-level visual features because there are only crowd behavior labels available as ground-truth information in crowd datasets. However, there is a huge semantic gap between low-level motion/appearance features and high-level concept of crowd behaviors. In this paper, we tackle the problem by introducing an attribute-based scheme. While similar strategies have been employed for action and object recognition, to the best of our knowledge, for the first time it is shown that the crowd emotions can be used as attributes for crowd behavior understanding. We explore the idea of training a set of emotion-based classifiers, which can subsequently be used to indicate the crowd motion. In this scheme, we collect a large dataset of video clips and provide them with both annotations of "crowd behaviors" and "crowd emotions". We test the proposed emotion based crowd representation methods on our dataset. The obtained promising results demonstrate that the crowd emotions enable the construction of more descriptive models for crowd behaviors. We aim at publishing the dataset with the article, to be used as a benchmark for the communities. PMID- 27512639 TI - Effect of skin infiltration with ropivacaine on postoperative pain in patients undergoing craniotomy. AB - BACKGROUND: Local anesthetic infiltration has been used to manage postoperative pain in various surgeries. The present study was aimed to investigate the effect of skin infiltration with 0.5 % ropivacaine on postoperative pain in patients undergoing craniotomy. METHODS: One hundred and six patients with ASA I/II scheduled to undergo elective craniotomy were enrolled during March to November in 2015 in this prospective, randomized, placebo-controlled, double-blind study. After the anesthesia induction, skin along the incision was infiltrated with 0.5 % ropicavaine (group R, n = 53) or 0.9 % normal saline (group C, n = 53), respectively. Morphine was used as rescue analgesic postoperatively. Morphine consumption during the first 24 postoperative hours was recorded as the primary outcome, and the time to first rescue requirement was also recorded. Pain was assessed at 2, 4, 8, 24 h, 7 days, 3 months after surgery by visual analog scale (VAS). Heart rate and mean arterial pressure were recorded before anesthesia induction (T1), after anesthesia induction (T2), after scalp infiltration (T3), during skull drilling (T4), mater cutting (T5) and skin closure (T6). RESULTS: Morphine consumption during the first 24 postoperative hours was significantly higher in group C than in group R (13.36 [6.5, 20] vs. 6.3 [0, 10] mg, P < 0.05). The first time of patients needed rescue analgesic was prolonged in group R as compared with group C (6.16 [3.4, 8.0] vs. 3.87 [2.3, 4] h, P < 0.05). Postoperative VAS and hemodynamic signs during the first 24 h showed no significant difference in two groups. The incidence of persistent pain on 7 days and 3 months postoperatively had no significant differences between two groups. Besides one patient (2 %) enduring moderate pain (VAS 4-7) in group C, the number of patients suffering from mild pain (VAS 1-3) was 17 (33.3 %) in group R and 17 (34 %) in group C 3 months after surgery. CONCLUSION: The results suggest 0.5 % ropivacaine scalp infiltration before skin incision has favorable analgesic effect in reducing morphine consumption and prolong the time of first rescue analgesic requirement after surgery. Trial registration Chinese Clinical Trial Registry (http://www.chictr.org.cn/) registration number: ChiCTR-IPR-14005717. PMID- 27512640 TI - A novel mutation in the CDH1 gene in a Spanish family with hereditary diffuse gastric cancer. AB - Hereditary diffuse gastric cancer (HDGC) is an inherited form of diffuse type gastric cancer. Germline CDH1 mutations have been identified in approximately 15 50 % of affected kindred that meet the clinical criteria for HDGC. If any of the criteria is met the individual is referred to genetic counseling and CDH1 testing is offered. In this report we present the case of a Spanish family with HDGC harboring a novel CDH1 mutation. A 47 year-old female with a diagnostic of gastric adenocarcinoma and some of her relatives were tested. Study of the entire CDH1 gene, including intron-exon boundaries, by PCR and sequencing and immunohistochemical determination of the expression of E-cadherin were performed. A novel heterozygous deletion in exon 9 of CDH1 gene (c.1220_1220delC, p.P407Qfs10), was found in the proband, one sister and a nephew. It generates a premature stop codon giving rise to a truncated protein that leads to a pathogenic variant. Expression of E-cadherin was absent or frankly reduced in the proband's tumor but normal in tumor cells of great-uncle. After these results, the sister underwent prophylactic total gastrectomy, and the nephew is under annual endoscopic surveillance. Personal or familial history of diffuse gastric cancer, above all at young age, should encourage CDH1 genetic testing. In this sense, the review of the criteria and the addition in the last guideline of the recommendation: "other families in which genetic testing may also be considered" broadens the number of individuals at risk detected. Since there are not reliable methods for early detection, DGC is usually diagnosed at an advanced stage and consequently associated with a poorer outcome. Thus, CDH1 mutations detection contributes to an improvement in diagnosis and therapeutic intervention. PMID- 27512641 TI - Remediation of copper contaminated soil by using different particle sizes of apatite: a field experiment. AB - The particle size of apatite is one of the critical factors that influence the adsorption of heavy metals on apatite in the remediation of heavy metal contaminated soils using apatite. However, little research has been done evaluating the impact of different particle sizes of apatite on immobilization remediation of heavy metal polluted soils in field. In this study, the adsorption isothermal experiments of copper on three kinds of apatite was tested, and the field experiment by using different particle sizes apatite [nano-hydroxyapatite (NAP), micro-hydroxyapatite (MAP), ordinary particle apatite (OAP)] at a same dosage of 25.8 t/ha (1.16 %, W/W) was also conducted. Ryegrass was chosen as the test plant. The ryegrass biomass, the copper contents in ryegrass and the copper fractionations in soil were determined after field experiments. Results of adsorption experiments showed that the adsorption amounts of copper on OAP was the lowest among different particles. The adsorption amounts of copper on MAP was higher than NAP at high copper equilibrium concentration (>1 mmol L(-1)), an opposite trend was obtained at low copper concentration (<1 mmol L(-1)). In the field experiment, we found that the application of different apatites could effectively increase the soil pH, decrease the available copper concentration in soil, provide more nutrient phosphate and promote the growth of ryegrass. The ryegrass biomass and the copper accumulation in ryegrass were the highest in MAP among all treatments. The effective order of apatite in phytoremediation of copper contaminated field soil was MAP > NAP > OAP, which was attributed to the high adsorption capacity of copper and the strong releasing of phosphate by MAP. PMID- 27512642 TI - Linguistic research in the empirical paradigm as outlined by Mario Bunge. AB - In view of the critique of the methodology of the dominant interdisciplinary research involving language studies as the main component, in particular clinical linguistics, Cummings (Pragmatic disorders. Perspectives in pragmatics, philosophy and psychology, vol 3. Springer, Dordrecht, 2014) proposes that "It is perhaps appropriate at this point to move the debate onto non-empirical grounds." In Cummings (2014: 113) she starts such a debate on the grounds of the philosophy of language and pragmatics. In this article, I propose to expand that debate by including the input of the philosophy of science. I start the discussion by presenting the way one may carry out language research in the paradigm of empirical sciences from the perspective outlined in Bunge (Scientific research. Strategy and philosophy. Berlin, Springer, 1967; Method, model and matter (synthese library). D. Reidel Publishing Company, Dordrecht, 1973; Emergence and convergence: qualitative novelty and the unity of knowledge. University of Toronto Press, Toronto, 2003) and constrained by Altmann's (Towards a theory of language. Glottometrica 1:1-25, 1978) assumption about self-originating and self regulatory nature of language. PMID- 27512643 TI - Novel technique of vulvo-vaginal rejuvenation by lipofilling and injection of combined platelet-rich-plasma and hyaluronic acid: a case-report. AB - BACKGROUND: To describe a new surgical procedure and its results: the vulvo vaginal rejuvenation by lipofilling and an injection of combined platelet-rich plasma (PRP) and hyaluronic acid (HA). Sexual life for women is affected by the effect of aging and by post partum traumatism. There are no standard non-invasive treatments to offer to improve the trophic and dimensional alterations of the vulvo-vaginal area. The surgical procedure consists in a vaginoplasty by lipofilling of the posterior vaginal wall far from the vascular axes and with an injection of an injection of combined PRP and HA subcutaneously in the perineum. To illustrate the technique and evaluate its results, we present the case of a 39 year-old-female with history of episiotomy presented that vaginal laxity resistant to physical therapy. To assess the results regarding the sexual quality of life we used the modified Stabbatsberg self-rating scale. FINDINGS: There were no intra-operative complications with this simple procedure. During follow-up we observed an improvement in the modified Stabbatsberg scale and a vulvo-perineal rejuvenation by improving the vaginal trophicity and restoring a normal vaginal caliber. No post-operative complications occurred. CONCLUSIONS: Vulvo-vaginal rejuvenation lipofilling and an injection of combined platelet-rich-plasma and hyaluronic acid is a minimally invasive technique that is safe and easy to perform. Further studies are necessary to assess more thoroughly the effectiveness and safety of this procedure and assess medium and long term results. PMID- 27512644 TI - Vertebra segmentation based on two-step refinement. AB - Knowledge of vertebra location, shape, and orientation is crucial in many medical applications such as orthopedics or interventional procedures. Computed tomography (CT) offers a high contrast between bone and soft tissues, but automatic vertebra segmentation remains difficult. Hence, the wide range of shapes, aging, and degenerative joint disease alterations as well as the variety of pathological cases encountered in an aging population make automatic segmentation sometimes challenging. Besides, daily practice implies a need for affordable computation time. This paper aims to present a new automated vertebra segmentation method (using a first bounding box for initialization) for CT 3D data which tackles these problems. This method is based on two consecutive steps. The first one is a new coarse-to-fine method efficiently reducing the data amount to obtain a coarse shape of the vertebra. The second step consists in a hidden Markov chain (HMC) segmentation using a specific volume transformation within a Bayesian framework. Our method does not introduce any prior on the expected shape of the vertebra within the bounding box and thus deals with the most frequent pathological cases encountered in daily practice. We experiment this method on a set of standard lumbar, thoracic, and cervical vertebrae and on a public dataset, on pathological cases, and in a simple integration example. Quantitative and qualitative results show that our method is robust to changes in shapes and luminance and provides correct segmentation with respect to pathological cases. PMID- 27512645 TI - AprilTag array-aided extrinsic calibration of camera-laser multi-sensor system. AB - This paper presents a new algorithm for extrinsically calibrating a multi-sensor system including multiple cameras and a 2D laser scanner. On the basis of the camera pose estimation using AprilTag, we design an AprilTag array as the calibration target and employ a nonlinear optimization to calculate the single camera extrinsic parameters when multiple tags are in the field of view of the camera. The extrinsic parameters of camera-camera and laser-camera are then calibrated, respectively. A global optimization is finally used to refine all the extrinsic parameters by minimizing a re-projection error. This algorithm is adapted to the extrinsic calibration of multiple cameras even if there is non overlapping field of view. For algorithm validation, we have built a micro-aerial vehicle platform with multi-sensor system to collect real data, and the experiment results confirmed that the proposed algorithm yields great performance. PMID- 27512646 TI - Viscoelasticity of periodontal ligament: an analytical model. AB - BACKGROUND: Understanding of viscoelastic behaviour of a periodontal membrane under physiological conditions is important for many orthodontic problems. A new analytic model of a nearly incompressible viscoelastic periodontal ligament is suggested, employing symmetrical paraboloids to describe its internal and external surfaces. METHODS: In the model, a tooth root is assumed to be a rigid body, with perfect bonding between its external surface and an internal surface of the ligament. An assumption of almost incompressible material is used to formulate kinematic relationships for a periodontal ligament; a viscoelastic constitutive equation with a fractional exponential kernel is suggested for its description. RESULTS: Translational and rotational equations of motion are derived for ligament's points and special cases of translational displacements of the tooth root are analysed. Material parameters of the fractional viscoelastic function are assessed on the basis of experimental data for response of the periodontal ligament to tooth translation. A character of distribution of hydrostatic stresses in the ligament caused by vertical and horizontal translations of the tooth root is defined. CONCLUSIONS: The proposed model allows generalization of the known analytical models of the viscoelastic periodontal ligament by introduction of instantaneous and relaxed elastic moduli, as well as the fractional parameter. The latter makes it possible to take into account different behaviours of the periodontal tissue under short- and long-term loads. The obtained results can be used to determine loads required for orthodontic tooth movements corresponding to optimal stresses, as well as to simulate bone remodelling on the basis of changes in stresses and strains in the periodontal ligament caused by such movements. PMID- 27512647 TI - Medical Care for Swimmers. AB - Swimming is one of the most popular sports worldwide. Competitive swimming is one of the most watched sports during the Olympic Games. Swimming has unique medical challenges as a result of a variety of environmental and chemical exposures. Musculoskeletal overuse injuries, overtraining, respiratory problems, and dermatologic conditions are among the most common problems swimmers encounter. Although not unique to swimming, overtraining is a serious condition which can have significant negative impact on swimmers' health and performance. This review article is an attempt to discuss various issues that a medical team should consider when caring for swimmers. PMID- 27512648 TI - Dissecting asthma pathogenesis through study of patterns of cellular traffic indicative of molecular switches operative in inflammation. AB - BACKGROUND: Inflammation and degeneration are the two edged swords that impale a pulmonary system with the maladies like asthma and idiopathic pulmonary fibrosis. To explore critical role players that orchestrate the etiology and pathogenesis of these diseases, we used various lung disease models in mice in specific genetic knockout templates. MATERIALS AND METHODS: Acute and chronic allergic asthma and idiopathic pulmonary fibrosis model in mouse was developed in various genetic knockout templates namely alpha4Delta/ Delta(alpha41-/-), beta2-/-, and alpha4-/- beta2 mice, and the following parameters were measured to assess development of composite asthma phenotype- (i) airway hyperresponsiveness to methacholine by measuring lung resistance and compliance by invasive and Penh by non-invasive plethysmography as well as lung resistance and compliance using invasive plethysmography, (ii) in situ inflammation status in lung parenchyma and lung interstitium and also resultant airway remodelling measured by histochemical staining namely Masson's Trichrome staining and Hematoxylin&Eosin staining, (iii) formation of metaplastic goblet cells around lung airways by Alcian blue dye, (iv) measurement of Th1 and Th2 cytokines in serum and bronchoalveolar lavage fluid (BALf), (v) serum allergen-specific IgE. Specifically, ovalbumin-induced acute allergic asthma model in mice was generated in WT (wildtype) and KO (knockout) models and readouts of the composite asthma phenotype viz. airway hypersensitivity, serum OVA-specific IgE and IgG, Th2 cytokine in bronchoalveolar lavage fluid (BALf) and lymphocyte cell subsets viz. T, B cells, monocytes, macrophages, basophils, mast cells and eosinophils (by FACS and morphometry in H&E stained cell smears) were assessed in addition to lung and lymph node histology. RESULTS: We noticed a pattern of cellular traffic between bone marrow (BM)-> peripheral blood (PB) -> lung parenchyma (LP) -> (BALf) in terms of cellular recruitment of key cell sub-types critical for onset and development of the diseases which is different for maintenance and exacerbations in chronic cyclically occurring asthma that leads to airway remodelling. While inflammation is the central theme of this particular disease, degeneration and shift in cellular profile, subtly modifying the clinical nature of the disease were also noted. In addition we recorded the pattern of cell movement between the secondary lymphoid organs namely, the cervical, axillary, ingunal, and mesenteric lymph nodes vis-a-vis spleen and their sites of poiesis BM, PB and lung tissue. While mechanistic role is the chief domain of the integrins (alpha4 i.e. VLA-4 or alpha4beta1, VCAM-1; beta2 i.e. CD18 or ICAM-1). CONCLUDING REMARKS: The present paper thoroughly compares and formulates the pattern of cellular traffic among the three nodes of information throughput in allergic asthma immunobiology, namely, primary lymphoid organs (PLO), secondary lymphoid organs (SLO), and tissue spaces and cells where inflammation and degeneration is occurring within the purview of the disease pathophysiological onset and ancillary signals in the above models and reports some interesting findings with respect to adult lung stem cell niches and its resident progenitors and their role in pathogenesis and disease amelioration. PMID- 27512649 TI - Partnerships between the faith-based and medical sectors: Implications for preventive medicine and public health. AB - Interconnections between the faith-based and medical sectors are multifaceted and have existed for centuries, including partnerships that have evolved over the past several decades in the U.S. This paper outlines ten points of intersection that have engaged medical and healthcare professionals and institutions across specialties, focusing especially on primary care, global health, and community based outreach to underserved populations. In a time of healthcare resource scarcity, such partnerships-involving religious congregations, denominations, and communal and philanthropic agencies-are useful complements to the work of private sector medical care providers and of federal, state, and local public health institutions in their efforts to protect and maintain the health of the population. At the same time, challenges and obstacles remain, mostly related to negotiating the complex and contentious relations between these two sectors. This paper identifies pressing legal/constitutional, political/policy, professional/jurisdictional, ethical, and research and evaluation issues that need to be better addressed before this work can realize its full potential. PMID- 27512650 TI - A brief measure of Smokers' knowledge of lung cancer screening with low-dose computed tomography. AB - We describe the development and psychometric properties of a new, brief measure of smokers' knowledge of lung cancer screening with low-dose computed tomography (LDCT). Content experts identified key facts smokers should know in making an informed decision about lung cancer screening. Sample questions were drafted and iteratively refined based on feedback from content experts and cognitive testing with ten smokers. The resulting 16-item knowledge measure was completed by 108 heavy smokers in Houston, Texas, recruited from 12/2014 to 09/2015. Item difficulty, item discrimination, internal consistency and test-retest reliability were assessed. Group differences based upon education levels and smoking history were explored. Several items were dropped due to ceiling effects or overlapping constructs, resulting in a 12-item knowledge measure. Additional items with high item uncertainty were retained because of their importance in informed decision making about lung cancer screening. Internal consistency reliability of the final scale was acceptable (KR-20 = 0.66) and test-retest reliability of the overall scale was 0.84 (intraclass correlation). Knowledge scores differed across education levels (F = 3.36, p = 0.04), while no differences were observed between current and former smokers (F = 1.43, p = 0.24) or among participants who met or did not meet the 30-pack-year screening eligibility criterion (F = 0.57, p = 0.45). The new measure provides a brief, valid and reliable indicator of smokers' knowledge of key concepts central to making an informed decision about lung cancer screening with LDCT, and can be part of a broader assessment of the quality of smokers' decision making about lung cancer screening. PMID- 27512651 TI - The Office Guidelines Applied to Practice program improves secondary prevention of heart disease in Federally Qualified Healthcare Centers. AB - The burden of cardiovascular disease (CVD) among minority and low-income populations is well documented. This study aimed to assess the impact of patient activation and shared decision-making (SDM) on medication use through the Office Guidelines Applied to Practice (Office-GAP) intervention in Federally Qualified Healthcare Centers (FQHCs). Patients (243) with diabetes and CHD participated in Office-GAP between October 2010 and March 2014. Two-site (FQHCs) intervention/control design. Office-GAP integrates health literacy, communication skills education for patients and physicians, decision support tools, and SDM into routine care. MAIN MEASURES: 1) implementation rates, 2) medication use at baseline, 3, 6, and 12 months, and 3) predictors of medication use. Logistic regression with propensity scoring assessed impact on medication use. Intervention arm had 120 and control arm had 123 patients. We found that program elements were consistently used. Compared to control, the Office-GAP program significantly improved medications use from baseline: ACEIs or ARBs at 3 months (OR 1.88, 95% CI = 1.07; 3.30, p < 0.03), 6 months (OR 2.68, 95% CI = 1.58;4.54; p < 0.01); statin at 3 months (OR 2.00, 95% CI = 0.1.22; 3.27; p < 0.05), 6 months (OR 3.05, 95% CI = 1.72; 5.43; p < 0.01), Aspirin and/or clopidogrel at 3 months OR 1.59, 95% CI = 1.02, 2.48; p < 0.05), 6 months (OR 3.67, 95% CI = 1.67; 8.08; p < 0.01). Global medication adherence was predicted only by Office-GAP intervention presence and hypertension. Office-GAP resulted in increased use of guideline-based medications for secondary CVD prevention in underserved populations. The Office-GAP program could serve as a model for implementing guideline-based care for other chronic diseases. PMID- 27512652 TI - Unravelling the Glasgow effect: The relationship between accumulative bio- psychosocial stress, stress reactivity and Scotland's health problems. AB - To date, multiple hypotheses have been proposed for the Scottish effect and, more specifically, Glasgow's high mortality rate and the associated Glasgow effect. Previous authors have highlighted the improbability of a single factor as responsible for this effect with seventeen possible hypotheses presented. These have ranged from socio-economic factors, lifestyle and cultural factors such as sectarianism, and political and economic factors. Although these may all be contributory factors to this paradox, the underpinning reasons for the observed effect remain relatively unexplained. In this paper, we suggest that the compounding effect of a unique blend of accumulating life stressors may predispose Scots, and particularly socially-disadvantaged Glaswegians, to a wide range of health disorders. In short, a confluence of social, environmental, attitudinal and cultural stressors perhaps combine to negatively influence biological health. Future directions should consider the stress remediating role of physical activity, and the problems presented by barriers to participation in physical activity and exercise during key transitional stages of life. PMID- 27512654 TI - The predictors to medication adherence among adults with diabetes in the United Arab Emirates. AB - BACKGROUND: Diabetes is a chronic medical condition and adherence to medication in adults with diabetes is important. Identifying predictors to medication adherence in adults with diabetes would help identify vulnerable patients who are likely to benefit by improving their adherence levels. METHODS: We conducted a cross-sectional study at the Dubai Police Health Centre between February 2015 and November 2015. Questionnaires were used to collect socio-demographic, clinical and disease related variables and the primary measure of outcome was adherence levels as measured by the Morisky Medication Adherence Scale (MMAS-8(c)). Multivariate logistic regression was carried out to identify predictors to adherence. RESULTS: Four hundred and forty six patients were interviewed. Mean age 61 year +/- 11. 48.4 % were male. The mean time since diagnosis of diabetes was 3.2 years (Range 1-15 years). Two hundred and eighty eight (64.6 %) patients were considered non-adherent (MMAS-8(c) adherence score < 6) while 118 (26.5 %) had moderate adherence (MMAS-8(c) adherence score 6 = <8) and 40 (9.0 %) high adherence (MMAS-8(c) adherence scores <8) to their medication respectively. The strongest predictor for adherence as predicted by the multi-logistic regression model was the patient's level of education. A technical diploma certificate as compared to a primary school level of education was the strongest predictor of adherence (OR = 66.1 CI: 6.93 to 630.43); p < 0.001). The patient's age was also a predictor of adherence with older patients reporting higher levels of adherence (OR = 1.113 (CI: 1.045 to 1.185; p = 0.001 for every year increase in age). The duration of diabetes was also a predictor of adherence (OR = 1.830 (CI: 1.270 to 2.636; p = 0.001 for every year increase in the duration of diabetes). Other predictors to medication adherence include Insulin use, ethnicity and certain cultural behaviours. CONCLUSION: A number of important predictors to medication adherence in diabetics were identified in this study. Such predictors could help develop policies for improving adherence in diabetics. PMID- 27512653 TI - Does the Urinary Microbiome Play a Role in Urgency Urinary Incontinence and Its Severity? AB - OBJECTIVES: Traditionally, the urinary tract has been thought to be sterile in the absence of a clinically identifiable infection. However, recent evidence suggests that the urinary tract harbors a variety of bacterial species, known collectively as the urinary microbiome, even when clinical cultures are negative. Whether these bacteria promote urinary health or contribute to urinary tract disease remains unknown. Emerging evidence indicates that a shift in the urinary microbiome may play an important role in urgency urinary incontinence (UUI). The goal of this prospective pilot study was to determine how the urinary microbiome is different between women with and without UUI. We also sought to identify if characteristics of the urinary microbiome are associated with UUI severity. METHODS: We collected urine from clinically well-characterized women with UUI (n = 10) and normal bladder function (n = 10) using a transurethral catheter to avoid bacterial contamination from external tissue. To characterize the resident microbial community, we amplified the bacterial 16S rRNA gene by PCR and performed sequencing using Illumina MiSeq. Sequences were processed using the workflow package QIIME. We identified bacteria that had differential relative abundance between UUI and controls using DESeq2 to fit generalized linear models based on the negative binomial distribution. We also identified relationships between the diversity of the urinary microbiome and severity of UUI symptoms with Pearson's correlation coefficient. RESULTS: We successfully extracted and sequenced bacterial DNA from 95% of the urine samples and identified that there is a polymicrobial community in the female bladder in both healthy controls and women with UUI. We found the relative abundance of 14 bacteria significantly differed between control and UUI samples. Furthermore, we established that an increase in UUI symptom severity is associated with a decrease in microbial diversity in women with UUI. CONCLUSIONS: Our study provides further characterization of the urinary microbiome in both healthy controls and extensively phenotyped women with UUI. Our results also suggest that the urinary microbiome may play an important role in the pathophysiology of UUI and that the loss of microbial diversity may be associated with clinical severity. PMID- 27512655 TI - Oncolytic virotherapy: the questions and the promise. AB - Oncolytic virotherapy is a new strategy to reduce tumor burden through selective virus replication in rapidly proliferating cells. Oncolytic viruses are members of at least ten virus families, each with its advantages and disadvantages. Here, I briefly review the recent advances and key challenges, as exemplified by the best-studied platforms. Recent advances include preclinical proof of feasibility, clinical evidence of tolerability and effectiveness, and the development of new strategies to improve efficacy. These include engineered tumor selectivity and expression of antitumorigenic genes that could function independently of virus replication, identification of combinatorial therapies that accelerate intratumoral virus propagation, and modification of immune responses and vascular delivery for treatment of metastatic disease. Key challenges are to select "winners" from the distinct oncolytic platforms that can stimulate anti-cancer immunity without affecting virus replication and can lyse cancer stem cells, which are most likely responsible for tumor maintenance, aggressiveness, and recurrence. Preventing the emergence of resistant tumor cells during virotherapy through the activation of multiple death pathways, the development of a better understanding of the mechanisms of cancer stem-cell lysis, and the development of more meaningful preclinical animal models are additional challenges for the next generation of engineered viruses. PMID- 27512656 TI - Oncolytic virus therapy for cancer. AB - The use of oncolytic viruses to treat cancer is based on the selection of tropic tumor viruses or the generation of replication selective vectors that can either directly kill infected tumor cells or increase their susceptibility to cell death and apoptosis through additional exposure to radiation or chemotherapy. In addition, viral vectors can be modified to promote more potent tumor cell death, improve the toxicity profile, and/or generate host antitumor immunity. A variety of viruses have been developed as oncolytic therapeutics, including adenovirus, vaccinia virus, herpesvirus, coxsackie A virus, Newcastle disease virus, and reovirus. The clinical development of oncolytic viral therapy has accelerated in the last few years, with several vectors entering clinical trials for a variety of cancers. In this review, current strategies to optimize the therapeutic effectiveness and safety of the major oncolytic viruses are discussed, and a summary of current clinical trials is provided. Further investigation is needed to characterize better the clinical impact of oncolytic viruses, but there are increasing data demonstrating the potential promise of this approach for the treatment of human and animal cancers. PMID- 27512657 TI - Cell carriers for oncolytic viruses: current challenges and future directions. AB - The optimal route for clinical delivery of oncolytic viruses is thought to be systemic intravenous injection; however, the immune system is armed with several highly efficient mechanisms to remove pathogens from the circulatory system. To overcome the challenges faced in trying to delivery oncolytic viruses specifically to tumors via the bloodstream, carrier cells have been investigated to determine their suitability as delivery vehicles for systemic administration of oncolytic viruses. Cell carriers protect viruses from neutralization, one of the most limiting aspects of oncolytic virus interaction with the immune system. Cell carriers can also possess inherent tumor tropism, thus directing the delivery of the virus more specifically to a tumor. With preclinical studies already demonstrating the success and feasibility of this approach with multiple oncolytic viruses, clinical evaluation of cell-mediated delivery of viruses is on the horizon. Meanwhile, ongoing preclinical studies are aimed at identifying new cellular vehicles for oncolytic viruses and improving current promising cell carrier platforms. PMID- 27512658 TI - Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs. AB - Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVex(GM-CSF)]), is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with "standard-of-care" drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with "standard-of-care" drugs merits further investigation, both preclinically and in the clinic. Numerous publications report such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions. PMID- 27512659 TI - Arming viruses in multi-mechanistic oncolytic viral therapy: current research and future developments, with emphasis on poxviruses. AB - The field of oncolytic virology has made great strides in recent years. However, one key finding has been that the use of viral agents that replicate selectively in tumors is usually insufficient to achieve anything beyond small and transient responses. Instead, like most cancer therapies, oncolytic viruses are most effective in combination with other therapies, which is where they have proven therapeutic effects in clinical and preclinical studies. In cases of some of the smaller RNA viruses, effects can only be achieved through combination regimens with chemotherapy, radiotherapy, or targeted conventional therapies. However, larger DNA viruses are able to express one or more transgenes; thus, therapeutic mechanisms can be built into the viral vector itself. The incorporated approaches into arming oncolytic viruses through transgene expression will be the main focus of this review, including use of immune activators, prodrug converting enzymes, anti-angiogenic factors, and targeting of the stroma. This will focus on poxviruses as model systems with large cloning capacities, which have routinely been used as transgene expression vectors in different settings, including vaccine and oncolytic viral therapy. PMID- 27512660 TI - Critical analysis of an oncolytic herpesvirus encoding granulocyte-macrophage colony stimulating factor for the treatment of malignant melanoma. AB - Oncolytic viruses that selectively lyse tumor cells with minimal damage to normal cells are a new area of therapeutic development in oncology. An attenuated herpesvirus encoding the granulocyte-macrophage colony stimulating factor (GM CSF), known as talimogene laherparepvec (T-VEC), has been identified as an attractive oncolytic virus for cancer therapy based on preclinical tumor studies and results from early-phase clinical trials and a large randomized Phase III study in melanoma. In this review, we discuss the basic biology of T-VEC, describe the role of GM-CSF as an immune adjuvant, summarize the preclinical data, and report the outcomes of published clinical trials using T-VEC. The emerging data suggest that T-VEC is a safe and potentially effective antitumor therapy in malignant melanoma and represents the first oncolytic virus to demonstrate therapeutic activity against human cancer in a randomized, controlled Phase III study. PMID- 27512661 TI - Oncolytic viral therapy for pancreatic cancer: current research and future directions. AB - The development of targeted agents and chemotherapies for pancreatic cancer has only modestly affected clinical outcome and not changed 5-year survival. Fortunately the genetic and molecular mechanisms underlying pancreatic cancer are being rapidly uncovered and are providing opportunities for novel targeted therapies. Oncolytic viral therapy is one of the most promising targeted agents for pancreatic cancer. This review will look at the current state of the development of these self-replicating nanoparticles in the treatment of pancreatic cancer. PMID- 27512662 TI - Applications of coxsackievirus A21 in oncology. AB - The clinical management of cancer continues to be dominated by macroscopic surgical resection, radiotherapy, and cytotoxic drugs. The major challenge facing oncology is to achieve more selective, less toxic and effective methods of targeting disseminated tumors, a challenge oncolytic virotherapy may be well placed to meet. Characterization of coxsackievirus A21 (CVA21) receptor-based mechanism of virus internalization and lysis in the last decade has suggested promise for CVA21 as a virotherapy against malignancies which overexpress those receptors. Preclinical studies have demonstrated proof of principle, and with the results of early clinical trials awaited, CVA21 may be one of the few viruses to demonstrate benefit for patients. This review outlines the potential of CVA21 as an oncolytic agent, describing the therapeutic development of CVA21 in preclinical studies and early stage clinical trials. Preclinical evidence supports the potential use of CVA21 across a range of malignancies. Malignant melanoma is the most intensively studied cancer, and may represent a "test case" for future development of the virus. Although there are theoretical barriers to the clinical utility of oncolytic viruses like CVA21, whether these will block the efficacy of the virus in clinical practice remains to be established, and is a question which can only be answered by appropriate trials. As these data become available, the rapid journey of CVA21 from animal studies to clinical trials may offer a model for the translation of other oncolytic virotherapies from laboratory to clinic. PMID- 27512663 TI - Live attenuated measles virus vaccine therapy for locally established malignant glioblastoma tumor cells. AB - Glioblastoma multiforme is the most aggressive malignant primary brain tumor in humans, with poor prognosis. A new glioblastoma cell line (ANGM5) was established from a cerebral glioblastoma multiforme in a 72-year-old Iraqi man who underwent surgery for an intracranial tumor. This study was carried out to evaluate the antitumor effect of live attenuated measles virus (MV) Schwarz vaccine strain on glioblastoma multiforme tumor cell lines in vitro. Live attenuated MV Schwarz strain was propagated on Vero, human rhabdomyosarcoma, and human glioblastoma multiform (ANGM5) cell lines. The infected confluent monolayer appeared to be covered with syncytia with granulation and vacuolation, as well as cell rounding, shrinkage, and large empty space with cell debris as a result of cell lysis and death. Cell lines infected with virus have the ability for hemadsorption to human red blood cells after 72 hours of infection, whereas no hemadsorption of uninfected cells is seen. Detection of MV hemagglutinin protein by monoclonal antibodies in infected cells of all cell lines by immunocytochemistry assay gave positive results (brown color) in the cytoplasm of infected cells. Cell viability was measured after 72 hours of infection by 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Results showed a significant cytotoxic effect for MV (P<=0.05) on growth of ANGM5 and rhabdomyosarcoma cell lines after 72 hours of infection. Induction of apoptosis by MV was assessed by measuring mitochondrial membrane potentials in tumor cells after 48, 72, and 120 hours of infection. Apoptotic cells were counted, and the mean percentage of dead cells was significantly higher after 48, 72, and 120 hours of infection compared with control cells. This study concludes that live attenuated MV Schwarz vaccine induces the oncolytic effect in Iraqi tumor cell line ANGM5 and in the rhabdomyosarcoma cell line through syncytia in tumor cells, which is one of the causes of cell death. The MV vaccine strain has the ability to insert its hemagglutinin protein into the tumor cell surface, leading to modification of the antigenic surface of tumor cells that may induce an antitumor immune response, MV vaccine strain induced cell killing by direct cytolysis and apoptosis induction. These antitumor features may indicate the use of MV in the treatment of glioblastoma. PMID- 27512664 TI - Reovirus in cancer therapy: an evidence-based review. AB - Reovirus, a double-stranded ribonucleic acid virus and benign human pathogen, preferentially infects and kills cancer cells in its unmodified form, and is one of the leading oncolytic viruses currently undergoing clinical trials internationally. With 32 clinical trials completed or ongoing thus far, reovirus has demonstrated clinical therapeutic applicability against a multitude of cancers, including but not limited to breast cancer, prostate cancer, pancreatic cancer, malignant gliomas, advanced head and neck cancers, and metastatic ovarian cancers. Phase I trials have demonstrated that reovirus is safe to use via both intralesional/intratumoral and systemic routes of administration, with the most common adverse reactions being grade I/II toxicities, such as flu-like illness (fatigue, nausea, vomiting, headache, fever/chills, dizziness), diarrhea, and lymphopenia. In subsequent Phase II trials, reovirus administration was demonstrated to successfully decrease tumor size and promote tumor necrosis, thereby complementing compelling preclinical evidence of tumor destruction by the virus. Importantly, reovirus has been shown to be effective as a monotherapy, as well as in combination with other anticancer options, including radiation and chemotherapeutic agents, such as gemcitabine, docetaxel, paclitaxel, and carboplatin. Of note, the first Phase III clinical trial using reovirus in combination with paclitaxel and carboplatin for the treatment of head and neck cancers is under way. Based on the evidence from clinical trials, we comprehensively review the use of reovirus as an anticancer agent, acknowledge key obstacles, and suggest future directions to ultimately potentiate the efficacy of reovirus oncotherapy. PMID- 27512665 TI - Myxoma virus attenuates expression of activating transcription factor 4 (ATF4) which has implications for the treatment of proteasome inhibitor-resistant multiple myeloma. AB - The recent development of chemotherapeutic proteasome inhibitors, such as bortezomib, has improved the outcomes of patients suffering from the plasma cell malignancy multiple myeloma. Unfortunately, many patients treated with these drugs still suffer relapsing disease due to treatment-induced upregulation of the antiapoptotic protein Mcl1. We have recently demonstrated that an oncolytic poxvirus, known as myxoma, can rapidly eliminate primary myeloma cells by inducing cellular apoptosis. The efficacy of myxoma treatment on proteasome inhibitor-relapsed or -refractory myeloma, however, remains unknown. We now demonstrate that myxoma-based elimination of myeloma is not affected by cellular resistance to proteasome inhibitors. Additionally, myxoma virus infection specifically prevents expression of Mcl1 following induction of the unfolded protein response, by blocking translation of the unfolded protein response activating transcription factor (ATF)4. These results suggest that myxoma-based oncolytic therapy represents an attractive option for myeloma patients whose disease is refractory to chemotherapeutic proteasome inhibitors due to upregulation of Mcl1. PMID- 27512667 TI - The emerging therapeutic potential of the oncolytic immunotherapeutic Pexa-Vec (JX-594). AB - Oncolytic immunotherapeutics (OIs) are viruses designed to preferentially replicate in and lyse cancer cells, thereby triggering antitumor immunity. Numerous oncolytic platforms are currently in clinical development. Here we review preclinical and clinical experience with Pexa-Vec (pexastimogene devacirepvec, JX-594). Pexa-Vec is derived from a vaccinia vaccine strain that has been engineered to target cancer cells and express the therapeutic transgene granulocyte macrophage colony-stimulating factor (GM-CSF) in order to stimulate antitumor immunity. Key to its ability to target metastatic disease is the evolution of unique vaccinia virus characteristics that allow for effective systemic dissemination. Multiple mechanisms of action (MOA) for Pexa-Vec have been demonstrated in preclinical models and patients: 1) tumor cell infection and lysis, 2) antitumor immune response induction, and 3) tumor vascular disruption. This review will summarize data on the Pexa-Vec MOA as well as provide an overview of the Pexa-Vec clinical development program from multiple Phase I studies, Phase II studies in renal cell cancer and colorectal cancer, through Phase IIb clinical testing in patients with advanced hepatocellular carcinoma (primary liver cancer). PMID- 27512666 TI - The ex vivo purge of cancer cells using oncolytic viruses: recent advances and clinical implications. AB - Hematological malignancies are treated with intensive high-dose chemotherapy, with or without radiation. This is followed by hematopoietic stem cell (HSC) transplantation (HSCT) to rescue or reconstitute hematopoiesis damaged by the anticancer therapy. Autologous HSC grafts may contain cancer cells and purging could further improve treatment outcomes. Similarly, allogeneic HSCT may be improved by selectively purging alloreactive effector cells from the graft rather than wholesale immune cell depletion. Viral agents that selectively replicate in specific cell populations are being studied in experimental models of cancer and immunological diseases and have potential applications in the context of HSC graft engineering. This review describes preclinical studies involving oncolytic virus strains of adenovirus, herpes simplex virus type 1, myxoma virus, and reovirus as ex vivo purging agents for HSC grafts, as well as in vitro and in vivo experimental studies using oncolytic coxsackievirus, measles virus, parvovirus, vaccinia virus, and vesicular stomatitis virus to eradicate hematopoietic malignancies. Alternative ex vivo oncolytic virus strategies are also outlined that aim to reduce the risk of relapse following autologous HSCT and mitigate morbidity and mortality due to graft-versus-host disease in allogeneic HSCT. PMID- 27512668 TI - Extended disease-free interval of 6 years in a recurrent glioblastoma multiforme patient treated with G207 oncolytic viral therapy. AB - BACKGROUND: Glioblastoma multiforme (GBM) is a relentless primary central nervous system malignancy that remains resistant to conventional therapy despite major advances in clinical neurooncology. This report details the case of a patient who had failed conventional treatment for recurrent GBM and was ultimately treated with a genetically engineered herpes simplex virus (HSV) type 1 vector, G207. METHODS: Case report detailing the outcomes of one patient enrolled into the gene therapy arm of the Neurovir G207 protocol whereby stereotactic injection of 120 uL G207 viral suspension containing 1*10(7) plaque-forming units (or active viral particles) was made into the enhancing region of the tumor. RESULTS: In this patient, despite aggressive surgical resection, adjuvant radiotherapy and chemotherapy, tumor progression occurred. However, with G207 oncolytic therapy and brief exposures to second and third treatments, this patient had an extended survival time of 7.5 years and a 6-year apparent disease-free interval, an extraordinarily unusual finding in the pretemozolomide era. CONCLUSION: With minimal adjunctive chemotherapy, including one course of temozolomide, one course of procarbazine, and four cycles of irinotecan, the patient survived over 7 years before the next recurrence. Addition of G207 to this patient's traditional therapy may have been the critical treatment producing her prolonged survival. This report demonstrates the potential for long-term response to a one-time treatment with oncolytic HSV and encourages continued research on oncolytic viral therapy for GBM. PMID- 27512669 TI - Chemovirotherapy: combining chemotherapeutic treatment with oncolytic virotherapy. AB - Oncolytic virotherapy has made significant progress in recent years, however, widespread approval of virotherapeutics is still limited. Primarily, this is due to the fact that currently available virotherapeutics are mostly tested in monotherapeutic clinical trials exclusively (ie, not in combination with other therapies) and so far have achieved only small and often clinically insignificant responses. Given that the predominantly immunotherapeutic mechanism of virotherapeutics is somewhat time-dependent and rapidly growing tumors therefore exhibit only minor chances of being captured in time, scenarios with combination partners are postulated to be more effective. Combinatory settings would help to achieve a rapid stabilization or even reduction of onset tumor masses while providing enough time (numerous months) for achieving immuno(viro)therapeutic success. For this reason, combination strategies of virotherapy with highly genotoxic regimens, such as chemotherapy, are of major interest. A number of clinical trials bringing the concepts of chemotherapy and virotherapy together have previously been undertaken, but optimal scheduling of chemovirotherapy (maximizing the anti-tumor effect while minimizing the risk of overlapping toxicity) still constitutes a major challenge. Therefore, an overview of published as well as ongoing Phase I-III trials should improve our understanding of current challenges and future developments in this field. PMID- 27512670 TI - Therapeutic potential of oncolytic Newcastle disease virus: a critical review. AB - Newcastle disease virus (NDV) features a natural preference for replication in many tumor cells compared with normal cells. The observed antitumor effect of NDV appears to be a result of both selective killing of tumor cells and induction of immune responses. Genetic manipulations to change viral tropism and arming the virus with genes encoding for cytokines improved the oncolytic capacity of NDV. Several intracellular proteins in tumor cells, including antiapoptotic proteins (Livin) and oncogenic proteins (H-Ras), are relevant for the oncolytic activity of NDV. Defects in the interferon system, found in some tumor cells, also contribute to the oncolytic selectivity of NDV. Notwithstanding, NDV displays effective oncolytic activity in many tumor types, despite having intact interferon signaling. Taken together, several cellular systems appear to dictate the selective oncolytic activity of NDV. Some barriers, such as neutralizing antibodies elicited during NDV treatment and the extracellular matrix in tumor tissue appear to interfere with spread of NDV and reduce oncolysis. To further understand the oncolytic activity of NDV, we compared two NDV strains, ie, an attenuated virus (NDV-HUJ) and a pathogenic virus (NDV-MTH-68/H). Significant differences in amino acid sequence were noted in several viral proteins, including the fusion precursor (F0) glycoprotein, an important determinant of replication and pathogenicity. However, no difference in the oncolytic activity of the two strains was noted using human tumor tissues maintained as organ cultures or in mouse tumor models. To optimize virotherapy in clinical trials, we describe here a unique organ culture methodology, using a biopsy taken from a patient's tumor before treatment for ex vivo infection with NDV to determine the oncolytic potential on an individual basis. In conclusion, oncolytic NDV is an excellent candidate for cancer therapy, but more knowledge is needed to ensure success in clinical trials. PMID- 27512671 TI - Promising oncolytic agents for metastatic breast cancer treatment. AB - New therapies for metastatic breast cancer patients are urgently needed. The long term survival rates remain unacceptably low for patients with recurrent disease or disseminated metastases. In addition, existing therapies often cause a variety of debilitating side effects that severely impact quality of life. Oncolytic viruses constitute a developing therapeutic modality in which interest continues to build due to their ability to spare normal tissue while selectively destroying tumor cells. A number of different viruses have been used to develop oncolytic agents for breast cancer, including herpes simplex virus, adenovirus, vaccinia virus, measles virus, reovirus, and others. In general, clinical trials for several cancers have demonstrated excellent safety records and evidence of efficacy. However, the impressive tumor responses often observed in preclinical studies have yet to be realized in the clinic. In order for the promise of oncolytic virotherapy to be fully realized for breast cancer patients, effectiveness must be demonstrated in metastatic disease. This review provides a summary of oncolytic virotherapy strategies being developed to target metastatic breast cancer. PMID- 27512672 TI - Novel therapeutic strategies in human malignancy: combining immunotherapy and oncolytic virotherapy. AB - Results from randomized clinical trials over the last several years have finally begun to demonstrate the potential of oncolytic viral therapies to treat a variety of cancers. One reason for these successes has been the realization that this platform is most effective when considered primarily as an immunotherapy. Cancer immunotherapy has also made dramatic strides recently with antibodies capable of blocking immune checkpoint inhibitors and adoptive T-cell therapies, notably CAR T-cells, leading a panel of novel and highly clinically effective therapies. It is clear therefore that an understanding of how and when these complementary approaches can most effectively be combined offers the real hope of moving beyond simply treating the disease and toward starting to talk about curative therapies. In this review we discuss approaches to combining these therapeutic platforms, both through engineering the viral vectors to more beneficially interact with the host immune response during therapy, as well as through the direct combinations of different therapeutics. This primarily, but not exclusively focuses on strains of oncolytic vaccinia virus. Some of the results reported to date, primarily in pre-clinical models but also in early clinical trials, are dramatic and hold great promise for the future development of similar therapies and their translation into cancer therapies. PMID- 27512673 TI - Oncolytic virotherapy for head and neck cancer: current research and future developments. AB - Head and neck cancer (HNC) is the sixth most common malignancy worldwide. Despite recent advancements in surgical, chemotherapy, and radiation treatments, HNC remains a highly morbid and fatal disease. Unlike many other cancers, local control rather than systemic control is important for HNC survival. Therefore, novel local therapy in addition to systemic therapy is urgently needed. Oncolytic virotherapy holds promise in this regard as viruses can be injected intratumorally as well as intravenously with excellent safety profiles. This review will discuss the recent advancements in oncolytic virotherapy, highlighting some of the most promising candidates and modifications to date. PMID- 27512674 TI - On the potential of oncolytic virotherapy for the treatment of canine cancers. AB - Over 6 million dogs are diagnosed with cancer in the USA each year. Treatment options for many of these patients are limited. It is important that the veterinary and scientific communities begin to explore novel treatment protocols for dogs with cancer. Oncolytic viral therapy is a promising treatment option that may prove to be relatively inexpensive and effective against several types of cancer. The efficacy of oncolytic virus therapies has been clearly demonstrated in murine cancer models, but the positive outcomes observed in mice are not always seen in human cancer patients. These therapies should be thoroughly evaluated in dogs with spontaneously arising cancers to provide needed information about the potential effectiveness of virus treatment for human cancers and to promote the health of our companion animals. This article provides a review of the results of oncolytic virus treatment of canine cancers. PMID- 27512675 TI - Advances in the design and development of oncolytic measles viruses. AB - A successful oncolytic virus is one that selectively propagates and destroys cancerous tissue without causing excessive damage to the normal surrounding tissue. Oncolytic measles virus (MV) is one such virus that exhibits this characteristic and thus has rapidly emerged as a potentially useful anticancer modality. Derivatives of the Edmonston MV vaccine strain possess a remarkable safety record in humans. Promising results in preclinical animal models and evidence of biological activity in early phase trials contribute to the enthusiasm. Genetic modifications have enabled MV to evolve from a vaccine agent to a potential anticancer therapy. Specifically, alterations of the MV genome have led to improved tumor selectivity and delivery, therapeutic potency, and immune system modulation. In this article, we will review the advancements that have been made in the design and development of MV that have led to its use as a cancer therapy. In addition, we will discuss the evidence supporting its use, as well as the challenges associated with MV as a potential cancer therapeutic. PMID- 27512676 TI - Oncolytic virotherapy for human malignant mesothelioma: recent advances. AB - Cancer virotherapy is an attractive alternative to conventional treatments because it offers a wide range of antitumor effects due to 1) the diversity of the oncolytic viruses that are now available and 2) their multifaceted activities against both tumor cells and tumor vessels, in addition to their ability to induce antitumor immune responses. In this review, we summarize preclinical and clinical data regarding the targeting of malignant mesothelioma (MM) by oncolytic viruses. We also discuss the potential of other oncolytic viruses that have already shown antitumor effects against several malignancies in advanced clinical trials but are yet to be tested against MM cells. Finally, we review how the activation of the immune system and combinations with other types of anticancer treatments could support the development of oncolytic virotherapy for the treatment of MM. PMID- 27512677 TI - Oncolytic Sendai virus-based virotherapy for cancer: recent advances. AB - Many drugs have been developed and optimized for the treatment of cancer; however, it is difficult to completely cure cancer with anticancer drugs alone. Therefore, the development of new therapeutic technologies, in addition to new anticancer drugs, is necessary for more effective oncotherapy. Oncolytic viruses are one potential new anticancer strategy. Various oncolytic viruses have been developed for safe and effective oncotherapy. Recently, Sendai virus-based oncotherapy has been reported by several groups, and attention has been drawn to its unique anticancer mechanisms, which are different from those of the conventional oncolytic viruses that kill cancer cells by cancer cell-selective replication. Here, we introduce Sendai virus-based virotherapy and its anticancer mechanisms. PMID- 27512678 TI - Patient-derived mesenchymal stem cells as delivery vehicles for oncolytic virotherapy: novel state-of-the-art technology. AB - Oncolytic virotherapy is gaining interest in the clinic as a new weapon against cancer. In vivo administration of oncolytic viruses showed important limitations that decrease their effectiveness very significantly: the antiviral immune response causes the elimination of the therapeutic effect, and the poor natural ability of oncolytic viruses to infect micrometastatic lesions significantly minimizes the effective dose of virus. This review will focus on updating the technical and scientific foundations of one of the strategies developed to overcome these limitations, ie, using cells as vehicles for oncolytic viruses. Among many candidates, a special type of adult stem cell, mesenchymal stem cells (MSCs), have already been used in the clinic as cell vehicles for oncolytic viruses, partly due to the fact that these cells are actively being evaluated for other indications. MSC carrier cells are used as Trojan horses loaded with oncoviruses, are administered systemically, and release their cargos at the right places. MSCs are equipped with an array of molecules involved in cell arrest in the capillaries (integrins and selectins), migration toward specific parenchymal locations within tissues (chemokine receptors), and invasion and degradation of the extracellular matrix (proteases). In addition to anatomical targeting capacity, MSCs have a well-recognized role in modulating immune responses by affecting cells of the innate (antigen-presenting cells, natural killer cells) and adaptive immune system (effector and regulatory lymphocytes). Therefore, carrier MSCs may also modulate the immune responses taking place after therapy, ie, the antiviral and the antitumor immune responses. PMID- 27512679 TI - Mechanistic insights into the oncolytic activity of vesicular stomatitis virus in cancer immunotherapy. AB - Immunotherapy and oncolytic virotherapy have both shown anticancer efficacy in the clinic as monotherapies but the greatest promise lies in therapies that combine these approaches. Vesicular stomatitis virus is a prominent oncolytic virus with several features that promise synergy between oncolytic virotherapy and immunotherapy. This review will address the cytotoxicity of vesicular stomatitis virus in transformed cells and what this means for antitumor immunity and the virus' immunogenicity, as well as how it facilitates the breaking of tolerance within the tumor, and finally, we will outline how these features can be incorporated into the rational design of new treatment strategies in combination with immunotherapy. PMID- 27512680 TI - Targeting tumor vasculature through oncolytic virotherapy: recent advances. AB - The oncolytic virotherapy field has made significant advances in the last decade, with a rapidly increasing number of early- and late-stage clinical trials, some of them showing safety and promising therapeutic efficacy. Targeting tumor vasculature by oncolytic viruses (OVs) is an attractive strategy that offers several advantages over nontargeted viruses, including improved tumor viral entry, direct antivascular effects, and enhanced antitumor efficacy. Current understanding of the biological mechanisms of tumor neovascularization, novel vascular targets, and mechanisms of resistance has allowed the development of oncolytic viral vectors designed to target tumor neovessels. While some OVs (such as vaccinia and vesicular stomatitis virus) can intrinsically target tumor vasculature and induce vascular disruption, the majority of reported vascular targeted viruses are the result of genetic manipulation of their viral genomes. Such strategies include transcriptional or transductional endothelial targeting, "armed" viruses able to downregulate angiogenic factors, or to express antiangiogenic molecules. The above strategies have shown preclinical safety and improved antitumor efficacy, either alone, or in combination with standard or targeted agents. This review focuses on the recent efforts toward the development of vascular-targeted OVs for cancer treatment and provides a translational/clinical perspective into the future development of new generation biological agents for human cancers. PMID- 27512681 TI - Combining HDAC inhibitors with oncolytic virotherapy for cancer therapy. AB - Histone deacetylase (HDAC) enzymes play a critical role in the epigenetic regulation of cellular functions and signaling pathways in many cancers. HDAC inhibitors (HDACi) have been validated for single use or in combination with other drugs in oncologic therapeutics. An even more novel combination therapy with HDACi is to use them with an oncolytic virus. HDACi may lead to an amplification of tumor-specific lytic effects by facilitating increased cycles of viral replication, but there may also be direct anticancer effects of the drug by itself. Here, we review the molecular mechanisms of anti-cancer effects of the combination of oncolytic viruses with HDACi. PMID- 27512682 TI - Ultrasound-mediated oncolytic virus delivery and uptake for increased therapeutic efficacy: state of art. AB - The field of ultrasound (US) has changed significantly from medical imaging and diagnosis to treatment strategies. US contrast agents or microbubbles (MB) are currently being used as potential carriers for chemodrugs, small molecules, nucleic acids, small interfering ribonucleic acid, proteins, adenoviruses, and oncolytic viruses. Oncolytic viruses can selectively replicate within and destroy a cancer cell, thus making them a powerful therapeutic in treating late-stage or metastatic cancer. These viruses have been shown to have robust activity in clinical trials when injected directly into tumor nodules. However limitations in oncolytic virus' effectiveness and its delivery approach have warranted exploration of ultrasound-mediated delivery. Gene therapy bearing adenoviruses or oncolytic viruses can be coupled with MBs and injected intravenously. Following application of US energy to the target region, the MBs cavitate, and the resulting shock wave enhances drug, gene, or adenovirus uptake. Though the underlying mechanism is yet to be fully understood, there is evidence to suggest that mechanical pore formation of cellular membranes allows for the temporary uptake of drugs. This delivery method circumvents the limitations due to stimulation of the immune system that prevented intravenous administration of viruses. This review provides insight into this intriguing new frontier on the delivery of oncolytic viruses to tumor sites. PMID- 27512684 TI - The effects of conjugated linoleic acids on breast cancer: A systematic review. AB - Recently prevention strategies for breast cancer are focused on lifestyle modification such as diet. Some dietary factors such as Conjugated linoleic acid (CLA) can lower the risk of breast cancer, metastasis and some factors concerning this malignancy. Many studies have been established in this field, but their results are inconsistent. Therefore, we evaluated this association based on systematic review among published scientific literature. We performed an electronic search using PubMed, Cochrane, Scopus, Google Scholar and Persian database (Iran Medex, magiran) to identify relevant studies. We summarized the findings of 8 papers in this review. Although, three cohort studies were not overall identified a protective effect of CLA dietary intake or CLA content in breast tissue on breast cancer incidence, metastasis and death, one of them showed an inverse association after adjusting for age. Also, among case-control studies a weak inverse association between breast cancer risk and CLA dietary intake and serum levels among post-menopausal women was reported. Besides, a clinical trial showed that some indicator of breast tumor decreased after CLA administration among women with breast adenocarcinoma. Lacking published evidence suggested inconsistent results. So, further well-designed studies are required, particularly in considering the main breast cancer risk factors. PMID- 27512683 TI - Oncolytic virotherapy using herpes simplex virus: how far have we come? AB - Oncolytic virotherapy exploits the properties of human viruses to naturally cytolysis of cancer cells. The human pathogen herpes simplex virus (HSV) has proven particularly amenable for use in oncolytic virotherapy. The relative safety of HSV coupled with extensive knowledge on how HSV interacts with the host has provided a platform for manipulating HSV to enhance the targeting and killing of human cancer cells. This has culminated in the approval of talimogene laherparepvec for the treatment of melanoma. This review focuses on the development of HSV as an oncolytic virus and where the field is likely to head in the future. PMID- 27512685 TI - The effect of Prosopis farcta beans extract on blood biochemical parameters in streptozotocin-induced diabetic male rats. AB - BACKGROUND: The use of herbals in the treatment of diabetes mellitus is a well established practice in traditional medicine. The medicinal plant Prosopis farcta has some antioxidant activity, which may be useful in diabetic patients. Since, there is no report on the antidiabetic effect of the P. farcta, this study evaluated antidiabetic activity of P. farcta bean extract (PFE) in streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Hyperglycemia was induced in male albino Wistar rats by intraperitoneal injection of STZ (55 mg/kg body weight [BW]), after which, the animals were randomly allocated into six experimental groups as follows: Group 1: Normal rats (received normal saline), Groups 2 and 3: Normal rats received PFE; (50 and 75 mg/kg BW), Group 4: Diabetic control rats, Group 5: Diabetic rats received PFE (50 mg/kg BW), Group 6: Diabetic rats received PFE (75 mg/kg BW). Three days after induction of diabetes, rats were received an extract of PFE orally for 12 days. Blood samples were collected by cardiac puncture to determine liver enzymes; aspartate aminotransferase and alanine aminotransferase (AST and ALT), cholesterol, triglyceride (TG), high and low density lipoproteins (HDL and LDL). RESULTS: The administration of PFE (50 and 75 mg/kg) in STZ-induced diabetic rats significantly reduced the blood glucose levels when compared with the STZ-control group (227.2 +/- 12.00 and 259.6 +/- 7.03 vs. 454.6 +/- 12.66, P < 0.001). PFE in diabetic groups had no significant effect on the levels of cholesterol, TG, HDL, LDL, AST, and ALT compare to the STZ-control group. CONCLUSION: P. farcta could reduce blood glucose in diabetic rats. PMID- 27512686 TI - Development of new method and protocol for cryopreservation related to embryo and oocytes freezing in terms of fertilization rate: A comparative study including review of literature. AB - BACKGROUND: Cryopreservation is basically related to meritorious thin samples or small clumps of cells that are cooled quickly without loss. Our main objective is to establish and formulate an innovative method and protocol development for cryopreservation as a gold standard for clinical uses in laboratory practice and treatment. The knowledge regarding usefulness of cryopreservation in clinical practice is essential to carry forward the clinical practice and research. MATERIALS AND METHODS: We are trying to compare different methods of cryopreservation (in two dozen of cells) at the same time we compare the embryo and oocyte freezing interms of fertilization rate according to the International standard protocol. RESULTS: The combination of cryoprotectants and regimes of rapid cooling and rinsing during warming often allows successful cryopreservation of biological materials, particularly cell suspensions or thin tissue samples. Examples include semen, blood, tissue samples like tumors, histological cross sections, human eggs and human embryos. Although presently many studies have reported that the children born from frozen embryos or "frosties," show consistently positive results with no increase in birth defects or development abnormalities is quite good enough and similar to our study (50-85%). CONCLUSIONS: We ensure that cryopreservation technology provided useful cell survivability, tissue and organ preservation in a proper way. Although it varies according to different laboratory conditions, it is certainly beneficial for patient's treatment and research. Further studies are needed for standardization and development of new protocol. PMID- 27512687 TI - Imaging bacteria with radiolabelled quinolones, cephalosporins and siderophores for imaging infection: a systematic review. AB - Bacterial infections are still one of the main causes of patient morbidity and mortality worldwide. Nowadays, many imaging techniques, like computed tomography or magnetic resonance imaging, are used to identify inflammatory processes, but, although they recognize anatomical modifications, they cannot easily distinguish bacterial infective foci from non bacterial infections. In nuclear medicine, many efforts have been made to develop specific radiopharmaceuticals to discriminate infection from sterile inflammation. Several compounds (antimicrobial peptides, leukocytes, cytokines, antibiotics...) have been radiolabelled and tested in vitro and in vivo, but none proved to be highly specific for bacteria. Indeed factors, including the number and strain of bacteria, the infection site, and the host condition may affect the specificity of tested radiopharmaceuticals. Ciprofloxacin has been proposed and intensively studied because of its easy radiolabelling method, broad spectrum, and low cost, but at the same time it presents some problems such as low stability or the risk of antibiotic resistance. Therefore, in the present review studies with ciprofloxacin and other radiolabelled antibiotics as possible substitutes of ciprofloxacin are reported. Among them we can distinguish different classes, such as cephalosporins, fluoroquinolones, inhibitors of nucleic acid synthesis, inhibitors of bacterial cell wall synthesis and inhibitors of protein synthesis; then also others, like siderophores or maltodextrin-based probes, have been discussed as bacterial infection imaging agents. A systematic analysis was performed to report the main characteristics and differences of each antibiotic to provide an overview about the state of the art of imaging infection with radiolabelled antibiotics. PMID- 27512688 TI - Preclinical studies and prospective clinical applications for bacteria-targeted imaging: the future is bright. AB - Bacterial infections are a frequently occurring and major complication in human healthcare, in particular due to the rapid increase of antimicrobial resistance and the emergence of pan-drug-resistant microbes. Current anatomical and functional imaging modalities are insufficiently capable of distinguishing sites of bacterial infection from sterile inflammation. Therefore, definitive diagnosis of an infection can often only be obtained by tissue biopsy and subsequent culture and, occasionally, a definite diagnosis even appears to be impossible. To accurately diagnose bacterial infections early, novel imaging modalities are urgently needed. In this regard, bacteria-targeted imaging is an attractive option due to its specificity. Here, different bacteria-targeted imaging approaches are reviewed, and their promising future perspectives are discussed. PMID- 27512690 TI - Posterior maxillary segmental osteotomy for management of insufficient intermaxillary vertical space and intermolar width discrepancy: a case report. AB - BACKGROUNDS: Insufficient intermaxillary space is caused by non-restoration following tooth extraction in the past, and this involves eruption of the opposing teeth and changes of the arch structure. Such cases are difficult just by a simple prosthetic approach, and diversified treatment plans should be established. Among these, posterior maxillary segmental osteotomy (PMSO) is an efficient treatment option than extraction of opposing teeth as it surgically repositions multiple erupted teeth and alveolar bone. PMSO can preserve the natural teeth; therefore, it is being regarded as a treatment method which can improve insufficient intermaxillary space significantly. CASE PRESENTATION: In this case report, the first patient received PMSO in order to place an implant in the mandibular edentulous space after decreased vertical dimension is restored, and the second patient received PMSO along with orthodontic treatment to obtain the intermaxillary space and balance the interarch molar width. CONCLUSION: PMSO is the treatment of choice when occlusion is compromised in the presence of decreased vertical dimension or arch length discrepancy. PMID- 27512689 TI - The role of 90Y-radioembolization in downstaging primary and secondary hepatic malignancies: a systematic review. AB - Radioembolization (RE) is an emerging treatment strategy for patients with primary hepatic malignancies and metastatic liver disease. Though RE is primarily performed in the palliative setting, a shift toward the curative setting is seen. Currently, hepatic resection and in selected cases liver transplantation are the only curative options for patients with a hepatic malignancy. Unfortunately, at diagnosis most patients are not eligible for liver surgery due to the imbalance between the necessary liver resection and the remaining liver remnant. However, in borderline resectable cases, tumor volume reduction and/or increasing the future liver remnant can lead to a resectable situation. The combination of selective tumor treatment, the induction of hypertrophy of untreated liver segments, and its favourable toxicity profile make RE an appealing strategy for downstaging. The present review discusses the possibilities for RE in the preoperative setting as a downstaging tool or as a bridge to liver transplantation. PMID- 27512691 TI - Obesity in the Otsuka Long Evans Tokushima Fatty Rat: Mechanisms and Discoveries. AB - Understanding the neural systems underlying the controls of energy balance has been greatly advanced by identifying the deficits and underlying mechanisms in rodent obesity models. The current review focuses on the Otsuka Long Evans Tokushima Fatty (OLETF) rat obesity model. Since its recognition in the 1990s, significant progress has been made in identifying the causes and consequences of obesity in this model. Fundamental is a deficit in the cholecystokinin (CCK)-1 receptor gene resulting in the absence of CCK-1 receptors in both the gastrointestinal track and the brain. OLETF rats have a deficit in their ability to limit the size of meals and in contrast to CCK-1 receptor knockout mice, do not compensate for this increase in the size of their spontaneous meals, resulting in hyperphagia. Prior to becoming obese and in response to pair feeding, OLETF rats have increased expression of neuropeptide Y (NPY) in the compact region of the dorsomedial hypothalamus (DMH), and this overexpression contributes to their overall hyperphagia. Study of the OLETF rats has revealed important differences in the organization of the DMH in rats and mice and elucidated previously unappreciated roles for DMH NPY in energy balance and glucose homeostasis. PMID- 27512693 TI - The effect of an instructional program based on health belief model in decreasing cesarean rate among primiparous pregnant mothers. AB - INTRODUCTION: Although cesarean section has saved many mothers' and infants' lives, the problem is in its increasing prevalence. According to recent statistics, the current rate of cesarean in Iran is in fact 3-4 times as more than the standard rate defined by WHO. Therefore, the present study is aimed to estimate the effect of an instructional program based on health belief model on reducing cesarean rate among primiparous pregnant women. MATERIALS AND METHODS: In this semi-experimental research, 60 primiparous women who had visited Bandar Abbas Healthcare Centers were selected as the subjects. They were in their 26 30(th) week of pregnancy. They were selected in a multi-stage cluster sampling method (a combination of clustering and simple randomization), and were divided into two groups, subjects and control group. The data were gathered using a valid and reliable questionnaire. The instructional intervention was done after the completion of the pretest questionnaire based on the sub-constructs of the health belief model in six instructional sessions. 1 month after the intervention, posttest questionnaires were completed by the subjects in both groups. The data were analyzed using descriptive statistics, standard deviation, independent t test, and paired t-test. The significance level was set at <0.05. RESULTS: Two groups had a significant difference between awareness score, perceived sensitivity, intensity, benefits, barriers, self-efficacy, and the performance (P < 0.001). In the experimental group, nine subjects (30%) had a natural delivery. CONCLUSION: According to the findings of the current research, an instructional program illuminated (designed) by the health belief model can significantly influence pregnant women's awareness, intention, and choice of delivery type. PMID- 27512692 TI - The Split Second Effect: The Mechanism of How Equinus Can Damage the Human Foot and Ankle. AB - We are currently in the process of discovering that many, if not the majority, of the non-traumatic acquired adult foot and ankle problems are caused by a singular etiology: non-neuromuscular equinus or the isolated gastrocnemius contracture. There is no question that this biomechanical association exists and in time much more will be uncovered. There are three basic questions that must be answered: why would our calves tighten as we normally age, how does a tight calf, or equinus, actually cause problems remotely in the foot and ankle, and how do the forces produced by equinus cause so many seemingly unrelated pathologies in the foot and ankle? The purpose of this paper is to address the second question: how does a tight calf mechanically cause problems remotely in the foot and ankle? There has been little evidence in the literature addressing the biomechanical mechanisms by which equinus creates damaging forces upon the foot and ankle, and as a result, a precise, convincing mechanism is still lacking. Thus, the mere concept that equinus has anything to do with foot pathology is generally unknown or disregarded. The split second effect, described here, defines exactly how the silent equinus contracture creates incremental and significant damage and injury to the human foot and ankle resulting in a wide variety of pathological conditions. The split second effect is a dissenting theory based on 30 years of clinical and academic orthopedic foot and ankle experience, keen clinical observation along the way, and review of the developing literature, culminating in examination of many hours of slow motion video of normal and abnormal human gait. To my knowledge, no one has ever described the mechanism in detail this precise. PMID- 27512694 TI - Does Islamic spiritual program lead to successful aging? A randomized clinical trial. AB - CONTEXT: Successful aging is a pattern of aging that has gained much attention during recent years. One factor that has a negative impact on successful aging variables is hypertension. The phenomenon of aging when accompanied with hypertension promotes spiritual needs. The aim of this study was to examine the effect of the Islamic spiritual program on successful aging in elderly patients with hypertension who were referred to health centers of Isfahan, Iran, in 2014. SETTINGS AND DESIGN: This study was a randomized clinical trial. MATERIALS AND METHODS: The participants (52 elderly patients with hypertension) were randomly divided into experimental and control groups. While the control group received training related to health promotion, the Islamic spiritual program was implemented in the experimental group for eight sessions in two health centers of Isfahan. The data collection tools consisted of the 12-item General Health Questionnaire developed by Goldberg and the satisfaction with life scale developed by Diener. The questionnaires were completed in three steps; pretest, posttest, and follow-up (1-month). STATISTICAL ANALYSIS USED: Data were analyzed using SPSS statistical software version 20 and Chi-square, independent t-test, and repeated measures ANOVA. RESULTS: Statistical tests showed that the mean score of general health and life satisfaction of the experiment group had a meaningful difference from that of the control group in the posttest stage (P < 0.001). This difference was also meaningful in the follow-up stage (P < 0.001). CONCLUSION: The results of the study indicated the effectiveness of an Islamic spiritual program on successful aging variables. PMID- 27512695 TI - Coverage of health-related articles in major local newspapers of Manipur. AB - BACKGROUND: Newspapers have immense potential for generating health awareness on diverse issues such as hygiene, immunization, environmental pollution, and communicable disease. The present study was conducted to determine the frequency of coverage and types of health-related articles published in local newspapers of Manipur. MATERIALS AND METHODS: This was a cross-sectional study conducted among the most regularly published 10 local newspapers (4 English and 6 Manipuri) of Manipur from February 2011 to January 2012. Health-related articles published in everyday local newspapers were collected after careful search and finally entered into a design Proforma under different categories. Data were analyzed using SPSS version 16. RESULTS: Total health-related articles published were 10,874 and maximum articles were published during February (12.8%). Maximum health-related articles were published on Wednesday (16.1%). Among all the health-related articles, almost half were related with injury followed by public health articles. Maximum public health and injury-related articles were published on Monday, but medical topics were published more on Wednesday. Newspapers of both the languages were publishing public health articles more compared to medical topics. Public health (72.9%) and injury-related articles (95.9%) were published maximum in the news items section, but medical topics (45.8%) were published maximum in the health section of the newspaper. Newspapers of both the languages published maximum small size articles. CONCLUSIONS: There is a room for improvement for newspapers of both the languages regarding number of health related articles' publication, section of publication, and size of the health articles. PMID- 27512696 TI - Effect of self-instructional module on knowledge about ebola virus disease among Nigerian University students in Bengaluru, India. AB - BACKGROUND: The knowledge about Ebola virus disease (EVD) is very crucial in the response to the recent outbreak and in order to control its spread. This study was conducted to assess the effectiveness of self-instructional module (SIM) in enhancing knowledge of EVD among Nigerian students in Bengaluru, India. MATERIALS AND METHODS: A pre-experimental study design was employed, and a simple random sampling technique was used to select 60 participants. A pretest was conducted with the tool to assess the baseline knowledge of participants after which SIM was administered to all the participants in two episodes. The posttest was conducted after 7 days using the same tool to assess any gain in knowledge among the participants. Data were analyzed using SPSS at an alpha level of 0.001 and Descriptive analysis (such as percentage, frequency, mean and standard deviation [SD]) as well as independent t-test was conducted. RESULTS: Findings showed that the majority of the participants (53%) were males, studying for the undergraduate degree (85%), 36 participants (60%) were in arts/social courses. More than average of the participants (67%) had spent only 1-year in India. Majority (53.3%) had average knowledge but after the administration of the SIM, majority had very good knowledge about EVD. The mean pretest knowledge score was 16.03 with an SD of 2.951 while the mean posttest knowledge score was 28.22 with SD of 3.273. The calculated t value was 21.432 (P < 0.001). CONCLUSION: SIM was observed to be very effective in this study and therefore should be adopted by health personnel in order to convey health-related information to the public. PMID- 27512697 TI - Effect of anger management education on mental health and aggression of prisoner women. AB - BACKGROUND AND PURPOSE: "Uncontrolled anger" threats the compatible and health of people as serious risk. The effects of weaknesses and shortcomings in the management of anger, from personal distress and destruction interpersonal relationships beyond and linked to the public health problems, lack of compromises, and aggressive behavior adverse outcomes. This study investigates the effects of anger management education on mental health and aggression of prisoner women in Isfahan. MATERIALS AND METHODS: The single-group quasi experimental (pretest, posttest) by prisoner women in the central prison of Isfahan was done. Multi-stage random sampling method was used. Initially, 165 women were selected randomly and completed the Buss and Perry Aggression Questionnaire and the General Health Questionnaire-28, and among these, those with scores >78 (the cut point) in aggression scale was selected and among them 70 were randomly selected. In the next step, interventions in four 90 min training sessions were conducted. Posttest was performed within 1-month after the intervention. Data were analyzed using SPSS-20 software. RESULTS: Data analysis showed that anger management training was effective in reducing aggression (P < 0.001) and also had a positive effect on mental health (P < 0.001). CONCLUSION: According to the importance of aggression in consistency and individual and collective health and according to findings, presented educational programs on anger management is essential for female prisoners. PMID- 27512698 TI - Effects of a family centered program on perceived social support in patients with congestive heart failure: An interventional study. AB - BACKGROUND AND OBJECTIVES: Congestive heart failure is one of the most common cardiovascular diseases that have a progressive and chronic trend and influences individuals' and their families' various dimensions. Social support is one of the psychosocial factors that can have a positive effect on individuals' physical, mental and social status. Despite the existence of evidences, revealing the importance of family's support on patients' condition, family centered supportive interventions with goal of clinical outcomes improvement have been less conducted among these patients. Therefore, the present study aimed to investigate the effect of family supportive intervention on the level of the support, received among heart failure patients. MATERIALS AND METHODS: This is a two-group two stage clinical trial, conducted on 64 patients with cardiac failure, referring to selected educational centers and meeting the inclusion criteria, who were selected through convenient sampling. They were assigned to study (n = 32) and control (n = 32) groups through random allocation. Data were collected by questioning through a two-section medical records questionnaire and were analyzed by SPSS. RESULTS: Results of the study showed that mean scores of received support score were 13.7 (3.8) in the study and 0.8 (2.4) in the control group. Independent t-test showed a significant difference in mean changes of perceived support scores after the intervention between study and control groups (P < 0.001). CONCLUSIONS: Based on familial dimension in social support have a positive effect on patients' perceived support. Nurses, as professional members of health care team, and with an important role in education and care of cardiac failure patients, can support, educate and guide these patients through designing appropriate care plans and educating their family members. PMID- 27512699 TI - Experience of Behvarzes (Iranian primary healthcare providers) from giving primary health services in health houses. AB - BACKGROUND: Primary healthcare (PHC) providers play a major role in provision of public health in rural areas in Iran. They are considered as the key elements of health development in rural population. There is limited research on clarification of their experiences from provision of health services in their working conditions. This study aimed to clarify the experience of PHC providers from working conditions in giving primary health services in health houses (district branches of rural health care centers). MATERIALS AND METHODS: This is a content analysis qualitative study, conducted through personal and group interviews with 12 health workers working in health care centers in rural areas in Isfahan province, 2010. Sampling continued until data saturation. Data were analyzed through conventional content analysis and constant comparative method. RESULTS: Data analysis led to extraction of 11 categories, and finally, four themes of "ignoring the rights," "causing tension in working climate," "pressure or overload of expectations beyond the power," and "occupational worn out" were yielded from the categories. These themes reveal the concepts and nature of PHC providers' experiences from giving health care at health houses as the first level of PHC centers. CONCLUSION: The results of the present study showed that the PHC providers work in a tense condition in health houses. Although they devote themselves to the health of society members, their own health is neglected. Policy makers and authorities should amend working conditions of PHC providers through modification of resources and making supportive and collaborative strategies to improve the quality of services and promote the health level of the service receivers. PMID- 27512700 TI - Effect of physical activity on musculoskeletal discomforts among handicraft workers. AB - INTRODUCTION: Handicrafts seems to be one of the high-risk jobs regarding work related musculoskeletal disorders (WMSDs) which necessitate the implementation of different corrective intervention like regular physical activities. This study aimed to investigate the impact of physical activity on WMSDs among craftsmen. METHODS: This cross-sectional study was an analytical - descriptive study carried out on 100 craftsmen working in Isfahan, Iran, in 2013. The sampling method was census, and all workshops involved with this job were included. Information on demographic parameters and physical activity was collected by demographic forms. The data related to worker's musculoskeletal discomforts were conducted using Cornell Musculoskeletal Discomfort Questionnaire. The data were analyzed using statistical tests including independent t-test, Chi-square, and ANOVA. The statistical analysis was performed using SPSS 18. RESULTS: The highest percentages of complaints related to severe musculoskeletal discomfort were reported in right shoulder (%36), right wrist (%26), neck (%25), and upper right arm (%24), respectively. A significant relationship was observed between physical activity and musculoskeletal discomforts of left wrist (P = 0.012), lower back (P = 0.016), and neck (P = 0.006). DISCUSSION AND CONCLUSION: Based on the study results, it can be inferred that regular but not too heavy physical activity can have a positive impact on decreasing the musculoskeletal discomforts. PMID- 27512701 TI - The effect of assisted reproduction treatment on mental health in fertile women. AB - INTRODUCTION: The process of assisted reproductive treatment is a stressful situation in the treatment of infertile couples and it would harm the mental health of women. Fertile women who started infertility treatment due to male factor infertility have reported to experience less stress and depression than other women before the assisted reproductive process but considering the cultural and social factors and also the etiology of the assisted reproductive process, it could affect the metal health of these women. Therefore, this study was conducted to evaluate the mental health of fertile women who undergo assisted reproductive treatment due to male factor infertility. MATERIALS AND METHODS: This study was a prospective study on 70 fertile women who underwent assisted reproductive treatment due to male factor infertility. The exclusion criterion was to stop super ovulation induction. To assess mental health, anxiety and depression dimensions of the general health questionnaire were used. Before starting ovulation induction and after oocyte harvesting, the general health questionnaire was filled by women who were under treatment. Data were analyzed using multi variable linear regression, paired t-test, and Chi-square. RESULTS: The results showed that the mean score of depression and anxiety before ovulation induction and after oocyte harvesting were not significantly different; but the rate of mental health disorder in the depression dimension was significantly decreased after oocytes harvesting (31.7% vs. 39.7%). Also, there was a significant relation between the level of anxiety and depression before ovulation induction and after oocyte harvesting (P < 0.05). The anxiety level after oocyte harvesting had a positive and significant correlation with the economic situation (P < 0.05). CONCLUSION: This study revealed that the process of assisted reproductive treatment does not affect the mental health in fertile women independently, but these women start assisted reproductive process with high levels of depression and anxiety. Therefore, prior to the assisted reproductive treatment mental health consultation is needed. PMID- 27512702 TI - Validity, reliability and factor analysis of Persian version of schizophrenia quality of life scale. AB - CONTEXT: Exact measurement of quality of life (QOL) in schizophrenia patients for evaluation of the patient's deterioration and also to assess the efficacy of therapeutic Interventions has become a daily task, which requires accurate assessment tools. AIMS: This study was aimed to assess the psychometric properties of a Persian version of schizophrenia QOL scale (SQLS) as a common transcultural instrument. SETTINGS AND DESIGN: One hundred and fifty schizophrenia patients who referred to Psychiatric Clinic in Noor Hospital (Isfahan, Iran) have been selected using simple sampling method. SUBJECTS AND METHODS: Aside with SQLS, short form-36 general health (SF-36) and World Health Organization QOL-brief-26 (WHOQOL-BREF-26). Questionnaires were completed by the cases for determination of correlation coefficients. STATISTICAL ANALYSIS USED: The data were analyzed using descriptive statistics, factor analysis, Cronbach's coefficient alpha, Pearson correlation coefficient by Statistical Package for Social Sciences software, version 18 (SPSS-18). RESULTS: Total reliability of the questionnaire was reported by using Cronbach's coefficient alpha 0.84, reliability of individual relationships subscales was 0.91, signs 0/87, symptoms 0/72 and motivation/energy 0/61. Correlation coefficients of SF-36 with a total scale of SQLS and correlation coefficient of WHOQOL-BREF-26 with a total scale of SQLS were acceptable. Exploratory factor analysis using varimax rotation identified four principle components (interpersonal relationship, symptoms, signs, motivation, and energy), which will determine QOL at 52.7% variance. CONCLUSIONS: Persian version of the SQLS can be used as a simple, reliable and valid tool in Iranian population. PMID- 27512703 TI - Prescription to over-the-counter switches in the United States. AB - As the role of the pharmacist becomes more patient and counseling-centered, the healthcare market is changing to keep pace with more modern needs, such as self treatment. Self-treatment provides patients the ability to diagnose their own condition and pick an appropriate medication from the pharmacy to treat their symptoms. This process allows a certain freedom for consumers to actively engage in their own health. In order for patients to self-treat, access to over-the counter (OTC) medication is of prime importance. Many medications that are available as OTC today were previously labeled as prescription medications. As more safety studies and trials are conducted for different drugs, they can be deemed appropriate for use without a prescription. This review study discusses the process of switching of prescription medications to OTC medications in the United States and the implications of switching on patients, practitioners, drug makers, and insurers. PMID- 27512704 TI - Pharmaceutical laws and regulations in Iran: An overview. AB - The pharmaceutical legal framework is a very important infrastructure in achieving predefined goals in pharmaceutical sector: Accessibility, quality, and rational use of medicine. This study aims to review the current pharmaceutical sector-related legal provisions in Iran where the Food and Drug Organization (FDO) is in charge of regulating all issues related to the pharmaceutical sector. The main laws and regulations enacted by parliament and cabinet and even internal regulations enacted by the Ministry of Health or Iran FDO are reviewed. Different laws and regulations are categorized according to the main goals of Iran national drug policy. PMID- 27512705 TI - Critical review of drug promotional literature using the World Health Organization guidelines. AB - OBJECTIVE: Drug promotional literatures (DPLs) are used as a promotional tool to advertise new drugs entering the market to doctors. The objective of the present study is to evaluate the accuracy of DPLs by using the World Health Organization (WHO) criteria. METHODS: An observational study was conducted from March to August 2014. The DPLs were collected from various departments at R.L. Jalappa Hospital and Research Centre attached to Sri Devaraj Urs Medical College, Kolar, India. The literature was evaluated based on 11 criteria laid down by the WHO. FINDINGS: Two-hundred DPLs were evaluated. Cardiovascular drugs (34 [17%]) were promoted the most, followed by antidiabetic drugs (31 [15.5%]) and antimicrobial agents (29 [14.5%]). Single drug was promoted in 134 (67%) and fixed drug combination in 66 (33%) brochures. Manufacturer's name was mentioned in 194 (97%), but their address was mentioned in 109 (54.5%) claims only. Drug cost was revealed only in 12 (6%) DPLs. Each ingredient's generic name, brand name, and dosage form were mentioned in 197 (98%) brochures. Indication for use was stated in 193 (96.5%) claims. Contraindications, adverse effects, precautions, and drug interactions were listed in 68 (34.5%), 65 (32.5%), 65 (32.5%), and 58 (29%) advertisements. References were cited in 133 (66.5%) brochures. Only 63 (31.5%) literatures had relevant pictures of drugs being promoted and 59 (29.5%) had a graphical representation of pharmacological properties. A total of 131 (69%) DPLs followed 50% of the WHO criteria. CONCLUSION: Majority of DPLs satisfied only half of the WHO criteria for rational drug promotion and none of them fulfilled all the specified criteria. Incomplete or exaggerated information in DPLs may mislead and result in irrational prescription. Therefore, physicians should critically evaluate DPLs regarding updated scientific evidence required for quality patient care. PMID- 27512706 TI - Tenofovir in treatment of Iranian patients with chronic hepatitis B virus infection: An open-label case series. AB - OBJECTIVE: Tenofovir is among the first-line treatments for chronic hepatitis B (CHB) virus infection. We evaluated the efficacy and safety of Tenofovir in treatment of Iranian patients with CHB. METHODS: Forty treatment-native patients with CHB but without concurrent hepatitis C or human immunodeficiency virus infections were treated with Tenobiovir(TM) 300 mg/day. The hepatitis B virus (HBV) DNA load, hepatitis B e antigen (HBe Ag), anti-hepatitis B e antibody (HBe Ab), liver enzymes, and creatinine were measured before and at least 3 months after the treatment. FINDINGS: The mean age of patients was 38.1 +/- 12.4 years and 65% of them were male. Seventeen (42.5%) patients were HBe Ag-positive and 15 (37.5%) patients had alanine aminotransferase (ALT) of two times above the normal. The HBV DNA load was significantly decreased after the treatment (P < 0.001). Twenty-seven (67.5%) patients had viral load of <=2000 IU/ml and 22 (55%) patients had undetectable HBV DNA level after the treatment. Among positive HBe Ag patients, the HBe Ag became negative in 15 (88.2%) patients after the treatment and HBe Ab became positive in 3 (17.6%) patients. Liver enzymes' levels were significantly decreased after the treatment (P <0.05) and ALT transaminase level became normalized in 86.7% (13 out of 15) of cases with baseline levels twice the normal. CONCLUSION: Treatment response rate to Tenofovir in Iranian patients with CHB was high. The virological and serological response rate and safety of Tenofovir in our population was comparable to other populations. Considering availability and costs, Tenobiovir(TM) could be recommended as the first-line therapy of chronic HBV infection in Iran. PMID- 27512707 TI - Effect of antiepileptic drug therapy on thyroid hormones among adult epileptic patients: An analytical cross-sectional study. AB - OBJECTIVE: The objective of the study was to evaluate and compare the effect of conventional and newer antiepileptic drugs (AEDs) on thyroid hormone levels in adult epileptic patients. METHODS: A hospital-based, analytical cross-sectional study was conducted among the adult epileptic patients receiving conventional AEDs (Group 2) or newer AEDs (Group 3) for more than 6 months. Serum thyroid hormone levels including free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) were analyzed and the hormonal status was compared with healthy control subjects (Group 1). FINDINGS: Sodium valproate and phenytoin were commonly used conventional AEDs; levetiracetam and topiramate were common among the newer drugs. There was a statistically significant decrease in serum fT4 and increase in serum TSH levels (P < 0.0001) in patients on long-term therapy with conventional antiepileptic agents than in the control group. No significant change in thyroid hormone levels (fT3, fT4, and TSH; P = 0.68, 0.37, and 0.90, respectively) was observed with newer antiepileptics-treated patients when compared to control group. One-way analysis of variance followed by post hoc Dunnett's test was performed using SPSS version 17.0 software package. CONCLUSION: The present study showed that conventional AEDs have significant alteration in the thyroid hormone levels than the newer antiepileptics in adult epileptic patients. PMID- 27512708 TI - Malaria rapid diagnostic test evaluation at private retail pharmacies in Kumasi, Ghana. AB - OBJECTIVE: Malaria rapid diagnostic test (MRDT) provides a good alternative to malaria microscopy diagnosis, particularly in resource-constrained settings. This study therefore evaluated MRDT in private retail pharmacies (PRPs) as a critical step in community case malaria management. METHODS: In a prospective, cross-over, validation survey at six PRPs in the Ashanti Region of Ghana, 1200 patients presenting with fever in the preceding 48 h were sampled. Fingerstick blood samples were collected for preparation of thick and thin blood films for malaria microscopy. Categorized patients (600 each) went through the processes of MRDT or presumptive diagnosis (PD) of malaria. The malaria disease prevalence of the study area was established. Selectivity (Se), specificity (Sp), positive predictive value (PPV) along with false discovery rate (FDR), and negative predictive value (NPV) along with the false omission rate (FOR), and diagnostic odds ratio (DOR) of MRDT were then calculated. FINDINGS: While 43.0% tested positive using the MRDT, 57.0% tested negative. However, 62.0% MRDT-negative patients in addition to all the MRDT positives were given artemether lumefantrine. Of those diagnosed by PD, 98.2% were prescribed with an antimalarial (microscopy however confirmed only 70.3% as positive). Se and Sp of the MRDT were 90.68 +/- 11.18% and 98.68 +/- 1.19%, respectively. Malaria prevalence was estimated to be 43.3%. PPV was 98.0%, FDR was 2.0%, NPV was 98.0%, FOR was 2.0%, and DOR was 2366.43. CONCLUSION: Results highlighted good performance of MRDTs at PRPs which could inform decision toward its implementation. PMID- 27512709 TI - Quality of life in relapsing-remitting multiple sclerosis patients receiving CinnoVex compared with Avonex. AB - OBJECTIVE: There is an increasing recognition among clinicians and researchers that the impact of chronic illnesses and their treatments must be assessed in terms of their quality of life (QoL) in addition to more traditional measures of clinical outcomes. The aim of this study was to compare the QoL in patients with relapsing-remitting multiple sclerosis (RRMS) using Avonex or CinnoVex. METHODS: We conducted a cross-sectional study on one hundred patients with RRMS, fifty and fifty patients were being treated with Avonex (Biogen Idec, USA) and CinnoVex (CinnaGen, Iran), respectively. We used a disease-specific questionnaire for MS (Multiple Sclerosis Quality of Life-54 [MSQoL-54]). Both groups were tested for significant differences regarding sociodemographic. A multiple linear regression model was constructed to find factors that affected the different aspect of QoL of the whole sample of patients. FINDINGS: MS groups did not differ in physical and mental health composite scores as well as relative scales. The results of regression models for each subscale showed that age, marriage, and Expanded Disability Status Scale were associated with several subscales of the MSQoL-54 (P < 0.05). CONCLUSION: In this study, it was seen that there are no significant differences between QoL of Avonex and CinnoVex, but a limitation in our study the results may be different in other countries and even various areas in Iran. PMID- 27512710 TI - Adherence to stress-related mucosal damage prophylaxis guideline in patients admitted to the Intensive Care Unit. AB - OBJECTIVE: Concern about adverse effects of the inconsistent use of stress related mucosal damage prophylaxis in intensive care unit (ICU) is increasing. Hence, this study was designed to prospectively evaluate the rate of inappropriate stress ulcer prophylaxis (SUP) administration upon ICU admission, at ICU discharge and determine the adherence to American Society of Health-System Pharmacists (ASHP) guideline during ICU stay. METHODS: In this study, 200 patients were randomly selected from all ICU admissions during 9 months. Risk factors of stress ulcer were recorded daily during ICU stay and appropriateness of SUP administration was assessed according to the ASHP criteria. FINDINGS: Of all 160 (80%) patients who received SUP, 44.4% did not have indication; and among 95 patients with an indication for SUP administration, 6.3% did not receive it upon ICU admission. Consequently, 77 (38.5%) of 200 patients received inappropriate prophylaxis on ICU admission. In addition, 53.5% of patients had appropriate adherence to ASHP guideline during all days of ICU stay (44% and 2.5% of patients received SUP more than 120% and <80% of appropriate SUP duration, respectively). Moreover, 81.2% were continued on inappropriate prophylaxis upon transfer from the ICU. CONCLUSION: We concluded that although SUP administration included both overutilization and underutilization in this ICU, but high prevalence of SUP overutilization caused unnecessary hospital costs, personal monetary burden, and may increase adverse drug reactions. Therefore, educating physicians and cooperation of clinical pharmacists regarding implementing standard protocols could improve patterns of SUP administration. PMID- 27512711 TI - The use of sunscreen products among final year medicine and pharmacy students: A cross-sectional study of knowledge, attitude, practice, and perception. AB - OBJECTIVE: To evaluate the knowledge, attitude, perception, and practice of medical and pharmacy students toward the usage of sunscreen as protection for the skin against ultraviolet (UV) radiation. METHODS: This cross-sectional study was conducted among final year medical and pharmacy undergraduates at the International Islamic University Malaysia. Validated questionnaires were distributed to 134 medical students and 100 pharmacy students. Descriptive and inferential statistics were used where appropriate. FINDINGS: One hundred and sixty-one out of 234 participants completed the questionnaires. The participants comprised 101 medical students (75.4%) and sixty pharmacy students (60.0%). The majority of the respondents were females (102; 63.4%), and 59 (36.6%) were males. The median of the knowledge scores of the final year medical students was significantly lower than that of the final year pharmacy students (P < 0.001). The female students showed significantly higher knowledge scores than the male students (P = 0.027). This study reported that 24 (39.3%) pharmacy students were influenced by the media to use sunscreen, whereas 35 (34.7%) medical students were influenced the most by friends to use sunscreen. The final year pharmacy students had a better perception compared to the medical students, with the total perception score of the final year pharmacy students being significantly higher than that of the final year medical students (P = 0.020). Most of the participants were also aware of the harmful effects of UV radiation and had a positive reaction toward the usage of sunscreen to prevent those harmful effects. CONCLUSION: The knowledge and perception of final year pharmacy students were significantly higher than the knowledge and perception of final year medical students with regard to the usage of sunscreen. PMID- 27512712 TI - Evaluation of knowledge, attitude, and practice of community pharmacists toward administration of over-the-counter drugs for the treatment of diarrhea in children: A pretest-posttest survey. AB - OBJECTIVE: In this study, we aimed to assess knowledge, attitude, and practice of community pharmacists toward administration of over-the-counter (OTC) antidiarrheal drugs in our city pharmacies, Shiraz, Iran. METHODS: In this descriptive cross-sectional study, 90 pharmacies among 128 pharmacies in our city were randomly chosen. The study was designed into two phases: A standard questionnaire to determine the level of knowledge and attitude of pharmacists and a simulated client method to evaluate practice among them. An educational pamphlet was then given to the pharmacists. One month later, knowledge, attitude, and performance of studied pharmacists were evaluated again using the same method. FINDINGS: Our results showed that an average consultation time by female pharmacists was considerably more than male pharmacists (P < 0.001). Before intervention, only 37.8% of pharmacists performed appropriately by prescribing the proper medicine while this increased to 58.44% after intervention. The average score of pharmacists' knowledge was statistically increased (P < 0.001) and the pharmacists' performance was significantly improved (P < 0.001) after the educational intervention. In related to the attitude, pharmacists' tendency toward prescribing oral rehydration salt solutions (ORS) (P < 0.001) and their belief about the great effect of ORS on the treatment of diarrhea increased significantly after the intervention. CONCLUSION: It is concluded that training programs such as educational pamphlets and continuing educational seminars may play important roles in increasing pharmacists' knowledge and therefore improving their performance in prescribing OTC medicines. PMID- 27512713 TI - Clinical outcomes of a diabetes education program for patients with diabetes mellitus in the Micronesian community in Hawaii. AB - OBJECTIVE: Hawaii has diverse population made up of a cultural mix of different races. Due to different cultural and social influences and language barrier, many of the under-served population who migrated to Hawaii and having diabetes mellitus may be susceptible to long-term complications due to uncontrolled hyperglycemia and medication nonadherence. The purpose of this study was to evaluate the impact of a diabetes education program on the clinical outcomes in patients with diabetes mellitus in the Micronesian community of Hawaii. METHODS: This study included patients over age 18 years, with a diagnosis of type 2 diabetes mellitus. The diabetes education program was customized for its weekly classes to fit to the under-served population. Data were collected on participants on the 1(st) day and then 6 months after attending the education program. Data on primary and secondary endpoints were collected and analyzed. FINDINGS: The mean glycosylated hemoglobin A1c, fasting blood glucose, and triglyceride levels of participants fell significantly from baseline after attending the diabetes education program for 6 months. No significant changes were observed in other secondary outcomes during the study time period. CONCLUSION: Based on our findings, the diabetes education program that was tailored to the Micronesian population was successful in achieving glycemic goals, enhancing medication adherence, improving clinical outcomes, and also preventing long-term complications among its participants. PMID- 27512714 TI - Ganciclovir use evaluation in kidney transplantation departments. AB - OBJECTIVE: In this study, we evaluated certain aspects of the usage and administration of one lifesaving, high-cost medication, i.e., Ganciclovir for the prevention and treatment of cytomegalovirus (CMV) infection in transplant patients. METHODS: This study was performed from 2013 to 2015 by conducting a medication use evaluation (MUE) program in the kidney transplantation departments of two tertiary care hospitals in Isfahan, Iran. The MUE criteria for the drug were developed by applying drug information references. In every category of data, the number (percent) of cases, in which drug therapy was in accordance with the predetermined criteria, was calculated. FINDINGS: During the study period, 67 cases were observed. The only documented drug interaction was the minor interaction of Ganciclovir with mycophenolate mofetil in 77% of the patients. In all patients, intravenous (IV) infusion was the route of administration, mainly in the peripheral veins. Four patients showed adverse drug reaction, which leads to Ganciclovir discontinuation. Ganciclovir was administered despite contraindication in 34.3% of the patients. CONCLUSION: In this study, we faced a relatively unacceptable situation, in which Ganciclovir is handled somehow inappropriately. It seems necessary to develop an updated local guideline to approximate the administering pattern of such costly medications to standard protocols. PMID- 27512715 TI - Dapsone-induced pure red cell aplasia and cholestatic jaundice: A new experience for diagnosis and management. AB - Dapsone (4,4'- diaminodiphenylsulfone) is the parent compound of the sulfones, and it has potent antiparasitic, anti-inflammatory, and immunomodulatory effects. It is used in the treatment of leprosy, dermatitis herpetiformis, and prophylactically to prevent Pneumocystis pneumonia and toxoplasmosis in patients unable to tolerate trimethoprim with sulfamethoxazole. We hereby report a case of dapsone toxicity who developed pure red cell aplasia and cholestatic jaundice in a suspected case of dermatitis herpetiformis. Patient had an excellent response to corticosteroids after withdrawal of dapsone. PMID- 27512716 TI - Attitude of nurses and pharmacists on adverse drug reactions reporting in selected hospitals in Sokoto, Northwest Nigeria. AB - OBJECTIVE: Objective of this study was to assess the attitude of nurses and pharmacists towards adverse drug reactions (ADRs) reporting. METHODS: The questionnaire was designed based on extended "Inman seven deadly sins." Two hundred and seventy-two respondents were selected by stratified sampling technique. The questionnaires were delivered to the respondents at their places of practice. The data generated were analyzed by Sigma XL Software Inc. FINDINGS: There was no statistically significant relationship between demographic profiles and reporting attitude except for qualification. On extended "Inman seven deadly sins" awareness of reporting protocol and nearby center for ADRs reporting were low 27.3 and 7.5%, respectively. However, respondents' score on components of attitude of ADRs reporting is generally encouraging. On comparative basis, no statistical significance exists between pharmacists and nurses. CONCLUSION: The study showed that attitude of respondents towards ADRs reporting is good. However, there is a need for targeted health education intervention among these cadres of health-care professionals, especially on aspects of awareness of reporting protocol and reporting center. PMID- 27512717 TI - A study of medication-related problems in stroke patients: A need for pharmaceutical care. AB - OBJECTIVE: The study was aimed to assess the incidence and characteristics of drug-related problems (DRPs). METHODS: A prospective, observational study was conducted among 133 patients with stroke disease who were aged 18 years or older and admitted to the general medicine ward. During the 6 months study period, the incidence of DRPs was identified using the Pharmaceutical Care Network Europe Foundation classification system, version 6.2. FINDINGS: A total of 133 patients were screened for DRPs. Among them, 120 patients have at least one DRP. A total of 254 DRPs were identified (on average, 2.015 DRPs per each patient case). CONCLUSION: Increasing the evidence of the incidence of medication-related problems in tertiary care hospitals indicates the need for the establishment of a clinical pharmacist in hospital settings. PMID- 27512718 TI - A High Concentration of Genistein Induces Cell Death in Human Uterine Leiomyoma Cells by Autophagy. AB - Genistein, an estrogenic, soy-derived isoflavone, may play a protective role against hormone-related cancers. We have reported that a high concentration of genistein inhibits cell proliferation and induces apoptosis in human uterine smooth muscle cells, but not in leiomyoma (fibroid) cells. To better understand the differential cell death responses of normal and tumor cells to a high concentration of genistein, we treated uterine smooth muscle cells and uterine leiomyoma cells with 50 MUg/ml of genistein for 72 h and 168 h, and assessed for mediators of apoptosis, cytotoxicity and autophagy. We found that leiomyoma cells had increased protection from apoptosis by expressing an increased ratio of Bcl 2: bak at 72 h and 168 h; however, in smooth muscle cells, the Bcl-2: bak ratio was decreased at 72 h, but significantly rebounded by 168 h. The apoptosis extrinsic factors, Fas ligand and Fas receptor, were highly expressed in uterine smooth muscle cells following genistein treatment at both time points as evidenced by confocal microscopy. This was not seen in the uterine leiomyoma cells; however, cytotoxicity as indicated by elevated lactate dehydrogenase levels was significantly enhanced at 168 h. Increased immunoexpression of an autophagy/autophagosome marker was also observed in the leiomyoma cells, although minimally present in smooth muscle cells at 72 h. Ultrastructurally, there was evidence of autophagic vacuoles in the leiomyoma cells; whereas, the normal smooth muscle cells showed nuclear fragmentation indicative of apoptosis. In summary, our data show differential cell death pathways induced by genistein in tumor and normal uterine smooth muscle cells, and suggest novel cell death pathways that can be targeted for preventive and intervention strategies for inhibiting fibroid tumor cell growth in vivo. PMID- 27512719 TI - Ex vivo testing of intact eye globes under inflation conditions to determine regional variation of mechanical stiffness. AB - BACKGROUND: The eye globe exhibits significant regional variation of mechanical behaviour. The aim of this present study is to develop a new experimental technique for testing intact eye globes in a form that is representative of in vivo conditions, and therefore suitable for determining the material properties of the complete outer ocular tunic. METHODS: A test rig has been developed to provide closed-loop control of either applied intra-ocular pressure or resulting apical displacement; measurement of displacements across the external surface of the eye globe using high-resolution digital cameras and digital image correlation software; prevention of rigid-body motion and protection of the ocular surface from environmental drying. The method has been demonstrated on one human and one porcine eye globe, which were cyclically loaded. Finite element models based on specimen specific tomography, free from rotational symmetry, were used along with experimental pressure-displacement data in an inverse analysis process to derive the mechanical properties of tissue in different regions of the eye's outer tunic. RESULTS: The test method enabled monitoring of mechanical response to intraocular pressure variation across the surface of the eye globe. For the two eyes tested, the method showed a gradual change in the sclera's stiffness from a maximum at the limbus to a minimum at the posterior pole, while in the cornea the stiffness was highest at the centre and lowest in the peripheral zone. Further, for both the sclera and cornea, the load-displacement behaviour did not vary significantly between loading cycles. CONCLUSIONS: The first methodology capable of mechanically testing intact eye globes, with applied loads and boundary conditions that closely represent in vivo conditions is introduced. The method enables determination of the regional variation in mechanical behaviour across the ocular surface. PMID- 27512720 TI - Can Genetic Testing Coupled with Enhanced Dopaminergic Activation Reduce Recidivism Rates in the Workers Compensation Legacy Cases? PMID- 27512721 TI - Factors Associated With Emergency Department Visits: A Multistate Analysis of Adult Fee-for-Service Medicaid Beneficiaries. AB - OBJECTIVE: The objective of this study was to examine the association of patient- and county-level factors with the emergency department (ED) visits among adult fee-for-service (FFS) Medicaid beneficiaries residing in Maryland, Ohio, and West Virginia. METHODS: A cross-sectional design using retrospective observational data was implemented. Patient-level data were obtained from 2010 Medicaid Analytic eXtract files. Information on county-level health-care resources was obtained from the Area Health Resource file and County Health Rankings file. RESULTS: In adjusted analyses, the following patient-level factors were associated with higher number of ED visits: African Americans (incidence rate ratios [IRR] = 1.47), Hispanics (IRR = 1.63), polypharmacy (IRR = 1.89), and tobacco use (IRR = 2.23). Patients with complex chronic illness had a higher number of ED visits (IRR = 3.33). The county-level factors associated with ED visits were unemployment rate (IRR = 0.94) and number of urgent care clinics (IRR = 0.96). CONCLUSION: Patients with complex healthcare needs had a higher number of ED visits as compared to those without complex healthcare needs. The study results provide important baseline context for future policy analysis studies around Medicaid expansion options. PMID- 27512722 TI - Alopecia areata after denosumab treatment for osteoporosis. PMID- 27512723 TI - Identification of Asthma Subtypes Using Clustering Methodologies. AB - Asthma is a heterogeneous disease comprising a number of subtypes which may be caused by different pathophysiologic mechanisms (sometimes referred to as endotypes) but may share similar observed characteristics (phenotypes). The use of unsupervised clustering in adult and paediatric populations has identified subtypes of asthma based on observable characteristics such as symptoms, lung function, atopy, eosinophilia, obesity, and age of onset. Here we describe different clustering methods and demonstrate their contributions to our understanding of the spectrum of asthma syndrome. Precise identification of asthma subtypes and their pathophysiological mechanisms may lead to stratification of patients, thus enabling more precise therapeutic and prevention approaches. PMID- 27512724 TI - Optimization of a Clinically Relevant Model of White Matter Stroke in Mice: Histological and Functional Evidences. AB - BACKGROUND AND PURPOSE: White matter (WM) injury during stroke increases the risk of disability and gloomy prognosis of post-stroke rehabilitation. However, modeling of WM loss in rodents has proven to be challenging. METHODS: We report improved WM injury models in male C57BL/6 mice. Mice were given either endothelin 1 (ET-1) or L-N5-(1-iminoethyl)ornitine (L-NIO) into the periventricular white matter (PVWM), in the corpus callosum (CC), or in the posterior limb of internal capsule (PLIC). Anatomical and functional outcomes were quantified on day 7 post injection. RESULTS: Injection of ET-1 or L-NIO caused a small focal lesion in the injection site in the PVWM. No significant motor function deficits were observed in the PVWM lesion model. We next targeted the PLIC by using single or double injections of L-NIO and found that this strategy induced small focal infarction. Interestingly, injection of L-NIO in the PLIC also resulted in gliosis, and significant motor function deficits. CONCLUSIONS: By employing different agents, doses, and locations, this study shows the feasibility of inducing brain WM injury accompanied with functional deficits in mice. Selective targeting of the injury location, behavioral testing, and the agents chosen to induce WM injury are all keys to successfully develop a mouse model and subsequent testing of therapeutic interventions against WM injury. PMID- 27512725 TI - Large tumor suppressors 1 and 2 regulate Aurora-B through phosphorylation of INCENP to ensure completion of cytokinesis. AB - The tumor suppressor kinases LATS1 and LATS2 (LATS1/2) regulate not only organ size through the Hippo signaling pathway, but also cell-cycle checkpoints and apoptosis via other signaling cascades. We previously reported that LATS1/2 localize to the mitotic apparatus, where they are involved in the phosphorylation and activation of the mitotic kinase Aurora-B; however, the detailed mechanism of LATS1/2 action remains obscure. The activity of Aurora-B is stringently regulated by formation of the chromosomal passenger complex containing the inner centromere protein (INCENP), which leads to appropriate activation of Aurora-B during mitosis and cytokinesis. In this study, we found that LATS1/2 phosphorylated INCENP at S894 in the Thr-Ser-Ser motif. Moreover, the LATS-mediated phosphorylation of S894 was necessary and sufficient for the activation of Aurora B, which is required for completion of cytokinesis in cells engaged in multipolar division. We propose a novel mechanism for regulation of Aurora-B via INCENP phosphorylation by LATS1/2 during cytokinesis. PMID- 27512728 TI - Preparation and characterization of lithium ion conducting polymer electrolytes based on a blend of poly(vinylidene fluoride-co-hexafluoropropylene) and poly(methyl methacrylate). AB - Ion conducting polymer electrolytes composed of poly(vinylidene fluoride-co hexafluoropropylene) (PVdF-HFP), poly(methyl methacrylate) (PMMA) and lithium triflate (LiTf) were prepared using the solution casting method. Structural change and complex formation in the blend electrolyte systems were confirmed from the X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM) studies. Thermal properties of the samples were investigated by the differential scanning calorimetry (DSC) technique. The ionic conductivity of these polymer electrolytes was studied by impedance spectroscopy at various temperatures ranging from 303-393 K. The results reveal that the ionic conductivity of the polymer blend electrolytes depends on the PVdF HFP:PMMA composition as well as the temperature. Maximum room temperature conductivity of [Formula: see text] S cm(-1) was achieved with 22.5 wt.% PMMA. The blending of PVdF-HFP with PMMA improved the thermal stability and ionic conductivity of the polymer electrolyte. Estimated transference numbers suggest the charge transport is predominantly ionic. PMID- 27512727 TI - A small molecule-based strategy for endothelial differentiation and three dimensional morphogenesis from human embryonic stem cells. AB - The emerging models of human embryonic stem cell (hESC) self-organizing organoids provide a valuable in vitro platform for studying self-organizing processes that presumably mimic in vivo human developmental events. Here we report that through a chemical screen, we identified two novel and structurally similar small molecules BIR1 and BIR2 which robustly induced the self-organization of a balloon shaped three-dimensional structure when applied to two-dimensional adherent hESC cultures in the absence of growth factors. Gene expression analyses and functional assays demonstrated an endothelial identity of this balloon-like structure, while cell surface marker analyses revealed a VE cadherin(+)CD31(+)CD34(+)KDR(+)CD43(-) putative endothelial progenitor population. Furthermore, molecular marker labeling and morphological examinations characterized several other distinct DiI-Ac-LDL(+) multi-cellular modules and a VEGFR3(+) sprouting structure in the balloon cultures that likely represented intermediate structures of balloon-formation. PMID- 27512726 TI - 2-cyclohexylamino-5,8-dimethoxy-1,4-naphthoquinone inhibits LPS-induced BV2 microglial activation through MAPK/NF-kB signaling pathways. AB - AIMS: To verify the effects of several 5,8-dimethoxy-1,4-naphthoquinone (DMNQ) derivatives on LPS-induced NO production, cellular ROS levels and cytokine expression in BV-2 microglial cells. MAIN METHODS: An MTT assay and FACS flow cytometry were performed to assess the cellular viability and apoptosis and cellular ROS levels, respectively. To examine the expression of pro-inflammatory cytokines and cellular signaling pathways, semi-quantitative RT-PCR and Western blotting were also used in this study. KEY FINDINGS: Among the six newly synthesized DMNQ derivatives, 2-cyclohexylamino-5,8-dimethoxy-1,4-naphthoquinone (R6) significantly inhibited the NO production, cellular ROS levels and the cytokines expression in BV-2 microglial cells, which stimulated by LPS. Signaling study showed that compound R6 treatment also significantly down-regulated the LPS induced phosphorylation of MAPKs (ERK, JNK and p38) and decreased the degradation of IkappaB-alpha in BV2 microglial cells. SIGNIFICANCE: Our findings demonstrate that our newly synthesized compound derived from DMNQ, 2-cyclohexylamino-5,8 dimethoxy-1,4-naphthoquinone (R6), might be a therapeutic agent for the treatment of glia-mediated neuroinflammatory diseases. PMID- 27512729 TI - Histomorphometric parameters of normal full term placenta of Sudanese women. AB - The aim of the study was to provide values for morphometric parameters of histological components of normally delivered full term placentas of Sudanese women and compare them with reported parameters for other ethnic groups. A total of 200 histological sections, stained with hematoxylin and eosin and trichrome stains were used to give a final sample of 1000 fields saved as PowerPoint images for histomorphometry. A systematic random sampling procedure was adopted to ensure the optimum sample size that keeps the percentage error below 5% for the volume estimates. Standard stereological methods of point-counting and intersection-counting were applied to the microscopic fields to determine the volumes of placental components and surface area of fetal-maternal interface. The morphometric parameters showed no variations either between the placentas or between central and peripheral regions. The placental villi and the intervillus space occupied 65% and 35% of placental volume respectively with mean absolute values of 318 cm(3) and 169 cm(3). The mean absolute volume of the intervillus space was less than that of other ethnic groups by 8.67% but was significantly larger than that of the fetal capillaries which measured 41.2 cm(3). The ratio of the absolute volume of the intervillus space to the volume of the fetal blood capillaries was 4:1 in both Sudanese and other ethnic groups. In the placental villi the fetal connective tissue together with the contained blood vessels larger than capillaries occupied 88% of the villus volume. The mean surface area of the fetal-maternal interface of the placental villi (syncytiotrophoblast) was 12.59 M(2). PMID- 27512730 TI - Genetic factors for alcohol dependence and schizophrenia: common and rare variants. PMID- 27512731 TI - Angiotensin Receptors: Structure, Function, Signaling and Clinical Applications. AB - Angiotensinogen - a serpin family protein predominantly produced by the liver is systematically processed by proteases of the Renin Angiotensin system (RAS) generating hormone peptides. Specific cell surface receptors for at least three distinct angiotensin peptides produce distinct cellular signals that regulate system-wide physiological response to RAS. Two well characterized receptors are angiotensin type 1 receptor (AT1 receptor) and type 2 receptor (AT2 receptor). They respond to the octapeptide hormone angiotensin II. The oncogene product MAS is a putative receptor for Ang (1-7). While these are G-protein coupled receptors (GPCRs), the in vivo angiotensin IV binding sites may be type 2 transmembrane proteins. These four receptors together regulate cardiovascular, hemodynamic, neurological, renal, and endothelial functions; as well as cell proliferation, survival, matrix-cell interactions and inflammation. Angiotensin receptors are important therapeutic targets for several diseases. Thus, researchers and pharmaceutical companies are focusing on drugs targeting AT1 receptor than AT2 receptor, MAS and AngIV binding sites. AT1 receptor blockers are the cornerstone of current treatment for hypertension, heart failure, renal failure and many types of vascular diseases including atherosclerosis, aortic aneurism and Marfan syndrome. PMID- 27512732 TI - Dynamic view of postoperative pain evolution after total knee arthroplasty: a prospective observational study. AB - BACKGROUND: Having a dynamic view of postoperative pain resolution allows a better understanding of the transition towards chronic pain. Sleep and quality of life are important determinants of satisfaction after total knee arthroplasty (TKA), besides functional recovery and pain. METHODS: For 114 patients undergoing TKA we recorded the presence of pain at rest, pain evoked at movement and pain located at the incision site in the acute (postoperative day 1, 2, 3, 8), subacute (30 days, 3 months) and chronic (6 months and 1 year) period. Analgesics consumption and need of medical assistance for pain were questioned. Quality of life measured by the impact on enjoyment of life, sleep and mood were monitored. RESULTS: Average incidence for subacute pain was 54% at rest, 66% at mobilization. For chronic pain, the incidence was 14% at rest, 22% during mobilization. Pain at rest peaked at day 30 while pain during mobilization displayed a plateau between day 8 and 3 months. Three per cent of the patients complained at 1 year of pain at the incision site. 11% of patients still took analgesics one year after the surgery. More than 40% of patients reported moderate to severe alterations of sleep and quality of life in the acute period, decreasing to less than a half at one year. CONCLUSIONS: The trajectories of the different types of pain after TKA show their non-linear evolution, highlighting the need of a better pain control at precise moments. Sleep disturbances and alterations of quality of life are still present one year after the surgery. PMID- 27512733 TI - Resolution of osteosclerosis after alloHCT in systemic mastocytosis. PMID- 27512734 TI - CardioPulse: Regenerative medicine in the practice of cardiology. PMID- 27512735 TI - CardioPulse: Translational research in cardiovascular disease. PMID- 27512736 TI - CardioPulse: Progress in gene therapy for cardiovascular disease. PMID- 27512737 TI - CardioPulse: Gene linked to heart disease in women. PMID- 27512738 TI - [S2k-guideline Helicobacter pylori and gastroduodenal ulcer disease]. PMID- 27512739 TI - Response. PMID- 27512816 TI - The effects of passive stretching plus vibration on strength and activation of the plantar flexors. AB - This study examined the effects of passive stretching only (PS+CON) and passive stretching with the addition of continuous vibration (VIB) during post-passive stretching tests (PS+VIB) on peak torque (PT), percent voluntary inactivation (%VI), single stimulus twitch torque (TTSINGLE), and doublet stimuli twitch torque (TTDOUBLET) of the plantar flexors at a short (20 degrees plantar flexion (PF)) and long muscle length (15 degrees dorsiflexion (DF)). Fourteen healthy men (age = 22 +/- 3 years) performed isometric maximal voluntary contractions at PF and DF, and passive range of motion (PROM) assessments before and after 8 * 30 s passive stretches without (PS+CON) or with VIB (PS+VIB) administered continuously throughout post-passive stretching tests. The passive properties of the muscle tendon unit were assessed pre- and post-passive stretching via PROM, passive torque (PASSTQ), and musculotendinous stiffness (MTS) measurements. PT, TTSINGLE, and TTDOUBLET decreased, whereas, %VI increased following passive stretching at PF and DF (P < 0.05) with no significant differences between PS+CON and PS+VIB. PASSTQ and MTS decreased while PROM increased post-passive stretching during both trials (P < 0.05). The stretching-induced force/torque deficit and increases in %VI were evident following passive stretching at short and long muscle lengths. Although not statistically significant, effect size calculations suggested large and moderate differences in the absolute changes in PT (Cohen's d = 1.14) and %VI (Cohen's d = 0.54) from pre- to post-passive stretching between treatments, with PS+VIB having greater decreases of PT and higher %VI than PS+CON. The decrement in PT following passive stretching may be primarily neural in origin. PMID- 27512815 TI - "Weighing" the effects of exercise and intrinsic aerobic capacity: are there beneficial effects independent of changes in weight? AB - It has been known for centuries that regularly performed exercise has beneficial effects on metabolic health. Owing to its central role in locomotion and the fact that it accounts for a large majority of whole-body glucose disposal and fatty acid oxidation, the effects of exercise on skeletal muscle has been a central focus in exercise physiology research. With this being said it is becoming increasingly well recognized that both adipose tissue and liver metabolism are robustly modified by exercise, especially in conditions of obesity and insulin resistance. One of the difficult questions to address is if the effects of exercise are direct or occur secondary to exercise-induced weight loss. The purpose of this review is to highlight recent work that has attempted to tease out the protective effects of exercise, or intrinsic aerobic capacity, against metabolic and inflammatory challenges as it relates to the treatment and prevention of obesity and insulin resistance. Recent studies reporting improvements in liver and adipose tissue insulin action following a single bout of exercise will also be discussed. The research highlighted in this review sheds new insight into protective, anti-inflammatory effects of exercise that occur largely independent of changes in adiposity and body weight. PMID- 27512817 TI - Hydride-Based Electride Material, LnH2 (Ln = La, Ce, or Y). AB - In view of the strong electron-donating nature of H(-) and extensive vacancy formation in metals by hydrogen insertion, a series of LnH2+x (Ln = La, Ce, or Y) compounds with fluorite-type structures were verified to be the first hydride based electride, where itinerant electrons populating the cage are surrounded by H(-) anions. The electron transfer into the cage probably originates from Ln-cage covalent interaction. To the best of our knowledge, anion-rich electrides are extremely rare, and a key requirement for their formation is that the cage site is not occupied by lone pair electrons of the adjacent ions. In the case of LnH2, the cage site is surrounded by eight H(-) anions with isotopic electronic character caused by the lack of mixing of H p-orbital character. Notably, Ru loaded LnH2+x electride powders synthesized by hydrogen embrittlement (Ln = La or Ce) were found to work as efficient catalysts for ammonia synthesis at ambient pressure, without showing serious signs of hydrogen poisoning. There are several possible origins of the observed high catalytic activity in the hydride promotors: the small work function of LnH2+x derived from the covalent interaction between Ln cation and the H(-) sigma donor, and the formation of Ln nitride during catalytic reaction. PMID- 27512820 TI - Hand preferences for unimanual and bimanual coordinated actions in olive baboons (Papio anubis): Consistency over time and across populations. AB - The reliability of handedness data in nonhuman primates and variations of sample size across studies are critical issues for exploring their potential continuity with humans concerning hemispheric specialization. In this study, we investigated the consistency of handedness for unimanual and bimanual tasks in olive baboons (Papio anubis). For both tasks, we found a consistency of hand preferences over time among subjects retested 5 years later and a consistency of population-level handedness between 2 independent populations. Altogether, when combining the 2 samples, bimanual (N = 260) but not unimanual task (N = 220) elicited right handedness predominance. These findings demonstrate the reliability and robustness of predominance of right-handedness in olive baboons for bimanual coordinated behaviors. (PsycINFO Database Record PMID- 27512818 TI - Molecular and Dynamic Mechanism Underlying Drug Resistance in Genotype 3 Hepatitis C NS3/4A Protease. AB - Hepatitis C virus (HCV), affecting an estimated 150 million people worldwide, is the leading cause of viral hepatitis, cirrhosis and hepatocellular carcinoma. HCV is genetically diverse with six genotypes (GTs) and multiple subtypes of different global distribution and prevalence. Recent development of direct-acting antivirals against HCV including NS3/4A protease inhibitors (PIs) has greatly improved treatment outcomes for GT-1. However, all current PIs exhibit significantly lower potency against GT-3. Lack of structural data on GT-3 protease has limited our ability to understand PI failure in GT-3. In this study the molecular basis for reduced potency of current inhibitors against GT-3 NS3/4A protease is elucidated with structure determination, molecular dynamics simulations and inhibition assays. A chimeric GT-1a3a NS3/4A protease amenable to crystallization was engineered to recapitulate decreased sensitivity of GT-3 protease to PIs. High-resolution crystal structures of this GT-1a3a bound to 3 PIs, asunaprevir, danoprevir and vaniprevir, had only subtle differences relative to GT-1 despite orders of magnitude loss in affinity. In contrast, hydrogen bonding interactions within and with the protease active site and dynamic fluctuations of the PIs were drastically altered. The correlation between loss of intermolecular dynamics and inhibitor potency suggests a mechanism where polymorphisms between genotypes (or selected mutations) in the drug target confer resistance through altering the intermolecular dynamics of the protein-inhibitor complex. PMID- 27512821 TI - Differences in shoaling behavior in two species of freshwater fish (Danio rerio and Hyphessobrycon herbertaxelrodi). AB - Fish can gain significant adaptive advantages when living in a group and they exhibit a wide variety of types of collective motion. The scientific literature recognizes 2 main patterns: shoals (aggregations of individuals that remain close to each other), and schools (aggregations of aligned, or polarized, individuals). We analyzed the collective motion of 2 social fish species, zebrafish (Danio rerio) and black neon tetra (Hyphessobrycon herbertaxelrodi), and compared their patterns of movement and the effect of group size and environmental constraints such as water column height and tank geometry on the collective motion of both species. We recorded the movement of groups of fish (n = 10 and n = 20) using 2 tank geometries: a rectangular shape and a rectangular shape with rounded corners; and we also manipulated the water column height (15 and 25 cm). We extracted the individual fish trajectories and calculated indices of cohesion, coordination, group density and group shape. The results showed that the 2 species had different types of collective motion: the zebrafish's global motion matched that of a shoal, while the black neon tetra's motion matched that of a school. Indirect evidence indicated that the 2 species tended to occupy the vertical space differently while swimming in a group. Finally, we found that tank geometry did not affect group polarization, whereas group size had an effect on black neon tetra density, which was higher in small group sizes than in large ones. (PsycINFO Database Record PMID- 27512822 TI - Reasoning versus association in animal cognition: Current controversies and possible ways forward. AB - The study of animal cognition is rife with controversy, and among the most long standing and most intensely debated controversies in the field is the question of the extent to which the behavior of nonhuman animals can be fully understood on the basis of purely associative principles, or whether some behaviors exhibited by animals necessitate the assumption of inferential capacities in animals that defy an associative explanation. Remarkably, the continuing debate on the topic seems to be spawning little genuine progress in terms of substantial accumulation of new, generally accepted insights. As an introduction to a special section of the Journal of Comparative Psychology on the topic, the present article outlines a number of reasons for the stalemate and suggests ways to refertilize the debate. In particular, we claim that progress will not come from the adoption of general principles like Morgan's canon or the primacy of prediction over postdiction. Instead, emphasis should be placed on a careful analysis of what it is that different sides in the debate do and do not agree on and an increased willingness to engage in adversarial collaboration, in the spirit of a shared interest in furthering our understanding of animal behavior. PMID- 27512823 TI - Beyond the information (not) given: Representations of stimulus absence in rats (Rattus norvegicus). AB - Questions regarding the nature of nonhuman cognition continue to be of great interest within cognitive science and biology. However, progress in characterizing the relative contribution of "simple" associative and more "complex" reasoning mechanisms has been painfully slow-something that the tendency for researchers from different intellectual traditions to work separately has only exacerbated. This article reexamines evidence that rats respond differently to the nonpresentation of an event than they do if the physical location of that event is covered. One class of explanation for the sensitivity to different types of event absence is that rats' representations go beyond their immediate sensory experience and that covering creates uncertainty regarding the status of an event (thus impacting on the underlying causal model of the relationship between events). A second class of explanation, which includes associative mechanisms, assumes that rats represent only their direct sensory experience and that particular features of the covering procedures provide incidental cues that elicit the observed behaviors. We outline a set of consensus predictions from these two classes of explanation focusing on the potential importance of uncertainty about the presentation of an outcome. The example of covering the food-magazine during the extinction of appetitive conditioning is used as a test case for the derivation of diagnostic tests that are not biased by preconceived assumptions about the nature of animal cognition. (PsycINFO Database Record PMID- 27512824 TI - Associative learning as higher order cognition: Learning in human and nonhuman animals from the perspective of propositional theories and relational frame theory. AB - We aim to provide a new perspective on the old debate about whether evidence for higher order cognition in nonhuman animals can be reinterpreted in terms of associative learning. Our starting point is the idea that associative learning is best thought of as an effect (i.e., the impact of paired events on behavior) rather than a specific mental process (e.g., the formation of associations). This idea allows us to consider (a) propositional theories according to which associative learning is mediated by higher order mental processes akin to problem solving and (b) relational frame theory that allows one to think of seemingly simple associative learning effects as instances of a complex phenomenon known as arbitrarily applicable relational responding. Based on these 2 theories, we argue that (a) higher order cognition and associative learning are not necessarily mutually exclusive and (b) a more sophisticated conceptualization of higher order cognition is warranted. (PsycINFO Database Record PMID- 27512825 TI - Causal reasoning versus associative learning: A useful dichotomy or a strawman battle in comparative psychology? AB - The debate about whether or not one could/should ascribe reasoning abilities to animals has deep historical roots and seems very up-to-date in the light of the immense body of new empirical data originating from various species and research paradigms. Associative learning (AL) seems to be a ubiquitous low-level contender for any cognitive interpretation of animal behavior, mostly because of the assumed mechanistic simplicity and phylogenetic prevalence. However, the implicit assumption that AL is simple and therefore the most parsimonious mechanism to describe seemingly complex behavior can and must be questioned on various grounds. Using recent empirical findings with chimpanzees as an example, I argue that at times inferential reasoning might be the most likely candidate to account for performance differences between experimental and control conditions. Finally, a general conclusion drawn from the current debate(s) in the field of comparative psychology could be that a dichotomist battle of 2 conceptual camps-each of which is lacking a clear and homogeneous theoretical framework-is a scientific deadlock. (PsycINFO Database Record PMID- 27512826 TI - From Two to One Per Day Calibration of Dexcom G4 Platinum by a Time-Varying Day Specific Bayesian Prior. AB - BACKGROUND: In the DexCom G4 Platinum (DG4P) continuous glucose monitoring (CGM) sensor, the raw current signal generated by glucose-oxidase is transformed to glucose concentration by a calibration function whose parameters are periodically updated by matching self-monitoring of blood glucose references, usually twice a day, to compensate for sensor variability in time. The aim of this work is to reduce DG4P calibration frequency to once a day by a recently proposed Bayesian calibration algorithm, which employs a time-varying calibration function and suitable day-specific priors. METHODS: The database consists of 57 CGM signals that are collected by the DG4P for 7 days. The Bayesian calibration algorithm is used to calibrate the raw current signal following two different schedules, that is, two and one calibration per day. Calibrated glycemic profiles are compared with those originally acquired by the manufacturer, on days 1, 4, and 7, where frequent blood glucose references were available, by using standard metrics, that is, mean absolute relative difference (MARD), percentage of accurate glucose estimates, and percentage of data in the A-zone of Clarke Error Grid. RESULTS: The one per day Bayesian calibration algorithm has accuracy similar to that of two per day (11.8% vs. 11.7% MARD, respectively), and it is statistically better (P-value of 0.0411) than the manufacturer calibration algorithm, which requires two calibrations per day (13.1% MARD). CONCLUSIONS: A Bayesian calibration algorithm employing a time-varying calibration function and suitable priors enables a reduction of the calibrations of DG4P sensor from two to one per day. PMID- 27512827 TI - A Phytosterol-Enriched Spread Improves Lipid Profile and Insulin Resistance of Women with Gestational Diabetes Mellitus: A Randomized, Placebo-Controlled Double Blind Clinical Trial. AB - BACKGROUND: Gestational diabetes mellitus (GDM) has become a serious health risk among pregnant women throughout the world. Phytosterol-enriched margarines are capable of lowering total cholesterol (TC) and low-density lipoprotein (LDL), but little is known about its effects on GDM. We aimed to examine the effects of daily consumption of a phytosterol-enriched spread on insulin resistance and lipid profile in pregnant GDM women. METHODS: Pregnant women suffering from GDM in their second trimester were recruited and randomly assigned to consume a margarine spread either with or without phytosterols daily for 16 weeks. Serum lipid profile and glucose and insulin metabolisms were assessed at week 0 (baseline) and week 16 (end of trial). RESULTS: After 16 weeks, levels of triacylglycerol, TC, and LDL were significantly decreased, while high-density lipoprotein was significantly increased, compared with the baseline in the phytosterol group. In addition, in the same treatment group, glucose metabolic parameters, including fasting plasma glucose, serum insulin levels, the quantitative insulin check index, homeostasis model of assessment of insulin resistance, and beta-cell function, were also significantly improved. CONCLUSION: Daily consumption of a phytosterol-enriched spread improved insulin resistance and lipid profile in women with GDM. PMID- 27512829 TI - In Ovo Sexing of Domestic Chicken Eggs by Raman Spectroscopy. AB - Male birds of egg-laying hen strains have no commercial value and are culled immediately after hatching, raising concerns for animal welfare. Existing experimental methods for in ovo sexing require taking samples and are applicable after embryos' sexual differentiation. We demonstrate that Raman spectroscopy enables contactless in ovo sex determination of the domestic chicken (Gallus gallus f. dom.) already at day 3.5 of egg incubation. A sexing accuracy of 90% was obtained by analyzing the spectra of blood circulating in the extraembryonic vessels. The measurement is damage-free and barely affects the hatching rate. Sex recognition is achieved before the onset of sensitivity. Therefore, Raman spectroscopy provides an alternative to the culling of 1-day-old male chicks in laying hen production. PMID- 27512828 TI - An Integrated Multi-Omic Approach to Assess Radiation Injury on the Host Microbiome Axis. AB - Medical responders to radiological and nuclear disasters currently lack sufficient high-throughput and minimally invasive biodosimetry tools to assess exposure and injury in the affected populations. For this reason, we have focused on developing robust radiation exposure biomarkers in easily accessible biofluids such as urine, serum and feces. While we have previously reported on urine and serum biomarkers, here we assessed perturbations in the fecal metabolome resulting from exposure to external X radiation in vivo. The gastrointestinal (GI) system is of particular importance in radiation biodosimetry due to its constant cell renewal and sensitivity to radiation-induced injury. While the clinical GI symptoms such as pain, bloating, nausea, vomiting and diarrhea are manifested after radiation exposure, no reliable bioindicator has been identified for radiation-induced gastrointestinal injuries. To this end, we focused on determining a fecal metabolomic signature in X-ray irradiated mice. There is overwhelming evidence that the gut microbiota play an essential role in gut homeostasis and overall health. Because the fecal metabolome is tightly correlated with the composition and diversity of the microorganism in the gut, we also performed fecal 16S rRNA sequencing analysis to determine the changes in the microbial composition postirradiation. We used in-house bioinformatics tools to integrate the 16S rRNA sequencing and metabolomic data, and to elucidate the gut integrated ecosystem and its deviations from a stable host-microbiome state that result from irradiation. The 16S rRNA sequencing results indicated that radiation caused remarkable alterations of the microbiome in feces at the family level. Increased abundance of common members of Lactobacillaceae and Staphylococcaceae families, and decreased abundances of Lachnospiraceae, Ruminococcaceae and Clostridiaceae families were found after 5 and 12 Gy irradiation. The metabolomic data revealed statistically significant changes in the microbial-derived products such as pipecolic acid, glutaconic acid, urobilinogen and homogentisic acid. In addition, significant changes were detected in bile acids such as taurocholic acid and 12-ketodeoxycholic acid. These changes may be associated with the observed shifts in the abundance of intestinal microbes, such as R. gnavus , which can transform bile acids. PMID- 27512830 TI - Unsymmetric (MU-oxido)/(MU-pyrazolato) and Symmetric (MU-pyrazolato)2 Bridged Diosmium Frameworks: Electronic Structure and Magnetic Properties. AB - The present article deals with the structurally characterized unsymmetric oxido/pyrazolato-bridged [(bpy)2Os(III)(MU-oxido)(MU-pz)Os(III)(bpy)2](ClO4)3 ([1](ClO4)3) and symmetric dipyrazolato-bridged [(bpy)2Os(II)(MU pz)2Os(II)(bpy)2](ClO4)2 ([2](ClO4)2) (pz = pyrazolato, bpy = 2,2'-bipyridine) complexes with the Os...Os separations of 3.484 and 4.172 A, respectively. The anti-ferromagnetically coupled Os(III) centers [E(S = 1)-E(BS(1,1) S = 0) = 322.504 cm(-1)] in 1(3+) and diamagnetic (S = 0) 2(2+) exhibit well-resolved (1)H NMR resonances. [1](ClO4)3 shows temperature- and magnetic field-dependent paramagnetism at low magnetic field and diamagnetism at high magnetic field. 1(3+) and 2(2+) display successive metal-based oxidation processes involving the intermediate mixed-valent states and isovalent congeners: Os(IV)Os(IV) (1(5+)) >Os(III)Os(IV) (1(4+))?Os(III)Os(III) (1(3+))?Os(III)Os(II) (1(2+)) and Os(III)Os(III) (2(4+))->Os(II)Os(III) (2(3+))?Os(II)Os(II) (2(2+)) as well as bpy centered reductions. The effect of pi donor O(2-) and sigma/pi-donating pz(-) in 1(3+) and 2(2+), respectively, leads to varying oxidation state of the metal ions in the isolated complexes: Os(III)Os(III) versus Os(II)Os(II). UV-visible-near-IR electron paramagnetic resonance spectro-electrochemistry and density functional theory (DFT)/time-dependent DFT calculations collectively reveal overlapping of the metal- and ligand (pz, O, bpy)-based frontier orbitals in the delocalized mixed-valent states in 1(4+) and 1(2+) with comproportionation constant (Kc) value > 1 * 10(14) as well as in isovalent 1(3+), resulting in mixed metal/ligand to metal/ligand near-IR transitions in all the three states. The mixed-valent Os(II)Os(III) state in 2(3+) exhibits high Kc value of 1 * 10(22) corresponding to a strong electrochemical coupling situation. However, closeness of the bandwidth (Deltanu1/2, 4861 cm(-1)) of broad and weak intervalence charge transfer transition of 2(3+) at 1360 nm (epsilon/M(-1) cm(-1): 490) with the calculated Deltanu1/2 of 4121 cm(-1) based on the Hush formula as well as spin density distributions of Os1: 0.811/0.799, Os2: 0.045/0042, and pz: 0.162/0.173 in meso and rac diastereomeric forms, respectively, attribute its localized class II state. PMID- 27512831 TI - Design and Synthesis of Pyridone-Containing 3,4-Dihydroisoquinoline-1(2H)-ones as a Novel Class of Enhancer of Zeste Homolog 2 (EZH2) Inhibitors. AB - A new enhancer of zeste homolog 2 (EZH2) inhibitor series comprising a substituted phenyl ring joined to a dimethylpyridone moiety via an amide linkage has been designed. A preferential amide torsion that improved the binding properties of the compounds was identified for this series via computational analysis. Cyclization of the amide linker resulted in a six-membered lactam analogue, compound 18. This transformation significantly improved the ligand efficiency/potency of the cyclized compound relative to its acyclic analogue. Additional optimization of the lactam-containing EZH2 inhibitors focused on lipophilic efficiency (LipE) improvement, which provided compound 31. Compound 31 displayed improved LipE and on-target potency in both biochemical and cellular readouts relative to compound 18. Inhibitor 31 also displayed robust in vivo antitumor growth activity and dose-dependent de-repression of EZH2 target genes. PMID- 27512834 TI - Solvation of N,C-Protected Valine: Interactions with DMSO and a Chiral Solvating Agent. AB - Small protected amino acids find applications in many fields of chemistry. Their solvation, however, is often only studied in aqueous solution. In this contribution, the solvent-dependent conformational preferences of N,C-protected Boc-Val-NH-C3H7 are investigated by a combined VCD spectroscopic and theoretical approach. Replica exchange molecular dynamics simulations at the PM6 level and DFT calculations are both found to predict the conformational preferences in chloroform very well, which is confirmed by comparison of experimental and calculated IR and VCD spectra. In the case of DMSO, we find that solute-solvent interactions have to be taken into account explicitly in the simulation of the spectra. Furthermore, we show that the experimental spectra are better resembled by considering the conformational distribution obtained from the REMD simulations than from DFT. Finally, we also show that the weak interaction of Boc-Val-NH-C3H7 with a chiral solvating agent also induces a small VCD spectral signature. PMID- 27512836 TI - Clinical features of Hispanic thyroid cancer cases and the role of known genetic variants on disease risk. AB - Thyroid cancer (TC) is the second most common cancer among Hispanic women. Recent genome-wide association (GWA) and candidate studies identified 6 single nucleotide polymorphisms (SNPs; rs966423, rs2439302, rs965513, rs6983267, rs944289, and rs116909374), associated with increased TC risk in Europeans but their effects on disease risk have not been comprehensively tested in Hispanics. In this study, we aimed to describe the main clinicopathological manifestations and to evaluate the effects of known SNPs on TC risk and on clinicopathological manifestations in a Hispanic population.We analyzed 281 nonmedullary TC cases and 1146 cancer-free controls recruited in a multicenter population-based study in Colombia. SNPs were genotyped by Kompetitive allele specific polymerase chain reaction (KASP) technique. Association between genetic variants and TC risk was assessed by computing odds ratios (OR) and confidence intervals (CIs).Consistent with published data in U.S. Hispanics, our cases had a high prevalence of large tumors (>2 cm, 43%) and a high female/male ratio (5:1). We detected significant associations between TC risk and rs965513A (OR = 1.41), rs944289T (OR = 1.26), rs116909374A (OR = 1.96), rs2439302G (OR = 1.19), and rs6983267G (OR = 1.18). Cases carried more risk alleles than controls (5.16 vs. 4.78, P = 4.8 * 10). Individuals with >=6 risk alleles had >6-fold increased TC risk (OR = 6.33, P = 4.0 * 10) compared to individuals with <=2 risk alleles. rs944289T and rs116909374A were strongly associated with follicular histology (ORs = 1.61 and 3.33, respectively); rs2439302G with large tumors (OR = 1.50); and rs965513A with regional disease (OR = 1.92).To our knowledge, this is the first study of known TC risk variants in South American Hispanics and suggests that they increase TC susceptibility in this population and can identify patients at higher risk of severe disease. PMID- 27512837 TI - 23-Gauge vitrectomy with external drainage therapy as a novel procedure to displace massive submacular hemorrhage secondary to polypoidal choroidal vasculopathy. AB - INTRODUCTION: Massive subretinal hemorrhage (SRH) due to polypoidal choroidal vasculopathy (PCV) remains a challenging field and the best treatment is still not certain. In the present study, we performed a novel surgical method which combined 23-gauge vitrectomy with external drainage therapy for displace massive SRH secondary to PCV. METHODS: From April 2015 to July 2015, 4 consecutive patients with massive SRH secondary to PCV received 23-gauge transconjunctival sutureless vitrectomy with external drainage therapy. Massive SRH was drained by scleral tunnel which was created using 30-gauge ultrathin needles during vitrectomy. We assessed the feasibility and safety of this procedure by analyzing best-corrected vision acuity (BCVA), central foveal thickness (CFT), and complication. RESULTS: Four patients had a mean age of 63.8 +/- 6.4 years (range: 59-73 years). The average interval between onset of symptoms of SRH and surgery was 23.8 +/- 11.1 days (range: 10-35 days). Mean follow-up duration was 7.0 +/- 0.8 months. All patients completed 6 months follow-up. Mean BCVA gradually improved during the follow-up period. At 6 months after treatment, mean BCVA was significantly improved in comparison to preoperative findings (P = 0.043, paired t test). One month after treatment, mean CFT was significantly thinner than baseline (P = 0.002, paired t test). No serious ocular or systemic adverse events were observed to be associated with combination of 23-gauge vitrectomy with external drainage therapy during the 6 months follow-up period. CONCLUSIONS: Our results show that a combination of 23-gauge vitrectomy with external drainage therapy is a novel effective and safe procedure that may be a good alternative for massive SRH due to PCV. PMID- 27512838 TI - Trastuzumab improves locoregional control in HER2-positive breast cancer patients following adjuvant radiotherapy. AB - The benefit of adjuvant trastuzumab in disease-free and overall survival for human epidermal receptor 2-positive (HER2+) breast cancer patients is well established. However, the effect of trastuzumab on locoregional control remains unclear, particularly in patients treated with adjuvant radiotherapy (RT). In this study, we investigated the locoregional benefit of trastuzumab in patients with HER2+ breast cancer after adjuvant RT.Using a single institutional database, we identified 278 patients with stage II/III invasive HER2+ breast tumors receiving adjuvant RT between January 2008 and July 2011. We compared the locoregional outcomes of 134 patients who received trastuzumab to 144 patients without trastuzumab within the same period. Clinical and biological factors that might impact on the locoregional benefit of trastuzumab were also assessed.At the median follow-up of 45 months, trastuzumab significantly lowered the risk of locoregional recurrence (LRR) with a 3-year LRR rate of 2.4% versus 7.5% for the cohort with and without trastuzumab (P = 0.019). Trastuzumab was associated with a more significant locoregional benefit in the hormone receptor-positive (HR+)/HER2+ subgroup, with a 3-year LRR of 0% versus 6.7% in the cohort with and without trastuzumab (P = 0.027). For HR-/HER2+ breast tumor patients, the 3-year LRR rate was still lower for the cohort with trastuzumab (4.7% vs 8.6%). However, statistical significance was not found (P = 0.179). Both univariate and multivariate analyses confirmed that trastuzumab treatment was the only significant predictive factor for LRR (hazard ratio, 4.05; 95% confidence interval, 1.07-15.35; P = 0.039).Adjuvant trastuzumab in addition to RT is associated with significant reduced LRR risk in HER2+ breast cancer. PMID- 27512839 TI - Analysis of 4000 kidney transplantations in a single center: Across immunological barriers. AB - Kidney transplant (KT) is the optimal renal replacement therapy for patients with end-stage renal disease (ESRD). The demand for kidneys, however, continues to exceed the supply. To overcome this problem, efforts to extend the donor pool by including human leukocyte antigen (HLA)- and ABO-incompatible (ABOi) KTs are increasing. The aim of this article was to retrospectively review data on recipients, donor profiles, and clinical outcomes in 4000 cases of KT. In addition, we analyzed clinical outcomes in ABOi and flow-cytometric crossmatch (FCXM) positive KT in a subgroup analysis.This was a retrospective, observational study using data extracted from medical records. A total of 4000 consecutive patients who underwent KT at our institution from January 1990 to February 2015 were included in this study. KTs across immunological barriers such as ABO incompatible (276 cases, 6.9%), FCXM positive (97 cases, 2.4%), and positive complement-dependent cytotoxicity (CDC) XM KT (16 cases, 0.4%) were included.From a Kaplan-Meier analysis, overall patient survival (PS) rates after KT at 1, 5, 10, and 20 years were 96.9%, 95.1%, 92.0%, and 88.9%, respectively. The overall graft survival (GS) rates after KT at 1, 5, 10, and 20 years were 96.3%, 88.9%, 81.2%, and 67.4%, respectively. Our subgroup analysis suggested that overall PS, GS, death-censored GS, and rejection-free GS in ABOi KT showed no significant differences in comparison with ABO-compatible KT if adequate immunosuppressive treatment was performed. The overall PS rate in patients who underwent FCXM positive KT did not differ significantly from that of the control group during the 3-year follow-up (P = 0.34). The overall GS, death-censored GS, and rejection free GS also did not differ significantly between the FCXM KT and control groups (P = 0.99, 0.42, and 88).The outcomes of KTs continually improved during the study period, while the annual number of KTs increased. ABO or FCXM positive KTs can be performed safely with successful graft outcomes. PMID- 27512840 TI - Relation between primary tumor FDG avidity and site of first distant metastasis in patients with breast cancer. AB - Identification of tumor imaging features associated with metastatic pattern may allow better understanding of cancer dissemination. Here, we investigated how primary tumor F-fluorodeoxyglucose (FDG) avidity influences the first site of breast cancer metastasis.Subjects were 264 patients with advanced breast cancer who underwent positron emission tomography/computed tomography at diagnosis and had metastasis at presentation (n = 193) or metastatic relapse after surgery (n = 71). Primary tumor FDG avidity (maximum SUV [SUVmax] >=10.1) was compared with histology and first metastatic sites.The most common site of first metastasis was the bone, occurring in 62.7% of patients with metastasis at presentation and 38.0% of those with metastatic relapse. First metastasis to lung occurred in 30.1% and 35.2%, and to liver in 25.4% and 15.2% of respective groups. In patients with metastasis at presentation, primary tumors were FDG avid in 98/193 cases, and this was associated with more frequent first metastasis to lung (37.8% vs 22.1%; P = 0.018). In patients with metastasis relapse, primary tumors were FDG avid in 31/71 cases, and this was associated with more frequent first metastasis to lung (48.4% vs 25.0%; P = 0.041) and liver (29.0% vs 5.0%; P = 0.008). In patients with metastasis relapse, primary tumors that were FDG avid but hormone receptor negative had more first metastasis to lung (57.9% vs 26.9%; P = 0.016).FDG-avid primary breast tumors have favored first spread to the lung and liver, which suggests that tumor cells with heightened glycolytic activity better colonize these organs. PMID- 27512841 TI - The diagnostic value of 1.5-T diffusion-weighted MR imaging in detecting 5 to 10 mm metastatic cervical lymph nodes of nasopharyngeal carcinoma. AB - The aim of the study was to prospectively assess the diagnostic accuracy of 1.5 T diffusion-weighted imaging (DWI) for 5 to 10 mm metastatic cervical lymph nodes of patients with nasopharyngeal carcinoma (NPC). All patients with histopathologically confirmed NPC underwent DWI with 2 b values of 0 and 800 s/mm were enrolled. The shortest axial diameter and mean apparent diffusion coefficient (ADC) value were recorded when lymph nodes with a shortest axial diameter from 5 to 10 mm were measured. The correlation between the pathological diagnoses and mean ADC values in the benign and metastatic lymph nodes were compared using the Z test. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of DWI. Three hundred fourteen nodes of 52 patients with NPC consisted of 46.5% (146/314) metastatic lymph nodes and 53.5% (168/314) benign lymph nodes. The mean ADC value (*10 mm/s) of benign lymph nodes was (1.110 +/- 0.202), which was significantly higher than that of metastatic nodes (0.878 +/- 0.159) (P < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value, accuracy for differentiating metastatic from benign lymph nodes using a cutoff ADC value of 0.924 * 10 mm/s was 83.56%, 82.74%, 80.79%, 85.28%, and 82.80%, respectively. The area under the ROC curve was 0.851 (95% confidence intervals: 0.807-0.889). This study demonstrated that DWI is helpful in detecting 5 to 10 mm metastatic lymph nodes of patients with NPC. PMID- 27512842 TI - Association between peroxisome proliferator-activated receptor-alpha, delta, and gamma polymorphisms and risk of coronary heart disease: A case-control study and meta-analysis. AB - OBJECTIVES: Risk of coronary heart disease (CHD) has been suggested to be associated with polymorphisms of peroxisome proliferator-activated receptors (PPARs), while the results were controversial. We aimed to systematically assess the association between PPAR polymorphisms and CHD risk. METHODS: A case-control study with 446 subjects was conducted to evaluate the association between CHD risk and C161T polymorphism, which was of our special interest as this polymorphism showed different effects on risks of CHD and acute coronary syndrome (ACS). Meta-analyses were conducted to assess all PPAR polymorphisms. Either a fixed- or a random-effects model was adopted to estimate overall odds ratios (ORs). RESULTS: In the case-control study, T allele carriers of C161T polymorphism were not significantly associated with CHD risk (Odds ratio (OR) = 0.74, 95% confidence interval (CI) 0.47-1.15, P = 0.19), while T allele carriers showed higher risk of ACS (OR = 1.63, 95% CI 1.00-2.65, P = 0.048). The meta analysis indicated that compared with CC homozygous, T allele carriers had lower CHD risk (OR = 0.69, 95% CI 0.59-0.82, P < 0.001) but higher ACS risk (OR = 1.43, 95% CI 1.09-1.87, P = 0.010). Three other polymorphisms were also found to be significantly associated with CHD risk under dominant model: PPAR-alpha intron 7G/C polymorphism (CC+GC vs GG, OR 1.42, 95% CI 1.13-1.78, P = 0.003), L162V polymorphism (VV+LV vs LL, OR 0.74, 95% CI 0.56-0.97, P = 0.031), and PPAR-delta +294T/C polymorphism (CC+TC vs TT, OR 1.51, 95% CI 1.12-2.05, P = 0.007). CONCLUSIONS: The results suggested that PPAR-alpha intron 7G/C and L162V, PPAR delta +294T/C and PPAR-gamma C161T polymorphisms could affect CHD susceptibility, and C161T polymorphism might have different effects on CHD and ACS. PMID- 27512843 TI - Change in refraction after lens-sparing vitrectomy for rhegmatogenous retinal detachment and epiretinal membrane. AB - The aim of this study was to compare changes in refraction following lens-sparing vitrectomy between patients with rhegmatogenous retinal detachment (RRD) and epiretinal membrane (ERM) and to investigate factors associated with the change in refraction.We reviewed medical records of 49 eyes of 49 patients with RRD (53.6 +/- 7.8 years, mean +/- standard deviation) and 24 eyes of 24 patients with ERM (50.9 +/- 15.7 years) who underwent lens-sparing vitrectomy. Spherical equivalent refractive power was evaluated before and up to 18 months after surgery. The relationship between the change in refraction and several parameters was evaluated.A significant progressive myopic shift in refractive power was observed after vitrectomy in operated RRD and ERM eyes (P < 0.001, P = 0.016, respectively), with no significant difference in fellow eyes. The refraction values observed at >=3 and >=12 months following vitrectomy were significantly different as compared with those observed at baseline in the RRD group (P < 0.001) and the ERM group (P < 0.05), respectively. The change in refraction between the RRD and ERM groups was significant (P = 0.030). The multiple linear regression analysis showed that only age was significantly correlated with the change in refraction in RRD (P = 0.018) and ERM (P < 0.001) groups. The change in refraction was significantly and positively correlated with age in RRD (r = 0.461, P = 0.001) and ERM (r = -0.687, P < 0.001) groups. Following lens-sparing vitrectomy, cataract surgery was performed on 30 eyes after 0.89 +/- 0.26 years in the RRD group and on 10 eyes after 1.11 +/- 0.14 years in the ERM group; there was a significant difference in time to cataract surgery between the groups (P = 0.007). Kaplan-Meier survival analysis demonstrated that there was a significant difference in the rate of cataract surgeries between the RRD and ERM groups (P = 0.022).Following lens-sparing vitrectomy for RRD and ERM, a progressive myopic shift in refraction owing to nuclear sclerosis was observed. Core vitrectomy itself would cause a myopic shift of refraction. The only risk factor associated with cataract progression following lens-sparing vitrectomy is age for both types of patients. PMID- 27512844 TI - Association between body mass index and mortality in a prospective cohort of Chinese adults. AB - Obesity is associated with an increased risk of diabetes mellitus, hypertension, and coronary artery disease; however, the relation between body mass index (BMI) and the risk of all-cause mortality is controversial. We prospectively examined the relationship between BMI and all-cause mortality in 123,384 Chinese men and women who participated in the Kailuan health examination study from 2006 to 2007 and 2008 to 2009. Cases included 6218 deaths (5770 men and 448 women) that occurred during a mean follow-up period of 7.39 years. Relative risk was adjusted for factors such as age, serum lipid levels (ie, triglyceride, high-density lipoprotein, and low-density lipoprotein cholesterol), history of smoking and drinking, and physical activity, as well as a medical history of hypertension, diabetes, myocardial infarction, and stroke. Within the cohort, the lowest risk of all-cause mortality was seen among persons with a BMI of 24 to 28 kg/m in male, and the risk was elevated among persons with BMI levels lower or higher than that range. Moreover, all-cause mortality was greatest in the group with a BMI of <18.5 kg/m. In contrast, in female, a high BMI was associated with increased mortality, and a BMI of <18.5 kg/m was associated with the lowest risk. Further, a U-shaped association was seen between BMI and the risk of death from any cause among men and women, even after adjusting for confounding factors. In conclusion, underweight was associated with a substantially increased risk of all cause mortality in males. The excess risk of all-cause mortality with a high BMI, however, was seen among females. PMID- 27512845 TI - Significant contribution of subtype G to HIV-1 genetic complexity in Nigeria identified by a newly developed subtyping assay specific for subtype G and CRF02_AG. AB - While abundant sequence information is available from human immunodeficiency virus type 1 (HIV-1) subtypes A, B, C and CRF01_AE for HIV-1 vaccine design, sequences from West Africa are less represented. We sought to augment our understanding of HIV-1 variants circulating in 6 Nigerian cities as a step to subsequent HIV-1 vaccine development.The G/CRF02_AG multi-region hybridization assay (MHA) was developed to differentiate subtype G, CRF02_AG and their recombinants from other subtypes based on 7 HIV-1 segments. Plasma from 224 HIV-1 infected volunteers enrolled in a cohort examining HIV-1 prevalence, risk factor, and subtype from Makurdi (30), Abuja (18), Enugu (11), Kaduna (12), Tafa (95), and Ojo/Lagos (58) was analyzed using MHA. HIV-1 genomes from 42 samples were sequenced to validate the MHA and fully explore the recombinant structure of G and CRF02_AG variants.The sensitivity and specificity of MHA varied between 73 100% and 90-100%, respectively. The subtype distribution as identified by MHA among 224 samples revealed 38% CRF02_AG, 28% G, and 26% G/CRF02_AG recombinants while 8% remained nontypeable strains. In envelope (env) gp120, 38.84% of the samples reacted to a G probe while 31.25% reacted to a CRF02 (subtype A) probe. Full genome characterization of 42 sequences revealed the complexity of Nigerian HIV-1 variants.CRF02_AG, subtype G, and their recombinants were the major circulating HIV-1 variants in 6 Nigerian cities. High proportions of samples reacted to a G probe in env gp120 confirms that subtype G infections are abundant and should be considered in strategies for global HIV-1 vaccine development. PMID- 27512846 TI - CBCT-based 3D MRA and angiographic image fusion and MRA image navigation for neuro interventions. AB - Digital subtracted angiography (DSA) remains the gold standard for diagnosis of cerebral vascular diseases and provides intraprocedural guidance. This practice involves extensive usage of x-ray and iodinated contrast medium, which can induce side effects. In this study, we examined the accuracy of 3-dimensional (3D) registration of magnetic resonance angiography (MRA) and DSA imaging for cerebral vessels, and tested the feasibility of using preprocedural MRA for real-time guidance during endovascular procedures.Twenty-three patients with suspected intracranial arterial lesions were enrolled. The contrast medium-enhanced 3D DSA of target vessels were acquired in 19 patients during endovascular procedures, and the images were registered with preprocedural MRA for fusion accuracy evaluation. Low-dose noncontrasted 3D angiography of the skull was performed in the other 4 patients, and registered with the MRA. The MRA was overlaid afterwards with 2D live fluoroscopy to guide endovascular procedures.The 3D registration of the MRA and angiography demonstrated a high accuracy for vessel lesion visualization in all 19 patients examined. Moreover, MRA of the intracranial vessels, registered to the noncontrasted 3D angiography in the 4 patients, provided real-time 3D roadmap to successfully guide the endovascular procedures. Radiation dose to patients and contrast medium usage were shown to be significantly reduced.Three-dimensional MRA and angiography fusion can accurately generate cerebral vasculature images to guide endovascular procedures. The use of the fusion technology could enhance clinical workflow while minimizing contrast medium usage and radiation dose, and hence lowering procedure risks and increasing treatment safety. PMID- 27512847 TI - Microflow imaging of contrast-enhanced ultrasound for evaluation of neovascularization in peripheral lung cancer. AB - The aim of this study was to investigate the role of microflow imaging (MFI) of contrast-enhanced ultrasound (CEUS) for evaluating microvascular architecture of different types of peripheral lung cancer (PLC) and to explore the correlated pathological basis.Ninety-five patients with PLC were enrolled in this study. Two radiologists independently evaluated the microvascular architecture of PLC with MFI. The interobserver agreement was measured with Kappa test. The diagnosis value of MFI was calculated. With pathological analysis, the correlation between MFI and microvascular density (MVD)/microvascular diameter (MD) was evaluated.Of the 95 PLCs, MFI were mainly classified "dead wood" (27.4%, 25.3%), "vascular" (47.4%, 49.5%), and "cotton" (20.0%, 20.0%) patterns by the 2 readers. Kappa test showed a good agreement between the 2 readers (Kappa = 0.758). The "dead wood" can be regarded as a specific diagnostic factor for squamous carcinoma; the sensitivity, specificity, and accuracy was 62.9%, 93.3%, and 82.1%, respectively. The "vascular" and "cotton" patterns correlated well with adenocarcinoma and SCLC (small cell lung cancer); diagnostic sensitivity, specificity, and accuracy were 86.7%, 65.7%, and 78.9%, respectively. MVD of "dead wood" was lower than "vascular" and "cotton," while MD was bigger than the other 2 patterns (P < 0.05). There was a good correlation between MFI and histopathological types of PLC as well as between MFI and MVD/MD (P < 0.05).MFI has the advantage to display the microvascular architecture of PLCs and might become a promising diagnostic method of histopathological types of PLC. MFI features also correlated well with its pathological basis, including MVD and MD. PMID- 27512848 TI - Delayed traumatic diaphragmatic hernia: A case-series report and literature review. AB - BACKGROUND: Traumatic diaphragmatic hernias (TDHs) are sometimes difficult to identify at an early stage and can consequently result in diagnostic delays with life-threatening outcomes. It is the aim of this case study to highlight the difficulties encountered with the earlier detection of traumatic diaphragmatic hernias. METHODS: Clinical data of patients who received treatment for delayed traumatic diaphragmatic hernias in registers of the First Affiliated Hospital of Xi'an Jiaotong University from 1998 to 2014 were analyzed retrospectively. RESULTS: Six patients were included in this study. Left hemidiaphragm was affected in all of them. Most of the patients had a history of traffic accident and 1 a stab-penetrating injury. The interval from injury to developing symptoms ranged from 2 to 11 years (median 5 years). The hernial contents included the stomach, omentum, small intestine, and colon. Diaphragmatic injury was missed in all of them during the initial managements. All patients received operations once the diagnosis of delayed TDH was confirmed, and no postoperative mortality was detected. CONCLUSIONS: Delayed TDHs are not common, but can lead to serious consequences once occurred. Early detection of diaphragmatic injuries is crucial. Surgeons should maintain a high suspicion for injuries of the diaphragm in cases with abdominal or lower chest traumas, especially in the initial surgical explorations. We emphasize the need for radiographical follow-up to detect diaphragmatic injuries at an earlier stage. PMID- 27512849 TI - Peripheral platelet/lymphocyte ratio predicts lymph node metastasis and acts as a superior prognostic factor for cervical cancer when combined with neutrophil: Lymphocyte. AB - Inflammation-based indicators such as neutrophil/lymphocyte ratio (NLR), derived NLR (dNLR), and platelet/lymphocyte ratio (PLR) have been reported to possess significant predictive value for several types of cancer. We investigated the predictive value of these 3 biomarkers on lymph node metastasis (LNM) and clinical outcome in patients with stage Ib1-IIa cervical cancer undergoing radical surgery.A total of 407 patients with FIGO stage Ib1-IIa cervical cancer, who underwent radical surgery between January 2006 and December 2009 at the Department of Gynecological and Oncology of Shandong Cancer Hospital Affiliated to Shandong University were recruited. Binary logistic regression analysis was performed to determine the relationship between PLR, NLR, dNLR, and LNM. Multivariate Cox regression analysis was performed to determine the association between the 3 indices and recurrence-free survival (RFS) and overall survival (OS).Optimal cut-off values for the 3 indices were determined by applying receiver operating curve (ROC) analysis. Univariate and binary logistic regression analyses both indicate that PLR was significantly associated with increased LNM (P < 0.05). In the multivariate survival analysis, increased preoperative PLR and NLR were significantly associated with reduced RFS (P = 0.001 and P = 0.002, respectively), whereas a combination of both PLR and NLR revealed a more significant association with reduced RFS (P < 0.001). Furthermore, increased preoperative PLR and NLR were significantly associated with reduced OS (P = 0.007 and P = 0.009, respectively), whereas the combined use of PLR and NLR revealed a more significant association with reduced OS (P = 0.003).PLR is an independent risk factor for increased LNM and clinical outcome in patients with stage Ib1-IIa cervical cancer. A combination of PLR and NLR may enable better risk stratification for predicting survival. PMID- 27512850 TI - Increased TRPV1 and PAR2 mRNA expression levels are associated only with the esophageal reflux symptoms, but not with the extraesophageal reflux symptoms. AB - Transient receptor potential vanilloid-1 (TRPV1) receptor and proteinase activated receptor 2 (PAR2) have been implicated in the mechanism of acid-induced inflammation in gastroesophageal reflux disease (GERD). We aimed to evaluate TRPV1 and PAR2 mRNA expression levels in the GERD patients and their relationship with endoscopic findings and reflux symptoms.Sixteen healthy controls, 45 patients with erosive reflux disease (ERD), and 14 nonerosive reflux disease (NERD) patients received endoscopy and completed questionnaires. Quantitative real-time polymerase chain reactions (qPCR) of TRPV1, glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), PAR2, and interleukin (IL) 8 were performed in the distal esophagus specimen.The levels of TRPV1, GDNF, NGF, PAR2, and IL-8 mRNA expression were highest in the ERD group followed by NERD and control groups and the differences between control and ERD groups were statistically significant. Within the ERD group, patients with grade B in Los Angeles (LA) classification showed significantly higher levels of TRPV1, GDNF, and NGF mRNA expression than those with grade A. Presence of reflux symptoms was associated with significant higher levels of TRPV1, PAR2, and IL-8. Notably not extraesophageal but esophageal reflux symptoms were significantly associated with them.Upregulation of TRPV1 and PAR2 pathways might play a role in the development of distal esophageal inflammation and reflux symptoms. And extraesophageal reflux symptoms might not be associated with these processes. PMID- 27512851 TI - Body mass index and waist-to-height ratio among schoolchildren with visual impairment: A cross-sectional study. AB - Children and adolescents with visual impairments may be predisposed to excessive body mass due to restrictions in everyday functioning and the ability to take part in physical activity. This study aimed to estimate the prevalence of obesity, overweight, and abdominal obesity (AO) among blind and partially sighted schoolchildren and to determine whether sociodemographic factors and participation in physical education classes (PEC) are associated with excessive body weight or AO in this group.A cross-sectional sample of 141 partially sighted or blind schoolchildren aged 7 to 18.9 years were included in this study. Anthropometric measurements were performed, and sociodemographic variables and ability to attend PEC were recorded. Overweight and obesity were noted among 21.3% and 14.9% of students, respectively. Although more males than females had excessive body weight (39.2% vs 32.3%), the difference was not significant (chi square test [ch] = 3.197; probability value [P] = 0.362). There was a significant association between mean body mass index standard deviation score and age (results of ANOVA analysis [F] = 5.620; P = 0.0045). A waist-to-height ratio (WHtR) >=0.50 was observed among 27.7% of pupils. The prevalence of AO in boys and girls was 32.9% and 21.0%, respectively; this difference was not significant (ch = 2.48; P = 0.12). There was a significant relationship between mean WHtR and age (7-9 years: 0.477 +/- 0.050; 10-13 years: 0.484 +/- 0.065; >=14 years: 0.454 +/- 0.061; results of Kruskal-Wallis test [H] = 8.729; P = 0.023, respectively).Multivariate logistic regression analysis showed that none of the sociodemographic variables examined (except "having siblings") were significantly associated with the occurrence of overweight, obesity, and AO. Subjects with no siblings were 4 times more likely to have WHtR >= 0.5 (odds ratio [OR] = 4.22; 95% confidence interval [CI] = 1.33-17.8; P = 0.01).Overweight and obesity were almost 4 times more frequent (OR = 3.74; 95% CI 0.81-17.4) and AO 3 times more frequent (OR = 3.18, 95% CI 0.71-14.2) among students not participating in PEC. Excessive body mass and AO represent an urgent health problem among schoolchildren with visual impairments. Health education concerning healthy eating habits and physical activity should be provided to this group to reduce potential future health costs. PMID- 27512852 TI - Pemetrexed/cisplatin as first-line chemotherapy for advanced lung cancer with brain metastases: A case report and literature review. AB - BACKGROUND: Brain metastases (BMs) are a common and serious complication of non small cell lung cancer (NSCLC). Whole-brain radiotherapy (WBRT), surgery, and molecular targeted therapy are usually used to treat NSCLC with BM. Chemotherapeutic options for BM are limited by tumor resistance, ineffective agents, and the blood-brain barrier. Pemetrexed/cisplatin is the preferred chemotherapy in nonsquamous NSCLC, but the efficacy of this treatment for nonsquamous NSCLC with BM is uncertain. METHODS: We present a case of nonsquamous NSCLC with asymptomatic BM presenting with irritating cough and right shoulder back pain (unknown sensitizing epidermal growth factor receptor mutations or anaplastic lymphoma kinase). RESULTS: He benefited from administration of first line chemotherapy of pemetrexed/cisplatin. Partial remission was achieved in the primary lesion of the lungs and BM lesion. He was further given 3 cycles of pemetrexed monotherapy and WBRT. Complete remission was further achieved in BM lesion. CONCLUSION: The findings of clinical trials and theoretical studies about the current pemetrexed/cisplatin in the treatment of nonsquamous NSCLC with BM are also summarized to provide a reference for the application of pemetrexed/cisplatin in nonsquamous NSCLC with BM. Whether or not pemetrexed/cisplatin is definitely effective in nonsquamous NSCLC with BM must be proven by subsequent phase III clinical trials. PMID- 27512853 TI - Physiotherapists working in clinics have increased risk for new-onset spine disorders: a 12-year population-based study. AB - Health care professionals are known to have a high risk for work-related musculoskeletal disorders. However, the information on the risk of new-onset spine-related musculoskeletal disorders (SRMDs) in health care professionals is insufficient. This study aimed to investigate new-onset spine disorder associations among physical, occupational, and pharmacy health care professionals working in different workplaces.Taiwan's National Health Insurance Research Database for registered medical personnel claims from 2000 to 2011 was analyzed. An age- and sex-matched longitudinal cohort study of 7448 subjects (1682 physiotherapists, 1682 occupational therapists [OTs], and 3724 pharmacists) with or without new-onset spine disorders was conducted. The hazard ratios for the development of new-onset spine disorders were estimated among these 3 groups.The overall percentage of new-onset SRMD for physiotherapists is 32.12. The median time from obtaining a registered license to developing SRMD is 1.94 years. The log-rank test showed that physiotherapists have the least possibility of having a SRMD-free rate (P < 0.0001). The Cox model showed that physiotherapists have a higher risk of new-onset SRMD (hazard ratio: 1.65, 95% confidence interval: 1.48 1.84, P < 0.0001) compared with OTs and pharmacists. Physiotherapists working in clinics have a 2.40-fold increased risk of developing SRMD (95% confidence interval: 1.97-2.92, P < 0.0001) relative to OTs and pharmacists.This may be the first study regarding new-onset SRMD in physiotherapists based on a powerful nationwide population-based database. We conclude that working in clinics is a potential risk for new-onset SRMD in physiotherapists. Therefore, we suggest that physiotherapists should pay more attention to this issue to prevent the development of spine disorders. PMID- 27512854 TI - Socioeconomic inequities and cardiovascular disease-related disability in China: A population-based study. AB - The prevalence of disability has changed along with aggressive economic development in China. However, socioeconomic inequalities associated with cardiovascular disease (CVD)-related disability have not been explored. This is the first study to explore CVD-related disability among persons aged 45 years and older in China.Data were taken from the 2006 Second China National Sample Survey on Disability, which was a nationally representative, population-based survey. To derive a nationally representative sample, the survey used multistage, stratified, and cluster random sampling with probability proportional to size. We used standard weighting procedures to construct sample weights that considered the multistage, stratified, and cluster sampling survey scheme. Associations between CVD-related disability risk and socioeconomic inequality were examined using logistic regression.In this study, the weighted prevalence of CVD-related disability was 1.84 per 100 persons (95% confidence interval [CI]: 1.80-1.89), and 73% of CVD-related disability consisted of a single disability, including speech, physical, and intellectual disabilities, whereas 23% of CVD-related disability consisted of multiple disabilities, that is, any combination of speech, physical, and intellectual disabilities. A higher risk of CVD-related disability was observed among rural residents than urban residents as well as among males than females. Age presented consistent increased associations with CVD-related disability. Education inequality was strongly associated with the risk of multiple disabilities.To address the challenge of CVD-related disability in China, the government should adjust its strategies for health care systems to prevent disability. The widening discrepancy between urban and rural areas indicates that the most important priorities for disability prevention in China are to reinforce health promotion in the working age population and to improve health services in rural communities. PMID- 27512855 TI - Surgical treatment of double primary liver cancer: An observational study for a rare type of tumor. AB - Double primary liver cancer (DPLC) is a special type of clinical situation. As such, a detailed analysis of the surgical management and prognosis of patients with DPLC is lacking. The objective of the current study was to define the management and outcome of patients undergoing surgery for DPLC at a major hepatobiliary center.A total of 87 patients treated by surgical resection at the Eastern Hepatobiliary Surgery Hospital from January 1st, 2007 to October 31st, 2013 who had DPLC demonstrated by final pathological diagnosis were identified. Among these, 50 patients had complete clinical and prognostic data. Demographic and tumor characteristics as well as the prognosis were analyzed.The proportion of hepatitis B surface antigen (HBsAg) (+) and hepatitis B virus e antigen (HBeAg) (+), HBsAg (+), and HBeAg (-) hepatocirrhosis in all patients was 21.84%, 67.82%, and 63.22%, respectively. Incidental findings accounted for 58.62% of patients; among those who had symptoms, the main symptom was abdominal pain (31.03%). Nonanatomic wedge resection was the main operative approach (62.07%). Postoperatively, the main complications included seroperitoneum (11.49%), hypoproteinemia (10.34%), and pleural effusion (8.05%). Factors associated with disease-free survival (DFS) included intrahepatic cholangiocarcinoma (ICC) tumor size (P = 0.002) and use of postoperative prophylactic transcatheter arterial chemoembolization (TACE) treatment (P = 0.015). Meanwhile, hepatocellular carcinoma (HCC) size (P = 0.045), ICC size (P < 0.001), and liver function (including aspartate aminotransferase [P = 0.001] and r-glutamyl transferase [P < 0.001]) were associated with overall survival (OS).Hepatitis B virus (HBV) related hepatitis or cirrhosis is also an important factor in the pathogenesis of DPLC and surgical treatment is safe for it with low complication rates. In addition, it is effective to prolong DFS that DPLC patients undergo postoperative prophylactic TACE treatment. PMID- 27512856 TI - Physical activity to overcome the adversity of widowhood: Benefits beyond physical health. AB - Widowhood has been increasingly encountered because of increasing longevity of women, often characterized by social stigmatization and poor physical and mental health. However, applied research to overcome its adversity has been quite limited. The goal of this study is to explore the role of physical activity in improving the health of widows.A cohort of 446,582 adults in Taiwan who successively participated in a comprehensive medical screening program starting in 1994, including 232,788 women, was followed up for mortality until 2008. Each individual provided detailed health history, and extensive lab tests results.The number of widows increased with time trend. Every other woman above age 65 was a widow (44%). Widows were less active, more obese, and smoked and drank more, had sleep problems, were more depressed with taking sedatives or psychoactive drugs, leading to more suicides. In the global development of health policies by World Health Organization (WHO), physical activity is one of the main factors to reverse poor health. The poor health of inactive widow was mitigated when becoming fully active in this study. Exercise not only reduced the observed 18% increase in all-cause mortality, but also gained 4 years and as much as 14% mortality advantage over the married but inactive. More importantly, becoming physically active energized their mental status, improved sleep quality and quantity, reduced depressions and the need for psychoactive drugs, and increased socialization circles.Widows, a rapidly growing and socially stigmatized group, suffered from social and financial inequality and tended to develop poorer health. Sustained physical activity could be one of the ways for them to overcome and reverse some of the physical and mental adversities of widowhood, and improve their quality and quantity of life. PMID- 27512857 TI - Tissue expander placement and adjuvant radiotherapy after surgical resection of retroperitoneal liposarcoma offers improved local control. AB - Given that retroperitoneal liposarcoma (LPS) is extremely difficult to completely resect, and has a relatively high rate of recurrence, radiotherapy (RT) is the treatment of choice after surgical resection. However, it is difficult to obtain a sufficient radiation field because of the close proximity of surrounding organs. We introduce the use of tissue expanders (TEs) after LPS resection in an attempt to secure a sufficient radiation field and to improve recurrence-free survival.This study is a retrospective review of 53 patients who underwent surgical resection of LPS at Samsung Medical Center between January 1, 2005, and December 31, 2012, and had no residual tumor detected 2 months postoperatively. The median follow-up period was 38.9 months.Patients were divided into 3 groups. Those in group 1 (n = 17) had TE inserted and received postoperative RT. The patients in group 2 (n = 9) did not have TE inserted and received postoperative RT. Finally, those in group 3 (n = 27) did not receive postoperative RT. Multivariate analysis was performed to identify the risk factors associated with recurrence-free survival within 3 years. Younger age, history of LPS treatment, and RT after TE insertion (group 1 vs group 2 or 3) were significantly favorable factors influencing 3-year recurrence-free survival.TE insertion after LPS resection is associated with increased 3-year recurrence-free survival, most likely because it allows effective delivery of postoperative RT. PMID- 27512858 TI - Awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone patients: A pilot observational study. AB - Anesthesia followed by placement in the prone position takes time and may result in complications. This study aimed to evaluate the feasibility of awake nasotracheal fiberoptic intubation and self-positioning followed by anesthesia induction in prone-positioned patients under general anesthesia.Sixty-two patients (ASA physical status I-II) scheduled for awake nasotracheal fiberoptic intubation and prone self-positioning before surgery under general anesthesia were selected. Patient preparation began with detailed preoperative counseling regarding the procedure. Premedication with sedative and antisialagogue was followed by airway anesthesia with topical lidocaine; then, awake nasotracheal fiberoptic intubation was carried out. The patients then positioned themselves comfortably before induction of general anesthesia. The changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), incidence of coughing or gagging, and rate pressure product (RPP) were assessed. Statistical analysis was performed with repeated-measures one-way analysis of variance.Fifty eight of the 62 patients completed prone self-positioning smoothly. Compared with values before intubation, SBP, DBP, HR, and RPP were slightly increased after intubation, although the difference was not statistically significant (P > 0.05). One patient had moderate coughing and 1 patient had gagging during prone self positioning, which were tolerable.These findings indicated that awake nasotracheal fiberoptic intubation and self-positioning followed by induction of anesthesia is safe and feasible alternative to routine prone positioning after induction of general anesthesia. PMID- 27512859 TI - Laparoscopic duodenum-preserving pancreatic head resection: A case report. AB - BACKGROUND: Solid pseudopapillary neoplasms (SPNs) of the pancreas are uncommon neoplasms and are potentially malignant. Complete resection is advised due to rare recurrence and metastasis. Duodenum-preserving pancreatic head resection (DPPHR) is indicated for SPNs located in the pancreatic head and is only performed using the open approach. To the best of our knowledge, there are no reports describing laparoscopic DPPHR (LDPPHR) for SPNs. METHODS: Herein, we report a case of 41-year-old female presented with a 1-week history of epigastric abdominal discomfort, and founded an SPN of the pancreatic head by abdominal computed tomography/magnetic resonance, who was treated by radical LDPPHR without complications, such as pancreatic fistula and bile leakage. Histological examination of the resected specimen confirmed the diagnosis of SPN. RESULTS: The patient was discharged 1 week after surgery following an uneventful postoperative period. She was followed up 3 months without readmission and local recurrence according to abdominal ultrasound. CONCLUSION: LDPPHR is a safe, feasible, and effective surgical procedure for SPNs. PMID- 27512860 TI - Incidence and risk factors for the progression of proximal junctional kyphosis in degenerative lumbar scoliosis following long instrumented posterior spinal fusion. AB - The aim of this study was to identify the prevalence of proximal junctional kyphosis (PJK) in degenerative lumbar scoliosis (DLS) following long instrumented posterior spinal fusion, and to search for predictable risk factors for the progression of junctional kyphosis.In total 98 DLS patients with a minimum 2-year follow-up were reviewed prospectively. According to the occurrence of PJK at the last follow-up, patients were divided into 2 groups: PJK group and non-PJK group. To investigate risk values for the progression of PJK, 3 categorized factors were analyzed statistically: patient characteristics-preoperative data of age, sex, body mass index (BMI), bone mineral density (BMD) were investigated; surgical variables-the most proximal and distal levels of the instrumentation, the number of instrumented levels; pre- and postoperative radiographic parameters include the scoliotic angle, sagittal vertical axis, thoracic kyphosis, thoracolumbar junctional angle, lumbar lordosis, pelvic incidence, pelvic tilt, and sacral slope.PJK was developed in 17 of 98 patients (17.3%) until to the final follow-up and were enrolled as the PJK group, and 81 patients without PJK at final follow up were enrolled as the non-PJK group. There was no statistically significant difference between the 2 groups in age at operation (P = 0.900). The patient's sex was excluded in statistical analysis because of the predominance of female patients. There were statistically significant difference between the 2 groups in BMI ([25.5 +/- 1.7] kg/m in the PJK group and [23.6 +/- 1.9] kg/m in the non-PJK group, P < 0.001) and BMD ([-1.4 +/- 0.8] g/cm in the PJK group and [-0.7 +/- 0.3] g/cm in the non-PJK group, P < 0.001). No specific surgery-related variables were found to be associated with an increased risk of developing PJK, except when the most proximal instrumented vertebrae stopped at thoracolumbar junction (T11 L1). The upper instrumentation vertebrae (UIV) at thoracolumbar junction was more common in the PJK group than that in the non-PJK group (P = 0.007). No preoperative and early postoperative variable did reveal a statistically significant difference between the 2 groups. When included in a multivariate logistic regression model, BMI>25 kg/m, osteoporosis, and UIV at thoracolumbar junction were independently associated with PJK.In conclusion, osteoporosis, obesity, and UIV at thoracolumbar junction are risk factors for the development and progression of PJK in DLS patients following long instrumented posterior spinal fusion. Antiosteoporosis treatment extends the fusion level above the thoracolumbar region and controlling body weight before and after surgery could provide opportunities to reduce the rate of PJK and to improve therapeutic outcomes. PMID- 27512861 TI - Effectiveness of FDG-PET/CT for evaluating early response to induction chemotherapy in head and neck squamous cell carcinoma: A systematic review. AB - BACKGROUND: F-Fluoro-Deoxy-Glucose Positron Emission Tomography with Computed Tomography (F-FDG PET/CT) may be a powerful tool to predict treatment outcome. We aimed to review the effectiveness of F-FDG PET/CT in the assessment of early response to induction chemotherapy (IC) in patients with advanced Head and Neck Squamous Cell Cancer (HNSCC) without previous treatment. METHODS: PubMed, Cochrane Library, Science Direct and Web of Science were searched to May 2016. Reference lists of the included articles and additional studies identified by one nuclear medicine expert were screened for potential relevant studies that investigated the effectiveness of F-FDG PET/CT performed before and after IC. Three authors independently screened all retrieved articles, selected studies that met inclusion criteria and extracted data. The methodology of the selected studies was evaluated by using the risk of bias checklist of the Agency for Healthcare Research and Quality (AHRQ). RESULTS: Seven out of 170 eligible studies met our inclusion criteria. A total of 207 advanced HNSCC patients were evaluated with F-FDG PET/CT at baseline and after IC in the selected articles. Six from seven studies concluded that F-FDG PET/CT allowed early evaluation response to IC and predicted survival outcomes. CONCLUSION: The present systematic review confirms the potential value of F-FDG PET/CT as a diagnostic tool for early IV response assessment in HNSCC patients. However, the lack of standard definitions for response criteria and heterogeneous IC protocols indicate the need to further studies in order to better define the role of F-FDG PET/CT in these patients. PMID- 27512862 TI - Metabolic syndrome is a risk factor for adenoma occurrence at surveillance colonoscopy: A single-center experience in Korea. AB - We investigated the risk factors for adenoma occurrence at surveillance colonoscopy, especially focusing on patient characteristics, including metabolic factors.Surveillance colonoscopy intervals depend on baseline adenoma characteristics. However, patients' characteristics may also influence the occurrence of adenomas.Of 62,171 asymptomatic subjects who underwent colonoscopy for a health check-up between 2010 and 2011, 4869 subjects who underwent follow up colonoscopy between 2012 and 2013 were included in this longitudinal study. The risk of adenoma occurrence was assessed using Cox proportional hazards modeling.Of 4869 subjects, 2827 (58.1%), 1619 (33.3%), and 423 (8.7%) were assigned to the normal, low-risk, and high-risk groups, respectively, according to baseline adenoma characteristics. The mean interval between initial and follow up colonoscopy was 2.2 +/- 0.6 years. Certain patient factors, including older age (>=50 years; adjusted hazard ratio [aHR], 2.08; 95% CI, 1.73-2.49), male sex (aHR, 1.69; 95% CI, 1.30-2.19), metabolic syndrome (MetS) (aHR, 1.28; 95% CI, 1.09-1.51), obesity (aHR, 1.17; 95% CI, 1.02-1.34), elevated fasting blood glucose levels (aHR, 1.37; 95% CI, 1.19-1.58), and elevated triglyceride levels (aHR, 1.19; 95% CI, 1.03-1.37), as well as baseline adenoma characteristics, were associated with a higher risk of adenoma occurrence at follow-up colonoscopy. The cumulative incidence of adenoma occurrence in the high-risk group was higher than that in the low-risk group, whereas the incidence in the high-risk group without MetS was comparable with that in the low-risk group with MetS.Patient characteristics, such as MetS, obesity, older age, and male sex, in addition to adenoma characteristics, were independent risk factors for adenoma occurrence at surveillance colonoscopy. These patient characteristics may be considered in surveillance colonoscopy intervals. PMID- 27512863 TI - Perimenopausal syndrome and mood disorders in perimenopause: prevalence, severity, relationships, and risk factors. AB - Limited information was focused on perimenopausal syndrome and mood disorders (depression and anxiety) in a specific population: perimenopausal women. We aimed to investigate the prevalence and severity of perimenopausal syndrome and mood disorders, and to analyze their relationships and risk factors in perimenopausal women in Shanghai, China.A cross-sectional study was performed on 1062 women aged 40 to 60 years from 3 communities. The general conditions questionnaire, Kupperman index, self-rating depression scale, and self-rating anxiety scale were used. A multivariable logistic regression analysis was performed to identify risk factors for perimenopausal syndrome and mood disorders.The prevalence of perimenopausal syndrome, depression and anxiety, which were primarily associated with mild symptoms, was 10.92%, 25.99%, and 12.62%, respectively. The differences in the prevalence and severity of perimenopausal syndrome, in the prevalence of depression, and in the severity of anxiety in different age groups were statistically significant (P < 0.001, P = 0.028, P = 0.003, P = 0.002, respectively). The relationships between perimenopausal syndrome and mood disorders were strong and positive (P < 0.001). It was found that age, employment status, personality characteristics, menstruation, and constipation were risk factors for perimenopausal syndrome, but monthly household income was a protective factor. Also, higher income and better medical insurance were beneficial to depression. However, disharmonious family relationships, irregular menstruation, constipation, and severity of perimenopausal syndrome were harmful to depression. For anxiety, attitudes to children status, cesarean section times, and constipation were risk factors.We concluded that perimenopausal syndrome and mood disorders are common in perimenopausal women in Shanghai, whose associations are strong and positive. Many risk factors are associated with and shared between perimenopausal syndrome and mood disorders. Therefore, appropriate management of perimenopause is needed to alleviate the conditions. PMID- 27512864 TI - Zero-fluoroscopy catheter ablation of severe drug-resistant arrhythmia guided by Ensite NavX system during pregnancy: Two case reports and literature review. AB - BACKGROUND: Cardiac arrhythmias can occur during pregnancy. Owing to radiation exposure and other uncertain risks for the mother and fetus, catheter ablation has rarely been performed and is often delayed until the postpartum period. We reported 2 pregnant women who were experiencing severe arrhythmias and were successfully ablated without fluoroscopic guidance. We also carried out a literature review of cases of pregnant women who underwent zero-fluoroscopy ablation. METHODS AND RESULTS: One woman had drug-resistant and poorly tolerated frequent premature ventricular contraction (PVC) and ventricular tachycardia (VT). The other one had persistent and hardly terminated supraventricular tachycardia (SVT) via a right accessory pathway. The 2 patients were successfully underwent zero-fluoroscopy ablation guided by Ensite NavX system. The procedure time was 42 and 71 minutes, respectively. CONCLUSION: Catheter ablation of SVT or PVC/VT in pregnant patients can be safely and effectively performed with a completely zero-fluoroscopy approach guided by the Ensite NavX system. In the case of a drug refractory, life-threatening arrhythmia during pregnancy, catheter ablation may be considered. PMID- 27512865 TI - Plasma angiopoietin-2 is persistently elevated after non-small cell lung cancer surgery and stimulates angiogenesis in vitro. AB - Angiopoietin-2 (Ang2) is a key proangiogenic factor, but its role in surgery induced angiogenesis, a possible cause of cancer recurrence, is still elusive.We measured the plasma Ang2 levels in healthy controls (n = 42) and stage I-IV perioperative nonsmall cell lung cancer (NSCLC) patients (n = 227) with enzyme linked immunosorbent assay, and examined the impact of Ang2 in the plasmas on in vitro angiogenesis and proliferation of human umbilical vein endothelial cells and human microvascular endothelial cells.Ang2 plasma levels are significantly increased in untreated NSCLC patients (2697 +/- 1354 pg/mL) compared to control (1473 +/- 560.6 pg/mL) and positively associated with disease stage but not with histology. Ang2 plasma levels in stage I-IIIA NSCLC patients (n = 154) are elevated after the standard open thoracic surgery, following an approximate pattern to increase quickly in the 1st postoperative days (PODs, from preoperative 2342 +/- 1084 to POD1: 4485 +/- 1617 and POD3: 5370 +/- 1879 pg/mL), reach the peak about 2 weeks later (POD14: 6099 +/- 2280 pg/mL), drop slowly thereafter (POD28: 3877 +/- 1388 and POD42: 3365 +/- 1189 pg/mL), and remain significantly higher than preoperative 8 weeks after the procedure (POD56: 2937 +/- 943.3 pg/mL). The postoperative plasmas enhance in vitro angiogenesis and Ang2 removal from the plasmas can counteract the effect. The postoperative plasmas stimulate endothelial proliferation independently of Ang2.These results suggest that plasma Ang2 increases after NSCLC surgery and contributes to the proangiogenic property of the postoperative plasmas, thus supporting the possible administration of anti-Ang2 therapy for NSCLC in postoperative adjuvant setting. PMID- 27512867 TI - Decreased retinal nerve fiber layer thickness in patients with obstructive sleep apnea syndrome: A meta-analysis. AB - OBJECTIVE: To investigate the changes of retinal nerve fiber layer (RNFL) thickness in obstructive sleep apnea syndrome (OSAS) patients. METHODS: Relevant studies were selected from 3 major literature databases (PubMed, Cochrane Library, and EMBASE) without language restriction. Main inclusion criteria is that a case-control study in which RNFL thickness was measured by a commercial available optical coherence tomography (OCT) in OSAS patients. Meta-analysis was performed using STATA 12.0 software. Efficacy estimates were evaluated by weighted mean difference with corresponding 95% confidence intervals (CIs). Primary outcome evaluations were: the average changes of RNFL thickness in total OSAS patients, subgroup analysis of RNFL thickness changes in patients of different OSAS stages, and subgroup analysis of 4-quadrant RNFL thickness changes in total OSAS patients. RESULTS: Of the initial 327 literatures, 8 case-control studies with 763 eyes of OSA patients and 474 eyes of healthy controls were included (NOS scores >=6). For the people of total OSAS, there had an average 2.92 MUm decreased RNFL thickness compared with controls (95% CI: -4.61 to -1.24, P = 0.001). For subgroup analysis of OSAS in different stages, the average changes of RNFL thickness in mild, moderate, severe, and moderate to severe OSAS were 2.05 (95% CI: -4.40 to 0.30, P = 0.088), 2.32 (95% CI: -5.04 to 0.40, P = 0.094), 4.21 (95% CI: -8.36 to -0.06, P = 0.047), and 4.02 (95% CI: -7.65 to 0.40, P = 0.03), respectively. For subgroup analysis of 4-quadrant, the average changes of RNFL thickness in Superior, Nasal, Inferior, and Temporal quadrant were 2.43 (95% CI: -4.28 to -0.57, P = 0.01), 1.41 (95% CI: -3.33 to 0.51, P = 0.151), 3.75 (95% CI: -6.92 to -0.59, P = 0.02), and 0.98 (95% CI: -2.49 to 0.53, P = 0.203), respectively. CONCLUSION: Our study suggests that RNFL thickness in OSAS patients is much thinner than healthy population, especially in superior and inferior quadrant. The impact of OSAS disease on RNFL and visual function should be taken seriously in the further study. PMID- 27512866 TI - Venous thromboembolism has the same risk factors as atherosclerosis: A PRISMA compliant systemic review and meta-analysis. AB - BACKGROUND: Previous studies have shown that idiopathic pulmonary embolism is positively associated with other cardiovascular events, such as myocardial infarction and stroke, suggesting a potentially important association between atherosclerosis risk factors and venous thromboembolism (VTE). We performed a meta-analysis to evaluate the correlation between risk factors for atherosclerosis and VTE. METHODS: In December 2014, we searched MEDLINE and EMBASE for studies evaluating the associations between VTE and risk factors for atherosclerosis and pooled outcome data using random-effects meta-analysis. In addition, we analyzed publication bias. RESULTS: Thirty-three case-control and cohort studies with a total of 185,124 patients met the inclusion criteria. We found that participants with body mass index (BMI) >=30 kg/m had a significantly higher prevalence of VTE than those with BMI <30 kg/m in both case-control studies (odds ratio [OR] = 2.45, 95% confidence interval [CI]: 1.78-3.35) and cohort studies (relative risk [RR] = 2.39, 95% CI: 1.79-3.17). VTE was more prevalent in patients with hypertension than without hypertension (OR = 1.40, 95% CI: 1.06-1.84; RR = 1.36, 95% CI: 1.11-1.67). The findings were similar for VTE prevalence between patients with and without diabetes (OR = 1.78, 95% CI: 1.17 2.69; RR = 1.41, 95% CI: 1.20-1.66). Current smoking was significantly associated with VTE prevalence in case-control studies (OR = 1.34, 95% CI: 1.01-1.77), but not in cohort studies (RR = 1.29, 95% CI: 0.96-1.72). In addition, we found that total cholesterol and triglyceride concentrations were significantly higher in patients with VTE than without VTE (weighted mean differences [WMD] = 8.94 mg/dL, 95% CI: 3.52-14.35 mg/dL, and WMD = 14.00 mg/dL, 95% CI: 8.85-19.16 mg/dL, respectively). High-density lipoprotein cholesterol concentrations were significantly lower in patients with VTE than without VTE (WMD = -2.03 mg/dL, 95% CI: -3.42 to -0.63 mg/dL). Higher quality studies were more homogeneous, but confirmed the same significant associations. CONCLUSIONS: Based on our systematic review and meta-analysis, we observed a significant association between VTE and the risk factors for atherosclerosis. These results may make an important contribution to clinical practice regarding VTE treatment. PMID- 27512868 TI - Impact of protease inhibitors on the evolution of urinary markers: Subanalyses from an observational cross-sectional study. AB - Kidney injury (defined as the presence of albuminuria, proteinuria, glycosuria [without hyperglycemia], hematuria, and/or renal hypophosphatemia) is an emerging problem in human immunodeficiency virus (HIV)-infected patients, although few data are available on the role of protease inhibitors (PIs) in this condition.To determine the time to kidney injury in a cohort of HIV-infected patients receiving a PI-containing regimen.We report the results of a subanalysis of a published cross-sectional study. The subanalysis included only patients receiving PI-containing regimens for more than 6 months (377 of the overall 970 patients). We determined associated factors and constructed receiver operating characteristic curves to estimate time to kidney injury depending on the PI used.The percentage of patients with kidney injury was 27.7% for darunavir, 27.9% for lopinavir, and 30% for atazanavir. Time to kidney injury was as follows: 229 days for atazanavir/ritonavir (area under the curve [AUC], 0.639; sensitivity, 0.89; specificity, 0.41); 332 days for atazanavir/ritonavir plus tenofovir (AUC, 0.603; sensitivity, 0.75; and specificity, 0.29); 318 days for nonboosted atazanavir (AUC, 0.581; sensitivity, 0.89; and specificity, 0.29); 478 days for lopinavir/ritonavir (AUC, 0.566; sensitivity, 0.864; and specificity, 0.44); 1339 days for lopinavir/ritonavir plus tenofovir (AUC, 0.667; sensitivity, 0.86; and specificity, 0.77); 283 days for darunavir/ritonavir (AUC, 0.523; sensitivity, 0.80; and specificity, 0.261); and 286 days for darunavir/ritonavir plus tenofovir (AUC, 0.446; sensitivity, 0.789; and specificity, 0.245). The use of lopinavir/ritonavir without tenofovir was a protective factor (odds ratio = 1.772; 95%CI, 1.070-2.93; P = 0.026).For all PIs, the percentage of patients with kidney injury exceeded 27%, irrespective of tenofovir use. The longest time to kidney injury was recorded with lopinavir/ritonavir. These results demonstrate the need for renal monitoring, including urine samples, in patients receiving a PI-based regimen, even when tenofovir is not used concomitantly. PMID- 27512869 TI - Knowledge, attitudes, and beliefs about HIV pre-exposure prophylaxis among US Air Force Health Care Providers. AB - Providers are central to effective implementation of HIV pre-exposure prophylaxis (PrEP). Primary care providers (PCP) and infectious disease physicians (ID) in the US Air Force (USAF) participated in a cross-sectional survey regarding knowledge, attitudes, and beliefs toward HIV PrEP. Characteristics associated with PrEP knowledge were assessed in univariate and multivariate analyses.Among 403 (40% of 1015 providers) participants, 9% (PCP 383, ID 20) ever prescribed PrEP. In univariate analysis, years in practice, number of HIV-infected patients treated in the past 12 months, past prescription of antiretrovirals for HIV prevention, frequency of prescribing PrEP in the past 12 months, and ever being questioned by a patient about PrEP were associated with PrEP knowledge (P < 0.05). In multivariate analysis, providers who had ever prescribed antiretrovirals to prevent HIV (AOR: 2.37, 95% CI: 1.27-4.42) had greater odds of high PrEP knowledge. Despite concerns about medication side effects (overall 67%: PCP 68%, ID 85%) and prescribing PrEP without clear evidence (overall 60%: PCP 65%, ID 62%), 64% (PCP 65%, ID 85%) of participants indicated PrEP should be offered in the Military Health System and 68% (PCP 70%, ID 100%) disagreed with the statement that their patient population was not at risk for HIV infection.Successful PrEP implementation in the USAF will require continued education and training of primary care providers to improve knowledge and mitigate concerns about PrEP. PMID- 27512870 TI - Risk assessment model for invasive breast cancer in Hong Kong women. AB - No risk assessment tool is available for identifying high risk population of breast cancer (BCa) in Hong Kong. A case-control study including 918 BCa cases and 923 controls was used to develop the risk assessment model among Hong Kong Chinese women.Each participant received an in-depth interview to obtain their lifestyle and environmental risk factors. Least absolute shrinkage and selection operator (LASSO) selection model was used to select the optimal risk factors (LASSO-model). A risk score system was constructed to evaluate the cumulative effects of selected factors. Bootstrap simulation was used to test the internal validation of the model. Model performance was evaluated by receiver-operator characteristic curves and the area under the curve (AUC).Age, number of parity, number of BCa cases in 1st-degree relatives, exposure to light at night, and sleep quality were the common risk factors for all women. Alcohol drinking was included for premenopausal women; body mass index, age at menarche, age at 1st give birth, breast feeding, using of oral contraceptive, hormone replacement treatment, and history of benign breast diseases were included for postmenopausal women. The AUCs were 0.640 (95% CI, 0.598-0.681) and 0.655 (95% CI, 0.621-0.653) for pre- and postmenopausal women, respectively. Further subgroup evaluation revealed that the model performance was better for women aged 50 to 70 years or ER-positive.This BCa risk assessment tool in Hong Kong Chinese women based on LASSO selection is promising, which shows a slightly higher discriminative accuracy than those developed in other populations. PMID- 27512871 TI - Prevalence of cardiac sarcoidosis in white population: a case-control study: Proposal for a novel risk index based on commonly available tests. AB - Cardiac sarcoidosis (CS) is a life-threatening and underdiagnosed manifestation of the disease, which requires a complicated and expensive diagnostic pathway. There is a need for simple tool for practitioners to determine the risk of CS without access to specialized equipment.The aim of study was to determine the prevalence of CS in a group of patients diagnosed with or followed up because of sarcoidosis. A secondary objective was the search for factors associated with heart involvement.We performed a prospective case-control study (screening analysis) in consecutive sarcoidosis patients collected from October 2012 to September 2015. Cardiac magnetic resonance (CMR) imaging was performed to confirm or exclude cardiac involvement in all patients. The study was conducted in a hospital-based referral center for patients with sarcoidosis and other interstitial lung diseases.Analysis was performed in a group of 201 patients (all white) with biopsy-proven sarcoidosis, mean age 41.4 +/- 10.2, 121 of them (60.2%) males. Four patients with previously recognized cardiac diseases, which make CMR imaging for CS inconclusive, were not included.Cardiac involvement was detected by CMR in 49 patients (24.4%). Factors associated with an increased risk of CS (univariate analyses) included male sex (odds ratio [OR]: 2.5; 1.21-5.16, P = 0.01), cardiac-related symptoms (OR: 3.53; 1.81-6.89, P = 0.0002), extrathoracic sarcoidosis (OR: 3.48; 1.77-6.84, P = 0.0003), elevated serum NT proBNP (OR: 3.82; 1.55-9.42, P = 0.004), any electrocardiography abnormality (OR: 5.38; 2.48-11.67, P = 0.0001), and contemporary radiological progression sarcoidosis in the lungs (OR: 2.98; 1.52-5.84, P = 0.001). Abnormalities in echocardiography and Holter ECG were also risk factors, but not significant in multivariate analyses. A CS Risk Index was developed using a multivariate model to predict CS, achieving an accuracy of 82%, sensitivity of 50%, specificity of 94%, and likelihood ratio 8.1.CS was detected in one fourth of patients. A CS Risk Index based on the results of easily accessible tests is cost-effective and may help to identify patients who should be urgently referred for further diagnostic procedures. PMID- 27512872 TI - Successful kidney transplantation after desensitization in a patient with positive flow crossmatching and donor-specific anti-HLA-DP antibody: A Case report. AB - BACKGROUND: Traditionally, the presence of antibodies against human leukocyte antigen (HLA)-C and DP was considered to be associated with only a low risk of antibody-mediated rejection (ABMR) in kidney transplantation (KT), because the antigenicities of these proteins are weak. However, the clinical effects of HLA-C and -DP donor-specific HLA antibodies (DSHAs) have recently been reevaluated. METHODS: Here, we report the case of a retransplant patient with positive flow cytometry crossmatch (FCXM) and high level of HLA-DP DSHA who was desensitized using rituximab, plasmapheresis, and intravenous immunoglobulin. RESULTS: The epitope-based antibody reactivity was identified that the positive B-cell FCXM in our patient was attributable to the specific epitope. The patient underwent a successful retransplantation and has continued to do well for 10 month after KT. CONCLUSION: If an HLA-DP DSHA is present, it is important to detect any mismatched HLA-DP epitope pretransplantation and to monitor HLA-DP levels carefully. According to previous reports, anti-HLA-DP DSHA can induce ABMR soon after transplantation, but such ABMR can be prevented by pretransplantation desensitization and careful monitoring of DSHA levels. PMID- 27512873 TI - Prediction of motor outcome by shoulder subluxation at early stage of stroke. AB - We attempted to determine whether shoulder subluxation at the early stage of stroke can predict motor outcome in relation to the corticospinal tract (CST) state on diffusion tensor tractography.Fifty-nine stroke patients with severe hemiparesis were recruited. The patients were classified according to the distance of shoulder subluxation (group A: >=2 cm, group B: <2 cm) and the affected CST on diffusion tensor tractography at the first evaluation (CST type A the CST was discontinued at the stroke lesion; CST type B-the integrity of the CST was preserved). Motor function of the patients was evaluated twice (first: beginning of rehabilitation-24.1 +/- 16.6 days; second: discharge after first rehabilitation-58.5 +/- 24.1 days) using the Medical Research Council score, Motricity Index, and Modified Brunnstrom Classification.Regarding the improvement of the Medical Research Council for the finger extensor and upper Motricity Index, the order in terms of better recovery was as follows: group B-type B, group A-type B, group B-type A, and group A-type A (P < 0.05). The distance of shoulder subluxation showed significant correlation with improvement of the finger extensor (moderate negative correlation, r = -0.37) and improvement of the Modified Brunnstrom Classification (weak negative correlation, r = -0.29) (P < 0.05).The presence of shoulder subluxation at the early stage of stroke can be a predictor of motor outcome of the affected upper extremity and the degree of shoulder subluxation can be a predictor of the motor function of the affected hand. Therefore, our results suggest that shoulder subluxation in relation to the affected CST state at the early stage of stroke can be a prognostic factor for motor outcome. PMID- 27512875 TI - Effects of postimplantation systemic inflammatory response on long-term clinical outcomes after endovascular aneurysm repair of an abdominal aortic aneurysm. AB - The aim of this study was to determine the association between postimplantation syndrome (PIS) and long-term clinical outcomes after elective endovascular aneurysm repair (EVAR) of an abdominal aortic aneurysm.In this single-center, observational cohort study, a total of 204 consecutive patients undergoing EVAR were included. Primary outcome was long-term mortality from any cause; secondary outcomes included long-term mortality, systemic or implant-related complications, and secondary therapeutic procedures.The diagnosis of PIS was established in 64 patients (31.4%). PIS patients were more likely to receive woven polyester endografts and have a longer postoperative hospital stay and lower incidence of type II endoleaks. In multivariate analysis, PIS was significantly associated with a decreased risk of developing type II endoleaks (P = 0.044). During follow up period of 44 months, clinical outcomes showed no significant differences in mortality (P = 0.876), systemic (P = 0.668), or implant-related complications (P = 0.847), although rates of secondary therapeutic procedure were significantly higher in non-PIS patients (P = 0.037). The groups had similar rates of overall survival (P = 0.761) and other clinical outcomes (P = 0.562).Patients with and without PIS had similar long-term overall survival rates and other clinical outcomes. PIS was beneficial in preventing type II endoleaks during postoperative period. PMID- 27512874 TI - Comparative efficacy of interventions on nonalcoholic fatty liver disease (NAFLD): A PRISMA-compliant systematic review and network meta-analysis. AB - BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) has significantly increased over the last decades. Despite existence of several interventions, there remains unclear which interventions work the best. METHODS: A systematic review and network meta-analysis of randomized trials comparing efficacy of all treatment options in NAFLD were performed to determine comparative efficacy and safety of interventions in the management of NAFLD. Several electronic databases were searched up to Nov 15, 2015. Outcomes include liver histological outcomes (i.e., fibrosis), all-cause mortality, cirrhosis, and safety. A network meta-analysis was applied to estimate pooled risk ratios (RR). Quality of evidence was assessed using GRADE criteria. RESULTS: A total of 44 studies (n = 3802) were eligible. When compared with placebo, obeticholic acid (OCA) was the only intervention that significantly improved fibrosis with RR (95% CI) of 1.91 (1.15, 3.16), while pentoxyfylline (PTX) demonstrated improved fibrosis without statistical significance with RR (95% CI) of 2.27 (0.81, 6.36). Only thiazolidinedione (TZD) and vitamin E use resulted in significant increase in resolution of NASH, while OCA, TZD, and vitamin E significantly improved other outcomes including NAS, steatosis, ballooning, and inflammation outcomes. Quality of evidence varied from very low (i.e., metformin, PTX on mean change of ballooning grade) to high (OCA, TZD, vitamin E on improving histological outcomes). Limitations of this study were lack of relevant long-term outcomes (e.g., cirrhosis, death, safety), possible small study effect, and few head-to head studies. CONCLUSIONS: Our study suggests potential efficacy of OCA, TZD, and vitamin E in improving histologic endpoints in NAFLD. These findings are however based on a small number of studies. Additional studies are awaited to strengthen this network meta-analysis. PMID- 27512876 TI - A new automatic blood pressure kit auscultates for accurate reading with a smartphone: A diagnostic accuracy study. AB - The widely used oscillometric automated blood pressure (BP) monitor was continuously questioned on its accuracy. A novel BP kit named Accutension which adopted Korotkoff auscultation method was then devised. Accutension worked with a miniature microphone, a pressure sensor, and a smartphone. The BP values were automatically displayed on the smartphone screen through the installed App. Data recorded in the phone could be played back and reconfirmed after measurement. They could also be uploaded and saved to the iCloud. The accuracy and consistency of this novel electronic auscultatory sphygmomanometer was preliminarily verified here. Thirty-two subjects were included and 82 qualified readings were obtained. The mean differences +/- SD for systolic and diastolic BP readings between Accutension and mercury sphygmomanometer were 0.87 +/- 2.86 and -0.94 +/- 2.93 mm Hg. Agreements between Accutension and mercury sphygmomanometer were highly significant for systolic (ICC = 0.993, 95% confidence interval (CI): 0.989-0.995) and diastolic (ICC = 0.987, 95% CI: 0.979-0.991). In conclusion, Accutension worked accurately based on our pilot study data. The difference was acceptable. ICC and Bland-Altman plot charts showed good agreements with manual measurements. Systolic readings of Accutension were slightly higher than those of manual measurement, while diastolic readings were slightly lower. One possible reason was that Accutension captured the first and the last korotkoff sound more sensitively than human ear during manual measurement and avoided sound missing, so that it might be more accurate than traditional mercury sphygmomanometer. By documenting and analyzing of variant tendency of BP values, Accutension helps management of hypertension and therefore contributes to the mobile heath service. PMID- 27512877 TI - Efficacy of different dipeptidyl peptidase-4 (DPP-4) inhibitors on metabolic parameters in patients with type 2 diabetes undergoing dialysis. AB - Hyperglycemia is associated with increased mortality and morbidity in patients with type 2 diabetes mellitus (T2DM) who are undergoing dialysis. Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been widely used in end-stage renal disease (ESRD) patients with T2DM, there are few studies on their efficacy in this population. We studied the effect of 3 different DPP-4 inhibitors on metabolic parameters in ESRD patients with T2DM.Two hundred ESRD patients with T2DM who were treated with DPP-4 inhibitors (sitagliptin, vildagliptin, or linagliptin) were enrolled and analyzed retrospectively. The changes in glycated hemoglobin (HbA1c), fasting plasma glucose, and lipid profiles were assessed before and after 3 months of treatment with DPP-4 inhibitors. Subgroup analysis was done for each hemodialysis (HD) and peritoneal dialysis (PD) group.There was no significant difference in the decrease in the HbA1c level among sitagliptin, vildagliptin, and linagliptin treatment groups (-0.74 +/- 1.57, -0.39 +/- 1.45, and -0.08 +/- 1.40, respectively, P = 0.076). The changes in fasting blood glucose and lipid profiles were also not significantly different. In HD patients (n = 115), there was no difference in the HbA1c level among the 3 groups. In contrast, in PD patients (n = 85), HbA1c was reduced more after 3 months of treatment with sitagliptin compared with vildagliptin and linagliptin (-1.58 +/- 0.95, -0.46 +/- 0.98, -0.04 +/- 1.22, respectively, P = 0.001).There was no significant difference in the glucose-lowering effect between the different DPP-4 inhibitors tested in ESRD patients. In PD patients, sitagliptin tends to lower the HbA1c level more than the other inhibitors. The glucose-lowering efficacy of the 3 DPP-4 inhibitors was comparable. PMID- 27512878 TI - Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia: Report from Shanghai, China (2000-2015). AB - X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency. XLA patients typically present with very low numbers of peripheral B cells and a profound deficiency of all immunoglobulin isotypes. Most XLA patients carry mutations in Bruton tyrosine kinase (BTK) gene.The genetic background and clinical features of 174 Chinese patients with XLA were investigated. The relationship between specific BTK gene mutations and severity of clinical manifestations was also examined. Mutations were graded from mild to severe based on structural and functional prediction through bioinformatics analysis.One hundred twenty-seven mutations were identified in 142 patients from 124 families, including 45 novel mutations and 82 recurrent mutations that were distributed over the entire BTK gene sequence. Variation in phenotypes was observed, and there was a tendency of association between genotype and age of disease onset.This report constitutes the largest group of patients with BTK mutations in China. A genotype-phenotype correlation was observed in this study. Early diagnosis of congenital agammaglobulinemia should be based on clinical symptoms, family history, and molecular analysis of the BTK gene. PMID- 27512879 TI - Layer-specific analysis of dobutamine stress echocardiography for the evaluation of coronary artery disease. AB - Although dobutamine stress echocardiography (DSE) is a well-defined tool for the diagnosis of coronary artery disease (CAD), false-negative and false-positive results still occur. This study investigated the diagnostic role of layer specific analysis using 2-dimensional speckle-tracking echocardiography (STE) during DSE.A total of 121 patients who underwent DSE and showed normal wall motion and ejection fraction during baseline echocardiography were enrolled. All patients underwent coronary angiography after DSE within 2 weeks. The patients were divided into the following 4 groups according to DSE results and CAD status: negative DSE with no significant CAD (n = 73), positive DSE with significant CAD (n = 16), negative DSE with significant CAD (n = 17), and positive DSE with no significant CAD (n = 15). Layer-specific global longitudinal strain (GLS) was assessed in the endocardium, mid-myocardium, and epicardium by STE techniques.Patients with significant CAD were older, more male and showed higher glucose level compared to patients without CAD. But coronary risk factors and previous medications were not different between patients with and without CAD. There were no significant differences in whole myocardium or layer-specific GLS found in the baseline echocardiography. During recovery echocardiography, endocardial GLS was significantly different between patients with and without CAD, regardless of the DSE results. A receiver-operating characteristic curve analysis showed that endocardial GLS (>-16%) was superior for identifying significant CAD during the DSE recovery stage. Diagnostic accuracy was improved by applying the results of endocardial GLS compared with visual estimation of DSE.The assessment of layer-specific strain by STE during DSE was feasible, and the evaluation of poststress endocardial function is a more sensitive tool for the detection of CAD. PMID- 27512880 TI - Modeling the effectiveness of nebulized terbutaline for decompensated chronic obstructive pulmonary disease patients in the emergency department. AB - Short-acting beta2-agonists (SABA) are widely used in the emergency department (ED) to treat patients with decompensated chronic obstructive pulmonary disease (COPD). We sought to model the effectiveness of nebulized SABA (terbutaline) on clinically relevant parameters associated with a reduction in work of breathing or respiratory muscle fatigue in decompensated COPD patients admitted to the ED.Forty consecutive decompensated COPD patients (having received at least one dose of nebulized terbutaline during their stay in the ED) were included in an observational cohort study. The terbutaline dose received at time t was expressed as cumulative dose and as a rate (mg/day). The associations between the terbutaline dose and time-dependent outcome parameters (respiratory rate, heart rate, arterial blood gases, and, as a marker of terbutaline's systemic effect, serum potassium) were analyzed using a nonlinear, mixed-effects model. The effect of various covariates influencing terbutaline's effectiveness (baseline characteristics and concomitant treatments) was assessed on the model.Among the investigated patients, a total of 377 time-dependent observations were available for analysis. Neither the cumulative dose nor the dose rate at time t significantly influenced the arterial blood gas parameters or heart rate. The cumulative dose of terbutaline was associated with a lower serum potassium level (P < 0.001) and, less significantly, a lower respiratory frequency (P = 0.036). In a tertile analysis, the need for post-ED hospitalization was not associated with the cumulative dose or dose rate of terbutaline.Overall, the results of our modeling study strongly suggest that terbutaline dose did not influence time dependent outcomes other than serum potassium, and thus call into question the systematic administration of inhaled SABA to patients admitted to the ED for decompensated COPD. PMID- 27512881 TI - Defining and validating comorbidities and procedures in ICD-10 health data in ST elevation myocardial infarction patients. AB - Administrative health databases are used in research to define comorbid conditions, diagnosis, and procedures. Our objectives were to validate a diagnosis of ST-elevation myocardial infarction (STEMI) and invasive cardiac procedure coding against a comprehensive registry of STEMI patients and determine an optimal algorithm for defining comorbidities using administrative hospitalization and ambulatory databases, but without using a physician claims database, which is unavailable for use in many jurisdictions.A registry of consecutive STEMI patients was used to define a reference cohort and linked to the hospitalization and ambulatory databases. Four administrative case definitions for defining comorbidities, as well as STEMI diagnosis and in hospital procedures using the International Classification of Diseases, 10th Revision (ICD-10) and the Canadian Classification of Health Interventions (CCI) were evaluated. Metrics were used to evaluate algorithm performance and compare discriminative ability using the C statistic.The 3236 patients had median age of 60 years (interquartile range 52-71) and 75.7% were male. A diagnosis of STEMI was correctly identified in the administrative records for 3043 (94.0%) patients. In-hospital procedures (coronary artery bypass grafting, percutaneous coronary intervention, and angiogram) were well identified using administrative definitions (Kappa statistic 0.83-1.00). Validation of comorbidities varied by condition but an algorithm using 2 inpatient/ambulatory visits in the previous 2 years maximized PPV, ranging from 28.6% for previous heart failure to 95.7% for previous MI. The c statistic was similar for each of the methods, ranging from 0.76 to 0.80.ICD-10 and CCI codes can identify hospitalized STEMI patients with high sensitivity and accurately define in-hospital cardiac procedures. Comorbidities can be defined with high PPV using a definition of 2 inpatient/ambulatory visits in the previous 2 years. PMID- 27512882 TI - The constellation of skeletal deformities in a family with mixed types of mucopolysaccharidoses: Case report. AB - INTRODUCTION: A 13-year-old child was clinically diagnosed with mucopolysaccharidosis type VI-Maroteaux-Lamy syndrome (MPS VI) at the age of 5 years, and the diagnosis was confirmed biochemically and genetically (homozygous mutation in ARSB gene). At that time, his older brother manifested with increasing severe mental retardation. His urinary glycosaminoglycan excretion in urine was elevated, but there was only 1 mutation in the ARSB gene defining him as a healthy carrier of MPS VI. The 15-year-old boy was born with dysmorphic facial features, cleft lip and palate, and multiple contractures associated with profound skeletal deformities manifested, severe mental retardation, and seizures, leading to the diagnosis of cerebral palsy from birth on.Clinical and radiographic phenotypic characterization was the baseline tool to document the older sibling, parents, and relatives, all of them examined at the Orthopaedic Hospital of Speising, Vienna, Austria. The family history (from maternal and paternal sides) showed >10 subjects with variable clinical histories of hyperactivity and attention deficit disorder, depression, and a diversity of skeletal abnormalities, such as dysplastic spondylolisthesis, discovertebral degeneration, osteopenia, osteophytosis, and progressive degeneration of the weight bearing zones (mostly developed at middle age). METHODS: Eleven patients in a family with interrelated marriages (two male siblings of 15 and 13-year old), parents and relatives over three generations were enrolled. One of the siblings was diagnosed with Maroteaux-Lamy syndrome at the age of five-years and mutation of the ARBS gene has been encountered. The older sibling manifested at birth craniofacial abnormalities associated with multiple contracture and seizures. Cerebral palsy was the suggested diagnosis. Clinical and radiographic phenotypes were the baseline tool to document the older sibling, parents and relatives at the orthopaedic Hospital of Speising, Vienna, Austria. These were followed by whole Exome sequencing in three family subjects. RESULTS: A series of genetic studies in the older sibling showed homozygous mutation in GNS gene compatible with MPS IIID. Both parents are first related and were found to be heterozygous for N-acetylglucosamine-6-sulfatase GNS gene. Family history showed more than 10 subjects with variable clinical presentations such as dysplastic spondylolisthesis, disco-vertebral degeneration, osteopenia, osteophytosis, and progressive degeneration of the weight bearing zones (mostly developed at middle age). CONCLUSION: Owing to the multiple systemic involvements, a genetic cause was suspected and a molecular genetic investigation by using whole-exome sequencing method in 3 family subjects (trios) was performed: the 15-year-old boy and his parents. A homozygous splice-site-mutation in the GNS gene could be found, compatible with mucopolysaccharidosis-Sanfillipo syndrome (type IIID). Both parents are first related and were now found also to be heterozygous for the GNS gene mutation found in their older son. Therefore, both parents are heterozygous carriers for the ARSB gene mutation but also the GNS gene mutation. In the son with MPS VI, no mutation in the GNS gene was found, but the brother with MPS IIID was heterozygous for the ARSB gene mutation.We presume that the intrafamilial variability of clinical signs in different family members could be the result of various mutations in the ARSB/GNS genes in the carriers or potential modulating effects of other genes or differences in genetic backgrounds. PMID- 27512883 TI - Smoking habits and benign prostatic hyperplasia: A systematic review and meta analysis of observational studies. AB - Previous studies have warned against the promoting effects of cigarette smoking on benign prostatic hyperplasia (BPH). In contrast, some have argued that smoking confers a protective effect regarding BPH, while others have observed an aggravated effect. Thus, we performed this meta-analysis to determine whether cigarette use is associated with BPH risk.To identify articles from observational studies of relevance, a search was performed concurrent to March 21, 2016, on PubMed, Web of Science, Cochrane, EBSCO, and EMBASE databases. Random-effect model, according to the heterogeneity, was calculated to reveal the relative risks (RRs) and corresponding 95% confidence intervals (CIs).Eight articles were included in this meta-analysis, representing data for 44,100 subjects, of which 5221 (11.8%) had BPH as defined according to the criteria. Seven reports are concerned with analysis between nonsmokers and ex-smokers, in which no significant difference was observed (RR = 0.99, 95% CI 0.94-1.05). Another meta analysis of 7 studies indicated an observable trend, but without significant difference between groups of nonsmokers and current smokers (RR = 1.17, 95% CI 0.98-1.41). Between groups of heavy (6 articles; RR = 1.02, 95% CI 0.84-1.24) and light smokers (5 articles; RR = 0.90, 95% CI 0.71-1.15), again no significant difference appears. Finally, we combined individuals as never-smokers and ever smokers and still found no significant difference between the 2 groups of patients (RR = 1.03, 95% CI 0.92-1.15). Sensitivity analysis was displayed and confirmed the stability of the present results.Combined evidence from observational studies shows no significant association between cigarette smoking and BPH risk, either for ex-smokers or for current smokers. The trend of elevated BPH risk from smoking was observed only in current smokers compared with nonsmokers, while marginal significance was observed in comparing ever-smokers with never-smokers in operative patients with BPH. PMID- 27512884 TI - Risk factors for pulmonary complications following laparoscopic gastrectomy: A single-center study. AB - The risk factors associated with postoperative pulmonary complications (PPCs) following laparoscopic gastrectomy have not been well studied. We sought to identify the risk factors for PPCs following gastric cancer surgery.A retrospective analysis was performed on all gastric cancer patients in a prospective database who underwent a laparoscopic gastrectomy from 2004 to 2014. The potential risk factors for PPCs were evaluated.PPCs occurred in 6.8% (83/1205) of patients and included pneumonia in 56 (67.5%) patients, pleural effusion in 26 (31.3%) patients, and pulmonary embolism in 1 (1.2%) patient. The multivariate analysis identified the following significant risk factors for PPCs: advanced age (odds ratio [OR] = 1.043, 95% confidence interval [CI] = 1.021%, 1.066%), chronic obstructive pulmonary disease (COPD) (OR = 17.788, 95% CI = 2.618%, 120.838%), total gastrectomy (OR = 2.781, 95% CI = 1.726%, 4.480%), time to first diet (OR = 1.175, 95% CI = 1.060%, 1.302%), and postoperative hospital stay (OR = 1.015, 95% CI = 1.002%, 1.028%). The risk factors for pneumonia included advanced age (OR = 1.036, 95% CI = 1.010%, 1.063%), total gastrectomy (OR = 3.420, 95% CI = 1.960%, 5.969%), and time to first diet (OR = 1.207, 95% CI = 1.703%, 1.358%). Only pancreatectomy was a risk factor for pleural effusion (OR = 9.082, 95% CI = 2.412%, 34.206%).The frequency of PPCs in patients with gastric cancer who underwent laparoscopic surgery was relatively high. Patients with cardiac and pulmonary comorbidities and those who undergo total gastrectomy and combined resection should be considered at high risk. PMID- 27512885 TI - Elevated CD8 T-cell counts and virological failure in HIV-infected patients after combination antiretroviral therapy. AB - Elevated CD8 counts with combination antiretroviral therapy (cART) initiation may be an early warning indicator for future treatment failure. Thus, we investigated whether elevated CD8 counts were associated with virological failure (VF) in the first 4 years of cART in Asian HIV-infected patients in a multicenter regional cohort.We included patients from the TREAT Asia HIV Observational Database (TAHOD). Patients were included in the analysis if they started cART between 1996 and 2013 with at least one CD8 measurement within 6 months prior to cART initiation and at least one CD8 and viral load (VL) measurement beyond 6 months after starting cART. We defined VF as VL >=400 copies/mL after 6 months on cART. Elevated CD8 was defined as CD8 >=1200 cells/MUL. Time to VF was modeled using Cox regression analysis, stratified by site.In total, 2475 patients from 19 sites were included in this analysis, of whom 665 (27%) experienced VF in the first 4 years of cART. The overall rate of VF was 12.95 per 100 person-years. In the multivariate model, the most recent elevated CD8 was significantly associated with a greater hazard of VF (HR = 1.35, 95% CI 1.14-1.61; P = 0.001). However, the sensitivity analysis showed that time-lagged CD8 measured at least 6 months prior to our virological endpoint was not statistically significant (P = 0.420).This study indicates that the relationship between the most recent CD8 count and VF was possibly due to the CD8 cells reacting to the increase in VL rather than causing the VL increase itself. However, CD8 levels may be a useful indicator for VF in HIV-infected patients after starting cART. PMID- 27512886 TI - Effect of extracorporeal shock wave therapy on scar pain in burn patients: A prospective, randomized, single-blind, placebo-controlled study. AB - BACKGROUND: Extracorporeal shock wave therapy (ESWT) has been used to reduce pain in patients with various musculoskeletal diseases and wounds. We investigated the effect of ESWT on scar pain after complete wound epithelialization in burn patients. METHODS: A prospective, single-blind, placebo-controlled study was conducted from February 2014 to 2015. Forty patients with burn scar pain despite standard therapy (medication, physical therapy, and burn rehabilitation massage therapy) were randomized into ESWT or control (sham ESWT) groups. ESWT was administered at 100 impulses/cm (0.05-0.15 mJ/mm) once per week for 3 weeks. The treatment effects were assessed using the numerical rating scale (NRS), pain threshold, Nirschl pain phase system, and Roles and Maudsley scores. RESULTS: The characteristics of patients between the 2 study groups were balanced (P >0.05) for age, sex, and total burn surface area (%). In both groups, the NRS, pain threshold (Ib/cm), and Nirschl pain phase system values significantly improved (P <0.05) after 3 sessions of ESWT or sham therapy, and there were significant differences between the 2 groups in terms of these 3 variables (P <0.001, P <0.001, P = 0.013, respectively). The Roles and Maudsley scores significantly improved; among 20 patients, 17 reported a score of poor (85%) and 3 reported fair (15%) before ESWT, whereas 3 reported poor (15%), 8 reported fair (40%), 5 reported good (25%), and 4 reported excellent (20%) after ESWT (P = 0.004). The scores did not improve in the control group (P = 0.128). CONCLUSION: ESWT significantly reduced scar pain in burn patients after wound recovery. PMID- 27512887 TI - Efficacy of continuous epidural block in acute herpes zoster: Incidence and predictive factors of postherpetic neuralgia, a retrospective single-center study. AB - The aim of the present study was to investigate efficacy of continuous epidural block for prevent postherpetic neuralgia (PHN) progression in cases of acute herpes zoster with severe pain and also to identify predictive factors for PHN in such conditions.We retrospectively analyzed the clinical data of patients with herpes zoster who underwent continuous epidural block between March 2013 and October 2015. Time points were set as 1 month, 3 months, and 6 months after zoster onset. PHN was defined as the presence of pain with NRS >=3 at certain time points.The incidence of developing PHN was 38.1%, 27.0%, and 19.0% 1 month, 3 months, and 6 months after zoster onset, respectively. Age and duration of catheterization were predictive factors for PHN at 1 month. Age, duration of catheterization, and NRS at first visit were identified as predictive factors for PHN at 3 months. Presence of diabetes, duration of catheterization, and NRS during catheterization were significant predictive factors for PHN at 6 months.The incidence of PHN is higher in zoster patients with severe pain that requires continuous epidural block compared to incidence in the general population. Advanced age and severe initial pain intensity were predictive factors of PHN development. Prolonged catheterization resulting from weak response to treatment strongly suggested progression to PHN. PMID- 27512888 TI - Clinical significance of No. 10 and 11 lymph nodes posterior to the splenic vessel in D2 radical total gastrectomy: An observational study. AB - D2 lymphadenectomy is widely performed for advanced proximal gastric cancer, but complete dissection of No. 10 and 11 lymph nodes (LNs) is technically challenging, especially for those posterior to the splenic vessel. This study aimed to investigate the clinical significance of removing No. 10 and 11 LNs posterior to the splenic vessel in radical total gastrectomy. Between January 2013 and February 2015, 53 patients who underwent spleen-preserving D2 radical total gastrectomy were enrolled. While dissecting No. 10 and 11 LNs, we divided them into 2 parts, namely LNs anterosuperior and posterior to the splenic vessel, and the pathological data were reviewed. Sixteen patients underwent laparoscopy and 37 underwent laparotomy. No mortality was recorded. According to the pathological results, the TNM stages of the tumor were IIA in 11 patients (20.8%), IIB in 5 (9.4%), IIIA in 7 (13.2%), IIIB in 10 (18.9%), and IIIC in 20 (18.9%). The mean number of LNs retrieved was 30.3 +/- 12.3. The sum of No. 10 and 11 LNs posterior to the splenic vessel was 59 and the mean number was 1.11 +/ 1.47. One LN with metastasis was found in the special 59 regional LNs, and the metastasis rate was 1.9% (1/53). Concerning the low metastasis rate (1.9%) and difficult complete dissection of No. 10 and 11 LNs posterior to the splenic vessel, our initial analysis suggests that the rate of No. 10 and 11 LNs posterior to the splenic vessel metastasis was 1.9%, but further studies are needed to reveal its clinical significance in D2 radical total gastrectomy for advanced proximal gastric cancer. PMID- 27512889 TI - Cancer in first-degree relatives of people with celiac disease. AB - BACKGROUND: Celiac disease (CD) has been linked to cancer, especially lymphoproliferative malignancy (LPM). Earlier research has shown that first degree relatives (FDRs) to individuals with CD are at increased risk of autoimmunity including CD, but data on their risk of cancer are scarce and contradictory. We aimed to assess whether Swedish FDRs to individuals with CD are at increased risk of cancer. METHODS: Individuals with CD (identified through biopsy reports equal to Marsh grade III) were matched on sex, age, county, and calendar year with up to 5 control individuals. All FDRs (father, mother, sibling, offspring) of CD individuals ("celiac FDRs": n = 109,391) and controls (n = 548,465) were identified through Swedish healthcare registries. Through Cox regression, we calculated hazard ratios (HRs) for cancer incidence (all cancer, breast cancer, gastrointestinal cancer, and LPM). RESULTS: During follow-up, celiac FDRs experienced 10,750 unique cancers as opposed to 54,686 in-control FDRs. Celiac FDRs were at a slightly lower risk of any cancer (HR 0.97, 95% confidence interval [CI] 0.95-0.99), partially due to the lower risk of breast cancer (HR 0.92, 95% CI 0.87-0.98). The relative risks of LPM (HR 0.99, 95% CI 0.91-1.08) and gastrointestinal cancer (HR 0.98, 95%CI 0.93-1.03) were both close to 1. As opposed to earlier research, we found no excess risk of LPM in siblings to individuals with CD (HR 0.98, 95% CI 0.81-1.19). CONCLUSION: Celiac FDRs are not at increased risk of cancer, including LPM, arguing that shared genetics is unlikely to explain previous reports of an excess risk of LPM in patients with CD. PMID- 27512890 TI - A 10-year follow-up study of the association between calcium channel blocker use and the risk of dementia in elderly hypertensive patients. AB - Calcium channel blockers (CCBs) are widely used for reducing blood pressure of hypertensive patients. Recent reports document the beneficial effects of CCB for preventing dementia; however, the results are controversial. We aim to evaluate the risk of developing dementia among elderly hypertensive patients treated with CCB.We designed a retrospective population-based cohort study using the records of the National Health Insurance Research Database of Taiwan dated from 2000 to 2010. The study cohort comprised 82,107 hypertensive patients of more than 60 years of age, and 4004 propensity score (PS)-matched pairs were selected according to age, sex, year of hypertension diagnosis, and baseline comorbidities. We employed a robust Cox proportional hazard model to estimate the hazard ratio (HR) of developing dementia in the PS-matched cohort.The annual incidence of dementia in the CCB-exposure group was significantly lower than that in the comparator group (3.9 vs 6.9 per 1000 person-years, P < 0.01) during the follow-up period (4.4 +/- 2.5 years). Based on the PS-matched cohort, the adjusted HR of dementia in the CCB-exposure group was significantly lower than that in comparator group (HR = 0.53, 95% confidence interval: 0.39-0.72, P < 0.01). Sensitivity and subgroup analyses also confirmed similar findings.Our results provided evidence for an association between CCB use and a lower risk of developing dementia among the elderly hypertensive patients. Further studies are required to explore the causal relationship between CCB use and dementia. PMID- 27512891 TI - Topical Antimicrobials and the Open Surgical Wound. AB - BACKGROUND: Topical antiseptic and antibiotic agents have been used for the prevention of surgical site infections since Joseph Lister's original research on this subject. Although these agents are used extensively in clinical practice, evidence to support the use of topical antimicrobial agents remains limited. PATIENTS AND METHODS: The world literature on the use of antiseptic and antibiotic agents was evaluated to determine the current status of evidence to support the use of topical antimicrobial agents in the prevention of surgical site infections. RESULTS: Although several techniques of using topical antibiotic solutions, powders, antibiotic gauzes, and beads have some evidence for validation, there are equal numbers of reports that have failed to show benefit. There is little evidence to support the use of antiseptic solutions in the prevention of infections at the surgical site. CONCLUSIONS: Additional clinical trials are necessary to provide evidence to support any of the methods for using topical antimicrobial agents to present surgical site infections. Dilute antiseptic agents should be considered in future trials when antimicrobial activity can be identified without local toxicity. PMID- 27512893 TI - Widespread copper and lead contamination of household drinking water, New South Wales, Australia. AB - This study examines arsenic, copper, lead and manganese drinking water contamination at the domestic consumer's kitchen tap in homes of New South Wales, Australia. Analysis of 212 first draw drinking water samples shows that almost 100% and 56% of samples contain detectable concentrations of copper and lead, respectively. Of these detectable concentrations, copper exceeds Australian Drinking Water Guidelines (ADWG) in 5% of samples and lead in 8%. By contrast, no samples contained arsenic and manganese water concentrations in excess of the ADWG. Analysis of household plumbing fittings (taps and connecting pipework) show that these are a significant source of drinking water lead contamination. Water lead concentrations derived for plumbing components range from 108ug/L to 1440ug/L (n=28, mean - 328ug/L, median - 225ug/L). Analysis of kitchen tap fittings demonstrates these are a primary source of drinking water lead contamination (n=9, mean - 63.4ug/L, median - 59.0ug/L). The results of this study demonstrate that along with other potential sources of contamination in households, plumbing products that contain detectable lead up to 2.84% are contributing to contamination of household drinking water. Given that both copper and lead are known to cause significant health detriments, products for use in contact with drinking water should be manufactured free from copper and lead. PMID- 27512894 TI - A Virus-Mimicking, Endosomolytic Liposomal System for Efficient, pH-Triggered Intracellular Drug Delivery. AB - A novel multifunctional liposomal delivery platform has been developed to resemble the structural and functional traits of an influenza virus. Novel pseudopeptides were prepared to mimic the pH-responsive endosomolytic behavior of influenza viral peptides through grafting a hydrophobic amino acid, l phenylalanine, onto the backbone of a polyamide, poly(l-lysine isophthalamide), at various degrees of substitution. These pseudopeptidic polymers were employed to functionalize the surface of cholesterol-containing liposomes that mimic the viral envelope. By controlling the cholesterol proportion as well as the concentration and amphiphilicity of the pseudopeptides, the entire payload was rapidly released at endosomal pHs, while there was no release at pH 7.4. A pH triggered, reversible change in liposomal size was observed, and the release mechanism was elucidated. In addition, the virus-mimicking nanostructures efficiently disrupted the erythrocyte membrane at pH 6.5 characteristic of early endosomes, while they showed negligible cytotoxic effects at physiological pH. The efficient intracellular delivery of the widely used anticancer drug doxorubicin (DOX) by the multifunctional liposomes was demonstrated, leading to significantly increased potency against HeLa cancer cells over the DOX-loaded bare liposomes. This novel virus-mimicking liposomal system, with the incorporated synergy of efficient liposomal drug release and efficient endosomal escape, is favorable for efficient intracellular drug delivery. PMID- 27512895 TI - Pore Size Effect on Methane Adsorption in Mesoporous Silica Materials Studied by Small-Angle Neutron Scattering. AB - Methane adsorption in model mesoporous silica materials with the size range characteristic of shale is studied by small-angle neutron scattering (SANS). Size effect on the temperature-dependent gas adsorption at methane pressure about 100 kPa is investigated by SANS using MCM-41 and SBA-15 as adsorbents. Above the gas liquid condensation temperature, the thickness of the adsorption layer is found to be roughly constant as a function of the temperature. Moreover, the gas adsorption properties, such as the adsorbed layer thickness and the specific amount of adsorbed gas, have little dependence on the pore size being studied, i.e., pore radius of 16.5 and 34.1 A, but are mainly affected by the roughness of the pore surfaces. Hence, the surface properties of the pore wall are more dominant than the pore size in determining the methane gas adsorption of pores at the nanometer size range. Not surprisingly, the gas-liquid condensation temperature is observed to be sensitive to pore size and shifts to higher temperature when the pore size is smaller. Below the gas-liquid condensation temperature, even though the majority of gas adsorption experiments/simulations have assumed the density of confined liquid to be the same as the bulk density, the measured methane mass density in our samples is found to be appreciably smaller than the bulk methane density regardless of the pore sizes studied here. The mass density of liquid/solid methane in pores with different sizes shows different temperature dependence below the condensation temperature. With decreasing temperature, the methane density in larger pores (SBA-15) abruptly increases at approximately 65 K and then plateaus. In contrast, the density in smaller pores (MCM-41) monotonically increases with decreasing temperature before reaching a plateau at approximately 30 K. PMID- 27512896 TI - Polyamines: Small Molecules with a Big Role in Promoting Virus Infection. AB - Polyamines play important roles in a range of cellular processes. In this issue of Cell Host & Microbe, Mounce et al. (2016) link polyamine metabolism to the interferon response and demonstrate proviral effects for polyamines. The study points to the pathway as a potential novel pan-viral therapeutic target. PMID- 27512897 TI - When Mr. Fap Meets the Gals. AB - Fusobacteria are found to be overrepresented in the colorectal tumor microenvironment. In this issue of Cell Host & Microbe, Abed et al. (2016) describe a novel homing mechanism by which fusobacteria localize to tumors by recognizing a host polysaccharide (Gal-GalNAc) on cancer cells using a fusobacterial lectin, Fap2. PMID- 27512898 TI - Unhealthy Sugars in Bacterial Cytotoxicity. AB - Bacterial type three secretion systems (T3SSs) are central to virulence, but the processes stimulating their activation are unclear. In this issue of Cell Host & Microbe, Blondel et al. (2016) perform a genome-wide screen using CRISPR/Cas technology to identify a role for cell surface sulfation and fucosylation in cytotoxicity mediated by Vibrio parahaemolyticus T3SSs. PMID- 27512899 TI - Gut Check: IFNgamma Delays Mucosal Recovery during Antibiotic Therapy. AB - Antibiotic therapy has been largely ineffective in improving clinical outcomes following Salmonellosis, yet the reasons why remain obscure. In this issue of Cell Host & Microbe, Dolowschiak et al. (2016) report that IFNgamma produced by NK and T cells following antibiotic treatment of acute Salmonella infection limits mucosal remission. PMID- 27512900 TI - NAGging Hexokinase PEPs up NLRP3. AB - Recognition of peptidoglycan is integral to detection of gram-positive bacterial pathogens. In a recent issue of Cell, Wolf et al. (2016) report that detection of the N-acetylglucosamine component of peptidoglycan by the glycolytic enzyme hexokinase activates the NLRP3 inflammasome, revealing an intriguing interplay between pathogen detection and metabolism. PMID- 27512901 TI - Bacterial Stress Responses during Host Infection. AB - Pathogenic bacteria must withstand diverse host environments during infection. Environmental signals, such as pH, temperature, nutrient limitation, etc., not only trigger adaptive responses within bacteria to these specific stress conditions but also direct the expression of virulence genes at an appropriate time and place. An appreciation of stress responses and their regulation is therefore essential for an understanding of bacterial pathogenesis. This review considers specific stresses in the host environment and their relevance to pathogenesis, with a particular focus on the enteric pathogen Salmonella. PMID- 27512902 TI - Discrimination and Integration of Stress Signals by Pathogenic Bacteria. AB - For pathogenic bacteria, the ability to sense and respond to environmental stresses encountered within the host is critically important, allowing them to adapt to changing conditions and express virulence genes appropriately. This review considers the diverse molecular mechanisms by which stress conditions are sensed by bacteria, how related signals are discriminated, and how stress responses are integrated, highlighting recent studies in selected bacterial pathogens of clinical relevance. PMID- 27512903 TI - An Intrinsically Disordered Region of the DNA Repair Protein Nbs1 Is a Species Specific Barrier to Herpes Simplex Virus 1 in Primates. AB - Humans occasionally transmit herpes simplex virus 1 (HSV-1) to captive primates, who reciprocally harbor alphaherpesviruses poised for zoonotic transmission to humans. To understand the basis for the species-specific restriction of HSV-1 in primates, we simulated what might happen during the cross-species transmission of HSV-1 and found that the DNA repair protein Nbs1 from only some primate species is able to promote HSV-1 infection. The Nbs1 homologs that promote HSV-1 infection also interact with the HSV-1 ICP0 protein. ICP0 interaction mapped to a region of structural disorder in the Nbs1 protein. Chimeras reversing patterns of disorder in Nbs1 reversed titers of HSV-1 produced in the cell. By extending this analysis to 1,237 virus-interacting mammalian proteins, we show that proteins that interact with viruses are highly enriched in disorder, suggesting that viruses commonly interact with host proteins through intrinsically disordered domains. PMID- 27512906 TI - Plant TRAF Proteins Regulate NLR Immune Receptor Turnover. PMID- 27512904 TI - Fap2 Mediates Fusobacterium nucleatum Colorectal Adenocarcinoma Enrichment by Binding to Tumor-Expressed Gal-GalNAc. AB - Fusobacterium nucleatum is associated with colorectal cancer and promotes colonic tumor formation in preclinical models. However, fusobacteria are core members of the human oral microbiome and less prevalent in the healthy gut, raising questions about how fusobacteria localize to CRC. We identify a host polysaccharide and fusobacterial lectin that explicates fusobacteria abundance in CRC. Gal-GalNAc, which is overexpressed in CRC, is recognized by fusobacterial Fap2, which functions as a Gal-GalNAc lectin. F. nucleatum binding to clinical adenocarcinomas correlates with Gal-GalNAc expression and is reduced upon O glycanase treatment. Clinical fusobacteria strains naturally lacking Fap2 or inactivated Fap2 mutants show reduced binding to Gal-GalNAc-expressing CRC cells and established CRCs in mice. Additionally, intravenously injected F. nucleatum localizes to mouse tumor tissues in a Fap2-dependent manner, suggesting that fusobacteria use a hematogenous route to reach colon adenocarcinomas. Thus, targeting F. nucleatum Fap2 or host epithelial Gal-GalNAc may reduce fusobacteria potentiation of CRC. PMID- 27512907 TI - Magnetic properties of transition metal Mn, Fe and Co dimers on monolayer phosphorene. AB - We studied the geometries, electronic structure and magnetic properties of substitutional doping and adsorption of transition metal (Mn, Fe and Co) dimers on phosphorene monolayer in the framework of the generalized gradient approximation (GGA) and GGA + U. Electronic band structures and magnetic properties were dependent on the doping type and dopant materials. For Mn and Fe substitutional and adsorption dimers, we obtained semiconducting band structures with spin polarization. However, we found a half-metallic feature in Co substitutional dimer while the Co adsorption dimer showed a semiconducting behavior without any spin polarization. With GGA + U, all the systems showed spin polarized semiconducting band structures except Co adsorption dimer which remained unaffected. The hybridization between transition metal (TM) and phosphorene sheet contributed to suppressing the magnetic moment of TM dimers. For instance, the total magnetic moments of -2.0, 4.24 and 1.28 MU B/cell for Mn, Fe and Co substitutional dimers were obtained while the Mn and Fe adsorption dimers showed magnetic moments of -1.69 and 0.46 MU B/cell. These magnetic moments were enhanced with GGA + U. The same magnetic ground states were obtained both from GGA and GGA + U approaches except for the Mn dimers. We observed that the Mn and Fe substitutional dimers showed an out-of-plane magnetization while an in-plane magnetization was observed in Co substitutional dimer. The Mn adsorption dimer still displayed a perpendicular magnetization whereas the Fe adsorption dimer had an in-plane magnetization. We found that the both GGA and GGA + U showed the same magnetization direction in all the systems. PMID- 27512905 TI - Mycobacterial Acid Tolerance Enables Phagolysosomal Survival and Establishment of Tuberculous Infection In Vivo. AB - The blockade of phagolysosomal fusion is considered a critical mycobacterial strategy to survive in macrophages. However, viable mycobacteria have been observed in phagolysosomes during infection of cultured macrophages, and mycobacteria have the virulence determinant MarP, which confers acid resistance in vitro. Here we show in mice and zebrafish that innate macrophages overcome mycobacterial lysosomal avoidance strategies to rapidly deliver a substantial proportion of infecting bacteria to phagolysosomes. Exploiting the optical transparency of the zebrafish, we tracked the fates of individual mycobacteria delivered to phagosomes versus phagolysosomes and discovered that bacteria survive and grow in phagolysosomes, though growth is slower. MarP is required specifically for phagolysosomal survival, making it an important determinant for the establishment of mycobacterial infection in their hosts. Our work suggests that if pathogenic mycobacteria fail to prevent lysosomal trafficking, they tolerate the resulting acidic environment of the phagolysosome to establish infection. PMID- 27512909 TI - Iatrogenic common bile duct injuries: Increasing complexity in the laparoscopic era: A prospective cohort study. AB - PURPOSE: Iatrogenic bile duct injury (BDI) is the most significant associated complication to laparoscopic cholecystectomy (LC). Little is known about the evolution of the pattern of BDI in the era of laparoscopy. The aim of the study is to assess the pattern of post-LC BDIs managed in a tertiary referral centre. METHODS: Post-LC BDI referred over two decades were studied. Demographic data, type of BDI (classified using the Strasberg System), clinical symptoms, diagnostic investigations, timing of referral, post-referral management and morbidity were analysed. The pattern of injury, associated vascular injuries rate and their management were compared over two time periods (1992-2004,2005-2014). RESULTS: 78 BDIs were referred. During the second time period Strasberg A injuries decreased from 14% to 0 and Strasberg E1increased from 4% to 23%, the rate of associated vascular injury was six time higher (3.6% versus 22.7%), more patients had an attempted repair at the index hospital (16% versus 35%) sand fewer patients could be managed without surgical intervention at the referral hospital (28% versus 4%). CONCLUSION: Complexity of referred BDIs and rate of associated vascular injuries have increased over time. These findings led to more patients managed requiring surgical intervention at the referral hospital. PMID- 27512910 TI - Viewers prefer predictive cues. AB - Devaluation-by-inhibition hypothesis demonstrated that previously ignored items are judged more negatively than previously attended and novel items. Based on this view, the present study investigated the evaluation of preceding stimuli that presumably elicit attentional processes to task-relevant stimuli. Accordingly, we employed a Posner-type cueing task followed by evaluation of the preceding cues indicating left and right directions. The important manipulation is predictability of two different preceding cues which predict the target location with high or with low probability. In Experiment 1 with two different arrows, a low predictive arrow was judged more negatively than a high predictive cue. Experiment 2 using gaze cues of two persons instead of two different arrows supported the findings of Experiment 1. These findings are consistent with devaluation-by-inhibition, suggesting that cue items triggering attention to the target are devaluated when they have less predictability. PMID- 27512911 TI - RE16AuxAl13-x with RE = La-Nd, Sm (x<= 3.37): synthesis, crystal structure and physical properties of an intermetallic solid solution with barrelane analogue units. AB - During phase analytical investigations in the rare-earth element rich side of the ternary system cerium-gold-aluminum, the new ternary rare-earth (RE) gold aluminides with a composition of RE16AuxAl13-x (RE = La-Nd, Sm, x<= 3.37) have been synthesized first by reactive eutectics of RE/Au with Al. Single crystals of high quality can be obtained by this method. The title compounds can be selectively prepared by annealing arc-melted beads of appropriate composition below the peritectic point of the respective system. Like prototypic La16Al13, the representatives of the solid solution RE16AuxAl13-x (RE = La-Nd, Sm; x<= 3.37) crystallize in the hexagonal crystal system (space group P6[combining macron]2m, a = 916.6-890.4 pm, c = 1122.4-1090.1 pm) with one formula unit per unit cell. Single crystal investigations revealed Au/Al mixing on three of the four crystallographic aluminum sites. These sites form an empty (Au/Al)11 barrelane analogous unit, coordinated solely by the respective rare-earth atoms. In addition one independent Al site with a fivefold capped trigonal prismatic arrangement, a so called Edshammar polyhedron, exists. Magnetic measurements of Ce16Au3Al10 revealed two antiferromagnetic transitions with Neel-temperatures of 7.7(1) and 2.7(1) K and a magnetic moment of MUeff = 2.48(1) MUB, Pr16Au3Al10 shows ferromagentic ordering with a Curie-temperature of 19.8(1) K and a magnetic moment of MUeff = 3.58(1) MUB. PMID- 27512913 TI - Effect of antidepressants on spatial memory deficit induced by dizocilpine. AB - Cognitive deficits are a core symptom of schizophrenia. It is controversial whether antidepressants could improve cognitive symptoms in schizophrenia patients. The present study was designed to identify the therapeutic effect of antidepressants on cognitive deficits in schizophrenia. In the present study, adolescent rats were repeatedly exposed to dizocilpine, which can induce cognitive deficits associated with schizophrenia. Then these rats were treated by six antidepressants (fluvoxamine, sertraline, paroxetine, escitalopram, venlafaxine, mirtazapine) or vehicle. The rats in the control group were exposed to vehicle during the study. Lastly, all rats' spatial memory (a major part of cognition) was assessed using the Morris water maze (MWM) test, and the density of hippocampal parvalbumin (PV) interneurons was evaluated to explore possible mechanisms underlying spatial memory change in schizophrenia. The results of the present study supported the hypothesis of a therapeutic effect of fluvoxamine and escitalopram on spatial memory deficit induced by dizocilpine. Additionally, the data of the present study suggested that fluvoxamine and escitalopram remitted hippocampal PV interneuron reduction induced by dizocilpine. The neuroprotective effect of fluvoxamine and escitalopram may partly explain the therapeutic effect of antidepressants on spatial memory deficit in schizophrenia patients. PMID- 27512914 TI - Palate size and shape in schizophrenia. AB - The palate is considered typical of the structures in which schizophrenia-related minor physical anomalies may occur. In this study, we aimed to compare the dimensions and form of palate in patients with schizophrenia with nonpsychiatric controls in a blinded manner. Dental stone casts of 127 patients with schizophrenia and 127 controls were prepared from impressions of the maxillary dental arch. Palate dimensions were measured on the stone casts using a digital caliper and palatometer. Palate length did not differ significantly between the groups, but there was a significant difference in palate width and depth, which were significantly higher in the schizophrenia group. As a result of using multivariate analysis for assessing independent risk factors affecting patients with schizophrenia, furrowed palate shape, palate width, and ellipsoid maxillary dental arch shape were found to be significant. This study also revealed that patients with schizophrenia demonstrate certain gender-related predilections in the differences of palate parameters compared to same-sex controls. As the palate develops in conjunction with both the face and brain, our study findings can significantly contribute to the assumption that there might be structural abnormalities of the palate that could represent specific markers of embryological dysmorphogenesis underlying schizophrenia. PMID- 27512915 TI - Effects of state and trait anxiety on sleep structure: A polysomnographic study in 1083 subjects. AB - Anxiety affects millions of people and has been shown to co-occur in combination with sleep disturbances, generating heavy medical costs and a huge socio-medico economic burden. Sleep-studies in anxiety disorders are inconsistent and the effects of state and trait anxiety are unexplored. We selected 1083 patients from the database of a hospital sleep laboratory. The patients had polysomnography for different sleep disorders; their sleep initiation (sleep onset latency), sleep maintenance (total sleep time), non-rapid eye movement sleep-, and rapid eye movement sleep parameters; as well as their State-Trait Anxiety Inventory and Beck depression scale were measured. In order to be included in our study, individuals needed to score in the low or high range on the State and/or Trait Subscales of the State-Trait Anxiety Inventory. We found that both state and trait anxiety affected non-rapid eye movement sleep parameters. Sleep onset latency changes predominantly associated to state anxiety while rapid eye movement parameters related to trait anxiety. PMID- 27512916 TI - Evaluating the association between the SHANK3 gene and bipolar disorder. AB - BACKGROUND: Previous studies have shown that the genes involved in synaptic density and plasticity were downregulated in bipolar disorder (BD) postmortem brains. The SHANK3 (SH3 and multiple ankyrin repeat domain 3) protein is a scaffold protein enriched in the postsynaptic density of excitatory synapses, and recent findings were suggestive of a possible role of SHANK3 in the development of BD. In this study, we aimed to evaluate the genetic association between the gene encoding SHANK3 (SHANK3) and BD in Han Chinese. METHODS: Ten variants in SHANK3 were genotyped among 1482 individuals with or without BD. We measured the mRNA expression level of SHANK3 in patients with BD and controls. We then performed an eQTL analysis. RESULTS: In our sample set, there were no significant differences in allele, genotype and haplotype frequencies between the BD and control groups. Our results showed no significant difference in the level of peripheral SHANK3 expression between the BD patients and healthy controls. Further eQTL analysis showed that rs9616915 has functional effect on SHANK3 expression in the hippocampus. CONCLUSION: This study does not provide evidence for a major role of SHANK3 in the pathogenesis of BD. PMID- 27512917 TI - The optimisation of experience sampling protocols in people with schizophrenia. AB - Experience sampling methodology (ESM) involves completing questionnaires during daily life and has been used extensively in people with schizophrenia to assess symptoms and behaviours. Despite considerable advantages over interview measures, there is limited information about its external validity. Our aim is to investigate whether ESM protocol implementation is affected differentially in people with schizophrenia and healthy individuals by factors such as mood, medication and symptoms which would have implications for validity. Fifty-three people with schizophrenia and fifty-eight controls from the general population completed seven ESM questionnaires per day for six consecutive days. Compliance and acceptability, including overall experience, training and disruption of normal routines, were recorded. Overall questionnaire completion rate in people with schizophrenia was comparable to controls (i.e. over 70%). People with schizophrenia completed significantly fewer questionnaires in the morning but did not show fatigue effects over the experience sampling period. Excluding questionnaires in the morning did not significantly alter the findings. In the schizophrenia group medication level and symptoms did not influence adherence. However, higher disruption was associated with reduced questionnaire completion in this group. These findings suggest that minimising disruption may enhance validity and completion rates. ESM is a valid methodology to use with people with schizophrenia. PMID- 27512918 TI - Examining the role of self-discrepancy and self-directed style in bulimia nervosa. AB - Two of the primary components within Integrative Cognitive Affective Therapy (ICAT) are self-discrepancy and self-directed style. Self-discrepancy includes both actual:ideal (discrepancy between oneself and who one wishes they were) and actual:ought (discrepancy between oneself and who one believes they ought to be). Self-directed style in ICAT refers to a variety of behaviors emitted by a person toward the self including self-blaming and self-affirming. This study explored main effects and interactions between self-discrepancy and self-directed style in relation to global eating disorder (ED) psychopathology, depressive symptoms, and anxiety. Eighty treatment-seeking adults from the Midwest with BN or subthreshold BN completed interviews and self-report measures. Self-affirm and self-blame were associated with ED psychopathology, depressive symptoms, and anxiety. Actual:ideal discrepancy was related to anxiety and actual:ought discrepancy was related to anxiety and depressive symptoms. Interactions were found between self affirm and actual:ought discrepancy as well as self-blame and actual:ought discrepancy for depressive symptoms. High actual:ought was related to increased depressive symptoms regardless of levels of self-affirm or self-blame. Effect sizes for models were medium-to-large with anxiety models demonstrating the largest effects. This study provides further evidence supporting the ICAT model and treatment, which targets self-discrepancies, self-directed styles, and related emotional states. PMID- 27512919 TI - Altered plasma levels of chemokines in autism and their association with social behaviors. AB - Autism Spectrum Disorder (ASD) is a group of neurodevelopment disorders with an unclear etiology. Chemokines have been implicated in the etiology and pathogenesis of ASD. The current study investigated the plasma levels of seven chemokines (RANTES, Eotaxin, MIP-1 alpha, MIP-1 beta, MCP-1, IP-10, and MIG) in 42 young autistic patients and 35 age-matched typically developing (TD) children. The study also tested the association between these chemokine levels and social behaviors, as measured by the Social Responsiveness Scale (SRS). Compared to the TD children, RANTES, MIP-1alpha, and MIP-1beta were higher, while IP-10 and MIG were lower in the autistic patients, after correcting for multiple comparisons. Among these seven chemokines, MIP-1alpha, MIP-1beta and IP-10 levels were found to be associated with social behaviors in all the participants. Moreover, MIP 1alpha and IP-10 were found to be independent predictors of social behaviors. The results of our study support the hypothesis that altered chemokine levels are involved in the pathophysiology of ASD and they indicate that chemokines plasma levels could be potential biomarkers for ASD. PMID- 27512920 TI - Apathy, alexithymia, and depressive symptoms: Points of convergence and divergence. AB - This study determined convergence and divergence in the constructs of alexithymia, apathy, and depressive symptoms. Understanding of similarities and differences between these constructs will improve diagnostic accuracy for clinical and research purposes. Community-dwelling participants (N=622, M age=35.6 years, SD=13.1) completed online measures of alexithymia, depression, and apathy; 12.2% were alexithymic, 37.8% reported significant depressive symptoms, and 24.9% reported significant apathy. Exploratory Factor Analyses (EFAs) determined the best factor structure for the apathy, alexithymia, and depressive symptoms was comprised of three factors and accounted for 45.1% of item variance. The Depression, Apathy, and Alexithymia factors were defined most strongly by item content that is at the core of each construct. Depression was defined most highly by items assessing sadness, low self-esteem, and loneliness. The strongest item loadings for Alexithymia were difficulty identifying and describing feelings. Apathy was characterized by poor motivation, low interest, and lack of initiative. However, each of these core and defining features had significant cross-loadings on one of the other two factors. Negative affect shared variance with Apathy, low motivation shared variance with Depression, and difficulty describing and identify feelings shared variance with Depression and Apathy. Clinical and research implications are discussed. PMID- 27512921 TI - Serum levels of G protein-coupled estrogen receptor 1 (GPER1) in drug-naive patients with generalized anxiety disorder. AB - Sex hormones, particularly estrogen, are suggested to play a role in the physiopathology of generalized anxiety disorder (GAD). Estrogen functions through the estrogen receptors alpha and beta and the recently discovered G protein coupled estrogen receptor 1 (GPER1). This study aimed, for the first time, to evaluate serum GPER1 levels in drug-naive patients with GAD. This study included 40 newly diagnosed drug-naive patients with GAD aged between 18 and 50 years and 40 age- and gender-matched healthy controls. Medical histories were obtained, and physical examinations and laboratory tests were conducted; the Hamilton Anxiety Rating Scale (HAM-A) was also used for all participants. Serum GPER1 levels were measured. The serum GPER1 level was significantly higher in the patients with GAD than in the controls. A positive significant correlation was observed between the GPER1 level and the HAM-A score. The receiver operating characteristic analysis revealed a sensitivity, specificity, positive predictive value, and negative predictive value of 85.0%, 82.5%, 82.9%, and 84.6%, respectively, for the presence of anxiety when the serum GPER1 value was >=0.14 (the area under the curve was 0.904.). In conclusion, this study demonstrated that GPER1 levels were associated with the anxiety levels of patients, and that the serum GPER1 level was a valuable predictor of the presence of anxiety independent of gender. PMID- 27512922 TI - A preliminary analysis of microRNA-21 expression alteration after antipsychotic treatment in patients with schizophrenia. AB - Schizophrenia is a severe and debilitating psychiatric disorder of unknown etiology, and its diagnosis is essentially based on clinical symptoms. Despite growing evidence on the relation of altered expression of miRNAs and schizophrenia, most patients with schizophrenia usually had an extensive antipsychotic treatment history before miRNA expression profile analysis, and the pharmacological effects on miRNA expression are largely unknown. To overcome these impediments, miRNA microarray analysis was performed in peripheral blood mononuclear cells (PBMCs) obtained from patients with schizophrenia who were not on antipsychotic medication and healthy controls. Then, using quantitative real time reverse transcription polymerase chain reaction (qRT-PCR), we verified the top 10 miRNAs with the highest fold-change values from microarray analysis in 82 patients with schizophrenia and 43 healthy controls, and nine miRNAs demonstrated significant differences in expression levels. Finally, we compared these nine miRNA profiles before and after antipsychotic treatment. Our results revealed that serum miR-21 expression decreased strikingly in patients after antipsychotic treatment. The change of miR-21 expression was negatively correlated with improvement of positive, general psychopathology, and aggressiveness symptoms. This study preliminarily analyzed the possible changes in circulating miRNAs expression in response to antipsychotic medication for schizophrenia, and the molecular mechanisms of this needs to be further explored. PMID- 27512923 TI - Three peanut-allergic/sensitized phenotypes with gender difference. AB - BACKGROUND: Peanut-allergic reactions are heterogeneous ranging from mild symptoms to anaphylaxis. OBJECTIVE: Identify peanut-allergic/sensitized phenotypes to personalize patient management. METHODS: A combined factor and cluster analysis was used to study the phenotypes of 696 patients diagnosed with peanut sensitization and enrolled in the MIRABEL survey. The method was first applied to the 247 patients with an oral food challenge (OFC). It was then applied to the 449 patients without OFC to confirm the findings in an independent population. RESULTS: Three independent clusters emerged from the OFC subgroup. Cluster 1, 'Severe peanut allergy with little allergic multi-morbidity' (123 subjects), had the highest proportion of patients with positive OFC (92%), a medium level of peanut protein inducing a positive OFC (235 mg), lower percentage of allergic multi-morbidity (2% asthma plus atopic dermatitis (A + AD), no cases of A + AD + multiple food allergies (MFA)). Cluster 2, 'Severe peanut allergy with frequent allergic multi-morbidity' (62 subjects), had a high proportion of patients with positive OFC (85%) with the lowest level of peanut protein inducing a positive OFC (112 mg), 89% allergic subjects, 100% with allergic multi morbidity (A + AD) and 84% with A + AD + MFA. Cluster 3, 'Mild peanut allergic/sensitized phenotype' (62 subjects), had the lowest mean age, the lowest proportion of patients with positive OFC (53%) with a high level of peanut protein inducing a positive OFC (770 mg), a low percentage of allergic multi morbidity (48% A + AD + MFA). The two severe peanut-allergic phenotypes were more frequent in girls. The same clusters were found in the subgroup of patients without OFC. CONCLUSION & CLINICAL RELEVANCE: Besides the classic markers associated with lower threshold doses of OFC (such as SPT and rAra h 2), allergic multi-morbidity and female gender should also be taken into account to better adapt the progressive dosage of provocation tests. PMID- 27512925 TI - Gamma-glutamyltransferase-friend or foe within? AB - Gamma-glutamyltransferase (GGT) is a liver enzyme, which is located on the plasma membranes of most cells and organ tissues, but more commonly in hepatocytes, and is routinely used in clinical practice to help indicate liver injury and as a marker of excessive alcohol consumption. Among the liver enzymes, important advances have especially been made in understanding the physiological functions of GGT. The primary role of GGT is the extracellular catabolism of glutathione, the major thiol antioxidant in mammalian cells, which plays a relevant role in protecting cells against oxidants produced during normal metabolism; GGT, therefore, plays an important role in cellular defence. Beyond its physiological functions, circulating serum GGT has been linked to a remarkable array of chronic conditions and diseases, which include nonalcoholic fatty liver disease, vascular and nonvascular diseases and mortality outcomes. This review summarizes the available epidemiological and genetic evidence for the associations between GGT and these adverse outcomes, the postulated biologic mechanisms underlying these associations, outlines areas of outstanding uncertainty and the implications for clinical practice. PMID- 27512924 TI - Hemostasis biomarkers and risk of sepsis: the REGARDS cohort. AB - : Essentials Few studies have investigated the risk of sepsis by baseline hemostasis biomarkers measures. Baseline hemostasis biomarkers and risk of sepsis was examined using case-control study design. Increased fibrinogen, factor IX, and factor XI levels may be associated with risk of sepsis. Hemostasis biomarkers may provide a target for sepsis mitigation or prevention. SUMMARY: Background Sepsis is a major public health concern, responsible for more than 750 000 hospitalizations and 200 000 annual deaths in the USA. Few studies have investigated the association between baseline measurements of hemostasis biomarkers and the future risk of sepsis. Objective To determine whether hemostasis biomarkers levels measured at baseline in a cohort of community dwelling participants are associated with the risk of future sepsis events. Methods We performed a nested case-control study within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. We identified sepsis hospitalizations occurring over a 10-year period. There were 50 incident sepsis cases with baseline measurements of hemostasis (fibrinogen, factor VIII, FIX, FXI, protein C, and D-dimer). Using incidence density sampling, we matched the 50 sepsis cases with 200 controls by age, sex, and race. We used conditional logistic regression to evaluate the association between baseline hemostasis biomarkers and future sepsis events. Results Comparison of 50 sepsis cases with 200 non-sepsis controls showed that sepsis cases had lower education and income, were more likely to live in the stroke belt, had chronic lung disease, and had higher albumin level/creatinine level ratios (ACRs). Individuals with higher baseline fibrinogen levels (adjusted odds ratio [OR] per standard deviation: 1.40, 95% confidence interval [CI] 1.01-1.94), FIX levels ([OR] 1.46, 95% [CI] 1.03-2.07) and FXI levels ([OR]1.52, 95% [CI] 1.04-2.23) were more likely to experience a sepsis event. Conclusion Baseline fibrinogen, FIX and FXI levels are associated with future episodes of sepsis. Hemostasis biomarkers may provide targets for sepsis mitigation or prevention. PMID- 27512926 TI - Clinical risk factors for delayed bleeding after endoscopic submucosal dissection for colorectal tumors in Japanese patients. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is a curative, standard therapy for colorectal neoplasms. Some studies have investigated the risk factors for perforation during colorectal ESD. However, few studies have assessed the risk factors for delayed bleeding after colorectal ESD. We studied patients undergoing ESD for colorectal epithelial neoplasms to identify the risk factors for post-ESD bleeding. PATIENTS AND METHODS: We studied 124 consecutive patients undergoing ESD for colorectal epithelial neoplasms. To identify risk factors for delayed bleeding post-ESD, recurrent bleeding post-ESD was compared with patient related and tumor-related factors. RESULTS: Delayed bleeding after ESD occurred in 10 (8.1%) lesions of 124 colorectal tumors, and the median time from the end of ESD to the onset of bleeding was 18.5 h. Delayed bleeding was significantly higher in tumors located in rectums than in colons (P=0.021), and the number of occurrences of arterial bleeding during ESD was significantly higher in the delayed bleeding group than in the nondelayed bleeding group (P=0.002). The procedure time was significantly longer in the delayed bleeding group than in the nondelayed bleeding group (P=0.012). On multivariate logistic regression analysis, tumor location (odds ratio, 10.13; 95% confidence interval, 1.18-87.03; P=0.035) and three or more occurrences of arterial bleeding during ESD (odds ratio, 6.86; 95% confidence interval, 1.13-41.5; P=0.036) were significant independent risk factors for delayed bleeding. CONCLUSION: The presence of lesions in the rectum and three or more arterial bleeding occurrences during ESD were risk factors for post-ESD bleeding. Patients with these risk factors should be followed up carefully after ESD for colorectal epithelial neoplasms. PMID- 27512927 TI - Randomized-controlled trial of rifaximin versus norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis. AB - BACKGROUND AND AIMS: Spontaneous bacterial peritonitis (SBP) is a serious complication of liver cirrhosis with a high recurrence rate and a marked increase in mortality. Norfloxacin is used widely for the secondary prophylaxis of SBP; however, its extensive long-term use has led to an increase in the incidence of quinolone-resistant and Gram-positive SBP. Rifaximin is a nonabsorbable broad spectrum antibiotic and does not appear to promote emergence of resistance. The aim of this study was to compare the safety and efficacy of rifaximin versus norfloxacin for the secondary prevention of SBP in patients with liver cirrhosis and ascites. MATERIALS AND METHODS: Two hundred and sixty two cirrhotic patients with ascites and a previous episode of SBP were assigned randomly to receive either 1200 mg rifaximin or 400 mg of norfloxacin daily for 6 months. All patients were monitored clinically each month and with ascitic fluid examination at the end of 2 and 6 months if not clinically suspected of recurrence earlier. RESULTS: Recurrence of SBP was significantly lower in the rifaximin group (3.88 vs. 14.13%) compared with the norfloxacin group (P=0.04). The mortality rate was significantly decreased in the rifaximin group (13.74 vs. 24.43%) compared with the norfloxacin group (P=0.044). The causes of death between the two groups did not show a significant difference (P=0.377), but encephalopathy-related deaths were three folds higher in the norfloxacin group. There was a significant decrease in the side effects in the rifaximin group versus the norfloxacin group (P=0.033). CONCLUSION: Rifaximin was more effective than norfloxacin in the secondary prevention of SBP. Encephalopathy-related mortality and side effects were fewer in the rifaximin group. PMID- 27512928 TI - Cascade Biocatalysis for Sustainable Asymmetric Synthesis: From Biobased l Phenylalanine to High-Value Chiral Chemicals. AB - Sustainable synthesis of useful and valuable chiral fine chemicals from renewable feedstocks is highly desirable but remains challenging. Reported herein is a designed and engineered set of unique non-natural biocatalytic cascades to achieve the asymmetric synthesis of chiral epoxide, diols, hydroxy acid, and amino acid in high yield and with excellent ee values from the easily available biobased l-phenylalanine. Each of the cascades was efficiently performed in one pot by using the cells of a single recombinant strain over-expressing 4-10 different enzymes. The cascade biocatalysis approach is promising for upgrading biobased bulk chemicals to high-value chiral chemicals. In addition, combining the non-natural enzyme cascades with the natural metabolic pathway of the host strain enabled the fermentative production of the chiral fine chemicals from glucose. PMID- 27512929 TI - [Endobronchial Ultrasound Guided Needle Aspiration of a Lung Cyst and Eosinophilic Pneumonia]. AB - We report the case of a young male patient with a solitary pulmonary echinococcus cyst. The diagnosis of Cystic Echinococcosis is based on clinical findings, imaging and serology. In the setting of lung cysts the diagnosis can be difficult, particularly as the sensitivity of the serologic tests is lower compared to liver cysts. Bronchoscopic ultrasound of the cystic lesion and respectively the analysis of the cyst aspirate can lead to the diagnosis. In the present case an eosinophilic pneumonia as the result of the puncture has to be discussed. PMID- 27512930 TI - [Lung Cancer as an Occupational Disease]. AB - Lung cancer is one of the most frequently encountered cancer types. According to the latest WHO data, about 10 % of this disease are due to occupational exposure to cancerogens. Asbestos is still the number one carcinogen. Further frequent causes include quarz and ionizing radiation (uranium mining). Probable causes of the disease can be identified only with the help of detailed occupational history taken by a medical specialist and qualified exposure assessment. Without clarifying the cause of the disease, there is neither a correct insurance procedure nor compensation for the victim, and furthermore, required preventive measures cannot be initiated. PMID- 27512932 TI - [The Swedish Mozart]. PMID- 27512931 TI - [Exon-dependent Subgroup-analysis of the Non-interventional REASON-Study: PFS and OS in EGFR-mutated NSCLC Patients Treated with Gefitinib or Chemotherapy]. AB - PURPOSE: To analyze the influence of the localization of mutations in the epidermal growth factor receptor (EGFR) gene on progression-free (PFS) and overall survival (OS) in patients (pts) with locally advanced or metastatic non small cell lung cancer (NSCLC) treated with gefitinib (gef) or chemotherapy (CT) under real world conditions within the REASON study. METHODS: Subgroups of pts with mutations in exon 19 (n = 141), 18/20 (n = 43), and 21 (n = 104) were analyzed for PFS and OS according to gef or CT treatment and compared using the log-rank test. RESULTS: Pts with mutations in exon 19 and 18/20 treated with gef as first line therapy showed increased PFS and OS compared to CT. This increase was statistically significant in pts with exon 19 mutation (11.3 vs. 6.5 months), but was not found in pts with exon 21 mutation (9.1 vs. 9.3 months). Also, OS was significantly increased in patients with mutation in exon 19 treated with gef ever over all treatment lines compared to CT (21.8 vs. 10.6 months), whereas this was not found in pts with mutation in exon 21 (14.1 vs. 13.9 months). CONCLUSION: Localization and nature of EGFR mutations influences gefitinib treatment outcomes under routine conditions and should therefore be analyzed in detail. PMID- 27512933 TI - [Chronic Obstructive Pulmonary Disease (COPD) - Rational Diagnostics and Therapy]. AB - In general chronic obstructive pulmonary disease (COPD) can be diagnosed in family practice from history and spirometry. Inconclusive spirometry findings have to be assessed further by techniques available in a pulmonologist's office. Further testing is done for differential diagnostic reasons and for prognostic appraisal. Successful smoking cessation importantly alters the natural downhill course of the disease. Patient education and rehabilitative interventions (e. g. participation in lung sport groups) help to improve life quality. Medical therapies with bronchospasmolytics applied by inhalation as monotherapies, free and fixed combinations have symptomatic benefit. Considering the increase of pneumonia risk from inhaled corticosteroids their use should be restricted to patients with a straightforward indication, e. g. coexisting asthma. PMID- 27512934 TI - Chemoprevention of basal cell carcinoma: reply from authors. AB - The review started from the question whether early detection of BCC in the general (asymptomatic) population could lead to any benefit in terms of outcome and cost. In other words, should early detection efforts for skin cancer (secondary prevention) also include BCC? Review of available literature suggests that early detection and adequate treatment of BCC of the face could increase cost-effectiveness. Although these results could also pertain to patients who have had already a history of BCC, their setting is different since they may already be in a follow-up programme (tertiary prevention). This article is protected by copyright. All rights reserved. PMID- 27512935 TI - Spinal Cord Stimulation Modulates Gene Expression in the Spinal Cord of an Animal Model of Peripheral Nerve Injury. AB - BACKGROUND AND OBJECTIVES: Previously, we found that application of pulsed radiofrequency to a peripheral nerve injury induces changes in key genes regulating nociception concurrent with alleviation of paw sensitivity in an animal model. In the current study, we evaluated such genes after applying spinal cord stimulation (SCS) therapy. METHODS: Male Sprague-Dawley rats (n = 6 per group) were randomized into test and control groups. The spared nerve injury model was used to simulate a neuropathic pain state. A 4-contact microelectrode was implanted at the L1 vertebral level and SCS was applied continuously for 72 hours. Mechanical hyperalgesia was tested. Spinal cord tissues were collected and analyzed using real-time polymerase chain reaction to quantify levels of IL1beta, GABAbr1, subP, Na/K ATPase, cFos, 5HT3ra, TNFalpha, Gal, VIP, NpY, IL6, GFAP, ITGAM, and BDNF. RESULTS: Paw withdrawal thresholds significantly decreased in spared nerve injury animals and stimulation attenuated sensitivity within 24 hours (P = 0.049), remaining significant through 72 hours (P = 0.003). Nerve injury caused up-regulation of TNFalpha, GFAP, ITGAM, and cFOS as well as down regulation of Na/K ATPase. Spinal cord stimulation therapy modulated the expression of 5HT3ra, cFOS, and GABAbr1. Strong inverse relationships in gene expression relative to the amount of applied current were observed for GABAbr1 (R = -0.65) and Na/K ATPase (R = -0.58), and a positive linear correlations between 5HT3r (R = 0.80) and VIP (R = 0.50) were observed. CONCLUSIONS: Continuously applied SCS modulates expression of key genes involved in the regulation of neuronal membrane potential. PMID- 27512936 TI - Spinal Cord Stimulation for Treatment of Neuropathic Pain Associated With Erythromelalgia. AB - OBJECTIVE: Erythromelalgia is a rare disorder associated with neuropathic pain that commonly affects the lower extremities. This pain is often refractory to multimodal treatment. Both pharmacologic management and interventional anesthetic blocks have been used with varying and often limited success. To date, little experience has been gained with the use of spinal cord stimulation in treating pain associated with erythromelalgia. CASE REPORT: We present a case of successful treatment of pain secondary to erythromelalgia with a spinal cord stimulator in an 80-year-old woman. This patient had severe pain and debility secondary to erythromelalgia, having undergone trials of multiple medical therapies before presenting to our clinic. Dual-lead percutaneous spinal cord stimulation was successfully implanted without complication, leading to excellent pain control, now 18 months postimplant. CONCLUSIONS: Spinal cord stimulation may be a promising treatment of neuropathic pain associated with erythromelalgia. PMID- 27512938 TI - Editorial. PMID- 27512937 TI - Subdural Hematoma Associated With Labor Epidural Analgesia: A Case Series. AB - OBJECTIVE: This report aimed to describe the characteristics and impact of subdural hematoma (SDH) after labor epidural analgesia. CASE REPORTS: Eleven obstetric patients had SDHs associated with the use of labor epidural analgesia over 7 years at a tertiary care hospital. Ten of 11 patients had signs consistent with postdural puncture headache before the diagnosis of SDH. Five patients (45%) had a recognized unintentional dural puncture, 1 (9%) had a combined spinal epidural with a 24-gauge needle, and 5 (45%) had no recognized dural puncture. For 10 of the 11 cases, SDH was diagnosed at a mean of 4.1 days (range, 1-7 days) after performance of labor epidural analgesia; one case was diagnosed at 25 days. Ten (91%) of 11 cases had a second hospital stay for a mean of 2.8 days (range, 2 4 days) for observation, without further requirement for neurosurgical intervention. One case (9%) had decompressive hemicraniectomy after becoming unresponsive. The observed rate of labor epidural analgesia-associated SDH was 0.026% (11 in 42,969, approximately 1:3900), and the rate of SDH was 1.1% (5 in 437, approximately 1:87) if a recognized dural puncture occurred during epidural catheter placement. CONCLUSIONS: Subdural hematoma after labor epidural anesthesia is rare but potentially more common than historically estimated. Cases of postdural puncture headache after labor epidural anesthesia should be monitored closely for severe neurologic signs and symptoms that could herald SDH. PMID- 27512939 TI - A Wandering Pulmonary Nodule. PMID- 27512940 TI - Method for Direct Synthesis of alpha-Cyanomethyl-beta-dicarbonyl Compounds with Acetonitrile and 1,3-Dicarbonyls. AB - A novel and efficient method for the synthesis of alpha-cyanomethyl-beta dicarbonyls in moderate to excellent yields is developed by using inactive CH3CN and simple 1,3-dicarbonyls. A radical mechanism is proposed under the ESI-MS (electrospray ionization mass spectrometry) analysis results of control experiments. PMID- 27512941 TI - Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage-Gated Sodium Channels. AB - 11-Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C-C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu4 N][Ph3 SnF2 ], which directly constructs the crucial C-C bond at the C11 position in SEA. The NaV Ch-inhibitory activities of SEA and its derivatives were evaluated by means of cell-based assay. SEA showed an IC50 value of (47+/-12) nm, which is approximately twice as potent as decarbamoyl-STX (dcSTX). PMID- 27512942 TI - Enhanced up/down-conversion luminescence and heat: Simultaneously achieving in one single core-shell structure for multimodal imaging guided therapy. AB - Upon near-infrared (NIR) light irradiation, the Nd(3+) doping derived down conversion luminescence (DCL) in NIR region and thermal effect are extremely fascinating in bio-imaging and photothermal therapy (PTT) fields. However, the concentration quenching induced opposite changing trend of the two properties makes it difficult to get desired DCL and thermal effect together in one single particle. In this study, we firstly designed a unique NaGdF4:0.3%Nd@NaGdF4@NaGdF4:10%Yb/1%Er@NaGdF4:10%Yb @NaNdF4:10%Yb multiple core shell structure. Here the inert two layers (NaGdF4 and NaGdF4:10%Yb) can substantially eliminate the quenching effects, thus achieving markedly enhanced NIR-to-NIR DCL, NIR-to-Vis up-conversion luminescence (UCL), and thermal effect under a single 808 nm light excitation simultaneously. The UCL excites the attached photosensitive drug (Au25 nanoclusters) to generate singlet oxygen ((1)O2) for photodynamic therapy (PDT), while DCL with strong NIR emission serves as probe for sensitive deep-tissue imaging. The in vitro and in vivo experimental results demonstrate the excellent cancer inhibition efficacy of this platform due to a synergistic effect arising from the combined PTT and PDT. Furthermore, multimodal imaging including fluorescence imaging (FI), photothermal imaging (PTI), and photoacoustic imaging (PAI) has been obtained, which is used to monitor the drug delivery process, internal structure of tumor and photo therapeutic process, thus achieving the target of imaging-guided cancer therapy. PMID- 27512943 TI - Isoproterenol regulates CD44 expression in gastric cancer cells through STAT3/MicroRNA373 cascade. AB - Gastric cancer is a heterogeneous disease, and stem cells are thought to be the cell of origin contributed to this malignancy. However, studies with breast and intestinal cancer models show non-stem cancer cells can change their surface phenotype and convert into tumor-initiating cells induced by the signals emanating from surrounding tumor microenvironment. Here, we show that CD44 was expressed at different levels in gastric metastases compared with primary tumors, and also negatively correlated with the expression of miR-373. By using a panel of human gastric cancer cell lines and analysis of archived data from The Cancer Genomics Altas (TCGA) database, we verified the inverse correlation between CD44 and miR-373. Furthermore, the stress-associated hormone, isoproterenol, could increase the expression levels of "stem"-related proteins, such as CD44, Nanog, and Rex-1, and induce chemoresistance in gastric cancer cells. Transfection with miR-373, however, reversed not only the effect of isoproterenol on phenotypic conversion but also its effect on drug sensitivity. Isoproterenol triggered downstream target STAT3 mainly through beta2-adrenergic receptors (beta2-ARs). Activated STAT3 functioned as a miR-373 suppressor by binding to its promoter, which forms a positive feedback circuit to maintain CD44 activity and direct the phenotypic conversion from CD44(low) to CD44(hi) expression. Our data suggest an important role of beta2-AR/STAT3/miR-373 signaling on the transformation of gastric cancer cells. This study also suggests a potential therapeutic or preventive treatment for gastric cancer patients who are especially prone to psychosocial stress. PMID- 27512944 TI - Precise control of surface electrostatic forces on polymer brush layers with opposite charges for resistance to protein adsorption. AB - Various molecular interaction forces are generated during protein adsorption process on material surfaces. Thus, it is necessary to control them to suppress protein adsorption and the subsequent cell and tissue responses. A series of binary copolymer brush layers were prepared via surface-initiated atom transfer radical polymerization, by mixing the cationic monomer unit and anionic monomer unit randomly in various ratios. Surface characterization revealed that the constructed copolymer brush layers exhibited an uniform super-hydrophilic nature and different surface potentials. The strength of the electrostatic interaction forces operating on these mixed-charge copolymer brush surfaces was evaluated quantitatively using force-versus-distance (f-d) curve measurements by atomic force microscopy (AFM) and probes modified by negatively charged carboxyl groups or positively charged amino groups. The electrostatic interaction forces were determined based on the charge ratios of the copolymer brush layers. Notably, the surface containing equivalent cationic/anionic monomer units hardly interacted with both the charged groups. Furthermore, the protein adsorption force and the protein adsorption mass on these surfaces were examined by AFM f-d curve measurement and surface plasmon resonance measurement, respectively. To clarify the influence of the electrostatic interaction on the protein adsorption behavior on the surface, three kinds of proteins having negative, positive, and relatively neutral net charges under physiological conditions were used in this study. We quantitatively demonstrated that the amount of adsorbed proteins on the surfaces would have a strong correlation with the strength of surface-protein interaction forces, and that the strength of surface-protein interaction forces would be determined from the combination between the properties of the electrostatic interaction forces on the surfaces and the charge properties of the proteins. Especially, the copolymer brush surface composed of equivalent cationic/anionic monomer units exhibited no significant interaction forces, and dramatically suppressed the adsorption of proteins regardless of their charge properties. We conclude that the established methodology could elucidate relationship between the protein adsorption behavior and molecular interaction, especially the electrostatic interaction forces, and demonstrated that the suppression of the electrostatic interactions with the ionic functional groups would be important for the development of new polymeric biomaterials with a high repellency of protein adsorption. PMID- 27512945 TI - Parental infant jaundice colour card design successfully validated by comparing it with total serum bilirubin. AB - AIM: We designed a jaundice colour card that could be used by the parents of neonates and validated it by comparing it with total serum bilirubin levels. METHODS: There were 106 term Chinese neonates in the study. The majority weighed between 2500 g and 3499 g (63%) and had a gestational age of 37-40 weeks (77%). The jaundice colour card and photometric determination were used to screen for neonatal jaundice and compared with serum bilirubin. RESULTS: The bilirubin levels were measured by mothers using the jaundice colour card, and 67% of the measurements were taken at 11-20 days (range 3-30). The measurements at the infant's forehead, cheek and sternum showed strong correlations with total serum bilirubin. The mean differences between the total serum bilirubin and the jaundice colour card measurements from the forehead, cheek and sternum were 1.9 mg/dL, 0.3 mg/dL and 1.5 mg/dL, respectively. When total serum bilirubin >13 mg/dL was used as the cut-off point, the areas under the receiver operating characteristics curves were 0.934 for the forehead, 0.985 for the cheek and 0.966 for the sternum. CONCLUSION: We established the validity of the jaundice colour card as a parental measurement tool for jaundice in Chinese neonates, and the cheek was the best measurement site. PMID- 27512946 TI - In vivo enzymatic modulation of IgG antibodies prevents immune complex-dependent skin injury. AB - IgG antibodies are potent inducers of proinflammatory responses by cross-linking Fc receptors on innate immune effector cells resulting in tissue injury. The recently discovered enzymes endoglycosidase S (EndoS) and IgG-degrading enzyme (IdeS) of Streptococcus pyogenes are able to modulate the interaction between IgG antibodies and the Fc receptors, by hydrolysis of the glycan associated with the heavy chain of the IgG molecule (EndoS), or cleavage in the hinge region of the heavy IgG chain (IdeS). In this work, we investigated their ability to inhibit damage mediated by skin-bound antibodies in vivo in two different experimental models, the Arthus reaction, and epidermolysis bullosa acquisita, an autoimmune blistering skin disease associated with autoantibodies against type VII collagen. We demonstrate that both enzymes efficiently interfere with IgG-mediated proinflammatory processes, offering a great asset to specifically target pathological IgG antibodies in the skin and holding great promise for future applications in human therapy. PMID- 27512947 TI - Patient-oncologist alliance and psychosocial well-being in Chinese society strongly affect cancer management adherence with cancer of unknown primary. AB - BACKGROUND: Patient-oncologist alliance and psychosocial well-being have strong associations with adherence to cancer management. For patients with cancer of unknown primary (CUP), adherence is crucial to treatment or occult primary screening plans. There has been no study investigating the relationship between alliance, psychosocial factors, and adherence in such patients or in Chinese sociocultural settings. METHODS: The measures of alliance, psychosocial well being, and adherence willingness were administered to patients with CUP, with a mean age of 58.33 +/- 11.24 years. Multiple linear regression models were applied to investigate the independent relationship between alliance and adherence by controlling for socioeconomic and psychosocial confounders. RESULTS: Alliance was found to be independently and positively associated with greater adherence willingness and adherence to treatment and follow-up screening after controlling for significant confounders, including medical conditions, psychosocial well being variables, and socioeconomic factors. CONCLUSION: Stronger patient oncologist alliance may foster enhanced adherence to treatment and follow-up screening in patients with CUP. Patient-oncologist alliance seems affected by socioeconomic factors and psychosocial well-being in the Chinese sociocultural settings. PMID- 27512948 TI - Three-dimensional modelling identifies novel genetic dependencies associated with breast cancer progression in the isogenic MCF10 model. AB - The initiation and progression of breast cancer from the transformation of the normal epithelium to ductal carcinoma in situ (DCIS) and invasive disease is a complex process involving the acquisition of genetic alterations and changes in gene expression, alongside microenvironmental and recognized histological alterations. Here, we sought to comprehensively characterise the genomic and transcriptomic features of the MCF10 isogenic model of breast cancer progression, and to functionally validate potential driver alterations in three-dimensional (3D) spheroids that may provide insights into breast cancer progression, and identify targetable alterations in conditions more similar to those encountered in vivo. We performed whole genome, exome and RNA sequencing of the MCF10 progression series to catalogue the copy number and mutational and transcriptomic landscapes associated with progression. We identified a number of predicted driver mutations (including PIK3CA and TP53) that were acquired during transformation of non-malignant MCF10A cells to their malignant counterparts that are also present in analysed primary breast cancers from The Cancer Genome Atlas (TCGA). Acquisition of genomic alterations identified MYC amplification and previously undescribed RAB3GAP1-HRAS and UBA2-PDCD2L expressed in-frame fusion genes in malignant cells. Comparison of pathway aberrations associated with progression showed that, when cells are grown as 3D spheroids, they show perturbations of cancer-relevant pathways. Functional interrogation of the dependency on predicted driver events identified alterations in HRAS, PIK3CA and TP53 that selectively decreased cell growth and were associated with progression from preinvasive to invasive disease only when cells were grown as spheroids. Our results have identified changes in the genomic repertoire in cell lines representative of the stages of breast cancer progression, and demonstrate that genetic dependencies can be uncovered when cells are grown in conditions more like those in vivo. The MCF10 progression series therefore represents a good model with which to dissect potential biomarkers and to evaluate therapeutic targets involved in the progression of breast cancer. (c) 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 27512949 TI - Long noncoding RNA related to periodontitis interacts with miR-182 to upregulate osteogenic differentiation in periodontal mesenchymal stem cells of periodontitis patients. AB - Periodontitis impairs the osteogenic differentiation of human periodontal mesenchymal stem cells (hPDLSCs), but the underlying molecular mechanisms are still poorly understood. Long noncoding RNAs (lncRNAs) have been demonstrated to have significant roles under both physiologic and pathological conditions. In this study, we performed comprehensive lncRNA profiling by lncRNA microarray analysis and identified a novel lncRNA, osteogenesis impairment-related lncRNA of PDLSCs from periodontitis patients (lncRNA-POIR), the expression of which was significantly decreased in PDLSCs from periodontitis patients (pPDLSCs) and was upregulated by osteogenic induction. To study the functions of lncRNA-POIR, we prepared cells with overexpression and knockdown of lncRNA-POIR and found that lncRNA-POIR positively regulated osteogenic differentiation of hPDLSCs and pPDLSCs both in vitro and in vivo. Using quantitative real-time PCRs (qPCRs) and luciferase reporter assays, we demonstrated that lncRNA-POIR may act as a competing endogenous RNA (ceRNA) for miR-182, leading to derepression of its target gene, FoxO1. In this process, lncRNA-POIR and miR-182 suppress each other and form a network to regulate FoxO1. FoxO1 increased bone formation of pPDLSCs by competing with TCF-4 for beta-catenin and inhibiting the canonical Wnt pathway. Finally, inflammation increases miR-182 expression through the nuclear factor-kappaB pathway, and the miR-182 overexpression in the inflammatory microenvironment resulted in an imbalance in the lncRNA-POIR-miR-182 regulatory network. In conclusion, our results provide novel evidence that this lncRNA-miRNA (microRNA) regulatory network has a significant role in osteogenic differentiation of pPDLSCs and that it has potential as a therapeutic target in mesenchymal stem cells during inflammation. PMID- 27512950 TI - Glucolipotoxicity initiates pancreatic beta-cell death through TNFR5/CD40 mediated STAT1 and NF-kappaB activation. AB - Type 2 diabetes is a chronic metabolic disorder, where failure to maintain normal glucose homoeostasis is associated with, and exacerbated by, obesity and the concomitant-elevated free fatty acid concentrations typically found in these patients. Hyperglycaemia and hyperlipidaemia together contribute to a decline in insulin-producing beta-cell mass through activation of the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and signal transducer and activator of transcription (STAT)-1. There are however a large number of molecules potentially able to modulate NF-kappaB and STAT1 activity, and the mechanism(s) by which glucolipotoxicity initially induces NF kappaB and STAT1 activation is currently poorly defined. Using high-density microarray analysis of the beta-cell transcritptome, we have identified those genes and proteins most sensitive to glucose and fatty acid environment. Our data show that of those potentially able to activate STAT1 or NF-kappaB pathways, tumour necrosis factor receptor (TNFR)-5 is the most highly upregulated by glucolipotoxicity. Importantly, our data also show that the physiological ligand for TNFR5, CD40L, elicits NF-kappaB activity in beta-cells, whereas selective knockdown of TNFR5 ameliorates glucolipotoxic induction of STAT1 expression and NF-kappaB activity. This data indicate for the first time that TNFR5 signalling has a major role in triggering glucolipotoxic islet cell death. PMID- 27512951 TI - Golgi-associated LC3 lipidation requires V-ATPase in noncanonical autophagy. AB - Autophagy is an evolutionarily conserved catabolic process by which cells degrade intracellular proteins and organelles in the lysosomes. Canonical autophagy requires all autophagy proteins (ATGs), whereas noncanonical autophagy is activated by diverse agents in which some of the essential autophagy proteins are dispensable. How noncanonical autophagy is induced and/or inhibited is still largely unclear. In this study, we demonstrated that AMDE-1, a recently identified chemical that can induce canonical autophagy, was able to elicit noncanonical autophagy that is independent of the ULK1 (unc-51-like kinase 1) complex and the Beclin1 complex. AMDE-1-induced noncanonical autophagy could be specifically suppressed by various V-ATPase (vacuolar-type H(+)-ATPase) inhibitors, but not by disturbance of the lysosome function or the intracellular ion redistribution. Similar findings were applicable to a diverse group of stimuli that can induce noncanonical autophagy in a FIP200-independent manner. AMDE-1-induced LC3 lipidation was colocalized with the Golgi complex, and was inhibited by the disturbance of Golgi complex. The integrity of the Golgi complex was also required for multiple other agents to stimulate noncanonical LC3 lipidation. These results suggest that the Golgi complex may serve as a membrane platform for noncanonical autophagy where V-ATPase is a key player. V-ATPase inhibitors could be useful tools for studying noncanonical autophagy. PMID- 27512952 TI - Glial degeneration with oxidative damage drives neuronal demise in MPSII disease. AB - Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression. PMID- 27512953 TI - Protein cross-linking by chlorinated polyamines and transglutamylation stabilizes neutrophil extracellular traps. AB - Neutrophil extracellular trap (NET) ejected from activated dying neutrophils is a highly ordered structure of DNA and selected proteins capable to eliminate pathogenic microorganisms. Biochemical determinants of the non-randomly formed stable NETs have not been revealed so far. Studying the formation of human NETs we have observed that polyamines were incorporated into the NET. Inhibition of myeloperoxidase, which is essential for NET formation and can generate reactive chlorinated polyamines through hypochlorous acid, decreased polyamine incorporation. Addition of exogenous primary amines that similarly to polyamines inhibit reactions catalyzed by the protein cross-linker transglutaminases (TGases) has similar effect. Proteomic analysis of the highly reproducible pattern of NET components revealed cross-linking of NET proteins through chlorinated polyamines and E(gamma-glutamyl)lysine as well as bis-gamma-glutamyl polyamine bonds catalyzed by the TGases detected in neutrophils. Competitive inhibition of protein cross-linking by monoamines disturbed the cross-linking pattern of NET proteins, which resulted in the loss of the ordered structure of the NET and significantly reduced capacity to trap bacteria. Our findings provide explanation of how NETs are formed in a reproducible and ordered manner to efficiently neutralize microorganisms at the first defense line of the innate immune system. PMID- 27512955 TI - Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potent cancer cell-specific apoptosis-inducing cytokine with little toxicity to most normal cells. However, acquired resistance of cancer cells to TRAIL is a roadblock. Agents that can either potentiate the effect of TRAIL or overcome resistance to TRAIL are urgently needed. This article reports that ginsenoside compound K (CK) potentiates TRAIL-induced apoptosis in HCT116 colon cancer cells and sensitizes TRAIL-resistant colon cancer HT-29 cells to TRAIL. On a cellular mechanistic level, CK downregulated cell survival proteins including Mcl-1, Bcl 2, surviving, X-linked inhibitor of apoptosis protein and Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein, upregulated cell pro apoptotic proteins including Bax, tBid and cytochrome c, and induced the cell surface expression of TRAIL death receptor DR5. Reduction of DR5 levels by siRNAs significantly decreases CK- and TRAIL-mediated apoptosis. Importantly, our results indicate, for the first time, that DR5 upregulation is mediated by autophagy, as blockade of CK-induced autophagy by 3-MA, LY294002 or Atg7 siRNAs substantially decreases DR5 upregulation and reduces the synergistic effect. Furthermore, CK-stimulated autophagy is mediated by the reactive oxygen species-c Jun NH2-terminal kinase pathway. Moreover, we found that p53 and the C/EBP homologous (CHOP) protein is also required for DR5 upregulation but not related with autophagy. Our findings contribute significantly to the understanding of the mechanism accounted for the synergistic anticancer activity of CK and TRAIL, and showed a novel mechanism related with DR5 upregulation. PMID- 27512956 TI - KDM5A controls bone morphogenic protein 2-induced osteogenic differentiation of bone mesenchymal stem cells during osteoporosis. AB - Bone morphogenetic protein 2 (BMP2) has been used to induce bone regeneration by promoting osteogenic differentiation of bone marrow-derived mesenchymal stem cells (MSCs). However, its effect is attenuated in osteoporotic conditions by unknown mechanisms. In this study, we investigated the molecular mechanisms of reduced osteogenic effect of BMP2 in osteoporotic conditions. By interrogating the microarray data from osteoporosis patients, we revealed an upregulation of the epigenetic modifying protein lysine (K)-specific demethylase 5A (KDM5A) and decreased Runt-related transcription factor 2 (RUNX2) expression. Further studies were focused on the role of KDM5A in osteoporosis. We first established ovariectomized (OVX) mouse model and found that the BMP2-induced osteogenic differentiation of osteoporotic MSCs was impaired. The elevated level of KDM5A was confirmed in osteoporotic MSCs. Overexpression of KDM5A in normal MSCs inhibited BMP2-induced osteogenesis. Moreover, osteogenic differentiation of osteoporotic MSCs was restored by specific KDM5A short hairpin RNA or inhibitor. Furthermore, by chromatin immunoprecipitation assay we demonstrated that KDM5A functions as endogenous modulator of osteogenic differentiation by decreasing H3K4me3 levels on promoters of Runx2, depend on its histone methylation activity. More importantly, we found an inhibitory role of KDM5A in regulating bone formation in osteoporotic mice, and pretreatment with KDM5A inhibitor partly rescued the bone loss during osteoporosis. Our results show, for the first time, that KDM5A-mediated H3K4me3 modification participated in the etiology of osteoporosis and may provide new strategies to improve the clinical efficacy of BMP2 in osteoporotic conditions. PMID- 27512954 TI - Regulatory non-coding RNA: new instruments in the orchestration of cell death. AB - Non-coding RNA (ncRNA) comprises a substantial portion of primary transcripts that are generated by genomic transcription, but are not translated into protein. The possible functions of these once considered 'junk' molecules have incited considerable interest and new insights have emerged. The two major members of ncRNAs, namely micro RNA (miRNA) and long non-coding RNA (lncRNA), have important regulatory roles in gene expression and many important physiological processes, which has recently been extended to programmed cell death. The previous paradigm of programmed cell death only by apoptosis has recently expanded to include modalities of regulated necrosis (RN), and particularly necroptosis. However, most research efforts in this field have been on protein regulators, leaving the role of ncRNAs largely unexplored. In this review, we discuss important findings concerning miRNAs and lncRNAs that modulate apoptosis and RN pathways, as well as the miRNA-lncRNA interactions that affect cell death regulation. PMID- 27512957 TI - Oncogenic microtubule hyperacetylation through BEX4-mediated sirtuin 2 inhibition. AB - Five brain-expressed X-linked (BEX) gene members (BEX1-5) are arranged in tandem on chromosome X, and are highly conserved across diverse species. However, little is known about the function and role of BEX. This study represents a first attempt to demonstrate the molecular details of a novel oncogene BEX4. Among BEX proteins, BEX4 localizes to microtubules and spindle poles, and interacts with alpha-tubulin (alpha-TUB) and sirtuin 2 (SIRT2). The overexpression of BEX4 leads to the hyperacetylation of alpha-TUB by inhibiting SIRT2-mediated deacetylation. Furthermore, we found BEX4 expression conferred resistance to apoptotic cell death but led to acquisition of aneuploidy, and also increased the proliferating potential and growth of tumors. These results suggest that BEX4 overexpression causes an imbalance between TUB acetylation and deacetylation by SIRT2 inhibition and induces oncogenic aneuploidy transformation. PMID- 27512958 TI - Cell surface galectin-3 defines a subset of chemoresistant gastrointestinal tumor initiating cancer cells with heightened stem cell characteristics. AB - Recurrence of gastrointestinal adenocarcinomas after surgery and chemotherapy may be attributed, in part, to the presence of a small population of tumor-initiating cancer stem cells (CSC). The expression of galectin-3 (Gal3), a multifunctional oncolectin, has been associated with biological behaviors associated with CSC. We examined the ability of Gal3 to characterize the CSC phenotype, and to identify a clinically important gastrointestinal cancer CSC population. Human colorectal and pancreatic cancer cell lines were sorted to identify subpopulations expressing commonly used CSC markers, and Gal3-positive CSC subpopulations. The association of Gal3 with the stem cell properties and alterations of these phenotypes by manipulation of Gal3 expression was examined. Gastrointestinal cancer cell lines contain both Gal3-positive and Gal3-negative subpopulations. Gal3-positive CSCs are characterized by high ALDH activity, enhanced self-renewal ability in vitro (sphere formation) and tumor forming ability in vivo, and resistance to chemotherapeutic agents and death-receptor-mediated apoptosis compared to Gal3 negative CSCs. Silencing Gal3 modifies this behavior. Cell surface Gal3 expression identifies a subset of CSCs in gastrointestinal cancers with high levels of stem cell characteristics, including chemoresistance. This may provide a platform for developing treatment strategies that target CSC. PMID- 27512960 TI - Landscape spatial configuration is a key driver of wild bee demographics. AB - The majority of studies investigating the effects of landscape composition and configuration on bee populations have been conducted in regions of intensive agricultural production, ignoring regions which are dominated by seminatural habitats, such as the islands of the Aegean Archipelago. In addition, research so far has focused on the landscape impacts on bees sampled in cropped fields while the landscape effects on bees inhabiting seminatural habitats are understudied. Here, we investigate the impact of the landscape on wild bee assemblages in 66 phryganic (low scrubland) communities on 8 Aegean islands. We computed landscape metrics (total area and total perimeter-area ratio) in 4 concentric circles (250, 500, 750, and 1000 m) around the center of each bee sampling site including 3 habitat groups (namely phrygana, cultivated land, and natural forests). We further measured the local flower cover in 25 quadrats distributed randomly at the center of each sampling site. We found that the landscape scale is more important than the local scale in shaping abundance and species richness of bees. Furthermore, habitat configuration was more important than the total area of habitats, probably because it affects bees' movement across the landscape. Phrygana and natural forests had a positive effect on bee demographics, while cultivated land had a negative effect. This demonstrates that phryganic specialists drive bee assemblages in these seminatural landscapes. This finding, together with the shown importance of landscape scale, should be considered for the management of wild bees with special emphasis placed on the spatial configuration of seminatural habitats. PMID- 27512959 TI - Antitherapeutic antibody-mediated hepatotoxicity of recombinant human Apo2L/TRAIL in the cynomolgus monkey. AB - Apo2L/TRAIL is a member of the tumor necrosis factor superfamily and an important inducer of apoptosis. Recombinant human (rhu) Apo2L/TRAIL has been attractive as a potential cancer therapeutic because many types of tumor cells are sensitive to its apoptosis-inducing effects. Nonclinical toxicology studies were conducted to evaluate the safety of rhuApo2L/TRAIL for possible use in humans. The cynomolgus monkey was chosen for this safety assessment based on high protein sequence homology between human and cynomolgus Apo2L/TRAIL and comparable expression of their receptors. Although hepatotoxicity was observed in repeat-dose monkey studies with rhuApo2L/TRAIL, all animals that displayed hepatotoxicity had developed antitherapeutic antibodies (ATAs). The cynomolgus ATAs augmented the cytotoxicity of rhuApo2L/TRAIL but not of its cynomolgus counterpart. Of note, human and cynomolgus Apo2L/TRAIL differ by four amino acids, three of which are surface-exposed. In vivo studies comparing human and cynomolgus Apo2L/TRAIL supported the conclusion that these distinct amino acids served as epitopes for cross-species ATAs, capable of crosslinking rhuApo2L/TRAIL and thus triggering hepatocyte apoptosis. We describe a hapten-independent mechanism of immune mediated, drug-related hepatotoxicity - in this case - associated with the administration of a human recombinant protein in monkeys. The elucidation of this mechanism enabled successful transition of rhuApo2L/TRAIL into human clinical trials. PMID- 27512961 TI - Gap junction proteins and the wiring (Rewiring) of neuronal circuits. AB - The unique morphology and pattern of synaptic connections made by a neuron during development arise in part by an extended period of growth in which cell-cell interactions help to sculpt the arbor into its final shape, size, and participation in different synaptic networks. Recent experiments highlight a guiding role played by gap junction proteins in controlling this process. Ectopic and overexpression studies in invertebrates have revealed that the selective expression of distinct gap junction genes in neurons and glial cells is sufficient to establish selective new connections in the central nervous systems of the leech (Firme et al. [2012]: J Neurosci 32:14265-14270), the nematode (Rabinowitch et al. [2014]: Nat Commun 5:4442), and the fruit fly (Pezier et al., 2016: PLoS One 11:e0152211). We present here an overview of this work and suggest that gap junction proteins, in addition to their synaptic/communicative functions, have an instructive role as recognition and adhesion factors. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 575-586, 2017. PMID- 27512963 TI - Lifetime risk of stroke in young-aged and middle-aged Chinese population: the Chinese Multi-Provincial Cohort Study. AB - OBJECTIVE: Stroke is a major cause of premature death in China. Early prevention of stroke requires a more effective method to differentiate the stroke risk among young-aged and middle-aged individuals than the 10-year risk of cardiovascular disease. This study aimed to establish a lifetime stroke risk model and risk charts for the young-aged and middle-aged population in China. METHODS: The Chinese Multi-Provincial Cohort Study participants (n = 21 953) aged 35-84 years without cardiovascular disease at baseline were followed for 18 years (263 016 person-years). Modified Kaplan-Meier method was used to estimate the mean lifetime stroke risk up to age of 80 years and the lifetime stroke risk according to major stroke risk factors for the population aged 35-60 years. RESULTS: A total of 917 participants developed first-ever strokes. For the participants aged 35-40 years (98 stroke cases), the lifetime stroke risk was 18.0 and 14.7% in men and women, respectively. Blood pressure most effectively discriminated the lifetime stroke risk. The lifetime risk of stroke for the individuals with all risk factors optimal was 8-10 times lower compared with those with two or more high risk factors at age 35-60 years at baseline. CONCLUSION: In young-aged and middle-aged population, the lifetime stroke risk will keep very low if major risk factors especially blood pressure level is at optimal levels, but the risk substantially increases even with a slight elevation of major risk factors, which could not be identified using 10-year risk estimation. PMID- 27512964 TI - Hypertension types defined by clinic and ambulatory blood pressure in 14 143 patients referred to hypertension clinics worldwide. Data from the ARTEMIS study. AB - OBJECTIVE: The Ambulatory blood pressure Registry TEleMonitoring of hypertension and cardiovascular rISk project was designed to set up an international registry including clinic blood pressure (CBP) and ambulatory blood pressure (ABP) measurements in patients attending hypertension clinics in all five continents, aiming to assess different daily life hypertension types. METHODS: Cross sectional ABP, CBP and demographic data, medical history and cardiovascular risk profile were provided from existing databases by hypertension clinics. Hypertension types were evaluated considering CBP (>=140/90 mmHg) and 24-h ABP (>=130/80 mmHg). RESULTS: Overall, 14 143 patients from 27 countries across all five continents were analyzed (Europe 73%, Africa 3%, America 9%, Asia 14% and Australia 2%). Mean age was 57 +/- 14 years, men 51%, treated for hypertension 46%, cardiovascular disease 14%, people with diabetes 14%, dyslipidemia 33% and smokers 19%. The prevalence of hypertension was higher by CBP than by ABP monitoring (72 vs. 60%, P < 0.0001). Sustained hypertension (elevated CBP and ABP) was detected in 49% of patients. White-coat hypertension (WCH, elevated CBP with normal ABP) was more common than masked hypertension (elevated ABP with normal CBP) (23 vs. 10%; P < 0.0001). Sustained hypertension was more common in Europe and America and in elderly, men, obese patients with cardiovascular comorbidities. WCH was less common in Australia, America and Africa, and more common in elderly, obese women. Masked hypertension was more common in Asia and in men with diabetes. Smoking was a determinant for sustained hypertension and masked hypertension. CONCLUSION: Our analysis showed an unbalanced distribution of WCH and masked hypertension patterns among different continents, suggesting an interplay of genetic and environmental factors, and likely also different healthcare administrative and practice patterns. PMID- 27512965 TI - Vegetarian diet reduces the risk of hypertension independent of abdominal obesity and inflammation: a prospective study. AB - OBJECTIVES: A vegetarian diet may prevent elevation of blood pressures and lower the risk for hypertension through lower degrees of obesity, inflammation, and insulin resistance. This study investigated the association between a vegetarian diet and hypertension incidence in a cohort of Taiwanese adult nonsmokers and examined whether this association was mediated through inflammation, abdominal obesity, or insulin resistance (using fasting glucose as a proxy). METHODS: This matched cohort study was from the 1994-2008 MJ Health Screening Database. Each vegetarian was matched with five nonvegetarians by age, sex, and study site. The analysis included 4109 nonsmokers (3423 nonvegetarians and 686 vegetarians), followed for a median of 1.61 years. The outcome includes hypertension incidence, as well as SBP and DBP levels. Regression analysis was performed to assess the association between vegetarian diet and hypertension incidence or future blood pressure levels in the presence/absence of potential mediators. RESULTS: Vegetarians had a 34% lower risk for hypertension, adjusting for age and sex (odds ratio: 0.66, 95% confidence interval: 0.50-0.87; SBP: -3.3 mmHg, P < 0.001; DBP: -1.5 mmHg, P < 0.001). The results stay statistically significant after further adjustment for C-reactive protein, waist circumference, and fasting glucose (odds ratio: 0.72, 95% confidence interval: 0.55-0.86; SBP: -2.4 mmHg, P < 0.05; DBP: -1.1 mmHg, P < 0.05). The protective association between vegetarian diet and hypertension appeared to be consistent across age groups. CONCLUSION: Taiwanese vegetarians had lower incidence of hypertension than nonvegetarians. Vegetarian diets may protect against hypertension beyond lower abdominal obesity, inflammation, and insulin resistance. PMID- 27512966 TI - Preconception blood pressure and risk of preterm birth: a large cohort study in China. AB - BACKGROUND: To examine whether blood pressure (BP) in the preconceptional period was associated with preterm birth in Chinese women. METHODS: The data are from a large population-based cohort study established to evaluate the effectiveness of the campaign to prevent neural tube defects in 21 Chinese counties. We included 44 494 singleton live births delivered at gestational ages of 20-42 weeks to women who were registered before pregnancy in seven counties in southern China. Blood pressure was measured during registration by trained healthcare workers. We used logistic regression to evaluate the associations between prepregnancy blood pressure and increased risk of preterm birth, adjusting for potential confounders. RESULTS: The study size had 93% power (alpha=0.05) to detect an increase of 38% over the unexposed rate of 5.32% for preterm birth. The prevalence of hypertension of study population in prepregnancy was 4.55% (2023/44 494). The incidence of preterm birth was 5.73% for hypertension group and 5.32% for nonhypertension group. Compared with nonhypertension group, hypertension group did not show significant increased risk for preterm birth overall [adjusted risk ratio (RR)=1.10, 95% confidence interval (CI) 0.91-1.34], iatrogenic subtype [adjusted RR=1.21, 95% CI 0.78-1.88], or noniatrogenic subtype [adjusted RR=1.08, 95% CI 0.88-1.34]. When the participants with normal blood pressure were used as the reference, the adjusted RRs of noniatrogenic preterm birth were 0.79 (0.70 0.89) for prehypertensive women. CONCLUSION: Our results do not support the association between hypertension or higher blood pressure prior to pregnancy and the increased risk of preterm birth. PMID- 27512962 TI - Neurotransmitters: The Critical Modulators Regulating Gut-Brain Axis. AB - Neurotransmitters, including catecholamines and serotonin, play a crucial role in maintaining homeostasis in the human body. Studies on these neurotransmitters mainly revolved around their role in the "fight or flight" response, transmitting signals across a chemical synapse and modulating blood flow throughout the body. However, recent research has demonstrated that neurotransmitters can play a significant role in the gastrointestinal (GI) physiology. Norepinephrine (NE), epinephrine (E), dopamine (DA), and serotonin have recently been a topic of interest because of their roles in the gut physiology and their potential roles in GI and central nervous system pathophysiology. These neurotransmitters are able to regulate and control not only blood flow, but also affect gut motility, nutrient absorption, GI innate immune system, and the microbiome. Furthermore, in pathological states, such as inflammatory bowel disease (IBD) and Parkinson's disease, the levels of these neurotransmitters are dysregulated, therefore causing a variety of GI symptoms. Research in this field has shown that exogenous manipulation of catecholamine serum concentrations can help in decreasing symptomology and/or disease progression. In this review article, we discuss the current state-of-the-art research and literature regarding the role of neurotransmitters in regulation of normal GI physiology, their impact on several disease processes, and novel work focused on the use of exogenous hormones and/or psychotropic medications to improve disease symptomology. J. Cell. Physiol. 232: 2359-2372, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27512967 TI - Effect of renal sympathetic denervation on hepatic glucose metabolism and blood pressure in a rat model of insulin resistance. AB - OBJECTIVE: Hypertension and diabetes are associated with impaired glucose metabolism and insulin resistance. Chronic activation of the sympathetic nervous system may contribute to either condition. The purpose of this study was to investigate the effect of renal denervation on glucose kinetics and insulin signal pathways in high-fat diet (HFD)-fed rats. METHODS: We examined the effects of renal denervation on glucose kinetics and insulin sensitivity in HFD-fed rats with a hyperinsulinemic-euglycemic clamp technique combined with [3-H] glucose and [U-C]-lactate as a tracer. We also analyzed in vivo the flux through glucose 6-phosphatase and the relative contribution of gluconeogenesis and glycogenolysis in renal denervation rats. In addition, western blotting was used to identify the activities of insulin signaling proteins. RESULTS: Renal denervation in HFD-fed rats markedly decreased blood pressure and hepatic glucose production. Hepatic glucose production reduction in renal-denervation-treated rats includes decrease in glycogenolysis by 18.2% for left renal denervation or 31.9% for bilateral renal denervation and decrease in gluconeogenesis by 16.3% for left renal denervation or 42.8% for bilateral renal denervation. These changes were accompanied by decreased hepatic expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Importantly, renal denervation increased phosphorylation of insulin receptors, insulin receptor substrate-1 and Akt kinase in HFD-fed rats. CONCLUSION: These data corroborate the notion that renal denervation potentiates hepatic insulin sensitivity. PMID- 27512968 TI - Threshold for diagnosing hypertension by automated office blood pressure using random sample population data. AB - OBJECTIVE: Manual office blood pressure (BP) is still recommended for diagnosing hypertension. However, its predictive value is decreased by errors in measurement technique and the white-coat effect. The errors can be eliminated by automated office BP (AOBP) measurement taking multiple readings with the participant resting quietly alone. Therefore, use of AOBP in clinical practice requires a threshold value for hypertension diagnosis. The aim of the present study was to determine an AOBP threshold corresponding to the 140/90 mmHg manual office BP using data from a large random population sample. METHODS: In 2145 participants (mean age 47.3 +/- 11.3 years) randomly selected from a Brno population aged 25 64 years, BP was measured using manual mercury and automated office sphygmomanometers. RESULTS: Manual SBP (mean difference 6.39 +/- 9.76 mmHg) and DBP (mean difference 2.50 +/- 6.54 mmHg) were higher than the automated BP. According to polynomial regression, automated systole of 131.06 (95% confidence interval 130.43-131.70) and diastole of 85.43 (95% confidence interval 85.03 85.82) corresponded to the manual BP of 140/90 mmHg. Using this cut-off, the white-coat hypertension was present in 24% of participants with elevated manual BP, whereas 10% had masked hypertension and 11% masked uncontrolled hypertension. In individuals with masked uncontrolled hypertension, only AOBP was associated with the urinary albumin-creatinine ratio, whereas there was no association with manual BP. CONCLUSION: AOBP of 131/85 mmHg corresponds to the manual BP of 140/90 mmHg. This value may be used as a threshold for diagnosing hypertension using AOBP. However, outcome-driven studies are required to confirm this threshold. PMID- 27512969 TI - Histone deacetylase and GATA-binding factor 6 regulate arterial remodeling in angiotensin II-induced hypertension. AB - OBJECTIVE: Histone deacetylase (HDAC) inhibitors have been reported to improve essential and secondary hypertension. However, the specific HDAC that might serve as a therapeutic target and the associated upstream and downstream molecules involved in regulating hypertension remain unknown. Our study was aimed at investigating whether a selective inhibitor of class II HDAC (MC1568) modulates hypertension, elucidating the underlying mechanism. METHODS: Hypertension was established by administering angiotensin II (Ang II) to mice before treatment with MC1568. SBP was measured. RESULTS: Treatment with MC1568 reduced elevated SBP; attenuated arterial remodeling in the kidney's small arteries and thoracic aorta; and inhibited cell cycle regulatory gene expression, vascular smooth muscle cell (VSMC) proliferation, DNA synthesis, and VSMC hypertrophy in vivo and in vitro. Ang II enhanced the expression of phosphorylated HDAC4 and GATA-binding factor 6 (GATA6) proteins, which were specifically localized in the cytoplasm of cells in the arteries of kidneys and in aortas. Forced expression and knockdown of HDAC4 increased and decreased, respectively, the proliferation and expression of cell cycle genes in VSMCs. GATA6, a newly described binding partner of HDAC4, markedly enhanced the size and number of VSMCs. Calcium/calmodulin-dependent kinase IIalpha (CaMKIIalpha), but not HDAC4, translocated from the nucleus to the cytoplasm in response to Ang II. CaMKIIalpha and protein kinase D1 were associated with VSMC hypertrophy and hyperplasia via direct interaction with HDAC4. MC1568 treatment weakened the association between HDAC4 and CaMKIIalpha. CONCLUSION: These results suggest that class II HDAC inhibition attenuates hypertension by negatively regulating VSMC hypertrophy and hyperplasia via the CaMKIIalpha/protein kinase D1/HDAC4/GATA6 pathway. PMID- 27512970 TI - The association between blood pressure and lipid levels in Europe: European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice. AB - OBJECTIVES: Several studies have suggested a positive association between serum lipid levels and blood pressure (BP). This study investigated this association in a large population from 12 European countries. METHODS: Data were taken from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (ClinicalTrials.gov identifier: NCT00882336). Associations between BP and lipid levels in patients free from cardiovascular disease and with at least one major cardiovascular disease risk factor (N = 7641) were assessed using linear regression analyses. RESULTS: Overall, 72.8 and 64.8% of patients had hypertension and dyslipidaemia, respectively; 47.0% had both conditions. Regression coefficients (95% confidence interval) for the associations of LDL cholesterol, non-HDL cholesterol, total cholesterol and apolipoprotein B levels with SBP, adjusted for age, sex and BMI, were 0.93 mmHg/mmol per l (0.54-1.31), 1.07 mmHg/mmol per l (0.73-1.40), 1.02 mmHg/mmol per l (0.69-1.35) and 4.94 mmHg/g per l (3.43-6.46), respectively. The corresponding values (95% confidence interval) for the associations with DBP were 0.96 mmHg/mmol per l (0.73-1.19), 0.95 mmHg/mmol per l (0.75-1.15), 0.87 mmHg/mmol per l (0.67-1.07) and 4.33 mmHg/g per l (3.42-5.23), respectively. Most of these associations remained significant whether patients were treated with statins or not. CONCLUSION: Small but statistically significant associations between lipid levels and BP were observed in a large, multinational European population. Further research is warranted to assess the causality of this association and its implications on the management of patients with both hypertension and dyslipidaemia. PMID- 27512971 TI - A systematic review and meta-analysis of randomized controlled trials investigating the effects of supplementation with Nigella sativa (black seed) on blood pressure. AB - Several reports suggest a beneficial effect of Nigella sativa on cardiometabolic risk factors, including blood pressure (BP). However, the magnitude of the BP lowering effect of N. sativa remains controversial. We aimed to calculate this effect size of N. sativa through a systematic review and meta-analysis of randomized controlled trials (RCTs). PubMed, Cochrane Collaboration Library, and SCOPUS were used as data sources of RCTs published before 30 August 2015 (in English only) comparing N. sativa treatment with placebo or standard treatment. We used random effect models to estimate the difference in BP reductions, I index and chi statistics to measure and test the interstudy heterogeneity. Random effect metaregression models were applied to explore the associations between BP reduction and duration of treatment, dosage of N. sativa, and type of black seed as potential confounders. Publication bias was evaluated using funnel plot and Egger's regression asymmetry test. Total 11 RCTs, including 860 hypertensive or normotensive individuals were eligible, of which 10 compared N. sativa versus placebo and one versus standard treatment. SBP and DBP means decreased from 132.85 to 125.19 mmHg and from 82.63 to 77.74 mmHg after mean treatment duration of 8.3 weeks in N. sativa groups, respectively. The difference in reductions as compared with control/standard groups were -3.26 (-5.10, -1.42; I = 59%) mmHg in SBP and -2.80 (-4.28, -1.32; I = 60%) mmHg in DBP. Pharmaceutical preparations of N. sativa in powder and oil demonstrated a different lowering effect (in favour of the former) on both SBP and DBP. No association was observed between SBP lowering and time on treatment, N. sativa dosage or type of N. sativa. The results of Egger's test did not indicate any publication bias. Our meta-analysis suggests that short-term treatment with N. sativa powder can significantly reduce SBP and DBP levels. More evidence is needed, however, to strengthen the available evidence and to further explore the long-term BP-lowering effect of N. sativa. PMID- 27512972 TI - Effects of pentoxifylline on inflammatory markers and blood pressure: a systematic review and meta-analysis of randomized controlled trials. AB - INTRODUCTION: Pentoxifylline is a xanthine derivative with potential cardiovascular benefits. AIM: To evaluate the impact of pentoxifylline on blood pressure (BP) and plasma TNF-alpha, C-reactive protein (CRP) and IL-6 through a systematic review and meta-analysis of randomized controlled trials. METHODS: The protocol was registered (PROSPERO: CRD42016035988). The search included PUBMED, ProQuest, Scopus and EMBASE until 1 September 2015 to identify trials reporting BP or inflammatory markers during pentoxifylline therapy. Quantitative data synthesis was performed using a random-effects model, with weighted mean difference (WDF) and 95% confidence intervals (CIs) as summary statistics. RESULTS: Fifteen studies (16 treatment arms) were found to be eligible for inclusion. Meta-analysis did not suggest any effect of pentoxifylline on either SBP or DBP. Pentoxifylline treatment was associated with a significant reduction in plasma concentrations of TNF-alpha (WDF: -1.03 pg/ml, 95% CI: -1.54, -0.51; P < 0.001, 11 treatment arms) and CRP (WDF: -1.39 mg/l, 95% CI: -2.68, -0.10; P = 0.034, five treatment arms). No alteration in plasma IL-6 concentration was observed. The impact of pentoxifylline on plasma TNF-alpha levels was found to be positively associated with treatment duration (slope: 0.031; 95% CI: 0.004, 0.057; P = 0.023) but independent of pentoxifylline dose (slope: -0.0003; 95% CI: -0.002, 0.001; P = 0.687). CONCLUSION: Pentoxifylline did not alter BP or plasma IL-6 concentration, but significantly reduced circulating TNF-alpha and CRP concentrations. PMID- 27512973 TI - Accelerated progression of coronary artery calcification in hypertension but also prehypertension. AB - OBJECTIVE: To determine the role of hypertension for coronary artery calcification (CAC) progression. METHODS: The population-based Heinz Nixdorf Recall study recruited 4814 participants from a German urban population in 2000 2003. CAC was measured using electron-beam computed tomography at baseline and after 5 years. The present analyses refer to 3481 participants with repeat scan (coronary heart disease until 5 years excluded, age at baseline 45-74 years, and 53.1% women). Blood pressure (BP), Framingham risk factors, and antihypertensive medication were recorded at baseline. BP was staged according to Joint National Committee 7 guidelines. Participants under antihypertensive medication were classified as stage 2. CAC at 5 years was predicted from baseline using our dedicated, publicly available algorithm. CAC progression was accordingly classified as slow, expected, or rapid. RESULTS: Normotension was found in 20.5%, prehypertension in 27.2%, stage 1 hypertension in 15.8%, and stage 2 (ST2) in 36.5%. The frequency of rapid progression increases with BP stage (normotension: 16.7% to ST2: 21.1%, P = 0.004). Risk factor adjusted relative risk [RR (95% confidence interval), reference: normotension] of rapid progression was for prehypertension: 1.22 (0.98;1.51), stage 1: 1.29 (1.01;1.65), and ST2: 1.45 (1.17;1.79). Risk factor adjusted measures of CAC progression per 10 mmHg SBP were already elevated in women with BP below 140/90 mmHg: CAC onset, RR = 1.22 (1.07;1.40), rapid progression, RR = 1.17 (1.05;1.31), 5-year CAC progression, 6.7% (0.5;13.4). In men below 140/90 mmHg, only RR of rapid progression was considerably increased [RR = 1.11 (0.96;1.29)]. CONCLUSION: CAC progression, a sign of ongoing target organ damage, is already accelerated in prehypertensive patients, a substantial proportion of our urban population. PMID- 27512974 TI - Elevated estimated arterial age is associated with metabolic syndrome and low grade inflammation. AB - BACKGROUND: Arterial age can be estimated from equations relating arterial stiffness to age and blood pressure in large cohorts. We investigated whether estimated arterial age (eAA) was elevated in patients with the metabolic syndrome and/or known cardiovascular disease (CVD), which factors were associated with eAA and whether eAA added prognostic information. METHODS: In 1993, 2366 study participants, 41, 51, 61, and 71 years old, had traditional cardiovascular risk factors and carotid-femoral pulse wave velocity (cfPWV) measured. Risk groups were identified based on known CVD and components of metabolic syndrome, Systematic COronary Risk Evaluation, or Framingham risk score. From age, mean blood pressure, and cfPWV, eAA and estimated cfPWV (ePWV) were calculated. In 2006, the combined cardiovascular endpoint (CEP) of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for ischemic heart disease was registered. RESULTS: cfPWV and ePWV increased with ageing and cardiovascular risk (all P < 0.001), but ePWV increased more with ageing than cfPWV. The difference between eAA and chronological age was associated with male sex (beta = 0.14), higher heart rate (beta = 0.16 both P < 0.001), fasting glucose (beta = 0.08) soluble urokinase plasminogen activator receptor (beta = 0.06, both P < 0.01), and known CVD (beta = 0.06, P < 0.05) independently of age, SBP, and heart rate. Independently of Systematic COronary Risk Evaluation, eAA (hazard ratio = 1.20, P < 0.01) predicted CEP, but not as accurately as ePWV (hazard ratio = 1.58, P < 0.001) and cfPWV (hazard ratio = 1.32, P < 0.001) among apparently healthy study participants. CONCLUSION: Elevated eAA was associated with male sex, higher plasma glucose, and soluble urokinase plasminogen activator receptor and known CVD independently of age, SBP, and heart rate. PMID- 27512975 TI - Interrupting prolonged sitting with brief bouts of light walking or simple resistance activities reduces resting blood pressure and plasma noradrenaline in type 2 diabetes. AB - OBJECTIVE: Prolonged sitting is increasingly recognized as a ubiquitous cardiometabolic risk factor, possibly distinct from lack of physical exercise. We examined whether interrupting prolonged sitting with brief bouts of light intensity activity reduced blood pressure (BP) and plasma noradrenaline in type 2 diabetes (T2D). METHODS: In a randomized crossover trial, 24 inactive overweight/obese adults with T2D (14 men; mean +/- SD; 62 +/- 6 years) consumed standardized meals during 3 * 8 h conditions: uninterrupted sitting (SIT); sitting + half-hourly bouts of walking (3.2 km/h for 3-min) (light-intensity walking); and sitting + half-hourly bouts of simple resistance activities for 3 min (SRAs), each separated by 6-14 days washout. Resting seated BP was measured hourly (mean of three recordings, >=20-min postactivity). Plasma noradrenaline was measured at 30-min intervals for the first hour after meals and hourly thereafter. RESULTS: Compared with SIT, mean resting SBP and DBP were significantly reduced (P < 0.001) for both light-intensity walking (mean +/- SEM; -14 +/- 1/-8 +/- 1 mmHg) and SRA (-16 +/- 1/-10 +/- 1 mmHg), with a more pronounced effect for SRA (P < 0.05 versus light-intensity walking). Similarly, mean plasma noradrenaline was significantly reduced for both light-intensity walking (-0.3 +/- 0.1 nmol/l) and SRA (-0.6 +/- 0.1 nmol/l) versus SIT, with SRA lower than light-intensity walking (P < 0.05). Mean resting heart rate was lowered by light-intensity walking (-3 +/- 1 bpm; P < 0.05), but not SRA (-1 +/- 1 bpm). CONCLUSION: Interrupting prolonged sitting with brief bouts of light intensity walking or SRA reduces resting BP and plasma noradrenaline in adults with T2D, with SRA being more effective. Given the ubiquity of sedentary behaviors and poor adherence to structured exercise, this approach may have important implications for BP management in patients with T2D. PMID- 27512976 TI - Metoclopramide unmasks potentially misleading contralateral suppression in patients undergoing adrenal vein sampling for primary aldosteronism. AB - OBJECTIVE: As metoclopramide stimulates aldosterone secretion, we tested its usefulness in the assessment of lateralization of primary aldosteronism by adrenal vein sampling (AVS). DESIGN: Prospective within-patient study in consecutive patients undergoing AVS for primary aldosteronism subtyping. METHODS: We compared the diagnostic accuracy of baseline and postmetoclopramide lateralization index and relative (to cortisol) aldosterone secretion indices (RASI) for each adrenal gland with aldosterone-producing adenoma (APA) determined by the four corners criteria as the reference diagnosis. RESULTS: We recruited 93 consecutive patients (mean age: 52 years; women 31%). Metoclopramide increased plasma aldosterone in the inferior vena cava and in both adrenal veins. The postmetoclopramide lateralization index was accurate in identifying APA, but did not increase diagnostic accuracy over baseline lateralization index, because the RASI increased similarly in both sides. Conversely, metoclopramide raised RASI to values more than 0.90 bilaterally in non-APA patients allowing accurate identification of factitious aldosterone suppression. In contrast, RASI was 0.90 or less in 48% contralateral to the tumor in APA patients. Regression analysis showed the APA patients with persistent suppression of RASI contralaterally showed a more florid primary aldosteronism phenotype. CONCLUSION: Metoclopramide does not enhance lateralization of aldosterone excess in APA, but consistently increased the value of RASI in non-APA cases, thus unmasking potentially misleading suppression of aldosterone. Postmetoclopramide RASI may therefore allow a more precise diagnosis when AVS can be achieved only unilaterally. PMID- 27512977 TI - Creatine kinase inhibition lowers systemic arterial blood pressure in spontaneously hypertensive rats: a randomized controlled trial. AB - OBJECTIVE: Creatine kinase is reported to be a main predictor of blood pressure (BP) in the general population, with a strong correlation between resistance artery creatine kinase expression and clinical BP in humans. The enzyme rapidly regenerates ATP near cytoplasmic ATPases involved in pressor responses, including resistance artery contractility and renal sodium retention. Therefore, we assessed whether creatine kinase inhibition reduces BP. METHODS: We implemented the 'Animal Research: Reporting of In Vivo Experiments' guideline. In a 4-week randomized controlled trial, male 16-week-old spontaneously hypertensive rats (N = 16) were randomly assigned to the specific competitive creatine kinase inhibitor beta-guanidinopropionic acid (3%)-supplemented chow vs. standard chow. BP measured by the tail-cuff method was the main outcome. Other outcomes included vasodilation in isolated arteries and renal renin expression. RESULTS: Creatine kinase inhibition reduced BP safely and reversibly. Mean baseline BP of, respectively, 191.5 (standard error 4.3) mmHg SBP and 143.1 (4.1) mmHg DBP was reduced by, respectively, 42.7 (5.5) mmHg SBP and 35.6 (5.0) mmHg DBP (P < 0.001) compared with controls, with evidence of enhanced vasodilation and a diuretic effect. CONCLUSION: To our knowledge, this is the first report on the BP-lowering effect of creatine kinase inhibition. Our data indicate that modulation of the creatine kinase system is a potential novel treatment target for hypertension. PMID- 27512978 TI - C-reactive protein/oxidized low density lipoprotein/beta2-glycoprotein i complexes induce lipid accumulation and inflammatory reaction in macrophages via p38/mitogen-activated protein kinase and nuclear factor-kappaB signaling pathways. AB - Oxidized low-density lipoprotein (oxLDL) can bind to beta2-glycoprotein I (beta2GPI) and C-reactive protein (CRP) to form stable complexes, which exert certain effects in diabetic cardiovascular disease. A previous study by our group has confirmed that the resulting complexes promote atherosclerosis in diabetic BALB/c mice. The present study was designed to investigate the effects and potential mechanisms of oxLDL complexes on lipid accumulation and inflammatory reactions in RAW264.7 macrophages cultured in a hyperglycemic environment. Cultured cells were divided into seven groups, which were treated with phosphate buffered saline (control), CRP, beta2GPI, oxLDL, CRP/oxLDL, oxLDL/beta2GPI or CRP/oxLDL/beta2GPI. The results revealed the formation of foam cells in the oxLDL, CRP/oxLDL, oxLDL/beta2GPI as well as CRP/oxLDL/beta2GPI groups. Compared with oxLDL, the three complexes induced less lipid accumulation (P<0.05) through inhibiting the expression of CD36 mRNA and promoting the expression of and ABCG1 mRNA (P<0.05 vs. oxLDL). Furthermore, the levels of inflammatory factors interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha were elevated in the CRP/oxLDL and CRP/oxLDL/beta2GPI groups (P>0.05 vs. oxLDL), and obvious effects on p38/mitogen-activated protein kinase and nuclear factor (NF)-kappaB phosphorylation were also observed in these groups (P<0.05 vs. oxLDL). These results suggested that CRP/oxLDL/betaG2P1 complexes may induce lipid accumulation and inflammation in macrophages via the p38/MAPK and NF-kappaB signaling pathways. However, some differences were observed between the complexes, which may be attributed to the property of each constituent; therefore, further studies are required. PMID- 27512979 TI - Human Urinary Epithelial Cells as a Source of Engraftable Hepatocyte-Like Cells Using Stem Cell Technology. AB - Although several types of somatic cells have been reprogrammed into induced pluripotent stem cells (iPSCs) and then differentiated to hepatocyte-like cells (iHeps), the method for generating such cells from renal tubular epithelial cells shed in human urine and transplanting them into animal livers has not been described systematically. We report reprogramming of human urinary epithelial cells into iPSCs and subsequent hepatic differentiation, followed by a detailed characterization of the newly generated iHeps. The epithelial cells were reprogrammed into iPSCs by delivering the pluripotency factors OCT3/4, SOX2, KLF4, and MYC using methods that do not involve transgene integration, such as nucleofection of episomal (oriP/EBNA-1) plasmids or infection with recombinant Sendai viruses. After characterization of stable iPSC lines, a three-step differentiation toward hepatocytes was performed. The iHeps expressed a large number of hepatocyte-preferred genes, including nuclear receptors that regulate genes involved in cholesterol homeostasis, bile acid transport, and detoxification. MicroRNA profile of the iHeps largely paralleled that of primary human hepatocytes. The iHeps engrafted into the livers of Scid mice transgenic for mutant human SERPINA1 after intrasplenic injection. Thus, urine is a readily available source for generating human iHeps that could be potentially useful for disease modeling, pharmacological development, and regenerative medicine. PMID- 27512980 TI - Fusion of foreign T-cell epitopes and addition of TLR agonists enhance immunity against Neospora caninum profilin in cattle. AB - We demonstrated recently that immunization with recombinant Neospora caninum profilin (rNcPRO) induces limited protection and a regulatory T-cell response in mice. The aim of this study was to evaluate the immune response elicited by rNcPRO in cattle and assess a strategy to enhance its immunogenicity, combining the addition of T-cell epitopes and immune modulators. We developed a chimeric recombinant profilin fused to functional T-cell epitopes present in the N terminal sequence of vesicular stomatitis virus (VSV) glycoprotein G (rNcPRO/G). Groups of three cattle were immunized with two doses (2 weeks apart) of rNcPRO or rNcPRO/G formulated with alum hydroxide or a nanoparticulated soya-based adjuvant enriched with Toll-like receptor (TLR) 2 and TLR9 agonists, aimed to tackle the MyD88 pathway (AVECplus). rNcPRO induced only a primary immune response (IgM mediated), while antibodies in rNcPRO/G-vaccinated animals switched to IgG1 after the booster. The vaccine formulated with rNcPRO/G and AVECplus improved the production of systemic IFN-gamma and induced long-term recall B-cell responses. Overall, our study provides data supporting the use of T-cell epitopes from VSV glycoprotein G and TLR agonists to enhance and modulate immunity to peptide antigens in bovines, particularly when using small proteins from parasites for which immune responses are usually feeble. PMID- 27512982 TI - Incidentally Diagnosed Intracranial Sewing Needle in an Adult Patient: A Failed Infanticide Attempt? PMID- 27512981 TI - Acid Sphingomyelinase (ASM) is a Negative Regulator of Regulatory T Cell (Treg) Development. AB - BACKGROUND/AIMS: Regulatory T cell (Treg) is required for the maintenance of tolerance to various tissue antigens and to protect the host from autoimmune disorders. However, Treg may, indirectly, support cancer progression and bacterial infections. Therefore, a balance of Treg function is pivotal for adequate immune responses. Acid sphingomyelinase (ASM) is a rate limiting enzyme involved in the production of ceramide by breaking down sphingomyelin. Previous studies in T-cells have suggested that ASM is involved in CD28 signalling, T lymphocyte granule secretion, degranulation, and vesicle shedding similar to the formation of phosphatidylserine-exposing microparticles from glial cells. However, whether ASM affects the development of Treg has not yet been described. METHODS: Splenocytes, isolated Naive T lymphocytes and cultured T cells were characterized for various immune T cell markers by flow cytometery. Cell proliferation was measured by Carboxyfluorescein succinimidyl ester (CFSE) dye, cell cycle analysis by Propidium Iodide (PI), mRNA transcripts by q-RT PCR and protein expression by Western Blotting respectively. RESULTS: ASM deficient mice have higher number of Treg compared with littermate control mice. In vitro induction of ASM deficient T cells in the presence of TGF-beta and IL-2 lead to a significantly higher number of Foxp3+ induced Treg (iTreg) compared with control T-cells. Further, ASM deficient iTreg has less AKT (serine 473) phosphorylation and Rictor levels compared with control iTreg. Ceramide C6 led to significant reduction of iTreg in both ASM deficient and WT mice. The reduction in iTreg leads to induction of IL-1beta, IL-6 and IL-17 but not IFN-gamma mRNA levels. CONCLUSION: ASM is a negative regulator of natural and iTreg. PMID- 27512983 TI - Are new antibiotics better than beta-lactams for non-critical inpatients with community-acquired pneumonia? AB - Treatment for community-acquired pneumonia in immunocompetent adults is mainly empirical. Beta-lactam antibiotics have been traditionally considered first-line therapy. New antibiotics could be more effective but the evidence is not clear until now, and its use could entail greater costs, an increase in bacterial resistance and other adverse effects. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 36 randomized trials addressing this question. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded new antibiotics are not better than beta-lactam antibiotics for the treatment of non-critical inpatients with community-acquired pneumonia in relation to clinical failure or adverse effects. PMID- 27512985 TI - 10-Methyldodecanal, a Novel Attractant Pheromone Produced by Males of the South American Cerambycid Beetle Eburodacrys vittata. AB - We report the identification, synthesis, and field bioassay of a novel attractant pheromone produced by males of Eburodacrys vittata (Blanchard), a South American cerambycid beetle in the subfamily Cerambycinae. Headspace volatiles from males contained a sex-specific compound, identified as 10-methyldodecanal. In a field bioassay conducted in Brazil, significant numbers of males and females were caught in traps baited with synthesized racemic 10-methyldodecanal, consistent with the aggregation-sex pheromones produced by males of many cerambycine species. This compound represents a new structural class of cerambycid pheromones, and it is the first pheromone identified for a species in the tribe Eburiini. PMID- 27512984 TI - Combating a Global Threat to a Clonal Crop: Banana Black Sigatoka Pathogen Pseudocercospora fijiensis (Synonym Mycosphaerella fijiensis) Genomes Reveal Clues for Disease Control. AB - Black Sigatoka or black leaf streak disease, caused by the Dothideomycete fungus Pseudocercospora fijiensis (previously: Mycosphaerella fijiensis), is the most significant foliar disease of banana worldwide. Due to the lack of effective host resistance, management of this disease requires frequent fungicide applications, which greatly increase the economic and environmental costs to produce banana. Weekly applications in most banana plantations lead to rapid evolution of fungicide-resistant strains within populations causing disease-control failures throughout the world. Given its extremely high economic importance, two strains of P. fijiensis were sequenced and assembled with the aid of a new genetic linkage map. The 74-Mb genome of P. fijiensis is massively expanded by LTR retrotransposons, making it the largest genome within the Dothideomycetes. Melting-curve assays suggest that the genomes of two closely related members of the Sigatoka disease complex, P. eumusae and P. musae, also are expanded. Electrophoretic karyotyping and analyses of molecular markers in P. fijiensis field populations showed chromosome-length polymorphisms and high genetic diversity. Genetic differentiation was also detected using neutral markers, suggesting strong selection with limited gene flow at the studied geographic scale. Frequencies of fungicide resistance in fungicide-treated plantations were much higher than those in untreated wild-type P. fijiensis populations. A homologue of the Cladosporium fulvum Avr4 effector, PfAvr4, was identified in the P. fijiensis genome. Infiltration of the purified PfAVR4 protein into leaves of the resistant banana variety Calcutta 4 resulted in a hypersensitive-like response. This result suggests that Calcutta 4 could carry an unknown resistance gene recognizing PfAVR4. Besides adding to our understanding of the overall Dothideomycete genome structures, the P. fijiensis genome will aid in developing fungicide treatment schedules to combat this pathogen and in improving the efficiency of banana breeding programs. PMID- 27512986 TI - Ingenol Mebutate 150 mg as Physician-Directed Treatment of Bowen's Disease Under Occlusion. AB - Ingenol mebutate (IM) is a topical pharmacotherapy approved in Switzerland since 2012 for treating non-hypertrophic, non-hyperkeratotic actinic keratosis. We report a case with off-label use of IM where Bowen's disease has been successfully treated with physician-directed IM 0.015% gel under occlusion over the chest area. PMID- 27512987 TI - Correction: Associations of C-Reactive Protein, Granulocytes and Granulocyte-to Lymphocyte Ratio with Mortality from Breast Cancer in Non-Institutionalized American Women. AB - [This corrects the article DOI: 10.1371/journal.pone.0157482.]. PMID- 27512989 TI - HBV-Associated Postinfectious Acute Glomerulonephritis: A Report of 10 Cases. AB - Postinfectious acute glomerulonephritis (PIGN) may occur after various bacterial and viral infections. Hepatitis B virus (HBV) infection is a cause of chronic glomerulonephritis. We report here 10 cases (ages 7-20 years-old) of chronic HBV carriers with acute glomerulonephritis, with positive glomerular staining of hepatitis B surface antigen, and detectable presence of HBV DNA in the glomeruli. This form of PIGN, HBV-PIGN, has not been previously identified. To further characterize clinical and pathological features of HBV- PIGN, we selected 10 cases of age-matched non-HBV PIGN for comparison. While both HBV associated PIGN and non-HBV PIGN similarly presented as proteinuria, hematuria, and hypertension, there was a trend of higher acute kidney injury and worsened prognosis in HBV PIGN. 6 months after the onset, 4 patients with HBV associated PIGN did not show improvement from the disease, whereas all patients with non-HBV PIGN had complete or partial recovery. Pathologically, both HBV associated PIGN and non-HBV PIGN showed typical diffuse glomerular endocapillary proliferation, but HBV associated PIGN differed from classical PIGN with much fewer sub-epithelial glomerular "hump shape" immune complex depositions. In conclusion, we have identified a novel association of HBV infection with acute glomerulonephritis. PMID- 27512988 TI - The Invalidation of HspB1 Gene in Mouse Alters the Ultrastructural Phenotype of Muscles. AB - Even though abundance of Hsp27 is the highest in skeletal muscle, the relationships between the expression of HspB1 (encoding Hsp27) and muscle characteristics are not fully understood. In this study, we have analysed the effect of Hsp27 inactivation on mouse development and phenotype. We generated a mouse strain devoid of Hsp27 protein by homologous recombination of the HspB1 gene. The HspB1-/- mouse was viable and fertile, showing neither apparent morphological nor anatomical alterations. We detected a gender dimorphism with marked effects in males, a lower body weight (P < 0.05) with no obvious changes in the growth rate, and a lower plasma lipids profile (cholesterol, HDL and triglycerides, 0.001 < P< 0.05). The muscle structure of the animals was examined by optical microscopy and transmission electron microscopy. Not any differences in the characteristics of muscle fibres (contractile and metabolic type, shape, perimeter, cross-sectional area) were detected except a trend for a higher proportion of small fibres. Different myosin heavy chains electrophoretic profiles were observed in the HspB1-/- mouse especially the presence of an additional isoform. Electron microscopy revealed ultrastructural abnormalities in the myofibrillar structure of the HspB1-/- mouse mutant mice (e.g. destructured myofibrils and higher gaps between myofibrils) especially in the m. Soleus. Combined with our previous data, these findings suggest that Hsp27 could directly impact the organization of muscle cytoskeleton at the molecular and ultrastructural levels. PMID- 27512990 TI - Altered Vision-Related Resting-State Activity in Pituitary Adenoma Patients with Visual Damage. AB - OBJECTIVE: To investigate changes of vision-related resting-state activity in pituitary adenoma (PA) patients with visual damage through comparison to healthy controls (HCs). METHODS: 25 PA patients with visual damage and 25 age- and sex matched corrected-to-normal-vision HCs underwent a complete neuro-ophthalmologic evaluation, including automated perimetry, fundus examinations, and a magnetic resonance imaging (MRI) protocol, including structural and resting-state fMRI (RS fMRI) sequences. The regional homogeneity (ReHo) of the vision-related cortex and the functional connectivity (FC) of 6 seeds within the visual cortex (the primary visual cortex (V1), the secondary visual cortex (V2), and the middle temporal visual cortex (MT+)) were evaluated. Two-sample t-tests were conducted to identify the differences between the two groups. RESULTS: Compared with the HCs, the PA group exhibited reduced ReHo in the bilateral V1, V2, V3, fusiform, MT+, BA37, thalamus, postcentral gyrus and left precentral gyrus and increased ReHo in the precuneus, prefrontal cortex, posterior cingulate cortex (PCC), anterior cingulate cortex (ACC), insula, supramarginal gyrus (SMG), and putamen. Compared with the HCs, V1, V2, and MT+ in the PAs exhibited decreased FC with the V1, V2, MT+, fusiform, BA37, and increased FC primarily in the bilateral temporal lobe (especially BA20,21,22), prefrontal cortex, PCC, insular, angular gyrus, ACC, pre SMA, SMG, hippocampal formation, caudate and putamen. It is worth mentioning that compared with HCs, V1 in PAs exhibited decreased or similar FC with the thalamus, whereas V2 and MT+ exhibited increased FCs with the thalamus, especially pulvinar. CONCLUSIONS: In our study, we identified significant neural reorganization in the vision-related cortex of PA patients with visual damage compared with HCs. Most subareas within the visual cortex exhibited remarkable neural dysfunction. Some subareas, including the MT+ and V2, exhibited enhanced FC with the thalamic pulvinar, which indicates an important role in the compensatory mechanism following visual impairment. In addition, neural dysfunction within the visual cortex was associated with neural activity alternation in the higher-order cognitive cortex, especially subareas in default mode network (DMN) and salience network (SN). PMID- 27512991 TI - Role of SpdA in Cell Spreading and Phagocytosis in Dictyostelium. AB - Dictyostelium discoideum is a widely used model to study molecular mechanisms controlling cell adhesion, cell spreading on a surface, and phagocytosis. In this study we isolated and characterize a new mutant created by insertion of a mutagenic vector in the heretofore uncharacterized spdA gene. SpdA-ins mutant cells produce an altered, slightly shortened version of the SpdA protein. They spread more efficiently than WT cells when allowed to adhere to a glass substrate, and phagocytose particles more efficiently. On the contrary, a functional spdA knockout mutant where a large segment of the gene was deleted phagocytosed less efficiently and spread less efficiently on a substrate. These phenotypes were highly dependent on the cellular density, and were most visible at high cell densities, where secreted quorum-sensing factors inhibiting cell motility, spreading and phagocytosis are most active. These results identify the involvement of SpdA in the control of cell spreading and phagocytosis. The underlying molecular mechanisms, as well as the exact link between SpdA and cell spreading, remain to be established. PMID- 27512992 TI - Higher Ammonium Transamination Capacity Can Alleviate Glutamate Inhibition on Winter Wheat (Triticum aestivum L.) Root Growth under High Ammonium Stress. AB - Most of the studies about NH4+ stress mechanism simply address the effects of free NH4+, failing to recognize the changed nitrogen assimilation products. The objective of this study was to elucidate the effects of glutamate on root growth under high ammonium (NH4+) conditions in winter wheat (Triticum aestivum L.). Hydroponic experiments were conducted using two wheat cultivars, AK58 (NH4+ sensitive) and Xumai25 (NH4+-tolerant) with either 5 mM NH4+ nitrogen (AN) as stress treatment or 5 mM nitrate (NO3-) nitrogen as control. To evaluate the effects of NH4+-assimilation products on plant growth, 1 MUM L-methionine sulfoximine (MSO) (an inhibitor of glutamine synthetase (GS)) and 1 mM glutamates (a primary N assimilation product) were added to the solutions, respectively. The AN significantly reduced plant biomass, total root length, surface area and root volume in both cultivars, but less effect was observed in Xumai25. The inhibition effects were alleviated by the application of MSO but strengthened by the application of glutamate. The AN increased the activities of GS, glutamate dehydrogenase (GDH) in both cultivars, resulting in higher glutamate contents. However, its contents were decreased by the application of MSO. Compared to AK58, Xumai25 showed lower glutamate contents due to its higher activities of glutamic oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT). With the indole-3-acetic acid (IAA) contents decreasing in roots, the ratio of shoot to root in IAA was increased, and further increased by the application of glutamate, and reduced by the application of MSO, but the ratio was lower in Xumai25. Meanwhile, the total soluble sugar contents and its root to shoot ratio also showed similar trends. These results indicate that the NH4+-tolerant cultivar has a greater transamination ability to prevent glutamate over-accumulation to maintain higher IAA transport ability, and consequently promoted soluble sugar transport to roots, further maintaining root growth. PMID- 27512993 TI - Keratin 17 Is Induced in Oral Cancer and Facilitates Tumor Growth. AB - Keratin subtypes are selectively expressed depending on the cell type. They not only provide structural support, but regulate the metabolic processes and signaling pathways that control the growth of the epithelium. KRT17 (keratin 17) is induced in the regenerative epithelium and acts on diverse signaling pathways. Here, we demonstrate that KRT17 is invariably and permanently induced in oral squamous cell carcinoma (OSCC), as revealed by immunohistochemistry and cDNA microarray analysis. Two representative OSCC cell lines; KRT17-weakly expressing Ca9-22 and KRT17-highly expressing HSC3 were used to establish KRT17 overexpressing Ca9-22 and KRT17-knockdown HSC3 cells. Analysis of these cells revealed that KRT17 promoted cell proliferation and migration by stimulating the Akt/mTOR pathway. KRT17 also upregulated the expression of SLC2A1 (solute carrier family 2 member 1/Glut1) and glucose uptake. To further investigate the effect of KRT17 on tumorigenesis, KRT17-knockout HSC3 cells were established and were transplanted to the cephalic skin of nude mice. The tumors that developed from KRT17-knockout HSC3 cells had a lower Ki-67 labeling index and were significantly smaller compared to the controls. These results indicate that KRT17 stimulates the Akt/mTOR pathway and glucose uptake, thereby facilitating tumor growth. We could not confirm the relationship between KRT17 and SFN (stratifin) in the cells examined in this study. However, our study reinforces the concept that the cellular properties of cancer are regulated by a series of molecules similar to those found in wound healing. In OSCC, KRT17 acts as a pathogenic keratin that facilitates tumor growth through the stimulation of multiple signaling pathways, highlighting the importance of KRT17 as a multifunctional promoter of tumorigenesis. PMID- 27512994 TI - A Cost-Effectiveness Tool to Guide the Prioritization of Interventions for Rheumatic Fever and Rheumatic Heart Disease Control in African Nations. AB - BACKGROUND: Rheumatic heart disease (RHD) prevalence and mortality rates remain especially high in many parts of Africa. While effective prevention and treatment exist, coverage rates of the various interventions are low. Little is known about the comparative cost-effectiveness of different RHD interventions in limited resource settings. We developed an economic evaluation tool to assist ministries of health in allocating resources and planning RHD control programs. METHODOLOGY/PRINCIPAL FINDINGS: We constructed a Markov model of the natural history of acute rheumatic fever (ARF) and RHD, taking transition probabilities and intervention effectiveness data from previously published studies and expert opinion. Our model estimates the incremental cost-effectiveness of scaling up coverage of primary prevention (PP), secondary prevention (SP) and heart valve surgery (VS) interventions for RHD. We take a healthcare system perspective on costs and measure outcomes as disability-adjusted life-years (DALYs), discounting both at 3%. Univariate and probabilistic sensitivity analyses are also built into the modeling tool. We illustrate the use of this model in a hypothetical low income African country, drawing on available disease burden and cost data. We found that, in our hypothetical country, PP would be cost saving and SP would be very cost-effective. International referral for VS (e.g., to a country like India that has existing surgical capacity) would be cost-effective, but building in country VS services would not be cost-effective at typical low-income country thresholds. CONCLUSIONS/SIGNIFICANCE: Our cost-effectiveness analysis tool is designed to inform priorities for ARF/RHD control programs in Africa at the national or subnational level. In contrast to previous literature, our preliminary findings suggest PP could be the most efficient and cheapest approach in poor countries. We provide our model for public use in the form of a Supplementary File. Our research has immediate policy relevance and calls for renewed efforts to scale up RHD prevention. PMID- 27512995 TI - Thrombomodulin Influences the Survival of Patients with Non-Metastatic Colorectal Cancer through Epithelial-To-Mesenchymal Transition (EMT). AB - BACKGROUND: Treatment resistance and metastasis are the major causes of death among patients with colorectal cancer (CRC). Approximately 20% of surgically treated patients ultimately develop metastases during the follow-up period. Currently, the TNM system is the only available prognostic test. Therefore, the identification of new markers for CRC remains important. Thrombomodulin (TM), a glycoprotein, is involved in angiogenesis and has been linked to many malignant diseases. However, the function of TM in CRC remains unclear. METHODS: A total of 170 patients with CRC participated in this study. TM expression was analyzed via immunohistochemistry. Univariate (Kaplan-Meier) analysis was used to analyze patient outcomes, including overall survival (OS) and disease-free survival (DFS). TM expression was manipulated using shRNA or an overexpression system. Transwell migration assays, wound healing migration assays, and the xCELLigence biosensor system were used to detect cell proliferative and migratory capacities. RESULTS: TM expression in the tumor tissues significantly and positively correlated with the DFS and OS of non-metastatic patients with CRC (ps = 0.036 and 0.0218, respectively). Suppression of TM expression increased the proliferation and migration of DLD-1 cells. TM overexpression reduced the cells' proliferative and migratory capacities. Cyclooxygenase (COX)-2 expression was up regulated following TM silencing. Furthermore, the association between the migration of colon cancer cells and the levels of TM and epithelial-to mesenchymal transition (EMT) markers (fibronectin, vimentin and ezrin) was confirmed in HT29 and DLD-1 cells. CONCLUSIONS: Our study demonstrates that patients with non-metastatic CRC display low TM expression in their tumors and exhibit reduced DFS and OS. The enhanced expression of mesenchymal markers and COX-2 may be involved in the mechanisms that underlie recurrence in patients with cancer displaying low TM expression. PMID- 27512996 TI - Incidence of X and Y Chromosomal Aneuploidy in a Large Child Bearing Population. AB - BACKGROUND: X&Y chromosomal aneuploidies are among the most common human whole chromosomal copy number changes, but the population-based incidence and prevalence in the child-bearing population is unclear. METHODS: This retrospective analysis of prospectively collected data leveraged a routine non invasive prenatal test (NIPT) using parental genotyping to estimate the population-based incidence of X&Y chromosome variations in this population referred for NIPT (generally due to advanced maternal age). RESULTS: From 141,916 women and 29,336 men, 119 X&Y chromosomal abnormalities (prevalence: 1 in 1,439) were identified. Maternal findings include: 43 cases of 45,X (40 mosaic); 30 cases of 47,XXX (12 mosaic); 3 cases of 46,XX uniparental disomy; 2 cases of 46,XY/46,XX; 23 cases of mosaicism of unknown type; 2 cases of 47,XX,i(X)(q10). Paternal findings include: 2 cases of 47,XXY (1 mosaic); 10 cases of 47,XYY (1 mosaic); 4 partial Y deletions. CONCLUSIONS: Single chromosome aneuploidy was present in one of every 1,439 individuals considered in this study, showing 47,XXX; 47,XX,i(X)(q10); 47,XYY; 47,XXY, partial Y deletions, and a high level of mosaicism for 45,X. This expands significantly our understanding of X&Y chromosomal variations and fertility issues, and is critical for families and adults affected by these disorders. This current and extensive information on fertility will be beneficial for genetic counseling on prenatal diagnoses as well as for newly diagnosed postnatal cases. PMID- 27512997 TI - Understanding the Pathogenicity of Burkholderia contaminans, an Emerging Pathogen in Cystic Fibrosis. AB - Several bacterial species from the Burkholderia cepacia complex (Bcc) are feared opportunistic pathogens that lead to debilitating lung infections with a high risk of developing fatal septicemia in cystic fibrosis (CF) patients. However, the pathogenic potential of other Bcc species is yet unknown. To elucidate clinical relevance of Burkholderia contaminans, a species frequently isolated from CF respiratory samples in Ibero-American countries, we aimed to identify its key virulence factors possibly linked with an unfavorable clinical outcome. We performed a genome-wide comparative analysis of two isolates of B. contaminans ST872 from sputum and blood culture of a female CF patient in Argentina. RNA-seq data showed significant changes in expression for quorum sensing-regulated virulence factors and motility and chemotaxis. Furthermore, we detected expression changes in a recently described low-oxygen-activated (lxa) locus which encodes stress-related proteins, and for two clusters responsible for the biosynthesis of antifungal and hemolytic compounds pyrrolnitrin and occidiofungin. Based on phenotypic assays that confirmed changes in motility and in proteolytic, hemolytic and antifungal activities, we were able to distinguish two phenotypes of B. contaminans that coexisted in the host and entered her bloodstream. Whole genome sequencing revealed that the sputum and bloodstream isolates (each representing a distinct phenotype) differed by over 1,400 mutations as a result of a mismatch repair-deficient hypermutable state of the sputum isolate. The inferred lack of purifying selection against nonsynonymous mutations and the high rate of pseudogenization in the derived isolate indicated limited evolutionary pressure during evolution in the nutrient-rich, stable CF sputum environment. The present study is the first to examine the genomic and transcriptomic differences between longitudinal isolates of B. contaminans. Detected activity of a number of putative virulence factors implies a genuine pathogenic nature of this novel Bcc species. PMID- 27512998 TI - Re-Cloning the N27 Dopamine Cell Line to Improve a Cell Culture Model of Parkinson's Disease. AB - Parkinson's disease is characterized by the death of dopaminergic neurons in the substantia nigra. To understand the molecular mechanisms of the disease, an in vitro model is important. In the 1990s, we used the SV40 large T antigen to immortalize dopaminergic neurons derived from Embryonic Day 14 rat mesencephalon. We selected a clone for its high expression of dopaminergic neuron markers such as tyrosine hydroxylase (TH), and we named it 1RB3AN27 (N27). Because the original N27 cell line has been passaged many times, the line has become a mixture of cell types with highly variable expression of TH. In the current study, we have performed multiple rounds of clonal cultures and have identified a dopaminergic cell clone expressing high levels of TH and the dopamine transporter (DAT). We have named this new clone N27-A. Nearly 100% of N27-A cells express TH, DAT and Tuj1. Western blots have confirmed that N27-A cells have three to four times the levels of TH and DAT compared to the previous mixed population in N27. Further analysis has shown that the new clone expresses the dopamine neuron transcription factors Nurr1, En1, FoxA2 and Pitx3. The N27-A cells express the vesicular monoamine transporter (VMAT2), but do not express dopamine-beta hydroxylase (DbetaH), the enzyme responsible for converting dopamine to norepinephrine. Functional analysis has shown that N27-A cells are more sensitive than N27 cells to neurotoxins taken up by the dopamine transporter such as 6 hydroxydopamine and 1-methyl-4-phenylpyridine (MPP+). The DAT inhibitor nomifensine can block MPP+ induced toxicity. The non-selective toxic effects of hydrogen peroxide were similar in both cell lines. The N27-A cells show dopamine release under basal and depolarization conditions. We conclude that the new N27-A clone of the immortalized rat dopaminergic cell line N27 should provide an improved in vitro model for Parkinson's disease research. PMID- 27512999 TI - The Mass Loss and Humification of Stumps and Roots in Masson Pine Plantations Based on Log File Records. AB - Stumps account for a large proportion of coarse woody debris in managed forests, but their decay dynamics are poorly understood. The loss of mass and the degree of humification of the above-ground woody debris, below-ground woody debris, bark and root system (R1, 10 mm >= diameter > 0 mm; R2, 25 mm >= diameter >10 mm; 100 mm >= R3 > 25 mm; R4 > 100 mm) of Masson pine (Pinus massoniana) stump systems were evaluated in southwestern China in a chronosequence of plantations cut 1-15 years prior to the study. The results indicated that above-ground woody debris decomposed more quickly than below-ground woody debris and bark, whereas the degree of humification followed the opposite trend. Compared with one-year stumps, the mass losses of 15-year stump systems were 60.4% for above-ground woody debris, 42.1% for below-ground woody debris, 47.3% for bark, 69.9% for R1, 47.3% for R2, 51.0% for R3, and 83.2% for R4. In contrast, below-ground woody debris showed a greater degree of humification compared with other components in the stump system. Among the root system, fine roots (R1, diameter <= 10 mm) had the largest k value (0.09), whereas the decay rate of coarser roots (R2, R3, R4; diameter > 10 mm) increased with increasing root diameter. However, coarse roots showed a larger degree of humification (0.2-0.6) than fine roots (0.3-0.4). These results suggest that below-ground woody debris and coarse roots may display a higher degree of humification, showing greater short-term contributions to overall humification when compared with the other components in the stump system. PMID- 27513000 TI - PSO-Based Smart Grid Application for Sizing and Optimization of Hybrid Renewable Energy Systems. AB - This paper introduces an optimal sizing algorithm for a hybrid renewable energy system using smart grid load management application based on the available generation. This algorithm aims to maximize the system energy production and meet the load demand with minimum cost and highest reliability. This system is formed by photovoltaic array, wind turbines, storage batteries, and diesel generator as a backup source of energy. Demand profile shaping as one of the smart grid applications is introduced in this paper using load shifting-based load priority. Particle swarm optimization is used in this algorithm to determine the optimum size of the system components. The results obtained from this algorithm are compared with those from the iterative optimization technique to assess the adequacy of the proposed algorithm. The study in this paper is performed in some of the remote areas in Saudi Arabia and can be expanded to any similar regions around the world. Numerous valuable results are extracted from this study that could help researchers and decision makers. PMID- 27513001 TI - The Effect of Afforestation on Soil Moisture Content in Northeastern China. AB - Widespread afforestation programs sequester carbon from the atmosphere and mitigate the rising of atmospheric carbon dioxide (CO2). Meanwhile, afforestation carbon sequestration may cost soil water. However, changes in soil moisture content (SMC) after large-scale afforestation or reforestation have rarely been quantified. In this study, we measured changes in SMC following afforestation using a paired plots method with data from 757 plots in Northeastern China. We found a marginally significant decline in soil moisture content of the top 1-m soil (SMC0-1m) after afforestation (P = 0.08) at the regional scale. The SMC responses to afforestation also vary across species. For example, significant SMC decrease are found for Populus spp. plantations (P < 0.05) and plantations of Pinus sylvestris var. mongolica (P < 0.05). Splitting the first meter of the soil profile into different depth intervals revealed that SMC declined significantly in shallow layers (0-30 cm) for Populus spp. and Pinus sylvestris var. mongolica. We also found that when SMC in the control exceeded a specific threshold, SMC for all five tree species considered tended to decrease, suggesting that the effects of afforestation on soil hydrology vary across different regions. PMID- 27513002 TI - Association of grade configuration with school climate for 7th and 8th grade students. AB - Educational authorities have questioned whether middle schools provide the best school climate for 7th and 8th grade students, and proposed that other grade configurations such as K-8th grade schools may provide a better learning environment. The purpose of this study was to compare 7th and 8th grade students' perceptions of 4 key features of school climate (disciplinary structure, student support, student engagement, and prevalence of teasing and bullying) in middle schools versus elementary or high schools. Multilevel multivariate modeling in a statewide sample of 39,036 7th and 8th grade students attending 418 schools revealed that students attending middle schools had a more negative perception of school climate than students in schools with other grade configurations. Seventh grade students placed in middle schools reported lower disciplinary structure and a higher prevalence of teasing and bullying in comparison to those in elementary schools. Eighth grade students in middle schools reported poorer disciplinary structure, lower student engagement, and a higher prevalence of teasing and bullying compared to those in high schools. These findings can guide school psychologists in identifying aspects of school climate that may be troublesome for 7th and 8th grade students in schools with different grade configurations. (PsycINFO Database Record PMID- 27513004 TI - Synthesis of 3-Cyano-1H-indoles and Their 2'-Deoxyribonucleoside Derivatives through One-Pot Cascade Reactions. AB - An efficient and economical synthetic approach toward 3-cyano-1H-indoles through the reactions of 2-(2-bromophenyl)acetonitriles with aldehydes and aqueous ammonia is presented. Mechanically, this novel protocol involves a one-pot cascade procedure consisting of an aldol-type condensation, a copper-catalyzed amination by using aqueous ammonia as a cheap and safe nitrogen source, and an intramolecular Michael addition followed by a dehydrogenative aromatization. Interestingly, the indole products thus obtained were found to be ready substrates for the preparation of indole 2'-deoxyribonucleosides through an unprecedented and highly practical glycosylation procedure in which the required C-N bond formation and toluoyl protecting group removal were accomplished efficiently in one pot. PMID- 27513005 TI - Origin and Luminescence of Anomalous Red-Emitting Center in Rhombohedral Ba9Lu2Si6O24:Eu(2+) Blue Phosphor. AB - We obtain a blue phosphor, Ba9Lu2Si6O24:Eu(2+) (BLS:Eu(2+)), which shows a strong emission peak at 460 nm and a weak tail from 460 to 750 nm. A 610 nm red emission is observed for the first time in this kind of rhombohedral structure material, which is much different from the same crystal structure of Ba9Sc2Si6O24:Eu(2+) and Ba9Y2Si6O24:Eu(2+). The luminescence properties and decays from 10 to 550 K are discussed. The new red emission arises from a trapped exciton state of Eu(2+) at the Ba site with a larger coordination number (12-fold). It exhibits abnormal luminescence properties with a broad bandwidth and a large Stokes shift. Under the 400 nm excitation, the external quantum efficiency of BLS:Eu(2+) is 45.4%, which is higher than the 35.7% for the commercial blue phosphor BAM:Eu(2+). If the thermal stability of BLS:Eu(2+) can be improved, it will show promising applications in efficient near-UV-based white LEDs. PMID- 27513007 TI - The Silicon Version of Phosphine Chalcogenides: Synthesis and Bonding Analysis of Stabilized Heavy Silaaldehydes. AB - The synthesis of chalcogena-silaaldehydes (Ch = S, Se, Te), 15, stabilized by interaction with N-heterocylic carbenes (NHCs) is reported. Compounds 15 are formed by reaction of the NHC-stabilized hydridosilylene 13a with elemental chalcogens in moderate yields. X-ray diffraction analysis of all three variants of the chalcogena-silaaldehydes, 15, revealed short Si/Ch distances which are close to expected values for Si?Ch double bonds. The results of natural bond orbital and natural resonance theory analyses indicate strongly polarized Si-Ch bonds and suggest the occurrence of negative hyperconjugation, which is responsible for the short Si/Ch distances. These results indicate the isolobal relation between NHC-stabilized heavy silaaldehydes 15 and the well-known phosphine chalcogenides, R3PCh. PMID- 27513006 TI - Identification of a Cyanine-Dye Labeled Peptidic Ligand for Y1R and Y4R, Based upon the Neuropeptide Y C-Terminal Analogue, BVD-15. AB - Traceable truncated Neuropeptide Y (NPY) analogues with Y1 receptor (Y1R) affinity and selectivity are highly desirable tools in studying receptor location, regulation, and biological functions. A range of fluorescently labeled analogues of a reported Y1R/Y4R preferring ligand BVD-15 have been prepared and evaluated using high content imaging techniques. One peptide, [Lys(2)(sCy5), Arg(4)]BVD-15, was characterized as an Y1R antagonist with a pKD of 7.2 measured by saturation analysis using fluorescent imaging. The peptide showed 8-fold lower affinity for Y4R (pKD = 6.2) and was a partial agonist at this receptor. The suitability of [Lys(2)(sCy5), Arg(4)]BVD-15 for Y1R and Y4R competition binding experiments was also demonstrated in intact cells. The nature of the label was shown to be critical with replacement of sCy5 by the more hydrophobic Cy5.5 resulting in a switch from Y1R antagonist to Y1R partial agonist. PMID- 27513008 TI - Human Toll-like Receptor (TLR) 8-Specific Agonistic Activity in Substituted Pyrimidine-2,4-diamines. AB - Activation of human toll-like receptor-8 (TLR8) evokes a distinct cytokine profile favoring the generation of Type 1 helper T cells. A multiplexed high throughput screen had led to the identification of N(4)-butyl-5-iodo-6 methylpyrimidine-2,4-diamine as a pure TLR8 agonist, and a detailed structure activity relationship study of this chemotype was undertaken. A butyl substituent at N(4) was optimal, and replacement of the 5-iodo group with chloro, bromo, or fluoro groups led to losses in potency, as did the introduction of aromatic bulk. Drawing from our previous structure-based design, several 5-alkylamino derivatives were evaluated. Significant enhancement of potency was achieved in 5 (4-aminobutyl)-N(4)-butyl-6-methylpyrimidine-2,4-diamine. This compound potently induced Th1-biasing IFN-gamma and IL-12 in human blood, but lower levels of the proinflammatory cytokines IL-1beta, IL-6, and IL-8. These results suggest that the inflammatory and reactogenic propensities of this compound could be considerably more favorable than other TLR8 agonists under evaluation. PMID- 27513011 TI - Interactions of Nucleic Acid Bases with Temozolomide. Stacked, Perpendicular, and Coplanar Heterodimers. AB - Temozolomide (TMZ) was paired with each of the five nucleic acid bases, and the potential energy surface searched for all minima, in the context of dispersion corrected density functional theory and MP2 methods. Three types of arrangements were observed, with competitive stabilities. Coplanar H-bonding structures, reminiscent of Watson-Crick base pairs were typically the lowest in energy, albeit by a small amount. Also very stable were perpendicular arrangements that included one or more H-bonds. The two monomers were stacked approximately parallel to one another in the third category, some of which contained weak and distorted H-bonds. Dispersion was found to be a dominating attractive force, largest for the stacked structures, and smallest for the coplanar dimers. PMID- 27513013 TI - Efficient Pathway for Preparing Hollow Particles: Site-Specific Crosslinking of Spherical Polymer Particles with Photoresponsive Groups That Play a Dual Role in Shell Crosslinking and Core Shielding. AB - Site-specific a posteriori photocrosslinking of homogeneous spherical polymer particles and subsequent removal of the particle core-the self-templating strategy-has been developed as an efficient pathway for hollow particle formation. In this approach, homogeneous polymer particles containing linear polymers bearing post-crosslinkable side-chain groups are first synthesized, and the photoinduced crosslinking occurred only at the shell region in the homogeneous polymer particles. Our fundamental studies clarified that the remaining non-crosslinked photoresponsive groups in the shell region played a crucial role in shielding the core region from photoirradiation. The shell selective crosslinking was successfully applied to hollow polymer particle formation by core removal. This facile route to polymeric hollow particle formation via a self-templating strategy has great potential to be used as an alternative because the route has high mass productivity and high simplicity as a result of the non-use of additional sacrificial template particles and highly toxic solvents. PMID- 27513014 TI - Submillisecond Dynamics of Mastoparan X Insertion into Lipid Membranes. AB - The mechanism of protein insertion into a lipid bilayer is poorly understood because the kinetics of this process is difficult to measure. We developed a new approach to study insertion of the antimicrobial peptide Mastoparan X into zwitterionic lipid vesicles, using a laser-induced temperature-jump to initiate insertion on the microsecond time scale and infrared and fluorescence spectroscopies to follow the kinetics. Infrared probes the desolvation of the peptide backbone and yields biphasic kinetics with relaxation lifetimes of 12 and 117 MUs, whereas fluorescence probes the intrinsic tryptophan residue located near the N-terminus and yields a single exponential phase with a lifetime of 440 MUs. Arrhenius analysis of the temperature-dependent rates yields an activation energy for insertion of 96 kJ/mol. These results demonstrate the complexity of the insertion process and provide mechanistic insight into the interplay between peptides and the lipid bilayer required for peptide transport across cellular membranes. PMID- 27513017 TI - Significant Improvement in Thermal and UV Resistances of UHMWPE Fabric through in Situ Formation of Polysiloxane-TiO2 Hybrid Layers. AB - Anatase nanocrystalline titanium dioxide coatings were produced on ultrahigh molecular weight polyethylene (UHMWPE) fabric by radiation-induced graft polymerization of gamma-methacryloxypropyl trimethoxysilane (MAPS) and subsequent cohydrolysis of the graft chains (PMAPS) with tetrabutyl titanate, followed by boiling water treatment for 180 min. The resulting material was coded as UHMWPE-g PMAPS/TiO2 and characterized by attenuated total reflection infrared spectrometry, differential scanning calorimetry, X-ray diffraction, thermal gravimetry, and ultraviolet absorption spectroscopy, among others. The predominant form of TiO2 in the thin film was anatase. The coating layer was composed of two sublayers: an inner part consisting of an organic-inorganic hybrid layer to prevent photocatalytic degradation of the matrix by TiO2 film, and an outer part consisting of anatase nanocrystalline TiO2 capable of UV absorption. This UHMWPE-g-PMAPS/TiO2 composite exhibited much better thermal resistance than conventional UHMWPE fabric, as reflected by the higher melting point, decreased maximum degradation rate, and higher char yield at 700 degrees C. Compared with UHMWPE fabric, UHMWPE-g-PMAPS/TiO2 exhibited significantly enhanced UV absorption and excellent duration of UV illumination. Specifically, the UV absorption intensity was 2.4-fold higher than that of UHMWPE fabric; the retention of the break strength of UHMWPE-g-PMAPS/TiO2 reached 92.3% after UV irradiation. This work provides an approach for addressing the issue of self degradation of TiO2-coated polymeric materials due to the inherent photoactivity of TiO2. PMID- 27513018 TI - Lessons from Genome Wide Association Studies. PMID- 27513019 TI - Lessons from Genome-Wide Association Studies in Reproductive Medicine. PMID- 27513020 TI - An Introduction to Genome-Wide Association Studies: GWAS for Dummies. AB - Although the genetic origin of many human diseases and phenotypes has been long and widely recognized, identification of the causative gene alleles has been limited, slow, and cumbersome. This has changed substantially with the introduction of genome-wide association studies (GWASs) a decade ago, fueled by studies and reference projects of human genetic diversity and the development of novel DNA analysis technology applicable to high-throughput and large-scale data generation. Although GWASs essentially combine epidemiological study designs with molecular genetic analysis techniques, it has also fundamentally changed the way in which research was done in human genetics by the introduction of large consortia of collaborating investigators. GWASs have over flooded many clinical and basic research areas with gene discoveries, including those in reproductive medicine. This review describes aspects of GWAS methodology and how this field of human genetics is developing. PMID- 27513021 TI - Genetics, Genome-Wide Association Studies, and Menarche. AB - Puberty is characterized by maturation of the hypothalamic-pituitary-gonadal axis, development of secondary sexual features, increased linear growth velocity, maturation of the epiphyses limiting additional growth, and achievement of menarche. The age at menarche appears to have a significant genetic component. With the advent of genome-wide association studies (GWASs), the genome has been interrogated to find associations between specific loci and age at menarche. It is apparent that multiple genetic loci, epigenetic mechanisms, and environmental factors modulate this biological event crucial for reproductive competence. PMID- 27513022 TI - Lessons from Genome-Wide Association Studies in Reproductive Medicine: Menopause. AB - In recent years, common genetic variants have been identified by genome-wide association studies (GWASs) that have led to the detection of 44 genetic loci associated with approximately 6% of common variation in age at natural menopause. In the latest GWAS, doubling the sample size to approximately 70,000 women more than doubled the number of signals identified, from 17 to 56. In addition, low frequency coding variants (< 5% minor allele frequency), with relatively large effect sizes, have been identified in two genes, by analyzing genome-wide exome data. GWAS has been very successful in identifying novel biological pathways involved in reproductive aging. Approximately two-thirds of the loci reported so far include genes involved in DNA damage response (DDR), highlighting the importance of this pathway in determining oocyte reserve. In addition, GWAS demonstrates that the hypothalamic-pituitary axis is involved in menopause timing as well as puberty timing, showing the first genetic link between timing of the start and end of reproductive life. Genetic variants have been used to explore the causal relationships between menopause timing and breast cancer. These studies demonstrate that for a 1 year increase in menopause age, there is a 6% increase in breast cancer risk, a value approximately double the estimate from epidemiological studies. Prolonged exposure to estrogen during reproductive life is the likely mechanism, rather than a direct effect of DDR variants on cancer risk. Further work is needed to determine the mechanism for the effect of each variant identified by GWAS and more variants will undoubtedly be discovered as sample sizes increase, denser single nucleotide polymorphism arrays and reference genomes are used, and populations from diverse ethnic groups are studied. PMID- 27513023 TI - Genome-Wide Association Studies for Polycystic Ovary Syndrome. AB - Over the past several years, the field of reproductive medicine has witnessed great advances in genome-wide association studies (GWASs) of polycystic ovary syndrome (PCOS), leading to identification of several promising genes involved in hormone action, type 2 diabetes, and cell proliferation. This review summarizes the key findings and discusses their potential implications with regard to genetic mechanisms of PCOS. Limitations of GWAS are evaluated, emphasizing the understanding of the reasons for variability in results between individual studies. Root causes of misinterpretations of GWASs are also addressed. Finally, the impact of GWAS on future directions of multi- and interdisciplinary studies is discussed. PMID- 27513024 TI - Primary Ovarian Insufficiency. AB - Primary ovarian insufficiency (POI), also known as premature ovarian failure or premature menopause, is defined as cessation of menstruation before the expected age of menopause. Potential etiologies for POI can be divided into genetic, autoimmune, and iatrogenic categories. This review will try to summarize the genetic basis of POI focusing on recent data that are available using newer genetic techniques such as genome-wide association studies, whole-exome sequencing (WES), or next-generation sequencing techniques. By using these techniques, many genes have arisen that play some role in the pathophysiology of POI. Some of them have been replicated in other studies; however, the majority has not been proven yet to be unequivocally causative through functional validation studies. Elucidating the genetic and molecular basis of POI is of paramount importance not only in understanding ovarian physiology but also in providing genetic counseling and fertility guidance. Once additional variants are detected, it might become possible to predict the age of (premature) menopause in women at risk for POI. Women having certain perturbations of POI can be offered the option of oocyte cryopreservation, with later thawing and use in assisted reproductive technology at an appropriate age. PMID- 27513025 TI - Genetic Association Studies in Uterine Fibroids: Risk Alleles Presage the Path to Personalized Therapies. AB - Uterine leiomyoma (UL) is the most common tumor of the female reproductive system. Epidemiological analyses, including familial aggregation, twin studies, and racial discrepancies in disease prevalence and morbidity, indicated genetic factors influence risk for developing UL. Genome-wide association studies (GWASs) are a powerful method for identifying genetic variants that are associated with elevated risk for a common, complex disease. To date, three genome-wide scans for UL have been performed: a GWAS in Japanese women, a genome-wide linkage and association study in women of European decent, and an admixture-based analysis in African American women. Results from each of the three genome-wide scans performed have had varying success in identifying unique loci associated with predisposition to developing UL. Here, we address the evidence for a genetic basis for UL risk, discuss genetic association studies and their results, and identify challenges and future directions for UL GWAS analyses. PMID- 27513027 TI - Benefit of TeamSTEPPS Rounding Improvement Project on Infection-Related Monitoring. AB - BACKGROUND: Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS) was developed to improve teamwork and patient safety. It was shown to benefit patient care in complex clinical settings including intensive care units (ICUs). Our two trauma/surgical ICUs received TeamSTEPPS training, but only Unit 1 participated in a TeamSTEPPS Rounding Improvement Project (TRIP). Our goal was to assess any unintended benefit to infection-related monitoring and prevention from TRIP. We hypothesized that TRIP implementation in ICUs would be associated with increased monitoring, resulting in improved antibiotic and invasive catheter/tube stewardship. METHODS: From September through November 2014, observers prospectively collected data on rounds in both units. Unit personnel were blinded to the data collection process. Monitoring parameters obtained for each patient encounter included review of invasive catheter/tube presence and review of antibiotic indication and course. For patients who received antibiotic and had invasive catheter/tube, we conducted a retrospective review for treatment parameters such as antibiotic duration and adherence to treatment plan, inappropriate antibiotics duration, and invasive catheter/tube duration. RESULTS: A total of 416 patient encounters were observed. The use of invasive catheter/tube was reviewed on rounds substantially more in Unit 1 than Unit 2 (83% vs. 51%, p < 0.005). In the 135 encounters with patients on antibiotic, review of antibiotic indication, stop date, day into course, and all three components occurred substantially more in Unit 1. On the basis of the 65 different antibiotic courses encompassed by the 135 encounters, antibiotic duration, adherence to antibiotic treatment plan, and inappropriate antibiotic days were not substantially different between the units. From the same 135 encounters, 125 encounters also had invasive catheter/tube placement. Substantially more discussion of catheter/tube presence occurred in Unit 1, but the duration of its presence was not substantially different. CONCLUSION: The TeamSTEPPS Rounding Improvement Project was associated with an unintended, increased discussion and monitoring of antibiotic and invasive catheter/tube usage. However, this did not translate into substantial immediate treatment differences. PMID- 27513028 TI - Synthesis and Properties of Sila[n]helicenes via Dehydrogenative Silylation of C H Bonds under Rhodium Catalysis. AB - Use of a rhodium catalyst with (R)-(S)-BPPFA ligand allows efficient synthesis of sila[n]helicenes via dehydrogenative silylation of C-H bonds. By selecting the proper ligands, the current method provides the ability to prepare unsymmetrical sila[n]helicene derivatives without any oxidants. The resulting sila[6]helicene is a rare example of a five-membered ring-fused [6]helicene, which was isolated as a single pure enantiomer without substituents on the terminal benzene rings. PMID- 27513026 TI - Beyond Endometriosis Genome-Wide Association Study: From Genomics to Phenomics to the Patient. AB - Endometriosis is a heritable, complex chronic inflammatory disease, for which much of the causal pathogenic mechanism remains unknown. Genome-wide association studies (GWAS) to date have identified 12 single nucleotide polymorphisms at 10 independent genetic loci associated with endometriosis. Most of these were more strongly associated with revised American Fertility Society stage III/IV, rather than stage I/II. The loci are almost all located in intergenic regions that are known to play a role in the regulation of expression of target genes yet to be identified. To identify the target genes and pathways perturbed by the implicated variants, studies are required involving functional genomic annotation of the surrounding chromosomal regions, in terms of transcription factor binding, epigenetic modification (e.g., DNA methylation and histone modification) sites, as well as their correlation with RNA transcription. These studies need to be conducted in tissue types relevant to endometriosis-in particular, endometrium. In addition, to allow biologically and clinically relevant interpretation of molecular profiling data, they need to be combined and correlated with detailed, systematically collected phenotypic information (surgical and clinical). The WERF Endometriosis Phenome and Biobanking Harmonisation Project is a global standardization initiative that has produced consensus data and sample collection protocols for endometriosis research. These now pave the way for collaborative studies integrating phenomic with genomic data, to identify informative subtypes of endometriosis that will enhance understanding of the pathogenic mechanisms of the disease and discovery of novel, targeted treatments. PMID- 27513029 TI - Influence of skeletal class in the morphology of cervical vertebrae: A study using cone beam computed tomography. AB - OBJECTIVES: To quantify the prevalence of cervical vertebrae anomalies and to analyze any association between them and skeletal malocclusions or head posture positions in the same study. MATERIALS AND METHODS: Two hundred forty patients who were attending the Department of Orthodontics of the University of Valencia for orthodontic treatment were selected and divided into three groups: skeletal Class I (control group, 0 degrees = 4 degrees ), and Class III (ANB <= 0 degrees ) according to ANB Steiner angle. The morphology of the first five cervical vertebrae was analyzed with cone beam computed tomography to identify any anomalies. Intra- and interobserver error methods were calculated. RESULTS: Dehiscence and fusion of one unit (both 23.3%) and partial cleft (11.7%) were the most frequent anomalies, while occipitalization was the least common (3.3%). Dehiscence anomaly was observed when the control group was compared with Classes II and III and partial cleft anomaly when Class I was compared with Class III. Furthermore, NSBa and ss-N sm/ANB angles were associated with partial cleft anomaly, while NSL/NL angle and extended head posture were associated with fusion anomaly. CONCLUSIONS: Fusion, dehiscence, and partial cleft were the most frequent cervical vertebrae anomalies. Dehiscence and partial cleft were found to present statistically significant differences between Class I and Classes II and III. Cervical vertebrae anomalies and head posture were associated with fusion. PMID- 27513030 TI - Modern trends in Class III orthognathic treatment: A time series analysis. AB - OBJECTIVE: To examine the current trends in surgical-orthodontic treatment for patients with Class III malocclusion using time-series analysis. MATERIALS AND METHODS: The records of 2994 consecutive patients who underwent orthognathic surgery from January 1, 2004, through December 31, 2015, at Seoul National University Dental Hospital, Seoul, Korea, were reviewed. Clinical data from each surgical and orthodontic treatment record included patient's sex, age at the time of surgery, malocclusion classification, type of orthognathic surgical procedure, place where the orthodontic treatment was performed, orthodontic treatment modality, and time elapsed for pre- and postoperative orthodontic treatment. RESULTS: Out of the orthognathic surgery patients, 86% had Class III malocclusion. Among them, two-jaw surgeries have become by far the most common orthognathic surgical treatment these days. The age at the time of surgery and the number of new patients had seasonal variations, which demonstrated opposing patterns. There was neither positive nor negative correlation between pre- and postoperative orthodontic treatment time. Elapsed orthodontic treatment time for both before and after Class III orthognathic surgeries has been decreasing over the years. CONCLUSION: Results of the time series analysis might provide clinicians with some insights into current surgical and orthodontic management. PMID- 27513031 TI - Eyes on New Product Development. PMID- 27513068 TI - High dielectric permittivity and improved mechanical and thermal properties of poly(vinylidene fluoride) composites with low carbon nanotube content: effect of composite processing on phase behavior and dielectric properties. AB - The composite processing technique and nanofiller concentration and its functionalization significantly alter the properties of polymer nanocomposites. To realize this, multi-walled carbon nanotubes (CNT) were dispersed in a poly(vinylidene fluoride) (PVDF) matrix at carefully selected CNT concentrations by two illustrious methods, such as solution-cast and melt-mixing. Notwithstanding the processing method, CNTs induced predominantly the gamma-phase in PVDF, instead of the commonly obtained beta-phase upon nanofiller incorporation, and imparted significant improvements in dielectric properties. Acid-treatment of CNT improved its dispersion and interfacial adhesion significantly with PVDF, and induced a higher gamma-phase content and better dielectric properties in PVDF as compared to pristine CNT. Further, the gamma phase content was found to be higher in solution-cast composites than that in melt-mixed counterparts, most likely due to solvent-induced crystallization in a controlled environment and slow solvent evaporation in the former case. However, interestingly, the melt-mixed composites showed a significantly higher dielectric constant at the onset of the CNT networked-structure as compared to the solution cast composites. This suggests the possible role of CNT breakage during melt mixing, which might lead to higher space-charge polarization at the polymer-CNT interface, and in turn an increased number of pseudo-microcapacitors in these composites than the solution-cast counterparts. Notably, PVDF with 0.13 vol% (volume fraction, f c = 0.0013) of acid-treated CNTs, prepared by melt-mixing, displayed the relative permittivity of ~217 and capacitance of ~5430 pF, loss tangent of ~0.4 at 1 kHz and an unprecedented figure of merit of ~10(5). We suggest a simple hypothesis for the gamma-phase formation and evolution of the high dielectric constant in these composites. Further, the high-dielectric composite film showed marked improvements in mechanical and thermal properties over the neat PVDF film. These composites with exceptional dielectric properties and concomitant improvement in mechanical and thermal properties offer a great promise for use in flexible and mechanically robust charge storage devices. PMID- 27513069 TI - Fucoidan reduces oxidative stress by regulating the gene expression of HO-1 and SOD-1 through the Nrf2/ERK signaling pathway in HaCaT cells. AB - Fucoidan, a sulfated polysaccharide, is found in edible brown algae. In the present study, the molecular mechanisms of fucoidan against mild oxidative stress in human keratinocytes were investigated. The current study indicated that fucoidan significantly augmented the antioxidants heme oxygenase-1 (HO-1) and superoxide dismutase-1 (SOD-1) via the upregulation of nuclear factor erythroid 2 related factor 2 (Nrf2) and markedly reduced the cytoplasmic stability of kelch like ECH-associated protein 1. The upregulation of HO-1 and SOD-1 detected in the fucoidan-treated cells may be responsible for the increased resistance to mild oxidative stress, indicating that fucoidan may augment the activities of antioxidant enzymes via stimulating Nrf2. This is the first report, to the best of our knowledge, to demonstrate that fucoidan attenuates oxidative stress by regulating the gene expression of SOD-1 and HO-1 via the Nrf2/extracellular signal-regulated kinase signaling pathway. PMID- 27513070 TI - Cardiovascular Health Status by Occupational Group - 21 States, 2013. AB - Cardiovascular disease (CVD) accounts for one of every three deaths in the United States, making it the leading cause of mortality in the country (1). The American Heart Association established seven ideal cardiovascular health behaviors or modifiable factors to improve CVD outcomes in the United States. These cardiovascular health metrics (CHMs) are 1) not smoking, 2) being physically active, 3) having normal blood pressure, 4) having normal blood glucose, 5) being of normal weight, 6) having normal cholesterol levels, and 7) eating a healthy diet (2). Meeting six or all seven CHMs is associated with a lower risk for all cause, CVD, and ischemic heart disease mortalities compared with the risk to persons who meet none or only one CHM (3). Fewer than 2% of U.S. adults meet all seven of the American Heart Association's CHMs (4). Cardiovascular morbidity and mortality account for an estimated annual $120 billion in lost productivity in the workplace; thus, workplaces are viable settings for effective health promotion programs (5). With over 130 million employed persons in the United States, accounting for about 55% of all U.S. adults, the working population is an important demographic group to evaluate with regard to cardiovascular health status. To determine if an association between occupation and CHM score exists, CDC analyzed data from the 2013 Behavioral Risk Factor Surveillance System (BRFSS) industry and occupation module, which was implemented in 21 states. Among all occupational groups, community and social services employees (14.6%), transportation and material moving employees (14.3%), and architecture and engineering employees (11.6%) had the highest adjusted prevalence of meeting two or fewer CHMs. Transportation and material moving employees also had the highest prevalence of "not ideal" ("0" [i.e., no CHMs met]) scores for three of the seven CHMs: physical activity (54.1%), blood pressure (31.9%), and weight (body mass index [BMI]; 75.5%). Disparities in cardiovascular health status exist among U.S. occupational groups, making occupation an important consideration in employer sponsored health promotion activities and allocation of prevention resources. PMID- 27513071 TI - Isolated (hypoxic) hepatic perfusion with high-dose chemotherapy in patients with unresectable liver metastases of uveal melanoma: results from two experienced centres. AB - Uveal melanoma patients have a poor survival after the diagnosis of metastatic disease. Isolated hepatic perfusion (IHP) was developed to treat patients with unresectable metastases confined to the liver. This retrospective analysis focuses on treatment characteristics, complications, toxicity and survival after IHP. Patients with uveal melanoma metastases confined to the liver treated with IHP in two experienced hepato-pancreatic-biliary surgery centres (Erasmus MC Cancer Institute and Leiden University Medical Center) were included. Between March 1999 and April 2009, 30 patients were treated with IHP. The duration of surgery was 3.7 h (Erasmus MC Cancer Institute) versus 8.7 h (Leiden University Medical Center) and also the dosage of melphalan differed: 1 mg/kg body weight (n=12) versus a dose of 170-200 mg (n=18) or melphalan (100 mg) combined with oxaliplatin (50 or 100 mg) (n=3). The length of hospital stay was 10 days. Two patients developed occlusion of the hepatic artery and died, respectively, 3 days and 1.5 months after surgery. Progression-free survival was 6 (1-16) months and recurrences occurred mainly in the liver. The median overall survival was 10 (3 50) months. IHP is a potentially beneficial treatment modality resulting in a reasonable overall survival for uveal melanoma patients. Because of considerable morbidity related to the open procedure, a percutaneous system has been developed and is currently being investigated. PMID- 27513072 TI - CE: Original Research: Predicting Injurious Falls in the Hospital Setting: Implications for Practice. AB - : BACKGROUND: Despite years of research and increasingly evidence-based practice, falls continue to be the most commonly reported adverse events experienced by hospitalized adults. Yet a majority of the relevant research has focused on predicting and preventing falls in general; there has been little focus on injurious falls. PURPOSE: The purpose of this retrospective study was to determine which patient factors are associated with injurious falls in hospitalized adults. METHODS: The study site's adverse event reporting database was used to identify 1,369 patients who fell between January 1, 2006, and October 31, 2013. Of these, 381 (27.8%) subjects suffered injurious falls. Variables of interest included age, sex, fall history, use of diuretics, use of central nervous system medications, cognitive impairment, primary discharge diagnoses, abnormal laboratory values, impaired mobility, and body mass index. FINDINGS: Bivariate analysis revealed a statistically significant association between injurious falls and having a primary discharge diagnosis of "symptoms, signs, and ill-defined conditions." Having this discharge diagnosis was a significant predictor of injurious falls. CONCLUSIONS: Findings from this study may help hospital clinicians to better identify which patients are most at risk for injurious falls and to create better fall-related injury prevention interventions. PMID- 27513073 TI - CE: Military Sexual Trauma in Male Service Members. AB - : The experience of military sexual trauma (MST), which can result from assault, battery, or harassment of a sexual nature, may jeopardize the mental health of service members as well as that of their family members, colleagues, and community members. Although a greater proportion of female than male service members are subjected to MST, the Department of Defense estimates that the absolute numbers of affected men and women, across all ranks and branches of military service, are nearly equal because roughly 85% of military members are men. Little research has explored the effects of MST on men. This article discusses the unique ways in which men may experience MST, and examines how social stereotypes of masculinity, myths surrounding sexual assault, and military culture and structure often influence a man's interpretation of an attack and his likelihood of reporting the incident or seeking treatment. It describes current treatments for MST-related mental health conditions and addresses implications for nurses and other health care professionals. PMID- 27513074 TI - Assessment of CK17 as a Marker for the Diagnosis of Differentiated Vulvar Intraepithelial Neoplasia. AB - Differentiated vulvar intraepithelial neoplasia (dVIN), precursor of vulvar squamous cell carcinoma, is human papilloma virus independent and often found in a background of lichen sclerosus (LS) and lichen simplex chronicus (LSC). Subtle histologic findings make the diagnosis of dVIN difficult, and, although the use of p53 and Ki-67 has been of some value, there is a need for a better immunohistochemical marker. Cytokeratin 17 (CK17), a cytoskeletal intermediate filament protein, has previously been used in the diagnosis of anogenital lesions. Here we evaluated CK17 in dVIN in comparison with LS, LSC, and usual VIN (uVIN/HSIL). Twenty-nine cases of dVIN, 9 cases of uVIN, 8 cases of LS, and 7 of LSC were evaluated using CK17, Ki-67, and p53. All 29 dVIN cases displayed immunoreactivity for CK17, with 27 (93%) showing intermediate to strong and diffuse reactivity. No cases of uVIN displayed diffuse CK17 expression, whereas 63% of LS and 29% of LSC displayed intermediate to strong diffuse immunoreactivity, confined to the upper half of the epithelium. P53 and Ki-67 expression was present in varying degrees in all types of lesions, displaying limited discriminatory power for dVIN. Our findings suggest that CK17, although not specific for dVIN, when combined with histologic findings, Ki-67, and p53 immunohistochemistry, can be a marker of vulvar dysplasia and serve as an adjunct in the diagnosis of dVIN. Specifically, in small biopsies, the presence of diffuse suprabasal or full thickness expression strongly favors a diagnosis of dVIN over LSC, whereas focal and/or superficial expression supports a diagnosis of LSC. PMID- 27513075 TI - Collision Signet-Ring Stromal Tumor and Steroid Cell Tumor of the Ovary: Report of the First Case. AB - To date, the vast majority of collision tumors in the ovary include either a teratoma, sex cord-stromal tumor, or both. Here we report the first case of a collision tumor consisting of a steroid cell tumor and a signet-ring stromal tumor. PMID- 27513076 TI - Metastatic Ovarian Tumors Originating From a Small Bowel Adenocarcinoma - A Case Report and Brief Literature Review. AB - Approximately 1.6% of tumors metastatic to the ovary of nongynecologic origin are from a small bowel adenocarcinoma (SBA). However, the incidence of SBA is extremely rare (0.23 cases/100,000 people), which suggests a high frequency of ovarian metastasis, although the reason is unknown. To identify the characteristics of ovarian tumor metastasis from SBA, we reviewed 72 cases reported in the English literature, including the case presented in this report. The mean age of the patients was 46.7 yr. Solitary ovarian metastasis was observed in 67% of the cases, and ovarian metastasis was accompanied by peritoneal dissemination in 33% of the cases. Although duodenal adenocarcinoma has the highest incidence among the SBAs, jejunal adenocarcinoma, particularly that at the proximal end, is the type of SBA that most frequently metastasizes to the ovary. Among the cases of ovarian metastasis from SBA, 51% were bilateral, 33% were unilateral to the right ovary, and 16% were unilateral to the left ovary. PMID- 27513077 TI - Mucinous Differentiation With Tumor Infiltrating Lymphocytes Is a Feature of Sporadically Methylated Endometrial Carcinomas. AB - Defects in the DNA mismatch-repair system are identified in ~25%-30% of endometrial carcinomas (ECs). Whereas some ECs are due to germline Lynch syndrome (LS)-associated mutations, the majority demonstrate sporadic MLH1 promoter hypermethylation (MLH1hm). MLH1hm characterizes a unique subset of colorectal cancers with a relatively poor prognosis; however, the morphology and behavior of sporadically methylated ECs (SMECs) are less well understood. We herein review the clinicopathologic features of 34 SMECs diagnosed at The University of Virginia and compare them with LS-associated and Lynch-like endometrial cancers. Most SMECs were centered in the uterine fundus (74%) and displayed Grade 1 (35%) or Grade 2 (41%) endometrioid morphology. Mucinous differentiation was present in 50%, and 65% showed tumor-infiltrating lymphocytes. Cases with undifferentiated components or sarcomatous differentiation were relatively rare (9%). Most SMECs presented at stage 1 or 2 (91%). When compared with LS and Lynch-like endometrial cancers, SMECs occurred ~8 yr later and were significantly more likely to show conventional endometrioid morphology (P=0.04), mucinous differentiation (P=0.002), and tumor-infiltrating lymphocytes (P=0.002). These findings suggest that SMECs constitute a clinicopathologically distinct subset of mismatch-repair deficient/high-level microsatellite instability tumors. Future studies are needed to further understand the implications of MLH1hm on the prognosis and treatment of endometrial cancer. PMID- 27513078 TI - Extrauterine Placental Site Trophoblastic Tumor Involving the Vagina. AB - Very few cases of placental site trophoblastic tumor (PSTT) primarily involving extrauterine sites have been reported to date. We report a case of a 29-year-old female who presented with a vaginal nodule 9 months after delivery at an outside hospital which was initially diagnosed as a poorly differentiated squamous cell carcinoma. Subsequently she was referred to our institute, and on the basis of histology, mildly elevated serum beta-HCG level, and immunohistochemistry, PSTT was diagnosed. After the completion of chemotherapy, the vaginal nodule completely regressed and serum beta-hCG returned to baseline. Her follow-up has been unremarkable. This case highlights the importance of the fact that PSTT can be easily misdiagnosed at extrauterine sites in the absence of proper clinical, histologic, and immunohistochemical correlation. PMID- 27513079 TI - Thin HSIL of the Cervix: Detecting a Variant of High-grade Squamous Intraepithelial Lesions With a p16INK4a Antibody. AB - The WHO defines thin high-grade squamous intraepithelial lesions (HSIL) as a high grade intraepithelial lesion of the cervix that is usually <=9 cells thick. These lesions usually develop in early metaplastic squamous epithelium without anteceding low-grade squamous intraepithelial lesions (LSIL). The prevalence of thin HSIL is not well documented. We evaluated different characteristics of thin HSIL at time of treatment. We studied 25 formalin-fixed and paraffin-embedded conization specimens processed as step-serial sections. HSIL<=9 cells thick were classified as thin HSIL. HSIL>=10 cells thick were classified as classic HSIL. Immunohistochemical p16 staining was used to confirm lesions of thin HSIL. Overall, 19 (76%) specimens contained both thin HSIL and classic HSIL, 4 (16%) contained thin HSIL only, 1 (4%) contained classic-type HSIL only, and 1 (4%) contained thin HSIL and LSIL. Thin HSILs developed in both the columnar surface epithelium and deep cervical glandular epithelium. Most thin HSILs were 5 cells thick. All HSILs (thin and classic) were located inside the transformation zone and had a median horizontal extension of 8 mm (range, 0.3 to 21 mm). Our findings suggest that thin HSILs are frequent findings, that they coexist with classic HSIL, and preferably arise in the exposed parts of the transformation zone including the glandular crypts. PMID- 27513080 TI - The Added Value of Pathology Review in Vulvar Cancer: Results From a Population based Cohort Study. AB - We conducted a population-based patterns of care study of vulvar carcinoma. This paper describes the changes in reporting based on pathology review. This is a retrospective population-based cohort study. We obtained all pathology records available from the provincial cancer registry for primary invasive squamous cell carcinoma of the vulva diagnosed between 1998 and 2007. Pathology reviews were conducted centrally by a group of gynecologic pathologists and were identified during abstraction. Corresponding original reports were matched to pathology review reports based on accession numbers. We compared the reported value for presence/absence of invasion, grade, depth, thickness, size, lymphovascular space invasion, peripheral margin status, and deep margin status in the original and review report. A total of 1011 vulvar resection reports were identified. From these, we identified 316 pairs of original/review reports. Missing data were common but improved in the reviews. In total, 55 (17%) reports had at least 1 change from the original to the review based on presence of invasion, depth, lymphovascular space invasion, or margin. When we included reports where a variable was missing in the original but then completed in the review, there were clinically relevant changes in 210 reports (66%). Vulvar carcinoma is a rare diagnosis and pathology reviews resulted in potentially important clinical changes in a significant proportion of cases. Referral pathologists play an important role in contributing to high-quality clinical decisions. PMID- 27513081 TI - Lipomatous Angiomyofibroblastoma of the Vulva: Report of a Rare Variant. AB - Angiomyofibroblastoma is a rare and benign tumor that usually involves vulvovaginal area in women of reproductive age and early menopause. We report a lipomatous angiomyofibroblastoma in a 55-year-old multigravid woman. This tumor measured 9 cm in size and contained prominent mature adipose tissue that comprised approximately 50% of the tumor. PMID- 27513082 TI - The AMPK Activator Aicar Ameliorates Age-Dependent Myocardial Injury in Murine Hemorrhagic Shock. AB - The development of myocardial dysfunction in patients with hemorrhagic shock is significantly impacted by the patient age. AMP-activated protein kinase (AMPK) is a pivotal orchestrator of energy homeostasis, which coordinates metabolic recovery after cellular stress. We investigated whether AMPK-regulated pathways are age-dependent in hemorrhage-induced myocardial injury and whether AMPK activation by 5-amino-4-imidazolecarboxamide riboside (AICAR) affords cardioprotective effects. Anesthetized C57/BL6 young (3-5 months old) and mature (9-12 months old) male mice were subjected to hemorrhagic shock by blood withdrawing followed by resuscitation with shed blood and Lactated Ringer's solution. Mice were sacrificed at 3 h after resuscitation, and plasma and hearts were harvested for biochemical assays. Vehicle-treated mature mice exhibited higher myocardial injury and higher levels of plasma biomarkers of cardiovascular injury (endocan and follistatin) when compared with young mice. Cardiac cell mitochondrial structure was also markedly impaired in vehicle-treated mature mice when compared with young mice. At molecular analysis, an increase of the phosphorylated catalytic subunit pAMPKalpha was associated with nuclear translocation of the peroxisome proliferator-activated receptor gamma coactivator alpha in young, but not mature mice. No changes in autophagy were observed as evaluated by the conversion of the light-chain (LC)3B-I protein to LC3B-II form. Treatment with AICAR ameliorated myocardial damage in both age groups. However, AICAR therapeutic effects were less effective in mature mice than young mice and involved distinct mechanisms of action. Thus, our data demonstrate that during hemorrhagic shock AMPK-dependent metabolic mechanisms are important for mitigating myocardial injury. However, these mechanisms are less competent with age. PMID- 27513083 TI - Circulatory Failure During Noninhaled Forms of Cyanide Intoxication. AB - Our objective was to determine how circulatory failure develops following systemic administration of potassium cyanide (KCN). We used a noninhaled modality of intoxication, wherein the change in breathing pattern would not influence the diffusion of CN into the blood, akin to the effects of ingesting toxic levels of CN. In a group of 300 to 400 g rats, CN-induced coma (CN i.p., 7 mg/kg) produced a central apnea within 2 to 3 min along with a potent and prolonged gasping pattern leading to autoresuscitation in 38% of the animals. Motor deficits and neuronal necrosis were nevertheless observed in the surviving animals. To clarify the mechanisms leading to potential autoresuscitation versus asystole, 12 urethane-anesthetized rats were then exposed to the lowest possible levels of CN exposure that would lead to breathing depression within 7 to 8 min; this dose averaged 0.375 mg/kg/min i.v. At this level of intoxication, a cardiac depression developed several minutes only after the onset of the apnea, leading to cardiac asystole as PaO2 reached value approximately 15 Torr, unless breathing was maintained by mechanical ventilation or through spontaneous gasping. Higher levels of KCN exposure in 10 animals provoked a primary cardiac depression, which led to a rapid cardiac arrest by pulseless electrical activity (PEA) despite the maintenance of PaO2 by mechanical ventilation. These effects were totally unrelated to the potassium contained in KCN. It is concluded that circulatory failure can develop as a direct consequence of CN-induced apnea but in a narrow range of exposure. In this "low" range, maintaining pulmonary gas exchange after exposure, through mechanical ventilation (or spontaneous gasping), can reverse cardiac depression and restore spontaneous breathing. At higher level of intoxication, cardiac depression is to be treated as a specific and spontaneously irreversible consequence of CN exposure, leading to a PEA. PMID- 27513084 TI - Simvastatin Attenuates Acute Lung Injury via Regulating CDC42-PAK4 and Endothelial Microparticles. AB - BACKGROUND: Simvastatin has lung vascular-protective effects via augmentation of endothelial barrier function. Accordingly, on the basis of our previous study, we hypothesized that endothelial cell (EC) protection by simvastatin is dependent on the stabilization on cytoskeletons. METHODS: Sixty C57BL/6 mice were divided into two experimental groups: lipopolysaccharide (LPS) group (L group) and LPS+simvastatin treated group (L+S group). All mice in these two groups received an intraperitoneal injection of LPS (10 mg/kg/d). Simvastatin was administered intraperitoneally immediately after the LPS injection in animals of the L+S group at a dose of 20 mg/kg/day. Lung injury degree and the protective effects of simvastatin against LPS-induced lung injury were assessed at the time-points of 24, 48, and 72 h postinjection. Serum alanine transaminase (ALT), serum creatinine (Scr) were identified to assess the hepatic and renal side-effects of simvastatin. RESULTS: LPS inhibited the cytoskeletal regulating proteins of Cdc42 and PAK4, and was accompanied by an increased circulating endothelial microparticles (EMPs) level. The adherent junction (AJ) protein of VE-cadherin was also decreased by LPS, and was accompanied by a thickening alveolar wall, increased lung W/D values, and high albumin concentration in bronchoalveolar lavage. Protective effects of simvastatin against LPS-induced lung injury were illustrated by regulating and stabilizing cytoskeletons, as well as intercellular AJs. The values of ALT and Scr were all lower than the common upper limits according to assay kits. CONCLUSION: An increased serous EMP level associated with Cdc42-PAK4 can be deemed as a useful pulmonary injury marker in LPS-treated mice, and our results might be more relevant in guiding the clinical treatment of ALI by intervening Cdc42-PAK4 or EMPs. PMID- 27513085 TI - Novel Approach in Monocyte Intracellular TNF Measurement: Application to Sepsis Induced Immune Alterations. AB - OBJECTIVE: The monitoring of septic shock induced immunosuppression has been proposed to identify patients who could benefit from specific immunoadjuvant therapies. Among potential biomarkers to monitor immunological status, functional testing remains the gold standard because it directly measures the capacity of a cell population to respond to an immune challenge. We investigated a new approach in intracellular staining for flow cytometry to measure tumor necrosis factor (iTNF) produced in vitro by monocytes in response to lipopolysaccharide. DESIGN, SETTING, SUBJECTS, AND INTERVENTIONS: Observational study in intensive care unit and immunology laboratory of a university medical center. Sixteen septic shock patients and eight control subjects were included. MAIN RESULTS: Monocyte iTNF was determined by flow cytometry in whole blood and completed in 2.5 h according to a no-wash, no centrifuge procedure. Lipopolysaccharide challenge induced a tremendous expression of iTNF that was statistically more pronounced in controls than in patients. This was observed when results were expressed as medians of fluorescence intensity (median: 16.1 [IQR: 14.5-19.1] vs. 5 [4.0-8.0], P = 0.0001) or as percentages of positive cells (99.7 [99.6-99.8] vs. 85 [74-97], P = 0.0001). iTNF expression was correlated to monocyte HLA-DR expression in patients and controls. CONCLUSIONS: These preliminary results illustrate the feasibility of immune functional testing on a routine manner in septic shock patients. They now deserve to be widely assessed and validated in various intensive care unit conditions. This could be a major step to characterize the rapidly changing immune response overtime and thus permit personalized medicine. PMID- 27513087 TI - Selective Unidirectional Horizontal Saccadic Paralysis From Acute Ipsilateral Pontine Stroke. AB - BACKGROUND: Impairment of unidirectional horizontal saccades with sparing of smooth pursuit has been described in human lesions in the dorsomedial pons. They have been too large to allow localization to the pontine paramedian reticular formation (PPRF). METHODS: Single case report. RESULTS: A patient with impaired rightward saccades but spared rightward pursuit eye movements had a brain MRI showing a discrete area of restricted diffusion in the region corresponding to the PPRF. CONCLUSIONS: This case provides support for the concept that PPRF lesions in humans may selectively impair unidirectional horizontal saccades. PMID- 27513088 TI - A dismantling study of the Partners for Change Outcome Management System. AB - The current study used a dismantling design to investigate the relative efficacy of components of the Partners for Change Outcome Management System (PCOMS; Duncan, 2012). Clients (n = 94) from a university counseling center were randomly assigned to 1 of 3 conditions: PCOMS Full, Outcome Rating Scale (ORS)-only, or Session Rating Scale (SRS)-only and nested within therapists (n = 12). Results from hierarchical linear modeling and a 2-way analysis of variance indicated no statistically significant differences in outcome or rate of change on the Behavior Symptom Checklist-18 (BSI-18; Derogatis, 2001) across all 3 conditions. These findings suggest that using either the ORS or SRS component of the PCOMS may yield equivalent outcomes to that of the full PCOMS. Additional dismantling studies with various populations and settings are needed to further clarify the relative influence of the ORS, SRS, and full PCOMS on client outcomes. (PsycINFO Database Record PMID- 27513089 TI - Scope and Limitations of Typical Copper-Free Bioorthogonal Reactions with DNA: Reactive 2'-Deoxyuridine Triphosphates for Postsynthetic Labeling. AB - Four triphosphates of 2'-deoxyuridine that carried the following bioorthogonally reactive groups were synthesized by organic-chemical methods. Two triphosphates with tetrazines and one with a cyclopropene moiety were designed for Diels-Alder reactions with inverse electron demand, and one triphosphate with a tetrazole core was designed for the "photoclick" cycloaddition. These triphosphates were not only successfully applied for oligonucleotide preparation by standard DNA polymerases, including Hemo KlenTaq, Vent, and Deep Vent, but also bypassed for full length primer extension products. Fluorescent labeling of the primer extension products was achieved by fluorophores with reactive counterparts and analyzed by polyacrylamide gel electrophoresis mobility shifts. The tetrazine oligonucleotide conjugates were reacted with carboxymethylmonobenzocyclooctyne- and bicyclononyne-modified fluorophores. The yield of these postsynthetic reactions could significantly be improved by a more stable but still reactive nicotinic acid-derived tetrazine and by changing the key experimental conditions, mainly the pH of 7.2 and the temperature of 45-55 degrees C. The cyclopropene oligonucleotide conjugate could be successfully labeled with a tetrazine-modified rhodamine in very good yields. The "photoclick" cycloaddition between tetrazole oligonucleotide conjugates and a maleimide-modified dye worked quantitatively. The combination of primer extension, bypass, and bioorthogonal modification works also for double and triple labeling using the cyclopropene-modified 2' deoxyuridine triphosphate. PMID- 27513091 TI - Sulfonyl-Substituted Heteroleptic Cyclometalated Iridium(III) Complexes as Blue Emitters for Solution-Processable Phosphorescent Organic Light-Emitting Diodes. PMID- 27513092 TI - Structural Diversity of Cadmium(II) Coordination Polymers Induced by Tuning the Coordination Sites of Isomeric Ligands. AB - When the coordination sites of ligands were shifted, the solvothermal reactions of four positional isomeric asymmetrical pyridyldicarboxylatic acids with Cd(NO3)2 generated four new coordination polymers, [Cd(L1)(DMF)3].DMF.H2O (1), [H2N(CH3)2]2[Cd(L2)2].3DMF.H2O (2), [Cd(L3)(H2O)2] (3), and [Cd(L4)].1.5DMF (4), where DMF = N,N-dimethylformamide, H2L1 = 2-(3'-carboxylphenyl)isonicotinic acid, H2L2 = 2-(4'-carboxylphenyl)isonicotinic acid, H2L3 = 5-(3' carboxylphenyl)nicotic acid, and H2L4 = 2-(3'-pyridyl)terephthalic acid. 1 shows a rare 2D fabric structure. 2 discloses a grid-layer structure with heterochiral helical chains and in which three sets of layers stack in different directions, affording an unprecedented 2D + 2D + 2D -> 3D polycatenating framework with 3D intersecting porous systems. 3 also displays a 2D layer possessing strong intralayer pi...pi interactions and interlayer hydrogen bonds. 4 contains a rare Cd2(COO)4 paddle-wheel unit and forms a 3D framework with 1D open channels. The carboxyl and pyridyl groups of the positional isomeric H2L1-H2L4 ligands show distinct bridging fashions, which leads to the production of versatile architectures of 1-4, and their effects on the crystal structures are discussed. 1-4 reveal solid-state photoluminescence stemming from intraligand charge transfer. 2 and 4 show high selectivity for CO2 over CH4 but with different CO2 adsorption enthalpies. Grand canonical Monte Carlo simulations identified the multiple adsorption sites in 2 for CO2. PMID- 27513096 TI - Formation of a Three-Electron Sulfur-Sulfur Bond as a Probe for Interaction between Side Chains of Methionine Residues. AB - The mechanism of oxidation processes of l-Met-(Pro)n-l-Met peptides that contain two Met residues located on the N- and C-terminal and separated by a defined number (n = 0-4) of proline residues was investigated in aqueous solutions using pulse radiolysis. The use of such peptides allowed for distance control between the sulfur atoms located in the side chains of the Met residues. The formation of a contact between the side chains of the Met residues was probed by the observation of transients with sigma*-type 2c-3e S?S and S?O bonds as well as of alpha-(alkylthio)alkyl radicals (alphaS). This approach enabled the monitoring, in real time, of the efficiency and kinetics of interactions between methionine side chains. Such knowledge is important, inter alia, for long-distance electron transfer processes because methionine side chains can serve as relay stations and also for many aspects of protein folding when the formation of a contact between two amino acid residues in an unfolded polypeptide chain plays a central role in protein-folding mechanisms. The yields of these transients (measured as G-values) were found to be dependent on the number of Pro residues; however, they were not dependent in a simple way on the average distance ?rS-S? between the sulfur atoms in Met residues. A decrease in the yield of the (S?S)(+) species with an increase in the number of Pro residues in the bridge occurred at the expense of an increase in the yields of the intramolecular three-electron-bonded (S?O)(+) radical cations and alphaS radicals. A detailed understanding of these trends in the chemical yields was developed by modeling the underlying chemical kinetics with Langevin dynamical simulations of the various oligoproline peptide chains and combining them with a simple statistical mechanical theory on the end-to-end contact rates for polymer chains. This analysis showed that the formation of a contact between terminal Met residues in the peptides with 0-2 Pro residues was controlled by the activated formation of (S?S)(+) whereas in the peptides with 3 and 4 Pro residues, by the relative diffusion of the sulfur radical cation and unoxidized sulfur atom. In this picture, the dynamics of the other radical products can be seen to be only indirectly dependent on the length of the proline bridges because their formation is in competition with (S?S)(+) formation. PMID- 27513093 TI - Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus. AB - Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure-activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented. PMID- 27513098 TI - Microfluidics-Produced Collagen Fibers Show Extraordinary Mechanical Properties. AB - Collagens are widely used as biomaterials in drug-delivery and tissue engineering applications due to their biodegradability, biocompatibility and hypoallergenicity. Besides gelatin-based materials, collagen microfibers are in the focus of biomedical research. Commonly, man-made fibers are produced by wet spinning yielding fiber diameters higher than 8 MUm. Here, assembly and continuous production of single collagen type I microfibers were established using a microfluidic chip. Microfluidics-produced microfibers exhibited tensile strength and Young's modulus exceeding that of fibers produced in classical wet spinning devices and even that of natural tendon and they showed lower diameters. Their structural orientation was examined by polarized Fourier transform infrared spectroscopy (FTIR) showing fibril alignment within the microfiber. Cell culture tests using the neuronal cell line NG108-15 showed cell alignment and axon growth along the microfiber axes inaugurating potential applications in, for example, peripheral nerve repair. PMID- 27513100 TI - Shrinking the Synchrotron: Tabletop Extreme Ultraviolet Absorption of Transition Metal Complexes. AB - We show that the electronic structure of molecular first-row transition-metal complexes can be reliably measured using tabletop high-harmonic XANES at the metal M2,3 edge. Extreme ultraviolet photons in the 50-70 eV energy range probe 3p -> 3d transitions, with the same selection rules as soft X-ray L2,3-edge absorption (2p -> 3d excitation). Absorption spectra of model complexes are sensitive to the electronic structure of the metal center, and ligand field multiplet simulations match the shapes and peak-to-peak spacings of the experimental spectra. This work establishes high-harmonic spectroscopy as a powerful tool for studying the electronic structure of molecular inorganic, bioinorganic, and organometallic compounds. PMID- 27513102 TI - Tissue-engineered human psoriatic skin supplemented with cytokines as an in vitro model to study plaque psoriasis. AB - AIM: Psoriasis is a chronic inflammatory skin disease. To study its complex etiology, a psoriatic skin substitute model supplemented with a cytokine cocktail has been used. MATERIALS & METHODS: Reconstructed psoriatic skin substitutes were supplemented with a cocktail of four cytokines: TNF-alpha, IL-1alpha, IL-6 and IL 17A, to monitor their impact on gene expression by DNA microarray. RESULTS: Gene profiling analyses identified several deregulated genes reported as being also deregulated in psoriasis skin in vivo (S100A12, IL-8, DEFB4A and KYNU). The expression of those genes was dramatically increased compared with basal levels of controls (p < 0.005 to < 0.05). CONCLUSION: Psoriatic substitutes supplemented with a cocktail of TNF-alpha, IL-1alpha, IL-6 and IL-17A showed similar transcriptome alterations to those found in psoriasis. PMID- 27513103 TI - Use of Low-Dose Recombinant Activated Factor VII in the Off-Label Setting: A Comment to "The Judicious Use of Recombinant Factor VIIa". PMID- 27513104 TI - Can we improve referrals for fertility preservation? Evolution of practices after the creation of a fertility network. PMID- 27513105 TI - KIF21A mutation in two Chinese families with congenital fibrosis of the extraocular muscles type 1 and 3. AB - Congenital fibrosis of the extraocular muscles (CFEOM) is a hereditary ocular disease and can be classified into three subtypes. The aim of the present study was to determine the genetic basis and describe the clinical phenotype of CFEOM type 1 and 3. Two Chinese families with CFEOM type 1 and 3 were identified. The patients and their family members were subjected to comprehensive ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination, assessment of palpebral fissure size, levator function, ocular motility, and cover and forced duction tests. Genomic DNA was extracted from the leukocytes of venous blood samples collected from the two families and from 200 unrelated control subjects from the same population. Coding exons of the KIF21A gene were amplified using polymerase chain reaction analysis and sequenced directly in the two probands. The detected mutations were further analyzed in all available family members and the unrelated control subjects. A heterozygous mutation, c.2860C>T (p.R954W), in KIF21A was identified in the two families, and this was cosegregated with the presence of the diseases in the two families, however, it was absent in the 200 normal control subjects. Among the three affected family members with CFEOM1, differences were observed with regard to the presence of aberrant eye movement. The results indicated that, in the patients with CFEOM1 and CFEOM3, the disease was caused by the same KIF21A gene mutation. The KIF21A gene may be a major disease-causing gene for Chinese patients with CFEOM3. Phenotypic heterogeneity was observed in the patients with CFEOM1. PMID- 27513154 TI - Incidence of Neonatal Abstinence Syndrome - 28 States, 1999-2013. AB - Neonatal abstinence syndrome (NAS) is a postnatal drug withdrawal syndrome that occurs primarily among opioid-exposed infants shortly after birth, often manifested by central nervous system irritability, autonomic overreactivity, and gastrointestinal tract dysfunction (1). During 2000-2012, the incidence of NAS in the United States significantly increased (2,3). Several recent publications have provided national estimates of NAS (2,3); however, data describing incidence at the state level are limited. CDC examined state trends in NAS incidence using all payer, hospital inpatient delivery discharges compiled in the State Inpatient Databases of the Healthcare Cost and Utilization Project (HCUP) during 1999-2013. Among 28 states with publicly available data in HCUP during 1999-2013, the overall NAS incidence increased 300%, from 1.5 per 1,000 hospital births in 1999, to 6.0 per 1,000 hospital births in 2013. During the study period, significant increases in NAS incidence occurred in 25 of 27 states with at least 3 years of data, with annual incidence rate changes ranging from 0.05 (Hawaii) to 3.6 (Vermont) per 1,000 births. In 2013, NAS incidence ranged from 0.7 cases per 1,000 hospital births (Hawaii) to 33.4 cases per 1,000 hospital births (West Virginia). The findings underscore the importance of state-based public health programs to prevent unnecessary opioid use and to treat substance use disorders during pregnancy, as well as decrease the incidence of NAS. PMID- 27513155 TI - Locoregional Recurrence After Sentinel Lymph Node Dissection With or Without Axillary Dissection in Patients With Sentinel Lymph Node Metastases: Long-term Follow-up From the American College of Surgeons Oncology Group (Alliance) ACOSOG Z0011 Randomized Trial. AB - BACKGROUND AND OBJECTIVE: The early results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in locoregional recurrence for patients with positive sentinel lymph nodes (SLNs) randomized either to axillary lymph node dissection (ALND) or sentinel lymph node dissection (SLND) alone. We now report long-term locoregional recurrence results. METHODS: ACOSOG Z0011 prospectively examined overall survival of patients with SLN metastases undergoing breast-conserving therapy randomized to undergo ALND after SLND or no further axillary specific treatment. Locoregional recurrence was prospectively evaluated and compared between the groups. RESULTS: Four hundred forty-six patients were randomized to SLND alone and 445 to SLND and ALND. Both groups were similar with respect to age, Bloom-Richardson score, Estrogen Receptor status, adjuvant systemic therapy, histology, and tumor size. Patients randomized to ALND had a median of 17 axillary nodes removed compared with a median of only 2 SLNs removed with SLND alone (P < 0.001). ALND, as expected, also removed more positive lymph nodes (P < 0.001). At a median follow-up of 9.25 years, there was no statistically significant difference in local recurrence-free survival (P = 0.13). The cumulative incidence of nodal recurrences at 10 years was 0.5% in the ALND arm and 1.5% in the SLND alone arm (P = 0.28). Ten-year cumulative locoregional recurrence was 6.2% with ALND and 5.3% with SLND alone (P = 0.36). CONCLUSION: Despite the potential for residual axillary disease after SLND, SLND without ALND offers excellent regional control for selected patients with early metastatic breast cancer treated with breast-conserving therapy and adjuvant systemic therapy. PMID- 27513156 TI - Per-oral Endoscopic Myotomy (POEM) After the Learning Curve: Durable Long-term Results With a Low Complication Rate. AB - OBJECTIVE: We aimed to report long-term outcomes for patients undergoing per-oral endoscopic myotomy (POEM) after our initial 15-case learning curve. BACKGROUND: POEM has become an established, natural-orifice surgical approach for treating esophageal motility disorders. To date, published outcomes and comparative effectiveness studies have included patients from the early POEM experience. METHODS: Consecutive patients undergoing POEM after our initial 15 cases, with a minimum of 1-year postoperative follow-up, were included. Treatment success was defined as an Eckardt score <=3 without reintervention. Gastroesophageal reflux was defined by abnormal pH-testing or reflux esophagitis >Los Angeles grade A. RESULTS: Between January 2012 and March 2015, 115 patients underwent POEM at a single, high-volume center. Operative time was 101 +/- 29 minutes, with 95% (109/115) of patients discharged on postoperative day 1. Clavien-Dindo grade III complications occurred in 2.7%, one of which required diagnostic laparoscopy to rule out Veress needle injury to the gall bladder. The rate of grade I complications was 15.2%. At an average of 2.4 years post-POEM (range 12-52 months), the overall success rate was 92%. Objective evidence of reflux was present in 40% for all patients and 33% for patients with a body mass index <35 kg/m and no hiatal hernia. CONCLUSIONS: POEM performed by experienced surgeons provided durable symptomatic relief in 94% of patients with nonspastic achalasia and 90% of patients with type 3 achalasia/spastic esophageal motility disorders, with a low rate of complications. The rate of gastroesophageal reflux was comparable with prior studies of both POEM and laparoscopic Heller myotomy. PMID- 27513157 TI - No Need for Routine Drainage After Pancreatic Head Resection: The Dual-Center, Randomized, Controlled PANDRA Trial (ISRCTN04937707). AB - OBJECTIVE: This dual-center, randomized, controlled, noninferiority trial aimed to prove that omission of drains does not increase reintervention rates after pancreatic surgery. BACKGROUND: There is considerable uncertainty regarding intra abdominal drainage after pancreatoduodenectomy. METHODS: Patients undergoing pancreatic head resection with pancreaticojejunal anastomosis were randomized to intra-abdominal drainage versus no drainage. Primary endpoint was overall reintervention rate (relaparotomy or radiologic intervention). Secondary endpoints were clinically relevant pancreatic fistula (grade B/C), mortality, morbidity, and hospital stay. The planned sample size was 188 patients per group. RESULTS: A total of 438 patients were randomized. Forty-three patients (9.8%) were excluded because no pancreatic anastomosis was performed, and 395 patients (202 drain, 193 no-drain) were analyzed. Reintervention rates were not inferior in the no-drain group (drain 21.3%, no-drain 16.6%; P = 0.0004). Overall in hospital mortality (3.0%) was the same in both groups (drain 3.0%, no-drain 3.1%; P = 0.936). Overall surgical morbidity (41.8%) was comparable (P = 0.741). Clinically relevant pancreatic fistula (grade B/C: drain 11.9%, no-drain 5.7%; P = 0.030) and fistula-associated complications (drain 26.4%; no drain 13.0%; P = 0.0008) were significantly reduced in the no-drain group. Operation time (P = 0.093), postoperative hemorrhage (P = 0.174), intra-abdominal abscess formation (P = 0.199), biliary leakage (P = 0.382), delayed gastric emptying (P = 0.062), burst abdomen (P = 0.480), wound infection (P = 0.758), and hospital stay (P = 0.487) did not show significant differences. CONCLUSIONS: Omission of drains was not inferior to intra-abdominal drainage in terms of postoperative reintervention and superior in terms of clinically relevant pancreatic fistula rate and fistula associated complications. There is no need for routine prophylactic drainage after pancreatic resection with pancreaticojejunal anastomosis. PMID- 27513159 TI - Photolysis Kinetics of Toluene, Ethylbenzene, and Xylenes at Ice Surfaces. AB - Benzene, toluene, ethylbenzene, and xylenes (BTEX) are important organic pollutants. These compounds do not undergo direct photolysis in natural waters because their absorbance spectra do not overlap with solar radiation at the Earth's surface. Recent research has suggested that benzene is able to undergo direct photolysis when present at ice surfaces. However, the photolysis of toluene, ethylbenzene, and xylenes (TEX) at ice surfaces has not been investigated. Using fluorescence spectroscopy, photolysis rate constants were measured for TEX in water, in ice cubes, and in ice granules which reflect reactivity at ice surfaces. No photolysis was observed in water or ice cubes. Photolysis was observed in ice granules; rate constants were (4.5 +/- 0.5) * 10( 4) s(-1) (toluene), (5.4 +/- 0.3) * 10(-4) s(-1) (ethylbenzene), and (3.8 +/- 1.2) * 10(-4) s(-1) (xylenes). Photolysis of TEX molecules appears to be enabled by a red shift in the absorbance spectra at ice surfaces, although photosensitization may also occur. The results suggest that direct photolysis could be an important removal pathway for TEX in snow-covered environments. PMID- 27513160 TI - A structurally flexible triazolate-based metal-organic framework featuring coordinatively unsaturated copper(i) sites. AB - The novel metal-organic framework CFA-8 (Coordination Framework Augsburg University-8), [Cu2(tqpt)], containing the organic linker H2-tqpt {H2-tqpt = 6,6,14,14-tetramethyl-6,14-dihydroquinoxalino[2,3-b]phenazinebis-triazole}, has been synthesized. Reaction of H2-tqpt and anhydrous CuCl2 in N,N dimethylacetamide (DMA) yields CFA-8 as orange crystals with lenticular shape. This framework shows a reversible breathing effect and is robust upon solvent removal. It has been characterized by single-crystal and powder X-ray diffraction, TGA, IR spectroscopy and gas sorption measurements. CO adsorption isotherms show that Cu(i) sites in this framework are able to bind carbon monoxide forming a weak complex which has been additionally characterized by IR spectroscopy and synchrotron powder X-ray diffraction measurements. PMID- 27513161 TI - Effect of UV Photofunctionalization on Osseointegration in Aged Rats. AB - OBJECTIVES: This study evaluated the effect of photofunctionalization on osseointegration under the biologically adverse conditions of aging. MATERIALS: First of all, bone marrow-derived osteoblastic cells from young (8 weeks old) and aged (15 months old) rats were biologically characterized. Then, the osteoblasts from aged rats were seeded on titanium discs with and without photofunctionalization, and assessed for initial cell attachment and osteoblastic functions. Titanium mini-implants, with and without photofunctionalization, were placed in the femur of aged rats, and the strength of osseointegration was measured at week 2 of healing. Periimplant tissue was examined morphologically and chemically using scanning electron microscopy and energy dispersive x-ray spectroscopy, respectively. RESULTS: Cells from the aged rats showed substantially reduced biological capabilities compared with those derived from young rats. The cells from aged rats showed significantly increased cell attachment and the expression of osteoblastic function on photofunctionalized titanium than on untreated titanium. In addition, the strength of osseointegration was increased by 40% in aged rats carrying the photofunctionalized implants. Robust bone formation was observed around the photofunctionalized implants with strong elemental peaks of calcium and phosphorus, whereas the tissue around untreated implants showed weaker calcium and phosphate signals than titanium ones. CONCLUSION: These in vivo and in vitro results corroboratively demonstrate that photofunctionalization is effective for enhancing osseointegration in aged rats. PMID- 27513162 TI - Maxillary Sinus Grafting With Biphasic Bone Ceramic or Autogenous Bone: Clinical, Histologic, and Histomorphometric Results From a Randomized Controlled Clinical Trial. AB - PURPOSE: The present, randomized, controlled clinical trial compared the histologic and histomorphometric results from maxillary sinus augmentation with either biphasic calcium phosphate (BCP) (60% hydroxyapatite and 40% beta tricalcium phosphate) or autogenous bone (AB) as bone-grafting materials. MATERIAL AND METHODS: Ten patients received bilateral sinus elevation surgery with intraoral AB chips (control group) on one side and BCP (test group) on the contralateral side. After a healing period of 6 to 8 months, implant sites were created and trephine cores were harvested for histological and histomorphometric analysis of the grafted areas. RESULTS: The histological examination of biopsies showed BCP particles interconnected by bridges of a vital newly formed bone. Histomorphometry demonstrated that the amount of newly formed bone in the control group (36.8%) was significantly greater than that in the BCP (28.2%) group (P = 0.0032). BCP and AB cores revealed an average of residual graft particles of 32.9% and 4.8%, respectively. The average percentage of soft tissue components was 38.9% in the BCP cores and 58.4% in the AB cores. CONCLUSIONS: Based on our findings, the amount of vital bone formation was significantly higher for AB than that for BCP. However, BCP seemed to be a biocompatible and osteoconductive material that can be used with success as a bone substitute in maxillary sinus procedures. PMID- 27513163 TI - The Effect of Osteotomy Dimension on Implant Insertion Torque, Healing Mode, and Osseointegration Indicators: A Study in Dogs. AB - PURPOSE: This study investigated the effect of the osteotomy diameter for implant placement torque and its effect on the osseointegration. MATERIALS AND METHODS: Eight male beagle dogs received 48 implants (3.75 mm * 10 mm) in their right and left radius, 3 implants per side and allowed to heal for 3 weeks. Three experimental groups were evaluated. Group 1: implant with an undersized osteotomy of 3.0 mm; group 2: osteotomy of 3.25 mm, and group 3: osteotomy of 3.5 mm. The insertion torque was recorded for all implants. Histological sectioning and histometric analysis were performed evaluating bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO). RESULTS: Implants of group 1 presented statistically higher insertion torque than those of groups 2 and 3 (P < 0.01). No differences in BIC or BAFO were observed between the groups. From a morphologic standpoint, substantial deviations in healing mode were observed between groups. CONCLUSION: Based on the present methodology, the experimental alterations of surgical technic can be clinically used with no detrimental effect over the osseointegration process. PMID- 27513164 TI - Direct Construction of 4-Hydroxybenzils via Para-Selective C-C Bond Coupling of Phenols and Aryl Methyl Ketones. AB - A highly para-selective C-C bond coupling is presented between phenols C(sp(2)) and aryl methyl ketones C(sp(3)), which enables the direct construction of 4 hydroxybenzil derivatives. This practical method exhibits a broad substrate scope and large-scale applicability and represents a general gateway to the hydroxybenzil natural product family. Mechanistic investigations indicated that the combination of HI with DMSO realized the oxidative carbonylation of aryl methyl ketones, while boric acid acted as a dual-functional relay reagent to promote this transformation. PMID- 27513165 TI - Tubing-Electrospinning: A One-Step Process for Fabricating Fibrous Matrices with Spatial, Chemical, and Mechanical Gradients. AB - Guiding newly generated tissues in a gradient pattern, thereby precisely mimicking inherent tissue morphology and subsequently arranging the intimate networks between adjacent tissues, is essential to raise the technical levels of tissue engineering and facilitate its transition into the clinic. In this study, a straightforward electrospinning method (the tubing-electrospinning technique) was developed to create fibrous matrices readily with diverse gradient patterns and to induce patterned cellular responses. Gradient fibrous matrices can be produced simply by installing a series of polymer-containing lengths of tubing into an electrospinning circuit and sequentially processing polymers without a time lag. The loading of polymer samples with different characteristics, including concentration, wettability, and mechanical properties, into the tubing system enabled unique features in fibrous matrices, such as longitudinal gradients in fiber density, surface properties, and mechanical stiffness. The resulting fibrous gradients were shown to arrange cellular migration and residence in a gradient manner, thereby offering efficient cues to mediate patterned tissue formation. The one-step process using tubing-electrospinning apparatus can be used without significant modifications regardless of the type of fibrous gradient. Hence, the tubing-electrospinning system can serve as a platform that can be readily used by a wide-range of users to induce patterned tissue formation in a gradient manner, which will ultimately improve the functionality of tissue engineering scaffolds. PMID- 27513166 TI - Surgical Navigation Technology Based on Augmented Reality and Integrated 3D Intraoperative Imaging: A Spine Cadaveric Feasibility and Accuracy Study. AB - STUDY DESIGN: A cadaveric laboratory study. OBJECTIVE: The aim of this study was to assess the feasibility and accuracy of thoracic pedicle screw placement using augmented reality surgical navigation (ARSN). SUMMARY OF BACKGROUND DATA: Recent advances in spinal navigation have shown improved accuracy in lumbosacral pedicle screw placement but limited benefits in the thoracic spine. 3D intraoperative imaging and instrument navigation may allow improved accuracy in pedicle screw placement, without the use of x-ray fluoroscopy, and thus opens the route to image-guided minimally invasive therapy in the thoracic spine. METHODS: ARSN encompasses a surgical table, a motorized flat detector C-arm with intraoperative 2D/3D capabilities, integrated optical cameras for augmented reality navigation, and noninvasive patient motion tracking. Two neurosurgeons placed 94 pedicle screws in the thoracic spine of four cadavers using ARSN on one side of the spine (47 screws) and free-hand technique on the contralateral side. X-ray fluoroscopy was not used for either technique. Four independent reviewers assessed the postoperative scans, using the Gertzbein grading. Morphometric measurements of the pedicles axial and sagittal widths and angles, as well as the vertebrae axial and sagittal rotations were performed to identify risk factors for breaches. RESULTS: ARSN was feasible and superior to free-hand technique with respect to overall accuracy (85% vs. 64%, P < 0.05), specifically significant increases of perfectly placed screws (51% vs. 30%, P < 0.05) and reductions in breaches beyond 4 mm (2% vs. 25%, P < 0.05). All morphometric dimensions, except for vertebral body axial rotation, were risk factors for larger breaches when performed with the free-hand method. CONCLUSION: ARSN without fluoroscopy was feasible and demonstrated higher accuracy than free-hand technique for thoracic pedicle screw placement. LEVEL OF EVIDENCE: N/A. PMID- 27513167 TI - The Significance of TRPV4 Channels and Hemichannels in the Lens and Ciliary Epithelium. AB - To function normally, all cells must maintain ion homeostasis, establish a membrane potential, and regulate water content. These actions require active Na-K transport provided by Na,K-ATPase. The lens, however, is made up almost entirely of fiber cells that have little or no Na,K-ATPase activity. Lens ion and water homeostasis rely on Na,K-ATPase activity in a small number of cells at the periphery of epithelium monolayer. Therefore, the function of the epithelium must be integrated with the needs of the fiber mass. This suggests that a remote control mechanism may adjust Na,K-ATPase activity to match increases or decreases of ion leakage, which may occur a considerable distance away. Here, we review evidence that TRPV4 channels in the epithelium become activated when the lens is subjected to osmotic- or damage-induced swelling. This triggers a chain of events in the lens epithelium that opens connexin hemichannels, allowing ATP release that stimulates purinergic receptors, activates Src family tyrosine kinases, and increases Na,K-ATPase activity. Recent studies also revealed functional connexin hemichannels along with TRPV4 channels in nonpigmented ciliary epithelial (NPE) cells that secrete aqueous humor into the eye. Because TRPV4 channels are mechanosensitive, we speculate they might enable the NPE to respond to stimuli such as mechanical distortion associated with volume homeostasis during fluid transfer across the ciliary epithelium or changes in intraocular pressure. PMID- 27513168 TI - Macrolide-Resistant Mycobacterium avium Complex Lung Disease: Analysis of 102 Consecutive Cases. AB - RATIONALE: The management of macrolide-resistant Mycobacterium avium complex (MR MAC) pulmonary disease is difficult and is thought to be analogous to that of multidrug-resistant tuberculosis (MDR-TB). OBJECTIVES: This study aimed to clarify the cause of MR-MAC, to see how its management affected outcome, and to compare its prognosis with that of MDR-TB. METHODS: The medical records of 102 consecutive cases with MR-MAC pulmonary disease at three tertiary hospitals for mycobacteriosis in metropolitan Tokyo and one in Aichi prefecture from 2005 to 2014 were reviewed. The data of 311 consecutive cases with MDR-TB were extracted from the medical data at Fukujuji Hospital. MEASUREMENTS AND MAIN RESULTS: Of the 90 patients who met the criteria, 53 (58.9%) received inappropriate first-line treatment, and 28 (31.1%) deviated from the standard treatment because of the adverse effects of ethambutol. The survival rates for MR-MAC disease and MDR-TB were not significantly different (P = 0.6). Multivariate analysis showed that the combination of aminoglycoside and surgery resulted in the best treatment outcome (P = 0.02), although neither of the two factors reached significance by themselves. The continuation of clarithromycin and the addition of fluoroquinolones did not improve the outcome for the treatment of disease caused by MR-MAC. CONCLUSIONS: Inappropriate prescription patterns and deviations from the standard treatment because of adverse drug reactions appeared to be the main causes of macrolide resistance in this patient series. Drug sensitivity testing should be performed at diagnosis to identify macrolide resistance and patients who may benefit from other therapy. PMID- 27513169 TI - Hip-Extensor Strength, Trunk Posture, and Use of the Knee-Extensor Muscles During Running. AB - CONTEXT: Diminished hip-muscle performance has been proposed to contribute to various knee injuries. OBJECTIVE: To determine the association between hip extensor muscle strength and sagittal-plane trunk posture and the relationships among hip-extensor muscle strength and hip- and knee-extensor work during running. DESIGN: Descriptive laboratory study. SETTING: Musculoskeletal biomechanical laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 40 asymptomatic recreational runners, 20 men (age = 27.1 +/- 7.0 years, height = 1.74 +/- 0.69 m, mass = 71.1 +/- 8.2 kg) and 20 women (age = 26.2 +/- 5.8 years, height = 1.65 +/- 0.74 m, mass = 60.6 +/- 6.6 kg), participated. MAIN OUTCOME MEASURE(S): Maximum isometric strength of the hip extensors was assessed using a dynamometer. Sagittal-plane trunk posture (calculated relative to the global vertical axis) and hip- and knee-extensor work (sum of energy absorption and generation) during the stance phase of running were quantified while participants ran over ground at a controlled speed of 3.4 m/s. We used Pearson product moment correlations to examine the relationships among hip-extensor strength, mean sagittal-plane trunk-flexion angle, hip-extensor work, and knee-extensor work. RESULTS: Hip-extensor strength was correlated positively with trunk-flexion angle (r = 0.55, P < .001) and hip-extensor work (r = 0.46, P = .003). It was correlated inversely with knee-extensor work (r = -0.39, P = .01). All the correlations remained after adjusting for sex. CONCLUSIONS: Our findings suggest that runners with hip-extensor weakness used a more upright trunk posture. This strategy led to an overreliance on the knee extensors and may contribute to overuse running injuries at the knee. PMID- 27513171 TI - Is More Always Better in Designing Workplace Wellness Programs?: A Comparison of Wellness Program Components Versus Outcomes. AB - OBJECTIVE: Assess whether adding more components to a workplace wellness program is associated with better outcomes by measuring the relationship of program components to one another and to employee participation and perceptions of program effectiveness. METHODS: Data came from a 2014 survey of 24,393 employees of 81 employers about services offered, leadership, incentives, and promotion. Logistic regressions were used to model the relationship between program characteristics and outcomes. RESULTS: Components individually are related to better outcomes, but this relationship is weaker in the presence of other components and non-significant for incentives. Within components, a moderate level of services and work time participation opportunities are associated with higher participation and effectiveness. CONCLUSIONS: The "more of everything" approach does not appear to be advisable for all programs. Programs should focus on providing ample opportunities for employees to participate and initiatives like results-based incentives. PMID- 27513170 TI - Employee Health Behaviors, Self-Reported Health Status, and Association With Absenteeism: Comparison With the General Population. AB - OBJECTIVES: To perform a comparison between health behaviors and health status of employees with those of the general population, to evaluate the association between employee health behaviors, health status, and absenteeism. METHODS: Cross sectional study enrolled 2433 employees from 16 Korean companies in 2014, and recruited 1000 general population randomly in 2012. The distribution of employee health behaviors, health status, and association with absenteeism were assessed. RESULTS: Employees had significantly worse health status and low rates of health behaviors maintenance compared with the general population. Multiple logistic regression model revealed that regular exercise, smoking cessation, work life balance, proactive living, religious practice, and good physical health status were associated with lower absenteeism. CONCLUSIONS: Maintaining health behaviors and having good health status were associated with less absenteeism. This study suggests investment of multidimensional health approach in workplace health and wellness (WHW) programs. PMID- 27513172 TI - Associations Between the Self-Reported Frequency of Hearing Chemical Alarms in Theater and Visuospatial Function in Gulf War Veterans. AB - OBJECTIVE: The aim of this study was to examine the relationship between the self reported frequencies of hearing chemical alarms during deployment and visuospatial function in Gulf War (GW) veterans. METHODS: The relationship between the self-reported frequency of hearing chemical alarms, neurobehavioral, and volumetric brain imaging data was examined with correlational, regression, and mediation analyses. RESULTS: The self-reported frequency of hearing chemical alarms was inversely associated with and significantly predicted performance on a visuospatial task (ie, Block Design) over and above potentially confounding variables, including concurrent, correlated GW-related exposures. This effect was partially mediated by the relationship between hearing chemical alarms and lateral occipital cortex volume. CONCLUSIONS: Exposure to substances that triggered chemical alarms during GW deployment likely had adverse effects on veterans' brain structure and function, warranting further investigation of whether these GW veterans are at an increased risk for dementia. PMID- 27513173 TI - No Association Between Unintentional Head Injuries and Early-Life Exposure to Tetrachloroethylene (PCE)-Contaminated Drinking Water. AB - OBJECTIVE: Because of emerging evidence that early-life exposure to the solvent tetrachloroethylene (PCE) has long-lasting neurological consequences, we examined the risk of unintentional head injuries following prenatal and childhood exposure to PCE-contaminated drinking water. METHODS: Participants provided information on head injuries and other relevant characteristics in a self-administered questionnaire. Exposure to PCE was modeled using a leaching and transport algorithm set in water system modeling software. RESULTS: We did not observe any evidence of an increased risk of any type of head injury among exposed participants. CONCLUSIONS: PCE is a widespread water pollutant. Thus, documenting possible health effects of early-life exposure is vital for ensuring that drinking water regulations adequately protect vulnerable populations. PMID- 27513174 TI - Numerical cognition explains age-related changes in third-party fairness. AB - Young children share fairly and expect others to do the same. Yet little is known about the underlying cognitive mechanisms that support fairness. We investigated whether children's numerical competencies are linked with their sharing behavior. Preschoolers (aged 2.5-5.5) participated in third-party resource allocation tasks in which they split a set of resources between 2 puppets. Children's numerical competence was assessed using the Give-N task (Sarnecka & Carey, 2008; Wynn, 1990). Numerical competence-specifically knowledge of the cardinal principle explained age-related changes in fair sharing. Although many subset-knowers (those without knowledge of the cardinal principle) were still able to share fairly, they invoked turn-taking strategies and did not remember the number of resources they shared. These results suggest that numerical cognition serves as an important mechanism for fair sharing behavior, and that children employ different sharing strategies (division or turn-taking) depending on their numerical competence. (PsycINFO Database Record PMID- 27513175 TI - Highly Sensitive Formation of Stable Surface Relief Structures in Bisanthracene Films with Spatially Patterned Photopolymerization. AB - A facile method for the fabrication of a highly sensitive surface relief is demonstrated, which operates on the principle of spatially patterned photopolymerization-induced mass transport in the amorphous films of a series of bisanthracene compounds. The stability of the resultant colorless transparent relief structure is dramatically improved owing to the polymerization of the bisanthracene. PMID- 27513176 TI - Synthesis of the Reported Pyranonaphthoquinone Structure of the Indoleamine-2,3 dioxygenase Inhibitor Annulin B by Regioselective Diels-Alder Reaction. AB - Annulin B, isolated from the marine hydroid isolated from Garveia annulata, is a potent inhibitor of the tryptophan catabolizing enzyme indoleamine-2,3 dioxygenase (IDO). A synthesis of the reported pyranonaphthoquinone structure is described, in which the key step is a regioselective Diels-Alder reaction between a pyranobenzoquinone dienophile and a silyl ketene acetal diene. PMID- 27513177 TI - Synthesis, Structure, and Tandem Mass Spectrometric Characterization of the Diastereomers of Quinic Acid. AB - (-)-Quinic acid possess eight possible stereoisomers, which occur both naturally and as products of thermal food processing. In this contribution, we have selectively synthesized four isomers, namely, epi-quinic acid, muco-quinic acid, cis-quinic acid, and scyllo-quinic acid, to develop a tandem LC-MS method identifying all stereoisomeric quinic acids. Four derivatives have been unambiguously characterized by single-crystal X-ray crystallography. The missing diastereomers of quinic acid were obtained by nonselective isomerization of (-) quinic acid using acetic acid/concentrated H2SO4 allowing chromatographic separation and assignment of all diastereomers of quinic acid. We report for the first time that a full set of stereoisomers are reliably distinguishable on the basis of their tandem mass spectrometric fragment spectra as well as their elution order. A rationale for characteristic fragmentation mechanisms is proposed. In this study, we also observed that muco-quinic acid, scyllo-quinic acid, and epi-quinic acid are present in hydrolyzed Guatemalan roasted coffee sample as possible products of roasting. PMID- 27513178 TI - Solid-State Synthesis and Structure of the Enigmatic Ammonium Octaborate: (NH4)2[B7O9(OH)5].3/4B(OH)3.5/4H2O. AB - The compound known since the 19th century as ammonium octaborate was structurally characterized revealing the ammonium salt of the ribbon isomer of the heptaborate anion, [B7O9(OH)5](2-), with boric acid and water molecules. Of composition (NH4)2B7.75O12.63.4.88H2O, it approximates the classical ammonium octaborate composition (NH4)2B8O13.6H2O and has the structural formula {(NH4)2[B7O9(OH)5]}4.3B(OH)3.5H2O. It spontaneously forms at room temperature in solid-state mixtures of ammonium tetraborate and ammonium pentaborate. It crystallizes in the monoclinic space group P21/c with a = 11.4137(2) A, b = 11.8877(2) A, c = 23.4459(3) A, beta = 90.092(1) degrees , V = 3181.19(8) A(3), and Z = 2 and contains well-ordered ammonium cations and [B7O9(OH)5](2-) anions and disordered B(OH)3 and H2O molecules linked by extensive H bonding. Expeditious solid-state formation of the heptaborate anion under ambient conditions has important implications for development of practical syntheses of industrially useful borates. PMID- 27513181 TI - Nanoscrews: Asymmetrical Etching of Silver Nanowires. AB - World's smallest screws with helical threads are synthesized via mild etching of Ag nanowires. With detailed characterization, we show that this nanostructure arises not from the transformation of the initial lattice, but the result of a unique etching mode. Three-dimensional printed models are used to illustrate the evolution of etch pits, from which a possible mechanism is postulated. PMID- 27513183 TI - Drug-Specific Design of Telodendrimer Architecture for Effective Doxorubicin Encapsulation. AB - Designing a versatile nanocarrier platform that can be tailored to deliver specific drug payloads is challenging. In general, effective drug encapsulation, high drug-loading capacity, uniform shape and size distribution, and enhanced stability are among the fundamental attributes of a successful nanocarrier design. These physiochemical features of the nanocarriers are intimately tied to the specific drug payload that they are tasked to deliver. The molecular architecture of the nanocarrier's scaffold often needs to be tuned for each drug, especially if the target drugs are structurally and chemically distinct as in the case of doxorubicin (DOX) and paclitaxel (PTX). Starting from our previously reported telodendrimeric block copolymer platform optimized for PTX, we analyze three generations of telodendrimer architectures to arrive at the design that is capable of encapsulating another important chemotherapeutic drug, DOX. Multiple long-time-scale self-assembly simulations were performed both in atomistic and coarse-grained resolutions to generate equilibrated DOX-encapsulated nanocarriers. The results show how subtle changes in the molecular architecture of the telodendrimer head groups have profound effects on the nanocarrier size, morphology, and asphericity. The simulation results are in agreement with the experimental data for DOX-encapsulated nanocarriers. This work emphasizes the increasing role of molecular simulations in the rational design of nanocarriers, thereby eliminating the trial and error method that has been prevalent in experimental synthesis. The molecular-level insights gained from the simulations will be used to design the next generation of drug-specific nanocarriers. PMID- 27513184 TI - Preferential Cancer Cell Self-Recognition and Tumor Self-Targeting by Coating Nanoparticles with Homotypic Cancer Cell Membranes. AB - The ultimate goal in cancer therapy and diagnosis is to achieve highly specific targeting to cancer cells. Coated with the source cancer cell membrane specifically derived from the homologous tumors, the nanoparticles are identified with the self-recognition internalization by the source cancer cell lines in vitro and the highly tumor-selective targeting "homing" to the homologous tumor in vivo even in the competition of another heterologous tumor. As the result, MNP@DOX@CCCM nanovehicle showed strong potency for tumor treatment in vivo and the MR imaging. This bioinspired strategy shows great potential for precise therapy/diagnosis of various tumors merely by adjusting the cell membrane source accordingly on the nanoparticle surface. PMID- 27513186 TI - Two Pathways for Dissociation of Highly Energized syn-CH3CHOO to OH Plus Vinoxy. AB - Ozonolysis of alkenes is an important nonphotolytic source of hydroxl radicals in the troposphere. The reaction proceeds through cycloaddition and subsequent decomposition to a carbonyl oxide, known as Criegee intermediates. Ozonolysis of alkene releases about 50 kcal/mol excess energy to form highly energized Criegee molecules, which can be stabilized and undergo further reaction or dissociate to OH+vinoxy products. The dissociation dynamics of partially stabilized Criegee (syn-CH3CHOO) has been thoroughly studied recently, in which the molecules dissociate by first isomerizing to vinyl hydroperoxide (VHP). Here we examine the dissociation dynamics of highly energized syn-CH3CHOO (42 kcal/mol), and a second, prompt dissociation path is discovered. The dissociation dynamics of these two paths are carefully examined through the animation of trajectories and the energy distributions of products. The new prompt path reveals a distinctly different translational energy and internal energy distributions of products compared to the known path through VHP. PMID- 27513187 TI - Exosomes derived from human mesenchymal stem cells promote gastric cancer cell growth and migration via the activation of the Akt pathway. AB - Mesenchymal stem cells (MSCs) are a component of the tumor microenvironment and can promote the development of gastric cancer through paracrine mechanism. However, the effects of MSC-exosomes (MSC-ex) on gastric cancer are less clear. The present study reported that MSC-ex promoted the proliferative and metastatic potential of gastric cancer cells ex vivo. It was found that MSC-ex enhanced the migration and invasion of HGC-27 cells via the induction of the epithelial mesenchymal transition. MSC-ex increased the expression of mesenchymal markers and reduced the expression of epithelial markers in gastric cancer cells. MSC-ex also enhanced the tumorigenicity of gastric cancer cells ex vivo. MSC-ex induced the stemness of gastric cancer cells. The expression of octamer-binding transcription factor 4, ex determining region Y-box 2 and Lin28B significantly increased in gastric cancer cells treated with MSC-ex. The present study further demonstrated that MSC-ex elicited these biological effects predominantly via the activation of the protein kinase B signaling pathway. Taken together, the present findings provided novel evidence for the role of MSC-ex in gastric cancer and a new opportunity for improving the efficiency of gastric cancer treatment by targeting MSC-ex. PMID- 27513189 TI - Human-derived feeder fibroblasts for the culture of epithelial cells for clinical use. AB - AIM: To investigate human oral mucosal fibroblasts (HOMF) and human limbal fibroblasts (HLF) as alternatives to murine 3T3 feeder fibroblasts currently used to support epithelial cell expansion for the treatment of limbal epithelial stem cell deficiency. METHODS: HLF and HOMF were compared with 3T3s for their ability to support the culture of human limbal epithelial cells and human oral mucosal epithelial cells. RESULTS: HOMF, but not HLF, were equivalent to 3T3s in terms of the number of epithelial population doublings achieved. Human limbal epithelial cells co-cultured with HOMF or 3T3s had similar expression of corneal and putative stem cell markers. CONCLUSION: HOMF are a suitable and safer feeder fibroblast alternative to 3T3s for the production of epithelial cells for clinical use. PMID- 27513190 TI - miRNA-24-3p promotes cell proliferation and regulates chemosensitivity in head and neck squamous cell carcinoma by targeting CHD5. AB - AIM: To investigate the role of miR-24-3p in tumorigenesis and chemosensitivity in head and neck squamous cell carcinoma (HNSCC). METHODS: Growth rate and colony formation assays were performed after transfection with miR-24-3p mimic and inhibitor in cultured SCC-15 cells, followed by a CellTiter-Glo(r) assay. Western blot and luciferase assays were performed to investigate the direct target of miR 24-3p. Xenograft mouse model was used to evaluate combinatorial effects of miR-24 3p inhibitor and 5-fluorouracil. RESULTS & CONCLUSION: Inhibition of miR-24-3p reduced cell proliferation, colony formation efficiency and reversed chemoresistance in HNSCC cells. CHD5 is the direct target of miR-24-3p which is required for the regulatory role of miR-24-3p in chemoresistance. miR-24-3p may represent a new therapeutic target for the improvement of clinical outcome in HNSCC. PMID- 27513192 TI - Development of carrier testing for common inborn errors of metabolism in the Wisconsin Plain population. AB - PURPOSE: This community project is an initiative through the University of Wisconsin Biochemical Genetics Clinic and the Wisconsin Newborn Screening Program to identify members of the Plain population who are at risk for having children with maple syrup urine disease (MSUD) or propionic acidemia (PA) or who have PA. METHODS: Because of the high prevalence of metabolic conditions in the Plain population and the importance of early intervention, a statewide outreach project was developed to provide targeted variant analysis of the common MSUD and PA pathogenic variants in this population through health-care provider distribution of blood spot testing kits. Awareness was achieved through outreach efforts with the state midwives guild and Plain population meetings. RESULTS: Eighty individuals were tested; diagnosis was confirmed for three adults with PA and one couple was identified as being at risk for having a child with PA. Genetic counseling was provided to those identified. Follow-up diagnostic testing was completed for the at-risk couple's children; none were found to be affected. CONCLUSION: This initiative successfully provided accessible clinical testing for MSUD and PA for a high-risk population. Early identification of at-risk couples sets the foundation for early care of at-risk neonates, thereby improving future clinical outcomes.Genet Med 19 3, 352-356. PMID- 27513191 TI - A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome. AB - BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7 dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3 methylglutaryl-coenzyme A reductase inhibitor that crosses the blood-brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles. METHODS: Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, double-blind, placebo controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period. RESULTS: No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 +/- 8.4% on placebo to 6.1 +/- 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist-C when subjects were taking simvastatin. CONCLUSION: This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be relatively safe in patients with SLOS, improves the serum dehydrocholesterol-to-total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS.Genet Med 19 3, 297-305. PMID- 27513193 TI - Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases. AB - PURPOSE: Diagnostic exome sequencing (DES) is now a commonly ordered test for individuals with undiagnosed genetic disorders. In addition to providing a diagnosis for characterized diseases, exome sequencing has the capacity to uncover novel candidate genes for disease. METHODS: Family-based DES included analysis of both characterized and novel genetic etiologies. To evaluate candidate genes for disease in the clinical setting, we developed a systematic, rule-based classification schema. RESULTS: Testing identified a candidate gene among 7.7% (72/934) of patients referred for DES; 37 (4.0%) and 35 (3.7%) of the genes received evidence scores of "candidate" and "suspected candidate," respectively. A total of 71 independent candidate genes were reported among the 72 patients, and 38% (27/71) were subsequently corroborated in the peer-reviewed literature. This rate of corroboration increased to 51.9% (27/52) among patients whose gene was reported at least 12 months previously. CONCLUSIONS: Herein, we provide transparent, comprehensive, and standardized scoring criteria for the clinical reporting of candidate genes. These results demonstrate that DES is an integral tool for genetic diagnosis, especially for elucidating the molecular basis for both characterized and novel candidate genetic etiologies. Gene discoveries also advance the understanding of normal human biology and more common diseases.Genet Med 19 2, 224-235. PMID- 27513194 TI - Personalized risk prediction for type 2 diabetes: the potential of genetic risk scores. AB - PURPOSE: Using effect estimates from genome-wide association studies (GWAS), we identified a genetic risk score (GRS) that has the strongest association with type 2 diabetes (T2D) status in a population-based cohort and investigated its potential for prospective T2D risk assessment. METHODS: By varying the number of single-nucleotide polymorphisms (SNPs) and their respective weights, alternative versions of GRS can be computed. They were tested in 1,181 T2D cases and 9,092 controls of the Estonian Biobank cohort. The best-fitting GRS was chosen for the subsequent analysis of incident T2D (386 cases). RESULTS: The best fit was provided by a novel doubly weighted GRS that captures the effect of 1,000 SNPs. The hazard for incident T2D was 3.45 times (95% CI: 2.31-5.17) higher in the highest GRS quintile compared with the lowest quintile, after adjusting for body mass index and other known predictors. Adding GRS to the prediction model for 5 year T2D risk resulted in continuous net reclassification improvement of 0.324 (95% CI: 0.211-0.444). In addition, a significant effect of the GRS on all-cause and cardiovascular mortality was observed. CONCLUSION: The proposed GRS would improve the accuracy of T2D risk prediction when added to the currently used set of predictors.Genet Med 19 3, 322-329. PMID- 27513195 TI - Medical applications of Cu, Zn, and S isotope effects. AB - This review examines recent applications of stable copper, zinc and sulfur isotopes to medical cases and notably cancer. The distribution of the natural stable isotopes of a particular element among coexisting molecular species varies as a function of the bond strength, the ionic charge, and the coordination, and it also changes with kinetics. Ab initio calculations show that compounds in which a metal binds to oxygen- (sulfate, phosphate, lactate) and nitrogen-bearing moieties (histidine) favor heavy isotopes, whereas bonds with sulfur (cysteine, methionine) favor light isotopes. Oxidized cations (e.g., Cu(ii)) and low coordination numbers are expected to favor heavy isotopes relative to their reduced counterparts (Cu(i)) and high coordination numbers. Here we discuss the first observations of Cu, Zn, and S isotopic variations, three elements closely related along multiple biological pathways, with emphasis on serum samples of healthy volunteers and of cancer patients. It was found that heavy isotopes of Zn and to an even greater extent Cu are enriched in erythrocytes relative to serum, while the difference is small for sulfur. Isotopic variations related to age and sex are relatively small. The 65Cu/63Cu ratio in the serum of patients with colon, breast, and liver cancer is conspicuously low relative to healthy subjects. The characteristic time over which Cu isotopes may change with disease progression (a few weeks) is consistent with both the turnover time of the element and albumin half-life. A parallel effect on sulfur isotopes is detected in a few un-medicated patients. Copper in liver tumor tissue is isotopically heavy. In contrast, Zn in breast cancer tumors is isotopically lighter than in healthy breast tissue. 66Zn/64Zn is very similar in the serum of cancer patients and in controls. Possible reasons for Cu isotope variations may be related to the cytosolic storage of Cu lactate (Warburg effect), release of intracellular copper from cysteine clusters (metallothionein), or the hepatocellular and biosynthetic dysfunction of the liver. We suggest that Cu isotope metallomics will help evaluate the homeostasis of this element during patient treatment, notably by chelates and blockers of Cu trafficking, and understand the many biochemical pathways in which this element is essential. PMID- 27513196 TI - The Time-Dependent Transfer Factor of Radiocesium from Soil to Game Animals in Japan after the Fukushima Dai-ichi Nuclear Accident. AB - Since the Fukushima Dai-ichi accident, monitoring of tissues from hunted game animals ensures compliance with the standard food limits for radionuclides in Japan. We quantified the transfer of (137)Cs from contaminated land to game animals using the Aggregated transfer factor (Tag = activity concentration in meat [Bq kg(-1) fw]/amount in soil [Bq m(-2)]) of (137)Cs for Asian black bear, wild boar, sika deer, green pheasant, copper pheasant and wild duck, collected between 2011 and 2015. Open data sources were used from Fukushima, Miyagi, Ibaraki, Tochigi, and Gunma prefectures. Our initially compiled data showed that the maximum reported (137)Cs activity concentration in wild boar after the Fukushima Dai-ichi accident were lower than those reported after the Chernobyl accident. The geometric mean Tag values (m(2)kg(-1) fw) of (137)Cs in 2015 for Asian black bear, wild boar, sika deer and copper pheasant were similar (1.9-5.1) * 10(-3) while those for green pheasant and wild duck were about 1 order of magnitude lower at (1.0-2.2) * 10(-4). Effective half-lives were 1.2-6.9 y except for sika deer and copper pheasant where no decreases were found. In contrast to the Chernobyl accident, no seasonal change occurred in the meat (137)Cs activity concentrations of the wild animals during the study period. PMID- 27513197 TI - Auditory capture of visual motion: effects on perception and discrimination. AB - We asked whether the perceived direction of visual motion and contrast thresholds for motion discrimination are influenced by the concurrent motion of an auditory sound source. Visual motion stimuli were counterphasing Gabor patches, whose net motion energy was manipulated by adjusting the contrast of the leftward-moving and rightward-moving components. The presentation of these visual stimuli was paired with the simultaneous presentation of auditory stimuli, whose apparent motion in 3D auditory space (rightward, leftward, static, no sound) was manipulated using interaural time and intensity differences, and Doppler cues. In experiment 1, observers judged whether the Gabor visual stimulus appeared to move rightward or leftward. In experiment 2, contrast discrimination thresholds for detecting the interval containing unequal (rightward or leftward) visual motion energy were obtained under the same auditory conditions. Experiment 1 showed that the perceived direction of ambiguous visual motion is powerfully influenced by concurrent auditory motion, such that auditory motion 'captured' ambiguous visual motion. Experiment 2 showed that this interaction occurs at a sensory stage of processing as visual contrast discrimination thresholds (a criterion-free measure of sensitivity) were significantly elevated when paired with congruent auditory motion. These results suggest that auditory and visual motion signals are integrated and combined into a supramodal (audiovisual) representation of motion. PMID- 27513198 TI - Is the Wnt/beta-catenin pathway involved in the anti-inflammatory activity of glucocorticoids in spinal cord injury? AB - The Wnt canonical or the Wnt/beta-catenin pathway has been implicated in the regulation of several physiopathological pathways such as inflammation. Glucocorticoids (GCs) are administered widely to treat inflammation in several diseases, including spinal cord injury (SCI). The aim of this study was to evaluate whether the Wnt canonical pathway is involved in experimental SCI and whether it is implicated in the anti-inflammatory activity of two different GCs: the methylprednisolone sodium succinate (MPSS), considered the standard treatment for acute SCI, and mometasone furoate (MF), mainly administered for the treatment of airway and skin diseases. Experimental SCI was induced in mice by surgical spinal cord compression at the T6-T7 level. Then, mice were treated with MPSS (6 mg/kg) or MF (0.1 mg/kg) for 7 days until they were killed. Both GCs were found to modulate the Wnt canonical pathway, but in particular, the MF treatment was shown to restore completely the downregulated pathway in SCI. The MF treatment also significantly increased peroxisome proliferator-activated receptor-gamma, a Wnt target gene with anti-inflammatory properties, compared with MPSS, and it also inhibited the levels of the proinflammatory cytokines interleukin 1beta and tumor necrosis factor-alpha. Here, we suggest that MF has more efficacy than MPSS in inhibiting inflammation in an SCI experimental model and we propose the beta catenin/peroxisome proliferator-activated receptor-gamma axis as the mechanism by which MF exerts these beneficial effects. PMID- 27513199 TI - Isoflurane attenuates mouse microglial engulfment induced by lipopolysaccharide and interferon-gamma possibly by inhibition of p38 mitogen-activated protein kinase. AB - Microglial engulfment is a basic function to clean up dead and injured cells and invaders, such as bacteria. This study was designed to assess the effects of isoflurane on the microglial engulfment induced by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) and the involvement of p38 mitogen-activated protein kinase (MAPK) in these effects. C8-B4 microglial cells were exposed to 1, 2, and 3% isoflurane at 2 h after the initiation of LPS (100 ng/ml) and IFN-gamma (1 ng/ml) stimulation. Fluorescent immunostaining was performed to assess the percentage of cells with engulfment of fluorescent microspheres after stimulation for 24 h. P38 and phosphorylated p38 were determined by Western blotting. Isoflurane concentration dependently decreased microglial engulfment stimulated by LPS and IFN-gamma. LPS and IFN-gamma increased the phosphorylated p38 in microglial cells. This upregulation was decreased by isoflurane. SB203580, a p38 MAPK inhibitor, abolished the LPS-induced and IFN-gamma-induced increase of engulfment activity, whereas anisomycin, a p38 MAPK activator, partly reversed the isoflurane-decreased microglial engulfment activity. These results suggest that isoflurane reduces LPS-induced and IFN-gamma-induced microglial engulfment and that these effects may be mediated by inhibiting p38 MAPK. PMID- 27513200 TI - Temporal prediction restores the evaluative processing of delayed action feedback: an electrophysiological study. AB - The evaluative processing of the valence of action feedback is reflected by an event-related brain potential component called feedback-related negativity (FRN) or reward positivity (RewP). Recent studies have shown that FRN/RewP is markedly reduced when the action-feedback interval is long (e.g. 6000 ms), indicating that an increase in the action-feedback interval can undermine the evaluative processing of the valence of action feedback. The aim of the present study was to investigate whether or not such undermined evaluative processing of delayed action feedback could be restored by improving the accuracy of the prediction in terms of the timing of action feedback. With a typical gambling task in which the participant chose one of two cards and received an action feedback indicating monetary gain or loss, the present study showed that FRN/RewP was significantly elicited even when the action-feedback interval was 6000 ms, when an auditory stimulus sequence was additionally presented during the action-feedback interval as a temporal cue. This result suggests that the undermined evaluative processing of delayed action feedback can be restored by increasing the accuracy of the prediction on the timing of the action feedback. PMID- 27513201 TI - Protective effects of quercetin on dieldrin-induced endoplasmic reticulum stress and apoptosis in dopaminergic neuronal cells. AB - Dieldrin, an organochlorine pesticide still used in several developing countries, has been proposed as a risk factor for Parkinson's disease. Quercetin is one of the potent bioactive flavonoids present in numerous plants. In this study, we investigated the protective effects of quercetin on neurotoxicity induced by dieldrin in cultured dopaminergic SN4741 cells. Our initial experiments showed that quercetin (10-40 MUM) dose dependently prevented dieldrin (20 MUM)-induced cytotoxicity in SN4741 cells. Pretreatment for 1 h with quercetin before dieldrin application could significantly suppress dieldrin-induced apoptotic characteristics, including nuclear condensation, DNA fragmentation, and caspase 3/7 activation. Results showed that dieldrin-induced markers of endoplasmic reticulum (ER) stress response such as chaperone GRP78, heme oxygenase-1, and phosphorylation of the alpha subunit of eukaryotic initiation factor 2. In addition, dieldrin reduced antiapoptotic Bcl-2 expression, but significantly elevated a proapoptotic transcription factor CHOP. Furthermore, RNA interference to CHOP almost completely repressed dieldrin-induced apoptotic cell death. Interestingly, quercetin prevented the changes in dieldrin-induced ER stress markers. These results suggest that quercetin may suppress the ER stress-CHOP pathway and dieldrin-induced apoptosis in dopaminergic neurons. PMID- 27513202 TI - Differentiated adipose-derived stem cells promote the recovery of nociceptor function in rats. AB - The loss of nociceptive function in the skin because of trauma or surgery can impair the quality of life. The recovery of nociceptor function is mediated by two different axonal responses: nerve growth factor (NGF)-dependent collateral sprouting of undamaged nerves and NGF-independent regeneration of damaged nerves. We reported previously that adipose-derived stem cells (ASCs) can transdifferentiate into Schwann cell (SC)-like cells (dASCs) and that transplantation of dASCs increases axonal density in skin flaps. In the present study, we used an animal model that allowed for the individual assessment of collateral sprouting and regeneration. In-vitro differentiation of ASCs to dASCs significantly increased the production of NGF and brain-derived neurotrophic factor (BDNF) to levels comparable with SCs. In-vivo experiments showed that dASC and SC transplantation significantly increased the area of the mechano nociceptive field in both collateral sprouting and regeneration models, whereas ASC transplantation exerted no significant effect. Antibody blocking experiment showed that these effects of dASC transplantation in the regeneration model were partly mediated by BDNF. Interestingly, the final areas of nociceptive fields between the two experimental models did not differ significantly for any treatment condition. These results indicate that dASC transplantation differentially facilitates collateral sprouting and axonal regeneration by delivering NGF and other neurotrophic factors (e.g. BDNF), respectively. Although there is a limit to nociceptive field enlargement irrespective of axonal response, dASC transplantation could present a new approach for improving nociceptive function in denervated skin. PMID- 27513203 TI - Molecular cloning, expression analysis and miRNA prediction of vascular endothelial growth factor A (VEGFAa and VEGFAb) in pond loach Misgurnus anguillicaudatus, an air-breathing fish. AB - Vascular endothelial growth factor A (VEGFA) is the most studied and the best characterized member of the VEGF family and is a key regulator of angiogenesis via its ability to affect the proliferation, migration, and differentiation of endothelial cells. In this study, the full-length cDNAs encoding VEGFAa and VEGFAb from pond loach, Misgurnus anguillicaudatus, were isolated. The VEGFAa is constituted by an open reading frame (ORF) of 570bp encoding for a peptide of 189 amino acid residues, a 639bp 5'-untranslated region (UTR) and a 2383bp 3' UTR. The VEGFAb is constituted by an ORF of 687bp encoding for a peptide of 228 amino acid residues, a 560bp 5' UTR and a 1268bp 3' UTR. Phylogenetic analysis indicated that the VEGFAa and VEGFAb of pond loach were conserved in vertebrates. Expression levels of VEGFAa and VEGFAb were detected by RT-qPCR at different development stages of pond loach and in different tissues of 6-month-old, 12 month-old and 24-month-old pond loach. Moreover, eight predicted miRNAs (miR-200, miR-29, miR-218, miR-338, miR-103, miR-15, miR-17 and miR-223) targeting VEGFAa and VEGFAb were validated by an intestinal air-breathing inhibition experiment. This study will be of value for further studies into the function of VEGFA and its corresponding miRNAs, which will shed a light on the vascularization and accessory air-breathing process in pond loach. PMID- 27513204 TI - The use of brincidofovir for the treatment of mixed dsDNA viral infection. AB - Double-stranded DNA (dsDNA) viral infections constitute a major complication following solid organ and stem cell transplantation. Few therapeutic options are currently available for the treatment of such infections in highly immunocompromised hosts. Brincidofovir is an oral investigational drug with broad antiviral activity against dsDNA viruses in vitro, but clinical experience is limited. Here we report a young female who developed a mixed infection with adenovirus, cytomegalovirus, Epstein-Barr virus and BK polyomavirus after an allogeneic stem cell transplant, and was successfully treated with brincidofovir. PMID- 27513205 TI - Toxoplasma gondii Infection Potentiates Cognitive Impairments of Alzheimer's Disease in the BALB/c Mice. AB - This study tests the hypothesis that in chronic Toxoplasma gondii infection communication among immune cells promotes neuroinflammation through cytokine networks and potentiate cognitive impairments in BALB/c mice with Alzheimer's disease (AD). The animal model of Toxoplasma infection was established by the intraperitoneal inoculation of 20-25 tissue cysts from the Tehran strain of T. gondii . We injected amyloid-beta 1-42 peptide (Abeta1-42, 1 and 2 MUl) into the hippocampus of BALB/c mice to establish an animal model of AD. The behavioral experiments such as spatial learning and memory were performed using the Morris water maze test. The mRNA levels of TNF-alpha, IL-1beta, IFN-gamma, and inducible nitric oxide synthase (iNOS) were examined by real-time PCR. We found that T. gondii infection caused AD-like symptoms and impaired learning and memory functions of the infected BALB/c mice. We also found that in Toxoplasma infection + Abeta1-42 (1 MUl) group, T. gondii infection could potentiate AD in infected mice receiving subdoses of Abeta1-42 (1 MUl) and caused considerable impairment in learning and memory functions similar to AD group. Comparison of the results demonstrated that mRNA levels of IL-1beta, TNF-alpha, IFN-gamma, and iNOS significantly (P < 0.001) increased in T. gondii + Abeta1-42 (1 MUl) in comparison with the other tested groups. The obtained results showed that chronic T. gondii infection communication among immune cells promotes neuroinflammation through cytokine networks and induces pathological progression of AD in the mice brain, whereas the presence of neuroanatomical Toxoplasma tissue cysts in the brain could also affect the behavioral functions in T. gondii -infected mice. PMID- 27513206 TI - Evaluating the Impact of National Public Health Department Accreditation - United States, 2016. AB - In 2011, the nonprofit Public Health Accreditation Board (PHAB) launched the national, voluntary public health accreditation program for state, tribal, local, and territorial public health departments. As of May 2016, 134 health departments have achieved 5-year accreditation through PHAB and 176 more have begun the formal process of pursuing accreditation. In addition, Florida, a centralized state in which the employees of all 67 local health departments are employees of the state, achieved accreditation for the entire integrated local public health department system in the state. PHAB-accredited health departments range in size from a small Indiana health department that serves approximately 17,000 persons to the much larger California Department of Public Health, which serves approximately 38 million persons. Collectively, approximately half the U.S. population, or nearly 167 million persons, is covered by an accredited health department. Forty-two states and the District of Columbia now have at least one nationally accredited health department. In a survey conducted through a contract with a social science research organization during 2013-2016, >90% of health departments that had been accredited for 1 year reported that accreditation has stimulated quality improvement and performance improvement opportunities, increased accountability and transparency, and improved management processes. PMID- 27513207 TI - Ultrasound harmonic enhanced imaging using eigenspace-based coherence factor. AB - Tissue harmonic imaging (THI) utilizes harmonic signals generating within the tissue as the result of nonlinear acoustic wave propagation. With inadequate transmitting acoustic energy, THI is incapable to detect the small objects since poor harmonic signals have been generated. In most cases, high transmission energy cannot be guaranteed because of the imaging safety issue or specific imaging modality such as the plane wave imaging (PWI). Discrimination of small point targets such as calcification, however, is particularly important in the ultrasound diagnosis. Few efforts have been made to pursue the THI with high resolution and good small target visibility at the same time. In this paper, we proposed a new eigenspace-based coherence factor (ESBCF) beamformer to solve this problem. A new kind of coherence factor (CF), named as ESBCF, is firstly proposed to detect the point targets. The detected region-of-interest (ROI) is then enhanced adaptively by using a newly developed beamforming method. The ESBCF combines the information from signal eigenspace and coherence factor by expanding the CF to the covariance matrix of signal. Analogous to the image processing but in the radio frequency (RF) data domain, the proposed method fully utilizes the information from the fundamental and harmonic components. The performance of the proposed method is demonstrated by simulation and phantom experiments. The improvement of the point contrast ratio (PCR) is 7.6dB in the simulated data, and 6.0dB in the phantom experiment. Thanks to the improved small point detection ability of the ESBCF, the proposed beamforming algorithm can enhance the PCR considerably and maintain the high resolution of the THI at the same time. PMID- 27513208 TI - NMR Spectra Transformed by Electron-Nuclear Coupling as Indicator of Structural Peculiarities of Magnetically Active Molecular Systems. AB - The peculiarities of nuclear spin relaxation in the paramagnetic systems have been analyzed taking into account the exchange processes. The analysis is based on the modified Solomon-Bloembergen equations. In this line, the conditions of detecting of the NMR signals of samples are discussed depending on resonance frequency of the NMR spectrometer and characteristic relaxation time. On this basis, (1)H NMR spectra of cobalt semiquinolate complex have been analyzed. It has been shown that the satellite signals observed in the spectrum are caused by hyperfine coupling of the tert-butyl group protons with alpha and beta states (localized on pz orbital of the aromatic carbon) of unpaired electron spin. The relaxation process of the resonance protons is controlled by paramagnetic dipole dipole coupling. The contact hyperfine coupling does not contribute to the paramagnetic broadening. A mechanism involving paramagnetic molecular structures, which are responsible for intramolecular exchange processes in the cobalt semiquinolate complex, is given. PMID- 27513209 TI - Inhibition of coagulation proteases Xa and IIa decreases ischemia-reperfusion injuries in a preclinical renal transplantation model. AB - Coagulation is an important pathway in the pathophysiology of ischemia reperfusion injuries. In particular, deceased after circulatory death (DCD) donors undergo a no-flow period, a strong activator of coagulation. Hence, therapies influencing the coagulation cascade must be developed. We evaluated the effect of a new highly specific and effective anti-Xa/IIa molecule, with an integrated innovative antidote site (EP217609), in a porcine preclinical model mimicking injuries observed in DCD donor kidney transplantation. Kidneys were clamped for 60 minutes (warm ischemia), then flushed and preserved for 24 hours at 4 degrees C in University of Wisconsin (UW) solution (supplemented or not). EP217609-supplemented UW solution (UW-EP), compared with unfractionated heparin supplemented UW solution (UW-UFH) or UW alone (UW). A mechanistic investigation was conducted in vitro: addition of EP217609 to endothelial cells during hypoxia at 4 degrees C in the UW solution inhibited thrombin generation during reoxygenation at 37 degrees C in human plasma and reduced tumor necrosis factor alpha, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 messenger RNA cell expressions. In vivo, function recovery was markedly improved in the UW-EP group. Interestingly, levels of thrombin-antithrombin complexes (reflecting thrombin generation) were reduced 60 minutes after reperfusion in the UW-EP group. In addition, 3 months after transplantation, lower fibrosis, epithelial-mesenchymal transition, inflammation, and leukocyte infiltration were observed. Using this new dual anticoagulant, anti-Xa/IIa activity during kidney flush and preservation is protected by reducing thrombin generation at revascularization, improving early function recovery, and decreasing chronic lesions. Such an easy-to-deploy clinical strategy could improve marginal graft outcome. PMID- 27513212 TI - Therapeutic potential of Taraxacum officinale against HCV NS5B polymerase: In vitro and In silico study. AB - Discovery of alternative and complementary regimens for HCV infection treatment is a need of time from clinical as well as economical point of views. Low cost of bioactive natural compounds production, high biochemical diversity and inexistent/milder side effects contribute to new therapies. Aim of this study is to clarify anti-HCV role of Taraxacum officinale, a natural habitat plant rich of flavonoids. In this study, methanol extract of T. officinale leaves was initially analyzed for its cytotoxic activity in human hepatoma (Huh-7) and CHO cell lines. Hepatoma cells were transfected with pCR3.1/Flagtag/HCV NS5B gene cloned vector (genotype 1a) along with T. officinale extract. Considering NS5B polymerase as potential therapeutic drug target, twelve phytochemicals of T. officinale were selected as ligands for molecular interaction with NS5B protein using Molecular Operating Environment (MOE) software. Sofosbuvir (Sovaldi: brand name) currently approved as new anti-HCV drug, was used as standard in current study for comparative analysis in computational docking screening. HCV NS5B polymerase as name indicates plays key role in viral genome replication. On the basis of which NS5B gene is targeted for determining antiviral role of T. officinale extract and 65% inhibition of NS5B expression was documented at nontoxic dose concentration (200MUg/ml) using Real-time PCR. In addition, 57% inhibition of HCV replication was recorded when incubating Huh-7 cells with high titer serum of HCV infected patients along with leaves extract. Phytochemicals for instance d-glucopyranoside (-31.212 Kcal/mol), Quercetin (-29.222 Kcal/mol), Luteolin (-26.941 Kcal/mol) and some others displayed least binding energies as compared to standard drug Sofosbuvir (-21.0746 Kcal/mol). Results of our study strongly revealed that T. officinale leaves extract potentially blocked the viral replication and NS5B gene expression without posing any toxic effect on normal fibroblast cells of body. PMID- 27513211 TI - Toward revision of antimicrobial therapies in hematopoietic stem cell transplantation: target the pathogens, but protect the indigenous microbiota. AB - Host microbiota plays important roles in providing colonization resistance to pathogens and instructing development and function of the immune system. Antibiotic treatments intended to target pathogens further weaken the host defenses and may paradoxically increase the risk of systemic infections. This consequence is especially problematic in patients undergoing hematopoietic stem cell transplantation, where the mucosal defenses are already weakened by the conditioning regimens. This review discusses the roles that indigenous microbiota plays in protecting the host and maintaining immune homeostasis. In addition, we highlight possible strategies that are being developed to allow targeted antimicrobial therapy against pathogens, while minimizing the harm to indigenous microbiota. PMID- 27513213 TI - Synergistic production of TNFalpha and IFNalpha by human pDCs incubated with IFNlambda3 and IL-3. AB - In this study, we investigated whether IFNlambda3 and IL-3 reciprocally influence their capacity to activate various functions of human plasmacytoid dendritic cells (pDCs). In fact, we preliminarily observed that IFNlambda3 upregulates the expression of the IL-3Ralpha (CD123), while IL-3 augments the expression of IFNlambdaR1 in pDCs. As a result, we found that combination of IFNlambda3 and IL 3 induces a strong potentiation in the production of TNFalpha, IFNalpha, as well as in the expression of Interferon-Stimulated Gene (ISG) mRNAs by pDCs, as compared to either IFNlambda3 or IL-3 alone. In such regard, we found that endogenous IFNalpha autocrinally promotes the expression of ISG mRNAs in IL-3-, but not in IFNlambda3 plus IL-3-, treated pDCs. Moreover, we uncovered that the production of IFNalpha by IFNlambda3 plus IL-3-treated pDCs is mostly dependent on endogenously produced TNFalpha. Altogether, our data demonstrate that IFNlambda3 and IL-3 collaborate to promote, at maximal levels, discrete functional responses of human pDCs. PMID- 27513214 TI - Assembly and Folding of Twisted Baskets in Organic Solvents. AB - A synthetic method for obtaining enantiopure and twisted baskets of type (P)-3 is described. These chiral cavitands were found to fold quinoline gates, at the rim of their twisted platform, in acetonitrile and give molecular capsules that assemble into large unilamellar vesicles. In a less polar dichloromethane, however, cup-shaped (P)-3 packed into vesicles but with the quinoline gates in an unfolded orientation. The ability of twisted baskets to form functional nanostructured materials could be of interest for building stereoselective sensors and catalysts. PMID- 27513210 TI - High-resolution characterization of the human microbiome. AB - The human microbiome plays an important and increasingly recognized role in human health. Studies of the microbiome typically use targeted sequencing of the 16S rRNA gene, whole metagenome shotgun sequencing, or other meta-omic technologies to characterize the microbiome's composition, activity, and dynamics. Processing, analyzing, and interpreting these data involve numerous computational tools that aim to filter, cluster, annotate, and quantify the obtained data and ultimately provide an accurate and interpretable profile of the microbiome's taxonomy, functional capacity, and behavior. These tools, however, are often limited in resolution and accuracy and may fail to capture many biologically and clinically relevant microbiome features, such as strain-level variation or nuanced functional response to perturbation. Over the past few years, extensive efforts have been invested toward addressing these challenges and developing novel computational methods for accurate and high-resolution characterization of microbiome data. These methods aim to quantify strain-level composition and variation, detect and characterize rare microbiome species, link specific genes to individual taxa, and more accurately characterize the functional capacity and dynamics of the microbiome. These methods and the ability to produce detailed and precise microbiome information are clearly essential for informing microbiome based personalized therapies. In this review, we survey these methods, highlighting the challenges each method sets out to address and briefly describing methodological approaches. PMID- 27513215 TI - Protective effects of miR-25 against hypoxia/reoxygenation-induced fibrosis and apoptosis of H9c2 cells. AB - It has been previously demonstrated that microRNA (miR)-25 plays critical roles in collagen deposition. Ischemia/reperfusion injury to the myocardium results in fibrosis and collagen deposition. However, whether miR-25 is involved in the development of hypoxia/reoxygenation (H/R)-induced fibrosis in cardiomyocytes or not remains largely unknown. For this purpose, in the present study, cardiomyocyte H9c2 cells were subjected to H/R. The techniques of flow cytometry, western blot analysis and RT-qPCR were used and we observed increases in the cell apoptosis rate and fibrosis as well as blocking of the cell cycle in the G1 phase. Moreover, the expression of miR-25 was downregulated after H/R and high mobility group box 1 (HMGB1) expression was increased. We also found that the overexpression of miR-25 under conditions of H/R inhibited fibrosis and cell apoptosis as well as reversing the cell cycle blocking. Additionally, the targeting of HMGB1 by miR-25 was confirmed by a dual-luciferase reporter gene assay. Moreover, the effects of miR-25 were further enhanced by a transforming growth factor-beta1 (TGF-beta1)/Smad3 inhibitor, SB431542, as fibrosis was reduced and apoptosis was suppressed. In conclusion, the protective effects of miR-25 against H/R-induced fibrosis and apoptosis H9c2 cells were due to direct targeting of HMGB1 through the downregulation of the TGF-beta1/Smad3 signaling pathway. PMID- 27513216 TI - Iron complexes of a bidentate picolyl-NHC ligand: synthesis, structure and reactivity. AB - The synthesis, structure and reactivity of bidentate picolyl N-heterocyclic carbene (NHC) iron compounds were studied. Compounds [FeBr(HL)2]Br (1), [FeBr(HL)(HMDS)] (2) and [FeBr2(HL)] (3) (HL = 1-mesityl-3-(pyridin-2 ylmethyl)imidazol-1-ylidene, HMDS = hexamethyldisilazide) were prepared from H2LBr with suitable amounts of Fe(HMDS)2 or in situ prepared [Fe(HMDS)Br]. The deprotonation of 1 with 2 eq. of LiHMDS gave [FeL2] (4), featuring dearomatized pyridine moieties with exocyclic C-C double bonds. The protonation of 4 with 2 eq. of PPh3.HBr results in the formation of 1. Attempted deprotonation of 3 using benzyl Grignard as the base resulted in transmetalation products [FeBnBr(HL)] (5) and [FeBn2(HL)] (6). Exposure of 6 to CO resulted in the formation of diamagnetic compound [Fe(CO)3(HL)] (7) and dibenzyl ketone. Prolonged exposure of 7 to CO with heating induces pyridine dissociation, affording [Fe(CO)4(HL-kappaC)] (8). Treatment of compound 6 with an equimolar amount of p-methoxybenzyl bromide yielded homo- and cross-coupling products. PMID- 27513217 TI - The Dilemma of Blood Transfusion: Strict or Liberal? PMID- 27513218 TI - Porous Materials with Tunable Structure and Mechanical Properties via Templated Layer-by-Layer Assembly. AB - The deposition of stiff and strong coatings onto porous templates offers a novel strategy for fabricating macroscale materials with controlled architectures at the micro- and nanoscale. Here, layer-by-layer assembly is utilized to fabricate nanocomposite-coated foams with highly customizable properties by depositing polymer-nanoclay coatings onto open-cell foam templates. The compressive mechanical behavior of these materials evolves in a predictable manner that is qualitatively captured by scaling laws for the mechanical properties of cellular materials. The observed and predicted properties span a remarkable range of density-stiffness space, extending from regions of very soft elastomer foams to very stiff, lightweight honeycomb and lattice materials. PMID- 27513219 TI - MRI reconstruction with joint global regularization and transform learning. AB - Sparsity based regularization has been a popular approach to remedy the measurement scarcity in image reconstruction. Recently, sparsifying transforms learned from image patches have been utilized as an effective regularizer for the Magnetic Resonance Imaging (MRI) reconstruction. Here, we infuse additional global regularization terms to the patch-based transform learning. We develop an algorithm to solve the resulting novel cost function, which includes both patchwise and global regularization terms. Extensive simulation results indicate that the introduced mixed approach has improved MRI reconstruction performance, when compared to the algorithms which use either of the patchwise transform learning or global regularization terms alone. PMID- 27513220 TI - Behavioral patterns of environmental performance evaluation programs. AB - During the past decades numerous environmental performance evaluation programs have been developed and implemented on different geographic scales. This paper develops a taxonomy of environmental management behavioral patterns in order to provide a practical comparison tool for environmental performance evaluation programs. Ten such programs purposively selected are mapped against the identified four behavioral patterns in the form of diagnosis, negotiation, learning, and socialization and learning. Overall, we found that schemes which serve to diagnose environmental abnormalities are mainly externally imposed and have been developed as a result of technical debates concerning data sources, methodology and ranking criteria. Learning oriented scheme is featured by processes through which free exchange of ideas, mutual and adaptive learning can occur. Scheme developed by higher authority for influencing behaviors of lower levels of government has been adopted by the evaluated to signal their excellent environmental performance. The socializing and learning classified evaluation schemes have incorporated dialogue, participation, and capacity building in program design. In conclusion we consider the 'fitness for purpose' of the various schemes, the merits of our analytical model and the future possibilities of fostering capacity building in the realm of wicked environmental challenges. PMID- 27513221 TI - Effects of diazinon on adaptation to sea-water by the endangered Persian sturgeon, Acipenser persicus, fingerlings. AB - To replenish the depleting populations of sturgeon fishes especially Persian sturgeon, Acipenser persicus in the Caspian Sea, millions of Persian sturgeon fingerlings are farmed through artificial propagation and released into the Iranian river estuaries annually. Fish osmoregulation is a vital physiological process that can be affected during the release. Many Iranian river estuaries are under the influence of pesticides originating from farming activities that may affect osmoregulation. In this study, Persian sturgeon fingerlings were exposed to sublethal concentrations (0, 0.18, 0.54, 0.9mgL(-)(1)) of diazinon for 96h (short-term trial) and 12 days (long-term trial) in fresh water (FW) and then fish were exposed in brackish water (BW) for 24h. After 96h and 12 days of exposure in FW, the lower levels of plasma triidothyronine (T3), thyroxine (T4), Na(+), Cl(-), K(+), gill Na(+)/K(+)- ATPase activity and number of chloride cells were observed in exposed fish (0.54 and 0.9mgL(-)(1) diazinon) compared to control group and 0.18mgL(-)(1) diazinon treatment. Also, higher levels of plasma cortisol (except 0.18mgL(-)(1) diazinon treatment in long-term trial) were observed in diazinon exposed fish compared to control group. However, gill Na(+)/K(+)-ATPase activity and the number of chloride cells were higher in fingerlings exposed to diazinon compared than control. When fish were exposed in BW for 24h, the following changes occurred: (a) in short-term trial: increases in cortisol and Cl(-) levels (0.54mgL(-)(1) diazinon ), Na(+) (0.9mgL(-)(1) diazinon ) and gill Na(+)/K(+)-ATPase activity (0.18mgL(-)(1) diazinon ). In control group, cortisol, T4, Na(+), gill Na(+)/K(+)-ATPase activity and the number of chloride cells increased significantly. (b) In long-term trial: increases in K(+) levels in fish exposed to 0.9mgL(-)(1) diazinon, Na+ in all diazinon concentrations and decreases in chloride cells number in fish exposed to 0.18mgL( )(1) diazinon. In control group, significant increases were observed in cortisol, T3, Na(+) and chloride cells number. Finally, gill showed many histopathological damages during exposure in FW and BW. Our results suggest that the contamination of river estuaries with diazinon may alter the osmoregulation ability of released Persian sturgeon fingerlings, which could lead to a failure in their restocking program in the Caspian Sea. PMID- 27513222 TI - Development, validation, and application of a method for selected avermectin determination in rural waters using high performance liquid chromatography and fluorescence detection. AB - Avermectins (AVM) are macrocyclic lactones used in livestock and agriculture. A quantitative method of high performance liquid chromatography with fluorescence detection for the determination of eprinomectin, abamectin, doramectin and ivermectin in rural water samples was developed and validated. The method was employed to study samples collected in the Pito Aceso River microbasin, located in the Bom Jardim municipality, Rio de Janeiro State, Brazil. Samples were extracted by solid phase extraction using a polymeric stationary phase, the eluted fraction was re-concentrated under a gentle N2 flow and derivatized to allow AVM determination using liquid chromatography with fluorescence detection. The excitation and emission wavelengths of the derivatives were 365 and 470nm, respectively, and a total chromatographic run of 12min was achieved. Very low limits of quantification (22-58ngL(-1)) were found after re-concentration using N2. Recovery values varied from 85.7% to 119.2% with standard deviations between 1.2% and 10.2%. The validated method was applied in the determination of AVM in 15 water samples collected in the Pito Aceso River microbasin, but most of them were free of AVM or showed only trace levels of these compounds, except for a sample that contained doramectin (9.11ugL(-1)). The method is suitable for routine analysis with satisfactory recovery, sensitivity, and selectivity. PMID- 27513223 TI - Comparison of the Tolerability of Diclofenac and Nepafenac. AB - PURPOSE: Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the prevention and treatment of inflammation and pain following cataract surgery. Preservative-free diclofenac and nepafenac drops are commonly used ophthalmic NSAIDs. The purpose of this study was to compare the tolerability of diclofenac to that of nepafenac. METHODS: In this prospective patient-blinded study, consecutive patients undergoing cataract surgery were included. One drop of nepafenac 0.1% and diclofenac sodium 0.1% were instilled in the right and left eyes, respectively, one immediately after the other, 1 day before surgery. Visual analog scale (scale 0-10) was used to measure patient discomfort, itching, burning, and pain at 1 second (s), 15 s, 1 minute (min), and 5 min postadministration. RESULTS: Overall, 44 eyes of 22 patients were included in this study. Diclofenac and nepafenac had high and similar tolerability at all time points with no significant difference regarding all aspects of tolerability. A vast majority of patients (72%) did not prefer 1 drop over the other in terms of overall comfort. CONCLUSIONS: Both diclofenac and nepafenac seem to have similar high tolerability. Diclofenac may be an affordable alternative to nepafenac and therefore should be considered by prescribing physicians, specifically in preoperative cataract patients. PMID- 27513224 TI - CT Radiation Dose Reduction in Robot-assisted Pediatric Spinal Surgery. AB - STUDY DESIGN: Retrospective consecutive cohort series. OBJECTIVE: The aim of this study was to develop a low-dose computed tomography (CT) protocol for use in robot-assisted pediatric spinal surgery. SUMMARY OF BACKGROUND DATA: CT scans are utilized preoperatively for preoperative planning, by navigation software during robot-assisted surgery, and postoperatively to assess surgical implant placement. Traditionally high radiation doses produced by CT scanning are a concern in the highly radiosensitive pediatric population. METHODS: We developed a low-dose protocol using phantom scans. A cohort of patients undergoing CT scanning using the low-dose protocol was collected. Further, a matching cohort of patients who underwent standard scanning was collected. Image quality was assessed by observer ratings. Radiation doses and image quality metrics were compared for the standard and low-dose protocol patients. RESULTS: Effective dose significantly decreased 84% to 91% depending on patient size and whether the scan was preoperative or postoperative. All scans were compatible with the navigation software. No clinically significant differences in image quality were observed between low dose and standard patient cohorts. CONCLUSIONS: Task-based CT protocol optimization can produce acceptable image quality with dose comparable to standard two-view radiography. LEVEL OF EVIDENCE: 2. PMID- 27513225 TI - Prospective Comparison of Age- and Sex-related Differences in Quantifiable 10-S Grip and Release and 10-S Step Test Results for Diagnosis of Cervical Spondylotic Myelopathy in 454 Patients With Cervical Spondylotic Myelopathy and 818 Asymptomatic Subjects. AB - STUDY DESIGN: A prospective comparison. OBJECTIVE: The purpose of this prospective study was to verify the clinical effectiveness of the 10-s grip and release (G&R) and 10-s step quantitative tests for assessing the severity of cervical spondylotic myelopathy (CSM) and to compare age- and sex-related differences in the results between large cohorts of CSM patients and asymptomatic subjects. SUMMARY OF BACKGROUND DATA: To determine the severity of CSM, objective and reproducible means of measuring patient disability are essential. No studies have evaluated differences in quantitative test results between a large series of CSM patients and healthy subjects. METHODS: Four hundred fifty-four CSM patients and 818 asymptomatic subjects were included. The Japanese subjects were in their 40s to 70s and were divided according to their age by decade. The 10-s G&R and 10 s step tests were used to quantitatively assess performance. The severity of myelopathy before surgery was evaluated according to a scoring system proposed by the Japanese Orthopaedic Association for cervical myelopathy (JOA score) in the CSM patients. RESULTS: In the CSM patients, the 10-s G&R and step test results significantly correlated with the JOA score (P < 0.0001). The number of the 10-s G&R and step tests significantly decreased with age in both groups. There was a difference in the 10-s G&R and step test results between males and females. In the asymptomatic subjects, the number of the 10-s G&R and step tests in the females was less than that in the males. The numbers in the 10-s G&R and step tests were significantly lower in CSM patients than those in asymptomatic subjects in each decade (P < 0.01). CONCLUSION: The 10-s G&R and 10-s step tests were useful for quantitatively assessing CSM severity, and age and sex differences in results should be considered in screening. LEVEL OF EVIDENCE: 2. PMID- 27513226 TI - How Reliable Are the Reported Genetic Associations in Disc Degeneration?: The Influence of Phenotypes, Age, Population Size, and Inclusion Sequence in 809 Patients. AB - STUDY DESIGN: Prospective genetic association study. OBJECTIVE: The aim of this study was to document the variations in the genetic associations, when different magnetic resonance imaging (MRI) phenotypes, age stratification, cohort size, and sequence of cohort inclusion are varied in the same study population. SUMMARY OF BACKGROUND DATA: Genetic associations with disc degeneration have shown high inconsistency, generally attributed to hereditary factors and ethnic variations. However, the effect of different phenotypes, size of the study population, age of the cohort, etc have not been documented clearly. METHODS: Seventy-one single nucleotide polymorphisms (SNPs) of 41 candidate genes were correlated to six MRI markers of disc degeneration (annular tears, Pfirmann grading, Schmorl nodes, Modic changes, Total Endplate Damage score, and disc bulge) in 809 patients with back pain and/or sciatica. In the same study group, the correlations were then retested for different age groups, different sample, size and sequence of subject inclusion (first 404 and the second 405) and the differences documented. RESULTS: The mean age of population (M: 455, F: 354) was 36.7 +/- 10.8 years. Different genetic associations were found with different phenotypes: disc bulge with three SNPs of CILP; annular tears with rs2249350 of ADAMTS5 and rs11247361 IGF1R; modic changes with VDR and MMP20; Pfirmann grading with three SNPs of MMP20 and Schmorl node with SNPs of CALM1 and FN1 and none with Total End Plate Score.Subgroup analysis based on three age groups and dividing the total population into two groups also completely changed the associations for all the six radiographic parameters. CONCLUSION: In the same study population, SNP associations completely change with different phenotypes. Variations in age, inclusion sequence, and sample size resulted in change of genetic associations. Our study questions the validity of previous studies and necessitates the need for standardizing the description of disc degeneration, phenotype selection, study sample size, age, and other variables in future studies. LEVEL OF EVIDENCE: 4. PMID- 27513227 TI - Comparing National Inpatient Sample and National Surgical Quality Improvement Program: An Independent Risk Factor Analysis for Risk Stratification in Anterior Cervical Discectomy and Fusion. AB - STUDY DESIGN: Retrospective study of prospectively collected data. OBJECTIVE: To explore interdatabase reliability between National Inpatient Sample (NIS) and National Surgical Quality Improvement Program (NSQIP) for anterior cervical discectomy and fusion (ACDF) in data collection and its impact on subsequent statistical analyses. SUMMARY OF BACKGROUND DATA: Clinical studies in orthopedics using national databases are ubiquitous, but analytical differences across databases are largely unexplored. METHODS: A retrospective cohort study of patients undergoing ACDF surgery was performed in NIS and NSQIP. Key demographic variables, comorbidities, intraoperative characteristics, and postoperative complications were analyzed via bivariate and multivariate analyses. RESULTS: A total of 112,162 patients were identified from NIS and 10,617 from NSQIP. Bivariate analysis revealed small, but significant, differences between patient demographics, whereas patient comorbidities and ACDF intraoperative variables were largely much more distinct across the two databases. Multivariate analysis identified independent risk factors between NIS and NSQIP for mortality, cardiac complications, and postoperative sepsis, some of which were identified in both but most of which were unique to one database. Identification of independent risk factors from both databases specifically highlights their greater validity and importance in stratifying patient risks. In addition, NSQIP was found to be a more accurate predictor for complications based on the average areas under the receiver-operating curve (CNSQIP = 0.83 vs. CNIS = 0.81) across the multivariate models. Complication rate analysis between inpatient and outpatient settings in NSQIP showed the importance of at least 30-day patient follow up, which was devoid in NIS data tabulation and further marked its weakness compared with NSQIP. CONCLUSION: Despite having largely similar patient demographics, this study highlights critical risk factors for ACDF and demonstrates how different patient profiles can be across NIS and NSQIP, the impact of such differences on identification of independent risk factors, and how NSQIP is ultimately better suited for adverse-event studies. LEVEL OF EVIDENCE: 3. PMID- 27513228 TI - Seroprevalence of measles, mumps, rubella, and varicella amongphysicians and nurses in Jordan. AB - BACKGROUND/AIM: Measles, mumps, rubella, and varicella can affect susceptible healthcare workers who might subsequently spread the infection to susceptible patients and workers. Here, we aim to determine the seroprevalence of these infections among physicians and nurses and to compare the history of varicella with the results of varicella antibodies among study participants. MATERIALS AND METHODS: Two randomly selected groups, one group of physicians and one of nurses, from a university hospital in Jordan were interviewed and their serum IgG antibodies were measured. RESULTS: The physicians and nurses group had 252 and 241 participants, respectively. The physicians group had significantly more males and younger participants. The percentage of individuals in the physician and nurse groups with positive antibodies to measles was 75.4% and 75.1%, respectively; mumps, 88.5% and 94.2%; rubella, 89.3% and 87.1%; and varicella, 92.1% and 92.5%. Immunity was similar between the 2 groups except for mumps, where significantly more nurses were immune. The positive and negative predictive values for the history of varicella to predict immunity in all participants were 95% and 13.5%, respectively. CONCLUSION: A small but important proportion of our healthcare workers are still susceptible to measles, mumps, rubella, and varicella. In addition, the recall history to varicella showed suboptimal ability to predict immunity. PMID- 27513229 TI - Evaluation of tetanus antibody levels in adults in Yozgat, Turkey. AB - BACKGROUND/AIM: To assess the immune status against tetanus in relation to self declared vaccination status among an adult population in Yozgat, Turkey. METHODS: Questionnaires and blood specimens were collected from 267 individuals over 18 years of age in Yozgat, Turkey. Antitetanus antibodies were determined quantitatively by enzyme-linked immunosorbent assay. RESULTS: Among the 267 subjects (mean age 43.4 +/- 15.6; male:female, 133:134) 168 (62.9%) had protective level of tetanus antibody titers. There was a characteristic distribution of the tetanus antibody titers in different age groups as it dropped with increasing age. Protective immunity was obtained in 74.1% of urban and 47.9% of rural participants. The lowest immunity was observed among farmers (53.3%) and housewives (55.6%) when compared to other occupations. Protective antibody titers were detected in 25% of the individuals who had not finished any school, while the rate was 83.7% in those who had graduated from university. While the protection rate in women who had been vaccinated during pregnancy was 78.3%, this rate was 39.2% in nonvaccinated women. CONCLUSION: Our findings confirm that only 62.9% of the population is immunized against tetanus, with a lack of coverage in particular for the elderly and in rural areas. It is necessary to follow the recommendations for 10-year boosters for tetanus. PMID- 27513230 TI - Oxidative stress-induced DNA damage and homocysteine accumulation may beinvolved in ovarian cancer progression in both young and old patients. AB - BACKGROUND/AIM: Biochemical, environmental, and genetic factors such as oxidative stress-induced DNA damage and homocysteine (Hcy) accumulation in the blood are involved in the development and progression of ovarian cancer. This study measured some biomarkers closely linked to the progression of ovarian cancer and also found their correlates. MATERIALS AND METHODS: Thirty patients were diagnosed with ovarian cancer using pelvic examination, transvaginal ultrasound, and cancer antibody (CA-125) measurement. Total oxidative stress (TOS), DNA damage, Hcy, malondialdehyde (MDA), total antioxidant status (TAS), and other biochemical parameters were determined. RESULTS: TOS and DNA damage were positively and significantly correlated between themselves and were involved in causation of tumors as reflected by significantly (P < 0.001) higher CA-125, erythrocyte sedimentation rate (ESR), creatinine, and C-reactive protein (CRP) in both young and old patients. Both were significantly correlated with Hcy, LDL cholesterol, alanine aminotransferase, aspartate aminotransferase, CRP, MDA, and CA-125. However, they were negatively correlated with TAS. Thus, excessive inflammation and oxidative stress caused an increase in DNA damage and enhanced Hcy content, leading to development of ovarian cancer. CONCLUSION: This study suggests the use of antioxidants as drugs to reduce oxidative stress, DNA damage, and other causes of cancer development. PMID- 27513231 TI - Correlation between HFE gene polymorphisms and increased risk of coronary artery disease among patients with type 2 diabetes in Iran. AB - BACKGROUND/AIM: Diabetes mellitus is a risk factor for cardiovascular diseases (CVDs), which are among the major causes of deaths in type 2 diabetes (T2D). The purpose of the present study was to determine the association of C282Y and H63D mutations in the HFE gene with increased risk of coronary artery disease (CAD) in T2D patients. MATERIALS AND METHODS: Two hundred and ninety individuals were divided into two groups: a case group and a control group. Genomic DNA of peripheral venous blood cells was extracted and the HFE gene mutations were analyzed using the PCR-RFLP technique. RESULTS: Data analysis revealed a significant difference between the allele frequencies of H63D and C282Y mutations between the case group and the controls (P < 0.05). The relationships between the GA and GG genotypes in C282Y and H63D mutations in terms of fasting blood sugar (FBS), lipid profile (total cholesterol, triglycerides, high-density lipoproteins (HDL), low-density lipoproteins), body mass index (BMI), HbA1c, micro albuminuria, and creatine levels did not show a significant differences between the two groups (P > 0.05). Using a logistic regression model, BMI, FBS, HDL, and total cholesterol levels were significantly different with independent predictors of CVD (P < 0.05). CONCLUSION: Our results revealed a significant correlation between C282Y and H63D mutations and the development of CAD in T2D patients. PMID- 27513232 TI - Clinical outcomes and optical performance of four differentmultifocal intraocular lenses. AB - BACKGROUND/AIM: The purpose of the present study was to evaluate clinical outcomes and optical performance of 4 different multifocal intraocular lenses (IOLs). MATERIALS AND METHODS: Ninety eyes of 51 patients who received Reviol MFM 611, Reviol MFM 625, Acri.LISA, and ReSTOR SN6AD3 multifocal IOLs after cataract surgery were retrospectively evaluated. The patients were similar in terms of age, sex, cataract hardness and axial length. The mean outcome measures were uncorrected and corrected distance visual acuity (UDVA, CDVA), distance-corrected intermediate and near visual acuity (DCIVA, DCNVA), intra or postoperative complications, and contrast sensitivity (CS) results under mesopic conditions. The mean follow up period was 10.5 months (range: 6-12 months). RESULTS: All cases were within +/- 0.75 D of emmetropia. Postoperative increase in UDVA and DCNVA was statistically significant in all groups. The Acri.LISA group showed slightly lower DCIVA compared with the other IOLs. CS was clinically similar between the groups. None of the patients developed any early or late postoperative complication or neuroadaptation problem, which necessitated explantation of the lens. CONCLUSION: All four multifocal lens designs provided satisfactory visual functions and CS results in patients who fulfilled the criteria for multifocal lens implantation. PMID- 27513233 TI - The utility of the TIMI risk index on admission for predicting angiographic no reflow after primary percutaneous coronary intervention in patients with STEMI. AB - BACKGROUND/AIM: The thrombolysis in myocardial infarction (TIMI) risk score (TRS), and the TIMI risk index (TRI) have been reported in coronary artery disease patients. We investigated whether admission TRI is associated with no reflow (NRF) in patients undergoing primary percutaneous coronary intervention (p PCI). MATERIALS AND METHODS: ST-segment elevation myocardial infarction (STEMI) patients treated with p-PCI were included in the study. TRI was calculated on admission using specified variables. We defined the angiographic NRF phenomenon as a coronary TIMI flow grade of <=2 after the vessel was recanalized or a TIMI flow grade of 3 together with a final myocardial blush grade (MBG) of <2 in a manner as described in previous studies. RESULTS: A total of 371 patients (aged 62 +/- 14 years; 73/27 men to women ratio) who underwent p-PCI were enrolled in the study. In terms of age, NRF patients were older than reflow patients (P < 0.017 for MBG). Killip class III-IV designations were more common in NRF patients (P = 0.029 for MBG). TRI (P = 0.014 for MBG) values were significantly greater in the NRF group. TRI was an independent predictor of NRF according to MBG flow (P = 0.003, B = -0.035, Exp B = 0966, 95% CI, 0.944-0.988). CONCLUSION: Admission TRI may predict the development of NRF phenomenon after p-PCI in patients with acute STEMI. PMID- 27513234 TI - Effectiveness of P6 acupoint electrical stimulation in preventing postoperativenausea and vomiting following laparoscopic surgery. AB - BACKGROUND/AIM: The effects of pericardium 6 (P6) electrical stimulation in patients at risk of postoperative nausea and vomiting (PONV) following laparoscopic surgery were evaluated. MATERIALS AND METHODS: Eighty patients for laparoscopic surgery with at least one of the determined risks (nonsmoker, female, previous PONV/motion sickness, or postoperative opioid use) were randomized into either an active or sham group. At the end of surgery, Reletex electrical acustimulation was placed at the P6 acupoint. The active group had grade 3 strength and the sham group had inactivated electrodes covered by silicone. It was worn for 24 h following surgery. PONV scores were recorded. RESULTS: The active group had significantly shorter durations of surgery and lower PONV incidence over 24 h (35.1% versus 64.9%, P = 0.024) and this was attributed to the lower incidence of nausea (31.4% versus 68.6%, P = 0.006). The overall incidence of vomiting was not significantly different between the groups, but it was higher in the sham group of patients with PONV risk score 3 (23.9%, P = 0.049). CONCLUSION: In patients at high risk for PONV, P6 acupoint electrical stimulation lowers the PONV incidence by reducing the nausea component. However, this reduction in nausea is not related to increasing PONV risk scores. PMID- 27513235 TI - Polymorphisms in androgen metabolism genes AR, CYP1B1, CYP19, and SRD5A2and prostate cancer risk and aggressiveness in Bulgarian patients. AB - BACKGROUND/AIM: The aim of our study was to elucidate the role of polymorphisms in AR, CYP1B1, CYP19, and SRD5A2 genes for prostate cancer (PC) development in Bulgarian patients. MATERIALS AND METHODS: We genotyped 246 PC patients and 261 controls (155 with benign prostate hyperplasia and 107 healthy population controls) using direct sequencing, PCR-RFLP, SSCP, and fragment analysis. RESULTS: The allele and genotype frequencies of most of the studied variants did not differ significantly between cases and controls. Increased frequencies of the C/C genotype and C allele of rs1056837 in CYP1B1, and genotype 7/8 of the (TTTA)n repeat polymorphism in CYP19, were observed in patients in comparison with controls.The 8/9 and the 7/12 genotypes of (TTTA)n in CYP19 showed suggestive evidence for association with decreased prostate cancer risk and the risk for aggressive disease, respectively. The haplotype analysis revealed 2 CYP1B1 haplotypes associated with PC risk reduction. CONCLUSION: Some CYP1B1 haplotypes and genotypes of the CYP19 (TTTA)n repeat appeared to be associated with disease risk or aggressiveness in Bulgarian PC patients. In contrast, the SRD5A2 polymorphisms (V89L and (TA)n repeat), the CAG repeat in AR, and the Arg264Cys variant in CYP19A1 are most likely not implicated in prostate carcinogenesis. PMID- 27513236 TI - The relationship of breast arterial calcification detected in mammographic examinations with cardiovascular diseases, cardiovascular risk factors, parity, and breastfeeding. AB - BACKGROUND/AIM: We aimed to detect the incidence of breast arterial calcification (BAC) in patients that underwent mammography and to reveal the relationship of BAC with cardiovascular diseases, cardiovascular risk factors, parity, and breastfeeding. MATERIALS AND METHODS: A total of 1195 female patients were included in this study. Cases that were positive for BAC during mammography were recorded. The relationship of BAC with age, body mass index, parity, breastfeeding, menopause, smoking, alcohol consumption, oral contraceptive use, hormone replacement therapy, and histories of hypertension (HT), diabetes mellitus (DM), coronary artery disease (CAD), and cerebral vascular diseases were investigated. RESULTS: Overall, 97 of 1195 cases were positive for BAC. In univariate analysis, age, educational status, parity, breastfeeding, menopause, hyperlipidemia, and DM, HT, and CAD histories were found to be separate risk factors that had an effect on the development of BAC. The effects of age, parity, and breastfeeding history were maintained in the logistic regression analysis (P = 0.001, P = 0.001, P = 0.024, respectively; P < 0.05 was significant), while the significance of the other analyzed variables was lost (P > 0.05). CONCLUSION: We found that BAC is associated with age, parity, and breastfeeding but not with cardiovascular diseases and cardiovascular risk factors. PMID- 27513237 TI - Celiac disease in children with chronic constipation. AB - BACKGROUND/AIM: Chronic constipation (CC) and celiac disease (CD) are the most common conditions encountered in pediatric gastroenterology. The association of these two disorders has not been evaluated properly. We analyzed the prevalence and outcome of CD in children with CC. MATERIALS AND METHODS: The study included children with CC (n = 313) and healthy children (n = 990). Serum IgA and IgA antitissue transglutaminase antibodies (IgA-tTG) were studied in all subjects. Intestinal biopsy and HLA-DQ2/DQ8 typing was performed in subjects with elevated IgA-tTG. RESULTS: Serology was positive in 8 children (2.5%) with CC and 6 children (0.6%) from the control group (P < 0.05). Histopathological examination revealed total villous atrophy in two subjects in the control group. Other subjects had Marsh 0-1 lesions. All patients with CC and 4 children from the control group were classified as having potential CD. Two children in the control group had silent CD. Spontaneous loss of serum tTG-IgA occured in 75% of the subjects with potential CD at the end of the 1st year. CONCLUSION: Our study revealed that serological evaluation CD may be omitted in children with CC at initial examination. It may be perform in selected patients such as those associated with prolonged symptoms or malnutrition. PMID- 27513238 TI - The antioxidant and antimutagenic activities of Ankaferd blood stopper,a natural hemostatic agent used in dentistry. AB - BACKGROUND/AIM: This study investigated the antioxidant and antimutagenic properties of Ankaferd blood stopper (ABS), a plant-based topical hemostatic agent used in Turkey to treat external hemorrhages and bleeding during dental surgery. While previous studies have examined the antimicrobial, antiinflammatory, and anticarcinogenic properties of ABS, to our knowledge, this is the first study to report on the antioxidant and antimutagenic activities of this drug. MATERIALS AND METHODS: Antioxidant activity was evaluated using DPPH radical-scavenging and beta-carotene-linoleic acid tests. Antimutagenic activity was assessed using the Ames Salmonella/microsome mutagenicity test with the bacterial mutant strains Salmonella typhimurium TA98 and TA100. RESULTS: Although ABS demonstrated no free-radical-scavenging activity in DPPH assays at the tested concentrations, beta-carotene-linoleic acid testing found ABS to have a total antioxidant activity rate of 47.06 +/- 4.41%. Antimutagenic effects were observed on TA100 at plate concentrations of 5%, 0.5%, and 0.05%, and on TA98 only at a plate concentration of 5%. CONCLUSION: ABS was shown to possess antioxidant and antimutagenic properties that could be of potential value in the fields of medicine and dentistry. PMID- 27513239 TI - Treatment of mixed astigmatism: early clinical outcomes withWaveLight and Technolas excimer lasers. AB - BACKGROUND/AIM: We aimed to compare the results of WaveLight Allegretto Wave Eye Q 400 Hz and Technolas 217z100 excimer lasers in the treatment of mixed astigmatism. MATERIALS AND METHODS: Forty-nine patients who underwent laser in situ keratomileusis for mixed astigmatism were included in this retrospective study. Twenty-eight eyes of 21 patients were treated with WaveLight and 46 eyes of 28 patients were treated with the Technolas excimer laser. The patients' visual acuities and refractive values were evaluated on postoperative day 1 and at 1 and 3 months. RESULTS: In the WaveLight and Technolas groups, cylindrical refractive errors at month 3 were -0.92 +/- 0.28 D and -0.88 +/- 0.46 D, respectively. Spherical equivalent values for the groups at month 3 were -0.38 +/ 0.73 D and -0.33 +/- 0.20 D, respectively. There was no significant difference in postoperative uncorrected distance visual acuity at month 3 between the two groups (P = 0.671). At postoperative month 3, 70% of patients treated with WaveLight and 100% of patients treated with Technolas had an uncorrected distance visual acuity of 20/25 or better (P = 0.211). CONCLUSION: There were no significant differences in refraction and visual acuity between the WaveLight and Technolas groups during a 3-month follow-up period after laser in situ keratomileusis for mixed astigmatism. PMID- 27513240 TI - eNOS gene polymorphisms in paraffin-embedded tissues of prostate cancer patients. AB - BACKGROUND/AIM: The purpose of the present study was to investigate whether endothelial nitric oxide synthase (eNOS) gene polymorphisms play a role in prostate cancer (PCa). MATERIALS AND METHODS: We examined three eNOS gene polymorphisms (T-786C promoter region, G894T, and Intron 4 VNTR 4a/b) at extracted DNAs from 50 formalin-fixed paraffin-embedded tissues of PCa patients. For the controls, blood samples obtained from 50 healthy men were studied. Genotyping of molecular variants was performed by PCR-RFLP technique. RESULTS: We found that the TC genotype of the T-786C polymorphism was associated with PCa risk (OR: 3.325, CI: 1.350-8.188, P = 0.008). The eNOS G894T polymorphism was also associated with PCa. The frequency of the 894T allele was significantly higher in PCa patients. No association was identified between intron 4 VNTR polymorphism and PCa. CONCLUSION: We found significant differences in genotypic and allelic frequencies between PCa patients and controls for eNOS T-786C and G894T polymorphisms. The presence of the T-786C genotype and 894T allele in carriers increased the risk of PCa. No association was found between intron 4 VNTR polymorphism and PCa patients. PMID- 27513241 TI - Effects of blood pressure and sex on heart-vessel coupling in essential hypertension. AB - BACKGROUND/AIM: This study aimed to investigate the impact of blood pressure and sex on heart-vessel coupling in patients with essential hypertension via ultrasound. MATERIALS AND METHODS: We studied 76 patients with essential hypertension (48 males and 28 females) and 65 healthy controls (33 males and 32 females). Coupling parameters were obtained using ultrasound technology combined with brachial artery blood pressure measurement. RESULTS: The Ea and Ees were higher in the hypertension group than in the control group (P < 0.01), with no statistically significant difference in Ea/Ees between the two groups (P >0.05). After subjects were classified by sex, the Ea and Ees of males and females in the hypertension group were higher than those in the control group (P < 0.05 or P < 0.01), while the Ea/Ees was lower in hypertensive females than in control females (P < 0.05). CONCLUSION: In female patients with essential hypertension, heart vessel coupling was easily damaged, and systolic blood pressure was associated with heart-vessel coupling damage to some extent. PMID- 27513242 TI - Categorization of ureteroscopy complications and investigation of associated factors by using the modified Clavien classification system. AB - BACKGROUND/AIM: The purpose of the present study was to review the complications of ureteroscopy (URS) by using the modified Clavien classification system (MCCS) and to investigate the factors associated with complications. MATERIALS AND METHODS: Data regarding 811 patients who underwent URS for ureteral calculus were analyzed. Peroperative and postoperative complications were recorded. The patients were divided into seven groups depending on the severity of the complications. The association of sex, stone size, number, and localization with each MCCS grade was also evaluated. RESULTS: The average age was 45 years. The success of the procedure after one session was 93.5%. Complications were recorded in 57.9% of the patients. According to the MCCS, grade I, II, IIIa, IIIb, IVa, IVb, and V complications were documented in 29.8%, 7.1%, 8.6%, 11%, 0%, 1.2%, and 0% of the patients, respectively. The factors associated with the complications graded by MCCS were sex, stone size, number of stones, and localization. In addition, in multivariate analysis, history of previous surgeries for urolithiasis, orifice dilatation, and instrument size were associated with complications. CONCLUSION: According to MCCS, sex, history of previous surgeries for urolithiasis, orifice dilatation, size of the instrument, stone size, number of stones, and localization are associated with different grades of complications in URS. PMID- 27513243 TI - Premenstrual syndrome and life quality in Turkish health science students. AB - BACKGROUND/AIM: The purpose of the present study was to investigate the incidence of PMS, risk factors affecting PMS symptoms, and life quality in health science students. MATERIALS AND METHODS: A total of 608 volunteer female students studying at the health campus of a state university in Turkey were included in the study. The participants were asked to fill out questionnaires on sociodemographic data, PMS symptoms, and SF-36 life quality tests. RESULTS: The overall frequency of PMS among participants was 84.5%. The average PMS and general health SF scores were 118.34 +/- 37.3 and 20.03 +/- 3.72, respectively. Students who had irregular breakfast, drank >=2 cups of coffee/day, and consumed alcohol or fast food had higher PMS scores. Irregular menstruation and family history increased PMS scores and decreased life quality (P < 0.05). The life quality of the students significantly decreased as the severity of PMS increased (P < 0.001). CONCLUSION: Low body mass index, family history, irregular menstruation, bad eating habits such as fast food consumption and irregular breakfasts, and coffee and alcohol consumption increased PMS risk significantly. In order to improve their life quality, students should be informed about the symptoms, risk factors, and management options of PMS. PMID- 27513244 TI - Brachiobasilic arteriovenous fistula with transpositionof the basilic vein: a multicenter study. AB - BACKGROUND/AIM: The aim of this paper was to present our 3-year multicenter experience in creating a vascular access using the basilic vein. The third choice in creating vascular access is the brachiobasilic arteriovenous fistula (AVFs) with transposition of the basilic vein. MATERIALS AND METHODS: During 2010-2012, out of a total of 874 AVFs that were performed in our two centers, 54 were brachiobasilic fistulas (6.71%), performed on 54 patients. All surgical procedures were performed by two surgical teams, one for each center. There were no significant differences regarding the patients' age, sex, and comorbidities between the two centers. RESULTS: We reported a total of six postoperative complications (11.10%): two wound infections, two arm edemas, one hematoma, and one bleeding (due to a collateral ligature slippage), which required surgical intervention the same day. None of the other complications required another surgery. The first year patency rate was 89.79% (four fistulas failed due to thrombosis and one due to perforation) and the second year patency rate was 62.12%. CONCLUSION: The brachiobasilic AVF with transposition of the basilic vein, according to the latest guidelines, remains a well-documented and feasible third option in creating vascular access with better results than graft fistulas. PMID- 27513245 TI - Childhood acute lymphoblastic leukemia: refusal and abandonmentof treatment in the southeast of Iran. AB - BACKGROUND/AIM: Acute lymphoblastic leukemia (ALL) accounts for 25% of all malignancies in children. ALL treatment has standard protocols, and treatment abandonment is a main cause of treatment failure. Therefore, this study aimed to assess the relationship between socioeconomic status and rate as well as cause of abandoned treatment in children with ALL in the southeast of Iran. MATERIALS AND METHODS: This retrospective, descriptive cohort study was conducted with ALL patients at the Ali Asghar Hospital in the city of Zahedan. The study population included 22 children with different subtypes of ALL who had abandoned their treatment. A structural questionnaire was filled out by patients or their parents. Results were assessed using descriptive and analytical tests. RESULTS: The rate of treatment abandonment was 24.4% (22 patients).We had 18 ALL-L1 (78.3%) and four ALL-L2 (17.4%) patients. Reasons for treatment abandonment were low family income, transportation difficulties, the father's education status, conviction about ALL's incurability, and reference to spiritual means, respectively. CONCLUSION: Low family income, transportation difficulties, the father's education status, belief about ALL's incurability, and reference to spiritual means were the most common associations with ALL treatment abandonment in that order. Financial problems in this part of the country can impose high costs to the healthcare system. PMID- 27513246 TI - Evaluation of the relationship between migraine disorder andoral comorbidities: multicenter randomized clinical trial. AB - BACKGROUND/AIM: Although migraine is a common disorder, there is a lack of research investigating the possible relationship between migraine and oral health. The aim of the present study was to explore the relationship between temporomandibular disorders, bruxism, dental caries, periodontal status, and migraine disorder in a multicenter, parallel, case-controlled clinical study. MATERIALS AND METHODS: A total of 2001 participants were divided into two groups: migraineurs (nm = 998) and nonmigraineurs (nh = 1003). International Headache Society's Second Edition of International Classification of Headache Disorders and modified Migraine Disability Assessment surveys were administered to evaluate the level of migraine; a pretreatment questionnaire and the World Health Organization oral health assessment form were used to determine the oral comorbidities and their possible effects on DMFT index, gingival plaque index, existence of temporomandibular disorders, bruxism, and consistency of daily oral hygiene habits. RESULTS: The mean age was 39.6 +/- 10.5 years. Female patients seemed to experience migraine attacks more than male patients (64%). The frequency of gastroesophageal reflux was higher in migraineurs in comparison with nonmigraineurs (47%) and tooth wear and abrasion also seemed more frequent (76%). DMFT and plaque index scores showed significant differences for both groups. CONCLUSION: There is a strong relationship between migraine and oral health status. The existence of reflux in addition to migraine leads to higher dental problems. PMID- 27513247 TI - Effects of a self-management educational program on metabolic control in type 2 diabetes. AB - BACKGROUND/AIM: India has 63 million diabetic people and the overall prevalence of diabetes in this country is 8.37%. Lifestyle modification by education is the most cost-effective strategy to have better metabolic control. The aim of this study was to investigate the effects of a self-management educational program on control of type 2 diabetes. MATERIALS AND METHODS: It was a randomized controlled interventional study conducted among 306 patients with type 2 diabetes mellitus attending the Diabetic Clinic at G.T.B. Hospital, Delhi, from March 2010 to May 2013. The intervention was in the form of group education based on a self management program, which was earlier developed in the pilot study. RESULTS: The baseline characteristics were comparable in the two groups. After 6 months, there was a significant improvement in the HbA1c levels (P = 0.0001), physical activity level (P = 0.001), and BMI (P = 0.001) in the study group as compared to the control group and this difference persisted even when analysis was done using generalized estimation equations. CONCLUSION: The findings of this study proved that a self-management educational program is an essential component in the management of diabetes and provided concrete evidence that this is an effective instrument in the control of body weight, blood pressure, and glycated Hb levels in type 2 diabetes. PMID- 27513248 TI - Evaluation of Borrelia burgdorferi sensu lato seroprevalencein the province of Bolu, Turkey. AB - BACKGROUND/AIM: The aim of the present study was to determine the seroprevalence of Borrelia burgdorferi sensu lato in the city center and the province of Bolu, Turkey. MATERIALS AND METHODS: A stratified sampling method was used to determine the study population. A total of 196 blood samples were collected. A questionnaire was completed by each participant in the study. ELISA was performed and positive serologic results were confirmed using western blotting. Data were analyzed statistically using the chi-square test. RESULTS: Seropositivity rates of B. burgdorferi IgM and IgG were determined as 14.8% (29/196) and 13.7% (27/196) respectively by ELISA. A total of nine serum samples (4.6%) were found positive for IgG, and seven samples (3.8%) were positive for IgM according to western blotting. Seropositivity rates were found to be higher in people living in rural areas (11.1%), in women (8.3%), in people who were illiterate (10.0%), in people engaged in agriculture (10.8%), and in the age group of 40-60 years (10.0%). No statistically significant difference was found between seropositivity rates and survey data. CONCLUSION: The seroprevalence of Lyme disease was determined in our region. Detection of endemic regions of Lyme disease with determination of seropositivity rates will increase the awareness among clinicians about this disease. PMID- 27513249 TI - Investigation of enteropathogenic Escherichia coli and Shiga toxin producingEscherichia coli associated with hemolytic uremic syndrome in Izmir Province, Turkey. AB - BACKGROUND/AIM: The purpose of this study was to investigate Shiga toxin producing Escherichia coli (STEC) and enteropathogenic Escherichia coli (EPEC) strains originating from diarrheagenic patients. MATERIALS AND METHODS: A total of 102 patients with diarrhea between October 2012 and January 2013 were enrolled in this study. Multiplex and standard polymerase chain reactions were performed to detect and distinguish STEC and EPEC strains. O serotyping of EPEC was carried out by monovalent antisera. The O and H serotyping of STEC strains was performed at the Refik Saydam Institute, Ankara. RESULTS: A total of 5 (3.42%) strains were identified as STEC, and 3 strains (2.05%) were atypical EPEC. One of the STEC serotypes was O157:H7 carrying VT1, Stx1A, and escv genes. The other STEC strain was identified as O174:H21, which is associated with hemolytic uremic syndrome and consists of VT2 and Stx2A genes. One of the EPEC and three of the STEC serotypes were nontypeable. The serotypes of the atypical EPEC strains were identified as O114 and O26. CONCLUSION: To the best of our knowledge, this is the first report of O174:H21 from the Izmir region that was shown to be a Shiga toxin producing non-O157 serotype of STEC. PMID- 27513250 TI - Impact of different anesthetic managements in outcomes of transcatheteraortic valve implantation: the first Turkish experience. AB - BACKGROUND/AIM: Transcatheter aortic valve implantation (TAVI) has emerged as a new therapy in aortic stenosis patients with high operative risk. Advances in experiences have shifted the choice of anesthesia from general to local anesthesia and sedation for these patients. We compared our anesthetic experiences in our institute in a period of 2.5 years. MATERIALS AND METHODS: A total of 151 (86 females, 65 males, mean age 76 years) symptomatic aortic stenosis patients undergoing transfemoral TAVI under general anesthesia (GA) (n = 79) and local anesthesia and sedation (LAS) (n = 72) were evaluated retrospectively in regards to anesthetic issues. RESULTS: The mean European System for Cardiac Operative Risk Evaluation (EuroSCORE) values of patients in the GA and LAS groups were 17 and 12, respectively. The anesthesia duration was significantly shorter in the LAS group (P < 0.001) and 16.7% of the patients in the LAS group were switched to general anesthesia. Length of stay in the intensive care unit was similar in the two groups. CONCLUSION: TAVI, applied in high-risk populations, has many challenges for anesthesiologists. With technological advances, it is possible to perform these procedures under sedation with variable advantages. Thus, future studies in regard to anesthesia are required for the success of the procedure and patient safety. PMID- 27513251 TI - Increased IL-17 and TGF-beta serum levels in peripheral blood of patients with beta-thalassemia major: implication for continual transfusions role in T helper17 mediated proinflammatory responses. AB - BACKGROUND/AIM: Recent studies have shown that IL-17-producing CD4+ T helper (Th17) cells play an important role in proinflammatory processes. In this report we analyzed IL-17, IL-21, and TGF-beta serum levels in the peripheral blood of Iranian beta-thalassemia major patients that clinically exhibited splenectomy and iron overload. MATERIALS AND METHODS: Blood samples were collected from 43 beta thalassemia patients and 43 healthy individuals with no history of malignancies or autoimmune disorders. Then serum levels of IL-17, IL-21, and TGF-beta were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: The levels of IL 17 (P = 0.005) and TGF-beta (P < 0.001) were significantly higher in the thalassemia patients compared to the healthy control. No significant differences in the level of serum IL-21 was observed between the patients and controls. There were no significant differences in serum levels of IL-17, IL-21, and TGF-beta between patients with high or low serum levels of ferritin. CONCLUSION: Multiple blood transfusions cause constant immune stimulation, as a result of repeated exposure to new alloantigens. This might have significant effects on the stimulation of cytokine producing cells in those patients and cytokine profile can be used as a related marker for assessing disease severity and consequently therapeutic intervention. PMID- 27513252 TI - Sevoflurane versus propofol for electroconvulsive therapy: effects on seizure parameters, anesthesia recovery, and the bispectral index. AB - BACKGROUND/AIM: In this prospective randomized cross-over study we compare the effects of sevoflurane versus propofol for electroconvulsive therapy (ECT) anesthesia. MATERIALS AND METHODS: Twenty four patients (ASA I-III, 18-65 years old) receiving ECT three times per week were included. Anesthesia was induced with either propofol (0.75 mg/kg iv) or 5% sevoflurane in 100% oxygen. Consecutive ECT sessions followed a 2 * 2 crossover design and a 2-day washout period until the 10th ECT. Intravenous succinylcholine (1 mg/kg) was administered while bispectral index (BIS) values were <=60%. RESULTS: Electromyogram and electroencephalogram seizure duration, postictal suppression index, BIS values, mean arterial blood pressure (MAP), heart rate, times to start of spontaneous respiration, eye opening, understanding verbal commands, and side effects were compared. No differences were found between the regimens for seizure activity and recovery. At the end of ECT, MAP was higher with sevoflurane. Although BIS values were higher after sevoflurane, no differences between the regimens were found in terms of the need of muscle relaxants and in hypnosis levels. CONCLUSION: Sevoflurane (5%) may be an effective alternative to propofol for induction of anesthesia for ECT. PMID- 27513253 TI - Intravitreal bevacizumab for retinopathy of prematurity in infants ineligible for laser therapy. AB - BACKGROUND/AIM: To evaluate refractive and strabismic results and the efficacy of intravitreal bevacizumab in retinopathy of prematurity (ROP) ineligible for laser therapy. MATERIALS AND METHODS: Thirty-nine eyes of 20 consecutive infants with high-risk prethreshold ROP (11 infants with Zone I and 9 infants with Zone II disease) who were ineligible for laser therapy due to systemic and/or ocular conditions were treated with intravitreal bevacizumab. Recurrent retinopathy was treated with laser ablation. The final follow-up examination was performed at 29.8 +/- 6.0 months of corrected age. RESULTS: All eyes responded to the initial treatment with intravitreal bevacizumab. ROP recurred in 8 eyes (36%) with initial Zone I disease and in only 2 eyes (11%) with initial Zone II disease, which were successfully treated with laser ablation. No eye developed myopia higher than 5.0 diopters. At 2.5 years, the Zone I eyes that had received laser treatment appeared to be more myopic than the Zone I eyes treated only with intravitreal bevacizumab (P = 0.038). A tendency for a higher incidence of strabismus after additional laser therapy was also noted, but was not significant (P = 0.22). CONCLUSION: Avoidance or even deferral of laser ablation with intravitreal bevacizumab may lead to less myopization in ROP compared with conventional laser treatment. PMID- 27513254 TI - Epidemiology and cost of drug treatment of cancer in Northern Cyprus. AB - BACKGROUND/AIM: To determine the epidemiology, the sociodemographic features, the incidence and prevalence rate of cancer, and the cost of drug treatment in Northern Cyprus. MATERIALS AND METHODS: All of the oncology prescriptions, cancer pathology reports, and cancer referrals to overseas for 2011 were collected from the state hospitals, the only private university hospital that provides oncology services, and the Ministry of Health to prepare an epidemiological database. The total cost of drug treatment at the state hospitals and cost of the most frequent five cancer types were also calculated using the therapy protocols and the expense of the drugs. RESULTS: The total incidence rate for all cancer cases in 2011 was 201 per 100,000 and the prevalence rate was 460 per 100,000. The five most common cancer types were breast (19.8%), prostate (12.6%), colorectal (9.7%), thyroid (6.4%), and lung (5.6%). The cost of drug treatment for cancer at the state hospitals comprises 25% of the total medical budget of the Directorate of Pharmaceuticals. Almost 1/3 of this amount was spent on drug treatment of breast cancer. CONCLUSION: Breast cancer is the most frequent and the most costly cancer type in Northern Cyprus. Of all the districts, the Guzelyurt-Lefke District has the highest cancer rate. PMID- 27513255 TI - Levels of nitric oxide, asymmetric dimethyl arginine, symmetric dimethyl arginine,and L-arginine in patients with obsessive-compulsive disorder. AB - BACKGROUND/AIM: We aimed to investigate and compare to healthy controls the variations in the levels of nitric oxide (NO), asymmetric dimethyl arginine (ADMA), symmetric dimethyl arginine (SDMA), and L-arginine levels in patients with obsessive-compulsive disorder (OCD). MATERIALS AND METHODS: We enrolled 30 patients with OCD and 30 healthy controls in the study consecutively. Diagnostic interviews of all participants were conducted with the Structured Clinical Interview for Axis I Disorders (SCID-I), and sociodemographic data of the participants were recorded. Patients scoring 10 points or more on the Yale-Brown Obsessive-Compulsive Scale were enrolled in the study. RESULTS: The NO levels of patients with OCD were increased compared to the control group, but the increase was not statistically significant (P > 0.05). However, patients with OCD had significantly lower levels of ADMA, SDMA, and L-arginine compared with the controls (P < 0.001). CONCLUSION: We found a significant decrease in ADMA, SDMA, and L-arginine as NO inhibitors between the groups, possibly because of an increase in NO. However, the insignificant increase in NO suggests that ADMA, SDMA, and L-arginine play direct and potentially important roles in OCD biology. PMID- 27513256 TI - NF-kappaBeta and SOD expression in preeclamptic placentas. AB - BACKGROUND/AIM: Preeclampsia is a leading cause of maternal death in the developing world. Our aim was to quantify and compare messenger (mRNA) expression of nuclear factor-kappa beta (NF-kappaBeta) and superoxide dismutase (SOD) in control patients with preeclampsia and without preeclampsia with or without familial hereditary background. MATERIALS AND METHODS: Four groups of patients were formed depending on the presence or absence of preeclampsia and presence or absence of familial history for preeclampsia. NF-kappaBeta and SOD were measured in human placentas by real-time quantitative polymerase chain reaction. The 2 DeltaDeltact analysis method was used to measure the difference in the relative expression of the target genes in each group of patients. RESULTS: In NF kappaBeta expression, there was an increase of 23.35% in the group of women with preeclampsia versus women with preeclampsia without familial history. Regarding SOD, there was a reduction of about 33.33% in the expression in women with preeclampsia with familial history versus women with preeclampsia without familial history. CONCLUSION: Familial presence of preeclampsia could predispose to altered expression in SOD and NF-kappaBeta. PMID- 27513257 TI - The effect of addition of ketamine to lidocaine on postoperative pain in rhinoplasties. AB - BACKGROUND/AIM: The objective of this study was to examine the effect of addition of subanesthetic doses of ketamine to an epinephrine-lidocaine solution on postoperative pain, analgesic use, and patient comfort during rhinoplasties. MATERIALS AND METHODS: Ninety patients were randomly divided into three groups: Group L, lidocaine with epinephrine; Group K, lidocaine with epinephrine plus ketamine; and Group S (control group), physiological saline solution with epinephrine. The local anesthetic solution was injected as preincisionally with intranasal submucosal infiltration following induction of general anesthesia. We evaluated visual pain score, analgesic demand, Wilson sedation score, and antiemetic demand at 5, 15, and 30 min and 1, 2, 4, 6, 8, 16, and 24 h after the operation. The patient satisfaction score was checked 24 h after the operation. RESULTS: Visual pain score was significantly reduced in Group K in comparison with the other groups and this group did not need any rescue analgesics (P < 0.05). The postoperative patient satisfaction scores were highest in Group K compared with the other groups (P < 0.05). CONCLUSION: Addition of ketamine solution to lidocaine for infiltration block during rhinoplasty was successful in decreasing pain during postoperative periods and reducing analgesic consumption during the first 24 h after the operation. PMID- 27513258 TI - Complications of tracheobronchial foreign bodies. AB - BACKGROUND/AIM: Tracheobronchial foreign bodies may cause several complications in the respiratory system. We aimed to present the complications of tracheobronchial foreign bodies. MATERIALS AND METHODS: Between January 1990 and March 2015, 813 patients with suspected tracheobronchial foreign body aspiration were hospitalized in our department. Patients with complications related to foreign bodies in airways were included in this study. We retrospectively evaluated the records of patients according to symptoms, foreign body type, localizations, and complications. RESULTS: A foreign body was found in 701 of 813 patients (86.2%). Complications related to foreign bodies settled in airways were seen in 96 patients (13.7%). The most common complications were atelectasis and pneumonia in 36 (5.1%) and 26 (3.7%) patients, respectively. Other complications were bronchiectasis (n = 12, 1.7%), cardiopulmonary arrest (n = 11, 1.6%), bronchostenosis (n = 3, 0.4%), death (n = 2, 0.3%), migration of foreign body (n = 2, 0.3%), pneumomediastinum (n = 2, 0.3%), tracheal perforation (n = 1, 0.15%), pneumothorax (n = 1, 0.15%), and hemoptysis (n = 1, 0.15%). Coughing (n = 74, 77.1%) and diminished respiratory sounds (59.3%, n = 57) were the most common findings. CONCLUSION: Careful evaluation and rapid intervention are life-saving methods in tracheobronchial foreign body aspirations. PMID- 27513259 TI - Long-term assessment of coronary care unit patient profile and outcomes: analyses of the 12-years patient records. AB - BACKGROUND/AIM: The aim of this study was to determine the patient profile, treatment, and outcomes of a coronary care unit (CCU) by retrospective screening of 12-year patient records. MATERIALS AND METHODS: The data of 13,463 patients admitted to the CCU of a tertiary referral hospital between 1 January 1997 and 30 June 2008 were collected. The patients were assessed with respect to demographics, admission diagnosis, treatment, and outcomes. RESULTS: The mean age of patients was 61 +/- 13 years (66.7%, male). While the diagnosis of acute coronary syndrome (ACS) accounted for 65%, the rate of ST elevation myocardial infarction (STEMI) was 43.4%. Thrombolytic therapy was administered to 48.7% of the patients with STEMI. Systolic heart failure was the most frequent disease (11.9%) among the non-ACS diagnoses. The mortality rate of the CCU was 12.7% on average; it increased gradually after 2005 when the CCU became a general intensive care unit. CONCLUSION: This study is one of the largest comprehensive analyses of patient profile and outcomes of a CCU. Despite advances in the diagnosis and treatment of cardiac emergencies, the mortality rate of the CCU was high. Serving as a general intensive care unit, the absence of a coronary angiography laboratory and lower use of thrombolytic therapy for STEMI might be responsible factors. PMID- 27513260 TI - Evaluation of behavioral problems in patients with monosymptomaticnocturnal enuresis: a prospective controlled trial. AB - BACKGROUND/AIM: The aim of the present study was to evaluate the behavioral and emotional patterns of patients with nocturnal enuresis (NE) and compare them with those of healthy subjects. MATERIALS AND METHODS: Thirty-eight children and adolescents with monosymptomatic NE who were admitted to our hospital's pediatric and urologic outpatient clinics and 46 age-matched, healthy subjects were enrolled in this study. To compare behavioral patterns in these patients, the Child Behavior Checklist (CBCL) was used. Patients' ages, occupations, educational, and socioeconomic status, and mothers' age at delivery were compared in the two groups. One-way ANOVA was used for statistical analysis. RESULTS: Enuretic children were found to have more behavioral problems than nonenuretic children with regard to social (P = 0.008) and attention (P = 0.018) problems. There were no significant differences in anxiety or attractiveness problems between the groups (P > 0.05); however, patients with enuresis were more likely to exhibit these behavioral problems than healthy subjects. The demographics of the patients were significantly different in the two groups in favor of the control group. CONCLUSION: It was shown that patients with enuresis have more social and attention problems than the control group. Treating these patients effectively will increase the likelihood that they will not develop behavioral problems. PMID- 27513261 TI - Potential drug-drug interactions in a medical intensive care unit of a university hospital. AB - BACKGROUND/AIM: Drug-drug interactions (DDIs) can impact patient safety. Occurrence of clinically important DDIs is higher for intensive care unit (ICU) patients. This observational study aimed to evaluate the potential DDIs in medical ICU patients of a university hospital. MATERIALS AND METHODS: The Medical Pharmacology Department organized consultation reports for ICU patients in order to detect the DDIs. To focus on clinically important DDIs, interactions in the C, D, or X risk rating categories of the Lexi-Interact online database were analyzed. Frequency and clinical risk rating categories of DDIs were detected. Relationship between number of prescriptions and DDIs were assessed. The most frequent drug/drug groups were identified. RESULTS: Of 101 ICU patients, 45.5% were found to have DDIs. We detected 125 C (72.2%), 37 D (21.4%), and 11 X (6.4%) risk category interactions. A statistically significant increase in the number of DDIs was shown with the number of prescriptions (P = 0.002). The most frequent DDIs were between agents acting on the cardiovascular system and corticosteroids (12.8%). CONCLUSION: Results of this study show that pharmacological consultation plays a critical role in the recognition of DDIs for improvement of medication management and effective therapeutic endpoints without any adverse or toxic reactions. PMID- 27513262 TI - Evaluation of the gastrointestinal findings of nodulocystic acnepatients during systemic isotretinoin therapy. AB - BACKGROUND/AIM: Systemic isotretinoin treatment is an effective treatment modality for nodulocystic acne, the clinical use of which has been associated with reports of adverse events. We conducted a prospective study with the aim of determining the possible gastrointestinal and laboratory findings of nodulocystic acne patients during systemic isotretinoin treatment. MATERIALS AND METHODS: Seventy patients with nodulocystic acne completed the study. During the monthly follow-up visits, liver function tests and lipid profiles of the patients were evaluated and gastrointestinal system complaints were examined. RESULTS: We recorded a significant elevation in liver function tests and lipid profiles of the patients, the most prominent elevation being in plasma triglyceride concentrations. We observed that nausea, dyspepsia, abdominal pain, and diarrhea were the rare gastrointestinal symptoms encountered during systemic isotretinoin therapy. Constipation and anorectal bleeding were relatively more common symptoms and there seemed to be a relation between these two symptoms. CONCLUSION: Our study is the first to analyze the gastrointestinal findings of patients during systemic isotretinoin treatment. Dermatologists and gastroenterologists must keep in mind that, as well as known laboratory findings like hypertriglyceridemia and elevated liver function tests, systemic isotretinoin therapy may also cause significant clinical gastrointestinal findings. PMID- 27513263 TI - Prospects of curcumin as an additive in storage solutions: a study on erythrocytes. AB - BACKGROUND/AIM: Curcumin, a naturally occurring antioxidant, shows a wide variety of medicinal properties. The possibility of utilizing curcumin as an additive in storage solutions of blood has not been explored. The purpose of this study was to analyze the effect of curcumin on erythrocytes during storage. MATERIALS AND METHODS: Blood obtained from rats was stored (4 degrees C) for 20 days in citrate-phosphate-dextrose-adenine-1 solution. Samples were divided into four groups: 1) Controls; 2) Curcumin 10 mM; 3) Curcumin 30 mM; and 4) Curcumin 60 mM. Every fifth day, hemoglobin, superoxide, antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase (GSH-Px)), lipid peroxidation (conjugate dienes and malondialdehyde (MDA)), protein oxidation (advanced oxidation protein products (AOPP) and sulfhydryls (P-SH)), and hemolysis were analyzed. RESULTS: Hemoglobin was successfully maintained, while superoxide dismutase increased initially and decreased towards the end of storage. Superoxide, catalase, GSH-Px, conjugate dienes, and AOPP were lower in the curcumin groups than they were in the controls. MDA was higher in the curcumin groups than in the controls. P-SH increased in the curcumin groups, while hemolysis increased in all groups. CONCLUSION: Curcumin maintained hemoglobin and modulated antioxidant enzymes throughout storage. However, curcumin could not protect all proteins and lipids from oxidative damage completely. This study opens up new avenues for using curcumin, in combination with other antioxidants, as a component in storage solutions. PMID- 27513264 TI - Evaluation of brain perfusion in Alzheimer disease with perfusion computed tomography and comparison to elderly patient without dementia. AB - BACKGROUND/AIM: The aim of this study was to evaluate perfusion computed tomography (PCT) findings in patients with Alzheimer disease and to compare them with those of patients without dementia. MATERIALS AND METHODS: PCT was performed in 35 patients: 20 with Alzheimer disease (mean age, 69.7 +/- 5.5 years) and 15 control subjects (mean age, 67.5 +/- 3.5 years). Control subjects were elderly individuals with no cognitive problems who were admitted with headaches. All PCT examinations were performed on a 4-slice CT unit. The PCT analysis software program was used to calculate regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), regional time-to-peak (rTTP) values in the bilateral frontal, temporal, and occipital cortices, and bilateral lentiform nucleus. RESULTS: rCBF values in the bilateral frontal and temporal cortices and bilateral lentiform nucleus were significantly lower in the patients with Alzheimer disease than in the control subjects. There were no significant differences in rCBV values between Alzheimer disease and the control group. rTTP values in all cortical areas and bilateral lentiform nucleus were significantly higher in the patients with Alzheimer disease than in the control subjects. CONCLUSION: PCT is a rapid and reliable imaging modality for evaluating brain perfusion in Alzheimer disease. PMID- 27513265 TI - The incidence of 18F-FDG PET/CT thyroid incidentalomas andthe prevalence of malignancy: a prospective study. AB - BACKGROUND/AIM: To determine the prevalence of malignancy in thyroid incidentalomas (TIs) detected by fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). MATERIALS AND METHODS: 18F-FDG PET/CT images were evaluated prospectively for the presence of thyroid uptake. The patients with a TI were evaluated by an endocrinologist according to the predefined diagnostic algorithm. The final diagnosis was obtained clinically and/or by pathology. RESULTS: TI was detected in 4.2% of 4204 patients. A malignant thyroid nodule was diagnosed in 29% and 33% of the focal and diffuse focal uptake groups, respectively. However, no malignancy was detected in the diffuse uptake group. The standardized maximum uptake values (SUVmax) of the nodules were significantly higher in patients with thyroid malignancy than in patients with benign nodules (P = 0.006). The calculated cut-off value of SUVmax for malignancy was 3.5. In 2 patients in whom the cytopathological diagnosis was benign, malignancy was diagnosed after total thyroidectomy. CONCLUSION: A malignant nodule was present in one-third of the patients with focal or diffuse focal uptake. A SUVmax value of 3.5 was considered as a cut-off value for the differentiation of a malignant lesion. Benign cytology in fine-needle aspiration biopsy for 2 patients underestimated a thyroid malignancy. PMID- 27513266 TI - Three-dimensional cephalometric norms of Turkish Cypriots using CBCTimages reconstructed from a volumetric rendering program in vivo. AB - BACKGROUND/AIM: The aim of this study was to create a database of 3D cephalometric measurements of Turkish Cypriot patients using a 3D rendering software program. MATERIALS AND METHODS: The study population comprised 121 subjects who had undergone cone beam CT imaging (CBCT). Invivo 5.1 software was used to generate cephalograms from the CBCT dataset that were then linked to the 3D hard-tissue surface representations. In total, 38 angular and 28 linear widely used measurements were recorded. RESULTS: The results demonstrated that males had significantly larger mean values than females for all linear measurements, except for dentoalveolar parameters (P < 0.05). Additionally, significant differences were found in most of the mandibular anteroposterior and vertical measurements, especially SNB, GoGn/SN, FMA, and MP/SN, between the sexes (P < 0.05). CONCLUSION: This is the first population-based study to focus solely on Turkish Cypriots' craniofacial anatomy and orthodontic characteristics. The present findings will produce 3D cephalometric normative data for the Cypriot population and will be valuable for oral and maxillofacial surgeons and orthodontists in Cyprus, the UK, Australia, Turkey, and other European countries who treat a large number of Turkish Cypriot patients. PMID- 27513267 TI - 1H-magnetic resonance spectroscopy in first episode and chronic schizophrenia patients. AB - BACKGROUND/AIM: The aim of this study was to compare metabolite levels of the dorsolateral prefrontal cortex (DLPFC), anterior cingulate gyrus (ACG), thalamus, and hippocampus in patients with chronic schizophrenia (CSPs) and first psychotic episode patients (FEPs) by the use of magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: Thirty CSPs, 20 FEPs, and 30 healthy subjects participated in this study. N-Acetylaspartate (NAA), creatine, choline (Cho), and myoinositol levels of the DLPFC, ACG, thalamus, and hippocampus were measured by 1H-MRS. RESULTS: It was determined that the NAA/Cho ratio was lower in both the FEPs and CSPs than the healthy controls in the DLPFC. DLPFC Cho levels were also higher in CSPs than healthy controls. NAA levels in CSPs were significantly lower than in the control group in the hippocampus. There was no significant difference in neurometabolite levels and ratios in the ACG and thalamus between the groups. CONCLUSION: This study supports neuronal dysfunction or loss of neuronal integrity in the DLPFC and hippocampus in CSPs. FEPs showed less neuronal dysfunction in the DLPFC, but not in the hippocampus. Our results suggest that schizophrenic patients show brain metabolic changes with the onset of the disorder in the DLPFC; these changes could be more apparent in the hippocampus as the disease progresses to chronic stages. PMID- 27513268 TI - PaCaHa inhibits proliferation of human cancer cells in vitro. AB - BACKGROUND/AIM: The aim of this study was to investigate the antiproliferative and cytotoxic effects of a newly synthesized molecule named paracetamol acetohydroxamic acid (PaCaHa) on human neoplastic cell lines. MATERIALS AND METHODS: A549, CRL 2923, HeLa, and ARPE were treated with various concentrations of PaCaHa and DMSO (vehicle control). The cytotoxic/cytostatic effects of PaCaHa were determined after a 24-h incubation period and compared to the DMSO control. The cytotoxic and antiproliferative effects were determined by the trypan blue dye exclusion and MTT methods. RESULTS: A higher susceptibility to PaCaHA was found in CRL 2923 and HeLa cells, while A549 and ARPE cells were less responsive to PaCaHa. The percent of cytotoxicity resulting from 400 ug/mL of PaCaHa were >90 for CRL-2923 and HeLa, 68 for A549, and 64 for ARPE cells. The cytotoxic difference between CRL-2923/HeLa and ARPE/A549 cells was significant (P < 0.05). CONCLUSION: PaCaHa showed dose dependent cytotoxic and antiproliferative effects on three distinct human cancer cell lines. The differential effect of PaCaHa on different cancer cell lines suggests that PaCaHa could have a potential antitumor effect on specific cancer types. These results support further comprehensive studies on PaCaHa and its derivatives. PMID- 27513269 TI - Determination of virulence and multidrug resistance genes with polymerase chain reaction method in vancomycin-sensitive and -resistant enterococci isolated from clinical samples. AB - BACKGROUND/AIM: Enterococci play an important role in nosocomial infections. Therefore, this study investigates multidrug resistance (MDR)1 gene areas in the pathogenicity of enterococci and virulence genes in both vancomycin-sensitive enterococci (VSE) and vancomycin-resistant enterococci (VRE) strains. MATERIALS AND METHODS: Virulence genes and MDR genes of enterococci were investigated by polymerase chain reaction (PCR). RESULTS: We evaluated a total of 116 isolates, 93 being VRE and 23 being VSE. In this study, 95.6% of VRE (n = 93) were Enterococcus faecium (n = 89) and 4.3% were E. faecalis (n = 4), while 17.4% of VSE (n = 23) were E. faecium (n = 4) and 82.6% were E. faecalis (n = 19). The vanA MDR1 gene was detected in all VRE isolates. Among virulence genes, esp and hyl were detected in E. faecium, an enterococcus with the highest resistance to vancomycin, and gelE was detected in E. faecalis, an enterococcus with the highest sensitivity to vancomycin. Three or more virulence genes were identified only in VSE strains. We consider that it is a significant result that VSE had more virulence genes than VRE. Only esp was seen in VRE E. faecium strains. CONCLUSION: This study includes experimental results on the association of virulence characteristics in VRE and VSE strains. PMID- 27513270 TI - Investigating the in vitro synergistic activities of several antibiotic combinationsagainst carbapenem-resistant Acinetobacter baumannii isolates. AB - BACKGROUND/AIM: Acinetobacter baumannii (A. baumannii) is one of the most common healthcare-associated infectious agents worldwide. The aim of this study was to investigate the in vitro synergistic activities of several antibiotic combinations against carbapenem-resistant (CR) A. baumannii isolates. MATERIALS AND METHODS: Eighteen CR A. baumannii strains were isolated from the patients who were hospitalized in the intensive care unit between June 2012 and August 2012. The in vitro effects of single and binary combinations of meropenem (MEM), colistin (CST), tigecycline (TGC), and sulbactam (SUL) on these isolates were determined using the Epsilometer test (E-test) method. RESULTS: All 18 isolates were resistant to MEM and SUL and susceptible to CST. TGC was detected as susceptible in two of the isolates and intermediate susceptibility results were observed in the remaining isolates. With MEM-CST and MEM-TGC combinations, synergism was determined against all isolates. The synergistic and/or additive effect ratios were detected in MEM-SUL, CST-SUL, TGC-SUL, and CST-TGC combinations as 16.7%, 38.9%, 16.7%, and 5.6%, respectively. CONCLUSION: Among the tested antimicrobial combinations, the in vitro combination of MEM with TGC or CST was most effective against the CR A. baumannii strains. PMID- 27513271 TI - Molecular prevalence and antibiotics resistance pattern of class A bla CTX-M-1 and bla TEM-1 beta lactamases in uropathogenic Escherichia coli isolates from Pakistan. AB - BACKGROUND/AIM: Extended spectrum beta lactamase (ESBL) production among E. coli is one of the principal mechanisms that augment resistance to antibiotics. In the current study the molecular detection of class A beta lactamases among uropathogenic Escherichia coli was evaluated. MATERIALS AND METHODS: A total of 355 urine samples were collected from a tertiary care hospital in Peshawar. The ESBL production among E. coli isolates was detected by using the disc synergy diffusion method. Moreover, the molecular detection of bla TEM-1 and bla CTX-M-1 ESBLs, the antibiotic resistance pattern, and the minimum inhibitory concentrations (MICs) were also documented. RESULTS: Among the 355 urine samples, 157 isolates were E. coli, and 23.56% of the isolates were ESBL E. coli. Among phenotypic ESBL producers, bla CTX-M-1 and bla TEM-1 were found in 59.45% and 40.54% of the isolates, respectively. A high resistance rate was observed against aztreonam (97.29%), while the lowest resistance was observed against imipenem (2.7%). The MICs of ESBLs E. coli for ceftriaxone, ciprofloxacin, and gentamicin was >512 ug/mL, 4 ug/mL to 128 ug/mL, and 1 ug/mL to 14 ug/mL respectively. CONCLUSION: The present study showed that bla CTX-M-1 ESBL production is more prevalent in our clinical E. coli isolates. More often the ESBLs were resistant to commonly used antibiotics. PMID- 27513272 TI - An investigation of the bactericidal activity of chlorhexidine digluconateagainst multidrug-resistant hospital isolates. AB - BACKGROUND/AIM: Hospital infections are among the most prominent medical problems around the world. Using proper biocides in an appropriate way is critically important in overcoming this problem. Several reports have suggested that microorganisms may develop resistance or reduce their susceptibility to biocides, similar to the case with antibiotics. In this study we aimed to determine the antimicrobial activity of chlorhexidine digluconate against clinical isolates. MATERIALS AND METHODS: The susceptibility of 120 hospital isolated strains of 7 bacterial genera against chlorhexidine digluconate was determined by agar dilution test, using minimum inhibitory concentration (MIC) values and the EN 1040 Basic Bactericidal Activity Test to determine the bactericidal activity. According to MIC values, Pseudomonas aeruginosa and Stenotrophomonas maltophilia were found to be less susceptible to chlorhexidine digluconate. RESULTS: Quantitative suspension test results showed that 4% chlorhexidine digluconate was effective against antibiotic resistant and susceptible bacteria after 5 min of contact time and can be safely used in our hospital. However, concentrations below 4% chlorhexidine digluconate caused a decrease in bactericidal activity, especially for Staphylococcus aureus and P. aeruginosa. CONCLUSION: It is crucial to use biocides at appropriate concentrations and to perform surveillance studies to trace resistance or low susceptibility patterns of S. aureus, P. aeruginosa, and other hospital isolates. PMID- 27513273 TI - Hepatoprotective and antidiabetic activities of Fraxinus angustifolia Vahl extracts in animal models: characterization by high performance liquid chromatography analysis. AB - BACKGROUND/AIM: The present study was designed to explore antidiabetic and hepatoprotective potentials of Fraxinus angustifolia leaf (FAL) and bark (FAB) extracts in vivo. MATERIALS AND METHODS: Streptozotocin (STZ)-induced diabetic rats, pretreated with the extracts (25 and 50 mg/kg), were monitored for fasting blood glucose (FBG) levels. Hepatoprotective potential was examined after injection of an excessive dose of paracetamol (10 g/60 kg) by analysis of biochemical parameters (transaminases, bilirubin), malondialdehyde (MDA) levels, and histological sections. high performance liquid chromatography analysis was also performed for partial characterization. RESULTS: A considerable hypoglycemic effect was noticed 2 h after the STZ-induction, with a higher efficiency (P < 0.05) for FAL (68%) as compared with FAB (57%). A significant (P < 0.05) reduction in MDA was observed for paracetamol-fed mice pretreated with FAL (50 mg/kg), FAB (50 mg/kg), or both (25 mg/kg each) extracts, and the MDA levels for the three conditions were 0.290 +/- 0.034, 0.340 +/- 0.038, and 0.25 +/- 0.058 nmoles/mg of liver tissue, respectively). Hence, simultaneous treatment provided a better protection. Histological observations confirmed the higher hepatoprotective potential of FAL over FAB extracts. CONCLUSION: The obtained results indicate the possibility of pharmacological exploitation of F. angustifolia extracts in the treatment of diabetes and associated liver diseases. PMID- 27513274 TI - Intestinal trefoil factor increased the Bcl-2 level in a necrotizingenterocolitis neonate rat model. AB - BACKGROUND/AIM: The aim of this study was to investigate the therapeutic effect of intestinal trefoil factor (ITF) on necrotizing enterocolitis (NEC) by observing the pathological changes and detecting the protein level differences in Caspase-3, Bax, and Bcl-2 in an NEC neonate rat model. MATERIALS AND METHODS: A Wistar rat model of NEC was established and 30 one-day-old neonate Wistar rats were randomly divided into three groups including a normal control (group A), NEC rats treated with 0.2 ml physiological saline through intraperitoneal (i.p.) injection (group B), and NEC rats treated with 0.2 mg ITF by i.p injection (group C). RESULTS: Compared with group B, there were statistically significant differences in Caspase-3, Bax, and Bcl-2 levels in groups A and C(P < 0.05). Moreover, there was a significant difference in the Bcl-2 level between groups A and B (P < 0.05). CONCLUSION: ITF alleviated injury of the intestinal tract in neonate rats with NEC and this mechanism was possibly related to a reduction in the expression of Caspase-3 and Bax and the increase in Bcl-2 expression. PMID- 27513275 TI - The effects of bupivacaine combined with different adjuvants on block onset and duration and on ion channel expressions (SCN9A, TRPM) in sciatic nerve block in rats. AB - BACKGROUND/AIM: The objective of this experimental study was to examine the effects of epinephrine, dexmedetomidine, and clonidine added as adjuvants to bupivacaine on block onset and effect times, as well as the effects on the Na+ and Ca+2 channel gene expressions, which may indicate cell damage in the sciatic nerve cell membrane. MATERIALS AND METHODS: Rats were divided into five groups: Group S (sham), saline solution; Group B, bupivacaine; Group BD, bupivacaine + dexmedetomidine; Group BC, bupivacaine + clonidine; and Group BE, bupivacaine + epinephrine. For each group, 0.2 mL of local anesthetic was injected into the sciatic nerve bifurcation point of the right leg. Sensory (proprioceptive and nociceptive block) and motor block onset and ending times were recorded. RESULTS: The shortest onset time for the examined sciatic block was observed in the BC group, whereas the longest sensory and motor block times were observed in the BD group. The present data suggest suppressed TRPM7 and increased TRPM2 in the groups other than the BE group. CONCLUSION: Clonidine is more suitable for fast onset of peripheral nerve blocks, whereas the addition of dexmedetomidine is better in terms of duration. Because the SCN9A and TRPM2,4,7 expression ratios of the BE group showed the least amount of change, this group had the best cellular integrity. PMID- 27513276 TI - Paternal exposure to low-dose lead acetate: effect on implantation rate,pregnancy outcome, and sex ratio in mice. AB - BACKGROUND/AIM: It has been reported from in vivo exposed experimental animals that paternal lead exposure reduces birth rate; however, there is limited evidence to suggest a decrease in the proportion of male births. This study investigated the role of paternal exposure to lower lead acetate doses on early embryonic development (implantation) and the sex ratio of their offspring. MATERIALS AND METHODS: In total 180 Swiss Webster mice were used (60 male and 120 female). The males were divided into 3 groups: G1 (untreated group), G2 (treated daily with 50 ug/kg BW lead acetate), and G3 (treated daily with 100 ug/kg BW lead acetate). The implantation success rate, pregnancy outcome, and sex ratio were measured. RESULTS: The results showed a highly significant reduction in both the percentage of implantation rate and the number of offspring in the G3 mice, but there was no signification difference for the G2 mice. There was a slight insignificant reduction in the number of newborn males compared with females for both G2 and G3 mice. CONCLUSION: The findings of this study suggest lead exposure in experimental animals reduces implantation rate with paternal BLL of 28 ug/dL and the sex ratio for offspring showed a slight insignificant reduction with both paternal BLLs of 23.5 ug/dL and 28 ug/dL. PMID- 27513277 TI - First report on the distribution of 3435C>T ABCB1/MDR1polymorphism in healthy Bosniak population. PMID- 27513279 TI - Why Your ZIP Code Matters More Than Your Genetic Code: Promoting Healthy Outcomes from Mother to Child. AB - Health equity has long been the dominant theme in the work of the Aetna Foundation. Recent data have focused on disparities through another lens, particularly the correlation between where people live (i.e., ZIP code) and their quality-and length-of life. In various cities across America, average life expectancies in certain communities are 20-30 years shorter than those mere miles away. In general, health disparities are founded on a complex interplay of racial, economic, educational, and other social factors. For example, breastfeeding rates in the United States differ significantly depending upon the race and income of the mother. Government policy makers are acutely aware of these disparities, but recent health system reforms have focused predominately on the processes used to administer, finance, and deliver care. What is needed is an approach that considers the health and wellness of all people in a geographic area, beyond established patients, and that measures more than clinical factors such as genetics, environmental health, social circumstances, and individual behaviors. Solutions also must extend beyond the traditional healthcare arena. In particular, novel technological innovations show promise to bridge gaps between our healthcare capabilities and the needs of underserved populations. Digital tools are poised to revolutionize measurement, diagnostics, treatment, and global aspect of our healthcare system. The Aetna Foundation views technology as a core strategy in reducing health inequities through an approach that addresses both clinical and social factors in populations to dismantle the persistent paradigm of ZIP code as personal health destiny. PMID- 27513278 TI - Efficacy and Safety of Long-Term Sirolimus Therapy for Asian Patients with Lymphangioleiomyomatosis. AB - RATIONALE: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression. OBJECTIVES: To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM. METHODS: We conducted a single-arm, open-label, investigator-initiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml. MEASUREMENTS AND MAIN RESULTS: Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2 year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%); microcytosis in 10 patients; loss of body weight in 33 patients; and increase in blood pressure that required treatment in 5 patients. FEV1, FVC, and quality-of-life parameters were stable in the overall study cohort during the study period, but baseline to 2-year improvements in lung function occurred in the subset of patients with a prior history of chylothorax. CONCLUSIONS: Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function. PMID- 27513281 TI - Synergetic Solvent Engineering of Film Nanomorphology to Enhance Planar Perylene Diimide-Based Organic Photovoltaics. AB - Solvent additive has proven as a useful protocol for improving the film nanomorphology of polymer donor (D): fullerene acceptor (A) blends in bulk heterojunction (BHJ) photovoltaic cells. By contrast, the effect of such solvent additive on nonfullerene BHJ cells based on perylene diimide acceptor, for instance, is less effective because of their highly planar structure and strong pi-aggregation in solid state. Here we choose N,N'-bis(1-ethylpropyl)-perylene 3,4,9,10-tetracarboxylic diimide (PDI) and thieno[3,4-b]thiophene-alt benzodithiophene (PTB7) as a model D:A blend system to investigate how solvent engineering strategy synergistically impacts the blend film nanomorphology. Based on the differences of solvent volatility and solubility, various host solvents chloroform (CF) and chlorobenzene (CB) and solvent additives-chloronaphthalene (CN) and 1,8-diiodooctane (DIO) are selected for comparative studies. It is found that the pi-aggregation of PDIs can be largely suppressed by using low-boiling point (Tb) CF solvent, yet enlarged by using high-Tb CB. Moreover, CN additive provides good solubility of PDI molecules and hence reduces large PDI aggregates in CB system, while DIO exhibiting poor solubility works oppositely. By contrast, DIO that presents larger Tb difference with CF prolongs the film-forming, which assists in optimizing the PDI aggregation and increases the intermixed PTB7:PDI phases more significantly than CN in CF system, yielding the finest phase separation morphology and balanced charge mobility. Consequently, the inverted BHJ cells based on CF-processed PTB7:PDI blend film with 0.4 vol % DIO exhibit the highest PCE of 3.55% with a fill factor of 56%, both of which are among the best performance for such a paradigm PTB7:PDI blend-based BHJ cells. PMID- 27513280 TI - Simultaneously elevated exhaled nitric oxide and serum-eosinophil cationic protein relate to recent asthma events in asthmatics in a cross-sectional population-based study. AB - BACKGROUND: We have reported that increased fraction of exhaled nitric oxide (FeNO), a measure of TH2 -driven airway inflammation, and blood eosinophil count, a marker of systemic eosinophil inflammation, correlated with asthma attacks in a population-based study. OBJECTIVE: To investigate the relation between simultaneously elevated FeNO and serum eosinophil cationic protein (S-ECP) levels and asthma events among asthmatics. METHODS: Measurements of FeNO (elevated >= 25 ppb) and S-ECP (elevated >= 20 ng/mL) were performed in 339 adult asthmatics. Asthma events (attacks and symptoms) were self-reported. RESULTS: Simultaneously normal S-ECP and FeNO levels were found in 48% of the subjects. Subjects with simultaneously elevated S-ECP and FeNO (13% of the population) had a higher prevalence of asthma attacks in the preceding 3 months than subjects with normal S-ECP and FeNO (51% vs. 25%, P = 0.001). This was not found for subjects with singly elevated S-ECP (P = 0.14) or FeNO (P = 0.34) levels. Elevated S-ECP and FeNO levels were independently associated with asthma attacks in the preceding 3 months after adjusting for potential confounders (OR (95% CI) 4.2 (2.0-8.8). CONCLUSIONS: Simultaneously elevated FeNO and S-ECP levels were related to a higher likelihood of asthma attacks in the preceding 3 months. This indicates that there is a value in measuring both FeNO and systemic eosinophilic inflammation in patients with asthma to identify individuals at high risk of exacerbations. CLINICAL RELEVANCE: FeNO and S-ECP are markers for inflammation in asthma, but are dependent on different inflammatory pathways and weakly correlated. Simultaneous measurements of both offer better risk characterization of adult asthmatics. PMID- 27513282 TI - Novel porous poly(propylene fumarate-co-caprolactone) scaffolds fabricated by thermally induced phase separation. AB - Scaffolds with porous structures are highly applicable for tissue engineering and regenerative medicine. In the present study, 3-dimensional poly(propylene fumarate-co-caprolactone) [P(PF-co-CL)] scaffolds were fabricated from a P(PF-co CL)-dioxane-water ternary system through thermally induced phase separation (TIPS). Cloud points of P(PF-co-CL) in dioxane-water solutions increased with increased solute concentration, but increased dioxane composition decreased cloud point. Among 3 polymer concentrations (4, 8, and 12 wt%), 8 wt% P(PF-co-CL) scaffolds exhibited the best pore interconnectivity, with large, regular sized pores. Scaffolds were formed in 3 solutions with different dioxane-water ratios (74/26, 78/22, and 82/18 wt/wt); the 78/22 wt/wt scaffold had finger-shaped patterns with better interconnectivity than scaffolds from the other two ratios. Higher dioxane-water ratios resulted in a larger contact angle and thus less wettability for the fabricated scaffold, while scaffolds fabricated from higher concentrations of P(PF-co-CL) or high dioxane-water ratios had better biomineralization after soaking in simulated body fluid. In vitro cell viability testing showed the scaffolds had good biocompatibility with both bone and nerve cells. The results indicate that the polymer concentration and solvents ratio significantly affect the formation of porous structures, and optimum processing parameters were found to be 8% polymer concentration and 22% to 24% water content. These porous P(PF-co-CL) scaffolds fabricated via TIPS may be useful in various tissue engineering applications (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 226-235, 2017. PMID- 27513283 TI - Maternal anxiety and physiological reactivity as mechanisms to explain overprotective primiparous parenting behaviors. AB - In this study, we sought to determine whether the affective and physiological experience of primiparous, or first-time, motherhood is distinct from multiparous motherhood, how the child's level of inhibited temperament impacts it, and if such a temperament results in overprotective parenting behaviors. A total of 117 mothers and their 24-month-old toddlers participated in novelty tasks designed to elicit parenting behaviors and toddler's typical fear reactions. Mothers also completed a battery of questionnaires. Results suggest that primiparous mothers experienced more worry, which was associated with increased overprotective parenting behaviors. Primiparous mothers also demonstrated greater physiological (i.e., cortisol) reactivity while watching their first-born children interact with novel stimuli, but how this related to overprotective parenting was dependent on the child's level of inhibition. Specifically, primiparous mothers displayed more cortisol reactivity with their uninhibited toddlers, which indirectly linked parity to less overprotective parenting behaviors. Primiparous mothers of highly inhibited toddlers displayed greater overprotective parenting behaviors, independent of maternal cortisol reactivity. The results indicate that the transition to motherhood is a unique experience associated with greater worry and physiological reactivity and is meaningfully influenced by the toddler's temperament. Distinctions in both observed and self-reported overprotective parenting are evident through considering the dynamic interaction of these various aspects. (PsycINFO Database Record PMID- 27513284 TI - Happy Family Kitchen: A community-based research for enhancing family communication and well-being in Hong Kong. AB - Urban families worldwide are often characterized by busy working lives which leave little time for family gatherings and communication. The Happy Family Kitchen project, which emphasized cooking and dining with family members, was conducted in a deprived district in Hong Kong. We hypothesized that the community based family intervention, derived from a positive psychology framework, can improve family communication, family well-being, and subjective happiness. Twenty three social service units organized and delivered the intervention programs for 1,419 individuals from 612 families. The core intervention was developed with emphasis on 1 of 5 positive psychology themes: gratitude, flow, happiness, health, and savoring. Intervention outcomes were assessed at preintervention, immediate postintervention, and 6 weeks and 12 weeks postintervention. Results showed that family communication, family well-being, and subjective happiness improved with small effect sizes which were sustained up to 12 weeks. The gratitude intervention improved all of the outcome measures. Qualitative data provided additional evidence for effectiveness with in-depth insights into family dynamics. We concluded that this brief intervention was a low-cost and simple approach to improve family communication and well-being. (PsycINFO Database Record PMID- 27513285 TI - Low-income, nonresident fathers' coparenting with multiple mothers and relatives: Effects on fathering. AB - Low-income, nonresident fathers are often involved in complex coparenting networks that may involve multiple mothers, relatives, and other adults. However, the coparenting literature has often obscured this complexity through limiting attention to father-mother relationships. The current study used family systems theory to examine the effects of fathers' coparenting with mothers and relatives on fathers' parenting self-efficacy, father-child closeness, and father-child conflict. Predictors included the number of fathers' coparenting mothers and relatives, the quality of those coparenting relationships, and coparenting alliances specifically between fathers and the biological mother of a target child. Approximately 19% of a community sample of fathers (N = 401) reported more than 1 mother in their coparenting network, and 63% reported at least 1 relative. Overall, fathers who reported having more-cooperative coparenting relatives in their networks reported higher parenting self-efficacy and father-child closeness. We further noted a race or ethnicity interaction effect for closeness and conflict, such that having more-cooperative coparenting relatives was associated with increased closeness for non-Hispanic Black fathers but not for non-Hispanic White fathers. Amount of cooperation with coparenting relatives was associated with increased conflict for non-Hispanic Black fathers but not for Hispanic fathers. Implications for future research and practice are discussed. (PsycINFO Database Record PMID- 27513286 TI - Adolescent functioning in housing and family contexts: A mixed methods study. AB - Although adolescents begin to seek autonomy and strive to be out of the home on their own, the housing context remains the primary setting of their daily lives. Using survey and ethnographic data from Welfare, Children, and Families: A Three City Study (e.g., Winston et al., 1999), this study explored quantitatively and qualitatively how two salient aspects of the housing context, physical housing problems and household size, were associated with low-income adolescents' emotional and academic functioning, and how these associations were modified by mother-adolescent relationships (specifically, trust and communication) and gender. Results of cross-lagged hierarchical linear models suggest that adolescents living in homes with more housing problems had more mental health symptoms, whereas living in larger households was associated with higher achievement, but only in the context of lower quality mother-adolescent relationships. Qualitative analyses helped to interpret these results by illuminating potential pathways underlying associations observed in quantitative results. PMID- 27513287 TI - "It takes two to take": Caregiving style, relational entitlement, and medication adherence. AB - Partners' support has been associated with both patients' increased and decreased inclination toward health-promoting behaviors. Our hypothesis for understanding this enigma is that it is the interplay between partners' manner of care provision and patients' ability to accept these care efforts that may best predict patients' adherence. Thus, the current study's main goal was to examine the contribution of the interaction between caregivers' support style (sensitive and compulsive) and cardiac patients' sense of relational entitlement (restricted, excessive, assertive, entitlement expectations) to patients' medication adherence. The Adult Caregiving Questionnaire, the Sense of Relational Entitlement Scale, and the Medication Adherence Report Scale were administered to 114 cardiac patients and their partners, during patients' hospitalizations and 6 months later. The lowest levels of medication adherence were detected among patients high on restricted entitlement who were married to partners high on compulsive caregiving style. These findings strengthen our claim that it is the interaction between recipients' personality and providers' support style which explain self-regulatory processes that arise during times of family medical crises. (PsycINFO Database Record PMID- 27513288 TI - Elucidating the pH-Dependent Structural Transition of T7 Bacteriophage Endolysin. AB - Bacteriophages are the most abundant and diverse biological entities on earth. Bacteriophage endolysins are unique peptidoglycan hydrolases and have huge potential as effective enzybiotics in various infectious models. T7 bacteriophage endolysin (T7L), also known as N-acetylmuramoyl-l-alanine amidase or T7 lysozyme, is a 17 kDa protein that lyses a range of Gram-negative bacteria by hydrolyzing the amide bond between N-acetylmuramoyl residues and the l-alanine of the peptidoglycan layer. Although the activity profiles of several of the T7 family members have been known for many years, the molecular basis for their pH dependent differential activity is not clear. In this study, we explored the pH induced structural, stability, and activity characteristics of T7L by applying a variety of biophysical techniques and protein nuclear magnetic resonance (NMR) spectroscopy. Our studies established a reversible structural transition of T7L below pH 6 and the formation of a partially denatured conformation at pH 3. This low-pH conformation is thermally stable and exposed its hydrophobic pockets. Further, NMR relaxation measurements and structural analysis unraveled that T7L is highly dynamic in its native state and a network of His residues are responsible for the observed pH-dependent conformational dynamics and transitions. As bacteriophage chimeric and engineered endolysins are being developed as novel therapeutics against multiple drug resistance pathogens, we believe that our results are of great help in designing these entities as broadband antimicrobial and/or antibacterial agents. PMID- 27513289 TI - The Effect of Delivery System and Light Activation on Tooth Whitening Efficacy and Hydrogen Peroxide Penetration. AB - PURPOSE: To evaluate the whitening efficacy of a new two-layer technology in office system compared to a conventional gel-type system and determine hydrogen peroxide penetration (HPP) into the pulp cavity. MATERIALS AND METHODS: Extracted molars (n = 60) were assigned to group NC: glycerol gel; group QPRO: 20% HP varnish (Zoom Quick Pro, Philips Oral Healthcare); group ZOOM_NL: 25% HP gel (Zoom Chairside Whitening); and group ZOOM_WL: 25% HP gel (Zoom Chairside Whitening) with light-activation. HPP levels were estimated with leucocrystal violet and horseradish-peroxidase. Instrumental color measurements were performed at baseline (T0 ), 1-day post first whitening (T1 ), 1-day post second whitening (T2 ), 1-day post third whitening (T3 ), and 1-month post whitening (T4 ). One way analysis of variance followed by post hoc Tukey's HSD test was performed to detect difference in DeltaE* and HP penetration levels (alpha = 0.05). RESULTS: DeltaE* of NC was lower than other groups, whereas DeltaE* of ZOOM_WL was greater than the other three groups, at T3 and T4 . Mean HPP level obtained from ZOOM_WL (1.568 +/- 0.753 MUg/mL) was significantly greater than those obtained from the other groups, whereas the mean HPP level observed in NC group (-0.131 +/- 0.003 MUg/mL) was significantly lower than the other groups. CONCLUSIONS: Tooth whitening efficacy and HPP levels vary based on whitening systems used. CLINICAL SIGNIFICANCE: The two-layer technology in-office varnish system may be an alternative whitening option to reduce chair time in the office. (J Esthet Restor Dent 28:313-320, 2016). PMID- 27513290 TI - A Study of Boratriazaroles: An Underdeveloped Class of Heterocycles. AB - Boratriazaroles were discovered in the late 1960s, and since then, a variety of substituted boratriazarole derivatives have been prepared. However, no study has compared the properties of these BN heterocycles with their carbon-based analogues. In this work, we have prepared a series of boratriazarole derivatives and have investigated how structural variations in the five-member heterocycle affect photophysical and electronic properties. Boratriazaroles exhibit absorption and emission spectra comparable to those of their azacycle analogues but have a markedly lower quantum yield. The quantum yield can be increased with the incorporation of a 2-pyridyl substitution on the boratriazaroles, and the structural and optoelectronic properties are further influenced by the nature of the B-aryl substituent. Introducing an electron-deficient p-cyano group on the B phenyl substituent creates a twisted intramolecular charge transfer state that causes a large Stokes shift and positive solvatochromism. Our work should serve to guide future synthetic efforts toward the application of boratriazaroles in materials science. PMID- 27513293 TI - MicroRNA Let-7b inhibits keratinocyte migration in cutaneous wound healing by targeting IGF2BP2. AB - Wound healing is a complex process which involves proliferation and migration of keratinocyte for closure of epidermal injuries. A member of microRNA family, let 7b, has been expressed in mammalian skin, but its exact role in keratinocyte migration is still not in knowledge. Here, we showed that let-7b regulates keratinocyte migration by targeting the insulin-like growth factor IGF2BP2. Overexpression of let-7b led to reduced HaCaT cell migration, while knockdown of let-7b resulted in enhanced migration. Furthermore, let-7b was decreased during wound healing in wild-type mice, which led us to construct the transgenic mice with overexpression of let-7b in skin. The re-epithelialization of epidermis of let-7b transgenic mice was reduced during wound healing. Using bioinformatics prediction software and a reporter gene assay, we found that IGF2BP2 was a target of let-7b, which contributes to keratinocyte migration. Introduction of an expression vector of IGF2BP2 also rescued let-7b-induced migration deficiency, which confirms that IGF2BP2 is an important target for let-7b regulation. Our findings suggest that let-7b significantly delayed the re-epithelialization possibly due to reduction of keratinocyte migration and restraints IGF2BP2 during skin wound healing. PMID- 27513294 TI - Descending projections from the inferior colliculus to the dorsal cochlear nucleus are excitatory. AB - Ascending projections of the dorsal cochlear nucleus (DCN) target primarily the contralateral inferior colliculus (IC). In turn, the IC sends bilateral descending projections back to the DCN. We sought to determine the nature of these descending axons in order to infer circuit mechanisms of signal processing at one of the earliest stages of the central auditory pathway. An anterograde tracer was injected in the IC of CBA/Ca mice to reveal terminal characteristics of the descending axons. Retrograde tracer deposits were made in the DCN of CBA/Ca and transgenic GAD67-EGFP mice to investigate the cells giving rise to these projections. A multiunit best frequency was determined for each injection site. Brains were processed by using standard histologic methods for visualization and examined by fluorescent, brightfield, and electron microscopy. Descending projections from the IC were inferred to be excitatory because the cell bodies of retrogradely labeled neurons did not colabel with EGFP expression in neurons of GAD67-EGFP mice. Furthermore, additional experiments yielded no glycinergic or cholinergic positive cells in the IC, and descending projections to the DCN were colabeled with antibodies against VGluT2, a glutamate transporter. Anterogradely labeled endings in the DCN formed asymmetric postsynaptic densities, a feature of excitatory neurotransmission. These descending projections to the DCN from the IC were topographic and suggest a feedback pathway that could underlie a frequency-specific enhancement of some acoustic signals and suppression of others. The involvement of this IC-DCN circuit is especially noteworthy when considering the gating of ascending signal streams for auditory processing. J. Comp. Neurol. 525:773-793, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27513295 TI - A Catalyst-Controlled Aerobic Coupling of ortho-Quinones and Phenols Applied to the Synthesis of Aryl Ethers. AB - ortho-Quinones are underutilized six-carbon-atom building blocks. We herein describe an approach for controlling their reactivity with copper that gives rise to a catalytic aerobic cross-coupling with phenols. The resulting aryl ethers are generated in high yield across a broad substrate scope under mild conditions. This method represents a unique example where the covalent modification of an ortho-quinone is catalyzed by a transition metal, creating new opportunities for their utilization in synthesis. PMID- 27513296 TI - Cost-effectiveness of supervised exercise therapy compared with endovascular revascularization for intermittent claudication. AB - BACKGROUND: Current guidelines recommend supervised exercise therapy (SET) as the preferred initial treatment for patients with intermittent claudication. The availability of SET programmes is, however, limited and such programmes are often not reimbursed. Evidence for the long-term cost-effectiveness of SET compared with endovascular revascularization (ER) as primary treatment for intermittent claudication might aid widespread adoption in clinical practice. METHODS: A Markov model was constructed to determine the incremental costs, incremental quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio of SET versus ER for a hypothetical cohort of patients with newly diagnosed intermittent claudication, from the Dutch healthcare payer's perspective. In the event of primary treatment failure, possible secondary interventions were repeat ER, open revascularization or major amputation. Data sources for model parameters included original data from two RCTs, as well as evidence from the medical literature. The robustness of the results was tested with probabilistic and one way sensitivity analysis. RESULTS: Considering a 5-year time horizon, probabilistic sensitivity analysis revealed that SET was associated with cost savings compared with ER (-?6412, 95 per cent credibility interval (CrI) -?11 874 to -?1939). The mean difference in effectiveness was -0.07 (95 per cent CrI -0.27 to 0.16) QALYs. ER was associated with an additional ?91 600 per QALY gained compared with SET. One-way sensitivity analysis indicated more favourable cost effectiveness for ER in subsets of patients with low quality-of-life scores at baseline. CONCLUSION: SET is a more cost-effective primary treatment for intermittent claudication than ER. These results support implementation of supervised exercise programmes in clinical practice. PMID- 27513298 TI - Consuming energy drinks at the age of 14 predicted legal and illegal substance use at 16. AB - AIM: This study examined whether consuming energy drinks at the age of 14 predicted substance use at 16. METHODS: We followed 621 youths from an area of Switzerland who completed a longitudinal online survey in both 2012 and 2014 when they were 14 and 16 years of age. At 14, participants, who were divided into nonenergy drink users (n = 262), occasional users (n = 183) and regular users (n = 176), reported demographic, health-related and substance use data. Substance use at 16 was assessed through logistic regression using nonusers as the reference group and controlling for significant variables at 14. RESULTS: At the bivariate level, energy drink consumption was associated with substance use at both 14 and 16. Energy drink consumers were also more likely to be male, older, less academic, sleep less on schooldays and live in an urban area. In the multivariate analysis, smokers, alcohol misusers and cannabis users at the age of 16 were significantly more likely to have been regular energy drink users at the age of 14. CONCLUSION: Consuming energy drinks at 14 years of age predicted using legal and illegal substances at 16. Health providers should screen young adolescents for energy drink use and closely monitor weekly users. PMID- 27513299 TI - Photoswitchable NIR-Emitting Gold Nanoparticles. AB - Photo-switching of the NIR emission of gold nanoparticles (GNP) upon photo isomerization of azobenzene ligands, bound to the surface, is demonstrated. Photophysical results confirm the occurrence of an excitation energy transfer process from the ligands to the GNP that produces sensitized NIR emission. Because of this process, the excitation efficiency of the gold core, upon excitation of the ligands, is much higher for the trans form than for the cis one, and t->c photo-isomerization causes a relevant decrease of the GNP NIR emission. As a consequence, photo-isomerization can be monitored by ratiometric detection of the NIR emission upon dual excitation. The photo-isomerization process was followed in real-time through the simultaneous detection of absorbance and luminescence changes using a dedicated setup. Surprisingly, the photo-isomerization rate of the ligands, bound to the GNP surface, was the same as measured for the chromophores in solution. This outcome demonstrated that excitation energy transfer to gold assists photo-isomerization, rather than competing with it. These results pave the road to the development of new, NIR emitting, stimuli-responsive nanomaterials for theranostics. PMID- 27513300 TI - The Rho-ROCK pathway as a new pathological mechanism of innate immune subversion in chronic myeloid leukaemia. AB - CD1d-restricted invariant natural killer T (iNKT) cells are believed to play a key role in cancer immune surveillance, and are functionally deficient in patients with chronic myeloid leukaemia (CML). Herein, we have hypothesized that this defect might originate from BCR-ABL-dependent dysfunctions in myeloid dendritic cells (mDCs). Indeed, flow cytometry and confocal microscopy revealed that cell surface expression of CD1d was downregulated in CML mDCs, relative to healthy donor (HD) controls. The decreased cell surface display of CD1d could not be ascribed to defective mDC differentiation, as attested by normal expression of HLA-DR and the CD86 maturation marker. On the other hand, reduced membrane expression was not associated with decreased intracytoplasmic levels of CD1d or its mRNA transcripts, consistent with intracellular retention. In vitro treatment of CML mDCs with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 partially restored both cell surface CD1d expression and CD1d-mediated antigen presentation, whereas it had no effect on HD mDCs. An inhibitor of BCR-ABL tyrosine kinase (TK), imatinib mesylate (IM), had no such activity. Similar recovery of CD1d expression occurred with fasudil, another ROCK inhibitor that is commonly used in clinical trials. Our data support the conclusion that BCR-ABL dependent ROCK, but not TK, is involved in CD1d downregulation. We propose that ROCK, which is most likely activated by the DH/PH domain of BCR-ABL, mediates iNKT-cell immune subversion in CML patients by downregulating CD1d expression on CML mDCs. Our study reveals the ROCK-mDC axis as a new potential target to restore immune surveillance in patients with CML, offering new therapeutic perspectives for CML treatment. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27513301 TI - DNA-PK activity is associated with caspase-dependent myogenic differentiation. AB - Differentiation of myoblasts into myotubes is essential for skeletal muscle development and regeneration. Caspase-3 and caspase-9 are required for efficient myoblast differentiation. The caspase-activated endonuclease activity, CAD, and the DNA-damage repair protein XRCC1 have also been shown to be required to complete differentiation. DNA-damage associated with differentiation is accompanied by phosphorylation of Histone 2AX, an event normally catalysed by kinases ATR, ATM or DNA-PK. However, the kinase responsible for phosphorylation during differentiation is not known. Here we show that inhibition of DNA-PK, but not of ATR or ATM, blocked histone phosphorylation during differentiation. We also show that DNA-PK inhibition and siRNA-mediated DNA-PK knockdown blocked cell fusion. These data implicate a new role for DNA-PK in myogenic differentiation. PMID- 27513303 TI - A subjective utilitarian theory of moral judgment. AB - Current theories hypothesize that moral judgments are difficult because rational and emotional decision processes compete. We present a fundamentally different theory of moral judgment: the Subjective Utilitarian Theory of moral judgment. The Subjective Utilitarian Theory posits that people try to identify and save the competing item with the greatest "personal value." Moral judgments become difficult only when the competing items have similar personal values. In Experiment 1, we estimate the personal values of 104 items. In Experiments 2-5, we show that the distributional overlaps of the estimated personal values account for over 90% of the variance in reaction times (RTs) and response choices in a moral judgment task. Our model fundamentally restructures our understanding of moral judgments from a competition between decision processes to a competition between similarly valued items. (PsycINFO Database Record PMID- 27513302 TI - A general benevolence dimension that links neural, psychological, economic, and life-span data on altruistic tendencies. AB - [Correction Notice: An Erratum for this article was reported in Vol 145(10) of Journal of Experimental Psychology: General (see record 2016-46925-004). In the article, there was an error in the Task, Stimuli, and Procedures section. In the 1st sentence in the 6th paragraph, "Following the scanning phase, participants completed self-report questionnaires meant to reflected the Prosocial Disposition construct: the agreeableness scale from the Big F, which includes empathic concern and perspective-taking, and a scale of personality descriptive adjectives related to altruistic behavior (Wood, Nye, & Saucier, 2010)." should have read: "Following the scanning phase, participants completed self-report questionnaires that contained scales to reflect the Prosocial Disposition construct: the Big Five Inventory (BFI; John et al., 1991), from which we used the agreeableness scale to measure prosocial disposition; the Interpersonal Reactivity Index (IRI; Davis, 1980), from which we used the empathic concern and perspective-taking scales; and a scale of personality descriptive adjectives related to altruistic behavior (Wood, Nye, & Saucier, 2010)."] Individual and life span differences in charitable giving are an important economic force, yet the underlying motives are not well understood. In an adult, life span sample, we assessed manifestations of prosocial tendencies across 3 different measurement domains: (a) psychological self-report measures, (b) actual giving choices, and (c) fMRI-derived, neural indicators of "pure altruism." The latter expressed individuals' activity in neural valuation areas when charities received money compared to when oneself received money and thus reflected an altruistic concern for others. Results based both on structural equation modeling and unit-weighted aggregate scores revealed a strong higher-order General Benevolence dimension that accounted for variability across all measurement domains. The fact that the neural measures likely reflect pure altruistic tendencies indicates that General Benevolence is based on a genuine concern for others. Furthermore, General Benevolence exhibited a robust increase across the adult life span, potentially providing an explanation for why older adults typically contribute more to the public good than young adults. PMID- 27513304 TI - Bootstrapping agency: How control-relevant information affects motivation. AB - How does information about one's control over the environment (e.g., having an own-action effect) influence motivation? The control-based response selection framework was proposed to predict and explain such findings. Its key tenant is that control relevant information modulates both the frequency and speed of responses by determining whether a perceptual event is an outcome of one's actions or not. To test this framework empirically, the current study examines whether and how temporal and spatial contiguity/predictability-previously established as being important for one's sense of agency-modulate motivation from control. In 5 experiments, participants responded to a cue, potentially triggering a perceptual effect. Temporal (Experiments 1a-c) and spatial (Experiments 2a and b) contiguity/predictability between actions and their potential effects were experimentally manipulated. The influence of these control relevant factors was measured, both indirectly (through their effect on explicit judgments of agency) and directly on response time and response frequency. The pattern of results was highly consistent with the control-based response selection framework in suggesting that control relevant information reliably modulates the impact of "having an effect" on different levels of action selection. We discuss the implications of this study for the notion of motivation from control and for the empirical work on the sense of agency. (PsycINFO Database Record PMID- 27513305 TI - Overcoming approach and withdrawal habits: Approaching former enemies is easier than withdrawing from former friends. AB - Both everyday intuition and experimental evidence suggest that habits are difficult to change. However, despite the abundance of research, it is unknown whether the ease of habit breaking differs with respect to the most elementary forms of behavior, approach versus withdrawal. In the present study, we addressed this question by monitoring the formation and overriding of approach and withdrawal habits. In an initial habit-formation phase, participants intensely practiced approach or withdrawal behavior to neutral everyday objects (Experiments 1) and emotionally laden persons (Experiment 2) until strong behavioral habits were formed. In a subsequent habit-breaking phase, they were asked to change their behavior for half of the approach stimuli to withdrawal, and for half of the withdrawal stimuli to approach. Two intriguing results were observed. First, the results in the habit-formation phase showed that the typically observed speed advantage of approach over withdrawal cannot be diminished by practice. Second, the results in the habit-breaking phase showed that overriding a withdrawal habit by approach is easier than overriding an approach habit by withdrawal. In the latter case, participants were more often caught by their older habit, even when responses were bolstered by appropriate emotions. Thus, other than reflected in everyday thinking, approaching former enemies seems to be easier than withdrawing from former friends. (PsycINFO Database Record PMID- 27513306 TI - Doing is for feeling. AB - In 2 experiments we show that preferences can be formed by transfer of valence from an unconditioned stimulus (US) to an action and then from this valence-laden action to a novel conditioned stimulus (CS) even though the US and CS were never presented together. This result expands the approach of intersecting regularities (Hughes, De Houwer, & Perugini, 2016) to yet another realm of evaluative learning. In addition, our approach to evaluative learning suggests theoretical links between the formation of preferences due to actions and general research on action control. In summary, we discovered an additional route via which humans may acquire novel preferences and we propose a mental mechanism that may play an important role in the perceptuomotor system that controls many daily life behaviors. (PsycINFO Database Record PMID- 27513307 TI - Mistaking minds and machines: How speech affects dehumanization and anthropomorphism. AB - Treating a human mind like a machine is an essential component of dehumanization, whereas attributing a humanlike mind to a machine is an essential component of anthropomorphism. Here we tested how a cue closely connected to a person's actual mental experience-a humanlike voice-affects the likelihood of mistaking a person for a machine, or a machine for a person. We predicted that paralinguistic cues in speech are particularly likely to convey the presence of a humanlike mind, such that removing voice from communication (leaving only text) would increase the likelihood of mistaking the text's creator for a machine. Conversely, adding voice to a computer-generated script (resulting in speech) would increase the likelihood of mistaking the text's creator for a human. Four experiments confirmed these hypotheses, demonstrating that people are more likely to infer a human (vs. computer) creator when they hear a voice expressing thoughts than when they read the same thoughts in text. Adding human visual cues to text (i.e., seeing a person perform a script in a subtitled video clip), did not increase the likelihood of inferring a human creator compared with only reading text, suggesting that defining features of personhood may be conveyed more clearly in speech (Experiments 1 and 2). Removing the naturalistic paralinguistic cues that convey humanlike capacity for thinking and feeling, such as varied pace and intonation, eliminates the humanizing effect of speech (Experiment 4). We discuss implications for dehumanizing others through text-based media, and for anthropomorphizing machines through speech-based media. (PsycINFO Database Record PMID- 27513308 TI - Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening. AB - Disrupting the interaction between mixed lineage leukemia (MLL) fusion protein and menin provides a therapeutic approach for MLL-mediated leukemia. Here, we aim to discover novel inhibitors targeting the menin-MLL interface with virtual screening. Both structure-based molecular docking and ligand-based pharmacophore models were established, and the models used for compound screening show a remarkable ability to retrieve known active ligands from decoy molecules. Verified by a fluorescence polarization assay, five hits with novel scaffolds were identified. Among them, DCZ_M123 exhibited potent inhibitory activity with an IC50 of 4.71 +/- 0.12 MUM and a KD of 14.70 +/- 2.13 MUM, and it can effectively inhibit the human MLL-rearranged leukemia cells MV4;11 and KOPN8 with GI50 values of 0.84 MUM and 0.54 MUM, respectively. PMID- 27513309 TI - Static magnetic field induced epigenetic changes in wheat callus. AB - Deoxyribonucleic acid (DNA) is always damaged by endogenous and exogenous factors. Magnetic field (MF) is one of these exogenous factors. When repair mechanisms are not sufficient, mainly because of imbalance in damage or mistakes in repair mechanisms, methylation of DNA results in polymorphism-related abnormalities. In this study, low intensity static magnetic field-induced DNA damage and methylation in wheat calli were investigated by using Random Amplified Polymorphic DNA and Coupled Restriction Enzyme Digestion-Random Amplification techniques. Calli were derived from mature embryos of wheat. Both 7- and 14-day old wheat calli were exposed to 7 mT (millitesla) static MF for 24, 48, 72, 96, or 120 h of incubation period. The highest change in polymorphism rate was obtained in calli exposed to 7 mT MF for 120 h in both 7- and 14-day-old calli. Increase in MF duration caused DNA hypermethylation in both 7- and 14-day-old calli. Polymorphism and DNA methylation ratio were higher in 7-day-old calli. The highest methylation level with a value of 25.1% was found in 7-day-old calli exposed to MF for 120 h. Results suggested that low intensity static magnetic field may trigger genomic instability and DNA methylation. Bioelectromagnetics. 37:504-511, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27513310 TI - Modulation of growth cone filopodial length by carbon monoxide. AB - Carbon monoxide (CO) is physiologically produced via heme degradation by heme oxygenase enzymes. Whereas CO has been identified as an important physiological signaling molecule, the roles it plays in neuronal development and regeneration are poorly understood. During these events, growth cones guide axons through a rich cellular environment to locate target cells and establish synaptic connections. Previously, we have shown that another gaseous signaling molecule, nitric oxide (NO), has potent effects on growth cone motility. With NO and CO sharing similar cellular targets, we wanted to determine whether CO affected growth cone motility as well. We assessed how CO affected growth cone filopodial length and determined the signaling pathway by which this effect was mediated. Using two well-characterized neurons from the freshwater snail, Helisoma trivolvis, it was found that the CO donor, carbon monoxide releasing molecule-2 (CORM-2), increased filopodial length. CO utilized a signaling pathway that involved the activation of soluble guanylyl cyclase, protein kinase G, and ryanodine receptors. While increases in filopodial length often occur from robust increases in intracellular calcium levels, the timing in which CO increased filopodial length corresponded with low basal calcium levels in growth cones. Taken together with findings of a heme oxygenase-like protein in the Helisoma nervous system, these results provide evidence for CO as a modulator of growth cone motility and implicate CO as a neuromodulatory signal during neuronal development and/or regeneration. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 677-690, 2017. PMID- 27513311 TI - Nimesulide Silver Metallodrugs, Containing the Mitochondriotropic, Triaryl Derivatives of Pnictogen; Anticancer Activity against Human Breast Cancer Cells. AB - Novel silver(I) metallo-drugs of the nonsteroidal anti-inflammatory drug nimesulide (nim) and the mitochondriotropic triaryl derivatives of pnictogen ligands (tpE, E = P (tpp, tptp, or totp), As (tpAs), Sb (tpSb)) with the formulas {[Ag(nim) (tpp)2]DMF} (1), [Ag(nim) (tptp)2] (2), [Ag(nim) (totp)] (3), [Ag(nim) (tpAs)2] (4), and [Ag(nim) (tpSb)3] (5) ((tpp = triphenyphosphine, tptp = tri(p tolyl)phosphine, totp = tri(o-tolyl)phosphine, tpAs = triphenylarsine, tpSb = triphenylantimony, and DMF = dimethylformamide) were synthesized and characterized by melting point, vibrational spectroscopy (mid-Fourier transform IR), (1)H NMR, UV-visible spectroscopic techniques, and X-ray crystallography. The in vitro cytotoxic activity of 1-5 against human breast adenocarcinoma cancer cell lines: MCF-7 (estrogen receptor (ER) positive) and MDA-MB-231 (ER negative) was determined. The genotoxicity on normal human fetal lung fibroblast cells (MRC 5) caused by 1-5 was evaluated by fluorescence microscopy. The absence of micronucleus in MRC-5 cells confirms the in vitro non toxicity behavior of the compounds. Because of the morphology of the cells, an apoptotic pathway was concluded for the cell death. The apoptotic pathway, especially though the mitochondrion damage, was confirmed by DNA fragmentation, cell cycle arrest, and permeabilization of the mitochondrial membrane tests. The molecular mechanism of action of 1-5 was further studied by (i) the binding affinity of 1-5 toward the calf thymus (CT) DNA, (ii) the inhibitory activity of 1-5 against lipoxygenase (an enzyme that oxidizes polyunsaturated fatty acids to leukotrienes or prostaglandins), and (iii) the catalytic activity of 1-5 on the oxidation of linoleic acid (an acid that partakes in membrane fluidity, membrane enzyme activities, etc.) to hyperoxolinoleic acid by oxygen. PMID- 27513314 TI - Pnictogen-Silicon Analogues of Benzene. AB - Since the discovery of the first "inorganic benzene" (borazine, B3N3H6), the synthesis of other noncarbon derivatives is an ongoing challenge in Inorganic Chemistry. Here we report on the synthesis of the first pnictogen-silicon congeners of benzene, the triarsa- and the triphospha-trisilabenzene [(PhC(NtBu)2)3Si3E3] (E = P (1a), As (1b)) by a simple metathesis reaction. These compounds are formed by the reaction of [Cp"2Zr(eta(1:1)-E4)] (E = P, As; Cp" = C5H3tBu2) with [PhC(NtBu)2SiCl] in toluene at room temperature along with the silicon pnictogen congeners of the cyclobutadiene, [(PhC(NtBu)2)2Si2E2] (E = P (2a), As (2b)), which is unprecedented for the arsenic system 2b. All compounds were comprehensively characterized, and density functional theory calculations were performed to verify the stability and the aromatic character of the triarsa- and the triphospha-trisilabenzene. PMID- 27513312 TI - Chronic Kidney Disease Classification in Systolic Blood Pressure Intervention Trial: Comparison Using Modification of Diet in Renal Disease and CKD Epidemiology Collaboration Definitions. AB - BACKGROUND: Interventional trials have used either the Modification of Diet in Renal Disease (MDRD) or chronic kidney disease (CKD)-Epidemiology Collaboration (CKD-EPI) equation for determination of estimated glomerular filtration rate (eGFR) to define whether participants have stages 3-5 CKD. The equation used to calculate eGFR may influence the number and characteristics of participants designated as having CKD. METHODS: We examined the classification of CKD at baseline using both equations in the Systolic Blood Pressure Intervention Trial (SPRINT). eGFR was calculated at baseline using fasting serum creatinine values from a central laboratory. RESULTS: Among 9,308 participants with baseline CKD classification using the 4-variable MDRD equation specified in the SPRINT protocol, 681 (7.3%) participants were reclassified to a less advanced CKD stage (higher eGFR) and 346 (3.7%) were reclassified to a more advanced CKD stage (lower eGFR) when the CKD-EPI equation was used to calculate eGFR. For eGFRs <90 ml/min/1.73 m2, participants <75 years were more likely to be reclassified to a less advanced CKD stage; this reclassification was more likely to occur in non blacks rather than blacks. Participants aged >=75 years were more likely to be reclassified to a more advanced than a less advanced CKD stage, regardless of baseline CKD stage. Reclassification of baseline CKD status (eGFR <60 ml/min/1.73 m2) occurred in 3% of participants. CONCLUSIONS: Use of the MDRD equation led to a higher percentage of participants being classified as having CKD stages 3-4. Younger and non-black participants were more likely to be reclassified as not having CKD using the CKD-EPI equation. PMID- 27513316 TI - Advanced Potential Energy Surfaces for Molecular Simulation. AB - Advanced potential energy surfaces are defined as theoretical models that explicitly include many-body effects that transcend the standard fixed-charge, pairwise-additive paradigm typically used in molecular simulation. However, several factors relating to their software implementation have precluded their widespread use in condensed-phase simulations: the computational cost of the theoretical models, a paucity of approximate models and algorithmic improvements that can ameliorate their cost, underdeveloped interfaces and limited dissemination in computational code bases that are widely used in the computational chemistry community, and software implementations that have not kept pace with modern high-performance computing (HPC) architectures, such as multicore CPUs and modern graphics processing units (GPUs). In this Feature Article we review recent progress made in these areas, including well-defined polarization approximations and new multipole electrostatic formulations, novel methods for solving the mutual polarization equations and increasing the MD time step, combining linear-scaling electronic structure methods with new QM/MM methods that account for mutual polarization between the two regions, and the greatly improved software deployment of these models and methods onto GPU and CPU hardware platforms. We have now approached an era where multipole-based polarizable force fields can be routinely used to obtain computational results comparable to state-of-the-art density functional theory while reaching sampling statistics that are acceptable when compared to that obtained from simpler fixed partial charge force fields. PMID- 27513317 TI - Graphene-Based Fluorescence-Quenching-Related Fermi Level Elevation and Electron Concentration Surge. AB - Intermolecular p-orbital overlaps in unsaturated pi-conjugated systems, such as graphene and fluorescent molecules with aromatic structure, serve as the electron exchanged path. Using Raman-mapping measurements, we observe that the fluorescence intensity of fluorescein isothiocyanate (FITC) is quenched by graphene, whereas it persists in graphene-absent substrates (SiO2). After identifying a mechanism related to photon-induced electron transfer (PET) that contributes to this fluorescence quenching phenomenon, we validate this mechanism by conducting analyses on Dirac point shifts of FITC-coated graphene. From these shifts, Fermi level elevation and the electron-concentration surge in graphene upon visible-light impingements are acquired. Finally, according to this mechanism, graphene-based biosensors are fabricated to show the sensing capability of measuring fluorescently labeled-biomolecule concentrations. PMID- 27513319 TI - Overexpression of microRNA-497 suppresses cell proliferation and induces apoptosis through targeting paired box 2 in human ovarian cancer. AB - MicroRNAs are a class of endogenous, small non-coding RNAs which are tightly involved in evolution and progression of human cancers. MicroRNA-497 has been reported as tumor-suppressor in various human cancer. However, the role of miR 497 in ovarian cancer is still poorly known. We investigated the expression level and cellular function of miR-497 in human ovarian cancer. In this study, the expression of miR-497 in ovarian cancer tissues and SKOV3 cells was detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). CCK-8 assay was used to analysis the cell proliferation. Transwell assay was performed to analysis cell migration and invasion. Cell apoptosis was evaluated by flow cytometry. Luciferase assay was performed to verify a putative target site of miR 497 in the 3'UTR of PAX2 mRNA. The results showed that miR-497 was markedly decreased in ovarian cancer tissues and SKOV3 cells. Moreover, overexpression of miR-497 in SKOV3 cells induced PAX2 protein expression and resulted in inhibition of cell proliferation, migration and invasion, and induction of cell apoptosis. In addition, we confirmed that PAX2 is a direct target gene of miR-497. Furthermore, Silencing of PAX2 by RNA interference suppressed cell proliferation and promoted cell apoptosis in vitro. Taken together, our study rationally present that miR-497 has a potential role as a useful diagnostic and therapeutic biomarker for human ovarian cancer. PMID- 27513321 TI - Qualification of computerized monitoring systems in a cell therapy facility compliant with the good manufacturing practices. AB - AIM: Computerized systems (CS) are essential in the development and manufacture of cell-based medicines and must comply with good manufacturing practice, thus pushing academic developers to implement methods that are typically found within pharmaceutical industry environments. MATERIALS & METHODS: Qualitative and quantitative risk analyses were performed by Ishikawa and Failure Mode and Effects Analysis, respectively. RESULTS: A process for qualification of a CS that keeps track of environmental conditions was designed and executed. The simplicity of the Ishikawa analysis permitted to identify critical parameters that were subsequently quantified by Failure Mode Effects Analysis, resulting in a list of test included in the qualification protocols. CONCLUSION: The approach presented here contributes to simplify and streamline the qualification of CS in compliance with pharmaceutical quality standards. PMID- 27513322 TI - Comparative Genomics of the Sigatoka Disease Complex on Banana Suggests a Link between Parallel Evolutionary Changes in Pseudocercospora fijiensis and Pseudocercospora eumusae and Increased Virulence on the Banana Host. AB - The Sigatoka disease complex, caused by the closely-related Dothideomycete fungi Pseudocercospora musae (yellow sigatoka), Pseudocercospora eumusae (eumusae leaf spot), and Pseudocercospora fijiensis (black sigatoka), is currently the most devastating disease on banana worldwide. The three species emerged on bananas from a recent common ancestor and show clear differences in virulence, with P. eumusae and P. fijiensis considered the most aggressive. In order to understand the genomic modifications associated with shifts in the species virulence spectra after speciation, and to identify their pathogenic core that can be exploited in disease management programs, we have sequenced and analyzed the genomes of P. eumusae and P. musae and compared them with the available genome sequence of P. fijiensis. Comparative analysis of genome architectures revealed significant differences in genome size, mainly due to different rates of LTR retrotransposon proliferation. Still, gene counts remained relatively equal and in the range of other Dothideomycetes. Phylogenetic reconstruction based on a set of 46 conserved single-copy genes strongly supported an earlier evolutionary radiation of P. fijiensis from P. musae and P. eumusae. However, pairwise analyses of gene content indicated that the more virulent P. eumusae and P. fijiensis share complementary patterns of expansions and contractions in core gene families related to metabolism and enzymatic degradation of plant cell walls, suggesting that the evolution of virulence in these two pathogens has, to some extent, been facilitated by convergent changes in metabolic pathways associated with nutrient acquisition and assimilation. In spite of their common ancestry and shared host specificity, the three species retain fairly dissimilar repertoires of effector proteins, suggesting that they likely evolved different strategies for manipulating the host immune system. Finally, 234 gene families, including seven putative effectors, were exclusively present in the three Sigatoka species, and could thus be related to adaptation to the banana host. PMID- 27513323 TI - Early Sexual Intercourse: Prospective Associations with Adolescents Physical Activity and Screen Time. AB - OBJECTIVES: To assess the prospective associations of physical activity behaviors and screen time with early sexual intercourse initiation (i.e., before 15 years) in a large sample of adolescents. METHODS: We used two waves of data from the Rotterdam Youth Monitor, a longitudinal study conducted in the Netherlands. The analysis sample consisted of 2,141 adolescents aged 12 to 14 years (mean age at baseline = 12.2 years, SD = 0.43). Physical activity (e.g., sports outside school), screen time (e.g., computer use), and early sexual intercourse initiation were assessed by means of self-report questionnaires. Logistic regression models were tested to assess the associations of physical activity behaviors and screen time (separately and simultaneously) with early sexual intercourse initiation, controlling for confounders (i.e., socio-demographics and substance use). Interaction effects with gender were tested to assess whether these associations differed significantly between boys and girls. RESULTS: The only physical activity behavior that was a significant predictor of early sexual intercourse initiation was sports club membership. Adolescent boys and girls who were members of a sports club) were more likely to have had early sex (OR = 2.17; 95% CI = 1.33, 3.56. Significant gender interaction effects indicated that boys who watched TV >=2 hours/day (OR = 2.00; 95% CI = 1.08, 3.68) and girls who used the computer >=2 hours/day (OR = 3.92; 95% CI = 1.76, 8.69) were also significantly more likely to have engaged in early sex. CONCLUSION: These findings have implications for professionals in general pediatric healthcare, sexual health educators, policy makers, and parents, who should be aware of these possible prospective links between sports club membership, TV watching (for boys), and computer use (for girls), and early sexual intercourse initiation. However, continued research on determinants of adolescents' early sexual initiation is needed to further contribute to the strategies for improving adolescents' healthy sexual development and behaviors. PMID- 27513324 TI - Life with Bacterial Secretion Systems. PMID- 27513325 TI - Health-care provider communication with expectant parents during a prenatal diagnosis: an integrative review. AB - The pregnancy and health-care experience of expectant parents who receive a prenatal diagnosis of their unborn infant is distinctively fraught with uncertainty. Health-care providers (HCPs) that care for parents during this uncertain time have an exceptional opportunity to positively impact parental outcomes. An integrative literature review was conducted to explore HCPs' impact on parents' experiences of receiving a prenatal diagnosis. Thirty-three articles met study inclusion criteria (n=18 qualitative; 6 quantitative; 9 mixed methods). HCP communication was the major theme identified, because of its overarching impact on parents' experiences of receiving a prenatal diagnosis of their unborn infant. Parents' perception of the information communicated to them about their unborn infant's diagnosis by their HCP, and the manner in which that information is communicated to them, affects parents' ability to cope with the diagnosis. Recommendations for health-care delivery models, and for future research are discussed. PMID- 27513326 TI - Electronic communication preferences among mothers in the neonatal intensive care unit. AB - OBJECTIVE: Mobile communication with the medical-care team has the potential to decrease stress among parents of infants admitted to the neonatal intensive care unit (NICU). We assessed mobile use and communication preferences in a population of urban minority NICU mothers. STUDY DESIGN: A 30-question English language survey was administered to mothers of NICU patients. RESULTS: The survey was completed by 217 mothers, 75% were Black, and 75% reported annual household income below $20 000. Only 56% had a computer with Internet access at home, but 79% used smartphones. Most (79%) have searched the Internet for health information in the past year. Receiving electronic messages about their babies was viewed favorably, and text messaging was the preferred platform. The majority of mothers felt electronic messaging would improve communication but should not replace verbal communication. CONCLUSION: Mobile communication is used widely in this population of NICU mothers and could potentially improve provider-parent communication and reduce parental stress. PMID- 27513327 TI - The state of point-of-care ultrasonography use and training in neonatal-perinatal medicine and pediatric critical care medicine fellowship programs. AB - OBJECTIVE: The current state of point-of-care ultrasonography (POCUS) use and education in neonatal-perinatal medicine (NPM) and pediatric critical care medicine (PCCM) is unknown. Our aim was to quantify POCUS use, training and perceptions regarding education and barriers among the United States NPM and PCCM fellowship programs. STUDY DESIGN: A 14-question survey was emailed to the fellowship directors of all the United States NPM and PCCM fellowship programs. RESULTS: The response rate was 55% (52/95) and 59% (39/66) for NPM and PCCM programs, respectively. Over 90% of respondents in both groups believe that fellows and attendings should receive POCUS training. PCCM programs, compared with NPM, had greater access to POCUS machines (97% vs 63%, P<0.001), and more often used POCUS for diagnoses and management (76% vs 29%, P<0.001) and procedural guidance (95% vs 37%, P<0.001). The most common indications were cardiac/hemodynamics, pulmonary pathology and vascular access in both specialties. PCCM reported more training to fellows (90% vs 29%, P<0.001). Both group perceived lack of time to learn, lack of equipment/funds, liability concerns, lack of personnel to train physicians and cardiology/radiology resistance as significant barriers to POCUS implementation. CONCLUSIONS: Both NPM and PCCM fellowship programs believe in the benefits of POCUS and that their physicians should receive the necessary training. Compared with PCCM, NPM fellowships programs have less access to POCUS machines and less frequently use POCUS and train their fellows and attendings. There remain significant barriers to utilization of POCUS, especially in NPM. PMID- 27513328 TI - Disparities in Depressive Symptoms and Antidepressant Treatment by Gender and Race/Ethnicity among People Living with HIV in the United States. AB - OBJECTIVE: To describe disparities along the depression treatment cascade, from indication for antidepressant treatment to effective treatment, in HIV-infected individuals by gender and race/ethnicity. METHODS: The Center for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS) cohort includes 31,000 HIV infected adults in routine clinical care at 8 sites. Individuals were included in the analysis if they had a depressive symptoms measure within one month of establishing HIV care at a CNICS site. Depressive symptoms were measured using the validated Patient Health Questionnaire-9 (PHQ-9). Indication for antidepressant treatment was defined as PHQ-9 >= 10 or a current antidepressant prescription. Antidepressant treatment was defined as a current antidepressant prescription. Evidence-based antidepressant treatment was considered treatment changes based on a person's most recent PHQ-9, in accordance with clinical guidelines. We calculated the cumulative probability of moving through the depression treatment cascade within 24 months of entering CNICS HIV care. We used multivariable Cox proportional hazards models to estimate associations between gender, race/ethnicity, and a range of depression outcomes. RESULTS: In our cohort of HIV-infected adults in routine care, 47% had an indication for antidepressant treatment. Significant drop-offs along the depression treatment cascade were seen for the entire study sample. However, important disparities existed. Women were more likely to have an indication for antidepressant treatment (HR 1.54; 95% CI 1.34, 1.78), receive antidepressant treatment (HR 2.03; 95% CI 1.53, 2.69) and receive evidence-based antidepressant treatment (HR 1.67; 95% CI 1.03, 2.74), even after accounting for race/ethnicity. Black non Hispanics (HR 0.47, 95% CI 0.35, 0.65), Hispanics (HR 0.63, 95% CI 0.44, 0.89) and other race/ethnicities (HR 0.35, 95% CI 0.17, 0.73) were less likely to initiate antidepressant treatment, compared to white non-Hispanics. CONCLUSIONS: In our cohort of HIV-infected adults depressive symptoms were common. Important disparities in the prevalence of depressive symptoms and receipt of antidepressant treatment existed by gender and race/ethnicity. PMID- 27513330 TI - Are Price Limits Effective? An Examination of an Artificial Stock Market. AB - We investigated the inter-day effects of price limits policies that are employed in agent-based simulations. To isolate the impact of price limits from the impact of other factors, we built an artificial stock market with higher frequency price limits hitting. The trading mechanisms in this market are the same as the trading mechanisms in China's stock market. Then, we designed a series of simulations with and without price limits policy. The results of these simulations demonstrate that both upper and lower price limits can cause a volatility spillover effect and a trading interference effect. The process of price discovery will be delayed if upper price limits are imposed on a stock market; however, this phenomenon does not occur when lower price limits are imposed. PMID- 27513329 TI - Differential Expression Pattern of THBS1 and THBS2 in Lung Cancer: Clinical Outcome and a Systematic-Analysis of Microarray Databases. AB - Thrombospondin 1 and thrombospondin 2 (THBS1 and THBS2) share similar multifunctional domains, and are known to be antiangiogenic. However, the expression pattern of THBS1 and THBS2 is different, and the specific role of THBS2 in different subtypes of lung cancer remains largely unclear. To evaluate the significance of THBS1 and THBS2 in the development of lung cancer, the present study performed a microarray-based systematic-analysis to determine the transcript levels of thrombospondins and their relation to the prognosis in lung cancer. THBS1 was in general underexpressed in lung cancer; in contrast, mRNA levels of THBS2 were markedly overexpressed in a number of datasets of non-small cell lung carcinoma (NSCLC), including lung adenocarcinoma (AC) and squamous cell carcinoma. Similar expression pattern of THBS1 and THBS2 was verified in pulmonary AC cell lines with real-time PCR analysis. The survival of lung AC patients with high THBS2 mRNA expression levels was poorer than patients with low levels of expression of THBS2. In a microarray-based analysis, genes coexpressed with THBS1 or THBS2 were determined. Pulmonary AC patients with a high expression level of sevenTSHB1-coexpressed genes (CCL5, CDH11, FYB, GZMK, LA-DQA1, PDE4DIP, and SELL) had better survival rates than those with a low expression level. Patients with a high expression of seven TSHB2-coexpressed genes (CHI3L1, COL5A2, COL11A1, FAP, MXRA5, THY1, and VCAN) had poor survival rates. Downregulation of VCAN and THBS2 with shRNA inhibited the cell proliferation in the A549 cell line. In summary, THBS1 functions as a tumor suppressor in lung adenocarcinoma. However, THBS2 may play a double-edged role in the progression of lung AC, i.e. anti-angiogenic and oncogenic function. Further study on the mechanism underlying the activity of THBS2 is warranted to have further implications for cancer diagnosis and treatment of pulmonary AC. PMID- 27513331 TI - Home-Based and Facility-Based Directly Observed Therapy of Tuberculosis Treatment under Programmatic Conditions in Urban Tanzania. AB - INTRODUCTION: Decentralization of Directly Observed Treatment (DOT) for tuberculosis (TB) to the community (home-based DOT) has improved the coverage of TB treatment and reduced the burden to the health care facilities (facility-based DOT). We aimed to compare TB treatment outcomes in home-based and facility-based DOT under programmatic conditions in an urban setting with a high TB burden. METHODOLOGY: A retrospective analysis of a cohort of adult TB patients (>=15 years) routinely notified between 2010 and 2013 in two representative TB sub districts in the Temeke district, Dar es Salaam, Tanzania. We assessed differences in treatment outcomes by calculating Risk Ratios (RRs). We used logistic regression to assess the association between DOT and treatment outcomes. RESULTS: Data of 4,835 adult TB patients were analyzed, with a median age of 35 years, 2,943 (60.9%) were men and TB/HIV co-infection prevalence of 39.9%. A total of 3,593 (74.3%) patients were treated under home-based DOT. Patients on home-based DOT were more likely to die compared to patients on facility-based DOT (RR 2.04, 95% Confidence Interval [95% CI]: 1.52-2.73), and more likely to complete TB treatment (RR 1.14, 95% CI: 1.06-1.23), but less likely to have a successful treatment outcome (RR 0.94, 95% CI: 0.92-0.97). Home-based DOT was preferred by women (adjusted Odds Ratio [aOR] 1.55, 95% CI: 1.34-1.80, p<0.001), older people (aOR 1.01 for each year increase, 95% CI: 1.00-1.02, p = 0.001) and patients with extra-pulmonary TB (aOR 1.45, 95% CI: 1.16-1.81, p = 0.001), but less frequently by patients on a retreatment regimen (aOR 0.12, 95% CI: 0.08 0.19, p<0.001). CONCLUSIONS/SIGNIFICANCE: TB patients under home-based DOT had more frequently risk factors of death such as older age, HIV infection and sputum smear-negative TB, and had higher mortality compared to patients under facility based DOT. Further operational research is needed to monitor the implementation of DOT under programmatic conditions. PMID- 27513332 TI - Anti-Vascular Endothelial Growth Factor Antibody Suppresses ERK and NF-kappaB Activation in Ischemia-Reperfusion Lung Injury. AB - Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions like lung transplantation, acute pulmonary embolism after thrombolytic therapy, re-expansion of collapsed lung from pneumothorax or pleural effusion, cardiopulmonary bypass and etc. Because mortality remains high despite advanced medical care, prevention and treatment are important clinical issues for IR-induced ALI. Vascular endothelial growth factor (VEGF) has a controversial role in ALI. We therefore conducted this study to determine the effects of anti-VEGF antibody in IR-induced ALI. In the current study, the IR induced ALI was conducted in a rat model of isolated-perfused lung in situ in the chest. The animals were divided into the control, control + preconditioning anti VEGF antibody (bevacizumab, 5mg/kg), IR, IR + preconditioning anti-VEGF antibody (1mg/kg), IR+ preconditioning anti-VEGF antibody (5mg/kg) and IR+ post-IR anti VEGF antibody (5mg/kg) group. There were eight adult male Sprague-Dawley rats in each group. The IR caused significant pulmonary micro-vascular hyper permeability, pulmonary edema, neutrophilic infiltration in lung tissues, increased tumor necrosis factor-alpha, and total protein concentrations in bronchoalveolar lavage fluid. VEGF and extracellular signal-regulated kinase (ERK) were increased in IR-induced ALI. Administration of preconditioning anti VEGF antibody significantly suppressed the VEGF and ERK expressions and attenuated the IR-induced lung injury. This study demonstrates the important role of VEGF in early IR-induced ALI. The beneficial effects of preconditioning anti VEGF antibody in IR-induced ALI include the attenuation of lung injury, pro inflammatory cytokines, and neutrophilic infiltration into the lung tissues. PMID- 27513333 TI - An Activity Index for Raw Accelerometry Data and Its Comparison with Other Activity Metrics. AB - Accelerometers have been widely deployed in public health studies in recent years. While they collect high-resolution acceleration signals (e.g., 10-100 Hz), research has mainly focused on summarized metrics provided by accelerometers manufactures, such as the activity count (AC) by ActiGraph or Actical. Such measures do not have a publicly available formula, lack a straightforward interpretation, and can vary by software implementation or hardware type. To address these problems, we propose the physical activity index (AI), a new metric for summarizing raw tri-axial accelerometry data. We compared this metric with the AC and another recently proposed metric for raw data, Euclidean Norm Minus One (ENMO), against energy expenditure. The comparison was conducted using data from the Objective Physical Activity and Cardiovascular Health Study, in which 194 women 60-91 years performed 9 lifestyle activities in the laboratory, wearing a tri-axial accelerometer (ActiGraph GT3X+) on the hip set to 30 Hz and an Oxycon portable calorimeter, to record both tri-axial acceleration time series (converted into AI, AC, and ENMO) and oxygen uptake during each activity (converted into metabolic equivalents (METs)) at the same time. Receiver operating characteristic analyses indicated that both AI and ENMO were more sensitive to moderate and vigorous physical activities than AC, while AI was more sensitive to sedentary and light activities than ENMO. AI had the highest coefficients of determination for METs (0.72) and was a better classifier of physical activity intensity than both AC (for all intensity levels) and ENMO (for sedentary and light intensity). The proposed AI provides a novel and transparent way to summarize densely sampled raw accelerometry data, and may serve as an alternative to AC. The AI's largely improved sensitivity on sedentary and light activities over AC and ENMO further demonstrate its advantage in studies with older adults. PMID- 27513334 TI - Are virus-induced cancers more sensitive to checkpoint inhibitors? PMID- 27513335 TI - Collective Behavior of Market Participants during Abrupt Stock Price Changes. AB - Under uncertainty, human and animal collectives often respond stochastically to events they encounter. Human or animal individuals behave depending on others' actions, and sometimes follow choices that are sub-optimal for individuals. Such mimetic behaviors are enhanced during emergencies, creating collective behavior of a group. A stock market that is about to crash, as markets did immediately after the Lehman Brothers bankruptcy, provides illustrative examples of such behaviors. We provide empirical evidence proving the existence of collective behavior among stock market participants in emergent situations. We investigated the resolution of extreme supply-and-demand order imbalances by increased balancing counter orders: buy and sell orders for excess supply and demand respectively, during times of price adjustment, so-called special quotes on the Tokyo Stock Exchange. Counter orders increase positively depending on the quantity of revealed counter orders: the accumulated orders in the book until then. Statistics of the coming counter order are well described using a logistic regression model with the ratio of revealed orders until then to the finally revealed orders as the explanatory variable. Results given here show that the market participants make Bayesian estimations of optimal choices to ascertain whether to order using information about orders of other participants. PMID- 27513336 TI - Assessing and Managing the Current and Future Pest Risk from Water Hyacinth, (Eichhornia crassipes), an Invasive Aquatic Plant Threatening the Environment and Water Security. AB - Understanding and managing the biological invasion threats posed by aquatic plants under current and future climates is a growing challenge for biosecurity and land management agencies worldwide. Eichhornia crassipes is one of the world's worst aquatic weeds. Presently, it threatens aquatic ecosystems, and hinders the management and delivery of freshwater services in both developed and developing parts of the world. A niche model was fitted using CLIMEX, to estimate the potential distribution of E. crassipes under historical and future climate scenarios. Under two future greenhouse gas emission scenarios for 2080 simulated with three Global Climate Models, the area with a favourable temperature regime appears set to shift polewards. The greatest potential for future range expansion lies in Europe. Elsewhere in the northern hemisphere temperature gradients are too steep for significant geographical range expansion under the climate scenarios explored here. In the Southern Hemisphere, the southern range boundary for E. crassipes is set to expand southwards in Argentina, Australia and New Zealand; under current climate conditions it is already able to invade the southern limits of Africa. The opportunity exists to prevent its spread into the islands of Tasmania in Australia and the South Island of New Zealand, both of which depend upon hydroelectric facilities that would be threatened by the presence of E. crassipes. In Europe, efforts to slow or stop the spread of E. crassipes will face the challenge of limited internal biosecurity capacity. The modelling technique demonstrated here is the first application of niche modelling for an aquatic weed under historical and projected future climates. It provides biosecurity agencies with a spatial tool to foresee and manage the emerging invasion threats in a manner that can be included in the international standard for pest risk assessments. It should also support more detailed local and regional management. PMID- 27513337 TI - The Dual NOD1/NOD2 Agonism of Muropeptides Containing a Meso-Diaminopimelic Acid Residue. AB - Muropeptides are fragments of peptidoglycan that trigger innate immune responses by activating nucleotide-binding oligomerization domain (NOD) 1 and NOD2. Muropeptides from Gram-negative bacteria contain a meso-diaminopimelic acid (meso DAP) residue in either a terminal or a non-terminal position. While the former ones are known to be recognized by NOD1, much less is known about recognition of muropeptides with non-terminal meso-DAP, which are most abundant moieties of Gram negative peptidoglycans. Here, we developed a novel system to assess biological activity of muropeptides, based on CRISPR/Cas9-mediated knockout (KO) of NOD1 and NOD2 genes in modified HEK293T cells. Using NOD1/NOD2 knockout and overexpression systems, as well as human monocytes and macrophages, we refine the current view of muropeptide recognition. We show that NOD2 can recognize different natural muropeptides containing a meso-DAP residue (preferably in a non-terminal position), provided they are present at micromolar concentrations. NOD2 accepts muropeptides with long and branched peptide chains and requires an intact N acetylmuramyl residue. Muropeptides with non-terminal meso-DAP can activate NOD1 as well, but, in this case, probably require peptidase pre-processing to expose the meso-DAP residue. Depending on NOD1/NOD2 ratio in specific cell types, meso DAP-containing muropeptides can be recognized either primarily via NOD2 (in monocytes) or via NOD1 (in monocyte-derived macrophages and HEK293T-derived cells). The dual NOD1/NOD2 agonism of meso-DAP-containing muropeptides should be taken into account when assessing cellular responses to muropeptides and designing muropeptide immunostimulants and vaccine adjuvants. PMID- 27513340 TI - Silver nanoparticle functionalized glass fibers for combined surface-enhanced Raman scattering spectroscopy (SERS)/surface-assisted laser desorption/ionization (SALDI) mass spectrometry via plasmonic/thermal hot spots. AB - We presented the fabrication of a silver nanoparticle (Ag NP) functionalized glass fiber (Ag-GF) substrate for combined surface-enhanced Raman scattering spectroscopy (SERS)/surface-assisted laser desorption/ionization (SALDI) mass spectrometry. Ag NPs were immobilized onto the surface of glass fibers through a simple sputter deposition process. The SERS and SALDI activities strongly depended on the nanostructures of the deposited Ag NPs on the GFs. The closely packed Ag NPs with a size of 20-50 nm and an inter-particle nanoscale gap of less than 10 nm were effective for the simultaneously enhanced SERS/SALDI substrate via plasmonic/thermal "hot spots", while the interconnected continuous Ag film reduced both the SERS/SALDI activities. The SERS enhanced factor (EFSERS) and SALDI enhanced factor (EFSALDI) were newly proposed. Finally, the concentration dependent signal intensities of SERS and SALD-MS of sulfur compounds using an identical Ag NP-GF substrate were examined, and the linear dependence relationship in the log-log plot was demonstrated for the combined quantitative SERS/SALDI-MS analysis. PMID- 27513339 TI - The Effect of Protandim(r) Supplementation on Athletic Performance and Oxidative Blood Markers in Runners. AB - The purpose of this study determined if oral supplementation of Protandim(r) (a nutraceutical) for 90 days improved 5-km running performance and reduced serum thiobarbituric acid-reacting substances (TBARS) at rest, an indicator of oxidative stress. Secondary objectives were to measure whole blood superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GPX), at rest and 10 minutes after completion of the race before and after supplementation as well as quality of life. In a double-blind, randomized, placebo controlled trial, 38 runners [mean (SD) = 34 (7) yrs; BMI = 22 (2) kg/m2] received either 90 days of Protandim(r) [1 pill a day, n = 19)] or placebo (n = 19). Randomization was done in blocks of two controlling for sex and 5-km baseline performance. A 5-km race was performed at baseline and after 90 days of supplementation, with blood samples taken before and 10-min after each race. Fasting blood samples were acquired at baseline, after 30, 60, and 90 days of supplementation. TBARS, SOD, GPX, and GSH were assayed in an out-of-state accredited lab. Running performance was not altered by Protandim(r) or placebo [20.3 (2.1) minutes, with an -8 (33) seconds change in 5-km time regardless of group]. There was no change in TBARS, SOD, or GPX (at rest) after three months of Protandim(r) supplementation compared to placebo. However, in a subgroup >= 35 years of age, there was a 2-fold higher increase in SOD in those taking Protandim(r) for three months compared to those on placebo (p = 0.038). The mean post-race change in TBARS (compared to pre-race) increased by about 20% in half of the subjects, but was not altered between groups, even after three months of supplementation. Quality of life was also not different between the two conditions. In conclusion, Protandim(r) did not (1) alter 5-km running time, (2) lower TBARS at rest (3) raise antioxidant enzyme concentrations compared to placebo (with exception of SOD in those >= 35 years old) or, (4) affect quality of life compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT02172625. PMID- 27513338 TI - A Public Database of Memory and Naive B-Cell Receptor Sequences. AB - The vast diversity of B-cell receptors (BCR) and secreted antibodies enables the recognition of, and response to, a wide range of epitopes, but this diversity has also limited our understanding of humoral immunity. We present a public database of more than 37 million unique BCR sequences from three healthy adult donors that is many fold deeper than any existing resource, together with a set of online tools designed to facilitate the visualization and analysis of the annotated data. We estimate the clonal diversity of the naive and memory B-cell repertoires of healthy individuals, and provide a set of examples that illustrate the utility of the database, including several views of the basic properties of immunoglobulin heavy chain sequences, such as rearrangement length, subunit usage, and somatic hypermutation positions and dynamics. PMID- 27513342 TI - Allopolyploid Origin of Chenopodium album s. str. (Chenopodiaceae): A Molecular and Cytogenetic Insight. AB - Reticulate evolution is characterized by occasional hybridization between two species, creating a network of closely related taxa below and at the species level. In the present research, we aimed to verify the hypothesis of the allopolyploid origin of hexaploid C. album s. str., identify its putative parents and estimate the frequency of allopolyploidization events. We sampled 122 individuals of the C. album aggregate, covering most of its distribution range in Eurasia. Our samples included putative progenitors of C. album s. str. of both ploidy levels, i.e. diploids (C. ficifolium, C. suecicum) and tetraploids (C. striatiforme, C. strictum). To fulfil these objectives, we analysed sequence variation in the nrDNA ITS region and the rpl32-trnL intergenic spacer of cpDNA and performed genomic in-situ hybridization (GISH). Our study confirms the allohexaploid origin of C. album s. str. Analysis of cpDNA revealed tetraploids as the maternal species. In most accessions of hexaploid C. album s. str., ITS sequences were completely or nearly completely homogenized towards the tetraploid maternal ribotype; a tetraploid species therefore served as one genome donor. GISH revealed a strong hybridization signal on the same eighteen chromosomes of C. album s. str. with both diploid species C. ficifolium and C. suecicum. The second genome donor was therefore a diploid species. Moreover, some individuals with completely unhomogenized ITS sequences were found. Thus, hexaploid individuals of C. album s. str. with ITS sequences homogenized to different degrees may represent hybrids of different ages. This proves the existence of at least two different allopolyploid lineages, indicating a polyphyletic origin of C. album s. str. PMID- 27513341 TI - FmvB: A Francisella tularensis Magnesium-Responsive Outer Membrane Protein that Plays a Role in Virulence. AB - Francisella tularensis is the causative agent of the lethal disease tularemia. Despite decades of research, little is understood about why F. tularensis is so virulent. Bacterial outer membrane proteins (OMPs) are involved in various virulence processes, including protein secretion, host cell attachment, and intracellular survival. Many pathogenic bacteria require metals for intracellular survival and OMPs often play important roles in metal uptake. Previous studies identified three F. tularensis OMPs that play roles in iron acquisition. In this study, we examined two previously uncharacterized proteins, FTT0267 (named fmvA, for Francisella metal and virulence) and FTT0602c (fmvB), which are homologs of the previously studied F. tularensis iron acquisition genes and are predicted OMPs. To study the potential roles of FmvA and FmvB in metal acquisition and virulence, we first examined fmvA and fmvB expression following pulmonary infection of mice, finding that fmvB was upregulated up to 5-fold during F. tularensis infection of mice. Despite sequence homology to previously characterized iron-acquisition genes, FmvA and FmvB do not appear to be involved iron uptake, as neither fmvA nor fmvB were upregulated in iron-limiting media and neither DeltafmvA nor DeltafmvB exhibited growth defects in iron limitation. However, when other metals were examined in this study, magnesium-limitation significantly induced fmvB expression, DeltafmvB was found to express significantly higher levels of lipopolysaccharide (LPS) in magnesium-limiting medium, and increased numbers of surface protrusions were observed on DeltafmvB in magnesium-limiting medium, compared to wild-type F. tularensis grown in magnesium-limiting medium. RNA sequencing analysis of DeltafmvB revealed the potential mechanism for increased LPS expression, as LPS synthesis genes kdtA and wbtA were significantly upregulated in DeltafmvB, compared with wild-type F. tularensis. To provide further evidence for the potential role of FmvB in magnesium uptake, we demonstrated that FmvB was outer membrane-localized. Finally, DeltafmvB was found to be attenuated in mice and cytokine analyses revealed that DeltafmvB-infected mice produced lower levels of pro-inflammatory cytokines, including GM-CSF, IL-3, and IL-10, compared with mice infected with wild-type F. tularensis. Taken together, although the function of FmvA remains unknown, FmvB appears to play a role in magnesium uptake and F. tularensis virulence. These results may provide new insights into the importance of magnesium for intracellular pathogens. PMID- 27513343 TI - Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart. AB - Platelet-derived growth factors (PDGFs) are key regulators of mesenchymal cells in vertebrate development. To what extent PDGFs also exert beneficial homeostatic or reparative roles in adult organs, as opposed to adverse fibrogenic responses in pathology, are unclear. PDGF signaling plays critical roles during heart development, during which forced overexpression of PDGFs induces detrimental cardiac fibrosis; other studies have implicated PDGF signaling in post-infarct myocardial repair. Different PDGFs may exert different effects mediated through the two PDGF receptors (PDGFRalpha and PDGFRbeta) in different cell types. Here, we assessed responses induced by five known PDGF isoforms in the adult mouse heart in the context of adenovirus vector-mediated inflammation. Our results show that different PDGFs have different, in some cases even opposing, effects. Strikingly, whereas the major PDGFRalpha agonists (PDGF-A and -C) decreased the amount of scar tissue and increased the numbers of PDGFRalpha-positive fibroblasts, PDGFRbeta agonists either induced large scars with extensive inflammation (PDGF-B) or dampened the adenovirus-induced inflammation and produced a small and dense scar (PDGF-D). These results provide evidence for PDGF isoform-specific inflammation-modulating functions that may have therapeutic implications. They also illustrate a surprising complexity in the PDGF-mediated pathophysiological responses. PMID- 27513344 TI - Efficacy and Safety of Topical Pidobenzone 4% as Adjuvant Treatment for Solar Lentigines: Result of a Randomized, Controlled, Clinical Trial. AB - BACKGROUND/OBJECTIVE: This study aims at the evaluation of the efficacy and safety of a combination therapy based on pidobenzone 4% and fractional CO2 laser or cryotherapy in the treatment of solar lentigines and the prevention of eventual posttreatment hyperchromia. METHODS: Efficacy was clinically evaluated by grading the pigmentation level with the Skin Tone Color Scale (STCS), and by grading patients' impression through a Visual Analog Scale (VAS). RESULTS: Our study shows that the associated treatment was safe and that it improves the therapeutic results on solar lentigines and prevents postiatrogenic hyperpigmentation compared with physical therapy alone. CONCLUSION: The combination of cryotherapy and pidobenzone 4% has been found to be the most useful treatment. PMID- 27513345 TI - Ingenol Mebutate vs. Daylight Photodynamic Therapy in a Kidney Transplant Recipient. AB - We present the case of a 73-year-old male patient who had received a first renal transplant at 36 years and a second one at the age of 55 years. He is currently under immunosuppression with everolimus 2.5 mg/day and prednisone 5 mg/day. The patient presented with multiple actinic keratoses on both cheeks and the forehead and received treatment by ingenol mebutate 150 ug/g gel daily on 3 consecutive days on his right cheek and methyl aminolevulinate (MAL) photodynamic therapy activated by daylight (MAL-dPDT) on the forehead and the left cheek. MAL-dPDT treatment proved a feasible, repeatable, physician-directed method of treating field cancerization with limited morbidity for a period of 6 days. Treatment with ingenol mebutate gel was a feasible, possibly self-directed method of treating field cancerization with limited morbidity for 10 days in this immunosuppressed patient. Both treatments showed similar efficacy. At the time of treatment, the MAL daylight PDT ran at 3 times the cost of ingenol mebutate gel. PMID- 27513346 TI - Therapists' Inadequate Feelings and Long-Term Effect of Transference Work. PMID- 27513347 TI - Cervical cancer: Screening, management, and prevention. AB - Cervical cancer incidence in the United States is estimated to affect 12,900 women in 2016, with 4,100 deaths. Screening for this cancer with Pap test and adjunct human papillomavirus testing has made cervical cancer a treatable disease. This article reviews screening, treatment recommendations, and prevention for cervical cancer. PMID- 27513348 TI - Mitochondrial genome association study with peripheral arterial disease and venous thromboembolism. AB - BACKGROUND AND AIMS: Peripheral arterial disease (PAD) and venous thromboembolism (VTE) are vascular traits sharing common modifiable and non-modifiable risk factors. These vascular pathologies have known nuclear-encoded genetic risk factors and the mitochondrial DNA may account for part of the missing heritability. To determine if PAD and VTE have a dual genetic control (mitochondrial and nuclear), we hereby investigated the association of mitochondrial DNA polymorphisms and haplogroups with these vascular traits. METHODS: The association of mitochondrial single nucleotide polymorphisms (mtSNPs) and haplogroups was tested in 1652 PAD cases and 1629 controls from the eMERGE PAD genome-wide association study (GWAS), and 1241 VTE cases and 1278 controls from the GENEVA GWAS of venous thrombosis (dbGaP accession numbers phs000203.v1.p1 and phs000289.v2.p1, respectively). RESULTS: 66 and 72 mtSNPs passed quality control filters and were tested for association with PAD and VTE, respectively. Significant evidence of population stratification could not be detected in both datasets. Three mtSNPs (m.477T > C, m.9667A > G, and m.10915T > C) were nominally associated (3.01 * 10(-3) <= pa <= 3.96 * 10(-2)) with PAD in the logistic regression adjusted for confounding factors, and m.11914G > A was nominally associated (pa = 4.14 * 10(-2)) with VTE. None of the nine major mitochondrial haplogroups were associated with either PAD or VTE. CONCLUSION: Unlike other vascular diseases such as stroke and diabetes, these results suggest that common mitochondrial variants individually or in combination do not play a major role in PAD and VTE susceptibility. PMID- 27513349 TI - Bisphosphonates for cardiovascular risk reduction: A systematic review and meta analysis. AB - BACKGROUND AND AIMS: Bisphosphonates might be effective in reducing cardiovascular events due to their ability to reduce calcification in arterial walls. We aimed to investigate the effects of treatment with bisphosphonates on the prevention of atherosclerotic processes and cardiovascular disease. METHODS: Pubmed, Embase and the Cochrane Library were systematically reviewed by two independent investigators for randomized controlled studies published up to January 2016, in which the effect of bisphosphonates on arterial wall disease, cardiovascular events, cardiovascular mortality or all-cause mortality were reported. There was no restriction for the type of population used in the trials. Random-effects models were used to calculate the pooled estimates. RESULTS: 61 trials reporting the effects of bisphosphonates on the outcomes of interest were included. Bisphosphonates had beneficial effects on arterial wall disease regarding arterial calcification (pooled mean percentage difference of 2 trials 11.52 (95% CI -16.51 to -6.52, p < 0.01, I(2) 13%), but not on arterial stiffness (pooled mean percentage difference of 2 trials -2.82; 95% CI -10.71-5.07; p = 0.48, I(2) 59%). No effect of bisphosphonate treatment on cardiovascular events was found (pooled RR of 20 trials 1.03; 95% CI 0.91-1.17, I(2) 16%), while a lower risk for cardiovascular mortality was observed in patients treated with bisphosphonates (pooled RR of 10 trials 0.81; 95% CI 0.64-1.02; I(2) 0%) although not statistically significant. Patients treated with bisphosphonates had a reduced risk of all-cause mortality (pooled RR of 48 trials 0.90; 95% CI 0.84 0.98; I(2) 53%). CONCLUSIONS: In this systematic review and meta-analysis it is shown that bisphosphonates reduce arterial wall calcification but have no effect on arterial stiffness or on cardiovascular events. Bisphosphonates tend to reduce the risk of cardiovascular mortality and reduce all-cause mortality in various patient groups, including osteoporosis and cancer patients. PMID- 27513350 TI - Outbreak of Plague in a High Malaria Endemic Region - Nyimba District, Zambia, March-May 2015. AB - Outbreaks of plague have been recognized in Zambia since 1917 (1). On April 10, 2015, Zambia's Ministry of Health was notified by the Eastern Provincial Medical Office of possible bubonic plague cases in Nyimba District. Eleven patients with acute fever and cervical lymphadenopathy had been evaluated at two rural health centers during March 28-April 9, 2015; three patients died. To confirm the outbreak and develop control measures, the Zambia Ministry of Health's Field Epidemiology Training Program (ZFETP) conducted epidemiologic and laboratory investigations in partnership with the University of Zambia's schools of Medicine and Veterinary Medicine and the provincial and district medical offices. Twenty one patients with clinically compatible plague were identified, with symptom onset during March 26-May 5, 2015. The median age was 8 years, and all patients were from the same village. Blood specimens or lymph node aspirates from six (29%) patients tested positive for Yersinia pestis by polymerase chain reaction (PCR). There is an urgent need to improve early identification and treatment of plague cases. PCR is a potential complementary tool for identifying plague, especially in areas with limited microbiologic capacity. Twelve (57%) patients, including all six with PCR-positive plague and all three who died, also tested positive for malaria by rapid diagnostic test (RDT). Plague patients coinfected with malaria might be misdiagnosed as solely having malaria, and appropriate antibacterial treatment to combat plague might not be given, increasing risk for mortality. Because patients with malaria might be coinfected with other pathogens, broad spectrum antibiotic treatment to cover other pathogens is recommended for all children with severe malaria, until a bacterial infection is excluded. PMID- 27513351 TI - First Introduction of Two Australian Temnocephalan Species into Africa with an Alien Host: Double Trouble. AB - The redclaw crayfish, Cherax quadricarinatus (Decapoda: Parastacidae), is native to Australia but has been introduced to South Africa as a warm-water aquaculture species. In a South African natural waterbody, examined crayfish had high intensity infections of 3 temnocephalan species on their body surfaces and within the branchial chambers. Temnocephalans were characterized using light and scanning electron microscopy and identified as Craspedella pedum, Diceratocephala boschmai, and Didymorchis sp. This is the first report of the introduction of Australian temnocephalans, C. pedum and Didymorchis sp., to Africa and expands the known distribution of these species beyond their presumptive native range. The present study also documents a naturalized population of C. quadricarinatus from a natural water body in South Africa, comprising a new geographical locality record. PMID- 27513352 TI - Life satisfaction in women with epilepsy during and after pregnancy. AB - OBJECTIVE: The aim of this study was to investigate life satisfaction in women with epilepsy during and after pregnancy. METHODS: The study was based on the Norwegian Mother and Child Cohort Study, including 102,265 women with and without epilepsy from the general population. Investigation took place at pregnancy weeks 15-19 and 6 and 18months postpartum. Women with epilepsy were compared with a reference group without epilepsy. RESULTS: The proportion of women with epilepsy was 0.6-0.7% at all three time points. Women with epilepsy reported lower life satisfaction and self-esteem both during and after pregnancy compared with the references. Single parenting correlated negatively with life satisfaction in epilepsy during the whole study period. Epilepsy was associated with lower levels of relationship satisfaction and higher levels of work strain during pregnancy and lower levels of self-efficacy and satisfactory somatic health 18months postpartum. Adverse life events, such as divorce, were more common in women with epilepsy compared with the references, and fewer women with epilepsy had a paid job 18months postpartum. SIGNIFICANCE: Reduced life satisfaction associated with epilepsy during and after pregnancy showed that, even in a highly developed welfare society, women with epilepsy struggle. Mothers with epilepsy and their partners should be examined for emotional complaints and partnership satisfaction during and after pregnancy. Validated screening tools are available for such measures. PMID- 27513353 TI - Japanese nursing students' sense of belonging: A story of Uchi (insider) and Soto (outsider). AB - Clinical placement experiences are the cornerstone of nursing education and a body of literature indicates that belongingness is fundamental to students' learning when undertaking placements. However, little is known about Japanese nursing students' sense of belonging and how it is influenced by their cultural values. The aim of this paper is to profile a study that: measured the extent to which Japanese nursing students' experience a sense of belonging in clinical placements, and explored the factors that impact on and are consequences of that experience. A mixed methods design was used with quantitative data collected using the Belongingness Scale-Clinical Placement Experience and qualitative data collected using semi-structured interviews. Ninety-two third and fourth year students from a large regional university in Japan completed the questionnaire; of these six also participated in interviews. The results identified similarities and differences between this and other studies of belongingness. Supportive and welcoming clinical environments facilitated participants' belongingness and motivation to learn. However, the belongingness scores of this sample were lower than those in all other studies. This may be explained, in part, by the Japanese cultural values of "Uchi (insider) and Soto" (outsider), which pervaded the participants' placement experiences and led to feelings of exclusion and alienation. PMID- 27513354 TI - Acute Kidney Injury in Pediatric Severe Sepsis: An Independent Risk Factor for Death and New Disability. AB - OBJECTIVES: The prevalence of septic acute kidney injury and impact on functional status of PICU survivors are unknown. We used data from an international prospective severe sepsis study to elucidate functional outcomes of children suffering septic acute kidney injury. DESIGN: Secondary analysis of patients in the Sepsis PRevalence, OUtcomes, and Therapies point prevalence study: acute kidney injury was defined on the study day using Kidney Disease Improving Global Outcomes definitions. Patients with no acute kidney injury or stage 1 acute kidney injury ("no/mild acute kidney injury") were compared with those with stage 2 or 3 acute kidney injury ("severe acute kidney injury"). The primary outcome was a composite of death or new moderate disability at discharge defined as a Pediatric Overall Performance Category score of 3 or higher and increased by 1 from baseline. SETTING: One hundred twenty-eight PICUs in 26 countries. PATIENTS: Children with severe sepsis in the Sepsis PRevalence, OUtcomes, and Therapies study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred two (21%) of 493 patients had severe acute kidney injury. More than twice as many patients with severe acute kidney injury died or developed new moderate disability compared with those with no/mild acute kidney injury (64% vs 30%; p < 0.001). Severe acute kidney injury was independently associated with death or new moderate disability (adjusted odds ratio, 2.5; 95% CI, 1.5-4.2; p = 0.001) after adjustment for age, region, baseline disability, malignancy, invasive mechanical ventilation, albumin administration, and the pediatric logistic organ dysfunction score. CONCLUSIONS: In a multinational cohort of critically ill children with severe sepsis and high mortality rates, septic acute kidney injury is independently associated with further increased death or new disability. PMID- 27513355 TI - Neuromuscular Recovery Is Prolonged After Immobilization or Superimposition of Inflammation With Immobilization Compared to Inflammation Alone: Data From a Preclinical Model. AB - OBJECTIVES: Recovery from ICU-acquired muscle weakness extends beyond hospital stay. We hypothesized that immobilization, more than inflammation, plays a prominent role in the delayed recovery from critical illness. DESIGN: Prospective, randomized, controlled, experimental study. SETTING: Animal laboratory, university hospital. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Animals were divided to have one hind limb immobilized (n = 129) or sham-immobilized (n = 129) on day -12. After surgery, rats were further assigned to two subgroups. To induce inflammation, rats received three IV injections of Corynebacterium parvum on days -12, -8, and -4. Controls received saline at the respective time-points. At day 0, the limbs were remobilized and recovery from inflammation and/or immobilization was followed for 36 days. MEASUREMENTS AND MAIN RESULTS: At day 0 and after 4, 12, or 36 days of recovery, maximum tetanic tension and tetanic fade (functional parameters = primary outcome variables) as well as nicotinic acetylcholine receptor expression, muscle mass, and histologic changes (structural parameters = secondary outcome variables) were measured. Impaired maximum tetanic tension, decreased tibialis muscle mass, and fiber diameter due to inflammation alone recovered by day 4. Tetanic fade was not affected by inflammation. Immobilization-induced loss of tibialis muscle mass, decreased fiber diameter, and tetanic fade did not return to normal until day 36, while maximum tetanic tension had recovered at that time. In the presence of inflammation and immobilization, the decrease in tibialis muscle mass, fiber diameter, and maximum tetanic tension, as well as decreased tetanic fade persisted until day 36. Up-regulation of nicotinic acetylcholine receptors normalized before day 4 following inflammation, but persisted until day 4 following immobilization. CONCLUSIONS: In our model, muscle function and structure recovered from inflammation within 4-12 days. Immobilization-induced neuromuscular changes, however, persisted even at day 36, especially if inflammation was concomitant. PMID- 27513356 TI - Incidence and Characteristics of Ventilator-Associated Events Reported to the National Healthcare Safety Network in 2014. AB - OBJECTIVE: Ventilator-associated event surveillance was introduced in the National Healthcare Safety Network in 2013, replacing surveillance for ventilator associated pneumonia in adult inpatient locations. We determined incidence rates and characteristics of ventilator-associated events reported to the National Healthcare Safety Network. DESIGN, SETTING, AND PATIENTS: We analyzed data reported from U.S. healthcare facilities for ventilator-associated events that occurred in 2014, the first year during which ventilator-associated event surveillance definitions were stable. We used negative binomial regression modeling to identify healthcare facility and inpatient location characteristics associated with ventilator-associated events. We calculated ventilator-associated event incidence rates, rate distributions, and ventilator utilization ratios in critical care and noncritical care locations and described event characteristics. MEASUREMENTS AND MAIN RESULTS: A total of 1,824 healthcare facilities reported 32,772 location months of ventilator-associated event surveillance data to the National Healthcare Safety Network in 2014. Critical care unit pooled mean ventilator-associated event incidence rates ranged from 2.00 to 11.79 per 1,000 ventilator days, whereas noncritical care unit rates ranged from 0 to 14.86 per 1,000 ventilator days. The pooled mean proportion of ventilator-associated events defined as infection-related varied from 15.38% to 47.62% in critical care units. Pooled mean ventilator utilization ratios in critical care units ranged from 0.24 to 0.47. CONCLUSIONS: We found substantial variability in ventilator-associated event incidence, proportions of ventilator-associated events characterized as infection-related, and ventilator utilization within and among location types. More work is needed to understand the preventable fraction of ventilator associated events and identify patient care strategies that reduce ventilator associated events. PMID- 27513357 TI - Carbon Monoxide Improves Efficacy of Mesenchymal Stromal Cells During Sepsis by Production of Specialized Proresolving Lipid Mediators. AB - OBJECTIVES: Mesenchymal stromal cells are being investigated as a cell-based therapy for a number of disease processes, with promising results in animal models of systemic inflammation and sepsis. Studies are ongoing to determine ways to further improve the therapeutic potential of mesenchymal stromal cells. A gas molecule that improves outcome in experimental sepsis is carbon monoxide. We hypothesized that preconditioning of mesenchymal stromal cells with carbon monoxide ex vivo would promote further therapeutic benefit when cells are administered in vivo after the onset of polymicrobial sepsis in mice. DESIGN: Animal study and primary cell culture. SETTING: Laboratory investigation. SUBJECTS: BALB/c mice. INTERVENTIONS: Polymicrobial sepsis was induced by cecal ligation and puncture. Mesenchymal stromal cells, mesenchymal stromal cells conditioned with carbon monoxide, fibroblasts, or fibroblasts-conditioned with carbon monoxide were delivered by tail vein injections to septic mice. The mice were assessed for survival, bacterial clearance, and the inflammatory response during sepsis in each of the groups. Mesenchymal stromal cells were also assessed for their ability to promote bacterial phagocytosis by neutrophils, the production of specialized proresolving lipid mediators, and their importance for mesenchymal stromal cells function using gene silencing. MEASUREMENTS AND MAIN RESULTS: Ex vivo preconditioning with carbon monoxide allowed mesenchymal stromal cells to be administered later after the onset of sepsis (6 hr), and yet maintain their therapeutic effect with increased survival. Carbon monoxide preconditioned mesenchymal stromal cells were also able to alleviate organ injury, improve bacterial clearance, and promote the resolution of inflammation. Mesenchymal stromal cells exposed to carbon monoxide, with docosahexaenoic acid substrate, produced specialized proresolving lipid mediators, particularly D-series resolvins, which promoted survival. Silencing of lipoxygenase pathways (5 lipoxygenase and 12/15-lipoxygenase), which are important enzymes for specialized proresolving lipid mediator biosynthesis, resulted in a loss of therapeutic benefit bestowed on mesenchymal stromal cells by carbon monoxide. CONCLUSIONS: Taken together, these data suggest that production of specialized proresolving lipid mediators contribute to improved mesenchymal stromal cell efficacy when exposed to carbon monoxide, resulting in an improved therapeutic response during sepsis. PMID- 27513358 TI - Lung Injury Prediction Score in Hospitalized Patients at Risk of Acute Respiratory Distress Syndrome. AB - OBJECTIVE: The Lung Injury Prediction Score identifies patients at risk for acute respiratory distress syndrome in the emergency department, but it has not been validated in non-emergency department hospitalized patients. We aimed to evaluate whether Lung Injury Prediction Score identifies non-emergency department hospitalized patients at risk of developing acute respiratory distress syndrome at the time of critical care contact. DESIGN: Retrospective study. SETTING: Five academic medical centers. PATIENTS: Nine hundred consecutive patients (>= 18 yr old) with at least one acute respiratory distress syndrome risk factor at the time of critical care contact. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Lung Injury Prediction Score was calculated using the worst values within the 12 hours before initial critical care contact. Patients with acute respiratory distress syndrome at the time of initial contact were excluded. Acute respiratory distress syndrome developed in 124 patients (13.7%) a median of 2 days (interquartile range, 2-3) after critical care contact. Hospital mortality was 22% and was significantly higher in acute respiratory distress syndrome than non-acute respiratory distress syndrome patients (48% vs 18%; p < 0.001). Increasing Lung Injury Prediction Score was significantly associated with development of acute respiratory distress syndrome (odds ratio, 1.31; 95% CI, 1.21-1.42) and the composite outcome of acute respiratory distress syndrome or death (odds ratio, 1.26; 95% CI, 1.18-1.34). A Lung Injury Prediction Score greater than or equal to 4 was associated with the development of acute respiratory distress syndrome (odds ratio, 4.17; 95% CI, 2.26-7.72), composite outcome of acute respiratory distress syndrome or death (odds ratio, 2.43; 95% CI, 1.68-3.49), and acute respiratory distress syndrome after accounting for the competing risk of death (hazard ratio, 3.71; 95% CI, 2.05-6.72). For acute respiratory distress syndrome development, the Lung Injury Prediction Score has an area under the receiver operating characteristic curve of 0.70 and a Lung Injury Prediction Score greater than or equal to 4 has 90% sensitivity (misses only 10% of acute respiratory distress syndrome cases), 31% specificity, 17% positive predictive value, and 95% negative predictive value. CONCLUSIONS: In a cohort of non-emergency department hospitalized patients, the Lung Injury Prediction Score and Lung Injury Prediction Score greater than or equal to 4 can identify patients at increased risk of acute respiratory distress syndrome and/or death at the time of critical care contact but it does not perform as well as in the original emergency department cohort. PMID- 27513359 TI - Age-Dependent Changes in the Pulmonary Renin-Angiotensin System Are Associated With Severity of Lung Injury in a Model of Acute Lung Injury in Rats. AB - OBJECTIVES: A growing body of evidence suggests that age affects the main pathophysiologic mechanisms of the acute respiratory distress syndrome. This may imply the need for developing age-tailored therapies for acute respiratory distress syndrome. However, underlying molecular mechanisms governing age-related susceptibility first need to be unraveled. In a rat model of acute lung injury, we investigated whether age affects the balance between the two key enzymes of the pulmonary renin-angiotensin system, angiotensin-converting enzyme, and angiotensin-converting enzyme 2. We hypothesized that aging shifts the balance toward the lung injury-promoting angiotensin-converting enzyme, which may form an explanation for the differences in severity of lung injury between different age groups. DESIGN: Prospective, randomized controlled animal study. SETTING: University medical research laboratory. SUBJECTS: Infant (15 +/- 2 d), juvenile (37 +/- 2 d), adult (4 +/- 0.2 mo), and elderly (19.5 +/- 0.5 mo) male RCCHan Wistar rats. INTERVENTIONS: Lung injury was induced by intratracheal administration of lipopolysaccharide (5 mg/kg) and 4 hours of mechanical ventilation (15 mL/kg). MEASUREMENTS AND MAIN RESULTS: In lipopolysaccharide exposed and mechanical ventilated rats, angiotensin-converting enzyme activity in bronchoalveolar lavage fluid increased 3.2-fold in elderly when compared with infants. No changes in bronchoalveolar lavage fluid angiotensin-converting enzyme 2 activity were found. In addition, membrane-bound angiotensin-converting enzyme activity decreased. Together with the presence of angiotensin-converting enzyme sheddase ADAM9 (a disintegrin and metalloproteinase domain-containing protein 9) and an age-dependent increase in tumor necrosis factor-alpha, an activator of ADAM9, these results indicate increased shedding of angiotensin-converting enzyme in the alveolar compartment, thereby shifting the balance toward the injurious pathway. This imbalance was associated with an increased inflammatory mediator response and more lung injury (wet-to-dry ratio and histology) in elderly rats. CONCLUSIONS: Increasing age is associated with an imbalance of the pulmonary renin-angiotensin system, which correlates with aggravated inflammation and more lung injury. These changes might form the ground for new therapeutic strategies in terms of dosing and effectiveness of renin-angiotensin system-modulating agents for treatment of acute respiratory distress syndrome. PMID- 27513360 TI - Dimensions and Role-Specific Mediators of Surrogate Trust in the ICU. AB - OBJECTIVE: In the ICU, discussions between clinicians and surrogate decision makers are often accompanied by conflict about a patient's prognosis or care plan. Trust plays a role in limiting conflict, but little is known about the determinants of trust in the ICU. We sought to identify the dimensions of trust and clinician behaviors conducive to trust formation in the ICU. DESIGN: Prospective qualitative study. SETTING: Medical ICU of a major urban university hospital. SUBJECTS: Surrogate decision makers of intubated, mechanically ventilated patients in the medical ICU. MEASUREMENTS AND MAIN RESULTS: Semistructured interviews focused on surrogates' general experiences in the ICU and on their trust in the clinicians caring for the patient. Interviews were audio-recorded, transcribed verbatim, and coded by two reviewers. Constant comparison was used to identify themes pertaining to trust. Thirty surrogate interviews revealed five dimensions of trust in ICU clinicians: technical competence, communication, honesty, benevolence, and interpersonal skills. Most surrogates emphasized the role of nurses in trust formation, frequently citing their technical competence. Trust in physicians was most commonly related to honesty and the quality of their communication with surrogates. CONCLUSIONS: Interventions to improve trust in the ICU should be role-specific, since surrogate expectations are different for physicians and nurses with regard to behaviors relevant to trust. Further research is needed to confirm our findings and explore the impact of trust modification on clinician-family conflict. PMID- 27513361 TI - Bone Marrow-Derived Endothelial Progenitor Cells Reduce Recurrent Miscarriage in Gestation. AB - Bone marrow-derived endothelial progenitor cells (EPCs) have been shown to contribute to not only angiogenesis in ischemic tissue but also neovascularization in uterine endometrium formation. Reduced neovascularization and elevation of serum soluble Flt1, a functional blockage of VEGF, in the development of placenta is thought to be one of the major causes of repeated miscarriages in gestation. We then examined whether transfusion of VEGF expressing extrinsic EPCs prevented frequent miscarriage via its promotional effect on neovascularization with a VEGFeNOS signaling pathway in a mouse miscarriage model. The results showed that systemic EPC transfusion significantly reduced the rate of miscarriage, and EPCs were frequently observed in the miscarriage placenta. In contrast, only a few EPCs were detected in the placenta of normal gestation. The vascular pattern was irregular, and vessel size was small in the miscarriage placenta compared with that of normal gestation. The placental vascular pattern in miscarriage tended to be normalized with increased vessel size up to a similar level as normal gestation by EPC recruitment. For the mechanistic insight, since soluble Flt1 inhibits EPC functions, it was suggested that the increased soluble Flt1 could suppress the recruited EPC functional activity in the miscarriage placenta. In vitro experiments by soluble Flt1 treatment in cultured EPCs suggested that the vascular abnormality could be partly due to the inhibition of eNOS expression by the increased amounts of soluble Flt1. These findings from animal experiments indicated that autologous EPC therapy may be a novel therapy to prevent miscarriage in high-risk pregnancies, such as preeclampsia. PMID- 27513362 TI - The retrieval and selection of arithmetic facts in oral arithmetic. AB - We examined the co-activation and the selection of arithmetic facts in oral arithmetic. In two experiments, participants had to verify whether simple additions were correct or not. In Experiment 1, additions were presented in the auditory-verbal format; in Experiment 2, additions were presented in the digit format but simulating the temporal sequence of auditory problems of Experiment 1. Results were similar in both experiments. Firstly, participants took the same time to respond when an addition was incorrect but the result was that of multiplying the operands (e.g., 2+4=8) relative to a control addition with unrelated result. Secondly, participants took more time to respond when the result of multiplying the operands of the first trial was presented again in a correct addition problem (e.g., 2+6=8) relative to a control addition. This pattern of results is discussed in terms of the temporal resolution to which auditory problems are resolved and the role of an inhibitory mechanism involved in the selection of arithmetic facts. PMID- 27513364 TI - Total Synthesis of Nuclear Factor of Activated T-Cells-68 (NFAT-68): Sequential Use of Chiral Allenylsilane and Titanium Alkoxide-Mediated Reductive Coupling Bond Construction. AB - Highly enantioenriched chiral allenylsilanes 4 were prepared in high yield through a scalable synthetic sequence, employing a modified copper-catalyzed SN2' reaction. These reagents were used for the production of enantioenriched homoproparglylic ethers 5, which were subjected to titanium alkoxide-mediated reductive coupling with acetylenic esters to produce (E,E)-dienes 6 bearing alpha,beta,gamma,delta-unsaturated esters. Both enantiomers of nuclear factor of activated T-cells-68 (NFAT-68) were synthesized in five steps with the sequential use of the two methods. PMID- 27513363 TI - The From Survivor to Thriver program: RCT of an online therapist-facilitated program for rape-related PTSD. AB - This study evaluated the efficacy of the From Survivor to Thriver program, an interactive, online therapist-facilitated cognitive-behavioral program for rape related PTSD. Eighty-seven college women with rape-related PTSD were randomized to complete the interactive program (n=46) or a psycho-educational self-help website (n=41). Both programs led to large reductions in interview-assessed PTSD at post-treatment (interactive d=2.22, psycho-educational d=1.10), which were maintained at three month follow-up. Both also led to medium- to large-sized reductions in self-reported depressive and general anxiety symptoms. Follow-up analyses supported that the therapist-facilitated interactive program led to superior outcomes among those with higher pre-treatment PTSD whereas the psycho educational self-help website led to superior outcomes for individuals with lower pre-treatment PTSD. Future research should examine the efficacy and effectiveness of online interventions for rape-related PTSD including whether treatment intensity matching could be utilized to maximize outcomes and therapist resource efficiency. PMID- 27513365 TI - Identification of five novel arginine vasopressin gene mutations in patients with familial neurohypophyseal diabetes insipidus. AB - Familial neurohypophyseal diabetes insipidus (FNDI) is a genetic disorder presenting with polyuria and polydipsia and is caused by mutations in the arginine vasopressin-neurophysin II (AVP-NPII) gene. The clinical manifestations of this disorder vary greatly depending on different mutations. The present study reports the genetic, clinical and biochemical characteristics of patients with FNDI caused by five novel mutations. Ten patients encompassing two pedigrees and four individual cases diagnosed with FNDI were included. Biochemical markers and magnetic resonance imaging (MRI) were evaluated and genomic DNA was sequenced. The results revealed that age at onset ranged from 1.0 to 11.0 years. Daily urine volumes ranged from 2.0 to 12.0 liters. One patient had mental retardation and three patients had puberty retardation; one patient had nausea, vomiting and mental retardation; and two patients had fever. Treatments, if given, included desmopressin and vasopressin tannate. Posterior pituitary T1-weighted MRI high intensity signals were absent in two cases and present in four cases. Sequencing revealed five novel mutations in the AVP-NPII gene. On the whole, the findings of the present study indicate that FNDI exhibits different clinical manifestations and a diverse age at onset. Posterior pituitary MRI does not provide a definite diagnosis of FNDI. We also identified five novel AVP-NPII mutations. Thus, an enhanced understanding of FNDI pathogenesis may provide a basis for the development of presymptomatic FNDI diagnotic tools. PMID- 27513366 TI - Monomeric and dimeric Al(iii) complexes for the production of polylactide. AB - A series of monometallic and bimetallic Al(iii) complexes with substituted naphthyl based Schiff base ligands have been prepared and characterised. When 1 aminonaphthalene based ligands were reacted with AlMe3 monometallic complexes were isolated, however, with 1,5 and 1,8-diaminonaphthalene based ligands bimetallic complexes were formed. In all cases 4-coordinate tetrahedral Al(iii) centres were observed in the solid state and in solution. There was little difference in rate of polymerisation of rac-lactide between the monometallic and bimetallic complexes based on 1,5-diaminonaphthalene. However, for the 1,8 diaminonaphthalene the complex was an order of magnitude faster than the monometallic and the analogous 1,5-system. Moreover, this complex was active at room temperature, which is rare for aluminium initiators, and PLA with a high degree (Pm = 0.82) of isotacticity was observed. PMID- 27513367 TI - Dynamic Contrast-Enhanced Computed Tomography-Derived Blood Volume and Blood Flow Correlate With Patient Outcome in Metastatic Renal Cell Carcinoma. AB - OBJECTIVES: The aim was to explore the potential for using dynamic contrast enhanced computed tomography as a noninvasive functional imaging biomarker before and during the early treatment of metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Dynamic contrast-enhanced computed tomography scans were performed at baseline and after 5 and 10 weeks' treatment in 69 prospectively included mRCC patients receiving treatment with interferon alpha and interleukin 2 (n = 26); interferon alpha, interleukin 2, and bevacizumab (n = 24); sunitinib (n = 7); pazopanib (n = 5); or temsirolimus (n = 7). Using a prototype software program (Advanced Perfusion and Permeability Application, Philips Healthcare, Best, the Netherlands), blood volume (BV), blood flow (BF), and permeability surface area product (PS) were calculated for each tumor at baseline, week 5, and week 10. These parameters as well as relative changes between baseline and weeks 5 and 10 were tested for associations with progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier curves and log-rank tests. RESULTS: Using the 25th percentile as the cutoff, baseline BV for all patients independent of subsequent treatment was statistically significantly associated with PFS (10.8 vs 5.3 months, P = 0.007) and OS (35.2 vs 13.3 months, P = 0.001), and baseline BF was significantly associated with OS (31.7 vs 14.6 months, P = 0.024) with high values for both parameters being associated with significantly longer PFS and OS. Baseline PS was not associated with PFS or OS.In patients treated with angiogenesis inhibitors (bevacizumab, sunitinib, pazopanib, or temsirolimus), the relative change in BV from baseline to week 5 using 25th percentile as the cutoff was associated with PFS (5.6 vs 24.8 months, P = 0.001) and OS (19.1 months vs not reached, P = 0.008) and from baseline to week 10 with PFS (8.1 vs 16.4 months, P = 0.014) and OS (15.5 months vs not reached, P = 0.002). The relative change in BF from baseline to week 5 using medians as the cutoff was associated with PFS (5.5 vs 14.3 months, P = 0.018) and OS (14.6 vs 31.7 months, P = 0.027). The relative change in BF from baseline to week 10 using 25th percentile as the cutoff was associated with PFS (8.3 vs 46.9 months, P = 0.011) and OS (19.1 vs 53.0 months, P = 0.006). For both parameters, the largest reductions during early treatment were associated with increased PFS and OS.In patients receiving immunotherapy only (interferon alpha and interleukin 2), relative changes in PS between baseline and weeks 5 and 10 were significantly associated with PFS with larger increases associated with longer PFS. In patients receiving angiogenesis inhibitors, the relative changes in PS between baseline and week 10 were significantly associated with PFS and OS with larger reductions associated with favorable outcomes. CONCLUSIONS: In patients with mRCC treated with angiogenesis inhibitors, the largest reductions in BV and BF between baseline and weeks 5 and 10 were associated with favorable outcomes. At baseline, the lowest BV and BF were associated with the poorest outcomes regardless of the subsequent treatment. Early reductions in PS were associated with favorable outcomes for those treated with angiogenesis inhibitors and with poor outcomes for those treated with immunotherapies. PMID- 27513369 TI - Alteration of sex hormone levels and steroidogenic pathway by several low molecular weight phthalates and their metabolites in male zebrafish (Danio rerio) and/or human adrenal cell (H295R) line. AB - Low molecular weight phthalates, such as diethyl phthalate (DEP), benzyl butyl phthalate (BBzP), or diisobutyl phthalate (DiBP), are suspected to disrupt endocrine system. However, their adverse effects on sex steroid hormones and underlying mechanisms are not well-documented. The aim of this study is to investigate the effects of major low molecular weight phthalates (LMWPs), i.e., DEP, BBzP, and DiBP, and their hydrolytic metabolites, on sex steroid hormone system, employing male zebrafish and/or a human adrenocortical carcinoma (H295R) cell. In male zebrafish, 14-day exposure to DEP, BBzP, or DiBP significantly decreased testosterone (T) concentrations. All test compounds significantly up regulated cyp19a gene expression, and down-regulated star and 3beta hsd genes in the male fish. In H295R cell, all test compounds except monoisobutyl phthalate (MiBP) reduced T concentrations and increased E2/T ratio. Gene expression changes in H295R cell, e.g., significant down-regulation of StAR gene and up-regulation of CYP19A gene, supported depressed synthesis of sex hormones in the adrenal cell. Our results show that not only DEP, BBzP, and DiBP, but also their hydrolytic metabolites disrupt sex hormone balances through modulating key steroidogenic genes in the human adrenal cells and in zebrafish. PMID- 27513370 TI - Kinetic study of time-dependent fixation of UVI on biochar. AB - Biochar, a by-product from the production of biofuel and syngas by gasification, was tested as a material for adsorption and fixation of UVI from aqueous solutions. A batch experiment was conducted to study the factors that influence the adsorption and time-dependent fixation on biochar at 20 degrees C, including pH, initial concentration of UVI and contact time. Uranium (UVI) adsorption was highly dependent on pH but adsorption on biochar was high over a wide range of pH values, from 4.5 to 9.0, and adsorption strength was time-dependent over several days. The experimental data for pH>7 were most effectively modelled using a Freundlich adsorption isotherm coupled to a reversible first order kinetic equation to describe the time-dependent fixation of UVI within the biochar structure. Desorption experiments showed that UVI was only sparingly desorbable from the biochar with time and isotopic dilution with 233UVI confirmed the low, or time-dependent, lability of adsorbed 238UVI. Below pH 7 the adsorption isotherm trend suggested precipitation, rather than true adsorption, may occur. However, across all pH values (4.5-9) measured saturation indices suggested precipitation was possible: autunite below pH 6.5 and either swartzite, liebigite or bayleyite above pH 6.5. PMID- 27513368 TI - Lung Function Trajectory in Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplant. AB - RATIONALE: The natural history of lung function in patients with bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplant is poorly characterized. Understanding the trajectory of lung function is necessary for prompt clinical recognition and treatment and also for the rational design of prospective studies. OBJECTIVES: To describe the longitudinal trajectory of lung function parameters, including FEV1, in patients with BOS after hematopoietic cell transplant. METHODS: Subjects with BOS defined by National Institutes of Health consensus guidelines criteria from a recent multicenter prospective trial of combination treatment with fluticasone, azithromycin and montelukast and a retrospective cohort from Fred Hutchinson Cancer Research Center were included. Longitudinal change in FEV1 for each patient was calculated on the basis of available pulmonary function tests in three periods: pre-BOS, from BOS diagnosis to 6 months, and 6-18 months after diagnosis. The effect of treatment on FEV1 trajectory was analyzed by univariate and multivariate linear regression. The Kaplan-Meier method was used to estimate survival. MEASUREMENTS AND MAIN RESULTS: The FEV1 percent predicted value at diagnosis was 46% (interquartile range, 35 57%) for trial participants and 53% (interquartile range, 41-64%) for the retrospective cohort. There was a concomitant mild reduction in FVC, as well as a marked reduction in forced expiratory flow, midexpiratory phase, at diagnosis. While there was individual heterogeneity, the overall FEV1 trajectory was characterized by a marked decline within 6 months prior to BOS diagnosis, followed by stability of FEV1 early after diagnosis and a slow rate of decline beyond 6 months. The effect of the trial medications on FEV1 trajectory after BOS diagnosis was a mean rate of change of 0.92% predicted per month (95% confidence interval, -0.53 to 2.37) compared with the retrospective cohort, but this was not statistically significant. Two-year overall survival rates were 76% and 72% for the study participants and the retrospective cohort patients, respectively. Earlier time to diagnosis after hematopoietic cell transplant and severity of FVC at diagnosis were significantly associated with reduced survival. CONCLUSIONS: The FEV1 trajectory in patients with BOS after hematopoietic cell transplant in a contemporary era of management follows a predominant pattern of rapid FEV1 decline in the 6 months prior to diagnosis, followed by FEV1 stabilization after diagnosis. PMID- 27513371 TI - Nanometer-sized emissions from municipal waste incinerators: A qualitative risk assessment. AB - Municipal waste incinerators (MWI) are beneficial alternatives to landfills for waste management. A recent constituent of concern in emissions from these facilities is incidental nanometer-sized particles (INPMWI), i.e., particles smaller than 1 micrometer in size that may deposit in the deepest parts of the lungs, cross into the bloodstream, and affect different regions of the body. With limited data, the public may fear INPMWI due to uncertainty, which may affect public acceptance, regulatory permitting, and the increased lowering of air quality standards. Despite limited data, a qualitative risk assessment paradigm can be applied to determine the relative risk due to INPMWI emissions. This review compiles existing data on nanometer-sized particle generation by MWIs, emissions control technologies used at MWIs, emission releases into the atmosphere, human population exposure, and adverse health effects of nanometer sized particles to generate a qualitative risk assessment and identify data gaps. The qualitative risk assessment conservatively concludes that INPMWI pose a low to moderate risk to individuals, primarily due to the lack of relevant toxicological data on INPMWI mixtures in ambient particulate matter. PMID- 27513372 TI - Understanding the sorption mechanisms of aflatoxin B1 to kaolinite, illite, and smectite clays via a comparative computational study. AB - In current adsorption studies of biotoxins to phyllosilicate clays, multiply weak bonding types regarding these adsorptions are not well known; the major attractive forces, especially for kaolinite and illite, are difficult to be identified as compared to smectite with exchangeable cations. Here, we discriminated the bonding types of aflatoxin B1 (AFB1) contaminant to these clays by combined batch experiment with model computation, expounded their bonding mechanisms which have been not quantitatively described by researchers. The observed adsorbent-to-solution distribution coefficients (Kd) of AFB1 presented in increasing order of 18.5-37.1, 141.6-158.3, and 354.6-484.7L/kg for kaolinite, illite, and smectite, respectively. Normalization of adsorbent-specific surface areas showed that adsorption affinity of AFB1 is mainly dependent on the outside surfaces of clay aggregates. The model computation and test of ionic effect further suggested that weakly electrostatic attractions ((Si/Al-OH)2?(OC)2) are responsible for AFB1-kaolinite adsorption (Kd, 18.5-37.1L/kg); a moderate electron-donor-acceptor attraction ((CO)2?K+?(O-Al)3) is related to AFB1-illite adsorption (Kd, 141.6-158.3L/kg); a strong calcium-bridging linkage ((CO)2?Ca2+?(O-Si)4) is involved in AFB1-smectite adsorption (Kd, 354.6 484.7L/kg). Changes in Gibbs free energy (DeltaG degrees ) suggested that the computed result is reliable, providing a good reproduction of AFB1-clay interaction. PMID- 27513373 TI - Chlortetracycline removal by using hydrogen based membrane biofilm reactor. AB - In the last years, increasing attention has been paid on the presence of antibiotics in aqueous environments due to their ecological damage and potential adverse effects on organisms. Membrane biofilm reactors (MBfR) have been gained a significant popularity as an advanced wastewater treatment technology in removing of organic micro-pollutants. In this study, the performance of H2-MBfR for simultaneous removal of nitrate and chlortetracycline, formation of transformation products and community analysis of the biofilm grown on the gas permeable hollow fiber membranes was evaluated by considering effect of the hydraulic retention time, surface loadings of target pollutants and H2 pressure. The results showed that the simultaneous chlortetracycline (96%) and nitrate removal (99%) took placed successfully under the conditions of 5h HRT and 2psi H2 pressure. It has been determined that the main elimination process was biodegradation and Betaproteobacteria species was responsible for chlortetracycline degradation. PMID- 27513375 TI - Low dose verapamil as an adjunct therapy for medically refractory epilepsy - An open label pilot study. AB - Previous studies using verapamil as an adjunct therapy to anti-seizure medications have used doses ranging from 120 to 240mg per day. However, despite showing promising results, there was an increased incidence of side effects. The aim of this study is to assess the efficacy and tolerability of low dose verapamil (20mg p.o. tid) as adjunct therapy to patient's anti-seizure medications irrespective of the type or etiology of the epilepsy. In an open label pilot study we enrolled 20 adult patients with history of epilepsy who continued to have a minimum of 2 seizures a month despite being on or having tried maximum tolerated doses of 3 or more standard antiepileptic drugs under the supervision of an epileptologist. 10 of the 19 patients (53%) who continued in the study had >50% reduction in seizure frequency. 2 of the patients (10%) had <50% seizure reduction. The remaining 7 patients (37%) had no reduction in their seizures. There was no discontinuation due to adverse events. P-Glycoprotein is a prototypical drug transporter that has been strongly implicated in drug resistance in epilepsy. Verapamil at a relatively low dose was well tolerated compared to previous studies which used up to 240mg per day and seems to have contributed to a statistically significant improvement in seizure control in patients with medically refractory epilepsy, especially in patients with Lennox Gastaut syndrome. A randomized double blind controlled study at this low dose with larger sample size may be more informative. PMID- 27513374 TI - Compromised GABAergic inhibition contributes to tumor-associated epilepsy. AB - Glioblastoma Multiforme (GBM) is the most common form of primary brain tumor with 30-50% of patients presenting with epilepsy. These tumor-associated seizures are often resistant to traditional antiepileptic drug treatment and persist after tumor resection. This suggests that changes in the peritumoral tissue underpin epileptogenesis. It is known that glioma cells extrude pathological concentrations of glutamate which is thought to play a role in tumor progression and the development of epilepsy. Given that pathological concentrations of glutamate have been shown to dephosphorylate and downregulate the potassium chloride cotransporter KCC2, we hypothesized that glioma-induced alterations in KCC2 in the peritumoral region may play a role in tumor-associated epilepsy. Consistent with this hypothesis, we observe a decrease in total KCC2 expression and a dephosphorylation of KCC2 at residue Ser940 in a glioma model which exhibits hyperexcitability and the development of spontaneous seizures. To determine whether the reduction of KCC2 could potentially contribute to tumor associated epilepsy, we generated mice with a focal knockdown of KCC2 by injecting AAV2-Cre-GFP into the cortex of floxed KCC2 mice. The AAV2-Cre-mediated knockdown of KCC2 was sufficient to induce the development of spontaneous seizures. Further, blocking NKCC1 with bumetanide to offset the loss of KCC2 reduced the seizure susceptibility in glioma-implanted mice. These findings support a mechanism of tumor-associated epilepsy involving downregulation of KCC2 in the peritumoral region leading to compromised GABAergic inhibition and suggest that modulating chloride homeostasis may be useful for seizure control. PMID- 27513376 TI - An Improved Surgical Technique for Pure Laparoscopic Left Hemihepatectomy: Ten Years Experience in a Tertiary Center. AB - BACKGROUND: This study details our experience with an improved surgical technique involving the hepatic pedicle during laparoscopic left hemihepatectomy (LLH). METHODS: We describe an improved laparoscopic technique to extraparenchymally divide the left hepatic pedicle. A retrospective analysis of all of the patients who underwent laparoscopic liver procedures between 2002 and 2012 was conducted. The patients were divided into two groups, an early LLH group (ELLH group) and a recent LLH group (RLLH group), based on the surgical approach used for the left hepatic pedicle. RESULTS: A total of 72 cases of LLH (26 ELLH and 46 RLLH) were identified. The RLLH group exhibited a shorter median operative time, median length of hospital stay, and lower median blood loss compared to the ELLH group (182, 162.5-223.7 versus 232.5, 200-357.5 minutes, P < .01; 5, 4.2-7 versus 7, 6 8.7 days, P < .05; 150, 100-257.5 versus 300, 200-337.5 mL, P < .05, respectively). No perioperative mortality was observed. CONCLUSIONS: This study confirms that our improved surgical technique for LLH is practical, safe, and effective. The main advantage of this method compared to other techniques is the possibility of attaining rapid and precise control of vascular inflow, thus facilitating LLH. PMID- 27513377 TI - A Daily Diary Analysis of Condom Breakage and Slippage During Vaginal Sex or Anal Sex Among Adolescent Women. AB - BACKGROUND: Adolescent women are disproportionately impacted by the adverse outcomes associated with sexual activity, including sexually transmitted infections (STI). Condoms as a means of prevention relies on use that is free of usage failure, including breakage and/or slippage. This study examined the daily prevalence of and predictors of condom breakage and/or slippage during vaginal sex and during anal sex among adolescent women. METHODS: Adolescent women (N = 387; 14 to 17 years) were recruited from primary care clinics for a longitudinal cohort study of STIs and sexual behavior. Data were daily partner-specific sexual diaries. Random intercept mixed-effects logistic regression was used to estimate the fixed effect of each predictor on condom breakage/slippage during vaginal or during anal sex (Stata, 13.0), adjusting model coefficients for the correlation between repeated within-participant diary entries. RESULTS: Condom slippage and/or breakage varied across sexual behaviors and was associated with individual specific (eg, age and sexual interest) and partner-specific factors (eg, negativity). Recent behavioral factors (eg, experiencing slippage and/or breakage in the past week) were the strongest predictors of current condom slippage and/or breakage during vaginal or anal sex. CONCLUSIONS: Factors associated with young women's condom breakage/slippage during vaginal or during anal sex should be integrated as part of STI prevention efforts and should be assessed as part of ongoing routine clinical care. PMID- 27513378 TI - Increased Partner Risk Characteristic Among Adolescents Using Alcohol In the Moment. AB - BACKGROUND: Alcohol is a recognized risk factor for sexually transmitted diseases acquisition, but the mechanism is unclear. Potentially, adolescents using alcohol in the 2 hours before sex (in-the-moment use) have riskier sexual partners. METHODS: We used multivariable logistic regression to examine the association between in-the-moment alcohol use and partner risk characteristics reported for the most recent sex among primarily 17- to 18-year-old adolescents originally recruited from a representative sample of Chicago public elementary schools. We created 3 composite partner risk profiles: partner familiarity risk (casual and unexpected), partner context risk (age discordance and met in public), and overall risk using all measures except partner alcohol use. RESULTS: Teens who reported any in-the-moment alcohol use were more likely than nondrinking teens to report casual (adjusted odds ratio [AOR], 3.2; 95% confidence interval [95% CI], 2.1-4.9), unexpected (AOR, 1.6; 95% CI, 1.0-2.5), age discordant (AOR, 3.0; 95% CI, 2.0-4.6), or met in public partners (AOR, 1.4; 95% CI, 1.0 to 2.1). For each composite measure, the number of partner risk characteristics reported increased linearly with the percent of teens drinking in the moment (Cochran-Armitage trend, P < 0.0001). Compared with zero characteristics, in-the-moment alcohol use was associated with increased odds of reporting 1 (AOR, 2.8; 95% CI, 1.7-4.5), 2 (AOR, 4.6; 95% CI, 2.7, 7.6), or 3 to 4 characteristics (AOR, 7.1; 95% CI, 3.3 15.3). CONCLUSIONS: Our findings expand the link between in-the-moment alcohol use and partner risk reported in prior studies to encompass adolescents' general sexual experiences and additional partner characteristics including the highly associated composite characteristics. PMID- 27513379 TI - Cost-Effectiveness of Dual Antimicrobial Therapy for Gonococcal Infections Among Men Who Have Sex With Men in the Netherlands. AB - BACKGROUND: In response to the rising threat of resistance to first-line antibiotics for gonorrhea, international guidelines recommend dual antimicrobial therapy. However, some countries continue to recommend monotherapy. We assess the cost-effectiveness of dual therapy with ceftriaxone and azithromycin compared with monotherapy with ceftriaxone, for control of gonorrhea among men who have sex with men in the Netherlands. METHODS: We developed a transmission model and calculated the numbers of new gonorrhea infections, consultations at health care specialists, tests, and antibiotic doses. With these numbers, we calculated costs and quality-adjusted life-years (QALY) with each treatment; and the incremental cost-effectiveness ratio (ICER) of dual therapy compared to monotherapy. The impact of gonorrhea on human immunodeficiency virus transmission was not included in the model. RESULTS: In the absence of initial resistance, dual therapy can delay the spread of ceftriaxone resistance by at least 15 years, compared to monotherapy. In the beginning, when there is no resistance, dual therapy results in high additional costs, without any QALY gains. When resistance spreads over time, the additional costs of dual therapy decline, the gained QALYs increase, the ICER drops off and, after 50 years, falls below &OV0556;20,000 per QALY gained. If azithromycin resistance is initially prevalent, resistance to the first-line treatment rises almost equally fast with both treatment strategies and the ICER remains extremely high. CONCLUSIONS: Compared with ceftriaxone monotherapy, dual therapy with ceftriaxone and azithromycin can considerably delay the spread of ceftriaxone resistance, but may only be cost-effective in the long run and in the absence of initial resistance. PMID- 27513380 TI - Deja vu? A Comparison of Syphilis Outbreaks in Houston, Texas. AB - BACKGROUND: After reaching an all-time low in 2000, syphilis incidence in the United States has increased as the burden shifted from heterosexuals to men who have sex with men (MSM). Houston, Texas, experienced 2 outbreaks of syphilis during this transformation in trends. Further evaluation is necessary to determine if these outbreaks occurred among the same subpopulations. METHODS: Surveillance data collected on all reported infectious syphilis cases in Houston from 1971 to 2013 were analyzed. Trends in incidence among MSM and human immunodeficiency virus-positive Houston residents were examined. Peak syphilis years subsequent to 1999, years 2007 and 2012, were compared to determine if outbreaks arose in distinctive subpopulations. Categorical variables between these years were compared using chi-square and Fisher's exact tests, whereas further associations between the years were evaluated using multivariable logistic regression. RESULTS: Incidence among MSM was 20.9 to 32.1 times higher than other men from 2005 to 2013. After adjusting for covariates, cases in 2012 were significantly more likely to be Hispanic (adjusted odds ratio [AOR] = 1.61; 95% confidence interval [95% CI], 1.03-2.53), reported meeting partners via the Internet (AOR, 1.74; 95% CI, 1.18-2.58), and engaged in anonymous sex (AOR, 1.92; 95% CI, 1.40-2.63) in comparison to cases in 2007. CONCLUSIONS: We found marked disparities of syphilis by subpopulation in Houston. Herein, we present evidence that outbreaks have been distinct in a major southern city with a high burden of syphilis. PMID- 27513381 TI - Full House: A Retrospective Analysis of High Sexually Transmitted Infection Prevalence among Adult Film Actors at a Singular Residence. AB - BACKGROUND: During a routine human immunodeficiency virus (HIV) investigation, Florida Department of Health staff identified a house (house A) in which over 150 individuals had resided at least briefly. Further investigation revealed that house A is used by the producer of a small adult film production company to board his actors. This report describes sexually transmitted infection (STI) prevalence among male actors in gay adult films residing in a common Florida residence. METHODS: LexisNexis Accurint was used to identify house A residents since October 2002 when the producer arrived. Information on STIs and interview data were obtained from Florida's STI surveillance system. An infection was considered to be associated with residence in house A if the date of diagnosis occurred 6 months before an individual's residence start date through 6 months after his residence end date. RESULTS: Excluding the producer, 150 men resided in house A starting from September 2003 to July 2015. Forty-six individuals had a reported case of HIV, syphilis, gonorrhea, and/or chlamydia with 92 infections total. Forty-two (46%) infections among 24 men were considered associated with residence in house A. CONCLUSIONS: LexisNexis Accurint was a useful tool for identifying house A residents, a highly mobile and highly sexually active population. There is a high prevalence of STIs among residents, but it is unclear where transmission is occurring. Settings like house A are good candidates for HIV pre exposure prophylaxis and active STI screenings and may be an opportunity for public health officials to intervene in high-risk groups to reduce STI rates in the community. PMID- 27513382 TI - Earlier Detection of Hepatitis C Virus Infection Through Routine Hepatitis C Virus Antibody Screening of Human Immunodeficiency Virus-Positive Men Who Have Sex With Men Attending A Sexually Transmitted Infection Outpatient Clinic: A Longitudinal Study. AB - BACKGROUND: In 2007, routine hepatitis C virus (HCV) antibody testing was introduced for men who have sex with men (MSM) with a human immunodeficiency virus (HIV)-positive or unknown status attending a Dutch sexually transmitted infection (STI) outpatient clinic. We evaluated whether this screening resulted in additional and earlier HCV diagnoses among MSM who also attend HIV clinics. METHODS: At first STI consultation, HIV-positive MSM and MSM opting-out of HIV testing (HIV-status-unknown) were tested for HCV antibodies (anti-HCV). During follow-up consultations, only previously HCV-negative men were tested. Retrospectively, STI clinic and HIV clinic HCV diagnosis dates were compared. RESULTS: One hundred twelve (6.4%) of 1742 (95% confidence interval [CI], 5.3 7.6%) HIV-positive and 3 (0.7%) of 446 (95% CI, 0.2-2.0%) HIV-status-unknown MSM tested anti-HCV-positive at first consultation. During follow-up consultations, 32 HIV-positive (incidence HCV-positive: 2.35/100 person years (PY) (95% CI, 1.66 3.33)) and 0 (1-sided, 97.5% CI, 0.0-3.76) HIV-status-unknown MSM became anti-HCV positive. Four (11.8%) of 34 HIV-positive MSM notified by their sexual partner of HCV tested anti-HCV-positive.Of 163 HIV-positive MSM with HCV antibodies, 78 reported a history of HCV. HCV diagnosis data at the HIV clinic was requested for the remaining 85 MSM and available for 54 MSM. Of these 54 MSM, 28 (51.9%) had their first HCV diagnosis at the STI clinic, of whom 7 concurrently with HIV. At their next scheduled HIV clinic consultation, 3 HCV cases probably would have been missed. CONCLUSIONS: The introduction of routine anti-HCV testing at the STI outpatient clinic resulted in additional and earlier HCV detection among HIV positive MSM. Testing should be continued among HIV-positive MSM, at least for those not (yet) under the care of an HIV clinic and those notified of HCV by their sexual partner. PMID- 27513383 TI - Attitudes and Willingness to Assume Risk of Experimental Therapy to Eradicate Genital Herpes Simplex Virus Infection. AB - BACKGROUND: Current treatment of genital herpes is focused on ameliorating signs and symptoms but is not curative. However, as potential herpes simplex virus (HSV) cure approaches are tested in the laboratory, we aimed to assess the interest in such studies by persons with genital herpes and the willingness to assume risks associated with experimental therapy. METHODS: We constructed an anonymous online questionnaire that was posted on websites that provide information regarding genital herpes. The questions collected demographic and clinical information on adults who self-reported as having genital herpes, and assessed attitudes toward and willingness to participate in HSV cure clinical research. RESULTS: Seven hundred eleven participants provided sufficient responses to be included in the analysis. Sixty-six percent were women; the median age was 37 years, and the median time since genital HSV diagnosis was 4.7 years. The willingness to participate in trials increased from 59.0% in phase 1 to 68.5% in phase 2, and 81.2% in phase 3 trials, and 40% reported willingness to participate even in the absence of immediate, personal benefits. The most desirable outcome was the elimination of risk for transmission to sex partner or neonate. The mean perceived severity of receiving a diagnosis of genital HSV-2 was 4.2 on a scale of 1 to 5. CONCLUSIONS: Despite suppressive therapy available, persons with genital herpes are interested in participating in clinical research aimed at curing HSV, especially in more advanced stages of development. PMID- 27513384 TI - Higher HPV16 and HPV18 Penile Viral Loads Are Associated With Decreased Human Papillomavirus Clearance in Uncircumcised Kenyan Men. AB - BACKGROUND: Whether higher penile human papillomavirus (HPV) viral load is associated with a lower rate of HPV clearance remains unknown. OBJECTIVES: We examined the association between penile HPV16 and HPV18 viral load and subsequent HPV clearance in uncircumcised Kenyan men. STUDY DESIGN: Participants were human immunodeficiency virus (HIV)-seronegative, sexually active, 18- to 24-year-old men randomized to the control arm of a male circumcision trial in Kisumu, Kenya. Men provided exfoliated penile cells from two anatomical sites (glans/coronal sulcus and shaft) every 6 months for 2 years. GP5+/6+ polymerase chain reaction was used to identify 44 HPV-DNA types. Human papillomavirus viral load testing was conducted using a LightCyler real-time polymerase chain reaction assay; viral load was classified as high (>250 copies/scrape) or low (<=250 copies/scrape), for nonquantifiable values. The Kaplan-Meier method and Cox regression modeling were used to examine the association between HPV viral load and HPV clearance. RESULTS: A total of 1097 men, with 291 HPV16 and 131 HPV18 cumulative infections over 24 months were analyzed. Human papillomavirus clearance at 6 months after first HPV detection was lower for high versus low viral load HPV16 infections in the glans (adjusted hazard ratio [aHR], 0.65; 95% confidence interval [CI], 0.46 0.92)] and shaft (aHR, 0.44; 95% CI, 0.16-0.90), and HPV18 infections in the glans (aHR, 0.05; 95% CI, 0.01-0.17). DISCUSSION: High versus low HPV viral load was associated with a reduced HPV clearance for HPV16 infections in the glans and shaft, and for HPV18 infections in the glans, among young uncircumcised men. Reduced clearance of high viral load HPV16 and HPV18 infections in men may increase HPV transmission to their female partners as well as enhance the development of penile lesions in comparison to men with low viral load HPV infections. PMID- 27513386 TI - A Case of Reactive Arthritis Associated With Lymphogranuloma Venereum Infection in a Woman. AB - We report the first case of reactive arthritis associated with lymphogranuloma venereum (LGV) in an Italian human immunodeficiency virus-negative woman with urogenital and rectal Chlamydia trachomatis L2 serovar infection. The LGV associated arthritis has to be considered even when classic symptoms of arthritis are missing and in case of asymptomatic or cryptic LGV localizations. PMID- 27513385 TI - Macrolide Resistance in Treponema pallidum Correlates With 23S rDNA Mutations in Recently Isolated Clinical Strains. AB - BACKGROUND: High rates of 23S rDNA mutations implicated in macrolide resistance have been identified in Treponema pallidum samples from syphilis patients in many countries. Nonetheless, some clinicians have been reluctant to abandon azithromycin as a treatment for syphilis, citing the lack of a causal association between these mutations and clinical evidence of drug resistance. Although azithromycin resistance has been demonstrated in vivo for the historical Street 14 strain, no recent T. pallidum isolates have been tested. We used the well established rabbit model of syphilis to determine the in vivo efficacy of azithromycin against 23S rDNA mutant strains collected in 2004 to 2005 from patients with syphilis in Seattle, Wash. METHODS: Groups of 9 rabbits were each infected with a strain containing 23S rDNA mutation A2058G (strains UW074B, UW189B, UW391B) or A2059G (strains UW228B, UW254B, and UW330B), or with 1 wild type strain (Chicago, Bal 3, and Mexico A). After documentation of infection, 3 animals per strain were treated with azithromycin, 3 were treated with benzathine penicillin G, and 3 served as untreated control groups. Treatment efficacy was documented by darkfield microscopic evidence of T. pallidum, serological response, and rabbit infectivity test. RESULTS: Azithromycin uniformly failed to cure rabbits infected with strains harboring either 23S rDNA mutation, although benzathine penicillin G was effective. Infections caused by wild type strains were successfully treated by either azithromycin or benzathine penicillin G. CONCLUSIONS: A macrolide resistant phenotype was demonstrated for all strains harboring a 23S rDNA mutation, demonstrating that either A2058G or A2059G mutation confers in vivo drug resistance. PMID- 27513387 TI - Human Immunodeficiency Virus Testing Practices and Interest in Self-Testing Options Among Young, Black Men Who Have Sex With Men in North Carolina. AB - BACKGROUND: Young, black men who have sex with men (YBMSM) experience disproportionately high human immunodeficiency virus (HIV) incidence in the United States. Relative to other at-risk populations, less is known about their HIV testing behaviors and preferences regarding self-testing. METHODS: We used an online survey to investigate testing practices and interest in self-testing among HIV-uninfected, 18- to 30-year-old YBMSM in North Carolina. RESULTS: From July 2014 to March 2015, 212 completed the survey; median age was 24 years. Among 175 (83%) who had ever been tested, 160 (91%) reported testing in the prior year, 124 (71%) tested at least every 6 months, and 71 (40%) tested at least quarterly. About three quarters (77%; n = 164) were aware of HIV self-testing; 35 (17%) had ever purchased rapid (n = 27) or dried blood spot-based (n = 14) kits. Participants aware of kits had greater intention to test in the next 6 months, were more likely to have income for basic necessities and to ask sex partners about HIV status, and were less likely to have a main sex partner or to have had transactional sex. Among 142 participants at least somewhat likely to self-test in the future, convenience (35%), privacy (23%), and rapid result delivery (18%) were the principal motivators. CONCLUSIONS: Eight of every 10 YBMSM have ever been tested for HIV, but intertest intervals remain unacceptably long for many. Awareness of and interest in self-testing is substantial, but few have used this method. Expanded use of self-tests could help increase the frequency of HIV testing in this epidemiologically important population. PMID- 27513388 TI - Emergency department visits caused by adverse drug reactions: results of aTurkish university hospital. AB - BACKGROUND/AIM: We aimed to evaluate adverse drug reaction (ADR)-related emergency department (ED) visits in the ED of the Dokuz Eylul University Hospital prospectively. MATERIALS AND METHODS: Patients who were admitted to the ED during 1-week periods of four different seasons between July 2010 and April 2011 were enrolled. Demographics of patients, previous ADR history, clinical progress, and outcomes were recorded. Causality assessment was done according to World Health Organization Uppsala Monitoring Centre categories. ADRs were categorized as certain, probable, or possible. RESULTS: Patients who were on medications (26.5%, n = 1838) were evaluated for ADR-related ED admissions. ADRs accounted for 5.9% of cases (n = 108). The most frequently affected systems were the gastrointestinal (35.2%, n = 38), dermatological (23.1%, n = 25), and hematological (10.2%, n = 11) systems (7.4%, n = 8). The most common causes of ADRs were antiinfectives (31.6%, n = 33). Amoxicillin, Coumadin, and paracetamol were the most common medications that caused ADRs. CONCLUSION: Nearly 6% of the admissions were ADR-related. ADRs should always be considered when patients who are on medication are admitted to the ED. Multicenter epidemiologic studies are required to know the real rates of ADR cases in EDs in Turkey. PMID- 27513389 TI - Evaluation of brainstem auditory evoked potentials and their relationshipwith levels of thyroid autoantibodies in patients with vitiligo. AB - BACKGROUND/AIM: Vitiligo is a common depigmenting disorder. The damage can also occur in similar ways to melanocytes within other organs. We evaluated the brainstem and auditory pathway functions by evaluating brainstem auditory evoked potentials (BAEPs) and whether there is any relationship between auditory functions and autoimmunity. MATERIALS AND METHODS: Forty patients with vitiligo and 20 healthy volunteers were enrolled. Thyroid functions and autoantibodies were examined and BAEP tests were assessed by a neurologist. RESULTS: Antithyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TGA) antibody positivity was higher in the patient group (P < 0.05). A negative correlation was detected between anti-TPO and lead III, IV, and V latency and I-III interpeak latency (IPL) of the right ear together with lead IV latency and I-V IPL of the left ear in the patient group. When each BAEP parameter was compared between the two groups, more abnormalities were detected in the V latency and III-V IPL of the left ear together with IV and V latency of the right ear. CONCLUSION: In this study the presence of a correlation between increased anti-TGA and anti-TPO levels and BAEP parameters may be related to an autoimmune-mediated mechanism. However, further studies are needed to be performed in a large patient series. PMID- 27513390 TI - Health-related behaviors and nutritional status of adolescents who study asboarders and day-students. AB - BACKGROUND/AIM: Boarders and day-students study together in regional boarding schools. This study was carried out to compare the health and nutritional status of boarders and day-students who study at regional boarding schools in Turkey. MATERIALS AND METHODS: A total 634 boarders and 492 day-students in the 4th-8th years of nine boarding schools in Giresun Province of Turkey were included. A questionnaire including 49 questions about sociodemographic characteristics and health and nutritional status was completed by the students. Height and weight measurements of the students were also taken. The chi-square test was used for statistical analyses. RESULTS: The boarders evaluated their health status as worse than the day-students. The proportion of the students having three meals a day was higher among the boarders than the day-students. According to BMI values, 11% of the boarders were evaluated as underweight, 77% as normal, 9.5% as overweight, and 2.5% as obese. These proportions were respectively 15.5%, 67.3%, 12.8%. and 4.5% for the day-students. CONCLUSION: The boarders have more regular diets and the proportion of normal-weighed boarders was higher than that of the day-students. However, they perceived their health as worse than the day-tudents. PMID- 27513391 TI - MEFV mutations in Iranian Azari Turkish patients with Henoch-Schonlein purpura. AB - BACKGROUND/AIM: The aim of the current study was to screen the rate of MEFV mutations in Henoch-Schonlein purpura (HSP) and to investigate the association of these mutations plus clinical symptoms with HSP disease in the Iranian Azari Turkish ethnic group. MATERIALS AND METHODS: The study groups included 40 unrelated HSP patients and 200 apparently healthy people without any kind of inflammatory diseases as a control group. Molecular screening was performed for eight main mutations, namely M694V, M694I, M680I, V726A, E148Q, R761H, P396S, and R408Q, using polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), and sequencing. RESULTS: Out of the 40 studied patients, 27 subjects (67.5%) did not show any mutation, whereas 10 patients (25%) were heterozygotes for one of the following mutations: M694V, M680I, V726A, E148Q. Moreover, three patients (7.5%) were compound heterozygotes for P369S and R408Q. The significant differences between the patient and control groups for M680I, V726A, E148Q, P396S, and R408Q were P = 0.0043, P = 0.0324, P = 0.0145, P = 0.0043, and P = 0.0043, respectively. Furthermore, no significant difference in clinical manifestations was observed between the two groups of patients with and without mutations. CONCLUSION: Based on the results, MEFV mutations could be considered effective genetic factors for development of HSP in the Iranian Azari Turkish ethnic group. PMID- 27513392 TI - Causes of open fractures: orthopaedic injuries related to home-made agricultural vehicles in the eastern Black Sea region of Turkey. AB - BACKGROUND/AIM: Small vehicles known locally as pat-pats, which are used in agricultural work, are forbidden in traffic. The inherent instability of the vehicle may result in accidents, both on farmland and in traffic. The aim of this study was to evaluate orthopaedic injuries related to pat-pats. MATERIALS AND METHODS: Patients hospitalised for pat-pat accidents in two central hospitals in Samsun between December 2006 and October 2013 were scanned using ICD codes. A total of 46 patients with orthopaedic injuries (43 male, 3 female) with a mean age of 36 +/- 13.3 years were evaluated. RESULTS: The most injured age group was between 10 and 49 years (n = 40, 87%), and accidents occurred most in summer (n = 30, 65%). Open fractures were determined in 42 (91%) patients. Amputation was necessary in 4 (8%) patients. The hospitalisation period was a mean of 17.1 +/- 14 days. A statistically significant relationship was determined between open fracture type and the hospitalisation period (P < 0.001). CONCLUSION: As most of the orthopaedic injuries related to home-made agricultural machines are open fractures, it is important to guard against these types of injuries. The regulations that these machines are not used in traffic should be enforced and safer practices should be applied for use in agriculture. PMID- 27513393 TI - Fluctuations of state anxiety, spinal structure, and postural stabilityacross the menstrual cycle in active women. AB - BACKGROUND/AIM: To investigate differences in state anxiety, spinal posture and mobility, postural competency, and stability across the menstrual cycle in active women. MATERIALS AND METHODS: Thirteen physically active women (18-25 years) with a regular menstrual cycle were recruited. Anxiety with the Spielberger State Trait Anxiety Inventory; spinal posture, mobility, and competency with a Spinal Mouse device (Idiag, Fehraltorf, Switzerland); and postural stability with a Biodex Balance System SD (Biodex Medical Systems, Inc., Shirley, NY, USA) were evaluated across phases of the menstrual cycle. RESULTS: No significant differences were observed between phases of the menstrual cycle for state anxiety, spinal posture, mobility, or competency (P > 0.05). No differences were found for static postural stability (P > 0.05); however, a significant difference was detected in dynamic postural stability within three phases of the menstrual cycle (P < 0.05). The highest values of overall stability, anterior-posterior and mediolateral indexes were at menses; the lowest values were at the midluteal phase. CONCLUSION: State anxiety, spinal posture, mobility, and postural competence did not change across the menstrual cycle. However, dynamic stability declined in menses. Improving awareness of dynamic stability impairment during menses may be important toward injury prevention in active women. PMID- 27513394 TI - The relationship between blood urea nitrogen levels and metabolic, biochemical, and histopathologic findings of nondiabetic, nonhypertensive patients with nonalcoholic fatty liver disease. AB - BACKGROUND/AIM: Nonalcoholic fatty liver disease (NAFLD) is known as the most common cause of chronic liver disease. It is accepted that the leading cause of death in patients with NAFLD is from coronary events. Blood urea nitrogen (BUN) was used as a prognostic indicator for cardiovascular disease. We aimed to investigate the relationship between BUN levels and metabolic, biochemical, and histopathologic findings of nondiabetic patients with NAFLD. MATERIALS AND METHODS: A total of 195 male patients with biopsy proven NAFLD and 82 healthy controls with normal liver and renal function tests and normal abdominal ultrasonography were enrolled in the study. BUN levels were reviewed retrospectively. RESULTS: The mean BUN levels of patients and controls were 13.07 (11.3-15.41) and 13.31 (10.97-15.87) mg/dL respectively. Patients were grouped as simple steatosis (n = 33, 16.9%), borderline nonalcoholic steatohepatitis (n = 64, 32.8%), and nonalcoholic steatohepatitis (n = 98, 50.3%), and the BUN levels of the histologic subgroups were 13.14 +/- 2.89, 14.34 +/- 3.04, and 13.71 +/- 3.21 mg/dL, respectively. We could not find any differences between the patient group and control group with respect to BUN levels. CONCLUSION: Our findings showed that there was no relationship between BUN levels and metabolic, biochemical, and histopathologic findings of patients with NAFLD. Further investigations, including in patients with late stages of NAFLD, are required. PMID- 27513395 TI - An unusual pathology with an undefined etiology:solitary fibrous tumors of the pleura. AB - BACKGROUND/AIM: The aim of the present study was to evaluate the etiology and clinical and pathological behavior of solitary fibrous tumors of the pleura (SFTPs), as well as the most appropriate surgical approach and the results of long-term follow-up of this condition. MATERIALS AND METHODS: Clinical and long term follow-up records of 14 patients who had surgery for SFTP between 2001 and 2014 were reviewed retrospectively. Etiological factors, diagnostic procedures, and clinical courses and outcomes for these patients were studied. RESULTS: Of the 14 patients, 8 were male (57%) and 6 were female (43%) patients. The mean age was 54.14 +/- 10.35 (41-75) years. There was no remarkable common etiological factor. Preoperative diagnosis was achieved only in 2 patients. Predominant symptoms were cough and chest pain. Complete resection was achieved in all patients. Video-assisted thoracic surgery (VATS) was performed in 8 patients. All but one patient were classified as having benign SFTP. The mean follow-up was 58.5 +/- 41.4 (10-132) months and no recurrence was noted in the follow-up. CONCLUSION: These rarely seen tumors of the pleura are usually benign and asymptomatic and their preoperative diagnosis is difficult. Clinical and pathological behavior is still unpredictable and the treatment consists of complete resection. Minimally invasive techniques such as VATS are recommended for surgery if the tumor size is appropriate. PMID- 27513396 TI - The effects of conscious sedation with nitrous oxide/oxygen on cognitive functions. AB - BACKGROUND/AIM: The aim of this study was to investigate the effects of conscious sedation with 40% nitrous oxide/oxygen (N2O/O2) on cognitive functions. MATERIALS AND METHODS: Forty dental patients referred to the sedation unit at Gazi University Faculty of Dentistry Department of Oral and Maxillofacial Surgery received a combination of 40% N2O/O2 inhalation for conscious sedation. Psychometric tests were applied three times: before sedation, during sedation, and at the end of the recovery, for assessing cognitive functions. RESULTS: The results of this study showed that the 40% N2O/O2 combination impaired cognitive functions during the conscious sedation. Recovery of most of the cognitive functions occurred 15 min after sedation. However, in addition to the persistence of 'hypnotic effects' and 'sensations of isolation' during the recovery period, 'motor loss value' showed more cognitive impairment 15 min after sedation than before the sedation period, and, thus, the ability to execute fine motor skills was not totally recovered by then. CONCLUSION: The results of this study could be crucial for informing patients about avoiding attentive activities soon after conscious sedation via 40% N2O/O2. PMID- 27513397 TI - Comparison between the use of saline and seawater for nasal obstruction in children under 2 years of age with acute upper respiratory infection. AB - BACKGROUND/AIM: The effectiveness of isotonic and hypertonic saline solutions used to open the nasal passage and improve clinical symptoms was compared in children under 2 years of age admitted with the common cold. MATERIALS AND METHODS: The study was performed as a randomized, prospective, and double-blind study. The study included 109 children. The children using saline (0.9%) and seawater (2.3%) as nasal drops (the patient group) and the control group (in which nasal drops were not administered) were compared. Seventy-four patients received nasal drops from package A (seawater) in single days and from package B (physiological saline) in double days. RESULTS: The mean age of the patients was 9.0 +/- 3.9 months and the numbers of boys and girls were 65 (59.6%) and 44 (40.4%), respectively. There was no significant difference between Groups A and B in terms of nasal congestion (P > 0.05). However, a significant difference was found between the control group and Groups A and B (P < 0.05). CONCLUSION: Relief was seen in nasal congestion, weakness, sleep quality, and nutrition with the use of both saline and seawater in children with the common cold. Seawater or saline drops may be added to standard treatment protocols. PMID- 27513398 TI - Varicocele: tissue stress in the etiology. AB - BACKGROUND/AIM: It is accepted that red blood cell distribution width (RDW) is a novel prognostic marker that reflects oxidative stress and chronic inflammation. In this study, we aimed to investigate the correlation between RDW and varicocele, the etiology of which has not fully elucidated yet. This study also aimed to study the mean platelet volume (MPV) values of the patient and control group. MATERIALS AND METHODS: RDW and MPV levels were measured in 50 varicocele subjects (group 1) and 48 healthy controls (group 2) from January 2012 to January 2014, retrospectively. RESULTS: MPV levels were significantly higher in group 1 than in group 2 (P < 0.001). Although the relationship was weak, the patients with varicocele had significantly lower RDW values than did the controls (r: 0.24 P = 0.026). Positive correlations were not found between varicocele grade and MPV and RDW values (P < 0.05). CONCLUSION: Higher MPV values are associated with increased odds of developing varicocele. PMID- 27513399 TI - Health promotion lifestyle profile scores are not associatedwith obesity in high school students. AB - BACKGROUND/AIM: Obesity is a cause of preventable morbidity and mortality with an increasing prevalence. Health promoting lifestyle activities maintain or improve an individual's health and in adolescence many habits are configured. The aim of this study was to determine the prevalence of overweight and obesity among adolescents and the relation between obesity and health promoting behaviors. MATERIALS AND METHODS: This is a cross-sectional study including 848 high school students aged 15-17. All students were administered a questionnaire including the Health Promotion Life-Style Profile Scale. Weight and height were measured and body mass index was calculated. Descriptive analysis, Pearson's chi-square test, Kruskal-Wallis and Mann-Whitney U tests, and multivariate logistic regression analysis were used. P < 0.05 was considered statistically significant. RESULTS: Of the included students, 80.8% (n = 685) had normal ranges of body mass index, 10.1% (n = 86) were overweight, and 9.1% (n = 77) were obese. The Health Promotion Life-Style Profile Scale average score was found to be 126.7 +/- 20.4. There was no significant difference between Health Promotion Life-Style Profile Scale and obesity (P = 0.921). CONCLUSION: Adolescence is an era of development when individuals start to implement their own features to life. According to this study adolescents do not perform health promoting lifestyles whether they are obese or not. PMID- 27513400 TI - Comparison of glomerular filtration rate measurements with the two-plasma sample technique using Tc-99m DTPA and other methods in donor candidates for renal transplantation. AB - BACKGROUND/AIM: Accurate measurement of glomerular filtration rate (GFR) in the evaluation of renal functions in potential kidney donors is associated with important outcomes for both the donor and recipient. We intended to determine the efficacy of various methods while estimating GFR in potential living kidney donors. MATERIALS AND METHODS: Fifty-three potential kidney donors (31 females, 22 males; mean age: 50.1 years) were included in this study. GFR was estimated simultaneously using the following methods: Gates' method, Cockcroft-Gault (CG) and modification of diet in renal disease (MDRD) prediction equations, and the two-plasma sample (TPS) technique. Using TPS as the reference method, the estimations of GFR with the other methods were compared with that of TPS. RESULTS: The mean +/- SD GFR was 86.43 +/- 11.37 mL min-1 1.73 m-2 with TPS. GFR values calculated using Gates' method and MDRD 1, MDRD 2, reexpressed MDRD, and CG prediction equations were 105.25 +/- 16.12 mL min-1 1.73 m-2, 114.63 +/- 32.51 mL min-1 1.73 m-2, 113.2 +/- 35.23 mL min-1 1.73 m-2, 104.23 +/- 23.12 mL min-1 1.73 m-2, and 99.35 +/- 20.01 mL min-1 1.73 m-2, respectively. While there was a strong statistically significant correlation between the TPS and Gates' methods, moderate correlation was found between TPS and the MDRD 1, MDRD 2, and reexpressed MDRD prediction equations. CONCLUSION: Our results indicated that the performance of Gates' method in total GFR estimation was better than the prediction equations in potential kidney donors. PMID- 27513401 TI - Plasma lipoprotein(a) levels are associated with the severity of coronaryheart disease in Han Chinese people. AB - BACKGROUND/AIM: The aim of this study was to investigate the association of lipoprotein(a) [Lp(a)] with the severity of coronary heart disease (CHD) in Han Chinese people. MATERIALS AND METHODS: Six hundred and seventy-nine patients with angiographically defined CHD were enrolled in this cross-sectional study. Fasting lipids were measured, and the severity of CHD was quantitatively assessed for each patient according to the number of stenotic coronary branches and the Gensini scoring system. RESULTS: The levels of Lp(a), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol (VLDL-C), and apolipoprotein (apo) B100 increased, while high-density lipoprotein cholesterol (HDL-C) and apoAI decreased significantly with the number of stenotic vessels. The levels of Lp(a) increased and HDL-C and apoAI decreased significantly with the Gensini scores. The logistic regression analyses showed that Lp(a) and HDL-C were independently associated with the number of stenotic coronary vessels after adjusting for age, weight, body mass index, sex, smoking, alcohol consumption, hypertension, diabetes, triglycerides, TC, LDL-C, VLDL-C, apoAI, and apoB100. However, only Lp(a) was independently associated with the Gensini scores after adjustment. CONCLUSION: Our data indicate that Lp(a) might be a useful marker in predicting the severity of coronary heart disease. PMID- 27513402 TI - Kinesiotaping as an alternative treatment method for carpal tunnel syndrome. AB - BACKGROUND/AIM: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy. Conservative treatment choices are not always satisfactory. The aim of this study was to investigate the effect of kinesiotaping (KT) on pain level, grip strength, and functional status compared with that of placebo KT and orthotic device (OD) in patients with CTS. MATERIALS AND METHODS: In this randomized, placebo-controlled study, participants were allocated into one of three groups: an experimental KT group (Group 1), a placebo KT group (Group 2), and an OD group (Group 3). Visual analogue scale (VAS) and Douleur Neuropathique 4 (DN4) scores, dynamometric grip strength measures, and the Boston CTS questionnaire (BQ) were the outcome measures. RESULTS: All groups significantly improved in terms of VAS scores (P < 0.05), DN4 scores (P < 0.05), and BQ scores (P < 0.05). Grip strength improved in Group 3 (P = 0.001). There was a significant difference among the groups with respect to BQ scores (P < 0.05). CONCLUSION: KT application for the treatment of CTS should be an alternative treatment choice. PMID- 27513403 TI - The high prevalence of Encephalitozoon intestinalis in patients receiving chemotherapy and children with growth retardation and the validity of real-time PCR in its diagnosis. AB - BACKGROUND/AIM: The aim of this study was to investigate the presence of Encephalitozoon intestinalis in different patient groups consisting of immunocompromised and immunocompetent individuals. MATERIALS AND METHODS: The stool samples of 100 patients consisting of 25 patients receiving chemotherapy and with acute gastrointestinal complaints, 25 with bone marrow transplant and acute gastrointestinal complaints, 25 with urticaria, and 25 with growth retardation were included in the study. As control groups, 25 subjects without any chronic disease but with acute gastrointestinal complaints and 25 healthy volunteers, making a total of 50 subjects, were included in the study. E. intestinalis was investigated by IFA-MAbs and molecular methods. RESULTS: Forty percent of patients receiving chemotherapy and with acute gastrointestinal complaints, 24% of patients with bone marrow transplant and acute gastrointestinal complaints, 20% of patients with urticaria, 40% of children with growth retardation, and 28% of patients without any chronic disease but with acute gastrointestinal complaints were determined as positive. CONCLUSION: To the best of our knowledge, this is the first report to assess the relationship between E. intestinalis and growth retardation. We think that the reliability of the use of molecular methods, especially real-time PCR, should be improved for the diagnosis of E. intestinalis. PMID- 27513404 TI - Rectal or intramuscular diclofenac reduces the incidence of pancreatitis afterendoscopic retrograde cholangiopancreatography. AB - BACKGROUND/AIM: Acute pancreatitis is the most common adverse event of endoscopic retrograde cholangiopancreatography (ERCP). We aimed to evaluate the efficacy of intramuscular diclofenac sodium for prophylaxis of post-ERCP pancreatitis (PEP) in comparison to the rectal form. MATERIALS AND METHODS: One hundred and fifty consecutive patients who underwent ERCP were enrolled in this single-center, prospective, randomized controlled study. Patients were randomized into three groups. The first group received 75 mg of diclofenac sodium via intramuscular route and the second group received 100 mg of diclofenac sodium rectally 30-90 min before the procedure. The third group served as the control group. Patients were evaluated for post-ERCP pancreatitis with serum amylase levels and abdominal pain 24 h after the procedure. RESULTS: The overall incidence of PEP was 6% (n = 9) and 2% (n = 1) in the intramuscular (IM) and rectal groups, respectively, and 14% in the control group (P = 0.014). Nineteen (12.7%) patients developed post ERCP abdominal pain (8% in IM, 10% in rectal, and 20% in control group; P = 0.154). Twenty-five (16.6%) patients developed post-ERCP hyperamylasemia (10% in IM, 12% in rectal, and 24% in control group; P = 0.03). CONCLUSION: Prophylaxis with diclofenac given rectally or intramuscularly is an effective option for the management of post-ERCP pancreatitis. PMID- 27513405 TI - Macrolide and lincosamide resistance in staphylococcal clinical isolates in Nablus, Palestine. AB - BACKGROUND/AIM: Macrolide and lincosamide antibiotics are used for the treatment of staphylococcal infections, especially for penicillin-allergic patients. In the present study, we evaluate the prevalence of resistance to macrolide and lincosamide antibiotics among staphylococci isolates. MATERIALS AND METHODS: A total of 200 staphylococcal clinical isolates were collected from January 2012 to April 2013. Minimal inhibitory concentrations of erythromycin and clindamycin were determined by agar dilution method. An erythromycin-clindamycin induction test was performed for isolates that were only resistant to erythromycin. Representative erythromycin-resistant isolates were examined for erythromycin resistance genes using PCR. RESULTS: Among staphylococci isolates, resistance frequencies of erythromycin and clindamycin were 65.5% and 20.5%, respectively. Erythromycin resistance was found to be mediated by putative efflux (50.4%) and target site modification (49.6%). Inducible target site modification resistance was detected in 19.1% of erythromycin-resistant isolates. Among the examined 36 staphylococci isolates, msr(A), erm(C), erm(A), and mef(A/E) genes were detected in 55.6%, 30.6%, 25%, and 0%, respectively. CONCLUSION: Results of the current study indicate the presence of high rates of macrolide resistance and inducible phenotypes among staphylococcal isolates. It is also essential to keep in mind variations of resistance rates among various age groups and specimen types. PMID- 27513406 TI - Comparison of the effects of PEEP levels on respiratory mechanics and elimination of volatile anesthetic agents in patients undergoing laparoscopic cholecystectomy; a prospective, randomized, clinical trial. AB - BACKGROUND/AIM: In laparoscopic procedures, intraabdominal carbon dioxide (CO2) insufflation can cause decreased compliance, increased airway resistance, and impaired ventilation-perfusion ratios. We aimed to investigate the effects of intraoperative positive end-expiratory pressure (PEEP) treatment on respiratory dynamics and elimination time of volatile anesthetic agents. MATERIALS AND METHODS: In the present study, 75 ASA I-II patients were randomized into 3 groups to receive 0 cmH2O PEEP (group I), 5 cmH2O PEEP (group II), or 8 cmH2O PEEP (group III). Hemodynamic parameters, peak and plateau inspiratory airway pressures (Ppeak, Pplateau), compliance values, the ratio of the fractions of inspired and expired concentration of sevoflurane (Fi/Fexp sevoflurane) at 1 MAC, times from 1 to 0.3 and 0.1 MAC and values for pulmonary function tests (PFT) were recorded. RESULTS: Ppeak and Pplateau in group III were higher; compliance values in group I and the extent of reduction in postoperative forced vital capacity (FVC) in group III were lower than those in the other groups (P < 0.05). No significant difference was observed between the groups regarding times from 1 to 0.3 MAC and times from 0.3 to 0.1 MAC. CONCLUSION: It was found that 8 cmH2O PEEP increased compliance without clinically significant pulmonary deterioration and that 8 cmH2O PEEP led to less impairment in postoperative PFTs compared to 0 and 5 cmH2O PEEP but had no effect on sevoflurane elimination time. PMID- 27513407 TI - Effect of the application of prophylactic central compartment lymph node dissectionon radioiodine ablation doses in patients with papillary thyroid carcinoma. AB - BACKGROUND/AIM: The aim of this study was to document the effect of the application of prophylactic central compartment dissection on radioiodine ablation activities for papillary thyroid carcinoma. MATERIALS AND METHODS: This retrospective study included 452 (383 females, 69 males; mean age = 46.69 years, min-max: 13-71) patients who received ablative radioiodine activity between April 2010 and December 2014. The histopathological reports of thyroidectomy and the administered radioiodine activity were evaluated. Frequencies of prophylactic central compartment dissection according to T stage of the primary tumor, detection rate of lymph node metastases, and its effect on radioiodine ablation activities were calculated. RESULTS: Prophylactic central compartment dissection was applied for a total of 252 (56%) patients. The T stages of these patients were T1a, T1b, T2, and T3 in 85 (34%), 106 (42%), 41 (16%), and 20 (8%) cases, respectively. The administered radioiodine ablation activity was affected by central compartment lymph node metastases in 112 (44%) patients. While 32 (29%) of these patients had papillary microcarcinoma (T1a), 48 (43%), 20 (18%), and 12 (11%) of them had T1b, T2, and T3 tumors, respectively. CONCLUSION: The application of prophylactic central compartment dissection affects the radioiodine ablation activity in approximately half of patients. This effect is more prominent in T1 stage tumors. PMID- 27513408 TI - Effects of resveratrol on the alterations of cavernosal eNOS and LOX-1 expression in the hypercholesterolemic condition: a preliminary study. AB - BACKGROUND/AIM: The aim of this study was to determine the effects of resveratrol on the alterations of cavernosal eNOS and LOX-1 mRNA expression in the hypercholesterolemic condition. MATERIALS AND METHODS: Twenty-one New Zealand white male rabbits were separated into three groups. Rabbits were fed with a normal dietary intake for the control group and a 2% cholesterol diet for the hypercholesterolemia and resveratrol groups for 6 weeks. Resveratrol 4 mg/kg daily was administered for the resveratrol group. Cavernosal LOX-1 and eNOS mRNA expressions were determined with real-time RT-PCR in all groups. The statistical analysis was performed with the Kruskal-Wallis and Mann-Whitney U tests. RESULTS: We found no difference between mean LOX-1 mRNA expression levels in the three groups. Lower mean eNOS mRNA expression level was determined in the hypercholesterolemia group when compared with the control group (P = 0.011). Mean eNOS mRNA expression level in the resveratrol group was similar to that in the control group but significantly higher than that in the hypercholesterolemia group (P < 0.001). CONCLUSION: This preliminary study demonstrates the beneficial effects of resveratrol on cavernosal eNOS expression. The presence of cavernosal LOX-1 expression was also shown for the first time. Resveratrol may be an alternative option in hypercholesterolemic erectile dysfunction with further studies supporting its beneficial effects on the corpus cavernosum. PMID- 27513409 TI - The efficacy of a through-the-scope sodium phosphate solution with completion colonoscopy on the same day as a salvage option for inadequate bowel cleansing. AB - BACKGROUND/AIM: The aim of this study was to investigate the efficacy of a through- the-scope sodium phosphate solution with completion colonoscopy on the same day as a salvage option for inadequate bowel preparation. MATERIALS AND METHODS: All participants were instructed to eat a low residual diet for 3 days before the scheduled colonoscopy and a clear liquid diet 18 h before the colonoscopy. The patients were asked to take split doses of an oral sennoside solution at 1800 and 2200 in the evening before the colonoscopy. In cases of inadequate bowel preparation detected during routine colonoscopy, a sodium phosphate solution was administered through the scope on the day of the colonoscopy procedure. The degree of bowel cleansing was assessed by the Boston Bowel Preparation Scale (BPS: 0-9). RESULTS: Almost excellent bowel cleansing was obtained with a statistically significant difference between the degree of bowel cleansing before and after the application of the sodium phosphate (Boston BPS: 5.48 +/- 1.01 vs. 8.88 +/- 0.33 respectively, P < 0.001). CONCLUSION: Through-the scope sodium phosphate with completion colonoscopy on the same day was shown to be an efficacious and acceptable method for inadequate bowel preparation. PMID- 27513410 TI - Coexistence of preeclampsia and inherited thrombophilia in Turkish pregnant women. AB - BACKGROUND/AIM: To examine the relationship of inherited thrombophilia and other thrombotic risk factors with preeclampsia (PE) in a population of pregnant Turkish women. MATERIALS AND METHODS: This was a case cross-sectional study in which 70 women with PE and 60 normal pregnant women were studied to find out the frequency of women with risk factors including inherited thrombophilia among preeclamptic cases. RESULTS: Hemoglobin, platelet count, uric acid, vitamin B12, folic acid, copper, homocysteine, plasminogen activator inhibitor-1, fibrinogen, protein S, protein C, activated protein C resistance values show significant differences in women with PE in comparison to women with normal pregnancy. CONCLUSION: There may be a link between inherited thrombophilia and PE, at least in a sample of Turkish pregnant women. We also propose that the association between thrombophilia and PE is stronger than suggested previously. Furthermore, copper is selectively elevated in women with PE as an independent marker. PMID- 27513411 TI - An analysis of the incidence of measles in Turkey since 1960. AB - BACKGROUND/AIM: The aims of this study were to evaluate measles incidence and the effect of elimination strategy interventions on the disease from 1960 to 2014 in Turkey. The administration of measles vaccine started in the rural regions in 1970; it was carried out as a campaign along with the National Vaccine Campaign in 1985, and it has been employed as combined measles, mumps, and rubella under the scope of the Measles Elimination Program (MEP) since 2006 in Turkey. While a dramatic decrease in the reporting of measles was observed between 2000 and 2010, the number of the cases has increased since 2011. MATERIALS AND METHODS: The time series of measles incidence was evaluated for possible structural changes with regression models using dummy variables, autocorrelated with error terms. RESULTS: The incidence of measles showed a statistically significant decline between 1985 and 1988 (P = 0.0072) and between 2005 and 2011 (P < 0.0001). However, a statistically significant increase in incidence was noted after 2013 (P = 0.0008). CONCLUSION: Over the last 54 years, the pattern of measles cases demonstrated a significant decline in incidence. However, the increase in incidence in 2013 should be carefully analyzed and interpreted in terms of the MEP. PMID- 27513412 TI - Reliability and validity of the Turkish version of myastheniagravis-quality of life questionnaire-15 item. AB - BACKGROUND/AIM: The myasthenia gravis-quality of life questionnaire 15 item (MG QOL15) is a validated, short, and easy to use disease-specific quality of life (QOL) tool in myasthenia gravis. Other than Turkish, a lot of versions of the MG QOL15 have been used in different languages in different cultures. Therefore, the aim of this study was to translate and construct a validated and adapted Turkish version of the MG-QOL15 [MG-QOL15(T)]. MATERIALS AND METHODS: After translation, back-translation, and comparison of the 2 English versions of the MG-QOL15, it was tested by 22 monolingual healthy individuals and then 23 patients with clinically stable MG. Afterwards, 11 voluntary patients out of these 23 patients were interviewed for a second time. During the second interview, the MG-QOL15(T) and the 36-item short-form health survey (Turkish version) were administered simultaneously. RESULTS: The MG-QOL15(T) was found to have high internal consistency (1st and 2nd evaluation Cronbach's alphas were 0.958 and 0.928, respectively), test-retest reliability, and concurrent validity. The MG-QOL15(T) was negatively correlated with physical functioning, general health, vitality, and social functioning domains and with the physical and mental composite scores of the SF-36. CONCLUSION: The MG-QOL15(T) is accepted to be a valid, reliable, valuable tool for measuring disease-specific QOL in Turkish patients with MG. PMID- 27513413 TI - Sleep quality and factors affecting sleep in elderly patientswith rheumatoid arthritis in Turkey. AB - BACKGROUND/AIM: Sleep disorders are more common in people with rheumatoid arthritis (RA). We aimed to determine the sleep quality in adult and elderly people with RA and the factors associated with sleep disorders in each group. MATERIALS AND METHODS: The study was conducted with 182 patients (83 elderly and 99 adult patients) diagnosed with RA. Data were collected through a patient identification form including sociodemographic and disease characteristics. The Health Assessment Questionnaire (HAQ) and Pittsburg Sleep Quality Index (PSQI) were used to assess quality of life and sleep. RESULTS: The mean PSQI scores of the elderly group were lower than those of adult subjects (P = 0.055). Patients in remission and those with knee involvement had significantly lower PSQI scores (P < 0.05). Mean PSQI scores of elderly single patients and subjects with sleep disorders and restless leg syndrome were significantly higher (P < 0.05). In elderly subjects, the pain and HAQ scores were positively correlated with the PSQI. CONCLUSION: Sleep quality of elderly rheumatoid arthritis patients was determined to be worse than that of adults; however, the difference was not statistically different. Factors negatively affecting sleep included pain, joints involved, high disease activity, and restless leg syndrome. PMID- 27513414 TI - The effectiveness of a back school program in lowerlimb amputees: a randomized controlled study. AB - BACKGROUND/AIM: A few studies have been carried out in lower limb amputees (LLAs) and they examined the incidence of and reasons for low back pain. The aim of this study was to assess the effectiveness of a back school program in LLAs with mechanical low back pain (MLBP). MATERIALS AND METHODS: Forty male unilateral transfemoral amputees with MLBP were randomly allocated into two groups. A back school program was applied to Group 1 over 2 weeks. A booklet for home use was given to each participant in Group 2. Pain was assessed using a visual analogue scale. Spinal flexibility measurements were obtained. For the assessment of back pain-related disability, the Oswestry Disability Index was used. Patients were assessed at baseline, at month 1, and at month 3. RESULTS: At the month 1 assessment, a reduction in pain intensity and disability, and increase in spinal flexibility measurements were detected in Group 1 only (P < 0.05). At the month 3 assessment, there were improvements in all measured parameters in both groups(P < 0.05). Group 1 had better results in all parameters compared with Group 2. CONCLUSION: The back school program, combined with an exercise program, decreased pain and disability and improved the spinal flexibility significantly in LLAs with MLBP. PMID- 27513415 TI - N-terminal-pro brain natriuretic peptide levels in children with allergic rhinitis. AB - BACKGROUND/AIM: Persistent upper airway obstruction may lead to increased pulmonary arterial pressure (PAP). The aim of this study was to evaluate N terminal pro brain natriuretic peptide (NT-proBNP) concentrations and PAP values in children with allergic rhinitis. MATERIALS AND METHODS: Sixty-six patients with allergic rhinitis and 22 healthy children were prospectively enrolled in this study. Plasma NT-proBNP levels were measured at first admission and after treatment. Simultaneously, echocardiography was done to assess pulmonary arterial hypertension, and rhinitis symptom scores were recorded. RESULTS: The median age of the study group was 9.0 (5.0-17.0) years; 26 were female. PAP was found to be normal in all the patients. There was a negative correlation between age and NT proBNP levels (r = -0.452, P < 0.01). Nasal blockage levels affected NT-proBNP levels mildly (P = 0.067). No significant difference between before and after nasal steroid treatment was observed in NT-proBNP levels. CONCLUSION: These results suggest that NT-proBNP level and PAP may not be affected in children with allergic rhinitis, and primarily this influence may be associated with the severity of nasal obstruction. PMID- 27513416 TI - ILP-2 modeling and virtual screening of an FDA-approved library:a possible anticancer therapy. AB - BACKGROUND/AIM: The members of the inhibitors of apoptosis protein (IAP) family inhibit diverse components of the caspase signaling pathway, notably caspase 3, 7, and 9. ILP-2 (BIRC-8) is the most recently identified member of the IAPs, mainly interacting with caspase 9. This interaction would eventually lead to death resistance in the case of cancerous cells. Therefore, structural modeling of ILP-2 and finding applicable inhibitors of its interaction with caspase 9 are a compelling challenge. MATERIALS AND METHODS: Three main protein modeling approaches along with various model refinement measures were harnessed to achieve a reliable 3D model, using state-of-the-art software. Thereafter, the selected model was employed to perform virtual screening of an FDA approved library. RESULTS: A model built by a combinatorial approach (homology and ab initio approaches) was chosen as the best model. Model refinement processes successfully bolstered the model quality. Virtual screening of the compound library introduced several high affinity inhibitor candidates that interact with functional residues of ILP2. CONCLUSION: Given the 3D structure of the ILP2 molecule, we found promising inhibitory molecules. In addition to high affinity towards the ILP2 molecule, these molecules interact with residues that play pivotal rules in ILP2 caspase interaction. These molecules would inhibit ILP2-caspase interaction and consequently would lead to reactivated cell apoptosis through the caspases pathway. PMID- 27513417 TI - Higher neutrophil to lymphocyte ratio is related to a lower ejectionfraction in bicuspid aortic valve patients. AB - BACKGROUND/AIM: Inflammation plays an important role in the pathophysiology of vascular disease. In this study, we aimed to evaluate the associations of neutrophil to lymphocyte ratio (NLR; an indicator of inflammation) with left ventricular ejection fraction and ascending aorta diameter in patients with a bicuspid aortic valve (BAV). MATERIALS AND METHODS: One hundred and thirty-nine consecutive patients with the diagnosis of BAV were enrolled in the study. Complete blood counts were analyzed for neutrophil and lymphocyte levels and NLR. The subjects were separated into two groups based on their ascending aorta diameter. The patients with ascending aorta diameter equal to or above 3.9 cm were included in group 1 whereas those with ascending aorta diameter below 3.9 cm were included in group 2. RESULTS: When the results were compared, it was demonstrated that there was a positive correlation between NLR and ascending aorta diameter (r: 0.485, P = 0.026), whereas there was a negative correlation between NLR and left ventricular end-diastolic diameter (r: 0.475, P = 0.030), left ventricular end-systolic diameter (r: 0.482, P = 0.027), and left ventricular ejection fraction (r: -0.467, P = 0.033) in BAV patients with ascending aorta dilatation (group 1). CONCLUSION: NLR is associated with ascending aorta diameter and left ventricular ejection fraction in BAV patients with ascending aorta dilatation. PMID- 27513418 TI - Do patients with neurogenic bladder treated with clean intermittentcatheterization need antibacterial prophylaxis? AB - BACKGROUND/AIM: In this study, we investigated the effectiveness of antibiotic prophylaxis (ABP) with respect to the incidence of symptomatic urinary tract infections (UTIs) and evaluated the development of renal scarring in patients treated with clean intermittent catheterization (CIC). MATERIALS AND METHODS: A total of 22 patients were included in the study. The patients were administered ABP in the first year (the ABP-received period) but not in the second year (the ABP-discontinued period). RESULTS: Twenty-eight of all cultures taken in the ABP received period (18.2%) and 25 (16.2%) of the ABP-discontinued cultures were considered to be indicative of symptomatic UTIs (P = 0.65). The multiple antibiotic resistance rate of microorganisms in cultures taken during the ABP discontinued period (47; 30.5%) was lower than that in those taken in the ABP received period (62; 40.3%), (P = 0.07). There was no difference between the ABP received and ABP-discontinued periods with respect to the development of new lesions according to dimercaptosuccinic acid results (P = 0.14). CONCLUSION: Routine ABP usage is not protective against the development of symptomatic UTIs and new lesions in neurogenic bladder patients receiving CIC. Furthermore, the growth of resistant microorganisms increased in the ABP-received period. PMID- 27513419 TI - Transesophageal echocardiography experience in thepediatric age group in a tertiary cardiac center. AB - BACKGROUND/AIM: The aim of this study was to evaluate the transesophageal echocardiography (TEE) findings of pediatric patients in a tertiary center where complex congenital heart surgery and interventional procedures have been performed. MATERIALS AND METHODS: All TEE studies performed between December 2009 and December 2014 were reviewed retrospectively. Patients were divided into 3 groups: perioperative, during interventional procedures, and due to other reasons. Demographic features, transthoracic echocardiography (TTE) reports, TEE reports, change in decision after TEE evaluation, and related complications were recorded. RESULTS: A total of 703 patients who had TEE evaluation were included in the study; 51% were female and 49% were male. The median age was 90 months (2 months to 18 years). TEE was performed perioperatively in 430 patients (61%), during cardiac catheterization-angiography and electrophysiology studies in 181 patients (26%), and due to other reasons in 92 patients (13%). Mismatches between TTE and TEE or changes in decision after TEE evaluation were present in 45 patients (10.4%) who had perioperative TEE, in 10 patients (5.5%) who had TEE during interventional procedures, and 22 patients (24%) who had TEE evaluation due to other reasons. No major complications were detected. CONCLUSION: Information acquired by TEE increases the clarity of future plans for the patient and helps to decrease the mortality and morbidity caused by unnecessary procedures. PMID- 27513420 TI - The effects of pulmonary hypertension on early outcomes inpatients undergoing coronary artery bypass surgery. AB - BACKGROUND/AIM: To investigate the effects of pulmonary hypertension on early clinical variables in patients undergoing coronary artery bypass grafting surgery. MATERIALS AND METHODS: The preoperative echocardiographic data of patients who underwent isolated coronary artery bypass surgery were evaluated retrospectively. A total of 1244 patients were included in the study. The patients were divided into two groups: one group consisted of patients with systolic pulmonary artery pressure (SPAP) values equal to or greater than 30 mmHg (Group 1, n = 184), while the other group consisted of patients with SPAP values below 30 mmHg (Group 2, n = 1060). RESULTS: Early mortality was similar in both groups (0% in Group 1 and 1.2% in Group 2; P > 0.05). Comparison of postoperative data indicated that Group 1 had a higher need for inotropic agent treatment, a longer average duration of ventilation, and a longer average duration of stay in the intensive care unit (P < 0.05). For the other variables, no significant differences were identified between patients with and without pulmonary hypertension (P > 0.05). CONCLUSION: Mild pulmonary hypertension (mean SPAP = 37.7 +/- 8.4 mmHg) was not associated with a significant difference in the mortality of patients undergoing coronary artery bypass grafting. For patients undergoing this type of coronary bypass surgery, lower morbidity and mortality rates can be achieved through comprehensive preoperative examinations and effective perioperative medical procedures. PMID- 27513421 TI - Proliferation and differentiation markers of colorectal adenocarcinomaand their correlation with clinicopathological factors. AB - BACKGROUND/AIM: The purpose of this study was to investigate proliferation and differentiation markers in colorectal adenocarcinoma and their correlation with clinicopathological factors. MATERIALS AND METHODS: Samples were collected from 38 patients with colorectal adenocarcinoma and 10 healthy controls. E-cadherin, carcinoembryonic antigen (mCEA), cyclin B1, vascular endothelial growth factor (VEGF), and erythropoietin (EPO) receptor (EPOR) were examined by immunohistochemistry; VEGF and EPO were examined by real-time PCR. RESULTS: The tumor samples were mostly characterized by large dimension (pT3), moderate level of differentiation (G2), negative lymph node status (N0), and no metastasis. Cyclin B1 and VEGF gene and protein expressions were significantly higher in tumor tissues than in control tissues; E-cadherin expression was significantly decreased in tumor samples and in positive correlation with mCEA. EPO was almost undetectable in tumor tissues of colorectal adenocarcinoma. Significant positive correlation was detected between tumor size and cyclin B1, tumor grade, and lymph node status. CONCLUSION: Decreased expression of EPO, high levels of VEGF and cyclin B1 expression, predominant moderate tumor differentiation, absence of metastasis, and negative lymph node status may suggest low level of aggressiveness, better prognosis, and longer patient survival. PMID- 27513422 TI - RETRACTED ARTICLE: DNA profiling in blood, buccal swabs, and hair follicles of transplantation patients. PMID- 27513423 TI - Correlation of Ki-67 proliferation index and 18-fluorodeoxyglucose uptake in colorectal incidental lesions detected by positron emission tomography-computed tomography. AB - BACKGROUND/AIM: To investigate whether focal high maximum standardized uptake value (SUVmax) determined by 18-fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) imaging is correlated with proliferation index in the colorectal region. MATERIALS AND METHODS: SUVmax values of 31 colorectal neoplasms that were incidentally detected during PET-CT examination were compared to dysplasia degree, histopathologic diagnosis, and immunohistochemical expression of the Ki-67 proliferation marker. RESULTS: Statistically significant correlations were found between SUVmax and Ki-67 proliferation index, dysplasia degree, and histopathologic diagnosis. Median SUVmax value was found to be significantly higher in high-risk lesions than low risk lesions. CONCLUSION: The Ki-67 proliferation index is an indicator of SUVmax in colorectal tract. SUVmax values can predict malignancy and prognosis in this region. Colonoscopy and biopsy should always be performed whenever a focal high FDG uptake is determined incidentally in a patient. PMID- 27513424 TI - The inhibitory effect of bacteriocin produced by Lactobacillus acidophilusATCC 4356 and Lactobacillus plantarum ATCC 8014 on planktonic cells and biofilms of Serratia marcescens. AB - BACKGROUND/AIM: The spread of antibiotic-resistant pathogens has resulted in the need for new treatments. The aim of the present study is to investigate the effect of bacteriocin from Lactobacillus acidophilus ATCC 4356 and Lactobacillus plantarum ATCC 8014 on planktonic and biofilm forms of Serratia marcescens strains. MATERIALS AND METHODS: The direct antagonism of the L. plantarum and L. acidophilus cell-free supernatant on S. marcescens cultures was determined using an optical density assay. The bacteriocin was partial purified by ammonium sulfate precipitation. Its molecular weight was analyzed with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The effect of bacteriocins on the biofilm of S. marcescens strains was then determined with 2,3,5-triphenyl tetrazolium chloride. RESULTS: The purified bacteriocin from L. plantarum ATCC 8014 and partially purified bacteriocin from L. acidophilus ATCC 4356 displayed noticeable inhibitory activity against planktonic and biofilm forms of S. marcescens strains. SDS-PAGE analysis revealed that the apparent molecular weight of bacteriocin from L. planetarium was 63 kDa, and that of bacteriocin from L. acidophilus was 68 or 48 kDa. CONCLUSION: The bacteriocins could be effective compounds to control surface-attached pathogenic bacteria and can be used as therapeutic agents after acceptable in vivo experimentation. PMID- 27513425 TI - Expression of maspin in testis tumors with germ cells andits relation with angiogenesis factors. AB - BACKGROUND/AIM: We aimed to evaluate the importance of maspin expression in testicular tumors with germ cells, its effect on prognosis, and the relation with angiogenesis factors. MATERIALS AND METHODS: The paraffin blocks of the orchiectomy materials of 32 patients who had undergone orchiectomy due to testicular tumors were taken within the scope of the study. The specimens of the cases included in the study group were reexamined under light microscope. RESULTS: While just one maspin-positive sample was found in the seminoma cases, maspin stained positively in 6 of the nonseminoma germ cell tumors (NSGCTs). No statistical difference was found between maspin and tumor stage, size, alpha fetoprotein values, vascular endothelial growth factor, Ki-67, and CD31. A statistically positive correlation was only determined between maspin and p53 (P < 0.001). CONCLUSION: Maspin protein, whose expression in some tumors is accepted as a poor prognostic factor, is also expressed in testicular tumors with germ cells. However, according to our study, it is difficult to say whether this protein is a favorable or poor prognostic factor in testicular tumors and to understand how the effect mechanism works. The positive correlation between maspin and p53 in the NSGCTs makes us think that maspin might have displayed an effect on the p53 pathway. PMID- 27513426 TI - Effects of resveratrol and cigarette smoking onbone healing: histomorphometric evaluation. AB - BACKGROUND/AIM: The aim of the present study is to investigate the effects of cigarette smoke (CS) and simultaneous application of resveratrol on bone healing histomorphometrically and to evaluate the effects of resveratrol on negative effects of CS. MATERIALS AND METHODS: For 4 weeks, Sprague Dawley rats were exposed to cigarette smoke at the equivalent of 6 cigarettes per day. After this period, monocortical defects were created in femurs by a trephine bur on day 28. Starting from the day of defect creation to the 28th postoperative day, rats were given 20 mg/kg body weight resveratrol. Histomorphometric examination of the number of osteoblasts and osteoclasts, as well as new bone area, was conducted. RESULTS: Investigations were carried out on 33 rats. Differences between osteoblast numbers in the control and CS groups were significant, and CS caused a reduction in the number of osteoblasts. Areas of new bone formation in the resveratrol and control groups were higher than in the smoking and smoking+resveratrol groups. CONCLUSION: Smoking appeared to have adverse effects upon bone healing and resveratrol administration helped to reduce these effects. PMID- 27513427 TI - Effects of 1-(2-trifluoromethylphenyl)-imidazole (TRIM) on receptor-independent and -dependent contractile responses in rat aorta. AB - BACKGROUND/AIM: This study investigates whether 1-(2-trifluoromethylphenyl) imidazole (TRIM), originally proposed as a nitric oxide synthase inhibitor and also suggested to be an inhibitor of store-operated calcium entry in mouse anococcygeal muscle, inhibits receptor-independent and -dependent responses in rat thoracic aorta. MATERIALS AND METHODS: Cyclopiazonic acid- and serotonin induced vascular responses were investigated in aortic segments isolated from male Sprague Dawley rats using isolated tissue experiments. Changes in intracellular calcium levels were also monitored via front surface fluorescence measurements in fura-2-loaded embryonic rat vascular smooth muscle cell line A7r5. RESULTS: TRIM inhibited serotonin-mediated vascular contractions without affecting cyclopiazonic acid-induced responses. In addition, TRIM caused a nonlinear rightward shift in the serotonin concentration-response curve, possibly via serotonin receptor modulation. CONCLUSION: TRIM may have an impact on investigation of tissue-specific receptor-independent and -dependent vascular responses. It may also be used as a lead compound in the development of selective serotonin receptor modulators. PMID- 27513428 TI - The effect of low-dose methotrexate on autologous fat graft survival. AB - BACKGROUND/AIM: The survival of autologous fat graft tissue is dependent on various factors such as vascularization and inflammation. The aim of the present study was to evaluate the possible beneficial effects of low-dose methotrexate (LD-MTX) on fat graft volume and survival. MATERIALS AND METHODS: A total of 13 male Wistar albino rats were divided into two groups, a control group and an LD MTX group. An autologous fat graft obtained from the inguinal region of each rat was transferred to its back. LD-MTX was administered intraperitoneally in the LD MTX group once a week for 4 weeks after the surgical procedure. The control group underwent surgery but was not administered MTX. Fat grafts were harvested for analyses. RESULTS: The results showed that 2 months postoperatively the fat graft weights of the control and LD-MTX groups were not significantly different. In addition, the vascularity of the grafts was higher in the LD-MTX group than it was in the control group. The mean lipid peroxidation levels were essentially the same in the two groups, but myeloperoxidation was significantly lower in the LD MTX group than it was in the other group. CONCLUSION: The results showed that LD MTX administration may not preserve the quality and volume of transplanted fat tissue in rats. PMID- 27513429 TI - The beneficial effects of almond (Prunus amygdalus Batsch) hull on serum lipid profile and antioxidant capacity in male rats. AB - BACKGROUND/AIM: Almond hull is produced in high amounts and mostly used as livestock feed. This study was designed to examine the impact of almond hull powder (AHP) administration on lipid profile and antioxidant activities in plasma and liver in hyperlipidemic rats. MATERIALS AND METHODS: As the first step, the antioxidant capacity and radical scavenging activity of AHP were determined using calorimetric methods. Then 36 adult male Wistar rats were randomly divided into 6 groups: group 1 with oral administration of 10% AHP, group 2 with oral administration of 20% AHP, group 3 with oral administration of 30% AHP, group 4 as a positive control with a high cholesterol diet, group 5 as a negative control with a normal diet, and group 6 as a sham group with a normal diet and 20% AHP. The rats were fed a hypercholesterolemic diet to create a hyperlipidemia rat model and then they received AHP for 30 days. RESULTS: Antioxidant and radical scavenging activity of the AHP extract showed a high content of antioxidants that exert potent radical scavenging activity. According to the results obtained, upon the administration of AHP the levels of cholesterol and triglycerides significantly decreased, while the antioxidant capacity of plasma increased. CONCLUSION: AHP with bioactive compounds and fiber can reduce total cholesterol and triglycerides and improve serum antioxidant capacity. PMID- 27513430 TI - Effects of cepae extract, allantoin, and heparin mixture on developing andalready formed epidural fibrosis in a rat laminectomy model. AB - BACKGROUND/AIM: The study was designed to investigate whether local administration of a mixture composed of cepae extract, allantoin, and heparin (CAH) decreased already formed epidural fibrosis (EF) at the laminectomy site. MATERIALS AND METHODS: Twenty-four adult male Sprague Dawley rats were equally divided into four groups. Laminectomy was performed at the L5 level in all rats. The group 2 and group 4 rats were treated with local drug administration. While the group 1 and 2 rats were sacrificed after 6 weeks, the remaining rats were reoperated and CAH mixture was applied in group 4. The vertebral columns of all rats were removed en bloc. Fibroblast numbers, EF, and arachnoidal involvement (AI) were evaluated. RESULTS: The results of the treatment groups were separately compared with the control groups. The numbers of fibroblasts in the treatment groups were significantly lower than those in the control groups (P < 0.001). The grade of EF in group 2 was significantly less than that in group 1 (P < 0.05). There was no statistically significant difference regarding EF and AI grade between group 3 and group 4, and local application of the drug on EF and AI yielded better results than in the control groups. CONCLUSION: The mixture composed of CAH might be a successful candidate for preventing EF in clinical practice. PMID- 27513431 TI - The consequences of aluminium intake on reproductive function in male rats:a three-generation study. AB - BACKGROUND/AIM: The effects of aluminium exposure on reproductive biomarkers in male rats were followed in a three-generation study. MATERIALS AND METHODS: Forty Wistar male rats (F0) were divided into the following groups: control (C), receiving only tap water, and three experimental (E) groups, receiving aluminium sulphate (AS) (E1: 200 ppb, E2: 400 ppb, and E3: 1000 ppb) in drinking water for a 6-month exposure period. To obtain F1, three males from each group were mated with previously unexposed females (1:2 sex ratios) that during gestation and lactation were exposed to the same AS levels as males. The F1 generation male offspring were divided as described and exposed to the same AS levels. The protocol to obtain F2 was similar to that described for F1. RESULTS: Significantly lower testosterone levels in rats exposed to AS and in generations F1 and F2 compared to the parental one, luteinising hormone (LH) fluctuations in F0 and a significant LH decrease in F2 and F3 generations, testis weight decrease, increased immobile and abnormal sperm, and histoarchitecture alterations in the testes were observed. Moreover, interval between deliveries increased. CONCLUSION: Chronic exposure to AS was significantly deleterious, producing a pronounced decrease in the sperm count and testosterone levels in all experimental groups. PMID- 27513432 TI - The effects of novokinin, an AT2 agonist, on blood pressure, vascular responses, and levels of ADMA, NADPH oxidase, and Rho kinase in hypertension induced by NOS inhibition and salt. AB - BACKGROUND/AIM: The effects of AT2 receptor agonist novokinin on blood pressure, eNOS, NADPH oxidase, protein arginine methyltransferases (PRMTs), and Rho kinase in hypertension were investigated. Furthermore, in isolated thoracic aorta rings, contractile and dilator responses were studied. MATERIALS AND METHODS: To develop hypertension, L-NAME was administered intraperitoneally and salt was given with tap water (1%) for 4 weeks. Novokinin was administered intraperitoneally for the last 2 weeks. Blood pressures were measured using the tail-cuff method and enzyme levels by real-time polymerase chain reaction in aortic tissues. RESULTS: Blood pressure increased significantly in hypertensive rats. Novokinin reduced the blood pressure in the hypertensive group. While the contractile responses to increasing doses of angiotensin II were increased, vascular reactivity (Emax) and sensitivity (EC50) to acetylcholine were decreased in hypertensive rats. In novokinin-treated hypertensive groups, the EC50 value decreased and the Emax value for acetylcholine significantly increased. The levels of Rho kinase and PRMT expression increased and the level of eNOS expression decreased in the hypertensive group. In novokinin-treated rats, ADMA, NADPH oxidase, and Rho kinase tended to decreased, but these changes did not reach statistical significance. CONCLUSION: Although further studies are needed to determine its effectiveness, the AT2 agonist novokinin may be a novel agent that is promising in terms of protective effects for the treatment of hypertension. PMID- 27513433 TI - Effectiveness of a single versus repeated administration of trimetazidine in the protection against warm ischemia/reperfusion injury of rat liver. AB - BACKGROUND/AIM: The aim of this study was to compare the effects of single and repeated trimetazidine (TMZ) administration against warm hepatic ischemia/reperfusion (I/R) injury and to explore the possible mechanisms affected by TMZ. MATERIALS AND METHODS: Wistar rats were divided into 4 groups (n = 6). Sham: rats were subjected to dissection. I/R: rats were subjected to 60 min of partial hepatic ischemia followed by 24 h of reperfusion. TMZ1: Same as I/R group but rats were pretreated with a single dose of TMZ (10 mg/kg, intraperitoneal injection) 30 min before warm ischemia. TMZ3: Same as I/R but rats were treated with 10 mg/kg TMZ for 3 successive days. RESULTS: TMZ treatment decreased liver injury, lipid peroxidation, and apoptosis. The repeated administration of TMZ conferred more protection than the single dose treatment concerning all studied parameters. In parallel, we noted a significant increase in phosphorylated adenosine monophosphate activated protein kinase (p-AMPK) and endothelial nitric oxide synthase (eNOS) levels in TMZ3 as compared to TMZ1. CONCLUSION: Repeated administration of TMZ for 3 days was more efficient than a single dose of TMZ in protecting the liver against I/R induced apoptosis and lipid peroxidation. These effects implicate AMPK and eNOS activation. PMID- 27513434 TI - Effects of naloxone and yohimbine in polycystic ovary syndrome: a rabbit model study. AB - BACKGROUND/AIM: To assess the therapeutic effects of naloxone and yohimbine on polycystic ovary syndrome (PCOS) in a rabbit model in terms of body weight and endocrinological parameters (luteinizing hormone, insulin, and estradiol). MATERIALS AND METHODS: A total of 50 adult, reproductively mature female rabbits (Oryctolagus cuniculus) were divided into five groups (n = 10/group). In the control group PCOS was not induced (negative control group), whereas in the remaining four groups (n = 40) PCOS was induced with a single i.m. injection of testosterone daily and were designated as follows: positive control, naloxone treated (NalT), yohimbine-treated (YohT), and naloxone+yohimbine-treated (NalYT) groups. RESULTS: A steadily ascending trend was noted in all of the studied parameters in the PCOS-induced group as compared to the negative control group. All the parameters showed a descending trend in the NalT group as compared to the positive control. Regarding the YohT and NalYT groups, all parameters showed a descending trend as compared to the positive control group except for estradiol. CONCLUSION: Naloxone therapy either alone or combined with yohimbine improves a wide range of the clinical manifestations of PCOS. Furthermore, we suggest this therapy as an alternative to the conventional therapy with insulin-lowering agents in vogue. PMID- 27513435 TI - Serum lithium levels are associated with white blood cell counts in bipolar disorder. PMID- 27513436 TI - The importance of coronary angiography for ischemic sign confirmationdetected by myocardial perfusion scintigraphy. PMID- 27513437 TI - Herbal self-medication use in Type 2 diabetes mellitus. PMID- 27513439 TI - Synthesis of Photo- and pH Dual-Sensitive Amphiphilic Copolymer PEG43-b-P(AA76-co NBA35-co-tBA9) and Its Micellization as Leakage-Free Drug Delivery System for UV Triggered Intracellular Delivery of Doxorubicin. AB - Novel photo- and pH dual-sensitive amphiphilic copolymers containing photolabile o-nitrobenzyl (NB) groups were designed via combination of ATRP, hydrolyzation, and simple esterification reaction and self-assembled into stimuli-regulated amphiphilic micelles in aqueous solution. On the basis of the optimization of the morphology and particle size of the micelles via modulating the number of the photocleavable o-nitrobenzyl acrylate (NBA) units, the unique ones assembled from PEG43-b-P(AA76-co-NBA35-co-tBA9) with an average hydrodynamic diameter (Dh) of 163 nm was selected as a potential drug delivery system (DDS) for UV-triggered delivery of doxorubicin (DOX). The micelles possessed a favorable drug-loading capacity (DLC) of 27.5%, with the hydrodynamic diameter of 213 nm after DOX loading. Most importantly, the DOX-loaded PEG43-b-P(AA76-co-NBA35-co-tBA9) micelles exhibited a cumulative DOX release ratio of only 3.69% in the simulated physiological medium within 6 days without UV-irradiation, indicating their potential as leakage-free DDS. As in the acidic media mimicking the tumor microenvironment, a high cumulative DOX release ratio of 74.70% was achieved within 6 days after UV-irradiation for 20 min, showing a sustained release behavior. Under UV-irradiation, the photolabile o-nitrobenzyl moieties were cleaved off, the amphiphilic copolymer transformed into a water-soluble polymer, favoring the metabolism of drug carriers, and the micelles were demicellized to accelerate the drug release in a triggered or on-demand manner. PMID- 27513438 TI - Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection. AB - BACKGROUND: Rhinovirus (RV) infection in asthma induces varying degrees of airway inflammation (e.g. neutrophils), but the underlying mechanisms remain unclear. OBJECTIVE: The major goal was to determine the role of genetic variation [e.g. single nucleotide polymorphisms (SNPs)] of Toll-interacting protein (Tollip) in airway epithelial responses to RV in a type 2 cytokine milieu. METHODS: DNA from blood of asthmatic and normal subjects was genotyped for Tollip SNP rs5743899 AA, AG and GG genotypes. Human tracheobronchial epithelial (HTBE) cells from donors without lung disease were cultured to determine pro-inflammatory and antiviral responses to IL-13 and RV16. Tollip knockout and wild-type mice were challenged with house dust mite (HDM) and infected with RV1B to determine lung inflammation and antiviral response. RESULTS: Asthmatic subjects carrying the AG or GG genotype (AG/GG) compared with the AA genotype demonstrated greater airflow limitation. HTBE cells with AG/GG expressed less Tollip. Upon IL-13 and RV16 treatment, cells with AG/GG (vs. AA) produced more IL-8 and expressed less antiviral genes, which was coupled with increased NF-kappaB activity and decreased expression of LC3, a hallmark of the autophagic pathway. Tollip co localized and interacted with LC3. Inhibition of autophagy decreased antiviral genes in IL-13- and RV16-treated cells. Upon HDM and RV1B, Tollip knockout (vs. wild-type) mice demonstrated higher levels of lung neutrophilic inflammation and viral load, but lower levels of antiviral gene expression. CONCLUSIONS AND CLINICAL RELEVANCE: Our data suggest that Tollip SNP rs5743899 may predict varying airway response to RV infection in asthma. PMID- 27513440 TI - Tissue fibrosis: a pathomechanistically unresolved challenge and scary clinical problem. PMID- 27513442 TI - Oxytocin and behavior: Lessons from knockout mice. AB - It is well established that the nonapeptide oxytocin (Oxt) is important for the neural modulation of behaviors in many mammalian species. Since its discovery in 1906 and synthesis in the early 1950s, elegant pharmacological work has helped identify specific neural substrates on which Oxt exerts its effects. More recently, mice with targeted genetic disruptions of the Oxt system-i.e., both the peptide and its receptor (the Oxtr)-have further defined Oxt's actions and laid some important scientific groundwork for studies in other species. In this article, we highlight the scientific contributions that various mouse knockouts of the Oxt system have made to our understanding of Oxt's modulation of behavior. We specifically focus on how the use of these mice has shed light on our understanding of social recognition memory, maternal behavior, aggression, and several nonsocial behaviors. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 190-201, 2017. PMID- 27513443 TI - Competitive colonization of prosthetic surfaces by staphylococcus aureus and human cells. AB - Implantation of a biomaterial provides an adhesion substratum both to host cell integration and to contaminating bacteria. We studied simultaneous competitive adhesion of Staphylococcus aureus in serial 1:10 dilutions of 108 colony forming units (CFU)/mL and human osteogenic sarcoma (SaOS-2) or primary osteoblast (hOB) cells, both 1x105 cells/mL, to the surfaces of titanium, polydimethylsiloxane and polystyrene. The bacterial adherence and human cell proliferation, cytotoxicity and production of reactive oxygen species (ROS) were studied using fluorometric (fluorescent microscopy and flow cytometry) and colorimetric methods (MTT, LDH and crystal violet). The bacterial cell viability was also evaluated using the drop plate method. The presence of bacteria resulted in reduced adherence of human cells to the surface of the biomaterials, increased production of ROS, and into increased apoptosis. On the other hand, the presence of either type of human cells was associated with a reduction of bacterial colonization of the biomaterial with Staphylococcus aureus. These results suggest that increasing colonization of the biomaterial surface in vitro by one negatively affects colonization by the other. Host cell integration to an implant surface reduces bacterial contamination, which opens novel opportunities for the design of infection-resistant biomaterials in current implantology and future regenerative medicine. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 62 72, 2017. PMID- 27513444 TI - Rethinking the Pregnancy Planning Paradigm: Unintended Conceptions or Unrepresentative Concepts? PMID- 27513446 TI - What Happens after Activation of Ascaridole? Reactive Compounds and Their Implications for Skin Sensitization. AB - To replace animal testing and improve the prediction of skin sensitization, significant attention has been directed to the use of alternative methods. The direct peptide reactivity assay (DPRA), the regulatory agencies' approved alternative in chemico method, has been applied for understanding the sensitization capacity of activated ascaridole. Ascaridole, the oxidative metabolite of alpha-terpinene, is considered to be one of the components responsible for the contact allergy associated with essential oils derived from Chenopodium and Melaleuca species. The recently developed high-throughput screening based on the dansyl cysteamine (HTS-DCYA) method was applied to understand the reported enhanced reactivity of activated ascaridole and possibly to identify the resulting elusive radical or other reactive species. For the first time, a substituted cyclohexenone was identified as a potential electrophilic intermediate resulting in higher depletion of nucleophilic DCYA, along with several nonreactive byproducts of ascaridole via a radical degradation mechanism. Formation of electrophilic species via radical degradation is one of the possible pathways should be considered for the peptide reactivity of in aged tea tree oil or oils rich in terpinenes along with commonly believed reactants, allylic-epoxides and allylic-peroxides. PMID- 27513447 TI - Three-dimensional imaging of shear bands in bulk metallic glass composites. AB - The mechanism of the increase in ductility in bulk metallic glass matrix composites over monolithic bulk metallic glasses is to date little understood, primarily because the interplay between dislocations in the crystalline phase and shear bands in the glass could neither be imaged nor modelled in a validated way. To overcome this roadblock, we show that shear bands can be imaged in three dimensions by atom probe tomography from density variations in the reconstructed atomic density, which density-functional theory suggests being a local-work function effect. Imaging of near-interface shear bands in Ti48 Zr20 V12 Cu5 Be15 bulk metallic glass matrix composite permits measurement of their composition, thickness, branching and interactions with the dendrite interface. These results confirm that shear bands here nucleate from stress concentrations in the glass due to intense, localized plastic deformation in the dendrites rather than intrinsic structural inhomogeneities. PMID- 27513445 TI - The Tumor-Associated Variant RAD51 G151D Induces a Hyper-Recombination Phenotype. AB - The RAD51 protein plays a key role in the homology-directed repair of DNA double strand breaks and is important for maintaining genome stability. Here we report on a novel human RAD51 variant found in an aggressive and therapy-refractive breast carcinoma. Expression of the RAD51 G151D variant in human breast epithelial cells increases the levels of homology-directed repair. Expression of RAD51 G151D in cells also promotes high levels of chromosomal aberrations and sister chromatid exchanges. In vitro, the purified RAD51 G151D protein directly and significantly enhances DNA strand exchange activity in the presence of RPA. In concordance with this result, co-incubation of G151D with BRCA2 resulted in a much higher level of strand-exchange activity compared to WT RAD51. Strikingly, the RAD51 G151D variant confers resistance to multiple DNA damaging agents, including ionizing radiation, mitomycin C, and doxorubicin. Our findings demonstrate that the RAD51 G151D somatic variant has a novel hyper-recombination phenotype and suggest that this property of the protein is important for the repair of DNA damage, leading to drug resistance. PMID- 27513448 TI - The impact of obesity on outcomes and complications after top-down retropubic midurethral sling. AB - AIMS: Obese women (BMI >= 30 kg/m2 ) have been considered at higher risk for postoperative complications and failure in efficacy after SUI surgery. We compare the outcomes in this population with non-obese women (BMI < 30 kg/m2 ) undergoing top-down retropubic polypropylene midurethral sling (RPM). METHODS: We retrospectively identified 328 non-obese women and 294 obese women who underwent RPM. Evaluation included SEAPI (stress incontinence, emptying, anatomy, protection, inhibition) assessment and validated QoL questionnaires. Cure was defined as absence of subjective and objective SUI and no additional procedures to correct SUI. Perioperative details were abstracted from the hospital and clinic charts. Groups and outcomes were statistically compared. RESULTS: All women had a minimum follow up of 12 months. Preoperative demographic variables, SEAPI scores, and QoL indices were similar between BMI groups. SUI cure rates were significantly higher for non-obese women (82.9% vs. 74.5%; P < 0.01). When controlling for concomitant pelvic surgery, cure rates were not statistically different (76.9% vs. 73.7%; P = 0.65). Statistically significant improvement in SEAPI scores and QoL indices was achieved in both groups. Overall, obese women had no increase in complications compared with the non-obese. The chance of passing an initial postoperative voiding trial was statistically higher in the obese group. CONCLUSIONS: Obese women have similar success rates and significant improvement in QoL as non-obese women after RPM. Obesity alone does not appear to be a risk factor for additional complications during sling surgery and obese women may have earlier return to normal voiding after surgery. PMID- 27513450 TI - Rapid Identification of the Receptor-Binding Specificity of Influenza A Viruses by Fluorogenic Glycofoldamers. AB - The re-emergence of influenza raises a global concern that viral pandemics can unpredictably occur. However, effective approaches that can probe the infection risk of influenza viruses for humans are rare. In this work, we develop a glycofoldamer that can rapidly identify the glycan-receptor specificity of influenza viruses in a high-throughput manner. The coupling of glycan receptors that can be recognized by hemagglutinin (a surface protein on the virion capsid of influenza) to a fluorogenic-dye foldamer produces the glycofoldamers with minimal fluorescence in aqueous solution. After interaction with human-infecting virus strains for only five minutes, the fluorescence intensity of the glycofoldamer is remarkably enhanced with a blue-shifted emission peak. The probes have also proven effective for the rapid identification of 1) the human- or bird-infecting properties of influenza viruses in a high-throughput manner and 2) the receptor-specificity switch of a virus strain by mutations. PMID- 27513449 TI - The RNA-Binding Protein, Polypyrimidine Tract-Binding Protein 1 (PTBP1) Is a Key Regulator of CD4 T Cell Activation. AB - We have previously shown that the RNA binding protein, polypyrimidine tract binding protein (PTBP1) plays a critical role in regulating the expression of CD40L in activated CD4 T cells. This is achieved mechanistically through message stabilization at late times of activation as well as by altered distribution of CD40L mRNA within distinct cellular compartments. PTBP1 has been implicated in many different processes, however whether PTBP1 plays a broader role in CD4 T cell activation is not known. To examine this question, experiments were designed to introduce shRNA into primary human CD4 T cells to achieve decreased, but not complete ablation of PTBP1 expression. Analyses of shPTB-expressing CD4 T cells revealed multiple processes including cell proliferation, activation-induced cell death and expression of activation markers and cytokines that were regulated in part by PTBP1 expression. Although there was an overall decrease in the steady state level of several activation genes, only IL-2 and CD40L appeared to be regulated by PTBP1 at the level of RNA decay suggesting that PTBP1 is critical at different regulatory steps of expression that is gene-specific. Importantly, even though the IL-2 protein levels were reduced in cells with lowered PTBP1, the steady-state level of IL-2 mRNA was significantly higher in these cells suggesting a block at the translational level. Evaluation of T cell activation in shPTB-expressing T cells revealed that PTBP1 was linked primarily to the activation of the PLCgamma1/ERK1/2 and the NF-kappaB pathways. Overall, our results reveal the importance of this critical RNA binding protein in multiple steps of T cell activation. PMID- 27513452 TI - The effect of pain on task switching: pain reduces accuracy and increases reaction times across multiple switching paradigms. AB - Pain disrupts attention, which may have negative consequences for daily life for people with acute or chronic pain. It has been suggested that switching between tasks may leave us particularly susceptible to pain-related attentional disruption, because we need to disengage our attention from one task before shifting it onto another. Switching tasks typically elicit lower accuracies and/or longer reaction times when participants switch to a new task compared with repeating the same task, and pain may exacerbate this effect. We present 3 studies to test this hypothesis. In study 1, participants completed 2 versions of an alternating runs switching task under pain-free and thermal pain-induction conditions. Pain did not affect performance on either task. In studies 2 and 3, we examined 7 versions of the switching task using large general population samples, experiencing a variety of naturally occurring pain conditions, recruited and tested on the internet. On all tasks, participants with pain had longer reaction times on both switch and repeat trials compared with participants without pain, but pain did not increase switch costs. In studies 2 and 3, we also investigated the effects of type of pain, duration of pain, and analgesics on task performance. We conclude that pain has a small dampening effect on performance overall on switching tasks. This suggests that pain interrupts attention even when participants are engaged in a trial, not only when attention has been disengaged for shifting to a new task set. PMID- 27513453 TI - Nudix Effectors: A Common Weapon in the Arsenal of Plant Pathogens. PMID- 27513454 TI - Gait in children and adolescents with Charcot-Marie-Tooth disease: a systematic review. AB - Symptoms of Charcot-Marie-Tooth (CMT) disease typically arise in childhood or adolescence with gait difficulty most common. A systematic review was conducted to synthesise, review, and characterise gait in paediatric CMT. Health-related electronic databases were reviewed with search terms related to CMT and gait. Of 454 articles, 10 articles describing seven studies met eligibility criteria; samples ranged from 1 to 81, included mixed CMT sub-types and had a participant mean age of 13 years. Assessments included a variety of methods to examine only barefoot gait. Heterogeneity of gait patterns was noted. Children and adolescents with CMT walked slower, most likely due to shorter stride length. Common kinematic and kinetic abnormalities included significant foot drop during swing, reduced calf muscle power, and proximal compensatory mechanisms in the lower limb. Little data were found to inform typical functional gait characteristics or change over time. Of note, barefoot assessment does not reflect function in everyday life where footwear is commonly worn. With limited existing literature, future studies of gait in paediatric CMT need to evaluate the influence of diagnostic sub-types and disease progression; the effect of factors such as footwear and the environment; and to explore changes in gait and function throughout childhood and adolescence. PMID- 27513455 TI - RAMP1 suppresses mucosal injury from dextran sodium sulfate-induced colitis in mice. AB - BACKGROUND AND AIMS: Calcitonin gene-related peptide (CGRP) is thought to be involved in the modulation of intestinal motility. CGRP receptor is composed of receptor activity-modifying protein (RAMP) 1 combined with calcitonin receptor like receptor (CRLR) for CGRP. The study investigated the role of CGRP in mice with experimentally induced colitis. METHODS: The study used dextran sodium sulfate (DSS) to induce colitis in mice. The study compared the severity of colitis in wild-type (WT) mice, mice treated with a CGRP receptor antagonist (CGRP8-37 ), and RAMP1 knockout (-/- ) mice. Pathological changes in the mucosa were assessed, and inflammatory cells and cytokine levels were measured. RESULTS: The severity of inflammation in DSS-induced colitis increased markedly in CGRP8 37 -treated mice and RAMP1-/- mice compared with WT mice. RAMP1-/- mice showed more severe damage compared with CGRP8-37 -treated mice. The number of periodic acid-Schiff-positive cells decreased in CGRP8-37 -treated mice compared with WT mice and was even further decreased in RAMP1-/- mice. RAMP1 was expressed by macrophages, mast cells, and T-cells. RAMP1-/- mice exhibited excessive accumulation of macrophages and mast cells into the colonic tissue with increased levels of tumor necrosis factor-alpha and interleukin-1beta as compared with WT mice. Infiltration of T-cells into the colonic mucosa, which was associated with the expression of T helper (Th) cytokines including Th1 (interferon gamma) and Th17 (IL-17), was augmented in RAMP1-/- mice. CONCLUSIONS: The findings of this study suggest that RAMP1 exerted mucosal protection in DSS-induced colitis via attenuation of recruitment of inflammatory cells and of pro-inflammatory cytokines. PMID- 27513456 TI - The next generation of novel therapies for the management of relapsed multiple myeloma. AB - The advent of various novel therapies such as immunomodulators and proteasome inhibitors has transformed the treatment paradigm for patients with multiple myeloma (MM). As a result, the overall survival has improved dramatically over the last decade. Despite these advances, MM remains mostly incurable and most patients experience disease relapse after enjoying a period of disease control or remission. Fortunately, the scientific community continues to make strides in developing 'next-generation' therapies for the management of patients with relapsed MM. This review will summarize the efficacy of some of the newest therapeutic agents available for the treatment of patients with relapsed MM after their upfront treatment with the original novel agents such as thalidomide, lenalidomide and bortezomib. PMID- 27513458 TI - Concerted Rattling in CsAg5 Te3 Leading to Ultralow Thermal Conductivity and High Thermoelectric Performance. AB - Thermoelectric (TE) materials convert heat energy directly into electricity, and introducing new materials with high conversion efficiency is a great challenge because of the rare combination of interdependent electrical and thermal transport properties required to be present in a single material. The TE efficiency is defined by the figure of merit ZT=(S(2) sigma) T/kappa, where S is the Seebeck coefficient, sigma is the electrical conductivity, kappa is the total thermal conductivity, and T is the absolute temperature. A new p-type thermoelectric material, CsAg5 Te3 , is presented that exhibits ultralow lattice thermal conductivity (ca. 0.18 Wm(-1) K(-1) ) and a high figure of merit of about 1.5 at 727 K. The lattice thermal conductivity is the lowest among state-of the-art thermoelectrics; it is attributed to a previously unrecognized phonon scattering mechanism that involves the concerted rattling of a group of Ag ions that strongly raises the Gruneisen parameters of the material. PMID- 27513459 TI - Geography of Genetic Structure in Barley Wild Relative Hordeum vulgare subsp. spontaneum in Jordan. AB - Informed collecting, conservation, monitoring and utilization of genetic diversity requires knowledge of the distribution and structure of the variation occurring in a species. Hordeum vulgare subsp. spontaneum (K. Koch) Thell., a primary wild relative of barley, is an important source of genetic diversity for barley improvement and co-occurs with the domesticate within the center of origin. We studied the current distribution of genetic diversity and population structure in H. vulgare subsp. spontaneum in Jordan and investigated whether it is correlated with either spatial or climatic variation inferred from publically available climate layers commonly used in conservation and ecogeographical studies. The genetic structure of 32 populations collected in 2012 was analyzed with 37 SSRs. Three distinct genetic clusters were identified. Populations were characterized by admixture and high allelic richness, and genetic diversity was concentrated in the northern part of the study area. Genetic structure, spatial location and climate were not correlated. This may point out a limitation in using large scale climatic data layers to predict genetic diversity, especially as it is applied to regional genetic resources collections in H. vulgare subsp. spontaneum. PMID- 27513460 TI - Alkali Metal Hydridotriphenylborates [(L)M][HBPh3] (M = Li, Na, K): Chemoselective Catalysts for Carbonyl and CO2 Hydroboration. AB - Light alkali metal hydridotriphenylborates M[HBPh3] (M = Li, Na, K), characterized as tris{2-(dimethylamino)ethyl}amine (L) complexes [(L)M][HBPh3], act as efficient catalysts for the chemoselective hydroboration of a wide range of aldehydes and ketones using pinacolborane HBpin. The lithium derivative showed a remarkably high TOF of >=17 s(-1). These compounds also catalyze the hydroborative reduction of CO2 to give formoxyborane HCO2Bpin without any over reduction. PMID- 27513457 TI - Role of Proteome Physical Chemistry in Cell Behavior. AB - We review how major cell behaviors, such as bacterial growth laws, are derived from the physical chemistry of the cell's proteins. On one hand, cell actions depend on the individual biological functionalities of their many genes and proteins. On the other hand, the common physics among proteins can be as important as the unique biology that distinguishes them. For example, bacterial growth rates depend strongly on temperature. This dependence can be explained by the folding stabilities across a cell's proteome. Such modeling explains how thermophilic and mesophilic organisms differ, and how oxidative damage of highly charged proteins can lead to unfolding and aggregation in aging cells. Cells have characteristic time scales. For example, E. coli can duplicate as fast as 2-3 times per hour. These time scales can be explained by protein dynamics (the rates of synthesis and degradation, folding, and diffusional transport). It rationalizes how bacterial growth is slowed down by added salt. In the same way that the behaviors of inanimate materials can be expressed in terms of the statistical distributions of atoms and molecules, some cell behaviors can be expressed in terms of distributions of protein properties, giving insights into the microscopic basis of growth laws in simple cells. PMID- 27513463 TI - Total Synthesis of Anticancer Agent EBC-23. AB - Total synthesis of spiroketal EBC-23 has been described by two divergent approaches from three simple building blocks. Gold-catalyzed cycloisomerization of alkynol and acid-mediated spirocyclization of diketalketone were successfully utilized to effect spiroketal formation. A Cu(I)-P(Cy)3-catalyzed protocol for the highly regio- and stereocontrolled hydroboration of internal propargylic alcohol was effectively applied toward the beta-hydroxy ketone via vinylboronates. PMID- 27513462 TI - MicroRNA-21 Increases Proliferation and Cisplatin Sensitivity of Osteosarcoma Derived Cells. AB - Osteosarcoma is the most common primary bone tumor and poor prognosis for osteosarcoma patients is mainly due to chemotherapy resistance. MicroRNAs are important to maintain pathophysiological mechanisms of cancer and influence cell sensitivity to chemotherapy. In this study, we tested the functions of microRNA 21 for malignant features as well as for drug resistance of osteosarcoma. We used Northern blot to measure microRNA-21 levels in osteosarcoma-derived cell lines. MicroRNA-21 activity was modulated by either expressing a sponge to decrease its activity in an osteosarcoma-derived cell line expressing high levels of microRNA 21 or by introducing pri-microRNA-21 in a cell line with low endogenous levels. Cell migration was determined in a scratch assay and cell proliferation was measured by performing growth curve analysis. Sensitivity of the cells towards chemotherapeutics was investigated by performing cell viability assays and calculating the IC50 values. While cell migration was unaffected by modulated microRNA-21 levels, microRNA-21 inhibition slowed proliferation and exogenously expressed microRNA-21 promoted this process. Modulated microRNA-21 activity failed to effect sensitivity of osteosarcoma-derived cell lines to doxorubicin or methotrexate. Contrarily, reduction of microRNA-21 activity resulted in enhanced resistance towards cisplatin while ectopic expression of microRNA-21 showed the opposite effect. Increased microRNA-21 levels repressed the expression of Sprouty2 and ectopic expression of Sprouty2 was able to largely rescue the observed effects of microRNA-21 in osteosarcoma. In summary, our data indicate that in osteosarcoma microRNA-21 expression is an important component for regulation of cell proliferation and for determining sensitivity to cisplatin. PMID- 27513464 TI - Developmental Origins of Disease - Crisis Precipitates Change. AB - The concept of developmental origins of diseases has gained a huge interest in recent years and is a constantly emerging scientific field. First observations hereof originated from epidemiological studies, linking impaired birth outcomes to adult chronic, noncommunicable disease. By now there is a considerable amount of both epidemiological and experimental evidence highlighting the impact of early life events on later life disease susceptibility. Albeit far from being completely understood, more recent studies managed to elucidate underlying mechanisms, with epigenetics having become almost synonymous with developmental programming. The aim of this review was to give a comprehensive overview of various aspects and mechanisms of developmental origins of diseases. Starting from initial research foci mainly centered on a nutritionally impaired intrauterine environment, more recent findings such as postnatal nutrition, preterm birth, paternal programming and putative interventional approaches are summarized. The review outlines general underlying mechanisms and particularly discusses mechanistic explanations for sexual dimorphism in developmental programming. Furthermore, novel hypotheses are presented emphasizing a non mendelian impact of parental genes on the offspring's phenotype. PMID- 27513465 TI - WNT2 Promotes Cervical Carcinoma Metastasis and Induction of Epithelial Mesenchymal Transition. AB - BACKGROUND: Previously, we found an 11-gene signature could predict pelvic lymph node metastasis (PLNM), and WNT2 is one of the key genes in the signature. This study explored the expression and underlying mechanism of WNT2 in PLNM of cervical cancer. METHODS: WNT2 expression level in cervical cancer was detected using western blotting, quantitative PCR, and immunohistochemistry. Two WNT2 specific small interfering RNAs (siRNAs) were used to explore the effects of WNT2 on invasive and metastatic ability of cancer cells, and to reveal the possible mechanism of WNT2 affecting epithelial-mesenchymal transition (EMT). The correlation between WNT2 expression and PLNM was further investigated in clinical cervical specimens. RESULTS: Both WNT2 mRNA and protein expression was upregulated in cervical cancer. High WNT2 expression was significantly associated with tumor size, lymphovascular space involvement, positive parametrium, and most importantly, PLNM. PLNM and WNT2 expression were independent prognostic factors for overall survival and disease-free survival. WNT2 knockdown inhibited SiHa cell motility and invasion and reversed EMT by inhibiting the WNT2/beta-catenin pathway. WNT2 overexpression in cervical cancer was associated with beta-catenin activation and induction of EMT, which further contributed to metastasis in cervical cancer. CONCLUSION: WNT2 might be a novel predictor of PLNM and a promising prognostic indicator in cervical cancer. PMID- 27513466 TI - Longitudinal Evaluation of Segmental Arterial Mediolysis in Splanchnic Arteries: Case Series and Systematic Review. AB - BACKGROUND: Segmental arterial mediolysis (SAM) is a rare non-atherosclerotic, non-inflammatory vascular disorder varying widely in clinical course. The purpose of this study is to analyze detailing clinical and imaging manifestations over time in patients with SAM through a literature review and to suggest an optimal management strategy. METHODS: A retrospective review of eight consecutive patients diagnosed with SAM between January, 2000 and January, 2012 was conducted. All presented with acute-onset abdominal or flank pain. Clinical features, imaging studies, and laboratory findings served as grounds for diagnosis, having excluded more common conditions (ie, fibromuscular dysplasia, collagen vascular disorders, or arteritis). CT angiography was done initially and repeated periodically (Week 1, Month 3, then yearly). Treatment was conservative, utilizing endovascular intervention as warranted by CT diagnostics. In a related systematic review, all English literature from 1976 to 2015 was screened via the PubMed database, assessing patient demographics, affected arteries, clinical presentations, and treatment methods. FINDINGS: Ultimately, 25 arterial lesions identified in eight patients (median age, 62.8 years; range, 40-84 years) were monitored for a median period of 26 months (range, 15-57 months). At baseline, celiac axis (3/8, 37.5%), superior mesenteric (4/8, 50%), and common hepatic (2/8, 25%) arteries were involved, in addition to isolated lesions of right renal, splenic, right colic, middle colic, gastroduodenal, left gastric, right gastroepiploic, proper hepatic, right hepatic, and left hepatic arteries. Compared with prior publications, celiac axis and superior mesenteric artery were more commonly affected in cohort. Arterial dissections (n = 8), aneurysms (n = 5), stenoses or occlusions (n = 4), and a single pseudoaneurysm were documented. Despite careful conservative management, new splanchnic arterial lesions (n = 4) arose during follow-up. Considering the few available reports of new arterial lesions in the literature, newly developing pathology is a distinctive feature of our patients, four of whom eventually required endovascular interventions. CONCLUSIONS: Careful clinical observation via periodic CT angiography is required in patients with SAM, checking for newly developing lesions. The natural history of SAM should be clarified in a larger patient population. PMID- 27513469 TI - Botulinum toxin therapy in Frey's syndrome: a retrospective study of 440 treatments in 100 patients. AB - OBJECTIVE: Frey's syndrome is characterised as sweating, redness and warmth of the parotideal area and is often treated with botulinum toxin A. The objective of this retrospective study was to prove whether the toxin dosage and time-to treatment intervals change after repeated botulinum toxin injections. STUDY DESIGN/METHODS: The charts of patients, who were treated for Frey's syndrome during the last 16 years, were assessed. Three brands of botulinum toxin A were available for therapy. The Minor test was used to confirm the sweating before each treatment and to determine the toxin dosage. Constant amount of botulinum toxin was injected per cm2 of the affected area. Patients consulted our department for the next treatment as soon as they felt disturbed by recurring sweating and when the sweating was objectively evident in the Minor test. Time intervals between treatments and injected toxin dosages were assessed. RESULTS: In total, 100 patients received 440 treatments in 16 years. Repeated injections, median 4.0, were carried out in 70.5% of patients. Median time interval to the first injection was 2.8 years. Median time interval between treatments was 12.0 months and showed to be steady (anova, P = .49, F = 1.01). CONCLUSION: Duration of effect of botulinum toxin on Frey's syndrome was long-lasting and stable with no significantly different time intervals between treatments. The extent of the sweating area did not vary significantly after repeated treatments and required a constant dose of botulinum toxin A. PMID- 27513467 TI - Brains of Native and Alien Mesocarnivores in Biomonitoring of Toxic Metals in Europe. AB - Mercury (Hg), lead (Pb) and cadmium (Cd) are involved in mammalian brain damage. However, little is known about Pb and Cd brain levels in wildlife that reflect the geochemical background. The aims of the study include the estimation of Hg, Pb and Cd concentrations, and the determination of relationships between these elements in the brains of 94 mesocarnivores. Road-killed or hunted animals were obtained from north-western Poland near the Polish-German border. The investigation covered the native Eurasian otter Lutra lutra, badger Meles meles, pine marten Martes martes, beech marten M. foina, European polecat Mustela putorius, red fox Vulpes vulpes, and alien species: feral and ranch American mink Neovison vison, raccoon Procyon lotor and raccoon dog Nyctereutes procyonoides. Depending on the diet and environmental pollution, the carnivore brains accumulated toxic metals in varying amounts. The highest median Hg levels (in mg/kg dry weight, dw) were found in the piscivorous Eurasian otter and feral mink (2.44 and 3.96), Pb in the omnivorous raccoon (0.47), while Cd in minks (~0.06). We indicated that Pb-based ammunition is a significant source of the element in scavengers from hunting area, and we also found a significant correlation between Pb and Cd levels in the fox brain. Finally, this study is the first to suggest background levels for brain Pb and Cd in mesocarnivores (<0.50 and <0.04 mg/kg dw, respectively). PMID- 27513470 TI - Overexpression of long non-coding RNA MFI2 promotes cell proliferation and suppresses apoptosis in human osteosarcoma. AB - The long non-coding RNA MFI2 antisense RNA is overexpressed in human cancer tissues and its increased expression is associated with occurrence and metastasis of cancer. However, the underlying mechanism in evolution and progression of human osteosarcoma is not well known. In the present study, we aimed to evaluate the molecular mechanism of lncRNA MFI2 in promoting osteosarcoma cell proliferation and suppressing apoptosis. We found that the lncRNA MFI2 was significantly overexpressed in human osteosarcoma tissues. Knockdown of lncRNA MFI2 expression suppressed MG63 and SAOS-2 cell proliferation, migration and invasion, and induced cell apoptosis. Furthermore, the expression of forkhead box P4 (FOXP4) was significantly increased and it was positively associated with lncRNA MFI2 expression in tumor tissues. In addition, knockdown of FOXP4 expression by RNA interference strategy inhibited osteosarcoma cell proliferation, migration and invasion, and promoted cell apoptosis. All the results indicated lncRNA MFI2 could promote proliferation and migration of osteosarcoma cells by regulating FOXP4 expression, which suggested critical roles of lncRNA MFI2 and FOXP4 in occurrence and development of human osteosarcoma. PMID- 27513471 TI - Population-Based Incidence Rates of First-Ever Stroke in Central Vietnam. AB - INTRODUCTION: Stroke incidence data with methodologically acceptable design in Southeast Asia countries is limited. This study aimed to determine incidence of age-, sex- and subtype-specific first-ever stroke (FES) in Vietnam. METHODS: We conducted a hospital-based retrospective study, targeting all stroke cases hospitalized at a solo-provider hospital in our study site of Nha Trang from January 2009 to December 2011 with International Classification of Diseases, 10th revision (ICD-10) codes I60-69. We calculated positive predictive values (PPVs) of each ICD-10-coded stroke by conducting a detailed case review of 190 randomly selected admissions with ICD-10 codes of I60-I69. These PPVs were then used to estimate annual incident stroke cases from the computerized database. National census data in 2009 was used as a denominator. RESULTS: 2,693 eligible admissions were recorded during the study period. The crude annual incidence rate of total FES was 90.2 per 100,000 population (95% CI 81.1-100.2). The age-adjusted incidence of FES was 115.7 (95% CI 95.9-139.1) when adjusted to the WHO world populations. Importantly, age-adjusted intracerebral hemorrhage was as much as one third of total FES: 36.9 (95% CI 26.1-51.0). CONCLUSIONS: We found a considerable proportion of FES in Vietnam to be attributable to intracerebral hemorrhage, which is as high or exceeding levels seen in high-income countries. A high prevalence of improperly treated hypertension in Vietnam may underlie the high prevalence of intracerebral hemorrhagic stroke in this population. PMID- 27513472 TI - MixMC: A Multivariate Statistical Framework to Gain Insight into Microbial Communities. AB - Culture independent techniques, such as shotgun metagenomics and 16S rRNA amplicon sequencing have dramatically changed the way we can examine microbial communities. Recently, changes in microbial community structure and dynamics have been associated with a growing list of human diseases. The identification and comparison of bacteria driving those changes requires the development of sound statistical tools, especially if microbial biomarkers are to be used in a clinical setting. We present mixMC, a novel multivariate data analysis framework for metagenomic biomarker discovery. mixMC accounts for the compositional nature of 16S data and enables detection of subtle differences when high inter-subject variability is present due to microbial sampling performed repeatedly on the same subjects, but in multiple habitats. Through data dimension reduction the multivariate methods provide insightful graphical visualisations to characterise each type of environment in a detailed manner. We applied mixMC to 16S microbiome studies focusing on multiple body sites in healthy individuals, compared our results with existing statistical tools and illustrated added value of using multivariate methodologies to fully characterise and compare microbial communities. PMID- 27513473 TI - SRCIN1 Suppressed Osteosarcoma Cell Proliferation and Invasion. AB - SRCIN1 (SRC kinase signalling inhibitor 1) is a new tumor suppressor gene. Previous studies showed that SRCIN1 played a tumor suppressor role in the development of lung cancer and breast cancer. However, the role of SRCIN1 in osteosarcoma is still unknown. In this study, we demonstrated that SRCIN1 was downregulated in osteosarcoma cell lines compared with osteoblastic cell line. Moreover, SRCIN1 was downregulated in osteosarcoma tissues compared with the adjacent tissues. Further investigation revealed that overexpression of SRCIN1 inhibited the osteosarcoma cell line MG-63 proliferation. This effect was confirmed by measuring the ki-67 and PCNA expression. SRCIN1 overexpression promoted E-cadherin expression and suppressed N-cadherin, Vimentin and Snail expression, suggesting that SRCIN1 overexpression inhibited EMT of the osteosarcoma cell. In addition, ectopic expression of SRCIN1 inhibited the MG-63 cell colony formation and invasion. These data suggested that SRCIN1 acted as a tumor suppressor gene in the development of osteosarcoma. PMID- 27513474 TI - Is One Trial Sufficient to Obtain Excellent Pressure Pain Threshold Reliability in the Low Back of Asymptomatic Individuals? A Test-Retest Study. AB - The assessment of pressure pain threshold (PPT) provides a quantitative value related to the mechanical sensitivity to pain of deep structures. Although excellent reliability of PPT has been reported in numerous anatomical locations, its absolute and relative reliability in the lower back region remains to be determined. Because of the high prevalence of low back pain in the general population and because low back pain is one of the leading causes of disability in industrialized countries, assessing pressure pain thresholds over the low back is particularly of interest. The purpose of this study study was (1) to evaluate the intra- and inter- absolute and relative reliability of PPT within 14 locations covering the low back region of asymptomatic individuals and (2) to determine the number of trial required to ensure reliable PPT measurements. Fifteen asymptomatic subjects were included in this study. PPTs were assessed among 14 anatomical locations in the low back region over two sessions separated by one hour interval. For the two sessions, three PPT assessments were performed on each location. Reliability was assessed computing intraclass correlation coefficients (ICC), standard error of measurement (SEM) and minimum detectable change (MDC) for all possible combinations between trials and sessions. Bland Altman plots were also generated to assess potential bias in the dataset. Relative reliability for both intra- and inter- session was almost perfect with ICC ranged from 0.85 to 0.99. With respect to the intra-session, no statistical difference was reported for ICCs and SEM regardless of the conducted comparisons between trials. Conversely, for inter-session, ICCs and SEM values were significantly larger when two consecutive PPT measurements were used for data analysis. No significant difference was observed for the comparison between two consecutive measurements and three measurements. Excellent relative and absolute reliabilities were reported for both intra- and inter-session. Reliable measurements can be equally achieved when using the mean of two or three consecutive PPT measurements, as usually proposed in the literature, or with only the first one. Although reliability was almost perfect regardless of the conducted comparison between PPT assessments, our results suggest using two consecutive measurements to obtain higher short term absolute reliability. PMID- 27513475 TI - Effects of a randomized gratitude intervention on death-related fear of recurrence in breast cancer survivors. AB - OBJECTIVE: Among the most prevalent and distressing concerns endorsed by breast cancer survivors is fear of cancer recurrence (FOR), and one of the most salient facets is the worry that a recurrence of cancer could cause one's death. The primary goal of the present study was to test the effects of a brief, low-cost gratitude intervention on overall FOR and death-related FOR, positing pursuit of meaningful goals as a theoretically driven putative mediator. To replicate published tests of similar gratitude-eliciting interventions, positive affect (PA) was also considered as an outcome. METHOD: Sixty-seven women with early stage breast cancer were randomly assigned to either a 6-week online gratitude intervention or a 6-week online control condition. Outcomes were assessed at pre- and posttreatment, as well as 1 month and 3 months after the end of treatment. The mediator, meaningful goal pursuit, was measured via assessments over the 6 week intervention period. RESULTS: Results revealed that patients in the gratitude intervention experienced a significant decrease in death-related FOR compared to the control condition. Moreover, this effect was significantly mediated by meaningful goal pursuit (and not by PA). The gratitude intervention was also found to prevent declines in PA observed in the control condition. CONCLUSIONS: Overall, findings support the notion that a brief gratitude intervention can promote well-being and psychological adaptation to cancer by stimulating the pursuit of meaningful goals and subsequently reducing death related FOR. (PsycINFO Database Record PMID- 27513476 TI - A model of parental distress and factors that mediate its link with parental monitoring of youth diabetes care, adherence, and glycemic control. AB - OBJECTIVE: Parental monitoring of adolescents' diabetes self-care is associated with better adherence and glycemic control (A1c). A number of parent-level factors are associated with higher levels of parental monitoring, including lower levels of parental distress (depressive symptoms, stress, anxiety), as well as higher levels of parental self-efficacy for diabetes management and authoritative parenting. Often studied in isolation, these factors may be best considered simultaneously as they are interrelated and are associated with parental monitoring and youth adherence. METHOD: Structural equation modeling with a cross sectional sample of 257 parent/youth (aged 11-14) dyads: (a) examined a broad model of parental factors (i.e., parental distress, parental diabetes self efficacy, authoritative parenting), and (b) assessed their relation to parental monitoring, youth adherence, and A1c. Post hoc analyses of variance (ANOVAs) evaluated clinical implications of daily parental monitoring. RESULTS: Parental distress was not related directly to parental monitoring. Instead less distress related indirectly to more monitoring via higher parental self-efficacy and more authoritative parenting which, in turn, related to better adherence and A1c. Higher parental self-efficacy also related directly to better youth adherence and then to better A1c. Clinically, more parental monitoring related to more daily blood glucose checks and to better A1c (8.48% vs. 9.17%). CONCLUSIONS: A broad model of parent-level factors revealed more parental distress was linked only indirectly to less monitoring via lower parental self-efficacy and less authoritative parenting. Behaviorally, more parental monitoring related to better adherence and to clinically better A1c in adolescents. Further study of parent level factors that relate to parental distress and monitoring of adherence appears warranted. (PsycINFO Database Record PMID- 27513477 TI - Brief psychological intervention in patients with cervical cancer: A randomized controlled trial. AB - OBJECTIVES: The diagnosis and treatment of cancer is considered a major life stress that has potential effects on one's psychological well-being. This study investigated the possible benefits of a brief psychological intervention based on gratitude and mindfulness for positive and negative affect in patients with cervical cancer and explored the potentially mediating role of rumination and reappraisal. METHODS: A randomized controlled trial was conducted in 3 public hospitals in China between April 2014 and December 2014. One-hundred twenty postoperative cervical cancer patients were randomly assigned into an intervention group or a wait-list control group. Participants completed self report measures of positive and negative affect, rumination, and reappraisal before and after the 4-week intervention or waiting period. The outcome effects of the intervention were analyzed by generalized estimating equations (GEE). Mediation analyses were performed using a nonparametric bootstrapping procedure. RESULTS: GEE results indicated significant Time * Group interaction effects on positive affect (B = 1.60, chi2 = 25.90, p < .001), negative affect (B = -2.13, chi2 = 28.02, p < .001), rumination (B = -2.48, chi2 = 6.48, p = .011), and reappraisal (B = 3.28, chi2 = 41.17, p < .001) for the intervention. The effect of the intervention on positive and negative affect was mediated by changes in rumination and reappraisal respectively. CONCLUSIONS: The brief psychological intervention improved positive affect and reappraisal and reduced negative affect and rumination in women with cervical cancer. Findings support the beneficial effects for implementing this brief psychological intervention in oncology. (PsycINFO Database Record PMID- 27513478 TI - Longitudinal associations between self-regulation and health across childhood and adolescence. AB - OBJECTIVE: There is some evidence to suggest that one's ability to delay gratification is associated with a lower body mass index (BMI) and slower overall weight gain. Less is known about the role that a broader set of self-regulatory skills, including attention focusing, inhibitory control, and impulsivity, might play in fostering not only a healthy weight but also better overall health and health-related behaviors such as sleep. METHOD: Participants in the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development were followed from birth through age 15 beginning in 1991. Self regulation was assessed when children were 4.5 years old, whereas health-related outcomes were assessed regularly between toddlerhood and adolescence. Structural equation modeling was used to test direct associations between self-regulation and either physical health or sleep in childhood and adolescence. RESULTS: Findings suggest that there are long-term benefits of self-regulation, indexed by multiple dimensions, for children's health-related outcomes. Children with better self-regulatory skills demonstrated smaller increases in standardized BMI scores and maintained greater mother-reported health across childhood and adolescence. Furthermore, better self-regulation predicted fewer sleep problems and longer sleep duration when children were 8 and 11 but not when they were 15. CONCLUSIONS: Early self-regulation, marked by numerous skills, appears to have long-term benefits for children's health-related outcomes. These findings provide some evidence that targeting childhood self-regulatory skills for improvement may help reduce poor health-related outcomes later in life and offer important insight into potential avenues for intervention. (PsycINFO Database Record PMID- 27513479 TI - The Spatio-Temporal Distribution of Particulate Matter during Natural Dust Episodes at an Urban Scale. AB - Dust storms are a common phenomenon in arid and semi-arid areas, and their impacts on both physical and human environments are of great interest. Number of studies have associated atmospheric PM pollution in urban environments with origin in natural soil/dust, but less evaluated the dust spatial patterns over a city. We aimed to analyze the spatial-temporal behavior of PM concentrations over the city of Beer Sheva, in southern Israel, where dust storms are quite frequent. PM data were recorded during the peak of each dust episode simultaneously in 23 predetermined fixed points around the city. Data were analyzed for both dust days and non-dust days (background). The database was constructed using Geographic Information System and includes distributions of PM that were derived using inverse distance weighted (IDW) interpolation. The results show that the daily averages of atmospheric PM10 concentrations during the background period are within a narrow range of 31 to 48 MUg m-3 with low variations. During dust days however, the temporal variations are significant and can range from an hourly PM10 concentration of 100 MUg m-3 to more than 1280 MUg m-3 during strong storms. IDW analysis demonstrates that during the peak time of the storm the spatial variations in PM between locations in the city can reach 400 MUg m-3. An analysis of site and storm contribution to total PM concentration revealed that higher concentrations are found in parts of the city that are proximal to dust sources. The results improve the understanding of the dynamics of natural PM and the dependence on wind direction. This may have implications for environmental and health outcomes. PMID- 27513480 TI - [Not Available]. AB - La deteccion de la desnutricion hospitalaria continua de plena actualidad en la literatura medica y, a pesar de que desde hace dos decadas dejo de ser un tema novedoso, constituye un elemento recurrente en la bibliografia y motivo de abordajes monograficos en congresos y reuniones cientificas. PMID- 27513481 TI - [Not Available]. AB - Introduccion: la composicion lipidica de las formulas de nutricion parenteral (NP) se postula como posible factor de evolucion clinica.Objetivo: evaluar las diferencias en eficacia y seguridad de dos emulsiones lipidicas en NP.Material y metodos: estudio clinico prospectivo de pacientes posquirurgicos sometidos a NP durante mas de 7 dias en un periodo de 2 anos. Se administraron de forma indistinta 2 tipos de emulsiones lipidicas: enriquecida con acidos grasos omega 3 (SMOFlipid Fresenius Kabi(r)) o con acido oleico omega 9 (Clinoleic Baxter(r)). Se analizaron variables epidemiologicas, analiticas, complicaciones infecciosas y mortalidad.Resultados: se estudio un total de 154 pacientes con edad media de 64,36 +/- 13,73 anos, de los que 95 eran hombres (61%), 78 (51%) recibieron SMOFlipid(r) y 76 (49%) Clinoleic(r). La estancia media fue de 16,91 +/- 4,23 dias, la duracion de la NP 9,68 +/- 3,25 dias y la mortalidad del 11%. Se diagnosticaron 58 (37%) infecciones. No existieron diferencias significativas en cuanto a los parametros analiticos lipidicos, hepaticos o nutricionales (medidos al inicio y al 7.o dia) ni en su evolucion (estancia media, complicaciones infecciosas ni mortalidad) entre los dos grupos de pacientes.Conclusion: los pacientes sometidos a NP presentan similares caracteristicas evolutivas con independencia de la emulsion lipidica utilizada. La bibliografia actual apunta a un beneficio de la disminucion del aporte de acidos grasos omega 9, pero no se han encontrado diferencias significativas entre las formulas comparadas. PMID- 27513482 TI - [Not Available]. AB - OBJECTIVE: We investigate the influence of caloric and protein deficit on mortality and length of hospital stay of critically ill patients. METHODS: A cohort prospective study including 100 consecutive patients in a tertiary intensive care unit (ICU) receiving enteral or parenteral nutrition. The daily caloric and protein deficit were collected each day for a maximum of 30 days. Energy deficits were divided into critical caloric deficit (>= 480 kcal/day) and non-critical caloric deficit (<= 480 kcal/day); and in critical protein deficit (>= 20 g/day) and non-critical protein deficit (<= 20 g/day). The findings were correlated with hospital stay and mortality. RESULTS: The mortality rate was 33%. Overall, the patients received 65.4% and 67.7% of the caloric and protein needs. Critical caloric deficit was found in 72% of cases and critical protein deficit in 70% of them. There was a significant correlation between length of stay and accumulated caloric deficit (R = 0.37; p < 0.001) and protein deficit (R = 0.28; p < 0.001). The survival analysis showed that mortality was greater in patients with both critical caloric (p < 0.001) and critical protein deficits (p < 0.01). The Cox regression analysis showed that critical protein deficit was associated with higher mortality (HR 0.25, 95% CI 0.07-0.93, p = 0.03). CONCLUSIONS: The incidence of caloric and protein deficit in the ICU is high. Both caloric and protein deficits increase the length of hospital stay, and protein deficit greater than 20 g/day is an independent factor for mortality in critical care unit. PMID- 27513483 TI - [Not Available]. AB - INTRODUCTION: Enteral nutrition is an important therapy for severely critically ill patients. The timing and amount of energy have been highly debated. OBJECTIVE: The aim of the present study was to directly compare the timing and the caloric targets in critically ill patients. METHODS: Retrospective cohort study conducted at a single center, comparing timing and caloric goal for critically ill patients. Patients were stratified according to the start of nutritional therapy (24, 48, or more than 48 h) and the amount of energy delivered (target adequacy of previously calculated percentage in the first week). Statistical analysis was performed using parametric and non-parametric tests for independent samples and logistic regression. The results were expressed as mean +/- standard deviation or incidence and percentage. RESULTS AND DISCUSSION: There were no differences in major clinical outcomes in relation to the achievement of percentage of caloric goal at the end of the first week of the study. The beginning of caloric intake on the first day of hospitalization was associated with reduced mortality in the intensive care unit, but not with hospital mortality. The strategy of an early and limited amount of calories seems to be associated with a better outcome. Prospective studies evaluating and comparing these strategies are recommended. PMID- 27513484 TI - [Not Available]. AB - BACKGROUND: The different body components may contribute to the development of insulin resistance and type 2 diabetes mellitus. The aim of the present study was to examine the association of fat mass and fat free mass indices with markers of insulin resistance, independently of each other and giving, at the same time, gender-specific information in a wide cohort of European adolescents. METHODS: A cross-sectional study in a school setting was conducted in 925 (430 males) adolescents (14.9 +/- 1.2 years). Weight, height, anthropometric, bioimpedance and blood parameters were measured. Indices for fat mass and fat free mass, and homeostatic model assessment (HOMA) were calculated. Multiple regression analyses were performed adjusting for several confounders including fat free mass and fat mass when possible. RESULTS: Indices of fat mass were positively associated with HOMA (all p < 0.01) after adjusting for all the confounders including fat free mass indices, in both sexes. Fat free mass indices were associated with HOMA, in both males and females, after adjusting for center, pubertal status, socioeconomic status and cardiorespiratory fitness, but the associations disappear when including fat mass indices in the adjustment's model. CONCLUSION: Fat mass indices derived from different methods are positively associated with insulin resistance independently of several confounders including fat free mass indices. In addition, the relationship of fat free mass with insulin resistance is influenced by the amount of fat mass in European adolescents. Nevertheless, future studies should focus not only on the role of fat mass, but also on other body components such as fat free mass because its role could vary depending of the level and distribution of fat mass. PMID- 27513485 TI - [Not Available]. AB - Anorexia nervosa (AN) is the most prevalent of eating disorders in children and adolescents, and its treatment is long and complex, involving a multidisciplinary team. Nutritional rehabilitation and restoration of a healthy body weight is one of the central goals in the initial stages of inpatient treatment. However, current recommendations on initial energy requirements for these patients are inconsistent, with a clear lack of controlled studies, available scientific evidence and global consensus on the most effective and safe refeeding practices in hospitalized adolescents with anorexia nervosa (AN). Conservative refeeding recommendations have been classically established in order to prevent the refeeding syndrome. Nevertheless, various works have recently appeared advocating a higher initial caloric intake, without observing more complications or refeeding syndrome, and allowing a shorter average stay. We present our experience in the treatment of restricting AN with a conservative progressive treatment. We have obtained good results with this approach, which was well tolerated by patients, with no observing complications. As a consequence, the medical team could establish a pact about the therapeutic goals with the patients in an easier way. PMID- 27513486 TI - [Not Available]. AB - Introduccion: el bajo peso al nacer (BPN) es un factor de riesgo para desarrollar obesidad en la vida adulta.Objetivo: evaluar diferencias en la composicion corporal de ninos de entre 8 y 10 anos de edad con y sin antecedente de BPN.Metodos: fue un estudio observacional, transversal comparativo. Participaron 112 ninos (95 con adecuado peso al nacer [APN] y 17 con BPN). Se realizo antropometria (peso, talla, circunferencias de cintura y cadera, pliegue cutaneo de triceps [PCT] y subescapular [PCSE]).Resultados: se encontro una prevalencia combinada del 41% para sobrepeso y obesidad en ambos grupos de estudio. El porcentaje de grasa corporal total fue menor en las ninas con BPN (no significativo); sin embargo, el indicador PCT-PCSE fue significativamente mas alto (p = 0,04) que el de las ninas con APN. En contra de lo esperado, al estratificar segun porcentaje de grasa y peso al nacer, se encontro que el grupo con BPN presento un porcentaje de grasa bajo (p < 0,05) en comparacion con el grupo de APN, siendo 6 veces mayor la posibilidad de que un nino con BPN presente porcentaje de grasa total bajo a esta edad.Conclusiones: a estas edades no se encontro mayor porcentaje de grasa en el grupo con BPN en comparacion con el de APN; sin embargo, las ninas con BPN presentaron mayor deposicion de grasa troncal que las de APN. La deposicion de grasa es un indicador que hay que considerar, y no unicamente el indice de masa corporal, en la evaluacion nutricia infantil. PMID- 27513487 TI - [Not Available]. AB - Introduccion: los supervivientes de leucemia aguda (LA) infantil presentan un riesgo incrementado de alteraciones metabolicas y cardiovasculares que aumentan su morbimortalidad a largo plazo.Objetivo: estimar la prevalencia de obesidad, resistencia a la insulina, dislipemia e hipertension arterial como factores de riesgo cardiometabolico (FRCM) en un grupo de supervivientes de LA infantil, y analizar las posibles causas asociadas a su desarrollo.Material y metodos: estudio observacional retrospectivo en 47 supervivientes de LA tratados en un periodo de 4 anos, que recibieron seguimiento durante 10 anos.Resultados: el 40% de los participantes presentaron al menos un FRCM durante el seguimiento, siendo la dislipemia (aumento LDL) el mas frecuente (38,3%), seguido de obesidad/sobrepeso (31,9%) y HTA sistolica (23,4%). El sexo femenino se establecio como factor de riesgo parael desarrollo de todos ellos (RR 1,6; RR 3,16; RR 1,69; p < 0,05). Ningun superviviente desarrollo diabetes mellitus, pero si resistencia a la insulina el 19,4%. Los pacientes con leucemias de peor pronostico presentaron mayor riesgo de desarrollar obesidad, resistencia a la insulina y aumento de LDL (RR 3,56; RR 4,08; RR 2,53; p < 0,05). Los pacientes tratados con trasplante de progenitores hematopoyeticos presentaron mayor riesgo de obesidad, aumento de LDL e HTA sistolica (RR 2,86; RR 2,39; RR 3,12; p<0,05). La radioterapia se asocio de igual modo con un incremento de resistencia a la insulina e hipertension arterial sistolica (RR 2,47; RR 2,53; p < 0,05).Conclusiones: existe un aumento en la prevalencia de obesidad/sobrepeso, dislipemia, resistencia a la insulina y alteracion de la tension arterial sistolica en supervivientes de leucemia aguda infantil a lo largo del tiempo, especialmente en aquellos con enfermedades y tratamientos mas agresivos. PMID- 27513488 TI - [Not Available]. AB - Objetivo: el presente estudio tuvo por objetivos: a) determinar los valores de referencia de la condicion muscular mediante el indice general de fuerza (IGF); y b) estudiar si el IGF esta asociado con indicadores de adiposidad en ninos y adolescentes escolares de Bogota, Colombia.Metodos: del total de 7.268 ninos y adolescentes (9-17,9 anos) evaluados en el estudio FUPRECOL, 4.139 (57%) fueron mujeres. Se evaluo el IGF como marcador del desempeno muscular a partir de la tipificacion de las pruebas de fuerza prensil (FP) y salto de longitud (SL). El IGF se recodifico en cuartiles (Q), siendo el Q4 la posicion con mejor valor del IGF. El indice de masa corporal (IMC), la circunferencia de cintura (CC), el indice cintura/talla (ICT) y el porcentaje de grasa corporal (% GC) por bioimpedancia electrica se midieron como marcadores de adiposidad.Resultados: la edad media de los evaluados fue 12,8 +/- 2,3 anos. Se aprecia una tendencia hacia un incremento del nivel de condicion fisica muscular en los varones conforme aumenta la edad, y hacia la estabilidad o un ligero aumento en el caso de las mujeres. El IGF se relacionoinversamente con el ICT y % GC en los varones (r = 0,280, r = -0,327, p < 0,01), respectivamente. Los escolares ubicados en el Q4 del IGF presentaron menores valores en marcadores de adiposidad IMC, CC, ICT y % GC, p < 0,01, que su contraparte del Q1.Conclusion: se presentan valores de referencia del IGF a partir de la estandarizacion de los resultados obtenidos en la FP y SL. La evaluacion de la fuerza muscular en edades tempranas permitira implementar programas de prevencion de riesgo cardiovascular y metabolico futuro. PMID- 27513489 TI - [Not Available]. AB - Introduccion: la malnutricion en el anciano que ingresa en el hospital es bastante frecuente y condiciona no solo la extension de la estancia hospitalaria, sino el pronostico o la aparicion de otras patologias. Su valoracion puede basarse en medidas antropometricas, parametros bioquimicosy test nutricionales.Objetivos: valorar si la circunferencia de pantorrilla es un indicador valido de desnutricion en el paciente anciano recien hospitalizado, analizando la posible influencia del sexo y la edad.Material y metodos: estudio descriptivo en 907 pacientes ancianos pluripatologicos a su ingreso en el hospital, con una edad media de 82,13 +/- 7,08 anos. Se han realizado determinaciones bioquimicas incluyendo recuento de linfocitos, colesterol total, transferrina y albumina.Se aplicaron en cada paciente las escalas de cribado nutricional MNA, NRS y VGS. Finalmente se determino la circunferencia de la pantorrilla.Resultados: los test nutricionales muestran un porcentaje de desnutricion medio del 75%. Los parametros bioquimicos muestran un porcentaje de desnutricion que oscila del 63,4% al 76,7%, y la circunferencia de la pantorrilla un 74,2%. La prevalencia de desnutricion es mayor en mujeres, independientemente del parametro utilizado en su determinacion. El aumento en la edad, particularmente a partir de los 85 anos, y con todos los parametros analizados, tambien condiciona un mayor grado de desnutricion. Todos los parametros estudiados se correlacionan con la circunferencia de la pantorrilla, estableciendose el concepto "estar desnutrido" en el punto de corte de 29 cm, para ambos sexos y en todos los grupos de edad (sensibilidad 99,31%).Conclusiones: un 75% de la poblacion anciana presenta desnutricion a su ingreso en el hospital. La circunferencia de la pantorrilla es un marcador de desnutricion en el anciano de facil determinacion y alta sensibilidad, independiente del sexo y la edad. PMID- 27513490 TI - [Not Available]. AB - INTRODUCTION: There are few studies assessing overall diet and food patterns of the oldest population. OBJECTIVES: To examine food groups consumption (grams and servings) and their compliance with the dietary guidelines in community-dwelling very old Spanish adults. The relationship with the risk of malnutrition was also studied. METHODS: Within the cross-sectional health study of elderly people of Villanueva de la Canada (Madrid, Spain), in 98 non-institutionalized elders aged >= 80 years (66% women) food consumption was calculated from a 24-hour dietary recall and nutritional risk was assessed by Mini Nutritional Assessment (MNA). Statistical significance was evaluated at 95% confidence level (p < 0.05). RESULTS: Men consumed significantly higher amounts of snacks/pickles and alcoholic beverages. The consumption of cereals/grain products (2 servings/day), vegetables (1.5 servings/day) and meat, fish, eggs (1.4 servings/day), was below desirable levels. As nutritional status got worse, fruit consumption was significantly smaller (p = 0.039). Relatively weak but highly significant correlations were found between MNA and oils/fats, fruits and alcoholic beverages. After adjustment for energy intake, oils and fats and fruits associations disappeared whereas a negative association between milk/dairy products and MNA was found. CONCLUSIONS: Dietary patterns of the elderly population of Villanueva are departing from the traditional Mediterranean diet and though adequate consumption of fruits, milk/dairy products, oils/fats and sugar/confectionery has been achieved, cereals/grain products, vegetables and the meat, fish, eggs group consumption was below the desirable levels. Deterioration of the nutritional status coincided with a reduction in the consumption of all food groups except for ready meals and milk/dairy products whose consumption increased. Further research on the influence of fruit, milk/dairy products, wine and olive oil consumption on nutritional status is required. PMID- 27513491 TI - [Not Available]. AB - INTRODUCTION: Adiponectin, an adipocyte derived peptide, has anti-inflammatory and antiatherogenic effects, and improves insulin sensitivity. However, little is known about dietary predictors and their interactions with lifestyle on adiponectin concentrations, in apparently healthy young adults. OBJECTIVE: To evaluate the associations between plasma concentrations of adiponectin with dietary components and lifestyle in apparently healthy young adults. METHODS: Anthropometric and body composition, systolic and diastolic blood pressure, diet and lifestyle data of 157 healthy young adults, aged 18 and 35, were collected and analyzed. Blood samples were collected after fasting for 12 hours to determine adiponectin concentrations. Dietary and anthropometric indexes were calculated and analyzed. RESULTS: Adiponectin concentrations were significantly higher for women compared to men; and there was an indirect and significant correlation between adiponectin concentrations with BMI. There was a significant association between adiponectin concentrations with the healthy eating index, calories, lipids, proteins, fibers, riboflavin, and phosphorus, among others; and a tendency with carbohydrates and niacin. In multiple linear regression analysis, fiber and riboflavin (r2 = 0.0928; p = 0.0013) and carbohydrates and phosphorus were associated with the concentrations of adiponectin. The association with carbohydrates and phosphorus suffered interaction with gender (r2 = 0.2400; p < 0.0001), as well as the association with phosphorus also suffered interaction with physical activity (r2 = 0.1275; p = 0.0003). CONCLUSION: Plasma concentrations of adiponectin, in healthy young adults, seem to be modulated by components of diet depending on gender and physical activity. PMID- 27513492 TI - [Not Available]. AB - BACKGROUND: Vaspin is a newly-identifi ed adipocytokine associated with insulin resistance (IR). OBJECTIVE: The aim of this study was to investigate the correlation between plasma vaspin concentrations and IR and determine whether this association is affected by body composition, physical activity and pubertal stage in adolescents. METHODS: Were studied 484 Brazilian adolescents aged 10-14 years whose anthropometric, clinical, biochemical, and lifestyle measurements were analized. We evaluated the correlation between vaspin and risk factors for IR in adolescents with normal and high body fat percentage (%BF) and did a logistic regression to calculate the odds ratio for IR according to vaspin quartiles sex specifi c for the sample. RESULTS: Vaspin was positively correlated with IR in adolescents with high %BF (r = 0.23, p = 0.003). The logistic regression analysis adjusted for sex, age, BMI, and pubertal stage showed that adolescents in the 2nd (OR = 0.43, 95% CI = 0.23-0.80, p = 0.008) and 3rd (OR = 0.46, 95% CI = 0.25-0.85, p = 0.014) quartile of vaspin concentration had a lower risk for IR. When the model was adjusted for %BF and physical activity, the association remained statically signifi cant only for adolescents in the 2nd quartile. CONCLUSION: Vaspin was correlated positively with risk factors associated with insulin metabolism in adolescents with high %BF. Vaspin was associated with a reduced risk of IR independently of BMI and pubertal stage and the association was infl uenced by body fat and physical activity in these adolescents. PMID- 27513493 TI - [Not Available]. AB - Objetivo: el objetivo de este estudio es evaluar las propiedades psicometricas del cuestionario de disfrute por el ejercicio fisico (PACES) en adolescentes con sobrepeso y obesidad.Metodos: participaron 139 adolescentes con sobrepeso y obesidad: 91 ninas (edad = 13,85 +/- 1,92 anos; indice de masa corporal [IMC] = 26,83 +/- 3,16 kg/m2) y 48 ninos (edad = 14,29 +/- 1,62 anos; IMC = 28,31 +/- 3,74 kg/m2). Para analizar el disfrute por la actividad fisica se empleo el cuestionario Physical Activity Enjoyment Scale (PACES).Resultados: los resultados del analisis factorial exploratorio y confirmatorio han mostrado una estructura de dos factores; a su vez el PACES presenta una consistencia interna muy alta (alfa de Cronbach = 0,908). La fiabilidad test-retest indica una buena concordancia temporal (Spearman rho = 0,815, p < 0,001). Por ultimo, el PACES en adolescentes con sobrepeso y obesidad manifiesta una validez convergente adecuada con la intencionalidad de ser activo (MIFA), la atraccion por la actividad fisica (CAPA), la resistencia cardiorrespiratoria y los pliegues suprailiacoy subescapular.Conclusion: los resultados confirman que el PACES es una medida valida y fiable del disfrute por la actividad fisica en adolescentes con sobrepeso y obesidad. El disfrute por la actividad fisica puede ser relevante en la participacion de los adolescentes con sobrepeso y obesidad en estas actividades. PMID- 27513494 TI - [Not Available]. AB - BACKGROUND: Mutation analysis has identified a G-> A transition in the promoter region of TNF-alpha gene at position -308 (rs1800629). OBJECTIVE: The aim of our study was to investigate the influence of polymorphism in -308 GA promoter variant of the TNF alpha gene on metabolic response and weight loss secondary to two hypocaloric diets. METHOD: A sample of 283 obese subjects was enrolled in a consecutive prospective way. In the basal visit, patients were randomly allocated during 9 months to diet HP (high protein/low carbohydrate hypocaloric diet) and diet S (standard hypocaloric diet). RESULTS: There were no significant differences between the positive effects on weight loss in either genotype group with both diets. With both diets and only in wild genotype (diet HP vs. diet S), total cholesterol (-9.1 +/- 3.4 mg/dL vs. -6.9 +/- 2.0 mg/dL; p > 0.05), LDL cholesterol (-9.0 +/- 2.9 mg/dL vs. -6.5 +/- 2.1 mg/dL; p > 0.05) and triglycerides (-23.1 +/- 5.1 mg/dL vs. -12.3 +/- 4.8 mg/dL; p < 0.05) decreased. The improvement in triglycerides was higher in subjects without A allele. With diet HP and only in wild genotype, insulin levels (-3.1 +/- 1.8 UI/L; p < 0.05) and HOMA-R (-0.8 +/- 0.1 units; p < 0.05) decreased. CONCLUSION: Carriers of -308 GG promoter variant of TNF-alpha gene have a better metabolic response than -308 GA obese with a high protein hypocaloric diet. PMID- 27513495 TI - [Not Available]. AB - BACKGROUND: The use of sagittal abdominal diameter (SAD) has been proposed for screening cardio-metabolic risk factors; however, its accuracy can be influenced by the choice of thresholds values. AIM: To determine the SAD threshold values for cardio-metabolic risk factors in Mexican adults; to assess whether parallel and serial SAD testing can improve waist circumference (WC) sensitivity and specificity; and to analyze the effect of considering SAD along with WC and body mass index (BMI) in detecting cardio-metabolic risk. METHODS: This cross sectional study was conducted during 2012-2014 in Northeast Mexico (n = 269). Data on anthropometric, clinical, and biochemical measurements were collected. Sex-adjusted receiver-operating characteristic curves (ROC) were obtained using hypertension, dysglycemia, dyslipidemia and insulin resistance as individual outcomes and metabolic syndrome as a composite outcome. Age-adjusted odds ratios and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: The threshold value for SAD with acceptable combination of sensitivity and specificity was 24.6 cm in men and 22.5 cm in women. Parallel SAD testing improved WC sensitivity and serial testing improved WC specificity. The co occurrence of high WC/high SAD increased the risk for insulin resistance by 2.4 fold (95% CI: 1.1-5.3), high BMI/high SAD by 4.3-fold (95% CI: 1.7-11.9) and SAD alone by 2.2-fold (95% CI: 1.2.-4.2). CONCLUSIONS: The use of SAD together with traditional obesity indices such as WC and BMI has advantages over using either of these indices alone. SAD may be a powerful screening tool for interventions for high-risk individuals. PMID- 27513496 TI - [Not Available]. AB - Introduccion: la categorizacion del estado nutricional a traves del indice de masa corporal (IMC) es uno de los recursos de valoracion clinica mas utilizados en el sindrome metabolico (SM). Sin embargo, es desconocida su capacidad para identificar las diferencias en la composicion corporal.Objetivo: determinar si las variaciones en el estado nutricional se reflejan en la composicion corporal en mujeres con SM e identificar la concordancia de clasificacion del riesgo cardiometabolico entre el estado nutricional e indices antropometricos.Material y metodos: la muestra incluyo 136 mujeres (edad 42 +/- 3,5 anos) con SM. Se evaluo el estado nutricional, masa muscular, masa adiposa, perimetro de cintura (PC), indice cintura-cadera (ICC) e indice cintura-estatura (ICE). Se compararon los valores de composicion corporale indices antropometricos; adicionalmente se determino la concordancia clasificatoria del riesgo cardiometabolico entre los indices y el IMC.Resultados: solo la edad (p = 0,358), estatura (p = 0,209) y porcentaje de adiposidad (p = 0,234) no mostraron diferencias significativas entre los grupos. La mejor concordancia clasificatoria del riesgo cardiometabolico se observo en el PC > 88 cm (94,9%) e ICE >= 0,5 (94,1%) al categorizar el IMC en normopeso vs. exceso de peso; mientras que el PC > 88 cm obtuvo mejor concordancia separando al grupo en normopeso-sobrepesovs. obesidad (85,3%), aunque la sensibilidad y especificidad fueron mas homogeneas con el ICC >= 0,85.Conclusion: el IMC no logra identificar las variaciones de la adiposidad corporal en mujeres con SM agrupadas segun su estado nutricional. El IMC presenta mejor sensibilidad que especificidad respecto a los indices considerados para determinar riesgo cardiometabolico en mujeres con SM. PMID- 27513497 TI - [Not Available]. AB - BACKGROUND: Heart failure (HF) patients develop important changes in body composition, but only a small number of studies have evaluated the associations between these changes and functional class deterioration in a prospective manner. OBJECTIVE: The aim of this study was to evaluate whether changes in bioimpedance parameters were associated with NYHA functional class deterioration over six months. METHODS: A total of 275 chronic stable HF patients confirmed by echocardiography were recruited. Body composition measurements were obtained by whole body bioelectrical impedance with multiple frequency equipment (BodyStat QuadScan 4000). We evaluated functional class using the New York Heart Association (NYHA) classification at baseline and after six months. RESULTS: According to our results, 66 (24%) subjects exhibited functional class deterioration, while 209 improved or exhibited no change. A greater proportion of patients exhibited higher extracellular water (> 5%), and these patients developed hypervolemia, according to location on the resistance/reactance graph. A 5% decrease in resistance/height was associated with functional class deterioration with an OR of 1.42 (95% CI 1.01-2.0, p = 0.04). CONCLUSIONS: Body composition assessment through bioelectrical impedance exhibited a valuable performance as a marker of functional class deterioration in stable HF patients. PMID- 27513498 TI - [Not Available]. AB - Introduccion: a pesar de que las caracteristicas antropometricas es uno de los metodos utilizados dentro de la seleccion de talentos deportivos, son pocos los estudios que han analizado el perfil morfologico del jugador de beisbol de elite.Objetivo: analizar el perfil antropometrico de los jugadores de beisbol de elite nacional de forma global y segun el puesto ocupado.Material y metodos: Doscientos diecisiete jugadores de beisbol masculino (edad: 23,87 +/- 5,32 anos) de la Division de Honor espanola participaron en el presente estudio. A todos ellos se les clasifico segun su posicion de juego y se les realizo una valoracion antropometrica. Posteriormente se calculo su somatotipo, composicion corporal, indice de masa corporal (IMC) y sumatorio de seis pliegues.Resultados: los jugadores no mostraron diferencias significativas en funcion de su posicion en el campo en la talla, el peso, los pliegues triceps, subescapular, biceps, supraespinal, abdominal y pierna, ni en el sumatorio de seis pliegues o el diametro biestiloideo. Si que se encontrarondiferencias significativas en el pliegue del muslo, perimetros del brazo contraido y pierna y diametros biepicondileo del humero y femur. Tampoco se hallaron diferencias significativas en el IMC, la composicion corporal o el somatotipo. Los valores de endomorfia fueron altos, los de mesomorfia altos o medio-altos y los de ectomorfia bajos, siendo la clasificacion del somatotipo mesoendomorfo o endomorfo-mesomorfo segun la posicion de juego.Conclusion: existe una gran homogeneidad en el perfil antropometrico de los jugadores de beisbol segun su posicion de juego, diferenciandose unicamente en algunas variables antropometricas como perimetros y diametros. PMID- 27513499 TI - [Not Available]. AB - Introduccion: actualmente los programas de entrenamiento intervalicos de alta intensidad parecen ser una forma de optimizar el tiempo, provocando cambios en la composicion corporal debido a la activacion de diferentes mecanismos hormonales y metabolicos.Objetivo: observar el efecto de cuatro semanas de entrenamiento de esprints repetidos basados en la prueba de Wingate sobre la potencia y la composicion corporal en adultos jovenes.Metodos: los participantes (22,4 +/- 1,8 anos) fueron asignados aleatoriamente a un grupo experimental o a un grupo control. Antes de comenzar y al acabar el periodo experimental, a los sujetos se les realizo una densitometria de cuerpo completo y una prueba de Wingate. El grupo experimental realizo 12 sesiones de esprints repetidos, realizando de 3 a 6 esprints de 30 segundos con un tiempo de recuperacion de 4 minutos. El grupo control continuo con su rutina diaria y no se le aplico ningun tipo de intervencion.Resultados: en el grupo experimental, la potencia media y maxima incremento un 9,4-16,5% (p < 0,001). Ademas, disminuyo la masa grasa total un 8,1% (p < 0,028) y la grasa abdominal un 10,0% (p < 0,038). El grupo control no sufrio cambios en ninguna de las variables estudiadas.Conclusiones: cuatro semanas de entrenamiento de esprints repetidos basados en la prueba de Wingate con un volumen especifico de ~3 minutos por sesion y una frecuencia de 3 sesiones por semana, muestra mejoras estadisticamente significativas en la potencia maxima y media. Ademas, provoca cambios en la composicion corporal, principalmente en la masa grasa total y de la zona abdominal. PMID- 27513500 TI - [Not Available]. AB - Introduccion y objetivos: las enfermedades cardiovasculares (ECV) son la principal causa de muerte mundial, por ello el objetivo de este estudio es analizar los factores de riesgo de ECV en los trabajadores de la Universidad de Alicante.Material y metodos: estudio transversal descriptivo. Muestra aleatoria (n = 124), 46,6% mujeres y 53,4% hombres, de edades entre 25-68 anos. Recogida de datos mediante cuestionario online autocumplimentado. VARIABLES: sociodemograficas, peso y talla autorreferidos, consumo de tabaco, actividad fisica, consumo diario de aceite de oliva, hortalizas-verduras, mantequilla margarina-nata y consumo semanal de reposteria comercial y frutos secos. Se realizo un analisis descriptivo con el paquete estadistico SPSS 19.0.Resultados: el 12% de mujeres y el 10,5% de los hombres mayores de 44 anos presentan obesidad; ademas, el 32% de mujeres y el 23,7% de los hombres no realizan actividad fisica. Consume aceite de oliva a diario el total de la muestra a estudio.Conclusion: los habitos alimentarios de los estudiados se asemejan a los patrones dieteticos mediterraneos considerados saludables. Destacar el cumplimiento de las recomendaciones de consumo de aceite de oliva y la realizacion de actividad fisica habitual como protectores de las ECV. El entorno laboral de la poblacion estudiada favorece unos habitos saludables. PMID- 27513501 TI - [Not Available]. AB - Objetivo: asociar patrones alimentarios con la autopercepcion del estado nutricional en estudiantes universitarios chilenos de Nutricion y Dietetica.Material y metodos: estudio transversal en el que se evaluo a 634 estudiantes de Nutricion y Dietetica, de los cuales un 86,4% eran mujeres. A cada alumno se le mostraron siete modelos anatomicos correspondientes a valores de indice de masa corporal (IMC) de 18, 22, 25, 27, 30, 35 y 40 kg/m2. Cada estudiante debia elegir el modelo con el que mejor se identificaba. Posteriormente, se realizo la evaluacion antropometrica, se calculo el IMC real comparandolo posteriormente con el IMC percibido, y finalmente se le aplico una encuesta alimentaria.Resultados: se observa que los sujetos que sobreestiman su peso presentan un menor porcentaje de cumplimiento en el consumo de frutas y verduras al dia; en cambio, el mayor porcentaje de sujetos que sigue las recomendaciones se encuentra en el grupo que se ve igual. Hay unaasociacion entre una buena percepcion de la imagen corporal y el consumo de 3 o mas porciones de frutas al dia OR = 0,554 (IC 95%; 0,360-0,852), 2 o mas porciones de verduras al dia OR = 0,438 (IC 95%; 0,283-0,678) y un consumo de alcohol menor de una vez a la semanaOR = 0,451 (IC 95%; 0,270-0,752).Conclusion: los estudiantes que registran una ingesta adecuada de verduras y frutas autodefinen su alimentacion como saludable e ideal y tienden a autopercibirse coherentemente en relacion con su estado nutricional; ademas, estos sujetos son los que presentan una ingesta menor de alimentos poco saludables. PMID- 27513502 TI - [Not Available]. AB - BACKGROUND AND AIM: The prevalence of hospital malnutrition (HM) is variable, explained by the variability of patients, the nutritional evaluation method used among others. The aim is to determine the frequency of malnutrition in hospitals in Latin America, and estimate its association with mortality and length of hospital stay. METHODS: This is an analytical, observational cohort study that included 7,973 patients of both genders, 18 and older, who provided their consent. The survey was administered during the first three days of admission. The nutritional status was estimated using Subjective Global Assessment (SGA) and the Nutrition Risk Screening (NRS), body mass index (BMI), percentage of change of weight (PCW) and co-morbidities. Serum albumin was obtained from the clinical chart. Length of stay (LOS) and the survival status at discharge (dead or alive) were also recorded. RESULTS: By SGA: 10.9% had severe malnutrition and 34% moderate malnutrition. By NRS: 36.9% had nutritional risk. Univariate analysis showed that NRS score and serum albumin were prognostic factors for mortality: NRS 3-4 (OR: 2.3, 95% CI: 1.9-2.8), NRS 5-7 (OR: 5.8, 95% CI: 4.9-6.9), serum albumin < 2.5 g/dl, (OR: 2.9, 95% CI: 2.2-3.8). These results were consistent and similar to a multivariate analysis. Both NRS and serum albumin were also independently and clinically associated to LOS. CONCLUSIONS: The prevalence of hospital malnutrition in Latin America is high. Our results show that screening with NRS and serum albumin can identify hospital malnutrition as well as providing clinically relevant prognostic value. PMID- 27513503 TI - [Not Available]. AB - INTRODUCTION: Nutrition research has traditionally promoted a nutrient-based approach; however, to evaluate population compliance with dietary recommendations, researchers have increasingly used dietary pattern analysis. OBJECTIVE: To assess the relationship between dietary patterns and vitamin D and calcium intake in an adult Mexican population. METHODS: We characterized the dietary patterns of 8,456 men and women aged 20-80 years who were participating in the Health Workers Cohort Study. Information on participants' sociodemographic conditions and physical activity was collected via self-administered questionnaires. A food frequency questionnaire was used to assess diet. In a cross-sectional analysis, we examined dietary patterns in relation to vitamin D and calcium consumption. RESULTS: Factor analysis revealed 3 major dietary patterns. Pattern 1, labeled as "prudent pattern", was characterized by high positive loads for the consumption of fresh vegetables, fresh fruits, whole grains, oils, and legumes. The second dietary pattern, named as "dairy and fish pattern", was positively correlated with intake of dairy foods, fish and other seafood, milk and whole grains. Finally, dietary pattern 3 was associated with higher intake of red meat, soft drinks, fats, eggs, white meat and alcoholic beverages. Of these, the "dairy and fish pattern" was positively and significantly associated with vitamin D and calcium consumption (r = 0.42, p < 0.001; and r = 0.20, p < 0.001 respectively). Conversely, the third dietary pattern was negatively associated with vitamin D and calcium intake (r = -0.28, p < 0.001; and r = -0.41, p < 0.001, respectively). CONCLUSIONS: In summary, our findings show that dietary patterns represented by high consumption of milk, dairy products, whole grains, fish are associated with higher consumption of vitamin D and calcium in Mexican adult population. Additionally, our results highlight the importance of following an appropriate dietary pattern to achieve adequate consumption of nutrients. PMID- 27513504 TI - [Not Available]. AB - Introduccion: en la actualidad existe un deficit en la evaluacion de comedores dirigidos a ninos menores de 3 anos, a pesar de que se han realizado numerosas intervenciones en los comedores escolares con el fin de conseguir una alimentacion segura y adecuada.Objetivo: realizar una evaluacion nutricional de los menus ofertados en los centros de educacion infantil de Sevilla.Material y metodos: se evaluo la frecuencia, variedad, rotacion de alimentos, metodos culinarios e informacion de los menus de seis centros infantiles de Sevilla. Se valoro el aporte energetico y nutricional mediante el programa Dietowin(r) y el metodo de pesada.Resultados: las frutas y verduras fueron deficitarias en la mayoria de los menus, y excesivas la carne, patatas, pasta y arroz. Se observo una escasa variedad de recetas por grupo de alimentos y no se daba una informacion completa del menu. Sin embargo, la variedad de procesos culinarios y la rotacion de alimentos fueron adecuadas. Aunque la energia y el aporte de carbohidratos (~55%) se ajustaban a las necesidades, se observo un aporte excesivo de proteinas (~19%) y deficiente de lipidos (< 30%), sobre todo de grasas insaturadas. Respecto a los micronutrientes,solo vitamina C, E y calcio estaban por debajo de lo recomendado.Conclusiones: los centros de educacion infantil estan haciendo un gran esfuerzo por cumplir las recomendaciones nutricionales, pero todavia deben disminuir el aporte proteico y aumentar las grasas insaturadas de la dieta. Ademas, deben fomentar la oferta de frutas y verduras, ampliar la variedad de recetas, dar mayor informacion y disminuir el aporte de alimentos carnicos. PMID- 27513505 TI - [Not Available]. AB - BACKGROUND: Many factors can influence an athlete to consume dietary supplements, such as age, sex and sports, among others. Few studies regarding the prevalence and associated factors are available for athletes, especially in developing countries. OBJECTIVE: The aim of the study was to determine the factors associated with the consumption of dietary supplements among Brazilian athletes. MATERIAL AND METHODS: This is a cross-sectional study involving 182 athletes of both sexes. The athletes answered a questionnaire containing sociodemographic and sports information, current consumption of supplements, consumption of pharmacological substances and information on body image disorder (Body Shape Questionnaire) and muscle dysmorphia (Muscle Appearance Satisfaction Scale). Analyses were performed using Pearson's Chi-squared test, the crude prevalence ratio (PR) and Poisson regression with robust variance. RESULTS: In the bivariate analysis, the male gender, age between 25-29 years, engaging in a remunerated activity, consumption of pharmacological substances, body image disorder, risk of muscle dysmorphia, power modality athletes and lack of medical care were factors associated with supplement intake. After the regression analysis, the consumption of supplements was associated with the male gender (PR: 1.68; 95% CI: 1.01; 2.78; p = 0.044), use of pharmacological substances (PR: 1.77; 95 %: 1.37; 2.27; p < 0.001) and the risk of muscle dysmorphia (PR: 1.75; 95% CI: 1.37; 2.23; p < 0.001). CONCLUSIONS: The results of this research clearly demonstrate the importance of professionals working closely with athletes to continuously monitor their use of supplements, since it was an alimentary behavior associated with other risk behavior (pharmacological use) as well as image disorders (muscle dysmorphia). PMID- 27513506 TI - [Not Available]. AB - Introduccion: la hipercolesterolemia es uno de los principales factores de riesgo en la enfermedad cardiovascular. Los esteroles vegetales se han postulado como agentes reguladores y beneficiosos para el control de esta.Objetivo: analizar el efecto de los esteroles vegetales anadidos en una leche en la reduccion del colesterol plasmatico en adultos jovenes.Metodos: ensayo clinico, controlado, aleatorizado, doble ciego y cruzado. Los esteroles (2,24 g diarios) fueron administrados en dos tomas de 350 ml de una leche comercial desnatada, durante dos periodos de 3 semanas, separados por una "fase de lavado" de 2 semanas, en el grupo experimental. Al grupo control se le administro la misma cantidad de leche desnatada, sin esteroles. Tanto al inicio como al final de cadaperiodo de intervencion se extrajeron muestras sanguineas. Se analizaron la composicion corporal, habitos de salud y los siguientes marcadores sanguineos: perfil lipidico, hematologico, inflamacion, etc.Resultados: se incluyeron 54 personas en el estudio con una edad media de 38,8 +/- 7,3 anos. La diferencia porcentual entre los marcadores basales y finales para el colesterol total, colesterol-LDL, colesterol-HDL, trigliceridos y colesterol no-HDL fueron del 9,73%, 12,5%, 1,9%, 3,15% y 13,2%, respectivamente. Se obtuvieron diferencias estadisticamente significativas entre el grupo experimental y el grupo control, para todos los marcadores analizados excepto para los trigliceridos.Conclusion: los esteroles vegetales suministrados en un alimento de consumo habitual, como la leche, pueden ser una estrategia terapeutica no farmacologica para el control de la hipercolesterolemia de alto interes sanitario. PMID- 27513507 TI - [Not Available]. AB - OBJECTIVE: The present study aims to compare the vertical counts registered by GT1M, GT3X and ActiTrainer. METHODS: Treadmill activities, repeated sit-stands and rest were completed by 31 young, 31 adults and 35 older adults while wearing the accelerometers (GT1M, GT3X and ActiTrainer) on their right hips. Independent sample t-test analyses were performed to determine differences between counts in each age group and activities along with the Bland & Altman analysis to determine the degree of agreement. In order to determine the correction factor for the ActiTrainer counts, the linear regression forward analysis was used to minimize differences with the GT3X and the GT1M counts. RESULTS: Differences among ActiTrainer, GT1M, and GT3X were revealed in all activities except in rest. The counts for ActiTrainer were significantly lower than those of GT3X and GT1M. The correction factor for ActiTrainer with GT1M (GT1M counts = 3185.564 + 649.647; *ActiTrainer counts - 36.163; *weight [kg] - 7.545 *age [years] r = 0.864; r2 = 0.746; r2 corrected = 0.745; SEE = 1451) and GT3X (GT3X counts = 3501.977 + 705.662 *ActiTrainer counts - 40.523 *weight [kg] - 11.864 *age [years] r = 0.901; r2 = 0.812; r2 corrected = 0.811; SEE = 310.160) reduced these differences. CONCLUSION: The GT1M and GT3X vertical counts may be compared. However, a correction factor to decrease differences to compare ActiTrainer counts with those of GT1M or GT3X counts must be applied. PMID- 27513508 TI - [Not Available]. AB - The endangered causes of Taxus chinensis var. maireiin the Taihang Mountains are analyzed in three sides in connection with the situation that is resources increasing attenuation.The first is biological factors such as pollination barriers, deeply dormancy seed, cannot vegetative propagation under natural conditions, poor adaptability of seedling to environment and slow growth. The second is environmental factors such as very limited distribution environment and position in community. The third is interference of persons and other animals.According to these factors, we provide three measures to protect Taxus chinensis var. maireiin three sides that protect existing resources, breed subsequent resources and find new pathway of producing taxol. PMID- 27513509 TI - [Not Available]. AB - OBJECTIVES: The association between fish consumption and the risk of breast cancer has not been established yet. Results from epidemiological studies are inconsistent. We conducted a meta-analysis to examine the association between fish consumption and the risk of breast cancer. METHODS: We identified eligible studies in Medline and EMBASE up to February 2015 and the reference lists of original studies and review articles on this topic. Summary relative risks with their 95% confidence intervals were calculated with a random-effects model. RESULTS: We identified 27 studies eligible for analysis. The summary relative risk of breast cancer for the highest consumption of fish compared with the lowest was 0.96 (95% CI = 0.87-1.07), with evidence of heterogeneity (Q = 69.09, p < 0.001, I2 = 68.0%). Four studies investigated lean fish consumption and revealed that there was a small increase in the risk of breast cancer (summary RR = 1.09, 95% CI = 1.00-1.19). As only four studies were included in the subgroup analysis, results must be interpreted with caution. CONCLUSIONS: The overall current literature on fish consumption and the risk of breast cancer suggested no association. Further well-designed prospective studies are needed to explore fish consumption in relation to breast cancer risk. PMID- 27513510 TI - [Not Available]. AB - Objetivo: analizar la concordancia de dos metodos de medicion (Google MapsTM vs. Sistema de Informacion Geografica) para la determinacion de la distancia desde el domicilio familiar hasta el colegio.Metodos: un total de 542 escolares de entre 8 11 anos de edad (media = 9,36 +/- 0,6) del sur de Espana participaron en el estudio, facilitando la direccion de su domicilio familiar. La distancia desde el domicilio familiar al colegio se calculo mediante la utilizacion de dos programas diferentes:Google MapsTM y Sistema de Informacion Geografica (GIS) en ruta y en linea recta. La asociacion entre ambos metodos fue analizada utilizando la correlacion de Spearman y el grado de acuerdo a traves del coeficiente de correlacion intraclase (ICC), asi como el metodo Bland Altman.Resultados: la correlacion entre ambos metodos de medicion propuestos fue muy significativa (r = 0,966, p < 0,001; r = 0,984, p < 0,001; y r = 0,954, p < 0,001, respectivamente), y la concordancia fue excelente (ICC = 0,96, p < 0,001; ICC = 0,92, p < 0,001; ICC = 0,97, p < 0,001).Conclusiones: los metodos de medicion estudiados podrian ser utilizados en funcion de las necesidades de la investigacion, al presentar ambos una alta concordancia. Sin embargo, se recomienda la utilizacion del Sistema de Informacion Geografica en ruta si se cuenta con medios yfinanciacion, por tratarse de un metodo constatado en fiabilidad y validez. PMID- 27513511 TI - [Not Available]. AB - La fuerza influye directamente en el estado de salud y en la capacidad de fitness, motivo por el que el entrenamiento contra resistencias o resistance training (RT) se incluye dentro de aquellos programas de ejercicio encaminados a mejorar la salud y calidad de vida. Debido a que muchasenfermedades cursan con alteracion de la masa y funcionalidad muscular y a que el RT es la principal modalidad de ejercicio encaminada a mejorar la funcion muscular, el objetivo de la presente revision bibliografica ha sido exponer las evidencias actuales sobre las adaptaciones delRT, asi como su posible aplicacion en patologias como la obesidad, diabetes, dislipemia, hipertension, cancer, Parkinson, esclerosis multiple o fibromialgia. El RT en estas enfermedades puede aumentar los niveles de masa muscular, disminuyendo los niveles de masa grasa, los nivelesde acidos grasos en sangre y la glucemia, incrementando la sensibilidad a la insulina, y disminuyendo los niveles de citokinas inflamatorias. El RT, ademas, mejora el gasto cardiaco y la funcionalidad endotelial, regulando la tension arterial e incrementando el consumo de oxigeno. Las ganancias de fuerza muscular mejoran la funcionalidad y la calidad de vida, especialmente en poblacion con una afectacion neuromuscular grave, como pudieran ser los enfermos de esclerosis multiple, fibromialgia o Parkinson. Por ello, el RT debe ser incorporado como parte del tratamiento en las personas que presentan determinado tipo de patologias. PMID- 27513512 TI - [Not Available]. AB - El indice de masa corporal (IMC) otorga uno de los indices mas usados para determinar el estado nutricional de la poblacion a nivel mundial, donde a pesar de existir recomendaciones claras y definidas para su interpretacion como el sexo, edad, raza, entre otros, normalmente se estandariza su clasificacion, independiente de las variables, aumentando el error en el resultado y en la clasificacion del estado nutricional.El uso de la composicion corporal a traves de la antropometria entrega mayor informacion que el IMC, siendo la masa grasa y la masa muscular los principales resultados utiles.Este articulo presenta una revision de las ecuaciones existentes y propone aquellas mas simples y con menor error de estimacion para ser usadas como una herramienta que reemplace o complemente al IMC, favoreciendo una mejor comprension e interpretacion del estado nutricional y nivelde actividad fisica en ninos y adolescentes. PMID- 27513513 TI - [Not Available]. AB - Introduccion: la disfagia es un sintoma que se refiere a la dificultad para mover el bolo alimentario desde la boca al estomago. A pesar de su relevancia y de la gravedad de sus posibles complicaciones, es poco conocida y estudiada. La prevalencia de la disfagia orofaringea en enfermosde alzheimer es de un 84% y puede originar complicaciones de gran trascendencia clinica como consecuencia de las alteraciones en la eficacia de la deglucion, y en la seguridad de la misma.Objetivo: conocer el estado actual del conocimiento en relacion al abordaje de la disfagia en enfermos de alzheimer, localizando aquellos factores que permitan un diagnostico precoz que facilite la prevencion de complicaciones y la eleccion de la pauta de actuacion mas adecuada.Metodologia: revision sistematica. Estudios publicados entre 2005 y 2014 en ingles y castellano. Bases de datos: PubMed, Cochrane, Scopus, Elsevier, Scielo y Dialnet. Terminos MeSH empleados: disfagia, dysphagia, alzheimer, modified y texture food.Resultados: el diagnostico en los pacientes de alzheimer se realiza mediante metodos clinicos y exploraciones complementarias como la videofluoroscopia, considerada como el estandar para el estudio de la disfagia orofaringea, ya que permite identificar entre 1/3 y 1/4 de los pacientes que presentan aspiraciones silentes no diagnosticables clinicamente. Existen estrategias terapeuticas que incluyen cambios en el volumen y viscosidad del bolo, cambios posturales, maniobras deglutorias, procedimientos de rehabilitacion y tecnicas de incremento sensorial que han demostrado su eficacia, pero se trata de una labor compleja que exige un abordaje multidisciplinar para un correctodiagnostico y tratamiento.Conclusiones: existe una escasa evidencia cientifica en el abordaje de la disfagia y un gran desconocimiento en cuanto a la alimentacion de los enfermos de alzheimer. Esta patologia necesita una intervencion multidisciplinar en la cual las medidas dieteticas desempenan un papel primordial. PMID- 27513514 TI - [Not Available]. AB - Objetivos: dar a conocer las recomendaciones relacionadas con la Nutricion Humana y Dietetica (NHyD) de la Guia de Practica Clinica para el manejo de la enfermedad de Parkinson del Sistema Nacional de Salud (GPC-EP/SNS) y favorecer su difusion e implementacion en la practica. El objetivo secundario es presentar la implicacion de los profesionales de la NHyD en la elaboracion de la guia.Material y metodos: siguiendo el Manual Metodologico de Elaboracion de Guias de Practica Clinica en el Sistema Nacional de Salud, se formularon las preguntas clinicas, se realizo una busqueda sistematica para cada pregunta en bases de datos (PubMed/Medline, Embase, Cochrane Library, CRD, LILACS, IBECS y ClinicalTrials), se definieron los criterios de elegibilidad, al menos dos investigadores seleccionaron los estudios, se realizo lectura critica de la literatura se resumio en tablas de sintesis de evidencia y se establecieron las recomendaciones.Resultados: se propusieron 14 preguntas relacionadas directamente con NHyD-Parkinson, de las cuales solamente 3 pudieron incluirse. Se formulo una pregunta relacionada con la terapia de logopedia aplicada en personas con EP que presentan problemas de deglucion, tratamiento donde se imbrican los profesionales de la NHyD. De 642 articulos localizados, unicamente 2 pudieron ser incluidos para contestar las correspondientes preguntas. De las evidencias halladas, se derivaron 11 recomendaciones directa o indirectamente relacionados con la NHyD.Conclusiones: la implicacion de profesionales sanitarios en equipos multidisciplinares mejora el resultado final de las guias y la atencion sanitaria de los pacientes. Es necesario que los profesionales sanitarios de la NHyD (los/las dietistas nutricionistas) se impliquen en iniciativas basadas en la mejor evidencia cientifica disponible y que formen parte de los equipos de trabajo multidisciplinares. PMID- 27513515 TI - Dance participation and academic performance in youth girls AB - Dance is a predominant type of physical activity among girls. Dance characteristics imply skills associated to health-related physical fitness, as well as others such as learning and memory, mental representation, imagination and creativity, which are related to cognitive development. Although dance has been shown to influence physical health among youth girls, whether dance may influence academic performance and cognition in youth remains to be elucidated. The objective of this work was to examine the association between participation in dance and academic performance in youth girls. PMID- 27513516 TI - Antibody to CMRF35-Like Molecule 2, CD300e A Novel Biomarker Detected in Patients with Fulminant Type 1 Diabetes. AB - AIMS/HYPOTHESIS: Fulminant type 1 diabetes (FT1D) is a distinct subtype of type 1 diabetes and is fatal without immediate diagnosis and treatment. At present, there are no biomarkers for early and predictive detection of FT1D. METHODS: First, we analyzed a total of 6 serum samples from 3 patients with FT1D (1 sample in the acute and 1 in the sub-acute phases from each patient) by seromic analysis. Second, titres of the antibody were measured by ELISA in sera from 30 patients with FT1D (both in the acute and sub-acute phases), 13 patients with FT1D in the chronic phase, 32 patients with autoimmune type 1 (type 1A) diabetes (T1AD), 30 patients with type 2 diabetes (T2D), 23 patients with autoimmune thyroid disease (AITD) and 31 healthy control subjects (HC). RESULTS: Seromic analysis revealed 9 antibodies which showed high signals from all 3 patients with FT1D in the acute phase. Among them, the titre of anti-CD300e antibody was significantly higher in FT1D patients in the acute phase than that in T1AD, T2D, AITD patients and HC, as determined by ELISA (P<0.01, respectively). The titre of anti-CD300e antibody was also higher in FT1D in the acute phase than that in the sub-acute phase (P = 0.0018, Wilcoxon signed-rank test). The titre of anti-LGALS3 antibody in FT1D patients in the acute phase did not differ from that in patients with FT1D in the sub-acute phase, T1AD, T2D, AITD and HC. CONCLUSION/INTERPRETATION: The titre of a novel antibody, anti-CD300e, was high in sera from patients with FT1D. This antibody might be a diagnostic marker and provide new insight into the pathogenesis of FT1D. PMID- 27513517 TI - Association of FMO3 Variants and Trimethylamine N-Oxide Concentration, Disease Progression, and Mortality in CKD Patients. AB - Elevated levels of circulating pro-atherogenic uremic solutes, particularly trimethylamine N-oxide (TMAO), have been implicated in cardiovascular disease development in patients with chronic kidney disease (CKD). TMAO is generated from trimethylamine (TMA) via metabolism by hepatic flavin-containing monooxygenase isoform 3 (FMO3). We determined the functional effects of three common FMO3 variants at amino acids 158, 308, and 257 on TMAO concentrations in a prospective cohort study and evaluated associations of polymorphisms with CKD progression and mortality. Each additional minor allele at amino acid 158 was associated with a 0.38 MUg/mL higher circulating TMAO (p = 0.01) and with faster rates of annualized relative eGFR decline. Participants with 0, 1 and 2 variant alleles averaged an eGFR loss of 8%, 12%, and 14% per year, respectively (p-for trend = 0.05). Compared to participants with the homozygous reference allele, heterozygous and homozygous variant participants had a 2.0-fold (95% CI: 0.85, 4.6) and 2.2-fold (95% CI: 0.89, 5.48) higher risk of mortality, respectively (p for-trend = 0.04). No associations with clinical outcomes were observed for allelic variants at amino acids 257 or 308. Understanding the contribution of genetic variation of FMO3 to disease progression and all-cause mortality can guide recommendations for diet modification or pharmacotherapy in CKD patients at increased risk of adverse outcomes. PMID- 27513518 TI - Tumor-Specific Peptide, Selected from a Phage Peptide Library, Enhances Antitumor Activity of Lactaptin. AB - A recombinant analogue of lactaptin (RL2), a new potential anticancer molecule, induces apoptosis in cultured tumor cells. The tumor suppression efficacy of RL2 was shown against mouse hepatoma-1 cells and MDA-MB-231 human breast adenocarcinoma cells. The RL2-based therapeutic drug lactaptin is distributed evenly throughout the organism, which reduces its antitumor efficacy. In the current study, we obtained a genetic construct that allows production of the recombinant fusion protein T3-RL2, consisting of RL2 and T3 peptide (YTYDPWLIFPAN), in E. coli cells. T3 peptide was selected from a phage peptide library as a result of two screenings: in vitro using MDA-MB-231 cell culture and in vivo using a mouse xenograft model of breast cancer MDA-MB-231. It was shown that the displayed peptide T3 provides binding and internalization of phage particles by MDA-MB-231 cells and their specific accumulation in MDA-MB-231 tumor tissue. In addition, based on the nucleotide sequences coding RL2 and the known tumor-targeting peptide iRGD, we obtained genetic constructs that provide synthesis of fusion proteins RL2-iRGD and RL-iRGD-His. We studied the cytotoxic activity of fusion proteins T3-RL2, RL2-iRGD and RL-iRGD-His in vitro using MDA MB-231 and MCF-7 human adenocarcinoma cells. The in vitro results showed that the fusion proteins inhibit proliferation of both cell cultures, and their cytotoxic activity is higher than that of RL2. In vivo experiments on the study of the antitumor efficacy of the obtained fusion proteins demonstrated that T3-RL2 protein significantly inhibits MDA-MB-231 tumor growth in a xenograft model compared with RL2, while the antitumor effect of RL2-iRGD and RL-iRGD-His proteins is comparable to the effect of RL2. PMID- 27513519 TI - Correlating optic nerve sheath diameter with opening intracranial pressure in pediatric traumatic brain injury. AB - INTRODUCTION: The use of clinical markers to predict intracranial pressure (ICP) is desirable as a first-line measure to assist in decision making as to whether invasive monitoring is required. Correlations between ICP and optic nerve sheath diameter (ONSD) using CT and MRI have been observed in adult populations. However, data on this modality in children is less well documented. METHODS: ONSD was measured by independent observers and correlated with opening ICP at insertion of invasive monitoring probes in pediatric traumatic brain injury patients admitted to Addenbrookes Hospital between January 2009 and December 2013. RESULTS: Thirty-six patients with a mean age of 8.2 y were admitted to the Pediatric Intensive Care Unit (PICU) with a traumatic head injury and required invasive neurosurgical monitoring. The median ICP was 18 +/- 10 mmHg (median +/- IQR), the median right ONSD was 5.6 +/- 2.5 mm and the left was 5.9 +/- 3.2 mm. The Intraclass correlation between observers was 0.91 (P < 0.0001). The correlation of mean ONSD and max ONSD with ICP was 0.712 (P < 0.0001) and 0.713 (P < 0.0001), respectively. Area under ROC curve for both mean and max ONSD is 0.85 (95% CI: 0.73-0.98). CONCLUSION: Where pediatric patients present with an ONSD of over 6.1 mm following a traumatic brain injury (TBI), ICP monitoring should be implemented. PMID- 27513520 TI - Effects of Venous Superdrainage and Arterial Supercharging on Dorsal Perforator Flap in a Rat Model. AB - OBJECTIVE: To comparatively assess the effects of venous superdrainage and arterial supercharging on dorsal perforator flap survival. MATERIALS AND METHODS: Sixty male Sprague-Dawley rats (450-550g) were randomly divided into three groups (n = 20), including control group (Control) and experimental groups A (venous superdrainage, Exp. A) and B (arterial supercharging, Exp. B). At postoperative day 7, survival areas of the flaps were evaluated and all animals underwent angiography. Laser Doppler was used to evaluate flap perfusion from 0h to 7days after surgery. Histology with hematoxylin and eosin staining was used to count microvessels. Tissue of "Choke vessels"was excised for quantification of hypoxia inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) by western blot assay at 6h and 7days after surgery. RESULTS: In the Exp. A group, almost all flaps survived (98.2+/-1.6%); in the Exp. B and control group, survival areas accounted for 78.8+/-8.5% and 60.3+/-7.8%, respectively (P <0.001). In addition, Exp. A animals showed improved anastomosis of choke vessels 2 compared with the Exp. B and Control groups. Furthermore, flap blood flow and partial pressure of oxygen in the Exp. A group were significantly higher compared with values obtained for the Exp. B and Control groups, from 6 hours to 7 days after surgery. More microvessels were found in the Exp. A group (11.65+/-1.33) than in Exp. B (9.25+/-0.34) and control (7.25+/-0.91) animals on POD 7. The relative expression level of HIF-1alpha and VEGF were significant at 6h and 7days after surgery. CONCLUSIONS: Venous superdrainage in rat dorsal perforator flap is more effective than arterial supercharging in promoting flap survival, and could effectively alter hemodynamics in the microcirculation and stimulate blood vessel formation. PMID- 27513521 TI - Impact of enumeration method on diversity of Escherichia coli genotypes isolated from surface water. AB - : There are numerous regulatory-approved Escherichia coli enumeration methods, but it is not known whether differences in media composition and incubation conditions impact the diversity of E. coli populations detected by these methods. A study was conducted to determine if three standard water quality assessments, Colilert(r) , USEPA Method 1603, (modified mTEC) and USEPA Method 1604 (MI), detect different populations of E. coli. Samples were collected from six watersheds and analysed using the three enumeration approaches followed by E. coli isolation and genotyping. Results indicated that the three methods generally produced similar enumeration data across the sites, although there were some differences on a site-by-site basis. The Colilert(r) method consistently generated the least diverse collection of E. coli genotypes as compared to modified mTEC and MI, with those two methods being roughly equal to each other. Although the three media assessed in this study were designed to enumerate E. coli, the differences in the media composition, incubation temperature, and growth platform appear to have a strong selective influence on the populations of E. coli isolated. This study suggests that standardized methods of enumeration and isolation may be warranted if researchers intend to obtain individual E. coli isolates for further characterization. SIGNIFICANCE AND IMPACT OF THE STUDY: This study characterized the impact of three USEPA-approved Escherichia coli enumeration methods on observed E. coli population diversity in surface water samples. Results indicated that these methods produced similar E. coli enumeration data but were more variable in the diversity of E. coli genotypes observed. Although the three methods enumerate the same species, differences in media composition, growth platform, and incubation temperature likely contribute to the selection of different cultivable populations of E. coli, and thus caution should be used when implementing these methods interchangeably for downstream applications which require cultivated isolates. PMID- 27513523 TI - Notes from the Field: Shigellosis Outbreak Among Men Who Have Sex with Men and Homeless Persons - Oregon, 2015-2016. AB - In July 2015, Shigella sonnei infections with a specific pulsed-field gel electrophoresis (PFGE) pattern linked to a multistate outbreak were recognized among men who have sex with men (MSM) in the Portland metropolitan area, and an outbreak investigation was initiated. During November 2015, isolates with PFGE patterns indistinguishable from the outbreak strain were identified in cases reported in four women, none of whom had epidemiologic links to other affected persons; however, three reported homelessness. In the ensuing months, additional S. sonnei infections were reported among homeless persons in the Portland area. PMID- 27513522 TI - West Nile virus-infected human dendritic cells fail to fully activate invariant natural killer T cells. AB - West Nile virus (WNV) infection is a mosquito-borne zoonosis with increasing prevalence in the United States. WNV infection begins in the skin, and the virus replicates initially in keratinocytes and dendritic cells (DCs). In the skin and cutaneous lymph nodes, infected DCs are likely to interact with invariant natural killer T cells (iNKTs). Bidirectional interactions between DCs and iNKTs amplify the innate immune response to viral infections, thus controlling viral load and regulating adaptive immunity. iNKTs are stimulated by CD1d-bound lipid antigens or activated indirectly by inflammatory cytokines. We exposed human monocyte derived DCs to WNV Kunjin and determined their ability to activate isolated blood iNKTs. DCs became infected as judged by synthesis of viral mRNA and Envelope and NS-1 proteins, but did not undergo significant apoptosis. Infected DCs up regulated the co-stimulatory molecules CD86 and CD40, but showed decreased expression of CD1d. WNV infection induced DC secretion of type I interferon (IFN), but no or minimal interleukin (IL)-12, IL-23, IL-18 or IL-10. Unexpectedly, we found that the WNV-infected DCs stimulated human iNKTs to up regulate CD69 and produce low amounts of IL-10, but not proinflammatory cytokines such as IFN-gamma or tumour necrosis factor (TNF)-alpha. Both CD1d and IFNAR blockade partially abrogated this iNKT response, suggesting involvement of a T cell receptor (TCR)-CD1d interaction and type I interferon receptor (IFNAR) signalling. Thus, WNV infection interferes with DC-iNKT interactions by preventing the production of proinflammatory cytokines. iNKTs may be a source of IL-10 observed in human flavivirus infections and initiate an anti-inflammatory innate response that limits adaptive immunity and immune pathology upon WNV infection. PMID- 27513524 TI - P2-Type Na0.67Ni0.23Mg0.1Mn0.67O2 as a High-Performance Cathode for a Sodium-Ion Battery. AB - There is intense interest in sodium-ion batteries as an alternative to lithium ion batteries for electric storage applications because of the low-cost and abundant sodium resources. Na0.67Ni0.33-xMgxMn0.67O2 compounds (x = 0, 0.02, 0.05, 0.1, or 0.15) were prepared by a sol-gel method and used as a cathode for sodium-ion batteries. The X-ray powder diffraction measurements demonstrated that the obtained samples have a pure P2 phase. Na0.67Ni0.23Mg0.1Mn0.67O2 delivers an initial reversible capacity of 105 mAh g(-1) in the potential region from 2.0 to 4.5 V at a charge/discharge current density of 48 mA g(-1). Moreover, the cyclability is improved by doping Mg. The capacity of Na0.67Ni0.23Mg0.1Mn0.67O2 can remain at approximately 84.9 mAh g(-1) at a current density of 48 mA g(-1) after 100 cycles. The improved high rate performance of Na0.67Ni0.23Mg0.1Mn0.67O2 was attributed to the increased lattice parameters and d spacing of the Na(+) layer. Therefore, Mg-doped Na0.67Ni0.23Mg0.1Mn0.67O2 is a promising cathode for sodium-ion batteries with excellent rate and cyclic performance. PMID- 27513526 TI - Decidual Vasculopathy: Placental Location and Association with Ischemic Lesions. AB - Decidual vasculopathy (DV) is a general term for a number of lesions involving uteroplacental vessels. It is often seen in preeclamptic placentas and indicates a disorder of uteroplacental malperfusion and is associated with placental ischemia and infarction. Although some have advocated submitting special sections in order to better document DV, it is unclear which placental sections have the highest yield in demonstrating these abnormal vessels. 76 consecutive cases of decidual vasculopathy were identified and evaluated for location of DV, as well as presence of other lesions of ischemic change, infarcts and retroplacental hematomas. Sections reviewed were the membrane roll, full thickness sections of the placental disc, and sections specifically of the basal plate. DV was found in the membrane roll (MR) in 67.1% of cases, in full thickness sections (FT) in 32.9% and in the basal plate (BP) in 25.0% of cases (p value = 0.004). DV was exclusive to the MR in 53.9%, the FT in 14.5% and the BP in 9.2%. DV was present in 2 locations in 19.7% and in all 3 locations in 2.6%. The presence of DV in any location (MR, FT, BP) was associated with placental ischemic change but not specifically with infarcts or retroplacental hematomas. The specific location of DV showed no difference in the presence of placental lesions. Our findings indicate DV is often present in one location, and is associated with lesions of malperfusion. It is recommended that when clinically indicated, additional sections are submitted to demonstrate decidual vasculopathy. PMID- 27513527 TI - Ingenol Mebutate for Lentigo Maligna: A Case Report. AB - BACKGROUND: Lentigo maligna (LM) is a melanoma in situ on sun-damaged skin, with a strong predilection to the head and neck area of the elderly. Many therapeutic modalities have been proposed in the treatment of this pathology, including surgery, cryotherapy, radiotherapy and topical imiquimod. Up to date surgical excision remains the treatment of choice with the lowest recurrence rate. Recently, a new topical treatment with ingenol mebutate has been described to be efficacious and well tolerated in the treatment of melanoma in situ. OBJECTIVE: We sought to demonstrate that ingenol mebutate might be an efficacious and well tolerated treatment in a patient suffering from LM on an aesthetically challenging location. METHODS: Case report. RESULTS: After therapeutic failure with imiquimod 5% cream, a new topical treatment with ingenol mebutate gel 0.015% once daily on 3 consecutive days was initiated. Despite visible inflammation, no macroscopic lesion clearance was observed. While the first follow-up using reflectance confocal microscopy (RCM) performed at 6 weeks after the completion of the therapy showed no signs of LM, the second follow-up examination at 12 weeks using RCM and biopsy confirmed recurrence of the lesion. CONCLUSION: Ingenol mebutate cannot be considered a standard treatment modality for all types of LM. Further studies are needed to evaluate the prerequisites that can ensure therapeutic success. PMID- 27513528 TI - Group Cognitive Behaviour Therapy for Chronic Fatigue Syndrome. PMID- 27513529 TI - MCPIP-1, Alias Regnase-1, Controls Epithelial Inflammation by Posttranscriptional Regulation of IL-8 Production. AB - Pattern recognition receptors are critical for the detection of invading microorganisms. They activate multiple pathways that lead to the induction of proinflammatory responses and pathogen clearance. The intensity and duration of this immune reaction must be tightly controlled spatially and temporally in every tissue by different negative regulators. We hypothesized that monocyte chemoattractant protein-1-induced protein-1 (MCPIP-1) might play a role in maintaining immune homeostasis in the epithelium both under physiological conditions and upon bacterial infection. To this end, we examined the distribution of the MCPIP-1 transcript and protein in various tissues. The MCPIP 1 protein level was higher in epithelial cells than in myeloid cells. MCPIP-1 exerted RNase activity towards the interleukin (IL)-8 transcript and the lifespan of IL-8 was determined by the presence of the stem-loops/hairpin structures at the 3'UTR region of IL-8 mRNA. Moreover, using fully active, purified recombinant MCPIP-1 protein, we elucidated the mechanism by which MCPIP-1 controls the IL-8 mRNA level. In conclusion, we uncovered a novel IL-8-dependent mechanism via which MCPIP-1 maintains epithelial homeostasis. This study reveals for the first time that MCPIP-1 plays a crucial anti-inflammatory role not only in myeloid cells but also in epithelial cells. PMID- 27513530 TI - Microbial investigation of biofilms recovered from endotracheal tubes using sonication in intensive care unit pediatric patients. AB - OBJECTIVES: To compare cultured microorganisms identified on endotracheal tubes biofilms through sonication technique with traditional tracheal aspirate collected at extubation of pediatric intensive care unit patients. METHODS: Demographic and epidemiological data were analyzed to identify factors possibly related with the microbiological profile of the two collection methods. Associations between categorical and continuous variables were analyzed using the chi-square or Fisher's exact test, or Student's t test. p-Value <0.05 were considered significant. RESULTS: Thirty endotracheal tubes and tracheal aspirates samples from 27 subjects were analyzed. Only one patient presented the clinical diagnosis of ventilator-associated pneumonia. Overall, 50% of bacteria were Gram negative bacilli, followed by Gram-positive bacteria in 37%, and fungi in 10%. No statistically significant difference on the distribution of Gram-positive or Gram negative bacteria (p=0.996), and fungi (p=0.985) were observed between the collection methods. Pseudomonas spp. was the most frequent microorganism identified (23.8%), followed by Streptococcus spp. (18.5%), Acinetobacter spp. (15.9%), coagulase-negative staphylococci (11.2%), and Klebsiella spp. (8.6%). Concordant results between methods amounted to 83.3%. Pseudomonas aeruginosa and Acinetobacter baumannii showed carbapenem resistance in 50% and 43.7% of the isolates, respectively. In general, cultures after endotracheal tubes sonication (non-centrifuged sonication fluid and centrifuged sonication fluid) yielded bacteria with higher rates of antimicrobial resistance compared to tracheal aspirates cultures. Additionally, in 12 subjects (40%), we observed discrepancies regarding microbiologic profiles of cultures performed using the collection methods. CONCLUSIONS: Our study demonstrated that sonication technique can be applied to ET biofilms to identify microorganisms attached to their surface with a great variety of species identified. However, we did not find significant differences in comparison with the traditional tracheal aspirate culture approach. PMID- 27513531 TI - Assessment of an intervention aimed at early discontinuation of intravenous antimicrobial therapy in a Brazilian University hospital. AB - Many interventions demonstrate success in adapting the duration of intravenous antibiotic therapy, but few studies have been conducted in developing countries. The aim of this study was to evaluate the effectiveness of an intervention in the induction of early discontinuation of intravenous antimicrobial therapy and/or its switch to oral therapy. The study employed a before-after intervention design that consisted of displaying a message in the computerized prescription on the third day and suspension of the prescription on the fifth day of intravenous antimicrobial therapy. A total of 465 patients were followed during the control period (CP) and 440 in the intervention period (IP). The intravenous therapy was switched to oral therapy for 11 (2.4%) patients during the CP and 25 (5.7%) in the IP (p=0.011), and was discontinued for 82 (17.6%) patients during the CP and 106 (24.1%) in the IP (p=0.017). During the IP there was a significant increase of patients who had their antimicrobial treatment discontinued before the seventh day of intravenous treatment, 37.40% (49/131) in the IP and 16.13% (15/93) in the CP (p=0.0005). The duration of intravenous antimicrobial therapy decreased by one day, but it was not significant (p=0.136). It is concluded that the proposed intervention is effective in promoting the early discontinuation of antimicrobial treatment and/or switch to oral therapy. As long as a computerized system for prescription already exists, it is easy and inexpensive to be implemented, especially in hospitals in developing countries. PMID- 27513532 TI - Patient, Process, and System Predictors of Iatrogenic Withdrawal Syndrome in Critically Ill Children. AB - OBJECTIVE: To generate a multidimensional predictive model of risk factors for iatrogenic withdrawal syndrome in critically ill children. DESIGN: Secondary analysis of prospective data from the Randomized Evaluation of Sedation Titration for Respiratory Failure clinical trial. SETTING: PICU. PATIENTS: Children who received greater than or equal to 5 days of sedation during mechanical ventilation for acute respiratory failure. INTERVENTIONS: The Randomized Evaluation of Sedation Titration for Respiratory Failure study tested the effect of a nurse-led, goal-directed sedation protocol on clinical outcomes. There was no additional intervention in this secondary analysis. MEASUREMENTS AND MAIN RESULTS: Data included 1,157 children from 31 PICUs. Iatrogenic withdrawal syndrome was defined as having at least two Withdrawal Assessment Tool-Version 1 scores greater than or equal to 3 after the start of opioid weaning. Logistic regression with generalized estimating equations to account for clustering by site was used to evaluate patient, process, and healthcare system risk factors for iatrogenic withdrawal syndrome. Subjects with iatrogenic withdrawal syndrome (544/1,157; 47%) were younger and more likely to have preexisting cognitive or functional impairment. They also received higher sedative doses and longer exposure periods. In multivariable analyses, significant predictors of iatrogenic withdrawal syndrome included younger age, preexisting cognitive impairment, higher preweaning mean daily opioid dose, longer duration of sedation, receipt of three or more preweaning sedative classes, higher nursing workload, and more one to-one nurse staffing. CONCLUSIONS: Iatrogenic withdrawal syndrome is common in children recovering from critical illness, and several risk factors are predictive, including patient characteristics, sedative exposure, additional sedative agents, and system-level factors. High-risk patients could be identified before weaning to better prevent iatrogenic withdrawal syndrome among at-risk patients. PMID- 27513533 TI - Overtreatment of Heparin-Induced Thrombocytopenia in the Surgical ICU. AB - OBJECTIVE: Recent studies reveal a high occurrence of overdiagnosis of heparin induced thrombocytopenia in surgical patients with critical illness. The optimal criteria for diagnosis of heparin-induced thrombocytopenia remain unclear, contributing to unnecessary treatment. We reviewed patients who were admitted to surgical ICUs and were suspected of heparin-induced thrombocytopenia to identify how often patients were correctly treated. DESIGN: In this clinical prospective study, data were collected including age, sex, antiplatelet factor 4/heparin enzyme-linked immunosorbent assay, serotonin release assay, and Warkentin 4Ts scores. Heparin-induced thrombocytopenia-positive patients were defined as those with both positive antiplatelet factor 4/heparin enzyme-linked immunosorbent assay (optical density, >= 0.40) and positive serotonin release assay results. SETTING: Urban tertiary medical center. PATIENTS: Patients admitted to the surgical and cardiac ICU who were presumed to have heparin-induced thrombocytopenia and underwent antiplatelet factor 4/heparin enzyme-linked immunosorbent assay and serotonin release assay testing between January 1, 2011, and August 1, 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 135 patients had 4Ts, antiplatelet factor 4/heparin enzyme-linked immunosorbent assay, and serotonin release assay scores. A total of 11 patients (8.1%) had positive serotonin release assay and 80 patients had positive antiplatelet factor 4/heparin enzyme-linked immunosorbent assay; 10 patients were identified as heparin-induced thrombocytopenia positive. Positive serotonin release assay was noted in nine of 11 patients (81.8%) with antiplatelet factor 4/heparin enzyme-linked immunosorbent assay optical density greater than or equal to 2.0, compared with one of 22 patients (4.5%) with optical density values of 0.85-1.99, and one of 102 patients (1.0%) with optical density values of 0-0.84. Out of 135 patients, 29 patients (21.5%) received treatment with argatroban, lepirudin, or fondaparinux: 10 of 10 heparin-induced thrombocytopenia-positive patients (100%) compared with 19 of 125 heparin-induced thrombocytopenia-negative patients (15%). CONCLUSIONS: Overtreatment of heparin-induced thrombocytopenia in the surgical ICU continues even with recent increased caution encouraging a higher antiplatelet factor 4/heparin enzyme-linked immunosorbent assay optical density threshold before initiating treatment. More stringent criteria should be used to determine when to order serologic testing and when the results of such testing should prompt a change in anticoagulant treatment. If antiplatelet factor 4/heparin enzyme-linked immunosorbent assay is used to consider immediate treatment, an optical density greater than or equal to 2.0 may be a more appropriate threshold. PMID- 27513534 TI - Atrial Fibrillation Following Out-of-Hospital Cardiac Arrest and Targeted Temperature Management-Are We Giving It the Attention it Deserves? AB - OBJECTIVES: Atrial fibrillation has been associated with increased mortality in the general population and mixed populations of critical ill. Atrial fibrillation can also affect patients during post-cardiac arrest care. We sought to assess the prognostic implications of atrial fibrillation following out-of-hospital cardiac arrest, including relation to the level of targeted temperature management. DESIGN: A post hoc analysis of a prospective randomized trial. SETTING: Thirty six ICUs. PATIENTS: We included 897 (96%) of the 939 comatose out-of-hospital cardiac arrest survivors from the targeted temperature management trial (year, 2010-2013) with data on heart rhythm on day 2. INTERVENTIONS: Targeted temperature management at 33 degrees C or 36 degrees C. MEASUREMENTS AND MAIN RESULTS: Endpoints included cumulative proportion of atrial fibrillation following out-of-hospital cardiac arrest and 180-day all-cause mortality and specific death causes stratified by atrial fibrillation. Atrial fibrillation on day 2 was used as primary endpoint analyses to exclude effects of short-term atrial fibrillation related to resuscitation and initial management. The cumulative proportions of atrial fibrillation were 15% and 11% on days 1 and 2, respectively. Forty-three percent of patients with initial atrial fibrillation the first day were reported with sinus rhythm on day 2. No difference was found between the groups treated with targeted temperature management at 33 degrees C and 36 degrees C. Patients affected by atrial fibrillation had significantly higher 180-day mortality (atrial fibrillation: 66% vs no-atrial fibrillation: 43%; plogrank < 0.0001 and unadjusted hazard ratio, 1.75 [1.35-2.30]; p < 0.0001). The association between atrial fibrillation and higher mortality remained significant (adjusted hazard ratio, 1.34 [1.01-1.79]; p < 0.05) adjusted for potential confounders. Atrial fibrillation was independently associated with increased risk of cardiovascular death and multiple-organ failure (adjusted hazard ratio, 2.07 [1.39-3.09]; p < 0.001), whereas no association with higher risk of death from cerebral causes was found. CONCLUSIONS: Atrial fibrillation was independently associated with higher mortality, primarily driven by cardiovascular causes and multiple-organ failure, and may thus identify a vulnerable subpopulation. Whether treatment to prevent atrial fibrillation is associated with an improved prognosis remains to be established. PMID- 27513535 TI - Association of Freestanding Children's Hospitals With Outcomes in Children With Critical Illness. AB - OBJECTIVES: Little is known about the relationship between freestanding children's hospitals and outcomes in children with critical illness. The purpose of this study was to evaluate the association of freestanding children's hospitals with outcomes in children with critical illness. DESIGN: Propensity score matching was performed to adjust for potential confounding variables between patients cared for in freestanding or nonfreestanding children's hospitals. We tested the sensitivity of our findings by repeating the primary analyses using inverse probability of treatment weighting method and regression adjustment using the propensity score. SETTING: Retrospective study from an existing national database, Virtual PICU Systems (LLC) database. PATIENTS: Patients less than 18 years old admitted to one of the participating PICUs in the Virtual PICU Systems, LLC database were included (2009-2014). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 538,967 patients from 140 centers were included. Of these, 323,319 patients were treated in 60 freestanding hospitals. In contrast, 215,648 patients were cared for in 80 nonfreestanding hospitals. By propensity matching, 134,656 patients were matched 1:1 in the two groups (67,328 in each group). Prior to matching, patients in the freestanding hospitals were younger, had greater comorbidities, had higher severity of illness scores, had higher incidence of cardiac arrest, had higher resource utilization, and had higher proportion of patients undergoing complex procedures such as cardiac surgery. Before matching, the outcomes including mortality were worse among the patients cared for in the freestanding hospitals (freestanding vs nonfreestanding, 2.5% vs 2.3%; p < 0.001). After matching, the majority of the study outcomes were better in freestanding hospitals (freestanding vs nonfreestanding, mortality: 2.1% vs 2.8%, p < 0.001; standardized mortality ratio: 0.77 [0.73-0.82] vs 0.99 [0.87-0.96], p < 0.001; reintubation: 3.4% vs 3.8%, p < 0.001; good neurologic outcome: 97.7% vs 97.1%, p = 0.001). CONCLUSIONS: In this large observational study, we demonstrated that ICU care provided in freestanding children's hospitals is associated with improved risk adjusted survival chances compared to nonfreestanding children's hospitals. However, the clinical significance of this change in mortality should be interpreted with caution. It is also possible that the hospital structure may be a surrogate of other factors that may bias the results. PMID- 27513536 TI - Mindfulness and Coping Are Inversely Related to Psychiatric Symptoms in Patients and Informal Caregivers in the Neuroscience ICU: Implications for Clinical Care. AB - OBJECTIVE: To assess the correlation of psychosocial resiliency factors (mindfulness and coping) with symptoms of posttraumatic stress, anxiety, and depression in patients recently admitted to the neuroscience ICU and their primary informal caregivers. DESIGN: A descriptive, cross-sectional correlational study. SETTING: Neuroscience ICU in a major medical center. PARTICIPANTS: A total of 78 dyads of patients (total n = 81) and their primary caregivers (total n = 92) from June to December 2015. Study enrollment occurred within the first 2 weeks of patient admission to the neuroscience ICU. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Dyads completed self-report measures of mindfulness (Cognitive and Affective Mindfulness Scale-Revised), coping (Measure of Coping Status-A), posttraumatic stress (Posttraumatic Checklist-Specific Stressor), anxiety (Hospital Anxiety and Depression Scale-A), and depression (Hospital Anxiety and Depression Scale-D). Rates of clinically significant posttraumatic stress, anxiety, and depressive symptoms were high and comparable between patient and caregiver samples. Own psychological resilience factors and psychiatric symptoms were strongly correlated for both patients and caregivers. Depressive symptoms were interdependent between patients and their caregivers, and one's own mindfulness was independently related to one's partner's depressive symptoms. CONCLUSIONS: Rates of clinically significant psychiatric symptoms were high, equally prevalent in patients and caregivers, and interdependent between patients and their caregivers. For both patients and caregivers, psychological resiliency factors were associated with both self and partner psychiatric symptoms. Findings suggest that attending to the psychiatric health of both patients and caregivers in the neuroscience ICU is a priority and that patients and their caregivers must be considered together in a system to fully address either individual's psychiatric symptoms. PMID- 27513537 TI - Pediatric Sepsis Biomarker Risk Model-II: Redefining the Pediatric Sepsis Biomarker Risk Model With Septic Shock Phenotype. AB - OBJECTIVE: The Pediatric Sepsis Biomarker Risk Model (PERSEVERE), a pediatric sepsis risk model, uses biomarkers to estimate baseline mortality risk for pediatric septic shock. It is unknown how PERSEVERE performs within distinct septic shock phenotypes. We tested PERSEVERE in children with septic shock and thrombocytopenia-associated multiple organ failure (TAMOF), and in those without new onset thrombocytopenia but with multiple organ failure (MOF). DESIGN: PERSEVERE-based mortality risk was generated for each study subject (n = 660). A priori, we determined that if PERSEVERE did not perform well in both the TAMOF and the MOF cohorts, we would revise PERSEVERE to incorporate admission platelet counts. SETTING: Multiple PICUs in the United States. INTERVENTIONS: Standard care. MEASUREMENTS AND MAIN RESULTS: PERSEVERE performed well in the TAMOF cohort (areas under the receiver operating characteristic curves [AUC], 0.84 [95% CI, 0.77-0.90]), but less well in the MOF cohort (AUC, 0.71 [0.61-0.80]). PERSEVERE was revised using 424 subjects previously reported in the derivation phase. PERSEVERE-II had an AUC of 0.89 (0.85-0.93) and performed equally well across TAMOF and MOF cohorts. PERSEVERE-II performed well when tested in 236 newly enrolled subjects. Sample size calculations for a clinical trial testing the efficacy of plasma exchange for children with septic shock and TAMOF indicated PERSEVERE-II-based stratification could substantially reduce the number of patients necessary, when compared with no stratification. CONCLUSIONS: Testing PERSEVERE in the context of septic shock phenotypes prompted a revision incorporating platelet count. PERSEVERE-II performs well upon testing, independent of TAMOF or MOF status. PERSEVERE-II could potentially serve as a prognostic enrichment tool. PMID- 27513538 TI - Computational Analysis Supports an Early, Type 17 Cell-Associated Divergence of Blunt Trauma Survival and Mortality. AB - OBJECTIVE: Blunt trauma patients may present with similar demographics and injury severity yet differ with regard to survival. We hypothesized that this divergence was due to different trajectories of systemic inflammation and utilized computational analyses to define these differences. DESIGN: Retrospective clinical study and experimental study in mice. SETTING: Level 1 trauma center and experimental laboratory. PATIENTS: From a cohort of 493 victims of blunt trauma, we conducted a pairwise, retrospective, case-control study of patients who survived over 24 hours but ultimately died (nonsurvivors; n = 19) and patients who, after ICU admission, went on to be discharged(survivors; n = 19). INTERVENTIONS: None in patients. Neutralizing anti-interleukin-17A antibody in mice. MEASUREMENTS AND MAIN RESULTS: Data on systemic inflammatory mediators assessed within the first 24 hours and over 7 days were analyzed with computational modeling to infer dynamic networks of inflammation. Network density among inflammatory mediators in nonsurvivors increased in parallel with organ dysfunction scores over 7 days, suggesting the presence of early, self sustaining, pathologic inflammation involving high-mobility group protein B1, interleukin-23, and the Th17 pathway. Survivors demonstrated a pattern commensurate with a self-resolving, predominantly lymphoid response, including higher levels of the reparative cytokine interleukin-22. Mice subjected to trauma/hemorrhage exhibited reduced organ damage when treated with anti interleukin-17A. CONCLUSIONS: Variable type 17 immune responses are hallmarks of organ damage, survival, and mortality after blunt trauma and suggest a lymphoid cell-based switch from self-resolving to self-sustaining inflammation. PMID- 27513539 TI - Long-Term Survival Rate in Patients With Acute Respiratory Failure Treated With Noninvasive Ventilation in Ordinary Wards. AB - OBJECTIVE: Noninvasive ventilation is a life-saving technique increasingly used to treat acute respiratory failure. Noninvasive ventilation has been applied mostly in ICUs, but several reasons brought to an increasing application of noninvasive ventilation in ordinary wards. Few articles evaluated the outcomes of patients receiving noninvasive ventilation including long-term follow-up. The aim of the present study was to assess 1-year survival rate of patients treated with noninvasive ventilation outside the ICU for acute respiratory failure of heterogeneous causes and to identify the predictors of long-term mortality. DESIGN: Prospective, observational, pragmatic study. SETTING: Ordinary wards of a teaching hospital. PATIENTS: Consecutive patients treated with noninvasive ventilation for acute respiratory failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two-hundred and twenty-patients were enrolled. Mortality rates at 30-day, 90-days, and 1-year follow-up were 20%, 26%, and 34%. When excluding patients with "do-not-resuscitate" status, mortality rates were 13%, 19%, and 28%. The multivariate analyses identified solid cancer, pneumonia in hematologic patients, and do-not-resuscitate status as independent predictors of mortality with postoperative acute respiratory failure associated with improved survival. The same predictors were confirmed when excluding do-not-resuscitate patients from the analyses. CONCLUSIONS: Noninvasive ventilation applied in ordinary wards was effective, with long-term outcomes not different from those reported for ICU settings. Solid cancer, pneumonia in hematologic malignancies, and do-not resuscitate status predicted mortality, whereas patients with postoperative acute respiratory failure had the best survival rate. Additional studies are required to evaluate noninvasive ventilation efficacy in the wards compared with ICU. PMID- 27513540 TI - Long-Term Mental Health Problems After Delirium in the ICU. AB - OBJECTIVES: To determine whether delirium during ICU stay is associated with long term mental health problems defined as symptoms of anxiety, depression, and posttraumatic stress disorder. DESIGN: Prospective cohort study. SETTING: Survey study, 1 year after discharge from a medical-surgical ICU in the Netherlands. PATIENTS: One-year ICU survivors of an ICU admission lasting more than 48 hours, without a neurologic disorder or other condition that would impede delirium assessment during ICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One year after discharge, ICU survivors received a survey containing the Hospital Anxiety and Depression Scale with a subscale for symptoms of depression and a subscale for symptoms of anxiety, and the Impact of Event Scale 15 item measuring symptoms of posttraumatic stress disorder. Participants were classified as having experienced no delirium (n = 270; 48%), a single day of delirium (n = 86; 15%), or multiple days of delirium (n = 211; 37%) during ICU stay. Log-binomial regression was used to assess the association between delirium and symptoms of anxiety, depression, and posttraumatic stress disorder. The study population consisted of 567 subjects; of whom 246 subjects (43%) reported symptoms of anxiety (Hospital Anxiety and Depression Scale with a subscale for anxiety, >= 8), and 254 (45%) symptoms of depression (Hospital Anxiety and Depression Scale with a subscale for depression, >= 8). In 220 patients (39%), the Impact of Event Scale 15 item was greater than or equal to 35, indicating a high probability of posttraumatic stress disorder. There was substantial overlap between these mental health problems-63% of the subjects who scored positive for the presence of any three of the mental health problems, scored positive for all three. No association was observed between either a single day or multiple days of delirium and symptoms of anxiety, depression, or posttraumatic stress disorder. CONCLUSIONS: Although symptoms of anxiety, depression, and posttraumatic stress disorder were found to be common 1 year after critical illness, the occurrence of delirium during ICU stay did not increase the risk of these long-term mental health problems. PMID- 27513541 TI - Increased Ratio of Visceral to Subcutaneous Adipose Tissue in Septic Patients Is Associated With Adverse Outcome. AB - OBJECTIVES: Visceral and subcutaneous adipose tissue may contribute differentially to the septic inflammatory response. Accordingly, we tested the hypothesis that the ratio of visceral to subcutaneous adipose tissue is associated with altered sepsis outcome. DESIGN: A retrospective analysis from a cohort of sepsis patients admitted between 2004 and 2009. SETTING: A mixed medical-surgical ICU at St. Paul's Hospital in Vancouver, Canada. PATIENTS: Patients older than 16 years old who had sepsis and underwent abdominal CT scan (n = 257) for clinical reasons. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured the visceral adipose tissue and subcutaneous adipose tissue areas and calculated the visceral adipose tissue-to-subcutaneous adipose tissue ratio. Visceral adipose tissue/subcutaneous adipose tissue was not correlated with body mass index (r = -0.015, p = NS) and therefore provides additional unique information independent of body mass index. Sepsis patients with higher visceral adipose tissue/subcutaneous adipose tissue had greater 90-day mortality than patients with lower visceral adipose tissue/subcutaneous adipose tissue (log rank test, linear-by linear association p < 0.005). After adjustment for significant covariates using Cox regression, increased visceral adipose tissue/subcutaneous adipose tissue quartile was significantly associated with increased 90-day mortality with hazard ratios of 2.01 (95% CI, 1.01-3.99) for the third visceral adipose tissue/subcutaneous adipose tissue quartile compared with the first quartile and 2.32 (95% CI, 1.15-4.69) for the highest visceral adipose tissue/subcutaneous adipose tissue quartile when compared with the first quartile. Increased mortality for patients with higher visceral adipose tissue/subcutaneous adipose tissue was found for both patients with body mass index less than 25 kg/m (p = 0.004) and for body mass index greater than or equal to 25 kg/m (p = 0.023). Furthermore, we found significantly greater need for mechanical ventilation, renal replacement therapy, and ICU stay in patients in the highest visceral adipose tissue/subcutaneous adipose tissue quartile. The ratio of proinflammatory (interleukin-8) to anti-inflammatory (interleukin-10) plasma cytokine levels was greater in patients with higher visceral adipose tissue/subcutaneous adipose tissue than in those with lower visceral adipose tissue/subcutaneous adipose tissue (p = 0.043). CONCLUSIONS: Visceral obesity, defined by a high visceral adipose tissue-to-subcutaneous adipose tissue ratio, contributes to adverse outcome in sepsis patients perhaps because of a greater pro- versus anti-inflammatory response. PMID- 27513542 TI - Peripheral IV Insulin Infusion Infiltration Presenting as "Insulin Resistance". AB - OBJECTIVES: We present the case of a 66-year-old woman who developed hypoglycemia following the prolonged infiltration of a high dose continuous peripheral IV insulin infusion. STUDY SELECTION: Case report. DATA SOURCES AND EXTRACTION: PubMed was searched for relevant literature on exogenous hyperinsulinemic hypoglycemia. DATA SYNTHESIS: The patient was postlung transplantation and was receiving high doses of glucocorticoids. Despite increasing the peripheral IV insulin rate, hyperglycemia persisted. We discovered that the IV insulin infusion line infiltrated, resulting in a large subcutaneous insulin depot, estimated to be 450 units of regular insulin. She subsequently experienced prolonged hypoglycemia that was managed with concentrated dextrose containing fluids. In our literature search, there were no similar case reports. The literature on insulin overdose, usually from suicide attempts, can help guide the management of iatrogenic hyperinsulinemic hypoglycemia. Important management considerations include anticipated duration of hypoglycemia, supplemental glucose, fluid management, and electrolyte monitoring. CONCLUSION: Peripheral IV insulin infusion infiltration should be considered when patients do not respond to increasing rates of insulin infusion. PMID- 27513543 TI - Protocolized Sepsis Care Is Not Helpful for Patients. PMID- 27513544 TI - The Target Temperature for Post Cardiac Arrest Patients Should Be 36 degrees C. PMID- 27513545 TI - Neuromuscular Blocking Agents and Neuromuscular Dysfunction Acquired in Critical Illness: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The relationship between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness remains unclear. We examined the association between neuromuscular blocking agents and ICU-acquired weakness, critical illness polyneuropathy, and critical illness myopathy. DATA SOURCES: PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature, and bibliographies of included studies were searched from database inception until September 24, 2015. STUDY SELECTION: Randomized controlled trials and prospective observational studies examining the association between neuromuscular blocking agents and ICU-acquired weakness, critical illness polyneuropathy, or critical illness myopathy. DATA EXTRACTION: One author screened titles/abstracts. Two authors independently reviewed full text and extracted data from included studies. Meta-analysis was performed using the DerSimonian-Laird random effects model (OpenMetaAnalyst 10.10 for OS.X). We assessed reporting bias with funnel plots and heterogeneity with the I statistic. DATA SYNTHESIS: Of 2,170 titles/abstracts screened, 99 full texts were selected for review, yielding one randomized controlled trial and 18 prospective observational studies, for a total of 2,254 patients. The randomized controlled trial did not show an association between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness (odds ratio, 1.21; 95% CI, 0.67-2.19), but pooled data from all included studies suggested a modest association (odds ratio, 1.25; 95% CI, 1.06 1.48; I = 16%). Funnel plots suggested reporting bias, and sensitivity analyses showed a disproportionate contribution from critical illness polyneuropathy/critical illness myopathy and severe sepsis/septic shock studies. CONCLUSIONS: This meta-analysis suggests a modest association between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness; limitations include studies with a high risk of bias and a disproportionate contribution from studies examining patients for critical illness polyneuropathy/critical illness myopathy and those with severe sepsis/septic shock. PMID- 27513546 TI - Comparing Time-Fixed Mortality Prediction Models and Their Effect on ICU Performance Metrics Using the Simplified Acute Physiology Score 3. AB - OBJECTIVES: To examine ICU performance based on the Simplified Acute Physiology Score 3 using 30-day, 90-day, or 180-day mortality as outcome measures and compare results with 30-day mortality as reference. DESIGN: Retrospective cohort study of ICU admissions from 2010 to 2014. SETTING: Sixty-three Swedish ICUs that submitted data to the Swedish Intensive Care Registry. PATIENTS: The development cohort was first admissions to ICU during 2011-2012 (n = 53,546), and the validation cohort was first admissions to ICU during 2013-2014 (n = 57,729). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Logistic regression was used to develop predictive models based on a first level recalibration of the original Simplified Acute Physiology Score 3 model but with 30-day, 90-day, or 180-day mortality as measures of outcome. Discrimination and calibration were excellent for the development dataset. Validation in the more recent 2013-2014 database showed good discrimination (C-statistic: 0.85, 0.84, and 0.83 for the 30-, 90-, and 180-d models, respectively), and good calibration (standardized mortality ratio: 0.99, 0.99, and 1.00; Hosmer-Lemeshow goodness of fit H-statistic: 66.4, 63.7, and 81.4 for the 30-, 90-, and 180-d models, respectively). There were modest changes in an ICU's standardized mortality ratio grouping (< 1.00, not significant, > 1.00) when follow-up was extended from 30 to 90 days and 180 days, respectively; about 11-13% of all ICUs. CONCLUSIONS: The recalibrated Simplified Acute Physiology Score 3 hospital outcome prediction model performed well on long term outcomes. Evaluation of ICU performance using standardized mortality ratio was only modestly sensitive to the follow-up time. Our results suggest that 30 day mortality may be a good benchmark of ICU performance. However, the duration of follow-up must balance between what is most relevant for patients, most affected by ICU care, least affected by administrative policies and practically feasible for caregivers. PMID- 27513547 TI - A Comparison of the Ability of the Physiologic Components of Medical Emergency Team Criteria and the U.K. National Early Warning Score to Discriminate Patients at Risk of a Range of Adverse Clinical Outcomes. AB - OBJECTIVE: To compare the ability of medical emergency team criteria and the National Early Warning Score to discriminate cardiac arrest, unanticipated ICU admission and death within 24 hours of a vital signs measurement, and to quantify the associated workload. DESIGN: Retrospective cohort study. SETTING: A large U.K. National Health Service District General Hospital. PATIENTS: Adults hospitalized from May 25, 2011, to December 31, 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied the National Early Warning Score and 44 sets of medical emergency team criteria to a database of 2,245,778 vital signs sets (103,998 admissions). The National Early Warning Score's performance was assessed using the area under the receiver-operating characteristic curve and compared with sensitivity/specificity for different medical emergency team criteria. Area under the receiver-operating characteristic curve (95% CI) for the National Early Warning Score for the combined outcome (i.e., death, cardiac arrest, or unanticipated ICU admission) was 0.88 (0.88-0.88). A National Early Warning Score value of 7 had sensitivity/specificity values of 44.5% and 97.4%, respectively. For the 44 sets of medical emergency team criteria studied, sensitivity ranged from 19.6% to 71.2% and specificity from 71.5% to 98.5%. For all outcomes, the position of the National Early Warning Score receiver-operating characteristic curve was above and to the left of all medical emergency team criteria points, indicating better discrimination. Similarly, the positions of all medical emergency team criteria points were above and to the left of the National Early Warning Score efficiency curve, indicating higher workloads (trigger rates). CONCLUSIONS: When medical emergency team systems are compared to a National Early Warning Score value of greater than or equal to 7, some medical emergency team systems have a higher sensitivity than National Early Warning Score values of greater than or equal to 7. However, all of these medical emergency team systems have a lower specificity and would generate greater workloads. PMID- 27513548 TI - Cardiac Ultrasound Is a Competency of Critical Care Medicine. PMID- 27513549 TI - Fate of the drug chlorpromazine in river water according to laboratory assays. Identification and evolution over time of degradation products. Sorption to sediment. AB - Toxic effects of the non-biodegradable drug chlorpromazine and its degradation products have been reported on microorganisms in aqueous media. Here, chlorpromazine degradation assays in forced and non-forced conditions have been done to know its persistence and degradation products in river water. Sunlight irradiation promotes the complete degradation of chlorpromazine (2 MUg L(-1)) in less than 4 h, but if the exposure to sunlight is limited chlorpromazine is detected during 4 weeks in river water. Sixteen degradation products in surface water are described for first time after solid-phase extraction and analysis by ultra-pressure liquid chromatography/quadrupole time-of-flight/mass spectrometry; their structures are proposed from the molecular formulae of the fragment-ions observed in high-resolution tandem mass spectra. Hydroxylation and oxidation products such as chlorpromazine sulfoxide, 2-hydroxypromazine and 2 hydroxypromazine sulfoxide were predominant degradation products in the early stages; some benzo[1,4]thiazin-6-ol derivatives resulting from the breakdown of the phenothiazine core were the major and relatively stable products after 20 weeks under non-forced conditions. A degradation pathway of chlorpromazine in water is outlined. Moreover, it is shown that chlorpromazine is very strongly adsorbed on sediment while the degradation products that kept the promazine core have a notable capacity of sorption, too; sorption coefficients are calculated. Finally, a prediction about the toxicity of the degradation products in aquatic ecosystems suggests that some of them have toxicities similar, or even higher, than chlorpromazine. PMID- 27513550 TI - Copper accumulation in vineyard soils: Rhizosphere processes and agronomic practices to limit its toxicity. AB - Viticulture represents an important agricultural practice in many countries worldwide. Yet, the continuous use of fungicides has caused copper (Cu) accumulation in soils, which represent a major environmental and toxicological concern. Despite being an important micronutrient, Cu can be a potential toxicant at high concentrations since it may cause morphological, anatomical and physiological changes in plants, decreasing both food productivity and quality. Rhizosphere processes can, however, actively control the uptake and translocation of Cu in plants. In particular, root exudates affecting the chemical, physical and biological characteristics of the rhizosphere, might reduce the availability of Cu in the soil and hence its absorption. In addition, this review will aim at discussing the advantages and disadvantages of agronomic practices, such as liming, the use of pesticides, the application of organic matter, biochar and coal fly ashes, the inoculation with bacteria and/or mycorrhizal fungi and the intercropping, in alleviating Cu toxicity symptoms. PMID- 27513551 TI - Dermal uptake and percutaneous penetration of ten flame retardants in a human skin ex vivo model. AB - The dermal uptake and percutaneous penetration of ten organic flame retardants was measured using an ex vivo human skin model. The studied compounds were DBDPE, BTBPE, TBP-DBPE, EH-TBB, BEH-TEBP, alpha, beta and gamma-HBCDD as well as syn- and anti-DDC-CO. Little or none of the applied flame retardants was recovered in either type of the receptor fluids used (physiological and worst-case). However, significant fractions were recovered in the skin depot, particularly in the upper skin layers. The primary effect of the worst-case receptor fluid was deeper penetration into the skin. The recovered mass was used to calculate lower- and upper-bound permeability coefficients kp. Despite large structural variation between the studied compounds, a clear, significant decreasing trend of kp was observed with increasing log Kow. The results indicate that the dermis may provide a significant barrier for these highly lipophilic compounds. However, based on our results, dermal uptake should be considered in exposure assessments, though it may proceed in a time-lagged manner compared to less hydrophobic compounds. PMID- 27513552 TI - Utilization of phosphorus loaded alkaline residue to immobilize lead in a shooting range soil. AB - The alkaline residue generated from the production of soda ash using the ammonia soda method has been successfully used in removing phosphorus (P) from aqueous solution. But the accumulation of P-containing solid after P removal is an undesirable menace to the environment. To achieve the goal of recycling, this study explored the feasibility of reusing the P loaded alkaline residue as an amendment for immobilization of lead (Pb) in a shooting range soil. The main crystalline phase and micromorphology of amendments were determined using X-ray diffraction (XRD) and scanning electron microscopy-electron dispersion spectroscopy (SEM-EDS) methods. The toxicity characteristic leaching procedure (TCLP), sequential extraction procedure, and physiologically based extraction test (PBET) were employed to evaluate the effectiveness of Pb immobilization in soil after 45 d incubation. Treatment with P loaded alkaline residue was significantly effective in reducing the TCLP and PBET extractable Pb concentrations in contrast to the untreated soil. Moreover, a positive change in the distribution of Pb fractions was observed in the treated soil, i.e., more than 60% of soil-Pb was transformed to the residual fraction compared to the original soil. On the other hand, P loaded amendments also resulted in a drastic reduction in phytoavailable Pb to the winter wheat and a mild release of P as a nutrient in treated soil, which also confirmed the improvement of soil quality. PMID- 27513553 TI - Outdoor air pollution and human infertility: a systematic review. AB - Air pollution is a current research priority because of its adverse effects on human health, including on fertility. However, the mechanisms through which air pollution impairs fertility remain unclear. In this article, we perform a systematic review to evaluate currently available evidence on the impact of air pollution on fertility in humans. Several studies have assessed the impact of air pollutants on the general population, and have found reduced fertility rates and increased risk of miscarriage. In subfertile patients, women exposed to higher concentrations of air pollutants while undergoing IVF showed lower live birth rates and higher rates of miscarriage. After exposure to similar levels of air pollutants, comparable results have been found regardless of the mode of conception (IVF versus spontaneous conception), suggesting that infertile women are not more susceptible to the effects of pollutants than the general population. In addition, previous studies have not observed impaired embryo quality after exposure to air pollution, although evidence for this question is sparse. PMID- 27513555 TI - Systems metabolic engineering of Escherichia coli for the heterologous production of high value molecules-a veteran at new shores. AB - For more than fifty years, Escherichia coli has represented a remarkable success story in industrial biotechnology. Traditionally known as a producer of l-amino acids, E. coli has also entered the precious market of high-value molecules and is becoming a flexible, efficient production platform for various therapeutics, pre-biotics, nutraceuticals and pigments. This tremendous progress is enabled by systems metabolic engineering concepts that integrate systems biology and synthetic biology into the design and engineering of powerful E. coli cell factories. PMID- 27513556 TI - Transplantation of Pro-Oligodendroblasts, Preconditioned by LPS-Stimulated Microglia, Promotes Recovery After Acute Contusive Spinal Cord Injury. AB - Spinal cord injury (SCI) is a significant clinical challenge, and to date no effective treatment is available. Oligodendrocyte progenitor cell (OPC) transplantation has been a promising strategy for SCI repair. However, the poor posttransplantation survival and deficiency in differentiation into myelinating oligodendrocytes (OLs) are two major challenges that limit the use of OPCs as donor cells. Here we report the generation of an OL lineage population [i.e., pro oligodendroblasts (proOLs)] that is relatively more mature than OPCs for transplantation after SCI. We found that proOLs responded to lipopolysaccharide (LPS)-stimulated microglia conditioned medium (L+M) by preserving toll-like receptor 4 (TLR4) expression, improving cell viability, and enhancing the expression of a myelinating OL marker myelin basic protein (MBP), compared to other OL lineage cells exposed to either LPS-stimulated (L+M) or nonstimulated microglia conditioned medium (LM). When L+M-stimulated proOLs were intrathecally delivered through a lumbar puncture after a T10 thoracic contusive SCI, they promoted behavioral recovery, as assessed by the BassoBeattieBresnahan (BBB) locomotor rating scale, stride length, and slips on the grid tests. Histologically, transplantation of L+M proOLs caused a considerable increase in intralesional axon numbers and myelination, and less accumulation of invading macrophages when compared with the vehicle control or OPC transplantation. Thus, transplantation of proOLs, preconditioned by L+M, may offer a better therapeutic potential for SCI than OPCs since the former may have initiated the differentiation process toward OLs prior to transplantation. PMID- 27513554 TI - Environmental influences on reproductive health: the importance of chemical exposures. AB - Chemical exposures during pregnancy can have a profound and life-long impact on human health. Because of the omnipresence of chemicals in our daily life, there is continuous contact with chemicals in food, water, air, and consumer products. Consequently, human biomonitoring studies show that pregnant women around the globe are exposed to a variety of chemicals. In this review we provide a summary of current data on maternal and fetal exposure, as well as health consequences from these exposures. We review several chemical classes, including polychlorinated biphenyls, perfluoroalkyl substances, polybrominated diphenyl ethers, phenols, phthalates, pesticides, and metals. Additionally, we discuss environmental disparities and vulnerable populations, and future research directions. We conclude by providing some recommendations for prevention of chemical exposure and its adverse reproductive health consequences. PMID- 27513557 TI - 5-Azacytidine suppresses EC9706 cell proliferation and metastasis by upregulating the expression of SOX17 and CDH1. AB - 5-Azacytidine is a well-known anticancer drug that is clinically used in the treatment of breast cancer, melanoma and colon cancer. It has been reported that 5-azacytidine suppresses the biological behavior of esophageal cancer cells. However, corresponding mechanisms remain unclear. In this study, using Transwell invasion and cell proliferation assays, we demonstrated that 5-azacytidine significantly inhibited the metastasis and proliferation of EC9706 cells, and upregulated the expression of cadherin 1 (CDH1) and SRY-box containing gene 17 (SOX17). Moreover, the inhibition of the metastasis of the 5-azacytidine-treated EC9706 cells was impaired following transfection with siRNA targeting CDH1 (CDH1 siRNA), and the inhibition of cell proliferation was attenuated following the downregulation of SOX17 by siRNA targeting SOX17 (SOX17 siRNA). Furthermore, 5 azacytidine remarkably reduced the CDH1 and SOX17 promoter methylation levels, suggesting that 5-azacytidine upregulates the expression of SOX17 and CDH1 by inhibiting the methylation of the SOX17 and CDH1 promoter. The findings of our study confirm that 5-azacytidine suppresses the proliferation and metastasis of EC9706 esophageal cancer cells by upregulating the expression of CDH1 and SOX17. The expression levels of CDH1 and SOX17 negatively correlate with the promoter methylation levels. CDH1 and SOX17 are potential indicators of the clinical application of 5-azacytidine. PMID- 27513558 TI - The Economic Value of the Greater Montreal Blue Network (Quebec, Canada): A Contingent Choice Study Using Real Projects to Estimate Non-Market Aquatic Ecosystem Services Benefits. AB - This study used a contingent choice method to determine the economic value of improving various ecosystem services (ESs) of the Blue Network of Greater Montreal (Quebec, Canada). Three real projects were used and the evaluation focused on six ESs that are related to freshwater aquatic ecosystems: biodiversity, water quality, carbon sequestration, recreational activities, landscape aesthetics and education services. We also estimated the value associated with the superficies of restored sites. We calculated the monetary value that a household would be willing to pay for each additional qualitative or quantitative unit of different ESs, and these marginal values range from $0.11 to $15.39 per household per unit. Thus, under certain assumptions, we determined the monetary values that all Quebec households would allocate to improve each ES in Greater Montreal by one unit. The most valued ES was water quality ($13.5 million), followed by education services ($10.7 million), recreational activities ($8.9 million), landscape aesthetics ($4.1 million), biodiversity ($1.2 million), and carbon sequestration ($0.1 million). Our results ascribe monetary values to improved (or degraded) aquatic ecosystems in the Blue Network of Greater Montreal, but can also enhance economic analyses of various aquatic ecosystem restoration and management projects. PMID- 27513559 TI - Comparative Genomic Analyses Provide New Insights into the Evolutionary Dynamics of Heterochromatin in Drosophila. AB - The term heterochromatin has been long considered synonymous with gene silencing, but it is now clear that the presence of transcribed genes embedded in pericentromeric heterochromatin is a conserved feature in the evolution of eukaryotic genomes. Several studies have addressed the epigenetic changes that enable the expression of genes in pericentric heterochromatin, yet little is known about the evolutionary processes through which this has occurred. By combining genome annotation analysis and high-resolution cytology, we have identified and mapped 53 orthologs of D. melanogaster heterochromatic genes in the genomes of two evolutionarily distant species, D. pseudoobscura and D. virilis. Our results show that the orthologs of the D. melanogaster heterochromatic genes are clustered at three main genomic regions in D. virilis and D. pseudoobscura. In D. virilis, the clusters lie in the middle of euchromatin, while those in D. pseudoobscura are located in the proximal portion of the chromosome arms. Some orthologs map to the corresponding Muller C element in D. pseudoobscura and D. virilis, while others localize on the Muller B element, suggesting that chromosomal rearrangements that have been instrumental in the fusion of two separate elements involved the progenitors of genes currently located in D. melanogaster heterochromatin. These results demonstrate an evolutionary repositioning of gene clusters from ancestral locations in euchromatin to the pericentromeric heterochromatin of descendent D. melanogaster chromosomes. Remarkably, in both D. virilis and D. pseudoobscura the gene clusters show a conserved association with the HP1a protein, one of the most highly evolutionarily conserved epigenetic marks. In light of these results, we suggest a new scenario whereby ancestral HP1-like proteins (and possibly other epigenetic marks) may have contributed to the evolutionary repositioning of gene clusters into heterochromatin. PMID- 27513560 TI - Posttranslational Modifications of NPR1: A Single Protein Playing Multiple Roles in Plant Immunity and Physiology. PMID- 27513561 TI - Hydrodynamic trapping for rapid assembly and in situ electrical characterization of droplet interface bilayer arrays. AB - The droplet interface bilayer (DIB) is a modular technique for assembling planar lipid membranes between water droplets in oil. The DIB method thus provides a unique capability for developing digital, droplet-based membrane platforms for rapid membrane characterization, drug screening and ion channel recordings. This paper demonstrates a new, low-volume microfluidic system that automates droplet generation, sorting, and sequential trapping in designated locations to enable the rapid assembly of arrays of DIBs. The channel layout of the device is guided by an equivalent circuit model, which predicts that a serial arrangement of hydrodynamic DIB traps enables sequential droplet placement and minimizes the hydrodynamic pressure developed across filled traps to prevent squeeze-through of trapped droplets. Furthermore, the incorporation of thin-film electrodes fabricated via evaporation metal deposition onto the glass substrate beneath the channels allows for the first time in situ, simultaneous electrical interrogation of multiple DIBs within a sealed device. Combining electrical measurements with imaging enables measurements of membrane capacitance and resistance and bilayer area, and our data show that DIBs formed in different trap locations within the device exhibit similar sizes and transport properties. Simultaneous, single channel recordings of ion channel gating in multiple membranes are obtained when alamethicin peptides are incorporated into the captured droplets, qualifying the thin-film electrodes as a means for measuring stimuli-responsive functions of membrane-bound biomolecules. This novel microfluidic-electrophysiology platform provides a reproducible, high throughput method for performing electrical measurements to study transmembrane proteins and biomembranes in low-volume, droplet-based membranes. PMID- 27513562 TI - Anti-Hyperglycemic Agents and New-Onset Acute Myocardial Infarction in Diabetic Patients with End-Stage Renal Disease Undergoing Dialysis. AB - BACKGROUND: Diabetes and chronic kidney disease (CKD) are a high-stakes combination for cardiovascular disease. Patients with decreased kidney function and end-stage renal disease (ESRD) have increased risk of hypoglycemia when attaining better glycemic control, leading to higher risk of myocardial infarction (MI). For these patients, which kinds of anti-hyperglycemic agents would be associated with higher risk of MI is not clear. METHODS: We identified patients from a nation-wide database called Registry for Catastrophic Illness, which encompassed almost 100% of the patients receiving dialysis therapy in Taiwan from 1995 to 2008. Patients with diabetes and ESRD were selected as the study cohort. Propensity score adjustment and Cox's proportional hazards regression model were used to estimate the hazard ratios (HRs) for new-onset MI. RESULTS: Among 15,161 patients, 39% received insulin, 40% received sulfonylureas, 18% received meglitinides and 3% received thiazolidinedione (TZD). After a median follow-up of 1,357 days, the incidence of MI was significant increase in patients taking sulfonylureas (HR = 1.523, 95% confidence interval [CI] = 1.331-1.744), meglitinides (HR = 1.251, 95% CI = 1.048-1.494) and TZD (HR = 1.515, 95% CI = 1.071-2.145) by using patients receiving insulin therapy as the reference group. The risk of MI remains higher in other three groups in subgroup analyses. CONCLUSIONS: In conclusion, among diabetic patients with ESRD undergoing dialysis, the use of sulfonylureas, meglitinides and TZD are associated with higher risk of new-onset MI as compared with insulin. PMID- 27513563 TI - Development of a New Limiting-Antigen Avidity Dot Immuno-Gold Filtration Assay for HIV-1 Incidence. AB - Several laboratory assays on cross-sectional specimens for detecting recent HIV infections were developed, but these assays could not be applied in resource limited and high HIV-incidence areas. This study describes the development of a rapid assay that can simultaneously detect the presence of HIV-1 antibodies of current and/or recent infection. The dot immuno-gold filtration assay (DIGFA) was used to detect recent infection on the principle of antibody avidity changes between recent and long-term infections. The dot immuno-gold silver staining filtration assay (DIGSSA) increases the sensitivity and accuracy of antibody detection by adding a silver staining step to the DIGFA. In the meantime the digital results were produced by the scanner for ambiguous specimens. Further, HIV-1 routine diagnostic antibody was detected simultaneously for improving practicability. The performance of the assays was then assessed through five serum panels with known serological statuses and seroconversion dates. The proportion of false recent infection (PFR) of the DIGSSA was obtained. Through the optimization of basic parameters for DIGSSA, six specimens were all classified correctly. DIGSSA demonstrated good repeatability and high sensitivity. The agreement of DIGSSA with the BED assay was 92.10% (kappa = 0.65) and 95.36% with the LAg-Avidity assay (kappa = 0.75). Moreover, the gray values of DIGSSA correlated well with BED ODn (R2 = 0.9397) and LAg-Avidity ODn (R2 = 0.9549). The PFR of DIGSSA was 2.73%, which was lower than that of the BED assay but higher than that of the LAg-Avidity assay. The DIGSSA can feasibly be applied to detect HIV infection and estimate HIV incidence. PMID- 27513564 TI - Altered Immune Profiles of Natural Killer Cells in Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Natural killer (NK) cells are the main effective component of the innate immune system that responds to chronic hepatitis B (CHB) infection. Although numerous studies have reported the immune profiles of NK cells in CHB patients, they are limited by inconsistent results. Thus, we performed a meta analysis to characterize reliably the immune profiles of NK cells after CHB infection, specifically frequency, phenotype, and function. METHODS: A literature search of the computer databases MEDLINE, PUBMED, EMBASE, and Cochrane Center Register of Controlled Trails was performed and 19 studies were selected. The standard mean difference (SMD) and 95% confidence interval (CI) of each continuous variable was estimated with a fixed effects model when I2 < 50% for the test for heterogeneity, or the random effects model otherwise. Publication bias was evaluated using Begg's and Egger's tests. RESULTS: The meta-analysis of publications that reported frequency of peripheral NK cells showed that NK cell levels in CHB patients were significantly lower compared with that of healthy controls. A higher frequency of CD56bright NK subsets was found in CHB patients, but the CD56dim NK subsets of CHB patients and healthy controls were similar. CHB patients before and after antiviral therapy with nucleotide analogues (NUCs) showed no statistical difference in NK frequency. The activating receptors were upregulated, whereas inhibitory receptors were comparable in the peripheral NK cells of CHB individuals and healthy controls. NK cells of CHB patients displayed higher cytotoxic potency as evidenced by CD107a protein levels and conserved potency to produce interferon-gamma (IFNgamma), compared with their healthy counterparts. CONCLUSION: Our results revealed that CHB patients had a lower frequency of NK cells compared with healthy individuals not treatable with antiviral NUC therapy. With an activating phenotype, NK cells in CHB patients showed better cytotoxic potency and conserved IFNgamma production. PMID- 27513565 TI - Projecting the Global Distribution of the Emerging Amphibian Fungal Pathogen, Batrachochytrium dendrobatidis, Based on IPCC Climate Futures. AB - Projected changes in climate conditions are emerging as significant risk factors to numerous species, affecting habitat conditions and community interactions. Projections suggest species range shifts in response to climate change modifying environmental suitability and is supported by observational evidence. Both pathogens and their hosts can shift ranges with climate change. We consider how climate change may influence the distribution of the emerging infectious amphibian chytrid fungus, Batrachochytrium dendrobatidis (Bd), a pathogen associated with worldwide amphibian population losses. Using an expanded global Bd database and a novel modeling approach, we examined a broad set of climate metrics to model the Bd-climate niche globally and regionally, then project how climate change may influence Bd distributions. Previous research showed that Bd distribution is dependent on climatic variables, in particular temperature. We trained a machine-learning model (random forest) with the most comprehensive global compilation of Bd sampling records (~5,000 site-level records, mid-2014 summary), including 13 climatic variables. We projected future Bd environmental suitability under IPCC scenarios. The learning model was trained with combined worldwide data (non-region specific) and also separately per region (region specific). One goal of our study was to estimate of how Bd spatial risks may change under climate change based on the best available data. Our models supported differences in Bd-climate relationships among geographic regions. We projected that Bd ranges will shift into higher latitudes and altitudes due to increased environmental suitability in those regions under predicted climate change. Specifically, our model showed a broad expansion of areas environmentally suitable for establishment of Bd on amphibian hosts in the temperate zones of the Northern Hemisphere. Our projections are useful for the development of monitoring designs in these areas, especially for sensitive species and those vulnerable to multiple threats. PMID- 27513566 TI - sIgE Ana o 1, 2 and 3 accurately distinguish tolerant from allergic children sensitized to cashew nuts. AB - BACKGROUND: The double-blind, placebo-controlled food challenge test (DBPCFC) is the gold standard in cashew nut allergy. This test is costly, time consuming and not without side effects. Analysis of IgE reactivity to cashew nut components may reduce the need for food challenge tests. METHODS: In a prospective and multicentre study, children with suspected cashew nut allergy underwent a DBPCFC with cashew nut. Specific IgE to cashew nut and to the components Ana o 1, 2 and 3 were determined. A skin prick test (SPT) with cashew nut extract was performed. The association between the outcome of the food challenge test and specific IgE to Ana o 1, 2 and 3 was assessed with logistic regression analyses, unadjusted and adjusted for other diagnostic variables. Discriminative ability was quantified with a concordance index (c). RESULTS: A total of 173 children (103 boys, 60%) with a median age of 9 years were included. About 79% had a positive challenge test outcome. A steep rise in the risk of a positive challenge was observed for specific IgE to each individual component Ana o 1, 2 and 3 with estimated risks up to approximately 100%. Median values of Ana o 1, 2, 3 were 1.29 kU/l (range 0-100 kU/l), 4.77 kU/l (range 0-100 kU/l) and 8.33 kU/l (range 0 100 kU/l) respectively and varied significantly (p < 0.001). Specific IgE to Ana o 1, 2 and 3 was better distinguished between cashew-allergic and tolerant children (c = 0.87, 0.85 and 0.89, respectively) than specific IgE to cashew nut or SPT (c = 0.76 and 0.83, respectively). CONCLUSION: The major cashew nut allergens Ana o 1, 2 and 3 are each individually predictive for the outcome of food challenge tests in cashew-allergic children. PMID- 27513567 TI - Reproducible Construction of Surface Tension-Mediated Honeycomb Concave Microwell Arrays for Engineering of 3D Microtissues with Minimal Cell Loss. AB - The creation of engineered 3D microtissues has attracted prodigious interest because of the fact that this microtissue structure is able to mimic in vivo environments. Such microtissues can be applied extensively in the fields of regenerative medicine and tissue engineering, as well as in drug and toxicity screening. Here, we develop a novel method of fabricating a large number of dense honeycomb concave microwells via surface tension-mediated self-construction. More specifically, in order to control the curvature and shape of the concavity in a precise and reproducible manner, a custom-made jig system was designed and fabricated. By applying a pre-set force using the jig system, the shape of the honeycomb concave well was precisely and uniformly controlled, despite the fact that wells were densely packed. The thin wall between the honeycomb wells enables the minimization of cell loss during the cell-seeding process. To evaluate the performance of the honeycomb microwell array, rat hepatocytes were seeded, and spheroids were successfully formed with uniform shape and size. Liver-specific functions such as albumin secretion and cytochrome P450 were subsequently analyzed. The proposed method of fabricating honeycomb concave wells is cost effective, simple, and reproducible. The honeycomb well array can produce multiple spheroids with minimal cell loss, and can lead to significant contributions in tissue engineering and organ regeneration. PMID- 27513568 TI - Stimulation of Eryptosis by Caspofungin. AB - BACKGROUND/AIMS: The echinocandin antifungal agent caspofungin has been shown to trigger apoptosis of fungal cells. Beyond that, caspofungin is toxic for host mitochondria. Even though lacking mitochondria, erythrocytes may enter apoptosis like suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling involved in triggering of eryptosis include increase of cytosolic Ca2+ activity ([Ca2+]i), oxidative stress, ceramide, caspase activation and/or activation of p38 kinase, protein kinase C, and casein kinase. The present study explored, whether caspofungin induces eryptosis and, if so, to shed some light on the cellular mechanisms involved. METHODS: Flow cytometry was employed to determine phosphatidylserine exposure at the cell surface from annexin-V binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was quantified from hemoglobin concentration in the supernatant. RESULTS: A 48 hours exposure of human erythrocytes to caspofungin (>= 30 ug/ml) significantly increased the percentage of annexin-V binding cells, significantly decreased forward scatter, significantly enhanced hemolysis, but did not significantly increase Fluo3-fluorescence, DCFDA fluorescence or ceramide abundance. The effect of caspofungin on annexin-V binding was not significantly blunted by removal of extracellular Ca2+, by inhibition of caspases with pancaspase inhibitor zVAD (10 uM), or by addition of the antioxidant N-acetyl-cysteine (1 mM), p38 kinase inhibitor SB203580 (2 uM) or protein kinase C inhibitor staurosporine (1 uM). The effect of caspofungin on annexin-V-binding was, however, significantly blunted in the presence of casein kinase inhibitor D4476 (10 uM). CONCLUSIONS: Caspofungin triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect possibly involving activation of casein kinase. PMID- 27513569 TI - Combination of chlorogenic acid and salvianolic acid B protects against polychlorinated biphenyls-induced oxidative stress through Nrf2. AB - Caffeic acid derivatives (CADs) are well-known phytochemicals with multiple physiological and pharmacological activities. This study aimed to investigate the combined protective effects of CADs on PCB126-induced liver damages and oxidative stress in mice. Here, we used chemiluminescence and chose chlorogenic acid (CGA), salvianolic acid B (Sal B) as the best antioxidants. Then, mice were intragastrically administered with 60mg/kg/d CGA, Sal B, and CGA plus Sal B (1:1) for 3 weeks before exposing to 0.05mg/kg/d PCB126 for 2 weeks. We found that pretreatment with CGA, Sal B, and CGA plus Sal B effectively attenuated liver injury and cytotoxicity caused by PCB126, but improved the expressions of superoxide dismutase (SOD), glutathione reduced (GSH), heme oxygenase-1 (HO-1) and nuclear factor E2-related factor 2 (Nrf2), CGA plus Sal B especially, was found to have the best effects that indicated a synergetic protective effect. Taken together, as the Nrf2 regulates the cyto-protective response by up regulating the expression of antioxidant genes, we suggested that CGA plus Sal B had a combined protection on PCB126-induced tissue damages and that the Nrf2 signaling might be involved. PMID- 27513570 TI - Synthesis of High-Molecular-Weight Polyhydroxyalkanoates by Marine Photosynthetic Purple Bacteria. AB - Polyhydroxyalkanoate (PHA) is a biopolyester/bioplastic that is produced by a variety of microorganisms to store carbon and increase reducing redox potential. Photosynthetic bacteria convert carbon dioxide into organic compounds using light energy and are known to accumulate PHA. We analyzed PHAs synthesized by 3 purple sulfur bacteria and 9 purple non-sulfur bacteria strains. These 12 purple bacteria were cultured in nitrogen-limited medium containing acetate and/or sodium bicarbonate as carbon sources. PHA production in the purple sulfur bacteria was induced by nitrogen-limited conditions. Purple non-sulfur bacteria accumulated PHA even under normal growth conditions, and PHA production in 3 strains was enhanced by nitrogen-limited conditions. Gel permeation chromatography analysis revealed that 5 photosynthetic purple bacteria synthesized high-molecular-weight PHAs, which are useful for industrial applications. Quantitative reverse transcription polymerase chain reaction analysis revealed that mRNA levels of phaC and PhaZ genes were low under nitrogen limited conditions, resulting in production of high-molecular-weight PHAs. We conclude that all 12 tested strains are able to synthesize PHA to some degree, and we identify 5 photosynthetic purple bacteria that accumulate high-molecular weight PHA molecules. Furthermore, the photosynthetic purple bacteria synthesized PHA when they were cultured in seawater supplemented with acetate. The photosynthetic purple bacteria strains characterized in this study should be useful as host microorganisms for large-scale PHA production utilizing abundant marine resources and carbon dioxide. PMID- 27513571 TI - Mortality in the First 3 Months on Antiretroviral Therapy Among HIV-Positive Adults in Low- and Middle-income Countries: A Meta-analysis. AB - Previous meta-analyses reported mortality estimates of 12-month post antiretroviral therapy (ART) initiation; however, 40%-60% of deaths occur in the first 3 months on ART, a more sensitive measure of averted deaths through early ART initiation. To determine whether early mortality is dropping as treatment thresholds have increased, we reviewed studies of 3 months on ART initiation in low- to middle-income countries. Studies of 3-month mortality from January 2003 to April 2016 were searched in 5 databases. Articles were included that reported 3-month mortality from a low- to middle-income country; nontrial setting and participants were >=15. We assessed overall mortality and stratified by year using random effects models. Among 58 included studies, although not significant, pooled estimates show a decline in mortality when comparing studies whose enrollment of patients ended before 2010 (7.0%; 95% CI: 6.0 to 8.0) with the studies during or after 2010 (4.0%; 95% CI: 3.0 to 5.0). To continue to reduce early HIV-related mortality at the population level, intensified efforts to increase demand for ART through active testing and facilitated referral should be a priority. Continued financial investments by multinational partners and the implementation of creative interventions to mitigate multidimensional complex barriers of accessing care and treatment for HIV are needed. PMID- 27513572 TI - Difference in Aortic Stiffness Between Treated Middle-Aged HIV Type 1-Infected and Uninfected Individuals Largely Explained by Traditional Cardiovascular Risk Factors, With an Additional Contribution of Prior Advanced Immunodeficiency. AB - BACKGROUND: Patients with HIV, even with suppressed viremia on combination antiretroviral therapy, are at increased risk for cardiovascular disease. The underlying pathophysiology remains to be clarified. Aortic stiffness, known to be associated with cardiovascular disease in the general population, was investigated in a cohort of HIV type 1 (HIV 1)-infected and similar but uninfected individuals. METHODS: Aortic stiffness was assessed by measuring pulse wave velocity (PWV) with an Arteriograph. Five hundred seven HIV-uninfected and 566 HIV 1-infected individuals, predominantly with suppressed viremia on combination antiretroviral therapy, aged >=45 years, participating in the ongoing AGEhIV Cohort Study were included in the analysis. Multivariable linear regression was used to investigate whether HIV was independently associated with aortic stiffness, adjusting for traditional cardiovascular risk factors. RESULTS: Study groups were comparable in demographics; smoking and hypertension were more prevalent in HIV-infected participants. PWV was higher in the HIV-infected group (7.9 vs. 7.7 m/s, P = 0.004). After adjustment for mean arterial pressure, age, gender, and smoking, HIV status was not significantly associated with aortic stiffness. In HIV-infected participants, having a nadir CD4 T-cell count <=100 cells per cubic millimeter was independently associated with a higher PWV. CONCLUSIONS: The increased aortic stiffness in HIV-infected participants was largely explained by a higher prevalence of traditional cardiovascular risk factors, particularly smoking. Although HIV itself was not independently associated with higher aortic stiffness, a prior greater degree of immunodeficiency was. This suggests a detrimental effect of immunodeficiency on the aortic wall, possibly mediated by inflammation. PMID- 27513573 TI - Barriers to Viral Suppression Among Female Sex Workers: Role of Structural and Intimate Partner Dynamics. AB - OBJECTIVE: Despite global evidence that sex workers (SWs) are disproportionately impacted by HIV, data on HIV treatment outcomes among SWs living with HIV remains sparse. This study examined the correlates of undetectable plasma viral load (pVL) among street- and off-street SWs living with HIV and on antiretroviral therapy (ART) in Metro Vancouver, Canada. METHODS: Analyses drew on data (2010 2014) from a longitudinal cohort of SWs (An Evaluation of Sex Workers Health Access) and confidential linkages with the Drug Treatment Program (DTP) data on ART dispensation and outcomes. Bivariate and multivariable generalized linear mixed-effects models were used to identify longitudinal correlates of undetectable pVL (<50 copies/mL). RESULTS: Of the 72 SWs living with HIV who had ever used ART, 38.9% had an undetectable pVL at baseline. Although 84.7% had undetectable pVL at least once over the study period, 18.1% exhibited sustained undetectable pVL. In multivariable generalized linear mixed-effects model analyses, >=95% pharmacy refill adherence (adjusted odds ratio (AOR) = 4.21; 95% confidence interval (CI) 2.16 to 8.19) and length of time since diagnosis (AOR = 1.06; 95% CI: 1.00 to 1.13) were positively correlated with undetectable pVL. Having an intimate male partner (AOR = 0.35; 95% CI: 0.16 to 0.78) and being homelessness were negatively correlated with undetectable pVL (AOR = 0.22; 95% CI: 0.10 to 0.47). DISCUSSION/CONCLUSIONS: There is a need to more closely consider the social and structural contexts that shape SWs' experiences on ART and impact treatment outcomes, including the gendered power dynamics within intimate partnerships. Future research on HIV care among SWs is urgently needed, alongside structural and community-led interventions to support SWs' access to and retention in care. PMID- 27513574 TI - Association between Work-Related Stress and Risk for Type 2 Diabetes: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. AB - BACKGROUND/OBJECTIVE: The prevalence of type 2 diabetes is increasing rapidly around the world. Work-related stress is thought to be a major risk factor for type 2 diabetes; however, this association has not been widely studied, and the findings that have been reported are inconsistent. Therefore, we conducted a meta analysis of prospective cohort studies to explore the association between work related stress and risk for type 2 diabetes. METHODS: A systematic literature search and manual search limited to articles published in English were performed to select the prospective cohort studies evaluated the association between work related stress and risk for type 2 diabetes up to September 2014 from four electronic databases including PubMed, EMBASE, the Cochrane Library and Web of Science. A random-effects model was used to estimate the overall risk. RESULTS: No significant association was found between work-related stress and risk for type 2 diabetes based on meta-analysis of seven prospective cohort studies involving 214,086 participants and 5,511 cases (job demands: relative risk 0.94 [95% confidence interval 0.72-1.23]; decision latitude: relative risk 1.16 [0.85 1.58]; job strain: relative risk 1.12 [.0.95-1.32]). However, an association between work-related stress and risk for type 2 diabetes was observed in women (job strain: relative risk 1.22 [1.01-1.46]) (P = 0.04). A sensitivity analysis conducted by excluding one study in each turn yielded similar results. No publication bias was detected with a funnel plot despite the limited number of studies included in the analysis. CONCLUSIONS: The results of this meta-analysis did not confirm a direct association between work-related stress and risk for type 2 diabetes. In subgroup analyses we found job strain was a risk factor for type 2 diabetes in women. PMID- 27513575 TI - Inactivation of SmeSyRy Two-Component Regulatory System Inversely Regulates the Expression of SmeYZ and SmeDEF Efflux Pumps in Stenotrophomonas maltophilia. AB - SmeYZ efflux pump is a critical pump responsible for aminoglycosides resistance, virulence-related characteristics (oxidative stress susceptibility, motility, and secreted protease activity), and virulence in Stenotrophomonas maltophilia. However, the regulatory circuit involved in SmeYZ expression is little known. A two-component regulatory system (TCS), smeRySy, transcribed divergently from the smeYZ operon is the first candidate to be considered. To assess the role of SmeRySy in smeYZ expression, the smeRySy isogenic deletion mutant, KJDeltaRSy, was constructed by gene replacement strategy. Inactivation of smeSyRy correlated with a higher susceptibility to aminoglycosides concomitant with an increased resistance to chloramphenicol, ciprofloxacin, tetracycline, and macrolides. To elucidate the underlying mechanism responsible for the antimicrobials susceptibility profiles, the SmeRySy regulon was firstly revealed by transcriptome analysis and further confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and promoter transcription fusion constructs assay. The results demonstrate that inactivation of smeRySy decreased the expression of SmeYZ pump and increased the expression of SmeDEF pump, which underlies the DeltasmeSyRy-mediated antimicrobials susceptibility profile. To elucidate the cognate relationship between SmeSy and SmeRy, a single mutant, KJDeltaRy, was constructed and the complementation assay of KJDeltaRSy with smeRy were performed. The results support that SmeSy-SmeRy TCS is responsible for the regulation of smeYZ operon; whereas SmeSy may be cognate with another unidentified response regulator for the regulation of smeDEF operon. The impact of inverse expression of SmeYZ and SmeDEF pumps on physiological functions was evaluated by mutants construction, H2O2 susceptibility test, swimming, and secreted protease activity assay. The increased expression of SmeDEF pump in KJDeltaRSy may compensate, to some extents, the SmeYZ downexpression-mediated compromise with respect to its role in secreted protease activity. PMID- 27513576 TI - Estimates of the Direct Effect of Seawater pH on the Survival Rate of Species Groups in the California Current Ecosystem. AB - Ocean acidification (OA) has the potential to restructure ecosystems due to variation in species sensitivity to the projected changes in ocean carbon chemistry. Ecological models can be forced with scenarios of OA to help scientists, managers, and other stakeholders understand how ecosystems might change. We present a novel methodology for developing estimates of species sensitivity to OA that are regionally specific, and applied the method to the California Current ecosystem. To do so, we built a database of all published literature on the sensitivity of temperate species to decreased pH. This database contains 393 papers on 285 species and 89 multi-species groups from temperate waters around the world. Research on urchins and oysters and on adult life stages dominates the literature. Almost a third of the temperate species studied to date occur in the California Current. However, most laboratory experiments use control pH conditions that are too high to represent average current chemistry conditions in the portion of the California Current water column where the majority of the species live. We developed estimates of sensitivity to OA for functional groups in the ecosystem, which can represent single species or taxonomically diverse groups of hundreds of species. We based these estimates on the amount of available evidence derived from published studies on species sensitivity, how well this evidence could inform species sensitivity in the California Current ecosystem, and the agreement of the available evidence for a species/species group. This approach is similar to that taken by the Intergovernmental Panel on Climate Change to characterize certainty when summarizing scientific findings. Most functional groups (26 of 34) responded negatively to OA conditions, but when uncertainty in sensitivity was considered, only 11 groups had relationships that were consistently negative. Thus, incorporating certainty about the sensitivity of species and functional groups to OA is an important part of developing robust scenarios for ecosystem projections. PMID- 27513577 TI - Workplace Health Promotion and Mental Health: Three-Year Findings from Partnering Healthy@Work. AB - This study aimed to investigate the association between mental health and comprehensive workplace health promotion (WHP) delivered to an entire state public service workforce (~28,000 employees) over a three-year period. Government departments in a state public service were supported to design and deliver a comprehensive, multi-component health promotion program, Healthy@Work, which targeted modifiable health risks including unhealthy lifestyles and stress. Repeated cross-sectional surveys compared self-reported psychological distress (Kessler-10; K10) at commencement (N = 3406) and after 3 years (N = 3228). WHP availability and participation over time was assessed, and associations between the K10 and exposure to programs estimated. Analyses were repeated for a cohort subgroup (N = 580). Data were weighted for non-response. Participation in any mental health and lifestyle programs approximately doubled after 3 years. Both male and female employees with poorer mental health participated more often over time. Women's psychological distress decreased over time but this change was only partially attributable to participation in WHP, and only to lifestyle interventions. Average psychological distress did not change over time for men. Unexpectedly, program components directly targeting mental health were not associated with distress for either men or women. Cohort results corroborated findings. Healthy@Work was successful in increasing participation across a range of program types, including for men and women with poorer mental health. A small positive association of participation in lifestyle programs with mental health was observed for women but not men. The lack of association of mental health programs may have reflected program quality, its universality of application or other contextual factors. PMID- 27513578 TI - Clinicians and clients disagree: Five implications for clinical science. AB - Recent findings highlight the limited agreement between diagnostic ratings provided by practicing clinicians and the self-report and interview methods typically employed in research settings. Such discrepancies between the diagnoses assigned in research and applied settings greatly complicate the translation of empirical findings into practice. This review highlights these disagreements, offers explanations for these observed differences, and provides 5 implications for research. Specifically, we provide evidence that, despite criticisms, self reported psychopathology may be at least as valid as clinicians' unstructured diagnoses. Further, we highlight the need for research that provides clinicians with the most valid tools, including those that focus on dimensional constructs, rather than diagnostic categories. In addition, we recommend that adult psychopathology research incorporate methodologies from general personality for unraveling informant discrepancies. We highlight recent work that has provided valuable tools for incorporating metaperception-the extent to which one is aware of how they are perceived by others-for contextualizing these differences. We also underscore the utility of emerging technologies that provide rich data, such as ambulatory assessment, for overcoming the criterion problem. Finally, we recommend that advances in combining data from multiple sources from the childhood psychopathology literature, such as examining the extent to which discrepancies themselves might aid in diagnosis, be incorporated into adult psychopathology research. In sum, we hope that these implications inspire research that improves the science of diagnostic assessment in a way that might ultimately improve practice. (PsycINFO Database Record PMID- 27513579 TI - DHA but Not EPA Emulsions Preserve Neurological and Mitochondrial Function after Brain Hypoxia-Ischemia in Neonatal Mice. AB - BACKGROUND AND PURPOSE: Treatment with triglyceride emulsions of docosahexaenoic acid (tri-DHA) protected neonatal mice against hypoxia-ischemia (HI) brain injury. The mechanism of this neuroprotection remains unclear. We hypothesized that administration of tri-DHA enriches HI-brains with DHA/DHA metabolites. This reduces Ca2+-induced mitochondrial membrane permeabilization and attenuates brain injury. METHODS: 10-day-old C57BL/6J mice following HI-brain injury received tri DHA, tri-EPA or vehicle. At 4-5 hours of reperfusion, mitochondrial fatty acid composition and Ca2+ buffering capacity were analyzed. At 24 hours and at 8-9 weeks of recovery, oxidative injury, neurofunctional and neuropathological outcomes were evaluated. In vitro, hyperoxia-induced mitochondrial generation of reactive oxygen species (ROS) and Ca2+ buffering capacity were measured in the presence or absence of DHA or EPA. RESULTS: Only post-treatment with tri-DHA reduced oxidative damage and improved short- and long-term neurological outcomes. This was associated with increased content of DHA in brain mitochondria and DHA derived bioactive metabolites in cerebral tissue. After tri-DHA administration HI mitochondria were resistant to Ca2+-induced membrane permeabilization. In vitro, hyperoxia increased mitochondrial ROS production and reduced Ca2+ buffering capacity; DHA, but not EPA, significantly attenuated these effects of hyperoxia. CONCLUSIONS: Post-treatment with tri-DHA resulted in significant accumulation of DHA and DHA derived bioactive metabolites in the HI-brain. This was associated with improved mitochondrial tolerance to Ca2+-induced permeabilization, reduced oxidative brain injury and permanent neuroprotection. Interaction of DHA with mitochondria alters ROS release and improves Ca2+ buffering capacity. This may account for neuroprotective action of post-HI administration of tri-DHA. PMID- 27513580 TI - Multivitamin Use and Serum Vitamin B12 Concentrations in Older-Adult Metformin Users in REGARDS, 2003-2007. AB - Metformin, an insulin-sensitizing drug, is a first line treatment for type 2 diabetes. Long-term use of metformin has been associated with subsequent reductions in vitamin B12 concentrations. The objective of our study was to determine whether metformin use is associated with lower serum vitamin B12 concentrations in older adults, and whether concurrent use of multivitamins modifies this association. We examined 2,510 participants aged 50 years and over, participating in the national population-based Reasons for Geographic And Racial Differences in Stroke (REGARDS) Study. Multivariable linear and logistic regression models were used to assess associations between multivitamin use and serum vitamin B12 concentrations. We estimated adjusted odds ratios (aOR)s and confidence intervals (CI)s. Results were stratified by three metformin/diabetes sub-groups: 1) participants with diabetes who were metformin users; 2) participants with diabetes who were not metformin users; and 3) participants without diabetes. We found that diabetic metformin users had significantly lower geometric mean serum B12 concentrations (409 pmol/L) than the group with diabetes not taking metformin (485 pmol/L; P<0.01), and the group without diabetes (445 pmol/L; P = 0.02). The geometric mean serum B12 concentrations were greater for multivitamin users (509 pmol/L) compared to those who did not use multivitamins (376 pmol/L; p<0.01). Among the participants with diabetes who were on metformin therapy, multivitamin use was associated with geometric mean serum vitamin B12 concentrations that were 50% (or 161 pmol/L) higher, compared to those not using multivitamins. Among metformin users, multivitamin use was associated with lower prevalence of combined low and borderline vitamin B12 concentrations (aOR = 0.14; 95% CI = 0.04, 0.54) compared to those not using multivitamins. In conclusion, metformin use was associated with lower geometric mean serum vitamin B12 concentrations among diabetic older adults compared to their counterparts. Concurrent multivitamin use may potentially protect against low or borderline vitamin B12 concentrations in long-term metformin users. Additional research is needed to further examine this association as low or borderline vitamin B12 concentrations can be preventable, or treatable if detected at an early stage, in long-term metformin users. PMID- 27513581 TI - The Profile and Bioaccessibility of Phenolic Compounds in Cereals Influenced by Improved Extrusion Cooking Treatment. AB - The aim of this study was to investigate the effect of Improved Extrusion Cooking Treatment (IECT) on the phenolics and its bioaccessibility in cereals, represented by brown rice, wheat, and oat. Data showed that total phenolic content and total antioxidant activity in free form were significantly decreased, while the bound form was increased after IECT. After IECT, the total free phenolic acids of brown rice and wheat were significantly decreased by 5.88% and 45.66%, respectively, while the total bound phenolic acids of brown rice, wheat, and oat were significantly increased by 6.45%, 8.78%, and 9.10%, respectively. Brown rice provided the most bioaccessible phenolics and antioxidant compounds, followed by oat and wheat. IECT significantly decreased the bioaccessible phenolics of brown rice and oat by 31.09% and 30.95%, while it had minimal effect on the bioaccessible phenolics of wheat. These results showed that IECT greatly affected the phenolics and its bioaccessibiltiy of cereals, with the effect depending on cereal matrix and the sensitivity of free and bound phenolics. Furthermore, bioaccessible phenolic acids of raw and processed cereals were considerably low, and it slightly contributed to the bioaccessible phenolics. PMID- 27513583 TI - Preface. PMID- 27513582 TI - Insights into the Conformation of the Membrane Proximal Regions Critical to the Trimerization of the HIV-1 gp41 Ectodomain Bound to Dodecyl Phosphocholine Micelles. AB - The transitioning of the ectodomain of gp41 from a pre-hairpin to a six-helix bundle conformation is a crucial aspect of virus-cell fusion. To gain insight into the intermediary steps of the fusion process we have studied the pH and dodecyl phosphocholine (DPC) micelle dependent trimer association of gp41 by systematic deletion analysis of an optimized construct termed 17-172 (residues 528 to 683 of Env) that spans the fusion peptide proximal region (FPPR) to the membrane proximal external region (MPER) of gp41, by sedimentation velocity and double electron-electron resonance (DEER) EPR spectroscopy. Trimerization at pH 7 requires the presence of both the FPPR and MPER regions. However, at pH 4, the protein completely dissociates to monomers. DEER measurements reveal a partial fraying of the C-terminal MPER residues in the 17-172 trimer while the other regions, including the FPPR, remain compact. In accordance, truncating nine C terminal MPER residues (675-683) in the 17-172 construct does not shift the trimer-monomer equilibrium significantly. Thus, in the context of the gp41 ectodomain spanning residues 17-172, trimerization is clearly dependent on FPPR and MPER regions even when the terminal residues of MPER unravel. The antibody Z13e1, which spans both the 2F5 and 4E10 epitopes in MPER, binds to 17-172 with a Kd of 1 +/- 0.12 MUM. Accordingly, individual antibodies 2F5 and 4E10 also recognize the 17-172 trimer/DPC complex. We propose that binding of the C terminal residues of MPER to the surface of the DPC micelles models a correct positioning of the trimeric transmembrane domain anchored in the viral membrane. PMID- 27513584 TI - Augmenting SRIs for Obsessive-Compulsive Disorder: Patient Preference for Risperidone Does Not Limit Effectiveness of Exposure and Ritual Prevention. PMID- 27513585 TI - Ingenol Mebutate Treatment in a Patient with Gorlin Syndrome. AB - BACKGROUND: Gorlin syndrome, also known as the basal cell nevus syndrome (OMIM #109400), is a rare autosomal-dominant genetic disease. The disease, which shows mutation of the patched receptor gene (PTCH1) of the sonic hedgehog pathway, is characterized by developing multiple basal cell carcinomas (BCCs) in adolescent patients. Other clinical features include mandibular keratocysts, palmar and plantar pits, skeletal abnormalities and malformations central nervous system and genital tract. Gorlin-Goltz patients need multidisciplinary medical care and follow-up as well as genetic counseling if the patients want to have children. The treatment of multiple BCCs includes conventional surgery, micrographic Mohs surgery, cryotherapy, laser ablation, photodynamic therapy, imiquimod 5% cream, 5 fluorouracil cream as well as the sonic hedgehog pathway inhibitor vismodegib. CASE REPORT: We report the case of a 30-year-old woman seen in our dermatological department since 2003. All the above-mentioned modalities had been employed for her numerous BCCs. The patient grew wary of the surgical procedures because of the countless scars. We successfully treated multiple BCCs with ingenol mebutate without post-inflammatory scarring. At 8-month follow-up, the patient shows no recurrence of the treated lesions. CONCLUSION: Ingenol mebutate can be used to treat (superficial) BCCs in patients with Gorlin-Goltz syndrome as an additional modality. Close clinical follow-up is recommended. PMID- 27513586 TI - The Effect of Problem-Based Learning on Improvement of the Medical Educational Environment: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: The aim of this study was to evaluate the effect of problem-based learning on improving the medical educational environment. MATERIALS AND METHODS: All relevant studies on problem-based learning and the medical educational environment were searched for in PubMed, the Education Resources Information Center (ERIC) catalogue, Google Scholar, China National Knowledge Infrastructure (CNKI) and WanFang Data (WF) databases for material dating from 1969 to May 2015 without any language limitation. Six randomized controlled trials of problem based learning compared to traditional lecture-based learning were included. The Cochrane risk of bias tool was used to assess the quality of the included studies. Review Manager (Revman) version 5.3 software was used for data analysis. The effect size of the improvement on the medical educational environment was calculated as the mean difference and 95% confidence interval. Heterogeneity was evaluated with Cochrane's chi2 test and I2. Publication bias was assessed by funnel plot, Begg's rank correlation test, and Egg's linear regression test. RESULTS: The six included studies were at low risk of bias in all domains except for three that were at high risk of bias in the domain of allocation concealment. The pooled effect size showed that problem-based learning was better than lecture based learning in improving the medical educational environment, as measured by the Dundee Ready Education Environment Measure (DREEM), with statistically significant differences. No significant publication bias was observed. The sensitivity analysis showed that the result was reliable. CONCLUSIONS: This study showed that problem-based learning was able to improve the medical educational environment as measured by DREEM. However, further studies with larger sample sizes and high-quality data are needed. PMID- 27513587 TI - Targeting cancer cells via tumor-homing peptide CREKA functional PEG nanoparticles. AB - Targeting cell microenvironment via nano-particle based therapies holds great promise for the treatment of various diseases. One of the main challenges in targeted delivery of nanoparticles for cancer therapy is the reduced localization of delivery vehicles to the tumor site. The therapeutic efficacy of drugs can be improved by recruiting delivery vehicles towards specific region of tumorigenesis in the body. Here, we demonstrate an effective approach in creating PEG particles via water-in-water emulsion technique with a tumor-homing peptide CREKA functionalization. The CREKA conjugated hydrogel nanoparticles were found to be more effective at inducing Doxorubicin (DOX)-mediated apoptosis compared to that of particles conjugated with laminin peptide IKVAV. Fluorescence intensity analysis on confocal micrographs suggested significantly higher cellular uptake of CREKA conjugated PEG particles than internalization of nanoparticles in other groups. We observed that fibrin binding ability of PEG particles could be increased up to 94% through CREKA conjugation. Our results suggest the possibility of cancer cell targeting via CREKA-functional PEG nanoparticles. PMID- 27513588 TI - PLGA nanoparticles from nano-emulsion templating as imaging agents: Versatile technology to obtain nanoparticles loaded with fluorescent dyes. AB - The interest in polymeric nanoparticles as imaging systems for biomedical applications has increased notably in the last decades. In this work, PLGA nanoparticles, prepared from nano-emulsion templating, have been used to prepare novel fluorescent imaging agents. Two model fluorescent dyes were chosen and dissolved in the oil phase of the nano-emulsions together with PLGA. Nano emulsions were prepared by the phase inversion composition (PIC) low-energy method. Fluorescent dye-loaded nanoparticles were obtained by solvent evaporation of nano-emulsion templates. PLGA nanoparticles loaded with the fluorescent dyes showed hydrodynamic radii lower than 40nm; markedly lower than those reported in previous studies. The small nanoparticle size was attributed to the nano emulsification strategy used. PLGA nanoparticles showed negative surface charge and enough stability to be used for biomedical imaging purposes. Encapsulation efficiencies were higher than 99%, which was also attributed to the nano emulsification approach as well as to the low solubility of the dyes in the aqueous component. Release kinetics of both fluorescent dyes from the nanoparticle dispersions was pH-independent and sustained. These results indicate that the dyes could remain encapsulated enough time to reach any organ and that the decrease of the pH produced during cell internalization by the endocytic route would not affect their release. Therefore, it can be assumed that these nanoparticles are appropriate as systemic imaging agents. In addition, in vitro toxicity tests showed that nanoparticles are non-cytotoxic. Consequently, it can be concluded that the preparation of PLGA nanoparticles from nano-emulsion templating represents a very versatile technology that enables obtaining biocompatible, biodegradable and safe imaging agents suitable for biomedical purposes. PMID- 27513589 TI - Laparoscopic Treatment of a Retroduodenopancreatic Endometriotic Cyst Observed Postpartum. AB - Endometriosis occurs in 5%-10% of fertile women, usually in the pelvic region, such as the ovaries, uterine ligaments, pelvic peritoneum, and rectovaginal septum. A mesenteric endometriotic cyst is an exceptional observation and difficult to diagnose preoperatively. We report a case of a large mesenteric endometriotic cyst treated by laparoscopy. A 21-year-old Caucasian woman was admitted as an emergency to our Academic Hospital on the 30th day postpartum for abdominal pain and a palpable epigastric mass. A CT scan revealed a mass measuring 7.5 * 5.5 cm showing a fluid content, located below the pancreas. A preoperative diagnosis of mesenteric cyst was made and confirmed by MRI. A dissection of the mass from the inferior vena cava, pancreas, and duodenum was achieved by a laparoscopic approach. During the blunt dissection, avoiding any spillage, the cyst was aspirated to preserve a safe cleavage plane with the lower third of the duodenum showing tenacious adhesions to the mass. Histology revealed an endometriotic cyst of the mesenterium. To our knowledge, this is the first case reported in the literature of laparoscopic treatment of a retroduodenopancreatic endometriotic cyst observed postpartum. In dedicated centers, laparoscopic management could be the gold standard. PMID- 27513590 TI - Alternative Estimates of Lifetime Prevalence Of Abortion from Indirect Survey Questioning Methods. PMID- 27513591 TI - Isolation as a strategy for controlling the transmission of hepatitis C virus (HCV) infection in haemodialysis units. AB - BACKGROUND: The hepatitis C virus (HCV) infection affects about 2% of the world's population and can cause chronic liver infection and persistent long-term sequelae such as cirrhosis and liver cancer.The prevalence of HCV infection among people on haemodialysis is often higher than the general population. The virus is easily transmitted parenterally, and blood transfusions have previously played a significant role in transmission; however, erythropoietin therapy has reduced the need for transfusions, and coupled with improved screening of donated blood, has significantly decreased transmission by transfusion. Although control of hospital acquired infection has improved with the advent of biosafety measures, stopping HCV transmission in haemodialysis units remains challenging.Isolating people infected with HCV involves physical separation from others to limit direct or indirect transmission and includes a number of strategies during dialysis. The evidence for isolating people infected with HCV during haemodialysis is sparse with some inconsistencies. OBJECTIVES: To evaluate the benefits and harms of isolation of HCV-infected patients during haemodialysis on the transmission of HCV to other patients. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register to 26 November 2015 through contact with the Information Specialist using search terms relevant to this review. We also searched the Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to 2015), Web of Science Conference Proceedings Citation Index Science (CPCI-S, 1990 to 2015), ProQuest Dissertations & Theses Database (1990 to 2015), and Open Grey (1990 to 2015). SELECTION CRITERIA: We included randomised controlled trials (RCTs), quasi-RCTs and cluster RCTs evaluating the clinical benefits and harms of isolating HCV-infected patients during haemodialysis on the transmission of HCV to other patients. We considered incidence of dialysis acquired HCV infection, all-cause mortality, and adverse effects associated with isolation as the primary outcomes. DATA COLLECTION AND ANALYSIS: Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. MAIN RESULTS: Only one study, which included 12 centres was identified: four centres used dedicated haemodialysis machines for HCV-infected patients and eight centres used non-dedicated machines. The total number of patients enrolled was 593. One centre was excluded after randomisation. Random sequence generation was not described and allocation concealment was not performed. Participants and personnel were not blinded and blinding of outcome assessors was not reported. Only 74.5% of the patients were followed for 9 months; and 47.3% were followed for an additional 9 months. The authors only reported one outcome, measuring the difference in the incidence of HCV in both groups. The authors did not consider the exposure time, to determine the adjusted rate of seroconversion risk/patient-year. The study reported that the incidence of HCV infection during the first follow-up period (9 months) was 1.6% in the dedicated group, and 4.7% in the non-dedicated one (446 patients analysed out of 593 randomised; RR 0.34, 95% CI 0.11 to 1.07). During the second follow-up period (18 months) the incidence was 1.3% in the dedicated group and 5.8% in the control (281 patients analysed out of 593 randomised; RR 0.22, 95% CI 0.05 to 1.02). Therefore, we found no differences in terms of the number of participants developing HCV infection when comparing the dedicated group with the usual care. Moreover, the evidence was of very low quality, which means that we have very little confidence in the effect estimate. AUTHORS' CONCLUSIONS: The benefits and harms of isolation of HCV-infected patients during haemodialysis on the transmission of HCV to other patients are uncertain. Evidence from one short duration cluster-randomised study with a high risk of bias did not find differences in terms of the number of participants developing HCV infection when comparing the use of dedicated haemodialysis machines for HCV infected patients with the use of non-dedicated machines. PMID- 27513592 TI - DNA Translocation through Nanopores at Physiological Ionic Strengths Requires Precise Nanoscale Engineering. AB - Many important processes in biology involve the translocation of a biopolymer through a nanometer-scale pore. Moreover, the electrophoretic transport of DNA across nanopores is under intense investigation for single-molecule DNA sequencing and analysis. Here, we show that the precise patterning of the ClyA biological nanopore with positive charges is crucial to observe the electrophoretic translocation of DNA at physiological ionic strength. Surprisingly, the strongly electronegative 3.3 nm internal constriction of the nanopore did not require modifications. Further, DNA translocation could only be observed from the wide entry of the nanopore. Our results suggest that the engineered positive charges are important to align the DNA in order to overcome the entropic and electrostatic barriers for DNA translocation through the narrow constriction. Finally, the dependencies of nucleic acid translocations on the Debye length of the solution are consistent with a physical model where the capture of double-stranded DNA is diffusion-limited while the capture of single stranded DNA is reaction-limited. PMID- 27513593 TI - Cultural buffering as a protective factor against electronic cigarette use among Hispanic emergency department patients. AB - INTRODUCTION: Hispanics in the U.S. historically use tobacco at lower rates than other racial and ethnic groups. Cultural buffering, the process by which aspects of traditional Hispanic culture delay the adoption of unhealthy behaviors, is believed to be a protective factor against tobacco use. Electronic cigarettes (e cigarettes) are a new tobacco product that have not been extensively studied, and it is unknown if cultural factors that protect against tobacco use will buffer against e-cigarette use among the Hispanic population. METHODS: This cross sectional study was conducted at the emergency department (ED) in a safety-net hospital in 2014. Patients visiting the ED participated in a survey assessing demographics and substance use. Cultural buffering was operationalized as participants' primary language spoken at home. Multivariate logistic regression and generalized estimating equations examined the association between Hispanic cultural buffering and e-cigarette ever-use. RESULTS: Of the 1476 Hispanic ED patients (age: 46.6M+/-14.5SD, 49.3% male), 7.6% reported e-cigarette ever-use and 11.1% reported current combustible cigarette use. In adjusted models, Spanish speakers were half as likely to report e-cigarette ever-use (O.R.: 0.54, 95% C.I.: 0.34-0.84, p=0.007), compared with English speakers. Combustible cigarette use remained the most significant factor associated with e-cigarette ever-use (O.R.: 9.28, 95% C.I.:7.44-11.56, p<0.001). In higher-income neighborhoods, English speakers reported e-cigarette ever-use at higher rates than Spanish speakers (28.2% vs. 5.9%, p<0.001). CONCLUSIONS: Cultural buffering was protective against e-cigarette ever-use, especially in higher-income neighborhoods. These results support research on culturally-sensitive prevention programs for new and emerging tobacco products in Hispanic communities. PMID- 27513594 TI - Stages of physical dependence in New Zealand smokers: Prevalence and correlates. AB - BACKGROUND: Physically dependent smokers experience symptoms of wanting, craving or needing to smoke when too much time has passed since the last cigarette. There is interest in whether wanting, craving and needing represent variations in the intensity of a single physiological parameter or whether multiple physiological processes may be involved in the developmental progression of physical dependence. AIM: Our aim was to determine how a population of cigarette smokers is distributed across the wanting, craving and needing stages of physical dependence. METHODS: A nationwide survey of 2594 New Zealanders aged 15years and over was conducted in 2014. The stage of physical dependence was assessed using the Levels of Physical Dependence measure. Ordinal logistic regression analysis was used to assess relations between physical dependence and other variables. RESULTS: Among 590 current smokers (weighted 16.2% of the sample), 22.3% had no physical dependence, 23.5% were in the Wanting stage, 14.4% in the Craving stage, and 39.8% in the Needing stage. The stage of physical dependence was predicted by daily cigarette consumption, and the time to first cigarette, but not by age, gender, ethnicity or socioeconomic status. CONCLUSION: Fewer individuals were in the craving stage than either the wanting or needing stages. The resulting inverted U-shaped curve with concentrations at either extreme is difficult to explain as a variation of a single biological parameter. The data support an interpretation that progression through the stages of wanting, craving and needing may involve more than one physiological process. WHAT THIS RESEARCH ADDS: Physical dependence to tobacco develops through a characteristic sequence of wanting, craving and needing which correspond to changes in addiction pathways in the brain. It is important to neuroscience research to determine if the development of physical dependence involves changes in a single brain process, or multiple processes. Our data suggests that more than one physiologic process is involved in the progression of physical dependence. PMID- 27513596 TI - Gene Drives: Biological Shield or Ecological Menace? PMID- 27513597 TI - Antioxidative Theranostic Iron Oxide Nanoparticles toward Brain Tumors Imaging and ROS Production. AB - Gliomas are the most common primary brain tumor in humans. To date, the only treatment of care consists of surgical removal of the tumor bulk, irradiation, and chemotherapy, finally resulting in a very poor prognosis due to the lack of efficiency in diagnostics. In this context, nanomedicine combining both diagnostic and magnetic resonance imaging (MRI) and therapeutic applications is a relevant strategy referred to theranostic. Magnetic nanoparticles (NP) are excellent MRI contrast agents because of their large magnetic moment, which induces high transverse relaxivity (r2) characteristic and increased susceptibility effect (T2*). NP can be also used for drug delivery by coating their surface with therapeutic molecules. Preliminary in vitro studies show the high potential of caffeic acid (CA), a natural polyphenol, as a promising anticancer drug due to its antioxidant, anti-inflammatory, and antimetastatic properties. In this study, the antioxidative properties of iron oxide NP functionalized with caffeic acid (gammaFe2O3@CA NP) are investigated in vitro on U87-MG brain cancer cell lines. After intravenous injection of these NP in mice bearing a U87 glioblastoma, a negative contrast enhancement was specifically observed on 11.7 T MRI images in cancerous tissue, demonstrating a passive targeting of the tumor with these nanoplatforms. PMID- 27513598 TI - Adherence to insulin therapeutic regimens in patients with type 1 diabetes. A nationwide survey in Brazil. AB - AIMS: Determine the relationship between self-reported adherence to insulin therapeutic regimens in Brazilian patients with type 1 diabetes and demographic, clinical data, glycemic control and cardiovascular risk factors. METHODS: This was a cross-sectional, multicenter study conducted between August 2011 and August 2014 in 10 Brazilian cities. Data were obtained from 1698 patients, aged 30.0+/ 11.90years (55.5% females, 53.6% Caucasians) with a diabetes duration of 15.4+/ 1.9years. Adherence was evaluated using an adapted 4-item Morisky Medication Scale (MMAS) questionnaire. RESULTS: A total of 166 (9.8%), 717 (42.2%) and 815 (48.0%) of the patients reported maximal (group 0), moderate (group 1) and minimal (group 2) adherence to their insulin therapeutic regimen, respectively. A significant difference in HbA1c was observed in patients from group 2, 9.2+/-2.2% (77+/-25mmol/mol) compared to group 1, 8.9+/-2.0% (74+/-22mmol/mol) and group 0, 8.6+/-1.9% (71+/-21mmol/mol) (p=0.003). A multivariate logistic analysis revealed that the significant independent variables related to higher insulin therapeutic regimen adherence were older age, higher adherence to diet, lower rate of self reported hypoglycemia in the last month, low economic status and living in the Southeast region. Insulin therapeutic regimens, number of daily insulin injections, self-monitoring of blood glucose, gender, ethnicity and cardiovascular risk factors were not related to adherence. CONCLUSIONS: Most Brazilian T1D patients did not adhere to their prescribed insulin therapeutic regimen, according to the MMAS 4-item scale. This tool should be initially used to identify non-adherent patients and help them overcome the barriers to adherence to their prescriptions. PMID- 27513599 TI - Survey of U.S. Organ Procurement Organizations Regarding Pediatric Organ Donor Management. AB - OBJECTIVE: To describe the current practice of pediatric organ donor management in the United States for donors declared dead based upon neurologic criteria. The study directs particular attention to how pediatric donors are defined, the use of donor management guidelines, the use of donor management goals, and the involvement of pediatric critical care or transplantation expertise. DESIGN: Cross-sectional observational study using a web-based survey and follow-up telephone interview with respondents from U.S. organ procurement organizations. The study also incorporated organ procurement organization-specific data on organ yield for the 4-year period (2010-2013) preceding the study. SETTING: The 58 U.S. organ procurement organizations. SUBJECTS: Respondents chosen by each organ procurement organization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All 58 U.S. organ procurement organizations participated in the study. Fifty-two respondents (90%) indicated that their organ procurement organization distinguished pediatric from adult donors resulting in 28 unique pediatric definitions. Thirty-nine organ procurement organizations utilized some form of written pediatric management guidelines, and 27 (47%) maintained pediatric donor management goals; compliance was infrequently monitored for both guidelines (28%) and goals (33%). A pediatric intensivist was always or usually involved in pediatric donor management at 47 organ procurement organizations (81%); transplant/organ recovery surgeons were always or usually involved at 12 organ procurement organizations (21%). There was an increase in the number of organs transplanted per donor among donors 11-17 years old for organ procurement organizations that used donor management goals for the duration of the period studied (p < 0.01). There was also an increase in the ratio of observed/expected organs transplanted among donors of 0-10 years old for organ procurement organizations that always or usually consulted a transplant/organ recovery surgeon (p = 0.02) although this did not reach our threshold for statistical significance.. CONCLUSIONS: There is little consensus among organ procurement organizations regarding the definition of "pediatric" during organ donor management. Most organ procurement organizations employ written pediatric guidelines and use pediatric intensive care physicians for assistance in managing these donors. There is a positive association between the use of donor management goals and organ yield among pediatric donors in the 11- to 17-year age group. PMID- 27513600 TI - Utilizing a Collaborative Learning Model to Promote Early Extubation Following Infant Heart Surgery. AB - OBJECTIVE: To determine whether a collaborative learning strategy-derived clinical practice guideline can reduce the duration of endotracheal intubation following infant heart surgery. DESIGN: Prospective and retrospective data collected from the Pediatric Heart Network in the 12 months pre- and post clinical practice guideline implementation at the four sites participating in the collaborative (active sites) compared with data from five Pediatric Heart Network centers not participating in collaborative learning (control sites). SETTING: Ten children's hospitals. PATIENTS: Data were collected for infants following two index operations: 1) repair of isolated coarctation of the aorta (birth to 365 d) and 2) repair of tetralogy of Fallot (29-365 d). There were 240 subjects eligible for the clinical practice guideline at active sites and 259 subjects at control sites. INTERVENTIONS: Development and application of early extubation clinical practice guideline. MEASUREMENTS AND MAIN RESULTS: After clinical practice guideline implementation, the rate of early extubation at active sites increased significantly from 11.7% to 66.9% (p < 0.001) with no increase in reintubation rate. The median duration of postoperative intubation among active sites decreased from 21.2 to 4.5 hours (p < 0.001). No statistically significant change in early extubation rates was found in the control sites 11.7% to 13.7% (p = 0.63). At active sites, clinical practice guideline implementation had no statistically significant impact on median ICU length of stay (71.9 hr pre- vs 69.2 hr postimplementation; p = 0.29) for the entire cohort. There was a trend toward shorter ICU length of stay in the tetralogy of Fallot subgroup (71.6 hr pre- vs 54.2 hr postimplementation, p = 0.068). CONCLUSIONS: A collaborative learning strategy designed clinical practice guideline significantly increased the rate of early extubation with no change in the rate of reintubation. The early extubation clinical practice guideline did not significantly change postoperative ICU length of stay. PMID- 27513601 TI - Resection of the ethmoidal crest in sphenopalatine artery surgery. AB - BACKGROUND: In severe cases of epistaxis, in spite of several procedures described in the literature for its management, surgical treatment has been recognized by most authors as 1 of the most effective, especially when it includes ligation and/or electrocoagulation of the nasal branches of the sphenopalatine artery. The objective of this study is to determine the importance of ethmoid crest resection during sphenopalatine artery surgery, in the management of severe epistaxis. METHODS: We report a double-blinded randomized clinical trial, in which intervention was the ethmoid crest resection during electrocoagulation of the sphenopalatine artery. The study participants consisted of 42 patients with severe epistaxis and indication for surgical treatment, treated at the Otorhinolaryngology Emergency Room (ORL ER) of Hospital Sao Paulo, the teaching hospital of the Federal University of Sao Paulo. RESULTS: There was significant greater exposure of the arterial branch after removal of the ethmoidal crest (p = 0.009). The rate of bleeding within 48 hours of the procedure was significantly lower in the crest removal group. CONCLUSION: Resection of the ethmoid crest during sphenopalatine surgery proved to be feasible without additional risks, including promoting decrease in the overall surgical time. It provided better exposure of arterial branches of the sphenopalatine foramen, leading to a lower rebleeding rate within 48 hours. PMID- 27513602 TI - Variations in attack behaviours between Glossina palpalis gambiensis and G. tachinoides in a gallery forest suggest host specificity. AB - Tsetse flies Glossina palpalis gambiensis and G. tachinoides are among the major vectors of sleeping sickness (Human African Trypanosomiasis-HAT) and nagana (African Animal Trypanosomiasis - AAT) in West Africa. Both riparian species occur sympatrically in gallery forests of south west Burkina Faso, but little is known of their interspecies relationships although different authors think there may be some competition between them. The aim of this study was to check if sympatric species have different strategies when approaching a host. A man placed in a sticky cube (1 m * 1 m * 1 m) and a sticky black-blue-black target (1 m * 1 m) were used to capture tsetse along the Comoe river banks in a Latin Square design. The number and the height at which tsetse were caught by each capture method were recorded according to species and sex. Glossina p. gambiensis was more attracted to human bait than to the target, but both species were captured at a significantly higher height on the target compared with the human bait (P < 0.05). No significant difference in heights was found between G. tachinoides and G. p. gambiensis captured on targets (33 and 35 cm, respectively, P > 0.05). However, catches on human bait showed a significant difference in height between G. tachinoides and G. p. gambiensis (22.5 and 30.6 cm, respectively, P < 0.001). This study showed that these sympatric species had different attack behaviours to humans, which is not the case with the target. The implications of these findings are discussed. PMID- 27513603 TI - Stakeholders' views of recurrent sore throat, tonsillitis and their management: a qualitative interview study for the NAtional Trial of Tonsillectomy IN Adults (NATTINA Part 1). AB - OBJECTIVES: To determine the impact of recurrent sore throats and tonsillitis in adults and stakeholder views of treatment pathways. DESIGN: Qualitative semistructured interview design reporting novel data from a feasibility study for a UK national trial of tonsillectomy in adults. SETTING: Nine study sites linked to ear, nose and throat departments in National Health Service hospitals located across the United Kingdom. PARTICIPANTS: Fifteen patients, 11 general practitioners and 22 ear, nose and throat staff consented to in-depth interviews, which were analysed using a framework analysis approach. MAIN OUTCOME MEASURES: Views of stakeholder groups. RESULTS: Recurrent sore throats were reported to severely impact patients' family, work and social life. Ear, nose and throat staff stated that patients faced increasing barriers to secondary care service access. General practitioners were under pressure to reduce 'limited clinical value' surgical procedures. CONCLUSIONS: The findings from this study suggest that there is a disconnect between the attitudes of the stakeholders and the reality of recurrent sore throat, tonsillectomy procedures and service provision. More evidence for the role of tonsillectomy is needed from randomised controlled trials to determine whether it should continue to be ranked as a procedure of limited clinical effectiveness. PMID- 27513605 TI - Gold-Induced Fibril Growth: The Mechanism of Surface-Facilitated Amyloid Aggregation. AB - The question of how amyloid fibril formation is influenced by surfaces is crucial for a detailed understanding of the process in vivo. We applied a combination of kinetic experiments and molecular dynamics simulations to elucidate how (model) surfaces influence fibril formation of the amyloid-forming sequences of prion protein SUP35 and human islet amyloid polypeptide. The kinetic data suggest that structural reorganization of the initial peptide corona around colloidal gold nanoparticles is the rate-limiting step. The molecular dynamics simulations reveal that partial physisorption to the surface results in the formation of aligned monolayers, which stimulate the formation of parallel, critical oligomers. The general mechanism implies that the competition between the underlying peptide-peptide and peptide-surface interactions must strike a balance to accelerate fibril formation. PMID- 27513606 TI - Ultrathin Polymer Membranes with Patterned, Micrometric Pores for Organs-on Chips. AB - The basal lamina or basement membrane (BM) is a key physiological system that participates in physicochemical signaling between tissue types. Its formation and function are essential in tissue maintenance, growth, angiogenesis, disease progression, and immunology. In vitro models of the BM (e.g., Boyden and transwell chambers) are common in cell biology and lab-on-a-chip devices where cells require apical and basolateral polarization. Extravasation, intravasation, membrane transport of chemokines, cytokines, chemotaxis of cells, and other key functions are routinely studied in these models. The goal of the present study was to integrate a semipermeable ultrathin polymer membrane with precisely positioned pores of 2 MUm diameter in a microfluidic device with apical and basolateral chambers. We selected poly(l-lactic acid) (PLLA), a transparent biocompatible polymer, to prepare the semipermeable ultrathin membranes. The pores were generated by pattern transfer using a three-step method coupling femtosecond laser machining, polymer replication, and spin coating. Each step of the fabrication process was characterized by scanning electron microscopy to investigate reliability of the process and fidelity of pattern transfer. In order to evaluate the compatibility of the fabrication method with organs-on-a-chip technology, porous PLLA membranes were embedded in polydimethylsiloxane (PDMS) microfluidic devices and used to grow human umbilical vein endothelial cells (HUVECS) on top of the membrane with perfusion through the basolateral chamber. Viability of cells, optical transparency of membranes and strong adhesion of PLLA to PDMS were observed, thus confirming the suitability of the prepared membranes for use in organs-on-a-chip devices. PMID- 27513607 TI - 3D correlative morphological and elemental characterization of materials at the deep submicrometre scale. AB - This paper shows how X-ray computed nanotomography (CNT) can be correlated with focused ion beam time-of-flight secondary ion mass spectrometry (FIB-TOF-SIMS) tomography on the same sample to investigate both the morphological and elemental structure. This methodology is applicable to relatively large specimens with dimensions of several tens of microns whilst maintaining a high spatial resolution of the order of 100 nm. However, combining X-ray CNT and FIB-TOF-SIMS tomography requires innovative sample preparation protocols to allow both experiments to be conducted on exactly the same sample without chemically or structurally modifying the sample between measurements. Moreover, dedicated algorithms have been developed for effective data fusion that is biased with nine degrees of freedom. This methodology has been tested using a porous and heterogeneous solid oxide fuel cell (SOFC) that has features varying in size by three orders of magnitude - from hundreds of nanometre large pores and grains to tens of micron wide functional layers. PMID- 27513608 TI - The role of RNase 7 in innate cutaneous defense against Pseudomonas aeruginosa. AB - The ribonuclease RNase 7 is a major skin-derived human antimicrobial protein expressed in keratinocytes. Here we show that the gram-negative pathogen Pseudomonas aeruginosa secretes factor(s) that induced RNase 7 gene and protein expression in human primary keratinocytes. The metalloprotease inhibitor marimastat, the epidermal growth factor receptor (EGFR) inhibitor AG1478 and the EGFR blocking antibody cetuximab significantly attenuated this induction, indicating an important role of the EGFR for the P. aeruginosa-mediated RNase 7 induction. In line with this, siRNA-mediated downregulation of ADAM17, a metalloprotease known to proteolytically mediate the release of soluble EGFR ligands, decreased the P. aeruginosa-mediated RNase 7 induction in keratinocytes. The impact of the EGFR was also demonstrated in a human 3D skin equivalent where blockade of the EGFR diminished induction of RNase 7 by P. aeruginosa. Blockade of Toll-like receptor 5 (TLR5), a pattern recognition receptor (PRR) known to be activated by P. aeruginosa, only moderately reduced the P. aeruginosa-mediated RNase 7 induction in keratinocytes. The functional relevance of RNase 7 to participate in cutaneous defense against P. aeruginosa was demonstrated by antibodies that neutralized the antimicrobial activity of RNase 7. These antibodies significantly inhibited the capacity of human stratum corneum skin extracts to control growth of P. aeruginosa. Taken together, our results indicate that P. aeruginosa induces the expression of RNase 7 in keratinocytes in an EGFR dependent manner. Enhanced release of RNase 7 contributes to control cutaneous growth of P. aeruginosa. PMID- 27513609 TI - The Impact of Standardized Acuity Assessment and a Fast-Track on Length of Stay in Obstetric Triage: A Quality Improvement Study. AB - To prospectively assess the impact of a standardized 5-category Obstetrical Triage Acuity Scale (OTAS) and a fast-track for lower-acuity patients on patient flow. Length of stay (LOS) data of women presenting to obstetric triage were abstracted from the electronic medical record prior to (July 1, 2011, to March 30, 2012) and following OTAS implementation (April 1 to December 31, 2012). Following computerized simulation modeling, a fast-track for lower acuity women was implemented (January 1, 2013, to February 28, 2014). Prior to OTAS implementation (8085 visits), the median LOS was 105 (interquartile range [IQR] = 52-178) minutes. Following OTAS implementation (8131 visits), the median LOS decreased to 101 (IQR = 49-175) minutes (P = .04). The LOS did not correlate well with acuity. Simulation modeling predicted that a fast-track for OTAS 4 and 5 patients would reduce the LOS. The LOS for lower-acuity patients in the fast track decreased to 73 (IQR = 40-140) minutes (P = .005). In addition, the overall LOS (12 576 visits) decreased to 98 (IQR = 47-172) minutes (6.9% reduction; P < .001). Standardized assessment of acuity and a fast-track for lower acuity pregnant women decreased the overall LOS and the LOS of lower-acuity patients. PMID- 27513610 TI - Hapmnioides A-C, Rearranged Labdane-Type Diterpenoids from the Chinese Liverwort Haplomitrium mnioides. AB - Many exceptional labdane-type diterpenoids have been exclusively found in liverworts, which serve as taxonomic molecules or play important ecological roles in interactions among organisms. Three unprecedented labdane-type diterpenoids hapmnioides A (1), B (2), and C (3) formed through cascade rearrangement from the Chinese liverwort Haplomitrium mnioides are reported. Their structures were established by comprehensive spectroscopic analysis coupled with single-crystal X ray diffraction, and their anti-inflammatory activities were also preliminarily tested. PMID- 27513611 TI - Unpacking the public stigma of problem gambling: The process of stigma creation and predictors of social distancing. AB - Background and aims Public stigma diminishes the health of stigmatized populations, so it is critical to understand how and why stigma occurs to inform stigma reduction measures. This study aimed to examine stigmatizing attitudes held toward people experiencing problem gambling, to examine whether specific elements co-occur to create this public stigma, and to model explanatory variables of this public stigma. Methods An online panel of adults from Victoria, Australia (N = 2,000) was surveyed. Measures were based on a vignette for problem gambling and included demographics, gambling behavior, perceived dimensions of problem gambling, stereotyping, social distancing, emotional reactions, and perceived devaluation and discrimination. A hierarchical linear regression was conducted. Results People with gambling problems attracted substantial negative stereotypes, social distancing, emotional reactions, and status loss/discrimination. These elements were associated with desired social distance, as was perceived that problem gambling is caused by bad character, and is perilous, non-recoverable, and disruptive. Level of contact with problem gambling, gambling involvement, and some demographic variables was significantly associated with social distance, but they explained little additional variance. Discussion and conclusions This study contributes to the understanding of how and why people experiencing gambling problems are stigmatized. Results suggest the need to increase public contact with such people, avoid perpetuation of stereotypes in media and public health communications, and reduce devaluing and discriminating attitudes and behaviors. PMID- 27513612 TI - Isolated effect of material stiffness on valvular interstitial cell differentiation. AB - Previous methods for investigating material stiffness on cell behavior have focused on the use of substrates with limited ranges of stiffness and/or fluctuating surface chemistries. Using the co-polymer system of n-octyl methacrylate crosslinked with diethylene glycol dimethacrylate (DEGDMA/nOM), we developed a new cell culture platform to analyze the isolated effects of stiffness independent from changes in surface chemistry. Materials ranging from 25 kPa to 4,700 kPa were fabricated. Surface analysis including goiniometry and X ray photoelectron spectroscopy (XPS) confirmed consistent surface chemistry across all formulations examined. The mechanosensitive cell type valvular interstitial cell (VIC) was cultured DEGDMA/nOM substrates of differing stiffness. Results indicate that order of magnitude changes in stiffness do not increase gene expression of VIC alpha-smooth muscle actin (alphaSMA). However, structural organization of alphaSMA is altered on stiffer substrates, corresponding with the appearance of the osteoblastic marker osteocalcin and nodule formation. This research presents the co-polymer DEGDMA/nOM as ideal substrate to investigate the influence of stiffness on VIC differentiation without the confounding effects of changing material surface chemistry. (c) 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 51-61, 2017. PMID- 27513613 TI - NHC-Stabilized Silicon-Carbon Mixed Cumulene. AB - The NHC-stabilized silicon-carbon mixed cumulene (Me3Si)2C?Si(IPr)?Si(IPr)?C(SiMe3)2 (3, IPr = 1,3-diisopropyl-4,5-dimethyl imidazol-2-ylidene) has been prepared by reaction of Ar(SiMe3)NK with the NHC stabilized silene (Me3Si)2C?Si(SiMe3)Cl(IPr) (2) in toluene at low temperature via the elimination of trimethylsilyl and chloride groups from 2. X-ray crystal analysis of 3 indicated the formal C?Si?Si?C cumulene skeleton with the short Si Si double bond distance of 2.1896(10) A. DFT calculations disclosed its zwitterionic character. Reaction of 3 with diphenylacetylene resulted in the formation of a silatriafulvene with an exocyclic NHC-stabilized silene moiety. PMID- 27513614 TI - Real-world efficacy and safety of daclatasvir and asunaprevir therapy for hepatitis C virus-infected cirrhosis patients. AB - BACKGROUND AND AIMS: Daclatasvir and asunaprevir combination therapy has shown a high virological response for chronic genotype 1 hepatitis C virus (HCV) infected patients. However, the real-world efficacy and safety of the therapy for patients with cirrhosis are unknown. METHODS: A total of 252 patients with genotype 1 HCV infection (158 with chronic hepatitis and 94 with compensated liver cirrhosis) were treated with 24 weeks of daclatasvir and asunaprevir combination therapy. Plasma concentrations of daclatasvir and asunaprevir at day 5 of treatment, end of-treatment response, sustained virological response (SVR), and the frequencies of adverse events were analyzed. RESULT: Plasma asunaprevir concentration was significantly higher, and daclatasvir concentration tended to be higher, in cirrhosis patients compared with chronic hepatitis patients. End-of-treatment response was achieved in 95.6% and 94.7% of chronic hepatitis and cirrhosis patients, respectively, and SVR was achieved in 94.3% and 92.6%. Although pre treatment NS5A drug resistant-associated variants were detected, a high SVR rate was achieved when the population frequency of the variant was low. The frequencies of treatment-related adverse events in cirrhosis patients were similar to those in chronic hepatitis patients. Treatment discontinuation due to adverse events occurred in three and two patients in chronic hepatitis and cirrhosis groups, respectively; however, four out of five patients with treatment discontinuation nonetheless achieved SVR. CONCLUSION: Patients with compensated liver cirrhosis have similar virological response and tolerance for daclatasvir plus asunaprevir therapy to patients with chronic hepatitis. This combination therapy might offer a safe and effective treatment for chronic HCV infected patients with compensated cirrhosis. PMID- 27513615 TI - Direct Observation of Aggregation-Induced Backbone Conformational Changes in Tau Peptides. AB - In tau proteins, the hexapeptides in the R2 and R3 repeats are known to initiate tau fibril formation, which causes a class of neurodegenerative diseases called the taupathies. We show that in R3, in addition to the presence of the hexapeptides, the correct turn conformation upstream to it is also essential for producing prion-like fibrils that are capable of propagation. A time-dependent NMR aggregation assay of a slow fibril forming R3-S316P peptide revealed a trans to cis equilibrium shift in the peptide-bond conformation preceding P316 during the growth phase of the aggregation process. S316 was identified as the key residue in the turn that confers templating capacity on R3 fibrils to accelerate the aggregation of the R3-S316P peptide. These results on the specific interactions and conformational changes responsible for tau aggregation could prove useful for developing an efficient therapeutic intervention in Alzheimer's disease. PMID- 27513619 TI - Immunotherapy to Treat Cancer. AB - This issue of Clinical Pharmacology & Therapeutics focuses on immunotherapy as an approach to treat cancer by generating or augmenting an immune response against it. The enthusiasm for immunotherapy has waxed and waned over the past century. Enthusiasm for immunotherapy has risen over the past decade due, in part, to data showing that cancer immunotherapy consistently improves overall survival in select patients with advanced-stage cancer. Antitumor immunotherapy has broad potential and could be used to treat many different types of advanced-stage cancer due to the durable and robust response that it elicits across a diverse spectrum of cancers. This issue covers various aspects of relevant therapeutic topics ranging from discovery of chimeric antigen receptor (CAR) T cells, development of novel immunotherapies using novel pharmacokinetic/dynamic modeling tools, to the utilization of immune checkpoint therapy. Regarding utilization, this issue addresses biomarker selection strategies for personalized treatment of non-small cell lung cancer (NSCLC) with immune checkpoint therapy and also the management of the unique immune response adverse events (irAEs). PMID- 27513622 TI - Theoretical and Experimental Insight on Ag2CrO4 Microcrystals: Synthesis, Characterization, and Photoluminescence Properties. AB - Ag2CrO4 microcrystals were synthesized by means of the coprecipitation method without the use of a surfactant under three different conditions. On the basis of the theoretical and experimental results, we describe the relationship among the structural order/disorder effects, morphology, and photoluminescence of the Ag2CrO4 microcrystals. The experimental results were correlated with the theoretical findings for a deeper understanding of the relationship between the electronic structure, morphology, and photoluminescence properties. First principles computational studies were used to calculate the geometries of bulk Ag2CrO4 and its low-index (001), (011), (110), (010), (111), and (100) facets based on a slab model. A good agreement between the experimental and the theoretical morphologies was found by varying the ratio of the superficial energy values. PMID- 27513623 TI - Sampling Enhancement and Free Energy Prediction by the Flying Gaussian Method. AB - We present a novel sampling enhancement and free energy prediction technique based on parallel simulation of the studied system with a shared bias potential. This history-independent bias potential is defined using selected degrees of freedom (collective variables). Each parallel walker of the system bears a single Gaussian shaped bias potential centered in current values of collective variables. Sampling enhancement is achieved by concentration of multiple walkers in certain free energy minimum. The method was successfully demonstrated on selected molecular systems, and presumed advantages over methods based on a history-dependent bias potential are discussed. PMID- 27513624 TI - Electrolyzed Saline Irrigation for Elimination of Bacterial Colonization in the Empyema Space. AB - BACKGROUND: The empyema space is refractory to elimination of bacterial colonization. Electrolyzed saline (ES) was used as intra-pleural irrigation for rapid disinfection of the empyema space. PATIENTS AND METHODS: Twenty consecutive patients with para-pneumonic empyema were reviewed in this study from 2007 to 2015. The empyema space was irrigated by miniaturized thoracoscopic surgery (mini VATS), and the efficacy and safety of the use of ES were evaluated. RESULTS: Sixteen patients were male and four were female, with a mean age of 66.5 +/- 9.5 y (27-90 y). Bacterial cultures of the purulent effusions from all 20 patients had positive results. Seventeen patients subsequently underwent continuous catheter irrigation and drainage. No patient had chest pain during ES irrigation. Fever duration after mini VATS was 2.8 +/- 1.8 d (0-5 d). Catheter indwelling time was 10.3 +/- 7.2 d (3-33 d). Inflammatory markers significantly improved (p < 0.05) within a week after mini VATS. Eighteen patients achieved pleural disinfection, and two patients had residual pathogens, one of whom later died of lung abscess. Space closure was successful in 14 patients. No patient underwent subsequent open drainage. Nineteen (95%) patients were discharged from the hospital. This treatment was successful in 18 (90%) patients, and one (5.6%) patient experienced recurrence. CONCLUSIONS: The ES irrigation facilitates the rapid disinfection and closure of the empyema space. PMID- 27513625 TI - Errata: Vol. 65, No. 28. AB - In the MMWR report, "Projected Zika Virus Importation and Subsequent Ongoing Transmission after Travel to the 2016 Olympic and Paralympic Games - Country Specific Assessment, July 2016," an error occurred throughout in reporting the number of countries participating in the 2016 Olympic and Paralympic Games without evidence of past Zika transmission: 18 countries (not 19 as stated) met this criterion. Thus, the fourth sentence of the fourth paragraph should have read, "For 14 of these countries, estimated aviation travel from Rio de Janeiro in August 2016 compared with total aviation travel from all countries with local Zika virus transmission in 2015 was 0.01%-3.04% (Table 2)." In addition, in Table 2, Angola should not have been listed, and the title should have read, "Participating countries currently not reporting Zika outbreaks (n = 18) that met risk criteria for Zika virus importation and subsequent ongoing transmission attributed to travel to the Olympic and Paralympic Games, ranked by aviation travel volume* from Rio de Janeiro, Brazil - August 2016." PMID- 27513627 TI - Psychometric equivalence of electronic and telephone completion of the ICIQ modules. AB - AIMS: To assess the equivalence of touch-screen (hand-held iPad) and telephone completion of patient-completed International Consultation on Incontinence Questionnaire (ICIQ) modules by comparison with corresponding data collected using conventional paper-and-pencil methods. METHODS: Men and women, attending urology outpatients complaining of LUTS, were randomised to one of three groups which determined the order in which they completed three administrations of the same questionnaire: paper, iPad and telephone. Four ICIQ questionnaires were evaluated: ICIQ-MLUTS, ICIQ-LUTSqol, ICIQ-OABqol and ICIQ-UI SF. RESULTS: From August 2012 to October 2014 a total of 448 out of 491 (91%) recruits completed the first two administrations and were included in the analysis. Three hundred forty-eight out of 491 (71%) completed the phone administration. The intra-class correlation coefficient (ICC) and Kappa statistic were calculated where appropriate between completed pairs of administrations. Mean ICC correlations were high (>0.8) between paper and iPad administrations. Paired paper and phone administrations were less well correlated, although still high (mean ICC>0.75). This may be partly due to the practical limitation that the phone interview was completed up to a week later than the initial two administrations. There was no evidence that potential moderator effects (gender, age and experience with computers or touch screen devices) significantly affected overall reliability of scores between administrations. CONCLUSIONS: We can recommend the interchangeable use of ICIQ electronic or paper based questionnaires in a clinical or research setting. Self-report is preferable to telephone delivery where possible. Neurourol. Urodynam. 9999:XX-XX, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 27513630 TI - Exogenous hydrogen sulfide exerts proliferation, anti-apoptosis, migration effects and accelerates cell cycle progression in multiple myeloma cells via activating the Akt pathway. AB - Hydrogen sulfide (H2S), regarded as the third gaseous transmitter, mediates and induces various biological effects. The present study investigated the effects of H2S on multiple myeloma cell progression via amplifying the activation of Akt pathway in multiple myeloma cells. The level of H2S produced in multiple myeloma (MM) patients and healthy subjects was measured using enzyme-linked immunosorbent assay (ELISA). MM cells were treated with 500 umol/l NaHS (a donor of H2S) for 24 h. The expression levels of phosphorylated-Akt (p-Akt), Bcl-2 and caspase-3 were measured by western blot assay. Cell viability was detected by Cell Counting Kit 8 (CCK-8). The cell cycle was analyzed by flow cytometry. Our results show that the concentration of H2S was higher in MM patients and that it increased in parallel with disease progression. Treating MM cells with 500 umol/l NaHS for 24 h markedly increased the expression level of Bcl-2 and the activation of p-Akt, however, the expression level of caspase-3 was decreased, cell viability was increased, and cell cycle progression was accelerated in MM cells. NaHS also induced migration in MM cells in transwell migration assay. Furthermore, co treatment of MM cells with 500 umol/l NaHS and 50 umol/l LY294002 for 24 h significantly overset these effects. In conclusion, our findings demonstrate that the Akt pathway contributes to NaHS-induced cell proliferation, migration and acceleration of cell cycle progression in MM cells. PMID- 27513629 TI - Long-Term Training with a Brain-Machine Interface-Based Gait Protocol Induces Partial Neurological Recovery in Paraplegic Patients. AB - Brain-machine interfaces (BMIs) provide a new assistive strategy aimed at restoring mobility in severely paralyzed patients. Yet, no study in animals or in human subjects has indicated that long-term BMI training could induce any type of clinical recovery. Eight chronic (3-13 years) spinal cord injury (SCI) paraplegics were subjected to long-term training (12 months) with a multi-stage BMI-based gait neurorehabilitation paradigm aimed at restoring locomotion. This paradigm combined intense immersive virtual reality training, enriched visual tactile feedback, and walking with two EEG-controlled robotic actuators, including a custom-designed lower limb exoskeleton capable of delivering tactile feedback to subjects. Following 12 months of training with this paradigm, all eight patients experienced neurological improvements in somatic sensation (pain localization, fine/crude touch, and proprioceptive sensing) in multiple dermatomes. Patients also regained voluntary motor control in key muscles below the SCI level, as measured by EMGs, resulting in marked improvement in their walking index. As a result, 50% of these patients were upgraded to an incomplete paraplegia classification. Neurological recovery was paralleled by the reemergence of lower limb motor imagery at cortical level. We hypothesize that this unprecedented neurological recovery results from both cortical and spinal cord plasticity triggered by long-term BMI usage. PMID- 27513631 TI - The influence of early depressive symptoms, social support and decreasing self efficacy on depression 6 months post-stroke. AB - BACKGROUND: Post-stroke depression (PSD) is the most frequent mental disorder after stroke, affecting about 30% of stroke survivors. Despite extensive research, little is known about the influence of general self-efficacy (GSE) on PSD. We investigated the effect of GSE on depression six months post-stroke while controlling for established risk factors. METHODS: Eighty-eight patients from two rehabilitation centers with first-ever ischemic stroke were assessed around 8 weeks and 6 months after stroke. Baseline assessment included demographic variables, GSE scale, physical disability (Barthel-Index), stroke severity (modified NIH Scale), pre-stroke mental illness, cognitive status (Mini-Mental State-Test), social support (F-SozU Questionnaire) and depressiveness (Geriatric Depression Scale, GDS). Follow-up assessment included DSM-IV depression, GDS and GSE. The influence of each risk factor on PSD was analyzed by binary hierarchical regression. RESULTS: Baseline depressiveness (OR=1.41, p<.01) and social support (OR=.95, p=.03) predicted PSD. Decreasing GSE was associated with high baseline GSE (r=.51, p<.01) and influenced later PSD (OR=1.39, p<.01). LIMITATIONS: Patients' range of impairment may have been limited as sufficient speech comprehension and capacity for interview participation were required. Causal relationship between decreasing GSE and increasing GDS cannot be assumed based on correlations. DISCUSSION: Decreasing GSE was linked to PSD, especially in patients with high baseline GSE. This effect may be due to dissatisfaction with recovery following high expectations. Early depressive symptoms and low social support predicted PSD. Early screening for depressive symptoms and focusing on self-efficacy might help to prevent later depression. PMID- 27513632 TI - miR-221 targets HMGA2 to inhibit bleomycin-induced pulmonary fibrosis by regulating TGF-beta1/Smad3-induced EMT. AB - MicroRNA (miR)-221 plays an essential role in the epithelial-mesenchymal transition (EMT). High mobility group AT-hook 2 (HMGA2), is a key regulator of EMT. However, the role of miR-221 in pulmonary fibrosis, and the association between miR-221 and HMGA2 remain largely unknown. For this purpose, we examined the expression of miR-221 and HMGA2 in human idiopathic pulmonary fibrosis (IPF) tissues and pulmonary cells, namely the adenocarcinoma A549 and human bronchial epithelium (HBE) cell lines, and found that the expression of miR-221 was inhibited in both tissues and cells whereas high mRNA and protein expression of HMGA2 was observed. Additionally, transforming growth factor-beta1 (TGF-beta1) induced the EMT, characterized by the upregulated expression of the mesenchymal markers, namely N-cadherin, vimentin, alpha-smooth muscle actin, collagen I and collagen III, and the downregulated expression of the epithelial marker E cadherin in A549 and HBE cells. We then performed transfection with miR-221 mimics, and found that the expression of phosphorylated-Smad3 in miR-221 overexpressing cells was significantly downregulated, compared with that in the TGF-beta1-treated cells without transfection. Furthermore, the overexpression of miR-221 decreased the expression of HMGA2, suppressed the EMT, and inhibited the proliferation of A549 and HBE cells. HMGA2 was directly targeted by miR-221 which was confirmed by the dual-luciferase reporter gene assay. Finally, a mouse model of bleomycin (BLM)-induced pulmonary fibrosis was used to confirm the effect of miR-221 on EMT. Hematoxylin and eosin staining showed that BLM induced thicker alveolar walls and more collagen deposition, whereas miR-221 treatment reduced lung fibrosis and the tissues exhibited thinner alveolar walls and normal lung alveoli. Furthermore, the EMT process was suppressed following miR-221 injection. Taken together, these findings sugest that miR-221 targets HMGA2 to inhibit BLM induced pulmonary fibrosis through the TGF-beta1/Smad3 signaling pathway. PMID- 27513633 TI - Spinal Cord Stimulation Alters Protein Levels in the Cerebrospinal Fluid of Neuropathic Pain Patients: A Proteomic Mass Spectrometric Analysis. AB - OBJECTIVES: Electrical neuromodulation by spinal cord stimulation (SCS) is a well established method for treatment of neuropathic pain. However, the mechanism behind the pain relieving effect in patients remains largely unknown. In this study, we target the human cerebrospinal fluid (CSF) proteome, a little investigated aspect of SCS mechanism of action. METHODS: Two different proteomic mass spectrometry protocols were used to analyze the CSF of 14 SCS responsive neuropathic pain patients. Each patient acted as his or her own control and protein content was compared when the stimulator was turned off for 48 hours, and after the stimulator had been used as normal for three weeks. RESULTS: Eighty-six proteins were statistically significantly altered in the CSF of neuropathic pain patients using SCS, when comparing the stimulator off condition to the stimulator on condition. The top 12 of the altered proteins are involved in neuroprotection (clusterin, gelsolin, mimecan, angiotensinogen, secretogranin-1, amyloid beta A4 protein), synaptic plasticity/learning/memory (gelsolin, apolipoprotein C1, apolipoprotein E, contactin-1, neural cell adhesion molecule L1-like protein), nociceptive signaling (neurosecretory protein VGF), and immune regulation (dickkopf-related protein 3). CONCLUSION: Previously unknown effects of SCS on levels of proteins involved in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity are demonstrated. These findings, in the CSF of neuropathic pain patients, expand the picture of SCS effects on the neurochemical environment of the human spinal cord. An improved understanding of SCS mechanism may lead to new tracks of investigation and improved treatment strategies for neuropathic pain. PMID- 27513635 TI - Occurrence and Potential Biological Effects of Amphetamine on Stream Communities. AB - The presence of pharmaceuticals, including illicit drugs in aquatic systems, is a topic of environmental significance because of their global occurrence and potential effects on aquatic ecosystems and human health, but few studies have examined the ecological effects of illicit drugs. We conducted a survey of several drug residues, including the potentially illicit drug amphetamine, at 6 stream sites along an urban to rural gradient in Baltimore, Maryland, U.S.A. We detected numerous drugs, including amphetamine (3 to 630 ng L(-1)), in all stream sites. We examined the fate and ecological effects of amphetamine on biofilm, seston, and aquatic insect communities in artificial streams exposed to an environmentally relevant concentration (1 MUg L(-1)) of amphetamine. The amphetamine parent compound decreased in the artificial streams from less than 1 MUg L(-1) on day 1 to 0.11 MUg L(-1) on day 22. In artificial streams treated with amphetamine, there was up to 45% lower biofilm chlorophyll a per ash-free dry mass, 85% lower biofilm gross primary production, 24% greater seston ash-free dry mass, and 30% lower seston community respiration compared to control streams. Exposing streams to amphetamine also changed the composition of bacterial and diatom communities in biofilms at day 21 and increased cumulative dipteran emergence by 65% and 89% during the first and third weeks of the experiment, respectively. This study demonstrates that amphetamine and other biologically active drugs are present in urban streams and have the potential to affect both structure and function of stream communities. PMID- 27513636 TI - Affective Pictures and the Open Library of Affective Foods (OLAF): Tools to Investigate Emotions toward Food in Adults. AB - Recently, several sets of standardized food pictures have been created, supplying both food images and their subjective evaluations. However, to date only the OLAF (Open Library of Affective Foods), a set of food images and ratings we developed in adolescents, has the specific purpose of studying emotions toward food. Moreover, some researchers have argued that food evaluations are not valid across individuals and groups, unless feelings toward food cues are compared with feelings toward intense experiences unrelated to food, that serve as benchmarks. Therefore the OLAF presented here, comprising a set of original food images and a group of standardized highly emotional pictures, is intended to provide valid between-group judgments in adults. Emotional images (erotica, mutilations, and neutrals from the International Affective Picture System/IAPS) additionally ensure that the affective ratings are consistent with emotion research. The OLAF depicts high-calorie sweet and savory foods and low-calorie fruits and vegetables, portraying foods within natural scenes matching the IAPS features. An adult sample evaluated both food and affective pictures in terms of pleasure, arousal, dominance, and food craving, following standardized affective rating procedures. The affective ratings for the emotional pictures corroborated previous findings, thus confirming the reliability of evaluations for the food images. Among the OLAF images, high-calorie sweet and savory foods elicited the greatest pleasure, although they elicited, as expected, less arousal than erotica. The observed patterns were consistent with research on emotions and confirmed the reliability of OLAF evaluations. The OLAF and affective pictures constitute a sound methodology to investigate emotions toward food within a wider motivational framework. The OLAF is freely accessible at digibug.ugr.es. PMID- 27513637 TI - Metabolic Network for the Biosynthesis of Intra- and Extracellular alpha-Glucans Required for Virulence of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis synthesizes intra- and extracellular alpha-glucans that were believed to originate from separate pathways. The extracellular glucose polymer is the main constituent of the mycobacterial capsule that is thought to be involved in immune evasion and virulence. However, the role of the alpha glucan capsule in pathogenesis has remained enigmatic due to an incomplete understanding of alpha-glucan biosynthetic pathways preventing the generation of capsule-deficient mutants. Three separate and potentially redundant pathways had been implicated in alpha-glucan biosynthesis in mycobacteria: the GlgC-GlgA, the Rv3032 and the TreS-Pep2-GlgE pathways. We now show that alpha-glucan in mycobacteria is exclusively assembled intracellularly utilizing the building block alpha-maltose-1-phosphate as the substrate for the maltosyltransferase GlgE, with subsequent branching of the polymer by the branching enzyme GlgB. Some alpha-glucan is exported to form the alpha-glucan capsule. There is an unexpected convergence of the TreS-Pep2 and GlgC-GlgA pathways that both generate alpha maltose-1-phosphate. While the TreS-Pep2 route from trehalose was already known, we have now established that GlgA forms this phosphosugar from ADP-glucose and glucose 1-phosphate 1000-fold more efficiently than its hitherto described glycogen synthase activity. The two routes are connected by the common precursor ADP-glucose, allowing compensatory flux from one route to the other. Having elucidated this unexpected configuration of the metabolic pathways underlying alpha-glucan biosynthesis in mycobacteria, an M. tuberculosis double mutant devoid of alpha-glucan could be constructed, showing a direct link between the GlgE pathway, alpha-glucan biosynthesis and virulence in a mouse infection model. PMID- 27513638 TI - Prevalent Accumulation of Non-Optimal Codons through Somatic Mutations in Human Cancers. AB - Cancer is characterized by uncontrolled cell growth, and the cause of different cancers is generally attributed to checkpoint dysregulation of cell proliferation and apoptosis. Recent studies have shown that non-optimal codons were preferentially adopted by genes to generate cell cycle-dependent oscillations in protein levels. This raises the intriguing question of how dynamic changes of codon usage modulate the cancer genome to cope with a non-controlled proliferative cell cycle. In this study, we comprehensively analyzed the somatic mutations of codons in human cancers, and found that non-optimal codons tended to be accumulated through both synonymous and non-synonymous mutations compared with other types of genomic substitution. We further demonstrated that non-optimal codons were prevalently accumulated across different types of cancers, amino acids, and chromosomes, and genes with accumulation of non-optimal codons tended to be involved in protein interaction/signaling networks and encoded important enzymes in metabolic networks that played roles in cancer-related pathways. This study provides insights into the dynamics of codons in the cancer genome and demonstrates that accumulation of non-optimal codons may be an adaptive strategy for cancerous cells to win the competition with normal cells. This deeper interpretation of the patterns and the functional characterization of somatic mutations of codons will help to broaden the current understanding of the molecular basis of cancers. PMID- 27513639 TI - Effectiveness of Periosteal Stimulation Therapy and Home Exercise Program in the Rehabilitation of Patients With Advanced Knee Osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) of the knee is the most common form of joint disease. It is one of the major causes of impaired function that reduces quality of life in older people worldwide. Periosteal Stimulation Therapy (PST) with boosters in combination with home exercises may be a suitable treatment option for such patients. OBJECTIVES: To examine the effectiveness of PST with boosters in addition to a home-based exercise program as compared with Transcutaneous Electrical Nerve Stimulation (TENS) combined with the same home-based exercise program in the management of chronic pain and functional impairments associated with advanced knee OA. DESIGN: The study was a randomized controlled trial. MATERIALS AND METHODS: Sixty patients with Kellgren-Lawrence grade 3 or 4 knee OA were randomized to receive PST or TENS once a week for 10 weeks, followed by boosters for 6 months in addition to a home exercise program. Visual Analogue Scale (VAS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales were assessed at baseline, after the last PST session, and 6 months later. RESULTS: Pain VAS and KOOS subscales were improved in both PST and TENS groups at 10 weeks and 6 months after intervention, with a statistically significant difference between the groups at both follow-up periods. Reduced pain VAS and increased KOOS subscales in the PST group were statistically significantly different from the TENS group during both follow-up periods. CONCLUSION: PST with boosters combined with a home exercise program was shown to be beneficial for improving subjective knee pain and functional performance of older patients with advanced knee OA. PMID- 27513640 TI - Effect of Epidural Dexmedetomidine Combined With Ropivacaine in Labor Analgesia: A Randomized Double-Blinded Controlled Study. AB - BACKGROUND: The purpose of our study is to evaluate the effect of adding dexmedetomidine to epidural ropivacaine in patients undergoing labor epidural analgesia. METHODS: Eighty healthy women were randomly assigned to 2 groups: control group (R; n=40) received epidural 0.125% ropivacaine for labor analgesia, whereas the study group (D; n=40) received epidural 0.125% ropivacaine with dexmedetomidine in addition. The blood pressure, heart rate, and the severity of pain of the parturient was assessed, the duration of the first stage and the second stage of labor time, the rate of instrumental delivery and the rate of cesarean section were recorded. The side effects (nausea and vomiting), intensity of maternal sedation, and neonatal Apgar scores were also recorded. RESULTS: The visual analog scales, systolic blood pressure, diastolic blood pressure, and heart rates of D group were significant lower than that of R group at most time intervals after epidural analgesia. The duration of the first and second stage of labor, the rate of instrumental delivery and cesarean section, neonatal 1- and 5 minute Apgar scores, umbilical artery pH, maternal motor blockade scores, intensity of maternal sedation, and the incidence of maternal complications did not show significant difference between 2 groups. CONCLUSIONS: Low concentration of epidural ropivacaine (0.125%) combined with dexmedetomidine (0.5 MUg/kg) reduces the feeling of pain, and does not show the problems of motor blockage, hemodynamic instability, extension of production process, and complications such as nausea and vomiting. Our study was registered with Chinese Clinical Trial Registry (ChiCTR-IOR-15007263). PMID- 27513641 TI - Trends in the Nonmedical Use of OxyContin, United States, 2006 to 2013. AB - OBJECTIVES: The role of the opioid OxyContin in the opioid abuse epidemic has been well documented. In 2010, OxyContin was reformulated to make it more difficult to abuse. We assessed past-year OxyContin nonmedical use among a nationally representative population and among nonmedical users of opioid pain relievers in the United States between 2006 and 2013. MATERIALS AND METHODS: Data are from the National Survey on Drug Use and Health. Prevalence estimates of past year OxyContin nonmedical use overall and by sociodemographic, geographic, and substance use characteristics were calculated for each year, 2006 through 2013. Multivariable logistic regression was used to identify individual characteristics associated with past-year OxyContin nonmedical use before and after reformulation. RESULTS: In 2013, the of past-year nonmedical use of OxyContin among people 12 years and older in the United States was 0.5%. This was significantly lower than the prevalence in 2010 (0.7%; P<0.05), but was similar to that in 2006 to 2009 and 2011 to 2012. Among past-year nonmedical users of pain relievers in 2013, the prevalence of OxyContin nonmedical use was 13.0%. This was significantly higher than the prevalence in 2006 (10.5%; P<0.05), and was similar to that in 2007 through 2012. Groups with increased odds of using OxyContin nonmedically in the past-year were similar before and after reformulation (2009-2010 and 2012-2013, respectively). For 2012-2013, odds for past-year OxyContin nonmedical use after reformulation were greatest for: people reporting >=200 days of pain reliever nonmedical use, adjusted odds ratio (aOR)=3.61 (95% confidence interval [CI], 2.47-5.28); past-year heroin users, aOR=3.45 (95% CI, 2.22-5.37); and people with past-year pain reliever abuse or dependence, aOR=2.57 (95% CI, 1.88-3.51). DISCUSSION: The prevalence of past-year OxyContin nonmedical use in 2013, 3 years after reformulation, was significantly lower than the prevalence in the reformulation year, but similar to other years before and after reformulation. The prevalence of OxyContin nonmedical use among nonmedical users of pain relievers was higher than or similar to historical prevalence rates before reformulation. Groups with increased odds of OxyContin nonmedical use were similar before and after reformulation. PMID- 27513642 TI - The Influence of Seasonality and Community-Based Health Worker Provided Counselling on Exclusive Breastfeeding - Findings from a Cross-Sectional Survey in India. AB - BACKGROUND: Exclusive breastfeeding (EBF) during the first six months of life is considered a high impact but low-cost measure for reducing the morbidity and mortality among children. The current study investigated the association of seasonality and frontline worker(FLW) provided counselling with practice of EBF in Bihar, India. METHODS: We used the 'Lot Quality Assurance Sampling' technique to conduct a multi-stage sampling survey in 8 districts of Bihar. Regarding EBF, mothers of 0-5 (completed) months old children were asked if they had given only breastmilk to their children during the previous day, while mothers of 6-8 (completed) months old children were inquired about the total duration of EBF. We tested for association between EBF during the previous day with season of interview and EBF for full 6 months with nursing season. We also assessed if receiving counselling on EBF and complementary feeding had any association with relevant EBF indicators. RESULTS: Among the under-6 month old children, 76% received EBF during the previous day, whereas 92% of 6-8 (completed) months old children reportedly received EBF for the recommended duration. Proportion of 0-5 (completed) month old children receiving only breastmilk (during last 24 hours) decreased significantly with increasing age and with change of season from colder to warmer months. Odds of receiving only breastmilk during the previous day was significantly higher during the winter months (Adjusted odds ratio(AOR) = 1.50; 95% CI = 1.37, 1.63) compared to summer. Also, the children nursed primarily during the winter season had higher odds of receiving EBF for 6 months (AOR = 1.90, 95% CI = 1.43, 2.52) than those with non-winter nursing. Receiving FLW counselling was positively associated with breastfeeding exclusively, even after adjusting for seasonality and other covariates (AOR = 1.82; 95% CI = 1.67, 1.98). CONCLUSIONS: Seasonality is a significant but non-modifiable risk factor for EBF. However, FLW-counselling was found to increase practice of EBF irrespective of season. Scale-up of FLW-counselling services, with emphasis on summer months and mothers of older infants, can potentially reduce the impact of seasonality on EBF. PMID- 27513643 TI - Posterior Decompression and Fusion: Whole-Spine Functional and Clinical Outcomes. AB - The mobility of the spine and the change in the angle of the curvatures are directly related to spinal pain and spinal stenosis. The aim of the study was the evaluation of morphology and mobility of the spine in patients who were subjected to decompression and posterior fusion with pedicle screws. The treatment group consisted of 20 patients who underwent posterior fixation of lumbar spine (one and two level fusion). The control group consisted of 39 healthy subjects. Mobility and curvatures of the spine were measured with a non-invasive device, the Spinal Mouse. Pain was evaluated with the Visual Analogue Scale (VAS). The Oswestry Disability Index (ODI) and the SF-36 were used to evaluate the degree of the functional disability and the quality of life, respectively. The measurements were recorded preoperatively and at 3, 6 and 12 months postoperatively. The mobility of the lumbar spine in the sagittal plane increased (p = 0.009) at 12 months compared to the measurements at 3 months. The mobility of the thoracic spine in the frontal plane increased (p = 0.009) at 12 months compared to the preoperative evaluation. The results of VAS, ODI and SF-36 PCS improved significantly (p<0.001). The levels of fusion exhibited a strong linear correlation (r = 0.651, p = 0.002) with the total trunk inclination in the upright position. Although pain, quality of life and spinal mobility in the sagittal and frontal planes significantly improved in the treatment group, these patients still had limited mobility and decreased curves/angles values compared to control group. PMID- 27513644 TI - Combating the Sigatoka Disease Complex on Banana. PMID- 27513645 TI - Combustion reaction kinetics of guarana seed residue applying isoconversional methods and consecutive reaction scheme. AB - This work aims the study of decomposition kinetics of guarana seed residue using thermogravimetric analyzer under synthetic air atmosphere applying heating rates of 5, 10, and 15 degrees C/min, from room temperature to 900 degrees C. Three thermal decomposition stages were identified: dehydration (25.1-160 degrees C), oxidative pyrolysis (240-370 degrees C), and combustion (350-650 degrees C). The activation energies, reaction model, and pre-exponential factor were determined through four isoconversional methods, master plots, and linearization of the conversion rate equation, respectively. A scheme of two-consecutive reactions was applied validating the kinetic parameters of first-order reaction and two dimensional diffusion models for the oxidative pyrolysis stage (149.57kJ/mol, 6.97*10(10)1/s) and for combustion stage (77.98kJ/mol, 98.611/s), respectively. The comparison between theoretical and experimental conversion and conversion rate showed good agreement with average deviation lower than 2%, indicating that these results could be used for modeling of guarana seed residue. PMID- 27513646 TI - In situ activity recovery of aging biofilm in biological aerated filter: Surfactants treatment and mechanisms study. AB - In situ activity recovery of aging biofilm in the biological aerated filter (BAF) is an important but underappreciated problem. Lab-scaled BAFs were established in this study and three kinds of surfactants containing sodium dodecyl sulfate (SDS), sodium dodecyl benzene sulfonate (SDBS) and rhamnolipid were employed. Multiple indicators including effluent qualities, dissolved organic matters, biofilm physiology and morphology characteristics were investigated to explore the mechanisms. Results showed that removal rates of effluent COD in test groups significantly recovered to the level before aging. Compared with the control, effluent in SDBS and rhamnolipid-treated groups obtained more protein-like and humic-like substances, respectively. Furthermore, great live cell ratio, smooth surface and low adhesion force of biofilm were observed after rhamnolipid treatment, which was in consistent with good effluent qualities in the same group. This is the first report of applying rhamnolipid for in situ activity recovery of aging biofilm in bioreactors. PMID- 27513647 TI - Impact of partial nitritation degree and C/N ratio on simultaneous Sludge Fermentation, Denitrification and Anammox process. AB - This study presents a novel process (i.e. PN/SFDA) to remove nitrogen from low C/N domestic wastewater. The process mainly involves two reactors, a pre Sequencing Batch Reactor for partial nitritation (termed as PN-SBR) and an anoxic reactor for integrated Denitrification and Anammox with carbon sources produced from Sludge Fermentation (termed as SFDA). During long-term Runs, NO2(-)/NH4(+) ratio (i.e. NO2(-)-N/NH4(+)-N calculated by mole) in the PN-SBR effluent was gradually increased from 0.2 to 37 by extending aerobic duration, meaning that partial nitritation turning to full nitritation could be achieved. Impact of partial nitritation degree on SFDA process was investigated and the result showed that, NO2(-)/NH4(+) ratios between 2 and 10 were appropriate for the co-existence of denitrification and anammox together in the SFDA reactor, and denitrification instead of anammox contributed greater for nitrogen removal. Further batch tests indicated that anammox collaborated well with denitrification at low C/N (1.0 in this study). PMID- 27513648 TI - Simultaneous saccharification and fermentation of hemicellulose to butanol by a non-sporulating Clostridium species. AB - Production of lignocellulosic butanol has drawn increasing attention. However, currently few microorganisms can produce biofuels, particularly butanol, from lignocellulosic biomass via simultaneous saccharification and fermentation. Here we report discovery of a wild-type, mesophilic Clostridium sp. strain MF28 that ferments xylan to produce butanol (up to 3.2g/L) without the addition of saccharolytic enzymes and without any chemical pretreatments. Application of selective pressure from 2-deoxy-d-glucose facilitated isolation of strain MF28, which exhibits inactivation of genes (gid and ccp genes) responsible for carbon catabolite repression, thus allowing strain MF28 to simultaneously ferment a combination of glucose (30g/L), xylose (15g/L), and arabinose (15g/L) to produce 11.9g/L of butanol. Strain MF28 possesses several unique features: (i) non sporulating, (ii) no acetone/ethanol, (iii) complete hemicellulose-binding enzymatic domain, and (iv) absence of carbon catabolite repression. These unique characteristics demonstrate the industrial potential of strain MF28 for cost effective biofuel generation from lignocellulosic biomass. PMID- 27513649 TI - Hidden Genetic Diversity in an Asexually Reproducing Lichen Forming Fungal Group. AB - Asexual species with vegetative propagation of both symbiont partners (soredia) in lichens may harbor lower species diversity because they may indeed represent evolutionary dead ends or clones. In this study we aim to critically examine species boundaries in the sorediate lichen forming fungi Parmotrema reticulatum Parmotrema pseudoreticulatum complex applying coalescent-based approaches and other recently developed DNA-based methods. To this end, we gathered 180 samples from Africa, Asia, Australasia, Europe, North and South America and generated sequences of internal transcribed spacer of nuclear ribosomal DNA (ITS) and DNA replication licensing factor MCM7 (MCM7). The dataset was analysed using different approaches such as traditional phylogeny-maximum likelihood and Bayesian-genetic distances, automatic barcode gap discovery and coalescent-based methods-PTP, GMYC, spedeSTEM and *Beast-in order to test congruence among results. Additionally, the divergence times were also estimated to elucidate diversification events. Delimitations inferred from the different analyses are comparable with only minor differences, and following a conservative approach we propose that the sampled specimens of the P. reticulatum-P. pseudoreticulatum complex belong to at least eight distinct species-level lineages. Seven are currently classified under P. reticulatum and one as P. pseudoreticulatum. In this work we discuss one of only few examples of cryptic species that have so far been found in sorediate reproducing lichen forming fungi. Additionally our estimates suggest a recent origin of the species complex-during the Miocene. Consequently, the wide distribution of several of the cryptic species has to be explained by intercontinental long-distance dispersal events. PMID- 27513650 TI - The effects of exercise modality on maximal and submaximal exercise parameters obtained by graded maximal exercise testing. AB - BACKGROUND: Cardiopulmonary exercise testing (CPET) has become part of screening and evaluation in cardiology. The exercise modalities most often used in CPET are the treadmill (TM) and upright bicycle (UB). Nowadays, also the supine bicycle (SB) is becoming more often used, especially when combined with cardiac imaging. OBJECTIVES: Our aim was to examine whether a maximal CPET on a SB leads to similar results as TM and UB in terms of different CPET measures. Secondly, we explored whether peak VO2 relates to the person's preference and experience with the different exercise modalities. METHODS: Twelve healthy individuals (8 male; mean age 21.6, range 21-24) participated in a randomized controlled cross-over trial and performed 3 maximal CPETs on a TM, UB and SB. Repeated measures ANOVA was performed to evaluate differences between tests. Further, Intraclass correlation coefficients (ICC) and Bland-Altman plots were obtained. RESULTS: The SB CPET resulted in lower peak VO2 (2806+/-652ml.min(-1) (SB) vs 3329+/ 798ml.min(-1) (UB) and 3550+/-799ml.min(-1) (TM); p<0.001) and peak heart rate (179+/-8 beats.min(-1) (SB) vs 192+/-7 beats.min(-1) (UB) and 193+/-11 beats.min( 1) (TM); p<0.001). VE/VCO2-slope did not differ between the 3 modalities. Overall, ICC and Bland-Altman plots showed low agreement for SB measures. No influence of preference and experience on peak VO2 could be found. CONCLUSION: Upcoming maximal SB exercise tests, for evaluations in clinical settings, can't be considered as an evaluation of the maximal exercise capacity when compared to golden standard TM and UB. PMID- 27513651 TI - Differing predictive relationships between baseline LDL-C, systolic blood pressure, and cardiovascular outcomes. AB - BACKGROUND: Traditional cardiovascular risk factors, such as hypertension and dyslipidemia, predispose individuals to cardiovascular disease, particularly patients with diabetes. We investigated the predictive value of baseline systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) on the risk of vascular outcomes in a large population of patients at high risk of future cardiovascular events. METHODS: Data were pooled from the TNT (Treating to New Targets), CARDS (Collaborative Atorvastatin Diabetes Study), and IDEAL (Incremental Decrease in End-Points Through Aggressive Lipid Lowering) trials and included a total of 21,727 patients (TNT: 10,001; CARDS: 2838; IDEAL: 8888). The effect of baseline SBP and LDL-C on cardiovascular events, coronary events, and stroke was evaluated using a multivariate Cox proportional-hazards model. RESULTS: Overall, risk of cardiovascular events was significantly higher for patients with higher baseline SBP or LDL-C. Higher baseline SBP was significantly predictive of stroke but not coronary events. Conversely, higher baseline LDL-C was significantly predictive of coronary events but not stroke. Results from the subgroup with diabetes (5408 patients; TNT: 1501; CARDS: 2838; IDEAL: 1069) were broadly consistent with those of the total cohort: baseline SBP and LDL-C were significantly predictive of cardiovascular events overall, with the association to LDL-C predominantly related to an effect on coronary events. However, baseline SBP was not predictive of either coronary or stroke events in the pooled diabetic population. CONCLUSIONS: In this cohort of high-risk patients, baseline SBP and LDL-C were significantly predictive of cardiovascular outcomes, but this effect may differ between the cerebrovascular and coronary systems. TRIAL REGISTRATION NUMBER: NCT00327691 (TNT); NCT00327418 (CARDS); NCT00159835 (IDEAL). PMID- 27513652 TI - Outcome and incidence of appropriate implantable cardioverter-defibrillator therapy in patients with cardiac amyloidosis. AB - BACKGROUND: Cardiac amyloidosis (CA) is associated with a poor prognosis with the proposed mechanism of sudden cardiac death in the majority of patients being pulseless electrical activity. However, the incidence of ventricular arrhythmias (VA) and implantable cardioverter-defibrillator (ICD) indications in CA patients are unclear. We performed a detailed evaluation of our CA population undergoing ICD implantation and assessed appropriate ICD therapy and survival predictors. METHODS: We included consecutive patients from June 2008 to November 2014 in five centers. ICDs were systematically interrogated and clinical data recorded during follow-up. RESULTS: Forty-five patients (35 males, mean age 66+/-12years) with CA who underwent ICD implantation (84.4% primary prevention) were included. CA types were hereditary transthyretin in 27 patients (60%), light chain (AL) in 12 (27%) and senile in 6 (13%). After a mean follow-up of 17+/-14months, 12 patients (27%) had at least 1 appropriate ICD therapy occurring after 4.7+/-6.6months. Patients with or without ICD therapy had no significant differences in baseline characteristics, amyloidosis type, LVEF, and type of prevention although there was a trend towards a better 2D global longitudinal strain in patients with ICD therapy (P=0.08). Over the follow-up, 12 patients died (27%) and 6 underwent cardiac transplantation (13%). From multivariate analysis a worse prognosis was associated with higher NT-proBNP level (>6800pg/mL, HR=5.5[1.7-17.8]) and AL type (HR=4.9[1.5-16.3]). CONCLUSIONS: Appropriate ICD therapies are common (27%) in CA patients. No specific strong VA predictor could be identified. However, patients with advanced heart disease, especially with AL-CA, display a poorer outcome. PMID- 27513653 TI - Effects of early aldosterone antagonism on cardiac remodeling in rats with aortic stenosis-induced pressure overload. AB - Aldosterone plays a pivotal role in the pathophysiology of systolic heart failure. However, whether early aldosterone antagonism improves cardiac remodeling during persistent pressure overload is unsettled. We evaluated the effects of aldosterone antagonist spironolactone on cardiac remodeling in rats with ascending aortic stenosis (AS). METHODS: Three days after inducing AS, weaning rats were randomized to receive spironolactone (AS-SPR, 20mg/kg/day) or no drug (AS) for 18weeks, and compared with sham-operated rats. Myocardial function was studied in isolated left ventricular (LV) papillary muscles. STATISTICAL ANALYSES: ANOVA or Kruskal-Wallis tests. RESULTS: Echocardiogram showed that LV diastolic (Sham 8.73+/-0.57; AS 8.30+/-1.10; AS-SPR 9.19+/-1.15mm) and systolic (Sham 4.57+/-0.67; AS 3.61+/-1.49; AS-SPR 4.62+/-1.48mm) diameters, left atrial diameter (Sham 5.80+/-0.44; AS 7.15+/-1.22; AS-SPR 8.02+/-1.17mm), and LV mass were higher in AS-SPR than AS. Posterior wall shortening velocity (Sham 38.5+/-3.8; AS 35.6+/-5.6; AS-SPR 31.1+/-3.8mm/s) was lower in AS-SPR than Sham and AS; E/A ratio was higher in AS-SPR than Sham. Developed tension was lower in AS and AS-SPR than Sham. Time to peak tension was higher in AS-SPR than Sham and AS after post-rest contraction. Right ventricle weight was higher in AS SPR than AS, suggesting more severe heart failure in AS-SPR than AS. Interstitial collagen fractional area and myocardial hydroxyproline concentration were higher in AS than Sham. Metalloproteinase-2 and -9 activity, evaluated by zymography, did not differ between groups. CONCLUSION: Early spironolactone administration causes further hypertrophy in cardiac chambers, and left ventricular dilation and dysfunction in rats with AS-induced chronic pressure overload. PMID- 27513654 TI - Embolic stroke and after-admission atrial fibrillation. AB - BACKGROUND: Although atrial fibrillation (AF) is a leading cause of recurrent embolic stroke, secondary AF after stroke has been reported frequently. Because of the different treatment each uses, it is important to detect the exact stroke etiology. OBJECTIVES: The aim of this study was to compare the embolic stroke in patients with known AF and after-admission AF (AAAF). METHODS: Between October 2002 and July 2009, those who were diagnosed with AF (n=354) were enrolled in our study out of a total of 2026 acute ischemic stroke (IS) patients. The embolic lesion patterns were assessed by two stroke specialists who were blinded to the clinical information. RESULTS: Among 354 IS patients with AF, the number of patients with embolic stroke was 314. Patients with embolic stroke were younger and more likely to have larger left atrial (LA)/Aortic diameter ratio. Approximately 90.4% of those with known AF had embolic stroke, while <60% of patients with AAAF had embolic stroke. Nevertheless, anticoagulants were prescribed similarly in both groups at discharge. The LA/Aortic diameter ratio<1.5 was significantly related to AAAF. After adjusting for multiple co variables, compared to the patients with known AF, patients with AAAF had reduced risk of embolic stroke (Odds ratio 0.11, 95% Confidence interval 0.03-0.36, p value<0.001). CONCLUSIONS: Compared to AAAF after stroke, known AF was associated with embolic stroke. Therefore, we suggest that stroke etiology and some novel echocardiographic indicators such as LA enlargement might be contemplated before routine using of anticoagulants in IS patients with AF. PMID- 27513655 TI - Potential beneficial effect of some adipokines positively correlated with the adipose tissue content on the cardiovascular system. AB - Obesity is a risk factor of cardiovascular diseases. However, in the case of heart failure, obese and overweight patients have a more favourable prognosis compared to patients who have a normal body weight. This phenomenon is referred to as the "obesity paradox," and it is explained by, among others, a positive effect of adipokines produced by adipose tissue, particularly by the tissue located in the direct vicinity of the heart and blood vessels. The favourable effect on the cardiovascular system is mostly associated with adiponectin and omentin, but the levels of these substances are reduced in obese patients. Among the adipokines which levels are positively correlated with the adipose tissue content, favourable activity is demonstrated by apelin, progranulin, chemerin, TNF-alpha (tumour necrosis factor-)alpha, CTRP-3 (C1q/tumour necrosis factor (TNF) related protein), leptin, visfatin and vaspin. This activity is associated with the promotion of regeneration processes in the damaged myocardium, formation of new blood vessels, reduction of the afterload, improvement of metabolic processes in cardiomyocytes and myocardial contractile function, inhibition of apoptosis and fibrosis of the myocardium, as well as anti-inflammatory and anti atheromatous effects. The potential use of these properties in the treatment of heart failure and ischaemic heart disease, as well as in pulmonary hypertension, arterial hypertension and the limitation of the loss of cardiomyocytes during cardioplegia-requiring cardiosurgical procedures, is studied. The most advanced studies focus on analogues of apelin and progranulin. PMID- 27513656 TI - Frailty predicts major bleeding within 30days in elderly patients with Acute Coronary Syndrome. AB - OBJECTIVE: Bleeding in ACS patients is an independent marker of adverse outcomes. Its prognostic impact is even worse in elderly population. Current bleeding risk scores include chronological age but do not consider biologic vulnerability. No studies have assessed the effect of frailty on major bleeding. The aim of this study is to determine whether frailty status increases bleeding risk in patients with ACS. METHODS: This prospective and observational study included patients aged >=75years admitted due to type 1 myocardial infarction. Exclusion criteria were severe cognitive impairment, impossibility to measure handgrip strength, cardiogenic shock and limited life expectancy due to oncologic diseases. The primary endpoint was 30-day major bleeding defined as a decrease of >=3g/dl of haemoglobin or need of transfusion. RESULTS: A total of 190 patients were included. Frail patients (72, 37.9%) were older, with higher comorbidity features and with a higher CRUSADE score at admission. On univariate analysis, frailty predicted major bleeding during 30-day follow-up despite less frequent use of a P2Y12 inhibitor (66.2% vs 83.6%, p=0.007) and decreased catheterisation rate (69.4% vs 94.1%, p<0.001). Major bleeding was associated with increased all-cause mortality at day 30 (18.2% vs 2.5%, p<0.001). On multivariate analysis, frailty was an independent predictor for major bleeding. CONCLUSION: Frailty phenotype, as a marker of biological vulnerability, is an independent predictor of major bleeding in elderly patients with ACS. Frailty can play an important role in bleeding risk stratification and objective indices should be integrated into routine initial evaluation of these patients. PMID- 27513657 TI - Prognosis of heart failure with preserved ejection fraction treated with beta blockers: A propensity matched study in the community. AB - BACKGROUND: The effect of treatment with beta-blockers on the prognosis of patients newly diagnosed with heart failure with preserved ejection fraction (HFpEF) is unknown. OBJECTIVE: To analyze the relationship of commencing treatment with the beta-blockers bisoprolol or carvedilol (CT-betaB) with the prognosis of newly diagnosed HFpEF. METHODS: Prospective study over 10years on 2704 patients with HFpEF. Main outcomes were mortality (all-cause and cardiovascular), hospitalizations for HF worsening, and visits. The independent relationship between CT-betaB and the prognosis, stratifying patients for cardiovascular co-morbidity after propensity score-matching (985 patients CT betaB vs. another 985 patients non-CT-betaB), was analyzed. RESULTS: During a median follow-up of 1877.4days (interquartile range, 1-3651.2) 1600 died (81.2%), and 1702 were hospitalized (86.4%). CT-betaB was associated with a lower risk of mortality (all-cause: HR [CI 95%] 0.78 [0.71 to 0.85], and cardiovascular: 0.75 [0.69 to 0.82]), a lower hospitalization rate (per 100 persons-year), 15.8 vs. 19.2, and a lower 30-day readmission rate (per 100 persons-year), 4.0 vs. 5.8, (P<0.001 in all cases), even after adjustment for the propensity to take beta blockers or other medications, comorbidities, and other potential confounders. These effects of CT-betaB were independent of gender, and were observed in both patients taking high dose betaB (over the median dose) and lower dose betaB (under or equal to the median dose). CONCLUSIONS: In this propensity matched study, commencing treatment with bisoprolol or carvedilol, both at high and at lower doses, is associated with an improved prognosis of patients newly diagnosed with HFpEF. PMID- 27513658 TI - Effects of mitral valve repair on ventricular arrhythmia in patients with mitral valve prolapse syndrome: A report of two cases. PMID- 27513659 TI - Analysis of the Prevalence of and Factors Associated with Hearing Loss in Korean Adolescents. AB - BACKGROUND: Hearing loss can lead to a number of disabilities, subsequently reducing the quality of life. In general, hearing thresholds of adolescents are better than adults and the elderly. However, occasionally, adolescents acquire hearing loss for a number of reasons. In this study, our goal was to estimate the prevalence of hearing loss in the Korean population and to investigate the factors related to hearing thresholds in adolescents. METHODS: A cross-sectional study was conducted using data from the Korean National Health and Nutrition Examination Survey (KNHANES) between 2010 and 2012. We enrolled a total of 1,658 participants, ages 13 to 18 years. We investigated the prevalence of hearing loss and the factors associated with hearing thresholds at various frequencies (0.5, 1, 2, 3, 4, and 6 KHz). RESULTS: Weighted prevalence of unilateral and bilateral hearing loss in Korean adolescents was 2.2% and 0.4%, respectively. Weighted prevalence of hearing thresholds >= 20 dB at speech and high frequencies were 3.1% and 5.0%, respectively, for unilateral hearing loss and 0.7% and 1.9%, respectively, for bilateral. Age group, tympanometric data, and household income were significantly related to unilateral or bilateral hearing thresholds >= 20 dB at speech frequencies. Earphone use in noisy places was associated with bilateral hearing thresholds >= 20 dB at high frequencies. CONCLUSIONS: The prevalence of hearing loss in Korean adolescents was 2.6% using the general standard threshold associated with hearing loss. However, the prevalence of hearing thresholds >= 20 dB for speech and high frequencies was much higher. The results from this study provide an estimate of hearing loss in adolescents and suggest the need for early detection and hearing preservation programs among adolescents. PMID- 27513660 TI - Wildfire Suppression Costs for Canada under a Changing Climate. AB - Climate-influenced changes in fire regimes in northern temperate and boreal regions will have both ecological and economic ramifications. We examine possible future wildfire area burned and suppression costs using a recently compiled historical (i.e., 1980-2009) fire management cost database for Canada and several Intergovernmental Panel on Climate Change (IPCC) climate projections. Area burned was modelled as a function of a climate moisture index (CMI), and fire suppression costs then estimated as a function of area burned. Future estimates of area burned were generated from projections of the CMI under two emissions pathways for four General Circulation Models (GCMs); these estimates were constrained to ecologically reasonable values by incorporating a minimum fire return interval of 20 years. Total average annual national fire management costs are projected to increase to just under $1 billion (a 60% real increase from the 1980-2009 period) under the low greenhouse gas emissions pathway and $1.4 billion (119% real increase from the base period) under the high emissions pathway by the end of the century. For many provinces, annual costs that are currently considered extreme (i.e., occur once every ten years) are projected to become commonplace (i.e., occur once every two years or more often) as the century progresses. It is highly likely that evaluations of current wildland fire management paradigms will be necessary to avoid drastic and untenable cost increases as the century progresses. PMID- 27513661 TI - Numerical Simulation of Dry Granular Flow Impacting a Rigid Wall Using the Discrete Element Method. AB - This paper presents a clump model based on Discrete Element Method. The clump model was more close to the real particle than a spherical particle. Numerical simulations of several tests of dry granular flow impacting a rigid wall flowing in an inclined chute have been achieved. Five clump models with different sphericity have been used in the simulations. By comparing the simulation results with the experimental results of normal force on the rigid wall, a clump model with better sphericity was selected to complete the following numerical simulation analysis and discussion. The calculation results of normal force showed good agreement with the experimental results, which verify the effectiveness of the clump model. Then, total normal force and bending moment of the rigid wall and motion process of the granular flow were further analyzed. Finally, comparison analysis of the numerical simulations using the clump model with different grain composition was obtained. By observing normal force on the rigid wall and distribution of particle size at the front of the rigid wall at the final state, the effect of grain composition on the force of the rigid wall has been revealed. It mainly showed that, with the increase of the particle size, the peak force at the retaining wall also increase. The result can provide a basis for the research of relevant disaster and the design of protective structures. PMID- 27513662 TI - Prognostic and Diagnostic Significance of SDPR-Cavin-2 in Hepatocellular Carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor worldwide. Due to the lack of early prediction marker, numerous patients were diagnosed in their late stage. The family of cavins plays important roles in caveolae formation and cellular processes. Cavin-2, one of the members of cavins, has been reported as a suppresser in cancers. In this study, we have investigated its expression pattern and clinical significance in HCC. METHODS: RT-qPCR was performed to detect the expression of cavin-2. RESULTS: Cavin-2 was down-regulated in HCC and associated with tumor differentiation (r=-0.275, P=0.013) and tumor-node-metastasis (TNM) stage (r=-0.216, P=0.035). The Overall survival analysis showed that patients with lower cavin-2 expression had a relatively poor prognosis. Meanwhile, the multivariate analysis revealed that cavin-2 was an independent prognostic factor. The receiver operating characteristic curve analyses indicated that plasma cavin 2 presented a high accuracy (AUC=0.727, 0.865, 0.901) for diagnosing HCC cases from controls, hepatitis B and cirrhosis patients, respectively. Meanwhile, plasma cavin-2 showed a high sensitivity (88.4%, 89.9%) for detecting HCC with the serum alpha-fetoprotein (AFP) levels below 200 ng/ml from those hepatitis B and cirrhosis cases. CONCLUSION: Our data suggested that cavin-2 might be considered as a potential prognostic and diagnostic indicator in HCC. PMID- 27513663 TI - Ethanol and Acetaminophen Synergistically Induce Hepatic Aggregation and TCH346 Insensitive Nuclear Translocation of GAPDH. AB - The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) signals during cellular stress via several post-translational modifications that change its folding properties, protein-protein interactions and sub-cellular localization. We examined GAPDH properties in acute mouse liver injury due to ethanol and/or acetaminophen (APAP) treatment. Synergistic robust and time dependent nuclear accumulation and aggregation of GAPDH were observed only in combined, but not individual, ethanol/APAP treatments. The small molecule GAPDH targeting compound TCH346 partially attenuated liver damage possibly via mitochondrial mechanisms, and independent of nuclear accumulation and aggregation of GAPDH. These findings provide a novel potential mechanism for hepatotoxicity caused by combined alcohol and acetaminophen exposure. PMID- 27513664 TI - Predicting Trabecular Bone Stiffness from Clinical Cone-Beam CT and HR-pQCT Data; an In Vitro Study Using Finite Element Analysis. AB - Stiffness and shear moduli of human trabecular bone may be analyzed in vivo by finite element (FE) analysis from image data obtained by clinical imaging equipment such as high resolution peripheral quantitative computed tomography (HR pQCT). In clinical practice today, this is done in the peripheral skeleton like the wrist and heel. In this cadaveric bone study, fourteen bone specimens from the wrist were imaged by two dental cone beam computed tomography (CBCT) devices and one HR-pQCT device as well as by dual energy X-ray absorptiometry (DXA). Histomorphometric measurements from micro-CT data were used as gold standard. The image processing was done with an in-house developed code based on the automated region growing (ARG) algorithm. Evaluation of how well stiffness (Young's modulus E3) and minimum shear modulus from the 12, 13, or 23 could be predicted from the CBCT and HR-pQCT imaging data was studied and compared to FE analysis from the micro-CT imaging data. Strong correlations were found between the clinical machines and micro-CT regarding trabecular bone structure parameters, such as bone volume over total volume, trabecular thickness, trabecular number and trabecular nodes (varying from 0.79 to 0.96). The two CBCT devices as well as the HR-pQCT showed the ability to predict stiffness and shear, with adjusted R2 values between 0.78 and 0.92, based on data derived through our in-house developed code based on the ARG algorithm. These findings indicate that clinically used CBCT may be a feasible method for clinical studies of bone structure and mechanical properties in future osteoporosis research. PMID- 27513665 TI - Structure of Benthic Communities along the Taiwan Latitudinal Gradient. AB - The distribution and the structure of benthic assemblages vary with latitude. However, few studies have described benthic communities along large latitudinal gradients, and patterns of variation are not fully understood. Taiwan, lying between 21.90 degrees N and 25.30 degrees N, is located at the center of the Philippine-Japan arc and lies at the northern margin of coral reef development. A wide range of habitats is distributed along this latitudinal gradient, from extensive fringing coral reefs at the southern coast to non-reefal communities at the north. In this study, we examined the structure of benthic communities around Taiwan, by comparing its assemblages in four regions, analyzing the effects of the latitudinal gradient, and highlighting regional characteristics. A total of 25 sites, 125 transects, and 2,625 photographs were used to analyze the benthic communities. Scleractinian corals present an obvious gradient of increasing diversity from north to south, whereas macro-algae diversity is higher on the north-eastern coast. At the country scale, Taiwanese coral communities were dominated by turf algae (49%). At the regional scale, we observed an important heterogeneity that may be caused by local disturbances and habitat degradation that smooths out regional differences. In this context, our observations highlight the importance of managing local stressors responsible for reef degradation. Overall, this study provides an important baseline upon which future changes in benthic assemblages around Taiwan can be assessed. PMID- 27513666 TI - Cyclic Fatigue Resistance and Force Generated by OneShape Instruments during Curved Canal Preparation. AB - OBJECTIVES: To evaluate the cyclic fatigue resistance and the force generated by OneShape files during preparation of simulated curved canals. METHODS: Six OneShape files (the test) and six ProTaper F2 files (the control) were subject to the bending ability test. Another thirty files of each type were used to prepare artificial canals (n = 60), which were divided into 3 groups according to respective curvatures of the canals (30 degrees , 60 degrees , and 90 degrees ). The numbers of cycles to fatigue (NCF) as well as the positive and negative forces that were generated by files during canal preparation were recorded. The scanning electron microscopy was applied to detect the fracture surfaces. RESULTS: Compared with ProTaper F2 files, the bending loads of OneShape files were significantly lower at deflections of 45 degrees (P < .05), 60 degrees (P < .05) and 75 degrees (P < .01). No significant difference was found at 30 degrees . OneShape files presented a higher NCF in both 60 degrees and 90 degrees canals than the control (P < .01). No significant difference of NCF was found between OneShape and ProTaper files in 30 degrees canals. During the preparation of 30 degrees canals by both files, the negative forces were dominant. With the increase of the curvature, more positive forces were observed. When the OneShape Files were compared with the control, significant different forces were found at D3 and D2 (P < .05) in 30 degrees canals, at D2 (P < .05), D1 (P < .01) and D0 (P < .01) in 60 degrees canals, and at D4 and D3 (P < .01) in 90 degrees canals. CONCLUSIONS: OneShape files possessed a reliable flexibility and cyclic fatigue resistance. According to the assessments of the forces generated by files, OneShape instruments performed in a more fatigue-resistant way during curved canal preparation, compared with the ProTaper F2 files. PMID- 27513667 TI - A Multi-Species TaqMan PCR Assay for the Identification of Asian Gypsy Moths (Lymantria spp.) and Other Invasive Lymantriines of Biosecurity Concern to North America. AB - Preventing the introduction and establishment of forest invasive alien species (FIAS) such as the Asian gypsy moth (AGM) is a high-priority goal for countries with extensive forest resources such as Canada. The name AGM designates a group of closely related Lymantria species (Lepidoptera: Erebidae: Lymantriinae) comprising two L. dispar subspecies (L. dispar asiatica, L. dispar japonica) and three closely related Lymantria species (L. umbrosa, L. albescens, L. postalba), all considered potential FIAS in North America. Ships entering Canadian ports are inspected for the presence of suspicious gypsy moth eggs, but those of AGM are impossible to distinguish from eggs of innocuous Lymantria species. To assist regulatory agencies in their identification of these insects, we designed a suite of TaqMan(r) assays that provide significant improvements over existing molecular assays targeting AGM. The assays presented here can identify all three L. dispar subspecies (including the European gypsy moth, L. dispar dispar), the three other Lymantria species comprising the AGM complex, plus five additional Lymantria species that pose a threat to forests in North America. The suite of assays is built as a "molecular key" (analogous to a taxonomic key) and involves several parallel singleplex and multiplex qPCR reactions. Each reaction uses a combination of primers and probes designed to separate taxa through discriminatory annealing. The success of these assays is based on the presence of single nucleotide polymorphisms (SNPs) in the 5' region of mitochondrial cytochrome c oxidase I (COI) or in its longer, 3' region, as well as on the presence of an indel in the "FS1" nuclear marker, generating North American and Asian alleles, used here to assess Asian introgression into L. dispar dispar. These assays have the advantage of providing rapid and accurate identification of ten Lymantria species and subspecies considered potential FIAS. PMID- 27513668 TI - Ingenol Mebutate for Recalcitrant Chronic Actinic Cheilitis. AB - We present the case of a healthy 76-year-old man with a whitish, hyperkeratotic lesion of the lower lip diagnosed as actinic cheilitis (AC) previously treated with classic red light photodynamic therapy 5 years ago. Initial treatment with 5% imiquimod cream - also with intensified application - failed. After 2 cycles thrice daily, consecutive applications of 150 MUg/g ingenol mebutate gel at 3 weeks' interval, the lesions cleared completely. Surprisingly, no pustular or crusting reaction or other side effect occurred contrary to expectation. Remission was stable for 10 months, when recurrence occurred. Ingenol mebutate proved to be a feasible and safe treatment in this otherwise refractory case of AC. PMID- 27513669 TI - GaAs nanowires with oxidation-proof arsenic capping for the growth of an epitaxial shell. AB - We propose an arsenic-capping/decapping method, allowing the growth of an epitaxial shell around the GaAs nanowire (NW) core which is exposed to an ambient atmosphere, and without the introduction of impurities. Self-catalyzed GaAs NW arrays were firstly grown on Si(111) substrates by solid-source molecular beam epitaxy. Aiming for protecting the active surface of the GaAs NW core, the arsenic-capping/decapping method has been applied. To validate the effect of this method, different core/shell NWs have been fabricated. Analyses highlight the benefit of the As capping-decapping method for further epitaxial shell growth: an epitaxial shell with a smooth surface is achieved in the case of As-capped decapped GaAs NWs, comparable to the in situ grown GaAs/AlGaAs NWs. This As capping method opens a way for the epitaxial growth of heterogeneous material shells such as functional oxides using different reactors. PMID- 27513670 TI - Opposite Cannabis-Cognition Associations in Psychotic Patients Depending on Family History. AB - The objective of this study is to investigate cognitive performance in a first episode psychosis sample, when stratifying the interaction by cannabis use and familial or non-familial psychosis. Hierarchical-regression models were used to analyse this association in a sample of 268 first-episode psychosis patients and 237 controls. We found that cannabis use was associated with worse working memory, regardless of family history. However, cannabis use was clearly associated with worse cognitive performance in patients with no family history of psychosis, in cognitive domains including verbal memory, executive function and global cognitive index, whereas cannabis users with a family history of psychosis performed better in these domains. The main finding of the study is that there is an interaction between cannabis use and a family history of psychosis in the areas of verbal memory, executive function and global cognition: that is, cannabis use is associated with a better performance in patients with a family history of psychosis and a worse performance in those with no family history of psychosis. In order to confirm this hypothesis, future research should explore the actual expression of the endocannabinoid system in patients with and without a family history of psychosis. PMID- 27513671 TI - Feasibility and Outcome of a Short-Term Group Therapy for Inpatients with Comorbid Substance Use Disorders and Depression: The InterPersonal Kiesler-Circle Training (IPKCT). PMID- 27513673 TI - Maximum Urine Flow Rate of Less than 15ml/Sec Increasing Risk of Urine Retention and Prostate Surgery among Patients with Alpha-1 Blockers: A 10-Year Follow Up Study. AB - BACKGROUND: The aim of this study was to determine the subsequent risk of acute urine retention and prostate surgery in patients receiving alpha-1 blockers treatment and having a maximum urinary flow rate of less than 15ml/sec. METHODS: We identified patients who were diagnosed with benign prostate hyperplasia (BPH) and had a maximum uroflow rate of less than 15ml/sec between 1 January, 2002 to 31 December, 2011 from Taiwan's National Health Insurance Research Database into study group (n = 303). The control cohort included four BPH/LUTS patients without 5ARI used for each study group, randomly selected from the same dataset (n = 1,212). Each patient was monitored to identify those who subsequently developed prostate surgery and acute urine retention. RESULTS: Prostate surgery and acute urine retention are detected in 5.9% of control group and 8.3% of study group during 10-year follow up. Compared with the control group, there was increase in the risk of prostate surgery and acute urine retention in the study group (HR = 1.83, 95% CI: 1.16 to 2.91) after adjusting for age, comorbidities, geographic region and socioeconomic status. CONCLUSIONS: Maximum urine flow rate of less than 15ml/sec is a risk factor of urinary retention and subsequent prostate surgery in BPH patients receiving alpha-1 blocker therapy. This result can provide a reference for clinicians. PMID- 27513675 TI - Preventive Cardiovascular Nurses Association News. PMID- 27513674 TI - Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease. AB - BACKGROUND: The characteristic clinical heterogeneity and mostly slow-growing behavior of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) cause problems in finding appropriate treatments. Thus, the current therapy options are not satisfactory. PKI-587 is a highly potent, novel dual inhibitor of PI3K and mTORC1/C2. AIM: We assessed the effects of PKI-587 in different GEP-NEN tumor models, including the poorly differentiated cell line LCC-18, and compared them with those of the established mTORC1 inhibitor everolimus. METHODS: We treated BON, QGP-1, KRJ-I, and LCC-18 cell lines with increasing concentrations of the inhibitor PKI-587, and compared the results with those of everolimus and DMSO. We assessed the impact of the treatments on viability (WST-1 assay), on apoptotic processes (caspase 3/7 assay, JC-1), and on cell cycle regulation (flow cytometry). We determined alterations in signaling mediators by phosphor-specific Western blot analysis and conducted multiplexed gene expression analysis (nCounter(r) technology). RESULTS: In all cell lines, PKI-587 dose-dependently inhibited proliferation, whereas everolimus was less effective. Treatment with PKI-587 led to cell cycle arrest and induction of apoptosis and successfully suppressed activity of the direct mTORC1 target 4E-BP1, a crucial factor for tumor genesis only partially inhibited by everolimus. Gene expression analyses revealed relevant changes of RAS, MAPK, STAT, and PI3K pathway genes after treatment. Treatment-dependent and cell line-characteristic effects on AKT/Rb/E2F signaling regarding cell cycle control and apoptosis are extensively discussed in this paper. CONCLUSION: PI3K/mTOR dual targeting is a promising new therapeutic approach in neuroendocrine tumor disease that should be evaluated in further clinical trials. PMID- 27513676 TI - Reducing Disparities in Heart Disease Treatment and Outcomes Among Women: A Call to Action. PMID- 27513677 TI - 20 Things You Didn't Know About Exercise. PMID- 27513678 TI - The Impact of Breakthrough Therapy Designation on Development Strategies and Timelines for Nononcology Drugs and Vaccines. AB - The US Food and Drug Administration (FDA) Safety and Innovation Act (FDASIA, 2012) introduced the Breakthrough Therapy Designation (BTD), a new tool to expedite development of medicines to treat serious or life-threatening diseases. The majority of BTDs have gone to oncology drugs, and a recent publication by Shea et al.1 reviewed the impact of BTD on oncology drug development. This article reviews the impact of BTD on development strategies and timelines for nononcology drugs. PMID- 27513679 TI - Associations of Circulating PYY3-36 Concentrations with Metabolic Syndrome in Extremely Obese Subjects. AB - BACKGROUND: The gut hormone peptide YY3-36 (PYY3-36) plays major roles in regulation of appetite and energy metabolism, mediates beneficial effects of bariatric surgery, and may be a potential weight-reducing and glucose-modulating therapy. Obesity may influence the metabolic expression of circulating PYY3-36 and metabolic markers. We studied the relationship of PYY3-36 concentrations with metabolic syndrome (MetSyn) components, lipids, insulin resistance, and inflammatory biomarkers in subjects with extreme obesity. METHODS: We measured MetSyn components and PYY3-36, lipids, hormones, homeostasis model assessment (HOMA) index, and inflammatory biomarkers in consecutively referred patients (180 women and 111 men) aged 18-78 years with body mass index (BMI) >=40 kg/m2. Associations of PYY3-36 to components, insulin resistance, and biomarkers were examined with partial correlations and linear regression. RESULTS: PYY3-36 concentrations were not related to MetSyn components, HOMA index, or to inflammatory biomarker or leptin concentrations. PYY3-36 concentrations correlated with systolic blood pressure (r = 0.21; P < 0.0001) after adjustment for age and gender. In linear regression analysis, PYY3-36 concentrations were associated with systolic blood pressure after adjustment for age, gender, and central obesity in the entire sample (Beta 0.21; 95% CI 0.09-0.34) as well as in subjects not taking blood pressure-lowering medication (Beta 0.19; 95% CI 0.04 0.36). These associations were not statistically significant in the small subset of participants (22%) with type 2 diabetes. CONCLUSIONS: In extremely obese patients, fasting PYY3-36 concentrations were linked to systolic blood pressure, but not to other components of MetSyn, suggesting divergence between pathways of blood pressure and glucose/body weight regulation. However, this finding will need to be further investigated. PMID- 27513681 TI - Individual deals within teams: Investigating the role of relative i-deals for employee performance. AB - The authors extend i-deals theory to an individual-within-a-team context. Drawing upon social comparison theory, they contend that individuals will react to their own i-deals within the context of group members' i-deals. Therefore, they examine the role of relative i-deals (an individual's i-deals relative to the team's average) in relation to employee performance. Furthermore, integrating social comparison theory with social identity theory the authors assert that the behavioral outcomes of relative i-deals are influenced by the team's social and structural attributes of team orientation and task interdependence. Finally, they contend that the perceptions of one's relative standing with the leader, or leader-member exchange social comparison (LMXSC), mediate the i-deals-outcome relationship in groups with low team orientation and task interdependence. Results of multilevel modeling using time-lagged data from 321 employees nested in 46 teams demonstrated that the positive relationship between relative i-deals and employee performance was stronger in groups with low team orientation and task interdependence, and the mediation effect of LMXSC was stronger in teams with low rather than high team orientation. (PsycINFO Database Record PMID- 27513680 TI - Effects of Simazine Exposure on Neuronal Development-Related Factors in MN9D Cells. AB - BACKGROUND Simazine is a triazine herbicide used worldwide in both agricultural and non-agricultural fields that is frequently detected in surface water and groundwater. Due to its widespread use, an increasing amount of research has focused on the potentially serious environmental and health risks. MATERIAL AND METHODS We used Western blotting and real-time quantitative PCR to analyze the effects of simazine on dopamine neuronal development-related factors in MN9D dopaminergic cells. RESULTS The expression of tyrosine hydroxylase (TH) mRNA was significantly increased after treatment with 300 and 600 MUmol L-1 simazine after 24 and 48 h. Levels of nuclear-related receptor 1 (Nurr1) mRNA after 24- and 48-h exposure were decreased with 50 MUmol L-1 simazine, but increased with 600 MUmol L-1 simazine. Significant increases in TH and Nurr1 protein were observed in all simazine-treated groups at 24 and 48 h. The expression of neurogenin 2 and LIM homeobox transcription factor 1 beta (Lmx1b) mRNA were significantly increased after exposure to 600 MUmol L-1 simazine for 48 h, while the expression of wingless-type MMTV integration site family member 1 (Wnt1) mRNA was increased by all doses of simazine. CONCLUSIONS Simazine may have an impact on TH in MN9D cells through 2 mechanisms; one mechanism is through the Lmx1a/Ngn2 pathway, and the other mechanism is through the Lmx1b-pitx3/Wnt1-Nurr1 pathway. These 2 pathways likely do not operate in isolation, but rather together, during the cellular response to simazine exposure. PMID- 27513682 TI - Gingival crevicular fluid and saliva stress hormone levels in patients with chronic and aggressive periodontitis. AB - AIM: This cross-sectional study aims to analyse cortisol and dehydroepiandrosterone (DHEA) levels in gingival crevicular fluid (GCF) and saliva in generalized aggressive periodontitis (GAP) and generalized chronic periodontitis (GCP) patients, as well as in periodontally healthy individuals (C). MATERIAL AND METHODS: A total of 92 patients (31 C, 34 GCP and 27 GAP) were included in the study. Clinical parameters including plaque index, gingival index, bleeding on probing, probing depth and clinical attachment level; psychosocial measurements including Beck depression inventory and state-trait anxiety inventory; and hormone levels in GCF and saliva including cortisol and DHEA were evaluated. RESULTS: Gingival crevicular fluid cortisol and GCF/saliva DHEA values were significantly higher in the GAP group when compared to the other two groups (p < 0.05). The lowest values were in the C group and the difference between the GCP and GAP groups was statistically significant (p < 0.05). Salivary cortisol levels were comparable for the GAP and GCP groups (p > 0.05), and the C group had the lowest values in comparison with the other two groups (p < 0.05). CONCLUSIONS: Within the limits of this study, salivary/GCF cortisol and DHEA levels were suggested to be related with more severe and aggressive forms of periodontal disease. PMID- 27513683 TI - Structural transformation of synthetic hydroxyapatite under simulated in vivo conditions studied with ATR-FTIR spectroscopic imaging. AB - Hydroxyapatite and carbonate-substituted hydroxyapatite are widely used in bone tissue engineering and regenerative medicine. Both apatite materials were embedded into recently developed ceramic/polymer composites, subjected to Simulated Body Fluid (SBF) for 30days and characterized using ATR-FTIR spectroscopic imaging to assess their behaviour and structures. The specific aim was to detect the transition phases between both types of hydroxyapatite during the test and to analyze the surface modification caused by SBF. ATR-FTIR spectroscopic imaging was successfully applied to characterise changes in the hydroxyapatite lattice due to the elastic properties of the scaffolds. It was observed that SBF treatment caused a replacement of phosphates in the lattice of non-substituted hydroxyapatite by carbonate ions. A detailed study excluded the formation of pure A type carbonate apatite. In turn, CO32- content in synthetic carbonate-substituted hydroxyapatite decreased. The usefulness of ATR-FTIR spectroscopic imaging studies in the evaluation of elastic and porous beta-glucan hydroxyapatite composites has been demonstrated. PMID- 27513684 TI - Sensitive detection of maltose and glucose based on dual enzyme-displayed bacteria electrochemical biosensor. AB - Glucoamylase-displayed bacteria (GA-bacteria) and glucose dehydrogenase-displayed bacteria (GDH-bacteria) were co-immobilized on multi-walled carbon nanotubes (MWNTs) modified glassy carbon electrode (GCE) to construct GA-bacteria/GDH bacteria/MWNTs/GCE biosensor. The biosensor was developed by optimizing the loading amount and the ratio of GA-bacteria to GDH-bacteria. The as-prepared biosensor exhibited a wide dynamic range of 0.2-10mM and a low detection limit of 0.1mM maltose (S/N=3). The biosensor also had a linear response to glucose in the range of 0.1-2.0mM and a low detection limit of 0.04mM glucose (S/N=3). Interestingly, at the same concentration, glucose was 3.75-fold sensitive than that of maltose at the proposed biosensor. No interferences were observed for other possible mono- and disaccharides. The biosensor also demonstrated good long term storage stability and repeatability. Further, using both GDH bacteria/MWNTs/GCE biosensor and GA-bacteria/GDH-bacteria/MWNTs/GCE biosensor, glucose and maltose in real samples can be detected. Therefore, the proposed biosensor is capable of monitoring the food manufacturing and fermentation process. PMID- 27513685 TI - Heterogeneous Nucleation and Growth of Nanoparticles at Environmental Interfaces. AB - Mineral nucleation is a phase transformation of aqueous components to solids with an accompanying creation of new surfaces. In this evolutional, yet elusive, process, nuclei often form at environmental interfaces, which provide remarkably reactive sites for heterogeneous nucleation and growth. Naturally occurring nucleation processes significantly contribute to the biogeochemical cycles of important components in the Earth's crust, such as iron and manganese oxide minerals and calcium carbonate. However, in recent decades, these cycles have been significantly altered by anthropogenic activities, which affect the aqueous chemistry and equilibrium of both surface and subsurface systems. These alterations can trigger the dissolution of existing minerals and formation of new nanoparticles (i.e., nucleation and growth) and consequently change the porosity and permeability of geomedia in subsurface environments. Newly formed nanoparticles can also actively interact with components in natural and engineered aquatic systems, including those posing a significant hazard such as arsenic. These interactions can bilaterally influence the fate and transport of both newly formed nanoparticles and aqueous components. Due to their importance in natural and engineered processes, heterogeneous nucleation at environmental interfaces has started to receive more attention. However, a lack of time resolved in situ analyses makes the evaluation of heterogeneous nucleation challenging because the physicochemical properties of both the nuclei and surfaces significantly and dynamically change with time and aqueous chemistry. This Account reviews our in situ kinetic studies of the heterogeneous nucleation and growth behaviors of iron(III) (hydr)oxide, calcium carbonate, and manganese (hydr)oxide minerals in aqueous systems. In particular, we utilized simultaneous small-angle and grazing incidence small-angle X-ray scattering (SAXS/GISAXS) to investigate in situ and in real-time the effects of water chemistry and substrate identity on heterogeneously and homogeneously formed nanoscale precipitate size dimensions and total particle volume. Using this technique, we also provided a new platform for quantitatively comparing between heterogeneous and homogeneous nucleation and growth of nanoparticles and obtaining undiscovered interfacial energies between nuclei and surfaces. In addition, nanoscale surface characterization tools, such as in situ atomic force microscopy (AFM), were utilized to support and complement our findings. With these powerful nanoscale tools, we systematically evaluated the influences of environmentally abundant (oxy)anions and cations and the properties of environmental surfaces, such as surface charge and hydrophobicity. The findings, significantly enhanced by in situ observations, can lead to a more accurate prediction of the behaviors of nanoparticles in the environment and enable better control of the physicochemical properties of nanoparticles in engineered systems, such as catalytic reactions and energy storage. PMID- 27513687 TI - Poor Adherence to Lung-Protective Mechanical Ventilation in Pediatric Acute Respiratory Distress Syndrome. AB - OBJECTIVES: To determine the frequency of low-tidal volume ventilation in pediatric acute respiratory distress syndrome and assess if any demographic or clinical factors improve low-tidal volume ventilation adherence. DESIGN: Descriptive post hoc analysis of four multicenter pediatric acute respiratory distress syndrome studies. SETTING: Twenty-six academic PICU. PATIENTS: Three hundred fifteen pediatric acute respiratory distress syndrome patients. MEASUREMENTS AND MAIN RESULTS: All patients who received conventional mechanical ventilation at hours 0 and 24 of pediatric acute respiratory distress syndrome who had data to calculate ideal body weight were included. Two cutoff points for low-tidal volume ventilation were assessed: less than or equal to 6.5 mL/kg of ideal body weight and less than or equal to 8 mL/kg of ideal body weight. Of 555 patients, we excluded 240 for other respiratory support modes or missing data. The remaining 315 patients had a median PaO2-to-FIO2 ratio of 140 (interquartile range, 90-201), and there were no differences in demographics between those who did and did not receive low-tidal volume ventilation. With tidal volume cutoff of less than or equal to 6.5 mL/kg of ideal body weight, the adherence rate was 32% at hour 0 and 33% at hour 24. A low-tidal volume ventilation cutoff of tidal volume less than or equal to 8 mL/kg of ideal body weight resulted in an adherence rate of 58% at hour 0 and 60% at hour 24. Low-tidal volume ventilation use was no different by severity of pediatric acute respiratory distress syndrome nor did adherence improve over time. At hour 0, overweight children were less likely to receive low-tidal volume ventilation less than or equal to 6.5 mL/kg ideal body weight (11% overweight vs 38% nonoverweight; p = 0.02); no difference was noted by hour 24. Furthermore, in the overweight group, using admission weight instead of ideal body weight resulted in misclassification of up to 14% of patients as receiving low-tidal volume ventilation when they actually were not. CONCLUSIONS: Low-tidal volume ventilation is underused in the first 24 hours of pediatric acute respiratory distress syndrome. Age, Pediatric Risk of Mortality III, and pediatric acute respiratory distress syndrome severity were not associated with improved low-tidal volume ventilation adherence nor did adherence improve over time. Overweight children were less likely to receive low-tidal volume ventilation strategies in the first day of illness. PMID- 27513688 TI - Pharmacodynamics and Pharmacokinetics of Morphine After Cardiac Surgery in Children With and Without Down Syndrome. AB - OBJECTIVE: To compare the pharmacodynamics and pharmacokinetics of IV morphine after cardiac surgery in two groups of children-those with and without Down syndrome. DESIGN: Prospective, single-center observational trial. SETTING: PICU in a university-affiliated pediatric teaching hospital. PATIENTS: Twenty-one children with Down syndrome and 17 without, 3-36 months old, scheduled for cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: A loading dose of morphine (100 MUg/kg) was administered after coming off bypass; thereafter, morphine infusion was commenced at 40 MUg/kg/hr. During intensive care, nurses regularly assessed pain and discomfort with validated observational instruments (COMFORT-Behavior scale and Numeric Rating Scale-for pain). These scores guided analgesic and sedative treatment. Plasma samples were obtained for pharmacokinetic analysis. MEASUREMENTS AND MAIN RESULTS: Median COMFORT-Behavior and Numeric Rating Scale scores were not statistically significantly different between the two groups. The median morphine infusion rate during the first 24 hours after surgery was 31.3 MUg/kg/hr (interquartile range, 23.4-36.4) in the Down syndrome group versus 31.7 MUg/kg/hr (interquartile range, 25.1-36.1) in the control group (p = 1.00). Population pharmacokinetic analysis revealed no statistically significant differences in any of the pharmacokinetic variables of morphine between the children with and without Down syndrome. CONCLUSIONS: This prospective trial showed that there are no differences in pharmacokinetics or pharmacodynamics between children with and without Down syndrome if pain and distress management is titrated to effect based on outcomes of validated assessment instruments. We have no evidence to adjust morphine dosing after cardiac surgery in children with Down syndrome. PMID- 27513689 TI - Is early inflammation good or bad? Linking early immune changes to hypertrophic scarring. PMID- 27513690 TI - Cucurbit[8]uril Regulated Activatable Supramolecular Photosensitizer for Targeted Cancer Imaging and Photodynamic Therapy. AB - Activatable photosensitizers (aPSs) have emerged as promising photodynamic therapy (PDT) agents for simultaneous imaging and selective ablation of cancer. However, traditional synthetic aPSs are limited by complex design and tedious synthesis. Here, aPS regulated by cucurbit[8]uril (CB[8]) for targeted cancer imaging and PDT is reported. This system is based on the host-guest interaction between biotinylated toluidine blue (TB-B) and CB[8] to form 2TB-B@CB[8]. Moreover, a facile strategy to turn off/on the fluorescence and photodynamic activity of TB-B is developed through the reversible assembly/disassembly of 2TB B@CB[8]. This established system can achieve selective accumulation in tumor, light-up cancer imaging, and enhanced anticancer behavior. Therefore, this work provides a novel and promising strategy for the aPS build via simple and facile regulation of supramolecular chemistry. PMID- 27513691 TI - Association of BRCA1 Mutations with Impaired Ovarian Reserve: Connection Between Infertility and Breast/Ovarian Cancer Risk. AB - PURPOSE: Mutations in the BRCA1/2 genes are associated with breast and ovarian cancer susceptibility. Recent studies have suggested that the BRCA mutation might be associated with occult primary ovarian insufficiency. To evaluate fertility, several studies have validated anti-Mullerian hormone (AMH) as a direct biomarker for ovarian aging and it is considered a quantitative marker of ovarian reserve. We hypothesize that BRCA1 gene mutations will be negatively associated with AMH levels. METHODS: We evaluated 124 women aged 18-45 years participating in the Northwestern Ovarian Cancer Early Detection and Prevention Program. Patients with a history of cancer, ovarian surgery, or exposure to chemotherapy were excluded. Linear and logistic regression modeling were performed to evaluate the association between AMH levels, age, and BRCA1 mutation. In logistic models, the outcome 'low AMH' was defined as AMH <0.05 ng/mL. Logistic regression models were used to adjust for other factors, including body mass index (BMI), duration of birth control (BC), smoking, gravidity, and parity. RESULTS: Women with the BRCA1 mutation had a significant decline in AMH with age (p = 0.0011). BRCA1-positive women >35 years had 10 times the odds of a low AMH (<0.5 ng/mL) compared with women <=35 years. With adjustment for BMI, duration of BC, smoking, gravidity, parity, and age >35, BRCA1 was still strongly associated with a low AMH (p = 0.037). CONCLUSION: Women >35 with the BRCA1 mutation have a lower AMH, and hence ovarian reserve, than women without a BRCA mutation. Therefore, young adults with the BRCA1 mutation should be counseled regarding this potential decrease in ovarian reserve. PMID- 27513692 TI - Coagulation and non-coagulation effects of thrombin. AB - Thrombin is a multifunctional serine protease produced from prothrombin, and is a key regulator in hemostatic and non-hemostatic processes. It is the main effector protease in primary hemostasis by activating platelets, and plays a key role in secondary hemostasis. Besides its well-known functions in hemostasis, thrombin also plays a role in various non-hemostatic biological and pathophysiologic processes, predominantly mediated through activation of protease-activated receptors (PARs). Depending on several factors, such as the concentration of thrombin, the duration of activation, the location of PARs, the presence of coreceptors, and the formation of PAR heterodimers, activation of the receptor by thrombin can induce different cellular responses. Moreover, thrombin can have opposing effects in the same cell; it can induce both inflammatory and anti inflammatory signals. Owing to the complexity of thrombin's signal transduction pathways, the exact mechanism behind the dichotomy of thrombin is yet still unknown. In this review, we highlight the hemostatic and non-hemostatic functions of thrombin, and specifically focus on the non-hemostatic dual role of thrombin under various conditions and in relation to cardiovascular disease. PMID- 27513694 TI - Coinage Metal Pyrazolates [(3,5-(CF3)2Pz)M]3 (M = Au, Ag, Cu) as Buckycatchers. AB - The synthesis and characterization of supramolecular assemblies {C60[M3]4}infinity consisting of C60 and coinage metal pyrazolates [M3] (i.e., [(3,5-(CF3)2Pz)M]3, where Pz = pyrazolate and M = Au, Ag, and Cu) are reported. {C60[Cu3]4}infinity, {C60[Ag3]4}infinity and {C60[Au3]4}infinity form isomorphous crystals. The [M3] moieties adopt a concave conformation to complement the convex C60 surface. They exist as dimers of trimers (i.e., hexanuclear [M3]2 units) that are held together by three close M...M metallophilic interactions at 3.1580(17), 3.2046(7), and 3.2631(7) A for copper, silver, and gold systems, respectively. The [M3]2 moieties surround each C60 in a tetrahedral fashion, while each [M3]2 is sandwiched by two C60 molecules to form a supramolecular 3D assembly. PMID- 27513693 TI - Cannabinoid receptor interacting protein suppresses agonist-driven CB1 receptor internalization and regulates receptor replenishment in an agonist-biased manner. AB - Cannabinoid receptor interacting protein 1a (CRIP1a) is a CB1 receptor (CB1 R) distal C-terminus-associated protein that modulates CB1 R signaling via G proteins, and CB1 R down-regulation but not desensitization (Blume et al. [2015] Cell Signal., 27, 716-726; Smith et al. [2015] Mol. Pharmacol., 87, 747-765). In this study, we determined the involvement of CRIP1a in CB1 R plasma membrane trafficking. To follow the effects of agonists and antagonists on cell surface CB1 Rs, we utilized the genetically homogeneous cloned neuronal cell line N18TG2, which endogenously expresses both CB1 R and CRIP1a, and exhibits a well characterized endocannabinoid signaling system. We developed stable CRIP1a-over expressing and CRIP1a-siRNA-silenced knockdown clones to investigate gene dose effects of CRIP1a on CB1 R plasma membrane expression. Results indicate that CP55940 or WIN55212-2 (10 nM, 5 min) reduced cell surface CB1 R by a dynamin- and clathrin-dependent process, and this was attenuated by CRIP1a over-expression. CP55940-mediated cell surface CB1 R loss was followed by a cycloheximide sensitive recovery of surface receptors (30-120 min), suggesting the requirement for new protein synthesis. In contrast, WIN55212-2-mediated cell surface CB1 Rs recovered only in CRIP1a knockdown cells. Changes in CRIP1a expression levels did not affect a transient rimonabant (10 nM)-mediated increase in cell surface CB1 Rs, which is postulated to be as a result of rimonabant effects on 'non-agonist driven' internalization. These studies demonstrate a novel role for CRIP1a in agonist-driven CB1 R cell surface regulation postulated to occur by two mechanisms: 1) attenuating internalization that is agonist-mediated, but not that in the absence of exogenous agonists, and 2) biased agonist-dependent trafficking of de novo synthesized receptor to the cell surface. PMID- 27513695 TI - Age, Sex, Health Insurance, and Race Associated With Increased Rate of Emergent Pediatric Gastrointestinal Procedures. AB - OBJECTIVES: Few studies have examined the role health disparities play in pediatric gastrointestinal (GI) procedures. We hypothesized that health disparity factors affect whether patients undergo an emergent versus nonemergent GI procedure. The aims were to characterize the existing pediatric population undergoing GI procedures at our institution and assess specific risk factors associated with emergent versus nonemergent care. METHODS: We retrospectively reviewed the medical records of 2110 patients undergoing GI procedures from January 2012 to December 2014. Emergent procedures were performed on an urgent inpatient basis. All other procedures were considered nonemergent. Health disparity factors analyzed included age, sex, insurance type, race, and language. Logistic regression analysis identified the odds of undergoing emergent procedures for each factor. RESULTS: Most study patients were boys (58.2%), primarily insured by Medicaid (63.8%), white (44.0%), and spoke English (91.7%). Ten percent of all patients had an emergent procedure. Logistic regression analysis showed significant odds ratios (P value) for ages 18 years older (2.16, 0.003), females (0.62, 0.001), commercial insurance users (0.49, <0.0001), African Americans (1.94, <0.0001), and other race (1.72, 0.039). CONCLUSIONS: Health disparities in age, sex, insurance, and race appear to exist in this pediatric population undergoing GI procedures. Patients older than 18 years, African Americans, and other races were significantly more likely to have an emergent procedure. Girls and commercial insurance users were significantly less likely to have an emergent procedure. More research is necessary to understand why these relations exist and how to establish appropriate interventions. PMID- 27513696 TI - Normograms for the Extrahepatic Bile Duct Diameter in Children. AB - OBJECTIVE: The normal diameter of the extrahepatic bile duct (EHD) in children has been poorly studied. Prior studies have enrolled small subject numbers, have studied only specific pediatric age groups, or have potential bias due to loosely defined exclusion criteria. We sought to establish parameters for the normal diameter of the EHD in children from birth to late adolescence, including premature infants. METHODS: A 121/2-month institutional review board-approved, Health Insurance Portability and Accountability Act-compliant, retrospective chart review of all transabdominal ultrasounds performed on children (younger than 18 years) was conducted at a single pediatric tertiary referral center. Exclusion criteria included a past medical history of any pancreaticobiliary or hepatology disorder. New abnormal findings related to the liver, biliary system, or pancreas were also excluded. Recorded EHD measurements from review of the radiology reports were compiled. Estimated mean and 95% prediction intervals of EHD were calculated and reported for 6 nonoverlapping pediatric age groups. RESULTS: A total of 1016 ultrasounds on unique patients were included within the study. Estimated mean values and calculated 95% prediction intervals (in parentheses) for the diameter of the EHD were prematurity, 0.7 (0.3-1.7) mm; 0 to 2 months, 1.0 (0.4-2.3) mm; 3 to 11 months, 1.2 (0.5-2.9) mm; 1 to 4 years, 1.4 (0.6-3.3) mm; 5 to 12 years, 1.9 (0.8-4.3) mm; 13 to 17 years, 2.3 (1.0-5.2) mm. CONCLUSIONS: Our derived data of normal predicted parameters of the EHD diameter in children of all age groups will help guide clinicians in identifying those patients outside the norm that may benefit from additional testing. PMID- 27513697 TI - Insurance Among Young Adults With Inflammatory Bowel Disease: Changes Under the Affordable Care Act Dependent Provision. AB - BACKGROUND: A total of 20% to 30% of patients with inflammatory bowel disease (IBD) present before age 18 years, eventually requiring transfer to adult care. Vulnerability during transfer may be exacerbated by loss of insurance. A provision of the Affordable Care Act (ACA) allows young adults (YAs) to remain on parental private insurance through age 25 years. There has been a decrease in uninsured YAs since its implementation in 2010. Little is known about whether insurance coverage of YAs with IBD has been affected. OBJECTIVE: The aim of the present study was to determine whether the proportion of uninsured YAs with IBD has changed following the implementation of extended dependent eligibility under the ACA. METHODS: We conducted a cross-sectional analysis of hospitalized patients with IBD, identified in the Nationwide Inpatient Sample (NIS) using diagnostic codes, to estimate proportions of insurance coverage during the years 2006-2013. We compared 19 to 25 year olds to 2 to 18 and 26 to 35 year olds, unaffected by the provision, to account for underlying trends. RESULTS: From 2006 to 2010, 19 to 25 year olds had the highest proportion of uninsured, peaking at 14.1% in 2010. In 2011, the proportion decreased to 10.1%, below the proportion of uninsured 26 to 35 year olds (13.1%), remaining in this range through 2013. Private coverage increased in 2011 for 19 to 25 year olds, remaining stable for 26 to 35 year olds. DISCUSSION: Previous research cited 5% uninsured among all hospitalized patients with IBD. Our study indicates a higher proportion for YAs, decreasing after the ACA. Lack of insurance increases vulnerability during transfer but may be modifiable through policy change. Furthermore, research should analyze the effects of Medicaid expansion and health care exchanges. PMID- 27513698 TI - Into the Light: Reflections on Whole-Systems Research After a Case Series Finds Reversal of Alzheimer's. PMID- 27513699 TI - Evidence That Dry Needling Is the Intent to Bypass Regulation to Practice Acupuncture in the United States. PMID- 27513700 TI - Use of the Nosyl Group as a Functional Protecting Group in Applications of a Michael/Smiles Tandem Process. AB - Concise preparations of elaborated polycyclic and heterocyclic systems present in natural products were obtained using the nosyl group as a functional protecting group not only to mask the reactivity of a sensitive moiety but also to provide a structure desired in the final target. The group is transferred to the substrate during deprotection through a novel extension of the Truce-Smiles rearrangement in tandem with a 1,4-addition. This strategy provides access to a ring system laden with valuable functionalities for subsequent manipulations and can serve as a versatile building block for the construction of more complex molecular architectures such as indoles in a manner compatible with the concepts of green chemistry and atom economy. PMID- 27513701 TI - High occurrence of rhinitis symptoms in hairdressing apprentices. AB - BACKGROUND: Little is known about the occurrence of respiratory symptoms among hairdressing apprentices during their training. Therefore, in this study, we examined whether hairdressing apprentices are at increased risk of rhinitis and asthma symptoms when compared with other young adults from the general population. METHODS: A questionnaire was completed by 504 hairdressing apprentices and 1400 control participants from the general population with a similar age, gender, and geographic distribution. RESULTS: The 1-year prevalence of rhinitis symptoms was higher in hairdressing apprentices than in controls (58.1% vs 46.6%; odds ratio, 1.59; 95% confidence interval, 1.30-1.98), and the prevalence was higher among hairdressing apprentices in the last years of training compared with apprentices in the first year of training (62.4% vs 41.8%, p = 0.003). Current smoking was more common in hairdressing apprentices (28.4% vs 17.2%, p < 0.001). Asthma symptoms were equally common in the 2 groups; however, hairdressing apprentices had a later age of onset of wheezing than did the controls (18 years vs 14 years, p < 0.00001) and a decreased risk of wheezing (odds ratio, 0.72; 95% confidence interval, 0.54 to 0.95) after adjusting for smoking, education level, and degree of rurality. Bleaching products were the most frequently reported cause of rhinitis and asthma symptoms in hairdressing apprentices. CONCLUSIONS: Hairdressing apprentices seem to have an increased risk of occupational rhinitis, and bleaching products are the main cause of respiratory symptoms. In addition, our findings suggest that a healthy worker effect exists in relation to asthma among hairdressing apprentices. PMID- 27513702 TI - Melatonin as add-on treatment for epilepsy. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 6, 2012.Epilepsy is one of the most common chronic neurological disorders. Despite the plethora of antiepileptic drugs (AEDs) currently available, 30% of people continue having seizures. This group of people requires a more aggressive treatment, since monotherapy, the first choice scheme, fails to control seizures. Nevertheless, polytherapy often results in a number of unwanted effects, including neurological disturbances (somnolence, ataxia, dizziness), psychiatric and behavioural symptoms, and metabolic alteration (osteoporosis, inducement or inhibition of hepatic enzymes, etc.). The need for better tolerated AEDs is even more urgent in this group of people. Reports have suggested an antiepileptic role of melatonin with a good safety profile. OBJECTIVES: To assess the efficacy and tolerability of melatonin as add-on treatment for epilepsy. SEARCH METHODS: For the latest update, we searched the Cochrane Epilepsy Group's Specialized Register (12 January 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 12 January 2016), and MEDLINE (Ovid, 11 January 2016). We searched the bibliographies of any identified study for further references. We handsearched selected journals and conference proceedings. We applied no language restrictions. In addition, we contacted melatonin manufacturers (i.e. Nathura) and original investigators to identify any unpublished studies. SELECTION CRITERIA: Randomized controlled trials; double, single, or unblinded trials; parallel group or cross-over studies. People with epilepsy regardless of age and gender, including children and adults with disabilities. Administration of melatonin as add-on treatment to any AED(s) compared to add-on placebo or no add on treatment. DATA COLLECTION AND ANALYSIS: Review authors independently selected trials for inclusion according to pre-defined criteria, extracted relevant data, and evaluated the methodological quality of trials. We assessed the following outcomes: at least 50% seizure reduction, seizure freedom, adverse events, and quality of life. MAIN RESULTS: We included six publications, with 125 participants (106 aged under 18 years). Two different comparisons were available: melatonin versus placebo and melatonin 5 mg versus melatonin 10 mg. Despite our primary intention, due to insufficient information on outcomes, we were unable to perform any meta-analyses, but summarized data narratively. Four studies were randomized, double-blind, cross-over, placebo-controlled trials and two were randomized, double-blind, parallel, placebo-controlled trials. Only two studies provided the exact number of seizures during the trial compared to the baseline: none of the participants with seizures during the trial had a change in seizure frequency compared with the baseline. Two studies systematically evaluated adverse effects (worsening of headache was reported in a child with migraine under melatonin treatment). Only one study systematically evaluated quality of life, showing no statistically significant improvement in quality of life in the add-on melatonin group. AUTHORS' CONCLUSIONS: Included studies were of poor methodological quality, and did not systematically evaluate seizure frequency and adverse events, so that it was impossible to summarize data in a meta-analysis. It is not possible to draw any conclusion about the role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy. PMID- 27513703 TI - Surgical management of petrous apex cholesterol granulomas by an infralabyrinthine approach: our experience with fourteen cases. PMID- 27513705 TI - Cold Sintering: A Paradigm Shift for Processing and Integration of Ceramics. AB - This paper describes a sintering technique for ceramics and ceramic-based composites, using water as a transient solvent to effect densification (i.e. sintering) at temperatures between room temperature and 200 degrees C. To emphasize the incredible reduction in sintering temperature relative to conventional thermal sintering this new approach is named the "Cold Sintering Process" (CSP). Basically CSP uses a transient aqueous environment to effect densification by a mediated dissolution-precipitation process. CSP of NaCl, alkali molybdates and V2 O5 with small concentrations of water are described in detail, but the process is extended and demonstrated for a diverse range of chemistries (oxides, carbonates, bromides, fluorides, chlorides and phosphates), multiple crystal structures, and multimaterial applications. Furthermore, the properties of selected CSP samples are demonstrated to be essentially equivalent as samples made by conventional thermal sintering. PMID- 27513706 TI - The effects of air pollution on asthma hospital admissions in Adelaide, South Australia, 2003-2013: time-series and case-crossover analyses. AB - BACKGROUND: Air pollution can have adverse health effects on asthma sufferers, but the effects vary with geographic, environmental and population characteristics. There has been no long time-series study in Australia to quantify the effects of environmental factors including pollen on asthma hospitalizations. OBJECTIVES: This study aimed to assess the seasonal impact of air pollutants and aeroallergens on the risk of asthma hospital admissions for adults and children in Adelaide, South Australia. METHODS: Data on hospital admissions, meteorological conditions, air quality and pollen counts for the period 2003-2013 were sourced. Time-series analysis and case-crossover analysis were used to assess the short-term effects of air pollution on asthma hospitalizations. For the time-series analysis, generalized log-linear quasi Poisson and negative binomial regressions were used to assess the relationships, controlling for seasonality and long-term trends using flexible spline functions. For the case-crossover analysis, conditional logistic regression was used to compute the effect estimates with time-stratified referent selection strategies. RESULTS: A total of 36,024 asthma admissions were considered. Findings indicated that the largest effects on asthma admissions related to PM2.5 , NO2 , PM10 and pollen were found in the cool season for children (0-17 years), with the 5-day cumulative effects of 30.2% (95% CI: 13.4-49.6%), 12.5% (95% CI: 6.6-18.7%), 8.3% (95% CI: 2.5-14.4%) and 4.2% (95% CI: 2.2-6.1%) increases in risk of asthma hospital admissions per 10 unit increments, respectively. The largest effect for ozone was found in the warm season for children with the 5-day cumulative effect of an 11.7% (95% CI: 5.8-17.9%) increase in risk of asthma hospital admissions per 10 ppb increment in ozone level. CONCLUSION: Findings suggest that children are more vulnerable and the associations between exposure to air pollutants and asthma hospitalizations tended to be stronger in the cool season compared to the warm season, with the exception of ozone. This study has important public health implications and provides valuable evidence for the development of policies for asthma management. PMID- 27513707 TI - (eta(4)-Butadiene)Sn(0) Complexes: A New Approach for Zero-Valent p-Block Elements Utilizing a Butadiene as a 4pi-Electron Donor. AB - Research on zero-valent p-block elements is a recent hot topic in synthetic and theoretical chemistry because of their novel electronic states having two lone pairs in both the s- and p-orbitals. It is considered that sigma-donating ligands bearing large substituents are essential to stabilize these species. Herein, we propose a new approach using butadiene as a 4pi-electron donor to stabilize zero valent group 14 elements. During our study to explore the coordination chemistry of stannacyclopentadienyl ligands, unexpected products, in which the tin atom is coordinated by a butadiene in a eta(4)-fashion, were obtained. Because butadiene is a neutral 4pi-electron donating ligand, the formal oxidation number of the tin atoms of the products should be zero, which is supported by X-ray diffraction analysis and theoretical calculations. A mechanism for the formation of the products is also described. PMID- 27513708 TI - Understanding the Early Regime of Drop Spreading. AB - We present experimental data to characterize the spreading of a liquid drop on a substrate kept submerged in another liquid medium. They reveal that drop spreading always begins in a regime dominated by drop viscosity where the spreading radius scales as r ~ t with a nonuniversal prefactor. This initial viscous regime either lasts in its entirety or switches to an intermediate inertial regime where the spreading radius grows with time following the well established inertial scaling of r ~ t(1/2). This latter case depends on the characteristic viscous length scale of the problem. In either case, the final stage of spreading, close to equilibrium, follows Tanner's law. Further experiments performed on the same substrate kept in ambient air reveal a similar trend, albeit with limited spatiotemporal resolution, showing the universal nature of the spreading behavior. It is also found that, for early times of spreading, the process is similar to coalescence of two freely suspended liquid drops, making the presence of the substrate and consequently the three-phase contact line insignificant. PMID- 27513709 TI - Spectrum of epilepsy and electroencephalogram patterns in idic (15) syndrome. AB - Previous reports summarized the seizure types occurring in patients with idic(15) syndrome. To better define this issue, we retrospectively analyzed the evolution of electroencephalogram findings and seizures in 35 patients with confirmed idic(15). Epilepsy occurred in 28 patients (80%), with a median age of onset of 3 years 3 months. The initial seizures were infantile spasms associated with a hypsarrhythmic electroencephalogram (nine patients), focal/generalized tonic (seven patients), or atypical absences (eight patients). High doses of oral steroids were given in all nine children with infantile spasms, with remission of seizures and resolution of electroencephalogram abnormalities. Among them, three were seizure free at the time of evaluation, but six later developed Lennox Gastaut syndrome or Lennox-Gastaut-like syndrome. The eight patients with atypical absences developed Lennox-Gastaut syndrome or Lennox-Gastaut-like syndrome. Epilepsy was well controlled in 32% of the patients; satisfactorily controlled (seizures reduced >75%) in 21.4%; partially controlled (seizures reduced <50%) in 10.7%; and uncontrolled in 32%. One patient was not taking any anti-epileptic drugs by his parents' choice. Fourteen percent were on monotherapy; whereas the other 82% were on polytherapy. Seizures stopped at a median age of 5 years 5 months. The interictal electroencephalogram showed slow/sharp waves, and/or biphasic spikes-polyspikes, spike/wave complexes, and an excess of fast activity mainly over the fronto-temporal areas. Epilepsy is a major clinical challenge in patients with idic(15), associated with a poor prognosis in 55%. Frontal lobe seizures are a novel finding. (c) 2016 Wiley Periodicals, Inc. PMID- 27513710 TI - Estimating healthcare costs of acute gastroenteritis and human campylobacteriosis in Switzerland. AB - Rising numbers of campylobacteriosis case notifications in Switzerland resulted in an increased attention to acute gastroenteritis (AG) in general. Patients with a laboratory-confirmed Campylobacter infection perceive their disease as severe and around 15% of these patients are hospitalized. This study aimed at estimating healthcare costs due to AG and campylobacteriosis in Switzerland. We used official health statistics, data from different studies and expert opinion for estimating individual treatment costs for patients with different illness severity and for extrapolating overall costs due to AG and campylobacteriosis. We estimated that total Swiss healthcare costs resulting from these diseases amount to ?29-45 million annually. Data suggest that patients with AG consulting a physician without a stool diagnostic test account for ?9.0-24.2 million, patients with a negative stool test result for Campylobacter spp. for ?12.3 million, patients testing positive for Campylobacter spp. for ?1.8 million and hospitalized campylobacteriosis patients for ?6.5 million/year. Healthcare costs of campylobacteriosis are high and most likely increasing in Switzerland considering that campylobacteriosis case notifications steadily increased in the past decade. Costs and potential cost savings for the healthcare system should be considered when designing sectorial and cross-sectorial interventions to reduce the burden of human campylobacteriosis in Switzerland. PMID- 27513712 TI - Spin state switching of metal complexes by visible light or hard X-rays. AB - Electromagnetic stimuli of spin crossover compounds restricted to UV-vis light irradiation for many years could be recently extended to X-ray excitation. This review covers a large variety of light-induced effects, as well as recent analogues stimulated by X-ray irradiation which have not yet been reviewed. The focus is also on multistable multinuclear spin crossover compounds which are the subject of lively discussions within the spin crossover community. Their spin transition often occurs incompletely and with different switching mechanisms. In this review, we recall a predicted sequential switching induced thermally as well as a concerted stimulation mechanism by light irradiation for these interesting multifunctional materials. PMID- 27513713 TI - Minor neurological dysfunction in five year old very preterm children is associated with lower processing speed. AB - BACKGROUND: Minor neurological dysfunction (MND) is present in one quarter to one third of children born very preterm (VP). The more severe form, complex (c)-MND has been associated with learning disabilities, behavioural and motor problems. OBJECTIVE: To study the association between c-MND and neurocognitive and motor disabilities at age five in VP children without CP. METHODS: Ninety-four children born with gestational age<30weeks and/or a birth weight<1000g were assessed at five years corrected age. MND was classified according to Touwen. The Wechsler Preschool and Primary School Scale of Intelligence (WPPSI-III-NL) was used to measure intelligence. Simple reaction time, focused attention and visuomotor coordination were measured using the Amsterdam Neuropsychological Tasks, and working memory using a Digit Span Task. For motor skills the Movement Assessment Battery for children (M-ABC2) was used. RESULTS: Eighty-one percent was classified as 'normal' (no or simple (s-)-MND) and 19% as 'abnormal'(c-MND or mild CP). The abnormal group had a significantly lower processing speed quotient (PSQ), M-ABC percentile score and slower simple Reaction Time than the normal group. Verbal IQ, Performance IQ, working memory, focused attention and visuomotor coordination did not differ between groups. Exclusion of the mild CP cases (n=4) led to similar results. CONCLUSIONS: Five year old VP children with c MND have lower PSQ, slower reaction time, and poorer motor skills, than those without c-MND. Neurological examination should include identification of MND to help identify children at risk for neurocognitive disabilities. PMID- 27513714 TI - Vitamin D supplementation during pregnancy on infant anthropometric measurements and bone mass of mother-infant pairs: A randomized placebo clinical trial. AB - INTRODUCTION: Based on the essential role of vitamin D in the regulation of calcium metabolism, we evaluated the effects of 2000IUvitamin D/day in late pregnancy on infant's anthropometric measurements and bone mass parameters of mother-infant pairs. MATERIAL AND METHODS: In this randomized clinical trial, the main inclusion criteria were: aged 18 or older, no history of internal diseases and pregnancy complications, and a singleton live fetus. The intervention group received two 1000IU vitamin D3 pills (2000IU) daily from weeks 26-28 until childbirth. Maternal serum 25-hydroxyvitamin D, infants' anthropometric measurements (at birth, 4th and 8th weeks postnatal), and maternal and infant bone mass parameters were examined. RESULTS: The two groups were not statistically different in relation to baseline 25-hydroxyvitamin D concentrations. However, there was a significant difference between the study groups with regard to change in vitamin D status over time (p<0.001). In cross sectional analysis, the two groups were not different with respect to anthropometric measurements in three time points. Also, in repeated measure analysis, the two groups did not show any statistical differences concerning the infants' anthropometric measurements. The bone mass measurements of all the 28 mothers who belonged to the two study groups were not different. Finally, the bones mass measurements of the infants in the two study groups were not different. CONCLUSION: Ingestion of 2000IUvitamin D3/day during late pregnancy did not improve anthropometric measurements of infants from birth until the 8th week postnatal, nor improve the maternal and infant bone mass measurements. PMID- 27513716 TI - Review of Prosthetic Joint Infection from Listeria monocytogenes. AB - BACKGROUND: Prosthetic joint infection from Listeria monocytogenes is rare. We decided to shed light on this illness and review the reported cases to better understand its characteristics. PATIENTS AND METHODS: We conducted a comprehensive review of the English literature using PubMed. We also included one case that we had managed. RESULTS: We found 25 cases of prosthetic joint infection from L. monocytogenes reported individually and a retrospective study of 43 cases of joint and bone listerial infection, including 34 with prosthetic joint infection, conducted in France. We have described their clinical and para clinical features and tried to elaborate on the pathophysiology, treatment, and prevention. CONCLUSION: Prosthetic joint infection from L. monocytogenes is mainly late. Systemic inflammation may be absent. Although rare, it must be suspected in patients at high risk for both prosthetic joint and listerial infections. In addition, those patients must be instructed on appropriate preventive measures. PMID- 27513717 TI - Nuclear Magnetic Resonance Measurements and Electronic Structure of Pu(IV) in [(Me)4N]2PuCl6. AB - The synthesis, electronic structure, and characterization via single-crystal X ray diffraction, nuclear magnetic resonance (NMR) spectroscopy, and magnetic susceptibility of (Me4N)2PuCl6 are reported. NMR measurements were performed to both search for the direct (239)Pu resonance and to obtain local magnetic and electronic information at the Cl site through (35)Cl and (37)Cl spectra. No signature of (239)Pu NMR was observed. The temperature dependence of the Cl spectra was simulated by diagonalizing the Zeeman and quadrupolar Hamiltonians for (35)Cl, (37)Cl, and (14)N isotopes. Electronic structure calculations predict a magnetic Gamma5 triplet ground state of Pu(IV) in the crystalline electric field of the undistorted PuCl6 octahedron. A tetragonal distortion would result in a very small splitting (~20 cm(-1)) of the triplet ground state into a nonmagnetic singlet and a doublet state. The Cl shifts have an inflection point at T ~ 15 K, differing from the bulk susceptibility, indicating a nonmagnetic crystal field ground state. The Cl spin-lattice relaxation time is constant to T = 15 K, below which it rapidly increases, also supporting the nonmagnetic crystal field ground state. PMID- 27513718 TI - QuickStats: Age-Adjusted Death Rates* for Males Aged 15-44 Years, by the Five Leading Causes of Death(?) - United States, 1999 and 2014. AB - The age-adjusted death rate for males aged 15-44 years was 10% lower in 2014 (156.6 per 100,000 population) than in 1999 (174.1). Among the five leading causes of death, the age-adjusted rates for three were lower in 2014 than in 1999: cancer (from 17.1 to 12.8; 25% decline), heart disease (20.1 to 17.0; 15% decline), and homicide (15.7 to 13.8; 12% decline). The age-adjusted death rates for two of the five causes were higher in 2014 than in 1999: suicide (20.1 to 22.5; 12% increase), and unintentional injuries (from 48.7 to 51.0; 5% increase). PMID- 27513720 TI - Determination and correlation of lower limb anatomical parameters and bone age during skeletal growth (based on 1005 cases). AB - The aim of this study was to evaluate bone age and its correlation with the lower limbs' developing skeletal anatomy during growth. 1005 children and young adults were evaluated for bone age and 14 different parameters measured on lower-limb reconstructions from radiological examinations carried out with an EOS 2D/3D system in the course of routine orthopedic indicated diagnostic practice. Cervical vertebral morphology evaluation for bone age using the Hassel-Farman method, which describes six stages of maturity, was selected. Intra- and inter observer reliability tests for this method, and for the EOS 3D reconstructions were performed. Statistical analysis were performed using Spearman correlation, multiple linear regression, and t-test. The intra- and inter-observer reliability of the Hassel-Farman method and the EOS 3D lower-limb reconstruction were found to be excellent. Interestingly one bone age stage could include individuals across a 12.1 year range, and conversely individuals of the same calendar age could be of one of 3.2 different bone age stages. In the prepubertal age groups all six bone stages could be observed. Bone age revealed a stronger relationship, lower standard deviations with groups and proved to be a better discriminating variable than the calendar age by collodiaphyseal angle, femoral, and tibial torsion, femorotibial rotation, and mechanical tibiofemoral angle. Bone age is an indicator of skeletal maturity and may more accurately describe the growth of some lower limb parameters. As a result we suggest the consideration of bone age when evaluating lower-limb biomechanic-anatomical parameters. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1431-1441, 2017. PMID- 27513721 TI - Prevalence and survival benefit of adjuvant chemotherapy in stage III colon cancer patients: Comparison of overall and age-stratified results by multivariable modeling and propensity score methodology in a population-based cohort. AB - BACKGROUND: Few population-based studies have assessed the effectiveness of adjuvant chemotherapy (ACT) in stage III colon cancer patients according to age. We sought to quantify the prevalence of ACT use and the absolute and relative survival benefit of ACT overall and by age in a population-based cohort. METHODS: Stage III patients with adenocarcinoma of the colon identified by the Georgia Comprehensive Cancer Registry for the years 2000-07 were eligible (final N=3057). We utilized Poisson regression to obtain adjusted mortality rates (MR) and Cox proportional hazards models to obtain adjusted hazard ratios (HRs) for 5-year overall survival. We evaluated control of confounding by comparing HRs obtained via multivariable modeling (MM), propensity score weighting (PSW), and propensity score matching (PSM). RESULTS: Just over one-third of colon cancer patients did not receive ACT, and the proportion increased with age. Overall, receipt of ACT conferred an absolute (MR difference [No ACT rate-ACT rate] 25.4 deaths/1000 person-years [py], 95% confidence interval [CI]: 19.1-32.7 deaths/1000 py) and relative (MM HR=0.67, 95% CI: 0.59-0.76) survival benefit. The survival benefit was demonstrated across age groups. MM and propensity score methods yielded highly similar HRs. CONCLUSION: Unless contraindicated, efforts to ensure receipt of ACT for stage III colon cancer patients up to 84 years of age are needed to improve the prognosis of patients with node-positive disease. PMID- 27513722 TI - Burden of cancer attributable to tobacco smoking in member countries of the Association of Southeast Asian Nations (ASEAN), 2012. AB - BACKGROUND: Cancer is an increasing problem in ASEAN (Association of Southeast Asian Nations). Tobacco use is a well-established risk factor for many types of cancers. Evidence on burden of cancer attributable to tobacco is essential to raise public and political awareness of the negative effects of tobacco on cancer and to be used to stimulate political action aims at reducing smoking prevalence in ASEAN member countries. The objective of this study was to estimate burden of cancer attributable to tobacco smoking in ASEAN, 2012. METHODS: In this study, smoking prevalence was combined with Relative Risks (RRs) of cancer to obtain Smoking Attributable Fractions (SAFs). Cancer incidence and mortality data among individuals aged 15 years and older were derived from GLOBOCAN 2012. Fourteen types of cancer were included in the analysis. Sensitivity analyses were conducted to examine the impact of the use of alternative RRs and the use of alternative prevalence of smoking in some countries. RESULTS: The findings showed that tobacco smoking was responsible for 131,502 cancer incidence and 105,830 cancer mortality in ASEAN countries in 2012. In other words, tobacco smoking was accounted for 28.4% (43.3% in male and 8.5% in female) of cancer incidence and 30.5% (44.2% in male and 9.4% in female) of cancer mortality in ASEAN. When looking at the types of cancer, lung cancer showed the strongest association with tobacco smoking. Incidence of cancer and cancer mortality attributable to tobacco smoking varied by countries due to the differences in size of population, background risk of cancer, and prevalence of smoking in each country. According to the sensitivity analyses, RRs of lung cancer, pharynx cancer, and larynx cancer used in the estimates have significant impact on the estimates. CONCLUSIONS: As about one-third of cancer incidence and mortality in ASEAN are attributable to tobacco smoking ASEAN member countries are strongly encouraged to put in place stronger tobacco control policies and to strengthen the existing tobacco control measure in order to effectively control cancer. PMID- 27513723 TI - Energy Gap Tuning and Carrier Dynamics in Colloidal Ge1-xSnx Quantum Dots. AB - Optical transition energies and carrier dynamics in colloidally synthesized 2.0 +/- 0.8 nm Ge1-xSnx quantum dots (x = 0.055-0.236) having visible luminescence were investigated using steady-state and time-resolved photoluminescence (PL) spectroscopy supported by first-principles calculations. By changing Sn content from x = 0.055 to 0.236, experimentally determined HOMO-LUMO gap at 15 K was tuned from 1.88 to 1.61 eV. Considering the size and compositional variations, these values were consistent with theoretically calculated ones. At 15 K, time resolved PL revealed slow decay of luminescence (3-27 MUs), likely due to the recombination of spin-forbidden dark excitons and recombination of carriers trapped at surface states. Increasing Sn concentration to 23.6% led to 1 order of magnitude faster recombination. At 295 K, PL decays were 3 orders of magnitude faster (9-28 ns) owing to the thermal activation of bright excitons and carrier detrapping from surface states. PMID- 27513724 TI - Increasing flash droughts over China during the recent global warming hiatus. AB - The recent global warming slowdown or hiatus after the big El Nino event in 1997/98 raises the questions of whether terrestrial hydrological cycle is being decelerated and how do the hydrological extremes respond to the hiatus. However, the rapidly developing drought events that are termed as "flash droughts" accompanied by extreme heat, low soil moisture and high evapotranspiration (ET), occurred frequently around the world, and caused devastating impacts on crop yields and water supply. Here, we investigate the long-term trend and variability of flash droughts over China. Flash droughts are most likely to occur over humid and semi-humid regions, such as southern and northeastern China. Flash drought averaged over China increased by 109% from 1979 to 2010, and the increase was mainly due to a long term warming of temperature (50%), followed by the contributions from decreasing soil moisture and increasing ET. There was a slight drop in temperature after 1997, but the increasing trend of flash droughts was tripled. Further results indicate that the decreasing temperature was compensated by the accelerated drying trends of soil moisture and enhanced ET, leading to an acceleration of flash droughts during the warming hiatus. The anthropogenic warming in the next few decades may exacerbate future flash drought conditions in China. PMID- 27513725 TI - MicroRNA-106a suppresses proliferation, migration, and invasion of bladder cancer cells by modulating MAPK signaling, cell cycle regulators, and Ets-1-mediated MMP 2 expression. AB - Despite the clinical significance of tumorigenesis, little is known about the cellular signaling networks of microRNAs (miRs). Here we report a new finding that mir-106a regulates the proliferation, migration, and invasion of bladder cancer cells. Basal expression levels of mir-106a were significantly lower in bladder cancer cells than in normal urothelial cells. Overexpression of mir-106a suppressed the proliferation of bladder cancer cell line EJ. Transient transfection of mir-106a into EJ cells led to downregulation of ERK phosphorylation and upregulation of p38 and JNK phosphorylation over their levels in the control. Flow cytometry analysis revealed that mir-106a-transfected cells accumulated in the G1-phase of the cell cycle, and cyclin D1 and CDK6 were significantly downregulated. This G1-phase cell cycle arrest was due in part to the upregulation of p21CIP1/WAF1. In addition, mir-106a overexpression blocked the wound-healing migration and invasion of EJ cells. Furthermore, mir-106a transfection resulted in decreased expression of MMP-2 and diminished binding activity of transcription factor Ets-1 in EJ cells. Collectively, we report the novel mir-106a-mediated molecular signaling networks that regulate the proliferation, migration, and invasion of bladder cancer cells, suggesting that mir-106a may be a therapeutic target for treating advanced bladder tumors. PMID- 27513726 TI - Oil palm EgCBF3 conferred stress tolerance in transgenic tomato plants through modulation of the ethylene signaling pathway. AB - CBF/DREB1 is a group of transcription factors that are mainly involved in abiotic stress tolerance in plants. They belong to the AP2/ERF superfamily of plant specific transcription factors. A gene encoding a new member of this group was isolated from ripening oil palm fruit and designated as EgCBF3. The oil palm fruit demonstrates the characteristics of a climacteric fruit like tomato, in which ethylene has a major impact on the ripening process. A transgenic approach was used for functional characterization of the EgCBF3, using tomato as the model plant. The effects of ectopic expression of EgCBF3 were analyzed based on expression profiling of the ethylene biosynthesis-related genes, anti-freeze proteins (AFPs), abiotic stress tolerance and plant growth and development. The EgCBF3 tomatoes demonstrated altered phenotypes compared to the wild type tomatoes. Delayed leaf senescence and flowering, increased chlorophyll content and abnormal flowering were the consequences of overexpression of EgCBF3 in the transgenic tomatoes. The EgCBF3 tomatoes demonstrated enhanced abiotic stress tolerance under in vitro conditions. Further, transcript levels of ethylene biosynthesis-related genes, including three SlACSs and two SlACOs, were altered in the transgenic plants' leaves and roots compared to that in the wild type tomato plant. Among the eight AFPs studied in the wounded leaves of the EgCBF3 tomato plants, transcript levels of SlOSM-L, SlNP24, SlPR5L and SlTSRF1 decreased, while expression of the other four, SlCHI3, SlPR1, SlPR-P2 and SlLAP2, were up-regulated. These findings indicate the possible functions of EgCBF3 in plant growth and development as a regulator of ethylene biosynthesis-related and AFP genes, and as a stimulator of abiotic stress tolerance. PMID- 27513727 TI - Virus Infection of Plants Alters Pollinator Preference: A Payback for Susceptible Hosts? AB - Plant volatiles play important roles in attraction of certain pollinators and in host location by herbivorous insects. Virus infection induces changes in plant volatile emission profiles, and this can make plants more attractive to insect herbivores, such as aphids, that act as viral vectors. However, it is unknown if virus-induced alterations in volatile production affect plant-pollinator interactions. We found that volatiles emitted by cucumber mosaic virus (CMV) infected tomato (Solanum lycopersicum) and Arabidopsis thaliana plants altered the foraging behaviour of bumblebees (Bombus terrestris). Virus-induced quantitative and qualitative changes in blends of volatile organic compounds emitted by tomato plants were identified by gas chromatography-coupled mass spectrometry. Experiments with a CMV mutant unable to express the 2b RNA silencing suppressor protein and with Arabidopsis silencing mutants implicate microRNAs in regulating emission of pollinator-perceivable volatiles. In tomato, CMV infection made plants emit volatiles attractive to bumblebees. Bumblebees pollinate tomato by 'buzzing' (sonicating) the flowers, which releases pollen and enhances self-fertilization and seed production as well as pollen export. Without buzz-pollination, CMV infection decreased seed yield, but when flowers of mock inoculated and CMV-infected plants were buzz-pollinated, the increased seed yield for CMV-infected plants was similar to that for mock-inoculated plants. Increased pollinator preference can potentially increase plant reproductive success in two ways: i) as female parents, by increasing the probability that ovules are fertilized; ii) as male parents, by increasing pollen export. Mathematical modeling suggested that over a wide range of conditions in the wild, these increases to the number of offspring of infected susceptible plants resulting from increased pollinator preference could outweigh underlying strong selection pressures favoring pathogen resistance, allowing genes for disease susceptibility to persist in plant populations. We speculate that enhanced pollinator service for infected individuals in wild plant populations might provide mutual benefits to the virus and its susceptible hosts. PMID- 27513728 TI - Extrapolation of a non-linear autoregressive model of pulmonary mechanics. AB - For patients with acute respiratory distress syndrome (ARDS), mechanical ventilation (MV) is an essential therapy in the intensive care unit (ICU). Suboptimal PEEP levels in MV can cause ventilator induced lung injury, which is associated with increased mortality, extended ICU stay, and high cost. The ability to predict the outcome of respiratory mechanics in response to changes in PEEP would thus provide a critical advantage in personalising and improving care. Testing the potentially dangerous high pressures would not be required to assess their impact. A nonlinear autoregressive (NARX) model was used to predict airway pressure in 19 data sets from 10 mechanically ventilated ARDS patients. Patient specific NARX models were identified from pressure and flow data over one, two, three, or four adjacent PEEP levels in a recruitment manoeuvre. Extrapolation of NARX model elastance functions allowed prediction of patient responses to PEEP changes to higher or lower pressures. NARX model predictions were more successful than those using a well validated first order model (FOM). The most clinically important results were for extrapolation up one PEEP step of 2cmH2O from the highest PEEP in the training data. When the NARX model was trained on one PEEP level, the mean RMS residual for the extrapolation PEEP level was 0.52 (90% CI: 0.47-0.57) cmH2O, compared to 1.50 (90% CI: 1.38-1.62) cmH2O for the FOM. When trained on four PEEP levels, the NARX result was 0.50 (90% CI: 0.42-0.58) cmH2O, and was 1.95 (90% CI: 1.71-2.19) cmH2O for the FOM. The results suggest that a full recruitment manoeuvre may not be required for the NARX model to obtain a useful estimate of the pressure waveform at higher PEEP levels. The methodology could thus allow clinicians to make informed decisions about ventilator PEEP settings while reducing the risk associated with high PEEP, and subsequent high peak airway pressures. PMID- 27513730 TI - Functional differences between neonatal and adult fibroblasts and keratinocytes: Donor age affects epithelial-mesenchymal crosstalk in vitro. AB - Clinical evidence suggests that healing is faster and almost scarless at an early neonatal age in comparison with that in adults. In this study, the phenotypes of neonatal and adult dermal fibroblasts and keratinocytes (nestin, smooth muscle actin, keratin types 8, 14 and 19, and fibronectin) were compared. Furthermore, functional assays (proliferation, migration, scratch wound closure) including mutual epithelial-mesenchymal interactions were also performed to complete the series of experiments. Positivity for nestin and alpha smooth muscle actin was higher in neonatal fibroblasts (NFs) when compared with their adult counterparts (adult fibroblasts; AFs). Although the proliferation of NFs and AFs was similar, they significantly differed in their migration potential. The keratinocyte experiments revealed small, poorly differentiated cells (positive for keratins 8, 14 and 19) in primary cultures isolated from neonatal tissues. Moreover, the neonatal keratinocytes exhibited significantly faster rates of healing the experimentally induced in vitro defects in comparison with adult cells. Notably, the epithelial/mesenchymal interaction studies showed that NFs in co-culture with adult keratinocytes significantly stimulated the adult epithelial cells to acquire the phenotype of small, non-confluent cells expressing markers of poor differentiation. These results indicate the important differences between neonatal and adult cells that may be associated with improved wound healing during the early neonatal period. PMID- 27513731 TI - Hemophagocytic Lymphohistocytosis in the Chinese Han Population May Be Associated with an STXBP2 Gene Polymorphism. AB - STUDY PURPOSE: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages. In this study, we aimed to explore the genetic factors involved in the pathogenesis of both acquired and familial type HLH. METHOD: The ION TORRENT semi-conductor sequencing method was used to sequence samples from 10 patients who were diagnosed or highly suspected of HLH. Then SNP rs2303116 of STXBP2 genotyping was performed by Sanger sequencing method on samples from 24 patients with HLH and 182 normal controls. Genotype frequencies were then compared and tested by multivariate logistic regression. Finally, the potential impact of rs2303116 on splicing factor binding ability was evaluated using the ESEfinder 3.0 online tool. RESULTS: A total of 92 variants were identified in 10 HLH patients, of which 24 variants were rare variants (MAF<0.01), while the remaining 68 variants were common variants (MAF>0.01). Among them, 8 different genetic variations in the STXBP2 sequence were identified. We focused on the synonymous SNP rs2303116, as 30% of patients had CT/TT genotype. SNP genotyping was further performed on 24 HLH patients and 182 healthy control cohorts, and the results indicated a significantly elevated CT/TT genotype frequency of rs2303116 in HLH patients compared with healthy controls (patients 37.5% VS. controls 13.2%, P = 0.009, OR = 3.900, 95% CI 1.537-9.899). Multivariate logistic regression analysis indicated that being female (OR 0.350, 95% CI 0.143-0.861, P = 0.018) and of an older age (>43y, OR 0.312, 95% CI 0.118 0.822, P = 0.014) were independent protective factors, and the rs2303116 CT/TTgenotype (OR 3.900, 95% CI 1.537-9.899, P = 0.009) was an independent risk factor for HLH pathogenesis. By comparing the clinical parameters between HLH patients with CT/TT and CCgenotypes, we found that the patients with CT/TT genotype had significantly lower levels of fibrinogen, indicating more aggravated macrophage activation. In silico analysis of splice factor binding to rs2303116 CT/TT genotypes showed significant decrease for SRSF1 but increase for SRSF6, which suggested abnormal splicing machinery was associated with HLH pathogenesis. CONCLUSION: Our study demonstrated for the first time that HLH patients had significantly higher frequencies of the STXBP2 gene polymorphism rs2303116 variant compared with a healthy Chinese Han population, through clinical comparisons and further predictions we suggested regulation of alternative splicing by alleles of SNP rs2303116 could be involved in HLH pathogenesis. PMID- 27513732 TI - Seasonal variations drive short-term dynamics and partitioning of recently assimilated carbon in the foliage of adult beech and pine. AB - 13 CO2 pulse-labelling experiments were performed in situ on adult beeches (Fagus sylvatica) and pines (Pinus pinaster) at different phenological stages to study seasonal and interspecific short-term dynamics and partitioning of recently assimilated carbon (C) in leaves. Polar fraction (PF, including soluble sugars, amino acids and organic acids) and starch were purified from foliage sampled during a 10-d chase period. C contents, isotopic compositions and 13 C dynamics parameters were determined in bulk foliage, PF and starch. Decrease in 13 C amount in bulk foliage followed a two-pool exponential model highlighting 13 C partitioning between 'mobile' and 'stable' pools, the relative proportion of the latter being maximal in beech leaves in May. Early in the growing season, new foliage acted as a strong C sink in both species, but although young leaves and needles were already photosynthesizing, the latter were still supplied with previous-year needle photosynthates 2 months after budburst. Mean 13 C residence times (MRT) were minimal in summer, indicating fast photosynthate export to supply perennial organ growth in both species. In late summer, MRT differed between senescing beech leaves and overwintering pine needles. Seasonal variations of 13 C partitioning and dynamics in field-grown tree foliage are closely linked to phenological differences between deciduous and evergreen trees. PMID- 27513733 TI - Isometric Contractions Are More Analgesic Than Isotonic Contractions for Patellar Tendon Pain: An In-Season Randomized Clinical Trial. AB - OBJECTIVE: This study aimed to compare the immediate analgesic effects of 2 resistance programs in in-season athletes with patellar tendinopathy (PT). Resistance training is noninvasive, a principle stimulus for corticospinal and neuromuscular adaptation, and may be analgesic. DESIGN: Within-season randomized clinical trial. Data analysis was conducted blinded to group. SETTING: Subelite volleyball and basketball competitions. PARTICIPANTS: Twenty jumping athletes aged more than 16 years, participating in games/trainings 3 times per week with clinically diagnosed PT. INTERVENTIONS: Two quadriceps resistance protocols were compared; (1) isometric leg extension holds at 60 degrees knee flexion (80% of their maximal voluntary isometric contraction) or (2) isotonic leg extension (at 80% of their 8 repetition maximum) 4 times per week for 4 weeks. Time under load and rest between sets was matched between groups. MAIN OUTCOME MEASURES: (1) Pain (0-10 numerical rating score) during single leg decline squat (SLDS), measured preintervention and postintervention sessions. (2) VISA-P, a questionnaire about tendon pain and function, completed at baseline and after 4 weeks. RESULTS: Twenty athletes with PT (18 men, mean 22.5 +/- 4.7 years) participated (isotonic n = 10, isometric n = 10). Baseline median SLDS pain was 5/10 for both groups (isotonic range 1-8, isometric range 2-8). Isometric contractions produced significantly greater immediate analgesia (P < 0.002). Week one analgesic response positively correlated with improvements in VISA-P at 4 weeks (r = 0.64). CONCLUSIONS: Both protocols appear efficacious for in-season athletes to reduce pain, however, isometric contractions demonstrated significantly greater immediate analgesia throughout the 4-week trial. Greater analgesia may increase the ability to load or perform. PMID- 27513734 TI - 1,25-Dihydroxyvitamin D Modulates Antibacterial and Inflammatory Response in Human Cigarette Smoke-Exposed Macrophages. AB - Cigarette smoking is associated with increased inflammation and defective antibacterial responses in the airways. Interestingly, vitamin D has been shown to suppress inflammation and to improve antibacterial defense. However, it is currently unknown whether vitamin D may modulate inflammation and antibacterial defects in human cigarette smoke (CS)-exposed airways. To explore these unresolved issues, alveolar macrophages obtained from non-smoking and smoking subjects as well as human cigarette smoke extract (CSE)-treated THP-1 macrophages were stimulated with 1,25-dihydroxyvitamin D (1,25(OH)2D) to address inflammatory and antibacterial responses. Although basal levels of inflammatory cytokines and chemokines did not differ between non-smoking and smoking subjects, 1,25(OH)2D did reduce levels of IL-6, TNF-alpha and MCP-1 in alveolar macrophages in response to LPS/IFN-gamma, although not statistically significant for TNF-alpha and IL-6 in smokers. CSE did not significantly alter vitamin D metabolism (expression levels of CYP24A1 or CYP27B1) in THP-1 macrophages. Furthermore, stimulation with 1,25(OH)2D reduced mRNA expression levels and/or protein levels of IL-8, TNF-alpha and MCP-1 in CSE-treated THP-1 macrophages. 1,25(OH)2D did not improve defects in phagocytosis of E. coli bacteria or the oxidative burst response in CSE-treated THP-1 macrophages or alveolar macrophages from smokers. However, 1,25(OH)2D significantly enhanced mRNA expression and/or protein levels of the antimicrobial peptide cathelicidin in alveolar macrophages and THP-1 macrophages, independently of CS exposure. In conclusion, our results provide the first evidence that vitamin D could be a new strategy for attenuating airway inflammation and improving antibacterial defense in CS-exposed airways. PMID- 27513735 TI - Effects of water scarcity and chemical pollution in aquatic ecosystems: State of the art. AB - Water scarcity is an expanding climate and human related condition, which drives and interacts with other stressors in freshwater ecosystems such as chemical pollution. In this study we provide an overview of the existing knowledge regarding the chemical fate, biological dynamics and the ecological risks of chemicals under water scarcity conditions. We evaluated a total of 15 studies dealing with the combined effects of chemicals and water scarcity under laboratory conditions and in the field. The results of these studies have been elaborated in order to evaluate additive, synergistic or antagonistic responses of the studied endpoints. As a general rule, it can be concluded that, in situations of water scarcity, the impacts of extreme water fluctuations are much more relevant than those of an additional chemical stressor. Nevertheless, the presence of chemical pollution may result in exacerbated ecological risks in some particular cases. We conclude that further investigations on this topic would take advantage on the focus on some specific issues. Experimental (laboratory and model ecosystem) studies should be performed on different biota groups and life stages (diapausing eggs, immature stages), with particular attention to those including traits relevant for the adaptation to water scarcity. More knowledge on species adaptations and recovery capacity is essential to predict community responses to multiple stressors and to assess the community vulnerability. Field studies should be performed at different scales, particularly in lotic systems, in order to integrate different functional dynamics of the river ecosystem. Combining field monitoring and experimental studies would be the best option to reach more conclusive, causal relationships on the effects of co-occurring stressors. Contribution of these studies to develop ecological models and scenarios is also suggested as an improvement for the prospective aquatic risk assessment of chemicals in (semi-)arid areas. PMID- 27513736 TI - Self-Enhanced Ultrasensitive Photoelectrochemical Biosensor Based on Nanocapsule Packaging Both Donor-Acceptor-Type Photoactive Material and Its Sensitizer. AB - In this work, a self-enhanced ultrasensitive photoelectrochemical (PEC) biosensor was established based on a functionalized nanocapsule packaging both donor acceptor-type photoactive material and its sensitizer. The functionalized nanocapsule with self-enhanced PEC responses was achieved first by packaging both the donor-acceptor-type photoactive material (poly{4,8-bis[5-(2 ethylhexyl)thiophen-2-yl]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl-alt-3-fluoro-2 [(2-ethylhexyl)carbonyl]thieno[3,4-b]thiophene-4,6-diyl}, PTB7-Th) and its sensitizer (nano-C60, fullerene) in poly(ethylene glycol) (PEG) to form a nanocapsule, which significantly enhanced PEC signal and stability of the PEC biosensor. Moreover, a quadratic enzymes-assisted target recycling amplification strategy was introduced to the system for ultrasensitive determination. Compared with other established PEC biosensors, our proposed self-enhanced approach showed higher effectivity, accuracy, sensitivity, and convenience without any addition of coreactant or sensitizers into the testing electrolyte for photocurrent amplification and performed excellent analytical properties for microRNA estimation down to femtomole level with microRNA-141 as a model. Additionally, the proposed PEC biosensor was employed for estimation of microRNA in different cancer cells and pharmacodynamic evaluation in cancer cells. This self-enhanced PEC strategy has laid the foundation for fabrication of simple, effective, and ultrasensitive PEC diagnostic devices, leading to the possibility for early diagnosis, timely stage estimation, and accurate prognosis judgment of disease. PMID- 27513737 TI - Simulation of a Real-Time Brain Computer Interface for Detecting a Self-Paced Hitting Task. AB - OBJECTIVES: An invasive brain-computer interface (BCI) is a promising neurorehabilitation device for severely disabled patients. Although some systems have been shown to work well in restricted laboratory settings, their utility must be tested in less controlled, real-time environments. Our objective was to investigate whether a specific motor task could be reliably detected from multiunit intracortical signals from freely moving animals in a simulated, real time setting. MATERIALS AND METHODS: Intracortical signals were first obtained from electrodes placed in the primary motor cortex of four rats that were trained to hit a retractable paddle (defined as a "Hit"). In the simulated real-time setting, the signal-to-noise-ratio was first increased by wavelet denoising. Action potentials were detected, and features were extracted (spike count, mean absolute values, entropy, and combination of these features) within pre-defined time windows (200 ms, 300 ms, and 400 ms) to classify the occurrence of a "Hit." RESULTS: We found higher detection accuracy of a "Hit" (73.1%, 73.4%, and 67.9% for the three window sizes, respectively) when the decision was made based on a combination of features rather than on a single feature. However, the duration of the window length was not statistically significant (p = 0.5). CONCLUSION: Our results showed the feasibility of detecting a motor task in real time in a less restricted environment compared to environments commonly applied within invasive BCI research, and they showed the feasibility of using information extracted from multiunit recordings, thereby avoiding the time-consuming and complex task of extracting and sorting single units. PMID- 27513738 TI - A multi-resolution investigation for postural transition detection and quantification using a single wearable. AB - BACKGROUND: Multi-resolution analyses involving wavelets are commonly applied to data derived from accelerometer-based wearable technologies (wearables) to identify and quantify postural transitions (PTs). Previous studies fail to provide rationale to inform their choice of wavelet and scale approximation when utilising discrete wavelet transforms. This study examines varying combinations of those parameters to identify best practice recommendations for detecting and quantifying sit-to-stand (SiSt) and stand-to-sit (StSi) PTs. METHODS: 39 young and 37 older participants completed three SiSt and StSi PTs on supported and unsupported chair types while wearing a single tri-axial accelerometer-based wearable on the lower back. Transition detection and duration were calculated through peak detection within the signal vector magnitude for a range of wavelets and scale approximations. A laboratory reference measure (2D video) was used for comparative analysis. RESULTS: Detection accuracy of wavelet and scale combinations for the transitions was excellent for both SiSt (87-97%) and StSi (82-86%) PT-types. The duration of PTs derived from the wearable showed considerable bias and poor agreement compared with the reference videos. No differences were observed between chair types and age groups respectively. CONCLUSIONS: Improved detection of PTs could be achieved through the incorporation of different wavelet and scale combinations for the assessment of specific PT types in clinical and free-living settings. An upper threshold of 5th scale approximations is advocated for improved detection of multiple PT-types. However, care should be taken estimating the duration of PTs using wearables. PMID- 27513739 TI - Gait six month and one-year after computer assisted Femur First THR vs. conventional THR. Results of a patient- and observer- blinded randomized controlled trial. AB - A prospective randomized controlled trial is presented that is used to compare gait performance between the computer assisted Femur First (CAS FF) operation method and conventional THR (CON). 60 patients underwent a 3D gait analysis of the lower extremity at pre-operative, 6 months post-operative and twelve months post-operative. Detailed verification experiments were facilitated to ensure the quality of data as well as to avoid over-interpreting of the data. The results confirm a similar data-quality as reported in the literature. Walking speed, range of motion and symmetry thereof improved over the follow-up period, without significant differences between the groups. While all parameters do significantly increase over the follow-up period for both groups, there were no significant differences between them at any given time-point. Patients undergoing CAS FF showed a trend to improved hip flexion angle indicating a possible long-term benefit. PMID- 27513740 TI - The rotational profile: A study of lower limb axial torsion, hip rotation, and the foot progression angle in healthy adults. AB - The purpose of this study was to compare the rotational profile of adults with higher versus lower foot progression angles (FPA). Tibial torsion, femoral torsion, hip internal and external rotation and FPA data were collected on one hundred two healthy volunteers. Data were stratified into Low, Mid, and High FPA groups to study relationships among the components of the rotational profile and if there were group differences in the magnitude of torsion angles. Direction of torsion was also studied as an attempt to look at the incidence of offsetting between the tibia and femur. Tibial torsion was significantly higher in the High FPA group (p<0.001) and was significantly related to the FPA (p<=0.01). Femoral torsion was related to hip internal rotation (p<0.05). Offsetting tibial and femoral torsions occurred in 59% of subjects with low FPA and 56% of subjects with high FPA. All subjects in the low FPA group with offsetting had tibial torsion that followed the FPA and the femurs that were directed opposite. In the High FPA group, 68% of subjects with offsetting had tibias that followed the FPA. Stratifying the data by FPA revealed there were significant differences in tibial torsion among the groups and provided evidence that tibial torsion influences the direction and magnitude of the FPA. Offsetting torsions between the tibia and femur were more common in people with higher and lower FPA and had clearer patterns where the tibia tended to follow the direction of the FPA. PMID- 27513741 TI - Anxiety is associated with freezing of gait and attentional set-shifting in Parkinson's disease: A new perspective for early intervention. AB - Previous research has shown that anxiety in Parkinson's disease (PD) is associated with freezing of gait (FOG), and may even contribute to the underlying mechanism. However, limited research has investigated whether PD patients with FOG (PD+FOG) have higher anxiety levels when compared directly to non-freezing PD patients (PD-NF) and moreover, how anxiety might contribute to FOG. The current study evaluated whether: (i) PD+FOG have greater anxiety compared to PD-NF, and (ii) anxiety in PD is related to attentional set-shifting, in order to better understand how anxiety might be contributing to FOG. In addition, we explored whether anxiety levels differed between those PD patients with mild FOG (PD+MildFOG) compared to PD-NF. Four hundred and sixty-one patients with PD (231 PD-NF, 180 PD+FOG, 50 PD+MildFOG) were assessed using the Freezing of Gait Questionnaire item 3 (FOG-Q3), Hospital Anxiety and Depression Scale (HADS), Digit Span Test, Logical Memory Retention Test and Trail Making Tests. Compared to PD-NF, PD+FOG had significantly greater anxiety (p<0.001). PD+MildFOG, however, demonstrated similar levels of anxiety as the PD+FOG. In all patients, the severity of anxiety symptoms was significantly correlated to their degree of self-reported FOG on FOG-Q3 (p<0.001) and TMT B-A (p=0.039). Similar results were found for depression. In conclusion, these results confirm the key role played by anxiety in FOG and also suggest that anxiety might be a promising biomarker for FOG. Future research should consider whether treating anxiety with pharmacological and/or cognitive behavioural therapies at early stages of gait impairment in PD may alleviate troublesome FOG. PMID- 27513742 TI - Xenopsylla brasiliensis Fleas in Plague Focus Areas, Madagascar. PMID- 27513743 TI - Chronic Inhibition of STAT3/STAT5 in Treatment-Resistant Human Breast Cancer Cell Subtypes: Convergence on the ROS/SUMO Pathway and Its Effects on xCT Expression and System xc- Activity. AB - Pharmacologically targeting activated STAT3 and/or STAT5 has been an active area of cancer research. The cystine/glutamate antiporter, system xc-, contributes to redox balance and export of intracellularly produced glutamate in response to up regulated glutaminolysis in cancer cells. We have previously shown that blocking STAT3/5 using the small molecule inhibitor, SH-4-54, which targets the SH2 domains of both proteins, increases xCT expression, thereby increasing system xc- activity in human breast cancer cells. The current investigation demonstrates that chronic SH-4-54 administration, followed by clonal selection of treatment resistant MDA-MB-231 and T47D breast cancer cells, elicits distinct subtype dependent effects. xCT mRNA and protein levels, glutamate release, and cystine uptake are decreased relative to untreated passage-matched controls in triple negative MDA-MB-231 cells, with the inverse occurring in estrogen-responsive T47D cells. This "ying-yang" effect is linked with a shifted balance between the phosphorylation status of STAT3 and STAT5, intracellular ROS levels, and STAT5 SUMOylation/de-SUMOylation. STAT5 emerged as a definitive negative regulator of xCT at the transcriptional level, while STAT3 activation is coupled with increased system xc- activity. We propose that careful classification of a patient's breast cancer subtype is central to effectively targeting STAT3/5 as a therapeutic means of treating breast cancer, particularly given that xCT is emerging as an important biomarker of aggressive cancers. PMID- 27513744 TI - Assessing Finger Joint Biomechanics by Applying Equal Force to Flexor Tendons In Vitro Using a Novel Simultaneous Approach. AB - BACKGROUND: The flexor digitorum superficialis (FDS) and flexor digitorum profundus (FDP) are critical for finger flexion. Although research has recently focused on these tendons' coactivity, their contributions in different tasks remain unclear. This study created a novel simultaneous approach to investigate the coactivity between the tendons and to clarify their contributions in different tasks. METHODS: Ten human cadaveric hands were mounted on our custom frame with the FDS and FDP of the third finger looped through a mechanical pulley connected to a force transducer. Joint range of motion, tendon excursion and loading force were recorded during individual joint motion and free joint movement from rest to maximal flexion. Each flexor tendon's moment arm was then calculated. RESULTS: In individual motions, we found that the FDP contributed more than the FDS in proximal interphalangeal (PIP) joint motion, with an overall slope of 1.34 and all FDP-to-FDS excursion (P/S) ratios greater than 1.0 with force increase. However, the FDP contributed less than the FDS in metacarpophalangeal (MCP) joint motion, with an overall slope of 0.95 and P/S ratios smaller than 1.0 throughout the whole motion except between 1.9% and 13.1% force. In free joint movement, the FDP played a greater role than the FDS, with an overall ratio of 1.37 and all P/S ratios greater than 1.0. CONCLUSIONS: The new findings include differences in finger performance and excursion amounts between the FDS and FDP throughout flexion. Such findings may provide the basis for new hand models and treatments. PMID- 27513745 TI - Correction: Hydrophobic Core Variations Provide a Structural Framework for Tyrosine Kinase Evolution and Functional Specialization. AB - [This corrects the article DOI: 10.1371/journal.pgen.1005885.]. PMID- 27513746 TI - Microstructural Correlates of Emotional Attribution Impairment in Non-Demented Patients with Amyotrophic Lateral Sclerosis. AB - Impairments in the ability to recognize and attribute emotional states to others have been described in amyotrophic lateral sclerosis patients and linked to the dysfunction of key nodes of the emotional empathy network. Microstructural correlates of such disorders are still unexplored. We investigated the white matter substrates of emotional attribution deficits in a sample of amyotrophic lateral sclerosis patients without cognitive decline. Thirteen individuals with either probable or definite amyotrophic lateral sclerosis and 14 healthy controls were enrolled in a Diffusion Tensor Imaging study and administered the Story based Empathy Task, assessing the ability to attribute mental states to others (i.e., Intention and Emotion attribution conditions). As already reported, a significant global reduction of empathic skills, mainly driven by a failure in Emotion Attribution condition, was found in amyotrophic lateral sclerosis patients compared to healthy subjects. The severity of this deficit was significantly correlated with fractional anisotropy along the forceps minor, genu of corpus callosum, right uncinate and inferior fronto-occipital fasciculi. The involvement of frontal commissural fiber tracts and right ventral associative fronto-limbic pathways is the microstructural hallmark of the impairment of high order processing of socio-emotional stimuli in amyotrophic lateral sclerosis. These results support the notion of the neurofunctional and neuroanatomical continuum between amyotrophic lateral sclerosis and frontotemporal dementia. PMID- 27513747 TI - Antiglycation and Antioxidant Properties of Momordica charantia. AB - The accumulation of advanced glycation endproducts (AGEs) and oxidative stress underlie the pathogenesis of diabetic complications. In many developing countries, diabetes treatment is unaffordable, and plants such as bitter gourd (or bitter melon; Momordica charantia) are used as traditional remedies because they exhibit hypoglycaemic properties. This study compared the antiglycation and antioxidant properties of aqueous extracts of M. charantia pulp (MCP), flesh (MCF) and charantin in vitro. Lysozyme was mixed with methylglyoxal and 0-15 mg/ml of M. charantia extracts in a pH 7.4 buffer and incubated at 37 degrees C for 3 days. Crosslinked AGEs were assessed using gel electrophoresis, and the carboxymethyllysine (CML) content was analyzed by enzyme-linked immunosorbent assays. The antioxidant activities of the extracts were evaluated using assays to assess DPPH (1,1-diphenyl-2-picryl-hydrazyl) and hydroxyl radical scavenging activities, metal-chelating activity and reducing power of the extracts. The phenolic, flavonol and flavonoid content of the extracts were also determined. All extracts inhibited the formation of crosslinked AGEs and CML in a dose dependent manner, with MCF being the most potent. The antioxidant activity of MCF was higher than that of MCP, but MCP showed the highest metal-chelating activity. MCF had the highest phenolic and flavonoid contents, whereas MCP had the highest flavonol content. M. charantia has hypoglycaemic effects, but this study shows that M. charantia extracts are also capable of preventing AGE formation in vitro. This activity may be due to the antioxidant properties, particularly the total phenolic content of the extracts. Thus, the use of M. charantia deserves more attention, as it may not only reduce hyperglycaemia but also protect against the build-up of tissue AGEs and reduce oxidative stress in patients with diabetes. PMID- 27513748 TI - The Integration of Epistasis Network and Functional Interactions in a GWAS Implicates RXR Pathway Genes in the Immune Response to Smallpox Vaccine. AB - Although many diseases and traits show large heritability, few genetic variants have been found to strongly separate phenotype groups by genotype. Complex regulatory networks of variants and expression of multiple genes lead to small individual-variant effects and difficulty replicating the effect of any single variant in an affected pathway. Interaction network modeling of GWAS identifies effects ignored by univariate models, but population differences may still cause specific genes to not replicate. Integrative network models may help detect indirect effects of variants in the underlying biological pathway. In this study, we used gene-level functional interaction information from the Integrative Multi species Prediction (IMP) tool to reveal important genes associated with a complex phenotype through evidence from epistasis networks and pathway enrichment. We test this method for augmenting variant-based network analyses with functional interactions by applying it to a smallpox vaccine immune response GWAS. The integrative analysis spotlights the role of genes related to retinoid X receptor alpha (RXRA), which has been implicated in a previous epistasis network analysis of smallpox vaccine. PMID- 27513749 TI - Comparison of Statistical Algorithms for the Detection of Infectious Disease Outbreaks in Large Multiple Surveillance Systems. AB - A large-scale multiple surveillance system for infectious disease outbreaks has been in operation in England and Wales since the early 1990s. Changes to the statistical algorithm at the heart of the system were proposed and the purpose of this paper is to compare two new algorithms with the original algorithm. Test data to evaluate performance are created from weekly counts of the number of cases of each of more than 2000 diseases over a twenty-year period. The time series of each disease is separated into one series giving the baseline (background) disease incidence and a second series giving disease outbreaks. One series is shifted forward by twelve months and the two are then recombined, giving a realistic series in which it is known where outbreaks have been added. The metrics used to evaluate performance include a scoring rule that appropriately balances sensitivity against specificity and is sensitive to variation in probabilities near 1. In the context of disease surveillance, a scoring rule can be adapted to reflect the size of outbreaks and this was done. Results indicate that the two new algorithms are comparable to each other and better than the algorithm they were designed to replace. PMID- 27513750 TI - Cadmium Exposure Enhances Bisphenol A-Induced Genotoxicity through 8-Oxoguanine DNA Glycosylase-1 OGG1 Inhibition in NIH3T3 Fibroblast Cells. AB - BACKGROUND: Both cadmium (Cd) and bisphenol A (BPA) are commonly encountered in humans' daily activities, but their combined genotoxic effects remain unclear. METHODS: In the present study, we exposed a mouse embryonic fibroblast cell line (NIH3T3) to Cd for 24 h, followed by a 24 h BPA exposure to evaluate toxicity. The cytotoxicity was evaluated by viability with CCK-8 assay and lactate dehydrogenase (LDH) release. Reactive oxygen species (ROS) production was measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA). And DNA damage was measured by 8-hydroxydeoxyguanosine (8-OHdG), phosphorylated H2AX (gammaH2AX) and the comet assay. The flow cytometry was used to detect cell cycle distribution, and apoptosis was determined by TUNEL assay and western blot against poly-ADP ribose polymerase (PARP). RESULTS: The results showed that Cd or BPA treatments alone (with the exception of BPA exposure at 50 MUM) did not alter cell viability. However, pre-treatment with Cd aggravated the BPA-induced reduction in cell viability; increased BPA-induced LDH release, ROS production, DNA damage and G2 phase arrest; and elevated BPA-induced TUNEL-positive cells and the expression levels of cleaved PARP. Cd exposure concurrently decreased the expression of 8 oxoguanine-DNA glycosylase-1 (OGG1), whereas OGG1 over-expression abolished the enhancement of Cd on BPA-induced genotoxicity and cytotoxicity. CONCLUSION: These findings indicate that Cd exposure aggravates BPA-induced genotoxicity and cytotoxicity through OGG1 inhibition. PMID- 27513751 TI - Genetic Structure of Modern Durum Wheat Cultivars and Mediterranean Landraces Matches with Their Agronomic Performance. AB - A collection of 172 durum wheat landraces from 21 Mediterranean countries and 20 modern cultivars were phenotyped in 6 environments for 14 traits including phenology, biomass, yield and yield components. The genetic structure of the collection was ascertained with 44 simple sequence repeat markers that identified 448 alleles, 226 of them with a frequency lower than 5%, and 10 alleles per locus on average. In the modern cultivars all the alleles were fixed in 59% of the markers. Total genetic diversity was HT = 0.7080 and the genetic differentiation value was GST = 0.1730. STRUCTURE software allocated 90.1% of the accessions in five subpopulations, one including all modern cultivars, and the four containing landrace related to their geographic origin: eastern Mediterranean, eastern Balkans and Turkey, western Balkans and Egypt, and western Mediterranean. Mean yield of subpopulations ranged from 2.6 t ha-1 for the western Balkan and Egyptian landraces to 4.0 t ha-1 for modern cultivars, with the remaining three subpopulations showing similar values of 3.1 t ha-1. Modern cultivars had the highest number of grains m-2 and harvest index, and the shortest cycle length. The diversity was lowest in modern cultivars (HT = 0.4835) and highest in landraces from the western Balkans and Egypt (HT = 0.6979). Genetic diversity and AMOVA indicated that variability between subpopulations was much lower (17%) than variability within them (83%), though all subpopulations had similar biomass values in all growth stages. A dendrogram based on simple sequence repeat data matched with the clusters obtained by STRUCTURE, improving this classification for some accessions that have a large admixture. landraces included in the subpopulation from the eastern Balkans and Turkey were separated into two branches in the dendrogram drawn with phenotypic data, suggesting a different origin for the landraces collected in Serbia and Macedonia. The current study shows a reliable relationship between genetic and phenotypic population structures, and the connection of both with the geographic origin of the landraces. PMID- 27513752 TI - Spheno-Occipital Synchondrosis Fusion Correlates with Cervical Vertebrae Maturation. AB - The aim of this study was to determine the relationship between the closure stage of the spheno-occipital synchondrosis and the maturational stage of the cervical vertebrae (CVM) in growing and young adult subjects using cone beam computed tomography (CBCT). CBCT images with an extended field of view obtained from 315 participants (148 females and 167 males; mean age 15.6 +/-7.3 years; range 6 to 23 years) were analyzed. The fusion status of the synchondrosis was determined using a five-stage scoring system; the vertebral maturational status was evaluated using a six-stage stratification (CVM method). Ordinal regression was used to study the ability of the synchondrosis stage to predict the vertebral maturation stage. Vertebrae and synchondrosis had a strong significant correlation (r = 0.89) that essential was similar for females (r = 0.88) and males (r = 0.89). CVM stage could be accurately predicted from synchondrosis stage by ordinal regression models. Prediction equations of the vertebral stage using synchondrosis stage, sex and biological age as predictors were developed. Thus this investigation demonstrated that the stage of spheno-occipital synchondrosis, as determined in CBCT images, is a reasonable indicator of growth maturation. PMID- 27513753 TI - Basal Complex and Basal Venation of Odonata Wings: Structural Diversity and Potential Role in the Wing Deformation. AB - Dragonflies and damselflies, belonging to the order Odonata, are known to be excellent fliers with versatile flight capabilities. The ability to fly over a wide range of speeds, high manoeuvrability and great agility are a few characteristics of their flight. The architecture of the wings and their structural elements have been found to play a major role in this regard. However, the precise influence of individual wing components on the flight performance of these insects remains unknown. The design of the wing basis (so called basal complex) and the venation of this part are responsible for particular deformability and specific shape of the wing blade. However, the wing bases are rather different in representatives of different odonate groups. This presumably reflects the dimensions of the wings on one hand, and different flight characteristics on the other hand. In this article, we develop the first three dimensional (3D) finite element (FE) models of the proximal part of the wings of typical representatives of five dragonflies and damselflies families. Using a combination of the basic material properties of insect cuticle, a linear elastic material model and a nonlinear geometric analysis, we simulate the mechanical behaviour of the wing bases. The results reveal that although both the basal venation and the basal complex influence the structural stiffness of the wings, it is only the latter which significantly affects their deformation patterns. The use of numerical simulations enabled us to address the role of various wing components such as the arculus, discoidal cell and triangle on the camber formation in flight. Our study further provides a detailed representation of the stress concentration in the models. The numerical analysis presented in this study is not only of importance for understanding structure-function relationship of insect wings, but also might help to improve the design of the wings for biomimetic micro-air vehicles (MAVs). PMID- 27513754 TI - Potential Impacts of Offshore Wind Farms on North Sea Stratification. AB - Advances in offshore wind farm (OWF) technology have recently led to their construction in coastal waters that are deep enough to be seasonally stratified. As tidal currents move past the OWF foundation structures they generate a turbulent wake that will contribute to a mixing of the stratified water column. In this study we show that the mixing generated in this way may have a significant impact on the large-scale stratification of the German Bight region of the North Sea. This region is chosen as the focus of this study since the planning of OWFs is particularly widespread. Using a combination of idealised modelling and in situ measurements, we provide order-of-magnitude estimates of two important time scales that are key to understanding the impacts of OWFs: (i) a mixing time scale, describing how long a complete mixing of the stratification takes, and (ii) an advective time scale, quantifying for how long a water parcel is expected to undergo enhanced wind farm mixing. The results are especially sensitive to both the drag coefficient and type of foundation structure, as well as the evolution of the pycnocline under enhanced mixing conditions-both of which are not well known. With these limitations in mind, the results show that OWFs could impact the large-scale stratification, but only when they occupy extensive shelf regions. They are expected to have very little impact on large-scale stratification at the current capacity in the North Sea, but the impact could be significant in future large-scale development scenarios. PMID- 27513755 TI - Selection of Suitable Reference Genes for RT-qPCR Normalization under Abiotic Stresses and Hormone Stimulation in Persimmon (Diospyros kaki Thunb). AB - The success of quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR) to quantify gene expression depends on the stability of the reference genes used for data normalization. To date, systematic screening for reference genes in persimmon (Diospyros kaki Thunb) has never been reported. In this study, 13 candidate reference genes were cloned from 'Nantongxiaofangshi' using information available in the transcriptome database. Their expression stability was assessed by geNorm and NormFinder algorithms under abiotic stress and hormone stimulation. Our results showed that the most suitable reference genes across all samples were UBC and GAPDH, and not the commonly used persimmon reference gene ACT. In addition, UBC combined with RPII or TUA were found to be appropriate for the "abiotic stress" group and alpha-TUB combined with PP2A were found to be appropriate for the "hormone stimuli" group. For further validation, the transcript level of the DkDREB2C homologue under heat stress was studied with the selected genes (CYP, GAPDH, TUA, UBC, alpha-TUB, and EF1-alpha). The results suggested that it is necessary to choose appropriate reference genes according to the test materials or experimental conditions. Our study will be useful for future studies on gene expression in persimmon. PMID- 27513756 TI - Ingenol Mebutate 500 ug on the Cheekbones with Concomitant Conjunctivitis. AB - Ingenol mebutate induces strong inflammation after a single application already. This must be taken into account when prescribing the drug, as mistakes in the application may results in severe side effects. Here, we report the case of a 72 year-old woman who applied ingenol mebutate on the cheekbones and developed a pronounced conjunctivitis, needing topical corticosteroids. The treatment was intended for the actinic keratosis she had on the chest, and the regimen of 2 consecutive once daily applications of ingenol mebutate at 500 ug/g had been prescribed as registered. The inadvertent application on the thin skin of the cheekbones led to a pronounced inflammation. With topical steroids followed by fusidic acid, both conjunctivitis and skin inflammation resolved within a few days. The skin showed erythema for a few weeks, but after 3 months, the patient presented a perfectly smooth skin and was very happy with the cosmetic outcome. This suggests that the cheekbones are a sensitive site for ingenol mebutate, but that intense inflammation should not scare physician or patient, as clinical remission with excellent healing can still be expected. PMID- 27513757 TI - Internet-Based Cognitive Behavioral Therapy for Social Anxiety with and without Guidance Compared to a Wait List in China: A Propensity Score Study. PMID- 27513759 TI - Erratum. PMID- 27513758 TI - D-Dimer Levels Predict Myocardial Injury in ST-Segment Elevation Myocardial Infarction: A Cardiac Magnetic Resonance Imaging Study. AB - OBJECTIVES: Elevated D-dimer levels on admission predict prognosis in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI), but the association of D-dimer levels with structural markers of myocardial injury in these patients is unknown. METHODS: We performed cardiac magnetic resonance (CMR) imaging in 208 patients treated with primary PCI for STEMI. CMR was performed a median of 3 days after the index procedure. Of the 208 patients studied, 75 patients had D-dimer levels above the normal range on admission (>0.5 MUg/mL; high D-dimer group) while 133 had normal levels (<=0.5 MUg/mL; low D-dimer group). The primary outcome was myocardial infarct size assessed by CMR. Secondary outcomes included area at risk (AAR), microvascular obstruction (MVO) area, and myocardial salvage index (MSI). RESULTS: In CMR analysis, myocardial infarct size was larger in the high D-dimer group than in the low D-dimer group (22.3% [16.2-30.5] versus 18.8% [10.7-26.7]; p = 0.02). Compared to the low D-dimer group, the high D-dimer group also had a larger AAR (38.1% [31.7-46.9] versus 35.8% [24.2-45.3]; p = 0.04) and a smaller MSI (37.7 [28.2-46.9] versus 47.1 [33.2-57.0]; p = 0.01). In multivariate analysis, high D-dimer levels were significantly associated with larger myocardial infarct (OR 2.59; 95% CI 1.37-4.87; p<0.01) and lower MSI (OR 2.62; 95% CI 1.44-4.78; p<0.01). CONCLUSIONS: In STEMI patients undergoing primary PCI, high D-dimer levels on admission were associated with a larger myocardial infarct size, a greater extent of AAR, and lower MSI, as assessed by CMR data. Elevated initial D-dimer level may be a marker of advanced myocardial injury in patients treated with primary PCI for STEMI. PMID- 27513760 TI - A gammaA-Crystallin Mouse Mutant Secc with Small Eye, Cataract and Closed Eyelid. AB - Cataract is the most common cause of visual loss in humans. A spontaneously occurred, autosomal dominant mouse mutant Secc, which displayed combined features of small eye, cataract and closed eyelid was discovered in our laboratory. In this study, we identified the mutation and characterized the cataract phenotype of this novel Secc mutant. The Secc mutant mice have eyelids that remain half closed throughout their life. The mutant lens has a significant reduction in size and with opaque spots clustered in the centre. Histological analysis showed that in the core region of the mutant lens, the fiber cells were disorganized and clefts and vacuoles were observed. The cataract phenotype was evident from new born stage. We identified the Secc mutation by linkage analysis using whole genome microsatellite markers and SNP markers. The Secc locus was mapped at chromosome 1 flanked by SNPs rs3158129 and rs13475900. Based on the chromosomal position, the candidate cataract locus gamma-crystallin gene cluster (Cryg) was investigated by sequencing. A single base deletion (299delG) in exon 3 of Cryga which led to a frame-shift of amino acid sequence from position 91 was identified. As a result of this mutation, the sequences of the 3rd and 4th Greek key motifs of the gammaA-crystallin are replaced with an unrelated C-terminal peptide of 75 residues long. Coincidentally, the point mutation generated a HindIII restriction site, allowing the identification of the CrygaSecc mutant allele by RFLP. Western blot analysis of 3-week old lenses showed that the expression of gamma-crystallins was reduced in the CrygaSecc mutant. Furthermore, in cell transfection assays using CrygaSecc mutant cDNA expression constructs in 293T, COS-7 and human lens epithelial B3 cell lines, the mutant gammaA crystallins were enriched in the insoluble fractions and appeared as insoluble aggregates in the transfected cells. In conclusion, we have demonstrated that the Secc mutation leads to the generation of CrygaSecc proteins with reduced solubility and prone to form aggregates within lens cells. Accumulation of mutant proteins in the lens fibers would lead to cataract formation in the Secc mutant. PMID- 27513761 TI - The Effect of the Exon-3-Deleted Growth Hormone Receptor on Pegvisomant-Treated Acromegaly: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The common exon 3 deletion polymorphism of the growth hormone receptor (d3-GHR) is associated with disease severity in acromegaly patients. The GHR antagonist pegvisomant (PEGV) is highly effective in treating severe acromegaly. Response to PEGV treatment seems to be influenced by d3-GHR and appears to be more responsive to PEGV, although available results remain conflicting. OBJECTIVE: To assess the influence of d3-GHR on the responsiveness of acromegaly patients to PEGV by compiling the evidence derived from the largest available studies. DESIGN: A systematic review of the literature identified three published studies and one conference abstract. Acromegaly patients (n = 324, 49.7% d3-GHR carriers) were treated with either PEGV monotherapy or PEGV combined with long-acting somatostatin analogues and/or cabergoline. A meta-analysis of raw data from these studies was performed. RESULTS: No significant effect of the d3-GHR was observed while bringing insulin-like growth factor I (IGF-I) levels below the upper limit of normal with PEGV, which was defined as the lowest IGF-I level during PEGV treatment (mean difference: -2.3%; 95% CI: -6.5 to 1.8, p = 0.270). The PEGV dose required to achieve the lowest IGF-I levels was also not significantly influenced by individuals carrying d3-GHR (mean difference: 4.1 mg weekly; 95% CI: -5.1 to 13.2, p = 0.385). For both outcomes, separate analysis of PEGV monotherapy and combination treatment gave similar results. CONCLUSION: Our findings suggest that the d3-GHR polymorphism has no effect on biochemical disease control in acromegaly, as it is not of added value for either the prediction of PEGV responsiveness or the determination of the required PEGV dose. PMID- 27513762 TI - Spanish version of the Kidney Disease Knowledge Survey (KiKS) in Peru: cross cultural adaptation and validation. AB - INTRODUCTION: Chronic kidney disease (CKD) affects 50 million people globally. Several studies show the importance of implementing interventions that enhance patients? knowledge about their disease. In 2011 the Kidney Disease Knowledge Survey (KiKS) was developed: a questionnaire that assesses the specific knowledge about chronic kidney disease in pre-dialysis patients. OBJECTIVE: To translate to Spanish, culturally adapt and validate the Kidney Disease Knowledge Survey questionnaire in a population of patients with pre-dialysis chronic kidney disease. METHODS: We carried out a Spanish translation and cross-cultural adaptation of the Kidney Disease Knowledge Survey questionnaire. Subsequently, we determined its validity and reliability. We determined the validity through construct validity; and reliability by evaluating its internal consistency and its intra-observer reliability (test-retest). RESULTS: We found a good internal consistency (Kuder-Richardson = 0.85). The intra-observer reliability was measured by the intra-class correlation coefficient that yielded a value of 0.78 (95% CI: 0.5-1.0). This value indicated a good reproducibility; also, the mean difference of -1.1 test-retest SD 6.0 (p = 0.369) confirms this finding. CONCLUSION: The translated Spanish version of the Kidney Disease Knowledge Survey is acceptable and equivalent to the original version; it also has a good reliability, validity and reproducibility. Therefore, it can be used in a population of patients with pre-dialysis chronic kidney disease. PMID- 27513764 TI - Emerging Roles of in Situ Generated Quinone Methides in Metal-Free Catalysis. AB - ortho-Quinone methides have emerged recently as useful electrophiles in metal free catalysis. New strategies to access these species in situ that are compatible with simultaneous nucleophile generation have provided a suite of innovative and selective transformations accessing heterocycles for use in organic synthesis. PMID- 27513763 TI - Dying blood mononuclear cell secretome exerts antimicrobial activity. AB - BACKGROUND: Several activities are attributed to antimicrobial peptides (AMPs), including bacterial killing, leucocyte recruitment and angiogenesis. Despite promises of advanced cellular therapies for treatment of diabetic foot ulcer, it is currently accepted that paracrine factors rather than cellular components are causative for the observed effects. Whether AMPs are present in the mononuclear cell (MNC) secretome (MNC-sec) of white blood cells that are beneficial in experimental wound healing is not known. MATERIALS AND METHODS: Antimicrobial activity of the secretomes of nonirradiated (MNC-sec) and gamma-irradiated MNCs (MNC-sec rad) was analysed by microdilution assay. AMPs were determined by quantitative real-time PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Whether human MNC-sec rad causes AMP secretion in vivo was examined in an experimental rat model. Image flow cytometry was used to determine the type of cell death induced in MNCs after exposure to gamma-radiation. RESULTS: The antimicrobial activity assay revealed a bactericidal activity of MNC-sec rad and to a lesser degree also of MNC-sec. Image flow cytometry showed that gamma irradiation of MNCs induced early apoptosis followed mainly by necroptosis. RT PCR and ELISA revealed a high abundance of different AMPs in the secretome of MNCs. In addition, human MNC-sec elicited an increase in de novo endogenous AMP production in rats in vivo. CONCLUSION: We provide evidence that the secretome of MNCs has direct and indirect positive effects on the immune defence system, including augmentation of antibacterial properties. Our data further suggest that necroptosis could play a key role for the release of paracrine factors and the therapeutic action of MNC-sec rad. PMID- 27513765 TI - Clinical Considerations for Vascularized Composite Allotransplantation of the Eye. AB - Vascularized composite allotransplantation represents a potential shift in approaches to reconstruction of complex defects resulting from congenital differences as well as trauma and other acquired pathology. Given the highly specialized function of the eye and its unique anatomical components, vascularized composite allotransplantation of the eye is an appealing method for restoration, replacement, and reconstruction of the nonfunctioning eye. Herein, we describe conventional treatments for eye restoration and their shortcomings as well as recent research and events that have brought eye transplantation closer to a potential clinical reality. In this article, we outline some potential considerations in patient selection, donor facial tissue procurement, eye tissue implantation, surgical procedure, and potential for functional outcomes. PMID- 27513766 TI - Facing The World in Vietnam: Feedback From Trainees on the Educational Value of Surgical Missions to Help Patients With Craniofacial Deformities. AB - BACKGROUND: Education and training of local healthcare staff is a crucial component of a surgical mission. Facing The World (FTW) is a UK-based craniofacial charity that provides facial reconstructive surgery to children with complex, craniofacial anomalies. As part of its global initiative, FTW has developed a training outreach program in Vietnam. The aim of this study was to analyze feedback data to evaluate the educational value of the training program and identify areas for improvement. METHODS: Feedback was obtained through both 5 point Likert scale and open-ended response questions on written questionnaires. Six postmission reports were reviewed, and used as a base for the content of the questionnaires. Selective sampling was used, with questionnaires distributed to all Vietnamese and UK trainees who have been part of the FTW training program. RESULTS: Seven Vietnamese trainee questionnaires were completed, a response rate of 87.5%. Twelve UK trainees completed the feedback questionnaire, giving a response rate of 85.7%. One hundred percent of local trainees and 83.3% of UK trainees found the training program to be useful or very useful, with no trainees deeming the training program not useful or of no use at all. CONCLUSION: The training missions offered by FTW have successfully provided education to both UK and Vietnamese surgeons in Craniofacial surgical techniques and patient care. No negative responses were identified in both questionnaires. The feedback provides evidence of FTW's effective training program, while allowing insight into where further improvements can be made. PMID- 27513767 TI - Anterior Fontanelle Wormian Bone With Exomphalos Major and Dysmorphic Facial Features: A Previously Unseen Association? AB - Wormian bones are independent ossification centers found within cranial sutures or fontanelles. Though common in adult populations, their presence in children can be associated with several conditions such as osteogenesis imperfecta, hypothyroidism, pyknodysostosis, cleidocranial dysostosis, rickets, and acrocallosal syndrome. These conditions encompass a large range of clinical features but there has only been 1 other reported patient of exomphalos occurring concurrently with these ossicles. The authors present the case of a child with an anterior fontanellar Wormian bone, dysmorphic facial features, and exomphalos major born to unaffected parents. The pattern of features seen in this child did not closely match any condition commonly associated with Wormian bones. The only other reported case of both Wormian bone and exomphalos was in a child with acrocallosal syndrome who presented with more severe dysmorphic features than seen here. It is possible that this patient represents a previously unknown association between acrocallosal syndrome and exomphalos or a less severe variant of the condition. Conversely, this patient may possibly illustrate a newly discovered association between Wormian bones, facial dysmorphism, and midline abdominal defects. PMID- 27513768 TI - A Cheap Hand-Made Mandibular External Fixator? AB - The external mandibular fixator is one of the tools that maxillofacial have to contain complex fractures, in particular in the context of ballistic traumas or comminuted fractures.The authors present a craft external fixator inspired from Joe Hall Morris fixation. This technique, particularly cheap, can be an alternative to a conventional external fixator. The authors report their advices and tricks to guide the implementation of that external fixator and avoid pitfalls. Indications of this surgical device are discussed. PMID- 27513769 TI - Three-Dimensional Printing of Reduction Template in the Contouring of Craniofacial Fibrous Dysplasia. AB - BACKGROUND: Contouring is a minimal invasive procedure to remove excess lesions and restore facial appearance of patients with craniofacial fibrous dysplasia; however, it is difficult to measure the amount of excess lesions. This study is to demonstrate the use of reduction template produced by three-dimensional printer in contouring procedure. METHODS: Computed tomography data were reconstructed into a three-dimensional model by Mimics software. The unaffected side was mirrored and superimposed on the affected side. Excess fibrous dysplasia lesions were calculated by Boolean operations. Lesions to be removed were separated and saved as stereolithography file. This model was further constructed in 3-matic package of Mimics software, and several holes were designed to indicate the variation in depth. Finally, the virtual model was exported into three-dimensional printer to produce physical template. RESULTS: With the direct guidance of three-dimensional reduction template, contouring procedure was performed easily and accurately. Good facial symmetry was achieved with reduced operative time and loss of bleeding. CONCLUSIONS: The application of reduction template produced by three-dimensional printer in contouring procedure improves the efficient and safety of surgery. Good outcomes are obtained without extra requirement in craniofacial surgery. PMID- 27513770 TI - Quantifying Craniometric Change Early After Fronto-Orbital Advancement in Metopic Synostosis. AB - Frontal orbital advancement (FOA) for metopic synostosis results in cranial vault expansion, supporting underlying growth of the developing brain and improving head shape. Previous studies have shown that FOA in younger infants leads to a greater incidence of long-term growth restriction of intracranial volume; however, it is still unknown as to whether this is due to undercorrection at the time of surgery versus primary suture pathology. The purpose of our study is to provide a method for objective analyses of intracranial volumes in the early post FOA period. A retrospective chart review was conducted on patients who underwent FOA over a 10-year period by a single surgeon. Data collected included patient characteristics and clinical outcomes. Radiological analysis of intracranial volumes pre- and post-FOA was determined using Amira volume-rendering software. Average increase in intracranial volume at 6 weeks post-FOA was 139.27 mL (80.01 225.25 mL) with average relative cranial vault expansion of 18.1% (3.3-48%). Patients who underwent FOA older than 12 months of age had an average increase in intracranial volume of 8.5% (3.3-13.1%). Patients younger than 12 months had a statistically higher average increase of 25% (12.8-48%). Frontal orbital advancement effectively increases intracranial volume in patients with metopic synostosis. When compared with older patients, patients younger than 1 year of age have a greater relative increase in intracranial volume in the immediate postoperative period. Quantifying cranial vault expansion after FOA can assist surgeons in surgical planning as well as in measuring and monitoring clinical outcomes within and across craniofacial centers regardless of technique. PMID- 27513771 TI - Surgical Template to Minimize the Damage of Tooth Buds in Young Children With Mandibular Distraction Osteogenesis. AB - BACKGROUND: Mandibular distraction osteogenesis has become one of the most powerful reconstructive techniques for the treatment of mandibular deformities in young children. Damage to the tooth buds is often cited as a complication of it. The purpose of this study was to precisely design the osteotomy line and avoid the damage of tooth buds at the mandibular angle area with the help of surgical template. METHODS: Six patients aged from 6 to 10 years were selected in this study. Three-dimensional computed tomography data was put into Mimics software for preoperative planning the osteotomy line and the accurate placement of the distractor based on the exact position of tooth follicle. And then the surgical template was manufactured by a three-dimensional printer with rapid prototyping technique. The surgeons were guided to perform the osteotomy aided with the prefabricated template through an intraoral approach. Distraction began 7 days postoperation with a rate of 1 mm/d and the distractor was removed after a 6 to 8 months consolidation period. The tooth buds were observed through radiographs that were performed at 5 time intervals: before distraction, at the end of latency, at the end of distraction, at the end of consolidation and 2 years of the postoperation to remove the distractor. RESULTS: The average follow-up time is 24 months. Facial appearance and occlusal plane of all the young patients were greatly improved without complications. From the radiological observation, the tooth buds was intact after the surgery and the second molar normally erupted after removing the distractor. CONCLUSIONS: The surgical template was considered to be helpful in improving the surgical accuracy and avoiding the tooth buds damage during mandibular distraction osteogenesis. PMID- 27513772 TI - Virtual Assessment of Sex: Linear and Angular Traits of the Mandibular Ramus Using Three-Dimensional Computed Tomography. AB - Morphometric analysis of the mandibular ramus (MR) provides highly accurate data to discriminate sex. The objective of this study was to demonstrate the utility and accuracy of MR morphometric analysis for sex identification in a Turkish population.Four hundred fifteen Turkish patients (18-60 y; 201 male and 214 female) who had previously had multidetector computed tomography scans of the cranium were included in the study. Multidetector computed tomography images were obtained using three-dimensional reconstructions and a volume-rendering technique, and 8 linear and 3 angular values were measured. Univariate, bivariate, and multivariate discriminant analyses were performed, and the accuracy rates for determining sex were calculated.Mandibular ramus values produced high accuracy rates of 51% to 95.6%. Upper ramus vertical height had the highest rate at 95.6%, and bivariate analysis showed 89.7% to 98.6% accuracy rates with the highest ratios of mandibular flexure upper border and maximum ramus breadth. Stepwise discrimination analysis gave a 99% accuracy rate for all MR variables.Our study showed that the MR, in particular morphometric measures of the upper part of the ramus, can provide valuable data to determine sex in a Turkish population. The method combines both anthropological and radiologic studies. PMID- 27513773 TI - Clinical, Morphological, and Molecular Evaluations of Bone Regeneration With an Additive Manufactured Osteosynthesis Plate. AB - There is limited information on the biological status of bone regenerated with microvascular fibula flap combined with biomaterials. This paper describes the clinical, histological, ultrastructural, and molecular picture of bone regenerated with patient-customized plate, used for mandibular reconstruction in combination with microvascular osteomyocutaneous fibula flap. The plate was virtually planned and additively manufactured using electron beam melting. This plate was retrieved from the patient after 33 months. Microcomputed tomography, backscattered-scanning electron microscopy, histology, and quantitative polymerase chain reaction were employed to evaluate the regenerated bone and the flap bone associated with the retrieved plate. At retrieval, the posterior two thirds of the plate were in close adaptation with the underlying flap, whereas soft tissue was observed between the native mandible and the anterior one-third. The histological and structural analyses showed new bone regeneration, ingrowth, and osseointegration of the posterior two-thirds. The histological observations were supported by the gene expression analysis showing higher expression of bone formation and remodeling genes under the posterior two-thirds compared with the anterior one-third of the plate. The observation of osteocytes in the flap indicated its viability. The present data endorse the suitability of the customized, additively manufactured plate for the vascularized fibula mandibular reconstruction. Furthermore, the combination of the analytical techniques provides possibilities to deduce the structural and molecular characteristics of bone regenerated using this procedure. PMID- 27513775 TI - Le Fort I Disassembly for the Management of Juvenile Ossifying Fibroma Extending To the Skull Base. AB - Ossifying fibroma is a rare benign osteogenic neoplasm arising from undifferentiated cells of the periodontal ligament. Ossifying fibroma have a well defined border that differentiates it from fibrous dysplasia clinically; these tumors manifest as a round or ovoid, expansile, painless, slow-growing mass may displace the roots of adjacent teeth and also cause root resorption. A variety of approaches for resection of the maxilla have been described. Most involve the use of facial and lip-splitting incisions to gain wide access. Surgical approach specifically to the ossifying fibroma located in the midface includes the Le Fort I approach, Caldwell-Luc access, lateral rhinotomy with medial or total maxillectomy, external ethmoidectomy, and endoscopic surgery. The access through Le Fort I disassembly is a versatile approach not only because of the aesthetic potential in using intraoral incision but also due to its minimal invasiveness, lesser complications and gives the possibility of reconstruction in a single operation. Le Fort I disassembly followed by an excision appears to be a versatile, secure, and satisfactory option. PMID- 27513777 TI - A New Method of Directing Endoscope Pathway in Single-Nostril Transpheoidal Approach for Safety by Using Volume Rendering With Thin-Section Computed Tomographic Image. AB - OBJECTIVE: This study aims to locate important structures surrounding the sella node and measure the distances and angles between signalized points by using both three-dimensional reconstruction technique and volume-rendering. These distances and angles can provide more accurate reference for surgeries in pituitary adenomas. METHODS: Ninty volunteers' skulls were scanned and thin-section computed tomographic images were displayed. The highest point of saddle node on double sides were marked as point A (right) and A1 (left), the highest point of posterior Clinton process on double side as B (right) and B1 (left). And the point of alas minor ossis sphenoridalis with sohenoidal creast was marked as point O. For the latter can not been distinguished in images, point O was used to replace the anterior nasal spine, which can accurately locate the median sagittal plane. The result of three-dimensional reconstruction is used to measure the distance between O and A, A1, B, B1 and angles between OA, OA1, OB, OB1 and their projection line on the standard horizontal plane (alpha, alpha1, beta, beta1). Analyzing the difference by examining the significance difference between both sides can also help the authors to determine whether there is a symmetric difference. RESULTS: The distance of OA was measured as 23.2 (6.5) mm [range, 11.2-45.2 mm; 95% confidence interval (CI), 21.9-24.4 mm]. The distance of OA1 was measured as 23.4 (5.7) mm (range, 9.9-47.2 mm; 95% CI, 22.2-24.6 mm). The distance of OB was measured as 31.1 (5.5) mm (range, 17.8-45.2 mm; 95% CI, 30.0 32.2 mm). The distance of OB1 was measured as 31.2 (6.0) mm (range, 10.1-47.8 mm; 95% CI, 30.0-32.5 mm). The angle of alpha was measured as 81.1 (10.0) degrees (range, 60-137.5 degrees , 95% CI, 79.0-83.2 degrees ). The angle of alpha1 was measured as 81.3 (8.5) degrees (range, 60-97.4 degrees , 95% CI, 79.5-83.1 degrees ). The angle of beta was measured as 91.5 (5.2) degrees (range, 74.9 102.2 degrees , 95% CI, 90.5-92.6 degrees ). The angle of beta1 was measured as 91.0 (6.6) degrees (range, 74.7-104.7 degrees , 95% CI, 89.2-92.0 degrees ). CONCLUSIONS: The above results can facilitate the location of these structures and minimize surgical trauma to optic chiasm and carotid artery surrounding. The method is especially effective in promising more secure and accurate direction to guide surgeons during surgeries in pituitary adenomas. PMID- 27513779 TI - Possibility of Using Standard Plates for Orbital Fracture. AB - OBJECTIVES: Absorbable plates are sometimes grafted for treating orbital fractures. These plates cannot be readily processed to fit the shape of the fracture site, particularly when the fracture encompasses a broad area from the medial toward the inferior wall. Preparing the plates in a standard shape beforehand will be useful. Thus, in this study, the authors measured the orbital wall distance in healthy orbits to determine the mean orbital size with the ultimate goal of developing and clinically applying a standard plate for orbital fracture. METHODS: Measurements were performed for the left eye orbit on computed tomography images using a three-dimensional medical image processing workstation. The authors measured the orbital wall distances and angle of healthy orbits in 40 males and 40 females to determine the mean size of the orbit. RESULTS: In healthy orbits, no significant difference was noticeable in the angle between medial wall and inferior wall between males and females. The medial, inferior, and medial + inferior wall distances were markedly longer in males than in females (P < 0.05). DISCUSSIONS: The orbital shapes had the same pattern in males and females. The standard plate would be adaptable to all cases if it were produced with the medial wall + inferior wall distance greater than the maximum value in males and trimmed to fit the orbit form of the patient. CONCLUSIONS: The results would be the basis of creating a standard plate and using it after appropriate adjustments. PMID- 27513780 TI - Temporal High-Resolution Computed Tomography and Magnetic Resonance Imaging of Congenital Inner Ear Anomalies in Children. AB - Imaging plays an important role in determining indications of cochlear implantation and choosing candidates for the procedure in children. Temporal high resolution computed tomography (HRCT) and magnetic resonance imaging (MRI) can display precisely the complex anatomic structure of inner ear. Although HRCT permits detailed imaging of bony structures, MRI gives valuable information about membranous labyrinth, internal acoustic canal, and vestibulocochlear nerve. Magnetic resonance imaging examination of the brain should be performed at the same time to evaluate any coexistent brain parenchymal abnormality. These imaging modalities are complementary methods in evaluating congenital inner ear anomalies. The aim of this pictorial essay is to reviewing temporal HRCT and MRI findings of congenital inner ear anomalies. PMID- 27513781 TI - Chondromatosis of the Temporomandibular Joint as a Consequence of Persistent Long Lasting Joint Dysfunction: Late Diagnosis of a Rare Occurrence. AB - The authors present a rare patient of right synovial chondromatosis (SC) of the temporomandibular joint in which diagnosis was late and delay led to SC extension to the cranial base. Synovial chondromatosis is a rare benign disorder characterized by multiple cartilaginous free-floating nodules originated from the synovial membrane of large articular joints of the body. Differential diagnosis is with neoplasm and radical surgical removal is essential. The patient came to the authors' observation complaining about long-lasting temporomandibular joint dysfunction. The patient already underwent either functional or medical therapy in times without any improvement. Clinical examination showed limited mouth opening and swelling of the right preauricolar region with no signs of facial nerve palsy and without paresthesia or hearing loss. No history of recent trauma was recorded. Magnetic resonance imaging showed a mucous-like hyperintense mass with small hypointense spots inside. A preoperative computed tomography scan was performed and showed a mass extending from the superior aspect of the temporomandibular joint to the glenoid fossa, which was partially eroded. The patient underwent either open joint surgery or arthroscopy of the superior joint space and a large number of chondrocytes were removed. No complications were recorded postoperatively and the patient completely recovered after 6 months. Histology confirmed the diagnosis of synovial condromatosys of the right temporomandibular joint. PMID- 27513782 TI - Positional Relationship of Ethmoidal Foramens With Reference to the Nasion and Its Significance in Orbital Surgery. AB - PURPOSE: The aim of the study was to elucidate the positional relationship of the ethmoidal foramens (EFs) with reference to the nasion to facilitate prediction of the exact location of EFs, the optic canal (OC), and the frontoethmoidal suture (FS), and thereby avoid complications during complex surgery involving the medial wall of the orbit. MATERIALS AND METHODS: One hundred two intact orbits of 57 embalmed cadavers were dissected in this observational anatomic study. Nasion' (N') was defined as the intersection point of the medial orbit margin with the horizontal line through the nasion, and this was used as a reference point. N'-OC was defined as the straight line joining N' and OC. The locations of the anterior ethmoidal foramen (AEF), posterior ethmoidal foramen (PEF), and OC were determined with reference to N'. The vertical distances from N'-OC to EFs and to FS were also determined. RESULTS: The N'-AEF, AEF-PEF, and PEF-OC distances were 18.4, 15.3, and 8.3 mm, respectively. Vertically, AEF and PEF were situated at 0.2 mm below and 0.4 mm above N'-OC, respectively. At the same reference points, N'-OC was situated at 0.4 and 0.6 mm above FS, respectively. CONCLUSIONS: N', AEF, PEF, and OC were considered to be situated on the same straight line, and N' OC could be regarded as coinciding with FS. This means that N' is an easily identifiable and reliable landmark for identifying EFs, OC, and FS. Our navigational parameters with reference to N' will help surgeons to enhance the safety of orbital surgery. PMID- 27513783 TI - Excellent Result With the Use of Single-Dose OK-432 in Cervical Macrocystic Lymphangioma. AB - Though the lymphangioma is a benign neoplasm, it may make an invasion to vital structures by progressively growing. For lymphangioma, which progressed in such a way, surgical treatment has high morbidity and recurrence risk. On these cases, OK-432 is a frequently used sclerotherapy agent. The authors report the result they obtained by the use of single-dose OK-432 on an inoperable pediatric cervical macrocystic lymphangioma case and also their experiences. PMID- 27513784 TI - The Effects of Nigella Sativa Seed Extract on Bone Healing in an Experimental Model. AB - The purpose of this study was to histologically evaluate the effects on bone healing of nigella sativa seed extract applied on calvarial defects in an ovariectomized rat model. The study included 32 female rats weighing 280 to 310 g with an average age of 3 months. A defect was created with a trephine burr on each rat calvarium. The rats were divided into 2 groups (control and study) of 8 animals each. All the defects were grafted with a gelatin sponge mixed with normal saline. In the study group, nigella sativa seed extract was applied systemically using an oro-gastric tube. Half of the animals in each group were sacrificed after 2 weeks, and the others after 4 weeks. In the control groups, the defects were not completely filled with regenerated bone. Osteoblast cells were observed more in the study groups. A higher rate of osteoclasts was determined in the control groups. In addition, the nigella sativa group had a statistically greater amount of bone formation than the others group at both 2 weeks and 4 weeks (P <0.05). The systemic application of nigella sativa seed extract demonstrated incredibly positive effects on enhanced bone healing in this experimental osteoporotic model. PMID- 27513785 TI - Rehabilitation With Mandibular Implant-Retained Complete Overdenture Using the Association of Two Retention Systems. AB - This article reports a case of oral rehabilitation with two-implant-retained mandibular overdenture using bar/clip and ball attachment bilaterally on the distal side. A patient aged 69 years, fully edentulous, presented herself to private practice complaining about the instability of mandibular denture. Several possibilities of rehabilitation with advantages and disadvantages were explained to the patient, based in the clinical and radiograph examinations, and patient desire, in which she opted by conventional maxillary complete denture and two implant-retained mandibular overdenture. Two external hexagon implants of 3.75 * 10 mm were placed in anterior area of mandible. The fabrication of the metal framework with bar/clip and ball attachment bilaterally on the distal side was planned based on prior arrangement of the artificial teeth. Internal adaptation and occlusal adjustments were performed in the day of insertion of finalized denture and instructions about maintenance and sanitation. The patient showed satisfaction with the final result of her treatment, and no complications were observed during this period. The association of bar/clip with ball system may be viable as option of retention for mandibular implant-retained complete overdenture; however, further randomized controlled trials are necessary to obtain detailed knowledge about the topic. PMID- 27513786 TI - Foreign Body in the Nasal Septum: Lyodura Extrusion. AB - In otorhinolaryngologic fields, Lyodura had been used mainly in otological procedures, such as tympanoplasty, myringoplasty, and mastoidectomy. However, so far in rhinologic area, there is only 1 report that Lyodura was used for closure of cerebrospinal fluid leaks. This report describes a 54-year-old woman presented with recurrent purulent discharge for 4-month duration because of Lyodura extrusion from the septum. On the basis of authors' experience, the authors highlight that the complete removal of exposed Lyodura from the nasal septum may be difficult because of adhesion to the surrounding septal mucosal flap. So, the authors suggest unilaterally wide mucosal incision using mucosal defect site may be necessary for completely removing Lyodura. PMID- 27513787 TI - A Primary Cerebellar Glioblastoma Multiforme Mimicking Vestibular Schwannoma. AB - Cerebellar glioblastoma multiforme (cGBM) is rare in adults, accounting for <1% of all patients with glioblastoma multiforme (GBM). The accurate diagnosis of cGBM is important for establishing a suitable therapeutic schedule. However, the diagnosis of cerebellar GBM is not usually suspected preoperatively because of its rarity. Generally, patients with cGBMs typically presented with symptoms of raised intracranial pressure, and infrequently cerebellar symptoms such as gait ataxia and disequilibrium. Nevertheless, the authors reported a cGMB patient, with his clinical presentations and imaging characteristics mimicking a vestibular schwannoma. To the best of our knowledge, this is the first reported patient with cGBM mimicking a vestibular schwannoma. Furthermore, the diagnosis, treatment, and prognosis for cGBM were broadly investigated. PMID- 27513788 TI - Finger rolls: an improvised applicator for atraumatic, sterile application of finger tourniquets. PMID- 27513789 TI - Adult distal radius fractures classification systems: essential clinical knowledge or abstract memory testing? AB - Classification systems should be tools for concise communication, which ideally can predict prognosis and guide treatment. They should be relevant, reproducible, reliable, properly validated and most importantly simple to use and understand. There are 15 described distal radius classification systems present in the literature in the past 70 years, of which 8 are discussed in this paper. For each classification, we give an insight into its history, strengths and weaknesses, and provide evidence from the literature on reliability and reproducibility. Sadly, on completion of this paper we have not found a distal radius fracture classification that proved to be useful. Failings range from poor reproducibility and reliability, and over-complexity mainly emanating from the inability to classify this spectrum of injury in all of its manifestations. Consequently, we would suggest that classification systems for acute adult distal radius fractures are not useful clinical knowledge but mainly historical and/or research tools. Moreover, we would discourage trainees from spending time learning these classifications, as they serve not as essential clinical knowledge but more as forms of abstract memory testing. PMID- 27513790 TI - Operative treatment of calcaneal fractures: improved outcomes and low complications rates with a strict management protocol. AB - This is a retrospective review of 80 intra-articular calcaneal fractures treated with open reduction and internal fixation by a specialist team under supervision of a single surgeon in a tertiary centre between 2005 and 2014. The fractures were evaluated with plain radiography and computed tomography, and graded using the Eastwood-Atkins classification. A lateral approach was used and all fractures were fixed with calcaneal plates. All patients had clinical and radiological follow-up. Clinical assessment included foot and ankle disability index, SF-36(r) and Kerr-Atkins scores. The mean follow-up duration was 72 months (range: 12-130 months). The mean age of patients was 49 years (range: 17-73 years). There were three open fractures and eight patients had other injuries. The mean Bohler's angle improved from 6 degrees preoperatively to 26 degrees postoperatively. The mean foot and ankle disability index score was 78.62, the mean SF-36(r) scores were 45.5 (physical component) and 52.6 (mental component), and the mean Kerr Atkins score was 72 (range: 36-100). Early complications included one case of screw protrusion in the subtalar joint (which warranted a repeat procedure), one sural nerve injury and one wound breakdown, which healed with non-operative measures. Twelve patients had symptomatic subtalar joint osteoarthritis. Four of these had subtalar fusion. We believe that our strict protocols of patient selection, intraoperative and postoperative management produced long-term results comparable with those in the peer reviewed literature. PMID- 27513791 TI - Adult respiratory distress syndrome. AB - Adult respiratory distress syndrome (ARDS) has now been described as a sequela to such diverse conditions as burns, amniotic fluid embolism, acute pancreatitis, trauma, sepsis and damage as a result of elective surgery in general. Patients with ARDS require immediate intubation, with the average patient now being ventilated for between 8 and 11 days. While the acute management of ARDS is conducted by the critical care team, almost any surgical patient can be affected by the condition and we believe that it is important that a broader spectrum of hospital doctors gain an understanding of the nature of the pathology and its current treatment. PMID- 27513792 TI - Venous thromboembolism after total knee replacement or total hip replacement: what can be learnt from root-cause analysis? AB - INTRODUCTION Because of the high risk of venous thromboembolism (VTE) in total hip replacement (THR) and total knee replacement (TKR), guidelines are used widely to enhance effective (yet safe) prophylaxis. If patients develop VTEs despite use of such guidelines, then the reasons are that the guidelines were: (i) followed but the VTE occurred anyway; (ii) not implemented appropriately. All VTEs are assessed routinely by root-cause analysis (RCA). METHODS The records and subsequent RCA reports for each patient who experienced clinically significant VTE after THR or TKR were reviewed. We established adherence to the guidelines (deemed to be 'unavoidable' with scope to improve the guidelines) and non adherence (deemed to be 'avoidable' with scope to improve implementation). RESULTS Of 2,214 patients undergoing THR (n=1,330) or TKR (n=884), 25 (1.13%) experienced VTE. Four THR patients experienced VTE (2 of which were avoidable) and 21 TKR patients experienced VTE (5 of which were avoidable). There were significantly more VTEs in TKR patients than THR patients (p<0.0001). CONCLUSIONS A proportion of patients will experience VTE even if guidelines are followed (a baseline effect). Administration of chemical prophylaxis earlier might reduce this baseline effect further. This approach should be taken cautiously with due respect for the alternative risk of bleeding. Improvement in hospital routine may reduce the risk of VTE yet further. PMID- 27513793 TI - A method for performing intraoperative enteroscopy. PMID- 27513794 TI - Difficult urethral catheterisation made safer: visualising the 'blind' hydrophilic wire. PMID- 27513795 TI - Laparoscopic use of a 90-degree cross-stapling device for low rectal division. PMID- 27513796 TI - Subchondral bone purchase can aid femoral head extraction. PMID- 27513797 TI - Characteristics and computed tomography evaluation of primary retroperitoneal tumours: report of 113 cases. AB - INTRODUCTION Benign and malignant primary retroperitoneal tumours (PRT) have different clinical manifestations and pathological characteristics. We explore the characteristics and evaluate the value of computed tomography (CT) for PRT. METHODS Fifty-six benign and fifty-seven malignant PRT with clinical, radiographic and surgical data were retrospectively investigated. Statistical analysis was carried out using SPSS software. RESULTS We found that mean size of benign tumours was 12.4 +/- 7.7cm but 20.7 +/- 11.6cm in malignant cases (P < 0.05). The accuracy of CT localisation was approximately 70%. The sensitivity and specificity of CT diagnosis for benign tumours were 96% and 85%, respectively; 51 (91%) underwent complete resection among benign cases but 42 (74%) in malignant cases (P < 0.05). Sensitivity of CT evaluation for invaded organs and vessels was 50% and 65%, respectively, and specificity was 88% and 81%, respectively. CONCLUSIONS Large size, no capsule, irregular margin, heterogeneous density and specific enhancement pattern on CT are highly suggestive of malignancy. CT is the most useful tool in assessing the size and characteristics of PRT but it does not have the sensitivity to assess the involvement of organs and vessels. PMID- 27513798 TI - Outcomes of regional transfers of ruptured abdominal aortic aneurysm in a UK vascular network. AB - INTRODUCTION Rupture of abdominal aortic aneurysm is a surgical emergency. In order to improve operative outcomes, vascular services have been centralised in the United Kingdom. This means that a patient may present to a hospital with a ruptured aneurysm, but require transfer to a vascular centre for definitive treatment. METHODS This retrospective cohort study identified patients who underwent surgery for ruptured abdominal aortic aneurysm in a tertiary vascular centre over a 2-year period. Data on demographics and originating unit were recorded. Outcomes assessed included 30-day mortality, operative mortality and postoperative morbidity. RESULTS We identified 70 patients who underwent surgery for ruptured abdominal aortic aneurysm in the 2-year period; 36 presented directly to the vascular unit (VU), 14 to referral unit 1 (RU1) and 20 to referral unit 2 (RU2); 30-day mortality rates were 27.7% (VU), 35.5% (RU1) and 30.0% (RU2), respectively. There was no statistical difference in mortality between units. Postoperative complications were seen in 35.9% of VU patients, 78.6% of RU1 patients and 70% of RU2 patients. This was statistically significant between VU and RU1 (P = 0.006) and VU and RU2 (P = 0.02). Direct operative complications were seen in 9 patients, gastrointestinal complications in 9, limb complications in 6 and systemic complications in 40. CONCLUSION This study found that site of presentation does not affect mortality but is associated with increased morbidity. This is a complex issue, which will require a prospective multicentre study to investigate further. PMID- 27513799 TI - Cellacast(r) Splint as an adjunct to postoperative neck dressings for burns patients. PMID- 27513801 TI - Tensioned fine wire for proximal femur traction table reduction in amputees. PMID- 27513800 TI - Initial UK experience with transversus abdominis muscle release for posterior components separation in abdominal wall reconstruction of large or complex ventral hernias: a combined approach by general and plastic surgeons. AB - Introduction Large, complicated ventral hernias are an increasingly common problem. The transversus abdominis muscle release (TAMR) is a recently described modification of posterior components separation for repair of such hernias. We describe our initial experience with TAMR and sublay mesh to facilitate abdominal wall reconstruction. Methods The study is a retrospective review of patients undergoing TAMR performed synchronously by gastrointestinal and plastic surgeons. Results Twelve consecutive patients had their ventral hernias repaired using the TAMR technique from June 2013 to June 2014. Median body mass index was 30.8kg/m2 (range 19.0-34.4kg/m2). Four had a previous ventral hernia repair. Three had previous laparostomies. Four had previous stomas and three had stomas created at the time of the abdominal wall reconstruction. Average transverse distance between the recti was 13cm (3-20cm). Median operative time was 383 minutes (150 550 minutes) and mesh size was 950cm2 (532-2400cm2). Primary midline fascial closure was possible in all cases, with no bridging. Median length of hospital stay was 7.5 days (4-17 days). Three developed minor abdominal wall wound complications. At median review of 24 months (18-37 months), there have been no significant wound problems, mesh infections or explants, and none has developed recurrence of their midline ventral hernia. Visual analogue scales revealed high patient satisfaction levels overall and with their final aesthetic appearance. Conclusions We believe that TAMR offers significant advantages over other forms of components separation in this patient group. The technique can be adopted successfully in UK practice and combined gastrointestinal and plastic surgeon operating yields good results. PMID- 27513802 TI - A novel method for practising local skin flaps. PMID- 27513803 TI - Serious tonsil infections versus tonsillectomy rates in Wales: A 15-year analysis. AB - INTRODUCTION Sore throat and tonsillitis place a significant burden on the National Health Service. National guideline criteria for gauging the severity of sore throat and tonsillitis have reduced the number of tonsillectomies performed, which is thought to have increased the rate of tonsil-related infections. METHODS Data was extracted from the prospective Patient Episode Database of Wales and analysed to determine the annual number of tonsillectomies for recurrent tonsillitis, adjusted for population changes. Admissions to acute hospitals for tonsillitis, peritonsillar abscess and deep neck space abscesses were also examined. RESULTS Between 1999 and 2014, hospital admissions for tonsillitis rose three-fold (r=0.968), while admissions for peritonsillar abscess rose by 48% (r=0.857) and retro or parapharyngeal abscess admissions also increased (r=0.709). In contrast, the number of tonsillectomies per 100,000 population gradually decreased (r=-0.16). There was a positive correlation between the incidence of tonsillitis and admissions for peritonsillar abscess (adjusted r2 0.631; p=0.015) and retropharyngeal abscess (adjusted r2 0.442; p=0.00254). There was a statistically significant negative correlation between the incidence of tonsillitis and the number of tonsillectomies performed (adjusted r2=-0.07; p=0.0235). CONCLUSIONS The significant rise in tonsillitis in Wales raises the question as to whether we should revisit the criteria for tonsillectomy. The perceived cost saving from limiting certain procedures should not prevent healthcare policymakers from considering all other evidence. The rise in peritonsillar, retropharyngeal and parapharyngeal abscess is alarming, as they are associated with significant morbidity and mortality. PMID- 27513804 TI - A novel technique for the explantation of a cemented femoral hip prosthesis. PMID- 27513805 TI - Aorto-oesophageal fistula after oesophageal stent placement in a patient with a Roux-en-Y gastric bypass. AB - A 43-year-old female patient suffered from persistent anastomotic leakage after Roux-en-Y gastric bypass for morbid obesity. Endoscopic stenting of the anastomotic leakage was performed. The patient presented with haematemesis 3 weeks later. An aorto-oesophageal fistula was diagnosed, most likely due to ulceration of the oesophageal stent. The fistula was closed with an endovascular covered aortic stent and a new gastrojejunostomy was created. One year after surgery, the patient is in good condition. Endoscopic stents are increasingly being used to treat anastomotic leakage in bariatric patients. An aorto oesophageal fistula is a life-threatening complication of stent placement, early clinical recognition is essential. More data are needed on the complications of anastomotic stenting in bariatric patients. PMID- 27513806 TI - Natural variation in maternal sensitivity is reflected in maternal brain responses to infant stimuli. AB - Increasing evidence suggests that discrete neural networks that mediate emotion processing are activated when mothers respond to infant's images or cries. Accumulating data also indicate that natural variation in maternal caregiving behavior is related to maternal oxytocin (OT) levels. However, brain activation to infant cues has not been studied comparing mothers at disparate ends of the "maternal sensitivity" spectrum. Based on observed mother-infant play interaction at 4-6 months postpartum in 80 antenatally recruited mothers, 15 mothers with the highest sensitivity (HSMs) and 15 mothers with the lowest sensitivity (LSMs) were followed at 7-9 months using functional magnetic resonance imaging (fMRI) to examine brain responses to viewing videos of their "own" versus an "unknown" infant in 3 affect states (neutral, happy, and sad). Plasma OT measurements were taken from mothers following play interactions with their infant. Compared with LSMs, HSMs showed significantly greater brain activation in right superior temporal gyrus (STG) in response to own versus unknown neutral infant and to own happy versus neutral control. Changes in brain activation were significantly negatively correlated with plasma OT responses in HSMs mothers. Conversely, compared with HSMs, LSMs showed no significant activation difference in response to own infant separately or in contrast to unknown infant. Activation of STG may index sensitive maternal response to own infant stimuli. Sensitive parenting may have its unique profile in relation to brain responses which can act as biomarkers for future intervention studies that enhance sensitivity of maternal care. (PsycINFO Database Record PMID- 27513807 TI - Blocking serotonin but not dopamine reuptake alters neural processing during perceptual decision making. AB - Dopamine and serotonin have opponent interactions on aspects of impulsivity. Therefore we wanted to test the hypothesis that dopamine and serotonin would have opposing effects on speed-accuracy trade offs in a perceptual decision making task. Unlike other behavioral measures of impulsivity, perceptual decision making allows us to determine whether decreasing premature responses, often interpreted as decreased impulsivity, corresponds to increased behavioral performance. We administered GBR-12909 (a dopamine transporter blocker), escitalopram (a serotonin transporter blocker), or saline in separate sessions to 3 rhesus macaques. We found that animals had slower reaction times (RTs) on escitalopram than on GBR-12909 or saline. However, they were also least accurate on escitalopram. Animals were faster, although nonsignificantly, on GBR than saline and had equivalent accuracy. Administration of GBR-12909 did cause animals to be faster in error trials than correct trials. Therefore, from the point of view of RTs the animals were less impulsive on escitalopram. However, the decreased accuracy of the monkeys shows that they were not able to make use of their slower response times to make more accurate decisions. Therefore, impulsivity was reduced on escitalopram, but at the expense of a slower information-processing rate in the perceptual inference task. (PsycINFO Database Record PMID- 27513808 TI - Amine-Appended Hierarchical Ca-A Zeolite for Enhancing CO2 /CH4 Selectivity of Mixed-Matrix Membranes. AB - An amine-appended hierarchical Ca-A zeolite that can selectively capture CO2 was synthesized and incorporated into inexpensive membrane polymers, in particular polyethylene oxide and Matrimid, to design mixed-matrix membranes with high CO2 /CH4 selectivities. Binary mixture permeation testing reveals that amine-appended mesoporous Ca-A is highly effective in improving CO2 /CH4 selectivity of polymeric membranes. In particular, the CO2 /CH4 selectivity of the polyethylene oxide membrane increases from 15 to 23 by incorporating 20 wt % amine-appended Ca A zeolite. Furthermore, the formation of filler/polymer interfacial defects, which is typically found in glassy polymer-zeolite pairs, is inhibited owing to the interaction between the amine groups on the external surface of zeolites and polymer chains. Our results suggest that the amine-appended hierarchial Ca-A, which was utilized in membrane fabrication for the first time, is a good filler material for fabricating a CO2 -selective mixed-matrix membrane with defect-free morphology. PMID- 27513809 TI - Does dentifrice use help to remove plaque? A systematic review. AB - AIMS: The aim of this systematic review was to establish the efficacy of brushing with and without a dentifrice for dental plaque removal. MATERIALS AND METHODS: MEDLINE-PubMed, Cochrane-CENTRAL, EMBASE and other electronic databases were searched. The inclusion criteria were randomized controlled trials and controlled clinical trials and subjects >=18 years of age with good general health. Studies that evaluated the effect of toothbrushing with a dentifrice compared to brushing without a dentifrice were included. Data were extracted from the eligible studies, and a meta-analysis was performed where feasible. RESULT: The search was conducted until June 2016 and retrieved 10 eligible publications that included 20 comparisons. On average, 49.2% of plaque was removed when brushing was performed with a dentifrice, and 50.3% of plaque was removed when toothbrushing was performed without a dentifrice. The descriptive analysis indicated that the majority of the comparisons did not show an additional effect of dentifrice use. Regarding the meta-analysis of post-brushing scores, no significant difference was observed between toothbrushing with and without a dentifrice (DiffM 0.00, 95%CI [-0.05: 0.05], p = 0.91). The meta-analysis of incremental data (as means or percentages) supported and strengthened these findings. CONCLUSION: The cumulative evidence for this systematic review demonstrates that there is moderate certainty that toothbrushing with a dentifrice does not provide an added effect for the mechanical removal of dental plaque. PMID- 27513810 TI - Characteristics of Metabolic Syndrome in Morbidly Obese Subjects. AB - BACKGROUND: Metabolic syndrome (MetSyn) magnifies risks of cardiovascular disease (CVD) and type 2 diabetes, but its expression varies within the obese population. We examined body mass index (BMI), metabolic traits, and fat distribution in morbidly obese individuals. METHODS: Lipids and inflammatory, oxidative stress and hepatic biomarkers in 346 women and 203 men (BMI >=35 kg/m2 and co-morbidity or >=40 kg/m2) were stratified by MetSyn components (1-5, excluding diabetes). Age- and smoking-adjusted partial correlations were calculated. Dual-energy X-ray absorptiometry was measured in 206 participants. RESULTS: Apolipoprotein B, ferritin, uric acid, and alanine aminotransferase (ALT) concentrations worsened with increasing MetSyn components (P <= 0.0001), while BMI and LDL-cholesterol showed no association. BMI correlated inversely with triglycerides (r = -0.16, P = 0.03) and positively with HDL-cholesterol in men (r = 0.16, P = 0.02), but not in women. BMI correlated with C-reactive protein (CRP) (r = 0.32, P < 0.0001; r = 0.24, P < 0.0001 in men and women, respectively) and white blood cell count (r = 0.24, P = 0.001 in men; r = 0.15, P = 0.008 in women). Truncal fat percentage correlated to CRP (r = 0.31, P = 0.03; r = 0.20, P = 0.02 in men and women, respectively). In women, number of MetSyn components was inversely related to truncal and peripheral fat (r = -0.20, P = 0.02; r = -0.42, P < 0.0001, respectively) as was ALT (r = -0.21, P = 0.009; r = -0.38, P < 0.0001, respectively) and triglycerides with peripheral fat (r = -0.38, P < 0.0001), while HDL cholesterol was positively associated with truncal and peripheral fat (r = 0.26; P = 0.001). CONCLUSIONS: BMI and fat distribution showed expected associations to inflammation biomarkers, but paradoxical relations between fat indices, and MetSyn components and biomarkers were seen. This suggests a need for better markers of CVD risk in morbid obesity. PMID- 27513811 TI - Green fluorescent protein chromophore derivative suppresses ultraviolet A-induced JNK-signalling and apoptosis in keratinocytes and adverse effects in zebrafish embryos. AB - Solar ultraviolet (UV) light has been recognized as the important environmental hazard and contributes to diverse skin damage such as cell death, photoageing and even carcinogenesis. Revelation of harmful responses attributed to UVA radiation has promoted the development of photoprotective agents against UVA-induced skin damage. In the present study, we tried to evaluate the potential protective effects of a synthetic green fluorescent protein (GFP) chromophore derivative, 4 chlorobenzyldene-1, 2-dimethylimidazolinone (Cl-BDI, called TC-22) on UVA- and UVB- induced stress responses in skin. The HaCaT keratinocytes were used to evaluate the cellular effects. Zebrafish (Danio rerio), which is regarded as a useful and cost-effective alternative to some mammalian models, was applied as the in vivo animal model. In HaCaT keratinocytes, TC-22 was able to obviously decrease UVA-induced cell death. Dissection of the UVA-induced signalling pathways revealed that TC-22 could suppress the activation of JNK and caspase 3, but not of ERK and p38. Reduction of UVA-induced cleavage of caspase 3 and sub-G1 phase accumulation by pretreatment of TC-22 was also observed. In zebrafish, we showed that UVA irradiation could decrease the survival and hatching rate, suppress heart beats of embryos and enhance the pigmentation of larvae. Pretreatment of TC-22 could significantly reverse UVA-induced the suppression in hatching of eggs and heart beating of embryos and also lowered the UVA-induced pigmentation in zebrafish. Collectively, we demonstrate that TC-22, a GFP chromophore derivative, can ameliorate the UVA-induced stress responses in both epidermal keratinocytes and zebrafish, suggesting the potential use of TC-22 in photoprotection in the future. PMID- 27513812 TI - Second Generation of Aldol Reaction. AB - Since the discovery of the Mukaiyama aldol reaction more than 40 years ago, several landmark publications have inspired researchers in the field. The Mukaiyama AR is one of the most significant named reactions in organic synthesis. In the past few decades, development of the modern AR has been at the forefront in addressing the challenges of regio-, chemo-, diastereo-, and enantioselectivity in organic synthesis. All of these selectivity challenges maybe present in a single pair of reactants, thus controlling the outcome of such a process has great practical value. More than 10 years ago, our group became involved in this iconic carbon-carbon bond-forming process and attempted to very closely investigate all possible features of the AR to solve several issues still encountered by chemists, most notably the selectivity challenges mentioned above. In this context, our group initiated the second generation of the AR based on a Lewis or Bronsted acid-catalyzed process in conjunction with the use of a "super silyl" (tris(trimethylsilyl)silyl) directing group, which has demonstrated unrivalled properties in controlling the outcome of the AR. Using the extraordinary power of the super silyl group, we were able to develop new methods and concepts that broadly impacted the ability to control the selectivity attributes and thus allowed for a highly stereoselective construction of polyketide, halogenated polyketide, polypropionate, and polyol scaffolds through inter- and/or intramolecular aldolization protocols. Our diastereoselective ARs of super silyl enol ethers and aldehydes have shown great efficiency and modularity in producing exclusively and preferentially syn- or anti-adducts, creating up to four new adjacent stereocenters in a one-pot sequential manner and under mild reaction conditions. The super silyl-directed AR does not only provide a solution to stereochemistry control challenges, but also offers an efficient, modular and high yielding technique toward nontrivial construction of complex architectures with unprecedented ease. We believe that the new Lewis- or Bronsted acid-catalyzed super-silyl-directed AR processes chronicled in our laboratories have come to maturity and now offer a "road map" for strategic stereoselective synthesis of polyketide-like units. Herein we report our recent achievements in the diastereoselective C-C bond formation, through the super-silyl-directed AR, toward the synthesis of complex and sophisticated hydroxy aldehydes. We would like to note that due to the extremely broad range of work reported in this field, only stereoselective AR involving aldehyde-derived super SEEs will be discussed in this Account. PMID- 27513813 TI - Synthesis, in vitro and in vivo small-animal SPECT evaluation of novel technetium labeled bile acid analogues to study (altered) hepatic transporter function. AB - INTRODUCTION: Hepatobiliary transport mechanisms are crucial for the excretion of substrate toxic compounds. Drugs can inhibit these transporters, which can lead to drug-drug interactions causing toxicity. Therefore, it is important to assess this early during the development of new drug candidates. The aim of the current study is the (radio)synthesis, in vitro and in vivo evaluation of a technetium labeled chenodeoxycholic and cholic acid analogue: [(99m)Tc]-DTPA-CDCA and [(99m)]Tc-DTPA-CA, respectively, as biomarker for disturbed transporter functionality. METHODS: [99mTc]-DTPA-CDCA([(99m)Tc]-3a) and [99mTc]-DTPA-CA ([(99m)Tc]-3b) were synthesized and evaluated in vitro and in vivo. Uptake of both tracers was investigated in NTCP, OCT1, OATP1B1, OATP1B3 transfected cell lines. Km and Vmax values were determined and compared to [(99m)Tc]-mebrofenin ([(99m)Tc]-MEB). Efflux was investigated by means of CTRL, MRP2 and BSEP transfected inside-out vesicles. Metabolite analysis was performed using pooled human liver S9. Wild type (n=3) and rifampicin treated (n=3) mice were intravenously injected with 37MBq of tracer. After dynamic small-animal SPECT and short CT acquisitions, time-activity curves of heart, liver, gallbladder and intestines were obtained. RESULTS: We demonstrated that OATP1B1 and OATP1B3 are the involved uptake transporters of both compounds. Both tracers show a higher affinity compared to [(99m)Tc]-MEB, but are in a similar range as endogenous bile acids for OATP1B1 and OATP1B3. [(99m)Tc]-3a shows higher affinities compared to [(99m)Tc]-3b. Vmax values were lower compared to [(99m)Tc]-MEB, but in the same range as endogenous bile acids. MRP2 was identified as efflux transporter. Less than 7% of both radiotracers was metabolized in the liver. In vitro results were confirmed by in vivo results. Uptake in the liver and efflux to gallbladder + intestines and urinary bladder of both tracers was observed. Transport was inhibited by rifampicin. CONCLUSION: The involved transporters were identified; both tracers are taken up in the hepatocytes by OATP1B1 andOATP1B3 with Km and Vmax values in the same range as endogenous bile acids and are secreted into bile canaliculi via MRP2. Dynamic small-animal SPECT imaging can be a useful noninvasive method of visualizing and quantifying hepatobiliary transporter functionality and disturbances thereof in vivo, which could predict drug pharmacokinetics. PMID- 27513814 TI - Evaluation of the Antihyperglycemic Effect of Minor Steviol Glycosides in Normoglycemic and Induced-Diabetic Wistar Rats. AB - Steviol glycosides are a family of compounds found in Stevia rebaudiana Bertoni that are responsible for sweetness capacity. The antihyperglycemic effect of the two major steviol glycosides, Rebaudioside A and Stevioside, has been studied and it has been found that despite having the same common structure, only Stevioside exerts an antihyperglycemic effect. Although other steviol derivatives are found in smaller amounts (minor steviol glycosides) in S. rebaudiana, whether or not they possess antihyperglycemic activity has not been evaluated. The aim of this study was to evaluate the antihyperglycemic effect of minor steviol glycosides in normoglycemic and diabetic (streptozotocin/nicotinamide) Wistar rats. Rats were subjected to an intraperitoneal glucose tolerance test (IPGTT) both before and after chronic treatment (28 days). After 6 h of fasting, IPGTT was conducted in pentobarbital-anesthetized rats using 1 g/kg of glucose plus 20 mg/kg of the minor glycoside (Dulcoside A, Rebaudioside B, C, D, or Steviolbioside) or control treatment (distilled water, glibenclamide, or metformin); the blood of the tip of the tail was collected at time 0, 15, 30, 60, and 120 min.; and blood glucose was measured, and its net area under the curve (AUCnet) was calculated. After 28-day chronic oral administration, IPGTT was again performed. Differences were considered significant at P < .05 by one-way ANOVA. Acute intraperitoneal or chronic oral administration of 20 mg/kg of minor steviol glycosides had no antihyperglycemic effect in normoglycemic or induced-diabetic Wistar rats. Considering the dose tested, it is unlikely that these glycosides have an effect on glucose in diabetic or normoglycemic humans. PMID- 27513815 TI - Very High Plasma Concentrations of a Monoclonal Antibody against the Human Insulin Receptor Are Produced by Subcutaneous Injection in the Rhesus Monkey. AB - Brain penetration of recombinant protein drugs is possible following the re engineering of the drug as an IgG fusion protein. The IgG domain is a monoclonal antibody (mAb) against an endogenous blood-brain barrier (BBB) receptor transporter, such as the insulin receptor. One such mAb targets the human insulin receptor (HIR) and is active in Rhesus monkeys. Prior work has measured the plasma pharmacokinetics of HIRMAb-derived fusion proteins following intravenous (IV) infusion. However, an alternative method of administration for chronic treatment of brain disease is the subcutaneous (SQ) route. The extent to which an antibody against the insulin receptor undergoes systemic distribution and clearance is unknown. Therefore, in the present study, the rate of plasma clearance of the HIRMAb is measured in Rhesus monkeys following IV or SQ administration of 3, 10, and 30 mg/kg doses of the antibody. The HIRMAb is readily absorbed into the systemic circulation following SQ injection with a 42% plasma bioavailability. The rate of plasma clearance of the antibody, 0.04-0.06 mL/min/kg, is the same following either IV or SQ administration. Owing to the slow rate of plasma clearance of the antibody, high concentrations of the HIRMAb are sustained in plasma for days after the SQ injection. The plasma concentration of the HIRMAb exceeds 0.8 mg/mL, which is 9% of the entire plasma IgG pool in the primate, after the SQ injection of the high dose, 30 mg/kg, of the antibody. In summary, the pharmacokinetics of plasma clearance of the HIRMAb are such that HIRMAb-derived fusion proteins can be developed as protein therapeutics for the brain with chronic SQ administration on a weekly or twice-weekly regimen. PMID- 27513816 TI - In Situ Strategy to Encapsulate Antibiotics in a Bioinspired CaCO3 Structure Enabling pH-Sensitive Drug Release Apt for Therapeutic and Imaging Applications. AB - Herein we demonstrate a bioinspired method involving macromolecular assembly of anionic polypeptide with cationic peptide-oligomer that allows for in situ encapsulation of antibiotics like tetracycline in CaCO3 microstructure. In a single step one-pot process, the encapsulation of the drug occurs under desirable environmentally benign conditions resulting in drug loaded CaCO3 microspheres. While this tetracycline-loaded sample exhibits pH dependent in vitro drug-release profile and excellent antibacterial activity, the encapsulated drug or the dye conjugated peptide emits fluorescence suitable for optical imaging and detection, thereby making it a multitasking material. The efficacy of tetracycline loaded calcium carbonate microspheres as pH dependent drug delivery vehicles is further substantiated by performing cell viability experiments using normal and cancer cell lines (in vitro). Interestingly, the pH-dependent drug release enables selective cytotoxicity toward cancer cell lines as compared to the normal cells, thus having the potential for further development of therapeutic applications. PMID- 27513817 TI - Systems biology insights into the meaning of the platelet's dual-receptor thrombin signaling. AB - : Essentials Roles of the two thrombin receptors in platelet signaling are poorly understood. Computational systems biology modeling was used together with continuous flow cytometry. Dual-receptor system has wide-range sensitivity to thrombin and optimal response dynamics. Procoagulant platelet formation is determined by donor-specific activities of the two receptors. SUMMARY: Background Activation of human platelets with thrombin proceeds via two protease-activated receptors (PARs), PAR1 and PAR4, that have identical main intracellular signaling responses. Although there is evidence that they have different cleavage/inactivation kinetics (and some secondary variations in signaling), the reason for such redundancy is not clear. Methods We developed a multicompartmental stochastic computational systems biology model of dual receptor thrombin signaling in platelets to gain insight into the mechanisms and roles of PAR1 and PAR4 functioning. Experiments employing continuous flow cytometry of washed human platelets were used to validate the model and test its predictions. Activity of PAR receptors in donors was evaluated by mRNA measurement and by polymorphism sequencing. Results Although PAR1 activation produced rapid and short-lived response, signaling via PAR4 developed slowly and propagated in time. Response of the dual-receptor system was both rapid and prolonged in time. Inclusion of PAR1/PAR4 heterodimer formation promoted PAR4 signaling in the medium range of thrombin concentration (about 10 nm), with little contribution at high and low thrombin. Different dynamics and dose dependence of procoagulant platelet formation in healthy donors was associated with individual variations in PAR1 and PAR4 activities and particularly by the Ala120Thr polymorphism in the F2RL3 gene encoding PAR4. Conclusions The dual receptor combination is critical to produce a response combining three critical advantages: sensitivity to thrombin concentration, rapid onset and steady propagation; specific features of the protease-activated receptors do not allow combination of all three in a single receptor. PMID- 27513819 TI - Preferential binding of a stable G3BP ribonucleoprotein complex to intron retaining transcripts in mouse brain and modulation of their expression in the cerebellum. AB - Neuronal granules play an important role in the localization and transport of translationally silenced messenger ribonucleoproteins in neurons. Among the factors associated with these granules, the RNA-binding protein G3BP1 (stress granules assembly factor) is involved in neuronal plasticity and is induced in Alzheimer's disease. We immunopurified a stable complex containing G3BP1 from mouse brain and performed high-throughput sequencing and cross-linking immunoprecipitation to identify the associated RNAs. The G3BP-complex contained the deubiquitinating protease USP10, CtBP1 and the RNA-binding proteins Caprin-1, G3BP2a and splicing factor proline and glutamine rich, or PSF. The G3BP-complex binds preferentially to transcripts that retain introns, and to non-coding sequences like 3'-untranslated region and long non-coding RNAs. Specific transcripts with retained introns appear to be enriched in the cerebellum compared to the rest of the brain and G3BP1 depletion decreased this intron retention in the cerebellum of G3BP1 knockout mice. Among the enriched transcripts, we found an overrepresentation of genes involved in synaptic transmission, especially glutamate-related neuronal transmission. Notably, G3BP1 seems to repress the expression of the mature Grm5 (metabotropic glutamate receptor 5) transcript, by promoting the retention of an intron in the immature transcript in the cerebellum. Our results suggest that G3BP is involved in a new functional mechanism to regulate non-coding RNAs including intron-retaining transcripts, and thus have broad implications for neuronal gene regulation, where intron retention is widespread. PMID- 27513820 TI - Formation of Higher Silanes in Low-Temperature Silane (SiH4) Ices. AB - A novel approach for the synthesis and identification of higher silanes (SinH2n+2, where n <= 19) is presented. Thin films of (d4-)silane deposited onto a cold surface were exposed under ultra-high-vacuum conditions to energetic electrons and sampled on line and in situ via infrared and ultraviolet-visible spectroscopy. Gas phase products released by fractional sublimation in the warm up phase after the irradiation were probed via a reflectron time-of-flight mass spectrometer coupled with a tunable vacuum ultraviolet photon ionization source. The formation mechanisms of (higher) silanes were investigated by irradiating codeposited 1:1 silane (SiH4)/d4-silane (SiD4) ices, suggesting that both radical radical recombination and radical insertion pathways contribute to the formation of disilane along with higher silanes up to nonadecasilane (Si19H40). PMID- 27513821 TI - N-Acylsaccharins: Stable Electrophilic Amide-Based Acyl Transfer Reagents in Pd Catalyzed Suzuki-Miyaura Coupling via N-C Cleavage. AB - The development of efficient catalytic methods for N-C bond cleavage in amides remains an important synthetic challenge. The first Pd-catalyzed Suzuki-Miyaura cross-coupling of N-acylsaccharins with boronic acids by selective N-C bond activation is reported. The reaction enables preparation of a variety of functionalized diaryl and alkyl-aryl ketones with broad functional group tolerance and in good to excellent yields. Of general interest, N-acylsaccharins serve as new, highly reactive, bench-stable, economical, amide-based, electrophilic acyl transfer reagents via acyl-metal intermediates. Mechanistic studies strongly support the amide N-C(O) bond twist as the enabling feature of N acylsaccharins in the N-C bond cleavage. PMID- 27513822 TI - Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. AB - RATIONALE: We previously identified two acute respiratory distress syndrome (ARDS) subphenotypes in two separate randomized controlled trials with differential response to positive end-expiratory pressure. OBJECTIVES: To identify these subphenotypes in a third ARDS cohort, to test whether subphenotypes respond differently to fluid management strategy, and to develop a practical model for subphenotype identification. METHODS: We used latent class analysis of baseline clinical and plasma biomarker data to identify subphenotypes in FACTT (Fluid and Catheter Treatment Trial; n = 1,000). Logistic regression was used to test for an interaction between subphenotype and treatment for mortality. We used stepwise modeling to generate a model for subphenotype identification in FACTT and validated its accuracy in the two cohorts in which we previously identified ARDS subphenotypes. MEASUREMENTS AND MAIN RESULTS: We confirmed that a two-class (two-subphenotype) model best described the study population. Subphenotype 2 was again characterized by higher inflammatory biomarkers and hypotension. Fluid management strategy had significantly different effects on 90 day mortality in the two subphenotypes (P = 0.0039 for interaction); mortality in subphenotype 1 was 26% with fluid-conservative strategy versus 18% with fluid liberal, whereas mortality in subphenotype 2 was 40% with fluid-conservative strategy versus 50% in fluid-liberal. A three-variable model of IL-8, bicarbonate, and tumor necrosis factor receptor-1 accurately classified the subphenotypes. CONCLUSIONS: This analysis confirms the presence of two ARDS subphenotypes that can be accurately identified with a limited number of variables and that responded differently to randomly assigned fluid management. These findings support the presence of ARDS subtypes that may require different treatment approaches. PMID- 27513823 TI - Stability-based assessment of Monteggia-type injuries predicts failure of treatment. AB - Paediatric Monteggia-type injuries are complicated by treatment failure and posterior interosseous nerve palsy, without reliable predictive indicators. Outcome is considered to be good, with little patient-reported evidence. We propose novel radiographic parameters. A total of 33 Monteggia-type injuries were analysed. Posterior interosseous nerve palsy was strongly predicted by the Radial Head Displacement Index. The presence of two or more of three novel instability markers was associated strongly with treatment failure. Patient-reported outcome measures were almost uniformly excellent. We advocate the use of a new, inclusive, stability-based classification of Monteggia-type injuries to predict patients who require accurate internal fixation. PMID- 27513824 TI - Mobile clinics for women's and children's health. AB - BACKGROUND: The accessibility of health services is an important factor that affects the health outcomes of populations. A mobile clinic provides a wide range of services but in most countries the main focus is on health services for women and children. It is anticipated that improvement of the accessibility of health services via mobile clinics will improve women's and children's health. OBJECTIVES: To evaluate the impact of mobile clinic services on women's and children's health. SEARCH METHODS: For related systematic reviews, we searched the Database of Abstracts of Reviews of Effectiveness (DARE), CRD; Health Technology Assessment Database (HTA), CRD; NHS Economic Evaluation Database (NHS EED), CRD (searched 20 February 2014).For primary studies, we searched ISI Web of Science, for studies that have cited the included studies in this review (searched 18 January 2016); WHO ICTRP, and ClinicalTrials.gov (searched 23 May 2016); Cochrane Central Register of Controlled Trials (CENTRAL), part of The Cochrane Library. www.cochranelibrary.com (including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register) (searched 7 April 2015); MEDLINE, OvidSP (searched 7 April 2015); Embase, OvidSP (searched 7 April 2015); CINAHL, EbscoHost (searched 7 April 2015); Global Health, OvidSP (searched 8 April 2015); POPLINE, K4Health (searched 8 April 2015); Science Citation Index and Social Sciences Citation Index, ISI Web of Science (searched 8 April 2015); Global Health Library, WHO (searched 8 April 2015); PAHO, VHL (searched 8 April 2015); WHOLIS, WHO (searched 8 April 2015); LILACS, VHL (searched 9 April 2015). SELECTION CRITERIA: We included individual- and cluster randomised controlled trials (RCTs) and non-RCTs. We included controlled before and-after (CBA) studies provided they had at least two intervention sites and two control sites. Also, we included interrupted time series (ITS) studies if there was a clearly defined point in time when the intervention occurred and at least three data points before and three after the intervention. We defined the intervention of a mobile clinic as a clinic vehicle with a healthcare provider (with or without a nurse) and a driver that visited areas on a regular basis. The participants were women (18 years or older) and children (under the age of 18 years) in low-, middle-, and high-income countries. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of studies identified by the search strategy, extracted data from the included studies using a specially-designed data extraction form based on the Cochrane EPOC Group data collection checklist, and assessed full-text articles for eligibility. All authors performed analyses, 'Risk of bias' assessments, and assessed the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Two cluster-RCTs met the inclusion criteria of this review. Both studies were conducted in the USA.One study tested whether offering onsite mobile mammography combined with health education was more effective at increasing breast cancer screening rates than offering health education only, including reminders to attend a static clinic for mammography. Women in the group offered mobile mammography and health education may be more likely to undergo mammography within three months of the intervention than those in the comparison group (55% versus 40%; odds ratio (OR) 1.83, 95% CI 1.22 to 2.74; low certainty evidence).A cost-effectiveness analysis of mammography at mobile versus static units found that the total cost per patient screened may be higher for mobile units than for static units. The incremental costs per patient screened for a mobile over a stationary unit were USD 61 and USD 45 for a mobile full digital unit and a mobile film unit respectively.The second study compared asthma outcomes for children aged two to six years who received asthma care from a mobile asthma clinic and children who received standard asthma care from the usual (static) primary provider. Children who receive asthma care from a mobile asthma clinic may experience little or no difference in symptom-free days, urgent care use and caregiver-reported medication use compared to children who receive care from their usual primary care provider. All of the evidence was of low certainty. AUTHORS' CONCLUSIONS: The paucity of evidence and the restricted range of contexts from which evidence is available make it difficult to draw conclusions on the impacts of mobile clinics on women's and children's health compared to static clinics. Further rigorous studies are needed in low-, middle-, and high-income countries to evaluate the impacts of mobile clinics on women's and children's health. PMID- 27513825 TI - Transcranial magnetic stimulation for the treatment of epilepsy. AB - BACKGROUND: Epilepsy is a highly prevalent neurological condition characterized by repeated unprovoked seizures with various etiologies. Although antiepileptic medications produce clinical improvement in most individuals, nearly a third of individuals have drug-resistant epilepsy that carries significant morbidity and mortality. There remains a need for non-invasive and more effective therapies for this population. Transcranial magnetic stimulation (TMS) uses electromagnetic coils to excite or inhibit neurons, with repetitive pulses at low-frequency producing an inhibitory effect that could conceivably reduce cortical excitability associated with epilepsy. OBJECTIVES: To assess the evidence for the use of TMS in individuals with drug-resistant epilepsy compared with other available treatments in reducing seizure frequency, improving quality of life, reducing epileptiform discharges, antiepileptic medication use, and side-effects. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid 1946 to 10 March 2016), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) up to March 2016. We also searched SCOPUS (1823 to June 2014) as a substitute for Embase (but it is no longer necessary to search SCOPUS, because randomized controlled trials (RCTs) and quasi-RCTs in EMBASE are now included in CENTRAL). SELECTION CRITERIA: Eligible studies were RCTs that were double-blinded, single-blinded or unblinded, and placebo, no treatment, or active controlled, which used repetitive transcranial magnetic stimulation (rTMS) without restriction of frequency, duration, intensity, or setup (focal or vertex treatment) on patients with drug-resistant epilepsy. The search revealed 274 records from the databases, that after selection provided seven full-text relevant studies for inclusion. Of the seven studies included, five were completed studies with published data and included randomized, blinded trials. The total number of participants in the seven trials was 230. DATA COLLECTION AND ANALYSIS: We extracted information from each trial including methodological data; participant demographics including baseline seizure frequency, type of epileptic drugs taken; intervention details and intervention groups for comparison; potential biases; and outcomes and time points, primarily change in seizure frequency or responder rates, as well as quality of life and epileptiform discharges, adverse effects, and changes in medication use. MAIN RESULTS: Two of the seven studies analyzed showed a statistically significant reduction in seizure rate from baseline (72% and 78.9% reduction of seizures per week from the baseline rate, respectively). The other five studies showed no statistically significant difference in seizure frequency following rTMS treatment compared with controls. We were not able to combine the results of the trials in analysis due to differences in the designs of the studies. Four studies evaluated our secondary endpoint of mean number of epileptic discharges, and three of the four showed a statistically significant reduction in discharges. Quality of life was not assessed in any of the studies. Adverse effects were uncommon among the studies and typically involved headache, dizziness, and tinnitus. No significant changes in medication use were found in the trials. AUTHORS' CONCLUSIONS: Overall, we judged the quality of evidence for the primary outcomes of this review to be low. There is evidence that rTMS is safe and not associated with any adverse events, but given the variability in technique and outcome reporting that prevented meta-analysis, the evidence for efficacy of rTMS for seizure reduction is still lacking despite reasonable evidence that it is effective at reducing epileptiform discharges. PMID- 27513827 TI - Bicontinuous Nanoporous Frameworks: Caged Longevity for Enzymes. AB - The preparation of bicontinuous nanoporous covalent frameworks, which are promising for caging active enzymes, is demonstrated. The frameworks have three- dimensionally continuous, hydrophilic pores with widths varying between 5 and 30 nm. Enzymes were infiltrated into the bicontinuous pore by applying a pressured enzyme solution. The new materials and methods allowed the amount of caged proteins to be controlled precisely. The resulting enzyme-loaded framework films could be recycled many times with nearly no loss of catalytic activity. Entropic trapping of proteins by a bicontinuous pore with the right size distribution is an unprecedented strategy toward facile in vitro utilization of biocatalysts. PMID- 27513828 TI - DNA Clutch Probes for Circulating Tumor DNA Analysis. AB - Progress toward the development of minimally invasive liquid biopsies of disease is being bolstered by breakthroughs in the analysis of circulating tumor DNA (ctDNA): DNA released from cancer cells into the bloodstream. However, robust, sensitive, and specific methods of detecting this emerging analyte are lacking. ctDNA analysis has unique challenges, since it is imperative to distinguish circulating DNA from normal cells vs mutation-bearing sequences originating from tumors. Here we report the electrochemical detection of mutated ctDNA in samples collected from cancer patients. By developing a strategy relying on the use of DNA clutch probes (DCPs) that render specific sequences of ctDNA accessible, we were able to readout the presence of mutated ctDNA. DCPs prevent reassociation of denatured DNA strands: they make one of the two strands of a dsDNA accessible for hybridization to a probe, and they also deactivate other closely related sequences in solution. DCPs ensure thereby that only mutated sequences associate with chip-based sensors detecting hybridization events. The assay exhibits excellent sensitivity and specificity in the detection of mutated ctDNA: it detects 1 fg/MUL of a target mutation in the presence of 100 pg/MUL of wild-type DNA, corresponding to detecting mutations at a level of 0.01% relative to wild type. This approach allows accurate analysis of samples collected from lung cancer and melanoma patients. This work represents the first detection of ctDNA without enzymatic amplification. PMID- 27513829 TI - 8-Anilino-1-naphthalenesulfonate/Layered Double Hydroxide Ultrathin Films: Small Anion Assembly and Its Potential Application as a Fluorescent Biosensor. AB - The fluorescent dye 8-anilino-1-naphthalenesulfonate (ANS) is a widely used fluorescent probe molecule for biochemistry analysis. This paper reported the fabrication of ANS/layered double hydroxide nanosheets (ANS/LDH)n ultrathin films (UTFs) via the layer-by-layer small anion assembly technique based on electrostatic interaction and two possible weak interactions: hydrogen-bond and induced electrostatic interactions between ANS and positive-charged LDH nanosheets. The obtained UTFs show a long-range-ordered periodic layered stacking structure and weak fluorescence in dry air or water, but it split into three narrow strong peaks in a weak polarity environment induced by the two-dimensional (2D) confinement effect of the LDH laminate; the fluorescence intensity increases with decreasing the solvent polarity, concomitant with the blue shift of the emission peaks, which show good sensoring reversibility. Meanwhile, the UTFs exhibit selective fluorescence enhancement to the bovine serum albumin (BSA)-like protein biomolecules, and the rate of fluorescence enhancement with the protein concentration is significantly different with the different protein aggregate states. The (ANS/LDH)n UTF has the potential to be a novel type of biological flourescence sensor material. PMID- 27513832 TI - Structural diversity of halocarbonyl molybdenum and tungsten PNP pincer complexes through ligand modifications. AB - This work presents a comparative study of a series of halocarbonyl Mo(ii) and W(ii) complexes of the types [M(PNP)(CO)3X]X and [M(PNP)(CO)2X2] (M = Mo, W; X = I, Br), featuring PNP pincer ligands based on a 2,6-diaminopyridine scaffold. The complexes were prepared and fully characterized. The syntheses of these complexes were accomplished by treatment of [M(PNP)(CO)3] with stoichiometric amounts of I2 and Br2, respectively. The modification of the 2,6-diaminopyridine scaffold by introducing NMe and NPh instead of NH spacers with concomitant modification of the phosphine moieties changed the steric and electronic properties of the PNP ligand significantly. While in the case of NH linkers exclusively cationic seven coordinate complexes of the type [M(PNP)(CO)3X](+) were obtained with NMe and NPh spacers neutral seven-coordinate complexes of the type [M(PNP)(CO)2X2] were afforded. In the case of the latter, when the reaction is performed in the presence of CO also [M(PNP)(CO)3X](+) complexes are formed which slowly lose CO to give [M(PNP)(CO)2X2]. The halocarbonyl tungsten chemistry parallels that of molybdenum. The only exception is molybdenum in conjunction with the PNP(Me)-iPr ligand, where the coordinatively unsaturated complex [Mo(PNP(Me)-iPr)(CO)X2] is formed. DFT mechanistic studies reveal that the seven-coordinate complexes should be the thermodynamic as well as the kinetic products. Since [Mo(PNP(Me) iPr)(CO)X2] is the observed product it suggests that the reaction follows an alternative path. Structures of representative complexes were determined by X-ray single crystal analyses. PMID- 27513830 TI - Phenotypic evolution of UNC80 loss of function. AB - Failure to thrive arises as a complication of a heterogeneous group of disorders. We describe two female siblings with spastic paraplegia and global developmental delay but also, atypically for the HSPs, poor weight gain classified as failure to thrive. After extensive clinical and biochemical investigations failed to identify the etiology, we used exome sequencing to identify biallelic UNC80 mutations (NM_032504.1:c.[3983-3_3994delinsA];[2431C>T]. The paternally inherited NM_032504.1:c.3983-3_3994delinsA is predicted to encode p.Ser1328Argfs*19 and the maternally inherited NM_032504.1:c.2431C>T is predicted to encode p.Arg811*. No UNC80 mRNA was detectable in patient cultured skin fibroblasts, suggesting UNC80 loss of function by nonsense mediated mRNA decay. Further supporting the UNC80 mutations as causative of these siblings' disorder, biallelic mutations in UNC80 have recently been described among individuals with an overlapping phenotype. This report expands the disease spectrum associated with UNC80 mutations. (c) 2016 Wiley Periodicals, Inc. PMID- 27513834 TI - Alopecia areata in patients with inflammatory bowel disease: an overview. AB - Alopecia areata (AA) is one of the most common causes of non-scarring hair loss, which is associated with the premature induction of hair follicle regression. The pathogenesis of AA is unknown, although it is believed that a complicated autoimmune mechanism with Th1 lymphocytes and proinfammatory cytokines, such as IFN-gamma, TNF-alpha, IL-1 and IL-2, may be involved. AA may occur as a single disease entity or coexist with other autoimmunological disorders. In some cases the relationship with infammatory bowel disease (IBD) was observed and the link between molecular pathways and main proinfammatory cytokines in IBD and AA has been suggested. AA is also described in literature as a side efect of biological therapy with the anti-TNF-alpha agents. To address the association between AA and IBD, in this review we discuss the most relevant clinical studies and case reports found in MEDLINE, Pubmed and EMBASE. PMID- 27513835 TI - Urine NGAL is useful in the clinical evaluation of renal function in the early course of acute pancreatitis. AB - INTRODUCTION: Acute Kidney Injury (AKI) is a serious early complications in patients with acute pancreatitis (AP) that signifcantly increases mortality rates compared to patients without AKI. The early diagnosis of AKI during its treatable phases and implementation of appropriate treatment protocols can improve outcomes for this group of patients. A promising biomarker for AKI is neutrophil gelatinase-associated lipocalin (NGAL). AIM: This study evaluated the diagnostic value of NGAL concentrations in serum and in urine for patients developing AKI as an early complication of AP compared to AP patients without AKI. MATERIAL AND METHODS: The study group composed of 65 patients (34 men and 31 women) with a mean age of 62.2 +/- 16 years with AP and hospitalized in the Surgery Department of the Direct Hospital in Sucha Beskidzka, Poland between January and December 2014. Serum NGAL (sNGAL) levels were measured with the BioVendor ELISA kit, and urine NGAL (uNGAL) with the Abbott ARCHITECT Analyzer. RESULTS: In the early phase of AP, 11 patients (17%) developed AKI, including 10 patients with stage 1 and one with stage 2. AKI was associated with more severe AP, higher BISAP scores, the need for more intensive treatment, longer hospital stays and higher mortality. Both serum and urine NGAL concentrations were signifcantly higher in patients with AKI throughout the study and signifcantly predicted AKI in simple and multiple logistic regression adjusted for age, sex and comorbidities. Serum and urine NGAL concentrations were signifcantly correlated with levels of serum urea, creatinine, urine albumin, and the maximum change in serum creatinine. Serum and urine NGAL levels also correlated positively with direct neutrophil counts and CRP concentrations throughout the study. CONCLUSIONS: The measurement of NGAL levels, particularly in urine, is simple, easy to interpret, routinely available, and clinically useful in the assessment of dynamic changes in kidney function for patients with AP. PMID- 27513836 TI - Vascular density, angiogenesis and pro-angiogenic factors in uterine fibroids. AB - Angiogenesis is a process of development of new vessels from the preexisting vascular network of a host. This is process which is seen in many physiological situations but it accompanies also a development of different lesions, i.e. neoplasms. Uterine fibroids are one of the most frequent lesions which affect human internal female genital tracts. Authors briefly review most important pro angiogenic factors, based on their own observation as well as reviewing current literature. They pay much attention to vascular density which is significantly changed in the uterine tumors. PMID- 27513837 TI - Blood vessels of the shin - anterior tibial artery - anatomy and embryology - own studies and review of the literature. AB - Injuries of the lower leg are rather frequent in every day orthopedic routine. Process of healing takes quite a long time and is commonly dependent on the proper vasculature. e study was carried out on 50 human lower legs obtained during autopsies. The anatomy of the vascular system of the leg was studied using classical anatomical dissection methods. Based also on literature we have reviewed the current knowledge on the vascularization of the lower leg and its embryological background. PMID- 27513838 TI - Experimental gender related obesity effect of diet. AB - INTRODUCTION: High-calorie diet is responsible for excessive weight gain. Obesity has recently become world epidemics, affecting not only adults but also children, which makes it the biggest health problem in the world. Yet the underlying mechanism remains a matter of debate. OBJECTIVES: The aim of this study is to clarify the role of gender in high fat diet induced obesity in pups and adult animals. MATERIALS AND METHODS: Female rats were fed low/ high fat diet during mating, pregnancy and lactation. The offspring and adult rats fed different diet had their body weight and temperature measurements taken twice a week. On the 21st day of the experiment the animals underwent anesthesia in order to have their blood samples collected for lipid profile. RESULTS: After 3 weeks on HF diet female pups body weight was higher than in control group (p <0.05). Contrary to the female pups, the increase in body weight was higher (p <0.05) in male pups and occurred after 2 and 3 weeks. In adult female rats body weight increased after 2 weeks on HF, while in adult male group such weight gain was observed no sooner than after 3 weeks. A er three weeks of the experiment body weight was correlated positively (r = 0.941) with lipid profile of adult both gender groups on HF diet. CONCLUSIONS: In male pups group body weight increased faster and achieved higher values then in female pups. On the contrary, in adult group of females body weight increased faster than in male rats and achieved similar values. PMID- 27513839 TI - Terapeutic importance of apoptosis pathways in pancreatic cancer. AB - Recent studies indicate the significant role of apoptosis and the genes that control it in the process of carcinogenesis. Apoptosis or programmed cell death is a complex process that controls cell proliferation and maintenance of accounting for the necessary balance in the body. Disturbances of apoptotic signalling pathways directly lead to the development and progression of cancer. This also applies to pancreatic cancer, which is characterized by poor prognosis and resistance to treatment. In recent years progress has been made concerning the complex pathways of apoptosis, which allowed the development of new therapeutic strategies. This article reviews current knowledge on apoptosis pathways and their role in treatment of pancreatic cancer. PMID- 27513840 TI - Morphology, topography and clinical signi cance of the jugular foramen. AB - The paper describes morphological variants of the jugular foramen of the human skull and discusses the reasons for its frequent asymmetry. Bilateral disproportions between the anteroposterior and mediolateral diameters of the jugular foramina were analyzed. We established that the jugular foramen is extremely narrow when its anteroposterior diameter is less than 5.0 mm. When the mediolateral diameter exceeds 20.0 mm, then the foramen exhibits extreme widening. PMID- 27513841 TI - The effect of peripheral chronic salsolinol administration on fat pad adipocytes morphological parameters. AB - Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) is thought to regulate dopaminergic neurons and to act as a mediator in the neuroendocrine system. We have previously reported that exogenous salsolinol evokes enteric neuronal cell death, leading to the impairment of myenteric neurons density and abnormal intestinal transit in rats. We also observed significant reduction of body weight, related to the disrupted gastrointestinal homeostasis. e aim of current study was to evaluate the influence of prolonged salsolinol administration body weight, food intake, adipose tissue accumulation and fad pad adipocyte morphological parameters assessed by image analysis. Male Wistar rats were subjected to continuous intraperitoneal low dosing of salsolinol - 200 mg/kg in total with ALZET osmotic mini-pumps (Durtec, USA) for 2 or 4 weeks with either normal or high-fat diet. Appropriate groups served as the controls. Food intake, body weight were measured each morning. Both epididymal fat pads were dissected, weighted and processed for routine hematoxylin and eosin staining. e following parameters: cell area, perimeter, long and short axis, aspect ratio and circularity factor were assessed in stained specimens with the image analysis system (Multiscan, Poland). Salsolinol administration significantly reduced total body mass with no differences in total food intake between the groups. The epididymal fat pad weight over final body mass ratio was lower in salsolinol treated rats on high fat diet in comparison with the control groups. e area, perimeter, short and long axis of the fad pad adipocytes were significantly decreased in salsolinol treated animals in comparison with relevant controls. Salsolinol targets some regulatory mechanisms concerned with the basic rat metabolism. Prolonged peripheral salsolinol administration in rats significantly decreases the adipocyte size, and such effect is related to the weight loss and reduced adipose tissue accumulation. PMID- 27513842 TI - Is It Necessary To Place Prophylactically an Abdominal Drain To Prevent Surgical Site Infection in Abdominal Operations? A Systematic Meta-Review. AB - BACKGROUND: There is still uncertainty regarding the use of prophylactic drainage in abdominal surgical procedures. This meta-review aimed to summarize systematic reviews and meta-analyses evaluating abdominal drain placement in patients undergoing abdominal procedures, with a focus on surgical site infection and death from infections. METHODS: Systematic reviews and meta-analyses identified in MEDLINE, EMBASE, CINHAL, Cochrane Central Register of Controlled Trials, World Health Organization Regional Medical Databases, and African Index Medicus were reviewed. RESULTS: Fifteen systematic reviews and meta-analyses concerning prophylactic abdominal drainage in abdominal operations were included in this analysis. The median score of methodologic quality was eight (6-10). The majority of meta-analyses found no benefits of prophylactic drainage in reducing surgical site infection, but no significant differences were identified. Three studies demonstrated a significant difference in favor of no drainage, with two regarding cholecystectomy and one on appendectomy (p < 0.05). The quality of evidence provided by each review was mainly low and very low. CONCLUSIONS: Most reviews fail to detect an increased incidence of surgical site infection in the setting of drainage placement but also fail to attribute any specific benefits to the presence of a drain in abdominal procedures. PMID- 27513843 TI - Sexual Identity, Sex of Sexual Contacts, and Health-Related Behaviors Among Students in Grades 9-12 - United States and Selected Sites, 2015. AB - PROBLEM: Sexual identity and sex of sexual contacts can both be used to identify sexual minority youth. Significant health disparities exist between sexual minority and nonsexual minority youth. However, not enough is known about health related behaviors that contribute to negative health outcomes among sexual minority youth and how the prevalence of these health-related behaviors compare with the prevalence of health-related behaviors among nonsexual minorities. REPORTING PERIOD: September 2014-December 2015. DESCRIPTION OF THE SYSTEM: The Youth Risk Behavior Surveillance System (YRBSS) monitors six categories of priority health-related behaviors among youth and young adults: 1) behaviors that contribute to unintentional injuries and violence; 2) tobacco use; 3) alcohol and other drug use; 4) sexual behaviors related to unintended pregnancy and sexually transmitted infections, including human immunodeficiency virus infection; 5) unhealthy dietary behaviors; and 6) physical inactivity. In addition, YRBSS monitors the prevalence of obesity and asthma and other priority health-related behaviors. YRBSS includes a national school-based Youth Risk Behavior Survey (YRBS) conducted by CDC and state and large urban school district school-based YRBSs conducted by state and local education and health agencies. For the 2015 YRBSS cycle, a question to ascertain sexual identity and a question to ascertain sex of sexual contacts was added for the first time to the national YRBS questionnaire and to the standard YRBS questionnaire used by the states and large urban school districts as a starting point for their YRBS questionnaires. This report summarizes results for 118 health-related behaviors plus obesity, overweight, and asthma by sexual identity and sex of sexual contacts from the 2015 national survey, 25 state surveys, and 19 large urban school district surveys conducted among students in grades 9-12. RESULTS: Across the 18 violence related risk behaviors nationwide, the prevalence of 16 was higher among gay, lesbian, and bisexual students than heterosexual students and the prevalence of 15 was higher among students who had sexual contact with only the same sex or with both sexes than students who had sexual contact with only the opposite sex. Across the 13 tobacco use-related risk behaviors, the prevalence of 11 was higher among gay, lesbian, and bisexual students than heterosexual students and the prevalence of 10 was higher among students who had sexual contact with only the same sex or with both sexes than students who had sexual contact with only the opposite sex. Similarly, across the 19 alcohol or other drug use-related risk behaviors, the prevalence of 18 was higher among gay, lesbian, and bisexual students than heterosexual students and the prevalence of 17 was higher among students who had sexual contact with only the same sex or with both sexes than students who had sexual contact with only the opposite sex. This pattern also was evident across the six sexual risk behaviors. The prevalence of five of these behaviors was higher among gay, lesbian, and bisexual students than heterosexual students and the prevalence of four was higher among students who had sexual contact with only the same sex or with both sexes than students who had sexual contact with only the opposite sex. No clear pattern of differences emerged for birth control use, dietary behaviors, and physical activity. INTERPRETATION: The majority of sexual minority students cope with the transition from childhood through adolescence to adulthood successfully and become healthy and productive adults. However, this report documents that sexual minority students have a higher prevalence of many health-risk behaviors compared with nonsexual minority students. PUBLIC HEALTH ACTION: To reduce the disparities in health-risk behaviors among sexual minority students, it is important to raise awareness of the problem; facilitate access to education, health care, and evidence-based interventions designed to address priority health-risk behaviors among sexual minority youth; and continue to implement YRBSS at the national, state, and large urban school district levels to document and monitor the effect of broad policy and programmatic interventions on the health-related behaviors of sexual minority youth. PMID- 27513844 TI - AMPK Mediates Glucocorticoids Stress-Induced Downregulation of the Glucocorticoid Receptor in Cultured Rat Prefrontal Cortical Astrocytes. AB - Chronic stress induces altered energy metabolism and plays important roles in the etiology of depression, in which the glucocorticoid negative feedback is disrupted due to imbalanced glucocorticoid receptor (GR) functions. The mechanism underlying the dysregulation of GR by chronic stress remains elusive. In this study, we investigated the role of AMP-activated protein kinase (AMPK), the key enzyme regulating cellular energy metabolism, and related signaling pathways in chronic stress-induced GR dysregulation. In cultured rat cortical astrocytes, glucocorticoid treatment decreased the level, which was accompanied by the decreased expression of liver kinase B1 (LKB1) and reduced phosphorylation of AMPK. Glucocorticoid-induced effects were attenuated by glucocorticoid-inducible kinase 1 (SGK1) inhibitor GSK650394, which also inhibited glucocorticoid induced phosphorylation of Forkhead box O3a (FOXO3a). Furthermore, glucocorticoid-induced down-regulation of GR was mimicked by the inhibition of AMPK and abolished by the AMPK activators or the histone deacetylase 5 (HDAC5) inhibitors. In line with the role of AMPK in GR expression, AMPK activator metformin reversed glucocorticoid induced reduction of AMPK phosphorylation and GR expression as well as behavioral alteration of rats. Taken together, these results suggest that chronic stress activates SGK1 and suppresses the expression of LKB1 via inhibitory phosphorylation of FOXO3a. Downregulated LKB1 contributes to reduced activation of AMPK, leading to the dephosphorylation of HDAC5 and the suppression of transcription of GR. PMID- 27513846 TI - Action Sport Cameras as an Instrument to Perform a 3D Underwater Motion Analysis. AB - Action sport cameras (ASC) are currently adopted mainly for entertainment purposes but their uninterrupted technical improvements, in correspondence of cost decreases, are going to disclose them for three-dimensional (3D) motion analysis in sport gesture study and athletic performance evaluation quantitatively. Extending this technology to sport analysis however still requires a methodologic step-forward to making ASC a metric system, encompassing ad-hoc camera setup, image processing, feature tracking, calibration and 3D reconstruction. Despite traditional laboratory analysis, such requirements become an issue when coping with both indoor and outdoor motion acquisitions of athletes. In swimming analysis for example, the camera setup and the calibration protocol are particularly demanding since land and underwater cameras are mandatory. In particular, the underwater camera calibration can be an issue affecting the reconstruction accuracy. In this paper, the aim is to evaluate the feasibility of ASC for 3D underwater analysis by focusing on camera setup and data acquisition protocols. Two GoPro Hero3+ Black (frequency: 60Hz; image resolutions: 1280*720/1920*1080 pixels) were located underwater into a swimming pool, surveying a working volume of about 6m3. A two-step custom calibration procedure, consisting in the acquisition of one static triad and one moving wand, carrying nine and one spherical passive markers, respectively, was implemented. After assessing camera parameters, a rigid bar, carrying two markers at known distance, was acquired in several positions within the working volume. The average error upon the reconstructed inter-marker distances was less than 2.5mm (1280*720) and 1.5mm (1920*1080). The results of this study demonstrate that the calibration of underwater ASC is feasible enabling quantitative kinematic measurements with accuracy comparable to traditional motion capture systems. PMID- 27513847 TI - Coordination of deep hip muscle activity is altered in symptomatic femoroacetabular impingement. AB - Diagnosis of femoroacetabular impingement (FAI) is increasing, yet the associated physical impairments remain poorly defined. This morphological hip condition can cause joint pain, stiffness, impaired function, and eventually hip osteoarthritis. This exploratory study compared coordination of deep hip muscles between people with and without symptomatic FAI using analysis of muscle synergies (i.e., patterns of activity of groups of muscles activated in synchrony) during gait. Fifteen individuals (11 males) with symptomatic FAI (clinical examination and imaging) and 14 age- and sex-comparable controls without morphological FAI underwent testing. Intramuscular fine-wire and surface electrodes recorded electromyographic activity of selected deep and superficial hip muscles. A non-negative matrix factorization algorithm extracted three synergies which were compared between groups. Information regarding which muscles were activated together in the FAI group (FAI group synergy vector) was used to reconstruct individual electromyography patterns and compare groups. Variance accounted for (VAF) by three synergies was less for the control (94.8 [1.4]%) than FAI (96.0 [1.0]%) group (p = 0.03). VAF of obturator internus was significantly higher in the FAI group (p = 0.02). VAF of the reconstructed individual electromyography patterns with the FAI or control group vector were significantly higher for the FAI group (p < 0.01). Following reconstruction, VAF of quadratus femoris was significantly more reduced in controls (p = 0.04), indicating greater between-subject variability. Coordination of deep hip muscles in the synergy related to hip joint control during early swing differed between groups. This phase involves movement towards the impingement position, which has relevance for the interpretation of synergy differences and potential clinical importance. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1494-1504, 2017. PMID- 27513848 TI - Extent of Signal Hyperintensity on Unenhanced T1-weighted Brain MR Images after More than 35 Administrations of Linear Gadolinium-based Contrast Agents. AB - Purpose To explore the extent of signal hyperintensity in the brain on unenhanced T1-weighted magnetic resonance (MR) images with increasing gadolinium-based contrast agent (GBCA) doses in patients who received 35 or more linear GBCA administrations. Materials and Methods In this institutional review board approved HIPAA-compliant retrospective study, picture archiving and communication systems of two tertiary referral hospitals were searched to identify patients who received 35 or more linear GBCA administrations. Unenhanced T1-weighted images of the brain in patients after six, 12, and 24 GBCA administrations and after the final GBCA administration were independently reviewed by three radiologists to identify sites where T1 signal intensity was increasing. Areas identified by all three observers as increasing in T1 signal intensity when compared with baseline images were further analyzed with a quantitative region of interest analysis measuring the rate of signal increase per injection and the total change after 24 linear GBCA administrations relative to reference tissues that did not show T1 shortening. Results Qualitative analysis of 13 patients with 39-59 linear GBCA administrations showed visually detectable T1 shortening in the dentate nucleus (n = 13), globus pallidus (n = 13), substantia nigra (n = 13), posterior thalamus (n = 12), red nucleus (n = 10), colliculi (n = 10), superior cerebellar peduncle (n = 7), caudate nucleus (n = 4), whole thalamus (n = 3), and putamen (n = 2). Quantitative analysis enable confirmation of signal intensity increases on unenhanced T1-weighted images relative to reference tissues in the dentate nucleus (0.53% signal intensity increase per injection, P < .001), globus pallidus (0.23% increase, P = .009), posterior thalamus (0.26% increase, P < .001), substantia nigra (0.25% increase, P = .01), red nucleus (0.25% increase, P = .01), cerebellar peduncle (0.19% increase, P = .001), and colliculi (0.21% increase, P = .02). Conclusion Increased signal intensity on unenhanced T1 weighted images was seen in the posterior thalamus, substantia nigra, red nucleus, cerebellar peduncle, colliculi, dentate nucleus, and globus pallidus. (c) RSNA, 2016. PMID- 27513849 TI - 18F Fluorocholine Dynamic Time-of-Flight PET/MR Imaging in Patients with Newly Diagnosed Intermediate- to High-Risk Prostate Cancer: Initial Clinical-Pathologic Comparisons. AB - Purpose To investigate the initial clinical value of fluorine 18 (18F) fluorocholine (FCH) dynamic positron emission tomography (PET)/magnetic resonance (MR) imaging by comparing its parameters with clinical-pathologic findings in patients with newly diagnosed intermediate- to high-risk prostate cancer (PCa) who plan to undergo radical prostatectomy. Materials and Methods The institutional review board approved the study protocol, and informed written consent was obtained from all subjects for this HIPAA-compliant study. Twelve men (mean age +/- standard deviation, 61.7 years +/- 8.4; range, 46-74 years) with untreated intermediate- to high-risk PCa characterized according to Cancer of the Prostate Risk Assessment (CAPRA) underwent preoperative FCH dynamic PET/MR imaging followed by radical prostatectomy between April and November 2015. PET/MR imaging parameters including average and maximum K1 (delivery rate constant) and standardized uptake values (SUVs) and Prostate Imaging Reporting and Data System (PI-RADS) version 2 scores were measured and compared with clinical-pathologic characteristics. For statistical analysis, the Spearman rank correlation and Mann Whitney U tests were performed. Results Of the PET parameters, maximum SUV of primary tumors showed significant correlations with several clinical-pathologic parameters including serum prostate-specific antigen level (rho = 0.71, P = .01), pathologic stage (rho = 0.59, P = .043), and postsurgical CAPRA score (rho = 0.72, P = .008). The overall PI-RADS score showed significant correlations with pathologic tumor volume (rho = 0.81, P < .001), percentage of tumor cells with Gleason scores greater than 3 (rho = 0.59, P = .02), and postsurgical CAPRA score (rho = 0.58, P = .046). The high-risk postsurgical CAPRA score patient group had a significantly higher maximum SUV than did the intermediate-risk group. Combined PET and MR imaging showed improved sensitivity (88%) for prediction of pathologic extraprostatic extension compared with that with MR imaging (50%) and PET (75%) performed separately. Conclusion Maximum SUVs and PI-RADS scores from FCH PET/MR imaging show good correlation with clinical-pathologic characteristics, such as postsurgical CAPRA score, which are related to prognosis in patients with newly diagnosed intermediate- to high-risk PCa. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27513850 TI - Detection of Steatohepatitis in a Rat Model by Using Spectroscopic Shear-Wave US Elastography. AB - Purpose To compare low- versus high-frequency ultrasonographic (US) elastography for detection of steatohepatitis in rats by using histopathologic findings as the reference standard. Materials and Methods Between March and September 2014, after receiving approval from the institutional animal care committee, 60 male Sprague Dawley rats were fed either a standard chow for 4 weeks or a methionine- and choline-deficient diet for 1, 4, 8, or 12 weeks to induce a continuum of steatohepatitis severity. Liver shear stiffness was assessed in vivo by using US elastography at low (40-130-Hz) and high (130-220-Hz) frequencies. Histologic features (steatosis, inflammation, and fibrosis) and modified nonalcoholic steatohepatitis categories were used as reference standards. Definite steatohepatitis was divided into steatohepatitis with fibrosis stage 1 or lower and stage 2 and higher. Analyses included the Kendall tau correlation, multivariable linear regression analyses, Kruskal-Wallis rank sum test, and post hoc Dunn test with Holm correction. Results Correlations between liver shear stiffness and histologic features were higher at high frequencies than at low frequencies (low frequency: 0.08, 0.24, and 0.20 for steatosis, inflammation, and fibrosis, respectively; high frequency: 0.11, 0.35, and 0.50, respectively). The absolute value of multivariable regression coefficients was higher at high frequencies for the presence of steatosis, inflammation grade, and fibrosis stage (low frequency: -0.475, 0.157, and 0.209, respectively; high frequency: -0.893, 0.357, and 0.447, respectively). The model fit was better at high frequencies (adjusted R2 = 0.57) than at low frequencies (adjusted R2 = 0.21). There was a significant difference between steatohepatitis categories at both low and high frequencies (P = .022 and P < .001, respectively). Conclusion Liver shear stiffness measured with US elastography provided better distinction of steatohepatitis categories at high frequencies than at low frequencies. Further, liver shear stiffness decreased with steatosis and increased with inflammation and fibrosis at both low and high frequencies. (c) RSNA, 2016 Online supplemental material is available for this article. PMID- 27513851 TI - Predicting Ligand Binding Sites on Protein Surfaces by 3-Dimensional Probability Density Distributions of Interacting Atoms. AB - Predicting ligand binding sites (LBSs) on protein structures, which are obtained either from experimental or computational methods, is a useful first step in functional annotation or structure-based drug design for the protein structures. In this work, the structure-based machine learning algorithm ISMBLab-LIG was developed to predict LBSs on protein surfaces with input attributes derived from the three-dimensional probability density maps of interacting atoms, which were reconstructed on the query protein surfaces and were relatively insensitive to local conformational variations of the tentative ligand binding sites. The prediction accuracy of the ISMBLab-LIG predictors is comparable to that of the best LBS predictors benchmarked on several well-established testing datasets. More importantly, the ISMBLab-LIG algorithm has substantial tolerance to the prediction uncertainties of computationally derived protein structure models. As such, the method is particularly useful for predicting LBSs not only on experimental protein structures without known LBS templates in the database but also on computationally predicted model protein structures with structural uncertainties in the tentative ligand binding sites. PMID- 27513852 TI - Meeting Report: Translational Considerations of Novel Vector Management Approaches. PMID- 27513853 TI - The Relationship between Gray Matter Quantitative MRI and Disability in Secondary Progressive Multiple Sclerosis. AB - PURPOSE: In secondary progressive Multiple Sclerosis (SPMS), global neurodegeneration as a driver of disability gains importance in comparison to focal inflammatory processes. However, clinical MRI does not visualize changes of tissue composition outside MS lesions. This quantitative MRI (qMRI) study investigated cortical and deep gray matter (GM) proton density (PD) values and T1 relaxation times to explore their potential to assess neuronal damage and its relationship to clinical disability in SPMS. MATERIALS AND METHODS: 11 SPMS patients underwent quantitative T1 and PD mapping. Parameter values across the cerebral cortex and deep GM structures were compared with 11 healthy controls, and correlation with disability was investigated for regions exhibiting significant group differences. RESULTS: PD was increased in the whole GM, cerebral cortex, thalamus, putamen and pallidum. PD correlated with disability in the whole GM, cerebral cortex, putamen and pallidum. T1 relaxation time was prolonged and correlated with disability in the whole GM and cerebral cortex. CONCLUSION: Our study suggests that the qMRI parameters GM PD (which likely indicates replacement of neural tissue with water) and cortical T1 (which reflects cortical damage including and beyond increased water content) are promising qMRI candidates for the assessment of disease status, and are related to disability in SPMS. PMID- 27513854 TI - Effect of Obesity on Acute Ozone-Induced Changes in Airway Function, Reactivity, and Inflammation in Adult Females. AB - We previously observed greater ozone-induced lung function decrements in obese than non-obese women. Animal models suggest that obesity enhances ozone-induced airway reactivity and inflammation. In a controlled exposure study, we compared the acute effect of randomized 0.4ppm ozone and air exposures (2 h with intermittent light exercise) in obese (N = 20) (300.05). In addition, after induced differentiation, the lipid droplet production significantly decreased, and the percentages of methylation in the promoter regions of C/EBPalpha, PPARgamma, and aP2 genes were 0.9%, 80%, and 76%, respectively. In contrast, the percentages of methylation in the negative control groups were 0.5%, 67.5%, and 58%, respectively. CONCLUSION: TDG gene knockdown could inhibit the differentiation of pig preadipocytes and affect the DNA methylation levels of some transcription factors. PMID- 27513858 TI - Changes in Knee Laxity and Relaxin Receptor Isoforms Expression (RXFP1/RXFP2) in the Knee throughout Estrous Cycle Phases in Rodents. AB - The changes in knee laxity and relaxin receptor expression at different phases of rodent estrous cycle are not known. Here, changes in the parameter were investigated in rats at different phases of the estrous cycle. Estrous cycle phases of intact female rats were determined by cytological examination of the vaginal smear. Following phase identification, blood was collected for serum hormone analyses. Knee passive range of motion (ROM) was determined by using a digital miniature goniometer. The animals were then sacrificed and patellar tendon, collateral ligaments and hamstring muscles were harvested for relaxin/insulin-like family peptide receptor 1 and 2 (RXFP1/RXFP2) analyses. Knee passive ROM was the highest at proestrus followed by diestrus and the lowest at estrus. Estrogen level was the highest at proestrus while progesterone and relaxin levels were the highest at diestrus. A strong correlation was observed between relaxin and progesterone levels. At proestrus, expression of RXFP1 and RXFP2 proteins and mRNAs were the highest at proestrus followed by diestrus and estrus. The finding shows that higher level of progesterone and relaxin in diestrus might be responsible for higher laxity of knee joint in rats. PMID- 27513859 TI - The Motivational Salience of Faces Is Related to Both Their Valence and Dominance. AB - Both behavioral and neural measures of the motivational salience of faces are positively correlated with their physical attractiveness. Whether physical characteristics other than attractiveness contribute to the motivational salience of faces is not known, however. Research with male macaques recently showed that more dominant macaques' faces hold greater motivational salience. Here we investigated whether dominance also contributes to the motivational salience of faces in human participants. Principal component analysis of third-party ratings of faces for multiple traits revealed two orthogonal components. The first component ("valence") was highly correlated with rated trustworthiness and attractiveness. The second component ("dominance") was highly correlated with rated dominance and aggressiveness. Importantly, both components were positively and independently related to the motivational salience of faces, as assessed from responses on a standard key-press task. These results show that at least two dissociable components underpin the motivational salience of faces in humans and present new evidence for similarities in how humans and non-human primates respond to facial cues of dominance. PMID- 27513860 TI - Quality of Care Is Improved by Rapid Short Incubation MALDI-ToF Identification from Blood Cultures as Measured by Reduced Length of Stay and Patient Outcomes as Part of a Multi-Disciplinary Approach to Bacteremia in Pediatric Patients. AB - Sepsis has seen an incremental increase in cases of about 13% annually in the USA and accounts for approximately 4400 deaths among pediatric patients. Early identification of the specific pathogen allows the clinician to ensure that the antibiotic coverage is optimal, an intervention that has been shown to improve patient outcomes in sepsis. Our study's objective was to assess the impact of a rapid Bruker MALDI-Tof identification protocol on pediatric sepsis cases by assessing various indicators. We assessed the quality of care by measuring the following indicators; time to identification of the pathogen, initiation of the most appropriate antibiotic, length of stay (LOS) in hospital and patient outcomes, using a retrospective review over three consecutive years. In total 92 pediatric patients, similar in age and gender distributions were assessed; 37 in 2012, 33 in 2013 and 22 in 2014. The introduction of MALDI-TOF identification in 2013 led to a significant decrease in time to identify a pathogen by 21.03 hours (p = 1.95E-05). A short incubation MALDI-TOF identification protocol in 2014 further reduced time to identification by 17.75 hours (p = 2.48E-3). Overall in 2014 this led to a trend to earlier optimization of antibiotics by 20.2 hours (p = 0.14) and a reduction in length of stay after the implementation of MALDI-ToF identification in 2013 of 3.07 days and a further reduction of 8.92 days after the introduction of the rapid short incubation identification protocol using MALDI-Tof in 2014 (P = 0.12). By evaluating the subgroup of patients where antibiotics were changed, our study confirmed that patients received appropriate therapy 48.8% (20.2 hours) earlier compared to conventional methods leading to a decrease in length of stay of 23.65 days after the implementation of MALDI-ToF identification and a further reduction of 9.82 days in 2014 compared to 2012 (p = 0.02). In 2014 outcomes between the patients needing a change in their antibiotic compared to the patients where the empirical therapy was considered to be optimal were similar with respect to length of stay; 13.04 and 10.93 days (p = 0.34). In the 2012 group there was a significant increase in the length of stay in the group needing change in excess of 30 days (p = 0.02) compared to the group where empirical therapy was considered to be optimal, this clearly showed an improvement in the quality of care received after the rapid identification was instituted in 2014. The 2012 group had a four times overall increased sepsis associated mortality risk compared to the 2014 group and when empirical antibiotics needed to be optimized this risk was 7 times compared to the 2014 group. We conclude that rapid identification of bacterial pathogens in pediatric blood cultures with a rapid incubation MALDI-TOF identification protocol plays an important role in improving quality of care as part of a multidisciplinary approach to pediatric bacteremia and sepsis. PMID- 27513862 TI - Ingenol Mebutate 500 MUg for Treatment of the Scalp in Refractory Field Cancerization. AB - Patients suffering from chronic lymphocytic leukemia often develop actinic keratosis (AK) and squamous cell carcinoma in sun-exposed areas. In these particular patients, who have a suboptimal immune function, AK treatment can be particularly challenging. We report the case of a patient who failed to respond to most AK treatments, including 5-FU, imiquimod and photodynamic therapy, but responded to ingenol mebutate. We started with 3 applications of 150 MUg/g (registered treatment of the scalp) and also 2 applications of 500 MUg/g (registered in for trunk and extremities). Both treatments were well tolerated, but only the latter led to significant clinical success. This suggests that 500 MUg/g of ingenol mebutate may represent an interesting therapeutic option in patients with mild immunosuppression. PMID- 27513861 TI - HDACi Valproic Acid (VPA) and Suberoylanilide Hydroxamic Acid (SAHA) Delay but Fail to Protect against Warm Hepatic Ischemia-Reperfusion Injury. AB - BACKGROUND: Histone deacetylases (HDAC) catalyze N-terminal deacetylation of lysine-residues on histones and multiple nuclear and cytoplasmic proteins. In various animal models, such as trauma/hemorrhagic shock, ischemic stroke or myocardial infarction, HDAC inhibitor (HDACi) application is cyto- and organoprotective and promotes survival. HDACi reduce stress signaling, cell death and inflammation. Hepatic ischemia-reperfusion (I/R) injury during major liver resection or transplantation increases morbidity and mortality. Assuming protective properties, the aim of this study was to investigate the effect of the HDACi VPA and SAHA on warm hepatic I/R. MATERIAL AND METHODS: Male Wistar-Kyoto rats (age: 6-8 weeks) were randomized to VPA, SAHA, vehicle control (pre-) treatment or sham-groups and underwent partial no-flow liver ischemia for 90 minutes with subsequent reperfusion for 6, 12, 24 and 60 hours. Injury and regeneration was quantified by serum AST and ALT levels, by macroscopic aspect and (immuno-) histology. HDACi treatment efficiency, impact on MAPK/SAPK activation and Hippo-YAP signaling was determined by Western blot. RESULTS: Treatment with HDACi significantly enhanced hyperacetylation of Histone H3-K9 during I/R, indicative of adequate treatment efficiency. Liver injury, as measured by macroscopic aspect, serum transaminases and histology, was delayed, but not alleviated in VPA and SAHA treated animals. Importantly, tissue destruction was significantly more pronounced with VPA. SAPK-activation (p38 and JNK) was reduced by VPA and SAHA in the early (6h) reperfusion phase, but augmented later on (JNK, 24h). Regeneration appeared enhanced in SAHA and VPA treated animals and was dependent on Hippo-YAP signaling. CONCLUSIONS: VPA and SAHA delay warm hepatic I/R injury at least in part through modulation of SAPK activation. However, these HDACi fail to exert organoprotective effects, in this setting. For VPA, belated damage is even aggravated. PMID- 27513863 TI - The Harm of Contact and Non-Contact Sexual Abuse: Health-Related Quality of Life and Mental Health in a Population Sample of Swiss Adolescents. PMID- 27513864 TI - Intricate Macrophage-Colorectal Cancer Cell Communication in Response to Radiation. AB - Both cancer and tumour-associated host cells are exposed to ionizing radiation when a tumour is subjected to radiotherapy. Macrophages frequently constitute the most abundant tumour-associated immune population, playing a role in tumour progression and response to therapy. The present work aimed to evaluate the importance of macrophage-cancer cell communication in the cellular response to radiation. To address this question, we established monocultures and indirect co cultures of human monocyte-derived macrophages with RKO or SW1463 colorectal cancer cells, which exhibit higher and lower radiation sensitivity, respectively. Mono- and co-cultures were then irradiated with 5 cumulative doses, in a similar fractionated scheme to that used during cancer patients' treatment (2 Gy/fraction/day). Our results demonstrated that macrophages sensitize RKO to radiation-induced apoptosis, while protecting SW1463 cells. Additionally, the co culture with macrophages increased the mRNA expression of metabolism- and survival-related genes more in SW1463 than in RKO. The presence of macrophages also upregulated glucose transporter 1 expression in irradiated SW1463, but not in RKO cells. In addition, the influence of cancer cells on the expression of pro and anti-inflammatory macrophage markers, upon radiation exposure, was also evaluated. In the presence of RKO or SW1463, irradiated macrophages exhibit higher levels of pro-inflammatory TNF, IL6, CCL2 and CCR7, and of anti inflammatory CCL18. However, RKO cells induce an increase of macrophage pro inflammatory IL1B, while SW1463 cells promote higher pro-inflammatory CXCL8 and CD80, and also anti-inflammatory VCAN and IL10 levels. Thus, our data demonstrated that macrophages and cancer cells mutually influence their response to radiation. Notably, conditioned medium from irradiated co-cultures increased non-irradiated RKO cell migration and invasion and did not impact on angiogenesis in a chicken embryo chorioallantoic membrane assay. Overall, the establishment of primary human macrophage-cancer cell co-cultures revealed an intricate cell communication in response to ionizing radiation, which should be considered when developing therapies adjuvant to radiotherapy. PMID- 27513865 TI - The Relationship between T1 Sagittal Angle and Sagittal Balance: A Retrospective Study of 119 Healthy Volunteers. AB - T1 sagittal angle has been reported to be used as a parameter for assessing sagittal balance and cervical lordosis. However, no study has been performed to explore the relationship between T1 sagittal angle and sagittal balance, and whether T1 sagittal angle could be used for osteotomy guidelines remains unknown. The aim of our study is to explore the relationship between T1 sagittal angle and sagittal balance, determine the predictors for T1 sagittal angle, and determine whether T1 sagittal angle could be used for osteotomy guidelines to restore sagittal balance. Medical records of healthy volunteers in our outpatient clinic from January 2014 to August 2015 were reviewed, and their standing full-spine lateral radiographs were evaluated. Demographic and radiological parameters were collected and analyzed, including age, gender, T1 sagittal angle, maxTK, maxLL, SS, PT, and PI. Correlation coefficients between T1 sagittal angle and other spinopelvic parameters were determined. In addition, multiple regression analysis was performed to establish predictive radiographic parameters for T1 sagittal angle as the primary contributors. A total of 119 healthy volunteers were recruited in our study with a mean age of 34.7 years. It was found that T1 sagittal angle was correlated with maxTK with very good significance (r = 0.697, P<0.001), maxLL with weak significance (r = 0.206, P = 0.024), SS with weak significance (r = 0.237, P = 0.009), PI with very weak significance (r = 0.189, P = 0.039), SVA with moderate significance (r = 0.445, P<0.001), TPA with weak significance (r = 0.207, P = 0.023), and T1SPI with weak significance (r = 0.309, P = 0.001). The result of multiple regression analysis showed that T1 sagittal angle could be predicted by using the following regression equation: T1 sagittal angle = 0.6 * maxTK-0.2 * maxLL + 8. In the healthy population, T1 sagittal angle could be considered as a useful parameter for sagittal balance; however, it could not be thoroughly replaced for SVA. maxTK was the primary contributor to T1 sagittal angle. According to this equation, we could restore sagittal balance by surgically changing thoracic kyphosis and lumbar lordosis, which could serve as a guideline for osteotomy. PMID- 27513866 TI - Sexual Health and Quality of Life Assessment among Ovarian Cancer Patients during Chemotherapy. AB - BACKGROUND: During the last decades many successful efforts have been made in order to increase life expectancy in ovarian cancer (OC) patients. However, just a few studies have investigated the impact of OC on quality of life (QoL) and sexual function in OC cases during treatment. OBJECTIVE: The aim of this study was to evaluate the QoL and sexual function of OC patients during chemotherapy (CT). PATIENTS AND METHODS: Forty-nine subjects were enrolled and filled in the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-OV28, Female Sexual Function Index (FSFI) and Female Sexual Distress Scale (FSDS) questionnaires. The results were evaluated globally and consequently stratified into several groups: single surgery versus multiple surgeries, age <=48 years versus >48 years, and first-line CT versus multiple lines of CT. RESULTS: Menopause-related symptoms, body image and attitude toward the disease were significantly worse during first-line CT (p = 0.018, p = 0.029 and p = 0.006, respectively). Sexual outcomes resulted in better scores in younger patients in all questionnaires (FSFI: p = 0.001; FSDS: p = 0.048; specific EORTC QLQ-OV28 items: p = 0.022). Scores concerning body image, attitude toward the disease and CT-associated symptoms resulted worse in patients after the first surgery (p = 0.017, p = 0.002 and p = 0.012, respectively). CONCLUSION: Our study confirms that OC has a detrimental impact on QoL and intimacy, particularly in younger patients, during the first course of CT and after the first cytoreductive surgery. PMID- 27513868 TI - Composite Hybrid Cluster Built from the Integration of Polyoxometalate and a Metal Halide Cluster: Synthetic Strategy, Structure, and Properties. AB - A step-by-step synthetic strategy, setting up a bridge between the polyoxometalate (POM) and metal halide cluster (MHC) systems, is demonstrated to construct an unprecedented composite hybrid cluster built up from one high nuclearity cationic MHC [Cu8I6](2+) and eight Anderson-type anionic POMs [HCrMo6O18(OH)6](2-) cross-linked by a tripodal alcohol derivative. PMID- 27513867 TI - Crystal Structure of the SPOC Domain of the Arabidopsis Flowering Regulator FPA. AB - The Arabidopsis protein FPA controls flowering time by regulating the alternative 3'-end processing of the FLOWERING LOCUS (FLC) antisense RNA. FPA belongs to the split ends (SPEN) family of proteins, which contain N-terminal RNA recognition motifs (RRMs) and a SPEN paralog and ortholog C-terminal (SPOC) domain. The SPOC domain is highly conserved among FPA homologs in plants, but the conservation with the domain in other SPEN proteins is much lower. We have determined the crystal structure of Arabidopsis thaliana FPA SPOC domain at 2.7 A resolution. The overall structure is similar to that of the SPOC domain in human SMRT/HDAC1 Associated Repressor Protein (SHARP), although there are also substantial conformational differences between them. Structural and sequence analyses identify a surface patch that is conserved among plant FPA homologs. Mutations of two residues in this surface patch did not disrupt FPA functions, suggesting that either the SPOC domain is not required for the role of FPA in regulating RNA 3' end formation or the functions of the FPA SPOC domain cannot be disrupted by the combination of mutations, in contrast to observations with the SHARP SPOC domain. PMID- 27513869 TI - Utterances in infant-directed speech are shorter, not slower. AB - It has become a truism in the literature on infant-directed speech (IDS) that IDS is pronounced more slowly than adult-directed speech (ADS). Using recordings of 22 Japanese mothers speaking to their infant and to an adult, we show that although IDS has an overall lower mean speech rate than ADS, this is not the result of an across-the-board slowing in which every vowel is expanded equally. Instead, the speech rate difference is entirely due to the effects of phrase final lengthening, which disproportionally affects IDS because of its shorter utterances. These results demonstrate that taking utterance-internal prosodic characteristics into account is crucial to studies of speech rate. PMID- 27513870 TI - When pumpkin is closer to onion than to squash: The structure of the second language lexicon. AB - The current research investigated the organization of the second language mental lexicon. Twenty-seven English-Hebrew bilingual speakers (who spoke Hebrew as their second language) completed a semantic fluency task in each of their languages, and 24 native Hebrew speakers completed the task in Hebrew. Responses were compared within and across groups, using computational tools. The analyses indicated that the lexical network of the second language displayed greater local connectivity and less modular community structure than the network in the native language, both in the entire sample and in a sub-sample of bilinguals whose Hebrew vocabulary was matched to that of the native Hebrew speakers. These findings suggest that the lexical network of the second language is not as well organized as is the network of the first language, even in highly proficient bilinguals. The structural characteristics of the second language lexicon might be affected by factors related to language learning history, including age of acquisition and language use. PMID- 27513871 TI - Word learning in linguistic context: Processing and memory effects. AB - During language acquisition, children exploit syntactic cues within sentences to learn the meanings of words. Yet, it remains unknown how this strategy develops alongside an ability to access cues during real-time language comprehension. This study investigates how on-line sensitivity to syntactic cues impacts off-line interpretation and recall of word meanings. Adults and 5-year-olds heard novel words embedded in sentences that were (1) consistent with an agent-first bias (e.g., "The blicket will be eating the seal"->"the blicket" is an agent), (2) required revision of this bias (e.g., "The blicket will be eaten by the seal" >"the blicket" is a theme), or (3) weakened this bias through a familiar NP1 (e.g., "The seal will be eating/eaten by the blicket"->"the seal" is an agent or theme). Across both ages, eye-movements during sentences revealed decreased sensitivity to syntactic cues in contexts that required syntactic revision. In children, the magnitude of on-line sensitivity was positively associated with the accuracy of learning after the sentence. Parsing challenges during the word learning task also negatively impacted children's later memory for word meanings during a recall task. Altogether, these results suggest that real-time demands impact word learning, through interpretive failures and memory interference. PMID- 27513872 TI - Micro-CT Imaging Reveals Mekk3 Heterozygosity Prevents Cerebral Cavernous Malformations in Ccm2-Deficient Mice. AB - Mutations in CCM1 (aka KRIT1), CCM2, or CCM3 (aka PDCD10) gene cause cerebral cavernous malformation in humans. Mouse models of CCM disease have been established by deleting Ccm genes in postnatal animals. These mouse models provide invaluable tools to investigate molecular mechanism and therapeutic approaches for CCM disease. However, the full value of these animal models is limited by the lack of an accurate and quantitative method to assess lesion burden and progression. In the present study we have established a refined and detailed contrast enhanced X-ray micro-CT method to measure CCM lesion burden in mouse brains. As this study utilized a voxel dimension of 9.5MUm (leading to a minimum feature size of approximately 25MUm), it is therefore sufficient to measure CCM lesion volume and number globally and accurately, and provide high resolution 3-D mapping of CCM lesions in mouse brains. Using this method, we found loss of Ccm1 or Ccm2 in neonatal endothelium confers CCM lesions in the mouse hindbrain with similar total volume and number. This quantitative approach also demonstrated a rescue of CCM lesions with simultaneous deletion of one allele of Mekk3. This method would enhance the value of the established mouse models to study the molecular basis and potential therapies for CCM and other cerebrovascular diseases. PMID- 27513873 TI - Requesting workplace accommodations: Impact of self-efficacy, outcome expectancy, and positive affect. AB - OBJECTIVE: The purpose of this study was to examine the impacts of self-efficacy, outcome expectancy, and positive affect on intentions to request workplace accommodations among people with disabilities (PWDs). METHOD: Seven-hundred and fourteen adults with disabilities participated in an online survey study. This study used structural equation modeling to examine the impact of self-efficacy, outcome expectancy, and positive affect on intentions to request workplace accommodations. RESULTS: The results showed that self-efficacy, outcome expectancy, and positive affect accounted for 55.1% of the variance in accommodation request intentions. CONCLUSIONS: Accommodation request is a complex process that involves cognitive and affective factors for individuals with disabilities. Rehabilitation professionals need to help PWDs boost their level of self-efficacy and outcome expectancy by engaging in accommodation request and goal-setting skills training. In addition, rehabilitation professionals should assist PWDs to recognize the significance of positive affect in the process of accommodation request. (PsycINFO Database Record PMID- 27513874 TI - Mental health and professional help-seeking among college students with disabilities. AB - OBJECTIVE: Research has demonstrated that providing appropriate supports and services on campus can improve both mental health and academic outcomes for students with disabilities (Emerson, Honey, Madden, & Llewellyn, 2009; Stumbo, Martin, & Hedrick, 2009), but little is known about the specific mental health needs of this population. The purpose of this exploratory study, therefore, was to identify the mental health needs of college students with various types of disabilities. METHOD: Researchers analyzed data, collected by the Center for Collegiate Mental Health, of 5,696 students with, and without, disabilities who utilized counseling services on campuses in the 2013-14 academic year. A nonclinical (students not in counseling) sample of 1,620 students with, and without, disabilities was also explored. RESULTS: Compared to students without disabilities, students with disabilities report more anxiety and academic-related distress, as well as higher rates of suicide ideation, suicide attempts, and nonsuicidal self-injury among both students in counseling and not in counseling. CONCLUSIONS: Although in certain areas students with disabilities show similar levels of distress as students without disabilities, students with disabilities have higher levels of distress in areas which could impact their academic success. Self-harming tendencies are higher for students with disabilities overall, but more so for specific disability types. (PsycINFO Database Record PMID- 27513875 TI - Clinical utility and characteristics of the brown location test for individuals with right temporal lobe epilepsy. AB - This Rehabilitation Measures Database summary provides a review of the characteristics of the BLT for individuals with right temporal lobe epilepsy. A full review of the BLT as well as reviews of over 300 other instruments can be found at www.rehabmeasures.org. (PsycINFO Database Record PMID- 27513876 TI - Second-Trimester Anterior Cervical Angle in a Low-Risk Population as a Marker for Spontaneous Preterm Delivery. AB - OBJECTIVE: The aim of this article is to assess the use of the anterior cervical angle (ACA) as a predictor of spontaneous preterm delivery (sPTD) at 20+0-24+6 weeks of gestation in an unselected population. METHODS: We conducted a nested case-control study that included 93 women who later delivered spontaneously <34 weeks of gestation and 225 controls. The ACA was assessed retrospectively on all selected images using ImageJ(r) software. The concordance correlation coefficient was determined for the assessment of interobserver variability. Continuous variables were adjusted by maternal characteristics and expressed as the z-score or multiples of the expected normal median (MoM) of the unaffected group. Logistic regression analysis was used to evaluate whether any maternal characteristics and ultrasound variables were significantly associated with sPTD <34 weeks. RESULTS: ACA z-score values were significantly greater in women who later delivered <34 weeks compared to controls (ACA z-score = 1.32 +/- 0.57 vs. 0.09 +/- 0.35; p = 0.035). The best prediction of sPTD <34 weeks was provided by a model that combined cervical length (CL) MoM, ACA z-score and maternal characteristics. For a fixed false-positive rate of 10%, the detection rate for this model was 37.6%. CONCLUSION: A model combining maternal history, CL and ACA at 20+0-24+6 weeks of gestation can predict approximately 40% of the severe preterm births. PMID- 27513877 TI - Should prophylactic measures to prevent postpolypectomy bleeding after resection of large colorectal polyps be used? AB - Post-polypectomy bleeding after colonoscopy with resection of large colorectal polyps can cause significant morbidity (readmission for monitoring, transfusion, repeat endoscopy and therapy) and a significant cost to hospitals and insurers. Nevertheless prophylactic endoscopic measures could reduce risk of post polypectomy bleeding. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified two systematic reviews including 10 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded prophylactic endoscopic measures could be effective in reducing post-polypectomy bleeding after resection of large colorectal polyps. PMID- 27513878 TI - Semantic parafoveal-on-foveal effects and preview benefits in reading: Evidence from Fixation Related Potentials. AB - During reading parafoveal information can affect the processing of the word currently fixated (parafovea-on-fovea effect) and words perceived parafoveally can facilitate their subsequent processing when they are fixated on (preview effect). We investigated parafoveal processing by simultaneously recording eye movements and EEG measures. Participants read word pairs that could be semantically associated or not. Additionally, the boundary paradigm allowed us to carry out the same manipulation on parafoveal previews that were displayed until reader's gaze moved to the target words. Event Related Potentials time-locked to the prime-preview presentation showed a parafoveal-on-foveal N400 effect. Fixation Related Potentials time locked to the saccade offset showed an N400 effect related to the prime-target relationship. Furthermore, this later effect interacted with the semantic manipulation of the previews, supporting a semantic preview benefit. These results demonstrate that at least under optimal conditions foveal and parafoveal information can be simultaneously processed and integrated. PMID- 27513879 TI - To move or not to move? Exploring the relationship between residential mobility, risk of cardiovascular disease and ethnicity in New Zealand. AB - Residential mobility can have negative impacts on health, with some studies finding that residential mobility can contribute to widening health gradients in the population. However, ethnically differentiated experiences of residential mobility and the relationship with health are neglected in the literature. To examine the relationship between residential mobility, risk of cardiovascular disease (CVD) and ethnicity, we constructed a cohort of 2,077,470 participants aged 30 + resident in New Zealand using encrypted National Health Index (eNHI) numbers linked to individual level routinely recorded data. Using binary logistic regression, we model the risk of CVD for the population stratified by ethnic group according to mover status, baseline deprivation and transitions between deprivation statuses. We show that the relationship between residential mobility and CVD varies between ethnic groups and is strongly influenced by the inter relationship between residential mobility and deprivation mobility. Whilst residential mobility is an important determinant of CVD, much of the variation between ethnic groups is explained by contrasting deprivation experiences. To reduce inequalities in CVD within New Zealand, policies must focus on residentially mobile Maori, Pacific and South Asian populations who already have a heightened risk of CVD living in more deprived areas. PMID- 27513880 TI - Evaluation of Long-Term Cochlear Implant Use in Subjects With Acquired Unilateral Profound Hearing Loss: Focus on Binaural Auditory Outcomes. AB - INTRODUCTION: Cochlear implantation (CI) in subjects with unilateral profound sensorineural hearing loss was investigated. The authors of the present study demonstrated the binaural auditory outcomes in a 12- and 36-month prospective cohort outcome study. The present study aimed to do a long-term (LT) evaluation of the auditory outcomes in an analogous study group. DESIGN: LT evaluation was derived from 12 single-sided deaf (SSD) CI recipients and from 11 CI recipients with asymmetric hearing loss (AHL). A structured interview was conducted with each subjects. Speech perception in noise and sound localization were assessed in a CIOFF and in a CION condition. Four binaural effects were calculated: summation effect (S0N0), squelch effect (S0NCI), combined head shadow effect (SCIN0), and spatial release from masking (SRM). At the LT evaluation, the contribution of a CI or a bone conduction device on speech perception in noise was investigated in two challenging spatial configurations in the SSD group. RESULTS: All (23/23) subjects wore their CI 7 days a week at LT follow-up evaluation, which ranged from 3 to 10 years after implantation. In the SSD group, a significant combined head shadow effect of 3.17 dB and an SRM benefit of 4.33 dB were found. In the AHL group, on the other hand, the summation effect (2.00 dB), the squelch effect (2.67 dB), the combined head shadow effect (3.67 dB), and SRM benefit (2.00 dB) were significant at LT testing. In both the spatial challenging configurations, the speech in noise results was significantly worse in the condition with the bone conduction device compared with the unaided condition. No negative effect was found for the CION condition. A significant benefit in the CION condition was found for sound localization compared with the CIOFF condition in the SSD group and in the AHL group. CONCLUSION: All subjects wore their CI 7 days a week at LT follow-up evaluation. The presence of binaural effects has been demonstrated with speech in noise testing, sound localization, and subjective evaluation. In the AHL group, all investigated binaural effects were found to be significant. In the SSD group on the other hand, only SRM and the head shadow, the two most robust binaural effects, were significantly present. However, it took 12M before the SSD and the AHL subjects significantly benefit from the head shadow effect. These reported results could guide counseling of future CI candidates with SSD and AHL in general. PMID- 27513881 TI - Eye Movements in Strategic Choice. AB - In risky and other multiattribute choices, the process of choosing is well described by random walk or drift diffusion models in which evidence is accumulated over time to threshold. In strategic choices, level-k and cognitive hierarchy models have been offered as accounts of the choice process, in which people simulate the choice processes of their opponents or partners. We recorded the eye movements in 2 * 2 symmetric games including dominance-solvable games like prisoner's dilemma and asymmetric coordination games like stag hunt and hawk dove. The evidence was most consistent with the accumulation of payoff differences over time: we found longer duration choices with more fixations when payoffs differences were more finely balanced, an emerging bias to gaze more at the payoffs for the action ultimately chosen, and that a simple count of transitions between payoffs-whether or not the comparison is strategically informative-was strongly associated with the final choice. The accumulator models do account for these strategic choice process measures, but the level-k and cognitive hierarchy models do not. (c) 2015 The Authors. Journal of Behavioral Decision Making published by John Wiley & Sons Ltd. PMID- 27513882 TI - Thrombomodulin enhances complement regulation through strong affinity interactions with factor H and C3b-Factor H complex. AB - INTRODUCTION: Coagulation and complement systems are simultaneously activated at sites of tissue injury, leading to thrombin generation and opsonisation with C3b. Thrombomodulin (TM) is a cell-bound regulator of thrombin activation, but can also enhance the regulatory activity of complement factor H (FH), thus accelerating the degradation of C3b into inactive iC3b. OBJECTIVES: This study sought to determine the biophysical interaction affinities of two recombinant TM analogs with thrombin, FH and C3b in order to analyze their ability to regulate serum complement activity. METHODS: Surface plasmon resonance (SPR) analysis was used to determine binding affinities of TM analogs with FH and C3b, and compared to thrombin as positive control. The capacity of the two recombinant TM analogs to regulate complement in serum was tested in standard complement hemolytic activity assays. RESULTS: SPR analysis showed that both TM analogs bind FH and C3b-Factor H with nanomolar and C3b with micromolar affinity; binding affinity for its natural ligand thrombin was several fold higher than for FH. At a physiological relevant concentration, TM inhibits complement hemolytic activity in serum via FH dependent and independent mechanisms. CONCLUSIONS: TM exhibits significant binding affinity for complement protein FH and C3b-FH complex and its soluble form is capable at physiologically relevant concentrations of inhibiting complement activation in serum. PMID- 27513883 TI - Polycystic ovary syndrome and psychiatric disorders: Co-morbidity and heritability in a nationwide Swedish cohort. AB - Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting 5-15% of reproductive-aged women and characterized by high levels of circulating androgens. Given that androgens have been implicated in the aetiology of several psychiatric disorders, it was hypothesized that women with PCOS have high risk for psychiatric comorbidity. We aimed to investigate this risk amongst women with PCOS, as well as in their siblings, to elucidate if familial factors underlie any potential associations. Using the Swedish national registers, we identified all women diagnosed with PCOS between 1990 and 2013 (n=24,385), their full-siblings (n=25,921), plus matched individuals (1:10/100) from the general population and their full-siblings. Psychiatric disorder diagnoses were identified including schizophrenia, bipolar disorder, depressive and anxiety disorders, eating disorders, personality and gender identity disorder, autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), tics, attempted and completed suicide. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression and adjusted ORs (AOR) were determined by adjustment for comorbid psychiatric disorders. Overall, women with PCOS had an increased odds of having at least one psychiatric disorder (OR=1.56 [95CI%, 1.51-1.61]). Crude ORs showed associations with nearly all psychiatric disorders included in this study. Following adjustment for comorbid psychiatric disorders, women with PCOS were still at a significantly increased risk for bulimia, schizophrenia, bipolar disorder, depressive and anxiety disorders, personality disorders, with the highest AORs for ASD (AOR=1.55 [95%CI, 1.32 1.81]) and tics (AOR=1.65 [95%CI, 1.10-2.47]). Significantly higher AORs were found for ASD in both brothers and sisters of women with PCOS, and for depressive, anxiety, and schizophrenia spectrum disorders in the sisters only. Notably, the crude ORs for attempted suicide were 40% higher in women with PCOS and 16% higher in their unaffected sisters. However, the AORs were greatly attenuated indicating that underlying psychiatric comorbidity is important for this association. Women with PCOS had higher risks for a range of psychiatric disorders not shown before. Elevated risk in their siblings suggests shared familial factors between PCOS and psychiatric disorders. This study is an important first step towards identifying the underlying mechanisms for risk of psychiatric disorders in women with PCOS. Health professionals treating women with PCOS should be aware that these patients - as well as their family members - are important targets for mental health care. PMID- 27513884 TI - Coarse-Grained Simulations of Polymer-Grafted Nanoparticles: Structural Stability and Interfacial Behavior. AB - In the tertiary oil recovery method known as "polymer flooding", the viscosity of the injected water is increased by dissolving partially hydrolyzed polyacrylamide so as to lower the mobility ratio and raise the vertical and areal sweep efficiencies. However, its drawbacks include the degradation of the polymer in the reservoir due to (1) shear while passing through chokes, perforations, and pore throats, (2) morphological changes induced by divalent ions, and (3) complete hydrolysis of the polymer at high temperatures. These factors adversely affect the viscosity of the polymer flood. Past experimental research showed that polymer-grafted nanoparticles (PNPs) could achieve the same viscosity enhancement at lower quantities than traditional linear polymers. The PNPs have the putative advantage of greater stability when confronted with the aforementioned reservoir conditions. In this work, we use dissipative particle dynamics (DPD) to simulate the oil-PNP-water system at the mesoscale and estimate its sensitivity to brine in ways that could serve as guidelines to experiments. We study the effect of salinity on the structure of linear and branched polyelectrolytes before extending the DPD model to PNPs at the oil-water interface. To this end, we parameterize the interactions of the polymer with the oil and water phases, and broadly map out solvent conditions that change the graft's morphology and affect the interfacial behavior of the grafted particle. We find that the equilibrium location of the grafted nanoparticle in an oil-brine system depends on its grafting density and the salinity. PMID- 27513885 TI - Defining and Detecting Complex Peak Relationships in Mass Spectral Data: The Mz.unity Algorithm. AB - Analysis of a single analyte by mass spectrometry can result in the detection of more than 100 degenerate peaks. These degenerate peaks complicate spectral interpretation and are challenging to annotate. In mass spectrometry-based metabolomics, this degeneracy leads to inflated false discovery rates, data sets containing an order of magnitude more features than analytes, and an inefficient use of resources during data analysis. Although software has been introduced to annotate spectral degeneracy, current approaches are unable to represent several important classes of peak relationships. These include heterodimers and higher complex adducts, distal fragments, relationships between peaks in different polarities, and complex adducts between features and background peaks. Here we outline sources of peak degeneracy in mass spectra that are not annotated by current approaches and introduce a software package called mz.unity to detect these relationships in accurate mass data. Using mz.unity, we find that data sets contain many more complex relationships than we anticipated. Examples include the adduct of glutamate and nicotinamide adenine dinucleotide (NAD), fragments of NAD detected in the same or opposite polarities, and the adduct of glutamate and a background peak. Further, the complex relationships we identify show that several assumptions commonly made when interpreting mass spectral degeneracy do not hold in general. These contributions provide new tools and insight to aid in the annotation of complex spectral relationships and provide a foundation for improved data set identification. Mz.unity is an R package and is freely available at https://github.com/nathaniel-mahieu/mz.unity as well as our laboratory Web site http://pattilab.wustl.edu/software/ . PMID- 27513886 TI - Association between serum vitamin D, retinol and zinc status, and acute respiratory infections in underweight and normal-weight children aged 6-24 months living in an urban slum in Bangladesh. AB - We conducted a longitudinal assessment in 466 underweight and 446 normal-weight children aged 6-24 months living in the urban slum of Dhaka, Bangladesh to determine the association between vitamin D and other micronutrient status with upper respiratory tract infection (URI) and acute lower respiratory infection (ALRI). Incidence rate ratios of URI and ALRI were estimated using multivariable generalized estimating equations. Our results indicate that underweight children with insufficient and deficient vitamin D status were associated with 20% and 23 25% reduced risk of URI, respectively, compared to children with sufficient status. Underweight children, those with serum retinol deficiency were at 1.8 [95% confidence interval (CI) 1.4-2.4] times higher risk of ALRI than those with retinol sufficiency. In normal-weight children there were no significant differences between different vitamin D status and the incidence of URI and ALRI. However, normal-weight children with zinc insufficiency and those that were serum retinol deficient had 1.2 (95% CI 1.0-1.5) times higher risk of URI and 1.9 (95% CI 1.4-2.6) times higher risk of ALRI, respectively. Thus, our results should encourage efforts to increase the intake of retinol-enriched food or supplementation in this population. However, the mechanisms through which vitamin D exerts beneficial effects on the incidence of childhood respiratory tract infection still needs further research. PMID- 27513887 TI - The class III peroxidase PRX17 is a direct target of the MADS-box transcription factor AGAMOUS-LIKE15 (AGL15) and participates in lignified tissue formation. AB - Several physiological functions have been attributed to class III peroxidases (PRXs) in plants, but the in planta role of most members of this family still remains undetermined. Here, we report the first functional characterization of PRX17 (At2g22420), one of the 73 members of this family in Arabidopsis thaliana. Localization of PRX17 was examined by transient expression in Nicotiana benthamiana. Loss- and gain-of-function mutants in A. thaliana were studied. Regulation at the gene and protein levels was analyzed using beta-glucuronidase (GUS) activity, quantitative reverse transcriptase (qRT)-PCR, zymography, and chromatin immunoprecipitation. Phenotypes were characterized including lignin and xylan contents. PRX17 was expressed in various tissues, including vascular tissues, and PRX17 was localized to the cell wall. In prx17, the lignin content was reduced in the stem and siliques and bolting was delayed, while the opposite phenotype was observed in 35S:PRX17 plants, together with a significant increase of lignin and xylan immunofluorescence signal. Finally, we demonstrated that the transcription factor AGAMOUS-LIKE15 (AGL15) binds to the PRX17 promoter and regulates PRX17 expression level. This converging set of structural, transcriptomic and physiological data suggests that PRX17, under the control of AGL15, contributes to developmental programs by playing an essential role in regulating age-dependent lignified tissue formation, including changes in cell wall properties. PMID- 27513888 TI - Follow up with HPV test and cytology as test of cure, 6 months after conization, is reliable. AB - INTRODUCTION: Human papillomavirus (HPV) infection is an objective marker with a high sensitivity for finding cervical dysplasia. The objective of the current study is to investigate whether HPV testing, combined with liquid-based cytology, is reliable as a test of cure after the loop electrical excision procedure (LEEP). MATERIAL AND METHODS: The LEEP was performed in 330 women for excision of cervical dysplasia. Follow up consisted of HPV testing and liquid-based cytology at six, 12, and 36 months after treatment. Patients with negative co-testing after 6 months were re-examined after 3 years. Patients who tested positive for high-risk HPV and/or dysplasia were followed up 12 months postoperatively. RESULTS: At 6 months, the co-testing was double negative in 169 of 260 tested cases (65%). A positive high-risk HPV test (n = 40) was associated with cytological abnormalities (p < 0.001). After 3 years, 227 of 275 examined cases (83%) co-tested negative, including 154 patients who had already tested negative at 6 months and 37 cases with viral clearance at 12 months. Of 26 patients with high-risk HPV at the 3-year follow up, six had LSIL findings on liquid-based cytology, but neither HSIL lesions nor glandular atypia or cervical cancer was found. A negative high-risk HPV test showed a negative predictive value for HSIL of 100% (95% CI 99.8-100%). CONCLUSIONS: Negative co-testing 6 months after LEEP can be considered a reliable test of cure as 3-year follow-up results are consistent with neither HSIL or cancer. PMID- 27513889 TI - The Planar Blatter Radical: Structural Chemistry of 1,4 Dihydrobenzo[e][1,2,4]triazin-4-yls. AB - Two planarized analogues of the prototypical Blatter radical (1), peri-annulated 1S and 1O , are demonstrated and provide a new platform for molecular and supramolecular engineering, and for tuning electronic and magnetic properties of the radical. Planarization of 1 results in bathochromic shift to the near-IR region, greater spin delocalization, and anodic shift of the reduction potential only for 1S . Magnetization studies revealed nearly ideal paramagnetic behavior at high temperatures for both radicals 1S and 1O with one-dimensional ferromagnetic interaction in the former (2J=14.4 cm(-1) ) and antiferromagnetic interactions in 1O at low temperatures. PMID- 27513890 TI - Systematic Review and Meta-Analysis of Doxycycline Efficacy for Rectal Lymphogranuloma Venereum in Men Who Have Sex with Men. AB - Rectal lymphogranuloma venereum (LGV) has reemerged as a sexually transmitted infection among men who have sex with men (MSM), particularly those who are HIV positive. We undertook a systematic review and meta-analysis to determine the efficacy of doxycycline (100 mg 2*/d for 21 days) for rectal LGV in MSM. Nine studies were included: 4 prospective, 4 retrospective, and 1 combined retrospective and prospective. In total, 282 MSM with rectal LGV were included in the studies. All studies reported using nucleic acid amplification tests to assess microbial cure. Most patients (>80%) had symptomatic rectal infection. The fixed-effects pooled efficacy for doxycycline was 98.5% (95% CI 96.3%-100%, I (2) = 0%; p = 0.993). Doxycycline at 100 mg twice daily for 21 days demonstrated a high microbial cure rate. These data support doxycycline at this dosage and duration as first-line therapy for rectal LGV in MSM. PMID- 27513891 TI - CD10 down expression in follicular lymphoma correlates with gastrointestinal lesion involving the stomach and large intestine. AB - Follicular lymphoma (FL) shows co-expression of B-cell lymphoma 2 (BCL2) and CD10, whereas downexpression of CD10 is occasionally experienced in gastrointestinal (GI) FL with unknown significance. Gastrointestinal FL is a rare variant of FL, and its similarity with mucosa-associated lymphoid tissue lymphoma was reported. We investigated the clinicopathological and genetic features of CD10 downexpressed (CD10down ) GI-FL. The diagnosis of CD10down FL was carried out with a combination of pathological and molecular analyses. The incidence of CD10down GI-FL was shown in 35/172 (20.3%) cases, which was more frequent than nodal FL (3.5%, P < 0.001). The difference was additionally significant between GI-FL and nodal FL when the analysis was confined to primary GI-FL (55.2% vs 3.5%, P < 0.001). Compared to CD10+ GI-FL, CD10down GI-FL significantly involved the stomach or large intestine (P = 0.015), and additionally showed the downexpression of BCL6 (P < 0.001). The follicular dendritic cell meshwork often showed a duodenal pattern in the CD10down group (P = 0.12). Furthermore, a lymphoepithelial lesion was observed in 5/12 (40%) gastric FL cases, which indicated caution in the differentiation of mucosa-associated lymphoid tissue lymphoma. Molecular analyses were undertaken in seven cases of CD10down GI-FL, and an identical clone was found between CD10down follicles and CD10+ BCL2+ neoplastic follicles. In the diagnosis of cases with CD10down BCL2+ follicles, careful examination with molecular studies should be carried out. PMID- 27513894 TI - The Structure and Torsional Dynamics of Two Methyl Groups in 2-Acetyl-5 methylfuran as Observed by Microwave Spectroscopy. AB - The molecular-beam Fourier transform microwave spectrum of 2-acetyl-5-methylfuran is recorded in the frequency range 2-26.5 GHz. Quantum chemical calculations calculate two conformers with trans or cis configuration of the acetyl group, both of which are assigned in the experimental spectrum. All rotational transitions split into quintets due to the internal rotations of two nonequivalent methyl groups. By using the program XIAM, the experimental spectra can be simulated with standard deviations within the measurement accuracy, and yield well-determined rotational and internal rotation parameters, inter alia the V3 potentials. Whereas the V3 barrier height of the ring-methyl rotor does not change for the two conformers, that of the acetyl-methyl rotor differs by about 100 cm-1 . The predicted values from quantum chemistry are only on the correct order of magnitude. PMID- 27513892 TI - Targeting of the P2X7 receptor in pancreatic cancer and stellate cells. AB - The ATP-gated receptor P2X7 (P2X7R) is involved in regulation of cell survival and has been of interest in cancer field. Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer and new markers and therapeutic targets are needed. PDAC is characterized by a complex tumour microenvironment, which includes cancer and pancreatic stellate cells (PSCs), and potentially high nucleotide/side turnover. Our aim was to determine P2X7R expression and function in human pancreatic cancer cells in vitro as well as to perform in vivo efficacy study applying P2X7R inhibitor in an orthotopic xenograft mouse model of PDAC. In the in vitro studies we show that human PDAC cells with luciferase gene (PancTu-1 Luc cells) express high levels of P2X7R protein. Allosteric P2X7R antagonist AZ10606120 inhibited cell proliferation in basal conditions, indicating that P2X7R was tonically active. Extracellular ATP and BzATP, to which the P2X7R is more sensitive, further affected cell survival and confirmed complex functionality of P2X7R. PancTu-1 Luc migration and invasion was reduced by AZ10606120, and it was stimulated by PSCs, but not by PSCs from P2X7(-/-) animals. PancTu-1 Luc cells were orthotopically transplanted into nude mice and tumour growth was followed noninvasively by bioluminescence imaging. AZ10606120-treated mice showed reduced bioluminescence compared to saline-treated mice. Immunohistochemical analysis confirmed P2X7R expression in cancer and PSC cells, and in metaplastic/neoplastic acinar and duct structures. PSCs number/activity and collagen deposition was reduced in AZ10606120-treated tumours. PMID- 27513895 TI - Upregulation of microRNA-34a enhances the DDP sensitivity of gastric cancer cells by modulating proliferation and apoptosis via targeting MET. AB - Cisplatin (DDP) based chemotherapy is still the main strategy of human gastric cancer (GC) treatment. However, drug resistance is a major obstacle for DDP chemotherapy. Recent studies indicated that the resistance could be modulated by the regulation of dysregulated microRNAs (miRs). Previous study also found miR 34a was associated with cell proliferation and apoptosis in human GC; however, the relationship between miR-34a and DDP resistance still remains unexplored. The purpose of this study was to investigate whether miR-34a is associated with DDP resistance in human GC cells. Our study found that the expression of miR-34a was significantly decreased in DDP resistance human GC tissues and DDP resistance human GC SGC7901/DDP cells compared with normal GC tissues and cells. Upregulation of miR-34a enhanced the DDP sensitivity of SGC7901/DDP cells to DDP through the inhibition of cell proliferation and induction of cell apoptosis; on the other hand downregulation of miR-34a could weaken the DDP sensitivity of SGC7901 cells to DDP. Further study found that MET was a direct target of miR-34a and the regulation of MET could affect the DDP sensitivity of SGC7901/DDP cells. Moreover, our study also indicated that up-regulation of miR-34a could decrease the expression of MET in SGC7901/DDP cells. Therefore, our findings suggested miR 34a could modulate human gastric cancer cell DDP sensitivity by regulation of cell proliferation and apoptosis via targeting MET, potentially benefiting human GC treatment in the future. PMID- 27513896 TI - Anisotropic thermal motion in transition-metal carbonyls from experiments and ab initio theory. AB - The thermal motion of atoms in crystals is quantified by anisotropic displacement parameters (ADPs). Here we show that dispersion-corrected periodic density functional theory can be used to compute accurate ADPs for transition metal carbonyls, which serve as model systems for crystalline organometallic and coordination compounds. PMID- 27513897 TI - Outpatient induction of labour in the UK: a survey of practice. AB - OBJECTIVE: To identify the current UK use of outpatient procedures for cervical ripening prior to induction of labour. STUDY DESIGN: Postal survey of consultant led obstetric units within the United Kingdom. A questionnaire was sent by post to 210 NHS consultant led obstetric units within the UK. Units that provided outpatient induction of labour (OP IOL) were asked complete a series of questions defining their protocol for risk stratification and management. RESULTS: The survey had a 78% response rate. 17.6% of units stated that they currently or soon will provide OP IOL. All units were willing to provide OP IOL for post-dates singleton pregnancies and none provided this service for women with a previous caesarean or multiple pregnancy. 96% of inductions were initiated in a hospital setting prior to discharge home. 84% of units used Propess((r)) to initiate OP IOL and 96% had a fetal assessment with CTG. Only 40% of units had a clear mechanism for assessment once the woman had gone home. 72% of units performed regular audit of their practice. CONCLUSIONS: We suggest that robust comparative research within a UK context is urgently required to establish the safety and cost effectiveness of outpatient induction of labour before this technique becomes fully embedded in clinical care without an adequate evidence base. PMID- 27513898 TI - Self-Monitoring of Intraocular Pressure Outside of Normal Office Hours Using Rebound Tonometry: Initial Clinical Experience in Patients With Normal Tension Glaucoma. AB - PURPOSE: To determine the value and accuracy of 24-hour intraocular pressure (IOP) phasing using Icare ONE rebound tonometry (RTONE), in subjects with normal tension glaucoma (NTG). METHODS: Eighteen consecutive patients with treated NTG were studied, all subjects had undergone 24-hour IOP phasing during a 1-year period. Each patient had daytime (08:00 to 16:00) IOP phasing with Goldmann applanation tonometer at 2-hourly intervals; at these same time points an IOP reading was also obtained by the patient using RTONE. Self-measured IOPs were then recorded at home using RTONE between 18:00 and 06:00 (at 2-hourly intervals). The frequency with which the phasing results altered clinical management was evaluated. RESULTS: The mean peak IOP was significantly higher during nighttime phasing (15.78+/-4.8 mm Hg) compared with daytime phasing (12.83+/-2.7 mm Hg, P=0.0018) and clinic IOP measurements (11.8+/-1.6 mm Hg, P<0.0001). Following IOP phasing a change in management occurred in 10 of 18 patients (56%). In the majority of these patients, a peak IOP was identified during nighttime phasing compared with daytime phasing, this difference was significant (P=0.0090). There were strong correlations between the IOP measurements obtained with Goldmann applanation tonometer and RTONE (Spearman r values >0.60, P<0.001). CONCLUSIONS: This study suggests that in patients with NTG with progression that is disproportionate to their clinic IOP measurements, 24-hour phasing can reveal higher IOP spikes than those identified during typical office hours. RTONE is a safe, easy to use, and accurate device for self monitoring of IOP. PMID- 27513899 TI - Ab Interno Trabeculectomy With the Trabectome as a Valuable Therapeutic Option for Failed Filtering Blebs. AB - PURPOSE: Uncontrolled intraocular pressure (IOP) after glaucoma filtration surgery is a challenging problem in the management of glaucoma patients. The Trabectome is a device for selective electroablation of the trabecular meshwork through a clear cornea incision without affecting the conjunctiva. Minimally invasive glaucoma surgery using the Trabectome is safe and effective as primary glaucoma surgery. Here we investigate the results of ab interno trabeculectomy with the Trabectome for IOP control in patients with a failed filtering bleb. METHODS: A total of 60 eyes of 60 consecutive patients with primary open-angle glaucoma (POAG) or pseudoexfoliative glaucoma (PXG) were enrolled in this single center observational study. Trabectome surgery was performed alone or in combination with phacoemulsification by 2 experienced surgeons. IOP readings and number of IOP lowering medication as primary outcome parameters were taken by an independent examiner. Intraoperative and postoperative medication were recorded systematically. RESULTS: Mean IOP before surgery was 24.5+/-3.5 mm Hg and decreased to 15.7+/-3.4 (-36%) after mean follow-up of 415 days. The number of necessary IOP lowering medication dropped from 2.1+/-1.3 to 1.8+/-1.2 (14% reduction from baseline). A total of 25% (n=15) of cases reported here needed additional surgery after 517 days (range: 6 to 1563 d). No major complications were observed. After mean follow-up, we found a qualified success rate for PXG of 87% and 50% for POAG as revealed by the Kaplan-Meier analysis according to the definitions for success in advanced glaucoma cases according to the World Glaucoma Association (40% reduction from baseline IOP and maximum IOP of 15 mm Hg). DISCUSSION: Trabectome surgery for uncontrolled IOP after trabeculectomy is safe and effective especially in PXG patients. Given the demanding subgroup of patients studied here, it is not surprising that success rates are lower compared with previous studies investigating the Trabectome for primary glaucoma surgery. The number of necessary IOP lowering medication drops at first, but seems to reach preoperative values after 20 months of follow-up. Trabectome surgery should be considered as a valuable escape procedure for patients with failed filtering blebs and uncontrolled IOP. PMID- 27513900 TI - Trabeculectomy and Combined Phacoemulsification-Trabeculectomy: Outcomes and Risk Factors for Failure in Primary Angle Closure Glaucoma. AB - PURPOSE: To evaluate tonometric outcomes of patients with primary angle closure glaucoma (PACG) who have undergone trabeculectomy with mitomycin C (MMC) with and without concurrent phacoemulsification and to identify risk factors for postoperative failure. PATIENTS AND METHODS: Retrospective cohort study of 44 eyes of 33 phakic patients who underwent trabeculectomy with MMC with or without combined phacoemulsification for PACG. The primary endpoint was qualified tonometric success at 12 months according to predefined criteria. LogMAR visual acuity, number of glaucoma medications, and postoperative complications were also evaluated. Cox proportional hazard regression analysis was performed to identify potential risk factors for trabeculectomy failure. RESULTS: Mean intraocular pressure (IOP) decreased from 21.3+/-7.9 to 12.2+/-3.9 mm Hg at 12 months (P<0.001) in all patients. A significant reduction in mean number of glaucoma medications (P<0.001) was also seen. There was no change in logMAR visual acuity (P=0.39) after 12 months. There were no significant intergroup differences in mean IOP (P=0.42), number of glaucoma medications (P=0.85), or logMAR visual acuity (P=0.42) between the trabeculectomy versus combined surgery groups after 12 months. Increased age, greater baseline IOP, limbus-based conjunctival flaps, and MMC duration >1 minute were associated with decreased risk of surgical failure. Concurrent phacoemulsification at the time of trabeculectomy did not alter tonometric success or rate of complications. CONCLUSIONS: In phakic patients with PACG, trabeculectomy with MMC significantly reduces IOP and number of glaucoma medications at 12 months without change in visual acuity. However, success rates are modest when based on more demanding tonometric criteria. PMID- 27513901 TI - The Association of Chronic Topical Prostaglandin Analog Use With Meibomian Gland Dysfunction. AB - PURPOSE: To evaluate the association of long-term prostaglandin analog (PGA) use with meibomian gland dysfunction (MGD) in medically treated glaucoma patients. MATERIALS AND METHODS: This was a prospective cross-sectional study conducted at a single academic setting. In total, 70 eyes of 70 patients with a medical diagnosis of glaucoma who were on long-term (>12 mo) topical hypotensive medication(s) were included. Patients were classified based on whether they were on PGA or non-PGA class of medication(s). MGD was defined based on meibomian gland terminal duct obstruction and graded between 1 and 5 based on severity. For all subjects, ocular surface disease index questionnaire, break-up time, lissamine green staining, and Schirmer test (under topical anesthesia) was administered. Student t test, Mann-Whitney U test, and chi test was used in statistical evaluations. Forty-five age-matched healthy control subjects who were not on any topical medications were also included. RESULTS: In total, 25 patients (35.7%) were on PGA monotherapy, 21 (30.0%) were treated with fixed or unfixed PGA combination regimens, and 24 (34.3%) were on non-PGA medications. MGD prevalence was higher in patients treated with PGA monotherapy (92.0%) compared with those receiving non-PGA therapy (58.3%) (P=0.02). Obstructive type of MGD was detected in the majority of patients treated with PGAs (95.7%). Grade 2 and 3 MGD was noted in 80.5% of patients on PGA. Patients on PGA had worse ocular surface disease index and ocular surface test results (P<0.001) compared with those of control subjects. CONCLUSIONS: Long-term administration of PGA is associated with obstructive type of MGD. PMID- 27513902 TI - Evaluation of Interocular Retinal Nerve Fiber Layer Thickness Symmetry as a Diagnostic Modality for Glaucoma. AB - PURPOSE OF THE STUDY: The purpose of study was to measure the diagnostic utility of interocular retinal nerve fiber layer (RNFL) symmetry and interocular RNFL thickness comparison. METHODS: Both eyes of 103 normal subjects and 106 glaucoma patients (31 patients with early glaucoma and 75 patients with moderate to severe glaucoma) received comprehensive ophthalmologic evaluation including visual field testing and optic disc scanning using optical coherence tomography. RNFL thickness values for 256 measurement points were rearranged according to a new reference line connecting the optic disc center and the foveola. The interocular RNFL thickness symmetry value and absolute and fractional interocular difference in RNFL thickness were calculated and compared between groups. Area under the receiver operating characteristic curves (AUROCs) were calculated and compared. RESULT: Among the parameters reflecting whole RNFL status, the corrected interocular RNFL thickness symmetry exhibited the largest AUROCs at all glaucoma stages. RNFL thickness and absolute and fractional interocular difference in RNFL thickness exhibited largest AUROC in the inferotemporal area, regardless of glaucoma stage. In the early glaucoma group, absolute and fractional interocular RNFL thickness differences in the temporal and superotemporal areas exhibited equal to or larger AUROCs than RNFL thickness. The AUROCs for RNFL thickness were greater than those for absolute and fractional interocular RNFL thickness differences in the moderate to severe glaucoma group except in the nasal and temporal area. CONCLUSIONS: The corrected interocular RNFL thickness symmetry value is an effective diagnostic tool for glaucoma. Interocular comparison of RNFL thickness has good diagnostic performance and gives information about the RNFL beyond just the RNFL thickness itself. PMID- 27513903 TI - Comparison of Smartphone Ophthalmoscopy With Slit-Lamp Biomicroscopy for Grading Vertical Cup-to-Disc Ratio. AB - PURPOSE OF THE STUDY: The purpose of the study was to determine the agreement between smartphone ophthalmoscopy and slit-lamp indirect biomicroscopy when assessing vertical cup-to-disc ratios (VCDRs). MATERIALS AND METHODS: This was a clinical-based, prospective, comparative instrument study performed in 110 patients with ocular hypertension (OH) or primary open angle glaucoma (POAG). Patients underwent estimation of VCDR by undilated smartphone ophthalmoscopy and slit-lamp biomicroscopy by 2 masked glaucoma specialists. RESULTS: The differences between the mean VCDR estimations obtained by each techniques were not statistically significant. Overall exact agreement between the 2 modalities was found in 21 of 29 eyes (72.4%; simple kappa=0.63, confidence interval, 0.52 0.73, P<0.001) in POAG patients and in 52 of 78 eyes (66.7%) in OH patients. The optic nerve head was not gradable with smartphone ophthalmoscopy in 1 eye with POAG and in 2 eyes with OH because of media opacities and/or small pupil diameter. CONCLUSIONS: Smartphone ophthalmoscopy showed substantial agreement with slit-lamp examination for the estimation of the VCDR. The ubiquitous diffusion of the smartphones, together with their connectivity and portability features, enables an extensive benefit for this technology to be used in glaucoma screening, especially in low-resource settings. PMID- 27513904 TI - Acquired Corneal Neuropathy and Photoallodynia Associated With Malposition of an Ex-PRESS Shunt. AB - PURPOSE: Corneal neuropathy is a recently described disease process that is not well understood and is likely underdiagnosed as a result. This is the first reported case of an acquired corneal neuropathy associated with malposition of an Ex-PRESS shunt. METHODS: A single case report. RESULTS: We report the case of a 50-year-old man with a history of multiple procedures for glaucoma who subsequently developed photoallodynia and corneal neuropathy in association with malposition of an Ex-PRESS shunt in the peripheral cornea. Laser confocal microscopy (HRT3/RCM) of the cornea showed the presence of neuromas, decreased nerve density, and a significant increase of dendritiform immune cells consistent with our diagnosis. Initial treatment with steroid pulse therapy did not result in decreased inflammation or symptomatic improvement leading to surgical explantation of the shunt. One month after surgery, there was noticeable improvement in the patient's pain and photoallodynia (approximately 40%) as well as the abnormalities seen on confocal microscopy. CONCLUSIONS: We hypothesize that poor Ex-PRESS shunt positioning can act as a nidus for corneal inflammation, resulting in corneal neuropathy and lowering of the nociception threshold. PMID- 27513905 TI - Intraocular Pressure Outcomes Following Transscleral Diode Cyclophotocoagulation Using Long and Short Duration Burns. AB - PURPOSE: The purpose of this study was to compare outcomes of transscleral diode cyclophotocoagulation using short duration (SD) versus longer duration (LD) treatment. PATIENTS AND METHODS: Data were collected retrospectively on patients with glaucoma who underwent cyclophotocoagulation with LD (4000 ms) treatment with variable power <=1000 mW versus SD using 1500 ms with variable power <=2000 mW. The outcome measures included: intraocular pressure (IOP) at 12 months, decrease in number of antiglaucoma medications, complications and visual acuity (VA) at the final follow-up visit. RESULTS: There were 71 patients and 70 patients in the SD and LD groups, respectively. The mean IOP+/-SD pretreatment baseline was 33+/-10 versus 36+/-10 mm Hg for SD and LD groups, respectively (P>0.05). At 1 year postoperatively, the IOP decreased significantly in both groups (16.7 vs. 17.4 mm Hg for SD and LD, respectively; P<0.0001). This decrease in IOP was comparable between groups (P=0.5). The average number of IOP lowering medications were 2.5 and 2.9 at baseline in the SD and LD groups, respectively, and decreased to 1.3 in both groups (P=0.83). The mean LogMAR VA decreased significantly from 1.87 at baseline to 1.96 at 1 year in the SD group (P=0.276), and 2.03 to 2.3 (P<=0.001) in the LD group, this change was comparable (0.19; P=0.075) between the 2 groups. Complications were also comparable. CONCLUSIONS: Both LD and SD burns during cyclophotocoagulation effectively lowered IOP at 1 year. Neither treatment resulted in a greater reduction of IOP. LD treatment appeared to result in a decrease in VA and greater postoperative inflammation. PMID- 27513906 TI - Progressive Retinal Nerve Fiber Layer Atrophy Associated With Enlarging Peripapillary Pit. AB - PURPOSE: To report a case in which progressive retinal nerve fiber layer (RNFL) atrophy was observed along with enlargement of the peripapillary pit. PATIENTS AND METHODS: A 34-year-old male was diagnosed with primary open-angle glaucoma and followed up for 4 years with regular ophthalmic examinations. Both eyes were myopic (-10 D, OD and -10.5 D, OS), and untreated intraocular pressures were 18 mm Hg (OD) and 16 mm Hg (OS). RESULTS: A subtle depression of the superotemporal peripapillary area was deepened and emerged as a peripapillary pit during the follow-up period. With the enlargement of the peripapillary pit, a RNFL defect at the location of pit widened and thinned continuously. The enlargement of the pit was documented by the spectral-domain optical coherence tomography posterior pole scanning. CONCLUSIONS: Progressive RNFL atrophy was observed with enlargement of the peripapillary pit. The finding suggests that tensile stress derived from the scleral stretching may have significant influence on the integrity of the RNFL. PMID- 27513907 TI - Corneal Densitometry: A New Technique for Objective Assessment of Corneal Clarity in Pseudoexfoliation Syndrome. AB - PURPOSE: To evaluate the corneal clarity quantitatively by using corneal densitometry in patients with pseudoexfoliation syndrome (PES) and to compare the results with those of healthy control subjects. MATERIALS AND METHODS: Corneal densitometry measurement of patients with bilateral PES and healthy control subjects was carried out by Scheimpflug corneal topography (PentacamHR). For densitometry analysis, the 12-mm diameter area of the cornea was subdivided into 4 concentric radial zones (0 to 2, 2 to 6, 6 to 10, 10 to 12 mm) and also into anterior, central, and posterior layers based on corneal depth. Corneal densitometry measurements were expressed in gray scale unit and only the data from the right eyes of subjects were used for statistical analysis. RESULTS: A total of 176 patients [89 with PES (52 male, 37 female) and 87 healthy control subjects (52 male, 35 female)] were enrolled in the study. There was no significant difference between the mean corneal densitometry values at anterior 120 MUm, central, and posterior 60 MUm of the cornea in all concentric radial zones (P>0.05 for all). Corneal densitometry was positively correlated with age in both groups (r=0.558, P<0.001 in PES; r=0.584, P<0.001 in control group). CONCLUSIONS: Corneal densitometry that enables the objective assessment of corneal clarity was found to be similar in patients with bilateral PES and healthy control subjects. It is positively correlated with increasing age in both groups. However, microstructural changes that contribute to the corneal densitometry and the clinical relevance of these findings should be further highlighted in future studies. PMID- 27513908 TI - Temperate Assumptions: How Where We Work Influences How We Think. AB - Scientists have been observing the natural world for centuries and have long been intrigued by the high biodiversity and complexity of the tropics. They also usually had North American or European-in other words, outsider-perspectives and frequently concluded that the tropics were qualitatively different from the temperate regions in their ecology, evolution, and behavior. In particular, the tropics were seen as having a more benign abiotic environment, which in turn fostered more complex biotic relationships, with increased competition and other interactions. This may or may not be the case. Regardless, these ideas establish the temperate regions of the world as a kind of model system, a norm to which the tropics are compared and seen as different or unusual. The tropics are warmer or more diverse, rather than the temperate zone being cooler or less diverse. Such an attitude makes it difficult both to appreciate the scope of variation in nature and to develop accurate and general models for ecological and evolutionary processes. PMID- 27513909 TI - Ecological Causes and Consequences of Intratropical Migration in Temperate Breeding Migratory Birds. AB - New discoveries from direct tracking of temperate-breeding passerines show that intratropical migration (ITM) occurs in a growing number of species, which has important implications for understanding their evolution of migration, population dynamics, and conservation needs. Our large sample size ([Formula: see text]) for purple martins (Progne subis subis) tracked with geolocators to winter sites in Brazil, combined with geolocator deployments at breeding colonies across North America, allowed us to test hypotheses for ITM, something which has not yet been possible to do for other species. ITM in purple martins was not obligate; only 44% of individuals exhibited ITM, and movements were not coordinated in time or space. We found no evidence to support the resource hypothesis; rainfall and temperature experienced by individual birds during their last 2 weeks at their first roost site were similar to conditions at their second roost site after ITM. Birds generally migrated away from the heavily forested northwestern Amazon to less forested regions to the south and east. ITM in this aerial insectivore appears to support the competition-avoidance hypothesis and may be triggered by increasing local density in the core wintering region. Full life cycle models and migratory networks will need to incorporate ITM to properly address seasonal carryover effects and identify which wintering regions are most important for conservation. PMID- 27513910 TI - Polyandry, Predation, and the Evolution of Frog Reproductive Modes. AB - Frog reproductive modes are complex phenotypes that include egg/clutch characteristics, oviposition site, larval development, and sometimes, parental care. Two evident patterns in the evolution of these traits are the higher diversity of reproductive modes in the tropics and the apparent progression from aquatic to terrestrial reproduction, often attributed to higher fitness resulting from decreased predation on terrestrial eggs and tadpoles. Here, we propose that sexual selection-and not only natural selection due to predation-favors terrestrial breeding by reducing the loss of fitness due to polyandry. To examine this novel selective mechanism, we reconstructed the evolution of reproductive diversity in two frog families (Hylidae and Leptodactylidae) and tested for concerted evolution of egg and tadpole development sites with specific mating behaviors. We found that oviposition and tadpole development sites are evolving independently, do not show the same diversity and/or directionality in terms of terrestriality, and thus may be diversifying due to different selective mechanisms. In both families, terrestrial egg deposition is correlated with amplexus that is hidden from competing males, and in hylids, testes mass was significantly larger and more variable in males with exposed amplexus that are vulnerable to polyandry. Our results indicate that intrasexual selection has been an underappreciated mechanism promoting diversification of frog reproductive modes. PMID- 27513911 TI - Biogeochemistry and Geographical Ecology: Embracing All Twenty-Five Elements Required to Build Organisms. AB - Biogeochemistry is a key but relatively neglected part of the abiotic template that underlies ecology. The template has a geography, one that is increasingly being rearranged in this era of global change. Justus von Liebig's law of the minimum has played a useful role in focusing attention on biogeochemical regulation of populations, but given that ~25+ elements are required to build organisms and that these organisms use and deplete nutrients in aggregates of communities and ecosystems, we make the case that it is time to move on. We review available models that suggest the many different mechanisms that give rise to multiple elements, or colimitation. We then review recent empirical data that show that rates of decomposition and primary productivity may be limited by multiple elements. In that light, given the tropics' high species diversity and generally more weathered soils, we predict that colimitation at community and ecosystem scales is more prevalent closer to the equator. We conclude with suggestions for how to move forward with experimental studies of colimitation. PMID- 27513912 TI - Is There a Temperate Bias in Our Understanding of How Climate Change Will Alter Plant-Herbivore Interactions? A Meta-analysis of Experimental Studies. AB - Climate change can drive major shifts in community composition and interactions between resident species. However, the magnitude of these changes depends on the type of interactions and the biome in which they take place. We review the existing conceptual framework for how climate change will influence tropical plant-herbivore interactions and formalize a similar framework for the temperate zone. We then conduct the first biome-specific tests of how plant-herbivore interactions change in response to climate-driven changes in temperature, precipitation, ambient CO2, and ozone. We used quantitative meta-analysis to compare predicted and observed changes in experimental studies. Empirical studies were heavily biased toward temperate systems, so testing predicted changes in tropical plant-herbivore interactions was virtually impossible. Furthermore, most studies investigated the effects of CO2 with limited plant and herbivore species. Irrespective of location, most studies manipulated only one climate change factor despite the fact that different factors can act in synergy to alter responses of plants and herbivores. Finally, studies of belowground plant-herbivore interactions were also rare; those conducted suggest that climate change could have major effects on belowground subsystems. Our results suggest that there is a disconnection between the growing literature proposing how climate change will influence plant-herbivore interactions and the studies testing these predictions. General conclusions will also be hampered without better integration of above- and belowground systems, assessing the effects of multiple climate change factors simultaneously, and using greater diversity of species in experiments. PMID- 27513913 TI - Macroecology of Sexual Selection: A Predictive Conceptual Framework for Large Scale Variation in Reproductive Traits. AB - Abiotic factors exert direct and indirect influences on behavioral, morphological, and life-history traits. Because some of these traits are related to reproduction, there is a causal link between climatic conditions and the expression of reproductive traits. This link allows us to generate predictions on how reproductive traits vary in large geographic scales. Here we formalize this macroecological framework, present some general predictions, and explore empirical examples using harvestmen as study organisms. Our results show that the length of breeding season in harvestmen is primarily influenced by the number of warm months and that precipitation plays a secondary role in modulating the period devoted to reproduction. Moreover, we show that the probability of resource defense polygyny increases with longer breeding seasons and that the presence of this type of mating system positively affects the magnitude of sexual dimorphism in harvestmen. Finally, the presence of postovipositional parental care is also influenced by the length of breeding season but not by actual evapotranspiration, which is our proxy for the intensity of biotic interactions. We argue that the macroecological framework proposed here may be a fruitful field of investigation, with important implications for our understanding of sexual selection and the evolution of reproductive traits in both animals and plants. PMID- 27513914 TI - Geographical Variation in the Availability of Natural History Field Guides? Personal Reflections, Causes, and Consequences. PMID- 27513915 TI - Differential functional readthrough over homozygous nonsense mutations contributes to the bleeding phenotype in coagulation factor VII deficiency. AB - : Essentials Potentially null homozygous Factor(F)7 nonsense mutations are associated to variable bleeding symptoms. Readthrough of p.Ser112X (life threatening) and p.Cys132X (moderate) stop codons was investigated. Readthrough mediated insertion of wild-type or tolerated residues produce functional proteins. Functional readthrough over homozygous F7 nonsense mutations contributes to the bleeding phenotype. SUMMARY: Background Whereas the rare homozygous nonsense mutations causing factor (F)VII deficiency may predict null conditions that are almost completely incompatible with life, they are associated with appreciable differences in hemorrhagic symptoms. The misrecognition of premature stop codons (readthrough) may account for variable levels of functional full-length proteins. Objectives To experimentally evaluate the basal and drug induced levels of FVII resulting from the homozygous p.Cys132X and p.Ser112X nonsense mutations that are associated with moderate (132X) or life-threatening (112X) symptoms, and that are predicted to undergo readthrough with (132X) or without (112X) production of wild-type FVII. Methods We transiently expressed recombinant FVII (rFVII) nonsense and missense variants in human embryonic kidney 293 cells, and evaluated secreted FVII protein and functional levels by ELISA, activated FX generation, and coagulation assays. Results The levels of functional FVII produced by p.Cys132X and p.Ser112X mutants (rFVII-132X, 1.1% +/- 0.2% of wild-type rFVII; rFVII-112X, 0.5% +/- 0.1% of wild-type rFVII) were compatible with the occurrence of spontaneous readthrough, which was magnified by the addition of G418 - up to 12% of the wild-type value for the rFVII-132X nonsense variant. The predicted missense variants arising from readthrough abolished (rFVII-132Trp/Arg) or reduced (rFVII-112Trp/Cys/Arg, 22-45% of wild-type levels) secretion and function. These data suggest that the appreciable rescue of p.Cys132X function was driven by reinsertion of the wild-type residue, whereas the minimal p.Ser112X function was explained by missense changes permitting FVII secretion and function. Conclusions The extent of functional readthrough might explain differences in the bleeding phenotype of patients homozygous for F7 nonsense mutations, and prevent null conditions even for the most readthrough unfavorable mutations. PMID- 27513916 TI - Chronic lithium treatment rectifies maladaptive dopamine release in the nucleus accumbens. AB - Chronic lithium treatment effectively reduces behavioral phenotypes of mania in humans and rodents. The mechanisms by which lithium exerts these actions are poorly understood. Pre-clinical and clinical evidence have implicated increased mesolimbic dopamine (DA) neurotransmission with mania. We used fast-scan cyclic voltammetry to characterize changes in extracellular DA concentrations in the nucleus accumbens (NAc) core evoked by 20 and 60 Hz electrical stimulation of the ventral tegmental area (VTA) in C57BL6/J mice treated either acutely or chronically with lithium. The effects of chronic lithium treatment on the availability of DA for release were assessed by depleting readily releasable DA using short inter-train intervals, or administering d-amphetamine acutely to mobilize readily releasable DA. Chronic, but not acute, lithium treatment decreased the amplitude of DA responses in the NAc following 60 Hz pulse train stimulation. Neither lithium treatment altered the kinetics of DA release or reuptake. Chronic treatment did not impact the progressive reduction in the amplitude of DA responses when, using 20 or 60 Hz pulse trains, the VTA was stimulated every 6 s to deplete DA. Specifically, the amplitude of DA responses to 60 Hz pulse trains was initially reduced compared to control mice, but by the fifth pulse train, there was no longer a treatment effect. However, chronic lithium treatment attenuated d-amphetamine-induced increases in DA responses to 20 Hz pulse trains stimulation. Our data suggest that long-term administration of lithium may ameliorate mania phenotypes by normalizing the readily releasable DA pool in VTA axon terminals in the NAc. Read the Editorial Highlight for this article on Page 520. PMID- 27513917 TI - OMPcontact: An Outer Membrane Protein Inter-Barrel Residue Contact Prediction Method. AB - In the two transmembrane protein types, outer membrane proteins (OMPs) perform diverse important biochemical functions, including substrate transport and passive nutrient uptake and intake. Hence their 3D structures are expected to reveal these functions. Because experimental structures are scarce, predicted 3D structures are more adapted to OMP research instead, and the inter-barrel residue contact is becoming one of the most remarkable features, improving prediction accuracy by describing the structural information of OMPs. To predict OMP structures accurately, we explored an OMP inter-barrel residue contact prediction method: OMPcontact. Multiple OMP-specific features were integrated in the method, including residue evolutionary covariation, topology-based transmembrane segment relative residue position, OMP lipid layer accessibility, and residue evolution conservation. These features describe the properties of a residue pair in different respects: sequential, structural, evolutionary, and biochemical. Within a 3-residues slide window, a Support Vector Machine (SVM) could accurately determinate the inter-barrel contact residue pair using above features. A 5-fold cross-valuation process was applied in testing the OMPcontact performance against a non-redundant OMP set with 75 samples inside. The tests compared four evolutionary covariation methods and screen analyzed the adaptive ones for inter barrel contact prediction. The results showed our method not only efficiently realized the prediction, but also scored the possibility for residue pairs reliably. This is expected to improve OMP tertiary structure prediction. Therefore, OMPcontact will be helpful in compiling a structural census of outer membrane protein. PMID- 27513919 TI - Differences in sensitivity to parenting depending on child temperament: A meta analysis. AB - Several models of individual differences in environmental sensitivity postulate increased sensitivity of some individuals to either stressful (diathesis-stress), supportive (vantage sensitivity), or both environments (differential susceptibility). In this meta-analysis we examine whether children vary in sensitivity to parenting depending on their temperament, and if so, which model can best be used to describe this sensitivity pattern. We tested whether associations between negative parenting and negative or positive child adjustment as well as between positive parenting and positive or negative child adjustment would be stronger among children higher on putative sensitivity markers (difficult temperament, negative emotionality, surgency, and effortful control). Longitudinal studies with children up to 18 years (k = 105 samples from 84 studies, Nmean = 6,153) that reported on a parenting-by-temperament interaction predicting child adjustment were included. We found 235 independent effect sizes for associations between parenting and child adjustment. Results showed that children with a more difficult temperament (compared with those with a more easy temperament) were more vulnerable to negative parenting, but also profited more from positive parenting, supporting the differential susceptibility model. Differences in susceptibility were expressed in externalizing and internalizing problems and in social and cognitive competence. Support for differential susceptibility for negative emotionality was, however, only present when this trait was assessed during infancy. Surgency and effortful control did not consistently moderate associations between parenting and child adjustment, providing little support for differential susceptibility, diathesis-stress, or vantage sensitivity models. Finally, parenting-by-temperament interactions were more pronounced when parenting was assessed using observations compared to questionnaires. (PsycINFO Database Record PMID- 27513920 TI - Bone regeneration in mandibular fractures after the application of autologous mesenchymal stem cells, a randomized clinical trial. AB - BACKGROUND/AIM: Facial injury in adults can commonly result in fractures of the mandible. Autologous mesenchymal stem cells (AMSCs) transplantation is proposed as an alternative to conventional graft treatment to improve bone regeneration. The aim was to evaluate the effectiveness of AMSCs application in mandibular fractures to reduce regeneration time and increase bone quality. MATERIALS AND METHODS: This study was a single-blind controlled clinical trial conducted in patients with mandibular angle fractures. Patients were divided into two groups: study group fracture reduction plus application of AMSCs and control group only fracture reduction. AMSCs were obtained from adipose tissue 24 h before the procedure. Intensity and density were evaluated in normal bone and fractured bone at 4 and 12 weeks after surgery using panoramic radiography and computed tomography. RESULTS: A total of 20 patients, 10 in each group, were included. The study group had a mean age of 31.2 +/- 6.3 years, and the control group mean age was 29.7 +/- 7.2 years. All patients were male. Bone quality measured in grey levels at week 4 was 108.82 +/- 3.4 vs 93.92 +/- 2.6 (P = 0.000) using panoramic radiography and 123 +/- 4.53 vs 99.72 +/- 5.72 (P = 0.000) using computed tomography. At week 12, the measurements were 153.53 +/- 1.83 vs 101.81 +/- 4.83 (P = 0.000) using panoramic radiography and 165.4 +/- 4.2 vs 112.9 +/- 2.0 (P = 0.000) using tomography in the study and control groups, respectively. CONCLUSION: Similar ossification values were obtained after 4 weeks when the use of AMSCs was compared to simple fracture reduction. However, after 12 weeks, the AMSCs group had a 36.48% higher ossification rate. PMID- 27513921 TI - Cobalt Carbonate Hydroxide Nanowire Array on Ti Mesh: An Efficient and Robust 3D Catalyst for On-Demand Hydrogen Generation from Alkaline NaBH4 Solution. AB - In this work, for the first time, a cobalt carbonate hydroxide (Co(CO3 )0.5 (OH)?0.11 H2 O) nanowire array on Ti mesh (CHNA/Ti) was applied to drive the dehydrogenation of alkaline NaBH4 solution for on-demand hydrogen production. Compared with other nanostructured Co-based catalyst systems, CHNA/Ti can be activated more quickly and separated easily from fuel solutions. This self supported cobalt salt nanowire array catalyst works as an efficient and robust 3D catalyst for the hydrolysis reaction of NaBH4 with a hydrogen generation rate of 4000 mL min-1 gCo-1 and a low apparent activation energy of 39.78 kJ mol-1 and offers an attractive system for on-demand hydrogen generation. PMID- 27513922 TI - Differences in sensitivity to microstructure between cyclic- and impact-based microindentation of human cortical bone. AB - Unlike the known relationships between traditional mechanical properties and microstructural features of bone, the factors that influence the mechanical resistance of bone to cyclic reference point microindention (cRPI) and impact microindention (IMI) have yet to be identified. To determine whether cRPI and IMI properties depend on microstructure, we indented the tibia mid-shaft, the distal radius, and the proximal humerus from 10 elderly donors using the BioDent and OsteoProbe (neighboring sites). As the only output measure of IMI, bone material strength index (BMSi) was significantly different across all three anatomical sites being highest for the tibia mid-shaft and lowest for the proximal humerus. Total indentation distance (inverse of BMSi) was higher for the proximal humerus than for the tibia mid-shaft but was not different between other anatomical comparisons. As a possible explanation for the differences in BMSi, pore water, as determined by 1 H nuclear magnetic resonance, was lowest for the tibia and highest for the humerus. Moreover, the local intra-cortical porosity, as determined by micro-computed tomography, was negatively correlated with BMSi for both arm bones. BMSi was also positively correlated with peak bending stress of cortical bone extracted from the tibia mid-shaft. Microstructural correlations with cRPI properties were not significant for any of the bones. The one exception was that average energy dissipated during cRPI was negatively correlated with local tissue mineral density in the tibia mid-shaft. With higher indentation force and larger tip diameter than cRPI, only IMI appears to be sensitive to the underlying porosity of cortical bone. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1442-1452, 2017. PMID- 27513923 TI - Angiogenic Factor AGGF1 Activates Autophagy with an Essential Role in Therapeutic Angiogenesis for Heart Disease. AB - AGGF1 is an angiogenic factor with therapeutic potential to treat coronary artery disease (CAD) and myocardial infarction (MI). However, the underlying mechanism for AGGF1-mediated therapeutic angiogenesis is unknown. Here, we show for the first time that AGGF1 activates autophagy, a housekeeping catabolic cellular process, in endothelial cells (ECs), HL1, H9C2, and vascular smooth muscle cells. Studies with Atg5 small interfering RNA (siRNA) and the autophagy inhibitors bafilomycin A1 (Baf) and chloroquine demonstrate that autophagy is required for AGGF1-mediated EC proliferation, migration, capillary tube formation, and aortic ring-based angiogenesis. Aggf1+/- knockout (KO) mice show reduced autophagy, which was associated with inhibition of angiogenesis, larger infarct areas, and contractile dysfunction after MI. Protein therapy with AGGF1 leads to robust recovery of myocardial function and contraction with increased survival, increased ejection fraction, reduction of infarct areas, and inhibition of cardiac apoptosis and fibrosis by promoting therapeutic angiogenesis in mice with MI. Inhibition of autophagy in mice by bafilomycin A1 or in Becn1+/- and Atg5 KO mice eliminates AGGF1-mediated angiogenesis and therapeutic actions, indicating that autophagy acts upstream of and is essential for angiogenesis. Mechanistically, AGGF1 initiates autophagy by activating JNK, which leads to activation of Vps34 lipid kinase and the assembly of Becn1-Vps34-Atg14 complex involved in the initiation of autophagy. Our data demonstrate that (1) autophagy is essential for effective therapeutic angiogenesis to treat CAD and MI; (2) AGGF1 is critical to induction of autophagy; and (3) AGGF1 is a novel agent for treatment of CAD and MI. Our data suggest that maintaining or increasing autophagy is a highly innovative strategy to robustly boost the efficacy of therapeutic angiogenesis. PMID- 27513924 TI - Efficient Gene Tree Correction Guided by Genome Evolution. AB - MOTIVATIONS: Gene trees inferred solely from multiple alignments of homologous sequences often contain weakly supported and uncertain branches. Information for their full resolution may lie in the dependency between gene families and their genomic context. Integrative methods, using species tree information in addition to sequence information, often rely on a computationally intensive tree space search which forecloses an application to large genomic databases. RESULTS: We propose a new method, called ProfileNJ, that takes a gene tree with statistical supports on its branches, and corrects its weakly supported parts by using a combination of information from a species tree and a distance matrix. Its low running time enabled us to use it on the whole Ensembl Compara database, for which we propose an alternative, arguably more plausible set of gene trees. This allowed us to perform a genome-wide analysis of duplication and loss patterns on the history of 63 eukaryote species, and predict ancestral gene content and order for all ancestors along the phylogeny. AVAILABILITY: A web interface called RefineTree, including ProfileNJ as well as a other gene tree correction methods, which we also test on the Ensembl gene families, is available at: http://www ens.iro.umontreal.ca/~adbit/polytomysolver.html. The code of ProfileNJ as well as the set of gene trees corrected by ProfileNJ from Ensembl Compara version 73 families are also made available. PMID- 27513925 TI - Equilibrium Dynamics of beta-N-Methylamino-L-Alanine (BMAA) and Its Carbamate Adducts at Physiological Conditions. AB - Elevated incidences of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia complex (ALS/PDC) is associated with beta-methylamino-L-alanine (BMAA), a non protein amino acid. In particular, the native Chamorro people living in the island of Guam were exposed to BMAA by consuming a diet based on the cycad seeds. Carbamylated forms of BMAA are glutamate analogues. The mechanism of neurotoxicity of the BMAA is not completely understood, and BMAA acting as a glutamate receptor agonist may lead to excitotoxicity that interferes with glutamate transport systems. Though the interaction of BMAA with bicarbonate is known to produce carbamate adducts, here we demonstrate that BMAA and its primary and secondary adducts coexist in solution and undergoes a chemical exchange among them. Furthermore, we determined the rates of formation/cleavage of the carbamate adducts under equilibrium conditions using two-dimensional proton exchange NMR spectroscopy (EXSY). The coexistence of the multiple forms of BMAA at physiological conditions adds to the complexity of the mechanisms by which BMAA functions as a neurotoxin. PMID- 27513926 TI - Testing and Treating Women after Unsuccessful Conservative Treatments for Overactive Bladder or Mixed Urinary Incontinence: A Model-Based Economic Evaluation Based on the BUS Study. AB - OBJECTIVE: To compare the cost-effectiveness of bladder ultrasonography, clinical history, and urodynamic testing in guiding treatment decisions in a secondary care setting for women failing first line conservative treatment for overactive bladder or urgency-predominant mixed urinary incontinence. DESIGN: Model-based economic evaluation from a UK National Health Service (NHS) perspective using data from the Bladder Ultrasound Study (BUS) and secondary sources. METHODS: Cost effectiveness analysis using a decision tree and a 5-year time horizon based on the outcomes of cost per woman successfully treated and cost per Quality-Adjusted Life-Year (QALY). Deterministic and probabilistic sensitivity analyses, and a value of information analysis are also undertaken. RESULTS: Bladder ultrasonography is more costly and less effective test-treat strategy than clinical history and urodynamics. Treatment on the basis of clinical history alone has an incremental cost-effectiveness ratio (ICER) of L491,100 per woman successfully treated and an ICER of L60,200 per QALY compared with the treatment of all women on the basis of urodynamics. Restricting the use of urodynamics to women with a clinical history of mixed urinary incontinence only is the optimal test-treat strategy on cost-effectiveness grounds with ICERs of L19,500 per woman successfully treated and L12,700 per QALY compared with the treatment of all women based upon urodynamics. Conclusions remained robust to sensitivity analyses, but subject to large uncertainties. CONCLUSIONS: Treatment based upon urodynamics can be seen as a cost-effective strategy, and particularly when targeted at women with clinical history of mixed urinary incontinence only. Further research is needed to resolve current decision uncertainty. PMID- 27513927 TI - Measure, Then Show: Grasping Human Evolution Through an Inquiry-Based, Data driven Hominin Skulls Lab. AB - Incomprehension and denial of the theory of evolution among high school students has been observed to also occur when teachers are not equipped to deliver a compelling case also for human evolution based on fossil evidence. This paper assesses the outcomes of a novel inquiry-based paleoanthropology lab teaching human evolution to high-school students. The inquiry-based Be a Paleoanthropologist for a Day lab placed a dozen hominin skulls into the hands of high-school students. Upon measuring three variables of human evolution, students explain what they have observed and discuss findings. In the 2013/14 school year, 11 biology classes in 7 schools in the Greater New Orleans area participated in this lab. The interviewed teacher cohort unanimously agreed that the lab featuring hominin skull replicas and stimulating student inquiry was a pedagogically excellent method of delivering the subject of human evolution. First, the lab's learning path of transforming facts to data, information to knowledge, and knowledge to acceptance empowered students to themselves execute part of the science that underpins our understanding of deep time hominin evolution. Second, although challenging, the hands-on format of the lab was accessible to high-school students, most of whom were readily able to engage the lab's scientific process. Third, the lab's exciting and compelling pedagogy unlocked higher order thinking skills, effectively activating the cognitive, psychomotor and affected learning domains as defined in Bloom's taxonomy. Lastly, the lab afforded students a formative experience with a high degree of retention and epistemic depth. Further study is warranted to gauge the degree of these effects. PMID- 27513928 TI - Challenges to the Design of Clinical Trials for Live-Attenuated Tetravalent Dengue Vaccines. PMID- 27513929 TI - Serum-Based Quantification of MYCN Gene Amplification in Young Patients with Neuroblastoma: Potential Utility as a Surrogate Biomarker for Neuroblastoma. AB - We previously developed a method for determining MYCN gene amplification status using cell-free DNA fragments released from cancer cells into the blood of patients with neuroblastoma (NB). Here, we analyzed the relationship between MYCN amplification (MNA) status and neuroblastoma prognosis. We screened serum samples from 151 patients with NB for MNA, using real-time quantitative PCR, and compared the results with MYCN status determined using paired tumor samples. We additionally investigated whether MNA status correlates with patient survival. When a cut-off value of 5 was used, serum-based MNA analysis was found to show good sensitivity (86%) and very high specificity (95%). The sensitivities for stage 1 and 2 might be acceptable, even though it is not as good as for stage 3 and 4 (67% for stage 1 and 2, 92% for stage 3, and 87% for stage 4). MNA status correlated with overall survival in our cohort of 82 patients, with survival data available (p < 0.01). The hazard ratio of MNA status was 4.98 in patients diagnosed at less than 18 months of age (95% confidence interval, 1.00-24.78), and 1.41 (95% confidence interval, 0.63-3.14) for those diagnosed at 18 months of age or older. Serum-based MNA analysis is rapid and non-invasive compared with tumor-based MNA analysis, and has potential to predict tumor MNA status. There is still a room to improve the sensitivity of the test for tumors of stages 1 and 2, nonetheless this assay might help to determine therapeutic strategies prior to tumor biopsy, especially for patients with a life-threatening condition, as well as for patients of less than 18 months of age whose risk-grouping and treatment allocation depends on their MNA status. PMID- 27513930 TI - Angiostrongylus cantonensis and A. malaysiensis Broadly Overlap in Thailand, Lao PDR, Cambodia and Myanmar: A Molecular Survey of Larvae in Land Snails. AB - Angiostrongylus cantonensis is a zoonotic nematode parasite causing human eosinophilic meningitis (or meningoencephalitis) worldwide. A closely related species, Angiostrongylus malaysiensis, might also be a human pathogen. Larvae were obtained from land snails in Lao PDR, Cambodia, Myanmar and Thailand. We sequenced two nuclear gene regions (nuclear ribosomal ITS2 and SSU rRNA) and a portion of one mitochondrial gene (COI) from these larvae. Angiostrongylus cantonensis and A. malaysiensis were identified. This is the first report of the molecular identification of the two Angiostrongylus species in Lao PDR, Cambodia and Myanmar. The regional distributions of the two species broadly overlap. Phylogenetic relationships were inferred including data from Angiostrongylus species deposited in public databases. All the gene regions we sequenced have potential value in distinguishing between species of Angiostrongylus. The COI gene exhibited the greatest intraspecific variation in the study region (five haplotypes in A. cantonensis and four in A. malaysiensis) and might be suitable for more detailed phylogeographic studies. PMID- 27513931 TI - Relationship between VEGF Gene Polymorphisms and Serum VEGF Protein Levels in Patients with Rheumatoid Arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is one of the chronic autoimmune diseases, with genetic and environmental predisposition, and synovial angiogenesis is considered to be a notable stage in its pathogenesis. Angiogenesis or vascular proliferation has been suggested to be a pivotal mechanism involved in both inflammation/immune activation and joint invasion and destruction. RA may be considered an "angiogenic disease" because it is associated with active tissue neovascularization. Vascular endothelial growth factor (VEGF) promotes vascular permeability, regulates angiogenesis, endothelial cell proliferation and migration, chemotaxis, and capillary hyper permeability and therefore is involved in the development of inflammation. VEGF is the most potent proangiogenic molecule promoting the angiogenic phenotype of RA and is upregulated in RA. OBJECTIVES: The aim of the study was to identify functional VEGF variants and their possible association with VEGF expression, susceptibility to and severity of RA. METHODS: 581 RA patients and of 341 healthy individuals were examined for 1154 A/G, -2578 A/C VEGF gene polymorphisms by PCR-RFLP method and for -634 G/C VEGF gene polymorphisms by TaqMan SNP genotyping assay. Serum VEGF levels in RA patients and controls were measured by ELISA. RESULTS: The -1154 A/G VEGF gene polymorphism under the codominant, recessive (AA+AG vs. GG) and dominant (AA vs. AG+GG) models were associated with RA (p = 0.0009; p = 0.004; p = 0.017, respectively). VEGF -2578 A/C revealed differences in the case-control distribution in codominant, recessive, dominant and overdominant models (all p<0.0001). Furthermore, the -634 G/C VEGF gene SNP was not correlated with susceptibility to RA in Polish population. The genotype-phenotype analysis showed significant association between the VEGF -1154 A/G and -634 G/C and mean value of the hemoglobin (all p = 0.05), additionally they relevated that the number of women with the polymorphic allele -2578 C was lower than the number of women with wild type allele -2578A (p = 0.006). Serum VEGF levels were significantly higher in RA patients than in control groups (both p = 0,0001). CONCLUSION: Present findings indicated that VEGF genetic polymorphism as well as VEGF protein levels may be associated with the susceptibility to RA in the Polish population. PMID- 27513932 TI - Long Term Effects on Risk Factors for Cardiovascular Disease after 12-Months of Aerobic Exercise Intervention - A Worksite RCT among Cleaners. AB - OBJECTIVES: Occupational groups exposed to high occupational physical activity have an increased risk for cardiovascular disease (CVD). This may be explained by the high relative aerobic workload. Enhanced cardiorespiratory fitness reduces the relative aerobic workload. Thus, the aim was to evaluate the 12-months effects of worksite aerobic exercise on risk factors for CVD among cleaners. METHODS: One hundred and sixteen cleaners aged 18-65 years were randomized to a group performing aerobic exercise and a reference group receiving lectures. Outcomes were collected at baseline and after 12-months. A repeated measures 2*2 multi-adjusted mixed-model design was applied to compare the between-group differences using intention-to-treat analysis. RESULTS: Between-group differences (p<0.05) were found favouring the aerobic exercise group: cardiorespiratory fitness 2.15 (SE 1.03) mlO2/min/kg, aerobic workload -2.15 (SE 1.06) %HRR, resting HR -5.31 (SE 1.61) beats/min, high sensitive C-reactive protein -0.65 (SE 0.24) MUg/ml. The blood pressure was unaltered. Stratified analyses on relative aerobic workload at baseline revealed that those with relative aerobic workloads >=30% of HRR seems to impose a notable adverse effect on resting and ambulatory blood pressure. CONCLUSION: This long-term worksite aerobic exercise intervention among cleaners led to several beneficial effects, but also potential adverse effects among those with high relative aerobic workloads. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN86682076. PMID- 27513933 TI - Live-Cell, Label-Free Identification of GABAergic and Non-GABAergic Neurons in Primary Cortical Cultures Using Micropatterned Surface. AB - Excitatory and inhibitory neurons have distinct roles in cortical dynamics. Here we present a novel method for identifying inhibitory GABAergic neurons from non GABAergic neurons, which are mostly excitatory glutamatergic neurons, in primary cortical cultures. This was achieved using an asymmetrically designed micropattern that directs an axonal process to the longest pathway. In the current work, we first modified the micropattern geometry to improve cell viability and then studied the axon length from 2 to 7 days in vitro (DIV). The cell types of neurons were evaluated retrospectively based on immunoreactivity against GAD67, a marker for inhibitory GABAergic neurons. We found that axons of non-GABAergic neurons grow significantly longer than those of GABAergic neurons in the early stages of development. The optimal threshold for identifying GABAergic and non-GABAergic neurons was evaluated to be 110 MUm at 6 DIV. The method does not require any fluorescence labelling and can be carried out on live cells. The accuracy of identification was 98.2%. We confirmed that the high accuracy was due to the use of a micropattern, which standardized the development of cultured neurons. The method promises to be beneficial both for engineering neuronal networks in vitro and for basic cellular neuroscience research. PMID- 27513934 TI - Historical Biogeography of the Marine Snail Littorina saxatilis Inferred from Haplotype and Shell Morphology Evolution in NW Spain. AB - The marine snail Littorina saxatilis exhibits extreme morphological variation between and within geographical regions and represents an excellent model for assessing local adaptation. Previous studies support the hypothesis of parallel evolution in sympatry of two morphologically different ecotypes (named as RB and SU) that co-inhabit different habitats from Galician rocky shores (NW Spain), and which are interrupted by sheltered areas inhabited by a different morph never studied before (named as SRB). Here, we use morphological and mitochondrial DNA (mtDNA) sequence data to test hypotheses on the origin and diversification of SRB snails and to assess their evolutionary relationships with RB and SU ecotypes. Our results show that the SRB morph displays the largest size and shell elongation and the smallest relative shell aperture, representing an extreme type of the RB vs. SU polymorphism, which has been linked to adaptation to sheltered ecological factors. Phylogenetic analysis shows that the SRB morph shares ancestry with RB and SU ecotypes, rejecting the hypothesis that the SRB morph marks relict populations from which these ecotypes evolved in Galician coasts. Our data support that genetic differentiation among SRB, RB and SU morphs results from a general pattern of restricted gene flow and isolation by distance linked to the colonization of Galician coasts by two independent mtDNA lineages, rather than from a random fragmentation of the initial distributional range. Therefore, the confinement of distinct lineages to specific geographical areas denote evident limits to the distances these snails can disperse. Morphological analysis indicates no association between mtDNA lineage and a specific morphotype, and suggests the independent gain of convergent morphological patterns within each mtDNA lineage in populations occupying contrasting habitats following the colonization of Galician coasts. PMID- 27513935 TI - Silica-Triggered Autoimmunity in Lupus-Prone Mice Blocked by Docosahexaenoic Acid Consumption. AB - Occupational exposure to respirable crystalline silica (cSiO2, quartz) is etiologically linked to systemic lupus erythematosus (lupus) and other human autoimmune diseases (ADs). In the female NZBWF1 mouse, a widely used animal model that is genetically prone to lupus, short-term repeated intranasal exposure to cSiO2 triggers premature initiation of autoimmune responses in the lungs and kidneys. In contrast to cSiO2's triggering action, consumption of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) prevents spontaneous onset of autoimmunity in this mouse strain. The aim of this study was to test the hypothesis that consumption of DHA will prevent cSiO2-triggered autoimmunity in the female NZBWF1 mouse. Mice (6 wk old) were fed isocaloric AIN-93G diets containing 0.0, 0.4, 1.2 or 2.4% DHA. Two wk after initiating feeding, mice were intranasally instilled with 1 mg cSiO2 once per wk for 4 wk and maintained on experimental diets for an additional 12 wk. Mice were then sacrificed and the lung, blood and kidney assessed for markers of inflammation and autoimmunity. DHA was incorporated into lung, red blood cells and kidney from diet in a concentration-dependent fashion. Dietary DHA dose-dependently suppressed cSiO2 triggered perivascular leukocyte infiltration and ectopic lymphoid tissue neogenesis in the lung. DHA consumption concurrently inhibited cSiO2-driven elevation of proinflammatory cytokines, B-cell proliferation factors, IgG and anti-dsDNA Ig in both bronchoalveolar lavage fluid and plasma. DHA's prophylactic effects were further mirrored in reduced proteinuria and glomerulonephritis in cSiO2-treated mice. Taken together, these results reveal that DHA consumption suppresses cSiO2 triggering of autoimmunity in female NZBWF1 mice as manifested in the lung, blood and kidney. Our findings provide novel insight into how dietary modulation of the lipidome might be used to prevent or delay triggering of AD by cSiO2. Such knowledge opens the possibility of developing practical, low cost preventative strategies to reduce the risk of initiating AD and subsequent flaring in cSiO2-exposed individuals. Additional research in this model is required to establish the mechanisms by which DHA suppresses cSiO2-induced autoimmunity and to ascertain unique lipidome signatures predictive of susceptibility to cSiO2-triggered AD. PMID- 27513936 TI - Successful Treatment of Relapsing Bowen's Disease with Ingenol Mebutate: The Use of Dermoscopy to Monitor the Therapeutic Response. AB - Ingenol mebutate (IM) has recently been approved for the topical treatment of actinic keratoses. It appears to have a dual mechanism of action: rapid necrosis after gel application and a subsequent immune-mediated response, which targets any residual dysplastic epidermal cells. We report the successful treatment of a woman, who had been relapsing into Bowen's disease (BD) on her right forefinger for 8 years. During her clinical history, she had received an allogeneic, HLA identical stem cell transplant for myeloproliferative syndrome with a JAK2V617F mutation and lobectomy of the pulmonary right lower lobe for adenocarcinoma. We used dermoscopy to monitor the therapeutic response of BD. We discuss IM gel as a possible therapeutic option for BD. PMID- 27513937 TI - Evaluation of Tetrahydrobiopterin Therapy with Large Neutral Amino Acid Supplementation in Phenylketonuria: Effects on Potential Peripheral Biomarkers, Melatonin and Dopamine, for Brain Monoamine Neurotransmitters. AB - BACKGROUND: Phenylketonuria (PKU) is due to a defective hepatic enzyme, phenylalanine (Phe) hydroxylase. Transport of the precursor amino acids from blood into the brain for serotonin and dopamine synthesis is reported to be inhibited by high blood Phe concentrations. Deficiencies of serotonin and dopamine are involved in neurocognitive dysfunction in PKU. OBJECTIVE: (1) To evaluate the effects of sapropterin (BH4) and concurrent use of large neutral amino acids (LNAA) on the peripheral biomarkers, melatonin and dopamine with the hypothesis they reflect brain serotonin and dopamine metabolism. (2) To evaluate synergistic effects with BH4 and LNAA. (3) To determine the effects of blood Phe concentrations on the peripheral biomarkers concentrations. METHODS: Nine adults with PKU completed our study consisting of four 4-week phases: (1) LNAA supplementation, (2) Washout, (3) BH4 therapy, and (4) LNAA with BH4 therapy. An overnight protocol measured plasma amino acids, serum melatonin, and 6 sulfatoxymelatonin and dopamine in first void urine after each phase. RESULTS: (1) Three out of nine subjects responded to BH4. A significant increase of serum melatonin levels was observed in BH4 responders with decreased blood Phe concentration. No significant change in melatonin, dopamine or Phe levels was observed with BH4 in the subjects as a whole. (2) Synergistic effects with BH4 and LNAA were observed in serum melatonin in BH4 responders. (3) The relationship between serum melatonin and Phe showed a significant negative slope (p = 0.0005) with a trend toward differing slopes among individual subjects (p = 0.066). There was also a negative association overall between blood Phe and urine 6 sulfatoxymelatonin and dopamine (P = 0.040 and 0.047). CONCLUSION: Blood Phe concentrations affected peripheral monoamine neurotransmitter biomarker concentrations differently in each individual with PKU. Melatonin levels increased with BH4 therapy only when blood Phe decreased. Monitoring peripheral neurotransmitter metabolites may assist in optimizing individualized treatment in PKU. PMID- 27513938 TI - Outcomes in Patients with Vestibular Schwannoma after Subtotal Resection and Adjuvant Radiosurgery. AB - BACKGROUND: The debate continues with a limited number of publications describing outcomes in patients with vestibular schwannoma (VS) treated with planned subtotal resection (STR) plus stereotactic radiosurgery (SRS). Here we present our experience. METHODS: This is a retrospective review of 22 patients with VS Koos grade III and IV who were treated with STR followed by SRS. Tumor volumes, facial nerve function, hearing preservation, and the presence of trigeminal neuropathy were noted. Spearman's rank test was used to correlate facial nerve grade with postoperative tumor residual tumor volume. RESULTS: Tumor control was achieved in all patients with a mean follow-up of 28 months. No patient required other treatment beyond the original surgery and adjuvant SRS during this period. After a mean postoperative period of 28 months, 19/22 patients had excellent (House-Brackmann I or II) facial nerve function grading. Improved facial nerve function was positively correlated with larger residual tumor volume (rs = 0.63). Kaplan-Meier curve showed around 80% probability for regaining facial nerve function after initial deterioration. Four patients reported postoperative facial numbness at the side of surgery, with 3 cases showing improvement within a month. Temporary postoperative caudal cranial nerve dysfunction was observed in 2 patients. CONCLUSION: Hybrid strategy of STR and adjuvant SRS provides patients with large VS excellent tumor control and a good clinical outcome. PMID- 27513939 TI - Sources and Dynamics of Inorganic Carbon within the Upper Reaches of the Xi River Basin, Southwest China. AB - The carbon isotopic composition (delta13C) of dissolved and particulate inorganic carbon (DIC; PIC) was used to compare and analyze the origin, dynamics and evolution of inorganic carbon in two headwater tributaries of the Xi River, Southwest China. Carbonate dissolution and soil CO2 were regarded as the primary sources of DIC on the basis of delta13CDIC values which varied along the Nanpan and Beipan Rivers, from -13.90/00 to 8.10/00. Spatial trends in DIC differed between the two rivers (i.e., the tributaries), in part because factors controlling pCO2, which strongly affected carbonate dissolution, differed between the two river basins. Transport of soil CO2 and organic carbon through hydrologic conduits predominately controlled the levels of pCO2 in the Nanpan River. However, pCO2 along the upper reaches of the Nanpan River also was controlled by the extent of urbanization and industrialization relative to agriculture. DIC concentrations in the highly urbanized upper reaches of the Nanpan River were typical higher than in other carbonate-dominated areas of the upper Xi River. Within the Beipan River, the oxidation of organic carbon is the primary process that maintains pCO2 levels. The pCO2 within the Beipan River was more affected by sulfuric acid from coal industries, inputs from a scenic spot, and groundwater than along the Nanpan River. With regards to PIC, the contents and delta13C values in the Nanpan River were generally lower than those in the Beipan River, indicating that chemical and physical weathering contributes more marine carbonate detritus to the PIC along the Beipan River. The CO2 evasion flux from the Nanpan River was higher than that in the Beipan River, and generally higher than along the middle and lower reaches of the Xi River, demonstrating that the Nanpan River is an important net source of atmospheric CO2 in Southwest China. PMID- 27513940 TI - Self-Reported Adherence to Trifluridine and Tipiracil Hydrochloride for Metastatic Colorectal Cancer: A Retrospective Cohort Study. AB - BACKGROUND: A novel oral agent that consists of trifluridine and tipiracil hydrochloride (TFTD) has been established as salvage-line treatment for metastatic colorectal cancer (mCRC). Adherence to TFTD is crucial to maintaining appropriate curative effects. This study sought to clarify adherence to TFTD and identify candidate factors deteriorating adherence at our institution. METHODS: A total of 50 consecutive mCRC patients who received TFTD monotherapy between June 1, 2014 and July 31, 2015 were analyzed in this study. Adherence to TFTD was checked by pharmacists using a self-reported treatment diary and interviewing nonadherents at a pharmaceutical outpatient clinic. The adherence rate was defined as the number of patient intakes per 20 scheduled intakes in one cycle. We retrospectively surveyed the factors from the electronic patient record associated with reduced adherence. We measured relative dose intensity, defined as the dose intensity divided by the initial dose (each in milligrams per square meter per week). RESULTS: Patient characteristics were as follows: males/females, 20/30; median age, 61 years (range, 34-83 years); performance status 0/1, 37/13. Median relative dose intensity of TFTD was 91.0%. Adherence rates were 95.0% for the first cycle of TFTD, 97.3% for the second cycle, 98.0% for the third cycle, and 98.2% for the fourth cycle. Factors associated with deteriorated adherence to TFTD were nausea/vomiting/decreased appetite (27.1%, 23 instances), pain (25.9%, 22 instances), neutropenia (11.8%, 10 instances), and missed dose (4.7%, 4 instances). Increased nonadherence to TFTD was associated with Eastern Cooperative Oncology Group performance status 1, while increased TFTD adherence in the first cycle was associated with prior regimens >=4. CONCLUSIONS: The high frequency of treatment-related gastrointestinal disorder is the main factor affecting adherence to TFTD. Intensive supportive care in the management of these symptoms could assist adequate adherence to TFTD in mCRC patients. PMID- 27513941 TI - The Etiology, Incidence, and Impact of Preservation Fluid Contamination during Liver Transplantation. AB - The role of contaminated preservation fluid in the development of infection after liver transplantation has not been fully elucidated. To assess the incidence and etiology of contaminated preservation fluid and determine its impact on the subsequent development of infection after liver transplantation, we prospectively studied 50 consecutive liver transplants, and cultured the following samples in each instance: preservation fluid (immediately before and at the end of the back table procedure, and just before implantation), blood, and bile from the donor, and ascitic fluid from the recipient. When any culture was positive, blood cultures were obtained and targeted antimicrobial therapy was started. We found that the incidence of contaminated preservation fluid was 92% (46 of 50 cases of liver transplantation per year), but only 28% (14/50) were contaminated by recognized pathogens. Blood and bile cultures from the donor were positive in 28% and 6% respectively, whereas ascitic fluid was positive in 22%. The most frequently isolated microorganisms were coagulase-negative staphylococci. In nine cases, the microorganisms isolated from the preservation fluid concurred with those grown from the donor blood cultures, and in one case, the isolate matched with the one obtained from bile culture. No liver transplant recipient developed an infection due to the transmission of an organism isolated from the preservation fluid. Our findings indicate that contamination of the preservation fluid is frequent in liver transplantation, and it is mainly caused by saprophytic skin flora. Transmission of infection is low, particularly among those recipients given targeted antimicrobial treatment for organisms isolated in the preservation fluid. PMID- 27513942 TI - Denervation-Induced Activation of the Ubiquitin-Proteasome System Reduces Skeletal Muscle Quantity Not Quality. AB - It is well known that the ubiquitin-proteasome system is activated in response to skeletal muscle wasting and functions to degrade contractile proteins. The loss of these proteins inevitably reduces skeletal muscle size (i.e., quantity). However, it is currently unknown whether activation of this pathway also affects function by impairing the muscle's intrinsic ability to produce force (i.e., quality). Therefore, the purpose of this study was twofold, (1) document how the ubiquitin-proteasome system responds to denervation and (2) identify the physiological consequences of these changes. To induce soleus muscle atrophy, C57BL6 mice underwent tibial nerve transection of the left hindlimb for 7 or 14 days (n = 6-8 per group). At these time points, content of several proteins within the ubiquitin-proteasome system were determined via Western blot, while ex vivo whole muscle contractility was specifically analyzed at day 14. Denervation temporarily increased several key proteins within the ubiquitin-proteasome system, including the E3 ligase MuRF1 and the proteasome subunits 19S, alpha7 and beta5. These changes were accompanied by reductions in absolute peak force and power, which were offset when expressed relative to physiological cross-sectional area. Contrary to peak force, absolute and relative forces at submaximal stimulation frequencies were significantly greater following 14 days of denervation. Taken together, these data represent two keys findings. First, activation of the ubiquitin-proteasome system is associated with reductions in skeletal muscle quantity rather than quality. Second, shortly after denervation, it appears the muscle remodels to compensate for the loss of neural activity via changes in Ca2+ handling. PMID- 27513943 TI - Maternal Plasma Nerve Growth Factor at the 11+0-13+6 Weeks' Scan as a Potential Angiogenic Marker of Preeclampsia: A Pilot Study. AB - OBJECTIVE: The aim of this study was to determine the role of nerve growth factor (NGF) in the first-trimester screening for preeclampsia (PE). METHODS: Uterine artery Doppler (UtAD) was determined transvaginally. Maternal concentrations of NGF were assessed in 42 patients who subsequently developed PE and in 95 controls. Quantile and multivariate regression analyses were performed for the NGF and UtAD adjustment and expressed as the multiple of the median (MoM) of the unaffected group. Logistic regression analysis was conducted to identify the best model for the prediction of PE. RESULTS: The maternal plasma concentration of NGF exhibited a trend towards lower values in patients who subsequently developed early-onset PE (e-PE) compared to controls (10.7 vs. 38.2 pg/ml, respectively; p = not significant). The median MoM NGF in the all-PE, e-PE and control groups was 0.97 (95% CI 0.13-3.36), 0.62 (95% CI 0.16-2.19) and 1.00 (95% CI 0.20-2.94), respectively (p = not significant). The best predictors of PE were previous PE, chronic hypertension and UtAD. With a false-positive rate of 10%, the detection rates (DRs) of all-PE and e-PE were 38 and 50%, respectively. The addition of MoM NGF did not improve the DR of PE. CONCLUSION: First-trimester NGF tends to be lower in patients who subsequently develop e-PE. PMID- 27513944 TI - Influence of physicochemical parameters and high pressure processing on the volatile compounds of Serrano dry-cured ham after prolonged refrigerated storage. AB - One hundred and three volatile compounds were detected by solid-phase microextraction followed by gas chromatography-mass spectrometry in 30 ripened Serrano dry-cured hams, submitted or not to high pressure processing (HPP) and afterwards held for 5months at 4 degrees C. The effect of ham physicochemical parameters and HPP (600MPa for 6min) on volatile compounds was assessed. Physicochemical parameters primarily affected the levels of acids, alcohols, alkanes, esters, benzene compounds, sulfur compounds and some miscellaneous compounds. Intramuscular fat content was the physicochemical parameter with the most pronounced effect on the volatile fraction of untreated Serrano ham after refrigerated storage, influencing the levels of 38 volatile compounds while aw, salt content and salt-in-lean ratio respectively influenced the levels of 4, 4 and 5 volatile compounds. HPP treatment affected 21 volatile compounds, resulting in higher levels of alkanes and ketones and lower levels of esters and secondary alcohols, what might affect Serrano ham odor and aroma after 5months of refrigerated storage. PMID- 27513945 TI - Application of quantitative magnetization transfer magnetic resonance imaging for characterization of dry-cured hams. AB - Quantitative magnetization transfer magnetic resonance imaging (qMT-MRI) was employed to characterize dry-cured ham tissues differing in anatomical positions and processing protocols. Experimentally obtained MR images of dry-cured ham sections were analyzed by the well-established binary-spin-bath (BSB) model. The model enabled an efficient discrimination between a free-water proton pool and a restricted-macromolecular proton pool. Significant differences in restricted pool sizes were found among different ham sections. Values of the restricted pool size obtained by the model were in a good agreement with chemically determined protein content. The study confirmed the feasibility of the applied qMT-MRI as a nondestructive tool for characterization of dry-cured ham tissues. PMID- 27513946 TI - Evolutionary Games of Multiplayer Cooperation on Graphs. AB - There has been much interest in studying evolutionary games in structured populations, often modeled as graphs. However, most analytical results so far have only been obtained for two-player or linear games, while the study of more complex multiplayer games has been usually tackled by computer simulations. Here we investigate evolutionary multiplayer games on graphs updated with a Moran death-Birth process. For cycles, we obtain an exact analytical condition for cooperation to be favored by natural selection, given in terms of the payoffs of the game and a set of structure coefficients. For regular graphs of degree three and larger, we estimate this condition using a combination of pair approximation and diffusion approximation. For a large class of cooperation games, our approximations suggest that graph-structured populations are stronger promoters of cooperation than populations lacking spatial structure. Computer simulations validate our analytical approximations for random regular graphs and cycles, but show systematic differences for graphs with many loops such as lattices. In particular, our simulation results show that these kinds of graphs can even lead to more stringent conditions for the evolution of cooperation than well-mixed populations. Overall, we provide evidence suggesting that the complexity arising from many-player interactions and spatial structure can be captured by pair approximation in the case of random graphs, but that it need to be handled with care for graphs with high clustering. PMID- 27513947 TI - The Sulfamate Small Molecule CAIX Inhibitor S4 Modulates Doxorubicin Efficacy. AB - Carbonic anhydrase IX (CAIX) is a tumor-specific protein that is upregulated during hypoxic conditions where it is involved in maintaining the pH balance. CAIX causes extracellular acidification, thereby limiting the uptake of weak basic chemotherapeutic agents, such as doxorubicin, and decreasing its efficacy. The aim of this study was to determine if doxorubicin efficacy can be increased when combined with the selective sulfamate CAIX inhibitor S4. The effect of S4 on doxorubicin efficacy was tested in vitro using cell viability assays with MDA-MB 231, FaDu, HT29 -CAIX high and HT29 -CAIX low cell lines. In addition, the efficacy of this combination therapy was investigated in tumor xenografts of the same cell lines. The addition of S4 in vitro increased the efficacy of doxorubicin in the MDA-MB-231 during hypoxic exposure (IC50 is 0.25 versus 0.14 uM, p = 0.0003). Similar results were observed for HT29-CAIX high with S4 during normoxia (IC50 is 0.20 versus 0.08 uM, p<0.0001) and in the HT29 -CAIX low cells (IC50 is 0.09 uM, p<0.0001). In vivo doxorubicin treatment was only effective in the MDA-MB-231 xenografts, but the efficacy of doxorubicin was decreased when combined with S4. In conclusion, the efficacy of doxorubicin treatment can be increased when combined with the selective sulfamate CAIX inhibitor S4 in vitro in certain cell lines. Nevertheless, in xenografts S4 did not enhance doxorubicin efficacy in the FaDu and HT29 tumor models and decreased doxorubicin efficacy in the MDA-MB-231 tumor model. These results stress the importance of better understanding the role of CAIX inhibitors in intratumoral pH regulation before combining them with standard treatment modalities, such as doxorubicin. PMID- 27513948 TI - Impact of cyclometalated ruthenium(II) complexes on lactate dehydrogenase activity and cytotoxicity in gastric and colon cancer cells. AB - Lactate dehydrogenase (LDH) is a redox enzyme often overexpressed in cancer cells allowing their survival in stressful metabolic tumor environment. Ruthenium(II) complexes have been shown to impact on the activity of purified horseradish peroxidase and glucose oxidase but the physiological relevance remains unclear. In this study we investigated how ruthenium complexes impact on the activity of LDH in vitro and in cancer cells and performed a comparative study using polypyridine ruthenium(II) complex [Ru(bpy)3]2+ (1) and its structurally related cyclometalated 2-phenylpyridinato counterpart [Ru(phpy)(bpy)2]+ (2) (bpy=2,2' bipyridine, phpyH=2-phenylpyridine). We show that the cytotoxicity in gastric and colon cancer cells induced by 2 is significantly higher compared to 1. The kinetic inhibition mechanisms on purified LDH and the corresponding inhibition constants Ki or i0.5 values were calculated. Though complexes 1 and 2 are structurally very similar (one Ru-C bond in 2 replaces one Ru-N bond in 1), their inhibition modes are different. Cyclometalated complex 2 behaves exclusively as a non-competitive inhibitor of LDH from rabbit muscle (LDHrm), strongly suggesting that 2 does not interact with LDH in the vicinities of either lactate/pyruvate or NAD+/NADH binding sites. Sites of interaction of 1 and 2 with LDHrm were revealed theoretically through computational molecular docking. Inhibition of LDH activity by 2 was confirmed in cancer cells. Altogether, these results revealed an inhibition of LDH activity by ruthenium complex through a direct interaction structurally tuned by a Ru-C bond. PMID- 27513949 TI - Visible light-induced formation of corrole-manganese(V)-oxo complexes: Observation of multiple oxidation pathways. AB - Two manganese(V)-oxo corroles [MnV(Cor)O] that differ in their electronic environments were produced by visible light irradiation of highly photo-labile corrole-manganese(IV) bromates. The corrole ligands under study include 5,10,15 tris(pentafluorophenyl)corrole (TPFC), and 5,10,15-triphenylcorrole (TPC). The kinetics of oxygen transfer atom (OAT) reactions with various organic reductants by these photo-generated MnV(Cor)O were also studied in CH3CN and CH2Cl2 solutions. MnV(Cor)O exhibits remarkable solvent and ligand effect on its reactivity and spectral behavior. In the more electron-deficient TPFC system and in the polar solvent CH3CN, MnV(Cor)O returned MnIII corrole in the end of oxidation reactions. However, in the less polar solvent CH2Cl2 or in the less electron-deficient TPC system, MnIV product was formed instead of MnIII. Furthermore, with the same substrates and in the same solvent, the order of reactivity of MnV(Cor)O was TPC>TPFC, which is inverted from that expected based on the electron-demand of corrole ligands. Our spectral and kinetic results in this study provide compelling evidence in favor of multiple oxidation pathways, where MnV(Cor)O may serve as direct two-electron oxidant or undergo a disproportionation reaction to form a manganese(VI)-oxo corrole as the true oxidant. The choice of pathways is strongly dependent on the nature of the solvent and the corrole ligand. PMID- 27513950 TI - Auditory Stimuli Coding by Postsynaptic Potential and Local Field Potential Features. AB - The relation between physical stimuli and neurophysiological responses, such as action potentials (spikes) and Local Field Potentials (LFP), has recently been experimented in order to explain how neurons encode auditory information. However, none of these experiments presented analyses with postsynaptic potentials (PSPs). In the present study, we have estimated information values between auditory stimuli and amplitudes/latencies of PSPs and LFPs in anesthetized rats in vivo. To obtain these values, a new method of information estimation was used. This method produced more accurate estimates than those obtained by using the traditional binning method; a fact that was corroborated by simulated data. The traditional binning method could not certainly impart such accuracy even when adjusted by quadratic extrapolation. We found that the information obtained from LFP amplitude variation was significantly greater than the information obtained from PSP amplitude variation. This confirms the fact that LFP reflects the action of many PSPs. Results have shown that the auditory cortex codes more information of stimuli frequency with slow oscillations in groups of neurons than it does with slow oscillations in neurons separately. PMID- 27513951 TI - Invasive Non-typhoidal Salmonella Infections in Asia: Clinical Observations, Disease Outcome and Dominant Serovars from an Infectious Disease Hospital in Vietnam. AB - Invasive non-typhoidal Salmonella (iNTS) infections are now a well-described cause of morbidity and mortality in children and HIV-infected adults in sub Saharan Africa. In contrast, the epidemiology and clinical manifestations of iNTS disease in Asia are not well documented. We retrospectively identified >100 cases of iNTS infections in an infectious disease hospital in Southern Vietnam between 2008 and 2013. Clinical records were accessed to evaluate demographic and clinical factors associated with iNTS infection and to identify risk factors associated with death. Multi-locus sequence typing and antimicrobial susceptibility testing was performed on all organisms. Of 102 iNTS patients, 71% were HIV-infected, >90% were adults, 71% were male and 33% reported intravenous drug use. Twenty-six/92 (28%) patients with a known outcome died; HIV infection was significantly associated with death (p = 0.039). S. Enteritidis (Sequence Types (ST)11) (48%, 43/89) and S. Typhimurium (ST19, 34 and 1544) (26%, 23/89) were the most commonly identified serovars; S. Typhimurium was significantly more common in HIV-infected individuals (p = 0.003). Isolates from HIV-infected patients were more likely to exhibit reduced susceptibility against trimethoprim sulfamethoxazole than HIV-negative patients (p = 0.037). We conclude that iNTS disease is a severe infection in Vietnam with a high mortality rate. As in sub Saharan Africa, HIV infection was a risk factor for death, with the majority of the burden in this population found in HIV-infected adult men. PMID- 27513952 TI - Comparative Digital Gene Expression Analysis of the Arabidopsis Response to Volatiles Emitted by Bacillus amyloliquefaciens. AB - Some plant growth-promoting rhizobacteria (PGPR) regulated plant growth and elicited plant basal immunity by volatiles. The response mechanism to the Bacillus amyloliquefaciens volatiles in plant has not been well studied. We conducted global gene expression profiling in Arabidopsis after treatment with Bacillus amyloliquefaciens FZB42 volatiles by Illumina Digital Gene Expression (DGE) profiling of different growth stages (seedling and mature) and tissues (leaves and roots). Compared with the control, 1,507 and 820 differentially expressed genes (DEGs) were identified in leaves and roots at the seedling stage, respectively, while 1,512 and 367 DEGs were identified in leaves and roots at the mature stage. Seventeen genes with different regulatory patterns were validated using quantitative RT-PCR. Numerous DEGs were enriched for plant hormones, cell wall modifications, and protection against stress situations, which suggests that volatiles have effects on plant growth and immunity. Moreover, analyzes of transcriptome difference in tissues and growth stage using DGE profiling showed that the plant response might be tissue-specific and/or growth stage-specific. Thus, genes encoding flavonoid biosynthesis were downregulated in leaves and upregulated in roots, thereby indicating tissue-specific responses to volatiles. Genes related to photosynthesis were downregulated at the seedling stage and upregulated at the mature stage, respectively, thereby suggesting growth period specific responses. In addition, the emission of bacterial volatiles significantly induced killing of cells of other organism pathway with up regulated genes in leaves and the other three pathways (defense response to nematode, cell morphogenesis involved in differentiation and trichoblast differentiation) with up-regulated genes were significantly enriched in roots. Interestingly, some important alterations in the expression of growth-related genes, metabolic pathways, defense response to biotic stress and hormone-related genes were firstly founded response to FZB42 volatiles. PMID- 27513953 TI - Postpartum Loss to HIV Care and HIV Viral Suppression among Previously Diagnosed HIV-Infected Women with a Live Birth in New York State. AB - Mother-to-child-transmission of HIV in the United States has been greatly reduced, with clear benefits for the child. However, little is known about factors that predict maternal loss to HIV care in the postpartum year. This retrospective cohort study included 980 HIV-positive women, diagnosed with HIV at least one year before pregnancy, who had a live birth during 2008-2010 in New York State. Women who did not meet the following criterion in the 12 months after the delivery-related hospital discharge were considered to be lost to HIV care: two or more laboratory tests (CD4 or HIV viral load), separated by at least 90 days. Adjusted relative risks (aRR) and 95% confidence intervals (CI) for predictors of postpartum loss to HIV care were identified with Poisson regression, solved using generalized estimating equations. Having an unsuppressed (>200 copies/mL) HIV viral load in the postpartum year was also evaluated. Overall, 24% of women were loss to HIV care during the postpartum year. Women with low participation in HIV care during preconception were more likely to be lost to HIV care during the postpartum year (aRR: 2.70; 95% CI: 2.09-3.49). In contrast, having a low birth weight infant was significantly associated with a decreased likelihood of loss to HIV care (aRR: 0.72; 95% CI: 0.53-0.98). While 75% of women were virally suppressed at the last viral load before delivery only 44% were continuously suppressed in the postpartum year; 12% had no viral load test reported in the postpartum year and 44% had at least one unsuppressed viral load test. Lack of engagement in preconception HIV-related health care predicts postpartum loss to HIV care for HIV-positive parturient women. Many women had poor viral control during the postpartum period, increasing the risk of disease progression and infectivity. PMID- 27513954 TI - Laguerre Filter Analysis with Partial Least Square Regression Reveals a Priming Effect of ERK and CREB on c-FOS Induction. AB - Signaling networks are made up of limited numbers of molecules and yet can code information that controls different cellular states through temporal patterns and a combination of signaling molecules. In this study, we used a data-driven modeling approach, the Laguerre filter with partial least square regression, to describe how temporal and combinatorial patterns of signaling molecules are decoded by their downstream targets. The Laguerre filter is a time series model used to represent a nonlinear system based on Volterra series expansion. Furthermore, with this approach, each component of the Volterra series expansion is expanded by Laguerre basis functions. We combined two approaches, application of a Laguerre filter and partial least squares (PLS) regression, and applied the combined approach to analysis of a signal transduction network. We applied the Laguerre filter with PLS regression to identify input and output (IO) relationships between MAP kinases and the products of immediate early genes (IEGs). We found that Laguerre filter with PLS regression performs better than Laguerre filter with ordinary regression for the reproduction of a time series of IEGs. Analysis of the nonlinear characteristics extracted using the Laguerre filter revealed a priming effect of ERK and CREB on c-FOS induction. Specifically, we found that the effects of a first pulse of ERK enhance the subsequent effects on c-FOS induction of treatment with a second pulse of ERK, a finding consistent with prior molecular biological knowledge. The variable importance of projections and output loadings in PLS regression predicted the upstream dependency of each IEG. Thus, a Laguerre filter with partial least square regression approach appears to be a powerful method to find the processing mechanism of temporal patterns and combination of signaling molecules by their downstream gene expression. PMID- 27513955 TI - Precursor B Cells Increase in the Lung during Airway Allergic Inflammation: A Role for B Cell-Activating Factor. AB - BACKGROUND: B cells, key cells in allergic inflammation, differentiate in the bone marrow and their precursors include pro-B, pre-B and immature B cells. Eosinophil progenitor cells increase in the lung after allergen exposure. However, the existence and possible role of B cell precursors in the lung during allergic inflammation remains elusive. METHODS: A BALB/c mouse model of allergic airway inflammation was utilized to perform phenotypic and quantification analyses of pro-B and pre-B cells in the lung by flow cytometry. B cell maturation factors IL-7 and B cell-activating factor (BAFF) and their receptors (CD127 and BAFFR, BCMA, TACI, respectively) were also evaluated in the lung and serum. The effect of anti-BAFF treatment was investigated both in vivo (i.p. administration of BAFF-R-Ig fusion protein) and in vitro (colony forming cell assay). Finally, BAFF levels were examined in the bronchoalveolar lavage (BAL) of asthmatic patients and healthy controls. RESULTS: Precursor pro and pre-B cells increase in the lung after allergen exposure, proliferate in the lung tissue in vivo, express markers of chemotaxis (CCR10 and CXCR4) and co-stimulation (CD40, CD86) and are resistant to apoptosis (Bax). Precursor B cells express receptors for BAFF at baseline, while after allergen challenge both their ligand BAFF and the BCMA receptor expression increases in B cell precursors. Blocking BAFFR in the lung in vivo decreases eosinophils and proliferating precursor B cells. Blocking BAFFR in bone marrow cultures in vitro reduces pre-B colony formation units. BAFF is increased in the BAL of severe asthmatics. CONCLUSION: Our data support the concept of a BAFF-mediated role for B cell precursors in allergic airway inflammation. PMID- 27513956 TI - RNase activity of sialic acid-binding lectin from bullfrog eggs drives antitumor effect via the activation of p38 MAPK to caspase-3/7 signaling pathway in human breast cancer cells. AB - Sialic acid-binding lectin obtained from bullfrog eggs (SBL) induces cell death in cancer cells but not in normal cells. This antitumor effect is mediated through its ribonuclease (RNase) activity. However, the underlying molecular mechanisms remain unclear. We found that the p38 mitogen-activated protein kinase (MAPK) signaling pathway was activated when SBL induced cell death in three human breast cancer cell lines: SK-BR-3, MCF-7, and MDA-MB231. The suppression of p38 MAPK phosphorylation by a p38 MAPK inhibitor as well as short interference RNA knockdown of p38 MAPK expression significantly decreased cell death and increased the cell viability of SBL-treated MDA-MB231 cells. H103A, an SBL mutant lacking in RNase activity, showed decreased SBL-induced cell death compared with native SBL. However, the loss of RNase activity of SBL had no effect on its internalization into cells. The H103A mutant also displayed decreased phosphorylation of p38 MAPK. Moreover, SBL promoted caspase-3/7 activation followed by a cleavage of poly (ADP-ribose)-polymerase, whereas the SBL mutant, H103A, lost this ability. The SBL-induced caspase-3/7 activation was suppressed by the p38 MAPK inhibitor, SB203580, as well as pan-caspase inhibitor, zVAD-fmk. In the presence of zVAD-fmk, the SBL-induced cell death was decreased. In addition, the cell viability of SBL-treated MDA-MB231 cells recovered by zVAD-fmk treatment. Taken together, our results suggest that the RNase activity of SBL leads to breast cancer cell death through the activation of p38 MAPK followed by the activation of caspase-3/7. PMID- 27513957 TI - Bowenoid Actinic Keratosis and Bowen's Disease Treated Successfully with Ingenol Mebutate. AB - Ingenol mebutate (IM) is a topical pharmacotherapy approved in Switzerland since 2012 for treating non-hypertrophic, non-hyperkeratotic actinic keratosis (AK). We report 2 cases with off-label use of IM. The first case of bowenoid AK was treated with 150 MUg IM for 3 consecutive days with an almost complete clinical remission of the lesion. The second case of Bowen's disease was treated with 500 MUg IM for 2 consecutive days leading to complete clinical remission. PMID- 27513958 TI - Flow Scales of Influence on the Settling Velocities of Particles with Varying Characteristics. AB - The settling velocities of natural, synthetic, and industrial particles were measured in a grid turbulence facility using optical measurement techniques. Particle image velocimetry and 2D particle tracking were used to measure the instantaneous velocities of the flow and the particles' trajectories simultaneously. We find that for particles examined in this study (Rep = 0.4 123), settling velocity is either enhanced or unchanged relative to stagnant flow for the range of investigated turbulence conditions. The smallest particles' normalized settling velocities exhibited the most consistent trends when plotted versus the Kolmogorov-based Stokes numbers suggesting that the dissipative scales influence their dynamics. In contrast, the mid-sized particles were better characterized with a Stokes number based on the integral time scale. The largest particles were largely unaffected by the flow conditions. Using proper orthogonal decomposition (POD), the flow pattern scales are compared to particle trajectory curvature to complement results obtained through dimensional analysis using Stokes numbers. The smallest particles are found to have trajectories with curvatures of similar scale as the small flow scales (higher POD modes) whilst mid-sized particle trajectories had curvatures that were similar to the larger flow patterns (lower POD modes). The curvature trajectories of the largest particles did not correspond to any particular flow pattern scale suggesting that their trajectories were more random. These results provide experimental evidence of the "fast tracking" theory of settling velocity enhancement in turbulence and demonstrate that particles align themselves with flow scales in proportion to their size. PMID- 27513959 TI - Carbonic Anhydrases in Cnidarians: Novel Perspectives from the Octocorallian Corallium rubrum. AB - Although the ability to elaborate calcium carbonate biominerals was apparently gained independently during animal evolution, members of the alpha carbonic anhydrases (alpha-CAs) family, which catalyze the interconversion of CO2 into HCO3-, are involved in the biomineralization process across metazoans. In the Mediterranean red coral Corallium rubrum, inhibition studies suggest an essential role of CAs in the synthesis of two biominerals produced in this octocoral, the axial skeleton and the sclerites. Hitherto no molecular characterization of these enzymes was available. In the present study we determined the complete set of alpha-CAs in C. rubrum by data mining the genome and transcriptome, and measured their differential gene expression between calcifying and non-calcifying tissues. We identified six isozymes (CruCA1-6), one cytosolic and five secreted/membrane bound among which one lacked two of the three zinc-binding histidines and was so referred to as a carbonic anhydrase related protein (CARP). One secreted isozyme (CruCA4) showed specific expression both by qPCR and western-blot in the calcifying tissues, suggesting its involvement in biomineralization. Moreover, phylogenetic analyses of alpha-CAs, identified in six representative cnidarians with complete genome, support an independent recruitment of alpha-CAs for biomineralization within anthozoans. Finally, characterization of cnidarian CARPs highlighted two families: the monophyletic cytosolic CARPs, and the polyphyletic secreted CARPs harboring a cnidarian specific cysteine disulfide bridge. Alignment of the cytosolic CARPs revealed an evolutionary conserved R-H-Q motif in place of the characteristic zinc-binding H-H-H necessary for the catalytic function of alpha-CAs. PMID- 27513960 TI - Linagliptin Ameliorates Methylglyoxal-Induced Peritoneal Fibrosis in Mice. AB - Recent studies have reported increases of methylglyoxal (MGO) in peritoneal dialysis patients, and that MGO-mediated inflammation plays an important role in the development of peritoneal fibrosis through production of transforming growth factor-beta1 (TGF-beta1). Linagliptin, a dipeptidyl peptidase-4 inhibitor, exerts anti-inflammatory effects independent of blood glucose levels. In this study, we examined whether linagliptin suppresses MGO-induced peritoneal fibrosis in mice. Male C57/BL6 mice were divided into three groups: control, MGO injection plus saline, and MGO injection plus linagliptin (n = 6 per group). Peritoneal fibrosis was induced by daily intraperitoneal injection of saline containing 40 mmol/L MGO for 21 days. Saline was administered intraperitoneally to the control group. Linagliptin (10 mg/kg) or saline were administrated by once-daily oral gavage from 3 weeks before starting MGO injections. Immunohistochemical staining revealed that linagliptin suppressed expression of alpha-smooth muscle actin and fibroblast-specific protein-1, deposition of type I and III collagen, and macrophage (F4/80) infiltration. Peritoneal equilibration testing showed improved peritoneal functions in mice treated with linagliptin. Peritoneal injection of MGO increased plasma levels of glucagon-like peptide-1 (GLP-1) in mice, and a further increase was observed in linagliptin-treated mice. Although MGO increased plasma glucose levels, linagliptin did not decrease plasma glucose levels. Moreover, linagliptin reduced the TGF-beta1 concentration in the peritoneal fluid of MGO-treated mice. GLP-1 receptor (GLP-1R) was expressed in monocytes/macrophages and linagliptin suppressed GLP-1R expression in MGO injected mice. These results suggest that oral administration of linagliptin ameliorates MGO-induced peritoneal fibrosis. PMID- 27513961 TI - Metabolic Response to Heat Stress in Late-Pregnant and Early Lactation Dairy Cows: Implications to Liver-Muscle Crosstalk. AB - Climate changes lead to rising temperatures during summer periods and dramatic economic losses in dairy production. Modern high-yielding dairy cows experience severe metabolic stress during the transition period between late gestation and early lactation to meet the high energy and nutrient requirements of the fetus or the mammary gland, and additional thermal stress during this time has adverse implications on metabolism and welfare. The mechanisms enabling metabolic adaptation to heat apart from the decline in feed intake and milk yield are not fully elucidated yet. To distinguish between feed intake and heat stress related effects, German Holstein dairy cows were first kept at thermoneutral conditions at 15 degrees C followed by exposure to heat-stressed (HS) at 28 degrees C or pair-feeding (PF) at 15 degrees C for 6 days; in late-pregnancy and again in early lactation. Liver and muscle biopsies and plasma samples were taken to assess major metabolic pathway regulation using real-time PCR and Western Blot. The results indicate that during heat stress, late pregnant cows activate Cahill but reduce Cori cycling, prevent increase in skeletal muscle fatty acid oxidation, and utilize increased amounts of pyruvate for gluconeogenesis, without altering ureagenesis despite reduced plane of nutrition. These homeorhetic adaptations are employed to reduce endogenous heat production while diverting amino acids to the growing fetus. Metabolic adaptation to heat stress in early lactation involves increased long-chain fatty acid degradation in muscle peroxisomes, allowance for muscle glucose utilization but diminished hepatic use of amino acid-derived pyruvate for gluconeogenesis and reduced peroxisomal fatty acid oxidation and ATP production in liver of HS compared to PF cows in early lactation. Consequently, metabolic adaptation to heat stress and reduced feed intake differ between late pregnancy and early lactation of dairy cows to maintain energy supply for fetus development or milk production simultaneously reducing endogenous heat production. PMID- 27513962 TI - Acid-sensing ion channels and transient-receptor potential ion channels in zebrafish taste buds. AB - Sensory information from the environment is required for life and survival, and it is detected by specialized cells which together make up the sensory system. The fish sensory system includes specialized organs that are able to detect mechanical and chemical stimuli. In particular, taste buds are small organs located on the tongue in terrestrial vertebrates that function in the perception of taste. In fish, taste buds occur on the lips, the flanks, and the caudal (tail) fins of some species and on the barbels of others. In fish taste receptor cells, different classes of ion channels have been detected which, like in mammals, presumably participate in the detection and/or transduction of chemical gustatory signals. However, since some of these ion channels are involved in the detection of additional sensory modalities, it can be hypothesized that taste cells sense stimuli other than those specific for taste. This mini-review summarizes current knowledge on the presence of transient-receptor potential (TRP) and acid-sensing (ASIC) ion channels in the taste buds of teleosts, especially adult zebrafish. Up to now ASIC4, TRPC2, TRPA1, TRPV1 and TRPV4 ion channels have been found in the sensory cells, while ASIC2 was detected in the nerves supplying the taste buds. PMID- 27513963 TI - Progressive Decline in Height Standard Deviation Scores in the First 5 Years of Life Distinguished Idiopathic Growth Hormone Deficiency from Familial Short Stature and Constitutional Delay of Growth. AB - BACKGROUND: Familial short stature (FSS) and constitutional delay of growth (CDG) are the most frequent norm variants in children presenting with short stature. Knowing the growth patterns of these entities in the first years of life might be helpful to distinguish them from growth hormone deficiency (GHD) or other chronic diseases. METHODS: We studied the height in the first 5 years of life in 26 children with FSS, in 38 children with CDG and in 14 children with idiopathic GHD. RESULTS: Height standard deviation scores (SDS) did not change between birth and 6 months of life, while height SDS decreased significantly afterwards in GHD, FSS, and CDG. The loss of height SDS was higher in the first 2 years of life than between 2 and 5 years of life in children with CDG (-0.92 vs. -0.11; p = 0.003) or FSS (-0.79 vs. -0.01; p = 0.002). In idiopathic GHD, the loss of height SDS did not differ between the first 2 years of life and the next 3 years (-0.78 vs. 0.77; p = 0.821). CONCLUSION: Children with FSS and CDG showed a decline in height SDS mainly in the first 2 years of life, whereas the height SDS of children with idiopathic GHD decreased almost continuously over the first 5 years of life. PMID- 27513964 TI - Farm-scale evaluation of the impact of Cry1Ab Bt maize on canopy nontarget arthropods: a 3-year study. AB - The cultivation of Cry1Ab-expressing genetically modified MON810 (Bt maize) has led to public concern in Europe, regarding its impact on nontarget arthropods (NTAs). We have assessed the potential effects of DKC 6451 YG (MON810) maize on canopy NTAs in a farm-scale study performed in Central Spain during 3 years. The study focused on hemipteran herbivores (leafhoppers and planthoppers) and hymenopteran parasitic wasps (mymarids) collected by yellow sticky traps, which accounted for 72% of the total number of insects studied. The dynamics and abundance of these groups varied among years, but no significant differences were found between Bt and non-Bt maize, indicating that Bt maize had no negative effect on these taxa. Nonetheless, the Cry1Ab toxin was detected in 2 different arthropods collected from Bt maize foliage, the cicadellids Zyginidia scutellaris and Empoasca spp. A retrospective power analysis on the arthropod abundance data for our field trials has determined that Z. scutellaris and the family Mymaridae have high capacity to detect differences between the Bt maize and its isogenic counterpart. The use of these canopy NTAs as surrogates for assessing environmental impacts of Bt maize is discussed. PMID- 27513965 TI - Difficult 32-Fr Double-Lumen Tube Intubation in a Small Japanese Woman With Narrow Transverse Width of the Cricoid Cartilage. AB - We encountered difficulty in inserting a 32-Fr left double-lumen tube (DLT) in a small 75-year-old Japanese woman (height, 144 cm). The 32-Fr DLT with 10.1 * 11.2 mm tracheal diameter could not pass through the cricoid cartilage with a 9.2-mm transverse inner width. The transverse inner width of the cricoid cartilage, in addition to the tracheal and bronchial diameter, can be measured using computed tomography or ultrasonography in small women. Thus, a 28-Fr DLT or single-lumen tube and a blocker can be selected instead of a 32-Fr DLT when the width of the cricoid cartilage is <10 mm. PMID- 27513966 TI - Anesthetic Considerations for Neuraxial Anesthesia in Pregnant Patients With Pityriasis Rosea With Skin Lesions Covering the Lumbar Spine. AB - Pityriasis rosea (PR) is an acute exanthematous skin disease that is likely due to reactivation of human herpesviruses (HHVs) 6b and 7. In contrast to herpes simplex and zoster (alphaherpesviruses), HHV-6b and -7 (betaherpesviruses) are not found predominantly in skin lesions. This difference in virion location may decrease the possibility of causing central nervous system infection through skin contamination, but the risk for hematogenous spread likely remains the same. This article uses the first-known epidural placement through active PR to illustrate risk-benefit considerations when deciding between neuraxial and general anesthesia for obstetric patients with PR. PMID- 27513967 TI - Periarticular Morphine-Induced Sphincter of Oddi Spasm Causing Severe Pain and Bradycardia in an Awake Patient Under Spinal Anesthesia: An Important Diagnostic Consideration. AB - Sphincter of Oddi spasm from opioids has been documented, presenting as severe epigastric pain and potentially overlooked in a differential diagnosis. We present a case of sphincter of Oddi spasm from periarticular morphine in a patient under spinal anesthesia, causing severe distress and treated effectively with glucagon. It is important for anesthesiologists using opioids to consider it as a cause of perioperative pain and be familiar with treatment as it may be refractory by conventional use of opioids for pain relief. It is also important to consider the systemic effects of periarticular absorption, as evident by our case. PMID- 27513968 TI - Anesthetic Management for Cesarean Delivery in a Patient With Pulmonary Emboli, Pulmonary Hypertension, and Right Ventricular Failure. AB - The maternal mortality rate for parturients with severe pulmonary hypertension is 30% to 50%. General, epidural, and combined low-dose spinal-epidural anesthesia have been used successfully for cesarean deliveries in patients with pulmonary hypertension. We describe a cesarean delivery performed using an intrathecal catheter in a 25-year-old morbidly obese (body mass index, 82 kg/m) woman (gravida 3, para 2 at 32 weeks of gestation) who had severe pulmonary hypertension, right ventricular failure, pulmonary emboli, and obstructive sleep apnea. We discuss the anesthetic considerations for parturients with severe pulmonary hypertension undergoing cesarean delivery including the selection of anesthetic technique, vasopressors, and uterotonic agents. PMID- 27513969 TI - Bilateral Continuous Suprascapular Nerve Blocks for Bilateral Shoulder Hemiarthroplasty. AB - We report a novel case of a patient undergoing a bilateral shoulder hemiarthroplasty for chronic bilateral shoulder dislocations with proximal humeral fractures. Bilateral selective suprascapular nerve catheters were placed preoperatively with the intent to provide continuous local anesthetic-based analgesia while sparing diaphragmatic function. Postoperative respiratory mechanics were relatively spared while numerical rating scale pain scores were suggestive of analgesic benefit. PMID- 27513970 TI - Successful Anticoagulation Using Argatroban During Transcatheter Aortic Valve Implantation in a Patient With Heparin-Induced Thrombocytopenia. AB - We report the first case of transfemoral transcatheter aortic valve implantation with a history of heparin-induced thrombocytopenia that was successfully managed with perioperative argatroban. PMID- 27513971 TI - Continuous Noninvasive Hemodynamic Monitoring in an Infant With Tetra-Amelia. AB - Tetra-amelia syndrome is a congenital disorder associated with near or complete absence of all 4 limbs. Noninvasive hemodynamic monitoring may be difficult or impossible in such patients. We describe the use of a finger cuff blood pressure system for continuous noninvasive blood pressure monitoring in an infant with near-complete tetra-amelia undergoing laparoscopic gastrostomy tube placement. This case suggests the potential use of such a blood pressure monitoring system for other patients with comparable deformities. PMID- 27513972 TI - Continuous Quadratus Lumborum Block for Postoperative Pain in Total Hip Arthroplasty: A Case Report. AB - A 69-year-old man with a history of chronic pain and opioid use presented for total hip arthroplasty. In the interests of ensuring early mobilization and pain control, we chose a continuous quadratus lumborum block technique, a novel ultrasound-guided block that has not yet been described for total hip arthroplasty, hypothesizing that it would be motor-sparing. While the perineural catheter was infused, the patient required no IV opioids. He was able to ambulate on the first postoperative day, reporting pain scores between 0 and 3/10. The quadratus lumborum block is a promising technique that, in our patient, was motor sparing and provided excellent pain control. PMID- 27513973 TI - Fhit loss-associated initiation and progression of neoplasia in vitro. AB - The FHIT gene, encompassing an active common fragile site, FRA3B, is frequently silenced in preneoplasia and cancer, through gene rearrangement or methylation of regulatory sequences. Silencing of Fhit protein expression causes thymidine kinase 1 downregulation, resulting in dNTP imbalance, and spontaneous replication stress that leads to chromosomal aberrations, allele copy number variations, insertions/deletions, and single-base substitutions. Thus, Fhit, which is reduced in expression in the majority of human cancers, is a genome "caretaker" whose loss initiates genome instability in preneoplastic lesions. To follow the early genetic alterations and functional changes induced by Fhit loss that may recapitulate the neoplastic process in vitro, we established epithelial cell lines from kidney tissues of Fhit-/- and +/+ mouse pups early after weaning, and subjected cell cultures to nutritional and carcinogen stress, which +/+ cells did not survive. Through transcriptome profiling and protein expression analysis, we observed changes in the Trp53/p21 and survivin apoptotic pathways in -/- cells, and in expression of proteins involved in epithelial-mesenchymal transition. Some Fhit-deficient cell lines showed anchorage-independent colony formation and increased invasive capacity in vitro. Furthermore, cells of stressed Fhit-/- cell lines formed s.c. and metastatic tumors in nude mice. Collectively, we show that Fhit loss and subsequent thymidine kinase 1 inactivation, combined with selective pressures, leads to neoplasia-associated alterations in genes and gene expression patterns in vitro and in vivo. PMID- 27513974 TI - MAB_3551c encodes the primary triacylglycerol synthase involved in lipid accumulation in Mycobacterium abscessus. AB - Slow growing pathogenic mycobacteria utilize host-derived lipids and accumulate large amounts of triacylglycerol (TAG) in the form of intracytoplasmic lipid inclusions (ILI), serving as a source of carbon and energy during prolonged infection. Mycobacterium abscessus is an emerging and rapidly growing species capable to induce severe and chronic pulmonary infections. However, whether M. abscessus, like Mycobacterium tuberculosis, possesses the machinery to acquire and store host lipids, remains unaddressed. Herein, we aimed at deciphering the contribution of the seven putative M. abscessus TAG synthases (Tgs) in TAG synthesis/accumulation thanks to a combination of genetic and biochemical techniques and a well-defined foamy macrophage (FM) model along with electron microscopy. Targeted gene deletion and functional complementation studies identified the MAB_3551c product, Tgs1, as the major Tgs involved in TAG production. Tgs1 exhibits a preference for long acyl-CoA substrates and site directed mutagenesis demonstrated that His144 and Gln145 are essential for enzymatic activity. Importantly, in the lipid-rich intracellular context of FM, M. abscessus formed large ILI in a Tgs1-dependent manner. This supports the ability of M. abscessus to assimilate host lipids and the crucial role of Tgs1 in intramycobacterial TAG production, which may represent important mechanisms for long-term storage of a rich energy supply. PMID- 27513975 TI - Correction: Recalculating the Net Use Gap: A Multi-Country Comparison of ITN Use versus ITN Access. AB - [This corrects the article DOI: 10.1371/journal.pone.0097496.]. PMID- 27513976 TI - QTLs Associated with Agronomic Traits in the Cutler * AC Barrie Spring Wheat Mapping Population Using Single Nucleotide Polymorphic Markers. AB - We recently reported three earliness per se quantitative trait loci (QTL) associated with flowering and maturity in a recombinant inbred lines (RILs) population derived from a cross between the spring wheat (Triticum aestivum L.) cultivars 'Cutler' and 'AC Barrie' using 488 microsatellite and diversity arrays technology (DArT) markers. Here, we present QTLs associated with flowering time, maturity, plant height, and grain yield using high density single nucleotide polymorphic (SNP) markers in the same population. A mapping population of 158 RILs and the two parents were evaluated at five environments for flowering, maturity, plant height and grain yield under field conditions, at two greenhouse environments for flowering, and genotyped with a subset of 1809 SNPs out of the 90K SNP array and 2 functional markers (Ppd-D1 and Rht-D1). Using composite interval mapping on the combined phenotype data across all environments, we identified a total of 19 QTLs associated with flowering time in greenhouse (5), and field (6) conditions, maturity (5), grain yield (2) and plant height (1). We mapped these QTLs on 8 chromosomes and they individually explained between 6.3 and 37.8% of the phenotypic variation. Four of the 19 QTLs were associated with multiple traits, including a QTL on 2D associated with flowering, maturity and grain yield; two QTLs on 4A and 7A associated with flowering and maturity, and another QTL on 4D associated with maturity and plant height. However, only the QTLs on both 2D and 4D had major effects, and they mapped adjacent to well-known photoperiod response Ppd-D1 and height reducing Rht-D1 genes, respectively. The QTL on 2D reduced flowering and maturity time up to 5 days with a yield penalty of 436 kg ha-1, while the QTL on 4D reduced plant height by 13 cm, but increased maturity by 2 days. The high density SNPs allowed us to map eight moderate effect, two major effect, and nine minor effect QTLs that were not identified in our previous study using microsatellite and DArT markers. Results from this study provide additional information to wheat researchers developing early maturing and short stature spring wheat cultivars. PMID- 27513977 TI - Danio rerio embryos on Prozac - Effects on the detoxification mechanism and embryo development. AB - In the past decade the presence of psychopharmaceuticals, including fluoxetine (FLU), in the aquatic environment has been associated with the increasing trend in human consumption of these substances. Aquatic organisms are usually exposed to chronic low doses and, therefore, risk assessments should evaluate the effects of these compounds in non-target organisms. Teleost fish possess an array of active defence mechanisms to cope with the deleterious effects of xenobiotics. These include ABC transporters, phase I and II of cellular detoxification and oxidative stress enzymes. Hence, the present study aimed at characterising the effect of FLU on embryo development of the model teleost zebrafish (Danio rerio) concomitantly with changes in the detoxification mechanisms during early developmental phases. Embryos were exposed to different concentrations of FLU (0.0015, 0.05, 0.1, 0.5 and 0.8MUM) for 80hours post fertilization. Development was screened and the impact in the transcription of key genes, i.e., abcb4, abcc1, abcc2, abcg2, cyp1a, cyp3a65, gst, sod, cat, ahr, pxr, pparalpha, pparbeta, ppargamma, rxraa, rxrab, rxrbb, rxrga, rxrgb, raraa, rarab, rarga evaluated. In addition, accumulation assays were performed to measure the activity of ABC proteins and antioxidant enzymes (CAT and Cu/ZnSOD) after exposure to FLU. Embryo development was disrupted at the lowest FLU concentration tested (0.0015MUM), which is in the range of concentrations found in WWTP effluents. Embryos exposed to higher concentrations of FLU decreased Cu/Zn SOD, and increased CAT (0.0015 and 0.5MUM) enzymatic activity. Exposure to higher concentrations of FLU decreased the expression of most genes belonging to the detoxification system and upregulated cat at 0.0015MUM of FLU. Most of the tested concentrations downregulated pparalpha, pparbeta, ppargamma, and raraa, rxraa, rxrab, rxrbb rxrgb and ahr gene expression while pxr was significantly up regulated at all tested concentrations. In conclusion, this study shows that FLU can impact zebrafish embryo development, at concentrations found in effluents of WWTPs, concomitantly with changes in antioxidant enzymes, and the transcription of key genes involved in detoxification and development. These finding raises additional concerns supporting the need to monitor the presence of this compound in aquatic reservoirs. PMID- 27513979 TI - Intracranial angiomatous meningiomas: A 15-year, multicenter study. AB - BACKGROUND: Angiomatous meningiomas (AMs) represent a rare subtype of meningiomas in which the vascular component prevail. They represent less than 1% of all intracranial tumors and approximately 2.1% of all meningeal tumors (Hasselblatt et al., 2004). The purpose of this study was to determine the clinical characteristics, radiological features and prognosis of AMs based on a Tunisian multicenter experience in the management of 58 successive cases of intracranial AMs. To the best of our knowledge, this is the largest series reported to date. METHODS: We retrospectively reviewed 58 patients of AM treated in the departments of Neurosurgery of The Tunisian National Institute of Neurology, Sahloul University Hospital and Fattouma Bourguiba University Hospital from January 2001 to December 2015. Clinical characteristics, radiographic features and treatment modality, in the form of radical surgery, were noted. Statistical analysis was done with regards to recurrence free survival (RFS) and overall survival (OS) using Kaplan-Meier survival analysis. RESULTS: The median age of the patients on admission was 53.0 years (8-78). Twenty-two patients were males and thirty-six were females. The median duration of symptoms prior to presentation was six months. Signs of increased intracranial pressure were the most common presenting symptom followed by seizures, motor weakness and cranial nerves paresis. Cystic changes were observed in 50% of cases, moderate to severe peritumoral edema in 81% of cases and multiple signal voids suggestive of blood vessels in 86.2% of cases. Forty-two patients underwent Simpson I excision (72.4%) while fourteen had Simpson II excision (24.1%). A Simpson III resection was realized in two patients (3.5%). The surgical resection was hemorrhagic in 63.8% of cases and in 13.8% of cases, several blood transfusions were necessary to maintain hemodynamic stability. No adjunctive treatment was administered. Six out of the fifty-six patients of the Simpson I/II groups recurred while one of the two patients with Simpson III resection had tumor regrowth. Median duration of RFS was 103 months. Second surgery was realized in all cases with no subsequent recurrence. The extent of tumor resection and the location were found to correlate with the risk of developing recurrences (P=0.001). CONCLUSIONS: AMs represent a rare subtype of meningioma characterized by variable cystic components, large peritumoral edema and multiple areas of vascular signal voids. The mainstay of the treatment is gross total resection, ideally following a preoperative embolization. The fate of the tumor remnant after incomplete tumor resection still needs to be evaluated and we do not recommend the systematic use of post-operative adjuvant RT in all cases. As local recurrence can develop many years after initial treatment, Long term follow-up is mandatory. PMID- 27513978 TI - Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. AB - INTRODUCTION: Alzheimer's disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstem's locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]). METHODS: The methods include unbiased stereological analyses in human brainstems to estimate LC volume and neuronal population in controls and individuals across all AD stages. RESULTS: As the Braak stage increases by 1 unit, the LC volume decreases by 8.4%. Neuronal loss started only midway through AD progression. Age-related changes spare the LC. DISCUSSION: The long gap between NFT accumulation and neuronal loss suggests that a second trigger may be necessary to induce neuronal death in AD. Imaging studies should determine whether LC volumetry can replicate the stage wise atrophy observed here and how these changes are specific to AD. LC volumetry may develop into a screening biomarker for selecting high-yield candidates to undergo expensive and less accessible positron emission tomography scans and to monitor AD progression from presymptomatic stages. PMID- 27513980 TI - Lower cervical levels: Increased risk of early dysphonia following anterior cervical spine surgery. AB - OBJECTIVES: The present study aimed to re-evaluate the incidence of early dysphonia after anterior cervical spine surgery (ACSS) and to determine the related risk factors. CLINICAL MATERIALS AND METHODS: Patients underwent ACSS between January 2011 and December 2013 at two sites were identified retrospectively from hospital's patient databases. A total of 233 cases were included in this study. Dysphonia developed 1 month postoperatively was recorded. Follow-up was conducted in all positive-response patients. Those reporting severe or persistent voice symptoms were referred to otolaryngologists for further assessments and (or) treatments. Pre and intraoperative factors were collected to determine their relationships with dysphonia one month postoperatively. RESULTS: 45 patients developed dysphonia at one month, including 23 males and 22 females, yielding to an incidence of 19.3%. 34 cases resolved themselves in 3 months, leaving the remaining 11 patients considered to be severe or persistent cases. However, 10 of them recovered spontaneously in the next 9 months, while the last case received vocal cord medialization and returned to almost normal speech function at 18 months. In univariate analysis, only approaching level involving C6-C7 or (and) C7-T1 was significantly associated with postoperative dysphonia (P<0.001). This association was not weakened in multiple logistic regression analysis (OR 2.348, 95% CI 1.467-3.659, P<0.001). CONCLUSION: The incidence of early dysphonia following ACSS was relatively high and approaching at lower cervical levels was an independent predictive factor. PMID- 27513981 TI - The developmental transcriptome atlas of the biofuel crop Camelina sativa. AB - Camelina sativa is currently being embraced as a viable industrial bio-platform crop due to a number of desirable agronomic attributes and the unique fatty acid profile of the seed oil that has applications for food, feed and biofuel. The recent completion of the reference genome sequence of C. sativa identified a young hexaploid genome. To complement this work, we have generated a genome-wide developmental transcriptome map by RNA sequencing of 12 different tissues covering major developmental stages during the life cycle of C. sativa. We have generated a digital atlas of this comprehensive transcriptome resource that enables interactive visualization of expression data through a searchable database of electronic fluorescent pictographs (eFP browser). An analysis of this dataset supported expression of 88% of the annotated genes in C. sativa and provided a global overview of the complex architecture of temporal and spatial gene expression patterns active during development. Conventional differential gene expression analysis combined with weighted gene expression network analysis uncovered similarities as well as differences in gene expression patterns between different tissues and identified tissue-specific genes and network modules. A high-quality census of transcription factors, analysis of alternative splicing and tissue-specific genome dominance provided insight into the transcriptional dynamics and sub-genome interplay among the well-preserved triplicated repertoire of homeologous loci. The comprehensive transcriptome atlas in combination with the reference genome sequence provides a powerful resource for genomics research which can be leveraged to identify functional associations between genes and understand the regulatory networks underlying developmental processes. PMID- 27513982 TI - Skin punch biopsy sectioning: before or after tissue processing? AB - BACKGROUND: We intended to study whether there is a meaningful difference in microscopic examination between dividing a biopsy section into two equal parts before tissue processing (first method) or after (second method). METHODS: A total of 400 cases were included in the study. Punch biopsies (PB) were cut into two pieces using the first method in 200 cases and just before paraffin embedding in another 200 cases using the second method. We microscopically evaluated the epidermal mesh view, the presence of a cross-cut hair follicle and bow shape because of epidermal angling, the presence of two pieces on the slide and if there was a difference of >2 mm between the parts, and the number of new sections and new slides. RESULTS: Cross-cut hair follicle (p = 0.018), epidermal mesh view (p = 0.036), difference of >2 mm between the parts (p = 0.008), the number of new sections (p < 0.001) and new slides (p < 0.001) were considerably higher when the first method was used compared with the second method. The presence of two pieces was less (p < 0.001) when using the first method. CONCLUSIONS: We noted a meaningful difference in the quality of microscopic evaluation between the first and second methods. Better sections were obtained with the second method. In addition, the decrease in the number of new slides will reduce workload, archival work and cost. PMID- 27513983 TI - Peak Systolic Velocity Measurements with Transcranial Doppler Ultrasound Is a Predictor of Incident Stroke among the General Population in China. AB - BACKGROUND AND OBJECTIVE: It is necessary to develop an effective and low-cost screening tool for identifying Chinese people at high risk of stroke. Transcranial Doppler ultrasound (TCD) is a powerful predictor of stroke in the pediatric sickle cell disease population, as demonstrated in the STOP trial. Our study was conducted to determine the prediction value of peak systolic velocities as measured by TCD on subsequent stroke risk in a prospective cohort of the general population from Beijing, China. METHODS: In 2002, a prospective cohort study was conducted among 1392 residents from 11 villages of the Shijingshan district of Beijing, China. The cohort was scheduled for follow up with regard to incident stroke in 2005, 2007, and 2012 by a study team comprised of epidemiologists, nurses, and physicians. Univariate and multivariate Cox proportional hazard regression models were used to determine the factors associated with incident stroke. RESULTS: Participants identified by TCD criteria as having intracranial stenosis had a 3.6-fold greater risk of incident stroke (hazard ratio (HR) 3.57, 95% confidence interval (CI) 1.86-6.83, P<0.01) than those without TCD evidence of intracranial stenosis. The association remained significant in multivariate analysis (HR 2.53, 95% CI 1.31-4.87) after adjusting for other risk factors or confounders. Older age, cigarette smoking, hypertension, and diabetes mellitus remained statistically significant as risk factors after controlling for other factors. CONCLUSIONS: The study confirmed the screening value of TCD among the general population in urban China. Increasing the availability of TCD screening may help identify subjects as higher risk for stroke. PMID- 27513984 TI - What can psychoanalysis contribute to the current refugee crisis?: Preliminary reports from STEP-BY-STEP: A psychoanalytic pilot project for supporting refugees in a "first reception camp" and crisis interventions with traumatized refugees. PMID- 27513985 TI - Recent Chikungunya Virus Infection in 2 Travelers Returning from Mogadishu, Somalia, to Italy, 2016. PMID- 27513986 TI - Can We Predict Individual Combined Benefit and Harm of Therapy? Warfarin Therapy for Atrial Fibrillation as a Test Case. AB - OBJECTIVES: To construct and validate a prediction model for individual combined benefit and harm outcomes (stroke with no major bleeding, major bleeding with no stroke, neither event, or both) in patients with atrial fibrillation (AF) with and without warfarin therapy. METHODS: Using the Kaiser Permanente Colorado databases, we included patients newly diagnosed with AF between January 1, 2005 and December 31, 2012 for model construction and validation. The primary outcome was a prediction model of composite of stroke or major bleeding using polytomous logistic regression (PLR) modelling. The secondary outcome was a prediction model of all-cause mortality using the Cox regression modelling. RESULTS: We included 9074 patients with 4537 and 4537 warfarin users and non-users, respectively. In the derivation cohort (n = 4632), there were 136 strokes (2.94%), 280 major bleedings (6.04%) and 1194 deaths (25.78%) occurred. In the prediction models, warfarin use was not significantly associated with risk of stroke, but increased the risk of major bleeding and decreased the risk of death. Both the PLR and Cox models were robust, internally and externally validated, and with acceptable model performances. CONCLUSIONS: In this study, we introduce a new methodology for predicting individual combined benefit and harm outcomes associated with warfarin therapy for patients with AF. Should this approach be validated in other patient populations, it has potential advantages over existing risk stratification approaches as a patient-physician aid for shared decision-making. PMID- 27513987 TI - Giant Interfrontal Encephalocele in an Infant: A Rare Entity. AB - Interfrontal encephalocele is one of the rare varieties of anterior encephalocele, and a giant interfrontal encephalocele is extremely rare. The authors could find only one case report of giant interfrontal encephalocele in the literature. Anterior encephaloceles are more prevalent in South-East Asia and some northern parts of India. Giant encephalocele poses a great challenge to neurosurgeons and neuroanesthetists during surgery, as these infants usually have a low birth weight and a large sac, thus making the infant prone to hypothermia and blood loss among other risks. We encountered a patient with a giant interfrontal encephalocele aged 1 month. The rarity of this case prompted us to this report. PMID- 27513988 TI - Enhanced Electrochemical Kinetics on Conductive Polar Mediators for Lithium Sulfur Batteries. AB - Lithium-sulfur (Li-S) batteries have been recognized as promising substitutes for current energy-storage technologies owing to their exceptional advantage in energy density. The main challenge in developing highly efficient and long-life Li-S batteries is simultaneously suppressing the shuttle effect and improving the redox kinetics. Polar host materials have desirable chemisorptive properties to localize the mobile polysulfide intermediates; however, the role of their electrical conductivity in the redox kinetics of subsequent electrochemical reactions is not fully understood. Conductive polar titanium carbides (TiC) are shown to increase the intrinsic activity towards liquid-liquid polysulfide interconversion and liquid-solid precipitation of lithium sulfides more than non polar carbon and semiconducting titanium dioxides. The enhanced electrochemical kinetics on a polar conductor guided the design of novel hybrid host materials of TiC nanoparticles grown within a porous graphene framework (TiC@G). With a high sulfur loading of 3.5 mg cm-2 , the TiC@G/sulfur composite cathode exhibited a substantially enhanced electrochemical performance. PMID- 27513989 TI - Population pharmacokinetics of a new long-acting recombinant coagulation factor IX albumin fusion protein for patients with severe hemophilia B. AB - Essentials The new recombinant factor IX (FIX) albumin fusion protein (rIX-FP) has a prolonged half-life. A population pharmacokinetic (PK) model was based on FIX activity levels of hemophilia B patients. The model was used to simulate different dosing scenarios of rIX-FP to help guide dosing. The population PK model supported prolonged dosing of rIX-FP with intervals of up to 2 weeks. Click to hear Prof.Makris's presentation on new treatments in hemophilia SUMMARY: Background The recombinant fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP; Idelvion(r) ) exhibits a longer half-life than plasma-derived factor IX (FIX) and the commercially available recombinant FIX products. Objectives (i) Characterize the population pharmacokinetics (PK) of rIX-FP in hemophilia B patients, (ii) identify covariates that are potential determinants of rIX-FP PK variability and (iii) simulate different dosing scenarios of rIX-FP following single and steady-state dosing. Patients/Methods A population PK model was developed based on FIX activity levels of 104 patients who had received treatment with rIX-FP. Patients were aged 1-65 years with FIX activity <= 2 IU dL-1 . PK sampling was performed for up to 14 days (336 h). Results Simulation of a single intravenous infusion of rIX-FP (25-75 IU kg-1 ) predicted that the median trough exogenous FIX activity levels would remain > 5 IU dL-1 for up to 16 days in adolescents/adults aged >= 12 years, up to 12 days in children aged 6 to < 12 years, and up to 9.5 days in children aged < 6 years. For steady-state dosing, the median trough exogenous FIX activity levels were maintained at > 5 IU dL-1 for the duration of the dosing interval for the 25, 35 and 40 IU kg-1 weekly regimens and for 75 IU kg-1 every 14 days in adolescents/adults, and for the 35 and 40 IU kg-1 weekly regimens in children. Conclusion The population PK model developed here correlates well with observed clinical data and supports prolonged dosing of rIX-FP with intervals of up to 2 weeks. PMID- 27513990 TI - Genetic Determinants for Pyomelanin Production and Its Protective Effect against Oxidative Stress in Ralstonia solanacearum. AB - Ralstonia solanacearum is a soil-borne plant pathogen that infects more than 200 plant species. Its broad host range and long-term survival under different environmental stress conditions suggest that it uses a variety of mechanisms to protect itself against various types of biotic and abiotic stress. R. solanacearum produces a melanin-like brown pigment in the stationary phase when grown in minimal medium containing tyrosine. To gain deeper insight into the genetic determinants involved in melanin production, transposon-inserted mutants of R. solanacearum strain SL341 were screened for strains with defective melanin producing capability. In addition to one mutant already known to be involved in pyomelanin production (viz., strain SL341D, with disruption of the hydroxphenylpyruvate dioxygenase gene), we identified three other mutants with disruption in the regulatory genes rpoS, hrpG, and oxyR, respectively. Wild-type SL341 produced pyomelanin in minimal medium containing tyrosine whereas the mutant strains did not. Likewise, homogentisate, a major precursor of pyomelanin, was detected in the culture filtrate of the wild-type strain but not in those of the mutant strains. A gene encoding hydroxyphenylpyruvate dioxygenase exhibited a significant high expression in wild type SL341 compared to other mutant strains, suggesting that pyomelanin production is regulated by three different regulatory proteins. However, analysis of the gene encoding homogentisate dioxygenase revealed no significant difference in its relative expression over time in the wild-type SL341 and mutant strains, except for SL341D, at 72 h incubation. The pigmented SL341 strain also exhibited a high tolerance to hydrogen peroxide stress compared with the non-pigmented SL341D strain. Our study suggests that pyomelanin production is controlled by several regulatory factors in R. solanacearum to confer protection under oxidative stress. PMID- 27513992 TI - Post-flowering night respiration and altered sink activity account for high night temperature-induced grain yield and quality loss in rice (Oryza sativa L.). AB - High night temperature (HNT) is a major constraint to sustaining global rice production under future climate. Physiological and biochemical mechanisms were elucidated for HNT-induced grain yield and quality loss in rice. Contrasting rice cultivars (N22, tolerant; Gharib, susceptible; IR64, high yielding with superior grain quality) were tested under control (23 degrees C) and HNT (29 degrees C) using unique field-based tents from panicle initiation till physiological maturity. HNT affected 1000 grain weight, grain yield, grain chalk and amylose content in Gharib and IR64. HNT increased night respiration (Rn) accounted for higher carbon losses during post-flowering phase. Gharib and IR64 recorded 16 and 9% yield reduction with a 63 and 35% increase in average post-flowering Rn under HNT, respectively. HNT altered sugar accumulation in the rachis and spikelets across the cultivars with Gharib and IR64 recording higher sugar accumulation in the rachis. HNT reduced panicle starch content in Gharib (22%) and IR64 (11%) at physiological maturity, but not in the tolerant N22. At the enzymatic level, HNT reduced sink strength with lower cell wall invertase and sucrose synthase activity in Gharib and IR64, which affected starch accumulation in the developing grain, thereby reducing grain weight and quality. Interestingly, N22 recorded lower Rn-mediated carbon losses and minimum impact on sink strength under HNT. Mechanistic responses identified will facilitate crop models to precisely estimate HNT-induced damage under future warming scenarios. PMID- 27513991 TI - Calpain inhibition reduces structural and functional impairment of retinal ganglion cells in experimental optic neuritis. AB - Optic neuritis (ON), inflammation of the optic nerve, is strongly associated with multiple sclerosis. ON pathology is characterized by attack of autoreactive T cells against optic nerve antigens, resulting in demyelination, death of retinal ganglion cells, and cumulative visual impairment. A model of experimental autoimmune encephalomyelitis (EAE) was utilized to study the onset and progression of ON and the neuroprotective efficacy of oral treatment with the calpain inhibitor SNJ 1945. EAE was actively induced in B10.PL mice with myelin basic protein on Days 0 and 2, and mice received twice daily oral dosing of SNJ 1945 from Day 9 until sacrificing (Day 26). Visual function was determined by electroretinogram recordings and daily measurement of optokinetic responses (OKR) to a changing pattern stimulus. Optic nerve and retinal histopathology was investigated by immunohistochemical and luxol fast blue staining. EAE mice manifested losses in OKR thresholds, a measurement of visual acuity, which began early in the disease course. There was a significant bias toward unilateral OKR impairment among EAE-ON eyes. Treatment with SNJ 1945, initiated after the onset of OKR threshold decline, improved visual acuity, pattern electroretinogram amplitudes, and paralysis, with attenuation of retinal ganglion cell death. Furthermore, calpain inhibition spared oligodendrocytes, prevented degradation of axonal neurofilament protein, and attenuated reactive astrocytosis. The trend of early, unilateral visual impairment in EAE-ON parallels the clinical presentation of ON exacerbations associated with multiple sclerosis. Calpain inhibition may represent an ideal candidate therapy for the preservation of vision in clinical ON. As in multiple sclerosis (MS) patients, optic neuritis (ON) and early, primarily monocular loss in spatial acuity is observed in a rodent model (EAE, experimental autoimmune encephalomyelitis). Daily oral treatment with the calpain inhibitor SNJ 1945 preserves visual acuity and preserves retinal ganglion cells (Brn3a, brain-specific homeobox/POU domain protein 3A) and their axons (MOSP, myelin oligodendrocyte-specific protein). Calpain inhibition may represent a candidate therapy for the preservation of vision in ON. PMID- 27513993 TI - 1 H and 13 C NMR spectral assignments of a new cyclic peptide from Glycosmis lucida Wall. Ex Huang. PMID- 27513994 TI - Identification of a novel mutation in PLA2G6 gene in a Chinese pedigree with familial cortical myoclonic tremor with epilepsy. AB - PURPOSE: Familial cortical myoclonic tremor with epilepsy (FCMTE) is an epileptic syndrome with autosomal dominant inheritance, of which four genetic subtypes (FCMTE1-4) have been reported. In the present study, we described the clinical and neurophysiologic features of a newly diagnosed Chinese FCMTE family, and investigated the genetic cause for this disease. METHODS: Clinical information was obtained from affected and normal individuals of an FCMTE family comprising 41 members. Electroencephalographies were analyzed in five of six affected members (including the proband). Brain magnetic resonance imaging, somatosensory evoked potential with C-reflex analysis and magnetoencephalography was performed in the proband. Genomic DNA of three affected and two unaffected individuals was analyzed to detect the genetic mutations by using whole-exome sequencing. RESULTS: The inheritance pattern of the pedigree was autosomal dominant. A novel missense mutation c.475C>T (p.Ala159Thr) of PLA2G6 were identified in this family. The mutated locus is highly conserved among other species. The mutation is predicted to have a functional impact, and completely co-segregated with the phenotype. CONCLUSION: This study identifies a novel PLA2G6 mutation that is the possible genetic cause of FCMTE in this family. This mutation and associated clinical features expand the spectrum and phenotypes of PLA2G6-related disorders including neurodegenerative diseases. PMID- 27513995 TI - Cervical and Breast Cancer Screening Among Mexican Migrant Women, 2013. AB - INTRODUCTION: Information on cervical and breast cancer screening among Latinas in the United States is limited. Even less information is available on screening practices of migrant women who engage in circular migration. We examined rates of cervical and breast cancer screening and the extent to which sociodemographics and other characteristics explain screening practices of Mexican migrant women who return to Mexico from the United States. METHODS: We used data from a cross sectional probability survey of Mexico-born migrant women who returned, through Tijuana, to Mexico from the United States in 2013. The sample consisted of women who returned involuntarily (via deportation) or voluntarily; 177 reported authorized documentation status, and 36 reported unauthorized documentation status in the previous 12 months. Descriptive statistics were calculated and logistic regressions were estimated. RESULTS: Of 36 undocumented migrant women, 8 (22.2%) had a Papanicolaou test and 11 (30.6%) had a mammogram in the previous year; of 177 documented migrants, 83 (46.9%) had a Papanicolaou test and 68 (38.4%) had a mammogram. Undocumented migrants were less likely than documented migrants to receive a Papanicolaou test (odds ratio [OR] = 0.29; 95% confidence interval [CI], 0.12-0.67); the likelihood was similar after adjustment for sociodemographic, migration, and acculturation factors (adjusted OR = 0.33; 95% CI, 0.12-0.90). Having health insurance (adjusted OR = 4.17; 95% CI, 1.80-9.65) and a regular source of health care (adjusted OR = 2.83; 95% CI, 1.05-7.65) were significant predictors of receiving a mammogram but not a Papanicolaou test. CONCLUSION: Public health programs are needed to improve access to cervical and breast cancer screenings for Latina migrant women in general and undocumented circular migrants in particular. PMID- 27513996 TI - Developing a Tool to Assess the Capacity of Out-of-School Time Program Providers to Implement Policy, Systems, and Environmental Change. AB - BACKGROUND: Little is known about public health practitioners' capacity to change policies, systems, or environments (PSEs), in part due to the absence of measures. To address this need, we partnered with the Alliance for a Healthier Generation (Alliance) to develop and test a theory-derived measure of the capacity of out-of-school time program providers to improve students' level of nutrition and physical activity through changes in PSEs. COMMUNITY CONTEXT: The measure was developed and tested through an engaged partnership with staff working on the Alliance's Healthy Out-of-School Time (HOST) Initiative. In total, approximately 2,000 sites nationwide are engaged in the HOST Initiative, which serves predominantly high-need children and youths. METHODS: We partnered with the Alliance to conduct formative work that would help develop a survey that assessed attitudes/beliefs, social norms, external resources/supports, and self efficacy. The survey was administered to providers of out-of-school time programs who were implementing the Alliance's HOST Initiative. OUTCOME: Survey respondents were 185 out-of-school time program providers (53% response rate). Exploratory factor analysis yielded a 4-factor model that explained 44.7% of the variance. Factors pertained to perceptions of social norms (6 items) and self-efficacy to build support and engage a team (4 items) and create (5 items) and implement (3 items) an action plan. INTERPRETATION: We report initial development and factor analysis of a tool that the Alliance can use to assess the capacity of after school time program providers, which is critical to targeting capacity-building interventions and assessing their effectiveness. Study findings also will inform the development of measures to assess individual capacity to plan and implement other PSE interventions. PMID- 27513997 TI - Comparison of 2 Disability Measures, Behavioral Risk Factor Surveillance System, 2013. AB - INTRODUCTION: Beginning in 2013, in addition to the 2-item disability question set asked since 2001, Behavioral Risk Factor Surveillance System (BRFSS) began using 5 of the 6 items from the US Department of Health and Human Services recommended disability question set. We assess and compare disability prevalence using the 2-question and 5-question sets and describe characteristics of respondents who identified as having a disability using each question set. METHODS: We used data from the 2013 BRFSS to estimate the prevalence of disability for each question set and the 5 specific types of disability. Among respondents identified by each disability question set, we calculated the prevalence of selected demographic characteristics, health conditions, health behaviors, and health status. RESULTS: With the 2-question set, 21.6% of adults had a disability and with the 5-question set, 22.7% of adults had disability. A total of 51.2% of adults who identified as having a disability with either the 2 question or 5-question set reported having disabilities with both sets. Adults with different disability types differed by demographic and health characteristics. CONCLUSION: The inclusion of the 5 new disability questions in BRFSS provides a level of detail that can help develop targeted interventions and programs and can guide the adaptation of existing health promotion programs to be more inclusive of adults who experience specific types of disabilities. PMID- 27513998 TI - Using Photovoice and Asset Mapping to Inform a Community-Based Diabetes Intervention, Boston, Massachusetts, 2015. AB - INTRODUCTION: Diabetes self-management takes place within a complex social and environmental context. This study's objective was to examine the perceived and actual presence of community assets that may aid in diabetes control. METHODS: We conducted one 6-hour photovoice session with 11 adults with poorly controlled diabetes in Boston, Massachusetts. Participants were recruited from census tracts with high numbers of people with poorly controlled diabetes (diabetes "hot spots"). We coded the discussions and identified relevant themes. We further explored themes related to the built environment through community asset mapping. Through walking surveys, we evaluated 5 diabetes hot spots related to physical activity resources, walking environment, and availability of food choices in restaurants and food stores. RESULTS: Community themes from the photovoice session were access to healthy food, restaurants, and prepared foods; food assistance programs; exercise facilities; and church. Asset mapping identified 114 community assets including 22 food stores, 22 restaurants, and 5 exercise facilities. Each diabetes hot spot contained at least 1 food store with 5 to 9 varieties of fruits and vegetables. Only 1 of the exercise facilities had signage regarding hours or services. Memberships ranged from free to $9.95 per month. Overall, these findings were inconsistent with participants' reports in the photovoice group. CONCLUSION: We identified a mismatch between perceptions of community assets and built environment and the objective reality of that environment. Incorporating photovoice and community asset mapping into a community-based diabetes intervention may bring awareness to underused neighborhood resources that can help people control their diabetes. PMID- 27514000 TI - Supporting fathers is essential in the child health field. PMID- 27514001 TI - Medical champions can make a difference in initiating culture change. PMID- 27514002 TI - Cooled infants with encephalopathy: are heavier infants with weaker heart at a cutaneous disadvantage? PMID- 27514003 TI - Sleep problems in children with dyslexia: understanding the role of sleep in neurocognitive development through the lens of developmental disorders. PMID- 27514004 TI - Role of connectome-based analysis techniques in functional neuroimaging investigations of neurodevelopmental disorders. PMID- 27514005 TI - What else are you hoping for? Fostering hope in paediatric serious illness. PMID- 27514006 TI - Nebulised hypertonic saline for acute bronchiolitis or 'there and back again' to use Tolkien's subtitle for The Hobbit. PMID- 27514007 TI - Validating a robust double-quantum-filtered (1) H MRS lactate measurement method in high-grade brain tumours. AB - (1) H MRS measurements of lactate are often confounded by overlapping lipid signals. Double-quantum (DQ) filtering eliminates lipid signals and permits single-shot measurements, which avoid subtraction artefacts in moving tissues. This study evaluated a single-voxel-localized DQ filtering method qualitatively and quantitatively for measuring lactate concentrations in the presence of lipid, using high-grade brain tumours in which the results could be compared with standard acquisition as a reference. Paired standard acquisition and DQ-filtered (1) H MR spectra were acquired at 3T from patients receiving treatment for glioblastoma, using fLASER (localization by adiabatic selective refocusing using frequency offset corrected inversion pulses) single-voxel localization. Data were acquired from 2 * 2 * 2 cm(3) voxels, with a repetition time of 1 s and 128 averages (standard acquisition) or 256 averages (DQ-filtered acquisition), requiring 2.15 and 4.3 min respectively. Of 37 evaluated data pairs, 20 cases (54%) had measureable lactate (fitted Cramer-Rao lower bounds <= 20%) in either the DQ-filtered or the standard acquisition spectra. The measured DQ-filtered lactate signal was consistently downfield of lipid (1.33 +/- 0.03 ppm vs 1.22 +/- 0.08 ppm; p = 0.002), showing that it was not caused by lipid breakthrough, and that it matched the lactate signal seen in standard measurements (1.36 +/- 0.02 ppm). In the absence of lipid, similar lactate concentrations were measured by the two methods (mean ratio DQ filtered/standard acquisition = 1.10 +/- 0.21). In 7/20 cases with measurable lactate, signal was not measureable in the standard acquisition owing to lipid overlap but was quantified in the DQ-filtered acquisition. Conversely, lactate was undetected in seven DQ-filtered acquisitions but visible using the standard acquisition. In conclusion, the DQ filtering method has proven robust in eliminating lipid and permits uncontaminated measurement of lactate. This is important validation prior to use in tissues outside the brain, which contain large amounts of lipid and which are often susceptible to motion. PMID- 27514008 TI - Trends in the characteristics, dose-limiting toxicities and efficacy of phase I oncology trials: The Cancer Research UK experience. AB - INTRODUCTION: Phase I oncology trials have evolved over the years, and these changes could have implications for future studies and patients. METHODS: Adult trials sponsored by Cancer Research UK Centre for Drug Development between 1995 and 2013 were analysed. Forty-nine trials were divided into two groups based on the starting date for recruitment: 1995-2003 (24 trials, n = 603) and 2004-2013 (25 trials, n = 750) for comparative purposes. RESULTS: From 1995-2003 to 2004 2013, there was a shift towards studying non-cytotoxic agents that are administered orally. In later trials, patients tended to have better performance status, were older, had greater disease burden, and were more likely to have received prior treatment. In 2004-2013, wider variety of dose escalation designs were used, and studies were more likely to be multicentre, target/disease specific, conducted in first-/any-line setting and to require tumour biopsy. The overall incidence of dose-limiting toxicities (DLTs) was unchanged (10.9%; risk of death 0.4%), but DLTs such as neuropathy, stomatitis and thrombocytopaenia were less frequent in the more recent trials, while elevated liver enzymes were more frequent. Non-classical DLTs emerged in the later trials, including hypertension, hypophosphataemia, cardiac and ophthalmic toxicities. Disease control rate (DCR) increased from 27.9% (1995-2003) to 36.0% (2004-2013; P = 0.0033) due to higher rates of disease stabilisation. CONCLUSION: Changes in trial designs, therapeutic agents, patient characteristics and DLTs were observed. Although the nature of DLTs changed, the incidence was similar in the two time periods and DCR improved, suggesting that the benefit-risk balance for patients participating in early-phase trials remains acceptable. PMID- 27514009 TI - LPS injection reprograms the expression and the 3' UTR of a CAP gene by alternative polyadenylation and the formation of a GAIT element in Ciona intestinalis. AB - The diversification of cellular functions is one of the major characteristics of multicellular organisms which allow cells to modulate their gene expression, leading to the formation of transcripts and proteins with different functions and concentrations in response to different stimuli. CAP genes represent a widespread family of proteins belonging to the cysteine-rich secretory protein, antigen 5 and pathogenesis-related 1 superfamily which, it has been proposed, play key roles in the infection process and the modulation of immune responses in host animals. The ascidian Ciona intestinalis represents a group of proto-chordates with an exclusively innate immune system that has been widely studied in the field of comparative and developmental immunology. Using this biological system, we describe the identification of a novel APA mechanism by which an intronic polyadenylation signal is activated by LPS injection, leading to the formation of a shorter CAP mRNA capable of expressing the first CAP exon plus 19 amino acid residues whose sequence is contained within the first intron of the annotated gene. Furthermore, such an APA event causes the expression of a translational controlling cis-acting GAIT element which is not present in the previously isolated CAP isoform and identified in the 3'-UTR of other immune-related genes, suggesting an intriguing scenario in which both transcriptional and post transcriptional control mechanisms are involved in the activation of the CAP gene during inflammatory response in C. intestinalis. PMID- 27514010 TI - Severe Plasmodium vivax cerebral malaria complicated by hemophagocytic lymphohistiocytosis treated with artesunate and doxycycline. AB - Malaria-related hemophagocytic lymphohistiocytosis is a rare, potentially fatal, hyperinflammatory disease entity which can be challenging to diagnose and treat. It is usually associated with Plasmodium falciparum infection. It is less frequently associated with Plasmodium vivax. Here we report an unusual case of a 23-year-old healthy Nigerian man who presented with fever, microangiopathic hemolytic anemia, acute renal failure, and confusion, and was diagnosed as having cerebral malaria-related hemophagocytic lymphohistiocytosis caused by P. vivax infection. He was successfully treated with intravenous artesunate and doxycycline with dramatic clinical improvement. PMID- 27514011 TI - Mesenchymal stem cells in corneal neovascularization: Comparison of different application routes. AB - The purpose of the present study is to investigate the effect of mesenchymal stem cells in corneal neovascularization and wound healing, and to compare the effectiveness of two possible application routes, subconjunctival injection and amniotic membrane transplantation. Chemical injury was induced by application of sodium hydroxide to the rats' corneas. After 7 days, the animals were divided into three groups. Different treatment methods were used for each group as follows: i) Group 1, injection of bone marrow-derived mesenchymal stem cells (BMSCs) under the conjunctiva; ii) group 2, transplantation of amniotic membranes, previously seeded with BMSCs; and iii) group 3, the untreated control group. The eyes were examined using a slit lamp on a weekly basis. After 4 weeks, the animals were sacrificed and corneas were removed for further examination. Corneal flat mounts were made following ink perfusion for improved vessel visualization, image capturing and quantitative evaluation. enzyme-linked immunosorbent assay was performed to detect the levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9). Reverse transcription-quantitative polymerase chain reaction was used for detection of VEGF-A, MMP-9, Toll-like receptor (TLR)2 and TLR4 gene expression levels. Cryosections were used for histological examination and immunostaining. Statistical analysis (Welch's one-way analysis of variance) demonstrated a significant difference between the groups [P<=0.05, confidence interval (CI) 95%]. The level of injury in group 1 was significantly different from groups 2 and 3. Measurement of the vessel area and VEGF gene expression levels had a similar difference among the groups (P<=0.05, CI 95%), however the differences for TLR2 and TLR4 were not statistically significant. BMSCs were previously transduced with the green fluorescent protein gene by lentivirus to track the movement of the cells following transplantation. The transplanted cells enhanced corneal wound healing by trophic factor production and immune-regulatory effect, rather than by direct transdifferentiation into corneal cells. The results of the current study demonstrated that BMSCs enhance corneal wound healing and decrease the area of neovascularization. Furthermore, the comparison of two application routes indicated that single subconjunctival injection appeared more effective than transplantation with amniotic membrane. PMID- 27514012 TI - High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization. AB - BACKGROUND & AIMS: Efficacy of radioembolization is derived from radioinduced damage, whereas tumour dosimetry is not considered as yet in prospective clinical trials. OBJECTIVES: This study evaluates the impact of tumour dose (TD), based on 99m Tc macroaggregated albumin (MAA) quantification, on response and overall survival (OS). MATERIALS AND METHODS: We consecutively included 85 patients with hepatocellular carcinoma treated with 90 Y-loaded glass microspheres. TD was calculated using a quantitative analysis of the MAA SPECT/CT. Responses were assessed after 3 months using the European Association for the Study of the Liver criteria. OS was assessed using Kaplan-Meier tests. RESULTS: Response rate was 80.3% on lesion-based analysis (n=132), and 77.5% on patient-based analysis. The response rate was only 9.1% for patients with TD <205 Gy against 89.7% for those with TD >=205 Gy (P<10-7 ). Non-portal vein thrombosis (PVT) patients exhibited a median OS of 11.75 m (95% CI: 3-30.7 m) for TD <205 Gy, and 25 m (95% CI: 15-34.7 m) for TD >=205 Gy (P=.0391). PVT patients exhibited a 4.35 m median OS (95% CI: 2-8 m) for TD<205 Gy, and 15.7 m (95% CI: 9.5-25.5 m) for TD >=205 Gy, (P=.0004), with HR of 6.99. PVT patients exhibited a median OS of 3.6 m (95% CI: 2-8 m) when PVT MAA targeting was poor or with TD <205 Gy (poor candidate), vs 17.5 m (95% CI: 11-26.5 m) for the others identified as good candidates (P<.0001), with HR of 12.85. CONCLUSION: This study confirms the highly predictive value of MAA-based TD evaluation for response and OS. TD evaluation and PVT MAA targeting should be further evaluated in ongoing trials, whereas personalized dosimetry should be implemented in new trial designs. PMID- 27514014 TI - Analysis of residual content of used syringes collected from low threshold facilities in Lausanne, Switzerland. AB - BACKGROUND: For the first time in Switzerland, an analysis of residual contents from used syringes collected from low threshold facilities was performed. This preliminary study is part of a wider project aiming to understand patterns of injecting drug use over time. METHODS: Among the 100,000 syringes exchanged annually by the ABS foundation (Accueil Bas Seuil), 113 were collected following a purposive sampling method and analysed by gas chromatography coupled with mass spectrometry (GC-MS). RESULTS: Four syringes (4% of the sample population) contained no substances take into consideration the limit of the method. Cocaine was the most commonly observed compound and was detected in 77 syringes (68%), whilst users reported syringes with cocaine among those analysed in this study. Heroin was detected in 49 syringes (43%) and reported by 53 users returning syringes; midazolam was detected in 31 syringes (27%) and reported as the medicine Dormicum((r)) in 22 occurrences. No new or unusual illicit drug was detected in the sample. CONCLUSION: The results show the presence of cocaine in more than half of the sample, an absence of new or unusual illicit drugs, as well as very few traces of methadone, which suggests that this substitution drug is rarely injected. This preliminary study also demonstrates the potential of this developed methodology for monitoring purposes. An ongoing and more systematic approach could allow to detect modifications in drug use patterns among the target population as well as the appearance of new and hazardous substances. Such systematic and timely results could allow an adaptation of harm reduction interventions. PMID- 27514013 TI - Long-term survival and regeneration of neuronal and vasculature cells inside the core region after ischemic stroke in adult mice. AB - Focal cerebral ischemia results in an ischemic core surrounded by the peri infarct region (penumbra). Most research attention has been focused on penumbra while the pattern of cell fates inside the ischemic core is poorly defined. In the present investigation, we tested the hypothesis that, inside the ischemic core, some neuronal and vascular cells could survive the initial ischemic insult while regenerative niches might exist many days after stroke in the adult brain. Adult mice were subjected to focal cerebral ischemia induced by permanent occlusion of distal branches of the middle cerebral artery (MCA) plus transient ligations of bilateral common carotid artery (CCA). The ischemic insult uniformly reduced the local cerebral blood flow (LCBF) by 90%. Massive cell death occurred due to multiple mechanisms and a significant infarction was cultivated in the ischemic cortex 24 h later. Nevertheless, normal or even higher levels of brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) persistently remained in the core tissue, some NeuN-positive and Glut-1/College IV-positive cells with intact ultrastructural features resided in the core 7-14 days post stroke. BrdU-positive but TUNEL-negative neuronal and endothelial cells were detected in the core where extensive extracellular matrix infrastructure developed. Meanwhile, GFAP-positive astrocytes accumulated in the penumbra and Iba-1-positive microglial/macrophages invaded the core several days after stroke. The long term survival of neuronal and vascular cells inside the ischemic core was also seen after a severe ischemic stroke induced by permanent embolic occlusion of the MCA. We demonstrate that a therapeutic intervention of pharmacological hypothermia could save neurons/endothelial cells inside the core. These data suggest that the ischemic core is an actively regulated brain region with residual and newly formed viable neuronal and vascular cells acutely and chronically after at least some types of ischemic strokes. PMID- 27514015 TI - Development of a novel immunoassay for herbal cannabis using a new fluorescent antibody probe, "Ultra Quenchbody". AB - We developed a novel immunoassay for herbal cannabis based on a new immunoassay principle that uses Ultra Quenchbody ("UQ-body"), a recombinant antibody Fab fragment fluorolabeled at the N-terminal regions. When the antigen binds to anti Delta(9)-tetrahydrocannabinol (THC) UQ-body, the fluorescence intensity (FI) decreases. The analytical conditions of the immunoassay were optimized based on the FI reduction rate (FIRR). Following are the steps in the final analytical procedure: (1) 10mg of samples were extracted with 1ml of a 60:40 mixture of methanol and phosphate-buffered saline (PBS); (2) the extract was filtered through a centrifugal 0.2-MUm polytetrafluoroethylene membrane filter; (3) the filtrate was diluted 100 times with extraction solvent; (4) 6-MUl diluted solution was mixed with 19-MUl PBS and 75-MUl UQ-body solution; and (5) FIRR was measured under 275-mV excitation light. Herbal cannabis samples containing >=4.0 mg/g THC gave FIRRs of >=5.2%. FIRRs of negative samples (cigarette, tea, spice, and so-called "synthetic marijuana") were <=3.1%. When setting the FIRR threshold to 5.0%, cannabis samples containing >=4.0-mg/g THC were correctly judged as positive without being affected by false positives caused by the negative samples. This detection limit was lower than total THC level (10-200mg/g) in most herbal cannabis samples seized in Japan. In seven of the 10 cannabis samples, the results of the UQ-body test were comparable with those of the Duquenois-Levine test. Thus, the UQ-body-based immunoassay is presumed to be an effective and objective drug screening method for herbal cannabis; however, to show the true usefulness, it is necessary to test a number of real case samples in the field situation. PMID- 27514016 TI - Elemental and molecular profiling of licit, illicit, and niche tobacco. AB - The recognition of differences between regulated large-scale mass manufactured products and the uncontrolled cultivation of tobaccos for illicit purposes plays a significant role within identification of provenance. This research highlights X-ray fluorescence and Fourier transform infrared spectroscopy as useful analytical techniques for the rapid identification of tobacco samples of unknown provenance. Identification of key discriminative features within each technique allowed for the development of typical characteristic profiles for each type of tobacco. Analysis using X-ray fluorescence highlights chlorine, potassium, calcium and iron as key elemental indicators of tobacco provenance. Significant levels of chlorine seen within Snus samples prompted attempts to visualise chlorine containing regions and structures within the sample. Scanning electron microscopy images showed crystalline structures visible within the Snus tobacco, structures which Energy dispersive X-ray spectroscopy qualitatively confirmed to contain chlorine. Chloride levels within Snus samples were quantified using ion chromatography with levels found to range between 0.87mgmL(-1) and 1.28mg. Additionally, FTIR indicated that absorbances attributed to carbonyl stretching at 1050-1150cm(-1), alkane bending at 1350-1480cm(-1) and amide I stretching at 1600-1700cm(-1) highlighting a spectral fingerprint region that allowed for the clear differentiation between different types of tobaccos using PCA analysis, but was limited by differentiation between provenance of cigarettes and hand rolled tobacco. X-ray fluorescence and Fourier transform infrared spectroscopy yielded different information with regards tobacco discrimination and provenance, however both methods overall analysis time and cost reduced indicating usefulness as potential handheld analytical techniques in the field. PMID- 27514017 TI - Effects of elevated carbon dioxide on stomatal characteristics and carbon isotope ratio of Arabidopsis thaliana ecotypes originating from an altitudinal gradient. AB - Stomatal functioning regulates the fluxes of CO2 and water vapor between vegetation and atmosphere and thereby influences plant adaptation to their habitats. Stomatal traits are controlled by external environmental and internal cellular signaling. The objective of this study was to quantify the effects of CO2 enrichment (CE) on stomatal density (SD)-related properties, guard cell length (GCL) and carbon isotope ratio (delta13 C) of a range of Arabidopsis thaliana ecotypes originating from a wide altitudinal range [50-1260 m above sea level (asl)], and grown at 400 and 800 ppm [CO2 ], and thereby elucidate the possible adaptation and acclimation responses controlling stomatal traits and water use efficiency (WUE). There was a highly significant variation among ecotypes in the magnitude and direction of response of stomatal traits namely, SD and stomatal index (SI) and GCL, and delta13 C to CE, which represented a short term acclimation response. A majority of ecotypes showed increased SD and SI with CE with the response not depending on the altitude of origin. Significant ecotypic variation was shown in all stomatal traits and delta13 C at each [CO2 ]. At 400 ppm, means of SD, SI and GCL for broad altitudinal ranges, i.e. low (<100 m), mid (100-400 m) and high (>400 m), increased with increasing altitude, which represented an adaptation response to decreased availability of CO2 with altitude. delta13 C was negatively correlated to SD and SI at 800 ppm but not at 400 ppm. Our results highlight the diversity in the response of key stomatal characters to CE and altitude within the germplasm of A. thaliana and the need to consider this diversity when using A. thaliana as a model plant. PMID- 27514018 TI - Spatial and temporal dimensions of fire activity in the fire-prone eastern Canadian taiga. AB - The forest age mosaic is a fundamental attribute of the North American boreal forest. Given that fires are generally lethal to trees, the time since last fire largely determines the composition and structure of forest stands and landscapes. Although the spatiotemporal dynamics of such mosaics has long been assumed to be random under the overwhelming influence of severe fire weather, no long-term reconstruction of mosaic dynamics has been performed from direct field evidence. In this study, we use fire length as a proxy for fire extent across the fire prone eastern Canadian taiga and systematically reconstruct the spatiotemporal variability of fire extent and fire intervals, as well as the resulting forest age along a 340-km transect for the 1840-2013 time period. Our results indicate an extremely active fire regime over the last two centuries, with an overall burn rate of 2.1% of the land area yr-1 , mainly triggered by seasonal anomalies of high temperature and severe drought. However, the rejuvenation of the age mosaic was strongly patterned in space and time due to the intrinsically lower burn rates in wetland-dominated areas and, more importantly, to the much-reduced likelihood of burning of stands up to 50 years postfire. An extremely high burn rate of ~5% yr-1 would have characterized our study region during the last century in the absence of such fuel age effect. Although recent burn rates and fire sizes are within their range of variability of the last 175 years, a particularly severe weather event allowed a 2013 fire to spread across a large fire refuge, thus shifting the abundance of mature and old forest to a historic low. These results provide reference conditions to evaluate the significance and predict the spatiotemporal dynamics and impacts of the currently strengthening fire activity in the North American boreal forest. PMID- 27514019 TI - Consequences of coinfection with protective symbionts on the host phenotype and symbiont titres in the pea aphid system. AB - Symbiotic associations between microbes and insects are widespread, and it is frequent that several symbionts share the same host individual. Hence, interactions can occur between these symbionts, influencing their respective abundance within the host with consequences on its phenotype. Here, we investigate the effects of multiple infections in the pea aphid, Acyrthosiphon pisum, which is the host of an obligatory and several facultative symbionts. In particular, we study the influence of a coinfection with 2 protective symbionts: Hamiltonella defensa, which confers protection against parasitoids, and Rickettsiella viridis, which provides protection against fungal pathogens and predators. The effects of Hamiltonella-Rickettsiella coinfection on the respective abundance of the symbionts, host fitness and efficacy of enemy protection were studied. Asymmetrical interactions between the 2 protective symbionts have been found: when they coinfect the same aphid individuals, the Rickettsiella infection affected Hamiltonella abundance within hosts but not the Hamiltonella-mediated protective phenotype while the Hamiltonella infection negatively influences the Rickettsiella-mediated protective phenotype but not its abundance. Harboring the 2 protective symbionts also reduced the survival and fecundity of host individuals. Overall, this work highlights the effects of multiple infections on symbiont abundances and host traits that are likely to impact the maintenance of the symbiotic associations in natural habitats. PMID- 27514020 TI - Microbial elements as the initial triggers in the pathogenesis of polymorphic light eruption? AB - The primary trigger of polymorphic light eruption (PLE) remains to be uncovered. We hypothesize that PLE may be initiated by elements resulting from UV-induced damage to microbial communities of the skin, leading to a cascade of events eventually resulting in the skin rash of the disease. One mechanism by which epidermal injury by UV radiation could trigger PLE are danger signals such as damage or pathogen associated molecular patterns DAMP/PAMPs or commensal associated molecular patterns (CAMPs). Such triggers could be produced due to UV induced stress on microbial communities of the skin and exacerbate inflammatory responses by inducing the innate immune system through antimicrobial peptides (AMPs) such as psoriasin, RNase7, HBD-2 and LL-37. These AMPs also actively take part in initiating adaptive immunity. That signals derived from microbial rather than human elements may initiate PLE is supported by series of observations, including the PLE-protective effect of topically applied microbial-derived DNA repair enzymes. PMID- 27514021 TI - Dependence of thoracic fluid content with anthropometric-geometric factors in impedance cardiography. PMID- 27514022 TI - Tungsten(VI) Carbyne/Bis(carbene) Tautomerization Enabled by N-Donor SBA15 Surface Ligands: A Solid-State NMR and DFT Study. AB - Designing supported well-defined bis(carbene) complexes remains a key challenge in heterogeneous catalysis. The reaction of W(=CtBu)(CH2 tBu)3 with amine modified mesoporous SBA15 silica, which has vicinal silanol/silylamine pairs [(=SiOH)(=SiNH2 )], leads to [(=SiNH2 -)(=SiO-)W(=CHtBu)(CH2 tBu)2 ] and [(=SiNH2 -)(=SiO-)W(=CHtBu)2 (CH2 tBu). Variable temperature, (1) H-(1) H 2D double quantum, (1) H-(13) C HETCOR, and HETCOR with spin diffusion solid-state NMR spectroscopy demonstrate tautomerization between the alkyl alkylidyne and the bis(alkylidene) on the SBA15 surface. Such equilibrium is possible through the coordination of W to the surface [(=Si-OH)(=Si-NH2 )] groups, which act as a [N,O] pincer ligand. DFT calculations provide a rationalization for the surface complex tautomerization and support the experimental results. This direct observation of such a process shows the strong similarity between molecular mechanisms in homogeneous and heterogeneous catalysis. In propane metathesis (at 150 degrees C), the tungsten bis(carbene) tautomer is favorable, with a turnover number (TON) of 262. It is the highest TON among all the tungsten alkyl-supported catalysts. PMID- 27514023 TI - MAP Kinase-Dependent RUNX2 Phosphorylation Is Necessary for Epigenetic Modification of Chromatin During Osteoblast Differentiation. AB - RUNX2, an essential transcription factor for osteoblast differentiation and bone formation is activated by ERK/MAP kinase-dependent phosphorylation. However, relationship between these early events and specific epigenetic modifications of chromatin during osteoblast differentiation have not been previously examined. Here, we explore these relationships using chromatin immunoprecipitation (ChIP) to detect chromatin modifications in RUNX2-binding regions of Bglap2 and Ibsp. Growth of MC3T3-E1c4 preosteoblast cells in differentiation conditions rapidly induced Bglap2 and lbsp mRNAs. For both genes, osteogenic stimulation increased chromatin-bound P-ERK, P-RUNX2, p300, and RNA polymerase II as well as histone H3K9 and H4K5 acetylation. The level of H3K4 di-methylation, another gene activation-associated histone mark, also increased. In contrast, levels of the gene repressive marks, H3K9 mono-, di-, and tri-methylation in the same regions were reduced. Inhibition of MAP kinase signaling blocked differentiation dependent chromatin modifications and Bglap2 and Ibsp expression. To evaluate the role of RUNX2 phosphorylation in these responses, RUNX2-deficient C3H10T1/2 cells were transduced with adenovirus encoding wild type or phosphorylation site mutant RUNX2 (RUNX2 S301A/S319A). Wild type RUNX2, but not the non-phosphorylated mutant, increased H3K9 and H4K5 acetylation as well as chromatin-associated P ERK, p300, and polymerase II. Thus, RUNX2 phosphorylation is necessary for subsequent epigenetic changes required for osteoblast gene expression. Taken together, this study reveals a molecular mechanism through which osteogenic genes are controlled by a MAPK and P-RUNX2-dependent process involving epigenetic modifications of specific promoter regions. J. Cell. Physiol. 232: 2427-2435, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27514024 TI - Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis. AB - Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, but the genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated the genomic and transcriptomic landscape of adenomas with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and intestinal-type early gastric cancer (EGC). The results were validated in an independent cohort that included EGCs directly adjacent to adenoma (EGC-adenomas) that were in the process of malignant transformation, and de novo EGCs that do not seem to have been derived from adenoma. The expression patterns clearly divided into normal, LGD, and EGC, whereas those of HGD overlapped with LGD or EGC. These results suggest that HGD is the critical stage determining malignant transformation. We found that genes related to focal adhesion and extracellular matrix receptor interaction pathways were upregulated as LGD progressed to EGC, whereas canonical Wnt signalling and peroxisome proliferator-activated receptor (PPAR) signalling pathway genes were downregulated in EGC. Genomic alterations such as somatic mutation, gene fusion and copy number variation increased gradually from LGD to EGC. APC mutations were present in 67% of LGDs, 58% of HGDs, and 18% of EGCs. RNF43 mutations were present only in HGD and EGC, and TP53 mutations were present only in EGC. In a validation cohort, RNF43 mutations were present in 35.2% of EGC-adenomas, but in only 8.6% of de novo EGCs. This is the first study to investigate the genomic and transcriptomic landscape of multistep gastric carcinogenesis. We investigated important alterations and their related pathways in each step as tumours progressed from LGD to HGD and eventually to EGC. We suggest that mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. Given these findings and Wnt dependency in tumours with RNF43 mutation, intestinal-type gastric cancer or adenoma with RNF43 mutation might represent a promising indication for Wnt-targeted agents. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 27514025 TI - Conformational quiescence of ADAMTS-13 prevents proteolytic promiscuity. AB - Essentials Recently, ADAMTS-13 has been shown to undergo substrate induced conformation activation. Conformational quiescence of ADAMTS-13 may serve to prevent off-target proteolysis in plasma. Conformationally active ADAMTS-13 variants are capable of proteolysing the Aalpha chain of fibrinogen. This should be considered as ADAMTS-13 variants are developed as potential therapeutic agents. Click to hear Dr Zheng's presentation on structure function and cofactor dependent regulation of ADAMTS-13 SUMMARY: Background Recent work has revealed that ADAMTS-13 circulates in a 'closed' conformation, only fully interacting with von Willebrand factor (VWF) following a conformational change. We hypothesized that this conformational quiescence also maintains the substrate specificity of ADAMTS-13 and that the 'open' conformation of the protease might facilitate proteolytic promiscuity. Objectives To identify a novel substrate for a constitutively active gain of function (GoF) ADAMTS-13 variant (R568K/F592Y/R660K/Y661F/Y665F). Methods Fibrinogen proteolysis was characterized using SDS PAGE and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Fibrin formation was monitored by turbidity measurements and fibrin structure visualized by confocal microscopy. Results ADAMTS-13 exhibits proteolytic activity against the Aalpha chain of human fibrinogen, but this is only manifest on its conformational activation. Accordingly, the GoF ADAMTS-13 variant and truncated variants such as MDTCS exhibit this activity. The cleavage site has been determined by LC-MS/MS to be Aalpha chain Lys225-Met226. Proteolysis of fibrinogen by GoF ADAMTS-13 impairs fibrin formation in plasma-based assays, alters clot structure and increases clot permeability. Although GoF ADAMTS-13 does not appear to proteolyse preformed cross-linked fibrin, its proteolytic activity against fibrinogen increases the susceptibility of fibrin to tissue-type plasminogen activator (t-PA)-induced lysis by plasmin and increases the fibrin clearance rate more than 8-fold compared with wild-type (WT) ADAMTS-13 (EC50 values of 3.0 +/- 1.7 nm and 25.2 +/- 9.7 nm, respectively) in in vitro thrombosis models. Conclusion The 'closed' conformation of ADAMTS-13 restricts its specificity and protects against fibrinogenolysis. Induced substrate promiscuity will be important as ADAMTS-13 variants are developed as potential therapeutic agents against thrombotic thrombocytopenic purpura (TTP) and other cardiovascular diseases. PMID- 27514028 TI - Improvising in Three Dimensions. AB - Lyle Hatch navigates 3D worlds and sometimes arrives at the surreal, regularly producing an immense catalog of imagery. With Mandelbulb 3D as his creative environment of choice, Hatch generates seemingly endless amounts of evocative and colorful imagery. PMID- 27514029 TI - Topic- and Time-Oriented Visual Text Analysis. AB - To facilitate the process of converting textual data into actionable knowledge, visual text analysis has become a popular topic with active research efforts contributed by researchers worldwide. Here the authors present the benefits of combing text analysis (topic models in particular) with interactive visualization. They then highlight examples from prior work on topic- and time oriented visual text analysis and discuss challenges that warrant additional future research. PMID- 27514026 TI - The composition and organization of Drosophila heterochromatin are heterogeneous and dynamic. AB - Heterochromatin is enriched for specific epigenetic factors including Heterochromatin Protein 1a (HP1a), and is essential for many organismal functions. To elucidate heterochromatin organization and regulation, we purified Drosophila melanogaster HP1a interactors, and performed a genome-wide RNAi screen to identify genes that impact HP1a levels or localization. The majority of the over four hundred putative HP1a interactors and regulators identified were previously unknown. We found that 13 of 16 tested candidates (83%) are required for gene silencing, providing a substantial increase in the number of identified components that impact heterochromatin properties. Surprisingly, image analysis revealed that although some HP1a interactors and regulators are broadly distributed within the heterochromatin domain, most localize to discrete subdomains that display dynamic localization patterns during the cell cycle. We conclude that heterochromatin composition and architecture is more spatially complex and dynamic than previously suggested, and propose that a network of subdomains regulates diverse heterochromatin functions. PMID- 27514027 TI - Epigenetic gene regulation by histone demethylases: emerging role in oncogenesis and inflammation. AB - Histone N-terminal tails of nucleosomes are the sites of complex regulation of gene expression through post-translational modifications. Among these modifications, histone methylation had long been associated with permanent gene inactivation until the discovery of Lys-specific demethylase (LSD1), which is responsible for dynamic gene regulation. There are more than 30 members of the Lys demethylase (KDM) family, and with exception of LSD1 and LSD2, all other KDMs possess the Jumonji C (JmjC) domain exhibiting demethylase activity and require unique cofactors, for example, Fe(II) and alpha-ketoglutarate. These cofactors have been targeted when devising KDM inhibitors, which may yield therapeutic benefit. KDMs and their counterpart Lys methyltransferases (KMTs) regulate multiple biological processes, including oncogenesis and inflammation. KDMs' functional interactions with retinoblastoma (Rb) and E2 factor (E2F) target promoters illustrate their regulatory role in cell cycle progression and oncogenesis. Recent findings also demonstrate the control of inflammation and immune functions by KDMs, such as KDM6B that regulates the pro-inflammatory gene expression and CD4+ T helper (Th) cell lineage determination. This review will highlight the mechanisms by which KDMs and KMTs regulate the target gene expression and how epigenetic mechanisms may be applied to our understanding of oral inflammation. PMID- 27514030 TI - Precision Agriculture: Using Low-Cost Systems to Acquire Low-Altitude Images. AB - Low cost remote sensing imagery has the potential to make precision farming feasible in developing countries. In this article, the authors describe image acquisition from eucalyptus, bean, and sugarcane crops acquired by low-cost and low-altitude systems. They use different approaches to handle low-altitude images in both the RGB and NIR (near-infrared) bands to estimate and quantify plantation areas. PMID- 27514031 TI - Predicting Moves-on-Stills for Comic Art Using Viewer Gaze Data. AB - Comic art consists of a sequence of panels of different shapes and sizes that visually communicate the narrative to the reader. The move-on-stills technique allows such still images to be retargeted for digital displays via camera moves. Today, moves-on-stills can be created by software applications given user provided parameters for each desired camera move. The proposed algorithm uses viewer gaze as input to computationally predict camera move parameters. The authors demonstrate their algorithm on various comic book panels and evaluate its performance by comparing their results with a professional DVD. PMID- 27514032 TI - Designing for Insight: A Case Study from Tennis Player Analysis. AB - Visualization is an important tool, necessary for making sense of vast amounts of data. Many data science projects make use of visualization techniques to illustrate and explain their results. But complex interactive visualizations can also be excellent exploration tools to help guide the analysis, detect early signs of problems and irregularities, suggest new discoveries, and test the effectiveness and efficiency of scientific models. This article describes a combinatory design process that uses a method of incremental addition to create increasingly complex arrangements and thus create new ways to see data and discover new insights. PMID- 27514034 TI - City-Scale Localization for Cameras with Known Vertical Direction. AB - We consider the problem of localizing a novel image in a large 3D model, given that the gravitational vector is known. In principle, this is just an instance of camera pose estimation, but the scale of the problem introduces some interesting challenges. Most importantly, it makes the correspondence problem very difficult so there will often be a significant number of outliers to handle. To tackle this problem, we use recent theoretical as well as technical advances. Many modern cameras and phones have gravitational sensors that allow us to reduce the search space. Further, there are new techniques to efficiently and reliably deal with extreme rates of outliers. We extend these methods to camera pose estimation by using accurate approximations and fast polynomial solvers. Experimental results are given demonstrating that it is possible to reliably estimate the camera pose despite cases with more than 99 percent outlier correspondences in city-scale models with several millions of 3D points. PMID- 27514035 TI - A Novel Nonparametric Maximum Likelihood Estimator for Probability Density Functions. AB - Parametric maximum likelihood (ML) estimators of probability density functions (pdfs) are widely used today because they are efficient to compute and have several nice properties such as consistency, fast convergence rates, and asymptotic normality. However, data is often complex making parametrization of the pdf difficult, and nonparametric estimation is required. Popular nonparametric methods, such as kernel density estimation (KDE), produce consistent estimators but are not ML and have slower convergence rates than parametric ML estimators. Further, these nonparametric methods do not share the other desirable properties of parametric ML estimators. This paper introduces a nonparametric ML estimator that assumes that the square-root of the underlying pdf is band-limited (BL) and hence "smooth". The BLML estimator is computed and shown to be consistent. Although convergence rates are not theoretically derived, the BLML estimator exhibits faster convergence rates than state-of-the-art nonparametric methods in simulations. Further, algorithms to compute the BLML estimator with lesser computational complexity than that of KDE methods are presented. The efficacy of the BLML estimator is shown by applying it to (i) density tail estimation and (ii) density estimation of complex neuronal receptive fields where it outperforms state-of-the-art methods used in neuroscience. PMID- 27514036 TI - Deep Visual-Semantic Alignments for Generating Image Descriptions. AB - We present a model that generates natural language descriptions of images and their regions. Our approach leverages datasets of images and their sentence descriptions to learn about the inter-modal correspondences between language and visual data. Our alignment model is based on a novel combination of Convolutional Neural Networks over image regions, bidirectional Recurrent Neural Networks (RNN) over sentences, and a structured objective that aligns the two modalities through a multimodal embedding. We then describe a Multimodal Recurrent Neural Network architecture that uses the inferred alignments to learn to generate novel descriptions of image regions. We demonstrate that our alignment model produces state of the art results in retrieval experiments on Flickr8K, Flickr30K and MSCOCO datasets. We then show that the generated descriptions outperform retrieval baselines on both full images and on a new dataset of region-level annotations. Finally, we conduct large-scale analysis of our RNN language model on the Visual Genome dataset of 4.1 million captions and highlight the differences between image and region-level caption statistics. PMID- 27514037 TI - Learning to Segment Human by Watching YouTube. AB - An intuition on human segmentation is that when a human is moving in a video, the video-context (e.g., appearance and motion clues) may potentially infer reasonable mask information for the whole human body. Inspired by this, based on popular deep convolutional neural networks (CNN), we explore a very-weakly supervised learning framework for human segmentation task, where only an imperfect human detector is available along with massive weakly-labeled YouTube videos. In our solution, the video-context guided human mask inference and CNN based segmentation network learning iterate to mutually enhance each other until no further improvement gains. In the first step, each video is decomposed into supervoxels by the unsupervised video segmentation. The superpixels within the supervoxels are then classified as human or non-human by graph optimization with unary energies from the imperfect human detection results and the predicted confidence maps by the CNN trained in the previous iteration. In the second step, the video-context derived human masks are used as direct labels to train CNN. Extensive experiments on the challenging PASCAL VOC 2012 semantic segmentation benchmark demonstrate that the proposed framework has already achieved superior results than all previous weakly-supervised methods with object class or bounding box annotations. In addition, by augmenting with the annotated masks from PASCAL VOC 2012, our method reaches a new state-of-the-art performance on the human segmentation task. PMID- 27514038 TI - Randomly Perturbed B-Splines for Nonrigid Image Registration. AB - B-splines are commonly utilized to construct the transformation model in free form deformation (FFD) based registration. B-splines become smoother with increasing spline order. However, a higher-order B-spline requires a larger support region involving more control points, which means higher computational cost. In general, the third-order B-spline is considered as a good compromise between spline smoothness and computational cost. A lower-order function is seldom used to construct the transformation model for registration since it is less smooth. In this research, we investigated whether lower-order B-spline functions can be utilized for more efficient registration, while preserving smoothness of the deformation by using a novel random perturbation technique. With the proposed perturbation technique, the expected value of the cost function given probability density function (PDF) of the perturbation is minimized by a stochastic gradient descent optimization. Extensive experiments on 2D synthetically deformed brain images, and real 3D lung and brain scans demonstrated that the novel randomly perturbed free-form deformation (RPFFD) approach improves the registration accuracy and transformation smoothness. Meanwhile, lower-order RPFFD methods reduce the computational cost substantially. PMID- 27514039 TI - Robust Retinal Vessel Segmentation via Locally Adaptive Derivative Frames in Orientation Scores. AB - This paper presents a robust and fully automatic filter-based approach for retinal vessel segmentation. We propose new filters based on 3D rotating frames in so-called orientation scores, which are functions on the Lie-group domain of positions and orientations [Formula: see text]. By means of a wavelet-type transform, a 2D image is lifted to a 3D orientation score, where elongated structures are disentangled into their corresponding orientation planes. In the lifted domain [Formula: see text], vessels are enhanced by means of multi-scale second-order Gaussian derivatives perpendicular to the line structures. More precisely, we use a left-invariant rotating derivative (LID) frame, and a locally adaptive derivative (LAD) frame. The LAD is adaptive to the local line structures and is found by eigensystem analysis of the left-invariant Hessian matrix (computed with the LID). After multi-scale filtering via the LID or LAD in the orientation score domain, the results are projected back to the 2D image plane giving us the enhanced vessels. Then a binary segmentation is obtained through thresholding. The proposed methods are validated on six retinal image datasets with different image types, on which competitive segmentation performances are achieved. In particular, the proposed algorithm of applying the LAD filter on orientation scores (LAD-OS) outperforms most of the state-of-the-art methods. The LAD-OS is capable of dealing with typically difficult cases like crossings, central arterial reflex, closely parallel and tiny vessels. The high computational speed of the proposed methods allows processing of large datasets in a screening setting. PMID- 27514041 TI - Generating Multi-Destination Maps. AB - Multi-destination maps are a kind of navigation maps aimed to guide visitors to multiple destinations within a region, which can be of great help to urban visitors. However, they have not been developed in the current online map service. To address this issue, we introduce a novel layout model designed especially for generating multi-destination maps, which considers the global and local layout of a multi-destination map. We model the layout problem as a graph drawing that satisfies a set of hard and soft constraints. In the global layout phase, we balance the scale factor between ROIs. In the local layout phase, we make all edges have good visibility and optimize the map layout to preserve the relative length and angle of roads. We also propose a perturbation-based optimization method to find an optimal layout in the complex solution space. The multi-destination maps generated by our system are potential feasible on the modern mobile devices and our result can show an overview and a detail view of the whole map at the same time. In addition, we perform a user study to evaluate the effectiveness of our method, and the results prove that the multi-destination maps achieve our goals well. PMID- 27514042 TI - Shape Synthesis from Sketches via Procedural Models and Convolutional Networks. AB - Procedural modeling techniques can produce high quality visual content through complex rule sets. However, controlling the outputs of these techniques for design purposes is often notoriously difficult for users due to the large number of parameters involved in these rule sets and also their non-linear relationship to the resulting content. To circumvent this problem, we present a sketch-based approach to procedural modeling. Given an approximate and abstract hand-drawn 2D sketch provided by a user, our algorithm automatically computes a set of procedural model parameters, which in turn yield multiple, detailed output shapes that resemble the user's input sketch. The user can then select an output shape, or further modify the sketch to explore alternative ones. At the heart of our approach is a deep Convolutional Neural Network (CNN) that is trained to map sketches to procedural model parameters. The network is trained by large amounts of automatically generated synthetic line drawings. By using an intuitive medium, i.e., freehand sketching as input, users are set free from manually adjusting procedural model parameters, yet they are still able to create high quality content. We demonstrate the accuracy and efficacy of our method in a variety of procedural modeling scenarios including design of man-made and organic shapes. PMID- 27514043 TI - A Visual Analytics Approach for Understanding Reasons behind Snowballing and Comeback in MOBA Games. AB - To design a successful Multiplayer Online Battle Arena (MOBA) game, the ratio of snowballing and comeback occurrences to all matches played must be maintained at a certain level to ensure its fairness and engagement. Although it is easy to identify these two types of occurrences, game developers often find it difficult to determine their causes and triggers with so many game design choices and game parameters involved. In addition, the huge amounts of MOBA game data are often heterogeneous, multi-dimensional and highly dynamic in terms of space and time, which poses special challenges for analysts. In this paper, we present a visual analytics system to help game designers find key events and game parameters resulting in snowballing or comeback occurrences in MOBA game data. We follow a user-centered design process developing the system with game analysts and testing with real data of a trial version MOBA game from NetEase Inc. We apply novel visualization techniques in conjunction with well-established ones to depict the evolution of players' positions, status and the occurrences of events. Our system can reveal players' strategies and performance throughout a single match and suggest patterns, e.g., specific player' actions and game events, that have led to the final occurrences. We further demonstrate a workflow of leveraging human analyzed patterns to improve the scalability and generality of match data analysis. Finally, we validate the usability of our system by proving the identified patterns are representative in snowballing or comeback matches in a one-month-long MOBA tournament dataset. PMID- 27514044 TI - SemanticTraj: A New Approach to Interacting with Massive Taxi Trajectories. AB - Massive taxi trajectory data is exploited for knowledge discovery in transportation and urban planning. Existing tools typically require users to select and brush geospatial regions on a map when retrieving and exploring taxi trajectories and passenger trips. To answer seemingly simple questions such as "What were the taxi trips starting from Main Street and ending at Wall Street in the morning?" or "Where are the taxis arriving at the Art Museum at noon typically coming from?", tedious and time consuming interactions are usually needed since the numeric GPS points of trajectories are not directly linked to the keywords such as "Main Street", "Wall Street", and "Art Museum". In this paper, we present SemanticTraj, a new method for managing and visualizing taxi trajectory data in an intuitive, semantic rich, and efficient means. With SemanticTraj, domain and public users can find answers to the aforementioned questions easily through direct queries based on the terms. They can also interactively explore the retrieved data in visualizations enhanced by semantic information of the trajectories and trips. In particular, taxi trajectories are converted into taxi documents through a textualization transformation process. This process maps GPS points into a series of street/POI names and pick-up/drop off locations. It also converts vehicle speeds into user-defined descriptive terms. Then, a corpus of taxi documents is formed and indexed to enable flexible semantic queries over a text search engine. Semantic labels and meta-summaries of the results are integrated with a set of visualizations in a SemanticTraj prototype, which helps users study taxi trajectories quickly and easily. A set of usage scenarios are presented to show the usability of the system. We also collected feedback from domain experts and conducted a preliminary user study to evaluate the visual system. PMID- 27514045 TI - Correlated Photon Mapping for Interactive Global Illumination of Time-Varying Volumetric Data. AB - We present a method for interactive global illumination of both static and time varying volumetric data based on reduction of the overhead associated with re computation of photon maps. Our method uses the identification of photon traces invariant to changes of visual parameters such as the transfer function (TF), or data changes between time-steps in a 4D volume. This lets us operate on a variant subset of the entire photon distribution. The amount of computation required in the two stages of the photon mapping process, namely tracing and gathering, can thus be reduced to the subset that are affected by a data or visual parameter change. We rely on two different types of information from the original data to identify the regions that have changed. A low resolution uniform grid containing the minimum and maximum data values of the original data is derived for each time step. Similarly, for two consecutive time-steps, a low resolution grid containing the difference between the overlapping data is used. We show that this compact metadata can be combined with the transfer function to identify the regions that have changed. Each photon traverses the low-resolution grid to identify if it can be directly transferred to the next photon distribution state or if it needs to be recomputed. An efficient representation of the photon distribution is presented leading to an order of magnitude improved performance of the raycasting step. The utility of the method is demonstrated in several examples that show visual fidelity, as well as performance. The examples show that visual quality can be retained when the fraction of retraced photons is as low as 40%-50%. PMID- 27514046 TI - SmartAdP: Visual Analytics of Large-scale Taxi Trajectories for Selecting Billboard Locations. AB - The problem of formulating solutions immediately and comparing them rapidly for billboard placements has plagued advertising planners for a long time, owing to the lack of efficient tools for in-depth analyses to make informed decisions. In this study, we attempt to employ visual analytics that combines the state-of-the art mining and visualization techniques to tackle this problem using large-scale GPS trajectory data. In particular, we present SmartAdP, an interactive visual analytics system that deals with the two major challenges including finding good solutions in a huge solution space and comparing the solutions in a visual and intuitive manner. An interactive framework that integrates a novel visualization driven data mining model enables advertising planners to effectively and efficiently formulate good candidate solutions. In addition, we propose a set of coupled visualizations: a solution view with metaphor-based glyphs to visualize the correlation between different solutions; a location view to display billboard locations in a compact manner; and a ranking view to present multi-typed rankings of the solutions. This system has been demonstrated using case studies with a real-world dataset and domain-expert interviews. Our approach can be adapted for other location selection problems such as selecting locations of retail stores or restaurants using trajectory data. PMID- 27514047 TI - Visual Analysis of MOOC Forums with iForum. AB - Discussion forums of Massive Open Online Courses (MOOC) provide great opportunities for students to interact with instructional staff as well as other students. Exploration of MOOC forum data can offer valuable insights for these staff to enhance the course and prepare the next release. However, it is challenging due to the large, complicated, and heterogeneous nature of relevant datasets, which contain multiple dynamically interacting objects such as users, posts, and threads, each one including multiple attributes. In this paper, we present a design study for developing an interactive visual analytics system, called iForum, that allows for effectively discovering and understanding temporal patterns in MOOC forums. The design study was conducted with three domain experts in an iterative manner over one year, including a MOOC instructor and two official teaching assistants. iForum offers a set of novel visualization designs for presenting the three interleaving aspects of MOOC forums (i.e., posts, users, and threads) at three different scales. To demonstrate the effectiveness and usefulness of iForum, we describe a case study involving field experts, in which they use iForum to investigate real MOOC forum data for a course on JAVA programming. PMID- 27514048 TI - AxiSketcher: Interactive Nonlinear Axis Mapping of Visualizations through User Drawings. AB - Visual analytics techniques help users explore high-dimensional data. However, it is often challenging for users to express their domain knowledge in order to steer the underlying data model, especially when they have little attribute-level knowledge. Furthermore, users' complex, high-level domain knowledge, compared to low-level attributes, posits even greater challenges. To overcome these challenges, we introduce a technique to interpret a user's drawings with an interactive, nonlinear axis mapping approach called AxiSketcher. This technique enables users to impose their domain knowledge on a visualization by allowing interaction with data entries rather than with data attributes. The proposed interaction is performed through directly sketching lines over the visualization. Using this technique, users can draw lines over selected data points, and the system forms the axes that represent a nonlinear, weighted combination of multidimensional attributes. In this paper, we describe our techniques in three areas: 1) the design space of sketching methods for eliciting users' nonlinear domain knowledge; 2) the underlying model that translates users' input, extracts patterns behind the selected data points, and results in nonlinear axes reflecting users' complex intent; and 3) the interactive visualization for viewing, assessing, and reconstructing the newly formed, nonlinear axes. PMID- 27514049 TI - Toward Theoretical Techniques for Measuring the Use of Human Effort in Visual Analytic Systems. AB - Visual analytic systems have long relied on user studies and standard datasets to demonstrate advances to the state of the art, as well as to illustrate the efficiency of solutions to domain-specific challenges. This approach has enabled some important comparisons between systems, but unfortunately the narrow scope required to facilitate these comparisons has prevented many of these lessons from being generalized to new areas. At the same time, advanced visual analytic systems have made increasing use of human-machine collaboration to solve problems not tractable by machine computation alone. To continue to make progress in modeling user tasks in these hybrid visual analytic systems, we must strive to gain insight into what makes certain tasks more complex than others. This will require the development of mechanisms for describing the balance to be struck between machine and human strengths with respect to analytical tasks and workload. In this paper, we argue for the necessity of theoretical tools for reasoning about such balance in visual analytic systems and demonstrate the utility of the Human Oracle Model for this purpose in the context of sensemaking in visual analytics. Additionally, we make use of the Human Oracle Model to guide the development of a new system through a case study in the domain of cybersecurity. PMID- 27514050 TI - AnaFe: Visual Analytics of Image-derived Temporal Features-Focusing on the Spleen. AB - We present a novel visualization framework, AnaFe, targeted at observing changes in the spleen over time through multiple image-derived features. Accurate monitoring of progressive changes is crucial for diseases that result in enlargement of the organ. Our system is comprised of multiple linked views combining visualization of temporal 3D organ data, related measurements, and features. Thus it enables the observation of progression and allows for simultaneous comparison within and between the subjects. AnaFe offers insights into the overall distribution of robustly extracted and reproducible quantitative imaging features and their changes within the population, and also enables detailed analysis of individual cases. It performs similarity comparison of temporal series of one subject to all other series in both sick and healthy groups. We demonstrate our system through two use case scenarios on a population of 189 spleen datasets from 68 subjects with various conditions observed over time. PMID- 27514051 TI - NameClarifier: A Visual Analytics System for Author Name Disambiguation. AB - In this paper, we present a novel visual analytics system called NameClarifier to interactively disambiguate author names in publications by keeping humans in the loop. Specifically, NameClarifier quantifies and visualizes the similarities between ambiguous names and those that have been confirmed in digital libraries. The similarities are calculated using three key factors, namely, co-authorships, publication venues, and temporal information. Our system estimates all possible allocations, and then provides visual cues to users to help them validate every ambiguous case. By looping users in the disambiguation process, our system can achieve more reliable results than general data mining models for highly ambiguous cases. In addition, once an ambiguous case is resolved, the result is instantly added back to our system and serves as additional cues for all the remaining unidentified names. In this way, we open up the black box in traditional disambiguation processes, and help intuitively and comprehensively explain why the corresponding classifications should hold. We conducted two use cases and an expert review to demonstrate the effectiveness of NameClarifier. PMID- 27514052 TI - Visualizing Dimension Coverage to Support Exploratory Analysis. AB - Data analysis involves constantly formulating and testing new hypotheses and questions about data. When dealing with a new dataset, especially one with many dimensions, it can be cumbersome for the analyst to clearly remember which aspects of the data have been investigated (i.e., visually examined for patterns, trends, outliers etc.) and which combinations have not. Yet this information is critical to help the analyst formulate new questions that they have not already answered. We observe that for tabular data, questions are typically comprised of varying combinations of data dimensions (e.g., what are the trends of Sales and Profit for different Regions?). We propose representing analysis history from the angle of dimension coverage (i.e., which data dimensions have been investigated and in which combinations). We use scented widgets [30] to incorporate dimension coverage of the analysts' past work into interaction widgets of a visualization tool. We demonstrate how this approach can assist analysts with the question formation process. Our approach extends the concept of scented widgets to reveal aspects of one's own analysis history, and offers a different perspective on one's past work than typical visualization history tools. Results of our empirical study showed that participants with access to embedded dimension coverage information relied on this information when formulating questions, asked more questions about the data, generated more top-level findings, and showed greater breadth of their analysis without sacrificing depth. PMID- 27514053 TI - Magnostics: Image-Based Search of Interesting Matrix Views for Guided Network Exploration. AB - In this work we address the problem of retrieving potentially interesting matrix views to support the exploration of networks. We introduce Matrix Diagnostics (or Magnostics), following in spirit related approaches for rating and ranking other visualization techniques, such as Scagnostics for scatter plots. Our approach ranks matrix views according to the appearance of specific visual patterns, such as blocks and lines, indicating the existence of topological motifs in the data, such as clusters, bi-graphs, or central nodes. Magnostics can be used to analyze, query, or search for visually similar matrices in large collections, or to assess the quality of matrix reordering algorithms. While many feature descriptors for image analyzes exist, there is no evidence how they perform for detecting patterns in matrices. In order to make an informed choice of feature descriptors for matrix diagnostics, we evaluate 30 feature descriptors-27 existing ones and three new descriptors that we designed specifically for MAGNOSTICS-with respect to four criteria: pattern response, pattern variability, pattern sensibility, and pattern discrimination. We conclude with an informed set of six descriptors as most appropriate for Magnostics and demonstrate their application in two scenarios; exploring a large collection of matrices and analyzing temporal networks. PMID- 27514054 TI - Characterizing Guidance in Visual Analytics. AB - Visual analytics (VA) is typically applied in scenarios where complex data has to be analyzed. Unfortunately, there is a natural correlation between the complexity of the data and the complexity of the tools to study them. An adverse effect of complicated tools is that analytical goals are more difficult to reach. Therefore, it makes sense to consider methods that guide or assist users in the visual analysis process. Several such methods already exist in the literature, yet we are lacking a general model that facilitates in-depth reasoning about guidance. We establish such a model by extending van Wijk's model of visualization with the fundamental components of guidance. Guidance is defined as a process that gradually narrows the gap that hinders effective continuation of the data analysis. We describe diverse inputs based on which guidance can be generated and discuss different degrees of guidance and means to incorporate guidance into VA tools. We use existing guidance approaches from the literature to illustrate the various aspects of our model. As a conclusion, we identify research challenges and suggest directions for future studies. With our work we take a necessary step to pave the way to a systematic development of guidance techniques that effectively support users in the context of VA. PMID- 27514055 TI - PhenoStacks: Cross-Sectional Cohort Phenotype Comparison Visualizations. AB - Cross-sectional phenotype studies are used by genetics researchers to better understand how phenotypes vary across patients with genetic diseases, both within and between cohorts. Analyses within cohorts identify patterns between phenotypes and patients (e.g., co-occurrence) and isolate special cases (e.g., potential outliers). Comparing the variation of phenotypes between two cohorts can help distinguish how different factors affect disease manifestation (e.g., causal genes, age of onset, etc.). PhenoStacks is a novel visual analytics tool that supports the exploration of phenotype variation within and between cross sectional patient cohorts. By leveraging the semantic hierarchy of the Human Phenotype Ontology, phenotypes are presented in context, can be grouped and clustered, and are summarized via overviews to support the exploration of phenotype distributions. The design of PhenoStacks was motivated by formative interviews with genetics researchers: we distil high-level tasks, present an algorithm for simplifying ontology topologies for visualization, and report the results of a deployment evaluation with four expert genetics researchers. The results suggest that PhenoStacks can help identify phenotype patterns, investigate data quality issues, and inform data collection design. PMID- 27514056 TI - Designing Progressive and Interactive Analytics Processes for High-Dimensional Data Analysis. AB - In interactive data analysis processes, the dialogue between the human and the computer is the enabling mechanism that can lead to actionable observations about the phenomena being investigated. It is of paramount importance that this dialogue is not interrupted by slow computational mechanisms that do not consider any known temporal human-computer interaction characteristics that prioritize the perceptual and cognitive capabilities of the users. In cases where the analysis involves an integrated computational method, for instance to reduce the dimensionality of the data or to perform clustering, such non-optimal processes are often likely. To remedy this, progressive computations, where results are iteratively improved, are getting increasing interest in visual analytics. In this paper, we present techniques and design considerations to incorporate progressive methods within interactive analysis processes that involve high dimensional data. We define methodologies to facilitate processes that adhere to the perceptual characteristics of users and describe how online algorithms can be incorporated within these. A set of design recommendations and according methods to support analysts in accomplishing high-dimensional data analysis tasks are then presented. Our arguments and decisions here are informed by observations gathered over a series of analysis sessions with analysts from finance. We document observations and recommendations from this study and present evidence on how our approach contribute to the efficiency and productivity of interactive visual analysis sessions involving high-dimensional data. PMID- 27514057 TI - A Grammar-based Approach for Modeling User Interactions and Generating Suggestions During the Data Exploration Process. AB - Despite the recent popularity of visual analytics focusing on big data, little is known about how to support users that use visualization techniques to explore multi-dimensional datasets and accomplish specific tasks. Our lack of models that can assist end-users during the data exploration process has made it challenging to learn from the user's interactive and analytical process. The ability to model how a user interacts with a specific visualization technique and what difficulties they face are paramount in supporting individuals with discovering new patterns within their complex datasets. This paper introduces the notion of visualization systems understanding and modeling user interactions with the intent of guiding a user through a task thereby enhancing visual data exploration. The challenges faced and the necessary future steps to take are discussed; and to provide a working example, a grammar-based model is presented that can learn from user interactions, determine the common patterns among a number of subjects using a K-Reversible algorithm, build a set of rules, and apply those rules in the form of suggestions to new users with the goal of guiding them along their visual analytic process. A formal evaluation study with 300 subjects was performed showing that our grammar-based model is effective at capturing the interactive process followed by users and that further research in this area has the potential to positively impact how users interact with a visualization system. PMID- 27514059 TI - A Visual Analytics Approach for Categorical Joint Distribution Reconstruction from Marginal Projections. AB - Oftentimes multivariate data are not available as sets of equally multivariate tuples, but only as sets of projections into subspaces spanned by subsets of these attributes. For example, one may find data with five attributes stored in six tables of two attributes each, instead of a single table of five attributes. This prohibits the visualization of these data with standard high-dimensional methods, such as parallel coordinates or MDS, and there is hence the need to reconstruct the full multivariate (joint) distribution from these marginal ones. Most of the existing methods designed for this purpose use an iterative procedure to estimate the joint distribution. With insufficient marginal distributions and domain knowledge, they lead to results whose joint errors can be large. Moreover, enforcing smoothness for regularizations in the joint space is not applicable if the attributes are not numerical but categorical. We propose a visual analytics approach that integrates both anecdotal data and human experts to iteratively narrow down a large set of plausible solutions. The solution space is populated using a Monte Carlo procedure which uniformly samples the solution space. A level of-detail high dimensional visualization system helps the user understand the patterns and the uncertainties. Constraints that narrow the solution space can then be added by the user interactively during the iterative exploration, and eventually a subset of solutions with narrow uncertainty intervals emerges. PMID- 27514058 TI - Blockwise Human Brain Network Visual Comparison Using NodeTrix Representation. AB - Visually comparing human brain networks from multiple population groups serves as an important task in the field of brain connectomics. The commonly used brain network representation, consisting of nodes and edges, may not be able to reveal the most compelling network differences when the reconstructed networks are dense and homogeneous. In this paper, we leveraged the block information on the Region Of Interest (ROI) based brain networks and studied the problem of blockwise brain network visual comparison. An integrated visual analytics framework was proposed. In the first stage, a two-level ROI block hierarchy was detected by optimizing the anatomical structure and the predictive comparison performance simultaneously. In the second stage, the NodeTrix representation was adopted and customized to visualize the brain network with block information. We conducted controlled user experiments and case studies to evaluate our proposed solution. Results indicated that our visual analytics method outperformed the commonly used node-link graph and adjacency matrix design in the blockwise network comparison tasks. We have shown compelling findings from two real-world brain network data sets, which are consistent with the prior connectomics studies. PMID- 27514060 TI - Commanding a Brain-Controlled Wheelchair Using Steady-State Somatosensory Evoked Potentials. AB - In this work, we propose a novel brain-controlled wheelchair, one of the major applications of brain-machine interfaces (BMIs), that allows an individual with mobility impairments to perform daily living activities independently. Specifically, we propose to use a steady-state somatosensory evoked potential (SSSEP) paradigm, which elicits brain responses to tactile stimulation of specific frequencies, for a user's intention to control a wheelchair. In our system, a user had three possible commands by concentrating on one of three vibration stimuli, which were attached to the left-hand, right-hand, and right foot, to selectively control the wheelchair. The three stimuli were associated with three wheelchair commands: turn-left, turn-right, and move-forward. From a machine learning perspective, we also devise a novel feature representation by combining spatial and spectral characteristics of brain signals. In order to validate the effectiveness of the proposed SSSEP-based system, we considered two different tasks: 1) a simple obstacle-avoidance task within a limited time and; 2) a driving task along the predefined trajectory of about 40 m length, where there were a narrow pathway, a door, and obstacles. In both experiments, we recruited 12 subjects and compared the average time of motor imagery (MI) and SSSEP-based controls to complete the task. With the SSSEP-based control, all subjects successfully completed the task without making any collision while four subjects failed it with MI-based control. It is also noteworthy that in terms of the average time to complete the task, the SSSEP-based control outperformed the MI-based control. In the other more challenging task, all subjects successfully reached the target location. PMID- 27514062 TI - Linear Channel Modeling and Error Analysis for Intra/Inter-Cellular Ca2+ Molecular Communication. AB - The use of intra/inter-cellular calcium ion (Ca2+) signaling for molecular communication (MC) is investigated in this paper. In particular, the elevation of the intracellular Ca2+ concentration upon the external excitation, i.e., Ca2+ wave generation, and the intercellular propagation of Ca2+ wave over consecutive cells are studied for information transmission. The main objective of this paper is to develop a linear channel model for intra/inter-cellular Ca2+ MC. In this context, the end-to-end Ca2+ MC system is studied under three blocks: the wave generation, the gap junctional (intercellular) propagation, and the intracellular propagation. The wave generation block captures the intracellular Ca2+ signaling pathway including the release of Ca2+ from the organelles and the buffers inside a cell, and the intake from the extracellular space. The gap junctional (intercellular) propagation block captures the Ca2+ transition through the gap junctions between the touching cells. The intracellular propagation block defines the effect of the cytoplasmic diffusion. Using the developed blocks for the different biophysical phenomena, the end-to-end channel gain and delay formulas are derived. Furthermore, the bit error probability is studied to reveal the impact of the detection threshold. This work provides the basis for the modeling, analysis and the design of Ca2+ MC systems. PMID- 27514063 TI - ML-Space: Hybrid Spatial Gillespie and Particle Simulation of Multi-Level Rule Based Models in Cell Biology. AB - Spatio-temporal dynamics of cellular processes can be simulated at different levels of detail, from (deterministic) partial differential equations via the spatial Stochastic Simulation algorithm to tracking Brownian trajectories of individual particles. We present a spatial simulation approach for multi-level rule-based models, which includes dynamically hierarchically nested cellular compartments and entities. Our approach ML-Space combines discrete compartmental dynamics, stochastic spatial approaches in discrete space, and particles moving in continuous space. The rule-based specification language of ML-Space supports concise and compact descriptions of models and to adapt the spatial resolution of models easily. PMID- 27514065 TI - A 30 $?mu?text{W}$ Remotely Powered Local Temperature Monitoring Implantable System. AB - An implantable local temperature monitoring system for a laboratory mouse is presented. Magnetic coupling is used to remotely power the passive implant. The temperatures of two local points are monitored by thermistors. A low-power readout circuit is implemented by directly amplifying and resolving the sensor response in the time domain. A free-running oscillator operating at 868 MHz transmits the sensor data to the base station. The average power dissipation of the implant is decreased by time interleaving between the sensor readout and the data communication. The power transfer to the implant is also time interleaved with other operations to avoid interference with data communication. A voltage regulation loop for the implant based on controlling the duration of powering the base station power amplifier is also described. A prototype chip is implemented in 0.18 [Formula: see text] CMOS. The implant requires average RF power of 29.5 [Formula: see text] for operation and is capable of measuring two thermistors with accuracy of +/-0.05 degrees C. PMID- 27514066 TI - Tactile Apparent Motion on the Torso Modulates Perceived Forward Self-Motion Velocity. AB - The present study investigated whether a tactile flow created by a matrix of vibrators in a seat pan simultaneously presented with an optical flow in peripheral vision enhances the perceived forward velocity of self-motion. A brief tactile motion stimulus consisted of four successive rows of vibration, and the interstimulus onset between the tactile rows was varied to change the velocity of the tactile motion. The results show that the forward velocity of self-motion is significantly overestimated for rapid tactile flows and underestimated for slow ones, compared with optical flow alone or non-motion vibrotactile stimulation conditions. In addition, the effect with a temporal tactile rhythm without changing the stimulus location was smaller than that with spatiotemporal tactile motion, with the interstimulus onset interval to elicit a clear sensation of tactile apparent motion. These findings suggest that spatiotemporal tactile motion is effective in inducing a change in the perceived forward velocity of self-motion. PMID- 27514067 TI - Randomized Prediction Games for Adversarial Machine Learning. AB - In spam and malware detection, attackers exploit randomization to obfuscate malicious data and increase their chances of evading detection at test time, e.g., malware code is typically obfuscated using random strings or byte sequences to hide known exploits. Interestingly, randomization has also been proposed to improve security of learning algorithms against evasion attacks, as it results in hiding information about the classifier to the attacker. Recent work has proposed game-theoretical formulations to learn secure classifiers, by simulating different evasion attacks and modifying the classification function accordingly. However, both the classification function and the simulated data manipulations have been modeled in a deterministic manner, without accounting for any form of randomization. In this paper, we overcome this limitation by proposing a randomized prediction game, namely, a noncooperative game-theoretic formulation in which the classifier and the attacker make randomized strategy selections according to some probability distribution defined over the respective strategy set. We show that our approach allows one to improve the tradeoff between attack detection and false alarms with respect to the state-of-the-art secure classifiers, even against attacks that are different from those hypothesized during design, on application examples including handwritten digit recognition, spam, and malware detection.In spam and malware detection, attackers exploit randomization to obfuscate malicious data and increase their chances of evading detection at test time, e.g., malware code is typically obfuscated using random strings or byte sequences to hide known exploits. Interestingly, randomization has also been proposed to improve security of learning algorithms against evasion attacks, as it results in hiding information about the classifier to the attacker. Recent work has proposed game-theoretical formulations to learn secure classifiers, by simulating different evasion attacks and modifying the classification function accordingly. However, both the classification function and the simulated data manipulations have been modeled in a deterministic manner, without accounting for any form of randomization. In this paper, we overcome this limitation by proposing a randomized prediction game, namely, a noncooperative game-theoretic formulation in which the classifier and the attacker make randomized strategy selections according to some probability distribution defined over the respective strategy set. We show that our approach allows one to improve the tradeoff between attack detection and false alarms with respect to the state of-the-art secure classifiers, even against attacks that are different from those hypothesized during design, on application examples including handwritten digit recognition, spam, and malware detection. PMID- 27514068 TI - Multiparametric Non-Negative Matrix Factorization for Longitudinal Variations Detection in White-Matter Fiber Bundles. AB - Processing of longitudinal diffusion tensor imaging (DTI) data is a crucial challenge to better understand pathological mechanisms of complex brain diseases such as multiple sclerosis (MS) where white-matter (WM) fiber bundles are variably altered by inflammatory events. In this study, we propose a new fully automated method to detect longitudinal changes in diffusivity metrics along WM fiber bundles. The proposed method is divided in three main parts: 1) preprocessing of longitudinal diffusion acquisitions, 2) WM fiber-bundle extraction, and 3) application of nonnegative matrix factorization and density based local outliers algorithms to detect and delineate longitudinal variations appearing in the cross section of the WM fiber bundle. In order to validate our method, we introduce a new model to simulate real longitudinal changes based on a generalized Gaussian probability density function. Moreover, we applied our method on longitudinal data. High level of performances were obtained for the detection of small longitudinal changes along the WM fiber bundles in MS patients. PMID- 27514069 TI - A Scalable Approach to Capacitated Arc Routing Problems Based on Hierarchical Decomposition. AB - The capacitated arc routing problem (CARP) is a challenging optimization problem with lots of applications in the real world. Numerous approaches have been proposed to tackle this problem. Most of these methods, albeit showing good performance on CARP instances of small and median sizes, do not scale well to large-scale CARPs, e.g., taking at least a few hours to achieve a satisfactory solution on a CARP instance with thousands of tasks. In this paper, an efficient and scalable approach is proposed for CARPs. The key idea of the proposed approach is to hierarchically decompose the tasks involved in a CARP instance into subgroups and solve the induced subproblems recursively. The output of the subproblems at the lower layer in the hierarchy is treated as virtual tasks and new subproblems are formulated based on these virtual tasks using clustering techniques. By this means, the number of tasks (or virtual tasks) decreases rapidly from the bottom to the top layers of the hierarchy, and the sizes of all subproblems at each layer can be kept tractable even for very large-scale CARPs. Empirical studies are conducted on CARP instances with up to 3584 tasks, which are an order of magnitude larger than the number of tasks involved in all CARP instances investigated in the literature. The results show that the proposed approach significantly outperforms existing methods in terms of scalability. Since the proposed hierarchical decomposition scheme is designed to obtain a good permutation of tasks in a CARP instance, it may also be generalized to other hard optimization problems that can be formulated as permutation-based optimization problems. PMID- 27514071 TI - Cooperative Exploration and Networking While Preserving Collision Avoidance. AB - Monitoring of large complex environments, such as underwater environments, is an important task in surveillance. An information (sensor) network can be built to achieve the task. To build an information network in an unknown workspace, we use multiple robots deploying information nodes. While robots build the network, they localize themselves as well as deployed nodes in the global coordinate system. Our multirobot networking strategy is as follows: each robot iteratively visits a frontier, which borders an unsensed area, until all areas are explored. As multiple robots explore the workspace, a robot must avoid colliding with another robot as well as with an obstacle. Hence, we introduce collision avoidance control laws and integrate the control laws with our cooperative networking strategy. Using MATLAB simulations, we verify the scalability and effectiveness of both our networking strategy and the collision avoidance control laws. PMID- 27514072 TI - Influence of sizes of abutments and fixation screws on dental implant system: a non-linear finite element analysis. AB - The purpose of this study is to discuss the influence of sizes of abutments and fixation screws on immediately loaded dental implants in mandibular bones using nonlinear finite element methods. Abutments with three unilateral wall thicknesses and fixation screws with three diameters are analyzed to compare the stresses and deformations under a vertical or oblique force of 130 N. The nonlinearity due to friction contacts between the fixation screw, the abutment, the implant, and the bone is taken into account. The results showed that improper sizes of abutments and fixation screws would increase the stress and deformation of the dental implant system. If possible, the diameter of fixation screw should not be smaller than Phi1.0 mm, the diameter between Phi1.0 mm and Phi1.2 mm is acceptable. The fixation screw diameter preferably exceeds Phi1.4 mm. The unilateral wall thickness >0.5 mm is optimal selection for abutments. PMID- 27514073 TI - Holoentropy enabled-decision tree for automatic classification of diabetic retinopathy using retinal fundus images. AB - Diabetic retinopathy (DR) is the most common diabetic eye disease. Doctors are using various test methods to detect DR. But, the availability of test methods and requirements of domain experts pose a new challenge in the automatic detection of DR. In order to fulfill this objective, a variety of algorithms has been developed in the literature. In this paper, we propose a system consisting of a novel sparking process and a holoentropy-based decision tree for automatic classification of DR images to further improve the effectiveness. The sparking process algorithm is developed for automatic segmentation of blood vessels through the estimation of optimal threshold. The holoentropy enabled decision tree is newly developed for automatic classification of retinal images into normal or abnormal using hybrid features which preserve the disease-level patterns even more than the signal level of the feature. The effectiveness of the proposed system is analyzed using standard fundus image databases DIARETDB0 and DIARETDB1 for sensitivity, specificity and accuracy. The proposed system yields sensitivity, specificity and accuracy values of 96.72%, 97.01% and 96.45%, respectively. The experimental result reveals that the proposed technique outperforms the existing algorithms. PMID- 27514074 TI - Congenital diaphragmatic hernia: endotracheal fluid phospholipidic profile following tracheal occlusion in an experimental model. AB - OBJECTIVE: To compare endotracheal fluid (EF) and amniotic fluid (AF) phospholipidic profile changes following tracheal occlusion (TO) in the congenital diaphragmatic hernia (CDH) fetal lamb model, in order to support the efficacy of TO on lung maturity. METHODS: A diaphragmatic defect was induced at 70 days' gestation, TO was carried out at day 102 and cesarean section at 136 days' gestation. EF and AF samples, collected at delivery, were evaluated using mass spectrometry (the analysis focused on palmitoyloleoyl-phosphatidylcholine [POPC, PC(18:1/16:0)], dipalmitoyl-phosphatidylcholine [DPPC, PC(16:0/16:0)] and sphingomyelins [SMs]). RESULTS: The effects of CDH and TO were different on AF and EF. POPC levels were higher than DPPC levels in AF of healthy lambs. Following induction of the diaphragmatic malformation, an evident decrease in POPC was noted, while a substantial return to normal POPC levels and an increased DPPC peak were prompted by the TO. After CDH induction, a decrease in N-palmitoyl D-sphingomyelin [SM(d18:1/16:0)] was revealed (P<0.01) and an increased peak in SMs in AF was prompted by the TO (P=0.05). While the most represented phosphatidylcholine (PC) species in EF of healthy lambs was DPPC, CDH induced a decrease in the DPPC peak and treatment with TO induced its partial recovery. SMs were detectable only in healthy EF samples. CONCLUSION: The phospholipid recovery profile following TO suggests the potential role of this therapy in restoring processes involved in surfactant-mediated lung maturation, even though other interactions involved in AF turnover should be considered. Moreover, these metabolites could be used as biomarkers of fetal pulmonary development. PMID- 27514075 TI - Biomarkers of spontaneous preterm birth: a systematic review of studies using multiplex analysis. AB - OBJECTIVE: Despite decades of research on risk indicators of spontaneous preterm birth (PTB), reliable biomarkers are still not available to screen or diagnose high-risk pregnancies. Several biomarkers in maternal and fetal compartments have been mechanistically linked to PTB, but none of them are reliable predictors of pregnancy outcome. This systematic review was conducted to synthesize the knowledge on PTB biomarkers identified using multiplex analysis. MATERIALS AND METHODS: Three electronic databases (PubMed, EMBASE and Web of Science) were searched for studies in any language reporting the use of multiplex assays for maternal biomarkers associated with PTB published from January 2005 to March 2014. RESULTS: Retrieved citations (3631) were screened, and relevant studies (33) were selected for full-text reading. Ten studies were included in the review. Forty-two PTB-related proteins were reported, and RANTES and IL-10 (three studies) followed by MIP-1beta, GM-CSF, Eotaxin, and TNF-RI (two studies) were reported more than once in maternal serum. However, results could not be combined due to heterogeneity in type of sample, study population, assay, and analysis methods. CONCLUSION: By this systematic review, we conclude that multiplex assays are a potential technological advancement for identifying biomarkers of PTB, although no single or combination of biomarkers could be identified to predict PTB risk. PMID- 27514076 TI - Glutathione and glutathione derivatives in immunotherapy. AB - Reduced glutathione (GSH) is the most prevalent non-protein thiol in animal cells. Its de novo and salvage synthesis serves to maintain a reduced cellular environment, which is important for several cellular functions. Altered intracellular GSH levels are observed in a wide range of pathologies, including several viral infections, as well as in aging, all of which are also characterized by an unbalanced Th1/Th2 immune response. A central role in influencing the immune response has been ascribed to GSH. Specifically, GSH depletion in antigen-presenting cells (APCs) correlates with altered antigen processing and reduced secretion of Th1 cytokines. Conversely, an increase in intracellular GSH content stimulates IL-12 and/or IL-27, which in turn induces differentiation of naive CD4+ T cells to Th1 cells. In addition, GSH has been shown to inhibit the replication/survival of several pathogens, i.e. viruses and bacteria. Hence, molecules able to increase GSH levels have been proposed as new tools to more effectively hinder different pathogens by acting as both immunomodulators and antimicrobials. Herein, the new role of GSH and its derivatives as immunotherapeutics will be discussed. PMID- 27514078 TI - Phenylboronic acid-decorated gelatin nanoparticles for enhanced tumor targeting and penetration. AB - Phenylboronic acid-decorated nanoparticles (NPs) were prepared for tumor-targeted drug delivery. 3-carboxyphenylboronic acid (3-CPBA) was modified on the surface of conventional gelatin NPs (designated as NP1) to give tumor-targeting NPs (designated as NP2). The morphology and stability of NP1 and NP2 were then investigated using transmission electron microscopy, scanning electron microscopy, and dynamic light scattering. The results show that both NP1 and NP2 are spherical-like and kinetically stable under various conditions. Doxorubicin hydrochloride (DOX) was used as a model anticancer drug and was loaded into NP1 (NP1-DOX) and NP2 (NP2-DOX). The i n vitro cellular uptake and cytotoxicity of NP1-DOX and NP2-DOX were measured using SH-SY5Y cells, H22 cells, and HepG2 cells. Tumor penetration, accumulation, and antitumor activity were investigated using SH-SY5Y tumor-like spheroids and H22 tumor-bearing mice. All results demonstrated that the conjugation of 3-CPBA can efficiently enhance non-targeted NPs' tumor-homing activity, thus improving their tumor accumulation and antitumor effect. PMID- 27514079 TI - Rapid laser sintering of metal nano-particles inks. AB - Fast sintering is of importance in additive metallization processes and especially on sensitive substrates. This work explores the mechanisms which set limits to the laser sintering rate of metal nano-particle inks. A comparison of sintering behavior of three different ink compositions with laser exposure times from micro-seconds to seconds reveals the dominant factor to be the organic content (OC) in the ink. With a low OC silver ink, of 2% only, sintering time falls below 100 MUs with resistivity <*4 bulk silver. Still shorter exposure times result in line delamination and deformation with a similar outcome when the OC is increased. PMID- 27514080 TI - Mesoporous InN/In2O3 heterojunction with improved sensitivity and selectivity for room temperature NO2 gas sensing. AB - Establishing heterostructures is a good strategy to improve gas sensing performance, and has been studied extensively. In this work, mesoporous InN/In2O3 composite (InNOCs) heterostructures were prepared through a simple two-step strategy involving hydrothermal synthesis of In2O3 and subsequent nitriding into InN-composite In2O3 heterostructures. We found that the InN content has great influence on the resistance of InNOCs, and thus, the gas sensing performance. In particular, InNOC-36.9 (with InN content of 36.9% in the composites) shows an excellent sensing response towards different concentrations of NO2, as well as good stability after one week of exposure to 200 ppb NO2 at room temperature. The highest sensing response (DeltaR/R0 ) is up to 1.8 for the low NO2 concentration of 5 ppb. Even more significantly, the theoretical limit of detection (LOD) of the InNOC-36.9 sensor is 31.7 ppt based on a signal-to-noise ratio of 3 (the measured LOD is 5 ppb), which is far below the US NAAQS value (NO2: 53 ppb). In addition, a rational band structure model combined with a surface reaction model is proposed to explain the sensing mechanism. PMID- 27514077 TI - Scavengers of reactive gamma-ketoaldehydes extend Caenorhabditis elegans lifespan and healthspan through protein-level interactions with SIR-2.1 and ETS-7. AB - Isoketals (IsoKs) are highly reactive gamma-ketoaldehyde products of lipid peroxidation that covalently adduct lysine side chains in proteins, impairing their function. Using C. elegans as a model organism, we sought to test the hypothesis that IsoKs contribute to molecular aging through adduction and inactivation of specific protein targets, and that this process can be abrogated using salicylamine (SA), a selective IsoK scavenger. Treatment with SA extends adult nematode longevity by nearly 56% and prevents multiple deleterious age related biochemical and functional changes. Testing of a variety of molecular targets for SA's action revealed the sirtuin SIR-2.1 as the leading candidate. When SA was administered to a SIR-2.1 knockout strain, the effects on lifespan and healthspan extension were abolished. The SIR-2.1-dependent effects of SA were not mediated by large changes in gene expression programs or by significant changes in mitochondrial function. However, expression array analysis did show SA dependent regulation of the transcription factor ets-7 and associated genes. In ets-7 knockout worms, SA's longevity effects were abolished, similar to sir-2.1 knockouts. However, SA dose-dependently increases ets-7 mRNA levels in non functional SIR-2.1 mutant, suggesting that both are necessary for SA's complete lifespan and healthspan extension. PMID- 27514081 TI - [PECULIARITIES OF COURSE OF TRAUMATIC DISEASE IN THE INJURED PERSONS IN COMBINED CRANIOABDOMINAL TRAUMA]. AB - Prospective investigation of the traumatic disease course was conducted in 71 injured persons, suffering a combined cranioabdominal trauma with the objective to determine the main functional systems and dynamics of their state severity. The occurrence rate and the severity degree of cardiovascular insufficiency were determined--in accordance to indices of the integrative body rheography and integrative dual frequency impedansometry, respiratory insufficiency (PaO2/FiO2 ratio), the organ insufficiency severity (in accordance to SOFA scale). There was established, that changes in respiratory and cardiovascular systems are corresponding to the staged pathogenetic characteristics of the traumatic disease periods. So on, it is expedient to perform the urgent and postponed operative interventions in a period of their relative stabilization. The presence of severe craniocerebral trauma, as a part of a combined cranioabdominal trauma causes significant and durable impairment of the functional systems activity. PMID- 27514082 TI - [BACTERIOLOGICAL ASPECTS OF AN ACUTE APPENDICITIS]. AB - Peculiarities of microflora in the appendix mucosa and abdominal exudate in different morphological forms of an acute appendicitis (AA) were studied up. In accordance to the bacteriological investigations data, anaerobic, and aerobic microorganisms in AA were revealed in a monoculture and in association, more frequently--obligate anaer- obes (bacteroids) with E. coli--in 82 (80.39%) observations, staphylococcus--in 52 (50.98%), fecal streptococcus--in 19 (18.63%). With progression of inflammatory process and destructive changes in the appendix wall the quantity of bacteroids and enterobacteria have had enhanced, while the quantity of lacto- and bifidumflora-- reduced. PMID- 27514083 TI - [SUBTOTAL COLECTOMY WITH MESORECTUMECTOMY IN SURGICAL TREATMENT OF A HIRSCHSPRUNG'S DISEASE IN ADULTS]. AB - Hirschsprung's disease (HD) in adults constitutes a rare cause of chronic constipation. Surgical intervention constitutes the only one radical method of treatment of HD. The investigation objective was to improve the functional results of treatment of HD in adults, using a new surgical approach elaboration. The method of surgical treatment of a HD in adults was proposed, which envisages a conduction of distal subtotal colecto- my and total mesorectumectomy with formation of a coecoreservoiroanal anastomosis. Application of the method proposed have had promoted an essential reduction of unfair functional results in a remote postoperative period. PMID- 27514084 TI - [SURGICAL TREATMENT OF COMPLICATED GASTRODUODENAL ULCER]. AB - Results of operative treatment of 437 patients with complicated gastroduodenal ulcer were summarized. The modern views on the problem of conservative therapy for gas- troduodenal ulcer were presented. A rational individual approach with a certain terms is necessary for conservative treatment of gastroduodenal ulcer. A real way for improve- ment of the patients treatment results--it is a combination of effective conservative treatment with a timely established indications for a planned operative treatment before dangerous complications occur. PMID- 27514085 TI - [SYSTEMIC CYTOKINOTHERAPY, USING BETALEUKIN IN A COMPLEX TREATMENT OF AN ACUTE GASTRODUODENAL ULCER BLEEDING]. AB - Results of surgical treatment for an acute ulcer gastroduodenal bleeding in 120 patients, ageing 16-75 yrs old, were analyzed. In 20 of them a gastric ulcer was a cause of bleeding, while in 84--a duodenal ulcer, and in 16--a coexistent gastroduodenal ulcer. The bleeding activity was estimated in accordance to J. Forrest classification. In 57 patients (a comparison group) preoperatively and postoperatively a complex of a standard basal conservative therapy without immunocorrection was conducted, and in 63 (the main group)--a systemic cytokinotherapy (SCKTH), using betaleukin, was applied postoperatively additionally in a complex of therapy. A content of CD3+, CD4+, CD8+, CD19+, IgA, IgM, IgG was estimated in dynamics, as well as circulating immune complexes, phagocytic index, phagocytic number. There was established, that a dysbalance depth in the immune status have had depended upon the blood loss severity. The SCKTH application is pathogenetically substantiated, it promotes the immune status normalization, as well as a more favorable course of postoperative period and the results of treatment improvement. PMID- 27514086 TI - [PROPHYLAXIS OF COMPLICATIONS OF LAPAROSCOPIC CHOLECYSTECTOMY IN PATIENTS WITH THE ISCHEMIC HEART DISEASE]. AB - Results of examination and surgical tratment of 56 patients, suffering chronic calculous cholecystitis with concomitant schemic heart disease, were analyzed. In all the patients a laparoscopic cholecystectomy was performed. Monitoring of cardiovascular compli- cations was estimated with the help of a Helter recording of EGG intraoperatively and in the early postoperative period. Depending on a kind of preoperative preparation done, the patients were divided on two groups: those, to whom cardioprotection using a Vasopro preparation was conducted, and those without cardioprotection. Depending on the intraoperative pneumoperitoneum regime used in every group two subgroups were delineated: in intraabdominal pressure 5-7.9 mm Hg and 8-10 mm Hg. In the patients, to whom cardioprotection was conducted and operative intervention in a carboxyperitoneum regime performed while intraabdominal pressure 5-7.9 mm Hg, a frequency of cardiovascular complications was lesser than in a control group. PMID- 27514087 TI - [FACTORIAL ANALYSIS IN PROGNOSTICATION OF INFECTIOUS COMPLICATIONS AFTER SIMULTANT OPERATIVE INTERVENTIONS FOR BILIARY CALCULOUS DISEASE]. AB - Prognostication of postoperative complications, having a certain high risk of occurrence in surgical treatment of biliary calculous disease, using laparoscopic and open access, peculiarly while performing simultant operative interventions, may promote the treatment efficacy rising in such patients. A multifactorial disperse analysis, using Statistica 6 for Windows (StatSoft), was applied for prognostication of risk for the infectious complications occurrence while a simultant operative interventions conduction for biliary calculous disease. The indices, which, in accordance to the pathophysiological processes character, may influence the postoperative complications occurrence rate, were analyzed. During conduction of this procedure, a great quantity of the parameters, which were determined in the patients, were transformed to a lesser quantity of independent causes. In the one cause a several variables were cojoined, which, as a rule, correlate with each other closely. On a subsequent stage a sum of the points of the prognosis causes for the risk of the postoperative purulent complications occurrence, as the points sum for the status severity and the operative intervention severity, were calculated. A prognostical validity of the algorithm proposed was tested in clinical conditions, its significance was estimated. PMID- 27514088 TI - [A FITZ-HUGH-CURTIS SYNDROME AS A PREMISE OF THE INFLAMMATORY DISEASES OF A HEPATOPANCREATOBILIARY ZONE ORGANS]. AB - A content of a biliary ways microflora and its correlation with clinical form and severity of inflammatory-destructive processes in hepatopancreatobiliary zone were studied up. The investigation objective was the optimization of a treatment- diagnostic tactics for the complications and remote recurrences rate reduction in a complicated biliary calculous disease. There was established, that a standard bacteriological investigation do not give a possibility to estimate some causes of a biliary ducts affection, a chlamidial infection in particular. So on, for the individual antibacterial therapy choosing a more detailed and modern examination of patients is needed. PMID- 27514089 TI - [MORPHOLOGICAL CRITERIA OF THE ENTERAL INSUFFICIENCE SEVERITY IN A DIFFUSE PERITONITIS FOR DETERMINATION OF A SUBSEQUENT TACTICS OF THE PATIENTS TREATMENT]. AB - The results of treatment of 87 patients for diffuse peritonitis (DP) were analyzed, in whom the enteral insufficiency (El) was estimated. The small intestine biopsies for morphological investigations were taken during its resection performance on the border between the pathologically changed and intact wall. Comparative morphometric analysis of destructive and inflammatory processes in a small intestine was conducted for establishment of morphological criteria for the EI prognosis in a DP. Morphological criteria of the EI severity were established for determination of a subsequent tactics for the patients' treatment and prognosis. PMID- 27514090 TI - [THE ROLE OF COMPUTER TOMOGRAPHY WHILE CHOOSING THE ABDOMINOPLASTY METHOD]. AB - The role of computer tomography (CT), while choosing the abdominoplasty method in the patients with different types of the anterior abdominal wall deformity present. For CT date the anterior abdominal wall deformity type was determined in the accordance to it--the operation volume needed. Depending on the changes degree the patients were divided on 5 groups, and in accordance to the deformity type present a necessary correction was made. The CT application have had permitted to determine the changes degree in the anterior abdominal wall, and to choose a necessary volume of abdominoplasty precisely. PMID- 27514091 TI - [PROPHYLAXIS OF POSTOPERATIVE HYPERALGESIA, BASED ON MORPHOLOGICAL SUBSTANTIATION OF THE ANALGESIA METHOD]. AB - The investigation was conducted in 20 children, operated on for abdominal oncological diseases in a 2010-2015 yrs period, using various methods of analgesia. While application of a constant infusion of high doses of phentanyl--1 4 MKr/(kg x h) in perioperative period the occurrence of the opiate-induced hyperalgesia is possible with the accompanied morphological changes in intestinal wall; in anesthesia of a transverse abdominal muscle (a TAP-blockade) and combined spinal epidural analgesia such changes were not observed. PMID- 27514092 TI - [EFFICACY OF RADIOFREQUENCY ABLATION OF AORTORENAL SYMPATHETIC NODES IN PATIENTS IN ARTERIAL HYPERTENSION]. AB - Efficacy of radiofrequency ablation (RFA) of prevertebral sympathetic nodes, concern- ing the arterial pressure lowering in 36 patients, suffering hypertonic disease and coex- istent heart diseases, was analyzed. In 12 mo after RFA a systolic arterial pressure lowering at average throughout the group by (3.24 +/- 1.15) kPa, or (24.3 +/- 8.6) mm Hg, diastolic arterial pressure--by (1.51 +/- 0.45) kPa, or (11.3 +/- 3.4) mm Hg was noted. RFA of prevertebral sympathetic nodes have had promoted a stable lowering of arterial pressure in patients, suffering chronic hypersympathicotony. PMID- 27514093 TI - [THE COMPARATIVE ANALYSIS RESULTS OF ENDOVASCULAR LASER COAGULATION AND A STANDARD PHLEBECTOMY IN THE TREATMENT OF CHRONIC DISEASES OF THE LOWER EXTREMITIES VEINS]. AB - The results of treatment of 58 patients, suffering chronic diseases of the lower extremities veins, were analyzed. In 28 patients a vertical reflux was eliminated using endovascular laser coagulation, in 32 patients--a standard phlebectomy in accordance to Babcock method was performed. The complications rate was compared as well as the term of the patients' stationary treatment. After elimination of endovascular laser coag- ulation the complications rate and severity is significantly lesser, than after a standard phiebectomy. In accordance to the ultrasonographic duplex scanning data in 12 mo in one patient a partial recanalization of large subcutaneous vein was noted. A total fibrous transformation of the coagulated venous trunks was achieved in 95.24% of the patients. Duration of postoperative stationary treatment have had reduced from (4.8 +/- 0.8) to (1.2 +/- 0.1) days (p < 0.001). PMID- 27514094 TI - [POSSIBILITIES OF MODERN TECHNOLOGIES IN THE TREATMENT OF PLEURAL EMPYEMA]. AB - The data, concerning videothoracoscopic operations application in the acute pleural empyema treatment in 462 patients, were adduced. Efficacy of videothoracoscopic operations, using electrowelding and radiofrequency surgical complexes with possibility to eliminate pulmonary-pleural fistulas, was shown. Positive clinical effect was noted in 443 (95.9%) patients, duration of stationary treatment have constituted 11.1 days at average. The complications have had occurred in 19 (4.1%) patients. All the patients are alive. PMID- 27514095 TI - [MODERN APPROACHES TO TREATMENT OF A DONOR'S WOUNDS IN THE INJURED PERSONS WITH THE BURNS]. AB - The impact of the treatment method proposed, using antioxidant therapy in patients, suffering the burns, on the speed and efficacy of the donor's wounds healing in their extremities was studied. In a control group of patients a standard treatment of the donor's wounds in extremities was conducted, while in the main group of patients the treatment was added with lymphotropic injection of antioxidant preparation Mexidol. Due to application of the method proposed, the wounds healing in the main group of the injured persons have had occurred significantly faster, than in the patients of a control group, and the complications of the wounds healing were absent. PMID- 27514096 TI - [STUDYING OF MORPHOLOGICAL PECULIARITIES OF SUBMANDIBULAR SALIVARY GLANDS AFTER GASTRIC RESECTION IN EXPERIMENT]. AB - The impact of gastric resection on the submandibular salivary gland (SSG) state, using histological and histochemical methods of investigation in experiment, was studied up. A relative mass of a SSG after gastric resection conduction have had reduced, and the accompanying changes in stroma were revealed with the gland's secretion enhancement. Essential dystrophic changes in the SSG parenchyma and stroma after gastric resection conduction may cause a pronounced disorders of their function. PMID- 27514097 TI - [THE BONE DEFECT HEALING UNDER THE INFLUENCE OF RADIAL EXTRACORPOREAL SHOCK-WAVE THERAPY IN EXPERIMENT]. AB - In experiment on 24 rabbits the processes of reparative osteogenesis in perforated defect of proximal tibial metaphysis under the influence of extracorporeal shock-wave therapy were studied. In accordance to data of clinical, roentgenological and morphological investiagations, conducted in terms 5, 15, 30 and 45 days of observation, there was established, that under the influence of extracorporeal shock-wave therapy in the bone marrow in the traumatic region a vasodilatation, as well as the blood cells exit from capillaries and sinusoid vessels with creation of massive regions of osseous endostal regenerate, guaranteeing the tibial integrity restoration, occurs. PMID- 27514098 TI - [METABOLIC CHANGES OF SKELETAL MUSCLES IN TRAUMATIC INJURY OF PERIPHERAL NERVE AND AUTOPLASTY IN EXPERIMENT]. AB - The changes in metabolism of the amine acids, enzymes, electrolytes, fat acids (FA) in skeletal muscles of anterior and posterior extremities of rats in significant defects of peripheral nerve and its autoplasty were studied in experimental investigation. Metabolic changes in skeletal muscles are accompanied by significant intensity of proteolysis, lowering of the enzymes activity, energetic metabolism and in a less extent of the electrolytes balance and the FA metabolism. After autoplasty of big defects in the traumatized nerve the proteins' synthesis and restoration of activity of lactate dehydrogenase and creatine phosphokinase constitute the markers of muscular tissue restoration. Surgical restoration of the nerve is accompanied by a protein synthesis activation in muscles, but normalization of the enzyme systems indices, the lipids metabolism and the electrolytes balance was not observed. Metabolic dysbalance needs a certain pharmacological correction and prevention of a progress of pathological process in skeletal muscles. PMID- 27514099 TI - [THE WAYS OF IMPROVEMENT OF A GASTRIC CANCER SURGICAL TREATMENT]. PMID- 27514100 TI - [PERFORATION OF PEPTIC ULCER: NONSTANDARD SITUATIONS AND NONSTANDARD DECISIONS]. PMID- 27514101 TI - [MALROTATION BOWEL PATIENT IF STRANGULATED INGUINAL HERNIA]. PMID- 27514102 TI - [ENDOVASCULAR ARREST OF EROSIVE BLEEDING FROM THE TONGUE ARTERY]. PMID- 27514103 TI - [OBSERVATION OF A FEMORAL ARTERY EMBOLISM, CAUSED BY A BULLET]. PMID- 27514104 TI - Washington Brings Renewed Focus to Payment Models of the Future. PMID- 27514105 TI - New Directions in CMS Bundling: 2016 Update. PMID- 27514106 TI - Improving Patient Flow Utilizing a Collaborative Learning Model. AB - This initiative utilized a collaborative learning approach to increase knowledge and experience in process improvement and systems thinking while targeting improved patient flow in seven radiology modalities. Teams showed improvements in their project metrics and collectively streamlined the flow for 530 patients per day by improving patient lead time, wait time, and first case on-time start rates. In a post-project survey of 50 project team members, 82% stated they had more effective solutions as a result of the process improvement methodology, 84% stated they will be able to utilize the process improvement tools again in the future, and 98% would recommend participating in another project to a colleague. PMID- 27514107 TI - Lean Six Sigma and Employee Development. PMID- 27514108 TI - Enhancing the Imaging Experience for Pediatric Patients. AB - The University of Maryland Medical Center's goal was to improve the safety and comfort of pediatric imaging by enhancing the experience for children. Two pediatric radiologists and two child life specialists worked together to create a training program to help guide radiology technologists on how to approach and interact with children undergoing medical imaging. The results of surveys administered to technologists and parents or caregivers helped refine the strategy for both creating training sessions for technologists and reading materials for children and their parents to optimally prepare for the procedures. Training sessions included information on language choices, developmental considerations, comfort techniques, patient- and family-centered care practices, procedural support techniques, and coping styles. Through the implementation of learning sessions and distraction resources for technologists, and the development of preparation books, the imaging experience for pediatric patients at UMMC has improved. PMID- 27514109 TI - De-nied! AB - It is important to remain current on the latest edit and modifier guidelines from the AMA, CMS, and your contracted payors. Failure to use modifiers correctly can result in under- or overpayments and can put a provider at risk of penalties. Also, since payors vary in how they adjudicate claims with modifiers, it is important to monitor payments for claims with modifiers to make certain you are being paid correctly. PMID- 27514110 TI - ICD-10: Intervertebral Disc Disease. PMID- 27514111 TI - Business Intelligence in Hospital Management. AB - Business intelligence (BI) is a worthwhile investment, and will play a significant role in hospital management in the near future. Implementation of BI is challenging and requires resources, skills, and a strategy, but enables management to have easy access to relevant analysis of data and visualization of important key performance indicators (KPI). Modern BI applications will help to overcome shortages of common "hand-made" analysis, save time and money, and will enable even managers to do "self-service" analysis and reporting. PMID- 27514112 TI - Observations from a Healthcare User. PMID- 27514113 TI - Responsibility Training. PMID- 27514114 TI - [Metamorphosis of psychology between 1860 and 1989 and their reflections in the Leipzig, Berlin and Halle academies]. AB - The study discusses the approach to psychology and psychological topics in three scientific academies, the Saxon Society of Sciences, the Prussian Academy of Sciences and the Leopoldina Academy of Sciences. Four different uses of the academies emerge: academies as a scene of transdisciplinary exchange and emergence of new ideas, as a location for the presentation of normal scientific research, as an arena of proclamations in science policy, and as a reputation generating scene for a new, arising science-based profession and its associated scientific discipline. PMID- 27514115 TI - [Medical anthropology in academies: on the criticism of natural science medicine exemplified by Viktor von Weizsacker]. AB - Viktor von Weizsacker (1886-1957) founded his concept of medical anthropology as a clinician educated in internal medicine and neurology. He tried to broaden natural scientific medicine psychosomatically focussing on the "sick human". The natural scientific approach would exclude subjectivity, and therefore he propagated the "introduction of the subject' (Einfuhrung des Subjekts) into the life sciences. His own sensory physiological experiments and Sigmund Freud's psychoanalysis inspired him essentially since the 1920s. In his main work Der Gestaltkreis (gestalt circle) published in 1940 he stressed the "entity of perceiving and moving" (Einheit von Wahrnehmen und Bewegen) in regard to relevant aspects of medicine. In 1932, Weizsacker became a member of the Heidelberg Academy of Sciences, whose president he was from 1947 till 1949; 1942 he became a member of the Leopoldina. Primarily his merits as a neurologist were highly appreciated. His medical anthropology was not relevant for his election by the two academies. Nevertheless, there was a certain repudiation against the objectivistic and materialistic Weltanschauung within the scientific community. So, Paracelsus and Goethe were highly estimated as natural philosophical guides for own conceptions. This was especially evident for the circle around Wilhelm Troll and Karl Lothar Wolf in Halle, both members of the Leopoldina, who were fascinated by Goethe's concept of "Gestalt". Weizsacker's lecture on "Gestalt und Zeit" in Halle in 1942 fitted in the concept of those natural scientists. PMID- 27514116 TI - [History of anatomy - academy history. On the development of scientific academies in the Third Reich exemplified by anatomy]. AB - Research on the history of National Socialism has for decades ignored the German academies of sciences as well as the subject of anatomy. This was due to the rather minor roles the societies played in the scientific policy of the Third Reich and role anatomy played in medicine during this period of time. Recent investigations in both subjects were able to show how worthwhile the dealing with seemingly minor aspects of National Socialist policies is: Those aspects can especially help to sharpen the historical judgment of scientific and political actions. On the basis of recent archival research this article tries to present and analyze the subject of anatomy and the academies of sciences regarding their reciprocal relationship between 1933 and 1945. Besides the Leopoldina, the Prussian and the Bavarian Academies of Sciences will be focused on: By the examples of the anatomists represented in these societies it can be shown how anatomy as well as the societies developed under National Socialism and which general tendencies, entanglements and differences are relevant for the matter. The insight in this relationship focuses on the one hand on the anatomists represented in the societies. On the other hand it deals with the presence of anatomical research in the society, their meetings and publications, and especially with ideology and crimes reflected in this research. PMID- 27514117 TI - [Association of the Berlin German Academy of Science and the German Leopoldina Academy of Natural Scientists with the Nazi medical crimes of its members after 1945]. AB - The paper examines how two renowned academies based in East Germany handled the Nazi medical crimes of its members after 1945. It should be noted that both institutions were differently affected by these crimes. This applies both in terms of number of incriminated members, which is a consequence of the different membership structure of the two academies, as well as the extent of their involvement. Despite being apparently the less affected of the two, the former Prussian Academy of Sciences responded more radically to the Nazi past of its members and removed those accounted guilty from the academy before it was reopened by the Soviet military administration on 1 July 1946. The reasons for this are to be found mainly in the exposed situation of the academy, which was in the center of the Soviet occupying power. The Leopoldina did not make such adjustments of the membership lists. The reasons for the moderate dealing with the Nazi crimes of its members are primarily in the attitude of the leading representatives of the Leopoldina in Halle after 1945, in the continuity of the members, and thus the thought structures--regardless of the ruling political systems--and in the particular status of the Leopoldina as an all-German academy tolerated by the SED. PMID- 27514118 TI - Floor Plans. AB - More and more hospitals, design firms and others are recognizing the value that nurses can bring to facility design. PMID- 27514119 TI - DOING THEIR HOMEWORK. AB - One health care network is proving the value of community health workers to reach patients at home. The effort improves population health, identifies patients who are at risk of illness and averts preventable hospitalizations. PMID- 27514120 TI - The Most Vexing Problem in IT. AB - The inability to share patient records from one physician to the next and one hospital to the next is a huge roadblock in efforts to improve health care delivery. Some hospitals are fed up, and they're taking the bull by the horns. PMID- 27514121 TI - PAY CHECKS. AB - Hospital boards are well-versed in overseeing executive compensation Now they're being encouraged to take a greater role in physician compensation, too, to improve strategic alignment and reduce risk. PMID- 27514122 TI - When Words Matter. AB - Too often, terminology used in a hospital is inconsistent and can hurt planning, operations, communication and credibility. Hhere's how boards can encourage a consistent lexicon. PMID- 27514123 TI - Preserving a Legacy. AB - When a nonprofit hospital is bought by a for-profit health care system, a central concern for boards is preserving the charitable mission, values and legacy of their organization. PMID- 27514124 TI - Exploring Community Health Needs. AB - The Health Research & Educational Trust has five recommendations to maximize the effectiveness of a hospital's community health assessment. PMID- 27514125 TI - [CHARACTERISTICS OF VAGINAL ECOSYSTEM IN ENDOCERVICITIS CHLAMYDIALIS]. AB - The study aims: 1. To analyze and study the specifics of microbiocenoses of exocervix at endocervicitis chlamydialis, to differentiate the spectrum of stimuli, and establish the leading role of Chl. trachomatis in the genesis of this process. 2. To determine the leading role of the method of direct (bed-side) microscopy for early and rapid diagnosis of cervicitis and conducting etiotropic therapy. We determined the incidence of endocervicitis chlamydialis, with cause Chl. trachomatis-45.1%, (319 DIF (+) patients out of 708 surveyed), p <0.05, in the Rousse region. Studies indicator presence or absence of vaginal infection, Trichomonas vaginalis, Gardnerella, Candida, Staphiloocus aureus, E. coli, Proteus, Streptoccocus agalactae, the differences between the two samples in terms of the variable was not statistically significant. In our study, in patients with endocervicitis, the incidence of Trichom. vaginalis is 7.0%, Gardnerella-24.4%, Candida-21.4%, Streptococcus agalactae-7.1%, Staphylococcus aureus-6.3%, E. coli-0.4%, Proteus-0.2%. The frequency of Trichomonas vaginalis, npu nauueHmku c endocervicitis chlamydialis e 3.2%, Gardnerella-10.8%, Candida alb. -9.2%, Candida tropicans-0.2% Streptoccocus agalactae-3.3%, Staphyllococus aureus-2.4%, E.coli-0.0%, Proteus-0.0%.The majority of patients with endocervicitis chlamydialis, no other co-infection unless Chl. trachomatis. PMID- 27514126 TI - [EARLY DETECTION OF PREECLAMPSIA]. AB - The preeclampsia is one of the most serious complications in the second half of the pregnancy with a high risk of perinatal maternal and neonatal mortality. The study is aiming to determine which pregnant women have a higher risk of developing preeclampsia with a view to the subsequent antenatal care, on the base of the individual factors. MATERIAL AND METODS: From prospectively followed pacients is collected information by a questionnaire and sonographic examination at 11-13 weeks of gestation/w.g./ + 6 days, at the point of biochemical screening implementation. Selected is a group of women with one fetus pregnancy, non smokers, without chromosomal and structural anomalies of the fetus, excluding those taking prophylactic low-dose of aspirin. The Doppler examination was transabdominaly performed on the ascending branch of the A. Uterina at the level of OICC.Pusatility and resistance index /Pi and Ri/ are bilaterally evaluated and converted to MoM for the relevant age of gestation. RESULTS: The information about the taken values of Pi, Ri, the presence of diastolic incisures and the development of preeclampsia /PE/ or pregnancy indused hypertension /PIH/ is analyzed at 205 pregnant women. Out of them high values of Pi have 9 pregnant women, who subsequently developed PE or PlH. CONCLUSIONS: The measurement of Pi at 12-13 weeks of gestation and presence of diastolic incisures have prognostic importance for the development of PE in the later period of pregnancy. The values of Ri, taken at 12-13 weeks of gestation have not essential importance in the forecast of preeclamsia development. PMID- 27514127 TI - [PROGNOSTIC MODELS IN MODERN MANAGEMENT OF VULVAR CANCER]. AB - AIM: The aim of the research was to evaluate and analyse prognosis and prognostic factors in patients with squamous cell vulvar carcinoma after primary surgery with individual approach applied during the course of treatment. MATERIALS AND METHODS: In the period between January 2000 and July 2010, 113 patients with squamous cell carcinoma of the vulva were diagnosed and operated on at Gynecologic Oncology Clinic of Medical University, Pleven. All the patients were monitored at the same clinic. Individual approach was applied to each patient and whenever it was possible, more conservative operative techniques were applied. The probable clinicopathological characteristics influencing the overall survival and recurrence free survival were analyzed. Univariate statistical analysis and Cox regression analysis were made in order to evaluate the characteristics, which were statistically significant for overall survival and survival without recurrence. A multivariate logistic regression analysis (Forward Wald procedure) was applied to evaluate the combined influence of the significant factors. While performing the multivariate analysis, the synergic effect of the independent prognostic factors of both kinds of survivals was also evaluated. RESULTS: Approaching individually each patient, we applied the following operative techniques: 1. Deep total radical vulvectomy with separate incisions for lymph dissection (LD) or without dissection--68 (60.18 %) patients. 2. En-bloc vulvectomy with bilateral LD without vulva reconstruction--10 (8.85%) 3. Modified radical vulvactomy (hemivulvectomy, patial vulvactomy)--25 (22.02%). 4. wide local excision--3 (2.65%). 5. Simple (total /partial) vulvectomy--5 (4.43%) patients. 6. En-bloc resection with reconstruction--2 (1.77%) After a thorough analysis of the overall survival and recurrence free survival, we made the conclusion that the relapse occurrence and clinical stage of FIGO were independent prognostic factors for overall survival and the independent prognostic factors for recurrence free survival were: metastatic inguinal nodes (unilateral or bilateral), tumor size (above or below 3 cm) and lymphovascular space invasion. On the basis of these results we created two prognostic models: 1. A prognostic model of overall survival 2. A prognostic model for survival without recurrence. CONCLUSIONS: Following the surgical staging of the disease, were able to gather and analyse important clinicopathological indexes, which gave us the opportunity to form prognostic groups for overall survival and recurrence free survival. PMID- 27514128 TI - [LASER CONISATION VS. COLD KNIFE CONISATION FOR CIN]. AB - For the period of 5 years (2008-2012) at the outpatient department and the operation theater of Tokuda hospital 280 conisations were done--135 lasers and 145 cold knifes. Indications for the operation were common, with no specific choice for the aim of comparison. All patients had proven colposcopic or histologic dysplasia of the cervix. The operations were performed 2 or 3 days after menstruation. Laser conisations received local anesthesia and were not hospitalized. Cold knife conisations were done at the operation theater under regional anesthesia, they attended the hospital for 24 hours, had vaginal tapenade and urethral catheter. Indications for the operation were as follows: CIN I-14 laser and 38 cold knife conisations; CIN II-30 laser and 28 cold knife conisations; CIN III--CIS-73 laser and 74 cold knife conisations. The follow up is: 2 months after the operation-colposcopy and every 3 months afterwards--PAP smear and colposcopy for 1 year. PMID- 27514129 TI - [CLINICO-MORPHOLOGICAL STUDY OF 68 CASES OF INVASIVE ENDOCERVICAL ADENOCARCINOMA]. AB - Recent studies have demonstrate an increase in both relative and absolute frequency of the cervical adenocarcinoma (ECA) with incidence about 10-25% of all cervical malignancy. THE AIM: clinicopathological study of invasive ECA. MATERIALS AND METHOD: From 2007 to end of 2011, 68 cases of invasive ECA were collected. The tumors were classified according the WHO classification of tumors of Tumors of the Female Reproductive Organs 2014. RESULTS: The distribution of different histological types of ECA was as follow: Usual type-29 (42.65%); Endometroid type-15 (22.06%); Adenosquamous type-15 (22.06%); Villoglandular type 6 (8.82%); Signet-ring type-2 (2.94%); and Intestinal type-1(1.47%). The middle age of patients was 45 years and varied in large diapason 27-73 years. A synchrony presence of CIN and glandular dysplasia even to AIS in some cases with usual and adenosquamous type were detected. The clinical and morphological data of every type ECA was analised. PMID- 27514130 TI - [CONSERVATIVE MANAGEMENT OF PLACENTA ACCRETE DURING VAGINAL DELIVERY]. AB - Conservative management of placenta accrete consists in leaving the entire placenta accreta in situ after vaginal delivery of the fetus. This behavior requires active monitoring the vital signs of mother, genital status and paraclinical indicators for an extended period after birth. Monitoring is suspended after full absorption of the placenta. The success of the conservative approach depends on: the adopted protocol formanagement of placenta accreta, whether the diagnosis is known before birth, the possible of application techniques, reducing blood flow to the uterus, keeping the placental period and others. The smallest success with vaginal birth, is when the diagnosis of placenta accreta is not know in advance and proceed with aggressive attempts to extract the placenta, followed by profuse bleeding from the uterus. As additional methods of securing conservative management is reported use of Methotrexate, with unproven effectiveness and embolization of a. Iliaca interna and a. uterine, which require a qualified team and have a lot of complications. Complications of conservative management of placenta accreta are: febrility and genital bleeding, which are the cause of late hysterectomy in about 35% of cases. lnfestion may be not always prevent by application of broad spectrum antibiotics. Late bleeding is usually associated with an active inflammatory process. Low-grade and low grade temperature increase of leukocytes and CRP may be due to necrotic changes in the placenta without the infection process. Tracking involution of the placenta is through abdominal and transvaginal ultrasound, magnetic resonance, using hysteroscopy through serial monitoring the level of hCG. From literature data the time for resorption of the placenta varies from 4 months to 1 year. It is essential to determine the time when it is safely to extract the placenta move in order to prevent late complications of conservative management. Our experience and some authors suggest that there may be instrumental extraction under ultrasound control at 8-10 days after birth. PMID- 27514131 TI - [Medical and social aspects of interruption of the pregnancy]. PMID- 27514132 TI - [CONSERVATIVE TREATMENT OF MAYER-ROKITANSKY-KUSTER-HAUSER SYNDROME. REVIEW OF LITERATURE AND OUR EXPERIENCE]. AB - Mayer-Rokitansky-Kuster-Hauser syndrome is a part of the group of abnormalities known as "Anomalies of the fusion of the Mullerian ducts". It is characterized by normal development of breasts and hairs, normal appearance of external genitalia, normal feminine genotype (46XX), normal FSH, LH, E2 and Test. levels, normal ovaries and congenital absence of uterus and the whole or the upper two thirds of the vagina. It is observed in about 15% of the cases with primary amenorrhea and the incidence is about 1:4500-6000. Etiologycal factors such as lack of estrogen/gestagen receptors, deletions or mutations of genes that stop the fusion, as well as the activation of anti-Mullerian hormone (AMH), are considered. The etiology is being explored but there is no consensus yet. The diagnosis is confirmed during a clinical examination, which takes place because of a primary amenorrhea (often happening at the age of 16), and the absence of a uterus and vagina is proved. The therapy should be handled by a multidisciplinary team including obstetrician, trained midwife, psychologist, specialist in imaging and psycho-sexual counseling. The idea for surgical creation of vagina (neovagina) dates many years ago. The first known documents date back to 1817 and over the years a variety of methods are offered usage of amnion, dura mater, peritoneum, skin grafts, different parts of the intestine, cellulose, etc. The first method of non-surgical treatment is offered by the Czech gynecologist Frank. His ambition was to build a vagina by gradual dilatation of the tissue while applying dilatators with successively increasing length and thickness. The method was further developed by Ingram (1981) and nowadays by Edmonds (2012). He reported about 245 patients treated during the last 12 years by his team. 232 of them had a success in anatomic aspect (95%), 13 did not complete the treatment due to psychological or cultural problems. The experts from American College of Obstetricians and Gynecologists include in their "Committee Opinion" from May 2013 the following lines: "Non-surgical creation of the vagina is the appropriate first line approach in most patients". Briefly is presented our experience in this field--14 girls at the age of 16-18, successfully treated with dilatation in the III Gynecology Clinic in University hospital "Maichin dom", Sofia, Bulgaria. PMID- 27514133 TI - [ENDOMETRIAL POLYPS--CLINICOPATHOLOGICAL FEATURES OF MALIGNANCY AND THERAPEUTIC ATTITUDE]. AB - Endometrial polyps represent a localized overgrowth of the endometrium, projecting above the epithelium. Endometrialpolyps maybe single or multiple, may measure from a few millimeters to centimeters, and maybe sessile or pedunculated. The use of transvaginal ultrasound is inevitably entailing a significant increase in the number of women diagnosed with endometrial polyps. Endometrial polyps are usually benign although some may be precancerous or cancerous. The prevalence of malignant change in EMPs varies from 0.8 to 8%. Hysteroscopic polypectomy is effective and safe as both a diagnostic and therapeutic intervention. It remains the gold standard for treatment. Given that most polyps are not malignant, there is an option for expectant management with no intervention. It is impotant to evaluate the prevalence of endometrial premalignant and malignant polyps in premenopausal and postmenopausal women, as well as the clinical, ultrasound, and hysteroscopic factors associated with malignancy. Asymptomatic postmenopausal polyps are unlikely to be malignant and observation is an option after discussion with the patient. PMID- 27514134 TI - [CO2 LASER SURGERY IN GYNECOLOGY--NEW HORIZONS]. AB - AIM: Short history of laser procedures in gynecology, benefits and new horizons. PMID- 27514135 TI - [LAPAROSCOPIC TREATMENT OF INTRALIGAMENTAL LEIOMYOMA PER MAGNA]. AB - Uterine myoma is the most frequent benign tumor of female organs. Intraligamentary myomas in the broad ligament are rare. We present a case of 50 years old patient with 22 cm intraligamentary myoma with cystic degeneration, who is referred to the Gynecological Department of Ob/Gyn Hospital "Dr. Shterev" with complains of severe pain. This case is interesting for its rareness and diagnostic dilemma, because degenerative myomas can imitate malignant mass. Total laparoscopic hysterectomy with ablastic vaginal morcellation of the specimen in endobag was performed. The patient was discharged from the clinic next day. PMID- 27514136 TI - [NEW APPROACH IN DIAGNOSTIC ALGORITHM OF AN INFECTIOUS AGENTS (PARVOVIRUS B19 AND CHLAMYDIA TRACHOMATIS) INVOLVED IN THE DEVELOPMENT OF PATHOLOGICAL PREGNANCY]. AB - Viral infections during pregnancy, along with some form of accompanying pregnancy diseases such as diabetes, cardiovascular, gastrointestinal, kidney and others, are a major cause of arising complications and mortality of mother and fetus. AIM: To improved the laboratory diagnostic approach in the study of women with pathological pregnancy, including improve treatment and prognostic character of the outcome of pregnancy, with the inclusion of two infectious agent parvovirus B19 and Chlamydia trachomatis. To determine types of anemia in pregnant women with parvovirus B19 and Chlamydia trachomatis infection and to select the correct therapeutic approach. MATERIALS AND METHODS: A total 36 serum samples from pregnant women with anemia (n = 22), nonimmune hydrops fetalis (n = 8) and fetal ascites (n = 6) were tested. The study included three newborns (n = 3), tested on the occasion of a possible maternal-fetal infections. The serological (indirect ELISA tests) and molecular (B19V-PCR test) methods were used. In anemic pregnant women were evaluated iron homeostasis parameters with CLIA, AAS and NEPH methods. RESULTS: In 6/36 (16.66%) patients B19V-IgM positive result was detected. Among the study patients with anemia, non-immune hydrops fetalis and fetal ascites incidence of proven B19V-IgM antibodies was 18.18% (4/22), 12.5% (1/8) and 16.66% (1/6), respectively. Protective B19-IgG antibodies in 25/39 (64.10%) samples were found. A positive PCR signal was showed in all patients with positive B19V-IgM, and 1 patient with anemia and positive B19V-IgG result. The three newborns were positive for B19V-IgG antibodies (maternal) and negative for acute viral infection. Present Chlamydia trachomatis infection in 6/36 (16.66%) and past infection in 5/36 (13.89%) patients was demonstrated. The anemia was evaluated as iron-deficiency according to low hepcidin levels 2.54 +/- 0.4 MUg/I compared to pregnant control group which included women without anemia 25.9 +/- 2.8 MUg/I. CONCLUSION: In view of the varied transmission B19V and the wide range of complications arising as a result of chlamydia, screening for these viral agents of pregnant women and women of childbearing age is an important approach for monitoring of pregnancy. PMID- 27514137 TI - [INFLUENCE OF STIMULATION PROTOCOL ON MATURITY AND MORPHOLOGICAL FEATURES OF OOCYTES IN PATIENTS WITH LOW OVARIAN RESERVE: STUDY OF 72 IVF/ICSI TREATMENT CYCLES]. AB - The current study presents the results of a retrospective and prospective observation of the maturity and morphological features of the oocytes and the way they are influenced by the therapeutic approaches and the protocol for controlled ovarian hypersimulation (COH) in patients with low ovarian reserve. MATERIALS AND METHODS: The study includes 184 oocytes, derived from 72 patients with low ovarian reserve involved in an infertility treatment program through in vitro fertilization from February 2011 to February 2014. The applied therapeutic approaches and COH protocols are microdose agonist short protocol, antagonist short protocol, mild stimulation protocol and natural cycle in vitro fertilization. RESULTS: Our study hasn't found a statistically significant dependence between the applied ovarian stimulation protocol and the maturity and morphology. PMID- 27514138 TI - [POSSIBILITIES AND LIMITATIONS ANALYSIS OF SCREENING IN PREGNANT WOMEN FOR DOWN SYNDROME AND OTHER COMMON CHROMOSOMAL DISORDERS OVER A PERIOD OF TWO YEARS]. AB - Maternal biochemical screening and the new non-invasive prenatal screening tests as well as prenatal diagnostic tests as tools to fight serious chromosomal diseases have their possibilities and limitations. The article presents analysis of the results in 7 201 pregnant women: 4426 first trimester and 2775 second trimester biochemical screening, together with 994 calculated integrated risks performed in the Laboratory of medical genetics in 2013 and 2014 year. A matter of mass screening in both periods is the criterion of efficiency--financially justified reasons on the basis of comparison "sensitivity" of different approaches. First trimester screening revealed 5 (71.42%) cases of chromosomal disease and 1 (14.28%) case with large congenital anomaly. From second trimester biochemical screening 3 (60%) cases were revealed. Chromosomal pathology in pregnant women with calculated integrated risk was found in 7 (70%) cases. From a total of 22 screened pregnant women with prenatal or postnatal verified diagnosis of Down syndrome, Edvards, Patau or Turner, highest detection rate is found in first trimester screening--6 of 7 (85.7%). Contingent approach is most widely used in Europe and we confidently recommend it. PMID- 27514139 TI - [LAPAROSCOPIC BURCH COLPOSUSPENSION WITH PARAVAGINAL REPAIR]. AB - Genuine urinary stress incontinence (GUSI) is defined by the International Continence Society (ICS) as involuntary loss of urine coincident with increased intra-abdominal pressure in the absence of a detrusor contraction or an over distended bladder. If the patient demonstrates a cystocele secondary to a paravaginal defect, a paravaginal defect repair should be performed before the colposuspension. The laparoscopic retropubic colposuspension gained popularity because of its reported advantages of improved visualization, shorter hospital stay, faster recovery and decreased blood loss. A review of our experience revealed 11 of 24 patients had a Burch urethropexy and paravaginal repair and 13 of 24 a Burch urethropexy alone. Average operative time was 80 min, estimated blood loss of less than 50 ml and hospital stays less than 48 h. PMID- 27514140 TI - [ANTENATAL APPLICATION OF CORTICOSTEROIDS IN LATE PRETERM BIRTHS]. AB - The aim of the following study is to present the current evidence of antenatal use of corticoids in premature birth. The benefits of antenatal use of corticosteroids after 34 week of gestation is still a process of discussion. PMID- 27514141 TI - [CALCIUM LEVELS IN URINE SAMPLE IN PREGNANT WOMEN WITH PREECLAPMSIA]. AB - Hypertensive disorders during pregnancy are still leading cause for maternal and perinatal death. Calcium metabolism is impaired significantly in women with preeclampsia. Measurement of calcium levels in 24 hours urine sample is easy, modern, fast and not expensive predictive test to reveal women in high risk of developing preeclampsia in late pregnancy. The severity of condition strongly correlates with decrease level of calcium excretion in urine. PMID- 27514142 TI - [BENEFITS AND RISKS AT IMPLEMENTATION OF PROPHILACTIC VACCINES FOR CERVICAL CANCER]. AB - The aim of this review is to present the benefits and risks of the implementation of prophylactic vaccines for cervical cancer. The classical understanding of human papilloma virus (HPV) infection and its role for the cervical oncogenesis, as well as, the place of prophylactic HPV vaccines are discussed. Results concerning the effectiveness of vaccines 10 years after their introduction and data about their safety are presented. Reports of the use in practice of the new 9-valent HPV vaccine and the first results of its implementation are studied. PMID- 27514143 TI - [PREGNANCY AND DELIVERY IN A PATIENT WITH CHARCOT-MARIE-TOOTH DISEASE]. AB - We report a case of a 34 years old primigravida with Charcot-Marie-Tooth disease (CMTD). The course of pregnancy was uneventful with no deterioration of symptoms due to the disease. Performed amniocentesis showed healthy fetus. Planned cesarean section with spinal anesthesia was performed because of the restricted pelvis. The possible issues of combination pregnancy and CMTD are discussed. PMID- 27514144 TI - [DISSEMINATED PERITONEAL LEYOMYOMATOSIS AFTER LAPAROSCOPIC MORCELLATION--A CASE REPORT]. AB - We presented a case of 41-year-old patient underwent two laparoscopic Myomectomies and current laparotomy regarding suspection of necrotic leiomyoma. Intraoperative finding was suggestive of disseminated malignancy, but gefrir study showed benign smooth muscle tumors. The patient underwent total hysterectomy with right adnesectomy and total omentectomy. After histological and immunohistochemical study of the entire macroscopic material the final diagnosis was disseminated peritoneal leiomyomatosis. This disease is rare, but in recent years, in connection with the widespread introduction of laparoscopic surgery the reports of disseminated peritoneal leiomyomatosis occurring after laparoscopic morcellation, were frequent. PMID- 27514145 TI - [LOCALLY ADVANCED CERVICAL CANCER IN THE PUERPERIUM--CASE REPORT]. AB - The cervical cancer is the most common gynaecological neoplasma during pregnancy. The average frequency during pregnancy and 1 year post partum is around 1 case per 2 200 pregnancies. The authors present a case of locally advanced cervical cancer (IV stage), diagnosed 30 days after Cesarean section. 5-years survival of this stage is 15%. PMID- 27514146 TI - [LAPAROSCOPIC TREATMENT OF PRIMARY ABDOMINAL PREGNANCY: A CASE REPORT AND REVIEW OF THE LITERATURE]. AB - Abdominal pregnancies are 1.4% of all ectopic pregnancies. They are mostly complicated and usually managed by laparotomy, but laparoscopy is an alternative method which some surgeons perform instead of laparotomy, especially in early pregnancy. We reported a 29 year old woman with supra pubic pain and vaginal bleeding. After sonographic evaluations, ectopic pregnancy was diagnosed and the patient underwent laparoscopic surgery for termination of pregnancy. Laparoscopy is a successful alternative method of surgery for abdominal pregnancies in first trimester. PMID- 27514147 TI - [THE ROLE OF MOTHER'S MILK AND BREAST FEEDING. MEDICAL PROBLEMS DURING THE LACTATION PERIOD LACTOBACILUS FERMENTUM--A NEW APPROACH TOWARDS THE PREVENTION AND THE TREATMENT OF ACUTE AND SUBACUTE MASTITIS]. AB - Breast feeding provides a lot of short and long-term benefits for the mother and the baby. It prevents the baby of gastrointestinal, urinary and respiratory infections, atopical conditions and assures long-term protection of cardiovascular and metabolic diseases. The breast feeding decreases the risk for the mother of ovary and breast carcinoma and creates a positive emotional bond between the mother and the baby Mother's milk is a species specific; its content is relatively stable regardless of mother's age race, way and place of living. Mother's milk is not sterile. There is a 10 year international trial held in Spanish and Finnish universities. It has identified and count all microorganisms in mother's milk (more than 700) and proved that their content and quantity varies according the age of the baby. Mother's milk is a source of lactobacillus for baby's intestines and most of them have probiotic potential. Lactobacillus fermentum Lc40 (hereditum) is isolated from mother's milk. It has a good viability in gastrointestinal system, high level of adhesion to intestinal epithelium cells, produces glutation--strong antioxidant, good antibacterial activity to entero-pathogens and potential of increasing the immunologic response. Clinical trials reveal that Lactobacillus fermentum plays important role to microflora balance of mother's milk in mastitis during lactation. Many trials estimating the efficiency of lactobacillus fermentum in prevention and treatment of acute and subacute mastitis have been carried out. The results of them open a new door in front of us in the treatment of these conditions- treatment with probiotics instead of antibiotics. PMID- 27514148 TI - Dentistry as an Endurance Sport. PMID- 27514149 TI - CDA Well-Being. PMID- 27514150 TI - Dental Problems. PMID- 27514151 TI - Mrs. Jellyby and the Hot Rock. PMID- 27514152 TI - The Oral Microbiome: Critical for Understanding Oral Health and Disease. PMID- 27514153 TI - Dental Calculus and the Evolution of the Human Oral Microbiome. AB - Characterizing the evolution of the oral microbiome is a challenging, but increasingly feasible, task. Recently, dental calculus has been shown to preserve ancient biomolecules from the oral microbiota, host tissues and diet for tens of thousands of years. As such, it provides a unique window into the ancestral oral microbiome. This article reviews recent advancements in ancient dental calculus research and emerging insights into the evolution and ecology of the human oral microbiome. PMID- 27514154 TI - Subgingival Microbiome Shifts and Community Dynamics in Periodontal Diseases. AB - High-throughput 16S rRNA gene sequencing has allowed the characterization of subgingival microbiome shifts from health to periodontitis identifying health associated, periodontitis-associated and core species, which preserve their proportions from health to disease. The development of gingivitis is also characterized by distinct shifts. Microbiome shifts resemble microbial successions and result from interspecies interactions and community adaptation to the changing environment as inflammation ensues. Gingivitis-associated and core species are proposed as likely mediators of microbiome transitions. PMID- 27514155 TI - Understanding Caries From the Oral Microbiome Perspective. AB - Dental caries is a major disease of the oral cavity with profound clinical significance. Caries results from a transition of a healthy oral microbiome into an acidogenic community of decreased microbial diversity in response to excessive dietary sugar intake. Microbiological cultivation, molecular identification, gene expression and metabolomic analyses show the importance of the entire microbial community in understanding the role of the microbiome in the pathology of caries. PMID- 27514156 TI - Uncultured Members of the Oral Microbiome. AB - Around one-third of oral bacteria cannot be cultured using conventional methods. Some bacteria have specific requirements for nutrients while others may be inhibited by substances in the culture media or produced by other bacteria. Oral bacteria have evolved as part of multispecies biofilms, and many thus require interaction with other bacterial species to grow. In vitro models have been developed that mimic these interactions and have been used to grow previously uncultivated organisms. PMID- 27514157 TI - Preservation of Property: A Critical Obligation. PMID- 27514158 TI - A Patient's Right to Access Records Q-and-A. PMID- 27514159 TI - Undertreatment, an Ethical Issue. PMID- 27514160 TI - A Dentist's Guide to Fitness. PMID- 27514161 TI - [COMPARISON OF LAPAROSCOPIC ASSISTED VAGINAL HYSTERECTOMY AND VAGINAL HYSTERECTOMY FOR BENIGN DISEASES AND LESIONS OF THE FEMALE GENITAL SYSTEM]. AB - OBJECTIVE: To compare the efficacy of laparoscopic assisted vaginal hysterectomy (LAVH) and vaginal hysterectomy (VH) carried out on the occasion of non-malignant diseases and lesions of the female genital system, by assessing the: operative time, price, blood loss, hospital stay, intra and postoperative complications, satisfaction of the patient. MATERIALS AND METHODS: The study included 187 women aged 38-71 years, with hysterectomy with or without salpingo-oophorectomy by LAVH 58 (31%) women or VH-129 (69%) women, on the occasion of non-malignant diseases and lesions of the female genital system. The patients are including in the study groups according to including and excluding criteria. Operation preparation, research and intra and postoperative follow-up of patients in both groups were the same. Standard, as performance is the surgical technique in both groups. The indicators are analyzed with the statistical program SPSS 10.1 for windows. Shi square test, Fisher exact test were used in appropriate cases. RESULTS: No significant difference between groups in terms of age (LAVH 48.7 +/- 3.2 years; VH 52.7 +/- 4.8 yrs), live births (1-3)/2 (1-2), total weight (62.6 kg/59 +/- 7.2 kg) weight of the uterus (227 +/-116.5/234 +/-: 68.3). Most often Indications for LAVH are: CIN/CA in situ coli uteri--16.1%; myoma uteri--22.5%; ovarian tumor- 15.5%, etc. Indications for VH: genital prolapse--53.5%; CIN/CA in situ--14.7%; recurrent endometrial polyp--14%, etc. Operative time: LAVH (126 +/- 18.2), VH (68 +/- 11.1), (p <= 0.05). Intraoperative blood loss: LAVH (16 +/- 7 average drop in hemoglobin Hb), VH (10 +/- 5 decline in Hb array) (p <= 0.05). We didn't find out significant differences between the patients of both groups in terms of hospital stay and satisfaction with the carried out operation. Intraoperative complications are more in the LAVH group and almos absence in VH group. Post operative complications occur without statistical differences (we exclude urinary infections) in both groups studied. CONCLUSIONS: In our study the VH showed better or equal results in the studied indicators in comparison with LAVH, therefore it is surgical intervention of choice compared to LAVH for removal of the uterus with or without the adnexa in non-malignant diseases and lesions of the female genital system. LAVH is the right choice in comparison with VH only in ovarian tumors and when we expected problems in women small pelvis. PMID- 27514162 TI - [LAPAROSCOPIC PELVIC LYMPNADENECTOMY OF EARLY ENDOMETRIAL CANCER]. AB - Lymphadenectomy has traditionally been performed using large incisions during laparotomy. Since the initial report by Dargent and colleagues in the late 1980s, laparoscopic lymphadenectomy has been utilized in the management of gynecologic malignancies. After Dargent's description of the first pelvic lymphadenectomy performed laparoscopically, Nezhat et al. described the first para-aortic lymphadenectomy performed laparoscopically forcancer of the uterine cervix. Many raports since have described the safety and effectiveness of laparoscopic lymphadenectomy for gynecologic malignancies. PMID- 27514163 TI - [OBESITY AND GYNECOLOGICAL CANCER]. AB - An analysis of 329 patients with gynecological cancer, 120 of them were without obesity and 209 of them were with obesity. Only 36.47% of the cases were with normal weight. There is a trend of increasing obesity with age, with a peak in the age group 60-69 years. The distribution of patients according to BMI and stage of the disease there is a downward trend in the obesity with increasing stage. In both groups of patients (with and without obesity), the volume and type of surgery were carried out depending on the type of tumor process (localization) and stage of the disease. Radical histerectomy with pelvic lymph node dissection (with or without omentectomy) is carried out in 141 patients, of which only 6 were of normal weight, and 135 patients (95.7%) were of different stage of obesity. Total hysterectomy with pelvic lymph node dissection (with or without omentectomy) is carried out in 123 patients, of which only 2 were of normal weight, and 121 patients (98.4%) were of different stage of obesity. Our results show that the volume of surgery in patients with gynecological cancer does not depend the obesity and depend the stage of disease. PMID- 27514164 TI - [PRIMARY CYTOREDUCTIVE SURGERY VERSUS NEOADJUVANT CHEMOTHERARY IN TREATMENT OF ADVANCED OVARIAN CANCER (STAGE III C-IV). OUR AND FOREIGN EXPERIENCE]. AB - INTRODUCTION: The advanced ovarian cancer usually have bad prognosis. The main methods for treatment of these types of tumors are: primary cytoreductive surgery and platin-based chemotherapy. AIM: Our aim was to evaluate our and foreign experience in treatment of advanced ovarian cancer stage III C--IV treated by neodjuvant chemotherapy followed by cytoreductive surgery and patients treated by primary cytoreductive surgery followed by adjuvant chemotherapy. We wanted to research the survival rate, postoperative adverse effects, mortality rate, the size of residual tumor and the metastases in these patients. MATERIAL AND METHODS: We researched for 10 years period--50 patients treated by primary cytoreductive surgery and 50 patients treated by neoadjuvant chemotherapy. RESULTS: The postoperative adverse effects and mortality rate are lower by neoadjuvant chemotherapy followed by cytoreductive surgery. The most important independent prognostic factor for overall survival rate was the lack of residual tumor in both types of treatment. CONCLUSION: The neoadjuvant chemotherapy followed by cytoreductive surgery in ovarian cancer stage III C--IV is considered as a standard treatment. PMID- 27514165 TI - [ADHERING TO MEDICAL STANDARTS, EVIDENCE-BASED STAGING IN GYNECOLOGICAL CANCER]. AB - Among the key factors that influence the survival of patients is adherence to medical treatment standards. Indicators are assessing the degree of adherence to medical standards and represent the relative shares (%) of patients who fulfilled the relevant aspect of any subject. Data from the BNCR of 9842 cases of patients with malignant diseases of the female reproductive diagnosed in 2011-2013 in Bulgaria has been analyzed. Patients with tumors of the vulva were incorrectly staged in 15% to 30% of the cases, and those with vaginal tumors were incorrectly staged in 20% to 23% of cases. In patients with malignant tumors of the cervix incorrect staging was established in 19% to 47% of the cases. Patients with tumors of the uterus were incorrectly staged in 6% to 26% of the cases. Among the patients with ovarian tumors were incorrectly staged in 18% to 43%. Our results show that one in three patients with gynecological cancer in Bulgaria was incorrectly staged. We recommend using the current TNM and FIGO systems. PMID- 27514166 TI - [RECONSTRUCTIVE AND COSMETIC SURGERY IN TREATMENT OF VULVAR CANCER]. AB - The aim of our research work was to show our results in the field of reconstructive and cosmetic surgery for vulvar cancer. MATERIAL AND METHODS: We evaluated 18 patients for 10 years period. RESULTS: We applied all surgical techniques that are possible at the moment in the world: laps from mons pubis, rhomboid flaps, myocutaneous flaps from gluteal region. We used surgical techniques with the following muscle groups: musculus gracilis, musculus gluteus maximus, musculus tensor fasciae latae, musculus rectus abdominis. CONCLUSIONS: With our research work we tried to better the quality of life of our patients, to achieve better esthetic and cosmetic effect after very radical surgical interventions connected with vulvar cancer. PMID- 27514167 TI - [COMORBIDITIES IN PATIENTS WITH ONCOGYNECOLOGICAL CANCER]. AB - Comorbidities may directly affect the prognosis of the disease of interest or may indirectly affect the prognosis by affecting the choice of treatment. The aim of this study is to determine comorbidities in pacients with gynecological cancer. The study included 100 consecutive pacients for the period 01.01.2014-08.-5.2014 in Gynecological department of Specialized Hospital for ActivTratament in Oncology. The most common disease are arterial hipertony diabetes and obesity. In most patients, establish one or more accompanying illnesses that increase with age. PMID- 27514168 TI - The role of laparoscopy in the case of suspected advanced ovarian cancer (ascites, CA-125)]. PMID- 27514169 TI - [A case of isolated massive presacral lymphatic metastasis in stage I uterine cervical cancer]. PMID- 27514170 TI - [Labial fusion in postmenopausal women--a clinical case]. AB - Labial fusion is benign genital disorder, which more frequent in children at 6 years old and less in women in reproductive and postmenopausal age. It can be congenital or acquired condition. Its etiology is unclear. The low serum estrogen concentration is the basic cause of labial fusion. As a result of physiological hypoestrogenism in the vulvar skin and mucosa come on atrophic changes, which together with the chronic inflammatory changes lead to labial adhesia with subsequent partial or total obstruction of the vagina and/or the urethra. The treatment can be conservative or surgical depending on the degree of labial fusion. We perform two clinical cases respectively of total and partial vulvarsynechiae in postmenopausal women. The clinical picture of the patient with total synechiae is represented by a difficult and prolonged micturition and urinary incontinence, while in patients with partial synechiae is represented by an inability to carry out sexual intercourse. PMID- 27514171 TI - Promises, promises. PMID- 27514172 TI - The future is bright. PMID- 27514173 TI - [Not Available]. PMID- 27514174 TI - REPLY FROM FINTAN HOURIHAN. PMID- 27514176 TI - Agenda setter. PMID- 27514175 TI - [Not Available]. PMID- 27514177 TI - Understanding your practice's costs. PMID- 27514178 TI - Establishing expectations. PMID- 27514179 TI - Baby steps: a systematic approach to the infant oral health visit. PMID- 27514180 TI - Clinical and radiographic assessment of maxillary canine eruption status in a group of 11- to 14-year-old Irish children. AB - OBJECTIVE: The aim of this study was to investigate the prevalence of potentially ectopic maxillary canines and associated dental features in a group of 11- to 14 year-old children. PARTICIPANTS: Examination took place of a normal dlistribution of Irish schoolchildren age between I11 and 14 years in order to record the number of subjects with indications for radiographic investigation of . potentially ectopic maxillary canines. METHODS: Those subjects identified subsequently underwent radiographic examination and the number of subjects with potentially ectopic maxillary canines was established. Correlations within the latter sub-sample with anomalous or missing laterals, type of occlusion and female:male ratio were investigated. RESULTS: A total of 480 children were screened. Of the children aged 11 to 14 years, 32 (6.6%) had clinical indications for radiographic examination of potentially ectopic maxillary canines according to the criteria that had been set out. There were 11 maxillary canines, in 10 subjects, that had an unfavourable position for eruption and were considered to be potentially ectopic, and so 1.1% of the maxillary canines reviewed in this study showed a potential ectopic eruption position. CONCLUSIONS: The prevalence of potentially ectopic maxillary canines and associated dental features in an Irish population was found to be similar to those in other countries, and the practice of careful supervision and early diagnosis of any eruption disturbances of the permanent maxillary canines continues to be considered important due to the risks associated with their eruption. PMID- 27514181 TI - Primary Ewing sarcoma of the coronoid process of mandible. AB - Ewing sarcoma (ES) is a rare, primary malignancy of the bone that occurs mainly in childhood and early adolescence. ES usually occurs in long bones of the axial skeleton. Although uncommon in the jaws, ES at this site is most likely to occur in the posterior mandible. The outcome for patients with localised disease has improved over the decades, due to better combination chemotherapies and better methods of local control. We present the clinicopathologic features and management of a case of ES that developed in the left coronoid process of the mandible of a 31-year-old male. Chemotherapy and, later, a segmental mandibulectomy were used to achieve local control. A fibula-free flap repair was performed with good aesthetic results. This case elucidates the importance of the interdisciplinary approach required for the evaluation and treatment of this aggressive neoplasm. PMID- 27514182 TI - More than a professional body. PMID- 27514183 TI - Evaluation of certain food additives and contaminants. Eightieth report of the Joint FAO/WHO Expert Committee on Food Additives. AB - This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food additives and contaminants and to prepare specifications for identity and purity. The first part of the report contains a brief description of general considerations addressed at the meeting, including updates on matters of interest to the work of the Committee. A summary follows of the Committee's evaluations of technical, toxicological and/or dietary exposure data for seven food additives (benzoates; lipase from Fusarium heterosporum expressed in Ogataea polymorpha; magnesium stearate; maltotetraohydrolase from Pseudomonas stutzeri expressed in Bacillus licheniformis; mixed beta-glucanase, cellulase and xylanase from Rasamsonia emersonii; mixed beta-glucanase and xylanase from Disporotrichum dimorphosporum; polyvinyl alcohol (PVA)- polyethylene glycol (PEG) graft copolymer) and two groups of contaminants (non-dioxin-like polychlorinated biphenyls and pyrrolizidine alkaloids). Specifications for the following food additives were revised or withdrawn: advantame; annatto extracts (solavnt extracted bixin, ad solvent-extracted norbixin); food additives containing aluminium and/or silicon (aluminium silicate; calcium aluminium silicate; calcium silicate; silicon dioxide, amorphous; sodium aluminium silicate); and glycerol ester of gum rosin. Annexed to the report are tables or text summarizing the toxicological and dietary exposure information and information on specifications as well as the Committees recommendations on the food additives and contaminants considered at this meeting. PMID- 27514184 TI - WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fiftieth report. AB - The Expert Committee on Specifications for Pharmaceutical Preparations works towards clear, independent and practical standards and guidelines for the quality assurance of medicines. Standards are developed by the Committee through worldwide consultation and an international consensus-building process. The following new guidelines were adopted and recommended for use. Good pharmacopoeial practices; FIP-WHO technical guidelines: points to consider in the provision by health-care professionals of children-specific preparations that are not available as authorized products; Guidance on good manufacturing practices for biological products; Guidance on good manufacturing practices: inspection report, including Appendix 1: Model inspection report; Guidance on good data and record management practices; Good trade and distribution practices for starting materials; Guidelines on the conduct of surveys of the quality of medicines; Collaborative procedure between the World Health Organization (WHO) prequalification team and national regulatory authorities in the assessment and accelerated national registration of WHO-prequalified pharmaceutical products and vaccines; Guidance for organizations performing in vivo bioequivalence studies; and World Health Organization (WHO) general guidance on variations to multisource pharmaceutical products. PMID- 27514185 TI - [Rheumatology: Progress in Diagnosis and Treatments. Editorial: Treatnnt for rheumatic diseases-present and future]. PMID- 27514186 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: I. Progress in Diagnostic Method; 1. Autoantibodies in systemic rheumatic diseases]. PMID- 27514187 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: I. Progress in Diagnostic Method; 2. Imaging in rheumatoid arthritis]. PMID- 27514188 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: II. Differential Diagnosis; 1. Clinical symptoms and physical findings which differentiate between rheumatoid arthritis and other diseases]. PMID- 27514189 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: II. Differential Diagnosis; 2. Differential diagnosis in rheumatic diseases based on laboratory and radiological findings]. PMID- 27514190 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: III. Rheumatiod Arthritis and Allied Conditions; 1. Rheumatoid arthritis]. PMID- 27514191 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: III. Rheumatoid Arthritis and Allied Conditions; 2. Allied Conditions, 1) Spondyloarthritis]. PMID- 27514192 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: III. Rheumatoid Arthritis and Allied Conditions; 2. Allied Conditions. 2) Polymyalgia rheumatica]. PMID- 27514193 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: III. Rheumatoid Arthritis and Allied Conditions; 2. Allied Conditions, 3) Adult Still disease]. PMID- 27514194 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: III. Rheumatoid Arthritis and Allied Conditions; 2. Allied Conditions, 4) RS3PE syndrome]. PMID- 27514195 TI - [Rheumatology: Progress in Diagnosis and Treatments Topics: IV. Collagen Diseases Except for Rheumatoid Arthritis and Hot Topics; 1. Systemic lupus erythematosus]. PMID- 27514196 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: IV. Collagen Diseases Except for Rheumatoid Arthritis and Hot Topics; 2. Antiphospholipid syndrome]. PMID- 27514197 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: IV. Collagen Diseases Except for Rheumatoid Arthritis and Hot Topics: 3. Systemic sclerosis (Scleroderma)]. PMID- 27514198 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: IV. Collagen Diseases Except for Rheumatoid Arthritis and Hot Topics; 4. Polymyositis and dermatomyositis]. PMID- 27514199 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: IV. Collagen Diseases Except for Rheumatoid Arthritis and Hot Topics; 5. Vasculitic syndrome]. PMID- 27514200 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: IV. Collagen Diseases Except for Rheumatoid Arthritis and Hot Topics; 6. Mixed connective tissue disease]. PMID- 27514201 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: IV. Collagen Diseases Except for Rheumatoid Arthritis and Hot Topics; 7. Sjogren's syndrome]. PMID- 27514202 TI - [Rheumatology: Progress in Diagnosis and Treatments. Topics: IV. Collagen Diseases Except for Rheumatoid Arthritis and Hot Topics; 8. IgG4-related disease]. PMID- 27514203 TI - [Discussion Meeting on Clinical update in rheumatic diseases]. PMID- 27514204 TI - [Discussion Meeting on "The Journal of the Japanese Society of Internal Medicine" by looking back on the past]. PMID- 27514205 TI - [Case Report; A case of nephrotic syndrome with Wilson's disease]. PMID- 27514206 TI - [Case Report; A case of adult human herpes virus-6 associated hemophagocytic syndrome with mixed connective tissue disease]. PMID- 27514207 TI - [Case Report; A case of rhabdomyolysis following water intoxication derived from both psychogenic polydipsia and syndrome of inappropriate secretion of antidiuretic hormone (SIADH)]. PMID- 27514208 TI - [Case Report; Primary central nervous system lymphoma mimicking progressive multifocal leukoencephalopathy in a patient with acquired immune deficiency syndrome]. PMID- 27514209 TI - [The Cutting-edge of Medicine; Severe fever with thrombocytopenia syndrome in Japan: challenges for the future]. PMID- 27514210 TI - [The Cutting-edge of Medicine; Rapidly progressive glomerulonephritis]. PMID- 27514211 TI - [The Cutting-edge of Medicine: Hereditary autoinflammatory diseases: diagnosis and management]. PMID- 27514212 TI - [Series: For Attending Physicians; Seeking to Understand the Diversity of Medicine; Complex health problems in primary care]. PMID- 27514213 TI - [How Does the Physician Interpret the Patient's Narrative as It Relates to the Physical Exam?; A case with obesity treated by low carbohydrate diet (LCD)]. PMID- 27514214 TI - [How Does the Physician Interpret the Patient's Narrative as It Relates to the Physical Exam?; A case of chronic constipation with abdominal pain]. PMID- 27514215 TI - Migrant nurses need more support. PMID- 27514216 TI - Emulating Emily Rushton's 'climate change journey'. PMID- 27514217 TI - Negotiating court systems. PMID- 27514218 TI - Correcting assertions. PMID- 27514219 TI - MSF seeks expect nurses. PMID- 27514220 TI - The president comments. PMID- 27514221 TI - Support for assisted dying. PMID- 27514222 TI - Equal pay settlement on the horizon? PMID- 27514223 TI - Vaccinate-or-mask policy 'coercive'. PMID- 27514224 TI - Nursing loses two of its pioneering spirits. PMID- 27514225 TI - A nursing journey from Keralas to Christchurch. PMID- 27514226 TI - Telling the truth about health underfunding. PMID- 27514227 TI - Nurse migration raises complex issues. PMID- 27514228 TI - COPD: obstructed lungs. AB - CHRONIC OBSTRUCTIVE pulmonary diseases (COPD) affect 14 per cent of the population over 40 years of age. With an ageing population, the number of those requiring care for COPD is expected to increase, having a significant effect on health-care resources. COPD is projected to become the third leading cause of death globally by 2020. This disease has a major impact on economic and social well-being, and on quality of life. It is regarded as largely preventable but, once developed, is a progressive and complex condition characterised by frequent exacerbations and co-morbidities. Smoking is the primary cause of COPD but up to 30 per cent of those with COPD have never smoked. It is increasingly recognised COPD may have its origins prenatally and in early childhood. Treating exacerbations, improving exercise capacity, and delaying progression of disease are key management strategies. No curative or disease modifying therapies are available. Nurses are essential in providing comprehensive care to patients in both acute care and for long-term management. They also have a vital role to play in preserving healthy lung function in the early years of life to reduce the risk of COPD in older age. PMID- 27514229 TI - Introducing ePortfolios into nursing schools. PMID- 27514230 TI - Developing a strategy to make nursing visible. PMID- 27514231 TI - NZNO pursues payroll problems. PMID- 27514232 TI - Regional conventions: Influencing health. PMID- 27514233 TI - Removing barriers to EN employment. PMID- 27514234 TI - Red Blood Cell Transfusion and Clinical Outcomes in Extremely Low Birth Weight Preterm Infants. AB - BACKGROUND: Red blood cell (RBC) transfusion is often considered a life-saving measure in critically ill neonates. The smallest and least mature infants tend to receive the largest amount of transfusions. RBC transfusion itself has also been suggested as an independent risk factor of poor clinical outcome in critical patients. Our aim is to study if there are associations between RBC transfusion and in-hospital mortality, short-term morbidities, and late neurodevelopmental outcome in extremely low birth weight (ELBW) preterm infants. METHODS: A cohort of ELBW preterm infants admitted to our neonatal intensive care unit from January 2009 to December 2010 were recruited. The number of RBC transfusions within 7 days, 30 days, and 60 days of life were recorded. Clinical outcomes including in hospital mortality, development of retinopathy of prematurity (ROP), necrotizing enterocolitis, chronic lung disease, and later neurodevelopmental outcome were assessed with follow-up of up to 2 years of age. Multivariable logistic regression was used to estimate the associations between RBC transfusion and clinical outcomes. RESULTS: A total of 98 ELBW preterm infants survived at the time of discharge. Of these survivors, the mean numbers of RBC transfusions were 2.5 +/- 1.7, 7.4 +/- 3.1, and 11.3 +/- 4.5 times within 7 days, 30 days, and 60 days after birth, respectively. The number of transfusions within 7 days of life was correlated with risk of death before 1 month of age (odds ratio: 1.54, 95% confidence interval: 1.04-2.27, p = 0.03) and the number of transfusions within 30 days was correlated with risk of developing threshold ROP (odds ratio: 1.27, 95% confidence interval: 1.04-1.55, p = 0.02). The number of transfusions within 7 days of life was positively correlated with cognitive performance (Mental Developmental Index score) at 18-24 months of corrected age. CONCLUSION: RBC transfusion has a negative impact on survival in ELBW infants. It increases the risk of developing ROP and affects late neurodevelopment. Decisions of blood transfusion in these very immature infants should be made cautiously taking these deleterious results into consideration. PMID- 27514235 TI - Piezoelectric and Dielectric Properties of Multilayered BaTiO3/(Ba,Ca)TiO3/CaTiO3 Thin Films. AB - Highly oriented multilayered BaTiO3-(Ba,Ca)TiO3-CaTiO3 thin films were fabricated on Nb-doped (001) SrTiO3 (Nb:STO) substrates by pulsed laser deposition. The configurations of multilayered BaTiO3-(Ba,Ca)TiO3-CaTiO3 thin films are designed with the thickness ratio of 1:1:1 and 2:1:1 and total thickness ~300 nm. Microstructural characterization by X-ray diffraction indicates that the as deposited thin films are highly c-axis oriented and large in-plane strain is determined in BaTiO3 and CaTiO3 layers. Piezoresponse force microscopy (PFM) studies reveal an intense in-plane polarization component, whereas the out-of plane shows inferior phase contrast. The optimized combination is found to be the BaTiO3-(Ba0.85Ca0.15)TiO3-CaTiO3 structure with combination ratio 2:1:1, which displays the largest domain switching amplitude under DC electric field, the largest room-temperature dielectric constant ~646, a small dielectric loss of 0.03, and the largest dielectric tunability of ~50% at 400 kV/cm. These results suggest that the enhanced dielectric and tunability performance are greatly associated with the large in-plane polarization component and domain switching. PMID- 27514236 TI - Depression screening for prescribed medications with mental health risk: Considerations for clinical decision support, workflow redesign, and health information exchange arrangements. AB - OBJECTIVE: Depression screening should be increased when prevailing knowledge underscoring medication-associated mental health risk is highest. Depression screening in primary care practices when medications with mental health risk were prescribed was estimated while considering the absence and presence of clinical decision support systems. MATERIALS AND METHODS: A cross-sectional, descriptive study using the National Ambulatory Medical Care Survey (NAMCS) data from 2008 to 2010 was conducted. Primary care physician visits were classified based on whether a medication prescribed had a contraindication, severe warning, moderate warning, adverse event only, or no documented mental health risk. Adjusted odds of depression screening for each risk warning level were estimated while controlling for important sociodemographic factors and presence of computerized systems for medication warnings and guideline recommendations. RESULTS: Depression screening at primary care practice visits when medications were prescribed was 2.1% and increased to 2.8% or higher when medications had a moderate or severe mental health risk warning or medication-disease contraindication. Depression screening was increased at visits when at least one medication was prescribed that had a contraindication (AOR = 6.31, P < 0.001), severe warning (AOR = 2.04, P = 0.003), or moderate warning (AOR = 2.50, P = 0.012) for mental health risk, but not for mental health adverse event only warnings alone (AOR = 1.54, P = 0.074). DISCUSSION: Depression screening is increased when medications were prescribed with a documented mental health risk. Presence of clinical decision support systems may help discern between minor and major medication-associated mental health risks. CONCLUSIONS: Appropriately, positioned warning systems with targeted content, workflow redesign, and health information exchange may improve depression screening in at-risk patients. PMID- 27514237 TI - Diagnostic immunohistochemistry through Rosai-coloured glasses. AB - Over the past three decades, Immunohistochemistry has materially changed the practice of diagnostic surgical pathology. Foundational observations in this field were critical to a reasoned assessment of both the risks and opportunities that immunohistochemistry afforded the surgical pathologist, and our current practice draws heavily on those early assessments. As we collectively look to and acknowledge those who recognized the value of this technique and who helped guide its development as a companion to (not a replacement for) histomorphologic evaluation, we are drawn to those whose mastery of detail and ability to draw common patterns from seemingly unrelated phenomena helped define the diagnostic power of immunohistochemistry. The focus of this review is on one individual, Dr. Juan Rosai, whose contributions transcend the simple linkage of molecular observations to morphology, recognizing novel patterns in both form and color (the latter often the lovely shades of diaminobenzidine), seemingly viewing our diagnostic world at times through an entirely different lens. By looking at Dr. Rosai's early work in this field, reviewing a selection of his seminal observations, particularly in the Immunohistochemistry of thyroid and thymic neoplasia, revisiting how his special insight is often guided by the work of the early masters of morphology, and how his mentorship of others has helped shaped academic surgical pathology practice, perhaps we can get a glimpse through that lens. PMID- 27514238 TI - Extending the Clinical Phenotype of Adenosine Deaminase 2 Deficiency. AB - Adenosine deaminase 2 deficiency is an autoinflammatory disease, characterized by various forms of vasculitis. We describe 5 patients with adenosine deaminase 2 deficiency with various hematologic manifestations, including pure red cell aplasia, with no evidence for vasculitis. PMID- 27514240 TI - Neonatal-Onset Urticaria and Fever. PMID- 27514239 TI - Antenatal Betamethasone: A Prolonged Time Interval from Administration to Delivery Is Associated with an Increased Incidence of Severe Intraventricular Hemorrhage in Infants Born before 28 Weeks Gestation. AB - OBJECTIVE: To examine the effects of antenatal steroids on severe intraventricular hemorrhage (IVH) in infants born during the IVH vulnerable period (<28 weeks gestational age) and to evaluate rates of IVH correlated with the time interval between treatment or retreatment and birth. STUDY DESIGN: A total of 429 infants (<28 weeks gestation), who delivered >=24 hours after the first betamethasone (BMZ) course (2 doses), were divided into groups based on the interval between the first course of BMZ and delivery: <10 days or >=10 days. The primary outcome was severe IVH. Multiple regression analyses were performed to adjust for potential confounders. RESULTS: Three hundred ninety-two infants delivered after a single BMZ course (312 delivered <10 days; 80 >=10 days). The incidence of severe IVH was 17% for infants delivered >=10 days and 7% for those delivered <10 days after a single BMZ course (aOR 4.16; 95% CI 1.59-10.87, P = .004); 37 infants (born >=10 days from the first BMZ course) received a second/rescue BMZ course. The incidence of severe IVH among infants receiving a second/rescue course was 8%, which was similar to the incidence among infants born <10 days (aOR 1.7; 95% CI 0.41-6.6, P = .48). CONCLUSIONS: In infants born before 28 weeks gestation, delivery >=10 days from the first BMZ course is associated with a higher incidence of severe IVH; a second/rescue course may reverse this effect. PMID- 27514241 TI - Molluscum Mimicker: Juvenile Xanthogranulomas with Associated Juvenile Myelomonocytic Leukemia. PMID- 27514242 TI - Botulinum Toxin Use in Refractory Pain and Other Symptoms in Parkinsonism. AB - BACKGROUND: Parkinson's disease (PD) and other parkinsonian syndromes are chronic, progressive neurodegenerative diseases. With advancing disease, both motor and non-motor symptoms represent a considerable burden and symptom relief and quality of life improvement become the main goal of treatment. Botulinum toxins (BTX) are an effective treatment modality for many neurological conditions. METHODS: To understand the potential usefulness of BTX in this population, we performed a retrospective chart review of all patients with a clinical diagnosis of idiopathic PD and atypical parkinsonism who received treatment with BTX injections in our center from 1995 to 2014 for a variety of symptoms. Response to BTX was assessed using a subjective Clinical Global Impression. RESULTS: Records of 160 patients were reviewed. Probable idiopathic PD was the diagnosis in 117 patients (73.1%). The main indication for BTX treatment was pain (50.6% of cases). Other indications were the treatment of functional impairment resulting from dystonia (26.25%), sialorrhea (18.75%), freezing of gait, and camptocormia. Considering pain as indication, 81% of all patients with PD reported benefits after the first BTX injections. This benefit was maintained after the last recorded visit without significant difference in outcome compared with the first injection (p=0.067). Similar results were observed in patients with atypical parkinsonism. CONCLUSIONS: Our results confirm the safety and efficacy of different uses of BTX in the symptomatic treatment of patients with parkinsonism even in advanced stages of the disease, and suggest BTX treatment could have a safe and useful role in the treatment of pain in this population. PMID- 27514243 TI - Effect of general health screening and lifestyle counselling on incidence of diabetes in general population: Inter99 randomised trial. AB - : We aimed to examine the effect of a large population-based multifactorial screening and lifestyle intervention programme on 10-year incidence of diabetes. In a randomised trial of the general Danish population initiated in 1999-2001 59,616 men and women aged 30-60years were assigned to a five year screening and lifestyle counselling programme (n=11,629) or control group (n=47,987) and followed for ten years in nationwide registers. Intention to treat was applied and risk of diabetes was modeled by Cox regression and expressed as hazard ratios (HRs). We found that 1692 individuals had diabetes at baseline. Among 57,924 individuals without diabetes at baseline, 1267 emigrated, 2593 died and 3369 (Intervention group=684, Control group=2685) developed diabetes. We saw no significant difference in diabetes incidence between the groups after 10-year follow-up (Grey's test: p=0.22). In the first year of follow-up, incidence of diabetes was significantly higher in the intervention group than the control group (HR=1.68, 95%CI 1.29 to 2.29). We observed no difference in incidence of diabetes between the groups in the follow-up intervals from 1 to 6years or after 6-10years (HR=0.94, 0.83 to 1.06; HR=1.03, 0.91 to 1.17). Inviting the general population to participate in a repeated screening and lifestyle counselling programme over five years did not result in lower incidence of diabetes after 10years of follow-up. As expected, significantly more individuals were diagnosed with diabetes in the intervention group during the first year, but this was not followed by a decrease in the following years. TRIALS REGISTRATION: Clinical trials NCT00289237. PMID- 27514244 TI - The role of food insecurity in developmental psychopathology. AB - Food security is a condition achieved when all members of a household have access to adequate food at all times for a healthy, active lifestyle. As of 2014, 14% of households in the United States were food insecure. Previous research has suggested that household food insecurity is associated with numerous adverse medical and psychosocial outcomes across the lifespan. In this narrative review, we examine current research on food insecurity, specifically as it relates to child psychopathology and risk factors thereof: namely, parental mental illness and poor diet and metabolic health. Moreover, we begin to speculate about behavioral and physiological mechanisms by which these conditions may influence one another, and discuss possible interventions through enhanced screening and treatment, parent training, and provision of high quality foods to vulnerable households. Further research is needed to the effects of child and parental mental health on metabolic outcomes in families with food insecurity. PMID- 27514245 TI - Diet quality, risk factors and access to care among low-income uninsured American adults in states expanding Medicaid vs. states not expanding under the affordable care act. AB - BACKGROUND: The Affordable Care Act (ACA) Medicaid expansion varies in availability across states. PURPOSE: We compared characteristics of low-income uninsured residents in both Medicaid nonexpanding and expanding states with respect to their dietary quality, health risk factors, and access to care. METHODS: Data from the 2007-2012 National Health and Nutrition Examination Survey was matched with the Kaiser Family Foundation Medicaid expansion data. Bivariate and multivariate regressions were estimated to assess differences across expanding and non-expanding states. RESULT: The non-expansion group had a lower Healthy Eating Index score (41.8 vs. 44.1, p-value=0.006), a higher Body Mass Index (29.9 vs. 28.9, p-value=0.032), higher obesity prevalence (41% vs. 33%, p value=0.007), and lower asthma prevalence (14.8% vs. 19.7%, p-value=0.037) compared with the expansion group. CONCLUSIONS: Differences across states in Medicaid coverage under the ACA may lead to widening disparities in health outcomes between expanding and non-expanding states. PMID- 27514246 TI - Training fast or slow? Exercise for depression: A randomized controlled trial. AB - Exercise can be used to treat depression but there is a lack of evidence regarding the optimal intensity and mode. Our aim was to compare the effects of different exercise intensities on post-treatment depression severity. People aged 18-67years with mild to moderate depression (Patient Health Questionnaire-9 score of >=10) participated in a single-blind, parallel randomized control trial lasting 12-weeks (Sweden 2011-2013). Four treatment arms were included: treatment as usual (TAU) (n=310), light exercise (yoga or similar n=106), moderate exercise (aerobic conditioning, n=105) and vigorous exercise (aerobic conditioning, n=99). Depression severity was measured at baseline and post-treatment using the Montgomery-Asberg Depression Rating Scale (MADRS). Differences between the groups in depression severity at post-treatment were analysed using linear regression. Differences in exercise intensity were confirmed by heart rate monitoring. At post-treatment, the light (-4.05 Confidence Interval (CI)=-5.94, -2.17), moderate (-2.08 CI=-3.98, -0.18) and vigorous exercise groups (-3.13 CI=-5.07, -1.19) had reduced their MADRS scores significantly more than TAU. No significant differences were found between the exercise groups, and no significant interaction effect was observed between group and gender. In conclusion, exercise, whether performed at a low (yoga or similar), moderate or vigorous intensity (aerobic training) is effective in treating mild to moderate depression and is at least as effective as treatment as usual by a physician. PMID- 27514247 TI - Regular family breakfast was associated with children's overweight and parental education: Results from the ENERGY cross-sectional study. AB - INTRODUCTION: This study aims to assess (i) the prevalence of having regular family breakfast, lunch, dinner (i.e. 5-7days/week together with their family) among 10-12year olds in Europe, (ii) the association between family meals and child weight status, and (iii) potential differences in having family meals according to country of residence, gender, ethnicity and parental levels of education. METHODS: 7716 children (mean age: 11.5+/-0.7years, 52% girls) in eight European countries (Belgium, Greece, Hungary, The Netherlands, Norway, Slovenia, Spain, Switzerland) participated in a cross-sectional school-based survey in 2010. Data on family meals were self-reported by the parents and children's height and weight were objectively measured to determine overweight status. Binary regression analyses assessed the associations of having regular family meals (adjusted for potential confounders) with children's overweight/obesity and to assess potential differences in having family meals according to gender, ethnicity and parental education, in the total sample and for each country respectively. RESULTS: The prevalence of regular family meals was 35%, 37% and 76% for breakfast, lunch and dinner respectively. Having regular family breakfast, but not lunch or dinner, was inversely associated with overweight (OR=0.78 (95% CI 0.67-0.91)). Children of higher educated parents were more likely to have regular family breakfast (1.63 (95% CI 1.42-1.86)) and less likely to have regular family lunch (0.72 (95% CI 0.63-0.82)) compared to children of lower educated parents. CONCLUSION: This study showed that having regular family breakfast - but not other family meals- was inversely associated with children's weight status. PMID- 27514248 TI - Increasing reach by offering choices: Results from an innovative model for statewide services for smoking cessation. AB - Although state quitlines provide free telephone counseling and often include nicotine replacement therapy (NRT), reach remains limited (1-2% in most states). More needs to be done to engage all smokers in the quitting process. A possible strategy is to offer choices of cessation services through quitlines and to reduce registration barriers. In March 2014, ClearWay MinnesotaSM implemented a new model for QUITPLAN(r) Services, the state's population-wide cessation services. Tobacco users could choose the QUITPLAN(r) Helpline or one or more Individual QUITPLAN(r) Services (NRT starter kit, text messaging, email program, or quit guide). The program website was redesigned, online enrollment was added, and a new advertising campaign was created and launched. In 2014-2015, we evaluated whether these changes increased reach. We also assessed quit attempts, quit outcomes, predictors of 30-day abstinence, and average cost per quit via a seven-month follow-up survey. Between March 2014-February 2015, 15,861 unique tobacco users registered, which was a 169% increase over calendar year 2013. The majority of participants made a quit attempt (83.7%). Thirty-day point prevalence abstinence rates (responder rates) were 26.1% for QUITPLAN Services overall, 29.6% for the QUITPLAN Helpline, and 25.5% for Individual QUITPLAN Services. Several variables predicted quit outcomes, including receiving only one call from the Helpline and using both the Helpline and the NRT starter kit. Providing greater choice of cessation services and reducing registration barriers have the potential to engage more tobacco users, foster more quit attempts, and ultimately lead to long-term cessation and reductions in prevalence. PMID- 27514249 TI - Risk factors for late-life depression: A prospective cohort study among older women. AB - Depression prevention requires identifying key risk contributors. Prior studies have identified several factors related to late-life depression but have seldom addressed factors jointly or in dose-response fashion. This study aimed to examine a wide range of potential predisposing factors and to estimate individual and joint contributions to risk of late-life depression in women. A total of 21,728 women aged >=65years, without prior depression, in the Nurses' Health Study conducted in the United States were followed from 2000 to 2010. Demographic, social, lifestyle/behavioral and health variables were selected a priori from the literature or previous findings in this cohort. Depression was defined as physician/clinician-diagnosed depression, regular antidepressant use, or the presence of severe depressive symptoms. During 10-year follow-up, 3945 incident cases were identified. After simultaneous multivariable-adjustment, multiple factors in the domains of social stress (lower self-rated societal position and high volume of caregiving to disabled/ill relatives), unfavorable lifestyle (smoking, physical inactivity, heavy or binge drinking), and poor physical health (multiple comorbidity burden, excessive sleep, difficulty falling/staying asleep, bodily pain, and physical/functional limitation or disability) were significantly associated with higher depression risk; many featured dose-response relationships. Sensitivity analyses that excluded outcomes within 2years yielded similar estimates. The total population attributable fraction for all factors was 55.5%. Physical/functional limitation accounted for one-quarter of population attributable fraction, followed by problematic sleep, inadequate exercise, and pain (combining for one-third of population attributable fraction). Efforts to remediate or prevent these factors may contribute to an efficient strategy for late-life depression prevention in women. PMID- 27514251 TI - Health-related quality of life of patients on antiretroviral treatment in Botswana: A cross-sectional study. AB - OBJECTIVE: Antiretroviral therapy (ART) affords longevity to patients infected with the human immune deficiency virus (HIV). Since little is known about the health-related quality of life (HRQoL) of persons who have been on ART for at least five years, the present study investigated the HRQoL of these patients in Botswana. METHOD: Medical records, structured interviews, and the World Health Organization Quality of Life-BREF (WHOQoL-HIV-BREF) instrument were employed to obtain information from 456 respondents. RESULTS: Univariate and multivariate regression analyses showed that respondents' highest scores were in the "physical" domain (mean = 15.8, SD = 3.5), while the lowest scores were in the "environment" domain (mean = 12.9, SD = 2.5). Thus, the physical domain had the greatest impact on patients' overall HRQoL. Self-education about HIV-related issues was significantly correlated with all domains of HRQoL scores: physical (rho = -2.32, CI 95% = -3.02, -1.61); psychological (rho = -2.26, CI 95% = -2.87, -1.65); independence (rho = -1.81, CI 95% = -2.54, -1.06); social relationships (rho = -1.40, CI 95% = -2.13, -0.67); environment (rho = -1.58, CI 95% = -2.13, 1.04); and spirituality (rho = -1.70, CI 95% = -82.27, -1.13). SIGNIFICANCE OF RESULTS: HRQoL assessments can identify and address patients' needs, and it is important that guidelines be developed that will yield improved care to ART patients in Botswana. PMID- 27514252 TI - Immunotherapeutic strategies for sexually transmitted viral infections: HIV, HSV and HPV. AB - More than 1 million sexually transmitted infections (STIs) are acquired each day globally. Etiotropic drugs cannot effectively control infectious diseases therefore, there is a dire need to explore alternative strategies especially those based on the regulation of immune system. The review discusses all rational approaches to develop better understanding towards immunotherapeutic strategies based on modulation of immune system in an attempt to curb the elevating risk of infectious diseases such as HIV, HPV and HSV because of their high prevalence. Development of monoclonal antibodies, vaccines and several other immune based treatments are promising alternative strategies that are offering new opportunities to eradicate pathogens. PMID- 27514250 TI - A review of the literature on contingency management in the treatment of substance use disorders, 2009-2014. AB - This report describes a systematic literature review of voucher and related monetary-based contingency management (CM) interventions for substance use disorders (SUDs) over 5.2years (November 2009 through December 2014). Reports were identified using the search engine PubMed, expert consultations, and published bibliographies. For inclusion, reports had to (a) involve monetary based CM; (b) appear in a peer-reviewed journal; (c) include an experimental comparison condition; (d) describe an original study; (e) assess efficacy using inferential statistics; (f) use a research design allowing treatment effects to be attributed to CM. Sixty-nine reports met inclusion criteria and were categorized into 7 research trends: (1) extending CM to special populations, (2) parametric studies, (3) extending CM to community clinics, (4) combining CM with pharmacotherapies, (5) incorporating technology into CM, (6) investigating longer term outcomes, (7) using CM as a research tool. The vast majority (59/69, 86%) of studies reported significant (p<0.05) during-treatment effects. Twenty-eight (28/59, 47%) of those studies included at least one follow-up visit after CM was discontinued, with eight (8/28, 29%) reporting significant (p<0.05) effects. Average effect size (Cohen's d) during treatment was 0.62 (95% CI: 0.54, 0.70) and post-treatment it was 0.26 (95% CI: 0.11, 0.41). Overall, the literature on voucher-based CM over the past 5years documents sustained growth, high treatment efficacy, moderate to large effect sizes during treatment that weaken but remain evident following treatment termination, and breadth across a diverse set of SUDs, populations, and settings consistent with and extending results from prior reviews. PMID- 27514253 TI - [Investigation of indium exposure in workers in indium smelting plant]. AB - OBJECTIVE: To investigate the internal and external exposure levels of indium (In)in workers in an In smelting plant, and to analyze its distribution characteristics. METHODS: A survey was performed in 63 employed workers with more than one year of experience working in an In smelting plant in 2014. The personal air samples for 31 workers were collected, and the whole blood, serum, and urine samples of all the 63 workers were collected to do the occupational health examination at the same time. In levels in all samples were determined by inductively coupled plasma mass spectrometry. RESULTS: The smelter workers had a higher In exposure level in the air than the office workers (2.26 MUg/m(3) vs 0.82 MUg/m(3), P>0.05). There was a significant difference in In exposure level in the air between the workers doing different types of jobs (P<0.05). The In exposure levels in the air in the metathesis workers and electrolysis workers were 26.10 MUg/m(3) and 20.99 MUg/m(3), respectively, which were significantly higher than those in other workers (P<0.05). The smelter workers had significantly higher geometric means of In levels in the whole blood, serum, and urine than the office workers (0.44 MUg/L vs 0.09 MUg/L, P<0.05; 0.35 MUg/L vs 0.09 MUg/L, P<0.05; 0.26 MUg/L vs 0.12 MUg/L, P<0.05). There were significant differences in In levels in the whole blood, serum, and urine between the workers doing different types of jobs (P<0.05). The metathesis workers (13.0 MUg/L, 4.02 MUg/L, and 2.93 MUg/L)and electrolysis workers (5.71 MUg/L, 5.14 MUg/L, and 4.26 MUg/L)had higher In levels in the whole blood, serum, and urine than other workers. The In level in the whole blood was positively correlated with the In levels in the urine and serum (rs=0.601, P<0.05; rs=0.823, P<0.05). The In levels in the whole blood and urine were positively correlated with the In level in the air(rs=0.483, P<0.05; rs=0.428, P<0.05). CONCLUSION: In the In smelting plant, the In concentrations in the air are lower than the standard value, but the workers have higher In levels in body. The In level in the whole blood is positively correlated with the In levels in the serum and urine. The In levels in the whole blood and urine are positively correlated with the In level in the air. PMID- 27514254 TI - [Effects of job content on psychological stress in young recruits]. AB - OBJECTIVE: To explore the effects of job content on psychological stress in young recruits. METHODS: In October 2014, 625 young recruits enrolled in one troop of Xinjiang Military Command in 2014 were chosen as subjects by multi-stage stratified random sampling. The Chinese version of the job content questionnaire (JCQ)and the psychological stress self evaluation test (PEST)were used to investigate the subjects. The subjects were divided into two groups with scores higher and lower than the mean score of three subscales (job requirement, degree of autonomy, and social support)of JCQ to explore the effects of job content on psychological stress in young recruits. The correlation of psychological stress with three subscales of job content was evaluated using the Pearson' s correlation analysis. Binary logistic regression analysis was used to analyze the influencing factors for psychological stress. RESULTS: The PEST score of young recruits was 49.98+/-9.98. Forty-five (7.68%)out of them had scores of >=70 points and were diagnosed with high levels of psychological stress. When the subjects were grouped based on socio-demographic characteristics, a high level of psychological stress was significantly more frequent in subjects less than 20 years of age than in those not less than 20 years of age, in smoking subjects than in non-smoking subjects, and in urban residents than in rural residents (10.42% vs 5.03%, P<0.05; 10.14% vs 5.33%, P<0.05; 10.85% vs 5.88% , P <0.05). There were no significant differences in educational level or identity before recruitment between subjects with different levels of psychological stress (P>0.05). In various job content domains that had impacts on psychological stress, subjects with a low score of social support had significantly higher PEST scores than those with a high score of social support (50.96+/-10.35 vs 48.49+/ 9.22, P<0.01). The PEST score was negatively correlated with the degree of autonomy and social support (r=-0.103, P<0.05; r=-0.239, P<0.05). The results of logistic regression analysis showed that job requirement and social support were influencing factors for psychological stress (OR=0.718, 95% CI= 0.718 (0.607~0.851), P<0.05; OR=1.185, 95% CI=1.185 (1.087~1.292), P<0.05). CONCLUSION: Psychological stress of young recruits in army is not optimistic. Psychological stress is weakly negatively correlated with social support. The low scores on job requirement subscale and social support subscale may be potential protective factor and risk factor for psychological stress, respectively. PMID- 27514255 TI - [Changes in levels of human nutritious metabolites after exposure to abnormal acceleration of sea state]. AB - OBJECTIVE: To investigate the changes in the levels of human blood nutritious metabolites and its major regulating factors after exposure to abnormal acceleration of sea state, and to provide clues for further investigating the mechanism of fatigue due to maritime operations. METHODS: Using randomly sampling method, 60 healthy male adults from one troop were selected as the subjects on April 20, 2010. All subjects were exposed to six degrees of freedom motion simulator ship for 15 min. Their blood samples were collected before and after exposure to abnormal acceleration immediately. The metabolomic technology was used to measure the levels of nutritious metabolites in the serum. Enzyme - linked immunosorbent assay or radioimmunoassay was used to measure the levels of glucocorticoids, adrenaline, insulin, glucagon, ghrelin, resistin, leptin, and gastric inhibitory peptide. RESULTS: After exposure to abnormal acceleration, the subjects showed significant decreases in the levels of serum essential amino acids, such as L-lysine[(23.63+/-8.24)*10(6) vs(32.83+/-13.58)*10(6), P<0.05], L methionine[(4.16+/-1.12)*10(6) vs(5.80+/-1.69)*10(6), P<0.05], and L tryptophan[(29.38+/-8.56)*10(6) vs (35.93+/-11.82)*10(6), P<0.05], and the levels of some non-essential amino acids, such as L-histidine[(1.69+/-0.55)*10(6) vs(2.16+/-0.92)*10(6), P<0.05] and 4-hydroxy- L-proline[(3.21+/-1.50)* 10(6) vs (7.92+/-4.79)*10(6), P<0.05]. After exposure to abnormal acceleration, the subjects had significant increases in the levels of serum carbohydrate metabolites, such as glucose[(2412.40+/-700.36)*10(6) vs(1939.30+/-554.33)*10(6), P< 0.05] and pyruvic acid[(9.97+/-5.96)*10(6) vs(2.43+/-1.34)*10(6), P<0.05], and the levels of fat metabolites, such as beta-hydroxybutyric acid[(37.47+/ 60.21)*10(6) vs(10.29+/-20.64)*10(6), P<0.05], oleic acid[(31.94+/-30.39)*10(6) vs (15.94+/-10.37)*10(6), P<0.05], and linoleic acid[(26.19+/-19.16)* 10(6) vs (13.58+/-6.29)* 10(6), P<0.05]. After exposure to abnormal acceleration, the subjects had significant increases in the levels of serum glucocorticoids [(743.63+/-129.06)nmol/L vs (539.66+/-155.58)nmol/L, P<0.05], adrenaline[(725.04+/-367.08)pmol/L vs (482.58+/-194.97)pmol/L, P<0.05], glucagon[(5.85+/-1.57)pmol/L vs(5.18+/-1.64)pmol/L, P<0.05], and ghrelin[(62.55+/ 32.34)pmol/L vs (40.47+/-22.18)pmol/L, P<0.05], and decreases in the levels of serum insulin[(107.41+/-21.09)pmol/L vs(150.89+/-48.65)pmol/L, P<0.05], gastric inhibitory peptide[(41.05+/-17.91)pmol/L vs(170.34+/-82.64) pmol/L, P<0.05], leptin[(25.62+/-21.75)nmol/L vs (46.50+/-27.40)nmol/L, P<0.05], and resistin[(209.24+/-107.65)nmol/L vs (535.04+/-263.13)nmol/L, P<0.05]. CONCLUSION: After exposure to abnormal acceleration of sea state, the levels of serum nutritious metabolites show significant changes and the levels of fatigue associated products, such as serum pyruvic acid, increase significantly, which may be related to induced stress response and changes in the levels of metabolic regulators. PMID- 27514256 TI - [Association between serum aluminium level and methylation of amyloid precursor protein gene in workers engaged in aluminium electrolysis]. AB - OBJECTIVE: To investigate the association between serum aluminium level and methylation of the promoter region of amyloid precursor protein (APP)gene in workers engaged in aluminium electrolysis. METHODS: In 2012, 366 electrolysis workers in an aluminium factory were enrolled as exposure group (working years >10 and age >40 years)and divided into low-exposure group and high-exposure group based on the median serum aluminium level. Meanwhile, 102 workers in a cement plant not exposed to aluminium were enrolled as control group. Graphite furnace atomic absorption spectrometry was used to measure serum aluminium level, methylation specific PCR was used to measure the methylation rate of the promoter region of APP gene, and ELI-SA was used to measure the protein expression of APP in lymphocytes in peripheral blood. RESULTS: The exposure group had a significantly higher serum aluminium level than the control group (45.07 MUg/L vs 30.51 MUg/L, P< 0.01). The exposure group had a significantly lower methylation rate of the promoter region of APP gene than the control group (18.85% vs 25.49%, P=0.025), and the high-exposure group had a significantly lower methylation rate of the promoter region of APP gene than the low-exposure group (15.84% vs 21.85%, P<0.05). The exposure group had a significantly higher protein expression of APP in lymphocytes in peripheral blood than the control group (66.73 ng/ml vs 54.17 ng/ml, P<0.05); compared with the low-exposure group (65.39 ng/ml), the high exposure group showed an increase in the protein expression of APP in lymphocytes in peripheral blood (67.22 ng/ml), but there was no significant difference between these two groups (P>0.05). The multivariate logistic regression analysis showed that with reference to the control group, low aluminium exposure (OR=1.86, 95% CI 1.67~3.52)and high aluminium exposure (OR=2.98, 95% CI 1.97~4.15)were risk factors for a reduced methylation rate of the promoter region of APP gene. CONCLUSION: Reduced methylation of the promoter region of APP gene may be associated with increased serum aluminium level, and downregulated methylation of the promoter region of APP gene may accelerate APP gene transcription. PMID- 27514257 TI - [Metabolic syndrome and its influencing factors in professional automobile drivers in a company]. AB - OBJECTIVE: To investigate the prevalence of metabolic syndrome (MS)in 259 professional automobile drivers, and to put forward targeted suggestions on protection. METHODS: In October 2014, 114 male bus drivers and 145 male taxi drivers in a transportation service company were enrolled as investigation group, and 121 non-operating male staff were enrolled as control group. Physical examination and a questionnaire survey were conducted for both groups, and the results were analyzed. RESULTS: The bus drivers and taxi drivers had significantly higher prevalence rates of MS than the nonoperating staff(17.5%/13.1% vs 3.3%, P<0.05). The results of univariate logistic analysis showed that smoking(OR=2.58, 95%CI 1.14~5.88), exercise (OR=0.21, 95% CI 0.10~0.43), meal time (OR=0.27, 95% CI 0.13~0.59), and a family history of chronic diseases (OR=2.26, 95% CI 1.13~4.50)were associated with MS, and each independent variable showed significant differences between groups (P<0.05). Multivariate logistic regression analysis showed that with age remaining the same, smoking was the risk factor for MS in professional automobile drivers (OR=5.25, 95%CI 2.00~13.80), and meal time (20~40 min)(OR= 0.20, 95%CI 0.09~0.44)and exercise (OR=0.13, 95% CI 0.06~0.30)were protective factors against MS. CONCLUSION: Professional automobile drivers have a higher prevalence rate of MS than non-operating staff, which should be taken seriously by working personnel. PMID- 27514258 TI - [Association between psychosocial work environment and workplace bullying among office workers]. AB - OBJECTIVE: To assess the prevalence of bullying in companies and health care center and identify the association between psychosocial environment and workplace bullying. METHODS: A total of 847 employees at in business building companies and 146 employees at one community health service center were invited to this survey by cluster sampling during October to December 2014, using anonymous questionnaires including the general demographic information, job characteristics, job stress core scale, the social capital scale, and NAQ-R. RESULTS: The rate of targets of bullying in the two kinds of workplaces were 13.1% and 5.6% respectively. Workplace bullying was associated with employee's education level(chi(2)=11.17, P=0.019)and the area his or her families live in(chi(2)=5.66, P=0.017). In addition, workplace bullying was significantly associated with psychosocial work environment. Job demand was positively correlated with workplace bullying (OR=2.24, 95% CI=1.34~3.74), and workplace social support was negatively associated with workplace bullying (OR= 0.33, 95% CI=0.18~0.60). CONCLUSION: Workplace bullying can be reduced by adjusting certain working conditions that negatively affect employees who are susceptible to being bullied, giving their individual and job characteristic. Moreover, workplace bullying could also be reduced if job demands are limited and job control and social capital are increased. PMID- 27514259 TI - [KAP research and intervention effects of health education on prevention and control of occupational diseases in occupational groups in Jinzhou, China]. AB - OBJECTIVE: To investigate the current status of knowledge, attitude, and practice (KAP)on the prevention and control of occupational diseases in occupational groups in Jinzhou, China, and to evaluate the intervention effects of health education. METHODS: Using the cluster random sampling method, 1000 workers who underwent occupational health examination in Jinzhou Center for Disease Control and Prevention from September 2014 to April 2015 were enrolled in this study. They were equally and randomly divided into intervention group and control group. The intervention group received health education for 6 months through bulletin board, promotion materials, expert lecture, Q&A session, and other relevant educational events. The questionnaire survey was performed before and after intervention. The control group received the questionnaire survey but not the health education. RESULTS: The overall awareness rate of prevention and control knowledge was 75.34% in 990 workers in Jinzhou, China. After the intervention, the intervention group had a significantly higher awareness rate of prevention and control knowledge than the control group (89.87%~98.86% vs 71.25%~80.82%, P<0.05); the intervention group had a significantly higher attitude accuracy for" whether occupational health examination is necessary or not" and " is willing to received the training on occupational health knowledge" than the control group(chi(2)=57.857, P<0.05; chi(2)=70.683, P<0.05); and the intervention group had a significantly higher rate of correct behavior for" whether help the business management personnel to carry out the prevention and control of occupational diseases or not" and"whether actively understand the occupational hazards of job" (chi(2)=102.186, P<0.05; chi(2)=91.159, P<0.05). CONCLUSION: Health education can significantly increase the awareness rate of prevention and control knowledge on occupational diseases in occupational groups in Jinzhou, China. However, the more structured and longterm comprehensive intervention is necessary for improving their attitude and behavior. PMID- 27514260 TI - [Influencing factors for the use of earplugs in workers exposed to noise in a city]. AB - OBJECTIVE: To investigate the current status of hearing loss and the use of earplugs in workers exposed to noise who have been provided earplugs in a city, as well as major influencing factors for the use of earplugs. METHODS: Cluster random sampling was used to conduct a questionnaire survey in workers exposed to noise who had been provided earplugs in 15 enterprises with noise exposure in a city from June to December, 2014. RESULTS: In the workers exposed to noise who had been provided earplugs, the rate of high-frequency anomaly in both ears was 57.8%, and the workers who kept wearing earplugs only accounted for 55.4%. The results of binary logistic regression analysis showed that the protective factors for the use of earplugs included workers' own feeling of hearing condition (OR=1.704), comfort of earplugs (OR= 1.892), enterprise's inspection of the use of earplugs (OR=1.461), workers' knowledge of the function and usage of earplugs (OR=1.581), workers' understanding of the necessity of earplugs (OR=4.482), workers' initiative to search for related data (OR=4.029), the use of earplugs by colleagues (OR=5.071), and reminders from family members or friends (OR=2.678) (all P<0.05). CONCLUSION: The workers exposed to noise in this city have a high rate of abnormal hearing, and only half of the workers keep wearing earplugs during work. The use of earplugs is related to the factors including workers' own feeling of hearing condition, comfort of earplugs, workers' knowledge of protection, the enterprise' s management of hearing protection, and environmental support. PMID- 27514261 TI - [Chromosome aberration and micronucleus frequency in peripheral blood lymphocytes in radiation workers]. AB - OBJECTIVE: To investigate chromosome aberration and micronucleus frequency in peripheral blood lymphocytes in workers engaged in radiation for a long time, to reduce occupational hazard caused by ionizing radiation, and to further strengthen health surveillance. METHODS: A total of 366 members of medical staff engaged in radiation work who underwent physical examinations in Hangzhou Hospital of Prevention and Treatment of Occupation Diseases from 2014 to 2015 were enrolled as radiation group, consisting of staff engaged in X-ray diagnosis, diagnostic radiology, radiotherapy, and interventional radiology. Another 100 members of medical staff without exposure to radiation were enrolled as control group. Whole blood culture was used to measure chromosome aberration and micronucleus frequency in peripheral blood lymphocytes. RESULTS: The radiation group had a significantly higher rate of chromosome aberration than the control group (0.30% vs 0.09% , chi(2)= 13.43, P<0.01), as well as a significantly higher micronucleus frequency than the control group (2.090/00 vs 0.080/00, chi(2)=74.4, P<0.01). The abnormal rates of chromosome aberration and micronucleus showed no significant differences across radiation workers with different working years (P>0.05). The staff engaged in X-ray diagnosis, diagnostic radiology, radiotherapy, and interventional radiology had rates of chromosome aberration of 0.25%, 0.25%, 0.23%, and 0.41%, respectively, which showed a significant difference between the staff at these four posts (chi(2)=8.22, P<0.05); the micronucleus frequencies in the staff at these four posts were 1.360/00, 1.280/00, 1.140/00, and 3.790/00, respectively, and showed a significant difference between the staff at these four posts (chi(2)=251.09, P<0.01). CONCLUSION: Radiation workers are exposed to lowdose ionizing radiation for a long time, which may cause significant increases in the rate of chromosome aberration and micronucleus frequency in peripheral blood lymphocytes. PMID- 27514262 TI - [Field investigation of occupational disease diagnosis in Guangdong Provincial Hospital for Occupational Disease Prevention and Treatment from 2009 to 2014: an analysis of 136 cases]. AB - OBJECTIVE: To investigate the characteristics of 136 patients with occupational diseases, to summarize key techniques used in field investigation, and to provide a scientific basis for the development of standard operating procedures for field investigation of occupational disease diagnosis. METHODS: Field investigation and routine data analysis were performed to analyze the cases diagnosed by Guangdong Provincial Hospital for Occupational Disease Prevention and Treatment from January 2009 to December 2014. RESULTS: A total of 136 cases of occupational diseases were diagnosed by Guangdong Provincial Hospital for Occupational Disease Prevention and Treatment from 2009 to 2014, and there were 66 cases of leukemia, 18 cases of suspected occupational benzene poisoning, 12 cases of suspected occupational handarm vibration disease, and 11 cases of suspected pneumoconiosis. Of all these patients, 41.91% were engaged in at least three types of work, 70.59% were exposed to at least three types of chemicals, 25.74% experienced changes in technical processes and chemicals, and 47.06% had disputes on the chemicals they were exposed to during verification by both parties. Occupational hazard factors were detected. Most samples (358)were used to measure benzene concentration in workplace air, among which 11.7% had a benzene concentration of >6.00 mg/m(3)(exceeding standard), 13.41% had a benzene concentration of 3.26~6.00 mg/m(3), 75.42% had a benzene concentration of<0.03 to <3.25 mg/m(3). The samples of suspected occupational hand-arm vibration disease, suspected pneumoconiosis, and suspected occupational noiseinduced hearing loss had high overstandard rates (100%, 93.8%, and 83.3%, respectively). CONCLUSION: Field investigation of occupational disease diagnosis reveals large numbers of cases of leukemia, suspected occupational benzene poisoning, suspected occupational hand arm vibration disease, and suspected pneumoconiosis. The key aspects of field investigation include confirmation of the history of occupational exposure, identification of occupational hazard factors, confirmation of the changes in technical processes and chemicals, detection of occupational hazard factors, sampling and analysis of raw materials, and epidemiological investigation of workers with the same type of work. PMID- 27514263 TI - [The current situation of physical activity of basic level civil servants in Anhui province]. PMID- 27514264 TI - [Aluminuminduced impairment in primary cultured rat choroid plexus epithelial cells]. AB - OBJECTIVE: To investigate the impairment in primary cultured rat choroid plexus epithelial cells (CPECs)induced by aluminum. METHODS: The choroid plexus isolated from Sprague-Dawley rats 14 days old was cut into pieces and digested by trypsin in the sterile area. The obtained single cells were cultured in DMEM with 1% epidermal growth factor and 20% fetal calf serum. Five days later, immunohistochemistry with anti-transthyretin antibody was used to identify the purity of cultured cells. The well-grown cells were treated with aluminum lactate at different concentrations (0, 100, 400, and 1 600 MUmol/L for control, lowdose, mediumdose, and highdose groups). Fortyeight hours later, the cell viability, apoptotic rate, level of reactive oxygen species (ROS), and activity of superoxide dismutase (SOD)were measured in each group to evaluate the impairment in primary cultured rat CPECs by aluminum. RESULTS: More than 95% of the cultured cells were identified as CPECs. The medium-and high-dose groups had significantly lower cell viability than the control group(86.74%+/-4.03% vs 100%, P<0.01; 81.90%+/-9.17% vs 100%, P<0.01). The high-dose group had significantly lower cell viability than the lowdose group (81.90%+/-9.17% vs 92.92%+/-8.81%, P<0.01). The medium-and high-dose groups had significantly higher apoptotic rates than the control group (7.26%+/-0.99% vs 1.29%+/-0.03%, P<0.01; 22.25%+/-1.55% vs 1.29%+/ 0.03%, P<0.01)and the low-dose group (7.26%+/-0.99% vs 1.68%+/-0.27%, P<0.01; 22.25%+/-1.55% vs 1.68%+/-0.27%, P<0.01). The high-dose group had a significantly higher apoptotic rate than the medium-dose group (22.25%+/-1.55% vs 7.26%+/ 0.99%, P<0.01). The mediumand high-dose groups had significantly higher fluorescence intensity of ROS than the control group (22.23%+/-0.41% vs 17.24%+/ 0.09%, P<0.05; 25.10%+/-1.13% vs 17.24%+/-0.09%, P<0.05)and the lowdose group (22.23%+/-0.41% vs 18.31%+/-0.21%, P<0.05; 25.10%+/-1.13% vs 18.31%+/-0.21%, P<0.05). The highdose group had significantly higher fluorescence intensity of ROS than the mediumdose group (25.10%+/-1.13% vs 22.23%+/-0.41%, P< 0.05). The low-, medium-and high-dose groups had significantly lower SOD activity than the control group[(28.65+/-0.74)U/g Hb vs (37.35+/-1.05)U/g Hb, P<0.05; (22.75+/ 1.94)U/g Hb vs (37.35+/-1.05)U/g Hb, P<0.05; (13.29+/-0.64)U/g Hb vs(37.35+/ 1.05)U/g Hb, P<0.05]. The medium-and high-dose groups had significantly lower SOD activity than the low-dose group[(22.75+/-1.94)U/g Hb vs(28.65+/-0.74)U/g Hb, P<0.05; (13.29+/-0.64)U/g Hb vs (28.65+/-0.74)U/g Hb, P<0.05], while the high dose group had had significantly lower SOD activity than the medium-dose group[(13.29+/-0.64)U/g Hb vs (22.75+/-1.94)U/g Hb, P<0.05]. There were no significant differences in cell viability, apoptotic rate, level of ROS, or activity of SOD between any other two groups (P>0.05). CONCLUSION: Aluminum lactate may induce impairment in primary cultured rat CPECs. It reduces the cell viability, elevates the apoptotic rate, and causes oxidative stress. PMID- 27514265 TI - [Occupational asthma: an analysis of two cases]. AB - OBJECTIVE: To investigate the incidence of occupational asthma induced by occupational exposure to detergents and spices. METHODS: The occupational history, case data, and results of auxiliary examinations were collected from patients with asthma induced by occupational exposure to detergents and spices and submitted to the expert group for diagnosis of occupational diseases to obtain the diagnostic results. RESULTS: Both patients with asthma were exposed to asthmogenic substances in the working environment and developed the symptoms of asthma after a certain latency period. In case 1, the patient had positive results from bronchial dilation test and peak expiratory flow test; in case 2, the patient had positive results from allergen skin prick test for spices and essence and allergen bronchial provocation test. Therefore, the possibility of asthma induced by occupational factors could not be excluded. CONCLUSION: Occupational exposure to detergents and spices can induce occupational asthma. PMID- 27514266 TI - [Pulmonary siderosis: a case report and thought for the diagnosis]. PMID- 27514267 TI - [Peripheral nerve injury induced by occupational expsure to 1bromopropane in 4 cases]. PMID- 27514268 TI - [Treatment of a case of ataxia and pyramidal tract sign positive contact with the organic solvent]. PMID- 27514269 TI - [Determination of thiodiglycolic acid in urine by ion chromatography with solidphase extraction]. AB - OBJECTIVE: To establish a SPE-IC method to determine the thiodiglycolic acid in the urine of workers who were exposed to vinyl chloride monomer. METHODS: The samples were prepared by the process of being centrifuged and purified by C18 SPE column before separated by AS19 anion exchange column and detected by conductivity detector. The thiodiglycolic acid were characterized by the retention time and quantified by peak area and external standard method. RESULTS: The range of linearity was 0.05~50.00 MUg/ml, and the correlation coefficient was 0.999 9. The method detection limit was 0.1 MUg/ml and the method quantitative limit was 0.3 MUg/ml. The within-run precision was 1.26%~5.03% and the betweenrun precision was 0.50%~8.78%. The spiked recoveries were 80.10%~104.20%. Samples could bestored at-20 C for at least 2 weeks. The determination of thiodiglycolic acid could not be interfered by chloroacetic acid, dichloroacetic acid, trichloroacetic acid and other endogenous ionic compounds. CONCLUSION: This method is feasible for determination of thiodiglycolic acid in the urine of workers who were exposed to vinyl chloride monomer. PMID- 27514270 TI - [Determination of bromoform in the air of workplace by solvent desorption gas chromatography]. AB - OBJECTIVE: To establish the method of solvent desorption gas chromatography for determination of bromoform in workplace air. METHODS: Bromoform in the air was adsorbed by activated carbon tube sampling and solvent desorption using carbon disulfide, then analyed by GC with DB-FFAP capillary column. RESULTS: The linear regression equation is y=1.22x-0.81 (r=0.999 9)between 0.57~300.00 MUg/ml of target concentration in the air. The detection limit was 0.17 MUg /ml. The relative standard deviations of the batch and inter batch were 1.7%~3.6%, 2.8%~6.3%, respectively. The sampling efficiency was 100%. The overall desorption efficiency was 95.0%. The breakthrough capacity was more than 0.61 mg(100 mg activated carbon). CONCLUSION: The method is suitable to determine bromoform in the air of workplace. PMID- 27514271 TI - [Graphite furnace atomic absorption spectrometry for determination of thallium in blood]. AB - OBJECTIVE: Colloidal palladium was used as chemical modifier in the determination of blood thallium by graphite furnace atomic absorption spectrometry. METHODS: Blood samples were precipitated with 5% (V/V)nitric acid, and then determined by GFAAS with colloidal palladium used as a chemical modifier. 0.2% (W/V)sodium chloride was added in the standard series to improve the matrix matching between standard solution and sample. RESULTS: The detection limit was 0.2 MUg/L. The correlation coefficient was 0.9991. The recoveries were between 93.9% to 101.5%.The relative standard deviations were between 1.8% to 2.7%.The certified reference material of whole blood thallium was determined and the result was within the reference range Conclusion: The method is accurate, simple and sensitive, and it can meet the needs of detection thallium in blood entirely. PMID- 27514272 TI - [Determination of hippuric acid and methylhippuric acid in urine by high performance liquid chromatography after extracted with acetonitrile]. AB - OBJECTIVE: To establish pretreatment conditions of hippuric acid (HA)and methyl hippuric acid (MHA)in urine and HPLC conditions. METHODS: HA and MHA in urine were extracted with acetonitrile under acid condition and determinated by HPLC DAD. The operating conditions by HPLC were C18 column (150 mm* 4.6 mm, 5 MUm), methanol-0.2% acetic acid (contained 6.5 mmol/L potassium dihydrogen phosphate)(25?75, V/V) as mobile phase,1 ml/min as flow rate and wavelength was at 254 nm. RESULTS: The standard curves for HA, 2-MHA and 3-MHA(4-MHA)showed good linearity between 9.91~2 974.20 MUg/ml(r=0.999 98), 1.91~573.60 MUg/ml (r=0.999 84)and 2.00~598.65 MUg/ml (r=0.999 85), respectively. The mean recoveries were 96.38%~98.01%, 83.17%~94.05 %, 103.22%~104.45%, respectively. The within-run precision were 0.50%~1.20%, 0.51%~1.59%, 0.49%~0.95%, respectively, and the between-run precision were 1.70%~3.20%, 1.30%~2.67%, 0.86%~2.74%, respectively. The detection limit of HA, 2-MHA and 3-MHA(4-MHA)were 0.18 MUg/ml, 0.46 MUg/ml and 0.12 MUg/ml, and the low determination concentrations of the method were 0.36 MUg/ml, 0.92 MUg/ml and 0.24 MUg/ml(1 ml urine). The urine can be kept 15 days at 4 C refrigerator without significantly loss. CONCLUSION: This method with simply pretreatment conforms to the relevant requirements of guide for establishing occupational health standards-part 5: determination methods of chemicals in biological materials. It can be used to detect HA and MHA in urine for occupational population exposure to toluene and xylene. PMID- 27514273 TI - [Exploration on the problems in the process of the development of occupatieral disease prevention and control planning]. PMID- 27514274 TI - [Analysis for the systemof regulations and standards of occupational safety and health in British]. PMID- 27514275 TI - [The evolution of physical agents standards based on hygienic standards for the design of industrial enterprises]. PMID- 27514276 TI - [Research progress on the influence of occupational stress on industrial injury accident]. PMID- 27514277 TI - Co-immobilization of Palm and DNase I for the development of an effective anti infective coating for catheter surfaces. AB - Biomaterial-associated infections, in particular, catheter-associated infections (CAI) are a major problem in clinical practice due to their ability to resist antimicrobial treatment and the host immune system. This study aimed to co immobilize the antimicrobial lipopeptide Palm and the enzyme DNase I to introduce both antimicrobial and anti-adhesive functionalities to polydimethylsiloxane (PDMS) material, using dopamine chemistry. Surface characterization confirmed the immobilization of both compounds and no leaching of Palm from the surfaces for up to 5days. Co-immobilization of both agents resulted in a bifunctional coating with excellent surface antimicrobial and anti-biofilm properties against both Staphylococcus aureus and Pseudomonas aeruginosa. The modified surfaces demonstrated superior biocompatibility. To better discriminate co-adhesion of both species on modified surfaces, PNA FISH (Fluorescence in situ hybridization using peptide nucleic acid probes) was employed, and results showed that P. aeruginosa was the dominant organism, with S. aureus adhering afterwards on P. aeruginosa agglomerates. Furthermore, Palm immobilization exhibited no propensity to develop bacterial resistance, as opposite to the immobilization of an antibiotic. The overall results highlighted that co-immobilization of Palm and DNase I holds great potential to be applied in the development of catheters. STATEMENT OF SIGNIFICANCE: Catheter-associated infections (CAI) are the most common hospital-acquired infections worldwide. Several coating strategies have been proposed to fight these infections but most of them present some important limitations, including the emergence of resistant bacteria and toxicity concerns. The present work describes a two-step polydopamine-based surface modification strategy to successfully co-immobilize an antimicrobial peptide (Palm) and an enzyme targeting an important component of biofilm matrix (DNase I). This immobilization approach imparted polydimethylsiloxane surfaces with both anti adhesive and antimicrobial properties against the adhesion of relevant bacteria as single and dual-species, with excellent stability and biocompatible and anti biofilm properties, holding, therefore, great potential in the development of catheters able to prevent CAI. PMID- 27514278 TI - FES-induced co-activation of antagonist muscles for upper limb control and disturbance rejection. AB - Control systems for human movement based on Functional Electrical Stimulation (FES) have shown to provide excellent performance in different experimental setups. Nevertheless, there is still a limited number of such applications available today on worldwide markets, indicating poor performance in real settings, particularly for upper limb rehabilitation and assistance. Based on these premises, in this paper we explore the use of an alternative control strategy based on co-activation of antagonist muscles using FES. Although co contraction may accelerate fatigue when compared to single-muscle activation, knowledge from motor control indicate it may be useful for some applications. We have performed a simulation and experimental study designed to evaluate whether controllers that integrate such features can modulate joint impedance and, by doing so, improving performance with respect to disturbance rejection. The simulation results, obtained using a novel model including proprioceptive feedback and anatomical data, indicate that both stiffness and damping components of joint impedance may be modulated by using FES-induced co-activation of antagonist muscles. Preliminary experimental trials were conducted on four healthy subjects using surface electrodes. While the simulation investigation predicted a maximum 494% increase in joint stiffness for wrist flexion/extension, experiments provided an average elbow stiffness increase of 138% using lower stimulation intensity. Closed-loop experiments in which disturbances were applied have demonstrated that improved behavior may be obtained, but increased joint stiffness and other issues related to simultaneous stimulation of antagonist muscles may indeed produce greater errors. PMID- 27514279 TI - Hydrodynamic dispensing and electrical manipulation of attolitre droplets. AB - Dispensing and manipulation of small droplets is important in bioassays, chemical analysis and patterning of functional inks. So far, dispensing of small droplets has been achieved by squeezing the liquid out of a small orifice similar in size to the droplets. Here we report that instead of squeezing the liquid out, small droplets can also be dispensed advantageously from large orifices by draining the liquid out of a drop suspended from a nozzle. The droplet volume is adjustable from attolitre to microlitre. More importantly, the method can handle suspensions and liquids with viscosities as high as thousands mPa s markedly increasing the range of applicable liquids for controlled dispensing. Furthermore, the movement of the dispensed droplets is controllable by the direction and the strength of an electric field potentially allowing the use of the droplet for extracting analytes from small sample volume or placing a droplet onto a pre-patterned surface. PMID- 27514280 TI - Stereoselective synthesis of vinylsilanes via copper-catalyzed silylation of alkenes with silanes. AB - An efficient and stereoselective synthesis of vinylsilanes via copper-catalyzed direct silylation of alkenes with silanes was developed. This study offers a new and expedient strategy for the synthesis of synthetically useful alkenyl organosilicon compounds in satisfactory yields and may provide a low-cost and environmentally benign alternative to currently employed precious metal systems for alkene silylation. Moreover, the transformation is proposed to proceed via a radical process and exhibits a broad substrate scope and good functional group tolerance. PMID- 27514281 TI - Dissociable effects of the prodrug phendimetrazine and its metabolite phenmetrazine at dopamine transporters. AB - Phendimetrazine (PDM) is a clinically available anorectic and a candidate pharmacotherapy for cocaine addiction. PDM has been hypothesized to function as a prodrug that requires metabolism to the amphetamine-like monoamine transporter substrate phenmetrazine (PM) to produce its pharmacological effects; however, whether PDM functions as an inactive prodrug or has pharmacological activity on its own remains unclear. The study aim was to determine PDM pharmacological mechanisms using electrophysiological, neurochemical, and behavioral procedures. PDM blocked the endogenous basal hDAT (human dopamine transporter) current in voltage-clamped (-60 mV) oocytes consistent with a DAT inhibitor profile, whereas its metabolite PM induced an inward hDAT current consistent with a DAT substrate profile. PDM also attenuated the PM-induced inward current during co-application, providing further evidence that PDM functions as a DAT inhibitor. PDM increased nucleus accumbens dopamine levels and facilitated electrical brain stimulation reinforcement within 10 min in rats, providing in vivo evidence supporting PDM pharmacological activity. These results demonstrate that PDM functions as a DAT inhibitor that may also interact with the pharmacological effects of its metabolite PM. Overall, these results suggest a novel mechanism for PDM therapeutic effects via initial PDM DAT inhibition followed by PM DAT substrate induced dopamine release. PMID- 27514283 TI - Sample Dimensionality Effects on d' and Proportion of Correct Responses in Discrimination Testing. AB - Products in the food and beverage industry have varying levels of dimensionality ranging from pure water to multicomponent food products, which can modify sensory perception and possibly influence discrimination testing results. The objectives of the study were to determine the impact of (1) sample dimensionality and (2) complex formulation changes on the d' and proportion of correct response of the 3 AFC and triangle methods. Two experiments were conducted using 47 prescreened subjects who performed either triangle or 3-AFC test procedures. In Experiment I, subjects performed 3-AFC and triangle tests using model solutions with different levels of dimensionality. Samples increased in dimensionality from 1-dimensional sucrose in water solution to 3-dimensional sucrose, citric acid, and flavor in water solution. In Experiment II, subjects performed 3-AFC and triangle tests using 3-dimensional solutions. Sample pairs differed in all 3 dimensions simultaneously to represent complex formulation changes. Two forms of complexity were compared: dilution, where all dimensions decreased in the same ratio, and compensation, where a dimension was increased to compensate for a reduction in another. The proportion of correct responses decreased for both methods when the dimensionality was increased from 1- to 2-dimensional samples. No reduction in correct responses was observed from 2- to 3-dimensional samples. No significant differences in d' were demonstrated between the 2 methods when samples with complex formulation changes were tested. Results reveal an impact on proportion of correct responses due to sample dimensionality and should be explored further using a wide range of sample formulations. PMID- 27514282 TI - Somatic KCNJ5 mutation occurring early in adrenal development may cause a novel form of juvenile primary aldosteronism. AB - We report a case of non-familial juvenile primary aldosteronism (PA). Super selective adrenal venous sampling identified less aldosterone production in the right inferior adrenal segment than others. Bilateral adrenalectomy sparing the segment normalized blood pressure and improved PA. Both adrenals had similar histologies, consisting of a normal adrenal cortex and aldosterone synthase positive hyperplasia/adenoma. An aldosterone-driving KCNJ5 mutation was detected in the lesions, but not in the histologically normal cortex. After taking into account that the two adrenal glands displayed a similar histological profile, as well as the fact that hyperplastic lesions in both glands exhibited a common KCNJ5 mutation, we conclude that the specific mutation may have occurred at an adrenal precursor mesodermal cell, at an early stage of development; its daughter cells were mixed with non-mutant cells and dispersed into both adrenal glands, resulting into a form of the condition known as genetic mosaicism. PMID- 27514284 TI - 19 F NMR transverse and longitudinal relaxation filter experiments for screening: a theoretical and experimental analysis. AB - Ligand-based 19 F NMR screening represents an efficient approach for performing binding assays. The high sensitivity of the methodology to receptor binding allows the detection of weak affinity ligands. The observable NMR parameters that are typically used are the 19 F transverse relaxation rate and isotropic chemical shift. However, there are few cases where the 19 F longitudinal relaxation rate should also be used. A theoretical and experimental analysis of the 19 F NMR transverse and longitudinal relaxation rates at different magnetic fields is presented along with proposed methods for improving the sensitivity and dynamic range of these experiments applied to fragment-based screening. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27514285 TI - Spectral and kinetic effects accompanying the assembly of core complexes of Rhodobacter sphaeroides. AB - In the present work, spectral and kinetic changes accompanying the assembly of the light-harvesting 1 (LH1) complex with the reaction center (RC) complex into monomeric RC-LH1 and dimeric RC-LH1-PufX core complexes of the photosynthetic purple bacterium Rhodobacter sphaeroides are systematically studied over the temperature range of 4.5-300K. The samples were interrogated with a combination of optical absorption, hole burning, fluorescence excitation, steady state and picosecond time resolved fluorescence spectroscopy. Fair additivity of the LH1 and RC absorption spectra suggests rather weak electronic coupling between them. A low-energy tail revealed at cryogenic temperatures in the absorption spectra of both monomeric and dimeric core complexes is proved to be due to the special pair of the RC. At selected excitation intensity and temperature, the fluorescence decay time of core complexes is shown to be a function of multiple factors, most importantly of the presence/absence of RCs, the supramolecular architecture (monomeric or dimeric) of the complexes, and whether the complexes were studied in a native membrane environment or in a detergent - purified state. PMID- 27514286 TI - Epilepsy: Noninvasive detection of deep brain seizures. PMID- 27514289 TI - Trial watch: Phase III trial of anti-tau drug generates mixed messages. PMID- 27514288 TI - Epilepsy: A dietary supplement for SUDEP prevention? PMID- 27514290 TI - In the news: AAIC 2016 lights up Toronto. PMID- 27514287 TI - Myeloid cells - targets of medication in multiple sclerosis. AB - Discussions of multiple sclerosis (MS) pathophysiology tend to focus on T cells and B cells of the adaptive immune response. The innate immune system is less commonly considered in this context, although dendritic cells, monocytes, macrophages and microglia - collectively referred to as myeloid cells - have prominent roles in MS pathogenesis. These populations of myeloid cells function as antigen-presenting cells and effector cells in neuroinflammation. Furthermore, a vicious cycle of interactions between T cells and myeloid cells exacerbates pathology. Several disease-modifying therapies are now available to treat MS, and insights into their mechanisms of action have largely focused on the adaptive immune system, but these therapies also have important effects on myeloid cells. In this Review, we discuss the evidence for the roles of myeloid cells in MS and the experimental autoimmune encephalomyelitis model of MS, and consider how interactions between myeloid cells and T cells and/or B cells promote MS pathology. Finally, we discuss the direct and indirect effects of existing MS medications on myeloid cells. PMID- 27514291 TI - Supportive and symptomatic management of amyotrophic lateral sclerosis. AB - The main aims in the care of individuals with amyotrophic lateral sclerosis (ALS) are to minimize morbidity and maximize quality of life. Although no cure exists for ALS, supportive and symptomatic care provided by a specialist multidisciplinary team can improve survival. The basis for supportive management is shifting from expert consensus guidelines towards an evidence-based approach, which encourages the use of effective treatments and could reduce the risk of harm caused by ineffective or unsafe interventions. For example, respiratory support using noninvasive ventilation has been demonstrated to improve survival and quality of life, whereas evidence supporting other respiratory interventions is insufficient. Increasing evidence implicates a causal role for metabolic dysfunction in ALS, suggesting that optimizing nutrition could improve quality of life and survival. The high incidence of cognitive dysfunction and its impact on prognosis is increasingly recognized, although evidence for effective treatments is lacking. A variety of strategies are used to manage the other physical and psychological symptoms, the majority of which have yet to be thoroughly evaluated. The need for specialist palliative care throughout the disease is increasingly recognized. This Review describes the current approaches to symptomatic and supportive care in ALS and outlines the current guidance and evidence for these strategies. PMID- 27514292 TI - Pre-eclampsia and risk of infantile haemangioma. AB - BACKGROUND: Infantile haemangioma is the most common tumour of infancy, but the association with pre-eclampsia is poorly understood. OBJECTIVES: We determined the relationship between variants of pre-eclampsia and risk of infantile haemangioma. METHODS: We carried out a retrospective cohort study of hospital data for all live births between 1989 and 2013 in Quebec, Canada. We identified 14 240 neonates with, and 1 930 564 without haemangioma before discharge, and determined whether early- or late-onset pre-eclampsia was documented on the maternal chart. We used log-binomial regression to compute prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between pre eclampsia and infantile haemangioma, adjusted for maternal characteristics. RESULTS: The prevalence of any haemangioma was higher for pre-eclampsia than for no pre-eclampsia (81.3 vs. 72.9 per 10 000), with a PR of 1.15 (95% CI 1.06-1.25) after adjustment for maternal characteristics. Pre-eclampsia with onset before 34 weeks' gestation was associated with cutaneous (PR 2.32, 95% CI 1.68-3.21), noncutaneous (PR 3.66, 95% CI 2.49-5.37) and unspecified haemangioma (PR 2.49, 95% CI 1.77-3.49). However, the association between early-onset pre-eclampsia and haemangioma was attenuated once long neonatal length of hospital stays was accounted for. There was no association with late-onset pre-eclampsia after 34 weeks, and associations were weaker for other variants including severe pre eclampsia and pre-eclampsia with low birthweight. CONCLUSIONS: Early-onset pre eclampsia is associated with increased risk of haemangioma at birth, but detection bias due to longer hospital stays and closer follow-up may be part of the reason. PMID- 27514294 TI - Adverse Effects of Psychotropic Medications: A Call to Action. AB - Adverse effects are common, bothersome, and a leading cause of discontinuation of treatment. The methodology for evaluating adverse effects of medications has been greatly neglected, however, especially in comparison to the methodology for assessment of efficacy of medications. Existing methods for assessment and reporting of adverse effects have important limitations leading to lack of much needed data related to adverse effects. Lastly, there is little systematic research into management of most adverse effects. A series of recommendations are made in this article about how to improve identification, assessment, reporting, and management of adverse effects. PMID- 27514293 TI - Degree connectivity in body dysmorphic disorder and relationships with obsessive and compulsive symptoms. AB - Individuals with body dysmorphic disorder (BDD) and obsessive-compulsive disorder (OCD) are categorized within the same major diagnostic group and both show regional brain hyperactivity in the orbitofrontal cortex (OFC) and the basal ganglia during symptom provocation. While recent studies revealed that degree connectivity of these areas is abnormally high in OCD and positively correlates with symptom severity, no study has investigated degree connectivity in BDD. We used functional magnetic resonance imaging (fMRI) to compare the local and distant degree of functional connectivity in all brain areas between 28 unmedicated BDD participants and 28 demographically matched healthy controls during a face-processing task. Correlational analyses tested for associations between degree connectivity and symptom severity assessed by the BDD version of the Yale-Brown obsessive-compulsive scale (BDD-Y-BOCS). Reduced local amygdalar connectivity was found in participants with BDD. No differences in distant connectivity were found. BDD-Y-BOCS scores significantly correlated with the local connectivity of the posterior-lateral OFC, and distant connectivity of the posterior-lateral and post-central OFC, respectively. These findings represent preliminary evidence that individuals with BDD exhibit brain-behavioral associations related to obsessive thoughts and compulsive behaviors that are highly similar to correlations previously found in OCD, further underscoring their related pathophysiology. This relationship could be further elucidated through investigation of resting-state functional connectivity in BDD, ideally in direct comparison with OCD and other obsessive-compulsive and related disorders. PMID- 27514295 TI - Core Concepts Involving Adverse Psychotropic Drug Effects: Assessment, Implications, and Management. AB - Adverse effects from psychiatric drugs can profoundly influence treatment adherence and outcomes. Good care involves addressing adverse effects no differently than any other component of treatment. Knowledge about adverse effect assessment and management fosters a proper context that helps clinicians not sacrifice a drug's potential therapeutic benefits because of greater concerns about its tolerability. This article provides an overview of basic concepts related to the assessment and management of suspected adverse effects from psychotropic drugs. Key points are discussed regarding clinical, pharmacogenetic, pharmacokinetic, and pharmacodynamic risk factors for treatment-emergent adverse effects, alongside recommendations for their systematic assessment. PMID- 27514296 TI - Drug-Induced Extrapyramidal Syndromes: Implications for Contemporary Practice. AB - The development of drugs to treat psychosis is a fascinating nexus for understanding mechanisms underlying disorders of mind and movement. Although the risk of drug-induced extrapyramidal syndromes has been mitigated by the acceptance of less potent dopamine antagonists, expansive marketing and off-label use has increased the number of susceptible people who may be at risk for these neurologic effects. Clinicians need to be familiar with advances in diagnosis and management, which are reviewed herein. A better understanding of drug-induced effects on the motor circuit may improve patient safety, enhance antipsychotic effectiveness, and provide insights into mechanisms underlying antipsychotic activity in parallel brain circuits. PMID- 27514297 TI - Serotonin Reuptake Inhibitors and Risk of Abnormal Bleeding. AB - Serotonin reuptake inhibitors (SRIs) increase the risk of abnormal bleeding by lowering platelet serotonin and hence the efficiency of platelet-driven hemostasis; by increasing gastric acidity and possibly gastric ulceration; and by other mechanisms. The upper gastrointestinal tract is the commonest site of SRI related abnormal bleeding; bleeding at this location may be increased by concurrent nonsteroidal anti-inflammatory drug therapy and by treatment with antiplatelet or anticoagulant drugs. Bleeding at this location may be reduced by concurrent administration of acid-suppressing drugs. PMID- 27514298 TI - Sexual Dysfunction Due to Psychotropic Medications. AB - Sexual functioning is important to assess in patients with psychiatric illness as both the condition and associated treatment may contribute to sexual dysfunction (SD). Antidepressant medications, mood stabilizers, antipsychotics, and antianxiety agents may be associated with SD related to drug mechanism of action. Sexual adverse effects may be related to genetic risk factors, impact on neurotransmitters and hormones, and psychological elements. Effective strategies to manage medication-induced sexual dysfunction are initial choice of a drug unlikely to cause SD, switching to a different medication, and adding an antidote to reverse SD. Appropriate interventions should be determined on a clinical case by-case basis. PMID- 27514299 TI - Adverse Effects in the Pharmacologic Management of Bipolar Disorder During Pregnancy. AB - Management of bipolar disorder during pregnancy often involves medications with potential adverse effects, including risks to the mother and fetus. Although some specifics are known, many medications continue to have incompletely characterized reproductive safety profiles. Women with bipolar disorder who are planning pregnancy face challenging decisions about their treatment; careful risk-benefit discussions are necessary. With the goal of further informing these discussions, this article reviews the data currently available regarding medication safety in the management of bipolar disorder during pregnancy, with specific attention to lithium, valproic acid, lamotrigine, carbamazepine, and antipsychotic medications. PMID- 27514300 TI - Adverse Effects of Second-Generation Antipsychotics as Adjuncts to Antidepressants: Are the Risks Worth the Benefits? AB - Over the past decades, several adjunctive therapies have been introduced for treatment-resistant depression (TRD), and these strategies have ebbed and flowed in popularity. Currently, adjunctive therapy with the second-generation antipsychotics (SGAs) is most commonly used by psychiatrists. Four SGAs are FDA approved for indications related to TRD (aripiprazole, brexpiprazole, olanzapine, and quetiapine extended release); some evidence also supports use of risperidone and ziprasidone as adjunctive therapies. This article briefly reviews the role of adjunctive therapy with SGAs in contemporary algorithms for TRD, considering both the evidence of benefit and the adverse effects. PMID- 27514301 TI - Adverse Effects of Psychotropic Medications on Sleep. AB - Psychotropic medications such as antidepressants, antipsychotics, stimulants, and benzodiazepines are widely prescribed. Most of these medications are thought to exert their effects through modulation of various monoamines as well as interactions with receptors such as histamine and muscarinic cholinergic receptors. Through these interactions, psychotropics can also have a significant impact on sleep physiology, resulting in both beneficial and adverse effects on sleep. PMID- 27514302 TI - Antidepressants and Suicidality. AB - We review the evidence that antidepressants either increase or decrease the risk for suicidal ideation and behavior in adolescents. Meta-analyses of randomized clinical trials (RCTs) indicate a small increased risk for suicidal events in adolescents and young adults, but a protective effect in older adults. In contrast, pharmacoepidemiologic studies show a protective effect across the life span. Explanations for occurrence of suicidal events in younger patients and for the apparent contradiction between RCT and pharmacoepidemiologic studies are offered. Guidance for clinicians is provided on explaining the risk-benefit ratio of antidepressants and how to monitor and attenuate for suicidal risk. PMID- 27514303 TI - Adverse Effects of Electroconvulsive Therapy. AB - Electroconvulsive therapy (ECT) is an effective treatment commonly used for depression and other major psychiatric disorders. We discuss potential adverse effects (AEs) associated with ECT and strategies for their prevention and management. Common acute AEs include headache, nausea, myalgia, and confusion; these are self-limiting and are managed symptomatically. Serious but uncommon AEs include cardiovascular, pulmonary, and cerebrovascular events; these may be minimized with screening for risk factors and by physiologic monitoring. Although most cognitive AEs of ECT are short-lasting, troublesome retrograde amnesia may rarely persist. Modifications of and improvements in treatment techniques minimize cognitive and other AEs. PMID- 27514304 TI - The Neglected Side of Suffering. PMID- 27514305 TI - Vein of Galen aneurysmal malformation (VGAM) in the fetus: retrospective analysis of perinatal prognostic indicators in a two-center series of 49 cases. AB - OBJECTIVE: Vein of Galen aneurysmal malformation (VGAM) is a rare fetal anomaly, the neurological outcome of which can be good with appropriate perinatal management. However, most fetal series are too small to allow reliable statistical assessment of potential prognostic indicators. Our aim was to assess, in a two-center series of 49 cases, the prognostic value of several prenatal variables, in order to identify possible prenatal indicators of poor outcome, in terms of mortality and cerebral disability. METHODS: This was a retrospective study involving 49 cases of VGAM diagnosed prenatally and managed at two centers over a 17-year period (1999-2015). All cases had undergone detailed prenatal cerebral and cardiac assessment by grayscale ultrasound, color and pulsed-wave Doppler and magnetic resonance imaging (MRI). Ultrasound and MRI examination reports and images were reviewed and outcome information was obtained from medical reports. Volume of the VGAM (on ultrasound and MRI) was calculated and development of straight-sinus dilatation, ventriculomegaly and other major brain abnormalities was noted. Cardiothoracic ratio, tricuspid regurgitation and reversed blood flow across the aortic isthmus were evaluated on fetal echocardiography. Major brain lesions were considered by definition to be associated with poor outcome in all cases. Pregnancy and fetoneonatal outcome were known in all cases. Fetoneonatal outcome and brain damage were considered as dependent variables in the statistical evaluation. Poor outcome was defined as death, late termination of pregnancy due to association with related severe brain anomalies or severe neurological impairment. RESULTS: At a mean follow-up time of 20 (range, 0-72) months, 36.7% of the whole series and 52.9% of the cases which did not undergo late termination were alive and free of adverse sequelae. Five (10.2%) cases showed progression of the lesion between diagnosis and delivery. On univariate analysis, dilatation of the straight sinus, VGAM volume >= 20 000 mm3 and tricuspid regurgitation were all significantly related to poor outcome. However, on logistic regression analysis, the only variables associated significantly with poor outcome were tricuspid regurgitation and, to a lesser extent, VGAM volume >= 20 000 mm3 . The former was also the only variable associated with brain damage. CONCLUSIONS: Major brain lesions, tricuspid regurgitation and, to a lesser extent, VGAM volume >= 20 000 mm3 are the only prenatal variables associated with poor outcome in fetal VGAM. Prenatal multidisciplinary counseling should be based on these variables. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27514306 TI - Transformation of atenolol, metoprolol, and carbamazepine in soils: The identification, quantification, and stability of the transformation products and further implications for the environment. AB - Pharmaceuticals are a large group of substances that have been recognized as environmental contaminants in recent years. Research on the pharmaceutical fate in soils is currently limited or missing. In this study, three pharmaceuticals (atenolol (ATE), carbamazepine (CAR), and metoprolol (MET)) were introduced to soils and exposed for 61 day under aerobic conditions. Thirteen different soils were used in the study to increase the understanding of pharmaceutical behaviour in the soil matrix. Ten metabolites were detected and tentatively identified. Some of them, such as atenolol acid (AAC), carbamazepine 10,11-epoxide (EPC), 10,11-dihydrocarbamazepine (DHC), trans-10,11-Dihydro-10,11-dihydroxy carbamazepine (RTC), and metoprolol acid (MAC), were consequently confirmed using commercial reference standards. It was concluded that the aerobic conditions of the experiment determined the pharmaceutical degradation pathway of studied compounds in the soils. The different amounts/rates and degradation of the transformation products can be attributed to differences in the soil properties. ATE degraded relatively quickly compared with CAR, whereas MET degradation in the soils was unclear. The persistence of CAR and its metabolites, in combination with low CAR sorption, enable the transportation of CAR and its metabolites within soils and into the ground water. Thus, CAR may cause adverse effects on the environment and humans. PMID- 27514307 TI - Coherent control of light-matter interactions in polarization standing waves. AB - We experimentally demonstrate that standing waves formed by two coherent counter propagating light waves can take a variety of forms, offering new approaches to the interrogation and control of polarization-sensitive light-matter interactions in ultrathin (subwavelength thickness) media. In contrast to familiar energy standing waves, polarization standing waves have constant electric and magnetic energy densities and a periodically varying polarization state along the wave axis. counterintuitively, anisotropic ultrathin (meta)materials can be made sensitive or insensitive to such polarization variations by adjusting their azimuthal angle. PMID- 27514309 TI - The efficacy of video monitoring-supported student self-evaluation of dental explorer skills in dental hygiene education. AB - OBJECTIVE: The objective of this study was to investigate whether having dental hygiene students monitor video recordings of their dental explorer skills is an effective means of proper self-evaluation in dental hygiene education. METHODS: The study participants comprised students of a dental hygiene training school who had completed a module on explorer skills using models, and a dental hygiene instructor who was in charge of lessons. Questions regarding 'posture', 'grip', 'finger rest' and 'operation' were set to evaluate explorer skills. Participants rated each item on a two-point scale: 'competent (1)' or 'not competent (0)'. The total score was calculated for each evaluation item in evaluations by students with and without video monitoring, and in evaluations by the instructor with video monitoring. Mean scores for students with and without video monitoring were compared using a t-test, while intraclass correlation coefficients were found by reliability analysis of student and instructor evaluations. RESULTS: A total of 37 students and one instructor were subject to analysis. The mean score for evaluations with and without video monitoring differed significantly for posture (P < 0.0001), finger rest (P = 0.0006) and operation (P < 0.0001). The intraclass correlation coefficient between students and instructors for evaluations with video monitoring ranged from 0.90 to 0.97 for the four evaluation items. CONCLUSION: The results of this study suggested that having students monitor video recordings of their own explorer skills may be an effective means of proper self-evaluation in specialized basic education using models. PMID- 27514310 TI - Clinical assessment of rosacea severity: oriental score vs. quantitative assessment method with imaging and biomedical tools. AB - BACKGROUND: Rosacea is a common chronic inflammatory disorder affecting facial skin. Currently, no accurate and objective method is available for assessing the severity of rosacea. Most studies use the National Rosacea Society Standard (NRSS) grading method, which lacks objectivity and yields varying results. METHODS: Eighteen patients with rosacea were included. Clinical severity was assessed on the basis of the NRSS grade, Investigators' Global Assessment, Patients' Global Assessment, and Dermatology Quality of Life Index. A skin color analysis system was used to measure the facial area showing erythema, and biophysical parameters of facial skin (transepidermal water loss and skin surface hydration) were examined. To find statistical significant in classification severity of the rosacea, statistical analysis was performed with all parameters. RESULTS: A significant correlation (P < 0.05) was found between the NRSS grade, facial area showing erythema, and biophysical parameters. The latter two factors differed significantly among patients with rosacea of different levels of severity (mild, moderate, severe; P < 0.05). CONCLUSION: Color imaging systems can be useful and reliable for evaluating the severity of rosacea, in addition to biophysical parameter assessment. The combination of these two analytical methods enabled objective and quantitative evaluation of the severity of rosacea. PMID- 27514308 TI - Morphine decreases the pro-angiogenic interaction between breast cancer cells and macrophages in vitro. AB - Interactions between the various cell types that constitute a solid tumour are essential to the biology of the tumour. We evaluated the effect of morphine on the proangiogenic interaction taking place between macrophages and breast cancer cells in vitro. The conditioned medium (CM) from breast cancer cells co-cultured with macrophages elicited endothelial cell proliferation and tube formation. This effect was inhibited if the co-culture occurred in the presence of morphine. The CM from breast cancer cells or macrophages grown individually, whether or not prepared in the presence of morphine, was ineffective in stimulating EC proliferation or tube formation. Using a mouse antibody array, we identified several angiogenesis-regulating factors differentially expressed in the CM of co cultured cells prepared in the presence or absence of morphine, amongst which interleukin (IL)-6, tumour necrosis factor (TNF)-alpha and vascular endothelial growth factor (VEGF)-A. VEGF was induced in both cell types by the co-culture and this was prevented by morphine in a non-naloxone reversible fashion. The effect of CM from co-cultured cells on endothelial tube formation, but not proliferation, was prevented by anti-VEGF neutralizing antibody. Our results indicate that morphine prevents, in part via modulating VEGF-A expression, the pro-angiogenic interaction between macrophages and breast cancer cells. PMID- 27514311 TI - Comparative study of different histologic classifications in the degree of differentiation in endometrial adenocarcinoma. AB - PURPOSE: To evaluate the concordance among the available histologic classifications for endometrial adenocarcinoma using interobserver and intraobserver agreement as well as the association of tumor histologic degree in the above mentioned classifications with cellular proliferation measured by Ki 67. METHODS: Seventy women who underwent surgical treatment of endometrial adenocarcinoma with histologic confirmation of endometrioid type were included in the study. Two experienced pathologists randomly analyzed the slides in 3 distinct timeframes with a maximum of 25 slides/timeframe. Tumor slides were classified according to the degree of differentiation using 4 different classifications: International Federation of Gynecology and Obstetrics (FIGO), modified FIGO, Lax, and Alkushi. RESULTS: Intraobserver agreement was reasonable for classification of FIGO (k 0.469 and 0.538), very good for modified FIGO (k 0.661 and 0.768), moderate for Lax classification (k 0.496 and 0.466), and moderate/good for Alkushi classification (k 0.528 and 0.736). Interobserver concordance was regular for FIGO classification (k = 0.271 and 0.343), good/moderate for modified FIGO classification (k = 0.661 and 0.522, respectively), regular/moderate for Lax classification (k = 0.258 and 0.465, respectively), and regular for Alkushi classification (k = 0.283 and 0.402). CONCLUSIONS: The prognostic value of histologic grading in endometrial carcinoma and its importance for a successful therapeutic plan have been documented repeatedly, but the best grading system, in terms of prognostication, reproducibility, ease of use, and universality (e.g., applicability to all tumor cell types), has not been unequivocally defined. PMID- 27514312 TI - Variation in hospital utilization at the end of life for patients with cancer in the Emilia-Romagna region of Italy. AB - INTRODUCTION: Despite the preference of many patients to die at home, high proportions of patients with advanced cancer undergo major procedures, receive intensive care, and die in the hospital. The goal of this study is to examine variation in hospital utilization and site of death for patients dying with poor prognosis cancer in the Regione Emilia-Romagna (RER), Italy. METHODS: We conducted a retrospective, population-level study using administrative data. Patients were included if they died in 2012 and had at least one hospital admission for metastatic or poor-prognosis cancer within 180 days of death. Variations in the use of the hospital, intensive care, and procedures performed were evaluated. RESULTS: 11,470 patients died with metastatic or poor-prognosis cancer in 2012. Seventy-eight percent of patients were hospitalized in the last month of life while 50.7% of patients died in the hospital. Results varied by local health authority from 38.3% to 69.3%. Of patients who had an ICU stay, 55.1% in the community hospitals and 59.8% in the teaching hospitals were admitted to the ICU on the day of death or the day before death. 7.5% of patients underwent a major procedure in the last 30 days of life. CONCLUSIONS: The overall high rate, and substantial variation, in hospital care at the end of life offers the RER the opportunity to evaluate if increasing availability of palliative care, along with provider and patient education, could reduce utilization of high cost hospital care and increase patient and family satisfaction. PMID- 27514313 TI - Analysis of clinical and pathological characteristics, treatment methods, survival, and prognosis of uterine papillary serous carcinoma. AB - PURPOSE: Uterine papillary serous carcinoma (UPSC) is an atypical variant of endometrial carcinoma with a poor prognosis. It is commonly associated with an increased risk of extrauterine disease. The aim of this study was to investigate clinical and pathological characteristics, therapeutic methods, and prognostic factors in women with UPSC. METHODS: All patients who underwent surgery for UPSC at a single high-volume cancer center between January 1995 and December 2010 were retrospectively reviewed. Patients who did not undergo surgical staging and those with mixed tumor histology were excluded. Univariate and multivariate regression models were used to identify the risk factors for overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 46 patients were included, the majority of whom having stage I disease (IA, 13 [28.2%] and IB, 12 [26.7%]). Stages II, III, and IV were identified in 5 (10.9%), 8 (17.4%), and 8 (17.4%) women, respectively. Optimal cytoreduction was obtained in 67.3% of patients. Recurrences developed in 8 (17.4%) patients. Multivariate analysis confirmed that lymphovascular space invasion (LVSI) (odds ratio [OR] 26.83, p = 0.003) was the only independent prognostic factor for OS, whereas LVSI and optimal cytoreduction were found to be independent prognostic factors for PFS (OR 6.91, p = 0.013 and OR 2.69, p = 0.037, respectively). The 5-year overall survival rate was 63%. CONCLUSIONS: Our study demonstrated that LVSI is the only independent prognostic factor for OS, whereas LVSI and optimal cytoreduction are independent prognostic factors for PFS in patients with UPSC. PMID- 27514314 TI - Rationale and protocol of AIRC IG-13218, short-term radiotherapy for early prostate cancer with concomitant boost to the dominant lesion. AB - INTRODUCTION: Of the different treatments for early prostate cancer, hypofractionated external-beam radiotherapy is one of the most interesting and studied options. METHODS: The main objective of this phase II clinical study is to evaluate the feasibility, in terms of the incidence of acute side effects, of a new ultra-hypofractionated scheme for low- or intermediate-risk prostate cancer patients treated with the latest imaging and radiotherapy technology, allowing dose escalation to the dominant intraprostatic lesion identified by multiparametric magnetic resonance imaging. Secondary endpoints of the study are the evaluation of the long-term tolerability of the treatment in terms of late side effects, quality of life, and efficacy (oncological outcome). RESULTS: The study is ongoing, and we expect to complete recruitment by the end of 2016. CONCLUSIONS: Like in previous studies, we expect ultra-hypofractionated radiation treatment for prostate cancer to be well tolerated and effective. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01913717. PMID- 27514315 TI - Factors related to treatment outcomes in low-risk gestational neoplasia. AB - OBJECTIVE: To define the factors associated with methotrexate (MTX) resistance in patients with low-risk gestational trophoblastic neoplasia (GTN). METHODS: A total of 63 patients with low-risk GTN according to International Federation of Gynecology and Obstetrics (FIGO) criteria were included. A total of 37 (58.7%) patients were treated with successive doses of 1 mg/kg intramuscular (IM) MTX on days 1, 3, 5, and 7, and 0.1 mg/kg IM folinic acid (FA) on days 2, 4, 6, and 8, until beta-human chorionic gonadotropin (hCG) levels were normalized. After the beta-hCG value dropped to the normal level, an additional cycle of MTX/FA was administered. This protocol is defined as the standard protocol. In a watchful waiting protocol, the same 8-day IM MTX/FA regimen was given only once (n = 8) or twice (n = 18) to 26 (41.3%) patients and patients in whom beta-hCG values declined were subjected to follow-up and no additional cycles were administered as long as there was a decrease in beta-hCG value. Clinical response and factors affecting therapeutic outcomes were analyzed retrospectively. RESULTS: Of 63 patients, 47 (74.3%) were cured with primary MTX/FA treatment irrespective of any protocol. Of the 16 patients who were not able to be treated with primary MTX/FA, 3 were treated with single-agent actinomycin-D and 11 were treated with multi agent chemotherapy. Univariate analysis showed that a pretreatment beta-hCG level of >=5000 IU/L was related to reduced therapeutic response (p = 0.001). The FIGO score, antecedent gestational pathology, and treatment with standard or watchful waiting protocol were not related to treatment response. CONCLUSIONS: The level of beta-hCG prior to therapy is an important factor for predicting therapeutic outcomes. It should be noted that the success of the therapy decreases notably in case of high beta-hCG level. PMID- 27514316 TI - Combined modality therapy for thoracic and head and neck cancers: a review of updated literature based on a consensus meeting. AB - PURPOSE: Combined modality therapy is a mainstay option for thoracic malignancies and head and neck cancers. The integration of different strategies is based on the multidisciplinary approach of modern clinical oncology. Radiation oncologists have to be educated, trained, and updated to provide state-of-the-art care to cancer patients and thus educational meetings are crucial. METHODS: The Italian Association of Radiation Oncology Young Members Working Group (AIRO Giovani) organized its 8th national meeting, focused on combination therapy in lung, esophageal, and head and neck cancer (with a specific focus on larynx preservation strategies for larynx/hypopharynx tumors), involving young professionals working in Italy. The meeting was addressed to young radiation oncologists, presenting state-of-the-art knowledge, based on the latest evidence in this field. We performed a review of the current literature based on the highlights of the Congress. RESULTS: The multimodality approach of head and neck and thoracic malignancies includes surgery, chemotherapy, and radiotherapy, but also has to take into account new information and data coming from basic and translational research and including molecular biology, genetics, and immunology. All these aspects are crucial for the treatment of non-small-cell lung cancer and esophageal, esophagogastric junction, and larynx/hypopharynx malignancies. The integration of different treatments in the clinical decision-making process to combine therapies is crucial. CONCLUSIONS: Combination therapy has proved to be a consolidated approach in these specific oncologic settings, highlighting the importance of multimodality management in modern clinical oncology. Dedicated meetings on specific topics are helpful to improve knowledge and skills of young professionals in radiation oncology. PMID- 27514317 TI - Experience with belatacept rescue therapy in kidney transplant recipients. AB - In kidney transplant recipients with chronic graft dysfunction, long-term immunosuppression with calcineurin inhibitors (CNIs) or mTOR inhibitors (mTORi) can be challenging due to adverse effects, such as nephrotoxicity and proteinuria. Seventy-nine kidney transplant recipients treated with CNI-based or mTORi-based maintenance immunosuppression who had CNI-induced nephrotoxicity or severe adverse events were switched to belatacept. Mean time from transplantation to belatacept conversion was 69.0 months. Mean estimated glomerular filtration rate (eGFR) +/- standard deviation at baseline was 26.1 +/- 15.0 ml/min/1.73 m2 , increasing to 34.0 +/- 15.2 ml/min/1.73 m2 at 12 months postconversion (P < 0.0005). Renal function improvements were also seen in patients with low eGFR (<25 ml/min/1.73 m2 ) or high proteinuria (>500 mg/l) at conversion. The Kaplan Meier estimates for patient and graft survival at 12 months were 95.0% and 85.6%, respectively. The discontinuation rate due to adverse events was 7.9%. One case of post-transplant lymphoproliferative disorder occurred at 17 months postconversion. For comparison, a historical control group of 41 patients converted to mTORi-based immunosuppression because of biopsy-confirmed CNI induced toxicity was examined; eGFR increased from 27.6 +/- 7.2 ml/min/1.73 m2 at baseline to 31.1 +/- 11.9 ml/min/1.73 m2 at 12 months (P = 0.018). Belatacept based immunosuppression may be an alternative regimen for kidney transplant recipients with CNI- or mTORi-induced toxicity. PMID- 27514318 TI - Tip in-light on: Advantages, challenges, and applications of combining AFM and Raman microscopy on biological samples. AB - Scanning probe microscopies and spectroscopies, especially AFM and Confocal Raman microscopy are powerful tools to characterize biological materials. They are both non-destructive methods and reveal mechanical and chemical properties on the micro and nano-scale. In the last years the interest for increasing the lateral resolution of optical and spectral images has driven the development of new technologies that overcome the diffraction limit of light. The combination of AFM and Raman reaches resolutions of about 50-150 nm in near-field Raman and 1.7-50 nm in tip enhanced Raman spectroscopy (TERS) and both give a molecular information of the sample and the topography of the scanned surface. In this review, the mentioned approaches are introduced, the main advantages and problems for application on biological samples discussed and some examples for successful experiments given. Finally the potential of colocated AFM and Raman measurements is shown on a case study of cellulose-lignin films: the topography structures revealed by AFM can be related to a certain chemistry by the colocated Raman scan and additionally the mechanical properties be revealed by using the digital pulsed force mode. Microsc. Res. Tech. 80:30-40, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 27514320 TI - Influence of Polymer Electronics on Selective Dispersion of Single-Walled Carbon Nanotubes. AB - The separation and isolation of semiconducting and metallic single-walled carbon nanotubes (SWNTs) on a large scale remains a barrier to many commercial applications. Selective extraction of semiconducting SWNTs by wrapping and dispersion with conjugated polymers has been demonstrated to be effective, but the structural parameters of conjugated polymers that dictate selectivity are poorly understood. Here, we report nanotube dispersions with a poly(fluorene-co pyridine) copolymer and its cationic methylated derivative, and show that electron-deficient conjugated pi-systems bias the dispersion selectivity toward metallic SWNTs. Differentiation of semiconducting and metallic SWNT populations was carried out by a combination of UV/Vis-NIR absorption spectroscopy, Raman spectroscopy, fluorescence spectroscopy, and electrical conductivity measurements. These results provide new insight into the rational design of conjugated polymers for the selective dispersion of metallic SWNTs. PMID- 27514319 TI - Comparison of a vascular closure device versus the radial approach to reduce access site complications in non-ST-segment elevation acute coronary syndrome patients: The angio-seal versus the radial approach in acute coronary syndrome trial. AB - OBJECTIVES: To compare the radial versus femoral approach using Angio-Seal for the incidence of access site complications among non-ST-segment elevation acute coronary syndrome patients undergoing invasive strategy. BACKGROUND: Arterial access is a major site of complications after invasive coronary procedures. Vascular closure devices provide more comfort to patients decreasing time to hemostasis and need for bed rest. However, the inconsistency of data proving their safety limits their routine adoption as a strategy to prevent vascular complications. METHODS: Single-center non-inferiority trial where 240 patients were randomized to radial or femoral access using Angio-Seal. The primary objective was the occurrence of complications at the arterial puncture site until 30 days after the procedure. RESULTS: There were no baseline clinical differences between groups, except for a greater prevalence of female patients in the radial group (33.3 vs. 20.0%, P = 0.020). Hemostasis was achieved in the entire radial group with the use of TR Band and in 95% of the procedures in the femoral group with Angio-Seal (P = 0.029). Except for a higher incidence of asymptomatic arterial occlusion in the radial group, there were no differences among the other analyzed outcomes. According to the noninferiority test, the use of Angio-Seal was noninferior to the radial approach, considering the margin of 15% (12.5 vs. 13.3%, difference -0.83%, 95% CI -9.31 - 7.65, P for noninferiority <0.001). CONCLUSIONS: Angio-Seal seems noninferior in the incidence of access site complications at 30 days when compared with the radial approach. (c) 2016 Wiley Periodicals, Inc. PMID- 27514321 TI - Supramolecular Interactions Direct the Formation of Two Structural Polymorphs from One Building Unit in a One-Pot Synthesis. AB - Two polymorphs of supramolecular isomers, a discrete dimer and a zig-zag chain, having the same chemical composition, [Mn(Hbit)Cl2 ] (Hbit=1-methyl-2-(1H-1,2,3 triazol-4-yl)-1H-benzo[d]imidazole), were obtained solvothermally in a one-pot synthesis. The isomers differ in a number of ways: orange blocks versus pale yellow needles, triclinic P1? versus orthorhombic Pbcn, double MU2 -Cl versus alternate single and triple MU2 -Cl, coordination number 5 versus 6, and antiparallel versus parallel near-neighbor orientation of Hbit. The packing in each case is driven by the supramolecular interactions, H-bonds (N-H???Cl, C H???Cl) and pi???pi overlaps, calculated to be in the range 20-36 kcal mol-1 . Calculations gave a difference of only 2 kcal mol-1 in favor of the dimer, which confirms with the observation of principally the dimer at short reaction time. ESI-MS spectra of the dissolved crystals reveal the same fragments with similar distributions. The presence of two fragments at m/z 286.96 [MnIV (Hbit)Cl-2H]+ and 323.94 [MnIII (Hbit)Cl2 ]+ indicates that [Mn(Hbit)Cl2 ] is the building unit in both cases; thus, the different orientations of the ligands lead to the two polymorphs stabilized by the respective supramolecular interactions. Importantly, the chain form represents the first example with alternate single and triple MU2 Cl bridges. The magnetic interactions are weakly antiferromagnetic in both cases, with J in the range 0.07-0.34 cm-1 ; however, high-field EPR analysis reveals moderate magneto-anisotropy with D=0.26(1) cm-1 , E=0.06(1) cm-1 and D=0.17(1) cm 1 , E=0.03(1) cm-1 , respectively. PMID- 27514322 TI - Outcome of living donor liver transplantation using right liver allografts with multiple arterial supply. AB - A right liver graft with multiple hepatic artery (HA) stumps can be found in approximately 5% of living donor liver transplantation (LDLT) using a right lobe graft. From January 2000 to June 2014, 1149 patients underwent LDLT procedures. Thirty patients with LDLT using a right lobe graft with multiple HA stumps and 149 patients with LDLT using a right lobe graft with a single HA stump were enrolled. These patients were divided into 3 groups: single HA (group 1, n = 149), multiple HAs with total reconstruction (group 2, n = 19), and multiple HAs with selective partial reconstruction (group 3, n = 11). Selective partial reconstruction was performed only when pulsatile back-bleeding was confirmed after larger HA reconstruction and sufficient intrahepatic arterial flow was confirmed by Doppler ultrasound (DUS). In group 2, the donor HAs were smaller (P < .001), and HA reconstruction took longer (P < .001). However, there was no significant difference among the groups regarding the arterial complication rate, biliary complication rate, and patient and graft survival. In conclusion, selective partial reconstruction of HA stumps for LDLT using a right lobe graft was feasible when intrahepatic arterial communication was confirmed by pulsatile back-bleeding from the smaller artery and DUS. Liver Transplantation 22 1649-1655 2016 AASLD. PMID- 27514324 TI - Read all about it. PMID- 27514323 TI - Magnetic molecularly imprinted polymers for the determination of beta-agonist residues in milk by ultra high performance liquid chromatography with tandem mass spectrometry. AB - A simple, accurate, and highly sensitive analytical method was developed in this study for the determination of nine beta-agonists in milk. In this method, a new magnetic adsorbent of molecularly imprinted polymers/magnetic nanoparticles prepared by simple physical blending was adopted, which enabled magnetic solid phase extraction. Thus, the resultant material can be separated from the solvent rapidly and conveniently by a magnet. Two kinds of molecularly imprinted polymer/magnetic nanoparticles materials were fabricated, and the characteristics of materials such as the ratio, pH, amount, desorption, and regeneration were investigated. The analytes were quantified by ultra high performance liquid chromatography coupled to an electrospray ionization tandem mass spectrometer operating in multiple reaction monitoring modes. The detection limit of the method was 0.003-0.3 MUg/L, and the detection capability was 0.01-0.3 MUg/L. The recoveries of these compounds were 65.7-114% at three spiked levels. Reproducibility represented by relative standard deviation was 11.2% or less. The method was successfully applied to the screening of real samples obtained from local markets and confirmation of the suspected target analytes. PMID- 27514325 TI - Oral health: An evidence-based approach. PMID- 27514326 TI - Managing drug addicts. PMID- 27514327 TI - Depression and dental outcomes. PMID- 27514328 TI - Antimicrobial resistance: COMs and OMFSs. PMID- 27514334 TI - What does the future hold for orthodontics? PMID- 27514331 TI - Course report: Intravenous conscious sedation training for the whole team. PMID- 27514336 TI - Edwin Russell Bishop. PMID- 27514337 TI - Rosalind (Ros) C. Randall. PMID- 27514338 TI - Making time for what's important: what elements should we value when planning practice-based professional training? AB - Newly qualified professional healthcare graduates, whether training to become doctors, dentists, veterinary surgeons or nurses, tend to need some support as they take their first steps along that bumpy road from university to confident, competent practice. We identify some key features of the UK programme of dental practice-based training to acknowledge its strengths - 12 months of clinical practice within a well-established dental team, one-to-one weekly meetings with the same dedicated mentor, regular peer learning with the same group of peers over 12 months and the opportunity to observe role models from the profession including training programme directors and other general dental practitioners (GDPs). This educational programme is unique to dentistry and this article outlines why we believe it is important to value these features when designing postgraduate professional training in healthcare sciences. PMID- 27514339 TI - A change in the NICE guidelines on antibiotic prophylaxis. AB - Since 2008, NICE clinical guidelines have stated: 'Antibiotic prophylaxis against infective endocarditis is not recommended for people undergoing dental procedures'. This put UK guidance at odds with guidance in the rest of the world, where antibiotic prophylaxis is recommended for patients at high-risk of infective endocarditis undergoing invasive dental procedures. Many dentists also felt this wording prohibited the use of antibiotic prophylaxis, regardless of the wishes of the patient or their personal risk of infective endocarditis and made it difficult for them to use their clinical judgment to deliver individualised care in the best interests of their patients. NICE have now changed this guidance to 'Antibiotic prophylaxis against infective endocarditis is not recommended routinely for people undergoing dental procedures.' This article examines the implications of this small but important change. PMID- 27514340 TI - A personal perspective and update on erosive tooth wear - 10 years on: Part 1 - Diagnosis and prevention. AB - Tooth wear has been recognised as an increasing problem over the past 10 years. Recent data from epidemiological studies indicate that the condition is common with prevalence of dentine exposure in adults ranging between 2% and 10% and visible surface changes on teeth observed up to 30% of European adults. The Basic Erosive Wear Examination (BEWE) was designed for general practitioners to score the severity using similar protocols as the Basic Periodontal Examination (BPE). The role of the BEWE is partly to increase awareness, but also a means to record the severity in the clinical notes. Over the past 10 years toothpaste manufacturers have launched products to prevent progression of erosive tooth wear using specially formulated fluorides or calcium based products. Probably the most important preventive advice is to reduce the frequency of acidic foods and drinks, particularly outside meal times. PMID- 27514341 TI - Reconnecting the mouth to the body. AB - The relationship between patient-reported general health and lifestyle factors and oral health outcomes. PMID- 27514342 TI - Is the provision of sedation fair? AB - Conscious sedation: is this provision equitable? Analysis of sedation services provided within primary dental care in England, 2012-2014. PMID- 27514343 TI - Energy or taste: why are teenagers drinking sports drinks? AB - A survey of sports drinks consumption among adolescents. PMID- 27514344 TI - 'Social anonymity': The ethics of facial transplantation. AB - '...unlikely to make people 'beautiful'; rather '[i]t will make them look normal and forgettable - that is its virtue'. PMID- 27514345 TI - Botulinum toxin - neuropathic pain: Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): a randomised, double blind, placebo-controlled trial. AB - When treated with botulinum toxin A, those patients with peripheral neuropathic pain and allodynia (triggering of pain from stimuli which do not normally provoke pain) at baseline, would appear to have a better outcome. PMID- 27514346 TI - Botulinum toxin - intraorally: Intraoral administration of botulinum toxin for trigeminal neuropathic pain. AB - Intraoral administration was used in addition to the conventional extraoral administration of botulinum toxin. PMID- 27514350 TI - Corrigendum. PMID- 27514360 TI - Erratum. PMID- 27514349 TI - Orthodontics in antiquity: myth or reality. AB - Malocclusion, although a common finding in today's world, appears to have been less frequent in antiquity. There are references to overcrowding, delayed exfoliation of deciduous teeth and basic orthodontic treatment in the writings of classical authors such as Hippocrates, Celsus and Galen. However, early authentic archaeological finds of dental appliances are extremely rare. Considerable attention has focussed on gold banded devices excavated from ancient Etruscan sites in central Italy which have been dated to around the seventh to the fourth centuries BC, with a number of authors suggesting an orthodontic function for these appliances. This paper reviews the evidence for the possible treatment of malocclusions in antiquity and concludes that the use of orthodontic appliances to facilitate tooth movement is not supported by the available evidence. PMID- 27514348 TI - An assessment of student experiences and learning based on a novel undergraduate e-learning resource. AB - Purpose/objectives The aims of this study were to describe the development of a novel e-learning resource and to assess its impact on student learning experiences and orthodontic knowledge.Methods Thirty-two 4th year dental undergraduate students at Queen Mary University of London were randomly allocated to receive electronic access to e-learning material covering various undergraduate orthodontic topics over a 6-week period. Thirty-one control students were not given access during the study period. All students were asked to complete electronic quizzes both before (T0) and after (T1) the study period and a general questionnaire concerning familiarity with e-learning. The test group also completed a user satisfaction questionnaire at T1. Two focus groups were also undertaken to explore learners' experiences and suggestions in relation to the resource.Results The mean quiz result improved by 3.9% and 4.5% in the control and test groups, respectively. An independent t-test, however, demonstrated a lack of statistical significance in knowledge gain between control and test groups (P = 0.941). The qualitative feedback indicated that students believed that use of the resource enhanced knowledge and basic understanding with students expressing a wish to ingrain similar resources in other areas of undergraduate teaching.Conclusions Use of the novel orthodontic e-resource by 4th year undergraduate students over a 6-week period did not result in a significant improvement in subject knowledge. However, the e-learning has proven popular among undergraduates and the resources will continue to be refined. PMID- 27514364 TI - The unbearable lightness of simplicity. PMID- 27514362 TI - Discovery of HLA-B*58:80, a novel HLA-B*58 variant, in a Taiwanese bone marrow donor. AB - One nucleotide substitution at residue 133 of HLA-B*58:01:01:01 results in a novel allele, HLA-B*58:80. PMID- 27514363 TI - Pemphigus foliaceus with circinated plaques and neutrophil pustules. AB - Pemphigus is a group of autoimmune intraepidermal bullous diseases; being pemphigus foliaceus (PF) and pemphigus vulgaris (PV) the most common subtypes. Pustular variants are scarcely reported for both PV and PF. The purpose of this manuscript was to describe the clinical, microscopic and immunologic findings of an atypical case of PF presenting with pustules, including a review of the literature. PF is described as blisters and because this entity is rare, it is not known for the general medical community that they are other clinical features that can be seen as this one we present here with pustules. PMID- 27514365 TI - Characterization of loxoprofen transport in Caco-2 cells: the involvement of a proton-dependent transport system in the intestinal transport of loxoprofen. AB - Loxoprofen, a propionate non-steroidal anti-inflammatory drug (NSAID), is used widely in East Asian countries. However, little is known about the transport mechanisms contributing to its intestinal absorption. The objectives of this study were to characterize the intestinal transport of loxoprofen using the human intestinal Caco-2 cell model. The transport of loxoprofen was investigated in cellular uptake studies. The uptake of loxoprofen into Caco-2 cells was pH- and concentration-dependent, and was described by a Michaelis-Menten equation with passive diffusion (Km : 4.8 mm, Vmax : 142 nmol/mg protein/30 s, and Kd : 2.2 MUl/mg protein/30 s). Moreover, the uptake of loxoprofen was inhibited by a typical monocarboxylate transporter (MCT) inhibitor as well as by various monocarboxylates. The uptake of [14 C] l-lactic acid, a typical MCT substrate, in Caco-2 cells was saturable with relatively high affinity for MCT. Because loxoprofen inhibited the uptake of [14 C] l-lactic acid in a noncompetitive manner, it was unlikely that loxoprofen uptake was mediated by high-affinity MCT(s). Our results suggest that transport of loxoprofen in Caco-2 cells is, at least in part, mediated by a proton-dependent transport system. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 27514347 TI - Evaluating denture cleanliness of patients in a regional dental hospital. AB - Aims To evaluate the quality of clinical record keeping and determine quality of denture cleanliness; record baseline denture cleanliness for 60 patients; introduce denture hygiene instruction (DHI); and then re-assess the patients for improvement and enhanced record keeping.Methods Analysis of patients' denture hygiene instruction record keeping (n = 60) was undertaken retrospectively. The Denture Cleanliness Index (DCI) was utilised to assess denture cleanliness (best score 0, worst score 4). Baseline DCI scores were taken and individual DHI was delivered. After one month, patients were reviewed and scored, with record keeping quality analysed.Results At baseline, 11.7% (n = 7) of patients had DCI scores of <=2, improving to 93.8% (n = 45) after one month, demonstrating short term improvement in denture cleanliness. Only 63% (n = 38) of patients had evidence of a record of DHI within their notes at baseline, improving to 100% at recall.Conclusions New patient information leaflet and clinical guidelines on denture hygiene have been written and implemented. The results of this study suggest that this may be a relatively straightforward method to achieve a short term improvement in denture cleanliness. The implementation of a DCI score is helpful in allowing patients to improve denture hygiene and its wider use is supported. PMID- 27514366 TI - Systematic review of interventions for depression and anxiety in persons with inflammatory bowel disease. AB - BACKGROUND: Depression and anxiety are common in inflammatory bowel disease (IBD) and can affect disease outcomes, including quality of life and success of disease treatment. Successful management of psychiatric comorbidities may improve outcomes, though the effectiveness of existing treatments in IBD is unknown. METHODS: We searched multiple online databases from inception until March 25, 2015, without restrictions on language, date, or location of publication. We included controlled clinical trials conducted in persons with IBD and depression or anxiety. Two independent reviewers reviewed all abstracts and full-text articles and extracted information including trial and participant characteristics. We also assessed the risk of bias. RESULTS: Of 768 unique abstracts, we included one trial of pharmacological anxiety treatment in IBD (48 participants), which found an improvement in anxiety symptoms (p < 0.001). There was a high risk of bias in this trial. We found no controlled clinical trials on the treatment of depression in persons with IBD and depression and no controlled clinical trials reporting on psychological interventions for anxiety or depression in IBD. CONCLUSIONS: Only one trial examined an intervention for anxiety in adults with IBD and no trials studied depression in adults with IBD. The level of evidence is low because of the risk of bias and limited evidence. PMID- 27514367 TI - PCR detection of Burkholderia multivorans in water and soil samples. AB - BACKGROUND: Although semi-selective growth media have been developed for the isolation of Burkholderia cepacia complex bacteria from the environment, thus far Burkholderia multivorans has rarely been isolated from such samples. Because environmental B. multivorans isolates mainly originate from water samples, we hypothesized that water rather than soil is its most likely environmental niche. The aim of the present study was to assess the occurrence of B. multivorans in water samples from Flanders (Belgium) using a fast, culture-independent PCR assay. RESULTS: A nested PCR approach was used to achieve high sensitivity, and specificity was confirmed by sequencing the resulting amplicons. B. multivorans was detected in 11 % of the water samples (n = 112) and 92 % of the soil samples (n = 25) tested. The percentage of false positives was higher for water samples compared to soil samples, showing that the presently available B. multivorans recA primers lack specificity when applied to the analysis of water samples. CONCLUSIONS: The results of the present study demonstrate that B. multivorans DNA is commonly present in soil samples and to a lesser extent in water samples in Flanders (Belgium). PMID- 27514368 TI - New insights into discrepancies between self-reported and accelerometer-measured moderate to vigorous physical activity among women - the mPED trial. AB - BACKGROUND: The aims of this report were 1) to describe the duration of moderate to vigorous physical activity (MVPA) and the proportion of participants meeting the recommended criterion of at least 150 min of MVPA per week as measured by the 7 Day Physical Activity Recall Questionnaire (7D-PAR) and accelerometer among women who were enrolled in the mPED trial; 2) to assess the level of agreement of the two measures using a Bland-Altman plot; and 3) to describe the positive and negative predictive values (PPV and NPV, respectively) of meeting the guidelines by calculating the percentage of women meeting the physical activity recommendation by the 7D-PAR who also met this recommendation based on data from the accelerometer. METHODS: Baseline data on duration of MVPA from the mPED trial were analyzed for 215 women. Among the women who met the recommended criterion by the 7D-PAR (self-report), we calculated the proportion of individuals who also met it by the accelerometer (objective measure). A Bland Altman Plot was used to assess concordance between the two measures. RESULTS: The mean age was 52.4 (+/ 11.2) years; 54.4 % were white; and 48.8 % were single or divorced. While median MVPA was 160 min/week by the 7D-PAR, it was only 24 min/week in the accelerometer. A total of 117 women met the 150-min criterion by the 7D-PAR. Of these, only 18 also met the criterion by the objective measure (PPV 15.4 %, 95 % CI 9.4-23.2 %). Among the 98 women who did not meet the criterion by the 7D-PAR, none met it by the accelerometer (NPV 100 %). A Bland Altman plot showed the mean difference of +145 min between the two measures with a 95 % limit of agreement at + 471 to -181 min. CONCLUSIONS: The large discrepancy between the self-reported and objective measures of MVPA meeting the 150-min criterion suggests that self reported physical activity measures should be used with caution in intervention studies. While our data suggest that self-report could be used to identify a physically inactive sample, it would be likely to over-estimate the proportions of women who become active in one or both arms of trials of interventions promoting MVPA. TRIAL REGISTRATION: ClinicalTrials.gov NCT01280812. PMID- 27514369 TI - Multiple systemic embolism in infective endocarditis underlying in Barlow's disease. AB - BACKGROUND: Systemic embolism, especially septic embolism, is a severe complication of infective endocarditis (IE). However, concurrent embolism to the brain, coronary arteries, and spleen is very rare. Because of the risk of hemorrhage or visceral rupture, anticoagulants are recommended only if an indication is present, e.g. prosthetic valve. Antiplatelet therapy in IE is controversial, but theoretically, this therapy has the potential to prevent and treat thrombosis and embolism in IE. Unfortunately, clinical trial results have been inconclusive. CASE PRESENTATION: We describe a previously healthy 50-year old man who presented with dysarthria secondary to bacterial endocarditis with multiple cerebral, coronary, splenic, and peripheral emboli; antibiotic therapy contributed to the multiple emboli. Emergency splenectomy was performed, with subsequent mitral valve repair. Pathological examination confirmed mucoid degeneration and mitral valve prolapse (Barlow's disease) as the underlying etiology of the endocardial lesion. Continuous antibiotics were prescribed, postoperatively. Transthoracic echocardiography at 1.5, 3, and 6 months after the onset of his illness showed no severe regurgitation, and there was no respiratory distress, fever, or lethargy during follow-up. CONCLUSIONS: Although antibiotic use in IE carries a risk of septic embolism, these drugs have bactericidal and antithrombotic benefits. It is important to consider that negative blood culture and symptom resolution do not confirm complete elimination of bacteria. However, vegetation size and Staphylococcus aureus infection accurately predict embolization. It is also important to consider that bacteria can be segregated from the microbicide when embedded in platelets and fibrin. Therefore, antimicrobial therapy with concurrent antiplatelet therapy should be considered carefully. PMID- 27514370 TI - Biomimetic coatings enhance tribocorrosion behavior and cell responses of commercially pure titanium surfaces. AB - Biofunctionalized surfaces for implants are currently receiving much attention in the health care sector. Our aims were (1) to create bioactive Ti-coatings doped with Ca, P, Si, and Ag produced by microarc oxidation (MAO) to improve the surface properties of biomedical implants, (2) to investigate the TiO2 layer stability under wear and corrosion, and (3) to evaluate human mesenchymal stem cells (hMSCs) responses cultured on the modified surfaces. Tribocorrosion and cell experiments were performed following the MAO treatment. Samples were divided as a function of different Ca/P concentrations and treatment duration. Higher Ca concentration produced larger porous and harder coatings compared to the untreated group (p < 0.001), due to the presence of rutile structure. Free potentials experiments showed lower drops (-0.6 V) and higher coating lifetime during sliding for higher Ca concentration, whereas lower concentrations presented similar drops (-0.8 V) compared to an untreated group wherein the drop occurred immediately after the sliding started. MAO-treated surfaces improved the matrix formation and osteogenic gene expression levels of hMSCs. Higher Ca/P ratios and the addition of Ag nanoparticles into the oxide layer presented better surface properties, tribocorrosive behavior, and cell responses. MAO is a promising technique to enhance the biological, chemical, and mechanical properties of dental implant surfaces. PMID- 27514371 TI - Combination treatment with mirabegron and solifenacin in patients with overactive bladder: exploratory responder analyses of efficacy and evaluation of patient reported outcomes from a randomized, double-blind, factorial, dose-ranging, Phase II study (SYMPHONY). AB - PURPOSE: This large dose-ranging study explored the benefits of different combinations of mirabegron and solifenacin on health-related quality of life (HRQoL), based on patient-reported outcomes (PROs), and patients ('responders') achieving clinically meaningful improvements in efficacy and HRQoL. METHODS: SYMPHONY (NCT01340027) was a Phase II, placebo- and monotherapy-controlled, dose ranging, 12-week trial. Adult patients with overactive bladder (OAB) for >=3 months were randomized to 1 of 12 groups: 6 combination (solifenacin 2.5/5/10 mg + mirabegron 25/50 mg), 5 monotherapy (solifenacin 2.5/5/10 mg, or mirabegron 25/50 mg), or placebo. Change from baseline to end of treatment was assessed, versus placebo and solifenacin 5 mg in: PROs (OAB-q [Symptom Bother/total HRQoL] and Patient Perception of Bladder Condition score), and responders achieving minimally important differences (MIDs) in PROs and predetermined clinically meaningful improvements in efficacy (e.g. <8 micturitions/24 h). Changes in PROs and responders were analysed using an ANCOVA model and logistic regression, respectively. RESULTS: The Full Analysis Set included 1278 patients. Combination therapy of solifenacin 5/10 mg + mirabegron 25/50 mg significantly improved PROs versus solifenacin 5 mg and placebo, and significantly more responders achieved MIDs in PROs and efficacy. Micturition frequency normalization was approximately twofold greater with 10 + 25 mg (OR 2.06 [95 % CI 1.11, 3.84; p = 0.023]) and 5 + 50 mg (OR 1.91 [95 % CI 1.14, 3.21; p = 0.015]) versus solifenacin 5 mg. CONCLUSION: Combining mirabegron 25/50 mg and solifenacin 5/10 mg improves objective and subjective efficacy outcomes compared with placebo or solifenacin 5 mg. PMID- 27514372 TI - Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users' views. AB - BACKGROUND: Whole-exome sequencing (WES) consists in the capture, sequencing and analysis of all exons in the human genome. Originally developed in the research context, this technology is now increasingly used clinically to inform patient care. The implementation of WES into healthcare poses significant organizational, regulatory, and ethical hurdles, which are widely discussed in the literature. METHODS: In order to inform future policy decisions on the integration of WES into standard clinical practice, we performed a systematic literature review to identify the most important challenges directly reported by technology users. RESULTS: Out of 2094 articles, we selected and analyzed 147 which reported a total of 23 different challenges linked to the production, analysis, reporting and sharing of patients' WES data. Interpretation of variants of unknown significance, incidental findings, and the cost and reimbursement of WES-based tests were the most reported challenges across all articles. CONCLUSIONS: WES is already used in the clinical setting, and may soon be considered the standard of care for specific medical conditions. Yet, technology users are calling for certain standards and guidelines to be published before this technology replaces more focused approaches such as gene panels sequencing. In addition, a number of infrastructural adjustments will have to be made for clinics to store, process and analyze the amounts of data produced by WES. PMID- 27514373 TI - Cost of rotavirus diarrhea for programmatic evaluation of vaccination in Vietnam. AB - BACKGROUND: Rotavirus is the most common etiology of diarrhea-associated hospitalizations and clinic visits in Vietnamese children < 5 years old. To estimate the economic burden of rotavirus-associated formal healthcare encounters, an economic study was conducted. METHODS: A cost-of-illness study was performed from a societal perspective. Data were collected from children below the age of five years who presented to a clinic or hospital with symptoms of acute gastroenteritis (AGE). Patient-specific information on resource use and cost was obtained through caregiver interviews and medical chart review. Costs are presented in 2014 US dollar ($). RESULTS: A total of 557 children with symptoms of AGE were enrolled from March through June 2009, with mean age of 16.5 months. Of the 340 outpatients and 217 admitted patients enrolled, 41 % tested rotavirus positive. It was found that, from a societal perspective, the mean total cost of AGE was $175. Costs of patients with and without rotavirus were $217 and $158, respectively. From multiple regression analysis, it was found that rotavirus infection, patient age and receiving oral rehydration solution before visiting health facility had significant effect on the costs. CONCLUSIONS: This study clearly demonstrated substantial economic burden of AGE including rotavirus disease. They were significantly greater than the previously reported cost estimates in Vietnam. These updated costs of illness result in more favorable vaccine cost-effectiveness than in previous economic evaluations. PMID- 27514374 TI - Association between mesothelin expression and survival outcomes in patients with triple-negative breast cancer: a protocol for a systematic review. AB - BACKGROUND: Mesothelin is a membrane-bound glycoprotein. Although the biologic function of mesothelin is not very clear, researchers have found that it plays a role in the survival, proliferation, and migration of tumor cells. Identified as a tumor-associated biomarker, mesothelin is more often overexpressed in triple negative breast cancer (TNBC) than in common luminal breast tumor subtype or normal tissues. The objective of this review is to determine the association between the expression of mesothelin and overall survival in patients with TNBC. METHODS/DESIGN: We will search the following electronic databases: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Web of Science with no time or language restriction. Prospective or retrospective longitudinal studies that investigate mesothelin expression in TNBC or the prognosis of TNBC with mesothelin baseline measurement will be selected. Two reviewers will independently assess every abstract or full text for inclusion. Data on clinical outcomes, as well as on study design, research setting, study population, demographic characteristics of the participants, and methodological quality, will be extracted using a structured codebook developed by the authors. A pooled measure of associations will be assessed through meta-analyses if appropriate. Heterogeneity across the included studies will be evaluated using the I (2) statistics. Findings will be reported according to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The quality of evidence and risk of bias of the studies will be evaluated. DISCUSSION: The aim of this systematic review is to synthesize the evidence regarding the association between the expression of mesothelin and the survival outcomes of patients with TNBC. A better understanding of the expression frequency and prognostic value of mesothelin in TNBC will be essential to identifying a novel therapeutic target. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016036212. PMID- 27514375 TI - Transcriptomics of liver and muscle in Holstein cows genetically divergent for fertility highlight differences in nutrient partitioning and inflammation processes. AB - BACKGROUND: The transition between pregnancy and lactation is a major physiological change for dairy cows. Complex systemic and local processes involving regulation of energy balance, galactopoiesis, utilisation of body reserves, insulin resistance, resumption of oestrous cyclicity and involution of the uterus can affect animal productivity and hence farm profitability. Here we used an established Holstein dairy cow model of fertility that displayed genetic and phenotypic divergence in calving interval. Cows had similar genetic merit for milk production traits, but either very good genetic merit for fertility traits ('Fert+'; n = 8) or very poor genetic merit for fertility traits ('Fert-'; n = 8). We used RNA sequencing to investigate gene expression profiles in both liver and muscle tissue biopsies at three distinct time-points: late pregnancy, early lactation and mid lactation (-18, 1 and 147 days relative to parturition, respectively). RESULTS: We found 807 and 815 unique genes to be differentially expressed in at least one time-point in liver and muscle respectively, of which 79 % and 83 % were only found in a single time-point; 40 and 41 genes were found differentially expressed at every time-point indicating possible systemic or chronic dysregulation. Functional annotation of all differentially expressed genes highlighted two physiological processes that were impacted at every time point in the study, These were immune and inflammation, and metabolic, lipid and carbohydrate-binding. CONCLUSION: These pathways have previously been identified by other researchers. We show that several specific genes which are differentially regulated, including IGF-1, might impact dairy fertility. We postulate that an increased burden of reactive oxidation species, coupled with a chronic inflammatory state, might reduce dairy cow fertility in our model. PMID- 27514376 TI - The estrogen-related receptors (ERRs): potential targets against bone loss. AB - Bone loss and the resulting skeletal fragility is induced by several pathological or natural conditions, the most prominent of which being aging as well as the decreased levels of circulating estrogens in post-menopause females. To date, most treatments against bone loss aim at preventing excess bone resorption. We here summarize data indicating that the estrogen-related receptors (ERRs) alpha and gamma prevent bone formation. Inhibiting these receptors may thus constitute an anabolic approach by increasing bone formation. PMID- 27514377 TI - Female cats, but not males, adjust responsiveness to arousal in the voice of kittens. AB - BACKGROUND: The infant cry is the most important communicative tool to elicit adaptive parental behaviour. Sex-specific adaptation, linked to parental investment, may have evolutionary shaped the responsiveness to changes in the voice of the infant cries. The emotional content of infant cries may trigger distinctive responsiveness either based on their general arousing properties, being part of a general affect encoding rule, or based on affective perception, linked to parental investment, differing between species. To address this question, we performed playback experiments using infant isolation calls in a species without paternal care, the domestic cat. We used kitten calls recorded in isolation contexts inducing either Low arousal (i.e., isolation only) or High arousal (i.e., additional handling), leading to respective differences in escape response of the kittens. We predicted that only females respond differently to playbacks of Low versus High arousal kitten isolation calls, based on sex differences in parental investment. RESULTS: Findings showed sex-specific responsiveness of adult cats listening to kitten isolation calls of different arousal conditions, with only females responding faster towards calls of the High versus the Low arousal condition. Breeding experience of females did not affect the result. Furthermore, female responsiveness correlated with acoustic parameters related to spectral characteristics of the fundamental frequency (F0): Females responded faster to kitten calls with lower F0 at call onset, lower minimum F0 and a steeper slope of the F0. CONCLUSIONS: Our study revealed sex specific differences in the responsiveness to kitten isolation calls of different arousal conditions independent of female breeding experience. The findings indicated that features of F0 are important to convey the arousal state of an infant. Taken together, the results suggest that differences in parental investment evolutionary shaped responsiveness (auditory sensitivity/ motivation) to infant calls in a sex-specific manner in the domestic cat. PMID- 27514378 TI - Lipopolysaccharide induces SBD-1 expression via the P38 MAPK signaling pathway in ovine oviduct epithelial cells. AB - BACKGROUND: Beta defensins are secreted from ovine oviduct epithelial cells (OOECs) in response to microbial infection, and are potential alternatives to antibiotic agents in the treatment of microorganism infection, particularly given the abuse of antibiotic agents and the increasing number of drug-resistant bacteria. The aberrant expression of defensins may result in disorders involving organ and oviduct inflammation, such as salpingitis. METHODS: In the present study, we investigated the effects of LPS on the mRNA expression levels of sheep beta-defensin-1 (SBD-1) in ovine oviduct epithelial cells. The OOECs in vitro culturing system were established and treated with different concentrations of LPS for indicated time. In addition, MAPK inhibitors and TLR4 antibodies were pretreated to investigate the potential mechanism which involves in LPS regulating SBD-1 expression. RESULTS: LPS markedly upregulated SBD-1 expression in a concentration- and time-dependent manner. Treatment with 100 ng/mL LPS resulted in the phosphorylation of JNK, ERK and P38 MAPK. Interestingly, the LPS stimulated SBD-1 expression was attenuated by pretreatment with the P38 MAPK inhibitors SB203580 and SB202190 but not the JNK inhibitor SP600125, while the ERK inhibitor PD98059 had a minor effect. Furthermore, treatment with a Toll-like receptor 4 (TLR4) neutralizing antibody significantly decreased P38 MAPK phosphorylation and LPS induced SBD-1 expression. CONCLUSIONS: Together, these findings suggest that SBD-1 is upregulated by LPS via the TLR4 receptor, mainly through the P38 MAPK signaling pathway in ovine oviduct epithelial cells to protect the ovine oviduct epithelium from pathogen invasion. PMID- 27514379 TI - Self-reported practices among traditional birth attendants surveyed in western Kenya: a descriptive study. AB - BACKGROUND: The high rate of home deliveries conducted by unskilled birth attendants in resource-limited settings is an important global health issue because it is believed to be a significant contributing factor to maternal and newborn mortality. Given the large number of deliveries that are managed by unskilled or traditional birth attendants outside of health facilities, and the fact that there is on-going discussion regarding the role of traditional birth attendants in the maternal newborn health (MNH) service continuum, we sought to ascertain the practices of traditional birth attendants in our catchment area. The findings of this descriptive study might help inform conversations regarding the roles that traditional birth attendants can play in maternal-newborn health care. METHODS: A structured questionnaire was used in a survey that included one hundred unskilled birth attendants in western Kenya. Descriptive statistics were employed. RESULTS: Inappropriate or outdated practices were reported in relation to some obstetric complications and newborn care. Encouraging results were reported with regard to positive relationships that traditional birth attendants have with their local health facilities. Furthermore, high rates of referral to health facilities was reported for many common obstetric emergencies and similar rates for reporting of pregnancy outcomes to village elders and chiefs. CONCLUSIONS: Potentially harmful or outdated practices with regard to maternal and newborn care among traditional birth attendants in western Kenya were revealed by this study. There were high rates of traditional birth attendant referrals of pregnant mothers with obstetric complications to health facilities. Policy makers may consider re-educating and re-defining the roles and responsibilities of traditional birth attendants in maternal and neonatal health care based on the findings of this survey. PMID- 27514382 TI - Rapid Development of Omentum Metastasis Following Stereotactic Body Radiotherapy (Sbrt) to Para-Aortic Lymph Nodes from Colon Cancer. PMID- 27514380 TI - Traditional medicine practices among community members with diabetes mellitus in Northern Tanzania: an ethnomedical survey. AB - BACKGROUND: Diabetes is a growing burden in sub-Saharan Africa where traditional medicines (TMs) remain a primary form of healthcare in many settings. In Tanzania, TMs are frequently used to treat non-communicable diseases, yet little is known about TM practices for non-communicable diseases like diabetes. METHODS: Between December 2013 and June 2014, we assessed TM practices, including types, frequencies, reasons, and modes, among randomly selected community members. To further characterize TMs relevant for the local treatment of diabetes, we also conducted focus groups and semi-structured interviews with key informants. RESULTS: We enrolled 481 adults of whom 45 (9.4 %) had diabetes. The prevalence of TM use among individuals with diabetes was 77.1 % (95 % CI 58.5-89.0 %), and the prevalence of using TMs and biomedicines concurrently was 37.6 % (95 % CI 20.5-58.4 %). Many were using TMs specifically to treat diabetes (40.3 %; 95 % CI 20.5-63.9), and individuals with diabetes reported seeking healthcare from traditional healers, elders, family, friends, and herbal vendors. We identified several plant-based TMs used toward diabetes care: Moringa oleifera, Cymbopogon citrullus, Hagenia abyssinica, Aloe vera, Clausena anisata, Cajanus cajan, Artimisia afra, and Persea americana. CONCLUSIONS: TMs were commonly used for diabetes care in northern Tanzania. Individuals with diabetes sought healthcare advice from many sources, and several individuals used TMs and biomedicines together. The TMs commonly used by individuals with diabetes in northern Tanzania have a wide range of effects, and understanding them will more effectively shape biomedical practitices and public health policies that are patient-centered and sensitive to TM preferences. PMID- 27514381 TI - Relationship between TMEM16A/anoctamin 1 and LRRC8A. AB - TMEM16A/anoctamin 1/ANO1 and VRAC/LRRC8 are independent chloride channels activated either by increase in intracellular Ca(2+) or cell swelling, respectively. In previous studies, we observed overlapping properties for both types of channels. (i) TMEM16A/ANO1 and LRRC8 are inhibited by identical compounds, (ii) the volume-regulated anion channel VRAC requires compartmentalized Ca(2+) increase to be fully activated, (iii) anoctamins are activated by cell swelling, (iv) both channels have a role for apoptotic cell death, (v) both channels are possibly located in lipid rafts/caveolae like structures, and (vi) VRAC and anoctamin 1 currents are not additive when each are fully activated. In the present study, we demonstrate in different cell types that loss of LRRC8A expression not only inhibited VRAC, but also attenuated Ca(2+) activated Cl(-) currents. Moreover, expression of LRRC8A enhanced Ca(2+) activated Cl(-) currents, and both LRRC8A and ANO1 could be coimmunoprecipitated. We found that LRRC8A becomes accessible to biotinylation upon exposure to hypotonic bath solution, while membrane capacitance was not enhanced. When intracellular Ca(2+) was increased in ANO1-expressing cells, the membrane capacitance was enhanced and increased binding of FM4-64 to the membrane was observed. As this was not seen in cells lacking ANO1 expression, a role of ANO1 for exocytosis was suggested. We propose that ANO1 and LRRC8A are activated in parallel. Thus, ionomycin or purinergic stimulation will not only activate ANO1 but also LRRC8 currents. Cell swelling will not only activate LRRC8/VRAC, but also stimulate ANO1 currents by enhancing compartmentalized Ca(2+) increase and/or through swelling induced autocrine release of ATP. PMID- 27514384 TI - Retraction Note to: Assessment of neuromuscular block at the orbicularis oris, corrugator supercilii, and adductor pollicis muscles. PMID- 27514383 TI - Effect of transcatheter aortic valve implantation on intraoperative left ventricular end-diastolic pressure. AB - Transcatheter aortic valve implantation (TAVI) for patients with aortic stenosis is a less invasive alternative to surgical aortic valve replacement. Despite this, careful anesthetic management, especially strict control of blood pressure and fluid management, is necessary. During TAVI, normalization of left ventricular afterload due to aortic balloon valvuloplasty and prosthetic valve deployment is expected to result in rapid improvement of systolic function and consequent improvement in diastolic function. However, the early effect of TAVI on left ventricular diastolic function is less clear. We hypothesized that TAVI induces a rapid decrease in left ventricular end-diastolic pressure (LVEDP) after valve deployment. This retrospective observational study included 71 patients who had undergone TAVI using the transfemoral approach with a balloon-expandable valve under general anesthesia. Intraoperative LVEDP was measured using an intracardiac catheter. The severity of residual aortic regurgitation (AR) was assessed using the Sellers criteria. The mean (SD) LVEDP was 17.8 (5.3) mmHg just before TAVI and increased significantly to 27.3 (8.2) mmHg immediately after prosthetic valve deployment (p < 0.0001). The change in LVEDP was 8.7 (8.6) mmHg in patients with low residual AR (Sellers <=1) and 11.0 (7.1) mmHg in those with high residual AR (Sellers >=2); however, this difference was not significant. No correlation was found between the LVEDP change and intraoperative fluid balance. In conclusion, LVEDP increased significantly in the early period after valve deployment during TAVI, regardless of residual AR severity. It was suggested that the tolerability of fluid load could be reduced at that time. PMID- 27514385 TI - Vital role for the J-domain protein Mdj1 in asexual development, multiple stress tolerance, and virulence of Beauveria bassiana. AB - Mdj1 is a member of the Hsp40 family containing a DnaJ or J domain. Here, we have examined the functions of an Mdj1 orthologue (56.68 kDa) in Beauveria bassiana, a filamentous fungal insect pathogen widely applied in biological control of insect pests. Deletion of mdj1 in B. bassiana resulted in significant growth defects on a variety of complex and minimal media. The Deltamdj1 mutant exhibited not only a drastic reduction (92 %) in aerial conidiation during optimal cultivation but also a remarkable decrease (77 %) in submerged blastospore production. Compared to wild-type, the deletion mutant was significantly more sensitive to the stresses of cell wall perturbation, high osmolarity, oxidation, carbendazim fungicide, several metal ions, and acidic/alkaline pH during conidial germination and/or colony growth. In the mutant, conidial thermotolerance and UV-B resistance decreased by 61 and 25 %, respectively, and virulence to Galleria mellonella larvae was largely attenuated. Transcript levels of many phenotype-related genes were drastically suppressed in the absence of mdj1, accompanied with impaired cell walls and reduced intracellular anti-stress molecules, including superoxide dismutases, catalases, glycerol, trehalose, and mannitol. These data indicate that Mdj1 plays a vital role in normal fungal development and contributes significantly to the biological control potential of B. bassiana against insect pests. PMID- 27514387 TI - Correction. PMID- 27514386 TI - Sugiyamaella mastotermitis sp. nov. and Papiliotrema odontotermitis f.a., sp. nov. from the gut of the termites Mastotermes darwiniensis and Odontotermes obesus. AB - Two novel yeast species were isolated from the guts of two different termite species. A new member of the genus Sugiyamaella was isolated from the hindgut and nest material of the lower Australian termite Mastotermes darwiniensis. The second novel yeast species, isolated from the higher termite Odontotermes obesus, was identified as a member of the genus Papiliotrema. Both yeast species were able to hydrolyse xylan, methylumbelliferyl beta-xylobiose and methylumbelliferyl beta-xylotriose. The ability to debranch different hemicellulose side chains and growth without the addition of external vitamins was observed. A symbiotic role of the novel yeast species is indicated, especially in respect to xylan degradation and the production of vitamins. Here, we describe these species as Sugiyamaella mastotermitis sp. nov., MycoBank 816574 (type strain MD39VT=DSM 100793T=CBS 14182T), and Papiliotrema odontotermitis f.a., sp. nov., MycoBank 816575 (type strain OO5T=DSM 100791T=CBS 14181T). Additionally, we transfer Candida qingdaonensis to the genus Sugiyamaella and propose the following combination: Sugiyamaella qingdaonensis f.a., comb. nov., MycoBank 816576. PMID- 27514388 TI - [Quality in urology]. PMID- 27514390 TI - The Iodine Status of Queensland Preschool Children After the Introduction of Mandatory Iodine Fortification in Bread: An Exploratory Study Using a Convenience Sample. AB - Introduction Appropriate dietary iodine is essential for thyroid hormone synthesis, especially in young children. Following an iodine fortification in bread initiative, approximately 6 % of Australian preschool children were expected to have an excessive iodine status. The aim of this study was to document the current iodine status of preschool children using urinary iodine concentration (UIC) as a biomarker of iodine intake. Methods A convenience sample of fifty-one preschool children, aged 2-3 years, were recruited from south east Queensland. UIC was ascertained from spot morning and afternoon urine samples collected on two consecutive days and food frequency questionnaires were completed for each participant. Dietary iodine intake was extrapolated from UIC assuming 90 % of dietary iodine is excreted in urine and a urine volume of 0.5 L/day. Results A median UIC of 223.3 MUg/L was found. The calculated median dietary iodine intake was 124.8 MUg/day (SD 47.0) with 9.8 % of samples above the upper level of 200 MUg for dietary iodine for children within this age group. No foods were associated with UIC. Discussion Limited by sample size and recruitment strategies, no association was found between usual food intake and UIC. Extrapolated dietary iodine intake indicated that children within this cohort consumed adequate amounts of dietary iodine, although the number of children consuming above the upper limit of 300 MUg/day was almost double of expected. The development of a UIC criteria to assess appropriate parameters for varying degrees of iodine status is required for the monitoring of iodine nutrition in this vulnerable age group. PMID- 27514389 TI - The Impact of Race and Neighborhood Racial Composition on Preventable Readmissions for Diabetic Medicare Home Health Beneficiaries. AB - BACKGROUND: The recommended home health financial penalty program for preventable readmission does not factor race/ethnicity and neighborhood racial compositions into the determination of preventable readmission rates. Home health agencies may avoid beneficiaries from certain racial/ethnic groups and neighborhoods if these two factors have an effect on preventable readmissions. We examined the association between preventable readmissions with race/ethnicity and neighborhood racial composition. METHODS: Several 2009 national data were used, such as the Master Beneficiary Summary File, Medicare Provider Analysis and Review File, and Outcome Assessment Information Set. Our sample consisted of diabetic Medicare home health beneficiaries (African-Americans and Whites only). We analyzed predictors of time-to-first 30-day preventable readmission, including short/long term diabetic complications, chronic obstructive pulmonary disease/asthma, bacterial pneumonia, dehydration, urinary tract infection, hypertension, heart failure, angina without procedure, uncontrolled diabetes, and lower-extremity amputation. RESULTS: There were 86,567, 17,262, and 11,392 observations in neighborhoods with low (6 % African-Americans), moderate (35 % African Americans), and high (76 % African-Americans) density of African-Americans, respectively. Using Cox regression models, we found that in neighborhoods with moderate and high density of African-Americans, African-Americans had 21 % (hazard ratio (HR) 1.21; 95 % confidence interval (CI) 1.04-1.39) and 24 % (HR 1.24; 95 % CI 1.01-1.52) significantly higher hazards of 30-day preventable readmissions than Whites, respectively. CONCLUSION: Race and neighborhood racial compositions are beyond home health providers' control. These two factors should be considered as covariates for the preventable readmissions in the recommended home health financial penalty program. PMID- 27514391 TI - Enhancing HIV Treatment Access and Outcomes Amongst HIV Infected Children and Adolescents in Resource Limited Settings. AB - Introduction Increasing access to HIV-related care and treatment for children aged 0-18 years in resource-limited settings is an urgent global priority. In 2011-2012 the percentage increase in children accessing antiretroviral therapy was approximately half that of adults (11 vs. 21 %). We propose a model for increasing access to, and retention in, paediatric HIV care and treatment in resource-limited settings. Methods Following a rapid appraisal of recent literature seven main challenges in paediatric HIV-related care and treatment were identified: (1) lack of regular, integrated, ongoing HIV-related diagnosis; (2) weak facility-based systems for tracking and retention in care; (3) interrupted availability of dried blood spot cards (expiration/stock outs); (4) poor quality control of rapid HIV testing; (5) supply-related gaps at health facility-laboratory interface; (6) poor uptake of HIV testing, possibly relating to a fatalistic belief about HIV infection; (7) community-associated reasons e.g. non-disclosure and weak systems for social support, resulting in poor retention in care. Results To increase sustained access to paediatric HIV-related care and treatment, regular updating of Policies, review of inter-sectoral Plans (at facility and community levels) and evaluation of Programme implementation and impact (at national, subnational, facility and community levels) are non negotiable critical elements. Additionally we recommend the intensified implementation of seven main interventions: (1) update or refresher messaging for health care staff and simple messaging for key staff at early childhood development centres and schools; (2) contact tracing, disclosure and retention monitoring; (3) paying particular attention to infant dried blood spot (DBS) stock control; (4) regular quality assurance of rapid HIV testing procedures; (5) workshops/meetings/dialogues between health facilities and laboratories to resolve transport-related gaps and to facilitate return of results to facilities; (6) community leader and health worker advocacy at creches, schools, religious centres to increase uptake of HIV testing and dispel fatalistic beliefs about HIV; (7) use of mobile communication technology (m-health) and peer/community supporters to maintain contact with patients. Discussion and Conclusion We propose that this package of facility, community and family-orientated interventions are needed to change the trajectory of the paediatric HIV epidemic and its associated patterns of morbidity and mortality, thus achieving the double dividend of improving HIV-free survival. PMID- 27514392 TI - A Matched Comparison of Per Oral Endoscopic Myotomy to Laparoscopic Heller Myotomy in the Treatment of Achalasia. AB - BACKGROUND: Per oral endoscopic myotomy (POEM) is increasingly utilized to treat patients with achalasia. Early results have demonstrated significant improvement of symptoms, but there are concerns about postoperative reflux. With only limited comparative data available, we sought to compare POEM to laparoscopic Heller myotomy (LHM) with partial fundoplication. METHODS: This is a retrospective review of 42 POEM and 84 LHM patients undergoing primary myotomy for achalasia. Patients were matched by achalasia type, by Eckardt and dysphagia scores, and by quality of life (QOL) metrics. Analysis at 6-12-month follow-up evaluated these metrics, PPI use, pH, manometric, and endoscopic data. RESULTS: We matched 25 patients with achalasia types I (6), II (13), and III (6). Follow-up was longer for LHM at 158.1 (36.5-272.9) weeks versus 36.2 (22.2-41.2) weeks (p = 0.001). Eckardt scores, QOL metrics, and dysphagia significantly improved in both groups. DeMeester scores and total percent time less than 4 were abnormal in both groups and comparable (p = 0.925 and p = 0.838). Esophagitis was seen in 53.4 % (POEM) and 31.6 % (LHM) (Yates' p = 0.91), and PPI use was equivalent at 36 %. CONCLUSION: Early clinical outcomes are excellent with POEM and comparable to the standard of care LHM. Long-term follow-up is required as concerns for reflux persist. PMID- 27514394 TI - The evolution of big ideas: Molecular biology has seen many grand visions come and go and some others come back. PMID- 27514393 TI - Association of serum adiponectin concentration with aortic arterial stiffness in chronic kidney disease: from the KNOW-CKD study. AB - BACKGROUND: High serum adiponectin levels predict all-cause and cardiovascular mortality in chronic kidney disease (CKD). However, the relationship between serum adiponectin concentration and arterial stiffness in CKD is not well established. The aim of this study was to assess this relationship by measuring pulse wave velocity (PWV) in CKD patients. METHODS: Serum adiponectin concentration was measured in 716 CKD patients in the prospective KoreaN cohort study for Outcome in patients With Chronic Kidney Disease. The study group consisted of 415 men and 301 women; mean age was 53.1 years, and baseline estimated glomerular filtration rate (eGFR) was 51 +/- 29 ml/min per 1.73 m2. Heart to femoral PWV (hfPWV) and mean brachial to ankle PWV (baPWV) served as indicators of aortic artery stiffness and arterial stiffness, respectively. RESULTS: Increasing quartiles of serum adiponectin levels were associated with women, lower eGFRs and body mass indices, and higher urinary albumin-creatinine ratios. Serum adiponectin concentration also correlated with hfPWV and mean baPWV, even after adjusting for age and sex. It independently associated with hfPWV (B 0.028; 95 % confidence interval, 0.004-0.051; P = 0.020) but not mean baPWV in a multivariable linear regression analysis. In a multivariable logistic regression analysis, it correlated significantly with the highest quartile of hfPWVs but not mean baPWVs. CONCLUSION: The independent and significant correlation of serum adiponectin concentration with hfPWV in CKD patients implicates adiponectin in CKD-associated aortic stiffness. PMID- 27514395 TI - Prognostic significance of androgen receptor expression in invasive breast cancer: transcriptomic and protein expression analysis. AB - Differential prognostic roles of Androgen Receptor (AR) have been proposed in breast cancer (BC) depending on tumour oestrogen receptor (ER) status. This study aimed to evaluate the prognostic and/or predictive significance of AR expression in invasive BC. In this study AR expression was studied on a large (n = 1141) consecutive series of early-stage (I-III) BC using tissue microarray and immunohistochemistry (IHC). AR mRNA expression was assessed in a subset of cases. The prognostic impact of AR mRNA expression was externally validated using the online BC gene expression data sets (n = 25 data sets, 4078 patients). Nuclear AR IHC expression was significantly associated with features of good prognosis including older age, smaller tumour size, lower grade and lobular histology particularly in the ER-positive tumours. AR was associated with ER-related markers GATA3, FOXa1, RERG and BEX1. Negative association was observed with HER2, p53, Ki67, TK1, CD71 and AGTR1. AR Overexpression was associated with longer survival (p < 0.001), independent of tumour size, grade, stage [p = 0.033, hazard ratio (HR) = 0.80 95 % CI = 0.64-0.98]. Similar associations were maintained in ER+ tumours in univariate and multivariate analysis (p < 0.01) both in patients with and without adjuvant endocrine or chemotherapy. AR mRNA expression showed significant association with tumour grade, molecular subtypes, and longer 10 and 15 years survival in luminal BC. In the external validation cohorts, AR gene expression data were associated with improved patients' outcome (p < 0.001, HR = 0.84, 95 % CI 0.79-0.90). AR is not only an independent prognostic factor in ER positive luminal BC but is also expressed in ER-negative tumours. AR could act as a molecular target in patients with ER-positive disease predicting response to adjuvant therapy. PMID- 27514396 TI - Vigorous physical activity and risk of breast cancer in the African American breast cancer epidemiology and risk consortium. AB - The relationship between physical activity and breast cancer risk has been extensively studied among women of European descent, with most studies reporting inverse associations. However, data on American women of African ancestry (AA) and by tumor subtypes are sparse. Thus, we examined associations of vigorous exercise and breast cancer risk overall, and by estrogen receptor (ER) status, in the African American Breast Cancer Epidemiology and Risk Consortium. We pooled data from four large studies on 2482 ER+ cases, 1374 ER- cases, and 16,959 controls. Multivariable logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for the risk of breast cancer overall, and polytomous logistic regression was used to model the risk of ER+ and ER- cancer. Recent vigorous exercise was associated with a statistically significant, modestly decreased risk for breast cancer overall (OR 0.88, 95 % CI 0.81-0.96) and for ER+ cancer (OR 0.88, 95 % CI 0.80-0.98), but not for ER- cancer (OR 0.93, 95 % CI 0.82-1.06). Overall, there was no strong evidence of effect modification by age, menopausal status, body mass index, and parity. However, our data were suggestive of modification by family history, such that an inverse association was present among women without a family history but not among those with a relative affected by breast cancer. Results from this large pooled analysis provide evidence that vigorous physical activity is associated with a modestly reduced risk of breast cancer in AA women, specifically ER+ cancer. PMID- 27514398 TI - Corrigendum. PMID- 27514397 TI - Adjuvant systemic therapy in early breast cancer: impact of guideline changes and clinicopathological factors associated with nonadherence at a nation-wide level. AB - Over recent years, adjuvant systemic treatment guidelines (AST) for early-stage breast cancer have changed considerably. We aimed to assess the impact of these guideline changes on the administration of AST in early-stage breast cancer patients and to what extent these guidelines are adhered to at a nation-wide level. We used Netherlands Cancer Registry data to describe trends in AST prescription, adherence to AST guidelines, and to identify clinicopathological determinants of nonadherence. Between 1990 and 2012, 231,648 Dutch patients were diagnosed with early breast cancer, of whom 124,472 received AST. Adjuvant endocrine treatment (ET) use increased from 23 % of patients (1990) to 56 % (2012), and chemotherapy from 11 to 44 %. In 2009-2012, 8 % of patients received ET and 3 % received chemotherapy without guideline indication. Conversely, 10-29 % of patients did not receive ET and chemotherapy, respectively, despite a guideline indication. Unfavorable clinicopathological characteristics generally decreased the chance of undertreatment and increased the chance for overtreatment. Remarkable was the increased chance of ET undertreatment in younger women (RR < 35 vs 60-69 years 1.79; 95 % CI 1.30-2.47) and in women with HER2+ disease (RR 1.64; 95 % CI 1.46-1.85). Over the years, AST guidelines expanded resulting in much more Dutch early breast cancer patients receiving AST. In the majority of cases, AST administration was guideline concordant, but the high frequency of chemotherapy undertreatment in some subgroups suggests limited AST guideline support in these patients. PMID- 27514399 TI - Landscape of Research on Older Adults' Health in the Arab Region: Is It Demography-Driven or Development-Dependent? AB - Objectives: To describe the quantity, methods, themes, and collaboration profiles of research on older adults' health in the Arab world, and map research productivity against demographic, economic, and development indicators. Methods: A scoping review of research on older adults' health drawing from 7 databases and covering the period 1994-2013. Results: Aging research output has increased 6 fold over the study period, with middle-income countries showing the sharpest rise. The majority of the reviewed publications are descriptive in nature, oriented toward examining the extent of disease or factors associated with various morbidity and mortality outcomes (88.5%). Despite the increasing regional instability, there is a dearth of studies on "seniors in emergencies." Collaboration with international coauthors (16.0%) has been more frequent than with regional coauthors (4.2%). Correlation analysis suggests that research production has been more strongly influenced by literacy rates than by population aging indicators, Gross Domestic Product, or government investment in research and development. Discussion: This study lays the basis for a "roadmap" for research on older adults' health in the Arab region. It calls for cooperation among various stakeholders to produce a targeted and well-informed research agenda that is more responsive to emerging and context-specific needs of older adults in the region. PMID- 27514400 TI - The state of ethical-legal oaths in UK medical practice today: Is it time to look at standardising? AB - The taking of an ethical-legal oath is a "rite of passage" for many medical practitioners. A 1997 paper noted that half of medical schools in the UK administer an oath. I performed a survey of UK medical schools to see whether these are still used today. An electronic survey was sent to 31 UK medical schools, asking them whether the Hippocratic Oath (in any version) was taken by their medical students; non-respondents were followed up by telephone. Information was obtained from 21 UK medical schools, giving a response rate of 68% (21/31). A total of 18 (86%) institutions use an oath. Ethical-legal oaths are therefore taken in the vast majority of UK medical schools today. However, a great variety are used, and there are advantages in standardisation. My recommendation is that the Standard Medical Oath of the UK (SMOUK) is adopted by all medical schools, and that this is also taken regularly by doctors as part of revalidation. PMID- 27514401 TI - Benign male genital dermatoses. PMID- 27514402 TI - Ageless beauty. PMID- 27514403 TI - Improving value-add work and satisfaction in medical residents training: a resident-led quality improvement project employing the lean method to improve hospital supply usage. AB - PURPOSE: Our hospital has a Housestaff Quality Council that fosters education and mentorship of medical residents for quality improvement methodologies. Medical residents on our council identified non-standardised storage rooms as a source of medical resident inefficiency and dissatisfaction. To improve value-add work, medical residents implemented and evaluated a quality improvement project of storage room supplies using the lean method. METHODS: Using 5S principle and lean methodology, we designed and implemented a standardised supply cart with physician specific supplies. Between April 2014 and April 2015, 40 random observations (20 residents and 20 nurses) both before and after the standardised supply cart implementation were made. The duration time to locate an item was measured in seconds. The paths taken to locate items were drawn as spaghetti diagrams. Nurses served as our control group given that their supplies were not moved in the implementation. Fifty residents were surveyed to assess their satisfaction. RESULTS: Implementation of the standardised supply cart reduced the time for residents to locate an item per visit from 50.8 to 30.2 s in one unit (p<0.05) and 127 to 28.3 s in the second unit (p<0.05). Mean time savings per day per resident were 5 min. The spaghetti diagrams indicated that finding supplies became more efficient after the intervention for residents. After the intervention, 92% of residents reported finding supplies more rapidly and 86% reported less frustration with finding supplies. CONCLUSIONS: Residents applied the 5S principles and lean methodology to identify and solve a problem that created inefficiency and dissatisfaction. PMID- 27514404 TI - Do early internalizing and externalizing problems predict later irritability in adolescents with attention-deficit/hyperactivity disorder? AB - OBJECTIVE: Irritable mood is common in children with attention deficit/hyperactivity disorder. Research to date has primarily comprised cross sectional studies; thus, little is known about the antecedents of irritability. Furthermore, existing cross-sectional studies generally focus on the association between irritability and comorbidities and do not examine broader aspects of functioning. Finally, previous research has neglected to include child-report of irritability. This study aimed to address these gaps using data from a longitudinal study of children with attention-deficit/hyperactivity disorder. METHOD: Children aged 5-13 years (mean = 10.2; standard deviation = 1.9) with attention-deficit/hyperactivity disorder were recruited from pediatric practices across Victoria, Australia. This study reports on those who had reached adolescence (12 years or older, mean = 13.8; standard deviation = 1.2) at the 3 year follow-up ( n = 140). Internalizing and externalizing problems were measured using the Strengths and Difficulties Questionnaire. At follow-up, parent-reported and adolescent self-reported irritability was assessed using the Affective Reactivity Index. Parent and adolescent outcomes measured at follow-up included attention-deficit/hyperactivity disorder symptom severity, sleep, behavior and parent mental health. RESULTS: Children with externalizing problems at age 10 had higher parent-reported irritability (beta = 0.31, 95% confidence interval = [0.17,-0.45], p = 0.001) in adolescence. Cross-sectional analyses found that irritability was associated with increased attention-deficit/hyperactivity disorder symptom severity and sleep problems; poorer emotional, behavioral and social functioning; and poorer parent mental health. CONCLUSION: Our findings highlight the importance of assessing for and managing early conduct problems in children with attention-deficit/hyperactivity disorder, as these predict ongoing irritability which, in turn, is associated with poorer functioning across a number of domains. PMID- 27514405 TI - Systematic review of interventions for Indigenous adults with mental and substance use disorders in Australia, Canada, New Zealand and the United States. AB - OBJECTIVE: The aim of this study was to systematically review the evidence-base for the effectiveness of culturally unadapted, culturally adapted and culture based interventions for Indigenous adults with mental or substance use disorders. METHODS: We conducted a systematic search of scientific databases, government websites and web-based Indigenous research repositories. We sought studies using designs comparing an intervention group to a control/comparator group or pre- and post-test designs, published between 2000 and 2015 examining interventions to improve individual-level outcomes (e.g. remission, symptoms, quality of life, functioning) or service-level outcomes (e.g. number of interventions delivered) for Indigenous adults with mental or substance use disorders in Australia, Canada, New Zealand or the United States. RESULTS: A total of 16 studies met inclusion criteria. Virtually all North American studies (6 US and 1 Canadian) evaluated culturally unadapted interventions, all of which were interventions for substance use. Two-thirds of Australian and New Zealand studies evaluated culturally adapted interventions and included samples with mental disorders. Of eight culturally unadapted psychological/psychosocial, pharmacological and educational intervention studies, seven reported significant improvements on at least one measure of psychological well-being, mental health problem severity, or significantly reduced alcohol or illicit drug use. Of seven culturally adapted psychological/psychosocial intervention studies, all reported significant improvement on at least one measure of symptoms of mental illness, functioning, and alcohol use. One culture-based psychological/psychosocial intervention study significantly reduced problem severity in medical and psychiatric domains. CONCLUSION: There remains inconclusive evidence regarding interventions due to a small and methodologically weak evidence-base. The literature would be enhanced by intervention replication and outcome standardisation, validating the outcome instruments used in Indigenous populations, including sample size calculations and using stronger research designs (e.g. interrupted time-series designs). Robust implementation and outcomes research is needed to further progress evidence-based practice in Indigenous mental health. PMID- 27514408 TI - [Performance evaluation of two N95 filtering-facepiece respirators on decomposition products of sulfur hexafluoride]. AB - OBJECTIVE: To assess the filtration efficiency of two N95 filtering-facepiece respirators (FFRs) for the decomposition products of sulfur hexafluoride (SF6). METHODS: Two types of N95 FFRs (the particulate and the acid-proof respirators) were selected in this study. The decomposition products of SF6, including particles, hydrogen fluoride (HF) and sulfur dioxide (SO2) , were measured under experimental condition by using TSI PortaCount Plus, fluorine ion-selective electrodes and spectrophotometer separately. The filtration efficiency was then calculated and compared. RESULTS: Both two models of N95 respirators had lowest filtration efficiency larger than 95% for particles under airflow ranged from 10 to 95 L/min. When exposed to different concentrations of HF (low: 0.00~1.99 mg/m(3), middle: 2.00~3.99 mg/m(3), high: >4 mg/m(3)) , the acid-proof N95 respirator was more effective than the particulate respirator (P<0.05) with a filtration efficiency of 98.83%, 99.08%, and 99.03% versus 48.44%, 45.71%, and 47.31%. For four SO2 concentration ranges (0.00~2.49 mg/m(3), 2.50~4.99 mg/m(3), 5.00~9.99 mg/m(3), and >10.00 mg/m(3)) , the acid-proof respirator showed a high filtration efficiency within exposure to 1.5 hours: 95.73%, 98.67%, 98.14%, and 97.78%, respectively, when exposure duration extended to 4 hours, the filtration efficiency of the acid-proof respirator decreased to 91.97%, 82.28%, 70.12%, and 58.56%, respectively. CONCLUSION: Both the particulate and the acid-proof N95 FFRs met national standards on the particulate filtration efficiency. The acid proof N95 respirator demonstrates to be more effective in filtering HF and SO2 than the particulate respirator. The filtration efficiency could decrease to an unsafe condition under longer exposure duration, timely replacement of respirator is recommended at the workplace. PMID- 27514407 TI - Transcription Factor KLF5 Binds a Cyclin E1 Polymorphic Intronic Enhancer to Confer Increased Bladder Cancer Risk. AB - : It is well established that environmental toxins, such as exposure to arsenic, are risk factors in the development of urinary bladder cancer, yet recent genome wide association studies (GWAS) provide compelling evidence that there is a strong genetic component associated with disease predisposition. A single nucleotide polymorphism (SNP), rs8102137, was identified on chromosome 19q12, residing 6 kb upstream of the important cell-cycle regulator and proto-oncogene, Cyclin E1 (CCNE1). However, the functional role of this variant in bladder cancer predisposition has been unclear because it lies within a non-coding region of the genome. Here, it is demonstrated that bladder cancer cells heterozygous for this SNP exhibit biased allelic expression of CCNE1 with 1.5-fold more transcription occurring from the risk allele. Furthermore, using chromatin immunoprecipitation assays, a novel enhancer element was identified within the first intron of CCNE1 that binds Kruppel-like Factor 5 (KLF5), a known transcriptional activator in bladder cancer. Moreover, the data reveal that the presence of rs200996365, a SNP in high-linkage disequilibrium with rs8102137 residing in the center of a KLF5 motif, alters KLF5 binding to this genomic region. Through luciferase assays and CRISPR-Cas9 genome editing, a novel polymorphic intronic regulatory element controlling CCNE1 transcription is characterized. These studies uncover how a cancer-associated polymorphism mechanistically contributes to an increased predisposition for bladder cancer development. IMPLICATIONS: A polymorphic KLF5 binding site near the CCNE1 gene explains genetic risk identified through GWAS. Mol Cancer Res; 14(11); 1078-86. (c)2016 AACR. PMID- 27514409 TI - [Benzoquinone induce autophagy in HL60 cells and the role of reactive oxygen species in induced autophagy]. AB - OBJECTIVE: To investigate whether autophagy can be induced by 1, 4-benzoquinone (1, 4-BQ) in HL60 cells, as well as the role of reactive oxygen species (ROS) in induced autophagy. METHODS: In order to determine a suitable 1, 4-BQ treatment concentration for autophagy detection in HL60 cells, the cell vitality were examined by CCK8 assay. Logarithmic-growth-phased cells were divided into control group, 1, 4-BQ group (10MUmol/L 1, 4-BQ, 24 h) , NAC group (antioxidant n-acetyl cysteine, 5mmol/L, 24 h) and the 1, 4-BQ+NAC group (5 mmol/L NAC were preincubated for 1h prior to the treatment with 10 MUmol/L 1, 4-BQ for 24 h). The autophagic acidic vesicle were inspected by acridine orange staining, LC3 were detected by immunofluorescence staining, and expressions of LC3 and Beclin1 were quantitatively detected by Western blot. RESULTS: The results from cell viability test indicated that 1, 4-BQ exhibited a dose-dependent toxicity to HL60 cells. Compared with control group.the cell viability in 20.0,40.0MUmol/L concentration were decreased obviously, and the differences had statistical significance (P<0.05). Compare with contrd group acidic vesicle, LC3II, LC3II/LC3I and Beclin1 protein expressions were increased in 1, 4-BQ group, after both respectively 12.4% and 27%, the differences had statistital significance. While 1, 4-BQ+NAC group was observed that acidic vesicle, LC3 and Beclin1 protein level were markedly lower than 1, 4-BQ group, after both decreased 12.6% and 22.6% respectively, both the difference were statistically significant (P<0.05). CONCLUSION: 1, 4-BQ can induce autophagy in HL60 cells, the induction of autophagy is at least partly resulted from ROS. Antioxidant can effectively suppress the occurrence of induced autophagy. PMID- 27514406 TI - Ercc1 Deficiency Promotes Tumorigenesis and Increases Cisplatin Sensitivity in a Tp53 Context-Specific Manner. AB - : KRAS-mutant lung adenocarcinoma is among the most common cancer entities and, in advanced stages, typically displays poor prognosis due to acquired resistance against chemotherapy, which is still largely based on cisplatin-containing combination regimens. Mechanisms of cisplatin resistance have been extensively investigated, and ERCC1 has emerged as a key player due to its central role in the repair of cisplatin-induced DNA lesions. However, clinical data have not unequivocally confirmed ERCC1 status as a predictor of the response to cisplatin treatment. Therefore, we employed an autochthonous mouse model of Kras-driven lung adenocarcinoma resembling human lung adenocarcinoma to investigate the role of Ercc1 in the response to cisplatin treatment. Our data show that Ercc1 deficiency in Tp53-deficient murine lung adenocarcinoma induces a more aggressive tumor phenotype that displays enhanced sensitivity to cisplatin treatment. Furthermore, tumors that relapsed after cisplatin treatment in our model develop a robust etoposide sensitivity that is independent of the Ercc1 status and depends solely on previous cisplatin exposure. Our results provide a solid rationale for further investigation of the possibility of preselection of lung adenocarcinoma patients according to the functional ERCC1- and mutational TP53 status, where functionally ERCC1-incompetent patients might benefit from sequential cisplatin and etoposide chemotherapy. IMPLICATIONS: This study provides a solid rationale for the stratification of lung adenocarcinoma patients according to the functional ERCC1- and mutational TP53 status, where functionally ERCC1-incompetent patients could benefit from sequential cisplatin and etoposide chemotherapy. Mol Cancer Res; 14(11); 1110-23. (c)2016 AACR. PMID- 27514410 TI - [Effects of malathion on testicular enzyme activities and sperm quality of male rats]. AB - OBJECTIVE: The aim of this study is to investigate the effects of sub chronic exposure to malathion on testicular enzyme activities and sperm quality of male rats. METHODS: Forty male rats were divided into four groups: three exposure groups and a control group. Malathion was administered orally to male rats at 0, 33.75, 54.00, and 108.00 mg/kg for 60 days to evaluate the toxic alterations in sperm dynamics and testicular enzyme activities including ACP,LDH,SDH and gamma GT. The control rats were administered with an equivalent volume of distilled water in the same manner.After sacrificed, the testes were collected and weighed. RESULTS: The body weight and the testis weight of animals showed a decreasing tendency, and there was a statistical difference between the 54.00, 108.00 mg/kg groups, and the control group (P<0.05). Malathion brought about marked reduction in testicular sperm counts, sperm motility, and significant growth of sperm malformation rate in 108.00 mg/kg group. A significant decrease in the activities of testicular enzyme ACP and gamma-GT was observed in malathion exposed rats, while the activities of LDH was significant increased and there were no obvious effects on the activities of SDH. The activities of ACP, gamma-GT and LDH showed a statistical difference between the 108.00 mg/kg groups, and the control group. CONCLUSION: Malathion reduced the sperm counts and sperm motility, increased the malformation rate and reduced the activities of testicular enzymies of male rats. PMID- 27514411 TI - [Clinical value of serum presepsin (SCD14-ST) concentration measurement in patients with pesticide poisoning]. AB - OBJECTIVE: To investigate the value of serum presepsin concentration measurement in the clinical diagnosis and treatment of patients with pesticide poisoning patients. METHODS: A total of 160 patients with pesticide poisoning were enrolled as study subjects and divided into moderate organophosphate pesticide poisoning group (40 patients) , severe organophosphate pesticide poisoning group (40 patients) , abamectin pesticide poisoning group (40 patients) , and paraquat poisoning group (40 patients). A total of 20 healthy volunteers were enrolled as the control group. All the patients with poisoning received conventional treatment of pesticide poisoning immediately after admission, and serum presepsin concentration was measured on days 1 (within 24 hours after poisoning) , 3, and 7 of admission, and biochemical and radiological parameters related to the patient's condition were also examined. The patients with a Presepsin concentration of >800 pg/ml on day 1 of admission were randomly divided into conventional treatment group and ulinastatin treatment group, and the treatment outcome was compared between the two groups. RESULTS: Compared with the healthy control group, the groups with pesticide poisoning showed significant increases in serum Presepsin concentrations, with the highest degree of increase on day 1 (P <0.05). The serum Presepsin concentration was positively correlated with alanine aminotransferase, aspartate aminotransferase, creatine kinase, creatine kinase MB, lactate dehydrogenase, serum creatinine, blood urea nitrogen, interleukin-18, and white blood cell count, but negatively correlated with cholinesterase. In the conventional treatment group and ulinastatin treatment group, the overall response rate was 68% and 78.8%, respectively, with a significant difference between the two groups (P<0.05). In 40 patients with paraquat poisoning, 32 experienced an increase in serum presepsin concentration, and among these 32 patients, 27 (83%) experienced exudation on lung CT. CONCLUSION: Serum Presepsin concentration measurement can assist early diagnosis, evaluation of disease severity, and guidance for clinical medication in patients with pesticide poisoning, especially in those with severe pesticide poisoning and a tendency to multiple organ failure. PMID- 27514412 TI - [Effect and mechanism of interleukin-8 expression induced by wood smoke particles in primary human airway epithelial cells]. AB - OBJECTIVE: To investigate the effect and mechanism of interleukin-8 expression induced by wood smoke particles (WSP) in primary human airway epithelial cells. METHODS: Primary human bronchial epithelial cells (HBEC) were collected through fiberbronchoscopic brushing and incubated with different concentration of WSP (0, 12.5, 25.0, 50.0, 100.0 MUg/ml). Levels of IL-8 protein in cell culture supernatant were measured using enzyme-linked immune sorbent assay. The specific inhibitors for epidermal growth factor receptor (EGFR) and p38 kinase signaling pathways were employed to pretreat HBEC, respectively, prior to incubation with 100 MUg/ml WSP to investigate the mechanism of IL-8 expression induced by WSP. RESULTS: The expression of IL-8 was significant increased in a dose-dependent manner after exposure HBEC to different concentration of WSP for 24h. The levels of IL-8 expression were (4546.67+/-1421.42) rhog/ml in (PD153035+WSP) group and (2803.33+/-865.00) rhog/ml in (SB203580+WSP) group respectively, which were significant decreased compared with the level of (12896.67+/-1373.11) rhog/ml in WSP group (P<0.05). CONCLUSION: WSP could induce IL-8 expression by means of EGFR and p38 signaling pathways. PMID- 27514413 TI - [Blood cerebrospinal fluid barrier damage of rats induced by lead acetate or nano lead exposure]. AB - OBJECTIVE: To investigate the damage of blood-cerebrospinal fluid barrier (BCB) of rats induced by lead and nano-lead exposure in order to provide the basis for mechanism study of lead neurotoxicity. METHODS: 39 male rats were randomly divided into control group, lead acetate exposed group and nano-lead exposed group. Rats in lead acetate exposed group and nano-lead exposed group were given 20 mg/kg lead acetate or nano-lead by oral gavage and rats in control groups were given the same amount saline for 9 weeks.Morris maze was used to test the learning function, serum albumin and CSF albumin were determined by ELISA. Confocal laser scanning microscope was applied to detect ZO-1 and Occludin protein expression in choroid plexus, real time-PCR was used to test the expression of ZO-1 and Occludin mRNA expression. Pathological changes of choroid plexus cells were observed by the electron microscopy. RESULTS: Compared with the control group, the escape latency of rats in lead acetate or nano-lead exposure group were longer and times of across platform were less. The levels of CSF albumin and the CSF albumin index in lead acetate or nano-lead exposed rats were obviously higher, and the fluorescence intensity of ZO-1, Occludin as well as mRNA expressions were lower than those in control group(P<0.05). Compared with lead acetate exposed group, the levels of CSF albumin and the CSF albumin index in nano-lead exposure group were higher. The fluorescence intensity and mRNA expressions of ZO-1, Occludin in nano-lead exposure group were than those in lead acetate group(P<0.05). Electron microscopy revealed that lead acetate or nano lead exposure could induce shorter microvillus of choroid plexus epithelial cells, mitochondrion destruction and partial disconnection in intracellular junctions between two adjacent epithelial cells. CONCLUSION: Lead acetate and nano-lead exposed can result in the blood-cerebrospinal fluid barrier damage, which may involve in the process of lead induced neurotoxicity. Meanwhile, nano lead exposure can induced in more worse damage in terms of blood-results in blood cerebrospinal fluid barrier function. PMID- 27514414 TI - [Report on 11 cases occupational acute arsine poisoning]. PMID- 27514415 TI - [Effects of long term and low dose Di- (2-ethylhexyl) phthalate exposure on global genome DNA methylation in HePG2 cells]. AB - OBJECTIVE: To explore the potential effects of long-term and low-dose Di- (2 ethylhexyl) phthalate (DEHP) exposure on whole genome DNA methylation status and cytotoxicity of HePG2 cells. METHODS: HePG2 cells were exposed to 1.5,15.0 and 150.0 MUmol/L DEHP for 24 hours, after continuous exposure for 20 generations, mRNA and protein expression level of DNA (cytosine-5) -methyltransferase 1 (DNMT 1) , whole genome DNA methylation, cell apoptosis levels and cell cycle were determined in both DEHP exposed cells and control cells. RESULTS: After DEHP exposure, the mRNA and protein expression levels of DNMT 1 were decreased significantly (P<0.05 or P<0.01). The genome DNA methylation levels of HePG2 cells were down-regulated along with the increasing of DEHP exposure level (15.0, 150.0 MUmol/L, P<0.05 and P<0.01). In term of cell apoptosis rates, only the late stage cell apoptosis rates of the highest DEHP dosage group (150.0 MUmol/L DEHP) were observed to have a significant increase (P<0.05). There were no significant alterations in term of cell cycle. CONCLUSION: After long term and low dose DEHP exposure, the whole genome DNA methylation levels of HePG2 cells were down regulated obviously, which might be one of the most important toxic mechanism of DEHP to induce pathophysiologic changes. Meanwhile, a certain content of cell apoptosis were observed in highest dosage group of DEHP exposure, which showed cytotoxicty of DEHP. However, there are no significant effects of DEHP exposure on cell cycles. PMID- 27514416 TI - [Effects of forsythia suspense on the liver gene expression levels of rats with sepsis model]. AB - OBJECTIVE: To study the effects of forsythia extract on the liver gene expression levels of rats with sepsis model. METHODS: The 90 Wistar rats were randomly divided into three groups: sham operation group (n=30) , sepsis model group (n=30) and forsythia group (n=30). The survival rates at 48 h and 72 h were observed for all groups. The sepsis model and forsythia group rats were prepared by "CLP" method. 72 h later the rats were sacrificed by removed the vertebra. Under sterile conditions,cut the size of about 10 mm*10 mm*3 mm rat liver tissue and placed in liquid nitrogen for use. The same with the sham operation group. The gene expression levels of livers in all groups were detected by the Applications Rat Genome 230 2.0 microarray,and the relative strength of both the fluorescence signal ratio>2 or <-2 screening significantly different genes, by the US National Center for Biotechnology Information (NCBI) database query gene function and classify. RESULTS: Forsythia group 48 h, 72 h rat mortality rates were 30% and 50%, the sepsis model group 48 h, 72 h rat mortality rates were 46.7% and 70%, two groups 48 h, 72 h mortality rates were compared, the differences were statistically significant (P<0.05). 72 hours after CLP, the genes with up-regulation in sepsis model group/sham operation group and with down regulation in Forsythia group/sepsis model group were 14. The genes with down regulation in sepsis model group/sham operation group and with up-regulation in Forsythia group/sepsis model group were 11. The genes involves immune-related genes 8, metabolism genes 5, material transport two related genes, cell adhesion two related genes, cell proliferation, differentiation and apoptosis related genes 4, transcriptional regulation genes 2and other related gene. CONCLUSION: Forsythia can reduce the 48, 72 h mortality of rats with sepsis and can regulate abnormal sepsis liver genes which associated with tissue immunity, inflammation, metabolism occur regression expression. PMID- 27514417 TI - [An investigation on job burnout of medical personnel in a top three hospital]. AB - OBJECTIVE: To investigate job burnout status of medical Personnel in a top three hospitals, in order to provide basic data for intervention of the hospital management. METHODS: A total of 549 doctors and nurses were assessed by Maslach Burnout Inventory-Human Service Survey (MBI-HSS). SPSS 19.0 software package was applied to data description and analysis, including univariate analysis and orderly classification Logistic regression analysis. RESULTS: The rate of high job burnout of doctors and nurses are 36.3% and 42.8% respectively. Female subjects got higher scores (29.4+/-13.5) on emotional exhaustion than male subjects (26.2+/-12.8) compared with.Doctors got lower scores (28.2+/-15.9) on emotional exhaustion and higher scores (31.4+/-9.3) on personal accomplishment than nurses.Compared with subjects with higher professional title, young subjects with primary professional title got lower scores on personal accomplishment.Subjects with 11-20 years working age got the highest scores on depersonalization.Among all the test departments, medical personnel of emergency department got the highest scores (31.9+/-12.6) on emotional exhaustion,while the lowest scores (28.1+/-8.0) on personal accomplishment. According to the results of orderly classification Logistic regression analysis, age, job type,professional qualifications and clinical departments type entered the regression model. CONCLUSION: Physical resources and emotional resources of medical personnel are overdraft so that they got some high degree of job burnout.Much more attention should be paid to professional mental health of nurses,and personnel who at low age,got low professional titles.Positive measures should be provided, including management mechanism,organizational culture, occupational protection and psychological intervention. PMID- 27514418 TI - [Survival analysis of patients with pneumoconiosis from 1963 to 2014 in Yueyang]. AB - OBJECTIVE: To know the incidence and survival rate of patients with pneumoconiosis in Yueyang and investigate the related factors of death hazard ratio. METHODS: A total; of 1404 patients with pneumoconiosis were diagnosed and reported from 1963.1-2014.12. Log Rank method and Cox regression model were used to make the survival analysis. RESULTS: The case fatality rate of pneumoconiosis was 24.57%,and rose with the increase of pneumoconiosis stage, the average course of disease was (14.7+/-8.7) years, the average age of death was (60.6+/-11.3) years, tuberculosis,Chronic cardiopulmonary disease and pneumonia were the top three cause of death for patients. The survival rates which included three stages of pneumoconiosis patients and the patients whether or not complicated with tuberculosis were significant statistical differences. Cox regression analysis revealed that the main impact. factors for the survival of patients with pneumoconiosis and the value of. the death hazard ratios (RR) of above seven factors were silicosis (2.28) ,the increase of pneumoconiosis stage (1.77) ,pneumoconiosis complicated with tuberculosis (1.29) ,the increase of stage promotion (1.20) ,the increase of age of the first contacting dust (1.08) ,the expansion of the scale of enterprise (0.55) and the later period of contacting dust (0.37). CONCLUSION: Prevention of pneumoconiosis should focus on silicosis in Yueyang, the prevention and treatment of pneumoconiosis complicated with tuberculosis is an important means for improving the survival of patients. PMID- 27514419 TI - [The immunological effects of phthalanilic acid on mice]. AB - OBJECTIVE: To explore the effects of phthalanilic acid on immune system in mice from the respects of blood, tissues, cell and cytokines. And to find sensitive index of immunological effects and offer experimental data for toxicological safety evaluation. METHODS: 60 balb/c mice were randomly divided into 4 groups. The mice in control group were given soybean oil. The mice in group 2 to 4 were given phthalanilic acid at dose 30 mg/kg, 100 mg/kg and 300 mg/kg by gavage respectively for 28 days. After 24 hours of the last contamination, the histopathology of spleen and thymus, immunologic factors and cell multiplication of lymphocyte were analysed. The data were analysed by SPSS. RESULTS: After contamination for 28 days, 300 mg/kg phthalanilic acid could cause that the cell multiplication of lymphocyte were inhibited. Spleens were damaged at the dose of 100 mg/kg. The concentration of IFN-gamma and IL-4[ (843.31+/-14.81) pg/ml and (1174.44+/-7.32) pg/ml] in thymus were increased significantly (P<0.05) at the dose of 30 mg/kg. CONCLUSION: Different doses of phthalanilic acid may damnify the immune system of mice at different degrees for 28 days continuous contamination. Phthalanilic acid might have immunotoxicity. PMID- 27514420 TI - [Clinical analysis on 473 cases of occupational acute acrylonitrile poisoning]. PMID- 27514421 TI - [Emergency management of 9 patients with acute aconite poisoning]. PMID- 27514422 TI - [A case report of hands tremor caused by organophosphorus and cypermethrin mixed pesticide poisoning]. PMID- 27514423 TI - [Analysis on influencing factors of prognosis of patients with acute organophosphorus pesticide poisoning]. AB - OBJECTIVE: To analyze the relationship between risk factors and prognosis of acute organophosphorus pesticide poisoning (AOPP). METHODS: The clinical data including APACHEII, D-dimer, C-reactive protein, procalcitonin, lactic acid of the 67 cases of acute organophosphorus pesticide poisoning which respectively divided into survival group and death group by the outcome were collected. The independent influcing factors were got by logistic regression analysis. RESULTS: The analysis showed that APACHEII, D-dimer,C-reactive protein and Procalcitonin were influencing factors to evaluate prognosis of AOPP (P<0.05) .Meanwhile, APACHEII and CRP were the independent influencing factors to evaluate prognosis of AOPP (P<0.05). APACHEII26was the optimum thresholds to acess the prognosis of AOPP and its Youden index was largest. CONCLUSION: APACHEII and CRP played an important role in the assessment of prognosis on AOPP. When APACHEIIwas more than 26, it suggested the patient of AOPP will have a bad prognosis. PMID- 27514424 TI - [Impact of coal workers' pneumoconiosis complicated by lymph node fibrosis in lung cancer on surgical treatment]. AB - OBJECTIVE: To investigate the impact of coal workers' pneumoconiosis complicated by the pathological changes in lymph nodes in lung cancer on surgical treatment. METHODS: A total of 63 patients with non-small cell lung cancer who received pulmonary lobectomy and systemic mediastinal lymph node dissection were enrolled and divided into the group with coal workers' pneumoconiosis complicated by lung cancer (30 patients) and the non-pneumoconiosis liver cancer group (33 patients). The short-term outcome was compared between the two groups and confirmed by lymph node fibrosis shown by postoperative pathological examination. The predictive value of lymphadenectasis on chest CT was analyzed. RESULTS: Compared with the non-pneumoconiosis liver cancer group, the group with coal workers' pneumoconiosis complicated by lung cancer had significant increases in time of operation, intraoperative blood loss, postoperative extubation time, and length of hospital stay (P<0.05). The patients were divided into groups according to the presence or absence of lymph node fibrosis, and the group with lymph node fibrosis had a significantly longer time of operation and greater intraoperative blood loss than the group without lymph node fibrosis (P<0.05). CONCLUSION: When coal workers' pneumoconiosis is complicated by lung cancer, severe lymph node fibrosis often causes difficulties in surgery, and thoracotomy may be a safe and effective therapeutic method. PMID- 27514425 TI - [An inhalation poison caused by thermal degradation products of fluorine polymer]. PMID- 27514426 TI - [A case of mis-intravenous injection of thinner poisning]. PMID- 27514427 TI - [A case of acute carbon monoxide poisoning with pancreatitis as the prominent dinical manifestation]. PMID- 27514429 TI - [A case report of hemoperfusion treat kidney damage caused eating fish gall bladder poisoning]. PMID- 27514428 TI - [Analysis of hemoperfusion in the treatment of thinner poisoning effect]. AB - OBJECTIVE: To investigate the combination of drugs in blood perfusion-based rescue therapy of acute poisoning thinners. METHODS: Our department were retrospectively analyzed in May 2011 to October 2014, 54 cases thinners poisoning patients choose the thinner should be 44 cases of acute poisoning patients were divided into two groups. Toluene, xylene group 8 cases; Halogenated hydrocarbon group 34cases; Give blood perfusion 3 to 7 times, compared before and after the blood perfusion of toxicant concentration, results and biochemical indicators. RESULTS: By selection of 44 patients with acute thinners poisoning in 42 patients were successfully treated, the cure rate was 96%. And treatment in patients with successful both in toluene, xylene, or halogenated hydrocarbon group after blood perfusion its toxicant concentration significantly decreased; 42 patients blood perfusion treatment of the indexes of liver function after than before treatment significantly improved. CONCLUSION: The early hemoperfusion is a very effective way of acute poisoning thinners currently rescue. PMID- 27514430 TI - [Determination of trace cobalt in human urine by graphite furnace atomic absorption spectrometr]. AB - OBJECTIVE: To establish a method to determine cobalt in human urine by graphite furnace atomic absorption spectrometry. METHODS: Urine with 2% nitric acid diluted two-fold, to quantify the curve, graphite furnace atomic absorption spectrometric detection. RESULTS: Co was linear within 2.5~40.0 ng/ml with r>0.999. Spike experiment showed that Co received good recovery rate, which was 90.8%~94.8%. Intra-assay precisions were 3.2%~5.1% for Co, inter-assay precisions were 4.4%~5.2% for Co. CONCLUSION: The method by using graphite furnace atomic absorption spectrometr to determine urine Co was fast, accurate and with low matrix effect. It could meet the requirement in GBZ/T 210.5-2008. PMID- 27514431 TI - [Determination of trace cobalt and tungsten in human urine by inductively coupled plasma mass spectrometry]. AB - OBJECTIVE: To establish a method to determine cobalt and tungsten in human urine by ICP-MS. METHODS: Both Co and W were linear within 0.05~10.00 ng/ml with r>0.999. Spike experiment showed that both Co and W received good recovery rate, which were 90%~97%. Intra-assay precisions were 3.2%~5.1% for Co and 2.2%~4.1% for W, inter-assay precisions were 4.4%~5.2% for Co and 3.7%~4.5% for W. RESULTS: CONCLUSION: The method by using ICP-MS to determine urine Co and W was fast, accurate and with low matrix effect. It could meet the requirement in GBZ/T 210.5 2008. PMID- 27514432 TI - [Monitoring and clinical treatment of naphthalene poisoning]. PMID- 27514433 TI - [Progress on predictors of patients with acute paraquat poisoning]. PMID- 27514434 TI - [Diagnosis and research progress of occupational asthma]. PMID- 27514435 TI - A Molecular Tetrapod for Organic Photovoltaics. AB - The synthesis and characterization of a molecular tetrapod, SFBTD, featuring a tetraphenylsilane center and four identical conjugated arms, which structurally resembles breakwaters in common wave-reducing shore constructions, are reported. Cyclic voltammetry reveals that SFBTD has a medium band gap of ca. 2.0 eV and a low-lying HOMO energy level at ca. -5.2 eV. Absorption spectroscopy, X-ray diffraction, and differential scanning calorimetry experiments reveal a low degree of crystallinity in this compound and slow crystallization kinetics. Bulk heterojunction organic photovoltaics (OPVs) employing SFBTD and fullerene derivatives exhibit power conversion efficiencies (PCEs) up to 1.05% and open circuit voltage (VOC) values as high as 1.02 V. To the best of our knowledge, this is the highest PCE obtained for OPVs employing molecular tetrapods as donor materials. These devices are relatively thermally stable due to the known ability of breakwater tetrapods to interlock, preventing dislodging and sliding. The lack of favorable phase separations and low hole mobilities of the blend films are the major factors limiting the device performance. Ternary blend devices by the addition of three low band gap poly(thienylene vinylene) (PTV) derivatives were fabricated and tested. We found that the added PTVs acted to be either the major hole conductor or a competing hole conduction channel depending on the HOMO level positions relative to that of SFBTD. Some of the ternary OPV devices out performed the corresponding binary counterparts employing SFBTD or PTVs alone, suggesting cooperative effects in the ternary systems. PMID- 27514436 TI - Development of a simultaneous optical/PET imaging system for awake mice. AB - Simultaneous measurements of multiple physiological parameters are essential for the study of brain disease mechanisms and the development of suitable therapies to treat them. In this study, we developed a measurement system for simultaneous optical imaging and PET for awake mice. The key elements of this system are the OpenPET, optical imaging and fixation apparatus for an awake mouse. The OpenPET is our original open-type PET geometry, which can be used in combination with another device because of the easily accessible open space of the former. A small prototype of the axial shift single-ring OpenPET was used. The objective lens for optical imaging with a mounted charge-coupled device camera was placed inside the open space of the AS-SROP. Our original fixation apparatus to hold an awake mouse was also applied. As a first application of this system, simultaneous measurements of cerebral blood flow (CBF) by laser speckle imaging (LSI) and [(11)C]raclopride-PET were performed under control and 5% CO2 inhalation (hypercapnia) conditions. Our system successfully obtained the CBF and [(11)C]raclopride radioactivity concentration simultaneously. Accumulation of [(11)C]raclopride was observed in the striatum where the density of dopamine D2 receptors is high. LSI measurements could be stably performed for more than 60 minutes. Increased CBF induced by hypercapnia was observed while CBF under the control condition was stable. We concluded that our imaging system should be useful for investigating the mechanisms of brain diseases in awake animal models. PMID- 27514437 TI - Methodological reporting quality of randomized controlled trials: A survey of seven core journals of orthopaedics from Mainland China over 5 years following the CONSORT statement. AB - BACKGROUND: In recent years, the number of randomized controlled trials (RCTs) in the field of orthopaedics is increasing in Mainland China. However, randomized controlled trials (RCTs) are inclined to bias if they lack methodological quality. Therefore, we performed a survey of RCT to assess: (1) What about the quality of RCTs in the field of orthopedics in Mainland China? (2) Whether there is difference between the core journals of the Chinese department of orthopedics and Orthopaedics Traumatology Surgery & Research (OTSR). MATERIAL AND METHODS: This research aimed to evaluate the methodological reporting quality according to the CONSORT statement of randomized controlled trials (RCTs) in seven key orthopaedic journals published in Mainland China over 5 years from 2010 to 2014. All of the articles were hand researched on Chongqing VIP database between 2010 and 2014. Studies were considered eligible if the words "random", "randomly", "randomization", "randomized" were employed to describe the allocation way. Trials including animals, cadavers, trials published as abstracts and case report, trials dealing with subgroups analysis, or trials without the outcomes were excluded. In addition, eight articles selected from Orthopaedics Traumatology Surgery & Research (OTSR) between 2010 and 2014 were included in this study for comparison. The identified RCTs are analyzed using a modified version of the Consolidated Standards of Reporting Trials (CONSORT), including the sample size calculation, allocation sequence generation, allocation concealment, blinding and handling of dropouts. RESULTS: A total of 222 RCTs were identified in seven core orthopaedic journals. No trials reported adequate sample size calculation, 74 (33.4%) reported adequate allocation generation, 8 (3.7%) trials reported adequate allocation concealment, 18 (8.1%) trials reported adequate blinding and 16 (7.2%) trials reported handling of dropouts. In OTSR, 1 (12.5%) trial reported adequate sample size calculation, 4 (50.0%) reported adequate allocation generation, 1 (12.5%) trials reported adequate allocation concealment, 2 (25.0%) trials reported adequate blinding and 5 (62.5%) trials reported handling of dropouts. There were statistical differences as for sample size calculation and handling of dropouts between papers from Mainland China and OTSR (P<0.05). CONCLUSION: The findings of this study show that the methodological reporting quality of RCTs in seven core orthopaedic journals from the Mainland China is far from satisfaction and it needs to further improve to keep up with the standards of the CONSORT statement. LEVEL OF EVIDENCE: Level III case control. PMID- 27514438 TI - Fibroblast growth factor and vascular endothelial growth factor play a critical role in endotheliogenesis from human adipose-derived stem cells. AB - OBJECTIVE: Adipose-derived stem cells (ASCs) are a potential adult mesenchymal stem cell source for restoring endothelial function in patients with critical limb ischemia. Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) play a major role in angiogenesis and wound healing. This study evaluated the effects of FGF and VEGF on the proliferation, migration, and potential endothelial differentiation of human ASCs with regards to their use as endothelial cell substitutes. METHODS: ASCs were isolated from clinical lipoaspirates and cultured in M199 medium with fetal bovine serum (10%), FGF2 (10 ng/mL), VEGF (50 ng/mL), or combinations of FGF2 and VEGF. Cell proliferation rates, viability, and migration were measured by growth curves, MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and scratch assays. For cell attachment determinations, ASCs were seeded onto a scaffold of small intestinal submucosa for 5 days. Endothelial differentiation capabilities of ASCs were confirmed by expression of endothelial cell-specific markers using quantitative polymerase chain reaction, immunofluorescence staining, and cord formation on Matrigel (BD Biosciences, San Jose, Calif). PD173074, a selective inhibitor of FGF receptor, was used to confirm the importance of FGF signaling. RESULTS: ASCs treated with FGF or combinations of FGF and VEGF showed increased proliferation rates and consistent differentiation toward an endothelial cell lineage increase in platelet endothelial cell adhesion molecule (CD31), von Willebrand factor, endothelial nitric oxide synthase, and vascular endothelial cadherin message, and in protein and cord formation on Matrigel. FGF and VEGF stimulated ASC migration and increased the attachment and retention after seeding onto a matrix graft of small intestinal submucosa. Blockade of FGF signaling with PD173074 abrogated ASC endothelial cell differentiation potential. CONCLUSIONS: These results indicate that FGF and VEGF are ASC promoters for proliferation, migration, attachment, and endothelial differentiation. FGF and VEGF have a costimulatory effect on ASC endotheliogenesis. These results further suggest that ASCs with enhanced FGF signaling may potentially be used for tissue engineering and cell-based therapies in patients with critical limb ischemia. PMID- 27514439 TI - The role of passive sampling in monitoring the environmental impacts of produced water discharges from the Norwegian oil and gas industry. AB - Stringent and periodic iteration of regulations related to the monitoring of chemical releases from the offshore oil and gas industry requires the use of ever changing, rapidly developing and technologically advancing techniques. Passive samplers play an important role in water column monitoring of produced water (PW) discharge to seawater under Norwegian regulation, where they are used to; i) measure aqueous concentrations of pollutants, ii) quantify the exposure of caged organisms and investigate PW dispersal, and iii) validate dispersal models. This article summarises current Norwegian water column monitoring practice and identifies research and methodological gaps for the use of passive samplers in monitoring. The main gaps are; i) the range of passive samplers used should be extended, ii) differences observed in absolute concentrations accumulated by passive samplers and organisms should be understood, and iii) the link between PW discharge concentrations and observed acute and sub-lethal ecotoxicological end points in organisms should be investigated. PMID- 27514440 TI - Isolation and characterization of lignocellulose nanofibers from different wheat straw pulps. AB - Wheat straw was cooked under different pulping processes: Soda (100 degrees C, 7% NaOH, 150min), Kraft (170 degrees C, 16% alkalinity, 25% sulfidity, 40min) and Organosolv (210 degrees C, 60% ethanol, 60min). Once the pulps were obtained, lignocellulose nanofibers (LCNF) were isolated by mechanical process and TEMPO mediated oxidation followed by a high pressure homogenization. After pulping process, the different pulps were characterized and its chemical composition was determined. The pulps characterization indicates that the Soda process is the process that, despite producing less delignification, retains much of the hemicelluloses in the pulp, being this content a key factor in the nanofibrillation process. Regarding the LCNF obtained by mechanical process, those nanofibers isolated from Organosolv wheat pulp (OWP) and Kraft wheat pulp (KWP) show low values for nanofibrillation yield, specific surface area and greater diameter. However, those nanofibers isolated from Soda wheat pulp (SWP) reach much higher values for these parameters and presents a diameter of 14nm, smaller than those obtained by TEMPO-mediated oxidation from OWP. Smaller diameters are generally obtained in TEMPO-oxidized LCNF. This work concludes that the lignin content does not affect greatly to obtain LCNF as does the hemicellulose content, so it is accurate to use a soft pulping process. PMID- 27514441 TI - Interpenetrating hydrogels of O-carboxymethyl Tamarind gum and alginate for monitoring delivery of acyclovir. AB - In this work, an interpenetrating hydrogel network was constructed using varying combination of O-carboxymethyl Tamarind gum (CTG) and alginate by Ca+2 ion induced gelation method. The hydrogels were characterized by FTIR spectroscopy, Field emission scanning electron microscopy (FESEM), energy dispersive X-ray (EDX) and differential scanning calorimetry (DSC) analyses. The hydrogels were spherical in shape with rough surface textures. Depending on the alginate: CTG mass ratio, the hydrogel particles entrapped a maximum of ~70% acyclovir. The drug release from interpenetrating hydrogels was 18-23% in HCl solution (pH1.2) in 2h. The drug release became faster in phosphate buffer solution (pH6.8) as the proportion of CTG was increased from 25% to 50%. However, the drug release was still slower than that observed for hydrogel particles of sodium alginate alone. Overall, the drug release tendency of the particles was higher in phosphate buffer solution than that in HCl solution. The non-Fickian drug release behavior was assumed after fitting the drug release data into Korsmeyer-Peppas model. The drug release was found to control by diffusion and swelling kinetics of the hydrogels. Thus, CTG gum could effectively retard drug release when used in combination with sodium alginate at an optimized mass ratio. PMID- 27514442 TI - Modified pectin from Theobroma cacao induces potent pro-inflammatory activity in murine peritoneal macrophage. AB - In vitro effects of acetylated pectin (OP) isolated from cacao pod husks (Theobroma cacao L.), its partially deacetylated and de-esterified form (MOP), and a commercial homogalacturonan (PG) were investigated on murine peritoneal macrophages. MOP stood out among the studied pectins. After 48h of incubation, compared with the control group, it was able to promote significant macrophage morphological differentiation from resident to activated stage and also stimulated nitric oxide production, which reached a level of 85% of that of LPS stimulus. In the presence of the highest tested concentration of MOP (200MUg.mL 1), the levels of the cytokines TNF-alpha (6h) and IL-12 and IL-10 (48h) increased substantially in relation to untreated cells. Our results show that the partial deacetylation and de-esterification of pectin extracted from cacao pod husks (T. cacao L.) produced a polymer with greater ability than its native form to activate macrophages to a cytotoxic phenotype. Like this, they provide the possibility of a therapeutic application to MOP, which could lead to a decreased susceptibility to microbial infection besides antitumor activity. Additionally, the present results also corroborate with the proposition of that the chemical modifications of the biopolymers can result in an improved molecule with new possibilities of application. PMID- 27514443 TI - Dietary litchi pulp polysaccharides could enhance immunomodulatory and antioxidant effects in mice. AB - The purpose of this study was to investigate the immunomodulatory and antioxidant activities of litchi pulp polysaccharides (LP) in cyclophosphamide (Cy)-induced mice. The administration of LP (50, 100 and 200mg/kg/d) remarkably enhanced mesenteric lymph node cells proliferation and serum IgA. Moreover, IL-6, TNF alpha, IgG and IgM levels in serum were significantly improved in a dose dependent manner with LP treatment. Dietary LP induced systemic immune responses including stimulating the proliferation of splenocytes, balancing the ratio of spleen lymphocyte subsets, up-regulating the thymus and spleen indices. Thus, we speculate litchi polysaccharides would express their systemic immunomodulatory effects by triggering the intestinal mucosal immunity. Likewise, LP also significantly increased total antioxidant capacity, as well as superoxidase dismutase and glutathione peroxidase activity, while decreasing malondialdehyde levels in the serum and liver. The immunomodulatory activity of LP was accompanied with its antioxidant activity, which might be related with its structure and prebiotic effect. This is a novel study on the relationship between the immunomodulatory and antioxidant activities of litchi polysaccharides. PMID- 27514444 TI - Structural and thermodynamic studies of the tobacco calmodulin-like rgs-CaM protein. AB - The tobacco calmodulin-like protein rgs-CaM is involved in host defense against virus and is reported to possess an associated RNA silencing suppressor activity. Rgs-CaM is also believed to act as an antiviral factor by interacting and targeting viral silencing suppressors for autophagic degradation. Despite these functional data, calcium interplay in the modulation of rgs-CaM is still poorly understood. Here we show that rgs-CaM displays a prevalent alpha-helical conformation and possesses three functional Ca2+-binding sites. Using computational modeling and molecular dynamics simulation, we demonstrate that Ca2+ binding to rgs-CaM triggers expansion of its tertiary structure with reorientation of alpha-helices within the EF-hands. This conformational change leads to the exposure of a large negatively charged region that may be implicated in the electrostatic interactions between rgs-CaM and viral suppressors. Moreover, the kd values obtained for Ca2+ binding to the three functional sites are not within the affinity range of a typical Ca2+ sensor. PMID- 27514445 TI - A Prospective, Randomized Study of an Expanded Polytetrafluoroethylene Stent Graft versus Balloon Angioplasty for In-Stent Restenosis in Arteriovenous Grafts and Fistulae: Two-Year Results of the RESCUE Study. AB - PURPOSE: To assess the safety and efficacy of an expanded polytetrafluoroethylene stent graft versus balloon angioplasty for the treatment of in-stent restenosis in the venous outflow of hemodialysis access grafts and fistulae. MATERIALS AND METHODS: Two hundred seventy-five patients were randomized at 23 US sites to stent-graft placement or percutaneous transluminal angioplasty (PTA). Primary study endpoints were access circuit primary patency (ACPP) at 6 months and safety through 30 days; secondary endpoints were evaluated through 24 months. RESULTS: ACPP at 6 months was significantly higher in the stent-graft group (18.6%) versus the PTA group (4.5%; P < .001), and freedom from safety events (30 days) was comparable (stent graft, 96.9%; PTA, 96.4%; P = .003 for noninferiority). The separation in ACPP survival curves remained through 12 months (stent graft, 6.2%; PTA, 1.5%). Treatment area primary patency (TAPP) was superior for the stent graft group (66.4%) versus the PTA group (12.3%) at 6 months (P < .001), with a survivorship difference in favor of stent-graft placement maintained through 24 months (stent graft, 15.6%; PTA, 2.2%). ACPP and TAPP for the stent-graft group were better than those for the PTA group when compared within central and peripheral vein subgroups (P < .001). In central veins, TAPP was 13.6% in the stent-graft group versus 4.3% in the PTA group at 24 months (P < .001). CONCLUSIONS: Stent-graft use provided better ACPP and TAPP than PTA when treating in-stent restenosis in patients receiving dialysis with arteriovenous grafts and fistulae. PMID- 27514446 TI - Mitochondrial fragmentation in neuronal degeneration: Toward an understanding of HD striatal susceptibility. AB - Huntington's disease (HD) is an autosomal-dominant progressive neurodegenerative disorder that primarily affects medium spiny neurons within the striatum. HD is caused by inheritance of an expanded CAG repeat in the HTT gene, resulting in a mutant huntingtin (mHtt) protein containing extra glutamine residues. Despite the advances in understanding the molecular mechanisms involved in HD the preferential vulnerability of the striatum remains an intriguing question. This review discusses current knowledge that links altered mitochondrial dynamics with striatal susceptibility in HD. We also highlight how the modulation of mitochondrial function may constitute an attractive therapeutic approach to reduce mHtt-induced toxicity and therefore prevent the selective striatal neurodegeneration. PMID- 27514447 TI - Secretory expression of a heterologous protein, Aiio-AIO6BS, in Bacillus subtilis via a non-classical secretion pathway. AB - The quenching enzyme AIO6 (AiiO-AIO6) has been reported as a feed additive preparation for application in aquaculture and biological control of pathogenic Aeromonas hydrophila. We developed an economical strategy to express AIO6BS (AiiO AIO6BS, codon optimized AIO6 in Bacillus subtilis) in Bacillus subtilis for facilitating its widespread application. Promoter p43 without the signal peptide was used for secretory expression of AIO6BS in B. subtilis. Western blotting analysis demonstrated that AIO6BS was successfully expressed and secreted into the cell culture. Expression analysis of AIO6BS in the single or double mutant of the lytC and lytD genes for cell autolysis in B. subtilis 1A751 and cell autolysis-resistant engineered strain LM2531 derived from the wild type 168 indicated that the release of the heterologous protein AIO6BS was not simply mediated by cell lysis. Expression level of AIO6BS did not change in the mutants of B. subtilis that harbored mutations in the secA, tatAC, or ecsA genes compared with that in the parent wild type strain. These results suggested the AIO6BS protein was likely secreted via a non-classical secretion pathway. The expression analysis of the various N- or C-terminal truncated gene products indicated that AIO6BS probably acts as an export signal to direct its self-secretion across the cell membrane. PMID- 27514448 TI - SIRT1 controls cell proliferation by regulating contact inhibition. AB - Contact inhibition keeps cell proliferation in check and serves as a built-in protection against cancer development by arresting cell division upon cell-cell contact. Yet the complete mechanism behind this anti-cancer process remains largely unclear. Here we present SIRT1 as a novel regulator of contact inhibition. SIRT1 performs a wide variety of functions in biological processes, but its involvement in contact inhibition has not been explored to date. We used NIH3T3 cells, which are sensitive to contact inhibition, and H460 and DU145 cancer cells, which lack contact inhibition, to investigate the relationship between SIRT1 and contact inhibition. We show that SIRT1 overexpression in NIH3T3 cells overcomes contact inhibition while SIRT1 knockdown in cancer cells restores their lost contact inhibition. Moreover, we demonstrate that p27 protein expression is controlled by SIRT1 in contact inhibition. Overall, our findings underline the critical role of SIRT1 in contact inhibition and suggest SIRT1 inhibition as a potential strategy to suppress cancer cell growth by restoring contact inhibition. PMID- 27514449 TI - Diethylnitrosamine-induced expression of germline-specific genes and pluripotency factors, including vasa and oct4, in medaka somatic cells. AB - Various methods have been developed to reprogram mammalian somatic cells into pluripotent cells as well as to directly reprogram somatic cells into other cell lineages. We are interested in applying these methods to fish, and here, we examined whether mRNA expression of germline-specific genes (vasa, nanos2, -3) and pluripotency factors (oct4, sox2, c-myc, nanog) is inducible in somatic cells of Japanese medaka (Oryzias latipes). We found that the expression of vasa is induced in the gut and regenerating fin by exposure to a carcinogen, diethylnitrosamine (DEN). Induction of vasa in the gut started on the 5th day of treatment with >50 ppm DEN. In addition, nanos2, -3, oct4, sox2, klf4, c-myc, and nanog were also expressed simultaneously in some vasa-positive gut and regenerating fin samples. Vasa-positive cells were detected by immunohistochemistry (IHC) in the muscle surrounding the gut and in the wound epidermis, blastema, and fibroblast-like cells in regenerating fin. In vasa:GFP transgenic medaka, green fluorescent protein (GFP) fluorescence appeared in the wound epidermis and fibroblast-like cells in the regenerating fin following DEN exposure, in agreement with the IHC data. Our data show that mRNA expression of genes relevant to germ cell specification and pluripotency can be induced in fish somatic cells by exposure to DEN, suggesting the possibility of efficient and rapid cell reprogramming of fish somatic cells. PMID- 27514450 TI - MicroRNA-2400 promotes bovine preadipocyte proliferation. AB - MicroRNAs (miRNAs) play critical roles in the proliferation of bovine preadipocytes. miR-2400 is a novel and unique miRNA from bovines. In the present study, we separated and identified preadipocytes from bovine samples. miR-2400 overexpression increased the rate of preadipocyte proliferation, which was analyzed with a combination of EdU and flow cytometry. Simultaneously, functional genes related to proliferation (PCNA, CCND2, CCNB1) were also increased, which was detected by real-time PCR. Furthermore, luciferase reporter assays showed that miR-2400 bound directly to the 3'untranslated regions (3'UTRs) of PRDM11 mRNA. These data suggested that miR-2400 could promote preadipocyte proliferation by targeting PRDM11. PMID- 27514451 TI - Analysis and quality control of carbohydrates in therapeutic proteins with fluorescence HPLC. AB - Conbercept is an Fc fusion protein with very complicated carbohydrate profiles which must be carefully monitored through manufacturing process. Here, we introduce an optimized fluorescence derivatization high-performance liquid chromatographic method for glycan mapping in conbercept. Compared with conventional glycan analysis method, this method has much better resolution and higher reproducibility making it excellent for product quality control. PMID- 27514452 TI - Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders. AB - Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and they serve to be a promising therapeutic target for several neurodegenerative disorders, which includes Parkinson disease, Alzheimer's disease, Huntington disease and Amyotrophic Lateral Sclerosis. PPARs play an important role in the downregulation of mitochondrial dysfunction, proteasomal dysfunction, oxidative stress, and neuroinflammation, which are the major causes of the pathogenesis of neurodegenerative disorders. In this review, we discuss about the role of PPARs as therapeutic targets in neurodegenerative disorders. Several experimental approaches suggest potential application of PPAR agonist as well as antagonist in the treatment of neurodegenerative disorders. Several epidemiological studies found that the regular usage of PPAR activating non-steroidal anti-inflammatory drugs is effective in decreasing the progression of neurodegenerative diseases including PD and AD. We also reviewed the neuroprotective effects of PPAR agonists and associated mechanism of action in several neurodegenerative disorders both in vitro as well as in vivo animal models. PMID- 27514453 TI - SMARTER De-Stressed Cereal Breeding. AB - In cereal breeding programs, improved yield potential and stability are ultimate goals when developing new varieties. To facilitate achieving these goals, reproductive success under stressful growing conditions is of the highest priority. In recent times, small RNA (sRNA)-mediated pathways have been associated with the regulation of genes involved in stress adaptation and reproduction in both model plants and several cereals. Reproductive and physiological traits such as flowering time, reproductive branching, and root architecture can be manipulated by sRNA regulatory modules. We review sRNA mediated pathways that could be exploited to expand crop diversity with adaptive traits and, in particular, the development of high-yielding stress-tolerant cereals: SMARTER cereal breeding through 'Small RNA-Mediated Adaptation of Reproductive Targets in Epigenetic Regulation'. PMID- 27514454 TI - Take a Trip Through the Plant and Fungal Transportome of Mycorrhiza. AB - Soil nutrient acquisition and exchanges through symbiotic plant-fungus interactions in the rhizosphere are key features for the current agricultural and environmental challenges. Improved crop yield and plant mineral nutrition through a fungal symbiont has been widely described. In return, the host plant supplies carbon substrates to its fungal partner. We review here recent progress on molecular players of membrane transport involved in nutritional exchanges between mycorrhizal plants and fungi. We cover the transportome, from the transport proteins involved in sugar fluxes from plants towards fungi, to the uptake from the soil and exchange of nitrogen, phosphate, potassium, sulfate, and water. Together, these advances in the comprehension of the mycorrhizal transportome will help in developing the future engineering of new agro-ecological systems. PMID- 27514455 TI - Macrophages induce resistance to 5-fluorouracil chemotherapy in colorectal cancer through the release of putrescine. AB - The development of chemoresistance to 5-fluorouracil (5-FU) is a major obstacle for sustained effective treatment of colorectal cancer (CRC), with the mechanisms being not fully understood. Here we demonstrated that tumor associated macrophages (TAMs) became activated during treatment with 5-FU and secreted factors that protected the CRC cells against chemotherapy with 5-FU. By performing metabolomics analysis, we identified putrescine, a member of polyamines, inducing resistance to 5-FU-triggered CRC apoptosis and tumor suppression via JNK-caspase-3 pathway. Noteworthily, either pharmacological or genetic blockage of ornithine decarboxylase (ODC) prevented TAMs-induced chemoresistance to 5-FU in vitro and in vivo. Our findings show that TAMs are potent mediators of resistance to 5-FU chemotherapy and uncover potential targets to enhance chemotherapy sensitivity in patients with CRC. PMID- 27514456 TI - A new and simple suturing technique applied after surgery to correct ingrown toenails may improve clinical outcomes: A randomized controlled trial. AB - INTRODUCTION: In the present study, we investigated the efficacy of a new suturing technique applied after the Winograd procedure has been completed. METHODS: This study was prospective, randomized, and controlled. In total, 128 patients were recruited and divided into two groups. The outcomes of those treated with the new suturing technique (group I) were compared with those of patients treated with the traditional suturing technique (group II), both of which were applied after the Winograd procedure had been completed. The clinical outcomes and recurrence rates of the two groups were compared. RESULTS: Patients in group I required significantly more time to return to work or school than did those in group II (p = 0.015). We found no significant difference between youths (age < 18 years, n = 55) and adults (age >= 19 years, n = 69) in this context (p = 0.161). The recurrence rate was significantly higher in group II than in group I (p = 0.011). The extent of satisfaction was significantly higher in group I (p = 0.042). CONCLUSIONS: Our new suturing technique is associated with lower recurrence and higher satisfaction rates. However, the times elapsing before shoes could be worn were similar in the two groups. PMID- 27514457 TI - Cerebral Air Embolism During Air Flight-Neuroimaging and Management. PMID- 27514458 TI - Leg Lift Valsalva Maneuver for Treatment of Supraventricular Tachycardias. AB - Clinical question Can conversion to sinus rhythm for a supraventricular tachycardia be enhanced by a postural modification to the Valsalva maneuver? Article chosen Appelboam A, Reuben A, Mann C, et al. Postural modification of the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial. Lancet 2015;386(10005):1747 53. 1 OBJECTIVE: To determine effectiveness of a postural modification of the Valsalva involving leg elevation and supine positioning. PMID- 27514459 TI - Synthesis of cyclic carbonates from diols and CO2 catalyzed by carbenes. AB - The synthesis of cyclic carbonates from epoxides and CO2 is a well-established reaction, whereas the synthesis of cyclic carbonates from diols and CO2 is considerably more challenging, and few efficient catalysts are available. Here, we describe heterocyclic carbene catalysts, including one derived from a cheap and efficient thiazolium salt, for this latter reaction. The reaction proceeds at atmospheric pressure in the presence of an alkyl halide and Cs2CO3. Reaction mechanisms for the transformations involved are also proposed. PMID- 27514460 TI - Elevated cardiac 3-deoxyglucosone, a highly reactive intermediate in glycation reaction, in doxorubicin-induced cardiotoxicity in rats. AB - 3-Deoxyglucosone (3-DG) is a highly reactive carbonyl intermediate in glycation reaction (also known as Maillard reaction) and plays an important role in diabetic complications. We investigated the potential involvement of 3-DG in doxorubicin (DXR)-induced cardiotoxicity. Male Crl:CD(SD) rats received intravenous injections of DXR at 2mg/kg, once weekly, for 6 weeks, with/without daily intraperitoneal treatment with 3-DG scavenging agents, i.e., aminoguanidine (AG, 25mg/kg/day) and pyridoxamine (PM, 60mg/kg/day). Cardiac levels of 3-DG, thiobarbituric acid reactive substances (TBARS), fructosamine, and pentosidine, plasma glucose levels and cardiac troponin I (cTnI), echocardiography, and histopathology were assessed at 4 and 6 weeks after treatment. Cardiac 3-DG levels were significantly increased by DXR treatment at 4 and 6 weeks. Cardiac fructosamine levels and plasma glucose were not altered by DXR; however, TBARS levels in the heart were significantly increased at 4 and 6 weeks, suggesting that the enhanced generation of 3-DG is not attributed to any abnormal glycemic status, but may be related to oxidative stress by DXR. An advanced glycation end product, pentosidine, was significantly increased by DXR treatment at 6 weeks. Intervention by AG and PM ameliorated the DXR-induced echocardiographic abnormalities, increased cTnI in plasma, and histopathological lesion as well as normalizing the elevation of 3-DG and pentosidine levels. These results suggest that 3-DG is generated by DXR and involved, at least in part, in the pathogenesis of DXR-cardiotoxicity through glycation reaction. PMID- 27514461 TI - Fundamentals of Pharmacogenetics in Personalized, Precision Medicine. AB - This article introduces fundamental principles of pharmacogenetics as applied to personalized and precision medicine. Pharmacogenetics establishes relationships between pharmacology and genetics by connecting phenotypes and genotypes in predicting the response of therapeutics in individual patients. We describe differences between precision and personalized medicine and relate principles of pharmacokinetics and pharmacodynamics to applications in laboratory medicine. We also review basic principles of pharmacogenetics, including its evolution, how it enables the practice of personalized therapeutics, and the role of the clinical laboratory. These fundamentals are a segue for understanding specific clinical applications of pharmacogenetics described in subsequent articles in this issue. PMID- 27514462 TI - Pharmacogenetics in Oral Antithrombotic Therapy. AB - Certain antithrombotic drugs exhibit high patient-to-patient variability that significantly impacts the safety and efficacy of therapy. Pharmacogenetics offers the possibility of tailoring drug treatment to patients based on individual genotypes, and this type of testing has been recommended for 2 oral antithrombotic agents, warfarin and clopidogrel, to influence use and guide dosing. Limited studies have identified polymorphisms that affect the metabolism and activity of newer oral antithrombotic drugs, without clear evidence of the clinical relevance of such polymorphisms. This article provides an overview of the current status of pharmacogenetics in oral antithrombotic therapy. PMID- 27514464 TI - Pharmacogenetics and Personalized Medicine in Pain Management. AB - Genetic research heralds a new therapeutic approach to pain management. Increasing literature demonstrates individual genetic vulnerabilities to specific pain types and mechanisms, partially explaining differing responses to similar pain stimuli. Furthermore, analgesics demonstrate great variability among carriers of different genotypes. Family history and genotyping promise to play an important role in the future approach to pain therapies. As advances continue in the genetics of pain and analgesia, pharmacotherapy will depend more on an individualized, targeted approach and less on empiricism. PMID- 27514463 TI - Laboratory Medicine in the Clinical Decision Support for Treatment of Hypercholesterolemia: Pharmacogenetics of Statins. AB - Statin responsiveness is an area of great research interest given the success of the drug class in the treatment of hypercholesterolemia and in primary and secondary prevention of cardiovascular disease. Interrogation of the patient's genome for gene variants will eventually guide anti-hyperlipidemic intervention. In this review, we discuss methodological approaches to discover genetic markers predictive of class-wide and drug-specific statin efficacy and safety. Notable pharmacogenetic findings are summarized from hypothesis-free genome wide and hypothesis-led candidate gene association studies. Physiogenomic models and clinical decision support systems will be required for DNA-guided statin therapy to reach practical use in medicine. PMID- 27514465 TI - Pharmacogenomics in Psychiatric Practice. AB - Pharmacogenomic testing in psychiatry is becoming an established clinical procedure. Several vendors provide clinical interpretation of combinatorial pharmacogenomic testing of gene variants that have documented predictive implications regarding either pharmacologic response or adverse effects in depression and other psychiatric conditions. Such gene profiles have demonstrated improvements in outcome in depression, and reduction of cost of care of patients with inadequate clinical response. Additionally, several new gene variants are being studied to predict specific response in individuals. Many of these genes have demonstrated a role in the pathophysiology of depression or specific depressive symptoms. This article reviews the current state-of-the-art application of psychiatric pharmacogenomics. PMID- 27514466 TI - Clinical Utility and Economic Impact of CYP2D6 Genotyping. AB - Pharmacogenetics examines an individual's genetic makeup to help predict the safety and efficacy of medications. Practical application optimizes treatment selection to decrease the failure rate of medications and improve clinical outcomes. Lack of efficacy is costly due to adverse drug reactions and increased hospital stays. Cytochrome P450 2D6 (CYP2D6) metabolizes roughly 25% of all drugs. Detecting variants that cause altered CYP2D6 enzymatic activity identifies patients at risk of adverse drug reactions or therapeutic failure with standard dosages of medications metabolized by CYP2D6. This article discusses the clinical application of pharmacogenetics to improve care and decrease costs. PMID- 27514467 TI - The Pharmacist's Perspective on Pharmacogenetics Implementation. AB - The future for pharmacogenetics will continue to expand. Pharmacists can apply and incorporate drug knowledge in collaboration with other health providers using pharmacogenetics. Patients benefit with enhanced therapeutic outcomes that could lead to more streamlined drug approaches, fewer follow-up visits, cost savings, and shorter times to achieve therapeutic outcomes. As more drug-gene pathways are discovered and use of this knowledge increases, the potential for algorithm development for medication use will occur, resulting in better patient outcomes, higher standard of care, and reflect evidence-based medicine. PMID- 27514468 TI - The Future of Precision Medicine in Oncology. AB - Precision medicine in oncology focuses on identifying which therapies are most effective for each patient based on genetic characterization of the cancer. Traditional chemotherapy is cytotoxic and destroys all cells that are rapidly dividing. The foundation of precision medicine is targeted therapies and selecting patients who will benefit most from these therapies. One of the newest aspects of precision medicine is liquid biopsy. A liquid biopsy includes analysis of circulating tumor cells, cell-free nucleic acid, or exosomes obtained from a peripheral blood draw. These can be studied individually or in combination and collected serially, providing real-time information as a patient's cancer changes. PMID- 27514469 TI - Understanding the Food and Drug Administration's Jurisdiction Over Laboratory Developed Tests and Divisions Between Food, Drug, and Cosmetic Act-Regulated and Clinical Laboratory Improvement Amendments of 1988-Regulated Activities. AB - The scope of FDA's jurisdiction over laboratory-developed tests (LDTs), and whether FDA has such jurisdiction at all, has been a heavily debated issue over the past several years. If FDA moves forward with its guidance, or Congress takes action to reform LDT and IVD regulation, a fundamental question that needs to be answered is how to divide activities regulated by FDCA from those regulated by CLIA. In this article, we consider FDA's authority to regulate LDTs and the policy implications of regulation, and discuss an idea for a fact-driven framework to distinguish FDCA- and CLIA- activities. PMID- 27514470 TI - Extracellular Vesicles Move Toward Use in Clinical Laboratories. AB - Extracellular vesicles (EVs) are membranous particles found in a variety of biofluids that encapsulate molecular information from the cell, which they originate from. This rich source of information that is easily obtained can then be mined to find diagnostic biomarkers. This article explores the current biological understanding of EVs and specific methods to isolate and analyze them. A case study of a company leading the charge in using EVs in diagnostic assays is provided. PMID- 27514471 TI - Preface. PMID- 27514472 TI - DELLA proteins are common components of symbiotic rhizobial and mycorrhizal signalling pathways. AB - Legumes form symbiotic associations with either nitrogen-fixing bacteria or arbuscular mycorrhizal fungi. Formation of these two symbioses is regulated by a common set of signalling components that act downstream of recognition of rhizobia or mycorrhizae by host plants. Central to these pathways is the calcium and calmodulin-dependent protein kinase (CCaMK)-IPD3 complex which initiates nodule organogenesis following calcium oscillations in the host nucleus. However, downstream signalling events are not fully understood. Here we show that Medicago truncatula DELLA proteins, which are the central regulators of gibberellic acid signalling, positively regulate rhizobial symbiosis. Rhizobia colonization is impaired in della mutants and we provide evidence that DELLAs can promote CCaMK IPD3 complex formation and increase the phosphorylation state of IPD3. DELLAs can also interact with NSP2-NSP1 and enhance the expression of Nod-factor-inducible genes in protoplasts. We show that DELLA is able to bridge a protein complex containing IPD3 and NSP2. Our results suggest a transcriptional framework for regulation of root nodule symbiosis. PMID- 27514473 TI - ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing. AB - The processing of MHC class I antigenic precursor peptides by the endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 is an important event in the cell biology of antigen presentation. To date, the molecular context by which the ERAP enzymes trim precursor peptides, and how ERAPs shape peptide repertoires, remain open questions. Using ERAP1 and ERAP2 heterodimers (ERAP1/2), and N-terminally extended model and natural peptides in their free and HLA-B*0801-bound forms, we characterized the mode of action of ERAPs. We provide evidence that ERAP1/2 can trim MHC I-bound precursor peptides to their correct and final lengths, albeit more slowly than the corresponding free precursors. Trimming of MHC I-bound precursors by ERAP1/2 increases the conformational stability of MHC I/peptide complexes. From the data, we propose a molecular mechanistic model of ERAP1/2 as peptide editors. Overall, our study provides new findings on a significant issue of the ERAP-mediated processing pathway of MHC class I antigens. PMID- 27514474 TI - Influence of grain boundary characteristics on thermal stability in nanotwinned copper. AB - High density grain boundaries provide high strength, but may introduce undesirable features, such as high Fermi levels and instability. We investigated the kinetics of recovery and recrystallization of Cu that was manufactured to include both nanotwins (NT) and high-angle columnar boundaries. We used the isothermal Johnson-Mehl-Avrami-Kolmogorov (JMAK) model to estimate activation energy values for recovery and recrystallization and compared those to values derived using the non-isothermal Kissinger equation. The JMAK model hinges on an exponent that expresses the growth mechanism of a material. The exponent for this Cu was close to 0.5, indicating low-dimensional microstructure evolution, which is associated with anisotropic twin coarsening, heterogeneous recrystallization, and high stability. Since this Cu was of high purity, there was a negligible impurity-drag-effect on boundaries. The twin coarsening and heterogeneous recrystallization resulted from migration of high-angle columnar boundaries with their triple junctions in one direction, assisted by the presence of high concentration vacancies at boundaries. Analyses performed by electron energy loss spectroscopy of atomic columns at twin boundaries (TBs) and in the interior showed similar plasma peak shapes and L3 edge positions. This implies that values for conductivity and Fermi level are equal for atoms at TBs and in the interior. PMID- 27514475 TI - Legumain is activated in macrophages during pancreatitis. AB - Pancreatitis is an inflammatory disease of the pancreas characterized by dysregulated activity of digestive enzymes, necrosis, immune infiltration, and pain. Repeated incidence of pancreatitis is an important risk factor for pancreatic cancer. Legumain, a lysosomal cysteine protease, has been linked to inflammatory diseases such as atherosclerosis, stroke, and cancer. Until now, legumain activation has not been studied during pancreatitis. We used a fluorescently quenched activity-based probe to assess legumain activation during caerulein-induced pancreatitis in mice. We detected activated legumain by ex vivo imaging, confocal microscopy, and gel electrophoresis. Compared with healthy controls, legumain activity in the pancreas of caerulein-treated mice was increased in a time-dependent manner. Legumain was localized to CD68(+) macrophages and was not active in pancreatic acinar cells. Using a small-molecule inhibitor of legumain, we found that this protease is not essential for the initiation of pancreatitis. However, it may serve as a biomarker of disease, since patients with chronic pancreatitis show strongly increased legumain expression in macrophages. Moreover, the occurrence of legumain-expressing macrophages in regions of acinar-to-ductal metaplasia suggests that this protease may influence reprogramming events that lead to inflammation-induced pancreatic cancer. PMID- 27514477 TI - Acetylcholine-producing T cells in the intestine regulate antimicrobial peptide expression and microbial diversity. AB - The cholinergic anti-inflammatory pathway reduces systemic tumor necrosis factor (TNF) via acetylcholine-producing memory T cells in the spleen. These choline acetyltransferase (ChAT)-expressing T cells are also found in the intestine, where their function is unclear. We aimed to characterize these cells in mouse and human intestine and delineate their function. We made use of the ChAT enhanced green fluorescent protein (eGFP) reporter mice. CD4Cre mice were crossed to ChATfl/fl mice to achieve specific deletion of ChAT in CD4+ T cells. We observed that the majority of ChAT-expressing T cells in the human and mouse intestine have characteristics of Th17 cells and coexpress IL17A, IL22, and RORC The generation of ChAT-expressing T cells was skewed by dendritic cells after activation of their adrenergic receptor beta2 To evaluate ChAT T cell function, we generated CD4-specific ChAT-deficient mice. CD4ChAT-/- mice showed a reduced level of epithelial antimicrobial peptides lysozyme, defensin A, and ang4, which was associated with an enhanced bacterial diversity and richness in the small intestinal lumen in CD4ChAT-/- mice. We conclude that ChAT-expressing T cells in the gut are stimulated by adrenergic receptor activation on dendritic cells. ChAT expressing T cells may function to mediate the host AMP secretion, microbial growth and expansion. PMID- 27514476 TI - Soluble bioactive microbial mediators regulate proteasomal degradation and autophagy to protect against inflammation-induced stress. AB - Bifidobacterium breve and other Gram-positive gut commensal microbes protect the gastrointestinal epithelium against inflammation-induced stress. However, the mechanisms whereby these bacteria accomplish this protection are poorly understood. In this study, we examined soluble factors derived from Bifidobacterium breve and their impact on the two major protein degradation systems within intestinal epithelial cells, proteasomes and autophagy. Conditioned media from gastrointestinal Gram-positive, but not Gram-negative, bacteria activated autophagy and increased expression of the autophagy proteins Atg5 and Atg7 along with the stress response protein heat shock protein 27. Specific examination of media conditioned by the Gram-positive bacterium Bifidobacterium breve (Bb-CM) showed that this microbe produces small molecules (<3 kDa) that increase expression of the autophagy proteins Atg5 and Atg7, activate autophagy, and inhibit proteasomal enzyme activity. Upregulation of autophagy by Bb-CM was mediated through MAP kinase signaling. In vitro studies using C2BBe1 cells silenced for Atg7 and in vivo studies using mice conditionally deficient in intestinal epithelial cell Atg7 showed that Bb-CM-induced cytoprotection is dependent on autophagy. Therefore, this work demonstrates that Gram-positive bacteria modify protein degradation programs within intestinal epithelial cells to promote their survival during stress. It also reveals the therapeutic potential of soluble molecules produced by these microbes for prevention and treatment of gastrointestinal disease. PMID- 27514478 TI - Probiotic Saccharomyces boulardii CNCM I-745 prevents outbreak-associated Clostridium difficile-associated cecal inflammation in hamsters. AB - C. difficile infection (CDI) is a common debilitating nosocomial infection associated with high mortality. Several CDI outbreaks have been attributed to ribotypes 027, 017, and 078. Clinical and experimental evidence indicates that the nonpathogenic yeast Saccharomyces boulardii CNCM I-745 (S.b) is effective for the prevention of CDI. However, there is no current evidence suggesting this probiotic can protect from CDI caused by outbreak-associated strains. We used established hamster models infected with outbreak-associated C. difficile strains to determine whether oral administration of live or heat-inactivated S.b can prevent cecal tissue damage and inflammation. Hamsters infected with C. difficile strain VPI10463 (ribotype 087) and outbreak-associated strains ribotype 017, 027, and 078 developed severe cecal inflammation with mucosal damage, neutrophil infiltration, edema, increased NF-kappaB phosphorylation, and increased proinflammatory cytokine TNFalpha protein expression. Oral gavage of live, but not heated, S.b starting 5 days before C. difficile infection significantly reduced cecal tissue damage, NF-kappaB phosphorylation, and TNFalpha protein expression caused by infection with all strains. Moreover, S.b-conditioned medium reduced cell rounding caused by filtered supernatants from all C. difficile strains. S.b-conditioned medium also inhibited toxin A- and B-mediated actin cytoskeleton disruption. S.b is effective in preventing C. difficile infection by outbreak-associated via inhibition of the cytotoxic effects of C. difficile toxins. PMID- 27514479 TI - The kielin/chordin-like protein KCP attenuates nonalcoholic fatty liver disease in mice. AB - Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease and is increasing with the rising rate of obesity in the developed world. Signaling pathways known to influence the rate of lipid deposition in liver, known as hepatic steatosis, include the transforming growth factor (TGF) superfamily, which function through the SMAD second messengers. The kielin/chordin-like protein (KCP) is a large secreted protein that can enhance bone morphogenetic protein signaling while suppressing TGF-beta signaling in cells and in genetically modified mice. In this report, we show that aging KCP mutant (Kcp-/-) mice are increasingly susceptible to developing hepatic steatosis and liver fibrosis. When young mice are put on a high-fat diet, Kcp-/- mice are also more susceptible to developing liver pathology, compared with their wild type littermates. Furthermore, mice that express a Pepck-KCP transgene (KcpTg) in the liver are resistant to developing liver pathology even when fed a high-fat diet. Analyses of liver tissues reveal a significant reduction of P-Smad3, consistent with a role for KCP in suppressing TGF-beta signaling. Transcriptome analyses show that livers from Kcp-/- mice fed a normal diet are more like wild type livers from mice fed a high-fat diet. However, the KCP transgene can suppress many of the changes in liver gene expression that are due to a high-fat diet. These data demonstrate that shifting the TGF-beta signaling paradigm with the secreted regulatory protein KCP can significantly alter the liver pathology in aging mice and in diet-induced NAFLD. PMID- 27514480 TI - Ion channelopathies in functional GI disorders. AB - In the gastrointestinal (GI) tract, abnormalities in secretion, absorption, motility, and sensation have been implicated in functional gastrointestinal disorders (FGIDs). Ion channels play important roles in all these GI functions. Disruptions of ion channels' ability to conduct ions can lead to diseases called ion channelopathies. Channelopathies can result from changes in ion channel biophysical function or expression due to mutations, posttranslational modification, and accessory protein malfunction. Channelopathies are strongly established in the fields of cardiology and neurology, but ion channelopathies are only beginning to be recognized in gastroenterology. In this review, we describe the state of the emerging field of GI ion channelopathies. Several recent discoveries show that channelopathies result in alterations in GI motility, secretion, and sensation. In the epithelium, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) or CFTR-associating proteins result in channelopathies with constipation or diarrhea as phenotypes. In the muscle, mutations in the SCN5A-encoded voltage-gated sodium channel NaV1.5 are associated with irritable bowel syndrome. In the sensory nerves, channelopathies of voltage-gated sodium channels NaV1.7 and NaV1.9 (encoded by SCN9A, SCN11A, respectively) manifest by either GI hyper- or hyposensation. Recent advances in structural biology and ion channel biophysics, coupled with personalized medicine, have fueled rapid discoveries of novel channelopathies and direct drug targeting of specific channelopathies. In summary, the emerging field of GI ion channelopathies has significant implications for functional GI disease stratification, diagnosis, and treatment. PMID- 27514481 TI - Monosodium glutamate inhibits the lymphatic transport of lipids in the rat. AB - It is not well understood how monosodium glutamate (MSG) affects gastrointestinal physiology, especially regarding the absorption and the subsequent transport of dietary lipids into lymph. Thus far, there is little information about how the ingestion of MSG affects the lipid lipolysis, uptake, intracellular esterification, and formation and secretion of chylomicrons. Using lymph fistula rats treated with the infusion of a 2% MSG solution before a continuous infusion of triglyceride, we show that MSG causes a significant decrease in both triglyceride and cholesterol secretion into lymph. Intriguingly, the diminished lymphatic transport of triglyceride and cholesterol was not caused by an accumulation of these labeled lipids in the intestinal lumen or in the intestinal mucosa. Rather, it is a result of increased portal transport in the animals fed acutely the lipid plus 2% MSG in the lipid emulsion. This is a first demonstration of MSG on intestinal lymphatic transport of lipids. PMID- 27514482 TI - Measurement of strains experienced by viscerofugal nerve cell bodies during mechanosensitive firing using digital image correlation. AB - Mechanosensory neurons detect physical events in the local environments of the tissues that they innervate. Studies of mechanosensitivity of neurons or nerve endings in the gut have related their firing to strain, wall tension, or pressure. Digital image correlation (DIC) is a technique from materials engineering that can be adapted to measure the local physical environments of afferent neurons at high resolution. Flat-sheet preparations of guinea pig distal colon were set up with arrays of tissue markers in vitro. Firing of single viscerofugal neurons was identified in extracellular colonic nerve recordings. The locations of viscerofugal nerve cell bodies were inferred by mapping firing responses to focal application of the nicotinic receptor agonist 1,1-dimethyl-4 phenylpiperazinium iodide. Mechanosensory firing was recorded during load-evoked uniaxial or biaxial distensions. Distension caused movement of surface markers which was captured by video imaging. DIC tracked the markers, interpolating the mechanical state of the gut at the location of the viscerofugal nerve cell body. This technique revealed heterogeneous load-evoked strain within preparations. Local strains at viscerofugal nerve cell bodies were usually smaller than global strain measurements and correlated more closely with mechanosensitive firing. Both circumferential and longitudinal strain activated viscerofugal neurons. Simultaneous loading in circumferential and longitudinal axes caused the highest levels of viscerofugal neuron firing. Multiaxial strains, reflecting tissue shearing and changing area, linearly correlated with mechanosensory firing of viscerofugal neurons. Viscerofugal neurons were mechanically sensitive to both local circumferential and local longitudinal gut strain, and appear to lack directionality in their stretch sensitivity. PMID- 27514484 TI - Lysyl oxidase activity in human skin is increased by chronic ultraviolet radiation exposure and smoking. PMID- 27514483 TI - Hepatocellular autophagy modulates the unfolded protein response and fasting induced steatosis in mice. AB - Autophagy and the unfolded protein response (UPR) are key cellular homeostatic mechanisms and are both involved in liver diseases, including nonalcoholic fatty liver disease (NAFLD). Although increasing but conflicting results link these mechanisms to lipid metabolism, their role and potential cross talk herein have been poorly investigated. Therefore, we assessed the effects of hepatocyte specific autophagy deficiency on liver parenchyma, the UPR, and lipid metabolism. Adult hepatocellular-specific autophagy-deficient mice (Atg7F/FAlb-Cre+) were compared with their autophagy-competent littermates (Atg7+/+Alb-Cre+). Livers were analyzed by electron microscopy, histology, real-time qPCR, and Western blotting. Atg7F/FAlb-Cre+ mice developed hepatomegaly with significant parenchymal injury, as shown by inflammatory infiltrates, hepatocellular apoptosis, pericellular fibrosis, and a pronounced ductular reaction. Surprisingly, the UPR exhibited a pathway-selective pattern upon autophagy deficiency. The activity of the adaptive activating transcription factor 6 (ATF6) pathway was abolished, whereas the proapoptotic protein kinase RNA-like ER kinase pathway was increased compared with Atg7+/+Alb-Cre+ mice. The inositol-requiring enzyme-1alpha signal was unaltered. Fasting-induced steatosis was absent in Atg7F/FAlb-Cre+ mice. Remarkably, some isolated islands of fat-containing and autophagy-competent cells were observed in these livers. Hepatocellular autophagy is essential for parenchymal integrity in mice. Moreover, in the case of autophagy deficiency, the three different UPR branches are pathway selectively modulated. Attenuation of the ATF6 pathway might explain the observed impairment of fasting-induced steatosis. Finally, autophagy and lipid droplets are directly linked to each other. PMID- 27514485 TI - Microwave-Assisted Extraction, Chemical Structures, and Chain Conformation of Polysaccharides from a Novel Cordyceps Sinensis Fungus UM01. AB - Cordyceps sinensis is a well-known tonic food with broad medicinal properties. The aim of the present study was to investigate the optimization of microwave assisted extraction (MAE) and characterize chemical structures and chain conformation of polysaccharides from a novel C. sinensis fungus UM01. Ion exchange and gel filtration chromatography were used to purify the polysaccharides. The chemical structure of purified polysaccharide was determined through gas chromatography-mass spectrometry. Moreover, high performance size exclusion chromatography combined with refractive index detector and multiangle laser light scattering were conducted to analyze the molecular weight (Mw ) and chain conformation of purified polysaccharide. Based on the orthogonal design L9 , optimal MAE conditions could be obtained through 1300 W of microwave power, with a 5-min irradiation time at a solid to water ratio of 1:60, generating the highest extraction yield of 6.20%. Subsequently, the polysaccharide UM01-S1 was purified. The UM01-S1 is a glucan-type polysaccharide with a (1->4)-beta-d glucosyl backbone and branching points located at O-3 of Glcp with a terminal-d Glcp. The Mw , radius of gyration (Rg ) and hydrodynamic radius (Rh ) of UM01-S1 were determined as 5.442 * 10(6) Da, 21.8 and 20.2 nm, respectively. Using the polymer solution theory, the exponent (nu) value of the power law function was calculated as 0.38, and the shape factor (rho = Rg /Rh ) was 1.079, indicating that UM01-S1 has a sphere-like conformation with a branched structure in an aqueous solution. These results provide fundamental information for the future application of polysaccharides from cultured C. sinensis in health and functional food area. PMID- 27514486 TI - Estimating risk of malignancy in adnexal masses: external validation of the ADNEX model and comparison with other frequently used ultrasound methods. AB - OBJECTIVES: To validate externally the performance of the Assessment of Different NEoplasias in the adneXa (ADNEX) model and compare this model with other frequently used models in the differentiation between benign and malignant adnexal masses. METHODS: In this retrospective diagnostic accuracy study, we assessed data collected prospectively from patients with adnexal pathology who underwent real-time transvaginal or transrectal ultrasound by a single expert ultrasonographer in a tertiary care hospital between July 2011 and July 2015. The presence of a malignancy was determined by subjective assessment and use of four prediction models: the ADNEX model, simple ultrasound-based rules (simple rules), Logistic Regression model 2 (LR2) and the Risk of Malignancy Index (RMI), of which three different variants were assessed. Pathology was the clinical reference standard. RESULTS: In total, 851 consecutive patients underwent ultrasound examination for an adnexal mass. For 326 patients (128 premenopausal and 198 postmenopausal), pathology results were available (211 (64.7%) benign; 115 (35.3%) malignant) and these were included in the analysis. The area under the receiver-operating characteristics curve (AUC) of the ADNEX model for the discrimination between benign and malignant tumors was 0.93 (95% CI, 0.89-0.95). AUCs for the subtypes of malignancy (i.e. borderline, Stage I-IV and metastatic adnexal tumors) ranged between 0.60 and 0.90. Only subjective assessment (AUC, 0.96 (95% CI, 0.93-0.98)) was superior to the ADNEX model (P = 0.01) in differentiating malignant from benign tumors. AUCs for the other models were 0.92 (95% CI, 0.89-0.95) for LR2, 0.85 (95% CI, 0.81-0.89) for RMI-I, 0.82 (95% CI, 0.77-0.86) for RMI-II and 0.84 (95% CI, 0.80-0.88) for RMI-III. At the proposed cut-off of >= 10%, the ADNEX model had the highest sensitivity (0.98 (95% CI, 0.93-1.00)) but the lowest specificity (0.62 (95% CI, 0.55-0.68)) compared with the other models. Both subjective assessment (sensitivity, 0.90 (95% CI, 0.83 0.95); specificity 0.91 (95% CI, 0.86-0.94)) and the simple rules model with inconclusive cases classified by subjective assessment (sensitivity, 0.89 (95% CI, 0.81-0.94); specificity, 0.90 (95% CI, 0.85-0.94)) had lower sensitivity, but their sensitivity and specificity were better balanced. CONCLUSIONS: Although the test performance of subjective assessment by an expert remains superior, the ADNEX model can help in the differentiation between benign and malignant ovarian tumors. The advantage of the ADNEX model as a polytomous model remains to be shown. (c) 2016 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. PMID- 27514487 TI - Protective Effect of Curcumin Against Acute Ultraviolet B Irradiation-induced Photo-damage. AB - Ultraviolet B (UVB) irradiation is one of the most dangerous insults for skin and causes sunburn, erythema, photoaging and photocarcinogenesis. Curcumin (diferuloylmethane), a yellow spice derived from dried rhizomes of Curcuma longa, has been shown to possess significant anti-inflammatory, antioxidant, anticarcinogenic, antimutagenic, anticoagulant and anti-infective effects. However, the protective effects of curcumin against acute photo-damage are poorly understood. In this study, we investigated the photoprotective effects of curcumin against UVB-induced acute photo-damage in hairless mice and immortalized human keratinocytes (HaCaT). Topical application of curcumin significantly inhibited acute UVB (540 mJ cm-2 , for 3 successive days)-induced inflammatory cells, collagen accrementition derangement and lipid peroxidation, and effectively induced NF-E2-related factor 2 (Nrf2) nuclear accumulation in uncovered (Uncv) hairless mice skin. Treatment of HaCaT cells with curcumin significantly attenuated acute UVB (300 mJ cm-2 )-induced lactate dehydrogenase release, intracellular reactive oxygen species production and DNA damage, activated the expression of the phase II detoxifying enzymes and promoted DNA repair activity. The photoprotective effect provided by curcumin was potential associated with modulation of Nrf2-dependent antioxidant response. Our study suggested that curcumin is a potential agent for preventing and/or treating UV radiation-induced acute inflammation and photoaging. PMID- 27514488 TI - Classic Spotlight: Hfq, from a Specific Host Factor for Phage Replication to a Global Player in Riboregulation. PMID- 27514489 TI - Classic Spotlight: Look, Max-No Math Required! PMID- 27514492 TI - Abeta Induces Excitotoxicity Mediated by APC/C-Cdh1 Depletion That Can Be Prevented by Glutaminase Inhibition Promoting Neuronal Survival. AB - The E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) is activated by the fizzy-related protein homolog/CDC20-like protein 1 (cdh1) in post-mitotic neurons. Growing evidence suggests that dysregulation of APC/C-Cdh1 is involved in neurodegenerative diseases. Here we show in neurons that oligomers of amyloid beta (Abeta), a peptide related to Alzheimer's disease, cause proteasome dependent degradation of cdh1. This leads to a subsequent increase in glutaminase (a degradation target of APC/C-Cdh1), which causes an elevation of glutamate levels and further intraneuronal Ca(2+) dysregulation, resulting in neuronal apoptosis. Glutaminase inhibition prevents glutamate excitotoxicity and apoptosis in Abeta treated neurons. Furthermore, glutamate also decreases cdh1 and leads to accumulation of glutaminase, suggesting that there may be a positive feedback loop of cdh1 inactivation. We confirmed the main findings in vivo using microinjection of either Abeta or glutamate in the CA1 region of the rat hippocampus. We show here for the first time in vivo that both Abeta and glutamate cause nuclear exclusion of cdh1 and an increase in glutaminase. These results show that maintaining normal APC/C-Cdh1 activity may be a useful target in Alzheimer's disease treatment. PMID- 27514493 TI - Biosorption of Pb (II) from aqueous solution by extracellular polymeric substances extracted from Klebsiella sp. J1: Adsorption behavior and mechanism assessment. AB - The adsorption performance and mechanism of extracellular polymeric substances (EPS) extracted from Klebsiella sp. J1 for soluble Pb (II) were investigated. The maximum biosorption capacity of EPS for Pb (II) was found to be 99.5 mg g(-1) at pH 6.0 and EPS concentration of 0.2 g/L. The data for adsorption process satisfactorily fitted to both Langmuir isotherm and pseudo-second order kinetic model. The mean free energy E and activation energy Ea were determined at 8.22- 8.98 kJ mol(-1) and 42.46 kJ mol(-1), respectively. The liquid-film diffusion step might be the rate-limiting step. The thermodynamic parameters (DeltaG(o), DeltaH(o) and DeltaS(o)) revealed that the adsorption process was spontaneous and exothermic under natural conditions. The interactions between EPS system and Pb (II) ions were investigated by qualitative analysis methods (i.e Zeta potential, FT-IR and EDAX). Based on the strong experimental evidence from the mass balance of the related elements participating in the sorption process, an ion exchange process was identified quantitatively as the major mechanism responsible for Pb (II) adsorption by EPS. Molar equivalents of both K(+) and Mg(2+) could be exchanged with Pb(2+) molar equivalents in the process and the contribution rate of ion exchange to adsorption accounted for 85.72% (Deltamequiv = -0.000541). PMID- 27514494 TI - Enhanced proliferation and differentiation effects of a CGRP- and Sr-enriched calcium phosphate cement on bone mesenchymal stem cells. AB - INTRODUCTION: Because of its good osteoconductivity, strontium (Sr) ranelate has been extensively used as a bone substitute for the treatment of bone disorders. To facilitate treatment, Sr is also incorporated into calcium phosphate cement (Sr-CPC); however, the Sr from Sr-CPC is not sufficient to induce a significant increase of bone mass in an ovariectomized rat model. To improve the efficiency of Sr-CPC, we developed a calcitonin gene-related peptide (CGRP)- and Sr-enriched CPC (CGRP-Sr-CPC). METHODS: We used X-ray diffraction and Fourier transform infrared spectroscopy to measure properties of CGRP-Sr-CPC. We also employed a cell proliferation assay, alkaline phosphatase (ALP) assay and real-time PCR to assess the effects of CPC implants on proliferation and differentiation of bone mesenchymal stem cells (BMSCs) from an ovariectomized rat model. RESULTS: CGRP did not change the composition, pore sizes and compressive strength of the cement body as compared with Sr-CPC. Meanwhile, CGRP-Sr-CPC did not show cell cytotoxicity to BMSCs. Further, CGRP and Sr released from CGRP-Sr-CPC significantly enhanced the cell proliferation of BMSCs and increased the activity of ALP during differentiation of BMSCs, compared with CGRP- or Sr-CPC. Moreover, CGRP-Sr-CPC significantly up-regulated the expression levels of osteogenic differentiation-related genes including Alp, Bmp2, Osteonectin and Runx2 during differentiation. CONCLUSIONS: These findings demonstrate the optimized effects of CGRP- and Sr-enriched CPC in promoting proliferation and osteogenic differentiation of BMSCs, suggesting the potential ability of this novel cement to assist the formation of new bone during osteoporosis-induced bone disorders. PMID- 27514496 TI - Elucidating the anti-Staphylococcus aureus antibody response by immunoproteomics. AB - Staphylococcus aureus is a notorious pathogen both in- and outside hospitals as well as a frequent colonizer in healthy individuals. Immunoproteomics techniques have been employed to shed light on the human adaptive immune response to S. aureus in health and disease. Since priming of immune memory, a key property of the adaptive immune system, is the basis of successful vaccination, immunoproteomics holds promise for paving the way to an effective S. aureus vaccine. PMID- 27514495 TI - Use of autologous epithelium transplantation on various scaffolds to cover tissue loss in oral cavity: long-term observation. AB - BACKGROUND: The aim of this study was to investigate the application of mucous membrane keratinocyte cultures on amniotic membrane and on poly(L-lactic acid) (PLLA) Purasorb PL38 to cover tissue loss in the oral cavity. Developments in molecular biology techniques and tissue engineering allow the culturing and identification of cells that can be anchored in the wound to achieve integrity of the tissue. Transplantation of tissues obtained from the patient's own cells is superior to allogenous transplantation where there is a possibility of transfection, rejection and the need for long-term immunosuppression. METHODS: In 9 patients (15 procedures) keratinocytes cultured on amniotic membrane and PLLA were transplanted to cover antro-oral fistulas and bone loss after osteoradionecrosis. RESULTS: In all 6 patients with outlasting antro-oral fistulas, the defects were healed. In 3 patients with 5 cases of tissue loss after osteoradionecrosis, we obtained healing of the wound in only 1 case. Histological examination of the cultures indicated that cultured cells formed well-differentiated layers, very similar to the keratinocytes of mucous membranes, although those seeded on amniotic membrane formed a single layer of cells, while those seeded on the PLLA scaffold were arranged on 2 or more layers: these differences were shown to be statistically significant with a morphometric analysis. CONCLUSIONS: Autologous transplants of epithelium cultured on amniotic membrane and PLLA constitute a new and effective way of covering nonhealing tissue loss in the oral cavity in chosen cases, using modern methods of tissue engineering. PMID- 27514497 TI - An integrated approach to infer dynamic protein-gene interactions - A case study of the human P53 protein. AB - Investigating the dynamics of genetic regulatory networks through high throughput experimental data, such as microarray gene expression profiles, is a very important but challenging task. One of the major hindrances in building detailed mathematical models for genetic regulation is the large number of unknown model parameters. To tackle this challenge, a new integrated method is proposed by combining a top-down approach and a bottom-up approach. First, the top-down approach uses probabilistic graphical models to predict the network structure of DNA repair pathway that is regulated by the p53 protein. Two networks are predicted, namely a network of eight genes with eight inferred interactions and an extended network of 21 genes with 17 interactions. Then, the bottom-up approach using differential equation models is developed to study the detailed genetic regulations based on either a fully connected regulatory network or a gene network obtained by the top-down approach. Model simulation error, parameter identifiability and robustness property are used as criteria to select the optimal network. Simulation results together with permutation tests of input gene network structures indicate that the prediction accuracy and robustness property of the two predicted networks using the top-down approach are better than those of the corresponding fully connected networks. In particular, the proposed approach reduces computational cost significantly for inferring model parameters. Overall, the new integrated method is a promising approach for investigating the dynamics of genetic regulation. PMID- 27514498 TI - Steroids can reduce warm ischemic reperfusion injury in a porcine donation after circulatory death model with ex vivo lung perfusion evaluation. AB - Donation after circulatory death (DCD) is being used to increase the number of transplantable organs. The role and timing of steroids in DCD donation and ex vivo lung perfusion (EVLP) has not been thoroughly investigated. In this study, we investigated the effect of steroids on warm ischemic injury in a porcine model (n = 6/group). Following cardiac arrest, grafts were left untouched in the donor (90-min warm ischemia). Graft function was assessed after 6 h of EVLP. In the MP group, 500 mg methylprednisolone was given prior to cardiac arrest and during EVLP. In the CONTR group, no steroids were added. Median lung compliance (13 ml/cmH2 0) was significantly better preserved in the CONTR group than in the MP group (30.5 ml/cmH2 0). Also, median wet-to-dry weight (6.11 vs. 6.94) and CT density (182.5 vs. 352.9 g/l) were significantly better in the MP group than in the CONTR group, respectively. There was no difference in oxygenation and pulmonary vascular resistance. Perfusate cytokine analysis showed a significant reduction in IL-1beta, IL-8, IFN-alpha, IL-10, TNF-alpha, and IFN-gamma in MP. Cytokines in bronchoalveolar lavage were not decreased except for IFN-gamma. We demonstrated that warm ischemic injury in DCD donation can be attenuated by steroids when given prior to warm ischemia and during EVLP. Ethical context of donor preconditioning should be discussed further. PMID- 27514500 TI - Desymmetrizing Electron-Deficient Diboranes(4): Diverse Products and Their Reactivity. AB - A comprehensive study of the reactivity of Lewis bases with dihalodiboranes(4) is presented. Diaryldihalodiboranes provide rearranged monoadducts when treated with cyclic (alkyl)(amino)carbenes, but halide-bridged adducts when treated with a range of pyridyl bases. Alternatively, the combination of diaminodihalodiboranes with strong carbene donors leads to boraborenium salts. The reduction and halide abstraction reactivity of these adducts was also explored, leading to intramolecular C-H activation and the first 1,2-bis(borenium) dication. PMID- 27514499 TI - Prognostic value of renal function in patients with aortic stenosis treated with transcatheter aortic valve replacement. AB - OBJECTIVES: The objectives of the present study were to analyze the variation of renal function after transcatheter aortic valve replacement (TAVR) focused on acute kidney injury (AKI) and its impact on short- and mid-term mortality. BACKGROUND: Changes on renal function after TAVR and their impact on clinical outcomes are incompletely understood until now. METHODS: At two tertiary centers 221 consecutive patients were submitted to TAVR. Kidney injury was defined according to VARC-2 criteria. Patients were classified according to the presence (group 1) or absence (group 2) of AKI. Creatinine values were collected daily until seventh day after procedure, 1 month, 6 months, and then 1 year after TAVR. RESULTS: At baseline, groups were similar, except for EuroSCORE II (8.66% vs. 7.34%, P = 0.02) and glomerular filtration rate (GFR) (39.59 vs. 48.49 mL/min.1.73 m2 , P = 0.002). Overall 30 day-mortality and 1-year mortality were 6.3% and 14.0%, respectively. Both 30-day mortality (23.1% vs. 1.2%, P < 0.001) and 1-year mortality (44.2% vs. 4.7%, P < 0.001) were higher in group 1. After multivariable-adjusted models, the only independent predictor for AKI after TAVR was baseline GFR (HR: 1.37, 95% CI: 1.08-1.77, P = 0.01). The independent risk factors for 1-year mortality were AKI (HR: 15.66, 95% CI: 6.07-44.63, P < 0.001), COPD (HR: 3.14, 95% CI: 1.05-9.40, P = 0.04) and aortic regurgitation grade postprocedure >= 2 (P = 0.05) also after multivariate analysis. CONCLUSIONS: In this TAVR cohort, baseline GFR was the only independent predictor of AKI, which negatively impacted on 30-day and 1-year mortality. (c) 2016 Wiley Periodicals, Inc. PMID- 27514501 TI - Ion-Pair Complexation with Dibenzo[21]Crown-7 and Dibenzo[24]Crown-8 bis-Urea Receptors. AB - Synthesis and ion-pair complexation properties of novel ditopic bis-urea receptors based on dibenzo[21]crown-7 (R(1) ) and dibenzo[24]crown-8 (R(2) ) scaffolds have been studied in the solid state, solution, and gas phase. In a 4:1 CDCl3 /[D6 ]DMSO solution, both receptors clearly show positive heterotropic cooperativity toward halide anions when complexed with Rb(+) or Cs(+) , with the halide affinity increasing in order I(-) = 3 months was 19.6 % (95 % CI 14.6 % to 24.6 %) with a mean +/- SD duration of pain of 6 . 5 +/- 5 . 7 years and a higher prevalence for women. The prevalence of neuropathic pain in the respondents reporting chronic pain was 19 . 7 % (95 % CI 14 . 6-24 . 7), equivalent to 3 . 9 % (95 % CI 2 . 8 to 5 . 0 %) of the general adult population. Only, 71 (29 . 8 %) of respondents reported that their pain was being adequately controlled. CONCLUSIONS: The prevalence of chronic pain in the general adult population of Libya was approximately 20 % and comparable with Europe and North America. This suggests that chronic pain is a public health problem in Libya. Risk factors are being a woman, advanced age and unemployment. There is a need for improved health policies in Libya to ensure that patients with chronic pain receive effective management. PMID- 27514514 TI - Continued efforts to translate diabetes cardiovascular outcome trials into clinical practice. AB - Diabetic patients suffer from a high rate of cardiovascular events and such risk increases with HbA1c. However, lowering HbA1c does not appear to yield the same benefit on macrovascular endpoints, as observed for microvascular endpoints. As the number of glucose-lowering medications increases, clinicians have to consider several open questions in the management of type 2 diabetes, one of which is the cardiovascular risk profile of each regimen. Recent placebo-controlled cardiovascular outcome trials (CVOTs) have responded to some of these questions, but careful interpretation is needed. After general disappointment around CVOTs assessing safety of DPP-4 inhibitors (SAVOR, TECOS, EXAMINE) and the GLP-1 receptor agonist lixisenatide (ELIXA), the EMPA-REG Outcome trial and the LEADER trial have shown superiority of the SGLT2-I empagliflozin and the GLP-1RA liraglutide, respectively, on the 3-point MACE outcome (cardiovascular death, non fatal myocardial infarction or stroke) and cardiovascular, as well as all-cause mortality. While available mechanistic studies largely support a cardioprotective effect of GLP-1, the ability of SGLT2 inhibitor(s) to prevent cardiovascular death was unexpected and deserves future investigation. We herein review the results of completed CVOTs of glucose-lowering medications and suggest a possible treatment algorithm based on cardiac and renal co-morbidities to translate CVOT findings into clinical practice. PMID- 27514515 TI - Chronic viral hepatitis: policy, regulation, and strategies for its control and elimination in Ethiopia. AB - BACKGROUND: Hepatitis B and C are silent killers not yet recognized as major public health challenges in many developing countries with huge disease burden. In Ethiopia, Hepatitis B is endemic with an average prevalence of 10.8 %, and the prevalence of Hepatitis C is 2 %. The prevalence of both infections, however, is likely to be underreported due to the lack of diagnostic facilities and appropriate surveillance systems. Ethiopia is also among the many Sub-Sahara African countries lacking a coordinated and systematic national response to chronic viral hepatitis. The objective of this study is to examine the current level of response to viral Hepatitis B & C in Ethiopia with the aim to bring identified gaps to the attention of relevant stakeholders and policy makers. METHODS: This cross-sectional qualitative study was based on semi-structured in depth interviews with 21 key informants from health facilities, health offices, pharmaceutical companies, regulatory bodies, professional association and blood bank units. Participants were selected purposively based on their role in the national hepatitis response. The investigators also reviewed available policy and strategy documents, standards of practice and surveys, and paid visits to pharmaceutical premises to check the availability of antiviral drugs. Thematic analysis was employed to make sense of the data. During the data analysis process, all the authors critically read the materials, and data was triangulated by source, interpreter view and thematic perspective to ensure accurate representation and comprehensiveness, and validation of the interviewees' responses. Once each investigator reviewed the data independently, the team reached a common understanding of the scope and contexts of the information attained. Data were subsequently reduced to key concepts, and case stories were taken with successive revisions. The key concepts were later coded into most basic meaningful categories. The World Health Organization (WHO) global hepatitis response framework was used to organize the analysis. RESULTS: Ethiopia is in the process of preparing strategic plan and guidelines for viral hepatitis. However, the country still lacks the required partnerships, and resource mobilization as a national health response is limited. Community awareness on the disease transmission and its sequel is poor. Viral hepatitis screening services are not widely available except for the occasional mandatory medical checkups for work or travel purposes. Healthcare providers often take no further action after diagnosing patients with viral hepatitis due to lack of treatment guidelines and strategic frameworks for screening, diagnosis, and treatment. Besides, drugs that are effective in the treatment of viral hepatitis are not available, mainly due to regulatory challenges. CONCLUSIONS: Viral hepatitis and its disease burden are getting little attention in Ethiopia and many low-income countries. The levels of technical guidance and financial support from the international community are low. To date, the response to the infections in Ethiopia is patchy. Thus, the country needs to formulate policy and strategies in the areas of disease surveillance, risk group identification and screening, use of the birth dose of hepatitis B vaccine, and care and treatment. Improving availability of data on viral hepatitis, access to low-cost generic drugs and developing and dissemination of treatment guidelines are also critical. Leveraging the successful Health Extension Program for a hepatitis response, and exploring ways to learn from and integrate into the HIV/AIDS program should also be considered. PMID- 27514516 TI - Transcriptional profiling analysis of Penicillium digitatum, the causal agent of citrus green mold, unravels an inhibited ergosterol biosynthesis pathway in response to citral. AB - BACKGROUND: Green mold caused by Penicillium digitatum is the most damaging postharvest diseases of citrus fruit. Previously, we have observed that citral dose-dependently inhibited the mycelial growth of P. digitatum, with the minimum inhibitory concentration (MIC) of 1.78 mg/mL, but the underlying molecular mechanism is barely understood. RESULTS: In this study, the transcriptional profiling of the control and 1/2MIC-citral treated P. digitatum mycelia after 30 min of exposure were analyzed by RNA-Seq. A total of 6355 genes, including 2322 up-regulated and 4033 down-regulated genes, were found to be responsive to citral. These genes were mapped to 155 KEGG pathways, mainly concerning mRNA surveillance, RNA polymerase, RNA transport, aminoacyl-tRNA biosynthesis, ABC transporter, glycolysis/gluconeogenesis, citrate cycle, oxidative phosphorylation, sulfur metabolism, nitrogen metabolism, inositol phosphate metabolism, fatty acid biosynthesis, unsaturated fatty acids biosynthesis, fatty acid metabolism, and steroid biosynthesis. Particularly, citral exposure affected the expression levels of five ergosterol biosynthetic genes (e.g. ERG7, ERG11, ERG6, ERG3 and ERG5), which corresponds well with the GC-MS results, the reduction in ergosterol content, and accumulation of massive lanosterol. In addition, ERG11, the gene responsible for lanosterol 14alpha-demethylase, was observed to be the key down-regulated gene in response to citral. CONCLUSION: Our present finding suggests that citral could exhibit its antifungal activity against P. digitatum by the down-regulation of ergosterol biosynthesis. PMID- 27514517 TI - Evolution of the locomotory system in eels (Teleostei: Elopomorpha). AB - BACKGROUND: Living anguilliform eels represent a distinct clade of elongated teleostean fishes inhabiting a wide range of habitats. Locomotion of these fishes is highly influenced by the elongated body shape, the anatomy of the vertebral column, and the corresponding soft tissues represented by the musculotendinous system. Up to now, the evolution of axial elongation in eels has been inferred from living taxa only, whereas the reconstruction of evolutionary patterns and functional ecology in extinct eels still is scarce. Rare but excellently preserved fossil eels from the Late Cretaceous and Cenozoic were investigated here to gain a better understanding of locomotory system evolution in anguilliforms and, consequently, their habitat occupations in deep time. RESULTS: The number of vertebrae in correlation with the body length separates extinct and extant anguilliforms. Even if the phylogenetic signal cannot entirely be excluded, the analyses performed here reveal a continuous shortening of the vertebral column with a simultaneous increase in vertebral numbers in conjunction with short lateral tendons throughout the order. These anatomical changes contradict previous hypotheses based on extant eels solely. CONCLUSIONS: The body curvatures of extant anguilliforms are highly flexible and can be clearly distinguished from extinct species. Anatomical changes of the vertebral column and musculotendinous system through time and between extinct and extant anguilliforms correlate with changes of the body plan and swimming performance and reveal significant shifts in habitat adaptation and thus behaviour. Evolutionary changes in the skeletal system of eels established here also imply that environmental shifts were triggered by abiotic rather than biotic factors (e.g., K/P boundary mass extinction event). PMID- 27514519 TI - [Epidemiology of common diseases in ophthalmology]. PMID- 27514518 TI - Minimally invasive surgery using intraoperative electron-beam radiotherapy for the treatment of soft tissue sarcoma of the extremities with tendon involvement. AB - BACKGROUND: When a soft tissue sarcoma (STS) is located at the distal part of an extremity and involves the tendon, a wide excision usually causes severe functional disability. We therefore developed a minimally invasive surgical technique using intraoperative electron-beam radiotherapy (IOERT) to reduce the incidence of post-operative functional disability in patients with peri-/intra tendinous STS. We assessed the clinical outcomes of the novel minimally invasive surgery. METHODS: The study population included five patients who received treatment for distal extremity STSs. After elevating the tumor mass, including the tendon and nerve from the tumor bed with a wide margin, a lead board was inserted beneath the tumor mass to shield the normal tissue. IOERT (25-50 Gy) was then applied, and the tumor excised with care taken to maintain the continuity of the tendon. RESULTS: In a desmoid patient, local recurrence was observed outside the irradiated field. No cases of neuropathy or bone necrosis were observed. The mean limb function score was excellent in all patients. None of the high-grade sarcoma patients had local recurrence or distant metastasis. CONCLUSIONS: Although the current study is only a pilot study with a small number of patients, it shows that this minimally invasive procedure has the potential to become a standard treatment option for selected patients. TRIAL REGISTRATION: H17-250 (registered 2 November 2005) and H25-250 (modified from H17-250, registered 5 December 2013). PMID- 27514520 TI - [Cherry-red spot in a 13-month-old child]. PMID- 27514521 TI - [Atypical wet AMD]. PMID- 27514522 TI - [Optic disc pit-associated maculopathy and iris-retinochoroidal-coloboma - a rare combination]. AB - Kranenburg's syndrome is defined as central serous detachment associated with an optic disc pit. We report the interesting and very seldom combination of Kranenburg's syndrome and iris-retinochoroidal-coloboma. Reattachment was achieved after vitrectomy, peeling of epiretinal membranes, laser coagulation adjacent and temporal to the optic disc and gas endotamponade. Coincidence of this syndrome with an iris-retinochoroidal-coloboma is extremely rare. Both coloboma and optic disc pit are based on closure defects during week 6 of embryogenesis. PMID- 27514523 TI - Kikiskawawasow - prenatal healthcare provider perceptions of effective care for First Nations women: an ethnographic community-based participatory research study. AB - BACKGROUND: Pregnant Indigenous women suffer a disproportionate burden of risk and adverse outcomes relative to non-Indigenous women. Although there has been a call for improved prenatal care, examples are scarce. Therefore, we explored the characteristics of effective care with First Nations women from the perspective of prenatal healthcare providers (HCPs). METHODS: We conducted an ethnographic community-based participatory research study in collaboration with a large Cree First Nations community in Alberta, Canada. We carried out semi-structured interviews with 12 prenatal healthcare providers (HCPs) that were recorded, transcribed, and subjected to qualitative content analysis. RESULTS: According to the participants, relationships and trust, cultural understanding, and context specific care were key features of effective prenatal care and challenge the typical healthcare model. HCPs that are able to foster sincere, non-judgmental, and enjoyable interactions with patients may be more effective in treating pregnant First Nations women, and better able to express empathy and understanding. Ongoing HCP cultural understanding specific to the community served is crucial to trusting relationships, and arises from real experiences and learning from patients over and above relying only on formal cultural sensitivity training. Consequently, HCPs report being better able to adapt a more flexible, all-inclusive, and accessible approach that meets specific needs of patients. CONCLUSIONS: Aligned with the recommendations of the Truth and Reconciliation Commission of Canada, improving prenatal care for First Nations women needs to allow for genuine relationship building with patients, with enhanced and authentic cultural understanding by HCPs, and care approaches tailored to women's needs, culture, and context. PMID- 27514524 TI - Quercetin and Cisplatin combined treatment altered cell cycle and mitogen activated protein kinase expressions in malignant mesotelioma cells. AB - BACKGROUND: Malignant mesothelioma is a locally aggressive and highly lethal neoplasm of pleural, peritoneal and pericardial mesothelial cells without successful therapy. Previously, we reported that Quercetin in combination with Cisplatin inhibits cell proliferation and activates caspase-9 and -3 enzymes in different malignant mesothelioma cell lines. Moreover, Quercetin + Cisplatin lead to accumulation of both SPC111 and SPC212 cell lines in S phase. METHODS: In present work, 84 genes involved in cell growth and proliferation have analysed by using RT(2)-PCR array system and protein profile of mitogen activated protein kinase (MAPK) family proteins investigated by western blots. RESULTS: Our results showed that Quercetin and Quercetin + Cisplatin modulated gene expression of cyclins, cyclin dependent kinases and cyclin dependent kinases inhibitors. In addition genes involved in JNK, p38 and MAPK/ERK pathways were up regulated. Moreover, while p38 and JNK phosphorylations were increased, ERK phosphorylations were decreased after using Quercetin + Cisplatin. CONCLUSION: This research has clarified our previous results and detailed mechanism of anti-carcinogenic potential of Quercetin alone and incombination with Cisplatin on malignant mesothelioma cells. PMID- 27514525 TI - Downregulation of KDM4A Suppresses the Survival of Glioma Cells by Promoting Autophagy. AB - Glioma is the most common type of primary intracranial tumor and has a poor prognosis. It has been reported that lysine-specific demethylase 4A (KDM4A) can promote tumor progression; however, its role in human glioma remains unclear. Western blot and qRT-PCR analyses showed that KDM4A was highly expressed in U87MG and T98G cells. 48 h after transfection with siKDM4A, the protein level of KDM4A was significantly downregulated. The silenced expression of KDM4A in T98G or U87MG cells inhibited cell viability and invasion, and aggravated cell apoptosis. We found that the siKDM4A led to a significant increase in acidic vesicular organelles (AVOs) and upregulated the expression of autophagy-related proteins, including LC3B-phosphatidylethanolamine conjugate, a cytosolic form of LC3B (LC3B II/LC3B-I) and Beclin 1 in T98G and U87MG cells. Further studies demonstrated that after pretreatment with 3-MA (3 mmol/L) for 48 h, siKDM4A-transfected cells showed a prominent decrease in LC3B-II/LC3B-I and Beclin 1, accompanied by increased viability and invasion and decreased apoptosis. Our results suggest that the inhibition of KDM4A expression might efficiently suppress glioma cell survival by promoting autophagy, providing a promising agent for treating malignant gliomas. PMID- 27514527 TI - Strategy based on kinetics of O-(2-[18F] fluoroethyl)-L-tyrosine ([18F] FET). PMID- 27514526 TI - A Conceptualization of the Utility of Subjective Cognitive Decline in Clinical Trials of Preclinical Alzheimer's Disease. AB - This commentary outlines a conceptual model for subjective cognitive decline (SCD) in relation to Alzheimer's disease (AD) biomarkers in the preclinical stages of disease and a framework for effectively utilizing SCD in secondary prevention clinical trials. Mounting evidence supports the notion that SCD is sensitive to encroaching Abeta-amyloid and neurodegeneration. SCD has also been shown to provide additive information of AD-dementia risk beyond what is known about the biomarker status of the individual. Thus, we provide recommendations for the implementing SCD measurement in clinical trials. We argue that SCD can be measured at three catch points within the course of the clinical trial: firstly, at the initial recruitment and screening phase; secondly, to create more robust estimates of rates of AD-dementia progression; and finally, to measure subjective experiences of cognitive change and quality of life over the course of the trial as a proxy of clinically meaningful functional improvement. We provide recommendations of how SCD can be approached at each of these points. SCD is an important component of the preclinical AD-dementia trajectory. Future studies need to elucidate the interactive influence of Abeta-amyloid and tau on SCD from a spatiotemporal perspective. Even as this evidence accrues, it is clear that SCD can provide unique and additive information about rates of progression and subjectively experienced cognitive change within clinical trials. PMID- 27514529 TI - Saccharibacillus qingshengii sp. nov., isolated from a lead-cadmium tailing. AB - A Gram-stain-positive, strictly aerobic strain, H6T, was isolated from a soil sample of lead-cadmium tailing in Qixia district, Nanjing (China). Cells of the strain are rod-shaped and colonies on LB agar are red. Strain H6T has subpolar and polar flagella and the optimal condition for growth is 30 degrees C, with 1 % (w/v) NaCl and at pH 7.0. Based on the 16S rRNA gene sequences, phylogenetic analysis showed that strain H6T was closely related to the genus Saccharibacillus, and the closest relatives were Saccharibacillus deserti WLJ055T (99.0 % 16S rRNA gene sequence similarity), Saccharibacillus kuerlensis HR1T (97.0 %) and Saccharibacillus sacchari GR21T (96.4 %). The DNA-DNA relatedness value between strain H6T and S. deserti WLJ055T was 55.0 %. The major polar lipids of strain H6T were diphosphatidylglycerol, phosphatidylglycerol, phosphoglycolipid and three unknown glycolipids. The DNA G+C content was 58.4 mol% and MK-7 was the major isoprenoid quinone. The major fatty acids were anteiso-C15 : 0 and C16 : 0. meso-Diaminopimelic acid was detected in the peptidoglycan. Based on the phylogenetic, biochemical and chemotaxonomic data, strain H6T represents a novel species of the genus Saccharibacillus, for which the name Saccharibacillus qingshengii sp. nov., is proposed. The type strain is H6T (=CCTCC AB 2016001T=JCM 31172T). PMID- 27514528 TI - Guidelines to PET measurements of the target occupancy in the brain for drug development. AB - This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations. PMID- 27514530 TI - Over-expression of long noncoding RNA BANCR inhibits malignant phenotypes of human bladder cancer. AB - BACKGROUND: Accumulating evidences indicated that lncRNAs play crucial regulatory roles in oncogenesis and progression of cancers. BRAF activated non-coding RNA (BANCR) has been identified to contribute to the progression of some human cancers. However, the relationship between BANCR and bladder cancer (BC) is largely unclear. METHODS: BANCR expression levels in BC, paired non-cancer tissues and BC cell lines were detected by real-time quantitative RT-PCR (qRT PCR). The relationships between BANCR expression levels and the clinical characteristics were evaluated. BANCR expression was enhanced by transfecting a pcDNA-BANCR vector. We used both CCK-8 assay and Edu assay to detect cell proliferation. We also detect cell apoptosis and migration by using ELISA assay, Flow cytometry and transwell assay, respectively. All statistical analyses were executed by using the SPSS 20.0 software. RESULTS: BANCR expression levels were remarkably decreased in BC tissues compared with adjacent noncancerous tissues. BANCR expression levels in two BC cell lines were also significantly down regulated. Clinicopathologic analysis revealed that low BANCR expression was positively correlated with TNM stage, but not associated with other clinicopathological characteristics. BANCR has been successfully overexpressed in BC cell lines (T24 and SW780) by transfecting a pcDNA-BANCR vector. Cell proliferation inhibition, apoptosis induction and migration suppression were also observed in pCDNA-BANCR-transfected T24 and SW780 cells. CONCLUSIONS: These data suggested that BANCR represents a tumor suppressor player in bladder cancer, contributes to tumor proliferation, apoptosis and migration, and may serve as a new candidate biomarker and a potential therapeutic target for patients with BC. PMID- 27514531 TI - Metabolic signatures and risk of type 2 diabetes in a Chinese population: an untargeted metabolomics study using both LC-MS and GC-MS. AB - AIMS/HYPOTHESIS: Metabolomics has provided new insight into diabetes risk assessment. In this study we characterised the human serum metabolic profiles of participants in the Singapore Chinese Health Study cohort to identify metabolic signatures associated with an increased risk of type 2 diabetes. METHODS: In this nested case-control study, baseline serum metabolite profiles were measured using LC-MS and GC-MS during a 6-year follow-up of 197 individuals with type 2 diabetes but without a history of cardiovascular disease or cancer before diabetes diagnosis, and 197 healthy controls matched by age, sex and date of blood collection. RESULTS: A total of 51 differential metabolites were identified between cases and controls. Of these, 35 were significantly associated with diabetes risk in the multivariate analysis after false discovery rate adjustment, such as increased branched-chain amino acids (leucine, isoleucine and valine), non-esterified fatty acids (palmitic acid, stearic acid, oleic acid and linoleic acid) and lysophosphatidylinositol (LPI) species (16:1, 18:1, 18:2, 20:3, 20:4 and 22:6). A combination of six metabolites including proline, glycerol, aminomalonic acid, LPI (16:1), 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid and urea showed the potential to predict type 2 diabetes in at-risk individuals with high baseline HbA1c levels (>=6.5% [47.5 mmol/mol]) with an AUC of 0.935. Combined lysophosphatidylglycerol (LPG) (12:0) and LPI (16:1) also showed the potential to predict type 2 diabetes in individuals with normal baseline HbA1c levels (<6.5% [47.5 mmol/mol]; AUC = 0.781). CONCLUSIONS/INTERPRETATION: Our findings show that branched-chain amino acids and NEFA are potent predictors of diabetes development in Chinese adults. Our results also indicate the potential of lysophospholipids for predicting diabetes. PMID- 27514533 TI - Src is required for migration, phagocytosis, and interferon beta production in Toll-like receptor-engaged macrophages. AB - As an evolutionarily conserved mechanism, innate immunity controls self-nonself discrimination to protect a host from invasive pathogens. Macrophages are major participants of the innate immune system. Through the activation of diverse Toll like receptors (TLRs), macrophages are triggered to initiate a variety of functions including locomotion, phagocytosis, and secretion of cytokines that requires the participation of tyrosine kinases. Fgr, Hck, and Lyn are myeloid specific Src family kinases. Despite their constitutively high expression in macrophages, their absence does not impair LPS responsiveness. In contrast, Src, a barely detectable tyrosine kinase in resting macrophages, becomes greatly inducible in response to TLR engagement, implicating its role in macrophage activation. Indeed, silencing Src suppresses the activated TLR-mediated migration, phagocytosis, and interferon-beta (IFN-beta) secretion in macrophages. And these physiological defects can be restored by the introduction of siRNA resistant Src. Notably, the elevated expression and activity of Src is inducible nitric oxide synthase (iNOS)-dependent. Due to (1) iNOS being a NF-kappaB target, which can be induced by various TLR ligands, (2) Src can mediate NF-kappaB activation, therefore, there ought to exist a loop of signal amplification that regulates macrophage physiology in response to the engagement of TLRs. PMID- 27514532 TI - IRS proteins and diabetic complications. AB - IRS proteins are cellular adaptor molecules that mediate many of the key metabolic actions of insulin. When tyrosine is phosphorylated by the activated insulin receptor, IRS proteins recruit downstream effectors, such as phosphoinositide 3-kinase and mitogen-activated protein kinase, in order to elicit cellular responses such as glucose uptake, lipid metabolism and cell proliferation. There are two main IRS proteins in humans (IRS1 and IRS2), both of which are widely expressed. Given their central role in the insulin signalling pathway, it is not surprising that male mice lacking Irs1 or Irs2 present with elevated blood glucose or type 2 diabetes, respectively. For reasons yet to be identified, female Irs2 (-/-) mice do not develop type 2 diabetes. A number of organs are affected by complications of diabetes; macrovascular complications include stroke and coronary artery disease, while nephropathy, neuropathy and retinopathy fall into the category of microvascular complications. Given the serious consequences of these complications on patient morbidity and mortality, it is essential to identify the molecular pathogenesis underlying diabetic complications, with a view to improving therapeutic intervention and patient outcomes. A number of recently published papers have converged on the hypothesis that the loss of insulin signalling and IRS proteins is instrumental to the development and/or progression of diabetic complications. This review will summarise some highlights from the published work in which this hypothesis is discussed. PMID- 27514534 TI - EPA or DHA enhanced oxidative stress and aging protein expression in brain of d galactose treated mice. AB - BACKGROUND: Effects of eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, 22:6) upon fatty acid composition, oxidative and inflammatory factors and aging proteins in brain of d-galactose (DG) treated aging mice were examined. METHODS: Each fatty acid at 7 mg/kg BW/week was supplied for 8 weeks. Brain aging was induced by DG treatment (100 mg/kg body weight) via daily subcutaneous injection for 8 weeks. RESULTS: DG, EPA and DHA treatments changed brain fatty acid composition. DG down-regulated brain Bcl-2 expression and up-regulated Bax expression. Compared with DG groups, EPA and DHA further enhanced Bax expression. DG decreased glutathione content, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production, the intake of EPA or DHA caused greater ROS and GSSG formation. DG treatments up-regulated the protein expression of p47(phox) and gp91(phox), and the intake of EPA or DHA led to greater p47(phox) and gp91(phox) expression. DG increased brain prostaglandin E2 (PGE2) levels, and cyclooxygenase (COX)-2 expression and activity, the intake of EPA or DHA reduced brain COX-2 activity and PGE2 formation. DG enhanced brain p53, p16 and p21 expression. EPA and DHA intake led to greater p21 expression, and EPA only caused greater p53 and p16 expression. CONCLUSION: These findings suggest that these two PUFAs have toxic effects toward aging brain. PMID- 27514535 TI - Left subclavian artery-esophageal fistula induced by a paper star: a case report. AB - A subclavian artery-esophageal fistula usually occurs on the right side of an aberrant subclavian artery. It also rarely appears in the site between a non aberrant subclavian artery and the esophagus due to the ingestion of a foreign body. Upper gastrointestinal bleeding in the case of a subclavian artery esophageal fistula is rare but often fatal. Here, we report on a 62-year-old male patient with a left subclavian arteryesophageal fistula complicated by hemorrhagic shock. He swallowed a foreign body at a birthday party. An upper gastrointestinal endoscopy indicated a paper star lodged at 20 cm from the incisors, inducing a kissing esophageal ulcer around the esophageal sphincter. One month later, he suffered an unusually strong episode of hematemesis. Subsequently, a computed tomography angiography was performed and demonstrated a left subclavian artery-esophageal fistula. Finally, the fistula induced by the ingestion of a paper star was successfully treated by endovascular stent grafting. PMID- 27514536 TI - SIRT1/Atg5/autophagy are involved in the antiatherosclerosis effects of ursolic acid. AB - The purpose of this study was to investigate the antiatherosclerosis effects of ursolic acid (UA) in high-fat diet-fed quails (Coturnix coturnix) and potential mechanism. Quails were treated with high-fat diet (14 % pork oil, 1 % cholesterol w/w) with or without UA (50, 150, or 300 mg/kg/day) for 10 weeks. Serum lipid profile was assessed at 0, 4.5, and 10 weeks. After 10 weeks, serum antioxidant status and morphology of aorta were assessed. Additionally, human umbilical vein endothelial cells (HUVECs) were exposed to 100 MUg/ml oxidized low-density lipoprotein (ox-LDL) for 24 h, with or without pretreatment with UA (5, 10 or 20 MUM) for 16 h, autophagy inhibitor 3-MA 5 mM for 2 h, or SIRT1 inhibitor EX-527 10 MUM for 2 h. Cell viability and oxidative stress status were assessed and autophagy status was determined. Acetylation of lysine residue on Atg5 was assessed with immunoprecipitation. In results, high-fat diet negatively affected serum lipid profile and antioxidant status in quails and induced significant histological changes. Cotreatment with UA remarkably alleviated such changes. In HUVECs, ox-LDL treatment induced significant cytotoxicity along with oxidative stress, while UA cotreatment alleviated such changes significantly. UA treatment induced autophagy, enhanced SIRT1 expression, and decreased acetylation of lysine residue on Atg5. Cotreatment with 3-MA or EX-527 effectively abolished UA's protective effects. In summary, UA exerted antiatherosclerosis effects in quails and protected HUVECs from ox-LDL induced cytotoxicity, and the mechanism is associated with increased SIRT1 expression, decreased Atg5 acetylation on lysine residue, and increased autophagy. PMID- 27514537 TI - CNTF-ACM promotes mitochondrial respiration and oxidative stress in cortical neurons through upregulating L-type calcium channel activity. AB - A specialized culture medium termed ciliary neurotrophic factor-treated astrocyte conditioned medium (CNTF-ACM) allows investigators to assess the peripheral effects of CNTF-induced activated astrocytes upon cultured neurons. CNTF-ACM has been shown to upregulate neuronal L-type calcium channel current activity, which has been previously linked to changes in mitochondrial respiration and oxidative stress. Therefore, the aim of this study was to evaluate CNTF-ACM's effects upon mitochondrial respiration and oxidative stress in rat cortical neurons. Cortical neurons, CNTF-ACM, and untreated control astrocyte-conditioned medium (UC-ACM) were prepared from neonatal Sprague-Dawley rat cortical tissue. Neurons were cultured in either CNTF-ACM or UC-ACM for a 48-h period. Changes in the following parameters before and after treatment with the L-type calcium channel blocker isradipine were assessed: (i) intracellular calcium levels, (ii) mitochondrial membrane potential (DeltaPsim), (iii) oxygen consumption rate (OCR) and adenosine triphosphate (ATP) formation, (iv) intracellular nitric oxide (NO) levels, (v) mitochondrial reactive oxygen species (ROS) production, and (vi) susceptibility to the mitochondrial complex I toxin rotenone. CNTF-ACM neurons displayed the following significant changes relative to UC-ACM neurons: (i) increased intracellular calcium levels (p < 0.05), (ii) elevation in DeltaPsim (p < 0.05), (iii) increased OCR and ATP formation (p < 0.05), (iv) increased intracellular NO levels (p < 0.05), (v) increased mitochondrial ROS production (p < 0.05), and (vi) increased susceptibility to rotenone (p < 0.05). Treatment with isradipine was able to partially rescue these negative effects of CNTF-ACM (p < 0.05). CNTF ACM promotes mitochondrial respiration and oxidative stress in cortical neurons through elevating L-type calcium channel activity. PMID- 27514538 TI - Mitoprotective antioxidant EUK-134 stimulates fatty acid oxidation and prevents hypertrophy in H9C2 cells. AB - Oxidative stress is an important contributory factor for the development of cardiovascular diseases like hypertension-induced hypertrophy. Mitochondrion is the major source of reactive oxygen species. Hence, protecting mitochondria from oxidative damage can be an effective therapeutic strategy for the prevention of hypertensive heart disease. Conventional antioxidants are not likely to be cardioprotective, as they cannot protect mitochondria from oxidative damage. EUK 134 is a salen-manganese complex with superoxide dismutase and catalase activity. The possible role of EUK-134, a mitoprotective antioxidant, in the prevention of hypertrophy of H9C2 cells was examined. The cells were stimulated with phenylephrine (50 MUM), and hypertrophy was assessed based on cell volume and expression of brain natriuretic peptide and calcineurin. Enhanced myocardial lipid peroxidation and protein carbonyl content, accompanied by nuclear factor kappa B gene expression, confirmed the presence of oxidative stress in hypertrophic cells. Metabolic shift was evident from reduction in the expression of medium-chain acyl-CoA dehydrogenase. Mitochondrial oxidative stress was confirmed by the reduced expression of mitochondria-specific antioxidant peroxiredoxin-3 and enhanced mitochondrial superoxide production. Compromised mitochondrial function was apparent from reduced mitochondrial membrane potential. Pretreatment with EUK-134 (10 MUM) was effective in the prevention of hypertrophic changes in H9C2 cells, reduction of oxidative stress, and prevention of metabolic shift. EUK-134 treatment improved the oxidative status of mitochondria and reversed hypertrophy-induced reduction of mitochondrial membrane potential. Supplementation with EUK-134 is therefore identified as a novel approach to attenuate cardiac hypertrophy and lends scope for the development of EUK-134 as a therapeutic agent in the management of human cardiovascular disease. PMID- 27514540 TI - Creep and stress relaxation of human red cell membrane. AB - In contrast to most mechanical properties of the red cell, experimental information on stress relaxation (SR) of the membrane skeleton is scarce. On the other hand, many postulates or assumptions as to the value of the characteristic time of SR [Formula: see text] can be found in the literature. Here, an experiment is presented that allows measurement of [Formula: see text] up to values of about 10 h. The membrane skeleton was deformed passively by changing the spontaneous curvature of the bilayer thus transforming the natively biconcave red cells into echinocytes. This shape and the concomitant deformation of the skeleton were kept up to 4 h by incubation at 37 C. During this period, no plastic deformation (creep) was observed. After the incubation, the spontaneous curvature was returned to normal. The resulting shape was smooth showing no remnants of the echinocytic shape. Both observations indicate [Formula: see text] 10 h. This result is in gross disagreement to postulates or assumptions existing in the literature. PMID- 27514539 TI - Implementation of 2011 Duty Hours Regulations through a Workload Reduction Strategy and Impact on Residency Training. AB - BACKGROUND: Training programs have implemented the 2011 ACGME duty hour regulations (DHR) using "workload compression" (WLC) strategies, attempting to fit similar clinical responsibilities into fewer working hours, or workload reduction (WLR) approaches, reducing the number of patient encounters per trainee. Many have expressed concern that these strategies could negatively impact patient care and learner outcomes. OBJECTIVE: This study evaluates the medical knowledge and clinical impact of a WLR intervention in a single institution. DESIGN & PARTICIPANTS: Nonrandomized intervention study with comparison to a historical control study among 58 PGY-1 internal medicine trainees in the 2 years after duty hour implementation [exposure cohort (EC), 7/1/2011-6/30/2013], compared to 2 years before implementation [comparison cohort (CC), 7/1/2009-6/30/2011]. MAIN MEASURES: Process outcomes were average inpatient encounters, average new inpatient admissions, and average scheduled outpatient encounters per PGY-1 year. Performance outcomes included trainee inpatient and outpatient days on service, In-Training Examination (ITE) scores as an objective surrogate of medical knowledge, Case-Mix Index (CMI), and quality of care measures (30-day readmission rate, 30-day mortality rate, and average length of stay). KEY RESULTS: Baseline characteristics and average numbers of inpatient encounters per PGY-1 class were similar between the EC and CC. However, the EC experienced fewer new inpatient admissions (157.47 +/- 40.47 vs. 181.72 +/- 25.45; p < 0.01), more outpatient encounters (64.80 +/- 10.85 vs. 56.98 +/- 6.59; p < 0.01), and had similar ITE percentiles (p = 0.58). Patients of similar complexity cared for by the EC also had a greater reduction in readmissions (21.21 % to 19.08 %; p < 0.01) than the hospital baseline (12.07 to 11.14 %; p < 0.01). CONCLUSIONS: Our WLR resulted in a small decrease in the average number of new inpatient admissions and an increase in outpatient encounters. ITE and care quality outcomes were maintained or improved. While there is theoretical concern that reducing PGY-1 inpatient admissions volumes may negatively impact education and clinical care measures, this study found no evidence of such a trade-off. PMID- 27514541 TI - The effect of loading rate on the development of early damage in articular cartilage. AB - Experimental reports suggest that cartilage damage depends on strain magnitude. Additionally, because of its poro-viscoelastic nature, strain magnitude in cartilage can depend on strain rate. The present study explores whether cartilage damage may develop dependent on strain rate, even when the presented damage numerical model is strain-dependent but not strain-rate-dependent. So far no experiments have been distinguished whether rate-dependent cartilage damage occurs in the collagen or in the non-fibrillar network. Thus, this research presents a finite element analysis model where, among others, collagen and non fibrillar matrix are incorporated as well as a strain-dependent damage mechanism for these components. Collagen and non-fibrillar matrix stiffness decrease when a given strain is reached until complete failure upon reaching a maximum strain. With such model, indentation experiments at increasing strain rates were simulated on cartilage plugs and damage development was monitored over time. Collagen damage increased with increasing strain rate from 21 to 42 %. In contrast, damage in the non-fibrillar matrix decreased with increasing strain rates from 72 to 34 %. Damage started to develop at a depth of approximately 20 % of the sample height, and this was more pronounced for the slow and modest loading rates. However, the most severe damage at the end of the compression step occurred at the surface for the plugs subjected to 120 mm/min strain rate. In conclusion, the present study confirms that the location and magnitude of damage in cartilage may be strongly dependent on strain rate, even when damage occurs solely through a strain-dependent damage mechanism. PMID- 27514542 TI - How Valid is Placebo in the Indian Setting? AB - BACKGROUND: The Placebo is defined as an inert substance with a potent therapeutic effect. Its effect is attributed to its psychological and neurobiological effect. Its use in Psychiatric drug practice, drug trials and clinical practice is common, especially in India. Currently there is a debate whether to use it or not as there are ethical, moral and legal issues. Also, its mechanism of action is not known. DISCUSSION: The Indian Psychiatry scenario is muddled in relation to use of placebo in Randomized Controlled Trials or Psychiatric clinical practice. Despite the scepticism associated with this phenomenon physicians get influenced by it. The present article focuses on the reviews done so far on the efficacy and use of placebo and also the points in favour and against the same in drug trials and psychiatric clinical practice. SUMMARY: A number of controversies are associated with this biologically inert substance which has no pharmacological role. Currently in medical sciences many scientific studies have been done solely on placebo. The development in this area may have future implications for further research. PMID- 27514543 TI - The interaction of Wnt-11 and signalling cascades in prostate cancer. AB - Prostate cancer (PCa) is the second most common cancer among the male population. Conventional therapies target androgen signalling, which drives tumour growth; however, they provide limited survival benefits for patients. It is essential, therefore, to develop a more specific biomarker than the current gold standard, PSA testing. The Wnt signalling pathway induces expression of target genes through cell surface receptors. A non-canonical member of this family, Wnt-11, is evolutionarily highly conserved and is normally expressed by various cells in the developing embryo, as well as in the heart, liver and skeletal muscle of adult humans. We comprehensively review several cell signalling pathways to explain how they interact with Wnt-11, demonstrating its use as a potential biomarker for PCa. Several studies have shown that the expression of Wnt-11 is associated with gastric, renal and colorectal adenocarcinomas and PCa. Moreover, Wnt-11 affects extracellular matrix composition and cytoskeletal rearrangement, and it is required for proliferation and/or survival during cell differentiation. It was found that PCa cell lines express high levels of Wnt-11, which allows differentiation of the epithelial prostate tumour cells to neuron-like (NE) cells. The NE cells produce additional factors that can cause regression after treatment. Accumulating evidence shows that Wnt-11 could be a potential biomarker in diagnosing PCa. Many studies have shown both non-canonical and canonical Wnts interact with several signalling cascades such as PKC, JNK, NF-kappaB, Rho, PKA and PI3K. In particular, evidence demonstrates Wnt-11 is involved in the progression of PCa, thus it could have the potential to become both a specific disease marker and an important therapeutic target. PMID- 27514544 TI - Calcium role in human carcinogenesis: a comprehensive analysis and critical review of literature. AB - The central role played by calcium ion in biological systems has generated an interest for its potential implication in human malignancies. Thus, lines of research, on possible association of calcium metabolism regulation with tumorigenesis, implying disruptions and/or alterations of known molecular pathways, have been extensively researched in the recent decades. This paper is a critical synthesis of these findings, based on a functional approach of the calcium signaling toolkit. It provides strong support that this ubiquitous divalent cation is involved in cancer initiation, promotion, and progression. Different pathways have been outlined, involving equally different molecular and cellular structures. However, if the association between calcium and cancer can be described as constant, it is not always linear. We have identified several influencing factors among which the most relevant are (i) the changes in local or tissular concentrations of free calcium and (ii) the histological and physiological types of tissue involved. Such versatility at the molecular level may probably account for the conflicting findings reported by the epidemiological literature on calcium dietary intake and the risk to develop certain cancers such as the prostatic or mammary neoplasms. However, it also fuels the hypothesis that behind each cancer, a specific calcium pathway can be evidenced. Identifying such molecular interactions is probably a promising approach for further understanding and treatment options for the disease. PMID- 27514545 TI - [Protective effect of Nrf2 activation by curcumin against lead-induced toxicity and apoptosis in SH-SY5Y cells]. AB - OBJECTIVE: To study the protective effect of nuclear factor erythroid 2-related factor 2 (Nrf2) activation by curcumin against lead-induced toxicity and apoptosis in SH-SY5Y human neuroblastoma cells and its impact on expression of apoptosis-related proteins. METHODS: After the cells were treated with 0, 0.5, 1, 5, or 10 MUmol/L curcumin for 24 hours, nucleoprotein was extracted and electrophoretic mobility shift assay was used to measure Nrf2-antioxidant responsive element (ARE) binding capacity. The optimal concentration of curcumin was figured out for treating cells. After pretreatment with 5 MUmol/L curcumin for 24 hours, cells were exposed to lead acetate at different concentrations (0, 5, 25, and 125 MUmol/L for control, low-dose, medium-dose, and high-dose groups). The 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry, and Western blot were used to evaluate cell viability, apoptosis, and expression of apoptosis-related proteins, respectively. RESULTS: Curcumin of 5 MUmol/L caused significantly increased cell viability in low-, medium-, and high-dose groups exposed to lead acetate for 12 hours (98.42%+/-1.12% vs 92.92%+/ 0.14%, P<0.05; 95.30%+/-1.17% vs 91.15%+/-0.67%, P<0.05; 94.50%+/-1.45% vs 85.98%+/-0.45%, P<0.05). Curcumin of 5 MUmol/L also caused significantly increased cell viability in medium-and high-dose groups exposed to lead acetate for 24 hours (93.10%+/-1.63% vs 88.40%+/-4.13%, P<0.05; 90.13%+/-2.03% vs 83.63%+/-3.42%, P<0.05). The high-dose group had a significantly higher apoptotic rate than the control group 6.17%+/-1.31% vs 3.30%+/-0.53%, P<0.05). Curcumin of 5.0 MUmol/L significantly reduced the apoptotic rate in the high-dose group (2.97%+/-0.15% vs 6.17%+/-1.31%, P<0.05). Exposure to lead acetate elevated the expression of Bax, cytochrome C, and caspase-3 and reduced Bcl-2 expression. Curcumin of 5.0 MUmol/L significantly reduced the expression of Bax, cytochrome C, and caspase-3 in the high-dose group (P<0.05). CONCLUSION: Nrf2 activation by curcumin has a protective effect against lead-induced toxicity and apoptosis in SH-SY5Y cells. The protective effect of Nrf2 against apoptosis may be associated with the regulation of apoptosis-related proteins. PMID- 27514546 TI - [Influence of manganese exposure via intracerebral injection on behavioristics and substantia nigra dopaminergic neurons in rats]. AB - OBJECTIVE: To investigate the changes in behavioristics, substantia nigra tyrosine hydroxylase (TH) immunoreactive cells, and ultrastructure of substantia nigra neurons in rats after manganese exposure via intracerebral injection. METHODS: A total of 72 healthy male Sprague-Dawley rats were randomly divided into exposure group and control group, with 36 rats in each group. The stereotactic technique was used for injection of 1 MUl MnCl2.4H2O (1 mol/L) into the corpus striatum in the exposure group, and the control group was injected with the same volume of normal saline. The changes in rotational behavior, number of TH immunoreactive cells in the substantia nigra, and ultrastructure of the substantia nigra induced by apomorphine were observed at 8 hours and 1, 3, 7, 15, and 30 days after injection, and this measure was compared with manganese exposure via intraperitoneal injection. RESULTS: After apomorphine induction for 30 minutes, the exposure group showed a gradual increase in the number of rotations over the time of manganese exposure (F= 176.921, P<0.01) and a significantly higher number of rotations than the control group (F=482.654, P<0.01). The exposure group showed a gradual reduction in the mean A value of TH immunoreactive cells in the injured substantia nigra over the time of exposure (F=12.009, P<0.01) , and this value differed significantly between the injured substantia nigra in the exposure group and the contralateral substantia nigra in the exposure group and the injured side in the control group (F=36.131, P<0.01). At 3, 7, 15, and 30 days after exposure, the injured substantia nigra showed a significantly lower mean A value of TH immunoreactive cells than the contralateral side in the exposure group (all P<0.01). At 7, 15, and 30 days, the injured substantia nigra in the exposure group showed a significantly lower mean A value than the injured side in the control group (all P<0.01). After manganese exposure, substantia nigra neurons showed the changes including mitochondrial swelling, dilatation of the endoplasmic reticulum, and demyelination of nerve fibers in different stages, which suggested the dynamic process of dopaminergic neuron injuries. Compared with manganese exposure via intraperitoneal injection, manganese exposure via intracerebral injection can induce behavioral changes and injuries of the substantia nigra-striatum system more quickly. CONCLUSION: Manganese exposure via intracerebral injection induces behavioral changes and injuries of substantia nigra dopaminergic neurons in rats within a short time. PMID- 27514548 TI - [Association between XRCC1 polymorphisms and chromosome damage in workers exposed to benzene in jewelcrafting industry]. AB - OBJECTIVE: To investigate the association between the gene polymorphisms of the DNA damage repair gene X-ray repair cross-complementing gene 1 (XRCC1) and susceptibility to chromosome damage in workers exposed to low-concentration benzene in the jewelcrafting industry. METHODS: A total of 286 workers exposed to benzene in jewelcrafting enterprises were enrolled as study subjects from January 2013 to December 2014. Gas chromatography was used to measure benzene concentration in workplace, cytokinesis-block micronucleus test was used to analyze the level of chromosome damage in peripheral blood, and the Sequenom technique was used to determine the single nucleotide polymorphisms of XRCC1. RESULTS: The time-weighted average concentration of benzene in workplace was <0.6~1.8 mg/m(3), lower than the national occupational exposure limit (6 mg/m(3)). The distribution of allele frequencies met the Hardy-Weinberg equilibrium in genetics (P>0.05). Increase in age (RR=1.38, 95%CI 1.06~3.75) and increase in working years (RR=1.45, 95%CI 1.18~2.58) were risk factors for the increase in micronucleus frequency. Compared with those with the wild-type homozygous genotype, the individuals with XRCC1 rs25487 CT genotype showed a significantly higher risk of increase in micronucleus frequency (RR=1.51, 95% CI 1.28~3.87, P<0.05) , and the individuals with XRCC1 rs1799782 AA genotype also showed a significantly higher risk of increase in micronucleus frequency (RR=1.65, 95% CI 1.30~3.12, P<0.05). There was no clear association between XRCC1 rs25489 polymorphisms and micronucleus frequency (P>0.05). CONCLUSION: Exposure to low-concentration benzene may cause chromosome damage in workers exposed to benzene, and the XRCC1 polymorphisms rs 25487 and rs1799782 may be associated with chromosome damage induced by benzene. PMID- 27514547 TI - [Association between hypertension and serum microRNA21 and microRNA133a in ocean seamen]. AB - OBJECTIVE: To investigate the prevalence of hypertension in ocean seamen and major influencing factors, as well as the association between hypertension and serum microRNA21 and microRNA133a. METHODS: Health examination and a questionnaire survey were performed for 780 ocean seamen who underwent physical examination in an international travel healthcare center in Fujian, China from January to June, 2014. TaqMan RT-qPCR was used to measure the serum levels of microRNA21 and microRNA133a in seamen with hypertension. RESULTS: The prevalence of hypertension differed significantly between the ocean seamen with different ages, education levels, marital status, body mass index (BMI) values, drinking frequencies, and numbers of sailing years (P<0.05). The prevalence rate of hypertension in the ocean seamen increased with the increasing drinking frequency (chi(2)=9.02, P<0.05) , decreased with the increase in degree of education (chi(2)=11.578, P<0.05) , and increased with the increase in the number of sailing years (chi(2)=28.06, P<0.05). The hypertensive ocean seamen had significantly higher expression levels of microRNA21 and MicroRNA133a than the healthy ocean seamen (microRNA21: 7.87+/-5.46 vs 1.03+/-0.80, P<0.05; MicroRNA133a: 7.45+/-1.94 vs 4.52+/-1.15, P<0.05). The multivariate analysis showed that a high level of microRNA21 (OR=1.61, 95% CI: 1.22~2.11) , a high level of microRNA133a (OR=1.52, 95% CI: 1.24~1.87) , drinking (OR=1.64, 95% CI: 1.08~2.50) , overweight based on BMI (OR=1.18, 95%CI: 1.07~1.30) , and many sailing years (OR=2.89, 95% CI: 1.14~7.30) were risk factors for hypertension. CONCLUSION: The prevention and treatment of hypertension in ocean seamen should be enhanced. Excessive drinking should be controlled, and sailing time should be arranged reasonably. The microRNA21 and microRNA133a may be associated with the development and progression of hypertension in ocean seamen. PMID- 27514549 TI - [Toxic effect of trichloroethylene on liver cells with CYP3A4 gene defect]. AB - OBJECTIVE: To investigate the toxic effect of trichloroethylene on liver cells with CYP3A4 gene defect. METHODS: The normal human liver cells (L02 cells) and liver cells with CYP3A4 gene defect were exposed to trichloroethylene at different doses (0.0, 0.4, 0.8, 1.6, 3.2, and 6.4 mmol/L). CCK8 assay and RT-qPCR were used to measure cell viability and changes in the expression of apoptosis genes and oncogenes. RESULTS: After being exposed to trichloroethylene at doses of 1.6, 3.2, and 6.4 mmol/L, the liver cells with CYP3A4 gene defect showed significantly higher cell viability than L02 cells (0.91+/-0.06/0.89+/ 0.05/0.85+/-0.07 vs 0.80+/-0.04/0.73+/-0.06/0.67+/-0.07, P<0.05). The L02 cells in the 0.8~3.2 mmol/L trichloroethylene groups showed significant increases in the expression of the apoptosis genes caspase-3, caspase-8, and caspase-9 (P<0.05) , as well as the oncogenes c-myc, c-fos, and k-ras (P<0.05). Compared with the L02 cells, the cells with CYP3A4 gene defect showed significant reductions in the expression of the apoptosis genes caspase-3, caspase-8, and caspase-9 and the oncogenes c-myc, c-fos, and k-ras (P<0.05). CONCLUSION: Trichloroethylene exposure has a less effect on the expression of apoptosis genes and oncogenes in liver cells with CYP3A4 gene defect than in normal human liver cells, suggesting that CYP3A4 gene defect reduces the inductive effect of trichloroethylene on apoptosis genes and oncogenes. PMID- 27514550 TI - [Influence of two positions for measuring instrument adapter on measurement of hand-transmitted vibration in grinding machine]. AB - OBJECTIVE: To investigate the influence of two positions for measuring instrument adapter on the measurement of hand-transmitted vibration in grinding machine using the intraclass correlation coefficient (ICC) of reliability assessment index, and to provide a basis for studies on the measurement standard for hand transmitted vibration. METHODS: With reference to the measurement standard for hand-transmitted vibration ISO 5349 Mechanical vibration-Measurement and evaluation of human exposure to hand-transmitted vibration-Part 1: General requirements and Mechanical vibration-Measurement and evaluation of human exposure to hand-transmitted vibration-Part 2: Practical guidance for measurement at the workplace, the domestic AWA5936 hand-transmitted vibration measuring instrument and SVAN-106 hand-transmitted vibration measuring instrument from Poland were used to measure hand-transmitted vibration in 3 workers for grinding machine in a foundry for 5 days continuously from September to October, 2014, and Y-axis data were recorded and compared. RESULTS: In worker A, the "T" -shaped adapter had a significantly higher mean Y-axis accelerated speed effective value than the "O" -shaped adapter [4.34 m/s(2) (95%CI 4.05(-)4.63) vs 2.32 m/s(2) (95%CI 2.27~2.38) , t=13.781, P<0.01]. In workers B and C, AWA5936 "U" -shaped adapter (placed at the position of the handle of grinding machine) had lower degrees of data variation of 12.55% and 15.77%, respectively, suggesting good data stability. The measurement results showed significant differences across different positions of adapter (P<0.01) and between all adapters except "O" shaped and line-shaped adapters (all P<0.01) , while the measurement results showed no significant differences between the "O" -shaped and line-shaped adapters (P>0.01). The comparison of the measurement results of AWA5936 vibration measuring instrument with an "U" -shaped adapter and SVAN-106 vibration measuring instrument with an "S" -shaped adapter showed an ICC of >0.80 (ICC=0.82) , while the comparison of the measurement results of AWA5936 vibration measuring instrument with an "O" -shaped adapter and SVAN-106 vibration measuring instrument showed an ICC of <0.40. CONCLUSION: SVAN-106 vibration measuring instrument with an "S" -shaped adapter placed at the palm and AWA5936 vibration measuring instrument with an "U" -shaped adapter placed at the handle of grinding machine can give comparable measurement results with good reliability. PMID- 27514551 TI - [A survey of mental health status in armored vehicle crew]. AB - OBJECTIVE: To investigate the mental health status in armored vehicle crew (commanders, gunners, and drivers) , to know the level of mental health in them, and to provide educational intervention. METHODS: In April 2009, 120 male armored vehicle crew with >2 driving years were enrolled as battle group, and 70 male persons within the same age group who were not engaged in armored vehicle operation were enrolled as control group. The Symptom Checklist-90 (SCL-90) was used to evaluate the mental status of the 180 subjects. RESULTS: Compared with the control group, the battle group showed significantly higher scores on the subscales of obsessive-compulsive symptom, interpersonal sensitivity, depression, anxiety, phobic anxiety, and paranoid ideation (t=2.323, 3.250, 3.158, 2.712, 2.391, and 2.137, all P<0.05) , as well as significantly higher total score, number of positive items, and average score of positive symptoms (t=4.128, 4.357, and 4.632, all P<0.05). In the battle group, the scores on the subscales of somatization, obsessive-compulsive symptom, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, psychoticism, and additional items, total score, number of positive items, and average score of positive symptoms were significantly lower than the military reference values (t=4.364, 5.127, 5.280, 3.783, 7.012, 5.361, 4.369, 6.167, 6.476, 3.558, 6.357, 4.379, and 6.763, all P<0.05). CONCLUSION: A survey should be performed on the mental health status of armored vehicle crew, including obsessive-compulsive symptom, interpersonal sensitivity, depression, and anxiety. Mental health service for the crew should be enhanced to improve their psychological quality. PMID- 27514552 TI - [Research on the work-related disease and its influencing factors of midwives in Fujian Province]. PMID- 27514553 TI - [Investigation on occupational health status of workers in Xinjiang coal-fired power plant]. PMID- 27514554 TI - [Intervention of systolic pressure and left ventricular hypertrophy in rats under cold stress]. AB - OBJECTIVE: To investigate the effects of different drugs on systolic blood pressure (SBP) and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats under cold stress. METHODS: A total of 40 male spontaneously hypertensive rats aged 10 weeks (160~200 g) were given adaptive feeding for 7 days at a temperature of 20+/-1 degrees C and then randomly divided into control group, cold stress group, metoprolol group, amlodipine group, and benazepril group, with 8 rats in each group. SBP, body weight, and heart rate were measured once a week. After the rats were sacrificed by exsanguination, left ventricular weight (LVW) was measured, and left ventricular weight index (LVWI; mg/g) was calculated. Radioimmunoassay was used to measure the concentrations of endothelin 1 (ET-1) and angiotensin-II (Ang-II) in plasma and myocardium, and the chemical method was used to measure the concentrations of nitric oxide (NO) in plasma and myocardium. RT-PCR was used to measure the mRNA expression of endothelin-A receptor. RESULTS: Compared with the cold stress group, all medication groups showed significant reductions in SBP since week 5 (P<0.05). The cold stress group showed a significant increase in LVWI compared with the control group (3.38+/ 0.27 mg/g vs 2.89+/-0.19 mg/g, P<0.05). The amlodipine group showed a significant reduction in LVWI compared with the cold stress group (2.98+/-0.28 mg/g vs 3.38+/ 0.27 mg/g, P<0.05). The cold stress group showed a significant reduction in plasma NO concentration compared with the control group (104.9+/-19.5 MUmol/L vs 129.3+/-17.8 MUmol/L, P<0.05) ; compared with the cold stress group, all the medication groups showed significant increases in blood NO concentration (P<0.05). The cold stress group showed a significant increase in myocardial ET-1 concentration compared with the control group (6.3+/-1.5 pg/100 mg vs 4.5+/-1.9 pg/100 mg, P<0.05) ; compared with the cold stress group, the amlodipine group showed a significant reduction in myocardial ET-1 concentration (4.4+/-1.0 pg/100 mg vs 6.3+/-1.5 pg/100 mg, P<0.05). The cold stress group had significantly higher mRNA expression of endothelin-A receptor than the control group (0.86+/ 0.23 vs 0.45+/-0.16, P<0.01) ; compared with the cold stress group, the amlodipine group showed a significant reduction in the mRNA expression of endothelin-A receptor (0.41+/-0.14 vs 0.86+/-0.23, P<0.01). CONCLUSION: Amlodipine can reduce the increase in SBP and inhibit LVH in spontaneously hypertensive rats under cold stress. PMID- 27514555 TI - [Effects of expression of calpain mRNA in rabbits exposed to vibration by hind legs]. AB - OBJECTIVE: To study the effects of expression of calpain mRNA in rabbits exposed to vibration by hind legs. METHODS: 32 New Zealand rabbits were randomly divided into a control group and 3 experimental groups according to 4-hour energy equivalent frequency-weighted acceleration[ahw (4)]: low (4.33 m/s(2)) , moderate (8.67 m/s(2)) and high (17.34 m/s(2)) intensity group to accepted the vibration by hind legs. 45 ds later, brain and skeletal muscle tissue of rabbits were taken to detect the expression of calpain-1 and calpain-2 mRNA by RT-qPCR technique. RESULTS: The relative content of calpain-1 mRNA in the brain tissues in rabbits of low, medium and high intensity group were 8.35+/-3.75,9.64+/-4.54,5.10+/-5.26. While the relative content of calpain-2 mRNA in the brain tissues in rabbits of low, medium and high intensity group were 7.34+/-4.97,8.50+/-5.66, 8.16+/-5.59. Compared with the control group (1.10+/-0.29, 0.56+/-0.43) , the expression of calpain-1 and calpain-2 mRNA of the intensity groups showed an significantly increasing trend (P<0.01). In skeletal muscle tissue, the relative content of calpain-1 mRNA were 4.36+/-2.05, 7.37+/-4.06, 12.46+/-6.21.Compared with the control group (0.98+/-0.59) , the expression of calpain-1 mRNA of experiment groups were significantly higher (P<0.05) .The expression of calpain-2 mRNA of the intensity groups had no significantly difference with the control group (P>0.05). CONCLUSION: The expression of calpain-1 and calpain-2 mRNA can be promoted by the vibration by the hind legs. PMID- 27514556 TI - [Influence of puerarin on proliferative activity of human fetal scleral fibroblasts and expression of collagen type I and matrix metalloproteinase-2 in power frequency electromagnetic field]. AB - OBJECTIVE: To investigate the influence of puerarin on the proliferative activity of human fetal scleral fibroblasts (HFSFs) and the expression of collagen type I and matrix metalloproteinase-2 (MMP-2) in HFSFs in the power frequency electromagnetic field. METHODS: HFSFs were cultured and divided into four radiation groups (0.2 mT, 50 Hz) and control group. Puerarin at concentrations of 0.0, 1.0, 5.0, and 10.0 MUmol/L was added to the four radiation groups, respectively. The methyl thiazolyl tetrazolium colorimetry was used to measure the influence on the proliferative activity of HFSFs, Western blot and RT-qPCR were used to measure the protein and mRNA expression of collagen type I and MMP-2 induced by puerarin in the power frequency electromagnetic field. RESULTS: The radiation groups and control group showed significant increases in the proliferative activity of HFSFs over the culture time (F= 959.472 and 279.468, both P<0.01). At 24 and 48 hours, the radiation groups showed significantly lower proliferative activity than the control group (0.432+/-0.038/0.591+/-0.017 vs 0.536+/-0.034/0.801+/-0.020, both P<0.01). With the increasing concentration of puerarin (0.0, 1.0, 5.0, and 10.0 MUmol/L) , the proliferative activity of HFSFs significantly increased, with A values of 0.598+/-0.031, 0.809+/-0.041, 0.910+/ 0.037, and 0.983+/-0.054, respectively (P<0.05). After exposure for 24 hours, the radiation groups showed significantly lower protein expression of collagen type I and significantly higher protein expression of MMP-2 (t=7.917 and 7.831, both P<0.01) ; compared with the 0.0 MUmol/L puerarin group, the 1.0, 5.0, and 10.0 MUmol/L puerarin groups showed significant increases in the protein expression of collagen type I and significant reductions in the protein expression of MMP-2 (all P<0.01). Compared with the control group, the radiation groups showed significant reductions in the mRNA expression of collagen type I and MMP-2 (t=17.293 and 16.378, both P<0.01) ; compared with the 0.0 MUmol/L puerarin group, the 1.0, 5.0, and 10.0 MUmol/L puerarin groups showed significant increases in the mRNA expression of collagen type I and significant reductions in the mRNA expression of MMP-2 (P<0.01). CONCLUSION: Puerarin can inhibit the reduction in the proliferative activity of HFSFs in the power frequency electromagnetic field, upregulate the expression of collagen type I, downregulate the expression of MMP-2, and thus exert its protective effect. PMID- 27514557 TI - [Application of standardization of medical care model for chronic mild lead poisoning]. AB - OBJECTIVE: To standardize the treatment and evaluate the clinical application effectiveness of clinical pathway (CP) in chronic mild lead poisoning. METHODS: 60 patients with chronic mild lead poisoning hospitalized from Jan. 2014 to Dec.2014 were enrolled for the study group, 60 patients with chronic mild lead poisoning hospitalized from Jan.2013 to Dec.2013 were enrolled for the control group. The study group were cared according to clinical pathway, the control group received routine therapy; the clinical application effectiveness were compared between the two groups. RESULTS: No adverse drug reactions occurred in both groups. The curative ratio was significantly higher in the study group than in the control group (96.7% vs 86.0%, P<0.05) , the rate of patients' satisfaction to medical care significantly higher in the study group (98.3% vs 88.3%, P<0.05) , the rate of health education awareness higher in the study group (95.0% vs 81.7%, P<0.05) , the course of treatment shorter in the study group (3.2+/-0.6 vs 3.4+/-0.7, P<0.05) , the medical cost less in the study group (5773.5 yuan+/-1242.1 yuan vs 6354.7 yuan+/-1177.0 yuan, P<0.05) , the length of hospitalization was shorter in the study group (21.9 d+/-6.7 d vs 24.6 d+/-7.9 d, P<0.05). The variation rate of clinical pathway was 13.3% in clinical pathway group. CONCLUSION: The implementation of clinical pathway could improve the curative ratio, satisfaction, and health education awareness. The course of treatment, length of hospital stay and costs of hospitalization in the study group could be obviously shorter and less, and there is a little variation rate in the clinical pathway. PMID- 27514558 TI - [Clinical analysis of chronic lead poisoning and liver function damage]. PMID- 27514559 TI - [Early reduction of frostbite for depth of management of occupational acute finger]. PMID- 27514560 TI - [A case of chronic myeloid leukemia caused by benzene]. PMID- 27514563 TI - [Evaluation of uncertainty for determination of manganese dioxide in air of workplace by flame atomic absorption spectrometry]. PMID- 27514561 TI - [Determination of HVA and VMA in urine using high performance liquid chromatography-tandem mass spectrometry]. AB - OBJECTIVE: To establish a method for the determination of homovanillic acid (HVA) and vanil mandelic acid (VMA) in urine, using high performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS) detection. METHODS: A 200 MUl volume of urine sample added with 20 MUl chlorzoxazone internal standard was mixed in a centrifuge tube, then added 100MUL methanol (containing 1% acetic acid) , vortex mixed and centrifuged at 13 000 rpm for 1 min. A 10 MUl volume of the above supernatant solution was injected into HPLC/MS/MS system for quantitative analysis. RESULTS: With internal standard method, the calibration curves of HVA and VMA were linear in the range of 20~10 000 ng/ml and 20~7 500 ng/ml, with correlation coefficient of 0.995 6 and 0.997 0, respectively. The LOQ of HVA and VMA was 4.69 ng/ml and 2.33 ng/ml, respectively. The method recoveries were in the range of 85.72%~117.95% for HVA, and 95.82%~113.78% for VMA. CONCLUSION: This method is simple, rapid and characterized with acceptable sensitivity and accuracy to meet the requirements for the analysis of homovanillic acid and vanilla mandelic acid. PMID- 27514562 TI - [Determination of trace gallium by graphite furnace atomic absorption spectrometry in urine]. AB - OBJECTIVE: To establish a method for determination trace gallium in urine by graphite furnace atomic absorption spectrometry (GFAAS). METHODS: The ammonium dihydrogen phosphate was matrix modifier. The temperature effect about pyrolysis (Tpyr) and atomization temperature were optimized for determination of trace gallium. The method of technical standard about within-run, between-run and recoveries of standard were optimized. RESULTS: The method showed a linear relationship within the range of 0.20~80.00 MUg/L (r=0.998). The within-run and between-run relative standard deviations (RSD) of repetitive measurement at 5.0, 10.0, 20.0 MUg/L concentration levels were 2.1%~5.5% and 2.3%~3.0%. The detection limit was 0.06 MUg/L. The recoveries of gallium were 98.2%~101.1%. CONCLUSION: This method is simple, low detection limit, accurate, reliable and reproducible. It has been applied for determination of trace gallium in urine samples those who need occupation health examination or poisoning diagnosis. PMID- 27514564 TI - [Risk assessment on occupational exposure to sulfuric acid and sodiumhydroxide in workplace]. PMID- 27514565 TI - [Standardization of medical report for occupational physical examination in Gansu Province]. PMID- 27514566 TI - [Problems and countermeasures in the implementation of Technical Specifications for Occupational Health Surveillance on noise-exposed workers]. PMID- 27514567 TI - [The principle and application of TCR gene mutation test]. PMID- 27514569 TI - Hybrid Copper-Silver Conductive Tracks for Enhanced Oxidation Resistance under Flash Light Sintering. AB - We developed a simple method to prepare hybrid copper-silver conductive tracks under flash light sintering. The developed metal nanoparticle-based ink is convenient because its preparation process is free of any tedious washing steps. The inks were composed of commercially available copper nanoparticles which were mixed with formic acid, silver nitrate, and diethylene glycol. The role of formic acid is to remove the native copper oxide layer on the surface of the copper nanoparticles. In this way, it facilitates the formation of a silver outer shell on the surface of the copper nanoparticles through a galvanic replacement. In the presence of formic acid, the copper nanoparticles formed copper formate, which was present in the unsintered tracks. However, under illumination by a xenon flash light, the copper formate was then converted to copper. Moreover, the resistance of the copper-only films increased by 6 orders of magnitude when oxidized at high temperatures (~220 degrees C). However, addition of silver nitrate to the inks suppressed the oxidation of the hybrid copper-silver films, and the resistance changes in these inks at high temperatures were greatly reduced. In addition, the hybrid inks proved to be advantageous for use in electrical circuits as they demonstrated a stable electrical conductivity after exposure to ambient air at 180 degrees C. PMID- 27514568 TI - Reliability and validity of the patient disability-oriented diagnostic nomenclature system for prosthetic dentistry. AB - PURPOSE: The Japan Prosthodontic Society (JPS) has proposed a new diagnostic nomenclature system (DNS), based on pathogenesis and etiology, to facilitate and improve prosthodontic treatment. This system specifies patient disability and the causative factor (i.e. "B (disability) caused by A (causative factor)"). The purpose of this study was to examine the reliability and validity of this DNS. STUDY SELECTION: The JPS Clinical Guideline Committee assessed mock patient charts and formulated disease names using the new DNS. Fifty validators, comprising prosthodontic specialists and dental residents, made diagnoses using the same patient charts. Reliability was evaluated as the consistency of the disease names among the validators, and validity was evaluated using the concordance rate of the disease names with the reference disease names. RESULTS: Krippendorff's alpha was 0.378 among all validators, 0.370 among prosthodontic specialists, and 0.401 among dental hospital residents. Krippendorff's alpha for 10 validators (3 specialists and 7 residents) with higher concordance rates was 0.524. Two validators (1 specialist and 1 resident) with the highest concordance rates had a Krippendorff's alpha of 0.648. Common disease names had higher concordance rates, while uncommon disease names showed lower concordance rates. These rates did not show correlation with clinical experience of the validator or time taken to devise the disease name. CONCLUSIONS: High reliability was not found among all validators; however, validators with higher concordance rates showed better reliability. Furthermore, common disease names had higher concordance rates. These findings indicate that the new DNS for prosthodontic dentistry exhibits clinically acceptable reliability and validity. PMID- 27514570 TI - Diffusion kurtosis imaging study on temporal lobe after nasopharyngeal carcinoma radiotherapy. AB - PURPOSE: Diffusion kurtosis imaging (DKI) is a MRI technique which can measure alterations in the diffusion of water molecules to reflect tissue changes in both white and grey matter. This study evaluated the potential of DKI for the early diagnosis of radiation-induced temporal lobe changes in the grey and white matter of the temporal lobe in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Sixty patients with NPC who had normal MRI brain scans were enrolled and underwent DKI at 1 week (n=20), 6 months (n=20) or 1 year (n=20) after radiotherapy; 20 normal control individuals were also evaluated. Nonlinear fitting routines and equations were used to calculate mean diffusion (MD) and mean kurtosis (MK) and fractional anisotropy (FA). Analysis of variance was used to compare the MK/MD/FA values of white and grey matter between groups. RESULTS: Compared to the normal control group, grey and white matter MK values were significantly higher at 1 week after radiotherapy and significantly lower at 6 months and 1 year after radiotherapy in patients with NPC, whereas the grey and white matter MD values were significantly lower at 1 week after radiotherapy and returned to normal by 6 months and 1 year after radiotherapy. CONCLUSION: DKI can be used to detect radiotherapy-induced changes in both the white and grey matter of temporal lobe in patients with NPC. MK and MD values may represent reliable indicators for the early diagnosis of radiation-induced temporal lobe changes in NPC. PMID- 27514571 TI - Eppur Si Muove: The dynamic nature of physiological control of renal blood flow by the renal sympathetic nerves. AB - Tubuloglomerular feedback and the myogenic response are widely appreciated as important regulators of renal blood flow, but the role of the sympathetic nervous system in physiological renal blood flow control remains controversial. Where classic studies using static measures of renal blood flow failed, dynamic approaches have succeeded in demonstrating sympathetic control of renal blood flow under normal physiological conditions. This review focuses on transfer function analysis of renal pressure-flow, which leverages the physical relationship between blood pressure and flow to assess the underlying vascular control mechanisms. Studies using this approach indicate that the renal nerves are important in the rapid regulation of the renal vasculature. Animals with intact renal innervation show a sympathetic signature in the frequency range associated with sympathetic vasomotion that is eliminated by renal denervation. In conscious rabbits, this sympathetic signature exerts vasoconstrictive, baroreflex control of renal vascular conductance, matching well with the rhythmic, baroreflex-influenced control of renal sympathetic nerve activity and complementing findings from other studies employing dynamic approaches to study renal sympathetic vascular control. In this light, classic studies reporting that nerve stimulation and renal denervation do not affect static measures of renal blood flow provide evidence for the strength of renal autoregulation rather than evidence against physiological renal sympathetic control of renal blood flow. Thus, alongside tubuloglomerular feedback and the myogenic response, renal sympathetic outflow should be considered an important physiological regulator of renal blood flow. Clinically, renal sympathetic vasomotion may be important for solving the problems facing the field of therapeutic renal denervation. PMID- 27514572 TI - Association of testosterone and BDNF serum levels with craving during alcohol withdrawal. AB - Preclinical and clinical studies show associations between testosterone and brain derived neurotrophic growth factor (BDNF) serum levels. BDNF and testosterone have been independently reported to influence alcohol consumption. Therefore, we aimed to investigate a possible interplay of testosterone and BDNF contributing to alcohol dependence. Regarding possible interplay of testosterone and BDNF and the activity of the hypothalamic pituitary axis (HPA), we included cortisol serum levels in our research. We investigated testosterone and BDNF serum levels in a sample of 99 male alcohol-dependent patients during alcohol withdrawal (day 1, 7, and 14) and compared them to a healthy male control group (n = 17). The testosterone serum levels were significantly (p < 0.001) higher in the patients' group than in the control group and decreased significantly during alcohol withdrawal (p < 0.001). The decrease of testosterone serum levels during alcohol withdrawal (days 1-7) was significantly associated with the BDNF serum levels (day 1: p = 0.008). In a subgroup of patients showing high cortisol serum levels (putatively mirroring high HPA activity), we found a significant association of BDNF and testosterone as well as with alcohol craving measured by the Obsessive and Compulsive Drinking Scale (OCDS). Our data suggest a possible association of BDNF and testosterone serum levels, which may be relevant for the symptomatology of alcohol dependence. Further studies are needed to clarify our results. PMID- 27514573 TI - Effect of electrolytic lesions of the dorsal diencephalic conduction system on the distribution of Fos-like immunoreactivity induced by rewarding electrical stimulation. AB - The dorsal diencephalic conduction system (DDC) is an important pathway of the brain reward circuitry, linking together forebrain and midbrain structures. The present work was aimed at describing the effect of a DDC lesion on the distribution of Fos-like immunoreactivity (FLIR) following intracranial self stimulation (ICSS) of the lateral hypothalamus (LH). Rats were implanted with monopolar electrodes and divided into three groups; the first two groups were trained to self-stimulate at the LH, whereas the third group received no stimulation and served as a control. Among the two groups that were trained for ICSS, one of them received a lesion at the DDC and was tested for ICSS on the subsequent 5days. On the last day of testing, control rats were placed in operant chambers without receiving any stimulation, and the remaining rats were allowed to receive the stimulation for 1h. All rats were then processed for FLIR. As previously shown, a lesion at the DDC resulted in significant attenuations of the rewarding effectiveness of LH stimulation. Results also show a higher FLIR in several reward-related areas following LH stimulation, especially in the hemisphere ipsilateral to the stimulation electrode. Compared to non-lesioned rats, lesioned animals had lower FLIR in certain brain regions, suggesting that those regions that were activated by the rewarding stimulation may be functionally interconnected with the DDC. PMID- 27514574 TI - Mitochondrial changes and oxidative stress in a mouse model of Zellweger syndrome neuropathogenesis. AB - Zellweger syndrome (ZS) is a peroxisome biogenesis disorder that involves significant neuropathology, the molecular basis of which is still poorly understood. Using a mouse model of ZS with brain-restricted deficiency of the peroxisome biogenesis protein PEX13, we demonstrated an expanded and morphologically modified brain mitochondrial population. Cultured fibroblasts from PEX13-deficient mouse embryo displayed similar changes, as well as increased levels of mitochondrial superoxide and membrane depolarization; this phenotype was rescued by antioxidant treatment. Significant oxidative damage to neurons in brain was indicated by products of lipid and DNA oxidation. Similar overall changes were observed for glial cells. In toto, these findings suggest that mitochondrial oxidative stress and aberrant mitochondrial dynamics are associated with the neuropathology arising from PEX13 deficiency. PMID- 27514575 TI - Subthalamic deep brain stimulation and dopaminergic medication in Parkinson's disease: Impact on inter-limb coupling. AB - Patients with Parkinson's disease (PD) often present with bimanual coordination deficits whose exact origins remain unclear. One aspect of bimanual coordination is inter-limb coupling. This is characterized by the harmonization of movement parameters between limbs. We assessed different aspects of bimanual coordination in patients with PD, including inter-limb coupling, and determined whether they are altered by subthalamic (STN) deep brain stimulation (DBS) or dopaminergic medication. Twenty PD patients were tested before STN DBS surgery; with and without medication. Post- surgery, patients were tested with their stimulators on and off as well as with and without medication. Patients were asked to perform a unimanual and bimanual rapid repetitive diadochokinesis task. The difference in mean amplitude and mean duration of cycles between hands was computed in order to assess inter-limb coupling. Also, mean angular velocity of both hands and structural coupling were computed for the bimanual task. There was a positive effect of medication and stimulation on mean angular velocity, which relates to clinical improvement. PD patients exhibited temporal inter-limb coupling that was not altered by either medication or STN stimulation. However, PD patients did not exhibit spatial inter-limb coupling. Again, this was not altered by medication or stimulation. Collectively, the results suggest that structures independent of the dopaminergic system and basal ganglia may mediate temporal and spatial inter-limb coupling. PMID- 27514576 TI - Optimisation of image reconstruction for phase-contrast x-ray Talbot-Lau imaging with regard to mechanical robustness. AB - X-ray grating-based phase-contrast imaging opens new opportunities, inter alia, in medical imaging and non-destructive testing. Because, information about the attenuation properties and about the refractive properties of an object are gained simultaneously. Talbot-Lau imaging requires the knowledge of a reference or free-field image. The long-term stability of a Talbot-Lau interferometer is related to the time span of the validity of a measured reference image. It would be desirable to keep the validity of the reference image for a day or longer to improve feasibility of Talbot-Lau imaging. However, for example thermal and other long-term external influences result in drifting effects of the phase images. Therefore, phases are shifting over time and the reference image is not valid for long-term measurements. Thus, artifacts occur in differential phase-contrast images. We developed an algorithm to determine the differential phase-contrast image with the help of just one calibration image, which is valid for a long time period. With the help of this algorithm, called phase-plane-fit method, it is possible to save measurement-time, as it is not necessary to take a reference image for each measurement. Additionally, transferring the interferometer technique from laboratory setups to conventional imaging systems the necessary rigidity of the system is difficult to achieve. Therefore, short-term effects like vibrations or distortions of the system lead to imperfections within the phase-stepping procedure. Consequently, artifacts occur in all three image modalities (differential phase-contrast image, attenuation image and dark-field image) of Talbot-Lau imaging. This is a problem with regard to the intended use of phase-contrast imaging for example in clinical routine or non-destructive testing. In this publication an algorithm of Vargas et al is applied and complemented to correct inaccurate phase-step positions with the help of a principal component analysis (PCA). Thus, it is possible to calculate the artifact free images. Subsequently, the whole algorithm is called PCA minimization algorithm. PMID- 27514577 TI - Sequences and expression of pathway-specific complement components in developing red-tailed phascogale (Phascogale calura). AB - Marsupials are born immunologically premature, relying on cells and molecules in maternal milk for immune protection. Both immunoglobulin and complement proteins have been identified in marsupial milk, but the expression of specific complement proteins remains largely unexplored. We report partial cDNA sequences for two complement-activating proteins, C3, C1r, CFP and MASP2, in liver tissues from red tailed phascogale (Phascogale calura). Conservation of functionally relevant motifs were identified in the translated cDNA sequences from phascogale C3, CFP and MASP2 and their eutherian homologues. Gene expression of representative molecules from each of the major complement pathways was also investigated in whole body tissues from 1 to 18 day old animals and liver tissues from 31-day to 14-month old animals. Average complement expression in whole bodies and liver tissues of C1r, CFP, MASP2 and C3 increased significantly in juveniles compared to pouch young, presumably due to the maturation of the young's own complement system. Comparing expression in liver tissues only, we found that the average CFP expression were higher in pouch young compared to juveniles, while results were still statistically similar to the average expression of all tissues for C1r, MASP2 and C3. The average complement expression then significantly decreased as the animals aged into adulthood. PMID- 27514578 TI - Dementia after Three Months and One Year from Stroke: New Onset or Previous Cognitive Impairment? AB - OBJECTIVE: Stroke is an important risk factor for dementia, but the exact mechanism involved in cognitive decline remains unclear. METHODS: Patients were divided into 2 groups: poststroke dementia group (PSD) and poststroke nondementia group (PSND). Variables and neuroradiological hallmarks were compared between 2 groups at 3 months (114 subjects) and 1 year (105 subjects) after stroke. RESULTS: Older age (OR 1.11, 95% CI 1.0-1.2; P < .05), education (OR .6, 95% CI .4-.8; P < .05), prestroke IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly; OR .78, 95% CI .1-5.9; P < .05), premorbid apathy (OR 2.03, 95% CI 1.1-3.7; P < .05), and medial temporal lobe atrophy (MTLA) (OR 6.14, 95% CI 1.4-26.2; P < .05) were independently associated with PSD at 3 months after a cerebrovascular event, whereas at 1-year follow-up older age (OR 1.1, 95% CI 1.0 1.2; P < .05), prestroke IQCODE (OR .05, 95% CI .0-.9; P < .05), MTLA (OR 1.3, 95% CI 1.0-1.6; P < .05), and APACHE II (Acute Physiology and Chronic Health Evaluation; OR .6, 95% CI .4-.9; P < .05) were independently associated with PSD. CONCLUSIONS: Acute cerebrovascular disease could not be the only one mechanism explaining PSD. Neurodegenerative pathology must be taken into account. PMID- 27514579 TI - Comparison of Baseline Heart Rate Variability in Stable Ischemic Heart Disease Patients with and without Stroke in Long-Term Observation. AB - GOAL: Decreased heart rate variability (HRV) has predictive value in postinfarction as well as in ischemic stroke patients. However, it is unknown if ischemic heart disease (IHD) patients who are at high risk of stroke have different HRV profile. The goal of this study was to compare baseline HRV (traditional and novel indices) in stable IHD patients with and without stroke in long-term observation. METHODS: A total of 139 consecutive patients with stable IHD scheduled for coronary angiography were enrolled. Five-minute electrocardiogram readings were taken. Traditional and novel HRV measures were calculated. After 70.06 +/- 4.297 months of follow-up, baseline HRV indices in patients who had had a stroke were compared with indices in patients without the aforementioned cerebrovascular event. RESULTS: During follow-up, 6 patients developed stroke. Compared to patients without such a cerebrovascular event, these patients with stroke had lower values for the following HRV indices: de Hann long-term irregularity (30,521 +/- 32,767 versus 46,678 +/- 25,328; P < .05), Yeh interval index (.0207 +/- .0208 versus .0326 +/- .0157; P < .05), Organ BAND (3.0563 +/- 3.328 versus 4.515 +/- 2.276; P < .05), Dalton standard deviation (SD) (17,887 +/- 17,636 versus 29,859 +/- 16,478; P < .05), Zugaib short-term variability (.004 +/- .00416 versus .00622 +/- .00418; P < .05), Zugaib long-term variability (.0161 +/- .0151 versus .0247 +/- .0115; P < .05), standard deviation of all NN intervals (8,954 +/- 8,812 versus 16,724 +/- 11,594; P < .05), total power (2,616 +/- 4,855 versus 4,678 +/- 4,653; P < .05), w2 (.71 +/- .338 versus 1.719 +/- 1.08; P < .05), w3 (1.399 +/- .924 versus 2.552 +/- 1.609; P < .05), and w4 (1.367 +/- 1.705 versus 2.824 +/- 2.027; P < .05). No significant differences in other analyzed indices were observed. CONCLUSIONS: Patients with IHD and stroke in long-term observation have different baseline profiles of HRV indices. Further investigations are needed to assess the usefulness of HRV analysis in stroke risk assessment. PMID- 27514580 TI - Stroke Laterality Bias in the Management of Acute Ischemic Stroke. AB - BACKGROUND: Little is known of the impact of stroke laterality on the management process and outcome of patients with acute ischemic stroke (AIS). METHODS: Consecutive patients admitted to a general hospital over 1 year with supratentorial AIS were eligible for inclusion in the study. Baseline characteristics and risk factors, delays in hospital admission, imaging, intrahospital transfer to an acute stoke unit, stroke severity and classification, length of hospital admission, as well as 10-year mortality were measured and compared among right and left hemisphere AIS patients. RESULTS: There were 141 patients (77 men, 64 women; median age 73 [interquartile range 63 79] years), There were 71 patients with left hemisphere AIS and 70 with right hemisphere AIS. Delays to hospital admission from stroke onset to neuroimaging were similar among right and left hemisphere AIS patients. Delay in transfer to an acute stroke unit (ASU) following hospital admission was on average 14 hours more for right hemisphere compared to left hemisphere AIS patients (P = .01). Laterality was not associated with any difference in 10-year survival. CONCLUSIONS: Patients with mild and nondominant AIS merit particular attention to minimize their intrahospital transfer time to an ASU. PMID- 27514581 TI - Cerebral Air Embolism with Pneumomediastinum Resulting from Emesis: A Case Report. AB - Cerebral air embolism (CAE) is a rare cause of stroke. Most cerebral air emboli are caused by iatrogenic factors, such as invasive cardiac and pulmonary procedures. Here, we report an unusual case of CAE not related to any medical intervention. An 87-year-old woman became unresponsive after vomiting. A computed tomography (CT) scan of the head 6 hours after the onset of the vomiting revealed multiple air emboli, mainly in the watershed area between the right anterior and middle cerebral arteries. Magnetic resonance imaging with T2* gradient echo showed the air emboli as granular hypointensities. Diffusion-weighted imaging revealed an area of hyperintensity along the cortical region of the right frontal lobe. Head CT scans showed that the size and number of the air emboli rapidly decreased on day 2 and disappeared on day 9. We also performed a chest CT and found pneumomediastinum, which gradually improved over the clinical course. We also found pulmonary fibrosis and bronchiectasis, suggesting an underlying pulmonary vulnerability. In this case, the emesis may have been a trigger for the CAE, which was followed by pneumomediastinum. This case suggests that CAE can occur in a noniatrogenic situation, especially in a patient with pulmonary vulnerability. PMID- 27514582 TI - Computational neuroanatomy using brain deformations: From brain parcellation to multivariate pattern analysis and machine learning. AB - The past 20 years have seen a mushrooming growth of the field of computational neuroanatomy. Much of this work has been enabled by the development and refinement of powerful, high-dimensional image warping methods, which have enabled detailed brain parcellation, voxel-based morphometric analyses, and multivariate pattern analyses using machine learning approaches. The evolution of these 3 types of analyses over the years has overcome many challenges. We present the evolution of our work in these 3 directions, which largely follows the evolution of this field. We discuss the progression from single-atlas, single registration brain parcellation work to current ensemble-based parcellation; from relatively basic mass-univariate t-tests to optimized regional pattern analyses combining deformations and residuals; and from basic application of support vector machines to generative-discriminative formulations of multivariate pattern analyses, and to methods dealing with heterogeneity of neuroanatomical patterns. We conclude with discussion of some of the future directions and challenges. PMID- 27514583 TI - Research Methods in Healthcare Epidemiology: Survey and Qualitative Research. AB - Surveys are one of the most frequently employed study designs in healthcare epidemiology research. Generally easier to undertake and less costly than many other study designs, surveys can be invaluable to gain insights into opinions and practices in large samples and may be descriptive and/or be used to test associations. In this context, qualitative research methods may complement this study design either at the survey development phase and/or at the interpretation/extension of results stage. This methods article focuses on key considerations for designing and deploying surveys in healthcare epidemiology and antibiotic stewardship, including identification of whether or not de novo survey development is necessary, ways to optimally lay out and display a survey, denominator measurement, discussion of biases to keep in mind particularly in research using surveys, and the role of qualitative research methods to complement surveys. We review examples of surveys in healthcare epidemiology and antimicrobial stewardship and review the pros and cons of methods used. A checklist is provided to help aid design and deployment of surveys in healthcare epidemiology and antimicrobial stewardship. Infect Control Hosp Epidemiol 2016;1 6. PMID- 27514585 TI - Optic nerve sheath diameter on computed tomography not predictive of neurological status post-cardiac arrest. AB - OBJECTIVE: Optic nerve sheath diameter (ONSD) measured on a head computed tomography (CT) has been suggested as a potential prognostic factor for poor neurological outcome after cardiac arrest. We performed a single centre retrospective cohort analysis to further investigate this relationship. METHODS: All patients >18 years of age admitted to St. Paul's Hospital in Vancouver, Canada who survived a cardiac arrest and had a CT scan of the head within 48 hours were included in the analysis. RESULTS: A total of 72 patients met inclusion criteria for the study; 54 (75.0%) of the patients had a poor neurological outcome, whereas 18 (25.0%) patients were discharged from the hospital with a good outcome. A CT head was obtained for patients in the good outcome group in a mean time of 9.3 hours (SD 10.0) compared to 10.2 hours (SD 11.2) for the poor outcome group (p=0.75). There was no difference in average ONSD observed between the two outcome groups (6.66 mm SD 0.78 v. 6.60 mm SD 0.82, p=0.77). Multiple logistic regression failed to show any association between ONSD and neurological outcome when adjusted for all other covariates (OR 1.32 95% CI 0.40-4.34, p=0.65). Setting an ONSD threshold of >8 mm (OR 2.32, 95% CI 0.14 39.40, p=0.55) or >7 mm (OR 0.28, 95% CI 0.03-2.77, p=0.28) also failed to show any association on neurological outcome. CONCLUSION: There was no observed difference in ONSD between those with a good neurological outcome and those with a poor outcome. ONSD was not an independent predictor of poor neurological outcome. PMID- 27514584 TI - RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells. AB - RUNX1 is a transcription factor functioning both as an oncogene and a tumor suppressor in breast cancer. RUNX1 alters chromatin structure in cooperation with chromatin modifier and remodeling enzymes. In this study, we examined the relationship between RUNX1-mediated transcription and genome organization. We characterized genome-wide RUNX1 localization and performed RNA-seq and Hi-C in RUNX1-depleted and control MCF-7 breast cancer cells. RNA-seq analysis showed that RUNX1 depletion led to up-regulation of genes associated with chromatin structure and down-regulation of genes related to extracellular matrix biology, as well as NEAT1 and MALAT1 lncRNAs. Our ChIP-Seq analysis supports a prominent role for RUNX1 in transcriptional activation. About 30% of all RUNX1 binding sites were intergenic, indicating diverse roles in promoter and enhancer regulation and suggesting additional functions for RUNX1. Hi-C analysis of RUNX1 depleted cells demonstrated that overall three-dimensional genome organization is largely intact, but indicated enhanced association of RUNX1 near Topologically Associating Domain (TAD) boundaries and alterations in long-range interactions. These results suggest an architectural role for RUNX1 in fine-tuning local interactions rather than in global organization. Our results provide novel insight into RUNX1-mediated perturbations of higher-order genome organization that are functionally linked with RUNX1-dependent compromised gene expression in breast cancer cells. PMID- 27514586 TI - Lymphangioleiomyomatosis. AB - Lymphangioleiomyomatosis is a rare multisystem disease predominantly affecting women that can occur sporadically or in association with tuberous sclerosis. Lung cysts progressively replace the lung parenchyma, which leads to dyspnea, recurrent pneumothorax, and in some cases respiratory failure. Patients may also have lymphatic disease in the thorax, abdomen, and pelvis, and renal angiomyolipomas. Treatment includes supportive care, bronchodilators, and for those with progressive disease, mammalian target of rapamycin (mTOR) inhibitors. PMID- 27514587 TI - Plastic Bronchitis. AB - Plastic bronchitis is an uncommon and probably underrecognized disorder, diagnosed by the expectoration or bronchoscopic removal of firm, cohesive, branching casts. It should not be confused with purulent mucous plugging of the airway as seen in patients with cystic fibrosis or bronchiectasis. Few medications have been shown to be effective and some are now recognized as potentially harmful. Current research directions in plastic bronchitis research include understanding the genetics of lymphatic development and maldevelopment, determining how abnormal lymphatic malformations contribute to cast formation, and developing new treatments. PMID- 27514588 TI - Nonmalignant Adult Thoracic Lymphatic Disorders. AB - The thoracic lymphatic disorders are a heterogeneous group of uncommon conditions that are associated with thoracic masses, interstitial pulmonary infiltrates, and chylous complications. Accurate diagnosis of the thoracic lymphatic disorders has important implications for the newest approaches to management, including embolization and treatment with antilymphangiogenic drugs. New imaging techniques to characterize lymphatic flow, such as dynamic contrast-enhanced magnetic resonance lymphangiogram, are redefining approaches to disease classification and therapy. PMID- 27514589 TI - Langerhans Cell Histiocytosis and Other Histiocytic Diseases of the Lung. AB - Several histiocytic disorders may affect the thoracic cavity. Pulmonary Langerhans cell histiocytosis (LCH) is the histiocytic disorder that most frequently manifests with thoracic involvement in adults and is associated with cigarette smoking. The histiocytic disorders follow variable clinical courses ranging from benign disease to life-threatening aggressive disorders. Although the pathogenesis is not fully understood, it is now apparent that some of these disorders are associated with activating mutations in cell proliferative/regulatory pathways. Management of these rare disorders must be individualized. Pharmacologic treatment may include the use of chemotherapeutic agents. Smoking cessation is imperative in the management of pulmonary LCH. PMID- 27514590 TI - Pulmonary Alveolar Proteinosis Syndrome. AB - Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by the accumulation of surfactant in alveoli and terminal airways resulting in respiratory failure. PAP comprises part of a spectrum of disorders of surfactant homeostasis (clearance and production). The surfactant production disorders are caused by mutations in genes required for normal surfactant production. The PAP syndrome is identified based on history, radiologic, and bronchoalveolar lavage and/or histopathologic findings. The diagnosis of PAP-causing diseases in secondary PAP requires further studies. Whole-lung lavage is the current standard therapy and promising new pharmacologic therapies are in development. PMID- 27514591 TI - Pulmonary Alveolar Microlithiasis. AB - Pulmonary alveolar microlithiasis (PAM) is a genetic lung disorder that is characterized by the accumulation of calcium phosphate deposits in the alveolar spaces of the lung. Mutations in the type II sodium phosphate cotransporter, NPT2b, have been reported in patients with PAM. PAM progresses gradually, often producing incremental dyspnea on exertion, desaturation in young adulthood, and respiratory insufficiency by late middle age. Treatment remains supportive, including supplemental oxygen therapy. For patients with end-stage disease, lung transplantation is available as a last resort. The recent development of a laboratory animal model has revealed several promising treatment approaches for future trials. PMID- 27514593 TI - Lymphocytic Interstitial Pneumonia. AB - Lymphocytic interstitial pneumonia (LIP) is a rare lung disease on the spectrum of benign pulmonary lymphoproliferative disorders. LIP is frequently associated with connective tissue diseases or infections. Idiopathic LIP is rare; every attempt must be made to diagnose underlying conditions when LIP is diagnosed. Computed tomography of the chest in patients with LIP may reveal ground-glass opacities, centrilobular and subpleural nodules, and randomly distributed thin walled cysts. Demonstrating polyclonality with immunohistochemistry is the key to differentiating LIP from lymphoma. The 5-year mortality remains between 33% and 50% and is likely to vary based on the underlying disease process. PMID- 27514594 TI - Birt-Hogg-Dube Syndrome. AB - Birt-Hogg-Dube syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the Folliculin gene and is characterized by the formation of fibrofolliculomas, early onset renal cancers, pulmonary cysts, and spontaneous pneumothoraces. The exact pathogenesis of tumor and lung cyst formation in BHD remains unclear. There is great phenotypic variability in the clinical features of BHD, and patients can present with any combination of skin, pulmonary, or renal findings. More than 80% of adult patients with BHD have pulmonary cysts on high-resolution computed tomography scan of the chest. PMID- 27514592 TI - Primary Ciliary Dyskinesia. AB - Primary ciliary dyskinesia (PCD) is a recessive genetically heterogeneous disorder of motile cilia with chronic otosinopulmonary disease and organ laterality defects in ~50% of cases. The prevalence of PCD is difficult to determine. Recent diagnostic advances through measurement of nasal nitric oxide and genetic testing has allowed rigorous diagnoses and determination of a robust clinical phenotype, which includes neonatal respiratory distress, daily nasal congestion, and wet cough starting early in life, along with organ laterality defects. There is early onset of lung disease in PCD with abnormal airflow mechanics and radiographic abnormalities detected in infancy and early childhood. PMID- 27514595 TI - alpha1-Antitrypsin Deficiency. AB - alpha1-Antitrypsin deficiency is an autosomal codominant condition that predisposes to emphysema and cirrhosis. The condition is common but grossly under recognized. Identifying patients' alpha1-antitrypsin deficiency has important management implications (ie, smoking cessation, genetic and occupational counseling, and specific treatment with the infusion of pooled human plasma alpha1-antitrypsin). The weight of evidence suggests that augmentation therapy slows the progression of emphysema in individuals with severe alpha1-antitrypsin deficiency. PMID- 27514597 TI - Hereditary Hemorrhagic Telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT) is an underrecognized and underdiagnosed autosomal-dominant angiodysplasia that has an estimated prevalence of 1 in 5000 individuals, with variable clinical presentations even within family members with identical mutations. The most common manifestations are telangiectasias of the skin and nasal mucosa. However, HHT can often be complicated by the presence of arteriovenous malformations and telangiectasias in the lungs, brain, gastrointestinal tract, and liver that are often silent and can lead to life-threatening complications of stroke and hemorrhage. This article reviews HHT for the pulmonologist, who is not uncommonly the first practitioner to encounter these patients. PMID- 27514596 TI - Hermansky-Pudlak Syndrome. AB - Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diatheses, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes, including HPS 1, HPS-2, and HPS-4. HPS pulmonary fibrosis shows many of the clinical, radiologic, and histologic features found in idiopathic pulmonary fibrosis, but occurs at a younger age. Despite knowledge of the underlying genetic defects, there are currently no definitive therapeutic or preventive approaches for HPS pulmonary fibrosis other than lung transplant. PMID- 27514598 TI - Pulmonary Capillary Hemangiomatosis and Pulmonary Veno-occlusive Disease. AB - This article provides an overview of pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH), two disorders that challenge clinicians, radiologists, and pathologists because they often mimic pulmonary arterial hypertension (PAH). The article reviews the features that differentiate PVOD and PCH from PAH. The article also describes the overlap of PVOD and PCH, highlighted by recent reports of families diagnosed with PVOD or PCH caused by EIF2AK4 mutations. In addition, the article outlines current approaches to the diagnosis and treatment of PVOD and PCH. PMID- 27514599 TI - Eosinophilic Lung Diseases. AB - Eosinophilic lung diseases especially comprise eosinophilic pneumonia or as the more transient Loffler syndrome, which is most often due to parasitic infections. The diagnosis of eosinophilic pneumonia is based on characteristic clinical imaging features and the demonstration of alveolar eosinophilia, defined as at least 25% eosinophils at BAL. Peripheral blood eosinophilia is common but may be absent at presentation in idiopathic acute eosinophilic pneumonia, which may be misdiagnosed as severe infectious pneumonia. All possible causes of eosinophilia, including drug, toxin, fungus related etiologies, must be thoroughly investigated. Extrathoracic manifestations should raise the suspicion of eosinophilic granulomatosis with polyangiitis. PMID- 27514601 TI - Immunoglobulin G4-Related Disease and the Lung. AB - Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disease with protean manifestations involving virtually any organ in the body. At initial clinical presentation, 1 or multiple organs may be involved. Initial descriptions focused on pancreatic disease. It has, however, become clear that IgG4-RD can cause an immune-mediated fibroinflammatory process, commonly manifesting as mass-like lesions, in various regions of the body including the thorax where any compartment can be involved. This pathologic process is characterized by infiltration of IgG4+ plasma cells and a propensity to fibrosis leading to organ dysfunction which can be prevented by early diagnosis and corticosteroid therapy. PMID- 27514600 TI - Hyper-IgE Syndromes and the Lung. AB - Elevated serum IgE has many etiologies including parasitic infection, allergy and asthma, malignancy, and immune dysregulation. The hyper-IgE syndromes caused by mutations in STAT3, DOCK8, and PGM3 are monogenic primary immunodeficiencies associated with high IgE, eczema, and recurrent infections. These primary immunodeficiencies are associated with recurrent pneumonias leading to bronchiectasis; however, each has unique features and genetic diagnosis is essential in guiding therapy, discussing family planning, and defining prognosis. This article discusses the clinical features of these primary immunodeficiencies with a particular focus on the pulmonary manifestations and discussion of the genetics, pathogenesis, and approaches to therapy. PMID- 27514602 TI - Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Neuroendocrine Hyperplasia of Infancy. AB - Although incidental reactive pulmonary neuroendocrine cell hyperplasia (PNECH) is seen on biopsy specimens in adults with chronic lung disease, disorders characterized by marked PNECH are rare. Primary hyperplasia of neuroendocrine cells in the lung and obstructive lung disease related to remodeling or physiologic constriction of small airways define diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) in the adult and neuroendocrine cell hyperplasia of infancy (NEHI) in children. DIPENCH and NEHI share a similar physiology, typical imaging appearance, and increased neuroendocrine cells on biopsy. However, there are important differences related to the underlying disease mechanisms leading to disparate outcomes. PMID- 27514603 TI - Benign Metastasizing Leiomyoma. AB - Benign metastasizing leiomyoma (BML) is a rare and poorly characterized disease affecting primarily premenopausal women. Asymptomatic patients are often diagnosed incidentally by radiographs or other lung-imaging procedures performed for other indications, and the diagnosis is eventually confirmed by biopsy. Patients with BML are usually treated pharmacologically with antiestrogen therapies or surgically with oophorectomy or hysterectomy. Antiestrogen therapy is typically efficacious and, in general, most patients have a favorable prognosis. Asymptomatic patients with a confirmed diagnosis of BML, may be followed conservatively without treatment. PMID- 27514604 TI - Rare Lung Diseases: Occasionally the "Horse" Has Stripes. PMID- 27514605 TI - Genitourinary infections in diabetic patients in the new era of diabetes therapy with sodium-glucose cotransporter-2 inhibitors. AB - AIMS: To review prevalence and significance of urinary tract (UTI) and genital infections (GI) in diabetes and the effects of sodium glucose cotransporter 2 (SGLT-2) inhibitors on these complications. DATA SYNTHESIS: The prevalence of asymptomatic bacteriuria (ASB) is 2-3 times higher in diabetic than in non diabetic women. The treatment of ASB has no impact on the development of UTIs and/or a decline in renal function. Therefore, there is no indication for screening for and/or treatment of ASB. The incidence of UTI is higher and frequently complicated in diabetic patients, particularly in those with longer duration of disease and of older age. There is no consistent evidence of an association between A1c levels, glycosuria and the risk of ASB and/or UTIs. Diabetes is a known risk factor for Candida colonization and GI, and a poor glycemic control is associated with a higher risk. While patients treated with SGLT-2 inhibitors may have a non-significant increased risk of UTI, they have a clearly increased risk of GI; most of these infections are mild, easy to treat, and the rate of recurrence is low. CONCLUSION: Diabetic patients are at high risk of UTIs and of GI. Only GI are associated with poor glycemic control. Although patients treated with SGLT-2 inhibitors have an increased 3-5 fold risk of GI, proper medical education can reduce this risk. PMID- 27514607 TI - Dietary fat intake modifies the influence of the FTO rs9939609 polymorphism on adiposity in adolescents: The HELENA cross-sectional study. AB - BACKGROUND AND AIMS: The fat mass and obesity associated gene (FTO) has been associated with obesity and dietary intake. The aims were: (i) To assess whether energy and macronutrient intakes were different across the FTOrs9939609 genotypes in adolescents, and (ii) to explore whether dietary fat intake modified the association of the rs9939609 polymorphism with adiposity. METHODS AND RESULTS: The FTOrs9939609 polymorphism was genotyped in 652 adolescents (53% females, 14.8 +/- 1.2 years, TT = 246, TA = 296, AA = 110). Energy and macronutrient intake were assessed by two non-consecutive 24 h-recalls. Weight, height, waist circumference and skinfold thicknesses were measured and body fat percent was calculated. Energy and macronutrient intake were similar across the FTOrs9939609 genotypes (P > 0.2). There were significant interactions between the FTO polymorphism and fat intake on adiposity estimates (P < 0.05). In adolescents whose fat intake was below 30% (N = 203), the A allele of rs9939609 was not associated with adiposity indices. In contrast, in adolescents whose fat intake was between 30% and 35% of energy (N = 190), the rs9939609 polymorphism was associated with a 1.9% higher body fat per risk allele (95%CI: 0.39, 3.33; P < 0.05), and in those whose fat intake was higher than 35% (N = 259), it was associated with a 2.8% higher body fat per risk allele (95%CI: 1.27, 4.43; P < 0.001). CONCLUSIONS: These findings support the concept that the deleterious effect of the FTOrs9939609 polymorphism on adiposity is exacerbated in adolescents consuming high fat diets. In contrast, the consumption of low fat diets (<30% of energy) may attenuate the genetic predisposition to obesity in risk allele carriers. PMID- 27514606 TI - The association of calcium supplementation and incident cardiovascular events in the Multi-ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND AND AIMS: Many US adults use calcium supplements to address inadequate dietary intake and improve bone health. However, recent reports have suggested that use of calcium supplements may elevate cardiovascular disease (CVD) risk. In this study, we examined associations between baseline calcium supplement use and incident myocardial infarction (MI) (n = 208 events) and CVD events (n = 641 events) over 10.3 years in men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 6236), with dietary calcium intake at baseline also examined as a supplementary objective. METHODS AND RESULTS: Using Cox proportional hazards models, no compelling associations between calcium intake from supplements or diet and incident CVD events were observed upon multivariate adjustment for potential confounders. An association with lower MI risk was observed comparing those with low levels of calcium supplement use (1-499 mg) to those using no calcium supplements (hazard ratio 0.69, 95% CI 0.48, 0.98, p = 0.039). Relationships were homogeneous by gender, race/ethnicity, or chronic kidney disease. Results were also similar when the analysis was limited to postmenopausal women only. CONCLUSION: Analysis of incident MI and CVD events in the MESA cohort does not support a substantial association of calcium supplement use with negative cardiovascular outcomes. PMID- 27514608 TI - Lp(a) and cardiovascular risk: Investigating the hidden side of the moon. AB - AIMS: This article reports current evidence on the association between Lp(a) and cardiovascular (CV) disease and on pathophysiological mechanisms. The available information on therapy for reduction of lipoprotein(a) is also discussed. DATA SYNTHESIS: Although some evidence is conflicting, Lp(a) seems to increase CV risk through stimulation of platelet aggregation, inhibition of tissue factor pathway inhibitor, alteration of fibrin clot structure and promotion of endothelial dysfunction and phospholipid oxidation. Lp(a) 3.5-fold higher than normal increases the risk of coronary heart disease and general CV events, particularly in those with LDL cholesterol >= 130 mg/dl. High Lp(a) values represent also an independent risk factor for ischemic stroke (more relevant in young stroke patients), peripheral artery disease (PAD) and aortic and mitral stenosis. Furthermore, high Lp(a) levels seem to be associated with increased risk of cardiovascular events in patients with chronic kidney disease, particularly in those undergoing percutaneous coronary intervention. CONCLUSIONS: Lipoprotein (a) (Lp[a]) seems to significantly influence the risk of cardiovascular events. The effects of statins and fibrates on Lp(a) are limited and extremely variable. Nicotinic acid was shown effective in reducing Lp(a) but, due to its side effects and serious adverse events during clinical trials, it is no longer considered a possible option for treatment. To date, the treatment of choice for high levels of Lp(a) in high CV risk patients is represented by LDL-Apheresis. Thanks to innovative technologies, new selectively inhibiting LPA drugs are being developed and tested. PMID- 27514609 TI - Erratum to: Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease. PMID- 27514610 TI - Heterologous expression of antigenic peptides in Bacillus subtilis biofilms. AB - BACKGROUND: Numerous strategies have been developed for the display of heterologous proteins in the surface of live bacterial carriers, which can be used as vaccines, immune-modulators, cancer therapy or bioremediation. Bacterial biofilms have emerged as an interesting approach for the expression of proteins of interest. Bacillus subtilis is a well-described, endospore-forming organism that is able to form biofilms and also used as a probiotic, thus making it a suitable candidate for the display of heterologous proteins within the biofilm. Here, we describe the use of TasA, an important structural component of the biofilms formed by B. subtilis, as a genetic tool for the display of heterologous proteins. RESULTS: We first engineered the fusion protein TasA-mCherry and showed that was widely deployed within the B. subtilis biofilms. A significant enhancement of the expression of TasA-mCherry within the biofilm was obtained when depleting both tasA and sinR genes. We subsequently engineered fusion proteins of TasA to antigenic peptides of the E. granulosus parasite, paramyosin and tropomyosin. Our results show that the antigens were well expressed within the biofilm as denoted by macrostructure complementation and by the detection of the fusion protein in both immunoblot and immunohistochemistry. In addition, we show that the recombinant endospores of B. subtilis preserve their biophysical and morphological properties. CONCLUSIONS: In this work we provide strong evidence pointing that TasA is a suitable candidate for the display of heterologous peptides, such as antigens, cytokines, enzymes or antibodies, in the B. subtilis biofilms. Finally, our data portray that the recombinant endospores preserve their morphological and biophysical properties and could be an excellent tool to facilitate the transport and the administration. PMID- 27514611 TI - Heart rate variability in chronic low back pain patients randomized to yoga or standard care. AB - BACKGROUND: Chronic pain can alter the autonomic balance with increased sympathetic activity reflected in altered heart rate variability (HRV). It has been proposed that yoga can be useful to correct the autonomic imbalance in patients with chronic pain who have reduced HRV. METHODS AND DESIGNS: In the present randomized controlled trial 62 patients with chronic low back pain associated with altered alignment of intervertebral discs (aged between 20 and 45 years, 32 males) were randomized to 2 groups. One group received yoga for 3 months while the other group carried out standard medical care based on the physician's advice. The duration was the same, i.e., 3 months. The heart rate variability and rate of respiration were assessed at baseline and at the end of 3 months. RESULTS: There was a significant difference in the baseline (pre) values between groups (p = 0.008) for respiration rate which was higher in the yoga group. The changes reported below are pre-post comparisons within each group. The yoga group showed a significant (p < 0.05; repeated measures ANOVA, post-hoc analyses) decrease in the LF power of HRV, rate of respiration and a significant increase in the HF power of HRV and in the pNN50. CONCLUSION: The results suggest that yoga practice can shift the autonomic balance towards vagal dominance in patients with chronic low back pain associated with altered alignment of intervertebral discs. TRIAL REGISTRATION: The study is registered with the Clinical Trials Registry of India ( CTRI/2012/11/003094 ) and can be accessed at. PMID- 27514612 TI - Basin entropy: a new tool to analyze uncertainty in dynamical systems. AB - In nonlinear dynamics, basins of attraction link a given set of initial conditions to its corresponding final states. This notion appears in a broad range of applications where several outcomes are possible, which is a common situation in neuroscience, economy, astronomy, ecology and many other disciplines. Depending on the nature of the basins, prediction can be difficult even in systems that evolve under deterministic rules. From this respect, a proper classification of this unpredictability is clearly required. To address this issue, we introduce the basin entropy, a measure to quantify this uncertainty. Its application is illustrated with several paradigmatic examples that allow us to identify the ingredients that hinder the prediction of the final state. The basin entropy provides an efficient method to probe the behavior of a system when different parameters are varied. Additionally, we provide a sufficient condition for the existence of fractal basin boundaries: when the basin entropy of the boundaries is larger than log2, the basin is fractal. PMID- 27514616 TI - Blister fluid and serum cytokine levels in severe sepsis in humans reflect skin dysfunction. AB - BACKGROUND: Knowledge of sepsis-related end-organ inflammation in vivo is limited. We investigated the cytokine response in skin and in serum in sepsis and its relation to multiorgan failure (MOF) and survival. METHODS: Cytokines were analysed in serum and in suction blister fluid of intact skin of 44 patients with severe sepsis and 15 healthy controls. Blister fluid and serum samples were collected within 48 h of the first sepsis-induced organ failure. This is a substudy of a larger follow-up study on wound healing in sepsis. RESULTS: Cytokine levels were higher in patients with sepsis vs. controls (interleukin [IL]-10, blisters: 65.9 vs. 4.3 pg/ml, P < 0.001, serum: 25.7 vs. 4.5 pg/ml, P = 0.004; IL-6, blisters: 41.9 vs. 0.03 pg/ml, P < 0.001, serum: 45.5 vs. 2.1 pg/ml, P < 0.001). Patients with MOF had higher levels of IL-10 (116.4 vs. 21.3 pg/ml, P = 0.015), IL-4 (0.7 vs. 0.07 pg/ml, P = 0.013) and basic fibroblast growth factor (bFGF) (25.9 vs. 9.5 pg/ml, P = 0.027) in blister fluid than patients without MOF. In blister fluid, survivors had lower levels of IL-10 (43.3 vs. 181.9 pg/ml, P = 0.024) and bFGF (15.8 vs. 31.9 pg/ml, P = 0.006) than non-survivors. In serum, survivors had higher levels of vascular endothelial growth factor (VEGF) (152.2 vs. 14.7 pg/ml, P = 0.012) and lower levels of IL-6 (38.5 vs. 91.1 pg/ml, P = 0.011) than non-survivors. The blister fluid levels of bFGF, TNF and VEGF did not correlate with the serum levels. CONCLUSIONS: Cytokine responses in skin blister fluid in patients with sepsis differed from those in healthy controls. PMID- 27514617 TI - The Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Healthy Japanese Volunteers. AB - The dosing regimen of prasugrel adjusted for Japanese patients was compared with that of clopidogrel by analyzing the pharmacokinetics and pharmacodynamics in 40 healthy Japanese subjects in a randomized, single-blind crossover study. In period 1, the subjects received either 300 mg clopidogrel or 20 mg prasugrel; after a >2-week interval (period 2), the drug was switched. Blood samples of 36 of the 40 subjects were collected for analysis of pharmacokinetics, pharmacodynamics, and CYP2C19 genotypes. The plasma concentration of the active metabolite of prasugrel increased rapidly and reached its peak 30 minutes postadministration, whereas that of the active metabolite of clopidogrel reached its peak 1 hour postadministration. The mean AUC and Cmax of the active metabolite of clopidogrel, but not those of prasugrel, were CYP2C19 genotype dependent. Prasugrel rapidly inhibited platelet aggregation, reaching its maximum effect 1 hour postadministration. Clopidogrel, on the other hand, showed maximum inhibition 2 hours postadministration. Platelet aggregation inhibition by clopidogrel was significantly lower in the poor-metabolizer subjects than in the extensive-metabolizer subjects. Overall, prasugrel inhibited platelet aggregation more rapidly and more effectively in healthy Japanese subjects than was observed for clopidogrel. PMID- 27514619 TI - Reflectance confocal microscopy as a noninvasive complementary tool in the diagnosis of psoriatic balanitis. PMID- 27514618 TI - Vaccinating with conserved Escherichia coli antigens does not alter the mouse intestinal microbiome. AB - BACKGROUND: Enterotoxigenic Escherichia coli (ETEC) causes diarrheal disease. Antigenic and structural heterogeneity among ETEC colonization factors has complicated vaccine development efforts. Identifying and characterizing conserved ETEC antigens that induce protective immunity is therefore of interest. We previously characterized three proteins (MipA, Skp, and ETEC_2479) that protected mice in an intranasal ETEC challenge model after vaccination. However, these proteins are conserved not only in multiple ETEC isolates, but also in commensal bacteria. While the impact of inactivated viral vaccines and live-attenuated bacterial vaccines on the host microbiota have been examined, the potential impact of using subunit vaccines consisting of antigens that are also encoded by commensal organisms has not been investigated. FINDINGS: We addressed this issue by characterizing changes to mouse intestinal microbiomes as a function of vaccination. We failed to observe significant changes to mouse health, to mouse weight gain as a function of time, or to the diversity or richness of mouse intestinal microbiomes, as measured by analyzing alpha- and beta-diversity, as well as overall community structure, before and after vaccination. CONCLUSIONS: We conclude that despite the conservation of MipA, Skp, and ETEC_2479 among Gram negative bacteria, vaccination with these antigens fails to alter significantly the host intestinal microbiome. PMID- 27514620 TI - Parental attitudes towards measles vaccination in the canton of Aargau, Switzerland: a latent class analysis. AB - BACKGROUND: Despite the successes of routine national childhood vaccination programmes, measles remains a public health concern. The purpose of this paper is to investigate how patterns of parental attitudes are linked to the decision making process for or against MMR vaccination. This exploratory study was designed to identify distinct patterns of attitudes towards or against measles vaccination through Latent Class Analysis (LCA) in a sub-sample of mothers living in the canton of Aargau in Switzerland. METHODS: Parents of young children below 36 months of age were randomly selected through parents' counsellors' registries. Among other questions, respondents were asked to state their agreement in response to 14 belief statements regarding measles vaccination on a 5-point Likert scale. To identify groups of parents showing distinct patterns of attitudes and beliefs regarding measles vaccination, we used Latent Class Analysis (LCA). RESULTS: The LCA showed three classes of parents with different attitudes and believes towards measles vaccination: The biggest group (class 1) are those having positive attitudes towards immunisation, followed by the second biggest group (class 2) which is characterised by having fearful attitudes and by showing uncertainty about immunisation. The third group (class 3) shows distinct patterns of critical attitudes against immunisation. Within this group over 90 % agree or totally agree that immunisation is an artificial intrusion into the natural immune system and therefore want to vaccinate their children only if necessary. CONCLUSION: We find that parents in the Canton Aargau who hesitate to vaccinate their children against measles, mumps and rubella show distinct opinions and attitudes. Health professionals should be aware of these perceptions to tailor their messages accordingly and positively influence these parents to vaccinate their children. Special attention needs to be given to those parents who are planning to vaccinate their children but are not following the national guidelines. PMID- 27514622 TI - Transthyretin Cardiac Amyloidosis: From Rare Monogenic Disease to Common Pathway in Heart Failure? PMID- 27514621 TI - Household air pollution and the lung microbiome of healthy adults in Malawi: a cross-sectional study. AB - BACKGROUND: Domestic combustion of biomass fuels, such as wood, charcoal, crop residue and dung causes Household Air Pollution (HAP). These inhaled particulates affect more than half of the world's population, causing respiratory problems such as infection and inflammatory lung disease. We examined whether the presence of black carbon in alveolar macrophages was associated with alterations in the lung microbiome in a Malawi population. METHODS: Bronchoalveolar lavage samples from 44 healthy adults were sequenced using 16S rDNA amplification to assess microbial diversity, richness and relative taxa abundance. Individuals were classified as high or low particulate exposure as determined by questionnaire and the percentage of black carbon within their alveolar macrophages. RESULTS: Subjects in the low and high particulate groups did not differ in terms of source of fuels used for cooking or lighting. There was no difference in alpha or beta diversity by particulate group. Neisseria and Streptococcus were significantly more abundant in samples from high particulate exposed individuals, and Tropheryma was found less abundant. Petrobacter abundance was higher in people using biomass fuel for household cooking and lighting, compared with exclusive use of electricity. CONCLUSIONS: Healthy adults in Malawi exposed to higher levels of particulates have higher abundances of potentially pathogenic bacteria (Streptococcus, Neisseria) within their lung microbiome. Domestic biomass fuel use was associated with an uncommon environmental bacterium (Petrobacter) associated with oil-rich niches. PMID- 27514623 TI - Immunosuppressive Therapy and Interferon-1beta in Acute Myocarditis. PMID- 27514624 TI - Atrioventricular Conduction Disorder as a First Manifestation of Arrhythmogenic Right Ventricular Dysplasia. PMID- 27514625 TI - Complex Coarctation and Anomalous Right Subclavian Artery. PMID- 27514626 TI - Introduction. PMID- 27514627 TI - Non-vitamin K oral anticoagulant treatment in elderly patients with atrial fibrillation and coronary heart disease. AB - Atrial fibrillation (AF) is the most frequent sustained arrhythmia. Overall prevalence is estimated to 5.5% and the incidence increases with age. As the population ages, the prevalence and costs of AF are expected to increase. AF is the most important cause of stroke in patients >75years. Until recently, Vitamin K antagonists (VKAs) were the only available oral anticoagulants (OACs) evaluated for long-term treatment of patients with AF with or without coronary heart disease (CHD). This situation was challenged by introduction of non-VKA oral anticoagulants (NOACs). In AF, use of NOACs seems to be as effective and safe as VKAs, especially in elderly patients. AF and CHD are frequently associated and the question of antithrombotic management in aging patients is delicate. In elderly patients experiencing a new AF episode after an acute coronary syndrome, triple antithrombotic therapy should be as short as possible in order to decrease the risk of major bleedings. To date, there is no specific study or available guidelines regarding the NOACs use specifically in elderly patients experiencing both AF and CHD. In this review, we try to provide a perspective on NOACs future incorporation into clinical practice in elderly patients with both AF and CHD. PMID- 27514628 TI - Invasive versus conservative strategy in acute coronary syndromes: The paradox in women's outcomes. AB - BACKGROUND: We explored benefits and risks of an early invasive compared with a conservative strategy in women versus men after non-ST elevation acute coronary syndromes (NSTE-ACS) using the ISACS-TC database. METHODS: From October 2010 to May 2014, 4145 patients were diagnosed as having a NSTE-ACS. We excluded 258 patients managed with coronary bypass surgery. Of the remaining 3887 patients, 1737 underwent PCI (26% women). The primary endpoint was the composite of 30-day mortality and severe left ventricular dysfunction defined as an ejection fraction <40% at discharge. RESULTS: Women were older and more likely to exhibit more risk factors and Killip Class >=2 at admission as compared with men. In patients who underwent PCI, peri-procedural myocardial injury was not different among sexes (3.1% vs. 3.2%). Women undergoing PCI experienced higher rates of the composite endpoint (8.9% vs. 4.9%, p=0.002) and 30-day mortality (4.4% vs. 2.0%, p=0.008) compared with men, whereas those who managed with only routine medical therapy (RMT) did not show any sex difference in outcomes. In multivariable analysis, female sex was associated with favorable outcomes (adjusted HR for the composite endpoint: 0.72, 95% CI: 0.58-0.91) in patients managed with RMT, but not in those undergoing PCI (adjusted HR: 0.96, 95% CI: 0.61-1.52). CONCLUSIONS: We observed a more favorable outcome in women than men when patients were managed with RMT. Women and men undergoing PCI have similar outcomes. These data suggest caution in extrapolating the results from men to women in an overall population of patients in the context of different therapeutic strategies. PMID- 27514630 TI - The effects of caregiver and household HIV on child development: a community based longitudinal study of young children. AB - OBJECTIVE: Many studies that document child outcomes in the context of parental HIV - which has been established as a risk factor for child development - focus on older children/adolescents. Studies also concentrate on the status of the primary caregiver, not other household members who might be infected. DESIGN: This study examined the effects of caregiver and household HIV on child development (4-13 years) in South Africa and Malawi (2011-2014). METHODS: Data were gathered from 989 children and their primary caregivers at baseline and repeated at 12-15 months follow-up (86.5% follow-up rate). Only caregivers of a single child and caregiver/child dyads without missing data were included, providing a sample of 808 dyads for analysis. Children were divided into three groups according to caregiver-reported HIV burden: having an HIV-positive primary caregiver (19.8%), having HIV in the household (14.2%) or no HIV (66%). RESULTS: The HIV burden was positively associated with an array of negative child outcomes, often mediated by caregiver depression levels. Family HIV burden at baseline affected child behavioural problems at follow-up indirectly through carer depression (B = 0.02; CI = 0.003, 0.06). Internalizing (B = 0.02; CI = 0.002, 0.05) and externalizing problems at follow-up (B = 0.01; CI = 0.0002, 0.03) were also indirectly affected by family HIV burden through caregiver depression. CONCLUSIONS: The data suggest that family HIV can affect child development, emphasizing the important role of depression in the pathway to such an effect. Community-based interventions directed at alleviating parental depression in the presence of HIV may help to interrupt the cycle of family HIV and adverse child outcomes. PMID- 27514631 TI - A public health perspective to environmental barriers and accessibility problems for senior citizens living in ordinary housing. AB - BACKGROUND: Housing environments that hinder performance of daily activities and impede participation in social life have negative health consequences particularly for the older segment of the population. From a public health perspective accessible housing that supports active and healthy ageing is therefore crucial. The objective of the present study was to make an inventory of environmental barriers and investigate accessibility problems in the ordinary housing stock in Sweden as related to the functional capacity of senior citizens. Particular attention was paid to differences between housing types and building periods and to identify environmental barriers generating the most accessibility problems for sub-groups of senior citizens. METHODS: Data on environmental barriers in dwellings from three databases on housing and health in old age was analysed (N = 1021). Four functional profiles representing large groups of senior citizens were used in analyses of the magnitude and severity of potential accessibility problems. Differences in terms of type of housing and building period were examined. RESULTS: High proportions of one-family houses as well as multi-dwellings had substantial numbers of environmental barriers, with significantly lower numbers in later building periods. Accessibility problems occurred already for senior citizens with few functional limitations, but more profound for those dependent on mobility devices. The most problematic housing sections were entrances in one-family houses and kitchens of multi-dwellings. CONCLUSIONS: Despite a high housing standard in the Swedish ordinary housing stock the results show substantial accessibility problems for senior citizens with functional limitations. To make housing accessible large-scale and systematic efforts are required. PMID- 27514632 TI - Immediate and early complications of the open Latarjet procedure: a retrospective review of a large consecutive case series. AB - BACKGROUND: Immediate and early postoperative complications of the Latarjet procedure are not well documented in the literature. The purpose of this study was to report the procedure-related complications of our large consecutive case series of 3 surgeons at a single high-volume center. METHODS: We conducted a retrospective chart review of 416 Latarjet procedures performed on 400 patients (16 patients had bilateral procedures) who underwent surgery by the 3 senior authors from October 2002 to July 2015. Immediate and early complications included hardware problems, infection, and neurologic injury. In addition, the patient's age and history of prior instability surgery were noted and evaluated as risk factors for complication. RESULTS: The overall complication rate was 5.0% (21 complications in 19 procedures). Thirteen neurologic injuries (3.1%) occurred to the axillary (7), musculocutaneous (4), and suprascapular (2) nerves, including 2 patients with multiple nerves affected. All but 2 patients had complete resolution of symptoms at time of last follow-up. Six infections (1.4%) developed, including 3 superficial infections treated with oral antibiotics and 3 deep infections requiring irrigation and debridement with intravenous antibiotics. Two early hardware-related complications (0.05%) were also noted. Increased age was associated with a higher complication rate. History of prior surgery was not associated with increased complications in our series. CONCLUSIONS: This study highlights the procedural complications of the Latarjet procedure. Neurologic injury was the most common complication in our series, with complete or near-complete recovery in 11 of 13 patients. PMID- 27514629 TI - A randomised controlled trial of adjunctive yoga and adjunctive physical exercise training for cognitive dysfunction in schizophrenia. AB - BACKGROUND: Yoga and physical exercise have been used as adjunctive intervention for cognitive dysfunction in schizophrenia (SZ), but controlled comparisons are lacking. Aims A single-blind randomised controlled trial was designed to evaluate whether yoga training or physical exercise training enhance cognitive functions in SZ, based on a prior pilot study. METHODS: Consenting, clinically stable, adult outpatients with SZ (n=286) completed baseline assessments and were randomised to treatment as usual (TAU), supervised yoga training with TAU (YT) or supervised physical exercise training with TAU (PE). Based on the pilot study, the primary outcome measure was speed index for the cognitive domain of 'attention' in the Penn computerised neurocognitive battery. Using mixed models and contrasts, cognitive functions at baseline, 21 days (end of training), 3 and 6 months post-training were evaluated with intention-to-treat paradigm. RESULTS: Speed index of attention domain in the YT group showed greater improvement than PE at 6 months follow-up (p<0.036, effect size 0.51). In the PE group, 'accuracy index of attention domain showed greater improvement than TAU alone at 6-month follow-up (p<0.025, effect size 0.61). For several other cognitive domains, significant improvements were observed with YT or PE compared with TAU alone (p<0.05, effect sizes 0.30-1.97). CONCLUSIONS: Both YT and PE improved attention and additional cognitive domains well past the training period, supporting our prior reported beneficial effect of YT on speed index of attention domain. As adjuncts, YT or PE can benefit individuals with SZ. PMID- 27514633 TI - Introducing the Surgical Therapeutic Index in trauma surgery: an assessment tool for the benefits and risks of operative fracture treatment strategies. AB - BACKGROUND: The Surgical Therapeutic Index (STI) has been described as an indicator of the benefits and risks of surgical treatment. The index is calculated by dividing the cure rate of an operative treatment by the complication rate. This study introduces the STI in trauma surgery by comparing the indices for surgical plate fixation (PF) and intramedullary fixation (IMF) of displaced midshaft clavicular fractures. METHODS: In a previously reported, randomized controlled fashion, 120 patients were assigned to PF or IMF. Cure was defined by a Disabilities of the Arm, Shoulder and Hand score of 8 or less. Complications were noted as present or not present for each follow-up assessment, and a panel of experts provided weights to the severity of complications. STIs were reported along with their 95% confidence intervals. The higher a procedure's STI, the higher the benefit/risk balance of that procedure. RESULTS: The nonweighted STI after 6 weeks was significantly higher in the PF group. During further follow- up, the differences leveled out and became nonsignificant. When weighting the STI for severity, the indices decrease but are significantly in favor of the PF group at 6 weeks and 6 months after surgery. At 1 year postoperatively, differences are not significant. CONCLUSION: The STI may be a reliable tool to assess the benefits and risks of operative fracture treatment. Further studies with consistent results of this new scoring system are needed before conclusions can be generalized. When determining the indices of PF and IMF, a significant difference in favor of PF was observed during the early phase of recovery. PMID- 27514634 TI - Safety and efficacy of shoulder arthroplasty following lower extremity periprosthetic joint infection. AB - BACKGROUND: The safety of arthroplasty in patients with a previous periprosthetic joint infection (PJI) remains unclear. The objective of this study was to determine whether patients with a history of a properly treated PJI complicating lower extremity arthroplasty can safely undergo shoulder arthroplasty without an increased risk of shoulder infection or compromise in their clinical outcomes. METHODS: Between 2002 and 2013, 36 patients with successful treatment of an infected lower extremity arthroplasty underwent a subsequent primary shoulder arthroplasty. Three were lost to follow-up. The remaining 33 shoulders were analyzed at a mean follow-up of 3.5 years for radiographic, clinical, and functional outcomes. Nine patients were receiving chronic antibiotic suppression at the time of their index shoulder arthroplasty. The mean time between PJI treatment and shoulder arthroplasty was 4.7 years (range, 0.7-13.1 years). RESULTS: Shoulder arthroplasty led to improved pain scores and range of motion. Excellent or satisfactory modified Neer ratings were achieved in 78.8% of patients. There was no difference in American Shoulder and Elbow Surgeons scores between the groups with and without chronic antibiotic suppression. There were 2 reoperations, both in patients not receiving chronic suppression. The indications were aseptic glenoid loosening and infection after a periprosthetic fracture. The final estimated survival free of infection was 93.3%. DISCUSSION/CONCLUSION: Shoulder arthroplasty in patients with a history of PJI complicating hip or knee arthroplasty seems to be safe, with a low rate of infection. Thus, previous lower extremity PJI should not be considered a relative contraindication to shoulder arthroplasty. PMID- 27514635 TI - Regarding "Metal-backed glenoid implant with polyethylene insert is not a viable long-term therapeutic option". PMID- 27514636 TI - Management of acute or late hematogenous infection after shoulder arthroplasty with irrigation, debridement, and component retention. AB - BACKGROUND: Irrigation and debridement (I&D) with component retention is an appealing alternative to both patients and surgeons for the management of acute or late hematogenous deep periprosthetic shoulder infection (PSI). However, the success rate and results of I&D are poorly documented. This study reports the outcomes and complications of this treatment strategy for acute and delayed-onset acute hematogenous PSI. METHODS: Between 1980 and 2010, 10 shoulders (9 patients) underwent I&D with component retention for the management on an acute or delayed onset acute hematogenous PSI at a single institution. Outcome data, including pain, range of motion, need for chronic oral antibiotic suppression therapy, eradication of infection, and need for further surgery were retrospectively collected. RESULTS: Deep infection recurred in 3 shoulders, which were eventually treated with resection arthroplasty. Of the remaining 6 patients (7 shoulders), 5 were prescribed chronic antibiotic suppression. At the most recent follow-up, pain was graded as none in 3 shoulders, mild in 1, moderate with activity in 3, moderate in 2, and severe in 1. Among shoulders with retained components, forward elevation was greater than 110 degrees in 6 (median, 140 degrees ; range, 30 degrees -160 degrees ), and external rotation was greater than 40 degrees in all shoulders (median, 50 degrees ; range, 40 degrees -90 degrees ). CONCLUSION: I&D allowed component retention in 70% of shoulders presenting with an acute or delayed-onset acute hematogenous infection. Most patients were prescribed chronic antibiotic suppression, and reasonable motion was maintained. PMID- 27514637 TI - Mixed neuropathy presenting clinically as an anterior interosseous nerve palsy following shoulder arthroscopy: a report of four cases. AB - BACKGROUND: Anterior interosseous nerve (AIN) palsies can arise spontaneously or be attributed to one of many causes. We present 4 cases, the largest series to date, in which a mixed peripheral neuropathy presented primarily as an AIN palsy following ipsilateral shoulder arthroscopy. In this report, we detail the patient's presenting symptoms, describe our management of the complication, and provide hypotheses for the mechanism behind the complication. METHODS: Four different surgeons performed the initial arthroscopic surgeries, but the senior author in all cases managed follow-up and treatment of the neuropathy. All patients were informed and agreed to have their cases published. RESULTS: All four patients experienced significant recovery, although 2 of 4 required AIN decompression and exploration because of failure to improve with conservative management. CONCLUSION: Whereas variables such as position, index surgical procedure, and use of regional anesthesia varied among our patients, the one constant was the fluid extravasation from the arthroscopy itself, and for this reason we believe that if there is one singular cause to explain all of these neuropathies, it would be increased pressure in the upper arm and forearm from fluid extravasation in patients with at-risk anatomy. Outside of prevention, recognizing this complication and providing appropriate intervention or referral to a surgeon capable of appropriate intervention are important for any surgeon performing shoulder arthroscopies. PMID- 27514638 TI - Structural and morphological peculiarities of hybrid Au/nanodiamond engineered nanostructures. AB - Nanostructured Au nano-platelets have been synthesized from an Au(III) complex by growth process triggered by nanodiamond (ND). An electroless synthetic route has been used to obtain 2D Au/ND architectures, where individual nanodiamond particles are intimately embedded into face-centered cubic Au platelets. The combined use of high resolution transmission electron microscopy (HR-TEM) and selected area electron diffraction (SAED), was able to reveal the unusual organization of these hybrid nanoparticles, ascertaining the existence of preferential crystallographic orientations for both nanocrystalline species and highlighting their mutual locations. Detailed information on the sample microstructure have been gathered by fast Fourier transform (FFT) and inverse fast Fourier transform (IFFT) of HR-TEM images, allowing us to figure out the role of Au defects, able to anchor ND crystallites and to provide specific sites for heteroepitaxial Au growth. Aggregates constituted by coupled ND and Au, represent interesting systems conjugating the best optoelectronics and plasmonics properties of the two different materials. In order to promote realistically the applications of such outstanding Au/ND materials, the cooperative mechanisms at the basis of material synthesis and their influence on the details of the hybrid nanostructures have to be deeply understood. PMID- 27514639 TI - Robotic splenectomy with ex vivo bench surgery and hemi-spleen autotransplant: the first report. AB - BACKGROUND: We describe our experience with what is, to our knowledge, the first case of robotic assisted ex vivo partial splenectomy with auto-transplantation for a benign non parasitic cyst. MATERIALS AND METHODS: The patient is a 32 year old female with a giant, benign splenic cyst causing persistent abdominal pain. Preoperative imaging showed a cystic lesion measuring 8.3 * 7.6 cm, in the middle portion of the spleen. Due to the central location of the bulky lesion a partial splenectomy was not feasible. As an alternative to a total splenectomy, a possible reimplantation of hemi-spleen after bench surgery was offered. We proceeded with a robotic total splenectomy and bench hemisplenectomy, preserving the lower pole and a portion of the middle segment of the organ. A robotic reconstruction of the splenic vessels was then performed intra-abdominally. The reperfusion was optimal. RESULTS: The total operative time was 305 min, with 78 min of robotic time. Postoperative ultrasound confirmed a patent arterial and venous flow. The postoperative course was uneventful and the patient was discharged on postoperative day 4. The pathology report was consistent with epithelial cyst of the spleen. The patient is doing well at 6-month follow-up. CONCLUSIONS: The optimized vision and dexterity provided by the robotic system allowed a safe and precise reconstruction of the splenic vessels, even in a deep and narrow operative field. Partial splenectomy with autotransplantation of the organ was thus achieved, avoiding a total splenectomy in a young patient. PMID- 27514640 TI - Factors Influencing ACT After Intravenous Bolus Administration of 100 IU/kg of Unfractionated Heparin During Cardiac Catheterization in Children. AB - Anticoagulation using intravenous bolus administration of unfractionated heparin (UFH) aims to prevent thromboembolic complications in children undergoing cardiac catheterization (CC). Optimal UFH dosage is needed to reduce bleeding complications. We analyzed the effect of bolus UFH on activated clotting time (ACT) in children undergoing CC focusing on age-dependent, anesthesia-related, or disease-related influencing factors. This retrospective single-center study of 183 pediatric patients receiving UFH during CC analyzed ACT measured at the end of CC. After bolus administration of 100 IU UFH/kg body weight, ACT values between 105 and 488 seconds were reached. Seventy-two percent were within target level of 160 to 240 seconds. Age-dependent differences were not obtained ( P = .407). The ACT values were lower due to hemodilution (total fluid and crystalloid administration during CC, both P < .001), with premedication of acetylsalicylic acid ( P = .014) and low-molecular-weight heparin ( P = .049). Arterial thrombosis (3.85%), venous thrombosis (0.55%), and bleeding (1.65%) following CC did not correlate with ACT values but occurred more frequently in children between 1 month and 1 year of age (91%). In conclusion, with a bolus of 100 IU UFH/kg, an ACT target level of 160 to 240 seconds can be achieved during CC in children in 72%, which is influenced by hemodilution and anticoagulant and antiplatelet premedication but not by age. PMID- 27514641 TI - GP recruits offered L20 000 to train in Scotland. PMID- 27514642 TI - The Impact of Primary Aggressor Laws on Single Versus Dual Arrest in Incidents of Intimate Partner Violence. AB - To combat the concern that mandatory arrest laws have resulted in officers unjustly arresting victims, states have enacted primary aggressor laws. Examining 3,078 incidents of intimate partner violence reported to the police in 25 jurisdictions in four states, the authors assess the impact of primary aggressor laws on the likelihood of both single and dual arrest. While dual arrests were more than twice as likely in a state without a primary arrest statute, an arrest was nearly a third less likely in a state with such a statute. The policy implications are discussed. PMID- 27514643 TI - Mechanisms Associated with Activation of Intracellular Metabotropic Glutamate Receptor, mGluR5. AB - The group 1 metabotropic glutamate receptor, mGluR5, is found on the cell surface as well as on intracellular membranes where it can mediate both overlapping and unique signaling effects. Previously we have shown that glutamate activates intracellular mGluR5 by entry through sodium-dependent transporters and/or cystine glutamate exchangers. Calibrated antibody labelling suggests that the glutamate concentration within neurons is quite high (~10 mM) raising the question as to whether intracellular mGluR5 is maximally activated at all times or whether a different ligand might be responsible for receptor activation. To address this issue, we used cellular, optical and molecular techniques to show that intracellular glutamate is largely sequestered in mitochondria; that the glutamate concentration necessary to activate intracellular mGluR5 is about ten fold higher than what is necessary to activate cell surface mGluR5; and uncaging caged glutamate within neurons can directly activate the receptor. Thus these studies further the concept that glutamate itself serves as the ligand for intracellular mGluR5. PMID- 27514644 TI - Upregulation of PSMB4 is Associated with the Necroptosis after Spinal Cord Injury. AB - Spinal cord injury (SCI) is one of the most common and severe complications in spine injury. It is difficult to prevent cell necroptosis and promote the survival of residual neurons after SCI. Proteasome beta-4 subunit (PSMB4) is the first proteasomal subunit with oncogenic properties promoting cancer cell survival and tumor growth in vivo, and our previous study showed that PSMB4 is significantly associated with neuronal apoptosis in neuroinflammation. However, PSMB4 function in the necroptosis after SCI is unkown. RIP3, a key regulatory factor of necroptosis, correlates with the induction of necroptosis in various types of cells and signaling pathway. Upregulation of the RIP3 expression may play a role as a novel molecular mechanism in secondary neural tissue damage following SCI. In this study, we established an acute spinal cord contusion injury model in adult rats to investigate the potential role of PSMB4 during the pathological process of SCI. We found PSMB4 expression was significantly up regulated 3 days after injury by western blot and immunohistochemical staining. Double immunofluorescent staining indicated obvious changes of PSMB4 expression occurred in neurons. Significant up-regulation of PSMB4 expression was observed in Rip3 positive neurons at 3 days after SCI, which indicated that PSMB4 might play a vital role in the regulation of Rip3. Overexpress and knockdown PSMB4 could intervene the RIP3 and Mixed lineage kinase domain-like protein (MLKL) pathway in Tumor necrosis factor-alpha (TNF-alpha) induced necroptosis cell model. Based on our experimental data, we boldly conclude that PSMB4 is associated with RIP3 involved necroptosis after SCI. PMID- 27514645 TI - Waiting time for radiation therapy after breast-conserving surgery in early breast cancer: a retrospective analysis of local relapse and distant metastases in 615 patients. AB - BACKGROUND: Postoperative radiotherapy after breast-conserving surgery (BCS) is the standard in the management of breast cancer. The optimal timing for starting postoperative radiation therapy has not yet been well defined. In this study, we aimed to evaluate if the time interval between BCS and postoperative radiotherapy is related to the incidence of local and distant relapse in women with early node negative breast cancer not receiving chemotherapy. METHODS: We retrospectively analyzed clinical data concerning 615 women treated from 1984 to 2010, divided into three groups according to the timing of radiotherapy: <=60, 61-120, and >120 days. To estimate the presence of imbalanced distribution of prognostic and treatment factors among the three groups, the chi2 test or the Fisher exact test were performed. Local relapse-free survival, distant metastasis-free survival (DMFS), and disease-free survival (DFS) were estimated with the Kaplan-Meier method, and multivariate Cox regression was used to test for the independent effect of timing of RT after adjusting for known confounding factors. The median follow-up time was 65.8 months. RESULTS: Differences in distribution of age, type of hormone therapy, and year of diagnosis were statistically significant. At 15 year follow-up, we failed to detect a significant correlation between time interval and the risk of local relapse (p = 0.09) both at the univariate and the multivariate analysis. The DMFS and the DFS univariate analysis showed a decreased outcome when radiotherapy was started early (p = 0.041 and p = 0.046), but this was not confirmed at the multivariate analysis (p = 0.406 and p = 0.102, respectively). CONCLUSIONS: Our results show that no correlation exists between the timing of postoperative radiotherapy and the risk of local relapse or distant metastasis development in a particular subgroup of women with node-negative early breast cancer. PMID- 27514647 TI - Hepatitis C virus prevention and treatment prioritization-ethical, economic and evidential dimensions of early rather than delayed treatment for people who inject drugs. PMID- 27514646 TI - MicroRNA-34b mediates hippocampal astrocyte apoptosis in a rat model of recurrent seizures. AB - BACKGROUND: Recurrent convulsions can cause irreversible astrocyte death, impede neuron regeneration, and further aggravate brain damage. MicroRNAs have been revealed as players in the progression of numerous diseases including cancer and Alzheimer's disease. Particularly, microRNA has been found linked to seizure induced neuronal death. In this study, a rat model of recurrent convulsions induced by flurothyl treatments was utilised to assess the alterations of microRNA expressions in hippocampus tissues. We also applied an in vitro model in which primary astrocytes were exposed to kainic acid to verify the targets of miR 34b-5p identified in the animal model. RESULTS: We discovered that miR-34b-5p, a member of the miR-34 family, increased significantly in flurothyl-treated rat hippocampus tissue. More surprisingly, this upregulation occurred concurrently with accumulating astrocyte apoptosis, indicating the involvement of miR-34b-5p in seizures caused astrocyte apoptosis. Results from the in vitro experiments further demonstrated that miR-34b-5p directly targeted Bcl-2 mRNA, translationally repressed Bcl-2 protein, and thus modulated cell apoptosis by influencing Bcl-2, Bax, and Caspase-3. CONCLUSION: Our findings prove microRNAs play a role in mediating recurrent convulsions-induced astrocyte death and further indicate that miR-34b-5p could acts as a regulator for astrocyte apoptosis induced by recurrent seizures. PMID- 27514648 TI - BCL2 and MYC are expressed at high levels in canine diffuse large B-cell lymphoma but are not predictive for outcome in dogs treated with CHOP chemotherapy. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common haematopoietic malignancy in dogs. Recently, MYC and BCL2 expression levels determined with immunohistochemistry (IHC) were found to be prognostic in people with DLBCL. We hypothesized that canine DLBCL can be similarly subdivided into prognostic subtypes based on expression of MYC and BCL2. Cases of canine DLBCL treated with CHOP chemotherapy were retrospectively collected and 43 dogs had available histologic tissue and complete clinical follow-up. Median values of percent immunoreactive versus immunonegative cells were used to determine positive or negative expression status. Completion of CHOP was significantly associated with a positive outcome. Compared with human patients, our canine DLBCL patients had high IHC expression of both MYC and BCL2, and relative expression levels of one or both markers were not associated with clinical outcome. PMID- 27514649 TI - Triple-Quadrupole Inductively Coupled Plasma-Mass Spectrometry with a High Efficiency Sample Introduction System for Ultratrace Determination of (135)Cs and (137)Cs in Environmental Samples at Femtogram Levels. AB - High yield fission products, (135)Cs and (137)Cs, have entered the environment as a result of anthropogenic nuclear activities. Analytical methods for ultratrace measurement of (135)Cs and (137)Cs are required for environmental geochemical and nuclear forensics studies. Here we report a highly sensitive method combining a desolvation sample introduction system (APEX-Q) with triple-quadrupole inductively coupled plasma mass spectrometry (AEPX-ICPMS/MS) for the determination of (135)Cs and (135)Cs/(137)Cs isotope ratio at femtogram levels. Using this system, we introduced only selected ions into the collision/reaction cell to react with N2O, significantly reducing the isobaric interferences ((135)Ba(+) and (137)Ba(+)) and polyatomic interferences ((95,97)Mo(40)Ar(+), (119)Sn(16)O(+), and (121)Sb(16)O(+)). Compared to the instrument setup of ICPMS/MS, the APEX-ICPMS/MS enables a 10-fold sensitivity increase. In addition, an effective chemical separation scheme consisting of ammonium molybdophosphate (AMP) Cs-selective adsorption and two-stage ion-exchange chromatographic separation was developed to remove major matrix and interfering elements from environmental samples (10-40 g). This separation method showed high decontamination factors (10(4)-10(7)) for major matrix elements (Al, Ca, K, Mg, Na, and Si) and interfering elements (Ba, Mo, Sb, and Sn). The high sensitivity of APEX-ICPMS/MS and the effective removal sample matrix allowed reliable analysis of (135)Cs and (137)Cs with extremely low detection limits (0.002 pg mL( 1), corresponding to 0.006 Bq mL(-1) (137)Cs). The accuracy and applicability of the APEX-ICPMS/MS method was validated by analysis of seven standard reference materials (soils, sediment, and plants). For the first time, ultratrace determination of (135)Cs and (135)Cs/(137)Cs isotope ratio at global fallout source environmental samples was achieved with the ICPMS technique. PMID- 27514650 TI - Laser Refrigeration of Ytterbium-Doped Sodium-Yttrium-Fluoride Nanowires. AB - Sodium yttrium fluoride (beta-NaYF4 ) nanowires (NWs) with a hexagonal crystal structure are synthesized using a low-cost hydrothermal process and are shown to undergo laser refrigeration based on an upconversion process leading to anti Stokes (blueshifted) photoluminescence. Single-beam laser trapping combined with forward light scattering is used to investigate cryophotonic laser refrigeration of individual NWs through analysis of their local Brownian dynamics. PMID- 27514651 TI - From the Editor. PMID- 27514652 TI - Target blood pressure for patients with hypertension: lower blood pressure is not better. PMID- 27514653 TI - Type 1 and 3 inositol trisphosphate receptors are required for extra-embryonic vascular development. AB - The embryonic-maternal interface of the placental labyrinth, allantois, and yolk sac are vital during embryogenesis; however, the precise mechanism underlying the vascularization of these structures remains unknown. Herein we focus on the role of inositol 1,4,5-trisphosphate (IP3) receptors (IP3R), which are intracellular Ca(2+) release channels, in placentation. Double knockout (DKO) of type 1 and 3 IP3Rs (IP3R1 and IP3R3, respectively) in mice resulted in embryonic lethality around embryonic day (E) 11.5. Because IP3R1 and IP3R3 were co-expressed in endothelial cells in the labyrinth, allantois, and yolk sac, we investigated extra-embryonic vascular development in IP3R1- and IP3R3-DKO mice. The formation of chorionic plates and yolk sac vessels seemed dysregulated around the timing of the chorio-allantoic attachment, immediately followed by the disorganization of allantoic vessels, the decreased expression of the spongiotrophoblast cell marker Tpbpa and the growth retardation of the embryos in DKO mice. Fluorescent immunohistochemistry demonstrated downregulation of a vascular endothelial marker, CD31, in labyrinth embryonic vessels and poor elongation of extra embryonic mesoderm into the labyrinth layer in DKO placenta, whereas the branching of the DKO chorionic trophoblast was initiated. In addition, allantoic and yolk sac vessels in extra-embryonic tissues were less remodeled in DKO mice. In vitro endothelial cord formation and migration activities of cultured vascular endothelial cells derived from human umbilical vein were downregulated under the inhibition of IP3R. Our results suggest that IP3R1 and IP3R3 are required for extra-embryonic vascularization in the placenta, allantois, and yolk sac. This is the first demonstration of the essential role of IP3/IP3Rs signaling in the development of the vasculature at the embryonic-maternal interface. PMID- 27514654 TI - Automating quality assurance of digital linear accelerators using a radioluminescent phosphor coated phantom and optical imaging. AB - Performing mechanical and geometric quality assurance (QA) tests for medical linear accelerators (LINAC) is a predominantly manual process that consumes significant time and resources. In order to alleviate this burden this study proposes a novel strategy to automate the process of performing these tests. The autonomous QA system consists of three parts: (1) a customized phantom coated with radioluminescent material; (2) an optical imaging system capable of visualizing the incidence of the radiation beam, light field or lasers on the phantom; and (3) software to process the captured signals. The radioluminescent phantom, which enables visualization of the radiation beam on the same surface as the light field and lasers, is placed on the couch and imaged while a predefined treatment plan is delivered from the LINAC. The captured images are then processed to self-calibrate the system and perform measurements for evaluating light field/radiation coincidence, jaw position indicators, cross-hair centering, treatment couch position indicators and localizing laser alignment. System accuracy is probed by intentionally introducing errors and by comparing with current clinical methods. The accuracy of self-calibration is evaluated by examining measurement repeatability under fixed and variable phantom setups. The integrated system was able to automatically collect, analyze and report the results for the mechanical alignment tests specified by TG-142. The average difference between introduced and measured errors was 0.13 mm. The system was shown to be consistent with current techniques. Measurement variability increased slightly from 0.1 mm to 0.2 mm when the phantom setup was varied, but no significant difference in the mean measurement value was detected. Total measurement time was less than 10 minutes for all tests as a result of automation. The system's unique features of a phosphor-coated phantom and fully automated, operator independent self-calibration offer the potential to streamline the QA process for modern LINACs. PMID- 27514655 TI - Bioactive gentixanthone and gentichromone from the whole plants of Gentianella acuta (Michx.) Hulten. AB - Five new compounds, gentixanthones A1 (1), A2 (2), and gentichromones A1-A3 (3 5), together with thirteen known xanthones (6-18) were obtained from the whole plants of Gentianella acuta (Michx.) Hulten. Their structures were elucidated by chemical and spectroscopic methods. Among them, compounds 6, 8, 13, 14, and 17 were obtained from Gentianella genus firstly, and 7, 12, 15, 16, and 18 were isolated from this plant for the first time. Meanwhile, inhibitory effects of 1 18 on motility of mouse isolated intestine tissue were determined. As results, xanthones 1, 2, 6, 7, 9, 10 and 14 were found to have significant reduce effect on intestine contraction tension, and structure-activity relationship was discussed. PMID- 27514656 TI - Quality profile determination of Chios mastic gum essential oil and detection of adulteration in mastic oil products with the application of chiral and non-chiral GC-MS analysis. AB - The determination of mastic oil profile, with emphasis on its chiral characteristics, could serve as a method for detecting adulteration in products found in the market with a claim of mastic oil content aiming towards protecting it from counterfeiting. Furthermore the evaluation of the raw material is crucial, as the profile is potentially affected by factors as mastic origin and storage time. Thus 45 authentic mastic oil samples were analyzed by GC-MS employing a chiral column and content limits for all major constituents were determined. The chiral GC-MS analysis proved that selected concentration ratios between these constituents, namely those of (-)/(+)-alpha-pinene (<=1:100) and ( )-alpha-pinene/myrcene (1.9:100-11:100) could serve as markers for the determination of mastic oil authenticity. Employing this methodology, the analysis of 25 mastic oils contained in cosmetic and dietary products, as well as an artificial mastic oil sample, exhibited several differentiations that could indicate adulteration either with artificial essential oils or volatile compounds, or the use of aged mastic oil. PMID- 27514657 TI - Extended Culture of Encapsulated Human Blastocysts in Alginate Hydrogel Containing Decidualized Endometrial Stromal Cells in the Presence of Melatonin. AB - Extended in vitro culture of human embryos beyond blastocyst stage could serve as a tool to explore the molecular and physiological mechanisms underlying embryo development and to identify factors regulating pregnancy outcomes. This study presents the first report on the maintenance of human embryo in vitro by alginate co-encapsulation of human blastocyst and decidualized endometrial stromal cells (EnSCs) under melatonin-fortified culture conditions. The effectiveness of the 3D culture system was studied through monitoring of embryo development in terms of survival time, viability, morphological changes, and production of the two hormones of 17b-oestradiol and human chorionic gonadotropin. The embryo structural integrity was preserved during alginate encapsulation; however, only 23 % of the encapsulated embryos could retain in the hydrogels over time and survived until day 4 post-encapsulation. The culture medium fortification with melatonin significantly elevated the maintenance rate of expanded embryos in alginate beads by 65 % and prolonged survival time of human embryos to day 5. Furthermore, embryo co-culture with EnSCs using melatonin-fortified medium increased the survival time of encapsulated embryos to 44 %. The levels of two measured hormones significantly rose at day 4 in comparison with day 2 post encapsulation especially in the group co-encapsulated with EnSCs and cultivated in melatonin-fortified culture medium. These data are the first evidence representing in vitro development of human embryos until day 10 post fertilization. This achievement can facilitate the investigation of the mechanisms regulating human embryo development. PMID- 27514658 TI - ESR1, ERBB2, and Ki67 mRNA expression predicts stage and grade of non-muscle invasive bladder carcinoma (NMIBC). AB - Pathological staging and grading are crucial for risk assessment in non-muscle invasive bladder cancer (NMIBC). Molecular grading might support pathological evaluation and minimize interobserver variability. In this study, the well established breast cancer markers ESR1, PGR, ERBB2, and MKI67 were evaluated as potential molecular markers to support grading and staging in NMIBC. We retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with NMIBC. Messenger RNA (mRNA) expression of the aforementioned markers was measured by single-step reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) using RNA-specific TaqMan assays. Relative gene expression was determined by normalization to two reference genes (CALM2 and B2M) using the 40-DeltaDeltaCT method and correlated to histopathological stage and grade. Pathological assessment was performed by an experienced uropathologist. Statistical analysis was performed using the SAS software JMP 9.0.0 version and GraphPad Prism 5.04. Of 381 cases of NMIBC, samples of 100 pTa and 255 pT1 cases were included in the final study. Spearman rank correlation revealed significant correlations between grade and expression of MKI67 (r = 0.52, p < 0.0001), ESR1 (r = 0.25, p < 0.0001), and ERBB2 (r = 0.18, p = 0.0008). In Mann-Whitney tests, MKI67 was significantly different between all grades (p < 0.0001), while ESR1 (p = 0.0006) and ERBB2 (p = 0.027) were significantly different between G2 and G3. Higher expression of MKI67 (r = 0.49; p < 0.0001), ERBB2 (r = 0.22; p < 0.0001), and ESR1 (r = 0.18; p = 0.0009) mRNA was positively correlated with higher stage. MKI67 (p < 0.0001), ERBB2 (p = 0.0058), and PGR (p = 0.0007) were significantly different between pTa and pT1. In NMIBC expression of ESR1, ERBB2 and MKI67 are significantly different between stage and grade. This potentially provides objective parameters for pathological evaluation. PMID- 27514660 TI - Models of reablement evaluation (MoRE): a study protocol of a quasi-experimental mixed methods evaluation of reablement services in England. AB - BACKGROUND: Reablement is a time-limited intervention that aims to support people to regain independence and enable them to resume their daily activities after they return home from an in-patient care setting, or to maintain independence to enable them to remain at home. There is some evidence that reablement can enhance independence and has the potential to contain costs. However, reablement services are funded and provided in different ways and by different organisations, and there is limited research evidence about the effectiveness of different reablement service models. This study will evaluate the effectiveness and cost effectiveness of different reablement service models and service users' and carers' experiences of reablement in England, UK. METHODS/DESIGN: The study will use a quasi-experimental mixed methods design that comprises three work packages (WP) extending over a period of 34 months. WP1 will conduct cluster analysis on survey data to develop a typology of current models of reablement services in order to describe the current reablement service landscape. WP2 will comprise a quantitative outcomes evaluation of the effectiveness of the different service models; a process evaluation and an economic evaluation. WP2 will be set within generic reablement services, where providers are using the most commonly employed generic reablement service types identified in WP1; the primary outcome measure is health-related quality of life measured by the EQ-5D-5L. WP3 will provide evidence about specialist reablement services and how specialist approaches and practices are organised and delivered. DISCUSSION: Managing demands on care services is, and will remain, a crucial factor for the UK National Health Service as the number of people with long-term conditions rise. There has been, and will continue to be, significant investment in reablement services. The proposed study will address several key areas where there is limited evidence regarding the organisation and delivery of reablement services in England, UK. Specifically, it will provide new evidence on different models of reablement services that will be of direct benefit to health and social care managers, commissioners and their partner organisations. PMID- 27514659 TI - Determining the mode of action of anti-mycobacterial C17 diyne natural products using expression profiling: evidence for fatty acid biosynthesis inhibition. AB - BACKGROUND: The treatment of microbial infections is becoming increasingly challenging because of limited therapeutic options and the growing number of pathogenic strains that are resistant to current antibiotics. There is an urgent need to identify molecules with novel modes of action to facilitate the development of new and more effective therapeutic agents. The anti-mycobacterial activity of the C17 diyne natural products falcarinol and panaxydol has been described previously; however, their mode of action remains largely undetermined in microbes. Gene expression profiling was therefore used to determine the transcriptomic response of Mycobacterium smegmatis upon treatment with falcarinol and panaxydol to better characterize the mode of action of these C17 diynes. RESULTS: Our analyses identified 704 and 907 transcripts that were differentially expressed in M. smegmatis after treatment with falcarinol and panaxydol respectively. Principal component analysis suggested that the C17 diynes exhibit a mode of action that is distinct to commonly used antimycobacterial drugs. Functional enrichment analysis and pathway enrichment analysis revealed that cell processes such as ectoine biosynthesis and cyclopropane-fatty-acyl-phospholipid synthesis were responsive to falcarinol and panaxydol treatment at the transcriptome level in M. smegmatis. The modes of action of the two C17 diynes were also predicted through Prediction of Activity Spectra of Substances (PASS). Based upon convergence of these three independent analyses, we hypothesize that the C17 diynes inhibit fatty acid biosynthesis, specifically phospholipid synthesis, in mycobacteria. CONCLUSION: Based on transcriptomic responses, it is suggested that the C17 diynes act differently than other anti-mycobacterial compounds in M. smegmatis, and do so by inhibiting phospholipid biosynthesis. PMID- 27514662 TI - Antagonist pharmacology of desensitizing and non-desensitizing nicotinic acetylcholine receptors in cockroach neurons. AB - Two alpha-bungarotoxin-sensitive nicotinic acetylcholine (ACh) receptor subtypes in neurons of the American cockroach have been identified as desensitizing (nAChD) and selectively inhibitable with 100nM imidacloprid, and non desensitizing (nAChN) and selectively inhibitable with 100pM methyllycaconitine. In this paper, the single-electrode voltage-clamp technique was used to measure concentration-response relations for the action of ACh and five antagonists on pharmacologically separated nAChD and nAChN receptors of acutely dissociated neurons from thoracic ganglia of the American cockroach. A dual bath and U-tube perfusion system was used to achieve rapid application of ACh in the continued presence of antagonists, which was essential to accurately measure inhibition by rapidly-reversible antagonists. ACh activated both receptors with an EC50 of 7MUM and the antagonist potencies were (nAChD/nAChN in nM): dihydro-beta-erythroidine: 1.0/5.6, d-tubocurarine: 1000/34, condelphine: 0.39/0.65, phencyclidine: 74/980 and mecamylamine 47/1150. While each of these antagonists displayed some subtype selectivity, none are selective enough to be used as subtype-selective tools. These results bring to a total of 16 the number of nicotinic compounds that have been measured on nAChD and nAChN currents. Characterization of these receptors is important for understanding the role of nAChRs in the insect nervous system and the mechanism of action of insecticides. PMID- 27514663 TI - Significance of oxygen carriers and role of liquid paraffin in improving validamycin A production. AB - Validamycin A (Val-A) synthesized by Streptomyces hygroscopicus 5008 is widely used as a high-efficient antibiotic to protect plants from sheath blight disease. A novel fermentation strategy was introduced to stimulate Val-A production by adding oxygen carriers. About 58 % increase in Val-A production was achieved using liquid paraffin. Further, biomass, carbon source, metabolic genes, and metabolic enzymes were studied. It was also found that the supplementation of liquid paraffin increased the medium dissolved oxygen and intracellular oxidative stress level. The expression of the global regulators afsR and soxR sensitive to ROS, ugp catalyzing synthesis of Val-A precursor, and Val-A structural genes was enhanced. The change of the activities of glucose-6-phosphate dehydrogenase and glyceraldehyde 3-phosphate dehydrogenase was observed, which reflected the redirection of carbon metabolic flux. Based on these results, liquid paraffin addition as an oxygen carrier could be a useful technique in industrial production of Val-A and our study revealed a redox-based secondary metabolic regulation in S. hygroscopicus 5008, which provided a new insight into the regulation of the biosynthesis of secondary metabolites. PMID- 27514664 TI - Correlated positions in protein evolution and engineering. AB - Statistical analysis of a protein multiple sequence alignment can reveal groups of positions that undergo interdependent mutations throughout evolution. At these so-called correlated positions, only certain combinations of amino acids appear to be viable for maintaining proper folding, stability, catalytic activity or specificity. Therefore, it is often speculated that they could be interesting guides for semi-rational protein engineering purposes. Because they are a fingerprint from protein evolution, their analysis may provide valuable insight into a protein's structure or function and furthermore, they may also be suitable target positions for mutagenesis. Unfortunately, little is currently known about the properties of these correlation networks and how they should be used in practice. This review summarises the recent findings, opportunities and pitfalls of the concept. PMID- 27514665 TI - Potential application of glycerol in the production of plant beneficial microorganisms. AB - This review highlights the importance of research for development of biofertilizer and biocontrol products based on the use of glycerol for further process scale-up to industrial microbiology. Glycerol can be used successfully in all stages of production of plant beneficial microorganisms. It serves as an excellent substrate in both submerged and solid-state fermentation processes with free and immobilized microbial cells. Glycerol is also one of the most attractive formulation agents that ensures high cell density and viability including in harsh environmental conditions. Future research is discussed to make this inexpensive material a base for industrial production of plant beneficial microorganisms. PMID- 27514666 TI - Bioprocess development for extracellular production of recombinant human interleukin-3 (hIL-3) in Pichia pastoris. AB - Human interleukin-3 (hIL-3) is a therapeutically important cytokine involved in the maturation and differentiation of various cells of the immune system. The codon-optimized hIL-3 gene was cloned in fusion with the N-terminus alpha-mating factor signal peptide of Saccharomyces cerevisiae under an inducible alcohol oxidase 1 (AOX1) and constitutive glyceraldehyde-3-phosphate dehydrogenase (GAP) promoter. A Zeocin concentration up to 2000 mg/L was used to select hyper producers. The shake flask cultivation studies in the Pichia pastoris GS115 host resulted a maximum recombinant hIL-3 expression level of 145 mg/L in the extracellular medium under the control of AOX1 promoter. The batch fermentation strategy allowed us to attain a fairly pure glycosylated hIL-3 protein in the culture supernatant at a final concentration of 475 mg/L with a high volumetric productivity of 4.39 mg/L/h. The volumetric product concentration achieved at bioreactor level was 3.28 folds greater than the shake flask results. The 6x His tagged protein was purified using Ni-NTA affinity chromatography and confirmed further by western blot analysis using anti-6x His tag antibody. The glycosylation of recombinant hIL-3 protein was confirmed in a PNGase F deglycosylation reaction where it showed a molecular weight band pattern similar to E. coli produced non-glycosylated hIL-3 protein. The structural properties of recombinant hIL-3 protein were confirmed by CD and fluorescence spectroscopy where protein showed 40 % alpha-helix, 12 % beta-sheets with an emission maxima at 343 nm. MALDI-TOF-TOF analysis was used to establish the protein identity. The biological activity of purified protein was confirmed by the human erythroleukemia TF-1 cell proliferation assay. PMID- 27514668 TI - Structural manipulation and tailoring of dielectric properties in SrTi1-xFexTaxO3 perovskites: Design of new lead free relaxors. AB - We report composition dependent structure evolution from SrTiO3 to SrFe0.5Ta0.5O3 by powder X-ray and neutron diffraction studies of SrTi1-2xFexTaxO3 (0.00 <= * <= 0.50) compositions. Structural studies reveal cubic (Pm3m) perovskite-type structure of the parent SrTiO3 for x up to 0.075 and cation disordered orthorhombic (Pbnm) perovskite-type structure for x >= 0.33. A biphasic region consisting of a mixture of cubic and orthorhombic structures is found in the range for 0.10 <= * <= 0.25. Dielectric studies reveal transformation from a normal dielectric to relaxor like properties with increasing Fe(3+) and Ta(5+) concentration. Dielectric response is maximum at x = 0.33 in the series. The results establish a protocol for designing new lead-free relaxor materials based on the co-substitution of Fe(3+) and Ta(5+) for Ti(4+) in SrTiO3. A complex interplay of strain effects arising from distribution of cations at the octahedral sites of the perovskite structure controls the dielectric properties. PMID- 27514667 TI - Gastric biomarkers: a global review. AB - BACKGROUND: Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. MAIN BODY: This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD L1, TP53, and microsatellite instability. CONCLUSION: A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes. PMID- 27514670 TI - Halomonas lutescens sp. nov., a halophilic bacterium isolated from a lake sediment. AB - A novel, Gram-stain-negative, facultatively anaerobic, halophilic bacterium, designated strain Q1UT, was isolated from a sediment sample collected from Qinghai Lake, PR China. The cells of the strain were short rod-shaped (0.2 0.3*0.6-2.5 um) and non-motile. Strain Q1UT formed yellowish colonies and grew at temperatures of 2-37 degrees C (optimum 30-33 degrees C), at pH 6.0-9.0 (optimum pH 7.0) and in the presence of 0-20 % (w/v) NaCl (optimum 7.5 %). The major cellular fatty acids were C18 : 1omega7c (58.6 %), C16 : 1omega7c and/or C16 : 1omega6c (14.8 %) and C16 : 0 (10.1 %). The polar lipids were identified as diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, unknown phospholipid and unknown lipids. The genomic DNA G+C content was 61.5 mol%, and the predominant respiratory ubiquinone Q-9. Based on phylogenetic analysis of the 16S rRNA gene sequences and concatenated 16S rRNA, gyrB and rpoD gene sequences, the isolate was found to belong to the genus Halomonas in the class Gammaproteobacteria. The most closely related species were Halomonas venusta DSM 4743T (98.3 % 16S rRNA sequence similarity), Halomonas songnenensis DSM 25870T (98.2 %) and Halomonas hydrothermalis DSM 15725T (98.2 %). DNA-DNA relatedness values between strain Q1UT and the type strains of eight other species of the genus Halomonas ranged from 21.3 % to 10.1 %. On the basis of phenotypic, phylogenetic and chemotaxonomic analyses, and DNA-DNA hybridization relatedness values, strain Q1UT is considered to represent a novel species of the genus Halomonas; the name Halomonas lutescens sp. nov. is proposed. The type strain is Q1UT (=CGMCC 1.15122T=KCTC 42517T). PMID- 27514669 TI - Mycobacterium tuberculosis H37Ra: a surrogate for the expression of conserved, multimeric proteins of M.tb H37Rv. AB - BACKGROUND: Obtaining sufficient quantities of recombinant M.tb proteins using traditional approaches is often unsuccessful. Several enzymes of the glycolytic cycle are known to be multifunctional, however relatively few enzymes from M.tb H37Rv have been characterized in the context of their enzymatic and pleiotropic roles. One of the primary reasons is the difficulty in obtaining sufficient amounts of functionally active protein. RESULTS: In the current study, using M.tb glyceraldehyde-3-phosphate dehydrogenase (GAPDH) we demonstrate that expression in E. coli or M. smegmatis results in insolubility and improper subcellular localization. In addition, expression of such conserved multisubunit proteins poses the problem of heteromerization with host homologues. Importantly the expression host dramatically affected the yield and functionality of GAPDH in terms of both enzymatic activity and moonlighting function (transferrin binding). The applicability of this system was further confirmed using two additional enzymes i.e. M.tb Pyruvate kinase and Enolase. CONCLUSIONS: Our studies establish that the attenuated strain M.tb H37Ra is a suitable host for the expression of highly hydrophobic, conserved, multimeric proteins of M.tb H37Rv. Significantly, this expression host overcomes the limitations of E. coli and M. smegmatis expression and yields recombinant protein that is qualitatively superior to that obtained by traditional methods. The current study highlights the fact that protein functionality (which is an an essential requirement for all in vitro assays and drug development) may be altered by the choice of expression host. PMID- 27514671 TI - Imaging biomarkers for steatohepatitis and fibrosis detection in non-alcoholic fatty liver disease. AB - There is a need, in NAFLD management, to develop non-invasive methods to detect steatohepatitis (NASH) and to predict advanced fibrosis stages. We evaluated a tool based on optical analysis of liver magnetic resonance images (MRI) as biomarkers for NASH and fibrosis detection by investigating patients with biopsy proven NAFLD who underwent magnetic resonance (MR) protocols using 1.5T General Electric (GE) or Philips devices. Two imaging biomarkers (NASHMRI and FibroMRI) were developed, standardised and validated using area under the receiver operating characteristic curve (AUROC) analysis. The results indicated NASHMRI diagnostic accuracy for steatohepatitis detection was 0.83 (95% CI: 0.73-0.93) and FibroMRI diagnostic accuracy for significant fibrosis determination was 0.85 (95% CI: 0.77-0.94). These findings were independent of the MR system used. We conclude that optical analysis of MRI has high potential to define non-invasive imaging biomarkers for the detection of steatohepatitis (NASHMRI) and the prediction of significant fibrosis (FibroMRI) in NAFLD patients. PMID- 27514672 TI - Identification of a naturally processed HLA-A*02:01-restricted CTL epitope from the human tumor-associated antigen Nectin-4. AB - Nectin-4 is a tumor antigen present on the surface of breast, ovarian and lung carcinoma cells. It is rarely present in normal adult tissues and is therefore a candidate target for cancer immunotherapy. Here, we identified a Nectin-4 antigenic peptide that is naturally presented to T cells by HLA-A2 molecules. We first screened the 502 nonamer peptides of Nectin-4 (510 amino acids) for binding to and off-rate from eight different HLA class I molecules. We then combined biochemical, cellular and algorithmic assays to select 5 Nectin-4 peptides that bound to HLA-A*02:01 molecules. Cytolytic T lymphocytes were obtained from healthy donors, that specifically lyzed HLA-A2(+) cells pulsed with 2 out of the 5 peptides, indicating the presence of anti-Nectin-4 CD8(+) T lymphocytes in the human T cell repertoire. Finally, an HLA-A2-restricted cytolytic T cell clone derived from a breast cancer patient recognized peptide Nectin-4145-153 (VLVPPLPSL) and lyzed HLA-A2(+) Nectin-4(+) breast carcinoma cells. These results indicate that peptide Nectin-4145-153 is naturally processed for recognition by T cells on HLA-A2 molecules. It could be used to monitor antitumor T cell responses or to immunize breast cancer patients. PMID- 27514675 TI - Analysis of relative kinematic index with normalized standing time between subjects with and without recurrent low back pain. AB - PURPOSE: Although subjects with recurrent low back pain (LBP) demonstrate altered postural control, their postural steadiness during one leg standing is unknown. The purpose of this study was to investigate postural steadiness based on relative kinematic index of the lower limbs and trunk with normalized standing time in subjects with recurrent LBP during dominant and non-dominant leg standing. METHODS: Sixty individuals participated in the study, including 29 subjects in the control group (18 male, 11 female) and 31 subjects with recurrent LBP (21 male, 10 female). The outcome measures included relative kinematic index of the body regions and normalized standing time during the one leg standing test. The relative kinematic index was the ratio between standstill time and successful standing time. The normalized standing time was defined as a ratio between the successful standing time and the requested standing time. RESULTS: The control group demonstrated significantly longer normalized standing time on the dominant (t = -2.57, p = 0.013) and non-dominant (t = -2.78, p = 0.007) legs than the LBP group. The relative kinematic index of the core spine model significantly decreased for the dominant (t = -3.01, p = 0.004) and non-dominant (t = -3.06, p = 0.003) legs in the LBP group. In addition, the kinematic index indicated pelvis and non-dominant shank during dominant leg standing (R 2 = 0.97) in the LBP group. In the control group, the pelvis was significantly correlated with the core spine model during standing on the dominant (R 2 = 0.95) and non dominant (R 2 = 0.97) legs. CONCLUSIONS: The relative kinematic index of the pelvis was found to be most significant for longer standing durations in both groups. In the LBP group, the shank and foot were significantly higher in addition to the pelvis due to possible compensatory motion. The control group took advantage of pelvic control with the core spine to minimize lower limb movements. Clinicians need to consider the core spine for pelvic control to refine postural adaptations in subjects with recurrent LBP. PMID- 27514677 TI - Quick Fire Presentations EUROSPINE 2016 Berlin, Germany, 5-7 October. PMID- 27514674 TI - Who is distressed? A comparison of psychosocial stress in pregnancy across seven ethnicities. AB - BACKGROUND: Calgary, Alberta has the fourth highest immigrant population in Canada and ethnic minorities comprise 28 % of its total population. Previous studies have found correlations between minority status and poor pregnancy outcomes. One explanation for this phenomenon is that minority status increases the levels of stress experienced during pregnancy. The aim of the present study was to identify specific types of maternal psychosocial stress experienced by women of an ethnic minority (Asian, Arab, Other Asian, African, First Nations and Latin American). METHODS: A secondary analysis of variables that may contribute to maternal psychosocial stress was conducted using data from the All Our Babies prospective pregnancy cohort (N = 3,552) where questionnaires were completed at < 24 weeks of gestation and between 34 and 36 weeks of gestation. Questionnaires included standardized measures of perceived stress, anxiety, depression, physical and emotional health, and social support. Socio-demographic data included immigration status, language proficiency in English, ethnicity, age, and socio economic status. RESULTS: Findings from this study indicate that women who identify with an ethnic minority were more likely to report symptoms of depression, anxiety, inadequate social support, and problems with emotional and physical health during pregnancy than women who identified with the White reference group. CONCLUSIONS: This study has identified that women of an ethic minority experience greater psychosocial stress in pregnancy compared to the White reference group. PMID- 27514673 TI - Antigen Presentation After Stroke. AB - Stroke induces a local inflammatory reaction and a plethora of innate immune responses in the brain where antigen-presenting cells become prominent. However, to date, it is still unclear whether antigen presentation is relevant to the neuropathological and functional outcome of stroke. Stroke does not trigger overt autoimmune reactions, but neural antigens have been found in lymphoid tissues of patient with stroke and it is unknown whether they promote tolerance or immune reactions that under certain conditions might contribute to the functional worsening observed in some patients. Autoantibodies to neural molecules have also been reported in patients with stroke, but the subclass of antibodies is important for their function, and the contribution of such findings to stroke outcome is not yet clear. Notably, stroke induces immunodepression highlighted by a transient lymphopenia, lymphoid organ atrophy, and monocyte deactivation. While these effects might reduce the chances of autoreactivity, they increase the risk of infection in patients with stroke and most frequently in those with severe stroke. Therefore any potential brain protective effect of stroke-induced immunodepression by attenuating or preventing lymphocyte-mediated brain damage is confounded by stroke severity and an increased incidence of infections. Systemic inflammation due to a number of comorbidities that are frequent in patients with stroke is also associated to a poor outcome. Herein, we review some relevant findings regarding the identification of neural antigens in stroke and discuss their potential contribution to the functional outcome of stroke. PMID- 27514678 TI - Oral Presentations EUROSPINE 2016 Berlin, Germany, 5-7 October. PMID- 27514676 TI - The effects of the three-dimensional deformity of adolescent idiopathic scoliosis on pulmonary function. AB - PURPOSE: Utilizing 2D measurements, previous studies have found that in AIS, increased thoracic Cobb and decreased thoracic kyphosis contribute to pulmonary dysfunction. Recent technology has improved our ability to measure and understand the true 3D deformity in AIS. The purpose of this study was to evaluate which 3D radiographic measures predict pulmonary dysfunction. METHODS: One hundred and sixty-three surgically treated AIS patients with preoperative PFTs (FEV, FVC, TLC) and EOS(r) imaging were identified at a single center. Each spine was reconstructed in 3D to obtain the true coronal, sagittal, and apical rotational deformities. These were then correlated with the patient's preoperative PFT measurements. Regression analysis was performed to determine the relative effect of each radiographic measure. RESULTS: There were 124 thoracic and 39 lumbar major curves. The range of preoperative thoracic and lumbar 3D coronal angle was 11-115 degrees and 11-98 degrees , respectively. The range of preoperative thoracic 3D kyphosis (T5-T12) and thoracic apical vertebral rotation was -56 to 44 degrees and 0-29 degrees , respectively. Increasing thoracic 3D Cobb and thoracic vertebral rotation and decreasing thoracic 3D kyphosis most significantly correlated with decreasing pulmonary function, especially FEV. In patients with the largest degree of thoracic deformity (3D Coronal Cobb > 80 degrees , 3D thoracic lordosis >20 degrees , and absolute apical rotation >25 degrees ), the majority of patients had moderate to severe pulmonary impairment (<=65 % predicted). 3D thoracic kyphosis was the most consistent predictor of FEV (r 2 = 0.087), FVC (r 2 = 0.069), and TLC (r 2 = 0.098) impairment. CONCLUSIONS: Larger thoracic coronal, sagittal, and axial deformities increase the risk of pulmonary impairment in patients with AIS. Of these, decreasing 3D thoracic kyphosis is the most consistent predictor. This information can guide surgeons in the decision making process for determining which surgical techniques to utilize and which component of the deformity to focus on. PMID- 27514679 TI - Posters Presentations EUROSPINE 2016 Berlin, Germany, 5-7 October. PMID- 27514681 TI - Oral Presentations EUROSPINE Spring Speciality Meeting, 12-13 May 2016 Krakow, Poland. PMID- 27514680 TI - Index: Abstracts EUROSPINE 2016 Berlin, Germany, 5-7 October. PMID- 27514682 TI - Quick Fire Presentations EUROSPINE Spring Speciality Meeting, 12-13 May 2016, Krakow, Poland. PMID- 27514683 TI - Announcements for issue 9, 2016. PMID- 27514684 TI - Index for EUROSPINE Spring Speciality Meeting, 12-13 May, Krakow, Poland. PMID- 27514685 TI - Adaptation and acclimation of traits associated with swimming capacity in Lake Whitefish (coregonus clupeaformis) ecotypes. AB - BACKGROUND: Improved performance in a given ecological niche can occur through local adaptation, phenotypic plasticity, or a combination of these mechanisms. Evaluating the relative importance of these two mechanisms is needed to better understand the cause of intra specific polymorphism. In this study, we reared populations of Lake Whitefish (Coregonus clupeaformis) representing the'normal' (benthic form) and the 'dwarf' (derived limnetic form) ecotypes in two different conditions (control and swim-training) to test the relative importance of adaptation and acclimation in the differentiation of traits related to swimming capacity. The dwarf whitefish is a more active swimmer than the normal ecotype, and also has a higher capacity for aerobic energy production in the swimming musculature. We hypothesized that dwarf fish would show changes in morphological and physiological traits consistent with reductions in the energetic costs of swimming and maintenance metabolism. RESULTS: We found differences in traits predicted to decrease the costs of prolonged swimming and standard metabolic rate and allow for a more active lifestyle in dwarf whitefish. Dwarf whitefish evolved a more streamlined body shape, predicted to lead to a decreased drag, and a smaller brain, which may decrease their standard metabolic rate. Contrary to predictions, we also found evidence of acclimation in liver size and metabolic enzyme activities. CONCLUSION: Results support the view that local adaptation has contributed to the genetically-based divergence of traits associated with swimming activity. Presence of post-zygotic barriers limiting gene flow between these ecotype pairs may have favoured repeated local adaptation to the limnetic niches. PMID- 27514686 TI - Elemental Composition of Plant Species from an Abandoned Tungsten Mining Area: Are They Useful for Biogeochemical Exploration and/or Phytoremediation Purposes? AB - We aimed to evaluate the elemental (W, Mo, Zn, Fe, Cu, Co, Bi, Mn, Cd, Cr, As) composition of some plant species spread around the abandoned tungsten mining area of Uludag Mountain. The plant species tested were Anthemis cretica and Trisetum flavescens which are grown in this area and they are pioneer species on these contaminated sites. W levels in soils were found up to 1378.6 +/- 672.3 mg/kg dry weight in contaminated areas. The leaf W contents of the selected plant species were found 41.1 +/- 24.4 and 31.1 +/- 15.5 mg/kg dry weight for A. cretica and T. flavescens, respectively. Our results indicate that the elemental composition of species changed by the increased tungsten and some element concentrations in soil without detrimental effect. So, these species can be useful tungsten removal and some elements from contaminated sites. PMID- 27514689 TI - Misdiagnosis of cerebral malaria initially as acute psychotic disorder and later as human rabies: a case report. AB - BACKGROUND: Cerebral malaria is arguably one of the most common non-traumatic encephalopathies in the developing world. Unless the diagnosis of cerebral malaria is made promptly, the consequence could be disastrous. Even though the diagnosis of cerebral malaria can be made relatively easily in majority of cases atypical presentation can often lead to misdiagnosis or delayed diagnosis. We report a case of an uncommon presentation of Plasmodium falciparum infection in a 17-year-old school girl with altered sensorium, seizures and phobic spasms. CASE PRESENTATION: A previously healthy 17-year-old school girl was admitted to our hospital with acute condition characterised by comatose state, recurrent seizures and phobic spasms. She initially presented to a local hospital with agitation and over talkativeness and was diagnosed as having an acute psychotic state. Few days later she became drowsy and developed recurrent seizures and marked phobic spasms which prompted the treating physician to diagnose human rabies. However, further investigations carried out in our unit (including rapid antigenic test for P. falciparum and peripheral blood smear) were positive for P. falciparum. She was treated as for cerebral malaria with intravenous quinine and discharge from hospital with no residual neurological deficit. CONCLUSION: Atypical presentation of cerebral malaria can often lead to misdiagnosis. This patient presented with encephalopathic illness with phobic spasms was initially misdiagnosed as human rabies. Therefore, the physicians in malarial endemic areas should be vigilant of similar presentations and should consider cerebral malaria as a possibility. PMID- 27514688 TI - Treatment-seeking behaviour for childhood fever among caretakers of Chivuna and Magoye rural communities of Mazabuka District, Zambia: a longitudinal study. AB - BACKGROUND: Treatment-seeking for childhood fever among caretakers in most rural parts of African region is still a major challenge. The aim of this study was to determine the treatment seeking behaviour for fever in under-5 children of Magoye and Chivuna rural areas of Mazabuka district in Zambia. METHODS: Treatment seeking behaviour was explored longitudinally among caretakers of 362 children aged 12-59 months with fever. The data was collected from caretakers using a structured interviewer-administered questionnaire at their homes. Chi-square test, one-sample test of proportions and logistic regression were the statistical methods used for data analysis. RESULTS: Of the 362 children with fever, 77 % of them had their treatment sought externally. In which 64 % had their treatment at health facility (HF), 18 % from community health workers (CHW), and 18 % from other sources. Early treatment (<= 24 h) was sought for 42 % of the fever episodes. In dry season, a child had 1.53 times more likely to have early treatment compared to rainy season [OR 1.53; 95 % CI 1.30, 1.80; p < 0.001]. A child in Chivuna was less likely to have early treatment compared to one in Magoye [OR 0.62; 95 % CI 0.50, 0.76; p < 0.001]. Caretakers had a reduced chance of 27 % [OR 0.73; 95 % CI 0.56, 0.95; p = 0.022] of seeking early treatment if they took a child to other sources compared to a HF. CONCLUSION: This study has revealed that seeking early and appropriate treatment was suboptimal in the study areas. Source of treatment, season and location were predictors of early treatment of fever among caretakers. Policies aimed at combating poor care seeking behaviour should not omit to address these factors. PMID- 27514687 TI - Heregulin-1beta and HER3 in hepatocellular carcinoma: status and regulation by insulin. AB - BACKGROUND: The heregulin-1beta/HER3-driven pathway is implicated in several epithelial malignancies and its blockade is currently undergoing clinical investigation. Paradoxically, the status and the regulation of this pathway is poorly known in hepatocellular carcinoma (HCC). METHODS: Using 85 HCC obtained after tumour resection, heregulin-1beta and HER3 expression was evaluated by real time RT-PCR, ELISA and/or immunohistochemistry. Statistics were performed to analyze associations between gene expression and clinicopathological parameters. The effects of insulin on the heregulin-1beta/HER3 pathway was investigated in four HCC cell lines. RESULTS: HER3 mRNA was upregulated in 52 % of tumours, while heregulin-1beta mRNA was downregulated in 82 %. Hepatitis B and C viral infections were respectively associated with high and low HER3 mRNA expression. No association was seen between neither HER3 or heregulin-1beta mRNA and prognostic factors, survival or recurrence. Immunohistochemistry showed predominant cytoplasmic staining of HER3 in tumours but the staining was nonreproducible. HER3 mRNA and protein levels were not correlated in liver tissues. In HCC cells, insulin promoted HER3 proteasomal degradation and inhibited heregulin-1beta stimulation of cell migration. HER3 and insulin receptor co-immunoprecipitated in these cells. The loss of insulin receptor expression by RNA interference sensitized cells to heregulin-1beta-induced AKT phosphorylation. CONCLUSIONS: Autocrine heregulin-1beta loop is uncommon in HCC and HER3 mRNA expression is differentially influenced by hepatitis viruses. Insulin is a negative regulator of HER3 protein expression and function in HCC cells. Altogether these data may explain why HER3 and heregulin-1beta expression have no prognostic value and suggest that HCC patients are unlikely to derive benefit from HER3-targeted monotherapies. PMID- 27514690 TI - Use of laboratory and administrative data to understand the potential impact of human parainfluenza virus 4 on cases of bronchiolitis, croup, and pneumonia in Alberta, Canada. AB - BACKGROUND: Human Parainfluenza Virus (hPIV) causes severe respiratory illness in infants and adults. Our study describes the association of hPIV1-4 with bronchiolitis, croup, and pneumonia using retrospective laboratory, administrative and public health data. Due to issues including the historic lack of hPIV4 in some commercial respiratory virus panels, the description of the impact of hPIV4 on croup, bronchiolitis, and pneumonia at population levels has often been limited. This study will use routine clinical laboratory data, and administrative data to provide a preliminary description of the impact of hPIV4 on these diseases in our population. METHODS: A three year cohort of patients positive for hPIV was linked with data from physician visits and hospital admissions to define cases and hospitalization status. International Classification of Disease (ICD-9) codes were used to determine if cases had croup, bronchiolitis, and pneumonia. We also looked at differences in hospitalization status, age and gender among hPIV1-4. All statistical analysis was done using SPSS (Version 19.0.0, IBM Corp(c) 2010) and Graphpad Prism V6 (GraphPad Software, Inc., 2012). RESULTS: Only hPIV1 and hPIV4 specimens had positivity rates greater than 5 % of all specimens sent for respiratory virus panel testing. hPIV1 exhibited a biennial pattern while the pattern for hPIV3 was less interpretable due to lower positivity rates. Circulation patterns for hPIV2 and hPIV4 were not assessed due to the low positivity rates of theses specimens. From 2010 to 2013, there were 2300 hPIV cases with hPIV3 (46 %) being the most common, followed by hPIV1 (27 %), hPIV4 (16 %) and hPIV2 (11 %). The median age was 2 years for all hPIV types. Males were slightly greater than females for hPIV1 and hPIV2, with an equal distribution for hPIV3 and slightly more females than males for hPIV4. hPIV1 and hPIV2 had the highest or proportion of croup while hPIV3 and hPIV4 had the highest proportion of pneumonia. Within hPIV4 cases, distributions of diseases were; pneumonia (21 %, 95 % CI 17.1-25.7), bronchiolitis (18 %, 95 % CI 14.3-22.5), croup (2 %, 95 % CI 0.8-3.9), mixed illness of any of pneumonia, bronchiolitis or croup (4 %, 95 % CI 2.5-7.0) or other respiratory diseases (54 %, 95 % CI 49.1-59.6). CONCLUSIONS: We used laboratory and administrative data to undertake a descriptive analysis of the association of hPIV1-4 with croup, bronchiolitis and pneumonia. hPIV4 appears to be more associated more with bronchiolitis and pneumonia and less with croup in our population. PMID- 27514691 TI - Examination of the Phenomenology and Clinical Correlates of Emetophobia in a Sample of Salvadorian Youths. AB - Emetophobia is an under-researched disorder characterized by a specific fear of vomiting. There is a paucity of research on this impairing condition, with extant examinations being largely limited to adult samples and online communities. The present study examined the incidence, phenomenology, and correlates of emetophobia in 305 Salvadorian youths. Caregivers completed a battery of questionnaires regarding the youth's symptoms of emetophobia, internalizing/externalizing symptoms, health anxiety, and obsessive-compulsive symptoms. Approximately 7.5 % of the sample was elevated on emetophobia symptoms, and higher levels of emetophobia symptoms were correlated with higher levels of internalizing, externalizing, health anxiety, and obsessive-compulsive symptoms, and lower levels of adaptive functioning. Youths meeting the cutoff for elevated emetophobia symptoms versus those who did not demonstrated significantly higher levels of externalizing behaviors, as well as general obsessive-compulsive symptoms, especially doubting/checking and neutralizing behaviors. These findings are hoped to help improve the conceptualization and treatment of this poorly understood disorder. PMID- 27514692 TI - Separation behavior of basic compounds on unbonded silicon oxynitride and silica high-performance liquid chromatography stationary phases with reversed-phase eluents. AB - Unbonded silicon oxynitride and silica high-performance liquid chromatography stationary phases have been evaluated and compared for the separation of basic compounds of differing molecular weight, pKa , and log D using aqueous/organic mobile phases. The influences of percentage of organic modifier, buffer pH, and concentration in the mobile phase on base retention were investigated on unbonded silicon oxynitride and silica phases. The results confirmed that unbonded silicon oxynitride and silica phases demonstrated excellent separation performance for model basic compounds and both the unbonded phases examined possessed a hydrophobic/adsorption and ion-exchange character. The silicon oxynitride stationary phase exhibited high hydrophilicity compared with silica with a reversed-phase mobile phase. An ion-exclusion-type mechanism becomes predominant for the separation of three aimed bases on the silicon oxynitride column at pH 2.8. Different from silicon oxynitride stationary phase, no obvious change for the retention time of three model bases on silica stationary phase at pH 2.8 can be observed. PMID- 27514693 TI - Factors associated with choosing the emergency department as the primary access point to health care: a Canadian population cross-sectional study. AB - OBJECTIVE: Approximately 4.3 million Canadians are without a primary care physician, of which 13% choose the emergency department (ED) as their regular access point to health care. We sought to identify factors associated with preferential ED use over other health services. We hypothesized that socioeconomic barriers (i.e., employment, health status, education) to primary care would also prevent access to ED alternatives. METHODS: Data from the Canadian Community Health Survey, 2007 to 2008, were analysed (N=134,073; response rate 93.5%). Our study population comprised 14,091 individuals identified without a primary care physician. Socioeconomic variables included employment, health, and education. Covariates included chronic health conditions, immigrant status, gender, age, and mental health. Prevalence estimates and 95% confidence intervals (CIs) for each variable were calculated. Weighted logistic regression models were constructed to evaluate the importance of individual risk factors and their interactions after adjustment for relevant covariates. RESULTS: The sample comprised 57.2% males from across Canada. Employment (OR 0.73 [95% CI: 0.59-0.90]), good health (OR 0.73 [95% CI 0.57-0.88]), and post-secondary education (OR 0.68 [95% CI 0.53-0.88]) reduced respondents use of the ED. The reduced odds of ED use were independent of chronic conditions, mental health, gender, poor mobility, province, and age. CONCLUSIONS: Low socioeconomic status dictates preferential ED use in those without a primary care physician. Specific policy and system development targeting this at-risk population are indicated to alter ED use patterns in this population. PMID- 27514694 TI - Effects of Organogel Hardness and Formulation on Acceptance of Frankfurters. AB - Different organogel formulations used as beef fat (BF) replacement (0%, 20%, 40%, 60%, and 80%) were utilized to optimize the mechanical properties of frankfurters. Organogels, made of canola oil (CO), included different concentrations of ethyl cellulose (EC) and sorbitan monostearate (SMS). They consisted of: 8% EC + 1.5% SMS referred to as organogel-I (OG-I), 8% EC + 3.0% SMS (OG-II), and 10% EC + 1.5% SMS (OG-III), which were found promising in a previous study when used at 100% replacement. Replacement of BF with organogels at all levels could bring down the very high hardness values (texture profile analysis and sensory) of frankfurters prepared using CO by itself, relative to the BF control. OG-I and OG-II quantity had no significant effect on hardness and springiness, being similar in many cases to the BF and lower than the CO control. Shear force values of all organogel treatments were not significantly different from one another, and were between the BF and CO controls. Smokehouse yield showed a pattern of decreasing losses with increasing organogel replacement level. Sensory analysis revealed that using CO by itself significantly increased hardness, but structuring the oil (via organogelation), brought it down to the BF control value in all OG-I and OG-II formulations. Juiciness was significantly reduced by using liquid oil but increased with raising the amount of organogels. Oiliness sensation increased with higher organogel substitution and was actually higher than the beef control. The study demonstrates the potential use of vegetable oil structuring in replacing the more saturated BF in emulsion-type meat products. PMID- 27514695 TI - Intermediate stages of electrochemical oxidation of single-crystalline platinum revealed by in situ Raman spectroscopy. AB - Understanding the atomistic details of how platinum surfaces are oxidized under electrochemical conditions is of importance for many electrochemical devices such as fuel cells and electrolysers. Here we use in situ shell-isolated nanoparticle enhanced Raman spectroscopy to identify the intermediate stages of the electrochemical oxidation of Pt(111) and Pt(100) single crystals in perchloric acid. Density functional theory calculations were carried out to assist in assigning the experimental Raman bands by simulating the vibrational frequencies of possible intermediates and products. The perchlorate anion is suggested to interact with hydroxyl phase formed on the surface. Peroxo-like and superoxo-like two-dimensional (2D) surface oxides and amorphous 3D alpha-PtO2 are sequentially formed during the anodic polarization. Our measurements elucidate the process of the electrochemical oxidation of platinum single crystals by providing evidence for the structure-sensitive formation of a 2D platinum-(su)peroxide phase. These results may contribute towards a fundamental understanding of the mechanism of degradation of platinum electrocatalysts. PMID- 27514696 TI - Evaluation of Interspinous Spacer Outcomes in Degenerative Lumbar Canal Stenosis: Clinical Study. AB - BACKGROUND: Lumbar spinal stenosis is a common diagnosis in elderly individuals, and the rates of surgery have risen all over the world. The optimal approach to provide satisfactory decompression and minimize complications for lumbar spinal stenosis remains controversial. OBJECTIVE: The purpose of this study was to evaluate the surgical outcome of interspinous spacers versus decompressive laminectomy in the management of degenerative lumbar canal stenosis. PATIENTS AND METHODS: Our prospective, comparative study included 2 groups of patients who were operated on in Ain Shams University Hospitals between January 2010 and December 2014. In the first group, 28 patients underwent decompression and additional implantation of an interspinous spacer (ISP). In the second group, 25 patients underwent decompressive laminectomy (DL). RESULTS: Our statistical results revealed no significant difference in outcome between the 2 groups regarding visual analog scale score for leg pain and Oswestry Low Back Pain Disability Index. However, the improvement (visual analog scale score) for back pain was better in the DL group. Complication and reoperation rates were higher in the ISP group. CONCLUSION: Although decompression and additional implantation of an ISP are safe procedures, they do not show better improvement in clinical outcome as compared with decompressive laminectomy. PMID- 27514697 TI - Redefining Congenital Atlantoaxial Dislocation: Objective Assessment in Each Plane Before and After Operation. AB - BACKGROUND: The C1-C2 joint has multiple degrees of freedom of movement and C1-C2 dislocation (AAD) is often multiplanar. The existing methodology to assess the dislocation is limited to few planes. The object of this study is to redefine and objectively assess congenital AAD in each possible plane, before and after the operation. METHODS: This study consisted of 95 patients of irreducible congenital AAD operated on with the posterior approach alone. Preoperative and postoperative computed tomography imaging was studied in the axial, coronal, and sagittal planes. The relationship of C1-C2 along with the C1-C2 joint inclination was studied in each plane. The extent and type of dislocation was objectively assessed in each plane (newer indices) and compared with follow-up imaging for correction. The preoperative and postoperative Japenese orthopaedics association scores were compared. RESULTS: The commonest variety (61 patients) was a combination of anteroposterior (AP) and vertical C1-C2 dislocation. Five patients had predominant APnteroposterior, 6 vertical, 4 axial rotational, 9 lateral angular tilt, and 3 had lateral transalational. Seven patients had a combination of dislocation in AP, vertical, and rotational planes. AP dislocation was seen with sagittal inclination of C1-C2 joints and vertical dislocation with coronal inclination. Asymmetry in the joint's sagittal inclination added to a rotational component, whereas asymmetry in the coronal angulation caused lateral angular tilt. Pure rotational or lateral translation dislocation had near-normal C1-C2 orientation. Preoperative Japenese orthopaedics association score was worst in the lateral tilt and the lateral translation. Correction in all planes was achieved in all patients. CONCLUSIONS: The objective assessment of C1-C2 dislocation and joints in each plane was to determine its management and help in achieving multiplanar correction. PMID- 27514698 TI - The DERIVO Embolization Device in the Treatment of Intracranial Aneurysms: Short- and Midterm Results. AB - OBJECTIVE: The DERIVO embolization device (DED) is a new nitinol flow diverter stent manufactured for the treatment of intracranial aneurysms. In this study, we evaluated the safety and efficacy of the DED in the treatment of intracranial aneurysms and present the short- and midterm results. METHODS: We treated 34 aneurysms using 26 devices in 24 patients with wide-necked, mostly medium-sized, and fusiform aneurysms. Fourteen of the patients included in the study were women and the other 10 were men. Headache was the most frequent symptom. Although 31 (91.2%) aneurysms were in the anterior circulation, 3 (8.8%) were in the posterior. Intracranial stent medication was accomplished in all patients. All patients were evaluated 1 day later for any ischemic lesion with diffusion weighted imaging. The first and second follow-up angiograms were planned to be performed after 3 and 9 months. RESULTS: In all patients, the treatment was successful. No hemorrhagic complication was seen on computed tomography scan performed immediately after the procedure. All patients were discharged without any neurologic deficit. Although 20 (71.4%) of 28 aneurysms in 20 patients were totally closed on the 3-month follow-up angiogram, 14 (77.8%) of 18 aneurysms in 9 patients were totally closed on the 9-month follow-up. General morbidity was 8.4%, and mortality was 4.3%. CONCLUSIONS: The DED seems effective and safe in the treatment of different kinds of intracranial aneurysms. PMID- 27514699 TI - En Route to Stimuli-Responsive Boron-, Nitrogen-, and Sulfur-Doped Polycyclic Aromatic Hydrocarbons. AB - Replacing both meso carbon atoms of the polycyclic aromatic hydrocarbon (PAH) bisanthene by boron atoms creates an efficient blue fluorophore with a strong electron-accepting character. The corresponding meso-B,S-doped bisanthene exhibits a solvent-dependent green-to-orange photoluminescence and undergoes a reversible reduction at E1/2 =-2.06 V (vs. FcH/FcH(+) ). After oxidation of the sulfur atom, the resulting sulfoxide emits in the blue range of the spectrum, shows only negligible solvatochromism, and a reversible redox transition at E1/2 =-1.74 V. Several related B, N- and B, S-containing PAHs have been prepared following the same modular synthetic procedure and are also described herein. In order to systematically compare their optoelectronic properties, all products have been investigated by cyclic voltammetry as well as UV/Vis absorption/emission spectroscopy. PMID- 27514701 TI - Closing the gap: astrocytes and brain metastasis. AB - Astrocytes are emerging as essential regulators of brain metastasis progression. In a current issue of Nature, Chen et al. identify a novel mechanism of astrocyte carcinoma interaction and exploit vulnerabilities therein to slow brain metastatic growth in pre-clinical models. PMID- 27514700 TI - Ferroptosis is an autophagic cell death process. AB - Ferroptosis is an iron-dependent form of regulated necrosis. It is implicated in various human diseases, including ischemic organ damage and cancer. Here, we report the crucial role of autophagy, particularly autophagic degradation of cellular iron storage proteins (a process known as ferritinophagy), in ferroptosis. Using RNAi screening coupled with subsequent genetic analysis, we identified multiple autophagy-related genes as positive regulators of ferroptosis. Ferroptosis induction led to autophagy activation and consequent degradation of ferritin and ferritinophagy cargo receptor NCOA4. Consistently, inhibition of ferritinophagy by blockage of autophagy or knockdown of NCOA4 abrogated the accumulation of ferroptosis-associated cellular labile iron and reactive oxygen species, as well as eventual ferroptotic cell death. Therefore, ferroptosis is an autophagic cell death process, and NCOA4-mediated ferritinophagy supports ferroptosis by controlling cellular iron homeostasis. PMID- 27514702 TI - Mitochondrial fusion fuels T cell memory. AB - Differences in mitochondrial structures determine the metabolic landscape of effector and memory T cell populations in vivo. PMID- 27514703 TI - Endoscopic biodegradable biliary stents in the treatment of benign biliary strictures: First report of clinical use in patients. AB - The first clinical experience of endoscopically inserted polydioxanone biodegradable biliary stents (BDBS) in the treatment of benign biliary strictures is reported. Two patients with a benign common bile duct stricture were endoscopically treated with 8-mm-bore BDBS during endoscopic retrograde cholangiography. Both BDBS insertions were technically successful and without adverse events. At 6 months, the stricture resolution was excellent and BDBS degradation was predicted in repeated magnetic resonance imaging. The first experience with endoscopic BDBS seems promising in the treatment of benign biliary strictures. During 6 months of follow up, BDBS seemed sufficient for remodeling and resolution of strictures. Further studies are needed to confirm the effectiveness of biodegradable biliary stents in endoscopic management of benign biliary strictures. PMID- 27514704 TI - Bioactive lipids accumulate in stored red blood cells despite leukoreduction: a targeted metabolomics study. AB - BACKGROUND: Accumulation of bioactive lipids during red blood cell (RBC) storage has been identified as a potential source of posttransfusion sequelae in vulnerable populations. Typically, white blood cells (WBCs) have been implicated in the generation of bioactive lipids, and leukoreduction has been seen as a solution to this issue. STUDY DESIGN AND METHODS: We developed a targeted metabolomics approach with isotope dilution to quantify a panel of bioactive lipids in both leukoreduced (LR) and nonleukoreduced (NLR) RBC units over the course of storage. RESULTS: Leukoreduction greatly attenuated the production of 12-hydroxyeicosatetraenoic acid (HETE), 12-hydroxyeicosapentaenoic acid, and 14 hydroxydocosahexaenoic acid (HDoHE), all three of which are mediated by 12 lipoxygenase present in WBCs and platelets. However, despite leukoreduction, micromolar levels of linoleic acid (LA), arachidonic acid (AA), and docosahexaenoic acid (DHA) were observed in the RBC units stored for 42 days. These major polyunsaturated fatty acids (PUFAs) and their oxidation products (oxylipins) also significantly increased with storage time, including 5-, 8-, 9-, 11-, 12-, and 15- HETEs from AA; 9- and 13-hydroxyoctadecadienoic acid (HODE); 9 , 10-, and 12,13-dihydroxyoctadecenoic acids from LA; and 14-, 16-, and 17-HDoHEs from DHA. The majority of PUFAs and oxylipins accumulated in the supernatant fraction. Large donor-to-donor variations were observed in both LR-RBC and NLR RBC units. CONCLUSION: While the exact role the accumulation of PUFAs and oxylipins plays in RBC unit quality and transfusion medical outcomes remains undetermined, the analytes of interest in this study may serve as biomarkers for lipid degradation and oxidation during storage and may induce changes in human physiology upon transfusion. PMID- 27514705 TI - Roadmap for improving patient and graft survival in the next 10 years. PMID- 27514706 TI - Adnexal tumor of probable Wolffian origin arising from retroperitoneal space. PMID- 27514707 TI - ABC Transporters and Drug Resistance in Patients with Epilepsy. AB - Resistance to antiepileptic drugs (AED) remains a major problem in clinical epileptology. This pharmacoresistance is independent of the choice of AEDs. Different hypotheses have been proposed to explain the neurobiological basis for pharmacoresistance in epilepsy. The transporter hypothesis is the mostly investigated theory. Hereby, overexpression of multidrug efflux transporters, such as P-glycoprotein (Pgp), at the blood-brain-barrier (BBB) is thought to be involved in pharmacoresistance in epilepsy by extruding AEDs from their target site. Accumulating evidence supports an overexpression of Pgp in pharmacoresistant epilepsy. Molecular Imaging studies provide unique opportunities for the in-vivo study of the transporter hypothesis in the central nervous system (CNS). Several studies demonstrated that positron emission tomography (PET) with [11C]-radiolabled Pgp substrates is a promising tool for in vivo investigation of Pgp function at the rat, monkey and human BBB. Quantification of Pgp over activity in epilepsy patients by in vivo imaging could be highly useful because altered treatment strategies or novel AED could then be applied. PMID- 27514708 TI - In Vitro and Ex Vivo Model Systems to Measure ABC Transporter Activity at the Blood-Brain Barrier. AB - With the aging population the occurrence of central nervous system diseases such as cancer, mental disorders and neurodegenerative diseases, is expected to increase and hence, the demand for effective drugs. However, the passage of drugs across the blood-brain barrier represents a major challenge in accomplishing efficient brain delivery of therapeutic agents. This highly efficient barrier is composed of a monolayer of capillary endothelial cells supported by pericytes and astrocytic end-feet, that together effectively shield the brain from the blood. The brain microvascular endothelial cells form a physical and metabolic barrier where paracellular and transcellular transport of molecules in and out of the brain is closely regulated, allowing nutrients to pass but preventing the entry of harmful neurotoxic substances, including drugs. For this purpose brain endothelial cells express efficient efflux pumps, such as ATP binding cassette (ABC) transporters, which limit the delivery of drugs into the brain. To treat the above-mentioned chronic central nervous system disorders, it is crucial to design compounds that can pass the blood-brain barrier and thus the ABC transporters. In order to achieve this, representative models of the blood-brain barrier with predictive validity are necessary. This review discusses the current in vitro and ex vivo model systems that are used to measure ABC transporter activity in order to study potential in vivo efficacy of blood-brain barrier-drug passage. PMID- 27514709 TI - Adolescent Cannabis Use: What is the Evidence for Functional Brain Alteration? AB - BACKGROUND: Cannabis use typically commences during adolescence, a period during which the brain undergoes profound remodeling in areas that are high in cannabinoid receptors and that mediate cognitive control and emotion regulation. It is therefore important to determine the impact of adolescent cannabis use on brain function. OBJECTIVE: We investigate the impact of adolescent cannabis use on brain function by reviewing the functional magnetic resonance imaging studies in adolescent samples. METHOD: We systematically reviewed the literature and identified 13 functional neuroimaging studies in adolescent cannabis users (aged 13 to 18 years) performing working memory, inhibition and reward processing tasks. RESULTS: The majority of the studies found altered brain function, but intact behavioural task performance in adolescent cannabis users versus controls. The most consistently reported differences were in the frontal-parietal network, which mediates cognitive control. Heavier use was associated with abnormal brain function in most samples. A minority of studies controlled for the influence of confounders that can also undermine brain function, such as tobacco and alcohol use, psychopathology symptoms, family history of psychiatric disorders and substance use. CONCLUSION: Emerging evidence shows abnormal frontal-parietal network activity in adolescent cannabis users, particularly in heavier users. Brain functional alterations may reflect a compensatory neural mechanism that enables normal behavioural performance. It remains unclear if cannabis exposure drives these alterations, as substance use and mental health confounders have not been systematically examined. PMID- 27514710 TI - Importance of ABC Transporters in Drug Development. AB - ATP-binding cassette (ABC) transporters are a huge family of ATP-dependent transmembrane proteins whose main function is exporting or importing substances or molecules through the cell membranes, plasma cell membrane, or inner membranes in organelles. They fulfill these functions by maintaining cell integrity, metabolism, and homeostasis. They are expressed in a variety of tissues as they transport numerous essential compounds including lipids and other signaling molecules. ABC transporters became widely studied since the discovery of their ability to carry a multitude of xenobiotics, including therapeutic drugs, and in light of the fact that they represent a hurdle for the treatment of resistant cancers. In contrast, the role of ABC transporters in neurological diseases like Alzheimer's and Parkinson's, depression, schizophrenia, and epilepsy remains controversial and their mechanism of action in these pathologies remains elusive, thus hindering the implementation of therapies aimed at modulating the functions of these transporters. To date, a number of natural and synthetic compounds are known to act as inhibitors, substrates, and even inducers of these transporters, being able to modulate their expression and/or function; however, their implication as therapeutic agents is far from reaching wide clinical utilization. This review highlights the importance of overcoming the challenges posed by ABC transporters in drug development. PMID- 27514711 TI - Design and Synthesis of New Selective P-gp Substrates and Inhibitors. AB - P-glycoprotein is an ATP-binding cassette transporter involved in drug absorption, distribution and excretion. It pumps a wide range of xenobiotic compounds out of the cells and plays a crucial role in Multi Drug Resistance. Moreover, recent studies have demonstrated that changes in P-gp function and/or expression at the blood brain barrier are implicated in the pathogenesis of neurological disorders such as therapy-refractory epilepsy, Alzheimer's and Parkinson's disease. In the last decades the studies have been addressed to the discovery of potent P-gp inhibitors able to revert pharmacoresistance and to the development of PET tracers to detect P-gp activity and expression for an early diagnosis and therapy monitoring of neurodegenerative disease. However, clinical trials have reported only limited success in reversing MDR and radiolabeled ligands were not actually useful to study differences of transporter function in different brain regions due to their low brain uptake. The difficulties into the discovery of new ligands is due to the use of different experimental assays, to the fact that P-gp is highly flexible protein with different binging sites and available crystallographic structures for the protein have inadequate resolution. To overcome these limitations research groups prefer computational approaches such as homology models in their structure-based design or ligand-based methodologies. A recent approach aimed to identify ligands which can interrupt ATP-binding and hydrolysis by P-gp, by interacting at the NBDs of the protein. In this review results from radiolabeled, substrates and inhibitors, for monitoring the activity and expression of P-gp, respectively, are presented. PMID- 27514712 TI - Altered Steroid Metabolism and Insulin Signaling in PCOS Endometria: Impact in Tissue Function. AB - BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine/ metabolic disorder characterized by hyperandrogenemia and in most cases, by hyperinsulinemia in addition to obesity. Besides ovarian dysfunction, endometrial physiology is also disrupted since this tissue is highly dependent on the action of steroids; in case of conception cycles, high percentage of abortion is observed. Because of the endocrine/metabolic alterations, PCOS-women present high probability to develop hyperplasia and endometrial cancer, where an imbalance of cell proliferation/apoptosis processes is detected. Additionally, insulin pathway and the endometrial energetic homeostasis are also compromised. METHODS: The aim of this review was to report molecular alterations related to insulinresistance and/or obesity in PCOS-women endometria that could drive to infertility. For this, several methods were employed: immunohistocytochemistry, qPCR, western blot, glucoseuptake, cell cultures, among others. RESULTS: Diminished levels and activity of several insulin signaling pathway molecules, like IRS 1/AS160/PKCzeta, were detected. Concomitantly, a defect in the synthesis and GLUT4 translocation to cell surface is induced. Oral administration of metformin (insulin sensitizer) to PCOS-patients increases GLUT4 endometrial levels, improving fertility of those patients. Another relevant feature is the high percentage of obesity in PCOS-women; adiponectin is an obesity marker and elicits an insulin-sensitizer action, being diminished in plasma of obese PCOSwomen similar to its endometrial level, adiponectin-receptors and APPL1, an adapter molecule of adiponectin pathway. Moreover, obesity and PCOS can induce a pro inflammatory environment, exaggerating the alterations in insulin pathway. CONCLUSION: The evidences obtained in PCOS-endometria clearly indicate that these molecular defects could partially explain the reproductive failures of these patients. PMID- 27514713 TI - Chronic recurrent osteomyelitis: A diagnostic and therapeutic challenge. AB - INTRODUCTION: Chronic recurrent osteomyelitis (CRO) is a rare disease characterised by unifocal or multifocal aseptic inflammatory bony lesions. OBJECTIVE: To evaluate clinical features and response to treatment with non steroidal anti-inflammatory drugs in patients with CRO. MATERIALS AND METHODS: A retrospective assessment was conducted on 5 children with OCR over a period of 8 years. They had been diagnosed based on clinical, laboratory findings, histological study of injuries, and imaging test. RESULTS: Multifocal disease was observed in 40% of cases, and unifocal in 60%. The large majority (80%) were male, with a mean age at diagnosis of 13 years (range: 11-15 years). The bones most frequently affected were the clavicle and tibia, representing 18.2%. The most common presenting symptom was pain in all patients, with fever being present in 20% of cases. Imaging studies such as CT and MRI were effective in 100%, and in all cases the biopsy reported a lymphoplasmacytic infiltrate. After a mean follow-up of 5.9 years, there was a good treatment response in 100%, with a mean recurrence at 5.25 months being observed. CONCLUSIONS: The anodyne results of most clinical studies to assess CRO, and the similarity in clinical presentation of this with many infectious or tumour diseases makes its diagnosis a real challenge. On the other hand treatment with NSAIDs can be considered a good initial therapeutic option. PMID- 27514715 TI - Prevention of post-disaster sequelae through efficient communication planning: analysis of information-seeking behaviours in Montana and Alabama. PMID- 27514716 TI - Dementia-related Bri2 BRICHOS is a versatile molecular chaperone that efficiently inhibits Abeta42 toxicity in Drosophila. AB - Formation of fibrils of the amyloid-beta peptide (Abeta) is suggested to play a central role in neurodegeneration in Alzheimer's disease (AD), for which no effective treatment exists. The BRICHOS domain is a part of several disease related proproteins, the most studied ones being Bri2 associated with familial dementia and prosurfactant protein C (proSP-C) associated with lung amyloid. BRICHOS from proSP-C has been found to be an efficient inhibitor of Abeta aggregation and toxicity, but its lung-specific expression makes it unsuited to target in AD. Bri2 is expressed in the brain, affects processing of Abeta precursor protein, and increased levels of Bri2 are found in AD brain, but the specific role of its BRICHOS domain has not been studied in vivo Here, we find that transgenic expression of the Bri2 BRICHOS domain in the Drosophila central nervous system (CNS) or eyes efficiently inhibits Abeta42 toxicity. In the presence of Bri2 BRICHOS, Abeta42 is diffusely distributed throughout the mushroom bodies, a brain region involved in learning and memory, whereas Abeta42 expressed alone or together with proSP-C BRICHOS forms punctuate deposits outside the mushroom bodies. Recombinant Bri2 BRICHOS domain efficiently prevents Abeta42 induced reduction in gamma-oscillations in hippocampal slices. Finally, Bri2 BRICHOS inhibits several steps in the Abeta42 fibrillation pathway and prevents aggregation of heat-denatured proteins, indicating that it is a more versatile chaperone than proSP-C BRICHOS. These findings suggest that Bri2 BRICHOS can be a physiologically relevant chaperone for Abeta in the CNS and needs to be further investigated for its potential in AD treatment. PMID- 27514714 TI - Three-year follow-up of a randomised controlled trial to reduce excessive weight gain in the first two years of life: protocol for the POI follow-up study. AB - BACKGROUND: The Prevention of Overweight in Infancy (POI) study was a four-arm randomised controlled trial (RCT) in 802 families which assessed whether additional education and support on sleep (Sleep group); food, physical activity and breastfeeding (FAB group); or both (Combination group), reduced excessive weight gain from birth to 2 years of age, compared to usual care (Control group). The study had high uptake at recruitment (58 %) and retention at 2 years (86 %). Although the FAB intervention produced no significant effect on BMI or weight status at 2 years, the odds of obesity were halved in those who received the sleep intervention, despite no apparent effect on sleep duration. We speculate that enhanced self-regulatory behaviours may exist in the Sleep group. Self regulation was not measured in our initial intervention, but extensive measures have been included in this follow-up study. Thus, the overall aim of the POI follow-up is to determine the extent to which augmented parental support and education on infant sleep, feeding, diet, and physical activity in the first 2 years of life reduces BMI at 3.5 and 5 years of age, and to determine the role of self-regulation in any such relationship. METHODS/DESIGN: We will contact all 802 families and seek renewed consent to participate in the follow-up study. The families have received no POI intervention since the RCT finished at 2 years of age. Follow-up data collection will occur when the children are aged 3.5 and 5 years (i.e. up to 3 years post-intervention). Outcomes of interest include child anthropometry, body composition (DXA scan), diet (validated food frequency questionnaire), physical activity (accelerometry), sleep (questionnaire and accelerometry), and self-regulation (questionnaires and neuropsychological assessment). DISCUSSION: Our follow-up study has been designed primarily to enable us to determine whether the intriguing benefit of the sleep intervention suggested at 2 years of age remains as children approach school age. However, cohort analyses will also investigate how BMI, self-regulation, and sleep consolidation develop during the early years. This information will be valuable to researchers and policy makers progressing the field of early childhood obesity prevention. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00892983 . PMID- 27514717 TI - Functional and mechanistic roles of the human proton-coupled folate transporter transmembrane domain 6-7 linker. AB - The proton-coupled folate transporter (PCFT; SLC46A1) is a folate-proton symporter expressed in solid tumors and is used for tumor-targeted delivery of cytotoxic antifolates. Topology modeling suggests that the PCFT secondary structure includes 12 transmembrane domains (TMDs) with TMDs 6 and 7 linked by an intracellular loop (positions 236-265) including His247, implicated as functionally important. Single-cysteine (Cys) mutants were inserted from positions 241 to 251 in Cys-less PCFT and mutant proteins were expressed in PCFT null (R1-11) HeLa cells; none were reactive with 2-aminoethyl methanethiosulfonate biotin, suggesting that the TMD6-7 loop is intracellular. Twenty-nine single alanine mutants spanning the entire TMD6-7 loop were expressed in R1-11 cells; activity was generally preserved, with the exception of the 247, 250, and 251 mutants, partly due to decreased surface expression. Coexpression of PCFT TMD1-6 and TMD7-12 half-molecules in R1-11 cells partially restored transport activity, although removal of residues 252-265 from TMD7-12 abolished transport. Chimeric proteins, including a nonhomologous sequence from a thiamine transporter (ThTr1) inserted into the PCFT TMD6-7 loop (positions 236-250 or 251 265), were active, although replacement of the entire loop with the ThTr1 sequence resulted in substantial loss of activity. Amino acid replacements (Ala, Arg, His, Gln, and Glu) or deletions at position 247 in wild-type and PCFT-ThTr1 chimeras resulted in differential effects on transport. Collectively, our findings suggest that the PCFT TMD6-7 connecting loop confers protein stability and may serve a unique functional role that depends on secondary structure rather than particular sequence elements. PMID- 27514719 TI - Who may benefit from robotic gastrectomy?: A subgroup analysis of multicenter prospective comparative study data on robotic versus laparoscopic gastrectomy. AB - AIMS: Robotic gastrectomy for gastric cancer has been proven to be a feasible and safe minimally invasive procedure. However, our previous multicenter prospective study indicated that robotic gastrectomy is not superior to laparoscopic gastrectomy. This study aimed to identify which subgroups of patients would benefit from robotic gastrectomy rather than from conventional laparoscopic gastrectomy. METHODS: A prospective multicenter comparative study comparing laparoscopic and robotic gastrectomy was previously conducted. We divided the patients into subgroups according to obesity, type of gastrectomy performed, and extent of lymph node dissection. Surgical outcomes were compared between the robotic and laparoscopic groups in each subgroup. RESULTS: A total of 434 patients were enrolled into the robotic (n = 223) and laparoscopic (n = 211) surgery groups. According to obesity and gastrectomy type, there was no difference in the estimated blood loss (EBL), number of retrieved lymph nodes, complication rate, open conversion rate, and the length of hospital stay between the robotic and laparoscopic groups. According to the extent of lymph node dissection, the robotic group showed a significantly lower EBL than did the laparoscopic group after D2 dissection (P = 0.021), while there was no difference in EBL in patients that did not undergo D2 dissection (P = 0.365). CONCLUSION: Patients with gastric cancer undergoing D2 lymph node dissection can benefit from less blood loss when a robotic surgery system is used. PMID- 27514720 TI - Prospective assessment of the quality of life in patients treated surgically for rectal cancer with lower anterior resection and abdominoperineal resection. AB - INTRODUCTION: Rectal cancer is the most common malignant neoplasm of the gastrointestinal tract. The aim of the study was to assess the quality of life in patients undergoing surgical treatment for the rectal cancer, either lower anterior or abdominoperineal resection. MATERIALS AND METHODS: 100 patients suffering from rectal cancer were selected for a prospective study (50-APR, 50 LAR). The quality of life was assessed two times: at the admission to the Department and 6 months following surgery. For assessment of the quality of life, two standard questionnaires were used, EORT QLQ-C30 and EORTC QLQ-C29. RESULTS: The studied groups were not different with respect to demographic factors. The patients who underwent LAR spent less time in hospital (p = 0.00001). The patients undergoing APR scored less with respect to physical ability (p = 0.0434), cognitive (p = 0.0363) and emotional state (p = 0.0463) and on symptom scale (nausea and vomiting - p: 0.0199, diarrhea - p: 0.0000, constipation (p = 0.0018)); however, the patients who were treated with LAR scored less on pain scale (p = 0.0189). The QLQ-C29 questionnaire revealed impaired functioning of patients 6 months following APR in terms of life chances (p = 0.0000) and problems with body weight (p = 0.0212). In both groups, the quality of life improved 6 months after surgery. CONCLUSIONS: LAR is a chance for better quality of life for many patients. Six months after surgery, the quality of life of patients improves regardless of the operating method (APR, LAR). PMID- 27514718 TI - Oral anticoagulation in patients with atrial fibrillation and medical non neoplastic disease in a terminal stage. AB - Many patients with non-neoplastic disease develop atrial fibrillation in advanced stages of their disease. The aim of this study is to determine the factors associated with the use of oral anticoagulants in patients with atrial fibrillation and non-neoplastic medical disease in a terminal stage, and whether their use is associated with a longer survival. Design is prospective, observational, multicentre study. Patients with atrial fibrillation and non neoplastic disease (severe not reversible organ insufficiency) in a terminal stage were included between February 2009 and September 2010. A 6-month follow-up was carried out. We included 314 patients with a mean (SD) age of 82.6 (7.0) years. Their mean (SD) scores in CHADS2 and ATRIA scales were 3.4 (1.2) and 4.7 (2.0), respectively. Anticoagulants were prescribed to 112 (37.5 %) patients. The use of anticoagulants was associated with age (OR 0.96 95 % CI 0.93-0.99, p = 0.046) and to the Barthel index (OR 1.01 95 % CI 1.00-1.02; p = 0.034). After performing a propensity score matching analysis, 262 patients were included in the survival analysis. After 6 months, 133 (50.8 %) patients were dead. The mortality is higher among patients who are not treated with oral anticoagulants (57.1 vs. 39.4 %; p = 0.006), but it is independently associated only with the Barthel index score (HR 0.99 95 % CI 0.98-1.00; p = 0.039), delirium (HR 1.60, 95 % CI 1.08-2.36; p = 0.018), anorexia (HR 1.58 95 % CI 1.05-2.38; p = 0.027), and with the use of calcium channel blockers (HR 0.50 95 % CI 0.30-0.84; p = 0.009). In patients with atrial fibrillation and non-neoplastic disease in a terminal stage, the use of oral anticoagulants is not independently associated with a higher probability of survival. PMID- 27514721 TI - Immunotherapy of melanoma. AB - Immunotherapy for advanced melanoma has progressed dramatically in the last five years with the approval of immune checkpoint inhibitors targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD 1). Inhibition of these targets can break cancer-immune tolerance and result in durable objective responses with significantly improved tolerability over cytokine-based immunotherapy. Ipilimumab is an inhibitor of CTLA-4 and the first in-class immune checkpoint inhibitor to demonstrate an improvement in overall survival in melanoma. Pembrolizumab and nivolumab target PD-1 and have improved single agent activity and tolerability in comparison to ipilimumab. The combination of nivolumab and ipilimumab results in even better response rates, reductions in tumor volume and progression free survival but at the expense of considerable autoimmune effects. Autoimmune side-effects and non-standard response kinetics represent a new challenge associated with cancer therapies that practitioners will have to become more familiar with as checkpoint inhibitors increasingly become part of mainstream oncological practice. Ongoing areas of investigation include drug development against novel immune targets; alternative treatment modalities, such as genetically modified oncolytic viruses; optimization of immunotherapy combination strategies; and the identification of reliable biomarkers to better guide treatment selection. PMID- 27514722 TI - Phenobarbital reduces EEG amplitude and propagation of neonatal seizures but does not alter performance of automated seizure detection. AB - OBJECTIVE: Phenobarbital increases electroclinical uncoupling and our preliminary observations suggest it may also affect electrographic seizure morphology. This may alter the performance of a novel seizure detection algorithm (SDA) developed by our group. The objectives of this study were to compare the morphology of seizures before and after phenobarbital administration in neonates and to determine the effect of any changes on automated seizure detection rates. METHODS: The EEGs of 18 term neonates with seizures both pre- and post phenobarbital (524 seizures) administration were studied. Ten features of seizures were manually quantified and summary measures for each neonate were statistically compared between pre- and post-phenobarbital seizures. SDA seizure detection rates were also compared. RESULTS: Post-phenobarbital seizures showed significantly lower amplitude (p<0.001) and involved fewer EEG channels at the peak of seizure (p<0.05). No other features or SDA detection rates showed a statistical difference. CONCLUSION: These findings show that phenobarbital reduces both the amplitude and propagation of seizures which may help to explain electroclinical uncoupling of seizures. The seizure detection rate of the algorithm was unaffected by these changes. SIGNIFICANCE: The results suggest that users should not need to adjust the SDA sensitivity threshold after phenobarbital administration. PMID- 27514723 TI - School meal provision, health, and cognitive function in a Nordic setting - the ProMeal-study: description of methodology and the Nordic context. AB - BACKGROUND: School meals, if both nutritious and attractive, provide a unique opportunity to improve health equality and public health. OBJECTIVE: To describe the study rationale, data collection, and background of participants in the study 'Prospects for promoting health and performance by school meals in Nordic countries' (ProMeal). The general aim was to determine whether overall healthiness of the diet and learning conditions in children can be improved by school lunches, and to capture the main concerns regarding school lunches among children in a Nordic context. DESIGN: A cross-sectional, multidisciplinary study was performed in Finland, Iceland, Norway, and Sweden on pupils (n=837) born in 2003. RESULTS: In total 3,928 pictures of school lunches were taken to capture pupils' school lunch intake. A mean of 85% of all parents responded to a questionnaire about socioeconomic background, dietary intake, and habitual physical activity at home. Cognitive function was measured on one occasion on 93% of the pupils during optimal conditions with a Stroop and a Child Operation Span test. A mean of 169 pupils also did an Integrated Visual and Auditory Continuous Performance Test after lunch over 3 days. In total, 37,413 10-sec observations of classroom learning behavior were performed. In addition, 753 empathy-based stories were written and 78 focus groups were conducted. The pupils had high socioeconomic status. CONCLUSIONS: This study will give new insights into which future interventions are needed to improve pupils' school lunch intake and learning. The study will provide valuable information for policy making, not least in countries where the history of school meals is shorter than in some of the Nordic countries. PMID- 27514724 TI - In vitro and in vivo bimodal effects of docosahexaenoic acid supplements on redox status and platelet function. AB - Docosahexaenoic acid (DHA) is a prominent nutrient of marine lipids. Together with eicosapentaenoic acid, it is recognized as a protective molecule against atherosclerosis and thrombosis through the regulation of blood cell functions, especially platelets. Its high unsaturation index may however make it prone to peroxidation, which is usually considered as deleterious. This short review takes into consideration this possibility related to DHA concentrations both in vitro and in vivo. It is suggested that protective effects of DHA on platelet activation depend on the reduction of oxidative stress, and appear bimodal with the abolishment of such a protection when DHA is used at relatively high concentrations. PMID- 27514725 TI - The mediating role of metacognition in the relationship between executive function and self-regulated learning. AB - BACKGROUND: Researchers have demonstrated significant relations among executive function, metacognition, and self-regulated learning. However, prior research emphasized the use of indirect measures of executive function and did not evaluate how specific executive functions are related to participants' self regulated learning. AIMS: The primary goals of the current study were to examine and test the relations among executive function, metacognition, and self regulated learning as well as to examine how self-regulated learning is informed by executive function. SAMPLE: The sample comprised 117 undergraduate students attending a large, Mid-Atlantic research university in the United States. METHODS: Participants were individually administered direct and indirect measures of executive function, metacognition, and self-regulated learning. A mediation model specifying the relations among the regulatory constructs was proposed. RESULTS: In multiple linear regression analyses, executive function predicted metacognition and self-regulated learning. Direct measures of inhibition and shifting accounted for a significant amount of the variance in metacognition and self-regulated learning beyond an indirect measure of executive functioning. Separate mediation analyses indicated that metacognition mediated the relationship between executive functioning and self-regulated learning as well as between specific executive functions and self-regulated learning. CONCLUSIONS: The findings of this study are supported by previous research documenting the relations between executive function and self-regulated learning, and extend prior research by examining the manner in which executive function and self regulated learning are linked. The findings provide initial support for executive functions as key processes, mediated by metacognition, that predict self regulated learning. Implications for the contribution of executive functions to self-regulated learning are discussed. PMID- 27514726 TI - Association between obesity and asthma - epidemiology, pathophysiology and clinical profile. AB - Obesity is a risk factor for asthma, and obese asthmatics have lower disease control and increased symptom severity. Several putative links have been proposed, including genetics, mechanical restriction of the chest and the intake of corticosteroids. The most consistent evidence, however, comes from studies of cytokines produced by the adipose tissue called adipokines. Adipokine imbalance is associated with both proinflammatory status and asthma. Although reverse causation has been proposed, it is now acknowledged that obesity precedes asthma symptoms. Nevertheless, prenatal origins of both conditions complicate the search for causality. There is a confirmed role of neuro-immune cross-talk mediating obesity-induced asthma, with leptin playing a key role in these processes. Obesity-induced asthma is now considered a distinct asthma phenotype. In fact, it is one of the most important determinants of asthma phenotypes. Two main subphenotypes have been distinguished. The first phenotype, which affects adult women, is characterised by later onset and is more likely to be non-atopic. The childhood obesity-induced asthma phenotype is characterised by primary and predominantly atopic asthma. In obesity-induced asthma, the immune responses are shifted towards T helper (Th) 1 polarisation rather than the typical atopic Th2 immunological profile. Moreover, obese asthmatics might respond differently to environmental triggers. The high cost of treatment of obesity-related asthma, and the burden it causes for the patients and their families call for urgent intervention. Phenotype-specific approaches seem to be crucial for the success of prevention and treatment. PMID- 27514727 TI - Geographic variation in cost of care for pituitary tumor surgery. AB - PURPOSE: Geography is known to affect cost of care in surgical procedures. Understanding the relationship between geography and hospital costs is pertinent in the effort to reduce healthcare costs. We studied the geographic variation in cost for transsphenoidal pituitary surgery in hospitals across New York State. METHODS: Using the Healthcare Cost and Utilization Project State Inpatient Database for New York from 2008 to 2011, we analyzed records of patients who underwent elective transsphenoidal pituitary tumor surgery and were discharged to home or self-care. N.Y. State was divided into five geographic regions: Buffalo, Rochester, Syracuse, Albany, and Downstate. These five regions were compared according to median charge and cost per day. RESULTS: From 2008 to 2011, 1803 transsphenoidal pituitary tumor surgeries were performed in New York State. Mean patient age was 50.7 years (54 % were female). Adjusting prices for length of stay, there was substantial variation in prices. Median charges per day ranged from $8485 to $13,321 and median costs per day ranged from $2962 to $6837 between the highest and lowest regions from 2008 to 2011. CONCLUSION: Within New York State, significant geographic variation exists in the cost for transsphenoidal pituitary surgery. The significance of and contributors to such variation is an important question for patients, providers, and policy makers. Transparency of hospital charges, costs, and average length of stay for procedures to the public provides useful information for informed decision-making, especially for a highly portable disease entity like pituitary tumors. PMID- 27514728 TI - A new survivin tracer tracks, delocalizes and captures endogenous survivin at different subcellular locations and in distinct organelles. AB - Survivin, the smallest member of the inhibitor of apoptosis protein family, plays a central role during mitosis and exerts a cytoprotective function. Survivin is highly expressed in most cancer types and contributes to multiple facets of carcinogenesis. The molecular mechanisms underlying its highly diverse functions need to be extensively explored, which is crucial for rational design of future personalized therapeutics. In this study, we have generated an alpaca survivin nanobody (SVVNb8) that binds with low nanomolar affinity to its target. When expressed as an intrabody in HeLa cells, SVVNb8 faithfully tracks survivin during different phases of mitosis without interfering with survivin function. Furthermore, coupling SVVNb8 with a subcellular delocalization tag efficiently redirects endogenous survivin towards the nucleus, the cytoplasm, peroxisomes and even to the intermembrane space of mitochondria where it presumably interacts with resident mitochondrial survivin. Based on our findings, we believe that SVVNb8 is an excellent instrument to further elucidate survivin biology and topography, and can serve as a model system to investigate mitochondrial and peroxisomal (survivin) protein import. PMID- 27514730 TI - Scotland prioritises action on child poverty. PMID- 27514729 TI - Environment shapes the fecal microbiome of invasive carp species. AB - BACKGROUND: Although the common, silver, and bighead carps are native and sparsely distributed in Eurasia, these fish have become abundant and invasive in North America. An understanding of the biology of these species may provide insights into sustainable control methods. The animal-associated microbiome plays an important role in host health. Characterization of the carp microbiome and the factors that affect its composition is an important step toward understanding the biology and interrelationships between these species and their environments. RESULTS: We compared the fecal microbiomes of common, silver, and bighead carps from wild and laboratory environments using Illumina sequencing of bacterial 16S ribosomal RNA (rRNA). The fecal bacterial communities of fish were diverse, with Shannon indices ranging from 2.3 to 4.5. The phyla Proteobacteria, Firmicutes, and Fusobacteria dominated carp guts, comprising 76.7 % of total reads. Environment played a large role in shaping fecal microbial community composition, and microbiomes among captive fishes were more similar than among wild fishes. Although differences among wild fishes could be attributed to feeding preferences, diet did not strongly affect microbial community structure in laboratory-housed fishes. Comparison of wild- and lab-invasive carps revealed five shared OTUs that comprised approximately 40 % of the core fecal microbiome. CONCLUSIONS: The environment is a dominant factor shaping the fecal bacterial communities of invasive carps. Captivity alters the microbiome community structure relative to wild fish, while species differences are pronounced within habitats. Despite the absence of a true stomach, invasive carp species exhibited a core microbiota that warrants future study. PMID- 27514731 TI - Percutaneous right ventricular assist device in sepsis due to right ventricular failure and pulmonary hypertension. PMID- 27514732 TI - The Validity and Reliability of Turkish Version of the Chemotherapy-induced Taste Alteration Scale (CiTAS). AB - The study was aimed to assess the validity and reliability of the Turkish version of the Chemotherapy-induced Taste Alteration Scale (CiTAS), and was conducted on adult patients receiving chemotherapy ( N = 184) in the Chemotherapy Unit and Hematology Clinic (Outpatient) of a university hospital between December 2013 and May 2014. The results showed that the Cronbach's alpha coefficient (.869) was satisfactory. The alpha value was .89 for the Decline in Basic Taste subscale, .70 for Discomfort subscale, .82 for Phantogeusia and Parageusia subscale, and .72 for General Taste Alterations subscale. The coefficients of the relationship between test-retest reliability results were significantly high ( r = .939, n = 28). The Turkish version of the CiTAS was a sufficient and suitable tool in evaluating the taste alterations associated with chemotherapy. PMID- 27514733 TI - In vitro differentiation potential of human haematopoietic CD34(+) cells towards pancreatic beta-cells. AB - Haematopoietic stem cells (HSCs) possess multipotent ability to differentiate into various types of cells on providing appropriate niche. In the present study, the differentiating potential of human HSCs into beta-cells of islets of langerhans was explored. Human HSCs were apheretically isolated from a donor and cultured. Phenotypic characterization of CD34 glycoprotein in the growing monolayer HSCs was confirmed by immunocytochemistry and flow cytometry techniques. HSCs were induced by selection with beta cell differentiating medium (BDM), which consists of epidermal growth factor (EGF), fibroblast growth factor (FGF), transferrin, Triiodo-l-Tyronine, nicotinamide and activin A. Distinct morphological changes of differentiated cells were observed on staining with dithizone (DTZ) and expression of PDX1, insulin and synaptophysin was confirmed by immunocytochemistry. Quantitative real-time polymerase chain reaction (qRT PCR) analysis revealed distinct expression of specific beta-cell markers, pancreatic and duodenal homeobox-1 (PDX1), glucose transporter-2 (GLUT-2), synaptophysin (SYP) and insulin (INS) in these differentiated cells compared to HSCs. Further, these cells exhibited elevated expression of INS gene at 10 mM glucose upon inducing with different glucose concentrations. The prominent feature of the obtained beta-cells was the presence of glucose sensors, which was determined by glucokinase activity and high glucokinase activity compared with CD34(+) stem cells. These findings illustrate the differentiation of CD34(+) HSCs into beta-cells of islets of langerhans. PMID- 27514734 TI - I Remember Better When I Paint. PMID- 27514736 TI - Outcomes After Revision Hip Arthroscopic Surgery in Adolescent Patients Compared With a Matched Cohort Undergoing Primary Arthroscopic Surgery. AB - BACKGROUND: The incidence of hip arthroscopic surgery is increasing in the young athlete. This has also led to increased numbers of revision hip arthroscopic surgery. HYPOTHESIS/PURPOSE: The purpose of this study was to describe the outcomes after revision hip arthroscopic surgery in patients <=18 years of age in comparison to a matched cohort of patients undergoing primary hip arthroscopic surgery. Our hypothesis was that patients undergoing revision hip arthroscopic surgery would demonstrate similar outcomes to those patients undergoing primary hip arthroscopic surgery. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Patients were included in the study if they underwent revision hip arthroscopic surgery by a single surgeon and did not undergo prior open hip surgery. Each patient in the revision hip arthroscopic surgery cohort was matched with 2 patients undergoing primary hip arthroscopic surgery from the same institution. Cohorts were matched by age, sex, and year of surgery. Preoperatively and at a minimum follow-up of 2 years, outcome scores were collected. The primary outcome measure was the Hip Outcome Score for activities of daily living scale (HOS-ADL), a self-reported validated outcome instrument, in addition to the HOS for sports scale (HOS-Sport), modified Harris Hip Score (mHHS), and 12-Item Short Form Health Survey Physical Component Summary (SF-12 PCS). RESULTS: Forty-two patients were included in the revision group and were matched with 84 patients in the primary group. The mean age in both groups was 16 years (range, 14-18 years). All female patients in the study were >=14 years of age, and all male patients were >=16 years of age. In patients undergoing revision, 13 underwent 1 prior surgical procedure, 22 underwent 2 prior surgical procedures, and 7 underwent >=3 prior surgical procedures. The mean time from last surgery to revision was 18.7 months (range, 4.7-74 months). Eleven patients (26%) had prior femoroacetabular impingement treated, which required osteoplasty or rim trimming at revision. Subsequent hip arthroscopic surgery was reported in 3 of 84 (4%) patients in the primary group and 6 of 42 (14%) patients in the revision group (P = .162). The mean follow-up in the revision group was 43 +/- 17 months, and scores significantly improved (HOS-ADL: 59.6 to 77.6; HOS-Sport: 37.6 to 64.8; mHHS: 55.3 to 74.3; SF-12 PCS: 41.0 to 50.4; P < .05). The mean follow up in the primary group was 45 +/- 18 months, and all scores significantly improved (HOS-ADL: 65.8 to 87.4; HOS-Sport: 46.3 to 79.9; mHHS: 57.5 to 84.2; SF 12 PCS: 39.0 to 51.8; P < .05). At follow-up, there were no significant differences between the primary and revision groups for the HOS-ADL values (P = .051) and SF-12 PCS values (P = .846). Patients in the primary group had significantly higher HOS-Sport values (P = .008), mHHS values (P = .008), and patient satisfaction (P = .008). Patients who underwent 1 prior hip arthroscopic procedure had a higher mean postoperative mHHS value (79.5 vs 72, respectively), HOS-ADL value (91.2 vs 73.4, respectively), and HOS-Sport value (76 vs 60, respectively) (P < .05) compared with those who underwent more than 1 prior procedure. Median patient satisfaction was 9.0 (range, 2-10) in the primary group and 8.0 (range, 2-10) in the revision group. CONCLUSION: In conclusion, young patients who required revision hip arthroscopic surgery showed significant improvement in patient-reported outcome scores; however, final outcome scores in the revision group for sport activity, general health, and satisfaction were lower than those in the primary group. Patients who underwent 1 revision surgical procedure had higher outcome scores than patients who underwent more than 1 revision surgical procedure. PMID- 27514737 TI - Results of Bone Peg Grafting for Capitellar Osteochondritis Dissecans in Adolescent Baseball Players. AB - BACKGROUND: Bone peg grafting (BPG) has been advocated for early-stage humeral capitellar osteochondritis dissecans (COCD). However, the clinical and radiological results of BPG, along with its indications, have not been described in detail. HYPOTHESIS: COCD classified as International Cartilage Repair Society (ICRS) osteochondritis dissecans (OCD) I or II in adolescent baseball players can be treated successfully by BPG. STUDY DESIGN: Case series; Level of evidence, 4 METHODS: Eleven male baseball players (age range at surgery, 13-16 years) who underwent BPG for COCD were enrolled in this study. No improvement had been seen in any patient after 6 months of preoperative nonthrowing observation. During surgery, 2 to 5 bone pegs were inserted into the COCD lesion after confirmation of lesion stability to the bony floor. All patients were directly evaluated at 12 and 24 months after surgery by physical findings, radiological prognosis, and magnetic resonance imaging (MRI). RESULTS: Of the 11 patients, 10 could return to comparable baseball ability levels within 12 months. The Timmerman-Andrews score improved significantly from a mean +/- SD of 171.8 +/- 12.1 preoperatively to 192.3 +/- 6.5 at the final observation. Radiological healing of the lesions was determined as complete in 8 patients and partial in 3. Patients possessing a centrally positioned lesion or a lesion <75% of the size of the capitellum tended most strongly to achieve complete radiological healing, while growth plate status appeared unrelated to outcome. The mean Henderson MRI score improved from 6.3 +/- 1.5 to 4.8 +/- 1.6 at 12 and 24 months after BPG, respectively. MRI findings also suggested that remodeling of COCD lesions had continued to up to 24 months postoperatively. CONCLUSION: BPG enabled 91% of COCD patients with ICRS OCD I or II to return to preoperative baseball abilities within 12 months. Integration of the grafted site may continue until at least 24 months postoperatively. An ICRS OCD I or II lesion with central positioning and/or occupying <75% of the size of the capitellum in the coronal plane is a good indication for BPG. PMID- 27514738 TI - Geometric Risk Factors Associated With Noncontact Anterior Cruciate Ligament Graft Rupture. AB - BACKGROUND: Anterior cruciate ligament (ACL) graft rupture occurs at a high rate, especially in young athletes. The geometries of the tibial plateau and femoral intercondylar notch are risk factors for first-time ACL injury; however, little is known about the relationship between these geometries and risk of ACL graft rupture. HYPOTHESIS: The geometric risk factors for noncontact graft rupture are similar to those previously identified for first-time noncontact ACL injury, and sex-specific differences exist. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Eleven subjects who suffered a noncontact ACL graft rupture and 44 subjects who underwent ACL reconstruction but did not experience graft rupture were included in the study. Using magnetic resonance imaging, the geometries of the tibial plateau subchondral bone, articular cartilage, meniscus, tibial spines, and femoral notch were measured. Risk factors associated with ACL graft rupture were identified using Cox regression. RESULTS: The following were associated with increased risk of ACL graft injury in males: increased posterior inferior-directed slope of the articular cartilage in the lateral tibial plateau measured at 2 locations (hazard ratio [HR] = 1.50, P = .029; HR = 1.39, P = .006), increased volume (HR = 1.45, P = .01) and anteroposterior length (HR = 1.34, P = .0023) of the medial tibial spine, and increased length (HR = 1.18, P = .0005) and mediolateral width (HR = 2.19, P = .0004) of the lateral tibial spine. In females, the following were associated with increased risk of injury: decreased volume (HR = 0.45, P = .02) and height (HR = 0.46, P = .02) of the medial tibial spine, decreased slope of the lateral tibial subchondral bone (HR = 0.72, P = .01), decreased height of the posterior horn of the medial meniscus (HR = 0.09, P = .001), and decreased intercondylar notch width at the anterior attachment of the ACL (HR = 0.72, P = .02). CONCLUSION: The geometric risk factors for ACL graft rupture are different for males and females. For females, a decreased femoral intercondylar notch width and a decreased height of the posterior medial meniscus were risk factors for ACL graft rupture that have also been found to be risk factors for first-time injury. There were no risk factors in common between ACL graft injury and first-time ACL injury for males. PMID- 27514739 TI - Adolescents' health choices related rights, duties and responsibilities: An integrative review. AB - BACKGROUND: Although the link between adolescents' health choices in relation to rights, duties and responsibilities is acknowledged, little is studied in this subject. AIM: To identify, describe and synthesize previous studies on adolescents' health choices in relation to rights, duties and responsibilities. Ethical considerations: Ethical approval is not needed as it is an integrative review of published literature. METHOD: The integrative review was used to review and synthesize current knowledge. Electronic and manual searches from 2009 to March 2014 were used to systematically identify earlier studies. RESULTS: The review identified 13 studies. Adolescents' health choices were linked to unsuccessfully exercised rights, arising from questioned autonomy and freedom, and their duties were hardly mentioned. CONCLUSION: Research into adolescents' health choices in relation to their rights, duties and responsibilities is still methodologically fragmented. In future, more research is needed to support adolescents' health promotion initiatives and increase their involvement opportunities. PMID- 27514740 TI - Lessons learned from nurses' requests for ethics consultation: Why did they call and what did they value? AB - BACKGROUND: An ongoing challenge for clinical ethics consultation is learning how colleagues in other healthcare professions understand, make use of, and evaluate clinical ethics consultation services. AIM: In pursuing such knowledge as part of clinical ethics consultation service quality assessment, clinical ethics consultation services can learn important information about the issues and concerns that prompt colleagues to request ethics consultation. Such knowledge allows for greater outreach, education, and responsiveness by clinical ethics consultation services to the concerns of clinician colleagues. DESIGN: This quality assessment project explores consultation requests and follow-up questionnaire responses voluntarily submitted from nurses who requested clinical ethics consultation. We present qualitative data analyzed using content analysis and constant comparison methods to identify key concerns that prompted requests as well as common themes among nurse requestors' evaluations of what was most important in clinical ethics consultations. Participants and context: A total of 41 nurses requesting clinical ethics consultation and 15 who returned the follow up questionnaire. Ethical considerations: Our Office of Research Compliance and Quality Improvement determined that our project was not considered human subjects research and so did not require institutional review board approval or exemption. However, efforts were made to avoid any sense of coercion and all data were de identified prior to analysis. FINDINGS: Our analysis revealed six main categories of issues that prompted nurses' requests for ethics consultation, as well as unifying themes around nurses' experiences, advocacy, and family support while caring for patients in the intersections of patients, families, and physicians. DISCUSSION: The insights gained from analyzing nurses' requests for and responses to clinical ethics consultation may serve as a resource for clinical ethics consultation services seeking to identify, respond to, and educate regarding issues of importance to nurse colleagues and may be a resource for nursing administrators and leadership seeking to identify and address common ethical issues nurses face. CONCLUSION: Ongoing work on clinical ethics consultation service quality improvement and engagement with our nursing colleagues about their concerns prompting-and their evaluations of-clinical ethics consultation are necessary. PMID- 27514741 TI - Nurse's perceptions of organisational barriers to delivering compassionate care: A qualitative study. AB - BACKGROUND: Compassionate care is an international priority of healthcare professionals. There is little understanding about how workplace issues impact provision of compassionate care in nursing practice. Therefore, it is important to address the workplace issues and organizational factors which may hinder compassionate care delivery within nursing practice. OBJECTIVE: The aim of this study was to explore workplace and organizational barriers to compassionate care from the nurses' perspective. RESEARCH DESIGN: The study used a qualitative exploratory design, and data were analyzed by conventional content analysis. Participants and research context: A total of 15 nurses working in different fields of nursing were recruited from four hospitals at northwest of Iran. Participants were selected by purposive sampling. Semistructured interviews were conducted for data collection. Ethical consideration: Ethical approval of this study was gained from the Ethical Review Board of Tabriz University of Medical Sciences. FINDINGS: The main theme which emerged from data analysis was "unsupportive organizational culture." This theme had two main categories including "excessive workload alongside inadequate staffing" and "the lack of value on compassionate care." DISCUSSION: Organizational barriers to development of compassionate in clinical practice were identified in this study. A closer examination of these barriers is required to move compassionate practice from an individual responsibility to a collective responsibility that is owned and shared by organizations. CONCLUSION: For compassionate care to flourish, policy makers, managers, and healthcare providers must foster an organizational atmosphere conducive to compassionate care. PMID- 27514742 TI - Formation energies and electronic structure of intrinsic vacancy defects and oxygen vacancy clustering in BaZrO3. AB - Ab initio density functional theory calculations are employed for exploring the thermodynamic stability, vacancy defect formation energy and electronic structure of pristine and non-stoichiometric BaZrO3. The electronic properties of BaZrO3 show the hole-doped and insulating nature of cation and oxygen vacancies, respectively. The changes in the electronic properties of intrinsic vacancy containing BaZrO3 are analyzed in terms of electronic band structure, charge density and effective Bader charges. The relative stability of the formation of charge neutral and fully charged intrinsic vacancy defects in BaZrO3 is investigated in different chemical growth environments and the full and partial Schottky reactions are computed. Calculations are also performed to study the effects of oxygen vacancy clustering in different crystallographic planes. These calculations enable us to predict n-type conductivity in non-stoichiometric BaZrO3, which is useful for tailoring the electrical conduction of this material. Our results suggest that the semiconducting, p- and n-type character of BaZrO3 can be realized to enhance its device application by means of intentional incorporation of vacancy defects. PMID- 27514743 TI - TRF2 Protein Interacts with Core Histones to Stabilize Chromosome Ends. AB - Mammalian chromosome ends are protected by a specialized nucleoprotein complex called telomeres. Both shelterin, a telomere-specific multi-protein complex, and higher order telomeric chromatin structures combine to stabilize the chromosome ends. Here, we showed that TRF2, a component of shelterin, binds to core histones to protect chromosome ends from inappropriate DNA damage response and loss of telomeric DNA. The N-terminal Gly/Arg-rich domain (GAR domain) of TRF2 directly binds to the globular domain of core histones. The conserved arginine residues in the GAR domain of TRF2 are required for this interaction. A TRF2 mutant with these arginine residues substituted by alanine lost the ability to protect telomeres and induced rapid telomere shortening caused by the cleavage of a loop structure of the telomeric chromatin. These findings showed a previously unnoticed interaction between the shelterin complex and nucleosomal histones to stabilize the chromosome ends. PMID- 27514744 TI - Functional and Structural Characterization of Novel Type of Linker Connecting Capsid and Nucleocapsid Protein Domains in Murine Leukemia Virus. AB - The assembly of immature retroviral particles is initiated in the cytoplasm by the binding of the structural polyprotein precursor Gag with viral genomic RNA. The protein interactions necessary for assembly are mediated predominantly by the capsid (CA) and nucleocapsid (NC) domains, which have conserved structures. In contrast, the structural arrangement of the CA-NC connecting region differs between retroviral species. In HIV-1 and Rous sarcoma virus, this region forms a rod-like structure that separates the CA and NC domains, whereas in Mason-Pfizer monkey virus, this region is densely packed, thus holding the CA and NC domains in close proximity. Interestingly, the sequence connecting the CA and NC domains in gammaretroviruses, such as murine leukemia virus (MLV), is unique. The sequence is called a charged assembly helix (CAH) due to a high number of positively and negatively charged residues. Although both computational and deletion analyses suggested that the MLV CAH forms a helical conformation, no structural or biochemical data supporting this hypothesis have been published. Using an in vitro assembly assay, alanine scanning mutagenesis, and biophysical techniques (circular dichroism, NMR, microcalorimetry, and electrophoretic mobility shift assay), we have characterized the structure and function of the MLV CAH. We provide experimental evidence that the MLV CAH belongs to a group of charged, E(R/K)-rich, single alpha-helices. This is the first single alpha-helix motif identified in viral proteins. PMID- 27514745 TI - Structural Insight into the 14-3-3 Protein-dependent Inhibition of Protein Kinase ASK1 (Apoptosis Signal-regulating kinase 1). AB - Apoptosis signal-regulating kinase 1 (ASK1, also known as MAP3K5), a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, regulates diverse physiological processes. The activity of ASK1 is triggered by various stress stimuli and is involved in the pathogenesis of cancer, neurodegeneration, inflammation, and diabetes. ASK1 forms a high molecular mass complex whose activity is, under non-stress conditions, suppressed through interaction with thioredoxin and the scaffolding protein 14-3-3. The 14-3-3 protein binds to the phosphorylated Ser-966 motif downstream of the ASK1 kinase domain. The role of 14 3-3 in the inhibition of ASK1 has yet to be elucidated. In this study we performed structural analysis of the complex between the ASK1 kinase domain phosphorylated at Ser-966 (pASK1-CD) and the 14-3-3zeta protein. Small angle x ray scattering (SAXS) measurements and chemical cross-linking revealed that the pASK1-CD.14-3-3zeta complex is dynamic and conformationally heterogeneous. In addition, structural analysis coupled with the results of phosphorus NMR and time resolved tryptophan fluorescence measurements suggest that 14-3-3zeta interacts with the kinase domain of ASK1 in close proximity to its active site, thus indicating this interaction might block its accessibility and/or affect its conformation. PMID- 27514746 TI - Plasticity of Myeloid Cells during Oral Barrier Wound Healing and the Development of Bisphosphonate-related Osteonecrosis of the Jaw. AB - Injury to the barrier tissue initiates a rapid distribution of myeloid immune cells from bone marrow, which guide sound wound healing. Bisphosphonates, a widely used anti-bone resorptive drug with minimal systemic side effects, have been linked to an abnormal wound healing in the oral barrier tissue leading to, in some cases, osteonecrosis of the jaw (ONJ). Here we report that the development of ONJ may involve abnormal phenotypic plasticity of Ly6G+/Gr1+ myeloid cells in the oral barrier tissue undergoing tooth extraction wound healing. A bolus intravenous zoledronate (ZOL) injection to female C57Bl/6 mice followed by maxillary first molar extraction resulted in the development of ONJ like lesion during the second week of wound healing. The multiplex assay of dissociated oral barrier cells exhibited the secretion of cytokines and chemokines, which was significantly modulated in ZOL mice. Tooth extraction induced distribution of Ly6G+/Gr1+ cells in the oral barrier tissue increased in ZOL mice at week 2. ONJ-like lesion in ZOL mice contained Ly6G+/Gr1+ cells with abnormal size and morphology as well as different flow cytometric staining intensity. When anti-Ly6G (Gr1) antibody was intraperitoneally injected for 5 days during the second week of tooth extraction, CD11b+GR1(hi) cells in bone marrow and Ly6G+ cells in the oral barrier tissue were depleted, and the development of ONJ-like lesion was significantly attenuated. This study suggests that local modulation of myeloid cell plasticity in the oral barrier tissue may provide the basis for pathogenesis and thus therapeutic as well as preventive strategy of ONJ. PMID- 27514747 TI - Retinal Hypercholesterolemia Triggers Cholesterol Accumulation and Esterification in Photoreceptor Cells. AB - The process of vision is impossible without the photoreceptor cells, which have a unique structure and specific maintenance of cholesterol. Herein we report on the previously unrecognized cholesterol-related pathway in the retina discovered during follow-up characterizations of Cyp27a1(-/-)Cyp46a1(-/-) mice. These animals have retinal hypercholesterolemia and convert excess retinal cholesterol into cholesterol esters, normally present in the retina in very small amounts. We established that in the Cyp27a1(-/-)Cyp46a1(-/-) retina, cholesterol esters are generated by and accumulate in the photoreceptor outer segments (OS), which is the retinal layer with the lowest cholesterol content. Mouse OS were also found to express the cholesterol-esterifying enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT1), but not lecithin-cholesterol acyltransferase (LCAT), and to differ from humans in retinal expression of ACAT1. Nevertheless, cholesterol esters were discovered to be abundant in human OS. We suggest a mechanism for cholesterol ester accumulation in the OS and that activity impairment of ACAT1 in humans may underlie the development of subretinal drusenoid deposits, a hallmark of age-related macular degeneration, which is a common blinding disease. We generated Cyp27a1(-/-)Cyp46a1(-/-)Acat1(-/-) mice, characterized their retina by different imaging modalities, and confirmed that unesterified cholesterol does accumulate in their OS and that there is photoreceptor apoptosis and OS degeneration in this line. Our results provide insights into the retinal response to local hypercholesterolemia and the retinal significance of cholesterol esterification, which could be cell-specific and both beneficial and detrimental for retinal structure and function. PMID- 27514748 TI - BnPME is progressively induced after microspore reprogramming to embryogenesis, correlating with pectin de-esterification and cell differentiation in Brassica napus. AB - BACKGROUND: Pectins are one of the main components of plant cell walls. They are secreted to the wall as highly methylesterified forms that can be de-esterified by pectin methylesterases (PMEs). The degree of methylesterification of pectins changes during development, PMEs are involved in the cell wall remodeling that occurs during diverse plant developmental processes. Nevertheless, the functional meaning of pectin-related wall remodeling in different cell types and processes remains unclear. In vivo, the microspore follows the gametophytic pathway and differentiates to form the pollen grain. In vitro, the microspore can be reprogrammed by stress treatments becoming a totipotent cell that starts to proliferate and follows the embryogenic pathway, a process known as microspore embryogenesis. RESULTS: To investigate if the change of developmental programme of the microspore towards embryogenesis involves changes in pectin esterification levels, which would cause the cell wall remodeling during the process, in the present study, dynamics of PME expression and degrees of pectin esterification have been analysed during microspore embryogenesis and compared with the gametophytic development, in Brassica napus. A multidisciplinary approach has been adopted including BnPME gene expression analysis by quantitative RT-PCR, fluorescence in situ hybridization, immuno-dot-blot and immunofluorescence with JIM5 and JIM7 antibodies to reveal low and highly-methylesterified pectins. The results showed that cell differentiation at advanced developmental stages involved induction of BnPME expression and pectin de-esterification, processes that were also detected in zygotic embryos, providing additional evidence that microspore embryogenesis mimics zygotic embryogenesis. By contrast, early microspore embryogenesis, totipotency and proliferation were associated with low expression of BnPME and high levels of esterified pectins. CONCLUSIONS: The results show that the change of developmental programme of the microspore involves changes in pectin esterification associated with proliferation and differentiation events, which may cause the cell wall remodeling during the process. The findings indicate pectin-related modifications in the cell wall during microspore embryogenesis, providing new insights into the role of pectin esterification and cell wall configuration in microspore totipotency, embryogenesis induction and progression. PMID- 27514749 TI - Validation and Comparison of Seven Mortality Prediction Models for Hospitalized Patients With Acute Decompensated Heart Failure. AB - BACKGROUND: Heart failure (HF) inpatient mortality prediction models can help clinicians make treatment decisions and researchers conduct observational studies; however, published models have not been validated in external populations. METHODS AND RESULTS: We compared the performance of 7 models that predict inpatient mortality in patients hospitalized with acute decompensated heart failure: 4 HF-specific mortality prediction models developed from 3 clinical databases (ADHERE [Acute Decompensated Heart Failure National Registry], EFFECT study [Enhanced Feedback for Effective Cardiac Treatment], and GWTG-HF registry [Get With the Guidelines-Heart Failure]); 2 administrative HF mortality prediction models (Premier, Premier+); and a model that uses clinical data but is not specific for HF (Laboratory-Based Acute Physiology Score [LAPS2]). Using a multihospital, electronic health record-derived data set (HealthFacts [Cerner Corp], 2010-2012), we identified patients >=18 years admitted with HF. Of 13 163 eligible patients, median age was 74 years; half were women; and 27% were black. In-hospital mortality was 4.3%. Model-predicted mortality ranges varied: Premier+ (0.8%-23.1%), LAPS2 (0.7%-19.0%), ADHERE (1.2%-17.4%), EFFECT (1.0%-12.8%), GWTG Eapen (1.2%-13.8%), and GWTG-Peterson (1.1%-12.8%). The LAPS2 and Premier models outperformed the clinical models (C statistics: LAPS2 0.80 [95% confidence interval 0.78-0.82], Premier models 0.81 [95% confidence interval 0.79-0.83] and 0.76 [95% confidence interval 0.74-0.78], and clinical models 0.68 to 0.70). CONCLUSIONS: Four clinically derived, inpatient, HF mortality models exhibited similar performance, with C statistics near 0.70. Three other models, 1 developed in electronic health record data and 2 developed in administrative data, also were predictive, with C statistics from 0.76 to 0.80. Because every model performed acceptably, the decision to use a given model should depend on practical concerns and intended use. PMID- 27514750 TI - Implications of Using Different Definitions on Outcomes in Worsening Heart Failure. AB - BACKGROUND: In-hospital worsening heart failure (WHF) is an important event that has inconsistent definitions used across trials. We used data from 2 acute heart failure (HF) trials from the National Institutes of Health HF Network, DOSE (Diuretic Optimization Strategies Evaluation) and ROSE (Renal Optimization Strategies), to understand event rates associated with different WHF definitions. METHODS AND RESULTS: We pooled data from 668 patients in DOSE and ROSE and assessed the relationship between WHF and the composite end point of rehospitalization, emergency room visits for HF, and mortality through 60 days. We also assessed for a differential relationship between the timing of WHF development and outcomes. The overall incidence of WHF was 14.6% (24.1% in DOSE, 6.3% in ROSE, and 5.0% in DOSE using the ROSE definition). WHF was associated with an increase in the composite end point (hazard ratio [HR], 1.64; 95% confidence interval [CI], 1.11-2.42; P=0.01). However, the association between WHF and outcomes was significantly stronger in ROSE than in DOSE (HR, 2.67; 95% CI, 1.45-4.91; P<0.01 and HR, 1.28; 95% CI, 0.79-2.08; P=0.31, respectively). Development of WHF between baseline to 24 hours compared with 24 to 48 hours or 48 to 72 hours demonstrated a trend toward improved outcomes (HR, 0.49; 95% CI, 0.21-1.17; P=0.11 and HR, 0.45; 95% CI, 0.20-1.04; P=0.06, respectively). CONCLUSIONS: A WHF definition that excluded the intensification of diuretics resulted in a lower event rate but a stronger association with outcomes. These data support the need for continued efforts to standardize WHF definitions in clinical trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00577135 (DOSE) and NCT01132846 (ROSE). PMID- 27514752 TI - Model Building as an Educational Hobby. PMID- 27514751 TI - Multistate Model to Predict Heart Failure Hospitalizations and All-Cause Mortality in Outpatients With Heart Failure With Reduced Ejection Fraction: Model Derivation and External Validation. AB - BACKGROUND: Outpatients with heart failure (HF) who are at high risk for HF hospitalization and death may benefit from early identification. We sought to develop and externally validate a model to predict both HF hospitalization and mortality that accounts for the semicompeting nature of the 2 outcomes and captures the risk associated with the transition from the stable outpatient state to the post-HF hospitalization state. METHODS AND RESULTS: A multistate model to predict HF hospitalization and all-cause mortality was derived using data (n=3834) from the HEAAL study (Heart Failure Endpoint evaluation of Angiotensin II Antagonist Losartan), a multinational randomized trial in symptomatic patients with reduced left ventricular ejection fraction. Twelve easily and reliably obtainable demographic and clinical predictors were prespecified for model inclusion. Model performance was assessed in the SCD-HeFT cohort (Sudden Cardiac Death in Heart Failure Trial; n=2521). At 1 year, the probability of being alive without HF hospitalization was 94% for a typical patient in the lowest risk quintile and 77% for a typical patient in the highest risk quintile and this variability in risk continued through 7 years of follow-up. The model c-index was 0.72 in the derivation cohort, 0.66 in the validation cohort, and 0.69 in the implantable cardiac defibrillator arm of the validation cohort. There was excellent calibration across quintiles of predicted risk. CONCLUSIONS: Our findings illustrate the advantages of a multistate modeling approach, providing estimates of HF hospitalization and death in the same model, comparison of predictors for the different outcomes and demonstrating the different trajectories of patients based on baseline characteristics and intermediary events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00000609 and NCT00090259. PMID- 27514753 TI - Tetramethylpyrazine Ameliorates Rotenone-Induced Parkinson's Disease in Rats: Involvement of Its Anti-Inflammatory and Anti-Apoptotic Actions. AB - Parkinson's disease (PD) is a slowly progressive neurodegenerative movement disorder. Apoptosis, neuroinflammation, and oxidative stress are the current hypothesized mechanisms for PD pathogenesis. Tetramethylpyrazine (TMP), the major bioactive component of Ligusticum wallichii Franchat (ChuanXiong), Family Apiaceae, reportedly has anti-apoptotic, anti-inflammatory and antioxidant effects. This study investigated the role of 'TMP' in preventing rotenone-induced neurobiological and behavioral sequelae. A preliminary dose-response study was conducted where rats received TMP (10, 20, and 40 mg/kg, i.p.) concomitantly with rotenone (2 mg/kg, s.c.) for 4 weeks. Catalepsy, locomotor activity, striatal dopamine content, and tyrosine hydroxylase "TH" and alpha-synuclein immunoreactivity were evaluated. The selected TMP dose (20 mg/kg) was used for western blot analysis of Bax, Bcl2, and DJ-1, immunohistochemical detection of nuclear factor kappa B (NF-kB), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX2), and glial fibrillary acidic protein (GFAP) expression, in addition to biochemical analysis of caspase-3 activity, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) levels. Results showed that TMP (20 mg/kg) significantly improved midbrain and striatal TH expression and striatal dopamine content as well as the motor deficits, compared to rotenone-treated group. These results were correlated with reduction in caspase-3 activity and alpha-synuclein expression, along with improvement of midbrain and striatal Bax/Bcl2 ratio compared to rotenone-treated group. TMP also attenuated rotenone-induced upregulation of Nrf2/HO-1 pathway. Furthermore, TMP downregulated rotenone-induced neuroinflammation markers: NF-kB, iNOS, COX2, and GFAP expression in both the midbrain and striatum. Taken together, the current study suggests that TMP is entitled to, at least partially, preventing PD neurobiological and behavioral deficits by virtue of its anti-apoptotic, anti inflammatory, and antioxidant actions. PMID- 27514754 TI - Phenotypical and Pharmacological Characterization of Stem-Like Cells in Human Pituitary Adenomas. AB - The presence and functional role of tumor stem cells in benign tumors, and in human pituitary adenomas in particular, is a debated issue that still lacks a definitive formal demonstration. Fifty-six surgical specimens of human pituitary adenomas were processed to establish tumor stem-like cultures by selection and expansion in stem cell-permissive medium or isolating CD133-expressing cells. Phenotypic and functional characterization of these cells was performed (1) ex vivo, by immunohistochemistry analysis on paraffin-embedded tissues; (2) in vitro, attesting marker expression, proliferation, self-renewal, differentiation, and drug sensitivity; and (3) in vivo, using a zebrafish model. Within pituitary adenomas, we identified rare cell populations expressing stem cell markers but not pituitary hormones; we isolated and expanded in vitro these cells, obtaining fibroblast-free, stem-like cultures from 38 pituitary adenoma samples. These cells grow as spheroids, express stem cell markers (Oct4, Sox2, CD133, and nestin), show sustained in vitro proliferation as compared to primary cultures of differentiated pituitary adenoma cells, and are able to differentiate in hormone expressing pituitary cells. Besides, pituisphere cells, apparently not tumorigenic in mice, engrafted in zebrafish embryos, inducing pro-angiogenic and invasive responses. Finally, pituitary adenoma stem-like cells express regulatory pituitary receptors (D2R, SSTR2, and SSTR5), whose activation by a dopamine/somatostatin chimeric agonist exerts antiproliferative effects. In conclusion, we provide evidence that human pituitary adenomas contain a subpopulation fulfilling biological and phenotypical signatures of tumor stem cells that may represent novel therapeutic targets for therapy-resistant tumors. PMID- 27514755 TI - Autophagy Inhibition Favors Survival of Rubrospinal Neurons After Spinal Cord Hemisection. AB - Spinal cord injuries (SCIs) are devastating conditions of the central nervous system (CNS) for which there are no restorative therapies. Neuronal death at the primary lesion site and in remote regions that are functionally connected to it is one of the major contributors to neurological deficits following SCI.Disruption of autophagic flux induces neuronal death in many CNS injuries, but its mechanism and relationship with remote cell death after SCI are unknown. We examined the function and effects of the modulation of autophagy on the fate of axotomized rubrospinal neurons in a rat model of spinal cord dorsal hemisection (SCH) at the cervical level. Following SCH, we observed an accumulation of LC3-positive autophagosomes (APs) in the axotomized neurons 1 and 5 days after injury. Furthermore, this accumulation was not attributed to greater initiation of autophagy but was caused by a decrease in AP clearance, as demonstrated by the build-up of p62, a widely used marker of the induction of autophagy. In axotomized rubrospinal neurons, the disruption of autophagic flux correlated strongly with remote neuronal death and worse functional recovery. Inhibition of AP biogenesis by 3-methyladenine (3-MA) significantly attenuated remote degeneration and improved spontaneous functional recovery, consistent with the detrimental effects of autophagy in remote damage after SCH. Collectively, our results demonstrate that autophagic flux is blocked in axotomized neurons on SCI and that the inhibition of AP formation improves their survival. Thus, autophagy is a promising target for the development of therapeutic interventions in the treatment of SCIs. PMID- 27514756 TI - Adiponectin Suppresses T Helper 17 Cell Differentiation and Limits Autoimmune CNS Inflammation via the SIRT1/PPARgamma/RORgammat Pathway. AB - T helper 17 (Th17) cells are vital components of the adaptive immune system involved in the pathogenesis of most autoimmune and inflammatory syndromes, and adiponectin(ADN) is correlated with inflammatory diseases such as multiple sclerosis (MS) and type II diabetes. However, the regulatory effects of adiponectin on pathogenic Th17 cell and Th17-mediated autoimmune central nervous system (CNS) inflammation are not fully understood. In this study, we demonstrated that ADN could inhibit Th1 and Th17 but not Th2 cells differentiation in vitro. In the in vivo study, we demonstrated that ADN deficiency promoted CNS inflammation and demyelination and exacerbated experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. Furthermore, ADN deficiency increased the Th1 and Th17 cell cytokines of both the peripheral immune system and CNS in mice suffering from EAE. It is worth mentioning that ADN deficiency predominantly promoted the antigen-specific Th17 cells response in autoimmune encephalomyelitis. In addition, in vitro and in vivo, ADN upregulated sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma (PPARgamma) and inhibited retinoid-related orphan receptor-gammat (RORgammat); the key transcription factor during Th17 cell differentiation. These results systematically uncovered the role and mechanism of adiponectin on pathogenic Th17 cells and suggested that adiponectin could inhibit Th17 cell mediated autoimmune CNS inflammation. PMID- 27514758 TI - Childhood cognitive ability and smoking initiation, relapse and cessation throughout adulthood: evidence from two British cohort studies. AB - AIMS: To test the relationship between early cognitive ability and major changes in smoking habits across adulthood, and test whether educational attainment mediates these associations. DESIGN: Prospective observational study to examine the link between cognitive ability and smoking initiation, relapse and cessation at multiple time-points throughout adulthood in a pooled analysis of two cohorts. SETTING: Great Britain 1981-2013. PARTICIPANTS: A total of 16 653 participants from two British cohorts; 7191 from the 1970 British Cohort Study (BCS) and 9462 from the 1958 National Child Development Study (NCDS). Participants were 52.9% female and 27.3% were smokers, 24.8% were ex-smokers and 47.9% reported never smoking. MEASUREMENTS: Cognitive ability was assessed at age 10 years in the BCS and 11 years in the NCDS. Outcomes were smoking initiation, relapse and cessation derived from changes in smoking status observed across five time-points between ages 26-42 in the BCS and six time-points between ages 23-55 in the NCDS. Educational attainment was examined as a mediating variable. Controls were age, gender, social class, self-control, psychological distress, parental smoking and a study indicator (BCS/NCDS). FINDINGS: In adjusted regression models, a 1 standard deviation increase in cognitive ability predicted a 0.5 percentage point (95% CI = -0.9 to -0.1) reduced probability of smoking and a 2.9 percentage point (95% CI = 2.1-3.7) higher probability of smoking cessation throughout adulthood, but did not change the likelihood of smoking relapse significantly. Differences in educational attainment explained approximately half the association between childhood cognitive ability and smoking initiation/cessation. CONCLUSIONS: Lower cognitive ability, measured in childhood before smoking is initiated, appears to predict a higher likelihood of taking up smoking and a lower likelihood of quitting in adulthood. Educational attainment appears to mediate this effect: children with higher cognitive ability tend to become more highly educated adults which, in turn, predicts lower rates of smoking initiation and increased rates of smoking cessation. PMID- 27514757 TI - Specificity of Pitx3-Dependent Gene Regulatory Networks in Subsets of Midbrain Dopamine Neurons. AB - Dysfunction of midbrain dopaminergic (mDA) neurons is involved in Parkinson's disease (PD) and neuropsychiatric disorders. Pitx3 is expressed in mDA neuron subsets of the substantia nigra compacta (SNc) and of the ventral tegmental area (VTA) that are degeneration-sensitive in PD. The genetic network(s) and mode(s) of action of Pitx3 in these mDA neurons remain poorly characterized. We hypothesized that, given their distinct neuronal identities, Pitx3-expressing neurons of SNc and VTA should differ in their Pitx3-controlled gene expression networks and this may involve subset-specific co-regulators. Expression profiling of purified mDA neuronal subsets indicates that Pitx3 regulates different sets of genes in SNc and VTA, such as activating the expression of primary cilium gene products specifically in VTA neurons. Interaction network analysis pointed to the participation of differentially expressed Lhx/Lmo family members in the modulation of Pitx3 action in SNc and VTA mDA neurons. Conversely, global binding patterns of Pitx3 on genomic DNA of human dopaminergic cells revealed that Pitx3 is often co-recruited to regions that foster the formation of GATA-bHLH-BRN complexes, which usually involve Lmo co-regulatory proteins. We focused on Lmo3 for its preferential expression in SNc neurons and demonstrated that it functions as a transcriptional co-activator of Pitx3 by enhancing its activity on genomic regulatory elements. In summary, we defined the SN and VTA-specific programs of Pitx3-dependent gene expression and identified Lmo3 as a SN-specific co-regulator of Pitx3-dependent transcription. PMID- 27514759 TI - Weight loss induced by bariatric surgery restores adipose tissue PNPLA3 expression. AB - BACKGROUND & AIMS: Obesity and its related co-morbidities such as non-alcoholic fatty liver disease (NAFLD) are increasing dramatically worldwide. The genetic variation in Patatin-like phospholipase domain-containing protein 3 (PNPLA3), which is also called adiponutrin (ADPN), in residue 148 (I148M, rs738409) has been associated with NAFLD. However, the regulation and function of PNPLA3 in metabolic diseases remains unclear. Laparoscopic gastric banding (LAGB) of severely obese patients reduces body weight, liver and adipose tissue inflammation. In this study, we investigated whether weight loss induced by LAGB affected PNPLA3 expression in hepatic and adipose tissue. METHODS: Liver and subcutaneous adipose tissue samples were collected from 28 severely obese patients before and 6 months after LAGB. PNPLA3 expression was assessed by quantitative real-time PCR. To understand whether inflammatory stimuli regulated PNPLA3 expression, we studied the effect of tumour necrosis factor alpha (TNFalpha) and lipopolysaccharide (LPS) on PNPLA3 expression in human adipocytes and hepatocytes. RESULTS: PNPLA3 was strongly expressed in the liver and clearly detectable in subcutaneous adipose tissue of obese patients. Weight loss induced by LAGB of severely obese patients led to significantly increased adipose, but not hepatic, tissue expression of PNPLA3. Subcutaneous PNPLA3 expression negatively correlated with body-mass-index, fasting glucose and fasting insulin. TNFalpha potently suppressed PNPLA3 expression in adipocytes but not hepatocytes. CONCLUSIONS: Weight loss induced by LAGB restored adipose tissue PNPLA3 expression which is suppressed by TNFalpha. Further studies will be required to determine the functional impact of PNPLA3 and its related genetic variation on adipose tissue inflammation and NAFLD. PMID- 27514760 TI - Enhanced Structural Stability and Photo Responsiveness of CH3 NH3 SnI3 Perovskite via Pressure-Induced Amorphization and Recrystallization. AB - An organic-inorganic halide CH3 NH3 SnI3 perovskite with significantly improved structural stability is obtained via pressure-induced amorphization and recrystallization. In situ high-pressure resistance measurements reveal an increased electrical conductivity by 300% in the pressure-treated perovskite. Photocurrent measurements also reveal a substantial enhancement in visible-light responsiveness. The mechanism underlying the enhanced properties is shown to be associated with the pressure-induced structural modification. PMID- 27514761 TI - Onconephrology: What Should the Internist Know About Targeted Therapy in Solid Tumors? AB - Advances in medical oncology has led cancer patients to live longer. Moreover, the field of molecular oncology is rapidly evolving, new therapies emerge, and drugs are approved quickly. This has led nephrologists to encounter new and partially unrecognized treatments of the targeted therapy agents with kidney adverse effects. These agents fall mainly into 2 categories affecting the vascular endothelial growth factor and endothelial growth factor pathways. This review covers the incidence of kidney disease induced by these agents, pathophysiologic mechanisms, and clinical presentation, and is the first to recommend an adequate management for each pathophysiology. PMID- 27514762 TI - Spontaneous Hemorrhage in a Renal Abscess Mimicking Renal Neoplasm. PMID- 27514763 TI - Influence of Fluid Balance on Morbidity and Mortality in Critically Ill Patients With Acute Kidney Injury. AB - INTRODUCTION: Fluid management in critically ill patients with acute kidney injury (AKI) is controversial. Our study is aimed to evaluate the association between fluid balance and patient outcome in AKI patients admitted to intensive care unit (ICU). MATERIALS AND METHODS: This prospective study was carried out at Lilavati Hospital and Research Centre on 130 critically ill patients with AKI admitted to ICU. Mean daily fluid balance (MDFB) was measured and its correlation with clinical characteristics and outcomes was assessed. RESULTS: During ICU stay, 48.2% patients had a positive and 52.8% had a negative MDFB. In the patients with positive MDFB, mean ICU stay was longer and ventilation requirement, duration of ventilation, inotrope requirement, and duration of inotrope were greater as compared to the group with negative MDFB. A significantly higher mortality rate were observed in the patients with positive MDFB as compared to negative MDFB (43.5% versus 7.4%). CONCLUSIONS: Negative fluid balance was independently associated with a significant reduction in mortality, ICU stay, ventilator requirement, and the need for renal replacement among critically ill patients with AKI. PMID- 27514764 TI - Renoprotective Effect of Plantago Major Against Nephrotoxicity and Oxidative Stress Induced by Cisplatin. AB - INTRODUCTION: The aim of this study was to investigate the possible renoprotective effect of Plantago major extract against cisplatin-induced nephrotoxicity in rats. MATERIALS AND METHODS: Rats were divided into 6 groups. The first group was the control, group 2 was treated with cisplatin (7 mg/kg, single dose), and groups 3 to 6 received cisplatin with vitamin E (100 mg/kg) and Plantago major extract at doses of 300 mg/kg, 600 mg/kg, and 1200 mg/kg, for 20 days. RESULTS: On day12, serum concentration of urea, creatinine, and potassium significantly increased and sodium concentration significantly decreased in the cisplatin group compared with the control rats. However, serum creatinine, urea, and potassium concentrations were significantly lower in all of the Plantago major groups compared to the cisplatin group. Also, there was a significant elevation in serum sodium concentration in the Plantago major 600 mg/kg group compared to the cisplatin group on day12. Injection of cisplatin caused a significant elevation in malondialdehyde concentration but a significant decrease in catalase activity and total thiol content compared to the control group. Plantago major extract at 1200 mg/kg significantly improved malondialdehyde concentration and total thiol content compared to the cisplatin group. Catalase activity with Plantago major significantly increased at all doses compared to the cisplatin group. CONCLUSIONS: The current study suggests that Plantago major extract and vitamin E are able to improve kidney function as well as oxidative stress in cisplatin-induced renal toxicity in the rat. PMID- 27514765 TI - Protective Effects of Hydroalcoholic Extract of Ferulago Angulata Against Gentamicin-induced Nephrotoxicity in Rats. AB - INTRODUCTION: Gentamicin can lead to acute tubular injury and kidney dysfunction. This study aimed to evaluate the effect of Ferulago angulata on kidney function and other markers in rats with gentamicin-induced nephrotoxicity. MATERIALS AND METHODS: Forty-eight male Wistar rats were divided into the following groups: group 1, the controls; group 2, rats receiving gentamicin (120 mg/kg body weight per day, intraperitoneal) for 7 days without treatment; groups 3, 4 and 5, rats receiving gentamicin for 7 days and oral treatment with 200 mg/kg, 400 mg/kg, and 800 mg/kg body weight per day of Ferulago angulate extract, respectively. Measurements included serum levels of creatinine, urea, uric acid, lipids, ferric reducing antioxidant power, and protein carbonyl; kidney and serum levels of malondialdehyde; and serum and renal levels of tumor necrosis factor-alpha. Histopathology of kidney tissue was examined as well as renal catalase, superoxide dismutase, and vitamin C. RESULTS: Compared to treatment with gentamicin only, treatment with Ferulago angulata resulted in a significantly higher high-density lipoprotein cholesterol, ferric-reducing antioxidant plasma, renal catalase, superoxide dismutase, and vitamin C levels. It was also associated with significantly lower serum levels of creatinine, urea, uric acid, malondialdehyde, protein carbonyl, tumor necrosis factor-alpha, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and very low density lipoprotein cholesterol. Ferulago angulate was linked with a lower renal gene expression of tumor necrosis factor-alpha. CONCLUSIONS: The present study suggests that Ferulago angulate extract has protective effects against nephrotoxicity due to gentamicin. PMID- 27514766 TI - Effects of Omega-3 Fatty Acid Supplementation on Inflammatory Cytokines and Advanced Glycation End Products in Patients With Diabetic Nephropathy: a Randomized Controlled Trial. AB - INTRODUCTION: This study was performed to evaluate the effects of omega-3 fatty acid supplementation on inflammatory cytokines and advanced glycation end products (AGEs) in patients with diabetic nephropathy (DN). MATERIALS AND METHODS: This randomized double-blind placebo-controlled trial was done on 60 patients with DN who were randomly divided into 2 groups to receive either 1000 mg/d of omega-3 fatty acid from flaxseed oil (n = 30) or placebo (n = 30) for 12 weeks. The primary outcome variables were tumor necrosis factor-alpha, receptor tumor necrosis factor-alpha and growth differentiation factor 15. Fasting blood samples were taken at the onset and the end of the study to quantify the related markers. RESULTS: Compared with the placebo, omega-3 fatty acid supplementation resulted in a significant decrease in serum AGEs (-2.3 +/- 2.8 AU versus 0.2 +/- 2.5 AU, P = .001). Despite a significant reduction in serum level of receptor for AGEs (-0.1 +/- 0.3 AU, P = .02) in the omega-3 fatty acid group, no significant difference was found between the two groups in terms of their effects on the receptor for AGEs. Supplementation with omega-3 fatty acid had no significant effect on the inflammatory cytokines as compared with the placebo. CONCLUSIONS: Our study demonstrated that omega-3 fatty acid supplementation among DN patients had favorable effects on AGEs and the receptor for AGEs. PMID- 27514767 TI - Association Between 25-Hydroxyvitamin D Level and Inflammatory and Nutritional Factors in Hemodialysis and Peritoneal dialysis Patients in Qom, Iran. AB - INTRODUCTION: This study aimed to evaluate the prevalence of vitamin D inadequacy in patients receiving maintenance hemodialysis and peritoneal dialysis (PD) and its association with inflammatory and nutritional factors. MATERIALS AND METHODS: A total of 176 hemodialysis and 32 PD patients participated in the study. Serum levels of 25-hydroxyvitamin D, albumin, parathyroid hormone, calcium, phosphorus, high-sensitivity C-reactive protein (HSCRP), and neutrophil-lymphocyte ratio (NLR) were measured. Data on body mass index were also collected. Stepwise multiple logistic regression analysis was used to identify predictors for 25 hydroxyvitamin D deficiency and its relationship with the nutritional and inflammatory factors. RESULTS: No significant association was found between 25 hydroxyvitamin D and age, body mass index, serum calcium, serum phosphorus, parathyroid hormone, serum albumin, dialysis quality, and duration of dialysis; while NLR and HSCRP were significantly associated with 25-hydroxyvitamin D in the hemodialysis patients only (P < .001 and P = .001, respectively). A positive correlation was found between NLR and HSCRP in both hemodialysis and PD patients. (r = 0.817; P < .001). This association was confirmed between an NLR greater than 3 and an HSCRP level greater than 3. CONCLUSIONS: Vitamin D deficiency was highly prevalent in our dialysis patients, and inadequate level of vitamin D was associated with inflammatory factors such as HSCRP and NLR in both hemodialysis and PD patients. An easy and inexpensive test of an NLR greater than 3 could be used as a measure of inflammation instead of HSCRP in both PD and hemodialysis patients. PMID- 27514768 TI - Zinc Supplementation in Treatment of Children With Urinary Tract Infection. AB - INTRODUCTION: Urinary tract infection (UTI) is very common in children. Precocious diagnosis and appropriate treatment are important because of the permanent disease complications. Zinc increases the response to treatment in many infections. In this study, we explored the effect of zinc in treating UTI. MATERIALS AND METHODS: Two hundred children with UTI were divided into 2 groups of 100 who were comparable in terms of age, sex, urine laboratory profiles, and clinical signs and symptoms. The control group received a standard treatment protocol for UTI and the intervention group received oral zinc sulfate syrup plus routine treatment of UTI. RESULTS: A faster recovery was observed in the patients receiving zinc, but abdominal pain was exacerbated by zinc and lasted longer. Three months after the treatment, there was no significant difference between the two groups in the time of fever stop and negative urine culture. CONCLUSIONS: In children with UTI, zinc supplementation has a positive effect in ameliorating severe dysuria and urinary frequency while the use of this medication is not recommended in the presence of abdominal pain. PMID- 27514769 TI - Inflammation, Left Ventricular Hypertrophy, and Mortality in End-stage Renal Disease. AB - INTRODUCTION: The aim of this study was to evaluate ventricular geometry, its relationship with the inflammatory markers, and mortality of patients with end stage renal disease on peritoneal and hemodialysis treatment. MATERIALS AND METHODS: We enrolled adult patients on long-term dialysis (hemodialysis and peritoneal dialysis) for more than 3 months. Two-dimensional echocardiography was performed by an experienced cardiologist who was blinded to all clinical details of patients. Cardiovascular mortality was assessed during a 2-year follow-up period. RESULTS: There were 129 participants, of whom 86 (66%) were on hemodialysis. Left ventricular hypertrophy was present in 86.7%; concentric hypertrophy was found in 64 (49.1%) and eccentric hypertrophy in 48 patients (37.2%). Patients with left ventricular hypertrophy were further divided into tertiles according to their left ventricular mass index. Logistic regression found pulse pressure as an independent risk factor associated with left ventricular mass index (odds ratio [OR], 1.04; 95% confidence interval (CI), 1.01 to 1.19; P = .047). Cardiovascular mortality rate was 15.5%. Multivariable analysis showed that C-reactive protein (OR, 1.06; 95% CI, 1.01 to 1.10; P = .01), pulse pressure (OR, 1.01; 95% CI, 1.0 to 1.26; P = .046), and left ventricular mass index (OR, 1.03; 95% CI, 1.01 to 1.21; P = .03) were independent risk factors for cardiovascular mortality. CONCLUSIONS: Concentric hypertrophy is the most frequent left ventricular geometry model in patients with chronic kidney disease. Inflammation, pulse pressure, and left ventricular hypertrophy are interrelated and all contribute to mortality and cardiovascular death risk among dialysis patients. PMID- 27514770 TI - Assessment of Circannual Rhythm in Plasma Level of Vitamin D Among Kidney Transplant Recipients in Mashhad. AB - We studied plasma vitamin D level in 96 kidney transplant recipients and its circannual rhythm. Blood samples were tested for 25-hydroxy vitamin D, parathyroid hormone, creatinine, phosphate, and calcium levels in winter and summer 2014. The mean age was 41 years, and the mean transplant age was 6.1 years. Plasma levels of 25-hydroxy vitamin D were 18.0 +/- 15.0 ng/mL in winter and 18.3 +/- 14.7 ng/mL in summer (P = .64). Parathyroid hormone was inversely correlated with vitamin D level in both seasons (r = -0.044, P < .001). There was no relationship between vitamin D and other variables. Our study showed vitamin D deficiency is prevalent among kidney transplant recipients both in winter and summer. Also, vitamin D level did not rise from winter to summer. It is recommended to routinely check on kidney transplant recipients' vitamin D status. PMID- 27514771 TI - Amyloidosis as a Renal Complication of Chronic Granulomatous Disease. AB - Chronic granulomatous disease is a rare primary immunodeficiency disorder, which leads to increased susceptibility to recurrent infections and severe inflammatory manifestations. There have been reports regarding different aspects of genitourinary involvement in chronic granulomatous disease, some of which are hydronephrosis, granulomatous cystitis, and glomerulonephritis, but among these complications, amyloidosis is rather rare. We report a patient with chronic granulomatous disease that developed amyloidosis later in the course of the disease. PMID- 27514772 TI - Esophageal Perforation in a Patient With Kidney Transplantation. AB - Esophageal perforation is a rupture of the esophageal wall, caused by iatrogenesis in 56% of cases. Perforation of the esophagus remains a challenge, and its incidence has increased as the use of endoscopic procedures has become more frequent. We report a 54-year-old woman with esophageal perforation 8 days after kidney transplantation. She had received a gastrointestinal consultation prior to her transplantation. This report highlights the fact that perforation may occur after any organ transplantation, especially during the initial 2 weeks after transplantation, when mycophenolate mofetil and cyclosporine as well as and high doses of corticosteroid are administered. If there is a delay in passage and a swallowing difficulty, high doses of immunosuppressive drugs are likely to cause ulceration and perforation. Preventive strategies including intravenous steroids for the first 2 to 3 weeks and divided doses of pills should be considered for such patients. PMID- 27514773 TI - Anti-cancer synergy of dichloroacetate and EGFR tyrosine kinase inhibitors in NSCLC cell lines. AB - Glycolysis has been observed as a predominant process for most cancer cells to utilize glucose, which was referred to as "Warburg Effect". Targeting critical enzymes, such as pyruvate dehydrogenase kinase (PDK) that inversely regulating the process of glycolysis could be a promising approach to work alone or in combination with other treatments for cancer therapy. EGFR inhibitors for Non Small-Cell Lung Cancer (NSCLC) treatment have been applied for decades in clinical practices with great success, but also their clinical benefits were somewhat hampered by the rising acquired-resistance. Combination drug therapy is an effective strategy to cope with the challenge. In this study, we utilized Dichloroacetate (DCA), a widely regarded PDK inhibitor, together with Erlotinib and Gefitinib, two well-known EGFR inhibitors, and demonstrated that the applications of DCA in combination with either Erlotinib or Gefitinib significantly attenuated the viability of EGFR mutant NSCLC cells (NCI-H1975 and NCI-H1650) in a synergistic manner. This synergistic outcome appears to be a combination effect in promoting apoptosis, rather than co-suppression of either EGFR or PDK signaling pathways. Moreover, we have shown that the combination treatment did not exhibit synergistic effect in other NSCLC cell lines without EGFR mutations (A549 or NCI-H460). Together, these observations suggested that combined targeting of EGFR and PDK in NSCLC cells exerted synergistic effects in an EGFR mutation-dependent fashion. PMID- 27514774 TI - Individual personality differences in goats predict their performance in visual learning and non-associative cognitive tasks. AB - Variation in common personality traits, such as boldness or exploration, is often associated with risk-reward trade-offs and behavioural flexibility. To date, only a few studies have examined the effects of consistent behavioural traits on both learning and cognition. We investigated whether certain personality traits ('exploration' and 'sociability') of individuals were related to cognitive performance, learning flexibility and learning style in a social ungulate species, the goat (Capra hircus). We also investigated whether a preference for feature cues rather than impaired learning abilities can explain performance variation in a visual discrimination task. We found that personality scores were consistent across time and context. Less explorative goats performed better in a non-associative cognitive task, in which subjects had to follow the trajectory of a hidden object (i.e. testing their ability for object permanence). We also found that less sociable subjects performed better compared to more sociable goats in a visual discrimination task. Good visual learning performance was associated with a preference for feature cues, indicating personality-dependent learning strategies in goats. Our results suggest that personality traits predict the outcome in visual discrimination and non-associative cognitive tasks in goats and that impaired performance in a visual discrimination tasks does not necessarily imply impaired learning capacities, but rather can be explained by a varying preference for feature cues. PMID- 27514775 TI - Quantification of Cancer Biomarkers in Serum Using Scattering-Based Quantitative Single Particle Intensity Measurement with a Dark-Field Microscope. AB - In this work, we developed a simple yet robust single particle scattering intensity measurement method for the quantification of cancer-related biomarkers. The design is based on the plasmonic coupling effect between noble metal nanoparticles. First, the primary and secondary antibodies were conjugated onto the surface of 60 nm gold nanoparticles (AuNPs, act as capture probes) and 50 nm silver nanoparticles (AgNPs, act as signal amplification probes) respectively. In the presence of corresponding antigen, a sandwiched immunocomplex was formed, resulting a significantly enhanced scattering intensity in contrast to that of individual probes. By measuring the intensity change of the particles with a dark field microscope (DFM), the amount of target protein could be accurately quantified. As a proof of concept experiment, quantification of three types of antigens, including carcinoembryonic antigen (CEA), prostate-specific antigen (PSA) and alpha fetoprotein (AFP) by this platform was demonstrated with limit of detection (LOD) of 1.7, 3.3, and 5.9 pM, respectively, with a linear dynamic range of 0 to 300 pM. Furthermore, to elucidate the potential in clinical application, the content of antigens in a serum sample was also quantified directly without additional sample pretreatment. In order to validate the reliability of this method, the measured result was also compared with that obtained by regular enzyme-linked immunosorbent assay (ELISA) kit, showing good consistency between these two data sets. Therefore, owing to the simplicity and accuracy of this method, it could be potentially applied for massive disease screening in clinical assay in the future. PMID- 27514776 TI - Potassium-competitive acid blockers: Advanced therapeutic option for acid-related diseases. AB - Acid-related diseases (ARDs), such as peptic ulcers and gastroesophageal reflux disease, represent a major health-care concern. Some major milestones in our understanding of gastric acid secretion and ARD treatment reached during the last 50years include 1) discovery of histamine H2-receptors and development of H2 receptor antagonists, 2) identification of H+,K+-ATPase as the parietal cell proton pump and development of proton pump inhibitors (PPIs), and 3) identification of Helicobacter pylori (H. pylori) as the major cause of peptic ulcers and development of effective eradication regimens. Although PPI treatments have been effective and successful, there are limitations to their efficacy and usage, i.e. short half-life, insufficient acid suppression, slow onset of action, and large variation in efficacy among patients due to CYP2C19 metabolism. Potassium-competitive acid blockers (P-CABs) inhibit H+,K+-ATPase in a reversible and K+-competitive manner, and exhibit almost complete inhibition of gastric acid secretion from the first dose. Many pharmaceutical companies have tried to develop P-CABs, but most of their clinical development has been discontinued due to safety concerns or a similar efficacy to PPIs. Revaprazan was developed in Korea and was the first P-CAB approved for sale. Vonoprazan, approved in 2014 in Japan, has a completely different chemical structure and higher pKa value compared to other P-CABs, and exhibits rapid onset of action and prolonged control of intragastric acidity. Vonoprazan is an effective treatment for ARDs that is especially effective in healing reflux esophagitis and for H. pylori eradication. P-CABs, such as vonoprazan, promise to further improve the management of ARDs. PMID- 27514777 TI - The influence of trematode parasite burden on gene expression in a mammalian host. AB - BACKGROUND: Parasites can profoundly impact their hosts and are responsible for a plethora of debilitating diseases. To identify global changes in host gene expression related to parasite infection, we sequenced, assembled, and annotated the liver transcriptomes of Balb/cj mice infected with the trematode parasite Schistosoma mansoni and compared the results to uninfected mice. We used two different methodologies (i.e. de novo and reference guided) to evaluate the influence of parasite sequences on host transcriptome assembly. RESULTS: Our results demonstrate that the choice of assembly methodology significantly impacted the proportion of parasitic reads detected from the host library, yet the presence of non-target (xenobiotic) sequences did not create significant structural errors in the assembly. After removing parasite sequences from the mouse transcriptomes, we analyzed host gene expression under different parasite infection levels and observed significant differences in the associated immunologic and metabolic responses based on infection level. In particular, genes associated with T-helper type 1 (Th-1) and T-helper type 2 (Th-2) were up regulated in infected mice whereas genes related to amino acid and carbohydrate metabolism were down-regulated in infected mice. These changes in gene expression scale with infection status and likely impact the evolutionary fitness of hosts. CONCLUSIONS: Overall, our data indicate that a) infected mice reduce the expression of key metabolic genes in direct proportion to their infection level; b) infected mice similarly increase the expression of key immune genes in response to infection; c) patterns of gene expression correspond to the pathological symptoms of schistosomiasis; and d) identifying and filtering out non-target sequences (xenobiotics) improves differential expression prediction. Our findings identify parasite targets for RNAi or other therapies and provide a better understanding of the pathology and host immune repertoire involved in response to S. mansoni infections. PMID- 27514778 TI - Implementation of a clinical practice guideline for schizophrenia in a specialist mental health center: an observational study. AB - BACKGROUND: In mental health settings, implementation of and adherence to clinical practice guidelines (CPGs) is low. Strategies are needed to overcome barriers and facilitate successful implementation of CPGs into standard care. The goals of this study were to develop a framework for the implementation of a CPG for schizophrenia for hospitalized service users in a mental health care facility, and to monitor adherence to the guideline. METHODS: An eight-step framework was developed based on project management principles: 1) the Appraisal Guideline for Research and Evaluation (AGREE) tool was used to rate and select a CPG; 2) an algorithm was created from the guideline; 3) a gap analysis identified clinical services and processes not conforming with the CPG recommendations; 4) a governance structure was created; 5) a modified Delphi process determined key outcome and process adherence metrics; 6) a project charter was developed; 7) clinical informatics ensured that systems and tools were in place to support the CPG; and 8) therapeutic services were realigned to match the requirements of the CPG within specified fiscal constraints. Percent adherence to the identified process adherence metrics was calculated before (March 2014) and for 12 months after implementation (April 2014-March 2015). RESULTS: The National Institute of Health and Care Excellence guideline scored highest on AGREE and was used to develop the algorithm. Cognitive behavior therapy for psychosis (CBT-P), art therapy and carer assessments were identified as gaps in care. Clinical global impression - Schizophrenia score was identified as the primary service user outcome variable and antipsychotic polypharmacy, metabolic monitoring, CBT-P referral and supported employment/vocational services referral as the primary process adherence measures. Adherence to guidance for metabolic monitoring (March 2014, 76.7 %; March 2015, 81.6 %), CBT-P referral (March 2014, 6.5 %; March 2015, 11.4 %) and vocational rehabilitation referral (March 2014, 36.6 %; March 2015, 49.1 %) were increased after CPG implementation. There was an initial increase in adherence to antipsychotic monotherapy (March 2014, 53.4 %; November 2014, 62.7 %), which decreased back toward baseline (March 2015, 55.1 %). CONCLUSIONS: The eight-step framework was used to implement a CPG process, though further quality improvements initiatives may be needed to improve adherence. PMID- 27514779 TI - Evaluation of hypercoagulability state in perinatal arterial ischemic stroke with rotation thromboelastometry. AB - BACKGROUND: Perinatal arterial ischemic stroke (PAIS) is an important cause of pediatric morbidity and mortality. The etiology of PAIS remains unknown. Several maternal-neonatal disorders, and especially prothrombotic risk factors, have been reported in infants with perinatal stroke (PS). Rotation thromboelastometry (ROTEM) can analyze the coagulation system, from the beginning of coagulation, through clot formation, and ending with fibrinolysis. The aim of this study was to evaluate the hypercoagulability state in PAIS patients using ROTEM. METHODS: Patients were obtained by evaluating hospital files retrospectively. Twenty patients with PAIS and 19 healthy controls were included in the study. Prothrombotic risk factors and standard coagulation parameters were collected for all patients. Thromboelastometry (TEM) analysis was performed with the ROTEM(r) Coagulation Analyzer model Gamma 2500 (Tem International, Munich, Germany). Patients were separated into two groups; Group 1 included PAIS patients with prothrombotic risk factors and Group 2 included patients with no prothrombotic risk factors. RESULTS: Group 1 includes six patients and Group 2 includes fourteen. Maternal risk factors were reported in 55 % and prothrombotic risk factors were detected in 30 % of the patients. ROTEM analyses were done mean age of 11.2 +/- 9.4 months. ROTEM analysis showed that maximum clot firmness (MCF) value on both groups was significantly higher than in the control group, which is consistent with a hypercoagulable state. There was no statistical difference between the MCF values of Group 1 and Group 2. No significant correlations were found between the ROTEM parameters and the hematological parameters. CONCLUSION: The etiology of PAIS is still unclear. Prothrombotic risk factors may be an important etiology for PAIS. However, standard hematological tests for evaluating prothrombotic risk factors are limited. In our study, ROTEM analyses showed higher maximum clot firmness in PAIS patients compared to controls. ROTEM analyses may suggest a hypercoagulable state due to abnormal fibrinolysis in PAIS patients. Normative data and further research is needed to validate our findings. PMID- 27514780 TI - Cloning and characterization of tyrosine hydroxylase (TH) from the pacific white leg shrimp Litopenaeus vannamei, and its expression following pathogen challenge and hypothermal stress. AB - Tyrosine hydroxylase (TH) belongs to the biopterin-dependent aromatic amino acid hydroxylase enzyme family, and it represents the first and rate-limiting step in the synthesis of catecholamines that are required for physiological and immune process in invertebrates and vertebrates. Cloned Litopenaeus vannamei TH (LvTH), containing a short alpha helix domain, a catalytic core, a regulatory domain, a phosphorylation site and two potential N-linked glycosylation sites as presented in vertebrate and insect THs without acidic region and signal peptide cleavage sites at the amino-terminal, exhibited a similarity of 60.0-61.2% and 45.0-47.0% to that of invertebrate and vertebrate THs, respectively. Further, LvTH expression was abundant in gill and haemocytes determined by quantitative real time PCR. L. vannamei challenged with Vibrio alginolyticus at 10(5) cfu shrimp( 1) revealed significant increase of LvTH mRNA expression in haemocytes within 30 120 min and in brain within 15-30 min followed with recuperation. In addition, shrimps exposed to hypothermal stress at 18 degrees C significantly increased LvTH expression in haemocytes and brain within 30-60 and 15-60 min, respectively. The TH activity and haemolymph glucose level (haemocytes-free) significantly increased in pathogen challenged shrimp at 120 min and 60 min, and in hypothermal stressed shrimp at 30-60 and 30 min, respectively. These results affirm that stress response initiates in the brain while haemocytes display later response. Further, the significant elevation of TH activity in haemolymph is likely to confer by TH that released from haemocytes. In conclusion, the cloned LvTH in our current study is a neural TH enzyme appears to be involved in the physiological and immune responses of whiteleg shrimp, L. vannamei suffering stressful stimulation. PMID- 27514781 TI - Identification and characterization of a novel Toll-like receptor 4 homologue in blunt snout bream, Megalobrama amblycephala. AB - Toll-like receptors (TLRs) are central players in the innate immune system in response to a wide range of pathogen infection. Among various TLRs, TLR4 plays a key role in recognition of bacterial lipopolysaccharides (LPS). In the present study, we identified and characterized a novel TLR4 homologue (maTLR4b) in blunt snout bream (Megalobrama amblycephala) which was significantly distinct from previously reported M. amblycephala TLR4 (tentatively named maTLR4a). The results showed that the complete cDNA sequence of maTLR4b was 3261 bp with an open reading frame encoding a polypeptide of 820 amino acids, and that its genomic sequence was 3793 bp, which had 3 exons. Structurally, the deduced maTLR4b protein showed a typical TLR domain architecture, including a signal peptide, eight leucine-rich repeats (LRRs) in the extracellular region, a transmembrane domain, and a Toll-Interleukin 1 receptor (TIR) domain in the cytoplasmic region. Phylogenetic analysis revealed that all TLR4s from teleost fish formed a monophyletic clade. Both maTLR4a and maTLR4b were divided into two distinct branches, and showed the highest level of similarity with the grass carp TLR4.2 and TLR4.4 homologue, respectively. MaTLR4b was constitutively expressed in all healthy tissues tested although at different levels. After LPS stimulation, the expression levels were significantly up-regulated in spleen, and peaked at 4 h between maTLR4a and maTLR4b, but with a distinct and complementary expression patterns. Taken together, these results suggested that maTLR4b is indeed a functional homologue of TLR4 in other species, which may play vital role in innate immune. PMID- 27514782 TI - Evolutionary analysis of the jacalin-related lectin family genes in 11 fishes. AB - Jacalin-related lectins are a type of carbohydrate-binding proteins, which are distributed across a wide variety of organisms and involved in some important biological processes. The evolution of this gene family in fishes is unknown. Here, 47 putative jacalin genes in 11 fish species were identified and divided into 4 groups through phylogenetic analysis. Conserved gene organization and motif distribution existed in each group, suggesting their functional conservation. Some fishes have eleven jacalin genes, while others have only one or zero gene in their genomes, suggesting dynamic changes in the number of jacalin genes during the evolution of fishes. Intragenic recombination played a key role in the evolution of jacalin genes. Synteny analyses of jacalin genes in some fishes implied conserved and dynamic evolution characteristics of this gene family and related genome segments. Moreover, a few functional divergence sites were identified within each group pairs. Divergent expression profiles of the zebra fish jacalin genes were further investigated in different stresses. The results provided a foundation for exploring the characterization of the jacalin genes in fishes and will offer insights for additional functional studies. PMID- 27514783 TI - Functional characterizations and expression profiles of ADAR2 gene, responsible for RNA editing, in response to GCRV challenge in grass carp (Ctenopharyngodon idella). AB - ADAR (adenosine deaminases acting on RNA)-mediated adenosine-to-inosine (A-to-I) editing to double-stranded RNA (dsRNA) is a critical arm of the antiviral response. The present study focused on the structural and functional characterizations of grass carp (Ctenopharyngodon idella) ADAR2 (CiADAR2) gene. The complete genomic sequence of CiADAR2 is 150,458 bp in length, containing 12 exons and 11 introns. The open reading frame (ORF) of 2100 bp encodes a polypeptide of 699 amino acids (aa) which contains three highly conservative domains - two N-terminal dsRNA binding domains (dsRBDs) and one C-terminal deaminase domain. The predicted crystal structure of CiADAR2 deaminase domain suggested a catalytic center form in the enzyme active site. CiADAR2 mRNA was ubiquitously expressed in the fifteen tested tissues, and was induced post GCRV challenge in spleen and head kidney and C. idella kidney (CIK) cells. The ex vivo expression of CiADAR2 protein was verified by the Flag (tag)-based western blot assay. Antiviral activity assay of CiADAR2 was manifested by the delayed appearance of cytopathic effect (CPE) and inhibition of GCRV yield at 48 h post infection. Furthermore, in CiADAR2 overexpression cells, mRNA expression levels of CiIFN1, CiTLR7 and CiTLR8 were facilitated at different time points after GCRV infection, comparing to those in control group. Taken together, it was indicated that ADAR2 was an antiviral cytokine against GCRV and anti-GCRV function mechanism might involve in the TLR7/8-regulated IFN-signaling. These findings suggested that CiADAR2 was a novel member engaging in antiviral innate immune defense in C. idella, which laid a foundation for the further mechanism research of ADAR2 in fishes. PMID- 27514784 TI - Molecular structure and immune-stimulated transcriptional modulation of the first teleostean IFP35 counterpart from rockfish (Sebastes schlegelii). AB - Interferons (IFNs) and IFN-inducible proteins play numerous physiological roles, particularly in antiviral defense mechanisms of the innate immune response with the presence of pathogens. IFN-induced protein-35 kDa (IFP35) is induced by Type II IFN (IFN-gamma); it is a cytoplasmic protein that can be translocated to the nucleus via the stimulation of IFN. In this study, we report the complete molecular characterization of the IFP35 cDNA sequence from the black rockfish in an effort to understand its role in the immune response. The coding sequence of RfIFP35 encoded a putative peptide of 371 amino acids containing two characteristic Nmi/IFP 35 domains (NIDs), which are highly conserved among its counterparts. The protein showed a molecular mass of 42.2 kDa with a theoretical pI of 5.05 and was predicted to be unstable because of its high instability index (49.37). Therefore, the protein-protein interaction is essential for its stability, which may be facilitated by the intrinsically disordered regions in this protein. According to cellular location prediction, the RfIFP35 protein is cytosolic. Phylogenetic analysis showed that RfIFP35 was cladded within the fish counterparts. Tissue distribution profiling revealed a ubiquitous presence of the protein in all examined tissues, with highest expression in the blood followed by the spleen tissues. The expression of RfIFP35 during immune challenge with poly I:C and lipopolysaccharide treatments affirms its putative importance in the first-line host defense system. RfIFN-gamma mRNA was significantly expressed at 6 h p.i. in blood and 3 h p.i. in the spleen following treatment with different immune stimulants, and its expression was higher compared to that of RfIFP35 mRNA. Therefore, the modulation patterns of both RfIFP35 and RfIFN-gamma suggest that RfIFP35 may be induced by RfIFN-gamma. PMID- 27514785 TI - The protective effects of taurine on acute ammonia toxicity in grass carp Ctenopharynodon idellus. AB - The four experimental groups were carried out to test the response of grass carp Ctenopharyngodon idella to ammonia toxicity and taurine: group 1 was injected with NaCl, group 2 was injected with ammonium acetate, group 3 was injected with ammonium acetate and taurine, and group 4 was injected taurine. Fish in group 2 had the highest ammonia content in the liver and brain, and alanine, arginine, glutamine, glutamate and glycine contents in liver. Brain alanine and glutamate of fish in group 2 were significantly higher than those of fish in group 1. Malondialdehyde content of fish in group 2 was the highest, but superoxide dismutase and glutathione activities were the lowest. Although fish in group 2 had the lowest red cell count and hemoglobin, the highest alkaline phosphatase, complement C3, C4 and total immunoglobulin contents appeared in this group. In addition, superoxide dismutase and glutathione activities, red cell count and hemoglobin of fish in group 3 were significantly higher than those of fish in group 2, but malondialdehyde content is the opposite. This study indicates that ammonia exerts its toxic effects by interfering with amino acid transport, inducing reactive oxygen species generation and malondialdehyde accumulation, leading to blood deterioration and over-activation of immune response. The exogenous taurine could mitigate the adverse effect of high ammonia level on fish physiological disorder. PMID- 27514786 TI - Dietary effects of adenosine monophosphate to enhance growth, digestibility, innate immune responses and stress resistance of juvenile red sea bream, Pagrus major. AB - Our study explored the dietary effects of adenosine monophosphate (AMP) to enhance growth, digestibility, innate immune responses and stress resistance of juvenile red sea bream. A semi-purified basal diet supplemented with 0% (Control), 0.1% (AMP-0.1), 0.2% (AMP-0.2), 0.4% (AMP-0.4) and 0.8% (AMP-0.8) purified AMP to formulate five experimental diets. Each diet was randomly allocated to triplicate groups of fish (mean initial weight 3.4 g) for 56 days. The results indicated that dietary AMP supplements tended to improve growth performances. One of the best ones was found in diet group AMP-0.2, followed by diet groups AMP-0.1, AMP-0.4 and AMP-0.8. The Apparent digestibility coefficients (dry matter, protein and lipid) also improved by AMP supplementation and the significantly highest dry matter digestibility was observed in diet group AMP 0.2. Fish fed diet groups AMP-0.2 and AMP-0.4 had significantly higher peroxidase and bactericidal activities than fish fed the control diet. Nitro-blue tetrazolium (NBT) activity was found to be significantly (P < 0.05) greater in fish fed diet groups AMP-0.4 and AMP-0.8. Total serum protein, lysozyme activity and agglutination antibody titer were also increased (P > 0.05) by dietary supplementation. In contrast, catalase activity decreased with AMP supplementation. Moreover, the fish fed AMP supplemented diets had better improvement (P < 0.05) in body lipid contents, condition factor, hematocrit content and glutamyl oxaloacetic transaminase (GOT) level than the control group. Supplementation also improved both freshwater and oxidative stress resistances. Interestingly, the fish fed diet groups AMP-0.2 and AMP-0.4 showed the least oxidative stress condition. Finally it is concluded that, dietary AMP supplementation enhanced the growth, digestibility, immune response and stress resistance of red sea bream. The regression analysis revealed that a dietary AMP supplementation between 0.2 and 0.4% supported weight gain and lysozyme activity as a marker of immune functions for red sea bream, which is also inline with the most of the growth and health performance parameters of fish under present experimental conditions. PMID- 27514787 TI - Cloning, characterization, and expression of the macrophage migration inhibitory factor gene from the black tiger shrimp (Penaeus monodon). AB - Macrophage migration inhibitory factor (MIF) is an ancient cytokine that engages in innate immune system of vertebrates and invertebrates. In this study, the MIF gene homologue (PmMIF) was cloned from the black tiger shrimp, Penaeus monodon. The full-length cDNA sequence of PmMIF was 838 bp and contained 78 bp 5' untranslated region (UTR) and 397 bp 3' UTR, and an open reading frame (ORF) of 363 bp which coded 120 amino acids (aa). Multiple alignment analysis showed that the deduced amino acid sequence shared 98% identities with MIF from closely related species of Litopenaeus vannamei. Quantitative real-time PCR (qRT-PCR) analysis indicated that PmMIF was highly expression observed in hepatotpancreas and gills. After Vibrio harveyi challenge, PmMIF mRNA level in hepatopancreas and gills were sharply up-regulated at 6 h post-injection, and reached the maximum at 12 h. PmMIF expression level in the hepatopancreas and gills were up-regulated markedly under low (2.3%) and high (4.3%) salinity exposure, respectively. PmMIF expression level in gills increased significantly at 12 h and reached peak values (2.5- fold, 6.4-fold and 1.8-fold compared with the control) at 12 h, 48 h and 12 h after zinc, cadmium and copper exposure, respectively. In the hepatopancreas, the expression of PmMIF reached maximum levels (8.5- fold, 6.2-fold and 2.1-fold compared with the control) at 24 h, 6 h and 48 h after zinc, cadmium and copper exposure, respectively. All the results indicate that PmMIF plays an important role in responding in the innate immune system of shrimps. PMID- 27514788 TI - Grouper (Epinephelus coioides) BCR signaling pathway was involved in response against Cryptocaryon irritans infection. AB - B cell antigen receptor (BCR) plays a crucial role in B cell development and antibody production. It comprises membrane immunoglobulin non-covalently associated with CD79a/CD79b heterodimer. After B cell activation, initial extracellular signals are transduced by BCR complex and amplified by two protein tyrosine kinases, LYN and SYK, which then trigger various pathways. In the present study, we cloned grouper genes for BCR accessory molecules, EcCD79a (669 bp) and EcCD79b (639 bp), as well as two protein tyrosine kinases, EcLYN (1482 bp) and EcSYK (1854 bp). Homology analysis showed that all four molecules had a relatively high amino acid identity compared with those in other animals. Among them, they all shared the highest identity with Takifugu rubripes (EcCD79a 49%, EcCD79b 52%, EcLYN 82% and EcSYK 77%). The conserved features and important functional residues were analyzed. Together with IgM and IgT, tissue distribution analysis showed that all six molecules were mainly expressed in immune organs, particularly systematic immune organs. In groupers infected with Cryptocaryon irritans, up-regulation of EcCD79a and b, EcIgM and EcIgT were not seen in the early stage skin and gill until 14-21 days. Up-regulation of EcCD79a was seen in head kidney at most time points, while EcCD79a and b were only significantly up regulated in day 14 spleen. Significant up-regulation of EcIgT were seen in day 21 head kidney and day 1, day14 spleen. Significant up-regulation of EcIgM were seen in day 1 head kidney and 12 h spleen. In addition, two protein kinase genes, EcLYN and EcSYK, were up-regulated in the skin at most time points, which suggested that B cells may be activated at the skin local infection site. PMID- 27514789 TI - Transapical tricuspid valve-in-ring implantation: An alternative approach to a challenging clinical scenario. AB - We report on a transapical tricuspid valve-in-ring implantation performed via right ventricular apex using the Sapien-XT-prosthesis. A 57-year-old woman with recurrent episodes of right heart failure and three previous sternotomies, including tricuspid valve repair with a 32 mm Carpentier-Edwards-Classic annuloplasty ring was admitted due to recurrent severe tricuspid regurgitation. Given the excessive surgical risk, a 29 mm Sapien-XT-prosthesis was selected for valve-in-ring implantation. Transapical valve-in-ring implantation procedure was uneventful. Predischarge echocardiography showed only trace paravalvular tricuspid regurgitation in the septal region. Transapical approach via right ventricular apex is a viable alternative for tricuspid valve-in-ring implantation in selected high-risk patients. (c) 2016 Wiley Periodicals, Inc. PMID- 27514790 TI - Is Ammonium Peroxydisulate Indispensable for Preparation of Aniline-Derived Iron Nitrogen-Carbon Electrocatalysts? AB - Iron and nitrogen co-doped carbon (Fe-N-C) materials are among the most active non-precious metal catalysts that could replace Pt-based electrocatalysts for the oxygen reduction reaction (ORR) in fuel cells and metal-air batteries. The synthesis of the Fe-N-C catalysts often involves the use of aniline as the precursor for both N and C and ammonium peroxydisulfate (APS) as an indispensable oxidative initiator for aniline polymerization. Herein, a detailed structure and catalytic ORR performance comparison of aniline-derived Fe-N-C catalysts synthesized with and without the use of APS is reported. The APS-free preparation, which uses Fe(III) ions as the Fe source as well as the aniline polymerization initiator, results in a simple Fe-N-C catalyst with a high activity for the ORR. We show that APS is not necessary for the preparation and even detrimental to the performance of the catalyst. PMID- 27514791 TI - Initial Molecular Recognition Steps of McjA Precursor during Microcin J25 Lasso Peptide Maturation. AB - Microcin J25 (MccJ25) has emerged as an excellent model to understand the maturation of ribosomal precursor peptides into the entangled lasso fold. MccJ25 biosynthesis relies on the post-translational modification of the precursor McjA by the ATP-dependent protease McjB and the lactam synthetase McjC. Here, using NMR spectroscopy, we showed that McjA is an intrinsically disordered protein without detectable conformational preference, which emphasizes the active role of the maturation machinery on the three-dimensional folding of MccJ25. We further showed that the N-terminal region of the leader peptide is involved in interaction with both maturation enzymes and identified a predominant interaction of V43-S55 in the core McjA sequence with McjC. Moreover, we demonstrated that residues K23-Q34 in the N-terminal McjA leader peptide tend to adopt a helical conformation in the presence of membrane mimics, implying a role in directing McjA to the membrane in the vicinity of the lasso synthetase/export machinery. These data provide valuable insights into the initial molecular recognition steps in the MccJ25 maturation process. PMID- 27514792 TI - Hypoparathyroidism: A rare mimic of amyotrophic lateral sclerosis. AB - INTRODUCTION: Amyotrophic lateral sclerosis (ALS) carries a grim prognosis. Various ALS mimics have been reported and should be excluded before confirming this diagnosis. METHODS: We report the case of a 61-year-old man who presented with progressively worsening limb weakness and dysphagia. His examination showed mixed upper and lower motor neuron signs without sensory impairment. ALS was suspected, however, atypical diffuse pain prompted diagnostic work-up to exclude other causes. RESULTS: Electrodiagnostic testing was suggestive of a sensorimotor polyneuropathy with superimposed diffuse active denervation suspicious for anterior horn cell degeneration. Brain MRI showed bilateral basal ganglia and thalamic calcifications. Laboratory studies confirmed the diagnosis of hypoparathyroidism. Treatment with calcium and vitamin D resulted in significant improvement at 6 months follow-up. CONCLUSIONS: Hypoparathyroidism, a treatable endocrinopathy, can rarely present clinically as ALS. In atypical cases, this should be ruled out before making a final diagnosis. Muscle Nerve, 2016 Muscle Nerve 55: 437-439, 2017. PMID- 27514793 TI - Preparation of Magnesium, Cobalt and Nickel Ferrite Nanoparticles from Metal Oxides using Deep Eutectic Solvents. AB - Natural deep eutectic solvents (DESs) dissolve simple metal oxides and are used as a reaction medium to synthesize spinel-type ferrite nanoparticles MFe2 O4 (M=Mg, Zn, Co, Ni). The best results for phase-pure spinel ferrites are obtained with the DES consisting of choline chloride (ChCl) and maleic acid. By employing DESs, the reactions proceed at much lower temperatures than usual for the respective solid-phase reactions of the metal oxides and at the same temperatures as synthesis with comparable calcination processes using metal salts. The method therefore reduces the overall required energy for the nanoparticle synthesis. Thermogravimetric analysis shows that the thermolysis process of the eutectic melts in air occurs in one major step. The phase-pure spinel-type ferrite particles are thoroughly characterized by X-ray diffraction, diffuse-reflectance UV/Vis spectroscopy, and scanning electron microscopy. The properties of the obtained nanoparticles are shown to be comparable to those obtained by other methods, illustrating the potential of natural DESs for processing metal oxides. PMID- 27514796 TI - The anterolateral thigh flap for soft tissue reconstruction in patients with tongue squamous cell carcinoma. AB - BACKGROUND: Surgery remains the first choice of treatment for tongue cancer. Immediate reconstruction should be performed after wide resection of tumour. The aim of this study was to evaluate the anterolateral thigh flap for reconstruction of lingual defects. METHODS: We report 39 consecutive oral tongue squamous cell carcinoma patients who underwent lingual reconstruction with the anterolateral thigh flap between 2009 and 2010. RESULTS: The width of the skin island was 4 to 5 cm and the length of the skin island was 6 to 8 cm in 31 patients with T2 tumour, while the width of the skin island was 5.5 to 6 cm and the length of the skin island was 9 to 12 cm in 8 patients with T3/4 tumours. The all flap survival rate was 97.5 % in our series. CONCLUSIONS: We could obtain sufficient flap volume using the anterolateral thigh flap for tongue reconstruction. The single perforator-based anterolateral thigh flap is a good option for soft tissue reconstruction in patients with oral tongue squamous cell carcinoma. PMID- 27514798 TI - Global RT-PCR and RT-qPCR Analysis of the mRNA Expression of the Human PTPome. AB - Comprehensive comparative gene expression analysis of the tyrosine phosphatase superfamily members (PTPome) under cell- or tissue-specific growth conditions may help to define their individual and specific role in physiology and disease. Semi quantitative and quantitative PCR are commonly used methods to analyze and measure gene expression. Here, we describe technical aspects of PTPome mRNA expression analysis by semi-quantitative RT-PCR and quantitative RT-PCR (RT qPCR). We provide a protocol for each method consisting in reverse transcription followed by PCR using a global platform of specific PTP primers. The chapter includes aspects from primer validation to the setup of the PTPome RT-qPCR platform. Examples are given of PTP-profiling gene expression analysis using a human breast cancer cell line upon long-term or short-term treatment with cell signaling-activation agents. PMID- 27514797 TI - The Extended Family of Protein Tyrosine Phosphatases. AB - In higher eukaryotes, the Tyr phosphorylation status of cellular proteins results from the coordinated action of Protein Tyrosine Kinases (PTKs) and Protein Tyrosine Phosphatases (PTPs). PTPs have emerged as highly regulated enzymes with diverse substrate specificity, and proteins with Tyr-dephosphorylation or Tyr dephosphorylation-like properties can be clustered as the PTPome. This includes proteins from the PTP superfamily, which display a Cys-based catalytic mechanism, as well as enzymes from other gene families (Asp-based phosphatases, His-based phosphatases) that have converged in protein Tyr-dephosphorylation-related functions by using non-Cys-based catalytic mechanisms. Within the Cys-based members of the PTPome, classical PTPs dephosphorylate specific phosphoTyr (pTyr) residues from protein substrates, whereas VH1-like dual-specificity PTPs dephosphorylate pTyr, pSer, and pThr residues, as well as nonproteinaceous substrates, including phosphoinositides and phosphorylated carbohydrates. In addition, several PTPs have impaired catalytic activity as a result of amino acid substitutions at their active sites, but retain regulatory functions related with pTyr signaling. As a result of their relevant biological activity, many PTPs are linked to human disease, including cancer, neurodevelopmental, and metabolic diseases, making these proteins important drug targets and molecular markers in the clinic. Here, a brief overview on the biochemistry and physiology of the different groups of proteins that belong to the mammalian PTPome is presented. PMID- 27514799 TI - Expression, Purification, and Kinetic Analysis of PTP Domains. AB - Protein tyrosine phosphatases (PTP) are a large group of enzymes which work together with protein tyrosine kinases to control the tyrosine phosphorylation of proteins, thus playing a major role in cellular signaling. Here, we provide detailed protocols for expression and purification of the catalytic domain of RPTPMU and full length Eya3 as well as the extracellular region of PTPBR7. Methods are described for evaluation of the purity of the recombinant proteins thus obtained. For the purified Eya3 phosphatase we provide protocols for enzyme activity assay using either chromogenic, fluorescent, or peptide substrates. Determination of kinetic parameters by different graphical and computer-based procedures is also described. PMID- 27514800 TI - Peptide Microarrays for Real-Time Kinetic Profiling of Tyrosine Phosphatase Activity of Recombinant Phosphatases and Phosphatases in Lysates of Cells or Tissue Samples. AB - A high-throughput method for the determination of the kinetics of protein tyrosine phosphatase (PTP) activity in a microarray format is presented, allowing real-time monitoring of the dephosphorylation of a 3-nitro-phosphotyrosine residue. The 3-nitro-phosphotyrosine residue is incorporated in potential PTP substrates. The peptide substrates are immobilized onto a porous surface in discrete spots. After dephosphorylation by a PTP, a 3-nitrotyrosine residue is formed that can be detected by a specific, sequence-independent antibody. The rate of dephosphorylation can be measured simultaneously on 12 microarrays, each comprising three concentrations of 48 clinically relevant peptides, using 1.0-5.0 MUg of protein from a cell or tissue lysate or 0.1-2.0 MUg of purified phosphatase. The data obtained compare well with solution phase assays involving the corresponding unmodified phosphotyrosine substrates. This technology, characterized by high-throughput (12 assays in less than 2 h), multiplexing and low sample requirements, facilitates convenient and unbiased investigation of the enzymatic activity of the PTP enzyme family, for instance by profiling of PTP substrate specificities, evaluation of PTP inhibitors and pinpointing changes in PTP activity in biological samples related to diseases. PMID- 27514801 TI - Tailor-Made Protein Tyrosine Phosphatases: In Vitro Site-Directed Mutagenesis of PTEN and PTPRZ-B. AB - In vitro site-directed mutagenesis (SDM) of protein tyrosine phosphatases (PTPs) is a commonly used approach to experimentally analyze PTP functions at the molecular and cellular level and to establish functional correlations with PTP alterations found in human disease. Here, using the tumor-suppressor PTEN and the receptor-type PTPRZ-B (short isoform from PTPRZ1 gene) phosphatases as examples, we provide a brief insight into the utility of specific mutations in the experimental analysis of PTP functions. We describe a standardized, rapid, and simple method of mutagenesis to perform single and multiple amino acid substitutions, as well as deletions of short nucleotide sequences, based on one step inverse PCR and DpnI restriction enzyme treatment. This method of SDM is generally applicable to any other protein of interest. PMID- 27514802 TI - Assays to Measure PTEN Lipid Phosphatase Activity In Vitro from Purified Enzyme or Immunoprecipitates. AB - PTEN is a one of the most frequently mutated tumor suppressors in human cancers. It is essential for regulating diverse biological processes and through its lipid phosphatase activity regulates the PI 3-Kinase signaling pathway. Sensitive phosphatase assays are employed to study the catalytic activity of PTEN against phospholipid substrates. Here we describe protocols to assay PTEN lipid phosphatase activity using either purified enzyme (purified PTEN lipid phosphatase assay) or PTEN immunopurified from tissues or cultured cells (cellular IP PTEN lipid phosphatase assay) against vesicles containing radiolabeled PIP3 substrate. PMID- 27514803 TI - Assessing the Biological Activity of the Glucan Phosphatase Laforin. AB - Glucan phosphatases are a recently discovered family of enzymes that dephosphorylate either starch or glycogen and are essential for proper starch metabolism in plants and glycogen metabolism in humans. Mutations in the gene encoding the only human glucan phosphatase, laforin, result in the fatal, neurodegenerative, epilepsy known as Lafora disease. Here, we describe phosphatase assays to assess both generic laforin phosphatase activity and laforin's unique glycogen phosphatase activity. PMID- 27514804 TI - Discovery and Evaluation of PRL Trimer Disruptors for Novel Anticancer Agents. AB - Overexpression of PRL phosphatases (PRL1, PRL2, and PRL3) has been found in a variety of late-stage tumors and their distant metastatic sites. Therefore, the oncogenic PRL phosphatases represent intriguing targets for cancer therapy. There is considerable interest in identifying small molecule inhibitors targeting PRLs as novel anticancer agents. However, it has been difficult to acquire phosphatase activity-based PRL inhibitors due to the unusual wide and shallow catalytic pockets of PRLs revealed by crystal structure studies. Here, we present a novel method to identify PRL1 inhibitors by targeting the PRL1 trimer interface and the procedure to characterize their biochemical and cellular activity. PMID- 27514805 TI - Analyzing Pseudophosphatase Function. AB - Pseudophosphatases regulate signal transduction cascades, but their mechanisms of action remain enigmatic. Reflecting this mystery, the prototypical pseudophosphatase STYX (phospho-serine-threonine/tyrosine-binding protein) was named with allusion to the river of the dead in Greek mythology to emphasize that these molecules are "dead" phosphatases. Although proteins with STYX domains do not catalyze dephosphorylation, this in no way precludes their having other functions as integral elements of signaling networks. Thus, understanding their roles in signaling pathways may mark them as potential novel drug targets. This chapter outlines common strategies used to characterize the functions of pseudophosphatases, using as an example MK-STYX [mitogen-activated protein kinase (MAPK) phospho-serine-threonine/tyrosine binding], which has been linked to tumorigenesis, apoptosis, and neuronal differentiation. We start with the importance of "restoring" (when possible) phosphatase activity in a pseudophosphatase so that the active mutant may be used as a comparison control throughout immunoprecipitation and mass spectrometry analyses. To this end, we provide protocols for site-directed mutagenesis, mammalian cell transfection, co immunoprecipitation, phosphatase activity assays, and immunoblotting that we have used to investigate MK-STYX and the active mutant MK-STYXactive. We also highlight the importance of utilizing RNA interference (RNAi) "knockdown" technology to determine a cellular phenotype in various cell lines. Therefore, we outline our protocols for introducing short hairpin RNA (shRNA) expression plasmids into mammalians cells and quantifying knockdown of gene expression with real-time quantitative PCR (qPCR). A combination of cellular, molecular, biochemical, and proteomic techniques has served as powerful tools in identifying novel functions of the pseudophosphatase MK-STYX. Likewise, the information provided here should be a helpful guide to elucidating the function of other pseudophosphatases. PMID- 27514806 TI - Crystallization of PTP Domains. AB - Protein crystallography is the most powerful method to obtain atomic resolution information on the three-dimensional structure of proteins. An essential step towards determining the crystallographic structure of a protein is to produce good quality crystals from a concentrated sample of purified protein. These crystals are then used to obtain X-ray diffraction data necessary to determine the 3D structure by direct phasing or molecular replacement if the model of a homologous protein is available. Here, we describe the main approaches and techniques to obtain suitable crystals for X-ray diffraction. We include tools and guidance on how to evaluate and design the protein construct, how to prepare Se-methionine derivatized protein, how to assess the stability and quality of the sample, and how to crystallize and prepare crystals for diffraction experiments. While general strategies for protein crystallization are summarized, specific examples of the application of these strategies to the crystallization of PTP domains are discussed. PMID- 27514807 TI - NMR Spectroscopy to Study MAP Kinase Binding to MAP Kinase Phosphatases. AB - NMR spectroscopy and other solution methods are increasingly being used to obtain novel insights into the mechanisms by which MAPK regulatory proteins bind and direct the activity of MAPKs. Here, we describe how interactions between the MAPK p38alpha and its regulatory proteins are studied using NMR spectroscopy, isothermal titration calorimetry, and small angle X-ray scattering (SAXS). PMID- 27514808 TI - Visualizing and Quantitating the Spatiotemporal Regulation of Ras/ERK Signaling by Dual-Specificity Mitogen-Activated Protein Phosphatases (MKPs). AB - The spatiotemporal regulation of the Ras/ERK pathway is critical in determining the physiological and pathophysiological outcome of signaling. Dual-specificity mitogen-activated protein kinase (MAPK) phosphatases (DUSPs or MKPs) are key regulators of pathway activity and may also localize ERK to distinct subcellular locations. Here we present methods largely based on the use of high content microscopy to both visualize and quantitate the subcellular distribution of activated (p-ERK) and total ERK in populations of mouse embryonic fibroblasts derived from mice lacking DUSP5, a nuclear ERK-specific MKP. Such methods in combination with rescue experiments using adenoviral vectors encoding wild-type and mutant forms of DUSP5 have allowed us to visualize specific defects in ERK regulation in these cells thus confirming the role of this phosphatase as both a nuclear regulator of ERK activity and localization. PMID- 27514809 TI - In Situ Proximity Ligation Assay (In Situ PLA) to Assess PTP-Protein Interactions. AB - Spatiotemporal aspects of protein-tyrosine phosphatase (PTP) activity and interaction partners for many PTPs are elusive. We describe here an elegant and relatively simple method, in situ proximity ligation assay (in situ PLA), which can be used to address these issues. The possibility to detect endogenous unmodified proteins in situ and to visualize individual interactions with spatial resolution is the major advantage of this technique. We provide protocols suitable to monitor association of the transmembrane PTPs PTPRJ/DEP-1/CD148 and PTPRB/VE-PTP with their substrates, the receptor tyrosine kinases FMS-like tyrosine kinase 3 (FLT3/CD135), and Tie2 and vascular endothelial growth factor receptor 2 (VEGFR2), respectively. Detailed description of method development and reagents as well as highlighting of critical factors will enable the reader to apply the method successfully to other PTP-protein interactions. PMID- 27514810 TI - Use of Dominant-Negative/Substrate Trapping PTP Mutations to Search for PTP Interactors/Substrates. AB - Phosphorylation of proteins on tyrosine residues is the consequence of coordinated action of tyrosine kinases (TKs), and protein tyrosine phosphatases (PTPs). Together, they regulate intermolecular interactions, subcellular localization, and activity of a variety of proteins. The level of total protein associated tyrosine phosphorylation in eukaryotic cells is only a small fraction of the total phosphorylation. PTPs, which have high specific activity compared to tyrosine kinases, play an important role in maintaining the tyrosine phosphorylation state of proteins and regulate signal transduction pathways and cellular responses. PTPs depend on specific invariant residues that enable binding to substrates phosphorylated at tyrosine and aid catalytic activity. Identification of PTP substrates has helped understand their role in distinct intracellular signaling pathways. Because of their high specific activity, the interaction between tyrosine phosphatases and their substrates is often very transient in the cellular context, and therefore identification of physiological substrates has been difficult. Single-site mutations in the enzymes stabilize interaction between the enzyme and its targets and have been used extensively to identify substrates. The mutations are either of the catalytic cysteine (Cys) residue or other invariant residues and have been classified as substrate trapping mutants (STMs). These mutants often serve as dominant negatives that can inactivate effector functions of a specific PTP within cells. Considering their association with human disorders, inhibiting specific PTPs is important therapeutically. Since the catalytic domains are largely conserved, developing small-molecule inhibitors to a particular enzyme has proven difficult and therefore alternate strategies to block functions of individual enzymes are seriously being investigated. We provide a description of methods that will be useful to design strategies of using dominant-negative and substrate-trapping mutants for identifying novel interacting partners and substrates of PTPs. PMID- 27514811 TI - Detection and Identification of Ligands for Mammalian RPTP Extracellular Domains. AB - Receptor protein tyrosine phosphatases (RPTPs) form a group of over 20 enzymes in vertebrates, each with unique ectodomains subject to potential extracellular interactions with ligands. It has recently become clear that a remarkably diverse range of ligands exist, including homophilic binders, adhesion molecules, neurotrophin receptors, and proteoglycans. Individual RPTPs can bind several ligands, and vice versa, suggesting that complex cell signaling networks exist. The identification of RPTP ligands and where they are located in tissues remains a challenge for a large number of these enzymes. Here we describe some powerful methods that have proved successful for several research groups, leading to our improved understanding of RPTP-ligand interactions and functional regulation. PMID- 27514812 TI - Production of Osteoclasts for Studying Protein Tyrosine Phosphatase Signaling. AB - Osteoclasts, specialized cells that degrade bone, are key components of the cellular system that regulates and maintains bone homeostasis. Aberrant function of osteoclasts can lead to pathological loss or gain of bone mass, such as in osteopetrosis, osteoporosis, and several types of cancer that metastasize to bone. Phosphorylation of osteoclast proteins on tyrosine residues is critical for formation of osteoclasts and for their proper function and responses to physiological signals. Here we describe preparation and growth of osteoclasts from bone marrow of mice, use of viral vectors to downregulate expression of endogenous proteins and to express exogenous proteins in osteoclasts, and analysis of signaling processes triggered by M-CSF, estrogen, and physical contact with matrix in these cells. PMID- 27514813 TI - Functional Analysis of Protein Tyrosine Phosphatases in Thrombosis and Hemostasis. AB - Platelets are small blood cells derived from cytoplasmic fragments of megakaryocytes and play an essential role in thrombosis and hemostasis. Platelet activation depends on the rapid phosphorylation and dephosphorylation of key signaling molecules, and a number of kinases and phosphatases have been identified as major regulators of platelet function. However, the investigation of novel signaling proteins has suffered from technical limitations due to the anucleate nature of platelets and their very limited levels of mRNA and de novo protein synthesis. In the past, experimental methods were restricted to the generation of genetically modified mice and the development of specific antibodies. More recently, novel (phospho)proteomic technologies and pharmacological approaches using specific small-molecule inhibitors have added additional capabilities to investigate specific platelet proteins.In this chapter, we report methods for using genetic and pharmacological approaches to investigate the function of platelet signaling proteins. While the described experiments focus on the role of the dual-specificity phosphatase 3 (DUSP3) in platelet signaling, the presented methods are applicable to any signaling enzyme. Specifically, we describe a testing strategy that includes (1) aggregation and secretion experiments with mouse and human platelets, (2) immunoprecipitation and immunoblot assays to study platelet signaling events, (3) detailed protocols to use selected animal models in order to investigate thrombosis and hemostasis in vivo, and (4) strategies for utilizing pharmacological inhibitors on human platelets. PMID- 27514814 TI - Functional Analysis of Dual-Specificity Protein Phosphatases in Angiogenesis. AB - Therapeutic perspectives targeting angiogenesis in cancer stimulated an intense investigation of the mechanisms triggering and governing angiogenic processes. Several publications have highlighted the importance of typical dual-specificity phosphatases (DSPs) or MKPs in endothelial cells and their role in controlling different biological functions implicated in angiogenesis such as migration, proliferation, apoptosis, tubulogenesis, and cell adhesion. However, among atypical DSPs, the only one investigated in angiogenesis was DUSP3. We recently identified this DSP as a new key player in endothelial cells and angiogenesis. In this chapter we provide with detailed protocols and models used to investigate the role of DUSP3 in endothelial cells and angiogenesis. We start the chapter with an overview of the role of several DSPs in angiogenesis. We continue with providing a full description of a highly efficient transfection protocol to deplete DUSP3 using small interfering RNA (siRNA) in the primary human umbilical vein endothelial cells (HUVEC). We next describe the major assays used to investigate different processes involved in angiogenesis such as tube formation assay, proliferation assay and spheroids sprouting assay. We finish the chapter by validating our results in DUSP3-knockout mice using in vivo angiogenesis assays such as Matrigel plug and Lewis lung carcinoma cell subcutaneous xenograft model followed by anti-CD31 immunofluorescence and ex vivo aortic ring assay. All methods described can be adapted to other phosphatases and signaling molecules. PMID- 27514815 TI - Studying Protein-Tyrosine Phosphatases in Zebrafish. AB - Protein-tyrosine phosphatases (PTPs) are a large family of signal transduction regulators that have an essential role in normal development and physiology. Aberrant activation or inactivation of PTPs is at the basis of many human diseases. The zebrafish, Danio rerio, is being used extensively to model major aspects of development and disease as well as the mechanism of regeneration of limbs and vital organs, and most classical PTPs have been identified in zebrafish. Zebrafish is an excellent model system for biomedical research because the genome is sequenced, zebrafish produce a large number of offspring, the eggs develop outside the mother and are transparent, facilitating intravital imaging, and transgenesis and (site-directed) mutagenesis are feasible. Together, these traits make zebrafish amenable for the analysis of gene and protein function. In this chapter we cover three manipulations of zebrafish embryos that we have used to study the effects of PTPs in development, regeneration, and biochemistry. Microinjection at the one-cell stage is at the basis of many zebrafish experiments and is described first. This is followed by a description for measuring regeneration of the embryonic caudal fin, a powerful and robust physiological assay. Finally, the considerable but manageable troubleshooting of several complications associated with preparing zebrafish embryos for immunoblotting is explained. Overall, this chapter provides detailed protocols for manipulating zebrafish embryo samples with a compilation of tips collected through extensive experience from the zebrafish research community. PMID- 27514816 TI - Live Staining of Drosophila Embryos with RPTP Fusion Proteins to Detect and Characterize Expression of Cell-Surface RPTP Ligands. AB - The activity and/or localization of receptor tyrosine kinases and phosphatases are controlled by binding to cell-surface or secreted ligands. Identification of ligands for receptor tyrosine phosphatases (RPTPs) is essential for understanding their in vivo functions during development and disease. Here we describe a novel in vivo method to identify ligands and binding partners for RPTPs by staining live-dissected Drosophila embryos. Live dissected embryos are incubated with RPTP fusion proteins to detect ligand binding in embryos. This method can be streamlined to perform large-scale screens for ligands as well as to search for embryonic phenotypes. PMID- 27514817 TI - Methods to Study Protein Tyrosine Phosphatases Acting on Yeast MAPKs. AB - Mitogen activated protein kinases (MAPK) pathways play a key role in orchestrating the eukaryotic cellular response to different stimuli. In this process, phosphorylation of both conserved threonine and tyrosine residues of MAPKs is essential for their activation. Identification of tyrosine and dual specificity protein phosphatases capable of dephosphorylating these phosphosites is thus critical to gain insight into their regulation. Due to the conservation of pivotal elements in eukaryotic signaling, yeast has turned into a valuable tool to increase the knowledge of MAPK signaling in other cell types. Here we describe an in vivo method to evaluate the capacity of a protein, from yeast or other origin, to act as a MAPK phosphatase. It relies on the ability of the phosphatase to reduce, when overexpressed, both the amount of activated MAPK and the transcription from a specific promoter regulated by the corresponding pathway. To this end, the pathway has to be previously activated, preferentially through overexpression of a hyperactive allele of an upstream component within the MAPK module. Additionally, the ability of an overexpressed "trapping" inactive phosphatase version to modify these readouts is also analyzed. Western blotting analysis with specific anti-phospho MAPK antibodies and flow cytometry based determination of fluorescence produced by GFP whose expression is driven by MAPK-regulated promoters are the selected techniques for monitoring these readouts. PMID- 27514818 TI - Transmission of biology and culture among post-contact Native Americans on the western Great Plains. AB - The transmission of genes and culture between human populations has major implications for understanding potential correlations between history, biological, and cultural variation. Understanding such dynamics in 19th century, post-contact Native Americans on the western Great Plains is especially challenging given passage of time, complexity of known dynamics, and difficulties of determining genetic patterns in historical populations for whom, even today, genetic data for their descendants are rare. Here, biometric data collected under the direction of Franz Boas from communities penecontemporaneous with the classic bison-hunting societies, were used as a proxy for genetic variation and analyzed together with cultural data. We show that both gene flow and "culture flow" among populations on the High Plains were mediated by geography, fitting a model of isolation-by-distance. Moreover, demographic and cultural exchange among these communities largely overrode the visible signal of the prior millennia of cultural and genetic histories of these populations. PMID- 27514819 TI - Mitochondria-Mediated Protein Regulation Mechanism of Polymorphs-Dependent Inhibition of Nanoselenium on Cancer Cells. AB - The present study was (i) to prepare two types of selenium nanoparticles, namely an amorphous form of selenium quantum dots (A-SeQDs) and a crystalline form of selenium quantum dots (C-SeQDs); and (ii) to investigate the nano-bio interactions of A-SeQDs and C-SeQDs in MCF-7, HepG2, HeLa, NIH/3T3, L929 cells and BRL-3A cells. It was found that A-SeQDs could induce the mitochondria mediated apoptosis, necrosis and death of cells, while C-SeQDs had much weaker effects. This polymorphs-dependent anti-proliferative activity of nano-selenium was scarcely reported. Further investigation demonstrated that A-SeQDs could differentially regulate 61 proteins and several pathways related to stress response, protein synthesis, cell migration and cell cycle, including "p38 MAPK Signaling", "p53 Signaling", "14-3-3-mediated Signaling", "p70S6K Signaling" and "Protein Ubiquitination Pathway". This was the first report to demonstrate the involvement of protein synthesis and post-translational modification pathways in the anti-proliferative activity associated with NMs. Compared with previously fragmentary studies, this study use a nanomics approach combining bioinformatics and proteomics to systematically investigate the nano-bio interactions of selenium nanoparticles in cancer cells. PMID- 27514820 TI - Production of human blood group B antigen epitope conjugated protein in Escherichia coli and utilization of the adsorption blood group B antibody. AB - BACKGROUND: In the process of ABO-incompatible (ABOi) organ transplantation, removal of anti-A and/or B antibodies from blood plasma is a promising method to overcome hyperacute rejection and allograft loss caused by the immune response between anti-A and/or B antibodies and the A and/or B antigens in the recipient. Although there are commercial columns to do this work, the application is still limited because of the high production cost. RESULTS: In this study, the PglB glycosylation pathway from Campylobacter jejuni was exploited to produce glycoprotein conjugated with Escherichia coli O86:B7 O-antigen, which bears the blood group B antigen epitope to absorb blood group B antibody in blood. The titers of blood group B antibody were reduced to a safe level without changing the clotting function of plasma after glycoprotein absorption of B antibodies in the plasma. CONCLUSIONS: We developed a feasible strategy for the specific adsorption/removal of blood group antibodies. This method will be useful in ABOi organ transplantation and universal blood transfusion. PMID- 27514821 TI - Brachybacterium aquaticum sp. nov., a novel actinobacterium isolated from seawater. AB - A pale-yellowish bacterium, strain KWS-1T, was isolated from seawater during a study of the bacterial diversity of the marine environment of the Kanyakumari coastal region of the Bay of Bengal, India, and was studied by using a polyphasic taxonomic approach. Strain KWS-1T had morphological and chemotaxonomic properties (cell-wall diamino acid, menaquinone and fatty acid profile) consistent with its classification in the genus Brachybacterium. Phylogenetic analysis of the 16S rRNA gene sequence showed that strain KWS-1T was related most closely to Brachybacterium paraconglomeratum JCM 17781T, followed by Brachybacterium saurashtrense DSM 23186T, Brachybacterium gingengisoli JCM 19356T, Brachybacterium faecium JCM 11609T and Brachybacterium conglomeratum JCM 11608T (98.45, 98.24, 98.12, 98.10 and 98.10 % similarity, respectively), whereas the sequence similarity values with respect to the other Brachybacterium species with validly published names were between 97.4 and 94.2 %. However, the DNA-DNA hybridization values between strain KWS-1T and the five most closely related species were less than the threshold value for species discrimination. The major lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylserine and the major quinone was menaquinone MK-7. The DNA G+C content of strain KWS-1T was 71.8 mol%. The above data in combination with the phenotypic distinctiveness of strain KWS-1T from other reference strains clearly indicate that the strain represents a novel species, for which the name Brachybacterium aquaticum sp. nov. is proposed. The type strain is KWS-1T (=MTCC 11836T=DSM 28796T=JCM 30059T). PMID- 27514822 TI - Analysis of 109 Consecutive Explanted Breast Implants: Correlation Between Suspected Implant Rupture and Surgical Findings. AB - INTRODUCTION: The use of breast implants is on the rise due to increases in breast reconstructive and aesthetic surgery. Implant rupture is a possible complication. Among assessment modalities for implant rupture detection, MRI is considered the gold standard. METHODS: We conducted a prospective analysis of 57 women after breast augmentation or postmastectomy reconstruction (109 implants), admitted to our department between 2010 and 2015 due to suspected implant rupture. We correlated surgical findings with symptoms, physical examination, imaging, and device specifications. RESULTS: Seventy-four explanted implants were preoperatively suspected as ruptured. Over a third were intact and unjustifiably explanted. MRI evaluation was the most accurate modality. Interestingly, 61 % of ruptured implants were left-sided. Patient's age, comorbidities, smoking, medications, presenting symptoms, implant duration, and volume did not correlate with implant rupture. CONCLUSIONS: Our study confirmed preexisting data regarding the importance of imaging diagnosis, with MRI being the most accurate modality in both diagnosing and ruling out implant rupture. Interestingly, our study showed that MRI was accurate in detecting all intact implants, unlike lower detection rates reported in previous studies, thus preventing unnecessary explantation. Another unique finding was that the left-sided implants were significantly prone for rupture. As iatrogenic damage is the most common cause of implant rupture, with most surgeons being right-handed, awareness during surgery must be augmented, with further investigation required for potential causes of this unexpected difference. Our study emphasizes the importance of understanding the causes of rupture and the need for evidence-based indications regarding imaging and replacement of implants. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 27514823 TI - Pharmacokinetic Effects of Cinnamic Acid, Amygdalin, Glycyrrhizic Acid and Liquiritin on Ephedra Alkaloids in Rats. AB - BACKGROUND AND OBJECTIVES: Ephedra alkaloids, including ephedrine (EP), pseudoephedrine (PEP) and methylephedrine (MEP), are sympathomimetic compounds with known toxicities but many Ephedra (Ephedrae herba) preparations, such as Ephedra decoction, have been clinically applied for centuries. In order to explore the possible detoxification mechanism of Ephedra alkaloids, four representative compounds in Ephedra decoction (cinnamic acid, amygdalin, glycyrrhizic acid and liquiritin) were studied for their pharmacokinetic effects on Ephedra alkaloids in Sprague-Dawley rats. METHODS: Animals were randomly divided into six groups, with six rats in each. Rats were treated orally with EP PEP-MEP (20 mg/kg EP + 20 mg/kg PEP + 20 mg/kg MEP) and different combinations of cinnamic acid (3.03 mg/kg), amygdalin (56.97 mg/kg), glycyrrhizic acid (12.42 mg/kg), liquiritin (3.79 mg/kg) with EP-PEP-MEP, and 20 mg/kg EP + 20 mg/kg PEP + 20 mg/kg MEP + 3.03 mg/kg cinnamic acid + 56.97 mg/kg amygdalin + 12.42 mg/kg glycyrrhizic acid + 3.79 mg/kg liquiritin. Blood samples (0.5 mL) were taken from the orbital sinus venous plexus into heparinized tubes at 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300 and 360 min (6 rats per time point in each group) following single administration. The concentrations of Ephedra alkaloids in rat plasma were determined using a validated high performance liquid chromatography method. RESULTS: Area under the concentration-time curve from 0 to 360 min (AUC0 t ) of EP, PEP and MEP were 666.99, 650.76 and 632.37 ug.min/mL, respectively. Maximum plasma concentration (C max) of EP, PEP and MEP were 4.15, 4.08 and 3.59 MUg/mL, respectively. Mean residence time (MRT) of EP, PEP and MEP were 197.00, 173.97 and 183.87 min, respectively, when the rats were treated with EP-PEP-MEP. Cinnamic acid increased the AUC0-t of EP while decreased C max of EP, amygdalin and glycyrrhizic acid increased C max and AUC0-t of EP and PEP, while liquiritin decreased AUC0-t of EP and PEP. The four representative compounds reduced MRT of EP, PEP and MEP, four compounds decreased AUC0-t of MEP. The EP-PEP-MEP + cinnamic acid + amygdalin + glycyrrhizic acid + liquiritin group increased AUC0-t of EP while decreased MRT of EP, increased MRT of PEP while decreased AUC0-t of PEP. The EP-PEP-MEP + cinnamic acid + amygdalin + glycyrrhizic acid + liquiritin group decreased MRT, AUC0-t and C max of MEP. CONCLUSIONS: Significant changes in pharmacokinetic parameters of EP, PEP and MEP were observed after oral administration with different combinations. The pharmacokinetic results reported here might provide reference for clinical usage of Ephedra alkaloids. PMID- 27514824 TI - Reasons for current pregnancy amongst grand multiparous Gambian women - a cross sectional survey. AB - BACKGROUND: While grand multiparity is now relatively rare in the developed world it is still common in Sub Saharan Africa. Although significant resources have been committed to providing modern contraceptive methods in the Gambia, the total fertility rate is still high at 5.6. Determining the reasons grand multiparous women proffer for the current pregnancy may help in understanding this trend and tailoring appropriate messages to address any specific concerns. METHOD: A cross sectional survey of grand multiparous women was carried out at the Royal Victoria Teaching Hospital (now Edward Francis Small Teaching Hospital) to determine the reasons for the current pregnancy. RESULTS: The prevalence of grand multiparity was 26.5 % while the average parity among the study population was 7.2 (sd 1.8). The most common reasons given for the current pregnancy were: the desire for another child (22.8 %), the pregnancy was unplanned - a "mistake" (18.4 %) and the need to replace a dead child (15.4 %). CONCLUSION: Grand multiparity is still very common in The Gambia. Additional efforts are required to target those with unplanned pregnancies. Improving child survival may also decrease the prevalence of grand multiparity. PMID- 27514825 TI - [Surgical treatment of de-novo scoliosis]. AB - BACKGROUND: De-novo scoliosis is most commonly associated with chronic back pain and in 70 % of cases with neurological symptoms of the lower extremities. In recent literature, the occurrence and severity of segmental lateral listhesis has been discussed as being an important prognostic factor of sagittal and frontal deformity progression. In general, operative interventions in patients with de novo scoliosis are associated with a high rate of complications. Therefore, conservative treatment modalities are recommended at early stages of the disease. If conservative management fails and a sufficient reduction of the patient's symptoms cannot be achieved, depending on the symptoms, a selective decompression, short-segment fusion or long-instrumented reduction and fusion are indicated. Additionally to the patient's symptoms, specific imaging diagnostics are necessary to develop an adequate surgical treatment strategy. TREATMENT: Selective decompression without fusion is indicated in patients with a fixed deformity and primarily neurologic pain or deficits. In conditions of a focal pathology as cause of significant low back pain and/or neurologic symptoms at early stages of deformity, a short segment fusion is the treatment of choice. However, short-segment fusion as a less-invasive procedure must not be performed in biplanar unbalanced patients and/or advanced de-novo scoliosis. In advanced degenerative de-novo scoliosis a long-segment reposition and fusion following an alignment correction are needed. Standardized pre-operative planning and perioperative management are highly critical to the post-operative success. CONCLUSION: All operative treatment strategies in patients with de-novo scoliosis can be successful but they require sophisticated and individual surgical indication. PMID- 27514826 TI - [Management of postoperative wound infections following spine surgery : First results of a multicenter study]. AB - INTRODUCTION: The number of spinal surgeries has increased significantly in the last decade, which has led to a correlating increase in the number of problems related to wound healing infection. Current literature has reported a spinal wound infection rate of 0.4 to 20 %. The gold standard for surgical restoration of the infection is to use supportive antibiotics, but this concept of wound management in infections is often not sufficiently standardized and shows a large variance between individual clinics. The present study is to first collect data on the number of wound infections, the clinic's internal standards, the use of methods and tools and the management of revisions in Germany. MATERIAL AND METHODS: A questionnaire has been designed for detecting the number of postoperative wound infections, which need to be treated surgically, and the various treatment regimens used. The questionnaire was sent to all members of the DWG (n = 1275). An example of the questionnaire was to determine clinical internal standards and the procedure for the initial treatment of wound infection, the procedure for second look surgery and the number of revisions requested to infection healing. RESULTS: The study has accepted 67 answer sheets covering a period from June 2013-November 2013. On average, the participating hospitals perform 582 spinal operations and an average of 8 revision surgeries due to infection annually. The average rate of infection was 1.7 %. 55 % reported having no fixed standard of care. 97 % reported wound irrigation and debridement during the first revision. Indication for second look revisions was based on the local examination of the wound conditions. On average 2.2 revisions had been performed to reach effective wound healing. 81 % of the colleagues showed readiness to participate in a multicenter trial. CONCLUSION: The results show that there is a need for uniform standards in the treatment of postoperative infections. Surgical debridement and lavage have a major role in the treatment of infection. The overall rate of postoperative infections, of the clinics surveyed, was approximately 1.7 % per year. The infections were healed with approximately 2 revisions utilizing variety of different treatment strategies. PMID- 27514827 TI - [Cement augmentation of pedicle screws : Pros and cons]. AB - Cement augmentation of pedicle screws biomechanically increases screw purchase in the bone. However, clinical complications may occur. The pros and cons of the technique are discussed from different clinical perspectives. PMID- 27514828 TI - [Multimodal therapy concepts for failed back surgery syndrome]. AB - Failed back surgery syndrome (FBSS) is a frequent complication (15-40 %) of lumbar disc surgery and is rarely successfully treated by surgery with the exception of a re-prolapse associated with radicular pain. Multimodal pain treatment, however, is indicated by a lack of pathoanatomical correlates, unclear cause and psychosocial risk factors.This review describes a standardized non operative treatment starting with broad interdisciplinary clarification by medical, psychological and physiotherapeutic means (assessment).If the conditions for multimodal pain therapy are met, the OPS 8-918-procedure can be applied to avoid chronic developing pain. In doing so, the already issued quality standards and guidelines for documentation should be respected. PMID- 27514829 TI - Combined suture and clipping for the reconstruction of a ruptured blister-like aneurysm. AB - Blister-like aneurysms of the internal carotid artery (ICA) present a severe therapeutical challenge. While several reconstructive techniques are in use in case of acute rupture sacrifice of the parent vessel may be required. We present a combined technique of micro-sutures and clip application to repair the parent vessel in an intraoperatively ruptured blister-like aneurysm. Following temporary trapping of an intraoperatively ruptured 7-mm blister-like aneurysm four 8-0 nylon sutures were applied to adapt the vessel walls and support the branches of subsequently applied mini-clips. The combination of micro-sutures and mini-clips might be a valuable alternative to direct clipping or suturing in some cases with intraoperative rupture of blister-like aneurysms. PMID- 27514830 TI - Reply to: "Residency program trainee-satisfaction correlate with results of the European board examination in neurosurgery". PMID- 27514832 TI - Associations of acute stress and overnight heart rate with feed efficiency in beef heifers. AB - Proxies have the potential to accelerate feed efficiency (residual feed intake (RFI); kg dry matter/day) improvement, assisting with the reduction of beef cattle feed costs and environmental impact. Heart rate (HR) (beats per minute (BPM)) is associated with feed efficiency and influenced by autonomic activity and peripheral metabolism, suggesting HR could be used as a proxy for feed efficiency. Objectives were to assess associations between overnight HR, lying patterns and RFI, and between acute stress HR and RFI. Heifer calves (n=107; 408+/-28 days of age, 341+/-42.2 kg) and yearling heifers (n=36; 604+/-92 days of age, 539+/-52.2 kg) were exposed to a performance test to determine productive performance. Overnight HR (electrode based) and lying patterns (accelerometer based) were monitored on a subgroup of heifer calves (n=40; 20 lowest RFI; 20 highest RFI). In the 10-min acute stress assessment, all heifers were individually exposed to the opening and closing of an umbrella and HR before (HRBEF), in response to (HRMAX), after (HRAFT) and change (HRCHG; HRAFT-HRBEF) as a result of exposure were determined. Using polynomial regression, rate of HR decrease pre-exposure (beta 1) and rates of HR increase (beta 2) and decrease (beta 3, beta 4) post-exposure were determined. Heifer calves in the overnight assessment were classified into equal RFI groups (low RFI; high RFI) and HR means were treated as repeated measures and compared using multiple regression. In the acute stress assessment, heifers were classified within cattle category into equal RFI groups (low RFI; high RFI) and means and polynomial regression parameters were compared using multiple regression. Low-RFI heifer calves had a lower overnight HR (69.2 v. 72.6 BPM), similar HR change from lying to standing intervals (8.9 v. 9.2 BPM) and similar time lying (61.1% v. 64.5%) compared with high-RFI heifer calves. Low-RFI heifer calves had a higher absolute HRMAX (162.9 v. 145.7 BPM) and beta 2 (-0.34 v. -0.20) than high-RFI heifer calves. Low-RFI yearling heifers had similar acute stress HR means and a lower beta 1 (0.003 v. 0.006) than high-RFI yearling heifers. Overnight HR and acute stress HR are potential indicators of RFI in heifer calves. However, acute stress HR results varied in yearling heifers, suggesting previous handling experience and/or age influence stress response. Pending further development (predictive ability, repeatability), the acute stress assessment could have potential for on-farm application as a feed efficiency proxy in young heifers with minimal handling experience. PMID- 27514831 TI - Genome-wide association study of copy number variation with lung function identifies a novel signal of association near BANP for forced vital capacity. AB - BACKGROUND: Genome-wide association studies of Single Nucleotide Polymorphisms (SNPs) have identified 55 SNPs associated with lung function. However, little is known about the effect of copy number variants (CNVs) on lung function, although CNVs represent a significant proportion of human genetic polymorphism. To assess the effect of CNVs on lung function quantitative traits, we measured copy number at 2788 previously characterised, common copy number variable regions in 6 independent cohorts (n = 24,237) using intensity data from SNP genotyping experiments. We developed a pipeline for genome-wide association analysis and meta-analysis of CNV genotypes measured across multiple studies using SNP genotype array intensity data from different platform technologies. We then undertook cohort-level genome-wide association studies of CNV with lung function in a subset of 4 cohorts (n < =12,403) with lung function measurements and meta analysed the results. Follow-up was undertaken for CNVs which were well tagged by SNPs, in up to 146,871 individuals. RESULTS: We generated robust copy number calls for 1962 out of 2788 (70 %) known CNV regions genome-wide, with 1103 measured with compatible class frequencies in at least 2 cohorts. We report a novel CNV association (discovery P = 0.0007) with Forced Vital Capacity (FVC) downstream of BANP on chromosome 16 that shows evidence of replication by a tag SNP in two independent studies (replication P = 0.004). In addition, we provide suggestive evidence (discovery P = 0.0002) for a role of complex copy number variation at a previously reported lung function locus, containing the rootletin gene CROCC, that is not tagged by SNPs. CONCLUSIONS: We demonstrate how common CNV regions can be reliably and consistently called across cohorts, using an existing calling algorithm and rigorous quality control steps, using SNP genotyping array intensity data. Although many common biallelic CNV regions were well-tagged by common SNPs, we also identified associations with untagged mulitallelic CNV regions thereby illustrating the potential of our approach to identify some of the missing heritability of complex traits. PMID- 27514833 TI - Subcompartmentalization by cross-membranes during early growth of Streptomyces hyphae. AB - Bacteria of the genus Streptomyces are a model system for bacterial multicellularity. Their mycelial life style involves the formation of long multinucleated hyphae during vegetative growth, with occasional cross-walls separating long compartments. Reproduction occurs by specialized aerial hyphae, which differentiate into chains of uninucleoid spores. While the tubulin-like FtsZ protein is required for the formation of all peptidoglycan-based septa in Streptomyces, canonical divisome-dependent cell division only occurs during sporulation. Here we report extensive subcompartmentalization in young vegetative hyphae of Streptomyces coelicolor, whereby 1 MUm compartments are formed by nucleic acid stain-impermeable barriers. These barriers possess the permeability properties of membranes and at least some of them are cross-membranes without detectable peptidoglycan. Z-ladders form during the early growth, but cross membrane formation does not depend on FtsZ. Thus, a new level of hyphal organization is presented involving unprecedented high-frequency compartmentalization, which changes the old dogma that Streptomyces vegetative hyphae have scarce compartmentalization. PMID- 27514834 TI - Presentation of Coping Strategies Associated with Physical and Mental Health During Health Check-ups. AB - We identified coping behaviors during regular health check-ups and examined whether they were related to physical and mental health. We assessed coping strategies with the Brief COPE scale in 201 people who underwent a regular health check-up in a clinic. We found several significant relationships between coping and physical/psychological conditions presented in health check-up: Humor and systolic blood pressure, Substance use and high-density lipoprotein cholesterol, Venting and low-density lipoprotein cholesterol, Self-blame and depression, and Behavioral disengagement and sleep disorder. By evaluating coping strategies and screening depression as part of a regular health check-up, General practitioner can provide psychological intervention such as cognitive behavioral therapy which may improve both mental and physical health of the people. PMID- 27514835 TI - Regulatory roles of interferon-inducible protein 204 on differentiation and vasculogenic activity of endothelial progenitor cells. AB - BACKGROUND: Endothelial progenitor cells (EPCs) have shown great potential in angiogenesis either by their differentiation into endothelial cells or by secretion of angiogenic factors. Interferon-inducible protein 204 (Ifi204) has been reported to participate in the regulation of cell growth and differentiation. However, its role in differentiation of EPCs remains unknown. We proposed that Ifi204 could modulate the differentiation and regenerative abilities of EPCs. METHODS: Ifi204-expressing lentivirus and Ifi204 siRNA were introduced into EPCs to overexpress and suppress the expression of Ifi204. Using fluorescence-activated cell sorting, immunocytochemistry, and quantitative PCR, endothelial markers including CD31, VE-cadherin, and vWF were detected in the modified EPCs. An in-vitro incorporation assay and a colony-forming assay were also performed. RESULTS: Evidence showed that Ifi204 inhibition decreased the endothelial differentiation and vasculogenic activities of EPCs in vitro. In mice with hindlimb ischemia, downregulation of Ifi204 in EPCs, which was tracked by our newly synthesized nanofluorogen, impaired neovascularization, with a corresponding reduction in hindlimb blood reperfusion by postoperative day 14. CONCLUSIONS: Ifi204 is required for EPC differentiation and neovascularization in vitro and in vivo. The regulatory roles of Ifi204 in EPC differentiation may benefit the clinical therapy of ischemic vascular diseases. PMID- 27514837 TI - Retrospective Analysis of Hanging Deaths in Ontario. AB - Hanging deaths from investigation standpoint are rarely problematic. Unusual circumstances can on occasion raise suspicion of foul play. Associated neck injuries are reported in the literature with variable frequency (from 0% to 76.8%). This study retrospectively analyzed 755 hanging deaths in Ontario (Canada) to evaluate the demographic features and circumstances of hanging fatalities, and the frequency of hanging-related neck injuries. A number of cases showed unusual/special circumstances (e.g., complex, double suicides, restraints). Among 632 cases with complete autopsies, hyoid and larynx fractures were present in 46 cases (7.3%) with the most common being isolated hyoid fractures. The incidence of cricoid fractures was 0.5% and cervical spine injuries, 1.1%. A higher incidence of neck injuries occurred among males, long drop hangings, and in cases with complete suspension. There was a tendency for the number of fractures to increase with increasing age and weight of the deceased. PMID- 27514836 TI - Home visiting and perinatal smoking: a mixed-methods exploration of cessation and harm reduction strategies. AB - BACKGROUND: Home visiting programs represent an important primary prevention strategy for adverse prenatal health behaviors; the various ways in which home visiting programs impact prenatal smoking cessation and reduction behaviors remain understudied. METHODS: Mixed methods approach using a retrospective cohort of propensity score matched home visiting clients and local-area comparison women with first births between 2008-2014 in a large Northeast state. Multivariable logistic and linear regression estimated third trimester prenatal tobacco smoking cessation and reduction. Additionally, qualitative interviews were conducted with 76 home visiting clients. RESULTS: A program effect was seen for smoking cessation such that clients who smoked less than ten cigarettes per day and those who smoked 20 or more cigarettes per day during the first trimester were more likely to achieve third trimester cessation than comparison women (p <0.01 and p = 0.01, respectively). Only for heavy smokers (20 or more cigarettes during the first trimester) was there a significant reduction in number of cigarettes smoked by the third trimester versus comparison women (p = 0.01). Clients expressed the difficulty of cessation, but addressed several harm-reduction strategies including reducing smoking in the house and wearing a smoking jacket. Clients also described smoking education that empowered them to ask others to not smoke or adopt other harm reducing behaviors when around their children. CONCLUSIONS: While a significant impact on smoking cessation was seen, this study finds a less clear impact on smoking reduction among women in home visiting programs. As home visiting programs continue to expand, it will be important to best identify effective ways to support tobacco-related harm reduction within vulnerable families. PMID- 27514838 TI - BRCA to the future: towards best testing practice in the era of personalised healthcare. PMID- 27514839 TI - New challenges for BRCA testing: a view from the diagnostic laboratory. AB - Increased demand for BRCA testing is placing pressures on diagnostic laboratories to raise their mutation screening capacity and handle the challenges associated with classifying BRCA sequence variants for clinical significance, for example interpretation of pathogenic mutations or variants of unknown significance, accurate determination of large genomic rearrangements and detection of somatic mutations in DNA extracted from formalin-fixed, paraffin-embedded tumour samples. Many diagnostic laboratories are adopting next-generation sequencing (NGS) technology to increase their screening capacity and reduce processing time and unit costs. However, migration to NGS introduces complexities arising from choice of components of the BRCA testing workflow, such as NGS platform, enrichment method and bioinformatics analysis process. An efficient, cost-effective accurate mutation detection strategy and a standardised, systematic approach to the reporting of BRCA test results is imperative for diagnostic laboratories. This review covers the challenges of BRCA testing from the perspective of a diagnostics laboratory. PMID- 27514840 TI - Finding all BRCA pathogenic mutation carriers: best practice models. AB - Identifying germline BRCA pathogenic mutations in patients with ovarian or breast cancer is a crucial component in the medical management of affected patients. Furthermore, the relatives of affected patients can be offered genetic testing. Relatives who test positive for a germline BRCA pathogenic mutation can take appropriate action to prevent cancer or have cancer diagnosed as early as possible for better treatment options. The recent discovery that BRCA pathogenic mutation status can inform treatment decisions in patients with ovarian cancer has led to an increased demand for BRCA testing, with testing taking place earlier in the patient care pathway. New approaches to genetic counselling may be required to meet this greater demand for BRCA testing. This review discusses the need for best practices for genetic counselling and BRCA testing; it examines the challenges facing current practice and looks at adapted models of genetic counselling. PMID- 27514841 TI - The biological effects and clinical implications of BRCA mutations: where do we go from here? AB - BRCA1 and BRCA2 are tumour-suppressor genes encoding proteins that are essential for the repair of DNA double-strand breaks by homologous recombination (HR). Cells that lack either BRCA1 or BRCA2 repair these lesions by alternative, more error-prone mechanisms. Individuals carrying germline pathogenic mutations in BRCA1 or BRCA2 are at highly elevated risk of developing breast and/or ovarian cancer. Genetic testing for germline pathogenic mutations in BRCA1 and BRCA2 has proved to be a valuable tool for determining eligibility for cancer screening and prevention programmes. In view of increasing evidence that the HR DNA repair pathway can also be disrupted by sequence variants in other genes, screening for other BRCA-like defects has potential implications for patient care. Additionally, there is a growing argument for directly testing tumours for pathogenic mutations in BRCA1, BRCA2 and other genes involved in HR-DNA repair as inactivation of these genes may be strictly somatic. Tumours in which HR-DNA repair is altered are most likely to respond to emerging targeted therapies, such as inhibitors of poly-ADP ribose polymerase. This review highlights the biological role of pathogenic BRCA mutations and other associated defects in DNA damage repair mechanisms in breast and ovarian cancer, with particular focus on implications for patient management strategies. PMID- 27514842 TI - A case of ovarian adenosquamous carcinoma arising from endometrioid adenocarcinoma: a case report and systematic review. AB - BACKGROUND: The aims of this report were to describe a case of ovarian adenosquamous carcinoma and to systematically review the pertinent literature. METHODS: We describe a case in which a 57-year-old woman had stage IC ovarian cancer histologically diagnosed as adenosquamous carcinoma. We also systematically reviewed the literature using the PubMed database. CASE PRESENTATION: Preoperative computed tomography and magnetic resonance imaging showed a tumor measuring 14 cm in diameter and containing solid areas. Tumor marker levels were as follows: CA125, 42.6 U/mL; CA 19-9, 134.1 U/mL; CEA, 0.9 ng/mL; and SCC, 1.6 ng/mL. The patient underwent multiple surgeries including total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, para-aortic lymph node biopsy, and total omentectomy. Based on the cytological features of the ascitic fluid, the tumor was diagnosed as a squamous cell carcinoma. Histological examination of an excised specimen showed the transition of an endometrioid adenocarcinoma to a squamous cell carcinoma. There was no evidence of any teratomas or endometriosis-related features. We considered the tumor to be an adenosquamous carcinoma, with the squamous cell carcinoma component arising from the endometrioid adenocarcinoma component. After surgery, the patient underwent 6 cycles of paclitaxel and carboplatin chemotherapy. There has been no recurrence to date, 66 months after the initial treatment. RESULTS: Histologically, the 8 adenosquamous carcinomas reported in the literature either arose from the mature cystic teratoma (4 cases) or endometriosis (3 cases) or were pure adenosquamous carcinomas (1 case). Our literature search uncovered no cases of ovarian adenosquamous carcinomas originating from endometrioid adenocarcinomas. CONCLUSIONS: This is the first reported case of an adenosquamous carcinoma arising from an endometrioid adenocarcinoma. Because such tumors are rare, their standard management is unclear. PMID- 27514844 TI - alpha-Diamine Nickel Catalysts with Nonplanar Chelate Rings for Ethylene Polymerization. AB - A series of novel alpha-diamine nickel complexes, (ArNH-C(Me)-(Me)C-NHAr)NiBr2 , 1: Ar=2,6-diisopropylphenyl, 2: Ar=2,6-dimethylphenyl, 3: Ar=phenyl), have been synthesized and characterized. X-ray crystallographic analysis showed that the coordination geometry of the alpha-diamine nickel complexes is markedly different from conventional alpha-diimine nickel complexes, and that the chelate ring (N-C C-N-Ni) of the alpha-diamine nickel complex is significantly distorted. The alpha diamine nickel catalysts also display different steric effects on ethylene polymerization in comparison to the alpha-diimine nickel catalyst. Increasing the steric hindrance of the alpha-diamine ligand by substitution of the o-methyl groups with o-isopropyl groups leads to decreased polymerization activity and molecular weight; however, catalyst thermal stability is significantly enhanced. Living polymerizations of ethylene can be successfully achieved using 1/Et2 AlCl at 35 degrees C or 2/Et2 AlCl at 0 degrees C. The bulky alpha-diamine nickel catalyst 1 with isopropyl substituents can additionally be used to control the branching topology of the obtained polyethylene at the same level of branching density by tuning the reaction temperature and ethylene pressure. PMID- 27514843 TI - Reduction of Streptococcus pneumoniae in upper respiratory tract cultures and a decreased incidence of related acute otitis media following introduction of childhood pneumococcal conjugate vaccines in a Swedish county. AB - BACKGROUND: The effect of pneumococcal conjugate vaccines (PCV) on invasive pneumococcal disease is frequently reported, but the impact on upper respiratory tract infections in a clinical setting is less documented. Our aim in this 5-year observational study was to investigate serotype changes in a large number of Streptococcus pneumoniae upper respiratory tract isolates following sequential introduction of PCV7 and pneumococcal Haemophilus influenza protein D conjugate vaccine (PHiD-CV10) in a Swedish county. METHODS: All bacterial isolates from the upper respiratory tract (nasopharynx, sinus or middle ear fluid) from patients with respiratory tract infections referred to a clinical microbiology laboratory prior to (2 years 2007-2008; n = 1566) and after introduction of PCV (3 years 2011-2013; n = 1707) were prospectively collected. Microbiological findings were compared between the two periods, and information from clinical referrals was recorded in order to explore changes in incidence of pneumococcal acute otitis media (AOM). RESULTS: Pneumococcal serotypes covered by PHiD-CV10 decreased from 45 to 12 % prior to and after immunization (p < 0.001), respectively. Despite non PHiD-CV10 serotypes increased from 49 to 80 %, a significant decline of 35 % in the absolute incidence of pneumocococal isolates (p < 0.001) was observed. Finally, the frequency of complicated AOM caused by S. pneumoniae decreased by 32 % (p < 0.001). CONCLUSIONS: After introduction of PCV in 2009, we have observed a significantly decreased number of pneumococcal isolates in the upper respiratory tract, a shift to non-PHiD-CV10 serotypes, and a reduction of complicated AOM. Our findings may have implications for future vaccine design. PMID- 27514845 TI - Value of adding GNAS testing to pancreatic cyst fluid KRAS and carcinoembryonic antigen analysis for the diagnosis of intraductal papillary mucinous neoplasms. AB - BACKGROUND AND AIM: Molecular analysis of pancreatic cyst fluid (PCF) has been proposed as a novel method for differentiating pancreatic cystic lesions (PCL). The present study aimed to investigate the value of GNAS testing when added to KRAS and carcinoembryonic antigen (CEA) testing of PCF for the diagnosis of intraductal papillary mucinous neoplasms (IPMN). METHODS: Prospectively collected endoscopic ultrasonography fine-needle aspiration (EUS-FNA) data were analyzed retrospectively for GNAS and KRAS mutations and CEA results. IPMN were histologically confirmed or supported by imaging and EUS-FNA findings (KRAS, CEA, cytology). Performance characteristics of GNAS added to KRAS and CEA for the diagnosis of IPMN were calculated. RESULTS: The study population consisted of 197 patients with cyst fluid test results. Cysts were histologically classified in 33 patients and by clinical criteria in 164 patients. The IPMN group included 108 patients and the non-IPMN group included 89 patients. GNAS was positive in 51 patients (47.2%) with IPMN. Forty-two of these patients (82.3%) also had a KRAS mutation. Adding GNAS to KRAS increased the diagnostic accuracy from 76.6% to 79.1% (P > 0.05). Adding GNAS to CEA increased the diagnostic accuracy from 66.4% to 80.7 % (P < 0.05), but did not achieve a diagnostic superiority to KRAS testing alone (80.7% vs 76.6%, P > 0.05). The diagnostic accuracy of the triple combination was significantly better than all single tests (P < 0.05). CONCLUSION: GNAS mutation is a highly specific test for IPMN. When GNAS testing is added to CEA and KRAS, a significantly greater overall accuracy (86.2%) is achieved. PMID- 27514846 TI - Functional and Clinical Significance of the Integrin Alpha Chain CD49d Expression in Chronic Lymphocytic Leukemia. AB - Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of neoplastic cells with the morphological appearance of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. CD49d, the alpha chain of the alpha4beta1 integrin heterodimer, is one of the main interactors between CLL cells and accessory cells in the microenvironmental sites and one of the main predictors of overall survival. In particular, CD49d is known to play a pivotal role in mediating both cell-cell and cell-matrix interactions in CLL-involved tissues eventually delivering prosurvival signals and protecting CLL cells from drug induced damages. Treatment strategies targeting the alpha4beta1 integrin could represent an interesting option in CLL. In this context, the recombinant anti CD49d antibody natalizumab demonstrated the potential to overcome stromal cell induced resistance of B cell lymphoma cells against cytotoxic drugs and rituximab in vitro. Moreover, a specific interest for the CD49d molecule raises from the clinical activity of the recently proposed inhibitors of kinases downstream the BCR that has been recently related with the inside-out activation of the alpha4beta1 integrin. In the review, we addressed in detail the role of CD49d in CLL cells, including clinical impact, relationship with specific cytogenetic features, and CD49d-dependent interactions in lymph node and bone marrow microenvironment responsible for growth- and survival- supporting signals, eventually influencing CLL prognosis and therapeutic options. PMID- 27514847 TI - Fast and improved separation of major coumarins in Ammi visnaga (L.) Lam. by supercritical fluid chromatography. AB - The first supercritical fluid chromatography method for the determination of five major coumarins (dihydrosamidin, visnadin, samidin, khellin, and visnagin) in Ammi visnaga fruits is described. Their baseline separation was possible in less than 5 min by using a UPC2 HSS C18 SB column with 1.8 MUm particle size and a mobile phase comprising CO2 , methanol, acetonitrile, and diethylamine. The type of stationary phase used was of particular relevance because, except for the selected one, the others did not resolve the two structural isomers dihydrosamidin and visnadin. Method validation confirmed that the procedure is linear (R2 >= 0.9996) in a concentration range from 6 to 480 MUg/mL, it is accurate (recovery rates: 97.2-103.6%) and precise (intraday deviation <= 6.6%, intraday deviation <= 1.7%); injecting 1 MUL of standard solution, the determined limit of detection was below 1.9 MUg/mL for all compounds. The analysis of different A. visnaga samples revealed their similar compositions, and khellin (0.75-1.01%) and visnagin (0.18-0.46%) were the dominant coumarins. Visnadin and dihydrosamidin, the individual quantification of which is described for the first time, were present at concentrations below 0.14%. PMID- 27514848 TI - Age-associated and tissue-specific expression of osteopontin in male Hu sheep reproductive tract. AB - Osteopontin (OPN) is indispensable in mammalian reproduction, but the role of OPN in male reproductive tract and fertility remains unclear. The objective of this study is to elucidate the function of OPN by unveiling the localization and expression of OPN in the reproductive tract (testis, epididymis, and ductus deferens) of male Hu sheep in different ages (10-days, 4-months, and 8-months). To accomplish this, the localization, mRNA and protein expression patterns of OPN in all samples were investigated. Immune staining showed that OPN was present in the testicular interstitium of prepubertal Hu sheep testis (10-days and 4-months group), while it was immunostained in acrosomes of spermatids nearby adluminal compartment of seminiferous tubules in sexual maturity Hu sheep testis (8-months group). The localization of OPN in epididymis gradually changed from the loose connective tissue to the apical region of principal cells (pseudostratified columnar epithelium) with growing (10-days to 8-months). In addition, increase trend was observed in the mRNA expression levels of OPN with growing in the same reproductive tissues (P<0.05). Furthermore, two different OPN isoforms of 30kDa and 34kDa were detected in the reproductive tract of male Hu sheep by western blot. Immunofluorescence detection showed that OPN was localized in the cauda epididymal spermatozoa. These results suggested that the expression of OPN might be closely related to spermatogenesis and spermatozoa function in Hu sheep. This will be helpful for us to understand how OPN regulate the high reproductive capacity in Hu sheep. PMID- 27514849 TI - Construction and characterization of osteogenic and vascular endothelial cell sheets from rat adipose-derived mesenchymal stem cells. AB - In this study, adipose-derived mesenchymal stem cells (ADSCs) were isolated from adipose tissues of rats. Flow cytometry identification showed that ADSCs of passage 3 highly expressed CD29 and CD44, but hardly expressed CD31 and CD45. Adipogenic, osteogenic, and chondrogenic differentiation were confirmed by the results of oil red O staining, alkaline phosphatase (ALP), and alcian blue staining, respectively. ADSCs at a density of 1*10(6)/cm(2) were cultured in the osteogenic medium and the osteogenic cell sheets could be obtained after 14 d. The cell sheets were positive with von kossa staining. The transmission electron microscopy (TEM) result showed that needle-like calcium salt crystals were deposited on the ECM. These results suggested that the osteogenic cell sheets may have potential osteogenesis ability. ADSCs at a density of 1*10(6)/cm(2) were cultured in the endothelial cell growth medium-2 and the endothelial cell sheets can be formed after 16 d of culture. The TEM image confirmed that the Weibel Palade corpuscle was seen in the cells. The expression of CD31 was positive, suggesting that the endothelial cell sheets may have a strong ability to form blood vessels. In this study, two types of cell sheets with the potential abilities of osteogenesis and blood vessels formation were obtained by induced culture of ADSCs in vitro, which lays a foundation to build vascularized tissue engineered bone for the therapy of bone defects. PMID- 27514850 TI - Engineering cell fate: Spotlight on cell-activation and signaling-directed lineage conversion. AB - Direct reprogramming of specialized cells into other cell types has revolutionized the fields of stem cell, differentiation, and regenerative medicine. Direct reprogramming technology can convert various differentiated cell types to other fates by the forced expression of lineage-specific transcription factors. In addition to this approach, transdifferentiation can be induced in somatic cells by a method named cell-activation and signaling-directed (CASD) lineage conversion, which uses pluripotency reprogramming factors in combination with specific differentiation signals. This approach is capable of generating tissue-specific progenitors in addition to functional mature cells through a challenging transitory (pluripotent or non-pluripotent) state. Interestingly, the CASD lineage conversion has been accomplished by using small molecules and growth factors in a chemical-only paradigm. This approach will have a substantial positive impact on the field and bring reprogramming technology into the translational pipeline. From the regenerative medicine perspective, in future, new therapies might be designed based on the patient's own cells that are directly reprogrammed into the desired cell types in vitro and in situ. This review provides an overview of direct reprogramming to different lineages and describes what is known about the cell-activation and signaling-directed transdifferentiation. PMID- 27514851 TI - A systematic review of randomised control trials of sexual health interventions delivered by mobile technologies. AB - BACKGROUND: Sexually transmitted infections (STIs) pose a serious public health problem globally. The rapid spread of mobile technology creates an opportunity to use innovative methods to reduce the burden of STIs. This systematic review identified recent randomised controlled trials that employed mobile technology to improve sexual health outcomes. METHODS: The following databases were searched for randomised controlled trials of mobile technology based sexual health interventions with any outcome measures and all patient populations: MEDLINE, EMBASE, PsycINFO, Global Health, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register, NHS Health Technology Assessment Database, and Web of Science (science and social science citation index) (Jan 1999-July 2014). Interventions designed to increase adherence to HIV medication were not included. Two authors independently extracted data on the following elements: interventions, allocation concealment, allocation sequence, blinding, completeness of follow-up, and measures of effect. Trials were assessed for methodological quality using the Cochrane risk of bias tool. We calculated effect estimates using intention to treat analysis. RESULTS: A total of ten randomised trials were identified with nine separate study groups. No trials had a low risk of bias. The trials targeted: 1) promotion of uptake of sexual health services, 2) reduction of risky sexual behaviours and 3) reduction of recall bias in reporting sexual activity. Interventions employed up to five behaviour change techniques. Meta-analysis was not possible due to heterogeneity in trial assessment and reporting. Two trials reported statistically significant improvements in the uptake of sexual health services using SMS reminders compared to controls. One trial increased knowledge. One trial reported promising results in increasing condom use but no trial reported statistically significant increases in condom use. Finally, one trial showed that collection of sexual health information using mobile technology was acceptable. CONCLUSIONS: The findings suggest interventions delivered by SMS interventions can increase uptake of sexual health services and STI testing. High quality trials of interventions using standardised objective measures and employing a wider range of behavioural change techniques are needed to assess if interventions delivered by mobile phone can alter safer sex behaviours carried out between couples and reduce STIs. PMID- 27514853 TI - Contribution of Aspartic Proteases in Candida Virulence. Protease Inhibitors against Candida Infections. AB - Candida species are the major opportunistic human pathogens accounting for 70-90% of all invasive fungal infections. Candida spp, especially C. albicans, are able to produce and secrete hydrolytic enzymes, particularly aspartic proteases (Saps). These enzymes production is an evolutionary adaptation of pathogens to utilize nutrients and survive in host. Sap1-10 are believed to contribute to the adhesion and invasion of host tissues through the degradation of cell surface structures. Aspartic proteases control several steps in innate immune evasion and they degrade proteins related to immunological defense (antibodies, complement and cytokines), allowing the fungus to escape from the first line of host defense. The existing ways to identify potential drug targets rely on specific subset like virulence genes, transcriptional and stress response factors. Candida virulence factors like Sap isoenzymes can be pivotal targets for drug development. The identification of mechanism of a non-canonical inflammasome exerted by Saps could open novel therapeutic strategies to dampen hyperinflammatory response in candidiasis. PMID- 27514852 TI - The catalytic subunit of magnesium-protoporphyrin IX monomethyl ester cyclase forms a chloroplast complex to regulate chlorophyll biosynthesis in rice. AB - KEY MESSAGE: YGL8 has the dual functions in Chl biosynthesis: one as a catalytic subunit of MgPME cyclase, the other as a core component of FLU-YGL8-LCAA-POR complex in Chl biosynthesis. Magnesium-protoporphyrin IX monomethyl ester (MgPME) cyclase is an essential enzyme involved in chlorophyll (Chl) biosynthesis. However, its roles in regulating Chl biosynthesis are not fully explored. In this study, we isolated a rice mutant yellow-green leaf 8 (ygl8) that exhibited chlorosis phenotype with abnormal chloroplast development in young leaves. As the development of leaves, the chlorotic plants turned green accompanied by restorations in Chl content and chloroplast ultrastructure. Map-based cloning revealed that the ygl8 gene encodes a catalytic subunit of MgPME cyclase. The ygl8 mutation caused a conserved amino acid substitution (Asn182Ser), which was related to the alterations of Chl precursor content. YGL8 was constitutively expressed in various tissues, with more abundance in young leaves and panicles. Furthermore, we showed that expression levels of some nuclear genes associated with Chl biosynthesis were affected in both the ygl8 mutant and YGL8 RNA interference lines. By transient expression in rice protoplasts, we found that N terminal 40 amino acid residues were enough to localize the YGL8 protein to chloroplast. In vivo experiments demonstrated a physical interaction between YGL8 and a rice chloroplast protein, low chlorophyll accumulation A (OsLCAA). Moreover, bimolecular fluorescence complementation assays revealed that YGL8 also interacted with the other two rice chloroplast proteins, viz. fluorescent (OsFLU1) and NADPH:protochlorophyllide oxidoreductase (OsPORB). These results provide new insights into the roles of YGL8, not only as a subunit with catalytic activity, but as a core component of FLU-YGL8-LCAA-POR complex required for Chl biosynthesis. PMID- 27514854 TI - General Aspects of Two-Component Regulatory Circuits in Bacteria: Domains, Signals and Roles. AB - All living organisms are subject to changing environments, which must be sensed in order to respond swiftly and efficiently. Two-component systems (TCS) are signal transduction regulatory circuits based typically on a membrane bound sensor kinase and a cytoplasmic response regulator, that is activated through a histidine to aspartate phosphorelay reactions. Activated response regulator acts usually as a transcription factor. The best known examples were identified in bacteria, but they are also found in fungi, algae and plants. Thus far, they are not found in mammals. Regulatory circuits coupled to two-component systems exhibit a myriad of responses to environmental stimuli such as: redox potential, pH, specific metabolites, pressure, light and more recently to specific antimicrobial peptides that activate a sensor kinase responsible for expressing virulence factors through the active response regulator. In this review we explore general aspects on two-component systems that ultimately can play a role on virulence regulation, also the intriguing domain properties of the sensor kinases that can be a potential target for antimicrobial compounds. Only a handful of sensor kinases are extensively characterized, the vast majority belong to what we call 'the dark matter of bacterial signal transduction' since no known signal, structure and biochemical properties are available. Regulatory circuits from vertebrate pathogenic organisms can explain virulence in terms of either response to environmental factors or specific niche occupancy. Hopefully, knowledge on these signal transduction systems can lead to identify novel molecules that target two-component systems, since the increase of drug resistant microorganisms is worrisome. PMID- 27514856 TI - Ecosystem fluxes of hydrogen in a mid-latitude forest driven by soil microorganisms and plants. AB - Molecular hydrogen (H2 ) is an atmospheric trace gas with a large microbe mediated soil sink, yet cycling of this compound throughout ecosystems is poorly understood. Measurements of the sources and sinks of H2 in various ecosystems are sparse, resulting in large uncertainties in the global H2 budget. Constraining the H2 cycle is critical to understanding its role in atmospheric chemistry and climate. We measured H2 fluxes at high frequency in a temperate mixed deciduous forest for 15 months using a tower-based flux-gradient approach to determine both the soil-atmosphere and the net ecosystem flux of H2 . We found that Harvard Forest is a net H2 sink (-1.4 +/- 1.1 kg H2 ha-1 ) with soils as the dominant H2 sink (-2.0 +/- 1.0 kg H2 ha-1 ) and aboveground canopy emissions as the dominant H2 source (+0.6 +/- 0.8 kg H2 ha-1 ). Aboveground emissions of H2 were an unexpected and substantial component of the ecosystem H2 flux, reducing net ecosystem uptake by 30% of that calculated from soil uptake alone. Soil uptake was highly seasonal (July maximum, February minimum), positively correlated with soil temperature and negatively correlated with environmental variables relevant to diffusion into soils (i.e., soil moisture, snow depth, snow density). Soil microbial H2 uptake was correlated with rhizosphere respiration rates (r = 0.8, P < 0.001), and H2 metabolism yielded up to 2% of the energy gleaned by microbes from carbon substrate respiration. Here, we elucidate key processes controlling the biosphere-atmosphere exchange of H2 and raise new questions regarding the role of aboveground biomass as a source of atmospheric H2 and mechanisms linking soil H2 and carbon cycling. Results from this study should be incorporated into modeling efforts to predict the response of the H2 soil sink to changes in anthropogenic H2 emissions and shifting soil conditions with climate and land-use change. PMID- 27514855 TI - Effectiveness of rotavirus vaccines against rotavirus infection and hospitalization in Latin America: systematic review and meta-analysis. AB - BACKGROUND: Rotavirus was the leading cause of childhood diarrhoea-related hospitalisations and death before the introduction of rotavirus vaccines. METHODS: We describe the effectiveness of rotavirus vaccines to prevent rotavirus infections and hospitalizations and the main rotavirus strains circulating before and after vaccine introduction through a systematic review and meta-analysis of studies published between 1990 and 2014. 203 studies were included to estimate the proportion of infections due to rotavirus and 10 to assess the impact of the vaccines. 41 of 46 studies in the post-vaccination period were used for meta analysis of genotypes, 20 to calculate VE against infection, eight for VE against hospitalisation and seven for VE against severe rotavirus-diarrhoea. RESULTS: 24.3 % (95 % CI 22.1-26.5) and 16.1 % (95 % CI 13.2-19.3) of cases of diarrhoea were due to rotavirus before and after vaccine introduction, respectively. The most prevalent G types after vaccine introduction were G2 (51.6 %, 95 % CI 38 65), G9 (14.5 %, 95 % CI 7-23) and G1 (14.2 %, 95 % CI 7-23); while the most prevalent P types were P[4] (54.1 %, 95 % CI 41-67) and P[8] (33 %, 95 % CI 22 46). G2P[4] was the most frequent genotype combination after vaccine introduction. Effectiveness was 53 % (95 % CI 46-60) against infection, 73 % (95 % CI, 66-78) against hospitalisation and 74 % (95 % CI, 68.0-78.0) against severe diarrhoea. Reductions in hospitalisations and mortality due to diarrhoea were observed in countries that adopted universal rotavirus vaccination. CONCLUSIONS: Rotavirus vaccines are effective in preventing rotavirus-diarrhoea in children in Latin America. The vaccines were associated with changes in genotype distribution. PMID- 27514857 TI - Danshensu Promotes Cholesterol Efflux in RAW264.7 Macrophages. AB - Contemporary research suggests that macrophage foam cell and cholesterol efflux defect play pivotal role in atherogenesis. We reported on the heretofore unknown therapeutic effect of Danshensu (DSS) in reducing intracellular cholesterol level and unraveled the mechanism of DSS promotes cholesterol efflux. Oxidized low density lipoprotein stimulation of Raw264.7 cells into foam cells, which were treated with DSS and co-treated with Simvastatin and Rosiglitazone. PPARgamma, ABCA1, ABCG1, SR-BI, CD36, and LXR-alpha mRNA were quantified by Real-Time PCR. Western blotting was used to determine protein expression of PPARgamma, ABCA1 and CD36. Cellular cholesterol handling was studied by measurement of intracellular lipid droplets concentration and cholesterol efflux. DSS significantly reduced scavenger receptor CD36 and its orthologue SR-BI. In addition, DSS stimulated the upregulation of cellular cholesterol exporters ABCA1 and ABCG1 to reduce intracellular lipid accumulation. DSS can reduce lipid deposition in Raw264.7 foam cells by balancing CD36 and ABCA1 protein expression. PMID- 27514858 TI - Genomic Analysis of Genes Involved in the Biosynthesis of Very Long Chain Polyunsaturated Fatty Acids in Thraustochytrium sp. 26185. AB - Thraustochytrium sp. 26185 is a marine protist that can produce a large amount of docosahexaenoic acid (DHA, 22:6n-3), an omega3 very long chain polyunsaturated fatty acid (VLCPUFA) of nutritional importance. However, the mechanism of how this fatty acid is synthesized and assembled into the storage lipid triacylglycerol is unclear. Here we report sequencing of the whole genome and genomic analysis of genes involved in the biosynthesis and assembly of the fatty acids in this species. Genome sequencing produced a total of 2,418,734,139 bp clean sequences with about 62 fold genome coverage. Annotation of the genome sequences revealed 10,797 coding genes. Among them, 10,216 genes could be assigned into 25 KOG classes where 451 genes were specifically assigned to the group of lipid transport and metabolism. Detailed analysis of these genes revealed co-existence of both aerobic pathway and anaerobic pathways for the biosynthesis of DHA in this species. However, in the aerobic pathway, a key gene encoding stearate Delta9 desaturase introducing the first double bond to long chain saturated fatty acid 18:0 was missing from the genome. Genomic survey of genes involved in the acyl trafficking among glycerolipids showed that, unlike plants, this protist did not possess phosphatidylcholine:diacylglycerol cholinephosphotransferase, an important enzyme in bridging two types of glycerolipids, diacylglycerols (DAG) and phosphatidylcholines (PtdCho). These results shed new insight on the biosynthesis and assembly of VLCPUFA in the Thraustochytrium. PMID- 27514859 TI - The Effect of Tailored Web-Based Feedback and Optional Telephone Coaching on Health Improvements: A Randomized Intervention Among Employees in the Transport Service Industry. AB - BACKGROUND: Lifestyle-related health problems are an important health concern in the transport service industry. Web- and telephone-based interventions could be suitable for this target group requiring tailored approaches. OBJECTIVE: To evaluate the effect of tailored Web-based health feedback and optional telephone coaching to improve lifestyle factors (body mass index-BMI, dietary intake, physical activity, stress, sleep, tobacco and alcohol consumption, disease history, self-perceived health, and motivation to change health habits), in comparison to no health feedback or telephone coaching. METHODS: Overall, 3,876 employees in the Swedish transport services were emailed a Web-based questionnaire. They were randomized into: control group (group A, 498 of 1238 answered, 40.23%), or intervention Web (group B, 482 of 1305 answered, 36.93%), or intervention Web + telephone (group C, 493 of 1333 answered, 36.98%). All groups received an identical questionnaire, only the interventions differed. Group B received tailored Web-based health feedback, and group C received tailored Web-based health feedback + optional telephone coaching if the participants' reported health habits did not meet the national guidelines, or if they expressed motivation to change health habits. The Web-based feedback was fully automated. Telephone coaching was performed by trained health counselors. Nine months later, all participants received a follow-up questionnaire and intervention Web + telephone. Descriptive statistics, the chi-square test, analysis of variance, and generalized estimating equation (GEE) models were used. RESULTS: Overall, 981 of 1473 (66.60%) employees participated at baseline (men: 66.7%, mean age: 44 years, mean BMI: 26.4 kg/m(2)) and follow-up. No significant differences were found in reported health habits between the 3 groups over time. However, significant changes were found in motivation to change. The intervention groups reported higher motivation to improve dietary habits (144 of 301 participants, 47.8%, and 165 of 324 participants, 50.9%, for groups B and C, respectively) and physical activity habits (181 of 301 participants, 60.1%, and 207 of 324 participants, 63.9%, for B and C, respectively) compared with the control group A (122 of 356 participants, 34.3%, for diet and 177 of 356 participants, 49.7%, for physical activity). At follow-up, the intervention groups had significantly decreased motivation (group B: P<.001 for change in diet; P<.001 for change in physical activity; group C: P=.007 for change in diet; P<.001 for change in physical activity), whereas the control group reported significantly increased motivation to change diet and physical activity (P<.001 for change in diet; P<.001 for change in physical activity). CONCLUSION: Tailored Web-based health feedback and the offering of optional telephone coaching did not have a positive health effect on employees in the transport services. However, our findings suggest an increased short-term motivation to change health behaviors related to diet and physical activity among those receiving tailored Web-based health feedback. PMID- 27514860 TI - shRNA mediated knockdown of Nav1.7 in rat dorsal root ganglion attenuates pain following burn injury. AB - BACKGROUND: Abnormal acute pain after burn injury still torments patients severely. In this study, we investigated that one voltage gated sodium channel Nav1.7 plays a vital role in lowering heat pain threshold after burn injury, and the hypothesis that knockdown of Nav1.7 attenuates pain following burn injury. METHODS: Sixty eight adult male Sprague-Dawley rats were divided into 4 treatment groups: (1) sham, which hind paw was put on the room temperature metal plate for 15 s (2) burn model, which hind paw was put on the 85 degrees C metal plate for 15 s. (3) Burn injury + lentiviral vector -SCN9AsiRNA-GFP (LV- SCN9AsiRNA-GFP group, n = 18), which receive the DRG microinjection of LV- SCN9AsiRNA-GFP on the zero day. (4) Burn injury + lentiviral vector negative control (LV-NC-GFP group, n = 18), which receive the DRG microinjection of empty lentiviral vector on the zero day. RESULTS: Both mechanical and heat threshold were measured from day 1 to 21. Meanwhile, expression of sodium channels Nav1.7 in injured dorsal root ganglia were measured on post-operative days 7(POD 7). Rats exhibited decreased thresholds on both mechanical allodynia and thermal withdrawl latency, accompanied by increased Nav1.7 and c-fos expression in dorsal root ganglion (DRG). And knockdown of Nav1.7 in L5DRG led to the attenuation of burn injury induced mechanical allodynia and thermal hyperalgesia in the rats. CONCLUSION: We provide evidence that shRNA mediated knockdown of Nav1.7 attenuates burn induced pain in rats as well as decreased the activiation of c-fos protein. PMID- 27514861 TI - Preoperative simulation regarding the appropriate port location for laparoscopic hepaticojejunostomy: a randomized study using a disease-specific training simulator. AB - PURPOSE: We verified the appropriate port location for laparoscopic hepaticojejunostomy using a comprehensive laparoscopic training simulator. METHODS: We developed a hepaticojejunostomy model, consist of common hepatic duct and intestine and participants required to place two sutures precisely using two different port locations (A: standard port location, B: modified port location). The order of tasks was randomly determined using the permuted block method (Group I: Task A -> Task B, Group II: Task B -> Task A). The time for task completion and total number of errors were recorded. In addition, we evaluated the spatial paths and velocity of both forceps. Statistical analyses were performed using a statistical software program. RESULTS: The time for the task, the total error score, and the spatial paths and velocity of both forceps were not significantly different between groups I and II. Furthermore, the port location and order of tasks (group I or group II) did not significantly affect the results. In contrast, there were significant differences in the performance between experts and novices, who were classified as such based on the total number of experienced endoscopic surgeries. CONCLUSION: Preoperative port simulation in advanced surgery using our artificial simulator is feasible and may facilitate minimally invasive surgery for children. PMID- 27514862 TI - Workshop Report: Crystal City VI-Bioanalytical Method Validation for Biomarkers. AB - With the growing focus on translational research and the use of biomarkers to drive drug development and approvals, biomarkers have become a significant area of research within the pharmaceutical industry. However, until the US Food and Drug Administration's (FDA) 2013 draft guidance on bioanalytical method validation included consideration of biomarker assays using LC-MS and LBA, those assays were created, validated, and used without standards of performance. This lack of expectations resulted in the FDA receiving data from assays of varying quality in support of efficacy and safety claims. The AAPS Crystal City VI (CC VI) Workshop in 2015 was held as the first forum for industry-FDA discussion around the general issues of biomarker measurements (e.g., endogenous levels) and specific technology strengths and weaknesses. The 2-day workshop served to develop a common understanding among the industrial scientific community of the issues around biomarkers, informed the FDA of the current state of the science, and will serve as a basis for further dialogue as experience with biomarkers expands with both groups. PMID- 27514863 TI - Assessment of fetal optic chiasm: an echoanatomic and reproducibility study. AB - OBJECTIVES: Our aims were: (1) to perform an echoanatomic correlation study, in order to confirm that the structure identified as the optic chiasm (OC) on ultrasound (US) is indeed this anatomical structure; (2) to assess and compare the reproducibility of two- (2D) and three-(3D) dimensional US in measurement of the OC in normal fetuses; and (3) to assess whether the spatial orientation of the OC changes with increasing gestational age. METHODS: For the echoanatomic study, the OC was studied in a neonatal specimen, deceased at 29 + 4 weeks, by passing a suture around the OC and visualizing the supposed OC structure on US while pulling gently on the suture. The reproducibility study included 39 women with normal pregnancy at 20-33 weeks undergoing routine obstetric US examination. After the routine exam, the OC was visualized on 2D-US, and a 2D image and 3D volume dataset were stored for offline measurement. On the 2D images, the diameters of the OC decussation and the optic tract proximal to the transducer were measured. For the 3D volume dataset, multiplanar image correlation with volume contrast imaging (VCI) was used to measure both these diameters and the chiasmocallosal angle (CCA). Two operators each took two sets of measurements of the diameters on 2D- and 3D-US, and intra- and interoperator variability were analyzed using Cronbach's alpha intraclass correlation coefficient (ICC), while a single operator took two sets of CCA measurements for assessment of intraoperator variability. Differences in CCA with increasing gestational age were also analyzed by regression, and CCA measurements were divided into three groups according to gestational age and their means compared by one-way ANOVA. RESULTS: During the echoanatomic experiment, when the sling suture was pulled, the hyperechoic X-shaped structure just below the circle of Willis identified on 2D US as the OC was displaced slightly and was eventually cut by the sling, confirming its identity as the OC. Intraoperator variability was low and almost identical for the two operators and the two imaging modalities for measurement of the decussation (ICC for 2D-US: 0.96 vs 0.95; 3D-US: 0.95 vs 0.96), but less so for the optic tract (ICC for 2D-US: 0.95 vs 0.91; 3D-US: 0.94 vs 0.83). Interoperator variability was low for the decussation (2D-US: 0.92; 3D-US: 0.92), but higher for the optic tracts (ICC for 2D-US: 0.80; 3D-US: 0.78). The difference between the mean measurement of the two operators was not statistically significantly different for the decussation, but it was for the optic tracts (P = 0.04). The CCA increased steadily between 20 and 30 gestational weeks and plateaued thereafter, at least until 33 weeks. CONCLUSIONS: The hyperechoic structure evident on 2D- and 3D-US, just below the circle of Willis, is indeed the OC. 2D-US is apparently as good as 3D-US for visualization of the OC. However, only measurement of the decussation showed low intra- and interoperator variability, whereas measurement of the optic tract is of questionable variability. As gestation advances between 20 and 30 weeks, the OC becomes more oblique in orientation. Copyright (c) 2016 ISUOG. Published by John Wiley & Sons Ltd. PMID- 27514864 TI - High-intensity drinking by underage young adults in the United States. AB - AIMS: To estimate (1) the prevalence of underage binge drinking, high-intensity drinking and intoxication among young adults aged 19/20 years; (2) change in these behaviors across the transition out of high school and across historical time; and (3) associations between these behaviors and key covariates, including college status. DESIGN, SETTING, PARTICIPANTS: Longitudinal data from the US nationally representative Monitoring the Future study included 1657 respondents first surveyed as 12th graders (modal age 18 years) in 2005-13 and again at modal age 19/20 years in 2006-14. MEASUREMENTS: Self-reported measures of alcohol use, demographics, college attendance and living situation. FINDINGS: Binge drinking (5+ drinks on one occasion) was reported by 24.2% [95% confidence interval (CI) = 22.0, 26.5] of young adults aged 19/20; 10.3% (CI = 8.7, 11.9) reported high intensity drinking of 10+ drinks; 4.2% (CI = 3.1, 5.2) reported 15+ drinks. Usual moderate/high intoxication when drinking was reported by 33.1% (CI = 30.6, 35.6); 29.6% (CI = 27.2, 32.0) reported usual sustained intoxication of 3+ hours. Significant variability (P < 0.001) in these behaviors from ages 18 to 19/20 was observed. Significant decreases (P < 0.05) across historical time in 5+ and 10+ drinking were found. Four-year college students not residing with parents had significantly higher odds of moderate/high intoxication, binge drinking and high intensity drinking compared with other groups (P < 0.001). CONCLUSIONS: Young adult underage binge drinking (5+ drinks on one occasion), high-intensity drinking (10+ and 15+ drinks) and intoxication are relatively common in the United States, and show meaningful variability across the transition out of high school. Four-year college students and those who do not live with their parents are more likely to engage in high-intensity drinking than their peers. PMID- 27514865 TI - Electrical Impedance Tomography in A Patient with Non-Specific Interstitial Pneumonia. PMID- 27514866 TI - Adult-born dentate granule cells show a critical period of dendritic reorganization and are distinct from developmentally born cells. AB - Adult-born dentate granule cells (abGCs) exhibit a critical developmental phase during function integration. The time window of this phase is debated and whether abGCs become indistinguishable from developmentally born mature granule cells (mGCs) is uncertain. We analyzed complete dendritic reconstructions from abGCs and mGCs using viral labeling. AbGCs from 21-77 days post intrahippocampal injection (dpi) exhibited comparable dendritic arbors, suggesting that structural maturation precedes functional integration. In contrast, significant structural differences were found compared to mGCs: AbGCs had more curved dendrites, more short terminal segments, a different branching pattern, and more proximal terminal branches. Morphological modeling attributed these differences to developmental dendritic pruning and postnatal growth of the dentate gyrus. We further correlated GC morphologies with the responsiveness to unilateral medial perforant path stimulation using the immediate-early gene Arc as a marker of synaptic activation. Only abGCs at 28 and 35 dpi but neither old abGCs nor mGCs responded to stimulation with a remodeling of their dendritic arbor. Summarized, abGCs stay distinct from mGCs and their dendritic arbor can be shaped by afferent activity during a narrow critical time window. PMID- 27514867 TI - Suspected sepsis: summary of NICE guidance. PMID- 27514868 TI - Intraprofessional collaboration and learning between specialists and general practitioners during postgraduate training: a qualitative study. AB - BACKGROUND: During postgraduate training, general practitioners and other specialists must learn how to deliver shared care to patients; however, the development of formal intraprofessional education is often hampered by curricular constraints. Delivering shared care in everyday work provides trainees with opportunities for informal learning from, about and with one another. METHODS: Twelve semi-structured interviews were undertaken with trainee general practitioners and specialists (internal medicine or surgery). A thematic analysis of the input was undertaken and a qualitative description developed. RESULTS: Trainees from different disciplines frequently interact, often by telephone, but generally they learn in a reactive manner. All trainees are highly motivated by the desire to provide good patient care. Specialist trainees learn about the importance of understanding the background of the patient from GPs, while GP trainees gain medical knowledge from the interaction. Trainees from different disciplines are not very motivated to build relationships with each other and have fewer opportunities to do so. Supervisors can play an important role in providing intraprofessional learning opportunities for trainees. CONCLUSIONS: During postgraduate training, opportunities for intraprofessional learning occur, but there is much room for improvement. For example, supervisors could increase the involvement of trainees in collaborative tasks and create more awareness of informal learning opportunities. This could assist trainees to learn collaborative skills that will enhance patient care. PMID- 27514869 TI - Idiopathic thrombotic thrombocytopenic purpura: strongest risk factor for relapse from remission is having had a relapse. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare, episodic clinical syndrome involving the production of thrombi in the microvasculature accompanied by thrombocytopenia and symptoms of organ ischemia. Idiopathic TTP develops when a patient produces antibodies that react with the protease ADAMTS13. The course after an episode is unpredictable; patients may relapse frequently or never. There is no laboratory value that can reliably predict potential relapse. STUDY DESIGN AND METHODS: To assess diagnostic and predictive values for risk of relapse, plasma samples from 27 patients with idiopathic TTP in remission were analyzed for anti-ADAMTS13 immunoglobulin (Ig)G, ADAMTS13 activity, and ADAMTS13 inhibitor titer. Patients were recruited at the Department of Hematology at the University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany. RESULTS: Anti-ADAMTS13 IgG was detected in 12 patients (44%); their median level of ADAMTS13 activity was nondetectable. Patients with anti-ADAMTS13 IgG had a median number of three previous relapses, whereas the 15 patients without presence of IgG (56%) had a median number of one previous relapse (p < 0.001; Mann-Whitney U test). The concentration of free anti-ADAMTS13 IgG and the levels measuring inhibitory activity (Bethesda unit) were positively correlated. CONCLUSION: A subgroup of TTP patients in remission with anti ADAMTS13 IgG and nondetectable ADAMTS13 activity showed an increased risk for relapsing disease as demonstrated by their number of past relapses. The positive correlation we observed between anti-ADAMTS13 IgG and inhibitor levels supports the theory of ADAMTS13 inhibition as the crucial mechanism causing severe deficiency in ADAMTS13 activity in TTP. PMID- 27514870 TI - Renal transplant among type 1 and type 2 diabetes patients in Spain: A population based study from 2002 to 2013. AB - BACKGROUND: To describe trends in the rates and short-term outcomes of renal transplants (RTx) among patients with or without diabetes in Spain (2002-2013). METHODS: We used national hospital discharge data to select all hospital admissions for RTx. We divided the study period into four three-year periods. Rates were calculated stratified by diabetes status: type 1 diabetes (T1DM), type 2 diabetes (T2DM) and no-diabetes. We analyzed Charlson comorbidity index (CCI), post-transplant infections, in-hospital complications of RTx, rejection, in hospital mortality and length of hospital stay. FINDINGS: We identified 25,542 RTx. Rates of RTx increased significantly in T2DM patients over time (from 9.3 cases/100,000 in 2002/2004 to 13.3 cases/100,000 in 2011/2013), with higher rates among people with T2DM for all time periods. T2DM patients were older and had higher CCI values than T1DM and non-diabetic patients (CCI>=1, 31.4%, 20.4% and 21.5%, respectively; P<0.05). Time trend analyses showed significant increases in infections, RTx-associated complications and rejection for all groups (all P values<0.05). Infection rates were greater in people with T2DM (20.8%) and T1DM (23.5%) than in non-diabetic people (18.7%; P<0.05). Time trend analyses (2002 2013) showed significant decreases in mortality during admission for RTx (OR 0.75, 95% CI 0.68-0.83). Diabetes was not associated with a higher in-hospital mortality (OR: 1.20, 95% CI 0.92-1.55). INTERPRETATION: RTx rates were higher and increased over time at a higher rate among T2DM patients. Mortality decreased over time in all groups. Diabetes does not predict mortality during admission for RTx. FUNDING: Instituto Salud Carlos III and URJC-Banco Santander. PMID- 27514871 TI - Dehydration of lactic acid to acrylic acid over lanthanum phosphate catalysts: the role of Lewis acid sites. AB - Lanthanum phosphate (LaP) nano-rods were synthesized using n-butylamine as a shape-directing agent (SDA). The resulting catalysts were applied in the dehydration of lactic acid to acrylic acid. Aiming to understand the nature of the active sites, the chemical and physical properties of LaP materials were studied using a variety of characterization techniques. This study showed that the SDA not only affected the porosity of the LaP materials but also modified the acid-base properties. Clearly, the modification of the acid-base properties played a more critical role in determining the catalytic performance than porosity. An optimized catalytic performance was obtained on the LaP catalyst with a higher concentration of Lewis acid sites. Basic sites showed negative effects on the stability of the catalysts. Good stability was achieved when the catalyst was prepared using the appropriate SDA/La ratio. PMID- 27514872 TI - Communication channels to promote evidence-based practice: a survey of primary care clinicians to determine perceived effects. AB - BACKGROUND: Research suggests that the channels through which evidence-based practices are communicated to healthcare professionals can shape the ways they engage with, and use, this information. For instance, there is evidence to suggest that information should be communicated via sources that are deemed to be credible, like government departments, professional bodies and peers. This article examines the contention that information should be communicated via credible sources. More specifically, the article examines the different communication channels through which primary care clinicians learnt of resources on evidence-based sexual healthcare - namely, clinical aides and online training programs. Furthermore, the article determines whether these communication channels influenced the perceived impact of the resources. METHODS: Primary care clinicians in Australia (n = 413), notably General Practitioners (n = 214) and Practice Nurses (n = 217), were surveyed on the GP Project - a suite of resources to promote evidence-based sexual healthcare within primary care. Survey items pertained to the source of information about the resources (or communication channel), perceived usefulness of the resources, frequency of use, subsequent contact with the Sexual Health Infoline and a sexual health clinic, as well as the perceived impact of the resources. To determine the relationships between the different communication channels and the perceived impact of the resources, a one way ANOVA using Tukey's post-hoc test, an independent sample t-test, a chi(2) test, and a Kruskal-Wallis H test were performed where appropriate. RESULTS: Of the respondents who were aware of the clinical aides (49.9%), the largest proportion became aware of these through an educational event or a colleague. Of those who were aware of the online training programs (36.9%), the largest proportion became aware of these through a professional body or government organisation, either directly or via their website. Although both resource types were reported to improve clinical practice, the reported use and the perceived impact of the resources were not influenced by the way the clinicians learnt of the resources. CONCLUSIONS: These findings cast doubt on the suggestion that the channels through which evidence-based practices are communicated to healthcare professionals shape the ways they engage with, and use, this information, as well as the perceived impact of this information. Given the importance of evidence based practices, these curious findings suggest that the source of this information might be of little consequence. PMID- 27514873 TI - Ivermectin exhibits potent anti-mitotic activity. AB - Ivermectin (IVM) is a pharmaceutical used as an anti-parasitic drug in livestock, companion animals and humans. The primary site of action of IVM is believed to be glutamate-gated chloride channels (GluCls). However we have recently reported a direct interaction between IVM and nematode tubulin with micromolar affinity. Here we report that IVM also interacts with mammalian tubulin. To test this possibility, we used the tubulin polymerization assay and found that IVM increased the degree of polymerization of mammalian tubulin. Furthermore when HeLa cells were exposed to IVM it stabilized the mammalian tubulin against the depolymerizing effects of cold temperatures, and prevented the replication of the HeLa cells in vitro. However, the IVM-induced inhibition of HeLa cell division was reversible. The data suggests that mammalian microtubules bound IVM and were stabilized by IVM at micromolar concentrations. IVM may thus affect the dynamics of tubulin polymerization and depolymerization, which in turn can result in cell death. Given that IVM is already approved for use in humans, its development as an anti-mitotic is a potentially appealing option. PMID- 27514874 TI - Variations in seroprevalences of canine leishmaniasis: Could it be a consequence of the population structure? AB - Canine leishmaniasis is a parasitic disease caused by Leishmania infantum and is transmitted by Phlebotominae vectors. Despite numerous publications on the subject, some essential aspects of the epidemiology are not yet sufficiently clear. We proposed a stochastic model with the aim of identifying some important gaps in the current knowledge of leishmaniasis, such as the frequency of vector infection or a dog's life expectancy depending on their purpose and their health status. We only found that the purpose was a significant factor. Furthermore, we detected relationships among age, gender and habitat with the dogs' purposes that can affect the calculation of the overall seroprevalence of the analysed sample. The development of this model will allow us to discard potential confounding factors as gender, age, purpose or habitat. PMID- 27514875 TI - In vitro anthelmintic activity of the Zizyphus joazeiro bark against gastrointestinal nematodes of goats and its cytotoxicity on Vero cells. AB - This study examined the in vitro effect of the Zizyphus joazeiro bark against gastrointestinal nematodes of goats and its cytotoxicity on Vero cells. The ovicidal activity of the crude hydroethanolic extract (CE), its partitioned hexane (HE) and aqueous extract (AE) and saponins fraction (SF), including betulinic acid (BA), a biogenetic compound from this plant found in HE, were investigated using the inhibition of egg hatch assay (EHA). Thereafter, the extracts and the SF were evaluated through the larval motility assay (LMA) and larval migration inhibition assay (LMIA). The AE and SF promoted a complete inhibition of the egg hatch, and the effective concentration to inhibit 50% (EC50) values was 1.9 and 1.3mg/mL, respectively. The highest percentages of inhibition in EHA observed after treatments with CE, HE and BA corresponded to 79, 48 and 17%, respectively. The extracts and SF did not show larvicidal activity in LMA and LMIA. The AE and SF demonstrated cytotoxic effects in 3-4,5 dimethylthiazol-2-yl, 2,5diphenyltetrazolium bromide (MTT) and trypan blue tests; however, SF was more toxic (50% inhibitory concentration, IC50=0.20mg/mL). The chemical characterization of the SF was made through Proton Nuclear Magnetic Resonance ((1)H NMR) and Electrospray Ionization Mass Spectrometry (ESI-MS) analyses, which led to the identification of two saponins known as Joazeiroside B and Lotoside A. The results obtained from the research of this saponin content provide important information about the biological activity, especially the anthelmintic effect present in the plant investigated. That also suggests the types of bioactive compounds that may be responsible for this antiparasitic activity exhibited by the plant extracts. PMID- 27514876 TI - Chilling requirements for hatching of a New Zealand isolate of Nematodirus filicollis. AB - The eggs of some species of the parasitic nematode Nematodirus require a period of chilling before they can hatch; N. filicollis is one such species. This study investigated this requirement for chilling in a New Zealand strain of this species. Eggs of N. filicollis were extracted from lamb's faeces and incubated at 20 degrees C to allow development to the third stage larvae within the egg. These eggs were then placed into tissue culture plates and incubated at: 2.7 degrees C (+/-0.99), 3.6 degrees C (+/-0.90), 4.7 degrees C (+/-0.35), 6.4 degrees C (+/ 0.37), 8.0 degrees C (+/-1.54) or 9.9 degrees C (+/-0.14) for up to 224 days. At 14day intervals until day 84, then every 28 days, one plate was removed from each temperature and placed at 13.1 degrees C (+/-0.44) for 14 days. Eggs were then assessed for hatching. From this data, chill units were calculated by subtracting the culture temperature from a constant threshold of 11 degrees C and multiplying by the number of days for which the sample was cultured; then the Gompertz model fitted. Even though hatching overall was low, a greater proportion of eggs hatched with chill accumulation. Maximum hatching of eggs required 800-1000 chill units. Consequently in the field, more than one season of chilling would be required before hatching. As such a generation time could take more than one year to complete. This is different to the hatching dynamics of N. spathiger, the other main species found in New Zealand sheep, which does not display this requirement for chilling and hatches immediately once the third stage larvae are developed. PMID- 27514877 TI - Chemical composition and in vitro activity of Calotropis procera (Ait.) latex on Haemonchus contortus. AB - Calotropis procera is among the species of medicinal plants that have traditionally been used for the treatment of parasites in small ruminants, stimulating the scientific validation of anthelmintic effects. This study aimed to investigate the chemical composition of ethyl acetate extract of Calotropis procera latex (EAECPL), assess the in vitro effect against Haemonchus contortus and the structural changes caused in the adult worm. The latex was collected, lyophilized and subjected to washing with the ethyl acetate solvent to obtain EAECPL. The constituents of the extract were isolated by column chromatography and identified by (13)C and (1)H nuclear magnetic resonance spectroscopy. The egg hatching test (EHT), larval development test (LDT) and adult worms motility test (WMT) were conducted to evaluate the effectiveness of EAECPL on eggs, larvae and adult of H. contortus, respectively. The worms obtained from the WMT, after 24h exposure to EAECPL or controls were observed on a scanning electron microscope (SEM). The results were analysed by variance analysis and compared with Tukey's test (P<0.05). Three compounds were isolated from EAECPL and identified as urs 19(29)-en-3-yl acetate, (3beta)-Urs-19(29)-en-3-ol, and 1-(2',5'-dimethoxyphenyl) glycerol. In the EHT, EAECPL inhibited larval hatching by 91.8% at dose of 4mg/ml. In the LDT 1mg/ml inhibited 99.8% larval development. In the WMT, EAECPL in the concentration of 100MUg/ml inhibited 100% motility of worms, 12h post exposition. In the SEM, obvious differences were not detected between the negative control worms and the worms treated with EAECPL. In this study, EAECPL showed an effect on inhibition egg hatching, larval development and motility of the adult worms of H. contortus. This should be related both to the identified compounds, as well as the other compounds present in the EAECPL, acting alone or synergistically. PMID- 27514878 TI - Filarioids infecting dogs in northeastern Brazil. AB - Species of filarial nematodes belonging to the genera Dirofilaria and Acanthocheilonema are recognised as common parasites of dogs throughout the world. Recently, other filarioids featured by the presence of dermal microfilariae (e.g., Onchocerca lupi and Cercopithifilaria spp.) have been recognised in Europe. In Brazil, reports of filarioids in dogs are limited to Dirofilaria immitis, Acanthocheilonema reconditum and Cercopithifilaria bainae. To investigate the distribution of filarial infections in dogs living in an endemic region from northeastern Brazil, blood and skin samples (n=104) were microscopically (modified Knott's test and skin snip sediment examination) and molecularly evaluated. Twenty-two dogs (21.15%) were positive at microscopic and/or molecular examination for at least one filarioid species, with 21 (20.19%) animals positive for blood microfilariae at molecular and/or at microscopic examination. Microfilariae of D. immitis were detected in 12 (11.54%) animals, with co-infection of D. immitis and A. reconditum observed in four (3.85%) individuals. One animal was positive for C. bainae at both microscopic and molecular examination. Analysis of sequence obtained in the present study showed significant alignment identity with that of C. bainae from Europe. Considering that in the area of study arthropod vectors (mosquitoes, fleas and ticks) are prevalent throughout the year, preventive measures should be disposed in order to avoid the animal infestation and pathogen infection. PMID- 27514879 TI - Microfilaricidal efficacy of a single administration of Advocate((r)) (Bayer Animal Health) in dogs naturally infected with Dirofilaria immitis or Dirofilaria repens. AB - The present study evaluated the microfilaricidal efficacy of a single application of the spot-on containing imidacloprid 10%/moxidectin 2.5% (Advocate((r)), Bayer Animal Health) in dogs naturally infected either by Dirofilaria immitis or Dirofilaria repens. Dogs living in north-eastern and central-southern Italy, endemic for D. immitis and D. repens respectively, were randomly screened. Sixteen animals, eight infected with D. immitis and eight with D. repens, and fulfilling inclusion criteria were enrolled. Dogs infected with D. immitis received an adulticide treatment prior to the study and Advocate((r)) 3 weeks after. The animals were divided in blocks of two (1:1, T1:T2) animals each, where Day 0 (D0) had an interval of 15days to compare T2 vs. T1 dogs during the first fortnight of examination (i.e. T2 dogs acted as control animals at each examination). At baseline (Days -15 and 0 for T2 and T1 dogs, respectively) the animals had a range of microfilaraemia of 180-99.700mff/ml (D. immitis) and 60 750 mff/ml (D. repens). All animals received a topical administration of Advocate((r)) at D0 and were examined for microfilariae with microscopic and molecular tests at D15, D30, D60 and D90. All animals scored negative for mff at the first control post-treatment and throughout the study, with the exception of two D. immitis- infected animals that had a 2 mff/ml count at D15, and then become negative from Day 30 onwards. No adverse events were observed. The present study demonstrates the safety and the high microfilaricidal efficacy (99.97% and 100% for D. immitis and D. repens, respectively) of a single dose of moxidectin contained in Advocate((r)) in naturally infected dogs. PMID- 27514880 TI - Seroprevalence of Neospora caninum in feral swine (Sus scrofa) in the United States. AB - The protozoon Neospora caninum is a major cause of abortion in cattle worldwide. Canids (Canis familiaris, Canis latrans, Canis lupus) are definitive hosts whereas many other animal species, including pigs, are intermediate hosts for the parasite. Between 2012 and 2014, serum samples from 1059 feral swine (Sus scrofa) from 29 states of the USA were tested for N. caninum antibodies, using the N. caninum agglutination test (NAT). Of these, 159 (15.0%) feral pigs from 21 states tested positive, with a range of titers of 1:25 (cut-off) (n=153), 1:200 (1), 1:400 (1), 1:800 (3) and 1:3200 (1). Results indicate widespread exposure of feral swine to N. caninum infection across the USA. PMID- 27514881 TI - Efficacy of osthole for Echinococcus granulosus in vitro and Echinococcus multilocularis in vivo. AB - Echinococcosis is a zoonotic infection caused by cestode species of the genus Echinococcus; in addition, this zoonosis has long been neglected as a parasitic disease and has limited treatment options. Clinical drugs such as benzimidazole derivatives have limited treatment efficacy. The current study evaluated a novel drug, osthole, with low toxicity and high activity against Echinococcus in vitro and in vivo. The results in vitro indicated that the viability of Echinococcus granulosus protoscoleces in the group treated with osthole (120MUM) decreased by 100% within 3days. In vivo experiments were conducted using parasite-infected mice. For this purpose, three groups of infected mice were treated daily for 6 weeks with albendazole (ABZ, 100mg/kg, positive control group), osthole (100mg/kg, experimental group), or honey/PBS (100mg/kg, negative control group), respectively. The osthole- and ABZ-treated groups presented a significant reduction in wet weight of metacestodes, increase in the level of interleukin (IL)-4 and the percentage of eosinophils compared with the control group. Osthole exhibited a high activity against echinococcosis in vivo. In addition, the toxicity of osthole was evaluated via an in vitro 3-(4,5)-dimethylthiahiazo(-z y1)-3,5-di-phenytetrazoliumromide (MTT) assay, as well as via morphological observation and calculation of liver and kidney function indexes in vivo. No obvious toxic effects of osthole were observed in our study. Therefore, this novel drug may be a promising alternative to benzimidazole in anti-echinococcosis chemotherapy. PMID- 27514882 TI - Comparison of different light sources for trapping Culicoides biting midges, mosquitoes and other dipterans. AB - The response of Culicoides biting midges, mosquitoes and other dipterans to different wavelengths was evaluated in a farm meadow in northern Spain. A total of 9449 specimens of 23 species of Culicoides, 5495 other ceratopogonids (non biting midges), 602 culicids and 12428 other mixed dipterans were captured. Centers for Disease Control and Prevention (CDC) suction light traps fitted with five light emitting diodes (LEDs) (white, green, red, blue, ultraviolet) were run for 15 consecutive nights. Significantly more Culicoides were collected in those traps fitted with green, blue or ultraviolet (UV) lights than in red and white baited LED traps for the most abundant species captured: C. punctatus (37.5%), C. cataneii (26.5%) and C. obsoletus/C. scoticus (20.4%). Similar results were obtained for non-Culicoides ceratopogonids, mosquitoes and other mixed dipterans. Wavelengths in green (570nm) resulted effective for targeting some Culicoides species, culicids and other midges. In a second trial, the effectiveness of 4-W white and UV tubes was compared to traps fitted with UV LED and a standard incandescent light bulb. More specimens of all taxa were collected with fluorescent black light (UV) traps than with the other light sources, except culicids, which were recovered in high numbers from fluorescent white light traps. PMID- 27514883 TI - Seroprevalence of Toxoplasma gondii in seabirds from Abrolhos Archipelago, Brazil. AB - Toxoplasma gondii is a coccidian parasite that infects almost all warm-blooded animals, including birds. Abrolhos is an archipelago of five islands, located in the Atlantic Ocean, 56 nautical kilometers from the south coast of the state of Bahia, northeastern Brazil. Part of this archipelago is a National Marine Park, which is a conservation area protected by the Brazilian government. The objective of this study was to determine the occurrence of T. gondii antibodies in sera of seabird's species Sula spp. and Phaeton spp. from breeding colonies located in the Islands of Santa Barbara and Redonda, Abrolhos's archipelago. Sera were tested by modified agglutination test, first screened at 1:5 dilution (cut-off point) and the positive samples were titrated at a two-fold serial dilution. Serum samples were obtained from 69 birds of four species: Sula dactylatra (23 birds), Sula leucogaster (19 birds), Phaeton aethereus (25 birds) and Phaeton lepturus (2 birds). Antibodies to T. gondii were found in 24 (34.8%) of 69 seabirds with titers that ranged from 5 to 640. Occurrence value in S. dactylatra was 34.8% (8/23), in S. leucogaster was 47.4% (9/19), in P. aethereus was 28% (7/25) and the 2 P. lepturus were negative. This is the first description of T. gondii antibodies in free ranging seabirds of the orders Suliformes and Phaethontiformes. PMID- 27514884 TI - Molecular characterisation of a disseminated Cryptosporidium infection in a Koi carp (Cyprinus carpio). AB - Cryptosporidium is a protozoan parasite that infects a wide range of hosts, yet relatively little is known about the epidemiology of cryptosporidiosis in fish. Here we report a disseminated Cryptosporidium infection in a male Koi carp (Cyprinus carpio), with parasite stages identified deep within the epithelium of the intestine, kidneys, spleen, liver and gills causing severe granulomatous inflammatory lesions. Molecular characterization at two loci; 18S ribosomal RNA (rRNA) and actin, revealed this to be a novel Cryptosporidium genotype, most closely related to Cryptosporidium molnari. PMID- 27514885 TI - Detection and quantification of Leishmania infantum in naturally and experimentally infected animal samples. AB - Leishmania infantum is one of the causative agents of visceral leishmaniasis (VL). VL is the most severe form of leishmaniasis and can be fatal if it is not properly treated. Although several PCR works are intended to detect L. infantum, in silico analysis of available primers and/or primer-probes reveals potential cross species amplification. Here, a TaqMan-based quantitative real time PCR (qPCR) assay was developed for specific detection and quantitation of L. infantum in tissue samples from experimentally or naturally infected animals, mice or dogs, respectively. For this assay, primers and probes were designed for the kinetoplast minicircle DNA of L. infantum. The qPCR assay achieved a detection limit of 0.01pg of parasite DNA, and allowed specific amplification of L. infantum in both asymptomatic and symptomatic naturally infected dogs with inter assay variation coefficients between 0.05-0.11. There was no cross amplification with dog DNA or with L. braziliensis, L. donovani, L. major, L. tropica or Trypanosoma cruzi. In addition, our assay detected a significantly higher parasite load in symptomatic than in the asymptomatic animals (p<0.0001). We believe this approach will be a valuable tool for the specific detection of L. infantum in regions of sympatric transmission of VL-causing parasites. PMID- 27514886 TI - Ovicidal and larvicidal activity of extracts of Opuntia ficus-indica against gastrointestinal nematodes of naturally infected sheep. AB - This study describes the in vitro anthelmintic activity of extracts from Opuntia ficus indica against gastrointestinal nematodes of sheep. The anthelmintic activity was evaluated by inhibition of egg hatching, larval development and larval migration assays. The residual aqueous fractions from cladodes and fruits showed higher ovicidal activity with EC50 values of 7.2mg/mL and 1.5mg/mL, respectively. The aqueous, hexane, and ethyl acetate fractions from fruits and the aqueous fraction from cladodes inhibited 100% of larval development at the lowest concentration tested (1.56mg/mL). The crude cladode and fruit ethanolic extracts inhibited larval migration and showed EC50 values of 0.74mg/mL and 0.27mg/mL, respectively. Phytochemical screening detected high concentrations of alkaloids, tannins, flavonoids, and saponins in the fruits and cladodes. The results demonstrated that O. ficus exhibits anthelmintic activity in vitro, suggesting that, beyond its nutritional potential, this plant can also be an ally for parasite control in sheep. PMID- 27514887 TI - Polarized M2 macrophages in dogs with visceral leishmaniasis. AB - The objective of the present study was to analyze the skin (nasal surface and ear regions), lymph nodes (popliteal and pre-scapular), spleen and liver of dogs with visceral leishmaniasis (VL), in order to investigate the relationship between the parasite load measured as DNA copy number of Alpha gene of DNA polymerase of Leishmania infantum by quantitative PCR and the number of M2 macrophages by immunohistochemistry. A set of 29 naturally infected dogs from an endemic area for VL were sampled and another set of six dogs negative for VL and from a non endemic area were analyzed as the control group (C). The spleen presented the highest number of Leishmania DNA copies, with significant differences between the groups G1 and G2 (with and without skin lesions, respectively). The M2 phenotype immunostaining predominated among the macrophages in granulomas and inflammatory infiltrates of samples from the skin, lymph nodes and spleens examined. The presence of M2 macrophages in dogs from infected group differed significantly from the control group, in all organs analyzed, excepted liver. The highest proportion of M2 macrophages coincided with the highest parasitism loads found in more susceptible organs of VL dogs, even in the skin, considered a more resistant organ, while the liver showed low parasitism load and low immunostaining for M2 macrophages with no significant differences between infected and negative groups. It was concluded that the predominance of M2 phenotype in VL dogs favored the multiplication of Leishmania infantum in organs of dogs that are more susceptible to Leishmania infection, as skin, lymph nodes and spleen. PMID- 27514888 TI - Ascarid infestation in captive Siberian tigers in China. AB - The Siberian tiger is endangered and is listed by the International Union for the Conservation of Nature; the captive environment is utilized to maintain Siberian tiger numbers. Little information regarding the prevalence of parasites in Siberian tigers is available. A total of 277 fecal samples of Siberian tigers were analyzed in this study. The microscopic analysis indicated the presence of ascarid eggs of Toxascaris leonina and Toxocara cati. The ascarid infection rate was 67.5% in Siberian tigers. The internal transcribed spacer-1 (ITS-1) phylogenetic analysis indicated that T. leonina belonged to Toxascaris and that Toxo. cati belonged to Toxocara. The infestation rate and intensity of T. leonina were higher than those of Toxo. cati. One-way analysis of variance showed that the presence of T. leonina was significantly associated with age (P<0.05). Temperature changes also influenced T. leonina and Toxo. cati infestation, and a rise in temperature caused an increase in the number of T. leonina and Toxo. cati eggs. This study provides a better understanding of ascarid infestation among the captive Siberian tigers and is helpful for the prevention of the spread of infectious parasitic diseases among other tigers in the zoo. PMID- 27514889 TI - Dominant fitness costs of resistance to fipronil in Musca domestica Linnaeus (Diptera: Muscidae). AB - House fly, Musca domestica L., (Diptera: Muscidae) a common pest of poultry, has developed resistance to the commonly used insecticide fipronil. The life history traits were examined in the fipronil-selected (Fipro-SEL), susceptible counterpart (UNSEL), and their hybrid progeny strains in order to design an effective resistant management strategy. Compared to the UNSEL strain, the Fipro SEL was 181.94-fold resistant to fipronil. This resistance was unstable after five generations without selection. The Fipro-SEL had a significantly longer larval duration, lower pupal weight, lower fecundity, lower hatchability, lower number of next generation larvae, lower intrinsic rate of population increase and lower biotic potential than the UNSEL strain. Most fitness parameters of the hybrid progeny were similar and significantly lower than that in the UNSEL strain, suggesting autosomal and dominant fitness costs. Compared to the UNSEL strain, relative the fitness of the Fipro-SEL, Hybrid1 and Hybrid2 was 0.13, 0.33 and 0.30, respectively. Fipronil resistance resulted in high fitness costs and these fitness costs were dominant and autosomal in the Fipro-SEL strain of M. domestica. Rotation of fipronil with other insecticides having no cross resistance should be useful for delaying the development of resistance in M. domestica. PMID- 27514890 TI - Equine antibody response to larval Parascaris equorum excretory-secretory products. AB - Parascaris equorum is an intestinal nematode of foals and young horses that can produce mild to severe pathology. Current diagnosis is limited to detection of patent infections, when parasite eggs are identified during fecal examinations. This study examined the use of larval P. equorum excretory-secretory (ES) products in a western blot test for diagnosis of prepatent equine P. equorum infection. Sera from adult mares negative for patent P. equorum infections, foals prior to consuming colostrum, and P. equorum infected foals were used as controls in this study. Study samples included sera from 18 broodmares prior to parturition and sera from their foals throughout the process of natural infection. Sera from study horses were examined for IgG(T) antibody recognition of ES products. Foals naturally infected with P. equorum possessed IgG(T) antibodies against 19kDa, 22kDa, 26kDa, and 34kDa ES products. However, passive transfer of colostral antibodies from mares was shown to preclude the use of the crude larval ES product-based western blot test for diagnosis of prepatent P. equorum infections in foals. PMID- 27514891 TI - Cross-resistance to moxidectin and ivermectin on a meat sheep farm in France. AB - Resistance to ivermectin and moxidectin was explored by a faecal egg count reduction test in two sheep flocks with suspected anthelmintic resistance. The FECRT confirmed one suspicion, with a mean percentage of reduction in egg excretion within the treated groups of 0% for ivermectin (CI 95%: -228 to 58) and 13% for moxidectin (CI 95%: -152 to 70). This was further explored by a controlled efficacy test. An experimental infection of 18 naive lambs was set up using infective larvae isolated from this flock (5000 L3/lamb). Compared to the control group, abomasal worm burdens (Teladorsagia circumcincta) were reduced by 90% [CI 95%: 81.5-94.8] and 85% [CI 95%: 72.4-92.2] after ivermectin (p<0.05) and moxidectin (p<0.05) treatment respectively. Again, compared to the control group, there was a reduction for intestinal strongyles (Trichostrongylus colubriformis) of 100% and 99% [CI 95%: 97.5-99.7] for ivermectin and moxidectin respectively. No difference was found between the efficacy of moxidectin and ivermectin. Pharmacokinetic values indicated that the strongyles were submitted to anthelmintic concentrations usually lethal to them. This trial demonstrated the first multiple resistance of ovine strongyles in France. PMID- 27514892 TI - Acaricidal activity of oregano oil and its major component, carvacrol, thymol and p-cymene against Psoroptes cuniculi in vitro and in vivo. AB - Oregano oil possesses marked antioxidant and antimicrobial activity and is widely applied in animal husbandry. In the present study, we aimed to investigate the acaricidal activities of oregano oil and its major component, carvacrol, thymol and p-cymene against Psoroptes cuniculi in vitro and in vivo. The results revealed that oregano oil exhibited significant acaricidal effects against P. cuniculi that were dose- and time-dependent response. In in vitro test, concentrations of 0.05% and 0.02% (v/v) killed all of the mites within 1h and 6h, respectively. Moreover, 0.1mg/ml (w/v) carvacrol, 0.2mg/ml (w/v) thymol and 1% p cymene (v/v) also possessed marked acaricidal activities, and compared with the control group, elicited mean mortalities of 84.00%, 96.00% and 66% at 24h, respectively. The median lethal times (LT50) against P. cuniculi of the concentrations of 0.02%, 0.01% and 0.005% (v/v) of oregano oil, thymol, carvacrol and p-cymene were 2.171h, 11.396h, 26.102h, and 4.424h, 8.957h and 15.201h, respectively. Meanwhile, twenty naturaly infested rabbits were used to four homogeneity groups: negative control (without treatment), positive control (treated with ivermectin), group treated with 1% of oregano oil and other group with 5% of oregano oil. All the treatments were topically. After the treatment of 1% and 5% oregano oil, the P. cuniculi were completely eliminated in the rabbits, and at the end of the test (day 20), the rabbits of all treatment groups exhibited favorable mental and physical statuses. These results indicated that oregano oil could be widely applied as a potential acaricidal agent in the treatment of animal acariasis in the future. PMID- 27514893 TI - A systematic review on the global occurrence of Taenia hydatigena in pigs and cattle. AB - Taenia hydatigena, a non-zoonotic tapeworm species shares the same intermediate hosts with other Taenia zoonotic species, such as Taenia solium in pigs and Taenia saginata in cattle. The occurrence of T. hydatigena in pigs and cattle may cause cross-reactions in immunodiagnostic tests and therefore, complicate the diagnosis of the zoonotic species. This study was conducted to systematically review the data on the prevalence of T. hydatigena in pigs and cattle, with the aim to assess the potential interference in serological diagnosis of zoonotic Taenia spp. due to T. hydatigena infection. We searched PubMed, Web of Science, Africa Journal Online, website http://www.google.com and article reference lists in English, French and Vietnamese with no restriction on research time and publication status. Eligible studies included observational studies that showed the occurrence of T. hydatigena. Twenty-six studies, divided into two animal groups, i.e. pigs and cattle, met the eligibility criteria for qualitative synthesis and 17 studies were included for the meta-analysis in three continents. T. hydatigena was found by necropsy in all included studies, which mostly were abattoir surveys. Overall, results showed the worldwide occurrence of T. hydatigena cysticercosis in pigs and cattle. In pigs, there was a marked higher prevalence in Asia and South America that was 17.2% (95% CI: 10.6-26.8%) and 27.5% (CI: 20.8-35.3%), respectively, compared to a low prevalence of 3.9% (95% CI: 1.9-7.9%) in Africa. Overall, the prevalence of T. hydatigena in cattle was low with a mean of 1.1% (95% CI: 0.2-5.2%). These results show that interpretation of results of sero-diagnostic tests for zoonotic Taenia species in pigs and cattle has to take into account the prevalence of T. hydatigena infections in different settings. PMID- 27514894 TI - F200Y polymorphism of the beta-tubulin isotype 1 gene in Haemonchus contortus and sheep flock management practices related to anthelmintic resistance in eastern Amazon. AB - The objective of the present study was to determine the frequency of the F200Y polymorphism in the beta-tubulin isotype 1 gene of Haemonchus contortus from various sheep flocks in eastern Amazon, and to identify management practices that may favor the emergence of resistance to anthelmintic drugs in the same area. In total, 305 specimens of H. contortus were collected from sheep at 12 farms located in the state of Para. An allele-specific PCR was performed to detect the F200Y polymorphism, and questionnaires were used to obtain information about the farms and flocks. All genotypes were detected as follows: 31% of the parasites were RR, 37% of the parasites were SR, and 32% were SS. The completed questionnaires revealed that all farms employed semi-intensive farming systems, performed suppressive anthelmintic treatment, and based their choice of drug on cost and availability rather than on any knowledge regarding drugs that remained effective on their property. It can thus be concluded that the SNP in codon 200 of the beta-tubulin isotype 1 gene is present in the H. contortus populations from eastern Amazon, and that a series of management practices that favor the emergence of anthelmintic resistance are employed on these farms. PMID- 27514895 TI - Comparison between anthelmintic treatment strategies against Ascaridia galli in commercial laying hens. AB - The efficacy of a sustainable deworming strategy based on targeted treatments (TT) against Ascaridia galli was investigated for the first time in laying hen flocks on a Swedish commercial farm. Three experimental protocols with different levels of treatment, e.g. targeted treatment (TT), conventional treatment (CT) and untreated (UT), were tested in randomly allocated flocks of two different bird hybrids. Every second week faecal egg counts (FECs) were determined from pooled faecal materials collected on trays (20*27cm) placed for a maximum of 12h on the litter belts. In the TT, anthelmintic administration (fenbendazole, 1mg/kg body weight for 5days) started at 22 weeks post placement (wpp) and was repeated twice when the pooled FECs surpassed the assigned threshold of 200 egg per gram faeces (EPG). The CT flocks were treated once at 27wpp using the same anthelmintic. Hens in the UT were not dewormed and served as controls. Additionally, FECs on cloacal contents, worm fecundity and worm burdens were determined at 19, 35 and 45wpp. None of the flocks became infected until after 16wpp. The cumulative pooled FECs at the end of the study were significantly (p<0.01) lower in the TT compared to both CT and UT. Although repeated treatment in the TT protocol did not affect the fecundity, a worm density-dependent increase in fecundity was observed. Cloacal FECs and the number of adult A. galli in TT at 35 and 45wpp were significantly lower compared to other flocks. This study provides evidence that the TT strategy is better in terms of lower worm burden and decreased cumulative environmental parasite egg numbers compared to CT strategy. The TT strategy should be considered as an alternative to the CT strategy with regard to A. galli control in commercial laying hens. PMID- 27514896 TI - Three-year evaluation of best practice guidelines for nematode control on commercial sheep farms in the UK. AB - Anthelmintics are commonly used on the majority of UK commercial sheep farms to reduce major economic losses associated with parasitic diseases. With increasing anthelmintic resistance worldwide, several countries have produced evidence based, best practice guidelines with an example being the UK's Sustainable Control of Parasites in Sheep (SCOPS) initiative. In 2012, a pilot study demonstrated that SCOPS-managed farms used fewer anthelmintic treatments than traditionally managed farms, with no impact on lamb productivity and worm burden. Building on these results, we collected data for three consecutive years (2012 2014) with the following aims: (1) To compare the effects of traditional and SCOPS-based parasite management on lamb productivity and worm burden; (2) To evaluate the effect of region and farm type on lamb productivity and worm burden; (3) To compare the frequency and patterns of use of anthelmintic treatment on traditional and SCOPS-managed farms. The study was carried out on 16 farms located in the North east and the South west of England and Wales. Lamb productivity was assessed by quantifying birth, mid-season and finish weights and calculating daily live-weight gains and time to finish in a cohort of 40-50 lambs on each farm. Five annual faecal egg counts were carried out on each farm to assess worm burden. No differences in lamb productivity and worm burdens were found between farms that adopted SCOPS guidelines and traditional farms across the three years. However, mean infection levels increased for both the SCOPS and the traditional groups. Lamb production was not significantly different for farm type and region but the effect of region on infection was significant. For both ewes and lambs, SCOPS farms carried out significantly fewer anthelmintic treatments per year, and used fewer anthelmintic doses/animal than traditional farms. The data suggest a trend to increasing use of anthelmintics in ewes on traditional but not on the SCOPS farms and a decreasing use of anthelmintics in lambs on both SCOPS and traditional farms. Across time, an increasing number of SCOPS farmers left their ewes and lambs untreated and the reverse was true for traditional farmers. Overall, farms implementing SCOPS guidelines used less anthelmintic treatments and less frequently than traditionally managed farms, without loss of animal performance or increased worm burden. Implementing SCOPS guidelines might have economic benefits for farmers, help reduce development of anthelmintic resistance on farms and decrease any environmental impact of anthelmintics. Furthermore, these data suggest some important epidemiological trends that should be investigated in long-term studies. PMID- 27514897 TI - Vaccine potential of recombinant cathepsinL1G against Fasciola gigantica in mice. AB - In this study, we characterized and investigated the vaccine potential of FgCatL1G against Fasciola gigantica infection in mice. Recombinant mature FgCatL1G (rmFgCatL1G) was expressed in Escherichia coli BL21. The vaccination was performed in Imprinting Control Region (ICR) mice (n=10) by subcutaneous injection with 50MUg of rmFgCatL1G combined with Freund's adjuvant. Two weeks after the second boost, mice were infected with 15 metacercariae by the oral route. The percents of protection of rmFgCatL1G vaccine were estimated to be 56.5% and 58.3% when compared with non vaccinated-infected and adjuvant-infected controls, respectively. Antibodies in the immune sera of vaccinated mice were shown by immunoblot to react with the native FgCatL1s in the extract of all stages of parasites and rmFgCatL1H, recombinant pro - FgCatL1 (rpFgCatL1). By immunohistochemistry, the immune sera also reacted with FgCatL1s in the caecal epithelial cells of the parasites. The levels of IgG1 and IgG2a in the immune sera, which are indicative of Th2 and Th1 immune responses, were also increased with IgG1 predominating. The levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) in rmFgCatL1G-immunized group showed no significant difference from the control groups, but pathological lesions of livers in rmFgCatL1G-immunized group showed significant decrease when compared to the control groups. This study indicates that rmFgCatL1G has a vaccine potential against F. gigantica in mice, and this potential will be tested in larger livestock animals. PMID- 27514898 TI - Prospective study investigating transplacental transmission of equine piroplasmosis in thoroughbred foals in Trinidad. AB - Equine piroplasmosis caused by Theileria equi and Babesia caballi is endemic in Trinidad and Tobago. Transmission occurs by ticks of the family Ixodidae. T. equi can also be transmitted transplacentally; however transplacental transmission of B. caballi is unknown. This study aims to investigate transplacental transmission of equine piroplasmosis from thoroughbred mares naturally infected via the tick vector. Whole blood and serum samples were collected from 117 mares in the fifth month of pregnancy. Blood samples were also collected from each of their foals (89 in total) within the first 36h of birth. Additionally, all foals were observed for clinical signs within 30days post - partum. All samples were examined microscopically for intra-erythrocytic piroplasms. Serum ELISA tests and PCR analysis on whole blood were performed to determine the presence of T. equi and B. caballi. Thirty-four (30.6%) mares and 14 (15.7%) of their foals were seropositive for T. equi. Twenty-seven (24.3%) mares were positive for T. equi by conventional (c) PCR. Real time (q) PCR analysis based on the ema - 1 gene revealed that seven (8%) foals were positive for T. equi. Eighty-nine (76.1%) mares and 38 (42.7%) foals were seropositive for B. caballi. Four (3.4%) mares were positive for B. caballi by cPCR. Three out of the four cPCR positive mares either had resorptions, or stillbirths for that pregnancy. From this study, there is strong evidence that transplacental transmission of B. caballi can occur leading to foetal losses. Six foals (7%) were positive for B. caballi by qPCR. Of these six, four were born to B. caballi seropositive mares. In this study a foal born of a T. equi seropositive mare was 55.7 times more likely to be serologically positive for T. equi than a foal born to a T. equi seronegative mare. Similarly a foal born of a B. caballi seropositive mare was 39.4 times more likely to be serologically positive for B. caballi than a foal born to a mare that was serologically negative for B. caballi at the fifth month of pregnancy. This is as a result of the ingestion of colostrum containing antibodies to these pathogens. Mares should be screened during pregnancy and their foals closely monitored at parturition for evidence of equine piroplasmosis so that treatment can be implemented earlier for a better prognosis. PMID- 27514899 TI - Molecular identification of Echinococcus granulosus isolates from ruminants in Greece. AB - Cystic echinococcosis is a parasitic disease caused by Echinococcus granulosus, a cestode with worldwide distribution. Data on the circulating Echinococcus granulosus genotypes in Greek livestock is scant. The aim of the present study was to conduct a genetic analysis of 82 Echinococcus granulosus isolates from ruminants in Greece, including areas which until today have not been the subject of studies. The analysis relied on a PCR assay targeting cytochrome c oxidase, subunit 1 gene (CO1), followed by bidirectional sequence analysis of the amplification product. Eighty (n=80) of the 82 (97.6%) isolates were allocated to Echinococcus granulosus sensu stricto (G1-G3) and were classified in 13 distinct haplotypes (9 common and 4 novel) with 12 polymorphic sites. The presence of the dominant haplotype EG1 as was documented in the European populations, was indicated in the country. Almost all regions shared the same common haplotype. In comparison to this predominant haplotype, the number of the nucleotide changes in all the other haplotypes ranged from 1 to 5. All nucleotide changes proved to be transitions (A<->G or C<->T). Two fertile hydatid cysts of sheep origin in different areas (Arkadia, Ilia) of the Peloponnese were identified as Echinococcus canadensis (G7 genotype). PMID- 27514900 TI - Spatial distribution and risk factors for Toxoplasma gondii seropositivity in cattle slaughtered for human consumption in Rondonia, North region, Brazil. AB - The present study aimed to evaluate Toxoplasma gondii seroprevalence in cattle slaughtered for human consumption from rural properties in the state of Rondonia, North region, Brazil; the seroprevalence was determined using indirect immunofluorescence assays (IFATs). Additionally, spatial distribution and risk factors associated with toxoplasmosis were also analyzed. Of the 1000 cattle serum samples examined, 53 (5.3%) were determined to be seropositive for T. gondii with antibody titers (IgG) >=64. In regard to results of the studied risk factors (presence of cats, cats with free access to cattle, breeding system, animal's gender, consumption of raw milk by humans on the property and cattle abortion in the last 12 months) and the odds ratio (OR) of each of these factors influencing cattle to acquire toxoplasmosis, only animals raised on a feeder/stocker/backgrounder system presented a higher probability of being seropositive for T. gondii (OR>=1, P=0.04) than cattle raised only in a feeder/stocker system. There was no association between the occurrence of reproductive problems and T. gondii seropositivity. Based on results obtained in the Brazilian state of Rondonia, it could be concluded that the presence of cats and their contact with cattle on each property, cattle breeding purpose and cattle abortion in the last 12 months were not considered risk factors for T. gondii infection in cattle. Considering that the presence of T. gondii was detected in animals slaughtered in the state of Rondonia, consuming raw or undercooked meat from seropositive cattle should be considered a route of transmission of T. gondii to humans. However, the prevalence of toxoplasmosis diagnosed in cattle from this state (5.30%) is lower than the prevalence of toxoplasmosis observed in South, Southeast and Center-West regions of Brazil, which may vary between 48.5% and 71.0%. The low prevalence of toxoplasmosis in cattle is highlighted in Rondonia, which is the sixth largest state for cattle slaughtering in Brazil and is responsible for producing 20% of all cattle meat exported by Brazil. PMID- 27514901 TI - Evaluation of the efficacy of monthly oral administration of afoxolaner plus milbemycin oxime (NexGard Spectra((r)), Merial) in the prevention of adult Spirocerca lupi establishment in experimentally infected dogs. AB - The nematode Spirocerca lupi (Rudolphi, 1809) is widely distributed but mostly occurs sporadically with stable populations only in certain geographic areas. This helminth mainly infects dogs and wild canids. Primary pathology relates to migration of third stage larvae (L3) damaging the thoracic aorta and establishment of adults in nodules in the oesophagus. The objective of the present study was to evaluate the efficacy of milbemycin oxime in combination with afoxolaner (NexGard Spectra((r)), Merial), administered monthly, in preventing establishment of adult worms after experimental infection. Two groups consisting of eight animals each were experimentally infected with 15 L3 on Days 28, -14 and -2, respectively (45 L3 per animal in total). Group 1 dogs served as untreated (negative) control, whereas animals in group 2 were treated with NexGard Spectra((r)) at a minimum dose of 0.5mg/kg milbemycin oxime on Day 0 and from then onwards every 28 days up to Day 140 (six treatment occasions). Endoscopy was performed on Day 112 and for some animals also Day 140. Necropsy for worm recovery and nodule/lesion scoring was performed on Day 168. All eight animals in the control group (group 1) presented with 1-3 nodules and worm counts ranging from 9 to 41. Six animals in the NexGard Spectra((r)) group presented with 1-4 nodules and worm counts ranging from 1 to 5. Significantly (p<0.05) fewer worms were collected from treated animals in the treated group (geometric mean 1.7) versus the negative control group (geometric mean 22.0) with 92.3% efficacy calculated. There was no significant (p>0.05) difference between groups with reference to number of nodules in the oesophagus. However, nodules in the control group were significantly (p<0.05) larger than those in the treated group. Number and size of lesions in the dorsal aorta did not differ statistically between groups 1 and 2. Because NexGard Spectra((r)) was administered 28 days after onset of inoculation, migrating and developing L3 caused damage to the aorta wall of animals in the treated group. Milbemycin oxime (administered as NexGard Spectra((r))) demonstrated effectiveness in reducing infection with adult Spirocerca lupi worms in the oesophagus. PMID- 27514902 TI - The use of epifluorescence microscopy and fluorescent dyes for visualization of Oxyuris equi eggs. AB - This study presents a new method for visualization of Oxyuris equi eggs collected by means of a clear adhesive tape applied to the perianal region of horses. The obtained results indicate that this protocol permits a quick, easy, clear and selective visualization of Oxyuris equi eggs even in the presence of feces and other material. Another advantage of this method is that it can be used with fluorescent dyes solubilized in water, which will stain biologic material without dissolving or altering the adhesive tape and is also environmentally safe. Other dyes currently used for staining biologic materials use organic solvents, which may be combined with acids or bases in their formulation, preventing their use with the tape method. PMID- 27514903 TI - Limited sharing of tick-borne hemoparasites between sympatric wild and domestic ungulates. AB - Tick-borne hemoparasites (TBHs) are a group of pathogens of concern in animal management because they are associated with a diversity of hosts, including both wild and domestic species. However, little is known about how frequently TBHs are shared across the wildlife-livestock interface in natural settings. Here, we compared the TBHs of wild Grant's gazelle (Nanger granti) and domestic sheep (Ovis aries) in a region of Kenya where these species extensively overlap. Blood samples collected from each species were screened for piroplasm and rickettsial TBHs by PCR-based amplification of 18S/16S ribosomal DNA, respectively. Overall, 99% of gazelle and 66% of sheep were positive for Babesia/Theileria, and 32% of gazelle and 47% sheep were positive for Anaplasma/Ehrlichia. Sequencing a subset of positive samples revealed infections of Theileria and Anaplasma. Sequences sorted into seven phylogenetically distinct genotypes-two Theileria, and five Anaplasma. With the exception of a putatively novel Anaplasma lineage from Grant's gazelle, these genotypes appeared to be divergent forms of previously described species, including T. ovis, A. ovis, A. bovis, and A. platys. Only one genotype, which clustered within the A. platys clade, contained sequences from both gazelle and sheep. This suggests that despite niche, habitat, and phylogenetic overlap, the majority of circulating tick-borne diseases may not be shared between these two focal species. PMID- 27514904 TI - Which is the best phenotypic trait for use in a targeted selective treatment strategy for growing lambs in temperate climates? AB - Targeted selective treatment (TST) requires the ability to identify the animals for which anthelmintic treatment will result in the greatest benefit to the entire flock. Various phenotypic traits have previously been suggested as determinant criteria for TST; however, the weight gain benefit and impact on anthelmintic efficacy for each determinant criterion is expected to be dependent upon the level of nematode challenge and the timing of anthelmintic treatment. A mathematical model was used to simulate a population of 10,000 parasitologically naive Scottish Blackface lambs (with heritable variation in host-parasite interactions) grazing on medium-quality pasture (grazing density=30 lambs/ha, crude protein=140g/kg DM, metabolisable energy=10MJ/kg DM) with an initial larval contamination of 1000, 3000 or 5000 Teladorsagia circumcincta L3/kg DM. Anthelmintic drenches were administered to 0, 50 or 100% of the population on a single occasion. The day of anthelmintic treatment was independently modelled for every day within the 121day simulation. Where TST scenarios were simulated (50% treated), lambs were either chosen by random selection or according to highest faecal egg count (FEC, eggs/g DM faeces), lowest live weight (LW, kg) or lowest growth rate (kg/day). Average lamb empty body weight (kg) and the resistance (R) allele frequency amongst the parasite population on pasture were recorded at slaughter (day 121) for each scenario. Average weight gain benefit and increase in R allele frequency for each determinant criterion, level of initial larval contamination and day of anthelmintic treatment were calculated by comparison to a non-treated population. Determinant criteria were evaluated according to average weight gain benefit divided by increase in R allele frequency to determine the benefit per R. Whilst positive phenotypic correlations were predicted between worm burden and FEC; using LW as the determinant criterion provided the greatest benefit per R for all levels of initial larval contamination and day of anthelmintic treatment. Hence, LW was identified as the best determinant criterion for use in a TST regime. This study supports the use of TST strategies as benefit per R predictions for all determinant criteria were greater than those predicted for the 100% treatment group, representing an increased long-term productive benefit resulting from the maintenance of anthelmintic efficacy. Whilst not included in this study, the model could be extended to consider other parasite species and host breed parameters, variation in climatic influences on larval availability and grass growth, repeated anthelmintic treatments and variable proportional flock treatments. PMID- 27514905 TI - Interaction of Trypanosoma evansi with the plasminogen-plasmin system. AB - Trypanosoma evansi is a widely-distributed haemoflagellated parasite of veterinary importance that infects a variety of mammals including horses, mules, camels, buffalos, cattle and deer. It is the causal agent of a trypanosomiasis known as Surra which produces epidemics of great economic importance in Africa, Asia and South America. The main pathology includes an enlarged spleen with hypertrophy of lymphoid follicles, congested lungs, neuronal degeneration and meningoencephalitis, where migration of the parasites from the blood to the tissues is essential. Most cells, including pathogenic cells, use diverse strategies for tissue invasion, such as the expression of surface receptors to bind plasminogen or plasmin. In this work, we show that T. evansi is able to bind plasminogen and plasmin on its surface. The analysis of this binding revealed a high affinity dissociation constant (Kd of 0.080+/-0.009MUM) and 1*10(5) plasminogen binding sites per cell. Also a second population of receptors with a Kd of 0.255+/-0.070MUM and 3.2*10(4) plasminogen binding sites per cell was determined. Several proteins with molecular masses between ~18 and ~70kDa are responsible for this binding. This parasite-plasminogen interaction may be important in the establishment of the infection in the vertebrate host, where the physiological concentration of available plasminogen is around 2MUM. PMID- 27514906 TI - A simulation model to investigate interactions between first season grazing calves and Ostertagia ostertagi. AB - A dynamic, deterministic model was developed to investigate the consequences of parasitism with Ostertagia ostertagi, the most prevalent and economically important gastrointestinal parasite of cattle in temperate regions. Interactions between host and parasite were considered to predict the level of parasitism and performance of an infected calf. Key model inputs included calf intrinsic growth rate, feed quality and mode and level of infection. The effects of these varied inputs were simulated on a daily basis for key parasitological (worm burden, total egg output and faecal egg count) and performance outputs (feed intake and bodyweight) over a 6 month grazing period. Data from published literature were used to parameterise the model and its sensitivity was tested for uncertain parameters by a Latin hypercube sensitivity design. For the latter each parameter tested was subject to a 20% coefficient of variation. The model parasitological outputs were most sensitive to the immune rate parameters that affected overall worm burdens. The model predicted the expected larger worm burdens along with disproportionately greater body weight losses with increasing daily infection levels. The model was validated against published literature using graphical and statistical comparisons. Its predictions were quantitatively consistent with the parasitological outputs of published experiments in which calves were subjected to different infection levels. The consequences of model weaknesses are discussed and point towards model improvements. Future work should focus on developing a stochastic model to account for calf variation in performance and immune response; this will ultimately be used to test the effectiveness of different parasite control strategies in naturally infected calf populations. PMID- 27514908 TI - Anode macrostructures influence electricity generation in microbial fuel cells for wastewater treatment. AB - Microbial fuel cells (MFCs) are devices that exploit microbes for generating electricity from organic substrates, including waste biomass and wastewater pollutants. MFCs have the potential to treat wastewater and simultaneously generate electricity. The present study examined how anode macrostructure influences wastewater treatment, electricity generation and microbial communities in MFCs. Cassette-electrode MFCs were equipped with graphite-felt anodes with three different macrostructures, flat-plate (FP), vertical-fin (VF), and horizontal-fin (HF) structures (these were composed of a same amount of graphite felt), and were continuously supplied with artificial wastewater containing starch as the major organic constituent. Polarization analyses revealed that MFCs equipped with VF and HF anodes generated 33% and 21% higher volumetric power densities, respectively, than that of MFCs equipped with FP anodes. Organics were also more efficiently removed from wastewater in MFCs with VF and HF anodes compared to reactors containing FP anodes. In addition, pyrosequencing of PCR amplified 16S rRNA gene fragments from microbial samples collected from the anodes showed that the presence of fins also affected the bacterial compositions in anode biofilms. Taken together, the findings presented here suggest that the modification of anodes with fins improves organics removal and electricity generation in MFCs. The optimization of anode macrostructure therefore appears to be a promising strategy for improving MFC performance without additional material costs. PMID- 27514907 TI - New alkalophilic beta-galactosidase with high activity in alkaline pH region from Teratosphaeria acidotherma AIU BGA-1. AB - A beta-d-galactosidase exhibiting high activity in the alkaline pH region was purified from Teratosphaeria acidotherma AIU BGA-1, which we previously isolated as a unique fungal producer of three acidophilic and one alkalophilic beta-d galactosidases (Isobe et al., J. Biosci. Bioeng., 116, 171-174, 2013). The enzyme was stable in the pH range 7.5-10.0 and exhibited optimal activity at pH 8.0 and 60 degrees C. The enzyme hydrolyzed 2-nitrophenyl beta-d-galactopyranoside, 4 nitrophenyl beta-d-galactopyranoside, and lactose, and the Km values were estimated to be 0.349 mM, 0.488 mM, and 701 mM, respectively. Chelating reagents (EDTA and o-phenanthroline) and metals (Cu2+and Ni2+) inhibited the enzyme activity, and Mn2+ was a good activator. The enzyme also exhibited transgalactosylation activity for lactose. The enzyme's molecular mass was estimated to be 180 kDa, and its structure was monomeric. Thus, the enzymatic and physicochemical characteristics of the alkalophilic beta-galactosidase in this study clearly differed from those of the previously known alkalophilic beta-d galactosidases. PMID- 27514909 TI - Paper-based colorimetric biosensor for antibiotics inhibiting bacterial protein synthesis. AB - Due to the presence of antibiotics in environmental water and their potential influence on the occurrence of antibiotic-resistant bacteria, development of a detection method suitable for the screening of environmental water for antibiotics is required. In this study, we developed a simple colorimetric paper based biosensor based on a novel principle for the detection of antibiotics inhibiting bacterial protein synthesis, including aminoglycosides, tetracycline, chloramphenicol, and macrolides. This biosensor is based on the detection of a color change induced by beta-galactosidase, which is synthesized on freeze-dried paper discs containing an in vitro transcription/translation system. When a water sample without antibiotics is applied to the paper discs, beta-galactosidase can be synthesized, and it hydrolyzes a colorimetric substrate, resulting in a color change from yellow to purple. By contrast, in the presence of antibiotics, the color change can be hampered due to an inhibition of beta-galactosidase synthesis. We investigated the effect of the incubation temperature and pH of water samples and confirmed that the paper discs showed the color change to purple in the ranges of 15-37 degrees C and pH 6-10. We observed concentration dependent color variations of the paper discs by the naked eye and further estimated detection limits to be 0.5, 2.1, 0.8, and 6.1 MUg/mL for paromomycin, tetracycline, chloramphenicol, and erythromycin, respectively, using digitized pictures. The paper-based biosensor proved to detect 0.5 MUg/mL paromomycin, spiked in real environmental water samples, by the naked eye. PMID- 27514910 TI - Undernutrition among adults in India: the significance of individual-level and contextual factors impacting on the likelihood of underweight across sub populations. AB - OBJECTIVE: To investigate the extent to which individual-level as well as macro level contextual factors influence the likelihood of underweight across adult sub populations in India. DESIGN: Population-based cross-sectional survey included in India's National Health Family Survey conducted in 2005-06. We disaggregated into eight sub-populations. SETTING: Multistage nationally representative household survey covering 99 % of India's population. SUBJECTS: The survey covered 124 385 females aged 15-49 years and 74 369 males aged 15-54 years. RESULTS: A social gradient in underweight exists in India. Even after allowing for wealth status, differences in the predicted probability of underweight persisted based upon rurality, age/maturity and gender. We found individual-level education lowered the likelihood of underweight for males, but no statistical association for females. Paradoxically, rural young (15-24 years) females from more educated villages had a higher likelihood of underweight relative to those in less educated villages; but for rural mature (>24 years) females the opposite was the case. Christians had a significantly lower likelihood of underweight relative to other socio-religious groups (OR=0.53-0.80). Higher state-level inequality increased the likelihood of underweight across most population groups, while neighbourhood inequality exhibited a similar relationship for the rural young population subgroups only. Individual states/neighbourhoods accounted for 5-9 % of the variation in the prediction of underweight. We found that rural young females represent a particularly highly vulnerable sub-population. CONCLUSIONS: Economic growth alone is unlikely to reduce the burden of malnutrition in India; accordingly, policy makers need to address the broader social determinants that contribute to higher underweight prevalence in specific demographic subgroups. PMID- 27514911 TI - Implementation of the cross-border healthcare directive in Poland: How not to encourage patients to seek care abroad? AB - In October 2014, after over 12 months of delay, Poland finally implemented directive 2011/24/EU on the application of patients' rights in cross-border healthcare. The implementing legislation in the area of cost reimbursement and prior authorization is very restrictive. The goal is to either defer the public payer's expenses into the future or to discourage patients from seeking care abroad or from seeking care altogether. The Polish government and the Ministry of Health, the key stakeholders in the implementation process, seemed to overlook the potential monetary benefits that the implementation of the directive could bring, for example, by promoting Poland as a destination for health tourism. Other stakeholders, such as patients and healthcare providers, had no real influence on the policy process. So far, the number of applications for planned treatment abroad has been very low and the majority of them were actually turned down as they did not meet the formal requirements. This number is likely to remain low in the future as accessing such care is cumbersome and not affordable for many patients. Overall, while the directive does not aim to encourage patients to seek cross-border healthcare, the current national regulations in Poland do not seem to facilitate access to cross-border healthcare, which is the main goal of the directive. PMID- 27514912 TI - Methods for Studying Ciliary Import Mechanisms. AB - Cilia and flagella are microtubule-based organelles that play important roles in human health by contributing to cellular motility as well as sensing and responding to environmental cues. Defects in cilia formation and function cause a broad class of human genetic diseases called ciliopathies. To carry out their specialized functions, cilia contain a unique complement of proteins that must be imported into the ciliary compartment. In this chapter, we describe methods to measure the permeability barrier of the ciliary gate by microinjection of fluorescent proteins and dextrans of different sizes into ciliated cells. We also describe a fluorescence recovery after photobleaching (FRAP) assay to measure the entry of ciliary proteins into the ciliary compartment. These assays can be used to determine the molecular mechanisms that regulate the formation and function of cilia in mammalian cells. PMID- 27514913 TI - Targeting of ASH Domain-Containing Proteins to the Centrosome. AB - A growing number of studies have used new generation technologies to characterize the protein constituents of cilia and centrosomes. This has led to the identification of a vast number of candidate ciliary or centrosomal proteins, whose subcellular localization needs to be investigated and validated. Here, we describe a simple and inexpensive method for analyzing the subcellular localization of candidate cilium- or centrosome-associated proteins, and we illustrate the utility as well as the pitfalls of this method by applying it to a group of ASH (ASPM, SPD-2, Hydin) domain-containing proteins, previously predicted to be cilia- or centrosome-associated proteins based on bioinformatic analyses. By generating plasmids coding for epitope-tagged full-length (FL) or truncated versions of the ASH domain-containing proteins TRAPPC8, TRAPPC13, NPHP4, and DLEC1, followed by expression and quantitative immunofluorescence microscopy (IFM) analysis in cultured human telomerase-immortalized retinal pigmented epithelial (hTERT-RPE1) cells, we could confirm that TRAPPC13 and NPHP4 are highly enriched at the base of primary cilia, whereas DLEC1 seems to associate specifically with motile cilia. Results for TRAPPC8 were inconclusive since epitope-tagged TRAPPC8 fusion proteins were unstable/degraded in cells, emphasizing the need for combining IFM analysis with western blotting in such studies. The method described should be applicable to other candidate ciliary or centrosomal proteins as well. PMID- 27514914 TI - Morphological and Functional Characterization of the Ciliary Pocket by Electron and Fluorescence Microscopy. AB - In many vertebrate cell types, the proximal part of the primary cilium is positioned within an invagination of the plasma membrane known as the ciliary pocket. Recent evidence points to the conclusion that the ciliary pocket comprises a unique site for exocytosis and endocytosis of ciliary proteins, which regulates the spatiotemporal trafficking of receptors into and out of the cilium to control its sensory function. In this chapter, we provide methods based on electron microscopy, 3D reconstruction of fluorescence images as well as live cell imaging suitable for investigating processes associated with endocytosis at the ciliary pocket. PMID- 27514915 TI - Methods to Study Interactions Between Ciliogenesis and Autophagy. AB - Autophagy is a catabolic pathway for the degradation and recycling of intracellular components, contributing to maintain cell homeostasis. Changes in autophagy activity can be monitored by a variety of biochemical and functional assays that should be used in combination. Recently, it has been described that signaling from the primary cilium modulates autophagy. This novel and reciprocal interaction will impact diverse aspects of the cell biology in healthy and pathophysiological conditions. Here, we describe methods to monitor autophagy activity in cilia mutants, as well as the use of autophagy mutants to monitor ciliogenesis. PMID- 27514916 TI - Recombinant Reconstitution and Purification of the IFT-B Core Complex from Chlamydomonas reinhardtii. AB - Eukaryotic cilia and flagella are assembled and maintained by intraflagellar transport (IFT), the bidirectional transport of proteins between the ciliary base and tip. IFT is mediated by the multi-subunit IFT complex, which simultaneously binds cargo proteins and the ciliary motors. So far 22 subunits of the IFT complex have been identified, but insights into the biochemical architecture and especially the three-dimensional structure of this machinery are only starting to emerge because of difficulties in obtaining homogeneous material suitable for structural analysis. Here, we describe a protocol for the purification and reconstitution of a complex containing nine Chlamydomonas reinhardtii IFT proteins, commonly known as the IFT-B core complex. In our hands, this protocol routinely yields several milligrams of pure complex suitable for structural analysis by X-ray crystallography and single-particle cryo-electron microscopy. PMID- 27514918 TI - A FRAP-Based Method for Monitoring Molecular Transport in Ciliary Photoreceptor Cells In Vivo. AB - The outer segment of rod and cone photoreceptor cells represents a highly modified primary sensory cilium. It renews on a daily basis throughout lifetime and effective vectorial transport to the cilium is essential for the maintenance of the photoreceptor cell function. Defects in molecules of transport modules lead to severe retinal ciliopathies. We have recently established a fluorescence recovery after photobleaching (FRAP)-based method to monitor molecular trafficking in living rodent photoreceptor cells. We irreversibly bleach the fluorescence of tagged molecules (e.g. eGFP-Rhodopsin) in photoreceptor cells of native vibratome sections through the retina by high laser intensity. In the laser scanning microscope, the recovery of the fluorescent signal is monitored over time and the kinetics of movements of molecules can be quantitatively ascertained. PMID- 27514917 TI - Methods for Studying Movement of Molecules Within Cilia. AB - The assembly of cilia and eukaryotic flagella (interchangeable terms) requires the import of numerous proteins from the cell body into the growing organelle. Proteins move into and inside cilia by diffusion and by motor-based intraflagellar transport (IFT). Many aspects of ciliary protein transport such as the distribution of unloading sites and the frequency of transport can be analyzed using direct in vivo imaging of fluorescently tagged proteins. Here, we will describe how to use total internal reflection fluorescence microcopy (TIRFM) to analyze protein transport in the flagella of the unicellular alga Chlamydomonas reinhardtii, a widely used model for cilia and cilia-related disease. PMID- 27514919 TI - Kymographic Analysis of Transport in an Individual Neuronal Sensory Cilium in Caenorhabditis elegans. AB - Intraflagellar Transport (IFT) is driven by molecular motors that travel upon microtubule-based ciliary axonemes. In the single-celled alga Chlamydomonas reinhardtii, movement of a single anterograde IFT motor, heterotrimeric kinesin II, is required to generate two identical motile flagella. The function of this canonical anterograde IFT motor is conserved among all eukaryotes, yet multicellular organisms can generate cilia of diverse structures and functions, ranging from simple threadlike non-motile primary cilia to the elaborate cilia that make up rod and cone photoreceptors in the retina. An emerging theme is that additional molecular motors modulate the canonical IFT machinery to give rise to differing ciliary morphologies. Therefore, a complete understanding of the trafficking of ciliary receptors, as well as the biogenesis, maintenance, specialization, and function of cilia, requires the characterization of motor molecules.Here, we describe in detail our method for measuring the motility of proteins in cilia or dendrites of C. elegans male-specific CEM ciliated sensory neurons using time-lapse microscopy and kymography of green fluorescent protein (GFP)-tagged motors, receptors, and cargos. We describe, as a specific example, OSM-3::GFP puncta moving in cilia, but also include (Fig. 1) with settings that have worked well for us measuring movement of heterotrimeric kinesin-II, IFT particles, and the polycystin TRP channel PKD-2. PMID- 27514920 TI - Visualization and Manipulation of Cilia and Intraciliary Calcium in the Zebrafish Left-Right Organizer. AB - Cilia play a key role in the determination of the left-right axis in vertebrates by generating and sensing flow of extraembryonic fluid at the left-right organizer (LRO). Perception of cilia-directed flow triggers a calcium signaling cascade which originates within the cilium itself and then is relayed into the surrounding mesendodermal tissue, thereby directing organ situs via the nodal pathway. Two types of cilia, motile and immotile, function simultaneously to coordinate and direct asymmetric intraciliary calcium signaling cues in the LRO. Here, we describe tools, reagents, and methodologies for the visualization and manipulation of both cilia types as well as intraciliary calcium signaling in the LRO of zebrafish. PMID- 27514921 TI - Methods for Studying Ciliary-Mediated Chemoresponse in Paramecium. AB - Paramecium is a useful model organism for the study of ciliary-mediated chemical sensing and response. Here we describe ways to take advantage of Paramecium to study chemoresponse.Unicellular organisms like the ciliated protozoan Paramecium sense and respond to chemicals in their environment (Van Houten, Ann Rev Physiol 54:639-663, 1992; Van Houten, Trends Neurosci 17:62-71, 1994). A thousand or more cilia that cover Paramecium cells serve as antennae for chemical signals, similar to ciliary function in a large variety of metazoan cell types that have primary or motile cilia (Berbari et al., Curr Biol 19(13):R526-R535, 2009; Singla V, Reiter J, Science 313:629-633, 2006). The Paramecium cilia also produce the motor output of the detection of chemical cues by controlling swimming behavior. Therefore, in Paramecium the cilia serve multiple roles of detection and response.We present this chapter in three sections to describe the methods for (1) assaying populations of cells for their behavioral responses to chemicals (attraction and repulsion), (2) characterization of the chemoreceptors and associated channels of the cilia using proteomics and binding assays, and (3) electrophysiological analysis of individual cells' responses to chemicals. These methods are applied to wild type cells, mutants, transformed cells that express tagged proteins, and cells depleted of gene products by RNA Interference (RNAi). PMID- 27514922 TI - STED and STORM Superresolution Imaging of Primary Cilia. AB - The characteristic lengths of molecular arrangement in primary cilia are below the diffraction limit of light, challenging structural and functional studies of ciliary proteins. Superresolution microscopy can reach up to a 20 nm resolution, significantly improving the ability to map molecules in primary cilia. Here we describe detailed experimental procedure of STED microscopy imaging and dSTORM imaging, two of the most powerful superresolution imaging techniques. Specifically, we emphasize the use of these two methods on imaging proteins in primary cilia. PMID- 27514923 TI - CLEM Methods for Studying Primary Cilia. AB - CLEM (correlated light and electron microscope) imaging is a highly useful technique for examining primary cilia. With CLEM, it is possible to determine the distribution of tagged proteins along the ciliary membrane and axoneme with high precision. Scanning electron microscopy (SEM) permits measurement of ciliary length and orientation in relation to nearby cellular structures in a 3D image; in optimal cases, this can be combined with superresolution microscopy of selected ciliary components as they enter or leave the cilium. This chapter discusses CLEM methods. In the method described in detail, samples are completely processed for sequential fluorescence and SEM observation. This method is ideal for robust antibody localization and minimizes image manipulation in correlating the fluorescent and SEM images. Alternative methods prepare samples for fluorescence imaging followed by processing for SEM then observation in the SEM. This method is ideal for optimal fluorescence imaging, particularly live cell imaging. PMID- 27514924 TI - Methods for Visualization of Neuronal Cilia. AB - Neuroscientists have been captivated by cilia ever since these slender, microtubule-based projections on the cell body were found to play critical roles in neuronal specification, maintenance, and function. In mammals, the most common cilia marker, acetylated alpha-tubulin, is extremely difficult to detect in neuronal cilia. Here, we describe methods to detect neuronal cilia in culture, in fixed sections, and in vivo, taking advantage of transgenic mice carrying fluorescently tagged cilia proteins. PMID- 27514925 TI - Methods to Study Centrosomes and Cilia in Drosophila. AB - Centrioles and cilia are highly conserved eukaryotic organelles. Drosophila melanogaster is a powerful genetic and cell biology model organism, extensively used to discover underlying mechanisms of centrosome and cilia biogenesis and function. Defects in centrosomes and cilia reduce fertility and affect different sensory functions, such as proprioception, olfaction, and hearing. The fly possesses a large diversity of ciliary structures and assembly modes, such as motile, immotile, and intraflagellar transport (IFT)-independent or IFT-dependent assembly. Moreover, all the diverse ciliated cells harbor centrioles at the base of the cilia, called basal bodies, making the fly an attractive model to better understand the biology of this organelle. This chapter describes protocols to visualize centrosomes and cilia by fluorescence and electron microscopy. PMID- 27514926 TI - Analysis of Axonemal Assembly During Ciliary Regeneration in Chlamydomonas. AB - Chlamydomonas reinhardtii is an outstanding model genetic organism for study of assembly of cilia. Here, methods are described for synchronization of ciliary regeneration in Chlamydomonas to analyze the sequence in which ciliary proteins assemble. In addition, the methods described allow analysis of the mechanisms involved in regulation of ciliary length, the proteins required for ciliary assembly, and the temporal expression of genes encoding ciliary proteins. Ultimately, these methods can contribute to discovery of conserved genes that when defective lead to abnormal ciliary assembly and human disease. PMID- 27514927 TI - Planaria as a Model System for the Analysis of Ciliary Assembly and Motility. AB - Planarian flatworms are carnivorous invertebrates with astounding regenerative properties. They have a ventral surface on which thousands of motile cilia are exposed to the extracellular environment. These beat in a synchronized manner against secreted mucus thereby propelling the animal forward. Similar to the nematode Caenorhabditis elegans, the planarian Schmidtea mediterranea is easy to maintain in the laboratory and is highly amenable to simple RNAi approaches through feeding with dsRNA. The methods are simple and robust, and the level of gene expression reduction that can be obtained is, in many cases, almost total. Moreover, cilia assembly and function is not essential for viability in this organism, as animals readily survive for weeks even with the apparent total absence of this organelle. Both genome and expressed sequence tag databases are available and allow design of vectors to target any desired gene of choice. Combined, these feature make planaria a useful model system in which to examine ciliary assembly and motility, especially in the context of a ciliated epithelium where many organelles beat in a hydrodynamically coupled synchronized manner. In addition, as planaria secrete mucus against which the cilia beat to generate propulsive force, this system may also prove useful for analysis of mucociliary interactions. In this chapter, we provide simple methods to maintain a planarian colony, knockdown gene expression by RNAi, and analyze the resulting animals for whole organism motility as well as ciliary architecture and function. PMID- 27514928 TI - Spontaneous myonecrosis in chronic myeloid leukaemia. PMID- 27514929 TI - Reclassification of Amycolicicoccus subflavus as Hoyosella subflava comb. nov. and emended descriptions of the genus Hoyosella and Hoyosella altamirensis. AB - 16S rRNA gene sequences of two type strains belonging to different genera within the suborder Corynebacterineae, namely Hoyosella altamirensis and Amycolicicoccus subflavus, show a similarity of 99.8 %. Therefore, in order to clarify their taxonomic relationship, a polyphasic recharacterization under the same conditions was carried out. The peptidoglycan of H. altamirensis NBRC 109631T and A. subflavus NBRC 109087T was of A1gamma type with meso-diaminopimelic acid as their diagnostic diamino acid. Both strains contained MK-8 as the only detected menaquinone, C16 : 0 and C18 : 1omega9c as the major fatty acids, and diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol as the principal polar lipids. The coincidences of these chemotaxonomic features suggested that H. altamirensis and A. subflavus should be assigned to the same genus. Meanwhile, the average nucleotide identity value between both strains and the results of physiological and biochemical tests indicated that H. altamirensis and A. subflavus should be affiliated to different species. Therefore, according to Rules 38 and 41a of the Bacteriological Code, it is proposed that Amycolicicoccus subflavus Wang et al. 2010 be reclassified as Hoyosella subflava comb. nov. (type strain DQS3-9A1T=CGMCC 4.3532T=DSM 45089T=JCM 17490T=NBRC 109087T) and the descriptions of the genus HoyosellaJurado et al. 2009 and Hoyosella altamirensisJurado et al. 2009 are emended accordingly. PMID- 27514930 TI - Reduced Graphene Oxide Membranes for Ultrafast Organic Solvent Nanofiltration. AB - Solvated reduced graphene oxide (S-rGO) membranes are stable in organic solvents, and strong acidic, alkaline, or oxidative media. They show high rejections to small molecules with charges the same as that of S-rGO coatings or neutral molecules larger than 3.4 nm, while retaining their high permeances to organic solvents. PMID- 27514931 TI - Acute and long-term outcomes of percutaneous balloon aortic valvuloplasty for the treatment of severe aortic stenosis. AB - OBJECTIVES: This study aimed to evaluate the indications, short- and long-term outcomes of balloon aortic valvuloplasty (BAV) in patients with severe aortic stenosis (AS). METHODS: A cohort of 112 patients with AS underwent 114 BAV procedures between October 2012 and July 2015 in two Polish interventional cardiology centers. Clinical and echocardiographic data were prospectively collected within 1, 6, and 12 months follow-up. RESULTS: BAV was performed as a bridge to TAVI (51.8%), surgical aortic valve replacement (AVR, 5.4%), before urgent noncardiac surgery (8.0%), for symptom relief (33.0%) and cardiogenic shock (1.8%). Periprocedural, in-hospital, 1-, 6-, 12-month mortality were 2.7%; 8.9%; 8.9%; 16.9%; 22.3%, respectively. Serious periprocedural adverse events occurred in 18.8% of patients. After the procedure, mean aortic valve area (AVA) increased from 0.59 +/- 0.18 to 0.82 +/- 0.24 cm2 , mean peak aortic valve gradient (pAVG) decreased from 94.0 +/- 27.6 to 65.4 +/- 20.0 mm Hg, mean aortic gradient decreased from 58.0 +/- 17.8 to 40.5 +/- 14.6 mm Hg, P < 0.05 for all. Left ventricular ejection fraction (LVEF) increased from median (interquartile range) of 53.5 (30 - 64) to 60 (45 - 65)% after 1 month (P < 0.05). In patients with impaired left ventricle function (LVEF <40%), LVEF significantly improved (median increase of 16%) after 1 and 6 months (P < 0.05). At 12 months patients had higher AVA, pAVG, and LVEF as compared to baseline (P < 0.05). CONCLUSIONS: BAV is a useful procedure in high-risk AS patients, where achieved effects can be sufficient in bridging patients for TAVI/AVR. (c) 2016 Wiley Periodicals, Inc. PMID- 27514932 TI - European evidence-based (S3) guideline for the treatment of acne - update 2016 - short version. PMID- 27514933 TI - Methods report on the development of the European evidence-based (S3) guideline for the treatment of acne - update 2016. PMID- 27514934 TI - Comparative transcriptome analysis of basal and zygote-located tip regions of peanut ovaries provides insight into the mechanism of light regulation in peanut embryo and pod development. AB - BACKGROUND: Peanut zygotes typically divide a few times to form a pre-embryo before further embryonic development halts under normal day/night photoperiods. Ovary elongation, however, continuesforming a downward growing peg-like structure. When the peg is buried in the soil, embryo development resumes in the darkness. The embryo-located region (ER) of the peg begins to enlarge and form a pod, while the basal region (BR) of the peg has a distinct fate. The molecular mechanisms governing these unique embryo development processes are unknown. RESULTS: In this study, histological analysis demonstrated that from 4 days after pollination to 3 days after soil penetration, the peanut pre-embryo remained morphologically similar. By 9 days after soil penetration, the embryo had changed to a globular embryo. Transcriptome analysis revealed differentially expressed genes in the ER and BR before and after peg soil penetration. In addition to light signaling and plant hormone metabolism genes, we identified differentially expressed genes in the ER that contribute to embryo development and pod formation processes, including MADS-box transcription factors, xyloglucan endotransglucosylase/hydrolase protein, cellulose synthase, homeobox-leucine zipper (HD-Zip) protein family genes, amino acid permease, and seed growth and embryo morphogenesis regulators (DA1, TCP3, and YABBY). CONCLUSIONS: A large number of genes were found to be differentially expressed in the ER and BR across three developmental peg stages. Exact changes in gene expression were also identified in the ER during early embryo and pod development. This information provides an expanded knowledgebase for understanding the mechanisms of early peanut pod formation. PMID- 27514935 TI - PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly. AB - RATIONALE: The molecular mechanism by which ATP-binding cassette transporter A1 (ABCA1) mediates cellular binding of apolipoprotein A-I (apoA1) and nascent high density lipoprotein (HDL) assembly is not well understood. OBJECTIVE: To determine the cell surface lipid that mediates apoA1 binding to ABCA1-expressing cells and the role it plays in nascent HDL assembly. METHODS AND RESULTS: Using multiple biochemical and biophysical methods, we found that apoA1 binds specifically to phosphatidylinositol (4,5) bis-phosphate (PIP2). Flow cytometry and PIP2 reporter-binding assays demonstrated that ABCA1 led to PIP2 redistribution from the inner to the outer leaflet of the plasma membrane. Enzymatic cleavage of cell surface PIP2 or decreased cellular PIP2 by knockdown of phosphatidylinositol-5-phosphate 4-kinase impaired apoA1 binding and cholesterol efflux to apoA1. PIP2 also increased the spontaneous solubilization of phospholipid liposomes by apoA1. Using site-directed mutagenesis, we found that ABCA1's PIP2 and phosphatidylserine translocase activities are independent from each other. Furthermore, we discovered that PIP2 is effluxed from cells to apoA1, where it is associated with HDL in plasma, and that PIP2 on HDL is taken up by target cells in a scavenger receptor-BI-dependent manner. Mouse plasma PIP2 levels are apoA1 gene dosage-dependent and are >1 MUM in apoA1 transgenic mice. CONCLUSIONS: ABCA1 has PIP2 floppase activity, which increases cell surface PIP2 levels that mediate apoA1 binding and lipid efflux during nascent HDL assembly. We found that PIP2 itself is effluxed to apoA1 and it circulates on plasma HDL, where it can be taken up via the HDL receptor scavenger receptor-BI. PMID- 27514936 TI - Testing the impact of local alcohol licencing policies on reported crime rates in England. AB - BACKGROUND: Excessive alcohol use contributes to public nuisance, antisocial behaviour, and domestic, interpersonal and sexual violence. We test whether licencing policies aimed at restricting its spatial and/or temporal availability, including cumulative impact zones, are associated with reductions in alcohol related crime. METHODS: Reported crimes at English lower tier local authority (LTLA) level were used to calculate the rates of reported crimes including alcohol-attributable rates of sexual offences and violence against a person, and public order offences. Financial fraud was included as a control crime not directly associated with alcohol abuse. Each area was classified as to its cumulative licensing policy intensity for 2009-2015 and categorised as 'passive', low, medium or high. Crime rates adjusted for area deprivation, outlet density, alcohol-related hospital admissions and population size at baseline were analysed using hierarchical (log-rate) growth modelling. RESULTS: 284 of 326 LTLAs could be linked and had complete data. From 2009 to 2013 alcohol-related violent and sexual crimes and public order offences rates declined faster in areas with more 'intense' policies (about 1.2, 0.10 and 1.7 per 1000 people compared with 0.6, 0.01 and 1.0 per 1000 people in 'passive' areas, respectively). Post-2013, the recorded rates increased again. No trends were observed for financial fraud. CONCLUSIONS: Local areas in England with more intense alcohol licensing policies had a stronger decline in rates of violent crimes, sexual crimes and public order offences in the period up to 2013 of the order of 4-6% greater compared with areas where these policies were not in place, but not thereafter. PMID- 27514937 TI - Levodopa/carbidopa intestinal gel therapy for advanced Parkinson Disease: AN early toxic effect for small nerve fibers? AB - INTRODUCTION: Peripheral neuropathy related to levodopa/carbidopa intestinal gel (LCIG) therapy for advanced Parkinson disease (PD) is under investigation and is debated in the literature. The purpose of the study was to detect whether small nerve fibers are damaged during LCIG infusion. METHODS: Five advanced PD patients were enrolled prior to starting LCIG infusion. Six PD patients on oral levodopa (LD) treatment and 6 PD patients naive to LD were also enrolled. Clinical examination, the Quantitative Sensory Testing battery testing, nerve conduction studies, and intraepidermal nerve fiber density examinations were collected at baseline and at 3, 6, and 12 months after LCIG infusion was started in the study cohort. RESULTS: After 3, 6, and 12 months, severe skin denervation and increased thermal thresholds were observed in the LCIG group. CONCLUSIONS: Significant damage to small nerve fibers was detected in PD patients soon after LCIG infusion had started, suggesting careful monitoring of small fiber impairment during LCIG is needed. Muscle Nerve, 2016 Muscle Nerve 54: 970-972, 2016. PMID- 27514938 TI - Usefulness of plain radiography for assessing hypouricemic treatment response in patients with tophaceous gout. AB - AIM: To investigate whether plain radiography is useful for assessing the changes in gouty tophi size following hypouricemic therapy. METHODS: Gout was diagnosed according to the American College of Rheumatology criteria. Before and after hypouricemic treatment, serum uric acid level was measured, and plain radiography was performed to measure gouty tophi size. The tophi were graded by measuring the maximum vertical and horizontal diameters, and they were scored by adding up the scores of the grades. The vertical diameter was measured on both sides of the proximal phalanges (PPs). The horizontal diameter was measured on the lateral side of the PPs. The maximum vertical diameter measurement was graded 0-4. The maximum horizontal diameter measurement was graded 0-3. RESULTS: Seven hundred first metatarsal phalangeal joints (MTPJ) of 350 patients with gout were assessed for gouty tophi. Tophi were observed using plain radiography in 174 MTPJs (24.9%) of 109 patients (31.1%). Follow-up plain radiography was performed in 60 of these patients. Before the treatment, the average serum uric acid level of these patients was 8.3 +/- 1.9 mg/dL, and the average tophi score was 3.7 +/- 2.5. After hypouricemic treatment, the uric acid level decreased to 5.9 +/- 1.6 mg/dL (P < 0.05), and the average tophi score decreased to 1.5 +/- 1.8 (P < 0.05). CONCLUSIONS: This new method for measuring gouty tophi using plain radiography may be useful for evaluating changes in gouty tophi size following hypouricemic treatment. PMID- 27514939 TI - 3D implementation of the symbol nomenclature for graphical representation of glycans. PMID- 27514940 TI - Feasibility of Intraoperative Extubation in Pediatric Heart Transplantation. AB - Based on described benefits of fast-tracking and early extubation in children undergoing congenital heart surgery, we applied this concept to selected children following uncomplicated orthotopic heart transplantation (OHT). In this case series, we report four patients who were extubated immediately after surgery in the operating room. A mild respiratory acidosis and hypercapnia were noted on the initial arterial blood gases, were well tolerated, and were normalized within 6 to 12 hours. There was no mortality among patients who were extubated in the operating room, and no patients required reintubation. We conclude that operating room extubation is feasible in selected patients undergoing OHT. PMID- 27514941 TI - Adolescent Femoroacetabular Impingement: Gender Differences in Hip Morphology. AB - PURPOSE: To compare the hip morphology of adolescent male patients and female patients who underwent hip arthroscopy for femoroacetabular impingement (FAI) and determine if gender differences exist. METHODS: We retrospectively reviewed the records of 177 adolescents, aged 13 to 18 years, who were treated for FAI with hip arthroscopy. We examined and analyzed preoperative magnetic resonance imaging (MRI) scans and plain radiographs, measuring the lateral center-edge angle, Tonnis angle, and alpha angle. The intraclass correlation coefficient between readers was calculated. We created multiple linear regression models incorporating age, gender, and body mass index (BMI) with the radiographic measurements. Intraoperative findings using the Outerbridge grading system, as well as procedure performed, were documented. We compared these findings with our preoperative imaging measurements using the chi2 test and the Wilcoxon rank sum test. RESULTS: The intraclass correlation coefficient showed moderate to strong agreement between the 3 image readers. The BMI- and age-adjusted mean alpha angle was higher in male patients than female patients on both plain radiographs (55.9 degrees vs 45.2 degrees , P < .0001) and axial oblique MRI scans (54.1 degrees vs 42.5 degrees , P < .0001). An alpha angle greater than 55 degrees was found in 38.9% of male patients compared with only 1% of female patients (P < .0001). The lateral center-edge angle and Tonnis angle on MRI scans and plain radiographs displayed no statistically significant differences between genders after we controlled for BMI and age. Male patients were more likely to have chondral damage intraoperatively than female patients (56.3% vs 32.5%, P = .0041). CONCLUSIONS: Distinct differences between genders were seen both on preoperative imaging and at the time of hip arthroscopy. We found that male patients with FAI displayed a larger mean alpha angle, and therefore a more severe cam-type deformity, than female patients. Our study also found that male patients were more likely to show evidence of chondral damage than female patients at the time of surgery. LEVEL OF EVIDENCE: Level IV. PMID- 27514942 TI - Return to Play of Rugby Players After Anterior Cruciate Ligament Reconstruction Using Hamstring Autograft: Return to Sports and Graft Failure According to Age. AB - PURPOSE: To assess return to play and the frequencies of graft failure in rugby players after anterior cruciate ligament (ACL) reconstruction using a hamstring autograft augmented with an artificial ligament and to compare outcomes between rugby players aged <20 and >=20 years over the long term. METHODS: A consecutive series of 146 rugby players who underwent ACL reconstruction with a hamstring autograft augmented with an artificial ligament were retrospectively reviewed. The study population was further divided into 2 groups aged <20 years and >20 years and compared. RESULTS: Twenty-five patients could not be followed up, and 121 (83%) were evaluated. Most patients (90%, <20 years; 92%, >=20 years) returned to play after ACL reconstruction. At an average follow-up period of 56.5 months, 16% of the patients sustained an ACL graft rupture. Regarding age, <20 years (n = 58, 48%) and >=20 years (n = 63, 52%), younger players had a significantly higher failure rate (23% vs 5%, respectively; P = .006) and a shorter time to failure (22.8 +/- 13.2 vs 35.4 +/- 15.4 months, respectively; P = .006) than older players. CONCLUSIONS: Rugby players were likely to return to play after ACL reconstruction with a hamstring autograft. However, there was a higher risk of graft failure in younger players than in older players. On the basis of this study, we conclude that the hamstring autograft may not be an appropriate graft source to use in a younger active population, including rugby players. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 27514943 TI - Knotless Suture Anchor With Suture Tape Quadriceps Tendon Repair Is Biomechanically Superior to Transosseous and Traditional Suture Anchor-Based Repairs in a Cadaveric Model. AB - PURPOSE: To compare the biomechanical properties of a knotless suture anchor with suture tape quadriceps tendon repair technique with transosseous and suture anchor repair techniques. METHODS: Twenty matched pairs of cadaveric knees underwent a quadriceps tendon avulsion followed by repair via the use of transosseous tunnels with #2 high-strength sutures, 5.5-mm biocomposite fully threaded suture anchors with #2 high-strength sutures, or 4.75-mm biocomposite knotless suture anchors with suture tape. Ten knees were repaired via transosseous repair and 10 via fully threaded suture anchor repair, and their matched specimens were repaired with suture tape and knotless anchors. Biomechanical analysis included displacement during cyclic loading over 250 cycles, construct stiffness, ultimate load to failure, and failure mode analysis. RESULTS: Compared with transosseous repairs, quadriceps tendons repaired with knotless suture tape demonstrated significantly less displacement during cyclic loading (cycles 1-20 3.6 +/- 1.3 vs 6.3 +/- 1.9 mm, P = .003; cycles 20-250 2.0 +/- 0.4 vs 3.1 +/- 0.9 mm, P = .011), improved construct stiffness (67 +/- 25 vs 26 +/- 12 N/mm, P = .001), and greater ultimate load to failure (616 +/- 149 vs 413 +/- 107 N, P = .004). Our repair technique also demonstrated improved biomechanical parameters compared with fully threaded suture anchor repair in initial displacement during cyclic loading (cycles 1-20 3.0 +/- 0.8 vs 5.1 +/- 0.9 mm, P < .001), construct stiffness (62 +/- 20 vs 28 +/- 10 N/mm, P = .001) and ultimate load to failure (579 +/- 129 vs 399 +/- 87 N, P = .006). CONCLUSIONS: Repair of quadriceps tendon ruptures with this knotless suture anchor with suture tape repair technique is biomechanically superior in cyclic displacement, construct stiffness, and ultimate load to failure compared with transosseous and fully threaded suture anchor techniques in cadaveric specimens. CLINICAL RELEVANCE: The demonstration that our repair technique is biomechanically superior to previously described techniques in a cadaveric setting suggests that consideration should be given to this technique. PMID- 27514944 TI - Behavioural biomarkers of typical Rett syndrome: moving towards early identification. AB - The dynamic course of Rett syndrome (RTT) is still said to begin with a period of apparently normal development although there is mounting evidence that individuals with RTT show behavioural peculiarities and abnormalities during their infancy. Their spontaneous general movements are abnormal from birth onwards. Normal cooing vocalisation and canonical babbling (if at all required) are interspersed with abnormalities such as proto-vowel and proto-consonant alternations produced on ingressive airstream, breathy voice characteristics, and pressed or high-pitched vocalisations. The gestural repertoire is limited. Certain developmental motor and speech-language milestones are not at all acquired or show a significant delay. Besides abnormal blinking, repetitive and/or long lasting tongue protrusion, and bizarre smiling, there are already the first body and/or hand stereotypies during the first year of life. We are currently on a promising way to define a specific set of behavioural biomarkers pinpointing RTT. PMID- 27514945 TI - Metabolomics in cardiovascular medicine: Not personalised, not diagnostic. PMID- 27514946 TI - Treatment for hepatitis C virus infection in India: Promising times. PMID- 27514947 TI - The changing face of community-acquired methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of infection, both in hospitalised patients with significant healthcare exposure and in patients without healthcare risk factors. Community-acquired methicillin resistant S. aureus (CA-MRSA) are known for their rapid community transmission and propensity to cause aggressive skin and soft tissue infections and community acquired pneumonia. The distinction between the healthcare-associated (HA)-MRSA and CA-MRSA is gradually fading owing to the acquisition of multiple virulence factors and genetic elements. The movement of CA-MRSA strains into the nosocomial setting limits the utility of using clinical risk factors alone to designate community or HA status. Identification of unique genetic characteristics and genotyping are valuable tools for MRSA epidemiological studies. Although the optimum pharmacotherapy for CA-MRSA infections has not been determined, many CA MRSA strains remain broadly susceptible to several non-beta-lactam antibacterial agents. This review aimed at illuminating the characteristic features of CA-MRSA, virulence factors, changing clinical settings and molecular epidemiology, insurgence into the hospital settings and therapy with drug resistance. PMID- 27514948 TI - Endemic Indian clones of Klebsiella pneumoniae-harbouring New Delhi metallo-beta lactamase-1 on a hybrid plasmid replicon type: A case of changing New Delhi metallo-beta-lactamase plasmid landscapes in India? AB - PURPOSE: blaNDM genes are MBL genes that confer resistance to carbapenems. Globally, they are associated with diverse clones and plasmids. In this study, we characterised three isolates of Klebsiella pneumoniae-harbouring blaNDM1 from patients undergoing chronic haemodialysis and renal transplantation. MATERIALS AND METHODS: 3 blaNDM1 -producing K. pneumoniae were isolated from end-stage renal disease patients undergoing haemodialysis and renal transplantation from a nephrology unit. All the three isolates were screened for clinically relevant resistant genes. Plasmid replicon content was analysed by polymerase chain reaction based replicon typing. Conjugation assays were done using azide resistant Escherichia coli J53 as the recipient strain. Multilocus sequence typing and variable number tandem repeat typing were done to find the clonality. Replicon sequence based typing was attempted to find the diversity of replicon associated sequences in IncHI3 plasmids. RESULTS: All the 3 blaNDM positive isolates possessed the New Delhi metallo-beta-lactamase-1 (NDM-1) allele with an IncHI3 plasmid which was not transferable in one isolate. The isolates were found to be sequence type 14 (ST14; 2 nos) and ST38 both of which were previously reported to be the NDM-producing K. pneumoniae STs prevalent in India. Replicon sequence analysis revealed limited sequence diversity within the repHI3 and repFIB locus. CONCLUSION: To the best of our knowledge, this is the first report of IncHI3, a newly assigned enterobacterial plasmid incompatibility group from India. This could either be a case of importation or a widely circulating NDM plasmid type in India. PMID- 27514949 TI - Scrub typhus and spotted fever among hospitalised children in South India: Clinical profile and serological epidemiology. AB - BACKGROUND: Rickettsial infections are re-emerging. In India, they are now being reported from several areas where they were previously unknown. OBJECTIVES: The objective of this study was to describe the epidemiology, clinical profile and outcome of serologically-confirmed scrub typhus and spotted fever among children in a tertiary care hospital in Bengaluru. MATERIALS AND METHODS: Hospitalised children aged <18 years, with clinical features suggestive of rickettsial disease admitted between January 2010 and October 2012 were included prospectively. Diagnosis was based on scrub typhus and spotted fever-specific IgM and IgG by enzyme-linked immunosorbent assay (ELISA). RESULTS: Of 103 children with clinical features suggestive of rickettsial illness, ELISA test confirmed 53 cases for scrub typhus, 23 cases for spotted fever group and 14 with mixed infection. The average age was 7.3 (+/-3.9) years and 44 (71.0%) children were male. Majority of cases were from Karnataka (50%), Andhra Pradesh (32.3%) and Tamil Nadu (17.7%). Common clinical features included fever (100%, average duration 11 days), nausea and vomiting (44%), rash (36%); eschar was rare. Compared to the ELISA test, Weil Felix test (OX-K titre of 1:80) had a sensitivity and specificity of 88.7% and 43.9%, respectively. Treatment with chloramphenicol or doxycycline was given to the majority of the children. Complications included meningoencephalitis (28%), shock (10%), retinal vasculitis (10%) and purpura fulminans (7%). CONCLUSIONS: These findings suggest that the burden of rickettsial infection among children in India is high, with a substantially high complication rate. Rickettsial-specific ELISA tests can help in early diagnosis and early institution of appropriate treatment that may prevent life-threatening complications. PMID- 27514950 TI - Human leucocyte antigen Class I and II alleles associated with anti-hepatitis C virus-positive patients of North India. AB - PURPOSE: Humans are the only known natural hosts of hepatitis C virus (HCV). This study was undertaken to examine the frequencies of human leucocyte antigens (HLAs) Class I and Class II genotype profiles in anti-HCV-infected patients of Northern India. MATERIALS AND METHODS: From a period of January 2013 to August 2014, 148 anti-HCV-positive patients of North India referred to the Department of Molecular Biology and Transplant Immunology, Indraprastha Apollo Hospitals, New Delhi, for performing HLA typing were included in the study. RESULTS: AFNx0102, AFNx0131 allele frequency decreased significantly in anti-HCV-positive patients. Frequencies for HLA-B loci did not reach any statistical significance. Among the Class II alleles, HLA-DRB1FNx0103 and HLA-DRB1FNx0110 were significantly higher in the patient population, and HLA-DRB1FNx0115 was significantly decreased in the patient population as compared to the controls. CONCLUSION: HLA-AFNx0133 was significantly increased as compared to control population and showed geographic variation in HCV-infected individuals of India. PMID- 27514951 TI - Distribution of Class II integrons and their contribution to antibiotic resistance within Enterobacteriaceae family in India. AB - BACKGROUND: Integrons are the main contributors to the development of multidrug resistance (MDR) among Gram-negative bacilli. There is a lack of knowledge about the molecular relation between gene cassettes and antibiotic resistance in India. OBJECTIVE: In this study, we have investigated the occurrence of Class II integron and their cassette array among Enterobacteriaceae. MATERIALS AND METHODS: A total of 268 MDR non-duplicate strains of Enterobacteriaceae were collected from Silchar Medical College and Hospital, Silchar, Assam, India, during June 2012 to May 2013. Polymerase chain reaction was performed for detection of the integrase genes and gene cassettes within the Class II integron which were further analysed by sequencing. RESULTS: Class II integron was observed in 47 isolates. Four different gene cassette arrangements were detected: dfrA1-sat2-aadA1; dfrA1-sat2-aadA1-orfX-ybeA-ybfA-ybfB-ybgA; dfrA12-sat2-aadA1; and dfrA1-linF-aadA1. The most prevalent cassette combination was dfrA1-sat2 aadA1. This study has also identified a set of gene cassette associated with linF gene instead of sat2 gene. CONCLUSION: Further investigation is required to determine the current situation and important reservoir of Class II integron for the transmission of drug resistance among Enterobacteriaceae and their contribution to antimicrobial resistance in hospital environment . PMID- 27514952 TI - Identification, antifungal resistance profile, in vitro biofilm formation and ultrastructural characteristics of Candida species isolated from diabetic foot patients in Northern India. AB - PURPOSE: Diabetic foot ulcers are a serious cause of diagnostic and therapeutic concern. The following study was undertaken to determine the fungal causes of diabetic foot ulcers, with their phenotypic and genotypic characterisation. MATERIALS AND METHODS: A total of 155 diabetic foot ulcers were studied for 1 year. Deep tissue specimen was collected from the wounds, and crushed samples were plated on Sabouraud dextrose agar with chloramphenicol (0.05 g). Identification was done by growth on cornmeal agar, germ tube formation and urease test. For molecular identification, conserved portion of the 18S rDNA region, the adjacent internal transcribed spacer 1 (ITS1) and a portion of the 28S rDNA region were amplified, using the ITS1 and ITS2 primers. Antifungal susceptibility against voriconazole, fluconazole and amphotericin B was determined by standard broth microdilution method. Biofilm formation was studied in three steps. First, on the surface of wells of microtiter plates followed by quantification of growth by fungal metabolism measurement. Finally, biofilms were analysed by scanning electron microscopy (SEM). RESULTS: Fungal aetiology was found in 75 patients (48.38%). All were identified as Candida species (100%). The prevalence of different species was Candida tropicalis (34.6%), Candida albicans (29.3%), Candida krusei (16.0%), Candida parapsilosis (10.6%), Candida glabrata (9.33%). All were susceptible to amphotericin B (100%). On microtiter plate, all the isolates were viable within 48 h showing biofilms. The metabolic activity of cells in the biofilm increased with cellular mass, especially in the first 24 h. On SEM, majority showed budding yeast form. CONCLUSION: Non-albicans Candida spp. with potential biofilm forming ability are emerging as a predominant cause of diabetic foot ulcers. PMID- 27514953 TI - Presence of viable Mycobacterium leprae in environmental specimens around houses of leprosy patients. AB - PURPOSE: Leprosy is a chronic systemic infectious disease caused by Mycobacterium leprae, one of the first organisms to be established as the cause for disease in humans. Because of high prevalence pockets of leprosy in the endemic regions, it is necessary to identify the possible sources of M. leprae in the environment and its mode of transmission. MATERIALS AND METHODS: Slit skin smears (SSSs) from lesions were collected in 70% ethanol from 50 leprosy cases staying in the leprosy resettlement village and hospital from a high endemic area. One hundred and sixty soil samples were collected from different areas around the leprosy hospital and from the resettlement village of cured leprosy patients where active cases also resided at the time of sample collection. M. leprae specific gene region (RLEP 129 bp) and 16S rRNA targets were used for polymerase chain reaction (PCR) based detection for the presence and viability of M. leprae. An rpoT region was also amplified to determine presence of numbers of 6 bp tandem repeats. RESULTS: All the SSS samples collected from patients showed three copies of rpoT region (6 bp tandem repeat, an ancient Indian type). Fifty-two soil samples showed presence of M. leprae DNA whereas M. leprae specific 16S rRNA gene was amplified in sixteen of these samples. PCR amplification and fragment length analysis showed 91 bp, i.e., three copies of the rpoT 6 bp tandem repeats from soil samples and similar three copies observed in patient samples. CONCLUSION: Presence of viable M. leprae in the soil having same rpoT genotype of M. leprae noted in patients suggests that it could be the same strain of M. leprae. M. leprae found in the soil could be the one that is excreted out by the patient. Significance of its viability in the environment and its pathogenicity with respect to transmission needs to be further explored. Findings of this study might provide possible insights for further exploration into understanding transmission patterns in leprosy and also will throw light on identifying potential for existence of extra human source or reservoirs of M. leprae, if any. PMID- 27514954 TI - Loop-mediated isothermal amplification assay for detection of Mycobacterium tuberculosis complex in infertile women. AB - BACKGROUND: Female genital tuberculosis (FGTB) has a profound impact on the reproductive health of patients including infertility. Conventional diagnostic techniques have low sensitivity and specificity as well as long turnaround time. There is a need of developing newer, rapid and practically adaptable technique, especially in low-income countries. OBJECTIVE: To standardize and evaluate loop mediated isothermal amplification (LAMP) technique for diagnosis of FGTB. METHODS: A total of 300 endometrial biopsy samples from infertile females were subjected to Ziehl-Neelsen (ZN) staining, Lowenstein-Jensen culture, automated culture (BACTEC mycobacterial growth indicator tube), histopathological examination (HPE), nucleic acid amplification by polymerase chain reaction (PCR) and LAMP technique. Composite gold standard (either smear/culture/HPE/PCR positive) was considered for calculation of outcome parameters. RESULTS: The observed sensitivities of ZN smear, culture, HPE, PCR and LAMP were 2.94%, 10.29%, 8.82%, 95.59% and 66.18%, respectively. Overall concordance between PCR and LAMP was 63%, which shows a good agreement. CONCLUSION: This study is the first to evaluate LAMP in the diagnosis of FGTB and found it to be a rapid and convenient technique, especially in low resource endemic settings. PMID- 27514955 TI - Prevalence of high-risk human papilloma virus types and cervical smear abnormalities in female sex workers in Chandigarh, India. AB - PURPOSE: Cervical cancer is the most common cancer among women in developing nations. Nearly 90% of the cases have been linked to the presence of high-risk human papillomavirus (hrHPV) types 16 and 18. The risk of cervical cancer may be high in female sex workers (FSWs) due to multiple sexual partners. This study aimed to determine the prevalence of cytological abnormalities and hrHPV types 16 and 18 in FSWs in Chandigarh, North India using the liquid-based cytology (LBC) approach. MATERIALS AND METHODS: The cervical brush samples were collected from 120 FSW and 98 age-matched healthy controls (HCs). These were subjected to pap smear using conventional method, LBC and the detection of hrHPV types 16 and 18 was carried out using polymerase chain reaction. RESULTS: The LBC samples showed better cytological details and also reduced the number of unsatisfactory smears from 11% in Pap to 1.5% in the LBC. A significantly higher number of inflammatory smears were reported in FSWs (51.7% vs. 34.7%, P = 0.01). The hrHPV types 16/18 were detected in 33/120 (27.5%) FSW versus 23/98 (23.5%) HCs. The risk of acquiring hrHPV was higher in FSWs, who had age at first sex <=25 years, higher income and the habit of smoking. CONCLUSION: The high prevalence of hrHPV among FSWs and HCs suggests the need for the implementation of effective National Screening Programme for early detection of hrHPV types to decrease the burden of cervical cancer, especially in high-risk population. PMID- 27514956 TI - Association of interleukin-28B rs12979860 and rs8099917 polymorphisms with sustained viral response in hepatitis C virus genotype 1 and 3 infected patients from the Indian subcontinent. AB - BACKGROUND: Polymorphisms of the IL28B gene (rs12979860 and rs8099917) have been shown to impact treatment responses in hepatitis C virus (HCV) infected patients. The association of these polymorphisms with sustained viral response (SVR) has been studied in HCV genotype 3 infected patients in India, but not in genotype 1. OBJECTIVES: This study aimed to determine the association of IL28B gene polymorphisms and other host and viral factors with treatment response in patients with HCV genotype 1 and 3 infection. MATERIALS AND METHODS: DNA from 42 HCV-infected patients on antiviral therapy was analysed for the IL28B polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Bidirectional sequencing was performed on a subset of samples for verification of PCR-RFLP results. Information on age, weight, height, diabetic status, pre-treatment viral load and alanine aminotransferase (ALT) levels was obtained from clinical records. The IL28B genotypes and the other factors were analysed for their association with SVR. RESULTS: The frequency distribution of rs12979860 CC/CT/TT genotypes was found to be 66.7%, 26.2% and 7.1%, respectively. For rs8099917 genotype, the TT/GT/GG distribution was 73.8%, 21.4% and 4.8%, respectively. SVR was seen in 61.9% of cases (55.6% in genotype 1 and 62.5% in genotype 3). CC genotype at rs12979860 and TT genotype at rs8099917 were significantly higher in responders (P = 0.013 and 0.042, respectively). Lower baseline ALT and rapid viral response were also found to be associated with SVR. On logistic regression analysis, CC genotype at rs12979860 emerged as the most powerful predictor of treatment response. CONCLUSION: IL28B polymorphisms are strong predictors of SVR in patients from the Indian subcontinent infected with HCV genotype 3 and genotype 1. PMID- 27514957 TI - Antimicrobial susceptibility testing of Brucella melitensis isolated from patients with acute brucellosis in a centre of Iran. AB - Structured to Purpose: Human brucellosis is one of the most common zoonotic infections worldwide, which remains one of the major problems for public health. Despite the World Health Organization's recommendation for human brucellosis treatment, sporadic cases of relapse have been reported. The aim of this study was to assess the susceptibility of Brucella isolates to common antibiotics that are prescribed by the physician for the treatment of brucellosis and also to determine the minimum inhibitory concentration 50% (MIC 50 ) and MIC 90 for these antibiotics. MATERIALS AND METHODS: Forty-eight Brucella strains were collected from patients with acute brucellosis. Species identification was made based on the conventional methods. MIC of rifampin, doxycycline, ciprofloxacin, trimethoprim- sulfamethoxazole, streptomycin, azithromycin and ceftriaxone was determined by E-test. RESULTS: All the 48 Brucella isolates (47 blood samples and one synovial fluid) were identified as Brucella melitensis. No antimicrobial resistant strains were recognised. Trimethoprim-sulfamethoxazole had the lowest MIC 50 (0.016 MUg/ml) and MIC 90 (0.064 MUg/ml), whereas MIC 50 and MIC 90 of streptomycin and azithromycin had the highest level at 0.625, 1.5 ug/ml and 0.25, 1 ug/ml, respectively. All the isolates were susceptible to rifampin, and only one of the isolates had a reduced sensitivity to rifampin (1 MUg/ml). CONCLUSIONS: Although all the Brucella isolates were susceptible, antimicrobial susceptibility test should be recommended in patients with recurrent brucellosis or life-threatening organ involvement. PMID- 27514958 TI - Reduced susceptibility to chlorhexidine disinfectant among New Delhi metallo-beta lactamase-1 positive Enterobacteriaceae and other multidrug-resistant organisms: Report from a tertiary care hospital in Karachi, Pakistan. AB - We analysed susceptibility of multidrug-resistant organisms (MDROs) including New Delhi metallo-beta-lactamase-1 positive Enterobacteriaceae to chlorhexidine and compared results to their susceptible counterparts. Susceptibilities of chlorhexidine digluconate in a standard (CHX-S) preparation and two commercial disinfectants containing different CHX concentrations (2% w/v and 4% w/w) were performed. MDROs had narrower range of higher CHX-S minimum inhibitory concentrations (MICs) as compared to pan-sensitive organisms. The MIC values for commercial disinfectants products for MDROs were many folds higher (20-600 times), than CHX-S for in vitro use. Increasing antibiotic resistance among bacterial isolates can be an indirect marker of reduced susceptibility to chlorhexidine in hospital setting. PMID- 27514959 TI - Distribution of genes encoding aminoglycoside-modifying enzymes among clinical isolates of methicillin-resistant staphylococci. AB - The objective of this study was to determine the distribution of genes encoding aminoglycoside-modifying enzymes (AMEs) and staphylococcal cassette chromosome mec (SCCmec) elements among clinical isolates of methicillin-resistant staphylococci (MRS). Antibiotic susceptibility test was done using Kirby-Bauer disk diffusion method. The presence of SCCmec types and AME genes, namely, aac (6')-Ie-aph (2''), aph (3')-IIIa and ant (4')-Ia was determined using two different multiplex polymerase chain reaction. The most encountered AME genes were aac (6')-Ie-aph (2'') (55.4%) followed by aph (3')-IIIa (32.3%) and ant (4') Ia gene (9%). SCCmec type I (34%) was predominant in this study. In conclusion, the aac (6')-Ie-aph (2'') was the most common AME gene and SCCmec type I was most predominant among the MRS isolates. PMID- 27514960 TI - The antibiotics of choice for the treatment of melioidosis in Indian set up. AB - Therapeutic options for the treatment of melioidosis caused by Burkholderia pseudomallei are limited due to the inherent resistance conferred by this pathogen to various groups of antibiotics. Witnessing an increase in the number of microbiological culture-confirmed cases of melioidosis at our settings in the past few years, we undertook this study to estimate the minimum inhibitory concentrations of clinical isolates of B. pseudomallei against the four commonly employed antimicrobial agents in the patient management at our settings, namely, ceftazidime, meropenem, trimethoprim-sulfamethoxazole and doxycycline. All isolates were susceptible to the antibiotics tested, except for one isolate which showed resistance to doxycycline (minimum inhibitory concentration [MIC]: 32 MUg/ml). MIC50 and 90 for all the four antibiotics were estimated. From this study, we conclude that the clinical isolates of B. pseudomallei from the southern part of India are well susceptible to the commonly employed antimicrobial agents for therapy. PMID- 27514961 TI - Reduced susceptibility of carbapenem-resistant Klebsiella pneumoniae to biocides: An emerging threat. AB - Dealing with carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strains, which are generally pan-drug resistant, is an uphill task for health care professionals. Owing to limited therapeutic options and the possibility of development of resistance to commonly used biocides in hospital settings, CR-Kp infections pose a serious threat of emergence of a dreaded pandemic. The aim of the study was to highlight the possibility of emergence of biocide resistance among CR-Kp strains. A case study was conducted in a Super-specialty Hospital in September 2015. A 65-year-old female patient post-laparotomy was admitted to the General Intensive Care Unit of a Super-specialty Hospital. CR-Kp was isolated from the blood and mucus trap samples of this patient. Susceptibility testing of three commonly used biocides in our hospital, namely sodium hypochlorite (4% available chlorine), 5% w/v povidone iodine (0.5% w/v of available iodine) and absolute ethanol (99.9%), respectively, was carried out using K. pneumoniae ATCC 700603 as control. The test isolate showed reduced susceptibility to sodium hypochlorite in comparison to K. pneumoniae ATCC 700603. The possibility of emergence of biocide resistance among CR-Kp strains poses a threat of disrupting our ongoing efforts for implementation of effective infection control measures. PMID- 27514962 TI - Multidrug resistance mediated by co-carriage of extended-spectrum beta lactamases, AmpC and New Delhi metallo-beta-lactamase-1 genes among carbapenem resistant Enterobacteriaceae at five Indian medical centres. AB - In this study, we evaluated the coexistence of extended-spectrum beta-lactamases (ESBL), AmpC and New Delhi metallo-beta-lactamase-1 (NDM-1) genes among carbapenem-resistant Enterobacteriaceae (CRE) recovered prospectively from patients at multiple sites. The study included 285 CRE strains from 2782 Gram negative Bacilli collected from multiple centres during 2007-2010, of which 87 were characterised. Standard and reference laboratory methods were used for resistance determination. Detection of blaNDM-1 , blaAmpC , blaTEM , blaSHV and blaCTX-M was done by polymerase chain reaction. High levels of antimicrobial resistance observed among study isolates. Co-carriage of ESBLs, AmpC and NDM-1 was 26.3%. Nosocomial origin among the co-carriage isolates was 64.3%, with 9.2% associated mortality. PMID- 27514963 TI - Epidemiology and patterns of drug resistance among tuberculosis patients in Northwestern Iran. AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) has emerged as an important global health concern and is on the rise throughout the world. OBJECTIVE: The aim of this study was to examine the epidemiology and pattern of TB drug resistance. METHODS: In this cross-sectional study, 180 pulmonary TB patients from two Northwestern provinces of Iran were selected. The first and second line drug susceptibility testing was carried out using the 1% proportion method on the Lphiwenstein-Jensen medium. Full demographic, environmental and clinical history was evaluated. RESULTS: Prevalence of resistance to any TB drug was 13.8%. Eight (4.4%) patients had MDR-TB (2.4% in the province of East Azerbaijan and 9.3% in the province of Ardabil) and one patient had extensively drug-resistant TB. Patient resistance to both isoniazid and streptomycin was the most prevalent at a rate of 8.3%. Patients showed the least resistance to ethambutol (2.8%). There was a significant relationship between the previous history of TB drug treatment and TB drug resistance. Migrants from rural to urban areas were in high-risk groups for the occurrence of TB drug resistance. CONCLUSION: In our study, prevalence of MDR was less than the global average. It is essential to monitor the patients with previous history of TB treatment and migrants by rapid and accurate techniques in terms of drug-resistance odds. PMID- 27514964 TI - Allele-specific duplex polymerase chain reaction to differentiate Mycobacterium abscessus subspecies and to detect highly clarithromycin-resistant isolates. AB - On the basis of the structural differences of erm, we used a duplex polymerase chain reaction (PCR) to differentiate Mycobacterium abscessus subsp. abscessus and subsp. massiliense isolates and to detect the point mutations of 23S rRNA gene that confer a high level of resistance to clarithromycin. Subsp. massiliense strains occupying almost half of the clinical isolates can be simply identified, and their clarithromycin susceptibility can be rapidly determined. PMID- 27514965 TI - A cross-sectional study on aetiology of diarrhoeal disease, India. AB - BACKGROUND: Global, regional and national estimates clearly place diarrhoeal diseases as a major, albeit to an extant neglected public health problem. Deaths of children aged <5 years owing to diarrhoea was estimated to be 1.87 million at the global level (uncertainty range from 1.56 to 2.19 million), which is approximately 19% of total child deaths. OBJECTIVES: The present report is a cross-sectional study undertaken to estimate the role of various aetiological agents causing diarrhoea in North Karnataka and adjoining areas of Maharashtra and Goa. METHODS: Three hundred stool samples were collected from patients seeking health care at KLES Dr. Prabhakar Kore Hospital and Medical Research Centre, Belgaum; and processed for detection of various bacterial, viral and parasitic agents. RESULTS: Bacterial pathogens attributed to 65.7% of diarrhoea cases, followed by viral infection (22%), parasitic infection (16.3%) and infection by Candida spp. (5.6%). The study identified Escherichia coli in general and Enteropathogenic E. coli in particular, and Group A Rotavirus to be the most frequently isolated pathogens among diarrhoea patients. CONCLUSION: The data generated from the current study will help the health officials for better interventional and treatment strategies for diarrhoeal diseases. PMID- 27514966 TI - Noncatheter-related bacteraemia due to Chryseobacterium indologenes in an immunocompetent patient. AB - Chryseobacterium indologenes belongs to a group of nonfermentative Gram-negative bacilli and is an uncommon human pathogen. It causes severe infections such as septicaemia and ventilator-associated pneumonia in immunocompromised patients or after prolonged hospitalisation. We report a case of a noncatheter-related bacteraemia in a 22-year-old immunocompetent female whose blood culture showed the growth of C. indologenes, identified by Vitek GNI system (bioMerieux, France). The patient responded to treatment with ciprofloxacin. The pathogenicity and virulence factors of C. indologenes remain unclear. This case indicates that C. indologenes might cause symptomatic disease in immunocompetent persons with otherwise no associated underlying risk factors. PMID- 27514967 TI - Post-traumatic endophthalmitis caused by Streptococcus parauberis: First human case report. AB - A 12-year-old boy presented with trauma to left eye with a wooden stick. On examination, there was full thickness corneal laceration with cataractous lens behind the laceration. The laceration was sutured, and intravitreal injections of vancomycin, ceftazidime and clindamycin were administered. Vitreous tap grew Streptococcus parauberis. The isolate was sensitive to amoxicillin, erythromycin and vancomycin, and topical vancomycin was used to treat the infection. We present the first case of human post-traumatic infective endophthalmitis caused by the rare agent S. parauberis. PMID- 27514968 TI - A rare glimpse into the morbid world of necrotising fasciitis: Flesh-eating bacteria Vibrio vulnificus. AB - Necrotising fasciitis is one of the fatal skin and soft tissue infections. Vibrio vulnificus is a rare cause of necrotising fasciitis; however, the disease is one of the major manifestations of the bacteria. Here, we report one such case in a middle-aged male patient. He presented with the signs of bilateral lower limb cellulitis and altered sensorium. V. vulnificus was isolated from blood culture and also from debrided tissue. Though the organism is well characterised, it is a rare causative agent of necrotising fasciitis. This case is a re-emphasis on active look out for this bacterium in patients presenting with necrotizsing fasciitis. PMID- 27514969 TI - Outbreak of enteric fever due to Salmonella Paratyphi A variety durazzo (2,12:a: ) in a hilly region of North India: A report of 43 cases. AB - Enteric fever due to Salmonella Paratyphi A (SPA) is a global problem occurring as outbreaks at times. An unusual SPA (2,12:a:-) variety durazzo has been reported rarely. We report an outbreak of enteric fever due to this variety affecting 43 individuals. The blood samples grew unusual mucoid, lactose non fermenting colonies with atypical biochemical reactions in sugar fermentation and amino acid decarboxylation. Isolates had sensitivity to ceftriaxone, chloramphenical, cotrimoxazole, intermediate susceptibility to ciprofloxacin and resistance to ampicillin and nalidixic acid. Identification was confirmed as SPA (2,12:a:-) at the National Salmonella Centre. PMID- 27514970 TI - Leptospirosis in sub-Himalayan region: A neglected entity. PMID- 27514971 TI - Awareness and practices regarding biomedical waste management among health-care workers in a tertiary care hospital in Delhi: Comment. PMID- 27514972 TI - Predatory publisher and impact factor: The murky landscape of scholastic publication. PMID- 27514973 TI - An unusual case of blackwater fever. PMID- 27514974 TI - Spontaneous septic arthritis due to Burkholderia cepacia in a 3-month-old pre term infant. PMID- 27514975 TI - Aeromonas : An unusual cause of lower gastrointestinal bleed. PMID- 27514976 TI - Azithromycin susceptibility among clinical isolates of Salmonella: Interfacing guidelines with routine practices. PMID- 27514977 TI - Daptomycin: A viable therapeutic option for vancomycin-resistant enterococcal urinary-tract infections in Indian medical settings? PMID- 27514978 TI - Occurrence of aac(6')-Ib variants among Enterobacteriaceae: Is aac(6')-Ib-cr the most predominant variant? PMID- 27514979 TI - Analysis of samples processed in automated blood culture system with blood culture samples processed by conventional manual method. PMID- 27514980 TI - Granulicatella adiacens : An unusual isolate from urethral discharge. PMID- 27514981 TI - Phthirus pubis in the eye. PMID- 27514982 TI - In vitro demonstration of potential virulence determinants among clinical isolates of various Candida species and its clinical implication in a Teaching Hospital in Eastern India. PMID- 27514983 TI - Presence of Epstein-Barr virus in gastric adenocarcinoma in Indian patients. PMID- 27514984 TI - Awareness about needlestick harms and health seeking behaviour among the Safai Karamcharis at Dr. Rajendra Prasad Government Medical College Kangra at Tanda (Himachal Pradesh). PMID- 27514985 TI - The neuronal mechanisms underlying improvement of impulsivity in ADHD by theta/beta neurofeedback. AB - Neurofeedback is increasingly recognized as an intervention to treat core symptoms of attention deficit hyperactivity disorder (ADHD). Despite the large number of studies having been carried out to evaluate its effectiveness, it is widely elusive what neuronal mechanisms related to the core symptoms of ADHD are modulated by neurofeedback. 19 children with ADHD undergoing 8 weeks of theta/beta neurofeedback and 17 waiting list controls performed a Go/Nogo task in a pre-post design. We used neurophysiological measures combining high-density EEG recording with source localization analyses using sLORETA. Compared to the waiting list ADHD control group, impulsive behaviour measured was reduced after neurofeedback treatment. The effects of neurofeedback were very specific for situations requiring inhibitory control over responses. The neurophysiological data shows that processes of perceptual gating, attentional selection and resource allocation processes were not affected by neurofeedback. Rather, neurofeedback effects seem to be based on the modulation of response inhibition processes in medial frontal cortices. The study shows that specific neuronal mechanisms underlying impulsivity are modulated by theta/beta neurofeedback in ADHD. The applied neurofeedback protocol could be particularly suitable to address inhibitory control. The study validates assumed functional neuroanatomical target regions of an established neurofeedback protocol on a neurophysiological level. PMID- 27514987 TI - Full data acquisition in Kelvin Probe Force Microscopy: Mapping dynamic electric phenomena in real space. AB - Kelvin probe force microscopy (KPFM) has provided deep insights into the local electronic, ionic and electrochemical functionalities in a broad range of materials and devices. In classical KPFM, which utilizes heterodyne detection and closed loop bias feedback, the cantilever response is down-sampled to a single measurement of the contact potential difference (CPD) per pixel. This level of detail, however, is insufficient for materials and devices involving bias and time dependent electrochemical events; or at solid-liquid interfaces, where non linear or lossy dielectrics are present. Here, we demonstrate direct recovery of the bias dependence of the electrostatic force at high temporal resolution using General acquisition Mode (G-Mode) KPFM. G-Mode KPFM utilizes high speed detection, compression, and storage of the raw cantilever deflection signal in its entirety at high sampling rates. We show how G-Mode KPFM can be used to capture nanoscale CPD and capacitance information with a temporal resolution much faster than the cantilever bandwidth, determined by the modulation frequency of the AC voltage. In this way, G-Mode KPFM offers a new paradigm to study dynamic electric phenomena in electroactive interfaces as well as a promising route to extend KPFM to the solid-liquid interface. PMID- 27514988 TI - Comparison of Phytochemical Composition and Biological Activities of Rubus ulmifolius Extracts Originating from Four Regions of Tunisia. AB - In the current study, the phenolic composition, antioxidant and antimicrobial activities of extracts from Rubus ulmifolius Schott leaves harvested in four localities (Sejnen, Tabarka, Faija and Ain drahem) in Tunisia were investigated for the first time. Great differences were found for the chemical composition, total phenol contents and biological activities among the evaluated extracts. HPLC analysis of methanolic extracts showed that the dominant compounds were kaempferol 3-O-rutinoside and naringenine. In addition, significant correlations were observed between antioxidant activities and phenolic contents. In fact, leaves collected from Sejnen presented higher total phenol content (53.32 mg GAE/g DW) and antioxidant activities (IC50 = 39.40 mg/l) than the others samples. All extracts showed significant antimicrobial activity against six used bacteria with the inhibition zones diameters and minimal inhibitory concentration values were in the range of 8 - 16 mm and 6.25 - 25 mg/ml, respectively. The highest antimicrobial activities were recorded in Sejnen extract against Gram-positive bacteria. PMID- 27514986 TI - Global transcriptional analysis suggests Lasiodiplodia theobromae pathogenicity factors involved in modulation of grapevine defensive response. AB - BACKGROUND: Lasiodiplodia theobromae is a fungus of the Botryosphaeriaceae that causes grapevine vascular disease, especially in regions with hot climates. Fungi in this group often remain latent within their host and become virulent under abiotic stress. Transcriptional regulation analysis of L. theobromae exposed to heat stress (HS) was first carried out in vitro in the presence of grapevine wood (GW) to identify potential pathogenicity genes that were later evaluated for in planta expression. RESULTS: A total of 19,860 de novo assembled transcripts were obtained, forty-nine per cent of which showed homology to the Botryosphaeriaceae fungi, Neofusicoccum parvum or Macrophomina phaseolina. Three hundred ninety-nine have homology with genes involved in pathogenic processes and several belonged to expanded gene families in others fungal grapevine vascular pathogens. Gene expression analysis showed changes in fungal metabolism of phenolic compounds; where genes encoding for enzymes, with the ability to degrade salicylic acid (SA) and plant phenylpropanoid precursors, were up-regulated during in vitro HS response, in the presence of GW. These results suggest that the fungal L-tyrosine catabolism pathway could help the fungus to remove phenylpropanoid precursors thereby evading the host defense response. The in planta up-regulation of salicylate hydroxylase, intradiol ring cleavage dioxygenase and fumarylacetoacetase encoding genes, further supported this hypothesis. Those genes were even more up-regulated in HS-stressed plants, suggesting that fungus takes advantage of the increased phenylpropanoid precursors produced under stress. Pectate lyase was up-regulated while a putative amylase was down regulated in planta, this could be associated with an intercellular growth strategy during the first stages of colonization. CONCLUSIONS: L. theobromae transcriptome was established and validated. Its usefulness was demonstrated through the identification of genes expressed during the infection process. Our results support the hypothesis that heat stress facilitates fungal colonization, because of the fungus ability to use the phenylpropanoid precursors and SA, both compounds known to control host defense. PMID- 27514989 TI - Impact of Precursor Compositions on the Structural and Photovoltaic Properties of Spray-Deposited Cu2 ZnSnS4 Thin Films. AB - Pure sulfide Cu2 ZnSnS4 thin films were fabricated on Mo-coated glass substrates by facile spray deposition of aqueous precursor solutions containing Cu(NO3 )2 , Zn(NO3 )2 , Sn(CH3 SO3 )2 , and thiourea followed by annealing at 600 degrees C. When a precursor solution containing a stoichiometric composition of Cu, Zn, and Sn was used, the resulting Cu2 ZnSnS4 thin film contained a Cu2-x S impurity phase owing to the evaporation of Sn components during the annealing process. The Cu2-x S impurity in the Cu2 ZnSnS4 thin film was removed by reducing the concentration of Cu in the precursor solution. This resulted in an improvement of the structural features (i.e., grain sizes and compactness) as well as the electric properties such as acceptor densities, the nature of the acceptor defects, and carrier lifetimes. A solar cell based on the Cu2 ZnSnS4 film with an empirically optimal composition showed conversion efficiency of 8.1 %. The value achieved was one of the best efficiencies of Cu2 ZnSnS4 -based cells derived from a non-vacuum process. PMID- 27514991 TI - Combination of Metabolomics with Cellular Assays Reveals New Biomarkers and Mechanistic Insights on Xenoestrogenic Exposures in MCF-7 Cells. AB - The disruptive potential of xenoestrogens like bisphenol A (BPA) lies in their 17beta-estradiol (E2)-like binding to estrogen receptors (ERs) followed by concomitant modulation of ER target gene expression. Unsurprisingly, most endocrine testing systems focus on the quantification of canonical transcripts or ER-sensitive reporters. However, only little information is available about the corresponding metabolomic changes in vitro. This knowledge gap becomes particularly relevant in the context of potential mixture effects, for example, as a consequence of coexposure to potentially estrogenically active pollutants (e.g., Cd2+). Such effects are often difficult to dissect with molecular tools, especially with regard to potential physiological relevance. Metabolomic biomarkers are well-suited to address this latter aspect as they provide a comprehensive readout of whole-cell physiology. Applying a targeted metabolomics approach (FIA-MS/MS), this study looked for biomarkers indicative of xenoestrogenic exposure in MCF-7 cells. Cells were treated with E2 and BPA in the presence or absence of Cd2+. Statistical analysis revealed a total of 11 amino acids and phospholipids to be related to the compound's estrogenic potency. Co exposure to Cd2+ modulated the estrogenic profile. However, the corresponding changes were found to be moderate with cellular assays such as the E-screen failing to record any Cd2+-specific estrogenic effects. Overall, metabolomics analysis identified proline as the most prominent estrogenic biomarker. Its increase could clearly be related to estrogenic exposure and concomitant ERalpha mediated induction of proliferation. Involvement of the latter was confirmed by siRNA-mediated knockdown studies as well as by receptor inhibition. Further, the underlying signaling was also found to involve the oncoprotein MYC. Taken together, this study provides insights into the underlying mechanisms of xenoestrogenic effects and exemplify the strength of the complementary use of metabolomics and cellular and molecular assays. PMID- 27514990 TI - Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer's disease. AB - Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, yet current therapeutic treatments are inadequate due to a complex disease pathogenesis. The plant polyphenol apigenin has been shown to have anti inflammatory and neuroprotective properties in a number of cell and animal models; however a comprehensive assessment has not been performed in a human model of AD. Here we have used a human induced pluripotent stem cell (iPSC) model of familial and sporadic AD, in addition to healthy controls, to assess the neuroprotective activity of apigenin. The iPSC-derived AD neurons demonstrated a hyper-excitable calcium signalling phenotype, elevated levels of nitrite, increased cytotoxicity and apoptosis, reduced neurite length and increased susceptibility to inflammatory stress challenge from activated murine microglia, in comparison to control neurons. We identified that apigenin has potent anti inflammatory properties with the ability to protect neurites and cell viability by promoting a global down-regulation of cytokine and nitric oxide (NO) release in inflammatory cells. In addition, we show that apigenin is able to protect iPSC derived AD neurons via multiple means by reducing the frequency of spontaneous Ca(2+) signals and significantly reducing caspase-3/7 mediated apoptosis. These data demonstrate the broad neuroprotective action of apigenin against AD pathogenesis in a human disease model. PMID- 27514992 TI - Fast live-cell conventional fluorophore nanoscopy with ImageJ through super resolution radial fluctuations. AB - Despite significant progress, high-speed live-cell super-resolution studies remain limited to specialized optical setups, generally requiring intense phototoxic illumination. Here, we describe a new analytical approach, super resolution radial fluctuations (SRRF), provided as a fast graphics processing unit-enabled ImageJ plugin. In the most challenging data sets for super resolution, such as those obtained in low-illumination live-cell imaging with GFP, we show that SRRF is generally capable of achieving resolutions better than 150 nm. Meanwhile, for data sets similar to those obtained in PALM or STORM imaging, SRRF achieves resolutions approaching those of standard single-molecule localization analysis. The broad applicability of SRRF and its performance at low signal-to-noise ratios allows super-resolution using modern widefield, confocal or TIRF microscopes with illumination orders of magnitude lower than methods such as PALM, STORM or STED. We demonstrate this by super-resolution live-cell imaging over timescales ranging from minutes to hours. PMID- 27514993 TI - Efficient sample preparation method based on solvent-assisted dispersive solid phase extraction for the trace detection of butachlor in urine and waste water samples. AB - In this work, an efficient sample preparation method termed solvent-assisted dispersive solid-phase extraction was applied. The used sample preparation method was based on the dispersion of the sorbent (benzophenone) into the aqueous sample to maximize the interaction surface. In this approach, the dispersion of the sorbent at a very low milligram level was achieved by inserting a solution of the sorbent and disperser solvent into the aqueous sample. The cloudy solution created from the dispersion of the sorbent in the bulk aqueous sample. After pre concentration of the butachlor, the cloudy solution was centrifuged and butachlor in the sediment phase dissolved in ethanol and determined by gas chromatography with flame ionization detection. Under the optimized conditions (solution pH = 7.0, sorbent: benzophenone, 2%, disperser solvent: ethanol, 500 MUL, centrifuged at 4000 rpm for 3 min), the method detection limit for butachlor was 2, 3 and 3 MUg/L for distilled water, waste water, and urine sample, respectively. Furthermore, the preconcentration factor was 198.8, 175.0, and 174.2 in distilled water, waste water, and urine sample, respectively. Solvent-assisted dispersive solid-phase extraction was successfully used for the trace monitoring of butachlor in urine and waste water samples. PMID- 27514994 TI - Robinson and madison have published no data on whether polyethylene glycol fusion repair prevents reinnervation accuracy in rat peripheral nerve. PMID- 27514995 TI - Antioxidative therapy in an ex vivo human cartilage trauma-model: attenuation of trauma-induced cell loss and ECM-destructive enzymes by N-acetyl cysteine. AB - OBJECTIVE: Mechanical trauma of articular cartilage results in cell loss and cytokine-driven inflammatory response. Subsequent accumulation of reactive oxygen (ROS) and nitrogen (RNS) species enhances the enzymatic degradation of the extracellular matrix (ECM). This study aims on the therapeutic potential of N acetyl cysteine (NAC) in a human ex vivo cartilage trauma-model, focusing on cell and chondroprotective features. DESIGN: Human full-thickness cartilage explants were subjected to a defined impact trauma (0.59 J) and treated with NAC. Efficiency of NAC administration was evaluated by following outcome parameters: cell viability, apoptosis rate, anabolic/catabolic gene expression, secretion and activity of matrix metalloproteinases (MMPs) and proteoglycan (PG) release. RESULTS: Continuous NAC administration increased cell viability and reduced the apoptosis rate after trauma. It also suppressed trauma-induced gene expression of ECM-destructive enzymes, such as ADAMTS-4, MMP-1, -2, -3 and -13 in a dosage- and time-depending manner. Subsequent suppression of MMP-2 and MMP-13 secretion reflected these findings on protein level. Moreover, NAC inhibited proteolytic activity of MMPs and reduced PG release. CONCLUSION: In the context of this ex vivo study, we showed not only remarkable cell- and chondroprotective features, but also revealed new encouraging findings concerning the therapeutically effective concentration and treatment-time regimen of NAC. Its defense against chondrocyte apoptosis and catabolic enzyme secretion recommends NAC as a multifunctional add-on reagent for pharmaceutical intervention after cartilage injury. Taken together, our data increase the knowledge on the therapeutic potential of NAC after cartilage trauma and presents a basis for future in vivo studies. PMID- 27514998 TI - Clinical and Molecular Aspects of MBD5-Associated Neurodevelopmental Disorder (MAND). PMID- 27514996 TI - Synovial macrophages promote TGF-beta signaling and protect against influx of S100A8/S100A9-producing cells after intra-articular injections of oxidized low density lipoproteins. AB - OBJECTIVE: Low-density lipoproteins (LDL) in inflamed synovium is oxidized and taken-up by synoviocytes. In this study, we investigate whether direct injection of oxidized LDL (oxLDL) into a normal murine knee joint induces joint pathology and whether synovial macrophages are involved in that process. DESIGN: Synovium was obtained from end-stage osteoarthritis (OA) patients in order to analyze LDL uptake. Murine knee joints were injected five consecutive days with oxLDL, LDL, or vehicle (phosphate buffered saline (PBS)). This procedure was repeated in mice depleted of synovial macrophages by intra-articular injection of clodronate liposomes 7 days prior to the consecutive injections. Joint pathology was investigated by immunohistochemistry, flow cytometry (FCM) and synovial RNA expression and protein production. RESULTS: Synovial tissue of OA patients showed extensive accumulation of apolipoprotein B. Multiple injections of oxLDL in murine knee joints significantly increased TGF-beta activity in synovial wash outs, but did not induce catabolic or inflammatory processes. In contrast, repeated injections of oxLDL in macrophage-depleted knee joints led to increased synovial thickening in combination with significantly upregulated protein and RNA levels of CCL2 and CCL3. FCM-analyses revealed increased presence of monocytes and neutrophils in the synovium, which was confirmed by immunohistochemistry. Also protein levels of S100A8/A9 were significantly increased in synovial wash outs of oxLDL-injected joints, as was expression of aggrecanase-induced neo epitopes. Interestingly, no raise in TGF-beta concentrations was measured in macrophage-depleted joints. CONCLUSIONS: OxLDL can affect joint pathology, since synovial macrophages promote anabolic processes after oxLDL injections. In absence of synovial macrophages, however, oxLDL induces production of pro inflammatory mediators and aggrecanase activity combined with increased influx of monocytes and neutrophils. PMID- 27514999 TI - Long-term culture of human odontoma-derived cells with a Rho kinase inhibitor. AB - Because of cellular senescence/apoptosis, no effective culture systems are available to maintain replication of cells from odontogenic tumors especially for odontoma, and, thus, the ability to isolate human odontoma-derived cells (hODCs) for functional studies is needed. The current study was undertaken to develop an approach to isolate hODCs and fully characterize the cells in vitro. The hODCs were cultured successfully with a Rho-associated protein kinase inhibitor (Y 27632) for an extended period with stabilized lengths of the telomeres to sustain a similar phenotype/property as the primary tumoral cells. While the hODCs showed stable long-term expansion with expression of major dental epithelial markers including dentin sialophosphoprotein (DSPP) even in the three-dimensional microenvironment, they lack the specific markers for the characteristics of stem cells. Moreover, cells from dental pulp showed significant up-regulation of DSPP when co-cultured with the hODCs, while control fibroblasts with the hODCs did not. Taken together, we propose that the hODCs can be isolated and expanded over the long term with Y-27632 to investigate not only the development of the hODCs but also other types of benign human tumors. PMID- 27515000 TI - Mitochondrial reactive oxygen species mediate the lipopolysaccharide-induced pro inflammatory response in human gingival fibroblasts. AB - Although periodontal diseases are initiated by bacteria that colonize the tooth surface and gingival sulcus, the host response is believed to play an essential role in the breakdown of connective tissue and bone. Mitochondrial reactive oxygen species (mtROS) have been proposed to regulate the activation of the inflammatory response by the innate immune system. However, the role of mtROS in modulating the response of human gingival fibroblasts (HGFs) to immune stimulation by lipopolysaccharides (LPS) has yet to be fully elucidated. Here, we showed that LPS from Porphyromonas gingivalis stimulated HGFs to increase mtROS production, which could be inhibited by treatment with a mitochondrial-targeted exogenous antioxidant (mito-TEMPO) or transfection with manganese superoxide dismutase (MnSOD). A time-course study revealed that an increase in the concentration of mtROS preceded the expression of inflammatory cytokines in HGFs. Mito-TEMPO treatment or MnSOD transfection also significantly prevented the LPS induced increase of interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha. Furthermore, suppressing LPS-induced mtROS generation inhibited the activation of p38, c-Jun N-terminal kinase, and inhibitor of nuclear factor kappaB kinase, as well as the nuclear localization of nuclear factor-kappaB. These results demonstrate that mtROS generation is a key signaling event in the LPS-induced pro-inflammatory response of HGFs. PMID- 27515001 TI - Time-lapse phenotyping of invasive glioma cells ex vivo reveals subtype-specific movement patterns guided by tumor core signaling. AB - The biology of glioblastoma invasion and its mechanisms are poorly understood. We demonstrate using time-lapse microscopy that grafting of glioblastoma (GBM) tumorspheres into rodent brain slices results in experimental ex vivo tumors with invasive properties that recapitulate the invasion observed after orthotopic transplantation into the rodent brain. The migratory movements and mitotic patterns were clearly modified by signals extrinsic to the invading cells. The cells migrated away from the tumorspheres, and removal of the spheres reduced the directed invasive movement. The cell cultures contained different populations of invasive cells that had distinct morphology and invasive behavior patterns. Grafts of the most invasive GBM culture contained 91+/-8% cells with an invasive phenotype, characterized by small soma with a distinct leading process. Conversely, the majority of cells in less invasive GBM grafts were phenotypically heterogeneous: only 6.3+/-4.1% of the cells had the invasive phenotype. Grafts of highly and moderately invasive cultures had different proportions of cells that advanced into the brain slice parenchyma during the observation period: 89.2+/ 2.2% and 23.1+/-6.8%, respectively. In grafts with moderately invasive properties, most of the cells (76.8+/-6.8%) invading the surrounding brain tissue returned to the tumor bulk or stopped centrifugal migration. Our data suggest that the invasion of individual GBM tumors can be conditioned by the prevalence of a cell fraction with particular invasive morphology and by signaling between the tumor core and invasive cells. These findings can be important for the development of new therapeutic strategies that target the invasive GBM cells. PMID- 27515003 TI - Systemic over-release of interleukin-17 in acute kidney injury after septic shock: Clinical and experimental evidence. AB - In order to investigate the role of T-helper 17 (Th17) cell activation in acute kidney injury (AKI) after septic shock, a two-stage approach was used. Firstly, peripheral blood mononuclear cells (PBMCs) and CD4-lymphocytes were isolated the first 24h after septic shock from 26 patients with AKI and 18 patients with chronic renal disease (CRD) without AKI and stimulated for the release of tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-10, IL-17, IL-22 and interferon-gamma (IFNgamma). Results were compared with 15 healthy volunteers and 13 patients with uncomplicated sepsis. Secondly, a murine model of multiple organ dysfunction (MODS) complicated with AKI and bacterial gut translocation was studied, and IL-10, IL-17, IL-22 and IFNgamma were measured in kidney homogenates. IL-17 was the only cytokine produced at greater quantities from PBMCs and CD4-lymphocytes of patients with septic shock and AKI than comparators. When PBMCs of patients with septic shock and AKI were ex-vivo stimulated, intracellular staining for IL-17 was greater in CD3(+)/CD4(+)/CD196(+) cells compared to patients with septic shock and CRD. IL-17 was released at greater amounts from PBMCs of non-survivors by septic shock and AKI but not of septic shock and CRD. In the murine model of MODS, a gradual decrease of IL-17, but not of IL-10, IL-22 and IFNgamma, of kidney homogenates was found indicating over consumption. These results suggest that AKI after septic shock is driven through IL-17 release by Th17 cells; this is gradually consumed in the kidney. PMID- 27515004 TI - Effect of genotyped cows in the reference population on the genomic evaluation of Holstein cattle. AB - This study evaluated the dependence of reliability and prediction bias on the prediction method, the contribution of including animals (bulls or cows), and the genetic relatedness, when including genotyped cows in the progeny-tested bull reference population. We performed genomic evaluation using a Japanese Holstein population, and assessed the accuracy of genomic enhanced breeding value (GEBV) for three production traits and 13 linear conformation traits. A total of 4564 animals for production traits and 4172 animals for conformation traits were genotyped using Illumina BovineSNP50 array. Single- and multi-step methods were compared for predicting GEBV in genotyped bull-only and genotyped bull-cow reference populations. No large differences in realized reliability and regression coefficient were found between the two reference populations; however, a slight difference was found between the two methods for production traits. The accuracy of GEBV determined by single-step method increased slightly when genotyped cows were included in the bull reference population, but decreased slightly by multi-step method. A validation study was used to evaluate the accuracy of GEBV when 800 additional genotyped bulls (POPbull) or cows (POPcow) were included in the base reference population composed of 2000 genotyped bulls. The realized reliabilities of POPbull were higher than those of POPcow for all traits. For the gain of realized reliability over the base reference population, the average ratios of POPbull gain to POPcow gain for production traits and conformation traits were 2.6 and 7.2, respectively, and the ratios depended on heritabilities of the traits. For regression coefficient, no large differences were found between the results for POPbull and POPcow. Another validation study was performed to investigate the effect of genetic relatedness between cows and bulls in the reference and test populations. The effect of genetic relationship among bulls in the reference population was also assessed. The results showed that it is important to account for relatedness among bulls in the reference population. Our studies indicate that the prediction method, the contribution ratio of including animals, and genetic relatedness could affect the prediction accuracy in genomic evaluation of Holstein cattle, when including genotyped cows in the reference population. PMID- 27515002 TI - Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells. AB - Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor alpha (ERalpha)+ breast cancer. We reported that ERalpha increases nuclear respiratory factor-1 (NRF-1), which regulates nuclear encoded mitochondrial gene transcription, in MCF-7 breast cancer cells and NRF-1 knockdown stimulates apoptosis. Whether NRF-1 and target gene expression is altered in endocrine resistant breast cancer cells is unknown. We measured NRF 1and metabolic features in a cell model of progressive TAM-resistance. NRF-1 and its target mitochondrial transcription factor A (TFAM) were higher in TAM resistant LCC2 and LCC9 cells than TAM-sensitive MCF-7 cells. Using extracellular flux assays we observed that LCC1, LCC2, and LCC9 cells showed similar oxygen consumption rate (OCR), but lower mitochondrial reserve capacity which was correlated with lower Succinate Dehydrogenase Complex, Subunit B in LCC1 and LCC2 cells. Complex III activity was lower in LCC9 than MCF-7 cells. LCC1, LCC2, and LCC9 cells had higher basal extracellular acidification (ECAR), indicating higher aerobic glycolysis, relative to MCF-7 cells. Mitochondrial bioenergetic responses to estradiol and 4-hydroxytamoxifen were reduced in the endocrine-resistant cells compared to MCF-7 cells. These results suggest the acquisition of altered metabolic phenotypes in response to long term antiestrogen treatment may increase vulnerability to metabolic stress. PMID- 27515005 TI - Overexpression of myosin VI regulates gastric cancer cell progression. AB - Myosin VI (MYO6) is a unique member of the myosin superfamily. Although it has been reported to participate in human cancer progression, the role of MYO6 in gastric cancer remains unclear. In this study, we found the expression of MYO6 gene was higher in gastric cancer tissues than in the normal tissues by Oncomine database mining and affects patient overall survival using the Kaplan-Meier plotter online analysis. Additionally, the expression levels of MYO6 were widely expressed in gastric cancer cells by quantitative real-time Polymerase Chain Reaction (qRT-PCR) and western blot assay. Then knockdown of MYO6 significantly suppressed the proliferation and colony formation abilities of AGS and MGC80-3 cells. Moreover, cell cycle analysis showed that inhibition of MYO6 induced cell cycle arrested in G0/G1 phase in AGS and MGC80-3 cells. Further analysis showed knockdown of MYO6 downregulated cell-cycle activators cyclin A and cyclin D1 and upregulated cell-cycle inhibitor p21, as determined by qRT-PCR and western blot analysis in MGC80-3 cells. Meanwhile, MYO6 inhibition significantly induced apoptosis in AGS and MGC80-3 cells. Also, knockdown of MYO6 increased the expression of apoptosis-related proteins Bax and cleaved Caspase-3, and decreased Bcl-2 expression by western blot analysis in MGC80-3 cells. In addition, MYO6 knockdown also inhibited cell migration ability in MGC80-3 cells. Taken together, our study indicates that MYO6 may play an important role in gastric cancer tumorigenesis and may serve as a potential therapeutic target in human gastric cancer. PMID- 27515006 TI - MicroRNA and target gene expression based clustering of oral cancer, precancer and normal tissues. AB - PURPOSE: Development of oral cancer is usually preceded by precancerous lesion. Despite histopathological diagnosis, development of disease specific biomarkers continues to be a promising field of study. Expression of miRNAs and their target genes was studied in oral cancer and two types of precancer lesions to look for disease specific gene expression patterns. METHODS: Expression of miR-26a, miR 29a, miR-34b and miR-423 and their 11 target genes were determined in 20 oral leukoplakia, 20 lichen planus and 20 cancer tissues with respect to 20 normal tissues using qPCR assay. Expression data were, then, used for cluster analysis of normal as well as disease tissues. RESULTS: Expression of miR-26a and miR-29a was significantly down regulated in leukoplakia and cancer tissues but up regulated in lichen planus tissues. Expression of target genes such as, ADAMTS7, ATP1B1, COL4A2, CPEB3, CDK6, DNMT3a and PI3KR1 was significantly down regulated in at least two of three disease types with respect to normal tissues. Negative correlations between expression levels of miRNAs and their targets were observed in normal tissues but not in disease tissues implying altered miRNA-target interaction in disease state. Specific expression profile of miRNAs and target genes formed separate clusters of normal, lichen planus and cancer tissues. CONCLUSION: Our results suggest that alterations in expression of selected miRNAs and target genes may play important roles in development of precancer to cancer. Expression profiles of miRNA and target genes may be useful to differentiate cancer and lichen planus from normal tissues, thereby bolstering their role in diagnostics. PMID- 27515007 TI - Efficient Enzymatic Preparation of (13) N-Labelled Amino Acids: Towards Multipurpose Synthetic Systems. AB - Nitrogen-13 can be efficiently produced in biomedical cyclotrons in different chemical forms, and its stable isotopes are present in the majority of biologically active molecules. Hence, it may constitute a convenient alternative to Fluorine-18 and Carbon-11 for the preparation of positron-emitter-labelled radiotracers; however, its short half-life demands for the development of simple, fast, and efficient synthetic processes. Herein, we report the one-pot, enzymatic and non-carrier-added synthesis of the (13) N-labelled amino acids l-[(13) N]alanine, [(13) N]glycine, and l-[(13) N]serine by using l-alanine dehydrogenase from Bacillus subtilis, an enzyme that catalyses the reductive amination of alpha keto acids by using nicotinamide adenine dinucleotide (NADH) as the redox cofactor and ammonia as the amine source. The integration of both l-alanine dehydrogenase and formate dehydrogenase from Candida boidinii in the same reaction vessel to facilitate the in situ regeneration of NADH during the radiochemical synthesis of the amino acids allowed a 50-fold decrease in the concentration of the cofactor without compromising reaction yields. After optimization of the experimental conditions, radiochemical yields were sufficient to carry out in vivo imaging studies in small rodents. PMID- 27515008 TI - Reflections on scientific collaboration between basic researchers and clinicians. AB - Early career researchers face uncertainties with respect to their job prospects due to dwindling job markets, decreased availability of funding and undefined career paths. As basic researchers and clinicians tend to have different approaches to scientific problems, there are many advantages from successful collaborations between them. Here, we discuss how collaborations between basic and clinical scientists should be promoted early in their careers. To achieve this, researchers, both basic and clinical, must be proactive during their training and early stages of their careers. Mentors can further augment collaborative links in many ways. We suggest that universities and institutions might reassess their involvement in promoting collaborations between basic and clinical researchers. We hope that this paper will serve as a reminder of the importance of such collaborations, and provide the opportunity for all members of the scientific community to reflect on and ameliorate their own contributions. PMID- 27515009 TI - Web-Based Virtual Microscopy of Digitized Blood Slides for Malaria Diagnosis: An Effective Tool for Skills Assessment in Different Countries and Environments. AB - BACKGROUND: Morphological examination of blood films remains the reference standard for malaria diagnosis. Supporting the skills required to make an accurate morphological diagnosis is therefore essential. However, providing support across different countries and environments is a substantial challenge. OBJECTIVE: This paper reports a scheme supplying digital slides of malaria infected blood within an Internet-based virtual microscope environment to users with different access to training and computing facilities. The feasibility of the approach was established, allowing users to test, record, and compare their own performance with that of other users. METHODS: From Giemsa stained thick and thin blood films, 56 large high-resolution digital slides were prepared, using high-quality image capture and 63x oil-immersion objective lens. The individual images were combined using the photomerge function of Adobe Photoshop and then adjusted to ensure resolution and reproduction of essential diagnostic features. Web delivery employed the Digital Slidebox platform allowing digital microscope viewing facilities and image annotation with data gathering from participants. RESULTS: Engagement was high with images viewed by 38 participants in five countries in a range of environments and a mean completion rate of 42/56 cases. The rate of parasite detection was 78% and accuracy of species identification was 53%, which was comparable with results of similar studies using glass slides. Data collection allowed users to compare performance with other users over time or for each individual case. CONCLUSIONS: Overall, these results demonstrate that users worldwide can effectively engage with the system in a range of environments, with the potential to enhance personal performance through education, external quality assessment, and personal professional development, especially in regions where educational resources are difficult to access. PMID- 27515010 TI - Optimization of fertilization characteristics of urine by addition of Nitrosomonas europaea bio-seed. AB - BACKGROUND: Because of the high concentration of nutrients in human urine, its utilization as an organic fertilizer has been notable throughout history. However, the nitrogen compounds in urine are not stable. Therefore, to convert urine into a suitable fertilizer, it is important to stabilize and adjust unstable nitrogen compounds such as ammonia. Because nitrification can influence the nitrogen profile, the use of nitrifying microorganisms can be useful for stabilizing the nitrogen profile of urine. This study investigated the changes in nitrogen compounds in pure urine and examined the effect of adding Nitrosomonas europaea bio-seed solution on these changes. RESULTS: It was found that the addition of bio-seed could reduce nitrogen loss as well as the time required to stabilize the nitrogen profile. Furthermore, the optimum concentration of bio seed (6 * 10(5) N. europaea cells L(-1) ) that not only leads to the least nutrient loss but also results in an adequate nitrate/ammonium ratio and regulates the amount of nitrate produced, thereby preventing over-fertilization, was determined. CONCLUSION: At this concentration, no dilution or dewatering is required, thus minimizing water and energy consumption. Usage of the optimum of concentration of bio-seed will also eliminate the need for inorganic chemical additives. (c) 2016 Society of Chemical Industry. PMID- 27515011 TI - Clinical utility of non-invasive prenatal testing in pregnancies with ultrasound anomalies. AB - OBJECTIVE: To evaluate the application of non-invasive prenatal testing (NIPT) as an alternative to invasive diagnostic prenatal testing in pregnancies with abnormal ultrasound findings. METHODS: This was a retrospective analysis of 251 singleton and multiple pregnancies at high risk for fetal chromosomal abnormality based on findings at sonographic examination, in which NIPT was performed as a first-tier genetic test. NIPT was performed by massively parallel sequencing of cell-free DNA in maternal plasma, allowing genome-wide detection of whole chromosome, as well as partial, autosomal aneuploidy. Sex chromosomes were not analyzed, according to the current protocol in Dutch laboratories. RESULTS: NIPT was performed at a median gestational age of 20 weeks, indicated by the presence of multiple congenital anomalies (n = 13), isolated structural anomalies (n = 57), increased nuchal translucency >= 3.5 mm (n = 58), soft markers (n = 73), growth restriction (n = 40) and other anomalies (n = 10). NIPT results were normal in 224 (89.2%) pregnancies, inconclusive in one (0.4%) and abnormal in 26 (10.4%). Most genetic aberrations detected by NIPT were common whole-chromosome aneuploidies: trisomy 21 (n = 13), trisomy 18 (n = 6) and trisomy 13 (n = 3). Four further NIPT results were abnormal; one was suspected of being confined placental mosaicism and one was of maternal origin. In those with normal NIPT results, sonographic follow-up or examination of the newborn indicated the need for diagnostic genetic testing in 33/224 (14.7%) pregnancies. Clinically relevant genetic aberrations were revealed in 7/224 (3.1%) cases, two of which were whole chromosome aneuploidies: trisomy 13 and monosomy X. As sex chromosomal aberrations are not included in NIPT analysis, the latter cannot be considered a false-negative result. Other discordant findings were subchromosomal aberrations (< 20 megabases, n = 2) and monogenic aberrations (n = 3). CONCLUSIONS: NIPT should not be recommended for genetic evaluation of the etiology of ultrasound anomalies, as both resolution and sensitivity, or negative predictive value, are inferior to those of conventional karyotyping and microarray analysis. Nonetheless, some pregnant women consider NIPT to be an acceptable alternative to invasive diagnostic testing. (c) 2016 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. PMID- 27515012 TI - The extent and nature of television food advertising to children in Xi'an, China. AB - BACKGROUND: To explore the extent and nature of television food advertising especially unhealthy food advertising to primary school children in Xi'an, China. METHODS: Television data were recorded for 2 weekdays and 2 weekend days between 6:00 and 22:00 during May and June in 2012 from a total of five television channels most popular with children in Xi'an. Pearson chi (2) tests and logistic regression were applied to determine differences in the proportion of healthy food, unhealthy food and miscellaneous food advertisements for different channels, programs, dates, viewing periods and the use of persuasive marketing tactics. RESULTS: Of the 5527 advertisements transcribed, 25.5 % were for food, among which 48.1 % were considered to be unhealthy. The frequency of food advertisements was 6 per hour per channel, including 3 unhealthy food advertisements. Compared with healthy and miscellaneous food advertisements, more unhealthy food advertisements were shown during afternoon, weekends and children's non-peak viewing times as well as on children's television channels, central television channels and non-children's programmes. Unhealthy foods contributed the highest proportion of all food advertisements containing promotional characters (51.7 %) and premium offers (59.1 %). Both promotional characters and premium offers appeared more on non-children's television channels. CONCLUSIONS: The majority of food advertisements were for unhealthy food. More unhealthy food ads were shown in children's non-peak time and afternoon as well as non-children's channels. More children-oriented persuasive marketing tactics were used in unhealthy food ads especially in non-children's channels. Therefore, intervening in the entrance of unhealthy foods into the market and establishing regulations related to food advertising especially unhealthy food advertisements are important strategies to prevent children's exposure to unhealthy food and childhood obesity. PMID- 27515013 TI - Water quality following extensive beetle-induced tree mortality: Interplay of aromatic carbon loading, disinfection byproducts, and hydrologic drivers. AB - The recent bark beetle epidemic across western North America may impact water quality as a result of elevated organic carbon release and hydrologic shifts associated with extensive tree dieback. Analysis of quarterly municipal monitoring data from 2004 to 2014 with discretization of six water treatment facilities in the Rocky Mountains by extent of beetle impact revealed a significant increasing trend in total organic carbon (TOC) and total trihalomethane (TTHM) production within high (?50% areal infestation) beetle impacted watersheds while no or insignificant trends were found in watersheds with lower impact levels. Alarmingly, the TTHM concentration trend in the high impact sites exceeded regulatory maximum contaminant levels during the most recent two years of analysis (2013-14). To evaluate seasonal differences, explore the interplay of water quality and hydrologic processes, and eliminate variability associated with municipal reporting, these treatment facilities were targeted for more detailed surface water sampling and characterization. Surface water samples collected from high impact watersheds exhibited significantly higher TOC, aromatic signatures, and disinfection byproduct (DBP) formation potential than watersheds with lower infestation levels. Spectroscopic analyses of surface water samples indicated that these heightened DBP precursor levels are a function of both elevated TOC loading and increased aromatic character. This association was heightened during precipitation and runoff events in high impact sites, supporting the hypothesis that altered hydrologic flow paths resulting from tree mortality mobilize organic carbon and elevate DBP formation potential for several months after runoff ceases. The historical trends found here likely underestimate the full extent of TTHM shifts due to monitoring biases with the extended seasonal release of DBP precursors increasing the potential for human exposure. Collectively, our analysis suggests that while water quality impacts continue to rise nearly one decade after infestation, significant increases in TOC mobilization and DBP precursors are limited to watersheds that experience extensive tree mortality. PMID- 27515014 TI - Effects of hydro- and thermopeaking on benthic macroinvertebrate drift. AB - The operation of storage hydropower plants is commonly linked to frequent fluctuations in discharge and water level (hydropeaking) of downstream river stretches and is often accompanied by cooling or warming of the water body downstream (cold or warm thermopeaking, respectively). The objective of this study is to assess the single and combined effects of hydropeaking and cold thermopeaking on the drift of selected aquatic macroinvertebrates in experimental flumes. The study specifically aims to (1) investigate the macroinvertebrate drift induced by hydropeaking, (2) identify taxon-specific drift patterns following combined hydropeaking and cold thermopeaking and (3) quantify diurnal drift differences under both impact types. Overall, hydropeaking induced significantly higher drift rates of most macroinvertebrate taxa. Combined hydropeaking and cold thermopeaking, however, revealed reduced total drift rates, however with strong taxon-specific response patterns. Hydropeaking during night led to significantly higher drift rates than during daytime, while in combination with thermopeaking the same trend was observable, although insignificant. Taxon specific analysis revealed lower drift rates following hydropeaking for rheophilic and interstitial taxa (e.g. Leuctra sp., Hydropsyche sp.), whereas many limnophilic taxa adapted to low current showed markedly increased drift (e.g. Lepidostoma hirtum and Leptoceridae). In line with previous studies, our results confirm a significant loss of limnophilic macroinvertebrate taxa following hydraulic stress. The mitigating effect of cold thermopeaking might be explained by behavioural patterns, but requires further investigation to clarify if macroinvertebrates actively avoid drift and intrude into the interstitial, when cold water is discharged. Our results imply that river restoration projects must address the hydrological regime and, if necessary need to include suitable management schemes for hydropower plants. Besides operative management measures, the construction of reservoirs to buffer hydropeaks or the diversion of hydropeaks into larger water bodies could mitigate hydropeaking effects and foster biological recovery including limnophilic taxa. PMID- 27515015 TI - Groundwater flow and geochemical evolution in the Central Flinders Ranges, South Australia. AB - The chemical characteristics of water in the Oratunga Area, Central Flinders Ranges, South Australia have been used to evaluate and determine the processes controlling water chemistry in addition to the sources of ions. The isotopic analysis results show that the groundwater is mainly meteoric. Based on the rock and water chemistry, ionic ratios, hydrochemical facies and saturation indices, the chemical evolution has been studied. The chemistry of groundwater revealed two types of water. Thus, in high topographic areas, low TDS, bicarbonate and mixed water types are dominated and support a rapid and direct recharge. While in the low topographic areas, high TDS and chloride compositions are the most common attributed to the accumulation of ions and groundwater evolution. Analysis of the ion concentration, head data and saturation indices shows a compositional trend that can be studied as an evolutionary system. The ionic ratios and hydrogeochemical modelling using NETPATH was used to quantify and verify the different hydrochemical processes. The resulting data shows that calcite dissolution/precipitation and cation exchange reactions are the major processes affecting groundwater chemical evolution of the groundwater in the basin. This study has provided a basis for a better understanding of the hydrogeologic setting in areas of a little data. PMID- 27515016 TI - Dust levels of polybrominated diphenyl ethers (PBDEs) and polybrominated dibenzo p-dioxins/furans (PBDD/Fs) in the Taiwanese elementary school classrooms: Assessment of the risk to school-age children. AB - Elementary school classroom dust is an important source of exposure to polybrominated dibenzo-p-dioxins/furans and diphenyl ethers (PBDD/DF/DEs) for school-age children. Our goal is thus to investigate concentrations of PBDD/DF/DEs in elementary school classroom dust to further assess the impact on school-age children via ingestion. The dust from classrooms, including both normal (NR) and computer classrooms (CR), was collected from six urban and four rural schools. Fourteen PBDEs and twelve PBDD/Fs were measured using high resolution gas-chromatography/high-resolution mass-spectrometry. The mean levels of Sigma14PBDEs in NR and CR dust from the urban classrooms were 370 and 2510ng/g and those whose dust from the rural classrooms were 464 and 1780ng/g. The means of SigmaPBDD/Fs were 0.0401ng-WHO2005-TEQ/g (concentration: 4.72ng/g) in urban NR dust, 0.0636ng-WHO2005-TEQ/g (7.51ng/g) in urban CR dust, 0.0281ng-WHO2005TEQ/g (3.60ng/g) in rural NR dust, and 0.0474ng-WHO2005TEQ/g (6.28ng/g) in rural CR dust. The PBDEs pattern in NR dust was quite different from that in CR dust, but the PBDD/Fs patterns in NR and CR dust were similar. A linearly significant correlation coefficient (n=20, r=0.862, p<0.001) was found between SigmaPBDEs and SigmaPBDD/Fs in NR and CR dust, indicating that the PBDEs and PBDD/Fs in the dust may be from the same sources in the elementary school classrooms. This study assessed the risks (daily intake and cancer and non-cancer risks) of PBDEs and PBDD/Fs for the children from the classroom dust, and the calculated risk values did not exceed the related thresholds. With regard to the exposure scenarios for school-age children in an indoor environment, the results suggest that they might ingest more dust PBDD/DF/DEs in their homes than in the schools. In conclusion, the exposure of Taiwanese elementary school children to PBDD/DF/DEs via indoor dust was with a safe range based on our findings. PMID- 27515017 TI - The changing prevalence of pulmonary infection in adults with cystic fibrosis: A longitudinal analysis. AB - BACKGROUND: Increased patient longevity and aggressive antibiotic treatment are thought to impact on the microbial composition of the airways of adults with cystic fibrosis (CF). In this study, we sought to determine if a temporal change in the airway microbiology of adults with CF has occurred over time. METHODS: Longitudinal analysis of sputum microbiology results was undertaken on patients attending a large adult CF centre. Clinical status and health outcomes of transitioning patients were also assessed. RESULTS: A decrease in the prevalence of Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia cepacia complex and Aspergillus spp. (p=0.001, p<0.001, p=0.002 and p<0.001, respectively) occurred. Improvements in lung function among transitioning patients infected with P. aeruginosa were observed. CONCLUSION: Overtime, a decline in the prevalence of many CF airway pathogens has occurred. Significantly, an incremental improvement in lung function was reported for transitioning patients with current P. aeruginosa infections. PMID- 27515018 TI - Decreasing age at first anal intercourse among men who have sex with men in China: a multicentre cross-sectional survey. AB - INTRODUCTION: Literature on the age at first anal intercourse (AFAI) among men who have sex with men (MSM) is limited. We aimed to elucidate the evolution of AFAI and the factors associated with early AFAI, based on a large sample of MSM in China. METHODS: We collected information on the demographics and sexual behaviours of MSM from seven large cities in China from 2012 to 2013. Blood samples were collected for HIV serology. AFAI was calculated for MSM born in different time periods. Linear regression models were used to explore factors associated with younger AFAI. RESULTS: A total of 4491 MSM (median age: 27 years, median AFAI: 21 years) were recruited. Median AFAI decreased steadily from 33 years of age among MSM born from 1940 to 1959 to 18 years of age among MSM born from 1990 to 1996. Factors significantly associated with younger AFAI included more recent birth cohort, being unmarried or living with a male partner, being a student or industry worker, the gender of the first partner being male, and using Rush or Ecstasy in the past six months (p for all <0.05). CONCLUSIONS: AFAI among MSM in China has considerably decreased over the past few decades. The decreasing AFAI and factors associated with younger AFAI point to the necessity of early sex education and control of recreational drug use among MSM in China. PMID- 27515019 TI - Is it time to combine untargeted antifungal strategies to reach the goal of 'early' effective treatment? PMID- 27515021 TI - Trajectories of cannabis use disorder: risk factors, clinical characteristics and outcomes. AB - AIMS: To estimate cannabis use disorder (CUD) trajectory classes from ages 14 to 30 years and compare classes on clinical characteristics, risk factors and psychosocial outcomes. DESIGN: Four waves (T1-T4) of data from an epidemiological study of psychopathology among a regionally representative sample. Trajectory classes described risk for CUD as a function of age. The number of classes was determined by model fit. SETTING: Participants were selected randomly from nine high schools in western Oregon, USA. PARTICIPANTS: The sample included 816 participants [age at T1 mean = 16.6, standard deviation (SD) = 1.2; 44% male; 8% non-white]. MEASUREMENTS: Participants completed diagnostic interviews, Child Trauma Questionnaire, Social Adjustment Scale and items adapted from the Wisconsin Manual for Assessing Psychotic-Like Experiences. FINDINGS: There were three CUD trajectory classes (Lo-Mendell-Rubin likelihood ratio test < 0.001): (1) persistent increasing risk; (2) maturing out, with increasing risk then decreasing risk; and (3) stable low risk. The persistent increasing class had later initial CUD onsets (eta2 = 0.16, P < 0.001) and greater cumulative CUD durations (eta2 = 0.26, P < 0.001). Male sex [odds ratio (OR) = 2.57, P = 0.018], externalizing disorders between ages 24 and 30 years (OR = 2.64, P < 0.001) and psychotic experiences during early adulthood (Cohen's d = 0.44, P = 0.016) discriminated between the persistent increasing and the maturing-out classes. CONCLUSIONS: Evidence suggests three distinguishable types of trajectory for development of cannabis use disorder starting in early teens: (1) persistent increasing risk; (2) maturing out, with increasing risk then decreasing risk; and (3) stable low risk. PMID- 27515022 TI - Mapping gains and losses in woody vegetation across global tropical drylands. AB - Woody vegetation in global tropical drylands is of significant importance for both the interannual variability of the carbon cycle and local livelihoods. Satellite observations over the past decades provide a unique way to assess the vegetation long-term dynamics across biomes worldwide. Yet, the actual changes in the woody vegetation are always hidden by interannual fluctuations of the leaf density, because the most widely used remote sensing data are primarily related to the photosynthetically active vegetation components. Here, we quantify the temporal trends of the nonphotosynthetic woody components (i.e., stems and branches) in global tropical drylands during 2000-2012 using the vegetation optical depth (VOD), retrieved from passive microwave observations. This is achieved by a novel method focusing on the dry season period to minimize the influence of herbaceous vegetation and using MODerate resolution Imaging Spectroradiometer (MODIS) Normalized Difference Vegetation Index (NDVI) data to remove the interannual fluctuations of the woody leaf component. We revealed significant trends (P < 0.05) in the woody component (VODwood ) in 35% of the areas characterized by a nonsignificant trend in the leaf component (VODleaf modeled from NDVI), indicating pronounced gradual growth/decline in woody vegetation not captured by traditional assessments. The method is validated using a unique record of ground measurements from the semiarid Sahel and shows a strong agreement between changes in VODwood and changes in ground observed woody cover (r2 = 0.78). Reliability of the obtained woody component trends is also supported by a review of relevant literatures for eight hot spot regions of change. The proposed approach is expected to contribute to an improved assessment of, for example, changes in dryland carbon pools. PMID- 27515023 TI - Framework Design and Influencing Factor Analysis of a Water Environmental Functional Zone-Based Effluent Trading System. AB - The efficacy of traditional effluent trading systems is questionable due to their neglect of seasonal hydrological variation and the creation of upstream hot spots within a watershed. Besides, few studies have been conducted to distinguish the impacts of each influencing factor on effluent trading systems outputs. In this study, a water environmental functional zone-based effluent trading systems framework was configured and a comprehensive analysis of its influencing factors was conducted. This proposed water environmental functional zone-based effluent trading systems was then applied for the control of chemical oxygen demand in the Beiyun River watershed, Beijing, China. Optimal trading results highlighted the integration of water quality constraints and different hydrological seasons, especially for downstream dischargers. The optimal trading of each discharger, in terms of pollutant reduction load and abatement cost, is greatly influenced by environmental and political factors such as background water quality, the location of river assessment points, and tradable discharge permits. In addition, the initial permit allowance has little influence on the market as a whole but does impact the individual discharger. These results provide information that is critical to understanding the impact of policy design on the functionality of an effluent trading systems. PMID- 27515024 TI - Does Wyoming's Core Area Policy Protect Winter Habitats for Greater Sage-Grouse? AB - Conservation reserves established to protect important habitat for wildlife species are used world-wide as a wildlife conservation measure. Effective reserves must adequately protect year-round habitats to maintain wildlife populations. Wyoming's Sage-Grouse Core Area policy was established to protect breeding habitats for greater sage-grouse (Centrocercus urophasianus). Protecting only one important seasonal habitat could result in loss or degradation of other important habitats and potential declines in local populations. The purpose of our study was to identify the timing of winter habitat use, the extent which individuals breeding in Core Areas used winter habitats, and develop resource selection functions to assess effectiveness of Core Areas in conserving sage grouse winter habitats in portions of 5 Core Areas in central and north-central Wyoming during winters 2011-2015. We found that use of winter habitats occured over a longer period than current Core Area winter timing stipulations and a substantial amount of winter habitat outside of Core Areas was used by individuals that bred in Core Areas, particularly in smaller Core Areas. Resource selection functions for each study area indicated that sage-grouse were selecting habitats in response to landscapes dominated by big sagebrush and flatter topography similar to other research on sage-grouse winter habitat selection. The substantial portion of sage-grouse locations and predicted probability of selection during winter outside small Core Areas illustrate that winter requirements for sage-grouse are not adequately met by existing Core Areas. Consequently, further considerations for identifying and managing important winter sage-grouse habitats under Wyoming's Core Area Policy are warranted. PMID- 27515025 TI - Characterization of a panARS-based episomal vector in the methylotrophic yeast Pichia pastoris for recombinant protein production and synthetic biology applications. AB - BACKGROUND: Recombinant protein production in the methylotrophic yeast Pichia pastoris largely relies on integrative vectors. Although the stability of integrated expression cassettes is well appreciated for most applications, the availability of reliable episomal vectors for this host would represent a useful tool to expedite cloning and high-throughput screening, ameliorating also the relatively high clonal variability reported in transformants from integrative vectors caused by off-target integration in the P. pastoris genome. Recently, heterologous and endogenous autonomously replicating sequences (ARS) were identified in P. pastoris by genome mining, opening the possibility of expanding the available toolbox to include efficient episomal plasmids. The aim of this technical report is to validate a 452-bp sequence ("panARS") in context of P. pastoris expression vectors, and to compare their performance to classical integrative plasmids. Moreover, we aimed to test if such episomal vectors would be suitable to sustain in vivo recombination, using fragments for transformation, directly in P. pastoris cells. RESULTS: A panARS-based episomal vector was evaluated using blue fluorescent protein (BFP) as a reporter gene. Normalized fluorescence from colonies carrying panARS-BFP outperformed the level of signal obtained from integrative controls by several-fold, whereas endogenous sequences, identified from the P. pastoris genome, were not as efficient in terms of protein production. At the single cell level, panARS-BFP clones showed lower interclonal variability but higher intraclonal variation compared to their integrative counterparts, supporting the idea that heterologous protein production could benefit from episomal plasmids. Finally, efficiency of 2-fragment and 3-fragment in vivo recombination was tested using varying lengths of overlapping regions and molar ratios between fragments. Upon optimization, minimal background was obtained for in vivo assembled vectors, suggesting this could be a quick and efficient method to generate of episomal plasmids of interest. CONCLUSIONS: An expression vector based on the panARS sequence was shown to outperform its integrative counterparts in terms of protein productivity and interclonal variability, facilitating recombinant protein expression and screening. Using optimized fragment lengths and ratios, it was possible to perform reliable in vivo recombination of fragments in P. pastoris. Taken together, these results support the applicability of panARS episomal vectors for synthetic biology approaches. PMID- 27515026 TI - Potential role of herbal remedies in stem cell therapy: proliferation and differentiation of human mesenchymal stromal cells. AB - Stem cell therapy has revolutionized modern clinical therapy with the potential of stem cells to differentiate into many different cell types which may help to replace different cell lines of an organism. Innumerous trials are carried out to merge new scientific knowledge and techniques with traditional herbal extracts that may result in less toxic, affordable, and highly available natural alternative therapeutics. Currently, mesenchyamal stromal cell (MSC) lines are treated with individual and mixtures of crude herbal extracts, as well as with purified compounds from herbal extracts, to investigate the mechanisms and effects of these on stem cell growth and differentiation. Human MSCs (hMSCs) possess multilineage, i.e., osteogenic, neurogenic, adipogenic, chondrogenic, and myogenic, differentiation abilities. The proliferative and differentiation properties of hMSCs treated with herbal extracts have shown promise in diseases such as osteoporosis, neurodegenerative disorders, and other tissue degenerative disorders. Well characterized herbal extracts that result in increased rates of tissue regeneration may be used in both stem cell therapy and tissue engineering for replacement therapy, where the use of scaffolds and vesicles with enhanced attaching and proliferative properties could be highly advantageous in the latter. Although the clinical application of herbal extracts is still in progress due to the variability and complexity of bioactive constituents, standardized herbal preparations will strengthen their application in the clinical context. We have critically reviewed the proliferative and differentiation effects of individual herbal extracts on hMSCs mainly derived from bone marrow and elaborated on the plausible underlying mechanisms of action. To be fruitfully used in reparative and regenerative therapy, future directions in this area of study should (i) make use of hMSCs derived from different non-traditional sources, including medical waste material (umbilical cord, Wharton's jelly, and placenta), (ii) take account of the vast numbers of herbal extracts used in traditional medicine globally, and (iii) investigate the mechanisms and pathways of their effects on hMSCs. PMID- 27515027 TI - Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators. AB - BACKGROUND: Cyclophosphamide (CPA) can activate immunogenic tumor cell death, which induces immune-based tumor ablation and long-term anti-tumor immunity in a syngeneic C57BL/6 (B6) mouse GL261 glioma model when CPA is given on a 6-day repeating metronomic schedule (CPA/6d). In contrast, we find that two other syngeneic B6 mouse tumors, LLC lung carcinoma and B16F10 melanoma, do not exhibit these drug-induced immune responses despite their intrinsic sensitivity to CPA cytotoxicity. METHODS: To elucidate underlying mechanisms, we investigated gene expression and molecular pathway changes associated with the disparate immune responsiveness of these tumors to CPA/6d treatment. RESULTS: Global transcriptome analysis indicated substantial elevation of basal GL261 immune infiltration and strong CPA/6d activation of GL261 immune stimulatory pathways and their upstream regulators, but without preferential depletion of negative immune regulators compared to LLC and B16F10 tumors. In LLC tumors, where CPA/6d treatment is shown to be anti-angiogenic, CPA/6d suppressed VEGFA target genes and down regulated cell adhesion and leukocyte transendothelial migration genes. In GL261 tumors implanted in adaptive immune-deficient scid mice, where CPA/6d-induced GL261 regression is incomplete and late tumor growth rebound can occur, T cell receptor signaling and certain cytokine-cytokine receptor responses seen in B6 mice were deficient. Extending the CPA treatment interval from 6 to 9 days (CPA/9d) - which results in a strong but transient natural killer cell response followed by early tumor growth rebound - induced fewer cytokines and increased expression of drug metabolism genes. CONCLUSIONS: These findings elucidate molecular response pathways activated by intermittent metronomic CPA treatment and identify deficiencies that characterize immune-unresponsive tumor models and drug schedules. PMID- 27515028 TI - Prognostic significance of preoperative serum Krebs von den Lungen-6 level in non small cell lung cancer. AB - OBJECTIVES: We retrospectively analyzed the prognostic significance of preoperative serum Krebs von den Lungen-6 (KL-6) level in non-small cell lung cancer (NSCLC) patients. METHODS: We enrolled 175 NSCLC patients who underwent curative surgery between 2009 and 2011. We subdivided the patients into 2 groups: with and without interstitial lung disease (ILD). Prognostic significance of serum KL-6 level was examined. RESULTS: The 5-year survival of patients with high serum KL-6 level was poor. Multivariate analysis also revealed the prognostic significance of serum KL-6 level. Serum KL-6 level was also a prognostic factor for patients without ILD. Although the number of patients with ILD was small, in patients with ILD, there was a trend towards an association between serum KL-6 level and patients' prognosis but this did not reach statistical significance. CONCLUSIONS: Serum KL-6 level is a prognostic factor for resected NSCLC patients, especially patients without ILD. There is a possibility that serum KL-6 level is a prognostic marker regardless of the presence of ILD. PMID- 27515030 TI - Compensation for visually specified coarticulation in liquid-stop contexts. AB - The question of whether speech perceivers use visual coarticulatory information in speech perception remains unanswered, despite numerous past studies. Across different coarticulatory contexts, studies have both detected (e.g., Mitterer in Perception & Psychophysics, 68, 1227-1240, 2006) and failed to detect (e.g., Vroomen & de Gelder in Language and Cognitive Processes, 16, 661-672. doi: 10.1080/01690960143000092 , 2001) visual effects. In this study, we focused on a liquid-stop coarticulatory context and attempted to resolve the contradictory findings of Fowler, Brown, and Mann (Journal of Experimental Psychology: Human Perception and Performance, 26, 877-888. doi: 10.1037/0096-1523.26.3.877 , 2000) and Holt, Stephens, and Lotto (Perception & Psychophysics, 67, 1102-1112. doi: 10.3758/BF03193635 , 2005). We used the original stimuli of Fowler et al. with modifications to the experimental paradigm to examine whether visual compensation can occur when acoustic coarticulatory information is absent (rather than merely ambiguous). We found that perceivers' categorizations of the target changed when coarticulatory information was presented visually using a silent precursor, suggesting that visually presented coarticulatory information can induce compensation. However, we failed to detect this effect when the same visual information was accompanied by an ambiguous auditory precursor, suggesting that these effects are weaker and less robust than auditory compensation. We discussed why this might be the case and examined implications for accounts of coarticulatory compensation. PMID- 27515031 TI - Predicting the sensory consequences of one's own action: First evidence for multisensory facilitation. AB - Predicting the sensory consequences of our own actions contributes to efficient sensory processing and might help distinguish the consequences of self- versus externally generated actions. Previous research using unimodal stimuli has provided evidence for the existence of a forward model, which explains how such sensory predictions are generated and used to guide behavior. However, whether and how we predict multisensory action outcomes remains largely unknown. Here, we investigated this question in two behavioral experiments. In Experiment 1, we presented unimodal (visual or auditory) and bimodal (visual and auditory) sensory feedback with various delays after a self-initiated buttonpress. Participants had to report whether they detected a delay between their buttonpress and the stimulus in the predefined task modality. In Experiment 2, the sensory feedback and task were the same as in Experiment 1, but in half of the trials the action was externally generated. We observed enhanced delay detection for bimodal relative to unimodal trials, with better performance in general for actively generated actions. Furthermore, in the active condition, the bimodal advantage was largest when the stimulus in the task-irrelevant modality was not delayed that is, when it was time-contiguous with the action-as compared to when both the task-relevant and task-irrelevant modalities were delayed. This specific enhancement for trials with a nondelayed task-irrelevant modality was absent in the passive condition. These results suggest that a forward model creates predictions for multiple modalities, and consequently contributes to multisensory interactions in the context of action. PMID- 27515032 TI - An Analysis of Operative Experiences of Junior General Surgical Residents and Correlation With the SCORE Curriculum. AB - OBJECTIVE: Junior surgical resident education at academic institutions is traditionally focused to preoperative and postoperative patient management. Our objective was to investigate the number and type of surgical procedures performed by junior general surgery residents in comparison with the American Board of Surgery requirements and the Surgical Council on Resident Education (SCORE) curriculum. DESIGN: This was a retrospective study using the Accreditation Counsel for Graduate Medical Education (ACGME) operative case logs of junior surgical residents. SETTING: The Ohio State University Wexner Medical Center, Columbus, OH; a tertiary academic medical center. PARTICIPANTS: We performed, an institutional review board approved, retrospective review of logged surgical cases from general surgical residents during postgraduate year (PGY) 1 and 2 from 2009 to 2015 at an academic medical center. Summary case logs were accessed from the ACGME. Procedures were extracted from the SCORE curriculum and correlated to corresponding ACGME defined procedures for total cases, major cases, and endoscopy. Minor cases and patient care cases were excluded as they were not clearly defined on the category report. SCORE procedures were excluded if there was not a corresponding ACGME procedure on the summary report. SCORE procedures and ACGME procedures were combined with each other if there was overlap with correlation. Statistics were performed on individual and total resident data. One sample student's t-test was used to compare total number of cases logged with the 250 case log ABS requirement and to compare the total major cases and endoscopy performed with those represented on SCORE. RESULTS: Overall, 26 residents completed both PGY-1 and 2 years from 2009 to 2015, and remained at the same institution for case logs to be accessed during the study period. A total of 21 residents (80.76%) completed 250 cases or more after their first 2 years of residency. Across all years, the mean case log was 349 cases (p = 0.20), and was statistically more than than 250 cases in 3 of the 5 class years. Junior residents completed a total mean of 312 major and endoscopy cases (89%) at the end of 2 years, which was statistically higher than the 75% testing hypothesis across all years (p < 0.01). Of major and endoscopy cases performed in total by the completion of the PGY-2 year, a mean of 275 cases (88%) were included in the SCORE curriculum. Using one-sample t-test, SCORE procedures represented more than 85% of the major and endoscopy cases logged (p < 0.01). Of all major and endoscopy cases logged that correlate to a SCORE procedure, 95% were found to be "core" and 5% were "advanced." CONCLUSIONS: Our study demonstrates that junior surgical residents meet the 250 case log requirement put forth by the ABS, and most major procedures and endoscopy performed correspond with the core cases of the SCORE curriculum at our institution. This study aid in the confirmation of the SCORE curriculum for junior residents, and those procedures which should be designated as core. PMID- 27515029 TI - Therapies for Parkinson's diseases: alternatives to current pharmacological interventions. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder caused by the selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although PD has been heavily researched, the precise etiology and pathogenesis for PD are still inconclusive. Consequently, current pharmacological treatments for PD are largely symptomatic rather than preventive and there is still no cure for this disease nowadays. Moreover, nonmotor symptoms caused by intrinsic PD pathology or side effects induced by currently used pharmacological interventions are gaining increasing attention and urgently need to be treated due to their influence on quality of life. As ancient traditional healing systems, Tai Chi, Yoga, acupuncture and natural products have long been considered as complementary or alternative therapeutic options for PD. Recently, several newly developed non-pharmacological therapeutic strategies, including deep brain stimulation, repetitive transcranial magnetic stimulation, near-infrared light, gene therapy and cell replacement therapy, have also been suggested to give benefits to relieve parkinsonian symptoms. This review will summarize and update the therapeutic potential and the most recent research progresses of these traditional and modern therapeutic options and highlight their clinical meaning for the therapy of not only PD but also other neurodegenerative diseases. PMID- 27515034 TI - Prevalence of prehypertension and associated risk factors among Chinese adults from a large-scale multi-ethnic population survey. AB - BACKGROUND: Up to date, most of previous studies about Chinese prehypertension were conducted based on a small sample or in only one province, which could not represent the general population in China. Furthermore, no information on the ethnic difference in prevalence of prehypertension has been reported in China. The aim of this study is to examine the sex-specific, age-specific and ethnic specific prevalence of prehypertension and associated risk factors in a large scale multi-ethnic Chinese adult population. METHODS: The subjects came from a large-scale population survey about Chinese physiological constants and health conditions conducted in six provinces. 47, 495 adults completed blood pressure measurement. Prehypertension was defined as not being on antihypertensive medications and having SBP of 120-139 mmHg and/or DBP of 80-89 mmHg. Odds ratio (OR) and its 95 % confidence interval (CI) from logistic models were used to reflect the prevalence of prehypertension. RESULTS: The mean age of all subjects was 43.9 +/- 16.8 years. The prevalence of hypertension and prehypertension for all them was 29.5 and 36.4 %, respectively. The prevalence of hypertension and prehypertension for males (33.2 and 41.1 %, respectively) was higher than that for females (27.0 and 33.2 %, respectively), and P < 0.001. The mean age of the subjects was 54.8 +/- 14.0 years for hypertensive, 44.0 +/- 16.0 years for prehypertensive and 35.3 +/- 14.5 years for normotensive. With aging, subjects had more odds of getting prehypertension. Multivariate logistic model indicated that males (OR = 2.076, 95 % CI: 1.952-2.208), laborers with mental work (OR = 1.084, 95 % CI: 1.020-1.152), Yi (OR = 1.347, 95 %CI: 1.210-1.500) and Hui subjects (OR = 1.133, 95 % CI: 1.024-1.253), alcohol drinkers (OR = 1.147, 95 % CI: 1.072-1.228), the generally obese (OR = 2.460, 95 % CI: 2.190-2.763), the overweight (OR = 1.667, 95 % CI: 1.563-1.788), the abdominally obese (OR = 1.371, 95 % CI: 1.280-1.467) and subjects with family history of cardiovascular diseases (OR = 1.132, 95 % CI: 1.045-1.226) had higher prevalence of prehypertension. Subjects with higher educational level (OR = 0.687, 95 % CI: 0.627-0.752 for university) and Miao (OR = 0.753, 95 % CI: 0.623-0.910), Tibetan (OR = 0.521, 95 % CI: 0.442-0.613), Tujia (OR = 0.779, 95 % CI: 0.677-0.898) subjects had lower prevalence. CONCLUSION: High prevalence rate of prehypertension was general in Chinese adults. Many sociodemographic characteristics were significantly associated with prehypertension. There were important clinical significance and public health significance about age-specific, gender-specific and ethnic specific Chinese prehypertension conditions studies. PMID- 27515035 TI - Convulsions with Gastroenteritis: Reflections on some Cases and Tentative Diagnostic Score. AB - BACKGROUND: Since 1980 a form of benign convulsion during mild gastroenteritis, called Convulsion With Gastroenteritis (CWG) has been described. However diagnostic criteria have not been well defined yet given the similarity of CWG with other diseases of young age and therefore diagnosis is done by exclusion, creating anxiety in parents. OBJECTIVE AND METHODS: We here report a series of cases admitted at our hospital and, making a review analysis of data available, propose a diagnostic score (CWGDS) in order to rapidly individuate the disease from history. RESULTS: Five cases of seizures associated to gastrointestinal symptoms were admitted to the Pediatric Unit of Eastern Liguria Hospital in La Spezia from January 2014 to April 2015. All these cases could be defined as CWG given their characteristics and benign evolution. We then prepared CWGDS from literature's data and compared our cases with the score itself, having 100% agreement between clinical diagnosis and diagnosis done by CWGDS. CONCLUSION: We propose a diagnostic score to help the clinician in diagnosing a benign condition such as CWG therefore avoiding as much as possible invasive procedures and reassuring parents. PMID- 27515036 TI - Intrauterine Intervention for the Treatment of Fetal Growth Restriction. AB - Fetal growth restriction (FGR) is associated with an increased incidence of fetal and neonatal death, and of neonatal morbidity. Babies born following FGR also are at risk of a range of postnatal complications, which may contribute to an increased incidence of disease later in life. There currently are no effective clinical interventions which improve perinatal survival, intrauterine growth and later outcomes of the FGR baby. Postnatal interventions aimed at promoting or accelerating growth in FGR babies to improve outcome, particularly neurodevelopmental outcomes, may further increase the risk of metabolic dysregulation and, therefore, the risk of developing chronic disease in adulthood. An intrauterine intervention to improve nutrition and growth in the FGR fetus may have the potential to decrease mortality and improve long-term outcomes by delaying preterm delivery and mitigating the need for and risks of accelerated postnatal growth. PMID- 27515033 TI - Advances in TRH signaling. AB - The activity of the hypothalamus-pituitary-thyroid axis (HPT) is coordinated by hypophysiotropic thyrotropin releasing hormone (TRH) neurons present in the paraventricular nucleus of the hypothalamus. Hypophysiotropic TRH neurons act as energy sensors. TRH controls the synthesis and release of thyrotropin, which activates the synthesis and secretion of thyroid hormones; in target tissues, transporters and deiodinases control their local availability. Thyroid hormones regulate many functions, including energy homeostasis. This review discusses recent evidence that covers several aspects of TRH role in HPT axis regulation. Knowledge about the mechanisms of TRH signaling has steadily increased. New transcription factors engaged in TRH gene expression have been identified, and advances made on how they interact with signaling pathways and define the dynamics of TRH neurons response to acute and/or long-term influences. Albeit yet incomplete, the relationship of TRH neurons activity with positive energy balance has emerged. The importance of tanycytes as a central relay for the feedback control of the axis, as well as for HPT responses to alterations in energy balance, and other stimuli has been reinforced. Finally, some studies have started to shed light on the interference of prenatal and postnatal stress and nutrition on HPT axis programing, which have confirmed the axis susceptibility to early insults. PMID- 27515037 TI - Development and validation of an Onchocerca ochengi microfilarial hamster model for onchocerciasis drug screens. AB - BACKGROUND: Onchocerciasis, caused by the parasitic nematode, Onchocerca volvulus afflicts some 37 million people worldwide, and is the second leading infectious cause of blindness globally. The only currently recommended drug for treatment of the disease, ivermectin, is only microfilaricidal and has serious adverse effects in individuals co-infected with high loads of Loa loa microfilariae (mf), prompting the search for new and better drugs. Onchocerciasis drug discovery studies have so far been based on in vivo models using Onchocerca species which are not the closest to O. volvulus, and which may therefore, not adequately mimic the natural infection in humans. Therefore, this study was carried out to develop a better drug screening model for onchocerciasis, based on the use of cow-derived O. ochengi, the closest known relative of O. volvulus. METHODS: Mf of O. ochengi were injected subcutaneously at the nape of Syrian hamsters (Mesocricetus auratus) and BALB/c mice. The skin, and especially the earlobes of the animals were examined for mf 15-31 days after infection. For selected model validation, the hamsters were treated with ivermectin at 150 or 600 MUg/kg body weight and examined 30 days after infection for mf. For L. loa studies in hamsters, isolated mf were injected intraperitoneally and animal organs were examined on day 26 for mf. RESULTS: The Syrian hamsters were found to be the more permissive to O. ochengi mf as fully viable mf were recovered from them on day 30, compared to BALB/c mice where such mf were recovered on day 15, but not 30. However, both animals were not permissive to L. loa mf even by day 15. Interestingly, more than 50 % of the total O. ochengi mf recovered were from the earlobes. The number of mf injected was directly proportional to the number recovered. Ivermectin at both concentrations tested completely eliminated the O. ochengi mf from the hamsters. CONCLUSION: This study reveals the Syrian hamster as an appropriate small animal model for screening of novel compounds against O. ochengi, the closest known relative of O. volvulus. PMID- 27515038 TI - Can a central blood volume deficit be detected by systolic pressure variation during spontaneous breathing? AB - BACKGROUND: Whether during spontaneous breathing arterial pressure variations (APV) can detect a volume deficit is not established. We hypothesized that amplification of intra-thoracic pressure oscillations by breathing through resistors would enhance APV to allow identification of a reduced cardiac output (CO). This study tested that hypothesis in healthy volunteers exposed to central hypovolemia by head-up tilt. METHODS: Thirteen healthy volunteers were exposed to central hypovolemia by 45 degrees head-up tilt while breathing through a facemask with 7.5 cmH2O inspiratory and/or expiratory resistors. A brachial arterial catheter was used to measure blood pressure and thus systolic pressure variation (SPV), pulse pressure variation and stroke volume variation . Pulse contour analysis determined stroke volume (SV) and CO and we evaluated whether APV could detect a 10 % decrease in CO. RESULTS: During head-up tilt SV decreased form 91 (+/-46) to 55 (+/-24) mL (mean +/- SD) and CO from 5.8 (+/-2.9) to 4.0 (+/-1.8) L/min (p < 0.05), while heart rate increased (65 (+/-11) to 75 (+/-13) bpm; P < 0.05). Systolic pressure decreased from 127 (+/-14) to 121 (+/-13) mmHg during head-up tilt, while SPV tended to increase (from 21 (+/-15)% to 30 (+/ 13)%). Yet during head-up tilt, a SPV >= 37 % predicted a decrease in CO >= 10 % with a sensitivity and specificity of 78 % and 100 %, respectively. CONCLUSION: In spontaneously breathing healthy volunteers combined inspiratory and expiratory resistors enhance SPV during head-up tilted induced central hypovolemia and allow identifying a 10 % reduction in CO. Applying inspiratory and expiratory resistors might detect a fluid deficit in spontaneously breathing patients. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02549482 Registered September 10(th) 2015. PMID- 27515040 TI - Discovery of Camptothecin Based Topoisomerase I Inhibitors: Identification Using an Atom Based 3D-QSAR, Pharmacophore Modeling, Virtual Screening and Molecular Docking Approach. AB - BACKGROUND: Camptothecin is a quinoline alkaloid, isolated from the Chinese tree Camptotheca acuminate which exhibits its cytotoxic activity by the inhibition of nuclear enzyme Topoisomerase I (topo I). Camptothecin and its analogues forms a covalent bond with DNA which can arrest the tumor growth by slowing the religation step of the enzyme and stabilize the covalent adduct between topo I and DNA. Besides its strong anticancer potential, the limited solubility as well as instability of the hydroxylactone ring (Ring E) limits the clinical application of Camptothecin. This study was undertaken to identify novel compounds having anticancer activity with mechanism of action similar to that of Camptothecin using scaffold perception technique. MATERIALS AND METHODS: We developed a common pharmacophore hypothesis using 32 camptothecin analogues, which was used for preliminary screening of large databases (ZINC "drug-like" database) to make sure, to include only compounds containing the key structural features needed to be Topoisomerase I inhibitors. In terms of a structure based approach, we systematically investigated various types of docking protocols to identify the most active compounds from the identified hit molecules. A post docking energy calculation was also carried out by MM/GBSA method. RESULTS: From the selected series of camptothecin analogs, a 3D-QSAR pharmacophore model was developed. The model consists of one acceptor site, one donor site, one hydrophobic site and two aromatic functions (ADHRR). Then, the pharmacophore model was employed as 3D search query to screen compounds from ZINC database which followed by molecular docking study and MM/GBSA calculation identified 2 lead molecules which, however, were not biologically validated. In silico studies reveals that the identified lead molecules have a better binding affinity than the co crystallized ligand. CONCLUSION: The identified molecules were able to bind to the active site of Topo-I enzyme similar to that of Camptothecin and the ADME properties were within the acceptable range defined for human use. The new molecules identified by virtual screening as such or on further optimization can be used as potential leads in designing Topoisomerase I inhibitors. PMID- 27515041 TI - High Throughput Screening: Developed Techniques for Cellulolytic and Xylanolytic Activities Assay. AB - High throughput screening (HTS) is a powerful tool in biotechnology. The search for new or improved enzymes with suitable biochemical properties for industrial processes, has resulted in high efforts and research activities to develop new methodologies for activity screening. In this context, important advances have been achieved for the screening of cellulases and xylanases activities from wild and recombinant microorganisms, and from sequence databases. These enzymes have a wide range of industrial applications, including food, animal feed, textile, pulp and paper industries and detergents. Cellulases and xylanases along with pectinases, represent 20% of the world enzyme market. Recently, cellulases and xylanases have been used on fermentable sugars recovered from lignocellulosic biomass for second-generation biorefineries, aimed to produce chemical and biofuel platforms. As a result, HTS methods for biomass or biomass-degrading enzymes are gaining importance. This article presents evidence of the studies carried out for HTS of cellulase and xylanase activities. PMID- 27515039 TI - Association of microRNA polymorphisms with the risk of head and neck squamous cell carcinoma in a Chinese population: a case-control study. AB - BACKGROUND: MicroRNA (miRNA) polymorphisms may alter miRNA-related processes, and they likely contribute to cancer susceptibility. Various studies have investigated the associations between genetic variants in several key miRNAs and the risk of human cancers; however, few studies have focused on head and neck squamous cell carcinoma (HNSCC) risk. This study aimed to evaluate the associations between several key miRNA polymorphisms and HNSCC risk in a Chinese population. METHODS: In this study, we genotyped five common single-nucleotide polymorphisms (SNPs) in several key miRNAs (miR-149 rs2292832, miR-146a rs2910164, miR-605 rs2043556, miR-608 rs4919510, and miR-196a2 rs11614913) and evaluated the associations between these SNPs and HNSCC risk according to cancer site with a case-control study including 576 cases and 1552 controls, which were matched by age and sex in a Chinese population. RESULTS: The results revealed that miR-605 rs2043556 [dominant model: adjusted odds ratio (OR) 0.71, 95% confidence interval (CI) 0.58-0.88; additive model: adjusted OR 0.74, 95% CI 0.62 0.89] and miR-196a2 rs11614913 (dominant model: adjusted OR 1.36, 95% CI 1.08 1.72; additive model: adjusted OR 1.28, 95% CI 1.10-1.48) were significantly associated with the risk of oral squamous cell carcinoma (OSCC). Furthermore, when these two loci were evaluated together based on the number of putative risk alleles (rs2043556 A and rs11614913 G), a significant locus-dosage effect was noted on the risk of OSCC (P trend < 0.001). However, no significant association was detected between the other three SNPs (miR-149 rs2292832, miR-146a rs2910164, and miR-608 rs4919510) and HNSCC risk. CONCLUSION: Our study provided the evidence that miR-605 rs2043556 and miR-196a2 rs11614913 may have an impact on genetic susceptibility to OSCC in Chinese population. PMID- 27515042 TI - Multiorgan transplantation. AB - Kidney transplantation has proven to be the gold standard therapy for severe chronic kidney disease (CKD) due to multiple etiologies in individuals deemed eligible from a surgical standpoint. While kidney transplantation is traditionally considered in conditions of native kidney disease such as diabetes and immunological or inherited causes of kidney disease, an increasing indication for kidney transplantation is kidney dysfunction in the setting of other severe organ dysfunction that requires transplant, such as severe liver or heart disease. In these settings, multiorgan transplantation is now commonly performed, with controversy regarding the appropriate utilization of kidneys transplanted both from a physiological perspective (distinguishing those who require a kidney transplant) and also from an ethical perspective (allocation of a scarce resource to a more morbid population). These issues persist in the setting of simultaneous pancreas-kidney transplant (SPK), in which utilization for patients with type 1 diabetes has been historically accepted. Questions of physiological benefit persist, and utilization is waning despite broader allocation policies that encourage SPK, including consideration for patients with type 2 diabetes. The purpose of this review will be to summarize the physiological data regarding multiorgan transplantation and place these into context while reviewing current allocation policy in the United States. PMID- 27515043 TI - [Not Available]. PMID- 27515044 TI - [Not Available]. PMID- 27515045 TI - [Not Available]. PMID- 27515046 TI - Placental insufficiency among high-risk pregnancies with a normal umbilical artery resistance index after 32weeks. AB - OBJECTIVE: To determine the incidence of abnormal multi-vessel Doppler values among advanced pregnancies at risk of suboptimal placentation but with a normal umbilical artery resistance index (RI), and to assess whether clinical and ultrasonography findings can identify them. METHODS: In a prospective cross sectional study at Tygerberg Hospital, South Africa, women with high-risk pregnancies but normal umbilical artery RI after 32weeks underwent ultrasonography (fetal biometry, liquor, and placenta maturation) and Doppler assessment (uterine, umbilical, and middle cerebral arteries) between February 11 and October 21, 2013. Study data were compared among four groups: fetuses with normal uterofetoplacental Doppler values and those with any abnormal pulsatility index, each subdivided into small for gestational age (SGA) and appropriate for gestational age (AGA) by estimated fetal weight. RESULTS: Of 210 participants, 72 (36.2%) had abnormal Doppler results, and 60 (28.6%) fetuses were SGA (38 [63.3%] with abnormal Doppler results). Clinical characteristics did not differ between groups with normal or abnormal Doppler values; however, among normal Doppler results, SGA pregnancies demonstrated poorer fundal growth (P=0.006). Significant associations existed between abnormal Doppler results and asymmetric growth, inappropriately advanced placental maturation, and reduced liquor volume (all P<=0.04), but with very low sensitivities (3.9%, 4.8%, and 14.5%, respectively). CONCLUSION: Maternal characteristics and imaging variables did not reliably identify more than one-third of pregnancies with evidence of suboptimal placentation. PMID- 27515047 TI - Single oxygen vacancies of (TiO2)35 as a prototype reduced nanoparticle: implication for photocatalytic activity. AB - Titanium dioxide (TiO2), as a semiconductor metal oxide, has been one of the most popular materials studied in the field of photocatalysis. In the present study, the properties of single oxygen vacancies of (TiO2)35, a prototype of an anatase nanoparticle, were investigated by DFT calculations. (TiO2)35 is the minimum sized model (~2 nm) for a bipyramidal nanoparticle with anatase phase and eight {101} facets. All the available oxygen vacancies at various sites according to position, coordination number, and distance from the center atom were examined. The geometric, energetic and electronic properties of the reduced TiO2 clusters were analyzed by hybrid DFT functionals with different Hartree-Fock exchange ratios (0, 12.5 and 25%). It was found that the structure of pristine (TiO2)35 is somewhat different from the bulk lattice, with a relatively high surface to volume ratio. Moreover, the particular highly (three)-coordinated oxygen atom is energetically the most favorable for oxygen vacancy formation from the nanoparticle mainly due to its substantially high relaxation energy. TiO2 nanoparticles have low oxygen vacancy formation energy and narrow band gap because of their defect states, and can be utilized as an efficient photocatalyst material. PMID- 27515048 TI - Toll-like receptors: promising therapeutic targets for inflammatory diseases. AB - The health of living organisms is constantly challenged by bacterial and viral threats. The recognition of pathogenic microorganisms by diverse receptors triggers a variety of host defense mechanisms, leading to their eradication. Toll like receptors (TLRs), which are type I transmembrane proteins, recognize specific signatures of the invading microbes and activate a cascade of downstream signals inducing the secretion of inflammatory cytokines, chemokines, and type I interferons. The TLR response not only counteracts the pathogens but also initiates and shapes the adaptive immune response. Under normal conditions, inflammation is downregulated after the removal of the pathogen and cellular debris. However, a dysfunctional TLR-mediated response maintains a chronic inflammatory state and leads to local and systemic deleterious effects in host cells and tissues. Such inappropriate TLR response has been attributed to the development and progression of multiple diseases such as cancer, autoimmune, and inflammatory diseases. In this review, we discuss the emerging role of TLRs in the pathogenesis of inflammatory diseases and how targeting of TLRs offers a promising therapeutic strategy for the prevention and treatment of various inflammatory diseases. Additionally, we highlight a number of TLR-targeting agents that are in the developmental stage or in clinical trials. PMID- 27515050 TI - Signal transducer and activator of transcription 3 as a therapeutic target for cancer and the tumor microenvironment. AB - Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that modulates the transcription of a variety of genes to regulate important biological functions, including cell proliferation, differentiation, survival, angiogenesis, and immune response. Constitutive activation of STAT3 is important in oncogenic signaling and occurs at high frequency in human cancers, including diverse solid tumors and hematologic malignancies. Moreover, it is associated with a poor prognosis. The tumor microenvironment has recently been recognized as a key condition for cancer progression, invasion, angiogenesis, metastasis, and drug resistance by activation of STAT3 signaling. Therefore, understanding the biology associated with STAT3-mediated signaling cascades in the tumor microenvironment may offer the therapeutic potential to treat human cancers. This review presents an overview of the critical roles of STAT3 in the tumor microenvironment related to cancer biology and discusses recent advancements in the development of anticancer drugs that therapeutically inhibit STAT3 signaling cascades. PMID- 27515051 TI - Myofibroblasts and inflammatory cells as players of cardiac fibrosis. AB - On myocardial infarction, many cells are injured or died owing to arterial occlusion. Intracellular molecules released from injured or dead cells initiate inflammatory responses that play important roles in cardiac remodeling including fibrosis. Fibrosis is an excess accumulation of extracellular collagen. Currently, drugs used to treat cardiac fibrosis are not commercially available. Myofibroblasts are responsible for the production and secretion of collagen. Infiltrating inflammatory cells interact with fibroblasts or other cells and promote myofibroblast formation. Inflammatory cells also modulate the activities of myofibroblasts. Regulation of collagen production is critical for modulating the progression of fibrosis. Hence, the manipulation of activities of inflammatory cells and myofibroblasts will provide promising therapeutic targets for treatment of cardiac fibrosis. PMID- 27515049 TI - Autophagy in the liver: cell's cannibalism and beyond. AB - Chronic liver disease and its progression to liver failure are induced by various etiologies including viral infection, alcoholic and nonalcoholic hepatosteatosis. It is anticipated that the prevalence of fatty liver disease will continue to rise due to the growing incidence of obesity and metabolic disorder. Evidence is accumulating to indicate that the onset of fatty liver disease is causatively linked to mitochondrial dysfunction and abnormal lipid accumulation. Current treatment options for this disease are limited. Autophagy is an integral catabolic pathway that maintains cellular homeostasis both selectively and nonselectively. As mitophagy and lipophagy selectively remove dysfunctional mitochondria and excess lipids, respectively, stimulation of autophagy could have therapeutic potential to ameliorate liver function in steatotic patients. This review highlights our up-to-date knowledge on mechanistic roles of autophagy in the pathogenesis of fatty liver disease and its vulnerability to surgical stress, with an emphasis on mitophagy and lipophagy. PMID- 27515052 TI - Farnesoid X receptor as a regulator of fuel consumption and mitochondrial function. AB - Maintenance of energy homeostasis is crucial for survival of organism. There exists a close link between energy metabolism and cell survival, which are coordinately regulated by common signaling pathways. Farnesoid X receptor (FXR) serves as a ligand-mediated transcription factor to regulate diverse genes involved in bile acid, lipid, and glucose metabolism, controlling cellular and systemic energy metabolism. Another important aspect on FXR biology is related to its beneficial effect on cell survival. FXR exerts antioxidative and cytoprotective effect, which is closely associated with the ability of FXR to regulate mitochondrial function. To maintain complex biological processes under homeostasis, FXR activity needs to be dynamically and tightly controlled by different signaling pathways and modifications. In this review, we discuss the role of FXR in the regulation of energy metabolism and cell survival, with the goal of understanding molecular basis for FXR regulation in physiological and pathological conditions. This information may be of assistance in understanding recent advancements of FXR research and strategies for the prevention and treatment of metabolic disorders. PMID- 27515053 TI - Activin A secreted by human mesenchymal stem cells induces neuronal development and neurite outgrowth in an in vitro model of Alzheimer's disease: neurogenesis induced by MSCs via activin A. AB - Alzheimer's disease (AD) is characterized by progressive loss of memory in addition to cortical atrophy. Cortical atrophy in AD brains begins in the parietal and temporal lobes, which are near the subventricular zone (SVZ). The aim of this study was to activate the neurogenesis in the SVZ of AD brains by human mesenchymal stem cells (hMSCs). Neural stem cells (NSCs) were isolated from SVZ of 4-month-old 5XFAD mice. Co-culture of hMSCs with SVZ-derived NSCs from 5XFAD mice induced neuronal development and neurite outgrowth. To examine the inducing factor of neurogenesis, human cytokine array was performed with co cultured media, and revealed elevated release of activin A from hMSCs. Also, we confirmed that the mRNA levels of activin A and activin receptor in the SVZ of 5XFAD mice were significantly lower than normal mice. Treatment of human recombinant activin A in SVZ-derived NSCs from 5XFAD mice induced neuronal development and neurite outgrowth. These data suggest that use of hMSCs and activin A to recover neurogenesis in future studies of cortical regeneration to treat AD. PMID- 27515054 TI - A novel mechanism for the pyruvate protection against zinc-induced cytotoxicity: mediation by the chelating effect of citrate and isocitrate. AB - Intracellular accumulation of free zinc contributes to neuronal death in brain injuries such as ischemia and epilepsy. Pyruvate, a glucose metabolite, has been shown to block zinc neurotoxicity. However, it is largely unknown how pyruvate shows such a selective and remarkable protective effect. In this study, we sought to find a plausible mechanism of pyruvate protection against zinc toxicity. Pyruvate almost completely blocked cortical neuronal death induced by zinc, yet showed no protective effects against death induced by calcium (ionomycin, NMDA) or ferrous iron. Of the TCA cycle intermediates, citrate, isocitrate, and to a lesser extent oxaloacetate, protected against zinc toxicity. We then noted with LC-MS/MS assay that exposure to pyruvate, and to a lesser degree oxaloacetate, increased levels of citrate and isocitrate, which are known zinc chelators. While pyruvate added only during zinc exposure did not reduce zinc toxicity, citrate and isocitrate added only during zinc exposure, as did extracellular zinc chelator CaEDTA, completely blocked it. Furthermore, addition of pyruvate after zinc exposure substantially reduced intracellular zinc levels. Our results suggest that the remarkable protective effect of pyruvate against zinc cytotoxicity may be mediated indirectly by the accumulation of intracellular citrate and isocitrate, which act as intracellular zinc chelators. PMID- 27515055 TI - Attenuation of Abeta toxicity by promotion of mitochondrial fusion in neuroblastoma cells by liquiritigenin. AB - Mitochondrial dynamics control mitochondrial morphology and function, and aberrations in these are associated with various neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. To identify novel regulators of mitochondrial dynamics, we screened a phytochemical library and identified liquiritigenin as a potent inducer of mitochondrial fusion. Treatment with liquiritigenin induced an elongated mitochondrial morphology in SK-N-MC cells. In addition, liquiritigenin rescued mitochondrial fragmentation induced by knockout of mitochondrial fusion mediators such as Mfn1, Mfn2, and Opa1. Furthermore, we found that treatment with liquiritigenin notably inhibited mitochondrial fragmentation and cytotoxicity induced by Abeta in SK-N-MC cells. PMID- 27515056 TI - The confusion continues: results from an American Association for the Surgery of Trauma survey on massive transfusion practices among United States trauma centers. AB - BACKGROUND: Massive transfusion practices have undergone several recent developments. We sought to examine institutional practices guiding hemostatic resuscitation in the setting of massive hemorrhage. STUDY DESIGN AND METHODS: A 37-question online survey was sent to American Association for the Surgery of Trauma members. RESULTS: A total of 191 surgeons from 125 institutions completed the survey. Level I and II centers composed 70 and 18% of responding sites, respectively. A total of 123 institutions have a massive transfusion protocol (MTP); 54% report having an MTP for less than 5 years. The number of coolers and units of red blood cells, plasma, and platelets are highly variable. Tranexamic acid is part of the MTP at 64% of centers; 26% continue to use recombinant activated Factor VII. MTP activation occurs more than five times per month at 32% of centers. MTPs are utilized for nontrauma patients in 82% of institutions. Point-of-care prothrombin time, international normalized ratio, and partial thromboplastin time testing is utilized in 37% of institutions. Only 9% routinely utilize thromboelastography or rotational thromboelastometry (TEG/ROTEM) within their MTP. Just 7% use a validated scoring system to guide MTP activation. The incorporation of TEG/ROTEM into the MTP is associated with the use of a scoring system in regression analysis (p = 0.024). CONCLUSION: Most institutions regularly activate recently implemented MTPs for trauma and nontrauma indications; however, few use validated scoring systems for MTP activation. MTP content is highly variable. Few institutions use TEG, while most have incorporated tranexamic acid into their protocol. The lack of consistent practices underscores the need for outcome-based studies to guide transfusion practices. PMID- 27515058 TI - Position 97 of HLA-B, a residue implicated in pathogenesis of ankylosing spondylitis, plays a key role in cell surface free heavy chain expression. AB - OBJECTIVE: Association of position 97 (P97) residue polymorphisms in human leucocyte antigen (HLA)-B, including HLA-B*27, with ankylosing spondylitis (AS) has recently been reported. We studied the effect of P97 variations on cell surface expression of the AS-associated HLA-B*27 and HLA-B*51, and the AS protective HLA-B*7. METHODS: Flow cytometry was used to measure surface expression of HLA-B*27 in C1R/HeLa cells expressing HLA-B*27 (N97) and six mutants at P97 (N97T, N97S, N97V, N97R, N97W and N97D). Transporter associated with antigen processing-deficient T2, tapasin-deficient 220, beta2m-deficient HCT15 and endoplasmic reticulum aminopeptidase 1 or beta2m-clustered regularly interspaced short palindromic repeats/Cas9-knockout HeLa cells were used to provide evidence for specific protein interactions. Surface expression of HLA B*7/HLA-B*51 P97 mutants was also studied. RESULTS: Mutation of HLA-B*27 P97 to the AS risk residue threonine increased cell surface free heavy chain (FHC) expression. Protective residues (serine or valine) and non-AS-associated residues (arginine or tryptophan) did not alter FHC expression. The N97D mutation reduced expression of conventional and FHC forms of HLA-B*27. Differences in FHC expression levels between HLA-B*27, HLA-B*27-N97T and HLA-B*27-N97D were dependent on the presence of functional beta2m. HLA-B*7, which has an AS protective serine at P97, expressed lower levels of FHC than HLA-B*27 or HLA B*51. Introduction of asparagine at P97 of both HLA-B*7 and HLA-B*51 increased FHC expression. CONCLUSIONS: The nature of P97 residue affects surface expression of HLA-B*27, B*7 and B*51, with AS-associated residues giving rise to higher FHC expression levels. The association of P97 amino acid polymorphisms with AS could be, at least in part, explained by its effect on HLA-B*27 FHC cell surface expression. PMID- 27515059 TI - Child height gain is associated with consumption of animal-source foods in livestock-owning households in Western Kenya. AB - OBJECTIVE: To clarify the pathways between household livestock and child growth by assessing the relationships between consumption of animal-source foods (ASF) and child growth and evaluating the household livestock correlates of child consumption of ASF. DESIGN: We conducted a longitudinal cohort study of anthropometry and 3 d feeding recalls among children <5 years old between June 2014 and May 2015. In addition, we collected data on wealth, livestock ownership and livestock diseases in the same households. We used linear and negative binomial mixed models to evaluate the relationships between household livestock characteristics, reported consumption of ASF and child growth. SETTING: An 1800 household surveillance catchment area in Western Kenya within the structure of human and animal health surveillance systems. SUBJECTS: Children (n 874) <5 years old. RESULTS: Among children >6 months old, reported frequency of egg and milk consumption was associated with increased monthly height gain (for each additional report of consumption over 3 d: adjusted beta (95 % CI)=0.010 (0.002, 0.019) cm/month and 0.008 (0.004, 0.013) cm/month, respectively). Poultry ownership was associated with higher reported frequency of egg, milk and chicken consumption (adjusted incidence rate ratio (95 % CI)=1.3 (1.2, 1.4), 1.4 (1.1, 1.6) and 1.3 (1.1, 1.4), respectively). Some livestock diseases were associated with lower reported frequency of ASF intake (livestock digestive diseases adjusted incidence rate ratio (95 % CI)=0.89 (0.78, 1.00)). CONCLUSIONS: Child height gain was associated with milk and egg consumption in this cohort. ASF consumption was related to both household livestock ownership and animal health. PMID- 27515057 TI - Consensus-based recommendations for the management of juvenile dermatomyositis. AB - BACKGROUND: In 2012, a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile dermatomyositis (JDM) is a rare disease within the group of paediatric rheumatic diseases (PRDs) and can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. Consequently, treatment regimens differ throughout Europe. OBJECTIVES: To provide recommendations for diagnosis and treatment of JDM. METHODS: Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of 19 experienced paediatric rheumatologists and 2 experts in paediatric exercise physiology and physical therapy, mainly from Europe. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at two consensus meetings using nominal group technique. Recommendations were accepted if >80% agreement was reached. RESULTS: In total, 7 overarching principles, 33 recommendations on diagnosis and 19 recommendations on therapy were accepted with >80% agreement among experts. Topics covered include assessment of skin, muscle and major organ involvement and suggested treatment pathways. CONCLUSIONS: The SHARE initiative aims to identify best practices for treatment of patients suffering from PRD. Within this remit, recommendations for the diagnosis and treatment of JDM have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JDM throughout Europe. PMID- 27515061 TI - Asymptomatic Bilateral Internal Carotid Artery Aneurysms with Distal High-grade Stenosis in a Patient with Type 1 Neurofibromatosis. PMID- 27515060 TI - Endometrial sampling devices for early diagnosis of endometrial lesions. AB - PURPOSE: Endometrial carcinoma is the most common gynecologic malignancy in both developed and some developing countries. Unlike cervical cancer, for which there is routine screening, only patients symptomatic for endometrial carcinoma typically seek medical help for its diagnosis and treatment. Dilatation and curettage (D&C) has been the standard procedure for evaluating suspicious endometrial lesions. The discomfort and injury caused by the D&C procedure, however, restrict its use as a screening method for early diagnosis of endometrial lesions. High-risk endometrial cancer patients would benefit from an effective and low-cost screening test. In recent years, several endometrial devices have been developed and proposed as screening tools. METHODS: We have reviewed and evaluated the literature relating to the endometrial sampling devices in clinical use or clinical trials, with the goal of comparing devices and identifying the most appropriate ones for screening for endometrial lesions. Eligible literature was identified from systematic PubMed searches, and the relevant data were extracted. Comments, letters, unpublished data, conference proceedings, and case reports were excluded from our search. Seventy-four articles on endometrial sampling devices were obtained for this review. RESULTS: The main screening devices for endometrial carcinoma are aspiration devices (such as the Vabra aspirator), Pipelle, Tao Brush, and SAP-1 device. Among these devices, the Tao Brush is the most promising endometrial sampler for screening for endometrial lesions. However, its sampling insufficiency, cost, and unsuccessful insertion rate (20 % in nulliparous and 8 % in parous women) are problematic. CONCLUSIONS: A more accurate and low-cost endometrial sampler, with improved specimen sufficiency and higher sensitivity for endometrial lesions, needs tobe developed and clinically verified. PMID- 27515062 TI - Vasa Nervorum as the Source of Corkscrew Collaterals in Thromboangiitis Obliterans (Buerger's Disease). PMID- 27515063 TI - How patients think about social responsibility of public hospitals in China? AB - BACKGROUND: Hospital social responsibility is receiving increasing attention, especially in China where major changes to the healthcare system have taken place. This study examines how patients viewed hospital social responsibility in China and explore the factors that influenced patients' perception of hospital social responsibility. METHODS: A cross-sectional survey was conducted, using a structured questionnaire, on a sample of 5385 patients from 48 public hospitals in three regions of China: Shanghai, Hainan, and Shaanxi. A multilevel regression model was employed to examine factors influencing patients' assessments of hospital social responsibility. Intra-class correlation coefficients (ICCs) were calculated to estimate the proportion of variance in the dependent variables determined at the hospital level. RESULTS: The scores for service quality, appropriateness, accessibility and professional ethics were positively associated with patients' assessments of hospital social responsibility. Older outpatients tended to give lower assessments, while inpatients in larger hospitals scored higher. After adjusted for the independent variables, the ICC rose from 0.182 to 0.313 for inpatients and from 0.162 to 0.263 for outpatients. The variance at the patient level was reduced by 51.5 and 48.6 %, respectively, for inpatients and outpatients. And the variance at the hospital level was reduced by 16.7 % for both groups. CONCLUSIONS: Some hospital and patient characteristics and their perceptions of service quality, appropriateness, accessibility and professional ethics were associated with their assessments of public hospital social responsibility. The differences were mainly determined at the patient level. More attention to law-abiding behaviors, cost-effective health services, and charitable works could improve perceptions of hospitals' adherence to social responsibility. PMID- 27515064 TI - A Novel Perspective on the Biology of Bilirubin in Health and Disease. AB - Unconjugated bilirubin (UCB) is known to be one of the most potent endogenous antioxidant substances. While hyperbilirubinemia has long been recognized as an ominous sign of liver dysfunction, recent data strongly indicate that mildly elevated bilirubin (BLB) levels can be protective against an array of diseases associated with increased oxidative stress. These clinical observations are supported by new discoveries relating to the role of BLB in immunosuppression and inhibition of protein phosphorylation, resulting in the modulation of intracellular signaling pathways in vascular biology and cancer, among others. Collectively, the evidence suggests that targeting BLB metabolism could be considered a potential therapeutic approach to ameliorate a variety of conditions. PMID- 27515065 TI - Ivo Pitanguy. PMID- 27515066 TI - Erythrocytes do not activate purified and platelet soluble guanylate cyclases even in conditions favourable for NO synthesis. AB - BACKGROUND: Direct interaction between Red blood cells (RBCs) and platelets is known for a long time. The bleeding time is prolonged in anemic patients independent of their platelet count and could be corrected by transfusion of RBCs, which indicates that RBCs play an important role in hemostasis and platelet activation. However, in the last few years, opposing mechanisms of platelet inhibition by RBCs derived nitric oxide (NO) were proposed. The aim of our study was to identify whether RBCs could produce NO and activate soluble guanylate cyclase (sGC) in platelets. METHODS: To test whether RBCs could activate sGC under different conditions (whole blood, under hypoxia, or even loaded with NO), we used our well-established and highly sensitive models of NO-dependent sGC activation in platelets and activation of purified sGC. The activation of sGC was monitored by detecting the phosphorylation of Vasodilator Stimulated Phosphoprotein (VASP(S239)) by flow cytometry and Western blot. ANOVA followed by Bonferroni's test and Student's t-test were used as appropriate. RESULTS: We show that in the whole blood, RBCs prevent NO-mediated inhibition of ADP and TRAP6 induced platelet activation. Likewise, coincubation of RBCs with platelets results in strong inhibition of NO-induced sGC activation. Under hypoxic conditions, incubation of RBCs with NO donor leads to Hb-NO formation which inhibits sGC activation in platelets. Similarly, RBCs inhibit activation of purified sGC, even under conditions optimal for RBC-mediated generation of NO from nitrite. CONCLUSIONS: All our experiments demonstrate that RBCs act as strong NO scavengers and prevent NO-mediated inhibition of activated platelets. In all tested conditions, RBCs were not able to activate platelet or purified sGC. PMID- 27515067 TI - First Comprehensive Proteome Analyses of Lysine Acetylation and Succinylation in Seedling Leaves of Brachypodium distachyon L. AB - Protein acetylation and succinylation are the most crucial protein post translational modifications (PTMs) involved in the regulation of plant growth and development. In this study, we present the first lysine-acetylation and lysine succinylation proteome analysis of seedling leaves in Brachypodium distachyon L (Bd). Using high accuracy nano LC-MS/MS combined with affinity purification, we identified a total of 636 lysine-acetylated sites in 353 proteins and 605 lysine succinylated sites in 262 proteins. These proteins participated in many biology processes, with various molecular functions. In particular, 119 proteins and 115 sites were found to be both acetylated and succinylated, simultaneously. Among the 353 acetylated proteins, 148 had acetylation orthologs in Oryza sativa L., Arabidopsis thaliana, Synechocystis sp. PCC 6803, and Glycine max L. Among the 262 succinylated proteins, 170 of them were found to have homologous proteins in Oryza sativa L., Escherichia coli, Sacchayromyces cerevisiae, or Homo sapiens. Motif-X analysis of the acetylated and succinylated sites identified two new acetylated motifs (K---K and K-I-K) and twelve significantly enriched succinylated motifs for the first time, which could serve as possible binding loci for future studies in plants. Our comprehensive dataset provides a promising starting point for further functional analysis of acetylation and succinylation in Bd and other plant species. PMID- 27515068 TI - Supramolecular Metallo-Bioadhesive for Minimally Invasive Use. AB - A novel metallo-bioadhesive to be used as tissue sealant in minimally invasive procedures is reported. Metal complexation can be used to render gelatin derivatives adhesive, which occurs in minutes, is efficient, and fully biodegradable within weeks. PMID- 27515069 TI - Development and validation of a simple risk score to predict 30-day readmission after percutaneous coronary intervention in a cohort of medicare patients. AB - OBJECTIVES: To develop a risk model that can be used to identify PCI patients at higher risk of readmission who may benefit from additional resources at the time of discharge. BACKGROUND: A high proportion of patients undergoing PCI are readmitted within 30 days of discharge. METHODS: The sample comprised patients aged >=65 years who underwent PCI at a CathPCI Registry(r)-participating hospital and could be linked with 100% Medicare fee-for-service claims between 01/2007 and 12/2009. The sample (n = 388,078) was randomly divided into risk score development (n = 193,899) and validation (n = 194,179) cohorts. We did not count as readmissions those associated with staged revascularization procedures. Multivariable logistic regression models using stepwise selection models were estimated to identify variables independently associated with all-cause 30-day readmission. RESULTS: The mean 30-day readmission rates for the development (11.36%) and validation (11.35%) cohorts were similar. In total, 19 variables were significantly associated with risk of 30-day readmission (P < 0.05), and model c-statistics were similar in the development (0.67) and validation (0.66) cohorts. The simple risk score based on 14 variables identified patients at high and low risk of readmission. Patients with a score of >=13 (15.4% of sample) had more than an 18.5% risk of readmission, while patients with a score <=6 (41.9% of sample) had less than an 8% risk of readmission. CONCLUSION: Among PCI patients, risk of readmission can be estimated using clinical factors present at the time of the procedure. This risk score may guide clinical decision-making and resource allocation for PCI patients at the time of hospital discharge. (c) 2016 Wiley Periodicals, Inc. PMID- 27515070 TI - Quality of life and patient benefit following transition from methotrexate to ustekinumab in psoriasis. AB - BACKGROUND: TRANSIT (NCT01059773) compared immediate and gradual transition from methotrexate to ustekinumab in psoriasis patients via multiple measures, including patient-reported outcomes. OBJECTIVE: To evaluate patient perception of treatment benefits in TRANSIT. METHODS: A total of 489 psoriasis patients received ustekinumab, with immediate cessation of methotrexate (Arm 1) or 4 weeks' overlap with decreasing methotrexate dose (Arm 2). Ustekinumab was administered at weeks 0, 4, 16, 28 and 40. Dermatology Life Quality Index (DLQI), EuroQol 5-item (EQ-5D), visual analogue scale (VAS) valuation technique and patient benefit index (PBI) were employed. Mean global PBI and sub-scores were calculated from the sum of the benefit items weighted by their respective relevance at baseline. Patient-relevant benefit was defined as PBI >=1 (scale: 0 [no benefit] to 4 [maximum benefit]). Correlations of global PBI with Psoriasis Area and Severity Index (PASI) and DLQI were examined. RESULTS: Relationships between PBI and clinical data were evaluable in 340 patients. The most important treatment goals at baseline included: 'be healed of all skin defects', 'have confidence in therapy', 'get better skin quickly' and 'regain control of the disease'. Benefit in PBI global score was achieved at week 4 by 93% of patients in Arm 1 and 91% in Arm 2. Global PBI scores increased in both Arms between weeks 4 and 52. Global PBI correlated weakly with PASI change from baseline (correlation coefficient range: -0.22 to -0.40), and moderately with DLQI (-0.29 to -0.54). Overall DLQI score was lower than baseline at all times; and the percentage of patients with an overall score of 0 or 1 increased with time. Correspondingly, EQ VAS scores increased with time. DLQI and EQ VAS results were similar between arms. CONCLUSIONS: Regardless of the strategy for transitioning from methotrexate, ustekinumab was associated with rapid and sustained improvement in patient-reported outcomes. PBI appears a suitable tool for assessing patient-relevant treatment benefits in psoriasis patients. PMID- 27515071 TI - Expression of Epitope-Tagged Proteins in Mammalian Cells in Culture. AB - Before the advent of molecular methods to tag proteins, visualization of proteins within cells required the use of antibodies directed against the protein of interest. Thus, only proteins for which antibodies were available could be visualized. Epitope tagging allows the detection of all proteins with existing sequence information, irrespective of the availability of antibodies directed against them. This technique involves the generation of DNA constructs that express the protein of interest tagged with an epitope that can be recognized by a commercially available antibody. Proteins can be tagged with a wide variety of epitopes using commercially available vectors that allow expression in mammalian cells. Epitope-tagged proteins are easily transfected into mammalian cell lines and, in most cases, tightly mimic the behavior of the endogenous protein. Tagged proteins exogenously expressed in cells provide different types of information depending on the subsequent detection approaches. Using immunofluorescence and immunoelectron microscopy with anti-tag antibodies, relative to known markers of cellular organelles, can provide information on the subcellular localization of the tagged protein and may provide clues regarding the protein's function. Immunofluorescence with anti-tag antibodies can also be utilized to assess the tagged protein's responses to cellular signals and pharmacological treatments. Immunoprecipitations with anti-tag antibodies can recover protein complexes containing the protein of interest, resulting in the identification of interacting proteins. Recovery of tagged proteins on affinity matrices allows their purification for use in biochemical assays. In addition, specialized fluorescent tags, such as the green fluorescent protein (GFP) allow the analysis of cellular dynamics in live cells in real time. PMID- 27515072 TI - Antibody Production with Synthetic Peptides. AB - Peptides (usually 10-20 amino acid residues in length) can be used as effectively as proteins in raising antibodies producing both polyclonal and monoclonal antibodies routinely with titers higher than 20,000. Peptide antigens do not function as immunogens unless they are conjugated to proteins. Production of high quality antipeptide antibodies is dependent upon peptide sequence selection, the success of peptide synthesis, peptide-carrier protein conjugation, the humoral immune response in the host animal, the adjuvant used, the peptide dose administered, the injection method, and the purification of the antibody. Peptide sequence selection is probably the most critical step in the production of antipeptide antibodies. Although the process for designing peptide antigens is not exact, several guidelines and computational B-cell epitope prediction methods can help maximize the likelihood of producing antipeptide antibodies that recognize the protein. Antibodies raised by peptides have become essential tools in life science research. Virtually all phospho-specific antibodies are now produced using phosphopeptides as antigens. Typically, 5-20 mg of peptide is enough for antipeptide antibody production. It takes 3 months to produce a polyclonal antipeptide antibody in rabbits that yields ~100 mL of serum which corresponds to ~8-10 mg of the specific antibody after affinity purification using a peptide column. PMID- 27515073 TI - Production and Purification of Polyclonal Antibodies. AB - Polyclonal antibodies consist of a mixture of antibodies produced by multiple B cell clones that have differentiated into antibody-producing plasma cells in response to an immunogen. Polyclonal antibodies raised against an antigen recognize multiple epitopes on a target molecule, which results in a signal amplification in indirect immunoassays including immune-electron microscopy. In this chapter, we present a basic procedure to generate polyclonal antibodies in rabbits. PMID- 27515074 TI - Preparation of Colloidal Gold Particles and Conjugation to Protein A/G/L, IgG, F(ab')2, and Streptavidin. AB - Colloidal gold probes, including protein A/G/L, IgG, F(ab')2, and streptavidin labeled with gold particles, are useful tools to localize antigens in cells and tissues by immunoelectron microscopy (IEM). This chapter describes different methods for the preparation of colloidal gold and conjugation of colloidal gold to protein A/G/L, IgG, and streptavidin. PMID- 27515075 TI - Helper-Dependent Adenoviral Vectors and Their Use for Neuroscience Applications. AB - Neuroscience research has been revolutionized by the use of recombinant viral vector technology from the basic, preclinical and clinical levels. Currently, multiple recombinant viral vector types are employed with each having its strengths and weaknesses depending on the proposed application. Helper-dependent adenoviral vectors (HdAd) are emerging as ideal viral vectors that solve a major need in the neuroscience field: (1) expression of transgenes that are too large to be packaged by other viral vectors and (2) rapid onset of transgene expression in the absence of cytotoxicity. Here, we describe the methods for large-scale production of HdAd viral vectors for in vivo use with neurospecific transgene expression. PMID- 27515076 TI - Localizing Proteins in Fixed Giardia lamblia and Live Cultured Mammalian Cells by Confocal Fluorescence Microscopy. AB - Confocal fluorescence microscopy and electron microscopy (EM) are complementary methods for studying the intracellular localization of proteins. Confocal fluorescence microscopy provides a rapid and technically simple method to identify the organelle in which a protein localizes but only EM can identify the suborganellular compartment in which that protein is present. Confocal fluorescence microscopy, however, can provide information not obtainable by EM but required to understand the dynamics and interactions of specific proteins. In addition, confocal fluorescence microscopy of cells transfected with a construct encoding a protein of interest fused to a fluorescent protein tag allows live cell studies of the subcellular localization of that protein and the monitoring in real time of its trafficking. Immunostaining methods for confocal fluorescence microscopy are also faster and less involved than those for EM allowing rapid optimization of the antibody dilution needed and a determination of whether protein antigenicity is maintained under fixation conditions used for EM immunogold labeling. This chapter details a method to determine by confocal fluorescence microscopy the intracellular localization of a protein by transfecting the organism of interest, in this case Giardia lamblia, with the cDNA encoding the protein of interest and then processing these organisms for double label immunofluorescence staining after chemical fixation. Also presented is a method to identify the organelle targeting information in the presequence of a precursor protein, in this case the presequence of the precursor to the Euglena light harvesting chlorophyll a/b binding protein of photosystem II precursor (pLHCPII), using live cell imaging of mammalian COS7 cells transiently transfected with a plasmid encoding a pLHCPII presequence fluorescent protein fusion and stained with organelle-specific fluorescent dyes. PMID- 27515077 TI - Using Fluorescent Protein Fusions to Study Protein Subcellular Localization and Dynamics in Plant Cells. AB - Studies of protein subcellular localization and dynamics are helpful in understanding the cellular functions of proteins in an organism. In the past decade, the use of green fluorescent protein (GFP) as a fusion tag has dramatically extended our knowledge in this field. Transient expression and stable transformation of GFP-tagged proteins have been wildly used to study protein localization in vivo in different systems. Although GFP-based tags provide a fast and convenient way to characterize protein properties in living cells, several reports have demonstrated that GFP fusions might not accurately reflect the localization of the native protein as GFP tags may alter the protein properties. To facilitate proper usage of GFP tags in plant cell biology study, we describe detailed protocols to identify possible inhibitory effects of fluorescent tags on protein subcellular localization and to determine if a fluorescently tagged protein is localized to the correct subcellular compartment. Using Arabidopsis Endomembrane protein 12 (EMP12) as an example, we first show the possible inhibitory effect of GFP tags on proper protein localization and then describe the immunofluorescence labeling method to verify the correct localization of GFP fusion proteins. Next, a method is presented using the ImageJ program with the Pearson-Spearman correlation (PSC) colocalization plug-in for statistical quantification of colocalization ratios of two fluorophores. Finally we provide a detailed method for protein dynamics studies using spinning disk confocal microscopy in Arabidopsis cells. PMID- 27515078 TI - Using FRAP or FRAPA to Visualize the Movement of Fluorescently Labeled Proteins or Cellular Organelles in Live Cultured Neurons Transformed with Adeno-Associated Viruses. AB - Fluorescence recovery after photobleaching (FRAP) and fluorescence redistribution after photoactivation (FRAPA) are complementary methods used to gauge the movement of proteins or sub-resolution organelles within cells. Using these methods we can determine the nature of the movement of labeled particles, whether it is random, constrained, or active, the coefficient of diffusion if applicable, binding and unbinding constants, and the direction of active transport. These two techniques have been extensively utilized to probe the cell biology of neurons. A practical outline of FRAP and FRAPA in cultured neurons is presented, including the preparation of the neurons and their infection with adeno-associated viral vectors. Considerations in planning such experiments are provided. PMID- 27515079 TI - Bimolecular Fluorescence Complementation (BiFC) Analysis of Protein-Protein Interactions and Assessment of Subcellular Localization in Live Cells. AB - Bimolecular fluorescence complementation (BiFC) is a fluorescence imaging technique used to visualize protein-protein interactions (PPIs) in live cells and animals. One unique application of BiFC is to reveal subcellular localization of PPIs. The superior signal-to-noise ratio of BiFC in comparison with fluorescence resonance energy transfer or bioluminescence resonance energy transfer enables its wide applications. Here, we describe how confocal microscopy can be used to detect and quantify PPIs and their subcellular localization. We use basic leucine zipper transcription factor proteins as an example to provide a step-by-step BiFC protocol using a Nikon A1 confocal microscope and NIS-Elements imaging software. The protocol given below can be readily adapted for use with other confocal microscopes or imaging software. PMID- 27515080 TI - Viral Injection and Cranial Window Implantation for In Vivo Two-Photon Imaging. AB - Two-photon (2P) imaging has proven to be a powerful tool for investigating neural structure and function both in brain slices and in intact systems. In vivo 2P imaging presents significant challenges in sample preparation, which are exacerbated in non-murine species. Here, we describe procedures for the effective virally mediated labeling of neurons and for the implantation of cranial windows for imaging. The procedures described here are applicable to a range of species, including mice, and are routinely used in ferrets and tree shrews to provide large-scale labeling of cortical volumes and high-quality imaging data. PMID- 27515081 TI - Imaging Synaptic Vesicle Exocytosis-Endocytosis with pH-Sensitive Fluorescent Proteins. AB - The introduction of pHluorin, a pH-sensitive GFP, by Miesenbock and colleagues provided a versatile tool to studies of vesicle trafficking, in particular synaptic vesicle exocytosis and endocytosis. By tagging pHluorin to the luminal region of the synaptic vesicular protein synaptobrevin (also called VAMP, vesicle associated membrane protein) or other synaptic vesicle-specific proteins such as the vesicular glutamate transporter-1, we are able to directly track synaptic vesicle endocytosis in response to stimuli in a molecularly specific manner. Here, we describe the process of imaging synaptic vesicle endocytosis in response to extracellular stimulation in dissociated neuronal cultures of hippocampal neurons obtained from rats-also applicable to mice-using pHluorin-tagged vesicular glutamate transporter-1 as a reporter. PMID- 27515082 TI - Immunogold Protein Localization on Grid-Glued Freeze-Fracture Replicas. AB - Immunogold labeling of freeze-fracture replicas has recently been used for high resolution visualization of protein localization in electron microscopy. This method has higher labeling efficiency than conventional immunogold methods for membrane molecules allowing precise quantitative measurements. However, one of the limitations of freeze-fracture replica immunolabeling is difficulty in keeping structural orientation and identifying labeled profiles in complex tissues like brain. The difficulty is partly due to fragmentation of freeze fracture replica preparations during labeling procedures and limited morphological clues on the replica surface. To overcome these issues, we introduce here a grid-glued replica method combined with SEM observation. This method allows histological staining before dissolving the tissue and easy handling of replicas during immunogold labeling, and keeps the whole replica surface intact without fragmentation. The procedure described here is also useful for matched double-replica analysis allowing further identification of labeled profiles in corresponding P-face and E-face. PMID- 27515083 TI - Pre-embedding Double-Label Immunoelectron Microscopy of Chemically Fixed Tissue Culture Cells. AB - Localization of specific proteins within cells at the nanometer level of resolution is central to understanding how these proteins function in cell processes such as motility and intracellular trafficking. Such localization can be achieved by combining transmission electron microscopy (TEM) with immunogold labeling. Here we describe a pre-embedding, indirect gold immunolabeling approach to localize two different proteins of interest with secondary antibodies labeled with gold particles of different sizes in cells grown on cover slips. In this protocol, the cells are immunolabeled prior to being embedded in an epoxy resin for ultrathin sectioning. The protocol also includes strategies for optimizing the balance between ultrastructure and antigen preservation, steps to minimize nonspecific antibody binding, and steps to optimize antibody penetration. PMID- 27515084 TI - Immunoelectron Microscopy of Cryofixed and Freeze-Substituted Plant Tissues. AB - Cryofixation and freeze-substitution techniques provide excellent preservation of plant ultrastructure. The advantage of cryofixation is not only in structural preservation, as seen in the smooth plasma membrane, but also in the speed in arresting cell activity. Immunoelectron microscopy reveals the subcellular localization of molecules within cells. Immunolabeling in combination with cryofixation and freeze-substitution techniques provides more detailed information on the immunoelectron-microscopic localization of molecules in the plant cell than can be obtained from chemically fixed tissues. Here, we introduce methods for immunoelectron microscopy of cryofixed and freeze-substituted plant tissues. PMID- 27515085 TI - Immunoelectron Microscopy of Cryofixed Freeze-Substituted Yeast Saccharomyces cerevisiae. AB - Immunolabeling electron microscopy is a challenging technique with demands for perfect ultrastructural and antigen preservation. High-pressure freezing offers an excellent way to fix cellular structure. However, its use for immunolabeling has remained limited because of the low frequency of labeling due to loss of protein antigenicity or accessibility. Here we present a protocol for immunogold labeling of the yeast Saccharomyces cerevisiae that gives specific and multiple labeling while keeping the finest structural details. We use the protocol to reveal the organization of individual nuclear pore complex proteins and the position of transport factors in the yeast Saccharomyces cerevisiae in relation to actual transport events. PMID- 27515086 TI - Pre-embedding Method of Electron Microscopy for Glycan Localization in Mammalian Tissues and Cells Using Lectin Probes. AB - In recent years, the study of glycans is progressing remarkably by the development of glycan analysis systems using mass spectrometry, glycan profiling systems using lectin microarrays, and glycoprotein analysis by the isotope-coded glycosylation site-specific tagging method. With these methodologies, glycan structures and biological functions are being elucidated. In the study of glycan function as well as disease diagnosis, it is important to examine the localization of glycans in tissues and cells. Histochemical methods using lectin probes can localize glycans in the tissues and cells. This chapter describes a pre-embedding electron microscopic method for glycan localization in which tissue sections and cells are incubated with lectin prior to embedding in resin. PMID- 27515087 TI - Pre-embedding Nanogold Silver and Gold Intensification. AB - Pre-embedding nanogold silver and gold intensification methods involve immunoreactions with nanogold-labeled antibodies and intensification of the nanogold particles before embedding and ultrathin sectioning. These highly sensitive methods show good resolution and ultrastructural preservation. They also are useful for simultaneous observation of immunolabeled cells under light and electron microscopes, and for three-dimensional immunoelectron microscopic analyses. Silver intensification is usually superior for immunolabeling. On the other hand, ultrastructural preservation is better when gold intensification is used. In this chapter, we introduce pre-embedding nanogold silver and gold intensification procedures for use primarily with cultured cells. PMID- 27515088 TI - Post-embedding Mammalian Tissue for Immunoelectron Microscopy: A Standardized Procedure Based on Heat-Induced Antigen Retrieval. AB - We describe a standardized method of fixation, antigen retrieval, and image contrasting for post-embedding immunoelectron microscopy. Tissues are fixed with formaldehyde solutions containing Ca(2+) and Mg(2+) ions at pH 7.4 and then at pH 8.5. After dehydration with dimethylformamide, the specimens are embedded in LR White resin. For antigen retrieval, ultrathin sections are heated in 0.5 M Tris HCl, pH 9.0, for 1-2 h at 95 degrees C. After immunogold labeling, the sections are treated with a mixture of tannic acid and glutaraldehyde, with OsO4 solution, and then double-stained with uranyl acetate and lead citrate. The standardized method yields strong and reproducible immunoreactions for many antigens showing excellent image contrast without destruction of fine structures. PMID- 27515089 TI - Pre- and Post-embedding Immunogold Labeling of Tissue Sections. AB - Despite the improved resolution capacities of fluorescence microscopy over the last 20 years, localization of specific proteins at the ultrastructural level with gold-conjugated antibodies remains a valuable technique in the cell biological tool chest. Ultrastructural immunolocalization of specific proteins in tissues rather than in cultured cells is often advantageous because, in tissues, the interactions between different cell types and with the extracellular matrix are maintained. Here, we describe two immunogold labeling procedures to localize at the ultrastructural level one or more proteins. In the first procedure (pre embedding), micrometer-thick tissue cryostat sections are immunostained prior to embedding for obtaining ultrathin sections suitable for TEM, while in the second procedure (post-embedding), tissues are embedded in a hydrophobic resin such as Lowicryl K4M and ultrathin sections are first obtained and then immunolabeled. While the former method is better at generating strong immunolabeling, the latter is better at preserving ultrastructure. PMID- 27515090 TI - Immunogold Labeling for Scanning Electron Microscopy. AB - Scanning electron microscopes are useful biological tools that can be used to image the surface of whole organisms, tissues, cells, cellular components, and macromolecules. Processes and structures that exist at surfaces can be imaged in pseudo, or real 3D at magnifications ranging from about 10* to 1,000,000*. Therefore a whole multicellular organism, such as a fly, or a single protein embedded in one of its cell membranes can be visualized. In order to identify that protein at high resolution, or to see and quantify its distribution at lower magnifications, samples can be labeled with antibodies. Any surface that can be exposed can potentially be studied in this way. Presented here is a generic method for immunogold labeling for scanning electron microscopy, using two examples of specimens: isolated nuclear envelopes and the cytoskeleton of mammalian culture cells. Various parameters for sample preparation, fixation, immunogold labeling, drying, metal coating, and imaging are discussed so that the best immunogold scanning electron microscopy results can be obtained from different types of specimens. PMID- 27515091 TI - Monitoring Synaptic Vesicle Protein Sorting with Enhanced Horseradish Peroxidase in the Electron Microscope. AB - Protein sorting is the fundamental cellular process that creates and maintains cell organelles and subcellular structures. The synaptic vesicle (SV) is a unique cell organelle that contains a plethora of specific SV proteins and its protein composition is crucial for its function. Thus understanding the mechanisms that sort proteins to SVs and other cell organelles is central to neuroscience and cell biology.While in the past protein sorting was studied in the fluorescence and confocal microscope, we here present a protocol that reveals SV protein trafficking and sorting in the electron microscope (EM). The protocol exploits tagging SV proteins with a new genetically encoded label for EM: enhanced horseradish peroxidase (eHRP). eHRP gained its high sensitivity through direct evolution of its catalytic activity and is detectable in the EM and LM after expression in neurons and other mammalian cells. The protocol describes the use of eHRP, labeling of SVs in cultured hippocampal neurons, and analysis via serial section reconstruction. PMID- 27515092 TI - Functional Nanoscale Imaging of Synaptic Vesicle Cycling with Superfast Fixation. AB - Functional imaging is the measurement of structural changes during an ongoing physiological process over time. In many cases, functional imaging has been implemented by tracking a fluorescent signal in live imaging sessions. Electron microscopy, however, excludes live imaging which has hampered functional imaging approaches on the ultrastructural level. This barrier was broken with the introduction of superfast fixation. Superfast fixation is capable of stopping and fixing membrane traffic at sufficient speed to capture a physiological process at a distinct functional state. Applying superfast fixation at sequential time points allows tracking of membrane traffic in a step-by-step fashion.This technique has been applied to track labeled endocytic vesicles at central synapses as they pass through the synaptic vesicle cycle. At synapses, neurotransmitter is released from synaptic vesicles (SVs) via fast activity dependent exocytosis. Exocytosis is coupled to fast endocytosis that retrieves SVs components from the plasma membrane shortly after release. Fluorescent FM dyes that bind to the outer leaflet of the plasma membrane enter the endocytic vesicle during membrane retrieval and remain trapped in endocytic vesicles have been widely used to study SV exo-endocytic cycling in live imaging sessions. FM dyes can also be photoconverted into an electron-dense diaminobenzidine polymer which allows the investigation of SV cycling in the electron microscope. The combination of FM labeling with superfast fixation made it possible to track the fine structure of endocytic vesicles at 1 s intervals. Because this combination is not specialized to SV cycling, many other cellular processes can be studied. Furthermore, the technique is easy to set up and cost effective.This chapter describes activity-dependent FM dye labeling of SVs in cultured hippocampal neurons, superfast microwave-assisted fixation, photoconversion of the fluorescent endocytic vesicles, and the analysis of individual synapses after serial section 3D reconstruction of individual synapses from electron micrographs. PMID- 27515093 TI - Expression of glycosylated alpha-dystroglycan in newborn skeletal and cardiac muscles of fukutin related protein (FKRP) mutant mice. AB - INTRODUCTION: Mutations in the Fukutin related protein (FKRP) gene are characterized by a lack of functionally glycosylated alpha-dystroglycan (F-alpha DG) in muscles. A small number of fibers retain the capacity to produce strong IIH6 reactive glycosylated-alpha-DG (g-alpha-DG) in muscles of both FKRP mutant animals and patients. METHODS: We examined the expression of g-alpha-DG in limb, diaphragm, and cardiac muscles of newborn FKRP mutants and LARGEmyd mice with IIH6 antibody. RESULTS: Near-normal levels of g-alpha-DG were detected in all 3 muscles in the FKRP448LNeo- mutant. Expression was limited within the first 8 postnatal days with decreasing levels. No expression was identified in LARGEmyd mice. CONCLUSIONS: Temporary expression of glycosylated-alpha-DG in newborn FKRP mutant muscles is LARGE- and mutant FKRP-dependent. The capability of mutant FKRP with a severe clinic phenotype to produce glycosylated-alpha-DG provides a new perspective for possible approaches to mitigate FKRP deficiency. Muscle Nerve 55: 582-590, 2017. PMID- 27515094 TI - Hoyosella rhizosphaerae sp. nov., a halotolerant actinobacterium isolated from rhizosphere soil of Suaeda salsa, and emended description of the genus Hoyosella. AB - A halotolerant actinobacterium, designated J12GA03T, was isolated from a rhizosphere soil sample of Suaeda salsa collected from a dried saline lake in Hebei Province, China. Cells were Gram-staining-positive, non-motile and non spore-forming cocci. Strain J12GA03T grew optimally at 28-37 degrees C, 0-3 % NaCl (w/v) and pH 6.5-7.5. It contained meso-diaminopimelic acid as the diagnostic diamino acid and arabinose, galactose and ribose as the diagnostic whole-cell sugars. MK-8 and MK-7 were detected as predominant menaquinones. Major fatty acids were C17 : 1omega8c, C16 : 0 and C17 : 0. Polar lipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol, phosphatidylglycerol, phosphoglycolipids, glycolipids, unidentified phospholipids and additional lipids. The muramyl residue was acetyl. Mycolic acids (34-38 carbon atoms) were present. The G+C content of the genomic DNA was 55.8 mol%. It shared the highest 16S rRNA gene sequence similarities with Amycolicicoccus subflavus DQS3-9A1T (98.18 %) and Hoyosella altamirensis OFN S31T (97.75 %). Phylogenetic trees showed that strain J12GA03T firmly formed a distinct monophyletic branch in the clade with A.subflavus DQS3-9A1T and H.altamirensis DSM 45258T. The levels of DNA-DNA relatedness with A.subflavus DSM 45089T and H.altamirensis DSM 45258T were 39.7+/-3.9 % and 35.7+/-3.0 %, respectively. Combining the evidence from the polyphasic taxonomic study, strain J12GA03T represents a novel species of the genus Hoyosella, for which the name Hoyosella rhizosphaerae sp. nov. is proposed. The type strain is J12GA03T (=DSM 101985T=CGMCC 1.15478T). PMID- 27515095 TI - Which one is more effective for the clinical treatment of chronic pain in knee osteoarthritis: radiofrequency neurotomy of the genicular nerves or intra articular injection? AB - OBJECTIVES: To compare the efficacy of intra-articular injection and radiofrequency (RF) neurotomy of genicular nerves in patients with chronic knee osteoarthritis (OA) pain. METHODS: Seventy-three patients with knee OA were included in the study. Patients were randomly assigned to Group IA (intra articular 2.5 mL of bupivacaine, 2.5 mg of morphine and 1 mL of betamethasone, 6 mL of fluid injection) or Group RF (RF neurotomy of the genicular nerves). The outcome measures included a pain scale (visual analog scale, VAS) and Western Ontario and McMaster Universities (WOMAC) Index of Osteoarthritis. RESULTS: No statistically significant difference was found between the two groups in baseline VAS-pain. In Group RF, a significant reduction was observed in VAS-pain at the first month (P < 0.001) and the third month (P < 0.001) in comparison to Group IA. Also in Group RF, a significant reduction was observed in WOMAC total scores in the first month (P < 0.001) in comparison to Group IA. CONCLUSION: This study is the first controlled study in the literature which compares RF genicular nerve to intra-articular injections. This study demonstrated that genicular nerve RF neurotomy is a safe and efficient treatment modality and provides functional improvement along with an analgesia in patients with chronic knee OA. PMID- 27515096 TI - Decreased expression of NR4A nuclear receptors in adenomyosis impairs endometrial decidualization. AB - STUDY QUESTION: How do NR4A receptors drive decidualization of human endometrial stromal cells (hESCs)? SUMMARY ANSWER: NR4A receptors modulate endometrial decidualization by transcriptional activation of FOXO1A, and in adenomyosis patients, the reduced expression of NR4A receptors in the eutopic endometrium may represent a novel mechanism to explain impaired decidualization and subfertility. WHAT IS KNOWN ALREADY: A close relationship between impaired decidualization and subfertility has been established. In human endometrial stromal cells, orphan nuclear receptor NR4A is a novel regulator of decidualization. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Eutopic endometrial tissues and hESCs from fertile controls (n = 56) and adenomyosis patients (n = 27) were collected for in vitro analysis. Primary hESCs isolated from eutopic endometrial tissues were used to evaluate the biological function of NR4A receptors. Adenovirus-mediated overexpression of NR4A and small interfering RNAs targeting NR4A, and FOXO1A were used to investigate the molecular mechanisms. Gene expression regulation was examined by real-time-quantitative PCR, immunostaining, and luciferase reporter assay. Artificial decidualization assay was performed to investigate the role of NR4A1 during decidualization in vivo. MAIN RESULTS AND THE ROLE OF CHANCE: NR4A modulates the decidualization of hESCs by upregulating prolactin (PRL) and insulin-like growth factor binding protein-1 (IGFBP-1) expression and transformation in vitro. Loss of uterine Nr4a1 results in female subfertility due to impaired decidualization. Mechanistically, NR4A binds to the nerve growth factor 1B (NGFI-B) -responsive element (NBRE) (-843 to -813) within the FOXO1A promoter region and regulates FOXO1A expression. Loss of FOXO1A significantly inhibits PRL and IGFBP-1 expression, as induced by NR4A. Moreover, the expression of NR4A and FOXO1A was lower in adenomyosis endometrial tissues compared to fertile controls, especially in stroma compartments. Ectopic NR4A expression rescued PRL and IGFBP-1 expression in adenomyotic hESCs to near-normal levels. Furthermore, PI3K/AKT signaling pathway involved in inducing NR4A expression under decidualization stimuli in hESCs and the level of p(Ser473)-AKT was significantly higher in stroma in endometrium from patients with adenomyosis. LIMITATIONS, REASONS FOR CAUTION: This is an in vitro study with a small sample size, utilizing stromal cell cultures from endometrial tissues of adenomyosis patients. Furthermore, results obtained should also be confirmed in a larger data set and with adenomyosis mouse models in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Identification of a positive agonist of NR4A receptors will be critical for the improved treatment of patients with conditions of insufficient decidualization-associated infertility, such as adenomyosis and endometriosis. LARGE SCALE DATA: N/A. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by the National Natural Science Foundation of China (81170570, G.J.Y. 81370683, G.J.Y. 81501251, Y.J. 31571189, H.X.S. and 81571402, G.J.Y.), and a special grant for clinical medicine science of Jiangsu Province (BL2014003, H.X.S.). The authors have no conflicts of interest to declare. PMID- 27515097 TI - Efficacy and safety of LAS41008 (dimethyl fumarate) in adults with moderate-to severe chronic plaque psoriasis: a randomized, double-blind, Fumaderm(r) - and placebo-controlled trial (BRIDGE). AB - BACKGROUND: Fumaric acid esters (FAEs) are recommended in international guidelines for induction and long-term treatment of adults with moderate-to severe chronic plaque psoriasis. The fixed combination Fumaderm(r) is approved in Germany, with dimethyl fumarate (DMF) being the main active ingredient. OBJECTIVES: To assess the efficacy and safety of a new formulation of DMF (LAS41008), compared with placebo and Fumaderm(r) , in adults with moderate-to severe chronic plaque psoriasis. METHODS: In this phase III, double-blind, placebo-controlled, noninferiority trial (BRIDGE, NCT01726933, EudraCT 2012 000055-13), patients were randomized to receive LAS41008, Fumaderm(r) or placebo (2 : 2 : 1) for 16 weeks, uptitrating to a maximum daily DMF dose of 720 mg, depending upon individual response. The coprimary end points were the percentage of patients achieving >= 75% improvement in Psoriasis Area and Severity Index (PASI 75) and the percentage achieving a score of 'clear' or 'almost clear' in the Physician's Global Assessment (PGA) at week 16. RESULTS: In total, 671 patients were randomized and included in the full analysis set (n = 267, LAS41008; n = 273, Fumaderm(r) ; n = 131, placebo). At week 16, 37.5% of patients treated with LAS41008 achieved PASI 75, compared with 15.3% receiving placebo (superiority for LAS41008 vs. placebo: P < 0.001) and 40.3% receiving Fumaderm(r) (noninferiority for LAS41008 vs. Fumaderm(r) : P < 0.001). Overall, 33% of patients treated with LAS41008 were 'clear' or 'almost clear' in the PGA at week 16, compared with 13.0% receiving placebo (P < 0.0001; LAS41008 superiority vs. placebo) and 37.4% receiving Fumaderm(r) . Most treatment-related adverse events were classed as 'mild' in severity. CONCLUSIONS: LAS41008 (DMF) is effective in the treatment of adults with moderate-to-severe chronic plaque psoriasis. PMID- 27515099 TI - Identification and functional analysis of invasion associated locus B (IalB) in Bartonella species. AB - Bartonellosis is caused by the genus Bartonella. Bartonella is widely distributed in the ruminants, cats, dogs, rodents and other mammals including humans. At least 13 species or subspecies of Bartonella are zoonotic, and each species appears to be highly adapted to one or a limited number of reservoir animals in which it is asymptomatic, while it can be transmitted to humans in which a variety of clinical manifestations can be caused. It was reported that Bartonella henselae infection rate among domestic cats was high in nature, making it one of the leading, important, and easily neglected zoonotic diseases. The aims of this study were to identify the expression, localization, immunogenicity and functional mechanism of Bartonella virulence factor IalB. We found that recombinant IalB protein could react with the serum from infected reservoir hosts and anti-IalB polyclonal antibodies could react with different Bartonella species by western blot analysis. According to these results, we proposed that IalB protein and anti-IalB antibodies would be good candidates for diagnosis of Bartonella infection by antigen-based anti-IalB antibodies or antibody-based IalB antigen capture immunoassay, respectively. We also found that IalB had a putative 22-amino-acid signal sequence and little IalB was localized to the outer membrane of Bartonella birtlesii by electron microscopy assay. Incubation with anti-IalB polyclonal antibodies resulted in inhibition of the invasion of mouse erythrocytes by B. birtlesii. According to these results, we propose that IalB could be a secreted protein that facilitates Bartonella entry into erythrocytes. In conclusion, these results improve our understanding of IalB as a candidate for immunodiagnosis and how IalB affects Bartonella-erythrocyte entry. PMID- 27515098 TI - Atlantic salmon populations reveal adaptive divergence of immune related genes - a duplicated genome under selection. AB - BACKGROUND: Populations of Atlantic salmon display highly significant genetic differences with unresolved molecular basis. These differences may result from separate postglacial colonization patterns, diversifying natural selection and adaptation, or a combination. Adaptation could be influenced or even facilitated by the recent whole genome duplication in the salmonid lineage which resulted in a partly tetraploid species with duplicated genes and regions. RESULTS: In order to elucidate the genes and genomic regions underlying the genetic differences, we conducted a genome wide association study using whole genome resequencing data from eight populations from Northern and Southern Norway. From a total of ~4.5 million sequencing-derived SNPs, more than 10 % showed significant differentiation between populations from these two regions and ten selective sweeps on chromosomes 5, 10, 11, 13-15, 21, 24 and 25 were identified. These comprised 59 genes, of which 15 had one or more differentiated missense mutation. Our analysis showed that most sweeps have paralogous regions in the partially tetraploid genome, each lacking the high number of significant SNPs found in the sweeps. The most significant sweep was found on Chr 25 and carried several missense mutations in the antiviral mx genes, suggesting that these populations have experienced differing viral pressures. Interestingly the second most significant sweep, found on Chr 5, contains two genes involved in the NF-KB pathway (nkap and nkrf), which is also a known pathogen target that controls a large number of processes in animals. CONCLUSION: Our results show that natural selection acting on immune related genes has contributed to genetic divergence between salmon populations in Norway. The differences between populations may have been facilitated by the plasticity of the salmon genome. The observed signatures of selection in duplicated genomic regions suggest that the recently duplicated genome has provided raw material for evolutionary adaptation. PMID- 27515101 TI - Hepatitis C virus plays hide and seek with neutralizing antibodies. PMID- 27515100 TI - Long-term prognostic value of risk scores after drug-eluting stent implantation for unprotected left main coronary artery: A pooled analysis of the ISAR-LEFT MAIN and ISAR-LEFT-MAIN 2 randomized clinical trials. AB - OBJECTIVES: To evaluate the long-term prognostic value of risk scores in the setting of drug-eluting stent (DES) implantation for uLMCA. BACKGROUND: Data on the prognostic value of novel risk scores developed to select the most appropriate revascularization strategy in patients undergoing DES implantation for uLMCA disease are relatively limited. METHODS: The study represents a patient level pooled analysis of the ISAR-LEFT-MAIN (607 patients randomized to paclitaxel-eluting or sirolimus-eluting stents) and the ISAR-LEFT-MAIN-2 (650 patients randomized to everolimus-eluting or zotarolimus-eluting stents) randomized trials. The Syntax Score (SxScore) as well the Syntax Score II (SS II), the EuroSCORE and the Global Risk Classification (GRC) were calculated. The primary outcome was all-cause mortality. RESULTS: At a mean follow-up of 3 years there were 160 deaths (12.7%). The death-incidence was significantly higher in the upper tertiles than in the intermediate or lower ones for all risk scores (log-rank test P < 0.01 for all comparisons). The discriminatory power of a multivariable model for prediction of 3-year mortality was significantly improved after the inclusion of EuroSCORE (adjusted area under the receiver operating characteristic (ROC) curve = 0.779, 95% confidence interval 0.747 to 0.810, P = 0.008), but not after the inclusion of SxScore, SS II, or GRC. CONCLUSIONS: In patients undergoing DES implantation for uLMCA disease, all evaluated risk scores were able to stratify the mortality risk at long-term follow-up. EuroSCORE was the only risk score that significantly improved the discriminatory power of a multivariable model to predict long-term mortality. (c) 2016 Wiley Periodicals, Inc. PMID- 27515103 TI - Type 1 diabetes mellitus and atrial function: A complex relationship. PMID- 27515102 TI - Cost of heart failure management in Turkey: results of a Delphi Panel. AB - OBJECTIVE: To analyze health-related cost of heart failure (HF) and to evaluate health-related source utilization aiming to provide data on the economic burden of HF in actual clinical practice in Turkey. METHODS: The study used the Delphi process of seeking expert consensus of opinion including 11 cardiologists who are experienced in HF. The standardized questionnaire comprised items to reflect the opinion of the expert panelists on the distribution of the HF patients in terms of demographic and clinical characteristics and background disease states. Costs related to out-patient follow-up, in-patient follow-up, medications, and other therapies were also evaluated. RESULTS: 34.1% of the HF patients were in the age range of 60-69 years, and 62.3% were males. Coronary heart disease was the leading cause of HF (59.6%); 63.6% of the HF patients had reduced ejection fraction (rEF) and 42.3% were in New York Heart Association (NYHA)-II class. Approximately 75 % of the patients were followed up by a cardiology unit. The total annual visit number was estimated as 3.41. Approximately 32% of HF patients were hospitalized 1.64 times a year, for an average of 6.77 days each time. The total annual costs of all HF patients and HF-rEF patients were estimated as 1.537 TL and as 2.141 TL, respectively. CONCLUSION: The analysis demonstrating the magnitude of the economic impact of HF management on Turkey's healthcare system may help facilitate health and social policy interventions to improve the prevention and treatment of HF. PMID- 27515104 TI - Fragmented QRS frequency in patients with cardiac syndrome X. PMID- 27515105 TI - F-18 FDG PET/CT images of a rare primer cardiac tumour: Primary Pericardial Mesothelioma. PMID- 27515106 TI - An extremely rare but possible complication of MitraClip: embolization of clip during follow-up. PMID- 27515107 TI - Relation between epicardial fat thickness and chronic obstructive pulmonary disease. PMID- 27515108 TI - Author's Reply.